diff --git a/.DS_Store b/.DS_Store
new file mode 100644
index 0000000..35cda23
Binary files /dev/null and b/.DS_Store differ
diff --git a/README.md b/README.md
index e69de29..a561bb4 100644
--- a/README.md
+++ b/README.md
@@ -0,0 +1,252 @@
+# HUNER
+
+This repository stands for applying and evaluating [HUNER pre-trained model](https://github.com/hu-ner/huner#models) (`"disease_all"`) on `"BC5CDR-Disease"` data set .
+
+## Installation
+
+1. [Install docker](https://docs.docker.com/install/)
+2. Download  pretrained model (`"disease_all"`) from [here](https://drive.google.com/open?id=12vdtSi3hg_htCXXROKkPV4jaDO3ep8OY), place it  into `huner/models` directory and untar it using
+
+```bash
+tar xzf disease_all.tar.gz
+```
+
+## Prediction
+
+For applying prediction on `BC5CDR-Disease` data set we need to remove labeles from `.tsv` file and convert it to pre-tokenized `.txt` file that tokens are seprated by whitespace.
+
+1. Use `tokenized_txt.py` in `helper` folder for preprocess your `.tsv` data and make it ready for using as model input.
+
+    e.g. `tokenized_test.txt`
+
+    ```
+    Selegiline - induced postural hypotension in Parkinson ' s disease : a longitudinal study on the effects of drug withdrawal .
+    ```
+
+2. Start HUNER server  using
+
+   ```bash
+    ./start_server.sh disease_all
+    ```
+
+    > model must reside in `models` directory .
+
+3. While server is running use another terminal tab for tagging input data using
+
+    ```bash
+    python client.py --name disease_all --assume_tokenized  /path/to/tokenized_test.txt OUTPUT.CONLL
+    ```
+
+    The output will then be written to `OUTPUT.CONLL` .
+
+### Result
+
+`OUTPUT.CONLL` sample result on `tokenized_test.txt` looks like this
+
+```
+Torsade	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+ventricular	POS	I-NP
+tachycardia	POS	I-NP
+during	POS	O
+low	POS	O
+dose	POS	O
+intermittent	POS	O
+dobutamine	POS	O
+treatment	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+dilated	POS	B-NP
+cardiomyopathy	POS	I-NP
+and	POS	O
+congestive	POS	B-NP
+heart	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+The	POS	O
+authors	POS	O
+describe	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+56	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+with	POS	O
+chronic	POS	O
+,	POS	O
+severe	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+secondary	POS	O
+to	POS	O
+dilated	POS	B-NP
+cardiomyopathy	POS	I-NP
+and	POS	O
+absence	POS	O
+of	POS	O
+significant	POS	O
+ventricular	POS	B-NP
+arrhythmias	POS	I-NP
+who	POS	O
+developed	POS	O
+QT	POS	B-NP
+prolongation	POS	I-NP
+and	POS	O
+torsade	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+ventricular	POS	I-NP
+tachycardia	POS	I-NP
+during	POS	O
+one	POS	O
+cycle	POS	O
+of	POS	O
+intermittent	POS	O
+low	POS	O
+dose	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mcg	POS	O
+/	POS	O
+kg	POS	O
+per	POS	O
+min	POS	O
+)	POS	O
+dobutamine	POS	O
+.	POS	O
+
+```
+
+## Evaluation
+
+We use [seqeval](https://github.com/chakki-works/seqeval) `classification_report(y_true, y_pred)` metric to evaluate HUNER model .
+
+### Setting up an environment
+
+1.  [Follow the installation instructions for Conda](https://conda.io/projects/conda/en/latest/user-guide/install/index.html?highlight=conda#regular-installation).
+2. Create a Conda environment called "seqeval" with Python 3.7.6:
+    ```bash
+    conda create -n seqeval python=3.7.6
+    ```
+3. Activate the Conda environment:
+
+    ```bash
+    conda activate seqeval
+    ```
+
+### Installation
+
+To install seqeval, simply run:
+
+```
+$ pip install seqeval[cpu]
+```
+
+If you want to install seqeval on GPU environment, please run:
+
+```bash
+$ pip install seqeval[gpu]
+```
+
+### Requirement
+
+* numpy >= 1.14.0
+
+### Preprocess and Evaluate
+
+Since `OUTPUT.CONLL` format is a little bit different from `BC5CDR-Disease` IOB schemed, we need to modify our `BC5CDR-Disease` data.
+
+* `BC5CDR-Disease`
+
+    ```
+    Torsade	B
+    de	I
+    pointes	I
+    ventricular	B
+    tachycardia	I
+    during	O
+    low	O
+    dose	O
+    intermittent	O
+    dobutamine	O
+    treatment	O
+    in	O
+    a	O
+    patient	O
+    with	O
+    dilated	B
+    cardiomyopathy	I
+    and	O
+    congestive	B
+    heart	I
+    failure	I
+    .	O
+
+    ```
+
+* `OUTPUT.CONLL`
+    ```
+    Torsade	POS	B-NP
+    de	POS	I-NP
+    pointes	POS	I-NP
+    ventricular	POS	I-NP
+    tachycardia	POS	I-NP
+    during	POS	O
+    low	POS	O
+    dose	POS	O
+    intermittent	POS	O
+    dobutamine	POS	O
+    treatment	POS	O
+    in	POS	O
+    a	POS	O
+    patient	POS	O
+    with	POS	O
+    dilated	POS	B-NP
+    cardiomyopathy	POS	I-NP
+    and	POS	O
+    congestive	POS	B-NP
+    heart	POS	I-NP
+    failure	POS	I-NP
+    .	POS	O
+    ```
+
+Use `test.tsv` or any file that you used it for prediction in `BC5CDR-Disease` data set and replace all `B` tags with `B-NP` and all `I` tags with `I-NP` using Exel .
+
+E.g.`test.tsv` shuold look like this after modification .
+
+```
+Torsade	B-NP
+de	I-NP
+pointes	I-NP
+ventricular	B-NP
+tachycardia	I-NP
+during	O
+low	O
+dose	O
+intermittent	O
+dobutamine	O
+treatment	O
+in	O
+a	O
+patient	O
+with	O
+dilated	B-NP
+cardiomyopathy	I-NP
+and	O
+congestive	B-NP
+heart	I-NP
+failure	I-NP
+.	O
+```
+
+Now use `evaluation.py` in `helper/evaluation` folder to evaluate model .
diff --git a/data/.DS_Store b/data/.DS_Store
new file mode 100644
index 0000000..7855dad
Binary files /dev/null and b/data/.DS_Store differ
diff --git a/data/BC5CDR-disease/.DS_Store b/data/BC5CDR-disease/.DS_Store
new file mode 100644
index 0000000..95123fb
Binary files /dev/null and b/data/BC5CDR-disease/.DS_Store differ
diff --git a/data/BC5CDR-disease/dev.tsv b/data/BC5CDR-disease/dev.tsv
new file mode 100644
index 0000000..171cbb6
--- /dev/null
+++ b/data/BC5CDR-disease/dev.tsv
@@ -0,0 +1,122034 @@
+22	O
+-	O
+oxacalcitriol	O
+suppresses	O
+secondary	B
+hyperparathyroidism	I
+without	O
+inducing	O
+low	B
+bone	I
+turnover	I
+in	O
+dogs	O
+with	O
+renal	B
+failure	I
+.	O
+
+BACKGROUND	O
+:	O
+Calcitriol	O
+therapy	O
+suppresses	O
+serum	O
+levels	O
+of	O
+parathyroid	O
+hormone	O
+(	O
+PTH	O
+)	O
+in	O
+patients	O
+with	O
+renal	B
+failure	I
+but	O
+has	O
+several	O
+drawbacks	O
+,	O
+including	O
+hypercalcemia	B
+and	O
+/	O
+or	O
+marked	O
+suppression	B
+of	I
+bone	I
+turnover	I
+,	O
+which	O
+may	O
+lead	O
+to	O
+adynamic	B
+bone	I
+disease	I
+.	O
+
+A	O
+new	O
+vitamin	O
+D	O
+analogue	O
+,	O
+22	O
+-	O
+oxacalcitriol	O
+(	O
+OCT	O
+)	O
+,	O
+has	O
+been	O
+shown	O
+to	O
+have	O
+promising	O
+characteristics	O
+.	O
+
+This	O
+study	O
+was	O
+undertaken	O
+to	O
+determine	O
+the	O
+effects	O
+of	O
+OCT	O
+on	O
+serum	O
+PTH	O
+levels	O
+and	O
+bone	O
+turnover	O
+in	O
+states	O
+of	O
+normal	O
+or	O
+impaired	B
+renal	I
+function	I
+.	O
+
+METHODS	O
+:	O
+Sixty	O
+dogs	O
+were	O
+either	O
+nephrectomized	O
+(	O
+Nx	O
+,	O
+N	O
+=	O
+38	O
+)	O
+or	O
+sham	O
+-	O
+operated	O
+(	O
+Sham	O
+,	O
+N	O
+=	O
+22	O
+)	O
+.	O
+
+The	O
+animals	O
+received	O
+supplemental	O
+phosphate	O
+to	O
+enhance	O
+PTH	O
+secretion	O
+.	O
+
+Fourteen	O
+weeks	O
+after	O
+the	O
+start	O
+of	O
+phosphate	O
+supplementation	O
+,	O
+half	O
+of	O
+the	O
+Nx	O
+and	O
+Sham	O
+dogs	O
+received	O
+doses	O
+of	O
+OCT	O
+(	O
+three	O
+times	O
+per	O
+week	O
+)	O
+;	O
+the	O
+other	O
+half	O
+were	O
+given	O
+vehicle	O
+for	O
+60	O
+weeks	O
+.	O
+
+Thereafter	O
+,	O
+the	O
+treatment	O
+modalities	O
+for	O
+a	O
+subset	O
+of	O
+animals	O
+were	O
+crossed	O
+over	O
+for	O
+an	O
+additional	O
+eight	O
+months	O
+.	O
+
+Biochemical	O
+and	O
+hormonal	O
+indices	O
+of	O
+calcium	O
+and	O
+bone	O
+metabolism	O
+were	O
+measured	O
+throughout	O
+the	O
+study	O
+,	O
+and	O
+bone	O
+biopsies	O
+were	O
+done	O
+at	O
+baseline	O
+,	O
+60	O
+weeks	O
+after	O
+OCT	O
+or	O
+vehicle	O
+treatment	O
+,	O
+and	O
+at	O
+the	O
+end	O
+of	O
+the	O
+crossover	O
+period	O
+.	O
+
+RESULTS	O
+:	O
+In	O
+Nx	O
+dogs	O
+,	O
+OCT	O
+significantly	O
+decreased	O
+serum	O
+PTH	O
+levels	O
+soon	O
+after	O
+the	O
+induction	O
+of	O
+renal	B
+insufficiency	I
+.	O
+
+In	O
+long	O
+-	O
+standing	O
+secondary	B
+hyperparathyroidism	I
+,	O
+OCT	O
+(	O
+0	O
+.	O
+03	O
+microg	O
+/	O
+kg	O
+)	O
+stabilized	O
+serum	O
+PTH	O
+levels	O
+during	O
+the	O
+first	O
+months	O
+.	O
+
+Serum	O
+PTH	O
+levels	O
+rose	O
+thereafter	O
+,	O
+but	O
+the	O
+rise	O
+was	O
+less	O
+pronounced	O
+compared	O
+with	O
+baseline	O
+than	O
+the	O
+rise	O
+seen	O
+in	O
+Nx	O
+control	O
+.	O
+
+These	O
+effects	O
+were	O
+accompanied	O
+by	O
+episodes	O
+of	O
+hypercalcemia	B
+and	O
+hyperphosphatemia	B
+.	O
+
+In	O
+animals	O
+with	O
+normal	O
+renal	O
+function	O
+,	O
+OCT	O
+induced	O
+a	O
+transient	O
+decrease	O
+in	O
+serum	O
+PTH	O
+levels	O
+at	O
+a	O
+dose	O
+of	O
+0	O
+.	O
+1	O
+microg	O
+/	O
+kg	O
+,	O
+which	O
+was	O
+not	O
+sustained	O
+with	O
+lowering	O
+of	O
+the	O
+doses	O
+.	O
+
+In	O
+Nx	O
+dogs	O
+,	O
+OCT	O
+reversed	O
+abnormal	O
+bone	O
+formation	O
+,	O
+such	O
+as	O
+woven	B
+osteoid	I
+and	O
+fibrosis	B
+,	O
+but	O
+did	O
+not	O
+significantly	O
+alter	O
+the	O
+level	O
+of	O
+bone	O
+turnover	O
+.	O
+
+In	O
+addition	O
+,	O
+OCT	O
+improved	O
+mineralization	O
+lag	O
+time	O
+,	O
+(	O
+that	O
+is	O
+,	O
+the	O
+rate	O
+at	O
+which	O
+osteoid	O
+mineralizes	O
+)	O
+in	O
+both	O
+Nx	O
+and	O
+Sham	O
+dogs	O
+.	O
+
+CONCLUSIONS	O
+:	O
+These	O
+results	O
+indicate	O
+that	O
+even	O
+though	O
+OCT	O
+does	O
+not	O
+completely	O
+prevent	O
+the	O
+occurrence	O
+of	O
+hypercalcemia	B
+in	O
+experimental	O
+dogs	O
+with	O
+renal	B
+insufficiency	I
+,	O
+it	O
+may	O
+be	O
+of	O
+use	O
+in	O
+the	O
+management	O
+of	O
+secondary	B
+hyperparathyroidism	I
+because	O
+it	O
+does	O
+not	O
+induce	O
+low	B
+bone	I
+turnover	I
+and	O
+,	O
+therefore	O
+,	O
+does	O
+not	O
+increase	O
+the	O
+risk	O
+of	O
+adynamic	B
+bone	I
+disease	I
+.	O
+
+Hypotension	B
+,	O
+bradycardia	B
+,	O
+and	O
+asystole	B
+after	O
+high	O
+-	O
+dose	O
+intravenous	O
+methylprednisolone	O
+in	O
+a	O
+monitored	O
+patient	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+hypotension	B
+,	O
+bradycardia	B
+,	O
+and	O
+asystole	B
+after	O
+intravenous	O
+administration	O
+of	O
+high	O
+-	O
+dose	O
+methylprednisolone	O
+in	O
+a	O
+73	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+who	O
+underwent	O
+electrocardiographic	O
+(	O
+ECG	O
+)	O
+monitoring	O
+throughout	O
+the	O
+episode	O
+.	O
+
+There	O
+was	O
+a	O
+history	O
+of	O
+ischemic	B
+cardiac	B
+disease	I
+9	O
+years	O
+earlier	O
+.	O
+
+The	O
+patient	O
+was	O
+admitted	O
+with	O
+a	O
+pulmonary	B
+-	I
+renal	I
+syndrome	I
+with	O
+hemoptysis	B
+,	O
+rapidly	O
+progressive	O
+renal	B
+failure	I
+,	O
+and	O
+hypoxemia	B
+that	O
+required	O
+mechanical	O
+ventilation	O
+in	O
+the	O
+intensive	O
+care	O
+unit	O
+.	O
+
+After	O
+receiving	O
+advanced	O
+cardiopulmonary	O
+resuscitation	O
+,	O
+the	O
+patient	O
+recovered	O
+cardiac	O
+rhythm	O
+.	O
+
+The	O
+ECG	O
+showed	O
+a	O
+junctional	O
+rhythm	O
+without	O
+ventricular	B
+arrhythmia	I
+.	O
+
+This	O
+study	O
+reviews	O
+the	O
+current	O
+proposed	O
+mechanisms	O
+of	O
+sudden	B
+death	I
+after	O
+a	O
+high	O
+dose	O
+of	O
+intravenous	O
+methylprednisolone	O
+(	O
+IVMP	O
+)	O
+.	O
+
+These	O
+mechanisms	O
+are	O
+not	O
+well	O
+understood	O
+because	O
+,	O
+in	O
+most	O
+cases	O
+,	O
+the	O
+patients	O
+were	O
+not	O
+monitored	O
+at	O
+the	O
+moment	O
+of	O
+the	O
+event	O
+.	O
+
+Rapid	O
+infusion	O
+and	O
+underlying	O
+cardiac	B
+disease	I
+were	O
+important	O
+risk	O
+factors	O
+in	O
+the	O
+case	O
+reported	O
+here	O
+,	O
+and	O
+the	O
+authors	O
+discount	O
+ventricular	B
+arrhythmia	I
+as	O
+the	O
+main	O
+mechanism	O
+.	O
+
+Worsening	O
+of	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+by	O
+motor	O
+and	O
+mental	O
+tasks	O
+.	O
+
+Ten	O
+patients	O
+who	O
+had	O
+Parkinson	B
+'	I
+s	I
+disease	I
+with	O
+disabling	O
+dyskinesia	B
+were	O
+included	O
+in	O
+this	O
+study	O
+to	O
+evaluate	O
+the	O
+role	O
+of	O
+mental	O
+(	O
+mental	O
+calculation	O
+)	O
+and	O
+motor	O
+(	O
+flexion	O
+/	O
+extension	O
+of	O
+right	O
+fingers	O
+,	O
+flexion	O
+/	O
+extension	O
+of	O
+left	O
+fingers	O
+,	O
+flexion	O
+/	O
+extension	O
+of	O
+the	O
+neck	O
+,	O
+speaking	O
+aloud	O
+)	O
+tasks	O
+on	O
+the	O
+worsening	O
+of	O
+peak	O
+-	O
+dose	O
+dyskinesia	B
+following	O
+administration	O
+of	O
+an	O
+effective	O
+single	O
+dose	O
+of	O
+apomorphine	O
+.	O
+
+Compared	O
+with	O
+the	O
+score	O
+at	O
+rest	O
+(	O
+1	O
+.	O
+3	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+)	O
+,	O
+a	O
+significant	O
+aggravation	O
+of	O
+the	O
+dyskinesia	B
+score	O
+was	O
+observed	O
+during	O
+speaking	O
+aloud	O
+(	O
+5	O
+.	O
+2	O
++	O
+/	O
+-	O
+1	O
+.	O
+1	O
+,	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+,	O
+movements	O
+of	O
+right	O
+(	O
+4	O
+.	O
+5	O
++	O
+/	O
+-	O
+1	O
+.	O
+0	O
+,	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+and	O
+left	O
+(	O
+3	O
+.	O
+7	O
++	O
+/	O
+-	O
+0	O
+.	O
+8	O
+,	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+fingers	O
+,	O
+movements	O
+of	O
+the	O
+neck	O
+(	O
+5	O
+.	O
+1	O
++	O
+/	O
+-	O
+1	O
+.	O
+0	O
+,	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+,	O
+and	O
+mental	O
+calculation	O
+(	O
+3	O
+.	O
+1	O
++	O
+/	O
+-	O
+1	O
+.	O
+0	O
+,	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+activation	O
+tasks	O
+such	O
+as	O
+"	O
+speaking	O
+aloud	O
+"	O
+could	O
+be	O
+used	O
+for	O
+objective	O
+assessment	O
+of	O
+dyskinesia	B
+severity	O
+.	O
+
+Urine	O
+N	O
+-	O
+acetyl	O
+-	O
+beta	O
+-	O
+D	O
+-	O
+glucosaminidase	O
+-	O
+-	O
+a	O
+marker	O
+of	O
+tubular	O
+damage	O
+?	O
+
+BACKGROUND	O
+:	O
+Although	O
+an	O
+indicator	O
+of	O
+renal	B
+tubular	I
+dysfunction	I
+,	O
+an	O
+increased	O
+urinary	O
+N	O
+-	O
+acetyl	O
+-	O
+beta	O
+-	O
+D	O
+-	O
+glucosaminidase	O
+(	O
+NAG	O
+)	O
+activity	O
+might	O
+reflect	O
+increased	O
+lysosomal	O
+activity	O
+in	O
+renal	O
+tubular	O
+cells	O
+.	O
+
+METHODS	O
+:	O
+Puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+)	O
+was	O
+administered	O
+to	O
+Sprague	O
+Dawley	O
+rats	O
+to	O
+induce	O
+proteinuria	B
+.	O
+
+Total	O
+protein	O
+,	O
+albumin	O
+,	O
+NAG	O
+activity	O
+and	O
+protein	O
+electrophoretic	O
+pattern	O
+were	O
+assessed	O
+in	O
+daily	O
+urine	O
+samples	O
+for	O
+33	O
+days	O
+.	O
+
+The	O
+morphological	O
+appearance	O
+of	O
+the	O
+kidneys	O
+was	O
+examined	O
+on	O
+days	O
+three	O
+,	O
+four	O
+,	O
+six	O
+,	O
+eight	O
+and	O
+thirty	O
+three	O
+and	O
+the	O
+NAG	O
+isoenzyme	O
+patterns	O
+on	O
+days	O
+zero	O
+,	O
+four	O
+,	O
+eight	O
+and	O
+thirty	O
+three	O
+.	O
+
+RESULTS	O
+:	O
+Following	O
+intravenous	O
+PAN	O
+urine	O
+volume	O
+and	O
+urine	O
+NAG	O
+activity	O
+increased	O
+significantly	O
+by	O
+day	O
+two	O
+,	O
+but	O
+returned	O
+to	O
+normal	O
+by	O
+day	O
+four	O
+.	O
+
+After	O
+day	O
+four	O
+all	O
+treated	O
+animals	O
+exhibited	O
+a	O
+marked	O
+rise	O
+in	O
+urine	O
+albumin	O
+,	O
+total	O
+protein	O
+excretion	O
+and	O
+NAG	O
+activity	O
+.	O
+
+Electrophoresis	O
+showed	O
+a	O
+generalised	O
+increase	O
+in	O
+middle	O
+and	O
+high	O
+molecular	O
+weight	O
+urine	O
+proteins	O
+from	O
+day	O
+four	O
+onwards	O
+.	O
+
+Protein	O
+droplets	O
+first	O
+appeared	O
+prominent	O
+in	O
+tubular	O
+cells	O
+on	O
+day	O
+four	O
+.	O
+
+Peak	O
+urine	O
+NAG	O
+activity	O
+and	O
+a	O
+change	O
+in	O
+NAG	O
+isoenzyme	O
+pattern	O
+coincided	O
+with	O
+both	O
+the	O
+peak	O
+proteinuria	B
+and	O
+the	O
+reduction	O
+in	O
+intracellular	O
+protein	O
+and	O
+NAG	O
+droplets	O
+(	O
+day	O
+six	O
+onwards	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+This	O
+animal	O
+model	O
+demonstrates	O
+that	O
+an	O
+increase	O
+in	O
+lysosomal	O
+turnover	O
+and	O
+hence	O
+urine	O
+NAG	O
+activity	O
+,	O
+occurs	O
+when	O
+increased	O
+protein	O
+is	O
+presented	O
+to	O
+the	O
+tubular	O
+cells	O
+.	O
+
+Urine	O
+NAG	O
+activity	O
+is	O
+thus	O
+a	O
+measure	O
+of	O
+altered	O
+function	O
+in	O
+the	O
+renal	O
+tubules	O
+and	O
+not	O
+simply	O
+an	O
+indicator	O
+of	O
+damage	O
+.	O
+
+Cauda	B
+equina	I
+syndrome	I
+after	O
+spinal	O
+anaesthesia	O
+with	O
+hyperbaric	O
+5	O
+%	O
+lignocaine	O
+:	O
+a	O
+review	O
+of	O
+six	O
+cases	O
+of	O
+cauda	B
+equina	I
+syndrome	I
+reported	O
+to	O
+the	O
+Swedish	O
+Pharmaceutical	O
+Insurance	O
+1993	O
+-	O
+1997	O
+.	O
+
+Six	O
+cases	O
+of	O
+cauda	B
+equina	I
+syndrome	I
+with	O
+varying	O
+severity	O
+were	O
+reported	O
+to	O
+the	O
+Swedish	O
+Pharmaceutical	O
+Insurance	O
+during	O
+the	O
+period	O
+1993	O
+-	O
+1997	O
+.	O
+
+All	O
+were	O
+associated	O
+with	O
+spinal	O
+anaesthesia	O
+using	O
+hyperbaric	O
+5	O
+%	O
+lignocaine	O
+.	O
+
+Five	O
+cases	O
+had	O
+single	O
+-	O
+shot	O
+spinal	O
+anaesthesia	O
+and	O
+one	O
+had	O
+a	O
+repeat	O
+spinal	O
+anaesthetic	O
+due	O
+to	O
+inadequate	O
+block	O
+.	O
+
+The	O
+dose	O
+of	O
+hyperbaric	O
+5	O
+%	O
+lignocaine	O
+administered	O
+ranged	O
+from	O
+60	O
+to	O
+120	O
+mg	O
+.	O
+
+Three	O
+of	O
+the	O
+cases	O
+were	O
+most	O
+likely	O
+caused	O
+by	O
+direct	O
+neurotoxicity	B
+of	O
+hyperbaric	O
+5	O
+%	O
+lignocaine	O
+.	O
+
+In	O
+the	O
+other	O
+3	O
+cases	O
+,	O
+direct	O
+neurotoxicity	B
+was	O
+also	O
+probable	O
+,	O
+but	O
+unfortunately	O
+radiological	O
+investigations	O
+were	O
+not	O
+done	O
+to	O
+definitely	O
+exclude	O
+a	O
+compressive	O
+aetiology	O
+.	O
+
+All	O
+cases	O
+sustained	O
+permanent	O
+neurological	B
+deficits	I
+.	O
+
+We	O
+recommend	O
+that	O
+hyperbaric	O
+lignocaine	O
+should	O
+be	O
+administered	O
+in	O
+concentrations	O
+not	O
+greater	O
+than	O
+2	O
+%	O
+and	O
+at	O
+a	O
+total	O
+dose	O
+preferably	O
+not	O
+exceeding	O
+60	O
+mg	O
+.	O
+
+Systemic	O
+toxicity	B
+following	O
+administration	O
+of	O
+sirolimus	O
+(	O
+formerly	O
+rapamycin	O
+)	O
+for	O
+psoriasis	B
+:	O
+association	O
+of	O
+capillary	B
+leak	I
+syndrome	I
+with	O
+apoptosis	O
+of	O
+lesional	O
+lymphocytes	O
+.	O
+
+BACKGROUND	O
+:	O
+Sirolimus	O
+(	O
+formerly	O
+rapamycin	O
+)	O
+is	O
+an	O
+immunosuppressive	O
+agent	O
+that	O
+interferes	O
+with	O
+T	O
+-	O
+cell	O
+activation	O
+.	O
+
+After	O
+2	O
+individuals	O
+with	O
+psoriasis	B
+developed	O
+a	O
+capillary	B
+leak	I
+syndrome	I
+following	O
+treatment	O
+with	O
+oral	O
+sirolimus	O
+lesional	O
+skin	O
+cells	O
+and	O
+activated	O
+peripheral	O
+blood	O
+cells	O
+were	O
+analyzed	O
+for	O
+induction	O
+of	O
+apoptosis	O
+.	O
+
+OBSERVATIONS	O
+:	O
+A	O
+keratome	O
+skin	O
+specimen	O
+from	O
+1	O
+patient	O
+with	O
+sirolimus	O
+-	O
+induced	O
+capillary	B
+leak	I
+syndrome	I
+had	O
+a	O
+2	O
+.	O
+3	O
+-	O
+fold	O
+increase	O
+in	O
+percentage	O
+of	O
+apoptotic	O
+cells	O
+(	O
+to	O
+48	O
+%	O
+)	O
+compared	O
+with	O
+an	O
+unaffected	O
+sirolimus	O
+-	O
+treated	O
+patient	O
+with	O
+psoriasis	B
+(	O
+21	O
+%	O
+)	O
+.	O
+
+Activated	O
+peripheral	O
+blood	O
+T	O
+cells	O
+from	O
+patients	O
+with	O
+psoriasis	B
+tended	O
+to	O
+exhibit	O
+greater	O
+spontaneous	O
+or	O
+dexamethasone	O
+-	O
+induced	O
+apoptosis	O
+than	O
+did	O
+normal	O
+T	O
+cells	O
+,	O
+particularly	O
+in	O
+the	O
+presence	O
+of	O
+sirolimus	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Severe	O
+adverse	O
+effects	O
+of	O
+sirolimus	O
+include	O
+fever	B
+,	O
+anemia	B
+,	O
+and	O
+capillary	B
+leak	I
+syndrome	I
+.	O
+
+These	O
+symptoms	O
+may	O
+be	O
+the	O
+result	O
+of	O
+drug	O
+-	O
+induced	O
+apoptosis	O
+of	O
+lesional	O
+leukocytes	O
+,	O
+especially	O
+activated	O
+T	O
+lymphocytes	O
+,	O
+and	O
+possibly	O
+release	O
+of	O
+inflammatory	O
+mediators	O
+.	O
+
+Because	O
+patients	O
+with	O
+severe	O
+psoriasis	B
+may	O
+develop	O
+capillary	B
+leak	I
+from	O
+various	O
+systemic	O
+therapies	O
+,	O
+clinical	O
+monitoring	O
+is	O
+advisable	O
+for	O
+patients	O
+with	O
+inflammatory	B
+diseases	I
+who	O
+are	O
+treated	O
+with	O
+immune	O
+modulators	O
+.	O
+
+Effect	O
+of	O
+lithium	O
+maintenance	O
+therapy	O
+on	O
+thyroid	O
+and	O
+parathyroid	O
+function	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+assess	O
+changes	O
+induced	O
+by	O
+lithium	O
+maintenance	O
+therapy	O
+on	O
+the	O
+incidence	O
+of	O
+thyroid	O
+,	O
+parathyroid	O
+and	O
+ion	O
+alterations	O
+.	O
+
+These	O
+were	O
+evaluated	O
+with	O
+respect	O
+to	O
+the	O
+duration	O
+of	O
+lithium	O
+therapy	O
+,	O
+age	O
+,	O
+sex	O
+,	O
+and	O
+family	O
+history	O
+(	O
+whether	O
+or	O
+not	O
+the	O
+patient	O
+had	O
+a	O
+first	O
+-	O
+degree	O
+relative	O
+with	O
+thyroid	B
+disease	I
+)	O
+.	O
+
+DESIGN	O
+:	O
+Prospective	O
+study	O
+.	O
+
+SETTING	O
+:	O
+Affective	O
+Disorders	O
+Clinic	O
+at	O
+St	O
+.	O
+
+Mary	O
+'	O
+s	O
+Hospital	O
+,	O
+Montreal	O
+.	O
+
+PATIENTS	O
+:	O
+One	O
+hundred	O
+and	O
+one	O
+patients	O
+(	O
+28	O
+men	O
+and	O
+73	O
+women	O
+)	O
+with	O
+bipolar	B
+disorder	I
+receiving	O
+lithium	O
+maintenance	O
+therapy	O
+ranging	O
+from	O
+1	O
+year	O
+'	O
+s	O
+to	O
+32	O
+years	O
+'	O
+duration	O
+.	O
+
+The	O
+control	O
+group	O
+consisted	O
+of	O
+82	O
+patients	O
+with	O
+no	O
+psychiatric	B
+or	O
+endocrinological	O
+diagnoses	O
+from	O
+the	O
+hospital	O
+'	O
+s	O
+out	O
+-	O
+patient	O
+clinics	O
+.	O
+
+OUTCOME	O
+MEASURES	O
+:	O
+Laboratory	O
+analyses	O
+of	O
+calcium	O
+,	O
+magnesium	O
+and	O
+thyroid	O
+-	O
+stimulating	O
+hormone	O
+levels	O
+performed	O
+before	O
+beginning	O
+lithium	O
+therapy	O
+and	O
+at	O
+biannual	O
+follow	O
+-	O
+up	O
+.	O
+
+RESULTS	O
+:	O
+Hypothyroidism	B
+developed	O
+in	O
+40	O
+patients	O
+,	O
+excluding	O
+8	O
+patients	O
+who	O
+were	O
+hypothyroid	B
+at	O
+baseline	O
+.	O
+
+All	O
+patients	O
+having	O
+first	O
+-	O
+degree	O
+relatives	O
+affected	O
+by	O
+thyroid	B
+illness	I
+had	O
+accelerated	O
+onset	O
+of	O
+hypothyroidism	B
+(	O
+3	O
+.	O
+7	O
+years	O
+after	O
+onset	O
+of	O
+lithium	O
+therapy	O
+)	O
+compared	O
+with	O
+patients	O
+without	O
+a	O
+family	O
+history	O
+(	O
+8	O
+.	O
+6	O
+years	O
+after	O
+onset	O
+of	O
+lithium	O
+therapy	O
+)	O
+.	O
+
+Women	O
+over	O
+60	O
+years	O
+of	O
+age	O
+were	O
+more	O
+often	O
+affected	O
+by	O
+hypothyroidism	B
+than	O
+women	O
+under	O
+60	O
+years	O
+of	O
+age	O
+(	O
+34	O
+.	O
+6	O
+%	O
+versus	O
+31	O
+.	O
+9	O
+%	O
+)	O
+.	O
+
+Magnesium	O
+levels	O
+in	O
+patients	O
+on	O
+lithium	O
+treatment	O
+were	O
+unchanged	O
+from	O
+baseline	O
+levels	O
+.	O
+
+After	O
+lithium	O
+treatment	O
+,	O
+calcium	O
+levels	O
+were	O
+higher	O
+than	O
+either	O
+baseline	O
+levels	O
+or	O
+control	O
+levels	O
+.	O
+
+Thus	O
+,	O
+lithium	O
+treatment	O
+counteracted	O
+the	O
+decrease	O
+in	O
+plasma	O
+calcium	O
+levels	O
+associated	O
+with	O
+aging	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Familial	O
+thyroid	B
+illness	I
+is	O
+a	O
+risk	O
+factor	O
+for	O
+hypothyroidism	B
+and	O
+hypercalcemia	B
+during	O
+lithium	O
+therapy	O
+.	O
+
+Severe	O
+immune	O
+hemolytic	B
+anemia	I
+associated	O
+with	O
+prophylactic	O
+use	O
+of	O
+cefotetan	O
+in	O
+obstetric	O
+and	O
+gynecologic	O
+procedures	O
+.	O
+
+Second	O
+-	O
+and	O
+third	O
+-	O
+generation	O
+cephalosporins	O
+,	O
+especially	O
+cefotetan	O
+,	O
+are	O
+increasingly	O
+associated	O
+with	O
+severe	O
+,	O
+sometimes	O
+fatal	O
+immune	O
+hemolytic	B
+anemia	I
+.	O
+
+We	O
+noticed	O
+that	O
+10	O
+of	O
+our	O
+35	O
+cases	O
+of	O
+cefotetan	O
+-	O
+induced	O
+hemolytic	B
+anemias	I
+were	O
+in	O
+patients	O
+who	O
+had	O
+received	O
+cefotetan	O
+prophylactically	O
+for	O
+obstetric	O
+and	O
+gynecologic	O
+procedures	O
+.	O
+
+Eight	O
+of	O
+these	O
+cases	O
+of	O
+severe	O
+immune	O
+hemolytic	B
+anemia	I
+are	O
+described	O
+.	O
+
+Effects	O
+of	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+on	O
+hemostasis	O
+in	O
+patients	O
+with	O
+aneurysmal	B
+subarachnoid	I
+hemorrhage	I
+.	O
+
+Platelet	O
+function	O
+is	O
+impaired	O
+by	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+(	O
+NSAIDs	O
+)	O
+with	O
+prominent	O
+anti	O
+-	O
+inflammatory	O
+properties	O
+.	O
+
+Their	O
+safety	O
+in	O
+patients	O
+undergoing	O
+intracranial	O
+surgery	O
+is	O
+under	O
+debate	O
+.	O
+
+Patients	O
+with	O
+aneurysmal	B
+subarachnoid	I
+hemorrhage	I
+(	O
+SAH	B
+)	O
+were	O
+randomized	O
+to	O
+receive	O
+either	O
+ketoprofen	O
+,	O
+100	O
+mg	O
+,	O
+three	O
+times	O
+a	O
+day	O
+(	O
+ketoprofen	O
+group	O
+,	O
+n	O
+=	O
+9	O
+)	O
+or	O
+a	O
+weak	O
+NSAID	O
+,	O
+acetaminophen	O
+,	O
+1	O
+g	O
+,	O
+three	O
+times	O
+a	O
+day	O
+(	O
+acetaminophen	O
+group	O
+,	O
+n	O
+=	O
+9	O
+)	O
+starting	O
+immediately	O
+after	O
+the	O
+diagnosis	O
+of	O
+aneurysmal	B
+SAH	B
+.	O
+
+Treatment	O
+was	O
+continued	O
+for	O
+3	O
+days	O
+postoperatively	O
+.	O
+
+Test	O
+blood	O
+samples	O
+were	O
+taken	O
+before	O
+treatment	O
+and	O
+surgery	O
+as	O
+well	O
+as	O
+on	O
+the	O
+first	O
+,	O
+third	O
+,	O
+and	O
+fifth	O
+postoperative	O
+mornings	O
+.	O
+
+Maximal	O
+platelet	B
+aggregation	I
+induced	O
+by	O
+6	O
+microM	O
+of	O
+adenosine	O
+diphosphate	O
+decreased	O
+after	O
+administration	O
+of	O
+ketoprofen	O
+.	O
+
+Aggregation	O
+was	O
+lower	O
+(	O
+P	O
+<	O
+.	O
+05	O
+)	O
+in	O
+the	O
+ketoprofen	O
+group	O
+than	O
+in	O
+the	O
+acetaminophen	O
+group	O
+just	O
+before	O
+surgery	O
+and	O
+on	O
+the	O
+third	O
+postoperative	O
+day	O
+.	O
+
+In	O
+contrast	O
+,	O
+maximal	O
+platelet	B
+aggregation	I
+increased	O
+in	O
+the	O
+acetaminophen	O
+group	O
+on	O
+the	O
+third	O
+postoperative	O
+day	O
+as	O
+compared	O
+with	O
+the	O
+pretreatment	O
+platelet	B
+aggregation	I
+results	O
+(	O
+P	O
+<	O
+.	O
+05	O
+)	O
+.	O
+
+One	O
+patient	O
+in	O
+the	O
+ketoprofen	O
+group	O
+developed	O
+a	O
+postoperative	O
+intracranial	O
+hematoma	B
+.	O
+
+Coagulation	O
+(	O
+prothrombin	O
+time	O
+[	O
+PT	O
+]	O
+,	O
+activated	O
+partial	O
+thromboplastin	O
+time	O
+[	O
+APPT	O
+]	O
+,	O
+fibrinogen	O
+concentration	O
+,	O
+and	O
+antithrombin	O
+III	O
+[	O
+AT	O
+III	O
+]	O
+)	O
+was	O
+comparable	O
+between	O
+the	O
+two	O
+groups	O
+.	O
+
+Ketoprofen	O
+but	O
+not	O
+acetaminophen	O
+impaired	O
+platelet	O
+function	O
+in	O
+patients	O
+with	O
+SAH	B
+.	O
+
+If	O
+ketoprofen	O
+is	O
+used	O
+before	O
+surgery	O
+on	O
+cerebral	O
+artery	B
+aneurysms	I
+,	O
+it	O
+may	O
+pose	O
+an	O
+additional	O
+risk	O
+factor	O
+for	O
+hemorrhage	B
+.	O
+
+Nitric	O
+oxide	O
+synthase	O
+expression	O
+in	O
+the	O
+course	O
+of	O
+lead	O
+-	O
+induced	O
+hypertension	B
+.	O
+
+We	O
+recently	O
+showed	O
+elevated	O
+reactive	O
+oxygen	O
+species	O
+(	O
+ROS	O
+)	O
+,	O
+reduced	O
+urinary	O
+excretion	O
+of	O
+NO	O
+metabolites	O
+(	O
+NOx	O
+)	O
+,	O
+and	O
+increased	O
+NO	O
+sequestration	O
+as	O
+nitrotyrosine	O
+in	O
+various	O
+tissues	O
+in	O
+rats	O
+with	O
+lead	O
+-	O
+induced	O
+hypertension	B
+.	O
+
+This	O
+study	O
+was	O
+designed	O
+to	O
+discern	O
+whether	O
+the	O
+reduction	O
+in	O
+urinary	O
+NOx	O
+in	O
+lead	O
+-	O
+induced	O
+hypertension	B
+is	O
+,	O
+in	O
+part	O
+,	O
+due	O
+to	O
+depressed	O
+NO	O
+synthase	O
+(	O
+NOS	O
+)	O
+expression	O
+.	O
+
+Male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+were	O
+randomly	O
+assigned	O
+to	O
+a	O
+lead	O
+-	O
+treated	O
+group	O
+(	O
+given	O
+lead	O
+acetate	O
+,	O
+100	O
+ppm	O
+,	O
+in	O
+drinking	O
+water	O
+and	O
+regular	O
+rat	O
+chow	O
+)	O
+,	O
+a	O
+group	O
+given	O
+lead	O
+and	O
+vitamin	O
+E	O
+-	O
+fortified	O
+chow	O
+,	O
+or	O
+a	O
+normal	O
+control	O
+group	O
+given	O
+either	O
+regular	O
+food	O
+and	O
+water	O
+or	O
+vitamin	O
+E	O
+-	O
+fortified	O
+food	O
+for	O
+12	O
+weeks	O
+.	O
+
+Tail	O
+blood	O
+pressure	O
+,	O
+urinary	O
+NOx	O
+excretion	O
+,	O
+plasma	O
+malondialdehyde	O
+(	O
+MDA	O
+)	O
+,	O
+and	O
+endothelial	O
+and	O
+inducible	O
+NOS	O
+(	O
+eNOS	O
+and	O
+iNOS	O
+)	O
+isotypes	O
+in	O
+the	O
+aorta	O
+and	O
+kidney	O
+were	O
+measured	O
+.	O
+
+The	O
+lead	O
+-	O
+treated	O
+group	O
+exhibited	O
+a	O
+rise	O
+in	O
+blood	O
+pressure	O
+and	O
+plasma	O
+MDA	O
+concentration	O
+,	O
+a	O
+fall	O
+in	O
+urinary	O
+NOx	O
+excretion	O
+,	O
+and	O
+a	O
+paradoxical	O
+rise	O
+in	O
+vascular	O
+and	O
+renal	O
+tissue	O
+eNOS	O
+and	O
+iNOS	O
+expression	O
+.	O
+
+Vitamin	O
+E	O
+supplementation	O
+ameliorated	O
+hypertension	B
+,	O
+lowered	O
+plasma	O
+MDA	O
+concentration	O
+,	O
+and	O
+raised	O
+urinary	O
+NOx	O
+excretion	O
+while	O
+significantly	O
+lowering	O
+vascular	O
+,	O
+but	O
+not	O
+renal	O
+,	O
+tissue	O
+eNOS	O
+and	O
+iNOS	O
+expression	O
+.	O
+
+Vitamin	O
+E	O
+supplementation	O
+had	O
+no	O
+effect	O
+on	O
+either	O
+blood	O
+pressure	O
+,	O
+plasma	O
+MDA	O
+,	O
+or	O
+NOS	O
+expression	O
+in	O
+the	O
+control	O
+group	O
+.	O
+
+The	O
+study	O
+also	O
+revealed	O
+significant	O
+inhibition	O
+of	O
+NOS	O
+enzymatic	O
+activity	O
+by	O
+lead	O
+in	O
+cell	O
+-	O
+free	O
+preparations	O
+.	O
+
+In	O
+conclusion	O
+,	O
+lead	O
+-	O
+induced	O
+hypertension	B
+in	O
+this	O
+model	O
+was	O
+associated	O
+with	O
+a	O
+compensatory	O
+upregulation	O
+of	O
+renal	O
+and	O
+vascular	O
+eNOS	O
+and	O
+iNOS	O
+expression	O
+.	O
+
+This	O
+is	O
+,	O
+in	O
+part	O
+,	O
+due	O
+to	O
+ROS	O
+-	O
+mediated	O
+NO	O
+inactivation	O
+,	O
+lead	O
+-	O
+associated	O
+inhibition	O
+of	O
+NOS	O
+activity	O
+,	O
+and	O
+perhaps	O
+stimulatory	O
+actions	O
+of	O
+increased	O
+shear	O
+stress	O
+associated	O
+with	O
+hypertension	B
+.	O
+
+Glyceryl	O
+trinitrate	O
+induces	O
+attacks	O
+of	O
+migraine	B
+without	I
+aura	I
+in	O
+sufferers	O
+of	O
+migraine	B
+with	I
+aura	I
+.	O
+
+Migraine	B
+with	I
+aura	I
+and	O
+migraine	B
+without	I
+aura	I
+have	O
+the	O
+same	O
+pain	B
+phase	O
+,	O
+thus	O
+indicating	O
+that	O
+migraine	B
+with	I
+aura	I
+and	O
+migraine	B
+without	I
+aura	I
+share	O
+a	O
+common	O
+pathway	O
+of	O
+nociception	O
+.	O
+
+In	O
+recent	O
+years	O
+,	O
+increasing	O
+evidence	O
+has	O
+suggested	O
+that	O
+the	O
+messenger	O
+molecule	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+is	O
+involved	O
+in	O
+pain	B
+mechanisms	O
+of	O
+migraine	B
+without	I
+aura	I
+.	O
+
+In	O
+order	O
+to	O
+clarify	O
+whether	O
+the	O
+same	O
+is	O
+true	O
+for	O
+migraine	B
+with	I
+aura	I
+,	O
+in	O
+the	O
+present	O
+study	O
+we	O
+examined	O
+the	O
+headache	B
+response	O
+to	O
+intravenous	O
+infusion	O
+of	O
+glyceryl	O
+trinitrate	O
+(	O
+GTN	O
+)	O
+(	O
+0	O
+.	O
+5	O
+microg	O
+/	O
+kg	O
+/	O
+min	O
+for	O
+20	O
+min	O
+)	O
+in	O
+12	O
+sufferers	O
+of	O
+migraine	B
+with	I
+aura	I
+.	O
+
+The	O
+specific	O
+aim	O
+was	O
+to	O
+elucidate	O
+whether	O
+an	O
+aura	O
+and	O
+/	O
+or	O
+an	O
+attack	O
+of	O
+migraine	B
+without	I
+aura	I
+could	O
+be	O
+induced	O
+.	O
+
+Fourteen	O
+healthy	O
+subjects	O
+served	O
+as	O
+controls	O
+.	O
+
+Aura	O
+symptoms	O
+were	O
+not	O
+elicited	O
+in	O
+any	O
+subject	O
+.	O
+
+Headache	B
+was	O
+more	O
+severe	O
+in	O
+migraineurs	B
+than	O
+in	O
+the	O
+controls	O
+during	O
+and	O
+immediately	O
+after	O
+GTN	O
+infusion	O
+(	O
+p	O
+=	O
+0	O
+.	O
+037	O
+)	O
+as	O
+well	O
+as	O
+during	O
+the	O
+following	O
+11	O
+h	O
+(	O
+p	O
+=	O
+0	O
+.	O
+008	O
+)	O
+.	O
+
+In	O
+the	O
+controls	O
+,	O
+the	O
+GTN	O
+-	O
+induced	O
+headache	B
+gradually	O
+disappeared	O
+,	O
+whereas	O
+in	O
+migraineurs	B
+peak	O
+headache	B
+intensity	O
+occurred	O
+at	O
+a	O
+mean	O
+time	O
+of	O
+240	O
+min	O
+post	O
+-	O
+infusion	O
+.	O
+
+At	O
+this	O
+time	O
+the	O
+induced	O
+headache	B
+in	O
+6	O
+of	O
+12	O
+migraineurs	B
+fulfilled	O
+the	O
+diagnostic	O
+criteria	O
+for	O
+migraine	B
+without	I
+aura	I
+of	O
+the	O
+International	O
+Headache	B
+Society	O
+.	O
+
+The	O
+results	O
+therefore	O
+suggest	O
+that	O
+NO	O
+is	O
+involved	O
+in	O
+the	O
+pain	B
+mechanisms	O
+of	O
+migraine	B
+with	I
+aura	I
+.	O
+
+Since	O
+cortical	O
+spreading	O
+depression	B
+has	O
+been	O
+shown	O
+to	O
+liberate	O
+NO	O
+in	O
+animals	O
+,	O
+this	O
+finding	O
+may	O
+help	O
+our	O
+understanding	O
+of	O
+the	O
+coupling	O
+between	O
+cortical	O
+spreading	O
+depression	B
+and	O
+headache	B
+in	O
+migraine	B
+with	I
+aura	I
+.	O
+
+Rapid	O
+reversal	O
+of	O
+life	O
+-	O
+threatening	O
+diltiazem	O
+-	O
+induced	O
+tetany	B
+with	O
+calcium	O
+chloride	O
+.	O
+
+We	O
+describe	O
+a	O
+patient	O
+who	O
+developed	O
+tetany	B
+with	O
+sudden	O
+respiratory	B
+arrest	I
+after	O
+the	O
+infusion	O
+of	O
+intravenous	O
+diltiazem	O
+.	O
+
+The	O
+administration	O
+of	O
+calcium	O
+chloride	O
+rapidly	O
+resolved	O
+the	O
+patient	O
+'	O
+s	O
+tetany	B
+with	O
+prompt	O
+recovery	O
+of	O
+respiratory	O
+function	O
+,	O
+averting	O
+the	O
+need	O
+for	O
+more	O
+aggressive	O
+airway	O
+management	O
+and	O
+ventilatory	O
+support	O
+.	O
+
+The	O
+emergency	O
+physician	O
+should	O
+be	O
+aware	O
+that	O
+life	O
+-	O
+threatening	O
+tetany	B
+may	O
+accompany	O
+the	O
+administration	O
+of	O
+intravenous	O
+diltiazem	O
+and	O
+that	O
+calcium	O
+chloride	O
+may	O
+be	O
+a	O
+rapid	O
+and	O
+effective	O
+remedy	O
+.	O
+
+Predictors	O
+of	O
+decreased	B
+renal	I
+function	I
+in	O
+patients	O
+with	O
+heart	B
+failure	I
+during	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitor	O
+therapy	O
+:	O
+results	O
+from	O
+the	O
+studies	O
+of	O
+left	B
+ventricular	I
+dysfunction	I
+(	O
+SOLVD	O
+)	O
+
+BACKGROUND	O
+:	O
+Although	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitor	O
+therapy	O
+reduces	O
+mortality	O
+rates	O
+in	O
+patients	O
+with	O
+congestive	B
+heart	I
+failure	I
+(	O
+CHF	B
+)	O
+,	O
+it	O
+may	O
+also	O
+cause	O
+decreased	B
+renal	I
+function	I
+.	O
+
+Little	O
+information	O
+is	O
+available	O
+to	O
+predict	O
+which	O
+patients	O
+are	O
+at	O
+highest	O
+risk	O
+for	O
+this	O
+complication	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+quantify	O
+specific	O
+clinical	O
+predictors	O
+of	O
+reduction	B
+in	I
+renal	I
+function	I
+in	O
+patients	O
+with	O
+CHF	B
+who	O
+are	O
+prescribed	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitor	O
+therapy	O
+.	O
+
+METHOD	O
+:	O
+We	O
+analyzed	O
+data	O
+from	O
+the	O
+Studies	O
+of	O
+Left	B
+Ventricular	I
+Dysfunction	I
+(	O
+SOLVD	O
+)	O
+,	O
+a	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+trial	O
+of	O
+enalapril	O
+for	O
+the	O
+treatment	O
+of	O
+CHF	B
+.	O
+
+There	O
+were	O
+3379	O
+patients	O
+randomly	O
+assigned	O
+to	O
+enalapril	O
+with	O
+a	O
+median	O
+follow	O
+-	O
+up	O
+of	O
+974	O
+days	O
+and	O
+3379	O
+patients	O
+randomly	O
+assigned	O
+to	O
+placebo	O
+with	O
+a	O
+mean	O
+follow	O
+-	O
+up	O
+of	O
+967	O
+days	O
+.	O
+
+Decreased	B
+renal	I
+function	I
+was	O
+defined	O
+as	O
+a	O
+rise	O
+in	O
+serum	O
+creatinine	O
+>	O
+/	O
+=	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+dL	O
+(	O
+44	O
+micromol	O
+/	O
+L	O
+)	O
+from	O
+baseline	O
+.	O
+
+We	O
+used	O
+time	O
+-	O
+to	O
+-	O
+event	O
+analysis	O
+to	O
+identify	O
+potential	O
+predictors	O
+of	O
+decrease	O
+in	O
+renal	O
+function	O
+including	O
+age	O
+,	O
+baseline	O
+ejection	O
+fraction	O
+,	O
+baseline	O
+creatinine	O
+,	O
+low	O
+systolic	O
+blood	O
+pressure	O
+(	O
+<	O
+100	O
+mm	O
+Hg	O
+)	O
+,	O
+history	O
+of	O
+hypertension	B
+,	O
+diabetes	B
+,	O
+and	O
+use	O
+of	O
+antiplatelet	O
+,	O
+diuretic	O
+,	O
+and	O
+beta	O
+-	O
+blocker	O
+therapy	O
+.	O
+
+RESULTS	O
+:	O
+Patients	O
+randomly	O
+assigned	O
+to	O
+enalapril	O
+had	O
+a	O
+33	O
+%	O
+greater	O
+likelihood	O
+of	O
+decreased	B
+renal	I
+function	I
+than	O
+controls	O
+(	O
+P	O
+=	O
+.	O
+003	O
+)	O
+.	O
+
+By	O
+multivariate	O
+analysis	O
+,	O
+in	O
+both	O
+the	O
+placebo	O
+and	O
+enalapril	O
+groups	O
+older	O
+age	O
+,	O
+diuretic	O
+therapy	O
+,	O
+and	O
+diabetes	B
+were	O
+associated	O
+with	O
+decreased	B
+renal	I
+function	I
+,	O
+whereas	O
+beta	O
+-	O
+blocker	O
+therapy	O
+and	O
+higher	O
+ejection	O
+fraction	O
+were	O
+renoprotective	O
+.	O
+
+Older	O
+age	O
+was	O
+associated	O
+with	O
+a	O
+greater	O
+risk	O
+of	O
+developing	O
+decreased	B
+renal	I
+function	I
+in	O
+both	O
+groups	O
+,	O
+but	O
+significantly	O
+more	O
+so	O
+in	O
+the	O
+enalapril	O
+group	O
+(	O
+enalapril	O
+:	O
+risk	O
+ratio	O
+[	O
+RR	O
+]	O
+1	O
+.	O
+42	O
+per	O
+10	O
+years	O
+,	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+1	O
+.	O
+32	O
+-	O
+1	O
+.	O
+52	O
+with	O
+enalapril	O
+;	O
+placebo	O
+:	O
+RR	O
+1	O
+.	O
+18	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+12	O
+-	O
+1	O
+.	O
+25	O
+)	O
+.	O
+
+Diuretic	O
+therapy	O
+was	O
+likewise	O
+associated	O
+with	O
+a	O
+greater	O
+risk	O
+of	O
+decreased	B
+renal	I
+function	I
+in	O
+the	O
+enalapril	O
+group	O
+(	O
+RR	O
+1	O
+.	O
+89	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+70	O
+-	O
+2	O
+.	O
+08	O
+)	O
+than	O
+in	O
+the	O
+placebo	O
+group	O
+(	O
+RR	O
+1	O
+.	O
+35	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+09	O
+-	O
+1	O
+.	O
+66	O
+)	O
+.	O
+
+Conversely	O
+,	O
+enalapril	O
+had	O
+a	O
+relative	O
+renoprotective	O
+effect	O
+(	O
+RR	O
+1	O
+.	O
+33	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+13	O
+-	O
+1	O
+.	O
+53	O
+)	O
+compared	O
+with	O
+placebo	O
+(	O
+RR	O
+1	O
+.	O
+96	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+57	O
+-	O
+2	O
+.	O
+44	O
+)	O
+in	O
+patients	O
+with	O
+diabetes	B
+.	O
+
+A	O
+lower	O
+risk	O
+of	O
+renal	B
+impairment	I
+was	O
+seen	O
+in	O
+both	O
+groups	O
+with	O
+beta	O
+-	O
+blocker	O
+therapy	O
+(	O
+RR	O
+0	O
+.	O
+70	O
+,	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+57	O
+-	O
+0	O
+.	O
+85	O
+)	O
+and	O
+higher	O
+baseline	O
+ejection	O
+fraction	O
+(	O
+RR	O
+0	O
+.	O
+93	O
+per	O
+5	O
+%	O
+increment	O
+,	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+91	O
+-	O
+0	O
+.	O
+96	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Enalapril	O
+use	O
+caused	O
+a	O
+33	O
+%	O
+increase	O
+in	O
+the	O
+risk	O
+of	O
+decreased	B
+renal	I
+function	I
+in	O
+patients	O
+with	O
+CHF	B
+.	O
+
+Diuretic	O
+use	O
+and	O
+advanced	O
+age	O
+increased	O
+this	O
+risk	O
+.	O
+
+Diabetes	B
+was	O
+associated	O
+with	O
+an	O
+increased	O
+risk	O
+of	O
+renal	B
+impairment	I
+in	O
+all	O
+patients	O
+with	O
+CHF	B
+,	O
+but	O
+this	O
+risk	O
+was	O
+reduced	O
+in	O
+the	O
+enalapril	O
+group	O
+compared	O
+with	O
+the	O
+placebo	O
+group	O
+.	O
+
+beta	O
+-	O
+Blocker	O
+therapy	O
+and	O
+higher	O
+ejection	O
+fraction	O
+were	O
+renoprotective	O
+in	O
+all	O
+patients	O
+regardless	O
+of	O
+therapy	O
+.	O
+
+Hypomania	B
+-	O
+like	O
+syndrome	O
+induced	O
+by	O
+olanzapine	O
+.	O
+
+We	O
+report	O
+a	O
+female	O
+patient	O
+with	O
+a	O
+diagnosis	O
+of	O
+a	O
+not	O
+otherwise	O
+specified	O
+psychotic	B
+disorder	I
+(	O
+DSM	O
+-	O
+IV	O
+)	O
+who	O
+developed	O
+hypomania	B
+shortly	O
+after	O
+the	O
+introduction	O
+of	O
+olanzapine	O
+treatment	O
+.	O
+
+Acetazolamide	O
+-	O
+induced	O
+Gerstmann	B
+syndrome	I
+.	O
+
+Acute	O
+confusion	B
+induced	O
+by	O
+acetazolamide	O
+is	O
+a	O
+well	O
+known	O
+adverse	O
+drug	O
+reaction	O
+in	O
+patients	O
+with	O
+renal	B
+impairment	I
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+acetazolamide	O
+-	O
+induced	O
+Gerstmann	B
+syndrome	I
+in	O
+a	O
+patient	O
+with	O
+normal	O
+renal	O
+function	O
+,	O
+to	O
+highlight	O
+predisposing	O
+factors	O
+that	O
+are	O
+frequently	O
+overlooked	O
+.	O
+
+Vasopressin	O
+in	O
+the	O
+treatment	O
+of	O
+milrinone	O
+-	O
+induced	O
+hypotension	B
+in	O
+severe	O
+heart	B
+failure	I
+.	O
+
+The	O
+use	O
+of	O
+phosphodiesterase	O
+inhibitors	O
+such	O
+as	O
+milrinone	O
+in	O
+the	O
+treatment	O
+of	O
+severe	O
+heart	B
+failure	I
+is	O
+frequently	O
+restricted	O
+because	O
+they	O
+cause	O
+vasodilation	O
+and	O
+hypotension	B
+.	O
+
+In	O
+patients	O
+with	O
+decompensated	O
+heart	B
+failure	I
+with	O
+hypotension	B
+after	O
+treatment	O
+with	O
+milrinone	O
+,	O
+low	O
+doses	O
+of	O
+vasopressin	O
+restored	O
+blood	O
+pressure	O
+without	O
+inhibiting	O
+the	O
+inotropic	O
+effect	O
+of	O
+milrinone	O
+.	O
+
+Treatment	O
+of	O
+tacrolimus	O
+-	O
+related	O
+adverse	O
+effects	O
+by	O
+conversion	O
+to	O
+cyclosporine	O
+in	O
+liver	O
+transplant	O
+recipients	O
+.	O
+
+When	O
+tacrolimus	O
+side	O
+effects	O
+persist	O
+despite	O
+dose	O
+reduction	O
+,	O
+conversion	O
+to	O
+cyclosporine	O
+-	O
+based	O
+immunosuppression	O
+(	O
+CyA	O
+)	O
+is	O
+necessary	O
+.	O
+
+We	O
+characterized	O
+tacrolimus	O
+side	O
+effects	O
+that	O
+warranted	O
+discontinuation	O
+of	O
+the	O
+drug	O
+,	O
+and	O
+outcomes	O
+after	O
+conversion	O
+.	O
+
+Of	O
+388	O
+liver	O
+recipients	O
+who	O
+received	O
+tacrolimus	O
+as	O
+primary	O
+immunosuppression	O
+,	O
+70	O
+required	O
+conversion	O
+to	O
+CyA	O
+.	O
+
+We	O
+recorded	O
+indication	O
+for	O
+conversion	O
+,	O
+whether	O
+conversion	O
+was	O
+early	O
+or	O
+late	O
+after	O
+transplantation	O
+,	O
+tacrolimus	O
+dose	O
+and	O
+trough	O
+blood	O
+level	O
+at	O
+conversion	O
+,	O
+and	O
+incidence	O
+of	O
+rejection	O
+after	O
+conversion	O
+.	O
+
+Conversion	O
+was	O
+early	O
+in	O
+29	O
+patients	O
+(	O
+41	O
+.	O
+4	O
+%	O
+)	O
+and	O
+late	O
+in	O
+41	O
+(	O
+58	O
+.	O
+6	O
+%	O
+)	O
+.	O
+
+Indications	O
+for	O
+early	O
+conversion	O
+were	O
+neurotoxicity	B
+(	O
+20	O
+)	O
+,	O
+(	B
+insulin	I
+-	I
+dependent	I
+)	I
+diabetes	I
+mellitus	I
+(	O
+IDDM	B
+)	O
+(	O
+5	O
+)	O
+,	O
+nephrotoxicity	B
+(	O
+3	O
+)	O
+,	O
+gastrointestinal	B
+(	I
+GI	I
+)	I
+toxicity	I
+(	O
+6	O
+)	O
+,	O
+and	O
+cardiomyopathy	B
+(	O
+1	O
+)	O
+,	O
+and	O
+for	O
+late	O
+conversion	O
+were	O
+neurotoxicity	B
+(	O
+15	O
+)	O
+,	O
+IDDM	B
+(	O
+12	O
+)	O
+,	O
+nephrotoxicity	B
+(	O
+3	O
+)	O
+,	O
+GI	B
+toxicity	I
+(	O
+5	O
+)	O
+,	O
+hepatotoxicity	B
+(	O
+6	O
+)	O
+,	O
+post	B
+-	I
+transplant	I
+lmphoproliferate	I
+disease	I
+(	O
+PTLD	B
+)	O
+(	O
+2	O
+)	O
+,	O
+cardiomyopathy	B
+(	O
+1	O
+)	O
+,	O
+hemolytic	B
+anemia	I
+(	O
+1	O
+)	O
+,	O
+and	O
+pruritus	B
+(	O
+1	O
+)	O
+.	O
+
+All	O
+early	O
+-	O
+conversion	O
+patients	O
+showed	O
+improvement	O
+/	O
+resolution	O
+of	O
+symptoms	O
+.	O
+
+Among	O
+late	O
+-	O
+conversion	O
+patients	O
+,	O
+37	O
+(	O
+90	O
+.	O
+2	O
+%	O
+)	O
+had	O
+improvement	O
+/	O
+resolution	O
+;	O
+in	O
+4	O
+(	O
+9	O
+.	O
+8	O
+%	O
+)	O
+,	O
+adverse	O
+effects	O
+persisted	O
+.	O
+
+The	O
+overall	O
+rejection	O
+rate	O
+was	O
+30	O
+%	O
+.	O
+
+Sixty	O
+-	O
+two	O
+patients	O
+(	O
+88	O
+.	O
+6	O
+%	O
+)	O
+are	O
+alive	O
+with	O
+functioning	O
+grafts	O
+686	O
++	O
+/	O
+-	O
+362	O
+days	O
+(	O
+range	O
+,	O
+154	O
+-	O
+1433	O
+days	O
+)	O
+after	O
+conversion	O
+.	O
+
+When	O
+tacrolimus	O
+side	O
+effects	O
+are	O
+unresponsive	O
+to	O
+dose	O
+reduction	O
+,	O
+conversion	O
+to	O
+CyA	O
+can	O
+be	O
+accomplished	O
+safely	O
+,	O
+with	O
+no	O
+increased	O
+risk	O
+of	O
+rejection	O
+and	O
+excellent	O
+long	O
+-	O
+term	O
+outcome	O
+.	O
+
+Ocular	O
+manifestations	O
+of	O
+juvenile	B
+rheumatoid	I
+arthritis	I
+.	O
+
+We	O
+followed	O
+210	O
+cases	O
+of	O
+juvenile	B
+rheumatoid	I
+arthritis	I
+closely	O
+for	O
+eleven	O
+years	O
+.	O
+
+Thirty	O
+-	O
+six	O
+of	O
+the	O
+210	O
+patients	O
+(	O
+17	O
+.	O
+2	O
+%	O
+)	O
+developed	O
+iridocyclitis	B
+.	O
+
+Iridocyclitis	B
+was	O
+seen	O
+most	O
+frequently	O
+in	O
+young	O
+female	O
+patients	O
+(	O
+0	O
+to	O
+4	O
+years	O
+)	O
+with	O
+the	O
+monoarticular	O
+or	O
+pauciatricular	O
+form	O
+of	O
+the	O
+arthritis	B
+.	O
+
+However	O
+,	O
+30	O
+%	O
+of	O
+the	O
+patients	O
+developed	O
+uveitis	B
+after	O
+16	O
+years	O
+of	O
+age	O
+.	O
+
+Although	O
+61	O
+%	O
+of	O
+patients	O
+had	O
+a	O
+noncontributory	O
+ocular	O
+history	O
+on	O
+entry	O
+,	O
+42	O
+%	O
+had	O
+active	O
+uveitis	B
+on	O
+entry	O
+.	O
+
+Our	O
+approach	O
+was	O
+effective	O
+in	O
+detecting	O
+uveitis	B
+in	O
+new	O
+cases	O
+and	O
+exacerbations	O
+of	O
+uveitis	B
+in	O
+established	O
+cases	O
+.	O
+
+Forty	O
+-	O
+four	O
+percent	O
+of	O
+patients	O
+with	O
+uveitis	B
+had	O
+one	O
+or	O
+more	O
+identifiable	O
+signs	O
+or	O
+symptoms	O
+,	O
+such	O
+as	O
+red	O
+eye	O
+,	O
+ocular	B
+pain	I
+,	O
+decreased	B
+visual	I
+acuity	I
+,	O
+or	O
+photophobia	B
+,	O
+in	O
+order	O
+of	O
+decreasing	O
+frequency	O
+.	O
+
+Even	O
+after	O
+early	O
+detection	O
+and	O
+prompt	O
+treatment	O
+,	O
+41	O
+%	O
+of	O
+cases	O
+of	O
+uveitis	B
+did	O
+not	O
+respond	O
+to	O
+more	O
+than	O
+six	O
+months	O
+of	O
+intensive	O
+topical	O
+treatment	O
+with	O
+corticosteroids	O
+and	O
+mydriatics	O
+.	O
+
+Despite	O
+this	O
+,	O
+there	O
+was	O
+a	O
+dramatic	O
+decrease	O
+in	O
+the	O
+50	O
+%	O
+incidence	O
+of	O
+blinding	O
+complications	O
+of	O
+uveitis	B
+cited	O
+in	O
+earlier	O
+studies	O
+.	O
+
+Cataract	B
+and	O
+band	B
+keratopathy	I
+occurred	O
+in	O
+only	O
+22	O
+and	O
+13	O
+%	O
+of	O
+our	O
+group	O
+,	O
+respectively	O
+.	O
+
+We	O
+used	O
+chloroquine	O
+or	O
+hydroxychloroquine	O
+in	O
+173	O
+of	O
+210	O
+cases	O
+and	O
+found	O
+only	O
+one	O
+case	O
+of	O
+chorioretinopathy	B
+attributable	O
+to	O
+these	O
+drugs	O
+.	O
+
+Systemically	O
+administered	O
+corticosteroids	O
+were	O
+used	O
+in	O
+75	O
+of	O
+210	O
+cases	O
+;	O
+a	O
+significant	O
+number	O
+of	O
+posterior	O
+subcapsular	O
+cataracts	B
+was	O
+found	O
+.	O
+
+Typical	O
+keratoconjunctivitis	B
+sicca	O
+developed	O
+in	O
+three	O
+of	O
+the	O
+uveitis	B
+cases	O
+.	O
+
+This	O
+association	O
+with	O
+uveitis	B
+and	O
+JRA	O
+was	O
+not	O
+noted	O
+previously	O
+.	O
+
+Surgical	O
+treatment	O
+of	O
+cataracts	B
+,	O
+band	B
+keratopathy	I
+,	O
+and	O
+glaucoma	B
+achieved	O
+uniformly	O
+discouraging	O
+results	O
+.	O
+
+Cyclophosphamide	O
+-	O
+induced	O
+cystitis	B
+in	O
+freely	O
+-	O
+moving	O
+conscious	O
+rats	O
+:	O
+behavioral	O
+approach	O
+to	O
+a	O
+new	O
+model	O
+of	O
+visceral	B
+pain	I
+.	O
+
+PURPOSE	O
+:	O
+To	O
+develop	O
+a	O
+model	O
+of	O
+visceral	B
+pain	I
+in	O
+rats	O
+using	O
+a	O
+behavioral	O
+approach	O
+.	O
+
+Cyclophosphamide	O
+(	O
+CP	O
+)	O
+,	O
+an	O
+antitumoral	O
+agent	O
+known	O
+to	O
+produce	O
+toxic	O
+effects	O
+on	O
+the	O
+bladder	O
+wall	O
+through	O
+its	O
+main	O
+toxic	O
+metabolite	O
+acrolein	O
+,	O
+was	O
+used	O
+to	O
+induce	O
+cystitis	B
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+CP	O
+was	O
+administered	O
+at	O
+doses	O
+of	O
+50	O
+,	O
+100	O
+and	O
+200	O
+mg	O
+.	O
+/	O
+kg	O
+.	O
+
+i	O
+.	O
+p	O
+.	O
+to	O
+male	O
+rats	O
+,	O
+and	O
+their	O
+behavior	O
+observed	O
+and	O
+scored	O
+.	O
+
+The	O
+effects	O
+of	O
+morphine	O
+(	O
+0	O
+.	O
+5	O
+to	O
+4	O
+mg	O
+.	O
+/	O
+kg	O
+.	O
+i	O
+.	O
+v	O
+.	O
+)	O
+on	O
+CP	O
+-	O
+induced	O
+behavioral	O
+modifications	O
+were	O
+tested	O
+administered	O
+alone	O
+and	O
+after	O
+naloxone	O
+(	O
+1	O
+mg	O
+.	O
+/	O
+kg	O
+.	O
+s	O
+.	O
+c	O
+.	O
+)	O
+.	O
+
+In	O
+addition	O
+,	O
+90	O
+minutes	O
+after	O
+CP	O
+injection	O
+,	O
+that	O
+is	O
+,	O
+at	O
+the	O
+time	O
+of	O
+administration	O
+of	O
+morphine	O
+,	O
+the	O
+bladder	O
+was	O
+removed	O
+in	O
+some	O
+rats	O
+for	O
+histological	O
+examination	O
+.	O
+
+Finally	O
+,	O
+to	O
+show	O
+that	O
+the	O
+bladder	O
+is	O
+essential	O
+for	O
+the	O
+CP	O
+-	O
+induced	O
+behavioral	O
+modifications	O
+,	O
+female	O
+rats	O
+also	O
+received	O
+CP	O
+at	O
+doses	O
+of	O
+200	O
+mg	O
+.	O
+/	O
+kg	O
+.	O
+
+i	O
+.	O
+p	O
+.	O
+and	O
+of	O
+20	O
+mg	O
+.	O
+by	O
+the	O
+intravesical	O
+route	O
+,	O
+and	O
+acrolein	O
+at	O
+doses	O
+of	O
+0	O
+.	O
+5	O
+mg	O
+.	O
+by	O
+the	O
+intravesical	O
+route	O
+and	O
+of	O
+5	O
+mg	O
+.	O
+/	O
+kg	O
+.	O
+
+i	O
+.	O
+v	O
+.	O
+RESULTS	O
+:	O
+CP	O
+dose	O
+-	O
+relatedly	O
+induced	O
+marked	O
+behavioral	O
+modifications	O
+in	O
+male	O
+rats	O
+:	O
+breathing	O
+rate	O
+decrease	O
+,	O
+closing	O
+of	O
+the	O
+eyes	O
+and	O
+occurrence	O
+of	O
+specific	O
+postures	O
+.	O
+
+Morphine	O
+dose	O
+-	O
+dependently	O
+reversed	O
+these	O
+behavioral	B
+disorders	I
+.	O
+
+A	O
+dose	O
+of	O
+0	O
+.	O
+5	O
+mg	O
+.	O
+/	O
+kg	O
+.	O
+produced	O
+a	O
+reduction	O
+of	O
+almost	O
+50	O
+%	O
+of	O
+the	O
+behavioral	O
+score	O
+induced	O
+by	O
+CP	O
+200	O
+mg	O
+.	O
+/	O
+kg	O
+.	O
+
+This	O
+effect	O
+was	O
+completely	O
+prevented	O
+by	O
+pretreatment	O
+with	O
+naloxone	O
+.	O
+
+At	O
+the	O
+time	O
+of	O
+administration	O
+of	O
+morphine	O
+,	O
+histological	O
+modifications	O
+of	O
+the	O
+bladder	O
+wall	O
+,	O
+such	O
+as	O
+chorionic	O
+and	O
+muscle	O
+layer	O
+edema	B
+,	O
+were	O
+observed	O
+.	O
+
+In	O
+female	O
+rats	O
+,	O
+CP	O
+200	O
+mg	O
+.	O
+/	O
+kg	O
+.	O
+
+i	O
+.	O
+p	O
+.	O
+produced	O
+the	O
+same	O
+marked	O
+behavioral	O
+modifications	O
+as	O
+those	O
+observed	O
+in	O
+male	O
+rats	O
+.	O
+
+Administered	O
+at	O
+the	O
+dose	O
+of	O
+20	O
+mg	O
+.	O
+intravesically	O
+,	O
+CP	O
+did	O
+not	O
+produce	O
+any	O
+behavioral	O
+effects	O
+,	O
+whereas	O
+acrolein	O
+at	O
+0	O
+.	O
+5	O
+mg	O
+.	O
+intravesically	O
+induced	O
+behavioral	O
+modifications	O
+identical	O
+to	O
+those	O
+under	O
+CP	O
+200	O
+mg	O
+.	O
+/	O
+kg	O
+.	O
+
+i	O
+.	O
+p	O
+.	O
+,	O
+with	O
+the	O
+same	O
+maximal	O
+levels	O
+.	O
+
+Conversely	O
+,	O
+acrolein	O
+5	O
+mg	O
+.	O
+/	O
+kg	O
+.	O
+
+i	O
+.	O
+v	O
+.	O
+did	O
+not	O
+produce	O
+any	O
+behavioral	O
+effects	O
+at	O
+all	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Overall	O
+,	O
+these	O
+results	O
+indicate	O
+that	O
+this	O
+experimental	O
+model	O
+of	O
+CP	O
+-	O
+induced	O
+cystitis	B
+may	O
+be	O
+an	O
+interesting	O
+new	O
+behavioral	O
+model	O
+of	O
+inflammatory	O
+visceral	B
+pain	I
+,	O
+allowing	O
+a	O
+better	O
+understanding	O
+of	O
+these	O
+painful	B
+syndromes	I
+and	O
+thus	O
+a	O
+better	O
+therapeutic	O
+approach	O
+to	O
+them	O
+.	O
+
+Prednisolone	O
+-	O
+induced	O
+muscle	B
+dysfunction	I
+is	O
+caused	O
+more	O
+by	O
+atrophy	B
+than	O
+by	O
+altered	O
+acetylcholine	O
+receptor	O
+expression	O
+.	O
+
+Large	O
+doses	O
+of	O
+glucocorticoids	O
+can	O
+alter	O
+muscle	O
+physiology	O
+and	O
+susceptibility	O
+to	O
+neuromuscular	O
+blocking	O
+drugs	O
+by	O
+mechanisms	O
+not	O
+clearly	O
+understood	O
+.	O
+
+We	O
+investigated	O
+the	O
+effects	O
+of	O
+moderate	O
+and	O
+large	O
+doses	O
+of	O
+prednisolone	O
+on	O
+muscle	O
+function	O
+and	O
+pharmacology	O
+,	O
+and	O
+their	O
+relationship	O
+to	O
+changes	O
+in	O
+muscle	O
+size	O
+and	O
+acetylcholine	O
+receptor	O
+(	O
+AChR	O
+)	O
+expression	O
+.	O
+
+With	O
+institutional	O
+approval	O
+,	O
+35	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+were	O
+randomly	O
+allocated	O
+to	O
+receive	O
+daily	O
+subcutaneous	O
+doses	O
+of	O
+10	O
+mg	O
+/	O
+kg	O
+prednisolone	O
+(	O
+P10	O
+group	O
+)	O
+,	O
+100	O
+mg	O
+/	O
+kg	O
+prednisolone	O
+(	O
+P100	O
+group	O
+)	O
+,	O
+or	O
+an	O
+equal	O
+volume	O
+of	O
+saline	O
+(	O
+S	O
+group	O
+)	O
+for	O
+7	O
+days	O
+.	O
+
+A	O
+fourth	O
+group	O
+of	O
+rats	O
+was	O
+pair	O
+fed	O
+(	O
+food	O
+restricted	O
+)	O
+with	O
+the	O
+P100	O
+rats	O
+for	O
+7	O
+days	O
+(	O
+FR	O
+group	O
+)	O
+.	O
+
+On	O
+Day	O
+8	O
+,	O
+the	O
+nerve	O
+-	O
+evoked	O
+peak	O
+twitch	O
+tensions	O
+,	O
+tetanic	B
+tensions	O
+,	O
+and	O
+fatigability	O
+,	O
+and	O
+the	O
+dose	O
+-	O
+response	O
+curves	O
+of	O
+d	O
+-	O
+tubocurarine	O
+in	O
+the	O
+tibialis	O
+cranialis	O
+muscle	O
+were	O
+measured	O
+in	O
+vivo	O
+and	O
+related	O
+to	O
+muscle	O
+mass	O
+or	O
+expression	O
+of	O
+AChRs	O
+.	O
+
+Rate	O
+of	O
+body	O
+weight	O
+gain	O
+was	O
+depressed	O
+in	O
+the	O
+P100	O
+,	O
+FR	O
+,	O
+and	O
+P10	O
+groups	O
+compared	O
+with	O
+the	O
+S	O
+group	O
+.	O
+
+Tibialis	O
+muscle	O
+mass	O
+was	O
+smaller	O
+in	O
+the	O
+P100	O
+group	O
+than	O
+in	O
+the	O
+P10	O
+or	O
+S	O
+groups	O
+.	O
+
+The	O
+evoked	O
+peak	O
+twitch	O
+and	O
+tetanic	B
+tensions	O
+were	O
+less	O
+in	O
+the	O
+P100	O
+group	O
+than	O
+in	O
+the	O
+P10	O
+or	O
+S	O
+groups	O
+,	O
+however	O
+,	O
+tension	O
+per	O
+milligram	O
+of	O
+muscle	O
+mass	O
+was	O
+greater	O
+in	O
+the	O
+P100	O
+group	O
+than	O
+in	O
+the	O
+S	O
+group	O
+.	O
+
+The	O
+50	O
+%	O
+effective	O
+dose	O
+of	O
+d	O
+-	O
+tubocurarine	O
+(	O
+microg	O
+/	O
+kg	O
+)	O
+in	O
+the	O
+tibialis	O
+muscle	O
+was	O
+smaller	O
+in	O
+the	O
+P10	O
+(	O
+33	O
+.	O
+6	O
++	O
+/	O
+-	O
+5	O
+.	O
+4	O
+)	O
+than	O
+in	O
+the	O
+S	O
+(	O
+61	O
+.	O
+9	O
++	O
+/	O
+-	O
+5	O
+.	O
+0	O
+)	O
+or	O
+the	O
+P100	O
+(	O
+71	O
+.	O
+3	O
++	O
+/	O
+-	O
+9	O
+.	O
+6	O
+)	O
+groups	O
+.	O
+
+AChR	O
+expression	O
+was	O
+less	O
+in	O
+the	O
+P10	O
+group	O
+than	O
+in	O
+the	O
+S	O
+group	O
+.	O
+
+The	O
+evoked	O
+tensions	O
+correlated	O
+with	O
+muscle	O
+mass	O
+(	O
+r	O
+(	O
+2	O
+)	O
+=	O
+0	O
+.	O
+32	O
+,	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+,	O
+however	O
+,	O
+not	O
+with	O
+expression	O
+of	O
+AChR	O
+.	O
+
+The	O
+50	O
+%	O
+effective	O
+dose	O
+of	O
+d	O
+-	O
+tubocurarine	O
+did	O
+not	O
+correlate	O
+with	O
+muscle	O
+mass	O
+or	O
+AChR	O
+expression	O
+.	O
+
+Our	O
+results	O
+suggest	O
+that	O
+the	O
+neuromuscular	B
+dysfunction	I
+after	O
+prednisolone	O
+is	O
+dose	O
+-	O
+dependent	O
+,	O
+and	O
+derives	O
+primarily	O
+from	O
+muscle	B
+atrophy	I
+and	O
+derives	O
+less	O
+so	O
+from	O
+changes	O
+in	O
+AChR	O
+expression	O
+.	O
+
+IMPLICATIONS	O
+:	O
+The	O
+mechanisms	O
+by	O
+which	O
+chronic	O
+glucocorticoid	O
+therapy	O
+alters	O
+neuromuscular	O
+physiology	O
+and	O
+pharmacology	O
+are	O
+unclear	O
+.	O
+
+We	O
+suggest	O
+that	O
+the	O
+observed	O
+effects	O
+are	O
+dose	O
+-	O
+dependent	O
+and	O
+derive	O
+primarily	O
+from	O
+muscle	B
+atrophy	I
+and	O
+derive	O
+less	O
+from	O
+changes	O
+in	O
+acetylcholine	O
+receptor	O
+expression	O
+.	O
+
+Apomorphine	O
+:	O
+an	O
+underutilized	O
+therapy	O
+for	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+Apomorphine	O
+was	O
+the	O
+first	O
+dopaminergic	O
+drug	O
+ever	O
+used	O
+to	O
+treat	O
+symptoms	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+While	O
+powerful	O
+antiparkinsonian	O
+effects	O
+had	O
+been	O
+observed	O
+as	O
+early	O
+as	O
+1951	O
+,	O
+the	O
+potential	O
+of	O
+treating	O
+fluctuating	O
+Parkinson	B
+'	I
+s	I
+disease	I
+by	O
+subcutaneous	O
+administration	O
+of	O
+apomorphine	O
+has	O
+only	O
+recently	O
+become	O
+the	O
+subject	O
+of	O
+systematic	O
+study	O
+.	O
+
+A	O
+number	O
+of	O
+small	O
+scale	O
+clinical	O
+trials	O
+have	O
+unequivocally	O
+shown	O
+that	O
+intermittent	O
+subcutaneous	O
+apomorphine	O
+injections	O
+produce	O
+antiparkinsonian	O
+benefit	O
+close	O
+if	O
+not	O
+identical	O
+to	O
+that	O
+seen	O
+with	O
+levodopa	O
+and	O
+that	O
+apomorphine	O
+rescue	O
+injections	O
+can	O
+reliably	O
+revert	O
+off	O
+-	O
+periods	O
+even	O
+in	O
+patients	O
+with	O
+complex	O
+on	O
+-	O
+off	O
+motor	O
+swings	O
+.	O
+
+Continuous	O
+subcutaneous	O
+apomorphine	O
+infusions	O
+can	O
+reduce	O
+daily	O
+off	O
+-	O
+time	O
+by	O
+more	O
+than	O
+50	O
+%	O
+in	O
+this	O
+group	O
+of	O
+patients	O
+,	O
+which	O
+appears	O
+to	O
+be	O
+a	O
+stronger	O
+effect	O
+than	O
+that	O
+generally	O
+seen	O
+with	O
+add	O
+-	O
+on	O
+therapy	O
+with	O
+oral	O
+dopamine	O
+agonists	O
+or	O
+COMT	O
+inhibitors	O
+.	O
+
+Extended	O
+follow	O
+-	O
+up	O
+studies	O
+of	O
+up	O
+to	O
+8	O
+years	O
+have	O
+demonstrated	O
+long	O
+-	O
+term	O
+persistence	O
+of	O
+apomorphine	O
+efficacy	O
+.	O
+
+In	O
+addition	O
+,	O
+there	O
+is	O
+convincing	O
+clinical	O
+evidence	O
+that	O
+monotherapy	O
+with	O
+continuous	O
+subcutaneous	O
+apomorphine	O
+infusions	O
+is	O
+associated	O
+with	O
+marked	O
+reductions	O
+of	O
+preexisting	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+.	O
+
+The	O
+main	O
+side	O
+effects	O
+of	O
+subcutaneous	O
+apomorphine	O
+treatment	O
+are	O
+related	O
+to	O
+cutaneous	O
+tolerability	O
+problems	O
+,	O
+whereas	O
+sedation	O
+and	O
+psychiatric	B
+complications	O
+play	O
+a	O
+lesser	O
+role	O
+.	O
+
+Given	O
+the	O
+marked	O
+degree	O
+of	O
+efficacy	O
+of	O
+subcutaneous	O
+apomorphine	O
+treatment	O
+in	O
+fluctuating	O
+Parkinson	B
+'	I
+s	I
+disease	I
+,	O
+this	O
+approach	O
+seems	O
+to	O
+deserve	O
+more	O
+widespread	O
+clinical	O
+use	O
+.	O
+
+Probing	O
+peripheral	O
+and	O
+central	O
+cholinergic	O
+system	O
+responses	O
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+pharmacological	O
+response	O
+to	O
+drugs	O
+that	O
+act	O
+on	O
+the	O
+cholinergic	O
+system	O
+of	O
+the	O
+iris	O
+has	O
+been	O
+used	O
+to	O
+predict	O
+deficits	O
+in	O
+central	O
+cholinergic	O
+functioning	O
+due	O
+to	O
+diseases	O
+such	O
+as	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+,	O
+yet	O
+correlations	O
+between	O
+central	O
+and	O
+peripheral	O
+responses	O
+have	O
+not	O
+been	O
+properly	O
+studied	O
+.	O
+
+This	O
+study	O
+assessed	O
+the	O
+effect	O
+of	O
+normal	O
+aging	O
+on	O
+(	O
+1	O
+)	O
+the	O
+tropicamide	O
+-	O
+induced	O
+increase	O
+in	O
+pupil	O
+diameter	O
+,	O
+and	O
+(	O
+2	O
+)	O
+the	O
+reversal	O
+of	O
+this	O
+effect	O
+with	O
+pilocarpine	O
+.	O
+
+Scopolamine	O
+was	O
+used	O
+as	O
+a	O
+positive	O
+control	O
+to	O
+detect	O
+age	O
+-	O
+dependent	O
+changes	O
+in	O
+central	O
+cholinergic	O
+functioning	O
+in	O
+the	O
+elderly	O
+.	O
+
+DESIGN	O
+:	O
+Randomized	O
+double	O
+-	O
+blind	O
+controlled	O
+trial	O
+.	O
+
+PARTICIPANTS	O
+:	O
+Ten	O
+healthy	O
+elderly	O
+(	O
+mean	O
+age	O
+70	O
+)	O
+and	O
+9	O
+young	O
+(	O
+mean	O
+age	O
+33	O
+)	O
+volunteers	O
+.	O
+
+INTERVENTIONS	O
+:	O
+Pupil	O
+diameter	O
+was	O
+monitored	O
+using	O
+a	O
+computerized	O
+infrared	O
+pupillometer	O
+over	O
+4	O
+hours	O
+.	O
+
+The	O
+study	O
+involved	O
+4	O
+sessions	O
+.	O
+
+In	O
+1	O
+session	O
+,	O
+tropicamide	O
+(	O
+20	O
+microL	O
+,	O
+0	O
+.	O
+01	O
+%	O
+)	O
+was	O
+administered	O
+to	O
+one	O
+eye	O
+and	O
+placebo	O
+to	O
+the	O
+other	O
+.	O
+
+In	O
+another	O
+session	O
+,	O
+tropicamide	O
+(	O
+20	O
+microL	O
+,	O
+0	O
+.	O
+01	O
+%	O
+)	O
+was	O
+administered	O
+to	O
+both	O
+eyes	O
+,	O
+followed	O
+23	O
+minutes	O
+later	O
+by	O
+the	O
+application	O
+of	O
+pilocarpine	O
+(	O
+20	O
+microL	O
+,	O
+0	O
+.	O
+1	O
+%	O
+)	O
+to	O
+one	O
+eye	O
+and	O
+placebo	O
+to	O
+the	O
+other	O
+.	O
+
+All	O
+eye	O
+drops	O
+were	O
+given	O
+in	O
+a	O
+randomized	O
+order	O
+.	O
+
+In	O
+2	O
+separate	O
+sessions	O
+,	O
+a	O
+single	O
+dose	O
+of	O
+scopolamine	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+,	O
+intravenously	O
+)	O
+or	O
+placebo	O
+was	O
+administered	O
+,	O
+and	O
+the	O
+effects	O
+on	O
+word	O
+recall	O
+were	O
+measured	O
+using	O
+the	O
+Buschke	O
+Selective	O
+Reminding	O
+Test	O
+over	O
+2	O
+hours	O
+.	O
+
+OUTCOME	O
+MEASURES	O
+:	O
+Pupil	O
+size	O
+at	O
+time	O
+points	O
+after	O
+administration	O
+of	O
+tropicamide	O
+and	O
+pilocarpine	O
+;	O
+scopolamine	O
+-	O
+induced	O
+impairment	B
+in	I
+word	I
+recall	I
+.	O
+
+RESULTS	O
+:	O
+There	O
+was	O
+no	O
+significant	O
+difference	O
+between	O
+elderly	O
+and	O
+young	O
+volunteers	O
+in	O
+pupillary	O
+response	O
+to	O
+tropicamide	O
+at	O
+any	O
+time	O
+point	O
+(	O
+p	O
+>	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+elderly	O
+group	O
+had	O
+a	O
+significantly	O
+greater	O
+pilocarpine	O
+-	O
+induced	O
+net	O
+decrease	O
+in	O
+pupil	O
+size	O
+85	O
+,	O
+125	O
+,	O
+165	O
+and	O
+215	O
+minutes	O
+after	O
+administration	O
+,	O
+compared	O
+with	O
+the	O
+young	O
+group	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Compared	O
+with	O
+the	O
+young	O
+group	O
+,	O
+the	O
+elderly	O
+group	O
+had	O
+greater	O
+scopolamine	O
+-	O
+induced	O
+impairment	B
+in	I
+word	I
+recall	I
+60	O
+,	O
+90	O
+and	O
+120	O
+minutes	O
+after	O
+administration	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+There	O
+is	O
+an	O
+age	O
+-	O
+related	O
+pupillary	O
+response	O
+to	O
+pilocarpine	O
+that	O
+is	O
+not	O
+found	O
+with	O
+tropicamide	O
+.	O
+
+Thus	O
+,	O
+pilocarpine	O
+may	O
+be	O
+useful	O
+to	O
+assess	O
+variations	O
+in	O
+central	O
+cholinergic	O
+function	O
+in	O
+elderly	O
+patients	O
+.	O
+
+Pain	B
+responses	O
+in	O
+methadone	O
+-	O
+maintained	O
+opioid	O
+abusers	O
+.	O
+
+Providing	O
+pain	B
+management	O
+for	O
+known	O
+opioid	O
+abusers	O
+is	O
+a	O
+challenging	O
+clinical	O
+task	O
+,	O
+in	O
+part	O
+because	O
+little	O
+is	O
+known	O
+about	O
+their	O
+pain	B
+experience	O
+and	O
+analgesic	O
+requirements	O
+.	O
+
+This	O
+study	O
+was	O
+designed	O
+to	O
+describe	O
+pain	B
+tolerance	O
+and	O
+analgesic	O
+response	O
+in	O
+a	O
+sample	O
+of	O
+opioid	B
+addicts	I
+stabilized	O
+in	O
+methadone	O
+-	O
+maintenance	O
+(	O
+MM	O
+)	O
+treatment	O
+(	O
+n	O
+=	O
+60	O
+)	O
+in	O
+comparison	O
+to	O
+matched	O
+nondependent	O
+control	O
+subjects	O
+(	O
+n	O
+=	O
+60	O
+)	O
+.	O
+
+By	O
+using	O
+a	O
+placebo	O
+-	O
+controlled	O
+,	O
+two	O
+-	O
+way	O
+factorial	O
+design	O
+,	O
+tolerance	O
+to	O
+cold	O
+-	O
+pressor	O
+(	O
+CP	O
+)	O
+pain	B
+was	O
+examined	O
+,	O
+both	O
+before	O
+and	O
+after	O
+oral	O
+administration	O
+of	O
+therapeutic	O
+doses	O
+of	O
+common	O
+opioid	O
+(	O
+hydromorphone	O
+2	O
+mg	O
+)	O
+and	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+(	O
+ketorolac	O
+10	O
+mg	O
+)	O
+analgesic	O
+agents	O
+.	O
+
+Results	O
+showed	O
+that	O
+MM	O
+individuals	O
+were	O
+significantly	O
+less	O
+tolerant	O
+of	O
+CP	O
+pain	B
+than	O
+control	O
+subjects	O
+,	O
+replicating	O
+previous	O
+work	O
+.	O
+
+Analgesic	O
+effects	O
+were	O
+significant	O
+neither	O
+for	O
+medication	O
+nor	O
+group	O
+.	O
+
+These	O
+data	O
+indicate	O
+that	O
+MM	O
+opioid	O
+abusers	O
+represent	O
+a	O
+pain	B
+-	I
+intolerant	I
+subset	O
+of	O
+clinical	O
+patients	O
+.	O
+
+Their	O
+complaints	O
+of	O
+pain	B
+should	O
+be	O
+evaluated	O
+seriously	O
+and	O
+managed	O
+aggressively	O
+.	O
+
+High	O
+-	O
+dose	O
+methylprednisolone	O
+may	O
+do	O
+more	O
+harm	O
+for	O
+spinal	B
+cord	I
+injury	I
+.	O
+
+Because	O
+of	O
+the	O
+National	O
+Acute	O
+Spinal	B
+Cord	I
+Injury	I
+Studies	O
+(	O
+NASCIS	O
+)	O
+,	O
+high	O
+-	O
+dose	O
+methylprednisolone	O
+became	O
+the	O
+standard	O
+of	O
+care	O
+for	O
+the	O
+acute	O
+spinal	B
+cord	I
+injury	I
+.	O
+
+In	O
+the	O
+NASCIS	O
+,	O
+there	O
+was	O
+no	O
+mention	O
+regarding	O
+the	O
+possibility	O
+of	O
+acute	O
+corticosteroid	O
+myopathy	B
+that	O
+high	O
+-	O
+dose	O
+methylprednisolone	O
+may	O
+cause	O
+.	O
+
+The	O
+dosage	O
+of	O
+methylprednisolone	O
+recommended	O
+by	O
+the	O
+NASCIS	O
+3	O
+is	O
+the	O
+highest	O
+dose	O
+of	O
+steroids	O
+ever	O
+being	O
+used	O
+during	O
+a	O
+2	O
+-	O
+day	O
+period	O
+for	O
+any	O
+clinical	O
+condition	O
+.	O
+
+We	O
+hypothesize	O
+that	O
+it	O
+may	O
+cause	O
+some	O
+damage	B
+to	I
+the	I
+muscle	I
+of	O
+spinal	B
+cord	I
+injury	I
+patients	O
+.	O
+
+Further	O
+,	O
+steroid	O
+myopathy	B
+recovers	O
+naturally	O
+and	O
+the	O
+neurological	O
+improvement	O
+shown	O
+in	O
+the	O
+NASCIS	O
+may	O
+be	O
+just	O
+a	O
+recording	O
+of	O
+this	O
+natural	O
+motor	O
+recovery	O
+from	O
+the	O
+steroid	O
+myopathy	B
+,	O
+instead	O
+of	O
+any	O
+protection	O
+that	O
+methylprednisolone	O
+offers	O
+to	O
+the	O
+spinal	B
+cord	I
+injury	I
+.	O
+
+To	O
+our	O
+knowledge	O
+,	O
+this	O
+is	O
+the	O
+first	O
+discussion	O
+considering	O
+the	O
+possibility	O
+that	O
+the	O
+methylprednisolone	O
+recommended	O
+by	O
+NASCIS	O
+may	O
+cause	O
+acute	O
+corticosteroid	O
+myopathy	B
+.	O
+
+Conversion	O
+to	O
+rapamycin	O
+immunosuppression	O
+in	O
+renal	O
+transplant	O
+recipients	O
+:	O
+report	O
+of	O
+an	O
+initial	O
+experience	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+aim	O
+of	O
+this	O
+study	O
+is	O
+to	O
+evaluate	O
+the	O
+effects	O
+of	O
+RAPA	O
+conversion	O
+in	O
+patients	O
+undergoing	O
+cyclosporine	O
+(	O
+CsA	O
+)	O
+or	O
+tacrolimus	O
+(	O
+Tac	O
+)	O
+toxicity	B
+.	O
+
+METHODS	O
+:	O
+Twenty	O
+renal	O
+transplant	O
+recipients	O
+were	O
+switched	O
+to	O
+fixed	O
+dose	O
+rapamycin	O
+(	O
+RAPA	O
+)	O
+(	O
+5	O
+mg	O
+/	O
+day	O
+)	O
+0	O
+to	O
+204	O
+months	O
+posttransplant	O
+.	O
+
+Drug	O
+monitoring	O
+was	O
+not	O
+initially	O
+used	O
+to	O
+adjust	O
+doses	O
+.	O
+
+The	O
+indications	O
+for	O
+switch	O
+were	O
+chronic	O
+CsA	O
+or	O
+Tac	O
+nephrotoxicity	B
+(	O
+12	O
+)	O
+,	O
+acute	O
+CsA	O
+or	O
+Tac	O
+toxicity	B
+(	O
+3	O
+)	O
+,	O
+severe	O
+facial	B
+dysmorphism	I
+(	O
+2	O
+)	O
+,	O
+posttransplant	B
+lymphoproliferative	I
+disorder	I
+(	O
+PTLD	B
+)	O
+in	O
+remission	O
+(	O
+2	O
+)	O
+,	O
+and	O
+hepatotoxicity	B
+in	O
+1	O
+.	O
+
+Follow	O
+-	O
+up	O
+is	O
+7	O
+to	O
+24	O
+months	O
+.	O
+
+RESULTS	O
+:	O
+In	O
+the	O
+12	O
+patients	O
+switched	O
+because	O
+of	O
+chronic	O
+nephrotoxicity	B
+there	O
+was	O
+a	O
+significant	O
+decrease	O
+in	O
+serum	O
+creatinine	O
+[	O
+233	O
++	O
+/	O
+-	O
+34	O
+to	O
+210	O
++	O
+/	O
+-	O
+56	O
+micromol	O
+/	O
+liter	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+at	O
+6	O
+months	O
+]	O
+.	O
+
+Facial	B
+dysmorphism	I
+improved	O
+in	O
+two	O
+patients	O
+.	O
+
+No	O
+relapse	O
+of	O
+PTLD	B
+was	O
+observed	O
+.	O
+
+Five	O
+patients	O
+developed	O
+pneumonia	B
+(	O
+two	O
+Pneumocystis	B
+carinii	I
+pneumonia	I
+,	O
+one	O
+infectious	B
+mononucleosis	I
+with	O
+polyclonal	O
+PTLD	B
+lung	O
+infiltrate	O
+)	O
+and	O
+two	O
+had	O
+bronchiolitis	B
+obliterans	I
+.	O
+
+There	O
+were	O
+no	O
+deaths	O
+.	O
+
+RAPA	O
+was	O
+discontinued	O
+in	O
+four	O
+patients	O
+,	O
+because	O
+of	O
+pneumonia	B
+in	O
+two	O
+,	O
+PTLD	B
+in	O
+one	O
+,	O
+and	O
+oral	O
+aphtous	B
+ulcers	I
+in	O
+one	O
+.	O
+
+RAPA	O
+levels	O
+were	O
+high	O
+(	O
+>	O
+15	O
+ng	O
+/	O
+ml	O
+)	O
+in	O
+7	O
+of	O
+13	O
+(	O
+54	O
+%	O
+)	O
+patients	O
+.	O
+
+CONCLUSIONS	O
+:	O
+RAPA	O
+conversion	O
+provides	O
+adequate	O
+immunosuppression	O
+to	O
+enable	O
+CsA	O
+withdrawal	O
+.	O
+
+However	O
+,	O
+when	O
+converting	O
+patients	O
+to	O
+RAPA	O
+drug	O
+levels	O
+should	O
+be	O
+monitored	O
+to	O
+avoid	O
+over	O
+-	O
+immunosuppression	O
+and	O
+adequate	O
+antiviral	O
+and	O
+Pneumocystis	B
+carinii	I
+pneumonia	I
+prophylaxis	O
+should	O
+be	O
+given	O
+.	O
+
+Electro	O
+-	O
+oculography	O
+,	O
+electroretinography	O
+,	O
+visual	O
+evoked	O
+potentials	O
+,	O
+and	O
+multifocal	O
+electroretinography	O
+in	O
+patients	O
+with	O
+vigabatrin	O
+-	O
+attributed	O
+visual	B
+field	I
+constriction	I
+.	O
+
+PURPOSE	O
+:	O
+Symptomatic	O
+visual	B
+field	I
+constriction	I
+thought	O
+to	O
+be	O
+associated	O
+with	O
+vigabatrin	O
+has	O
+been	O
+reported	O
+.	O
+
+The	O
+current	O
+study	O
+investigated	O
+the	O
+visual	O
+fields	O
+and	O
+visual	O
+electrophysiology	O
+of	O
+eight	O
+patients	O
+with	O
+known	O
+vigabatrin	O
+-	O
+attributed	O
+visual	B
+field	I
+loss	I
+,	O
+three	O
+of	O
+whom	O
+were	O
+reported	O
+previously	O
+.	O
+
+Six	O
+of	O
+the	O
+patients	O
+were	O
+no	O
+longer	O
+receiving	O
+vigabatrin	O
+.	O
+
+METHODS	O
+:	O
+The	O
+central	O
+and	O
+peripheral	O
+fields	O
+were	O
+examined	O
+with	O
+the	O
+Humphrey	O
+Visual	O
+Field	O
+Analyzer	O
+.	O
+
+Full	O
+visual	O
+electrophysiology	O
+,	O
+including	O
+flash	O
+electroretinography	O
+(	O
+ERG	O
+)	O
+,	O
+pattern	O
+electroretinography	O
+,	O
+multifocal	O
+ERG	O
+using	O
+the	O
+VERIS	O
+system	O
+,	O
+electro	O
+-	O
+oculography	O
+,	O
+and	O
+flash	O
+and	O
+pattern	O
+visual	O
+evoked	O
+potentials	O
+,	O
+was	O
+undertaken	O
+.	O
+
+RESULTS	O
+:	O
+Seven	O
+patients	O
+showed	O
+marked	O
+visual	B
+field	I
+constriction	I
+with	O
+some	O
+sparing	O
+of	O
+the	O
+temporal	O
+visual	O
+field	O
+.	O
+
+The	O
+eighth	O
+exhibited	O
+concentric	O
+constriction	O
+.	O
+
+Most	O
+electrophysiological	O
+responses	O
+were	O
+usually	O
+just	O
+within	O
+normal	O
+limits	O
+;	O
+two	O
+patients	O
+had	O
+subnormal	O
+Arden	O
+electro	O
+-	O
+oculography	O
+indices	O
+;	O
+and	O
+one	O
+patient	O
+showed	O
+an	O
+abnormally	O
+delayed	O
+photopic	O
+b	O
+wave	O
+.	O
+
+However	O
+,	O
+five	O
+patients	O
+showed	O
+delayed	O
+30	O
+-	O
+Hz	O
+flicker	O
+b	O
+waves	O
+,	O
+and	O
+seven	O
+patients	O
+showed	O
+delayed	O
+oscillatory	O
+potentials	O
+.	O
+
+Multifocal	O
+ERG	O
+showed	O
+abnormalities	O
+that	O
+sometimes	O
+correlated	O
+with	O
+the	O
+visual	O
+field	O
+appearance	O
+and	O
+confirmed	O
+that	O
+the	O
+deficit	O
+occurs	O
+at	O
+the	O
+retinal	O
+level	O
+.	O
+
+CONCLUSION	O
+:	O
+Marked	O
+visual	B
+field	I
+constriction	I
+appears	O
+to	O
+be	O
+associated	O
+with	O
+vigabatrin	O
+therapy	O
+.	O
+
+The	O
+field	O
+defects	O
+and	O
+some	O
+electrophysiological	O
+abnormalities	O
+persist	O
+when	O
+vigabatrin	O
+therapy	O
+is	O
+withdrawn	O
+.	O
+
+Myocardial	B
+ischemia	I
+due	O
+to	O
+coronary	B
+artery	I
+spasm	I
+during	O
+dobutamine	O
+stress	O
+echocardiography	O
+.	O
+
+Dobutamine	O
+stress	O
+echocardiography	O
+(	O
+DSE	O
+)	O
+is	O
+a	O
+useful	O
+and	O
+safe	O
+provocation	O
+test	O
+for	O
+myocardial	B
+ischemia	I
+.	O
+
+Until	O
+now	O
+,	O
+the	O
+test	O
+has	O
+been	O
+focused	O
+only	O
+on	O
+the	O
+organic	O
+lesion	O
+in	O
+the	O
+coronary	O
+artery	O
+,	O
+and	O
+positive	O
+DSE	O
+has	O
+indicated	O
+the	O
+presence	O
+of	O
+significant	O
+fixed	O
+coronary	B
+artery	I
+stenosis	I
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+is	O
+to	O
+examine	O
+whether	O
+myocardial	B
+ischemia	I
+due	O
+to	O
+coronary	B
+spasm	I
+is	O
+induced	O
+by	O
+dobutamine	O
+.	O
+
+We	O
+performed	O
+DSE	O
+on	O
+51	O
+patients	O
+with	O
+coronary	B
+spastic	I
+angina	I
+but	O
+without	O
+significant	O
+fixed	O
+coronary	B
+artery	I
+stenosis	I
+.	O
+
+All	O
+patients	O
+had	O
+anginal	B
+attacks	O
+at	O
+rest	O
+with	O
+ST	O
+elevation	O
+on	O
+the	O
+electrocardiogram	O
+(	O
+variant	B
+angina	I
+)	O
+.	O
+
+Coronary	O
+spasm	O
+was	O
+induced	O
+by	O
+intracoronary	O
+injection	O
+of	O
+acetylcholine	O
+,	O
+and	O
+no	O
+fixed	O
+coronary	B
+artery	I
+stenosis	I
+was	O
+documented	O
+on	O
+angiograms	O
+in	O
+all	O
+patients	O
+.	O
+
+DSE	O
+was	O
+performed	O
+with	O
+intravenous	O
+dobutamine	O
+infusion	O
+with	O
+an	O
+incremental	O
+doses	O
+of	O
+5	O
+,	O
+10	O
+,	O
+20	O
+,	O
+30	O
+,	O
+and	O
+40	O
+microg	O
+/	O
+kg	O
+/	O
+min	O
+every	O
+5	O
+minutes	O
+.	O
+
+Of	O
+the	O
+51	O
+patients	O
+,	O
+7	O
+patients	O
+showed	O
+asynergy	O
+with	O
+ST	O
+elevation	O
+.	O
+
+All	O
+7	O
+patients	O
+(	O
+13	O
+.	O
+7	O
+%	O
+)	O
+had	O
+chest	B
+pain	I
+during	O
+asynergy	O
+,	O
+and	O
+both	O
+chest	B
+pain	I
+and	O
+electrocardiographic	O
+changes	O
+were	O
+preceded	O
+by	O
+asynergy	O
+.	O
+
+These	O
+findings	O
+indicate	O
+that	O
+dobutamine	O
+can	O
+provoke	O
+coronary	B
+spasm	I
+in	O
+some	O
+patients	O
+with	O
+coronary	B
+spastic	I
+angina	I
+.	O
+
+When	O
+DSE	O
+is	O
+performed	O
+to	O
+evaluate	O
+coronary	B
+artery	I
+disease	I
+,	O
+not	O
+only	O
+fixed	O
+coronary	B
+stenosis	I
+,	O
+but	O
+also	O
+coronary	B
+spasm	I
+should	O
+be	O
+considered	O
+as	O
+a	O
+genesis	O
+of	O
+asynergy	O
+.	O
+
+Effect	O
+of	O
+intravenous	O
+metoprolol	O
+or	O
+intravenous	O
+metoprolol	O
+plus	O
+glucagon	O
+on	O
+dobutamine	O
+-	O
+induced	O
+myocardial	B
+ischemia	I
+.	O
+
+STUDY	O
+OBJECTIVE	O
+:	O
+To	O
+determine	O
+the	O
+effect	O
+of	O
+metoprolol	O
+on	O
+dobutamine	O
+stress	O
+testing	O
+with	O
+technetium	O
+-	O
+99m	O
+sestamibi	O
+single	O
+-	O
+photon	O
+emission	O
+computed	O
+tomography	O
+imaging	O
+and	O
+ST	O
+-	O
+segment	O
+monitoring	O
+,	O
+and	O
+to	O
+assess	O
+the	O
+impact	O
+of	O
+intravenous	O
+glucagon	O
+on	O
+metoprolol	O
+'	O
+s	O
+effects	O
+.	O
+
+DESIGN	O
+:	O
+Randomized	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+trial	O
+.	O
+
+SETTING	O
+:	O
+Community	O
+hospital	O
+.	O
+
+PATIENTS	O
+:	O
+Twenty	O
+-	O
+two	O
+patients	O
+with	O
+known	O
+reversible	O
+perfusion	O
+defects	O
+.	O
+
+INTERVENTION	O
+:	O
+Patients	O
+underwent	O
+dobutamine	O
+stress	O
+tests	O
+per	O
+standard	O
+protocol	O
+.	O
+
+Before	O
+dobutamine	O
+was	O
+begun	O
+,	O
+no	O
+therapy	O
+was	O
+given	O
+during	O
+the	O
+first	O
+visit	O
+,	O
+and	O
+patients	O
+were	O
+randomized	O
+on	O
+subsequent	O
+visits	O
+to	O
+receive	O
+metoprolol	O
+or	O
+metoprolol	O
+plus	O
+glucagon	O
+1	O
+mg	O
+.	O
+
+Metoprolol	O
+was	O
+dosed	O
+to	O
+achieve	O
+a	O
+resting	O
+predobutamine	O
+heart	O
+rate	O
+below	O
+65	O
+beats	O
+/	O
+minute	O
+or	O
+a	O
+total	O
+intravenous	O
+dose	O
+of	O
+20	O
+mg	O
+.	O
+
+MEASUREMENTS	O
+AND	O
+MAIN	O
+RESULTS	O
+:	O
+Metoprolol	O
+reduced	O
+maximum	O
+heart	O
+rate	O
+31	O
+%	O
+,	O
+summed	O
+stress	O
+scores	O
+29	O
+%	O
+,	O
+and	O
+summed	O
+difference	O
+scores	O
+43	O
+%	O
+versus	O
+control	O
+.	O
+
+Metoprolol	O
+plus	O
+glucagon	O
+also	O
+reduced	O
+the	O
+maximum	O
+heart	O
+rate	O
+29	O
+%	O
+versus	O
+control	O
+.	O
+
+Summed	O
+stress	O
+and	O
+summed	O
+difference	O
+scores	O
+were	O
+not	O
+significantly	O
+reduced	O
+,	O
+although	O
+they	O
+were	O
+18	O
+%	O
+and	O
+30	O
+%	O
+lower	O
+,	O
+respectively	O
+,	O
+than	O
+control	O
+.	O
+
+No	O
+significant	O
+differences	O
+were	O
+found	O
+in	O
+any	O
+parameter	O
+between	O
+metoprolol	O
+and	O
+metoprolol	O
+-	O
+glucagon	O
+.	O
+
+CONCLUSION	O
+:	O
+During	O
+dobutamine	O
+stress	O
+testing	O
+,	O
+metoprolol	O
+attenuates	O
+or	O
+eliminates	O
+evidence	O
+of	O
+myocardial	B
+ischemia	I
+.	O
+
+Glucagon	O
+1	O
+mg	O
+,	O
+although	O
+somewhat	O
+effective	O
+,	O
+does	O
+not	O
+correct	O
+this	O
+effect	O
+to	O
+the	O
+extent	O
+that	O
+it	O
+can	O
+be	O
+administered	O
+clinically	O
+.	O
+
+Evidence	O
+of	O
+functional	O
+somatotopy	O
+in	O
+GPi	O
+from	O
+results	O
+of	O
+pallidotomy	O
+.	O
+
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+explore	O
+the	O
+functional	O
+anatomy	O
+of	O
+the	O
+globus	O
+pallidus	O
+internus	O
+(	O
+GPi	O
+)	O
+by	O
+studying	O
+the	O
+effects	O
+of	O
+unilateral	O
+pallidotomy	O
+on	O
+parkinsonian	B
+'	O
+off	O
+'	O
+signs	O
+and	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+(	O
+LID	B
+)	O
+.	O
+
+We	O
+found	O
+significant	O
+positive	O
+correlations	O
+between	O
+the	O
+preoperative	O
+levodopa	O
+responsiveness	O
+of	O
+motor	O
+signs	O
+and	O
+the	O
+levodopa	O
+responsiveness	O
+of	O
+scores	O
+in	O
+timed	O
+tests	O
+(	O
+Core	O
+Assessment	O
+Program	O
+for	O
+Intracerebral	O
+Transplantations	O
+)	O
+in	O
+the	O
+contralateral	O
+limbs	O
+and	O
+the	O
+improvement	O
+in	O
+these	O
+scores	O
+after	O
+surgery	O
+,	O
+whereas	O
+there	O
+was	O
+no	O
+correlation	O
+with	O
+the	O
+improvement	O
+in	O
+LID	B
+.	O
+
+We	O
+also	O
+found	O
+a	O
+highly	O
+significant	O
+correlation	O
+(	O
+P	O
+:	O
+<	O
+0	O
+.	O
+0001	O
+,	O
+r	O
+=	O
+0	O
+.	O
+8	O
+)	O
+between	O
+the	O
+volume	O
+of	O
+the	O
+ventral	O
+lesion	O
+in	O
+the	O
+GPi	O
+and	O
+the	O
+improvement	O
+in	O
+LID	B
+in	O
+the	O
+contralateral	O
+limbs	O
+,	O
+whereas	O
+there	O
+was	O
+no	O
+correlation	O
+between	O
+the	O
+ventral	O
+volume	O
+and	O
+the	O
+improvement	O
+in	O
+parkinsonian	B
+'	O
+off	O
+'	O
+signs	O
+.	O
+
+The	O
+volumes	O
+of	O
+the	O
+total	O
+lesion	O
+cylinder	O
+and	O
+the	O
+dorsal	O
+lesion	O
+did	O
+not	O
+correlate	O
+with	O
+the	O
+outcome	O
+of	O
+either	O
+dyskinesias	B
+or	O
+parkinsonian	B
+'	O
+off	O
+'	O
+signs	O
+.	O
+
+The	O
+differential	O
+predictive	O
+value	O
+of	O
+levodopa	O
+responsiveness	O
+for	O
+the	O
+outcome	O
+of	O
+parkinsonian	B
+'	O
+off	O
+'	O
+signs	O
+and	O
+LID	B
+and	O
+the	O
+different	O
+correlations	O
+of	O
+ventral	O
+lesion	O
+volume	O
+with	O
+dyskinesias	B
+and	O
+parkinsonian	B
+'	O
+off	O
+'	O
+signs	O
+indicate	O
+that	O
+different	O
+anatomical	O
+or	O
+pathophysiological	O
+substrates	O
+may	O
+be	O
+responsible	O
+for	O
+the	O
+generation	O
+of	O
+parkinsonian	B
+'	O
+off	O
+'	O
+signs	O
+and	O
+dyskinesias	B
+.	O
+
+Whereas	O
+cells	O
+in	O
+a	O
+wider	O
+area	O
+of	O
+the	O
+GPi	O
+may	O
+be	O
+implicated	O
+in	O
+parkinsonism	B
+,	O
+the	O
+ventral	O
+GPi	O
+seems	O
+to	O
+be	O
+crucial	O
+for	O
+the	O
+manifestation	O
+of	O
+LID	B
+.	O
+
+We	O
+suggest	O
+that	O
+our	O
+observations	O
+are	O
+additional	O
+proof	O
+of	O
+the	O
+functional	O
+somatotopy	O
+of	O
+the	O
+systems	O
+within	O
+the	O
+GPi	O
+that	O
+mediate	O
+parkinsonism	B
+and	O
+dyskinesias	B
+,	O
+especially	O
+along	O
+the	O
+dorsoventral	O
+trajectory	O
+used	O
+in	O
+pallidotomy	O
+.	O
+
+The	O
+outcome	O
+of	O
+pallidotomy	O
+in	O
+which	O
+the	O
+lesion	O
+involves	O
+the	O
+ventral	O
+and	O
+dorsal	O
+GPi	O
+could	O
+be	O
+the	O
+net	O
+effect	O
+of	O
+alteration	O
+in	O
+the	O
+activity	O
+of	O
+pathways	O
+which	O
+mediate	O
+different	O
+symptoms	O
+,	O
+and	O
+hence	O
+could	O
+be	O
+variable	O
+.	O
+
+Screening	O
+for	O
+stimulant	O
+use	O
+in	O
+adult	O
+emergency	O
+department	O
+seizure	B
+patients	O
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+prevalence	O
+of	O
+positive	O
+plasma	O
+drug	O
+screening	O
+for	O
+cocaine	O
+or	O
+amphetamine	O
+in	O
+adult	O
+emergency	O
+department	O
+seizure	B
+patients	O
+.	O
+
+METHODS	O
+:	O
+This	O
+prospective	O
+study	O
+evaluated	O
+consecutive	O
+eligible	O
+seizure	B
+patients	O
+who	O
+had	O
+a	O
+plasma	O
+sample	O
+collected	O
+as	O
+part	O
+of	O
+their	O
+clinical	O
+evaluation	O
+.	O
+
+Plasma	O
+was	O
+tested	O
+for	O
+amphetamine	O
+and	O
+the	O
+cocaine	O
+metabolite	O
+benzoylecgonine	O
+using	O
+enzyme	O
+-	O
+mediated	O
+immunoassay	O
+methodology	O
+.	O
+
+Plasma	O
+samples	O
+with	O
+benzoylecgonine	O
+greater	O
+than	O
+150	O
+ng	O
+/	O
+mL	O
+or	O
+an	O
+amphetamine	O
+greater	O
+than	O
+500	O
+ng	O
+/	O
+mL	O
+were	O
+defined	O
+as	O
+positive	O
+.	O
+
+Patient	O
+demographics	O
+,	O
+history	O
+of	O
+underlying	O
+drug	O
+or	O
+alcohol	O
+-	O
+related	O
+seizure	B
+disorder	O
+,	O
+estimated	O
+time	O
+from	O
+seizure	B
+to	O
+sample	O
+collection	O
+,	O
+history	O
+or	O
+suspicion	O
+of	O
+cocaine	B
+or	I
+amphetamine	I
+abuse	I
+,	O
+results	O
+of	O
+clinical	O
+urine	O
+testing	O
+for	O
+drugs	O
+of	O
+abuse	O
+,	O
+and	O
+assay	O
+results	O
+were	O
+recorded	O
+without	O
+patient	O
+identifiers	O
+.	O
+
+RESULTS	O
+:	O
+Fourteen	O
+of	O
+248	O
+(	O
+5	O
+.	O
+6	O
+%	O
+,	O
+95	O
+%	O
+CI	O
+2	O
+.	O
+7	O
+%	O
+-	O
+8	O
+.	O
+5	O
+%	O
+)	O
+plasma	O
+samples	O
+were	O
+positive	O
+by	O
+immunoassay	O
+testing	O
+for	O
+benzoylecgonine	O
+and	O
+no	O
+samples	O
+(	O
+0	O
+%	O
+,	O
+95	O
+%	O
+CI	O
+0	O
+-	O
+1	O
+.	O
+2	O
+%	O
+)	O
+were	O
+positive	O
+for	O
+amphetamine	O
+.	O
+
+Positive	O
+test	O
+results	O
+were	O
+more	O
+common	O
+in	O
+patient	O
+visits	O
+where	O
+there	O
+was	O
+a	O
+history	O
+or	O
+suspicion	O
+of	O
+cocaine	B
+or	I
+amphetamine	I
+abuse	I
+(	O
+p	O
+<	O
+0	O
+.	O
+0005	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+During	O
+this	O
+study	O
+period	O
+,	O
+routine	O
+plasma	O
+screening	O
+for	O
+cocaine	O
+and	O
+amphetamines	O
+in	O
+adult	O
+seizure	B
+patients	O
+had	O
+a	O
+low	O
+yield	O
+.	O
+
+As	O
+a	O
+result	O
+,	O
+routine	O
+plasma	O
+screening	O
+would	O
+yield	O
+few	O
+cases	O
+of	O
+stimulant	O
+drug	O
+in	O
+which	O
+there	O
+was	O
+neither	O
+a	O
+history	O
+nor	O
+suspicion	O
+of	O
+drug	B
+abuse	I
+in	O
+this	O
+population	O
+.	O
+
+Contribution	O
+of	O
+sodium	O
+valproate	O
+to	O
+the	O
+syndrome	B
+of	I
+inappropriate	I
+secretion	I
+of	I
+antidiuretic	I
+hormone	I
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+62	O
+-	O
+year	O
+-	O
+old	O
+man	O
+who	O
+was	O
+administered	O
+sodium	O
+valproate	O
+(	O
+VPA	O
+)	O
+and	O
+who	O
+subsequently	O
+developed	O
+the	O
+syndrome	B
+of	I
+inappropriate	I
+secretion	I
+of	I
+antidiuretic	I
+hormone	I
+(	O
+SIADH	B
+)	O
+.	O
+
+He	O
+had	O
+been	O
+taking	O
+VPA	O
+for	O
+treatment	O
+of	O
+idiopathic	O
+generalized	O
+tonic	B
+-	I
+clonic	I
+convulsions	I
+since	O
+he	O
+was	O
+56	O
+years	O
+old	O
+.	O
+
+After	O
+substituting	O
+VPA	O
+with	O
+zonisamide	O
+,	O
+the	O
+serum	O
+sodium	O
+level	O
+returned	O
+to	O
+normal	O
+.	O
+
+We	O
+consider	O
+this	O
+episode	O
+of	O
+SIADH	B
+to	O
+be	O
+the	O
+result	O
+of	O
+a	O
+combination	O
+of	O
+factors	O
+including	O
+a	O
+weakness	B
+of	I
+the	I
+central	I
+nervous	I
+system	I
+and	O
+the	O
+long	O
+-	O
+term	O
+administration	O
+of	O
+VPA	O
+.	O
+
+Association	O
+of	O
+nitric	O
+oxide	O
+production	O
+and	O
+apoptosis	O
+in	O
+a	O
+model	O
+of	O
+experimental	O
+nephropathy	B
+.	O
+
+BACKGROUND	O
+:	O
+In	O
+recent	O
+studies	O
+increased	O
+amounts	O
+of	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+and	O
+apoptosis	O
+have	O
+been	O
+implicated	O
+in	O
+various	O
+pathological	O
+conditions	O
+in	O
+the	O
+kidney	O
+.	O
+
+We	O
+have	O
+studied	O
+the	O
+role	O
+of	O
+NO	O
+and	O
+its	O
+association	O
+with	O
+apoptosis	O
+in	O
+an	O
+experimental	O
+model	O
+of	O
+nephrotic	B
+syndrome	I
+induced	O
+by	O
+a	O
+single	O
+injection	O
+of	O
+adriamycin	O
+(	O
+ADR	O
+)	O
+.	O
+
+METHODS	O
+:	O
+The	O
+alteration	O
+in	O
+the	O
+NO	O
+pathway	O
+was	O
+assessed	O
+by	O
+measuring	O
+nitrite	O
+levels	O
+in	O
+serum	O
+/	O
+urine	O
+and	O
+by	O
+evaluating	O
+the	O
+changes	O
+in	O
+vascular	O
+reactivity	O
+of	O
+the	O
+isolated	O
+perfused	O
+rat	O
+kidney	O
+(	O
+IPRK	O
+)	O
+system	O
+.	O
+
+Rats	O
+were	O
+stratified	O
+into	O
+control	O
+groups	O
+and	O
+ADR	O
+-	O
+induced	O
+nephropathy	B
+groups	O
+.	O
+
+These	O
+two	O
+groups	O
+were	O
+then	O
+divided	O
+into	O
+:	O
+group	O
+1	O
+,	O
+animals	O
+receiving	O
+saline	O
+;	O
+and	O
+group	O
+2	O
+,	O
+animals	O
+receiving	O
+aminoguanidine	O
+(	O
+AG	O
+)	O
+which	O
+is	O
+a	O
+specific	O
+inhibitor	O
+of	O
+inducible	O
+-	O
+NO	O
+synthase	O
+.	O
+
+On	O
+day	O
+21	O
+,	O
+rats	O
+were	O
+sacrificed	O
+after	O
+obtaining	O
+material	O
+for	O
+biochemical	O
+analysis	O
+.	O
+
+RESULTS	O
+:	O
+Histopathological	O
+examination	O
+of	O
+the	O
+kidneys	O
+of	O
+rats	O
+treated	O
+with	O
+ADR	O
+revealed	O
+focal	O
+areas	O
+of	O
+mesangial	B
+proliferation	I
+and	O
+mild	O
+tubulointerstitial	B
+inflammation	I
+.	O
+
+They	O
+also	O
+had	O
+significantly	O
+higher	O
+levels	O
+of	O
+proteinuria	B
+compared	O
+with	O
+control	O
+and	O
+treatment	O
+groups	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Urine	O
+nitrite	O
+levels	O
+were	O
+significantly	O
+increased	O
+in	O
+the	O
+ADR	O
+-	O
+nephropathy	B
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+In	O
+the	O
+IPRK	O
+phenylephrine	O
+and	O
+acetylcholine	O
+related	O
+responses	O
+were	O
+significantly	O
+impaired	O
+in	O
+the	O
+ADR	O
+-	O
+nephropathy	B
+group	O
+.	O
+
+Apoptosis	O
+was	O
+not	O
+detected	O
+in	O
+controls	O
+.	O
+
+However	O
+,	O
+in	O
+the	O
+ADR	O
+-	O
+nephropathy	B
+group	O
+,	O
+numerous	O
+apoptotic	O
+cells	O
+were	O
+identified	O
+in	O
+the	O
+tubulointerstitial	O
+areas	O
+.	O
+
+Double	O
+staining	O
+revealed	O
+numerous	O
+interstitial	O
+apoptotic	O
+cells	O
+to	O
+stain	O
+for	O
+ED1	O
+,	O
+a	O
+marker	O
+for	O
+monocytes	O
+/	O
+macrophages	O
+.	O
+
+Treatment	O
+with	O
+AG	O
+prevented	O
+the	O
+impairment	O
+of	O
+renal	O
+vascular	O
+bed	O
+responses	O
+and	O
+reduced	O
+both	O
+urine	O
+nitrite	O
+levels	O
+and	O
+apoptosis	O
+to	O
+control	O
+levels	O
+.	O
+
+CONCLUSION	O
+:	O
+We	O
+suggest	O
+that	O
+interactions	O
+between	O
+NO	O
+and	O
+apoptosis	O
+are	O
+important	O
+in	O
+the	O
+pathogenesis	O
+of	O
+the	O
+ADR	O
+-	O
+induced	O
+nephrosis	B
+.	O
+
+Dual	O
+effects	O
+of	O
+melatonin	O
+on	O
+barbiturate	O
+-	O
+induced	O
+narcosis	B
+in	O
+rats	O
+.	O
+
+Melatonin	O
+affects	O
+the	O
+circadian	O
+sleep	O
+/	O
+wake	O
+cycle	O
+,	O
+but	O
+it	O
+is	O
+not	O
+clear	O
+whether	O
+it	O
+may	O
+influence	O
+drug	O
+-	O
+induced	O
+narcosis	B
+.	O
+
+Sodium	O
+thiopenthal	O
+was	O
+administered	O
+intraperitoneally	O
+into	O
+male	O
+rats	O
+pre	O
+-	O
+treated	O
+with	O
+melatonin	O
+(	O
+0	O
+.	O
+05	O
+,	O
+0	O
+.	O
+5	O
+,	O
+5	O
+and	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+Melatonin	O
+pre	O
+-	O
+treatment	O
+affected	O
+in	O
+a	O
+dual	O
+manner	O
+barbiturate	O
+narcosis	B
+,	O
+however	O
+,	O
+no	O
+dose	O
+-	O
+effect	O
+correlation	O
+was	O
+found	O
+.	O
+
+In	O
+particular	O
+,	O
+low	O
+doses	O
+reduced	O
+the	O
+latency	O
+to	O
+and	O
+prolonged	O
+the	O
+duration	O
+of	O
+barbiturate	O
+narcosis	B
+.	O
+
+In	O
+contrast	O
+,	O
+the	O
+highest	O
+dose	O
+of	O
+melatonin	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+caused	O
+a	O
+paradoxical	O
+increase	O
+in	O
+the	O
+latency	O
+and	O
+produced	O
+a	O
+sustained	O
+reduction	O
+of	O
+the	O
+duration	O
+of	O
+narcosis	B
+,	O
+and	O
+a	O
+reduction	O
+in	O
+mortality	O
+rate	O
+.	O
+
+Melatonin	O
+0	O
+.	O
+5	O
+and	O
+5	O
+mg	O
+/	O
+kg	O
+influenced	O
+the	O
+duration	O
+but	O
+not	O
+the	O
+latency	O
+of	O
+ketamine	O
+-	O
+or	O
+diazepam	O
+-	O
+induced	O
+narcosis	B
+.	O
+
+Thus	O
+,	O
+the	O
+dual	O
+action	O
+of	O
+melatonin	O
+on	O
+pharmacological	O
+narcosis	B
+seems	O
+to	O
+be	O
+specific	O
+for	O
+the	O
+barbiturate	O
+mechanism	O
+of	O
+action	O
+.	O
+
+Reduced	O
+cardiotoxicity	B
+and	O
+preserved	O
+antitumor	O
+efficacy	O
+of	O
+liposome	O
+-	O
+encapsulated	O
+doxorubicin	O
+and	O
+cyclophosphamide	O
+compared	O
+with	O
+conventional	O
+doxorubicin	O
+and	O
+cyclophosphamide	O
+in	O
+a	O
+randomized	O
+,	O
+multicenter	O
+trial	O
+of	O
+metastatic	O
+breast	B
+cancer	I
+.	O
+
+PURPOSE	O
+:	O
+To	O
+determine	O
+whether	O
+Myocet	O
+(	O
+liposome	O
+-	O
+encapsulated	O
+doxorubicin	O
+;	O
+The	O
+Liposome	O
+Company	O
+,	O
+Elan	O
+Corporation	O
+,	O
+Princeton	O
+,	O
+NJ	O
+)	O
+in	O
+combination	O
+with	O
+cyclophosphamide	O
+significantly	O
+reduces	O
+doxorubicin	O
+cardiotoxicity	B
+while	O
+providing	O
+comparable	O
+antitumor	O
+efficacy	O
+in	O
+first	O
+-	O
+line	O
+treatment	O
+of	O
+metastatic	O
+breast	B
+cancer	I
+(	O
+MBC	B
+)	O
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+Two	O
+hundred	O
+ninety	O
+-	O
+seven	O
+patients	O
+with	O
+MBC	B
+and	O
+no	O
+prior	O
+chemotherapy	O
+for	O
+metastatic	O
+disease	O
+were	O
+randomized	O
+to	O
+receive	O
+either	O
+60	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+of	O
+Myocet	O
+(	O
+M	O
+)	O
+or	O
+conventional	O
+doxorubicin	O
+(	O
+A	O
+)	O
+,	O
+in	O
+combination	O
+with	O
+600	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+of	O
+cyclophosphamide	O
+(	O
+C	O
+)	O
+,	O
+every	O
+3	O
+weeks	O
+until	O
+disease	O
+progression	O
+or	O
+unacceptable	O
+toxicity	B
+.	O
+
+Cardiotoxicity	B
+was	O
+defined	O
+by	O
+reductions	O
+in	O
+left	O
+-	O
+ventricular	O
+ejection	O
+fraction	O
+,	O
+assessed	O
+by	O
+serial	O
+multigated	O
+radionuclide	O
+angiography	O
+scans	O
+,	O
+or	O
+congestive	B
+heart	I
+failure	I
+(	O
+CHF	B
+)	O
+.	O
+
+Antitumor	O
+efficacy	O
+was	O
+assessed	O
+by	O
+objective	O
+tumor	B
+response	O
+rates	O
+(	O
+World	O
+Health	O
+Organization	O
+criteria	O
+)	O
+,	O
+time	O
+to	O
+progression	O
+,	O
+and	O
+survival	O
+.	O
+
+RESULTS	O
+:	O
+Six	O
+percent	O
+of	O
+MC	O
+patients	O
+versus	O
+21	O
+%	O
+(	O
+including	O
+five	O
+cases	O
+of	O
+CHF	B
+)	O
+of	O
+AC	O
+patients	O
+developed	O
+cardiotoxicity	B
+(	O
+P	O
+=	O
+.	O
+0002	O
+)	O
+.	O
+
+Median	O
+cumulative	O
+doxorubicin	O
+dose	O
+at	O
+onset	O
+was	O
+more	O
+than	O
+2	O
+,	O
+220	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+for	O
+MC	O
+versus	O
+480	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+for	O
+AC	O
+(	O
+P	O
+=	O
+.	O
+0001	O
+,	O
+hazard	O
+ratio	O
+,	O
+5	O
+.	O
+04	O
+)	O
+.	O
+
+MC	O
+patients	O
+also	O
+experienced	O
+less	O
+grade	O
+4	O
+neutropenia	B
+.	O
+
+Antitumor	O
+efficacy	O
+of	O
+MC	O
+versus	O
+AC	O
+was	O
+comparable	O
+:	O
+objective	O
+response	O
+rates	O
+,	O
+43	O
+%	O
+versus	O
+43	O
+%	O
+;	O
+median	O
+time	O
+to	O
+progression	O
+,	O
+5	O
+.	O
+1	O
+%	O
+versus	O
+5	O
+.	O
+5	O
+months	O
+;	O
+median	O
+time	O
+to	O
+treatment	O
+failure	O
+,	O
+4	O
+.	O
+6	O
+versus	O
+4	O
+.	O
+4	O
+months	O
+;	O
+and	O
+median	O
+survival	O
+,	O
+19	O
+versus	O
+16	O
+months	O
+.	O
+
+CONCLUSION	O
+:	O
+Myocet	O
+improves	O
+the	O
+therapeutic	O
+index	O
+of	O
+doxorubicin	O
+by	O
+significantly	O
+reducing	O
+cardiotoxicity	B
+and	O
+grade	O
+4	O
+neutropenia	B
+and	O
+provides	O
+comparable	O
+antitumor	O
+efficacy	O
+,	O
+when	O
+used	O
+in	O
+combination	O
+with	O
+cyclophosphamide	O
+as	O
+first	O
+-	O
+line	O
+therapy	O
+for	O
+MBC	B
+.	O
+
+The	O
+role	O
+of	O
+nitrergic	O
+system	O
+in	O
+lidocaine	O
+-	O
+induced	O
+convulsion	B
+in	O
+the	O
+mouse	O
+.	O
+
+The	O
+effects	O
+of	O
+N	O
+-	O
+nitro	O
+-	O
+L	O
+-	O
+arginine	O
+-	O
+methyl	O
+ester	O
+(	O
+L	O
+-	O
+NAME	O
+)	O
+a	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+synthase	O
+inhibitor	O
+and	O
+L	O
+-	O
+arginine	O
+,	O
+a	O
+NO	O
+precursor	O
+,	O
+were	O
+investigated	O
+on	O
+lidocaine	O
+-	O
+induced	O
+convulsions	B
+.	O
+
+In	O
+the	O
+first	O
+experiment	O
+,	O
+four	O
+groups	O
+of	O
+mice	O
+received	O
+physiological	O
+saline	O
+(	O
+0	O
+.	O
+9	O
+%	O
+)	O
+,	O
+L	O
+-	O
+arginine	O
+(	O
+300	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+,	O
+L	O
+-	O
+NAME	O
+(	O
+100	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+and	O
+diazepam	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+respectively	O
+.	O
+
+Thirty	O
+minutes	O
+after	O
+these	O
+injections	O
+,	O
+all	O
+mice	O
+received	O
+lidocaine	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+In	O
+the	O
+second	O
+experiment	O
+,	O
+four	O
+groups	O
+of	O
+mice	O
+received	O
+similar	O
+treatment	O
+in	O
+the	O
+first	O
+experiment	O
+,	O
+and	O
+30	O
+min	O
+after	O
+these	O
+injections	O
+,	O
+all	O
+mice	O
+received	O
+a	O
+higher	O
+dose	O
+of	O
+lidocaine	O
+(	O
+80	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+L	O
+-	O
+NAME	O
+(	O
+100	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+and	O
+diazepam	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+)	O
+significantly	O
+decreased	O
+the	O
+incidence	O
+of	O
+lidocaine	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+-	O
+induced	O
+convulsions	B
+.	O
+
+In	O
+contrast	O
+,	O
+the	O
+L	O
+-	O
+arginine	O
+treatment	O
+increased	O
+the	O
+incidence	O
+of	O
+lidocaine	O
+(	O
+80	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+-	O
+induced	O
+convulsions	B
+significantly	O
+.	O
+
+These	O
+results	O
+may	O
+suggest	O
+that	O
+NO	O
+is	O
+a	O
+proconvulsant	O
+mediator	O
+in	O
+lidocaine	O
+-	O
+induced	O
+convulsions	B
+.	O
+
+Erythropoietin	O
+restores	O
+the	O
+anemia	B
+-	O
+induced	O
+reduction	O
+in	O
+cyclophosphamide	O
+cytotoxicity	B
+in	O
+rat	O
+tumors	B
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+examine	O
+the	O
+impact	O
+of	O
+anemia	B
+prevention	O
+by	O
+recombinant	O
+human	O
+erythropoietin	O
+(	O
+rHuEPO	O
+)	O
+treatment	O
+on	O
+the	O
+cytotoxicity	B
+of	O
+cyclophosphamide	O
+in	O
+solid	O
+experimental	O
+tumors	B
+.	O
+
+Anemia	B
+was	O
+induced	O
+using	O
+a	O
+single	O
+dose	O
+of	O
+carboplatin	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+resulting	O
+in	O
+a	O
+long	O
+-	O
+lasting	O
+reduction	O
+(	O
+30	O
+%	O
+)	O
+of	O
+the	O
+hemoglobin	O
+concentration	O
+.	O
+
+In	O
+a	O
+second	O
+group	O
+,	O
+the	O
+development	O
+of	O
+anemia	B
+was	O
+prevented	O
+by	O
+rHuEPO	O
+(	O
+1000	O
+IU	O
+/	O
+kg	O
+)	O
+administered	O
+s	O
+.	O
+c	O
+.	O
+three	O
+times	O
+/	O
+week	O
+starting	O
+7	O
+days	O
+before	O
+carboplatin	O
+application	O
+.	O
+
+Four	O
+days	O
+after	O
+carboplatin	O
+treatment	O
+,	O
+tumors	B
+(	O
+DS	O
+-	O
+sarcoma	B
+of	O
+the	O
+rat	O
+)	O
+were	O
+implanted	O
+s	O
+.	O
+c	O
+.	O
+onto	O
+the	O
+hind	O
+food	O
+dorsum	O
+.	O
+
+Neither	O
+carboplatin	O
+nor	O
+rHuEPO	O
+treatment	O
+influenced	O
+tumor	B
+growth	O
+rate	O
+per	O
+se	O
+.	O
+
+When	O
+tumors	B
+were	O
+treated	O
+with	O
+a	O
+single	O
+dose	O
+of	O
+cyclophosphamide	O
+(	O
+60	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+5	O
+days	O
+after	O
+implantation	O
+,	O
+a	O
+growth	O
+delay	O
+with	O
+a	O
+subsequent	O
+regrowth	O
+of	O
+the	O
+tumors	B
+was	O
+observed	O
+.	O
+
+In	O
+the	O
+anemia	B
+group	O
+,	O
+the	O
+growth	O
+delay	O
+was	O
+significantly	O
+shorter	O
+compared	O
+with	O
+nonanemic	O
+controls	O
+(	O
+13	O
+.	O
+3	O
+days	O
+versus	O
+8	O
+.	O
+6	O
+days	O
+)	O
+.	O
+
+In	O
+the	O
+group	O
+where	O
+anemia	B
+was	O
+prevented	O
+by	O
+rHuEPO	O
+treatment	O
+,	O
+growth	O
+delay	O
+was	O
+comparable	O
+with	O
+that	O
+of	O
+nonanemic	O
+controls	O
+(	O
+13	O
+.	O
+3	O
+days	O
+)	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+chemotherapy	O
+-	O
+induced	O
+anemia	B
+reduces	O
+cytotoxicity	B
+of	O
+cyclophosphamide	O
+in	O
+tumors	B
+,	O
+whereas	O
+correction	O
+of	O
+anemia	B
+by	O
+rHuEPO	O
+treatment	O
+(	O
+epoetin	O
+alpha	O
+)	O
+increases	O
+the	O
+sensitivity	O
+,	O
+probably	O
+as	O
+a	O
+result	O
+of	O
+an	O
+improved	O
+oxygen	O
+supply	O
+to	O
+tumor	B
+tissue	O
+.	O
+
+Fatal	O
+haemorrhagic	B
+myocarditis	I
+secondary	O
+to	O
+cyclophosphamide	O
+therapy	O
+.	O
+
+Haemorrhagic	B
+myocarditis	I
+is	O
+a	O
+rare	O
+but	O
+important	O
+complication	O
+of	O
+cyclophosphamide	O
+therapy	O
+.	O
+
+Echocardiographic	O
+identification	O
+of	O
+the	O
+disorder	O
+can	O
+be	O
+made	O
+.	O
+
+We	O
+believe	O
+that	O
+the	O
+ultrasound	O
+features	O
+of	O
+this	O
+disorder	O
+have	O
+not	O
+been	O
+previously	O
+reported	O
+.	O
+
+Effects	O
+of	O
+verapamil	O
+on	O
+atrial	B
+fibrillation	I
+and	O
+its	O
+electrophysiological	O
+determinants	O
+in	O
+dogs	O
+.	O
+
+BACKGROUND	O
+:	O
+Atrial	B
+tachycardia	I
+-	O
+induced	O
+remodeling	O
+promotes	O
+the	O
+occurrence	O
+and	O
+maintenance	O
+of	O
+atrial	B
+fibrillation	I
+(	O
+AF	B
+)	O
+and	O
+decreases	O
+L	O
+-	O
+type	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+current	O
+.	O
+
+There	O
+is	O
+also	O
+a	O
+clinical	O
+suggestion	O
+that	O
+acute	O
+L	O
+-	O
+type	O
+Ca	O
+(	O
+2	O
+)	O
+channel	O
+blockade	O
+can	O
+promote	O
+AF	B
+,	O
+consistent	O
+with	O
+an	O
+AF	B
+promoting	O
+effect	O
+of	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+channel	O
+inhibition	O
+.	O
+
+METHODS	O
+:	O
+To	O
+evaluate	O
+the	O
+potential	O
+mechanisms	O
+of	O
+AF	B
+promotion	O
+by	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+channel	O
+blockers	O
+,	O
+we	O
+administered	O
+verapamil	O
+to	O
+morphine	O
+-	O
+chloralose	O
+anesthetized	O
+dogs	O
+.	O
+
+Diltiazem	O
+was	O
+used	O
+as	O
+a	O
+comparison	O
+drug	O
+and	O
+autonomic	O
+blockade	O
+with	O
+atropine	O
+and	O
+nadolol	O
+was	O
+applied	O
+in	O
+some	O
+experiments	O
+.	O
+
+Epicardial	O
+mapping	O
+with	O
+240	O
+epicardial	O
+electrodes	O
+was	O
+used	O
+to	O
+evaluate	O
+activation	O
+during	O
+AF	B
+.	O
+
+RESULTS	O
+:	O
+Verapamil	O
+caused	O
+AF	B
+promotion	O
+in	O
+six	O
+dogs	O
+,	O
+increasing	O
+mean	O
+duration	O
+of	O
+AF	B
+induced	O
+by	O
+burst	O
+pacing	O
+,	O
+from	O
+8	O
++	O
+/	O
+-	O
+4	O
+s	O
+(	O
+mean	O
++	O
+/	O
+-	O
+S	O
+.	O
+E	O
+.	O
+)	O
+to	O
+95	O
++	O
+/	O
+-	O
+39	O
+s	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+vs	O
+.	O
+control	O
+)	O
+at	O
+a	O
+loading	O
+dose	O
+of	O
+0	O
+.	O
+1	O
+mg	O
+/	O
+kg	O
+and	O
+228	O
++	O
+/	O
+-	O
+101	O
+s	O
+(	O
+P	O
+<	O
+0	O
+.	O
+0005	O
+vs	O
+.	O
+control	O
+)	O
+at	O
+a	O
+dose	O
+of	O
+0	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+.	O
+
+Underlying	O
+electrophysiological	O
+mechanisms	O
+were	O
+studied	O
+in	O
+detail	O
+in	O
+five	O
+additional	O
+dogs	O
+under	O
+control	O
+conditions	O
+and	O
+in	O
+the	O
+presence	O
+of	O
+the	O
+higher	O
+dose	O
+of	O
+verapamil	O
+.	O
+
+In	O
+these	O
+experiments	O
+,	O
+verapamil	O
+shortened	O
+mean	O
+effective	O
+refractory	O
+period	O
+(	O
+ERP	O
+)	O
+from	O
+122	O
++	O
+/	O
+-	O
+5	O
+to	O
+114	O
++	O
+/	O
+-	O
+4	O
+ms	O
+(	O
+P	O
+<	O
+0	O
+.	O
+02	O
+)	O
+at	O
+a	O
+cycle	O
+length	O
+of	O
+300	O
+ms	O
+,	O
+decreased	O
+ERP	O
+heterogeneity	O
+(	O
+from	O
+15	O
++	O
+/	O
+-	O
+1	O
+to	O
+10	O
++	O
+/	O
+-	O
+1	O
+%	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+,	O
+heterogeneously	O
+accelerated	O
+atrial	O
+conduction	O
+and	O
+decreased	O
+the	O
+cycle	O
+length	O
+of	O
+AF	B
+(	O
+94	O
++	O
+/	O
+-	O
+4	O
+to	O
+84	O
++	O
+/	O
+-	O
+3	O
+ms	O
+,	O
+P	O
+<	O
+0	O
+.	O
+005	O
+)	O
+.	O
+
+Diltiazem	O
+did	O
+not	O
+affect	O
+ERP	O
+,	O
+AF	B
+cycle	O
+length	O
+or	O
+AF	B
+duration	O
+,	O
+but	O
+produced	O
+conduction	O
+acceleration	O
+similar	O
+to	O
+that	O
+caused	O
+by	O
+verapamil	O
+(	O
+n	O
+=	O
+5	O
+)	O
+.	O
+
+In	O
+the	O
+presence	O
+of	O
+autonomic	O
+blockade	O
+,	O
+verapamil	O
+failed	O
+to	O
+promote	O
+AF	B
+and	O
+increased	O
+,	O
+rather	O
+than	O
+decreasing	O
+,	O
+refractoriness	O
+.	O
+
+Neither	O
+verapamil	O
+nor	O
+diltiazem	O
+affected	O
+atrial	O
+conduction	O
+in	O
+the	O
+presence	O
+of	O
+autonomic	O
+blockade	O
+.	O
+
+Epicardial	O
+mapping	O
+suggested	O
+that	O
+verapamil	O
+promoted	O
+AF	B
+by	O
+increasing	O
+the	O
+number	O
+of	O
+simultaneous	O
+wavefronts	O
+reflected	O
+by	O
+separate	O
+zones	O
+of	O
+reactivation	O
+in	O
+each	O
+cycle	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Verapamil	O
+promotes	O
+AF	B
+in	O
+normal	O
+dogs	O
+by	O
+promoting	O
+multiple	O
+circuit	O
+reentry	O
+,	O
+an	O
+effect	O
+dependent	O
+on	O
+intact	O
+autonomic	O
+tone	O
+and	O
+not	O
+shared	O
+by	O
+diltiazem	O
+.	O
+
+Calcitonin	O
+gene	O
+-	O
+related	O
+peptide	O
+levels	O
+during	O
+nitric	O
+oxide	O
+-	O
+induced	O
+headache	B
+in	O
+patients	O
+with	O
+chronic	O
+tension	B
+-	I
+type	I
+headache	I
+.	O
+
+It	O
+has	O
+been	O
+proposed	O
+that	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+induced	O
+headache	B
+in	O
+primary	B
+headaches	I
+may	O
+be	O
+associated	O
+with	O
+release	O
+of	O
+calcitonin	O
+gene	O
+-	O
+related	O
+peptide	O
+(	O
+CGRP	O
+)	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+we	O
+aimed	O
+to	O
+investigate	O
+plasma	O
+levels	O
+of	O
+CGRP	O
+during	O
+headache	B
+induced	O
+by	O
+the	O
+NO	O
+donor	O
+glyceryl	O
+trinitrate	O
+(	O
+GTN	O
+)	O
+in	O
+16	O
+patients	O
+with	O
+chronic	O
+tension	B
+-	I
+type	I
+headache	I
+and	O
+16	O
+healthy	O
+controls	O
+.	O
+
+The	O
+subjects	O
+were	O
+randomly	O
+allocated	O
+to	O
+receive	O
+0	O
+.	O
+5	O
+microg	O
+/	O
+kg	O
+/	O
+min	O
+GTN	O
+or	O
+placebo	O
+over	O
+20	O
+min	O
+on	O
+two	O
+headache	B
+-	O
+free	O
+days	O
+.	O
+
+Blood	O
+samples	O
+were	O
+collected	O
+at	O
+baseline	O
+,	O
+10	O
+,	O
+20	O
+and	O
+60	O
+min	O
+after	O
+start	O
+of	O
+infusion	O
+.	O
+
+Both	O
+patients	O
+and	O
+controls	O
+developed	O
+significantly	O
+stronger	O
+immediate	O
+headache	B
+on	O
+the	O
+GTN	O
+day	O
+than	O
+on	O
+the	O
+placebo	O
+day	O
+and	O
+the	O
+headache	B
+was	O
+significantly	O
+more	O
+pronounced	O
+in	O
+patients	O
+than	O
+in	O
+controls	O
+.	O
+
+There	O
+was	O
+no	O
+difference	O
+between	O
+the	O
+area	O
+under	O
+the	O
+CGRP	O
+curve	O
+(	O
+AUCCGRP	O
+)	O
+on	O
+GTN	O
+vs	O
+.	O
+placebo	O
+day	O
+in	O
+either	O
+patients	O
+(	O
+P	O
+=	O
+0	O
+.	O
+65	O
+)	O
+or	O
+controls	O
+(	O
+P	O
+=	O
+0	O
+.	O
+48	O
+)	O
+.	O
+
+The	O
+AUCCGRP	O
+recorded	O
+on	O
+the	O
+GTN	O
+day	O
+did	O
+not	O
+differ	O
+between	O
+patients	O
+and	O
+controls	O
+(	O
+P	O
+=	O
+0	O
+.	O
+36	O
+)	O
+.	O
+
+Both	O
+in	O
+patients	O
+and	O
+controls	O
+,	O
+CGRP	O
+levels	O
+changed	O
+significantly	O
+over	O
+time	O
+,	O
+on	O
+both	O
+the	O
+GTN	O
+and	O
+placebo	O
+days	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+present	O
+study	O
+indicates	O
+that	O
+NO	O
+-	O
+induced	O
+immediate	O
+headache	B
+is	O
+not	O
+associated	O
+with	O
+release	O
+of	O
+CGRP	O
+.	O
+
+Fluconazole	O
+-	O
+induced	O
+torsade	B
+de	I
+pointes	I
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+present	O
+a	O
+case	O
+of	O
+fluconazole	O
+-	O
+associated	O
+torsade	B
+de	I
+pointes	I
+(	O
+TDP	B
+)	O
+and	O
+discuss	O
+fluconazole	O
+'	O
+s	O
+role	O
+in	O
+causing	O
+TDP	B
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+68	O
+-	O
+year	O
+-	O
+old	O
+white	O
+woman	O
+with	O
+Candida	O
+glabrata	O
+isolated	O
+from	O
+a	O
+presacral	O
+abscess	O
+developed	O
+TDP	B
+eight	O
+days	O
+after	O
+commencing	O
+oral	O
+fluconazole	O
+The	O
+patient	O
+had	O
+no	O
+other	O
+risk	O
+factors	O
+for	O
+TDP	B
+,	O
+including	O
+coronary	B
+artery	I
+disease	I
+,	O
+cardiomyopathy	B
+,	O
+congestive	B
+heart	I
+failure	I
+,	O
+and	O
+electrolyte	O
+abnormalities	O
+There	O
+was	O
+a	O
+temporal	O
+association	O
+between	O
+the	O
+initiation	O
+of	O
+fluconazole	O
+and	O
+TDP	B
+.	O
+
+The	O
+TDP	B
+resolved	O
+when	O
+fluconazole	O
+was	O
+discontinued	O
+;	O
+however	O
+,	O
+the	O
+patient	O
+continued	O
+to	O
+have	O
+premature	B
+ventricular	I
+contractions	I
+and	O
+nonsustained	O
+ventricular	B
+tachycardia	I
+(	O
+NSVT	B
+)	O
+until	O
+six	O
+days	O
+after	O
+drug	O
+cessation	O
+DISCUSSION	O
+:	O
+Use	O
+of	O
+the	O
+Naranjo	O
+probability	O
+scale	O
+indicates	O
+a	O
+probable	O
+relationship	O
+between	O
+the	O
+use	O
+of	O
+fluconazole	O
+and	O
+the	O
+development	O
+of	O
+TDP	B
+.	O
+
+The	O
+possible	O
+mechanism	O
+is	O
+depression	B
+of	O
+rapidly	O
+activating	O
+delayed	O
+rectifier	O
+potassium	O
+currents	O
+.	O
+
+In	O
+our	O
+patient	O
+,	O
+there	O
+was	O
+no	O
+other	O
+etiology	O
+identified	O
+that	O
+could	O
+explain	O
+QT	B
+prolongation	I
+or	O
+TDP	B
+The	O
+complete	O
+disappearance	O
+of	O
+NSVT	B
+and	O
+premature	B
+ventricular	I
+contractions	I
+followed	O
+by	O
+normalization	O
+of	O
+QT	O
+interval	O
+after	O
+the	O
+drug	O
+was	O
+stopped	O
+strongly	O
+suggests	O
+fluconazole	O
+as	O
+the	O
+etiology	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Clinicians	O
+should	O
+be	O
+aware	O
+that	O
+fluconazole	O
+,	O
+even	O
+at	O
+low	O
+doses	O
+,	O
+may	O
+cause	O
+prolongation	B
+of	I
+the	I
+QT	I
+interval	I
+,	O
+leading	O
+to	O
+TDP	B
+.	O
+
+Serial	O
+electrocardiographic	O
+monitoring	O
+may	O
+be	O
+considered	O
+when	O
+fluconazole	O
+is	O
+administered	O
+in	O
+patients	O
+who	O
+are	O
+at	O
+risk	O
+for	O
+ventricular	B
+arrhythmias	I
+.	O
+
+Cutaneous	B
+leucocytoclastic	I
+vasculitis	I
+associated	O
+with	O
+oxacillin	O
+.	O
+
+A	O
+67	O
+-	O
+year	O
+-	O
+old	O
+man	O
+who	O
+was	O
+treated	O
+with	O
+oxacillin	O
+for	O
+one	O
+week	O
+because	O
+of	O
+Staphylococcus	B
+aureus	I
+bacteremia	I
+,	O
+developed	O
+renal	B
+failure	I
+and	O
+diffuse	O
+,	O
+symmetric	O
+,	O
+palpable	O
+purpuric	B
+lesions	I
+on	O
+his	O
+feet	O
+.	O
+
+Necrotic	B
+blisters	I
+were	O
+noted	O
+on	O
+his	O
+fingers	O
+.	O
+
+Skin	O
+biopsies	O
+showed	O
+findings	O
+diagnostic	O
+of	O
+leucocytoclastic	B
+vasculitis	I
+.	O
+
+Oxacillin	O
+was	O
+discontinued	O
+and	O
+patient	O
+was	O
+treated	O
+with	O
+corticosteroids	O
+.	O
+
+The	O
+rash	B
+disappeared	O
+after	O
+three	O
+weeks	O
+and	O
+renal	O
+function	O
+returned	O
+to	O
+normal	O
+.	O
+
+Leucocytoclastic	B
+vasculitis	I
+presents	O
+as	O
+palpable	O
+purpura	B
+of	O
+the	O
+lower	O
+extremities	O
+often	O
+accompanied	O
+by	O
+abdominal	B
+pain	I
+,	O
+arthralgia	B
+,	O
+and	O
+renal	B
+involvement	I
+.	O
+
+Etiologic	O
+factors	O
+or	O
+associated	O
+disorders	O
+include	O
+infections	B
+,	O
+medications	O
+,	O
+collagen	B
+vascular	I
+disease	I
+and	O
+neoplasia	B
+.	O
+
+However	O
+,	O
+in	O
+half	O
+of	O
+the	O
+cases	O
+no	O
+etiologic	O
+factor	O
+is	O
+identified	O
+.	O
+
+Usually	O
+it	O
+is	O
+a	O
+self	O
+-	O
+limited	O
+disorder	O
+,	O
+but	O
+corticosteroid	O
+therapy	O
+may	O
+be	O
+needed	O
+in	O
+life	O
+-	O
+threatening	O
+cases	O
+since	O
+early	O
+treatment	O
+with	O
+corticosteroids	O
+in	O
+severe	O
+cases	O
+can	O
+prevent	O
+complications	O
+.	O
+
+Oxacillin	O
+should	O
+be	O
+included	O
+among	O
+the	O
+drugs	O
+that	O
+can	O
+cause	O
+leucocytoclastic	B
+vasculitis	I
+.	O
+
+The	O
+renal	O
+pathology	O
+in	O
+a	O
+case	O
+of	O
+lithium	O
+-	O
+induced	O
+diabetes	B
+insipidus	I
+.	O
+
+A	O
+case	O
+of	O
+lithium	O
+-	O
+induced	O
+diabetes	B
+insipidus	I
+is	O
+reported	O
+.	O
+
+At	O
+necropsy	O
+microscopy	O
+shoed	O
+unique	O
+and	O
+extensive	O
+damage	O
+to	O
+cells	O
+lining	O
+the	O
+distal	O
+nephron	O
+.	O
+
+It	O
+is	O
+suggested	O
+that	O
+these	O
+changes	O
+represent	O
+a	O
+specific	O
+toxic	O
+effect	O
+of	O
+lithium	O
+,	O
+reported	O
+here	O
+for	O
+the	O
+first	O
+time	O
+in	O
+man	O
+.	O
+
+Cholestatic	B
+jaundice	I
+associated	O
+with	O
+the	O
+use	O
+of	O
+metformin	O
+.	O
+
+We	O
+report	O
+a	O
+patient	O
+who	O
+developed	O
+cholestatic	B
+jaundice	I
+shortly	O
+after	O
+initiation	O
+of	O
+treatment	O
+with	O
+metformin	O
+hydrochloride	O
+.	O
+
+Ultrasound	O
+of	O
+the	O
+liver	O
+and	O
+abdominal	O
+CT	O
+were	O
+normal	O
+.	O
+
+An	O
+ERCP	O
+showed	O
+normal	O
+biliary	O
+anatomy	O
+.	O
+
+A	O
+percutaneous	O
+liver	O
+biopsy	O
+was	O
+obtained	O
+showing	O
+marked	O
+cholestasis	B
+,	O
+with	O
+portal	O
+edema	B
+,	O
+ductular	O
+proliferation	O
+,	O
+and	O
+acute	O
+inflammation	B
+.	O
+
+Metformin	O
+hydrochloride	O
+was	O
+discontinued	O
+,	O
+and	O
+the	O
+patient	O
+'	O
+s	O
+jaundice	B
+resolved	O
+slowly	O
+over	O
+a	O
+period	O
+of	O
+several	O
+months	O
+.	O
+
+Given	O
+the	O
+onset	O
+of	O
+his	O
+jaundice	B
+2	O
+wk	O
+after	O
+the	O
+initiation	O
+of	O
+metformin	O
+,	O
+we	O
+believe	O
+that	O
+this	O
+case	O
+represents	O
+an	O
+example	O
+of	O
+metformin	O
+-	O
+associated	O
+hepatotoxicity	B
+,	O
+the	O
+first	O
+such	O
+case	O
+reported	O
+.	O
+
+Systemic	O
+toxicity	B
+and	O
+resuscitation	O
+in	O
+bupivacaine	O
+-	O
+,	O
+levobupivacaine	O
+-	O
+,	O
+or	O
+ropivacaine	O
+-	O
+infused	O
+rats	O
+.	O
+
+We	O
+compared	O
+the	O
+systemic	O
+toxicity	B
+of	O
+bupivacaine	O
+,	O
+levobupivacaine	O
+,	O
+and	O
+ropivacaine	O
+in	O
+anesthetized	O
+rats	O
+.	O
+
+We	O
+also	O
+compared	O
+the	O
+ability	O
+to	O
+resuscitate	O
+rats	O
+after	O
+lethal	O
+doses	O
+of	O
+these	O
+local	O
+anesthetics	O
+.	O
+
+Bupivacaine	O
+,	O
+levobupivacaine	O
+,	O
+or	O
+ropivacaine	O
+was	O
+infused	O
+at	O
+a	O
+rate	O
+of	O
+2	O
+mg	O
+.	O
+
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+
+min	O
+(	O
+-	O
+1	O
+)	O
+while	O
+electrocardiogram	O
+,	O
+electroencephalogram	O
+,	O
+and	O
+arterial	O
+pressure	O
+were	O
+continuously	O
+monitored	O
+.	O
+
+When	O
+asystole	B
+was	O
+recorded	O
+,	O
+drug	O
+infusion	O
+was	O
+stopped	O
+and	O
+a	O
+resuscitation	O
+sequence	O
+was	O
+begun	O
+.	O
+
+Epinephrine	O
+0	O
+.	O
+01	O
+mg	O
+/	O
+kg	O
+was	O
+administered	O
+at	O
+1	O
+-	O
+min	O
+intervals	O
+while	O
+external	O
+cardiac	O
+compressions	O
+were	O
+applied	O
+.	O
+
+Resuscitation	O
+was	O
+considered	O
+successful	O
+when	O
+a	O
+systolic	O
+arterial	O
+pressure	O
+>	O
+or	O
+=	O
+100	O
+mm	O
+Hg	O
+was	O
+achieved	O
+within	O
+5	O
+min	O
+.	O
+
+The	O
+cumulative	O
+doses	O
+of	O
+levobupivacaine	O
+and	O
+ropivacaine	O
+that	O
+produced	O
+seizures	B
+were	O
+similar	O
+and	O
+were	O
+larger	O
+than	O
+those	O
+of	O
+bupivacaine	O
+.	O
+
+The	O
+cumulative	O
+doses	O
+of	O
+levobupivacaine	O
+that	O
+produced	O
+dysrhythmias	B
+and	O
+asystole	B
+were	O
+smaller	O
+than	O
+the	O
+corresponding	O
+doses	O
+of	O
+ropivacaine	O
+,	O
+but	O
+they	O
+were	O
+larger	O
+than	O
+those	O
+of	O
+bupivacaine	O
+.	O
+
+The	O
+number	O
+of	O
+successful	O
+resuscitations	O
+did	O
+not	O
+differ	O
+among	O
+groups	O
+.	O
+
+However	O
+,	O
+a	O
+smaller	O
+dose	O
+of	O
+epinephrine	O
+was	O
+required	O
+in	O
+the	O
+Ropivacaine	O
+group	O
+than	O
+in	O
+the	O
+other	O
+groups	O
+.	O
+
+We	O
+conclude	O
+that	O
+the	O
+systemic	O
+toxicity	B
+of	O
+levobupivacaine	O
+is	O
+intermediate	O
+between	O
+that	O
+of	O
+ropivacaine	O
+and	O
+bupivacaine	O
+when	O
+administered	O
+at	O
+the	O
+same	O
+rate	O
+and	O
+that	O
+ropivacaine	O
+-	O
+induced	O
+cardiac	B
+arrest	I
+appears	O
+to	O
+be	O
+more	O
+susceptible	O
+to	O
+treatment	O
+than	O
+that	O
+induced	O
+by	O
+bupivacaine	O
+or	O
+levobupivacaine	O
+.	O
+
+Amphotericin	O
+B	O
+-	O
+induced	O
+seizures	B
+in	O
+a	O
+patient	O
+with	O
+AIDS	B
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+multiple	O
+episodes	O
+of	O
+seizure	B
+activity	O
+in	O
+an	O
+AIDS	B
+patent	O
+following	O
+amphotericin	O
+B	O
+infusion	O
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+46	O
+-	O
+year	O
+-	O
+old	O
+African	O
+-	O
+American	O
+man	O
+experienced	O
+recurrent	O
+grand	B
+mal	I
+seizures	I
+during	O
+intravenous	O
+infusion	O
+of	O
+amphotericin	O
+B	O
+,	O
+then	O
+petit	O
+mal	O
+seizures	B
+as	O
+the	O
+infusion	O
+was	O
+stopped	O
+and	O
+the	O
+drug	O
+concentrations	O
+decreased	O
+with	O
+time	O
+.	O
+
+The	O
+patients	O
+concurrent	O
+medications	O
+included	O
+didanosine	O
+,	O
+hydroxyzine	O
+,	O
+promethazine	O
+,	O
+hydrocortisone	O
+,	O
+and	O
+prochlorperazine	O
+.	O
+
+Despite	O
+administration	O
+of	O
+phenytoin	O
+and	O
+lorazepam	O
+,	O
+the	O
+seizures	B
+persisted	O
+and	O
+occurred	O
+only	O
+during	O
+amphotercin	O
+B	O
+administration	O
+.	O
+
+DISCUSSION	O
+:	O
+AIDS	B
+and	O
+cryptococcal	B
+meningitis	I
+,	O
+both	O
+of	O
+which	O
+the	O
+patient	O
+had	O
+,	O
+can	O
+potentially	O
+cause	O
+seizures	B
+.	O
+
+The	O
+patient	O
+had	O
+a	O
+history	O
+of	O
+alcohol	B
+abuse	I
+;	O
+alcohol	O
+intake	O
+as	O
+well	O
+as	O
+withdrawal	O
+can	O
+also	O
+cause	O
+seizures	B
+.	O
+
+Didanosine	O
+also	O
+has	O
+a	O
+potential	O
+for	O
+inducing	O
+seizures	B
+.	O
+
+However	O
+,	O
+these	O
+other	O
+potential	O
+causes	O
+of	O
+seizure	B
+were	O
+ruled	O
+out	O
+.	O
+
+The	O
+time	O
+course	O
+of	O
+events	O
+suggested	O
+that	O
+amphotericin	O
+B	O
+was	O
+the	O
+cause	O
+of	O
+the	O
+seizures	B
+in	O
+this	O
+AIDS	B
+patient	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Amphotericin	O
+B	O
+seems	O
+to	O
+be	O
+the	O
+probable	O
+cause	O
+of	O
+the	O
+seizures	B
+.	O
+
+To	O
+date	O
+,	O
+only	O
+three	O
+cases	O
+of	O
+seizures	B
+associated	O
+with	O
+amphotericin	O
+B	O
+have	O
+been	O
+reported	O
+in	O
+the	O
+literature	O
+,	O
+but	O
+healthcare	O
+providers	O
+should	O
+be	O
+aware	O
+of	O
+the	O
+potential	O
+for	O
+this	O
+rare	O
+adverse	O
+effect	O
+.	O
+
+Sirolimus	O
+and	O
+mycophenolate	O
+mofetil	O
+for	O
+calcineurin	O
+-	O
+free	O
+immunosuppression	O
+in	O
+renal	O
+transplant	O
+recipients	O
+.	O
+
+Calcineurin	O
+inhibitors	O
+,	O
+such	O
+as	O
+cyclosporine	O
+and	O
+tacrolimus	O
+,	O
+have	O
+been	O
+available	O
+for	O
+almost	O
+20	O
+years	O
+.	O
+
+Although	O
+these	O
+drugs	O
+are	O
+highly	O
+effective	O
+and	O
+represent	O
+the	O
+mainstay	O
+of	O
+transplant	O
+immunosuppression	O
+,	O
+they	O
+are	O
+associated	O
+with	O
+acute	O
+and	O
+chronic	O
+nephrotoxicity	B
+.	O
+
+Acute	O
+nephrotoxicity	B
+,	O
+which	O
+occurs	O
+in	O
+the	O
+early	O
+period	O
+after	O
+transplantation	O
+,	O
+leads	O
+to	O
+a	O
+higher	O
+rate	O
+of	O
+dialysis	O
+,	O
+and	O
+chronic	O
+nephrotoxicity	B
+may	O
+eventually	O
+result	O
+in	O
+graft	O
+loss	O
+.	O
+
+Acute	O
+and	O
+chronic	O
+nephrotoxicity	B
+is	O
+becoming	O
+more	O
+common	O
+as	O
+the	O
+use	O
+of	O
+marginal	O
+kidneys	O
+for	O
+transplantation	O
+increases	O
+.	O
+
+Two	O
+recently	O
+available	O
+immunosuppressive	O
+agents	O
+,	O
+mycophenolate	O
+mofetil	O
+and	O
+sirolimus	O
+(	O
+rapamycin	O
+)	O
+,	O
+have	O
+no	O
+nephrotoxicity	B
+.	O
+
+The	O
+use	O
+of	O
+these	O
+drugs	O
+in	O
+combination	O
+with	O
+other	O
+agents	O
+has	O
+led	O
+to	O
+the	O
+development	O
+of	O
+new	O
+paradigms	O
+of	O
+immunosuppressive	O
+therapy	O
+.	O
+
+This	O
+paper	O
+reviews	O
+the	O
+results	O
+of	O
+clinical	O
+trials	O
+that	O
+have	O
+investigated	O
+these	O
+new	O
+approaches	O
+to	O
+immunosuppression	O
+in	O
+renal	O
+transplant	O
+recipients	O
+.	O
+
+Tolerability	O
+of	O
+nimesulide	O
+and	O
+paracetamol	O
+in	O
+patients	O
+with	O
+NSAID	O
+-	O
+induced	O
+urticaria	B
+/	O
+angioedema	B
+.	O
+
+Previous	O
+studies	O
+evaluated	O
+the	O
+tolerance	O
+of	O
+nimesulide	O
+and	O
+paracetamol	O
+in	O
+subjects	O
+with	O
+cutaneous	O
+,	O
+respiratory	O
+and	O
+anaphylactoid	O
+reactions	O
+induced	O
+by	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+(	O
+NSAIDs	O
+)	O
+.	O
+
+In	O
+this	O
+study	O
+we	O
+investigated	O
+tolerability	O
+and	O
+reliability	O
+of	O
+nimesulide	O
+and	O
+paracetamol	O
+in	O
+a	O
+very	O
+large	O
+number	O
+of	O
+patients	O
+with	O
+an	O
+exclusive	O
+well	O
+-	O
+documented	O
+history	O
+of	O
+NSAID	O
+-	O
+induced	O
+urticaria	B
+/	O
+angioedema	B
+.	O
+
+Furthermore	O
+,	O
+we	O
+evaluated	O
+whether	O
+some	O
+factors	O
+have	O
+the	O
+potential	O
+to	O
+increase	O
+the	O
+risk	O
+of	O
+reaction	O
+to	O
+paracetamol	O
+and	O
+nimesulide	O
+.	O
+
+A	O
+single	O
+-	O
+placebo	O
+-	O
+controlled	O
+oral	O
+challenge	O
+procedure	O
+with	O
+nimesulide	O
+or	O
+paracetamol	O
+was	O
+applied	O
+to	O
+829	O
+patients	O
+with	O
+a	O
+history	O
+of	O
+NSAID	O
+-	O
+induced	O
+urticaria	B
+/	O
+angioedema	B
+.	O
+
+A	O
+total	O
+of	O
+75	O
+/	O
+829	O
+(	O
+9	O
+.	O
+4	O
+%	O
+)	O
+patients	O
+experienced	O
+reactions	O
+to	O
+nimesulide	O
+or	O
+paracetamol	O
+.	O
+
+Of	O
+the	O
+715	O
+patients	O
+tested	O
+with	O
+nimesulide	O
+62	O
+(	O
+8	O
+.	O
+6	O
+%	O
+)	O
+showed	O
+a	O
+positive	O
+test	O
+,	O
+while	O
+of	O
+114	O
+subjects	O
+submitted	O
+to	O
+the	O
+challenge	O
+with	O
+paracetamol	O
+,	O
+13	O
+(	O
+9	O
+.	O
+6	O
+%	O
+)	O
+did	O
+not	O
+tolerate	O
+this	O
+drug	O
+.	O
+
+Furthermore	O
+,	O
+18	O
+.	O
+28	O
+%	O
+of	O
+patients	O
+with	O
+a	O
+history	O
+of	O
+chronic	O
+urticaria	B
+and	O
+11	O
+.	O
+8	O
+%	O
+of	O
+subjects	O
+with	O
+an	O
+history	O
+of	O
+NSAID	O
+-	O
+induced	O
+urticaria	B
+/	O
+angioedema	B
+or	O
+angioedema	B
+alone	O
+(	O
+with	O
+or	O
+without	O
+chronic	O
+urticaria	B
+)	O
+resulted	O
+to	O
+be	O
+intolerant	O
+to	O
+alternative	O
+drugs	O
+.	O
+
+Taken	O
+together	O
+,	O
+our	O
+results	O
+confirm	O
+the	O
+good	O
+tolerability	O
+of	O
+nimesulide	O
+and	O
+paracetamol	O
+in	O
+patients	O
+who	O
+experienced	O
+urticaria	B
+/	O
+angioedema	B
+caused	O
+by	O
+NSAIDs	O
+.	O
+
+However	O
+,	O
+the	O
+risk	O
+of	O
+reaction	O
+to	O
+these	O
+alternative	O
+study	O
+drugs	O
+is	O
+statistically	O
+increased	O
+by	O
+a	O
+history	O
+of	O
+chronic	O
+urticaria	B
+and	O
+,	O
+above	O
+all	O
+,	O
+by	O
+a	O
+history	O
+of	O
+NSAID	O
+-	O
+induced	O
+angioedema	B
+.	O
+
+Comparison	O
+of	O
+aqueous	O
+and	O
+gellan	O
+ophthalmic	O
+timolol	O
+with	O
+placebo	O
+on	O
+the	O
+24	O
+-	O
+hour	O
+heart	O
+rate	O
+response	O
+in	O
+patients	O
+on	O
+treatment	O
+for	O
+glaucoma	B
+.	O
+
+PURPOSE	O
+:	O
+Topical	O
+beta	O
+-	O
+blocker	O
+treatment	O
+is	O
+routine	O
+therapy	O
+in	O
+the	O
+management	O
+of	O
+patients	O
+with	O
+glaucoma	B
+.	O
+
+Therapy	O
+results	O
+in	O
+systemic	O
+absorption	O
+,	O
+however	O
+,	O
+the	O
+degree	O
+of	O
+reduction	O
+of	O
+resting	O
+and	O
+peak	O
+heart	O
+rate	O
+has	O
+not	O
+been	O
+quantified	O
+.	O
+
+DESIGN	O
+:	O
+This	O
+trial	O
+evaluated	O
+the	O
+effect	O
+of	O
+placebo	O
+,	O
+0	O
+.	O
+5	O
+%	O
+aqueous	O
+timolol	O
+(	O
+timolol	O
+solution	O
+)	O
+and	O
+a	O
+0	O
+.	O
+5	O
+%	O
+timolol	O
+suspension	O
+that	O
+forms	O
+a	O
+gel	O
+on	O
+application	O
+to	O
+the	O
+conjunctiva	O
+(	O
+timolol	O
+gellan	O
+)	O
+on	O
+the	O
+24	O
+-	O
+hour	O
+heart	O
+rate	O
+in	O
+patients	O
+currently	O
+being	O
+treated	O
+for	O
+glaucoma	B
+to	O
+quantify	O
+the	O
+reduction	O
+in	O
+mean	O
+heart	O
+rate	O
+.	O
+
+METHODS	O
+:	O
+Forty	O
+-	O
+three	O
+Caucasian	O
+patients	O
+with	O
+primary	O
+open	B
+-	I
+angle	I
+glaucoma	I
+or	O
+ocular	B
+hypertension	I
+with	O
+a	O
+mean	O
+(	O
++	O
+/	O
+-	O
+SD	O
+)	O
+age	O
+of	O
+63	O
+(	O
++	O
+/	O
+-	O
+8	O
+)	O
+years	O
+were	O
+randomized	O
+and	O
+crossed	O
+over	O
+in	O
+a	O
+double	O
+-	O
+masked	O
+manner	O
+to	O
+14	O
+days	O
+of	O
+treatment	O
+with	O
+placebo	O
+(	O
+morning	O
+and	O
+evening	O
+in	O
+both	O
+eyes	O
+)	O
+,	O
+timolol	O
+solution	O
+(	O
+morning	O
+and	O
+evening	O
+in	O
+both	O
+eyes	O
+)	O
+,	O
+or	O
+timolol	O
+gellan	O
+(	O
+morning	O
+in	O
+both	O
+eyes	O
+with	O
+placebo	O
+in	O
+the	O
+evening	O
+)	O
+.	O
+
+On	O
+the	O
+13th	O
+day	O
+of	O
+each	O
+period	O
+,	O
+heart	O
+rate	O
+was	O
+recorded	O
+continuously	O
+during	O
+a	O
+typical	O
+,	O
+ambulant	O
+24	O
+-	O
+hour	O
+period	O
+.	O
+
+RESULTS	O
+:	O
+Both	O
+timolol	O
+solution	O
+and	O
+timolol	O
+gellan	O
+reduced	O
+the	O
+mean	O
+24	O
+-	O
+hour	O
+heart	O
+rate	O
+compared	O
+with	O
+placebo	O
+(	O
+P	O
+<	O
+or	O
+=	O
+.	O
+001	O
+)	O
+,	O
+and	O
+this	O
+reduction	O
+was	O
+most	O
+pronounced	O
+during	O
+the	O
+daytime	O
+(	O
+-	O
+7	O
+.	O
+5	O
+%	O
+change	O
+in	O
+mean	O
+heart	O
+rate	O
+,	O
+-	O
+5	O
+.	O
+7	O
+beats	O
+/	O
+min	O
+)	O
+.	O
+
+Timolol	O
+gellan	O
+showed	O
+a	O
+numerically	O
+but	O
+not	O
+significantly	O
+smaller	O
+reduction	O
+in	O
+24	O
+-	O
+hour	O
+heart	O
+rate	O
+,	O
+compared	O
+with	O
+timolol	O
+solution	O
+.	O
+
+During	O
+the	O
+night	O
+,	O
+the	O
+mean	O
+12	O
+-	O
+hour	O
+heart	O
+rate	O
+on	O
+placebo	O
+and	O
+timolol	O
+gellan	O
+were	O
+both	O
+significantly	O
+less	O
+than	O
+on	O
+timolol	O
+solution	O
+;	O
+the	O
+difference	O
+between	O
+solution	O
+and	O
+gellan	O
+treatments	O
+was	O
+statistically	O
+significant	O
+(	O
+P	O
+=	O
+.	O
+01	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Both	O
+timolol	O
+solution	O
+and	O
+timolol	O
+gellan	O
+decrease	O
+the	O
+mean	O
+24	O
+-	O
+hour	O
+heart	O
+rate	O
+compared	O
+with	O
+placebo	O
+.	O
+
+This	O
+response	O
+was	O
+most	O
+pronounced	O
+during	O
+the	O
+active	O
+daytime	O
+period	O
+.	O
+
+These	O
+data	O
+quantify	O
+the	O
+modest	O
+bradycardia	B
+associated	O
+with	O
+ophthalmic	O
+beta	O
+-	O
+blocker	O
+therapy	O
+in	O
+a	O
+typical	O
+patient	O
+population	O
+on	O
+therapy	O
+for	O
+glaucoma	B
+.	O
+
+Although	O
+exercise	O
+performance	O
+was	O
+not	O
+assessed	O
+in	O
+this	O
+trial	O
+,	O
+reductions	O
+of	O
+this	O
+magnitude	O
+should	O
+not	O
+have	O
+substantial	O
+clinical	O
+consequences	O
+.	O
+
+Management	O
+strategies	O
+for	O
+ribavirin	O
+-	O
+induced	O
+hemolytic	B
+anemia	I
+in	O
+the	O
+treatment	O
+of	O
+hepatitis	B
+C	I
+:	O
+clinical	O
+and	O
+economic	O
+implications	O
+.	O
+
+OBJECTIVES	O
+:	O
+Recently	O
+published	O
+studies	O
+have	O
+demonstrated	O
+increased	O
+efficacy	O
+and	O
+cost	O
+-	O
+effectiveness	O
+of	O
+combination	O
+therapy	O
+with	O
+interferon	O
+and	O
+alpha	O
+-	O
+2b	O
+/	O
+ribavirin	O
+compared	O
+with	O
+interferon	O
+-	O
+alpha	O
+monotherapy	O
+in	O
+the	O
+treatment	O
+of	O
+chronic	B
+hepatitis	I
+C	I
+(	O
+CHC	B
+)	O
+.	O
+
+Combination	O
+therapy	O
+is	O
+associated	O
+with	O
+a	O
+clinically	O
+important	O
+adverse	O
+effect	O
+:	O
+ribavirin	O
+-	O
+induced	O
+hemolytic	B
+anemia	I
+(	O
+RIHA	B
+)	O
+.	O
+
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+evaluate	O
+the	O
+direct	O
+health	O
+-	O
+care	O
+costs	O
+and	O
+management	O
+of	O
+RIHA	B
+during	O
+treatment	O
+of	O
+CHC	B
+in	O
+a	O
+clinical	O
+trial	O
+setting	O
+.	O
+
+METHODS	O
+:	O
+A	O
+systematic	O
+literature	O
+review	O
+was	O
+conducted	O
+to	O
+synthesize	O
+information	O
+on	O
+the	O
+incidence	O
+and	O
+management	O
+of	O
+RIHA	B
+.	O
+
+Decision	O
+-	O
+analytic	O
+techniques	O
+were	O
+used	O
+to	O
+estimate	O
+the	O
+cost	O
+of	O
+treating	O
+RIHA	B
+.	O
+
+Uncertainty	O
+was	O
+evaluated	O
+using	O
+sensitivity	O
+analyses	O
+.	O
+
+RESULTS	O
+:	O
+RIHA	B
+,	O
+defined	O
+as	O
+a	O
+reduction	O
+in	O
+hemoglobin	O
+to	O
+less	O
+than	O
+100	O
+g	O
+/	O
+L	O
+,	O
+occurs	O
+in	O
+approximately	O
+7	O
+%	O
+to	O
+9	O
+%	O
+of	O
+patients	O
+treated	O
+with	O
+combination	O
+therapy	O
+.	O
+
+The	O
+standard	O
+of	O
+care	O
+for	O
+management	O
+of	O
+RIHA	B
+is	O
+reduction	O
+or	O
+discontinuation	O
+of	O
+the	O
+ribavirin	O
+dosage	O
+.	O
+
+We	O
+estimated	O
+the	O
+direct	O
+cost	O
+of	O
+treating	O
+clinically	O
+significant	O
+RIHA	B
+to	O
+be	O
+170	O
+per	O
+patient	O
+receiving	O
+combination	O
+therapy	O
+per	O
+48	O
+-	O
+week	O
+treatment	O
+course	O
+(	O
+range	O
+68	O
+-	O
+692	O
+)	O
+.	O
+
+The	O
+results	O
+of	O
+the	O
+one	O
+-	O
+way	O
+sensitivity	O
+analyses	O
+ranged	O
+from	O
+57	O
+to	O
+317	O
+.	O
+
+In	O
+comparison	O
+,	O
+the	O
+cost	O
+of	O
+48	O
+weeks	O
+of	O
+combination	O
+therapy	O
+is	O
+16	O
+,	O
+459	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+direct	O
+cost	O
+of	O
+treating	O
+clinically	O
+significant	O
+RIHA	B
+is	O
+1	O
+%	O
+(	O
+170	O
+/	O
+16	O
+,	O
+459	O
+)	O
+of	O
+drug	O
+treatment	O
+costs	O
+.	O
+
+Questions	O
+remain	O
+about	O
+the	O
+optimal	O
+dose	O
+of	O
+ribavirin	O
+and	O
+the	O
+incidence	O
+of	O
+RIHA	B
+in	O
+a	O
+real	O
+-	O
+world	O
+population	O
+.	O
+
+Despite	O
+these	O
+uncertainties	O
+,	O
+this	O
+initial	O
+evaluation	O
+of	O
+the	O
+direct	O
+cost	O
+of	O
+treating	O
+RIHA	B
+provides	O
+an	O
+estimate	O
+of	O
+the	O
+cost	O
+and	O
+management	O
+implications	O
+of	O
+this	O
+clinically	O
+important	O
+adverse	O
+effect	O
+.	O
+
+Preliminary	O
+efficacy	O
+assessment	O
+of	O
+intrathecal	O
+injection	O
+of	O
+an	O
+American	O
+formulation	O
+of	O
+adenosine	O
+in	O
+humans	O
+.	O
+
+BACKGROUND	O
+:	O
+Preclinical	O
+studies	O
+of	O
+intrathecal	O
+adenosine	O
+suggest	O
+it	O
+may	O
+be	O
+effective	O
+in	O
+the	O
+treatment	O
+of	O
+acute	B
+and	I
+chronic	I
+pain	I
+in	O
+humans	O
+,	O
+and	O
+preliminary	O
+studies	O
+in	O
+volunteers	O
+and	O
+patients	O
+with	O
+a	O
+Swedish	O
+formulation	O
+of	O
+adenosine	O
+suggests	O
+it	O
+may	O
+be	O
+effective	O
+in	O
+hypersensitivity	B
+states	O
+but	O
+not	O
+with	O
+acute	O
+noxious	O
+stimulation	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+screen	O
+for	O
+efficacy	O
+of	O
+a	O
+different	O
+formulation	O
+of	O
+adenosine	O
+marketed	O
+in	O
+the	O
+US	O
+,	O
+using	O
+both	O
+acute	O
+noxious	O
+stimulation	O
+and	O
+capsaicin	O
+-	O
+evoked	O
+mechanical	O
+hypersensitivity	B
+.	O
+
+METHODS	O
+:	O
+Following	O
+Food	O
+and	O
+Drug	O
+Administration	O
+and	O
+institutional	O
+review	O
+board	O
+approval	O
+and	O
+written	O
+informed	O
+consent	O
+,	O
+65	O
+volunteers	O
+were	O
+studied	O
+in	O
+two	O
+trials	O
+:	O
+an	O
+open	O
+-	O
+label	O
+,	O
+dose	O
+-	O
+escalating	O
+trial	O
+with	O
+intrathecal	O
+adenosine	O
+doses	O
+of	O
+0	O
+.	O
+25	O
+-	O
+2	O
+.	O
+0	O
+mg	O
+and	O
+a	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+trial	O
+of	O
+adenosine	O
+,	O
+2	O
+mg	O
+.	O
+
+Cerebrospinal	O
+fluid	O
+was	O
+obtained	O
+for	O
+pharmacokinetic	O
+analysis	O
+,	O
+and	O
+pain	B
+ratings	O
+in	O
+response	O
+to	O
+acute	O
+heat	O
+stimuli	O
+and	O
+areas	O
+of	O
+mechanical	B
+hyperalgesia	I
+and	O
+allodynia	B
+after	O
+intradermal	O
+capsaicin	O
+injection	O
+were	O
+determined	O
+.	O
+
+RESULTS	O
+:	O
+Adenosine	O
+produced	O
+no	O
+effect	O
+on	O
+pain	B
+report	O
+to	O
+acute	O
+noxious	O
+thermal	O
+or	O
+chemical	O
+stimulation	O
+but	O
+reduced	O
+mechanical	B
+hyperalgesia	I
+and	O
+allodynia	B
+from	O
+intradermal	O
+capsaicin	O
+injection	O
+for	O
+at	O
+least	O
+24	O
+h	O
+.	O
+
+In	O
+contrast	O
+,	O
+residence	O
+time	O
+of	O
+adenosine	O
+in	O
+cerebrospinal	O
+fluid	O
+was	O
+short	O
+(	O
+<	O
+4	O
+h	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+These	O
+results	O
+show	O
+selective	O
+inhibition	O
+by	O
+intrathecal	O
+adenosine	O
+of	O
+hypersensitivity	B
+,	O
+presumed	O
+to	O
+reflect	O
+central	O
+sensitization	O
+in	O
+humans	O
+after	O
+peripheral	O
+capsaicin	O
+injection	O
+.	O
+
+The	O
+long	O
+-	O
+lasting	O
+effect	O
+is	O
+consistent	O
+with	O
+that	O
+observed	O
+in	O
+preliminary	O
+reports	O
+of	O
+patients	O
+with	O
+chronic	O
+neuropathic	B
+pain	I
+and	O
+is	O
+not	O
+due	O
+to	O
+prolonged	O
+residence	O
+of	O
+adenosine	O
+in	O
+cerebrospinal	O
+fluid	O
+.	O
+
+Delayed	O
+-	O
+onset	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+.	O
+
+BACKGROUND	O
+:	O
+Heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+presents	O
+5	O
+to	O
+12	O
+days	O
+after	O
+heparin	O
+exposure	O
+,	O
+with	O
+or	O
+without	O
+arterial	B
+or	I
+venous	I
+thromboemboli	I
+.	O
+
+Delayed	O
+recognition	O
+and	O
+treatment	O
+of	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+contribute	O
+to	O
+poor	O
+patient	O
+outcomes	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+describe	O
+and	O
+increase	O
+awareness	O
+of	O
+a	O
+clinical	O
+scenario	O
+in	O
+which	O
+the	O
+onset	O
+or	O
+manifestations	O
+of	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+are	O
+delayed	O
+.	O
+
+DESIGN	O
+:	O
+Retrospective	O
+case	O
+series	O
+.	O
+
+SETTING	O
+:	O
+Three	O
+large	O
+urban	O
+hospitals	O
+(	O
+with	O
+active	O
+cardiovascular	O
+surgery	O
+programs	O
+)	O
+.	O
+
+PATIENTS	O
+:	O
+14	O
+patients	O
+seen	O
+over	O
+a	O
+3	O
+-	O
+year	O
+period	O
+in	O
+whom	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+became	O
+apparent	O
+on	O
+delayed	O
+presentation	O
+with	O
+thromboembolic	B
+complications	O
+.	O
+
+MEASUREMENTS	O
+:	O
+Platelet	O
+counts	O
+,	O
+onset	O
+of	O
+objectively	O
+determined	O
+thromboembolism	B
+,	O
+results	O
+of	O
+heparin	O
+-	O
+induced	O
+platelet	O
+factor	O
+4	O
+antibody	O
+tests	O
+,	O
+and	O
+outcomes	O
+.	O
+
+RESULTS	O
+:	O
+Patients	O
+went	O
+home	O
+after	O
+hospitalizations	O
+that	O
+had	O
+included	O
+heparin	O
+exposure	O
+-	O
+-	O
+in	O
+most	O
+cases	O
+,	O
+with	O
+no	O
+thrombocytopenia	B
+recognized	O
+-	O
+-	O
+only	O
+to	O
+return	O
+to	O
+the	O
+hospital	O
+(	O
+median	O
+,	O
+day	O
+14	O
+)	O
+with	O
+thromboembolic	B
+complications	O
+.	O
+
+Thromboemboli	B
+were	O
+venous	O
+(	O
+12	O
+patients	O
+,	O
+7	O
+with	O
+pulmonary	B
+emboli	I
+)	O
+or	O
+arterial	O
+(	O
+4	O
+patients	O
+)	O
+or	O
+both	O
+.	O
+
+Platelet	O
+counts	O
+were	O
+mildly	O
+decreased	O
+in	O
+all	O
+but	O
+2	O
+patients	O
+on	O
+second	O
+presentation	O
+.	O
+
+On	O
+readmission	O
+,	O
+11	O
+patients	O
+received	O
+therapeutic	O
+heparin	O
+,	O
+which	O
+worsened	O
+the	O
+patients	O
+'	O
+clinical	O
+condition	O
+and	O
+,	O
+in	O
+all	O
+11	O
+cases	O
+,	O
+decreased	O
+the	O
+platelet	O
+count	O
+(	O
+mean	O
+at	O
+readmission	O
+,	O
+143	O
+x	O
+10	O
+(	O
+9	O
+)	O
+cells	O
+/	O
+L	O
+;	O
+mean	O
+nadir	O
+after	O
+heparin	O
+re	O
+-	O
+exposure	O
+,	O
+39	O
+x	O
+10	O
+(	O
+9	O
+)	O
+cells	O
+/	O
+L	O
+)	O
+.	O
+
+Results	O
+of	O
+serologic	O
+tests	O
+for	O
+heparin	O
+-	O
+induced	O
+antibodies	O
+were	O
+positive	O
+in	O
+all	O
+patients	O
+.	O
+
+Subsequent	O
+treatments	O
+included	O
+alternative	O
+anticoagulants	O
+(	O
+11	O
+patients	O
+)	O
+,	O
+thrombolytic	O
+drugs	O
+(	O
+3	O
+patients	O
+)	O
+,	O
+inferior	O
+vena	O
+cava	O
+filters	O
+(	O
+3	O
+patients	O
+)	O
+and	O
+,	O
+eventually	O
+,	O
+warfarin	O
+(	O
+11	O
+patients	O
+)	O
+.	O
+
+Three	O
+patients	O
+died	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Delayed	O
+-	O
+onset	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+is	O
+increasingly	O
+being	O
+recognized	O
+.	O
+
+To	O
+avoid	O
+disastrous	O
+outcomes	O
+,	O
+physicians	O
+must	O
+consider	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+whenever	O
+a	O
+recently	O
+hospitalized	O
+patient	O
+returns	O
+with	O
+thromboembolism	B
+;	O
+therapy	O
+with	O
+alternative	O
+anticoagulants	O
+,	O
+not	O
+heparin	O
+,	O
+should	O
+be	O
+initiated	O
+.	O
+
+Treatment	O
+of	O
+risperidone	O
+-	O
+induced	O
+hyperprolactinemia	B
+with	O
+a	O
+dopamine	O
+agonist	O
+in	O
+children	O
+.	O
+
+BACKGROUND	O
+:	O
+Risperidone	O
+,	O
+a	O
+potent	O
+antagonist	O
+of	O
+both	O
+serotonergic	O
+(	O
+5HT2A	O
+)	O
+and	O
+dopaminergic	O
+D2	O
+receptors	O
+is	O
+associated	O
+with	O
+hyperprolactinemia	B
+in	O
+adults	O
+and	O
+children	O
+.	O
+
+Chronically	O
+elevated	O
+prolactin	O
+levels	O
+in	O
+children	O
+with	O
+prolactinomas	B
+may	O
+be	O
+associated	O
+with	O
+arrested	O
+growth	O
+and	O
+development	O
+resulting	O
+in	O
+either	O
+delayed	B
+puberty	I
+or	O
+short	O
+stature	O
+.	O
+
+These	O
+possibilities	O
+stress	O
+the	O
+importance	O
+of	O
+developing	O
+a	O
+safe	O
+and	O
+effective	O
+approach	O
+to	O
+drug	O
+-	O
+induced	O
+hyperprolactinemia	B
+in	O
+youth	O
+.	O
+
+We	O
+report	O
+the	O
+successful	O
+treatment	O
+of	O
+risperidone	O
+-	O
+induced	O
+hyperprolactinemia	B
+with	O
+cabergoline	O
+in	O
+youth	O
+.	O
+
+METHODS	O
+:	O
+We	O
+undertook	O
+a	O
+retrospective	O
+case	O
+review	O
+of	O
+four	O
+children	O
+with	O
+risperidone	O
+-	O
+induced	O
+hyperprolactinemia	B
+treated	O
+with	O
+cabergoline	O
+.	O
+
+RESULTS	O
+:	O
+Four	O
+males	O
+(	O
+age	O
+6	O
+-	O
+11	O
+years	O
+)	O
+with	O
+Diagnostic	O
+and	O
+Statistical	O
+Manual	O
+of	O
+Mental	B
+Disorders	I
+(	O
+fourth	O
+edition	O
+)	O
+bipolar	B
+disorder	I
+or	O
+psychoses	B
+,	O
+with	O
+risperidone	O
+-	O
+induced	O
+elevations	O
+in	O
+serum	O
+prolactin	O
+levels	O
+(	O
+57	O
+.	O
+5	O
+-	O
+129	O
+ng	O
+/	O
+mL	O
+,	O
+normal	O
+5	O
+-	O
+15	O
+ng	O
+/	O
+mL	O
+)	O
+,	O
+were	O
+treated	O
+with	O
+cabergoline	O
+(	O
+mean	O
+dose	O
+2	O
+.	O
+13	O
++	O
+/	O
+-	O
+0	O
+.	O
+09	O
+mg	O
+/	O
+week	O
+)	O
+.	O
+
+When	O
+serum	O
+prolactin	O
+levels	O
+normalized	O
+in	O
+all	O
+four	O
+subjects	O
+(	O
+mean	O
+11	O
+.	O
+2	O
++	O
+/	O
+-	O
+10	O
+.	O
+9	O
+ng	O
+/	O
+mL	O
+)	O
+,	O
+the	O
+cabergoline	O
+dose	O
+was	O
+reduced	O
+to	O
+1	O
+mg	O
+/	O
+week	O
+in	O
+three	O
+of	O
+four	O
+subjects	O
+.	O
+
+The	O
+mean	O
+duration	O
+of	O
+therapy	O
+with	O
+cabergoline	O
+was	O
+523	O
+.	O
+5	O
++	O
+/	O
+-	O
+129	O
+.	O
+7	O
+days	O
+,	O
+and	O
+the	O
+mean	O
+duration	O
+of	O
+therapy	O
+with	O
+risperidone	O
+was	O
+788	O
+.	O
+5	O
++	O
+/	O
+-	O
+162	O
+.	O
+5	O
+days	O
+.	O
+
+Cabergoline	O
+was	O
+well	O
+tolerated	O
+without	O
+adverse	O
+effects	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Cabergoline	O
+may	O
+be	O
+useful	O
+for	O
+the	O
+treatment	O
+of	O
+risperidone	O
+-	O
+induced	O
+hyperprolactinemia	B
+in	O
+youth	O
+;	O
+however	O
+,	O
+further	O
+research	O
+is	O
+needed	O
+.	O
+
+Acute	O
+cholestatic	B
+hepatitis	I
+after	O
+exposure	O
+to	O
+isoflurane	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+acute	O
+cholestatic	B
+hepatitis	I
+following	O
+exposure	O
+to	O
+the	O
+inhalational	O
+anesthetic	O
+isoflurane	O
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+70	O
+-	O
+year	O
+-	O
+old	O
+healthy	O
+woman	O
+from	O
+Iraq	O
+developed	O
+acute	O
+cholestatic	B
+hepatitis	I
+3	O
+weeks	O
+following	O
+repair	O
+of	O
+the	O
+right	O
+rotator	O
+cuff	O
+under	O
+general	O
+anesthesia	O
+.	O
+
+There	O
+was	O
+no	O
+evidence	O
+for	O
+viral	O
+,	O
+autoimmune	O
+,	O
+or	O
+metabolic	O
+causes	O
+of	O
+hepatitis	B
+.	O
+
+No	O
+other	O
+medications	O
+were	O
+involved	O
+except	O
+for	O
+dipyrone	O
+for	O
+analgesia	B
+.	O
+
+The	O
+alanine	O
+aminotransferase	O
+was	O
+elevated	O
+to	O
+a	O
+peak	O
+concentration	O
+of	O
+1533	O
+U	O
+/	O
+L	O
+and	O
+the	O
+serum	O
+bilirubin	O
+reached	O
+a	O
+peak	O
+of	O
+17	O
+.	O
+0	O
+mg	O
+/	O
+dL	O
+.	O
+
+There	O
+was	O
+slow	O
+improvement	O
+over	O
+4	O
+months	O
+.	O
+
+Accidental	O
+reexposure	O
+by	O
+the	O
+patient	O
+to	O
+dipyrone	O
+was	O
+uneventful	O
+.	O
+
+DISCUSSION	O
+:	O
+The	O
+clinical	O
+and	O
+histologic	O
+picture	O
+of	O
+this	O
+case	O
+resembles	O
+halothane	B
+hepatitis	I
+,	O
+which	O
+has	O
+a	O
+significant	O
+mortality	O
+rate	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Isoflurane	O
+,	O
+a	O
+common	O
+anesthetic	O
+agent	O
+,	O
+can	O
+cause	O
+severe	O
+cholestatic	B
+hepatitis	I
+.	O
+
+Torsade	B
+de	I
+pointes	I
+induced	O
+by	O
+metoclopramide	O
+in	O
+an	O
+elderly	O
+woman	O
+with	O
+preexisting	O
+complete	O
+left	B
+bundle	I
+branch	I
+block	I
+.	O
+
+There	O
+is	O
+a	O
+growing	O
+list	O
+of	O
+drugs	O
+implicated	O
+in	O
+acquired	O
+long	B
+QT	I
+syndrome	I
+and	O
+torsade	B
+de	I
+pointes	I
+.	O
+
+However	O
+,	O
+the	O
+torsadogenic	O
+potential	O
+of	O
+metoclopramide	O
+,	O
+a	O
+commonly	O
+used	O
+antiemetic	O
+and	O
+prokinetic	O
+drug	O
+,	O
+has	O
+not	O
+been	O
+reported	O
+in	O
+the	O
+literature	O
+,	O
+despite	O
+its	O
+chemical	O
+similarity	O
+to	O
+procainamide	O
+.	O
+
+We	O
+report	O
+on	O
+a	O
+92	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+preexisting	O
+complete	O
+left	B
+bundle	I
+branch	I
+block	I
+who	O
+developed	O
+torsade	B
+de	I
+pointes	I
+after	O
+intravenous	O
+and	O
+oral	O
+administration	O
+of	O
+metoclopramide	O
+.	O
+
+This	O
+patient	O
+also	O
+developed	O
+torsade	B
+de	I
+pointes	I
+when	O
+cisapride	O
+and	O
+erythromycin	O
+were	O
+given	O
+simultaneously	O
+.	O
+
+These	O
+two	O
+episodes	O
+were	O
+suppressed	O
+successfully	O
+after	O
+discontinuing	O
+the	O
+offending	O
+drugs	O
+and	O
+administering	O
+class	O
+IB	O
+drugs	O
+.	O
+
+This	O
+is	O
+the	O
+first	O
+documentation	O
+that	O
+metoclopramide	O
+provokes	O
+torsade	B
+de	I
+pointes	I
+clinically	O
+.	O
+
+Metoclopramide	O
+should	O
+be	O
+used	O
+cautiously	O
+in	O
+patients	O
+with	O
+a	O
+risk	O
+of	O
+torsade	B
+de	I
+pointes	I
+.	O
+
+Dopamine	O
+D2	O
+receptor	O
+signaling	O
+controls	O
+neuronal	O
+cell	O
+death	O
+induced	O
+by	O
+muscarinic	O
+and	O
+glutamatergic	O
+drugs	O
+.	O
+
+Dopamine	O
+(	O
+DA	O
+)	O
+,	O
+through	O
+D1	O
+/	O
+D2	O
+receptor	O
+-	O
+mediated	O
+signaling	O
+,	O
+plays	O
+a	O
+major	O
+role	O
+in	O
+the	O
+control	O
+of	O
+epileptic	B
+seizures	I
+arising	O
+in	O
+the	O
+limbic	O
+system	O
+.	O
+
+Excitotoxicity	B
+leading	O
+to	O
+neuronal	O
+cell	O
+death	O
+in	O
+the	O
+affected	O
+areas	O
+is	O
+a	O
+major	O
+consequence	O
+of	O
+seizures	B
+at	O
+the	O
+cellular	O
+level	O
+.	O
+
+In	O
+this	O
+respect	O
+,	O
+little	O
+is	O
+known	O
+about	O
+the	O
+role	O
+of	O
+DA	O
+receptors	O
+in	O
+the	O
+occurrence	O
+of	O
+epilepsy	B
+-	O
+induced	O
+neuronal	O
+cell	O
+death	O
+.	O
+
+Here	O
+we	O
+analyze	O
+the	O
+occurrence	O
+of	O
+seizures	B
+and	O
+neurotoxicity	B
+in	O
+D2R	O
+-	O
+/	O
+-	O
+mice	O
+treated	O
+with	O
+the	O
+cholinergic	O
+agonist	O
+pilocarpine	O
+.	O
+
+We	O
+compared	O
+these	O
+results	O
+with	O
+those	O
+previously	O
+obtained	O
+with	O
+kainic	O
+acid	O
+(	O
+KA	O
+)	O
+,	O
+a	O
+potent	O
+glutamate	O
+agonist	O
+.	O
+
+Importantly	O
+,	O
+D2R	O
+-	O
+/	O
+-	O
+mice	O
+develop	O
+seizures	B
+at	O
+doses	O
+of	O
+both	O
+drugs	O
+that	O
+are	O
+not	O
+epileptogenic	O
+for	O
+WT	O
+littermates	O
+and	O
+show	O
+greater	O
+neurotoxicity	B
+.	O
+
+However	O
+,	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+result	O
+in	O
+a	O
+more	O
+widespread	O
+neuronal	O
+death	O
+in	O
+both	O
+WT	O
+and	O
+D2R	O
+-	O
+/	O
+-	O
+brains	O
+in	O
+comparison	O
+to	O
+KA	O
+.	O
+
+Thus	O
+,	O
+the	O
+absence	O
+of	O
+D2R	O
+lowers	O
+the	O
+threshold	O
+for	O
+seizures	B
+induced	O
+by	O
+both	O
+glutamate	O
+and	O
+acetylcholine	O
+.	O
+
+Moreover	O
+,	O
+the	O
+dopaminergic	O
+control	O
+of	O
+epilepsy	B
+-	O
+induced	O
+neurodegeneration	B
+seems	O
+to	O
+be	O
+mediated	O
+by	O
+distinct	O
+interactions	O
+of	O
+D2R	O
+signaling	O
+with	O
+these	O
+two	O
+neurotransmitters	O
+.	O
+
+Steroid	O
+structure	O
+and	O
+pharmacological	O
+properties	O
+determine	O
+the	O
+anti	O
+-	O
+amnesic	B
+effects	O
+of	O
+pregnenolone	O
+sulphate	O
+in	O
+the	O
+passive	O
+avoidance	O
+task	O
+in	O
+rats	O
+.	O
+
+Pregnenolone	O
+sulphate	O
+(	O
+PREGS	O
+)	O
+has	O
+generated	O
+interest	O
+as	O
+one	O
+of	O
+the	O
+most	O
+potent	O
+memory	O
+-	O
+enhancing	O
+neurosteroids	O
+to	O
+be	O
+examined	O
+in	O
+rodent	O
+learning	O
+studies	O
+,	O
+with	O
+particular	O
+importance	O
+in	O
+the	O
+ageing	O
+process	O
+.	O
+
+The	O
+mechanism	O
+by	O
+which	O
+this	O
+endogenous	O
+steroid	O
+enhances	O
+memory	O
+formation	O
+is	O
+hypothesized	O
+to	O
+involve	O
+actions	O
+on	O
+glutamatergic	O
+and	O
+GABAergic	O
+systems	O
+.	O
+
+This	O
+hypothesis	O
+stems	O
+from	O
+findings	O
+that	O
+PREGS	O
+is	O
+a	O
+potent	O
+positive	O
+modulator	O
+of	O
+N	O
+-	O
+methyl	O
+-	O
+d	O
+-	O
+aspartate	O
+receptors	O
+(	O
+NMDARs	O
+)	O
+and	O
+a	O
+negative	O
+modulator	O
+of	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+(	O
+A	O
+)	O
+receptors	O
+(	O
+GABA	O
+(	O
+A	O
+)	O
+Rs	O
+)	O
+.	O
+
+Moreover	O
+,	O
+PREGS	O
+is	O
+able	O
+to	O
+reverse	O
+the	O
+amnesic	B
+-	O
+like	O
+effects	O
+of	O
+NMDAR	O
+and	O
+GABA	O
+(	O
+A	O
+)	O
+R	O
+ligands	O
+.	O
+
+To	O
+investigate	O
+this	O
+hypothesis	O
+,	O
+the	O
+present	O
+study	O
+in	O
+rats	O
+examined	O
+the	O
+memory	O
+-	O
+altering	O
+abilities	O
+of	O
+structural	O
+analogs	O
+of	O
+PREGS	O
+,	O
+which	O
+differ	O
+in	O
+their	O
+modulation	O
+of	O
+NMDAR	O
+and	O
+/	O
+or	O
+GABA	O
+(	O
+A	O
+)	O
+R	O
+function	O
+.	O
+
+The	O
+analogs	O
+tested	O
+were	O
+:	O
+11	O
+-	O
+ketopregnenolone	O
+sulphate	O
+(	O
+an	O
+agent	O
+that	O
+is	O
+inactive	O
+at	O
+GABA	O
+(	O
+A	O
+)	O
+Rs	O
+and	O
+NMDARs	O
+)	O
+,	O
+epipregnanolone	O
+(	O
+[	O
+3beta	O
+-	O
+hydroxy	O
+-	O
+5beta	O
+-	O
+pregnan	O
+-	O
+20	O
+-	O
+one	O
+]	O
+sulphate	O
+,	O
+an	O
+inhibitor	O
+of	O
+both	O
+GABA	O
+(	O
+A	O
+)	O
+Rs	O
+and	O
+NMDARs	O
+)	O
+,	O
+and	O
+a	O
+newly	O
+synthesized	O
+(	O
+-	O
+)	O
+PREGS	O
+enantiomer	O
+(	O
+which	O
+is	O
+identical	O
+to	O
+PREGS	O
+in	O
+effects	O
+on	O
+GABA	O
+(	O
+A	O
+)	O
+Rs	O
+and	O
+NMDARs	O
+)	O
+.	O
+
+The	O
+memory	O
+-	O
+enhancing	O
+effects	O
+of	O
+PREGS	O
+and	O
+its	O
+analogs	O
+were	O
+tested	O
+in	O
+the	O
+passive	O
+avoidance	O
+task	O
+using	O
+the	O
+model	O
+of	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+.	O
+
+Both	O
+PREGS	O
+and	O
+its	O
+(	O
+-	O
+)	O
+enantiomer	O
+blocked	O
+the	O
+effects	O
+of	O
+scopolamine	O
+.	O
+
+The	O
+results	O
+show	O
+that	O
+,	O
+unlike	O
+PREGS	O
+,	O
+11	O
+-	O
+ketopregnenolone	O
+sulphate	O
+and	O
+epipregnanolone	O
+sulphate	O
+failed	O
+to	O
+block	O
+the	O
+effect	O
+of	O
+scopolamine	O
+,	O
+suggesting	O
+that	O
+altering	O
+the	O
+modulation	O
+of	O
+NMDA	O
+receptors	O
+diminishes	O
+the	O
+memory	O
+-	O
+enhancing	O
+effects	O
+of	O
+PREGS	O
+.	O
+
+Moreover	O
+,	O
+enantioselectivity	O
+was	O
+demonstrated	O
+by	O
+the	O
+ability	O
+of	O
+natural	O
+PREGS	O
+to	O
+be	O
+an	O
+order	O
+of	O
+magnitude	O
+more	O
+effective	O
+than	O
+its	O
+synthetic	O
+enantiomer	O
+in	O
+reversing	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+.	O
+
+These	O
+results	O
+identify	O
+a	O
+novel	O
+neuropharmacological	O
+site	O
+for	O
+the	O
+modulation	O
+of	O
+memory	O
+processes	O
+by	O
+neuroactive	O
+steroids	O
+.	O
+
+Activation	O
+of	O
+poly	O
+(	O
+ADP	O
+-	O
+ribose	O
+)	O
+polymerase	O
+contributes	O
+to	O
+development	O
+of	O
+doxorubicin	O
+-	O
+induced	O
+heart	B
+failure	I
+.	O
+
+Activation	O
+of	O
+the	O
+nuclear	O
+enzyme	O
+poly	O
+(	O
+ADP	O
+-	O
+ribose	O
+)	O
+polymerase	O
+(	O
+PARP	O
+)	O
+by	O
+oxidant	O
+-	O
+mediated	O
+DNA	O
+damage	O
+is	O
+an	O
+important	O
+pathway	O
+of	O
+cell	O
+dysfunction	O
+and	O
+tissue	O
+injury	O
+in	O
+conditions	O
+associated	O
+with	O
+oxidative	O
+stress	O
+.	O
+
+Increased	O
+oxidative	O
+stress	O
+is	O
+a	O
+major	O
+factor	O
+implicated	O
+in	O
+the	O
+cardiotoxicity	B
+of	O
+doxorubicin	O
+(	O
+DOX	O
+)	O
+,	O
+a	O
+widely	O
+used	O
+antitumor	O
+anthracycline	O
+antibiotic	O
+.	O
+
+Thus	O
+,	O
+we	O
+hypothesized	O
+that	O
+the	O
+activation	O
+of	O
+PARP	O
+may	O
+contribute	O
+to	O
+the	O
+DOX	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+Using	O
+a	O
+dual	O
+approach	O
+of	O
+PARP	O
+-	O
+1	O
+suppression	O
+,	O
+by	O
+genetic	O
+deletion	O
+or	O
+pharmacological	O
+inhibition	O
+with	O
+the	O
+phenanthridinone	O
+PARP	O
+inhibitor	O
+PJ34	O
+,	O
+we	O
+now	O
+demonstrate	O
+the	O
+role	O
+of	O
+PARP	O
+in	O
+the	O
+development	O
+of	O
+cardiac	B
+dysfunction	I
+induced	O
+by	O
+DOX	O
+.	O
+
+PARP	O
+-	O
+1	O
++	O
+/	O
++	O
+and	O
+PARP	O
+-	O
+1	O
+-	O
+/	O
+-	O
+mice	O
+received	O
+a	O
+single	O
+injection	O
+of	O
+DOX	O
+(	O
+25	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+)	O
+.	O
+
+Five	O
+days	O
+after	O
+DOX	O
+administration	O
+,	O
+left	O
+ventricular	O
+performance	O
+was	O
+significantly	O
+depressed	O
+in	O
+PARP	O
+-	O
+1	O
++	O
+/	O
++	O
+mice	O
+,	O
+but	O
+only	O
+to	O
+a	O
+smaller	O
+extent	O
+in	O
+PARP	O
+-	O
+1	O
+-	O
+/	O
+-	O
+ones	O
+.	O
+
+Similar	O
+experiments	O
+were	O
+conducted	O
+in	O
+BALB	O
+/	O
+c	O
+mice	O
+treated	O
+with	O
+PJ34	O
+or	O
+vehicle	O
+.	O
+
+Treatment	O
+with	O
+a	O
+PJ34	O
+significantly	O
+improved	O
+cardiac	B
+dysfunction	I
+and	O
+increased	O
+the	O
+survival	O
+of	O
+the	O
+animals	O
+.	O
+
+In	O
+addition	O
+PJ34	O
+significantly	O
+reduced	O
+the	O
+DOX	O
+-	O
+induced	O
+increase	O
+in	O
+the	O
+serum	O
+lactate	O
+dehydrogenase	O
+and	O
+creatine	O
+kinase	O
+activities	O
+but	O
+not	O
+metalloproteinase	O
+activation	O
+in	O
+the	O
+heart	O
+.	O
+
+Thus	O
+,	O
+PARP	O
+activation	O
+contributes	O
+to	O
+the	O
+cardiotoxicity	B
+of	O
+DOX	O
+.	O
+
+PARP	O
+inhibitors	O
+may	O
+exert	O
+protective	O
+effects	O
+against	O
+the	O
+development	O
+of	O
+severe	O
+cardiac	B
+complications	I
+associated	O
+with	O
+the	O
+DOX	O
+treatment	O
+.	O
+
+Spironolactone	O
+:	O
+is	O
+it	O
+a	O
+novel	O
+drug	O
+for	O
+the	O
+prevention	O
+of	O
+amphotericin	O
+B	O
+-	O
+related	O
+hypokalemia	B
+in	O
+cancer	B
+patients	O
+?	O
+
+OBJECTIVE	O
+:	O
+Nephrotoxicity	B
+is	O
+the	O
+major	O
+adverse	O
+effect	O
+of	O
+amphotericin	O
+B	O
+(	O
+AmB	O
+)	O
+,	O
+often	O
+limiting	O
+administration	O
+of	O
+full	O
+dosage	O
+.	O
+
+Selective	O
+distal	O
+tubular	O
+epithelial	O
+toxicity	B
+seems	O
+to	O
+be	O
+responsible	O
+for	O
+the	O
+profound	O
+potassium	O
+wasting	O
+that	O
+is	O
+a	O
+major	O
+clinical	O
+side	O
+effect	O
+of	O
+treatment	O
+with	O
+AmB	O
+.	O
+
+Potassium	O
+depletion	O
+also	O
+potentiates	O
+the	O
+tubular	O
+toxicity	B
+of	O
+AmB	O
+.	O
+
+This	O
+study	O
+was	O
+designed	O
+to	O
+assess	O
+the	O
+ability	O
+of	O
+spironolactone	O
+to	O
+reduce	O
+potassium	O
+requirements	O
+and	O
+to	O
+prevent	O
+hypokalemia	B
+in	O
+neutropenic	B
+patients	O
+on	O
+AmB	O
+treatment	O
+.	O
+
+METHODS	O
+:	O
+In	O
+this	O
+study	O
+26	O
+patients	O
+with	O
+various	O
+hematological	B
+disorders	I
+were	O
+randomized	O
+to	O
+receive	O
+either	O
+intravenous	O
+AmB	O
+alone	O
+or	O
+AmB	O
+and	O
+oral	O
+spironolactone	O
+100	O
+mg	O
+twice	O
+daily	O
+when	O
+developing	O
+a	O
+proven	O
+or	O
+suspected	O
+fungal	B
+infection	I
+.	O
+
+RESULTS	O
+:	O
+Patients	O
+receiving	O
+concomitant	O
+AmB	O
+and	O
+spironolactone	O
+had	O
+significantly	O
+higher	O
+plasma	O
+potassium	O
+levels	O
+than	O
+those	O
+receiving	O
+AmB	O
+alone	O
+(	O
+P	O
+=	O
+0	O
+.	O
+0027	O
+)	O
+.	O
+
+Those	O
+patients	O
+receiving	O
+AmB	O
+and	O
+spironolactone	O
+required	O
+significantly	O
+less	O
+potassium	O
+supplementation	O
+to	O
+maintain	O
+their	O
+plasma	O
+potassium	O
+within	O
+the	O
+normal	O
+range	O
+(	O
+P	O
+=	O
+0	O
+.	O
+022	O
+)	O
+.	O
+
+Moreover	O
+,	O
+urinary	O
+potassium	O
+losses	O
+were	O
+significantly	O
+less	O
+in	O
+patients	O
+receiving	O
+AmB	O
+and	O
+spironolactone	O
+than	O
+those	O
+receiving	O
+AmB	O
+alone	O
+(	O
+P	O
+=	O
+0	O
+.	O
+040	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+study	O
+showed	O
+that	O
+spironolactone	O
+can	O
+reduce	O
+potassium	O
+requirements	O
+and	O
+prevent	O
+hypokalemia	B
+by	O
+reducing	O
+urinary	O
+potassium	O
+loss	O
+in	O
+neutropenic	B
+patients	O
+on	O
+AmB	O
+treatment	O
+.	O
+
+Erectile	B
+dysfunction	I
+occurs	O
+following	O
+substantia	O
+nigra	O
+lesions	O
+in	O
+the	O
+rat	O
+.	O
+
+Erectile	O
+function	O
+was	O
+assessed	O
+6	O
+weeks	O
+following	O
+uni	O
+-	O
+and	O
+bilateral	O
+injections	O
+of	O
+6	O
+-	O
+hydroxydopamine	O
+in	O
+the	O
+substantia	O
+nigra	O
+nucleus	O
+of	O
+the	O
+brain	O
+.	O
+
+Behavioral	O
+apomorphine	O
+-	O
+induced	O
+penile	O
+erections	O
+were	O
+reduced	O
+(	O
+5	O
+/	O
+8	O
+)	O
+and	O
+increased	O
+(	O
+3	O
+/	O
+8	O
+)	O
+in	O
+uni	O
+-	O
+and	O
+bilateral	O
+lesioned	O
+animals	O
+.	O
+
+Intracavernous	O
+pressures	O
+,	O
+following	O
+electrical	O
+stimulation	O
+of	O
+the	O
+cavernous	O
+nerve	O
+,	O
+decreased	O
+in	O
+lesioned	O
+animals	O
+.	O
+
+Lesions	O
+of	O
+the	O
+substantia	O
+nigra	O
+were	O
+confirmed	O
+by	O
+histology	O
+.	O
+
+Concentration	O
+of	O
+dopamine	O
+and	O
+its	O
+metabolites	O
+were	O
+decreased	O
+in	O
+the	O
+striatum	O
+of	O
+substantia	O
+nigra	O
+lesioned	O
+rats	O
+.	O
+
+Lesions	O
+of	O
+the	O
+substantia	O
+nigra	O
+are	O
+therefore	O
+associated	O
+with	O
+erectile	B
+dysfunction	I
+in	O
+rats	O
+and	O
+may	O
+serve	O
+as	O
+a	O
+model	O
+to	O
+study	O
+erectile	B
+dysfunction	I
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+Nicotine	O
+potentiation	O
+of	O
+morphine	O
+-	O
+induced	O
+catalepsy	B
+in	O
+mice	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+effects	O
+of	O
+nicotine	O
+on	O
+catalepsy	B
+induced	O
+by	O
+morphine	O
+in	O
+mice	O
+have	O
+been	O
+investigated	O
+.	O
+
+Morphine	O
+but	O
+not	O
+nicotine	O
+induced	O
+a	O
+dose	O
+-	O
+dependent	O
+catalepsy	B
+.	O
+
+The	O
+response	O
+of	O
+morphine	O
+was	O
+potentiated	O
+by	O
+nicotine	O
+.	O
+
+Intraperitoneal	O
+administration	O
+of	O
+atropine	O
+,	O
+naloxone	O
+,	O
+mecamylamine	O
+,	O
+and	O
+hexamethonium	O
+to	O
+mice	O
+reduced	O
+catalepsy	B
+induced	O
+by	O
+a	O
+combination	O
+of	O
+morphine	O
+with	O
+nicotine	O
+.	O
+
+Intracerebroventricular	O
+injection	O
+of	O
+atropine	O
+,	O
+hexamethonium	O
+,	O
+and	O
+naloxone	O
+also	O
+decreased	O
+catalepsy	B
+induced	O
+by	O
+morphine	O
+plus	O
+nicotine	O
+.	O
+
+Intraperitoneal	O
+administration	O
+of	O
+atropine	O
+,	O
+but	O
+not	O
+intraperitoneal	O
+or	O
+intracerebroventricular	O
+injection	O
+of	O
+hexamethonium	O
+,	O
+decreased	O
+the	O
+effect	O
+of	O
+a	O
+single	O
+dose	O
+of	O
+morphine	O
+.	O
+
+It	O
+was	O
+concluded	O
+that	O
+morphine	O
+catalepsy	B
+can	O
+be	O
+elicited	O
+by	O
+opioid	O
+and	O
+cholinergic	O
+receptors	O
+,	O
+and	O
+the	O
+potentiation	O
+of	O
+morphine	O
+induced	O
+by	O
+nicotine	O
+may	O
+also	O
+be	O
+mediated	O
+through	O
+cholinergic	O
+receptor	O
+mechanisms	O
+.	O
+
+Force	O
+overflow	O
+and	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+We	O
+assessed	O
+force	O
+coordination	O
+of	O
+the	O
+hand	O
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+and	O
+its	O
+relationship	O
+to	O
+motor	O
+complications	O
+of	O
+levodopa	O
+therapy	O
+,	O
+particularly	O
+to	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+(	O
+LID	B
+)	O
+.	O
+
+We	O
+studied	O
+two	O
+groups	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+patients	O
+with	O
+(	O
+Parkinson	B
+'	I
+s	I
+disease	I
++	O
+LID	B
+,	O
+n	O
+=	O
+23	O
+)	O
+and	O
+without	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+(	O
+Parkinson	B
+'	I
+s	I
+disease	I
+-	O
+LID	B
+,	O
+n	O
+=	O
+10	O
+)	O
+,	O
+and	O
+age	O
+-	O
+matched	O
+healthy	O
+controls	O
+.	O
+
+The	O
+motor	O
+score	O
+of	O
+the	O
+Unified	O
+Parkinson	B
+'	I
+s	I
+Disease	I
+Rating	O
+Scale	O
+,	O
+a	O
+dyskinesia	B
+score	O
+and	O
+force	O
+in	O
+a	O
+grip	O
+-	O
+lift	O
+paradigm	O
+were	O
+assessed	O
+ON	O
+and	O
+OFF	O
+levodopa	O
+.	O
+
+A	O
+pathological	O
+increase	O
+of	O
+forces	O
+was	O
+seen	O
+in	O
+ON	O
+-	O
+state	O
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
++	O
+LID	B
+only	O
+.	O
+
+In	O
+Parkinson	B
+'	I
+s	I
+disease	I
++	O
+LID	B
+,	O
+the	O
+force	O
+involved	O
+in	O
+pressing	O
+down	O
+the	O
+object	O
+before	O
+lifting	O
+was	O
+significantly	O
+increased	O
+by	O
+levodopa	O
+(	O
+by	O
+61	O
+%	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+An	O
+overshooting	O
+of	O
+peak	O
+grip	O
+force	O
+by	O
+51	O
+%	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+and	O
+of	O
+static	O
+grip	O
+force	O
+by	O
+45	O
+%	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+was	O
+observed	O
+in	O
+the	O
+ON	O
+-	O
+compared	O
+with	O
+the	O
+OFF	O
+-	O
+drug	O
+condition	O
+.	O
+
+In	O
+contrast	O
+,	O
+no	O
+excessive	O
+force	O
+was	O
+found	O
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+-	O
+LID	B
+.	O
+
+Peak	O
+grip	O
+force	O
+in	O
+ON	O
+-	O
+state	O
+was	O
+140	O
+%	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+higher	O
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
++	O
+LID	B
+than	O
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+-	O
+LID	B
+,	O
+while	O
+static	O
+grip	O
+force	O
+was	O
+increased	O
+by	O
+138	O
+%	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+between	O
+groups	O
+.	O
+
+Severity	O
+of	O
+peak	O
+-	O
+dose	O
+dyskinesias	B
+was	O
+strongly	O
+correlated	O
+with	O
+grip	O
+force	O
+in	O
+ON	O
+-	O
+state	O
+(	O
+r	O
+=	O
+0	O
+.	O
+79	O
+with	O
+peak	O
+force	O
+,	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+No	O
+correlation	O
+was	O
+observed	O
+between	O
+forces	O
+and	O
+the	O
+motor	O
+score	O
+as	O
+well	O
+as	O
+with	O
+the	O
+daily	O
+dose	O
+of	O
+dopaminergic	O
+medication	O
+.	O
+
+Force	O
+excess	O
+was	O
+only	O
+observed	O
+in	O
+patients	O
+with	O
+LID	B
+and	O
+motor	O
+fluctuations	O
+.	O
+
+A	O
+close	O
+relationship	O
+was	O
+seen	O
+between	O
+the	O
+overshooting	O
+of	O
+forces	O
+and	O
+dyskinesias	B
+in	O
+the	O
+ON	O
+-	O
+drug	O
+condition	O
+.	O
+
+We	O
+postulate	O
+that	O
+both	O
+LID	B
+and	O
+grip	O
+force	O
+excess	O
+share	O
+common	O
+pathophysiological	O
+mechanisms	O
+related	O
+to	O
+motor	O
+fluctuations	O
+.	O
+
+Behavioral	O
+effects	O
+of	O
+MK	O
+-	O
+801	O
+on	O
+reserpine	O
+-	O
+treated	O
+mice	O
+.	O
+
+The	O
+effects	O
+of	O
+dizocilpine	O
+(	O
+MK	O
+-	O
+801	O
+)	O
+,	O
+a	O
+noncompetitive	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+receptor	O
+antagonist	O
+,	O
+were	O
+studied	O
+on	O
+dopamine	O
+-	O
+related	O
+behaviors	O
+induced	O
+by	O
+reserpine	O
+treatments	O
+.	O
+
+This	O
+study	O
+focuses	O
+on	O
+behavioral	O
+syndromes	O
+that	O
+may	O
+used	O
+as	O
+models	O
+for	O
+Parkinson	B
+'	I
+s	I
+disease	I
+,	O
+or	O
+tardive	B
+dyskinesia	I
+,	O
+and	O
+its	O
+response	O
+after	O
+glutamatergic	O
+blockage	O
+.	O
+
+Reserpine	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+administered	O
+once	O
+every	O
+other	O
+day	O
+for	O
+4	O
+days	O
+,	O
+produced	O
+increases	O
+in	O
+orofacial	B
+dyskinesia	I
+,	O
+tongue	O
+protrusion	O
+and	O
+vacuous	O
+chewing	O
+in	O
+mice	O
+,	O
+which	O
+are	O
+signs	O
+indicative	O
+of	O
+tardive	B
+dyskinesia	I
+.	O
+
+Reserpine	O
+also	O
+produced	O
+tremor	B
+and	O
+catalepsy	B
+,	O
+which	O
+are	O
+signs	O
+suggestive	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+MK	O
+-	O
+801	O
+(	O
+0	O
+.	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+administered	O
+30	O
+min	O
+before	O
+the	O
+observation	O
+test	O
+,	O
+prevented	O
+the	O
+vacuous	O
+chewing	O
+movements	O
+,	O
+tongue	O
+protrusions	O
+and	O
+catalepsy	B
+induced	O
+by	O
+reserpine	O
+.	O
+
+However	O
+,	O
+MK	O
+-	O
+801	O
+injection	O
+produced	O
+a	O
+significant	O
+increase	O
+of	O
+tremor	B
+in	O
+reserpine	O
+-	O
+treated	O
+mice	O
+.	O
+
+Reserpine	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+administered	O
+90	O
+min	O
+before	O
+the	O
+test	O
+and	O
+followed	O
+by	O
+apomophine	O
+injection	O
+(	O
+0	O
+.	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+5	O
+min	O
+before	O
+the	O
+test	O
+,	O
+did	O
+not	O
+produce	O
+oral	B
+dyskinesia	I
+in	O
+mice	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+reserpine	O
+induced	O
+increases	O
+in	O
+tremor	B
+and	O
+catalepsy	B
+compared	O
+to	O
+control	O
+mice	O
+.	O
+
+MK	O
+-	O
+801	O
+(	O
+0	O
+.	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+administration	O
+attenuated	O
+the	O
+catalepsy	B
+and	O
+tremor	B
+induced	O
+by	O
+reserpine	O
+.	O
+
+Pretreatment	O
+with	O
+reserpine	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+24	O
+h	O
+before	O
+the	O
+observation	O
+test	O
+produced	O
+increases	O
+in	O
+vacuous	O
+chewing	O
+movements	O
+and	O
+tongue	O
+protrusion	O
+,	O
+as	O
+well	O
+as	O
+increases	O
+in	O
+tremor	B
+and	O
+catalepsy	B
+,	O
+whereas	O
+MK	O
+-	O
+801	O
+(	O
+0	O
+.	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+injection	O
+90	O
+min	O
+before	O
+the	O
+test	O
+reversed	O
+the	O
+effects	O
+of	O
+reserpine	O
+.	O
+
+These	O
+results	O
+show	O
+that	O
+reserpine	O
+produces	O
+different	O
+and	O
+abnormal	B
+movements	I
+,	O
+which	O
+are	O
+related	O
+to	O
+dose	O
+and	O
+schedule	O
+employed	O
+and	O
+can	O
+be	O
+considered	O
+as	O
+parkinsonian	B
+-	O
+like	O
+and	O
+tardive	B
+dsykinesia	I
+signs	O
+.	O
+
+The	O
+glutamatergic	O
+blockage	O
+produced	O
+by	O
+NMDA	O
+can	O
+restore	O
+these	O
+signs	O
+,	O
+such	O
+as	O
+vacuous	O
+chewing	O
+movements	O
+,	O
+tongue	O
+protrusions	O
+,	O
+catalepsy	B
+and	O
+tremor	B
+according	O
+to	O
+the	O
+employed	O
+model	O
+.	O
+
+Risperidone	O
+-	O
+associated	O
+,	O
+benign	O
+transient	O
+visual	B
+disturbances	I
+in	O
+schizophrenic	B
+patients	O
+with	O
+a	O
+past	O
+history	O
+of	O
+LSD	O
+abuse	O
+.	O
+
+Two	O
+schizophrenic	B
+patients	O
+,	O
+who	O
+had	O
+a	O
+prior	O
+history	O
+of	O
+LSD	O
+abuse	O
+and	O
+who	O
+had	O
+previously	O
+developed	O
+EPS	B
+with	O
+classic	O
+antipsychotics	O
+,	O
+were	O
+successfully	O
+treated	O
+with	O
+risperidone	O
+.	O
+
+They	O
+both	O
+reported	O
+short	O
+episodes	O
+of	O
+transient	O
+visual	B
+disturbances	I
+,	O
+which	O
+appeared	O
+immediately	O
+after	O
+starting	O
+treatment	O
+with	O
+risperidone	O
+.	O
+
+This	O
+imagery	O
+resembled	O
+visual	B
+disturbances	I
+previously	O
+experienced	O
+as	O
+"	O
+flashbacks	O
+"	O
+related	O
+to	O
+prior	O
+LSD	O
+consumption	O
+.	O
+
+Risperidone	O
+administration	O
+was	O
+continued	O
+and	O
+the	O
+visual	B
+disturbances	I
+gradually	O
+wore	O
+off	O
+.	O
+
+During	O
+a	O
+six	O
+-	O
+month	O
+follow	O
+-	O
+up	O
+period	O
+,	O
+there	O
+was	O
+no	O
+recurrence	O
+of	O
+visual	B
+disturbances	I
+.	O
+
+This	O
+phenomenon	O
+may	O
+be	O
+interpreted	O
+as	O
+a	O
+benign	O
+,	O
+short	O
+-	O
+term	O
+and	O
+self	O
+-	O
+limiting	O
+side	O
+effect	O
+which	O
+does	O
+not	O
+contraindicate	O
+the	O
+use	O
+of	O
+risperidone	O
+or	O
+interfere	O
+with	O
+treatment	O
+.	O
+
+Conclusions	O
+based	O
+on	O
+two	O
+case	O
+reports	O
+should	O
+be	O
+taken	O
+with	O
+appropriate	O
+caution	O
+.	O
+
+Topiramate	O
+-	O
+induced	O
+nephrolithiasis	B
+.	O
+
+Topiramate	O
+is	O
+a	O
+recently	O
+developed	O
+antiepileptic	O
+medication	O
+that	O
+is	O
+becoming	O
+more	O
+widely	O
+prescribed	O
+because	O
+of	O
+its	O
+efficacy	O
+in	O
+treating	O
+refractory	B
+seizures	I
+.	O
+
+Urologists	O
+should	O
+be	O
+aware	O
+that	O
+this	O
+medication	O
+can	O
+cause	O
+metabolic	B
+acidosis	I
+in	O
+patients	O
+secondary	O
+to	O
+inhibition	O
+of	O
+carbonic	O
+anhydrase	O
+.	O
+
+In	O
+addition	O
+,	O
+a	O
+distal	O
+tubular	O
+acidification	O
+defect	O
+may	O
+result	O
+,	O
+thus	O
+impairing	O
+the	O
+normal	O
+compensatory	O
+drop	O
+in	O
+urine	O
+pH	O
+.	O
+
+These	O
+factors	O
+can	O
+lead	O
+to	O
+the	O
+development	O
+of	O
+calcium	O
+phosphate	O
+nephrolithiasis	B
+.	O
+
+We	O
+report	O
+the	O
+first	O
+two	O
+cases	O
+of	O
+topiramate	O
+-	O
+induced	O
+nephrolithiasis	B
+in	O
+the	O
+urologic	O
+literature	O
+.	O
+
+Ketamine	O
+in	O
+war	O
+/	O
+tropical	O
+surgery	O
+(	O
+a	O
+final	O
+tribute	O
+to	O
+the	O
+racemic	O
+mixture	O
+)	O
+.	O
+
+A	O
+technique	O
+of	O
+continuous	O
+intravenous	O
+anaesthesia	O
+with	O
+ketamine	O
+was	O
+used	O
+successfully	O
+during	O
+the	O
+Somalia	O
+civil	O
+war	O
+in	O
+1994	O
+and	O
+in	O
+north	O
+Uganda	O
+in	O
+1999	O
+for	O
+64	O
+operations	O
+in	O
+62	O
+patients	O
+,	O
+aged	O
+from	O
+6	O
+weeks	O
+to	O
+70	O
+years	O
+,	O
+undergoing	O
+limb	O
+and	O
+abdominal	O
+surgery	O
+including	O
+caesarian	O
+sections	O
+and	O
+interventions	O
+in	O
+neonates	O
+.	O
+
+Operations	O
+lasting	O
+up	O
+to	O
+2h	O
+could	O
+be	O
+performed	O
+in	O
+the	O
+absence	O
+of	O
+sophisticated	O
+equipment	O
+such	O
+as	O
+pulse	O
+oximeters	O
+or	O
+ventilators	O
+in	O
+patients	O
+on	O
+spontaneous	O
+ventilation	O
+breathing	O
+air	O
+/	O
+oxygen	O
+only	O
+.	O
+
+After	O
+premedication	O
+with	O
+diazepam	O
+,	O
+glycopyrrolate	O
+and	O
+local	O
+anaesthesia	O
+,	O
+and	O
+induction	O
+with	O
+standard	O
+doses	O
+of	O
+ketamine	O
+,	O
+a	O
+maintenance	O
+dose	O
+of	O
+10	O
+-	O
+20	O
+microg	O
+/	O
+kg	O
+/	O
+min	O
+of	O
+ketamine	O
+proved	O
+safe	O
+and	O
+effective	O
+.	O
+
+Emphasis	O
+was	O
+placed	O
+on	O
+bedside	O
+clinical	O
+monitoring	O
+,	O
+relying	O
+heavily	O
+on	O
+the	O
+heart	O
+rate	O
+.	O
+
+Diazepam	O
+,	O
+unless	O
+contraindicated	O
+or	O
+risky	O
+,	O
+remains	O
+the	O
+only	O
+necessary	O
+complementary	O
+drug	O
+to	O
+ketamine	O
+as	O
+it	O
+buffers	O
+its	O
+cardiovascular	O
+response	O
+and	O
+decreases	O
+the	O
+duration	O
+and	O
+intensity	O
+of	O
+operative	O
+and	O
+postoperative	O
+hallucinations	B
+.	O
+
+Local	O
+anaesthetic	O
+blocks	O
+were	O
+useful	O
+in	O
+decreasing	O
+the	O
+requirement	O
+for	O
+postoperative	O
+analgesia	B
+.	O
+
+An	O
+antisialogue	O
+was	O
+usually	O
+unnecessary	O
+in	O
+operations	O
+lasting	O
+up	O
+to	O
+2	O
+h	O
+,	O
+glycopyrrolate	O
+being	O
+the	O
+best	O
+choice	O
+for	O
+its	O
+lowest	O
+psychotropic	O
+and	O
+chronotropic	O
+effects	O
+,	O
+especially	O
+in	O
+a	O
+hot	O
+climate	O
+.	O
+
+Experience	O
+in	O
+war	O
+/	O
+tropical	O
+settings	O
+suggests	O
+this	O
+technique	O
+could	O
+be	O
+useful	O
+in	O
+civilian	O
+contexts	O
+such	O
+as	O
+outdoor	O
+life	O
+-	O
+saving	O
+emergency	O
+surgery	O
+or	O
+in	O
+mass	O
+casualties	O
+where	O
+,	O
+e	O
+.	O
+g	O
+.	O
+amputation	O
+and	O
+rapid	O
+extrication	O
+were	O
+required	O
+.	O
+
+Intravenous	O
+ribavirin	O
+treatment	O
+for	O
+severe	O
+adenovirus	B
+disease	I
+in	O
+immunocompromised	O
+children	O
+.	O
+
+BACKGROUND	O
+:	O
+Adenovirus	O
+is	O
+an	O
+important	O
+cause	O
+of	O
+morbidity	O
+and	O
+mortality	O
+in	O
+the	O
+immunocompromised	O
+host	O
+.	O
+
+The	O
+incidence	O
+of	O
+severe	O
+adenovirus	B
+disease	I
+in	O
+pediatrics	O
+is	O
+increasing	O
+in	O
+association	O
+with	O
+growing	O
+numbers	O
+of	O
+immunocompromised	O
+children	O
+,	O
+where	O
+case	O
+fatality	O
+rates	O
+as	O
+high	O
+as	O
+50	O
+%	O
+to	O
+80	O
+%	O
+have	O
+been	O
+reported	O
+.	O
+
+There	O
+are	O
+no	O
+approved	O
+antiviral	O
+agents	O
+with	O
+proven	O
+efficacy	O
+for	O
+the	O
+treatment	O
+of	O
+severe	O
+adenovirus	B
+disease	I
+,	O
+nor	O
+are	O
+there	O
+any	O
+prospective	O
+randomized	O
+,	O
+controlled	O
+trials	O
+of	O
+potentially	O
+useful	O
+anti	O
+-	O
+adenovirus	O
+therapies	O
+.	O
+
+Apparent	O
+clinical	O
+success	O
+in	O
+the	O
+treatment	O
+of	O
+severe	O
+adenovirus	B
+disease	I
+is	O
+limited	O
+to	O
+a	O
+few	O
+case	O
+reports	O
+and	O
+small	O
+series	O
+.	O
+
+Experience	O
+is	O
+greatest	O
+with	O
+intravenous	O
+ribavirin	O
+and	O
+cidofovir	O
+.	O
+
+Ribavirin	O
+,	O
+a	O
+guanosine	O
+analogue	O
+,	O
+has	O
+broad	O
+antiviral	O
+activity	O
+against	O
+both	O
+RNA	O
+and	O
+DNA	O
+viruses	O
+,	O
+including	O
+documented	O
+activity	O
+against	O
+adenovirus	O
+in	O
+vitro	O
+.	O
+
+Ribavirin	O
+is	O
+licensed	O
+in	O
+aerosol	O
+form	O
+for	O
+the	O
+treatment	O
+of	O
+respiratory	B
+syncytial	I
+virus	I
+infection	I
+,	O
+and	O
+orally	O
+in	O
+combination	O
+with	O
+interferon	O
+to	O
+treat	O
+hepatitis	B
+C	I
+.	O
+
+Intravenous	O
+ribavirin	O
+is	O
+the	O
+treatment	O
+of	O
+choice	O
+for	O
+infection	B
+with	I
+hemorrhagic	I
+fever	I
+viruses	I
+.	O
+
+The	O
+most	O
+common	O
+adverse	O
+effect	O
+of	O
+intravenous	O
+ribavirin	O
+is	O
+reversible	O
+mild	O
+anemia	B
+.	O
+
+The	O
+use	O
+of	O
+cidofovir	O
+in	O
+severe	O
+adenovirus	B
+infection	I
+has	O
+been	O
+limited	O
+by	O
+adverse	O
+effects	O
+,	O
+the	O
+most	O
+significant	O
+of	O
+which	O
+is	O
+nephrotoxicity	B
+.	O
+
+OBJECTIVE	O
+:	O
+We	O
+report	O
+our	O
+experience	O
+with	O
+intravenous	O
+ribavirin	O
+therapy	O
+for	O
+severe	O
+adenovirus	B
+disease	I
+in	O
+a	O
+series	O
+of	O
+immunocompromised	O
+children	O
+and	O
+review	O
+the	O
+literature	O
+.	O
+
+DESIGN	O
+/	O
+METHODS	O
+:	O
+We	O
+retrospectively	O
+reviewed	O
+the	O
+medical	O
+records	O
+of	O
+5	O
+children	O
+treated	O
+with	O
+intravenous	O
+ribavirin	O
+for	O
+documented	O
+severe	O
+adenovirus	B
+disease	I
+.	O
+
+Two	O
+patients	O
+developed	O
+adenovirus	O
+hemorrhagic	B
+cystitis	I
+after	O
+cardiac	O
+and	O
+bone	O
+marrow	O
+transplants	O
+,	O
+respectively	O
+.	O
+
+The	O
+bone	O
+marrow	O
+transplant	O
+patient	O
+also	O
+received	O
+intravenous	O
+cidofovir	O
+for	O
+progressive	O
+disseminated	O
+disease	O
+.	O
+
+An	O
+additional	O
+3	O
+children	O
+developed	O
+adenovirus	B
+pneumonia	I
+;	O
+2	O
+were	O
+neonates	O
+,	O
+1	O
+of	O
+whom	O
+had	O
+partial	O
+DiGeorge	B
+syndrome	I
+.	O
+
+The	O
+remaining	O
+infant	O
+had	O
+recently	O
+undergone	O
+a	O
+cardiac	O
+transplant	O
+.	O
+
+Intravenous	O
+ribavirin	O
+was	O
+administered	O
+on	O
+a	O
+compassionate	O
+-	O
+use	O
+protocol	O
+.	O
+
+RESULTS	O
+:	O
+Complete	O
+clinical	O
+recovery	O
+followed	O
+later	O
+by	O
+viral	O
+clearance	O
+was	O
+observed	O
+in	O
+2	O
+children	O
+:	O
+the	O
+cardiac	O
+transplant	O
+recipient	O
+with	O
+adenovirus	O
+hemorrhagic	B
+cystitis	I
+and	O
+the	O
+immunocompetent	O
+neonate	O
+with	O
+adenovirus	B
+pneumonia	I
+.	O
+
+The	O
+remaining	O
+3	O
+children	O
+died	O
+of	O
+adenovirus	B
+disease	I
+.	O
+
+Intravenous	O
+ribavirin	O
+therapy	O
+was	O
+well	O
+tolerated	O
+.	O
+
+Use	O
+of	O
+cidofovir	O
+in	O
+1	O
+child	O
+was	O
+associated	O
+with	O
+progressive	B
+renal	I
+failure	I
+and	O
+neutropenia	B
+.	O
+
+DISCUSSION	O
+:	O
+Our	O
+series	O
+of	O
+patients	O
+is	O
+representative	O
+of	O
+the	O
+spectrum	O
+of	O
+immunocompromised	O
+children	O
+at	O
+greatest	O
+risk	O
+for	O
+severe	O
+adenovirus	B
+disease	I
+,	O
+namely	O
+solid	O
+-	O
+organ	O
+and	O
+bone	O
+marrow	O
+transplant	O
+recipients	O
+,	O
+neonates	O
+,	O
+and	O
+children	O
+with	O
+immunodeficiency	B
+.	O
+
+Although	O
+intravenous	O
+ribavirin	O
+was	O
+not	O
+effective	O
+for	O
+all	O
+children	O
+with	O
+severe	O
+adenovirus	B
+disease	I
+in	O
+this	O
+series	O
+or	O
+in	O
+the	O
+literature	O
+,	O
+therapy	O
+is	O
+unlikely	O
+to	O
+be	O
+of	O
+benefit	O
+if	O
+begun	O
+late	O
+in	O
+the	O
+course	O
+of	O
+the	O
+infection	B
+.	O
+
+Early	O
+identification	O
+,	O
+eg	O
+by	O
+polymerase	O
+chain	O
+reaction	O
+of	O
+those	O
+patients	O
+at	O
+risk	O
+of	O
+disseminated	O
+adenovirus	B
+disease	I
+may	O
+permit	O
+earlier	O
+antiviral	O
+treatment	O
+and	O
+better	O
+evaluation	O
+of	O
+therapeutic	O
+response	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Two	O
+of	O
+5	O
+children	O
+with	O
+severe	O
+adenovirus	B
+disease	I
+treated	O
+with	O
+intravenous	O
+ribavirin	O
+recovered	O
+.	O
+
+The	O
+availability	O
+of	O
+newer	O
+rapid	O
+diagnostic	O
+techniques	O
+,	O
+such	O
+as	O
+polymerase	O
+chain	O
+reaction	O
+,	O
+may	O
+make	O
+earlier	O
+,	O
+more	O
+effective	O
+treatment	O
+of	O
+adenovirus	B
+infection	I
+possible	O
+.	O
+
+Given	O
+the	O
+seriousness	O
+and	O
+increasing	O
+prevalence	O
+of	O
+adenovirus	B
+disease	I
+in	O
+certain	O
+hosts	O
+,	O
+especially	O
+children	O
+,	O
+a	O
+large	O
+,	O
+multicenter	O
+clinical	O
+trial	O
+of	O
+potentially	O
+useful	O
+anti	O
+-	O
+adenoviral	O
+therapies	O
+,	O
+such	O
+as	O
+intravenous	O
+ribavirin	O
+,	O
+is	O
+clearly	O
+required	O
+to	O
+demonstrate	O
+the	O
+most	O
+effective	O
+and	O
+least	O
+toxic	O
+therapy	O
+.	O
+
+Delayed	O
+asystolic	B
+cardiac	B
+arrest	I
+after	O
+diltiazem	O
+overdose	B
+;	O
+resuscitation	O
+with	O
+high	O
+dose	O
+intravenous	O
+calcium	O
+.	O
+
+A	O
+51	O
+year	O
+old	O
+man	O
+took	O
+a	O
+mixed	O
+overdose	B
+including	O
+1	O
+.	O
+8	O
+-	O
+3	O
+.	O
+6	O
+g	O
+of	O
+diltiazem	O
+,	O
+paracetamol	O
+,	O
+aspirin	O
+,	O
+isosorbide	O
+nitrate	O
+,	O
+and	O
+alcohol	O
+.	O
+
+He	O
+initially	O
+presented	O
+to	O
+hospital	O
+after	O
+six	O
+hours	O
+with	O
+mild	O
+hypotension	B
+and	O
+was	O
+treated	O
+with	O
+activated	O
+charcoal	O
+and	O
+intravenous	O
+fluids	O
+.	O
+
+Eighteen	O
+hours	O
+after	O
+the	O
+overdose	B
+he	O
+had	O
+two	O
+generalised	O
+tonic	B
+-	I
+clonic	I
+seizures	I
+.	O
+
+The	O
+patient	O
+remained	O
+unresponsive	O
+with	O
+junctional	O
+bradycardia	B
+,	O
+unrecordable	O
+blood	O
+pressure	O
+,	O
+and	O
+then	O
+became	O
+asystolic	B
+.	O
+
+He	O
+was	O
+resuscitated	O
+with	O
+high	O
+dose	O
+(	O
+13	O
+.	O
+5	O
+g	O
+)	O
+intravenous	O
+calcium	O
+and	O
+adrenaline	O
+(	O
+epinephrine	O
+)	O
+.	O
+
+He	O
+required	O
+inotropic	O
+support	O
+and	O
+temporary	O
+pacing	O
+over	O
+the	O
+next	O
+48	O
+hours	O
+.	O
+
+This	O
+case	O
+suggests	O
+there	O
+is	O
+a	O
+role	O
+for	O
+aggressive	O
+high	O
+dose	O
+intravenous	O
+calcium	O
+therapy	O
+in	O
+severe	O
+diltiazem	O
+overdose	B
+,	O
+particularly	O
+with	O
+the	O
+onset	O
+of	O
+asystole	B
+.	O
+
+It	O
+should	O
+be	O
+considered	O
+early	O
+in	O
+cases	O
+of	O
+cardiac	B
+arrest	I
+after	O
+diltiazem	O
+overdose	B
+.	O
+
+The	O
+case	O
+also	O
+highlights	O
+the	O
+problems	O
+with	O
+delayed	O
+toxicity	B
+when	O
+whole	O
+bowel	O
+irrigation	O
+is	O
+not	O
+administered	O
+.	O
+
+Low	O
+-	O
+molecular	O
+-	O
+weight	O
+heparin	O
+for	O
+the	O
+treatment	O
+of	O
+patients	O
+with	O
+mechanical	O
+heart	O
+valves	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+interruption	O
+of	O
+oral	O
+anticoagulant	O
+(	O
+OAC	O
+)	O
+administration	O
+is	O
+sometimes	O
+indicated	O
+in	O
+patients	O
+with	O
+mechanical	O
+heart	O
+valves	O
+,	O
+mainly	O
+before	O
+noncardiac	O
+surgery	O
+,	O
+non	O
+-	O
+surgical	O
+interventions	O
+,	O
+and	O
+pregnancy	O
+.	O
+
+Unfractionated	O
+heparin	O
+(	O
+UH	O
+)	O
+is	O
+currently	O
+the	O
+substitute	O
+for	O
+selected	O
+patients	O
+.	O
+
+Low	O
+-	O
+molecular	O
+-	O
+weight	O
+heparin	O
+(	O
+LMWH	O
+)	O
+offers	O
+theoretical	O
+advantages	O
+over	O
+UH	O
+,	O
+but	O
+is	O
+not	O
+currently	O
+considered	O
+in	O
+clinical	O
+guidelines	O
+as	O
+an	O
+alternative	O
+to	O
+UH	O
+in	O
+patients	O
+with	O
+prosthetic	O
+valves	O
+.	O
+
+HYPOTHESIS	O
+:	O
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+review	O
+the	O
+data	O
+accumulated	O
+so	O
+far	O
+on	O
+the	O
+use	O
+of	O
+LMWH	O
+in	O
+this	O
+patient	O
+population	O
+and	O
+to	O
+discuss	O
+its	O
+applicability	O
+in	O
+common	O
+practice	O
+.	O
+
+METHODS	O
+:	O
+For	O
+this	O
+paper	O
+,	O
+the	O
+current	O
+medical	O
+literature	O
+on	O
+LMWH	O
+in	O
+patients	O
+with	O
+mechanical	O
+heart	O
+valves	O
+was	O
+extensively	O
+reviewed	O
+.	O
+
+RESULTS	O
+:	O
+There	O
+were	O
+eight	O
+series	O
+and	O
+six	O
+case	O
+reports	O
+.	O
+
+None	O
+of	O
+the	O
+studies	O
+was	O
+randomized	O
+,	O
+and	O
+only	O
+one	O
+was	O
+prospective	O
+.	O
+
+Data	O
+to	O
+establish	O
+the	O
+thromboembolic	B
+risk	O
+were	O
+incomplete	O
+.	O
+
+After	O
+excluding	O
+case	O
+reports	O
+,	O
+the	O
+following	O
+groups	O
+were	O
+constructed	O
+:	O
+(	O
+a	O
+)	O
+short	O
+-	O
+term	O
+administration	O
+,	O
+after	O
+valve	O
+insertion	O
+(	O
+n	O
+=	O
+212	O
+)	O
+;	O
+(	O
+b	O
+)	O
+short	O
+-	O
+term	O
+,	O
+perioperative	O
+(	O
+noncardiac	O
+)	O
+/	O
+periprocedural	O
+(	O
+n	O
+=	O
+114	O
+)	O
+;	O
+(	O
+c	O
+)	O
+long	O
+-	O
+term	O
+,	O
+due	O
+to	O
+intolerance	O
+to	O
+OAC	O
+(	O
+n	O
+=	O
+16	O
+)	O
+;	O
+(	O
+d	O
+)	O
+long	O
+-	O
+term	O
+,	O
+in	O
+pregnancy	O
+(	O
+n	O
+=	O
+10	O
+)	O
+.	O
+
+The	O
+incidence	O
+rate	O
+of	O
+thromboembolism	B
+was	O
+0	O
+.	O
+9	O
+%	O
+for	O
+all	O
+the	O
+studies	O
+and	O
+0	O
+.	O
+5	O
+,	O
+0	O
+,	O
+20	O
+,	O
+and	O
+0	O
+%	O
+in	O
+groups	O
+a	O
+,	O
+b	O
+,	O
+c	O
+,	O
+and	O
+d	O
+,	O
+respectively	O
+;	O
+for	O
+hemorrhage	B
+,	O
+the	O
+overall	O
+rate	O
+was	O
+3	O
+.	O
+4	O
+%	O
+(	O
+3	O
+.	O
+8	O
+,	O
+2	O
+.	O
+6	O
+,	O
+10	O
+,	O
+and	O
+0	O
+%	O
+for	O
+the	O
+respective	O
+groups	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+In	O
+patients	O
+with	O
+mechanical	O
+heart	O
+valves	O
+,	O
+short	O
+-	O
+term	O
+LMWH	O
+therapy	O
+compares	O
+favorably	O
+with	O
+UH	O
+.	O
+
+Data	O
+on	O
+mid	O
+-	O
+and	O
+long	O
+-	O
+term	O
+LMWH	O
+administration	O
+in	O
+these	O
+patients	O
+are	O
+sparse	O
+.	O
+
+Further	O
+randomized	O
+studies	O
+are	O
+needed	O
+to	O
+confirm	O
+the	O
+safety	O
+and	O
+precise	O
+indications	O
+for	O
+the	O
+use	O
+of	O
+LMWH	O
+in	O
+patients	O
+with	O
+mechanical	O
+heart	O
+valves	O
+.	O
+
+Cardiac	B
+arrest	I
+after	O
+intravenous	O
+metoclopramide	O
+-	O
+a	O
+case	O
+of	O
+five	O
+repeated	O
+injections	O
+of	O
+metoclopramide	O
+causing	O
+five	O
+episodes	O
+of	O
+cardiac	B
+arrest	I
+.	O
+
+We	O
+describe	O
+a	O
+patient	O
+where	O
+intravenous	O
+injection	O
+of	O
+metoclopramide	O
+was	O
+immediately	O
+followed	O
+by	O
+asystole	B
+repeatedly	O
+.	O
+
+The	O
+patient	O
+received	O
+metoclopramide	O
+10	O
+mg	O
+i	O
+.	O
+v	O
+.	O
+five	O
+times	O
+during	O
+48	O
+h	O
+.	O
+
+After	O
+interviewing	O
+the	O
+attending	O
+nurses	O
+and	O
+reviewing	O
+the	O
+written	O
+documentation	O
+,	O
+it	O
+is	O
+clear	O
+that	O
+every	O
+administration	O
+of	O
+metoclopramide	O
+was	O
+immediately	O
+(	O
+within	O
+s	O
+)	O
+followed	O
+by	O
+asystole	B
+.	O
+
+The	O
+asystole	B
+lasted	O
+15	O
+-	O
+30	O
+s	O
+on	O
+four	O
+occasions	O
+,	O
+on	O
+one	O
+occasion	O
+it	O
+lasted	O
+2	O
+min	O
+.	O
+
+The	O
+patient	O
+received	O
+atropine	O
+0	O
+.	O
+5	O
+-	O
+1	O
+mg	O
+and	O
+chest	O
+compressions	O
+,	O
+before	O
+sinus	O
+rhythm	O
+again	O
+took	O
+over	O
+.	O
+
+We	O
+interpret	O
+this	O
+as	O
+episodes	O
+of	O
+cardiac	B
+arrest	I
+caused	O
+by	O
+metoclopramide	O
+.	O
+
+The	O
+rapid	O
+injection	O
+via	O
+the	O
+central	O
+venous	O
+route	O
+and	O
+the	O
+concomitant	O
+tapering	O
+of	O
+dopamine	O
+infusion	O
+might	O
+have	O
+contributed	O
+in	O
+precipitating	O
+the	O
+adverse	O
+drug	O
+reaction	O
+.	O
+
+Immunohistochemical	O
+study	O
+on	O
+inducible	O
+type	O
+of	O
+nitric	O
+oxide	O
+(	O
+iNOS	O
+)	O
+,	O
+basic	O
+fibroblast	O
+growth	O
+factor	O
+(	O
+bFGF	O
+)	O
+and	O
+tumor	B
+growth	O
+factor	O
+-	O
+beta1	O
+(	O
+TGF	O
+-	O
+beta1	O
+)	O
+in	O
+arteritis	B
+induced	O
+in	O
+rats	O
+by	O
+fenoldopam	O
+and	O
+theophylline	O
+,	O
+vasodilators	O
+.	O
+
+Arteritis	B
+induced	O
+in	O
+rats	O
+by	O
+vasodilators	O
+,	O
+fenoldopam	O
+and	O
+theophylline	O
+,	O
+was	O
+examined	O
+immunohistochemically	O
+for	O
+expressions	O
+of	O
+inducible	O
+type	O
+of	O
+nitric	O
+oxide	O
+synthase	O
+(	O
+iNOS	O
+)	O
+,	O
+basic	O
+fibroblast	O
+growth	O
+factor	O
+(	O
+bFGF	O
+)	O
+and	O
+tumor	B
+growth	O
+factor	O
+-	O
+beta1	O
+(	O
+TGF	O
+-	O
+beta1	O
+)	O
+.	O
+
+Rats	O
+were	O
+administered	O
+fenoldopam	O
+for	O
+24	O
+hours	O
+by	O
+intravenous	O
+infusion	O
+with	O
+or	O
+without	O
+following	O
+repeated	O
+daily	O
+oral	O
+administrations	O
+of	O
+theophylline	O
+.	O
+
+Irrespective	O
+of	O
+theophylline	O
+administration	O
+,	O
+iNOS	O
+antigens	O
+were	O
+remarkably	O
+abundant	O
+in	O
+ED	O
+-	O
+1	O
+-	O
+positive	O
+cells	O
+on	O
+day	O
+5	O
+and	O
+8	O
+post	O
+-	O
+fenoldopam	O
+-	O
+infusion	O
+(	O
+DPI	O
+)	O
+;	O
+bFGF	O
+antigens	O
+were	O
+remarkably	O
+abundant	O
+in	O
+ED	O
+-	O
+1	O
+-	O
+positive	O
+cells	O
+on	O
+1	O
+and	O
+3	O
+DPI	O
+;	O
+TGF	O
+-	O
+beta1	O
+antigens	O
+were	O
+observed	O
+in	O
+ED	O
+-	O
+1	O
+-	O
+positive	O
+cells	O
+on	O
+and	O
+after	O
+5	O
+DPI	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+the	O
+peak	O
+expression	O
+of	O
+iNOS	O
+antigen	O
+was	O
+followed	O
+by	O
+that	O
+of	O
+bFGF	O
+antigen	O
+,	O
+and	O
+bFGF	O
+may	O
+have	O
+a	O
+suppressive	O
+effect	O
+on	O
+iNOS	O
+expression	O
+in	O
+these	O
+rat	O
+arteritis	B
+models	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+TGF	O
+-	O
+beta1	O
+was	O
+not	O
+considered	O
+to	O
+have	O
+a	O
+suppressive	O
+effect	O
+on	O
+iNOS	O
+expression	O
+in	O
+these	O
+models	O
+.	O
+
+The	O
+striatum	O
+as	O
+a	O
+target	O
+for	O
+anti	O
+-	O
+rigor	O
+effects	O
+of	O
+an	O
+antagonist	O
+of	O
+mGluR1	O
+,	O
+but	O
+not	O
+an	O
+agonist	O
+of	O
+group	O
+II	O
+metabotropic	O
+glutamate	O
+receptors	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+find	O
+out	O
+whether	O
+the	O
+metabotropic	O
+receptor	O
+1	O
+(	O
+mGluR1	O
+)	O
+and	O
+group	O
+II	O
+mGluRs	O
+,	O
+localized	O
+in	O
+the	O
+striatum	O
+,	O
+are	O
+involved	O
+in	O
+antiparkinsonian	O
+-	O
+like	O
+effects	O
+in	O
+rats	O
+.	O
+
+Haloperidol	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+ip	O
+)	O
+induced	O
+parkinsonian	B
+-	O
+like	O
+muscle	B
+rigidity	I
+,	O
+measured	O
+as	O
+an	O
+increased	O
+resistance	O
+of	O
+a	O
+rat	O
+'	O
+s	O
+hind	O
+foot	O
+to	O
+passive	O
+flexion	O
+and	O
+extension	O
+at	O
+the	O
+ankle	O
+joint	O
+.	O
+
+(	O
+RS	O
+)	O
+-	O
+1	O
+-	O
+aminoindan	O
+-	O
+1	O
+,	O
+5	O
+-	O
+dicarboxylic	O
+acid	O
+(	O
+AIDA	O
+;	O
+0	O
+.	O
+5	O
+-	O
+15	O
+microg	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+)	O
+,	O
+a	O
+potent	O
+and	O
+selective	O
+mGluR1	O
+antagonist	O
+,	O
+or	O
+(	O
+2R	O
+,	O
+4R	O
+)	O
+-	O
+4	O
+-	O
+aminopyrrolidine	O
+-	O
+2	O
+,	O
+4	O
+-	O
+dicarboxylate	O
+(	O
+2R	O
+,	O
+4R	O
+-	O
+APDC	O
+;	O
+7	O
+.	O
+5	O
+-	O
+15	O
+microg	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+)	O
+,	O
+a	O
+selective	O
+group	O
+II	O
+agonist	O
+,	O
+was	O
+injected	O
+bilaterally	O
+into	O
+the	O
+striatum	O
+of	O
+haloperidol	O
+-	O
+treated	O
+animals	O
+.	O
+
+AIDA	O
+in	O
+doses	O
+of	O
+7	O
+.	O
+5	O
+-	O
+15	O
+microg	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+diminished	O
+the	O
+haloperidol	O
+-	O
+induced	O
+muscle	B
+rigidity	I
+.	O
+
+In	O
+contrast	O
+,	O
+2R	O
+,	O
+4R	O
+-	O
+APDC	O
+injections	O
+were	O
+ineffective	O
+.	O
+
+The	O
+present	O
+results	O
+may	O
+suggest	O
+that	O
+the	O
+blockade	O
+of	O
+striatal	O
+mGluR1	O
+,	O
+but	O
+not	O
+the	O
+stimulation	O
+of	O
+group	O
+II	O
+mGluRs	O
+,	O
+may	O
+ameliorate	O
+parkinsonian	B
+muscle	B
+rigidity	I
+.	O
+
+A	O
+phase	O
+II	O
+study	O
+of	O
+thalidomide	O
+in	O
+advanced	O
+metastatic	O
+renal	B
+cell	I
+carcinoma	I
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+evaluate	O
+the	O
+toxicity	B
+and	O
+activity	O
+of	O
+thalidomide	O
+in	O
+patients	O
+with	O
+advanced	O
+metastatic	O
+renal	B
+cell	I
+cancer	I
+and	O
+to	O
+measure	O
+changes	O
+of	O
+one	O
+angiogenic	O
+factor	O
+,	O
+vascular	O
+endothelial	O
+growth	O
+factor	O
+(	O
+VEGF	O
+)	O
+165	O
+,	O
+with	O
+therapy	O
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+29	O
+patients	O
+were	O
+enrolled	O
+on	O
+a	O
+study	O
+of	O
+thalidomide	O
+using	O
+an	O
+intra	O
+-	O
+patient	O
+dose	O
+escalation	O
+schedule	O
+.	O
+
+Patients	O
+began	O
+thalidomide	O
+at	O
+400	O
+mg	O
+/	O
+d	O
+and	O
+escalated	O
+as	O
+tolerated	O
+to	O
+1200	O
+mg	O
+/	O
+d	O
+by	O
+day	O
+54	O
+.	O
+
+Fifty	O
+-	O
+nine	O
+per	O
+cent	O
+of	O
+patients	O
+had	O
+had	O
+previous	O
+therapy	O
+with	O
+IL	O
+-	O
+2	O
+and	O
+52	O
+%	O
+were	O
+performance	O
+status	O
+2	O
+or	O
+3	O
+.	O
+
+Systemic	O
+plasma	O
+VEGF165	O
+levels	O
+were	O
+measured	O
+by	O
+dual	O
+monoclonal	O
+ELISA	O
+in	O
+8	O
+patients	O
+.	O
+
+RESULTS	O
+:	O
+24	O
+patients	O
+were	O
+evaluable	O
+for	O
+response	O
+with	O
+one	O
+partial	O
+response	O
+of	O
+11	O
+months	O
+duration	O
+of	O
+a	O
+patient	O
+with	O
+hepatic	O
+and	O
+pulmonary	O
+metastases	B
+(	O
+4	O
+%	O
+)	O
+,	O
+one	O
+minor	O
+response	O
+,	O
+and	O
+2	O
+patients	O
+stable	O
+for	O
+over	O
+6	O
+months	O
+.	O
+
+Somnolence	B
+and	O
+constipation	B
+were	O
+prominent	O
+toxicities	B
+and	O
+most	O
+patients	O
+could	O
+not	O
+tolerate	O
+the	O
+1200	O
+mg	O
+/	O
+day	O
+dose	O
+level	O
+.	O
+
+Systemic	O
+plasma	O
+VEGF165	O
+levels	O
+did	O
+not	O
+change	O
+with	O
+therapy	O
+.	O
+
+CONCLUSION	O
+:	O
+These	O
+results	O
+are	O
+consistent	O
+with	O
+a	O
+low	O
+level	O
+of	O
+activity	O
+of	O
+thalidomide	O
+in	O
+renal	B
+cell	I
+carcinoma	I
+.	O
+
+Administration	O
+of	O
+doses	O
+over	O
+800	O
+mg	O
+/	O
+day	O
+was	O
+difficult	O
+to	O
+achieve	O
+in	O
+this	O
+patient	O
+population	O
+,	O
+however	O
+lower	O
+doses	O
+were	O
+practical	O
+.	O
+
+The	O
+dose	O
+-	O
+response	O
+relationship	O
+,	O
+if	O
+any	O
+,	O
+of	O
+thalidomide	O
+for	O
+renal	B
+cell	I
+carcinoma	I
+is	O
+unclear	O
+.	O
+
+Can	O
+lidocaine	O
+reduce	O
+succinylcholine	O
+induced	O
+postoperative	B
+myalgia	I
+?	O
+
+This	O
+study	O
+was	O
+undertaken	O
+to	O
+determine	O
+the	O
+effect	O
+of	O
+lidocaine	O
+pretreatment	O
+on	O
+reduction	O
+of	O
+succinylcholine	O
+-	O
+induced	O
+myalgia	B
+in	O
+patients	O
+undergoing	O
+general	O
+anesthesia	O
+for	O
+gynecological	O
+surgery	O
+.	O
+
+One	O
+hundred	O
+and	O
+thirty	O
+-	O
+five	O
+patients	O
+were	O
+assigned	O
+to	O
+one	O
+of	O
+three	O
+groups	O
+in	O
+a	O
+prospective	O
+,	O
+double	O
+blind	O
+,	O
+randomized	O
+manner	O
+.	O
+
+Group	O
+PS	O
+,	O
+the	O
+control	O
+group	O
+,	O
+received	O
+normal	O
+saline	O
+and	O
+succinylcholine	O
+1	O
+.	O
+5	O
+mg	O
+x	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+;	O
+Group	O
+LS	O
+,	O
+lidocaine	O
+1	O
+.	O
+5	O
+mg	O
+x	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+and	O
+succinylcholine	O
+1	O
+.	O
+5	O
+mg	O
+x	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+;	O
+Group	O
+PR	O
+,	O
+normal	O
+saline	O
+and	O
+rocuronium	O
+0	O
+.	O
+6	O
+mg	O
+x	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+
+Morphine	O
+0	O
+.	O
+1	O
+mg	O
+x	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+iv	O
+was	O
+given	O
+for	O
+premedication	O
+and	O
+all	O
+patients	O
+were	O
+monitored	O
+with	O
+a	O
+noninvasive	O
+blood	O
+pressure	O
+monitor	O
+,	O
+ECG	O
+and	O
+pulse	O
+oximetry	O
+.	O
+
+Anesthesia	O
+was	O
+induced	O
+with	O
+5	O
+mg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+thiopental	O
+iv	O
+.	O
+followed	O
+by	O
+succinylcholine	O
+(	O
+Group	O
+PS	O
+,	O
+LS	O
+)	O
+or	O
+rocuronium	O
+(	O
+Group	O
+PR	O
+)	O
+for	O
+tracheal	O
+intubation	O
+.	O
+
+Following	O
+administration	O
+of	O
+these	O
+agents	O
+,	O
+the	O
+presence	O
+,	O
+and	O
+degree	O
+of	O
+fasciculation	B
+were	O
+assessed	O
+visually	O
+on	O
+a	O
+four	O
+point	O
+scale	O
+by	O
+one	O
+investigator	O
+who	O
+was	O
+blinded	O
+to	O
+the	O
+drug	O
+administered	O
+.	O
+
+The	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+of	O
+each	O
+patient	O
+were	O
+monitored	O
+on	O
+nine	O
+occasions	O
+.	O
+
+Twenty	O
+-	O
+four	O
+hours	O
+later	O
+,	O
+any	O
+myalgia	B
+experienced	O
+was	O
+assessed	O
+according	O
+to	O
+a	O
+structured	O
+questionaire	O
+and	O
+graded	O
+by	O
+a	O
+four	O
+point	O
+scale	O
+by	O
+one	O
+investigator	O
+blinded	O
+to	O
+the	O
+intraoperative	O
+management	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+muscle	B
+fasciculation	I
+was	O
+not	O
+found	O
+in	O
+Group	O
+PR	O
+while	O
+the	O
+patients	O
+in	O
+Group	O
+LS	O
+had	O
+a	O
+lower	O
+incidence	O
+of	O
+muscle	B
+fasciculation	I
+than	O
+those	O
+in	O
+Group	O
+PS	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+At	O
+24	O
+h	O
+,	O
+the	O
+incidence	O
+of	O
+myalgia	B
+was	O
+higher	O
+in	O
+Group	O
+PS	O
+than	O
+in	O
+Group	O
+LS	O
+and	O
+PR	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+A	O
+correlation	O
+was	O
+not	O
+found	O
+between	O
+the	O
+incidence	O
+of	O
+myalgia	B
+and	O
+the	O
+occurrence	O
+of	O
+muscle	B
+fasciculation	I
+.	O
+
+The	O
+changes	O
+in	O
+systolic	O
+and	O
+diastolic	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+were	O
+not	O
+significant	O
+among	O
+the	O
+three	O
+groups	O
+.	O
+
+In	O
+conclusion	O
+,	O
+where	O
+succinylcholine	O
+is	O
+used	O
+,	O
+lidocaine	O
+is	O
+proven	O
+to	O
+be	O
+the	O
+useful	O
+pretreatment	O
+agent	O
+for	O
+the	O
+reduction	O
+of	O
+postoperative	B
+myalgia	I
+.	O
+
+Reduced	O
+sodium	O
+channel	O
+density	O
+,	O
+altered	O
+voltage	O
+dependence	O
+of	O
+inactivation	O
+,	O
+and	O
+increased	O
+susceptibility	O
+to	O
+seizures	B
+in	O
+mice	O
+lacking	O
+sodium	O
+channel	O
+beta	O
+2	O
+-	O
+subunits	O
+.	O
+
+Sodium	O
+channel	O
+beta	O
+-	O
+subunits	O
+modulate	O
+channel	O
+gating	O
+,	O
+assembly	O
+,	O
+and	O
+cell	O
+surface	O
+expression	O
+in	O
+heterologous	O
+cell	O
+systems	O
+.	O
+
+We	O
+generated	O
+beta2	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+to	O
+investigate	O
+the	O
+role	O
+of	O
+beta2	O
+in	O
+control	O
+of	O
+sodium	O
+channel	O
+density	O
+,	O
+localization	O
+,	O
+and	O
+function	O
+in	O
+neurons	O
+in	O
+vivo	O
+.	O
+
+Measurements	O
+of	O
+[	O
+(	O
+3	O
+)	O
+H	O
+]	O
+saxitoxin	O
+(	O
+STX	O
+)	O
+binding	O
+showed	O
+a	O
+significant	O
+reduction	O
+in	O
+the	O
+level	O
+of	O
+plasma	O
+membrane	O
+sodium	O
+channels	O
+in	O
+beta2	O
+(	O
+-	O
+/	O
+-	O
+)	O
+neurons	O
+.	O
+
+The	O
+loss	O
+of	O
+beta2	O
+resulted	O
+in	O
+negative	O
+shifts	O
+in	O
+the	O
+voltage	O
+dependence	O
+of	O
+inactivation	O
+as	O
+well	O
+as	O
+significant	O
+decreases	O
+in	O
+sodium	O
+current	O
+density	O
+in	O
+acutely	O
+dissociated	O
+hippocampal	O
+neurons	O
+.	O
+
+The	O
+integral	O
+of	O
+the	O
+compound	O
+action	O
+potential	O
+in	O
+optic	O
+nerve	O
+was	O
+significantly	O
+reduced	O
+,	O
+and	O
+the	O
+threshold	O
+for	O
+action	O
+potential	O
+generation	O
+was	O
+increased	O
+,	O
+indicating	O
+a	O
+reduction	O
+in	O
+the	O
+level	O
+of	O
+functional	O
+plasma	O
+membrane	O
+sodium	O
+channels	O
+.	O
+
+In	O
+contrast	O
+,	O
+the	O
+conduction	O
+velocity	O
+,	O
+the	O
+number	O
+and	O
+size	O
+of	O
+axons	O
+in	O
+the	O
+optic	O
+nerve	O
+,	O
+and	O
+the	O
+specific	O
+localization	O
+of	O
+Na	O
+(	O
+v	O
+)	O
+1	O
+.	O
+6	O
+channels	O
+in	O
+the	O
+nodes	O
+of	O
+Ranvier	O
+were	O
+unchanged	O
+.	O
+
+beta2	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+displayed	O
+increased	O
+susceptibility	O
+to	O
+seizures	B
+,	O
+as	O
+indicated	O
+by	O
+reduced	O
+latency	O
+and	O
+threshold	O
+for	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+,	O
+but	O
+seemed	O
+normal	O
+in	O
+other	O
+neurological	O
+tests	O
+.	O
+
+Our	O
+observations	O
+show	O
+that	O
+beta2	O
+-	O
+subunits	O
+play	O
+an	O
+important	O
+role	O
+in	O
+the	O
+regulation	O
+of	O
+sodium	O
+channel	O
+density	O
+and	O
+function	O
+in	O
+neurons	O
+in	O
+vivo	O
+and	O
+are	O
+required	O
+for	O
+normal	O
+action	O
+potential	O
+generation	O
+and	O
+control	O
+of	O
+excitability	O
+.	O
+
+Acute	B
+liver	I
+failure	I
+with	O
+concurrent	O
+bupropion	O
+and	O
+carbimazole	O
+therapy	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+fatal	O
+liver	B
+failure	I
+possibly	O
+associated	O
+with	O
+concurrent	O
+use	O
+of	O
+bupropion	O
+and	O
+carbimazole	O
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+41	O
+-	O
+year	O
+-	O
+old	O
+Chinese	O
+man	O
+with	O
+a	O
+history	O
+of	O
+hyperthyroidism	B
+had	O
+been	O
+treated	O
+with	O
+carbimazole	O
+and	O
+propranolol	O
+for	O
+the	O
+past	O
+5	O
+years	O
+.	O
+
+He	O
+received	O
+a	O
+10	O
+-	O
+day	O
+course	O
+of	O
+bupropion	O
+as	O
+an	O
+aid	O
+for	O
+smoking	O
+cessation	O
+10	O
+weeks	O
+prior	O
+to	O
+presentation	O
+.	O
+
+He	O
+developed	O
+acute	B
+liver	I
+failure	I
+with	O
+rapid	O
+deterioration	O
+of	O
+renal	O
+function	O
+.	O
+
+Liver	O
+biopsy	O
+showed	O
+evidence	O
+of	O
+nonspecific	O
+drug	B
+-	I
+induced	I
+acute	I
+liver	I
+injury	I
+.	O
+
+His	O
+condition	O
+was	O
+further	O
+complicated	O
+by	O
+sepsis	B
+and	O
+coagulopathy	B
+.	O
+
+Death	O
+resulted	O
+19	O
+days	O
+after	O
+the	O
+onset	O
+of	O
+symptoms	O
+.	O
+
+The	O
+likelihood	O
+that	O
+bupropion	O
+induced	O
+hepatotoxicity	B
+in	O
+our	O
+patient	O
+was	O
+possible	O
+,	O
+based	O
+on	O
+the	O
+Naranjo	O
+probability	O
+scale	O
+.	O
+
+DISCUSSION	O
+:	O
+Although	O
+there	O
+is	O
+increasing	O
+evidence	O
+of	O
+hepatotoxicity	B
+induced	O
+by	O
+bupropion	O
+,	O
+this	O
+is	O
+the	O
+first	O
+case	O
+of	O
+fatality	O
+that	O
+could	O
+have	O
+resulted	O
+from	O
+acute	B
+liver	I
+failure	I
+in	O
+a	O
+patient	O
+receiving	O
+bupropion	O
+while	O
+on	O
+concomitant	O
+treatment	O
+with	O
+carbimazole	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Clinicians	O
+should	O
+be	O
+aware	O
+of	O
+the	O
+possibility	O
+of	O
+acute	B
+liver	I
+insult	I
+induced	O
+by	O
+bupropion	O
+given	O
+concurrently	O
+with	O
+other	O
+hepatotoxic	B
+drugs	O
+.	O
+
+Pyeloureteral	O
+filling	O
+defects	O
+associated	O
+with	O
+systemic	O
+anticoagulation	O
+:	O
+a	O
+case	O
+report	O
+.	O
+
+The	O
+etiology	O
+of	O
+pyeloureteritis	B
+cystica	I
+has	O
+long	O
+been	O
+attributed	O
+to	O
+chronic	O
+infection	B
+and	O
+inflammation	B
+.	O
+
+A	O
+case	O
+is	O
+presented	O
+that	O
+is	O
+unique	O
+in	O
+that	O
+the	O
+acute	O
+onset	O
+and	O
+the	O
+rapid	O
+resolution	O
+of	O
+pyeloureteral	O
+filling	O
+defects	O
+in	O
+this	O
+patient	O
+were	O
+documented	O
+by	O
+radiography	O
+.	O
+
+There	O
+is	O
+no	O
+evidence	O
+of	O
+antecedent	O
+or	O
+concurrent	O
+infection	B
+in	O
+this	O
+patient	O
+.	O
+
+The	O
+disease	O
+occurred	O
+subsequent	O
+to	O
+the	O
+initiation	O
+of	O
+heparin	O
+therapy	O
+for	O
+suspected	O
+pelvic	O
+thrombophlebitis	B
+and	O
+cleared	O
+rapidly	O
+subsequent	O
+to	O
+its	O
+discontinuation	O
+.	O
+
+The	O
+rate	O
+of	O
+resolution	O
+of	O
+the	O
+radiographic	O
+findings	O
+may	O
+be	O
+helpful	O
+in	O
+distinguishing	O
+between	O
+true	O
+pyeloureteritis	B
+cystica	I
+and	O
+submucosal	B
+hemorrhage	I
+.	O
+
+Nephrotoxic	B
+effects	O
+in	O
+high	O
+-	O
+risk	O
+patients	O
+undergoing	O
+angiography	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+use	O
+of	O
+iodinated	O
+contrast	O
+medium	O
+can	O
+result	O
+in	O
+nephropathy	B
+.	O
+
+Whether	O
+iso	O
+-	O
+osmolar	O
+contrast	O
+medium	O
+is	O
+less	O
+nephrotoxic	B
+than	O
+low	O
+-	O
+osmolar	O
+contrast	O
+medium	O
+in	O
+high	O
+-	O
+risk	O
+patients	O
+is	O
+uncertain	O
+.	O
+
+METHODS	O
+:	O
+We	O
+conducted	O
+a	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+prospective	O
+,	O
+multicenter	O
+study	O
+comparing	O
+the	O
+nephrotoxic	B
+effects	O
+of	O
+an	O
+iso	O
+-	O
+osmolar	O
+,	O
+dimeric	O
+,	O
+nonionic	O
+contrast	O
+medium	O
+,	O
+iodixanol	O
+,	O
+with	O
+those	O
+of	O
+a	O
+low	O
+-	O
+osmolar	O
+,	O
+nonionic	O
+,	O
+monomeric	O
+contrast	O
+medium	O
+,	O
+iohexol	O
+.	O
+
+The	O
+study	O
+involved	O
+129	O
+patients	O
+with	O
+diabetes	B
+with	O
+serum	O
+creatinine	O
+concentrations	O
+of	O
+1	O
+.	O
+5	O
+to	O
+3	O
+.	O
+5	O
+mg	O
+per	O
+deciliter	O
+who	O
+underwent	O
+coronary	O
+or	O
+aortofemoral	O
+angiography	O
+.	O
+
+The	O
+primary	O
+end	O
+point	O
+was	O
+the	O
+peak	O
+increase	O
+from	O
+base	O
+line	O
+in	O
+the	O
+creatinine	O
+concentration	O
+during	O
+the	O
+three	O
+days	O
+after	O
+angiography	O
+.	O
+
+Other	O
+end	O
+points	O
+were	O
+an	O
+increase	O
+in	O
+the	O
+creatinine	O
+concentration	O
+of	O
+0	O
+.	O
+5	O
+mg	O
+per	O
+deciliter	O
+or	O
+more	O
+,	O
+an	O
+increase	O
+of	O
+1	O
+.	O
+0	O
+mg	O
+per	O
+deciliter	O
+or	O
+more	O
+,	O
+and	O
+a	O
+change	O
+in	O
+the	O
+creatinine	O
+concentration	O
+from	O
+day	O
+0	O
+to	O
+day	O
+7	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+creatinine	O
+concentration	O
+increased	O
+significantly	O
+less	O
+in	O
+patients	O
+who	O
+received	O
+iodixanol	O
+.	O
+
+From	O
+day	O
+0	O
+to	O
+day	O
+3	O
+,	O
+the	O
+mean	O
+peak	O
+increase	O
+in	O
+creatinine	O
+was	O
+0	O
+.	O
+13	O
+mg	O
+per	O
+deciliter	O
+in	O
+the	O
+iodixanol	O
+group	O
+and	O
+0	O
+.	O
+55	O
+mg	O
+per	O
+deciliter	O
+in	O
+the	O
+iohexol	O
+group	O
+(	O
+P	O
+=	O
+0	O
+.	O
+001	O
+;	O
+the	O
+increase	O
+with	O
+iodixanol	O
+minus	O
+the	O
+increase	O
+with	O
+iohexol	O
+,	O
+-	O
+0	O
+.	O
+42	O
+mg	O
+per	O
+deciliter	O
+[	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+-	O
+0	O
+.	O
+73	O
+to	O
+-	O
+0	O
+.	O
+22	O
+]	O
+)	O
+.	O
+
+Two	O
+of	O
+the	O
+64	O
+patients	O
+in	O
+the	O
+iodixanol	O
+group	O
+(	O
+3	O
+percent	O
+)	O
+had	O
+an	O
+increase	O
+in	O
+the	O
+creatinine	O
+concentration	O
+of	O
+0	O
+.	O
+5	O
+mg	O
+per	O
+deciliter	O
+or	O
+more	O
+,	O
+as	O
+compared	O
+with	O
+17	O
+of	O
+the	O
+65	O
+patients	O
+in	O
+the	O
+iohexol	O
+group	O
+(	O
+26	O
+percent	O
+)	O
+(	O
+P	O
+=	O
+0	O
+.	O
+002	O
+;	O
+odds	O
+ratio	O
+for	O
+such	O
+an	O
+increase	O
+in	O
+the	O
+iodixanol	O
+group	O
+,	O
+0	O
+.	O
+09	O
+[	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+0	O
+.	O
+02	O
+to	O
+0	O
+.	O
+41	O
+]	O
+)	O
+.	O
+
+No	O
+patient	O
+receiving	O
+iodixanol	O
+had	O
+an	O
+increase	O
+of	O
+1	O
+.	O
+0	O
+mg	O
+per	O
+deciliter	O
+or	O
+more	O
+,	O
+but	O
+10	O
+patients	O
+in	O
+the	O
+iohexol	O
+group	O
+(	O
+15	O
+percent	O
+)	O
+did	O
+.	O
+
+The	O
+mean	O
+change	O
+in	O
+the	O
+creatinine	O
+concentration	O
+from	O
+day	O
+0	O
+to	O
+day	O
+7	O
+was	O
+0	O
+.	O
+07	O
+mg	O
+per	O
+deciliter	O
+in	O
+the	O
+iodixanol	O
+group	O
+and	O
+0	O
+.	O
+24	O
+mg	O
+per	O
+deciliter	O
+in	O
+the	O
+iohexol	O
+group	O
+(	O
+P	O
+=	O
+0	O
+.	O
+003	O
+;	O
+value	O
+in	O
+the	O
+iodixanol	O
+group	O
+minus	O
+the	O
+value	O
+in	O
+the	O
+iohexol	O
+group	O
+,	O
+-	O
+0	O
+.	O
+17	O
+mg	O
+per	O
+deciliter	O
+[	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+-	O
+0	O
+.	O
+34	O
+to	O
+-	O
+0	O
+.	O
+07	O
+]	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Nephropathy	B
+induced	O
+by	O
+contrast	O
+medium	O
+may	O
+be	O
+less	O
+likely	O
+to	O
+develop	O
+in	O
+high	O
+-	O
+risk	O
+patients	O
+when	O
+iodixanol	O
+is	O
+used	O
+rather	O
+than	O
+a	O
+low	O
+-	O
+osmolar	O
+,	O
+nonionic	O
+contrast	O
+medium	O
+.	O
+
+Protective	O
+effect	O
+of	O
+edaravone	O
+against	O
+streptomycin	O
+-	O
+induced	O
+vestibulotoxicity	B
+in	O
+the	O
+guinea	O
+pig	O
+.	O
+
+This	O
+study	O
+investigated	O
+alleviation	O
+of	O
+streptomycin	O
+-	O
+induced	O
+vestibulotoxicity	B
+by	O
+edaravone	O
+in	O
+guinea	O
+pigs	O
+.	O
+
+Edaravone	O
+,	O
+a	O
+free	O
+radical	O
+scavenger	O
+,	O
+has	O
+potent	O
+free	O
+radical	O
+quenching	O
+action	O
+and	O
+is	O
+used	O
+in	O
+clinical	O
+practice	O
+to	O
+treat	O
+cerebral	B
+infarction	I
+.	O
+
+Streptomycin	O
+was	O
+administered	O
+to	O
+the	O
+inner	O
+ear	O
+by	O
+osmotic	O
+pump	O
+for	O
+24	O
+h	O
+,	O
+and	O
+edaravone	O
+(	O
+n	O
+=	O
+8	O
+)	O
+or	O
+saline	O
+(	O
+n	O
+=	O
+6	O
+)	O
+was	O
+intraperitoneally	O
+injected	O
+once	O
+a	O
+day	O
+for	O
+7	O
+days	O
+.	O
+
+We	O
+observed	O
+horizontal	O
+vestibulo	O
+-	O
+ocular	O
+reflex	O
+as	O
+a	O
+marker	O
+of	O
+postoperative	O
+vestibular	O
+function	O
+.	O
+
+Animals	O
+injected	O
+with	O
+saline	O
+showed	O
+statistically	O
+smaller	O
+gains	O
+than	O
+those	O
+injected	O
+with	O
+edaravone	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+edaravone	O
+suppresses	O
+streptomycin	O
+-	O
+induced	O
+vestibulotoxicity	B
+.	O
+
+Levodopa	O
+-	O
+induced	O
+oromandibular	O
+dystonia	B
+in	O
+progressive	B
+supranuclear	I
+palsy	I
+.	O
+
+Levodopa	O
+-	O
+induced	O
+dyskinesias	B
+have	O
+been	O
+reported	O
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+and	O
+multiple	B
+system	I
+atrophy	I
+.	O
+
+Cranial	O
+dystonias	B
+are	O
+rare	O
+in	O
+patients	O
+with	O
+progressive	B
+supranuclear	I
+palsy	I
+(	O
+PSP	B
+)	O
+.	O
+
+In	O
+this	O
+report	O
+we	O
+describe	O
+an	O
+unusual	O
+case	O
+of	O
+reversible	O
+levodopa	O
+-	O
+induced	O
+Oromandibular	B
+dystonia	I
+(	O
+OMD	B
+)	O
+in	O
+a	O
+PSP	B
+patient	O
+to	O
+highlight	O
+the	O
+importance	O
+of	O
+recognizing	O
+this	O
+drug	O
+related	O
+complication	O
+in	O
+the	O
+management	O
+of	O
+PSP	B
+,	O
+and	O
+discuss	O
+the	O
+possible	O
+underlying	O
+pathophysiology	O
+.	O
+
+Case	O
+report	O
+:	O
+Dexatrim	O
+(	O
+Phenylpropanolamine	O
+)	O
+as	O
+a	O
+cause	O
+of	O
+myocardial	B
+infarction	I
+.	O
+
+Phenylpropanolamine	O
+(	O
+PPA	O
+)	O
+is	O
+a	O
+sympathetic	O
+amine	O
+used	O
+in	O
+over	O
+-	O
+the	O
+-	O
+counter	O
+cold	O
+remedies	O
+and	O
+weight	O
+-	O
+control	O
+preparations	O
+worldwide	O
+.	O
+
+Its	O
+use	O
+has	O
+been	O
+associated	O
+with	O
+hypertensive	B
+episodes	O
+and	O
+hemorrhagic	B
+strokes	I
+in	O
+younger	O
+women	O
+.	O
+
+Several	O
+reports	O
+have	O
+linked	O
+the	O
+abuse	O
+of	O
+PPA	O
+with	O
+myocardial	B
+injury	I
+,	O
+especially	O
+when	O
+overdose	B
+is	O
+involved	O
+.	O
+
+We	O
+report	O
+here	O
+the	O
+first	O
+case	O
+of	O
+Dexatrim	O
+(	O
+PPA	O
+)	O
+-	O
+induced	O
+myocardial	B
+injury	I
+in	O
+a	O
+young	O
+woman	O
+who	O
+was	O
+using	O
+it	O
+at	O
+recommended	O
+doses	O
+for	O
+weight	O
+control	O
+.	O
+
+In	O
+addition	O
+,	O
+we	O
+review	O
+the	O
+7	O
+other	O
+cases	O
+of	O
+PPA	O
+related	O
+myocardial	B
+injury	I
+that	O
+have	O
+been	O
+reported	O
+so	O
+far	O
+.	O
+
+Physicians	O
+and	O
+patients	O
+should	O
+be	O
+alert	O
+to	O
+the	O
+potential	O
+cardiac	O
+risk	O
+associated	O
+with	O
+the	O
+use	O
+of	O
+PPA	O
+,	O
+even	O
+at	O
+doses	O
+generally	O
+considered	O
+to	O
+be	O
+safe	O
+.	O
+
+Differential	O
+diagnosis	O
+of	O
+high	O
+serum	O
+creatine	O
+kinase	O
+levels	O
+in	O
+systemic	B
+lupus	I
+erythematosus	I
+.	O
+
+We	O
+report	O
+the	O
+clinical	O
+and	O
+bioptic	O
+findings	O
+for	O
+a	O
+57	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+severe	O
+chloroquine	O
+-	O
+induced	O
+myopathy	B
+.	O
+
+Since	O
+1989	O
+,	O
+she	O
+had	O
+been	O
+suffering	O
+from	O
+systemic	B
+lupus	I
+erythematosus	I
+(	O
+SLE	B
+)	O
+with	O
+renal	B
+involvement	I
+and	O
+undergone	O
+periods	O
+of	O
+treatment	O
+with	O
+azathioprine	O
+and	O
+cyclophosphamide	O
+.	O
+
+Additional	O
+therapy	O
+with	O
+chloroquine	O
+(	O
+CQ	O
+)	O
+was	O
+started	O
+because	O
+of	O
+arthralgia	B
+.	O
+
+At	O
+the	O
+same	O
+time	O
+,	O
+slightly	O
+increased	O
+creatine	O
+kinase	O
+(	O
+CK	O
+)	O
+levels	O
+were	O
+noted	O
+.	O
+
+Myositis	B
+was	O
+suspected	O
+,	O
+and	O
+the	O
+patient	O
+was	O
+treated	O
+with	O
+steroids	O
+.	O
+
+The	O
+CK	O
+increase	O
+persisted	O
+,	O
+however	O
+,	O
+and	O
+she	O
+developed	O
+progressive	O
+muscular	B
+weakness	I
+and	O
+muscular	B
+atrophy	I
+.	O
+
+Routine	O
+controls	O
+revealed	O
+markedly	O
+elevated	O
+CK	O
+levels	O
+of	O
+1	O
+,	O
+700	O
+U	O
+/	O
+l	O
+.	O
+
+The	O
+neurological	O
+and	O
+electrophysiological	O
+findings	O
+were	O
+not	O
+typical	O
+of	O
+myositis	B
+.	O
+
+Thus	O
+,	O
+muscle	O
+biopsy	O
+of	O
+the	O
+deltoid	O
+muscle	O
+was	O
+performed	O
+in	O
+order	O
+to	O
+exclude	O
+polymyositis	B
+or	O
+toxic	O
+myopathy	B
+.	O
+
+As	O
+it	O
+revealed	O
+chloroquine	O
+-	O
+induced	O
+myopathy	B
+,	O
+medication	O
+was	O
+stopped	O
+.	O
+
+Discriminating	O
+between	O
+primary	O
+SLE	B
+-	O
+induced	O
+affection	B
+of	I
+the	I
+musculoskeletal	I
+system	I
+and	O
+drug	O
+-	O
+induced	O
+side	O
+effects	O
+is	O
+important	O
+for	O
+appropriate	O
+treatment	O
+of	O
+SLE	B
+patients	O
+.	O
+
+Seizure	B
+associated	O
+with	O
+sleep	B
+deprivation	I
+and	O
+sustained	O
+-	O
+release	O
+bupropion	O
+.	O
+
+This	O
+case	O
+report	O
+describes	O
+a	O
+generalized	O
+seizure	B
+associated	O
+with	O
+sustained	O
+-	O
+release	O
+bupropion	O
+use	O
+and	O
+sleep	B
+deprivation	I
+.	O
+
+The	O
+subject	O
+,	O
+a	O
+31	O
+-	O
+year	O
+-	O
+old	O
+female	O
+smoker	O
+,	O
+was	O
+participating	O
+in	O
+a	O
+clinical	O
+trial	O
+evaluating	O
+an	O
+investigational	O
+medication	O
+for	O
+smoking	O
+cessation	O
+that	O
+used	O
+sustained	O
+-	O
+release	O
+bupropion	O
+as	O
+an	O
+active	O
+control	O
+.	O
+
+After	O
+5	O
+weeks	O
+of	O
+bupropion	O
+use	O
+,	O
+the	O
+subject	O
+experienced	O
+a	O
+generalized	O
+tonic	O
+clonic	O
+seizure	B
+after	O
+staying	O
+up	O
+nearly	O
+all	O
+night	O
+packing	O
+and	O
+moving	O
+to	O
+a	O
+new	O
+residence	O
+.	O
+
+The	O
+patient	O
+had	O
+no	O
+other	O
+risk	O
+factors	O
+for	O
+seizures	B
+.	O
+
+We	O
+suggest	O
+that	O
+sleep	B
+deprivation	I
+may	O
+add	O
+to	O
+the	O
+risk	O
+of	O
+bupropion	O
+-	O
+associated	O
+seizures	B
+.	O
+
+Postoperative	B
+myalgia	I
+after	O
+succinylcholine	O
+:	O
+no	O
+evidence	O
+for	O
+an	O
+inflammatory	O
+origin	O
+.	O
+
+A	O
+common	O
+side	O
+effect	O
+associated	O
+with	O
+succinylcholine	O
+is	O
+postoperative	B
+myalgia	I
+.	O
+
+The	O
+pathogenesis	O
+of	O
+this	O
+myalgia	B
+is	O
+still	O
+unclear	O
+;	O
+inflammation	B
+has	O
+been	O
+suggested	O
+but	O
+without	O
+convincing	O
+evidence	O
+.	O
+
+We	O
+designed	O
+the	O
+present	O
+study	O
+to	O
+investigate	O
+whether	O
+an	O
+inflammatory	O
+reaction	O
+contributes	O
+to	O
+this	O
+myalgia	B
+.	O
+
+The	O
+incidence	O
+and	O
+severity	O
+of	O
+succinylcholine	O
+-	O
+associated	O
+myalgia	B
+was	O
+determined	O
+in	O
+64	O
+patients	O
+pretreated	O
+with	O
+saline	O
+or	O
+dexamethasone	O
+before	O
+succinylcholine	O
+(	O
+n	O
+=	O
+32	O
+for	O
+each	O
+)	O
+.	O
+
+Incidence	O
+and	O
+severity	O
+of	O
+myalgia	B
+did	O
+not	O
+differ	O
+significantly	O
+between	O
+the	O
+two	O
+groups	O
+:	O
+15	O
+patients	O
+in	O
+the	O
+dexamethasone	O
+group	O
+complained	O
+of	O
+myalgia	B
+compared	O
+with	O
+18	O
+patients	O
+in	O
+the	O
+saline	O
+group	O
+,	O
+and	O
+severe	O
+myalgia	B
+was	O
+reported	O
+by	O
+five	O
+patients	O
+and	O
+three	O
+patients	O
+,	O
+respectively	O
+(	O
+not	O
+significant	O
+)	O
+.	O
+
+At	O
+48	O
+h	O
+after	O
+surgery	O
+,	O
+12	O
+patients	O
+in	O
+both	O
+groups	O
+still	O
+suffered	O
+from	O
+myalgia	B
+(	O
+not	O
+significant	O
+)	O
+.	O
+
+In	O
+addition	O
+,	O
+interleukin	O
+-	O
+6	O
+(	O
+IL	O
+-	O
+6	O
+)	O
+as	O
+an	O
+early	O
+marker	O
+of	O
+inflammation	B
+was	O
+assessed	O
+in	O
+a	O
+subgroup	O
+of	O
+10	O
+patients	O
+pretreated	O
+with	O
+saline	O
+.	O
+
+We	O
+found	O
+an	O
+increase	O
+of	O
+IL	O
+-	O
+6	O
+for	O
+only	O
+three	O
+patients	O
+,	O
+but	O
+only	O
+one	O
+patient	O
+reported	O
+myalgia	B
+;	O
+no	O
+relationship	O
+between	O
+myalgia	B
+and	O
+the	O
+increase	O
+of	O
+IL	O
+-	O
+6	O
+was	O
+found	O
+.	O
+
+In	O
+conclusion	O
+,	O
+there	O
+is	O
+no	O
+evidence	O
+for	O
+an	O
+inflammatory	O
+origin	O
+of	O
+succinylcholine	O
+-	O
+associated	O
+myalgia	B
+.	O
+
+IMPLICATIONS	O
+:	O
+Administration	O
+of	O
+dexamethasone	O
+before	O
+succinylcholine	O
+was	O
+not	O
+effective	O
+in	O
+decreasing	O
+the	O
+incidence	O
+or	O
+the	O
+severity	O
+of	O
+succinylcholine	O
+-	O
+induced	O
+postoperative	B
+myalgia	I
+.	O
+
+Furthermore	O
+,	O
+there	O
+was	O
+no	O
+significant	O
+relationship	O
+between	O
+postoperative	B
+myalgia	I
+and	O
+time	O
+course	O
+of	O
+interleukin	O
+-	O
+6	O
+concentrations	O
+,	O
+a	O
+marker	O
+of	O
+inflammation	B
+.	O
+
+Pretreatment	O
+with	O
+dexamethasone	O
+is	O
+not	O
+justified	O
+to	O
+prevent	O
+postoperative	B
+myalgia	I
+after	O
+succinylcholine	O
+.	O
+
+Effect	O
+of	O
+lindane	O
+on	O
+hepatic	O
+and	O
+brain	O
+cytochrome	O
+P450s	O
+and	O
+influence	O
+of	O
+P450	O
+modulation	O
+in	O
+lindane	O
+induced	O
+neurotoxicity	B
+.	O
+
+Oral	O
+administration	O
+of	O
+lindane	O
+(	O
+2	O
+.	O
+5	O
+,	O
+5	O
+,	O
+10	O
+and	O
+15	O
+mg	O
+/	O
+kg	O
+,	O
+body	O
+weight	O
+)	O
+for	O
+5	O
+days	O
+was	O
+found	O
+to	O
+produce	O
+a	O
+dose	O
+-	O
+dependent	O
+increase	O
+in	O
+the	O
+activity	O
+of	O
+P450	O
+dependent	O
+7	O
+-	O
+ethoxyresorufin	O
+-	O
+O	O
+-	O
+deethylase	O
+(	O
+EROD	O
+)	O
+,	O
+7	O
+-	O
+pentoxyresorufin	O
+-	O
+O	O
+-	O
+dealkylase	O
+(	O
+PROD	O
+)	O
+and	O
+N	O
+-	O
+nitrosodimethylamine	O
+demethylase	O
+(	O
+NDMA	O
+-	O
+d	O
+)	O
+in	O
+rat	O
+brain	O
+and	O
+liver	O
+.	O
+
+A	O
+significant	O
+increase	O
+in	O
+the	O
+hepatic	O
+and	O
+brain	O
+P450	O
+monooxygenases	O
+was	O
+also	O
+observed	O
+when	O
+the	O
+duration	O
+of	O
+exposure	O
+of	O
+low	O
+dose	O
+(	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+of	O
+lindane	O
+was	O
+increased	O
+from	O
+5	O
+days	O
+to	O
+15	O
+or	O
+21	O
+days	O
+.	O
+
+As	O
+observed	O
+with	O
+different	O
+doses	O
+,	O
+the	O
+magnitude	O
+of	O
+induction	O
+in	O
+the	O
+activity	O
+of	O
+P450	O
+monooxygenases	O
+was	O
+several	O
+fold	O
+higher	O
+in	O
+liver	O
+microsomes	O
+when	O
+compared	O
+with	O
+the	O
+brain	O
+.	O
+
+Western	O
+blotting	O
+studies	O
+have	O
+indicated	O
+that	O
+the	O
+increase	O
+in	O
+the	O
+P450	O
+enzymes	O
+could	O
+be	O
+due	O
+to	O
+the	O
+increase	O
+in	O
+the	O
+expression	O
+of	O
+P450	O
+1A1	O
+/	O
+1A2	O
+,	O
+2B1	O
+/	O
+2B2	O
+and	O
+2E1	O
+isoenzymes	O
+.	O
+
+In	O
+vitro	O
+studies	O
+using	O
+organic	O
+inhibitors	O
+specific	O
+for	O
+individual	O
+P450	O
+isoenzymes	O
+and	O
+antibody	O
+inhibition	O
+experiments	O
+have	O
+further	O
+demonstrated	O
+that	O
+the	O
+increase	O
+in	O
+the	O
+activity	O
+of	O
+PROD	O
+,	O
+EROD	O
+and	O
+NDMA	O
+-	O
+d	O
+are	O
+due	O
+to	O
+the	O
+increase	O
+in	O
+the	O
+levels	O
+of	O
+P450	O
+2B1	O
+/	O
+2B2	O
+,	O
+1A1	O
+/	O
+1A2	O
+and	O
+2E1	O
+isoenzymes	O
+,	O
+respectively	O
+.	O
+
+Induction	O
+studies	O
+have	O
+further	O
+shown	O
+that	O
+while	O
+pretreatment	O
+of	O
+3	O
+-	O
+methylcholanthrene	O
+(	O
+MC	O
+)	O
+,	O
+an	O
+inducer	O
+of	O
+P4501A1	O
+/	O
+1A2	O
+,	O
+did	O
+not	O
+produce	O
+any	O
+significant	O
+effect	O
+in	O
+the	O
+incidence	O
+of	O
+lindane	O
+induced	O
+convulsions	B
+,	O
+pretreatment	O
+with	O
+phenobarbital	O
+(	O
+PB	O
+)	O
+,	O
+an	O
+inducer	O
+of	O
+P450	O
+2B1	O
+/	O
+2B2	O
+or	O
+ethanol	O
+,	O
+an	O
+inducer	O
+of	O
+P450	O
+2E1	O
+catalysed	O
+reactions	O
+,	O
+significantly	O
+increased	O
+the	O
+incidence	O
+of	O
+lindane	O
+induced	O
+convulsions	B
+.	O
+
+Similarly	O
+,	O
+when	O
+the	O
+P450	O
+-	O
+mediated	O
+metabolism	O
+of	O
+lindane	O
+was	O
+blocked	O
+by	O
+cobalt	O
+chloride	O
+incidence	O
+of	O
+convulsions	B
+was	O
+increased	O
+in	O
+animals	O
+treated	O
+with	O
+lindane	O
+indicating	O
+that	O
+lindane	O
+per	O
+se	O
+or	O
+its	O
+metabolites	O
+formed	O
+by	O
+PB	O
+or	O
+ethanol	O
+inducible	O
+P450	O
+isoenzymes	O
+are	O
+involved	O
+in	O
+its	O
+neurobehavioral	O
+toxicity	B
+.	O
+
+Absolute	O
+and	O
+attributable	O
+risk	O
+of	O
+venous	B
+thromboembolism	I
+in	O
+women	O
+on	O
+combined	O
+cyproterone	O
+acetate	O
+and	O
+ethinylestradiol	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+achieve	O
+absolute	O
+risk	O
+estimates	O
+of	O
+venous	B
+thromboembolism	I
+(	O
+VTE	B
+)	O
+among	O
+women	O
+on	O
+cyproterone	O
+acetate	O
+plus	O
+ethinylestradiol	O
+(	O
+CPA	O
+/	O
+EE	O
+)	O
+,	O
+and	O
+among	O
+women	O
+on	O
+combined	O
+oral	O
+contraceptives	O
+(	O
+COCs	O
+)	O
+.	O
+
+METHODS	O
+:	O
+From	O
+the	O
+Danish	O
+National	O
+Register	O
+of	O
+Patients	O
+(	O
+NRP	O
+)	O
+,	O
+1996	O
+to	O
+1998	O
+,	O
+the	O
+records	O
+of	O
+1	O
+.	O
+1	O
+million	O
+Danish	O
+women	O
+,	O
+ages	O
+15	O
+to	O
+44	O
+years	O
+,	O
+were	O
+searched	O
+for	O
+evidence	O
+of	O
+VTE	B
+.	O
+
+COC	O
+use	O
+was	O
+ascertained	O
+through	O
+mailed	O
+questionnaires	O
+.	O
+
+Sales	O
+statistics	O
+of	O
+COCs	O
+and	O
+CPA	O
+/	O
+EE	O
+were	O
+provided	O
+through	O
+Danish	O
+Drug	O
+Statistics	O
+.	O
+
+RESULTS	O
+:	O
+During	O
+the	O
+time	O
+frame	O
+of	O
+the	O
+study	O
+,	O
+330	O
+women	O
+were	O
+found	O
+to	O
+have	O
+had	O
+VTE	B
+while	O
+on	O
+COCs	O
+.	O
+
+Of	O
+these	O
+women	O
+,	O
+67	O
+were	O
+on	O
+levonorgestrel	O
+-	O
+containing	O
+COCs	O
+.	O
+
+Eleven	O
+were	O
+on	O
+CPA	O
+/	O
+EE	O
+.	O
+
+The	O
+corresponding	O
+absolute	O
+risk	O
+of	O
+VTE	B
+was	O
+3	O
+.	O
+4	O
+(	O
+range	O
+,	O
+3	O
+.	O
+1	O
+-	O
+3	O
+.	O
+8	O
+)	O
+per	O
+10	O
+000	O
+women	O
+years	O
+among	O
+the	O
+women	O
+on	O
+COCs	O
+,	O
+4	O
+.	O
+2	O
+(	O
+range	O
+,	O
+3	O
+.	O
+2	O
+-	O
+5	O
+.	O
+2	O
+)	O
+per	O
+10	O
+000	O
+women	O
+years	O
+among	O
+women	O
+on	O
+levonorgestrel	O
+-	O
+containing	O
+COCs	O
+,	O
+and	O
+3	O
+.	O
+1	O
+(	O
+range	O
+,	O
+1	O
+.	O
+3	O
+-	O
+4	O
+.	O
+9	O
+)	O
+per	O
+10	O
+000	O
+women	O
+years	O
+among	O
+the	O
+women	O
+on	O
+CPA	O
+/	O
+EE	O
+.	O
+
+CONCLUSION	O
+:	O
+Our	O
+results	O
+suggest	O
+the	O
+absolute	O
+risk	O
+of	O
+VTE	B
+among	O
+Danish	O
+women	O
+on	O
+COCs	O
+is	O
+similar	O
+to	O
+that	O
+among	O
+women	O
+taking	O
+CPA	O
+/	O
+EE	O
+.	O
+
+Comparison	O
+of	O
+developmental	O
+toxicology	O
+of	O
+aspirin	O
+(	O
+acetylsalicylic	O
+acid	O
+)	O
+in	O
+rats	O
+using	O
+selected	O
+dosing	O
+paradigms	O
+.	O
+
+BACKGROUND	O
+:	O
+Analysis	O
+of	O
+the	O
+literature	O
+for	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+(	O
+NSAIDs	O
+)	O
+suggests	O
+that	O
+a	O
+low	O
+incidence	O
+of	O
+developmental	B
+anomalies	I
+occurs	O
+in	O
+rats	O
+given	O
+NSAIDs	O
+on	O
+specific	O
+days	O
+during	O
+organogenesis	O
+.	O
+
+Aspirin	O
+(	O
+acetylsalicylic	O
+acid	O
+[	O
+ASA	O
+]	O
+)	O
+,	O
+an	O
+irreversible	O
+cyclooxygenase	O
+1	O
+and	O
+2	O
+inhibitor	O
+,	O
+induces	O
+developmental	B
+anomalies	I
+when	O
+administered	O
+to	O
+Wistar	O
+rats	O
+on	O
+gestational	O
+day	O
+(	O
+GD	O
+)	O
+9	O
+,	O
+10	O
+,	O
+or	O
+11	O
+(	O
+Kimmel	O
+CA	O
+,	O
+Wilson	O
+JG	O
+,	O
+Schumacher	O
+HJ	O
+.	O
+Teratology	O
+4	O
+:	O
+15	O
+-	O
+24	O
+,	O
+1971	O
+)	O
+.	O
+
+There	O
+are	O
+no	O
+published	O
+ASA	O
+studies	O
+using	O
+the	O
+multiple	O
+dosing	O
+paradigm	O
+of	O
+GDs	O
+6	O
+to	O
+17	O
+.	O
+
+Objectives	O
+of	O
+the	O
+current	O
+study	O
+were	O
+to	O
+compare	O
+results	O
+between	O
+Sprague	O
+-	O
+Dawley	O
+(	O
+SD	O
+)	O
+and	O
+Wistar	O
+strains	O
+when	O
+ASA	O
+is	O
+administered	O
+on	O
+GD	O
+9	O
+,	O
+10	O
+,	O
+or	O
+11	O
+;	O
+to	O
+compare	O
+the	O
+malformation	O
+patterns	O
+following	O
+single	O
+and	O
+multiple	O
+dosings	O
+during	O
+organogenesis	O
+in	O
+SD	O
+rats	O
+;	O
+and	O
+to	O
+test	O
+the	O
+hypothesis	O
+that	O
+maternal	O
+gastrointestinal	B
+toxicity	I
+confounds	O
+the	O
+detection	O
+of	O
+low	O
+incidence	O
+malformations	B
+with	O
+ASA	O
+when	O
+a	O
+multiple	O
+dosing	O
+paradigm	O
+is	O
+used	O
+.	O
+
+METHODS	O
+:	O
+ASA	O
+was	O
+administered	O
+as	O
+a	O
+single	O
+dose	O
+on	O
+GD	O
+9	O
+(	O
+0	O
+,	O
+250	O
+,	O
+500	O
+,	O
+or	O
+625	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+10	O
+(	O
+0	O
+,	O
+500	O
+,	O
+625	O
+,	O
+or	O
+750	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+or	O
+11	O
+(	O
+0	O
+,	O
+500	O
+,	O
+750	O
+,	O
+or	O
+1000	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+from	O
+GD	O
+6	O
+to	O
+GD	O
+17	O
+(	O
+0	O
+,	O
+50	O
+,	O
+125	O
+,	O
+or	O
+250	O
+mg	O
+/	O
+kg	O
+a	O
+day	O
+)	O
+in	O
+the	O
+multiple	O
+dose	O
+study	O
+to	O
+SD	O
+rats	O
+.	O
+
+Animals	O
+were	O
+killed	O
+on	O
+GD	O
+21	O
+,	O
+and	O
+fetuses	O
+were	O
+examined	O
+viscerally	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+literature	O
+evaluation	O
+suggested	O
+that	O
+NSAIDs	O
+induce	O
+ventricular	B
+septal	I
+defects	I
+(	O
+VSDs	B
+)	O
+and	O
+midline	B
+defects	I
+(	O
+MDs	B
+)	O
+in	O
+rats	O
+and	O
+diaphragmatic	B
+hernia	I
+(	O
+DH	B
+)	O
+,	O
+MDs	B
+,	O
+and	O
+VSDs	B
+in	O
+rabbits	O
+(	O
+Cook	O
+JC	O
+et	O
+al	O
+.	O
+,	O
+2003	O
+)	O
+;	O
+hence	O
+,	O
+the	O
+present	O
+study	O
+focused	O
+on	O
+these	O
+malformations	B
+,	O
+even	O
+though	O
+ASA	O
+induces	O
+several	O
+other	O
+low	O
+-	O
+incidence	O
+malformations	B
+.	O
+
+In	O
+single	O
+dose	O
+studies	O
+,	O
+DH	B
+,	O
+MD	B
+,	O
+and	O
+VSD	B
+were	O
+induced	O
+on	O
+GDs	O
+9	O
+and	O
+10	O
+.	O
+
+VSD	B
+also	O
+was	O
+noted	O
+following	O
+treatment	O
+on	O
+GD	O
+11	O
+.	O
+
+In	O
+contrast	O
+,	O
+DH	B
+and	O
+MD	B
+were	O
+noted	O
+in	O
+the	O
+multiple	O
+dose	O
+study	O
+design	O
+only	O
+in	O
+the	O
+high	O
+-	O
+dose	O
+group	O
+,	O
+and	O
+VSD	B
+was	O
+noted	O
+across	O
+all	O
+dose	O
+groups	O
+.	O
+
+CONCLUSIONS	O
+:	O
+High	O
+concordance	O
+in	O
+major	O
+developmental	B
+anomalies	I
+between	O
+Wistar	O
+and	O
+SD	O
+rats	O
+were	O
+noted	O
+with	O
+the	O
+exception	O
+of	O
+VSD	B
+in	O
+the	O
+SD	O
+rats	O
+and	O
+hydrocephalus	B
+in	O
+the	O
+Wistar	O
+rats	O
+.	O
+
+Variations	O
+and	O
+malformations	B
+were	O
+similar	O
+when	O
+ASA	O
+was	O
+administered	O
+as	O
+a	O
+single	O
+dose	O
+or	O
+during	O
+the	O
+period	O
+of	O
+organogenesis	O
+(	O
+GDs	O
+6	O
+to	O
+17	O
+)	O
+.	O
+
+It	O
+was	O
+also	O
+evident	O
+that	O
+,	O
+by	O
+titrating	O
+the	O
+dose	O
+to	O
+achieve	O
+a	O
+maximum	O
+tolerated	O
+dose	O
+,	O
+malformations	B
+that	O
+normally	O
+occur	O
+at	O
+low	O
+incidence	O
+,	O
+as	O
+reported	O
+from	O
+previous	O
+single	O
+dose	O
+studies	O
+,	O
+could	O
+also	O
+be	O
+induced	O
+with	O
+ASA	O
+given	O
+at	O
+multiple	O
+doses	O
+.	O
+
+Reversal	O
+of	O
+central	O
+benzodiazepine	O
+effects	O
+by	O
+flumazenil	O
+after	O
+intravenous	O
+conscious	O
+sedation	O
+with	O
+diazepam	O
+and	O
+opioids	O
+:	O
+report	O
+of	O
+a	O
+double	O
+-	O
+blind	O
+multicenter	O
+study	O
+.	O
+
+The	O
+Flumazenil	O
+in	O
+Intravenous	O
+Conscious	O
+Sedation	O
+with	O
+Diazepam	O
+Multicenter	O
+Study	O
+Group	O
+II	O
+.	O
+
+The	O
+efficacy	O
+and	O
+safety	O
+of	O
+a	O
+new	O
+benzodiazepine	O
+antagonist	O
+,	O
+flumazenil	O
+,	O
+were	O
+assessed	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+multicenter	O
+study	O
+.	O
+
+Flumazenil	O
+(	O
+mean	O
+dose	O
+,	O
+0	O
+.	O
+76	O
+mg	O
+)	O
+or	O
+placebo	O
+(	O
+mean	O
+dose	O
+,	O
+8	O
+.	O
+9	O
+ml	O
+)	O
+was	O
+administered	O
+intravenously	O
+to	O
+130	O
+and	O
+67	O
+patients	O
+,	O
+respectively	O
+,	O
+who	O
+had	O
+been	O
+given	O
+diazepam	O
+in	O
+conjunction	O
+with	O
+an	O
+opioid	O
+(	O
+fentanyl	O
+,	O
+meperidine	O
+,	O
+or	O
+morphine	O
+)	O
+for	O
+the	O
+induction	O
+and	O
+maintenance	O
+of	O
+intravenous	O
+conscious	O
+sedation	O
+for	O
+diagnostic	O
+or	O
+therapeutic	O
+surgical	O
+procedures	O
+.	O
+
+The	O
+group	O
+assessable	O
+for	O
+efficacy	O
+comprised	O
+122	O
+patients	O
+treated	O
+with	O
+flumazenil	O
+and	O
+64	O
+patients	O
+given	O
+placebo	O
+.	O
+
+After	O
+5	O
+minutes	O
+,	O
+80	O
+/	O
+115	O
+(	O
+70	O
+%	O
+)	O
+flumazenil	O
+-	O
+treated	O
+patients	O
+,	O
+compared	O
+with	O
+21	O
+/	O
+63	O
+(	O
+33	O
+%	O
+)	O
+placebo	O
+-	O
+treated	O
+patients	O
+,	O
+were	O
+completely	O
+awake	O
+and	O
+alert	O
+,	O
+as	O
+indicated	O
+by	O
+a	O
+score	O
+of	O
+5	O
+on	O
+the	O
+Observer	O
+'	O
+s	O
+Assessment	O
+of	O
+Alertness	O
+/	O
+Sedation	O
+Scale	O
+.	O
+
+Ninety	O
+-	O
+five	O
+percent	O
+of	O
+patients	O
+in	O
+each	O
+group	O
+who	O
+attained	O
+a	O
+score	O
+of	O
+5	O
+at	O
+the	O
+5	O
+-	O
+minute	O
+assessment	O
+showed	O
+no	O
+loss	O
+of	O
+alertness	O
+throughout	O
+the	O
+180	O
+-	O
+minute	O
+assessment	O
+period	O
+.	O
+
+Flumazenil	O
+-	O
+treated	O
+patients	O
+also	O
+performed	O
+significantly	O
+better	O
+on	O
+the	O
+Finger	O
+-	O
+to	O
+-	O
+Nose	O
+Test	O
+and	O
+the	O
+recall	O
+of	O
+pictures	O
+shown	O
+at	O
+the	O
+5	O
+-	O
+minute	O
+assessment	O
+.	O
+
+Flumazenil	O
+was	O
+well	O
+tolerated	O
+,	O
+with	O
+no	O
+serious	O
+adverse	O
+effects	O
+reported	O
+.	O
+
+Thirty	O
+-	O
+nine	O
+(	O
+30	O
+%	O
+)	O
+of	O
+flumazenil	O
+-	O
+treated	O
+patients	O
+,	O
+compared	O
+with	O
+17	O
+(	O
+25	O
+%	O
+)	O
+of	O
+placebo	O
+-	O
+treated	O
+patients	O
+had	O
+one	O
+or	O
+more	O
+drug	O
+-	O
+related	O
+adverse	O
+experiences	O
+.	O
+
+The	O
+most	O
+common	O
+adverse	O
+effects	O
+were	O
+nausea	B
+and	O
+vomiting	B
+in	O
+the	O
+flumazenil	O
+group	O
+and	O
+nausea	B
+and	O
+injection	O
+-	O
+site	O
+pain	B
+in	O
+the	O
+placebo	O
+group	O
+.	O
+
+Flumazenil	O
+was	O
+found	O
+to	O
+promptly	O
+reverse	O
+sedation	O
+induced	O
+by	O
+diazepam	O
+in	O
+the	O
+presence	O
+of	O
+opioids	O
+.	O
+
+Methylphenidate	O
+-	O
+induced	O
+obsessive	B
+-	I
+compulsive	I
+symptoms	I
+in	O
+an	O
+elderly	O
+man	O
+.	O
+
+An	O
+82	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+treatment	B
+-	I
+resistant	I
+depression	I
+and	O
+early	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+was	O
+started	O
+on	O
+methylphenidate	O
+.	O
+
+Significant	O
+obsessive	B
+-	I
+compulsive	I
+behavior	I
+ensued	O
+but	O
+diminished	O
+over	O
+several	O
+weeks	O
+when	O
+methylphenidate	O
+was	O
+replaced	O
+by	O
+fluvoxamine	O
+.	O
+
+The	O
+patient	O
+had	O
+no	O
+prior	O
+psychiatric	B
+history	O
+,	O
+but	O
+he	O
+had	O
+a	O
+sister	O
+with	O
+obsessive	B
+-	I
+compulsive	I
+disorder	I
+.	O
+
+It	O
+appears	O
+that	O
+methylphenidate	O
+precipitated	O
+the	O
+patient	O
+'	O
+s	O
+pathological	O
+behavior	O
+.	O
+
+Ciprofloxacin	O
+-	O
+induced	O
+acute	O
+interstitial	B
+nephritis	I
+and	O
+autoimmune	B
+hemolytic	I
+anemia	I
+.	O
+
+Ciprofloxacin	O
+has	O
+been	O
+associated	O
+with	O
+several	O
+side	O
+effects	O
+including	O
+interstitial	B
+nephritis	I
+and	O
+hemolytic	B
+anemia	I
+.	O
+
+The	O
+combination	O
+of	O
+both	O
+side	O
+effects	O
+is	O
+extremely	O
+rare	O
+.	O
+
+In	O
+this	O
+report	O
+,	O
+we	O
+describe	O
+a	O
+case	O
+of	O
+ciprofloxacin	O
+-	O
+induced	O
+interstitial	B
+nephritis	I
+and	O
+autoimmune	B
+hemolytic	I
+anemia	I
+.	O
+
+Hemolytic	B
+anemia	I
+improved	O
+after	O
+stopping	O
+the	O
+drug	O
+and	O
+initiation	O
+of	O
+steroid	O
+therapy	O
+.	O
+
+Unfortunately	O
+,	O
+acute	O
+interstitial	B
+nephritis	I
+was	O
+irreversible	O
+and	O
+the	O
+patient	O
+developed	O
+end	B
+-	I
+stage	I
+renal	I
+disease	I
+.	O
+
+Potential	O
+deleterious	O
+effect	O
+of	O
+furosemide	O
+in	O
+radiocontrast	O
+nephropathy	B
+.	O
+
+The	O
+purpose	O
+of	O
+the	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+efficacy	O
+of	O
+furosemide	O
+in	O
+addition	O
+to	O
+intravenous	O
+fluids	O
+in	O
+the	O
+prevention	O
+of	O
+radiocontrast	O
+nephropathy	B
+.	O
+
+18	O
+patients	O
+,	O
+referred	O
+to	O
+a	O
+radiocontrast	O
+study	O
+,	O
+considered	O
+at	O
+risk	O
+because	O
+of	O
+preexisting	O
+renal	B
+insufficiency	I
+,	O
+were	O
+enrolled	O
+in	O
+a	O
+prospective	O
+,	O
+randomized	O
+,	O
+controlled	O
+trial	O
+,	O
+performed	O
+at	O
+the	O
+secondary	O
+care	O
+center	O
+of	O
+a	O
+1	O
+,	O
+100	O
+-	O
+bed	O
+private	O
+university	O
+hospital	O
+.	O
+
+In	O
+addition	O
+to	O
+fluids	O
+,	O
+the	O
+treatment	O
+group	O
+received	O
+furosemide	O
+(	O
+mean	O
+dose	O
+110	O
+mg	O
+)	O
+intravenously	O
+30	O
+min	O
+prior	O
+to	O
+the	O
+injection	O
+of	O
+contrast	O
+material	O
+.	O
+
+The	O
+control	O
+group	O
+received	O
+fluids	O
+(	O
+mean	O
+3	O
+liters	O
+)	O
+.	O
+
+Radiological	O
+studies	O
+were	O
+mostly	O
+angiographies	O
+performed	O
+with	O
+both	O
+ionic	O
+and	O
+non	O
+-	O
+ionic	O
+contrast	O
+material	O
+,	O
+at	O
+an	O
+average	O
+dose	O
+of	O
+245	O
+ml	O
+.	O
+
+Renal	B
+function	I
+significantly	I
+deteriorated	I
+in	O
+the	O
+group	O
+pretreated	O
+with	O
+furosemide	O
+(	O
+p	O
+<	O
+0	O
+.	O
+005	O
+by	O
+ANOVA	O
+)	O
+,	O
+with	O
+a	O
+rise	O
+in	O
+serum	O
+creatinine	O
+from	O
+145	O
++	O
+/	O
+-	O
+13	O
+to	O
+182	O
++	O
+/	O
+-	O
+16	O
+mumol	O
+/	O
+l	O
+at	O
+24	O
+h	O
+,	O
+while	O
+no	O
+change	O
+occurred	O
+in	O
+the	O
+control	O
+group	O
+(	O
+from	O
+141	O
++	O
+/	O
+-	O
+6	O
+to	O
+142	O
++	O
+/	O
+-	O
+7	O
+mumol	O
+/	O
+l	O
+)	O
+.	O
+
+Renal	B
+failure	I
+was	O
+associated	O
+with	O
+weight	B
+loss	I
+in	O
+the	O
+furosemide	O
+-	O
+treated	O
+group	O
+.	O
+
+Furosemide	O
+may	O
+be	O
+deleterious	O
+in	O
+the	O
+prevention	O
+of	O
+radiocontrast	O
+nephropathy	B
+.	O
+
+Progestational	O
+agents	O
+and	O
+blood	B
+coagulation	I
+.	O
+
+VII	O
+.	O
+
+Thromboembolic	B
+and	O
+other	O
+complications	O
+of	O
+oral	O
+contraceptive	O
+therapy	O
+in	O
+relationship	O
+to	O
+pretreatment	O
+levels	O
+of	O
+blood	B
+coagulation	I
+factors	O
+:	O
+summary	O
+report	O
+of	O
+a	O
+ten	O
+-	O
+year	O
+study	O
+.	O
+
+During	O
+a	O
+ten	O
+-	O
+year	O
+period	O
+,	O
+348	O
+women	O
+were	O
+studied	O
+for	O
+a	O
+total	O
+of	O
+5	O
+,	O
+877	O
+patient	O
+months	O
+in	O
+four	O
+separate	O
+studies	O
+relating	O
+oral	O
+contraceptives	O
+to	O
+changes	O
+in	O
+hematologic	O
+parameters	O
+.	O
+
+Significant	O
+increases	O
+in	O
+certain	O
+factors	O
+of	O
+the	O
+blood	B
+coagulation	I
+and	O
+fibrinolysin	O
+systems	O
+(	O
+factors	O
+I	O
+,	O
+II	O
+,	O
+VII	O
+,	O
+VIII	O
+,	O
+IX	O
+,	O
+and	O
+X	O
+and	O
+plasminogen	O
+)	O
+were	O
+observed	O
+in	O
+the	O
+treated	O
+groups	O
+.	O
+
+Severe	O
+complications	O
+developed	O
+in	O
+four	O
+patients	O
+.	O
+
+All	O
+four	O
+had	O
+an	O
+abnormal	O
+blood	B
+coagulation	I
+profile	O
+,	O
+suggesting	O
+"	O
+hypercoagulability	B
+"	O
+before	O
+initiation	O
+of	O
+therapy	O
+.	O
+
+Some	O
+of	O
+these	O
+findings	O
+represented	O
+the	O
+most	O
+extreme	O
+abnormalities	O
+seen	O
+in	O
+the	O
+entire	O
+group	O
+of	O
+patients	O
+;	O
+some	O
+increased	O
+further	O
+during	O
+therapy	O
+.	O
+
+One	O
+of	O
+these	O
+patients	O
+developed	O
+a	O
+myocardial	B
+infarction	I
+before	O
+receiving	O
+any	O
+medication	O
+,	O
+shortly	O
+after	O
+the	O
+base	O
+-	O
+line	O
+values	O
+were	O
+obtained	O
+.	O
+
+One	O
+patient	O
+developed	O
+retinopathy	B
+19	O
+months	O
+after	O
+she	O
+began	O
+therapy	O
+,	O
+and	O
+another	O
+developed	O
+thrombophlebitis	B
+after	O
+27	O
+months	O
+of	O
+therapy	O
+.	O
+
+The	O
+fourth	O
+patient	O
+developed	O
+thrombophlebitis	B
+14	O
+days	O
+after	O
+initiation	O
+of	O
+contraceptive	O
+therapy	O
+.	O
+
+All	O
+four	O
+patients	O
+were	O
+of	O
+the	O
+A	O
+or	O
+AB	O
+blood	O
+group	O
+.	O
+
+Previous	O
+studies	O
+suggested	O
+the	O
+possiblility	O
+of	O
+increased	O
+propensity	O
+for	O
+thromboembolic	B
+episodes	I
+in	O
+patients	O
+possessing	O
+the	O
+A	O
+antigen	O
+.	O
+
+It	O
+appears	O
+from	O
+these	O
+data	O
+that	O
+hematologic	O
+work	O
+-	O
+ups	O
+may	O
+be	O
+useful	O
+in	O
+women	O
+who	O
+are	O
+about	O
+to	O
+start	O
+long	O
+-	O
+term	O
+oral	O
+contraceptive	O
+therapy	O
+.	O
+
+Orthostatic	B
+hypotension	I
+occurs	O
+following	O
+alpha	O
+2	O
+-	O
+adrenoceptor	O
+blockade	O
+in	O
+chronic	O
+prazosin	O
+-	O
+pretreated	O
+conscious	O
+spontaneously	O
+hypertensive	B
+rats	O
+.	O
+
+1	O
+.	O
+
+Studies	O
+were	O
+performed	O
+to	O
+evaluate	O
+whether	O
+chronic	O
+prazosin	O
+treatment	O
+alters	O
+the	O
+alpha	O
+2	O
+-	O
+adrenoceptor	O
+function	O
+for	O
+orthostatic	O
+control	O
+of	O
+arterial	O
+blood	O
+pressure	O
+in	O
+conscious	O
+spontaneously	O
+hypertensive	B
+rats	O
+(	O
+SHR	O
+)	O
+.	O
+
+2	O
+.	O
+
+Conscious	O
+SHR	O
+(	O
+male	O
+300	O
+-	O
+350	O
+g	O
+)	O
+were	O
+subjected	O
+to	O
+90	O
+degrees	O
+head	O
+-	O
+up	O
+tilts	O
+for	O
+60	O
+s	O
+following	O
+acute	O
+administration	O
+of	O
+prazosin	O
+(	O
+0	O
+.	O
+1	O
+mg	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+p	O
+.	O
+)	O
+or	O
+rauwolscine	O
+(	O
+3	O
+mg	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+v	O
+.	O
+)	O
+.	O
+
+Orthostatic	B
+hypotension	I
+was	O
+determined	O
+by	O
+the	O
+average	O
+decrease	O
+(	O
+%	O
+)	O
+in	O
+mean	O
+arterial	O
+pressure	O
+(	O
+MAP	O
+femoral	O
+)	O
+over	O
+the	O
+60	O
+-	O
+s	O
+tilt	O
+period	O
+.	O
+
+The	O
+basal	O
+MAP	O
+of	O
+conscious	O
+SHR	O
+was	O
+reduced	O
+to	O
+a	O
+similar	O
+extent	O
+by	O
+prazosin	O
+(	O
+-	O
+23	O
+%	O
+(	O
+-	O
+)	O
+-	O
+26	O
+%	O
+MAP	O
+)	O
+and	O
+rauwolscine	O
+(	O
+-	O
+16	O
+%	O
+(	O
+-	O
+)	O
+-	O
+33	O
+%	O
+MAP	O
+)	O
+.	O
+
+However	O
+,	O
+the	O
+head	O
+-	O
+up	O
+tilt	O
+induced	O
+orthostatic	B
+hypotension	I
+in	O
+the	O
+SHR	O
+treated	O
+with	O
+prazosin	O
+(	O
+-	O
+16	O
+%	O
+MAP	O
+,	O
+n	O
+=	O
+6	O
+)	O
+,	O
+but	O
+not	O
+in	O
+the	O
+SHR	O
+treated	O
+with	O
+rauwolscine	O
+(	O
+less	O
+than	O
++	O
+2	O
+%	O
+MAP	O
+,	O
+n	O
+=	O
+6	O
+)	O
+.	O
+
+3	O
+.	O
+
+Conscious	O
+SHR	O
+were	O
+treated	O
+for	O
+4	O
+days	O
+with	O
+prazosin	O
+at	O
+2	O
+mg	O
+kg	O
+-	O
+1	O
+day	O
+-	O
+1	O
+i	O
+.	O
+p	O
+.	O
+for	O
+chronic	O
+alpha	O
+1	O
+-	O
+adrenoceptor	O
+blockade	O
+.	O
+
+MAP	O
+in	O
+conscious	O
+SHR	O
+after	O
+chronic	O
+prazosin	O
+treatment	O
+was	O
+14	O
+%	O
+lower	O
+than	O
+in	O
+the	O
+untreated	O
+SHR	O
+(	O
+n	O
+=	O
+8	O
+)	O
+.	O
+
+Head	O
+-	O
+up	O
+tilts	O
+in	O
+these	O
+rats	O
+did	O
+not	O
+produce	O
+orthostatic	B
+hypotension	I
+when	O
+performed	O
+either	O
+prior	O
+to	O
+or	O
+after	O
+acute	O
+dosing	O
+of	O
+prazosin	O
+(	O
+0	O
+.	O
+1	O
+mg	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+Conversely	O
+,	O
+administration	O
+of	O
+rauwolscine	O
+(	O
+3	O
+mg	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+v	O
+.	O
+)	O
+in	O
+chronic	O
+prazosin	O
+treated	O
+SHR	O
+decreased	O
+the	O
+basal	O
+MAP	O
+by	O
+12	O
+-	O
+31	O
+%	O
+(	O
+n	O
+=	O
+4	O
+)	O
+,	O
+and	O
+subsequent	O
+tilts	O
+induced	O
+further	O
+drops	O
+of	O
+MAP	O
+by	O
+19	O
+-	O
+23	O
+%	O
+in	O
+these	O
+rats	O
+.	O
+
+4	O
+.	O
+
+The	O
+pressor	O
+responses	O
+and	O
+bradycardia	B
+to	O
+the	O
+alpha	O
+1	O
+-	O
+agonist	O
+cirazoline	O
+(	O
+0	O
+.	O
+6	O
+and	O
+2	O
+micrograms	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+v	O
+.	O
+)	O
+,	O
+the	O
+alpha	O
+2	O
+-	O
+agonist	O
+Abbott	O
+-	O
+53693	O
+(	O
+1	O
+and	O
+3	O
+micrograms	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+v	O
+.	O
+)	O
+,	O
+and	O
+noradrenaline	O
+(	O
+0	O
+.	O
+1	O
+and	O
+1	O
+.	O
+0	O
+micrograms	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+v	O
+.	O
+)	O
+were	O
+determined	O
+in	O
+conscious	O
+SHR	O
+with	O
+and	O
+without	O
+chronic	O
+prazosin	O
+pretreatment	O
+.	O
+
+Both	O
+the	O
+pressor	O
+and	O
+bradycardia	B
+effects	O
+of	O
+cirazoline	O
+were	O
+abolished	O
+in	O
+chronic	O
+prazosin	O
+treated	O
+SHR	O
+(	O
+n	O
+=	O
+4	O
+)	O
+as	O
+compared	O
+to	O
+the	O
+untreated	O
+SHR	O
+(	O
+n	O
+=	O
+4	O
+)	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+the	O
+pressor	O
+effects	O
+of	O
+Abbott	O
+-	O
+53693	O
+were	O
+similar	O
+in	O
+both	O
+groups	O
+of	O
+SHR	O
+,	O
+but	O
+the	O
+accompanying	O
+bradycardia	B
+was	O
+greater	O
+in	O
+SHR	O
+with	O
+chronic	O
+prazosin	O
+treatment	O
+than	O
+without	O
+such	O
+treatment	O
+.	O
+
+Furthermore	O
+,	O
+the	O
+bradycardia	B
+that	O
+accompanied	O
+the	O
+noradrenaline	O
+-	O
+induced	O
+pressor	O
+effect	O
+in	O
+SHR	O
+was	O
+similar	O
+with	O
+and	O
+without	O
+chronic	O
+prazosin	O
+treatment	O
+despite	O
+a	O
+47	O
+-	O
+71	O
+%	O
+reduction	O
+of	O
+the	O
+pressor	O
+effect	O
+in	O
+chronic	O
+alpha	O
+1	O
+-	O
+receptor	O
+blocked	O
+SHR	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+400	O
+WORDS	O
+)	O
+
+Hemolytic	B
+-	I
+uremic	I
+syndrome	I
+associated	O
+with	O
+ingestion	O
+of	O
+quinine	O
+.	O
+
+Hemolytic	B
+-	I
+uremic	I
+syndrome	I
+following	O
+quinine	O
+ingestion	O
+is	O
+a	O
+newly	O
+described	O
+phenomenon	O
+,	O
+with	O
+just	O
+two	O
+previous	O
+descriptions	O
+of	O
+4	O
+cases	O
+in	O
+the	O
+literature	O
+.	O
+
+We	O
+describe	O
+a	O
+5th	O
+case	O
+.	O
+
+The	O
+reaction	O
+may	O
+be	O
+mediated	O
+by	O
+the	O
+presence	O
+of	O
+antibodies	O
+reactive	O
+against	O
+platelets	O
+in	O
+the	O
+presence	O
+of	O
+quinine	O
+.	O
+
+Treatment	O
+has	O
+included	O
+use	O
+of	O
+plasma	O
+exchange	O
+,	O
+prednisone	O
+,	O
+aspirin	O
+,	O
+and	O
+dipyridamole	O
+.	O
+
+The	O
+patients	O
+have	O
+all	O
+regained	O
+some	O
+degree	O
+of	O
+renal	O
+function	O
+.	O
+
+However	O
+,	O
+it	O
+is	O
+unclear	O
+whether	O
+pharmacological	O
+treatment	O
+or	O
+spontaneous	O
+resolution	O
+is	O
+responsible	O
+for	O
+the	O
+improvement	O
+.	O
+
+Quinine	O
+-	O
+associated	O
+hemolytic	B
+-	I
+uremic	I
+syndrome	I
+probably	O
+occurs	O
+more	O
+often	O
+than	O
+is	O
+recognized	O
+.	O
+
+It	O
+is	O
+important	O
+to	O
+recognize	O
+this	O
+reaction	O
+when	O
+it	O
+occurs	O
+and	O
+to	O
+avoid	O
+further	O
+quinine	O
+exposure	O
+,	O
+since	O
+the	O
+reaction	O
+seems	O
+to	O
+be	O
+recurrent	O
+.	O
+
+Amnestic	B
+syndrome	I
+associated	O
+with	O
+propranolol	O
+toxicity	B
+:	O
+a	O
+case	O
+report	O
+.	O
+
+An	O
+elderly	O
+woman	O
+developed	O
+an	O
+Alzheimer	B
+-	O
+like	O
+subacute	O
+dementia	B
+as	O
+a	O
+result	O
+of	O
+propranolol	O
+toxicity	B
+.	O
+
+Analysis	O
+of	O
+the	O
+manifestations	O
+showed	O
+that	O
+severe	O
+impairment	O
+of	O
+memory	O
+accounted	O
+for	O
+virtually	O
+all	O
+of	O
+the	O
+abnormalities	O
+.	O
+
+There	O
+is	O
+evidence	O
+that	O
+cerebral	O
+reactions	O
+to	O
+drug	O
+toxicity	B
+can	O
+exhibit	O
+patterns	O
+that	O
+suggest	O
+highly	O
+selective	O
+involvement	O
+of	O
+functional	O
+subdivisions	O
+of	O
+the	O
+brain	O
+.	O
+
+Cefotetan	O
+-	O
+induced	O
+immune	O
+hemolytic	B
+anemia	I
+.	O
+
+Immune	O
+hemolytic	B
+anemia	I
+due	O
+to	O
+a	O
+drug	O
+-	O
+adsorption	O
+mechanism	O
+has	O
+been	O
+described	O
+primarily	O
+in	O
+patients	O
+receiving	O
+penicillins	O
+and	O
+first	O
+-	O
+generation	O
+cephalosporins	O
+.	O
+
+We	O
+describe	O
+a	O
+patient	O
+who	O
+developed	O
+anemia	B
+while	O
+receiving	O
+intravenous	O
+cefotetan	O
+.	O
+
+Cefotetan	O
+-	O
+dependent	O
+antibodies	O
+were	O
+detected	O
+in	O
+the	O
+patient	O
+'	O
+s	O
+serum	O
+and	O
+in	O
+an	O
+eluate	O
+prepared	O
+from	O
+his	O
+red	O
+blood	O
+cells	O
+.	O
+
+The	O
+eluate	O
+also	O
+reacted	O
+weakly	O
+with	O
+red	O
+blood	O
+cells	O
+in	O
+the	O
+absence	O
+of	O
+cefotetan	O
+,	O
+suggesting	O
+the	O
+concomitant	O
+formation	O
+of	O
+warm	O
+-	O
+reactive	O
+autoantibodies	O
+.	O
+
+These	O
+observations	O
+,	O
+in	O
+conjunction	O
+with	O
+clinical	O
+and	O
+laboratory	O
+evidence	O
+of	O
+extravascular	O
+hemolysis	B
+,	O
+are	O
+consistent	O
+with	O
+drug	O
+-	O
+induced	O
+hemolytic	B
+anemia	I
+,	O
+possibly	O
+involving	O
+both	O
+drug	O
+-	O
+adsorption	O
+and	O
+autoantibody	O
+formation	O
+mechanisms	O
+.	O
+
+This	O
+case	O
+emphasizes	O
+the	O
+need	O
+for	O
+increased	O
+awareness	O
+of	O
+hemolytic	O
+reactions	O
+to	O
+all	O
+cephalosporins	O
+.	O
+
+Use	O
+of	O
+dexamethasone	O
+with	O
+mesna	O
+for	O
+the	O
+prevention	O
+of	O
+ifosfamide	O
+-	O
+induced	O
+hemorrhagic	B
+cystitis	I
+.	O
+
+AIM	O
+:	O
+Hemorrhagic	B
+cystitis	I
+(	O
+HC	B
+)	O
+is	O
+a	O
+limiting	O
+side	O
+-	O
+effect	O
+of	O
+chemotherapy	O
+with	O
+ifosfamide	O
+(	O
+IFS	O
+)	O
+.	O
+
+In	O
+the	O
+study	O
+presented	O
+here	O
+,	O
+we	O
+investigated	O
+the	O
+use	O
+of	O
+dexamethasone	O
+in	O
+combination	O
+with	O
+mesna	O
+for	O
+the	O
+prevention	O
+of	O
+IFS	O
+-	O
+induced	O
+HC	B
+.	O
+
+METHODS	O
+:	O
+Male	O
+Wistar	O
+rats	O
+(	O
+150	O
+-	O
+200	O
+g	O
+;	O
+6	O
+rats	O
+per	O
+group	O
+)	O
+were	O
+treated	O
+with	O
+saline	O
+or	O
+mesna	O
+5	O
+min	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+before	O
+and	O
+2	O
+and	O
+6	O
+h	O
+after	O
+(	O
+v	O
+.	O
+o	O
+.	O
+)	O
+administration	O
+of	O
+IFS	O
+.	O
+
+One	O
+,	O
+two	O
+or	O
+three	O
+doses	O
+of	O
+mesna	O
+were	O
+replaced	O
+with	O
+dexamethasone	O
+alone	O
+or	O
+with	O
+dexamethasone	O
+plus	O
+mesna	O
+.	O
+
+Cystitis	B
+was	O
+evaluated	O
+24	O
+h	O
+after	O
+its	O
+induction	O
+by	O
+the	O
+changes	O
+in	O
+bladder	O
+wet	O
+weight	O
+and	O
+by	O
+macroscopic	O
+and	O
+microscopic	O
+analysis	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+replacement	O
+of	O
+the	O
+last	O
+dose	O
+or	O
+the	O
+last	O
+two	O
+doses	O
+of	O
+mesna	O
+with	O
+dexamethasone	O
+reduced	O
+the	O
+increase	O
+in	O
+bladder	O
+wet	O
+weight	O
+induced	O
+by	O
+IFS	O
+by	O
+84	O
+.	O
+79	O
+%	O
+and	O
+89	O
+.	O
+13	O
+%	O
+,	O
+respectively	O
+.	O
+
+In	O
+addition	O
+,	O
+it	O
+almost	O
+abolished	O
+the	O
+macroscopic	O
+and	O
+microscopic	O
+alterations	O
+induced	O
+by	O
+IFS	O
+.	O
+
+Moreover	O
+,	O
+the	O
+addition	O
+of	O
+dexamethasone	O
+to	O
+the	O
+last	O
+two	O
+doses	O
+of	O
+mesna	O
+was	O
+more	O
+efficient	O
+than	O
+three	O
+doses	O
+of	O
+mesna	O
+alone	O
+when	O
+evaluated	O
+microscopically	O
+.	O
+
+CONCLUSION	O
+:	O
+Dexamethasone	O
+in	O
+combination	O
+with	O
+mesna	O
+was	O
+efficient	O
+in	O
+blocking	O
+IFS	O
+-	O
+induced	O
+HC	B
+.	O
+
+However	O
+,	O
+the	O
+replacement	O
+of	O
+last	O
+two	O
+doses	O
+of	O
+mesna	O
+with	O
+saline	O
+or	O
+all	O
+of	O
+the	O
+mesna	O
+doses	O
+with	O
+dexamethasone	O
+did	O
+not	O
+prevent	O
+HC	B
+.	O
+
+All	O
+-	O
+trans	O
+-	O
+retinoic	O
+acid	O
+-	O
+induced	O
+erythema	B
+nodosum	I
+in	O
+patients	O
+with	O
+acute	B
+promyelocytic	I
+leukemia	I
+.	O
+
+Erythema	B
+nodosum	I
+associated	O
+with	O
+all	O
+-	O
+trans	O
+-	O
+retinoic	O
+acid	O
+(	O
+ATRA	O
+)	O
+for	O
+acute	B
+promyelocytic	I
+leukemia	I
+(	O
+APL	B
+)	O
+is	O
+very	O
+rare	O
+.	O
+
+We	O
+describe	O
+four	O
+patients	O
+with	O
+classic	O
+APL	B
+who	O
+developed	O
+erythema	B
+nodosum	I
+during	O
+ATRA	O
+therapy	O
+.	O
+
+Fever	B
+and	O
+subsequent	O
+multiple	O
+painful	B
+erythematous	B
+nodules	I
+over	O
+extremities	O
+developed	O
+on	O
+D11	O
+,	O
+D16	O
+,	O
+D17	O
+,	O
+and	O
+D19	O
+,	O
+respectively	O
+,	O
+after	O
+ATRA	O
+therapy	O
+.	O
+
+The	O
+skin	O
+biopsy	O
+taken	O
+from	O
+each	O
+patient	O
+was	O
+consistent	O
+with	O
+erythema	B
+nodosum	I
+.	O
+
+All	O
+patients	O
+received	O
+short	O
+course	O
+of	O
+steroids	O
+.	O
+
+Fever	B
+subsided	O
+rapidly	O
+and	O
+the	O
+skin	O
+lesions	O
+regressed	O
+completely	O
+.	O
+
+All	O
+patients	O
+achieved	O
+complete	O
+remission	O
+without	O
+withdrawal	O
+of	O
+ATRA	O
+.	O
+
+ATRA	O
+seemed	O
+to	O
+be	O
+the	O
+most	O
+possible	O
+etiology	O
+of	O
+erythema	B
+nodosum	I
+in	O
+our	O
+patients	O
+.	O
+
+Short	O
+-	O
+term	O
+use	O
+of	O
+steroid	O
+is	O
+very	O
+effective	O
+in	O
+ATRA	O
+-	O
+induced	O
+erythema	B
+nodosum	I
+.	O
+
+Effect	O
+of	O
+some	O
+convulsants	O
+on	O
+the	O
+protective	O
+activity	O
+of	O
+loreclezole	O
+and	O
+its	O
+combinations	O
+with	O
+valproate	O
+or	O
+clonazepam	O
+in	O
+amygdala	O
+-	O
+kindled	O
+rats	O
+.	O
+
+Loreclezole	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+exerted	O
+a	O
+significant	O
+protective	O
+action	O
+in	O
+amygdala	O
+-	O
+kindled	O
+rats	O
+,	O
+reducing	O
+both	O
+seizure	B
+and	O
+afterdischarge	O
+durations	O
+.	O
+
+The	O
+combinations	O
+of	O
+loreclezole	O
+(	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+with	O
+valproate	O
+,	O
+clonazepam	O
+,	O
+or	O
+carbamazepine	O
+(	O
+applied	O
+at	O
+their	O
+subprotective	O
+doses	O
+)	O
+also	O
+exhibited	O
+antiseizure	O
+effect	O
+in	O
+this	O
+test	O
+.	O
+
+However	O
+,	O
+only	O
+two	O
+first	O
+combinations	O
+occurred	O
+to	O
+be	O
+of	O
+pharmacodynamic	O
+nature	O
+.	O
+
+Among	O
+several	O
+chemoconvulsants	O
+,	O
+bicuculline	O
+,	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartic	O
+acid	O
+and	O
+BAY	O
+k	O
+-	O
+8644	O
+(	O
+the	O
+opener	O
+of	O
+L	O
+-	O
+type	O
+calcium	O
+channels	O
+)	O
+reversed	O
+the	O
+protective	O
+activity	O
+of	O
+loreclezole	O
+alone	O
+and	O
+its	O
+combination	O
+with	O
+valproate	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+bicuculline	O
+,	O
+aminophylline	O
+and	O
+BAY	O
+k	O
+-	O
+8644	O
+inhibited	O
+the	O
+anticonvulsive	O
+action	O
+of	O
+loreclezole	O
+combined	O
+with	O
+clonazepam	O
+.	O
+
+The	O
+results	O
+support	O
+the	O
+hypothesis	O
+that	O
+the	O
+protective	O
+activity	O
+of	O
+loreclezole	O
+and	O
+its	O
+combinations	O
+with	O
+other	O
+antiepileptics	O
+may	O
+involve	O
+potentiation	O
+of	O
+GABAergic	O
+neurotransmission	O
+and	O
+blockade	O
+of	O
+L	O
+-	O
+type	O
+of	O
+calcium	O
+channels	O
+.	O
+
+Mitochondrial	O
+DNA	O
+and	O
+its	O
+respiratory	O
+chain	O
+products	O
+are	O
+defective	O
+in	O
+doxorubicin	O
+nephrosis	B
+.	O
+
+BACKGROUND	O
+:	O
+Doxorubicin	O
+induces	O
+a	O
+self	O
+-	O
+perpetuating	O
+nephropathy	B
+characterized	O
+by	O
+early	O
+glomerular	B
+and	I
+late	I
+-	I
+onset	I
+tubular	I
+lesions	I
+in	O
+rats	O
+.	O
+
+We	O
+investigated	O
+the	O
+potential	O
+role	O
+of	O
+mitochondrial	B
+injury	I
+in	O
+the	O
+onset	O
+of	O
+these	O
+lesions	O
+.	O
+
+METHODS	O
+:	O
+Rats	O
+were	O
+treated	O
+with	O
+intravenous	O
+doxorubicin	O
+(	O
+1	O
+mg	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+week	O
+(	O
+-	O
+1	O
+)	O
+)	O
+for	O
+7	O
+weeks	O
+and	O
+were	O
+sacrificed	O
+either	O
+1	O
+week	O
+(	O
+'	O
+short	O
+-	O
+term	O
+'	O
+)	O
+or	O
+30	O
+weeks	O
+(	O
+'	O
+long	O
+-	O
+term	O
+'	O
+)	O
+following	O
+the	O
+last	O
+dose	O
+.	O
+
+Additional	O
+rats	O
+received	O
+a	O
+single	O
+dose	O
+either	O
+6	O
+days	O
+or	O
+2	O
+h	O
+prior	O
+to	O
+euthanasia	O
+.	O
+
+All	O
+rats	O
+were	O
+killed	O
+at	O
+48	O
+weeks	O
+of	O
+age	O
+.	O
+
+Glomerular	B
+and	I
+tubular	I
+injury	I
+was	O
+monitored	O
+and	O
+correlated	O
+to	O
+the	O
+activity	O
+or	O
+expression	O
+of	O
+respiratory	O
+chain	O
+components	O
+.	O
+
+Finally	O
+,	O
+we	O
+quantified	O
+both	O
+nuclear	O
+and	O
+mitochondrial	O
+DNA	O
+(	O
+mtDNA	O
+)	O
+as	O
+well	O
+as	O
+superoxide	O
+production	O
+and	O
+the	O
+4834	O
+base	O
+pair	O
+'	O
+common	O
+'	O
+mtDNA	O
+deletion	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+'	O
+long	O
+-	O
+term	O
+'	O
+group	O
+had	O
+significant	O
+glomerular	B
+and	I
+tubular	I
+lesions	I
+,	O
+depressed	O
+activities	O
+of	O
+mtDNA	O
+-	O
+encoded	O
+NADH	O
+dehydrogenase	O
+and	O
+cytochrome	O
+-	O
+c	O
+oxidase	O
+(	O
+COX	O
+)	O
+and	O
+increased	O
+citrate	O
+synthase	O
+activity	O
+.	O
+
+In	O
+addition	O
+,	O
+expression	O
+of	O
+the	O
+mtDNA	O
+-	O
+encoded	O
+COX	O
+subunit	O
+I	O
+was	O
+reduced	O
+and	O
+mtDNA	O
+levels	O
+were	O
+decreased	O
+.	O
+
+In	O
+'	O
+short	O
+-	O
+term	O
+'	O
+rats	O
+,	O
+there	O
+were	O
+fewer	O
+tubular	B
+lesions	I
+,	O
+but	O
+similar	O
+numbers	O
+of	O
+glomerular	B
+lesions	I
+activity	O
+.	O
+
+Among	O
+all	O
+animals	O
+,	O
+glomerular	B
+and	I
+tubular	I
+injury	I
+were	O
+inversely	O
+correlated	O
+with	O
+mtDNA	O
+levels	O
+,	O
+mtDNA	O
+-	O
+encoded	O
+respiratory	O
+chain	O
+activities	O
+and	O
+with	O
+the	O
+expression	O
+of	O
+the	O
+mtDNA	O
+-	O
+encoded	O
+respiratory	O
+chain	O
+subunit	O
+COX	O
+-	O
+I	O
+.	O
+
+Injury	O
+was	O
+positively	O
+correlated	O
+with	O
+superoxide	O
+production	O
+and	O
+the	O
+activities	O
+of	O
+nucleus	O
+-	O
+encoded	O
+mitochondrial	O
+or	O
+cytoplasmic	O
+enzymes	O
+.	O
+
+Kidneys	O
+from	O
+the	O
+'	O
+long	O
+-	O
+term	O
+'	O
+group	O
+showed	O
+more	O
+mtDNA	O
+deletions	O
+than	O
+in	O
+'	O
+short	O
+-	O
+term	O
+'	O
+animals	O
+and	O
+these	O
+were	O
+not	O
+observed	O
+in	O
+the	O
+other	O
+groups	O
+.	O
+
+CONCLUSIONS	O
+:	O
+These	O
+results	O
+suggest	O
+an	O
+important	O
+role	O
+for	O
+quantitative	O
+and	O
+qualitative	O
+mtDNA	O
+alterations	O
+through	O
+the	O
+reduction	O
+of	O
+mtDNA	O
+-	O
+encoded	O
+respiratory	O
+chain	O
+function	O
+and	O
+induction	O
+of	O
+superoxide	O
+in	O
+doxorubicin	O
+-	O
+induced	O
+renal	B
+lesions	I
+.	O
+
+A	O
+randomized	O
+,	O
+placebo	O
+-	O
+controlled	O
+,	O
+crossover	O
+study	O
+of	O
+ephedrine	O
+for	O
+SSRI	O
+-	O
+induced	O
+female	O
+sexual	B
+dysfunction	I
+.	O
+
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+whether	O
+ephedrine	O
+,	O
+an	O
+alpha	O
+-	O
+and	O
+beta	O
+-	O
+adrenergic	O
+agonist	O
+previously	O
+shown	O
+to	O
+enhance	O
+genital	O
+blood	O
+flow	O
+in	O
+women	O
+,	O
+has	O
+beneficial	O
+effects	O
+in	O
+reversing	O
+antidepressant	O
+-	O
+induced	O
+sexual	B
+dysfunction	I
+.	O
+
+Nineteen	O
+sexually	B
+dysfunctional	I
+women	O
+receiving	O
+either	O
+fluoxetine	O
+,	O
+sertraline	O
+,	O
+or	O
+paroxetine	O
+participated	O
+in	O
+an	O
+eight	O
+-	O
+week	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+,	O
+cross	O
+-	O
+over	O
+study	O
+of	O
+the	O
+effects	O
+of	O
+ephedrine	O
+(	O
+50	O
+mg	O
+)	O
+on	O
+self	O
+-	O
+report	O
+measures	O
+of	O
+sexual	O
+desire	O
+,	O
+arousal	O
+,	O
+orgasm	O
+,	O
+and	O
+sexual	O
+satisfaction	O
+.	O
+
+Although	O
+there	O
+were	O
+significant	O
+improvements	O
+relative	O
+to	O
+baseline	O
+in	O
+sexual	O
+desire	O
+and	O
+orgasm	O
+intensity	O
+/	O
+pleasure	O
+on	O
+50	O
+mg	O
+ephedrine	O
+1	O
+-	O
+hr	O
+prior	O
+to	O
+sexual	O
+activity	O
+,	O
+significant	O
+improvements	O
+in	O
+these	O
+measures	O
+,	O
+as	O
+well	O
+as	O
+in	O
+sexual	O
+arousal	O
+and	O
+orgasmic	O
+ability	O
+also	O
+were	O
+noted	O
+with	O
+placebo	O
+.	O
+
+These	O
+findings	O
+highlight	O
+the	O
+importance	O
+of	O
+conducting	O
+placebo	O
+-	O
+controlled	O
+trials	O
+for	O
+this	O
+condition	O
+.	O
+
+Does	O
+hormone	O
+therapy	O
+for	O
+the	O
+treatment	O
+of	O
+breast	B
+cancer	I
+have	O
+a	O
+detrimental	B
+effect	I
+on	I
+memory	I
+and	I
+cognition	I
+?	O
+
+A	O
+pilot	O
+study	O
+.	O
+
+This	O
+pilot	O
+study	O
+examines	O
+whether	O
+hormone	O
+therapy	O
+for	O
+breast	B
+cancer	I
+affects	O
+cognition	O
+.	O
+
+Patients	O
+participating	O
+in	O
+a	O
+randomised	O
+trial	O
+of	O
+anastrozole	O
+,	O
+tamoxifen	O
+alone	O
+or	O
+combined	O
+(	O
+ATAC	O
+)	O
+(	O
+n	O
+=	O
+94	O
+)	O
+and	O
+a	O
+group	O
+of	O
+women	O
+without	O
+breast	B
+cancer	I
+(	O
+n	O
+=	O
+35	O
+)	O
+completed	O
+a	O
+battery	O
+of	O
+neuropsychological	O
+measures	O
+.	O
+
+Compared	O
+with	O
+the	O
+control	O
+group	O
+,	O
+the	O
+patients	O
+were	O
+impaired	O
+on	O
+a	O
+processing	O
+speed	O
+task	O
+(	O
+p	O
+=	O
+0	O
+.	O
+032	O
+)	O
+and	O
+on	O
+a	O
+measure	O
+of	O
+immediate	O
+verbal	O
+memory	O
+(	O
+p	O
+=	O
+0	O
+.	O
+026	O
+)	O
+after	O
+controlling	O
+for	O
+the	O
+use	O
+of	O
+hormone	O
+replacement	O
+therapy	O
+in	O
+both	O
+groups	O
+.	O
+
+Patient	O
+group	O
+performance	O
+was	O
+not	O
+significantly	O
+related	O
+to	O
+length	O
+of	O
+treatment	O
+or	O
+measures	O
+of	O
+psychological	O
+morbidity	O
+.	O
+
+The	O
+results	O
+showed	O
+specific	O
+impairments	O
+in	O
+processing	O
+speed	O
+and	O
+verbal	O
+memory	O
+in	O
+women	O
+receiving	O
+hormonal	O
+therapy	O
+for	O
+the	O
+treatment	O
+of	O
+breast	B
+cancer	I
+.	O
+
+Verbal	O
+memory	O
+may	O
+be	O
+especially	O
+sensitive	O
+to	O
+changes	O
+in	O
+oestrogen	O
+levels	O
+,	O
+a	O
+finding	O
+commonly	O
+reported	O
+in	O
+studies	O
+of	O
+hormone	O
+replacement	O
+therapy	O
+in	O
+healthy	O
+women	O
+.	O
+
+In	O
+view	O
+of	O
+the	O
+increased	O
+use	O
+of	O
+hormone	O
+therapies	O
+in	O
+an	O
+adjuvant	O
+and	O
+preventative	O
+setting	O
+their	O
+impact	O
+on	O
+cognitive	O
+functioning	O
+should	O
+be	O
+investigated	O
+more	O
+thoroughly	O
+.	O
+
+Expression	O
+of	O
+p300	O
+protects	O
+cardiac	O
+myocytes	O
+from	O
+apoptosis	O
+in	O
+vivo	O
+.	O
+
+Doxorubicin	O
+is	O
+an	O
+anti	O
+-	O
+tumor	B
+agent	O
+that	O
+represses	O
+cardiac	O
+-	O
+specific	O
+gene	O
+expression	O
+and	O
+induces	O
+myocardial	O
+cell	O
+apoptosis	O
+.	O
+
+Doxorubicin	O
+depletes	O
+cardiac	O
+p300	O
+,	O
+a	O
+transcriptional	O
+coactivator	O
+that	O
+is	O
+required	O
+for	O
+the	O
+maintenance	O
+of	O
+the	O
+differentiated	O
+phenotype	O
+of	O
+cardiac	O
+myocytes	O
+.	O
+
+However	O
+,	O
+the	O
+role	O
+of	O
+p300	O
+in	O
+protection	O
+against	O
+doxorubicin	O
+-	O
+induced	O
+apoptosis	O
+is	O
+unknown	O
+.	O
+
+Transgenic	O
+mice	O
+overexpressing	O
+p300	O
+in	O
+the	O
+heart	O
+and	O
+wild	O
+-	O
+type	O
+mice	O
+were	O
+subjected	O
+to	O
+doxorubicin	O
+treatment	O
+.	O
+
+Compared	O
+with	O
+wild	O
+-	O
+type	O
+mice	O
+,	O
+transgenic	O
+mice	O
+exhibited	O
+higher	O
+survival	O
+rate	O
+as	O
+well	O
+as	O
+more	O
+preserved	O
+left	O
+ventricular	O
+function	O
+and	O
+cardiac	O
+expression	O
+of	O
+alpha	O
+-	O
+sarcomeric	O
+actin	O
+.	O
+
+Doxorubicin	O
+induced	O
+myocardial	O
+cell	O
+apoptosis	O
+in	O
+wild	O
+-	O
+type	O
+mice	O
+but	O
+not	O
+in	O
+transgenic	O
+mice	O
+.	O
+
+Expression	O
+of	O
+p300	O
+increased	O
+the	O
+cardiac	O
+level	O
+of	O
+bcl	O
+-	O
+2	O
+and	O
+mdm	O
+-	O
+2	O
+,	O
+but	O
+not	O
+that	O
+of	O
+p53	O
+or	O
+other	O
+members	O
+of	O
+the	O
+bcl	O
+-	O
+2	O
+family	O
+.	O
+
+These	O
+findings	O
+demonstrate	O
+that	O
+overexpression	O
+of	O
+p300	O
+protects	O
+cardiac	O
+myocytes	O
+from	O
+doxorubicin	O
+-	O
+induced	O
+apoptosis	O
+and	O
+reduces	O
+the	O
+extent	O
+of	O
+acute	O
+heart	B
+failure	I
+in	O
+adult	O
+mice	O
+in	O
+vivo	O
+.	O
+
+Methimazole	O
+-	O
+induced	O
+cholestatic	B
+jaundice	I
+.	O
+
+Methimazole	O
+is	O
+a	O
+widely	O
+used	O
+and	O
+generally	O
+well	O
+-	O
+tolerated	O
+antithyroid	O
+agent	O
+.	O
+
+A	O
+43	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+had	O
+severe	O
+jaundice	B
+and	O
+itching	B
+1	O
+month	O
+after	O
+receiving	O
+methimazole	O
+(	O
+10	O
+mg	O
+tid	O
+)	O
+and	O
+propranolol	O
+(	O
+20	O
+mg	O
+tid	O
+)	O
+for	O
+treatment	O
+of	O
+hyperthyroidism	B
+.	O
+
+The	O
+patient	O
+continued	O
+treatment	O
+for	O
+another	O
+4	O
+days	O
+after	O
+the	O
+appearance	O
+of	O
+jaundice	B
+until	O
+she	O
+finished	O
+both	O
+medications	O
+.	O
+
+When	O
+seen	O
+at	O
+the	O
+emergency	O
+department	O
+2	O
+weeks	O
+later	O
+,	O
+she	O
+still	O
+had	O
+severe	O
+icterus	B
+,	O
+pruritus	B
+,	O
+and	O
+hyperbilirubinemia	B
+,	O
+formed	O
+mainly	O
+of	O
+the	O
+conjugated	O
+fraction	O
+.	O
+
+Methimazole	O
+-	O
+induced	O
+cholestasis	B
+was	O
+diagnosed	O
+,	O
+and	O
+propranolol	O
+therapy	O
+was	O
+resumed	O
+.	O
+
+Over	O
+the	O
+following	O
+9	O
+days	O
+,	O
+the	O
+symptoms	O
+improved	O
+and	O
+plasma	O
+bilirubin	O
+levels	O
+were	O
+normal	O
+after	O
+12	O
+weeks	O
+without	O
+methimazole	O
+.	O
+
+In	O
+rare	O
+cases	O
+within	O
+the	O
+first	O
+few	O
+weeks	O
+of	O
+therapy	O
+,	O
+this	O
+drug	O
+can	O
+cause	O
+severe	O
+and	O
+reversible	O
+cholestatic	B
+jaundice	I
+.	O
+
+Physicians	O
+and	O
+patients	O
+should	O
+be	O
+aware	O
+of	O
+this	O
+adverse	O
+effect	O
+so	O
+that	O
+,	O
+upon	O
+occurrence	O
+,	O
+they	O
+can	O
+discontinue	O
+methimazole	O
+therapy	O
+and	O
+avoid	O
+unnecessary	O
+invasive	O
+procedures	O
+.	O
+
+Atrial	B
+fibrillation	I
+following	O
+chemotherapy	O
+for	O
+stage	O
+IIIE	O
+diffuse	O
+large	O
+B	O
+-	O
+cell	O
+gastric	B
+lymphoma	I
+in	O
+a	O
+patient	O
+with	O
+myotonic	B
+dystrophy	I
+(	O
+Steinert	B
+'	I
+s	I
+disease	I
+)	O
+.	O
+
+The	O
+authors	O
+describe	O
+the	O
+unusual	O
+association	O
+between	O
+diffuse	O
+B	O
+-	O
+cell	O
+gastric	B
+lymphoma	I
+and	O
+myotonic	B
+dystrophy	I
+,	O
+the	O
+most	O
+common	O
+form	O
+of	O
+adult	O
+muscular	B
+dystrophy	I
+,	O
+and	O
+sudden	O
+atrial	B
+fibrillation	I
+following	O
+one	O
+cycle	O
+of	O
+doxorubicin	O
+-	O
+based	O
+chemotherapy	O
+in	O
+the	O
+same	O
+patient	O
+.	O
+
+Atrial	B
+fibrillation	I
+or	O
+other	O
+cardiac	B
+arrhythmias	I
+are	O
+unusual	O
+complications	O
+in	O
+patients	O
+treated	O
+with	O
+chemotherapy	O
+.	O
+
+The	O
+cardiac	B
+toxicity	I
+intrinsically	O
+associated	O
+with	O
+the	O
+aggressive	O
+chemotherapy	O
+employed	O
+could	O
+function	O
+as	O
+a	O
+triggering	O
+factor	O
+for	O
+the	O
+arrhythmia	B
+in	O
+the	O
+predisposed	O
+myocardium	O
+of	O
+this	O
+patient	O
+.	O
+
+Hypersensitivity	B
+immune	O
+reaction	O
+as	O
+a	O
+mechanism	O
+for	O
+dilevalol	O
+-	O
+associated	O
+hepatitis	B
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+assess	O
+lymphocyte	O
+reactivity	O
+to	O
+dilevalol	O
+and	O
+to	O
+serum	O
+containing	O
+putative	O
+ex	O
+vivo	O
+dilevalol	O
+antigens	O
+or	O
+metabolites	O
+in	O
+a	O
+case	O
+of	O
+dilevalol	O
+-	O
+induced	O
+liver	B
+injury	I
+.	O
+
+PATIENT	O
+:	O
+A	O
+58	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+a	O
+clinical	O
+diagnosis	O
+of	O
+dilevalol	O
+-	O
+induced	O
+liver	B
+injury	I
+.	O
+
+METHODS	O
+:	O
+Peripheral	O
+blood	O
+mononuclear	O
+cells	O
+collected	O
+from	O
+the	O
+patient	O
+were	O
+cultured	O
+in	O
+the	O
+presence	O
+of	O
+a	O
+solution	O
+of	O
+dilevalol	O
+and	O
+also	O
+with	O
+sera	O
+collected	O
+from	O
+a	O
+volunteer	O
+before	O
+and	O
+after	O
+dilevalol	O
+intake	O
+.	O
+
+A	O
+similar	O
+protocol	O
+was	O
+performed	O
+with	O
+lymphocytes	O
+from	O
+a	O
+healthy	O
+subject	O
+.	O
+
+RESULTS	O
+:	O
+No	O
+lymphocyte	O
+proliferation	O
+was	O
+observed	O
+either	O
+in	O
+the	O
+patient	O
+or	O
+in	O
+the	O
+healthy	O
+volunteer	O
+in	O
+the	O
+presence	O
+of	O
+dilevalol	O
+solutions	O
+.	O
+
+A	O
+significant	O
+proliferative	O
+response	O
+to	O
+serum	O
+collected	O
+after	O
+dilevalol	O
+intake	O
+was	O
+observed	O
+in	O
+the	O
+case	O
+of	O
+the	O
+patient	O
+compared	O
+with	O
+the	O
+proliferative	O
+response	O
+to	O
+the	O
+serum	O
+collected	O
+before	O
+the	O
+drug	O
+intake	O
+.	O
+
+No	O
+reactivity	O
+was	O
+found	O
+when	O
+lymphocytes	O
+from	O
+the	O
+healthy	O
+subject	O
+were	O
+tested	O
+under	O
+similar	O
+conditions	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+methodology	O
+used	O
+allowed	O
+the	O
+detection	O
+of	O
+lymphocyte	O
+sensitization	O
+to	O
+sera	O
+containing	O
+ex	O
+vivo	O
+-	O
+prepared	O
+dilevalol	O
+antigens	O
+,	O
+suggesting	O
+the	O
+involvement	O
+of	O
+an	O
+immunologic	O
+mechanism	O
+in	O
+dilevalol	O
+-	O
+induced	O
+liver	B
+injury	I
+.	O
+
+Increased	O
+expression	O
+and	O
+apical	O
+targeting	O
+of	O
+renal	O
+ENaC	O
+subunits	O
+in	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+nephrotic	B
+syndrome	I
+in	O
+rats	O
+.	O
+
+Nephrotic	B
+syndrome	I
+is	O
+often	O
+accompanied	O
+by	O
+sodium	O
+retention	O
+and	O
+generalized	O
+edema	B
+.	O
+
+However	O
+,	O
+the	O
+molecular	O
+basis	O
+for	O
+the	O
+decreased	O
+renal	O
+sodium	O
+excretion	O
+remains	O
+undefined	O
+.	O
+
+We	O
+hypothesized	O
+that	O
+epithelial	O
+Na	O
+channel	O
+(	O
+ENaC	O
+)	O
+subunit	O
+dysregulation	O
+may	O
+be	O
+responsible	O
+for	O
+the	O
+increased	O
+sodium	O
+retention	O
+.	O
+
+An	O
+experimental	O
+group	O
+of	O
+rats	O
+was	O
+treated	O
+with	O
+puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+;	O
+180	O
+mg	O
+/	O
+kg	O
+iv	O
+)	O
+,	O
+whereas	O
+the	O
+control	O
+group	O
+received	O
+only	O
+vehicle	O
+.	O
+
+After	O
+7	O
+days	O
+,	O
+PAN	O
+treatment	O
+induced	O
+significant	O
+proteinuria	B
+,	O
+hypoalbuminemia	B
+,	O
+decreased	O
+urinary	O
+sodium	O
+excretion	O
+,	O
+and	O
+extensive	O
+ascites	B
+.	O
+
+The	O
+protein	O
+abundance	O
+of	O
+alpha	O
+-	O
+ENaC	O
+and	O
+beta	O
+-	O
+ENaC	O
+was	O
+increased	O
+in	O
+the	O
+inner	O
+stripe	O
+of	O
+the	O
+outer	O
+medulla	O
+(	O
+ISOM	O
+)	O
+and	O
+in	O
+the	O
+inner	O
+medulla	O
+(	O
+IM	O
+)	O
+but	O
+was	O
+not	O
+altered	O
+in	O
+the	O
+cortex	O
+.	O
+
+gamma	O
+-	O
+ENaC	O
+abundance	O
+was	O
+increased	O
+in	O
+the	O
+cortex	O
+,	O
+ISOM	O
+,	O
+and	O
+IM	O
+.	O
+
+Immunoperoxidase	O
+brightfield	O
+-	O
+and	O
+laser	O
+-	O
+scanning	O
+confocal	O
+fluorescence	O
+microscopy	O
+demonstrated	O
+increased	O
+targeting	O
+of	O
+alpha	O
+-	O
+ENaC	O
+,	O
+beta	O
+-	O
+ENaC	O
+,	O
+and	O
+gamma	O
+-	O
+ENaC	O
+subunits	O
+to	O
+the	O
+apical	O
+plasma	O
+membrane	O
+in	O
+the	O
+distal	O
+convoluted	O
+tubule	O
+(	O
+DCT2	O
+)	O
+,	O
+connecting	O
+tubule	O
+,	O
+and	O
+cortical	O
+and	O
+medullary	O
+collecting	O
+duct	O
+segments	O
+.	O
+
+Immunoelectron	O
+microscopy	O
+further	O
+revealed	O
+an	O
+increased	O
+labeling	O
+of	O
+alpha	O
+-	O
+ENaC	O
+in	O
+the	O
+apical	O
+plasma	O
+membrane	O
+of	O
+cortical	O
+collecting	O
+duct	O
+principal	O
+cells	O
+of	O
+PAN	O
+-	O
+treated	O
+rats	O
+,	O
+indicating	O
+enhanced	O
+apical	O
+targeting	O
+of	O
+alpha	O
+-	O
+ENaC	O
+subunits	O
+.	O
+
+In	O
+contrast	O
+,	O
+the	O
+protein	O
+abundances	O
+of	O
+Na	O
+(	O
++	O
+)	O
+/	O
+H	O
+(	O
++	O
+)	O
+exchanger	O
+type	O
+3	O
+(	O
+NHE3	O
+)	O
+,	O
+Na	O
+(	O
++	O
+)	O
+-	O
+K	O
+(	O
++	O
+)	O
+-	O
+2Cl	O
+(	O
+-	O
+)	O
+cotransporter	O
+(	O
+BSC	O
+-	O
+1	O
+)	O
+,	O
+and	O
+thiazide	O
+-	O
+sensitive	O
+Na	O
+(	O
++	O
+)	O
+-	O
+Cl	O
+(	O
+-	O
+)	O
+cotransporter	O
+(	O
+TSC	O
+)	O
+were	O
+decreased	O
+.	O
+
+Moreover	O
+,	O
+the	O
+abundance	O
+of	O
+the	O
+alpha	O
+(	O
+1	O
+)	O
+-	O
+subunit	O
+of	O
+the	O
+Na	O
+-	O
+K	O
+-	O
+ATPase	O
+was	O
+decreased	O
+in	O
+the	O
+cortex	O
+and	O
+ISOM	O
+,	O
+but	O
+it	O
+remained	O
+unchanged	O
+in	O
+the	O
+IM	O
+.	O
+
+In	O
+conclusion	O
+,	O
+the	O
+increased	O
+or	O
+sustained	O
+expression	O
+of	O
+ENaC	O
+subunits	O
+combined	O
+with	O
+increased	O
+apical	O
+targeting	O
+in	O
+the	O
+DCT2	O
+,	O
+connecting	O
+tubule	O
+,	O
+and	O
+collecting	O
+duct	O
+are	O
+likely	O
+to	O
+play	O
+a	O
+role	O
+in	O
+the	O
+sodium	O
+retention	O
+associated	O
+with	O
+PAN	O
+-	O
+induced	O
+nephrotic	B
+syndrome	I
+.	O
+
+The	O
+decreased	O
+abundance	O
+of	O
+NHE3	O
+,	O
+BSC	O
+-	O
+1	O
+,	O
+TSC	O
+,	O
+and	O
+Na	O
+-	O
+K	O
+-	O
+ATPase	O
+may	O
+play	O
+a	O
+compensatory	O
+role	O
+to	O
+promote	O
+sodium	O
+excretion	O
+.	O
+
+Pallidal	O
+stimulation	O
+:	O
+an	O
+alternative	O
+to	O
+pallidotomy	O
+?	O
+
+A	O
+resurgence	O
+of	O
+interest	O
+in	O
+the	O
+surgical	O
+treatment	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+came	O
+with	O
+the	O
+rediscovery	O
+of	O
+posteroventral	O
+pallidotomy	O
+by	O
+Laitinen	O
+in	O
+1985	O
+.	O
+
+Laitinen	O
+'	O
+s	O
+procedure	O
+improved	O
+most	O
+symptoms	O
+in	O
+drug	O
+-	O
+resistant	O
+PD	B
+,	O
+which	O
+engendered	O
+wide	O
+interest	O
+in	O
+the	O
+neurosurgical	O
+community	O
+.	O
+
+Another	O
+lesioning	O
+procedure	O
+,	O
+ventrolateral	O
+thalamotomy	O
+,	O
+has	O
+become	O
+a	O
+powerful	O
+alternative	O
+to	O
+stimulate	O
+the	O
+nucleus	O
+ventralis	O
+intermedius	O
+,	O
+producing	O
+high	O
+long	O
+-	O
+term	O
+success	O
+rates	O
+and	O
+low	O
+morbidity	O
+rates	O
+.	O
+
+Pallidal	O
+stimulation	O
+has	O
+not	O
+met	O
+with	O
+the	O
+same	O
+success	O
+.	O
+
+According	O
+to	O
+the	O
+literature	O
+pallidotomy	O
+improves	O
+the	O
+"	O
+on	O
+"	O
+symptoms	O
+of	O
+PD	B
+,	O
+such	O
+as	O
+dyskinesias	B
+,	O
+as	O
+well	O
+as	O
+the	O
+"	O
+off	O
+"	O
+symptoms	O
+,	O
+such	O
+as	O
+rigidity	B
+,	O
+bradykinesia	B
+,	O
+and	O
+on	O
+-	O
+off	O
+fluctuations	O
+.	O
+
+Pallidal	O
+stimulation	O
+improves	O
+bradykinesia	B
+and	O
+rigidity	B
+to	O
+a	O
+minor	O
+extent	O
+;	O
+however	O
+,	O
+its	O
+strength	O
+seems	O
+to	O
+be	O
+in	O
+improving	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+.	O
+
+Stimulation	O
+often	O
+produces	O
+an	O
+improvement	O
+in	O
+the	O
+hyper	B
+-	I
+or	I
+dyskinetic	I
+upper	O
+limbs	O
+,	O
+but	O
+increases	O
+the	O
+"	O
+freezing	O
+"	O
+phenomenon	O
+in	O
+the	O
+lower	O
+limbs	O
+at	O
+the	O
+same	O
+time	O
+.	O
+
+Considering	O
+the	O
+small	O
+increase	O
+in	O
+the	O
+patient	O
+'	O
+s	O
+independence	O
+,	O
+the	O
+high	O
+costs	O
+of	O
+bilateral	O
+implants	O
+,	O
+and	O
+the	O
+difficulty	O
+most	O
+patients	O
+experience	O
+in	O
+handling	O
+the	O
+devices	O
+,	O
+the	O
+question	O
+arises	O
+as	O
+to	O
+whether	O
+bilateral	O
+pallidal	O
+stimulation	O
+is	O
+a	O
+real	O
+alternative	O
+to	O
+pallidotomy	O
+.	O
+
+Effects	O
+of	O
+the	O
+cyclooxygenase	O
+-	O
+2	O
+specific	O
+inhibitor	O
+valdecoxib	O
+versus	O
+nonsteroidal	O
+antiinflammatory	O
+agents	O
+and	O
+placebo	O
+on	O
+cardiovascular	O
+thrombotic	B
+events	O
+in	O
+patients	O
+with	O
+arthritis	B
+.	O
+
+There	O
+have	O
+been	O
+concerns	O
+that	O
+the	O
+risk	O
+of	O
+cardiovascular	O
+thrombotic	B
+events	O
+may	O
+be	O
+higher	O
+with	O
+cyclooxygenase	O
+(	O
+COX	O
+)	O
+-	O
+2	O
+-	O
+specific	O
+inhibitors	O
+than	O
+nonselective	O
+nonsteroidal	O
+antiinflammatory	O
+drugs	O
+(	O
+NSAIDs	O
+)	O
+.	O
+
+We	O
+evaluated	O
+cardiovascular	O
+event	O
+data	O
+for	O
+valdecoxib	O
+,	O
+a	O
+new	O
+COX	O
+-	O
+2	O
+-	O
+specific	O
+inhibitor	O
+in	O
+approximately	O
+8000	O
+patients	O
+with	O
+osteoarthritis	B
+and	O
+rheumatoid	B
+arthritis	I
+treated	O
+with	O
+this	O
+agent	O
+in	O
+randomized	O
+clinical	O
+trials	O
+.	O
+
+The	O
+incidence	O
+of	O
+cardiovascular	O
+thrombotic	B
+events	O
+(	O
+cardiac	O
+,	O
+cerebrovascular	O
+and	O
+peripheral	O
+vascular	O
+,	O
+or	O
+arterial	O
+thrombotic	B
+)	O
+was	O
+determined	O
+by	O
+analyzing	O
+pooled	O
+valdecoxib	O
+(	O
+10	O
+-	O
+80	O
+mg	O
+daily	O
+)	O
+,	O
+nonselective	O
+NSAID	O
+(	O
+diclofenac	O
+75	O
+mg	O
+bid	O
+,	O
+ibuprofen	O
+800	O
+mg	O
+tid	O
+,	O
+or	O
+naproxen	O
+500	O
+mg	O
+bid	O
+)	O
+and	O
+placebo	O
+data	O
+from	O
+10	O
+randomized	O
+osteoarthritis	B
+and	O
+rheumatoid	B
+arthritis	I
+trials	O
+that	O
+were	O
+6	O
+-	O
+52	O
+weeks	O
+in	O
+duration	O
+.	O
+
+The	O
+incidence	O
+rates	O
+of	O
+events	O
+were	O
+determined	O
+in	O
+all	O
+patients	O
+(	O
+n	O
+=	O
+7934	O
+)	O
+and	O
+in	O
+users	O
+of	O
+low	O
+-	O
+dose	O
+(	O
+<	O
+or	O
+=	O
+325	O
+mg	O
+daily	O
+)	O
+aspirin	O
+(	O
+n	O
+=	O
+1051	O
+)	O
+and	O
+nonusers	O
+of	O
+aspirin	O
+(	O
+n	O
+=	O
+6883	O
+)	O
+.	O
+
+Crude	O
+and	O
+exposure	O
+-	O
+adjusted	O
+incidences	O
+of	O
+thrombotic	B
+events	O
+were	O
+similar	O
+for	O
+valdecoxib	O
+,	O
+NSAIDs	O
+,	O
+and	O
+placebo	O
+.	O
+
+The	O
+risk	O
+of	O
+serious	O
+thrombotic	B
+events	O
+was	O
+also	O
+similar	O
+for	O
+each	O
+valdecoxib	O
+dose	O
+.	O
+
+Thrombotic	B
+risk	O
+was	O
+consistently	O
+higher	O
+for	O
+users	O
+of	O
+aspirin	O
+users	O
+than	O
+nonusers	O
+of	O
+aspirin	O
+(	O
+placebo	O
+,	O
+1	O
+.	O
+4	O
+%	O
+vs	O
+.	O
+0	O
+%	O
+;	O
+valdecoxib	O
+,	O
+1	O
+.	O
+7	O
+%	O
+vs	O
+.	O
+0	O
+.	O
+2	O
+%	O
+;	O
+NSAIDs	O
+,	O
+1	O
+.	O
+9	O
+%	O
+vs	O
+.	O
+0	O
+.	O
+5	O
+%	O
+)	O
+.	O
+
+The	O
+rates	O
+of	O
+events	O
+in	O
+users	O
+of	O
+aspirin	O
+were	O
+similar	O
+for	O
+all	O
+3	O
+treatment	O
+groups	O
+and	O
+across	O
+valdecoxib	O
+doses	O
+.	O
+
+Short	O
+-	O
+and	O
+intermediate	O
+-	O
+term	O
+treatment	O
+with	O
+therapeutic	O
+(	O
+10	O
+or	O
+20	O
+mg	O
+daily	O
+)	O
+and	O
+supratherapeutic	O
+(	O
+40	O
+or	O
+80	O
+mg	O
+daily	O
+)	O
+valdecoxib	O
+doses	O
+was	O
+not	O
+associated	O
+with	O
+an	O
+increased	O
+incidence	O
+of	O
+thrombotic	B
+events	O
+relative	O
+to	O
+nonselective	O
+NSAIDs	O
+or	O
+placebo	O
+in	O
+osteoarthritis	B
+and	O
+rheumatoid	B
+arthritis	I
+patients	O
+in	O
+controlled	O
+clinical	O
+trials	O
+.	O
+
+Hypersensitivity	B
+myocarditis	B
+complicating	O
+hypertrophic	B
+cardiomyopathy	I
+heart	O
+.	O
+
+The	O
+present	O
+report	O
+describes	O
+a	O
+case	O
+of	O
+eosinophilic	B
+myocarditis	I
+complicating	O
+hypertrophic	B
+cardiomyopathy	I
+.	O
+
+The	O
+47	O
+-	O
+year	O
+-	O
+old	O
+female	O
+patient	O
+,	O
+known	O
+to	O
+have	O
+hypertrophic	B
+cardiomyopathy	I
+,	O
+was	O
+admitted	O
+with	O
+biventricular	B
+failure	I
+and	O
+managed	O
+aggressively	O
+with	O
+dobutamine	O
+infusion	O
+and	O
+other	O
+drugs	O
+while	O
+being	O
+assessed	O
+for	O
+heart	O
+transplantation	O
+.	O
+
+On	O
+transthoracic	O
+echocardiogram	O
+,	O
+she	O
+had	O
+moderate	O
+left	B
+ventricular	I
+dysfunction	I
+with	O
+regional	O
+variability	O
+and	O
+moderate	O
+mitral	B
+regurgitation	I
+.	O
+
+The	O
+recipient	O
+'	O
+s	O
+heart	O
+showed	O
+the	O
+features	O
+of	O
+apical	O
+hypertrophic	B
+cardiomyopathy	I
+and	O
+myocarditis	B
+with	O
+abundant	O
+eosinophils	O
+.	O
+
+Myocarditis	B
+is	O
+rare	O
+and	O
+eosinophilic	B
+myocarditis	I
+is	O
+rarer	O
+.	O
+
+It	O
+is	O
+likely	O
+that	O
+the	O
+hypersensitivity	B
+(	O
+eosinophilic	B
+)	O
+myocarditis	B
+was	O
+related	O
+to	O
+dobutamine	O
+infusion	O
+therapy	O
+.	O
+
+Eosinophilic	B
+myocarditis	I
+has	O
+been	O
+reported	O
+with	O
+an	O
+incidence	O
+of	O
+2	O
+.	O
+4	O
+%	O
+to	O
+7	O
+.	O
+2	O
+%	O
+in	O
+explanted	O
+hearts	O
+and	O
+may	O
+be	O
+related	O
+to	O
+multidrug	O
+therapy	O
+.	O
+
+Time	O
+trends	O
+in	O
+warfarin	O
+-	O
+associated	O
+hemorrhage	B
+.	O
+
+The	O
+annual	O
+incidence	O
+of	O
+warfarin	O
+-	O
+related	O
+bleeding	B
+at	O
+Brigham	O
+and	O
+Women	O
+'	O
+s	O
+Hospital	O
+increased	O
+from	O
+0	O
+.	O
+97	O
+/	O
+1	O
+,	O
+000	O
+patient	O
+admissions	O
+in	O
+the	O
+first	O
+time	O
+period	O
+(	O
+January	O
+1995	O
+to	O
+October	O
+1998	O
+)	O
+to	O
+1	O
+.	O
+19	O
+/	O
+1	O
+,	O
+000	O
+patient	O
+admissions	O
+in	O
+the	O
+second	O
+time	O
+period	O
+(	O
+November	O
+1998	O
+to	O
+August	O
+2002	O
+)	O
+of	O
+this	O
+study	O
+.	O
+
+The	O
+proportion	O
+of	O
+patients	O
+with	O
+major	O
+and	O
+intracranial	B
+bleeding	I
+increased	O
+from	O
+20	O
+.	O
+2	O
+%	O
+and	O
+1	O
+.	O
+9	O
+%	O
+,	O
+respectively	O
+,	O
+in	O
+the	O
+first	O
+time	O
+period	O
+,	O
+to	O
+33	O
+.	O
+3	O
+%	O
+and	O
+7	O
+.	O
+8	O
+%	O
+,	O
+respectively	O
+,	O
+in	O
+the	O
+second	O
+.	O
+
+Yohimbine	O
+treatment	O
+of	O
+sexual	B
+side	I
+effects	I
+induced	O
+by	O
+serotonin	O
+reuptake	O
+blockers	O
+.	O
+
+BACKGROUND	O
+:	O
+Preclinical	O
+and	O
+clinical	O
+studies	O
+suggest	O
+that	O
+yohimbine	O
+facilitates	O
+sexual	O
+behavior	O
+and	O
+may	O
+be	O
+helpful	O
+in	O
+the	O
+treatment	O
+of	O
+male	B
+impotence	I
+.	O
+
+A	O
+single	O
+case	O
+report	O
+suggests	O
+that	O
+yohimbine	O
+may	O
+be	O
+used	O
+to	O
+treat	O
+the	O
+sexual	B
+side	I
+effects	I
+of	O
+clomipramine	O
+.	O
+
+This	O
+study	O
+evaluated	O
+yohimbine	O
+as	O
+a	O
+treatment	O
+for	O
+the	O
+sexual	B
+side	I
+effects	I
+caused	O
+by	O
+serotonin	O
+reuptake	O
+blockers	O
+.	O
+
+METHOD	O
+:	O
+Six	O
+patients	O
+with	O
+either	O
+obsessive	B
+compulsive	I
+disorder	I
+,	O
+trichotillomania	B
+,	O
+anxiety	B
+,	O
+or	O
+affective	B
+disorders	I
+who	O
+suffered	O
+sexual	B
+side	I
+effects	I
+after	O
+treatment	O
+with	O
+serotonin	O
+reuptake	O
+blockers	O
+were	O
+given	O
+yohimbine	O
+on	O
+a	O
+p	O
+.	O
+r	O
+.	O
+n	O
+.	O
+basis	O
+in	O
+an	O
+open	O
+clinical	O
+trial	O
+.	O
+
+Various	O
+doses	O
+of	O
+yohimbine	O
+were	O
+used	O
+to	O
+determine	O
+the	O
+ideal	O
+dose	O
+for	O
+each	O
+patient	O
+.	O
+
+RESULTS	O
+:	O
+Five	O
+of	O
+the	O
+six	O
+patients	O
+experienced	O
+improved	O
+sexual	O
+functioning	O
+after	O
+taking	O
+yohimbine	O
+.	O
+
+One	O
+patient	O
+who	O
+failed	O
+to	O
+comply	O
+with	O
+yohimbine	O
+treatment	O
+had	O
+no	O
+therapeutic	O
+effects	O
+.	O
+
+Side	O
+effects	O
+of	O
+yohimbine	O
+included	O
+excessive	O
+sweating	O
+,	O
+increased	O
+anxiety	B
+,	O
+and	O
+a	O
+wound	O
+-	O
+up	O
+feeling	O
+in	O
+some	O
+patients	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+results	O
+of	O
+this	O
+study	O
+indicate	O
+that	O
+yohimbine	O
+may	O
+be	O
+an	O
+effective	O
+treatment	O
+for	O
+the	O
+sexual	B
+side	I
+effects	I
+caused	O
+by	O
+serotonin	O
+reuptake	O
+blockers	O
+.	O
+
+Future	O
+controlled	O
+studies	O
+are	O
+needed	O
+to	O
+further	O
+investigate	O
+the	O
+effectiveness	O
+and	O
+safety	O
+of	O
+yohimbine	O
+for	O
+this	O
+indication	O
+.	O
+
+Hemorrhagic	B
+cystitis	I
+complicating	O
+bone	O
+marrow	O
+transplantation	O
+.	O
+
+Hemorrhagic	B
+cystitis	I
+is	O
+a	O
+potentially	O
+serious	O
+complication	O
+of	O
+high	O
+-	O
+dose	O
+cyclophosphamide	O
+therapy	O
+administered	O
+before	O
+bone	O
+marrow	O
+transplantation	O
+.	O
+
+As	O
+standard	O
+practice	O
+at	O
+our	O
+institution	O
+,	O
+patients	O
+who	O
+are	O
+scheduled	O
+to	O
+receive	O
+a	O
+bone	O
+marrow	O
+transplant	O
+are	O
+treated	O
+prophylactically	O
+with	O
+forced	O
+hydration	O
+and	O
+bladder	O
+irrigation	O
+.	O
+
+In	O
+an	O
+attempt	O
+to	O
+obviate	O
+the	O
+inconvenience	O
+of	O
+bladder	O
+irrigation	O
+,	O
+we	O
+conducted	O
+a	O
+feasibility	O
+trial	O
+of	O
+uroprophylaxis	O
+with	O
+mesna	O
+,	O
+which	O
+neutralizes	O
+the	O
+hepatic	O
+metabolite	O
+of	O
+cyclophosphamide	O
+that	O
+causes	O
+hemorrhagic	B
+cystitis	I
+.	O
+
+Of	O
+97	O
+patients	O
+who	O
+received	O
+standard	O
+prophylaxis	O
+,	O
+4	O
+had	O
+symptomatic	O
+hemorrhagic	B
+cystitis	I
+.	O
+
+In	O
+contrast	O
+,	O
+two	O
+of	O
+four	O
+consecutive	O
+patients	O
+who	O
+received	O
+mesna	O
+uroprophylaxis	O
+before	O
+allogeneic	O
+bone	O
+marrow	O
+transplantation	O
+had	O
+severe	O
+hemorrhagic	B
+cystitis	I
+for	O
+at	O
+least	O
+2	O
+weeks	O
+.	O
+
+Because	O
+of	O
+this	O
+suboptimal	O
+result	O
+,	O
+we	O
+resumed	O
+the	O
+use	O
+of	O
+bladder	O
+irrigation	O
+and	O
+forced	O
+hydration	O
+to	O
+minimize	O
+the	O
+risk	O
+of	O
+hemorrhagic	B
+cystitis	I
+.	O
+
+Consensus	O
+statement	O
+concerning	O
+cardiotoxicity	B
+occurring	O
+during	O
+haematopoietic	O
+stem	O
+cell	O
+transplantation	O
+in	O
+the	O
+treatment	O
+of	O
+autoimmune	B
+diseases	I
+,	O
+with	O
+special	O
+reference	O
+to	O
+systemic	B
+sclerosis	I
+and	O
+multiple	B
+sclerosis	I
+.	O
+
+Autologous	O
+haematopoietic	O
+stem	O
+cell	O
+transplantation	O
+is	O
+now	O
+a	O
+feasible	O
+and	O
+effective	O
+treatment	O
+for	O
+selected	O
+patients	O
+with	O
+severe	O
+autoimmune	B
+diseases	I
+.	O
+
+Worldwide	O
+,	O
+over	O
+650	O
+patients	O
+have	O
+been	O
+transplanted	O
+in	O
+the	O
+context	O
+of	O
+phase	O
+I	O
+and	O
+II	O
+clinical	O
+trials	O
+.	O
+
+The	O
+results	O
+are	O
+encouraging	O
+enough	O
+to	O
+begin	O
+randomised	O
+phase	O
+III	O
+trials	O
+.	O
+
+However	O
+,	O
+as	O
+predicted	O
+,	O
+significant	O
+transplant	O
+-	O
+related	O
+morbidity	O
+and	O
+mortality	O
+have	O
+been	O
+observed	O
+.	O
+
+This	O
+is	O
+primarily	O
+due	O
+to	O
+complications	O
+related	O
+to	O
+either	O
+the	O
+stage	O
+of	O
+the	O
+disease	O
+at	O
+transplant	O
+or	O
+due	O
+to	O
+infections	B
+.	O
+
+The	O
+number	O
+of	O
+deaths	O
+related	O
+to	O
+cardiac	B
+toxicity	I
+is	O
+low	O
+.	O
+
+However	O
+,	O
+caution	O
+is	O
+required	O
+when	O
+cyclophosphamide	O
+or	O
+anthracyclines	O
+such	O
+as	O
+mitoxantrone	O
+are	O
+used	O
+in	O
+patients	O
+with	O
+a	O
+possible	O
+underlying	O
+heart	B
+damage	I
+,	O
+for	O
+example	O
+,	O
+systemic	B
+sclerosis	I
+patients	O
+.	O
+
+In	O
+November	O
+2002	O
+,	O
+a	O
+meeting	O
+was	O
+held	O
+in	O
+Florence	O
+,	O
+bringing	O
+together	O
+a	O
+number	O
+of	O
+experts	O
+in	O
+various	O
+fields	O
+,	O
+including	O
+rheumatology	O
+,	O
+cardiology	O
+,	O
+neurology	O
+,	O
+pharmacology	O
+and	O
+transplantation	O
+medicine	O
+.	O
+
+The	O
+object	O
+of	O
+the	O
+meeting	O
+was	O
+to	O
+analyse	O
+existing	O
+data	O
+,	O
+both	O
+published	O
+or	O
+available	O
+,	O
+in	O
+the	O
+European	O
+Group	O
+for	O
+Blood	O
+and	O
+Marrow	O
+Transplantation	O
+autoimmune	B
+disease	I
+database	O
+,	O
+and	O
+to	O
+propose	O
+a	O
+safe	O
+approach	O
+to	O
+such	O
+patients	O
+.	O
+
+A	O
+full	O
+cardiological	O
+assessment	O
+before	O
+and	O
+during	O
+the	O
+transplant	O
+emerged	O
+as	O
+the	O
+major	O
+recommendation	O
+.	O
+
+Does	O
+supplemental	O
+vitamin	O
+C	O
+increase	O
+cardiovascular	B
+disease	I
+risk	O
+in	O
+women	O
+with	O
+diabetes	B
+?	O
+
+BACKGROUND	O
+:	O
+Vitamin	O
+C	O
+acts	O
+as	O
+a	O
+potent	O
+antioxidant	O
+;	O
+however	O
+,	O
+it	O
+can	O
+also	O
+be	O
+a	O
+prooxidant	O
+and	O
+glycate	O
+protein	O
+under	O
+certain	O
+circumstances	O
+in	O
+vitro	O
+.	O
+
+These	O
+observations	O
+led	O
+us	O
+to	O
+hypothesize	O
+that	O
+a	O
+high	O
+intake	O
+of	O
+vitamin	O
+C	O
+in	O
+diabetic	B
+persons	O
+might	O
+promote	O
+atherosclerosis	B
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+objective	O
+was	O
+to	O
+examine	O
+the	O
+relation	O
+between	O
+vitamin	O
+C	O
+intake	O
+and	O
+mortality	O
+from	O
+cardiovascular	B
+disease	I
+.	O
+
+DESIGN	O
+:	O
+We	O
+studied	O
+the	O
+relation	O
+between	O
+vitamin	O
+C	O
+intake	O
+and	O
+mortality	O
+from	O
+total	O
+cardiovascular	B
+disease	I
+(	O
+n	O
+=	O
+281	O
+)	O
+,	O
+coronary	B
+artery	I
+disease	I
+(	O
+n	O
+=	O
+175	O
+)	O
+,	O
+and	O
+stroke	B
+(	O
+n	O
+=	O
+57	O
+)	O
+in	O
+1923	O
+postmenopausal	O
+women	O
+who	O
+reported	O
+being	O
+diabetic	B
+at	O
+baseline	O
+.	O
+
+Diet	O
+was	O
+assessed	O
+with	O
+a	O
+food	O
+-	O
+frequency	O
+questionnaire	O
+at	O
+baseline	O
+,	O
+and	O
+subjects	O
+initially	O
+free	O
+of	O
+coronary	B
+artery	I
+disease	I
+were	O
+prospectively	O
+followed	O
+for	O
+15	O
+y	O
+.	O
+
+RESULTS	O
+:	O
+After	O
+adjustment	O
+for	O
+cardiovascular	B
+disease	I
+risk	O
+factors	O
+,	O
+type	O
+of	O
+diabetes	B
+medication	O
+used	O
+,	O
+duration	O
+of	O
+diabetes	B
+,	O
+and	O
+intakes	O
+of	O
+folate	O
+,	O
+vitamin	O
+E	O
+,	O
+and	O
+beta	O
+-	O
+carotene	O
+,	O
+the	O
+adjusted	O
+relative	O
+risks	O
+of	O
+total	O
+cardiovascular	B
+disease	I
+mortality	O
+were	O
+1	O
+.	O
+0	O
+,	O
+0	O
+.	O
+97	O
+,	O
+1	O
+.	O
+11	O
+,	O
+1	O
+.	O
+47	O
+,	O
+and	O
+1	O
+.	O
+84	O
+(	O
+P	O
+for	O
+trend	O
+<	O
+0	O
+.	O
+01	O
+)	O
+across	O
+quintiles	O
+of	O
+total	O
+vitamin	O
+C	O
+intake	O
+from	O
+food	O
+and	O
+supplements	O
+.	O
+
+Adjusted	O
+relative	O
+risks	O
+of	O
+coronary	B
+artery	I
+disease	I
+were	O
+1	O
+.	O
+0	O
+,	O
+0	O
+.	O
+81	O
+,	O
+0	O
+.	O
+99	O
+,	O
+1	O
+.	O
+26	O
+,	O
+and	O
+1	O
+.	O
+91	O
+(	O
+P	O
+for	O
+trend	O
+=	O
+0	O
+.	O
+01	O
+)	O
+and	O
+of	O
+stroke	B
+were	O
+1	O
+.	O
+0	O
+,	O
+0	O
+.	O
+52	O
+,	O
+1	O
+.	O
+23	O
+,	O
+2	O
+.	O
+22	O
+,	O
+and	O
+2	O
+.	O
+57	O
+(	O
+P	O
+for	O
+trend	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+When	O
+dietary	O
+and	O
+supplemental	O
+vitamin	O
+C	O
+were	O
+analyzed	O
+separately	O
+,	O
+only	O
+supplemental	O
+vitamin	O
+C	O
+showed	O
+a	O
+positive	O
+association	O
+with	O
+mortality	O
+endpoints	O
+.	O
+
+Vitamin	O
+C	O
+intake	O
+was	O
+unrelated	O
+to	O
+mortality	O
+from	O
+cardiovascular	B
+disease	I
+in	O
+the	O
+nondiabetic	O
+subjects	O
+at	O
+baseline	O
+.	O
+
+CONCLUSION	O
+:	O
+A	O
+high	O
+vitamin	O
+C	O
+intake	O
+from	O
+supplements	O
+is	O
+associated	O
+with	O
+an	O
+increased	O
+risk	O
+of	O
+cardiovascular	B
+disease	I
+mortality	O
+in	O
+postmenopausal	O
+women	O
+with	O
+diabetes	B
+.	O
+
+Optical	O
+coherence	O
+tomography	O
+can	O
+measure	O
+axonal	O
+loss	O
+in	O
+patients	O
+with	O
+ethambutol	O
+-	O
+induced	O
+optic	B
+neuropathy	I
+.	O
+
+PURPOSE	O
+:	O
+To	O
+map	O
+and	O
+identify	O
+the	O
+pattern	O
+,	O
+in	O
+vivo	O
+,	O
+of	O
+axonal	B
+degeneration	I
+in	O
+ethambutol	O
+-	O
+induced	O
+optic	B
+neuropathy	I
+using	O
+optical	O
+coherence	O
+tomography	O
+(	O
+OCT	O
+)	O
+.	O
+
+Ethambutol	O
+is	O
+an	O
+antimycobacterial	O
+agent	O
+often	O
+used	O
+to	O
+treat	O
+tuberculosis	B
+.	O
+
+A	O
+serious	O
+complication	O
+of	O
+ethambutol	O
+is	O
+an	O
+optic	B
+neuropathy	I
+that	O
+impairs	O
+visual	O
+acuity	O
+,	O
+contrast	O
+sensitivity	O
+,	O
+and	O
+color	O
+vision	O
+.	O
+
+However	O
+,	O
+early	O
+on	O
+,	O
+when	O
+the	O
+toxic	O
+optic	B
+neuropathy	I
+is	O
+mild	O
+and	O
+partly	O
+reversible	O
+,	O
+the	O
+funduscopic	O
+findings	O
+are	O
+often	O
+subtle	O
+and	O
+easy	O
+to	O
+miss	O
+.	O
+
+METHODS	O
+:	O
+Three	O
+subjects	O
+with	O
+a	O
+history	O
+of	O
+ethambutol	O
+(	O
+EMB	O
+)	O
+-	O
+induced	O
+optic	B
+neuropathy	I
+of	O
+short	O
+-	O
+,	O
+intermediate	O
+-	O
+,	O
+and	O
+long	O
+-	O
+term	O
+visual	B
+deficits	I
+were	O
+administered	O
+a	O
+full	O
+neuro	O
+-	O
+ophthalmologic	O
+examination	O
+including	O
+visual	O
+acuity	O
+,	O
+color	O
+vision	O
+,	O
+contrast	O
+sensitivity	O
+,	O
+and	O
+fundus	O
+examination	O
+.	O
+
+In	O
+addition	O
+,	O
+OCT	O
+(	O
+OCT	O
+3000	O
+,	O
+Humphrey	O
+-	O
+Zeiss	O
+,	O
+Dublin	O
+,	O
+CA	O
+)	O
+was	O
+performed	O
+on	O
+both	O
+eyes	O
+of	O
+each	O
+subject	O
+using	O
+the	O
+retinal	O
+nerve	O
+fiber	O
+layer	O
+(	O
+RNFL	O
+)	O
+analysis	O
+protocol	O
+.	O
+
+OCT	O
+interpolates	O
+data	O
+from	O
+100	O
+points	O
+around	O
+the	O
+optic	O
+nerve	O
+to	O
+effectively	O
+map	O
+out	O
+the	O
+RNFL	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+results	O
+were	O
+compared	O
+to	O
+the	O
+calculated	O
+average	O
+RNFL	O
+of	O
+normal	O
+eyes	O
+accumulated	O
+from	O
+four	O
+prior	O
+studies	O
+using	O
+OCT	O
+,	O
+n	O
+=	O
+661	O
+.	O
+
+In	O
+all	O
+subjects	O
+with	O
+history	O
+of	O
+EMB	O
+-	O
+induced	O
+optic	B
+neuropathy	I
+,	O
+there	O
+was	O
+a	O
+mean	O
+loss	O
+of	O
+72	O
+%	O
+nerve	O
+fiber	O
+layer	O
+thickness	O
+in	O
+the	O
+temporal	O
+quadrant	O
+(	O
+patient	O
+A	O
+,	O
+with	O
+eventual	O
+recovery	O
+of	O
+visual	O
+acuity	O
+and	O
+fields	O
+,	O
+58	O
+%	O
+loss	O
+;	O
+patient	O
+B	O
+,	O
+with	O
+intermediate	O
+visual	B
+deficits	I
+,	O
+68	O
+%	O
+loss	O
+;	O
+patient	O
+C	O
+,	O
+with	O
+chronic	O
+visual	B
+deficits	I
+,	O
+90	O
+%	O
+loss	O
+)	O
+,	O
+with	O
+an	O
+average	O
+mean	O
+optic	O
+nerve	O
+thickness	O
+of	O
+26	O
++	O
+/	O
+-	O
+16	O
+microm	O
+.	O
+
+There	O
+was	O
+a	O
+combined	O
+mean	O
+loss	O
+of	O
+46	O
+%	O
+of	O
+fibers	O
+from	O
+the	O
+superior	O
+,	O
+inferior	O
+,	O
+and	O
+nasal	O
+quadrants	O
+in	O
+the	O
+(	O
+six	O
+)	O
+eyes	O
+of	O
+all	O
+three	O
+subjects	O
+(	O
+mean	O
+average	O
+thickness	O
+of	O
+55	O
++	O
+/	O
+-	O
+29	O
+microm	O
+)	O
+.	O
+
+In	O
+both	O
+sets	O
+(	O
+four	O
+)	O
+of	O
+eyes	O
+of	O
+the	O
+subjects	O
+with	O
+persistent	O
+visual	B
+deficits	I
+(	O
+patients	O
+B	O
+and	O
+C	O
+)	O
+,	O
+there	O
+was	O
+an	O
+average	O
+loss	O
+of	O
+79	O
+%	O
+of	O
+nerve	O
+fiber	O
+thickness	O
+in	O
+the	O
+temporal	O
+quadrant	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+OCT	O
+results	O
+in	O
+these	O
+patients	O
+with	O
+EMB	O
+-	O
+induced	O
+optic	B
+neuropathy	I
+show	O
+considerable	O
+loss	O
+especially	O
+of	O
+the	O
+temporal	O
+fibers	O
+.	O
+
+This	O
+is	O
+consistent	O
+with	O
+prior	O
+histopathological	O
+studies	O
+that	O
+show	O
+predominant	O
+loss	O
+of	O
+parvo	O
+-	O
+cellular	O
+axons	O
+(	O
+or	O
+small	O
+-	O
+caliber	O
+axons	O
+)	O
+within	O
+the	O
+papillo	O
+-	O
+macular	O
+bundle	O
+in	O
+toxic	O
+or	O
+hereditary	O
+optic	B
+neuropathies	I
+.	O
+
+OCT	O
+can	O
+be	O
+a	O
+valuable	O
+tool	O
+in	O
+the	O
+quantitative	O
+analysis	O
+of	O
+optic	B
+neuropathies	I
+.	O
+
+Additionally	O
+,	O
+in	O
+terms	O
+of	O
+management	O
+of	O
+EMB	O
+-	O
+induced	O
+optic	B
+neuropathy	I
+,	O
+it	O
+is	O
+important	O
+to	O
+properly	O
+manage	O
+ethambutol	O
+dosing	O
+in	O
+patients	O
+with	O
+renal	B
+impairment	I
+and	O
+to	O
+achieve	O
+proper	O
+transition	O
+to	O
+a	O
+maintenance	O
+dose	O
+once	O
+an	O
+appropriate	O
+loading	O
+dose	O
+has	O
+been	O
+reached	O
+.	O
+
+Hypoxia	B
+in	O
+renal	B
+disease	I
+with	O
+proteinuria	B
+and	O
+/	O
+or	O
+glomerular	O
+hypertension	B
+.	O
+
+Despite	O
+the	O
+increasing	O
+need	O
+to	O
+identify	O
+and	O
+quantify	O
+tissue	O
+oxygenation	O
+at	O
+the	O
+cellular	O
+level	O
+,	O
+relatively	O
+few	O
+methods	O
+have	O
+been	O
+available	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+developed	O
+a	O
+new	O
+hypoxia	B
+-	O
+responsive	O
+reporter	O
+vector	O
+using	O
+a	O
+hypoxia	B
+-	O
+responsive	O
+element	O
+of	O
+the	O
+5	O
+'	O
+vascular	O
+endothelial	O
+growth	O
+factor	O
+untranslated	O
+region	O
+and	O
+generated	O
+a	O
+novel	O
+hypoxia	B
+-	O
+sensing	O
+transgenic	O
+rat	O
+.	O
+
+We	O
+then	O
+applied	O
+this	O
+animal	O
+model	O
+to	O
+the	O
+detection	O
+of	O
+tubulointerstitial	O
+hypoxia	B
+in	O
+the	O
+diseased	B
+kidney	I
+.	O
+
+With	O
+this	O
+model	O
+,	O
+we	O
+were	O
+able	O
+to	O
+identify	O
+diffuse	O
+cortical	O
+hypoxia	B
+in	O
+the	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+nephrotic	B
+syndrome	I
+and	O
+focal	O
+and	O
+segmental	O
+hypoxia	B
+in	O
+the	O
+remnant	O
+kidney	O
+model	O
+.	O
+
+Expression	O
+of	O
+the	O
+hypoxia	B
+-	O
+responsive	O
+transgene	O
+increased	O
+throughout	O
+the	O
+observation	O
+period	O
+,	O
+reaching	O
+2	O
+.	O
+2	O
+-	O
+fold	O
+at	O
+2	O
+weeks	O
+in	O
+the	O
+puromycin	O
+aminonucleoside	O
+model	O
+and	O
+2	O
+.	O
+6	O
+-	O
+fold	O
+at	O
+4	O
+weeks	O
+in	O
+the	O
+remnant	O
+kidney	O
+model	O
+,	O
+whereas	O
+that	O
+of	O
+vascular	O
+endothelial	O
+growth	O
+factor	O
+showed	O
+a	O
+mild	O
+decrease	O
+,	O
+reflecting	O
+distinct	O
+behaviors	O
+of	O
+the	O
+two	O
+genes	O
+.	O
+
+The	O
+degree	O
+of	O
+hypoxia	B
+showed	O
+a	O
+positive	O
+correlation	O
+with	O
+microscopic	O
+tubulointerstitial	B
+injury	I
+in	O
+both	O
+models	O
+.	O
+
+Finally	O
+,	O
+we	O
+identified	O
+the	O
+localization	O
+of	O
+proliferating	O
+cell	O
+nuclear	O
+antigen	O
+-	O
+positive	O
+,	O
+ED	O
+-	O
+1	O
+-	O
+positive	O
+,	O
+and	O
+terminal	O
+dUTP	O
+nick	O
+-	O
+end	O
+labeled	O
+-	O
+positive	O
+cells	O
+in	O
+the	O
+hypoxic	B
+cortical	O
+area	O
+in	O
+the	O
+remnant	O
+kidney	O
+model	O
+.	O
+
+We	O
+propose	O
+here	O
+a	O
+possible	O
+pathological	O
+tie	O
+between	O
+chronic	O
+tubulointerstitial	O
+hypoxia	B
+and	O
+progressive	O
+glomerular	B
+diseases	I
+.	O
+
+Adequate	O
+timing	O
+of	O
+ribavirin	O
+reduction	O
+in	O
+patients	O
+with	O
+hemolysis	B
+during	O
+combination	O
+therapy	O
+of	O
+interferon	O
+and	O
+ribavirin	O
+for	O
+chronic	B
+hepatitis	I
+C	I
+.	O
+
+BACKGROUND	O
+:	O
+Hemolytic	B
+anemia	I
+is	O
+one	O
+of	O
+the	O
+major	O
+adverse	O
+events	O
+of	O
+the	O
+combination	O
+therapy	O
+of	O
+interferon	O
+and	O
+ribavirin	O
+.	O
+
+Because	O
+of	O
+ribavirin	O
+-	O
+related	O
+hemolytic	B
+anemia	I
+,	O
+dose	O
+reduction	O
+is	O
+a	O
+common	O
+event	O
+in	O
+this	O
+therapy	O
+.	O
+
+In	O
+this	O
+clinical	O
+retrospective	O
+cohort	O
+study	O
+we	O
+have	O
+examined	O
+the	O
+suitable	O
+timing	O
+of	O
+ribavirin	O
+reduction	O
+in	O
+patients	O
+with	O
+hemolysis	B
+during	O
+combination	O
+therapy	O
+.	O
+
+METHODS	O
+:	O
+Thirty	O
+-	O
+seven	O
+of	O
+160	O
+patients	O
+who	O
+had	O
+HCV	O
+-	O
+genotype	O
+1b	O
+,	O
+had	O
+high	O
+virus	O
+load	O
+,	O
+and	O
+received	O
+24	O
+-	O
+week	O
+combination	O
+therapy	O
+developed	O
+anemia	B
+with	O
+hemoglobin	O
+level	O
+<	O
+10	O
+g	O
+/	O
+dl	O
+or	O
+anemia	B
+-	O
+related	O
+signs	O
+during	O
+therapy	O
+.	O
+
+After	O
+that	O
+,	O
+these	O
+37	O
+patients	O
+were	O
+reduced	O
+one	O
+tablet	O
+of	O
+ribavirin	O
+(	O
+200	O
+mg	O
+)	O
+per	O
+day	O
+.	O
+
+After	O
+reduction	O
+of	O
+ribavirin	O
+,	O
+27	O
+of	O
+37	O
+patients	O
+could	O
+continue	O
+combination	O
+therapy	O
+for	O
+a	O
+total	O
+of	O
+24	O
+weeks	O
+(	O
+group	O
+A	O
+)	O
+.	O
+
+However	O
+,	O
+10	O
+of	O
+37	O
+patients	O
+with	O
+reduction	O
+of	O
+ribavirin	O
+could	O
+not	O
+continue	O
+combination	O
+therapy	O
+because	O
+their	O
+<	O
+8	O
+.	O
+5	O
+g	O
+/	O
+dl	O
+hemoglobin	O
+values	O
+decreased	O
+to	O
+or	O
+anemia	B
+-	O
+related	O
+severe	O
+side	O
+effects	O
+occurred	O
+(	O
+group	O
+B	O
+)	O
+.	O
+
+We	O
+assessed	O
+the	O
+final	O
+efficacy	O
+and	O
+safety	O
+after	O
+reduction	O
+of	O
+ribavirin	O
+in	O
+groups	O
+A	O
+and	O
+B	O
+.	O
+
+RESULTS	O
+:	O
+A	O
+sustained	O
+virological	O
+response	O
+(	O
+SVR	O
+)	O
+was	O
+29	O
+.	O
+6	O
+%	O
+(	O
+8	O
+/	O
+27	O
+)	O
+in	O
+group	O
+A	O
+and	O
+10	O
+%	O
+(	O
+1	O
+/	O
+10	O
+)	O
+in	O
+group	O
+B	O
+,	O
+respectively	O
+.	O
+
+A	O
+34	O
+.	O
+4	O
+%	O
+(	O
+12	O
+/	O
+27	O
+)	O
+of	O
+SVR	O
++	O
+biological	O
+response	O
+in	O
+group	O
+A	O
+was	O
+higher	O
+than	O
+10	O
+%	O
+(	O
+1	O
+/	O
+10	O
+)	O
+in	O
+group	O
+B	O
+(	O
+P	O
+=	O
+0	O
+.	O
+051	O
+)	O
+,	O
+with	O
+slight	O
+significance	O
+.	O
+
+With	O
+respect	O
+to	O
+hemoglobin	O
+level	O
+at	O
+the	O
+time	O
+of	O
+ribavirin	O
+reduction	O
+,	O
+a	O
+rate	O
+of	O
+continuation	O
+of	O
+therapy	O
+in	O
+patients	O
+with	O
+>	O
+or	O
+=	O
+10	O
+g	O
+/	O
+dl	O
+hemoglobin	O
+was	O
+higher	O
+than	O
+that	O
+in	O
+patients	O
+with	O
+<	O
+10	O
+g	O
+/	O
+dl	O
+(	O
+P	O
+=	O
+0	O
+.	O
+036	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Reduction	O
+of	O
+ribavirin	O
+at	O
+hemoglobin	O
+level	O
+>	O
+or	O
+=	O
+10	O
+g	O
+/	O
+dl	O
+is	O
+suitable	O
+in	O
+terms	O
+of	O
+efficacy	O
+and	O
+side	O
+effects	O
+.	O
+
+Aging	O
+process	O
+of	O
+epithelial	O
+cells	O
+of	O
+the	O
+rat	O
+prostate	O
+lateral	O
+lobe	O
+in	O
+experimental	O
+hyperprolactinemia	B
+induced	O
+by	O
+haloperidol	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+examine	O
+the	O
+influence	O
+of	O
+hyperprolactinemia	B
+,	O
+induced	O
+by	O
+haloperidol	O
+(	O
+HAL	O
+)	O
+on	O
+age	O
+related	O
+morphology	O
+and	O
+function	O
+changes	O
+of	O
+epithelial	O
+cells	O
+in	O
+rat	O
+prostate	O
+lateral	O
+lobe	O
+.	O
+
+The	O
+study	O
+was	O
+performed	O
+on	O
+sexually	O
+mature	O
+male	O
+rats	O
+.	O
+
+Serum	O
+concentrations	O
+of	O
+prolactin	O
+(	O
+PRL	O
+)	O
+and	O
+testosterone	O
+(	O
+T	O
+)	O
+were	O
+measured	O
+.	O
+
+Tissue	O
+sections	O
+were	O
+evaluated	O
+with	O
+light	O
+and	O
+electron	O
+microscopy	O
+.	O
+
+Immunohistochemical	O
+reactions	O
+for	O
+Anti	O
+-	O
+Proliferating	O
+Cell	O
+Nuclear	O
+Antigen	O
+(	O
+PCNA	O
+)	O
+were	O
+performed	O
+.	O
+
+In	O
+rats	O
+of	O
+the	O
+experimental	O
+group	O
+,	O
+the	O
+mean	O
+concentration	O
+of	O
+:	O
+PRL	O
+was	O
+more	O
+than	O
+twice	O
+higher	O
+,	O
+whereas	O
+T	O
+concentration	O
+was	O
+almost	O
+twice	O
+lower	O
+than	O
+that	O
+in	O
+the	O
+control	O
+group	O
+.	O
+
+Light	O
+microscopy	O
+visualized	O
+the	O
+following	O
+:	O
+hypertrophy	B
+and	O
+epithelium	O
+hyperplasia	B
+of	O
+the	O
+glandular	O
+ducts	O
+,	O
+associated	O
+with	O
+increased	O
+PCNA	O
+expression	O
+.	O
+
+Electron	O
+microscopy	O
+revealed	O
+changes	O
+in	O
+columnar	O
+epithelial	O
+cells	O
+,	O
+concerning	O
+organelles	O
+,	O
+engaged	O
+in	O
+protein	O
+synthesis	O
+and	O
+secretion	O
+.	O
+
+Relation	O
+of	O
+perfusion	O
+defects	O
+observed	O
+with	O
+myocardial	O
+contrast	O
+echocardiography	O
+to	O
+the	O
+severity	O
+of	O
+coronary	B
+stenosis	I
+:	O
+correlation	O
+with	O
+thallium	O
+-	O
+201	O
+single	O
+-	O
+photon	O
+emission	O
+tomography	O
+.	O
+
+It	O
+has	O
+been	O
+previously	O
+shown	O
+that	O
+myocardial	O
+contrast	O
+echocardiography	O
+is	O
+a	O
+valuable	O
+technique	O
+for	O
+delineating	O
+regions	O
+of	O
+myocardial	O
+underperfusion	O
+secondary	O
+to	O
+coronary	B
+occlusion	I
+and	O
+to	O
+critical	O
+coronary	B
+stenoses	I
+in	O
+the	O
+presence	O
+of	O
+hyperemic	B
+stimulation	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+whether	O
+myocardial	O
+contrast	O
+echocardiography	O
+performed	O
+with	O
+a	O
+stable	O
+solution	O
+of	O
+sonicated	O
+albumin	O
+could	O
+detect	O
+regions	O
+of	O
+myocardial	O
+underperfusion	O
+resulting	O
+from	O
+various	O
+degrees	O
+of	O
+coronary	B
+stenosis	I
+.	O
+
+The	O
+perfusion	O
+defect	O
+produced	O
+in	O
+16	O
+open	O
+chest	O
+dogs	O
+was	O
+compared	O
+with	O
+the	O
+anatomic	O
+area	O
+at	O
+risk	O
+measured	O
+by	O
+the	O
+postmortem	O
+dual	O
+-	O
+perfusion	O
+technique	O
+and	O
+with	O
+thallium	O
+-	O
+201	O
+single	O
+-	O
+photon	O
+emission	O
+tomography	O
+(	O
+SPECT	O
+)	O
+.	O
+
+During	O
+a	O
+transient	O
+(	O
+20	O
+-	O
+s	O
+)	O
+coronary	B
+occlusion	I
+,	O
+a	O
+perfusion	O
+defect	O
+was	O
+observed	O
+with	O
+contrast	O
+echocardiography	O
+in	O
+14	O
+of	O
+the	O
+15	O
+dogs	O
+in	O
+which	O
+the	O
+occlusion	O
+was	O
+produced	O
+.	O
+
+The	O
+perfusion	O
+defect	O
+correlated	O
+significantly	O
+with	O
+the	O
+anatomic	O
+area	O
+at	O
+risk	O
+(	O
+r	O
+=	O
+0	O
+.	O
+74	O
+;	O
+p	O
+less	O
+than	O
+0	O
+.	O
+002	O
+)	O
+.	O
+
+During	O
+dipyridamole	O
+-	O
+induced	O
+hyperemia	B
+,	O
+12	O
+of	O
+the	O
+16	O
+dogs	O
+with	O
+a	O
+partial	O
+coronary	B
+stenosis	I
+had	O
+a	O
+visible	O
+area	O
+of	O
+hypoperfusion	O
+by	O
+contrast	O
+echocardiography	O
+.	O
+
+The	O
+four	O
+dogs	O
+without	O
+a	O
+perfusion	O
+defect	O
+had	O
+a	O
+stenosis	O
+that	O
+resulted	O
+in	O
+a	O
+mild	O
+(	O
+0	O
+%	O
+to	O
+50	O
+%	O
+)	O
+reduction	O
+in	O
+dipyridamole	O
+-	O
+induced	O
+hyperemia	B
+.	O
+
+The	O
+size	O
+of	O
+the	O
+perfusion	O
+defect	O
+during	O
+stenosis	O
+correlated	O
+significantly	O
+with	O
+the	O
+anatomic	O
+area	O
+at	O
+risk	O
+(	O
+r	O
+=	O
+0	O
+.	O
+61	O
+;	O
+p	O
+=	O
+0	O
+.	O
+02	O
+)	O
+.	O
+
+Thallium	O
+-	O
+201	O
+SPECT	O
+demonstrated	O
+a	O
+perfusion	O
+defect	O
+in	O
+all	O
+14	O
+dogs	O
+analyzed	O
+during	O
+dipyridamole	O
+-	O
+induced	O
+hyperemia	B
+;	O
+the	O
+size	O
+of	O
+the	O
+perfusion	O
+defect	O
+correlated	O
+with	O
+the	O
+anatomic	O
+area	O
+at	O
+risk	O
+(	O
+r	O
+=	O
+0	O
+.	O
+58	O
+;	O
+p	O
+less	O
+than	O
+0	O
+.	O
+03	O
+)	O
+and	O
+with	O
+the	O
+perfusion	O
+defect	O
+by	O
+contrast	O
+echocardiography	O
+(	O
+r	O
+=	O
+0	O
+.	O
+58	O
+;	O
+p	O
+less	O
+than	O
+0	O
+.	O
+03	O
+)	O
+.	O
+
+Thus	O
+,	O
+myocardial	O
+contrast	O
+echocardiography	O
+can	O
+be	O
+used	O
+to	O
+visualize	O
+and	O
+quantitate	O
+the	O
+amount	O
+of	O
+jeopardized	O
+myocardium	O
+during	O
+moderate	O
+to	O
+severe	O
+degrees	O
+of	O
+coronary	B
+stenosis	I
+.	O
+
+The	O
+results	O
+obtained	O
+show	O
+a	O
+correlation	O
+with	O
+the	O
+anatomic	O
+area	O
+at	O
+risk	O
+similar	O
+to	O
+that	O
+obtained	O
+with	O
+thallium	O
+-	O
+201	O
+SPECT	O
+.	O
+
+The	O
+activation	O
+of	O
+spinal	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+receptors	O
+may	O
+contribute	O
+to	O
+degeneration	O
+of	O
+spinal	O
+motor	O
+neurons	O
+induced	O
+by	O
+neuraxial	O
+morphine	O
+after	O
+a	O
+noninjurious	O
+interval	O
+of	O
+spinal	B
+cord	I
+ischemia	I
+.	O
+
+We	O
+investigated	O
+the	O
+relationship	O
+between	O
+the	O
+degeneration	O
+of	O
+spinal	O
+motor	O
+neurons	O
+and	O
+activation	O
+of	O
+N	O
+-	O
+methyl	O
+-	O
+d	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+receptors	O
+after	O
+neuraxial	O
+morphine	O
+following	O
+a	O
+noninjurious	O
+interval	O
+of	O
+aortic	B
+occlusion	I
+in	O
+rats	O
+.	O
+
+Spinal	B
+cord	I
+ischemia	I
+was	O
+induced	O
+by	O
+aortic	B
+occlusion	I
+for	O
+6	O
+min	O
+with	O
+a	O
+balloon	O
+catheter	O
+.	O
+
+In	O
+a	O
+microdialysis	O
+study	O
+,	O
+10	O
+muL	O
+of	O
+saline	O
+(	O
+group	O
+C	O
+;	O
+n	O
+=	O
+8	O
+)	O
+or	O
+30	O
+mug	O
+of	O
+morphine	O
+(	O
+group	O
+M	O
+;	O
+n	O
+=	O
+8	O
+)	O
+was	O
+injected	O
+intrathecally	O
+(	O
+IT	O
+)	O
+0	O
+.	O
+5	O
+h	O
+after	O
+reflow	O
+,	O
+and	O
+30	O
+mug	O
+of	O
+morphine	O
+(	O
+group	O
+SM	O
+;	O
+n	O
+=	O
+8	O
+)	O
+or	O
+10	O
+muL	O
+of	O
+saline	O
+(	O
+group	O
+SC	O
+;	O
+n	O
+=	O
+8	O
+)	O
+was	O
+injected	O
+IT	O
+0	O
+.	O
+5	O
+h	O
+after	O
+sham	O
+operation	O
+.	O
+
+Microdialysis	O
+samples	O
+were	O
+collected	O
+preischemia	O
+,	O
+before	O
+IT	O
+injection	O
+,	O
+and	O
+at	O
+2	O
+,	O
+4	O
+,	O
+8	O
+,	O
+24	O
+,	O
+and	O
+48	O
+h	O
+of	O
+reperfusion	O
+(	O
+after	O
+IT	O
+injection	O
+)	O
+.	O
+
+Second	O
+,	O
+we	O
+investigated	O
+the	O
+effect	O
+of	O
+IT	O
+MK	O
+-	O
+801	O
+(	O
+30	O
+mug	O
+)	O
+on	O
+the	O
+histopathologic	O
+changes	O
+in	O
+the	O
+spinal	O
+cord	O
+after	O
+morphine	O
+-	O
+induced	O
+spastic	B
+paraparesis	I
+.	O
+
+After	O
+IT	O
+morphine	O
+,	O
+the	O
+cerebrospinal	O
+fluid	O
+(	O
+CSF	O
+)	O
+glutamate	O
+concentration	O
+was	O
+increased	O
+in	O
+group	O
+M	O
+relative	O
+to	O
+both	O
+baseline	O
+and	O
+group	O
+C	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+This	O
+increase	O
+persisted	O
+for	O
+8	O
+hrs	O
+.	O
+
+IT	O
+MK	O
+-	O
+801	O
+significantly	O
+reduced	O
+the	O
+number	O
+of	O
+dark	O
+-	O
+stained	O
+alpha	O
+-	O
+motoneurons	O
+after	O
+morphine	O
+-	O
+induced	O
+spastic	B
+paraparesis	I
+compared	O
+with	O
+the	O
+saline	O
+group	O
+.	O
+
+These	O
+data	O
+indicate	O
+that	O
+IT	O
+morphine	O
+induces	O
+spastic	B
+paraparesis	I
+with	O
+a	O
+concomitant	O
+increase	O
+in	O
+CSF	O
+glutamate	O
+,	O
+which	O
+is	O
+involved	O
+in	O
+NMDA	O
+receptor	O
+activation	O
+.	O
+
+We	O
+suggest	O
+that	O
+opioids	O
+may	O
+be	O
+neurotoxic	B
+in	O
+the	O
+setting	O
+of	O
+spinal	B
+cord	I
+ischemia	I
+via	O
+NMDA	O
+receptor	O
+activation	O
+.	O
+
+Acute	O
+low	B
+back	I
+pain	I
+during	O
+intravenous	O
+administration	O
+of	O
+amiodarone	O
+:	O
+a	O
+report	O
+of	O
+two	O
+cases	O
+.	O
+
+Amiodarone	O
+represents	O
+an	O
+effective	O
+antiarrhythmic	O
+drug	O
+for	O
+cardioversion	O
+of	O
+recent	O
+-	O
+onset	O
+atrial	B
+fibrillation	I
+(	O
+AF	B
+)	O
+and	O
+maintenance	O
+of	O
+sinus	O
+rhythm	O
+.	O
+
+We	O
+briefly	O
+describe	O
+two	O
+patients	O
+suffering	O
+from	O
+recent	O
+-	O
+onset	O
+atrial	B
+fibrillation	I
+,	O
+who	O
+experienced	O
+an	O
+acute	O
+devastating	O
+low	B
+back	I
+pain	I
+a	O
+few	O
+minutes	O
+after	O
+initiation	O
+of	O
+intravenous	O
+amiodarone	O
+loading	O
+.	O
+
+Notably	O
+,	O
+this	O
+side	O
+effect	O
+has	O
+not	O
+been	O
+ever	O
+reported	O
+in	O
+the	O
+medical	O
+literature	O
+.	O
+
+Clinicians	O
+should	O
+be	O
+aware	O
+of	O
+this	O
+reaction	O
+since	O
+prompt	O
+termination	O
+of	O
+parenteral	O
+administration	O
+leads	O
+to	O
+complete	O
+resolution	O
+.	O
+
+Quantitative	O
+drug	O
+levels	O
+in	O
+stimulant	O
+psychosis	B
+:	O
+relationship	O
+to	O
+symptom	O
+severity	O
+,	O
+catecholamines	O
+and	O
+hyperkinesia	B
+.	O
+
+To	O
+examine	O
+the	O
+relationship	O
+between	O
+quantitative	O
+stimulant	O
+drug	O
+levels	O
+,	O
+catecholamines	O
+,	O
+and	O
+psychotic	B
+symptoms	I
+,	O
+nineteen	O
+patients	O
+in	O
+a	O
+psychiatric	B
+emergency	O
+service	O
+with	O
+a	O
+diagnosis	O
+of	O
+amphetamine	O
+-	O
+or	O
+cocaine	O
+-	O
+induced	O
+psychosis	B
+were	O
+interviewed	O
+,	O
+and	O
+plasma	O
+and	O
+urine	O
+were	O
+collected	O
+for	O
+quantitative	O
+assays	O
+of	O
+stimulant	O
+drug	O
+and	O
+catecholamine	O
+metabolite	O
+levels	O
+.	O
+
+Methamphetamine	O
+or	O
+amphetamine	O
+levels	O
+were	O
+related	O
+to	O
+several	O
+psychopathology	O
+scores	O
+and	O
+the	O
+global	O
+hyperkinesia	B
+rating	O
+.	O
+
+HVA	O
+levels	O
+were	O
+related	O
+to	O
+global	O
+hyperkinesia	B
+but	O
+not	O
+to	O
+psychopathology	O
+ratings	O
+.	O
+
+Although	O
+many	O
+other	O
+factors	O
+such	O
+as	O
+sensitization	O
+may	O
+play	O
+a	O
+role	O
+,	O
+intensity	O
+of	O
+stimulant	O
+-	O
+induced	O
+psychotic	B
+symptoms	I
+and	O
+stereotypies	B
+appears	O
+to	O
+be	O
+at	O
+least	O
+in	O
+part	O
+dose	O
+-	O
+related	O
+.	O
+
+Pheochromocytoma	B
+unmasked	O
+by	O
+amisulpride	O
+and	O
+tiapride	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+describe	O
+the	O
+unmasking	O
+of	O
+pheochromocytoma	B
+in	O
+a	O
+patient	O
+treated	O
+with	O
+amisulpride	O
+and	O
+tiapride	O
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+42	O
+-	O
+year	O
+-	O
+old	O
+white	O
+man	O
+developed	O
+acute	O
+hypertension	B
+with	O
+severe	O
+headache	B
+and	O
+vomiting	B
+2	O
+hours	O
+after	O
+the	O
+first	O
+doses	O
+of	O
+amisulpride	O
+100	O
+mg	O
+and	O
+tiapride	O
+100	O
+mg	O
+.	O
+
+Both	O
+drugs	O
+were	O
+immediately	O
+discontinued	O
+,	O
+and	O
+the	O
+patient	O
+recovered	O
+after	O
+subsequent	O
+nicardipine	O
+and	O
+verapamil	O
+treatment	O
+.	O
+
+Abdominal	O
+ultrasound	O
+showed	O
+an	O
+adrenal	O
+mass	O
+,	O
+and	O
+postoperative	O
+histologic	O
+examination	O
+confirmed	O
+the	O
+diagnosis	O
+of	O
+pheochromocytoma	B
+.	O
+
+DISCUSSION	O
+:	O
+Drug	O
+-	O
+induced	O
+symptoms	O
+of	O
+pheochromocytoma	B
+are	O
+often	O
+associated	O
+with	O
+the	O
+use	O
+of	O
+substituted	O
+benzamide	O
+drugs	O
+,	O
+but	O
+the	O
+underlying	O
+mechanism	O
+is	O
+unknown	O
+.	O
+
+In	O
+our	O
+case	O
+,	O
+use	O
+of	O
+the	O
+Naranjo	O
+probability	O
+scale	O
+indicated	O
+a	O
+possible	O
+relationship	O
+between	O
+the	O
+hypertensive	B
+crisis	O
+and	O
+amisulpride	O
+and	O
+tiapride	O
+therapy	O
+.	O
+
+CONCLUSIONS	O
+:	O
+As	O
+of	O
+March	O
+24	O
+,	O
+2005	O
+,	O
+this	O
+is	O
+the	O
+first	O
+reported	O
+case	O
+of	O
+amisulpride	O
+-	O
+and	O
+tiapride	O
+-	O
+induced	O
+hypertensive	B
+crisis	O
+in	O
+a	O
+patient	O
+with	O
+pheochromocytoma	B
+.	O
+
+Physicians	O
+and	O
+other	O
+healthcare	O
+professionals	O
+should	O
+be	O
+aware	O
+of	O
+this	O
+potential	O
+adverse	O
+effect	O
+of	O
+tiapride	O
+and	O
+amisulpride	O
+.	O
+
+Minor	O
+neurological	B
+dysfunction	I
+,	O
+cognitive	O
+development	O
+,	O
+and	O
+somatic	O
+development	O
+at	O
+the	O
+age	O
+of	O
+3	O
+to	O
+7	O
+years	O
+after	O
+dexamethasone	O
+treatment	O
+in	O
+very	O
+-	O
+low	O
+birth	O
+-	O
+weight	O
+infants	O
+.	O
+
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+assess	O
+minor	O
+neurological	B
+dysfunction	I
+,	O
+cognitive	O
+development	O
+,	O
+and	O
+somatic	O
+development	O
+after	O
+dexamethasone	O
+therapy	O
+in	O
+very	O
+-	O
+low	O
+-	O
+birthweight	O
+infants	O
+.	O
+
+Thirty	O
+-	O
+three	O
+children	O
+after	O
+dexamethasone	O
+treatment	O
+were	O
+matched	O
+to	O
+33	O
+children	O
+without	O
+dexamethasone	O
+treatment	O
+.	O
+
+Data	O
+were	O
+assessed	O
+at	O
+the	O
+age	O
+of	O
+3	O
+-	O
+7	O
+years	O
+.	O
+
+Dexamethasone	O
+was	O
+started	O
+between	O
+the	O
+7th	O
+and	O
+the	O
+28th	O
+day	O
+of	O
+life	O
+over	O
+7	O
+days	O
+with	O
+a	O
+total	O
+dose	O
+of	O
+2	O
+.	O
+35	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+.	O
+
+Exclusion	O
+criteria	O
+were	O
+asphyxia	B
+,	O
+malformations	B
+,	O
+major	O
+surgical	O
+interventions	O
+,	O
+small	O
+for	O
+gestational	O
+age	O
+,	O
+intraventricular	O
+haemorrhage	B
+grades	O
+III	O
+and	O
+IV	O
+,	O
+periventricular	B
+leukomalacia	I
+,	O
+and	O
+severe	O
+psychomotor	B
+retardation	I
+.	O
+
+Each	O
+child	O
+was	O
+examined	O
+by	O
+a	O
+neuropediatrician	O
+for	O
+minor	O
+neurological	B
+dysfunctions	I
+and	O
+tested	O
+by	O
+a	O
+psychologist	O
+for	O
+cognitive	O
+development	O
+with	O
+a	O
+Kaufman	O
+Assessment	O
+Battery	O
+for	O
+Children	O
+and	O
+a	O
+Draw	O
+-	O
+a	O
+-	O
+Man	O
+Test	O
+.	O
+
+There	O
+were	O
+no	O
+differences	O
+in	O
+demographic	O
+data	O
+,	O
+growth	O
+,	O
+and	O
+socio	O
+-	O
+economic	O
+status	O
+between	O
+the	O
+two	O
+groups	O
+.	O
+
+Fine	O
+motor	O
+skills	O
+and	O
+gross	O
+motor	O
+function	O
+were	O
+significantly	O
+better	O
+in	O
+the	O
+control	O
+group	O
+(	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+In	O
+the	O
+Draw	O
+-	O
+a	O
+-	O
+Man	O
+Test	O
+,	O
+the	O
+control	O
+group	O
+showed	O
+better	O
+results	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+There	O
+were	O
+no	O
+differences	O
+in	O
+development	O
+of	O
+speech	O
+,	O
+social	O
+development	O
+,	O
+and	O
+the	O
+Kaufman	O
+Assessment	O
+Battery	O
+for	O
+Children	O
+.	O
+
+After	O
+dexamethasone	O
+treatment	O
+,	O
+children	O
+showed	O
+a	O
+higher	O
+rate	O
+of	O
+minor	O
+neurological	B
+dysfunctions	I
+.	O
+
+Neurological	O
+development	O
+was	O
+affected	O
+even	O
+without	O
+neurological	O
+diagnosis	O
+.	O
+
+Further	O
+long	O
+-	O
+term	O
+follow	O
+-	O
+up	O
+studies	O
+will	O
+be	O
+necessary	O
+to	O
+fully	O
+evaluate	O
+the	O
+impact	O
+of	O
+dexamethasone	O
+on	O
+neurological	O
+and	O
+cognitive	O
+development	O
+.	O
+
+Valproic	O
+acid	O
+I	O
+:	O
+time	O
+course	O
+of	O
+lipid	O
+peroxidation	O
+biomarkers	O
+,	O
+liver	B
+toxicity	I
+,	O
+and	O
+valproic	O
+acid	O
+metabolite	O
+levels	O
+in	O
+rats	O
+.	O
+
+A	O
+single	O
+dose	O
+of	O
+valproic	O
+acid	O
+(	O
+VPA	O
+)	O
+,	O
+which	O
+is	O
+a	O
+widely	O
+used	O
+antiepileptic	O
+drug	O
+,	O
+is	O
+associated	O
+with	O
+oxidative	O
+stress	O
+in	O
+rats	O
+,	O
+as	O
+recently	O
+demonstrated	O
+by	O
+elevated	O
+levels	O
+of	O
+15	O
+-	O
+F	O
+(	O
+2t	O
+)	O
+-	O
+isoprostane	O
+(	O
+15	O
+-	O
+F	O
+(	O
+2t	O
+)	O
+-	O
+IsoP	O
+)	O
+.	O
+
+To	O
+determine	O
+whether	O
+there	O
+was	O
+a	O
+temporal	O
+relationship	O
+between	O
+VPA	O
+-	O
+associated	O
+oxidative	O
+stress	O
+and	O
+hepatotoxicity	B
+,	O
+adult	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+were	O
+treated	O
+ip	O
+with	O
+VPA	O
+(	O
+500	O
+mg	O
+/	O
+kg	O
+)	O
+or	O
+0	O
+.	O
+9	O
+%	O
+saline	O
+(	O
+vehicle	O
+)	O
+once	O
+daily	O
+for	O
+2	O
+,	O
+4	O
+,	O
+7	O
+,	O
+10	O
+,	O
+or	O
+14	O
+days	O
+.	O
+
+Oxidative	O
+stress	O
+was	O
+assessed	O
+by	O
+determining	O
+plasma	O
+and	O
+liver	O
+levels	O
+of	O
+15	O
+-	O
+F	O
+(	O
+2t	O
+)	O
+-	O
+IsoP	O
+,	O
+lipid	O
+hydroperoxides	O
+(	O
+LPO	O
+)	O
+,	O
+and	O
+thiobarbituric	O
+acid	O
+reactive	O
+substances	O
+(	O
+TBARs	O
+)	O
+.	O
+
+Plasma	O
+and	O
+liver	O
+15	O
+-	O
+F	O
+(	O
+2t	O
+)	O
+-	O
+IsoP	O
+were	O
+elevated	O
+and	O
+reached	O
+a	O
+plateau	O
+after	O
+day	O
+2	O
+of	O
+VPA	O
+treatment	O
+compared	O
+to	O
+control	O
+.	O
+
+Liver	O
+LPO	O
+levels	O
+were	O
+not	O
+elevated	O
+until	O
+day	O
+7	O
+of	O
+treatment	O
+(	O
+1	O
+.	O
+8	O
+-	O
+fold	O
+versus	O
+control	O
+,	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Liver	O
+and	O
+plasma	O
+TBARs	O
+were	O
+not	O
+increased	O
+until	O
+14	O
+days	O
+(	O
+2	O
+-	O
+fold	O
+vs	O
+.	O
+control	O
+,	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Liver	B
+toxicity	I
+was	O
+evaluated	O
+based	O
+on	O
+serum	O
+levels	O
+of	O
+alpha	O
+-	O
+glutathione	O
+S	O
+-	O
+transferase	O
+(	O
+alpha	O
+-	O
+GST	O
+)	O
+and	O
+by	O
+histology	O
+.	O
+
+Serum	O
+alpha	O
+-	O
+GST	O
+levels	O
+were	O
+significantly	O
+elevated	O
+by	O
+day	O
+4	O
+,	O
+which	O
+corresponded	O
+to	O
+hepatotoxicity	B
+as	O
+shown	O
+by	O
+the	O
+increasing	O
+incidence	O
+of	O
+inflammation	B
+of	O
+the	O
+liver	O
+capsule	O
+,	O
+necrosis	B
+,	O
+and	O
+steatosis	B
+throughout	O
+the	O
+study	O
+.	O
+
+The	O
+liver	O
+levels	O
+of	O
+beta	O
+-	O
+oxidation	O
+metabolites	O
+of	O
+VPA	O
+were	O
+decreased	O
+by	O
+day	O
+14	O
+,	O
+while	O
+the	O
+levels	O
+of	O
+4	O
+-	O
+ene	O
+-	O
+VPA	O
+and	O
+(	O
+E	O
+)	O
+-	O
+2	O
+,	O
+4	O
+-	O
+diene	O
+-	O
+VPA	O
+were	O
+not	O
+elevated	O
+throughout	O
+the	O
+study	O
+.	O
+
+Overall	O
+,	O
+these	O
+findings	O
+indicate	O
+that	O
+VPA	O
+treatment	O
+results	O
+in	O
+oxidative	O
+stress	O
+,	O
+as	O
+measured	O
+by	O
+levels	O
+of	O
+15	O
+-	O
+F	O
+(	O
+2t	O
+)	O
+-	O
+IsoP	O
+,	O
+which	O
+precedes	O
+the	O
+onset	O
+of	O
+necrosis	B
+,	O
+steatosis	B
+,	O
+and	O
+elevated	O
+levels	O
+of	O
+serum	O
+alpha	O
+-	O
+GST	O
+.	O
+
+Assessment	O
+of	O
+perinatal	O
+hepatitis	B
+B	I
+and	O
+rubella	B
+prevention	O
+in	O
+New	O
+Hampshire	O
+delivery	O
+hospitals	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+evaluate	O
+current	O
+performance	O
+on	O
+recommended	O
+perinatal	O
+hepatitis	B
+B	I
+and	O
+rubella	B
+prevention	O
+practices	O
+in	O
+New	O
+Hampshire	O
+.	O
+
+METHODS	O
+:	O
+Data	O
+were	O
+extracted	O
+from	O
+2021	O
+paired	O
+mother	O
+-	O
+infant	O
+records	O
+for	O
+the	O
+year	O
+2000	O
+birth	O
+cohort	O
+in	O
+New	O
+Hampshire	O
+'	O
+s	O
+25	O
+delivery	O
+hospitals	O
+.	O
+
+Assessment	O
+was	O
+done	O
+on	O
+the	O
+following	O
+:	O
+prenatal	O
+screening	O
+for	O
+hepatitis	B
+B	I
+and	O
+rubella	B
+,	O
+administration	O
+of	O
+the	O
+hepatitis	B
+B	I
+vaccine	O
+birth	O
+dose	O
+to	O
+all	O
+infants	O
+,	O
+administration	O
+of	O
+hepatitis	B
+B	I
+immune	O
+globulin	O
+to	O
+infants	O
+who	O
+were	O
+born	O
+to	O
+hepatitis	O
+B	O
+surface	O
+antigen	O
+-	O
+positive	O
+mothers	O
+,	O
+rubella	B
+immunity	O
+,	O
+and	O
+administration	O
+of	O
+in	O
+-	O
+hospital	O
+postpartum	O
+rubella	B
+vaccine	O
+to	O
+rubella	B
+nonimmune	O
+women	O
+.	O
+
+RESULTS	O
+:	O
+Prenatal	O
+screening	O
+rates	O
+for	O
+hepatitis	B
+B	I
+(	O
+98	O
+.	O
+8	O
+%	O
+)	O
+and	O
+rubella	B
+(	O
+99	O
+.	O
+4	O
+%	O
+)	O
+were	O
+high	O
+.	O
+
+Hepatitis	B
+B	I
+vaccine	O
+birth	O
+dose	O
+was	O
+administered	O
+to	O
+76	O
+.	O
+2	O
+%	O
+of	O
+all	O
+infants	O
+.	O
+
+All	O
+infants	O
+who	O
+were	O
+born	O
+to	O
+hepatitis	O
+B	O
+surface	O
+antigen	O
+-	O
+positive	O
+mothers	O
+also	O
+received	O
+hepatitis	B
+B	I
+immune	O
+globulin	O
+.	O
+
+Multivariate	O
+logistic	O
+regression	O
+showed	O
+that	O
+the	O
+month	O
+of	O
+delivery	O
+and	O
+infant	O
+birth	O
+weight	O
+were	O
+independent	O
+predictors	O
+of	O
+hepatitis	B
+B	I
+vaccination	O
+.	O
+
+The	O
+proportion	O
+of	O
+infants	O
+who	O
+were	O
+vaccinated	O
+in	O
+January	O
+and	O
+February	O
+2000	O
+(	O
+48	O
+.	O
+5	O
+%	O
+and	O
+67	O
+.	O
+5	O
+%	O
+,	O
+respectively	O
+)	O
+was	O
+less	O
+than	O
+any	O
+other	O
+months	O
+,	O
+whereas	O
+the	O
+proportion	O
+who	O
+were	O
+vaccinated	O
+in	O
+December	O
+2000	O
+(	O
+88	O
+.	O
+2	O
+%	O
+)	O
+was	O
+the	O
+highest	O
+.	O
+
+Women	O
+who	O
+were	O
+born	O
+between	O
+1971	O
+and	O
+1975	O
+had	O
+the	O
+highest	O
+rate	O
+of	O
+rubella	B
+nonimmunity	O
+(	O
+9	O
+.	O
+5	O
+%	O
+)	O
+.	O
+
+In	O
+-	O
+hospital	O
+postpartum	O
+rubella	B
+vaccine	O
+administration	O
+was	O
+documented	O
+for	O
+75	O
+.	O
+6	O
+%	O
+of	O
+nonimmune	O
+women	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+study	O
+documents	O
+good	O
+compliance	O
+in	O
+New	O
+Hampshire	O
+'	O
+s	O
+birthing	O
+hospitals	O
+with	O
+national	O
+guidelines	O
+for	O
+perinatal	O
+hepatitis	B
+B	I
+and	O
+rubella	B
+prevention	O
+and	O
+highlights	O
+potential	O
+areas	O
+for	O
+improvement	O
+.	O
+
+Succinylcholine	O
+-	O
+induced	O
+masseter	B
+muscle	I
+rigidity	I
+during	O
+bronchoscopic	O
+removal	O
+of	O
+a	O
+tracheal	O
+foreign	O
+body	O
+.	O
+
+Masseter	B
+muscle	I
+rigidity	I
+during	O
+general	O
+anesthesia	O
+is	O
+considered	O
+an	O
+early	O
+warning	O
+sign	O
+of	O
+a	O
+possible	O
+episode	O
+of	O
+malignant	B
+hyperthermia	I
+.	O
+
+The	O
+decision	O
+whether	O
+to	O
+continue	O
+or	O
+discontinue	O
+the	O
+procedure	O
+depends	O
+on	O
+the	O
+urgency	O
+of	O
+the	O
+surgery	O
+and	O
+severity	O
+of	O
+masseter	B
+muscle	I
+rigidity	I
+.	O
+
+Here	O
+,	O
+we	O
+describe	O
+a	O
+case	O
+of	O
+severe	O
+masseter	B
+muscle	I
+rigidity	I
+(	O
+jaw	B
+of	I
+steel	I
+)	O
+after	O
+succinylcholine	O
+(	O
+Sch	O
+)	O
+administration	O
+during	O
+general	O
+anesthetic	O
+management	O
+for	O
+rigid	O
+bronchoscopic	O
+removal	O
+of	O
+a	O
+tracheal	O
+foreign	O
+body	O
+.	O
+
+Anesthesia	O
+was	O
+continued	O
+uneventfully	O
+with	O
+propofol	O
+infusion	O
+while	O
+all	O
+facilities	O
+were	O
+available	O
+to	O
+detect	O
+and	O
+treat	O
+malignant	B
+hyperthermia	I
+.	O
+
+Dexrazoxane	O
+protects	O
+against	O
+myelosuppression	B
+from	O
+the	O
+DNA	O
+cleavage	O
+-	O
+enhancing	O
+drugs	O
+etoposide	O
+and	O
+daunorubicin	O
+but	O
+not	O
+doxorubicin	O
+.	O
+
+PURPOSE	O
+:	O
+The	O
+anthracyclines	O
+daunorubicin	O
+and	O
+doxorubicin	O
+and	O
+the	O
+epipodophyllotoxin	O
+etoposide	O
+are	O
+potent	O
+DNA	O
+cleavage	O
+-	O
+enhancing	O
+drugs	O
+that	O
+are	O
+widely	O
+used	O
+in	O
+clinical	O
+oncology	O
+;	O
+however	O
+,	O
+myelosuppression	B
+and	O
+cardiac	B
+toxicity	I
+limit	O
+their	O
+use	O
+.	O
+
+Dexrazoxane	O
+(	O
+ICRF	O
+-	O
+187	O
+)	O
+is	O
+recommended	O
+for	O
+protection	O
+against	O
+anthracycline	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+EXPERIMENTAL	O
+DESIGN	O
+:	O
+Because	O
+of	O
+their	O
+widespread	O
+use	O
+,	O
+the	O
+hematologic	B
+toxicity	I
+following	O
+coadministration	O
+of	O
+dexrazoxane	O
+and	O
+these	O
+three	O
+structurally	O
+different	O
+DNA	O
+cleavage	O
+enhancers	O
+was	O
+investigated	O
+:	O
+Sensitivity	O
+of	O
+human	O
+and	O
+murine	O
+blood	O
+progenitor	O
+cells	O
+to	O
+etoposide	O
+,	O
+daunorubicin	O
+,	O
+and	O
+doxorubicin	O
++	O
+/	O
+-	O
+dexrazoxane	O
+was	O
+determined	O
+in	O
+granulocyte	O
+-	O
+macrophage	O
+colony	O
+forming	O
+assays	O
+.	O
+
+Likewise	O
+,	O
+in	O
+vivo	O
+,	O
+B6D2F1	O
+mice	O
+were	O
+treated	O
+with	O
+etoposide	O
+,	O
+daunorubicin	O
+,	O
+and	O
+doxorubicin	O
+,	O
+with	O
+or	O
+without	O
+dexrazoxane	O
+over	O
+a	O
+wide	O
+range	O
+of	O
+doses	O
+:	O
+posttreatment	O
+,	O
+a	O
+full	O
+hematologic	O
+evaluation	O
+was	O
+done	O
+.	O
+
+RESULTS	O
+:	O
+Nontoxic	O
+doses	O
+of	O
+dexrazoxane	O
+reduced	O
+myelosuppression	B
+and	O
+weight	B
+loss	I
+from	O
+daunorubicin	O
+and	O
+etoposide	O
+in	O
+mice	O
+and	O
+antagonized	O
+their	O
+antiproliferative	O
+effects	O
+in	O
+the	O
+colony	O
+assay	O
+;	O
+however	O
+,	O
+dexrazoxane	O
+neither	O
+reduced	O
+myelosuppression	B
+,	O
+weight	B
+loss	I
+,	O
+nor	O
+the	O
+in	O
+vitro	O
+cytotoxicity	B
+from	O
+doxorubicin	O
+.	O
+
+CONCLUSION	O
+:	O
+Although	O
+our	O
+findings	O
+support	O
+the	O
+observation	O
+that	O
+dexrazoxane	O
+reduces	O
+neither	O
+hematologic	O
+activity	O
+nor	O
+antitumor	O
+activity	O
+from	O
+doxorubicin	O
+clinically	O
+,	O
+the	O
+potent	O
+antagonism	O
+of	O
+daunorubicin	O
+activity	O
+raises	O
+concern	O
+;	O
+a	O
+possible	O
+interference	O
+with	O
+anticancer	O
+efficacy	O
+certainly	O
+would	O
+call	O
+for	O
+renewed	O
+attention	O
+.	O
+
+Our	O
+data	O
+also	O
+suggest	O
+that	O
+significant	O
+etoposide	O
+dose	O
+escalation	O
+is	O
+perhaps	O
+possible	O
+by	O
+the	O
+use	O
+of	O
+dexrazoxane	O
+.	O
+
+Clinical	O
+trials	O
+in	O
+patients	O
+with	O
+brain	O
+metastases	B
+combining	O
+dexrazoxane	O
+and	O
+high	O
+doses	O
+of	O
+etoposide	O
+is	O
+ongoing	O
+with	O
+the	O
+aim	O
+of	O
+improving	O
+efficacy	O
+without	O
+aggravating	O
+hematologic	B
+toxicity	I
+.	O
+
+If	O
+successful	O
+,	O
+this	O
+represents	O
+an	O
+exciting	O
+mechanism	O
+for	O
+pharmacologic	O
+regulation	O
+of	O
+side	O
+effects	O
+from	O
+cytotoxic	O
+chemotherapy	O
+.	O
+
+Assessment	O
+of	O
+the	O
+onset	O
+and	O
+persistence	O
+of	O
+amnesia	B
+during	O
+procedural	O
+sedation	O
+with	O
+propofol	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+assess	O
+patients	O
+'	O
+ability	O
+to	O
+repeat	O
+and	O
+recall	O
+words	O
+presented	O
+to	O
+them	O
+while	O
+undergoing	O
+procedural	O
+sedation	O
+with	O
+propofol	O
+,	O
+and	O
+correlate	O
+their	O
+recall	O
+with	O
+their	O
+level	O
+of	O
+awareness	O
+as	O
+measured	O
+by	O
+bispectral	O
+index	O
+(	O
+BIS	O
+)	O
+monitoring	O
+.	O
+
+METHODS	O
+:	O
+This	O
+was	O
+a	O
+prospective	O
+,	O
+single	O
+-	O
+intervention	O
+study	O
+of	O
+consenting	O
+adult	O
+patients	O
+undergoing	O
+procedural	O
+sedation	O
+with	O
+propofol	O
+between	O
+December	O
+28	O
+,	O
+2002	O
+,	O
+and	O
+October	O
+31	O
+,	O
+2003	O
+.	O
+
+BIS	O
+monitoring	O
+was	O
+initiated	O
+starting	O
+3	O
+minutes	O
+before	O
+the	O
+procedure	O
+and	O
+continuing	O
+until	O
+the	O
+patient	O
+had	O
+regained	O
+baseline	O
+mental	O
+status	O
+.	O
+
+At	O
+1	O
+-	O
+minute	O
+intervals	O
+during	O
+the	O
+procedural	O
+sedation	O
+,	O
+until	O
+the	O
+patient	O
+regained	O
+baseline	O
+mental	O
+status	O
+at	O
+the	O
+end	O
+of	O
+the	O
+procedure	O
+,	O
+a	O
+word	O
+from	O
+a	O
+standardized	O
+list	O
+was	O
+read	O
+aloud	O
+,	O
+and	O
+the	O
+patient	O
+was	O
+asked	O
+to	O
+immediately	O
+repeat	O
+the	O
+word	O
+to	O
+the	O
+investigator	O
+.	O
+
+The	O
+BIS	O
+score	O
+at	O
+the	O
+time	O
+the	O
+word	O
+was	O
+read	O
+and	O
+the	O
+patient	O
+'	O
+s	O
+ability	O
+to	O
+repeat	O
+the	O
+word	O
+were	O
+recorded	O
+.	O
+
+After	O
+the	O
+procedure	O
+,	O
+the	O
+patient	O
+was	O
+asked	O
+to	O
+state	O
+all	O
+of	O
+the	O
+words	O
+from	O
+the	O
+list	O
+that	O
+he	O
+or	O
+she	O
+could	O
+recall	O
+,	O
+and	O
+to	O
+identify	O
+the	O
+last	O
+word	O
+recalled	O
+from	O
+prior	O
+to	O
+the	O
+start	O
+of	O
+the	O
+procedure	O
+and	O
+the	O
+first	O
+word	O
+recalled	O
+from	O
+after	O
+the	O
+procedure	O
+was	O
+completed	O
+.	O
+
+RESULTS	O
+:	O
+Seventy	O
+-	O
+five	O
+consenting	O
+patients	O
+were	O
+enrolled	O
+;	O
+one	O
+patient	O
+was	O
+excluded	O
+from	O
+data	O
+analysis	O
+for	O
+a	O
+protocol	O
+violation	O
+.	O
+
+No	O
+serious	O
+adverse	O
+events	O
+were	O
+noted	O
+during	O
+the	O
+procedural	O
+sedations	O
+.	O
+
+The	O
+mean	O
+(	O
++	O
+/	O
+-	O
+standard	O
+deviation	O
+)	O
+time	O
+of	O
+data	O
+collection	O
+was	O
+16	O
+.	O
+4	O
+minutes	O
+(	O
++	O
+/	O
+-	O
+7	O
+.	O
+1	O
+;	O
+range	O
+5	O
+to	O
+34	O
+minutes	O
+)	O
+.	O
+
+The	O
+mean	O
+initial	O
+(	O
+preprocedure	O
+)	O
+BIS	O
+score	O
+was	O
+97	O
+.	O
+1	O
+(	O
++	O
+/	O
+-	O
+2	O
+.	O
+3	O
+;	O
+range	O
+92	O
+to	O
+99	O
+)	O
+.	O
+
+The	O
+mean	O
+lowest	O
+BIS	O
+score	O
+occurring	O
+during	O
+these	O
+procedural	O
+sedations	O
+was	O
+66	O
+.	O
+9	O
+(	O
++	O
+/	O
+-	O
+14	O
+.	O
+4	O
+;	O
+range	O
+33	O
+to	O
+91	O
+)	O
+.	O
+
+The	O
+mean	O
+lowest	O
+BIS	O
+score	O
+corresponding	O
+to	O
+the	O
+ability	O
+of	O
+the	O
+patient	O
+to	O
+immediately	O
+repeat	O
+words	O
+read	O
+from	O
+the	O
+list	O
+was	O
+77	O
+.	O
+1	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+74	O
+.	O
+3	O
+to	O
+80	O
+.	O
+0	O
+)	O
+.	O
+
+The	O
+mean	O
+highest	O
+BIS	O
+score	O
+corresponding	O
+to	O
+the	O
+inability	B
+to	I
+repeat	I
+words	I
+was	O
+81	O
+.	O
+5	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+78	O
+.	O
+1	O
+to	O
+84	O
+.	O
+8	O
+)	O
+.	O
+
+The	O
+mean	O
+BIS	O
+score	O
+corresponding	O
+to	O
+the	O
+last	O
+word	O
+recalled	O
+from	O
+prior	O
+to	O
+the	O
+initiation	O
+of	O
+the	O
+sedation	O
+was	O
+96	O
+.	O
+7	O
+(	O
++	O
+/	O
+-	O
+2	O
+.	O
+4	O
+;	O
+range	O
+84	O
+to	O
+98	O
+)	O
+.	O
+
+The	O
+mean	O
+BIS	O
+score	O
+corresponding	O
+to	O
+the	O
+first	O
+word	O
+recalled	O
+after	O
+the	O
+procedure	O
+was	O
+completed	O
+was	O
+91	O
+.	O
+2	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+88	O
+.	O
+1	O
+to	O
+94	O
+.	O
+3	O
+)	O
+.	O
+
+All	O
+patients	O
+recalled	O
+at	O
+least	O
+one	O
+word	O
+that	O
+had	O
+been	O
+read	O
+to	O
+them	O
+during	O
+the	O
+protocol	O
+.	O
+
+The	O
+mean	O
+lowest	O
+BIS	O
+score	O
+for	O
+any	O
+recalled	O
+word	O
+was	O
+91	O
+.	O
+5	O
+(	O
++	O
+/	O
+-	O
+11	O
+.	O
+1	O
+;	O
+range	O
+79	O
+to	O
+98	O
+)	O
+,	O
+and	O
+no	O
+words	O
+were	O
+recalled	O
+when	O
+the	O
+corresponding	O
+BIS	O
+score	O
+was	O
+less	O
+than	O
+90	O
+.	O
+
+CONCLUSIONS	O
+:	O
+There	O
+is	O
+a	O
+range	O
+of	O
+BIS	O
+scores	O
+during	O
+which	O
+sedated	O
+patients	O
+are	O
+able	O
+to	O
+repeat	O
+words	O
+read	O
+to	O
+them	O
+but	O
+are	O
+not	O
+able	O
+to	O
+subsequently	O
+recall	O
+these	O
+words	O
+.	O
+
+Furthermore	O
+,	O
+patients	O
+had	O
+no	O
+recall	O
+of	O
+words	O
+repeated	O
+prior	O
+to	O
+procedural	O
+sedation	O
+in	O
+BIS	O
+ranges	O
+associated	O
+with	O
+recall	O
+after	O
+procedural	O
+sedation	O
+,	O
+suggestive	O
+of	O
+retrograde	B
+amnesia	I
+.	O
+
+Amiodarone	O
+pulmonary	B
+toxicity	I
+.	O
+
+Amiodarone	O
+is	O
+an	O
+effective	O
+antiarrhythmic	O
+agent	O
+whose	O
+utility	O
+is	O
+limited	O
+by	O
+many	O
+side	O
+-	O
+effects	O
+,	O
+the	O
+most	O
+problematic	O
+being	O
+pneumonitis	B
+.	O
+
+The	O
+pulmonary	B
+toxicity	I
+of	O
+amiodarone	O
+is	O
+thought	O
+to	O
+result	O
+from	O
+direct	O
+injury	O
+related	O
+to	O
+the	O
+intracellular	O
+accumulation	O
+of	O
+phospholipid	O
+and	O
+T	O
+cell	O
+-	O
+mediated	O
+hypersensitivity	B
+pneumonitis	I
+.	O
+
+The	O
+clinical	O
+and	O
+radiographic	O
+features	O
+of	O
+amiodarone	O
+-	O
+induced	O
+pulmonary	B
+toxicity	I
+are	O
+characteristic	O
+but	O
+nonspecific	O
+.	O
+
+The	O
+diagnosis	O
+depends	O
+on	O
+exclusion	O
+of	O
+other	O
+entities	O
+,	O
+such	O
+as	O
+heart	B
+failure	I
+,	O
+infection	B
+,	O
+and	O
+malignancy	B
+.	O
+
+While	O
+withdrawal	O
+of	O
+amiodarone	O
+leads	O
+to	O
+clinical	O
+improvement	O
+in	O
+majority	O
+of	O
+cases	O
+,	O
+this	O
+is	O
+not	O
+always	O
+possible	O
+or	O
+advisable	O
+.	O
+
+Dose	O
+reduction	O
+or	O
+concomitant	O
+steroid	O
+therapy	O
+may	O
+have	O
+a	O
+role	O
+in	O
+selected	O
+patients	O
+.	O
+
+Two	O
+prodrugs	O
+of	O
+potent	O
+and	O
+selective	O
+GluR5	O
+kainate	O
+receptor	O
+antagonists	O
+actives	O
+in	O
+three	O
+animal	O
+models	O
+of	O
+pain	B
+.	O
+
+Amino	O
+acids	O
+5	O
+and	O
+7	O
+,	O
+two	O
+potent	O
+and	O
+selective	O
+competitive	O
+GluR5	O
+KA	O
+receptor	O
+antagonists	O
+,	O
+exhibited	O
+high	O
+GluR5	O
+receptor	O
+affinity	O
+over	O
+other	O
+glutamate	O
+receptors	O
+.	O
+
+Their	O
+ester	O
+prodrugs	O
+6	O
+and	O
+8	O
+were	O
+orally	O
+active	O
+in	O
+three	O
+models	O
+of	O
+pain	B
+:	O
+reversal	O
+of	O
+formalin	O
+-	O
+induced	O
+paw	O
+licking	O
+,	O
+carrageenan	O
+-	O
+induced	O
+thermal	B
+hyperalgesia	I
+,	O
+and	O
+capsaicin	O
+-	O
+induced	O
+mechanical	B
+hyperalgesia	I
+.	O
+
+Possible	O
+azithromycin	O
+-	O
+associated	O
+hiccups	B
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+persistent	O
+hiccups	B
+associated	O
+by	O
+azithromycin	O
+therapy	O
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+76	O
+-	O
+year	O
+-	O
+old	O
+man	O
+presented	O
+with	O
+persistent	O
+hiccups	B
+after	O
+beginning	O
+azithromycin	O
+for	O
+the	O
+treatment	O
+of	O
+pharyngitis	B
+.	O
+
+Hiccups	B
+were	O
+persistent	O
+and	O
+exhausting	O
+.	O
+
+Discontinuation	O
+of	O
+azithromycin	O
+and	O
+therapy	O
+with	O
+baclofen	O
+finally	O
+resolved	O
+hiccups	B
+.	O
+
+No	O
+organic	O
+cause	O
+of	O
+hiccups	B
+was	O
+identified	O
+despite	O
+extensive	O
+investigation	O
+.	O
+
+DISCUSSION	O
+:	O
+Pharmacotherapeutic	O
+agents	O
+have	O
+been	O
+uncommonly	O
+associated	O
+with	O
+hiccups	B
+.	O
+
+Corticosteroids	O
+(	O
+dexamethasone	O
+and	O
+methylprednisolone	O
+)	O
+,	O
+benzodiazepines	O
+(	O
+midazolam	O
+)	O
+and	O
+general	O
+anaesthesia	O
+have	O
+been	O
+the	O
+specific	O
+agents	O
+mentioned	O
+most	O
+frequently	O
+in	O
+the	O
+literature	O
+as	O
+being	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+hiccups	B
+.	O
+
+Few	O
+cases	O
+of	O
+drug	O
+-	O
+induced	O
+hiccups	B
+have	O
+been	O
+reported	O
+related	O
+to	O
+macrolide	O
+antimicrobials	O
+.	O
+
+Using	O
+the	O
+Naranjo	O
+adverse	O
+effect	O
+reaction	O
+probability	O
+scale	O
+this	O
+event	O
+could	O
+be	O
+classified	O
+as	O
+possible	O
+(	O
+score	O
+5	O
+points	O
+)	O
+,	O
+mostly	O
+because	O
+of	O
+the	O
+close	O
+temporal	O
+sequence	O
+,	O
+previous	O
+reports	O
+on	O
+this	O
+reaction	O
+with	O
+other	O
+macrolides	O
+and	O
+the	O
+absence	O
+of	O
+any	O
+alternative	O
+explanation	O
+for	O
+hiccups	B
+.	O
+
+Our	O
+hypothesis	O
+is	O
+that	O
+a	O
+vagal	O
+mechanism	O
+mediated	O
+by	O
+azithromycin	O
+could	O
+be	O
+the	O
+pathogenesis	O
+of	O
+hiccups	B
+in	O
+our	O
+patient	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Diagnosis	O
+of	O
+drug	O
+-	O
+induced	O
+hiccups	B
+is	O
+difficult	O
+and	O
+often	O
+achieved	O
+only	O
+by	O
+a	O
+process	O
+of	O
+elimination	O
+.	O
+
+However	O
+,	O
+macrolide	O
+antimicrobials	O
+have	O
+been	O
+reported	O
+to	O
+be	O
+associated	O
+with	O
+hiccups	B
+and	O
+vagal	O
+mechanism	O
+could	O
+explain	O
+the	O
+development	O
+of	O
+this	O
+side	O
+-	O
+effect	O
+.	O
+
+Calcium	O
+carbonate	O
+toxicity	B
+:	O
+the	O
+updated	O
+milk	B
+-	I
+alkali	I
+syndrome	I
+;	O
+report	O
+of	O
+3	O
+cases	O
+and	O
+review	O
+of	O
+the	O
+literature	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+describe	O
+3	O
+patients	O
+with	O
+calcium	O
+carbonate	O
+-	O
+induced	O
+hypercalcemia	B
+and	O
+gain	O
+insights	O
+into	O
+the	O
+cause	O
+and	O
+management	O
+of	O
+the	O
+milk	B
+-	I
+alkali	I
+syndrome	I
+.	O
+
+METHODS	O
+:	O
+We	O
+report	O
+the	O
+clinical	O
+and	O
+laboratory	O
+data	O
+in	O
+3	O
+patients	O
+who	O
+presented	O
+with	O
+severe	O
+hypercalcemia	B
+(	O
+corrected	O
+serum	O
+calcium	O
+>	O
+or	O
+=	O
+14	O
+mg	O
+/	O
+dL	O
+)	O
+and	O
+review	O
+the	O
+pertinent	O
+literature	O
+on	O
+milk	B
+-	I
+alkali	I
+syndrome	I
+.	O
+
+RESULTS	O
+:	O
+The	O
+3	O
+patients	O
+had	O
+acute	B
+renal	I
+insufficiency	I
+,	O
+relative	O
+metabolic	B
+alkalosis	I
+,	O
+and	O
+low	O
+parathyroid	O
+hormone	O
+(	O
+PTH	O
+)	O
+,	O
+PTH	O
+-	O
+related	O
+peptide	O
+,	O
+and	O
+1	O
+,	O
+25	O
+-	O
+dihydroxyvitamin	O
+D	O
+concentrations	O
+.	O
+
+No	O
+malignant	O
+lesion	O
+was	O
+found	O
+.	O
+
+Treatment	O
+included	O
+aggressive	O
+hydration	O
+and	O
+varied	O
+amounts	O
+of	O
+furosemide	O
+.	O
+
+The	O
+2	O
+patients	O
+with	O
+the	O
+higher	O
+serum	O
+calcium	O
+concentrations	O
+received	O
+pamidronate	O
+intravenously	O
+(	O
+60	O
+and	O
+30	O
+mg	O
+,	O
+respectively	O
+)	O
+,	O
+which	O
+caused	O
+severe	O
+hypocalcemia	B
+.	O
+
+Of	O
+the	O
+3	O
+patients	O
+,	O
+2	O
+were	O
+ingesting	O
+acceptable	O
+doses	O
+of	O
+elemental	O
+calcium	O
+(	O
+1	O
+g	O
+and	O
+2	O
+g	O
+daily	O
+,	O
+respectively	O
+)	O
+in	O
+the	O
+form	O
+of	O
+calcium	O
+carbonate	O
+.	O
+
+In	O
+addition	O
+to	O
+our	O
+highlighted	O
+cases	O
+,	O
+we	O
+review	O
+the	O
+history	O
+,	O
+classification	O
+,	O
+pathophysiologic	O
+features	O
+,	O
+and	O
+treatment	O
+of	O
+milk	B
+-	I
+alkali	I
+syndrome	I
+and	O
+summarize	O
+the	O
+cases	O
+reported	O
+from	O
+early	O
+1995	O
+to	O
+November	O
+2003	O
+.	O
+
+CONCLUSION	O
+:	O
+Milk	B
+-	I
+alkali	I
+syndrome	I
+may	O
+be	O
+a	O
+common	O
+cause	O
+of	O
+unexplained	O
+hypercalcemia	B
+and	O
+can	O
+be	O
+precipitated	O
+by	O
+small	O
+amounts	O
+of	O
+orally	O
+ingested	O
+calcium	O
+carbonate	O
+in	O
+susceptible	O
+persons	O
+.	O
+
+Treatment	O
+with	O
+hydration	O
+,	O
+furosemide	O
+,	O
+and	O
+discontinuation	O
+of	O
+the	O
+calcium	O
+and	O
+vitamin	O
+D	O
+source	O
+is	O
+adequate	O
+.	O
+
+Pamidronate	O
+treatment	O
+is	O
+associated	O
+with	O
+considerable	O
+risk	O
+for	O
+hypocalcemia	B
+,	O
+even	O
+in	O
+cases	O
+of	O
+initially	O
+severe	O
+hypercalcemia	B
+.	O
+
+Warfarin	O
+-	O
+induced	O
+leukocytoclastic	B
+vasculitis	I
+.	O
+
+Skin	O
+reactions	O
+associated	O
+with	O
+oral	O
+coumarin	O
+-	O
+derived	O
+anticoagulants	O
+are	O
+an	O
+uncommon	O
+occurrence	O
+.	O
+
+Leukocytoclastic	B
+vasculitis	I
+(	O
+LV	B
+)	O
+is	O
+primarily	O
+a	O
+cutaneous	B
+small	I
+vessel	I
+vasculitis	I
+,	O
+though	O
+systemic	O
+involvement	O
+may	O
+be	O
+encountered	O
+.	O
+
+We	O
+report	O
+4	O
+patients	O
+with	O
+late	O
+-	O
+onset	O
+LV	B
+probably	O
+due	O
+to	O
+warfarin	O
+.	O
+
+All	O
+4	O
+patients	O
+presented	O
+with	O
+skin	B
+eruptions	I
+that	O
+developed	O
+after	O
+receiving	O
+warfarin	O
+for	O
+several	O
+years	O
+.	O
+
+The	O
+results	O
+of	O
+skin	B
+lesion	I
+biopsies	O
+were	O
+available	O
+in	O
+3	O
+patients	O
+,	O
+confirming	O
+LV	B
+Cutaneous	I
+lesions	I
+resolved	O
+in	O
+all	O
+patients	O
+after	O
+warfarin	O
+was	O
+discontinued	O
+.	O
+
+In	O
+2	O
+of	O
+the	O
+4	O
+patients	O
+,	O
+rechallenge	O
+with	O
+warfarin	O
+led	O
+to	O
+recurrence	O
+of	O
+the	O
+lesions	O
+.	O
+
+LV	B
+may	O
+be	O
+a	O
+late	O
+-	O
+onset	O
+adverse	O
+reaction	O
+associated	O
+with	O
+warfarin	O
+therapy	O
+.	O
+
+Cocaine	O
+-	O
+induced	O
+brainstem	O
+seizures	B
+and	O
+behavior	O
+.	O
+
+A	O
+variety	O
+of	O
+abnormal	O
+sensory	O
+/	O
+motor	O
+behaviors	O
+associated	O
+with	O
+electrical	O
+discharges	O
+recorded	O
+from	O
+the	O
+bilateral	O
+brainstem	O
+were	O
+induced	O
+in	O
+adult	O
+WKY	O
+rats	O
+by	O
+mechanical	O
+(	O
+electrode	O
+implants	O
+)	O
+and	O
+DC	O
+electrical	O
+current	O
+stimulations	O
+and	O
+by	O
+acute	O
+and	O
+chronic	O
+administration	O
+of	O
+cocaine	O
+.	O
+
+The	O
+electrode	O
+implant	O
+implicated	O
+one	O
+side	O
+or	O
+the	O
+other	O
+of	O
+the	O
+reticular	O
+system	O
+of	O
+the	O
+brainstem	O
+but	O
+subjects	O
+were	O
+not	O
+incapacitated	O
+by	O
+the	O
+stimulations	O
+.	O
+
+Cocaine	O
+(	O
+40	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+injected	O
+subcutaneously	O
+for	O
+an	O
+acute	O
+experiment	O
+and	O
+subsequent	O
+20	O
+mg	O
+/	O
+kg	O
+doses	O
+twice	O
+daily	O
+for	O
+3	O
+days	O
+in	O
+a	O
+chronic	O
+study	O
+.	O
+
+Cocaine	O
+generated	O
+more	O
+abnormal	O
+behaviors	O
+in	O
+the	O
+brainstem	O
+perturbation	O
+group	O
+,	O
+especially	O
+the	O
+electrically	O
+perturbated	O
+subjects	O
+.	O
+
+The	O
+abnormal	O
+behaviors	O
+were	O
+yawning	O
+,	O
+retrocollis	O
+,	O
+hyperactivity	B
+,	O
+hypersensitivity	B
+,	O
+"	O
+beating	O
+drum	O
+"	O
+behavior	O
+,	O
+squealing	O
+,	O
+head	O
+bobbing	O
+,	O
+circling	O
+,	O
+sniffing	O
+,	O
+abnormal	O
+posturing	O
+,	O
+and	O
+facial	O
+twitching	O
+.	O
+
+Shifts	O
+in	O
+the	O
+power	O
+frequency	O
+spectra	O
+of	O
+the	O
+discharge	O
+patterns	O
+were	O
+noted	O
+between	O
+quiet	O
+and	O
+pacing	O
+behavioral	O
+states	O
+.	O
+
+Hypersensitivity	B
+to	O
+various	O
+auditory	O
+,	O
+tactile	O
+,	O
+and	O
+visual	O
+stimulation	O
+was	O
+present	O
+and	O
+shifts	O
+in	O
+the	O
+brainstem	O
+ambient	O
+power	O
+spectral	O
+frequency	O
+occurred	O
+in	O
+response	O
+to	O
+tactile	O
+stimulation	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+the	O
+brainstem	O
+generates	O
+and	O
+propagates	O
+pathological	O
+discharges	O
+that	O
+can	O
+be	O
+elicited	O
+by	O
+mechanical	O
+and	O
+DC	O
+electrical	O
+perturbation	O
+.	O
+
+Cocaine	O
+was	O
+found	O
+to	O
+activate	O
+the	O
+discharge	O
+system	O
+and	O
+thus	O
+induce	O
+abnormal	O
+behaviors	O
+that	O
+are	O
+generated	O
+at	O
+the	O
+discharge	O
+site	O
+and	O
+at	O
+distant	O
+sites	O
+to	O
+which	O
+the	O
+discharge	O
+propagates	O
+.	O
+
+Cognitive	O
+functions	O
+may	O
+also	O
+be	O
+involved	O
+since	O
+dopaminergic	O
+and	O
+serotonergic	O
+cellular	O
+elements	O
+at	O
+the	O
+brainstem	O
+level	O
+are	O
+also	O
+implicated	O
+.	O
+
+rTMS	O
+of	O
+supplementary	O
+motor	O
+area	O
+modulates	O
+therapy	O
+-	O
+induced	O
+dyskinesias	B
+in	O
+Parkinson	B
+disease	I
+.	O
+
+The	O
+neural	O
+mechanisms	O
+and	O
+circuitry	O
+involved	O
+in	O
+levodopa	O
+-	O
+induced	O
+dyskinesia	B
+are	O
+unclear	O
+.	O
+
+Using	O
+repetitive	O
+transcranial	O
+magnetic	O
+stimulation	O
+(	O
+rTMS	O
+)	O
+over	O
+the	O
+supplementary	O
+motor	O
+area	O
+(	O
+SMA	O
+)	O
+in	O
+a	O
+group	O
+of	O
+patients	O
+with	O
+advanced	O
+Parkinson	B
+disease	I
+,	O
+the	O
+authors	O
+investigated	O
+whether	O
+modulation	O
+of	O
+SMA	O
+excitability	O
+may	O
+result	O
+in	O
+a	O
+modification	O
+of	O
+a	O
+dyskinetic	B
+state	O
+induced	O
+by	O
+continuous	O
+apomorphine	O
+infusion	O
+.	O
+
+rTMS	O
+at	O
+1	O
+Hz	O
+was	O
+observed	O
+to	O
+markedly	O
+reduce	O
+drug	B
+-	I
+induced	I
+dyskinesias	I
+,	O
+whereas	O
+5	O
+-	O
+Hz	O
+rTMS	O
+induced	O
+a	O
+slight	O
+but	O
+not	O
+significant	O
+increase	O
+.	O
+
+Intracavitary	O
+chemotherapy	O
+(	O
+paclitaxel	O
+/	O
+carboplatin	O
+liquid	O
+crystalline	O
+cubic	O
+phases	O
+)	O
+for	O
+recurrent	O
+glioblastoma	B
+-	O
+-	O
+clinical	O
+observations	O
+.	O
+
+Human	O
+malignant	O
+brain	B
+tumors	I
+have	O
+a	O
+poor	O
+prognosis	O
+in	O
+spite	O
+of	O
+surgery	O
+and	O
+radiation	O
+therapy	O
+.	O
+
+Cubic	O
+phases	O
+consist	O
+of	O
+curved	O
+biocontinuous	O
+lipid	O
+bilayers	O
+,	O
+separating	O
+two	O
+congruent	O
+networks	O
+of	O
+water	O
+channels	O
+.	O
+
+Used	O
+as	O
+a	O
+host	O
+for	O
+cytotoxic	O
+drugs	O
+,	O
+the	O
+gel	O
+-	O
+like	O
+matrix	O
+can	O
+easily	O
+be	O
+applied	O
+to	O
+the	O
+walls	O
+of	O
+a	O
+surgical	O
+resection	O
+cavity	O
+.	O
+
+For	O
+human	O
+glioblastoma	B
+recurrences	O
+,	O
+the	O
+feasibility	O
+,	O
+safety	O
+,	O
+and	O
+short	O
+-	O
+term	O
+effects	O
+of	O
+a	O
+surgical	O
+intracavitary	O
+application	O
+of	O
+paclitaxel	O
+and	O
+carboplatin	O
+encapsulated	O
+by	O
+liquid	O
+crystalline	O
+cubic	O
+phases	O
+are	O
+examined	O
+in	O
+a	O
+pilot	O
+study	O
+.	O
+
+A	O
+total	O
+of	O
+12	O
+patients	O
+with	O
+a	O
+recurrence	O
+of	O
+a	O
+glioblastoma	B
+multiforme	O
+underwent	O
+re	O
+-	O
+resection	O
+and	O
+received	O
+an	O
+intracavitary	O
+application	O
+of	O
+paclitaxel	O
+and	O
+carboplatin	O
+cubic	O
+phases	O
+in	O
+different	O
+dosages	O
+.	O
+
+Six	O
+of	O
+the	O
+patients	O
+received	O
+more	O
+than	O
+15	O
+mg	O
+paclitaxel	O
+and	O
+suffered	O
+from	O
+moderate	O
+to	O
+severe	O
+brain	B
+edema	I
+,	O
+while	O
+the	O
+remaining	O
+patients	O
+received	O
+only	O
+a	O
+total	O
+of	O
+15	O
+mg	O
+paclitaxel	O
+.	O
+
+In	O
+the	O
+latter	O
+group	O
+,	O
+brain	B
+edema	I
+was	O
+markedly	O
+reduced	O
+and	O
+dealt	O
+medically	O
+.	O
+
+Intracavitary	O
+chemotherapy	O
+in	O
+recurrent	O
+glioblastoma	B
+using	O
+cubic	O
+phases	O
+is	O
+feasible	O
+and	O
+safe	O
+,	O
+yet	O
+the	O
+clinical	O
+benefit	O
+remains	O
+to	O
+be	O
+examined	O
+in	O
+a	O
+clinical	O
+phase	O
+II	O
+study	O
+.	O
+
+Lamotrigine	O
+associated	O
+with	O
+exacerbation	O
+or	O
+de	O
+novo	O
+myoclonus	B
+in	O
+idiopathic	B
+generalized	I
+epilepsies	I
+.	O
+
+Five	O
+patients	O
+with	O
+idiopathic	B
+generalized	I
+epilepsies	I
+(	O
+IGE	B
+)	O
+treated	O
+with	O
+lamotrigine	O
+(	O
+LTG	O
+)	O
+experienced	O
+exacerbation	O
+or	O
+de	O
+novo	O
+appearance	O
+of	O
+myoclonic	B
+jerks	I
+(	O
+MJ	B
+)	O
+.	O
+
+In	O
+three	O
+patients	O
+,	O
+LTG	O
+exacerbated	O
+MJ	B
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+with	O
+early	O
+aggravation	O
+during	O
+titration	O
+.	O
+
+MJ	B
+disappeared	O
+when	O
+LTG	O
+dose	O
+was	O
+decreased	O
+by	O
+25	O
+to	O
+50	O
+%	O
+.	O
+
+In	O
+two	O
+patients	O
+,	O
+LTG	O
+exacerbated	O
+MJ	B
+in	O
+a	O
+delayed	O
+but	O
+more	O
+severe	O
+manner	O
+,	O
+with	O
+myoclonic	B
+status	I
+that	O
+only	O
+ceased	O
+after	O
+LTG	O
+withdrawal	O
+.	O
+
+Absence	O
+of	O
+acute	O
+cerebral	O
+vasoconstriction	O
+after	O
+cocaine	O
+-	O
+associated	O
+subarachnoid	B
+hemorrhage	I
+.	O
+
+INTRODUCTION	O
+:	O
+Cocaine	O
+use	O
+has	O
+been	O
+associated	O
+with	O
+neurovascular	B
+complications	I
+,	O
+including	O
+arterial	O
+vasoconstriction	O
+and	O
+vasculitis	B
+.	O
+
+However	O
+,	O
+there	O
+are	O
+few	O
+studies	O
+of	O
+angiographic	O
+effects	O
+of	O
+cocaine	O
+on	O
+human	O
+cerebral	O
+arteries	O
+.	O
+
+Information	O
+on	O
+these	O
+effects	O
+could	O
+be	O
+obtained	O
+from	O
+angiograms	O
+of	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+subarachnoid	B
+hemorrhage	I
+(	O
+SAH	B
+)	O
+who	O
+underwent	O
+angiography	O
+shortly	O
+after	O
+cocaine	O
+use	O
+.	O
+
+METHODS	O
+:	O
+We	O
+screened	O
+patients	O
+with	O
+SAH	B
+retrospectively	O
+and	O
+identified	O
+those	O
+with	O
+positive	O
+urine	O
+toxicology	O
+for	O
+cocaine	O
+or	O
+its	O
+metabolites	O
+.	O
+
+Quantitative	O
+arterial	O
+diameter	O
+measurements	O
+from	O
+angiograms	O
+of	O
+these	O
+patients	O
+were	O
+compared	O
+to	O
+measurements	O
+from	O
+control	O
+patients	O
+with	O
+SAH	B
+who	O
+were	O
+matched	O
+for	O
+factors	O
+known	O
+to	O
+influence	O
+arterial	O
+diameter	O
+.	O
+
+Qualitative	O
+comparisons	O
+of	O
+small	O
+artery	O
+changes	O
+also	O
+were	O
+made	O
+.	O
+
+RESULTS	O
+:	O
+Thirteen	O
+patients	O
+with	O
+positive	O
+cocaine	O
+toxicology	O
+were	O
+compared	O
+to	O
+26	O
+controls	O
+.	O
+
+There	O
+were	O
+no	O
+significant	O
+differences	O
+between	O
+groups	O
+in	O
+the	O
+mean	O
+diameters	O
+of	O
+the	O
+intradural	O
+internal	O
+carotid	O
+,	O
+sphenoidal	O
+segment	O
+of	O
+the	O
+middle	O
+cerebral	O
+,	O
+precommunicating	O
+segment	O
+of	O
+the	O
+anterior	O
+cerebral	O
+,	O
+or	O
+basilar	O
+arteries	O
+(	O
+p	O
+greater	O
+than	O
+0	O
+.	O
+05	O
+for	O
+all	O
+comparisons	O
+,	O
+unpaired	O
+t	O
+-	O
+tests	O
+)	O
+.	O
+
+There	O
+also	O
+were	O
+no	O
+significant	O
+differences	O
+between	O
+groups	O
+when	O
+expressing	O
+diameters	O
+as	O
+the	O
+sum	O
+of	O
+the	O
+precommunicating	O
+segment	O
+of	O
+the	O
+anterior	O
+cerebral	O
++	O
+sphenoidal	O
+segment	O
+of	O
+the	O
+middle	O
+cerebral	O
++	O
+supraclinoid	O
+internal	O
+carotid	O
+artery	O
++	O
+basilar	O
+artery	O
+divided	O
+by	O
+the	O
+diameter	O
+of	O
+the	O
+petrous	O
+internal	O
+carotid	O
+artery	O
+(	O
+p	O
+greater	O
+than	O
+0	O
+.	O
+05	O
+,	O
+unpaired	O
+t	O
+-	O
+tests	O
+)	O
+.	O
+
+Qualitative	O
+assessments	O
+showed	O
+two	O
+arterial	O
+irregularities	O
+in	O
+the	O
+distal	O
+vasculature	O
+in	O
+each	O
+group	O
+.	O
+
+CONCLUSION	O
+:	O
+No	O
+quantitative	O
+evidence	O
+for	O
+narrowing	O
+of	O
+large	O
+cerebral	O
+arteries	O
+or	O
+qualitative	O
+angiographic	O
+evidence	O
+for	O
+distal	O
+narrowing	O
+or	O
+vasculitis	B
+could	O
+be	O
+found	O
+in	O
+patients	O
+who	O
+underwent	O
+angiography	O
+after	O
+aneurysmal	B
+SAH	B
+associated	O
+with	O
+cocaine	O
+use	O
+.	O
+
+Methamphetamine	O
+causes	O
+alterations	O
+in	O
+the	O
+MAP	O
+kinase	O
+-	O
+related	O
+pathways	O
+in	O
+the	O
+brains	O
+of	O
+mice	O
+that	O
+display	O
+increased	O
+aggressiveness	B
+.	O
+
+Aggressive	B
+behaviors	I
+have	O
+been	O
+reported	O
+in	O
+patients	O
+who	O
+suffer	O
+from	O
+some	O
+psychiatric	B
+disorders	I
+,	O
+and	O
+are	O
+common	O
+in	O
+methamphetamine	O
+(	O
+METH	O
+)	O
+abusers	O
+.	O
+
+Herein	O
+,	O
+we	O
+report	O
+that	O
+multiple	O
+(	O
+but	O
+not	O
+single	O
+)	O
+injections	O
+of	O
+METH	O
+significantly	O
+increased	O
+aggressiveness	B
+in	O
+male	O
+CD	O
+-	O
+1	O
+mice	O
+.	O
+
+This	O
+increase	O
+in	O
+aggressiveness	B
+was	O
+not	O
+secondary	O
+to	O
+METH	O
+-	O
+induced	O
+hyperactivity	B
+.	O
+
+Analysis	O
+of	O
+protein	O
+expression	O
+using	O
+antibody	O
+microarrays	O
+and	O
+Western	O
+blotting	O
+revealed	O
+differential	O
+changes	O
+in	O
+MAP	O
+kinase	O
+-	O
+related	O
+pathways	O
+after	O
+multiple	O
+and	O
+single	O
+METH	O
+injections	O
+.	O
+
+There	O
+were	O
+statistically	O
+significant	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+decreases	O
+in	O
+MEK1	O
+,	O
+Erk2p	O
+,	O
+GSK3alpha	O
+,	O
+14	O
+-	O
+3	O
+-	O
+3e	O
+,	O
+and	O
+MEK7	O
+in	O
+the	O
+striata	O
+of	O
+mice	O
+after	O
+multiple	O
+injections	O
+of	O
+METH	O
+.	O
+
+MEK1	O
+was	O
+significantly	O
+decreased	O
+also	O
+after	O
+a	O
+single	O
+injection	O
+of	O
+METH	O
+,	O
+but	O
+to	O
+a	O
+much	O
+lesser	O
+degree	O
+than	O
+after	O
+multiple	O
+injections	O
+of	O
+METH	O
+.	O
+
+In	O
+the	O
+frontal	O
+cortex	O
+,	O
+there	O
+was	O
+a	O
+statistically	O
+significant	O
+decrease	O
+in	O
+GSK3alpha	O
+after	O
+multiple	O
+(	O
+but	O
+not	O
+single	O
+)	O
+injections	O
+of	O
+METH	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+alterations	O
+in	O
+MAP	O
+kinase	O
+-	O
+related	O
+pathways	O
+in	O
+the	O
+prefronto	O
+-	O
+striatal	O
+circuitries	O
+might	O
+be	O
+involved	O
+in	O
+the	O
+manifestation	O
+of	O
+aggressive	B
+behaviors	I
+in	O
+mice	O
+.	O
+
+Amisulpride	O
+related	O
+tic	B
+-	I
+like	I
+symptoms	I
+in	O
+an	O
+adolescent	O
+schizophrenic	B
+.	O
+
+Tic	B
+disorders	I
+can	O
+be	O
+effectively	O
+treated	O
+by	O
+atypical	O
+antipsychotics	O
+such	O
+as	O
+risperidone	O
+,	O
+olanzapine	O
+and	O
+ziprasidone	O
+.	O
+
+However	O
+,	O
+there	O
+are	O
+two	O
+case	O
+reports	O
+that	O
+show	O
+tic	B
+-	I
+like	I
+symptoms	I
+,	O
+including	O
+motor	O
+and	O
+phonic	O
+variants	O
+,	O
+occurring	O
+during	O
+treatment	O
+with	O
+quetiapine	O
+or	O
+clozapine	O
+.	O
+
+We	O
+present	O
+a	O
+15	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+schizophrenic	B
+who	O
+developed	O
+frequent	O
+involuntary	B
+eye	I
+-	I
+blinking	I
+movements	I
+after	O
+5	O
+months	O
+of	O
+amisulpride	O
+treatment	O
+(	O
+1000	O
+mg	O
+per	O
+day	O
+)	O
+.	O
+
+The	O
+tic	B
+-	I
+like	I
+symptoms	I
+resolved	O
+completely	O
+after	O
+we	O
+reduced	O
+the	O
+dose	O
+of	O
+amisulpride	O
+down	O
+to	O
+800	O
+mg	O
+per	O
+day	O
+.	O
+
+However	O
+,	O
+her	O
+psychosis	B
+recurred	O
+after	O
+the	O
+dose	O
+reduction	O
+.	O
+
+We	O
+then	O
+placed	O
+her	O
+on	O
+an	O
+additional	O
+100	O
+mg	O
+per	O
+day	O
+of	O
+quetiapine	O
+.	O
+
+She	O
+has	O
+been	O
+in	O
+complete	O
+remission	O
+under	O
+the	O
+combined	O
+medications	O
+for	O
+more	O
+than	O
+one	O
+year	O
+and	O
+maintains	O
+a	O
+fair	O
+role	O
+function	O
+.	O
+
+No	O
+more	O
+tic	B
+-	I
+like	I
+symptoms	I
+or	O
+other	O
+side	O
+effects	O
+have	O
+been	O
+reported	O
+.	O
+
+Together	O
+with	O
+previously	O
+reported	O
+cases	O
+,	O
+our	O
+patient	O
+suggests	O
+that	O
+tic	B
+-	I
+like	I
+symptoms	I
+might	O
+occur	O
+in	O
+certain	O
+vulnerable	O
+individuals	O
+during	O
+treatment	O
+with	O
+atypical	O
+antipsychotics	O
+such	O
+as	O
+quetiapine	O
+,	O
+clozapine	O
+,	O
+or	O
+amisulpride	O
+.	O
+
+Chloroquine	O
+related	O
+complete	O
+heart	B
+block	I
+with	O
+blindness	B
+:	O
+case	O
+report	O
+.	O
+
+A	O
+27	O
+-	O
+year	O
+old	O
+African	O
+woman	O
+with	O
+history	O
+of	O
+regular	O
+chloroquine	O
+ingestion	O
+presented	O
+with	O
+progressive	O
+deterioration	B
+of	I
+vision	I
+,	O
+easy	O
+fatiguability	B
+,	O
+dyspnoea	B
+,	O
+dizziness	B
+progressing	O
+to	O
+syncopal	B
+attacks	I
+.	O
+
+Ophthalmological	O
+assessment	O
+revealed	O
+features	O
+of	O
+chloroquine	O
+retinopathy	B
+,	O
+cardiac	O
+assessment	O
+revealed	O
+features	O
+of	O
+heart	B
+failure	I
+and	O
+a	O
+complete	O
+heart	B
+block	I
+with	O
+right	B
+bundle	I
+branch	I
+block	I
+pattern	O
+.	O
+
+The	O
+heart	B
+block	I
+was	O
+treated	O
+by	O
+pacemaker	O
+insertion	O
+and	O
+the	O
+heart	B
+failure	I
+resolved	O
+spontaneously	O
+following	O
+chloroquine	O
+discontinuation	O
+.	O
+
+She	O
+however	O
+remains	O
+blind	B
+.	O
+
+Effects	O
+of	O
+suprofen	O
+on	O
+the	O
+isolated	O
+perfused	O
+rat	O
+kidney	O
+.	O
+
+Although	O
+suprofen	O
+has	O
+been	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+acute	B
+renal	I
+failure	I
+in	O
+greater	O
+than	O
+100	O
+subjects	O
+,	O
+the	O
+mechanism	O
+of	O
+damage	O
+remains	O
+unclear	O
+.	O
+
+The	O
+direct	O
+nephrotoxic	B
+effects	O
+of	O
+a	O
+single	O
+dose	O
+of	O
+15	O
+mg	O
+of	O
+suprofen	O
+were	O
+compared	O
+in	O
+the	O
+recirculating	O
+isolated	O
+rat	O
+kidney	O
+perfused	O
+with	O
+cell	O
+-	O
+free	O
+buffer	O
+with	O
+or	O
+without	O
+the	O
+addition	O
+of	O
+5	O
+mg	O
+/	O
+dL	O
+of	O
+uric	O
+acid	O
+.	O
+
+There	O
+were	O
+no	O
+significant	O
+differences	O
+in	O
+renal	O
+sodium	O
+excretion	O
+,	O
+oxygen	O
+consumption	O
+,	O
+or	O
+urinary	O
+flow	O
+rates	O
+in	O
+kidneys	O
+perfused	O
+with	O
+suprofen	O
+compared	O
+with	O
+the	O
+drug	O
+-	O
+free	O
+control	O
+groups	O
+.	O
+
+In	O
+contrast	O
+,	O
+a	O
+significant	O
+decline	O
+in	O
+glomerular	O
+filtration	O
+rate	O
+was	O
+found	O
+after	O
+the	O
+introduction	O
+of	O
+suprofen	O
+to	O
+the	O
+kidney	O
+perfused	O
+with	O
+uric	O
+acid	O
+;	O
+no	O
+changes	O
+were	O
+found	O
+with	O
+suprofen	O
+in	O
+the	O
+absence	O
+of	O
+uric	O
+acid	O
+.	O
+
+A	O
+significant	O
+decrease	O
+in	O
+the	O
+baseline	O
+excretion	O
+rate	O
+of	O
+uric	O
+acid	O
+was	O
+found	O
+in	O
+rats	O
+given	O
+suprofen	O
+,	O
+compared	O
+with	O
+drug	O
+-	O
+free	O
+controls	O
+.	O
+
+However	O
+,	O
+the	O
+fractional	O
+excretion	O
+of	O
+uric	O
+acid	O
+was	O
+unchanged	O
+between	O
+the	O
+groups	O
+over	O
+the	O
+experimental	O
+period	O
+.	O
+
+In	O
+summary	O
+,	O
+suprofen	O
+causes	O
+acute	B
+declines	I
+in	I
+renal	I
+function	I
+,	O
+most	O
+likely	O
+by	O
+directly	O
+altering	O
+the	O
+intrarenal	O
+distribution	O
+of	O
+uric	O
+acid	O
+.	O
+
+Microinjection	O
+of	O
+ritanserin	O
+into	O
+the	O
+CA1	O
+region	O
+of	O
+hippocampus	O
+improves	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+in	O
+adult	O
+male	O
+rats	O
+.	O
+
+The	O
+effect	O
+of	O
+ritanserin	O
+(	O
+5	O
+-	O
+HT2	O
+antagonist	O
+)	O
+on	O
+scopolamine	O
+(	O
+muscarinic	O
+cholinergic	O
+antagonist	O
+)	O
+-	O
+induced	O
+amnesia	B
+in	O
+Morris	O
+water	O
+maze	O
+(	O
+MWM	O
+)	O
+was	O
+investigated	O
+.	O
+
+Rats	O
+were	O
+divided	O
+into	O
+eight	O
+groups	O
+and	O
+bilaterally	O
+cannulated	O
+into	O
+CA1	O
+region	O
+of	O
+the	O
+hippocampus	O
+.	O
+
+One	O
+week	O
+later	O
+,	O
+they	O
+received	O
+repeatedly	O
+vehicles	O
+(	O
+saline	O
+,	O
+DMSO	O
+,	O
+saline	O
++	O
+DMSO	O
+)	O
+,	O
+scopolamine	O
+(	O
+2	O
+microg	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+saline	O
+/	O
+side	O
+;	O
+30	O
+min	O
+before	O
+training	O
+)	O
+,	O
+ritanserin	O
+(	O
+2	O
+,	O
+4	O
+and	O
+8	O
+microg	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+DMSO	O
+/	O
+side	O
+;	O
+20	O
+min	O
+before	O
+training	O
+)	O
+and	O
+scopolamine	O
+(	O
+2	O
+microg	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+;	O
+30	O
+min	O
+before	O
+ritanserin	O
+injection	O
+)	O
++	O
+ritanserin	O
+(	O
+4	O
+microg	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+DMSO	O
+)	O
+through	O
+cannulae	O
+each	O
+day	O
+.	O
+
+Animals	O
+were	O
+tested	O
+for	O
+four	O
+consecutive	O
+days	O
+(	O
+4	O
+trial	O
+/	O
+day	O
+)	O
+in	O
+MWM	O
+during	O
+which	O
+the	O
+position	O
+of	O
+hidden	O
+platform	O
+was	O
+unchanged	O
+.	O
+
+In	O
+the	O
+fifth	O
+day	O
+,	O
+the	O
+platform	O
+was	O
+elevated	O
+above	O
+the	O
+water	O
+surface	O
+in	O
+another	O
+position	O
+to	O
+evaluate	O
+the	O
+function	O
+of	O
+motor	O
+,	O
+motivational	O
+and	O
+visual	O
+systems	O
+.	O
+
+The	O
+results	O
+showed	O
+a	O
+significant	O
+increase	O
+in	O
+escape	O
+latencies	O
+and	O
+traveled	O
+distances	O
+to	O
+find	O
+platform	O
+in	O
+scopolamine	O
+-	O
+treated	O
+group	O
+as	O
+compared	O
+to	O
+saline	O
+group	O
+.	O
+
+Ritanserin	O
+-	O
+treated	O
+rats	O
+(	O
+4	O
+microg	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+/	O
+side	O
+)	O
+showed	O
+a	O
+significant	O
+decrease	O
+in	O
+the	O
+mentioned	O
+parameters	O
+as	O
+compared	O
+to	O
+DMSO	O
+-	O
+treated	O
+group	O
+.	O
+
+However	O
+,	O
+scopolamine	O
+and	O
+ritanserin	O
+co	O
+-	O
+administration	O
+resulted	O
+in	O
+a	O
+significant	O
+decrease	O
+in	O
+escape	O
+latencies	O
+and	O
+traveled	O
+distances	O
+as	O
+compared	O
+to	O
+the	O
+scopolamine	O
+-	O
+treated	O
+rats	O
+.	O
+
+Our	O
+findings	O
+show	O
+that	O
+microinjection	O
+of	O
+ritanserin	O
+into	O
+the	O
+CA1	O
+region	O
+of	O
+the	O
+hippocampus	O
+improves	O
+the	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+.	O
+
+PTU	O
+-	O
+associated	O
+vasculitis	B
+in	O
+a	O
+girl	O
+with	O
+Turner	B
+Syndrome	I
+and	O
+Graves	B
+'	I
+disease	I
+.	O
+
+Palpable	O
+purpura	B
+is	O
+a	O
+concerning	O
+clinical	O
+finding	O
+in	O
+pediatric	O
+patients	O
+and	O
+can	O
+have	O
+many	O
+causes	O
+,	O
+including	O
+infectious	O
+and	O
+autoimmune	O
+processes	O
+.	O
+
+A	O
+rare	O
+cause	O
+,	O
+drug	O
+-	O
+induced	O
+vasculitis	B
+,	O
+may	O
+result	O
+from	O
+the	O
+production	O
+of	O
+antineutrophil	O
+cytoplasmic	O
+antibodies	O
+(	O
+ANCAs	O
+)	O
+in	O
+response	O
+to	O
+a	O
+medication	O
+.	O
+
+We	O
+report	O
+a	O
+girl	O
+with	O
+Turner	B
+syndrome	I
+and	O
+Graves	B
+'	I
+disease	I
+who	O
+presented	O
+with	O
+palpable	O
+purpuric	B
+lesions	I
+.	O
+
+The	O
+diagnosis	O
+of	O
+propylthiouracil	O
+(	O
+PTU	O
+)	O
+-	O
+associated	O
+vasculitis	B
+was	O
+made	O
+by	O
+observation	O
+of	O
+consistent	O
+clinical	O
+features	O
+,	O
+the	O
+detection	O
+of	O
+elevated	O
+ANA	O
+and	O
+ANCA	O
+in	O
+the	O
+blood	O
+,	O
+and	O
+the	O
+observed	O
+clinical	O
+resolution	O
+of	O
+symptoms	O
+following	O
+withdrawal	O
+of	O
+PTU	O
+.	O
+
+Subsequent	O
+treatment	O
+of	O
+persistent	O
+hyperthyroidism	B
+with	O
+radioablation	O
+did	O
+not	O
+result	O
+in	O
+an	O
+exacerbation	O
+of	O
+the	O
+vasculitis	B
+,	O
+a	O
+complication	O
+described	O
+in	O
+prior	O
+case	O
+reports	O
+.	O
+
+Daidzein	O
+activates	O
+choline	O
+acetyltransferase	O
+from	O
+MC	O
+-	O
+IXC	O
+cells	O
+and	O
+improves	O
+drug	O
+-	O
+induced	O
+amnesia	B
+.	O
+
+The	O
+choline	O
+acetyltransferase	O
+(	O
+ChAT	O
+)	O
+activator	O
+,	O
+which	O
+enhances	O
+cholinergic	O
+transmission	O
+via	O
+an	O
+augmentation	O
+of	O
+the	O
+enzymatic	O
+production	O
+of	O
+acetylcholine	O
+(	O
+ACh	O
+)	O
+,	O
+is	O
+an	O
+important	O
+factor	O
+in	O
+the	O
+treatment	O
+of	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+(	O
+AD	B
+)	O
+.	O
+
+Methanolic	O
+extracts	O
+from	O
+Pueraria	O
+thunbergiana	O
+exhibited	O
+an	O
+activation	O
+effect	O
+(	O
+46	O
+%	O
+)	O
+on	O
+ChAT	O
+in	O
+vitro	O
+.	O
+
+Via	O
+the	O
+sequential	O
+isolation	O
+of	O
+Pueraria	O
+thunbergiana	O
+,	O
+the	O
+active	O
+component	O
+was	O
+ultimately	O
+identified	O
+as	O
+daidzein	O
+(	O
+4	O
+'	O
+,	O
+7	O
+-	O
+dihydroxy	O
+-	O
+isoflavone	O
+)	O
+.	O
+
+In	O
+order	O
+to	O
+investigate	O
+the	O
+effects	O
+of	O
+daidzein	O
+from	O
+Pueraria	O
+thunbergiana	O
+on	O
+scopolamine	O
+-	O
+induced	O
+impairments	B
+of	I
+learning	I
+and	I
+memory	I
+,	O
+we	O
+conducted	O
+a	O
+series	O
+of	O
+in	O
+vivo	O
+tests	O
+.	O
+
+Administration	O
+of	O
+daidzein	O
+(	O
+4	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+)	O
+to	O
+mice	O
+was	O
+shown	O
+significantly	O
+to	O
+reverse	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+,	O
+according	O
+to	O
+the	O
+results	O
+of	O
+a	O
+Y	O
+-	O
+maze	O
+test	O
+.	O
+
+Injections	O
+of	O
+scopolamine	O
+into	O
+mice	O
+resulted	O
+in	O
+impaired	O
+performance	O
+on	O
+Y	O
+-	O
+maze	O
+tests	O
+(	O
+a	O
+37	O
+%	O
+decreases	O
+in	O
+alternation	O
+behavior	O
+)	O
+.	O
+
+By	O
+way	O
+of	O
+contrast	O
+,	O
+mice	O
+treated	O
+with	O
+daidzein	O
+prior	O
+to	O
+the	O
+scopolamine	O
+injections	O
+were	O
+noticeably	O
+protected	O
+from	O
+this	O
+performance	O
+impairment	O
+(	O
+an	O
+approximately	O
+12	O
+%	O
+-	O
+21	O
+%	O
+decrease	O
+in	O
+alternation	O
+behavior	O
+)	O
+.	O
+
+These	O
+results	O
+indicate	O
+that	O
+daidzein	O
+might	O
+play	O
+a	O
+role	O
+in	O
+acetylcholine	O
+biosynthesis	O
+as	O
+a	O
+ChAT	O
+activator	O
+,	O
+and	O
+that	O
+it	O
+also	O
+ameliorates	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+.	O
+
+Urinary	O
+symptoms	O
+and	O
+quality	O
+of	O
+life	O
+changes	O
+in	O
+Thai	O
+women	O
+with	O
+overactive	B
+bladder	I
+after	O
+tolterodine	O
+treatment	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+study	O
+the	O
+urinary	O
+symptoms	O
+and	O
+quality	O
+of	O
+life	O
+changes	O
+in	O
+Thai	O
+women	O
+with	O
+overactive	B
+bladder	I
+(	O
+OAB	B
+)	O
+after	O
+tolterodine	O
+treatment	O
+.	O
+
+MATERIAL	O
+AND	O
+METHOD	O
+:	O
+Thirty	O
+women	O
+(	O
+aged	O
+30	O
+-	O
+77	O
+years	O
+)	O
+diagnosed	O
+as	O
+having	O
+OAB	B
+at	O
+the	O
+Gynecology	O
+Clinic	O
+,	O
+King	O
+Chulalongkorn	O
+Memorial	O
+Hospital	O
+from	O
+January	O
+to	O
+April	O
+2004	O
+were	O
+included	O
+in	O
+the	O
+present	O
+study	O
+.	O
+
+Tolterodine	O
+2	O
+mg	O
+,	O
+twice	O
+daily	O
+was	O
+given	O
+.	O
+
+After	O
+8	O
+weeks	O
+treatment	O
+,	O
+changes	O
+in	O
+micturition	O
+diary	O
+variables	O
+and	O
+tolerability	O
+were	O
+determined	O
+.	O
+
+Short	O
+form	O
+36	O
+(	O
+SF36	O
+)	O
+questionaires	O
+(	O
+Thai	O
+version	O
+)	O
+were	O
+given	O
+before	O
+and	O
+after	O
+8	O
+weeks	O
+of	O
+treatment	O
+.	O
+
+RESULTS	O
+:	O
+At	O
+8	O
+weeks	O
+,	O
+all	O
+micturition	O
+per	O
+day	O
+decreased	O
+from	O
+16	O
+.	O
+
+7	O
++	O
+/	O
+-	O
+5	O
+.	O
+
+3	O
+to	O
+6	O
+.	O
+
+7	O
++	O
+/	O
+-	O
+2	O
+.	O
+4	O
+times	O
+per	O
+day	O
+.	O
+
+The	O
+number	O
+of	O
+nocturia	B
+episodes	O
+decreased	O
+from	O
+5	O
+.	O
+4	O
++	O
+/	O
+-	O
+4	O
+.	O
+2	O
+to	O
+1	O
+.	O
+1	O
++	O
+/	O
+-	O
+1	O
+.	O
+0	O
+times	O
+per	O
+night	O
+.	O
+
+The	O
+most	O
+common	O
+side	O
+effect	O
+was	O
+dry	B
+month	I
+in	O
+5	O
+cases	O
+(	O
+16	O
+.	O
+7	O
+%	O
+)	O
+with	O
+2	O
+cases	O
+reporting	O
+a	O
+moderate	O
+degree	O
+and	O
+1	O
+case	O
+with	O
+severe	O
+degree	O
+.	O
+
+Only	O
+one	O
+case	O
+(	O
+3	O
+.	O
+3	O
+%	O
+)	O
+withdrew	O
+from	O
+the	O
+present	O
+study	O
+due	O
+to	O
+a	O
+severe	O
+dry	B
+mouth	I
+.	O
+
+The	O
+SF	O
+-	O
+36	O
+scores	O
+changed	O
+significantly	O
+in	O
+the	O
+domains	O
+of	O
+physical	O
+functioning	O
+,	O
+role	O
+function	O
+emotional	O
+,	O
+social	O
+function	O
+and	O
+mental	O
+heath	O
+.	O
+
+CONCLUSION	O
+:	O
+Tolterodine	O
+was	O
+well	O
+tolerated	O
+and	O
+its	O
+effects	O
+improved	O
+the	O
+quality	O
+of	O
+life	O
+in	O
+Thai	O
+women	O
+with	O
+OAB	B
+.	O
+
+Remifentanil	O
+pretreatment	O
+reduces	O
+myoclonus	B
+after	O
+etomidate	O
+.	O
+
+STUDY	O
+OBJECTIVE	O
+:	O
+The	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+compare	O
+the	O
+effect	O
+of	O
+pretreatment	O
+with	O
+remifentanil	O
+1	O
+microg	O
+/	O
+kg	O
+and	O
+the	O
+effect	O
+of	O
+gender	O
+on	O
+the	O
+incidence	O
+of	O
+myoclonus	B
+after	O
+anesthesia	O
+induction	O
+with	O
+etomidate	O
+.	O
+
+DESIGN	O
+:	O
+This	O
+was	O
+a	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+study	O
+.	O
+
+SETTING	O
+:	O
+The	O
+study	O
+was	O
+conducted	O
+at	O
+a	O
+university	O
+hospital	O
+.	O
+
+PATIENTS	O
+:	O
+Sixty	O
+patients	O
+were	O
+pretreated	O
+in	O
+a	O
+randomized	O
+double	O
+-	O
+blinded	O
+fashion	O
+with	O
+remifentanil	O
+1	O
+microg	O
+/	O
+kg	O
+or	O
+placebo	O
+.	O
+
+Two	O
+minutes	O
+after	O
+remifentanil	O
+or	O
+placebo	O
+injection	O
+,	O
+etomidate	O
+0	O
+.	O
+3	O
+mg	O
+/	O
+kg	O
+was	O
+given	O
+.	O
+
+MEASUREMENTS	O
+:	O
+Myoclonus	B
+was	O
+recorded	O
+with	O
+a	O
+scale	O
+of	O
+0	O
+to	O
+3	O
+.	O
+
+The	O
+grade	O
+of	O
+sedation	O
+(	O
+none	O
+,	O
+mild	O
+,	O
+moderate	O
+,	O
+severe	O
+)	O
+,	O
+nausea	B
+,	O
+pruritus	B
+,	O
+and	O
+apnea	B
+were	O
+recorded	O
+after	O
+injection	O
+of	O
+both	O
+drugs	O
+.	O
+
+MAIN	O
+RESULTS	O
+:	O
+The	O
+incidence	O
+of	O
+myoclonus	B
+was	O
+significantly	O
+lower	O
+in	O
+the	O
+remifentanil	O
+group	O
+(	O
+6	O
+.	O
+7	O
+%	O
+)	O
+than	O
+in	O
+the	O
+placebo	O
+group	O
+(	O
+70	O
+%	O
+)	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+None	O
+of	O
+the	O
+patients	O
+experienced	O
+sedation	O
+,	O
+apnea	B
+,	O
+nausea	B
+,	O
+or	O
+pruritus	B
+after	O
+injection	O
+of	O
+both	O
+drugs	O
+.	O
+
+In	O
+the	O
+placebo	O
+group	O
+,	O
+male	O
+patients	O
+were	O
+associated	O
+with	O
+significantly	O
+increased	O
+incidence	O
+of	O
+myoclonus	B
+after	O
+etomidate	O
+administration	O
+.	O
+
+CONCLUSION	O
+:	O
+Pretreatment	O
+with	O
+remifentanil	O
+1	O
+microg	O
+/	O
+kg	O
+reduced	O
+myoclonus	B
+after	O
+etomidate	O
+induction	O
+without	O
+side	O
+effects	O
+such	O
+as	O
+sedation	O
+,	O
+apnea	B
+,	O
+nausea	B
+,	O
+or	O
+pruritus	B
+.	O
+
+Men	O
+experience	O
+increased	O
+incidence	O
+of	O
+myoclonus	B
+than	O
+women	O
+after	O
+etomidate	O
+administration	O
+.	O
+
+Memory	O
+function	O
+and	O
+serotonin	O
+transporter	O
+promoter	O
+gene	O
+polymorphism	O
+in	O
+ecstasy	O
+(	O
+MDMA	O
+)	O
+users	O
+.	O
+
+Although	O
+3	O
+,	O
+4	O
+-	O
+methylenedioxymethamphetamine	O
+(	O
+MDMA	O
+or	O
+ecstasy	O
+)	O
+has	O
+been	O
+shown	O
+to	O
+damage	O
+brain	O
+serotonin	O
+(	O
+5	O
+-	O
+HT	O
+)	O
+neurons	O
+in	O
+animals	O
+and	O
+possibly	O
+humans	O
+,	O
+little	O
+is	O
+known	O
+about	O
+the	O
+long	O
+-	O
+term	O
+consequences	O
+of	O
+MDMA	O
+-	O
+induced	O
+5	O
+-	O
+HT	O
+neurotoxic	B
+lesions	I
+on	O
+functions	O
+in	O
+which	O
+5	O
+-	O
+HT	O
+is	O
+involved	O
+,	O
+such	O
+as	O
+cognitive	O
+function	O
+.	O
+
+Because	O
+5	O
+-	O
+HT	O
+transporters	O
+play	O
+a	O
+key	O
+element	O
+in	O
+the	O
+regulation	O
+of	O
+synaptic	O
+5	O
+-	O
+HT	O
+transmission	O
+it	O
+may	O
+be	O
+important	O
+to	O
+control	O
+for	O
+the	O
+potential	O
+covariance	O
+effect	O
+of	O
+a	O
+polymorphism	O
+in	O
+the	O
+5	O
+-	O
+HT	O
+transporter	O
+promoter	O
+gene	O
+region	O
+(	O
+5	O
+-	O
+HTTLPR	O
+)	O
+when	O
+studying	O
+the	O
+effects	O
+of	O
+MDMA	O
+as	O
+well	O
+as	O
+cognitive	O
+functioning	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+effects	O
+of	O
+moderate	O
+and	O
+heavy	O
+MDMA	O
+use	O
+on	O
+cognitive	O
+function	O
+,	O
+as	O
+well	O
+as	O
+the	O
+effects	O
+of	O
+long	O
+-	O
+term	O
+abstention	O
+from	O
+MDMA	O
+,	O
+in	O
+subjects	O
+genotyped	O
+for	O
+5	O
+-	O
+HTTLPR	O
+.	O
+
+A	O
+second	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+determine	O
+whether	O
+these	O
+effects	O
+differ	O
+for	O
+females	O
+and	O
+males	O
+.	O
+
+Fifteen	O
+moderate	O
+MDMA	O
+users	O
+(	O
+<	O
+55	O
+lifetime	O
+tablets	O
+)	O
+,	O
+22	O
+heavy	O
+MDMA	O
++	O
+users	O
+(	O
+>	O
+55	O
+lifetime	O
+tablets	O
+)	O
+,	O
+16	O
+ex	O
+-	O
+MDMA	O
++	O
+users	O
+(	O
+last	O
+tablet	O
+>	O
+1	O
+year	O
+ago	O
+)	O
+and	O
+13	O
+controls	O
+were	O
+compared	O
+on	O
+a	O
+battery	O
+of	O
+neuropsychological	O
+tests	O
+.	O
+
+DNA	O
+from	O
+peripheral	O
+nuclear	O
+blood	O
+cells	O
+was	O
+genotyped	O
+for	O
+5	O
+-	O
+HTTLPR	O
+using	O
+standard	O
+polymerase	O
+chain	O
+reaction	O
+methods	O
+.	O
+A	O
+significant	O
+group	O
+effect	O
+was	O
+observed	O
+only	O
+on	O
+memory	O
+function	O
+tasks	O
+(	O
+p	O
+=	O
+0	O
+.	O
+04	O
+)	O
+but	O
+not	O
+on	O
+reaction	O
+times	O
+(	O
+p	O
+=	O
+0	O
+.	O
+61	O
+)	O
+or	O
+attention	O
+/	O
+executive	O
+functioning	O
+(	O
+p	O
+=	O
+0	O
+.	O
+59	O
+)	O
+.	O
+
+Heavy	O
+and	O
+ex	O
+-	O
+MDMA	O
++	O
+users	O
+performed	O
+significantly	O
+poorer	O
+on	O
+memory	O
+tasks	O
+than	O
+controls	O
+.	O
+
+In	O
+contrast	O
+,	O
+no	O
+evidence	O
+of	O
+memory	B
+impairment	I
+was	O
+observed	O
+in	O
+moderate	O
+MDMA	O
+users	O
+.	O
+
+No	O
+significant	O
+effect	O
+of	O
+5	O
+-	O
+HTTLPR	O
+or	O
+gender	O
+was	O
+observed	O
+.	O
+
+While	O
+the	O
+use	O
+of	O
+MDMA	O
+in	O
+quantities	O
+that	O
+may	O
+be	O
+considered	O
+"	O
+moderate	O
+"	O
+is	O
+not	O
+associated	O
+with	O
+impaired	B
+memory	I
+functioning	I
+,	O
+heavy	O
+use	O
+of	O
+MDMA	O
+use	O
+may	O
+lead	O
+to	O
+long	O
+lasting	O
+memory	B
+impairments	I
+.	O
+
+No	O
+effect	O
+of	O
+5	O
+-	O
+HTTLPR	O
+or	O
+gender	O
+on	O
+memory	O
+function	O
+or	O
+MDMA	O
+use	O
+was	O
+observed	O
+.	O
+
+Role	O
+of	O
+mangiferin	O
+on	O
+biochemical	O
+alterations	O
+and	O
+antioxidant	O
+status	O
+in	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+in	O
+rats	O
+.	O
+
+The	O
+current	O
+study	O
+dealt	O
+with	O
+the	O
+protective	O
+role	O
+of	O
+mangiferin	O
+,	O
+a	O
+polyphenol	O
+from	O
+Mangifera	O
+indica	O
+Linn	O
+.	O
+
+(	O
+Anacardiaceae	O
+)	O
+,	O
+on	O
+isoproterenol	O
+(	O
+ISPH	O
+)	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+(	O
+MI	B
+)	O
+in	O
+rats	O
+through	O
+its	O
+antioxidative	O
+mechanism	O
+.	O
+
+Subcutaneous	O
+injection	O
+of	O
+ISPH	O
+(	O
+200	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+in	O
+1	O
+ml	O
+saline	O
+)	O
+to	O
+rats	O
+for	O
+2	O
+consecutive	O
+days	O
+caused	O
+myocardial	B
+damage	I
+in	O
+rat	O
+heart	O
+,	O
+which	O
+was	O
+determined	O
+by	O
+the	O
+increased	O
+activity	O
+of	O
+serum	O
+lactate	O
+dehydrogenase	O
+(	O
+LDH	O
+)	O
+and	O
+creatine	O
+phosphokinase	O
+isoenzymes	O
+(	O
+CK	O
+-	O
+MB	O
+)	O
+,	O
+increased	O
+uric	O
+acid	O
+level	O
+and	O
+reduced	O
+plasma	O
+iron	O
+binding	O
+capacity	O
+.	O
+
+The	O
+protective	O
+role	O
+of	O
+mangiferin	O
+was	O
+analyzed	O
+by	O
+triphenyl	O
+tetrazolium	O
+chloride	O
+(	O
+TTC	O
+)	O
+test	O
+used	O
+for	O
+macroscopic	O
+enzyme	O
+mapping	O
+assay	O
+of	O
+the	O
+ischemic	B
+myocardium	I
+.	O
+
+The	O
+heart	O
+tissue	O
+antioxidant	O
+enzymes	O
+such	O
+as	O
+superoxide	O
+dismutase	O
+,	O
+catalase	O
+,	O
+glutathione	O
+peroxidase	O
+,	O
+glutathione	O
+transferase	O
+and	O
+glutathione	O
+reductase	O
+activities	O
+,	O
+non	O
+-	O
+enzymic	O
+antioxidants	O
+such	O
+as	O
+cerruloplasmin	O
+,	O
+Vitamin	O
+C	O
+,	O
+Vitamin	O
+E	O
+and	O
+glutathione	O
+levels	O
+were	O
+altered	O
+in	O
+MI	B
+rats	O
+.	O
+
+Upon	O
+pretreatment	O
+with	O
+mangiferin	O
+(	O
+100	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+suspended	O
+in	O
+2	O
+ml	O
+of	O
+dimethyl	O
+sulphoxide	O
+)	O
+given	O
+intraperitoneally	O
+for	O
+28	O
+days	O
+to	O
+MI	B
+rats	O
+protected	O
+the	O
+above	O
+-	O
+mentioned	O
+parameters	O
+to	O
+fall	O
+from	O
+the	O
+normal	O
+levels	O
+.	O
+
+Activities	O
+of	O
+heart	O
+tissue	O
+enzymic	O
+antioxidants	O
+and	O
+serum	O
+non	O
+-	O
+enzymic	O
+antioxidants	O
+levels	O
+rose	O
+significantly	O
+upon	O
+mangiferin	O
+administration	O
+as	O
+compared	O
+to	O
+ISPH	O
+-	O
+induced	O
+MI	B
+rats	O
+.	O
+
+From	O
+the	O
+present	O
+study	O
+it	O
+is	O
+concluded	O
+that	O
+mangiferin	O
+exerts	O
+a	O
+beneficial	O
+effect	O
+against	O
+ISPH	O
+-	O
+induced	O
+MI	B
+due	O
+to	O
+its	O
+antioxidant	O
+potential	O
+,	O
+which	O
+regulated	O
+the	O
+tissues	O
+defense	O
+system	O
+against	O
+cardiac	B
+damage	I
+.	O
+
+Cardiovascular	O
+risk	O
+with	O
+cyclooxygenase	O
+inhibitors	O
+:	O
+general	O
+problem	O
+with	O
+substance	O
+specific	O
+differences	O
+?	O
+
+Randomised	O
+clinical	O
+trials	O
+and	O
+observational	O
+studies	O
+have	O
+shown	O
+an	O
+increased	O
+risk	O
+of	O
+myocardial	B
+infarction	I
+,	O
+stroke	B
+,	O
+hypertension	B
+and	O
+heart	B
+failure	I
+during	O
+treatment	O
+with	O
+cyclooxygenase	O
+inhibitors	O
+.	O
+
+Adverse	O
+cardiovascular	O
+effects	O
+occurred	O
+mainly	O
+,	O
+but	O
+not	O
+exclusively	O
+,	O
+in	O
+patients	O
+with	O
+concomitant	O
+risk	O
+factors	O
+.	O
+
+Cyclooxygenase	O
+inhibitors	O
+cause	O
+complex	O
+changes	O
+in	O
+renal	O
+,	O
+vascular	O
+and	O
+cardiac	O
+prostanoid	O
+profiles	O
+thereby	O
+increasing	O
+vascular	O
+resistance	O
+and	O
+fluid	O
+retention	O
+.	O
+
+The	O
+incidence	O
+of	O
+cardiovascular	O
+adverse	O
+events	O
+tends	O
+to	O
+increase	O
+with	O
+the	O
+daily	O
+dose	O
+and	O
+total	O
+exposure	O
+time	O
+.	O
+
+A	O
+comparison	O
+of	O
+individual	O
+selective	O
+and	O
+unselective	O
+cyclooxygenase	O
+inhibitors	O
+suggests	O
+substance	O
+-	O
+specific	O
+differences	O
+,	O
+which	O
+may	O
+depend	O
+on	O
+differences	O
+in	O
+pharmacokinetic	O
+parameters	O
+or	O
+inhibitory	O
+potency	O
+and	O
+may	O
+be	O
+contributed	O
+by	O
+prostaglandin	O
+-	O
+independent	O
+effects	O
+.	O
+
+Diagnostic	O
+markers	O
+such	O
+as	O
+N	O
+-	O
+terminal	O
+pro	O
+brain	O
+natriuretic	O
+peptide	O
+(	O
+NT	O
+-	O
+proBNP	O
+)	O
+or	O
+high	O
+-	O
+sensitive	O
+C	O
+-	O
+reactive	O
+protein	O
+might	O
+help	O
+in	O
+the	O
+early	O
+identification	O
+of	O
+patients	O
+at	O
+risk	O
+,	O
+thus	O
+avoiding	O
+the	O
+occurrence	O
+of	O
+serious	O
+cardiovascular	B
+toxicity	I
+.	O
+
+Pilocarpine	O
+seizures	B
+cause	O
+age	O
+-	O
+dependent	O
+impairment	B
+in	I
+auditory	I
+location	I
+discrimination	I
+.	O
+
+Children	O
+who	O
+have	O
+status	B
+epilepticus	I
+have	O
+continuous	O
+or	O
+rapidly	O
+repeating	O
+seizures	B
+that	O
+may	O
+be	O
+life	O
+-	O
+threatening	O
+and	O
+may	O
+cause	O
+life	O
+-	O
+long	O
+changes	O
+in	O
+brain	O
+and	O
+behavior	O
+.	O
+
+The	O
+extent	O
+to	O
+which	O
+status	B
+epilepticus	I
+causes	O
+deficits	B
+in	I
+auditory	I
+discrimination	I
+is	O
+unknown	O
+.	O
+
+A	O
+naturalistic	O
+auditory	O
+location	O
+discrimination	O
+method	O
+was	O
+used	O
+to	O
+evaluate	O
+this	O
+question	O
+using	O
+an	O
+animal	O
+model	O
+of	O
+status	B
+epilepticus	I
+.	O
+
+Male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+were	O
+injected	O
+with	O
+saline	O
+on	O
+postnatal	O
+day	O
+(	O
+P	O
+)	O
+20	O
+,	O
+or	O
+a	O
+convulsant	O
+dose	O
+of	O
+pilocarpine	O
+on	O
+P20	O
+or	O
+P45	O
+.	O
+
+Pilocarpine	O
+on	O
+either	O
+day	O
+induced	O
+status	B
+epilepticus	I
+;	O
+status	B
+epilepticus	I
+at	O
+P45	O
+resulted	O
+in	O
+CA3	O
+cell	O
+loss	O
+and	O
+spontaneous	O
+seizures	B
+,	O
+whereas	O
+P20	O
+rats	O
+had	O
+no	O
+cell	O
+loss	O
+or	O
+spontaneous	O
+seizures	B
+.	O
+
+Mature	O
+rats	O
+were	O
+trained	O
+with	O
+sound	O
+-	O
+source	O
+location	O
+and	O
+sound	O
+-	O
+silence	O
+discriminations	O
+.	O
+
+Control	O
+(	O
+saline	O
+P20	O
+)	O
+rats	O
+acquired	O
+both	O
+discriminations	O
+immediately	O
+.	O
+
+In	O
+status	B
+epilepticus	I
+(	O
+P20	O
+)	O
+rats	O
+,	O
+acquisition	O
+of	O
+the	O
+sound	O
+-	O
+source	O
+location	O
+discrimination	O
+was	O
+moderately	O
+impaired	O
+.	O
+
+Status	B
+epilepticus	I
+(	O
+P45	O
+)	O
+rats	O
+failed	O
+to	O
+acquire	O
+either	O
+sound	O
+-	O
+source	O
+location	O
+or	O
+sound	O
+-	O
+silence	O
+discriminations	O
+.	O
+
+Status	B
+epilepticus	I
+in	O
+rat	O
+causes	O
+an	O
+age	O
+-	O
+dependent	O
+,	O
+long	O
+-	O
+term	O
+impairment	B
+in	I
+auditory	I
+discrimination	I
+.	O
+
+This	O
+impairment	O
+may	O
+explain	O
+one	O
+cause	O
+of	O
+impaired	B
+auditory	I
+location	I
+discrimination	I
+in	O
+humans	O
+.	O
+
+Nerve	O
+growth	O
+factor	O
+and	O
+prostaglandins	O
+in	O
+the	O
+urine	O
+of	O
+female	O
+patients	O
+with	O
+overactive	B
+bladder	I
+.	O
+
+PURPOSE	O
+:	O
+NGF	O
+and	O
+PGs	O
+in	O
+the	O
+bladder	O
+can	O
+be	O
+affected	O
+by	O
+pathological	O
+changes	O
+in	O
+the	O
+bladder	O
+and	O
+these	O
+changes	O
+can	O
+be	O
+detected	O
+in	O
+urine	O
+.	O
+
+We	O
+investigated	O
+changes	O
+in	O
+urinary	O
+NGF	O
+and	O
+PGs	O
+in	O
+women	O
+with	O
+OAB	B
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+The	O
+study	O
+groups	O
+included	O
+65	O
+women	O
+with	O
+OAB	B
+and	O
+20	O
+without	O
+bladder	O
+symptoms	O
+who	O
+served	O
+as	O
+controls	O
+.	O
+
+Evaluation	O
+included	O
+patient	O
+history	O
+,	O
+urinalysis	O
+,	O
+a	O
+voiding	O
+diary	O
+and	O
+urodynamic	O
+studies	O
+.	O
+
+Urine	O
+samples	O
+were	O
+collected	O
+.	O
+
+NGF	O
+,	O
+PGE2	O
+,	O
+PGF2alpha	O
+and	O
+PGI2	O
+were	O
+measured	O
+using	O
+enzyme	O
+-	O
+linked	O
+immunosorbent	O
+assay	O
+and	O
+compared	O
+between	O
+the	O
+groups	O
+.	O
+
+In	O
+addition	O
+,	O
+correlations	O
+between	O
+urinary	O
+NGF	O
+and	O
+PG	O
+,	O
+and	O
+urodynamic	O
+parameters	O
+in	O
+patients	O
+with	O
+OAB	B
+were	O
+examined	O
+.	O
+
+RESULTS	O
+:	O
+Urinary	O
+NGF	O
+,	O
+PGE2	O
+and	O
+PGF2alpha	O
+were	O
+significantly	O
+increased	O
+in	O
+patients	O
+with	O
+OAB	B
+compared	O
+with	O
+controls	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+However	O
+,	O
+urinary	O
+PGI2	O
+was	O
+not	O
+different	O
+between	O
+controls	O
+and	O
+patients	O
+with	O
+OAB	B
+.	O
+
+In	O
+patients	O
+with	O
+OAB	B
+urinary	O
+PGE2	O
+positively	O
+correlated	O
+with	O
+volume	O
+at	O
+first	O
+desire	O
+to	O
+void	O
+and	O
+maximum	O
+cystometric	O
+capacity	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Urinary	O
+NGF	O
+,	O
+PGF2alpha	O
+and	O
+PGI2	O
+did	O
+not	O
+correlate	O
+with	O
+urodynamic	O
+parameters	O
+in	O
+patients	O
+with	O
+OAB	B
+.	O
+
+CONCLUSIONS	O
+:	O
+NGF	O
+and	O
+PGs	O
+have	O
+important	O
+roles	O
+in	O
+the	O
+development	O
+of	O
+OAB	B
+symptoms	O
+in	O
+female	O
+patients	O
+.	O
+
+Urinary	O
+levels	O
+of	O
+these	O
+factors	O
+may	O
+be	O
+used	O
+as	O
+markers	O
+to	O
+evaluate	O
+OAB	B
+symptoms	O
+.	O
+
+Definition	O
+and	O
+management	O
+of	O
+anemia	B
+in	O
+patients	O
+infected	B
+with	I
+hepatitis	I
+C	I
+virus	I
+.	O
+
+Chronic	B
+infection	I
+with	I
+hepatitis	I
+C	I
+virus	I
+(	O
+HCV	O
+)	O
+can	O
+progress	O
+to	O
+cirrhosis	B
+,	O
+hepatocellular	B
+carcinoma	I
+,	O
+and	O
+end	B
+-	I
+stage	I
+liver	I
+disease	I
+.	O
+
+The	O
+current	O
+best	O
+treatment	O
+for	O
+HCV	B
+infection	I
+is	O
+combination	O
+therapy	O
+with	O
+pegylated	O
+interferon	O
+and	O
+ribavirin	O
+.	O
+
+Although	O
+this	O
+regimen	O
+produces	O
+sustained	O
+virologic	O
+responses	O
+(	O
+SVRs	O
+)	O
+in	O
+approximately	O
+50	O
+%	O
+of	O
+patients	O
+,	O
+it	O
+can	O
+be	O
+associated	O
+with	O
+a	O
+potentially	O
+dose	O
+-	O
+limiting	O
+hemolytic	B
+anemia	I
+.	O
+
+Hemoglobin	O
+concentrations	O
+decrease	O
+mainly	O
+as	O
+a	O
+result	O
+of	O
+ribavirin	O
+-	O
+induced	O
+hemolysis	B
+,	O
+and	O
+this	O
+anemia	B
+can	O
+be	O
+problematic	O
+in	O
+patients	O
+with	O
+HCV	B
+infection	I
+,	O
+especially	O
+those	O
+who	O
+have	O
+comorbid	O
+renal	B
+or	I
+cardiovascular	I
+disorders	I
+.	O
+
+In	O
+general	O
+,	O
+anemia	B
+can	O
+increase	O
+the	O
+risk	O
+of	O
+morbidity	O
+and	O
+mortality	O
+,	O
+and	O
+may	O
+have	O
+negative	O
+effects	O
+on	O
+cerebral	O
+function	O
+and	O
+quality	O
+of	O
+life	O
+.	O
+
+Although	O
+ribavirin	O
+-	O
+associated	O
+anemia	B
+can	O
+be	O
+reversed	O
+by	O
+dose	O
+reduction	O
+or	O
+discontinuation	O
+,	O
+this	O
+approach	O
+compromises	O
+outcomes	O
+by	O
+significantly	O
+decreasing	O
+SVR	O
+rates	O
+.	O
+
+Recombinant	O
+human	O
+erythropoietin	O
+has	O
+been	O
+used	O
+to	O
+manage	O
+ribavirin	O
+-	O
+associated	O
+anemia	B
+but	O
+has	O
+other	O
+potential	O
+disadvantages	O
+.	O
+
+Viramidine	O
+,	O
+a	O
+liver	O
+-	O
+targeting	O
+prodrug	O
+of	O
+ribavirin	O
+,	O
+has	O
+the	O
+potential	O
+to	O
+maintain	O
+the	O
+virologic	O
+efficacy	O
+of	O
+ribavirin	O
+while	O
+decreasing	O
+the	O
+risk	O
+of	O
+hemolytic	B
+anemia	I
+in	O
+patients	O
+with	O
+chronic	B
+hepatitis	I
+C	I
+.	O
+
+Impact	O
+of	O
+alcohol	O
+exposure	O
+after	O
+pregnancy	O
+recognition	O
+on	O
+ultrasonographic	O
+fetal	O
+growth	O
+measures	O
+.	O
+
+BACKGROUND	O
+:	O
+More	O
+than	O
+3	O
+decades	O
+after	O
+Jones	O
+and	O
+Smith	O
+(	O
+1973	O
+)	O
+reported	O
+on	O
+the	O
+devastation	O
+caused	O
+by	O
+alcohol	O
+exposure	O
+on	O
+fetal	O
+development	O
+,	O
+the	O
+rates	O
+of	O
+heavy	O
+drinking	O
+during	O
+pregnancy	O
+remain	O
+relatively	O
+unchanged	O
+.	O
+
+Early	O
+identification	O
+of	O
+fetal	O
+alcohol	O
+exposure	O
+and	O
+maternal	O
+abstinence	O
+led	O
+to	O
+better	O
+infant	O
+outcomes	O
+.	O
+
+This	O
+study	O
+examined	O
+the	O
+utility	O
+of	O
+biometry	O
+for	O
+detecting	O
+alcohol	O
+-	O
+related	O
+fetal	O
+growth	B
+impairment	I
+.	O
+
+METHODS	O
+:	O
+We	O
+obtained	O
+fetal	O
+ultrasound	O
+measures	O
+from	O
+routine	O
+ultrasound	O
+examinations	O
+for	O
+167	O
+pregnant	O
+hazardous	O
+drinkers	O
+who	O
+were	O
+enrolled	O
+in	O
+a	O
+brief	O
+alcohol	O
+intervention	O
+study	O
+.	O
+
+The	O
+fetal	O
+measures	O
+for	O
+women	O
+who	O
+quit	O
+after	O
+learning	O
+of	O
+their	O
+pregnancies	O
+were	O
+compared	O
+with	O
+measures	O
+for	O
+women	O
+who	O
+continued	O
+some	O
+drinking	O
+throughout	O
+the	O
+course	O
+of	O
+their	O
+pregnancies	O
+.	O
+
+Because	O
+intensity	O
+of	O
+alcohol	O
+consumption	O
+is	O
+associated	O
+with	O
+poorer	O
+fetal	O
+outcomes	O
+,	O
+separate	O
+analyses	O
+were	O
+conducted	O
+for	O
+the	O
+heavy	O
+(	O
+average	O
+of	O
+>	O
+or	O
+=	O
+5	O
+drinks	O
+per	O
+drinking	O
+day	O
+)	O
+alcohol	O
+consumers	O
+.	O
+
+Fetal	O
+measures	O
+from	O
+the	O
+heavy	O
+-	O
+exposed	O
+fetuses	O
+were	O
+also	O
+compared	O
+with	O
+measures	O
+from	O
+a	O
+nondrinking	O
+group	O
+that	O
+was	O
+representative	O
+of	O
+normal	O
+,	O
+uncomplicated	O
+pregnancies	O
+from	O
+our	O
+clinics	O
+.	O
+
+Analyses	O
+of	O
+covariance	O
+were	O
+used	O
+to	O
+determine	O
+whether	O
+there	O
+were	O
+differences	O
+between	O
+groups	O
+after	O
+controlling	O
+for	O
+influences	O
+of	O
+gestational	O
+age	O
+and	O
+drug	B
+abuse	I
+.	O
+
+RESULTS	O
+:	O
+Nearly	O
+half	O
+of	O
+the	O
+pregnant	O
+drinkers	O
+abstained	O
+after	O
+learning	O
+of	O
+their	O
+pregnancies	O
+.	O
+
+When	O
+women	O
+reportedly	O
+quit	O
+drinking	O
+early	O
+in	O
+their	O
+pregnancies	O
+,	O
+fetal	O
+growth	O
+measures	O
+were	O
+not	O
+significantly	O
+different	O
+from	O
+a	O
+non	O
+-	O
+alcohol	O
+-	O
+exposed	O
+group	O
+,	O
+regardless	O
+of	O
+prior	O
+drinking	O
+patterns	O
+.	O
+
+Any	O
+alcohol	O
+consumption	O
+postpregnancy	O
+recognition	O
+among	O
+the	O
+heavy	O
+drinkers	O
+resulted	O
+in	O
+reduced	B
+cerebellar	I
+growth	I
+as	O
+well	O
+as	O
+decreased	B
+cranial	I
+to	I
+body	I
+growth	I
+in	O
+comparison	O
+with	O
+women	O
+who	O
+either	O
+quit	O
+drinking	O
+or	O
+who	O
+were	O
+nondrinkers	O
+.	O
+
+Amphetamine	O
+abuse	O
+was	O
+predictive	O
+of	O
+larger	O
+cranial	O
+to	O
+body	O
+growth	O
+ratios	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Alterations	O
+in	O
+fetal	O
+biometric	O
+measurements	O
+were	O
+observed	O
+among	O
+the	O
+heavy	O
+drinkers	O
+only	O
+when	O
+they	O
+continued	O
+drinking	O
+after	O
+becoming	O
+aware	O
+of	O
+their	O
+pregnancies	O
+.	O
+
+Although	O
+the	O
+reliance	O
+on	O
+self	O
+-	O
+reported	O
+drinking	O
+is	O
+a	O
+limitation	O
+in	O
+this	O
+study	O
+,	O
+these	O
+findings	O
+support	O
+the	O
+benefits	O
+of	O
+early	O
+abstinence	O
+and	O
+the	O
+potential	O
+for	O
+ultrasound	O
+examinations	O
+in	O
+the	O
+detection	O
+of	O
+fetal	O
+alcohol	O
+effects	O
+.	O
+
+Ethambutol	O
+-	O
+associated	O
+optic	B
+neuropathy	I
+.	O
+
+INTRODUCTION	O
+:	O
+Ethambutol	O
+is	O
+used	O
+in	O
+the	O
+treatment	O
+of	O
+tuberculosis	B
+,	O
+which	O
+is	O
+still	O
+prevalent	O
+in	O
+Southeast	O
+Asia	O
+,	O
+and	O
+can	O
+be	O
+associated	O
+with	O
+permanent	O
+visual	B
+loss	I
+.	O
+
+We	O
+report	O
+3	O
+cases	O
+which	O
+presented	O
+with	O
+bitemporal	B
+hemianopia	I
+.	O
+
+CLINICAL	O
+PICTURE	O
+:	O
+Three	O
+patients	O
+with	O
+ethambutol	O
+-	O
+associated	O
+toxic	O
+optic	B
+neuropathy	I
+are	O
+described	O
+.	O
+
+All	O
+3	O
+patients	O
+had	O
+loss	B
+of	I
+central	I
+visual	I
+acuity	I
+,	I
+colour	I
+vision	I
+(	I
+Ishihara	I
+)	I
+and	I
+visual	I
+field	I
+.	O
+
+The	O
+visual	B
+field	I
+loss	I
+had	O
+a	O
+bitemporal	O
+flavour	O
+,	O
+suggesting	O
+involvement	O
+of	O
+the	O
+optic	O
+chiasm	O
+.	O
+
+TREATMENT	O
+:	O
+Despite	O
+stopping	O
+ethambutol	O
+on	O
+diagnosis	O
+,	O
+visual	O
+function	O
+continued	O
+to	O
+deteriorate	O
+for	O
+a	O
+few	O
+months	O
+.	O
+
+Subsequent	O
+improvement	O
+was	O
+mild	O
+in	O
+2	O
+cases	O
+.	O
+
+In	O
+the	O
+third	O
+case	O
+,	O
+visual	O
+acuity	O
+and	O
+colour	O
+vision	O
+normalised	O
+but	O
+the	O
+optic	O
+discs	O
+were	O
+pale	O
+.	O
+
+OUTCOME	O
+:	O
+All	O
+3	O
+patients	O
+had	O
+some	O
+permanent	O
+loss	B
+of	I
+visual	I
+function	I
+.	O
+
+CONCLUSIONS	O
+:	O
+Ethambutol	O
+usage	O
+is	O
+associated	O
+with	O
+permanent	O
+visual	B
+loss	I
+and	O
+should	O
+be	O
+avoided	O
+if	O
+possible	O
+or	O
+used	O
+with	O
+caution	O
+and	O
+proper	O
+ophthalmological	O
+follow	O
+-	O
+up	O
+.	O
+
+The	O
+author	O
+postulates	O
+that	O
+in	O
+cases	O
+of	O
+ethambutol	O
+associated	O
+chiasmopathy	O
+,	O
+ethambutol	O
+may	O
+initially	O
+affect	O
+the	O
+optic	O
+nerves	O
+and	O
+subsequently	O
+progress	O
+to	O
+involve	O
+the	O
+optic	O
+chiasm	O
+.	O
+
+Possible	O
+neuroleptic	B
+malignant	I
+syndrome	I
+related	O
+to	O
+concomitant	O
+treatment	O
+with	O
+paroxetine	O
+and	O
+alprazolam	O
+.	O
+
+A	O
+74	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+depressive	B
+symptoms	I
+was	O
+admitted	O
+to	O
+a	O
+psychiatric	B
+hospital	O
+due	O
+to	O
+insomnia	B
+,	O
+loss	B
+of	I
+appetite	I
+,	O
+exhaustion	O
+,	O
+and	O
+agitation	B
+.	O
+
+Medical	O
+treatment	O
+was	O
+initiated	O
+at	O
+a	O
+daily	O
+dose	O
+of	O
+20	O
+mg	O
+paroxetine	O
+and	O
+1	O
+.	O
+2	O
+mg	O
+alprazolam	O
+.	O
+
+On	O
+the	O
+10th	O
+day	O
+of	O
+paroxetine	O
+and	O
+alprazolam	O
+treatment	O
+,	O
+the	O
+patient	O
+exhibited	O
+marked	O
+psychomotor	B
+retardation	I
+,	O
+disorientation	O
+,	O
+and	O
+severe	O
+muscle	B
+rigidity	I
+with	O
+tremors	B
+.	O
+
+The	O
+patient	O
+had	O
+a	O
+fever	B
+(	O
+38	O
+.	O
+2	O
+degrees	O
+C	O
+)	O
+,	O
+fluctuating	O
+blood	O
+pressure	O
+(	O
+between	O
+165	O
+/	O
+90	O
+and	O
+130	O
+/	O
+70	O
+mg	O
+mm	O
+Hg	O
+)	O
+,	O
+and	O
+severe	O
+extrapyramidal	B
+symptoms	I
+.	O
+
+Laboratory	O
+tests	O
+showed	O
+an	O
+elevation	O
+of	O
+creatine	O
+phosphokinase	O
+(	O
+2218	O
+IU	O
+/	O
+L	O
+)	O
+,	O
+aspartate	O
+aminotransferase	O
+(	O
+134	O
+IU	O
+/	O
+L	O
+)	O
+,	O
+alanine	O
+aminotransferase	O
+(	O
+78	O
+IU	O
+/	O
+L	O
+)	O
+,	O
+and	O
+BUN	O
+(	O
+27	O
+.	O
+9	O
+mg	O
+/	O
+ml	O
+)	O
+levels	O
+.	O
+
+The	O
+patient	O
+received	O
+bromocriptine	O
+and	O
+diazepam	O
+to	O
+treat	O
+his	O
+symptoms	O
+.	O
+
+7	O
+days	O
+later	O
+,	O
+the	O
+fever	B
+disappeared	O
+and	O
+the	O
+patient	O
+'	O
+s	O
+serum	O
+CPK	O
+levels	O
+were	O
+normalized	O
+(	O
+175	O
+IU	O
+/	O
+L	O
+)	O
+.	O
+
+This	O
+patient	O
+presented	O
+with	O
+symptoms	O
+of	O
+neuroleptic	B
+malignant	I
+syndrome	I
+(	O
+NMS	B
+)	O
+,	O
+thus	O
+demonstrating	O
+that	O
+NMS	B
+-	O
+like	O
+symptoms	O
+can	O
+occur	O
+after	O
+combined	O
+paroxetine	O
+and	O
+alprazolam	O
+treatment	O
+.	O
+
+The	O
+adverse	O
+drug	O
+reaction	O
+score	O
+obtained	O
+by	O
+the	O
+Naranjo	O
+algorithm	O
+was	O
+6	O
+in	O
+our	O
+case	O
+,	O
+indicating	O
+a	O
+probable	O
+relationship	O
+between	O
+the	O
+patient	O
+'	O
+s	O
+NMS	B
+-	O
+like	O
+adverse	O
+symptoms	O
+and	O
+the	O
+combined	O
+treatment	O
+used	O
+in	O
+this	O
+case	O
+.	O
+
+The	O
+involvement	O
+of	O
+physiologic	O
+and	O
+environmental	O
+aspects	O
+specific	O
+to	O
+this	O
+patient	O
+was	O
+suspected	O
+.	O
+
+Several	O
+risk	O
+factors	O
+for	O
+NMS	B
+should	O
+be	O
+noted	O
+in	O
+elderly	O
+depressive	B
+patients	O
+whose	O
+symptoms	O
+often	O
+include	O
+dehydration	B
+,	O
+agitation	B
+,	O
+malnutrition	B
+,	O
+and	O
+exhaustion	O
+.	O
+
+Careful	O
+therapeutic	O
+intervention	O
+is	O
+necessary	O
+in	O
+cases	O
+involving	O
+elderly	O
+patients	O
+who	O
+suffer	O
+from	O
+depression	B
+.	O
+
+Down	O
+-	O
+regulation	O
+of	O
+norepinephrine	O
+transporter	O
+function	O
+induced	O
+by	O
+chronic	O
+administration	O
+of	O
+desipramine	O
+linking	O
+to	O
+the	O
+alteration	O
+of	O
+sensitivity	O
+of	O
+local	O
+-	O
+anesthetics	O
+-	O
+induced	O
+convulsions	B
+and	O
+the	O
+counteraction	O
+by	O
+co	O
+-	O
+administration	O
+with	O
+local	O
+anesthetics	O
+.	O
+
+Alterations	O
+of	O
+norepinephrine	O
+transporter	O
+(	O
+NET	O
+)	O
+function	O
+by	O
+chronic	O
+inhibition	O
+of	O
+NET	O
+in	O
+relation	O
+to	O
+sensitization	O
+to	O
+seizures	B
+induce	O
+by	O
+cocaine	O
+and	O
+local	O
+anesthetics	O
+were	O
+studied	O
+in	O
+mice	O
+.	O
+
+Daily	O
+administration	O
+of	O
+desipramine	O
+,	O
+an	O
+inhibitor	O
+of	O
+the	O
+NET	O
+,	O
+for	O
+5	O
+days	O
+decreased	O
+[	O
+(	O
+3	O
+)	O
+H	O
+]	O
+norepinephrine	O
+uptake	O
+in	O
+the	O
+P2	O
+fractions	O
+of	O
+hippocampus	O
+but	O
+not	O
+cortex	O
+,	O
+striatum	O
+or	O
+amygdalae	O
+.	O
+
+Co	O
+-	O
+administration	O
+of	O
+lidocaine	O
+,	O
+bupivacaine	O
+or	O
+tricaine	O
+with	O
+desipramine	O
+reversed	O
+this	O
+effect	O
+.	O
+
+Daily	O
+treatment	O
+of	O
+cocaine	O
+increased	O
+[	O
+(	O
+3	O
+)	O
+H	O
+]	O
+norepinephrine	O
+uptake	O
+into	O
+the	O
+hippocampus	O
+.	O
+
+Daily	O
+administration	O
+of	O
+desipramine	O
+increased	O
+the	O
+incidence	O
+of	O
+appearance	O
+of	O
+lidocaine	O
+-	O
+induced	O
+convulsions	B
+and	O
+decreased	O
+that	O
+of	O
+cocaine	O
+-	O
+induced	O
+convulsions	B
+.	O
+
+Co	O
+-	O
+administration	O
+of	O
+lidocaine	O
+with	O
+desipramine	O
+reversed	O
+the	O
+changes	O
+of	O
+convulsive	B
+activity	O
+of	O
+lidocaine	O
+and	O
+cocaine	O
+induced	O
+by	O
+repeated	O
+administration	O
+of	O
+desipramine	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+down	O
+-	O
+regulation	O
+of	O
+hippocampal	O
+NET	O
+induced	O
+by	O
+chronic	O
+administration	O
+of	O
+desipramine	O
+may	O
+be	O
+relevant	O
+to	O
+desipramine	O
+-	O
+induced	O
+sensitization	O
+of	O
+lidocaine	O
+convulsions	B
+.	O
+
+Inhibition	O
+of	O
+Na	O
+(	O
++	O
+)	O
+channels	O
+by	O
+local	O
+anesthetics	O
+may	O
+regulate	O
+desipramine	O
+-	O
+induced	O
+down	O
+-	O
+regulation	O
+of	O
+NET	O
+function	O
+.	O
+
+Repeated	O
+administration	O
+of	O
+cocaine	O
+induces	O
+up	O
+-	O
+regulation	O
+of	O
+hippocampal	O
+NET	O
+function	O
+.	O
+
+Desipramine	O
+-	O
+induced	O
+sensitization	O
+of	O
+lidocaine	O
+seizures	B
+may	O
+have	O
+a	O
+mechanism	O
+distinct	O
+from	O
+kindling	O
+resulting	O
+from	O
+repeated	O
+administration	O
+of	O
+cocaine	O
+.	O
+
+Atorvastatin	O
+prevented	O
+and	O
+reversed	O
+dexamethasone	O
+-	O
+induced	O
+hypertension	B
+in	O
+the	O
+rat	O
+.	O
+
+To	O
+assess	O
+the	O
+antioxidant	O
+effects	O
+of	O
+atorvastatin	O
+(	O
+atorva	O
+)	O
+on	O
+dexamethasone	O
+(	O
+dex	O
+)	O
+-	O
+induced	O
+hypertension	B
+,	O
+60	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+were	O
+treated	O
+with	O
+atorva	O
+30	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+or	O
+tap	O
+water	O
+for	O
+15	O
+days	O
+.	O
+
+Dex	O
+increased	O
+systolic	O
+blood	O
+pressure	O
+(	O
+SBP	O
+)	O
+from	O
+109	O
++	O
+/	O
+-	O
+1	O
+.	O
+8	O
+to	O
+135	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+mmHg	O
+and	O
+plasma	O
+superoxide	O
+(	O
+5711	O
++	O
+/	O
+-	O
+284	O
+.	O
+9	O
+saline	O
+,	O
+7931	O
++	O
+/	O
+-	O
+392	O
+.	O
+8	O
+U	O
+/	O
+ml	O
+dex	O
+,	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+In	O
+this	O
+prevention	O
+study	O
+,	O
+SBP	O
+in	O
+the	O
+atorva	O
++	O
+dex	O
+group	O
+was	O
+increased	O
+from	O
+115	O
++	O
+/	O
+-	O
+0	O
+.	O
+4	O
+to	O
+124	O
++	O
+/	O
+-	O
+1	O
+.	O
+5	O
+mmHg	O
+,	O
+but	O
+this	O
+was	O
+significantly	O
+lower	O
+than	O
+in	O
+the	O
+dex	O
+-	O
+only	O
+group	O
+(	O
+P	O
+'	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Atorva	O
+reversed	O
+dex	O
+-	O
+induced	O
+hypertension	B
+(	O
+129	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+mmHg	O
+,	O
+vs	O
+.	O
+135	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+mmHg	O
+P	O
+'	O
+<	O
+0	O
+.	O
+05	O
+)	O
+and	O
+decreased	O
+plasma	O
+superoxide	O
+(	O
+7931	O
++	O
+/	O
+-	O
+392	O
+.	O
+8	O
+dex	O
+,	O
+1187	O
++	O
+/	O
+-	O
+441	O
+.	O
+2	O
+atorva	O
++	O
+dex	O
+,	O
+P	O
+<	O
+0	O
+.	O
+0001	O
+)	O
+.	O
+
+Plasma	O
+nitrate	O
+/	O
+nitrite	O
+(	O
+NOx	O
+)	O
+was	O
+decreased	O
+in	O
+dex	O
+-	O
+treated	O
+rats	O
+compared	O
+to	O
+saline	O
+-	O
+treated	O
+rats	O
+(	O
+11	O
+.	O
+2	O
++	O
+/	O
+-	O
+1	O
+.	O
+08	O
+microm	O
+,	O
+15	O
+.	O
+3	O
++	O
+/	O
+-	O
+1	O
+.	O
+17	O
+microm	O
+,	O
+respectively	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Atorva	O
+affected	O
+neither	O
+plasma	O
+NOx	O
+nor	O
+thymus	O
+weight	O
+.	O
+
+Thus	O
+,	O
+atorvastatin	O
+prevented	O
+and	O
+reversed	O
+dexamethasone	O
+-	O
+induced	O
+hypertension	B
+in	O
+the	O
+rat	O
+.	O
+
+Peripheral	B
+neuropathy	I
+caused	O
+by	O
+high	O
+-	O
+dose	O
+cytosine	O
+arabinoside	O
+treatment	O
+in	O
+a	O
+patient	O
+with	O
+acute	B
+myeloid	I
+leukemia	I
+.	O
+
+The	O
+central	O
+nervous	O
+system	O
+toxicity	B
+of	O
+high	O
+-	O
+dose	O
+cytosine	O
+arabinoside	O
+is	O
+well	O
+recognized	O
+,	O
+but	O
+the	O
+toxicity	B
+of	O
+cytosine	O
+arabinoside	O
+in	O
+the	O
+peripheral	O
+nervous	O
+system	O
+has	O
+been	O
+infrequently	O
+reported	O
+.	O
+
+A	O
+49	O
+-	O
+year	O
+-	O
+old	O
+Japanese	O
+man	O
+was	O
+diagnosed	O
+with	O
+acute	B
+myeloid	I
+leukemia	I
+.	O
+
+After	O
+he	O
+achieved	O
+complete	O
+remission	O
+,	O
+he	O
+received	O
+high	O
+-	O
+dose	O
+cytosine	O
+arabinoside	O
+treatment	O
+(	O
+2	O
+g	O
+/	O
+m2	O
+twice	O
+a	O
+day	O
+for	O
+5	O
+days	O
+;	O
+total	O
+,	O
+20	O
+g	O
+/	O
+m2	O
+)	O
+as	O
+consolidation	O
+therapy	O
+.	O
+
+The	O
+first	O
+course	O
+of	O
+high	O
+-	O
+dose	O
+cytosine	O
+arabinoside	O
+resulted	O
+in	O
+no	O
+unusual	O
+symptoms	O
+,	O
+but	O
+on	O
+day	O
+21	O
+of	O
+the	O
+second	O
+course	O
+of	O
+treatment	O
+,	O
+the	O
+patient	O
+complained	O
+of	O
+numbness	B
+in	O
+his	O
+right	O
+foot	O
+.	O
+
+Electromyogram	O
+and	O
+nerve	O
+-	O
+conduction	O
+studies	O
+showed	O
+peripheral	B
+neuropathy	I
+in	O
+both	O
+peroneal	O
+nerves	O
+.	O
+
+This	O
+neuropathy	B
+was	O
+gradually	O
+resolving	O
+;	O
+however	O
+,	O
+after	O
+the	O
+patient	O
+received	O
+allogeneic	O
+bone	O
+marrow	O
+transplantation	O
+,	O
+the	O
+symptoms	O
+worsened	O
+,	O
+with	O
+the	O
+development	O
+of	O
+graft	B
+-	I
+versus	I
+-	I
+host	I
+disease	I
+,	O
+and	O
+the	O
+symptoms	O
+subsequently	O
+responded	O
+to	O
+methylprednisolone	O
+.	O
+
+Although	O
+the	O
+mechanisms	O
+of	O
+peripheral	B
+neuropathy	I
+are	O
+still	O
+unclear	O
+,	O
+high	O
+-	O
+dose	O
+cytosine	O
+arabinoside	O
+is	O
+a	O
+therapy	O
+that	O
+is	O
+potentially	O
+toxic	O
+to	O
+the	O
+peripheral	O
+nervous	O
+system	O
+,	O
+and	O
+auto	O
+/	O
+alloimmunity	O
+may	O
+play	O
+an	O
+important	O
+role	O
+in	O
+these	O
+mechanisms	O
+.	O
+
+Effect	O
+of	O
+alpha	O
+-	O
+tocopherol	O
+and	O
+deferoxamine	O
+on	O
+methamphetamine	O
+-	O
+induced	O
+neurotoxicity	B
+.	O
+
+Methamphetamine	O
+(	O
+MA	O
+)	O
+-	O
+induced	O
+dopaminergic	O
+neurotoxicity	B
+is	O
+believed	O
+to	O
+be	O
+associated	O
+with	O
+the	O
+increased	O
+formation	O
+of	O
+free	O
+radicals	O
+.	O
+
+This	O
+study	O
+examined	O
+the	O
+effect	O
+of	O
+alpha	O
+-	O
+tocopherol	O
+(	O
+alpha	O
+-	O
+TC	O
+)	O
+,	O
+a	O
+scavenger	O
+of	O
+reactive	O
+oxygen	O
+species	O
+,	O
+and	O
+deferoxamine	O
+(	O
+DFO	O
+)	O
+,	O
+an	O
+iron	O
+chelator	O
+,	O
+on	O
+the	O
+MA	O
+-	O
+induced	O
+neurotoxicity	B
+.	O
+
+Male	O
+rats	O
+were	O
+treated	O
+with	O
+MA	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+,	O
+every	O
+2	O
+h	O
+for	O
+four	O
+injections	O
+)	O
+.	O
+
+The	O
+rat	O
+received	O
+either	O
+alpha	O
+-	O
+TC	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+)	O
+intraperitoneally	O
+for	O
+3	O
+days	O
+and	O
+30	O
+min	O
+prior	O
+to	O
+MA	O
+administration	O
+or	O
+DFO	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+subcutaneously	O
+30	O
+min	O
+before	O
+MA	O
+administration	O
+.	O
+
+The	O
+concentrations	O
+of	O
+dopamine	O
+(	O
+DA	O
+)	O
+,	O
+serotonin	O
+and	O
+their	O
+metabolites	O
+decreased	O
+significantly	O
+after	O
+MA	O
+administration	O
+,	O
+which	O
+was	O
+inhibited	O
+by	O
+the	O
+alpha	O
+-	O
+TC	O
+and	O
+DFO	O
+pretreatment	O
+.	O
+
+alpha	O
+-	O
+TC	O
+and	O
+DFO	O
+attenuated	O
+the	O
+MA	O
+-	O
+induced	O
+hyperthermia	B
+as	O
+well	O
+as	O
+the	O
+alterations	O
+in	O
+the	O
+locomotor	O
+activity	O
+.	O
+
+The	O
+level	O
+of	O
+lipid	O
+peroxidation	O
+was	O
+higher	O
+and	O
+the	O
+reduced	O
+glutathione	O
+concentration	O
+was	O
+lower	O
+in	O
+the	O
+MA	O
+-	O
+treated	O
+rats	O
+.	O
+
+These	O
+changes	O
+were	O
+significantly	O
+attenuated	O
+by	O
+alpha	O
+-	O
+TC	O
+and	O
+DFO	O
+.	O
+
+This	O
+suggests	O
+that	O
+alpha	O
+-	O
+TC	O
+and	O
+DFO	O
+ameliorate	O
+the	O
+MA	O
+-	O
+induced	O
+neuronal	B
+damage	I
+by	O
+decreasing	O
+the	O
+level	O
+of	O
+oxidative	O
+stress	O
+.	O
+
+Blockade	O
+of	O
+both	O
+D	O
+-	O
+1	O
+and	O
+D	O
+-	O
+2	O
+dopamine	O
+receptors	O
+may	O
+induce	O
+catalepsy	B
+in	O
+mice	O
+.	O
+
+1	O
+.	O
+
+The	O
+catalepsy	B
+induced	O
+by	O
+dopamine	O
+antagonists	O
+has	O
+been	O
+tested	O
+and	O
+the	O
+possible	O
+dopamine	O
+subtypes	O
+involved	O
+in	O
+catalepsy	B
+was	O
+determined	O
+.	O
+
+2	O
+.	O
+
+Dopamine	O
+antagonist	O
+fluphenazine	O
+,	O
+D	O
+-	O
+1	O
+antagonist	O
+SCH	O
+23390	O
+or	O
+D	O
+-	O
+2	O
+antagonist	O
+sulpiride	O
+induced	O
+catalepsy	B
+.	O
+
+The	O
+effect	O
+of	O
+fluphenazine	O
+and	O
+sulpiride	O
+was	O
+dose	O
+-	O
+dependent	O
+.	O
+
+Combination	O
+of	O
+SCH	O
+23390	O
+with	O
+sulpiride	O
+did	O
+not	O
+induce	O
+catalepsy	B
+potentiation	O
+.	O
+
+3	O
+.	O
+
+D	O
+-	O
+1	O
+agonist	O
+SKF	O
+38393	O
+or	O
+D	O
+-	O
+2	O
+agonist	O
+quinpirole	O
+decreased	O
+the	O
+catalepsy	B
+induced	O
+by	O
+fluphenazine	O
+,	O
+SCH	O
+23390	O
+or	O
+sulpiride	O
+.	O
+
+4	O
+.	O
+
+Combination	O
+of	O
+SKF	O
+38393	O
+with	O
+quinpirole	O
+did	O
+not	O
+cause	O
+potentiated	O
+inhibitory	O
+effect	O
+on	O
+catalepsy	B
+induced	O
+by	O
+dopamine	O
+antagonists	O
+.	O
+
+5	O
+.	O
+
+The	O
+data	O
+may	O
+indicate	O
+that	O
+although	O
+D	O
+-	O
+2	O
+receptor	O
+blockade	O
+is	O
+involved	O
+in	O
+catalepsy	B
+,	O
+the	O
+D	O
+-	O
+1	O
+receptor	O
+may	O
+plan	O
+a	O
+role	O
+.	O
+
+Sustained	O
+clinical	O
+improvement	O
+of	O
+a	O
+patient	O
+with	O
+decompensated	O
+hepatitis	B
+B	I
+virus	O
+-	O
+related	O
+cirrhosis	B
+after	O
+treatment	O
+with	O
+lamivudine	O
+monotherapy	O
+.	O
+
+Hepatitis	B
+B	I
+virus	I
+(	I
+HBV	I
+)	I
+infection	I
+,	O
+which	O
+causes	O
+liver	B
+cirrhosis	I
+and	O
+hepatocellular	B
+carcinoma	I
+,	O
+remains	O
+a	O
+major	O
+health	O
+problem	O
+in	O
+Asian	O
+countries	O
+.	O
+
+Recent	O
+development	O
+of	O
+vaccine	O
+for	O
+prevention	O
+is	O
+reported	O
+to	O
+be	O
+successful	O
+in	O
+reducing	O
+the	O
+size	O
+of	O
+chronically	O
+infected	O
+carriers	O
+,	O
+although	O
+the	O
+standard	O
+medical	O
+therapies	O
+have	O
+not	O
+been	O
+established	O
+up	O
+to	O
+now	O
+.	O
+
+In	O
+this	O
+report	O
+,	O
+we	O
+encountered	O
+a	O
+patient	O
+with	O
+decompensated	O
+HBV	O
+-	O
+related	O
+cirrhosis	B
+who	O
+exhibited	O
+the	O
+dramatic	O
+improvements	O
+after	O
+antiviral	O
+therapy	O
+.	O
+
+The	O
+patient	O
+was	O
+a	O
+50	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+.	O
+
+Previous	O
+conventional	O
+medical	O
+treatments	O
+were	O
+not	O
+effective	O
+for	O
+this	O
+patient	O
+,	O
+thus	O
+this	O
+patient	O
+had	O
+been	O
+referred	O
+to	O
+our	O
+hospital	O
+.	O
+
+However	O
+,	O
+the	O
+administration	O
+of	O
+lamivudine	O
+,	O
+a	O
+reverse	O
+transcriptase	O
+inhibitor	O
+,	O
+for	O
+23	O
+months	O
+dramatically	O
+improved	O
+her	O
+liver	O
+severity	O
+.	O
+
+During	O
+this	O
+period	O
+,	O
+no	O
+drug	O
+resistant	O
+mutant	O
+HBV	O
+emerged	O
+,	O
+and	O
+the	O
+serum	O
+HBV	O
+-	O
+DNA	O
+level	O
+was	O
+continuously	O
+suppressed	O
+.	O
+
+These	O
+virological	O
+responses	O
+were	O
+also	O
+maintained	O
+even	O
+after	O
+the	O
+antiviral	O
+therapy	O
+was	O
+discontinued	O
+.	O
+
+Moreover	O
+,	O
+both	O
+hepatitis	O
+B	O
+surface	O
+antigen	O
+and	O
+e	O
+antigen	O
+were	O
+observed	O
+to	O
+have	O
+disappeared	O
+in	O
+this	O
+patient	O
+.	O
+
+The	O
+administration	O
+of	O
+lamivudine	O
+to	O
+patients	O
+with	O
+HBV	O
+-	O
+related	O
+cirrhosis	B
+,	O
+like	O
+our	O
+present	O
+case	O
+,	O
+should	O
+be	O
+considered	O
+as	O
+an	O
+initial	O
+medical	O
+therapeutic	O
+option	O
+,	O
+especially	O
+in	O
+countries	O
+where	O
+liver	O
+transplantation	O
+is	O
+not	O
+reliably	O
+available	O
+.	O
+
+Antiarrhythmic	O
+effects	O
+of	O
+optical	O
+isomers	O
+of	O
+cibenzoline	O
+on	O
+canine	O
+ventricular	B
+arrhythmias	I
+.	O
+
+Antiarrhythmic	O
+effects	O
+of	O
+(	O
++	O
+)	O
+-	O
+cibenzoline	O
+and	O
+(	O
+-	O
+)	O
+-	O
+cibenzoline	O
+were	O
+examined	O
+using	O
+two	O
+canine	O
+ventricular	B
+arrhythmia	I
+models	O
+.	O
+
+Digitalis	O
+arrhythmia	B
+,	O
+which	O
+is	O
+suppressed	O
+by	O
+Na	O
+channel	O
+blockers	O
+,	O
+was	O
+induced	O
+by	O
+intermittent	O
+intravenous	O
+(	O
+i	O
+.	O
+v	O
+.	O
+)	O
+injection	O
+of	O
+ouabain	O
+in	O
+pentobarbital	O
+-	O
+anesthetized	O
+dogs	O
+.	O
+
+Adrenaline	B
+arrhythmia	I
+,	O
+which	O
+is	O
+suppressed	O
+by	O
+Ca	O
+channel	O
+blockers	O
+,	O
+was	O
+induced	O
+by	O
+adrenaline	O
+infusion	O
+in	O
+halothane	O
+-	O
+anesthetized	O
+dogs	O
+.	O
+
+Ten	O
+and	O
+5	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+(	O
++	O
+)	O
+-	O
+cibenzoline	O
+suppressed	O
+digitalis	O
+-	O
+and	O
+adrenaline	O
+-	O
+induced	O
+arrhythmias	B
+,	O
+respectively	O
+.	O
+
+The	O
+minimum	O
+effective	O
+plasma	O
+concentrations	O
+of	O
+(	O
++	O
+)	O
+-	O
+cibenzoline	O
+for	O
+digitalis	O
+-	O
+and	O
+adrenaline	O
+-	O
+induced	O
+arrhythmias	B
+were	O
+1	O
+.	O
+4	O
++	O
+/	O
+-	O
+0	O
+.	O
+4	O
+and	O
+2	O
+.	O
+0	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+micrograms	O
+/	O
+ml	O
+,	O
+respectively	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+,	O
+n	O
+=	O
+6	O
+)	O
+.	O
+
+A	O
+lower	O
+dose	O
+of	O
+1	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+of	O
+(	O
+-	O
+)	O
+-	O
+cibenzoline	O
+suppressed	O
+the	O
+digitalis	O
+-	O
+induced	O
+arrhythmia	B
+,	O
+whereas	O
+5	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+was	O
+needed	O
+to	O
+suppress	O
+adrenaline	O
+-	O
+induced	O
+arrhythmias	B
+.	O
+
+The	O
+minimum	O
+effective	O
+plasma	O
+concentrations	O
+of	O
+(	O
+-	O
+)	O
+-	O
+cibenzoline	O
+for	O
+digitalis	O
+-	O
+and	O
+adrenaline	O
+-	O
+induced	O
+arrhythmia	B
+were	O
+0	O
+.	O
+06	O
++	O
+/	O
+-	O
+0	O
+.	O
+04	O
+and	O
+0	O
+.	O
+7	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+micrograms	O
+/	O
+ml	O
+,	O
+respectively	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+,	O
+n	O
+=	O
+6	O
+)	O
+.	O
+
+The	O
+stronger	O
+antiarrhythmic	O
+effect	O
+of	O
+(	O
+-	O
+)	O
+-	O
+cibenzoline	O
+indicates	O
+that	O
+(	O
+-	O
+)	O
+-	O
+isomer	O
+may	O
+have	O
+an	O
+effect	O
+nearly	O
+5	O
+-	O
+20	O
+times	O
+stronger	O
+in	O
+suppressing	O
+Na	O
+channels	O
+,	O
+but	O
+effects	O
+of	O
+both	O
+drugs	O
+on	O
+Ca	O
+channels	O
+may	O
+be	O
+almost	O
+equipotent	O
+.	O
+
+Passage	O
+of	O
+mannitol	O
+into	O
+the	O
+brain	O
+around	O
+gliomas	B
+:	O
+a	O
+potential	O
+cause	O
+of	O
+rebound	O
+phenomenon	O
+.	O
+
+A	O
+study	O
+on	O
+21	O
+patients	O
+.	O
+
+AIM	O
+:	O
+Widespread	O
+use	O
+of	O
+mannitol	O
+to	O
+reduce	O
+brain	B
+edema	I
+and	O
+lower	O
+elevated	B
+ICP	I
+in	O
+brain	B
+tumor	I
+patients	O
+continues	O
+to	O
+be	O
+afflicted	O
+by	O
+the	O
+so	O
+-	O
+called	O
+rebound	O
+phenomenon	O
+.	O
+
+Leakage	O
+of	O
+mannitol	O
+into	O
+the	O
+brain	O
+parenchyma	O
+through	O
+an	O
+altered	O
+BBB	O
+and	O
+secondary	O
+reversal	O
+of	O
+osmotic	O
+gradient	O
+is	O
+considered	O
+the	O
+major	O
+cause	O
+of	O
+rebound	O
+.	O
+
+This	O
+has	O
+only	O
+been	O
+demonstrated	O
+experimentally	O
+in	O
+animals	O
+.	O
+
+As	O
+a	O
+contribution	O
+to	O
+this	O
+issue	O
+we	O
+decided	O
+to	O
+research	O
+the	O
+possible	O
+passage	O
+of	O
+mannitol	O
+into	O
+the	O
+brain	O
+after	O
+administration	O
+to	O
+21	O
+brain	B
+tumor	I
+patients	O
+.	O
+
+METHODS	O
+:	O
+Mannitol	O
+(	O
+18	O
+%	O
+solution	O
+;	O
+1	O
+g	O
+/	O
+kg	O
+)	O
+was	O
+administered	O
+as	O
+a	O
+bolus	O
+to	O
+patients	O
+(	O
+ten	O
+had	O
+malignant	B
+glioma	I
+,	O
+seven	O
+brain	O
+metastases	B
+and	O
+four	O
+meningioma	B
+)	O
+about	O
+30	O
+minutes	O
+before	O
+craniotomy	O
+.	O
+
+During	O
+resection	O
+,	O
+a	O
+sample	O
+of	O
+the	O
+surrounding	O
+edematous	B
+white	O
+matter	O
+was	O
+taken	O
+at	O
+the	O
+same	O
+time	O
+as	O
+a	O
+10	O
+ml	O
+venous	O
+blood	O
+sample	O
+.	O
+
+Mannitol	O
+concentrations	O
+were	O
+measured	O
+in	O
+plasma	O
+and	O
+white	O
+matter	O
+by	O
+a	O
+modified	O
+version	O
+of	O
+the	O
+enzyme	O
+assay	O
+of	O
+Blonquist	O
+et	O
+al	O
+.	O
+
+RESULTS	O
+:	O
+In	O
+most	O
+glioma	B
+patients	O
+,	O
+mannitol	O
+concentrations	O
+in	O
+white	O
+matter	O
+were	O
+2	O
+to	O
+6	O
+times	O
+higher	O
+than	O
+in	O
+plasma	O
+(	O
+mean	O
+3	O
+.	O
+5	O
+times	O
+)	O
+.	O
+
+In	O
+meningioma	B
+and	O
+metastases	B
+patients	O
+plasma	O
+concentrations	O
+of	O
+mannitol	O
+were	O
+higher	O
+than	O
+white	O
+matter	O
+concentrations	O
+except	O
+in	O
+three	O
+cases	O
+with	O
+infiltration	O
+by	O
+neoplastic	O
+cells	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+results	O
+of	O
+our	O
+study	O
+show	O
+that	O
+even	O
+after	O
+a	O
+single	O
+bolus	O
+,	O
+mannitol	O
+may	O
+leak	O
+through	O
+the	O
+altered	O
+BBB	O
+near	O
+gliomas	B
+,	O
+reversing	O
+the	O
+initial	O
+plasma	O
+-	O
+to	O
+-	O
+blood	O
+osmotic	O
+gradient	O
+,	O
+aggravating	O
+peritumoral	O
+edema	B
+and	O
+promoting	O
+rebound	O
+of	O
+ICP	O
+.	O
+
+Placebo	O
+-	O
+level	O
+incidence	O
+of	O
+extrapyramidal	B
+symptoms	I
+(	O
+EPS	B
+)	O
+with	O
+quetiapine	O
+in	O
+controlled	O
+studies	O
+of	O
+patients	O
+with	O
+bipolar	B
+mania	I
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+evaluate	O
+extrapyramidal	B
+symptoms	I
+(	O
+EPS	B
+)	O
+,	O
+including	O
+akathisia	B
+,	O
+with	O
+quetiapine	O
+in	O
+patients	O
+with	O
+bipolar	B
+mania	I
+.	O
+
+METHODS	O
+:	O
+Data	O
+were	O
+analyzed	O
+from	O
+four	O
+similarly	O
+designed	O
+,	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+3	O
+-	O
+to	O
+12	O
+-	O
+week	O
+studies	O
+.	O
+
+Two	O
+studies	O
+evaluated	O
+quetiapine	O
+monotherapy	O
+(	O
+up	O
+to	O
+800	O
+mg	O
+/	O
+day	O
+)	O
+(	O
+n	O
+=	O
+209	O
+)	O
+versus	O
+placebo	O
+(	O
+n	O
+=	O
+198	O
+)	O
+,	O
+with	O
+lithium	O
+or	O
+haloperidol	O
+monotherapy	O
+as	O
+respective	O
+active	O
+controls	O
+.	O
+
+Two	O
+studies	O
+evaluated	O
+quetiapine	O
+(	O
+up	O
+to	O
+800	O
+mg	O
+/	O
+day	O
+)	O
+in	O
+combination	O
+with	O
+a	O
+mood	O
+stabilizer	O
+(	O
+lithium	O
+or	O
+divalproex	O
+,	O
+QTP	O
++	O
+Li	O
+/	O
+DVP	O
+)	O
+(	O
+n	O
+=	O
+196	O
+)	O
+compared	O
+to	O
+placebo	O
+and	O
+mood	O
+stabilizer	O
+(	O
+PBO	O
++	O
+Li	O
+/	O
+DVP	O
+)	O
+(	O
+n	O
+=	O
+203	O
+)	O
+.	O
+
+Extrapyramidal	B
+symptoms	I
+were	O
+evaluated	O
+using	O
+the	O
+Simpson	O
+-	O
+Angus	O
+Scale	O
+(	O
+SAS	O
+)	O
+,	O
+the	O
+Barnes	O
+Akathisia	O
+Rating	O
+Scale	O
+(	O
+BARS	O
+)	O
+,	O
+adverse	O
+event	O
+reports	O
+and	O
+anticholinergic	O
+drug	O
+usage	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+incidence	O
+of	O
+EPS	B
+-	O
+related	O
+adverse	O
+events	O
+,	O
+including	O
+akathisia	B
+,	O
+was	O
+no	O
+different	O
+with	O
+quetiapine	O
+monotherapy	O
+(	O
+12	O
+.	O
+9	O
+%	O
+)	O
+than	O
+with	O
+placebo	O
+(	O
+13	O
+.	O
+1	O
+%	O
+)	O
+.	O
+
+Similarly	O
+,	O
+EPS	B
+-	O
+related	O
+adverse	O
+events	O
+with	O
+QTP	O
++	O
+Li	O
+/	O
+DVP	O
+(	O
+21	O
+.	O
+4	O
+%	O
+)	O
+were	O
+no	O
+different	O
+than	O
+with	O
+PBO	O
++	O
+Li	O
+/	O
+DVP	O
+(	O
+19	O
+.	O
+2	O
+%	O
+)	O
+.	O
+
+Adverse	O
+events	O
+related	O
+to	O
+EPS	B
+occurred	O
+in	O
+59	O
+.	O
+6	O
+%	O
+of	O
+patients	O
+treated	O
+with	O
+haloperidol	O
+(	O
+n	O
+=	O
+99	O
+)	O
+monotherapy	O
+,	O
+whereas	O
+26	O
+.	O
+5	O
+%	O
+of	O
+patients	O
+treated	O
+with	O
+lithium	O
+(	O
+n	O
+=	O
+98	O
+)	O
+monotherapy	O
+experienced	O
+adverse	O
+events	O
+related	O
+to	O
+EPS	B
+.	O
+
+The	O
+incidence	O
+of	O
+akathisia	B
+was	O
+low	O
+and	O
+similar	O
+with	O
+quetiapine	O
+monotherapy	O
+(	O
+3	O
+.	O
+3	O
+%	O
+)	O
+and	O
+placebo	O
+(	O
+6	O
+.	O
+1	O
+%	O
+)	O
+,	O
+and	O
+with	O
+QTP	O
++	O
+Li	O
+/	O
+DVP	O
+(	O
+3	O
+.	O
+6	O
+%	O
+)	O
+and	O
+PBO	O
++	O
+Li	O
+/	O
+DVP	O
+(	O
+4	O
+.	O
+9	O
+%	O
+)	O
+.	O
+
+Lithium	O
+was	O
+associated	O
+with	O
+a	O
+significantly	O
+higher	O
+incidence	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+of	O
+tremor	B
+(	O
+18	O
+.	O
+4	O
+%	O
+)	O
+than	O
+quetiapine	O
+(	O
+5	O
+.	O
+6	O
+%	O
+)	O
+;	O
+cerebellar	O
+tremor	B
+,	O
+which	O
+is	O
+a	O
+known	O
+adverse	O
+effect	O
+of	O
+lithium	O
+,	O
+may	O
+have	O
+contributed	O
+to	O
+the	O
+elevated	O
+rate	O
+of	O
+tremor	B
+in	O
+patients	O
+receiving	O
+lithium	O
+therapy	O
+.	O
+
+Haloperidol	O
+induced	O
+a	O
+significantly	O
+higher	O
+incidence	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+of	O
+akathisia	B
+(	O
+33	O
+.	O
+3	O
+%	O
+versus	O
+5	O
+.	O
+9	O
+%	O
+)	O
+,	O
+tremor	B
+(	O
+30	O
+.	O
+3	O
+%	O
+versus	O
+7	O
+.	O
+8	O
+%	O
+)	O
+,	O
+and	O
+extrapyramidal	B
+syndrome	I
+(	O
+35	O
+.	O
+4	O
+%	O
+versus	O
+5	O
+.	O
+9	O
+%	O
+)	O
+than	O
+quetiapine	O
+.	O
+
+No	O
+significant	O
+differences	O
+were	O
+observed	O
+between	O
+quetiapine	O
+and	O
+placebo	O
+on	O
+SAS	O
+and	O
+BARS	O
+scores	O
+.	O
+
+Anticholinergic	O
+use	O
+was	O
+low	O
+and	O
+similar	O
+with	O
+quetiapine	O
+or	O
+placebo	O
+.	O
+
+CONCLUSIONS	O
+:	O
+In	O
+bipolar	B
+mania	I
+,	O
+the	O
+incidence	O
+of	O
+EPS	B
+,	O
+including	O
+akathisia	B
+,	O
+with	O
+quetiapine	O
+therapy	O
+is	O
+similar	O
+to	O
+that	O
+with	O
+placebo	O
+.	O
+
+Is	O
+phenytoin	O
+administration	O
+safe	O
+in	O
+a	O
+hypothermic	B
+child	O
+?	O
+
+A	O
+male	O
+neonate	O
+with	O
+a	O
+Chiari	B
+malformation	I
+and	O
+a	O
+leaking	O
+myelomeningocoele	O
+underwent	O
+ventriculoperitoneal	O
+shunt	O
+insertion	O
+followed	O
+by	O
+repair	O
+of	O
+myelomeningocoele	O
+.	O
+
+During	O
+anaesthesia	O
+and	O
+surgery	O
+,	O
+he	O
+inadvertently	O
+became	O
+moderately	O
+hypothermic	B
+.	O
+
+Intravenous	O
+phenytoin	O
+was	O
+administered	O
+during	O
+the	O
+later	O
+part	O
+of	O
+the	O
+surgery	O
+for	O
+seizure	B
+prophylaxis	O
+.	O
+
+Following	O
+phenytoin	O
+administration	O
+,	O
+the	O
+patient	O
+developed	O
+acute	O
+severe	O
+bradycardia	B
+,	O
+refractory	O
+to	O
+atropine	O
+and	O
+adrenaline	O
+.	O
+
+The	O
+cardiac	O
+depressant	O
+actions	O
+of	O
+phenytoin	O
+and	O
+hypothermia	B
+can	O
+be	O
+additive	O
+.	O
+
+Administration	O
+of	O
+phenytoin	O
+in	O
+the	O
+presence	O
+of	O
+hypothermia	B
+may	O
+lead	O
+to	O
+an	O
+adverse	O
+cardiac	O
+event	O
+in	O
+children	O
+.	O
+
+As	O
+phenytoin	O
+is	O
+a	O
+commonly	O
+used	O
+drug	O
+,	O
+clinicians	O
+need	O
+to	O
+be	O
+aware	O
+of	O
+this	O
+interaction	O
+.	O
+
+Valproate	O
+-	O
+induced	O
+chorea	B
+and	O
+encephalopathy	B
+in	O
+atypical	O
+nonketotic	B
+hyperglycinemia	I
+.	O
+
+Nonketotic	B
+hyperglycinemia	I
+is	O
+a	O
+disorder	B
+of	I
+amino	I
+acid	I
+metabolism	I
+in	O
+which	O
+a	O
+defect	O
+in	O
+the	O
+glycine	O
+cleavage	O
+system	O
+leads	O
+to	O
+an	O
+accumulation	O
+of	O
+glycine	O
+in	O
+the	O
+brain	O
+and	O
+other	O
+body	O
+compartments	O
+.	O
+
+In	O
+the	O
+classical	O
+form	O
+it	O
+presents	O
+as	O
+neonatal	O
+apnea	B
+,	O
+intractable	O
+seizures	B
+,	O
+and	O
+hypotonia	B
+,	O
+followed	O
+by	O
+significant	O
+psychomotor	B
+retardation	I
+.	O
+
+An	O
+important	O
+subset	O
+of	O
+children	O
+with	O
+nonketotic	B
+hyperglycinemia	I
+are	O
+atypical	O
+variants	O
+who	O
+present	O
+in	O
+a	O
+heterogeneous	O
+manner	O
+.	O
+
+This	O
+report	O
+describes	O
+a	O
+patient	O
+with	O
+mild	O
+language	B
+delay	I
+and	O
+mental	B
+retardation	I
+,	O
+who	O
+was	O
+found	O
+to	O
+have	O
+nonketotic	B
+hyperglycinemia	I
+following	O
+her	O
+presentation	O
+with	O
+acute	O
+encephalopathy	B
+and	O
+chorea	B
+shortly	O
+after	O
+initiation	O
+of	O
+valproate	O
+therapy	O
+.	O
+
+Delayed	O
+institution	O
+of	O
+hypertension	B
+during	O
+focal	O
+cerebral	B
+ischemia	I
+:	O
+effect	O
+on	O
+brain	B
+edema	I
+.	O
+
+The	O
+effect	O
+of	O
+induced	O
+hypertension	B
+instituted	O
+after	O
+a	O
+2	O
+-	O
+h	O
+delay	O
+following	O
+middle	B
+cerebral	I
+artery	I
+occlusion	I
+(	O
+MCAO	B
+)	O
+on	O
+brain	B
+edema	I
+formation	O
+and	O
+histochemical	O
+injury	O
+was	O
+studied	O
+.	O
+
+Under	O
+isoflurane	O
+anesthesia	O
+,	O
+the	O
+MCA	O
+of	O
+14	O
+spontaneously	O
+hypertensive	B
+rats	O
+was	O
+occluded	O
+.	O
+
+In	O
+the	O
+control	O
+group	O
+(	O
+n	O
+=	O
+7	O
+)	O
+,	O
+the	O
+mean	O
+arterial	O
+pressure	O
+(	O
+MAP	O
+)	O
+was	O
+not	O
+manipulated	O
+.	O
+
+In	O
+the	O
+hypertensive	B
+group	O
+(	O
+n	O
+=	O
+7	O
+)	O
+,	O
+the	O
+MAP	O
+was	O
+elevated	O
+by	O
+25	O
+-	O
+30	O
+mm	O
+Hg	O
+beginning	O
+2	O
+h	O
+after	O
+MCAO	B
+.	O
+
+Four	O
+hours	O
+after	O
+MCAO	B
+,	O
+the	O
+rats	O
+were	O
+killed	O
+and	O
+the	O
+brains	O
+harvested	O
+.	O
+
+The	O
+brains	O
+were	O
+sectioned	O
+along	O
+coronal	O
+planes	O
+spanning	O
+the	O
+distribution	O
+of	O
+ischemia	B
+produced	O
+by	O
+MCAO	B
+.	O
+
+Specific	O
+gravity	O
+(	O
+SG	O
+)	O
+was	O
+determined	O
+in	O
+the	O
+subcortex	O
+and	O
+in	O
+two	O
+sites	O
+in	O
+the	O
+cortex	O
+(	O
+core	O
+and	O
+periphery	O
+of	O
+the	O
+ischemic	B
+territory	O
+)	O
+.	O
+
+The	O
+extent	O
+of	O
+neuronal	B
+injury	I
+was	O
+determined	O
+by	O
+2	O
+,	O
+3	O
+,	O
+5	O
+-	O
+triphenyltetrazolium	O
+staining	O
+.	O
+
+In	O
+the	O
+ischemic	B
+core	O
+,	O
+there	O
+was	O
+no	O
+difference	O
+in	O
+SG	O
+in	O
+the	O
+subcortex	O
+and	O
+cortex	O
+in	O
+the	O
+two	O
+groups	O
+.	O
+
+In	O
+the	O
+periphery	O
+of	O
+the	O
+ischemic	B
+territory	O
+,	O
+SG	O
+in	O
+the	O
+cortex	O
+was	O
+greater	O
+(	O
+less	O
+edema	B
+accumulation	O
+)	O
+in	O
+the	O
+hypertensive	B
+group	O
+(	O
+1	O
+.	O
+041	O
++	O
+/	O
+-	O
+0	O
+.	O
+001	O
+vs	O
+1	O
+.	O
+039	O
++	O
+/	O
+-	O
+0	O
+.	O
+001	O
+,	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+area	O
+of	O
+histochemical	O
+injury	O
+(	O
+as	O
+a	O
+percent	O
+of	O
+the	O
+cross	O
+-	O
+sectional	O
+area	O
+of	O
+the	O
+hemisphere	O
+)	O
+was	O
+less	O
+in	O
+the	O
+hypertensive	B
+group	O
+(	O
+33	O
++	O
+/	O
+-	O
+3	O
+%	O
+vs	O
+21	O
++	O
+/	O
+-	O
+2	O
+%	O
+,	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+data	O
+indicate	O
+that	O
+phenylephrine	O
+-	O
+induced	O
+hypertension	B
+instituted	O
+2	O
+h	O
+after	O
+MCAO	B
+does	O
+not	O
+aggravate	O
+edema	B
+in	O
+the	O
+ischemic	B
+core	O
+,	O
+that	O
+it	O
+improves	O
+edema	B
+in	O
+the	O
+periphery	O
+of	O
+the	O
+ischemic	B
+territory	O
+,	O
+and	O
+that	O
+it	O
+reduces	O
+the	O
+area	O
+of	O
+histochemical	O
+neuronal	B
+dysfunction	I
+.	O
+
+Behavioral	O
+effects	O
+of	O
+pubertal	O
+anabolic	O
+androgenic	O
+steroid	O
+exposure	O
+in	O
+male	O
+rats	O
+with	O
+low	O
+serotonin	O
+.	O
+
+The	O
+goal	O
+of	O
+this	O
+study	O
+was	O
+to	O
+assess	O
+the	O
+interactive	O
+effects	O
+of	O
+chronic	O
+anabolic	O
+androgenic	O
+steroid	O
+(	O
+AAS	O
+)	O
+exposure	O
+and	O
+brain	O
+serotonin	O
+(	O
+5	O
+-	O
+hydroxytryptamine	O
+,	O
+5	O
+-	O
+HT	O
+)	O
+depletion	O
+on	O
+behavior	O
+of	O
+pubertal	O
+male	O
+rats	O
+.	O
+
+Serotonin	O
+was	O
+depleted	O
+beginning	O
+on	O
+postnatal	O
+day	O
+26	O
+with	O
+parachlorophenylalanine	O
+(	O
+PCPA	O
+100	O
+mg	O
+/	O
+kg	O
+,	O
+every	O
+other	O
+day	O
+)	O
+;	O
+controls	O
+received	O
+saline	O
+.	O
+
+At	O
+puberty	O
+(	O
+P40	O
+)	O
+,	O
+half	O
+the	O
+PCPA	O
+-	O
+treated	O
+rats	O
+and	O
+half	O
+the	O
+saline	O
+-	O
+treated	O
+rats	O
+began	O
+treatment	O
+with	O
+testosterone	O
+(	O
+T	O
+,	O
+5	O
+mg	O
+/	O
+kg	O
+,	O
+5	O
+days	O
+/	O
+week	O
+)	O
+.	O
+
+Behavioral	O
+measures	O
+included	O
+locomotion	O
+,	O
+irritability	B
+,	O
+copulation	O
+,	O
+partner	O
+preference	O
+,	O
+and	O
+aggression	B
+.	O
+
+Animals	O
+were	O
+tested	O
+for	O
+aggression	B
+in	O
+their	O
+home	O
+cage	O
+,	O
+both	O
+with	O
+and	O
+without	O
+physical	O
+provocation	O
+(	O
+mild	O
+tail	O
+pinch	O
+)	O
+.	O
+
+Brain	O
+levels	O
+of	O
+5	O
+-	O
+HT	O
+and	O
+its	O
+metabolite	O
+,	O
+5	O
+-	O
+hydroxyindoleacetic	O
+acid	O
+(	O
+5	O
+-	O
+HIAA	O
+)	O
+,	O
+were	O
+determined	O
+using	O
+HPLC	O
+.	O
+
+PCPA	O
+significantly	O
+and	O
+substantially	O
+depleted	O
+5	O
+-	O
+HT	O
+and	O
+5	O
+-	O
+HIAA	O
+in	O
+all	O
+brain	O
+regions	O
+examined	O
+.	O
+
+Chronic	O
+T	O
+treatment	O
+significantly	O
+decreased	O
+5	O
+-	O
+HT	O
+and	O
+5	O
+-	O
+HIAA	O
+in	O
+certain	O
+brain	O
+areas	O
+,	O
+but	O
+to	O
+a	O
+much	O
+lesser	O
+extent	O
+than	O
+PCPA	O
+.	O
+
+Chronic	O
+exposure	O
+to	O
+PCPA	O
+alone	O
+significantly	O
+decreased	O
+locomotor	O
+activity	O
+and	O
+increased	O
+irritability	B
+but	O
+had	O
+no	O
+effect	O
+on	O
+sexual	O
+behavior	O
+,	O
+partner	O
+preference	O
+,	O
+or	O
+aggression	B
+.	O
+
+T	O
+alone	O
+had	O
+no	O
+effect	O
+on	O
+locomotion	O
+,	O
+irritability	B
+,	O
+or	O
+sexual	O
+behavior	O
+but	O
+increased	O
+partner	O
+preference	O
+and	O
+aggression	B
+.	O
+
+The	O
+most	O
+striking	O
+effect	O
+of	O
+combining	O
+T	O
++	O
+PCPA	O
+was	O
+a	O
+significant	O
+increase	O
+in	O
+attack	O
+frequency	O
+as	O
+well	O
+as	O
+a	O
+significant	O
+decrease	O
+in	O
+the	O
+latency	O
+to	O
+attack	O
+,	O
+particularly	O
+following	O
+physical	O
+provocation	O
+.	O
+
+Based	O
+on	O
+these	O
+data	O
+,	O
+it	O
+can	O
+be	O
+speculated	O
+that	O
+pubertal	O
+AAS	O
+users	O
+with	O
+low	O
+central	O
+5	O
+-	O
+HT	O
+may	O
+be	O
+especially	O
+prone	O
+to	O
+exhibit	O
+aggressive	B
+behavior	I
+.	O
+
+Effects	O
+of	O
+UMB24	O
+and	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+SM	O
+21	O
+,	O
+putative	O
+sigma2	O
+-	O
+preferring	O
+antagonists	O
+,	O
+on	O
+behavioral	O
+toxic	O
+and	O
+stimulant	O
+effects	O
+of	O
+cocaine	O
+in	O
+mice	O
+.	O
+
+Earlier	O
+studies	O
+have	O
+demonstrated	O
+that	O
+antagonism	O
+of	O
+sigma1	O
+receptors	O
+attenuates	O
+the	O
+convulsive	B
+,	O
+lethal	O
+,	O
+locomotor	O
+stimulatory	O
+and	O
+rewarding	O
+actions	O
+of	O
+cocaine	O
+in	O
+mice	O
+.	O
+
+In	O
+contrast	O
+,	O
+the	O
+contribution	O
+of	O
+sigma2	O
+receptors	O
+is	O
+unclear	O
+because	O
+experimental	O
+tools	O
+to	O
+selectively	O
+target	O
+this	O
+subtype	O
+are	O
+unavailable	O
+.	O
+
+To	O
+begin	O
+addressing	O
+this	O
+need	O
+,	O
+we	O
+characterized	O
+UMB24	O
+(	O
+1	O
+-	O
+(	O
+2	O
+-	O
+phenethyl	O
+)	O
+-	O
+4	O
+-	O
+(	O
+2	O
+-	O
+pyridyl	O
+)	O
+-	O
+piperazine	O
+)	O
+and	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+SM	O
+21	O
+(	O
+3alpha	O
+-	O
+tropanyl	O
+-	O
+2	O
+-	O
+(	O
+4	O
+-	O
+chorophenoxy	O
+)	O
+butyrate	O
+)	O
+in	O
+receptor	O
+binding	O
+and	O
+behavioral	O
+studies	O
+.	O
+
+Receptor	O
+binding	O
+studies	O
+confirmed	O
+that	O
+UMB24	O
+and	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+SM	O
+21	O
+display	O
+preferential	O
+affinity	O
+for	O
+sigma2	O
+over	O
+sigma1	O
+receptors	O
+.	O
+
+In	O
+behavioral	O
+studies	O
+,	O
+pretreatment	O
+of	O
+Swiss	O
+Webster	O
+mice	O
+with	O
+UMB24	O
+or	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+SM	O
+21	O
+significantly	O
+attenuated	O
+cocaine	O
+-	O
+induced	O
+convulsions	B
+and	O
+locomotor	O
+activity	O
+,	O
+but	O
+not	O
+lethality	O
+.	O
+
+When	O
+administered	O
+alone	O
+,	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+SM	O
+21	O
+produced	O
+no	O
+significant	O
+effects	O
+compared	O
+to	O
+control	O
+injections	O
+of	O
+saline	O
+,	O
+but	O
+UMB24	O
+had	O
+locomotor	O
+depressant	O
+actions	O
+.	O
+
+Together	O
+,	O
+the	O
+data	O
+suggest	O
+that	O
+sigma2	O
+receptor	O
+antagonists	O
+have	O
+the	O
+potential	O
+to	O
+attenuate	O
+some	O
+of	O
+the	O
+behavioral	O
+effects	O
+of	O
+cocaine	O
+,	O
+and	O
+further	O
+development	O
+of	O
+more	O
+selective	O
+,	O
+high	O
+affinity	O
+ligands	O
+are	O
+warranted	O
+.	O
+
+Cardiac	B
+arrest	I
+in	O
+a	O
+child	O
+with	O
+cerebral	B
+palsy	I
+undergoing	O
+sevoflurane	O
+induction	O
+of	O
+anesthesia	O
+after	O
+preoperative	O
+clonidine	O
+.	O
+
+Clonidine	O
+is	O
+a	O
+frequently	O
+administered	O
+alpha2	O
+-	O
+adrenergic	O
+agonist	O
+which	O
+can	O
+decrease	O
+heart	O
+rate	O
+and	O
+blood	O
+pressure	O
+.	O
+
+We	O
+present	O
+a	O
+case	O
+of	O
+a	O
+5	O
+-	O
+year	O
+-	O
+old	O
+child	O
+with	O
+cerebral	B
+palsy	I
+and	O
+seizure	B
+disorder	I
+,	O
+receiving	O
+clonidine	O
+for	O
+restlessness	B
+,	O
+who	O
+presented	O
+for	O
+placement	O
+of	O
+a	O
+baclofen	O
+pump	O
+.	O
+
+Without	O
+the	O
+knowledge	O
+of	O
+the	O
+medical	O
+personnel	O
+,	O
+the	O
+patient	O
+'	O
+s	O
+mother	O
+administered	O
+three	O
+doses	O
+of	O
+clonidine	O
+during	O
+the	O
+evening	O
+before	O
+and	O
+morning	O
+of	O
+surgery	O
+to	O
+reduce	O
+anxiety	B
+.	O
+
+During	O
+induction	O
+of	O
+anesthesia	O
+,	O
+the	O
+patient	O
+developed	O
+bradycardia	B
+and	O
+hypotension	B
+requiring	O
+cardiac	O
+resuscitation	O
+.	O
+
+There	O
+are	O
+no	O
+previous	O
+reports	O
+of	O
+clonidine	O
+-	O
+associated	O
+cardiac	B
+arrest	I
+in	O
+a	O
+child	O
+undergoing	O
+induction	O
+of	O
+anesthesia	O
+.	O
+
+Angiotensin	O
+-	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+inhibitor	O
+-	O
+associated	O
+angioedema	B
+of	O
+the	O
+stomach	O
+and	O
+small	O
+intestine	O
+:	O
+a	O
+case	O
+report	O
+.	O
+
+This	O
+is	O
+a	O
+case	O
+report	O
+on	O
+a	O
+45	O
+-	O
+year	O
+old	O
+African	O
+-	O
+American	O
+female	O
+with	O
+newly	O
+diagnosed	O
+hypertension	B
+,	O
+who	O
+was	O
+started	O
+on	O
+a	O
+combination	O
+pill	O
+of	O
+amlodipine	O
+/	O
+benazapril	O
+10	O
+/	O
+5	O
+mg	O
+.	O
+
+The	O
+very	O
+next	O
+day	O
+,	O
+she	O
+presented	O
+at	O
+the	O
+emergency	O
+room	O
+(	O
+ER	O
+)	O
+with	O
+abdominal	B
+pain	I
+,	O
+nausea	B
+and	O
+vomiting	B
+.	O
+
+Physical	O
+exam	O
+,	O
+complete	O
+metabolic	O
+panel	O
+,	O
+and	O
+hemogram	O
+were	O
+in	O
+the	O
+normal	O
+range	O
+.	O
+
+She	O
+was	O
+discharged	O
+from	O
+the	O
+ER	O
+after	O
+a	O
+few	O
+hours	O
+of	O
+treatment	O
+with	O
+fluid	O
+and	O
+analgesics	O
+.	O
+
+However	O
+,	O
+she	O
+returned	O
+to	O
+the	O
+ER	O
+the	O
+next	O
+day	O
+with	O
+the	O
+same	O
+complaints	O
+.	O
+
+This	O
+time	O
+the	O
+physical	O
+exam	O
+was	O
+significant	O
+for	O
+a	O
+distended	O
+abdomen	O
+with	O
+dullness	O
+to	O
+percussion	O
+.	O
+
+CT	O
+scan	O
+of	O
+the	O
+abdomen	O
+revealed	O
+markedly	O
+thickened	O
+antrum	O
+of	O
+the	O
+stomach	O
+,	O
+duodenum	O
+and	O
+jejunum	O
+,	O
+along	O
+with	O
+fluid	O
+in	O
+the	O
+abdominal	O
+and	O
+pelvic	O
+cavity	O
+.	O
+
+Angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitor	O
+(	O
+ACEI	O
+)	O
+-	O
+induced	O
+angioedema	B
+was	O
+suspected	O
+,	O
+and	O
+anti	O
+-	O
+hypertensive	B
+medications	O
+were	O
+discontinued	O
+.	O
+
+Her	O
+symptoms	O
+improved	O
+within	O
+the	O
+next	O
+24	O
+hours	O
+,	O
+and	O
+repeat	O
+CT	O
+after	O
+72	O
+hours	O
+revealed	O
+marked	O
+improvement	O
+in	O
+stomach	O
+and	O
+small	O
+bowel	O
+thickening	O
+and	O
+resolution	O
+of	O
+ascites	B
+.	O
+
+The	O
+recognition	O
+of	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+and	O
+angiotensin	O
+receptor	O
+blocker	O
+(	O
+ARB	O
+)	O
+intestinal	B
+angioedema	I
+constitutes	O
+a	O
+challenge	O
+to	O
+primary	O
+care	O
+physicians	O
+,	O
+internists	O
+,	O
+emergency	O
+room	O
+personal	O
+and	O
+surgeons	O
+.	O
+
+Carbamazepine	O
+-	O
+induced	O
+cardiac	B
+dysfunction	I
+.	O
+
+Characterization	O
+of	O
+two	O
+distinct	O
+clinical	O
+syndromes	O
+.	O
+
+A	O
+patient	O
+with	O
+sinus	O
+bradycardia	B
+and	O
+atrioventricular	B
+block	I
+,	O
+induced	O
+by	O
+carbamazepine	O
+,	O
+prompted	O
+an	O
+extensive	O
+literature	O
+review	O
+of	O
+all	O
+previously	O
+reported	O
+cases	O
+.	O
+
+From	O
+the	O
+analysis	O
+of	O
+these	O
+cases	O
+,	O
+two	O
+distinct	O
+forms	O
+of	O
+carbamazepine	O
+-	O
+associated	O
+cardiac	B
+dysfunction	I
+emerged	O
+.	O
+
+One	O
+patient	O
+group	O
+developed	O
+sinus	B
+tachycardias	I
+in	O
+the	O
+setting	O
+of	O
+a	O
+massive	O
+carbamazepine	O
+overdose	B
+.	O
+
+The	O
+second	O
+group	O
+consisted	O
+almost	O
+exclusively	O
+of	O
+elderly	O
+women	O
+who	O
+developed	O
+potentially	O
+life	O
+-	O
+threatening	O
+bradyarrhythmias	B
+or	O
+atrioventricular	B
+conduction	I
+delay	I
+,	O
+associated	O
+with	O
+either	O
+therapeutic	O
+or	O
+modestly	O
+elevated	O
+carbamazepine	O
+serum	O
+levels	O
+.	O
+
+Because	O
+carbamazepine	O
+is	O
+widely	O
+used	O
+in	O
+the	O
+treatment	O
+of	O
+many	O
+neurologic	O
+and	O
+psychiatric	B
+conditions	O
+,	O
+the	O
+recognition	O
+of	O
+the	O
+latter	O
+syndrome	O
+has	O
+important	O
+implications	O
+for	O
+the	O
+use	O
+of	O
+this	O
+drug	O
+in	O
+elderly	O
+patients	O
+.	O
+
+Detection	O
+of	O
+abnormal	O
+cardiac	O
+adrenergic	O
+neuron	O
+activity	O
+in	O
+adriamycin	O
+-	O
+induced	O
+cardiomyopathy	B
+with	O
+iodine	O
+-	O
+125	O
+-	O
+metaiodobenzylguanidine	O
+.	O
+
+Radiolabeled	O
+metaiodobenzylguanidine	O
+(	O
+MIBG	O
+)	O
+,	O
+an	O
+analog	O
+of	O
+norepinephrine	O
+(	O
+NE	O
+)	O
+,	O
+serves	O
+as	O
+an	O
+index	O
+of	O
+adrenergic	O
+neuron	O
+integrity	O
+and	O
+function	O
+.	O
+
+Using	O
+a	O
+rat	O
+model	O
+of	O
+adriamycin	O
+-	O
+induced	O
+cardiomyopathy	B
+,	O
+we	O
+tested	O
+the	O
+hypothesis	O
+that	O
+abnormal	O
+cardiac	O
+adrenergic	O
+neuron	O
+activity	O
+may	O
+appear	O
+and	O
+be	O
+exacerbated	O
+dose	O
+-	O
+dependently	O
+in	O
+adriamycin	O
+cardiomyopathy	B
+.	O
+
+The	O
+degree	O
+of	O
+vacuolar	B
+degeneration	I
+of	I
+myocardial	I
+cells	I
+was	O
+analyzed	O
+in	O
+relation	O
+to	O
+the	O
+duration	O
+of	O
+adriamycin	O
+treatment	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+,	O
+once	O
+a	O
+week	O
+)	O
+.	O
+
+There	O
+were	O
+no	O
+abnormalities	O
+or	O
+only	O
+isolated	O
+degeneration	O
+in	O
+the	O
+1	O
+-	O
+or	O
+2	O
+-	O
+wk	O
+treatment	O
+groups	O
+,	O
+isolated	O
+or	O
+scattered	O
+degeneration	O
+in	O
+half	O
+of	O
+the	O
+3	O
+-	O
+wk	O
+group	O
+,	O
+frequent	O
+scattered	O
+degeneration	O
+in	O
+the	O
+4	O
+-	O
+wk	O
+group	O
+,	O
+scattered	O
+or	O
+focal	O
+degeneration	O
+in	O
+the	O
+5	O
+-	O
+wk	O
+group	O
+,	O
+and	O
+extensive	O
+degeneration	O
+in	O
+the	O
+8	O
+-	O
+wk	O
+group	O
+.	O
+
+Myocardial	O
+accumulation	O
+of	O
+[	O
+125I	O
+]	O
+MIBG	O
+4	O
+hr	O
+after	O
+intravenous	O
+injection	O
+did	O
+not	O
+differ	O
+between	O
+the	O
+controls	O
+and	O
+the	O
+groups	O
+treated	O
+3	O
+wk	O
+or	O
+less	O
+.	O
+
+However	O
+,	O
+the	O
+4	O
+-	O
+wk	O
+group	O
+had	O
+a	O
+slightly	O
+lower	O
+accumulation	O
+in	O
+the	O
+right	O
+ventricular	O
+wall	O
+(	O
+82	O
+%	O
+of	O
+the	O
+control	O
+)	O
+and	O
+significantly	O
+lower	O
+accumulation	O
+in	O
+the	O
+left	O
+ventricular	O
+wall	O
+(	O
+about	O
+66	O
+%	O
+of	O
+the	O
+control	O
+:	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+In	O
+the	O
+5	O
+-	O
+wk	O
+group	O
+,	O
+MIBG	O
+accumulation	O
+in	O
+the	O
+right	O
+and	O
+left	O
+ventricular	O
+wall	O
+was	O
+35	O
+%	O
+and	O
+27	O
+%	O
+of	O
+that	O
+in	O
+controls	O
+,	O
+respectively	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+In	O
+the	O
+8	O
+-	O
+wk	O
+group	O
+,	O
+MIBG	O
+accumulation	O
+in	O
+the	O
+right	O
+and	O
+left	O
+ventricular	O
+wall	O
+was	O
+18	O
+%	O
+and	O
+14	O
+%	O
+of	O
+that	O
+in	O
+controls	O
+,	O
+respectively	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Thus	O
+,	O
+MIBG	O
+accumulation	O
+in	O
+the	O
+myocardium	O
+decreased	O
+in	O
+an	O
+adriamycin	O
+dose	O
+-	O
+dependent	O
+manner	O
+.	O
+
+The	O
+appearance	O
+of	O
+impaired	O
+cardiac	O
+adrenergic	O
+neuron	O
+activity	O
+in	O
+the	O
+presence	O
+of	O
+slight	O
+myocardial	B
+impairment	I
+(	O
+scattered	O
+or	O
+focal	O
+vacuolar	B
+degeneration	I
+)	O
+indicates	O
+that	O
+MIBG	O
+scintigraphy	O
+may	O
+be	O
+a	O
+useful	O
+method	O
+for	O
+detection	O
+of	O
+adriamycin	O
+-	O
+induced	O
+cardiomyopathy	B
+.	O
+
+Syncope	B
+and	O
+QT	B
+prolongation	I
+among	O
+patients	O
+treated	O
+with	O
+methadone	O
+for	O
+heroin	O
+dependence	O
+in	O
+the	O
+city	O
+of	O
+Copenhagen	O
+.	O
+
+BACKGROUND	O
+:	O
+Methadone	O
+is	O
+prescribed	O
+to	O
+heroin	O
+addicts	O
+to	O
+decrease	O
+illicit	O
+opioid	O
+use	O
+.	O
+
+Prolongation	O
+of	O
+the	O
+QT	O
+interval	O
+in	O
+the	O
+ECG	O
+of	O
+patients	O
+with	O
+torsade	B
+de	I
+pointes	I
+(	O
+TdP	B
+)	O
+has	O
+been	O
+reported	O
+in	O
+methadone	O
+users	O
+.	O
+
+As	O
+heroin	O
+addicts	O
+sometimes	O
+faint	O
+while	O
+using	O
+illicit	O
+drugs	O
+,	O
+doctors	O
+might	O
+attribute	O
+too	O
+many	O
+episodes	O
+of	O
+syncope	B
+to	O
+illicit	O
+drug	O
+use	O
+and	O
+thereby	O
+underestimate	O
+the	O
+incidence	O
+of	O
+TdP	B
+in	O
+this	O
+special	O
+population	O
+,	O
+and	O
+the	O
+high	O
+mortality	O
+in	O
+this	O
+population	O
+may	O
+,	O
+in	O
+part	O
+,	O
+be	O
+caused	O
+by	O
+the	O
+proarrhythmic	O
+effect	O
+of	O
+methadone	O
+.	O
+
+METHODS	O
+:	O
+In	O
+this	O
+cross	O
+-	O
+sectional	O
+study	O
+interview	O
+,	O
+ECGs	O
+and	O
+blood	O
+samples	O
+were	O
+collected	O
+in	O
+a	O
+population	O
+of	O
+adult	O
+heroin	O
+addicts	O
+treated	O
+with	O
+methadone	O
+or	O
+buprenorphine	O
+on	O
+a	O
+daily	O
+basis	O
+.	O
+
+Of	O
+the	O
+patients	O
+at	O
+the	O
+Drug	O
+Addiction	O
+Service	O
+in	O
+the	O
+municipal	O
+of	O
+Copenhagen	O
+,	O
+450	O
+(	O
+approximately	O
+52	O
+%	O
+)	O
+were	O
+included	O
+.	O
+
+The	O
+QT	O
+interval	O
+was	O
+estimated	O
+from	O
+12	O
+lead	O
+ECGs	O
+.	O
+
+All	O
+participants	O
+were	O
+interviewed	O
+about	O
+any	O
+experience	O
+of	O
+syncope	B
+.	O
+
+The	O
+association	O
+between	O
+opioid	O
+dose	O
+and	O
+QT	O
+,	O
+and	O
+methadone	O
+dose	O
+and	O
+reporting	O
+of	O
+syncope	B
+was	O
+assessed	O
+using	O
+multivariate	O
+linear	O
+regression	O
+and	O
+logistic	O
+regression	O
+,	O
+respectively	O
+.	O
+
+RESULTS	O
+:	O
+Methadone	O
+dose	O
+was	O
+associated	O
+with	O
+longer	O
+QT	O
+interval	O
+of	O
+0	O
+.	O
+140	O
+ms	O
+/	O
+mg	O
+(	O
+p	O
+=	O
+0	O
+.	O
+002	O
+)	O
+.	O
+
+No	O
+association	O
+between	O
+buprenorphine	O
+and	O
+QTc	O
+was	O
+found	O
+.	O
+
+Among	O
+the	O
+subjects	O
+treated	O
+with	O
+methadone	O
+,	O
+28	O
+%	O
+men	O
+and	O
+32	O
+%	O
+women	O
+had	O
+prolonged	B
+QTc	I
+interval	I
+.	O
+
+None	O
+of	O
+the	O
+subjects	O
+treated	O
+with	O
+buprenorphine	O
+had	O
+QTc	O
+interval	O
+>	O
+0	O
+.	O
+440	O
+s	O
+(	O
+(	O
+1	O
+/	O
+2	O
+)	O
+)	O
+.	O
+
+A	O
+50	O
+mg	O
+higher	O
+methadone	O
+dose	O
+was	O
+associated	O
+with	O
+a	O
+1	O
+.	O
+2	O
+(	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+1	O
+to	O
+1	O
+.	O
+4	O
+)	O
+times	O
+higher	O
+odds	O
+for	O
+syncope	B
+.	O
+
+CONCLUSIONS	O
+:	O
+Methadone	O
+is	O
+associated	O
+with	O
+QT	B
+prolongation	I
+and	O
+higher	O
+reporting	O
+of	O
+syncope	B
+in	O
+a	O
+population	O
+of	O
+heroin	O
+addicts	O
+.	O
+
+Neuroleptic	B
+malignant	I
+syndrome	I
+induced	O
+by	O
+ziprasidone	O
+on	O
+the	O
+second	O
+day	O
+of	O
+treatment	O
+.	O
+
+Neuroleptic	B
+malignant	I
+syndrome	I
+(	O
+NMS	B
+)	O
+is	O
+the	O
+rarest	O
+and	O
+most	O
+serious	O
+of	O
+the	O
+neuroleptic	O
+-	O
+induced	O
+movement	B
+disorders	I
+.	O
+
+We	O
+describe	O
+a	O
+case	O
+of	O
+neuroleptic	B
+malignant	I
+syndrome	I
+(	O
+NMS	B
+)	O
+associated	O
+with	O
+the	O
+use	O
+of	O
+ziprasidone	O
+.	O
+
+Although	O
+conventional	O
+neuroleptics	O
+are	O
+more	O
+frequently	O
+associated	O
+with	O
+NMS	B
+,	O
+atypical	O
+antipsychotic	O
+drugs	O
+like	O
+ziprasidone	O
+may	O
+also	O
+be	O
+a	O
+cause	O
+.	O
+
+The	O
+patient	O
+is	O
+a	O
+24	O
+-	O
+year	O
+-	O
+old	O
+male	O
+with	O
+a	O
+history	O
+of	O
+schizophrenia	B
+who	O
+developed	O
+signs	O
+and	O
+symptoms	O
+of	O
+NMS	B
+after	O
+2	O
+days	O
+of	O
+treatment	O
+with	O
+an	O
+80	O
+-	O
+mg	O
+/	O
+day	O
+dose	O
+of	O
+orally	O
+administrated	O
+ziprasidone	O
+.	O
+
+This	O
+case	O
+is	O
+the	O
+earliest	O
+(	O
+second	O
+day	O
+of	O
+treatment	O
+)	O
+NMS	B
+due	O
+to	O
+ziprasidone	O
+reported	O
+in	O
+the	O
+literature	O
+.	O
+
+Peripheral	O
+iron	O
+dextran	O
+induced	O
+degeneration	B
+of	I
+dopaminergic	I
+neurons	I
+in	O
+rat	O
+substantia	O
+nigra	O
+.	O
+
+Iron	O
+accumulation	O
+is	O
+considered	O
+to	O
+be	O
+involved	O
+in	O
+the	O
+pathogenesis	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+To	O
+demonstrate	O
+the	O
+relationship	O
+between	O
+peripheral	O
+iron	O
+overload	O
+and	O
+dopaminergic	O
+neuron	O
+loss	O
+in	O
+rat	O
+substantia	O
+nigra	O
+(	O
+SN	O
+)	O
+,	O
+in	O
+the	O
+present	O
+study	O
+we	O
+used	O
+fast	O
+cyclic	O
+voltammetry	O
+,	O
+tyrosine	O
+hydroxylase	O
+(	O
+TH	O
+)	O
+immunohistochemistry	O
+,	O
+Perls	O
+'	O
+iron	O
+staining	O
+,	O
+and	O
+high	O
+performance	O
+liquid	O
+chromatography	O
+-	O
+electrochemical	O
+detection	O
+to	O
+study	O
+the	O
+degeneration	B
+of	I
+dopaminergic	I
+neurons	I
+and	O
+increased	O
+iron	O
+content	O
+in	O
+the	O
+SN	O
+of	O
+iron	O
+dextran	O
+overloaded	O
+animals	O
+.	O
+
+The	O
+findings	O
+showed	O
+that	O
+peripheral	O
+iron	O
+dextran	O
+overload	O
+increased	O
+the	O
+iron	O
+staining	O
+positive	O
+cells	O
+and	O
+reduced	O
+the	O
+number	O
+of	O
+TH	O
+-	O
+immunoreactive	O
+neurons	O
+in	O
+the	O
+SN	O
+.	O
+
+As	O
+a	O
+result	O
+,	O
+dopamine	O
+release	O
+and	O
+content	O
+,	O
+as	O
+well	O
+as	O
+its	O
+metabolites	O
+contents	O
+were	O
+decreased	O
+in	O
+caudate	O
+putamen	O
+.	O
+
+Even	O
+more	O
+dramatic	O
+changes	O
+were	O
+found	O
+in	O
+chronic	O
+overload	O
+group	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+peripheral	O
+iron	O
+dextran	O
+can	O
+increase	O
+the	O
+iron	O
+level	O
+in	O
+the	O
+SN	O
+,	O
+where	O
+excessive	O
+iron	O
+causes	O
+the	O
+degeneration	B
+of	I
+dopaminergic	I
+neurons	I
+.	O
+
+The	O
+chronic	O
+iron	O
+overload	O
+may	O
+be	O
+more	O
+destructive	O
+to	O
+dopaminergic	O
+neurons	O
+than	O
+the	O
+acute	O
+iron	O
+overload	O
+.	O
+
+Attenuated	O
+disruption	O
+of	O
+prepulse	O
+inhibition	O
+by	O
+dopaminergic	O
+stimulation	O
+after	O
+maternal	O
+deprivation	O
+and	O
+adolescent	O
+corticosterone	O
+treatment	O
+in	O
+rats	O
+.	O
+
+The	O
+development	O
+of	O
+schizophrenia	B
+may	O
+include	O
+an	O
+early	O
+neurodevelopmental	O
+stress	O
+component	O
+which	O
+increases	O
+vulnerability	O
+to	O
+later	O
+stressful	O
+life	O
+events	O
+,	O
+in	O
+combination	O
+leading	O
+to	O
+overt	O
+disease	O
+.	O
+
+We	O
+investigated	O
+the	O
+effect	O
+of	O
+an	O
+early	O
+stress	O
+,	O
+in	O
+the	O
+form	O
+of	O
+maternal	O
+deprivation	O
+,	O
+combined	O
+with	O
+a	O
+later	O
+stress	O
+,	O
+simulated	O
+by	O
+chronic	O
+periadolescent	O
+corticosterone	O
+treatment	O
+,	O
+on	O
+behaviour	O
+in	O
+rats	O
+.	O
+
+Acute	O
+treatment	O
+with	O
+apomorphine	O
+caused	O
+disruption	O
+of	O
+prepulse	O
+inhibition	O
+(	O
+PPI	O
+)	O
+in	O
+controls	O
+and	O
+in	O
+rats	O
+that	O
+had	O
+undergone	O
+either	O
+maternal	O
+deprivation	O
+or	O
+corticosterone	O
+treatment	O
+,	O
+but	O
+was	O
+surprisingly	O
+absent	O
+in	O
+rats	O
+that	O
+had	O
+undergone	O
+the	O
+combined	O
+early	O
+and	O
+late	O
+stress	O
+.	O
+
+Amphetamine	O
+treatment	O
+significantly	O
+disrupted	O
+PPI	O
+in	O
+both	O
+non	O
+-	O
+deprived	O
+groups	O
+,	O
+but	O
+was	O
+absent	O
+in	O
+both	O
+maternally	O
+deprived	O
+groups	O
+.	O
+
+The	O
+serotonin	O
+-	O
+1A	O
+receptor	O
+agonist	O
+,	O
+8	O
+-	O
+OH	O
+-	O
+DPAT	O
+,	O
+induced	O
+a	O
+significant	O
+disruption	O
+of	O
+PPI	O
+in	O
+all	O
+groups	O
+.	O
+
+Amphetamine	O
+-	O
+induced	O
+locomotor	B
+hyperactivity	I
+was	O
+similar	O
+in	O
+all	O
+groups	O
+.	O
+
+These	O
+results	O
+show	O
+an	O
+inhibitory	O
+interaction	O
+of	O
+early	O
+stress	O
+,	O
+caused	O
+by	O
+maternal	O
+deprivation	O
+,	O
+combined	O
+with	O
+'	O
+adolescent	O
+'	O
+stress	O
+,	O
+simulated	O
+by	O
+corticosterone	O
+treatment	O
+,	O
+on	O
+dopaminergic	O
+regulation	O
+of	O
+PPI	O
+.	O
+
+The	O
+altered	O
+effects	O
+of	O
+apomorphine	O
+and	O
+amphetamine	O
+could	O
+indicate	O
+differential	O
+changes	O
+in	O
+dopamine	O
+receptor	O
+signalling	O
+leading	O
+to	O
+functional	O
+desensitisation	O
+,	O
+or	O
+altered	O
+modulation	O
+of	O
+sensory	O
+gating	O
+in	O
+the	O
+nucleus	O
+accumbens	O
+by	O
+limbic	O
+structures	O
+such	O
+as	O
+the	O
+hippocampus	O
+.	O
+
+An	O
+extremely	O
+rare	O
+case	O
+of	O
+delusional	B
+parasitosis	I
+in	O
+a	O
+chronic	B
+hepatitis	I
+C	I
+patient	O
+during	O
+pegylated	O
+interferon	O
+alpha	O
+-	O
+2b	O
+and	O
+ribavirin	O
+treatment	O
+.	O
+
+During	O
+treatment	O
+of	O
+chronic	B
+hepatitis	I
+C	I
+patients	O
+with	O
+interferon	O
+and	O
+ribavirin	O
+,	O
+a	O
+lot	O
+of	O
+side	O
+effects	O
+are	O
+described	O
+.	O
+
+Twenty	O
+-	O
+three	O
+percent	O
+to	O
+44	O
+%	O
+of	O
+patients	O
+develop	O
+depression	B
+.	O
+
+A	O
+minority	O
+of	O
+patients	O
+evolve	O
+to	O
+psychosis	B
+.	O
+
+To	O
+the	O
+best	O
+of	O
+our	O
+knowledge	O
+,	O
+no	O
+cases	O
+of	O
+psychogenic	B
+parasitosis	I
+occurring	O
+during	O
+interferon	O
+therapy	O
+have	O
+been	O
+described	O
+in	O
+the	O
+literature	O
+.	O
+
+We	O
+present	O
+a	O
+49	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+who	O
+developed	O
+a	O
+delusional	B
+parasitosis	I
+during	O
+treatment	O
+with	O
+pegylated	O
+interferon	O
+alpha	O
+-	O
+2b	O
+weekly	O
+and	O
+ribavirin	O
+.	O
+
+She	O
+complained	O
+of	O
+seeing	O
+parasites	O
+and	O
+the	O
+larvae	O
+of	O
+fleas	O
+in	O
+her	O
+stools	O
+.	O
+
+This	O
+could	O
+not	O
+be	O
+confirmed	O
+by	O
+any	O
+technical	O
+examination	O
+.	O
+
+All	O
+the	O
+complaints	O
+disappeared	O
+after	O
+stopping	O
+pegylated	O
+interferon	O
+alpha	O
+-	O
+2b	O
+and	O
+reappeared	O
+after	O
+restarting	O
+it	O
+.	O
+
+She	O
+had	O
+a	O
+complete	O
+sustained	O
+viral	O
+response	O
+.	O
+
+Hepatonecrosis	B
+and	O
+cholangitis	B
+related	O
+to	O
+long	O
+-	O
+term	O
+phenobarbital	O
+therapy	O
+:	O
+an	O
+autopsy	O
+report	O
+of	O
+two	O
+patients	O
+.	O
+
+Phenobarbital	O
+(	O
+PB	O
+)	O
+has	O
+a	O
+reputation	O
+for	O
+safety	O
+,	O
+and	O
+it	O
+is	O
+commonly	O
+believed	O
+that	O
+PB	O
+-	O
+related	O
+increases	O
+in	O
+serum	O
+aminotransferase	O
+levels	O
+do	O
+not	O
+indicate	O
+or	O
+predict	O
+the	O
+development	O
+of	O
+significant	O
+chronic	O
+liver	B
+disease	I
+.	O
+
+Here	O
+we	O
+report	O
+of	O
+two	O
+adult	O
+patients	O
+with	O
+a	O
+long	O
+history	O
+of	O
+epilepsy	B
+treated	O
+with	O
+PB	O
+who	O
+died	O
+suddenly	O
+:	O
+one	O
+as	O
+consequence	O
+of	O
+cardiac	B
+arrest	I
+,	O
+the	O
+other	O
+of	O
+acute	O
+bronchopneumonia	B
+.	O
+
+At	O
+autopsy	O
+,	O
+analysis	O
+of	O
+liver	O
+parenchyma	O
+revealed	O
+rich	O
+portal	O
+inflammatory	O
+infiltrate	O
+,	O
+which	O
+consisted	O
+of	O
+mixed	O
+eosinophil	O
+and	O
+monocyte	O
+cells	O
+,	O
+associated	O
+with	O
+several	O
+foci	O
+of	O
+necrosis	B
+surrounded	O
+by	O
+a	O
+hard	O
+ring	O
+of	O
+non	O
+-	O
+specific	O
+granulomatous	O
+tissue	O
+.	O
+
+Inflammatory	O
+reactions	O
+of	O
+internal	O
+and	O
+external	O
+hepatic	O
+biliary	O
+ducts	O
+were	O
+also	O
+seen	O
+.	O
+
+Our	O
+findings	O
+illustrate	O
+that	O
+PB	O
+may	O
+be	O
+associated	O
+with	O
+chronic	O
+liver	B
+damage	I
+,	O
+which	O
+may	O
+lead	O
+to	O
+more	O
+serious	O
+and	O
+deleterious	O
+consequences	O
+.	O
+
+For	O
+this	O
+reason	O
+,	O
+each	O
+clinician	O
+should	O
+recognize	O
+this	O
+entity	O
+in	O
+the	O
+differential	O
+diagnosis	O
+of	O
+PB	O
+-	O
+related	O
+asymptomatic	O
+chronic	B
+hepatic	I
+enzyme	I
+dysfunction	I
+.	O
+
+Delayed	O
+leukoencephalopathy	B
+with	O
+stroke	B
+-	O
+like	O
+presentation	O
+in	O
+chemotherapy	O
+recipients	O
+.	O
+
+BACKGROUND	O
+:	O
+A	O
+transient	O
+leukoencephalopathy	B
+mimicking	O
+cerebrovascular	B
+accident	I
+has	O
+been	O
+described	O
+as	O
+a	O
+complication	O
+of	O
+chemotherapy	O
+,	O
+most	O
+commonly	O
+in	O
+recipients	O
+of	O
+intrathecal	O
+methotrexate	O
+for	O
+childhood	O
+leukaemia	B
+.	O
+
+Recently	O
+published	O
+neuroimaging	O
+data	O
+suggest	O
+a	O
+common	O
+pathophysiology	O
+associated	O
+with	O
+a	O
+variety	O
+of	O
+chemotherapy	O
+agents	O
+and	O
+modes	O
+of	O
+administration	O
+.	O
+
+METHODS	O
+:	O
+We	O
+reviewed	O
+the	O
+medical	O
+literature	O
+for	O
+single	O
+reports	O
+and	O
+case	O
+series	O
+of	O
+patients	O
+presenting	O
+with	O
+stroke	B
+-	O
+like	O
+episodes	O
+while	O
+receiving	O
+systemic	O
+or	O
+intrathecal	O
+chemotherapy	O
+.	O
+
+We	O
+only	O
+included	O
+studies	O
+providing	O
+detailed	O
+neuroimaging	O
+data	O
+.	O
+
+Patients	O
+with	O
+cerebrovascular	B
+accidents	I
+were	O
+excluded	O
+.	O
+
+RESULTS	O
+:	O
+We	O
+identified	O
+27	O
+reports	O
+of	O
+toxic	O
+leukoencephalopathy	B
+in	O
+patients	O
+treated	O
+with	O
+methotrexate	O
+(	O
+intrathecal	O
+,	O
+systemic	O
+)	O
+,	O
+5	O
+-	O
+fluorouracil	O
+and	O
+its	O
+derivative	O
+carmofur	O
+,	O
+and	O
+capecitabine	O
+.	O
+
+Diffusion	O
+weighted	O
+imaging	O
+(	O
+DWI	O
+)	O
+of	O
+all	O
+patients	O
+revealed	O
+well	O
+demarcated	O
+hyperintense	O
+lesions	B
+within	I
+the	I
+subcortical	I
+white	I
+matter	I
+of	O
+the	O
+cerebral	O
+hemispheres	O
+and	O
+the	O
+corpus	O
+callosum	O
+,	O
+corresponding	O
+to	O
+areas	O
+of	O
+decreased	O
+proton	O
+diffusion	O
+on	O
+apparent	O
+diffusion	O
+coefficient	O
+(	O
+ADC	O
+)	O
+maps	O
+(	O
+available	O
+in	O
+21	O
+/	O
+27	O
+patients	O
+)	O
+.	O
+
+Lesions	O
+exceeded	O
+the	O
+confines	O
+of	O
+adjacent	O
+vascular	O
+territories	O
+.	O
+
+Complete	O
+resolution	O
+of	O
+symptoms	O
+within	O
+1	O
+-	O
+4	O
+days	O
+was	O
+accompanied	O
+by	O
+normalisation	O
+of	O
+ADC	O
+abnormalities	O
+.	O
+
+However	O
+,	O
+fluid	O
+attenuated	O
+inversion	O
+recovery	O
+(	O
+FLAIR	O
+)	O
+sequences	O
+frequently	O
+revealed	O
+persistent	O
+white	B
+matter	I
+abnormalities	I
+.	O
+
+CONCLUSIONS	O
+:	O
+Several	O
+pathophysiological	O
+models	O
+of	O
+delayed	O
+leukoencephalopathy	B
+after	O
+exposure	O
+to	O
+intrathecal	O
+or	O
+systemic	O
+chemotherapy	O
+have	O
+been	O
+proposed	O
+.	O
+
+DWI	O
+findings	O
+in	O
+this	O
+cohort	O
+are	O
+indicative	O
+of	O
+cytotoxic	B
+oedema	I
+within	I
+cerebral	I
+white	I
+matter	I
+and	O
+lend	O
+support	O
+to	O
+an	O
+at	O
+least	O
+partially	O
+reversible	O
+metabolic	O
+derangement	O
+as	O
+the	O
+basis	O
+for	O
+this	O
+syndrome	O
+.	O
+
+Prenatal	O
+exposure	O
+to	O
+fluoxetine	O
+induces	O
+fetal	B
+pulmonary	I
+hypertension	I
+in	O
+the	O
+rat	O
+.	O
+
+RATIONALE	O
+:	O
+Fluoxetine	O
+is	O
+a	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitor	O
+antidepressant	O
+widely	O
+used	O
+by	O
+pregnant	O
+women	O
+.	O
+
+Epidemiological	O
+data	O
+suggest	O
+that	O
+fluoxetine	O
+exposure	O
+prenatally	O
+increases	O
+the	O
+prevalence	O
+of	O
+persistent	O
+pulmonary	B
+hypertension	I
+syndrome	I
+of	O
+the	O
+newborn	O
+.	O
+
+The	O
+mechanism	O
+responsible	O
+for	O
+this	O
+effect	O
+is	O
+unclear	O
+and	O
+paradoxical	O
+,	O
+considering	O
+the	O
+current	O
+evidence	O
+of	O
+a	O
+pulmonary	B
+hypertension	I
+protective	O
+fluoxetine	O
+effect	O
+in	O
+adult	O
+rodents	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+evaluate	O
+the	O
+fluoxetine	O
+effect	O
+on	O
+fetal	O
+rat	O
+pulmonary	O
+vascular	O
+smooth	O
+muscle	O
+mechanical	O
+properties	O
+and	O
+cell	O
+proliferation	O
+rate	O
+.	O
+
+METHODS	O
+:	O
+Pregnant	O
+rats	O
+were	O
+treated	O
+with	O
+fluoxetine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+from	O
+Day	O
+11	O
+through	O
+Day	O
+21	O
+of	O
+gestation	O
+.	O
+
+MEASUREMENTS	O
+AND	O
+MAIN	O
+RESULTS	O
+:	O
+Fetuses	O
+were	O
+delivered	O
+by	O
+cesarean	O
+section	O
+.	O
+
+As	O
+compared	O
+with	O
+controls	O
+,	O
+fluoxetine	O
+exposure	O
+resulted	O
+in	O
+fetal	B
+pulmonary	I
+hypertension	I
+as	O
+evidenced	O
+by	O
+an	O
+increase	O
+in	O
+the	O
+weight	O
+ratio	O
+of	O
+the	O
+right	O
+ventricle	O
+to	O
+the	O
+left	O
+ventricle	O
+plus	O
+septum	O
+(	O
+P	O
+=	O
+0	O
+.	O
+02	O
+)	O
+and	O
+by	O
+an	O
+increase	O
+in	O
+pulmonary	O
+arterial	O
+medial	O
+thickness	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+Postnatal	O
+mortality	O
+was	O
+increased	O
+among	O
+experimental	O
+animals	O
+,	O
+and	O
+arterial	O
+oxygen	O
+saturation	O
+was	O
+96	O
++	O
+/	O
+-	O
+1	O
+%	O
+in	O
+1	O
+-	O
+day	O
+-	O
+old	O
+control	O
+animals	O
+and	O
+significantly	O
+lower	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+in	O
+fluoxetine	O
+-	O
+exposed	O
+pups	O
+(	O
+79	O
++	O
+/	O
+-	O
+2	O
+%	O
+)	O
+.	O
+
+In	O
+vitro	O
+,	O
+fluoxetine	O
+induced	O
+pulmonary	O
+arterial	O
+muscle	O
+contraction	O
+in	O
+fetal	O
+,	O
+but	O
+not	O
+adult	O
+,	O
+animals	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+and	O
+reduced	O
+serotonin	O
+-	O
+induced	O
+contraction	O
+at	O
+both	O
+ages	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+After	O
+in	O
+utero	O
+exposure	O
+to	O
+a	O
+low	O
+fluoxetine	O
+concentration	O
+the	O
+pulmonary	O
+arterial	O
+smooth	O
+muscle	O
+cell	O
+proliferation	O
+rate	O
+was	O
+significantly	O
+increased	O
+in	O
+fetal	O
+,	O
+but	O
+not	O
+adult	O
+,	O
+cells	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+In	O
+contrast	O
+to	O
+the	O
+adult	O
+,	O
+fluoxetine	O
+exposure	O
+in	O
+utero	O
+induces	O
+pulmonary	B
+hypertension	I
+in	O
+the	O
+fetal	O
+rat	O
+as	O
+a	O
+result	O
+of	O
+a	O
+developmentally	O
+regulated	O
+increase	O
+in	O
+pulmonary	O
+vascular	O
+smooth	O
+muscle	O
+proliferation	O
+.	O
+
+Disulfiram	O
+-	O
+induced	O
+transient	O
+optic	B
+and	I
+peripheral	I
+neuropathy	I
+:	O
+a	O
+case	O
+report	O
+.	O
+
+AIM	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+optic	B
+and	I
+peripheral	I
+neuropathy	I
+after	O
+chronic	O
+use	O
+of	O
+disulfiram	O
+for	O
+alcohol	B
+dependence	I
+management	O
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+A	O
+case	O
+report	O
+.	O
+
+RESULTS	O
+:	O
+A	O
+57	O
+-	O
+year	O
+-	O
+old	O
+male	O
+presented	O
+with	O
+gradual	O
+loss	B
+of	I
+vision	I
+in	O
+both	O
+eyes	O
+with	O
+intermittent	O
+headaches	B
+for	O
+2	O
+months	O
+.	O
+
+He	O
+also	O
+complained	O
+of	O
+paraesthesia	B
+with	O
+numbness	B
+in	O
+both	O
+feet	O
+.	O
+
+His	O
+vision	O
+was	O
+6	O
+/	O
+15	O
+and	O
+2	O
+/	O
+60	O
+in	O
+the	O
+right	O
+and	O
+left	O
+eyes	O
+,	O
+respectively	O
+.	O
+
+Fundoscopy	O
+revealed	O
+bilaterally	O
+swollen	O
+optic	O
+nerve	O
+heads	O
+.	O
+
+Visual	O
+field	O
+testing	O
+confirmed	O
+bilateral	O
+central	O
+-	O
+caecal	O
+scotomata	B
+.	O
+
+He	O
+had	O
+been	O
+taking	O
+disulfiram	O
+for	O
+alcohol	B
+dependence	I
+for	O
+the	O
+preceding	O
+3	O
+years	O
+.	O
+
+Disulfiram	O
+discontinuation	O
+lead	O
+to	O
+an	O
+immediate	O
+symptomatic	O
+improvement	O
+.	O
+
+CONCLUSION	O
+:	O
+Physicians	O
+initiating	O
+long	O
+-	O
+term	O
+disulfiram	O
+therapy	O
+should	O
+be	O
+aware	O
+of	O
+these	O
+adverse	O
+effects	O
+.	O
+
+They	O
+should	O
+recommend	O
+annual	O
+ophthalmic	O
+reviews	O
+with	O
+visual	O
+field	O
+testing	O
+.	O
+
+Patients	O
+should	O
+be	O
+reassured	O
+with	O
+respect	O
+to	O
+the	O
+reversibility	O
+of	O
+these	O
+adverse	O
+effects	O
+.	O
+
+Intraocular	O
+pressure	O
+in	O
+patients	O
+with	O
+uveitis	B
+treated	O
+with	O
+fluocinolone	O
+acetonide	O
+implants	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+the	O
+incidence	O
+and	O
+management	O
+of	O
+elevated	B
+intraocular	I
+pressure	I
+(	O
+IOP	O
+)	O
+in	O
+patients	O
+with	O
+uveitis	B
+treated	O
+with	O
+the	O
+fluocinolone	O
+acetonide	O
+(	O
+FA	O
+)	O
+intravitreal	O
+implant	O
+.	O
+
+DESIGN	O
+:	O
+Pooled	O
+data	O
+from	O
+3	O
+multicenter	O
+,	O
+double	O
+-	O
+masked	O
+,	O
+randomized	O
+,	O
+controlled	O
+,	O
+phase	O
+2b	O
+/	O
+3	O
+clinical	O
+trials	O
+evaluating	O
+the	O
+safety	O
+and	O
+efficacy	O
+of	O
+the	O
+0	O
+.	O
+59	O
+-	O
+mg	O
+or	O
+2	O
+.	O
+1	O
+-	O
+mg	O
+FA	O
+intravitreal	O
+implant	O
+or	O
+standard	O
+therapy	O
+were	O
+analyzed	O
+.	O
+
+RESULTS	O
+:	O
+During	O
+the	O
+3	O
+-	O
+year	O
+follow	O
+-	O
+up	O
+,	O
+71	O
+.	O
+0	O
+%	O
+of	O
+implanted	O
+eyes	O
+had	O
+an	O
+IOP	O
+increase	O
+of	O
+10	O
+mm	O
+Hg	O
+or	O
+more	O
+than	O
+baseline	O
+and	O
+55	O
+.	O
+1	O
+%	O
+,	O
+24	O
+.	O
+7	O
+%	O
+,	O
+and	O
+6	O
+.	O
+2	O
+%	O
+of	O
+eyes	O
+reached	O
+an	O
+IOP	O
+of	O
+30	O
+mm	O
+Hg	O
+or	O
+more	O
+,	O
+40	O
+mm	O
+Hg	O
+or	O
+more	O
+,	O
+and	O
+50	O
+mm	O
+Hg	O
+or	O
+more	O
+,	O
+respectively	O
+.	O
+
+Topical	O
+IOP	O
+-	O
+lowering	O
+medication	O
+was	O
+administered	O
+in	O
+74	O
+.	O
+8	O
+%	O
+of	O
+implanted	O
+eyes	O
+,	O
+and	O
+IOP	O
+-	O
+lowering	O
+surgeries	O
+,	O
+most	O
+of	O
+which	O
+were	O
+trabeculectomies	O
+(	O
+76	O
+.	O
+2	O
+%	O
+)	O
+,	O
+were	O
+performed	O
+on	O
+36	O
+.	O
+6	O
+%	O
+of	O
+implanted	O
+eyes	O
+.	O
+
+Intraocular	O
+pressure	O
+-	O
+lowering	O
+surgeries	O
+were	O
+considered	O
+a	O
+success	O
+(	O
+postoperative	O
+IOP	O
+of	O
+6	O
+-	O
+21	O
+mm	O
+Hg	O
+with	O
+or	O
+without	O
+additional	O
+IOP	O
+-	O
+lowering	O
+medication	O
+)	O
+in	O
+85	O
+.	O
+1	O
+%	O
+of	O
+eyes	O
+at	O
+1	O
+year	O
+.	O
+
+The	O
+rate	O
+of	O
+hypotony	B
+(	O
+IOP	O
+<	O
+/	O
+=	O
+5	O
+mm	O
+Hg	O
+)	O
+following	O
+IOP	O
+-	O
+lowering	O
+surgery	O
+(	O
+42	O
+.	O
+5	O
+%	O
+)	O
+was	O
+not	O
+different	O
+from	O
+that	O
+of	O
+implanted	O
+eyes	O
+not	O
+subjected	O
+to	O
+surgery	O
+(	O
+35	O
+.	O
+4	O
+%	O
+)	O
+(	O
+P	O
+=	O
+.	O
+09	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+Elevated	O
+IOP	O
+is	O
+a	O
+significant	O
+complication	O
+with	O
+the	O
+FA	O
+intravitreal	O
+implant	O
+but	O
+may	O
+be	O
+controlled	O
+with	O
+medication	O
+and	O
+surgery	O
+.	O
+
+Myocardial	O
+Fas	O
+ligand	O
+expression	O
+increases	O
+susceptibility	O
+to	O
+AZT	O
+-	O
+induced	O
+cardiomyopathy	B
+.	O
+
+BACKGROUND	O
+:	O
+Dilated	B
+cardiomyopathy	I
+(	O
+DCM	B
+)	O
+and	O
+myocarditis	B
+occur	O
+in	O
+many	O
+HIV	B
+-	I
+infected	I
+individuals	O
+,	O
+resulting	O
+in	O
+symptomatic	O
+heart	B
+failure	I
+in	O
+up	O
+to	O
+5	O
+%	O
+of	O
+patients	O
+.	O
+
+Highly	O
+active	O
+antiretroviral	O
+therapy	O
+(	O
+HAART	O
+)	O
+has	O
+significantly	O
+reduced	O
+morbidity	O
+and	O
+mortality	O
+of	O
+acquired	B
+immunodeficiency	I
+syndrome	I
+(	O
+AIDS	B
+)	O
+,	O
+but	O
+has	O
+resulted	O
+in	O
+an	O
+increase	O
+in	O
+cardiac	B
+and	I
+skeletal	I
+myopathies	I
+.	O
+
+METHODS	O
+AND	O
+RESULTS	O
+:	O
+In	O
+order	O
+to	O
+investigate	O
+whether	O
+the	O
+HAART	O
+component	O
+zidovudine	O
+(	O
+3	O
+'	O
+-	O
+azido	O
+-	O
+2	O
+'	O
+,	O
+3	O
+'	O
+-	O
+deoxythymidine	O
+;	O
+AZT	O
+)	O
+triggers	O
+the	O
+Fas	O
+-	O
+dependent	O
+cell	O
+-	O
+death	O
+pathway	O
+and	O
+cause	O
+cytoskeletal	O
+disruption	O
+in	O
+a	O
+murine	O
+model	O
+of	O
+DCM	B
+,	O
+8	O
+-	O
+week	O
+-	O
+old	O
+transgenic	O
+(	O
+expressing	O
+Fas	O
+ligand	O
+in	O
+the	O
+myocardium	O
+:	O
+FasL	O
+Tg	O
+)	O
+and	O
+non	O
+-	O
+transgenic	O
+(	O
+NTg	O
+)	O
+mice	O
+received	O
+water	O
+ad	O
+libitum	O
+containing	O
+different	O
+concentrations	O
+of	O
+AZT	O
+(	O
+0	O
+,	O
+0	O
+.	O
+07	O
+,	O
+0	O
+.	O
+2	O
+,	O
+and	O
+0	O
+.	O
+7	O
+mg	O
+/	O
+ml	O
+)	O
+.	O
+
+After	O
+6	O
+weeks	O
+,	O
+cardiac	O
+function	O
+was	O
+assessed	O
+by	O
+echocardiography	O
+and	O
+morphology	O
+was	O
+assessed	O
+by	O
+histopathologic	O
+and	O
+immunohistochemical	O
+methods	O
+.	O
+
+NTg	O
+and	O
+untreated	O
+FasL	O
+Tg	O
+mice	O
+showed	O
+little	O
+or	O
+no	O
+change	O
+in	O
+cardiac	O
+structure	O
+or	O
+function	O
+.	O
+
+In	O
+contrast	O
+,	O
+AZT	O
+-	O
+treated	O
+FasL	O
+Tg	O
+mice	O
+developed	O
+cardiac	B
+dilation	I
+and	O
+depressed	O
+cardiac	O
+function	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+,	O
+with	O
+concomitant	O
+inflammatory	O
+infiltration	O
+of	O
+both	O
+ventricles	O
+.	O
+
+These	O
+changes	O
+were	O
+associated	O
+with	O
+an	O
+increased	O
+sarcolemmal	O
+expression	O
+of	O
+Fas	O
+and	O
+FasL	O
+,	O
+as	O
+well	O
+as	O
+increased	O
+activation	O
+of	O
+caspase	O
+3	O
+,	O
+translocation	O
+of	O
+calpain	O
+1	O
+to	O
+the	O
+sarcolemma	O
+and	O
+sarcomere	O
+,	O
+and	O
+increased	O
+numbers	O
+of	O
+cells	O
+undergoing	O
+apoptosis	O
+.	O
+
+These	O
+were	O
+associated	O
+with	O
+changes	O
+in	O
+dystrophin	O
+and	O
+cardiac	O
+troponin	O
+I	O
+localization	O
+,	O
+as	O
+well	O
+as	O
+loss	O
+of	O
+sarcolemmal	O
+integrity	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+expression	O
+of	O
+Fas	O
+ligand	O
+in	O
+the	O
+myocardium	O
+,	O
+as	O
+identified	O
+in	O
+HIV	O
+-	O
+positive	O
+patients	O
+,	O
+might	O
+increase	O
+the	O
+susceptibility	O
+to	O
+HAART	O
+-	O
+induced	O
+cardiomyopathy	B
+due	O
+to	O
+activation	O
+of	O
+apoptotic	O
+pathways	O
+,	O
+resulting	O
+in	O
+cardiac	B
+dilation	I
+and	I
+dysfunction	I
+.	O
+
+Gastrointestinal	O
+tolerability	O
+of	O
+etoricoxib	O
+in	O
+rheumatoid	B
+arthritis	I
+patients	O
+:	O
+results	O
+of	O
+the	O
+etoricoxib	O
+vs	O
+diclofenac	O
+sodium	O
+gastrointestinal	O
+tolerability	O
+and	O
+effectiveness	O
+trial	O
+(	O
+EDGE	O
+-	O
+II	O
+)	O
+.	O
+
+OBJECTIVE	O
+:	O
+A	O
+randomised	O
+,	O
+double	O
+-	O
+blind	O
+study	O
+to	O
+compare	O
+the	O
+gastrointestinal	O
+(	O
+GI	O
+)	O
+tolerability	O
+,	O
+safety	O
+and	O
+efficacy	O
+of	O
+etoricoxib	O
+and	O
+diclofenac	O
+in	O
+patients	O
+with	O
+rheumatoid	B
+arthritis	I
+(	O
+RA	B
+)	O
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+A	O
+total	O
+of	O
+4086	O
+patients	O
+(	O
+mean	O
+age	O
+60	O
+.	O
+8	O
+years	O
+)	O
+diagnosed	O
+with	O
+RA	B
+were	O
+enrolled	O
+and	O
+received	O
+etoricoxib	O
+90	O
+mg	O
+daily	O
+(	O
+n	O
+=	O
+2032	O
+)	O
+or	O
+diclofenac	O
+75	O
+mg	O
+twice	O
+daily	O
+(	O
+n	O
+=	O
+2054	O
+)	O
+.	O
+
+Use	O
+of	O
+gastroprotective	O
+agents	O
+and	O
+low	O
+-	O
+dose	O
+aspirin	O
+was	O
+allowed	O
+.	O
+
+The	O
+prespecified	O
+primary	O
+end	O
+point	O
+consisted	O
+of	O
+the	O
+cumulative	O
+rate	O
+of	O
+patient	O
+discontinuations	O
+due	O
+to	O
+clinical	O
+and	O
+laboratory	O
+GI	O
+adverse	O
+experiences	O
+(	O
+AEs	O
+)	O
+.	O
+
+General	O
+safety	O
+was	O
+also	O
+assessed	O
+,	O
+including	O
+adjudicated	O
+thrombotic	B
+cardiovascular	I
+event	O
+data	O
+.	O
+
+Efficacy	O
+was	O
+evaluated	O
+using	O
+the	O
+Patient	O
+Global	O
+Assessment	O
+of	O
+Disease	O
+Status	O
+(	O
+PGADS	O
+;	O
+0	O
+-	O
+4	O
+point	O
+scale	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+Mean	O
+(	O
+SD	O
+;	O
+maximum	O
+)	O
+duration	O
+of	O
+treatment	O
+was	O
+19	O
+.	O
+3	O
+(	O
+10	O
+.	O
+3	O
+;	O
+32	O
+.	O
+9	O
+)	O
+and	O
+19	O
+.	O
+1	O
+(	O
+10	O
+.	O
+4	O
+;	O
+33	O
+.	O
+1	O
+)	O
+months	O
+in	O
+the	O
+etoricoxib	O
+and	O
+diclofenac	O
+groups	O
+,	O
+respectively	O
+.	O
+
+The	O
+cumulative	O
+discontinuation	O
+rate	O
+due	O
+to	O
+GI	B
+AEs	I
+was	O
+significantly	O
+lower	O
+with	O
+etoricoxib	O
+than	O
+diclofenac	O
+(	O
+5	O
+.	O
+2	O
+vs	O
+8	O
+.	O
+5	O
+events	O
+per	O
+100	O
+patient	O
+-	O
+years	O
+,	O
+respectively	O
+;	O
+hazard	O
+ratio	O
+0	O
+.	O
+62	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+0	O
+.	O
+47	O
+,	O
+0	O
+.	O
+81	O
+;	O
+p	O
+<	O
+or	O
+=	O
+0	O
+.	O
+001	O
+)	O
+)	O
+.	O
+
+The	O
+incidence	O
+of	O
+discontinuations	O
+for	O
+hypertension	B
+-	O
+related	O
+and	O
+oedema	B
+-	O
+related	O
+AEs	O
+were	O
+significantly	O
+higher	O
+with	O
+etoricoxib	O
+(	O
+2	O
+.	O
+5	O
+%	O
+and	O
+1	O
+.	O
+1	O
+%	O
+respectively	O
+)	O
+compared	O
+with	O
+diclofenac	O
+(	O
+1	O
+.	O
+5	O
+%	O
+and	O
+0	O
+.	O
+4	O
+%	O
+respectively	O
+;	O
+p	O
+<	O
+0	O
+.	O
+001	O
+for	O
+hypertension	B
+and	O
+p	O
+<	O
+0	O
+.	O
+01	O
+for	O
+oedema	B
+)	O
+.	O
+
+Etoricoxib	O
+and	O
+diclofenac	O
+treatment	O
+resulted	O
+in	O
+similar	O
+efficacy	O
+(	O
+PGADS	O
+mean	O
+changes	O
+from	O
+baseline	O
+-	O
+0	O
+.	O
+62	O
+vs	O
+-	O
+0	O
+.	O
+58	O
+,	O
+respectively	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Etoricoxib	O
+90	O
+mg	O
+demonstrated	O
+a	O
+significantly	O
+lower	O
+risk	O
+for	O
+discontinuing	O
+treatment	O
+due	O
+to	O
+GI	B
+AEs	I
+compared	O
+with	O
+diclofenac	O
+150	O
+mg	O
+.	O
+
+Discontinuations	O
+from	O
+renovascular	O
+AEs	O
+,	O
+although	O
+less	O
+common	O
+than	O
+discontinuations	O
+from	O
+GI	B
+AEs	I
+,	O
+were	O
+significantly	O
+higher	O
+with	O
+etoricoxib	O
+.	O
+
+Anxiogenic	O
+potential	O
+of	O
+ciprofloxacin	O
+and	O
+norfloxacin	O
+in	O
+rats	O
+.	O
+
+INTRODUCTION	O
+:	O
+The	O
+possible	O
+anxiogenic	O
+effects	O
+of	O
+fluoroquinolones	O
+,	O
+namely	O
+ciprofloxacin	O
+and	O
+norfloxacin	O
+,	O
+were	O
+investigated	O
+in	O
+adult	O
+Charles	O
+Foster	O
+albino	O
+rats	O
+of	O
+either	O
+sex	O
+,	O
+weighing	O
+150	O
+-	O
+200	O
+g	O
+.	O
+
+METHODS	O
+:	O
+The	O
+drugs	O
+were	O
+given	O
+orally	O
+,	O
+in	O
+doses	O
+of	O
+50	O
+mg	O
+/	O
+kg	O
+for	O
+five	O
+consecutive	O
+days	O
+and	O
+the	O
+experiments	O
+were	O
+performed	O
+on	O
+the	O
+fifth	O
+day	O
+.	O
+
+The	O
+tests	O
+included	O
+open	O
+-	O
+field	O
+exploratory	O
+behaviour	O
+,	O
+elevated	O
+plus	O
+maze	O
+and	O
+elevated	O
+zero	O
+maze	O
+,	O
+social	O
+interaction	O
+and	O
+novelty	O
+-	O
+suppressed	O
+feeding	O
+latency	O
+behaviour	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+results	O
+indicate	O
+that	O
+ciprofloxacin	O
+-	O
+and	O
+norfloxacin	O
+-	O
+treated	O
+rats	O
+showed	O
+anxious	B
+behaviour	I
+in	O
+comparison	O
+to	O
+control	O
+rats	O
+in	O
+all	O
+the	O
+parameters	O
+studied	O
+.	O
+
+However	O
+,	O
+ciprofloxacin	O
+-	O
+and	O
+norfloxacin	O
+-	O
+treated	O
+rats	O
+did	O
+not	O
+differ	O
+significantly	O
+from	O
+each	O
+other	O
+in	O
+various	O
+behavioural	O
+parameters	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+present	O
+experimental	O
+findings	O
+substantiate	O
+the	O
+clinically	O
+observed	O
+anxiogenic	O
+potential	O
+of	O
+ciprofloxacin	O
+and	O
+norfloxacin	O
+.	O
+
+Reduction	O
+of	O
+pain	B
+during	O
+induction	O
+with	O
+target	O
+-	O
+controlled	O
+propofol	O
+and	O
+remifentanil	O
+.	O
+
+BACKGROUND	O
+:	O
+Pain	B
+on	O
+injection	O
+of	O
+propofol	O
+is	O
+unpleasant	O
+.	O
+
+We	O
+hypothesized	O
+that	O
+propofol	O
+infusion	O
+pain	B
+might	O
+be	O
+prevented	O
+by	O
+infusing	O
+remifentanil	O
+before	O
+starting	O
+the	O
+propofol	O
+infusion	O
+in	O
+a	O
+clinical	O
+setting	O
+where	O
+target	O
+-	O
+controlled	O
+infusions	O
+(	O
+TCI	O
+)	O
+of	O
+both	O
+drugs	O
+were	O
+used	O
+.	O
+
+A	O
+prospective	O
+,	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+trial	O
+was	O
+performed	O
+to	O
+determine	O
+the	O
+effect	O
+-	O
+site	O
+concentration	O
+(	O
+Ce	O
+)	O
+of	O
+remifentanil	O
+to	O
+prevent	O
+the	O
+pain	B
+without	O
+producing	O
+complications	O
+.	O
+
+METHODS	O
+:	O
+A	O
+total	O
+of	O
+128	O
+patients	O
+undergoing	O
+general	O
+surgery	O
+were	O
+randomly	O
+allocated	O
+to	O
+receive	O
+normal	O
+saline	O
+(	O
+control	O
+)	O
+or	O
+remifentanil	O
+to	O
+a	O
+target	O
+Ce	O
+of	O
+2	O
+ng	O
+ml	O
+(	O
+-	O
+1	O
+)	O
+(	O
+R2	O
+)	O
+,	O
+4	O
+ng	O
+ml	O
+(	O
+-	O
+1	O
+)	O
+(	O
+R4	O
+)	O
+,	O
+or	O
+6	O
+ng	O
+ml	O
+(	O
+-	O
+1	O
+)	O
+(	O
+R6	O
+)	O
+administered	O
+via	O
+TCI	O
+.	O
+
+After	O
+the	O
+target	O
+Ce	O
+was	O
+achieved	O
+,	O
+the	O
+infusion	O
+of	O
+propofol	O
+was	O
+started	O
+.	O
+
+Remifentanil	O
+-	O
+related	O
+complications	O
+were	O
+assessed	O
+during	O
+the	O
+remifentanil	O
+infusion	O
+,	O
+and	O
+pain	B
+caused	O
+by	O
+propofol	O
+was	O
+evaluated	O
+using	O
+a	O
+four	O
+-	O
+point	O
+scale	O
+during	O
+the	O
+propofol	O
+infusion	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+incidence	O
+of	O
+pain	B
+was	O
+significantly	O
+lower	O
+in	O
+Groups	O
+R4	O
+and	O
+R6	O
+than	O
+in	O
+the	O
+control	O
+and	O
+R2	O
+groups	O
+(	O
+12	O
+/	O
+32	O
+and	O
+6	O
+/	O
+31	O
+vs	O
+26	O
+/	O
+31	O
+and	O
+25	O
+/	O
+32	O
+,	O
+respectively	O
+,	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Pain	B
+was	O
+less	O
+severe	O
+in	O
+Groups	O
+R4	O
+and	O
+R6	O
+than	O
+in	O
+the	O
+control	O
+and	O
+R2	O
+groups	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+However	O
+,	O
+both	O
+incidence	O
+and	O
+severity	O
+of	O
+pain	B
+were	O
+not	O
+different	O
+between	O
+Groups	O
+R4	O
+and	O
+R6	O
+.	O
+
+No	O
+significant	O
+complications	O
+were	O
+observed	O
+during	O
+the	O
+study	O
+.	O
+
+CONCLUSIONS	O
+:	O
+During	O
+induction	O
+of	O
+anaesthesia	O
+with	O
+TCI	O
+of	O
+propofol	O
+and	O
+remifentanil	O
+,	O
+a	O
+significant	O
+reduction	O
+in	O
+propofol	O
+infusion	O
+pain	B
+was	O
+achieved	O
+without	O
+significant	O
+complications	O
+by	O
+prior	O
+administration	O
+of	O
+remifentanil	O
+at	O
+a	O
+target	O
+Ce	O
+of	O
+4	O
+ng	O
+ml	O
+(	O
+-	O
+1	O
+)	O
+.	O
+
+Dexmedetomidine	O
+and	O
+cardiac	O
+protection	O
+for	O
+non	O
+-	O
+cardiac	O
+surgery	O
+:	O
+a	O
+meta	O
+-	O
+analysis	O
+of	O
+randomised	O
+controlled	O
+trials	O
+.	O
+
+We	O
+conducted	O
+a	O
+systematic	O
+review	O
+of	O
+the	O
+effects	O
+of	O
+dexmedetomidine	O
+on	O
+cardiac	O
+outcomes	O
+following	O
+non	O
+-	O
+cardiac	O
+surgery	O
+.	O
+
+We	O
+included	O
+prospective	O
+,	O
+randomised	O
+peri	O
+-	O
+operative	O
+studies	O
+of	O
+dexmedetomidine	O
+that	O
+reported	O
+mortality	O
+,	O
+cardiac	O
+morbidity	O
+or	O
+adverse	O
+drug	O
+events	O
+.	O
+
+A	O
+PubMed	O
+Central	O
+and	O
+EMBASE	O
+search	O
+was	O
+conducted	O
+up	O
+to	O
+July	O
+2007	O
+.	O
+
+The	O
+reference	O
+lists	O
+of	O
+identified	O
+papers	O
+were	O
+examined	O
+for	O
+further	O
+trials	O
+.	O
+
+Of	O
+425	O
+studies	O
+identified	O
+,	O
+20	O
+were	O
+included	O
+in	O
+the	O
+meta	O
+-	O
+analysis	O
+(	O
+840	O
+patients	O
+)	O
+.	O
+
+Dexmedetomidine	O
+was	O
+associated	O
+with	O
+a	O
+trend	O
+towards	O
+improved	O
+cardiac	O
+outcomes	O
+;	O
+all	O
+-	O
+cause	O
+mortality	O
+(	O
+OR	O
+0	O
+.	O
+27	O
+,	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+01	O
+-	O
+7	O
+.	O
+13	O
+,	O
+p	O
+=	O
+0	O
+.	O
+44	O
+)	O
+,	O
+non	O
+-	O
+fatal	O
+myocardial	B
+infarction	I
+(	O
+OR	O
+0	O
+.	O
+26	O
+,	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+04	O
+-	O
+1	O
+.	O
+60	O
+,	O
+p	O
+=	O
+0	O
+.	O
+14	O
+)	O
+,	O
+and	O
+myocardial	B
+ischaemia	I
+(	O
+OR	O
+0	O
+.	O
+65	O
+,	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+26	O
+-	O
+1	O
+.	O
+63	O
+,	O
+p	O
+=	O
+0	O
+.	O
+36	O
+)	O
+.	O
+
+Peri	O
+-	O
+operative	O
+hypotension	B
+(	O
+26	O
+%	O
+,	O
+OR	O
+3	O
+.	O
+80	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+91	O
+-	O
+7	O
+.	O
+54	O
+,	O
+p	O
+=	O
+0	O
+.	O
+0001	O
+)	O
+and	O
+bradycardia	B
+(	O
+17	O
+%	O
+,	O
+OR	O
+5	O
+.	O
+45	O
+,	O
+95	O
+%	O
+CI	O
+2	O
+.	O
+98	O
+-	O
+9	O
+.	O
+95	O
+,	O
+p	O
+<	O
+0	O
+.	O
+00001	O
+)	O
+were	O
+significantly	O
+increased	O
+.	O
+
+An	O
+anticholinergic	O
+did	O
+not	O
+reduce	O
+the	O
+incidence	O
+of	O
+bradycardia	B
+(	O
+p	O
+=	O
+0	O
+.	O
+43	O
+)	O
+.	O
+
+A	O
+randomised	O
+placebo	O
+-	O
+controlled	O
+trial	O
+of	O
+dexmedetomidine	O
+is	O
+warranted	O
+.	O
+
+Myocardial	B
+infarction	I
+in	O
+pregnancy	O
+associated	O
+with	O
+clomiphene	O
+citrate	O
+for	O
+ovulation	O
+induction	O
+:	O
+a	O
+case	O
+report	O
+.	O
+
+BACKGROUND	O
+:	O
+Clomiphene	O
+citrate	O
+(	O
+CC	O
+)	O
+is	O
+commonly	O
+prescribed	O
+for	O
+ovulation	O
+induction	O
+.	O
+
+It	O
+is	O
+considered	O
+safe	O
+,	O
+with	O
+minimal	O
+side	O
+effects	O
+.	O
+
+Thromboembolism	B
+is	O
+a	O
+rare	O
+but	O
+life	O
+-	O
+threatening	O
+complication	O
+that	O
+has	O
+been	O
+reported	O
+after	O
+ovulation	O
+induction	O
+with	O
+CC	O
+.	O
+
+Spontaneous	O
+coronary	B
+thrombosis	I
+or	O
+thromboembolism	B
+with	O
+subsequent	O
+clot	O
+lysis	O
+has	O
+been	O
+suggested	O
+as	O
+one	O
+of	O
+the	O
+most	O
+common	O
+causes	O
+of	O
+myocardial	B
+infarction	I
+(	O
+MI	B
+)	O
+during	O
+pregnancy	O
+,	O
+with	O
+a	O
+subsequently	O
+normal	O
+coronary	O
+angiogram	O
+.	O
+
+CASE	O
+:	O
+A	O
+33	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+a	O
+5	O
+-	O
+week	O
+gestation	O
+had	O
+recently	O
+received	O
+CC	O
+for	O
+ovulation	O
+induction	O
+and	O
+presented	O
+with	O
+chest	B
+pain	I
+.	O
+
+An	O
+electrocardiogram	O
+showed	O
+a	O
+lateral	O
+and	O
+anterior	O
+wall	O
+myocardial	B
+infarction	I
+.	O
+
+Cardiac	O
+enzymes	O
+showed	O
+a	O
+peak	O
+rise	O
+in	O
+troponin	O
+I	O
+to	O
+9	O
+.	O
+10	O
+ng	O
+/	O
+mL	O
+.	O
+
+An	O
+initial	O
+exercise	O
+stress	O
+test	O
+was	O
+normal	O
+.	O
+
+At	O
+the	O
+time	O
+of	O
+admission	O
+,	O
+the	O
+patient	O
+was	O
+at	O
+high	O
+risk	O
+of	O
+radiation	B
+injury	I
+to	O
+the	O
+fetus	O
+,	O
+so	O
+a	O
+coronary	O
+angiogram	O
+was	O
+postponed	O
+until	O
+the	O
+second	O
+trimester	O
+.	O
+
+It	O
+showed	O
+normal	O
+coronary	O
+vessels	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+appears	O
+to	O
+be	O
+the	O
+first	O
+reported	O
+case	O
+documenting	O
+a	O
+possible	O
+association	O
+between	O
+CC	O
+and	O
+myocardial	B
+infarction	I
+.	O
+
+Thrombosis	B
+might	O
+be	O
+a	O
+rare	O
+but	O
+hazardous	O
+complication	O
+of	O
+CC	O
+.	O
+
+Given	O
+this	O
+life	O
+-	O
+threatening	O
+complication	O
+,	O
+appropriate	O
+prophylactic	O
+measures	O
+should	O
+be	O
+used	O
+in	O
+high	O
+-	O
+risk	O
+woman	O
+undergoing	O
+ovarian	O
+stimulation	O
+.	O
+
+Reverse	O
+or	O
+inverted	O
+left	B
+ventricular	I
+apical	I
+ballooning	I
+syndrome	I
+(	O
+reverse	O
+Takotsubo	B
+cardiomyopathy	I
+)	O
+in	O
+a	O
+young	O
+woman	O
+in	O
+the	O
+setting	O
+of	O
+amphetamine	O
+use	O
+.	O
+
+Transient	O
+left	B
+ventricular	I
+apical	I
+ballooning	I
+syndrome	I
+was	O
+first	O
+described	O
+in	O
+Japan	O
+as	O
+"	O
+Takotsubo	B
+cardiomyopathy	I
+.	O
+"	O
+This	O
+syndrome	O
+has	O
+been	O
+identified	O
+in	O
+many	O
+other	O
+countries	O
+.	O
+
+Many	O
+variations	O
+of	O
+this	O
+syndrome	O
+have	O
+been	O
+recently	O
+described	O
+in	O
+the	O
+literature	O
+.	O
+
+One	O
+of	O
+the	O
+rarest	O
+is	O
+the	O
+reverse	O
+type	O
+of	O
+this	O
+syndrome	O
+,	O
+with	O
+hyperdynamic	O
+apex	O
+and	O
+complete	O
+akinesia	B
+of	O
+the	O
+base	O
+(	O
+as	O
+opposed	O
+to	O
+the	O
+classic	O
+apical	B
+ballooning	I
+)	O
+.	O
+
+In	O
+this	O
+article	O
+,	O
+we	O
+report	O
+an	O
+interesting	O
+case	O
+of	O
+a	O
+young	O
+woman	O
+who	O
+presented	O
+with	O
+this	O
+rare	O
+type	O
+of	O
+reverse	O
+apical	B
+ballooning	I
+syndrome	I
+occurring	O
+after	O
+amphetamine	O
+use	O
+.	O
+
+This	O
+report	O
+is	O
+followed	O
+by	O
+review	O
+of	O
+the	O
+literature	O
+.	O
+
+Results	O
+of	O
+a	O
+comparative	O
+,	O
+phase	O
+III	O
+,	O
+12	O
+-	O
+week	O
+,	O
+multicenter	O
+,	O
+prospective	O
+,	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+assessment	O
+of	O
+the	O
+efficacy	O
+and	O
+tolerability	O
+of	O
+a	O
+fixed	O
+-	O
+dose	O
+combination	O
+of	O
+telmisartan	O
+and	O
+amlodipine	O
+versus	O
+amlodipine	O
+monotherapy	O
+in	O
+Indian	O
+adults	O
+with	O
+stage	O
+II	O
+hypertension	B
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+evaluate	O
+the	O
+efficacy	O
+and	O
+tolerability	O
+of	O
+a	O
+new	O
+fixed	O
+-	O
+dose	O
+combination	O
+(	O
+FDC	O
+)	O
+of	O
+telmisartan	O
+40	O
+mg	O
++	O
+amlodipine	O
+5	O
+mg	O
+(	O
+T	O
++	O
+A	O
+)	O
+compared	O
+with	O
+amlodipine	O
+5	O
+-	O
+mg	O
+monotherapy	O
+(	O
+A	O
+)	O
+in	O
+adult	O
+Indian	O
+patients	O
+with	O
+stage	O
+II	O
+hypertension	B
+.	O
+
+METHODS	O
+:	O
+This	O
+comparative	O
+,	O
+Phase	O
+III	O
+,	O
+12	O
+-	O
+week	O
+,	O
+multicenter	O
+,	O
+prospective	O
+,	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+study	O
+was	O
+conducted	O
+in	O
+Indian	O
+patients	O
+aged	O
+18	O
+to	O
+65	O
+years	O
+with	O
+established	O
+stage	O
+II	O
+hypertension	B
+.	O
+
+Patients	O
+were	O
+treated	O
+with	O
+oral	O
+FDC	O
+of	O
+T	O
++	O
+A	O
+or	O
+A	O
+QD	O
+before	O
+breakfast	O
+for	O
+12	O
+weeks	O
+;	O
+blood	O
+pressure	O
+(	O
+BP	O
+)	O
+and	O
+heart	O
+rate	O
+were	O
+measured	O
+in	O
+the	O
+sitting	O
+position	O
+.	O
+
+Primary	O
+efficacy	O
+end	O
+points	O
+were	O
+reduction	O
+in	O
+clinical	O
+systolic	O
+BP	O
+(	O
+SBP	O
+)	O
+/	O
+diastolic	O
+BP	O
+(	O
+DBP	O
+)	O
+from	O
+baseline	O
+to	O
+study	O
+end	O
+and	O
+number	O
+of	O
+responders	O
+(	O
+ie	O
+,	O
+patients	O
+who	O
+achieved	O
+target	O
+SBP	O
+/	O
+DBP	O
+<	O
+130	O
+/	O
+<	O
+80	O
+mm	O
+Hg	O
+)	O
+at	O
+end	O
+of	O
+study	O
+.	O
+
+Tolerability	O
+was	O
+assessed	O
+by	O
+treatment	O
+-	O
+emergent	O
+adverse	O
+events	O
+,	O
+identified	O
+using	O
+physical	O
+examination	O
+,	O
+laboratory	O
+analysis	O
+,	O
+and	O
+electrocardiography	O
+.	O
+
+RESULTS	O
+:	O
+A	O
+total	O
+of	O
+210	O
+patients	O
+were	O
+enrolled	O
+in	O
+the	O
+study	O
+;	O
+203	O
+patients	O
+(	O
+143	O
+men	O
+,	O
+60	O
+women	O
+)	O
+completed	O
+the	O
+study	O
+while	O
+7	O
+were	O
+lost	O
+to	O
+follow	O
+-	O
+up	O
+(	O
+4	O
+patients	O
+in	O
+the	O
+T	O
++	O
+A	O
+group	O
+and	O
+3	O
+in	O
+the	O
+A	O
+group	O
+)	O
+and	O
+considered	O
+with	O
+-	O
+drawn	O
+.	O
+
+At	O
+study	O
+end	O
+,	O
+statistically	O
+significant	O
+percentage	O
+reductions	O
+from	O
+baseline	O
+within	O
+groups	O
+and	O
+between	O
+groups	O
+were	O
+observed	O
+in	O
+SBP	O
+(	O
+T	O
++	O
+A	O
+[	O
+-	O
+27	O
+.	O
+4	O
+%	O
+]	O
+;	O
+A	O
+[	O
+-	O
+16	O
+.	O
+6	O
+%	O
+]	O
+)	O
+and	O
+DBP	O
+(	O
+T	O
++	O
+A	O
+[	O
+-	O
+20	O
+.	O
+1	O
+%	O
+]	O
+;	O
+A	O
+[	O
+-	O
+13	O
+.	O
+3	O
+%	O
+]	O
+)	O
+(	O
+all	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Response	O
+rates	O
+were	O
+87	O
+.	O
+3	O
+%	O
+(	O
+89	O
+/	O
+102	O
+)	O
+in	O
+the	O
+T	O
++	O
+A	O
+group	O
+and	O
+69	O
+.	O
+3	O
+%	O
+(	O
+70	O
+/	O
+101	O
+)	O
+in	O
+the	O
+A	O
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+prevalences	O
+of	O
+adverse	O
+events	O
+were	O
+not	O
+significantly	O
+different	O
+between	O
+the	O
+2	O
+treatment	O
+groups	O
+(	O
+T	O
++	O
+A	O
+,	O
+16	O
+.	O
+0	O
+%	O
+[	O
+17	O
+/	O
+106	O
+]	O
+;	O
+A	O
+,	O
+15	O
+.	O
+4	O
+%	O
+[	O
+16	O
+/	O
+104	O
+]	O
+)	O
+.	O
+
+Peripheral	O
+edema	B
+was	O
+reported	O
+in	O
+8	O
+.	O
+5	O
+%	O
+patients	O
+(	O
+9	O
+/	O
+106	O
+)	O
+in	O
+the	O
+T	O
++	O
+A	O
+group	O
+compared	O
+with	O
+13	O
+.	O
+5	O
+%	O
+(	O
+14	O
+/	O
+104	O
+)	O
+in	O
+the	O
+A	O
+group	O
+,	O
+and	O
+cough	B
+was	O
+reported	O
+in	O
+3	O
+.	O
+8	O
+%	O
+patients	O
+(	O
+4	O
+/	O
+106	O
+)	O
+in	O
+the	O
+T	O
++	O
+A	O
+group	O
+and	O
+1	O
+.	O
+0	O
+%	O
+(	O
+1	O
+/	O
+104	O
+)	O
+patients	O
+in	O
+the	O
+A	O
+group	O
+;	O
+these	O
+differences	O
+did	O
+not	O
+reach	O
+statistical	O
+significance	O
+.	O
+
+The	O
+incidences	O
+of	O
+headache	B
+,	O
+dizziness	B
+,	O
+and	O
+diarrhea	B
+were	O
+similar	O
+between	O
+the	O
+2	O
+groups	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Among	O
+these	O
+Indian	O
+patients	O
+with	O
+stage	O
+II	O
+hypertension	B
+,	O
+the	O
+FDC	O
+of	O
+T	O
++	O
+A	O
+was	O
+found	O
+to	O
+be	O
+significantly	O
+more	O
+effective	O
+,	O
+with	O
+regard	O
+to	O
+BP	O
+reductions	O
+,	O
+than	O
+A	O
+,	O
+and	O
+both	O
+treatments	O
+were	O
+well	O
+tolerated	O
+.	O
+
+Increased	O
+mental	B
+slowing	I
+associated	O
+with	O
+the	O
+APOE	O
+epsilon4	O
+allele	O
+after	O
+trihexyphenidyl	O
+oral	O
+anticholinergic	O
+challenge	O
+in	O
+healthy	O
+elderly	O
+.	O
+
+OBJECTIVES	O
+:	O
+The	O
+objectives	O
+of	O
+this	O
+study	O
+were	O
+to	O
+examine	O
+the	O
+relationship	O
+between	O
+APOE	O
+epsilon4	O
+and	O
+subjective	O
+effects	O
+of	O
+trihexyphenidyl	O
+on	O
+measures	O
+reflecting	O
+sedation	O
+and	O
+confusion	B
+and	O
+to	O
+investigate	O
+the	O
+relationship	O
+between	O
+trihexyphenidyl	O
+-	O
+induced	O
+subjective	O
+effects	O
+and	O
+objective	O
+memory	O
+performance	O
+.	O
+
+METHODS	O
+:	O
+This	O
+study	O
+comprised	O
+24	O
+cognitively	O
+intact	O
+,	O
+health	O
+elderly	O
+adults	O
+(	O
+12	O
+APOE	O
+epsilon4	O
+carriers	O
+)	O
+at	O
+an	O
+outpatient	O
+geriatric	O
+psychiatry	O
+research	O
+clinic	O
+.	O
+
+This	O
+was	O
+a	O
+randomized	O
+,	O
+double	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+,	O
+three	O
+-	O
+way	O
+,	O
+crossover	O
+experimental	O
+design	O
+.	O
+
+All	O
+participants	O
+received	O
+1	O
+.	O
+0	O
+mg	O
+or	O
+2	O
+.	O
+0	O
+mg	O
+trihexyphenidyl	O
+or	O
+placebo	O
+administered	O
+in	O
+counterbalanced	O
+sequences	O
+over	O
+a	O
+period	O
+of	O
+three	O
+consecutive	O
+weeks	O
+.	O
+
+Bond	O
+and	O
+Lader	O
+'	O
+s	O
+visual	O
+analog	O
+scales	O
+and	O
+alternate	O
+versions	O
+of	O
+the	O
+Buschke	O
+Selective	O
+Reminding	O
+Test	O
+were	O
+administered	O
+in	O
+a	O
+repeated	O
+measures	O
+design	O
+at	O
+baseline	O
+,	O
+1	O
+,	O
+2	O
+.	O
+5	O
+,	O
+and	O
+5	O
+hours	O
+postdrug	O
+administration	O
+.	O
+
+RESULTS	O
+:	O
+A	O
+2	O
+.	O
+0	O
+-	O
+mg	O
+oral	O
+dose	O
+of	O
+trihexyphenidyl	O
+resulted	O
+in	O
+increased	O
+subjective	O
+ratings	O
+of	O
+mental	B
+slowness	I
+in	O
+carriers	O
+of	O
+the	O
+APOE	O
+epsilon4	O
+allele	O
+only	O
+.	O
+
+Drug	O
+effects	O
+as	O
+determined	O
+by	O
+difference	O
+scores	O
+between	O
+2	O
+.	O
+0	O
+mg	O
+trihexyphenidyl	O
+and	O
+placebo	O
+on	O
+ratings	O
+of	O
+mental	B
+slowness	I
+significantly	O
+correlated	O
+with	O
+total	O
+and	O
+delayed	O
+recall	O
+on	O
+the	O
+Buschke	O
+Selective	O
+Reminding	O
+Test	O
+in	O
+carriers	O
+of	O
+the	O
+APOE	O
+epsilon4	O
+allele	O
+only	O
+.	O
+
+However	O
+,	O
+no	O
+significant	O
+effects	O
+were	O
+found	O
+with	O
+other	O
+visual	O
+analog	O
+scales	O
+reflecting	O
+subjective	O
+sedation	O
+and	O
+clear	O
+-	O
+headedness	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+epsilon4	O
+allele	O
+in	O
+healthy	O
+elderly	O
+was	O
+associated	O
+with	O
+increased	O
+subjective	O
+mental	B
+slowing	I
+after	O
+trihexyphenidyl	O
+anticholinergic	O
+challenge	O
+.	O
+
+An	O
+evaluation	O
+of	O
+amikacin	O
+nephrotoxicity	B
+in	O
+the	O
+hematology	O
+/	O
+oncology	O
+population	O
+.	O
+
+Amikacin	O
+is	O
+an	O
+aminoglycoside	O
+commonly	O
+used	O
+to	O
+provide	O
+empirical	O
+double	O
+gram	O
+-	O
+negative	O
+treatment	O
+for	O
+febrile	B
+neutropenia	I
+and	O
+other	O
+suspected	O
+infections	B
+.	O
+
+Strategies	O
+of	O
+extended	O
+-	O
+interval	O
+and	O
+conventional	O
+dosing	O
+have	O
+been	O
+utilized	O
+extensively	O
+in	O
+the	O
+general	O
+medical	O
+population	O
+;	O
+however	O
+,	O
+data	O
+are	O
+lacking	O
+to	O
+support	O
+a	O
+dosing	O
+strategy	O
+in	O
+the	O
+hematology	O
+/	O
+oncology	O
+population	O
+.	O
+
+To	O
+evaluate	O
+amikacin	O
+-	O
+associated	O
+nephrotoxicity	B
+in	O
+an	O
+adult	O
+hematology	O
+/	O
+oncology	O
+population	O
+,	O
+a	O
+prospective	O
+,	O
+randomized	O
+,	O
+open	O
+-	O
+label	O
+trial	O
+was	O
+conducted	O
+at	O
+a	O
+university	O
+-	O
+affiliated	O
+medical	O
+center	O
+.	O
+
+Forty	O
+patients	O
+with	O
+a	O
+diagnosis	O
+consistent	O
+with	O
+a	O
+hematologic	B
+/	I
+oncologic	I
+disorder	I
+that	O
+required	O
+treatment	O
+with	O
+an	O
+aminoglycoside	O
+were	O
+randomized	O
+to	O
+either	O
+conventional	O
+or	O
+extended	O
+-	O
+interval	O
+amikacin	O
+.	O
+
+The	O
+occurrence	O
+of	O
+nephrotoxicity	B
+by	O
+means	O
+of	O
+an	O
+increase	O
+in	O
+serum	O
+creatinine	O
+and	O
+evaluation	O
+of	O
+efficacy	O
+via	O
+amikacin	O
+serum	O
+concentrations	O
+with	O
+respective	O
+pathogens	O
+were	O
+assessed	O
+.	O
+
+The	O
+occurrence	O
+of	O
+nephrotoxicity	B
+was	O
+similar	O
+between	O
+the	O
+conventional	O
+and	O
+extended	O
+-	O
+interval	O
+groups	O
+,	O
+at	O
+10	O
+%	O
+and	O
+5	O
+%	O
+,	O
+respectively	O
+(	O
+P	O
+=	O
+1	O
+.	O
+00	O
+)	O
+.	O
+
+Six	O
+patients	O
+in	O
+the	O
+conventional	O
+group	O
+had	O
+a	O
+positive	O
+culture	O
+,	O
+compared	O
+with	O
+none	O
+in	O
+the	O
+extended	O
+-	O
+interval	O
+group	O
+(	O
+P	O
+=	O
+0	O
+.	O
+002	O
+)	O
+.	O
+
+The	O
+occurrence	O
+of	O
+nephrotoxicity	B
+was	O
+similar	O
+between	O
+the	O
+two	O
+dosing	O
+regimens	O
+,	O
+but	O
+the	O
+distribution	O
+of	O
+risk	O
+factors	O
+was	O
+variable	O
+between	O
+the	O
+two	O
+groups	O
+.	O
+
+Efficacy	O
+could	O
+not	O
+be	O
+assessed	O
+.	O
+
+High	O
+dose	O
+dexmedetomidine	O
+as	O
+the	O
+sole	O
+sedative	O
+for	O
+pediatric	O
+MRI	O
+.	O
+
+OBJECTIVE	O
+:	O
+This	O
+large	O
+-	O
+scale	O
+retrospective	O
+review	O
+evaluates	O
+the	O
+sedation	O
+profile	O
+of	O
+dexmedetomidine	O
+.	O
+
+AIM	O
+:	O
+To	O
+determine	O
+the	O
+hemodynamic	O
+responses	O
+,	O
+efficacy	O
+and	O
+adverse	O
+events	O
+associated	O
+with	O
+the	O
+use	O
+of	O
+high	O
+dose	O
+dexmedetomidine	O
+as	O
+the	O
+sole	O
+sedative	O
+for	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+studies	O
+.	O
+
+BACKGROUND	O
+:	O
+Dexmedetomidine	O
+has	O
+been	O
+used	O
+at	O
+our	O
+institution	O
+since	O
+2005	O
+to	O
+provide	O
+sedation	O
+for	O
+pediatric	O
+radiological	O
+imaging	O
+studies	O
+.	O
+
+Over	O
+time	O
+,	O
+an	O
+effective	O
+protocol	O
+utilizing	O
+high	O
+dose	O
+dexmedetomidine	O
+as	O
+the	O
+sole	O
+sedative	O
+agent	O
+has	O
+evolved	O
+.	O
+
+METHODS	O
+/	O
+MATERIALS	O
+:	O
+As	O
+part	O
+of	O
+the	O
+ongoing	O
+Quality	O
+Assurance	O
+process	O
+,	O
+data	O
+on	O
+all	O
+sedations	O
+are	O
+reviewed	O
+monthly	O
+and	O
+protocols	O
+modified	O
+as	O
+needed	O
+.	O
+
+Data	O
+were	O
+analyzed	O
+from	O
+all	O
+747	O
+consecutive	O
+patients	O
+who	O
+received	O
+dexmedetomidine	O
+for	O
+MRI	O
+sedation	O
+from	O
+April	O
+2005	O
+to	O
+April	O
+2007	O
+.	O
+
+RESULTS	O
+:	O
+Since	O
+2005	O
+,	O
+the	O
+10	O
+-	O
+min	O
+loading	O
+dose	O
+of	O
+our	O
+dexmedetomidine	O
+protocol	O
+increased	O
+from	O
+2	O
+to	O
+3	O
+microg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+,	O
+and	O
+the	O
+infusion	O
+rate	O
+increased	O
+from	O
+1	O
+to	O
+1	O
+.	O
+5	O
+to	O
+2	O
+microg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+h	O
+(	O
+-	O
+1	O
+)	O
+.	O
+
+The	O
+current	O
+sedation	O
+protocol	O
+progressively	O
+increased	O
+the	O
+rate	O
+of	O
+successful	O
+sedation	O
+(	O
+able	O
+to	O
+complete	O
+the	O
+imaging	O
+study	O
+)	O
+when	O
+using	O
+dexmedetomidine	O
+alone	O
+from	O
+91	O
+.	O
+8	O
+%	O
+to	O
+97	O
+.	O
+6	O
+%	O
+(	O
+P	O
+=	O
+0	O
+.	O
+009	O
+)	O
+,	O
+reducing	O
+the	O
+requirement	O
+for	O
+adjuvant	O
+pentobarbital	O
+in	O
+the	O
+event	O
+of	O
+sedation	O
+failure	O
+with	O
+dexmedetomidine	O
+alone	O
+and	O
+decreased	O
+the	O
+mean	O
+recovery	O
+time	O
+by	O
+10	O
+min	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Although	O
+dexmedetomidine	O
+sedation	O
+was	O
+associated	O
+with	O
+a	O
+16	O
+%	O
+incidence	O
+of	O
+bradycardia	B
+,	O
+all	O
+concomitant	O
+mean	O
+arterial	O
+blood	O
+pressures	O
+were	O
+within	O
+20	O
+%	O
+of	O
+age	O
+-	O
+adjusted	O
+normal	O
+range	O
+and	O
+oxygen	O
+saturations	O
+were	O
+95	O
+%	O
+or	O
+higher	O
+.	O
+
+CONCLUSION	O
+:	O
+Dexmedetomidine	O
+in	O
+high	O
+doses	O
+provides	O
+adequate	O
+sedation	O
+for	O
+pediatric	O
+MRI	O
+studies	O
+.	O
+
+While	O
+use	O
+of	O
+high	O
+dose	O
+dexmedetomidine	O
+is	O
+associated	O
+with	O
+decreases	O
+in	O
+heart	O
+rate	O
+and	O
+blood	O
+pressure	O
+outside	O
+the	O
+established	O
+'	O
+awake	O
+'	O
+norms	O
+,	O
+this	O
+deviation	O
+is	O
+generally	O
+within	O
+20	O
+%	O
+of	O
+norms	O
+,	O
+and	O
+is	O
+not	O
+associated	O
+with	O
+adverse	O
+sequelae	O
+.	O
+
+Dexmedetomidine	O
+is	O
+useful	O
+as	O
+the	O
+sole	O
+sedative	O
+for	O
+pediatric	O
+MRI	O
+.	O
+
+Hepatotoxicity	B
+associated	O
+with	O
+sulfasalazine	O
+in	O
+inflammatory	O
+arthritis	B
+:	O
+A	O
+case	O
+series	O
+from	O
+a	O
+local	O
+surveillance	O
+of	O
+serious	O
+adverse	O
+events	O
+.	O
+
+BACKGROUND	O
+:	O
+Spontaneous	O
+reporting	O
+systems	O
+for	O
+adverse	O
+drug	O
+reactions	O
+(	O
+ADRs	O
+)	O
+are	O
+handicapped	O
+by	O
+under	O
+-	O
+reporting	O
+and	O
+limited	O
+detail	O
+on	O
+individual	O
+cases	O
+.	O
+
+We	O
+report	O
+an	O
+investigation	O
+from	O
+a	O
+local	O
+surveillance	O
+for	O
+serious	O
+adverse	O
+drug	O
+reactions	O
+associated	O
+with	O
+disease	O
+modifying	O
+anti	O
+-	O
+rheumatic	O
+drugs	O
+that	O
+was	O
+triggered	O
+by	O
+the	O
+occurrence	O
+of	O
+liver	B
+failure	I
+in	O
+two	O
+of	O
+our	O
+patients	O
+.	O
+
+METHODS	O
+:	O
+Serious	O
+ADR	O
+reports	O
+have	O
+been	O
+solicited	O
+from	O
+local	O
+clinicians	O
+by	O
+regular	O
+postcards	O
+over	O
+the	O
+past	O
+seven	O
+years	O
+.	O
+
+Patients	O
+'	O
+,	O
+who	O
+had	O
+hepatotoxicity	B
+on	O
+sulfasalazine	O
+and	O
+met	O
+a	O
+definition	O
+of	O
+a	O
+serious	O
+ADR	O
+,	O
+were	O
+identified	O
+.	O
+
+Two	O
+clinicians	O
+reviewed	O
+structured	O
+case	O
+reports	O
+and	O
+assessed	O
+causality	O
+by	O
+consensus	O
+and	O
+by	O
+using	O
+a	O
+causality	O
+assessment	O
+instrument	O
+.	O
+
+The	O
+likely	O
+frequency	O
+of	O
+hepatotoxicity	B
+with	O
+sulfasalazine	O
+was	O
+estimated	O
+by	O
+making	O
+a	O
+series	O
+of	O
+conservative	O
+assumptions	O
+.	O
+
+RESULTS	O
+:	O
+Ten	O
+cases	O
+were	O
+identified	O
+:	O
+eight	O
+occurred	O
+during	O
+surveillance	O
+.	O
+
+Eight	O
+patients	O
+were	O
+hospitalised	O
+,	O
+two	O
+in	O
+hepatic	B
+failure	I
+-	O
+one	O
+died	O
+after	O
+a	O
+liver	O
+transplant	O
+.	O
+
+All	O
+but	O
+one	O
+event	O
+occurred	O
+within	O
+6	O
+weeks	O
+of	O
+treatment	O
+.	O
+
+Seven	O
+patients	O
+had	O
+a	O
+skin	B
+rash	I
+,	O
+three	O
+eosinophilia	B
+and	O
+one	O
+interstitial	B
+nephritis	I
+.	O
+
+Five	O
+patients	O
+were	O
+of	O
+Black	O
+British	O
+of	O
+African	O
+or	O
+Caribbean	O
+descent	O
+.	O
+
+Liver	O
+enzymes	O
+showed	O
+a	O
+hepatocellular	O
+pattern	O
+in	O
+four	O
+cases	O
+and	O
+a	O
+mixed	O
+pattern	O
+in	O
+six	O
+.	O
+
+Drug	O
+-	O
+related	O
+hepatotoxicity	B
+was	O
+judged	O
+probable	O
+or	O
+highly	O
+probable	O
+in	O
+8	O
+patients	O
+.	O
+
+The	O
+likely	O
+frequency	O
+of	O
+serious	O
+hepatotoxicity	B
+with	O
+sulfasalazine	O
+was	O
+estimated	O
+at	O
+0	O
+.	O
+4	O
+%	O
+of	O
+treated	O
+patients	O
+.	O
+
+CONCLUSION	O
+:	O
+Serious	O
+hepatotoxicity	B
+associated	O
+with	O
+sulfasalazine	O
+appears	O
+to	O
+be	O
+under	O
+-	O
+appreciated	O
+and	O
+intensive	O
+monitoring	O
+and	O
+vigilance	O
+in	O
+the	O
+first	O
+6	O
+weeks	O
+of	O
+treatment	O
+is	O
+especially	O
+important	O
+.	O
+
+Complete	O
+atrioventricular	B
+block	I
+secondary	O
+to	O
+lithium	O
+therapy	O
+.	O
+
+Sinus	B
+node	I
+dysfunction	I
+has	O
+been	O
+reported	O
+most	O
+frequently	O
+among	O
+the	O
+adverse	O
+cardiovascular	O
+effects	O
+of	O
+lithium	O
+.	O
+
+In	O
+the	O
+present	O
+case	O
+,	O
+complete	O
+atrioventricular	B
+(	I
+AV	I
+)	I
+block	I
+with	O
+syncopal	B
+attacks	I
+developed	O
+secondary	O
+to	O
+lithium	O
+therapy	O
+,	O
+necessitating	O
+permanent	O
+pacemaker	O
+implantation	O
+.	O
+
+Serum	O
+lithium	O
+levels	O
+remained	O
+under	O
+or	O
+within	O
+the	O
+therapeutic	O
+range	O
+during	O
+the	O
+syncopal	B
+attacks	I
+.	O
+
+Lithium	O
+should	O
+be	O
+used	O
+with	O
+extreme	O
+caution	O
+,	O
+especially	O
+in	O
+patients	O
+with	O
+mild	O
+disturbance	O
+of	O
+AV	O
+conduction	O
+.	O
+
+Exaggerated	O
+expression	O
+of	O
+inflammatory	O
+mediators	O
+in	O
+vasoactive	O
+intestinal	O
+polypeptide	O
+knockout	O
+(	O
+VIP	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+with	O
+cyclophosphamide	O
+(	O
+CYP	O
+)	O
+-	O
+induced	O
+cystitis	B
+.	O
+
+Vasoactive	O
+intestinal	O
+polypeptide	O
+(	O
+VIP	O
+)	O
+is	O
+an	O
+immunomodulatory	O
+neuropeptide	O
+distributed	O
+in	O
+micturition	O
+pathways	O
+.	O
+
+VIP	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+exhibit	O
+altered	O
+bladder	O
+function	O
+and	O
+neurochemical	O
+properties	O
+in	O
+micturition	O
+pathways	O
+after	O
+cyclophosphamide	O
+(	O
+CYP	O
+)	O
+-	O
+induced	O
+cystitis	B
+.	O
+
+Given	O
+VIP	O
+'	O
+s	O
+role	O
+as	O
+an	O
+anti	O
+-	O
+inflammatory	O
+mediator	O
+,	O
+we	O
+hypothesized	O
+that	O
+VIP	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+would	O
+exhibit	O
+enhanced	O
+inflammatory	O
+mediator	O
+expression	O
+after	O
+cystitis	B
+.	O
+
+A	O
+mouse	O
+inflammatory	O
+cytokine	O
+and	O
+receptor	O
+RT2	O
+profiler	O
+array	O
+was	O
+used	O
+to	O
+determine	O
+regulated	O
+transcripts	O
+in	O
+the	O
+urinary	O
+bladder	O
+of	O
+wild	O
+type	O
+(	O
+WT	O
+)	O
+and	O
+VIP	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+with	O
+or	O
+without	O
+CYP	O
+-	O
+induced	O
+cystitis	B
+(	O
+150	O
+mg	O
+/	O
+kg	O
+;	O
+i	O
+.	O
+p	O
+.	O
+;	O
+48	O
+h	O
+)	O
+.	O
+
+Four	O
+binary	O
+comparisons	O
+were	O
+made	O
+:	O
+WT	O
+control	O
+versus	O
+CYP	O
+treatment	O
+(	O
+48	O
+h	O
+)	O
+,	O
+VIP	O
+(	O
+-	O
+/	O
+-	O
+)	O
+control	O
+versus	O
+CYP	O
+treatment	O
+(	O
+48	O
+h	O
+)	O
+,	O
+WT	O
+control	O
+versus	O
+VIP	O
+(	O
+-	O
+/	O
+-	O
+)	O
+control	O
+,	O
+and	O
+WT	O
+with	O
+CYP	O
+treatment	O
+(	O
+48	O
+h	O
+)	O
+versus	O
+VIP	O
+(	O
+-	O
+/	O
+-	O
+)	O
+with	O
+CYP	O
+treatment	O
+(	O
+48	O
+h	O
+)	O
+.	O
+
+The	O
+genes	O
+presented	O
+represent	O
+(	O
+1	O
+)	O
+greater	O
+than	O
+1	O
+.	O
+5	O
+-	O
+fold	O
+change	O
+in	O
+either	O
+direction	O
+and	O
+(	O
+2	O
+)	O
+the	O
+p	O
+value	O
+is	O
+less	O
+than	O
+0	O
+.	O
+05	O
+for	O
+the	O
+comparison	O
+being	O
+made	O
+.	O
+
+Several	O
+regulated	O
+genes	O
+were	O
+validated	O
+using	O
+enzyme	O
+-	O
+linked	O
+immunoassays	O
+including	O
+IL	O
+-	O
+1beta	O
+and	O
+CXCL1	O
+.	O
+
+CYP	O
+treatment	O
+significantly	O
+(	O
+p	O
+<	O
+or	O
+=	O
+0	O
+.	O
+001	O
+)	O
+increased	O
+expression	O
+of	O
+CXCL1	O
+and	O
+IL	O
+-	O
+1beta	O
+in	O
+the	O
+urinary	O
+bladder	O
+of	O
+WT	O
+and	O
+VIP	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+,	O
+but	O
+expression	O
+in	O
+VIP	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+with	O
+CYP	O
+treatment	O
+was	O
+significantly	O
+(	O
+p	O
+<	O
+or	O
+=	O
+0	O
+.	O
+001	O
+)	O
+greater	O
+(	O
+4	O
+.	O
+2	O
+-	O
+to	O
+13	O
+-	O
+fold	O
+increase	O
+)	O
+than	O
+that	O
+observed	O
+in	O
+WT	O
+urinary	O
+bladder	O
+(	O
+3	O
+.	O
+6	O
+-	O
+to	O
+5	O
+-	O
+fold	O
+increase	O
+)	O
+.	O
+
+The	O
+data	O
+suggest	O
+that	O
+in	O
+VIP	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+with	O
+bladder	B
+inflammation	I
+,	O
+inflammatory	O
+mediators	O
+are	O
+increased	O
+above	O
+that	O
+observed	O
+in	O
+WT	O
+with	O
+CYP	O
+.	O
+
+This	O
+shift	O
+in	O
+balance	O
+may	O
+contribute	O
+to	O
+increased	O
+bladder	B
+dysfunction	I
+in	O
+VIP	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+with	O
+bladder	B
+inflammation	I
+and	O
+altered	O
+neurochemical	O
+expression	O
+in	O
+micturition	O
+pathways	O
+.	O
+
+Debrisoquine	O
+phenotype	O
+and	O
+the	O
+pharmacokinetics	O
+and	O
+beta	O
+-	O
+2	O
+receptor	O
+pharmacodynamics	O
+of	O
+metoprolol	O
+and	O
+its	O
+enantiomers	O
+.	O
+
+The	O
+metabolism	O
+of	O
+the	O
+cardioselective	O
+beta	O
+-	O
+blocker	O
+metoprolol	O
+is	O
+under	O
+genetic	O
+control	O
+of	O
+the	O
+debrisoquine	O
+/	O
+sparteine	O
+type	O
+.	O
+
+The	O
+two	O
+metabolic	O
+phenotypes	O
+,	O
+extensive	O
+(	O
+EM	O
+)	O
+and	O
+poor	O
+metabolizers	O
+(	O
+PM	O
+)	O
+,	O
+show	O
+different	O
+stereoselective	O
+metabolism	O
+,	O
+resulting	O
+in	O
+apparently	O
+higher	O
+beta	O
+-	O
+1	O
+adrenoceptor	O
+antagonistic	O
+potency	O
+of	O
+racemic	O
+metoprolol	O
+in	O
+EMs	O
+.	O
+
+We	O
+investigated	O
+if	O
+the	O
+latter	O
+also	O
+applies	O
+to	O
+the	O
+beta	O
+-	O
+2	O
+adrenoceptor	O
+antagonism	O
+by	O
+metoprolol	O
+.	O
+
+The	O
+drug	O
+effect	O
+studied	O
+was	O
+the	O
+antagonism	O
+by	O
+metoprolol	O
+of	O
+terbutaline	O
+-	O
+induced	O
+hypokalemia	B
+.	O
+
+By	O
+using	O
+pharmacokinetic	O
+pharmacodynamic	O
+modeling	O
+the	O
+pharmacodynamics	O
+of	O
+racemic	O
+metoprolol	O
+and	O
+the	O
+active	O
+S	O
+-	O
+isomer	O
+,	O
+were	O
+quantitated	O
+in	O
+EMs	O
+and	O
+PMs	O
+in	O
+terms	O
+of	O
+IC50	O
+values	O
+,	O
+representing	O
+metoprolol	O
+plasma	O
+concentrations	O
+resulting	O
+in	O
+half	O
+-	O
+maximum	O
+receptor	O
+occupancy	O
+.	O
+
+Six	O
+EMs	O
+received	O
+0	O
+.	O
+5	O
+mg	O
+of	O
+terbutaline	O
+s	O
+.	O
+c	O
+.	O
+on	O
+two	O
+different	O
+occasions	O
+:	O
+1	O
+)	O
+1	O
+hr	O
+after	O
+administration	O
+of	O
+a	O
+placebo	O
+and	O
+2	O
+)	O
+1	O
+hr	O
+after	O
+150	O
+mg	O
+of	O
+metoprolol	O
+p	O
+.	O
+o	O
+.	O
+
+Five	O
+PMs	O
+were	O
+studied	O
+according	O
+to	O
+the	O
+same	O
+protocol	O
+,	O
+except	O
+for	O
+a	O
+higher	O
+terbutaline	O
+dose	O
+(	O
+0	O
+.	O
+75	O
+mg	O
+)	O
+on	O
+day	O
+2	O
+.	O
+
+Blood	O
+samples	O
+for	O
+the	O
+analysis	O
+of	O
+plasma	O
+potassium	O
+,	O
+terbutaline	O
+,	O
+metoprolol	O
+(	O
+racemic	O
+,	O
+R	O
+-	O
+and	O
+S	O
+-	O
+isomer	O
+)	O
+,	O
+and	O
+alpha	O
+-	O
+hydroxymetoprolol	O
+concentrations	O
+were	O
+taken	O
+at	O
+regular	O
+time	O
+intervals	O
+,	O
+during	O
+8	O
+hr	O
+after	O
+metoprolol	O
+.	O
+
+In	O
+PMs	O
+,	O
+metoprolol	O
+increased	O
+the	O
+terbutaline	O
+area	O
+under	O
+the	O
+plasma	O
+concentration	O
+vs	O
+.	O
+time	O
+curve	O
+(	O
++	O
+67	O
+%	O
+)	O
+.	O
+
+Higher	O
+metoprolol	O
+/	O
+alpha	O
+-	O
+hydroxymetoprolol	O
+ratios	O
+in	O
+PMs	O
+were	O
+predictive	O
+for	O
+higher	O
+R	O
+-	O
+/	O
+S	O
+-	O
+isomer	O
+ratios	O
+of	O
+unchanged	O
+drug	O
+.	O
+
+There	O
+was	O
+a	O
+difference	O
+in	O
+metoprolol	O
+potency	O
+with	O
+higher	O
+racemic	O
+metoprolol	O
+IC50	O
+values	O
+in	O
+PMs	O
+(	O
+72	O
++	O
+/	O
+-	O
+7	O
+ng	O
+.	O
+ml	O
+-	O
+1	O
+)	O
+than	O
+EMs	O
+(	O
+42	O
++	O
+/	O
+-	O
+8	O
+ng	O
+.	O
+ml	O
+-	O
+1	O
+,	O
+P	O
+less	O
+than	O
+.	O
+001	O
+)	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+The	O
+hemodynamics	O
+of	O
+oxytocin	O
+and	O
+other	O
+vasoactive	O
+agents	O
+during	O
+neuraxial	O
+anesthesia	O
+for	O
+cesarean	O
+delivery	O
+:	O
+findings	O
+in	O
+six	O
+cases	O
+.	O
+
+Oxytocin	O
+is	O
+a	O
+commonly	O
+used	O
+uterotonic	O
+that	O
+can	O
+cause	O
+significant	O
+and	O
+even	O
+fatal	O
+hypotension	B
+,	O
+particularly	O
+when	O
+given	O
+as	O
+a	O
+bolus	O
+.	O
+
+The	O
+resulting	O
+hypotension	B
+can	O
+be	O
+produced	O
+by	O
+a	O
+decrease	O
+in	O
+systemic	O
+vascular	O
+resistance	O
+or	O
+cardiac	O
+output	O
+through	O
+a	O
+decrease	O
+in	O
+venous	O
+return	O
+.	O
+
+Parturients	O
+with	O
+normal	O
+volume	O
+status	O
+,	O
+heart	O
+valves	O
+and	O
+pulmonary	O
+vasculature	O
+most	O
+often	O
+respond	O
+to	O
+this	O
+hypotension	B
+with	O
+a	O
+compensatory	O
+increase	O
+in	O
+heart	O
+rate	O
+and	O
+stroke	B
+volume	O
+.	O
+
+Oxytocin	O
+-	O
+induced	O
+hypotension	B
+at	O
+cesarean	O
+delivery	O
+may	O
+be	O
+incorrectly	O
+attributed	O
+to	O
+blood	B
+loss	I
+.	O
+
+Pulse	O
+power	O
+analysis	O
+(	O
+also	O
+called	O
+"	O
+pulse	O
+contour	O
+analysis	O
+"	O
+)	O
+of	O
+an	O
+arterial	O
+pressure	O
+wave	O
+form	O
+allows	O
+continuous	O
+evaluation	O
+of	O
+systemic	O
+vascular	O
+resistance	O
+and	O
+cardiac	O
+output	O
+in	O
+real	O
+time	O
+,	O
+thereby	O
+elucidating	O
+the	O
+causative	O
+factors	O
+behind	O
+changes	O
+in	O
+blood	O
+pressure	O
+.	O
+
+Pulse	O
+power	O
+analysis	O
+was	O
+conducted	O
+in	O
+six	O
+cases	O
+of	O
+cesarean	O
+delivery	O
+performed	O
+under	O
+neuraxial	O
+anesthesia	O
+.	O
+
+Hypotension	B
+in	O
+response	O
+to	O
+oxytocin	O
+was	O
+associated	O
+with	O
+a	O
+decrease	O
+in	O
+systemic	O
+vascular	O
+resistance	O
+and	O
+a	O
+compensatory	O
+increase	O
+in	O
+stroke	B
+volume	O
+,	O
+heart	O
+rate	O
+and	O
+cardiac	O
+output	O
+.	O
+
+Pulse	O
+power	O
+analysis	O
+may	O
+be	O
+helpful	O
+in	O
+determining	O
+the	O
+etiology	O
+of	O
+and	O
+treating	O
+hypotension	B
+during	O
+cesarean	O
+delivery	O
+under	O
+neuraxial	O
+anesthesia	O
+.	O
+
+Protective	O
+effects	O
+of	O
+antithrombin	O
+on	O
+puromycin	O
+aminonucleoside	O
+nephrosis	B
+in	O
+rats	O
+.	O
+
+We	O
+investigated	O
+the	O
+effects	O
+of	O
+antithrombin	O
+,	O
+a	O
+plasma	O
+inhibitor	O
+of	O
+coagulation	O
+factors	O
+,	O
+in	O
+rats	O
+with	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+nephrosis	B
+,	O
+which	O
+is	O
+an	O
+experimental	O
+model	O
+of	O
+human	O
+nephrotic	B
+syndrome	I
+.	O
+
+Antithrombin	O
+(	O
+50	O
+or	O
+500	O
+IU	O
+/	O
+kg	O
+/	O
+i	O
+.	O
+v	O
+.	O
+)	O
+was	O
+administered	O
+to	O
+rats	O
+once	O
+a	O
+day	O
+for	O
+10	O
+days	O
+immediately	O
+after	O
+the	O
+injection	O
+of	O
+puromycin	O
+aminonucleoside	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+/	O
+i	O
+.	O
+v	O
+.	O
+)	O
+.	O
+
+Treatment	O
+with	O
+antithrombin	O
+attenuated	O
+the	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+hematological	B
+abnormalities	I
+.	O
+
+Puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+renal	B
+dysfunction	I
+and	O
+hyperlipidemia	B
+were	O
+also	O
+suppressed	O
+.	O
+
+Histopathological	O
+examination	O
+revealed	O
+severe	O
+renal	B
+damage	I
+such	O
+as	O
+proteinaceous	O
+casts	O
+in	O
+tubuli	O
+and	O
+tubular	O
+expansion	O
+in	O
+the	O
+kidney	O
+of	O
+control	O
+rats	O
+,	O
+while	O
+an	O
+improvement	O
+of	O
+the	O
+damage	O
+was	O
+seen	O
+in	O
+antithrombin	O
+-	O
+treated	O
+rats	O
+.	O
+
+In	O
+addition	O
+,	O
+antithrombin	O
+treatment	O
+markedly	O
+suppressed	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+apoptosis	O
+of	O
+renal	O
+tubular	O
+epithelial	O
+cells	O
+.	O
+
+Furthermore	O
+,	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+increases	O
+in	O
+renal	O
+cytokine	O
+content	O
+were	O
+also	O
+decreased	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+thrombin	O
+plays	O
+an	O
+important	O
+role	O
+in	O
+the	O
+pathogenesis	O
+of	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+nephrotic	B
+syndrome	I
+.	O
+
+Treatment	O
+with	O
+antithrombin	O
+may	O
+be	O
+clinically	O
+effective	O
+in	O
+patients	O
+with	O
+nephrotic	B
+syndrome	I
+.	O
+
+Heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+after	O
+liver	O
+transplantation	O
+.	O
+
+BACKGROUND	O
+:	O
+Unfractionated	O
+heparin	O
+sodium	O
+(	O
+UFH	O
+)	O
+or	O
+low	O
+-	O
+molecular	O
+weight	O
+heparin	O
+(	O
+LMWH	O
+)	O
+is	O
+used	O
+in	O
+anticoagulant	O
+protocols	O
+at	O
+several	O
+institutions	O
+to	O
+prevent	O
+thrombosis	B
+after	O
+liver	O
+transplantation	O
+.	O
+
+Heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+(	O
+HIT	B
+)	O
+is	O
+an	O
+adverse	O
+immune	O
+-	O
+mediated	O
+reaction	O
+to	O
+heparin	O
+,	O
+resulting	O
+in	O
+platelet	O
+count	O
+decreases	O
+of	O
+more	O
+than	O
+50	O
+%	O
+.	O
+
+The	O
+frequencies	O
+of	O
+HIT	B
+after	O
+liver	O
+transplantation	O
+and	O
+platelet	O
+factor	O
+4	O
+/	O
+heparin	O
+-	O
+reactive	O
+antibody	O
+(	O
+HIT	B
+antibody	O
+)	O
+positivity	O
+in	O
+liver	O
+transplantation	O
+patients	O
+,	O
+however	O
+,	O
+are	O
+unknown	O
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+The	O
+32	O
+men	O
+and	O
+20	O
+women	O
+underwent	O
+living	O
+donor	O
+liver	O
+transplantation	O
+.	O
+
+We	O
+started	O
+LMWH	O
+(	O
+25	O
+IU	O
+/	O
+kg	O
+/	O
+h	O
+)	O
+on	O
+postoperative	O
+day	O
+(	O
+POD	O
+)	O
+1	O
+,	O
+switching	O
+to	O
+UFH	O
+(	O
+5000	O
+U	O
+/	O
+d	O
+)	O
+on	O
+POD	O
+2	O
+or	O
+3	O
+.	O
+
+The	O
+dose	O
+of	O
+UFH	O
+was	O
+changed	O
+according	O
+to	O
+the	O
+activated	O
+clotting	O
+time	O
+level	O
+.	O
+
+HIT	B
+antibody	O
+levels	O
+were	O
+measured	O
+the	O
+day	O
+before	O
+surgery	O
+and	O
+on	O
+POD	O
+7	O
+and	O
+14	O
+.	O
+
+Platelet	O
+count	O
+was	O
+measured	O
+daily	O
+for	O
+3	O
+weeks	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+average	O
+platelet	O
+counts	O
+preoperatively	O
+,	O
+and	O
+on	O
+POD	O
+7	O
+,	O
+14	O
+,	O
+and	O
+21	O
+were	O
+65	O
+,	O
+88	O
+,	O
+149	O
+,	O
+and	O
+169	O
+x	O
+10	O
+(	O
+9	O
+)	O
+/	O
+L	O
+,	O
+respectively	O
+.	O
+
+Two	O
+patients	O
+developed	O
+hepatic	O
+artery	O
+thrombosis	B
+on	O
+POD	O
+11	O
+and	O
+19	O
+,	O
+respectively	O
+,	O
+although	O
+they	O
+were	O
+HIT	B
+antibody	O
+-	O
+negative	O
+and	O
+their	O
+platelet	O
+counts	O
+were	O
+stable	O
+.	O
+
+In	O
+2	O
+other	O
+patients	O
+,	O
+the	O
+platelet	O
+count	O
+decreased	O
+suddenly	O
+from	O
+107	O
+x	O
+10	O
+(	O
+9	O
+)	O
+/	O
+L	O
+on	O
+POD	O
+4	O
+to	O
+65	O
+x	O
+10	O
+(	O
+9	O
+)	O
+/	O
+L	O
+on	O
+POD	O
+6	O
+and	O
+from	O
+76	O
+x	O
+10	O
+(	O
+9	O
+)	O
+/	O
+L	O
+on	O
+POD	O
+7	O
+to	O
+33	O
+x	O
+10	O
+(	O
+9	O
+)	O
+/	O
+L	O
+on	O
+POD	O
+9	O
+,	O
+respectively	O
+.	O
+
+The	O
+heparin	O
+-	O
+induced	O
+platelet	B
+aggregation	I
+test	O
+was	O
+negative	O
+in	O
+these	O
+patients	O
+.	O
+
+The	O
+percentage	O
+of	O
+HIT	B
+antibody	O
+-	O
+positive	O
+patients	O
+was	O
+0	O
+.	O
+5	O
+%	O
+preoperatively	O
+,	O
+5	O
+.	O
+6	O
+%	O
+on	O
+POD	O
+7	O
+,	O
+and	O
+5	O
+.	O
+6	O
+%	O
+on	O
+POD	O
+14	O
+.	O
+
+None	O
+of	O
+the	O
+subjects	O
+/	O
+patients	O
+developed	O
+UFH	O
+-	O
+related	O
+HIT	B
+.	O
+
+CONCLUSIONS	O
+:	O
+In	O
+our	O
+series	O
+,	O
+the	O
+occurrence	O
+of	O
+HIT	B
+after	O
+liver	O
+transplantation	O
+was	O
+uncommon	O
+.	O
+
+Doxorubicin	O
+cardiomyopathy	B
+-	O
+induced	O
+inflammation	B
+and	O
+apoptosis	O
+are	O
+attenuated	O
+by	O
+gene	O
+deletion	O
+of	O
+the	O
+kinin	O
+B1	O
+receptor	O
+.	O
+
+Clinical	O
+use	O
+of	O
+the	O
+anthracycline	O
+doxorubicin	O
+(	O
+DOX	O
+)	O
+is	O
+limited	O
+by	O
+its	O
+cardiotoxic	B
+effects	O
+,	O
+which	O
+are	O
+attributed	O
+to	O
+the	O
+induction	O
+of	O
+apoptosis	O
+.	O
+
+To	O
+elucidate	O
+the	O
+possible	O
+role	O
+of	O
+the	O
+kinin	O
+B1	O
+receptor	O
+(	O
+B1R	O
+)	O
+during	O
+the	O
+development	O
+of	O
+DOX	O
+cardiomyopathy	B
+,	O
+we	O
+studied	O
+B1R	O
+knockout	O
+mice	O
+(	O
+B1R	O
+(	O
+-	O
+/	O
+-	O
+)	O
+)	O
+by	O
+investigating	O
+cardiac	O
+inflammation	B
+and	O
+apoptosis	O
+after	O
+induction	O
+of	O
+DOX	O
+-	O
+induced	O
+cardiomyopathy	B
+.	O
+
+DOX	O
+control	O
+mice	O
+showed	O
+cardiac	B
+dysfunction	I
+measured	O
+by	O
+pressure	O
+-	O
+volume	O
+loops	O
+in	O
+vivo	O
+.	O
+
+This	O
+was	O
+associated	O
+with	O
+a	O
+reduced	O
+activation	O
+state	O
+of	O
+AKT	O
+,	O
+as	O
+well	O
+as	O
+an	O
+increased	O
+bax	O
+/	O
+bcl2	O
+ratio	O
+in	O
+Western	O
+blots	O
+,	O
+indicating	O
+cardiac	B
+apoptosis	I
+.	O
+
+Furthermore	O
+,	O
+mRNA	O
+levels	O
+of	O
+the	O
+proinflammatory	O
+cytokine	O
+interleukin	O
+6	O
+were	O
+increased	O
+in	O
+the	O
+cardiac	O
+tissue	O
+.	O
+
+In	O
+DOX	O
+B1R	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+,	O
+cardiac	B
+dysfunction	I
+was	O
+improved	O
+compared	O
+to	O
+DOX	O
+control	O
+mice	O
+,	O
+which	O
+was	O
+associated	O
+with	O
+normalization	O
+of	O
+the	O
+bax	O
+/	O
+bcl	O
+-	O
+2	O
+ratio	O
+and	O
+interleukin	O
+6	O
+,	O
+as	O
+well	O
+as	O
+AKT	O
+activation	O
+state	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+B1R	O
+is	O
+detrimental	O
+in	O
+DOX	O
+cardiomyopathy	B
+in	O
+that	O
+it	O
+mediates	O
+the	O
+inflammatory	O
+response	O
+and	O
+apoptosis	O
+.	O
+
+These	O
+insights	O
+might	O
+have	O
+useful	O
+implications	O
+for	O
+future	O
+studies	O
+utilizing	O
+B1R	O
+antagonists	O
+for	O
+treatment	O
+of	O
+human	O
+DOX	O
+cardiomyopathy	B
+.	O
+
+Detailed	O
+spectral	O
+profile	O
+analysis	O
+of	O
+penicillin	O
+-	O
+induced	O
+epileptiform	B
+activity	I
+in	O
+anesthetized	O
+rats	O
+.	O
+
+Penicillin	O
+model	O
+is	O
+a	O
+widely	O
+used	O
+experimental	O
+model	O
+for	O
+epilepsy	B
+research	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+we	O
+aimed	O
+to	O
+portray	O
+a	O
+detailed	O
+spectral	O
+analysis	O
+of	O
+penicillin	O
+-	O
+induced	O
+epileptiform	B
+activity	I
+in	O
+comparison	O
+with	O
+basal	O
+brain	O
+activity	O
+in	O
+anesthetized	O
+Wistar	O
+rats	O
+.	O
+
+Male	O
+Wistar	O
+rats	O
+were	O
+anesthetized	O
+with	O
+i	O
+.	O
+p	O
+.	O
+urethane	O
+and	O
+connected	O
+to	O
+an	O
+electrocorticogram	O
+setup	O
+.	O
+
+After	O
+a	O
+short	O
+period	O
+of	O
+basal	O
+activity	O
+recording	O
+,	O
+epileptic	B
+focus	O
+was	O
+induced	O
+by	O
+injecting	O
+400IU	O
+/	O
+2	O
+microl	O
+penicillin	O
+-	O
+G	O
+potassium	O
+into	O
+the	O
+left	O
+lateral	O
+ventricle	O
+while	O
+the	O
+cortical	O
+activity	O
+was	O
+continuously	O
+recorded	O
+.	O
+
+Basal	O
+activity	O
+,	O
+latent	O
+period	O
+and	O
+the	O
+penicillin	O
+-	O
+induced	O
+epileptiform	B
+activity	I
+periods	O
+were	O
+then	O
+analyzed	O
+using	O
+both	O
+conventional	O
+methods	O
+and	O
+spectral	O
+analysis	O
+.	O
+
+Spectral	O
+analyses	O
+were	O
+conducted	O
+by	O
+dividing	O
+the	O
+whole	O
+spectrum	O
+into	O
+different	O
+frequency	O
+bands	O
+including	O
+delta	O
+,	O
+theta	O
+(	O
+slow	O
+and	O
+fast	O
+)	O
+,	O
+alpha	O
+-	O
+sigma	O
+,	O
+beta	O
+(	O
+1	O
+and	O
+2	O
+)	O
+and	O
+gamma	O
+(	O
+1	O
+and	O
+2	O
+)	O
+bands	O
+.	O
+
+Our	O
+results	O
+show	O
+that	O
+the	O
+most	O
+affected	O
+frequency	O
+bands	O
+were	O
+delta	O
+,	O
+theta	O
+,	O
+beta	O
+-	O
+2	O
+and	O
+gamma	O
+-	O
+2	O
+bands	O
+during	O
+the	O
+epileptiform	B
+activity	I
+and	O
+there	O
+were	O
+marked	O
+differences	O
+in	O
+terms	O
+of	O
+spectral	O
+densities	O
+between	O
+three	O
+investigated	O
+episodes	O
+(	O
+basal	O
+activity	O
+,	O
+latent	O
+period	O
+and	O
+epileptiform	B
+activity	I
+)	O
+.	O
+
+Our	O
+results	O
+may	O
+help	O
+to	O
+analyze	O
+novel	O
+data	O
+obtained	O
+using	O
+similar	O
+experimental	O
+models	O
+and	O
+the	O
+simple	O
+analysis	O
+method	O
+described	O
+here	O
+can	O
+be	O
+used	O
+in	O
+similar	O
+studies	O
+to	O
+investigate	O
+the	O
+basic	O
+neuronal	O
+mechanism	O
+of	O
+this	O
+or	O
+other	O
+types	O
+of	O
+experimental	O
+epilepsies	B
+.	O
+
+High	O
+fat	O
+diet	O
+-	O
+fed	O
+obese	B
+rats	O
+are	O
+highly	O
+sensitive	O
+to	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+Often	O
+,	O
+chemotherapy	O
+by	O
+doxorubicin	O
+(	O
+Adriamycin	O
+)	O
+is	O
+limited	O
+due	O
+to	O
+life	O
+threatening	O
+cardiotoxicity	B
+in	O
+patients	O
+during	O
+and	O
+posttherapy	O
+.	O
+
+Recently	O
+,	O
+we	O
+have	O
+shown	O
+that	O
+moderate	O
+diet	O
+restriction	O
+remarkably	O
+protects	O
+against	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+This	O
+cardioprotection	O
+is	O
+accompanied	O
+by	O
+decreased	O
+cardiac	O
+oxidative	O
+stress	O
+and	O
+triglycerides	O
+and	O
+increased	O
+cardiac	O
+fatty	O
+-	O
+acid	O
+oxidation	O
+,	O
+ATP	O
+synthesis	O
+,	O
+and	O
+upregulated	O
+JAK	O
+/	O
+STAT3	O
+pathway	O
+.	O
+
+In	O
+the	O
+current	O
+study	O
+,	O
+we	O
+investigated	O
+whether	O
+a	O
+physiological	O
+intervention	O
+by	O
+feeding	O
+40	O
+%	O
+high	O
+fat	O
+diet	O
+(	O
+HFD	O
+)	O
+,	O
+which	O
+induces	O
+obesity	B
+in	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+(	O
+250	O
+-	O
+275	O
+g	O
+)	O
+,	O
+sensitizes	O
+to	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+A	O
+LD	O
+(	O
+10	O
+)	O
+dose	O
+(	O
+8	O
+mg	O
+doxorubicin	O
+/	O
+kg	O
+,	O
+ip	O
+)	O
+administered	O
+on	O
+day	O
+43	O
+of	O
+the	O
+HFD	O
+feeding	O
+regimen	O
+led	O
+to	O
+higher	O
+cardiotoxicity	B
+,	O
+cardiac	B
+dysfunction	I
+,	O
+lipid	O
+peroxidation	O
+,	O
+and	O
+80	O
+%	O
+mortality	O
+in	O
+the	O
+obese	B
+(	O
+OB	B
+)	O
+rats	O
+in	O
+the	O
+absence	O
+of	O
+any	O
+significant	O
+renal	B
+or	I
+hepatic	I
+toxicity	I
+.	O
+
+Doxorubicin	O
+toxicokinetics	O
+studies	O
+revealed	O
+no	O
+change	O
+in	O
+accumulation	O
+of	O
+doxorubicin	O
+and	O
+doxorubicinol	O
+(	O
+toxic	O
+metabolite	O
+)	O
+in	O
+the	O
+normal	O
+diet	O
+-	O
+fed	O
+(	O
+ND	O
+)	O
+and	O
+OB	B
+hearts	O
+.	O
+
+Mechanistic	O
+studies	O
+revealed	O
+that	O
+OB	B
+rats	O
+are	O
+sensitized	O
+due	O
+to	O
+:	O
+(	O
+1	O
+)	O
+higher	O
+oxyradical	O
+stress	O
+leading	O
+to	O
+upregulation	O
+of	O
+uncoupling	O
+proteins	O
+2	O
+and	O
+3	O
+,	O
+(	O
+2	O
+)	O
+downregulation	O
+of	O
+cardiac	O
+peroxisome	O
+proliferators	O
+activated	O
+receptor	O
+-	O
+alpha	O
+,	O
+(	O
+3	O
+)	O
+decreased	O
+plasma	O
+adiponectin	O
+levels	O
+,	O
+(	O
+4	O
+)	O
+decreased	O
+cardiac	O
+fatty	O
+-	O
+acid	O
+oxidation	O
+(	O
+666	O
+.	O
+9	O
++	O
+/	O
+-	O
+14	O
+.	O
+0	O
+nmol	O
+/	O
+min	O
+/	O
+g	O
+heart	O
+in	O
+ND	O
+versus	O
+400	O
+.	O
+2	O
++	O
+/	O
+-	O
+11	O
+.	O
+8	O
+nmol	O
+/	O
+min	O
+/	O
+g	O
+heart	O
+in	O
+OB	B
+)	O
+,	O
+(	O
+5	O
+)	O
+decreased	O
+mitochondrial	O
+AMP	O
+-	O
+alpha2	O
+protein	O
+kinase	O
+,	O
+and	O
+(	O
+6	O
+)	O
+86	O
+%	O
+drop	O
+in	O
+cardiac	O
+ATP	O
+levels	O
+accompanied	O
+by	O
+decreased	O
+ATP	O
+/	O
+ADP	O
+ratio	O
+after	O
+doxorubicin	O
+administration	O
+.	O
+
+Decreased	O
+cardiac	O
+erythropoietin	O
+and	O
+increased	O
+SOCS3	O
+further	O
+downregulated	O
+the	O
+cardioprotective	O
+JAK	O
+/	O
+STAT3	O
+pathway	O
+.	O
+
+In	O
+conclusion	O
+,	O
+HFD	O
+-	O
+induced	O
+obese	B
+rats	O
+are	O
+highly	O
+sensitized	O
+to	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B
+by	O
+substantially	O
+downregulating	O
+cardiac	O
+mitochondrial	O
+ATP	O
+generation	O
+,	O
+increasing	O
+oxidative	O
+stress	O
+and	O
+downregulating	O
+the	O
+JAK	O
+/	O
+STAT3	O
+pathway	O
+.	O
+
+Isoproterenol	O
+induces	O
+primary	O
+loss	O
+of	O
+dystrophin	O
+in	O
+rat	O
+hearts	O
+:	O
+correlation	O
+with	O
+myocardial	B
+injury	I
+.	O
+
+The	O
+mechanism	O
+of	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+damage	I
+is	O
+unknown	O
+,	O
+but	O
+a	O
+mismatch	O
+of	O
+oxygen	O
+supply	O
+vs	O
+.	O
+demand	O
+following	O
+coronary	O
+hypotension	B
+and	O
+myocardial	B
+hyperactivity	I
+is	O
+the	O
+best	O
+explanation	O
+for	O
+the	O
+complex	O
+morphological	O
+alterations	O
+observed	O
+.	O
+
+Severe	O
+alterations	O
+in	O
+the	O
+structural	O
+integrity	O
+of	O
+the	O
+sarcolemma	O
+of	O
+cardiomyocytes	O
+have	O
+been	O
+demonstrated	O
+to	O
+be	O
+caused	O
+by	O
+isoproterenol	O
+.	O
+
+Taking	O
+into	O
+account	O
+that	O
+the	O
+sarcolemmal	O
+integrity	O
+is	O
+stabilized	O
+by	O
+the	O
+dystrophin	O
+-	O
+glycoprotein	O
+complex	O
+(	O
+DGC	O
+)	O
+that	O
+connects	O
+actin	O
+and	O
+laminin	O
+in	O
+contractile	O
+machinery	O
+and	O
+extracellular	O
+matrix	O
+and	O
+by	O
+integrins	O
+,	O
+this	O
+study	O
+tests	O
+the	O
+hypothesis	O
+that	O
+isoproterenol	O
+affects	O
+sarcolemmal	O
+stability	O
+through	O
+changes	O
+in	O
+the	O
+DGC	O
+and	O
+integrins	O
+.	O
+
+We	O
+found	O
+different	O
+sensitivity	O
+of	O
+the	O
+DGC	O
+and	O
+integrin	O
+to	O
+isoproterenol	O
+subcutaneous	O
+administration	O
+.	O
+
+Immunofluorescent	O
+staining	O
+revealed	O
+that	O
+dystrophin	O
+is	O
+the	O
+most	O
+sensitive	O
+among	O
+the	O
+structures	O
+connecting	O
+the	O
+actin	O
+in	O
+the	O
+cardiomyocyte	O
+cytoskeleton	O
+and	O
+the	O
+extracellular	O
+matrix	O
+.	O
+
+The	O
+sarcomeric	O
+actin	O
+dissolution	O
+occurred	O
+after	O
+the	O
+reduction	O
+or	O
+loss	O
+of	O
+dystrophin	O
+.	O
+
+Subsequently	O
+,	O
+after	O
+lysis	O
+of	O
+myofilaments	O
+,	O
+gamma	O
+-	O
+sarcoglycan	O
+,	O
+beta	O
+-	O
+dystroglycan	O
+,	O
+beta1	O
+-	O
+integrin	O
+,	O
+and	O
+laminin	O
+alpha	O
+-	O
+2	O
+expressions	O
+were	O
+reduced	O
+followed	O
+by	O
+their	O
+breakdown	O
+,	O
+as	O
+epiphenomena	O
+of	O
+the	O
+myocytolytic	O
+process	O
+.	O
+
+In	O
+conclusion	O
+,	O
+administration	O
+of	O
+isoproterenol	O
+to	O
+rats	O
+results	O
+in	O
+primary	O
+loss	O
+of	O
+dystrophin	O
+,	O
+the	O
+most	O
+sensitive	O
+among	O
+the	O
+structural	O
+proteins	O
+that	O
+form	O
+the	O
+DGC	O
+that	O
+connects	O
+the	O
+extracellular	O
+matrix	O
+and	O
+the	O
+cytoskeleton	O
+in	O
+cardiomyocyte	O
+.	O
+
+These	O
+changes	O
+,	O
+related	O
+to	O
+ischaemic	B
+injury	I
+,	O
+explain	O
+the	O
+severe	O
+alterations	O
+in	O
+the	O
+structural	O
+integrity	O
+of	O
+the	O
+sarcolemma	O
+of	O
+cardiomyocytes	O
+and	O
+hence	O
+severe	O
+and	O
+irreversible	O
+injury	O
+induced	O
+by	O
+isoproterenol	O
+.	O
+
+Etiologic	O
+factors	O
+in	O
+the	O
+pathogenesis	O
+of	O
+liver	B
+tumors	I
+associated	O
+with	O
+oral	O
+contraceptives	O
+.	O
+
+Within	O
+the	O
+last	O
+several	O
+years	O
+,	O
+previously	O
+rare	O
+liver	B
+tumors	I
+have	O
+been	O
+seen	O
+in	O
+young	O
+women	O
+using	O
+oral	O
+contraceptive	O
+steroids	O
+.	O
+
+The	O
+Registry	O
+for	O
+Liver	B
+Tumors	I
+Associated	O
+with	O
+Oral	O
+Contraceptives	O
+at	O
+the	O
+University	O
+of	O
+California	O
+,	O
+Irvine	O
+,	O
+has	O
+clearly	O
+identified	O
+27	O
+cases	O
+.	O
+
+The	O
+recent	O
+literature	O
+contains	O
+44	O
+case	O
+reports	O
+.	O
+
+Common	O
+to	O
+these	O
+71	O
+cases	O
+has	O
+been	O
+a	O
+histopathologic	O
+diagnosis	O
+of	O
+focal	B
+nodular	I
+hyperplasia	I
+,	O
+adenoma	B
+,	O
+hamartoma	B
+,	O
+and	O
+hepatoma	B
+.	O
+
+Significant	O
+statistical	O
+etiologic	O
+factors	O
+include	O
+prolonged	O
+uninterrupted	O
+usage	O
+of	O
+oral	O
+contraceptive	O
+steroids	O
+.	O
+
+Eight	O
+deaths	O
+and	O
+liver	O
+rupture	B
+in	O
+18	O
+patients	O
+attest	O
+to	O
+the	O
+seriousness	O
+of	O
+this	O
+new	O
+potentially	O
+lethal	O
+adverse	O
+phenomenon	O
+.	O
+
+Ifosfamide	O
+continuous	O
+infusion	O
+without	O
+mesna	O
+.	O
+
+A	O
+phase	O
+I	O
+trial	O
+of	O
+a	O
+14	O
+-	O
+day	O
+cycle	O
+.	O
+
+Twenty	O
+patients	O
+received	O
+27	O
+courses	O
+of	O
+ifosfamide	O
+administered	O
+as	O
+a	O
+24	O
+-	O
+hour	O
+continuous	O
+infusion	O
+for	O
+14	O
+days	O
+without	O
+Mesna	O
+.	O
+
+The	O
+goal	O
+of	O
+the	O
+study	O
+was	O
+to	O
+deliver	O
+a	O
+dose	O
+rate	O
+and	O
+total	O
+cumulative	O
+dose	O
+of	O
+ifosfamide	O
+that	O
+would	O
+be	O
+comparable	O
+to	O
+standard	O
+bolus	O
+or	O
+short	O
+-	O
+term	O
+infusions	O
+administered	O
+with	O
+Mesna	O
+.	O
+
+Dose	O
+escalations	O
+proceeded	O
+from	O
+200	O
+to	O
+300	O
+,	O
+400	O
+,	O
+450	O
+,	O
+500	O
+,	O
+and	O
+550	O
+mg	O
+/	O
+m2	O
+/	O
+d	O
+.	O
+
+Four	O
+patients	O
+developed	O
+transient	O
+microscopic	O
+hematuria	B
+at	O
+400	O
+,	O
+450	O
+,	O
+and	O
+500	O
+mg	O
+/	O
+m2	O
+/	O
+d	O
+.	O
+
+There	O
+were	O
+no	O
+instances	O
+of	O
+macroscopic	O
+hematuria	B
+.	O
+
+At	O
+550	O
+mg	O
+/	O
+m2	O
+/	O
+d	O
+,	O
+three	O
+patients	O
+experienced	O
+nonurologic	O
+toxicity	B
+;	O
+confusion	B
+(	O
+1	O
+)	O
+,	O
+nausea	B
+(	O
+1	O
+)	O
+,	O
+and	O
+Grade	O
+2	O
+leukopenia	B
+(	O
+1	O
+)	O
+.	O
+
+The	O
+recommended	O
+dose	O
+of	O
+500	O
+mg	O
+/	O
+m2	O
+/	O
+d	O
+delivers	O
+a	O
+total	O
+dose	O
+of	O
+7	O
+g	O
+/	O
+m2	O
+per	O
+cycle	O
+,	O
+which	O
+is	O
+comparable	O
+to	O
+that	O
+delivered	O
+in	O
+clinical	O
+practice	O
+for	O
+bolus	O
+or	O
+short	O
+-	O
+term	O
+infusion	O
+.	O
+
+Because	O
+few	O
+patients	O
+received	O
+multiple	O
+courses	O
+over	O
+time	O
+,	O
+the	O
+cumulative	O
+effects	O
+are	O
+indeterminate	O
+in	O
+the	O
+present	O
+trial	O
+.	O
+
+The	O
+frequency	O
+and	O
+predictability	O
+of	O
+hematuria	B
+are	O
+not	O
+precise	O
+,	O
+and	O
+at	O
+least	O
+daily	O
+monitoring	O
+by	O
+urine	O
+Hematest	O
+is	O
+essential	O
+,	O
+adding	O
+Mesna	O
+to	O
+the	O
+infusate	O
+in	O
+patients	O
+with	O
+persistent	O
+hematuria	B
+.	O
+
+The	O
+protracted	O
+infusion	O
+schedule	O
+for	O
+ifosfamide	O
+permits	O
+convenient	O
+outpatient	O
+administration	O
+without	O
+Mesna	O
+and	O
+reduces	O
+the	O
+drug	O
+cost	O
+of	O
+clinical	O
+usage	O
+of	O
+this	O
+agent	O
+by	O
+up	O
+to	O
+890	O
+per	O
+cycle	O
+.	O
+
+Clinical	O
+activity	O
+was	O
+demonstrated	O
+in	O
+a	O
+single	O
+patient	O
+,	O
+but	O
+a	O
+comparative	O
+trial	O
+of	O
+standard	O
+bolus	O
+schedules	O
+with	O
+the	O
+protracted	O
+infusion	O
+schedule	O
+will	O
+be	O
+necessary	O
+to	O
+determine	O
+if	O
+the	O
+clinical	O
+effectiveness	O
+of	O
+the	O
+drug	O
+is	O
+maintained	O
+.	O
+
+A	O
+case	O
+of	O
+ventricular	B
+tachycardia	I
+related	O
+to	O
+caffeine	O
+pretreatment	O
+.	O
+
+Suboptimal	O
+seizure	B
+duration	O
+is	O
+commonly	O
+encountered	O
+in	O
+electroconvulsive	O
+therapy	O
+practice	O
+,	O
+especially	O
+in	O
+older	O
+patients	O
+with	O
+higher	O
+seizure	B
+thresholds	O
+.	O
+
+Intravenous	O
+caffeine	O
+is	O
+commonly	O
+used	O
+to	O
+improve	O
+seizure	B
+duration	O
+and	O
+quality	O
+in	O
+such	O
+patients	O
+and	O
+is	O
+generally	O
+well	O
+tolerated	O
+aside	O
+from	O
+occasional	O
+reports	O
+of	O
+relatively	O
+benign	O
+ventricular	B
+ectopy	I
+.	O
+
+We	O
+describe	O
+a	O
+patient	O
+with	O
+no	O
+previous	O
+history	O
+of	O
+cardiac	B
+disease	I
+or	O
+arrhythmia	B
+who	O
+developed	O
+sustained	O
+bigeminy	O
+and	O
+2	O
+brief	O
+runs	O
+of	O
+ventricular	B
+tachycardia	I
+after	O
+caffeine	O
+administration	O
+.	O
+
+Although	O
+intravenous	O
+caffeine	O
+is	O
+generally	O
+well	O
+tolerated	O
+,	O
+the	O
+clinician	O
+should	O
+be	O
+aware	O
+of	O
+the	O
+potential	O
+for	O
+unpredictable	O
+and	O
+serious	O
+ventricular	B
+arrhythmias	I
+.	O
+
+Fatal	O
+haemopericardium	B
+and	O
+gastrointestinal	B
+haemorrhage	I
+due	O
+to	O
+possible	O
+interaction	O
+of	O
+cranberry	O
+juice	O
+with	O
+warfarin	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+fatal	O
+internal	O
+haemorrhage	B
+in	O
+an	O
+elderly	O
+man	O
+who	O
+consumed	O
+only	O
+cranberry	O
+juice	O
+for	O
+two	O
+weeks	O
+while	O
+maintaining	O
+his	O
+usual	O
+dosage	O
+of	O
+warfarin	O
+.	O
+
+We	O
+propose	O
+that	O
+naturally	O
+occurring	O
+compounds	O
+such	O
+as	O
+flavonoids	O
+,	O
+which	O
+are	O
+present	O
+in	O
+fruit	O
+juices	O
+,	O
+may	O
+increase	O
+the	O
+potency	O
+of	O
+warfarin	O
+by	O
+competing	O
+for	O
+the	O
+enzymes	O
+that	O
+normally	O
+inactivate	O
+warfarin	O
+.	O
+
+While	O
+traditionally	O
+regarded	O
+as	O
+foodstuffs	O
+,	O
+consumption	O
+of	O
+fruit	O
+juices	O
+should	O
+be	O
+considered	O
+when	O
+patients	O
+develop	O
+adverse	O
+drug	O
+reactions	O
+.	O
+
+Effect	O
+of	O
+increasing	O
+intraperitoneal	O
+infusion	O
+rates	O
+on	O
+bupropion	O
+hydrochloride	O
+-	O
+induced	O
+seizures	B
+in	O
+mice	O
+.	O
+
+BACKGROUND	O
+:	O
+It	O
+is	O
+not	O
+known	O
+if	O
+there	O
+is	O
+a	O
+relationship	O
+between	O
+input	O
+rate	O
+and	O
+incidence	O
+of	O
+bupropion	O
+-	O
+induced	O
+seizures	B
+.	O
+
+This	O
+is	O
+important	O
+,	O
+since	O
+different	O
+controlled	O
+release	O
+formulations	O
+of	O
+bupropion	O
+release	O
+the	O
+active	O
+drug	O
+at	O
+different	O
+rates	O
+.	O
+
+METHODS	O
+:	O
+We	O
+investigated	O
+the	O
+effect	O
+of	O
+varying	O
+the	O
+intraperitoneal	O
+infusion	O
+rates	O
+of	O
+bupropion	O
+HCl	O
+120	O
+mg	O
+/	O
+kg	O
+,	O
+a	O
+known	O
+convulsive	B
+dose	O
+50	O
+(	O
+CD50	O
+)	O
+,	O
+on	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+bupropion	O
+-	O
+induced	O
+convulsions	B
+in	O
+the	O
+Swiss	O
+albino	O
+mice	O
+.	O
+
+A	O
+total	O
+of	O
+69	O
+mice	O
+,	O
+approximately	O
+7	O
+weeks	O
+of	O
+age	O
+,	O
+and	O
+weighing	O
+21	O
+.	O
+0	O
+to	O
+29	O
+.	O
+1	O
+g	O
+were	O
+randomly	O
+assigned	O
+to	O
+bupropion	O
+HCl	O
+120	O
+mg	O
+/	O
+kg	O
+treatment	O
+by	O
+intraperitoneal	O
+(	O
+IP	O
+)	O
+administration	O
+in	O
+7	O
+groups	O
+(	O
+9	O
+to	O
+10	O
+animals	O
+per	O
+group	O
+)	O
+.	O
+
+Bupropion	O
+HCl	O
+was	O
+infused	O
+through	O
+a	O
+surgically	O
+implanted	O
+IP	O
+dosing	O
+catheter	O
+with	O
+infusions	O
+in	O
+each	O
+group	O
+of	O
+0	O
+min	O
+,	O
+15	O
+min	O
+,	O
+30	O
+min	O
+,	O
+60	O
+min	O
+,	O
+90	O
+min	O
+,	O
+120	O
+min	O
+,	O
+and	O
+240	O
+min	O
+.	O
+
+The	O
+number	O
+,	O
+time	O
+of	O
+onset	O
+,	O
+duration	O
+and	O
+the	O
+intensity	O
+of	O
+the	O
+convulsions	B
+or	O
+absence	O
+of	O
+convulsions	B
+were	O
+recorded	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+results	O
+showed	O
+that	O
+IP	O
+administration	O
+of	O
+bupropion	O
+HCl	O
+120	O
+mg	O
+/	O
+kg	O
+by	O
+bolus	O
+injection	O
+induced	O
+convulsions	B
+in	O
+6	O
+out	O
+of	O
+10	O
+mice	O
+(	O
+60	O
+%	O
+of	O
+convulsing	O
+mice	O
+)	O
+in	O
+group	O
+1	O
+.	O
+
+Logistic	O
+regression	O
+analysis	O
+revealed	O
+that	O
+infusion	O
+time	O
+was	O
+significant	O
+(	O
+p	O
+=	O
+0	O
+.	O
+0004	O
+;	O
+odds	O
+ratio	O
+=	O
+0	O
+.	O
+974	O
+)	O
+and	O
+increasing	O
+the	O
+IP	O
+infusion	O
+time	O
+of	O
+bupropion	O
+HCl	O
+120	O
+mg	O
+/	O
+kg	O
+was	O
+associated	O
+with	O
+a	O
+91	O
+%	O
+reduced	O
+odds	O
+of	O
+convulsions	B
+at	O
+infusion	O
+times	O
+of	O
+15	O
+to	O
+90	O
+min	O
+compared	O
+to	O
+bolus	O
+injection	O
+.	O
+
+Further	O
+increase	O
+in	O
+infusion	O
+time	O
+resulted	O
+in	O
+further	O
+reduction	O
+in	O
+the	O
+odds	O
+of	O
+convulsions	B
+to	O
+99	O
+.	O
+8	O
+%	O
+reduction	O
+at	O
+240	O
+min	O
+.	O
+
+CONCLUSION	O
+:	O
+In	O
+conclusion	O
+,	O
+the	O
+demonstration	O
+of	O
+an	O
+inverse	O
+relationship	O
+between	O
+infusion	O
+time	O
+of	O
+a	O
+fixed	O
+and	O
+convulsive	B
+dose	O
+of	O
+bupropion	O
+and	O
+the	O
+risk	O
+of	O
+convulsions	B
+in	O
+a	O
+prospective	O
+study	O
+is	O
+novel	O
+.	O
+
+Graft	B
+-	I
+versus	I
+-	I
+host	I
+disease	I
+prophylaxis	O
+with	O
+everolimus	O
+and	O
+tacrolimus	O
+is	O
+associated	O
+with	O
+a	O
+high	O
+incidence	O
+of	O
+sinusoidal	B
+obstruction	I
+syndrome	I
+and	O
+microangiopathy	B
+:	O
+results	O
+of	O
+the	O
+EVTAC	O
+trial	O
+.	O
+
+A	O
+calcineurin	O
+inhibitor	O
+combined	O
+with	O
+methotrexate	O
+is	O
+the	O
+standard	O
+prophylaxis	O
+for	O
+graft	B
+-	I
+versus	I
+-	I
+host	I
+disease	I
+(	O
+GVHD	B
+)	O
+after	O
+allogeneic	O
+hematopoietic	O
+stem	O
+cell	O
+transplantation	O
+(	O
+HSCT	O
+)	O
+.	O
+
+Everolimus	O
+,	O
+a	O
+derivative	O
+of	O
+sirolimus	O
+,	O
+seems	O
+to	O
+mediate	O
+antileukemia	O
+effects	O
+.	O
+
+We	O
+report	O
+on	O
+a	O
+combination	O
+of	O
+everolimus	O
+and	O
+tacrolimus	O
+in	O
+24	O
+patients	O
+(	O
+median	O
+age	O
+,	O
+62	O
+years	O
+)	O
+with	O
+either	O
+myelodysplastic	B
+syndrome	I
+(	O
+MDS	B
+;	O
+n	O
+=	O
+17	O
+)	O
+or	O
+acute	B
+myeloid	I
+leukemia	I
+(	O
+AML	B
+;	O
+n	O
+=	O
+7	O
+)	O
+undergoing	O
+intensive	O
+conditioning	O
+followed	O
+by	O
+HSCT	O
+from	O
+related	O
+(	O
+n	O
+=	O
+4	O
+)	O
+or	O
+unrelated	O
+(	O
+n	O
+=	O
+20	O
+)	O
+donors	O
+.	O
+
+All	O
+patients	O
+engrafted	O
+,	O
+and	O
+only	O
+1	O
+patient	O
+experienced	O
+grade	O
+IV	O
+mucositis	B
+.	O
+
+Nine	O
+patients	O
+(	O
+37	O
+%	O
+)	O
+developed	O
+acute	O
+grade	O
+II	O
+-	O
+IV	O
+GVHD	B
+,	O
+and	O
+11	O
+of	O
+17	O
+evaluable	O
+patients	O
+(	O
+64	O
+%	O
+)	O
+developed	O
+chronic	O
+extensive	O
+GVHD	B
+.	O
+
+Transplantation	B
+-	I
+associated	I
+microangiopathy	I
+(	O
+TMA	B
+)	O
+occurred	O
+in	O
+7	O
+patients	O
+(	O
+29	O
+%	O
+)	O
+,	O
+with	O
+2	O
+cases	O
+of	O
+acute	B
+renal	I
+failure	I
+.	O
+
+The	O
+study	O
+was	O
+terminated	O
+prematurely	O
+because	O
+an	O
+additional	O
+6	O
+patients	O
+(	O
+25	O
+%	O
+)	O
+developed	O
+sinusoidal	B
+obstruction	I
+syndrome	I
+(	O
+SOS	B
+)	O
+,	O
+which	O
+was	O
+fatal	O
+in	O
+2	O
+cases	O
+.	O
+
+With	O
+a	O
+median	O
+follow	O
+-	O
+up	O
+of	O
+26	O
+months	O
+,	O
+the	O
+2	O
+-	O
+year	O
+overall	O
+survival	O
+rate	O
+was	O
+47	O
+%	O
+.	O
+
+Although	O
+this	O
+new	O
+combination	O
+appears	O
+to	O
+be	O
+effective	O
+as	O
+a	O
+prophylactic	O
+regimen	O
+for	O
+acute	O
+GVHD	B
+,	O
+the	O
+incidence	O
+of	O
+TMA	B
+and	O
+SOS	B
+is	O
+considerably	O
+higher	O
+than	O
+seen	O
+with	O
+other	O
+regimens	O
+.	O
+
+Longitudinal	O
+assessment	O
+of	O
+air	O
+conduction	O
+audiograms	O
+in	O
+a	O
+phase	O
+III	O
+clinical	O
+trial	O
+of	O
+difluoromethylornithine	O
+and	O
+sulindac	O
+for	O
+prevention	O
+of	O
+sporadic	O
+colorectal	B
+adenomas	I
+.	O
+
+A	O
+phase	O
+III	O
+clinical	O
+trial	O
+assessed	O
+the	O
+recurrence	O
+of	O
+adenomatous	B
+polyps	I
+after	O
+treatment	O
+for	O
+36	O
+months	O
+with	O
+difluoromethylornithine	O
+(	O
+DFMO	O
+)	O
+plus	O
+sulindac	O
+or	O
+matched	O
+placebos	O
+.	O
+
+Temporary	O
+hearing	B
+loss	I
+is	O
+a	O
+known	O
+toxicity	B
+of	O
+treatment	O
+with	O
+DFMO	O
+,	O
+thus	O
+a	O
+comprehensive	O
+approach	O
+was	O
+developed	O
+to	O
+analyze	O
+serial	O
+air	O
+conduction	O
+audiograms	O
+.	O
+
+The	O
+generalized	O
+estimating	O
+equation	O
+method	O
+estimated	O
+the	O
+mean	O
+difference	O
+between	O
+treatment	O
+arms	O
+with	O
+regard	O
+to	O
+change	O
+in	O
+air	O
+conduction	O
+pure	O
+tone	O
+thresholds	O
+while	O
+accounting	O
+for	O
+within	O
+-	O
+subject	O
+correlation	O
+due	O
+to	O
+repeated	O
+measurements	O
+at	O
+frequencies	O
+.	O
+
+Based	O
+on	O
+290	O
+subjects	O
+,	O
+there	O
+was	O
+an	O
+average	O
+difference	O
+of	O
+0	O
+.	O
+50	O
+dB	O
+between	O
+subjects	O
+treated	O
+with	O
+DFMO	O
+plus	O
+sulindac	O
+compared	O
+with	O
+those	O
+treated	O
+with	O
+placebo	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+-	O
+0	O
+.	O
+64	O
+to	O
+1	O
+.	O
+63	O
+dB	O
+;	O
+P	O
+=	O
+0	O
+.	O
+39	O
+)	O
+,	O
+adjusted	O
+for	O
+baseline	O
+values	O
+,	O
+age	O
+,	O
+and	O
+frequencies	O
+.	O
+
+In	O
+the	O
+normal	O
+speech	O
+range	O
+of	O
+500	O
+to	O
+3	O
+,	O
+000	O
+Hz	O
+,	O
+an	O
+estimated	O
+difference	O
+of	O
+0	O
+.	O
+99	O
+dB	O
+(	O
+-	O
+0	O
+.	O
+17	O
+to	O
+2	O
+.	O
+14	O
+dB	O
+;	O
+P	O
+=	O
+0	O
+.	O
+09	O
+)	O
+was	O
+detected	O
+.	O
+
+Dose	O
+intensity	O
+did	O
+not	O
+add	O
+information	O
+to	O
+models	O
+.	O
+
+There	O
+were	O
+14	O
+of	O
+151	O
+(	O
+9	O
+.	O
+3	O
+%	O
+)	O
+in	O
+the	O
+DFMO	O
+plus	O
+sulindac	O
+group	O
+and	O
+4	O
+of	O
+139	O
+(	O
+2	O
+.	O
+9	O
+%	O
+)	O
+in	O
+the	O
+placebo	O
+group	O
+who	O
+experienced	O
+at	O
+least	O
+15	O
+dB	O
+hearing	O
+reduction	O
+from	O
+baseline	O
+in	O
+2	O
+or	O
+more	O
+consecutive	O
+frequencies	O
+across	O
+the	O
+entire	O
+range	O
+tested	O
+(	O
+P	O
+=	O
+0	O
+.	O
+02	O
+)	O
+.	O
+
+Follow	O
+-	O
+up	O
+air	O
+conduction	O
+done	O
+at	O
+least	O
+6	O
+months	O
+after	O
+end	O
+of	O
+treatment	O
+showed	O
+an	O
+adjusted	O
+mean	O
+difference	O
+in	O
+hearing	O
+thresholds	O
+of	O
+1	O
+.	O
+08	O
+dB	O
+(	O
+-	O
+0	O
+.	O
+81	O
+to	O
+2	O
+.	O
+96	O
+dB	O
+;	O
+P	O
+=	O
+0	O
+.	O
+26	O
+)	O
+between	O
+treatment	O
+arms	O
+.	O
+
+There	O
+was	O
+no	O
+significant	O
+difference	O
+in	O
+the	O
+proportion	O
+of	O
+subjects	O
+in	O
+the	O
+DFMO	O
+plus	O
+sulindac	O
+group	O
+who	O
+experienced	O
+clinically	O
+significant	O
+hearing	B
+loss	I
+compared	O
+with	O
+the	O
+placebo	O
+group	O
+.	O
+
+The	O
+estimated	O
+attributable	O
+risk	O
+of	O
+ototoxicity	B
+from	O
+exposure	O
+to	O
+the	O
+drug	O
+is	O
+8	O
+.	O
+4	O
+%	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+-	O
+2	O
+.	O
+0	O
+%	O
+to	O
+18	O
+.	O
+8	O
+%	O
+;	O
+P	O
+=	O
+0	O
+.	O
+12	O
+)	O
+.	O
+
+There	O
+is	O
+a	O
+<	O
+2	O
+dB	O
+difference	O
+in	O
+mean	O
+threshold	O
+for	O
+patients	O
+treated	O
+with	O
+DFMO	O
+plus	O
+sulindac	O
+compared	O
+with	O
+those	O
+treated	O
+with	O
+placebo	O
+.	O
+
+Proteinase	O
+3	O
+-	O
+antineutrophil	O
+cytoplasmic	O
+antibody	O
+-	O
+(	O
+PR3	O
+-	O
+ANCA	O
+)	O
+positive	O
+necrotizing	O
+glomerulonephritis	B
+after	O
+restarting	O
+sulphasalazine	O
+treatment	O
+.	O
+
+A	O
+59	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+ulcerative	B
+colitis	I
+developed	O
+red	B
+eyes	I
+,	O
+pleural	B
+effusion	I
+,	O
+eosinophilia	B
+and	O
+urinary	B
+abnormalities	I
+after	O
+restarting	O
+of	O
+sulphasalazine	O
+treatment	O
+.	O
+
+Light	O
+microscopy	O
+of	O
+a	O
+kidney	O
+biopsy	O
+revealed	O
+segmental	B
+necrotizing	I
+glomerulonephritis	I
+without	O
+deposition	O
+of	O
+immunoglobulin	O
+or	O
+complement	O
+.	O
+
+Proteinase	O
+3	O
+-	O
+antineutrophil	O
+cytoplasmic	O
+antibody	O
+(	O
+PR3	O
+-	O
+ANCA	O
+)	O
+titer	O
+was	O
+elevated	O
+at	O
+183	O
+ELISA	O
+units	O
+(	O
+EU	O
+)	O
+in	O
+sera	O
+(	O
+normal	O
+range	O
+less	O
+than	O
+10	O
+EU	O
+)	O
+,	O
+myeloperoxidase	O
+-	O
+ANCA	O
+was	O
+negative	O
+.	O
+
+PR3	O
+-	O
+ANCA	O
+titer	O
+was	O
+250	O
+and	O
+1	O
+,	O
+070	O
+EU	O
+in	O
+pleural	B
+effusions	I
+on	O
+right	O
+and	O
+left	O
+side	O
+,	O
+respectively	O
+.	O
+
+Although	O
+cessation	O
+of	O
+sulphasalazine	O
+treatment	O
+resulted	O
+in	O
+improvements	O
+in	O
+fever	B
+,	O
+red	B
+eyes	I
+,	O
+chest	B
+pain	I
+,	O
+titer	O
+of	O
+C	O
+-	O
+reactive	O
+protein	O
+and	O
+volume	O
+of	O
+the	O
+pleural	B
+effusions	I
+,	O
+we	O
+initiated	O
+steroid	O
+therapy	O
+,	O
+because	O
+PR3	O
+-	O
+ANCA	O
+titer	O
+rose	O
+to	O
+320	O
+EU	O
+,	O
+eosinophil	O
+count	O
+increased	O
+to	O
+1	O
+,	O
+100	O
+cells	O
+/	O
+microl	O
+,	O
+and	O
+the	O
+pleural	B
+effusion	I
+remained	O
+.	O
+
+One	O
+month	O
+after	O
+steroid	O
+therapy	O
+,	O
+the	O
+pleural	B
+effusion	I
+disappeared	O
+,	O
+and	O
+PR3	O
+-	O
+ANCA	O
+titer	O
+normalized	O
+3	O
+months	O
+later	O
+.	O
+
+This	O
+case	O
+suggests	O
+that	O
+sulphasalazine	O
+can	O
+induce	O
+PR3	O
+-	O
+ANCA	O
+-	O
+positive	O
+necrotizing	O
+glomerulonephritis	B
+.	O
+
+Comparison	O
+of	O
+unilateral	O
+pallidotomy	O
+and	O
+subthalamotomy	O
+findings	O
+in	O
+advanced	O
+idiopathic	B
+Parkinson	I
+'	I
+s	I
+disease	I
+.	O
+
+A	O
+prospective	O
+,	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+pilot	O
+study	O
+to	O
+compare	O
+the	O
+results	O
+of	O
+stereotactic	O
+unilateral	O
+pallidotomy	O
+and	O
+subthalamotomy	O
+in	O
+advanced	O
+idiopathic	B
+Parkinson	I
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+refractory	O
+to	O
+medical	O
+treatment	O
+was	O
+designed	O
+.	O
+
+Ten	O
+consecutive	O
+patients	O
+(	O
+mean	O
+age	O
+,	O
+58	O
+.	O
+4	O
++	O
+/	O
+-	O
+6	O
+.	O
+8	O
+years	O
+;	O
+7	O
+men	O
+,	O
+3	O
+women	O
+)	O
+with	O
+similar	O
+characteristics	O
+at	O
+the	O
+duration	O
+of	O
+disease	O
+(	O
+mean	O
+disease	O
+time	O
+,	O
+8	O
+.	O
+4	O
++	O
+/	O
+-	O
+3	O
+.	O
+5	O
+years	O
+)	O
+,	O
+disabling	O
+motor	O
+fluctuations	O
+(	O
+Hoehn	O
+_	O
+Yahr	O
+stage	O
+3	O
+-	O
+5	O
+in	O
+off	O
+-	O
+drug	O
+phases	O
+)	O
+and	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+were	O
+selected	O
+.	O
+
+All	O
+patients	O
+had	O
+bilateral	O
+symptoms	O
+and	O
+their	O
+levodopa	O
+equivalent	O
+dosing	O
+were	O
+analysed	O
+.	O
+
+Six	O
+patients	O
+were	O
+operated	O
+on	O
+in	O
+the	O
+globus	O
+pallidus	O
+interna	O
+(	O
+GPi	O
+)	O
+and	O
+four	O
+in	O
+the	O
+subthalamic	O
+nucleus	O
+(	O
+STN	O
+)	O
+.	O
+
+Clinical	O
+evaluation	O
+included	O
+the	O
+use	O
+of	O
+the	O
+Unified	O
+Parkinson	B
+'	I
+s	I
+Disease	I
+Rating	O
+Scale	O
+(	O
+UPDRS	O
+)	O
+,	O
+Hoehn	O
+_	O
+Yahr	O
+score	O
+and	O
+Schwab	O
+England	O
+activities	O
+of	O
+daily	O
+living	O
+(	O
+ADL	O
+)	O
+score	O
+in	O
+'	O
+on	O
+'	O
+-	O
+and	O
+'	O
+off	O
+'	O
+-	O
+drug	O
+conditions	O
+before	O
+surgery	O
+and	O
+6	O
+months	O
+after	O
+surgery	O
+.	O
+
+There	O
+was	O
+statistically	O
+significant	O
+improvement	O
+in	O
+all	O
+contralateral	O
+major	O
+parkinsonian	B
+motor	O
+signs	O
+in	O
+all	O
+patients	O
+followed	O
+for	O
+6	O
+months	O
+.	O
+
+Levodopa	O
+equivalent	O
+daily	O
+intake	O
+was	O
+significantly	O
+reduced	O
+in	O
+the	O
+STN	O
+group	O
+.	O
+
+Changes	O
+in	O
+UPDRS	O
+,	O
+Hoehn	O
+_	O
+Yahr	O
+and	O
+Schwab	O
+England	O
+ADL	O
+scores	O
+were	O
+similar	O
+in	O
+both	O
+groups	O
+.	O
+
+Cognitive	O
+functions	O
+were	O
+unchanged	O
+in	O
+both	O
+groups	O
+.	O
+
+Complications	O
+were	O
+observed	O
+in	O
+two	O
+patients	O
+:	O
+one	O
+had	O
+a	O
+left	O
+homonymous	B
+hemianopsia	I
+after	O
+pallidotomy	O
+and	O
+another	O
+one	O
+developed	O
+left	O
+hemiballistic	O
+movements	O
+3	O
+days	O
+after	O
+subthalamotomy	O
+which	O
+partly	O
+improved	O
+within	O
+1	O
+month	O
+with	O
+Valproate	O
+1000	O
+mg	O
+/	O
+day	O
+.	O
+
+The	O
+findings	O
+of	O
+this	O
+study	O
+suggest	O
+that	O
+lesions	O
+of	O
+the	O
+unilateral	O
+STN	O
+and	O
+GPi	O
+are	O
+equally	O
+effective	O
+treatment	O
+for	O
+patients	O
+with	O
+advanced	O
+PD	B
+refractory	O
+to	O
+medical	O
+treatment	O
+.	O
+
+DSMM	O
+XI	O
+study	O
+:	O
+dose	O
+definition	O
+for	O
+intravenous	O
+cyclophosphamide	O
+in	O
+combination	O
+with	O
+bortezomib	O
+/	O
+dexamethasone	O
+for	O
+remission	O
+induction	O
+in	O
+patients	O
+with	O
+newly	O
+diagnosed	O
+myeloma	B
+.	O
+
+A	O
+clinical	O
+trial	O
+was	O
+initiated	O
+to	O
+evaluate	O
+the	O
+recommended	O
+dose	O
+of	O
+cyclophosphamide	O
+in	O
+combination	O
+with	O
+bortezomib	O
+and	O
+dexamethasone	O
+as	O
+induction	O
+treatment	O
+before	O
+stem	O
+cell	O
+transplantation	O
+for	O
+younger	O
+patients	O
+with	O
+newly	O
+diagnosed	O
+multiple	B
+myeloma	I
+(	O
+MM	B
+)	O
+.	O
+
+Thirty	O
+patients	O
+were	O
+treated	O
+with	O
+three	O
+21	O
+-	O
+day	O
+cycles	O
+of	O
+bortezomib	O
+1	O
+.	O
+3	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+on	O
+days	O
+1	O
+,	O
+4	O
+,	O
+8	O
+,	O
+and	O
+11	O
+plus	O
+dexamethasone	O
+40	O
+mg	O
+on	O
+the	O
+day	O
+of	O
+bortezomib	O
+injection	O
+and	O
+the	O
+day	O
+after	O
+plus	O
+cyclophosphamide	O
+at	O
+900	O
+,	O
+1	O
+,	O
+200	O
+,	O
+or	O
+1	O
+,	O
+500	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+on	O
+day	O
+1	O
+.	O
+
+The	O
+maximum	O
+tolerated	O
+dose	O
+of	O
+cyclophosphamide	O
+was	O
+defined	O
+as	O
+900	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+.	O
+
+At	O
+this	O
+dose	O
+level	O
+,	O
+92	O
+%	O
+of	O
+patients	O
+achieved	O
+at	O
+least	O
+a	O
+partial	O
+response	O
+.	O
+
+The	O
+overall	O
+response	O
+rate	O
+[	O
+complete	O
+response	O
+(	O
+CR	O
+)	O
+plus	O
+partial	O
+response	O
+(	O
+PR	O
+)	O
+]	O
+across	O
+all	O
+dose	O
+levels	O
+was	O
+77	O
+%	O
+,	O
+with	O
+a	O
+10	O
+%	O
+CR	O
+rate	O
+.	O
+
+No	O
+patient	O
+experienced	O
+progressive	O
+disease	O
+.	O
+
+The	O
+most	O
+frequent	O
+adverse	O
+events	O
+were	O
+hematological	B
+and	I
+gastrointestinal	I
+toxicities	I
+as	O
+well	O
+as	O
+neuropathy	B
+.	O
+
+The	O
+results	O
+suggest	O
+that	O
+bortezomib	O
+in	O
+combination	O
+with	O
+cyclophosphamide	O
+at	O
+900	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+and	O
+dexamethasone	O
+is	O
+an	O
+effective	O
+induction	O
+treatment	O
+for	O
+patients	O
+with	O
+newly	O
+diagnosed	O
+MM	B
+that	O
+warrants	O
+further	O
+investigation	O
+.	O
+
+Naloxone	O
+reversal	O
+of	O
+hypotension	B
+due	O
+to	O
+captopril	O
+overdose	B
+.	O
+
+The	O
+hemodynamic	O
+effects	O
+of	O
+captopril	O
+and	O
+other	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitors	O
+may	O
+be	O
+mediated	O
+by	O
+the	O
+endogenous	O
+opioid	O
+system	O
+.	O
+
+The	O
+opioid	O
+antagonist	O
+naloxone	O
+has	O
+been	O
+shown	O
+to	O
+block	O
+or	O
+reverse	O
+the	O
+hypotensive	B
+actions	O
+of	O
+captopril	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+an	O
+intentional	O
+captopril	O
+overdose	B
+,	O
+manifested	O
+by	O
+marked	O
+hypotension	B
+,	O
+that	O
+resolved	O
+promptly	O
+with	O
+the	O
+administration	O
+of	O
+naloxone	O
+.	O
+
+To	O
+our	O
+knowledge	O
+,	O
+this	O
+is	O
+the	O
+first	O
+reported	O
+case	O
+of	O
+captopril	O
+-	O
+induced	O
+hypotension	B
+treated	O
+with	O
+naloxone	O
+.	O
+
+Our	O
+experience	O
+demonstrates	O
+a	O
+possible	O
+role	O
+of	O
+naloxone	O
+in	O
+the	O
+reversal	O
+of	O
+hypotension	B
+resulting	O
+from	O
+captopril	O
+.	O
+
+Identification	O
+of	O
+a	O
+simple	O
+and	O
+sensitive	O
+microplate	O
+method	O
+for	O
+the	O
+detection	O
+of	O
+oversulfated	O
+chondroitin	O
+sulfate	O
+in	O
+heparin	O
+products	O
+.	O
+
+Heparin	O
+is	O
+a	O
+commonly	O
+implemented	O
+anticoagulant	O
+used	O
+to	O
+treat	O
+critically	O
+ill	O
+patients	O
+.	O
+
+Recently	O
+,	O
+a	O
+number	O
+of	O
+commercial	O
+lots	O
+of	O
+heparin	O
+products	O
+were	O
+found	O
+to	O
+be	O
+contaminated	O
+with	O
+an	O
+oversulfated	O
+chondroitin	O
+sulfate	O
+(	O
+OSCS	O
+)	O
+derivative	O
+that	O
+could	O
+elicit	O
+a	O
+hypotensive	B
+response	O
+in	O
+pigs	O
+following	O
+a	O
+single	O
+high	O
+-	O
+dose	O
+infusion	O
+.	O
+
+Using	O
+both	O
+contaminated	O
+heparin	O
+products	O
+and	O
+the	O
+synthetically	O
+produced	O
+derivative	O
+,	O
+we	O
+showed	O
+that	O
+the	O
+OSCS	O
+produces	O
+dose	O
+-	O
+dependent	O
+hypotension	B
+in	O
+pigs	O
+.	O
+
+The	O
+no	O
+observed	O
+effect	O
+level	O
+(	O
+NOEL	O
+)	O
+for	O
+this	O
+contaminant	O
+appears	O
+to	O
+be	O
+approximately	O
+1mg	O
+/	O
+kg	O
+,	O
+corresponding	O
+to	O
+a	O
+contamination	O
+level	O
+of	O
+approximately	O
+3	O
+%	O
+.	O
+
+We	O
+also	O
+demonstrated	O
+that	O
+OSCS	O
+can	O
+be	O
+identified	O
+in	O
+heparin	O
+products	O
+using	O
+a	O
+simple	O
+,	O
+inexpensive	O
+,	O
+commercially	O
+available	O
+heparin	O
+enzyme	O
+immunoassay	O
+(	O
+EIA	O
+)	O
+kit	O
+that	O
+has	O
+a	O
+limit	O
+of	O
+detection	O
+of	O
+approximately	O
+0	O
+.	O
+1	O
+%	O
+,	O
+well	O
+below	O
+the	O
+NOEL	O
+.	O
+
+This	O
+kit	O
+may	O
+provide	O
+a	O
+useful	O
+method	O
+to	O
+test	O
+heparin	O
+products	O
+for	O
+contamination	O
+with	O
+oversulfated	O
+GAG	O
+derivatives	O
+.	O
+
+5	O
+flourouracil	O
+-	O
+induced	O
+apical	B
+ballooning	I
+syndrome	I
+:	O
+a	O
+case	O
+report	O
+.	O
+
+The	O
+apical	B
+ballooning	I
+syndrome	I
+(	O
+ABS	B
+)	O
+is	O
+a	O
+recently	O
+described	O
+stress	O
+-	O
+mediated	O
+acute	B
+cardiac	I
+syndrome	I
+characterized	O
+by	O
+transient	O
+wall	O
+-	O
+motion	O
+abnormalities	O
+involving	O
+the	O
+apex	O
+and	O
+midventricle	O
+with	O
+hyperkinesis	B
+of	O
+the	O
+basal	O
+left	O
+ventricular	O
+(	O
+LV	O
+)	O
+segments	O
+without	O
+obstructive	O
+epicardial	B
+coronary	I
+disease	I
+.	O
+
+Cardiotoxicity	B
+is	O
+not	O
+an	O
+uncommon	O
+adverse	O
+effect	O
+of	O
+chemotherapeutic	O
+agents	O
+.	O
+
+However	O
+,	O
+there	O
+are	O
+no	O
+reports	O
+of	O
+ABS	B
+secondary	O
+to	O
+chemotherapeutic	O
+agents	O
+.	O
+
+We	O
+describe	O
+the	O
+case	O
+of	O
+a	O
+woman	O
+who	O
+developed	O
+the	O
+syndrome	O
+after	O
+chemotherapy	O
+for	O
+metastatic	O
+cancer	B
+.	O
+
+A	O
+79	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+presented	O
+with	O
+typical	O
+ischemic	B
+chest	B
+pain	I
+,	O
+elevated	O
+cardiac	O
+enzymes	O
+with	O
+significant	O
+ST	O
+-	O
+segment	O
+abnormalities	O
+on	O
+her	O
+electrocardiogram	O
+.	O
+
+She	O
+underwent	O
+recent	O
+chemotherapy	O
+with	O
+fluorouracil	O
+for	O
+metastatic	O
+colorectal	B
+cancer	I
+.	O
+
+Echocardiography	O
+revealed	O
+a	O
+wall	O
+-	O
+motion	O
+abnormality	O
+involving	O
+the	O
+apical	O
+and	O
+periapical	O
+segments	O
+which	O
+appeared	O
+akinetic	B
+.	O
+
+Coronary	O
+angiography	O
+revealed	O
+no	O
+obstructive	O
+coronary	O
+lesions	O
+.	O
+
+The	O
+patient	O
+was	O
+stabilized	O
+with	O
+medical	O
+therapy	O
+.	O
+
+Four	O
+weeks	O
+later	O
+she	O
+remained	O
+completely	O
+asymptomatic	O
+.	O
+
+Echocardiogram	O
+revealed	O
+a	O
+normal	O
+ejection	O
+fraction	O
+and	O
+a	O
+resolution	O
+of	O
+the	O
+apical	O
+akinesis	B
+.	O
+
+Pathogenetic	O
+mechanisms	O
+of	O
+cardiac	B
+complications	I
+in	O
+cancer	B
+patients	O
+undergoing	O
+chemotherapy	O
+include	O
+coronary	B
+vasospasm	I
+,	O
+endothelial	O
+damage	O
+and	O
+consequent	O
+thrombus	B
+formation	O
+.	O
+
+In	O
+our	O
+patient	O
+,	O
+both	O
+supraphysiologic	O
+levels	O
+of	O
+plasma	O
+catecholamines	O
+and	O
+stress	O
+related	O
+neuropeptides	O
+caused	O
+by	O
+cancer	B
+diagnosis	O
+as	O
+well	O
+as	O
+chemotherapy	O
+may	O
+have	O
+contributed	O
+the	O
+development	O
+of	O
+ABS	B
+.	O
+
+Rapid	O
+reversal	O
+of	O
+anticoagulation	O
+reduces	O
+hemorrhage	B
+volume	O
+in	O
+a	O
+mouse	O
+model	O
+of	O
+warfarin	O
+-	O
+associated	O
+intracerebral	B
+hemorrhage	I
+.	O
+
+Warfarin	O
+-	O
+associated	O
+intracerebral	B
+hemorrhage	I
+(	O
+W	O
+-	O
+ICH	B
+)	O
+is	O
+a	O
+severe	O
+type	O
+of	O
+stroke	B
+.	O
+
+There	O
+is	O
+no	O
+consensus	O
+on	O
+the	O
+optimal	O
+treatment	O
+for	O
+W	O
+-	O
+ICH	B
+.	O
+
+Using	O
+a	O
+mouse	O
+model	O
+,	O
+we	O
+tested	O
+whether	O
+the	O
+rapid	O
+reversal	O
+of	O
+anticoagulation	O
+using	O
+human	O
+prothrombin	O
+complex	O
+concentrate	O
+(	O
+PCC	O
+)	O
+can	O
+reduce	O
+hemorrhagic	O
+blood	O
+volume	O
+.	O
+
+Male	O
+CD	O
+-	O
+1	O
+mice	O
+were	O
+treated	O
+with	O
+warfarin	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+over	O
+24	O
+h	O
+)	O
+,	O
+resulting	O
+in	O
+a	O
+mean	O
+(	O
++	O
+/	O
+-	O
+s	O
+.	O
+d	O
+.	O
+)	O
+International	O
+Normalized	O
+Ratio	O
+of	O
+3	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+9	O
+.	O
+
+First	O
+,	O
+we	O
+showed	O
+that	O
+an	O
+intravenous	O
+administration	O
+of	O
+human	O
+PCC	O
+rapidly	O
+reversed	O
+anticoagulation	O
+in	O
+mice	O
+.	O
+
+Second	O
+,	O
+a	O
+stereotactic	O
+injection	O
+of	O
+collagenase	O
+was	O
+administered	O
+to	O
+induce	O
+hemorrhage	B
+in	O
+the	O
+right	O
+striatum	O
+.	O
+
+Forty	O
+-	O
+five	O
+minutes	O
+later	O
+,	O
+the	O
+animals	O
+were	O
+randomly	O
+treated	O
+with	O
+PCC	O
+(	O
+100	O
+U	O
+/	O
+kg	O
+)	O
+or	O
+saline	O
+i	O
+.	O
+v	O
+.	O
+(	O
+n	O
+=	O
+12	O
+per	O
+group	O
+)	O
+.	O
+
+Twenty	O
+-	O
+four	O
+hours	O
+after	O
+hemorrhage	B
+induction	O
+,	O
+hemorrhagic	O
+blood	O
+volume	O
+was	O
+quantified	O
+using	O
+a	O
+photometric	O
+hemoglobin	O
+assay	O
+.	O
+
+The	O
+mean	O
+hemorrhagic	O
+blood	O
+volume	O
+was	O
+reduced	O
+in	O
+PCC	O
+-	O
+treated	O
+animals	O
+(	O
+6	O
+.	O
+5	O
++	O
+/	O
+-	O
+3	O
+.	O
+1	O
+microL	O
+)	O
+compared	O
+with	O
+saline	O
+controls	O
+(	O
+15	O
+.	O
+3	O
++	O
+/	O
+-	O
+11	O
+.	O
+2	O
+microL	O
+,	O
+P	O
+=	O
+0	O
+.	O
+015	O
+)	O
+.	O
+
+In	O
+the	O
+saline	O
+group	O
+,	O
+45	O
+%	O
+of	O
+the	O
+mice	O
+developed	O
+large	O
+hematomas	B
+(	O
+i	O
+.	O
+e	O
+.	O
+,	O
+>	O
+15	O
+microL	O
+)	O
+.	O
+
+In	O
+contrast	O
+,	O
+such	O
+extensive	O
+lesions	O
+were	O
+never	O
+found	O
+in	O
+the	O
+PCC	O
+group	O
+.	O
+
+We	O
+provide	O
+experimental	O
+data	O
+suggesting	O
+PCC	O
+to	O
+be	O
+an	O
+effective	O
+acute	O
+treatment	O
+for	O
+W	O
+-	O
+ICH	B
+in	O
+terms	O
+of	O
+reducing	O
+hemorrhagic	O
+blood	O
+volume	O
+.	O
+
+Future	O
+studies	O
+are	O
+needed	O
+to	O
+assess	O
+the	O
+therapeutic	O
+potential	O
+emerging	O
+from	O
+our	O
+finding	O
+for	O
+human	O
+W	O
+-	O
+ICH	B
+.	O
+
+Long	O
+term	O
+hormone	O
+therapy	O
+for	O
+perimenopausal	O
+and	O
+postmenopausal	O
+women	O
+.	O
+
+BACKGROUND	O
+:	O
+Hormone	O
+therapy	O
+(	O
+HT	O
+)	O
+is	O
+widely	O
+used	O
+for	O
+controlling	O
+menopausal	O
+symptoms	O
+and	O
+has	O
+also	O
+been	O
+used	O
+for	O
+the	O
+management	O
+and	O
+prevention	O
+of	O
+cardiovascular	B
+disease	I
+,	O
+osteoporosis	B
+and	O
+dementia	B
+in	O
+older	O
+women	O
+.	O
+
+This	O
+is	O
+an	O
+updated	O
+version	O
+of	O
+the	O
+original	O
+Cochrane	O
+review	O
+first	O
+published	O
+in	O
+2005	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+assess	O
+the	O
+effect	O
+of	O
+long	O
+-	O
+term	O
+HT	O
+on	O
+mortality	O
+,	O
+cardiovascular	O
+outcomes	O
+,	O
+cancer	B
+,	O
+gallbladder	B
+disease	I
+,	O
+cognition	O
+,	O
+fractures	B
+and	O
+quality	O
+of	O
+life	O
+.	O
+
+SEARCH	O
+STRATEGY	O
+:	O
+We	O
+searched	O
+the	O
+following	O
+databases	O
+to	O
+November	O
+2007	O
+:	O
+Trials	O
+Register	O
+of	O
+the	O
+Cochrane	O
+Menstrual	B
+Disorders	I
+and	O
+Subfertility	O
+Group	O
+,	O
+Cochrane	O
+Central	O
+Register	O
+of	O
+Controlled	O
+Trials	O
+,	O
+MEDLINE	O
+,	O
+EMBASE	O
+,	O
+Biological	O
+Abstracts	O
+.	O
+
+Also	O
+relevant	O
+non	O
+-	O
+indexed	O
+journals	O
+and	O
+conference	O
+abstracts	O
+.	O
+
+SELECTION	O
+CRITERIA	O
+:	O
+Randomised	O
+double	O
+-	O
+blind	O
+trials	O
+of	O
+HT	O
+versus	O
+placebo	O
+,	O
+taken	O
+for	O
+at	O
+least	O
+one	O
+year	O
+by	O
+perimenopausal	O
+or	O
+postmenopausal	O
+women	O
+.	O
+
+HT	O
+included	O
+oestrogens	O
+,	O
+with	O
+or	O
+without	O
+progestogens	O
+,	O
+via	O
+oral	O
+,	O
+transdermal	O
+,	O
+subcutaneous	O
+or	O
+transnasal	O
+routes	O
+.	O
+
+DATA	O
+COLLECTION	O
+AND	O
+ANALYSIS	O
+:	O
+Two	O
+authors	O
+independently	O
+assessed	O
+trial	O
+quality	O
+and	O
+extracted	O
+data	O
+.	O
+
+MAIN	O
+RESULTS	O
+:	O
+Nineteen	O
+trials	O
+involving	O
+41	O
+,	O
+904	O
+women	O
+were	O
+included	O
+.	O
+
+In	O
+relatively	O
+healthy	O
+women	O
+,	O
+combined	O
+continuous	O
+HT	O
+significantly	O
+increased	O
+the	O
+risk	O
+of	O
+venous	B
+thrombo	I
+-	I
+embolism	I
+or	O
+coronary	O
+event	O
+(	O
+after	O
+one	O
+year	O
+'	O
+s	O
+use	O
+)	O
+,	O
+stroke	B
+(	O
+after	O
+three	O
+years	O
+)	O
+,	O
+breast	B
+cancer	I
+and	O
+gallbladder	B
+disease	I
+.	O
+
+Long	O
+-	O
+term	O
+oestrogen	O
+-	O
+only	O
+HT	O
+significantly	O
+increased	O
+the	O
+risk	O
+of	O
+venous	B
+thrombo	I
+-	I
+embolism	I
+,	O
+stroke	B
+and	O
+gallbladder	B
+disease	I
+(	O
+after	O
+one	O
+to	O
+two	O
+years	O
+,	O
+three	O
+years	O
+and	O
+seven	O
+years	O
+'	O
+use	O
+respectively	O
+)	O
+,	O
+but	O
+did	O
+not	O
+significantly	O
+increase	O
+the	O
+risk	O
+of	O
+breast	B
+cancer	I
+.	O
+
+The	O
+only	O
+statistically	O
+significant	O
+benefits	O
+of	O
+HT	O
+were	O
+a	O
+decreased	O
+incidence	O
+of	O
+fractures	B
+and	O
+(	O
+for	O
+combined	O
+HT	O
+)	O
+colon	B
+cancer	I
+,	O
+with	O
+long	O
+-	O
+term	O
+use	O
+.	O
+
+Among	O
+women	O
+aged	O
+over	O
+65	O
+who	O
+were	O
+relatively	O
+healthy	O
+(	O
+i	O
+.	O
+e	O
+.	O
+generally	O
+fit	O
+,	O
+without	O
+overt	O
+disease	O
+)	O
+and	O
+taking	O
+continuous	O
+combined	O
+HT	O
+,	O
+there	O
+was	O
+a	O
+statistically	O
+significant	O
+increase	O
+in	O
+the	O
+incidence	O
+of	O
+dementia	B
+.	O
+
+Among	O
+women	O
+with	O
+cardiovascular	B
+disease	I
+,	O
+long	O
+-	O
+term	O
+use	O
+of	O
+combined	O
+continuous	O
+HT	O
+significantly	O
+increased	O
+the	O
+risk	O
+of	O
+venous	B
+thrombo	I
+-	I
+embolism	I
+.	O
+One	O
+trial	O
+analysed	O
+subgroups	O
+of	O
+2839	O
+relatively	O
+healthy	O
+50	O
+to	O
+59	O
+year	O
+old	O
+women	O
+taking	O
+combined	O
+continuous	O
+HT	O
+and	O
+1637	O
+taking	O
+oestrogen	O
+-	O
+only	O
+HT	O
+,	O
+versus	O
+similar	O
+-	O
+sized	O
+placebo	O
+groups	O
+.	O
+
+The	O
+only	O
+significantly	O
+increased	O
+risk	O
+reported	O
+was	O
+for	O
+venous	B
+thrombo	I
+-	I
+embolism	I
+in	O
+women	O
+taking	O
+combined	O
+continuous	O
+HT	O
+:	O
+their	O
+absolute	O
+risk	O
+remained	O
+low	O
+,	O
+at	O
+less	O
+than	O
+1	O
+/	O
+500	O
+.	O
+
+However	O
+,	O
+this	O
+study	O
+was	O
+not	O
+powered	O
+to	O
+detect	O
+differences	O
+between	O
+groups	O
+of	O
+younger	O
+women	O
+.	O
+
+AUTHORS	O
+'	O
+CONCLUSIONS	O
+:	O
+HT	O
+is	O
+not	O
+indicated	O
+for	O
+the	O
+routine	O
+management	O
+of	O
+chronic	O
+disease	O
+.	O
+
+We	O
+need	O
+more	O
+evidence	O
+on	O
+the	O
+safety	O
+of	O
+HT	O
+for	O
+menopausal	O
+symptom	O
+control	O
+,	O
+though	O
+short	O
+-	O
+term	O
+use	O
+appears	O
+to	O
+be	O
+relatively	O
+safe	O
+for	O
+healthy	O
+younger	O
+women	O
+.	O
+
+Acute	B
+renal	I
+failure	I
+in	O
+patients	O
+with	O
+AIDS	B
+on	O
+tenofovir	O
+while	O
+receiving	O
+prolonged	O
+vancomycin	O
+course	O
+for	O
+osteomyelitis	B
+.	O
+
+Renal	B
+failure	I
+developed	O
+after	O
+a	O
+prolonged	O
+course	O
+of	O
+vancomycin	O
+therapy	O
+in	O
+2	O
+patients	O
+who	O
+were	O
+receiving	O
+tenofovir	O
+disoproxil	O
+fumarate	O
+as	O
+part	O
+of	O
+an	O
+antiretroviral	O
+regimen	O
+.	O
+
+Tenofovir	O
+has	O
+been	O
+implicated	O
+in	O
+the	O
+development	O
+of	O
+Fanconi	B
+syndrome	I
+and	O
+renal	B
+insufficiency	I
+because	O
+of	O
+its	O
+effects	O
+on	O
+the	O
+proximal	O
+renal	O
+tubule	O
+.	O
+
+Vancomycin	O
+nephrotoxicity	B
+is	O
+infrequent	O
+but	O
+may	O
+result	O
+from	O
+coadministration	O
+with	O
+a	O
+nephrotoxic	B
+agent	O
+.	O
+
+Clinicians	O
+should	O
+be	O
+aware	O
+that	O
+tenofovir	O
+may	O
+raise	O
+the	O
+risk	O
+of	O
+renal	B
+failure	I
+during	O
+prolonged	O
+administration	O
+of	O
+vancomycin	O
+.	O
+
+Recurrent	O
+dysosmia	B
+induced	O
+by	O
+pyrazinamide	O
+.	O
+
+Pyrazinamide	O
+can	O
+have	O
+adverse	O
+effects	O
+such	O
+as	O
+hepatic	B
+toxicity	I
+,	O
+hyperuricemia	B
+or	O
+digestive	O
+disorders	O
+.	O
+
+In	O
+rare	O
+cases	O
+,	O
+alterations	O
+in	O
+taste	O
+and	O
+smell	O
+function	O
+have	O
+been	O
+reported	O
+for	O
+pyrazinamide	O
+when	O
+combined	O
+with	O
+other	O
+drugs	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+reversible	O
+olfactory	B
+disorder	I
+related	O
+to	O
+pyrazinamide	O
+in	O
+a	O
+woman	O
+,	O
+with	O
+a	O
+positive	O
+rechallenge	O
+.	O
+
+The	O
+patient	O
+presented	O
+every	O
+day	O
+a	O
+sensation	O
+of	O
+smelling	O
+something	O
+burning	O
+15	O
+min	O
+after	O
+drug	O
+intake	O
+.	O
+
+Dysosmia	B
+disappeared	O
+completely	O
+after	O
+pyrazinamide	O
+withdrawal	O
+and	O
+recurred	O
+after	O
+its	O
+rechallenge	O
+.	O
+
+The	O
+case	O
+was	O
+reported	O
+to	O
+the	O
+Tunisian	O
+Centre	O
+of	O
+Pharmacovigilance	O
+.	O
+
+Mice	O
+lacking	O
+mPGES	O
+-	O
+1	O
+are	O
+resistant	O
+to	O
+lithium	O
+-	O
+induced	O
+polyuria	B
+.	O
+
+Cyclooxygenase	O
+-	O
+2	O
+activity	O
+is	O
+required	O
+for	O
+the	O
+development	O
+of	O
+lithium	O
+-	O
+induced	O
+polyuria	B
+.	O
+
+However	O
+,	O
+the	O
+involvement	O
+of	O
+a	O
+specific	O
+,	O
+terminal	O
+prostaglandin	O
+(	O
+PG	O
+)	O
+isomerase	O
+has	O
+not	O
+been	O
+evaluated	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+undertaken	O
+to	O
+assess	O
+lithium	O
+-	O
+induced	O
+polyuria	B
+in	O
+mice	O
+deficient	O
+in	O
+microsomal	O
+prostaglandin	O
+E	O
+synthase	O
+-	O
+1	O
+(	O
+mPGES	O
+-	O
+1	O
+)	O
+.	O
+
+A	O
+2	O
+-	O
+wk	O
+administration	O
+of	O
+LiCl	O
+(	O
+4	O
+mmol	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+day	O
+(	O
+-	O
+1	O
+)	O
+ip	O
+)	O
+in	O
+mPGES	O
+-	O
+1	O
++	O
+/	O
++	O
+mice	O
+led	O
+to	O
+a	O
+marked	O
+polyuria	B
+with	O
+hyposmotic	O
+urine	O
+.	O
+
+This	O
+was	O
+associated	O
+with	O
+elevated	O
+renal	O
+mPGES	O
+-	O
+1	O
+protein	O
+expression	O
+and	O
+increased	O
+urine	O
+PGE	O
+(	O
+2	O
+)	O
+excretion	O
+.	O
+
+In	O
+contrast	O
+,	O
+mPGES	O
+-	O
+1	O
+-	O
+/	O
+-	O
+mice	O
+were	O
+largely	O
+resistant	O
+to	O
+lithium	O
+-	O
+induced	O
+polyuria	B
+and	O
+a	O
+urine	O
+concentrating	O
+defect	O
+,	O
+accompanied	O
+by	O
+nearly	O
+complete	O
+blockade	O
+of	O
+high	O
+urine	O
+PGE	O
+(	O
+2	O
+)	O
+and	O
+cAMP	O
+output	O
+.	O
+
+Immunoblotting	O
+,	O
+immunohistochemistry	O
+,	O
+and	O
+quantitative	O
+(	O
+q	O
+)	O
+RT	O
+-	O
+PCR	O
+consistently	O
+detected	O
+a	O
+significant	O
+decrease	O
+in	O
+aquaporin	O
+-	O
+2	O
+(	O
+AQP2	O
+)	O
+protein	O
+expression	O
+in	O
+both	O
+the	O
+renal	O
+cortex	O
+and	O
+medulla	O
+of	O
+lithium	O
+-	O
+treated	O
++	O
+/	O
++	O
+mice	O
+.	O
+
+This	O
+decrease	O
+was	O
+significantly	O
+attenuated	O
+in	O
+the	O
+-	O
+/	O
+-	O
+mice	O
+.	O
+
+qRT	O
+-	O
+PCR	O
+detected	O
+similar	O
+patterns	O
+of	O
+changes	O
+in	O
+AQP2	O
+mRNA	O
+in	O
+the	O
+medulla	O
+but	O
+not	O
+in	O
+the	O
+cortex	O
+.	O
+
+Similarly	O
+,	O
+the	O
+total	O
+protein	O
+abundance	O
+of	O
+the	O
+Na	O
+-	O
+K	O
+-	O
+2Cl	O
+cotransporter	O
+(	O
+NKCC2	O
+)	O
+in	O
+the	O
+medulla	O
+but	O
+not	O
+in	O
+the	O
+cortex	O
+of	O
+the	O
++	O
+/	O
++	O
+mice	O
+was	O
+significantly	O
+reduced	O
+by	O
+lithium	O
+treatment	O
+.	O
+
+In	O
+contrast	O
+,	O
+the	O
+dowregulation	O
+of	O
+renal	O
+medullary	O
+NKCC2	O
+expression	O
+was	O
+significantly	O
+attenuated	O
+in	O
+the	O
+-	O
+/	O
+-	O
+mice	O
+.	O
+
+We	O
+conclude	O
+that	O
+mPGES	O
+-	O
+1	O
+-	O
+derived	O
+PGE	O
+(	O
+2	O
+)	O
+mediates	O
+lithium	O
+-	O
+induced	O
+polyuria	B
+likely	O
+via	O
+inhibition	O
+of	O
+AQP2	O
+and	O
+NKCC2	O
+expression	O
+.	O
+
+Preservation	O
+of	O
+renal	O
+blood	O
+flow	O
+during	O
+hypotension	B
+induced	O
+with	O
+fenoldopam	O
+in	O
+dogs	O
+.	O
+
+The	O
+introduction	O
+of	O
+drugs	O
+that	O
+could	O
+induce	O
+hypotension	B
+with	O
+different	O
+pharmacological	O
+actions	O
+would	O
+be	O
+advantageous	O
+because	O
+side	O
+effects	O
+unique	O
+to	O
+a	O
+specific	O
+drug	O
+could	O
+be	O
+minimized	O
+by	O
+selecting	O
+appropriate	O
+therapy	O
+.	O
+
+Specific	O
+dopamine	O
+-	O
+1	O
+,	O
+(	O
+DA1	O
+)	O
+and	O
+dopamine	O
+-	O
+2	O
+(	O
+DA2	O
+)	O
+receptor	O
+agonists	O
+are	O
+now	O
+under	O
+clinical	O
+investigation	O
+.	O
+
+Fenoldopam	O
+mesylate	O
+is	O
+a	O
+specific	O
+DA1	O
+receptor	O
+agonist	O
+that	O
+lowers	O
+blood	O
+pressure	O
+by	O
+vasodilatation	O
+.	O
+
+The	O
+hypothesis	O
+that	O
+fenoldopam	O
+could	O
+be	O
+used	O
+to	O
+induce	O
+hypotension	B
+and	O
+preserve	O
+blood	O
+flow	O
+to	O
+the	O
+kidney	O
+was	O
+tested	O
+.	O
+
+Systemic	O
+aortic	O
+blood	O
+pressure	O
+and	O
+renal	O
+blood	O
+flow	O
+were	O
+measured	O
+continuously	O
+with	O
+a	O
+carotid	O
+arterial	O
+catheter	O
+and	O
+an	O
+electromagnetic	O
+flow	O
+probe	O
+respectively	O
+,	O
+in	O
+order	O
+to	O
+compare	O
+the	O
+cardiovascular	O
+and	O
+renal	O
+vascular	O
+effects	O
+of	O
+fenoldopam	O
+and	O
+sodium	O
+nitroprusside	O
+in	O
+ten	O
+dogs	O
+under	O
+halothane	O
+general	O
+anaesthesia	O
+.	O
+
+Mean	O
+arterial	O
+pressure	O
+was	O
+decreased	O
+30	O
++	O
+/	O
+-	O
+8	O
+per	O
+cent	O
+from	O
+control	O
+with	O
+infusion	O
+of	O
+fenoldopam	O
+(	O
+3	O
+.	O
+4	O
++	O
+/	O
+-	O
+2	O
+.	O
+0	O
+micrograms	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+)	O
+and	O
+34	O
++	O
+/	O
+-	O
+4	O
+per	O
+cent	O
+with	O
+infusion	O
+of	O
+sodium	O
+nitroprusside	O
+(	O
+5	O
+.	O
+9	O
+micrograms	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+)	O
+(	O
+NS	O
+)	O
+.	O
+
+Renal	O
+blood	O
+flow	O
+(	O
+RBF	O
+)	O
+increased	O
+during	O
+fenoldopam	O
+-	O
+induced	O
+hypotension	B
+11	O
++	O
+/	O
+-	O
+7	O
+per	O
+cent	O
+and	O
+decreased	O
+21	O
++	O
+/	O
+-	O
+8	O
+per	O
+cent	O
+during	O
+sodium	O
+nitroprusside	O
+-	O
+induced	O
+hypotension	B
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+Sodium	O
+nitroprusside	O
+is	O
+a	O
+non	O
+-	O
+selective	O
+arteriolar	O
+and	O
+venous	O
+vasodilator	O
+that	O
+can	O
+produce	O
+redistribution	O
+of	O
+blood	O
+flow	O
+away	O
+from	O
+the	O
+kidney	O
+during	O
+induced	O
+hypotension	B
+.	O
+
+Fenoldopam	O
+is	O
+a	O
+selective	O
+dopamine	O
+-	O
+1	O
+(	O
+DA1	O
+)	O
+receptor	O
+agonist	O
+that	O
+causes	O
+vasodilatation	O
+to	O
+the	O
+kidney	O
+and	O
+other	O
+organs	O
+with	O
+DA1	O
+receptors	O
+and	O
+preserves	O
+blood	O
+flow	O
+to	O
+the	O
+kidney	O
+during	O
+induced	O
+hypotension	B
+.	O
+
+Seizures	B
+associated	O
+with	O
+levofloxacin	O
+:	O
+case	O
+presentation	O
+and	O
+literature	O
+review	O
+.	O
+
+PURPOSE	O
+:	O
+We	O
+present	O
+a	O
+case	O
+of	O
+a	O
+patient	O
+who	O
+developed	O
+seizures	B
+shortly	O
+after	O
+initiating	O
+treatment	O
+with	O
+levofloxacin	O
+and	O
+to	O
+discuss	O
+the	O
+potential	O
+drug	O
+-	O
+drug	O
+interactions	O
+related	O
+to	O
+the	O
+inhibition	O
+of	O
+cytochrome	O
+P450	O
+(	O
+CYP	O
+)	O
+1A2	O
+in	O
+this	O
+case	O
+,	O
+as	O
+well	O
+as	O
+in	O
+other	O
+cases	O
+,	O
+of	O
+levofloxacin	O
+-	O
+induced	O
+seizures	B
+.	O
+
+METHODS	O
+:	O
+Several	O
+biomedical	O
+databases	O
+were	O
+searched	O
+including	O
+MEDLINE	O
+,	O
+Cochrane	O
+and	O
+Ovid	O
+.	O
+
+The	O
+main	O
+search	O
+terms	O
+utilized	O
+were	O
+case	O
+report	O
+and	O
+levofloxacin	O
+.	O
+
+The	O
+search	O
+was	O
+limited	O
+to	O
+studies	O
+published	O
+in	O
+English	O
+.	O
+
+RESULTS	O
+:	O
+Six	O
+cases	O
+of	O
+levofloxacin	O
+-	O
+induced	O
+seizures	B
+have	O
+been	O
+reported	O
+in	O
+the	O
+literature	O
+.	O
+
+Drug	O
+-	O
+drug	O
+interactions	O
+related	O
+to	O
+the	O
+inhibition	O
+of	O
+CYP1A2	O
+by	O
+levofloxacin	O
+are	O
+likely	O
+involved	O
+in	O
+the	O
+clinical	O
+outcome	O
+of	O
+these	O
+cases	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Clinicians	O
+are	O
+exhorted	O
+to	O
+pay	O
+close	O
+attention	O
+when	O
+initiating	O
+levofloxacin	O
+therapy	O
+in	O
+patients	O
+taking	O
+medications	O
+with	O
+epileptogenic	O
+properties	O
+that	O
+are	O
+CYP1A2	O
+substrates	O
+.	O
+
+Dextran	O
+-	O
+etodolac	O
+conjugates	O
+:	O
+synthesis	O
+,	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+evaluation	O
+.	O
+
+Etodolac	O
+(	O
+E	O
+)	O
+,	O
+is	O
+a	O
+non	O
+-	O
+narcotic	O
+analgesic	O
+and	O
+antiinflammatory	O
+drug	O
+.	O
+
+A	O
+biodegradable	O
+polymer	O
+dextran	O
+has	O
+been	O
+utilized	O
+as	O
+a	O
+carrier	O
+for	O
+synthesis	O
+of	O
+etodolac	O
+-	O
+dextran	O
+conjugates	O
+(	O
+ED	O
+)	O
+to	O
+improve	O
+its	O
+aqueous	O
+solubility	O
+and	O
+reduce	O
+gastrointestinal	O
+side	O
+effects	O
+.	O
+
+An	O
+activated	O
+moiety	O
+,	O
+i	O
+.	O
+e	O
+.	O
+N	O
+-	O
+acylimidazole	O
+derivative	O
+of	O
+etodolac	O
+(	O
+EAI	O
+)	O
+,	O
+was	O
+condensed	O
+with	O
+the	O
+polysaccharide	O
+polymer	O
+dextran	O
+of	O
+different	O
+molecular	O
+weights	O
+(	O
+40000	O
+,	O
+60000	O
+,	O
+110000	O
+and	O
+200000	O
+)	O
+.	O
+
+IR	O
+spectral	O
+data	O
+confirmed	O
+formation	O
+of	O
+ester	O
+bonding	O
+in	O
+the	O
+conjugates	O
+.	O
+
+Etodolac	O
+contents	O
+were	O
+evaluated	O
+by	O
+UV	O
+-	O
+spectrophotometric	O
+analysis	O
+.	O
+
+The	O
+molecular	O
+weights	O
+were	O
+determined	O
+by	O
+measuring	O
+viscosity	O
+using	O
+the	O
+Mark	O
+-	O
+Howink	O
+-	O
+Sakurada	O
+equation	O
+.	O
+
+In	O
+vitro	O
+hydrolysis	O
+of	O
+ED	O
+was	O
+done	O
+in	O
+aqueous	O
+buffers	O
+(	O
+pH	O
+1	O
+.	O
+2	O
+,	O
+7	O
+.	O
+4	O
+,	O
+9	O
+)	O
+and	O
+in	O
+80	O
+%	O
+(	O
+v	O
+/	O
+v	O
+)	O
+human	O
+plasma	O
+(	O
+pH	O
+7	O
+.	O
+4	O
+)	O
+.	O
+
+At	O
+pH	O
+9	O
+,	O
+a	O
+higher	O
+rate	O
+of	O
+etodolac	O
+release	O
+from	O
+ED	O
+was	O
+observed	O
+as	O
+compared	O
+to	O
+aqueous	O
+buffer	O
+of	O
+pH	O
+7	O
+.	O
+4	O
+and	O
+80	O
+%	O
+human	O
+plasma	O
+(	O
+pH	O
+7	O
+.	O
+4	O
+)	O
+,	O
+following	O
+first	O
+-	O
+order	O
+kinetics	O
+.	O
+
+In	O
+vivo	O
+investigations	O
+were	O
+performed	O
+in	O
+animals	O
+.	O
+
+Acute	O
+analgesic	O
+and	O
+antiinflammatory	O
+activities	O
+were	O
+ascertained	O
+using	O
+acetic	O
+acid	O
+induced	O
+writhing	B
+model	O
+(	O
+mice	O
+)	O
+and	O
+carrageenan	O
+-	O
+induced	O
+rat	O
+paw	O
+edema	B
+model	O
+,	O
+respectively	O
+.	O
+
+In	O
+comparison	O
+to	O
+control	O
+,	O
+E	O
+and	O
+ED1	O
+-	O
+ED4	O
+showed	O
+highly	O
+significant	O
+analgesic	O
+and	O
+antiinflammatory	O
+activities	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Biological	O
+evaluation	O
+suggested	O
+that	O
+conjugates	O
+(	O
+ED1	O
+-	O
+ED4	O
+)	O
+retained	O
+comparable	O
+analgesic	O
+and	O
+antiinflammatory	O
+activities	O
+with	O
+remarkably	O
+reduced	O
+ulcerogenicity	O
+as	O
+compared	O
+to	O
+their	O
+parent	O
+drug	O
+-	O
+-	O
+etodolac	O
+.	O
+
+The	O
+antiarrhythmic	O
+effect	O
+and	O
+possible	O
+ionic	O
+mechanisms	O
+of	O
+pilocarpine	O
+on	O
+animal	O
+models	O
+.	O
+
+This	O
+study	O
+was	O
+designed	O
+to	O
+evaluate	O
+the	O
+effects	O
+of	O
+pilocarpine	O
+and	O
+explore	O
+the	O
+underlying	O
+ionic	O
+mechanism	O
+,	O
+using	O
+both	O
+aconitine	O
+-	O
+induced	O
+rat	O
+and	O
+ouabain	O
+-	O
+induced	O
+guinea	O
+pig	O
+arrhythmia	B
+models	O
+.	O
+
+Confocal	O
+microscopy	O
+was	O
+used	O
+to	O
+measure	O
+intracellular	O
+free	O
+-	O
+calcium	O
+concentrations	O
+(	O
+[	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+]	O
+(	O
+i	O
+)	O
+)	O
+in	O
+isolated	O
+myocytes	O
+.	O
+
+The	O
+current	O
+data	O
+showed	O
+that	O
+pilocarpine	O
+significantly	O
+delayed	O
+onset	O
+of	O
+arrhythmias	B
+,	O
+decreased	O
+the	O
+time	O
+course	O
+of	O
+ventricular	B
+tachycardia	I
+and	I
+fibrillation	I
+,	O
+reduced	O
+arrhythmia	B
+score	O
+,	O
+and	O
+increased	O
+the	O
+survival	O
+time	O
+of	O
+arrhythmic	B
+rats	O
+and	O
+guinea	O
+pigs	O
+.	O
+
+[	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+]	O
+(	O
+i	O
+)	O
+overload	O
+induced	O
+by	O
+aconitine	O
+or	O
+ouabain	O
+was	O
+reduced	O
+in	O
+isolated	O
+myocytes	O
+pretreated	O
+with	O
+pilocarpine	O
+.	O
+
+Moreover	O
+,	O
+M	O
+(	O
+3	O
+)	O
+-	O
+muscarinic	O
+acetylcholine	O
+receptor	O
+(	O
+mAChR	O
+)	O
+antagonist	O
+4	O
+-	O
+DAMP	O
+(	O
+4	O
+-	O
+diphenylacetoxy	O
+-	O
+N	O
+-	O
+methylpiperidine	O
+-	O
+methiodide	O
+)	O
+partially	O
+abolished	O
+the	O
+beneficial	O
+effects	O
+of	O
+pilocarpine	O
+.	O
+
+These	O
+data	O
+suggest	O
+that	O
+pilocarpine	O
+produced	O
+antiarrhythmic	O
+actions	O
+on	O
+arrhythmic	B
+rat	O
+and	O
+guinea	O
+pig	O
+models	O
+induced	O
+by	O
+aconitine	O
+or	O
+ouabain	O
+via	O
+stimulating	O
+the	O
+cardiac	O
+M	O
+(	O
+3	O
+)	O
+-	O
+mAChR	O
+.	O
+
+The	O
+mechanism	O
+may	O
+be	O
+related	O
+to	O
+the	O
+improvement	O
+of	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+handling	O
+.	O
+
+Effect	O
+of	O
+Hibiscus	O
+rosa	O
+sinensis	O
+on	O
+reserpine	O
+-	O
+induced	O
+neurobehavioral	O
+and	O
+biochemical	O
+alterations	O
+in	O
+rats	O
+.	O
+
+Effect	O
+of	O
+methanolic	O
+extract	O
+of	O
+Hibiscus	O
+rosa	O
+sinensis	O
+(	O
+100	O
+-	O
+300	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+studied	O
+on	O
+reserpine	O
+-	O
+induced	O
+orofacial	O
+dyskinesia	B
+and	O
+neurochemical	O
+alterations	O
+.	O
+
+The	O
+rats	O
+were	O
+treated	O
+with	O
+intraperitoneal	O
+reserpine	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+,	O
+ip	O
+)	O
+for	O
+3	O
+days	O
+every	O
+other	O
+day	O
+.	O
+
+On	O
+day	O
+5	O
+,	O
+vacuous	O
+chewing	O
+movements	O
+and	O
+tongue	O
+protrusions	O
+were	O
+counted	O
+for	O
+5	O
+min	O
+.	O
+
+Reserpine	O
+treated	O
+rats	O
+significantly	O
+developed	O
+vacuous	O
+chewing	O
+movements	O
+and	O
+tongue	O
+protrusions	O
+however	O
+,	O
+coadministration	O
+of	O
+Hibiscus	O
+rosa	O
+sinensis	O
+roots	O
+extract	O
+(	O
+100	O
+,	O
+200	O
+and	O
+300	O
+mg	O
+/	O
+kg	O
+,	O
+per	O
+orally	O
+)	O
+attenuated	O
+the	O
+effects	O
+.	O
+
+Biochemical	O
+analysis	O
+of	O
+brain	O
+revealed	O
+that	O
+the	O
+reserpine	O
+treatment	O
+significantly	O
+increased	O
+lipid	O
+peroxidation	O
+and	O
+decreased	O
+levels	O
+of	O
+superoxide	O
+dismutase	O
+(	O
+SOD	O
+)	O
+,	O
+catalase	O
+(	O
+CAT	O
+)	O
+and	O
+glutathione	O
+reductase	O
+(	O
+GSH	O
+)	O
+,	O
+an	O
+index	O
+of	O
+oxidative	O
+stress	O
+process	O
+.	O
+
+Coadministration	O
+of	O
+extract	O
+significantly	O
+reduced	O
+the	O
+lipid	O
+peroxidation	O
+and	O
+reversed	O
+the	O
+decrease	O
+in	O
+brain	O
+SOD	O
+,	O
+CAT	O
+and	O
+GSH	O
+levels	O
+.	O
+
+The	O
+results	O
+of	O
+the	O
+present	O
+study	O
+suggested	O
+that	O
+Hibiscus	O
+rosa	O
+sinensis	O
+had	O
+a	O
+protective	O
+role	O
+against	O
+reserpine	O
+-	O
+induced	O
+orofacial	O
+dyskinesia	B
+and	O
+oxidative	O
+stress	O
+.	O
+
+Dynamic	O
+response	O
+of	O
+blood	O
+vessel	O
+in	O
+acute	B
+renal	I
+failure	I
+.	O
+
+In	O
+this	O
+study	O
+we	O
+postulated	O
+that	O
+during	O
+acute	B
+renal	I
+failure	I
+induced	O
+by	O
+gentamicin	O
+the	O
+transient	O
+or	O
+dynamic	O
+response	O
+of	O
+blood	O
+vessels	O
+could	O
+be	O
+affected	O
+,	O
+and	O
+that	O
+antioxidants	O
+can	O
+prevent	O
+the	O
+changes	O
+in	O
+dynamic	O
+responses	O
+of	O
+blood	O
+vessels	O
+.	O
+
+The	O
+new	O
+approach	O
+to	O
+ex	O
+vivo	O
+blood	O
+vessel	O
+experiments	O
+in	O
+which	O
+not	O
+only	O
+the	O
+end	O
+points	O
+of	O
+vessels	O
+response	O
+within	O
+the	O
+time	O
+interval	O
+is	O
+considered	O
+,	O
+but	O
+also	O
+dynamics	O
+of	O
+this	O
+response	O
+,	O
+was	O
+used	O
+in	O
+this	O
+paper	O
+.	O
+
+Our	O
+results	O
+confirm	O
+the	O
+alteration	O
+in	O
+dynamic	O
+response	O
+of	O
+blood	O
+vessels	O
+during	O
+the	O
+change	O
+of	O
+pressure	O
+in	O
+gentamicin	O
+-	O
+treated	O
+animals	O
+.	O
+
+The	O
+beneficial	O
+effects	O
+of	O
+vitamin	O
+C	O
+administration	O
+to	O
+gentamicin	O
+-	O
+treated	O
+animals	O
+are	O
+also	O
+confirmed	O
+through	O
+:	O
+lower	O
+level	O
+of	O
+blood	O
+urea	O
+and	O
+creatinine	O
+and	O
+higher	O
+level	O
+of	O
+potassium	O
+.	O
+
+The	O
+pressure	O
+dynamic	O
+responses	O
+of	O
+isolated	O
+blood	O
+vessels	O
+show	O
+a	O
+faster	O
+pressure	O
+change	O
+in	O
+gentamicin	O
+-	O
+treated	O
+animals	O
+(	O
+8	O
+.	O
+07	O
++	O
+/	O
+-	O
+1	O
+.	O
+7	O
+s	O
+vs	O
+.	O
+5	O
+.	O
+64	O
++	O
+/	O
+-	O
+0	O
+.	O
+18	O
+s	O
+)	O
+.	O
+
+Vitamin	O
+C	O
+administration	O
+induced	O
+slowdown	O
+of	O
+pressure	O
+change	O
+back	O
+to	O
+the	O
+control	O
+values	O
+.	O
+
+The	O
+pressure	O
+dynamic	O
+properties	O
+,	O
+quantitatively	O
+defined	O
+by	O
+comparative	O
+pressure	O
+dynamic	O
+and	O
+total	O
+pressure	O
+dynamic	O
+,	O
+confirm	O
+the	O
+alteration	O
+in	O
+dynamic	O
+response	O
+of	O
+blood	O
+vessels	O
+during	O
+the	O
+change	O
+of	O
+pressure	O
+in	O
+gentamicin	O
+-	O
+treated	O
+animals	O
+and	O
+beneficial	O
+effects	O
+of	O
+vitamin	O
+C	O
+administration	O
+.	O
+
+Reversible	O
+myocardial	B
+hypertrophy	I
+induced	O
+by	O
+tacrolimus	O
+in	O
+a	O
+pediatric	O
+heart	O
+transplant	O
+recipient	O
+:	O
+case	O
+report	O
+.	O
+
+Tacrolimus	O
+is	O
+a	O
+potent	O
+immunosuppressant	O
+that	O
+is	O
+frequently	O
+used	O
+in	O
+organ	O
+transplantation	O
+.	O
+
+However	O
+,	O
+adverse	O
+effects	O
+include	O
+cardiac	B
+toxicity	I
+.	O
+
+Herein	O
+we	O
+describe	O
+transient	O
+myocardial	B
+hypertrophy	I
+induced	O
+by	O
+tacrolimus	O
+after	O
+heart	O
+transplantation	O
+.	O
+
+The	O
+hypertrophy	B
+caused	O
+no	O
+clinical	O
+symptoms	O
+but	O
+was	O
+noted	O
+because	O
+of	O
+elevation	O
+of	O
+plasma	O
+brain	O
+natriuretic	O
+peptide	O
+concentration	O
+and	O
+confirmed	O
+at	O
+echocardiography	O
+.	O
+
+Initially	O
+,	O
+allograft	O
+rejection	O
+was	O
+feared	O
+;	O
+however	O
+,	O
+myocardial	O
+biopsy	O
+samples	O
+revealed	O
+only	O
+interstitial	O
+edema	B
+and	O
+mild	O
+myocardial	B
+hypertrophy	I
+;	O
+neither	O
+cellular	O
+nor	O
+humoral	O
+rejection	O
+was	O
+detected	O
+.	O
+
+The	O
+blood	O
+tacrolimus	O
+concentration	O
+was	O
+higher	O
+than	O
+usual	O
+at	O
+that	O
+time	O
+;	O
+thus	O
+,	O
+tacrolimus	O
+dosage	O
+was	O
+reduced	O
+.	O
+
+Myocardial	B
+hypertrophy	I
+completely	O
+resolved	O
+upon	O
+reducing	O
+the	O
+target	O
+concentration	O
+of	O
+tacrolimus	O
+and	O
+did	O
+not	O
+recur	O
+,	O
+as	O
+confirmed	O
+at	O
+echocardiography	O
+and	O
+myocardial	O
+biopsy	O
+.	O
+
+Thus	O
+,	O
+we	O
+conclude	O
+that	O
+tacrolimus	O
+induces	O
+reversible	O
+myocardial	B
+hypertrophy	I
+.	O
+
+In	O
+patients	O
+receiving	O
+tacrolimus	O
+therapy	O
+,	O
+blood	O
+concentration	O
+should	O
+be	O
+carefully	O
+controlled	O
+and	O
+extreme	O
+attention	O
+paid	O
+to	O
+cardiac	O
+involvement	O
+.	O
+
+Nimodipine	O
+prevents	O
+memory	B
+impairment	I
+caused	O
+by	O
+nitroglycerin	O
+-	O
+induced	O
+hypotension	B
+in	O
+adult	O
+mice	O
+.	O
+
+BACKGROUND	O
+:	O
+Hypotension	B
+and	O
+a	O
+resultant	O
+decrease	O
+in	O
+cerebral	O
+blood	O
+flow	O
+have	O
+been	O
+implicated	O
+in	O
+the	O
+development	O
+of	O
+cognitive	B
+dysfunction	I
+.	O
+
+We	O
+tested	O
+the	O
+hypothesis	O
+that	O
+nimodipine	O
+(	O
+NIMO	O
+)	O
+administered	O
+at	O
+the	O
+onset	O
+of	O
+nitroglycerin	O
+(	O
+NTG	O
+)	O
+-	O
+induced	O
+hypotension	B
+would	O
+preserve	O
+long	O
+-	O
+term	O
+associative	O
+memory	O
+.	O
+
+METHODS	O
+:	O
+The	O
+passive	O
+avoidance	O
+(	O
+PA	O
+)	O
+paradigm	O
+was	O
+used	O
+to	O
+assess	O
+memory	O
+retention	O
+.	O
+
+For	O
+PA	O
+training	O
+,	O
+latencies	O
+(	O
+seconds	O
+)	O
+were	O
+recorded	O
+for	O
+entry	O
+from	O
+a	O
+suspended	O
+platform	O
+into	O
+a	O
+Plexiglas	O
+tube	O
+where	O
+a	O
+shock	O
+was	O
+automatically	O
+delivered	O
+.	O
+
+Latencies	O
+were	O
+recorded	O
+48	O
+h	O
+later	O
+for	O
+a	O
+testing	O
+trial	O
+.	O
+
+Ninety	O
+-	O
+six	O
+Swiss	O
+-	O
+Webster	O
+mice	O
+(	O
+30	O
+-	O
+35	O
+g	O
+,	O
+6	O
+-	O
+8	O
+wk	O
+)	O
+,	O
+were	O
+randomized	O
+into	O
+6	O
+groups	O
+1	O
+)	O
+saline	O
+(	O
+control	O
+)	O
+,	O
+2	O
+)	O
+NTG	O
+immediately	O
+after	O
+learning	O
+,	O
+3	O
+)	O
+NTG	O
+3	O
+h	O
+after	O
+learning	O
+,	O
+4	O
+)	O
+NTG	O
+and	O
+NIMO	O
+,	O
+5	O
+)	O
+vehicle	O
+,	O
+and	O
+6	O
+)	O
+NIMO	O
+alone	O
+.	O
+
+The	O
+extent	O
+of	O
+hypotension	B
+and	O
+changes	O
+in	O
+brain	O
+tissue	O
+oxygenation	O
+(	O
+PbtO	O
+(	O
+2	O
+)	O
+)	O
+and	O
+in	O
+cerebral	O
+blood	O
+flow	O
+were	O
+studied	O
+in	O
+a	O
+separate	O
+group	O
+of	O
+animals	O
+.	O
+
+RESULTS	O
+:	O
+All	O
+groups	O
+exhibited	O
+similar	O
+training	O
+latencies	O
+(	O
+17	O
+.	O
+0	O
++	O
+/	O
+-	O
+4	O
+.	O
+6	O
+s	O
+)	O
+.	O
+
+Mice	O
+subjected	O
+to	O
+hypotensive	B
+episodes	O
+showed	O
+a	O
+significant	O
+decrease	O
+in	O
+latency	O
+time	O
+(	O
+178	O
++	O
+/	O
+-	O
+156	O
+s	O
+)	O
+compared	O
+with	O
+those	O
+injected	O
+with	O
+saline	O
+,	O
+NTG	O
++	O
+NIMO	O
+,	O
+or	O
+delayed	O
+NTG	O
+(	O
+580	O
++	O
+/	O
+-	O
+81	O
+s	O
+,	O
+557	O
++	O
+/	O
+-	O
+67	O
+s	O
+,	O
+and	O
+493	O
++	O
+/	O
+-	O
+146	O
+s	O
+,	O
+respectively	O
+)	O
+.	O
+
+A	O
+Kruskal	O
+-	O
+Wallis	O
+1	O
+-	O
+way	O
+analysis	O
+of	O
+variance	O
+indicated	O
+a	O
+significant	O
+difference	O
+among	O
+the	O
+4	O
+treatment	O
+groups	O
+(	O
+H	O
+=	O
+15	O
+.	O
+34	O
+;	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+In	O
+a	O
+separate	O
+group	O
+of	O
+mice	O
+not	O
+subjected	O
+to	O
+behavioral	O
+studies	O
+,	O
+the	O
+same	O
+dose	O
+of	O
+NTG	O
+(	O
+n	O
+=	O
+3	O
+)	O
+and	O
+NTG	O
++	O
+NIMO	O
+(	O
+n	O
+=	O
+3	O
+)	O
+caused	O
+mean	O
+arterial	O
+blood	O
+pressure	O
+to	O
+decrease	O
+from	O
+85	O
+.	O
+9	O
++	O
+/	O
+-	O
+3	O
+.	O
+8	O
+mm	O
+Hg	O
+sem	O
+to	O
+31	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+8	O
+mm	O
+Hg	O
+sem	O
+and	O
+from	O
+86	O
+.	O
+2	O
++	O
+/	O
+-	O
+3	O
+.	O
+7	O
+mm	O
+Hg	O
+sem	O
+to	O
+32	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+mm	O
+Hg	O
+sem	O
+,	O
+respectively	O
+.	O
+
+Mean	O
+arterial	O
+blood	O
+pressure	O
+in	O
+mice	O
+treated	O
+with	O
+NIMO	O
+alone	O
+decreased	O
+from	O
+88	O
+.	O
+1	O
++	O
+/	O
+-	O
+3	O
+.	O
+8	O
+mm	O
+Hg	O
+to	O
+80	O
+.	O
+0	O
++	O
+/	O
+-	O
+2	O
+.	O
+9	O
+mm	O
+Hg	O
+.	O
+
+The	O
+intergroup	O
+difference	O
+was	O
+statistically	O
+significant	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+PbtO	O
+(	O
+2	O
+)	O
+decreased	O
+from	O
+51	O
+.	O
+7	O
++	O
+/	O
+-	O
+4	O
+.	O
+5	O
+mm	O
+Hg	O
+sem	O
+to	O
+33	O
+.	O
+8	O
++	O
+/	O
+-	O
+5	O
+.	O
+2	O
+mm	O
+Hg	O
+sem	O
+in	O
+the	O
+NTG	O
+group	O
+and	O
+from	O
+38	O
+.	O
+6	O
++	O
+/	O
+-	O
+6	O
+.	O
+1	O
+mm	O
+Hg	O
+sem	O
+to	O
+25	O
+.	O
+4	O
++	O
+/	O
+-	O
+2	O
+.	O
+0	O
+mm	O
+Hg	O
+sem	O
+in	O
+the	O
+NTG	O
++	O
+NIMO	O
+groups	O
+,	O
+respectively	O
+.	O
+
+There	O
+were	O
+no	O
+significant	O
+differences	O
+among	O
+groups	O
+.	O
+
+CONCLUSION	O
+:	O
+In	O
+a	O
+PA	O
+retention	O
+paradigm	O
+,	O
+the	O
+injection	O
+of	O
+NTG	O
+immediately	O
+after	O
+learning	O
+produced	O
+a	O
+significant	O
+impairment	O
+of	O
+long	O
+-	O
+term	O
+associative	O
+memory	O
+in	O
+mice	O
+,	O
+whereas	O
+delayed	O
+induced	O
+hypotension	B
+had	O
+no	O
+effect	O
+.	O
+
+NIMO	O
+attenuated	O
+the	O
+disruption	O
+in	O
+consolidation	O
+of	O
+long	O
+-	O
+term	O
+memory	O
+caused	O
+by	O
+NTG	O
+but	O
+did	O
+not	O
+improve	O
+latency	O
+in	O
+the	O
+absence	O
+of	O
+hypotension	B
+.	O
+
+The	O
+observed	O
+effect	O
+of	O
+NIMO	O
+may	O
+have	O
+been	O
+attributable	O
+to	O
+the	O
+preservation	O
+of	O
+calcium	O
+homeostasis	O
+during	O
+hypotension	B
+,	O
+because	O
+there	O
+were	O
+no	O
+differences	O
+in	O
+the	O
+PbtO	O
+(	O
+2	O
+)	O
+indices	O
+among	O
+groups	O
+.	O
+
+Metabotropic	O
+glutamate	O
+7	O
+receptor	O
+subtype	O
+modulates	O
+motor	O
+symptoms	O
+in	O
+rodent	O
+models	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+Metabotropic	O
+glutamate	O
+(	O
+mGlu	O
+)	O
+receptors	O
+modulate	O
+synaptic	O
+transmission	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+and	O
+represent	O
+promising	O
+therapeutic	O
+targets	O
+for	O
+symptomatic	O
+treatment	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+.	O
+
+Among	O
+the	O
+eight	O
+mGlu	O
+receptor	O
+subtypes	O
+,	O
+mGlu7	O
+receptor	O
+is	O
+prominently	O
+expressed	O
+in	O
+the	O
+basal	O
+ganglia	O
+,	O
+but	O
+its	O
+role	O
+in	O
+restoring	O
+motor	O
+function	O
+in	O
+animal	O
+models	O
+of	O
+PD	B
+is	O
+not	O
+known	O
+.	O
+
+The	O
+effects	O
+of	O
+N	O
+,	O
+N	O
+'	O
+-	O
+dibenzhydrylethane	O
+-	O
+1	O
+,	O
+2	O
+-	O
+diamine	O
+dihydrochloride	O
+(	O
+AMN082	O
+)	O
+,	O
+the	O
+first	O
+selective	O
+allosteric	O
+activator	O
+of	O
+mGlu7	O
+receptors	O
+,	O
+were	O
+thus	O
+tested	O
+in	O
+different	O
+rodent	O
+models	O
+of	O
+PD	B
+.	O
+
+Here	O
+,	O
+we	O
+show	O
+that	O
+oral	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+or	O
+intrastriatal	O
+administration	O
+(	O
+0	O
+.	O
+1	O
+and	O
+0	O
+.	O
+5	O
+nmol	O
+)	O
+of	O
+AMN082	O
+reverses	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+in	O
+rats	O
+.	O
+
+AMN082	O
+(	O
+2	O
+.	O
+5	O
+and	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+reduces	O
+apomorphine	O
+-	O
+induced	O
+rotations	O
+in	O
+unilateral	O
+6	O
+-	O
+hydroxydopamine	O
+(	O
+6	O
+-	O
+OHDA	O
+)	O
+-	O
+lesioned	O
+rats	O
+.	O
+
+In	O
+a	O
+more	O
+complex	O
+task	O
+commonly	O
+used	O
+to	O
+evaluate	O
+major	O
+akinetic	B
+symptoms	O
+of	O
+PD	B
+patients	O
+,	O
+5	O
+mg	O
+/	O
+kg	O
+AMN082	O
+reverses	O
+the	O
+increased	O
+reaction	O
+time	O
+to	O
+respond	O
+to	O
+a	O
+cue	O
+of	O
+bilateral	O
+6	O
+-	O
+OHDA	O
+-	O
+lesioned	O
+rats	O
+.	O
+
+In	O
+addition	O
+,	O
+AMN082	O
+reduces	O
+the	O
+duration	O
+of	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+in	O
+a	O
+mGlu7	O
+receptor	O
+-	O
+dependent	O
+manner	O
+in	O
+wild	O
+-	O
+type	O
+but	O
+not	O
+mGlu7	O
+receptor	O
+knockout	O
+mice	O
+.	O
+
+Higher	O
+doses	O
+of	O
+AMN082	O
+(	O
+10	O
+and	O
+20	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+)	O
+have	O
+no	O
+effect	O
+on	O
+the	O
+same	O
+models	O
+of	O
+PD	B
+.	O
+
+Overall	O
+these	O
+findings	O
+suggest	O
+that	O
+mGlu7	O
+receptor	O
+activation	O
+can	O
+reverse	O
+motor	O
+dysfunction	O
+associated	O
+with	O
+reduced	O
+dopamine	O
+activity	O
+.	O
+
+Selective	O
+ligands	O
+of	O
+mGlu7	O
+receptor	O
+subtypes	O
+may	O
+thus	O
+be	O
+considered	O
+as	O
+promising	O
+compounds	O
+for	O
+the	O
+development	O
+of	O
+antiparkinsonian	O
+therapeutic	O
+strategies	O
+.	O
+
+Sorafenib	O
+-	O
+induced	O
+acute	O
+myocardial	B
+infarction	I
+due	O
+to	O
+coronary	B
+artery	I
+spasm	I
+.	O
+
+A	O
+65	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+advanced	O
+renal	B
+cell	I
+carcinoma	I
+was	O
+admitted	O
+due	O
+to	O
+continuing	O
+chest	B
+pain	I
+at	O
+rest	O
+.	O
+
+Two	O
+weeks	O
+before	O
+his	O
+admission	O
+,	O
+sorafenib	O
+had	O
+been	O
+started	O
+.	O
+
+He	O
+was	O
+diagnosed	O
+with	O
+non	O
+-	O
+ST	O
+-	O
+elevation	O
+myocardial	B
+infarction	I
+by	O
+laboratory	O
+data	O
+and	O
+electrocardiogram	O
+.	O
+
+Enhanced	O
+heart	O
+magnetic	O
+resonance	O
+imaging	O
+also	O
+showed	O
+subendocardial	B
+infarction	I
+.	O
+
+However	O
+,	O
+there	O
+was	O
+no	O
+stenosis	O
+in	O
+coronary	O
+arteries	O
+on	O
+angiography	O
+.	O
+
+Coronary	B
+artery	I
+spasm	I
+was	O
+induced	O
+by	O
+a	O
+provocative	O
+test	O
+.	O
+
+Cessation	O
+of	O
+sorafenib	O
+and	O
+administration	O
+of	O
+Ca	O
+-	O
+channel	O
+blocker	O
+and	O
+nitrates	O
+ameliorated	O
+his	O
+symptoms	O
+,	O
+but	O
+relapse	O
+occurred	O
+after	O
+resumption	O
+of	O
+sorafenib	O
+.	O
+
+Addition	O
+of	O
+oral	O
+nicorandil	O
+reduced	O
+his	O
+symptoms	O
+and	O
+maintained	O
+stable	B
+angina	I
+status	O
+.	O
+
+We	O
+report	O
+the	O
+first	O
+case	O
+of	O
+sorafenib	O
+-	O
+induced	O
+coronary	B
+artery	I
+spasm	I
+.	O
+
+Sorafenib	O
+is	O
+a	O
+multikinase	O
+inhibitor	O
+that	O
+targets	O
+signaling	O
+pathways	O
+necessary	O
+for	O
+cellular	O
+proliferation	O
+and	O
+survival	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+the	O
+Rho	O
+/	O
+ROCK	O
+pathway	O
+has	O
+an	O
+important	O
+role	O
+in	O
+the	O
+pathogenesis	O
+of	O
+coronary	B
+artery	I
+spasm	I
+.	O
+
+Our	O
+report	O
+may	O
+show	O
+an	O
+adverse	O
+effect	O
+on	O
+the	O
+Rho	O
+/	O
+ROCK	O
+pathway	O
+by	O
+sorafenib	O
+use	O
+.	O
+
+A	O
+novel	O
+animal	O
+model	O
+to	O
+evaluate	O
+the	O
+ability	O
+of	O
+a	O
+drug	O
+delivery	O
+system	O
+to	O
+promote	O
+the	O
+passage	O
+through	O
+the	O
+BBB	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+investigation	O
+was	O
+to	O
+explore	O
+the	O
+potentiality	O
+of	O
+a	O
+novel	O
+animal	O
+model	O
+to	O
+be	O
+used	O
+for	O
+the	O
+in	O
+vivo	O
+evaluation	O
+of	O
+the	O
+ability	O
+of	O
+a	O
+drug	O
+delivery	O
+system	O
+to	O
+promote	O
+the	O
+passage	O
+through	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+(	O
+BBB	O
+)	O
+and	O
+/	O
+or	O
+to	O
+improve	O
+the	O
+brain	O
+localization	O
+of	O
+a	O
+bioactive	O
+compound	O
+.	O
+
+A	O
+Tween	O
+80	O
+-	O
+coated	O
+poly	O
+-	O
+L	O
+-	O
+lactid	O
+acid	O
+nanoparticles	O
+was	O
+used	O
+as	O
+a	O
+model	O
+of	O
+colloidal	O
+drug	O
+delivery	O
+system	O
+,	O
+able	O
+to	O
+trespass	O
+the	O
+BBB	O
+.	O
+
+Tacrine	O
+,	O
+administered	O
+in	O
+LiCl	O
+pre	O
+-	O
+treated	O
+rats	O
+,	O
+induces	O
+electrocorticographic	O
+seizures	B
+and	O
+delayed	O
+hippocampal	B
+damage	I
+.	O
+
+The	O
+toxic	O
+effects	O
+of	O
+tacrine	O
+-	O
+loaded	O
+poly	O
+-	O
+L	O
+-	O
+lactid	O
+acid	O
+nanoparticles	O
+(	O
+5mg	O
+/	O
+kg	O
+)	O
+,	O
+a	O
+saline	O
+solution	O
+of	O
+tacrine	O
+(	O
+5mg	O
+/	O
+kg	O
+)	O
+and	O
+an	O
+empty	O
+colloidal	O
+nanoparticle	O
+suspension	O
+were	O
+compared	O
+following	O
+i	O
+.	O
+p	O
+.	O
+administration	O
+in	O
+LiCl	O
+-	O
+pre	O
+-	O
+treated	O
+Wistar	O
+rats	O
+.	O
+
+All	O
+the	O
+animals	O
+treated	O
+with	O
+tacrine	O
+-	O
+loaded	O
+nanoparticles	O
+showed	O
+an	O
+earlier	O
+outcome	O
+of	O
+CNS	O
+adverse	O
+symptoms	O
+,	O
+i	O
+.	O
+e	O
+.	O
+epileptic	B
+onset	O
+,	O
+with	O
+respect	O
+to	O
+those	O
+animals	O
+treated	O
+with	O
+the	O
+free	O
+compound	O
+(	O
+10	O
+min	O
+vs	O
+.	O
+22	O
+min	O
+respectively	O
+)	O
+.	O
+
+In	O
+addition	O
+,	O
+tacrine	O
+-	O
+loaded	O
+nanoparticles	O
+administration	O
+induced	O
+damage	B
+of	I
+neuronal	I
+cells	I
+in	O
+CA1	O
+field	O
+of	O
+the	O
+hippocampus	O
+in	O
+all	O
+treated	O
+animals	O
+,	O
+while	O
+the	O
+saline	O
+solution	O
+of	O
+tacrine	O
+only	O
+in	O
+60	O
+%	O
+of	O
+animals	O
+.	O
+
+Empty	O
+nanoparticles	O
+provided	O
+similar	O
+results	O
+to	O
+control	O
+(	O
+saline	O
+-	O
+treated	O
+)	O
+group	O
+of	O
+animals	O
+.	O
+
+In	O
+conclusion	O
+,	O
+the	O
+evaluation	O
+of	O
+time	O
+-	O
+to	O
+-	O
+onset	O
+of	O
+symptoms	O
+and	O
+the	O
+severity	O
+of	O
+neurodegenerative	O
+processes	O
+induced	O
+by	O
+the	O
+tacrine	O
+-	O
+lithium	O
+model	O
+of	O
+epilepsy	B
+in	O
+the	O
+rat	O
+,	O
+could	O
+be	O
+used	O
+to	O
+evaluate	O
+preliminarily	O
+the	O
+capability	O
+of	O
+a	O
+drug	O
+delivery	O
+system	O
+to	O
+trespass	O
+(	O
+or	O
+not	O
+)	O
+the	O
+BBB	O
+in	O
+vivo	O
+.	O
+
+High	O
+-	O
+dose	O
+tranexamic	O
+Acid	O
+is	O
+associated	O
+with	O
+nonischemic	O
+clinical	O
+seizures	B
+in	O
+cardiac	O
+surgical	O
+patients	O
+.	O
+
+BACKGROUND	O
+:	O
+In	O
+2	O
+separate	O
+centers	O
+,	O
+we	O
+observed	O
+a	O
+notable	O
+increase	O
+in	O
+the	O
+incidence	O
+of	O
+postoperative	O
+convulsive	B
+seizures	B
+from	O
+1	O
+.	O
+3	O
+%	O
+to	O
+3	O
+.	O
+8	O
+%	O
+in	O
+patients	O
+having	O
+undergone	O
+major	O
+cardiac	O
+surgical	O
+procedures	O
+.	O
+
+These	O
+events	O
+were	O
+temporally	O
+coincident	O
+with	O
+the	O
+initial	O
+use	O
+of	O
+high	O
+-	O
+dose	O
+tranexamic	O
+acid	O
+(	O
+TXA	O
+)	O
+therapy	O
+after	O
+withdrawal	O
+of	O
+aprotinin	O
+from	O
+general	O
+clinical	O
+usage	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+review	O
+was	O
+to	O
+perform	O
+a	O
+retrospective	O
+analysis	O
+to	O
+examine	O
+whether	O
+there	O
+was	O
+a	O
+relation	O
+between	O
+TXA	O
+usage	O
+and	O
+seizures	B
+after	O
+cardiac	O
+surgery	O
+.	O
+
+METHODS	O
+:	O
+An	O
+in	O
+-	O
+depth	O
+chart	O
+review	O
+was	O
+undertaken	O
+in	O
+all	O
+24	O
+patients	O
+who	O
+developed	O
+perioperative	O
+seizures	B
+.	O
+
+Electroencephalographic	O
+activity	O
+was	O
+recorded	O
+in	O
+11	O
+of	O
+these	O
+patients	O
+,	O
+and	O
+all	O
+patients	O
+had	O
+a	O
+formal	O
+neurological	O
+evaluation	O
+and	O
+brain	O
+imaging	O
+studies	O
+.	O
+
+RESULTS	O
+:	O
+Twenty	O
+-	O
+one	O
+of	O
+the	O
+24	O
+patients	O
+did	O
+not	O
+have	O
+evidence	O
+of	O
+new	O
+cerebral	B
+ischemic	I
+injury	I
+,	O
+but	O
+seizures	B
+were	O
+likely	O
+due	O
+to	O
+ischemic	B
+brain	I
+injury	I
+in	O
+3	O
+patients	O
+.	O
+
+All	O
+patients	O
+with	O
+seizures	B
+did	O
+not	O
+have	O
+permanent	O
+neurological	B
+abnormalities	I
+.	O
+
+All	O
+24	O
+patients	O
+with	O
+seizures	B
+received	O
+high	O
+doses	O
+of	O
+TXA	O
+intraoperatively	O
+ranging	O
+from	O
+61	O
+to	O
+259	O
+mg	O
+/	O
+kg	O
+,	O
+had	O
+a	O
+mean	O
+age	O
+of	O
+69	O
+.	O
+9	O
+years	O
+,	O
+and	O
+21	O
+of	O
+24	O
+had	O
+undergone	O
+open	O
+chamber	O
+rather	O
+than	O
+coronary	O
+bypass	O
+procedures	O
+.	O
+
+All	O
+but	O
+one	O
+patient	O
+were	O
+managed	O
+using	O
+cardiopulmonary	O
+bypass	O
+.	O
+
+No	O
+evidence	O
+of	O
+brain	B
+ischemic	I
+,	O
+metabolic	O
+,	O
+or	O
+hyperthermia	B
+-	O
+induced	O
+causes	O
+for	O
+their	O
+seizures	B
+was	O
+apparent	O
+.	O
+
+CONCLUSION	O
+:	O
+Our	O
+results	O
+suggest	O
+that	O
+use	O
+of	O
+high	O
+-	O
+dose	O
+TXA	O
+in	O
+older	O
+patients	O
+in	O
+conjunction	O
+with	O
+cardiopulmonary	O
+bypass	O
+and	O
+open	O
+-	O
+chamber	O
+cardiac	O
+surgery	O
+is	O
+associated	O
+with	O
+clinical	O
+seizures	B
+in	O
+susceptible	O
+patients	O
+.	O
+
+Electrocardiographic	O
+changes	O
+and	O
+cardiac	B
+arrhythmias	I
+in	O
+patients	O
+receiving	O
+psychotropic	O
+drugs	O
+.	O
+
+Eight	O
+patients	O
+had	O
+cardiac	O
+manifestations	O
+that	O
+were	O
+life	O
+-	O
+threatening	O
+in	O
+five	O
+while	O
+taking	O
+psychotropic	O
+drugs	O
+,	O
+either	O
+phenothiazines	O
+or	O
+tricyclic	O
+antidepressants	O
+.	O
+
+Although	O
+most	O
+patients	O
+were	O
+receiving	O
+several	O
+drugs	O
+,	O
+Mellaril	O
+(	O
+thioridazine	O
+)	O
+appeared	O
+to	O
+be	O
+responsible	O
+for	O
+five	O
+cases	O
+of	O
+ventricular	B
+tachycardia	I
+,	O
+one	O
+of	O
+which	O
+was	O
+fatal	O
+in	O
+a	O
+35	O
+year	O
+old	O
+woman	O
+.	O
+
+Supraventricular	B
+tachycardia	I
+developed	O
+in	O
+one	O
+patient	O
+receiving	O
+Thorazine	O
+(	O
+chlorpromazine	O
+)	O
+.	O
+
+Aventyl	O
+(	O
+nortriptyline	O
+)	O
+and	O
+Elavil	O
+(	O
+amitriptyline	O
+)	O
+each	O
+produced	O
+left	B
+bundle	I
+branch	I
+block	I
+in	O
+a	O
+73	O
+year	O
+old	O
+woman	O
+.	O
+
+Electrocardiographic	O
+T	O
+and	O
+U	O
+wave	O
+abnormalities	O
+were	O
+present	O
+in	O
+most	O
+patients	O
+.	O
+
+The	O
+ventricular	B
+arrhythmias	I
+responded	O
+to	O
+intravenous	O
+administration	O
+of	O
+lidocaine	O
+and	O
+to	O
+direct	O
+current	O
+electric	O
+shock	O
+;	O
+ventricular	O
+pacing	O
+was	O
+required	O
+in	O
+some	O
+instances	O
+and	O
+intravenous	O
+administration	O
+of	O
+propranolol	O
+combined	O
+with	O
+ventricular	O
+pacing	O
+in	O
+one	O
+.	O
+
+The	O
+tachyarrhythmias	B
+generally	O
+subsided	O
+within	O
+48	O
+hours	O
+after	O
+administration	O
+of	O
+the	O
+drugs	O
+was	O
+stopped	O
+.	O
+
+Five	O
+of	O
+the	O
+eight	O
+patients	O
+were	O
+50	O
+years	O
+of	O
+age	O
+or	O
+younger	O
+;	O
+only	O
+one	O
+clearly	O
+had	O
+antecedent	O
+heart	B
+disease	I
+.	O
+
+Major	O
+cardiac	B
+arrhythmias	I
+are	O
+a	O
+potential	O
+hazard	O
+in	O
+patients	O
+without	O
+heart	B
+disease	I
+who	O
+are	O
+receiving	O
+customary	O
+therapeutic	O
+doses	O
+of	O
+psychotropic	O
+drugs	O
+.	O
+
+A	O
+prospective	O
+clinical	O
+trial	O
+is	O
+suggested	O
+to	O
+quantify	O
+the	O
+risk	O
+of	O
+cardiac	B
+complications	I
+to	O
+patients	O
+receiving	O
+phenothiazines	O
+or	O
+tricyclic	O
+antidepressant	O
+drugs	O
+.	O
+
+Sensitivity	O
+of	O
+erythroid	O
+progenitor	O
+colonies	O
+to	O
+erythropoietin	O
+in	O
+azidothymidine	O
+treated	O
+immunodeficient	B
+mice	O
+.	O
+
+The	O
+anaemia	B
+induced	O
+by	O
+3	O
+'	O
+-	O
+azido	O
+-	O
+3	O
+'	O
+dideoxythymidine	O
+(	O
+AZT	O
+)	O
+is	O
+poorly	O
+understood	O
+.	O
+
+We	O
+have	O
+used	O
+a	O
+murine	O
+model	O
+of	O
+AIDS	B
+,	O
+infection	B
+of	O
+female	O
+C57BL	O
+/	O
+6	O
+mice	O
+with	O
+LP	O
+-	O
+BM5	O
+murine	O
+leukaemia	B
+(	O
+MuLV	O
+)	O
+virus	O
+,	O
+to	O
+determine	O
+if	O
+AZT	O
+-	O
+induced	O
+anaemia	B
+is	O
+due	O
+,	O
+in	O
+part	O
+,	O
+to	O
+decreased	O
+responsiveness	O
+of	O
+erythropoietic	O
+precursors	O
+(	O
+BFU	O
+-	O
+e	O
+)	O
+to	O
+erythropoietin	O
+(	O
+EPO	O
+)	O
+.	O
+
+Mice	O
+in	O
+the	O
+early	O
+stage	O
+of	O
+LP	O
+-	O
+BM5	O
+MuLV	O
+disease	O
+were	O
+given	O
+AZT	O
+in	O
+their	O
+drinking	O
+water	O
+at	O
+1	O
+.	O
+0	O
+and	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+ml	O
+.	O
+
+AZT	O
+produced	O
+anaemia	B
+in	O
+both	O
+groups	O
+,	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+fashion	O
+.	O
+
+Despite	O
+the	O
+anaemia	B
+,	O
+the	O
+number	O
+of	O
+splenic	O
+and	O
+bone	O
+marrow	O
+BFU	O
+-	O
+e	O
+in	O
+AZT	O
+treated	O
+mice	O
+increased	O
+up	O
+to	O
+five	O
+-	O
+fold	O
+over	O
+levels	O
+observed	O
+in	O
+infected	O
+untreated	O
+animals	O
+after	O
+15	O
+d	O
+of	O
+treatment	O
+.	O
+
+Colony	O
+formation	O
+by	O
+splenic	O
+and	O
+bone	O
+marrow	O
+BFUe	O
+was	O
+stimulated	O
+at	O
+lower	O
+concentrations	O
+of	O
+EPO	O
+in	O
+mice	O
+receiving	O
+AZT	O
+for	O
+15	O
+d	O
+than	O
+for	O
+infected	O
+,	O
+untreated	O
+mice	O
+.	O
+
+By	O
+day	O
+30	O
+,	O
+sensitivity	O
+of	O
+both	O
+splenic	O
+and	O
+bone	O
+marrow	O
+BFU	O
+-	O
+e	O
+of	O
+treated	O
+animals	O
+returned	O
+to	O
+that	O
+observed	O
+from	O
+cells	O
+of	O
+infected	O
+untreated	O
+animals	O
+.	O
+
+The	O
+mean	O
+plasma	O
+levels	O
+of	O
+EPO	O
+observed	O
+in	O
+AZT	O
+treated	O
+mice	O
+were	O
+appropriate	O
+for	O
+the	O
+degree	O
+of	O
+anaemia	B
+observed	O
+when	O
+compared	O
+with	O
+phenylhydrazine	O
+(	O
+PHZ	O
+)	O
+treated	O
+mice	O
+.	O
+
+The	O
+numbers	O
+of	O
+BFU	O
+-	O
+e	O
+and	O
+the	O
+percentage	O
+of	O
+bone	O
+marrow	O
+erythroblasts	O
+observed	O
+were	O
+comparable	O
+in	O
+AZT	O
+and	O
+PHZ	O
+treated	O
+mice	O
+with	O
+similar	O
+degrees	O
+of	O
+anaemia	B
+.	O
+
+However	O
+,	O
+reticulocytosis	B
+was	O
+inappropriate	O
+for	O
+the	O
+degree	O
+of	O
+anaemia	B
+observed	O
+in	O
+AZT	O
+treated	O
+infected	O
+mice	O
+.	O
+
+AZT	O
+-	O
+induced	O
+peripheral	O
+anaemia	B
+in	O
+the	O
+face	O
+of	O
+increased	O
+numbers	O
+of	O
+BFU	O
+-	O
+e	O
+and	O
+increased	O
+levels	O
+of	O
+plasma	O
+EPO	O
+suggest	O
+a	O
+lesion	O
+in	O
+terminal	O
+differentiation	O
+.	O
+
+Sedation	O
+depth	O
+during	O
+spinal	O
+anesthesia	O
+and	O
+the	O
+development	O
+of	O
+postoperative	B
+delirium	I
+in	O
+elderly	O
+patients	O
+undergoing	O
+hip	B
+fracture	I
+repair	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+determine	O
+whether	O
+limiting	O
+intraoperative	O
+sedation	O
+depth	O
+during	O
+spinal	O
+anesthesia	O
+for	O
+hip	B
+fracture	I
+repair	O
+in	O
+elderly	O
+patients	O
+can	O
+decrease	O
+the	O
+prevalence	O
+of	O
+postoperative	B
+delirium	I
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+We	O
+performed	O
+a	O
+double	O
+-	O
+blind	O
+,	O
+randomized	O
+controlled	O
+trial	O
+at	O
+an	O
+academic	O
+medical	O
+center	O
+of	O
+elderly	O
+patients	O
+(	O
+>	O
+or	O
+=	O
+65	O
+years	O
+)	O
+without	O
+preoperative	O
+delirium	B
+or	O
+severe	O
+dementia	B
+who	O
+underwent	O
+hip	B
+fracture	I
+repair	O
+under	O
+spinal	O
+anesthesia	O
+with	O
+propofol	O
+sedation	O
+.	O
+
+Sedation	O
+depth	O
+was	O
+titrated	O
+using	O
+processed	O
+electroencephalography	O
+with	O
+the	O
+bispectral	O
+index	O
+(	O
+BIS	O
+)	O
+,	O
+and	O
+patients	O
+were	O
+randomized	O
+to	O
+receive	O
+either	O
+deep	O
+(	O
+BIS	O
+,	O
+approximately	O
+50	O
+)	O
+or	O
+light	O
+(	O
+BIS	O
+,	O
+>	O
+or	O
+=	O
+80	O
+)	O
+sedation	O
+.	O
+
+Postoperative	B
+delirium	I
+was	O
+assessed	O
+as	O
+defined	O
+by	O
+Diagnostic	O
+and	O
+Statistical	O
+Manual	O
+of	O
+Mental	B
+Disorders	I
+(	O
+Third	O
+Edition	O
+Revised	O
+)	O
+criteria	O
+using	O
+the	O
+Confusion	O
+Assessment	O
+Method	O
+beginning	O
+at	O
+any	O
+time	O
+from	O
+the	O
+second	O
+day	O
+after	O
+surgery	O
+.	O
+
+RESULTS	O
+:	O
+From	O
+April	O
+2	O
+,	O
+2005	O
+,	O
+through	O
+October	O
+30	O
+,	O
+2008	O
+,	O
+a	O
+total	O
+of	O
+114	O
+patients	O
+were	O
+randomized	O
+.	O
+
+The	O
+prevalence	O
+of	O
+postoperative	B
+delirium	I
+was	O
+significantly	O
+lower	O
+in	O
+the	O
+light	O
+sedation	O
+group	O
+(	O
+11	O
+/	O
+57	O
+[	O
+19	O
+%	O
+]	O
+vs	O
+23	O
+/	O
+57	O
+[	O
+40	O
+%	O
+]	O
+in	O
+the	O
+deep	O
+sedation	O
+group	O
+;	O
+P	O
+=	O
+.	O
+02	O
+)	O
+,	O
+indicating	O
+that	O
+1	O
+incident	O
+of	O
+delirium	B
+will	O
+be	O
+prevented	O
+for	O
+every	O
+4	O
+.	O
+7	O
+patients	O
+treated	O
+with	O
+light	O
+sedation	O
+.	O
+
+The	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+number	O
+of	O
+days	O
+of	O
+delirium	B
+during	O
+hospitalization	O
+was	O
+lower	O
+in	O
+the	O
+light	O
+sedation	O
+group	O
+than	O
+in	O
+the	O
+deep	O
+sedation	O
+group	O
+(	O
+0	O
+.	O
+5	O
++	O
+/	O
+-	O
+1	O
+.	O
+5	O
+days	O
+vs	O
+1	O
+.	O
+4	O
++	O
+/	O
+-	O
+4	O
+.	O
+0	O
+days	O
+;	O
+P	O
+=	O
+.	O
+01	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+use	O
+of	O
+light	O
+propofol	O
+sedation	O
+decreased	O
+the	O
+prevalence	O
+of	O
+postoperative	B
+delirium	I
+by	O
+50	O
+%	O
+compared	O
+with	O
+deep	O
+sedation	O
+.	O
+
+Limiting	O
+depth	O
+of	O
+sedation	O
+during	O
+spinal	O
+anesthesia	O
+is	O
+a	O
+simple	O
+,	O
+safe	O
+,	O
+and	O
+cost	O
+-	O
+effective	O
+intervention	O
+for	O
+preventing	O
+postoperative	B
+delirium	I
+in	O
+elderly	O
+patients	O
+that	O
+could	O
+be	O
+widely	O
+and	O
+readily	O
+adopted	O
+.	O
+
+The	O
+protective	O
+role	O
+of	O
+Nrf2	O
+in	O
+streptozotocin	O
+-	O
+induced	O
+diabetic	B
+nephropathy	I
+.	O
+
+OBJECTIVE	O
+:	O
+Diabetic	B
+nephropathy	I
+is	O
+one	O
+of	O
+the	O
+major	O
+causes	O
+of	O
+renal	B
+failure	I
+,	O
+which	O
+is	O
+accompanied	O
+by	O
+the	O
+production	O
+of	O
+reactive	O
+oxygen	O
+species	O
+(	O
+ROS	O
+)	O
+.	O
+
+Nrf2	O
+is	O
+the	O
+primary	O
+transcription	O
+factor	O
+that	O
+controls	O
+the	O
+antioxidant	O
+response	O
+essential	O
+for	O
+maintaining	O
+cellular	O
+redox	O
+homeostasis	O
+.	O
+
+Here	O
+,	O
+we	O
+report	O
+our	O
+findings	O
+demonstrating	O
+a	O
+protective	O
+role	O
+of	O
+Nrf2	O
+against	O
+diabetic	B
+nephropathy	I
+.	O
+
+RESEARCH	O
+DESIGN	O
+AND	O
+METHODS	O
+:	O
+We	O
+explore	O
+the	O
+protective	O
+role	O
+of	O
+Nrf2	O
+against	O
+diabetic	B
+nephropathy	I
+using	O
+human	O
+kidney	O
+biopsy	O
+tissues	O
+from	O
+diabetic	B
+nephropathy	I
+patients	O
+,	O
+a	O
+streptozotocin	O
+-	O
+induced	O
+diabetic	B
+nephropathy	I
+model	O
+in	O
+Nrf2	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+,	O
+and	O
+cultured	O
+human	O
+mesangial	O
+cells	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+glomeruli	O
+of	O
+human	O
+diabetic	B
+nephropathy	I
+patients	O
+were	O
+under	O
+oxidative	O
+stress	O
+and	O
+had	O
+elevated	O
+Nrf2	O
+levels	O
+.	O
+
+In	O
+the	O
+animal	O
+study	O
+,	O
+Nrf2	O
+was	O
+demonstrated	O
+to	O
+be	O
+crucial	O
+in	O
+ameliorating	O
+streptozotocin	O
+-	O
+induced	O
+renal	B
+damage	I
+.	O
+
+This	O
+is	O
+evident	O
+by	O
+Nrf2	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+having	O
+higher	O
+ROS	O
+production	O
+and	O
+suffering	O
+from	O
+greater	O
+oxidative	O
+DNA	O
+damage	O
+and	O
+renal	B
+injury	I
+compared	O
+with	O
+Nrf2	O
+(	O
++	O
+/	O
++	O
+)	O
+mice	O
+.	O
+
+Mechanistic	O
+studies	O
+in	O
+both	O
+in	O
+vivo	O
+and	O
+in	O
+vitro	O
+systems	O
+showed	O
+that	O
+the	O
+Nrf2	O
+-	O
+mediated	O
+protection	O
+against	O
+diabetic	B
+nephropathy	I
+is	O
+,	O
+at	O
+least	O
+,	O
+partially	O
+through	O
+inhibition	O
+of	O
+transforming	O
+growth	O
+factor	O
+-	O
+beta1	O
+(	O
+TGF	O
+-	O
+beta1	O
+)	O
+and	O
+reduction	O
+of	O
+extracellular	O
+matrix	O
+production	O
+.	O
+
+In	O
+human	O
+renal	O
+mesangial	O
+cells	O
+,	O
+high	O
+glucose	O
+induced	O
+ROS	O
+production	O
+and	O
+activated	O
+expression	O
+of	O
+Nrf2	O
+and	O
+its	O
+downstream	O
+genes	O
+.	O
+
+Furthermore	O
+,	O
+activation	O
+or	O
+overexpression	O
+of	O
+Nrf2	O
+inhibited	O
+the	O
+promoter	O
+activity	O
+of	O
+TGF	O
+-	O
+beta1	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+,	O
+whereas	O
+knockdown	O
+of	O
+Nrf2	O
+by	O
+siRNA	O
+enhanced	O
+TGF	O
+-	O
+beta1	O
+transcription	O
+and	O
+fibronectin	O
+production	O
+.	O
+
+CONCLUSIONS	O
+:	O
+This	O
+work	O
+clearly	O
+indicates	O
+a	O
+protective	O
+role	O
+of	O
+Nrf2	O
+in	O
+diabetic	B
+nephropathy	I
+,	O
+suggesting	O
+that	O
+dietary	O
+or	O
+therapeutic	O
+activation	O
+of	O
+Nrf2	O
+could	O
+be	O
+used	O
+as	O
+a	O
+strategy	O
+to	O
+prevent	O
+or	O
+slow	O
+down	O
+the	O
+progression	O
+of	O
+diabetic	B
+nephropathy	I
+.	O
+
+Metformin	O
+prevents	O
+experimental	O
+gentamicin	O
+-	O
+induced	O
+nephropathy	B
+by	O
+a	O
+mitochondria	O
+-	O
+dependent	O
+pathway	O
+.	O
+
+The	O
+antidiabetic	O
+drug	O
+metformin	O
+can	O
+diminish	O
+apoptosis	O
+induced	O
+by	O
+oxidative	O
+stress	O
+in	O
+endothelial	O
+cells	O
+and	O
+prevent	O
+vascular	B
+dysfunction	I
+even	O
+in	O
+nondiabetic	O
+patients	O
+.	O
+
+Here	O
+we	O
+tested	O
+whether	O
+it	O
+has	O
+a	O
+beneficial	O
+effect	O
+in	O
+a	O
+rat	O
+model	O
+of	O
+gentamicin	O
+toxicity	B
+.	O
+
+Mitochondrial	O
+analysis	O
+,	O
+respiration	O
+intensity	O
+,	O
+levels	O
+of	O
+reactive	O
+oxygen	O
+species	O
+,	O
+permeability	O
+transition	O
+,	O
+and	O
+cytochrome	O
+c	O
+release	O
+were	O
+assessed	O
+3	O
+and	O
+6	O
+days	O
+after	O
+gentamicin	O
+administration	O
+.	O
+
+Metformin	O
+treatment	O
+fully	O
+blocked	O
+gentamicin	O
+-	O
+mediated	O
+acute	B
+renal	I
+failure	I
+.	O
+
+This	O
+was	O
+accompanied	O
+by	O
+a	O
+lower	O
+activity	O
+of	O
+N	O
+-	O
+acetyl	O
+-	O
+beta	O
+-	O
+D	O
+-	O
+glucosaminidase	O
+,	O
+together	O
+with	O
+a	O
+decrease	O
+of	O
+lipid	O
+peroxidation	O
+and	O
+increase	O
+of	O
+antioxidant	O
+systems	O
+.	O
+
+Metformin	O
+also	O
+protected	O
+the	O
+kidney	O
+from	O
+histological	O
+damage	O
+6	O
+days	O
+after	O
+gentamicin	O
+administration	O
+.	O
+
+These	O
+in	O
+vivo	O
+markers	O
+of	O
+kidney	B
+dysfunction	I
+and	O
+their	O
+correction	O
+by	O
+metformin	O
+were	O
+complemented	O
+by	O
+in	O
+vitro	O
+studies	O
+of	O
+mitochondrial	O
+function	O
+.	O
+
+We	O
+found	O
+that	O
+gentamicin	O
+treatment	O
+depleted	O
+respiratory	O
+components	O
+(	O
+cytochrome	O
+c	O
+,	O
+NADH	O
+)	O
+,	O
+probably	O
+due	O
+to	O
+the	O
+opening	O
+of	O
+mitochondrial	O
+transition	O
+pores	O
+.	O
+
+These	O
+injuries	O
+,	O
+partly	O
+mediated	O
+by	O
+a	O
+rise	O
+in	O
+reactive	O
+oxygen	O
+species	O
+from	O
+the	O
+electron	O
+transfer	O
+chain	O
+,	O
+were	O
+significantly	O
+decreased	O
+by	O
+metformin	O
+.	O
+
+Thus	O
+,	O
+our	O
+study	O
+suggests	O
+that	O
+pleiotropic	O
+effects	O
+of	O
+metformin	O
+can	O
+lessen	O
+gentamicin	O
+nephrotoxicity	B
+and	O
+improve	O
+mitochondrial	O
+homeostasis	O
+.	O
+
+Risk	O
+of	O
+nephropathy	B
+after	O
+consumption	O
+of	O
+nonionic	O
+contrast	O
+media	O
+by	O
+children	O
+undergoing	O
+cardiac	O
+angiography	O
+:	O
+a	O
+prospective	O
+study	O
+.	O
+
+Despite	O
+increasing	O
+reports	O
+on	O
+nonionic	O
+contrast	O
+media	O
+-	O
+induced	O
+nephropathy	B
+(	O
+CIN	B
+)	O
+in	O
+hospitalized	O
+adult	O
+patients	O
+during	O
+cardiac	O
+procedures	O
+,	O
+the	O
+studies	O
+in	O
+pediatrics	O
+are	O
+limited	O
+,	O
+with	O
+even	O
+less	O
+focus	O
+on	O
+possible	O
+predisposing	O
+factors	O
+and	O
+preventive	O
+measures	O
+for	O
+patients	O
+undergoing	O
+cardiac	O
+angiography	O
+.	O
+
+This	O
+prospective	O
+study	O
+determined	O
+the	O
+incidence	O
+of	O
+CIN	B
+for	O
+two	O
+nonionic	O
+contrast	O
+media	O
+(	O
+CM	O
+)	O
+,	O
+iopromide	O
+and	O
+iohexol	O
+,	O
+among	O
+80	O
+patients	O
+younger	O
+than	O
+18	O
+years	O
+and	O
+compared	O
+the	O
+rates	O
+for	O
+this	O
+complication	O
+in	O
+relation	O
+to	O
+the	O
+type	O
+and	O
+dosage	O
+of	O
+CM	O
+and	O
+the	O
+presence	O
+of	O
+cyanosis	B
+.	O
+
+The	O
+80	O
+patients	O
+in	O
+the	O
+study	O
+consecutively	O
+received	O
+either	O
+iopromide	O
+(	O
+group	O
+A	O
+,	O
+n	O
+=	O
+40	O
+)	O
+or	O
+iohexol	O
+(	O
+group	O
+B	O
+,	O
+n	O
+=	O
+40	O
+)	O
+.	O
+
+Serum	O
+sodium	O
+(	O
+Na	O
+)	O
+,	O
+potassium	O
+(	O
+K	O
+)	O
+,	O
+and	O
+creatinine	O
+(	O
+Cr	O
+)	O
+were	O
+measured	O
+24	O
+h	O
+before	O
+angiography	O
+as	O
+baseline	O
+values	O
+,	O
+then	O
+measured	O
+again	O
+at	O
+12	O
+-	O
+,	O
+24	O
+-	O
+,	O
+and	O
+48	O
+-	O
+h	O
+intervals	O
+after	O
+CM	O
+use	O
+.	O
+
+Urine	O
+samples	O
+for	O
+Na	O
+and	O
+Cr	O
+also	O
+were	O
+checked	O
+at	O
+the	O
+same	O
+intervals	O
+.	O
+
+Risk	O
+of	O
+renal	B
+failure	I
+,	O
+Injury	B
+to	I
+the	I
+kidney	I
+,	O
+Failure	B
+of	I
+kidney	I
+function	I
+,	O
+Loss	B
+of	I
+kidney	I
+function	I
+,	O
+and	O
+End	O
+-	O
+stage	O
+renal	B
+damage	I
+(	O
+RIFLE	O
+criteria	O
+)	O
+were	O
+used	O
+to	O
+define	O
+CIN	B
+and	O
+its	O
+incidence	O
+in	O
+the	O
+study	O
+population	O
+.	O
+
+Accordingly	O
+,	O
+among	O
+the	O
+15	O
+CIN	B
+patients	O
+(	O
+18	O
+.	O
+75	O
+%	O
+)	O
+,	O
+7	O
+.	O
+5	O
+%	O
+of	O
+the	O
+patients	O
+in	O
+group	O
+A	O
+had	O
+increased	O
+risk	O
+and	O
+3	O
+.	O
+75	O
+%	O
+had	O
+renal	B
+injury	I
+,	O
+whereas	O
+5	O
+%	O
+of	O
+group	O
+B	O
+had	O
+increased	O
+risk	O
+and	O
+2	O
+.	O
+5	O
+%	O
+had	O
+renal	B
+injury	I
+.	O
+
+Whereas	O
+33	O
+.	O
+3	O
+%	O
+of	O
+the	O
+patients	O
+with	O
+CIN	B
+were	O
+among	O
+those	O
+who	O
+received	O
+the	O
+proper	O
+dosage	O
+of	O
+CM	O
+,	O
+the	O
+percentage	O
+increased	O
+to	O
+66	O
+.	O
+6	O
+%	O
+among	O
+those	O
+who	O
+received	O
+larger	O
+doses	O
+,	O
+with	O
+a	O
+significant	O
+difference	O
+in	O
+the	O
+incidence	O
+of	O
+CIN	B
+related	O
+to	O
+the	O
+different	O
+dosages	O
+of	O
+CM	O
+(	O
+p	O
+=	O
+0	O
+.	O
+014	O
+)	O
+.	O
+
+Among	O
+the	O
+15	O
+patients	O
+with	O
+CIN	B
+,	O
+6	O
+had	O
+cyanotic	O
+congenital	B
+heart	I
+diseases	I
+,	O
+but	O
+the	O
+incidence	O
+did	O
+not	O
+differ	O
+significantly	O
+from	O
+that	O
+for	O
+the	O
+noncyanotic	O
+patients	O
+(	O
+p	O
+=	O
+0	O
+.	O
+243	O
+)	O
+.	O
+
+Although	O
+clinically	O
+silent	O
+,	O
+CIN	B
+is	O
+not	O
+rare	O
+in	O
+pediatrics	O
+.	O
+
+The	O
+incidence	O
+depends	O
+on	O
+dosage	O
+but	O
+not	O
+on	O
+the	O
+type	O
+of	O
+consumed	O
+nonionic	O
+CM	O
+,	O
+nor	O
+on	O
+the	O
+presence	O
+of	O
+cyanosis	B
+,	O
+and	O
+although	O
+CIN	B
+usually	O
+is	O
+reversible	O
+,	O
+more	O
+concern	O
+is	O
+needed	O
+for	O
+the	O
+prevention	O
+of	O
+such	O
+a	O
+complication	O
+in	O
+children	O
+.	O
+
+Renal	O
+function	O
+and	O
+hemodynamics	O
+during	O
+prolonged	O
+isoflurane	O
+-	O
+induced	O
+hypotension	B
+in	O
+humans	O
+.	O
+
+The	O
+effect	O
+of	O
+isoflurane	O
+-	O
+induced	O
+hypotension	B
+on	O
+glomerular	O
+function	O
+and	O
+renal	O
+blood	O
+flow	O
+was	O
+investigated	O
+in	O
+20	O
+human	O
+subjects	O
+.	O
+
+Glomerular	O
+filtration	O
+rate	O
+(	O
+GFR	O
+)	O
+and	O
+effective	O
+renal	O
+plasma	O
+flow	O
+(	O
+ERPF	O
+)	O
+were	O
+measured	O
+by	O
+inulin	O
+and	O
+para	O
+-	O
+aminohippurate	O
+(	O
+PAH	O
+)	O
+clearance	O
+,	O
+respectively	O
+.	O
+
+Anesthesia	O
+was	O
+maintained	O
+with	O
+fentanyl	O
+,	O
+nitrous	O
+oxide	O
+,	O
+oxygen	O
+,	O
+and	O
+isoflurane	O
+.	O
+
+Hypotension	B
+was	O
+induced	O
+for	O
+236	O
+.	O
+9	O
++	O
+/	O
+-	O
+15	O
+.	O
+1	O
+min	O
+by	O
+increasing	O
+the	O
+isoflurane	O
+inspired	O
+concentration	O
+to	O
+maintain	O
+a	O
+mean	O
+arterial	O
+pressure	O
+of	O
+59	O
+.	O
+8	O
++	O
+/	O
+-	O
+0	O
+.	O
+4	O
+mmHg	O
+.	O
+
+GFR	O
+and	O
+ERPF	O
+decreased	O
+with	O
+the	O
+induction	O
+of	O
+anesthesia	O
+but	O
+not	O
+significantly	O
+more	O
+during	O
+hypotension	B
+.	O
+
+Postoperatively	O
+,	O
+ERPF	O
+returned	O
+to	O
+preoperative	O
+values	O
+,	O
+whereas	O
+GFR	O
+was	O
+higher	O
+than	O
+preoperative	O
+values	O
+.	O
+
+Renal	O
+vascular	O
+resistance	O
+increased	O
+during	O
+anesthesia	O
+but	O
+decreased	O
+when	O
+hypotension	B
+was	O
+induced	O
+,	O
+allowing	O
+the	O
+maintenance	O
+of	O
+renal	O
+blood	O
+flow	O
+.	O
+
+We	O
+conclude	O
+that	O
+renal	O
+compensatory	O
+mechanisms	O
+are	O
+preserved	O
+during	O
+isoflurane	O
+-	O
+induced	O
+hypotension	B
+and	O
+that	O
+renal	O
+function	O
+and	O
+hemodynamics	O
+quickly	O
+return	O
+to	O
+normal	O
+when	O
+normotension	O
+is	O
+resumed	O
+.	O
+
+Brainstem	B
+dysgenesis	I
+in	O
+an	O
+infant	O
+prenatally	O
+exposed	O
+to	O
+cocaine	O
+.	O
+
+Many	O
+authors	O
+described	O
+the	O
+effects	O
+on	O
+the	O
+fetus	O
+of	O
+maternal	O
+cocaine	B
+abuse	I
+during	O
+pregnancy	O
+.	O
+
+Vasoconstriction	O
+appears	O
+to	O
+be	O
+the	O
+common	O
+mechanism	O
+of	O
+action	O
+leading	O
+to	O
+a	O
+wide	O
+range	O
+of	O
+fetal	B
+anomalies	I
+.	O
+
+We	O
+report	O
+on	O
+an	O
+infant	O
+with	O
+multiple	B
+cranial	I
+-	I
+nerve	I
+involvement	I
+attributable	O
+to	O
+brainstem	B
+dysgenesis	I
+,	O
+born	O
+to	O
+a	O
+cocaine	B
+-	I
+addicted	I
+mother	O
+.	O
+
+A	O
+cross	O
+-	O
+sectional	O
+evaluation	O
+of	O
+the	O
+effect	O
+of	O
+risperidone	O
+and	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitors	O
+on	O
+bone	O
+mineral	O
+density	O
+in	O
+boys	O
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+effect	O
+of	O
+risperidone	O
+-	O
+induced	O
+hyperprolactinemia	B
+on	O
+trabecular	O
+bone	O
+mineral	O
+density	O
+(	O
+BMD	O
+)	O
+in	O
+children	O
+and	O
+adolescents	O
+.	O
+
+METHOD	O
+:	O
+Medically	O
+healthy	O
+7	O
+-	O
+to	O
+17	O
+-	O
+year	O
+-	O
+old	O
+males	O
+chronically	O
+treated	O
+,	O
+in	O
+a	O
+naturalistic	O
+setting	O
+,	O
+with	O
+risperidone	O
+were	O
+recruited	O
+for	O
+this	O
+cross	O
+-	O
+sectional	O
+study	O
+through	O
+child	O
+psychiatry	O
+outpatient	O
+clinics	O
+between	O
+November	O
+2005	O
+and	O
+June	O
+2007	O
+.	O
+
+Anthropometric	O
+measurements	O
+and	O
+laboratory	O
+testing	O
+were	O
+conducted	O
+.	O
+
+The	O
+clinical	O
+diagnoses	O
+were	O
+based	O
+on	O
+chart	O
+review	O
+,	O
+and	O
+developmental	O
+and	O
+treatment	O
+history	O
+was	O
+obtained	O
+from	O
+the	O
+medical	O
+record	O
+.	O
+
+Volumetric	O
+BMD	O
+of	O
+the	O
+ultradistal	O
+radius	O
+was	O
+measured	O
+using	O
+peripheral	O
+quantitative	O
+computed	O
+tomography	O
+,	O
+and	O
+areal	O
+BMD	O
+of	O
+the	O
+lumbar	O
+spine	O
+was	O
+estimated	O
+using	O
+dual	O
+-	O
+energy	O
+x	O
+-	O
+ray	O
+absorptiometry	O
+.	O
+
+RESULTS	O
+:	O
+Hyperprolactinemia	B
+was	O
+present	O
+in	O
+49	O
+%	O
+of	O
+83	O
+boys	O
+(	O
+n	O
+=	O
+41	O
+)	O
+treated	O
+with	O
+risperidone	O
+for	O
+a	O
+mean	O
+of	O
+2	O
+.	O
+9	O
+years	O
+.	O
+
+Serum	O
+testosterone	O
+concentration	O
+increased	O
+with	O
+pubertal	O
+status	O
+but	O
+was	O
+not	O
+affected	O
+by	O
+hyperprolactinemia	B
+.	O
+
+As	O
+expected	O
+,	O
+bone	O
+mineral	O
+content	O
+and	O
+BMD	O
+increased	O
+with	O
+sexual	O
+maturity	O
+.	O
+
+After	O
+adjusting	O
+for	O
+the	O
+stage	O
+of	O
+sexual	O
+development	O
+and	O
+height	O
+and	O
+BMI	O
+z	O
+scores	O
+,	O
+serum	O
+prolactin	O
+was	O
+negatively	O
+associated	O
+with	O
+trabecular	O
+volumetric	O
+BMD	O
+at	O
+the	O
+ultradistal	O
+radius	O
+(	O
+P	O
+<	O
+.	O
+03	O
+)	O
+.	O
+
+Controlling	O
+for	O
+relevant	O
+covariates	O
+,	O
+we	O
+also	O
+found	O
+treatment	O
+with	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitors	O
+(	O
+SSRIs	O
+)	O
+to	O
+be	O
+associated	O
+with	O
+lower	O
+trabecular	O
+BMD	O
+at	O
+the	O
+radius	O
+(	O
+P	O
+=	O
+.	O
+03	O
+)	O
+and	O
+BMD	O
+z	O
+score	O
+at	O
+the	O
+lumbar	O
+spine	O
+(	O
+P	O
+<	O
+.	O
+05	O
+)	O
+.	O
+
+These	O
+findings	O
+became	O
+more	O
+marked	O
+when	O
+the	O
+analysis	O
+was	O
+restricted	O
+to	O
+non	O
+-	O
+Hispanic	O
+white	O
+patients	O
+.	O
+
+Of	O
+13	O
+documented	O
+fractures	B
+,	O
+3	O
+occurred	O
+after	O
+risperidone	O
+and	O
+SSRIs	O
+were	O
+started	O
+,	O
+and	O
+none	O
+occurred	O
+in	O
+patients	O
+with	O
+hyperprolactinemia	B
+.	O
+
+CONCLUSIONS	O
+:	O
+This	O
+is	O
+the	O
+first	O
+study	O
+to	O
+link	O
+risperidone	O
+-	O
+induced	O
+hyperprolactinemia	B
+and	O
+SSRI	O
+treatment	O
+to	O
+lower	O
+BMD	O
+in	O
+children	O
+and	O
+adolescents	O
+.	O
+
+Future	O
+research	O
+should	O
+evaluate	O
+the	O
+longitudinal	O
+course	O
+of	O
+this	O
+adverse	O
+event	O
+to	O
+determine	O
+its	O
+temporal	O
+stability	O
+and	O
+whether	O
+a	O
+higher	O
+fracture	O
+rate	O
+ensues	O
+.	O
+
+Fear	O
+-	O
+potentiated	O
+startle	B
+,	O
+but	O
+not	O
+light	O
+-	O
+enhanced	O
+startle	B
+,	O
+is	O
+enhanced	O
+by	O
+anxiogenic	O
+drugs	O
+.	O
+
+RATIONALE	O
+AND	O
+OBJECTIVES	O
+:	O
+The	O
+light	O
+-	O
+enhanced	O
+startle	B
+paradigm	O
+(	O
+LES	O
+)	O
+is	O
+suggested	O
+to	O
+model	O
+anxiety	B
+,	O
+because	O
+of	O
+the	O
+non	O
+-	O
+specific	O
+cue	O
+and	O
+the	O
+long	O
+-	O
+term	O
+effect	O
+.	O
+
+In	O
+contrast	O
+,	O
+the	O
+fear	O
+-	O
+potentiated	O
+startle	B
+(	O
+FPS	O
+)	O
+is	O
+suggested	O
+to	O
+model	O
+conditioned	O
+fear	O
+.	O
+
+However	O
+,	O
+the	O
+pharmacological	O
+profiles	O
+of	O
+these	O
+two	O
+paradigms	O
+are	O
+very	O
+similar	O
+.	O
+
+The	O
+present	O
+study	O
+investigated	O
+the	O
+effects	O
+of	O
+putative	O
+anxiogenic	O
+drugs	O
+on	O
+LES	O
+and	O
+FPS	O
+and	O
+aimed	O
+at	O
+determining	O
+the	O
+sensitivity	O
+of	O
+LES	O
+for	O
+anxiogenic	O
+drugs	O
+and	O
+to	O
+potentially	O
+showing	O
+a	O
+pharmacological	O
+differentiation	O
+between	O
+these	O
+two	O
+paradigms	O
+.	O
+
+METHODS	O
+:	O
+Male	O
+Wistar	O
+rats	O
+received	O
+each	O
+dose	O
+of	O
+the	O
+alpha	O
+(	O
+2	O
+)	O
+-	O
+adrenoceptor	O
+antagonist	O
+yohimbine	O
+(	O
+0	O
+.	O
+25	O
+-	O
+1	O
+.	O
+0mg	O
+/	O
+kg	O
+)	O
+,	O
+the	O
+5	O
+-	O
+HT	O
+(	O
+2C	O
+)	O
+receptor	O
+agonist	O
+m	O
+-	O
+chlorophenylpiperazine	O
+(	O
+mCPP	O
+,	O
+0	O
+.	O
+5	O
+-	O
+2	O
+.	O
+0mg	O
+/	O
+kg	O
+)	O
+or	O
+the	O
+GABA	O
+(	O
+A	O
+)	O
+inverse	O
+receptor	O
+agonist	O
+pentylenetetrazole	O
+(	O
+PTZ	O
+,	O
+3	O
+-	O
+30mg	O
+/	O
+kg	O
+)	O
+and	O
+were	O
+subsequently	O
+tested	O
+in	O
+either	O
+LES	O
+or	O
+FPS	O
+.	O
+
+RESULTS	O
+:	O
+None	O
+of	O
+the	O
+drugs	O
+enhanced	O
+LES	O
+,	O
+whereas	O
+mCPP	O
+increased	O
+percentage	O
+FPS	O
+and	O
+yohimbine	O
+increased	O
+absolute	O
+FPS	O
+values	O
+.	O
+
+Furthermore	O
+,	O
+yohimbine	O
+increased	O
+baseline	O
+startle	B
+amplitude	O
+in	O
+the	O
+LES	O
+,	O
+while	O
+mCPP	O
+suppressed	O
+baseline	O
+startle	B
+in	O
+both	O
+the	O
+LES	O
+and	O
+FPS	O
+and	O
+PTZ	O
+suppressed	O
+baseline	O
+startle	B
+in	O
+the	O
+FPS	O
+.	O
+
+CONCLUSIONS	O
+:	O
+In	O
+contrast	O
+to	O
+findings	O
+in	O
+the	O
+FPS	O
+paradigm	O
+,	O
+none	O
+of	O
+the	O
+drugs	O
+were	O
+able	O
+to	O
+exacerbate	O
+the	O
+LES	O
+response	O
+.	O
+
+Thus	O
+,	O
+a	O
+clear	O
+pharmacological	O
+differentiation	O
+was	O
+found	O
+between	O
+LES	O
+and	O
+FPS	O
+.	O
+
+Rosaceiform	O
+dermatitis	B
+associated	O
+with	O
+topical	O
+tacrolimus	O
+treatment	O
+.	O
+
+We	O
+describe	O
+herein	O
+3	O
+patients	O
+who	O
+developed	O
+rosacea	B
+-	O
+like	O
+dermatitis	B
+eruptions	B
+while	O
+using	O
+0	O
+.	O
+03	O
+%	O
+or	O
+0	O
+.	O
+1	O
+%	O
+tacrolimus	O
+ointment	O
+for	O
+facial	B
+dermatitis	I
+.	O
+
+Skin	O
+biopsy	O
+specimens	O
+showed	O
+telangiectasia	B
+and	O
+noncaseating	O
+epithelioid	O
+granulomatous	O
+tissue	O
+formation	O
+in	O
+the	O
+papillary	O
+to	O
+mid	O
+dermis	O
+.	O
+
+Continuous	O
+topical	O
+use	O
+of	O
+immunomodulators	O
+such	O
+as	O
+tacrolimus	O
+or	O
+pimecrolimus	O
+should	O
+be	O
+regarded	O
+as	O
+a	O
+potential	O
+cause	O
+of	O
+rosaceiform	O
+dermatitis	B
+,	O
+although	O
+many	O
+cases	O
+have	O
+not	O
+been	O
+reported	O
+.	O
+
+Coenzyme	O
+Q10	O
+treatment	O
+ameliorates	O
+acute	O
+cisplatin	O
+nephrotoxicity	B
+in	O
+mice	O
+.	O
+
+The	O
+nephroprotective	O
+effect	O
+of	O
+coenzyme	O
+Q10	O
+was	O
+investigated	O
+in	O
+mice	O
+with	O
+acute	B
+renal	I
+injury	I
+induced	O
+by	O
+a	O
+single	O
+i	O
+.	O
+p	O
+.	O
+injection	O
+of	O
+cisplatin	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+Coenzyme	O
+Q10	O
+treatment	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+was	O
+applied	O
+for	O
+6	O
+consecutive	O
+days	O
+,	O
+starting	O
+1	O
+day	O
+before	O
+cisplatin	O
+administration	O
+.	O
+
+Coenzyme	O
+Q10	O
+significantly	O
+reduced	O
+blood	O
+urea	O
+nitrogen	O
+and	O
+serum	O
+creatinine	O
+levels	O
+which	O
+were	O
+increased	O
+by	O
+cisplatin	O
+.	O
+
+Coenzyme	O
+Q10	O
+significantly	O
+compensated	O
+deficits	O
+in	O
+the	O
+antioxidant	O
+defense	O
+mechanisms	O
+(	O
+reduced	O
+glutathione	O
+level	O
+and	O
+superoxide	O
+dismutase	O
+activity	O
+)	O
+,	O
+suppressed	O
+lipid	O
+peroxidation	O
+,	O
+decreased	O
+the	O
+elevations	O
+of	O
+tumor	B
+necrosis	B
+factor	O
+-	O
+alpha	O
+,	O
+nitric	O
+oxide	O
+and	O
+platinum	O
+ion	O
+concentration	O
+,	O
+and	O
+attenuated	O
+the	O
+reductions	O
+of	O
+selenium	O
+and	O
+zinc	O
+ions	O
+in	O
+renal	O
+tissue	O
+resulted	O
+from	O
+cisplatin	O
+administration	O
+.	O
+
+Also	O
+,	O
+histopathological	O
+renal	B
+tissue	I
+damage	I
+mediated	O
+by	O
+cisplatin	O
+was	O
+ameliorated	O
+by	O
+coenzyme	O
+Q10	O
+treatment	O
+.	O
+
+Immunohistochemical	O
+analysis	O
+revealed	O
+that	O
+coenzyme	O
+Q10	O
+significantly	O
+decreased	O
+the	O
+cisplatin	O
+-	O
+induced	O
+overexpression	O
+of	O
+inducible	O
+nitric	O
+oxide	O
+synthase	O
+,	O
+nuclear	O
+factor	O
+-	O
+kappaB	O
+,	O
+caspase	O
+-	O
+3	O
+and	O
+p53	O
+in	O
+renal	O
+tissue	O
+.	O
+
+It	O
+was	O
+concluded	O
+that	O
+coenzyme	O
+Q10	O
+represents	O
+a	O
+potential	O
+therapeutic	O
+option	O
+to	O
+protect	O
+against	O
+acute	O
+cisplatin	O
+nephrotoxicity	B
+commonly	O
+encountered	O
+in	O
+clinical	O
+practice	O
+.	O
+
+Reversible	O
+cholestasis	B
+with	O
+bile	B
+duct	I
+injury	I
+following	O
+azathioprine	O
+therapy	O
+.	O
+
+A	O
+case	O
+report	O
+.	O
+
+A	O
+67	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+,	O
+with	O
+primary	O
+polymyositis	B
+and	O
+without	O
+previous	O
+evidence	O
+of	O
+liver	B
+disease	I
+,	O
+developed	O
+clinical	O
+and	O
+biochemical	O
+features	O
+of	O
+severe	O
+cholestasis	B
+3	O
+months	O
+after	O
+initiation	O
+of	O
+azathioprine	O
+therapy	O
+.	O
+
+Liver	O
+biopsy	O
+showed	O
+cholestasis	B
+with	O
+both	O
+cytological	O
+and	O
+architectural	O
+alterations	O
+of	O
+interlobular	O
+bile	O
+ducts	O
+.	O
+
+Azathioprine	O
+withdrawal	O
+resulted	O
+after	O
+7	O
+weeks	O
+in	O
+the	O
+resolution	O
+of	O
+clinical	O
+and	O
+biochemical	O
+abnormalities	O
+.	O
+
+It	O
+is	O
+believed	O
+that	O
+this	O
+is	O
+the	O
+first	O
+reported	O
+case	O
+of	O
+reversible	O
+azathioprine	O
+-	O
+induced	O
+cholestasis	B
+associated	O
+with	O
+histological	O
+evidence	O
+of	O
+bile	B
+duct	I
+injury	I
+.	O
+
+Dopamine	O
+is	O
+not	O
+essential	O
+for	O
+the	O
+development	O
+of	O
+methamphetamine	O
+-	O
+induced	O
+neurotoxicity	B
+.	O
+
+It	O
+is	O
+widely	O
+believed	O
+that	O
+dopamine	O
+(	O
+DA	O
+)	O
+mediates	O
+methamphetamine	O
+(	O
+METH	O
+)	O
+-	O
+induced	O
+toxicity	B
+to	O
+brain	O
+dopaminergic	O
+neurons	O
+,	O
+because	O
+drugs	O
+that	O
+interfere	O
+with	O
+DA	O
+neurotransmission	O
+decrease	O
+toxicity	B
+,	O
+whereas	O
+drugs	O
+that	O
+increase	O
+DA	O
+neurotransmission	O
+enhance	O
+toxicity	B
+.	O
+
+However	O
+,	O
+temperature	O
+effects	O
+of	O
+drugs	O
+that	O
+have	O
+been	O
+used	O
+to	O
+manipulate	O
+brain	O
+DA	O
+neurotransmission	O
+confound	O
+interpretation	O
+of	O
+the	O
+data	O
+.	O
+
+Here	O
+we	O
+show	O
+that	O
+the	O
+recently	O
+reported	O
+ability	O
+of	O
+L	O
+-	O
+dihydroxyphenylalanine	O
+to	O
+reverse	O
+the	O
+protective	O
+effect	O
+of	O
+alpha	O
+-	O
+methyl	O
+-	O
+para	O
+-	O
+tyrosine	O
+on	O
+METH	O
+-	O
+induced	O
+DA	O
+neurotoxicity	B
+is	O
+also	O
+confounded	O
+by	O
+drug	O
+effects	O
+on	O
+body	O
+temperature	O
+.	O
+
+Further	O
+,	O
+we	O
+show	O
+that	O
+mice	O
+genetically	O
+engineered	O
+to	O
+be	O
+deficient	O
+in	O
+brain	O
+DA	O
+develop	O
+METH	O
+neurotoxicity	B
+,	O
+as	O
+long	O
+as	O
+the	O
+thermic	O
+effects	O
+of	O
+METH	O
+are	O
+preserved	O
+.	O
+
+In	O
+addition	O
+,	O
+we	O
+demonstrate	O
+that	O
+mice	O
+genetically	O
+engineered	O
+to	O
+have	O
+unilateral	O
+brain	O
+DA	O
+deficits	O
+develop	O
+METH	O
+-	O
+induced	O
+dopaminergic	B
+deficits	I
+that	O
+are	O
+of	O
+comparable	O
+magnitude	O
+on	O
+both	O
+sides	O
+of	O
+the	O
+brain	O
+.	O
+
+Taken	O
+together	O
+,	O
+these	O
+findings	O
+demonstrate	O
+that	O
+DA	O
+is	O
+not	O
+essential	O
+for	O
+the	O
+development	O
+of	O
+METH	O
+-	O
+induced	O
+dopaminergic	O
+neurotoxicity	B
+and	O
+suggest	O
+that	O
+mechanisms	O
+independent	O
+of	O
+DA	O
+warrant	O
+more	O
+intense	O
+investigation	O
+.	O
+
+Swallowing	O
+-	O
+induced	O
+atrial	B
+tachyarrhythmia	I
+triggered	O
+by	O
+salbutamol	O
+:	O
+case	O
+report	O
+and	O
+review	O
+of	O
+the	O
+literature	O
+.	O
+
+CASE	O
+:	O
+A	O
+49	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+experienced	O
+chest	O
+discomfort	O
+while	O
+swallowing	O
+.	O
+
+On	O
+electrocardiogram	O
+,	O
+episodes	O
+of	O
+atrial	B
+tachyarrhythmia	I
+were	O
+recorded	O
+immediately	O
+after	O
+swallowing	O
+;	O
+24	O
+-	O
+hour	O
+Holter	O
+monitoring	O
+recorded	O
+several	O
+events	O
+.	O
+
+The	O
+arrhythmia	B
+resolved	O
+after	O
+therapy	O
+with	O
+atenolol	O
+,	O
+but	O
+recurred	O
+a	O
+year	O
+later	O
+.	O
+
+The	O
+patient	O
+noticed	O
+that	O
+before	O
+these	O
+episodes	O
+he	O
+had	O
+been	O
+using	O
+an	O
+inhalator	O
+of	O
+salbutamol	O
+.	O
+
+After	O
+stopping	O
+the	O
+beta	O
+-	O
+agonist	O
+,	O
+and	O
+after	O
+a	O
+week	O
+with	O
+the	O
+atenolol	O
+,	O
+the	O
+arrhythmia	B
+disappeared	O
+.	O
+
+DISCUSSION	O
+:	O
+Swallowing	O
+-	O
+induced	O
+atrial	B
+tachyarrhythmia	I
+(	O
+SIAT	B
+)	O
+is	O
+a	O
+rare	O
+phenomenon	O
+.	O
+
+Fewer	O
+than	O
+50	O
+cases	O
+of	O
+SIAT	B
+have	O
+been	O
+described	O
+in	O
+the	O
+literature	O
+.	O
+
+This	O
+article	O
+summarizes	O
+all	O
+the	O
+cases	O
+published	O
+,	O
+creating	O
+a	O
+comprehensive	O
+review	O
+of	O
+the	O
+current	O
+knowledge	O
+and	O
+approach	O
+to	O
+SIAT	B
+.	O
+
+It	O
+discusses	O
+demographics	O
+,	O
+clinical	O
+characteristics	O
+and	O
+types	O
+of	O
+arrhythmia	B
+,	O
+postulated	O
+mechanisms	O
+of	O
+SIAT	B
+,	O
+and	O
+different	O
+treatment	O
+possibilities	O
+such	O
+as	O
+medications	O
+,	O
+surgery	O
+,	O
+and	O
+radiofrequency	O
+catheter	O
+ablation	O
+(	O
+RFCA	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+Salbutamol	O
+is	O
+presented	O
+here	O
+as	O
+a	O
+possible	O
+trigger	O
+for	O
+SIAT	B
+.	O
+
+Although	O
+it	O
+is	O
+difficult	O
+to	O
+define	O
+causality	O
+in	O
+a	O
+case	O
+report	O
+,	O
+it	O
+is	O
+logical	O
+to	O
+think	O
+that	O
+a	O
+beta	O
+-	O
+agonist	O
+like	O
+salbutamol	O
+(	O
+known	O
+to	O
+induce	O
+tachycardia	B
+)	O
+may	O
+be	O
+the	O
+trigger	O
+of	O
+adrenergic	O
+reflexes	O
+originating	O
+in	O
+the	O
+esophagus	O
+while	O
+swallowing	O
+and	O
+that	O
+a	O
+beta	O
+-	O
+blocker	O
+such	O
+as	O
+atenolol	O
+(	O
+that	O
+blocks	O
+the	O
+adrenergic	O
+activity	O
+)	O
+may	O
+relieve	O
+it	O
+.	O
+
+The	O
+ability	O
+of	O
+insulin	O
+treatment	O
+to	O
+reverse	O
+or	O
+prevent	O
+the	O
+changes	O
+in	O
+urinary	O
+bladder	O
+function	O
+caused	O
+by	O
+streptozotocin	O
+-	O
+induced	O
+diabetes	B
+mellitus	I
+.	O
+
+1	O
+.	O
+
+The	O
+effects	O
+of	O
+insulin	O
+treatment	O
+on	O
+in	O
+vivo	O
+and	O
+in	O
+vitro	O
+urinary	O
+bladder	O
+function	O
+in	O
+streptozotocin	O
+-	O
+diabetic	B
+rats	O
+were	O
+investigated	O
+.	O
+
+2	O
+.	O
+
+Diabetes	B
+of	O
+2	O
+months	O
+duration	O
+resulted	O
+in	O
+decreases	O
+in	O
+body	O
+weight	O
+and	O
+increases	O
+in	O
+fluid	O
+consumption	O
+,	O
+urine	O
+volume	O
+,	O
+frequency	O
+of	O
+micturition	O
+,	O
+and	O
+average	O
+volume	O
+per	O
+micturition	O
+;	O
+effects	O
+which	O
+were	O
+prevented	O
+by	O
+insulin	O
+treatment	O
+.	O
+
+3	O
+.	O
+
+Insulin	O
+treatment	O
+also	O
+prevented	O
+the	O
+increases	O
+in	O
+contractile	O
+responses	O
+of	O
+bladder	O
+body	O
+strips	O
+from	O
+diabetic	B
+rats	O
+to	O
+nerve	O
+stimulation	O
+,	O
+ATP	O
+,	O
+and	O
+bethanechol	O
+.	O
+
+4	O
+.	O
+
+Diabetes	B
+of	O
+4	O
+months	O
+duration	O
+also	O
+resulted	O
+in	O
+decreases	O
+in	O
+body	O
+weight	O
+,	O
+and	O
+increases	O
+in	O
+fluid	O
+consumption	O
+,	O
+urine	O
+volume	O
+,	O
+frequency	O
+of	O
+micturition	O
+,	O
+and	O
+average	O
+volume	O
+per	O
+micturition	O
+,	O
+effects	O
+which	O
+were	O
+reversed	O
+by	O
+insulin	O
+treatment	O
+for	O
+the	O
+final	O
+2	O
+months	O
+of	O
+the	O
+study	O
+.	O
+
+5	O
+.	O
+
+Insulin	O
+treatment	O
+reversed	O
+the	O
+increases	O
+in	O
+contractile	O
+responses	O
+of	O
+bladder	O
+body	O
+strips	O
+from	O
+diabetic	B
+rats	O
+to	O
+nerve	O
+stimulation	O
+,	O
+ATP	O
+,	O
+and	O
+bethanechol	O
+.	O
+
+6	O
+.	O
+
+The	O
+data	O
+indicate	O
+that	O
+the	O
+effects	O
+of	O
+streptozotocin	O
+-	O
+induced	O
+diabetes	B
+on	O
+urinary	O
+bladder	O
+function	O
+are	O
+both	O
+prevented	O
+and	O
+reversed	O
+by	O
+insulin	O
+treatment	O
+.	O
+
+Glutamatergic	O
+neurotransmission	O
+mediated	O
+by	O
+NMDA	O
+receptors	O
+in	O
+the	O
+inferior	O
+colliculus	O
+can	O
+modulate	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+.	O
+
+The	O
+inferior	O
+colliculus	O
+(	O
+IC	O
+)	O
+is	O
+primarily	O
+involved	O
+in	O
+the	O
+processing	O
+of	O
+auditory	O
+information	O
+,	O
+but	O
+it	O
+is	O
+distinguished	O
+from	O
+other	O
+auditory	O
+nuclei	O
+in	O
+the	O
+brainstem	O
+by	O
+its	O
+connections	O
+with	O
+structures	O
+of	O
+the	O
+motor	O
+system	O
+.	O
+
+Functional	O
+evidence	O
+relating	O
+the	O
+IC	O
+to	O
+motor	O
+behavior	O
+derives	O
+from	O
+experiments	O
+showing	O
+that	O
+activation	O
+of	O
+the	O
+IC	O
+by	O
+electrical	O
+stimulation	O
+or	O
+excitatory	O
+amino	O
+acid	O
+microinjection	O
+causes	O
+freezing	O
+,	O
+escape	O
+-	O
+like	O
+behavior	O
+,	O
+and	O
+immobility	O
+.	O
+
+However	O
+,	O
+the	O
+nature	O
+of	O
+this	O
+immobility	O
+is	O
+still	O
+unclear	O
+.	O
+
+The	O
+present	O
+study	O
+examined	O
+the	O
+influence	O
+of	O
+excitatory	O
+amino	O
+acid	O
+-	O
+mediated	O
+mechanisms	O
+in	O
+the	O
+IC	O
+on	O
+the	O
+catalepsy	B
+induced	O
+by	O
+the	O
+dopamine	O
+receptor	O
+blocker	O
+haloperidol	O
+administered	O
+systemically	O
+(	O
+1	O
+or	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+in	O
+rats	O
+.	O
+
+Haloperidol	O
+-	O
+induced	O
+catalepsy	B
+was	O
+challenged	O
+with	O
+prior	O
+intracollicular	O
+microinjections	O
+of	O
+glutamate	O
+NMDA	O
+receptor	O
+antagonists	O
+,	O
+MK	O
+-	O
+801	O
+(	O
+15	O
+or	O
+30	O
+mmol	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+)	O
+and	O
+AP7	O
+(	O
+10	O
+or	O
+20	O
+nmol	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+)	O
+,	O
+or	O
+of	O
+the	O
+NMDA	O
+receptor	O
+agonist	O
+N	O
+-	O
+methyl	O
+-	O
+d	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+,	O
+20	O
+or	O
+30	O
+nmol	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+)	O
+.	O
+
+The	O
+results	O
+showed	O
+that	O
+intracollicular	O
+microinjection	O
+of	O
+MK	O
+-	O
+801	O
+and	O
+AP7	O
+previous	O
+to	O
+systemic	O
+injections	O
+of	O
+haloperidol	O
+significantly	O
+attenuated	O
+the	O
+catalepsy	B
+,	O
+as	O
+indicated	O
+by	O
+a	O
+reduced	O
+latency	O
+to	O
+step	O
+down	O
+from	O
+a	O
+horizontal	O
+bar	O
+.	O
+
+Accordingly	O
+,	O
+intracollicular	O
+microinjection	O
+of	O
+NMDA	O
+increased	O
+the	O
+latency	O
+to	O
+step	O
+down	O
+the	O
+bar	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+glutamate	O
+-	O
+mediated	O
+mechanisms	O
+in	O
+the	O
+neural	O
+circuits	O
+at	O
+the	O
+IC	O
+level	O
+influence	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+and	O
+participate	O
+in	O
+the	O
+regulation	O
+of	O
+motor	O
+activity	O
+.	O
+
+Severe	O
+congestive	B
+heart	I
+failure	I
+patient	O
+on	O
+amiodarone	O
+presenting	O
+with	O
+myxedemic	B
+coma	I
+:	O
+a	O
+case	O
+report	O
+.	O
+
+This	O
+is	O
+a	O
+case	O
+report	O
+of	O
+myxedema	B
+coma	I
+secondary	O
+to	O
+amiodarone	O
+-	O
+induced	O
+hypothyroidism	B
+in	O
+a	O
+patient	O
+with	O
+severe	O
+congestive	B
+heart	I
+failure	I
+(	O
+CHF	B
+)	O
+.	O
+
+To	O
+our	O
+knowledge	O
+and	O
+after	O
+reviewing	O
+the	O
+literature	O
+there	O
+is	O
+one	O
+case	O
+report	O
+of	O
+myxedema	B
+coma	I
+during	O
+long	O
+term	O
+amiodarone	O
+therapy	O
+.	O
+
+Myxedema	B
+coma	I
+is	O
+a	O
+life	O
+threatening	O
+condition	O
+that	O
+carries	O
+a	O
+mortality	O
+reaching	O
+as	O
+high	O
+as	O
+20	O
+%	O
+with	O
+treatment	O
+.	O
+
+The	O
+condition	O
+is	O
+treated	O
+with	O
+intravenous	O
+thyroxine	O
+(	O
+T4	O
+)	O
+or	O
+intravenous	O
+tri	O
+-	O
+iodo	O
+-	O
+thyronine	O
+(	O
+T3	O
+)	O
+.	O
+
+Patients	O
+with	O
+CHF	B
+on	O
+amiodarone	O
+may	O
+suffer	O
+serious	O
+morbidity	O
+and	O
+mortality	O
+from	O
+hypothyroidism	B
+,	O
+and	O
+thus	O
+may	O
+deserve	O
+closer	O
+follow	O
+up	O
+for	O
+thyroid	O
+stimulating	O
+hormone	O
+(	O
+TSH	O
+)	O
+levels	O
+.	O
+
+This	O
+case	O
+report	O
+carries	O
+an	O
+important	O
+clinical	O
+application	O
+given	O
+the	O
+frequent	O
+usage	O
+of	O
+amiodarone	O
+among	O
+CHF	B
+patients	O
+.	O
+
+The	O
+myriad	O
+clinical	O
+presentation	O
+of	O
+myxedema	B
+coma	I
+and	O
+its	O
+serious	O
+morbidity	O
+and	O
+mortality	O
+stresses	O
+the	O
+need	O
+to	O
+suspect	O
+this	O
+clinical	O
+syndrome	O
+among	O
+CHF	B
+patients	O
+presenting	O
+with	O
+hypotension	B
+,	O
+weakness	B
+or	O
+other	O
+unexplained	O
+symptoms	O
+.	O
+
+Effects	O
+of	O
+active	O
+constituents	O
+of	O
+Crocus	O
+sativus	O
+L	O
+.	O
+,	O
+crocin	O
+on	O
+streptozocin	O
+-	O
+induced	O
+model	O
+of	O
+sporadic	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+in	O
+male	O
+rats	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+involvement	O
+of	O
+water	O
+-	O
+soluble	O
+carotenoids	O
+,	O
+crocins	O
+,	O
+as	O
+the	O
+main	O
+and	O
+active	O
+components	O
+of	O
+Crocus	O
+sativus	O
+L	O
+.	O
+extract	O
+in	O
+learning	O
+and	O
+memory	O
+processes	O
+has	O
+been	O
+proposed	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+the	O
+effect	O
+of	O
+crocins	O
+on	O
+sporadic	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+induced	O
+by	O
+intracerebroventricular	O
+(	O
+icv	O
+)	O
+streptozocin	O
+(	O
+STZ	O
+)	O
+in	O
+male	O
+rats	O
+was	O
+investigated	O
+.	O
+
+METHODS	O
+:	O
+Male	O
+adult	O
+Wistar	O
+rats	O
+(	O
+n	O
+=	O
+90	O
+and	O
+260	O
+-	O
+290	O
+g	O
+)	O
+were	O
+divided	O
+into	O
+1	O
+,	O
+control	O
+;	O
+2	O
+and	O
+3	O
+,	O
+crocins	O
+(	O
+15	O
+and	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+;	O
+4	O
+,	O
+STZ	O
+;	O
+5	O
+and	O
+6	O
+,	O
+STZ	O
++	O
+crocins	O
+(	O
+15	O
+and	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+groups	O
+.	O
+
+In	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+groups	O
+,	O
+rats	O
+were	O
+injected	O
+with	O
+STZ	O
+-	O
+icv	O
+bilaterally	O
+(	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+in	O
+first	O
+day	O
+and	O
+3	O
+days	O
+later	O
+,	O
+a	O
+similar	O
+STZ	O
+-	O
+icv	O
+application	O
+was	O
+repeated	O
+.	O
+
+In	O
+STZ	O
++	O
+crocin	O
+animal	O
+groups	O
+,	O
+crocin	O
+was	O
+applied	O
+in	O
+doses	O
+of	O
+15	O
+and	O
+30	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+,	O
+one	O
+day	O
+pre	O
+-	O
+surgery	O
+and	O
+continued	O
+for	O
+three	O
+weeks	O
+.	O
+
+Prescription	O
+of	O
+crocin	O
+in	O
+each	O
+dose	O
+was	O
+repeated	O
+once	O
+for	O
+two	O
+days	O
+.	O
+
+However	O
+,	O
+the	O
+learning	O
+and	O
+memory	O
+performance	O
+was	O
+assessed	O
+using	O
+passive	O
+avoidance	O
+paradigm	O
+,	O
+and	O
+for	O
+spatial	O
+cognition	O
+evaluation	O
+,	O
+Y	O
+-	O
+maze	O
+task	O
+was	O
+used	O
+.	O
+
+RESULTS	O
+:	O
+It	O
+was	O
+found	O
+out	O
+that	O
+crocin	O
+(	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+-	O
+treated	O
+STZ	O
+-	O
+injected	O
+rats	O
+show	O
+higher	O
+correct	O
+choices	O
+and	O
+lower	O
+errors	O
+in	O
+Y	O
+-	O
+maze	O
+than	O
+vehicle	O
+-	O
+treated	O
+STZ	O
+-	O
+injected	O
+rats	O
+.	O
+
+In	O
+addition	O
+,	O
+crocin	O
+in	O
+the	O
+mentioned	O
+dose	O
+could	O
+significantly	O
+attenuated	O
+learning	B
+and	I
+memory	I
+impairment	I
+in	O
+treated	O
+STZ	O
+-	O
+injected	O
+group	O
+in	O
+passive	O
+avoidance	O
+test	O
+.	O
+
+CONCLUSION	O
+:	O
+Therefore	O
+,	O
+these	O
+results	O
+demonstrate	O
+the	O
+effectiveness	O
+of	O
+crocin	O
+(	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+in	O
+antagonizing	O
+the	O
+cognitive	B
+deficits	I
+caused	O
+by	O
+STZ	O
+-	O
+icv	O
+in	O
+rats	O
+and	O
+its	O
+potential	O
+in	O
+the	O
+treatment	O
+of	O
+neurodegenerative	B
+diseases	I
+such	O
+as	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+.	O
+
+Serotonin	O
+6	O
+receptor	O
+gene	O
+is	O
+associated	O
+with	O
+methamphetamine	O
+-	O
+induced	O
+psychosis	B
+in	O
+a	O
+Japanese	O
+population	O
+.	O
+
+BACKGROUND	O
+:	O
+Altered	O
+serotonergic	O
+neural	O
+transmission	O
+is	O
+hypothesized	O
+to	O
+be	O
+a	O
+susceptibility	O
+factor	O
+for	O
+psychotic	B
+disorders	I
+such	O
+as	O
+schizophrenia	B
+.	O
+
+The	O
+serotonin	O
+6	O
+(	O
+5	O
+-	O
+HT6	O
+)	O
+receptor	O
+is	O
+therapeutically	O
+targeted	O
+by	O
+several	O
+second	O
+generation	O
+antipsychotics	O
+,	O
+such	O
+as	O
+clozapine	O
+and	O
+olanzapine	O
+,	O
+and	O
+d	O
+-	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B
+in	O
+rats	O
+is	O
+corrected	O
+with	O
+the	O
+use	O
+of	O
+a	O
+selective	O
+5	O
+-	O
+HT6	O
+receptor	O
+antagonist	O
+.	O
+
+In	O
+addition	O
+,	O
+the	O
+disrupted	O
+prepulse	O
+inhibition	O
+induced	O
+by	O
+d	O
+-	O
+amphetamine	O
+or	O
+phencyclidine	O
+was	O
+restored	O
+by	O
+5	O
+-	O
+HT6	O
+receptor	O
+antagonist	O
+in	O
+an	O
+animal	O
+study	O
+using	O
+rats	O
+.	O
+
+These	O
+animal	O
+models	O
+were	O
+considered	O
+to	O
+reflect	O
+the	O
+positive	O
+symptoms	O
+of	O
+schizophrenia	B
+,	O
+and	O
+the	O
+above	O
+evidence	O
+suggests	O
+that	O
+altered	O
+5	O
+-	O
+HT6	O
+receptors	O
+are	O
+involved	O
+in	O
+the	O
+pathophysiology	O
+of	O
+psychotic	B
+disorders	I
+.	O
+
+The	O
+symptoms	O
+of	O
+methamphetamine	O
+(	O
+METH	O
+)	O
+-	O
+induced	O
+psychosis	B
+are	O
+similar	O
+to	O
+those	O
+of	O
+paranoid	B
+type	I
+schizophrenia	I
+.	O
+
+Therefore	O
+,	O
+we	O
+conducted	O
+an	O
+analysis	O
+of	O
+the	O
+association	O
+of	O
+the	O
+5	O
+-	O
+HT6	O
+gene	O
+(	O
+HTR6	O
+)	O
+with	O
+METH	O
+-	O
+induced	O
+psychosis	B
+.	O
+
+METHOD	O
+:	O
+Using	O
+five	O
+tagging	O
+SNPs	O
+(	O
+rs6693503	O
+,	O
+rs1805054	O
+,	O
+rs4912138	O
+,	O
+rs3790757	O
+and	O
+rs9659997	O
+)	O
+,	O
+we	O
+conducted	O
+a	O
+genetic	O
+association	O
+analysis	O
+of	O
+case	O
+-	O
+control	O
+samples	O
+(	O
+197	O
+METH	O
+-	O
+induced	O
+psychosis	B
+patients	O
+and	O
+337	O
+controls	O
+)	O
+in	O
+the	O
+Japanese	O
+population	O
+.	O
+
+The	O
+age	O
+and	O
+sex	O
+of	O
+the	O
+control	O
+subjects	O
+did	O
+not	O
+differ	O
+from	O
+those	O
+of	O
+the	O
+methamphetamine	O
+dependence	O
+patients	O
+.	O
+
+RESULTS	O
+:	O
+rs6693503	O
+was	O
+associated	O
+with	O
+METH	O
+-	O
+induced	O
+psychosis	B
+patients	O
+in	O
+the	O
+allele	O
+/	O
+genotype	O
+-	O
+wise	O
+analysis	O
+.	O
+
+Moreover	O
+,	O
+this	O
+association	O
+remained	O
+significant	O
+after	O
+Bonferroni	O
+correction	O
+.	O
+
+In	O
+the	O
+haplotype	O
+-	O
+wise	O
+analysis	O
+,	O
+we	O
+detected	O
+an	O
+association	O
+between	O
+two	O
+markers	O
+(	O
+rs6693503	O
+and	O
+rs1805054	O
+)	O
+and	O
+three	O
+markers	O
+(	O
+rs6693503	O
+,	O
+rs1805054	O
+and	O
+rs4912138	O
+)	O
+in	O
+HTR6	O
+and	O
+METH	O
+-	O
+induced	O
+psychosis	B
+patients	O
+,	O
+respectively	O
+.	O
+
+CONCLUSION	O
+:	O
+HTR6	O
+may	O
+play	O
+an	O
+important	O
+role	O
+in	O
+the	O
+pathophysiology	O
+of	O
+METH	O
+-	O
+induced	O
+psychosis	B
+in	O
+the	O
+Japanese	O
+population	O
+.	O
+
+Neural	O
+correlates	O
+of	O
+S	O
+-	O
+ketamine	O
+induced	O
+psychosis	B
+during	O
+overt	O
+continuous	O
+verbal	O
+fluency	O
+.	O
+
+The	O
+glutamatergic	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+receptor	O
+has	O
+been	O
+implicated	O
+in	O
+the	O
+pathophysiology	O
+of	O
+schizophrenia	B
+.	O
+
+Administered	O
+to	O
+healthy	O
+volunteers	O
+,	O
+a	O
+subanesthetic	O
+dose	O
+of	O
+the	O
+non	O
+-	O
+competitive	O
+NMDA	O
+receptor	O
+antagonist	O
+ketamine	O
+leads	O
+to	O
+psychopathological	O
+symptoms	O
+similar	O
+to	O
+those	O
+observed	O
+in	O
+schizophrenia	B
+.	O
+
+In	O
+patients	O
+with	O
+schizophrenia	B
+,	O
+ketamine	O
+exacerbates	O
+the	O
+core	O
+symptoms	O
+of	O
+illness	O
+,	O
+supporting	O
+the	O
+hypothesis	O
+of	O
+a	O
+glutamatergic	B
+dysfunction	I
+.	O
+
+In	O
+a	O
+counterbalanced	O
+,	O
+placebo	O
+-	O
+controlled	O
+,	O
+double	O
+-	O
+blind	O
+study	O
+design	O
+,	O
+healthy	O
+subjects	O
+were	O
+administered	O
+a	O
+continuous	O
+subanesthetic	O
+S	O
+-	O
+ketamine	O
+infusion	O
+while	O
+differences	O
+in	O
+BOLD	O
+responses	O
+measured	O
+with	O
+fMRI	O
+were	O
+detected	O
+.	O
+
+During	O
+the	O
+scanning	O
+period	O
+,	O
+subjects	O
+performed	O
+continuous	O
+overt	O
+verbal	O
+fluency	O
+tasks	O
+(	O
+phonological	O
+,	O
+lexical	O
+and	O
+semantic	O
+)	O
+.	O
+
+Ketamine	O
+-	O
+induced	O
+psychopathological	O
+symptoms	O
+were	O
+assessed	O
+with	O
+the	O
+Positive	O
+and	O
+Negative	O
+Syndrome	O
+Scale	O
+(	O
+PANSS	O
+)	O
+.	O
+
+Ketamine	O
+elicited	O
+psychosis	B
+like	O
+psychopathology	O
+.	O
+
+Post	O
+-	O
+hoc	O
+t	O
+-	O
+tests	O
+revealed	O
+significant	O
+differences	O
+between	O
+placebo	O
+and	O
+ketamine	O
+for	O
+the	O
+amounts	O
+of	O
+words	O
+generated	O
+during	O
+lexical	O
+and	O
+semantic	O
+verbal	O
+fluency	O
+,	O
+while	O
+the	O
+phonological	O
+domain	O
+remained	O
+unaffected	O
+.	O
+
+Ketamine	O
+led	O
+to	O
+enhanced	O
+cortical	O
+activations	O
+in	O
+supramarginal	O
+and	O
+frontal	O
+brain	O
+regions	O
+for	O
+phonological	O
+and	O
+lexical	O
+verbal	O
+fluency	O
+,	O
+but	O
+not	O
+for	O
+semantic	O
+verbal	O
+fluency	O
+.	O
+
+Ketamine	O
+induces	O
+activation	O
+changes	O
+in	O
+healthy	O
+subjects	O
+similar	O
+to	O
+those	O
+observed	O
+in	O
+patients	O
+with	O
+schizophrenia	B
+,	O
+particularly	O
+in	O
+frontal	O
+and	O
+temporal	O
+brain	O
+regions	O
+.	O
+
+Our	O
+results	O
+provide	O
+further	O
+support	O
+for	O
+the	O
+hypothesis	O
+of	O
+an	O
+NMDA	O
+receptor	O
+dysfunction	O
+in	O
+the	O
+pathophysiology	O
+of	O
+schizophrenia	B
+.	O
+
+Long	O
+-	O
+term	O
+prognosis	O
+for	O
+transplant	O
+-	O
+free	O
+survivors	O
+of	O
+paracetamol	O
+-	O
+induced	O
+acute	B
+liver	I
+failure	I
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+prognosis	O
+for	O
+transplant	O
+-	O
+free	O
+survivors	O
+of	O
+paracetamol	O
+-	O
+induced	O
+acute	B
+liver	I
+failure	I
+remains	O
+unknown	O
+.	O
+
+AIM	O
+:	O
+To	O
+examine	O
+whether	O
+paracetamol	O
+-	O
+induced	O
+acute	B
+liver	I
+failure	I
+increases	O
+long	O
+-	O
+term	O
+mortality	O
+.	O
+
+METHODS	O
+:	O
+We	O
+followed	O
+up	O
+all	O
+transplant	O
+-	O
+free	O
+survivors	O
+of	O
+paracetamol	O
+-	O
+induced	O
+acute	B
+liver	I
+injury	I
+,	O
+hospitalized	O
+in	O
+a	O
+Danish	O
+national	O
+referral	O
+centre	O
+during	O
+1984	O
+-	O
+2004	O
+.	O
+
+We	O
+compared	O
+age	O
+-	O
+specific	O
+mortality	O
+rates	O
+from	O
+1	O
+year	O
+post	O
+-	O
+discharge	O
+through	O
+2008	O
+between	O
+those	O
+in	O
+whom	O
+the	O
+liver	B
+injury	I
+led	O
+to	O
+an	O
+acute	B
+liver	I
+failure	I
+and	O
+those	O
+in	O
+whom	O
+it	O
+did	O
+not	O
+.	O
+
+RESULTS	O
+:	O
+We	O
+included	O
+641	O
+patients	O
+.	O
+
+On	O
+average	O
+,	O
+age	O
+-	O
+specific	O
+mortality	O
+rates	O
+were	O
+slightly	O
+higher	O
+for	O
+the	O
+101	O
+patients	O
+whose	O
+paracetamol	O
+-	O
+induced	O
+liver	B
+injury	I
+had	O
+caused	O
+an	O
+acute	B
+liver	I
+failure	I
+(	O
+adjusted	O
+mortality	O
+rate	O
+ratio	O
+=	O
+1	O
+.	O
+70	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+02	O
+-	O
+2	O
+.	O
+85	O
+)	O
+,	O
+but	O
+the	O
+association	O
+was	O
+age	O
+-	O
+dependent	O
+,	O
+and	O
+no	O
+survivors	O
+of	O
+acute	B
+liver	I
+failure	I
+died	O
+of	O
+liver	B
+disease	I
+,	O
+whereas	O
+suicides	O
+were	O
+frequent	O
+in	O
+both	O
+groups	O
+.	O
+
+These	O
+observations	O
+speak	O
+against	O
+long	O
+-	O
+term	O
+effects	O
+of	O
+acute	B
+liver	I
+failure	I
+.	O
+
+More	O
+likely	O
+,	O
+the	O
+elevated	O
+mortality	O
+rate	O
+ratio	O
+resulted	O
+from	O
+incomplete	O
+adjustment	O
+for	O
+the	O
+greater	O
+prevalence	O
+of	O
+substance	B
+abuse	I
+among	O
+survivors	O
+of	O
+acute	B
+liver	I
+failure	I
+.	O
+
+CONCLUSIONS	O
+:	O
+Paracetamol	O
+-	O
+induced	O
+acute	B
+liver	I
+failure	I
+did	O
+not	O
+affect	O
+long	O
+-	O
+term	O
+mortality	O
+.	O
+
+Clinical	O
+follow	O
+-	O
+up	O
+may	O
+be	O
+justified	O
+by	O
+the	O
+cause	O
+of	O
+the	O
+liver	B
+failure	I
+,	O
+but	O
+not	O
+by	O
+the	O
+liver	B
+failure	I
+itself	O
+.	O
+
+In	O
+vivo	O
+characterization	O
+of	O
+a	O
+dual	O
+adenosine	O
+A2A	O
+/	O
+A1	O
+receptor	O
+antagonist	O
+in	O
+animal	O
+models	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+The	O
+in	O
+vivo	O
+characterization	O
+of	O
+a	O
+dual	O
+adenosine	O
+A	O
+(	O
+2A	O
+)	O
+/	O
+A	O
+(	O
+1	O
+)	O
+receptor	O
+antagonist	O
+in	O
+several	O
+animal	O
+models	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+is	O
+described	O
+.	O
+
+Discovery	O
+and	O
+scale	O
+-	O
+up	O
+syntheses	O
+of	O
+compound	O
+1	O
+are	O
+described	O
+in	O
+detail	O
+,	O
+highlighting	O
+optimization	O
+steps	O
+that	O
+increased	O
+the	O
+overall	O
+yield	O
+of	O
+1	O
+from	O
+10	O
+.	O
+0	O
+%	O
+to	O
+30	O
+.	O
+5	O
+%	O
+.	O
+
+Compound	O
+1	O
+is	O
+a	O
+potent	O
+A	O
+(	O
+2A	O
+)	O
+/	O
+A	O
+(	O
+1	O
+)	O
+receptor	O
+antagonist	O
+in	O
+vitro	O
+(	O
+A	O
+(	O
+2A	O
+)	O
+K	O
+(	O
+i	O
+)	O
+=	O
+4	O
+.	O
+1	O
+nM	O
+;	O
+A	O
+(	O
+1	O
+)	O
+K	O
+(	O
+i	O
+)	O
+=	O
+17	O
+.	O
+0	O
+nM	O
+)	O
+that	O
+has	O
+excellent	O
+activity	O
+,	O
+after	O
+oral	O
+administration	O
+,	O
+across	O
+a	O
+number	O
+of	O
+animal	O
+models	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+including	O
+mouse	O
+and	O
+rat	O
+models	O
+of	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+,	O
+mouse	O
+model	O
+of	O
+reserpine	O
+-	O
+induced	O
+akinesia	B
+,	O
+rat	O
+6	O
+-	O
+hydroxydopamine	O
+(	O
+6	O
+-	O
+OHDA	O
+)	O
+lesion	O
+model	O
+of	O
+drug	O
+-	O
+induced	O
+rotation	O
+,	O
+and	O
+MPTP	O
+-	O
+treated	O
+non	O
+-	O
+human	O
+primate	O
+model	O
+.	O
+
+Effects	O
+of	O
+the	O
+hippocampal	O
+deep	O
+brain	O
+stimulation	O
+on	O
+cortical	O
+epileptic	B
+discharges	O
+in	O
+penicillin	O
+-	O
+induced	O
+epilepsy	B
+model	O
+in	O
+rats	O
+.	O
+
+AIM	O
+:	O
+Experimental	O
+and	O
+clinical	O
+studies	O
+have	O
+revealed	O
+that	O
+hippocampal	O
+DBS	O
+can	O
+control	O
+epileptic	B
+activity	O
+,	O
+but	O
+the	O
+mechanism	O
+of	O
+action	O
+is	O
+obscure	O
+and	O
+optimal	O
+stimulation	O
+parameters	O
+are	O
+not	O
+clearly	O
+defined	O
+.	O
+
+The	O
+aim	O
+was	O
+to	O
+evaluate	O
+the	O
+effects	O
+of	O
+high	O
+frequency	O
+hippocampal	O
+stimulation	O
+on	O
+cortical	O
+epileptic	B
+activity	O
+in	O
+penicillin	O
+-	O
+induced	O
+epilepsy	B
+model	O
+.	O
+
+MATERIAL	O
+AND	O
+METHODS	O
+:	O
+Twenty	O
+-	O
+five	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+were	O
+implanted	O
+DBS	O
+electrodes	O
+.	O
+
+In	O
+group	O
+-	O
+1	O
+(	O
+n	O
+=	O
+10	O
+)	O
+hippocampal	O
+DBS	O
+was	O
+off	O
+and	O
+in	O
+the	O
+group	O
+-	O
+2	O
+(	O
+n	O
+=	O
+10	O
+)	O
+hippocampal	O
+DBS	O
+was	O
+on	O
+(	O
+185	O
+Hz	O
+,	O
+0	O
+.	O
+5V	O
+,	O
+1V	O
+,	O
+2V	O
+,	O
+and	O
+5V	O
+for	O
+60	O
+sec	O
+)	O
+following	O
+penicillin	O
+G	O
+injection	O
+intracortically	O
+.	O
+
+In	O
+the	O
+control	O
+group	O
+hippocampal	O
+DBS	O
+was	O
+on	O
+following	O
+8	O
+l	O
+saline	O
+injection	O
+intracortically	O
+.	O
+
+EEG	O
+recordings	O
+were	O
+obtained	O
+before	O
+and	O
+15	O
+minutes	O
+following	O
+penicillin	O
+-	O
+G	O
+injection	O
+,	O
+and	O
+at	O
+10th	O
+minutes	O
+following	O
+each	O
+stimulus	O
+for	O
+analysis	O
+in	O
+terms	O
+of	O
+frequency	O
+,	O
+amplitude	O
+,	O
+and	O
+power	O
+spectrum	O
+.	O
+
+RESULTS	O
+:	O
+High	O
+frequency	O
+hippocampal	O
+DBS	O
+suppressed	O
+the	O
+acute	O
+penicillin	O
+-	O
+induced	O
+cortical	O
+epileptic	B
+activity	O
+independent	O
+from	O
+stimulus	O
+intensity	O
+.	O
+
+In	O
+the	O
+control	O
+group	O
+,	O
+hippocampal	O
+stimulation	O
+alone	O
+lead	O
+only	O
+to	O
+diffuse	O
+slowing	O
+of	O
+cerebral	O
+bioelectrical	O
+activity	O
+at	O
+5V	O
+stimulation	O
+.	O
+
+CONCLUSION	O
+:	O
+Our	O
+results	O
+revealed	O
+that	O
+continuous	O
+high	O
+frequency	O
+stimulation	O
+of	O
+the	O
+hippocampus	O
+suppressed	O
+acute	O
+cortical	O
+epileptic	B
+activity	O
+effectively	O
+without	O
+causing	O
+secondary	O
+epileptic	B
+discharges	O
+.	O
+
+These	O
+results	O
+are	O
+important	O
+in	O
+terms	O
+of	O
+defining	O
+the	O
+optimal	O
+parameters	O
+of	O
+hippocampal	O
+DBS	O
+in	O
+patients	O
+with	O
+epilepsy	B
+.	O
+
+CCNU	O
+(	O
+lomustine	O
+)	O
+toxicity	B
+in	O
+dogs	O
+:	O
+a	O
+retrospective	O
+study	O
+(	O
+2002	O
+-	O
+07	O
+)	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+describe	O
+the	O
+incidence	O
+of	O
+haematological	B
+,	I
+renal	I
+,	I
+hepatic	I
+and	I
+gastrointestinal	I
+toxicities	I
+in	O
+tumour	O
+-	O
+bearing	O
+dogs	O
+receiving	O
+1	O
+-	O
+(	O
+2	O
+-	O
+chloroethyl	O
+)	O
+-	O
+3	O
+-	O
+cyclohexyl	O
+-	O
+1	O
+-	O
+nitrosourea	O
+(	O
+CCNU	O
+)	O
+.	O
+
+DESIGN	O
+:	O
+The	O
+medical	O
+records	O
+of	O
+206	O
+dogs	O
+that	O
+were	O
+treated	O
+with	O
+CCNU	O
+at	O
+the	O
+Melbourne	O
+Veterinary	O
+Specialist	O
+Centre	O
+between	O
+February	O
+2002	O
+and	O
+December	O
+2007	O
+were	O
+retrospectively	O
+evaluated	O
+.	O
+
+RESULTS	O
+:	O
+Of	O
+the	O
+206	O
+dogs	O
+treated	O
+with	O
+CCNU	O
+,	O
+185	O
+met	O
+the	O
+inclusion	O
+criteria	O
+for	O
+at	O
+least	O
+one	O
+class	O
+of	O
+toxicity	B
+.	O
+
+CCNU	O
+was	O
+used	O
+most	O
+commonly	O
+in	O
+the	O
+treatment	O
+of	O
+lymphoma	B
+,	O
+mast	B
+cell	I
+tumour	I
+,	O
+brain	B
+tumour	I
+,	O
+histiocytic	B
+tumours	I
+and	O
+epitheliotropic	B
+lymphoma	I
+.	O
+
+Throughout	O
+treatment	O
+,	O
+56	O
+.	O
+9	O
+%	O
+of	O
+dogs	O
+experienced	O
+neutropenia	B
+,	O
+34	O
+.	O
+2	O
+%	O
+experienced	O
+anaemia	B
+and	O
+14	O
+.	O
+2	O
+%	O
+experienced	O
+thrombocytopenia	B
+.	O
+
+Gastrointestinal	B
+toxicosis	I
+was	O
+detected	O
+in	O
+37	O
+.	O
+8	O
+%	O
+of	O
+dogs	O
+,	O
+the	O
+most	O
+common	O
+sign	O
+of	O
+which	O
+was	O
+vomiting	B
+(	O
+24	O
+.	O
+3	O
+%	O
+)	O
+.	O
+
+Potential	O
+renal	O
+toxicity	B
+and	O
+elevated	O
+alanine	O
+transaminase	O
+(	O
+ALT	O
+)	O
+concentration	O
+were	O
+reported	O
+in	O
+12	O
+.	O
+2	O
+%	O
+and	O
+48	O
+.	O
+8	O
+%	O
+of	O
+dogs	O
+,	O
+respectively	O
+.	O
+
+The	O
+incidence	O
+of	O
+hepatic	B
+failure	I
+was	O
+1	O
+.	O
+2	O
+%	O
+.	O
+
+CONCLUSIONS	O
+:	O
+CCNU	O
+-	O
+associated	O
+toxicity	B
+in	O
+dogs	O
+is	O
+common	O
+,	O
+but	O
+is	O
+usually	O
+not	O
+life	O
+threatening	O
+.	O
+
+Central	O
+vein	B
+thrombosis	I
+and	O
+topical	O
+dipivalyl	O
+epinephrine	O
+.	O
+
+A	O
+report	O
+is	O
+given	O
+on	O
+an	O
+83	O
+-	O
+year	O
+-	O
+old	O
+female	O
+who	O
+acquired	O
+central	O
+vein	B
+thrombosis	I
+in	O
+her	O
+seeing	O
+eye	O
+one	O
+day	O
+after	O
+having	O
+started	O
+topical	O
+medication	O
+with	O
+dipivalyl	O
+epinephrine	O
+for	O
+advanced	O
+glaucoma	B
+discovered	O
+in	O
+the	O
+other	O
+eye	O
+.	O
+
+From	O
+present	O
+knowledge	O
+about	O
+the	O
+effects	O
+of	O
+adrenergic	O
+eye	O
+drops	O
+on	O
+ocular	O
+blood	O
+circulation	O
+,	O
+it	O
+is	O
+difficult	O
+to	O
+suggest	O
+an	O
+association	O
+between	O
+the	O
+two	O
+events	O
+,	O
+which	O
+may	O
+be	O
+coincidental	O
+only	O
+.	O
+
+Benzylacyclouridine	O
+reverses	O
+azidothymidine	O
+-	O
+induced	O
+marrow	B
+suppression	I
+without	O
+impairment	O
+of	O
+anti	O
+-	O
+human	O
+immunodeficiency	B
+virus	O
+activity	O
+.	O
+
+Increased	O
+extracellular	O
+concentrations	O
+of	O
+uridine	O
+(	O
+Urd	O
+)	O
+have	O
+been	O
+reported	O
+to	O
+reduce	O
+,	O
+in	O
+vitro	O
+,	O
+azidothymidine	O
+(	O
+AZT	O
+)	O
+-	O
+induced	O
+inhibition	O
+of	O
+human	O
+granulocyte	O
+-	O
+macrophage	O
+progenitor	O
+cells	O
+without	O
+impairment	O
+of	O
+its	O
+antihuman	O
+immunodeficiency	B
+virus	O
+(	O
+HIV	O
+)	O
+activity	O
+.	O
+
+Because	O
+of	O
+the	O
+clinical	O
+toxicities	B
+associated	O
+with	O
+chronic	O
+Urd	O
+administration	O
+,	O
+the	O
+ability	O
+of	O
+benzylacyclouridine	O
+(	O
+BAU	O
+)	O
+to	O
+effect	O
+,	O
+in	O
+vivo	O
+,	O
+AZT	O
+-	O
+induced	O
+anemia	B
+and	O
+leukopenia	B
+was	O
+assessed	O
+.	O
+
+This	O
+agent	O
+inhibits	O
+Urd	O
+catabolism	O
+and	O
+,	O
+in	O
+vivo	O
+,	O
+increases	O
+the	O
+plasma	O
+concentration	O
+of	O
+Urd	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+,	O
+without	O
+Urd	O
+-	O
+related	O
+toxicity	B
+.	O
+
+In	O
+mice	O
+rendered	O
+anemic	B
+and	O
+leukopenic	B
+by	O
+the	O
+administration	O
+of	O
+AZT	O
+for	O
+28	O
+days	O
+in	O
+drinking	O
+water	O
+(	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+mL	O
+)	O
+,	O
+the	O
+continued	O
+administration	O
+of	O
+AZT	O
+plus	O
+daily	O
+BAU	O
+(	O
+300	O
+mg	O
+/	O
+kg	O
+,	O
+orally	O
+)	O
+partially	O
+reversed	O
+AZT	O
+-	O
+induced	O
+anemia	B
+and	O
+leukopenia	B
+(	O
+P	O
+less	O
+than	O
+.	O
+05	O
+)	O
+,	O
+increased	O
+peripheral	O
+reticulocytes	O
+(	O
+to	O
+4	O
+.	O
+9	O
+%	O
+,	O
+P	O
+less	O
+than	O
+.	O
+01	O
+)	O
+,	O
+increased	O
+cellularity	O
+in	O
+the	O
+marrow	O
+,	O
+and	O
+improved	O
+megaloblastosis	B
+.	O
+
+When	O
+coadministered	O
+with	O
+AZT	O
+from	O
+the	O
+onset	O
+of	O
+drug	O
+administration	O
+,	O
+BAU	O
+reduced	O
+AZT	O
+-	O
+induced	O
+marrow	B
+toxicity	I
+.	O
+
+In	O
+vitro	O
+,	O
+at	O
+a	O
+concentration	O
+of	O
+100	O
+mumol	O
+/	O
+L	O
+,	O
+BAU	O
+possesses	O
+minimal	O
+anti	O
+-	O
+HIV	O
+activity	O
+and	O
+has	O
+no	O
+effect	O
+on	O
+the	O
+ability	O
+of	O
+AZT	O
+to	O
+reverse	O
+the	O
+HIV	O
+-	O
+induced	O
+cytopathic	O
+effect	O
+in	O
+MT4	O
+cells	O
+.	O
+
+The	O
+clinical	O
+and	O
+biochemical	O
+implications	O
+of	O
+these	O
+findings	O
+are	O
+discussed	O
+.	O
+
+Lethal	O
+anuria	B
+complicating	O
+high	O
+dose	O
+ifosfamide	O
+chemotherapy	O
+in	O
+a	O
+breast	B
+cancer	I
+patient	O
+with	O
+an	O
+impaired	B
+renal	I
+function	I
+.	O
+
+A	O
+sixty	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+advanced	O
+breast	B
+cancer	I
+,	O
+previously	O
+treated	O
+with	O
+cisplatin	O
+,	O
+developed	O
+an	O
+irreversible	O
+lethal	O
+renal	B
+failure	I
+with	O
+anuria	B
+,	O
+the	O
+day	O
+after	O
+5	O
+g	O
+/	O
+m2	O
+bolus	O
+ifosfamide	O
+.	O
+
+Postrenal	B
+failure	I
+was	O
+excluded	O
+by	O
+echography	O
+.	O
+
+A	O
+prerenal	O
+component	O
+could	O
+have	O
+contributed	O
+to	O
+renal	B
+failure	I
+because	O
+of	O
+a	O
+transient	O
+hypotension	B
+,	O
+due	O
+to	O
+an	O
+increasing	O
+ascitis	O
+,	O
+occurring	O
+just	O
+before	O
+anuria	B
+.	O
+
+However	O
+,	O
+correction	O
+of	O
+the	O
+hemodynamic	O
+parameters	O
+did	O
+not	O
+improve	O
+renal	O
+function	O
+.	O
+
+Ifosfamide	O
+is	O
+a	O
+known	O
+nephrotoxic	B
+drug	O
+with	O
+demonstrated	O
+tubulopathies	B
+.	O
+
+We	O
+strongly	O
+suspect	O
+that	O
+this	O
+lethal	O
+anuria	B
+was	O
+mainly	O
+due	O
+to	O
+ifosfamide	O
+,	O
+occurring	O
+in	O
+a	O
+patient	O
+having	O
+received	O
+previous	O
+cisplatin	O
+chemotherapy	O
+and	O
+with	O
+poor	O
+kidney	O
+perfusion	O
+due	O
+to	O
+transient	O
+hypotension	B
+.	O
+
+We	O
+recommend	O
+careful	O
+use	O
+of	O
+ifosfamide	O
+in	O
+patients	O
+pretreated	O
+with	O
+nephrotoxic	B
+chemotherapy	O
+and	O
+inadequate	O
+renal	O
+perfusion	O
+.	O
+
+Nociceptive	O
+effects	O
+induced	O
+by	O
+intrathecal	O
+administration	O
+of	O
+prostaglandin	O
+D2	O
+,	O
+E2	O
+,	O
+or	O
+F2	O
+alpha	O
+to	O
+conscious	O
+mice	O
+.	O
+
+The	O
+effects	O
+of	O
+intrathecal	O
+administration	O
+of	O
+prostaglandins	O
+on	O
+pain	B
+responses	O
+in	O
+conscious	O
+mice	O
+were	O
+evaluated	O
+by	O
+using	O
+hot	O
+plate	O
+and	O
+acetic	O
+acid	O
+writhing	O
+tests	O
+.	O
+
+Prostaglandin	O
+D2	O
+(	O
+0	O
+.	O
+5	O
+-	O
+3	O
+ng	O
+/	O
+mouse	O
+)	O
+had	O
+a	O
+hyperalgesic	B
+action	O
+on	O
+the	O
+response	O
+to	O
+a	O
+hot	O
+plate	O
+during	O
+a	O
+3	O
+-	O
+60	O
+min	O
+period	O
+after	O
+injection	O
+.	O
+
+Prostaglandin	O
+E2	O
+showed	O
+a	O
+hyperalgesic	B
+effect	O
+at	O
+doses	O
+of	O
+1	O
+pg	O
+to	O
+10	O
+ng	O
+/	O
+mouse	O
+,	O
+but	O
+the	O
+effect	O
+lasted	O
+shorter	O
+(	O
+3	O
+-	O
+30	O
+min	O
+)	O
+than	O
+that	O
+of	O
+prostaglandin	O
+D2	O
+.	O
+
+Similar	O
+results	O
+were	O
+obtained	O
+by	O
+acetic	O
+acid	O
+writhing	O
+tests	O
+.	O
+
+The	O
+hyperalgesic	B
+effect	O
+of	O
+prostaglandin	O
+D2	O
+was	O
+blocked	O
+by	O
+simultaneous	O
+injection	O
+of	O
+a	O
+substance	O
+P	O
+antagonist	O
+(	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+100	O
+ng	O
+)	O
+but	O
+not	O
+by	O
+AH6809	O
+,	O
+a	O
+prostanoid	O
+EP1	O
+-	O
+receptor	O
+antagonist	O
+.	O
+
+Conversely	O
+,	O
+prostaglandin	O
+E2	O
+-	O
+induced	O
+hyperalgesia	B
+was	O
+blocked	O
+by	O
+AH6809	O
+(	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+500	O
+ng	O
+)	O
+but	O
+not	O
+by	O
+the	O
+substance	O
+P	O
+antagonist	O
+.	O
+
+Prostaglandin	O
+F2	O
+alpha	O
+had	O
+little	O
+effect	O
+on	O
+pain	B
+responses	O
+.	O
+
+These	O
+results	O
+demonstrate	O
+that	O
+both	O
+prostaglandin	O
+D2	O
+and	O
+prostaglandin	O
+E2	O
+exert	O
+hyperalgesia	B
+in	O
+the	O
+spinal	O
+cord	O
+,	O
+but	O
+in	O
+different	O
+ways	O
+.	O
+
+D	O
+-	O
+penicillamine	O
+in	O
+the	O
+treatment	O
+of	O
+localized	B
+scleroderma	I
+.	O
+
+Localized	B
+scleroderma	I
+has	O
+no	O
+recognized	O
+internal	O
+organ	O
+involvement	O
+but	O
+may	O
+be	O
+disfiguring	O
+and	O
+disabling	O
+when	O
+the	O
+cutaneous	O
+lesions	O
+are	O
+extensive	O
+or	O
+affect	O
+children	O
+.	O
+
+There	O
+is	O
+no	O
+accepted	O
+or	O
+proven	O
+treatment	O
+for	O
+localized	B
+scleroderma	I
+.	O
+
+Case	O
+reports	O
+of	O
+11	O
+patients	O
+with	O
+severe	O
+,	O
+extensive	O
+localized	B
+scleroderma	I
+who	O
+were	O
+treated	O
+with	O
+D	O
+-	O
+penicillamine	O
+are	O
+summarized	O
+in	O
+this	O
+article	O
+.	O
+
+This	O
+drug	O
+was	O
+judged	O
+to	O
+have	O
+a	O
+favorable	O
+effect	O
+on	O
+the	O
+disease	O
+course	O
+in	O
+7	O
+(	O
+64	O
+%	O
+)	O
+of	O
+11	O
+patients	O
+.	O
+
+Improvement	O
+began	O
+within	O
+3	O
+to	O
+6	O
+months	O
+and	O
+consisted	O
+of	O
+cessation	O
+of	O
+active	O
+cutaneous	O
+lesions	O
+in	O
+all	O
+7	O
+patients	O
+,	O
+skin	O
+softening	O
+in	O
+5	O
+,	O
+and	O
+more	O
+normal	O
+growth	O
+of	O
+the	O
+affected	O
+limb	O
+in	O
+2	O
+of	O
+3	O
+children	O
+.	O
+
+Joint	O
+stiffness	O
+and	O
+contractures	B
+also	O
+improved	O
+.	O
+
+The	O
+dose	O
+of	O
+D	O
+-	O
+penicillamine	O
+associated	O
+with	O
+a	O
+favorable	O
+response	O
+was	O
+as	O
+low	O
+as	O
+2	O
+to	O
+5	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+given	O
+over	O
+a	O
+period	O
+ranging	O
+from	O
+15	O
+to	O
+53	O
+months	O
+.	O
+
+D	O
+-	O
+Penicillamine	O
+caused	O
+nephrotic	B
+syndrome	I
+in	O
+1	O
+patient	O
+and	O
+milder	O
+reversible	O
+proteinuria	B
+in	O
+3	O
+other	O
+patients	O
+;	O
+none	O
+developed	O
+renal	B
+insufficiency	I
+.	O
+
+These	O
+data	O
+suggest	O
+that	O
+D	O
+-	O
+penicillamine	O
+may	O
+be	O
+effective	O
+in	O
+severe	O
+cases	O
+of	O
+localized	B
+scleroderma	I
+.	O
+
+Cerebral	B
+sinus	I
+thrombosis	I
+as	O
+a	O
+potential	O
+hazard	O
+of	O
+antifibrinolytic	O
+treatment	O
+in	O
+menorrhagia	B
+.	O
+
+We	O
+describe	O
+a	O
+42	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+who	O
+developed	O
+superior	O
+sagittal	B
+and	I
+left	I
+transverse	I
+sinus	I
+thrombosis	I
+associated	O
+with	O
+prolonged	O
+epsilon	O
+-	O
+aminocaproic	O
+acid	O
+therapy	O
+for	O
+menorrhagia	B
+.	O
+
+This	O
+antifibrinolytic	O
+agent	O
+has	O
+been	O
+used	O
+in	O
+women	O
+with	O
+menorrhagia	B
+to	O
+promote	O
+clotting	O
+and	O
+reduce	O
+blood	B
+loss	I
+.	O
+
+Although	O
+increased	O
+risk	O
+of	O
+thromboembolic	B
+disease	I
+has	O
+been	O
+reported	O
+during	O
+treatment	O
+with	O
+epsilon	O
+-	O
+aminocaproic	O
+acid	O
+,	O
+cerebral	B
+sinus	I
+thrombosis	I
+has	O
+not	O
+been	O
+previously	O
+described	O
+.	O
+
+Careful	O
+use	O
+of	O
+epsilon	O
+-	O
+aminocaproic	O
+acid	O
+therapy	O
+is	O
+recommended	O
+.	O
+
+Seizure	B
+activity	O
+with	O
+imipenem	O
+therapy	O
+:	O
+incidence	O
+and	O
+risk	O
+factors	O
+.	O
+
+Two	O
+elderly	O
+patients	O
+with	O
+a	O
+history	O
+of	O
+either	O
+cerebral	B
+vascular	I
+accident	I
+(	O
+CVA	B
+)	O
+or	O
+head	B
+trauma	I
+and	O
+no	O
+evidence	O
+of	O
+renal	B
+disease	I
+developed	O
+seizures	B
+while	O
+receiving	O
+maximum	O
+doses	O
+of	O
+imipenem	O
+/	O
+cilastatin	O
+.	O
+
+Neither	O
+patient	O
+had	O
+reported	O
+previous	O
+seizures	B
+or	O
+seizure	B
+-	O
+like	O
+activity	O
+nor	O
+was	O
+receiving	O
+anticonvulsant	O
+agents	O
+.	O
+
+All	O
+seizures	B
+were	O
+controlled	O
+with	O
+therapeutic	O
+doses	O
+of	O
+phenytoin	O
+.	O
+
+Both	O
+patients	O
+had	O
+received	O
+maximum	O
+doses	O
+of	O
+other	O
+beta	O
+-	O
+lactam	O
+antibiotics	O
+without	O
+evidence	O
+of	O
+seizure	B
+activity	O
+.	O
+
+Midline	O
+B3	O
+serotonin	O
+nerves	O
+in	O
+rat	O
+medulla	O
+are	O
+involved	O
+in	O
+hypotensive	B
+effect	O
+of	O
+methyldopa	O
+.	O
+
+Previous	O
+experiments	O
+in	O
+this	O
+laboratory	O
+have	O
+shown	O
+that	O
+microinjection	O
+of	O
+methyldopa	O
+onto	O
+the	O
+ventrolateral	O
+cells	O
+of	O
+the	O
+B3	O
+serotonin	O
+neurons	O
+in	O
+the	O
+medulla	O
+elicits	O
+a	O
+hypotensive	B
+response	O
+mediated	O
+by	O
+a	O
+projection	O
+descending	O
+into	O
+the	O
+spinal	O
+cord	O
+.	O
+
+The	O
+present	O
+experiments	O
+were	O
+designed	O
+to	O
+investigate	O
+the	O
+role	O
+of	O
+the	O
+midline	O
+cells	O
+of	O
+the	O
+B3	O
+serotonin	O
+neurons	O
+in	O
+the	O
+medulla	O
+,	O
+coinciding	O
+with	O
+the	O
+raphe	O
+magnus	O
+.	O
+
+In	O
+spontaneously	O
+hypertensive	B
+,	O
+stroke	B
+-	O
+prone	O
+rats	O
+,	O
+microinjection	O
+of	O
+methyldopa	O
+into	O
+the	O
+area	O
+of	O
+the	O
+midline	O
+B3	O
+serotonin	O
+cell	O
+group	O
+in	O
+the	O
+ventral	O
+medulla	O
+caused	O
+a	O
+potent	O
+hypotension	B
+of	O
+30	O
+-	O
+40	O
+mm	O
+Hg	O
+,	O
+which	O
+was	O
+maximal	O
+2	O
+-	O
+3	O
+h	O
+after	O
+administration	O
+and	O
+was	O
+abolished	O
+by	O
+the	O
+serotonin	O
+neurotoxin	O
+5	O
+,	O
+7	O
+-	O
+dihydroxytryptamine	O
+(	O
+5	O
+,	O
+7	O
+-	O
+DHT	O
+)	O
+injected	O
+intracerebroventricularly	O
+.	O
+
+However	O
+,	O
+intraspinal	O
+injection	O
+of	O
+5	O
+,	O
+7	O
+-	O
+DHT	O
+to	O
+produce	O
+a	O
+more	O
+selective	O
+lesion	O
+of	O
+only	O
+descending	O
+serotonin	O
+projections	O
+in	O
+the	O
+spinal	O
+cord	O
+did	O
+not	O
+affect	O
+this	O
+hypotension	B
+.	O
+
+Further	O
+,	O
+5	O
+,	O
+7	O
+-	O
+DHT	O
+lesion	O
+of	O
+serotonin	O
+nerves	O
+travelling	O
+in	O
+the	O
+median	O
+forebrain	O
+bundle	O
+,	O
+one	O
+of	O
+the	O
+main	O
+ascending	O
+pathways	O
+from	O
+the	O
+B3	O
+serotonin	O
+cells	O
+,	O
+did	O
+not	O
+affect	O
+the	O
+fall	O
+in	O
+blood	O
+pressure	O
+associated	O
+with	O
+a	O
+midline	O
+B3	O
+serotonin	O
+methyldopa	O
+injection	O
+.	O
+
+It	O
+is	O
+concluded	O
+therefore	O
+that	O
+,	O
+unlike	O
+the	O
+ventrolateral	O
+B3	O
+cells	O
+which	O
+mediate	O
+a	O
+methyldopa	O
+-	O
+induced	O
+hypotension	B
+via	O
+descending	O
+projections	O
+,	O
+the	O
+midline	O
+serotonin	O
+B3	O
+cells	O
+in	O
+the	O
+medulla	O
+contribute	O
+to	O
+the	O
+hypotensive	B
+action	O
+of	O
+methyldopa	O
+,	O
+either	O
+by	O
+way	O
+of	O
+an	O
+ascending	O
+projection	O
+which	O
+does	O
+not	O
+pass	O
+through	O
+the	O
+median	O
+forebrain	O
+bundle	O
+,	O
+or	O
+through	O
+a	O
+projection	O
+restricted	O
+to	O
+the	O
+caudal	O
+brainstem	O
+.	O
+
+Antiarrhythmic	O
+plasma	O
+concentrations	O
+of	O
+cibenzoline	O
+on	O
+canine	O
+ventricular	B
+arrhythmias	I
+.	O
+
+Using	O
+two	O
+-	O
+stage	O
+coronary	O
+ligation	O
+-	O
+,	O
+digitalis	O
+-	O
+,	O
+and	O
+adrenaline	O
+-	O
+induced	O
+canine	O
+ventricular	B
+arrhythmias	I
+,	O
+antiarrhythmic	O
+effects	O
+of	O
+cibenzoline	O
+were	O
+examined	O
+and	O
+the	O
+minimum	O
+effective	O
+plasma	O
+concentration	O
+for	O
+each	O
+arrhythmia	B
+model	O
+was	O
+determined	O
+.	O
+
+Cibenzoline	O
+suppressed	O
+all	O
+the	O
+arrhythmias	B
+,	O
+and	O
+the	O
+minimum	O
+effective	O
+plasma	O
+concentrations	O
+for	O
+arrhythmias	B
+induced	O
+by	O
+24	O
+-	O
+h	O
+coronary	O
+ligation	O
+,	O
+48	O
+-	O
+h	O
+coronary	O
+ligation	O
+,	O
+digitalis	O
+,	O
+and	O
+adrenaline	O
+were	O
+1	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+9	O
+(	O
+by	O
+8	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+,	O
+1	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+(	O
+by	O
+8	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+,	O
+0	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+(	O
+by	O
+2	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+,	O
+and	O
+3	O
+.	O
+5	O
++	O
+/	O
+-	O
+1	O
+.	O
+3	O
+(	O
+by	O
+5	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+micrograms	O
+/	O
+ml	O
+,	O
+respectively	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SDM	O
+,	O
+n	O
+=	O
+6	O
+-	O
+7	O
+)	O
+.	O
+
+The	O
+concentration	O
+for	O
+adrenaline	O
+-	O
+induced	O
+arrhythmia	B
+was	O
+significantly	O
+higher	O
+than	O
+those	O
+for	O
+the	O
+other	O
+types	O
+of	O
+arrhythmias	B
+.	O
+
+This	O
+pharmacological	O
+profile	O
+is	O
+similar	O
+to	O
+those	O
+of	O
+mexiletine	O
+and	O
+tocainide	O
+,	O
+and	O
+all	O
+three	O
+drugs	O
+have	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+stimulant	O
+action	O
+.	O
+
+Because	O
+cibenzoline	O
+had	O
+only	O
+weak	O
+hypotensive	B
+and	O
+sinus	O
+node	O
+depressive	B
+effects	O
+and	O
+was	O
+found	O
+to	O
+be	O
+orally	O
+active	O
+when	O
+given	O
+to	O
+coronary	O
+ligation	O
+arrhythmia	B
+dogs	O
+,	O
+its	O
+clinical	O
+usefulness	O
+is	O
+expected	O
+.	O
+
+Continuous	O
+ambulatory	O
+ECG	O
+monitoring	O
+during	O
+fluorouracil	O
+therapy	O
+:	O
+a	O
+prospective	O
+study	O
+.	O
+
+Although	O
+there	O
+have	O
+been	O
+anecdotal	O
+reports	O
+of	O
+cardiac	B
+toxicity	I
+associated	O
+with	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+therapy	O
+,	O
+this	O
+phenomenon	O
+has	O
+not	O
+been	O
+studied	O
+in	O
+a	O
+systematic	O
+fashion	O
+.	O
+
+We	O
+prospectively	O
+performed	O
+continuous	O
+ambulatory	O
+ECG	O
+monitoring	O
+on	O
+25	O
+patients	O
+undergoing	O
+5	O
+-	O
+FU	O
+infusion	O
+for	O
+treatment	O
+of	O
+solid	O
+tumors	B
+in	O
+order	O
+to	O
+assess	O
+the	O
+incidence	O
+of	O
+ischemic	B
+ST	O
+changes	O
+.	O
+
+Patients	O
+were	O
+monitored	O
+for	O
+23	O
++	O
+/	O
+-	O
+4	O
+hours	O
+before	O
+5	O
+-	O
+FU	O
+infusion	O
+,	O
+and	O
+98	O
++	O
+/	O
+-	O
+9	O
+hours	O
+during	O
+5	O
+-	O
+FU	O
+infusion	O
+.	O
+
+Anginal	B
+episodes	O
+were	O
+rare	O
+:	O
+only	O
+one	O
+patient	O
+had	O
+angina	B
+(	O
+during	O
+5	O
+-	O
+FU	O
+infusion	O
+)	O
+.	O
+
+However	O
+,	O
+asymptomatic	O
+ST	O
+changes	O
+(	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+1	O
+mm	O
+ST	O
+deviation	O
+)	O
+were	O
+common	O
+:	O
+six	O
+of	O
+25	O
+patients	O
+(	O
+24	O
+%	O
+)	O
+had	O
+ST	O
+changes	O
+before	O
+5	O
+-	O
+FU	O
+infusion	O
+v	O
+17	O
+(	O
+68	O
+%	O
+)	O
+during	O
+5	O
+-	O
+FU	O
+infusion	O
+(	O
+P	O
+less	O
+than	O
+.	O
+002	O
+)	O
+.	O
+
+The	O
+incidence	O
+of	O
+ischemic	B
+episodes	O
+per	O
+patient	O
+per	O
+hour	O
+was	O
+0	O
+.	O
+05	O
++	O
+/	O
+-	O
+0	O
+.	O
+02	O
+prior	O
+to	O
+5	O
+-	O
+FU	O
+infusion	O
+v	O
+0	O
+.	O
+13	O
++	O
+/	O
+-	O
+0	O
+.	O
+03	O
+during	O
+5	O
+-	O
+FU	O
+infusion	O
+(	O
+P	O
+less	O
+than	O
+.	O
+001	O
+)	O
+;	O
+the	O
+duration	O
+of	O
+ECG	O
+changes	O
+was	O
+0	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+minutes	O
+per	O
+patient	O
+per	O
+hour	O
+before	O
+5	O
+-	O
+FU	O
+v	O
+1	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+minutes	O
+per	O
+patient	O
+per	O
+hour	O
+during	O
+5	O
+-	O
+FU	O
+(	O
+P	O
+less	O
+than	O
+.	O
+01	O
+)	O
+.	O
+
+ECG	O
+changes	O
+were	O
+more	O
+common	O
+among	O
+patients	O
+with	O
+known	O
+coronary	B
+artery	I
+disease	I
+.	O
+
+There	O
+were	O
+two	O
+cases	O
+of	O
+sudden	B
+death	I
+,	O
+both	O
+of	O
+which	O
+occurred	O
+at	O
+the	O
+end	O
+of	O
+the	O
+chemotherapy	O
+course	O
+.	O
+
+We	O
+conclude	O
+that	O
+5	O
+-	O
+FU	O
+infusion	O
+is	O
+associated	O
+with	O
+a	O
+significant	O
+increase	O
+in	O
+silent	O
+ST	O
+segment	O
+deviation	O
+suggestive	O
+of	O
+ischemia	B
+,	O
+particularly	O
+among	O
+patients	O
+with	O
+coronary	B
+artery	I
+disease	I
+.	O
+
+The	O
+mechanism	O
+and	O
+clinical	O
+significance	O
+of	O
+these	O
+ECG	O
+changes	O
+remain	O
+to	O
+be	O
+determined	O
+.	O
+
+Nature	O
+,	O
+time	O
+course	O
+and	O
+dose	O
+dependence	O
+of	O
+zidovudine	O
+-	O
+related	O
+side	O
+effects	O
+:	O
+results	O
+from	O
+the	O
+Multicenter	O
+Canadian	O
+Azidothymidine	O
+Trial	O
+.	O
+
+To	O
+characterize	O
+the	O
+nature	O
+,	O
+time	O
+course	O
+and	O
+dose	O
+dependency	O
+of	O
+zidovudine	O
+-	O
+related	O
+side	O
+effects	O
+,	O
+we	O
+undertook	O
+a	O
+multicenter	O
+,	O
+prospective	O
+,	O
+dose	O
+-	O
+range	O
+finding	O
+study	O
+.	O
+
+Our	O
+study	O
+group	O
+consisted	O
+of	O
+74	O
+HIV	O
+-	O
+positive	O
+homosexual	O
+men	O
+belonging	O
+to	O
+groups	O
+II	O
+B	O
+,	O
+III	O
+and	O
+IV	O
+C2	O
+from	O
+the	O
+Centers	O
+for	O
+Disease	O
+Control	O
+(	O
+CDC	O
+)	O
+classification	O
+of	O
+HIV	B
+disease	I
+.	O
+
+Following	O
+a	O
+3	O
+-	O
+week	O
+observation	O
+period	O
+,	O
+volunteers	O
+were	O
+treated	O
+with	O
+zidovudine	O
+600	O
+mg	O
+/	O
+day	O
+for	O
+18	O
+weeks	O
+,	O
+900	O
+mg	O
+/	O
+day	O
+for	O
+9	O
+weeks	O
+and	O
+1200	O
+mg	O
+/	O
+day	O
+for	O
+9	O
+weeks	O
+,	O
+followed	O
+by	O
+a	O
+washout	O
+period	O
+of	O
+6	O
+weeks	O
+after	O
+which	O
+they	O
+were	O
+re	O
+-	O
+started	O
+on	O
+1200	O
+mg	O
+/	O
+day	O
+or	O
+the	O
+highest	O
+tolerated	O
+dose	O
+at	O
+8	O
+-	O
+hourly	O
+intervals	O
+.	O
+
+Subjects	O
+were	O
+randomly	O
+assigned	O
+to	O
+4	O
+-	O
+hourly	O
+or	O
+8	O
+-	O
+hourly	O
+regimens	O
+within	O
+CDC	O
+groups	O
+while	O
+taking	O
+600	O
+and	O
+1200	O
+mg	O
+/	O
+day	O
+.	O
+
+Clinical	O
+and	O
+laboratory	O
+evaluations	O
+were	O
+performed	O
+at	O
+3	O
+-	O
+week	O
+intervals	O
+.	O
+
+Symptomatic	O
+adverse	O
+effects	O
+were	O
+present	O
+in	O
+96	O
+%	O
+of	O
+subjects	O
+,	O
+most	O
+commonly	O
+nausea	B
+(	O
+64	O
+%	O
+)	O
+,	O
+fatigue	B
+(	O
+55	O
+%	O
+)	O
+and	O
+headache	B
+(	O
+49	O
+%	O
+)	O
+.	O
+
+These	O
+were	O
+generally	O
+self	O
+-	O
+limited	O
+,	O
+reappearing	O
+briefly	O
+at	O
+each	O
+dose	O
+increment	O
+.	O
+
+A	O
+decrease	O
+in	O
+hemoglobin	O
+occurred	O
+shortly	O
+after	O
+initiation	O
+of	O
+therapy	O
+.	O
+
+This	O
+was	O
+not	O
+dose	O
+dependent	O
+and	O
+reversed	O
+rapidly	O
+upon	O
+discontinuation	O
+of	O
+treatment	O
+.	O
+
+A	O
+red	O
+blood	O
+cell	O
+count	O
+decrease	O
+,	O
+a	O
+mean	O
+cell	O
+volume	O
+increase	O
+and	O
+a	O
+granulocyte	O
+count	O
+decrease	O
+developed	O
+early	O
+in	O
+a	O
+dose	O
+-	O
+independent	O
+fashion	O
+,	O
+reverting	O
+at	O
+least	O
+partially	O
+during	O
+the	O
+washout	O
+phase	O
+.	O
+
+The	O
+decrease	O
+in	O
+reticulocyte	O
+count	O
+was	O
+dose	O
+related	O
+between	O
+600	O
+and	O
+900	O
+mg	O
+/	O
+day	O
+with	O
+no	O
+further	O
+change	O
+when	O
+the	O
+dose	O
+was	O
+escalated	O
+to	O
+1200	O
+mg	O
+/	O
+day	O
+.	O
+
+Bone	O
+marrow	O
+changes	O
+occurred	O
+rapidly	O
+as	O
+demonstrated	O
+by	O
+megaloblastosis	B
+in	O
+95	O
+%	O
+of	O
+65	O
+specimens	O
+at	O
+week	O
+18	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+National	O
+project	O
+on	O
+the	O
+prevention	O
+of	O
+mother	O
+-	O
+to	O
+-	O
+infant	O
+infection	B
+by	I
+hepatitis	I
+B	I
+virus	I
+in	O
+Japan	O
+.	O
+
+In	O
+Japan	O
+,	O
+a	O
+nationwide	O
+prevention	O
+program	O
+against	O
+mother	O
+-	O
+to	O
+-	O
+infant	O
+infection	B
+by	I
+hepatitis	I
+B	I
+virus	I
+(	O
+HBV	O
+)	O
+started	O
+in	O
+1985	O
+.	O
+
+This	O
+program	O
+consists	O
+of	O
+double	O
+screenings	O
+of	O
+pregnant	O
+women	O
+and	O
+prophylactic	O
+treatment	O
+to	O
+the	O
+infants	O
+born	O
+to	O
+both	O
+hepatitis	O
+B	O
+surface	O
+antigen	O
+(	O
+HBsAg	O
+)	O
+and	O
+hepatitis	O
+B	O
+e	O
+antigen	O
+(	O
+HBeAg	O
+)	O
+positive	O
+mothers	O
+.	O
+
+These	O
+infants	O
+are	O
+treated	O
+with	O
+two	O
+injections	O
+of	O
+hepatitis	B
+B	I
+immune	O
+globulin	O
+(	O
+HBIG	O
+)	O
+and	O
+at	O
+least	O
+three	O
+injections	O
+of	O
+plasma	O
+derived	O
+hepatitis	O
+B	O
+vaccine	O
+.	O
+
+We	O
+sent	O
+questionnaires	O
+about	O
+the	O
+numbers	O
+of	O
+each	O
+procedure	O
+or	O
+examination	O
+during	O
+nine	O
+months	O
+of	O
+investigation	O
+period	O
+to	O
+each	O
+local	O
+government	O
+in	O
+1986	O
+and	O
+1987	O
+.	O
+
+93	O
+.	O
+4	O
+%	O
+pregnant	O
+women	O
+had	O
+the	O
+chance	O
+to	O
+be	O
+examined	O
+for	O
+HBsAg	O
+,	O
+and	O
+the	O
+positive	O
+rate	O
+was	O
+1	O
+.	O
+4	O
+to	O
+1	O
+.	O
+5	O
+%	O
+.	O
+
+The	O
+HBeAg	O
+positive	O
+rate	O
+in	O
+HBsAg	O
+positive	O
+was	O
+23	O
+to	O
+26	O
+%	O
+.	O
+
+The	O
+HBsAg	O
+positive	O
+rate	O
+in	O
+neonates	O
+and	O
+in	O
+infants	O
+before	O
+two	O
+months	O
+were	O
+3	O
+%	O
+and	O
+2	O
+%	O
+respectively	O
+.	O
+
+Some	O
+problems	O
+may	O
+arise	O
+,	O
+because	O
+27	O
+to	O
+30	O
+%	O
+of	O
+infants	O
+need	O
+the	O
+fourth	O
+vaccination	O
+in	O
+some	O
+restricted	O
+areas	O
+.	O
+
+Involvement	O
+of	O
+the	O
+mu	O
+-	O
+opiate	O
+receptor	O
+in	O
+peripheral	O
+analgesia	B
+.	O
+
+The	O
+intradermal	O
+injection	O
+of	O
+mu	O
+(	O
+morphine	O
+,	O
+Tyr	O
+-	O
+D	O
+-	O
+Ala	O
+-	O
+Gly	O
+-	O
+NMe	O
+-	O
+Phe	O
+-	O
+Gly	O
+-	O
+ol	O
+and	O
+morphiceptin	O
+)	O
+,	O
+kappa	O
+(	O
+trans	O
+-	O
+3	O
+,	O
+4	O
+-	O
+dichloro	O
+-	O
+N	O
+-	O
+methyl	O
+-	O
+N	O
+[	O
+2	O
+-	O
+(	O
+1	O
+-	O
+pyrrolidinyl	O
+)	O
+cyclohexyl	O
+]	O
+benzeneactemide	O
+)	O
+and	O
+delta	O
+(	O
+[	O
+D	O
+-	O
+Pen2	O
+.	O
+5	O
+]	O
+-	O
+enkephalin	O
+and	O
+[	O
+D	O
+-	O
+Ser2	O
+]	O
+-	O
+[	O
+Leu	O
+]	O
+enkephalin	O
+-	O
+Thr	O
+)	O
+selective	O
+opioid	O
+-	O
+agonists	O
+,	O
+by	O
+themselves	O
+,	O
+did	O
+not	O
+significantly	O
+affect	O
+the	O
+mechanical	O
+nociceptive	O
+threshold	O
+in	O
+the	O
+hindpaw	O
+of	O
+the	O
+rat	O
+.	O
+
+Intradermal	O
+injection	O
+of	O
+mu	O
+,	O
+but	O
+not	O
+delta	O
+or	O
+kappa	O
+opioid	O
+-	O
+agonists	O
+,	O
+however	O
+,	O
+produced	O
+dose	O
+-	O
+dependent	O
+inhibition	O
+of	O
+prostaglandin	O
+E2	O
+-	O
+induced	O
+hyperalgesia	B
+.	O
+
+The	O
+analgesic	O
+effect	O
+of	O
+the	O
+mu	O
+-	O
+agonist	O
+morphine	O
+was	O
+dose	O
+-	O
+dependently	O
+antagonized	O
+by	O
+naloxone	O
+and	O
+prevented	O
+by	O
+co	O
+-	O
+injection	O
+of	O
+pertussis	O
+toxin	O
+.	O
+
+Morphine	O
+did	O
+not	O
+,	O
+however	O
+,	O
+alter	O
+the	O
+hyperalgesia	B
+induced	O
+by	O
+8	O
+-	O
+bromo	O
+cyclic	O
+adenosine	O
+monophosphate	O
+.	O
+
+We	O
+conclude	O
+that	O
+the	O
+analgesic	O
+action	O
+of	O
+opioids	O
+on	O
+the	O
+peripheral	O
+terminals	O
+of	O
+primary	O
+afferents	O
+is	O
+via	O
+a	O
+binding	O
+site	O
+with	O
+characteristics	O
+of	O
+the	O
+mu	O
+-	O
+opioid	O
+receptor	O
+and	O
+that	O
+this	O
+action	O
+is	O
+mediated	O
+by	O
+inhibition	O
+of	O
+the	O
+cyclic	O
+adenosine	O
+monophosphate	O
+second	O
+messenger	O
+system	O
+.	O
+
+Involvement	O
+of	O
+locus	O
+coeruleus	O
+and	O
+noradrenergic	O
+neurotransmission	O
+in	O
+fentanyl	O
+-	O
+induced	O
+muscular	B
+rigidity	I
+in	O
+the	O
+rat	O
+.	O
+
+Whereas	O
+muscular	B
+rigidity	I
+is	O
+a	O
+well	O
+-	O
+known	O
+side	O
+effect	O
+that	O
+is	O
+associated	O
+with	O
+high	O
+-	O
+dose	O
+fentanyl	O
+anesthesia	O
+,	O
+a	O
+paucity	O
+of	O
+information	O
+exists	O
+with	O
+regard	O
+to	O
+its	O
+underlying	O
+mechanism	O
+(	O
+s	O
+)	O
+.	O
+
+We	O
+investigated	O
+in	O
+this	O
+study	O
+the	O
+possible	O
+engagement	O
+of	O
+locus	O
+coeruleus	O
+of	O
+the	O
+pons	O
+in	O
+this	O
+phenomenon	O
+,	O
+using	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+anesthetized	O
+with	O
+ketamine	O
+.	O
+
+Under	O
+proper	O
+control	O
+of	O
+respiration	O
+,	O
+body	O
+temperature	O
+and	O
+end	O
+-	O
+tidal	O
+CO2	O
+,	O
+intravenous	O
+administration	O
+of	O
+fentanyl	O
+(	O
+50	O
+or	O
+100	O
+micrograms	O
+/	O
+kg	O
+)	O
+consistently	O
+promoted	O
+an	O
+increase	O
+in	O
+electromyographic	O
+activity	O
+recorded	O
+from	O
+the	O
+gastrocnemius	O
+and	O
+abdominal	O
+rectus	O
+muscles	O
+.	O
+
+Such	O
+an	O
+induced	O
+muscular	B
+rigidity	I
+by	O
+the	O
+narcotic	O
+agent	O
+was	O
+significantly	O
+antagonized	O
+or	O
+even	O
+reduced	O
+by	O
+prior	O
+electrolytic	O
+lesions	O
+of	O
+the	O
+locus	O
+coeruleus	O
+or	O
+pretreatment	O
+with	O
+the	O
+alpha	O
+-	O
+adrenoceptor	O
+blocker	O
+,	O
+prazosin	O
+.	O
+
+Microinjection	O
+of	O
+fentanyl	O
+(	O
+2	O
+.	O
+5	O
+micrograms	O
+/	O
+50	O
+nl	O
+)	O
+directly	O
+into	O
+this	O
+pontine	O
+nucleus	O
+,	O
+on	O
+the	O
+other	O
+hand	O
+,	O
+elicited	O
+discernible	O
+electromyographic	O
+excitation	O
+.	O
+
+It	O
+is	O
+speculated	O
+that	O
+the	O
+induction	O
+of	O
+muscular	B
+rigidity	I
+by	O
+fentanyl	O
+may	O
+involve	O
+the	O
+coerulospinal	O
+noradrenergic	O
+fibers	O
+to	O
+the	O
+spinal	O
+motoneurons	O
+.	O
+
+Dexmedetomidine	O
+,	O
+acting	O
+through	O
+central	O
+alpha	O
+-	O
+2	O
+adrenoceptors	O
+,	O
+prevents	O
+opiate	O
+-	O
+induced	O
+muscle	B
+rigidity	I
+in	O
+the	O
+rat	O
+.	O
+
+The	O
+highly	O
+-	O
+selective	O
+alpha	O
+-	O
+2	O
+adrenergic	O
+agonist	O
+dexmedetomidine	O
+(	O
+D	O
+-	O
+MED	O
+)	O
+is	O
+capable	O
+of	O
+inducing	O
+muscle	B
+flaccidity	I
+and	O
+anesthesia	O
+in	O
+rats	O
+and	O
+dogs	O
+.	O
+
+Intense	O
+generalized	O
+muscle	B
+rigidity	I
+is	O
+an	O
+undesirable	O
+side	O
+effect	O
+of	O
+potent	O
+opiate	O
+agonists	O
+.	O
+
+Although	O
+the	O
+neurochemistry	O
+of	O
+opiate	O
+-	O
+induced	O
+rigidity	B
+has	O
+yet	O
+to	O
+be	O
+fully	O
+elucidated	O
+,	O
+recent	O
+work	O
+suggests	O
+a	O
+role	O
+for	O
+a	O
+central	O
+adrenergic	O
+mechanism	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+the	O
+authors	O
+determined	O
+if	O
+treatment	O
+with	O
+D	O
+-	O
+MED	O
+prevents	O
+the	O
+muscle	B
+rigidity	I
+caused	O
+by	O
+high	O
+-	O
+dose	O
+alfentanil	O
+anesthesia	O
+in	O
+the	O
+rat	O
+.	O
+
+Animals	O
+(	O
+n	O
+=	O
+42	O
+)	O
+were	O
+treated	O
+intraperitoneally	O
+with	O
+one	O
+of	O
+the	O
+following	O
+six	O
+regimens	O
+:	O
+1	O
+)	O
+L	O
+-	O
+MED	O
+(	O
+the	O
+inactive	O
+L	O
+-	O
+isomer	O
+of	O
+medetomidine	O
+)	O
+,	O
+30	O
+micrograms	O
+/	O
+kg	O
+;	O
+2	O
+)	O
+D	O
+-	O
+MED	O
+,	O
+10	O
+micrograms	O
+/	O
+kg	O
+;	O
+3	O
+)	O
+D	O
+-	O
+MED	O
+,	O
+30	O
+micrograms	O
+/	O
+kg	O
+;	O
+4	O
+)	O
+D	O
+-	O
+MED	O
+[	O
+30	O
+micrograms	O
+/	O
+kg	O
+]	O
+and	O
+the	O
+central	O
+-	O
+acting	O
+alpha	O
+-	O
+2	O
+antagonist	O
+,	O
+idazoxan	O
+[	O
+10	O
+mg	O
+/	O
+kg	O
+]	O
+;	O
+5	O
+)	O
+D	O
+-	O
+MED	O
+[	O
+30	O
+micrograms	O
+/	O
+kg	O
+]	O
+and	O
+the	O
+peripheral	O
+-	O
+acting	O
+alpha	O
+-	O
+2	O
+antagonist	O
+DG	O
+-	O
+5128	O
+[	O
+10	O
+mg	O
+/	O
+kg	O
+]	O
+,	O
+or	O
+;	O
+6	O
+)	O
+saline	O
+.	O
+
+Baseline	O
+electromyographic	O
+activity	O
+was	O
+recorded	O
+from	O
+the	O
+gastrocnemius	O
+muscle	O
+before	O
+and	O
+after	O
+drug	O
+treatment	O
+.	O
+
+Each	O
+rat	O
+was	O
+then	O
+injected	O
+with	O
+alfentanil	O
+(	O
+ALF	O
+,	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+sc	O
+)	O
+.	O
+
+ALF	O
+injection	O
+resulted	O
+in	O
+a	O
+marked	O
+increase	O
+in	O
+hindlimb	O
+EMG	O
+activity	O
+in	O
+the	O
+L	O
+-	O
+MED	O
+treatment	O
+group	O
+which	O
+was	O
+indistinguishable	O
+from	O
+that	O
+seen	O
+in	O
+animals	O
+treated	O
+with	O
+saline	O
+.	O
+
+In	O
+contrast	O
+,	O
+D	O
+-	O
+MED	O
+prevented	O
+alfentanil	O
+-	O
+induced	O
+muscle	B
+rigidity	I
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+fashion	O
+.	O
+
+The	O
+small	O
+EMG	O
+values	O
+obtained	O
+in	O
+the	O
+high	O
+-	O
+dose	O
+D	O
+-	O
+MED	O
+group	O
+were	O
+comparable	O
+with	O
+those	O
+recorded	O
+in	O
+earlier	O
+studies	O
+from	O
+control	O
+animals	O
+not	O
+given	O
+any	O
+opiate	O
+.	O
+
+The	O
+high	O
+-	O
+dose	O
+D	O
+-	O
+MED	O
+animals	O
+were	O
+flaccid	O
+,	O
+akinetic	B
+,	O
+and	O
+lacked	O
+a	O
+startle	B
+response	O
+during	O
+the	O
+entire	O
+experimental	O
+period	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Some	O
+central	O
+effects	O
+of	O
+repeated	O
+treatment	O
+with	O
+fluvoxamine	O
+.	O
+
+We	O
+investigated	O
+the	O
+effect	O
+of	O
+repeated	O
+treatment	O
+with	O
+fluvoxamine	O
+,	O
+a	O
+selective	O
+serotonin	O
+uptake	O
+inhibitor	O
+,	O
+on	O
+behavioral	O
+effects	O
+of	O
+dopaminomimetics	O
+and	O
+methoxamine	O
+and	O
+on	O
+the	O
+animal	O
+behavior	O
+in	O
+the	O
+"	O
+behavioral	O
+despair	O
+"	O
+test	O
+.	O
+
+A	O
+repeated	O
+treatment	O
+with	O
+fluvoxamine	O
+(	O
+twice	O
+daily	O
+for	O
+14	O
+days	O
+)	O
+potentiated	O
+in	O
+mice	O
+and	O
+in	O
+rats	O
+(	O
+weaker	O
+)	O
+the	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B
+.	O
+
+The	O
+hyperactivity	B
+induced	O
+by	O
+nomifensine	O
+in	O
+mice	O
+remained	O
+unaffected	O
+by	O
+fluvoxamine	O
+.	O
+
+The	O
+stimulation	O
+of	O
+locomotor	O
+activity	O
+by	O
+intracerebroventricularly	O
+administered	O
+methoxamine	O
+was	O
+not	O
+affected	O
+by	O
+repeated	O
+treatment	O
+with	O
+fluvoxamine	O
+.	O
+
+Given	O
+three	O
+times	O
+fluvoxamine	O
+had	O
+no	O
+effect	O
+on	O
+the	O
+immobilization	O
+time	O
+in	O
+the	O
+"	O
+behavioral	O
+despair	O
+"	O
+test	O
+in	O
+rats	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+fluvoxamine	O
+given	O
+repeatedly	O
+acts	O
+differently	O
+than	O
+citalopram	O
+,	O
+another	O
+selective	O
+serotonin	O
+uptake	O
+inhibitor	O
+,	O
+and	O
+differs	O
+also	O
+from	O
+other	O
+antidepressant	O
+drugs	O
+.	O
+
+Protective	O
+effect	O
+of	O
+a	O
+specific	O
+platelet	O
+-	O
+activating	O
+factor	O
+antagonist	O
+,	O
+BN	O
+52021	O
+,	O
+on	O
+bupivacaine	O
+-	O
+induced	O
+cardiovascular	B
+impairments	I
+in	O
+rats	O
+.	O
+
+Administration	O
+of	O
+the	O
+local	O
+anaesthetic	O
+bupivacaine	O
+(	O
+1	O
+.	O
+5	O
+or	O
+2	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+v	O
+.	O
+)	O
+to	O
+rats	O
+elicited	O
+a	O
+marked	O
+decrease	B
+of	I
+mean	I
+arterial	I
+blood	I
+pressure	I
+(	I
+MBP	I
+)	I
+and	I
+heart	I
+rate	I
+(	I
+HR	I
+)	I
+leading	O
+to	O
+death	O
+(	O
+in	O
+67	O
+%	O
+or	O
+90	O
+%	O
+of	O
+animals	O
+respectively	O
+)	O
+.	O
+
+Intravenous	O
+injection	O
+of	O
+the	O
+specific	O
+platelet	O
+-	O
+activating	O
+factor	O
+(	O
+PAF	O
+)	O
+antagonist	O
+BN	O
+52021	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+30	O
+min	O
+before	O
+bupivacaine	O
+administration	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+suppressed	O
+both	O
+the	O
+decrease	B
+of	I
+MBP	I
+and	I
+HR	I
+.	O
+
+In	O
+contrast	O
+,	O
+doses	O
+of	O
+1	O
+mg	O
+/	O
+kg	O
+BN	O
+52021	O
+given	O
+30	O
+min	O
+before	O
+or	O
+10	O
+mg	O
+/	O
+kg	O
+administered	O
+5	O
+min	O
+before	O
+i	O
+.	O
+v	O
+.	O
+injection	O
+of	O
+bupivacaine	O
+were	O
+ineffective	O
+.	O
+
+When	O
+BN	O
+52021	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+was	O
+injected	O
+immediately	O
+after	O
+bupivacaine	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+a	O
+partial	O
+reversion	O
+of	O
+the	O
+decrease	B
+of	I
+MBP	I
+and	I
+HR	I
+was	O
+observed	O
+,	O
+whereas	O
+the	O
+dose	O
+of	O
+10	O
+mg	O
+/	O
+kg	O
+was	O
+ineffective	O
+.	O
+
+A	O
+partial	O
+recovery	O
+of	O
+bupivacaine	O
+-	O
+induced	O
+ECG	O
+alterations	O
+was	O
+observed	O
+after	O
+pretreatment	O
+of	O
+the	O
+rats	O
+with	O
+BN	O
+52021	O
+.	O
+
+Since	O
+the	O
+administration	O
+of	O
+BN	O
+52021	O
+,	O
+at	O
+all	O
+doses	O
+studied	O
+,	O
+did	O
+not	O
+alter	O
+MBP	O
+and	O
+HR	O
+at	O
+the	O
+doses	O
+used	O
+,	O
+the	O
+bulk	O
+of	O
+these	O
+results	O
+clearly	O
+demonstrate	O
+a	O
+protective	O
+action	O
+of	O
+BN	O
+52021	O
+,	O
+a	O
+specific	O
+antagonist	O
+of	O
+PAF	O
+,	O
+against	O
+bupivacaine	O
+-	O
+induced	O
+cardiovascular	B
+toxicity	I
+.	O
+
+Thus	O
+,	O
+consistent	O
+with	O
+its	O
+direct	O
+effect	O
+on	O
+heart	O
+,	O
+PAF	O
+appears	O
+to	O
+be	O
+implicated	O
+in	O
+bupivacaine	O
+-	O
+induced	O
+cardiovascular	B
+alterations	I
+.	O
+
+The	O
+epidemiology	O
+of	O
+the	O
+acute	O
+flank	B
+pain	I
+syndrome	O
+from	O
+suprofen	O
+.	O
+
+Suprofen	O
+,	O
+a	O
+new	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drug	O
+,	O
+was	O
+marketed	O
+in	O
+early	O
+1986	O
+as	O
+an	O
+analgesic	O
+agent	O
+.	O
+
+Until	O
+physicians	O
+began	O
+reporting	O
+an	O
+unusual	O
+acute	O
+flank	B
+pain	I
+syndrome	O
+to	O
+the	O
+spontaneous	O
+reporting	O
+system	O
+,	O
+700	O
+,	O
+000	O
+persons	O
+used	O
+the	O
+drug	O
+in	O
+the	O
+United	O
+States	O
+.	O
+
+Through	O
+August	O
+1986	O
+,	O
+a	O
+total	O
+of	O
+163	O
+cases	O
+of	O
+this	O
+syndrome	O
+were	O
+reported	O
+.	O
+
+To	O
+elucidate	O
+the	O
+epidemiology	O
+of	O
+the	O
+syndrome	O
+,	O
+a	O
+case	O
+-	O
+control	O
+study	O
+was	O
+performed	O
+,	O
+comparing	O
+62	O
+of	O
+the	O
+case	O
+patients	O
+who	O
+had	O
+been	O
+reported	O
+to	O
+the	O
+spontaneous	O
+reporting	O
+system	O
+to	O
+185	O
+suprofen	O
+-	O
+exposed	O
+control	O
+subjects	O
+who	O
+did	O
+not	O
+have	O
+the	O
+syndrome	O
+.	O
+
+Case	O
+patients	O
+were	O
+more	O
+likely	O
+to	O
+be	O
+men	O
+(	O
+odds	O
+ratio	O
+,	O
+3	O
+.	O
+8	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+1	O
+.	O
+2	O
+-	O
+12	O
+.	O
+1	O
+)	O
+,	O
+suffer	O
+from	O
+hay	B
+fever	I
+and	O
+asthma	B
+(	O
+odds	O
+ratio	O
+,	O
+3	O
+.	O
+4	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+1	O
+.	O
+0	O
+-	O
+11	O
+.	O
+9	O
+)	O
+;	O
+to	O
+participate	O
+in	O
+regular	O
+exercise	O
+(	O
+odds	O
+ratio	O
+,	O
+5	O
+.	O
+9	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+1	O
+.	O
+1	O
+-	O
+30	O
+.	O
+7	O
+)	O
+,	O
+especially	O
+in	O
+the	O
+use	O
+of	O
+Nautilus	O
+equipment	O
+(	O
+p	O
+=	O
+0	O
+.	O
+02	O
+)	O
+;	O
+and	O
+to	O
+use	O
+alcohol	O
+(	O
+odds	O
+ratio	O
+,	O
+4	O
+.	O
+4	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+1	O
+.	O
+1	O
+-	O
+17	O
+.	O
+5	O
+)	O
+.	O
+
+Possible	O
+risk	O
+factors	O
+included	O
+young	O
+age	O
+,	O
+concurrent	O
+use	O
+of	O
+other	O
+analgesic	O
+agents	O
+(	O
+especially	O
+ibuprofen	O
+)	O
+,	O
+preexisting	O
+renal	B
+disease	I
+,	O
+a	O
+history	O
+of	O
+kidney	B
+stones	I
+,	O
+a	O
+history	O
+of	O
+gout	B
+,	O
+a	O
+recent	O
+increase	O
+in	O
+activity	O
+,	O
+a	O
+recent	O
+increase	O
+in	O
+sun	O
+exposure	O
+,	O
+and	O
+residence	O
+in	O
+the	O
+Sunbelt	O
+.	O
+
+These	O
+were	O
+findings	O
+that	O
+were	O
+suggestive	O
+but	O
+did	O
+not	O
+reach	O
+conventional	O
+statistical	O
+significance	O
+.	O
+
+These	O
+findings	O
+are	O
+consistent	O
+with	O
+the	O
+postulated	O
+mechanism	O
+for	O
+this	O
+unusual	O
+syndrome	O
+:	O
+acute	O
+diffuse	O
+crystallization	O
+of	O
+uric	O
+acid	O
+in	O
+renal	O
+tubules	O
+.	O
+
+Phlorizin	O
+-	O
+induced	O
+glycosuria	B
+does	O
+not	O
+prevent	O
+gentamicin	O
+nephrotoxicity	B
+in	O
+rats	O
+.	O
+
+Because	O
+rats	O
+with	O
+streptozotocin	O
+-	O
+induced	O
+diabetes	B
+mellitus	I
+(	O
+DM	B
+)	O
+have	O
+a	O
+high	O
+solute	O
+diuresis	O
+(	O
+glycosuria	B
+of	O
+10	O
+to	O
+12	O
+g	O
+/	O
+day	O
+)	O
+,	O
+we	O
+have	O
+suggested	O
+that	O
+this	O
+may	O
+in	O
+part	O
+be	O
+responsible	O
+for	O
+their	O
+resistance	O
+to	O
+gentamicin	O
+-	O
+induced	O
+acute	B
+renal	I
+failure	I
+(	O
+ARF	B
+)	O
+.	O
+
+The	O
+protection	O
+from	O
+gentamicin	O
+nephrotoxicity	B
+was	O
+studied	O
+in	O
+non	O
+-	O
+diabetic	B
+rats	O
+with	O
+chronic	O
+solute	O
+diuresis	O
+induced	O
+by	O
+blockage	O
+of	O
+tubular	O
+glucose	O
+reabsorption	O
+with	O
+phlorizin	O
+(	O
+P	O
+)	O
+.	O
+
+DM	B
+rats	O
+with	O
+mild	O
+glycosuria	B
+(	O
+similar	O
+in	O
+degree	O
+to	O
+that	O
+of	O
+the	O
+P	O
+treated	O
+animals	O
+)	O
+were	O
+also	O
+studied	O
+.	O
+
+Unanesthetized	O
+adult	O
+female	O
+,	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+were	O
+divided	O
+in	O
+four	O
+groups	O
+and	O
+studied	O
+for	O
+15	O
+days	O
+.	O
+
+Group	O
+1	O
+(	O
+P	O
+alone	O
+)	O
+received	O
+P	O
+,	O
+360	O
+mg	O
+/	O
+day	O
+,	O
+for	O
+15	O
+days	O
+;	O
+Group	O
+II	O
+(	O
+P	O
++	O
+gentamicin	O
+)	O
+;	O
+Group	O
+III	O
+(	O
+gentamicin	O
+alone	O
+)	O
+and	O
+Group	O
+IV	O
+(	O
+mild	O
+DM	B
++	O
+gentamicin	O
+)	O
+.	O
+
+Nephrotoxic	B
+doses	O
+(	O
+40	O
+mg	O
+/	O
+kg	O
+body	O
+wt	O
+/	O
+day	O
+)	O
+of	O
+gentamicin	O
+were	O
+injected	O
+during	O
+the	O
+last	O
+nine	O
+days	O
+of	O
+study	O
+to	O
+the	O
+animals	O
+of	O
+groups	O
+II	O
+to	O
+IV	O
+.	O
+
+In	O
+Group	O
+I	O
+,	O
+P	O
+induced	O
+a	O
+moderate	O
+and	O
+stable	O
+glycosuria	B
+(	O
+3	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+g	O
+/	O
+day	O
+,	O
+SE	O
+)	O
+,	O
+and	O
+no	O
+functional	O
+or	O
+morphologic	O
+evidence	O
+of	O
+renal	B
+dysfunction	I
+(	O
+baseline	O
+CCr	O
+2	O
+.	O
+1	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+ml	O
+/	O
+min	O
+,	O
+undetectable	O
+lysozymuria	O
+)	O
+or	O
+damage	O
+(	O
+tubular	B
+necrosis	I
+score	O
+[	O
+maximum	O
+4	O
+]	O
+,	O
+zero	O
+)	O
+.	O
+
+In	O
+Group	O
+II	O
+,	O
+P	O
+did	O
+not	O
+prevent	O
+gentamicin	O
+-	O
+ARF	B
+(	O
+maximal	O
+decrease	O
+in	O
+CCr	O
+at	O
+day	O
+9	O
+.	O
+89	O
+%	O
+,	O
+P	O
+less	O
+than	O
+0	O
+.	O
+001	O
+;	O
+peak	O
+lysozymuria	O
+,	O
+1863	O
++	O
+/	O
+-	O
+321	O
+micrograms	O
+/	O
+day	O
+;	O
+and	O
+tubular	B
+necrosis	I
+score	O
+,	O
+3	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+)	O
+.	O
+
+These	O
+values	O
+were	O
+not	O
+different	O
+from	O
+those	O
+of	O
+Group	O
+III	O
+:	O
+maximal	O
+decrease	O
+in	O
+CCr	O
+73	O
+%	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+;	O
+lysozymuria	O
+,	O
+2147	O
++	O
+/	O
+-	O
+701	O
+micrograms	O
+/	O
+day	O
+;	O
+tubular	B
+necrosis	I
+score	O
+,	O
+3	O
+.	O
+8	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Catalepsy	B
+induced	O
+by	O
+combinations	O
+of	O
+ketamine	O
+and	O
+morphine	O
+:	O
+potentiation	O
+,	O
+antagonism	O
+,	O
+tolerance	O
+and	O
+cross	O
+-	O
+tolerance	O
+in	O
+the	O
+rat	O
+.	O
+
+Previous	O
+studies	O
+demonstrated	O
+that	O
+both	O
+ketamine	O
+and	O
+morphine	O
+induced	O
+analgesia	B
+and	O
+catalepsy	B
+in	O
+the	O
+rat	O
+.	O
+
+Pre	O
+-	O
+treatment	O
+with	O
+ketamine	O
+produced	O
+cross	O
+-	O
+tolerance	O
+to	O
+morphine	O
+,	O
+whereas	O
+pretreatment	O
+with	O
+morphine	O
+did	O
+not	O
+induce	O
+cross	O
+-	O
+tolerance	O
+to	O
+ketamine	O
+but	O
+rather	O
+augmented	O
+the	O
+cataleptic	B
+response	O
+;	O
+this	O
+augmentation	O
+was	O
+attributed	O
+to	O
+residual	O
+morphine	O
+in	O
+the	O
+brain	O
+.	O
+
+The	O
+present	O
+studies	O
+explored	O
+the	O
+duration	O
+of	O
+the	O
+loss	O
+of	O
+righting	O
+reflex	O
+induced	O
+by	O
+sub	O
+-	O
+effective	O
+doses	O
+of	O
+ketamine	O
+and	O
+morphine	O
+,	O
+administered	O
+simultaneously	O
+.	O
+
+There	O
+was	O
+mutual	O
+potentiation	O
+between	O
+sub	O
+-	O
+effective	O
+doses	O
+of	O
+ketamine	O
+and	O
+morphine	O
+,	O
+but	O
+sub	O
+-	O
+effective	O
+doses	O
+of	O
+ketamine	O
+partly	O
+antagonized	O
+fully	O
+-	O
+effective	O
+doses	O
+of	O
+morphine	O
+.	O
+
+Latency	O
+to	O
+the	O
+loss	O
+of	O
+righting	O
+reflex	O
+,	O
+rigidity	B
+and	O
+behavior	O
+on	O
+recovery	O
+,	O
+reflected	O
+the	O
+relative	O
+predominance	O
+of	O
+ketamine	O
+or	O
+morphine	O
+in	O
+each	O
+combination	O
+.	O
+
+Naloxone	O
+inhibited	O
+the	O
+induced	O
+cataleptic	B
+effects	O
+.	O
+
+The	O
+degree	O
+and	O
+time	O
+course	O
+of	O
+development	O
+of	O
+tolerance	O
+to	O
+daily	O
+administration	O
+of	O
+sub	O
+-	O
+effective	O
+dose	O
+combinations	O
+of	O
+ketamine	O
+and	O
+morphine	O
+were	O
+similar	O
+.	O
+
+Rats	O
+,	O
+tolerant	O
+to	O
+ketamine	O
+-	O
+dominant	O
+combinations	O
+,	O
+were	O
+cross	O
+-	O
+tolerant	O
+to	O
+both	O
+drugs	O
+,	O
+while	O
+those	O
+tolerant	O
+to	O
+morphine	O
+-	O
+dominant	O
+combinations	O
+were	O
+cross	O
+-	O
+tolerant	O
+to	O
+morphine	O
+but	O
+showed	O
+either	O
+no	O
+cross	O
+-	O
+tolerance	O
+or	O
+an	O
+augmented	O
+response	O
+to	O
+ketamine	O
+.	O
+
+While	O
+the	O
+mutual	O
+potentiation	O
+,	O
+antagonism	O
+and	O
+tolerance	O
+suggest	O
+common	O
+mechanisms	O
+for	O
+the	O
+induced	O
+catalepsy	B
+,	O
+differences	O
+in	O
+latency	O
+,	O
+rigidity	B
+and	O
+behavior	O
+,	O
+asymmetry	O
+of	O
+cross	O
+-	O
+tolerance	O
+and	O
+a	O
+widely	O
+-	O
+different	O
+ID50	O
+for	O
+naloxone	O
+would	O
+argue	O
+against	O
+an	O
+action	O
+at	O
+a	O
+single	O
+opioid	O
+site	O
+.	O
+
+Hydrocortisone	O
+-	O
+induced	O
+hypertension	B
+in	O
+humans	O
+:	O
+pressor	O
+responsiveness	O
+and	O
+sympathetic	O
+function	O
+.	O
+
+Oral	O
+hydrocortisone	O
+increases	O
+blood	O
+pressure	O
+and	O
+enhances	O
+pressor	O
+responsiveness	O
+in	O
+normal	O
+human	O
+subjects	O
+.	O
+
+We	O
+studied	O
+the	O
+effects	O
+of	O
+1	O
+week	O
+of	O
+oral	O
+hydrocortisone	O
+(	O
+200	O
+mg	O
+/	O
+day	O
+)	O
+on	O
+blood	O
+pressure	O
+,	O
+cardiac	O
+output	O
+,	O
+total	O
+peripheral	O
+resistance	O
+,	O
+forearm	O
+vascular	O
+resistance	O
+,	O
+and	O
+norepinephrine	O
+spillover	O
+to	O
+plasma	O
+in	O
+eight	O
+healthy	O
+male	O
+volunteers	O
+.	O
+
+Although	O
+diastolic	O
+blood	O
+pressure	O
+remained	O
+unchanged	O
+,	O
+systolic	O
+blood	O
+pressure	O
+increased	O
+from	O
+119	O
+to	O
+135	O
+mm	O
+Hg	O
+(	O
+SED	O
++	O
+/	O
+-	O
+3	O
+.	O
+4	O
+,	O
+p	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+,	O
+associated	O
+with	O
+an	O
+increased	B
+cardiac	I
+output	I
+(	O
+5	O
+.	O
+85	O
+-	O
+7	O
+.	O
+73	O
+l	O
+/	O
+min	O
+,	O
+SED	O
++	O
+/	O
+-	O
+0	O
+.	O
+46	O
+,	O
+p	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+Total	O
+peripheral	O
+vascular	O
+resistance	O
+fell	O
+from	O
+15	O
+.	O
+1	O
+to	O
+12	O
+.	O
+2	O
+mm	O
+Hg	O
+/	O
+l	O
+/	O
+min	O
+(	O
+SED	O
++	O
+/	O
+-	O
+1	O
+.	O
+03	O
+,	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Resting	O
+forearm	O
+vascular	O
+resistance	O
+remained	O
+unchanged	O
+,	O
+but	O
+the	O
+reflex	O
+response	O
+to	O
+the	O
+cold	O
+pressor	O
+test	O
+was	O
+accentuated	O
+,	O
+the	O
+rise	O
+in	O
+resistance	O
+increasing	O
+from	O
+10	O
+.	O
+5	O
+mm	O
+Hg	O
+/	O
+ml	O
+/	O
+100	O
+ml	O
+/	O
+min	O
+(	O
+R	O
+units	O
+)	O
+before	O
+treatment	O
+to	O
+32	O
+.	O
+6	O
+R	O
+units	O
+after	O
+treatment	O
+(	O
+SED	O
++	O
+/	O
+-	O
+6	O
+.	O
+4	O
+,	O
+p	O
+less	O
+than	O
+0	O
+.	O
+025	O
+)	O
+.	O
+
+The	O
+rise	O
+in	O
+forearm	O
+vascular	O
+resistance	O
+accompanying	O
+intra	O
+-	O
+arterial	O
+norepinephrine	O
+(	O
+25	O
+,	O
+50	O
+,	O
+and	O
+100	O
+ng	O
+/	O
+min	O
+)	O
+was	O
+also	O
+significantly	O
+greater	O
+after	O
+hydrocortisone	O
+,	O
+increasing	O
+from	O
+an	O
+average	O
+of	O
+14	O
+.	O
+9	O
++	O
+/	O
+-	O
+2	O
+.	O
+4	O
+R	O
+units	O
+before	O
+treatment	O
+to	O
+35	O
+.	O
+1	O
++	O
+/	O
+-	O
+5	O
+.	O
+5	O
+R	O
+units	O
+after	O
+hydrocortisone	O
+(	O
+SED	O
++	O
+/	O
+-	O
+6	O
+.	O
+0	O
+,	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+A	O
+shift	O
+to	O
+the	O
+left	O
+in	O
+the	O
+dose	O
+-	O
+response	O
+relation	O
+and	O
+fall	O
+in	O
+threshold	O
+suggested	O
+increased	O
+sensitivity	O
+to	O
+norepinephrine	O
+after	O
+treatment	O
+.	O
+
+Measurement	O
+of	O
+resting	O
+norepinephrine	O
+spillover	O
+rate	O
+to	O
+plasma	O
+and	O
+norepinephrine	O
+uptake	O
+indicated	O
+that	O
+overall	O
+resting	O
+sympathetic	O
+nervous	O
+system	O
+activity	O
+was	O
+not	O
+increased	O
+.	O
+
+The	O
+rise	B
+in	I
+resting	I
+blood	I
+pressure	I
+with	O
+hydrocortisone	O
+is	O
+associated	O
+with	O
+an	O
+increased	B
+cardiac	I
+output	I
+(	O
+presumably	O
+due	O
+to	O
+increased	O
+blood	O
+volume	O
+)	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Neuromuscular	B
+blockade	I
+with	O
+magnesium	O
+sulfate	O
+and	O
+nifedipine	O
+.	O
+
+A	O
+patient	O
+who	O
+received	O
+tocolysis	O
+with	O
+nifedipine	O
+developed	O
+neuromuscular	B
+blockade	I
+after	O
+500	O
+mg	O
+of	O
+magnesium	O
+sulfate	O
+was	O
+administered	O
+.	O
+
+This	O
+reaction	O
+demonstrates	O
+that	O
+nifedipine	O
+can	O
+seriously	O
+potentiate	O
+the	O
+toxicity	B
+of	O
+magnesium	O
+.	O
+
+Caution	O
+should	O
+be	O
+exercised	O
+when	O
+these	O
+two	O
+tocolytics	O
+are	O
+combined	O
+.	O
+
+Chronic	O
+carbamazepine	O
+inhibits	O
+the	O
+development	O
+of	O
+local	O
+anesthetic	O
+seizures	B
+kindled	O
+by	O
+cocaine	O
+and	O
+lidocaine	O
+.	O
+
+The	O
+effects	O
+of	O
+carbamazepine	O
+(	O
+CBZ	O
+)	O
+treatment	O
+on	O
+local	O
+anesthetic	O
+-	O
+kindled	O
+seizures	B
+and	O
+lethality	O
+were	O
+evaluated	O
+in	O
+different	O
+stages	O
+of	O
+the	O
+kindling	O
+process	O
+and	O
+under	O
+different	O
+methods	O
+of	O
+CBZ	O
+administration	O
+.	O
+
+Chronic	O
+oral	O
+CBZ	O
+inhibited	O
+the	O
+development	O
+of	O
+both	O
+lidocaine	O
+-	O
+and	O
+cocaine	O
+-	O
+induced	O
+seizures	B
+,	O
+but	O
+had	O
+little	O
+effect	O
+on	O
+the	O
+fully	O
+developed	O
+local	O
+anesthetic	O
+seizures	B
+.	O
+
+Chronic	O
+CBZ	O
+also	O
+decreased	O
+the	O
+incidence	O
+of	O
+seizure	B
+-	O
+related	O
+mortality	O
+in	O
+the	O
+cocaine	O
+-	O
+injected	O
+rats	O
+.	O
+
+Acute	O
+CBZ	O
+over	O
+a	O
+range	O
+of	O
+doses	O
+(	O
+15	O
+-	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+had	O
+no	O
+effect	O
+on	O
+completed	O
+lidocaine	O
+-	O
+kindled	O
+or	O
+acute	O
+cocaine	O
+-	O
+induced	O
+seizures	B
+.	O
+
+Repeated	O
+i	O
+.	O
+p	O
+.	O
+injection	O
+of	O
+CBZ	O
+(	O
+15	O
+mg	O
+/	O
+kg	O
+)	O
+also	O
+was	O
+without	O
+effect	O
+on	O
+the	O
+development	O
+of	O
+lidocaine	O
+-	O
+or	O
+cocaine	O
+-	O
+kindled	O
+seizures	B
+.	O
+
+The	O
+differential	O
+effects	O
+of	O
+CBZ	O
+depending	O
+upon	O
+stage	O
+of	O
+seizure	B
+development	O
+suggest	O
+that	O
+distinct	O
+mechanisms	O
+underlie	O
+the	O
+development	O
+versus	O
+maintenance	O
+of	O
+local	O
+anesthetic	O
+-	O
+kindled	O
+seizures	B
+.	O
+
+The	O
+effectiveness	O
+of	O
+chronic	O
+but	O
+not	O
+repeated	O
+,	O
+intermittent	O
+injections	O
+of	O
+CBZ	O
+suggests	O
+that	O
+different	O
+biochemical	O
+consequences	O
+result	O
+from	O
+the	O
+different	O
+treatment	O
+regimens	O
+.	O
+
+The	O
+possible	O
+utility	O
+of	O
+chronic	O
+CBZ	O
+in	O
+preventing	O
+the	O
+development	O
+of	O
+toxic	O
+side	O
+effects	O
+in	O
+human	O
+cocaine	O
+users	O
+is	O
+suggested	O
+by	O
+these	O
+data	O
+,	O
+but	O
+remains	O
+to	O
+be	O
+directly	O
+evaluated	O
+.	O
+
+Magnetic	O
+resonance	O
+imaging	O
+of	O
+cerebral	O
+venous	B
+thrombosis	I
+secondary	O
+to	O
+"	O
+low	O
+-	O
+dose	O
+"	O
+birth	O
+control	O
+pills	O
+.	O
+
+The	O
+clinical	O
+and	O
+radiographic	O
+features	O
+of	O
+cerebral	O
+deep	B
+venous	I
+thrombosis	I
+in	O
+a	O
+21	O
+-	O
+year	O
+-	O
+old	O
+white	O
+woman	O
+are	O
+presented	O
+.	O
+
+This	O
+nulliparous	O
+patient	O
+presented	O
+with	O
+relatively	O
+mild	O
+clinical	O
+symptoms	O
+and	O
+progressing	O
+mental	O
+status	O
+changes	O
+.	O
+
+The	O
+only	O
+known	O
+risk	O
+factor	O
+was	O
+"	O
+low	O
+-	O
+dose	O
+"	O
+oral	O
+contraceptive	O
+pills	O
+.	O
+
+The	O
+magnetic	O
+resonance	O
+image	O
+(	O
+MRI	O
+)	O
+showed	O
+increased	O
+signal	O
+intensity	O
+from	O
+the	O
+internal	O
+cerebral	O
+veins	O
+,	O
+vein	O
+of	O
+Galen	O
+,	O
+and	O
+straight	O
+sinus	O
+.	O
+
+The	O
+diagnosis	O
+was	O
+confirmed	O
+by	O
+arterial	O
+angiography	O
+.	O
+
+Beta	O
+-	O
+2	O
+-	O
+adrenoceptor	O
+-	O
+mediated	O
+hypokalemia	B
+and	O
+its	O
+abolishment	O
+by	O
+oxprenolol	O
+.	O
+
+The	O
+time	O
+course	O
+and	O
+concentration	O
+-	O
+effect	O
+relationship	O
+of	O
+terbutaline	O
+-	O
+induced	O
+hypokalemia	B
+was	O
+studied	O
+,	O
+using	O
+computer	O
+-	O
+aided	O
+pharmacokinetic	O
+-	O
+dynamic	O
+modeling	O
+.	O
+
+Subsequently	O
+we	O
+investigated	O
+the	O
+efficacy	O
+of	O
+oxprenolol	O
+in	O
+antagonizing	O
+such	O
+hypokalemia	B
+,	O
+together	O
+with	O
+the	O
+pharmacokinetic	O
+interaction	O
+between	O
+both	O
+drugs	O
+.	O
+
+Six	O
+healthy	O
+subjects	O
+were	O
+given	O
+a	O
+0	O
+.	O
+5	O
+mg	O
+subcutaneous	O
+dose	O
+of	O
+terbutaline	O
+on	O
+two	O
+occasions	O
+:	O
+1	O
+hour	O
+after	O
+oral	O
+administration	O
+of	O
+a	O
+placebo	O
+and	O
+1	O
+hour	O
+after	O
+80	O
+mg	O
+oxprenolol	O
+orally	O
+.	O
+
+In	O
+the	O
+7	O
+-	O
+hour	O
+period	O
+after	O
+terbutaline	O
+administration	O
+,	O
+plasma	O
+samples	O
+were	O
+taken	O
+for	O
+determination	O
+of	O
+plasma	O
+potassium	O
+levels	O
+and	O
+drug	O
+concentrations	O
+.	O
+
+The	O
+sigmoid	O
+Emax	O
+model	O
+offered	O
+a	O
+good	O
+description	O
+of	O
+the	O
+relation	O
+between	O
+terbutaline	O
+concentrations	O
+and	O
+potassium	O
+effects	O
+.	O
+
+Oxprenolol	O
+caused	O
+decreases	O
+of	O
+65	O
+%	O
+and	O
+56	O
+%	O
+of	O
+terbutaline	O
+volume	O
+of	O
+distribution	O
+and	O
+clearance	O
+,	O
+respectively	O
+,	O
+and	O
+an	O
+increase	O
+of	O
+130	O
+%	O
+of	O
+its	O
+AUC	O
+.	O
+
+In	O
+spite	O
+of	O
+higher	O
+terbutaline	O
+concentrations	O
+after	O
+oxprenolol	O
+pretreatment	O
+,	O
+the	O
+hypokalemia	B
+was	O
+almost	O
+completely	O
+antagonized	O
+by	O
+the	O
+beta	O
+2	O
+-	O
+blocking	O
+action	O
+.	O
+
+A	O
+dystonia	B
+-	O
+like	O
+syndrome	O
+after	O
+neuropeptide	O
+(	O
+MSH	O
+/	O
+ACTH	O
+)	O
+stimulation	O
+of	O
+the	O
+rat	O
+locus	O
+ceruleus	O
+.	O
+
+The	O
+movement	B
+disorder	I
+investigated	O
+in	O
+these	O
+studies	O
+has	O
+some	O
+features	O
+in	O
+common	O
+with	O
+human	O
+idiopathic	O
+dystonia	B
+,	O
+and	O
+information	O
+obtained	O
+in	O
+these	O
+studies	O
+may	O
+be	O
+of	O
+potential	O
+clinical	O
+benefit	O
+.	O
+
+The	O
+present	O
+experimental	O
+results	O
+indicated	O
+that	O
+peptidergic	O
+stimulation	O
+of	O
+the	O
+LC	O
+resulted	O
+in	O
+a	O
+NE	O
+-	O
+mediated	O
+inhibition	O
+of	O
+cerebellar	O
+Purkinje	O
+cells	O
+located	O
+at	O
+terminals	O
+of	O
+the	O
+ceruleo	O
+-	O
+cerebellar	O
+pathway	O
+.	O
+
+However	O
+,	O
+it	O
+is	O
+not	O
+certain	O
+as	O
+to	O
+the	O
+following	O
+:	O
+(	O
+a	O
+)	O
+what	O
+receptors	O
+were	O
+stimulated	O
+by	O
+the	O
+ACTH	O
+N	O
+-	O
+terminal	O
+fragments	O
+at	O
+the	O
+LC	O
+that	O
+resulted	O
+in	O
+this	O
+disorder	O
+;	O
+(	O
+b	O
+)	O
+whether	O
+NE	O
+,	O
+released	O
+onto	O
+Purkinje	O
+cell	O
+synapses	O
+located	O
+at	O
+terminals	O
+of	O
+the	O
+ceruleo	O
+-	O
+cerebellar	O
+pathway	O
+,	O
+did	O
+indeed	O
+cause	O
+the	O
+long	O
+-	O
+term	O
+depression	B
+at	O
+Purkinje	O
+cell	O
+synapses	O
+(	O
+previously	O
+described	O
+by	O
+others	O
+)	O
+that	O
+resulted	O
+in	O
+the	O
+long	O
+duration	O
+of	O
+the	O
+movement	B
+disorder	I
+;	O
+(	O
+c	O
+)	O
+whether	O
+the	O
+inhibition	O
+of	O
+inhibitory	O
+Purkinje	O
+cells	O
+resulted	O
+in	O
+disinhibition	O
+or	O
+increased	O
+excitability	O
+of	O
+the	O
+unilateral	O
+cerebellar	O
+fastigial	O
+or	O
+interpositus	O
+nuclei	O
+,	O
+the	O
+output	O
+targets	O
+of	O
+the	O
+Purkinje	O
+cell	O
+axons	O
+,	O
+that	O
+may	O
+have	O
+been	O
+an	O
+important	O
+contributing	O
+factor	O
+to	O
+this	O
+disorder	O
+.	O
+
+These	O
+questions	O
+are	O
+currently	O
+being	O
+investigated	O
+.	O
+
+Enhanced	O
+stimulus	O
+-	O
+induced	O
+neurotransmitter	O
+overflow	O
+in	O
+epinephrine	O
+-	O
+induced	O
+hypertensive	B
+rats	O
+is	O
+not	O
+mediated	O
+by	O
+prejunctional	O
+beta	O
+-	O
+adrenoceptor	O
+activation	O
+.	O
+
+The	O
+present	O
+study	O
+examines	O
+the	O
+effect	O
+of	O
+6	O
+-	O
+day	O
+epinephrine	O
+treatment	O
+(	O
+100	O
+micrograms	O
+/	O
+kg	O
+per	O
+h	O
+,	O
+s	O
+.	O
+c	O
+.	O
+)	O
+on	O
+stimulus	O
+-	O
+induced	O
+(	O
+1	O
+Hz	O
+)	O
+endogenous	O
+neurotransmitter	O
+overflow	O
+from	O
+the	O
+isolated	O
+perfused	O
+kidney	O
+of	O
+vehicle	O
+-	O
+and	O
+epinephrine	O
+-	O
+treated	O
+rats	O
+.	O
+
+Renal	O
+catecholamine	O
+stores	O
+and	O
+stimulus	O
+-	O
+induced	O
+overflow	O
+in	O
+the	O
+vehicle	O
+-	O
+treated	O
+group	O
+consisted	O
+of	O
+norepinephrine	O
+only	O
+.	O
+
+However	O
+,	O
+epinephrine	O
+treatment	O
+resulted	O
+in	O
+the	O
+incorporation	O
+of	O
+epinephrine	O
+into	O
+renal	O
+catecholamine	O
+stores	O
+such	O
+that	O
+approximately	O
+40	O
+%	O
+of	O
+the	O
+catecholamine	O
+present	O
+was	O
+epinephrine	O
+while	O
+the	O
+norepinephrine	O
+content	O
+was	O
+reduced	O
+by	O
+a	O
+similar	O
+degree	O
+.	O
+
+Total	O
+tissue	O
+catecholamine	O
+content	O
+of	O
+the	O
+kidney	O
+on	O
+a	O
+molar	O
+basis	O
+was	O
+unchanged	O
+.	O
+
+Stimulus	O
+-	O
+induced	O
+fractional	O
+overflow	O
+of	O
+neurotransmitter	O
+from	O
+the	O
+epinephrine	O
+-	O
+treated	O
+kidneys	O
+was	O
+approximately	O
+twice	O
+normal	O
+and	O
+consisted	O
+of	O
+both	O
+norepinephrine	O
+and	O
+epinephrine	O
+in	O
+proportions	O
+similar	O
+to	O
+those	O
+found	O
+in	O
+the	O
+kidney	O
+.	O
+
+This	O
+difference	O
+in	O
+fractional	O
+overflow	O
+between	O
+groups	O
+was	O
+not	O
+affected	O
+by	O
+neuronal	O
+and	O
+extraneuronal	O
+uptake	O
+blockade	O
+.	O
+
+Propranolol	O
+had	O
+no	O
+effect	O
+on	O
+stimulus	O
+-	O
+induced	O
+overflow	O
+in	O
+either	O
+group	O
+.	O
+
+Phentolamine	O
+increased	O
+stimulus	O
+-	O
+induced	O
+overflow	O
+in	O
+both	O
+groups	O
+although	O
+the	O
+increment	O
+in	O
+overflow	O
+was	O
+greater	O
+in	O
+the	O
+epinephrine	O
+-	O
+treated	O
+group	O
+.	O
+
+In	O
+conclusion	O
+,	O
+chronic	O
+epinephrine	O
+treatment	O
+results	O
+in	O
+enhanced	O
+fractional	O
+neurotransmitter	O
+overflow	O
+.	O
+
+However	O
+,	O
+neither	O
+alterations	O
+in	O
+prejunctional	O
+beta	O
+-	O
+adrenoceptor	O
+influences	O
+nor	O
+alterations	O
+in	O
+neuronal	O
+and	O
+extraneuronal	O
+uptake	O
+mechanisms	O
+appear	O
+to	O
+be	O
+responsible	O
+for	O
+this	O
+alteration	O
+.	O
+
+Furthermore	O
+,	O
+data	O
+obtained	O
+with	O
+phentolamine	O
+alone	O
+do	O
+not	O
+suggest	O
+alpha	O
+-	O
+adrenoceptor	O
+desensitization	O
+as	O
+the	O
+cause	O
+of	O
+the	O
+enhanced	O
+neurotransmitter	O
+overflow	O
+after	O
+epinephrine	O
+treatment	O
+.	O
+
+GABA	O
+involvement	O
+in	O
+naloxone	O
+induced	O
+reversal	O
+of	O
+respiratory	B
+paralysis	I
+produced	O
+by	O
+thiopental	O
+.	O
+
+No	O
+agent	O
+is	O
+yet	O
+available	O
+to	O
+reverse	O
+respiratory	B
+paralysis	I
+produced	O
+by	O
+CNS	O
+depressants	O
+,	O
+such	O
+as	O
+general	O
+anesthetics	O
+.	O
+
+In	O
+this	O
+study	O
+naloxone	O
+reversed	O
+respiratory	B
+paralysis	I
+induced	O
+by	O
+thiopental	O
+in	O
+rats	O
+.	O
+
+25	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+v	O
+.	O
+thiopental	O
+produced	O
+anesthesia	O
+without	O
+altering	O
+respiratory	O
+rate	O
+,	O
+increased	O
+GABA	O
+,	O
+decreased	O
+glutamate	O
+,	O
+and	O
+had	O
+no	O
+effect	O
+on	O
+aspartate	O
+or	O
+glycine	O
+levels	O
+compared	O
+to	O
+controls	O
+in	O
+rat	O
+cortex	O
+and	O
+brain	O
+stem	O
+.	O
+
+Pretreatment	O
+of	O
+rats	O
+with	O
+thiosemicarbazide	O
+for	O
+30	O
+minutes	O
+abolished	O
+the	O
+anesthetic	O
+action	O
+as	O
+well	O
+as	O
+the	O
+respiratory	O
+depressant	O
+action	O
+of	O
+thiopental	O
+.	O
+
+50	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+v	O
+.	O
+thiopental	O
+produced	O
+respiratory	B
+arrest	I
+with	O
+further	O
+increase	O
+in	O
+GABA	O
+and	O
+decrease	O
+in	O
+glutamate	O
+again	O
+in	O
+cortex	O
+and	O
+brain	O
+stem	O
+without	O
+affecting	O
+any	O
+of	O
+the	O
+amino	O
+acids	O
+studied	O
+in	O
+four	O
+regions	O
+of	O
+rat	O
+brain	O
+.	O
+
+Naloxone	O
+(	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+v	O
+.	O
+)	O
+reversed	O
+respiratory	B
+paralysis	I
+,	O
+glutamate	O
+and	O
+GABA	O
+levels	O
+to	O
+control	O
+values	O
+in	O
+brain	O
+stem	O
+and	O
+cortex	O
+with	O
+no	O
+changes	O
+in	O
+caudate	O
+or	O
+cerebellum	O
+.	O
+
+These	O
+data	O
+suggest	O
+naloxone	O
+reverses	O
+respiratory	B
+paralysis	I
+produced	O
+by	O
+thiopental	O
+and	O
+involves	O
+GABA	O
+in	O
+its	O
+action	O
+.	O
+
+Diazepam	O
+facilitates	O
+reflex	O
+bradycardia	B
+in	O
+conscious	O
+rats	O
+.	O
+
+The	O
+effects	O
+of	O
+diazepam	O
+on	O
+cardiovascular	O
+function	O
+were	O
+assessed	O
+in	O
+conscious	O
+rats	O
+.	O
+
+Intravenous	O
+administration	O
+of	O
+diazepam	O
+(	O
+1	O
+-	O
+30	O
+mg	O
+kg	O
+-	O
+1	O
+)	O
+produced	O
+a	O
+dose	O
+-	O
+dependent	O
+decrease	O
+in	O
+both	O
+the	O
+mean	O
+arterial	O
+pressure	O
+and	O
+the	O
+heart	O
+rate	O
+.	O
+
+Also	O
+,	O
+reflex	O
+bradycardia	B
+was	O
+produced	O
+in	O
+rats	O
+by	O
+intravenous	O
+infusion	O
+of	O
+adrenaline	O
+(	O
+1	O
+.	O
+25	O
+-	O
+2	O
+.	O
+5	O
+micrograms	O
+kg	O
+-	O
+1	O
+)	O
+.	O
+
+Intravenous	O
+pretreatment	O
+of	O
+the	O
+rats	O
+with	O
+diazepam	O
+,	O
+although	O
+causing	O
+no	O
+change	O
+in	O
+the	O
+adrenaline	O
+-	O
+induced	O
+pressor	O
+effect	O
+,	O
+did	O
+enhance	O
+the	O
+adrenaline	O
+-	O
+induced	O
+reflex	O
+bradycardia	B
+.	O
+
+However	O
+,	O
+the	O
+diazepam	O
+enhancement	O
+of	O
+adrenaline	O
+-	O
+induced	O
+reflex	O
+bradycardia	B
+was	O
+antagonized	O
+by	O
+pretreatment	O
+of	O
+rats	O
+with	O
+an	O
+intravenous	O
+dose	O
+of	O
+picrotoxin	O
+(	O
+an	O
+agent	O
+blocks	O
+chloride	O
+channels	O
+by	O
+binding	O
+to	O
+sites	O
+associated	O
+with	O
+the	O
+benzodiazepine	O
+-	O
+GABA	O
+-	O
+chloride	O
+channel	O
+macromolecular	O
+complex	O
+)	O
+.	O
+
+The	O
+data	O
+indicate	O
+that	O
+diazepam	O
+acts	O
+through	O
+the	O
+benzodiazepine	O
+-	O
+GABA	O
+-	O
+chloride	O
+channel	O
+macromolecular	O
+complex	O
+within	O
+the	O
+central	O
+nervous	O
+system	O
+to	O
+facilitate	O
+reflex	O
+bradycardia	B
+mediated	O
+through	O
+baroreceptor	O
+reflexes	O
+in	O
+response	O
+to	O
+an	O
+acute	O
+increase	O
+in	O
+arterial	O
+pressure	O
+.	O
+
+Initial	O
+potassium	O
+loss	O
+and	O
+hypokalaemia	B
+during	O
+chlorthalidone	O
+administration	O
+in	O
+patients	O
+with	O
+essential	O
+hypertension	B
+:	O
+the	O
+influence	O
+of	O
+dietary	O
+sodium	O
+restriction	O
+.	O
+
+To	O
+investigate	O
+the	O
+initial	O
+potassium	O
+loss	O
+and	O
+development	O
+of	O
+hypokalaemia	B
+during	O
+the	O
+administration	O
+of	O
+an	O
+oral	O
+diuretic	O
+,	O
+metabolic	O
+balance	O
+studies	O
+were	O
+performed	O
+in	O
+ten	O
+patients	O
+with	O
+essential	O
+hypertension	B
+who	O
+had	O
+shown	O
+hypokalaemia	B
+under	O
+prior	O
+oral	O
+diuretic	O
+treatment	O
+.	O
+
+Chlorthalidone	O
+(	O
+50	O
+mg	O
+daily	O
+)	O
+was	O
+given	O
+for	O
+14	O
+days	O
+.	O
+
+Six	O
+patients	O
+received	O
+a	O
+normal	O
+-	O
+sodium	O
+diet	O
+and	O
+four	O
+a	O
+low	O
+-	O
+sodium	O
+(	O
+17	O
+mmol	O
+/	O
+day	O
+)	O
+diet	O
+.	O
+
+All	O
+patients	O
+had	O
+a	O
+normal	O
+initial	O
+total	O
+body	O
+potassium	O
+(	O
+40K	O
+)	O
+.	O
+
+The	O
+electrolyte	O
+balances	O
+,	O
+weight	O
+,	O
+bromide	O
+space	O
+,	O
+plasma	O
+renin	O
+activity	O
+,	O
+and	O
+aldosterone	O
+secretion	O
+rate	O
+were	O
+measured	O
+.	O
+
+In	O
+both	O
+groups	O
+a	O
+potassium	O
+deficit	O
+developed	O
+,	O
+with	O
+proportionally	O
+larger	O
+losses	O
+from	O
+the	O
+extracellular	O
+than	O
+from	O
+the	O
+intracellular	O
+compartment	O
+.	O
+
+In	O
+the	O
+normal	O
+-	O
+sodium	O
+group	O
+the	O
+highest	O
+mean	O
+potassium	O
+deficit	O
+was	O
+176	O
+mmol	O
+on	O
+day	O
+9	O
+,	O
+after	O
+which	O
+some	O
+potassium	O
+was	O
+regained	O
+;	O
+in	O
+the	O
+low	O
+-	O
+sodium	O
+group	O
+the	O
+highest	O
+deficit	O
+was	O
+276	O
+mmol	O
+on	O
+day	O
+13	O
+.	O
+
+The	O
+normal	O
+-	O
+sodium	O
+group	O
+showed	O
+an	O
+immediate	O
+but	O
+temporary	O
+rise	O
+of	O
+the	O
+renin	O
+and	O
+aldosterone	O
+levels	O
+;	O
+in	O
+the	O
+low	O
+-	O
+sodium	O
+group	O
+renin	O
+and	O
+aldosterone	O
+increased	O
+more	O
+slowly	O
+but	O
+remained	O
+elevated	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+dietary	O
+sodium	O
+restriction	O
+increases	O
+diuretic	O
+-	O
+induced	O
+potassium	O
+loss	O
+,	O
+presumably	O
+by	O
+an	O
+increased	O
+activity	O
+of	O
+the	O
+renin	O
+-	O
+angiotensin	O
+-	O
+aldosterone	O
+system	O
+,	O
+while	O
+sodium	O
+delivery	O
+to	O
+the	O
+distal	O
+renal	O
+tubules	O
+remains	O
+sufficiently	O
+high	O
+to	O
+allow	O
+increased	O
+potassium	O
+secretion	O
+.	O
+
+Reversal	O
+of	O
+neuroleptic	O
+-	O
+induced	O
+catalepsy	B
+by	O
+novel	O
+aryl	O
+-	O
+piperazine	O
+anxiolytic	O
+drugs	O
+.	O
+
+The	O
+novel	O
+anxiolytic	O
+drug	O
+,	O
+buspirone	O
+,	O
+reverses	O
+catalepsy	B
+induced	O
+by	O
+haloperidol	O
+.	O
+
+A	O
+series	O
+of	O
+aryl	O
+-	O
+piperazine	O
+analogues	O
+of	O
+buspirone	O
+and	O
+other	O
+5	O
+-	O
+hydroxytryptaminergic	O
+agonists	O
+were	O
+tested	O
+for	O
+their	O
+ability	O
+to	O
+reverse	O
+haloperidol	O
+induced	O
+catalepsy	B
+.	O
+
+Those	O
+drugs	O
+with	O
+strong	O
+affinity	O
+for	O
+5	O
+-	O
+hydroxytryptamine1a	O
+receptors	O
+were	O
+able	O
+to	O
+reverse	O
+catalepsy	B
+.	O
+
+Drugs	O
+with	O
+affinity	O
+for	O
+other	O
+5	O
+-	O
+HT	O
+receptors	O
+or	O
+weak	O
+affinity	O
+were	O
+ineffective	O
+.	O
+
+However	O
+,	O
+inhibition	O
+of	O
+postsynaptic	O
+5	O
+-	O
+HT	O
+receptors	O
+neither	O
+inhibited	O
+nor	O
+potentiated	O
+reversal	O
+of	O
+catalepsy	B
+and	O
+leaves	O
+open	O
+the	O
+question	O
+as	O
+to	O
+the	O
+site	O
+or	O
+mechanism	O
+for	O
+this	O
+effect	O
+.	O
+
+Glycopyrronium	O
+requirements	O
+for	O
+antagonism	O
+of	O
+the	O
+muscarinic	O
+side	O
+effects	O
+of	O
+edrophonium	O
+.	O
+
+We	O
+have	O
+compared	O
+,	O
+in	O
+60	O
+adult	O
+patients	O
+,	O
+the	O
+cardiovascular	O
+effects	O
+of	O
+glycopyrronium	O
+5	O
+micrograms	O
+kg	O
+-	O
+1	O
+and	O
+10	O
+micrograms	O
+kg	O
+-	O
+1	O
+given	O
+either	O
+simultaneously	O
+or	O
+1	O
+min	O
+before	O
+edrophonium	O
+1	O
+mg	O
+kg	O
+-	O
+1	O
+.	O
+
+Significant	O
+differences	O
+between	O
+the	O
+four	O
+groups	O
+were	O
+detected	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Both	O
+groups	O
+receiving	O
+10	O
+micrograms	O
+kg	O
+-	O
+1	O
+showed	O
+increases	O
+in	O
+heart	O
+rate	O
+of	O
+up	O
+to	O
+30	O
+beat	O
+min	O
+-	O
+1	O
+(	O
+95	O
+%	O
+confidence	O
+limits	O
+28	O
+-	O
+32	O
+beat	O
+min	O
+-	O
+1	O
+)	O
+.	O
+
+Use	O
+of	O
+glycopyrronium	O
+5	O
+micrograms	O
+kg	O
+-	O
+1	O
+provided	O
+greater	O
+cardiovascular	O
+stability	O
+and	O
+,	O
+given	O
+1	O
+min	O
+before	O
+the	O
+edrophonium	O
+,	O
+was	O
+sufficient	O
+to	O
+minimize	O
+early	O
+,	O
+edrophonium	O
+-	O
+induced	O
+bradycardias	B
+.	O
+
+This	O
+low	O
+dose	O
+of	O
+glycopyrronium	O
+provided	O
+good	O
+control	O
+of	O
+oropharyngeal	O
+secretions	O
+.	O
+
+Selective	O
+injection	O
+of	O
+iopentol	O
+,	O
+iohexol	O
+and	O
+metrizoate	O
+into	O
+the	O
+left	O
+coronary	O
+artery	O
+of	O
+the	O
+dog	O
+.	O
+
+Induction	O
+of	O
+ventricular	B
+fibrillation	I
+and	O
+decrease	O
+of	O
+aortic	O
+pressure	O
+.	O
+
+In	O
+twenty	O
+beagle	O
+dogs	O
+selective	O
+injections	O
+were	O
+made	O
+into	O
+the	O
+left	O
+coronary	O
+artery	O
+with	O
+iopentol	O
+,	O
+iohexol	O
+and	O
+metrizoate	O
+in	O
+doses	O
+of	O
+4	O
+ml	O
+,	O
+8	O
+ml	O
+and	O
+16	O
+ml	O
+.	O
+
+Thirty	O
+-	O
+six	O
+iopentol	O
+injections	O
+,	O
+35	O
+iohexol	O
+injections	O
+and	O
+37	O
+metrizoate	O
+injections	O
+were	O
+made	O
+.	O
+
+Frequencies	O
+of	O
+ventricular	B
+fibrillation	I
+were	O
+significantly	O
+lower	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+after	O
+iopentol	O
+(	O
+0	O
+%	O
+)	O
+and	O
+iohexol	O
+(	O
+3	O
+%	O
+)	O
+than	O
+after	O
+metrizoate	O
+(	O
+22	O
+%	O
+)	O
+.	O
+
+Iopentol	O
+and	O
+iohexol	O
+also	O
+produced	O
+significantly	O
+less	O
+decrease	O
+in	O
+aortic	O
+blood	O
+pressure	O
+than	O
+metrizoate	O
+at	O
+the	O
+different	O
+doses	O
+.	O
+
+Thyroid	O
+function	O
+and	O
+urine	O
+-	O
+concentrating	O
+ability	O
+during	O
+lithium	O
+treatment	O
+.	O
+
+It	O
+has	O
+been	O
+suggested	O
+that	O
+adenylate	O
+cyclase	O
+inhibition	O
+may	O
+be	O
+important	O
+in	O
+the	O
+development	O
+of	O
+both	O
+nephrogenic	B
+diabetes	I
+insipidus	I
+and	O
+hypothyroidism	B
+during	O
+lithium	O
+treatment	O
+.	O
+
+We	O
+measured	O
+serum	O
+thyroxine	O
+and	O
+urine	O
+-	O
+concentrating	O
+ability	O
+(	O
+Umax	O
+)	O
+in	O
+response	O
+to	O
+desmopressin	O
+(	O
+DDAVP	O
+)	O
+in	O
+85	O
+patients	O
+receiving	O
+lithium	O
+.	O
+
+Hypothyroidism	B
+developed	O
+in	O
+eight	O
+patients	O
+while	O
+they	O
+were	O
+taking	O
+lithium	O
+.	O
+
+Impaired	O
+Umax	O
+was	O
+found	O
+in	O
+both	O
+euthyroid	O
+and	O
+hypothyroid	B
+patients	O
+while	O
+some	O
+hypothyroid	B
+patients	O
+concentrated	O
+their	O
+urine	O
+well	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+the	O
+dominant	O
+mechanisms	O
+by	O
+which	O
+lithium	O
+exerts	O
+these	O
+two	O
+effects	O
+are	O
+different	O
+.	O
+
+Remodelling	O
+of	O
+nerve	O
+structure	O
+in	O
+experimental	O
+isoniazid	O
+neuropathy	B
+in	O
+the	O
+rat	O
+.	O
+
+The	O
+neuropathy	B
+caused	O
+by	O
+a	O
+single	O
+dose	O
+of	O
+isoniazid	O
+in	O
+rats	O
+was	O
+studied	O
+with	O
+a	O
+computer	O
+-	O
+assisted	O
+morphometric	O
+method	O
+.	O
+
+Scatter	O
+diagrams	O
+of	O
+the	O
+g	O
+ratio	O
+(	O
+quotient	O
+fibre	O
+diameter	O
+/	O
+axon	O
+diameter	O
+)	O
+define	O
+regenerating	O
+fibres	O
+as	O
+a	O
+distinct	O
+population	O
+,	O
+distinguishable	O
+from	O
+the	O
+surviving	O
+fibres	O
+by	O
+reduced	O
+sheath	O
+thickness	O
+and	O
+reduced	O
+axon	O
+calibre	O
+.	O
+
+There	O
+was	O
+also	O
+evidence	O
+of	O
+a	O
+subtle	O
+direct	O
+toxic	O
+effect	O
+on	O
+the	O
+entire	O
+fibre	O
+population	O
+,	O
+causing	O
+axon	O
+shrinkage	O
+masked	O
+by	O
+readjustment	O
+of	O
+the	O
+myelin	O
+sheath	O
+.	O
+
+Multicenter	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+multiple	O
+-	O
+dose	O
+,	O
+parallel	O
+-	O
+groups	O
+efficacy	O
+and	O
+safety	O
+trial	O
+of	O
+azelastine	O
+,	O
+chlorpheniramine	O
+,	O
+and	O
+placebo	O
+in	O
+the	O
+treatment	O
+of	O
+spring	B
+allergic	I
+rhinitis	I
+.	O
+
+Azelastine	O
+,	O
+a	O
+novel	O
+antiallergic	O
+medication	O
+,	O
+was	O
+compared	O
+with	O
+chlorpheniramine	O
+maleate	O
+and	O
+placebo	O
+for	O
+efficacy	O
+and	O
+safety	O
+in	O
+the	O
+treatment	O
+of	O
+spring	B
+allergic	I
+rhinitis	I
+in	O
+a	O
+multicenter	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+multiple	O
+-	O
+dose	O
+,	O
+parallel	O
+-	O
+groups	O
+study	O
+.	O
+
+One	O
+hundred	O
+fifty	O
+-	O
+five	O
+subjects	O
+participated	O
+.	O
+
+Subjects	O
+ranged	O
+in	O
+age	O
+from	O
+18	O
+to	O
+60	O
+years	O
+of	O
+age	O
+and	O
+had	O
+at	O
+least	O
+a	O
+2	O
+-	O
+year	O
+history	O
+of	O
+spring	B
+allergic	I
+rhinitis	I
+,	O
+confirmed	O
+by	O
+positive	O
+skin	O
+test	O
+to	O
+spring	O
+aeroallergens	O
+.	O
+
+Medications	O
+were	O
+given	O
+four	O
+times	O
+daily	O
+;	O
+the	O
+azelastine	O
+groups	O
+received	O
+0	O
+.	O
+5	O
+,	O
+1	O
+.	O
+0	O
+,	O
+or	O
+2	O
+.	O
+0	O
+mg	O
+in	O
+the	O
+morning	O
+and	O
+evening	O
+with	O
+placebo	O
+in	O
+the	O
+early	O
+and	O
+late	O
+afternoon	O
+;	O
+the	O
+chlorpheniramine	O
+group	O
+received	O
+4	O
+.	O
+0	O
+mg	O
+four	O
+times	O
+daily	O
+.	O
+
+Daily	O
+subject	O
+symptom	O
+cards	O
+were	O
+completed	O
+during	O
+a	O
+screening	O
+period	O
+to	O
+assess	O
+pretreatment	O
+symptoms	O
+and	O
+during	O
+a	O
+4	O
+-	O
+week	O
+treatment	O
+period	O
+while	O
+subjects	O
+received	O
+study	O
+medications	O
+.	O
+
+Individual	O
+symptoms	O
+,	O
+total	O
+symptoms	O
+,	O
+and	O
+major	O
+symptoms	O
+were	O
+compared	O
+to	O
+determine	O
+efficacy	O
+of	O
+medication	O
+.	O
+
+Elicited	O
+,	O
+volunteered	O
+,	O
+and	O
+observed	O
+adverse	O
+experiences	O
+were	O
+recorded	O
+for	O
+each	O
+subject	O
+and	O
+compared	O
+among	O
+groups	O
+.	O
+
+Vital	O
+signs	O
+,	O
+body	O
+weights	O
+,	O
+serum	O
+chemistry	O
+values	O
+,	O
+complete	O
+blood	O
+cell	O
+counts	O
+,	O
+urine	O
+studies	O
+,	O
+and	O
+electrocardiograms	O
+were	O
+obtained	O
+for	O
+each	O
+subject	O
+and	O
+compared	O
+among	O
+groups	O
+.	O
+
+Symptoms	O
+relief	O
+in	O
+the	O
+group	O
+receiving	O
+the	O
+highest	O
+concentration	O
+of	O
+azelastine	O
+(	O
+2	O
+.	O
+0	O
+mg	O
+twice	O
+daily	O
+)	O
+was	O
+statistically	O
+greater	O
+than	O
+in	O
+the	O
+placebo	O
+group	O
+during	O
+all	O
+weeks	O
+of	O
+the	O
+study	O
+.	O
+
+Lower	O
+doses	O
+of	O
+azelastine	O
+were	O
+statistically	O
+more	O
+effective	O
+than	O
+placebo	O
+only	O
+during	O
+portions	O
+of	O
+the	O
+first	O
+3	O
+weeks	O
+of	O
+the	O
+study	O
+.	O
+
+In	O
+contrast	O
+,	O
+although	O
+the	O
+chlorpheniramine	O
+group	O
+did	O
+have	O
+fewer	O
+symptoms	O
+than	O
+the	O
+placebo	O
+group	O
+during	O
+the	O
+study	O
+,	O
+the	O
+difference	O
+never	O
+reached	O
+statistical	O
+significance	O
+during	O
+any	O
+week	O
+of	O
+the	O
+study	O
+.	O
+
+There	O
+were	O
+no	O
+serious	O
+side	O
+effects	O
+in	O
+any	O
+of	O
+the	O
+treatment	O
+groups	O
+.	O
+
+Drowsiness	B
+and	O
+altered	B
+taste	I
+perception	I
+were	O
+increased	O
+significantly	O
+over	O
+placebo	O
+only	O
+in	O
+the	O
+high	O
+-	O
+dose	O
+azelastine	O
+group	O
+.	O
+
+Azelastine	O
+appears	O
+to	O
+be	O
+a	O
+safe	O
+,	O
+efficacious	O
+medication	O
+for	O
+seasonal	B
+allergic	I
+rhinitis	I
+.	O
+
+Toxicity	B
+due	O
+to	O
+remission	O
+inducing	O
+drugs	O
+in	O
+rheumatoid	B
+arthritis	I
+.	O
+
+Association	O
+with	O
+HLA	O
+-	O
+B35	O
+and	O
+Cw4	O
+antigens	O
+.	O
+
+Twenty	O
+-	O
+five	O
+patients	O
+with	O
+rheumatoid	B
+arthritis	I
+(	O
+RA	B
+)	O
+who	O
+developed	O
+toxicity	B
+while	O
+taking	O
+remission	O
+inducing	O
+drugs	O
+and	O
+30	O
+without	O
+toxicity	B
+were	O
+studied	O
+for	O
+possible	O
+associations	O
+with	O
+class	O
+I	O
+and	O
+II	O
+HLA	O
+antigens	O
+.	O
+
+A	O
+strong	O
+association	O
+has	O
+been	O
+found	O
+between	O
+nephritis	B
+and	O
+dermatitis	B
+due	O
+to	O
+Tiopronin	O
+(	O
+a	O
+D	O
+-	O
+Penicillamine	O
+like	O
+compound	O
+)	O
+and	O
+class	O
+I	O
+antigens	O
+B35	O
+-	O
+Cw4	O
+,	O
+and	O
+between	O
+dermatitis	B
+due	O
+to	O
+gold	O
+thiosulphate	O
+and	O
+B35	O
+.	O
+
+Compared	O
+to	O
+healthy	O
+controls	O
+a	O
+lower	O
+DR5	O
+frequency	O
+was	O
+observed	O
+in	O
+patients	O
+with	O
+RA	B
+except	O
+for	O
+the	O
+Tiopronin	O
+related	O
+nephritis	B
+group	O
+.	O
+
+Transient	O
+contralateral	B
+rotation	I
+following	O
+unilateral	O
+substantia	B
+nigra	I
+lesion	I
+reflects	O
+susceptibility	O
+of	O
+the	O
+nigrostriatal	O
+system	O
+to	O
+exhaustion	O
+by	O
+amphetamine	O
+.	O
+
+Following	O
+unilateral	O
+6	O
+-	O
+OHDA	O
+induced	O
+SN	B
+lesion	I
+,	O
+a	O
+transient	O
+period	O
+of	O
+contralateral	B
+rotation	I
+has	O
+been	O
+reported	O
+to	O
+precede	O
+the	O
+predominant	O
+ipsilateral	B
+circling	I
+.	O
+
+In	O
+order	O
+to	O
+clarify	O
+the	O
+nature	O
+of	O
+this	O
+initial	O
+contralateral	B
+rotation	I
+we	O
+examined	O
+the	O
+effect	O
+of	O
+the	O
+duration	O
+of	O
+recovery	O
+period	O
+after	O
+the	O
+lesion	O
+,	O
+on	O
+amphetamine	O
+-	O
+induced	O
+rotational	B
+behavior	I
+.	O
+
+Three	O
+days	O
+post	O
+lesion	O
+,	O
+most	O
+rats	O
+circled	O
+predominantly	O
+contralaterally	O
+to	O
+the	O
+lesion	O
+.	O
+
+Such	O
+contralateral	B
+rotation	I
+may	O
+result	O
+from	O
+either	O
+degeneration	O
+-	O
+induced	O
+breakdown	O
+of	O
+the	O
+DA	O
+pool	O
+,	O
+or	O
+lesion	O
+-	O
+induced	O
+increase	O
+of	O
+DA	O
+turnover	O
+in	O
+the	O
+spared	O
+neurons	O
+.	O
+
+A	O
+substantial	O
+degree	O
+of	O
+contralateral	O
+preference	O
+was	O
+still	O
+evident	O
+when	O
+amphetamine	O
+was	O
+administered	O
+for	O
+the	O
+first	O
+time	O
+24	O
+days	O
+after	O
+lesioning	O
+,	O
+indicating	O
+involvement	O
+of	O
+spared	O
+cells	O
+in	O
+the	O
+contralateral	B
+rotation	I
+.	O
+
+However	O
+,	O
+regardless	O
+of	O
+the	O
+duration	O
+of	O
+recovery	O
+(	O
+and	O
+irrespective	O
+of	O
+either	O
+lesion	O
+volume	O
+,	O
+amphetamine	O
+dose	O
+,	O
+or	O
+post	O
+-	O
+lesion	O
+motor	O
+exercise	O
+)	O
+,	O
+amphetamine	O
+-	O
+induced	O
+rotation	B
+tended	O
+to	O
+become	O
+gradually	O
+more	O
+ipsilateral	O
+as	O
+the	O
+observation	O
+session	O
+progressed	O
+,	O
+and	O
+all	O
+rats	O
+circled	O
+ipsilaterally	O
+to	O
+the	O
+lesion	O
+in	O
+response	O
+to	O
+further	O
+amphetamine	O
+injections	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+amphetamine	O
+has	O
+an	O
+irreversible	O
+effect	O
+on	O
+the	O
+post	O
+-	O
+lesion	O
+DA	O
+pool	O
+contributing	O
+to	O
+contralateral	B
+rotation	I
+.	O
+
+Mitomycin	O
+C	O
+associated	O
+hemolytic	B
+uremic	I
+syndrome	I
+.	O
+
+Mitomycin	O
+C	O
+associated	O
+Hemolytic	B
+Uremic	I
+Syndrome	I
+(	O
+HUS	B
+)	O
+is	O
+a	O
+potentially	O
+fatal	O
+but	O
+uncommon	O
+condition	O
+that	O
+is	O
+not	O
+yet	O
+widely	O
+recognised	O
+.	O
+
+It	O
+consists	O
+of	O
+microangiopathic	O
+hemolytic	B
+anemia	I
+,	O
+thrombocytopenia	B
+and	O
+progressive	O
+renal	B
+failure	I
+associated	O
+with	O
+mitomycin	O
+C	O
+treatment	O
+and	O
+affects	O
+about	O
+10	O
+%	O
+of	O
+patients	O
+treated	O
+with	O
+this	O
+agent	O
+.	O
+
+The	O
+renal	B
+failure	I
+usually	O
+develops	O
+about	O
+8	O
+-	O
+10	O
+mth	O
+after	O
+start	O
+of	O
+mitomycin	O
+C	O
+treatment	O
+and	O
+the	O
+mortality	O
+is	O
+approximately	O
+60	O
+%	O
+from	O
+renal	B
+failure	I
+or	O
+pulmonary	B
+edema	I
+.	O
+
+Renal	B
+lesions	I
+are	O
+similar	O
+to	O
+those	O
+seen	O
+in	O
+idiopathic	O
+HUS	B
+and	O
+include	O
+arteriolar	O
+fibrin	O
+thrombi	B
+,	O
+expanded	O
+subendothelial	O
+zones	O
+in	O
+glomerular	O
+capillary	O
+walls	O
+,	O
+ischemic	B
+wrinkling	O
+of	O
+glomerular	O
+basement	O
+membranes	O
+and	O
+mesangiolysis	O
+.	O
+
+The	O
+mechanism	O
+of	O
+action	O
+is	O
+postulated	O
+as	O
+mitomycin	O
+C	O
+-	O
+induced	O
+endothelial	O
+cell	O
+damage	O
+.	O
+
+We	O
+describe	O
+the	O
+clinical	O
+course	O
+and	O
+pathological	O
+findings	O
+in	O
+a	O
+65	O
+yr	O
+-	O
+old	O
+man	O
+with	O
+gastric	B
+adenocarcinoma	I
+who	O
+developed	O
+renal	B
+failure	I
+and	O
+thrombocytopenia	B
+while	O
+on	O
+treatment	O
+with	O
+mitomycin	O
+C	O
+and	O
+died	O
+in	O
+pulmonary	B
+edema	I
+.	O
+
+Ketanserin	O
+pretreatment	O
+reverses	O
+alfentanil	O
+-	O
+induced	O
+muscle	B
+rigidity	I
+.	O
+
+Systemic	O
+pretreatment	O
+with	O
+ketanserin	O
+,	O
+a	O
+relatively	O
+specific	O
+type	O
+-	O
+2	O
+serotonin	O
+receptor	O
+antagonist	O
+,	O
+significantly	O
+attenuated	O
+the	O
+muscle	B
+rigidity	I
+produced	O
+in	O
+rats	O
+by	O
+the	O
+potent	O
+short	O
+-	O
+acting	O
+opiate	O
+agonist	O
+alfentanil	O
+.	O
+
+Following	O
+placement	O
+of	O
+subcutaneous	O
+electrodes	O
+in	O
+each	O
+animal	O
+'	O
+s	O
+left	O
+gastrocnemius	O
+muscle	O
+,	O
+rigidity	B
+was	O
+assessed	O
+by	O
+analyzing	O
+root	O
+-	O
+mean	O
+-	O
+square	O
+electromyographic	O
+activity	O
+.	O
+
+Intraperitoneal	O
+ketanserin	O
+administration	O
+at	O
+doses	O
+of	O
+0	O
+.	O
+63	O
+and	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+prevented	O
+the	O
+alfentanil	O
+-	O
+induced	O
+increase	O
+in	O
+electromyographic	O
+activity	O
+compared	O
+with	O
+animals	O
+pretreated	O
+with	O
+saline	O
+.	O
+
+Chlordiazepoxide	O
+at	O
+doses	O
+up	O
+to	O
+10	O
+mg	O
+/	O
+kg	O
+failed	O
+to	O
+significantly	O
+influence	O
+the	O
+rigidity	B
+produced	O
+by	O
+alfentanil	O
+.	O
+
+Despite	O
+the	O
+absence	O
+of	O
+rigidity	B
+,	O
+animals	O
+that	O
+received	O
+ketanserin	O
+(	O
+greater	O
+than	O
+0	O
+.	O
+31	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+followed	O
+by	O
+alfentanil	O
+were	O
+motionless	O
+,	O
+flaccid	O
+,	O
+and	O
+less	O
+responsive	O
+to	O
+external	O
+stimuli	O
+than	O
+were	O
+animals	O
+receiving	O
+alfentanil	O
+alone	O
+.	O
+
+Rats	O
+that	O
+received	O
+ketanserin	O
+and	O
+alfentanil	O
+exhibited	O
+less	O
+rearing	O
+and	O
+exploratory	O
+behavior	O
+at	O
+the	O
+end	O
+of	O
+the	O
+60	O
+-	O
+min	O
+recording	O
+period	O
+than	O
+did	O
+animals	O
+that	O
+received	O
+ketanserin	O
+alone	O
+.	O
+
+These	O
+results	O
+,	O
+in	O
+combination	O
+with	O
+previous	O
+work	O
+,	O
+suggest	O
+that	O
+muscle	B
+rigidity	I
+,	O
+a	O
+clinically	O
+relevant	O
+side	O
+-	O
+effect	O
+of	O
+parenteral	O
+narcotic	O
+administration	O
+,	O
+may	O
+be	O
+partly	O
+mediated	O
+via	O
+serotonergic	O
+pathways	O
+.	O
+
+Pretreatment	O
+with	O
+type	O
+-	O
+2	O
+serotonin	O
+antagonists	O
+may	O
+be	O
+clinically	O
+useful	O
+in	O
+attenuating	O
+opiate	O
+-	O
+induced	O
+rigidity	B
+,	O
+although	O
+further	O
+studies	O
+will	O
+be	O
+necessary	O
+to	O
+assess	O
+the	O
+interaction	O
+of	O
+possibly	O
+enhanced	O
+CNS	O
+,	O
+cardiovascular	B
+,	I
+and	I
+respiratory	I
+depression	I
+.	O
+
+Antagonism	O
+of	O
+diazepam	O
+-	O
+induced	O
+sedative	O
+effects	O
+by	O
+Ro15	O
+-	O
+1788	O
+in	O
+patients	O
+after	O
+surgery	O
+under	O
+lumbar	O
+epidural	O
+block	O
+.	O
+
+A	O
+double	O
+-	O
+blind	O
+placebo	O
+-	O
+controlled	O
+investigation	O
+of	O
+efficacy	O
+and	O
+safety	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+assess	O
+the	O
+efficacy	O
+of	O
+Ro15	O
+-	O
+1788	O
+and	O
+a	O
+placebo	O
+in	O
+reversing	O
+diazepam	O
+-	O
+induced	O
+effects	O
+after	O
+surgery	O
+under	O
+epidural	O
+block	O
+,	O
+and	O
+to	O
+evaluate	O
+the	O
+local	O
+tolerance	O
+and	O
+general	O
+safety	O
+of	O
+Ro15	O
+-	O
+1788	O
+.	O
+
+Fifty	O
+-	O
+seven	O
+patients	O
+were	O
+sedated	O
+with	O
+diazepam	O
+for	O
+surgery	O
+under	O
+epidural	O
+anaesthesia	O
+.	O
+
+Antagonism	O
+of	O
+diazepam	O
+-	O
+induced	O
+effects	O
+by	O
+Ro15	O
+-	O
+1788	O
+was	O
+investigated	O
+postoperatively	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+placebo	O
+-	O
+controlled	O
+trial	O
+.	O
+
+The	O
+patient	O
+'	O
+s	O
+subjective	O
+assessment	O
+of	O
+mood	O
+rating	O
+,	O
+an	O
+objective	O
+test	O
+of	O
+performance	O
+,	O
+a	O
+test	O
+for	O
+amnesia	B
+,	O
+and	O
+vital	O
+signs	O
+were	O
+recorded	O
+for	O
+up	O
+to	O
+300	O
+min	O
+after	O
+administration	O
+of	O
+the	O
+trial	O
+drug	O
+.	O
+
+No	O
+significant	O
+differences	O
+between	O
+the	O
+two	O
+groups	O
+were	O
+observed	O
+for	O
+mood	O
+rating	O
+,	O
+amnesia	B
+,	O
+or	O
+vital	O
+signs	O
+.	O
+
+The	O
+Ro15	O
+-	O
+1788	O
+group	O
+showed	O
+a	O
+significant	O
+improvement	O
+in	O
+the	O
+performance	O
+test	O
+up	O
+to	O
+120	O
+min	O
+after	O
+administration	O
+of	O
+the	O
+drug	O
+.	O
+
+There	O
+was	O
+no	O
+evidence	O
+of	O
+reaction	O
+at	O
+the	O
+injection	O
+site	O
+.	O
+
+Chorea	B
+associated	O
+with	O
+oral	O
+contraception	O
+.	O
+
+Three	O
+patients	O
+developed	O
+chorea	B
+while	O
+receiving	O
+oral	O
+contraceptives	O
+.	O
+
+Two	O
+were	O
+young	O
+patients	O
+whose	O
+chorea	B
+developed	O
+long	O
+after	O
+treatment	O
+had	O
+been	O
+started	O
+and	O
+disappeared	O
+soon	O
+after	O
+it	O
+had	O
+been	O
+discontinued	O
+.	O
+
+The	O
+third	O
+patient	O
+had	O
+acute	O
+amphetamine	O
+-	O
+induced	O
+chorea	B
+after	O
+prolonged	O
+oral	O
+contraception	O
+.	O
+
+Prolonged	O
+administration	O
+of	O
+female	O
+sex	O
+hormones	O
+is	O
+a	O
+possible	O
+cause	O
+of	O
+chorea	B
+in	O
+women	O
+who	O
+have	O
+not	O
+previously	O
+had	O
+chorea	B
+or	O
+rheumatic	B
+fever	I
+.	O
+
+Co	O
+-	O
+carcinogenic	B
+effect	O
+of	O
+retinyl	O
+acetate	O
+on	O
+forestomach	B
+carcinogenesis	I
+of	O
+male	O
+F344	O
+rats	O
+induced	O
+with	O
+butylated	O
+hydroxyanisole	O
+.	O
+
+The	O
+potential	O
+modifying	O
+effect	O
+of	O
+retinyl	O
+acetate	O
+(	O
+RA	O
+)	O
+on	O
+butylated	O
+hydroxyanisole	O
+(	O
+BHA	O
+)	O
+-	O
+induced	O
+rat	O
+forestomach	B
+tumorigenesis	I
+was	O
+examined	O
+.	O
+
+Male	O
+F344	O
+rats	O
+,	O
+5	O
+weeks	O
+of	O
+age	O
+,	O
+were	O
+maintained	O
+on	O
+diet	O
+containing	O
+1	O
+%	O
+or	O
+2	O
+%	O
+BHA	O
+by	O
+weight	O
+and	O
+simultaneously	O
+on	O
+drinking	O
+water	O
+supplemented	O
+with	O
+RA	O
+at	O
+various	O
+concentrations	O
+(	O
+w	O
+/	O
+v	O
+)	O
+for	O
+52	O
+weeks	O
+.	O
+
+In	O
+groups	O
+given	O
+2	O
+%	O
+BHA	O
+,	O
+although	O
+marked	O
+hyperplastic	O
+changes	O
+of	O
+the	O
+forestomach	O
+epithelium	O
+were	O
+observed	O
+in	O
+all	O
+animals	O
+,	O
+co	O
+-	O
+administration	O
+of	O
+0	O
+.	O
+25	O
+%	O
+RA	O
+significantly	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+increased	O
+the	O
+incidence	O
+of	O
+forestomach	B
+tumors	I
+(	O
+squamous	B
+cell	I
+papilloma	I
+and	O
+carcinoma	B
+)	O
+to	O
+60	O
+%	O
+(	O
+9	O
+/	O
+15	O
+,	O
+2	O
+rats	O
+with	O
+carcinoma	B
+)	O
+from	O
+15	O
+%	O
+(	O
+3	O
+/	O
+20	O
+,	O
+one	O
+rat	O
+with	O
+carcinoma	B
+)	O
+in	O
+the	O
+group	O
+given	O
+RA	O
+-	O
+free	O
+water	O
+.	O
+
+In	O
+rats	O
+given	O
+1	O
+%	O
+BHA	O
+,	O
+RA	O
+co	O
+-	O
+administered	O
+at	O
+a	O
+dose	O
+of	O
+0	O
+.	O
+05	O
+,	O
+0	O
+.	O
+1	O
+,	O
+0	O
+.	O
+2	O
+or	O
+0	O
+.	O
+25	O
+%	O
+showed	O
+a	O
+dose	O
+-	O
+dependent	O
+enhancing	O
+effect	O
+on	O
+the	O
+development	O
+of	O
+the	O
+BHA	O
+-	O
+induced	O
+epithelial	B
+hyperplasia	I
+.	O
+
+Tumors	B
+,	O
+all	O
+papillomas	B
+,	O
+were	O
+induced	O
+in	O
+3	O
+rats	O
+(	O
+17	O
+%	O
+)	O
+with	O
+0	O
+.	O
+25	O
+%	O
+RA	O
+and	O
+in	O
+one	O
+rat	O
+(	O
+10	O
+%	O
+)	O
+with	O
+0	O
+.	O
+05	O
+%	O
+RA	O
+co	O
+-	O
+administration	O
+.	O
+
+RA	O
+alone	O
+did	O
+not	O
+induce	O
+hyperplastic	O
+changes	O
+in	O
+the	O
+forestomach	O
+.	O
+
+These	O
+findings	O
+indicate	O
+that	O
+RA	O
+acted	O
+as	O
+a	O
+co	O
+-	O
+carcinogen	O
+in	O
+the	O
+BHA	O
+forestomach	B
+carcinogenesis	I
+of	O
+the	O
+rat	O
+.	O
+
+A	O
+prospective	O
+study	O
+on	O
+the	O
+dose	O
+dependency	O
+of	O
+cardiotoxicity	B
+induced	O
+by	O
+mitomycin	O
+C	O
+.	O
+
+Since	O
+1975	O
+mitomycin	O
+C	O
+(	O
+MMC	O
+)	O
+has	O
+been	O
+suggested	O
+to	O
+be	O
+cardiotoxic	B
+,	O
+especially	O
+when	O
+combined	O
+with	O
+or	O
+given	O
+following	O
+doxorubicin	O
+.	O
+
+Data	O
+on	O
+dose	O
+dependency	O
+or	O
+incidence	O
+concerning	O
+this	O
+side	O
+effect	O
+were	O
+not	O
+known	O
+.	O
+
+We	O
+have	O
+initiated	O
+a	O
+prospective	O
+study	O
+to	O
+obtain	O
+some	O
+more	O
+data	O
+on	O
+these	O
+subjects	O
+.	O
+
+Forty	O
+-	O
+four	O
+MMC	O
+-	O
+treated	O
+patients	O
+were	O
+studied	O
+,	O
+37	O
+of	O
+them	O
+could	O
+be	O
+evaluated	O
+.	O
+
+All	O
+patients	O
+were	O
+studied	O
+by	O
+repeated	O
+physical	O
+examinations	O
+,	O
+chest	O
+X	O
+-	O
+rays	O
+,	O
+electro	O
+-	O
+and	O
+echocardiography	O
+and	O
+radionuclide	O
+left	O
+ventricular	O
+ejection	O
+fraction	O
+(	O
+EF	O
+)	O
+determinations	O
+.	O
+
+The	O
+results	O
+were	O
+evaluated	O
+per	O
+cumulative	O
+dose	O
+level	O
+.	O
+
+One	O
+of	O
+the	O
+patients	O
+developed	O
+cardiac	B
+failure	I
+after	O
+30	O
+mg	O
+m	O
+-	O
+2	O
+MMC	O
+and	O
+only	O
+150	O
+mg	O
+m	O
+-	O
+2	O
+doxorubicin	O
+.	O
+
+The	O
+cardiac	B
+failure	I
+was	O
+predicted	O
+by	O
+a	O
+drop	O
+in	O
+EF	O
+determined	O
+during	O
+a	O
+cold	O
+pressor	O
+test	O
+.	O
+
+None	O
+of	O
+the	O
+other	O
+patients	O
+developed	O
+clinical	O
+cardiotoxicity	B
+,	O
+nor	O
+did	O
+the	O
+studied	O
+parameters	O
+change	O
+.	O
+
+The	O
+literature	O
+on	O
+this	O
+subject	O
+was	O
+also	O
+reviewed	O
+.	O
+
+Based	O
+on	O
+the	O
+combined	O
+data	O
+from	O
+the	O
+present	O
+study	O
+and	O
+the	O
+literature	O
+,	O
+we	O
+suggest	O
+that	O
+MMC	O
+-	O
+related	O
+cardiotoxicity	B
+is	O
+dose	O
+dependent	O
+,	O
+occurring	O
+at	O
+cumulative	O
+dose	O
+levels	O
+of	O
+30	O
+mg	O
+m	O
+-	O
+2	O
+or	O
+more	O
+,	O
+mainly	O
+in	O
+patients	O
+also	O
+(	O
+previously	O
+or	O
+simultaneously	O
+)	O
+treated	O
+with	O
+doxorubicin	O
+.	O
+
+The	O
+incidence	O
+is	O
+likely	O
+to	O
+be	O
+less	O
+than	O
+10	O
+%	O
+even	O
+for	O
+this	O
+risk	O
+group	O
+.	O
+
+Reversible	O
+cerebral	B
+lesions	I
+associated	O
+with	O
+tiazofurin	O
+usage	O
+:	O
+MR	O
+demonstration	O
+.	O
+
+Tiazofurin	O
+is	O
+an	O
+experimental	O
+chemotherapeutic	O
+agent	O
+currently	O
+undergoing	O
+clinical	O
+evaluation	O
+.	O
+
+We	O
+report	O
+our	O
+results	O
+with	O
+magnetic	O
+resonance	O
+(	O
+MR	O
+)	O
+in	O
+demonstrating	O
+reversible	O
+cerebral	B
+abnormalities	I
+concurrent	O
+with	O
+the	O
+use	O
+of	O
+this	O
+drug	O
+.	O
+
+The	O
+abnormalities	O
+on	O
+MR	O
+were	O
+correlated	O
+with	O
+findings	O
+on	O
+CT	O
+as	O
+well	O
+as	O
+with	O
+cerebral	O
+angiography	O
+.	O
+
+The	O
+utility	O
+of	O
+MR	O
+in	O
+the	O
+evaluation	O
+of	O
+patients	O
+receiving	O
+this	O
+new	O
+agent	O
+is	O
+illustrated	O
+.	O
+
+Receptor	O
+mechanisms	O
+of	O
+nicotine	O
+-	O
+induced	O
+locomotor	B
+hyperactivity	I
+in	O
+chronic	O
+nicotine	O
+-	O
+treated	O
+rats	O
+.	O
+
+Rats	O
+were	O
+pretreated	O
+with	O
+saline	O
+or	O
+nicotine	O
+(	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+)	O
+by	O
+subcutaneously	O
+implanting	O
+each	O
+animal	O
+with	O
+an	O
+Alzet	O
+osmotic	O
+mini	O
+-	O
+pump	O
+which	O
+continuously	O
+released	O
+saline	O
+or	O
+nicotine	O
+for	O
+1	O
+,	O
+5	O
+and	O
+14	O
+days	O
+.	O
+
+At	O
+the	O
+end	O
+of	O
+each	O
+pretreatment	O
+period	O
+,	O
+animals	O
+were	O
+used	O
+for	O
+(	O
+i	O
+)	O
+determining	O
+their	O
+locomotor	O
+response	O
+to	O
+acutely	O
+injected	O
+nicotine	O
+(	O
+0	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+,	O
+s	O
+.	O
+c	O
+.	O
+)	O
+and	O
+(	O
+ii	O
+)	O
+measuring	O
+the	O
+density	O
+of	O
+L	O
+-	O
+[	O
+3H	O
+]	O
+nicotine	O
+and	O
+[	O
+3H	O
+]	O
+spiperone	O
+binding	O
+sites	O
+in	O
+the	O
+striatum	O
+.	O
+
+We	O
+observed	O
+no	O
+changes	O
+in	O
+nicotine	O
+-	O
+induced	O
+locomotor	O
+response	O
+,	O
+striatal	O
+L	O
+-	O
+[	O
+3H	O
+]	O
+nicotine	O
+and	O
+[	O
+3H	O
+]	O
+spiperone	O
+binding	O
+in	O
+the	O
+animals	O
+pretreated	O
+with	O
+nicotine	O
+for	O
+1	O
+day	O
+.	O
+
+In	O
+rats	O
+which	O
+were	O
+pretreated	O
+with	O
+nicotine	O
+for	O
+5	O
+days	O
+,	O
+there	O
+was	O
+a	O
+significant	O
+increase	O
+in	O
+the	O
+nicotine	O
+-	O
+stimulated	O
+locomotor	O
+response	O
+which	O
+was	O
+associated	O
+with	O
+an	O
+increase	O
+in	O
+the	O
+number	O
+of	O
+L	O
+-	O
+[	O
+3H	O
+]	O
+nicotine	O
+binding	O
+sites	O
+and	O
+also	O
+with	O
+an	O
+elevated	O
+dopamine	O
+(	O
+DA	O
+)	O
+level	O
+in	O
+the	O
+striatum	O
+.	O
+
+The	O
+number	O
+of	O
+striatal	O
+[	O
+3H	O
+]	O
+spiperone	O
+binding	O
+sites	O
+was	O
+not	O
+affected	O
+.	O
+
+In	O
+animals	O
+pretreated	O
+with	O
+nicotine	O
+for	O
+14	O
+days	O
+,	O
+the	O
+nicotine	O
+-	O
+induced	O
+locomotor	O
+response	O
+remained	O
+to	O
+be	O
+potentiated	O
+.	O
+
+However	O
+,	O
+this	O
+response	O
+was	O
+correlated	O
+with	O
+an	O
+elevated	O
+number	O
+of	O
+striatal	O
+[	O
+3H	O
+]	O
+spiperone	O
+binding	O
+sites	O
+,	O
+whereas	O
+the	O
+number	O
+of	O
+striatal	O
+L	O
+-	O
+[	O
+3H	O
+]	O
+nicotine	O
+binding	O
+sites	O
+and	O
+the	O
+striatal	O
+DA	O
+level	O
+were	O
+normal	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+chronic	O
+nicotine	O
+-	O
+treated	O
+rats	O
+develop	O
+locomotor	B
+hyperactivity	I
+in	O
+response	O
+to	O
+nicotine	O
+initially	O
+due	O
+to	O
+increases	O
+of	O
+both	O
+the	O
+density	O
+of	O
+nicotinic	O
+receptors	O
+and	O
+DA	O
+concentration	O
+,	O
+followed	O
+by	O
+inducing	O
+DA	O
+receptor	O
+supersensitivity	O
+in	O
+the	O
+striatum	O
+.	O
+
+Amelioration	O
+of	O
+bendrofluazide	O
+-	O
+induced	O
+hypokalemia	B
+by	O
+timolol	O
+.	O
+
+The	O
+beta	O
+adrenergic	O
+blocking	O
+drug	O
+,	O
+timolol	O
+,	O
+tended	O
+to	O
+correct	O
+the	O
+hypokalemia	B
+of	O
+short	O
+-	O
+term	O
+bendrofluazide	O
+treatment	O
+in	O
+6	O
+healthy	O
+male	O
+subjects	O
+and	O
+although	O
+the	O
+effect	O
+was	O
+small	O
+it	O
+was	O
+significant	O
+.	O
+
+Timolol	O
+also	O
+reduced	O
+the	O
+rise	O
+in	O
+plasma	O
+aldosterone	O
+and	O
+urine	O
+potassium	O
+excretion	O
+following	O
+bendrofluazide	O
+and	O
+increased	O
+the	O
+urine	O
+sodium	O
+/	O
+potassium	O
+ratio	O
+.	O
+
+There	O
+was	O
+no	O
+evidence	O
+of	O
+a	O
+shift	O
+of	O
+potassium	O
+from	O
+the	O
+intracellular	O
+to	O
+the	O
+extracellular	O
+space	O
+.	O
+
+St	B
+.	I
+
+Anthony	B
+'	I
+s	I
+fire	I
+,	O
+then	O
+and	O
+now	O
+:	O
+a	O
+case	O
+report	O
+and	O
+historical	O
+review	O
+.	O
+
+A	O
+rare	O
+case	O
+of	O
+morbid	O
+vasospasm	B
+,	O
+together	O
+with	O
+striking	O
+angiographic	O
+findings	O
+,	O
+is	O
+described	O
+secondary	O
+to	O
+the	O
+ingestion	O
+of	O
+methysergide	O
+by	O
+a	O
+48	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+.	O
+
+A	O
+brief	O
+review	O
+of	O
+the	O
+literature	O
+on	O
+similar	O
+cases	O
+is	O
+presented	O
+.	O
+
+A	O
+discussion	O
+of	O
+the	O
+history	O
+of	O
+ergot	O
+includes	O
+its	O
+original	O
+discovery	O
+,	O
+the	O
+epidemics	O
+of	O
+gangrene	B
+that	O
+it	O
+has	O
+caused	O
+through	O
+the	O
+ages	O
+and	O
+its	O
+past	O
+and	O
+present	O
+role	O
+in	O
+the	O
+management	O
+of	O
+migraine	B
+headache	I
+.	O
+
+Despite	O
+the	O
+advent	O
+of	O
+calcium	O
+channel	O
+blockers	O
+and	O
+beta	O
+-	O
+adrenergic	O
+antagonists	O
+,	O
+ergot	O
+preparations	O
+continue	O
+to	O
+play	O
+a	O
+major	O
+role	O
+in	O
+migraine	B
+therapy	O
+,	O
+so	O
+that	O
+the	O
+danger	O
+of	O
+St	B
+.	I
+
+Anthony	B
+'	I
+s	I
+fire	I
+persists	O
+.	O
+
+Cardiac	O
+transplantation	O
+:	O
+improved	O
+quality	O
+of	O
+survival	O
+with	O
+a	O
+modified	O
+immunosuppressive	O
+protocol	O
+.	O
+
+The	O
+effects	O
+on	O
+renal	O
+function	O
+on	O
+two	O
+different	O
+immunosuppressive	O
+protocols	O
+were	O
+evaluated	O
+retrospectively	O
+in	O
+two	O
+subsequent	O
+groups	O
+of	O
+heart	O
+transplant	O
+recipients	O
+.	O
+
+In	O
+group	O
+I	O
+,	O
+cyclosporine	O
+was	O
+given	O
+before	O
+the	O
+procedure	O
+at	O
+a	O
+loading	O
+dose	O
+of	O
+17	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+and	O
+then	O
+continued	O
+after	O
+the	O
+procedure	O
+to	O
+keep	O
+a	O
+whole	O
+blood	O
+level	O
+about	O
+1000	O
+ng	O
+/	O
+ml	O
+.	O
+
+In	O
+group	O
+II	O
+,	O
+cyclosporine	O
+was	O
+started	O
+only	O
+after	O
+the	O
+procedure	O
+at	O
+a	O
+lower	O
+dosage	O
+and	O
+was	O
+complemented	O
+by	O
+azathioprine	O
+,	O
+which	O
+was	O
+used	O
+for	O
+the	O
+first	O
+postoperative	O
+week	O
+.	O
+
+Group	O
+II	O
+showed	O
+a	O
+better	O
+perioperative	O
+renal	O
+function	O
+as	O
+determined	O
+by	O
+serum	O
+blood	O
+urea	O
+nitrogen	O
+and	O
+serum	O
+creatinine	O
+levels	O
+.	O
+
+Group	O
+II	O
+also	O
+showed	O
+a	O
+significant	O
+decrease	O
+of	O
+chronic	O
+nephrotoxicity	B
+secondary	O
+to	O
+long	O
+-	O
+term	O
+therapy	O
+with	O
+cyclosporine	O
+.	O
+
+Despite	O
+this	O
+improvement	O
+in	O
+late	O
+renal	O
+function	O
+,	O
+group	O
+II	O
+still	O
+shows	O
+a	O
+slow	O
+rise	O
+in	O
+serum	O
+creatinine	O
+.	O
+
+We	O
+think	O
+that	O
+even	O
+these	O
+lower	O
+dosages	O
+of	O
+cyclosporine	O
+can	O
+cause	O
+chronic	O
+nephrotoxicity	B
+and	O
+that	O
+further	O
+modification	O
+of	O
+the	O
+immunosuppressive	O
+regimen	O
+is	O
+required	O
+to	O
+completely	O
+abolish	O
+this	O
+toxic	O
+side	O
+effect	O
+.	O
+
+Ethopropazine	O
+and	O
+benztropine	O
+in	O
+neuroleptic	O
+-	O
+induced	O
+parkinsonism	B
+.	O
+
+In	O
+a	O
+12	O
+-	O
+week	O
+controlled	O
+study	O
+ethopropazine	O
+was	O
+compared	O
+to	O
+benztropine	O
+in	O
+the	O
+treatment	O
+of	O
+parkinsonism	B
+induced	O
+by	O
+fluphenazine	O
+enanthate	O
+in	O
+60	O
+schizophrenic	B
+outpatients	O
+.	O
+
+Ethopropazine	O
+and	O
+benztropine	O
+were	O
+found	O
+to	O
+be	O
+equally	O
+effective	O
+in	O
+controlling	O
+parkinsonian	B
+symptoms	I
+and	O
+were	O
+as	O
+efficacious	O
+as	O
+procyclidine	O
+,	O
+their	O
+previous	O
+antiparkinsonian	O
+drug	O
+.	O
+
+However	O
+,	O
+benztropine	O
+treated	O
+patients	O
+had	O
+a	O
+significant	O
+increase	O
+in	O
+tardive	B
+dyskinesia	I
+compared	O
+to	O
+their	O
+condition	O
+during	O
+procyclindine	O
+treatment	O
+,	O
+and	O
+significantly	O
+more	O
+anxiety	B
+and	O
+depression	B
+than	O
+ethopropazine	O
+treated	O
+patients	O
+.	O
+
+This	O
+suggests	O
+that	O
+benztropine	O
+is	O
+not	O
+the	O
+anticholinergic	O
+drug	O
+of	O
+choice	O
+in	O
+the	O
+treatment	O
+of	O
+neuroleptic	O
+-	O
+induced	O
+parkinsonian	B
+symptoms	I
+,	O
+because	O
+of	O
+its	O
+more	O
+toxic	O
+central	O
+and	O
+peripheral	O
+atropinic	O
+effect	O
+.	O
+
+Quinidine	O
+phenylethylbarbiturate	O
+-	O
+induced	O
+fulminant	O
+hepatitis	B
+in	O
+a	O
+pregnant	O
+woman	O
+.	O
+
+A	O
+case	O
+report	O
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+19	O
+-	O
+year	O
+-	O
+old	O
+Laotian	O
+patient	O
+affected	O
+by	O
+fulminant	O
+hepatitis	B
+during	O
+the	O
+third	O
+trimester	O
+of	O
+her	O
+pregnancy	O
+after	O
+a	O
+1	O
+-	O
+month	O
+administration	O
+of	O
+quinidine	O
+phenylethylbarbiturate	O
+.	O
+
+After	O
+delivery	O
+,	O
+the	O
+patient	O
+underwent	O
+orthotopic	O
+liver	O
+transplantation	O
+.	O
+
+The	O
+patient	O
+was	O
+in	O
+good	O
+condition	O
+16	O
+months	O
+after	O
+liver	O
+transplantation	O
+.	O
+
+Quinidine	O
+itself	O
+or	O
+phenylethylbarbiturate	O
+may	O
+be	O
+responsible	O
+for	O
+fulminant	O
+hepatitis	B
+in	O
+this	O
+patient	O
+.	O
+
+Mechanisms	O
+of	O
+myocardial	B
+ischemia	I
+induced	O
+by	O
+epinephrine	O
+:	O
+comparison	O
+with	O
+exercise	O
+-	O
+induced	O
+ischemia	B
+.	O
+
+The	O
+role	O
+of	O
+epinephrine	O
+in	O
+eliciting	O
+myocardial	B
+ischemia	I
+was	O
+examined	O
+in	O
+patients	O
+with	O
+coronary	B
+artery	I
+disease	I
+.	O
+
+Objective	O
+signs	O
+of	O
+ischemia	B
+and	O
+factors	O
+increasing	O
+myocardial	O
+oxygen	O
+consumption	O
+were	O
+compared	O
+during	O
+epinephrine	O
+infusion	O
+and	O
+supine	O
+bicycle	O
+exercise	O
+.	O
+
+Both	O
+epinephrine	O
+and	O
+exercise	O
+produced	O
+myocardial	B
+ischemia	I
+as	O
+evidenced	O
+by	O
+ST	O
+segment	O
+depression	B
+and	O
+angina	B
+.	O
+
+However	O
+,	O
+the	O
+mechanisms	O
+of	O
+myocardial	B
+ischemia	I
+induced	O
+by	O
+epinephrine	O
+were	O
+significantly	O
+different	O
+from	O
+those	O
+of	O
+exercise	O
+.	O
+
+Exercise	O
+-	O
+induced	O
+myocardial	B
+ischemia	I
+was	O
+marked	O
+predominantly	O
+by	O
+increased	O
+heart	O
+rate	O
+and	O
+rate	O
+-	O
+pressure	O
+product	O
+with	O
+a	O
+minor	O
+contribution	O
+of	O
+end	O
+-	O
+diastolic	O
+volume	O
+,	O
+while	O
+epinephrine	O
+-	O
+induced	O
+ischemia	B
+was	O
+characterized	O
+by	O
+a	O
+marked	O
+increase	O
+in	O
+contractility	O
+and	O
+a	O
+less	O
+pronounced	O
+increase	O
+in	O
+heart	O
+rate	O
+and	O
+rate	O
+-	O
+pressure	O
+product	O
+.	O
+
+These	O
+findings	O
+indicate	O
+that	O
+ischemia	B
+produced	O
+by	O
+epinephrine	O
+,	O
+as	O
+may	O
+occur	O
+during	O
+states	O
+of	O
+emotional	O
+distress	O
+,	O
+has	O
+a	O
+mechanism	O
+distinct	O
+from	O
+that	O
+due	O
+to	O
+physical	O
+exertion	O
+.	O
+
+Recent	O
+preclinical	O
+and	O
+clinical	O
+studies	O
+with	O
+the	O
+thymidylate	O
+synthase	O
+inhibitor	O
+N10	O
+-	O
+propargyl	O
+-	O
+5	O
+,	O
+8	O
+-	O
+dideazafolic	O
+acid	O
+(	O
+CB	O
+3717	O
+)	O
+.	O
+
+CB	O
+3717	O
+,	O
+N10	O
+-	O
+propargyl	O
+-	O
+5	O
+,	O
+8	O
+-	O
+dideazafolic	O
+acid	O
+,	O
+is	O
+a	O
+tight	O
+-	O
+binding	O
+inhibitor	O
+of	O
+thymidylate	O
+synthase	O
+(	O
+TS	O
+)	O
+whose	O
+cytotoxicity	B
+is	O
+mediated	O
+solely	O
+through	O
+the	O
+inhibition	O
+of	O
+this	O
+enzyme	O
+.	O
+
+Recent	O
+preclinical	O
+studies	O
+have	O
+focused	O
+on	O
+the	O
+intracellular	O
+formation	O
+of	O
+CB	O
+3717	O
+polyglutamates	O
+.	O
+
+Following	O
+a	O
+12	O
+-	O
+hour	O
+exposure	O
+of	O
+L1210	O
+cells	O
+to	O
+50	O
+microM	O
+[	O
+3H	O
+]	O
+CB	O
+3717	O
+,	O
+30	O
+%	O
+of	O
+the	O
+extractable	O
+radioactivity	O
+could	O
+be	O
+accounted	O
+for	O
+as	O
+CB	O
+3717	O
+tetra	O
+-	O
+and	O
+pentaglutamate	O
+,	O
+as	O
+determined	O
+by	O
+high	O
+-	O
+pressure	O
+liquid	O
+chromatography	O
+(	O
+HPLC	O
+)	O
+analyses	O
+.	O
+
+As	O
+inhibitors	O
+of	O
+isolated	O
+L1210	O
+TS	O
+,	O
+CB	O
+3717	O
+di	O
+-	O
+,	O
+tri	O
+-	O
+,	O
+tetra	O
+-	O
+and	O
+pentaglutamate	O
+are	O
+26	O
+-	O
+,	O
+87	O
+-	O
+,	O
+119	O
+-	O
+and	O
+114	O
+-	O
+fold	O
+more	O
+potent	O
+than	O
+CB	O
+3717	O
+,	O
+respectively	O
+,	O
+and	O
+their	O
+formation	O
+may	O
+,	O
+therefore	O
+,	O
+be	O
+an	O
+important	O
+determinant	O
+of	O
+CB	O
+3717	O
+cytotoxicity	B
+.	O
+
+In	O
+early	O
+clinical	O
+studies	O
+with	O
+CB	O
+3717	O
+,	O
+activity	O
+has	O
+been	O
+seen	O
+in	O
+breast	B
+cancer	I
+,	O
+ovarian	B
+cancer	I
+,	O
+hepatoma	B
+,	O
+and	O
+mesothelioma	B
+.	O
+
+Toxicities	B
+included	O
+hepatotoxicity	B
+,	O
+malaise	B
+,	O
+and	O
+dose	O
+-	O
+limiting	O
+nephrotoxicity	B
+.	O
+
+This	O
+latter	O
+effect	O
+is	O
+thought	O
+to	O
+be	O
+due	O
+to	O
+drug	O
+precipitation	O
+within	O
+the	O
+renal	O
+tubule	O
+as	O
+a	O
+result	O
+of	O
+the	O
+poor	O
+solubility	O
+of	O
+CB	O
+3717	O
+under	O
+acidic	O
+conditions	O
+.	O
+
+In	O
+an	O
+attempt	O
+to	O
+overcome	O
+this	O
+problem	O
+,	O
+a	O
+clinical	O
+trial	O
+of	O
+CB	O
+3717	O
+administered	O
+with	O
+alkaline	O
+diuresis	O
+is	O
+under	O
+way	O
+.	O
+
+Preliminary	O
+results	O
+at	O
+400	O
+and	O
+500	O
+mg	O
+/	O
+m2	O
+suggest	O
+that	O
+a	O
+reduction	O
+in	O
+nephrotoxicity	B
+may	O
+have	O
+been	O
+achieved	O
+with	O
+only	O
+1	O
+instance	O
+of	O
+renal	B
+toxicity	I
+in	O
+10	O
+patients	O
+.	O
+
+Hepatotoxicity	B
+and	O
+malaise	B
+are	O
+again	O
+the	O
+most	O
+frequent	O
+side	O
+effects	O
+.	O
+
+Evidence	O
+of	O
+antitumor	O
+activity	O
+has	O
+been	O
+seen	O
+in	O
+3	O
+patients	O
+.	O
+
+Pharmacokinetic	O
+investigations	O
+have	O
+shown	O
+that	O
+alkaline	O
+diuresis	O
+does	O
+not	O
+alter	O
+CB	O
+3717	O
+plasma	O
+levels	O
+or	O
+urinary	O
+excretion	O
+and	O
+that	O
+satisfactory	O
+urinary	O
+alkalinization	O
+can	O
+be	O
+readily	O
+achieved	O
+.	O
+
+Type	B
+B	I
+hepatitis	I
+after	O
+needle	O
+-	O
+stick	O
+exposure	O
+:	O
+prevention	O
+with	O
+hepatitis	B
+B	I
+immune	O
+globulin	O
+.	O
+
+Final	O
+report	O
+of	O
+the	O
+Veterans	O
+Administration	O
+Cooperative	O
+Study	O
+.	O
+
+Hepatitis	B
+B	I
+immune	O
+globulin	O
+(	O
+HBIG	O
+)	O
+and	O
+immune	O
+serum	O
+globulin	O
+(	O
+ISG	O
+)	O
+were	O
+examined	O
+in	O
+a	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+trial	O
+to	O
+assess	O
+their	O
+relative	O
+efficacies	O
+in	O
+preventing	O
+type	B
+B	I
+hepatitis	I
+after	O
+needle	O
+-	O
+stick	O
+exposure	O
+to	O
+hepatitis	O
+B	O
+surface	O
+antigen	O
+(	O
+HBsAG	O
+)	O
+-	O
+positive	O
+donors	O
+.	O
+
+Clinical	O
+hepatitis	B
+developed	O
+in	O
+1	O
+.	O
+4	O
+%	O
+of	O
+HBIG	O
+and	O
+in	O
+5	O
+.	O
+9	O
+%	O
+of	O
+ISG	O
+recipients	O
+(	O
+P	O
+=	O
+0	O
+.	O
+016	O
+)	O
+,	O
+and	O
+seroconversion	O
+(	O
+anti	O
+-	O
+HBs	O
+)	O
+occurred	O
+in	O
+5	O
+.	O
+6	O
+%	O
+and	O
+20	O
+.	O
+7	O
+%	O
+of	O
+them	O
+respectively	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Mild	O
+and	O
+transient	O
+side	O
+-	O
+effects	O
+were	O
+noted	O
+in	O
+3	O
+.	O
+0	O
+%	O
+of	O
+ISG	O
+and	O
+in	O
+3	O
+.	O
+2	O
+%	O
+of	O
+HBIG	O
+recipients	O
+.	O
+
+Available	O
+donor	O
+sera	O
+were	O
+examined	O
+for	O
+DNA	O
+polymerase	O
+(	O
+DNAP	O
+)	O
+and	O
+e	O
+antigen	O
+and	O
+antibody	O
+(	O
+HBeAg	O
+;	O
+anti	O
+-	O
+HBE	O
+)	O
+.	O
+
+Both	O
+DNAP	O
+and	O
+HBeAg	O
+showed	O
+a	O
+highly	O
+statistically	O
+significant	O
+correlation	O
+with	O
+the	O
+infectivity	O
+of	O
+HBsAg	O
+-	O
+positive	O
+donors	O
+.	O
+
+Hepatitis	B
+B	I
+immune	O
+globulin	O
+remained	O
+significantly	O
+superior	O
+to	O
+ISG	O
+in	O
+preventing	O
+type	B
+B	I
+hepatitis	I
+even	O
+when	O
+the	O
+analysis	O
+was	O
+confined	O
+to	O
+these	O
+two	O
+high	O
+-	O
+risk	O
+subgroups	O
+.	O
+
+The	O
+efficacy	O
+of	O
+ISG	O
+in	O
+preventing	O
+type	B
+B	I
+hepatitis	I
+cannot	O
+be	O
+ascertained	O
+because	O
+a	O
+true	O
+placebo	O
+group	O
+was	O
+not	O
+included	O
+.	O
+
+Production	O
+of	O
+autochthonous	O
+prostate	B
+cancer	I
+in	O
+Lobund	O
+-	O
+Wistar	O
+rats	O
+by	O
+treatments	O
+with	O
+N	O
+-	O
+nitroso	O
+-	O
+N	O
+-	O
+methylurea	O
+and	O
+testosterone	O
+.	O
+
+More	O
+than	O
+50	O
+%	O
+of	O
+Lobund	O
+-	O
+Wistar	O
+(	O
+L	O
+-	O
+W	O
+)	O
+strain	O
+rats	O
+developed	O
+large	O
+,	O
+palpable	O
+prostate	B
+adenocarcinomas	I
+(	O
+PAs	B
+)	O
+following	O
+treatments	O
+with	O
+N	O
+-	O
+nitroso	O
+-	O
+N	O
+-	O
+methylurea	O
+(	O
+CAS	O
+:	O
+684	O
+-	O
+93	O
+-	O
+5	O
+)	O
+and	O
+testosterone	O
+propionate	O
+[	O
+(	O
+TP	O
+)	O
+CAS	O
+:	O
+57	O
+-	O
+85	O
+-	O
+2	O
+]	O
+,	O
+and	O
+most	O
+of	O
+the	O
+tumor	B
+-	O
+bearing	O
+rats	O
+manifested	O
+metastatic	O
+lesions	O
+.	O
+
+The	O
+incubation	O
+periods	O
+averaged	O
+10	O
+.	O
+6	O
+months	O
+.	O
+
+Within	O
+the	O
+same	O
+timeframe	O
+,	O
+no	O
+L	O
+-	O
+W	O
+rat	O
+developed	O
+a	O
+similar	O
+palpable	O
+PA	B
+when	O
+treated	O
+only	O
+with	O
+TP	O
+.	O
+
+In	O
+L	O
+-	O
+W	O
+rats	O
+,	O
+TP	O
+acted	O
+as	O
+a	O
+tumor	B
+enhancement	O
+agent	O
+,	O
+with	O
+primary	O
+emphasis	O
+on	O
+the	O
+development	O
+of	O
+prostate	B
+cancer	I
+.	O
+
+Relative	O
+efficacy	O
+and	O
+toxicity	B
+of	O
+netilmicin	O
+and	O
+tobramycin	O
+in	O
+oncology	O
+patients	O
+.	O
+
+We	O
+prospectively	O
+compared	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+netilmicin	O
+sulfate	O
+or	O
+tobramycin	O
+sulfate	O
+in	O
+conjunction	O
+with	O
+piperacillin	O
+sodium	O
+in	O
+118	O
+immunocompromised	O
+patients	O
+with	O
+presumed	O
+severe	O
+infections	B
+.	O
+
+The	O
+two	O
+treatment	O
+regimens	O
+were	O
+equally	O
+efficacious	O
+.	O
+
+Nephrotoxicity	B
+occurred	O
+in	O
+a	O
+similar	O
+proportion	O
+in	O
+patients	O
+treated	O
+with	O
+netilmicin	O
+and	O
+tobramycin	O
+(	O
+17	O
+%	O
+vs	O
+11	O
+%	O
+)	O
+.	O
+
+Ototoxicity	B
+occurred	O
+in	O
+four	O
+(	O
+9	O
+.	O
+5	O
+%	O
+)	O
+of	O
+42	O
+netilmicin	O
+and	O
+piperacillin	O
+and	O
+in	O
+12	O
+(	O
+22	O
+%	O
+)	O
+of	O
+54	O
+tobramycin	O
+and	O
+piperacillin	O
+-	O
+treated	O
+patients	O
+.	O
+
+Of	O
+those	O
+evaluated	O
+with	O
+posttherapy	O
+audiograms	O
+,	O
+three	O
+of	O
+four	O
+netilmicin	O
+and	O
+piperacillin	O
+-	O
+treated	O
+patients	O
+had	O
+auditory	O
+thresholds	O
+return	O
+to	O
+baseline	O
+compared	O
+with	O
+one	O
+of	O
+nine	O
+tobramycin	O
+and	O
+piperacillin	O
+-	O
+treated	O
+patients	O
+.	O
+
+The	O
+number	O
+of	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+15	O
+-	O
+dB	O
+increases	O
+in	O
+auditory	O
+threshold	O
+as	O
+a	O
+proportion	O
+of	O
+total	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+15	O
+-	O
+dB	O
+changes	O
+(	O
+increases	O
+and	O
+decreases	O
+)	O
+was	O
+significantly	O
+lower	O
+in	O
+netilmicin	O
+and	O
+piperacillin	O
+-	O
+vs	O
+tobramycin	O
+and	O
+piperacillin	O
+-	O
+treated	O
+patients	O
+(	O
+18	O
+of	O
+78	O
+vs	O
+67	O
+of	O
+115	O
+)	O
+.	O
+
+We	O
+conclude	O
+that	O
+aminoglycoside	O
+-	O
+associated	O
+ototoxicity	B
+was	O
+less	O
+severe	O
+and	O
+more	O
+often	O
+reversible	O
+with	O
+netilmicin	O
+than	O
+with	O
+tobramycin	O
+.	O
+
+Urinary	O
+enzymes	O
+and	O
+protein	O
+patterns	O
+as	O
+indicators	O
+of	O
+injury	B
+to	I
+different	I
+regions	I
+of	I
+the	I
+kidney	I
+.	O
+
+Acute	B
+experimental	I
+models	I
+of	I
+renal	I
+damage	I
+to	O
+the	O
+proximal	O
+tubular	O
+,	O
+glomerular	O
+,	O
+and	O
+papillary	O
+regions	O
+of	O
+the	O
+rat	O
+were	O
+produced	O
+by	O
+administration	O
+of	O
+hexachloro	O
+-	O
+1	O
+:	O
+3	O
+-	O
+butadiene	O
+(	O
+HCBD	O
+)	O
+,	O
+puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+)	O
+,	O
+and	O
+2	O
+-	O
+bromoethylamine	O
+(	O
+BEA	O
+)	O
+,	O
+respectively	O
+.	O
+
+Several	O
+routine	O
+indicators	O
+of	O
+nephrotoxicity	B
+,	O
+the	O
+enzymes	O
+alkaline	O
+phosphatase	O
+and	O
+N	O
+-	O
+acetyl	O
+-	O
+beta	O
+-	O
+glucosaminidase	O
+,	O
+and	O
+the	O
+molecular	O
+weight	O
+of	O
+protein	B
+excretion	I
+were	O
+determined	O
+on	O
+urine	O
+samples	O
+.	O
+
+Tubular	O
+damage	O
+produced	O
+by	O
+HCBD	O
+or	O
+BEA	O
+was	O
+discriminated	O
+both	O
+quantitatively	O
+and	O
+qualitatively	O
+from	O
+glomerular	B
+damage	I
+produced	O
+by	O
+PAN	O
+.	O
+
+The	O
+latter	O
+was	O
+characterized	O
+by	O
+a	O
+pronounced	O
+increase	O
+in	O
+protein	B
+excretion	I
+,	O
+especially	O
+proteins	O
+with	O
+molecular	O
+weight	O
+greater	O
+than	O
+40	O
+,	O
+000	O
+Da	O
+.	O
+
+In	O
+contrast	O
+,	O
+protein	B
+excretion	I
+in	O
+tubular	O
+damage	O
+was	O
+raised	O
+only	O
+slightly	O
+and	O
+characterized	O
+by	O
+excretion	B
+of	I
+proteins	I
+of	O
+a	O
+wide	O
+range	O
+of	O
+molecular	O
+weights	O
+.	O
+
+Proximal	O
+tubular	O
+damage	O
+caused	O
+by	O
+HCBD	O
+and	O
+papillary	O
+damage	O
+caused	O
+by	O
+BEA	O
+were	O
+distinguished	O
+both	O
+by	O
+conventional	O
+urinalysis	O
+(	O
+volume	O
+and	O
+specific	O
+gravity	O
+)	O
+and	O
+by	O
+measurement	O
+of	O
+the	O
+two	O
+urinary	O
+enzymes	O
+.	O
+
+Alkaline	O
+phosphatase	O
+and	O
+glucose	O
+were	O
+markedly	O
+and	O
+transiently	O
+elevated	O
+in	O
+proximal	O
+tubular	O
+damage	O
+and	O
+N	O
+-	O
+acetyl	O
+-	O
+beta	O
+-	O
+glucosaminidase	O
+showed	O
+a	O
+sustained	O
+elevation	O
+in	O
+papillary	O
+damage	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+both	O
+selective	O
+urinary	O
+enzymes	O
+and	O
+the	O
+molecular	O
+weight	O
+pattern	O
+of	O
+urinary	O
+proteins	O
+can	O
+be	O
+used	O
+to	O
+provide	O
+diagnostic	O
+information	O
+about	O
+the	O
+possible	O
+site	O
+of	O
+renal	B
+damage	I
+.	O
+
+A	O
+catch	O
+in	O
+the	O
+Reye	B
+.	O
+
+Twenty	O
+-	O
+six	O
+cases	O
+of	O
+Reye	B
+syndrome	I
+from	O
+The	O
+Children	O
+'	O
+s	O
+Hospital	O
+,	O
+Camperdown	O
+,	O
+Australia	O
+,	O
+occurring	O
+between	O
+1973	O
+and	O
+1982	O
+were	O
+reviewed	O
+.	O
+
+Of	O
+these	O
+,	O
+20	O
+cases	O
+met	O
+the	O
+US	O
+Public	O
+Health	O
+Service	O
+Centers	O
+for	O
+Disease	O
+Control	O
+criteria	O
+for	O
+the	O
+diagnosis	O
+of	O
+Reye	B
+syndrome	I
+.	O
+
+Aspirin	O
+or	O
+salicylate	O
+ingestion	O
+had	O
+occurred	O
+in	O
+only	O
+one	O
+of	O
+the	O
+20	O
+cases	O
+(	O
+5	O
+%	O
+)	O
+,	O
+and	O
+paracetamol	O
+(	O
+acetaminophen	O
+)	O
+had	O
+been	O
+administered	O
+in	O
+only	O
+six	O
+of	O
+the	O
+cases	O
+(	O
+30	O
+%	O
+)	O
+.	O
+
+Pathologic	O
+confirmation	O
+of	O
+the	O
+diagnosis	O
+of	O
+Reye	B
+syndrome	I
+was	O
+accomplished	O
+in	O
+90	O
+%	O
+of	O
+the	O
+cases	O
+.	O
+
+The	O
+incidence	O
+of	O
+Reye	B
+syndrome	I
+in	O
+New	O
+South	O
+Wales	O
+,	O
+Australia	O
+,	O
+is	O
+estimated	O
+from	O
+this	O
+study	O
+to	O
+be	O
+approximately	O
+nine	O
+cases	O
+per	O
+1	O
+million	O
+children	O
+compared	O
+with	O
+recent	O
+US	O
+data	O
+of	O
+ten	O
+to	O
+20	O
+cases	O
+per	O
+1	O
+million	O
+children	O
+and	O
+three	O
+to	O
+seven	O
+cases	O
+per	O
+1	O
+million	O
+children	O
+in	O
+Great	O
+Britain	O
+.	O
+
+The	O
+mortality	O
+for	O
+these	O
+Reye	B
+syndrome	I
+cases	O
+in	O
+Australia	O
+was	O
+45	O
+%	O
+as	O
+compared	O
+with	O
+a	O
+32	O
+%	O
+case	O
+-	O
+fatality	O
+rate	O
+in	O
+the	O
+United	O
+States	O
+.	O
+
+In	O
+Australia	O
+,	O
+the	O
+pediatric	O
+usage	O
+of	O
+aspirin	O
+has	O
+been	O
+extremely	O
+low	O
+for	O
+the	O
+past	O
+25	O
+years	O
+(	O
+less	O
+than	O
+1	O
+%	O
+of	O
+total	O
+dosage	O
+units	O
+sold	O
+)	O
+,	O
+with	O
+paracetamol	O
+(	O
+acetaminophen	O
+)	O
+dominating	O
+the	O
+pediatric	O
+analgesic	O
+and	O
+antipyretic	O
+market	O
+.	O
+
+Reye	B
+syndrome	I
+may	O
+be	O
+disappearing	O
+from	O
+Australia	O
+despite	O
+a	O
+total	O
+lack	O
+of	O
+association	O
+with	O
+salicylates	O
+or	O
+aspirin	O
+ingestion	O
+,	O
+since	O
+there	O
+were	O
+no	O
+cases	O
+found	O
+at	O
+The	O
+Children	O
+'	O
+s	O
+Hospital	O
+in	O
+1983	O
+,	O
+1984	O
+,	O
+or	O
+1985	O
+.	O
+
+Postpartum	O
+psychosis	B
+induced	O
+by	O
+bromocriptine	O
+.	O
+
+Two	O
+multigravida	O
+patients	O
+with	O
+no	O
+prior	O
+psychiatric	B
+history	O
+were	O
+seen	O
+with	O
+postpartum	O
+psychosis	B
+,	O
+having	O
+received	O
+bromocriptine	O
+for	O
+inhibition	B
+of	I
+lactation	I
+.	O
+
+Bromocriptine	O
+given	O
+in	O
+high	O
+doses	O
+has	O
+been	O
+associated	O
+with	O
+psychosis	B
+in	O
+patients	O
+receiving	O
+the	O
+drug	O
+for	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+These	O
+cases	O
+demonstrate	O
+that	O
+bromocriptine	O
+may	O
+cause	O
+psychosis	B
+even	O
+when	O
+given	O
+in	O
+low	O
+doses	O
+.	O
+
+Hyperglycemic	B
+acidotic	I
+coma	I
+and	O
+death	O
+in	O
+Kearns	B
+-	I
+Sayre	I
+syndrome	I
+.	O
+
+This	O
+paper	O
+presents	O
+the	O
+clinical	O
+and	O
+metabolic	O
+findings	O
+in	O
+two	O
+young	O
+boys	O
+with	O
+long	O
+-	O
+standing	O
+Kearns	B
+-	I
+Sayre	I
+syndrome	I
+.	O
+
+Following	O
+short	O
+exposure	O
+to	O
+oral	O
+prednisone	O
+,	O
+both	O
+boys	O
+developed	O
+lethargy	B
+,	O
+increasing	O
+somnolence	B
+,	O
+polydipsia	B
+,	O
+polyphagia	B
+,	O
+and	O
+polyuria	B
+.	O
+
+Both	O
+presented	O
+in	O
+the	O
+emergency	O
+room	O
+with	O
+profound	O
+coma	B
+,	O
+hypotension	B
+,	O
+severe	O
+hyperglycemia	B
+,	O
+and	O
+acidosis	B
+.	O
+
+Nonketotic	O
+lactic	B
+acidosis	I
+was	O
+present	O
+in	O
+one	O
+and	O
+ketosis	B
+without	O
+a	O
+known	O
+serum	O
+lactate	O
+level	O
+was	O
+present	O
+in	O
+the	O
+other	O
+.	O
+
+Respiratory	B
+failure	I
+rapidly	O
+ensued	O
+and	O
+both	O
+patients	O
+expired	O
+in	O
+spite	O
+of	O
+efforts	O
+at	O
+resuscitation	O
+.	O
+
+We	O
+believe	O
+these	O
+two	O
+cases	O
+represent	O
+a	O
+newly	O
+described	O
+and	O
+catastrophic	O
+metabolic	B
+-	I
+endocrine	I
+failure	I
+in	O
+the	O
+Kearns	B
+-	I
+Sayre	I
+syndrome	I
+.	O
+
+Experimental	O
+cyclosporine	O
+nephrotoxicity	B
+:	O
+risk	O
+of	O
+concomitant	O
+chemotherapy	O
+.	O
+
+The	O
+role	O
+of	O
+cyclosporine	O
+(	O
+CSA	O
+)	O
+alone	O
+or	O
+in	O
+combination	O
+with	O
+various	O
+chemotherapeutics	O
+in	O
+the	O
+development	O
+of	O
+renal	B
+toxicity	I
+was	O
+evaluated	O
+in	O
+rats	O
+.	O
+
+Administration	O
+of	O
+20	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+CSA	O
+for	O
+4	O
+weeks	O
+caused	O
+renal	O
+functional	O
+and	O
+structural	O
+changes	O
+similar	O
+to	O
+those	O
+reported	O
+in	O
+man	O
+.	O
+
+The	O
+combined	O
+administration	O
+of	O
+CSA	O
+and	O
+various	O
+chemotherapeutic	O
+drugs	O
+with	O
+a	O
+nephrotoxic	B
+potential	O
+,	O
+such	O
+as	O
+gentamicin	O
+(	O
+at	O
+therapeutic	O
+doses	O
+)	O
+,	O
+amphothericin	O
+B	O
+and	O
+ketoconazole	O
+,	O
+which	O
+are	O
+frequently	O
+used	O
+in	O
+immunosuppressed	O
+patients	O
+,	O
+did	O
+not	O
+aggravate	O
+the	O
+CSA	O
+induced	O
+toxicity	B
+in	O
+the	O
+rat	O
+model	O
+.	O
+
+Gentamicin	O
+at	O
+toxic	O
+doses	O
+,	O
+however	O
+,	O
+increased	O
+CSA	O
+nephrotoxicity	B
+.	O
+
+Thus	O
+,	O
+the	O
+nephrotoxicity	B
+induced	O
+by	O
+CSA	O
+has	O
+a	O
+different	O
+pathogenetic	O
+mechanism	O
+.	O
+
+Diuretics	O
+,	O
+potassium	O
+and	O
+arrhythmias	B
+in	O
+hypertensive	B
+coronary	B
+disease	I
+.	O
+
+It	O
+has	O
+been	O
+proposed	O
+that	O
+modest	O
+changes	O
+in	O
+plasma	O
+potassium	O
+can	O
+alter	O
+the	O
+tendency	O
+towards	O
+cardiac	B
+arrhythmias	I
+.	O
+
+If	O
+this	O
+were	O
+so	O
+,	O
+patients	O
+with	O
+coronary	B
+artery	I
+disease	I
+might	O
+be	O
+especially	O
+susceptible	O
+.	O
+
+Thus	O
+,	O
+myocardial	O
+electrical	O
+excitability	O
+was	O
+measured	O
+in	O
+patients	O
+with	O
+mild	O
+essential	O
+hypertension	B
+and	O
+known	O
+coronary	B
+artery	I
+disease	I
+after	O
+8	O
+weeks	O
+of	O
+treatment	O
+with	O
+a	O
+potassium	O
+-	O
+conserving	O
+diuretic	O
+(	O
+amiloride	O
+)	O
+and	O
+a	O
+similar	O
+period	O
+on	O
+a	O
+potassium	O
+-	O
+losing	O
+diuretic	O
+(	O
+chlorthalidone	O
+)	O
+in	O
+a	O
+randomised	O
+study	O
+.	O
+
+Plasma	O
+potassium	O
+concentrations	O
+were	O
+on	O
+average	O
+1	O
+mmol	O
+/	O
+L	O
+lower	O
+during	O
+the	O
+chlorthalidone	O
+phase	O
+compared	O
+to	O
+amiloride	O
+therapy	O
+.	O
+
+Blood	O
+pressure	O
+and	O
+volume	O
+states	O
+as	O
+assessed	O
+by	O
+bodyweight	O
+,	O
+plasma	O
+renin	O
+and	O
+noradrenaline	O
+(	O
+norepinephrine	O
+)	O
+concentrations	O
+were	O
+similar	O
+on	O
+the	O
+2	O
+regimens	O
+.	O
+
+Compared	O
+to	O
+amiloride	O
+treatment	O
+,	O
+the	O
+chlorthalidone	O
+phase	O
+was	O
+associated	O
+with	O
+an	O
+increased	O
+frequency	O
+of	O
+ventricular	B
+ectopic	I
+beats	I
+(	O
+24	O
+-	O
+hour	O
+Holter	O
+monitoring	O
+)	O
+and	O
+a	O
+higher	O
+Lown	O
+grading	O
+,	O
+increased	O
+upslope	O
+and	O
+duration	O
+of	O
+the	O
+monophasic	O
+action	O
+potential	O
+,	O
+prolonged	O
+ventricular	O
+effective	O
+refractory	O
+period	O
+,	O
+and	O
+increased	O
+electrical	O
+instability	O
+during	O
+programmed	O
+ventricular	O
+stimulation	O
+.	O
+
+The	O
+above	O
+results	O
+indicate	O
+that	O
+because	O
+potassium	O
+-	O
+losing	O
+diuretic	O
+therapy	O
+can	O
+increase	O
+myocardial	O
+electrical	O
+excitability	O
+in	O
+patients	O
+with	O
+ischaemic	B
+heart	I
+disease	I
+,	O
+even	O
+minor	O
+falls	O
+in	O
+plasma	O
+potassium	O
+concentrations	O
+are	O
+probably	O
+best	O
+avoided	O
+in	O
+such	O
+patients	O
+.	O
+
+Transketolase	O
+abnormality	O
+in	O
+tolazamide	O
+-	O
+induced	O
+Wernicke	B
+'	I
+s	I
+encephalopathy	I
+.	O
+
+We	O
+studied	O
+a	O
+thiamine	O
+-	O
+dependent	O
+enzyme	O
+,	O
+transketolase	O
+,	O
+from	O
+fibroblasts	O
+of	O
+a	O
+diabetic	B
+patient	O
+who	O
+developed	O
+Wernicke	B
+'	I
+s	I
+encephalopathy	I
+when	O
+treated	O
+with	O
+tolazamide	O
+,	O
+in	O
+order	O
+to	O
+delineate	O
+if	O
+this	O
+patient	O
+also	O
+had	O
+transketolase	O
+abnormality	O
+[	O
+high	O
+Km	O
+for	O
+thiamine	O
+pyrophosphate	O
+(	O
+TPP	O
+)	O
+]	O
+,	O
+as	O
+previously	O
+reported	O
+in	O
+postalcoholic	O
+Wernicke	B
+-	I
+Korsakoff	I
+syndrome	I
+.	O
+
+In	O
+addition	O
+to	O
+this	O
+patient	O
+,	O
+we	O
+also	O
+studied	O
+this	O
+enzyme	O
+from	O
+three	O
+diabetic	B
+kindreds	O
+without	O
+any	O
+history	O
+of	O
+Wernicke	B
+'	I
+s	I
+encephalopathy	I
+and	O
+from	O
+four	O
+normal	O
+controls	O
+.	O
+
+We	O
+found	O
+that	O
+the	O
+above	O
+-	O
+mentioned	O
+patient	O
+and	O
+one	O
+of	O
+the	O
+diabetic	B
+kindreds	O
+with	O
+no	O
+history	O
+of	O
+Wernicke	B
+'	I
+s	I
+encephalopathy	I
+had	O
+abnormal	O
+transketolase	O
+as	O
+determined	O
+by	O
+its	O
+Km	O
+for	O
+TPP	O
+.	O
+
+These	O
+data	O
+suggest	O
+a	O
+similarity	O
+between	O
+postalcoholic	O
+Wernicke	B
+-	I
+Korsakoff	I
+syndrome	I
+and	O
+the	O
+patient	O
+with	O
+tolazamide	O
+-	O
+induced	O
+Wernicke	B
+'	I
+s	I
+encephalopathy	I
+from	O
+the	O
+standpoint	O
+of	O
+transketolase	O
+abnormality	O
+.	O
+
+Bradycardia	B
+due	O
+to	O
+trihexyphenidyl	O
+hydrochloride	O
+.	O
+
+A	O
+chronic	O
+schizophrenic	B
+patient	O
+was	O
+treated	O
+with	O
+an	O
+anticholinergic	O
+drug	O
+,	O
+trihexyphenidyl	O
+hydrochloride	O
+.	O
+
+The	O
+patient	O
+developed	O
+,	O
+paradoxically	O
+,	O
+sinus	O
+bradycardia	B
+.	O
+
+The	O
+reaction	O
+was	O
+specific	O
+to	O
+trihexyphenidyl	O
+and	O
+not	O
+to	O
+other	O
+anticholinergic	O
+drugs	O
+.	O
+
+This	O
+antidyskinetic	O
+drug	O
+is	O
+widely	O
+used	O
+in	O
+clinical	O
+psychiatric	B
+practice	O
+and	O
+physicians	O
+should	O
+be	O
+aware	O
+of	O
+this	O
+side	O
+effect	O
+.	O
+
+Post	O
+-	O
+operative	O
+rigidity	B
+after	O
+fentanyl	O
+administration	O
+.	O
+
+A	O
+case	O
+of	O
+thoraco	O
+-	O
+abdominal	O
+rigidity	B
+leading	O
+to	O
+respiratory	B
+failure	I
+is	O
+described	O
+in	O
+the	O
+post	O
+-	O
+operative	O
+period	O
+in	O
+an	O
+elderly	O
+patient	O
+who	O
+received	O
+a	O
+moderate	O
+dose	O
+of	O
+fentanyl	O
+.	O
+
+This	O
+was	O
+successfully	O
+reversed	O
+by	O
+naloxone	O
+.	O
+
+The	O
+mechanisms	O
+possibly	O
+implicated	O
+in	O
+this	O
+accident	O
+are	O
+discussed	O
+.	O
+
+Anti	O
+-	O
+carcinogenic	B
+action	O
+of	O
+phenobarbital	O
+given	O
+simultaneously	O
+with	O
+diethylnitrosamine	O
+in	O
+the	O
+rat	O
+.	O
+
+The	O
+present	O
+work	O
+has	O
+been	O
+planned	O
+in	O
+order	O
+to	O
+elucidate	O
+the	O
+effect	O
+of	O
+phenobarbital	O
+(	O
+PB	O
+:	O
+15	O
+mg	O
+per	O
+rat	O
+of	O
+ingested	O
+dose	O
+)	O
+on	O
+carcinogenesis	B
+when	O
+it	O
+is	O
+administered	O
+simultaneously	O
+with	O
+diethylnitrosamine	O
+(	O
+DEN	O
+:	O
+10	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+)	O
+.	O
+
+Wistar	O
+rats	O
+(	O
+180	O
+g	O
+)	O
+were	O
+treated	O
+by	O
+DEN	O
+alone	O
+or	O
+by	O
+DEN	O
++	O
+PB	O
+during	O
+2	O
+,	O
+4	O
+and	O
+6	O
+weeks	O
+according	O
+to	O
+our	O
+schedule	O
+for	O
+hepatocarcinogenesis	B
+.	O
+
+After	O
+the	O
+end	O
+of	O
+the	O
+treatment	O
+,	O
+the	O
+number	O
+and	O
+the	O
+size	O
+of	O
+induced	O
+PAS	O
+positive	O
+preneoplastic	B
+foci	I
+was	O
+significantly	O
+reduced	O
+when	O
+PB	O
+was	O
+given	O
+simultaneously	O
+with	O
+DEN	O
+for	O
+4	O
+and	O
+6	O
+weeks	O
+.	O
+
+The	O
+mitotic	O
+inhibition	O
+and	O
+the	O
+production	O
+of	O
+micronuclei	O
+normally	O
+observed	O
+after	O
+partial	O
+hepatectomy	O
+in	O
+DEN	O
+treated	O
+rats	O
+were	O
+also	O
+significantly	O
+decreased	O
+in	O
+DEN	O
++	O
+PB	O
+treated	O
+rats	O
+.	O
+
+When	O
+the	O
+treatment	O
+last	O
+only	O
+2	O
+weeks	O
+,	O
+the	O
+presence	O
+of	O
+PB	O
+did	O
+not	O
+change	O
+significantly	O
+the	O
+last	O
+parameters	O
+.	O
+
+In	O
+DEN	O
++	O
+PB	O
+treated	O
+rats	O
+,	O
+the	O
+survival	O
+was	O
+prolonged	O
+and	O
+the	O
+tumor	B
+incidence	O
+decreased	O
+as	O
+compared	O
+with	O
+the	O
+results	O
+obtained	O
+by	O
+DEN	O
+alone	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+PB	O
+,	O
+which	O
+promotes	O
+carcinogenesis	B
+when	O
+administered	O
+after	O
+the	O
+DEN	O
+treatment	O
+,	O
+reduces	O
+the	O
+carcinogen	O
+effect	O
+when	O
+given	O
+simultaneously	O
+with	O
+DEN	O
+.	O
+
+This	O
+'	O
+anti	O
+-	O
+carcinogen	O
+'	O
+effect	O
+acts	O
+on	O
+the	O
+initiation	O
+as	O
+well	O
+as	O
+on	O
+the	O
+promotion	O
+of	O
+the	O
+precancerous	B
+lesions	I
+.	O
+
+Biochemical	O
+investigations	O
+are	O
+in	O
+progress	O
+to	O
+obtain	O
+more	O
+information	O
+about	O
+this	O
+'	O
+paradoxical	O
+'	O
+PB	O
+effect	O
+.	O
+
+Bilateral	B
+optic	I
+neuropathy	I
+due	O
+to	O
+combined	O
+ethambutol	O
+and	O
+isoniazid	O
+treatment	O
+.	O
+
+The	O
+case	O
+of	O
+a	O
+40	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+who	O
+underwent	O
+an	O
+unsuccessful	O
+cadaver	O
+kidney	O
+transplantation	O
+and	O
+was	O
+treated	O
+with	O
+ethambutol	O
+and	O
+isoniazid	O
+is	O
+reported	O
+.	O
+
+A	O
+bilateral	B
+retrobulbar	I
+neuropathy	I
+with	O
+an	O
+unusual	O
+central	O
+bitemporal	O
+hemianopic	O
+scotoma	B
+was	O
+found	O
+.	O
+
+Ethambutol	O
+was	O
+stopped	O
+and	O
+only	O
+small	O
+improvement	O
+of	O
+the	O
+visual	O
+acuity	O
+followed	O
+.	O
+
+Isoniazid	O
+was	O
+discontinued	O
+later	O
+,	O
+followed	O
+by	O
+a	O
+dramatic	O
+improvement	O
+in	O
+the	O
+visual	O
+acuity	O
+.	O
+
+The	O
+hazards	O
+of	O
+optic	O
+nerve	O
+toxicity	B
+due	O
+to	O
+ethambutol	O
+are	O
+known	O
+.	O
+
+We	O
+emphasize	O
+the	O
+potential	O
+danger	O
+in	O
+the	O
+use	O
+of	O
+ethambutol	O
+and	O
+isoniazid	O
+.	O
+
+A	O
+prospective	O
+study	O
+of	O
+adverse	O
+reactions	O
+associated	O
+with	O
+vancomycin	O
+therapy	O
+.	O
+
+A	O
+prospective	O
+evaluation	O
+of	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+vancomycin	O
+was	O
+conducted	O
+in	O
+54	O
+consecutive	O
+patients	O
+over	O
+a	O
+16	O
+-	O
+month	O
+period	O
+.	O
+
+Vancomycin	O
+was	O
+curative	O
+in	O
+95	O
+%	O
+of	O
+43	O
+patients	O
+with	O
+proven	O
+infection	B
+.	O
+
+Drugs	O
+were	O
+ceased	O
+in	O
+six	O
+patients	O
+because	O
+of	O
+adverse	O
+reactions	O
+;	O
+in	O
+three	O
+of	O
+these	O
+vancomycin	O
+was	O
+considered	O
+the	O
+likely	O
+cause	O
+.	O
+
+Reactions	O
+included	O
+thrombophlebitis	B
+(	O
+20	O
+of	O
+54	O
+patients	O
+)	O
+,	O
+rash	B
+(	O
+4	O
+of	O
+54	O
+)	O
+,	O
+nephrotoxicity	B
+(	O
+4	O
+of	O
+50	O
+)	O
+,	O
+proteinuria	B
+(	O
+1	O
+of	O
+50	O
+)	O
+and	O
+ototoxicity	B
+(	O
+1	O
+of	O
+11	O
+patients	O
+tested	O
+by	O
+audiometry	O
+)	O
+.	O
+
+Thrombophlebitis	B
+occurred	O
+only	O
+with	O
+infusion	O
+through	O
+peripheral	O
+cannulae	O
+;	O
+nephrotoxicity	B
+and	O
+ototoxicity	B
+were	O
+confined	O
+to	O
+patients	O
+receiving	O
+an	O
+aminoglycoside	O
+plus	O
+vancomycin	O
+.	O
+
+We	O
+conclude	O
+that	O
+vancomycin	O
+,	O
+administered	O
+appropriately	O
+,	O
+constitutes	O
+safe	O
+,	O
+effective	O
+therapy	O
+for	O
+infections	B
+caused	O
+by	O
+susceptible	O
+bacteria	O
+.	O
+
+Factors	O
+associated	O
+with	O
+nephrotoxicity	B
+and	O
+clinical	O
+outcome	O
+in	O
+patients	O
+receiving	O
+amikacin	O
+.	O
+
+Data	O
+from	O
+60	O
+patients	O
+treated	O
+with	O
+amikacin	O
+were	O
+analyzed	O
+for	O
+factors	O
+associated	O
+with	O
+nephrotoxicity	B
+.	O
+
+In	O
+42	O
+of	O
+these	O
+patients	O
+,	O
+data	O
+were	O
+examined	O
+for	O
+factors	O
+associated	O
+with	O
+clinical	O
+outcome	O
+.	O
+
+Variables	O
+evaluated	O
+included	O
+patient	O
+weight	O
+,	O
+age	O
+,	O
+sex	O
+,	O
+serum	O
+creatinine	O
+level	O
+,	O
+creatinine	O
+clearance	O
+,	O
+duration	O
+of	O
+therapy	O
+,	O
+total	O
+dose	O
+,	O
+mean	O
+daily	O
+dose	O
+,	O
+organism	O
+minimum	O
+inhibitory	O
+concentration	O
+(	O
+MIC	O
+)	O
+,	O
+mean	O
+peak	O
+levels	O
+,	O
+mean	O
+trough	O
+levels	O
+,	O
+mean	O
+area	O
+under	O
+the	O
+serum	O
+concentration	O
+-	O
+time	O
+curve	O
+(	O
+AUC	O
+)	O
+,	O
+total	O
+AUC	O
+,	O
+mean	O
+AUC	O
+greater	O
+than	O
+MIC	O
+,	O
+total	O
+AUC	O
+greater	O
+than	O
+MIC	O
+,	O
+mean	O
+Schumacher	O
+'	O
+s	O
+intensity	O
+factor	O
+(	O
+IF	O
+)	O
+,	O
+total	O
+IF	O
+,	O
+In	O
+(	O
+mean	O
+maximum	O
+concentration	O
+[	O
+Cmax	O
+]	O
+/	O
+MIC	O
+)	O
+.	O
+
+Model	O
+-	O
+dependent	O
+pharmacokinetic	O
+parameters	O
+were	O
+calculated	O
+by	O
+computer	O
+based	O
+on	O
+a	O
+one	O
+-	O
+compartment	O
+model	O
+.	O
+
+When	O
+the	O
+parameters	O
+were	O
+examined	O
+individually	O
+,	O
+duration	O
+of	O
+therapy	O
+and	O
+total	O
+AUC	O
+correlated	O
+significantly	O
+(	O
+P	O
+less	O
+than	O
+.	O
+05	O
+)	O
+with	O
+nephrotoxicity	B
+.	O
+
+In	O
+contrast	O
+,	O
+a	O
+stepwise	O
+discriminant	O
+function	O
+analysis	O
+identified	O
+only	O
+duration	O
+of	O
+therapy	O
+(	O
+P	O
+less	O
+than	O
+.	O
+001	O
+)	O
+as	O
+an	O
+important	O
+factor	O
+.	O
+
+Based	O
+on	O
+this	O
+model	O
+and	O
+on	O
+Bayes	O
+'	O
+theorem	O
+,	O
+the	O
+predictive	O
+accuracy	O
+of	O
+identifying	O
+"	O
+nephrotoxic	B
+"	O
+patients	O
+increased	O
+from	O
+0	O
+.	O
+17	O
+to	O
+0	O
+.	O
+39	O
+.	O
+
+When	O
+examined	O
+individually	O
+,	O
+mean	O
+IF	O
+,	O
+MIC	O
+,	O
+total	O
+dose	O
+,	O
+mean	O
+daily	O
+dose	O
+,	O
+and	O
+ln	O
+(	O
+mean	O
+Cmax	O
+/	O
+MIC	O
+)	O
+correlated	O
+significantly	O
+(	O
+P	O
+less	O
+than	O
+.	O
+05	O
+)	O
+with	O
+cure	O
+.	O
+
+In	O
+contrast	O
+,	O
+a	O
+simultaneous	O
+multivariable	O
+analysis	O
+identified	O
+IF	O
+,	O
+MIC	O
+,	O
+and	O
+total	O
+dose	O
+according	O
+to	O
+one	O
+model	O
+and	O
+ln	O
+(	O
+mean	O
+Cmax	O
+/	O
+MIC	O
+)	O
+according	O
+to	O
+a	O
+second	O
+statistical	O
+model	O
+of	O
+parameters	O
+selected	O
+to	O
+have	O
+the	O
+greatest	O
+prospective	O
+value	O
+.	O
+
+Based	O
+on	O
+Bayes	O
+'	O
+theorem	O
+and	O
+the	O
+first	O
+model	O
+,	O
+the	O
+predictive	O
+accuracy	O
+of	O
+identifying	O
+patients	O
+not	O
+cured	O
+increased	O
+from	O
+0	O
+.	O
+19	O
+to	O
+0	O
+.	O
+83	O
+.	O
+
+For	O
+the	O
+second	O
+model	O
+,	O
+the	O
+predictive	O
+accuracy	O
+increased	O
+from	O
+0	O
+.	O
+19	O
+to	O
+0	O
+.	O
+50	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Cardiac	B
+toxicity	I
+of	O
+5	O
+-	O
+fluorouracil	O
+.	O
+
+Report	O
+of	O
+a	O
+case	O
+of	O
+spontaneous	O
+angina	B
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+a	O
+patient	O
+with	O
+colon	B
+carcinoma	I
+and	O
+liver	O
+metastasis	B
+who	O
+presented	O
+chest	B
+pain	I
+after	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+administration	O
+.	O
+
+Clinical	O
+electrocardiographic	O
+evolution	O
+was	O
+similar	O
+to	O
+that	O
+observed	O
+in	O
+Prinzmetal	B
+'	I
+s	I
+angina	I
+,	O
+and	O
+chest	B
+pain	I
+promptly	O
+resolved	O
+with	O
+nifedipine	O
+.	O
+
+These	O
+data	O
+suggest	O
+that	O
+coronary	B
+spasm	I
+may	O
+be	O
+the	O
+cause	O
+of	O
+cardiotoxicity	B
+due	O
+to	O
+5	O
+-	O
+FU	O
+,	O
+and	O
+that	O
+calcium	O
+antagonists	O
+may	O
+probably	O
+be	O
+used	O
+in	O
+the	O
+prevention	O
+or	O
+treatment	O
+of	O
+5	O
+-	O
+FU	O
+cardiotoxicity	B
+.	O
+
+Dose	O
+-	O
+related	O
+beneficial	O
+and	O
+adverse	O
+effects	O
+of	O
+dietary	O
+corticosterone	O
+on	O
+organophosphorus	O
+-	O
+induced	O
+delayed	O
+neuropathy	B
+in	O
+chickens	O
+.	O
+
+Tri	O
+-	O
+ortho	O
+-	O
+tolyl	O
+phosphate	O
+(	O
+TOTP	O
+)	O
+,	O
+360	O
+mg	O
+/	O
+kg	O
+,	O
+po	O
+,	O
+and	O
+0	O
+,	O
+0	O
+'	O
+-	O
+diisopropyl	O
+phosphorofluoridate	O
+(	O
+DFP	O
+)	O
+,	O
+1	O
+mg	O
+/	O
+kg	O
+sc	O
+,	O
+were	O
+administered	O
+to	O
+adult	O
+White	O
+Leghorn	O
+chickens	O
+24	O
+hr	O
+after	O
+they	O
+were	O
+placed	O
+on	O
+diets	O
+containing	O
+0	O
+to	O
+300	O
+ppm	O
+corticosterone	O
+.	O
+
+Supplemented	O
+diets	O
+were	O
+continued	O
+until	O
+clinical	O
+signs	O
+and	O
+lesions	O
+of	O
+delayed	O
+neuropathy	B
+appeared	O
+.	O
+
+Although	O
+low	O
+concentrations	O
+(	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+50	O
+ppm	O
+)	O
+of	O
+corticosterone	O
+had	O
+beneficial	O
+effects	O
+on	O
+TOTP	O
+-	O
+induced	O
+neuropathy	B
+,	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+200	O
+ppm	O
+exacerbated	O
+clinical	O
+signs	O
+in	O
+chickens	O
+given	O
+either	O
+TOTP	O
+or	O
+DFP	O
+.	O
+
+Neurotoxic	B
+esterase	O
+activities	O
+24	O
+hr	O
+after	O
+TOTP	O
+or	O
+DFP	O
+were	O
+less	O
+than	O
+20	O
+%	O
+of	O
+values	O
+measured	O
+in	O
+chickens	O
+not	O
+given	O
+organophosphorous	O
+compounds	O
+.	O
+
+Chickens	O
+given	O
+200	O
+ppm	O
+corticosterone	O
+without	O
+TOTP	O
+or	O
+DFP	O
+had	O
+significantly	O
+elevated	O
+activity	O
+of	O
+plasma	O
+cholinesterase	O
+and	O
+significantly	O
+inhibited	O
+activity	O
+of	O
+liver	O
+carboxylesterase	O
+.	O
+
+Degenerating	B
+myelinated	I
+fibers	I
+were	O
+also	O
+evident	O
+in	O
+distal	O
+levels	O
+of	O
+the	O
+peripheral	O
+nerves	O
+of	O
+chickens	O
+given	O
+TOTP	O
+or	O
+DFP	O
+.	O
+
+Hepatotoxicity	B
+of	O
+amiodarone	O
+.	O
+
+Amiodarone	O
+has	O
+proved	O
+very	O
+effective	O
+in	O
+the	O
+treatment	O
+of	O
+otherwise	O
+resistant	O
+cardiac	O
+tachyarrhythmias	B
+.	O
+
+The	O
+use	O
+of	O
+amiodarone	O
+has	O
+,	O
+however	O
+,	O
+been	O
+limited	O
+due	O
+to	O
+its	O
+serious	O
+side	O
+-	O
+effects	O
+.	O
+
+A	O
+patient	O
+with	O
+cholestatic	B
+hepatitis	I
+due	O
+to	O
+amiodarone	O
+treatment	O
+is	O
+presented	O
+below	O
+and	O
+a	O
+review	O
+of	O
+the	O
+hepatotoxicity	B
+of	O
+amiodarone	O
+is	O
+given	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+solid	O
+evidence	O
+exists	O
+of	O
+hepatic	B
+injury	I
+due	O
+to	O
+amiodarone	O
+treatment	O
+,	O
+including	O
+steatosis	B
+,	O
+alterations	O
+resembling	O
+alcoholic	B
+hepatitis	I
+,	O
+cholestatic	B
+hepatitis	I
+and	O
+micronodular	O
+cirrhosis	B
+of	I
+the	I
+liver	I
+.	O
+
+Patients	O
+receiving	O
+amiodarone	O
+should	O
+be	O
+regularly	O
+screened	O
+with	O
+respect	O
+to	O
+hepatic	O
+enzyme	O
+levels	O
+.	O
+
+Therapy	O
+should	O
+be	O
+discontinued	O
+on	O
+the	O
+suspicion	O
+of	O
+cholestatic	B
+injury	I
+or	O
+hepatomegaly	B
+.	O
+
+Promotional	O
+effects	O
+of	O
+testosterone	O
+and	O
+dietary	O
+fat	O
+on	O
+prostate	O
+carcinogenesis	B
+in	O
+genetically	O
+susceptible	O
+rats	O
+.	O
+
+Germfree	O
+(	O
+GF	O
+)	O
+Lobund	O
+strain	O
+Wistar	O
+(	O
+LW	O
+)	O
+rats	O
+,	O
+fed	O
+vegetable	O
+diet	O
+L	O
+-	O
+485	O
+,	O
+have	O
+developed	O
+prostate	B
+adenocarcinomas	I
+spontaneously	O
+(	O
+10	O
+%	O
+incidence	O
+)	O
+at	O
+average	O
+age	O
+34	O
+months	O
+.	O
+
+Conventional	O
+LW	O
+rats	O
+,	O
+implanted	O
+with	O
+testosterone	O
+at	O
+age	O
+4	O
+months	O
+,	O
+developed	O
+a	O
+higher	O
+incidence	O
+of	O
+prostate	B
+cancer	I
+after	O
+an	O
+average	O
+interval	O
+of	O
+14	O
+months	O
+:	O
+24	O
+%	O
+had	O
+developed	O
+gross	O
+tumors	B
+,	O
+and	O
+40	O
+%	O
+when	O
+it	O
+included	O
+microscopic	O
+tumors	B
+.	O
+
+Preliminary	O
+results	O
+indicate	O
+that	O
+testosterone	O
+-	O
+treated	O
+LW	O
+rats	O
+that	O
+were	O
+fed	O
+the	O
+same	O
+diet	O
+,	O
+which	O
+was	O
+supplemented	O
+with	O
+corn	O
+oil	O
+up	O
+to	O
+20	O
+%	O
+fat	O
+,	O
+developed	O
+prostate	B
+cancer	I
+after	O
+intervals	O
+of	O
+6	O
+-	O
+12	O
+months	O
+.	O
+
+Aged	O
+GF	O
+Sprague	O
+-	O
+Dawley	O
+(	O
+SD	O
+)	O
+rats	O
+have	O
+not	O
+developed	O
+prostate	B
+cancer	I
+spontaneously	O
+.	O
+
+Conventional	O
+SD	O
+rats	O
+fed	O
+diet	O
+L	O
+-	O
+485	O
+and	O
+treated	O
+with	O
+testosterone	O
+developed	O
+only	O
+prostatitis	B
+.	O
+
+Experimental	O
+designs	O
+should	O
+consider	O
+genetic	O
+susceptibility	O
+as	O
+a	O
+basic	O
+prerequisite	O
+for	O
+studies	O
+on	O
+experimental	O
+prostate	B
+cancer	I
+.	O
+
+Time	O
+course	O
+alterations	O
+of	O
+QTC	O
+interval	O
+due	O
+to	O
+hypaque	O
+76	O
+.	O
+
+Sequential	O
+measurement	O
+of	O
+QT	O
+interval	O
+during	O
+left	O
+ventricular	O
+angiography	O
+was	O
+made	O
+30	O
+seconds	O
+and	O
+one	O
+,	O
+three	O
+,	O
+five	O
+and	O
+ten	O
+minutes	O
+after	O
+injection	O
+of	O
+hypaque	O
+76	O
+.	O
+
+The	O
+subjects	O
+were	O
+ten	O
+patients	O
+found	O
+to	O
+have	O
+normal	O
+left	O
+ventricles	O
+and	O
+coronary	O
+arteries	O
+.	O
+
+Significant	O
+QTC	B
+prolongation	I
+occurred	O
+in	O
+30	O
+seconds	O
+to	O
+one	O
+minute	O
+in	O
+association	O
+with	O
+marked	O
+hypotension	B
+and	O
+elevation	O
+of	O
+cardiac	O
+output	O
+.	O
+
+Rat	O
+extraocular	O
+muscle	O
+regeneration	O
+.	O
+
+Repair	O
+of	O
+local	O
+anesthetic	O
+-	O
+induced	O
+damage	O
+.	O
+
+Local	O
+anesthetics	O
+that	O
+are	O
+commonly	O
+used	O
+in	O
+ophthalmic	O
+surgery	O
+(	O
+0	O
+.	O
+75	O
+%	O
+bupivacaine	O
+hydrochloride	O
+,	O
+2	O
+.	O
+0	O
+%	O
+mepivacaine	O
+hydrochloride	O
+,	O
+and	O
+2	O
+.	O
+0	O
+%	O
+lidocaine	O
+hydrochloride	O
+plus	O
+1	O
+:	O
+100	O
+,	O
+000	O
+epinephrine	O
+)	O
+were	O
+injected	O
+into	O
+the	O
+retrobulbar	O
+area	O
+of	O
+rat	O
+eyes	O
+.	O
+
+Controls	O
+were	O
+injected	O
+with	O
+physiological	O
+saline	O
+.	O
+
+All	O
+three	O
+anesthetics	O
+produced	O
+massive	O
+degeneration	O
+of	O
+the	O
+extraocular	O
+muscles	O
+.	O
+
+Muscle	B
+degeneration	I
+is	O
+followed	O
+by	O
+regeneration	O
+of	O
+the	O
+damaged	O
+muscle	O
+fibers	O
+.	O
+
+In	O
+addition	O
+to	O
+muscle	B
+damage	I
+,	O
+severe	O
+damage	O
+was	O
+also	O
+seen	O
+in	O
+harderian	O
+glands	O
+,	O
+especially	O
+after	O
+exposure	O
+to	O
+mepivacaine	O
+and	O
+lidocaine	O
+plus	O
+epinephrine	O
+.	O
+
+With	O
+these	O
+findings	O
+in	O
+rats	O
+,	O
+it	O
+is	O
+hypothesized	O
+that	O
+the	O
+temporary	O
+diplopia	B
+sometimes	O
+seen	O
+in	O
+patients	O
+after	O
+ophthalmic	O
+surgery	O
+might	O
+be	O
+due	O
+to	O
+anesthetic	O
+-	O
+induced	O
+damage	O
+to	O
+the	O
+extraocular	O
+muscles	O
+.	O
+
+Gentamicin	O
+nephropathy	B
+in	O
+a	O
+neonate	O
+.	O
+
+The	O
+clinical	O
+and	O
+autopsy	O
+findings	O
+in	O
+a	O
+premature	O
+baby	O
+who	O
+died	O
+of	O
+acute	B
+renal	I
+failure	I
+after	O
+therapy	O
+with	O
+gentamicin	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+)	O
+and	O
+penicillin	O
+are	O
+presented	O
+.	O
+
+The	O
+serum	O
+gentamicin	O
+concentration	O
+had	O
+reached	O
+toxic	O
+levels	O
+when	O
+anuria	B
+developed	O
+.	O
+
+Numerous	O
+periodic	O
+acid	O
+Schiff	O
+(	O
+PAS	O
+)	O
+positive	O
+,	O
+diastase	O
+resistant	O
+cytoplasmic	O
+inclusion	O
+bodies	O
+which	O
+appeared	O
+as	O
+myelin	O
+figures	O
+in	O
+cytosegresomes	O
+under	O
+the	O
+electron	O
+microscope	O
+were	O
+identified	O
+in	O
+the	O
+proximal	O
+convoluted	O
+tubules	O
+.	O
+
+The	O
+pathological	O
+changes	O
+induced	O
+by	O
+gentamicin	O
+in	O
+the	O
+human	O
+neonatal	O
+kidneys	O
+have	O
+not	O
+been	O
+previously	O
+reported	O
+.	O
+
+Induction	O
+by	O
+paracetamol	O
+of	O
+bladder	B
+and	I
+liver	I
+tumours	I
+in	O
+the	O
+rat	O
+.	O
+
+Effects	O
+on	O
+hepatocyte	O
+fine	O
+structure	O
+.	O
+
+Groups	O
+of	O
+male	O
+and	O
+female	O
+inbred	O
+Leeds	O
+strain	O
+rats	O
+were	O
+fed	O
+diets	O
+containing	O
+either	O
+0	O
+.	O
+5	O
+%	O
+or	O
+1	O
+.	O
+0	O
+%	O
+paracetamol	O
+by	O
+weight	O
+for	O
+up	O
+to	O
+18	O
+months	O
+.	O
+
+At	O
+the	O
+1	O
+.	O
+0	O
+%	O
+dosage	O
+level	O
+,	O
+20	O
+%	O
+of	O
+rats	O
+of	O
+both	O
+sexes	O
+developed	O
+neoplastic	O
+nodules	O
+of	O
+the	O
+liver	O
+,	O
+a	O
+statistically	O
+significant	O
+incidence	O
+.	O
+
+These	O
+rats	O
+also	O
+showed	O
+gross	O
+enlargement	O
+of	O
+their	O
+livers	O
+and	O
+an	O
+increase	O
+in	O
+foci	O
+of	O
+cellular	O
+alteration	O
+,	O
+the	O
+latter	O
+also	O
+being	O
+observed	O
+in	O
+the	O
+low	O
+dosage	O
+male	O
+rats	O
+.	O
+
+Papillomas	B
+of	O
+the	O
+transitional	O
+epithelium	O
+of	O
+the	O
+bladder	O
+developed	O
+in	O
+all	O
+paracetamol	O
+-	O
+treated	O
+groups	O
+,	O
+and	O
+three	O
+rats	O
+bore	O
+bladder	B
+carcinomas	I
+.	O
+
+However	O
+,	O
+significant	O
+yields	O
+of	O
+bladder	B
+tumours	I
+were	O
+only	O
+obtained	O
+from	O
+low	O
+dosage	O
+females	O
+and	O
+high	O
+dosage	O
+males	O
+.	O
+
+Additionally	O
+,	O
+20	O
+to	O
+25	O
+%	O
+of	O
+paracetamol	O
+-	O
+treated	O
+rats	O
+developed	O
+hyperplasia	B
+of	O
+the	O
+bladder	O
+epithelium	O
+,	O
+which	O
+was	O
+not	O
+coincident	O
+with	O
+the	O
+presence	O
+of	O
+bladder	B
+calculi	I
+.	O
+
+A	O
+low	O
+yield	O
+of	O
+tumours	B
+at	O
+various	O
+other	O
+sites	O
+also	O
+arose	O
+following	O
+paracetamol	O
+feeding	O
+.	O
+
+An	O
+electron	O
+microscope	O
+study	O
+of	O
+the	O
+livers	O
+of	O
+paracetamol	O
+-	O
+treated	O
+rats	O
+revealed	O
+ultrastructural	O
+changes	O
+in	O
+the	O
+hepatocytes	O
+that	O
+resemble	O
+those	O
+that	O
+result	O
+from	O
+exposure	O
+to	O
+a	O
+variety	O
+of	O
+known	O
+hepatocarcinogens	B
+.	O
+
+Transient	O
+hemiparesis	B
+:	O
+a	O
+rare	O
+manifestation	O
+of	O
+diphenylhydantoin	O
+toxicity	B
+.	O
+
+Report	O
+of	O
+two	O
+cases	O
+.	O
+
+Among	O
+the	O
+common	O
+side	O
+effects	O
+of	O
+diphenylhydantoin	O
+(	O
+DPH	O
+)	O
+overdose	B
+,	O
+the	O
+most	O
+frequently	O
+encountered	O
+neurological	O
+signs	O
+are	O
+those	O
+of	O
+cerebellar	B
+dysfunction	I
+.	O
+
+Very	O
+rarely	O
+,	O
+the	O
+toxic	O
+neurological	O
+manifestations	O
+of	O
+this	O
+drug	O
+are	O
+of	O
+cerebral	O
+origin	O
+.	O
+
+Two	O
+patients	O
+are	O
+presented	O
+who	O
+suffered	O
+progressive	O
+hemiparesis	B
+due	O
+to	O
+DPH	O
+overdose	B
+.	O
+
+Both	O
+had	O
+brain	O
+surgery	O
+before	O
+DPH	O
+treatment	O
+.	O
+
+It	O
+is	O
+assumed	O
+that	O
+patients	O
+with	O
+some	O
+cerebral	B
+damage	I
+are	O
+liable	O
+to	O
+manifest	O
+DPH	O
+toxicity	B
+as	O
+focal	O
+neurological	O
+signs	O
+.	O
+
+Tiapride	O
+in	O
+levodopa	O
+-	O
+induced	O
+involuntary	B
+movements	I
+.	O
+
+Tiapride	O
+,	O
+a	O
+substituted	O
+benzamide	O
+derivative	O
+closely	O
+related	O
+to	O
+metoclopramide	O
+,	O
+reduced	O
+levodopa	O
+-	O
+induced	O
+peak	O
+dose	O
+involuntary	B
+movements	I
+in	O
+16	O
+patients	O
+with	O
+idiopathic	B
+Parkinson	I
+'	I
+s	I
+disease	I
+.	O
+
+However	O
+,	O
+an	O
+unacceptable	O
+increase	O
+in	O
+disability	O
+from	O
+Parkinsonism	B
+with	O
+aggravation	O
+of	O
+end	O
+-	O
+of	O
+-	O
+dose	O
+akinesia	B
+led	O
+to	O
+its	O
+cessation	O
+in	O
+14	O
+patients	O
+.	O
+
+Tiapride	O
+had	O
+no	O
+effect	O
+on	O
+levodopa	O
+-	O
+induced	O
+early	O
+morning	O
+of	O
+"	O
+off	O
+-	O
+period	O
+"	O
+segmental	O
+dystonia	B
+.	O
+
+These	O
+results	O
+fail	O
+to	O
+support	O
+the	O
+notion	O
+that	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+are	O
+caused	O
+by	O
+overstimulation	O
+of	O
+a	O
+separate	O
+group	O
+of	O
+dopamine	O
+receptors	O
+.	O
+
+Quinidine	O
+hepatitis	B
+.	O
+
+Long	O
+-	O
+term	O
+administration	O
+of	O
+quinidine	O
+was	O
+associated	O
+with	O
+persistent	O
+elevation	O
+of	O
+serum	O
+concentrations	O
+of	O
+SGOT	O
+,	O
+lactic	O
+acid	O
+dehydrogenase	O
+,	O
+and	O
+alkaline	O
+phosphatase	O
+.	O
+
+Liver	O
+biopsy	O
+showed	O
+active	O
+hepatitis	B
+.	O
+
+Discontinuance	O
+of	O
+quinidine	O
+therapy	O
+led	O
+to	O
+normalization	O
+of	O
+liver	O
+function	O
+tests	O
+.	O
+
+A	O
+challenge	O
+dose	O
+of	O
+quinidine	O
+caused	O
+clinical	O
+symptoms	O
+and	O
+abrupt	O
+elevation	O
+of	O
+SGOT	O
+,	O
+alkaline	O
+phosphatase	O
+,	O
+and	O
+lactic	O
+acid	O
+dehydrogenase	O
+values	O
+.	O
+
+We	O
+concluded	O
+that	O
+this	O
+patient	O
+had	O
+quinidine	O
+hepatotoxicity	B
+and	O
+believe	O
+that	O
+this	O
+is	O
+the	O
+first	O
+case	O
+reported	O
+with	O
+liver	O
+biopsy	O
+documentation	O
+.	O
+
+This	O
+report	O
+also	O
+suggests	O
+that	O
+,	O
+even	O
+after	O
+long	O
+-	O
+term	O
+administration	O
+,	O
+the	O
+hepatic	B
+toxicity	I
+is	O
+reversible	O
+.	O
+
+Arterial	O
+thromboembolism	B
+in	O
+patients	O
+receiving	O
+systemic	O
+heparin	O
+therapy	O
+:	O
+a	O
+complication	O
+associated	O
+with	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+.	O
+
+Arterial	O
+thromboembolism	B
+is	O
+a	O
+recognized	O
+complication	O
+of	O
+systemic	O
+heparin	O
+therapy	O
+.	O
+
+Characteristic	O
+of	O
+the	O
+entity	O
+is	O
+arterial	B
+occlusion	I
+by	O
+platelet	O
+-	O
+fibrin	O
+thrombi	B
+with	O
+distal	O
+ischemia	B
+occurring	O
+four	O
+to	O
+twenty	O
+days	O
+after	O
+the	O
+initiation	O
+of	O
+heparin	O
+therapy	O
+,	O
+preceded	O
+by	O
+profound	O
+thrombocytopenia	B
+with	O
+platelet	O
+counts	O
+in	O
+the	O
+range	O
+of	O
+30	O
+,	O
+000	O
+to	O
+40	O
+,	O
+000	O
+per	O
+cubic	O
+millimeter	O
+.	O
+
+The	O
+clinically	O
+apparent	O
+occlusion	O
+may	O
+be	O
+preceded	O
+by	O
+gastrointestinal	B
+and	I
+musculoskeletal	I
+symptoms	I
+that	O
+appear	O
+to	O
+be	O
+ischemic	B
+in	O
+origin	O
+,	O
+and	O
+might	O
+serve	O
+to	O
+warn	O
+the	O
+clinician	O
+of	O
+these	O
+complications	O
+.	O
+
+Previous	O
+reports	O
+of	O
+these	O
+phenomena	O
+as	O
+well	O
+as	O
+recent	O
+studies	O
+of	O
+the	O
+effect	O
+of	O
+heparin	O
+are	O
+reviewed	O
+.	O
+
+The	O
+common	O
+factor	O
+relating	O
+thromboembolism	B
+and	O
+thrombocytopenia	B
+is	O
+heparin	O
+-	O
+induced	O
+platelet	B
+aggregation	I
+.	O
+
+Appropriate	O
+treatment	O
+consists	O
+of	O
+discontinuation	O
+of	O
+heparin	O
+,	O
+and	O
+anticoagulation	O
+with	O
+sodium	O
+warfarin	O
+if	O
+necessary	O
+.	O
+
+Vascular	O
+procedures	O
+are	O
+performed	O
+as	O
+indicated	O
+.	O
+
+Pharmacology	O
+of	O
+GYKI	O
+-	O
+41	O
+099	O
+(	O
+chlorpropanol	O
+,	O
+Tobanum	O
+)	O
+a	O
+new	O
+potent	O
+beta	O
+-	O
+adrenergic	O
+antagonist	O
+.	O
+
+The	O
+compound	O
+GYKI	O
+-	O
+41	O
+099	O
+,	O
+as	O
+a	O
+beta	O
+-	O
+adrenergic	O
+antagonist	O
+,	O
+is	O
+3	O
+-	O
+8	O
+times	O
+more	O
+potent	O
+than	O
+propranolol	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+.	O
+
+Its	O
+antiarrhythmic	O
+effectiveness	O
+surpasses	O
+that	O
+of	O
+propranolol	O
+and	O
+pindolol	O
+inhibiting	O
+the	O
+ouabain	O
+arrhythmia	B
+in	O
+dogs	O
+and	O
+cats	O
+.	O
+
+GYKI	O
+-	O
+41	O
+900	O
+has	O
+a	O
+negligible	O
+cardiodepressant	O
+activity	O
+;	O
+it	O
+is	O
+not	O
+cardioselective	O
+.	O
+
+The	O
+compound	O
+shows	O
+a	O
+rapid	O
+and	O
+long	O
+lasting	O
+effect	O
+.	O
+
+There	O
+was	O
+a	O
+prolonged	O
+elimination	O
+of	O
+the	O
+radioactivity	O
+after	O
+the	O
+injection	O
+of	O
+14C	O
+-	O
+41	O
+099	O
+to	O
+rats	O
+and	O
+dogs	O
+.	O
+
+The	O
+half	O
+life	O
+of	O
+the	O
+unlabeled	O
+substance	O
+in	O
+humans	O
+was	O
+more	O
+than	O
+10	O
+hours	O
+.	O
+
+Adverse	O
+reactions	O
+to	O
+bendrofluazide	O
+and	O
+propranolol	O
+for	O
+the	O
+treatment	O
+of	O
+mild	O
+hypertension	B
+.	O
+
+Report	O
+of	O
+Medical	O
+Research	O
+Council	O
+Working	O
+Party	O
+on	O
+Mild	O
+to	O
+Moderate	O
+Hypertension	B
+.	O
+
+Participants	O
+in	O
+the	O
+Medical	O
+Research	O
+Council	O
+treatment	O
+trial	O
+for	O
+mild	O
+hypertension	B
+are	O
+randomly	O
+allocated	O
+to	O
+one	O
+of	O
+four	O
+treatment	O
+groups	O
+:	O
+bendrofluazide	O
+,	O
+propranolol	O
+,	O
+or	O
+a	O
+placebo	O
+for	O
+either	O
+of	O
+these	O
+drugs	O
+.	O
+
+The	O
+trial	O
+is	O
+single	O
+-	O
+blind	O
+.	O
+
+23	O
+582	O
+patient	O
+-	O
+years	O
+of	O
+observation	O
+have	O
+been	O
+completed	O
+so	O
+far	O
+,	O
+10	O
+684	O
+on	O
+active	O
+drugs	O
+and	O
+12	O
+898	O
+on	O
+placebos	O
+.	O
+
+The	O
+results	O
+show	O
+an	O
+association	O
+between	O
+bendrofluazide	O
+treatment	O
+and	O
+impotence	B
+,	O
+and	O
+impotence	B
+also	O
+occurred	O
+more	O
+frequently	O
+in	O
+patients	O
+taking	O
+propranolol	O
+than	O
+in	O
+those	O
+taking	O
+placebos	O
+.	O
+
+Other	O
+adverse	O
+reactions	O
+significantly	O
+linked	O
+with	O
+active	O
+drugs	O
+include	O
+impaired	B
+glucose	I
+tolerance	I
+in	O
+men	O
+and	O
+women	O
+and	O
+gout	B
+in	O
+men	O
+,	O
+associated	O
+with	O
+bendrofluazide	O
+treatment	O
+,	O
+and	O
+Raynaud	B
+'	I
+s	I
+phenomenon	I
+and	O
+dyspnoea	B
+in	O
+men	O
+and	O
+women	O
+taking	O
+propranolol	O
+.	O
+
+No	O
+corneal	B
+disease	I
+is	O
+known	O
+to	O
+have	O
+occurred	O
+in	O
+the	O
+propranolol	O
+group	O
+.	O
+
+Mean	O
+serum	O
+potassium	O
+level	O
+fell	O
+,	O
+and	O
+urea	O
+and	O
+uric	O
+acid	O
+levels	O
+rose	O
+,	O
+in	O
+men	O
+and	O
+women	O
+taking	O
+bendrofluazide	O
+.	O
+
+In	O
+the	O
+propranolol	O
+group	O
+,	O
+serum	O
+potassium	O
+and	O
+uric	O
+acid	O
+levels	O
+rose	O
+in	O
+both	O
+sexes	O
+,	O
+but	O
+the	O
+urea	O
+level	O
+rose	O
+significantly	O
+in	O
+women	O
+only	O
+.	O
+
+Serotonergic	O
+drugs	O
+,	O
+benzodiazepines	O
+and	O
+baclofen	O
+block	O
+muscimol	O
+-	O
+induced	O
+myoclonic	B
+jerks	I
+in	O
+a	O
+strain	O
+of	O
+mice	O
+.	O
+
+In	O
+male	O
+Swiss	O
+mice	O
+,	O
+muscimol	O
+produced	O
+myoclonic	B
+jerks	I
+.	O
+
+A	O
+3	O
+mg	O
+/	O
+kg	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+dose	O
+induced	O
+this	O
+response	O
+in	O
+all	O
+of	O
+the	O
+mice	O
+tested	O
+and	O
+the	O
+peak	O
+response	O
+of	O
+73	O
+jerks	O
+per	O
+min	O
+was	O
+observed	O
+between	O
+27	O
+and	O
+45	O
+min	O
+.	O
+
+Increasing	O
+the	O
+brain	O
+serotonin	O
+levels	O
+by	O
+the	O
+administration	O
+of	O
+5	O
+-	O
+hydroxytryptophan	O
+(	O
+80	O
+-	O
+160	O
+mg	O
+/	O
+kg	O
+)	O
+in	O
+combination	O
+with	O
+a	O
+peripheral	O
+decarboxylase	O
+inhibitor	O
+resulted	O
+in	O
+an	O
+inhibition	O
+of	O
+the	O
+muscimol	O
+effect	O
+.	O
+
+However	O
+,	O
+in	O
+a	O
+similar	O
+experiment	O
+l	O
+-	O
+dopa	O
+(	O
+80	O
+-	O
+160	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+without	O
+effect	O
+.	O
+
+In	O
+doses	O
+of	O
+3	O
+-	O
+10	O
+mg	O
+/	O
+kg	O
+,	O
+the	O
+serotonin	O
+receptor	O
+agonist	O
+MK	O
+-	O
+212	O
+caused	O
+a	O
+dose	O
+-	O
+dependent	O
+blockade	O
+of	O
+the	O
+response	O
+of	O
+muscimol	O
+.	O
+
+Of	O
+the	O
+benzodiazepines	O
+,	O
+clonazepam	O
+(	O
+0	O
+.	O
+1	O
+-	O
+0	O
+.	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+found	O
+to	O
+be	O
+several	O
+fold	O
+more	O
+potent	O
+than	O
+diazepam	O
+(	O
+0	O
+.	O
+3	O
+-	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+in	O
+blocking	O
+the	O
+myoclonic	B
+jerks	I
+.	O
+
+While	O
+(	O
+-	O
+)	O
+-	O
+baclofen	O
+(	O
+1	O
+-	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+proved	O
+to	O
+be	O
+an	O
+effective	O
+antagonist	O
+of	O
+muscimol	O
+,	O
+its	O
+(	O
++	O
+)	O
+-	O
+isomer	O
+(	O
+5	O
+-	O
+20	O
+mg	O
+/	O
+kg	O
+)	O
+lacked	O
+this	O
+property	O
+.	O
+
+Considering	O
+the	O
+fact	O
+that	O
+5	O
+-	O
+HTP	O
+and	O
+the	O
+benzodiazepines	O
+have	O
+been	O
+found	O
+to	O
+be	O
+beneficial	O
+in	O
+the	O
+management	O
+of	O
+clinical	O
+myoclonus	B
+,	O
+the	O
+muscimol	O
+-	O
+induced	O
+myoclonus	B
+seems	O
+to	O
+be	O
+a	O
+satisfactory	O
+animal	O
+model	O
+that	O
+may	O
+prove	O
+useful	O
+for	O
+the	O
+development	O
+of	O
+new	O
+drug	O
+treatments	O
+for	O
+this	O
+condition	O
+.	O
+
+Our	O
+present	O
+study	O
+indicated	O
+the	O
+possible	O
+value	O
+of	O
+MK	O
+-	O
+212	O
+and	O
+(	O
+-	O
+)	O
+-	O
+baclofen	O
+in	O
+the	O
+management	O
+of	O
+clinical	O
+myoclonus	B
+.	O
+
+Adverse	O
+interaction	O
+between	O
+beta	O
+-	O
+adrenergic	O
+blocking	O
+drugs	O
+and	O
+verapamil	O
+-	O
+-	O
+report	O
+of	O
+three	O
+cases	O
+.	O
+
+Three	O
+patients	O
+with	O
+ischaemic	B
+heart	I
+disease	I
+developed	O
+profound	O
+cardiac	B
+failure	I
+,	O
+hypotension	B
+and	O
+bradycardia	B
+during	O
+combined	O
+therapy	O
+with	O
+verapamil	O
+and	O
+beta	O
+-	O
+adrenergic	O
+blocking	O
+drugs	O
+.	O
+
+This	O
+clinical	O
+picture	O
+resolved	O
+completely	O
+with	O
+cessation	O
+of	O
+the	O
+combined	O
+therapy	O
+.	O
+
+Baseline	O
+left	O
+ventricular	O
+function	O
+,	O
+assessed	O
+by	O
+cardiac	O
+catheterisation	O
+or	O
+nuclear	O
+angiography	O
+,	O
+was	O
+normal	O
+in	O
+two	O
+patients	O
+and	O
+only	O
+mildly	O
+reduced	O
+in	O
+the	O
+other	O
+.	O
+
+Simultaneously	O
+administration	O
+of	O
+beta	O
+-	O
+adrenergic	O
+blocking	O
+drugs	O
+and	O
+verapamil	O
+may	O
+result	O
+in	O
+profound	O
+adverse	O
+interactions	O
+and	O
+should	O
+only	O
+be	O
+administered	O
+with	O
+great	O
+caution	O
+.	O
+
+Comparison	O
+of	O
+the	O
+effectiveness	O
+of	O
+ranitidine	O
+and	O
+cimetidine	O
+in	O
+inhibiting	O
+acid	O
+secretion	O
+in	O
+patients	O
+with	O
+gastric	O
+hypersecretory	O
+states	O
+.	O
+
+The	O
+H2	O
+-	O
+histamine	O
+receptor	O
+antagonists	O
+ranitidine	O
+and	O
+cimetidine	O
+were	O
+compared	O
+for	O
+their	O
+abilities	O
+to	O
+control	O
+gastric	O
+acid	O
+hypersecretion	O
+on	O
+a	O
+short	O
+-	O
+and	O
+long	O
+-	O
+term	O
+basis	O
+in	O
+22	O
+patients	O
+with	O
+gastric	O
+acid	O
+hypersecretory	O
+states	O
+.	O
+
+Nineteen	O
+patients	O
+had	O
+Zollinger	B
+-	I
+Ellison	I
+syndrome	I
+,	O
+one	O
+patient	O
+had	O
+systemic	B
+mastocytosis	I
+,	O
+and	O
+two	O
+patients	O
+had	O
+idiopathic	O
+hypersecretion	O
+.	O
+
+The	O
+rates	O
+of	O
+onset	O
+of	O
+the	O
+action	O
+of	O
+cimetidine	O
+and	O
+ranitidine	O
+were	O
+the	O
+same	O
+.	O
+
+The	O
+actions	O
+of	O
+both	O
+drugs	O
+were	O
+increased	O
+by	O
+anticholinergic	O
+agents	O
+,	O
+and	O
+there	O
+was	O
+a	O
+close	O
+correlation	O
+between	O
+the	O
+daily	O
+maintenance	O
+dose	O
+of	O
+each	O
+drug	O
+needed	O
+to	O
+control	O
+acid	O
+secretion	O
+.	O
+
+However	O
+,	O
+ranitidine	O
+was	O
+threefold	O
+more	O
+potent	O
+than	O
+cimetidine	O
+both	O
+in	O
+acute	O
+inhibition	O
+studies	O
+and	O
+in	O
+the	O
+median	O
+maintenance	O
+dose	O
+needed	O
+(	O
+1	O
+.	O
+2	O
+g	O
+per	O
+day	O
+for	O
+ranitidine	O
+and	O
+3	O
+.	O
+6	O
+g	O
+per	O
+day	O
+for	O
+cimetidine	O
+)	O
+.	O
+
+Sixty	O
+percent	O
+of	O
+the	O
+males	O
+developed	O
+breast	O
+changes	O
+or	O
+impotence	B
+while	O
+taking	O
+cimetidine	O
+and	O
+in	O
+all	O
+cases	O
+these	O
+changes	O
+disappeared	O
+when	O
+cimetidine	O
+was	O
+replaced	O
+by	O
+ranitidine	O
+.	O
+
+Treatment	O
+with	O
+high	O
+doses	O
+of	O
+cimetidine	O
+(	O
+one	O
+to	O
+60	O
+months	O
+;	O
+median	O
+,	O
+11	O
+months	O
+)	O
+or	O
+ranitidine	O
+(	O
+two	O
+to	O
+31	O
+months	O
+;	O
+median	O
+,	O
+14	O
+months	O
+)	O
+was	O
+not	O
+associated	O
+with	O
+hepatic	B
+or	I
+hematologic	I
+toxicity	I
+or	O
+alterations	O
+of	O
+serum	O
+gastrin	O
+concentrations	O
+,	O
+but	O
+ranitidine	O
+therapy	O
+was	O
+associated	O
+with	O
+a	O
+significantly	O
+lower	O
+serum	O
+creatinine	O
+level	O
+than	O
+seen	O
+with	O
+cimetidine	O
+therapy	O
+.	O
+
+The	O
+results	O
+show	O
+that	O
+both	O
+drugs	O
+can	O
+adequately	O
+inhibit	O
+acid	O
+secretion	O
+in	O
+patients	O
+with	O
+gastric	O
+hypersecretory	O
+states	O
+.	O
+
+Both	O
+are	O
+safe	O
+at	O
+high	O
+doses	O
+,	O
+but	O
+ranitidine	O
+is	O
+threefold	O
+more	O
+potent	O
+and	O
+does	O
+not	O
+cause	O
+the	O
+antiandrogen	O
+side	O
+effects	O
+frequently	O
+seen	O
+with	O
+high	O
+doses	O
+of	O
+cimetidine	O
+.	O
+
+Epileptogenic	O
+properties	O
+of	O
+enflurane	O
+and	O
+their	O
+clinical	O
+interpretation	O
+.	O
+
+Three	O
+cases	O
+of	O
+EEG	O
+changes	O
+induced	O
+by	O
+single	O
+exposure	O
+to	O
+enflurane	O
+anesthesia	O
+are	O
+reported	O
+.	O
+
+In	O
+one	O
+patient	O
+,	O
+enflurane	O
+administered	O
+during	O
+a	O
+donor	O
+nephrectomy	O
+resulted	O
+in	O
+unexpected	O
+partial	O
+motor	O
+seizures	B
+.	O
+
+Until	O
+the	O
+cause	O
+of	O
+the	O
+seizures	B
+was	O
+correctly	O
+identified	O
+,	O
+the	O
+patient	O
+was	O
+inappropriately	O
+treated	O
+with	O
+anticonvulsants	O
+.	O
+
+Two	O
+other	O
+patients	O
+suffered	O
+from	O
+partial	O
+,	O
+complex	O
+and	O
+generalized	O
+seizures	B
+uncontrolled	O
+by	O
+medication	O
+.	O
+
+Epileptic	B
+foci	O
+delineated	O
+and	O
+activated	O
+by	O
+enflurane	O
+were	O
+surgically	O
+ablated	O
+and	O
+the	O
+patients	O
+are	O
+now	O
+seizure	B
+-	O
+free	O
+.	O
+
+Previous	O
+exposures	O
+to	O
+enflurane	O
+have	O
+to	O
+be	O
+disclosed	O
+to	O
+avoid	O
+mistakes	O
+in	O
+clinical	O
+interpretation	O
+of	O
+the	O
+EEG	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+enflurane	O
+may	O
+prove	O
+to	O
+be	O
+a	O
+safe	O
+fast	O
+acting	O
+activator	O
+of	O
+epileptic	B
+foci	O
+during	O
+corticography	O
+or	O
+depth	O
+electrode	O
+intraoperative	O
+recordings	O
+.	O
+
+Development	O
+of	O
+isoproterenol	O
+-	O
+induced	O
+cardiac	B
+hypertrophy	I
+.	O
+
+The	O
+development	O
+of	O
+cardiac	B
+hypertrophy	I
+was	O
+studied	O
+in	O
+adult	O
+female	O
+Wistar	O
+rats	O
+following	O
+daily	O
+subcutaneous	O
+injections	O
+of	O
+isoproterenol	O
+(	O
+ISO	O
+)	O
+(	O
+0	O
+.	O
+3	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+)	O
+.	O
+
+A	O
+time	O
+course	O
+was	O
+established	O
+for	O
+the	O
+change	O
+in	O
+tissue	O
+mass	O
+,	O
+RNA	O
+and	O
+DNA	O
+content	O
+,	O
+as	O
+well	O
+as	O
+hydroxyproline	O
+content	O
+.	O
+
+Heart	O
+weight	O
+increased	O
+44	O
+%	O
+after	O
+8	O
+days	O
+of	O
+treatment	O
+with	O
+a	O
+half	O
+time	O
+of	O
+3	O
+.	O
+4	O
+days	O
+.	O
+
+Ventricular	O
+RNA	O
+content	O
+was	O
+elevated	O
+26	O
+%	O
+after	O
+24	O
+h	O
+of	O
+a	O
+single	O
+injection	O
+and	O
+reached	O
+a	O
+maximal	O
+level	O
+following	O
+8	O
+days	O
+of	O
+therapy	O
+.	O
+
+The	O
+half	O
+time	O
+for	O
+RNA	O
+accumulation	O
+was	O
+2	O
+.	O
+0	O
+days	O
+.	O
+
+The	O
+total	O
+content	O
+of	O
+hydroxyproline	O
+remained	O
+stable	O
+during	O
+the	O
+first	O
+2	O
+days	O
+of	O
+treatment	O
+but	O
+increased	O
+46	O
+%	O
+after	O
+4	O
+days	O
+of	O
+therapy	O
+.	O
+
+Ventricular	O
+DNA	O
+content	O
+was	O
+unchanged	O
+during	O
+the	O
+early	O
+stage	O
+(	O
+1	O
+-	O
+4	O
+days	O
+)	O
+of	O
+hypertrophic	B
+growth	O
+but	O
+increased	O
+to	O
+a	O
+new	O
+steady	O
+-	O
+state	O
+level	O
+19	O
+%	O
+above	O
+the	O
+controls	O
+after	O
+8	O
+days	O
+of	O
+treatment	O
+.	O
+
+Intraventricular	O
+pressures	O
+and	O
+coronary	O
+flow	O
+measures	O
+were	O
+similar	O
+for	O
+control	O
+and	O
+experimental	O
+animals	O
+following	O
+4	O
+days	O
+of	O
+developed	O
+hypertrophy	B
+.	O
+
+However	O
+,	O
+dP	O
+/	O
+dt	O
+in	O
+the	O
+ISO	O
+-	O
+treated	O
+hearts	O
+was	O
+slightly	O
+but	O
+significantly	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+elevated	O
+.	O
+
+These	O
+data	O
+indicate	O
+that	O
+the	O
+adaptive	O
+response	O
+to	O
+ISO	O
+shows	O
+an	O
+early	O
+hypertrophic	B
+phase	O
+(	O
+1	O
+-	O
+4	O
+days	O
+)	O
+characterized	O
+by	O
+a	O
+substantial	O
+increase	O
+in	O
+RNA	O
+content	O
+and	O
+cardiac	O
+mass	O
+in	O
+the	O
+absence	O
+of	O
+changes	O
+in	O
+DNA	O
+.	O
+
+However	O
+,	O
+prolonged	O
+stimulation	O
+(	O
+8	O
+-	O
+12	O
+days	O
+)	O
+appears	O
+to	O
+represent	O
+a	O
+complex	O
+integration	O
+of	O
+both	O
+cellular	O
+hypertrophy	B
+and	O
+hyperplasia	B
+within	O
+the	O
+heart	O
+.	O
+
+Multiple	O
+side	O
+effects	O
+of	O
+penicillamine	O
+therapy	O
+in	O
+one	O
+patient	O
+with	O
+rheumatoid	B
+arthritis	I
+.	O
+
+Skin	B
+rashes	I
+,	O
+proteinuria	B
+,	O
+systemic	B
+lupus	I
+erythematosus	I
+,	O
+polymyositis	B
+and	O
+myasthenia	B
+gravis	I
+have	O
+all	O
+been	O
+recorded	O
+as	O
+complications	O
+of	O
+penicillamine	O
+therapy	O
+in	O
+patients	O
+with	O
+rheumatoid	B
+arthritis	I
+.	O
+
+A	O
+patient	O
+who	O
+had	O
+developed	O
+all	O
+5	O
+is	O
+now	O
+described	O
+.	O
+
+The	O
+skin	B
+lesion	I
+resembled	O
+elastosis	B
+perforans	I
+serpiginosa	I
+,	O
+which	O
+has	O
+been	O
+reported	O
+as	O
+a	O
+rare	O
+side	O
+effect	O
+in	O
+patients	O
+with	O
+Wilson	B
+'	I
+s	I
+disease	I
+but	O
+not	O
+in	O
+patients	O
+with	O
+rheumatoid	B
+arthritis	I
+treated	O
+with	O
+penicillamine	O
+.	O
+
+Obsolete	O
+but	O
+dangerous	O
+antacid	O
+preparations	O
+.	O
+
+One	O
+case	O
+of	O
+acute	O
+hypercalcaemia	B
+and	O
+two	O
+of	O
+recurrent	O
+nephrolithiasis	B
+are	O
+reported	O
+in	O
+patients	O
+who	O
+had	O
+regularly	O
+consumed	O
+large	O
+amounts	O
+of	O
+calcium	O
+carbon	O
+-	O
+ate	O
+-	O
+sodium	O
+bicarbonate	O
+powders	O
+for	O
+more	O
+than	O
+20	O
+years	O
+.	O
+
+The	O
+powders	O
+had	O
+been	O
+obtained	O
+from	O
+pharmacists	O
+unknown	O
+to	O
+the	O
+patients	O
+'	O
+medical	O
+practitioners	O
+.	O
+
+It	O
+is	O
+suggested	O
+that	O
+these	O
+preparations	O
+were	O
+responsible	O
+for	O
+the	O
+patient	O
+'	O
+s	O
+problems	O
+,	O
+and	O
+that	O
+such	O
+powders	O
+should	O
+no	O
+longer	O
+be	O
+freely	O
+obtainable	O
+.	O
+
+Doxorubicin	O
+cardiomyopathy	B
+in	O
+children	O
+with	O
+left	O
+-	O
+sided	O
+Wilms	B
+tumor	I
+.	O
+
+Two	O
+children	O
+with	O
+Wilms	B
+tumor	I
+of	O
+the	O
+left	O
+kidney	O
+experienced	O
+severe	O
+anthracycline	O
+cardiomyopathy	B
+after	O
+irradiation	O
+to	O
+the	O
+tumor	B
+bed	O
+and	O
+conventional	O
+dosage	O
+of	O
+doxorubicin	O
+.	O
+
+The	O
+cardiomyopathy	B
+is	O
+attributed	O
+1	O
+)	O
+to	O
+the	O
+fact	O
+that	O
+radiation	O
+fields	O
+for	O
+left	O
+Wilms	B
+tumor	I
+include	O
+the	O
+lower	O
+portion	O
+of	O
+the	O
+heart	O
+and	O
+2	O
+)	O
+to	O
+the	O
+interaction	O
+of	O
+doxorubicin	O
+and	O
+irradiation	O
+on	O
+cardiac	O
+muscle	O
+.	O
+
+It	O
+is	O
+recommended	O
+that	O
+doxorubicin	O
+dosage	O
+be	O
+sharply	O
+restricted	O
+in	O
+children	O
+with	O
+Wilms	B
+tumor	I
+of	O
+the	O
+left	O
+kidney	O
+who	O
+receive	O
+postoperative	O
+irradiation	O
+.	O
+
+Effects	O
+of	O
+calcitonin	O
+on	O
+rat	O
+extrapyramidal	O
+motor	O
+system	O
+:	O
+behavioral	O
+and	O
+biochemical	O
+data	O
+.	O
+
+The	O
+effects	O
+of	O
+i	O
+.	O
+v	O
+.	O
+c	O
+.	O
+injection	O
+of	O
+human	O
+and	O
+salmon	O
+calcitonin	O
+on	O
+biochemical	O
+and	O
+behavioral	O
+parameters	O
+related	O
+to	O
+the	O
+extrapyramidal	O
+motor	O
+system	O
+,	O
+were	O
+investigated	O
+in	O
+male	O
+rats	O
+.	O
+
+Calcitonin	O
+injection	O
+resulted	O
+in	O
+a	O
+potentiation	O
+of	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+and	O
+a	O
+partial	O
+prevention	O
+of	O
+apomorphine	O
+-	O
+induced	O
+hyperactivity	B
+.	O
+
+Moreover	O
+calcitonin	O
+induced	O
+a	O
+significant	O
+decrease	O
+in	O
+nigral	O
+GAD	O
+activity	O
+but	O
+no	O
+change	O
+in	O
+striatal	O
+DA	O
+and	O
+DOPAC	O
+concentration	O
+or	O
+GAD	O
+activity	O
+.	O
+
+The	O
+results	O
+are	O
+discussed	O
+in	O
+view	O
+of	O
+a	O
+primary	O
+action	O
+of	O
+calcitonin	O
+on	O
+the	O
+striatonigral	O
+GABAergic	O
+pathway	O
+mediating	O
+the	O
+DA	O
+-	O
+related	O
+behavioral	O
+messages	O
+of	O
+striatal	O
+origin	O
+.	O
+
+Naloxazone	O
+pretreatment	O
+modifies	O
+cardiorespiratory	O
+,	O
+temperature	O
+,	O
+and	O
+behavioral	O
+effects	O
+of	O
+morphine	O
+.	O
+
+Behavioral	O
+and	O
+cardiorespiratory	O
+responses	O
+to	O
+a	O
+lethal	O
+dose	O
+of	O
+morphine	O
+were	O
+evaluated	O
+in	O
+rats	O
+pretreated	O
+with	O
+saline	O
+or	O
+naloxazone	O
+,	O
+an	O
+antagonist	O
+of	O
+high	O
+-	O
+affinity	O
+mu	O
+1	O
+opioid	O
+receptors	O
+.	O
+
+Pretreatment	O
+with	O
+naloxazone	O
+significantly	O
+blocked	O
+morphine	O
+analgesia	B
+,	O
+catalepsy	B
+and	O
+hypothermia	B
+at	O
+a	O
+dose	O
+which	O
+completely	O
+eliminated	O
+high	O
+-	O
+affinity	O
+binding	O
+in	O
+brain	O
+membranes	O
+.	O
+
+Moreover	O
+,	O
+naloxazone	O
+significantly	O
+attenuated	O
+the	O
+morphine	O
+-	O
+induced	O
+hypotension	B
+and	O
+respiratory	B
+depression	I
+,	O
+whereas	O
+morphine	O
+-	O
+induced	O
+bradycardia	B
+was	O
+less	O
+affected	O
+.	O
+
+Results	O
+indicate	O
+that	O
+subpopulations	O
+of	O
+mu	O
+receptors	O
+may	O
+mediate	O
+selective	O
+behavioral	O
+and	O
+cardiorespiratory	O
+responses	O
+to	O
+morphine	O
+.	O
+
+Modification	O
+of	O
+drug	O
+action	O
+by	O
+hyperammonemia	B
+.	O
+
+Pretreatment	O
+with	O
+ammonium	O
+acetate	O
+(	O
+NH4Ac	O
+)	O
+(	O
+6	O
+mmol	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+approximately	O
+doubled	O
+the	O
+time	O
+morphine	O
+-	O
+treated	O
+mice	O
+remained	O
+on	O
+a	O
+hot	O
+surface	O
+and	O
+similarly	O
+increased	O
+muscular	O
+incoordination	B
+by	O
+diazepam	O
+,	O
+but	O
+NH4Ac	O
+treatment	O
+alone	O
+had	O
+no	O
+effect	O
+.	O
+
+Thus	O
+,	O
+hyperammonemia	B
+is	O
+capable	O
+of	O
+altering	O
+drug	O
+action	O
+and	O
+must	O
+be	O
+considered	O
+along	O
+with	O
+impaired	O
+drug	O
+metabolism	O
+in	O
+enhanced	O
+drug	O
+responses	O
+associated	O
+with	O
+liver	B
+disease	I
+.	O
+
+Experiments	O
+in	O
+vitro	O
+showed	O
+that	O
+acetylcholine	O
+-	O
+induced	O
+catecholamine	O
+release	O
+from	O
+bovine	O
+adrenal	O
+medulla	O
+is	O
+depressed	O
+as	O
+much	O
+as	O
+50	O
+%	O
+by	O
+0	O
+.	O
+3	O
+mM	O
+NH4Ac	O
+and	O
+KCl	O
+-	O
+induced	O
+contractions	O
+of	O
+guinea	O
+-	O
+pig	O
+ileum	O
+were	O
+inhibited	O
+20	O
+%	O
+by	O
+5	O
+mM	O
+NH4Ac	O
+.	O
+
+Addition	O
+of	O
+excess	O
+calcium	O
+reversed	O
+the	O
+depression	B
+in	O
+both	O
+tissues	O
+,	O
+but	O
+calcium	O
+-	O
+independent	O
+catecholamine	O
+release	O
+by	O
+acetaldehyde	O
+was	O
+not	O
+blocked	O
+by	O
+NH4Ac	O
+.	O
+
+These	O
+results	O
+suggested	O
+that	O
+ammonia	O
+blocks	O
+calcium	O
+channels	O
+.	O
+
+Parallels	O
+in	O
+the	O
+actions	O
+of	O
+NH4Ac	O
+and	O
+the	O
+calcium	O
+channel	O
+blocker	O
+verapamil	O
+support	O
+this	O
+concept	O
+.	O
+
+Both	O
+verapamil	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+and	O
+NH4Ac	O
+pretreatment	O
+enhanced	O
+morphine	O
+analgesia	B
+-	O
+and	O
+diazepam	O
+-	O
+induced	O
+muscular	O
+incoordination	B
+and	O
+antagonized	O
+amphetamine	O
+-	O
+induced	O
+motor	O
+activity	O
+,	O
+and	O
+neither	O
+verapamil	O
+nor	O
+NH4Ac	O
+affected	O
+the	O
+convulsant	O
+action	O
+of	O
+metrazol	O
+.	O
+
+The	O
+data	O
+suggest	O
+that	O
+hyperammonemia	B
+exerts	O
+a	O
+calcium	O
+channel	O
+blocking	O
+action	O
+which	O
+enhances	O
+the	O
+effects	O
+of	O
+central	O
+nervous	O
+system	O
+depressants	O
+and	O
+certain	O
+opioid	O
+analgesics	O
+.	O
+
+Levodopa	O
+-	O
+induced	O
+dyskinesia	B
+and	O
+thalamotomy	O
+.	O
+
+Levodopa	O
+-	O
+induced	O
+dyskinesia	B
+of	O
+the	O
+limbs	O
+in	O
+thirteen	O
+cases	O
+of	O
+Parkinsonism	B
+,	O
+which	O
+was	O
+choreic	O
+,	O
+ballistic	O
+or	O
+dystonic	B
+in	O
+type	O
+,	O
+was	O
+alleviated	O
+almost	O
+completely	O
+by	O
+stereotaxic	O
+surgery	O
+using	O
+a	O
+microelectrode	O
+technique	O
+for	O
+the	O
+ventralis	O
+oralis	O
+anterior	O
+and	O
+posterior	O
+nuclei	O
+of	O
+the	O
+thalamus	O
+,	O
+but	O
+much	O
+less	O
+by	O
+the	O
+ventralis	O
+intermedius	O
+nucleus	O
+.	O
+
+Control	O
+of	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+by	O
+thalamic	B
+lesions	I
+in	O
+the	O
+course	O
+of	O
+routine	O
+treatment	O
+of	O
+Parkinsonism	B
+is	O
+discussed	O
+.	O
+
+Treatment	O
+of	O
+ifosfamide	O
+-	O
+induced	O
+urothelial	B
+toxicity	I
+by	O
+oral	O
+administration	O
+of	O
+sodium	O
+2	O
+-	O
+mercaptoethane	O
+sulphonate	O
+(	O
+MESNA	O
+)	O
+to	O
+patients	O
+with	O
+inoperable	O
+lung	B
+cancer	I
+.	O
+
+The	O
+protective	O
+effect	O
+of	O
+oral	O
+administration	O
+of	O
+the	O
+thiol	O
+compound	O
+sodium	O
+2	O
+-	O
+mercaptoethane	O
+sulphonate	O
+(	O
+MESNA	O
+)	O
+against	O
+urothelial	B
+toxicity	I
+induced	O
+by	O
+ifosfamide	O
+(	O
+IF	O
+)	O
+was	O
+tested	O
+in	O
+a	O
+group	O
+of	O
+45	O
+patients	O
+with	O
+inoperable	O
+lung	B
+cancer	I
+under	O
+treatment	O
+with	O
+IF	O
+(	O
+2250	O
+mg	O
+/	O
+m2	O
+on	O
+days	O
+2	O
+-	O
+5	O
+)	O
+as	O
+part	O
+of	O
+a	O
+polychemotherapy	O
+regimen	O
+repeated	O
+in	O
+a	O
+4	O
+-	O
+week	O
+cycle	O
+.	O
+
+MESNA	O
+was	O
+given	O
+orally	O
+on	O
+the	O
+days	O
+of	O
+treatment	O
+with	O
+IF	O
+in	O
+3	O
+doses	O
+of	O
+840	O
+mg	O
+/	O
+m2	O
+,	O
+each	O
+administered	O
+at	O
+0	O
+hr	O
+(	O
+=	O
+injection	O
+of	O
+IF	O
+)	O
+,	O
+4	O
+hr	O
+and	O
+8	O
+hr	O
+p	O
+.	O
+i	O
+.	O
+
+Out	O
+of	O
+a	O
+total	O
+of	O
+88	O
+courses	O
+of	O
+this	O
+treatment	O
+we	O
+observed	O
+10	O
+episodes	O
+of	O
+asymptomatic	O
+microscopic	O
+haematuria	B
+and	O
+no	O
+episodes	O
+of	O
+gross	O
+haematuria	B
+.	O
+
+In	O
+this	O
+group	O
+of	O
+45	O
+patients	O
+under	O
+protection	O
+with	O
+MESNA	O
+there	O
+were	O
+5	O
+complete	O
+remissions	O
+and	O
+9	O
+partial	O
+remissions	O
+(	O
+total	O
+31	O
+%	O
+)	O
+.	O
+
+A	O
+further	O
+group	O
+of	O
+25	O
+patients	O
+under	O
+polychemotherapy	O
+with	O
+IF	O
+were	O
+treated	O
+by	O
+conventional	O
+prophylactic	O
+measures	O
+(	O
+raised	O
+fluid	O
+intake	O
+and	O
+forced	O
+diuresis	O
+)	O
+.	O
+
+In	O
+this	O
+group	O
+there	O
+were	O
+1	O
+complete	O
+and	O
+5	O
+partial	O
+remissions	O
+(	O
+total	O
+24	O
+%	O
+)	O
+,	O
+but	O
+nearly	O
+all	O
+patients	O
+developed	O
+either	O
+gross	O
+haematuria	B
+and	O
+/	O
+or	O
+symptoms	O
+of	O
+bladder	B
+irritation	I
+(	O
+cystitis	B
+and	O
+pollakisuria	B
+)	O
+.	O
+
+There	O
+were	O
+no	O
+appreciable	O
+differences	O
+between	O
+the	O
+MESNA	O
+series	O
+and	O
+the	O
+conventional	O
+prophylaxis	O
+series	O
+with	O
+respect	O
+to	O
+either	O
+haematological	O
+or	O
+systemic	O
+toxicity	B
+of	O
+the	O
+cytostatic	O
+treatment	O
+.	O
+
+Our	O
+results	O
+support	O
+the	O
+view	O
+that	O
+MESNA	O
+,	O
+given	O
+orally	O
+in	O
+conjunction	O
+with	O
+combined	O
+cytostatic	O
+regimens	O
+which	O
+include	O
+IF	O
+,	O
+simplifies	O
+the	O
+treatment	O
+and	O
+provides	O
+optimum	O
+protection	O
+for	O
+the	O
+urinary	O
+epithelium	O
+.	O
+
+Protection	O
+with	O
+oral	O
+MESNA	O
+is	O
+particularly	O
+suitable	O
+for	O
+outpatients	O
+.	O
+
+Myoclonic	B
+,	I
+atonic	I
+,	I
+and	I
+absence	I
+seizures	I
+following	O
+institution	O
+of	O
+carbamazepine	O
+therapy	O
+in	O
+children	O
+.	O
+
+Five	O
+children	O
+,	O
+aged	O
+3	O
+to	O
+11	O
+years	O
+,	O
+treated	O
+with	O
+carbamazepine	O
+for	O
+epilepsy	B
+,	O
+had	O
+an	O
+acute	O
+aberrant	O
+reaction	O
+characterized	O
+by	O
+the	O
+onset	O
+of	O
+myoclonic	B
+,	I
+atypical	I
+absence	I
+and	I
+/	I
+or	I
+atonic	I
+(	I
+minor	I
+motor	I
+)	I
+seizures	I
+within	O
+a	O
+few	O
+days	O
+.	O
+
+When	O
+the	O
+carbamazepine	O
+was	O
+discontinued	O
+,	O
+two	O
+of	O
+the	O
+children	O
+returned	O
+to	O
+their	O
+former	O
+state	O
+very	O
+quickly	O
+,	O
+two	O
+had	O
+the	O
+minor	O
+motor	O
+seizures	B
+resolve	O
+in	O
+3	O
+and	O
+6	O
+months	O
+,	O
+and	O
+one	O
+had	O
+the	O
+seizures	B
+persist	O
+.	O
+
+The	O
+child	O
+in	O
+whom	O
+the	O
+seizures	B
+persisted	O
+was	O
+later	O
+found	O
+to	O
+have	O
+ceroid	B
+lipofuscinosis	I
+.	O
+
+The	O
+other	O
+children	O
+are	O
+doing	O
+well	O
+on	O
+other	O
+anticonvulsants	O
+.	O
+
+Effect	O
+of	O
+prostaglandin	O
+synthetase	O
+inhibitors	O
+on	O
+experimentally	O
+induced	O
+convulsions	B
+in	O
+rats	O
+.	O
+
+To	O
+investigate	O
+the	O
+relationship	O
+of	O
+prostaglandins	O
+(	O
+PGs	O
+)	O
+to	O
+seizure	B
+induction	O
+,	O
+the	O
+effects	O
+of	O
+six	O
+PG	O
+synthetase	O
+inhibitors	O
+on	O
+convulsions	B
+induced	O
+by	O
+flurothyl	O
+,	O
+picrotoxin	O
+,	O
+pentetrazol	O
+(	O
+PTZ	O
+)	O
+,	O
+electroshock	O
+or	O
+bicuculline	O
+were	O
+evaluated	O
+.	O
+
+Ibuprofen	O
+,	O
+sulindac	O
+,	O
+mefenamic	O
+acid	O
+,	O
+and	O
+low	O
+dose	O
+meclofenamic	O
+acid	O
+increased	O
+the	O
+latency	O
+-	O
+to	O
+-	O
+onset	O
+in	O
+the	O
+flurothyl	O
+and	O
+/	O
+or	O
+PTZ	O
+models	O
+;	O
+the	O
+electroshock	O
+,	O
+picrotoxin	O
+and	O
+bicuculline	O
+models	O
+were	O
+not	O
+significantly	O
+affected	O
+by	O
+any	O
+of	O
+the	O
+pretreatment	O
+agents	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+PGs	O
+are	O
+involved	O
+in	O
+the	O
+mechanism	O
+(	O
+s	O
+)	O
+underlying	O
+fluorthyl	O
+-	O
+and	O
+PTZ	O
+-	O
+induced	O
+convulsions	B
+,	O
+but	O
+not	O
+picrotoxin	O
+-	O
+,	O
+electroshock	O
+-	O
+,	O
+or	O
+bicuculline	O
+-	O
+induced	O
+convulsions	B
+.	O
+
+Acute	O
+changes	O
+of	O
+blood	O
+ammonia	O
+may	O
+predict	O
+short	O
+-	O
+term	O
+adverse	O
+effects	O
+of	O
+valproic	O
+acid	O
+.	O
+
+Valproic	O
+acid	O
+(	O
+VPA	O
+)	O
+was	O
+given	O
+to	O
+24	O
+epileptic	B
+patients	O
+who	O
+were	O
+already	O
+being	O
+treated	O
+with	O
+other	O
+antiepileptic	O
+drugs	O
+.	O
+
+A	O
+standardized	O
+loading	O
+dose	O
+of	O
+VPA	O
+was	O
+administered	O
+,	O
+and	O
+venous	O
+blood	O
+was	O
+sampled	O
+at	O
+0	O
+,	O
+1	O
+,	O
+2	O
+,	O
+3	O
+,	O
+and	O
+4	O
+hours	O
+.	O
+
+Ammonia	O
+(	O
+NH3	O
+)	O
+was	O
+higher	O
+in	O
+patients	O
+who	O
+,	O
+during	O
+continuous	O
+therapy	O
+,	O
+complained	O
+of	O
+drowsiness	B
+(	O
+7	O
+patients	O
+)	O
+than	O
+in	O
+those	O
+who	O
+were	O
+symptom	O
+-	O
+free	O
+(	O
+17	O
+patients	O
+)	O
+,	O
+although	O
+VPA	O
+plasma	O
+levels	O
+were	O
+similar	O
+in	O
+both	O
+groups	O
+.	O
+
+By	O
+measuring	O
+VPA	O
+-	O
+induced	O
+changes	O
+of	O
+blood	O
+NH3	O
+content	O
+,	O
+it	O
+may	O
+be	O
+possible	O
+to	O
+identify	O
+patients	O
+at	O
+higher	O
+risk	O
+of	O
+obtundation	O
+when	O
+VPA	O
+is	O
+given	O
+chronically	O
+.	O
+
+Effect	O
+of	O
+captopril	O
+on	O
+pre	O
+-	O
+existing	O
+and	O
+aminonucleoside	O
+-	O
+induced	O
+proteinuria	B
+in	O
+spontaneously	O
+hypertensive	B
+rats	O
+.	O
+
+Proteinuria	B
+is	O
+a	O
+side	O
+effect	O
+of	O
+captopril	O
+treatment	O
+in	O
+hypertensive	B
+patients	O
+.	O
+
+The	O
+possibility	O
+of	O
+reproducing	O
+the	O
+same	O
+renal	B
+abnormality	I
+with	O
+captopril	O
+was	O
+examined	O
+in	O
+SHR	O
+.	O
+
+Oral	O
+administration	O
+of	O
+captopril	O
+at	O
+100	O
+mg	O
+/	O
+kg	O
+for	O
+14	O
+days	O
+failed	O
+to	O
+aggravate	O
+proteinuria	B
+pre	O
+-	O
+existing	O
+in	O
+SHR	O
+.	O
+
+Also	O
+,	O
+captopril	O
+treatment	O
+failed	O
+to	O
+potentiate	O
+or	O
+facilitate	O
+development	O
+of	O
+massive	O
+proteinuria	B
+invoked	O
+by	O
+puromycin	O
+aminonucleoside	O
+in	O
+SHR	O
+.	O
+
+Captopril	O
+had	O
+little	O
+or	O
+no	O
+demonstrable	O
+effects	O
+on	O
+serum	O
+electrolyte	O
+concentrations	O
+,	O
+excretion	O
+of	O
+urine	O
+,	O
+sodium	O
+and	O
+potassium	O
+,	O
+endogenous	O
+creatinine	O
+clearance	O
+,	O
+body	O
+weight	O
+,	O
+and	O
+food	O
+and	O
+water	O
+consumption	O
+.	O
+
+However	O
+,	O
+ketone	O
+bodies	O
+were	O
+consistently	O
+present	O
+in	O
+urine	O
+and	O
+several	O
+lethalities	O
+occurred	O
+during	O
+multiple	O
+dosing	O
+of	O
+captopril	O
+in	O
+SHR	O
+.	O
+
+Complete	O
+heart	B
+block	I
+following	O
+a	O
+single	O
+dose	O
+of	O
+trazodone	O
+.	O
+
+Forty	O
+minutes	O
+after	O
+receiving	O
+a	O
+single	O
+starting	O
+dose	O
+of	O
+trazodone	O
+,	O
+a	O
+patient	O
+developed	O
+complete	O
+heart	B
+block	I
+.	O
+
+The	O
+case	O
+illustrates	O
+that	O
+,	O
+despite	O
+the	O
+results	O
+of	O
+earlier	O
+studies	O
+,	O
+trazodone	O
+'	O
+s	O
+effect	O
+on	O
+cardiac	O
+conduction	O
+may	O
+be	O
+severe	O
+in	O
+individuals	O
+at	O
+risk	O
+for	O
+conduction	O
+delay	O
+.	O
+
+Phenobarbital	O
+-	O
+induced	O
+dyskinesia	B
+in	O
+a	O
+neurologically	B
+-	I
+impaired	I
+child	O
+.	O
+
+A	O
+2	O
+-	O
+year	O
+-	O
+old	O
+child	O
+with	O
+known	O
+neurologic	B
+impairment	I
+developed	O
+a	O
+dyskinesia	B
+soon	O
+after	O
+starting	O
+phenobarbital	O
+therapy	O
+for	O
+seizures	B
+.	O
+
+Known	O
+causes	O
+of	O
+movement	B
+disorders	I
+were	O
+eliminated	O
+after	O
+evaluation	O
+.	O
+
+On	O
+repeat	O
+challenge	O
+with	O
+phenobarbital	O
+,	O
+the	O
+dyskinesia	B
+recurred	O
+.	O
+
+Phenobarbital	O
+should	O
+be	O
+added	O
+to	O
+the	O
+list	O
+of	O
+anticonvulsant	O
+drugs	O
+that	O
+can	O
+cause	O
+movement	B
+disorders	I
+.	O
+
+Effects	O
+of	O
+amine	O
+pretreatment	O
+on	O
+ketamine	O
+catatonia	B
+in	O
+pinealectomized	O
+or	O
+hypophysectomized	O
+animals	O
+.	O
+
+The	O
+present	O
+studies	O
+were	O
+designed	O
+to	O
+clarify	O
+the	O
+role	O
+of	O
+catecholamines	O
+and	O
+pineal	O
+idolamines	O
+on	O
+ketamine	O
+-	O
+induced	O
+catatonia	B
+in	O
+the	O
+intact	O
+,	O
+pinealectomized	O
+or	O
+hypophysectomized	O
+chick	O
+and	O
+rat	O
+.	O
+
+In	O
+the	O
+pinealectomized	O
+chick	O
+,	O
+pretreatment	O
+with	O
+dopamine	O
+increased	O
+the	O
+duration	O
+of	O
+catatonia	B
+(	O
+DOC	O
+)	O
+after	O
+ketamine	O
+,	O
+but	O
+pretreatment	O
+with	O
+norepinephrine	O
+did	O
+not	O
+.	O
+
+The	O
+pineal	O
+indolamines	O
+exhibited	O
+mixed	O
+actions	O
+.	O
+
+Serotonin	O
+and	O
+N	O
+-	O
+acetyl	O
+serotonin	O
+which	O
+augmented	O
+ketamine	O
+DOC	O
+,	O
+did	O
+not	O
+do	O
+so	O
+in	O
+the	O
+absence	O
+of	O
+the	O
+pineal	O
+gland	O
+,	O
+whereas	O
+melatonin	O
+potentiated	O
+the	O
+ketamine	O
+DOC	O
+in	O
+both	O
+the	O
+intact	O
+and	O
+pinealectomized	O
+chick	O
+.	O
+
+Ketamine	O
+was	O
+more	O
+potent	O
+in	O
+the	O
+hypophysectomized	O
+chick	O
+and	O
+the	O
+circadian	O
+rhythm	O
+noted	O
+in	O
+the	O
+intact	O
+chick	O
+was	O
+absent	O
+;	O
+furthermore	O
+,	O
+melatonin	O
+did	O
+not	O
+augment	O
+the	O
+ketamine	O
+DOC	O
+whereas	O
+dopamine	O
+continued	O
+to	O
+do	O
+so	O
+.	O
+
+This	O
+study	O
+did	O
+not	O
+demonstrate	O
+a	O
+species	O
+difference	O
+regarding	O
+the	O
+role	O
+of	O
+the	O
+amines	O
+on	O
+the	O
+pineal	O
+in	O
+spite	O
+of	O
+the	O
+immature	O
+blood	O
+-	O
+brain	O
+barrier	O
+in	O
+the	O
+young	O
+chick	O
+and	O
+the	O
+intact	O
+barrier	O
+in	O
+the	O
+rat	O
+.	O
+
+In	O
+addition	O
+,	O
+these	O
+data	O
+indicate	O
+a	O
+direct	O
+role	O
+of	O
+the	O
+pituitary	O
+in	O
+the	O
+augmentation	O
+of	O
+ketamine	O
+DOC	O
+induced	O
+by	O
+melatonin	O
+.	O
+
+Furthermore	O
+,	O
+dopamine	O
+appeared	O
+to	O
+act	O
+on	O
+systems	O
+more	O
+closely	O
+involved	O
+with	O
+the	O
+induction	O
+of	O
+ketamine	O
+catatonia	B
+rather	O
+than	O
+directly	O
+on	O
+the	O
+pituitary	O
+.	O
+
+Heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+,	O
+thrombosis	B
+,	O
+and	O
+hemorrhage	B
+.	O
+
+Sixty	O
+-	O
+two	O
+patients	O
+with	O
+a	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+are	O
+reported	O
+.	O
+
+Clinical	O
+manifestations	O
+of	O
+this	O
+disorder	O
+include	O
+hemorrhage	B
+or	O
+,	O
+more	O
+frequently	O
+,	O
+thromboembolic	B
+events	O
+in	O
+patients	O
+receiving	O
+heparin	O
+.	O
+
+Laboratory	O
+testing	O
+has	O
+revealed	O
+a	B
+falling	I
+platelet	I
+count	I
+,	O
+increased	O
+resistance	O
+to	O
+heparin	O
+,	O
+and	O
+aggregation	O
+of	O
+platelets	O
+by	O
+the	O
+patient	O
+'	O
+s	O
+plasma	O
+when	O
+heparin	O
+is	O
+added	O
+.	O
+
+Immunologic	O
+testing	O
+has	O
+demonstrated	O
+the	O
+presence	O
+of	O
+a	O
+heparin	O
+-	O
+dependent	O
+platelet	O
+membrane	O
+antibody	O
+.	O
+
+The	O
+20	O
+deaths	O
+,	O
+52	O
+hemorrhagic	B
+and	I
+thromboembolic	I
+complications	I
+,	O
+and	O
+21	O
+surgical	O
+procedures	O
+to	O
+manage	O
+the	O
+complications	O
+confirm	O
+the	O
+seriousness	O
+of	O
+the	O
+disorder	O
+.	O
+
+Specific	O
+risk	O
+factors	O
+have	O
+not	O
+been	O
+identified	O
+;	O
+therefore	O
+,	O
+all	O
+patients	O
+receiving	O
+heparin	O
+should	O
+be	O
+monitored	O
+.	O
+
+If	O
+the	O
+platelet	O
+count	O
+falls	O
+to	O
+less	O
+than	O
+100	O
+,	O
+000	O
+/	O
+mm3	O
+,	O
+while	O
+the	O
+patient	O
+is	O
+receiving	O
+heparin	O
+,	O
+platelet	B
+aggregation	I
+testing	O
+,	O
+using	O
+the	O
+patient	O
+'	O
+s	O
+plasma	O
+,	O
+is	O
+indicated	O
+.	O
+
+Management	O
+consists	O
+of	O
+cessation	O
+of	O
+heparin	O
+,	O
+platelet	O
+anti	O
+-	O
+aggregating	O
+agents	O
+,	O
+and	O
+alternate	O
+forms	O
+of	O
+anticoagulation	O
+when	O
+indicated	O
+.	O
+
+Ventricular	B
+fibrillation	I
+from	O
+diatrizoate	O
+with	O
+and	O
+without	O
+chelating	O
+agents	O
+.	O
+
+The	O
+toxicity	B
+of	O
+Renografin	O
+76	O
+%	O
+was	O
+compared	O
+with	O
+that	O
+of	O
+Hypaque	O
+76	O
+%	O
+by	O
+selective	O
+injection	O
+of	O
+each	O
+into	O
+the	O
+right	O
+coronary	O
+artery	O
+of	O
+dogs	O
+.	O
+
+Renografin	O
+contains	O
+the	O
+chelating	O
+agents	O
+sodium	O
+citrate	O
+and	O
+disodium	O
+edetate	O
+,	O
+while	O
+Hypaque	O
+contains	O
+calcium	O
+disodium	O
+edetate	O
+and	O
+no	O
+sodium	O
+citrate	O
+.	O
+
+Ventricular	B
+fibrillation	I
+occurred	O
+significantly	O
+more	O
+often	O
+with	O
+Renografin	O
+,	O
+suggesting	O
+that	O
+chelating	O
+agents	O
+contribute	O
+to	O
+toxicity	B
+in	O
+coronary	O
+angiography	O
+.	O
+
+Long	O
+-	O
+term	O
+efficacy	O
+and	O
+toxicity	B
+of	O
+high	O
+-	O
+dose	O
+amiodarone	O
+therapy	O
+for	O
+ventricular	B
+tachycardia	I
+or	O
+ventricular	B
+fibrillation	I
+.	O
+
+Amiodarone	O
+was	O
+administered	O
+to	O
+154	O
+patients	O
+who	O
+had	O
+sustained	O
+,	O
+symptomatic	O
+ventricular	B
+tachycardia	I
+(	O
+VT	B
+)	O
+(	O
+n	O
+=	O
+118	O
+)	O
+or	O
+a	O
+cardiac	B
+arrest	I
+(	O
+n	O
+=	O
+36	O
+)	O
+and	O
+who	O
+were	O
+refractory	O
+to	O
+conventional	O
+antiarrhythmic	O
+drugs	O
+.	O
+
+The	O
+loading	O
+dose	O
+was	O
+800	O
+mg	O
+/	O
+day	O
+for	O
+6	O
+weeks	O
+and	O
+the	O
+maintenance	O
+dose	O
+was	O
+600	O
+mg	O
+/	O
+day	O
+.	O
+
+Sixty	O
+-	O
+nine	O
+percent	O
+of	O
+patients	O
+continued	O
+treatment	O
+with	O
+amiodarone	O
+and	O
+had	O
+no	O
+recurrence	O
+of	O
+symptomatic	O
+VT	B
+or	O
+ventricular	B
+fibrillation	I
+(	O
+VF	B
+)	O
+over	O
+a	O
+follow	O
+-	O
+up	O
+of	O
+6	O
+to	O
+52	O
+months	O
+(	O
+mean	O
++	O
+/	O
+-	O
+standard	O
+deviation	O
+14	O
+.	O
+2	O
++	O
+/	O
+-	O
+8	O
+.	O
+2	O
+)	O
+.	O
+
+Six	O
+percent	O
+of	O
+the	O
+patients	O
+had	O
+a	O
+nonfatal	O
+recurrence	O
+of	O
+VT	B
+and	O
+were	O
+successfully	O
+managed	O
+by	O
+continuing	O
+amiodarone	O
+at	O
+a	O
+higher	O
+dose	O
+or	O
+by	O
+the	O
+addition	O
+of	O
+a	O
+conventional	O
+antiarrhythmic	O
+drug	O
+.	O
+
+One	O
+or	O
+more	O
+adverse	O
+drug	O
+reactions	O
+occurred	O
+in	O
+51	O
+%	O
+of	O
+patients	O
+.	O
+
+Adverse	O
+effects	O
+forced	O
+a	O
+reduction	O
+in	O
+the	O
+dose	O
+of	O
+amiodarone	O
+in	O
+41	O
+%	O
+and	O
+discontinuation	O
+of	O
+amiodarone	O
+in	O
+10	O
+%	O
+of	O
+patients	O
+.	O
+
+The	O
+most	O
+common	O
+symptomatic	O
+adverse	O
+reactions	O
+were	O
+tremor	B
+or	O
+ataxia	B
+(	O
+35	O
+%	O
+)	O
+,	O
+nausea	B
+and	O
+anorexia	B
+(	O
+8	O
+%	O
+)	O
+,	O
+visual	B
+halos	I
+or	I
+blurring	I
+(	O
+6	O
+%	O
+)	O
+,	O
+thyroid	B
+function	I
+abnormalities	I
+(	O
+6	O
+%	O
+)	O
+and	O
+pulmonary	B
+interstitial	I
+infiltrates	I
+(	O
+5	O
+%	O
+)	O
+.	O
+
+Although	O
+large	O
+-	O
+dose	O
+amiodarone	O
+is	O
+highly	O
+effective	O
+in	O
+the	O
+long	O
+-	O
+term	O
+treatment	O
+of	O
+VT	B
+or	O
+VF	B
+refractory	O
+to	O
+conventional	O
+antiarrhythmic	O
+drugs	O
+,	O
+it	O
+causes	O
+significant	O
+toxicity	B
+in	O
+approximately	O
+50	O
+%	O
+of	O
+patients	O
+.	O
+
+However	O
+,	O
+when	O
+the	O
+dose	O
+is	O
+adjusted	O
+based	O
+on	O
+clinical	O
+response	O
+or	O
+the	O
+development	O
+of	O
+adverse	O
+effects	O
+,	O
+75	O
+%	O
+of	O
+patients	O
+with	O
+VT	B
+or	O
+VF	B
+can	O
+be	O
+successfully	O
+managed	O
+with	O
+amiodarone	O
+.	O
+
+Why	O
+may	O
+epsilon	O
+-	O
+aminocaproic	O
+acid	O
+(	O
+EACA	O
+)	O
+induce	O
+myopathy	B
+in	O
+man	O
+?	O
+
+Report	O
+of	O
+a	O
+case	O
+and	O
+literature	O
+review	O
+.	O
+
+A	O
+case	O
+of	O
+necrotizing	B
+myopathy	I
+due	O
+to	O
+a	O
+short	O
+epsilon	O
+-	O
+aminocaproic	O
+acid	O
+(	O
+EACA	O
+)	O
+treatment	O
+in	O
+a	O
+72	O
+year	O
+-	O
+old	O
+patient	O
+with	O
+subarachnoid	B
+haemorrhage	I
+(	O
+SAH	B
+)	O
+is	O
+described	O
+.	O
+
+Pathogenetic	O
+hypotheses	O
+are	O
+discussed	O
+.	O
+
+Cerebral	B
+hemorrhage	I
+associated	O
+with	O
+phenylpropanolamine	O
+in	O
+combination	O
+with	O
+caffeine	O
+.	O
+
+Phenylpropanolamine	O
+(	O
+PPA	O
+)	O
+is	O
+a	O
+drug	O
+that	O
+has	O
+been	O
+associated	O
+with	O
+serious	O
+side	O
+effects	O
+including	O
+stroke	B
+.	O
+
+It	O
+is	O
+often	O
+combined	O
+with	O
+caffeine	O
+in	O
+diet	O
+preparations	O
+and	O
+"	O
+look	O
+-	O
+alike	O
+"	O
+pills	O
+.	O
+
+In	O
+order	O
+to	O
+determine	O
+if	O
+PPA	O
+/	O
+caffeine	O
+can	O
+lead	O
+to	O
+stroke	B
+in	O
+normotensive	O
+and	O
+/	O
+or	O
+hypertensive	B
+rats	O
+,	O
+we	O
+administered	O
+the	O
+combination	O
+in	O
+six	O
+times	O
+the	O
+allowed	O
+human	O
+dose	O
+calculated	O
+on	O
+a	O
+per	O
+weight	O
+basis	O
+for	O
+the	O
+rats	O
+two	O
+times	O
+per	O
+day	O
+for	O
+five	O
+days	O
+.	O
+
+Subarachnoid	B
+and	I
+cerebral	I
+hemorrhage	I
+was	O
+noted	O
+in	O
+18	O
+%	O
+of	O
+the	O
+hypertensive	B
+rats	O
+.	O
+
+A	O
+single	O
+PPA	O
+/	O
+caffeine	O
+administration	O
+(	O
+same	O
+dose	O
+)	O
+lead	O
+to	O
+acute	O
+hypertension	B
+in	O
+both	O
+the	O
+normotensive	O
+and	O
+hypertensive	B
+animals	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+PPA	O
+/	O
+caffeine	O
+can	O
+lead	O
+to	O
+cerebral	B
+hemorrhage	I
+in	O
+previously	O
+hypertensive	B
+animals	O
+when	O
+administered	O
+in	O
+greater	O
+than	O
+the	O
+allowed	O
+dosage	O
+.	O
+
+An	O
+acute	O
+elevation	O
+in	O
+blood	O
+pressure	O
+may	O
+be	O
+a	O
+contributing	O
+factor	O
+.	O
+
+Renal	B
+papillary	I
+necrosis	I
+due	O
+to	O
+naproxen	O
+.	O
+
+A	O
+31	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+rheumatoid	B
+arthritis	I
+,	O
+who	O
+had	O
+previously	O
+been	O
+treated	O
+with	O
+sulindac	O
+,	O
+fenoprofen	O
+calcium	O
+,	O
+high	O
+dose	O
+salicylates	O
+and	O
+gold	O
+salts	O
+,	O
+developed	O
+renal	B
+papillary	I
+necrosis	I
+(	O
+RPN	B
+)	O
+4	O
+months	O
+after	O
+institution	O
+of	O
+naproxen	O
+therapy	O
+.	O
+
+No	O
+other	O
+factor	O
+predisposing	O
+to	O
+RPN	B
+could	O
+be	O
+discovered	O
+.	O
+
+Sulindac	O
+was	O
+substituted	O
+for	O
+naproxen	O
+and	O
+no	O
+further	O
+adverse	O
+renal	O
+effects	O
+occurred	O
+over	O
+the	O
+next	O
+12	O
+months	O
+.	O
+
+We	O
+review	O
+previous	O
+reports	O
+linking	O
+RPN	B
+to	O
+antiinflammatory	O
+drug	O
+use	O
+and	O
+discuss	O
+possible	O
+advantages	O
+of	O
+sulindac	O
+in	O
+patients	O
+who	O
+have	O
+experienced	O
+renal	B
+toxicity	I
+from	O
+other	O
+antiinflammatory	O
+agents	O
+.	O
+
+Nephrotoxic	B
+effects	O
+of	O
+aminoglycoside	O
+treatment	O
+on	O
+renal	O
+protein	O
+reabsorption	O
+and	O
+accumulation	O
+.	O
+
+To	O
+quantify	O
+the	O
+effects	O
+of	O
+gentamicin	O
+,	O
+kanamycin	O
+and	O
+netilmicin	O
+on	O
+renal	O
+protein	O
+reabsorption	O
+and	O
+accumulation	O
+,	O
+these	O
+drugs	O
+were	O
+administered	O
+to	O
+rats	O
+intraperitoneally	O
+(	O
+30	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+)	O
+for	O
+7	O
+,	O
+14	O
+or	O
+21	O
+days	O
+.	O
+
+Scanning	O
+electron	O
+microscopy	O
+of	O
+the	O
+glomerular	O
+endothelia	O
+,	O
+urinary	O
+measurements	O
+of	O
+sodium	O
+,	O
+potassium	O
+,	O
+endogenous	O
+lysozyme	O
+,	O
+N	O
+-	O
+acetyl	O
+-	O
+beta	O
+-	O
+D	O
+-	O
+glucosaminidase	O
+(	O
+NAG	O
+)	O
+as	O
+well	O
+as	O
+clearance	O
+and	O
+accumulation	O
+experiments	O
+after	O
+i	O
+.	O
+v	O
+.	O
+administration	O
+of	O
+egg	O
+-	O
+white	O
+lysozyme	O
+and	O
+measurements	O
+of	O
+inulin	O
+clearance	O
+(	O
+GFR	O
+)	O
+were	O
+done	O
+in	O
+each	O
+treatment	O
+group	O
+.	O
+
+Gentamicin	O
+administration	O
+decreased	O
+diameter	O
+,	O
+density	O
+and	O
+shape	O
+of	O
+endothelial	O
+fenestrae	O
+.	O
+
+Kanamycin	O
+and	O
+netilmicin	O
+appeared	O
+to	O
+have	O
+no	O
+effect	O
+at	O
+the	O
+dose	O
+used	O
+.	O
+
+All	O
+three	O
+aminoglycosides	O
+decreased	O
+GFR	O
+and	O
+increased	O
+urinary	O
+excretion	O
+of	O
+sodium	O
+and	O
+potassium	O
+.	O
+
+While	O
+gentamicin	O
+and	O
+kanamycin	O
+decreased	O
+the	O
+percentage	O
+reabsorption	O
+and	O
+accumulation	O
+of	O
+lysozyme	O
+after	O
+i	O
+.	O
+v	O
+.	O
+administration	O
+of	O
+egg	O
+-	O
+white	O
+lysozyme	O
+netilmicin	O
+had	O
+no	O
+effect	O
+.	O
+
+Daily	O
+excretion	O
+of	O
+total	O
+protein	O
+,	O
+endogenous	O
+lysozyme	O
+and	O
+NAG	O
+increased	O
+only	O
+after	O
+treatment	O
+with	O
+kanamycin	O
+and	O
+gentamicin	O
+.	O
+
+Thus	O
+,	O
+aminoglycosides	O
+may	O
+act	O
+as	O
+nephrotoxicants	O
+at	O
+glomerular	O
+and	O
+/	O
+or	O
+tubular	O
+level	O
+inducing	O
+impairment	B
+of	I
+renal	I
+reabsorption	I
+and	O
+accumulation	O
+of	O
+proteins	O
+.	O
+
+Induction	O
+of	O
+the	O
+obstructive	B
+sleep	I
+apnea	I
+syndrome	I
+in	O
+a	O
+woman	O
+by	O
+exogenous	O
+androgen	O
+administration	O
+.	O
+
+We	O
+documented	O
+airway	O
+occlusion	O
+during	O
+sleep	O
+and	O
+an	O
+abnormally	O
+high	O
+supraglottic	O
+resistance	O
+while	O
+awake	O
+in	O
+a	O
+54	O
+-	O
+yr	O
+-	O
+old	O
+woman	O
+who	O
+had	O
+developed	O
+physical	O
+changes	O
+and	O
+the	O
+syndrome	B
+of	I
+obstructive	I
+sleep	I
+apnea	I
+while	O
+being	O
+administered	O
+exogenous	O
+androgens	O
+.	O
+
+When	O
+the	O
+androgens	O
+were	O
+withdrawn	O
+,	O
+the	O
+patient	O
+'	O
+s	O
+physical	O
+changes	O
+,	O
+symptoms	O
+,	O
+sleep	O
+study	O
+,	O
+and	O
+supraglottic	O
+resistance	O
+all	O
+returned	O
+to	O
+normal	O
+.	O
+
+A	O
+rechallenge	O
+with	O
+androgen	O
+produced	O
+symptoms	O
+of	O
+obstructive	B
+sleep	I
+apnea	I
+that	O
+abated	O
+upon	O
+withdrawal	O
+of	O
+the	O
+hormone	O
+.	O
+
+Previous	O
+reports	O
+have	O
+favored	O
+a	O
+role	O
+of	O
+androgens	O
+in	O
+the	O
+pathogenesis	O
+of	O
+sleep	B
+apnea	I
+.	O
+
+Our	O
+report	O
+provides	O
+direct	O
+evidence	O
+for	O
+this	O
+role	O
+.	O
+
+Structural	O
+and	O
+functional	O
+measurements	O
+indicate	O
+that	O
+androgens	O
+exert	O
+a	O
+permissive	O
+or	O
+necessary	O
+action	O
+on	O
+the	O
+structural	O
+configuration	O
+of	O
+the	O
+oropharynx	O
+that	O
+predisposes	O
+to	O
+obstruction	O
+during	O
+sleep	O
+.	O
+
+Development	O
+of	O
+the	O
+obstructive	B
+sleep	I
+apnea	I
+syndrome	I
+must	O
+be	O
+considered	O
+a	O
+possible	O
+side	O
+effect	O
+of	O
+androgen	O
+therapy	O
+.	O
+
+Cardiotoxic	B
+and	O
+possible	O
+leukemogenic	O
+effects	O
+of	O
+adriamycin	O
+in	O
+nonhuman	O
+primates	O
+.	O
+
+10	O
+monkeys	O
+(	O
+macaques	O
+)	O
+received	O
+adriamycin	O
+by	O
+monthly	O
+intravenous	O
+injections	O
+at	O
+12	O
+mg	O
+/	O
+m2	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+8	O
+of	O
+the	O
+10	O
+monkeys	O
+developed	O
+congestive	B
+heart	I
+failure	I
+at	O
+an	O
+average	O
+cumulative	O
+adriamycin	O
+dose	O
+(	O
+310	O
+mg	O
+/	O
+m2	O
+)	O
+well	O
+below	O
+that	O
+considered	O
+the	O
+safe	O
+upper	O
+limit	O
+(	O
+550	O
+mg	O
+/	O
+m2	O
+)	O
+in	O
+man	O
+.	O
+
+Histologically	O
+,	O
+the	O
+myocardial	B
+lesions	I
+resembled	O
+those	O
+found	O
+in	O
+human	O
+anthracycline	O
+-	O
+induced	O
+cardiomyopathy	B
+.	O
+
+1	O
+of	O
+the	O
+10	O
+monkeys	O
+developed	O
+acute	B
+myeloblastic	I
+leukemia	I
+after	O
+receiving	O
+324	O
+mg	O
+/	O
+m2	O
+of	O
+adriamycin	O
+;	O
+the	O
+10th	O
+monkey	O
+is	O
+alive	O
+and	O
+well	O
+26	O
+months	O
+after	O
+the	O
+last	O
+dose	O
+of	O
+drug	O
+.	O
+
+Our	O
+results	O
+suggest	O
+that	O
+adriamycin	O
+is	O
+a	O
+more	O
+potent	O
+cardiotoxin	O
+in	O
+monkeys	O
+than	O
+in	O
+man	O
+,	O
+and	O
+that	O
+leukemia	B
+may	O
+be	O
+a	O
+consequence	O
+of	O
+prolonged	O
+treatment	O
+with	O
+this	O
+drug	O
+.	O
+
+Tricuspid	B
+valve	I
+regurgitation	I
+and	O
+lithium	O
+carbonate	O
+toxicity	B
+in	O
+a	O
+newborn	O
+infant	O
+.	O
+
+A	O
+newborn	O
+with	O
+massive	O
+tricuspid	B
+regurgitation	I
+,	O
+atrial	B
+flutter	I
+,	O
+congestive	B
+heart	I
+failure	I
+,	O
+and	O
+a	O
+high	O
+serum	O
+lithium	O
+level	O
+is	O
+described	O
+.	O
+
+This	O
+is	O
+the	O
+first	O
+patient	O
+to	O
+initially	O
+manifest	O
+tricuspid	B
+regurgitation	I
+and	O
+atrial	B
+flutter	I
+,	O
+and	O
+the	O
+11th	O
+described	O
+patient	O
+with	O
+cardiac	B
+disease	I
+among	O
+infants	O
+exposed	O
+to	O
+lithium	O
+compounds	O
+in	O
+the	O
+first	O
+trimester	O
+of	O
+pregnancy	O
+.	O
+
+Sixty	O
+-	O
+three	O
+percent	O
+of	O
+these	O
+infants	O
+had	O
+tricuspid	O
+valve	O
+involvement	O
+.	O
+
+Lithium	O
+carbonate	O
+may	O
+be	O
+a	O
+factor	O
+in	O
+the	O
+increasing	O
+incidence	O
+of	O
+congenital	B
+heart	I
+disease	I
+when	O
+taken	O
+during	O
+early	O
+pregnancy	O
+.	O
+
+It	O
+also	O
+causes	O
+neurologic	B
+depression	I
+,	O
+cyanosis	B
+,	O
+and	O
+cardiac	B
+arrhythmia	I
+when	O
+consumed	O
+prior	O
+to	O
+delivery	O
+.	O
+
+Effects	O
+of	O
+the	O
+novel	O
+compound	O
+aniracetam	O
+(	O
+Ro	O
+13	O
+-	O
+5057	O
+)	O
+upon	O
+impaired	B
+learning	I
+and	I
+memory	I
+in	O
+rodents	O
+.	O
+
+The	O
+effect	O
+of	O
+aniracetam	O
+(	O
+Ro	O
+13	O
+-	O
+5057	O
+,	O
+1	O
+-	O
+anisoyl	O
+-	O
+2	O
+-	O
+pyrrolidinone	O
+)	O
+was	O
+studied	O
+on	O
+various	O
+forms	O
+of	O
+experimentally	O
+impaired	B
+cognitive	I
+functions	I
+(	O
+learning	O
+and	O
+memory	O
+)	O
+in	O
+rodents	O
+and	O
+produced	O
+the	O
+following	O
+effects	O
+:	O
+(	O
+1	O
+)	O
+almost	O
+complete	O
+prevention	O
+of	O
+the	O
+incapacity	O
+to	O
+learn	O
+a	O
+discrete	O
+escape	O
+response	O
+in	O
+rats	O
+exposed	O
+to	O
+sublethal	O
+hypercapnia	B
+immediately	O
+before	O
+the	O
+acquisition	O
+session	O
+;	O
+(	O
+2	O
+)	O
+partial	O
+(	O
+rats	O
+)	O
+or	O
+complete	O
+(	O
+mice	O
+)	O
+prevention	O
+of	O
+the	O
+scopolamine	O
+-	O
+induced	O
+short	O
+-	O
+term	O
+amnesia	B
+for	O
+a	O
+passive	O
+avoidance	O
+task	O
+;	O
+(	O
+3	O
+)	O
+complete	O
+protection	O
+against	O
+amnesia	B
+for	O
+a	O
+passive	O
+avoidance	O
+task	O
+in	O
+rats	O
+submitted	O
+to	O
+electroconvulsive	O
+shock	O
+immediately	O
+after	O
+avoidance	O
+acquisition	O
+;	O
+(	O
+4	O
+)	O
+prevention	O
+of	O
+the	O
+long	O
+-	O
+term	O
+retention	O
+-	O
+or	O
+retrieval	O
+-	O
+deficit	O
+for	O
+a	O
+passive	O
+avoidance	O
+task	O
+induced	O
+in	O
+rats	O
+and	O
+mice	O
+by	O
+chloramphenicol	O
+or	O
+cycloheximide	O
+administered	O
+immediately	O
+after	O
+acquisition	O
+;	O
+(	O
+5	O
+)	O
+reversal	O
+,	O
+when	O
+administered	O
+as	O
+late	O
+as	O
+1	O
+h	O
+before	O
+the	O
+retention	O
+test	O
+,	O
+of	O
+the	O
+deficit	O
+in	O
+retention	O
+or	O
+retrieval	O
+of	O
+a	O
+passive	O
+avoidance	O
+task	O
+induced	O
+by	O
+cycloheximide	O
+injected	O
+2	O
+days	O
+previously	O
+;	O
+(	O
+6	O
+)	O
+prevention	O
+of	O
+the	O
+deficit	O
+in	O
+the	O
+retrieval	O
+of	O
+an	O
+active	O
+avoidance	O
+task	O
+induced	O
+in	O
+mice	O
+by	O
+subconvulsant	O
+electroshock	O
+or	O
+hypercapnia	B
+applied	O
+immediately	O
+before	O
+retrieval	O
+testing	O
+(	O
+24	O
+h	O
+after	O
+acquisition	O
+)	O
+.	O
+
+These	O
+improvements	O
+or	O
+normalizations	O
+of	O
+impaired	B
+cognitive	I
+functions	I
+were	O
+seen	O
+at	O
+oral	O
+aniracetam	O
+doses	O
+of	O
+10	O
+-	O
+100	O
+mg	O
+/	O
+kg	O
+.	O
+
+Generally	O
+,	O
+the	O
+dose	O
+-	O
+response	O
+curves	O
+were	O
+bell	O
+-	O
+shaped	O
+.	O
+
+The	O
+mechanisms	O
+underlying	O
+the	O
+activity	O
+of	O
+aniracetam	O
+and	O
+its	O
+'	O
+therapeutic	O
+window	O
+'	O
+are	O
+unknown	O
+.	O
+
+Piracetam	O
+,	O
+another	O
+pyrrolidinone	O
+derivative	O
+was	O
+used	O
+for	O
+comparison	O
+.	O
+
+It	O
+was	O
+active	O
+only	O
+in	O
+six	O
+of	O
+nine	O
+tests	O
+and	O
+had	O
+about	O
+one	O
+-	O
+tenth	O
+the	O
+potency	O
+of	O
+aniracetam	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+aniracetam	O
+improves	O
+cognitive	O
+functions	O
+which	O
+are	O
+impaired	O
+by	O
+different	O
+procedure	O
+and	O
+in	O
+different	O
+phases	O
+of	O
+the	O
+learning	O
+and	O
+memory	O
+process	O
+.	O
+
+Effect	O
+of	O
+calcium	O
+chloride	O
+on	O
+gross	O
+behavioural	O
+changes	O
+produced	O
+by	O
+carbachol	O
+and	O
+eserine	O
+in	O
+cats	O
+.	O
+
+The	O
+effect	O
+of	O
+calcium	O
+chloride	O
+injected	O
+into	O
+the	O
+cerebral	O
+ventricles	O
+of	O
+group	O
+-	O
+housed	O
+unanaesthetized	O
+cats	O
+upon	O
+vocalization	O
+(	O
+rage	O
+,	O
+hissing	O
+and	O
+snarling	O
+)	O
+,	O
+fighting	O
+(	O
+attack	O
+with	O
+paws	O
+and	O
+claws	O
+,	O
+defense	O
+with	O
+paws	O
+and	O
+claws	O
+and	O
+biting	O
+)	O
+,	O
+mydriasis	B
+,	O
+tremor	B
+and	O
+clonic	B
+-	I
+tonic	I
+convulsions	I
+produced	O
+by	O
+carbachol	O
+and	O
+eserine	O
+injected	O
+similarly	O
+was	O
+investigated	O
+.	O
+
+Calcium	O
+chloride	O
+depressed	O
+or	O
+almost	O
+completely	O
+abolished	O
+the	O
+vocalization	O
+and	O
+fighting	O
+due	O
+to	O
+carbachol	O
+and	O
+eserine	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+mydriasis	B
+,	O
+tremor	B
+and	O
+clonic	B
+-	I
+tonic	I
+convulsions	I
+evoked	O
+by	O
+carbachol	O
+and	O
+eserine	O
+were	O
+not	O
+significantly	O
+changed	O
+by	O
+calcium	O
+chloride	O
+.	O
+
+It	O
+is	O
+apparent	O
+that	O
+calcium	O
+chloride	O
+can	O
+"	O
+dissociate	O
+"	O
+vocalization	O
+and	O
+fighting	O
+from	O
+autonomic	O
+and	O
+motor	O
+phenomena	O
+such	O
+as	O
+mydriasis	B
+,	O
+tremor	B
+and	O
+clonic	B
+-	I
+tonic	I
+convulsions	I
+caused	O
+by	O
+carbachol	O
+and	O
+eserine	O
+.	O
+
+Calcium	O
+chloride	O
+inhibited	O
+the	O
+vocalization	O
+and	O
+fighting	O
+produced	O
+by	O
+carbachol	O
+and	O
+eserine	O
+most	O
+probably	O
+by	O
+a	O
+nonspecific	O
+stabilizing	O
+action	O
+on	O
+central	O
+muscarinic	O
+cholinoceptive	O
+sites	O
+.	O
+
+These	O
+results	O
+further	O
+support	O
+the	O
+view	O
+that	O
+calcium	O
+ions	O
+in	O
+excess	O
+have	O
+an	O
+atropine	O
+-	O
+like	O
+action	O
+also	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+.	O
+
+Thiazide	O
+diuretics	O
+,	O
+hypokalemia	B
+and	O
+cardiac	B
+arrhythmias	I
+.	O
+
+Thiazide	O
+diuretics	O
+are	O
+widely	O
+accepted	O
+as	O
+the	O
+cornerstone	O
+of	O
+antihypertensive	O
+treatment	O
+programs	O
+.	O
+
+Hypokalemia	B
+is	O
+a	O
+commonly	O
+encountered	O
+metabolic	O
+consequence	O
+of	O
+chronic	O
+thiazide	O
+therapy	O
+.	O
+
+We	O
+treated	O
+38	O
+patients	O
+(	O
+22	O
+low	O
+renin	O
+,	O
+16	O
+normal	O
+renin	O
+)	O
+with	O
+moderate	O
+diastolic	B
+hypertension	I
+with	O
+hydrochlorothiazide	O
+(	O
+HCTC	O
+)	O
+administered	O
+on	O
+a	O
+twice	O
+daily	O
+schedule	O
+.	O
+
+Initial	O
+dose	O
+was	O
+50	O
+mg	O
+and	O
+the	O
+dose	O
+was	O
+increased	O
+at	O
+monthly	O
+intervals	O
+to	O
+100	O
+mg	O
+,	O
+150	O
+mg	O
+and	O
+200	O
+mg	O
+daily	O
+until	O
+blood	O
+pressure	O
+normalized	O
+.	O
+
+The	O
+serum	O
+K	O
+during	O
+the	O
+control	O
+period	O
+was	O
+4	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+mEq	O
+/	O
+l	O
+an	O
+on	O
+50	O
+,	O
+100	O
+,	O
+150	O
+and	O
+200	O
+mg	O
+HCTZ	O
+daily	O
+3	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+,	O
+3	O
+.	O
+4	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+,	O
+2	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+,	O
+and	O
+2	O
+.	O
+4	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+mEq	O
+/	O
+l	O
+,	O
+respectively	O
+.	O
+
+Corresponding	O
+figures	O
+for	O
+whole	O
+body	O
+K	O
+were	O
+4107	O
++	O
+/	O
+-	O
+208	O
+,	O
+3722	O
++	O
+/	O
+-	O
+319	O
+,	O
+3628	O
++	O
+/	O
+-	O
+257	O
+,	O
+3551	O
++	O
+/	O
+-	O
+336	O
+,	O
+and	O
+3269	O
++	O
+/	O
+-	O
+380	O
+mEq	O
+,	O
+respectively	O
+.	O
+
+In	O
+13	O
+patients	O
+we	O
+observed	O
+the	O
+effects	O
+of	O
+HCTZ	O
+therapy	O
+(	O
+100	O
+mg	O
+daily	O
+)	O
+on	O
+the	O
+occurrence	O
+of	O
+PVC	O
+'	O
+s	O
+during	O
+rest	O
+as	O
+well	O
+as	O
+during	O
+static	O
+and	O
+dynamic	O
+exercise	O
+.	O
+
+During	O
+rest	O
+we	O
+observed	O
+0	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+08	O
+PVC	O
+beats	O
+/	O
+min	O
++	O
+/	O
+-	O
+SEM	O
+and	O
+during	O
+static	O
+and	O
+dynamic	O
+exercise	O
+0	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+06	O
+and	O
+0	O
+.	O
+8	O
++	O
+/	O
+-	O
+0	O
+.	O
+15	O
+,	O
+respectively	O
+.	O
+
+Corresponding	O
+figures	O
+during	O
+HCTZ	O
+therapy	O
+100	O
+mg	O
+daily	O
+were	O
+1	O
+.	O
+4	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+,	O
+3	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+and	O
+5	O
+.	O
+7	O
+4	O
+/	O
+-	O
+0	O
+.	O
+8	O
+,	O
+respectively	O
+.	O
+
+The	O
+occurrence	O
+of	O
+PVC	O
+'	O
+s	O
+correlated	O
+significantly	O
+with	O
+the	O
+fall	O
+in	O
+serum	O
+K	O
++	O
+observed	O
+r	O
+=	O
+0	O
+.	O
+72	O
+,	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+.	O
+
+In	O
+conclusion	O
+we	O
+found	O
+that	O
+thiazide	O
+diuretics	O
+cause	O
+hypokalemia	B
+and	O
+depletion	O
+of	O
+body	O
+potassium	O
+.	O
+
+The	O
+more	O
+profound	O
+hypokalemia	B
+,	O
+the	O
+greater	O
+the	O
+propensity	O
+for	O
+the	O
+occurrence	O
+of	O
+PVC	O
+'	O
+s	O
+.	O
+
+Circulating	O
+lysosomal	O
+enzymes	O
+and	O
+acute	B
+hepatic	I
+necrosis	I
+.	O
+
+The	O
+activities	O
+of	O
+the	O
+lysosomal	O
+enzymes	O
+acid	O
+and	O
+neutral	O
+protease	O
+,	O
+N	O
+-	O
+acetylglucosaminidase	O
+,	O
+and	O
+acid	O
+phosphatase	O
+were	O
+measured	O
+in	O
+the	O
+serum	O
+of	O
+patients	O
+with	O
+fulminant	B
+hepatic	I
+failure	I
+.	O
+
+Acid	O
+protease	O
+(	O
+cathepsin	O
+D	O
+)	O
+activity	O
+was	O
+increased	O
+about	O
+tenfold	O
+in	O
+patients	O
+who	O
+died	O
+and	O
+nearly	O
+fourfold	O
+in	O
+those	O
+who	O
+survived	O
+fulminant	B
+hepatic	I
+failure	I
+after	O
+paracetamol	O
+overdose	B
+,	O
+whereas	O
+activities	O
+were	O
+increased	O
+equally	O
+in	O
+patients	O
+with	O
+fulminant	B
+hepatic	I
+failure	I
+due	O
+to	O
+viral	B
+hepatitis	I
+whether	O
+or	O
+not	O
+they	O
+survived	O
+.	O
+
+A	O
+correlation	O
+was	O
+found	O
+between	O
+serum	O
+acid	O
+protease	O
+activity	O
+and	O
+prothrombin	O
+time	O
+,	O
+and	O
+the	O
+increase	O
+in	O
+cathepsin	O
+D	O
+activity	O
+was	O
+sustained	O
+over	O
+several	O
+days	O
+compared	O
+with	O
+aspartate	O
+aminotransferase	O
+,	O
+which	O
+showed	O
+a	O
+sharp	O
+early	O
+peak	O
+and	O
+then	O
+a	O
+fall	O
+.	O
+
+Circulating	O
+lysosomal	O
+proteases	O
+can	O
+damage	O
+other	O
+organs	O
+,	O
+and	O
+measurement	O
+of	O
+their	O
+activity	O
+may	O
+therefore	O
+be	O
+of	O
+added	O
+value	O
+in	O
+assessing	O
+prognosis	O
+in	O
+this	O
+condition	O
+.	O
+
+Hepatic	B
+veno	I
+-	I
+occlusive	I
+disease	I
+caused	O
+by	O
+6	O
+-	O
+thioguanine	O
+.	O
+
+Clinically	O
+reversible	O
+veno	B
+-	I
+occlusive	I
+disease	I
+of	I
+the	I
+liver	I
+developed	O
+in	O
+a	O
+23	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+acute	B
+lymphocytic	I
+leukemia	I
+after	O
+10	O
+months	O
+of	O
+maintenance	O
+therapy	O
+with	O
+6	O
+-	O
+thioguanine	O
+.	O
+
+Serial	O
+liver	O
+biopsies	O
+showed	O
+the	O
+development	O
+and	O
+resolution	O
+of	O
+intense	O
+sinusoidal	O
+engorgement	O
+.	O
+
+Although	O
+this	O
+disease	O
+was	O
+clinically	O
+reversible	O
+,	O
+some	O
+subintimal	O
+fibrosis	B
+about	O
+the	O
+terminal	O
+hepatic	O
+veins	O
+persisted	O
+.	O
+
+This	O
+case	O
+presented	O
+a	O
+unique	O
+opportunity	O
+to	O
+observe	O
+the	O
+histologic	O
+features	O
+of	O
+clinically	O
+reversible	O
+hepatic	B
+veno	I
+-	I
+occlusive	I
+disease	I
+over	O
+time	O
+,	O
+and	O
+may	O
+be	O
+the	O
+first	O
+case	O
+of	O
+veno	O
+-	O
+occlusive	O
+related	O
+solely	O
+to	O
+6	O
+-	O
+thioguanine	O
+.	O
+
+Chlorpropamide	O
+-	O
+induced	O
+optic	B
+neuropathy	I
+.	O
+
+A	O
+65	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+adult	B
+-	I
+onset	I
+diabetes	I
+treated	O
+with	O
+chlorpropamide	O
+(	O
+Diabenese	O
+)	O
+had	O
+a	O
+toxic	B
+optic	I
+neuropathy	I
+that	O
+resolved	O
+with	O
+discontinuation	O
+of	O
+chlorpropamide	O
+therapy	O
+.	O
+
+Visual	B
+loss	I
+occurs	O
+in	O
+diabetics	B
+for	O
+a	O
+variety	O
+of	O
+reasons	O
+,	O
+and	O
+accurate	O
+diagnosis	O
+is	O
+necessary	O
+to	O
+institute	O
+appropriate	O
+therapy	O
+.	O
+
+The	O
+possibility	O
+of	O
+a	O
+drug	O
+-	O
+induced	O
+optic	B
+neuropathy	I
+should	O
+be	O
+considered	O
+in	O
+the	O
+differential	O
+diagnosis	O
+of	O
+visual	B
+loss	I
+in	O
+diabetics	B
+.	O
+
+Plasma	O
+and	O
+urinary	O
+lipids	O
+and	O
+lipoproteins	O
+during	O
+the	O
+development	O
+of	O
+nephrotic	B
+syndrome	I
+induced	O
+in	O
+the	O
+rat	O
+by	O
+puromycin	O
+aminonucleoside	O
+.	O
+
+This	O
+study	O
+was	O
+undertaken	O
+to	O
+ascertain	O
+whether	O
+the	O
+alterations	O
+of	O
+plasma	O
+lipoproteins	O
+found	O
+in	O
+nephrotic	B
+syndrome	I
+induced	O
+by	O
+puromycin	O
+aminonucleoside	O
+were	O
+due	O
+to	O
+nephrotic	B
+syndrome	I
+per	O
+se	O
+,	O
+or	O
+,	O
+at	O
+least	O
+in	O
+part	O
+,	O
+to	O
+the	O
+aminonucleoside	O
+.	O
+
+The	O
+purpose	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+changes	O
+in	O
+plasma	O
+and	O
+urinary	O
+lipoproteins	O
+during	O
+the	O
+administration	O
+of	O
+puromycin	O
+aminonucleoside	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+for	O
+7	O
+days	O
+)	O
+and	O
+the	O
+subsequent	O
+development	O
+of	O
+nephrotic	B
+syndrome	I
+.	O
+
+Since	O
+massive	O
+albuminuria	B
+occurred	O
+after	O
+6	O
+days	O
+of	O
+treatment	O
+,	O
+the	O
+time	O
+-	O
+course	O
+study	O
+was	O
+divided	O
+into	O
+two	O
+stages	O
+:	O
+pre	O
+-	O
+nephrotic	B
+stage	O
+(	O
+day	O
+1	O
+-	O
+5	O
+)	O
+and	O
+nephrotic	B
+stage	O
+(	O
+day	O
+6	O
+-	O
+11	O
+)	O
+.	O
+
+In	O
+pre	O
+-	O
+nephrotic	B
+stage	O
+the	O
+plasma	O
+level	O
+of	O
+fatty	O
+acids	O
+,	O
+triacylglycerol	O
+and	O
+VLDL	O
+decreased	O
+while	O
+that	O
+of	O
+phospholipid	O
+,	O
+cholesteryl	O
+esters	O
+and	O
+HDL	O
+remained	O
+constant	O
+.	O
+
+Plasma	O
+apolipoprotein	O
+A	O
+-	O
+I	O
+tended	O
+to	O
+increase	O
+(	O
+40	O
+%	O
+increase	O
+at	O
+day	O
+5	O
+)	O
+.	O
+
+At	O
+the	O
+beginning	O
+of	O
+nephrotic	B
+stage	O
+(	O
+day	O
+6	O
+)	O
+the	O
+concentration	O
+of	O
+plasma	O
+albumin	O
+dropped	O
+to	O
+a	O
+very	O
+low	O
+level	O
+,	O
+while	O
+that	O
+of	O
+apolipoprotein	O
+A	O
+-	O
+I	O
+increased	O
+abruptly	O
+(	O
+4	O
+-	O
+fold	O
+increase	O
+)	O
+and	O
+continued	O
+to	O
+rise	O
+,	O
+although	O
+less	O
+steeply	O
+,	O
+in	O
+the	O
+following	O
+days	O
+.	O
+
+The	O
+plasma	O
+concentration	O
+of	O
+HDL	O
+followed	O
+the	O
+same	O
+pattern	O
+.	O
+
+Plasma	O
+VLDL	O
+and	O
+LDL	O
+increased	O
+at	O
+a	O
+later	O
+stage	O
+(	O
+day	O
+9	O
+)	O
+.	O
+
+Plasma	O
+apolipoprotein	O
+A	O
+-	O
+I	O
+was	O
+found	O
+not	O
+only	O
+in	O
+HDL	O
+(	O
+1	O
+.	O
+063	O
+-	O
+1	O
+.	O
+210	O
+g	O
+/	O
+ml	O
+)	O
+but	O
+also	O
+in	O
+the	O
+LDL	O
+density	O
+class	O
+(	O
+1	O
+.	O
+025	O
+-	O
+1	O
+.	O
+050	O
+g	O
+/	O
+ml	O
+)	O
+.	O
+
+In	O
+the	O
+pre	O
+-	O
+nephrotic	B
+stage	O
+lipoproteinuria	O
+was	O
+negligible	O
+,	O
+while	O
+in	O
+the	O
+early	O
+nephrotic	B
+stage	O
+the	O
+urinary	O
+loss	O
+of	O
+plasma	O
+lipoproteins	O
+consisted	O
+mainly	O
+of	O
+HDL	O
+.	O
+
+These	O
+observations	O
+indicate	O
+that	O
+puromycin	O
+aminonucleoside	O
+alters	O
+plasma	O
+lipoproteins	O
+by	O
+lowering	O
+VLDL	O
+and	O
+increasing	O
+HDL	O
+.	O
+
+It	O
+is	O
+likely	O
+that	O
+the	O
+early	O
+and	O
+striking	O
+increase	O
+of	O
+plasma	O
+HDL	O
+found	O
+in	O
+nephrotic	B
+rats	O
+is	O
+related	O
+to	O
+a	O
+direct	O
+effect	O
+of	O
+the	O
+drug	O
+on	O
+HDL	O
+metabolism	O
+.	O
+
+Fatal	O
+aplastic	B
+anemia	I
+following	O
+topical	O
+administration	O
+of	O
+ophthalmic	O
+chloramphenicol	O
+.	O
+
+A	O
+73	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+died	O
+of	O
+aplastic	B
+anemia	I
+less	O
+than	O
+two	O
+months	O
+after	O
+undergoing	O
+cataract	B
+extraction	O
+and	O
+beginning	O
+topical	O
+therapy	O
+with	O
+chloramphenicol	O
+.	O
+
+The	O
+first	O
+signs	O
+of	O
+pancytopenia	B
+began	O
+within	O
+one	O
+month	O
+of	O
+the	O
+surgery	O
+.	O
+
+The	O
+pattern	O
+of	O
+the	O
+aplastic	B
+anemia	I
+was	O
+associated	O
+with	O
+an	O
+idiosyncratic	O
+response	O
+to	O
+chloramphenicol	O
+.	O
+
+This	O
+was	O
+the	O
+second	O
+report	O
+of	O
+fatal	O
+aplastic	B
+anemia	I
+after	O
+topical	O
+treatment	O
+with	O
+chloramphenicol	O
+for	O
+ocular	O
+conditions	O
+,	O
+although	O
+two	O
+cases	O
+of	O
+reversible	O
+bone	B
+marrow	I
+hypoplasia	I
+have	O
+also	O
+been	O
+reported	O
+.	O
+
+Any	O
+other	O
+suspected	O
+cases	O
+of	O
+ocular	B
+toxicity	I
+associated	O
+with	O
+topically	O
+applied	O
+chloramphenicol	O
+should	O
+be	O
+reported	O
+to	O
+the	O
+National	O
+Registry	O
+of	O
+Drug	O
+-	O
+Induced	O
+Ocular	O
+Side	O
+Effects	O
+,	O
+Oregon	O
+Health	O
+Sciences	O
+University	O
+,	O
+Portland	O
+,	O
+OR	O
+97201	O
+.	O
+
+Midazolam	O
+compared	O
+with	O
+thiopentone	O
+as	O
+an	O
+induction	O
+agent	O
+.	O
+
+In	O
+patients	O
+premedicated	O
+with	O
+scopolamine	O
++	O
+morphine	O
+(	O
++	O
+5	O
+mg	O
+nitrazepam	O
+the	O
+evening	O
+before	O
+surgery	O
+)	O
+,	O
+the	O
+sleep	O
+-	O
+inducing	O
+effect	O
+of	O
+midazolam	O
+0	O
+.	O
+15	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+was	O
+clearly	O
+slower	O
+in	O
+onset	O
+than	O
+that	O
+of	O
+thiopentone	O
+4	O
+.	O
+67	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+Somewhat	O
+fewer	O
+cardiovascular	O
+and	O
+local	O
+sequelae	O
+were	O
+found	O
+in	O
+the	O
+midazolam	O
+group	O
+,	O
+but	O
+,	O
+although	O
+apnoea	B
+occurred	O
+less	O
+often	O
+in	O
+the	O
+midazolam	O
+group	O
+it	O
+lasted	O
+longer	O
+.	O
+
+On	O
+the	O
+whole	O
+,	O
+the	O
+differences	O
+between	O
+midazolam	O
+and	O
+thiopentone	O
+had	O
+no	O
+apparent	O
+clinical	O
+consequences	O
+.	O
+
+Midazolam	O
+is	O
+a	O
+new	O
+alternative	O
+agent	O
+for	O
+induction	O
+in	O
+combination	O
+anaesthesia	O
+.	O
+
+Extrapyramidal	O
+side	O
+effects	O
+and	O
+oral	O
+haloperidol	O
+:	O
+an	O
+analysis	O
+of	O
+explanatory	O
+patient	O
+and	O
+treatment	O
+characteristics	O
+.	O
+
+The	O
+incidence	O
+of	O
+extrapyramidal	O
+side	O
+effects	O
+(	O
+EPS	O
+)	O
+was	O
+evaluated	O
+in	O
+98	O
+patients	O
+treated	O
+with	O
+haloperidol	O
+.	O
+
+The	O
+incidence	O
+of	O
+parkinsonism	B
+was	O
+higher	O
+at	O
+higher	O
+doses	O
+of	O
+haloperidol	O
+and	O
+in	O
+younger	O
+patients	O
+.	O
+
+Prophylactic	O
+antiparkinsonian	O
+medication	O
+was	O
+effective	O
+in	O
+younger	O
+but	O
+not	O
+in	O
+older	O
+patients	O
+.	O
+
+However	O
+,	O
+these	O
+medications	O
+were	O
+more	O
+effective	O
+in	O
+both	O
+young	O
+and	O
+old	O
+patients	O
+when	O
+given	O
+after	O
+parkinsonism	B
+developed	O
+.	O
+
+Akathisia	B
+was	O
+controlled	O
+by	O
+the	O
+benzodiazepine	O
+lorazepam	O
+in	O
+14	O
+out	O
+of	O
+16	O
+patients	O
+,	O
+while	O
+prophylactic	O
+antiparkinsonians	O
+were	O
+ineffective	O
+.	O
+
+The	O
+present	O
+study	O
+points	O
+to	O
+patient	O
+characteristics	O
+that	O
+may	O
+be	O
+of	O
+significance	O
+in	O
+the	O
+development	O
+of	O
+EPS	O
+due	O
+to	O
+haloperidol	O
+.	O
+
+Deaths	O
+from	O
+local	O
+anesthetic	O
+-	O
+induced	O
+convulsions	B
+in	O
+mice	O
+.	O
+
+Median	O
+convulsant	O
+(	O
+CD50	O
+)	O
+and	O
+median	O
+lethal	O
+(	O
+LD50	O
+)	O
+doses	O
+of	O
+three	O
+representative	O
+local	O
+anesthetics	O
+were	O
+determined	O
+in	O
+adult	O
+mice	O
+to	O
+evaluate	O
+the	O
+threat	O
+to	O
+life	O
+of	O
+local	O
+anesthetic	O
+-	O
+induced	O
+convulsions	B
+.	O
+
+The	O
+CD50	O
+and	O
+LD50	O
+,	O
+respectively	O
+,	O
+were	O
+57	O
+.	O
+7	O
+and	O
+58	O
+.	O
+7	O
+mg	O
+/	O
+kg	O
+for	O
+bupivacaine	O
+,	O
+111	O
+.	O
+0	O
+and	O
+133	O
+.	O
+1	O
+mg	O
+/	O
+kg	O
+for	O
+lidocaine	O
+,	O
+and	O
+243	O
+.	O
+4	O
+and	O
+266	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+for	O
+chloroprocaine	O
+.	O
+
+When	O
+given	O
+intraperitoneally	O
+,	O
+bupivacaine	O
+thus	O
+was	O
+only	O
+about	O
+twice	O
+as	O
+toxic	O
+as	O
+lidocaine	O
+and	O
+four	O
+times	O
+as	O
+toxic	O
+as	O
+chloroprocaine	O
+.	O
+
+Convulsions	B
+always	O
+preceded	O
+death	O
+,	O
+except	O
+after	O
+precipitous	O
+cardiopulmonary	B
+arrest	I
+from	O
+extreme	O
+doses	O
+.	O
+
+A	O
+CD50	O
+dose	O
+of	O
+local	O
+anesthetic	O
+(	O
+causing	O
+convulsions	B
+in	O
+50	O
+%	O
+of	O
+mice	O
+)	O
+was	O
+fatal	O
+in	O
+90	O
+%	O
+of	O
+bupivacaine	O
+-	O
+induced	O
+seizures	B
+,	O
+in	O
+57	O
+%	O
+of	O
+the	O
+chloroprocaine	O
+group	O
+,	O
+and	O
+in	O
+6	O
+%	O
+of	O
+the	O
+lidocaine	O
+group	O
+.	O
+
+The	O
+narrow	O
+gap	O
+between	O
+convulsant	O
+and	O
+lethal	O
+doses	O
+of	O
+local	O
+anesthetics	O
+indicates	O
+that	O
+untreated	O
+convulsions	B
+present	O
+much	O
+more	O
+of	O
+a	O
+threat	O
+to	O
+life	O
+than	O
+heretofore	O
+appreciated	O
+.	O
+
+REM	B
+sleep	I
+deprivation	I
+changes	O
+behavioral	O
+response	O
+to	O
+catecholaminergic	O
+and	O
+serotonergic	O
+receptor	O
+activation	O
+in	O
+rats	O
+.	O
+
+The	O
+effects	O
+of	O
+REM	B
+sleep	I
+deprivation	I
+(	O
+REMD	B
+)	O
+on	O
+apomorphine	O
+-	O
+induced	O
+aggressiveness	B
+and	O
+quipazine	O
+-	O
+induced	O
+head	B
+twitches	I
+in	O
+rats	O
+were	O
+determined	O
+.	O
+
+Forty	O
+-	O
+eight	O
+hr	O
+of	O
+REMD	B
+increased	O
+apomorphine	O
+-	O
+induced	O
+aggressiveness	B
+,	O
+and	O
+reduced	O
+(	O
+immediately	O
+after	O
+completing	O
+of	O
+REMD	B
+)	O
+or	O
+increased	O
+(	O
+96	O
+hr	O
+after	O
+completing	O
+of	O
+REMD	B
+)	O
+quipazine	O
+-	O
+induced	O
+head	B
+twitches	I
+.	O
+
+Results	O
+are	O
+discussed	O
+in	O
+terms	O
+of	O
+similarity	O
+to	O
+pharmacological	O
+effects	O
+of	O
+other	O
+antidepressive	O
+treatments	O
+.	O
+
+Fatal	O
+aplastic	B
+anemia	I
+due	O
+to	O
+indomethacin	O
+-	O
+-	O
+lymphocyte	O
+transformation	O
+tests	O
+in	O
+vitro	O
+.	O
+
+Although	O
+indomethacin	O
+has	O
+been	O
+implicated	O
+as	O
+a	O
+possible	O
+cause	O
+of	O
+aplastic	B
+anemia	I
+on	O
+the	O
+basis	O
+of	O
+a	O
+few	O
+clinical	O
+observations	O
+,	O
+its	O
+role	O
+has	O
+not	O
+been	O
+definitely	O
+established	O
+.	O
+
+A	O
+case	O
+of	O
+fatal	O
+aplastic	B
+anemia	I
+is	O
+described	O
+in	O
+which	O
+no	O
+drugs	O
+other	O
+than	O
+allopurinol	O
+and	O
+indomethacin	O
+were	O
+given	O
+.	O
+
+Indomethacin	O
+was	O
+first	O
+given	O
+four	O
+weeks	O
+prior	O
+to	O
+the	O
+onset	O
+of	O
+symptoms	O
+.	O
+
+A	O
+positive	O
+lymphocyte	O
+transformation	O
+test	O
+with	O
+indomethacin	O
+in	O
+vitro	O
+further	O
+substantiates	O
+the	O
+potential	O
+role	O
+of	O
+this	O
+drug	O
+in	O
+causing	O
+aplastic	B
+anemia	I
+in	O
+a	O
+susceptible	O
+patient	O
+.	O
+
+Fortunately	O
+,	O
+this	O
+seems	O
+to	O
+be	O
+a	O
+very	O
+rare	O
+complication	O
+.	O
+
+Dose	O
+-	O
+effect	O
+and	O
+structure	O
+-	O
+function	O
+relationships	O
+in	O
+doxorubicin	O
+cardiomyopathy	B
+.	O
+
+The	O
+cardiomyopathy	B
+(	O
+CM	B
+)	O
+produced	O
+by	O
+the	O
+anticancer	O
+drug	O
+doxorubicin	O
+(	O
+DXR	O
+)	O
+(	O
+Adriamycin	O
+)	O
+provides	O
+a	O
+unique	O
+opportunity	O
+to	O
+analyze	O
+dose	O
+-	O
+effect	O
+and	O
+structure	O
+-	O
+function	O
+relationships	O
+during	O
+development	O
+of	O
+myocardial	B
+disease	I
+.	O
+
+We	O
+measured	O
+the	O
+degree	O
+of	O
+morphologic	O
+damage	O
+by	O
+ultrastructural	O
+examination	O
+of	O
+endomyocardial	O
+biopsy	O
+and	O
+the	O
+degree	O
+of	O
+performance	O
+abnormally	O
+by	O
+right	O
+heart	O
+catheterization	O
+in	O
+patients	O
+receiving	O
+DXR	O
+.	O
+
+Morphologic	O
+damage	O
+was	O
+variable	O
+but	O
+was	O
+proportional	O
+to	O
+the	O
+total	O
+cumulative	O
+DXR	O
+dose	O
+between	O
+100	O
+and	O
+600	O
+mg	O
+/	O
+m2	O
+.	O
+
+Performance	O
+abnormalities	O
+correlated	O
+weakly	O
+with	O
+dose	O
+,	O
+exhibited	O
+a	O
+curvilinear	O
+relationship	O
+,	O
+and	O
+had	O
+a	O
+"	O
+threshold	O
+"	O
+for	O
+expression	O
+.	O
+
+Catheterization	O
+abnormalities	O
+correlated	O
+well	O
+with	O
+morphologic	O
+damage	O
+(	O
+r	O
+=	O
+0	O
+.	O
+57	O
+to	O
+0	O
+.	O
+78	O
+)	O
+in	O
+a	O
+subgroup	O
+of	O
+patients	O
+in	O
+whom	O
+exercise	O
+hemodynamics	O
+were	O
+measured	O
+,	O
+and	O
+this	O
+relationship	O
+also	O
+exhibited	O
+a	O
+curvilinear	O
+,	O
+threshold	O
+configuration	O
+.	O
+
+In	O
+DXR	O
+-	O
+CM	B
+myocardial	B
+damage	I
+is	O
+proportional	O
+to	O
+the	O
+degree	O
+of	O
+cytotoxic	O
+insult	O
+(	O
+DXR	O
+dose	O
+)	O
+while	O
+myocardial	O
+function	O
+is	O
+preserved	O
+until	O
+a	O
+critical	O
+dose	O
+or	O
+degree	O
+of	O
+damage	O
+is	O
+reached	O
+,	O
+after	O
+which	O
+myocardial	O
+performance	O
+deteriorates	O
+rapidly	O
+.	O
+
+Massive	O
+cerebral	B
+edema	I
+associated	O
+with	O
+fulminant	O
+hepatic	B
+failure	I
+in	O
+acetaminophen	O
+overdose	B
+:	O
+possible	O
+role	O
+of	O
+cranial	O
+decompression	O
+.	O
+
+Cerebral	B
+edema	I
+may	O
+complicate	O
+the	O
+course	O
+of	O
+fulminant	B
+hepatic	I
+failure	I
+.	O
+
+Response	O
+to	O
+conventional	O
+therapy	O
+has	O
+been	O
+disappointing	O
+.	O
+
+We	O
+present	O
+a	O
+patient	O
+with	O
+fatal	O
+acetaminophen	O
+-	O
+induced	O
+fulminant	B
+hepatic	I
+failure	I
+,	O
+with	O
+signs	O
+and	O
+symptoms	O
+of	O
+cerebral	B
+edema	I
+,	O
+unresponsive	O
+to	O
+conventional	O
+medical	O
+therapy	O
+.	O
+
+Cranial	O
+decompression	O
+was	O
+carried	O
+out	O
+.	O
+
+A	O
+justification	O
+of	O
+the	O
+need	O
+for	O
+further	O
+evaluation	O
+of	O
+cranial	O
+decompression	O
+in	O
+such	O
+patients	O
+is	O
+presented	O
+.	O
+
+Subjective	O
+assessment	O
+of	O
+sexual	B
+dysfunction	I
+of	O
+patients	O
+on	O
+long	O
+-	O
+term	O
+administration	O
+of	O
+digoxin	O
+.	O
+
+Various	O
+data	O
+suggest	O
+that	O
+male	O
+patients	O
+who	O
+have	O
+received	O
+digoxin	O
+on	O
+a	O
+longterm	O
+basis	O
+have	O
+increased	O
+levels	O
+of	O
+serum	O
+estrogen	O
+and	O
+decreased	O
+levels	O
+of	O
+plasma	O
+testosterone	O
+and	O
+luteinizing	O
+hormone	O
+(	O
+LH	O
+)	O
+.	O
+
+This	O
+study	O
+was	O
+undertaken	O
+to	O
+investigate	O
+the	O
+links	O
+between	O
+the	O
+long	O
+-	O
+term	O
+administration	O
+of	O
+digoxin	O
+therapy	O
+and	O
+sexual	O
+behavior	O
+,	O
+and	O
+the	O
+effect	O
+of	O
+digoxin	O
+on	O
+plasma	O
+levels	O
+of	O
+estradiol	O
+,	O
+testosterone	O
+,	O
+and	O
+LH	O
+.	O
+
+The	O
+patients	O
+of	O
+the	O
+study	O
+and	O
+control	O
+group	O
+(	O
+without	O
+digoxin	O
+)	O
+were	O
+of	O
+similar	O
+cardiac	O
+functional	O
+capacity	O
+and	O
+age	O
+(	O
+25	O
+-	O
+40	O
+years	O
+)	O
+and	O
+were	O
+randomly	O
+selected	O
+from	O
+the	O
+rheumatic	B
+heart	I
+disease	I
+patients	O
+.	O
+
+A	O
+subjective	O
+assessment	O
+of	O
+sexual	O
+behavior	O
+in	O
+the	O
+study	O
+and	O
+control	O
+groups	O
+was	O
+carried	O
+out	O
+,	O
+using	O
+parameters	O
+such	O
+as	O
+sexual	O
+desire	O
+,	O
+sexual	O
+excitement	O
+,	O
+and	O
+frequency	O
+of	O
+sexual	O
+relations	O
+.	O
+
+Personal	O
+interviews	O
+and	O
+a	O
+questionnaire	O
+were	O
+also	O
+used	O
+for	O
+the	O
+evaluation	O
+of	O
+sexual	O
+behavior	O
+.	O
+
+The	O
+findings	O
+support	O
+the	O
+reports	O
+concerning	O
+digoxin	O
+effect	O
+on	O
+plasma	O
+estradiol	O
+,	O
+testosterone	O
+,	O
+and	O
+LH	O
+.	O
+
+The	O
+differences	O
+in	O
+the	O
+means	O
+were	O
+significant	O
+.	O
+
+Tests	O
+used	O
+to	O
+evaluate	O
+the	O
+changes	O
+in	O
+sexual	O
+behavior	O
+showed	O
+a	O
+significant	O
+decrease	B
+in	I
+sexual	I
+desire	I
+,	O
+sexual	O
+excitement	O
+phase	O
+(	O
+erection	O
+)	O
+,	O
+and	O
+frequency	O
+of	O
+sexual	O
+relations	O
+in	O
+the	O
+study	O
+group	O
+.	O
+
+Endometrial	B
+carcinoma	I
+after	O
+Hodgkin	B
+disease	I
+in	O
+childhood	O
+.	O
+
+A	O
+34	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+developed	O
+metastic	O
+endometrial	B
+carcinoma	I
+after	O
+Hodgkin	B
+disease	I
+in	O
+childhood	O
+.	O
+
+She	O
+had	O
+ovarian	B
+failure	I
+after	O
+abdominal	O
+irradiation	O
+and	O
+chemotherapy	O
+for	O
+Hodgkin	B
+disease	I
+,	O
+and	O
+received	O
+exogenous	O
+estrogens	O
+,	O
+a	O
+treatment	O
+implicated	O
+in	O
+the	O
+development	O
+of	O
+endometrial	B
+cancer	I
+in	O
+menopausal	O
+women	O
+.	O
+
+Young	O
+women	O
+on	O
+replacement	O
+estrogens	O
+for	O
+ovarian	B
+failure	I
+after	O
+cancer	B
+therapy	O
+may	O
+also	O
+have	O
+increased	O
+risk	O
+of	O
+endometrial	B
+carcinoma	I
+and	O
+should	O
+be	O
+examined	O
+periodically	O
+.	O
+
+Long	O
+-	O
+term	O
+lithium	O
+treatment	O
+and	O
+the	O
+kidney	O
+.	O
+
+Interim	O
+report	O
+on	O
+fifty	O
+patients	O
+.	O
+
+This	O
+is	O
+a	O
+report	O
+on	O
+the	O
+first	O
+part	O
+of	O
+our	O
+study	O
+of	O
+the	O
+effects	O
+of	O
+long	O
+-	O
+term	O
+lithium	O
+treatment	O
+on	O
+the	O
+kidney	O
+.	O
+
+Creatinine	O
+clearance	O
+,	O
+maximum	O
+urinary	O
+osmolality	O
+and	O
+24	O
+hour	O
+urine	O
+volume	O
+have	O
+been	O
+tested	O
+in	O
+50	O
+affectively	O
+ill	O
+patients	O
+who	O
+have	O
+been	O
+on	O
+long	O
+-	O
+term	O
+lithium	O
+for	O
+more	O
+than	O
+one	O
+year	O
+.	O
+
+These	O
+findings	O
+have	O
+been	O
+compared	O
+with	O
+norms	O
+and	O
+with	O
+values	O
+of	O
+the	O
+same	O
+tests	O
+from	O
+screening	O
+prior	O
+to	O
+lithium	O
+,	O
+available	O
+for	O
+most	O
+of	O
+our	O
+patients	O
+.	O
+
+No	O
+evidence	O
+was	O
+found	O
+for	O
+any	O
+reduction	O
+of	O
+glomerular	O
+filtration	O
+during	O
+lithium	O
+treatment	O
+.	O
+
+Low	O
+clearance	O
+values	O
+found	O
+in	O
+several	O
+patients	O
+could	O
+be	O
+accounted	O
+for	O
+by	O
+their	O
+age	O
+and	O
+their	O
+pre	O
+-	O
+lithium	O
+values	O
+.	O
+
+Urinary	O
+concentration	O
+defect	O
+appeared	O
+frequent	O
+but	O
+the	O
+extent	O
+of	O
+the	O
+impairment	O
+is	O
+difficult	O
+to	O
+assess	O
+because	O
+of	O
+the	O
+uncertainty	O
+about	O
+the	O
+norms	O
+applicable	O
+to	O
+this	O
+group	O
+of	O
+patients	O
+.	O
+
+The	O
+concentration	O
+defect	O
+appeared	O
+reversible	O
+,	O
+at	O
+least	O
+in	O
+part	O
+.	O
+
+Polyuria	B
+above	O
+3	O
+litres	O
+/	O
+24	O
+hours	O
+was	O
+found	O
+in	O
+10	O
+%	O
+of	O
+patients	O
+.	O
+
+An	O
+attempt	O
+is	O
+made	O
+to	O
+draw	O
+practical	O
+conclusions	O
+from	O
+the	O
+preliminary	O
+findings	O
+.	O
+
+Nephrotoxicity	B
+of	O
+cyclosporin	O
+A	O
+and	O
+FK506	O
+:	O
+inhibition	O
+of	O
+calcineurin	O
+phosphatase	O
+.	O
+
+Cyclosporin	O
+A	O
+(	O
+CsA	O
+;	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+Fujimycine	O
+(	O
+FK506	O
+;	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+but	O
+not	O
+the	O
+related	O
+macrolide	O
+immunosuppressant	O
+rapamycin	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+caused	O
+a	O
+reduction	O
+of	O
+glomerular	O
+filtration	O
+rate	O
+,	O
+degenerative	O
+changes	O
+of	O
+proximal	O
+tubular	O
+epithelium	O
+,	O
+and	O
+hypertrophy	B
+of	O
+the	O
+juxtaglomerular	O
+apparatus	O
+in	O
+male	O
+Wistar	O
+rats	O
+when	O
+given	O
+for	O
+10	O
+days	O
+.	O
+
+The	O
+molecular	O
+mechanisms	O
+of	O
+CsA	O
+and	O
+FK506	O
+toxicity	B
+were	O
+investigated	O
+.	O
+
+Cyclophilin	O
+A	O
+and	O
+FK506	O
+-	O
+binding	O
+protein	O
+,	O
+the	O
+main	O
+intracytoplasmic	O
+receptors	O
+for	O
+CsA	O
+and	O
+FK506	O
+,	O
+respectively	O
+,	O
+were	O
+each	O
+detected	O
+in	O
+renal	O
+tissue	O
+extract	O
+.	O
+
+In	O
+the	O
+kidney	O
+,	O
+high	O
+levels	O
+of	O
+immunoreactive	O
+and	O
+enzymatically	O
+active	O
+calcineurin	O
+were	O
+found	O
+which	O
+were	O
+inhibited	O
+by	O
+the	O
+immunosuppressants	O
+CsA	O
+and	O
+FK506	O
+,	O
+but	O
+not	O
+by	O
+rapamycin	O
+.	O
+
+Finally	O
+,	O
+specific	O
+immunophilin	O
+-	O
+drug	O
+-	O
+calcineurin	O
+complexes	O
+formed	O
+only	O
+in	O
+the	O
+presence	O
+of	O
+CsA	O
+and	O
+FK506	O
+,	O
+but	O
+not	O
+rapamycin	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+the	O
+nephrotoxic	B
+effects	O
+of	O
+CsA	O
+and	O
+FK506	O
+is	O
+likely	O
+mediated	O
+through	O
+binding	O
+to	O
+renal	O
+immunophilin	O
+and	O
+inhibiting	O
+calcineurin	O
+phosphatase	O
+.	O
+
+Acute	B
+renal	I
+failure	I
+in	O
+high	O
+dose	O
+carboplatin	O
+chemotherapy	O
+.	O
+
+Carboplatin	O
+has	O
+been	O
+reported	O
+to	O
+cause	O
+acute	B
+renal	I
+failure	I
+when	O
+administered	O
+in	O
+high	O
+doses	O
+to	O
+adult	O
+patients	O
+.	O
+
+We	O
+report	O
+a	O
+4	O
+1	O
+/	O
+2	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+who	O
+was	O
+treated	O
+with	O
+high	O
+-	O
+dose	O
+carboplatin	O
+for	O
+metastatic	O
+parameningeal	O
+embryonal	B
+rhabdomyosarcoma	I
+.	O
+
+Acute	B
+renal	I
+failure	I
+developed	O
+followed	O
+by	O
+a	O
+slow	O
+partial	O
+recovery	O
+of	O
+renal	O
+function	O
+.	O
+
+Possible	O
+contributing	O
+factors	O
+are	O
+discussed	O
+.	O
+
+Clinical	O
+evaluation	O
+on	O
+combined	O
+administration	O
+of	O
+oral	O
+prostacyclin	O
+analogue	O
+beraprost	O
+and	O
+phosphodiesterase	O
+inhibitor	O
+cilostazol	O
+.	O
+
+Among	O
+various	O
+oral	O
+antiplatelets	O
+,	O
+a	O
+combination	O
+of	O
+a	O
+novel	O
+prostacyclin	O
+analogue	O
+beraprost	O
+(	O
+BPT	O
+)	O
+and	O
+a	O
+potent	O
+phosphodiesterase	O
+inhibitor	O
+cilostazol	O
+(	O
+CLZ	O
+)	O
+may	O
+result	O
+in	O
+untoward	O
+clinical	O
+effects	O
+due	O
+to	O
+possible	O
+synergistic	O
+elevation	O
+of	O
+intracellular	O
+cAMP	O
+(	O
+cyclic	O
+adenosine	O
+3	O
+'	O
+,	O
+5	O
+'	O
+-	O
+monophosphate	O
+)	O
+.	O
+
+Thereby	O
+,	O
+a	O
+clinical	O
+study	O
+of	O
+the	O
+combined	O
+administration	O
+of	O
+the	O
+two	O
+agents	O
+was	O
+attempted	O
+.	O
+
+Twelve	O
+healthy	O
+volunteers	O
+were	O
+assigned	O
+to	O
+take	O
+BPT	O
+/	O
+CLZ	O
+in	O
+the	O
+following	O
+schedule	O
+;	O
+BPT	O
+:	O
+40	O
+micrograms	O
+at	O
+day	O
+1	O
+and	O
+120	O
+micrograms	O
+t	O
+.	O
+i	O
+.	O
+d	O
+.	O
+from	O
+day	O
+7	O
+to	O
+14	O
+,	O
+CLZ	O
+:	O
+200	O
+mg	O
+t	O
+.	O
+i	O
+.	O
+d	O
+.	O
+from	O
+day	O
+3	O
+to	O
+14	O
+.	O
+
+At	O
+various	O
+time	O
+intervals	O
+,	O
+physical	O
+examination	O
+and	O
+blood	O
+collection	O
+for	O
+ex	O
+vivo	O
+platelet	B
+aggregation	I
+and	O
+determination	O
+of	O
+intraplatelet	O
+cAMP	O
+were	O
+performed	O
+.	O
+
+Throughout	O
+the	O
+observation	O
+period	O
+,	O
+no	O
+significant	O
+alteration	O
+in	O
+vital	O
+signs	O
+was	O
+observed	O
+.	O
+
+Seven	O
+out	O
+of	O
+12	O
+subjects	O
+experienced	O
+headache	B
+of	O
+a	O
+short	O
+duration	O
+accompanying	O
+facial	B
+flush	I
+in	O
+one	O
+and	O
+nausea	B
+in	O
+one	O
+,	O
+especially	O
+after	O
+ingestion	O
+of	O
+CLZ	O
+.	O
+
+All	O
+of	O
+these	O
+symptoms	O
+,	O
+probably	O
+caused	O
+by	O
+the	O
+vasodilating	O
+effect	O
+of	O
+the	O
+two	O
+agents	O
+,	O
+were	O
+of	O
+mild	O
+degree	O
+and	O
+no	O
+special	O
+treatment	O
+was	O
+required	O
+.	O
+
+Intraplatelet	O
+cAMP	O
+content	O
+was	O
+gradually	O
+but	O
+significantly	O
+increased	O
+to	O
+9	O
+.	O
+84	O
++	O
+/	O
+-	O
+4	O
+.	O
+59	O
+pmol	O
+per	O
+10	O
+(	O
+9	O
+)	O
+platelets	O
+at	O
+day	O
+14	O
+in	O
+comparison	O
+with	O
+the	O
+initial	O
+value	O
+(	O
+6	O
+.	O
+87	O
++	O
+/	O
+-	O
+2	O
+.	O
+25	O
+pmol	O
+)	O
+.	O
+
+The	O
+platelet	O
+aggregability	O
+was	O
+significantly	O
+suppressed	O
+at	O
+various	O
+time	O
+intervals	O
+but	O
+no	O
+additive	O
+or	O
+synergistic	O
+inhibitory	O
+effect	O
+by	O
+the	O
+combined	O
+administration	O
+was	O
+noted	O
+.	O
+
+In	O
+conclusion	O
+,	O
+the	O
+combined	O
+administration	O
+of	O
+BPT	O
+/	O
+CLZ	O
+is	O
+safe	O
+at	O
+doses	O
+used	O
+in	O
+the	O
+study	O
+,	O
+though	O
+the	O
+beneficial	O
+clinical	O
+effect	O
+of	O
+the	O
+combined	O
+administration	O
+has	O
+yet	O
+to	O
+be	O
+elucidated	O
+.	O
+
+Pravastatin	O
+-	O
+associated	O
+myopathy	B
+.	O
+
+Report	O
+of	O
+a	O
+case	O
+.	O
+
+A	O
+case	O
+of	O
+acute	O
+inflammatory	B
+myopathy	I
+associated	O
+with	O
+the	O
+use	O
+of	O
+pravastatin	O
+,	O
+a	O
+new	O
+hydrophilic	O
+3	O
+-	O
+hydroxy	O
+-	O
+3	O
+methylglutaril	O
+coenzyme	O
+A	O
+reductase	O
+inhibitor	O
+,	O
+is	O
+reported	O
+.	O
+
+The	O
+patient	O
+,	O
+a	O
+69	O
+-	O
+year	O
+-	O
+old	O
+man	O
+was	O
+affected	O
+by	O
+non	B
+-	I
+insulin	I
+-	I
+dependent	I
+diabetes	I
+mellitus	I
+and	O
+hypertension	B
+.	O
+
+He	O
+assumed	O
+pravastatin	O
+(	O
+20	O
+mg	O
+/	O
+day	O
+)	O
+because	O
+of	O
+hypercholesterolemia	B
+.	O
+
+He	O
+was	O
+admitted	O
+with	O
+acute	O
+myopathy	B
+of	O
+the	O
+lower	O
+limbs	O
+which	O
+resolved	O
+in	O
+a	O
+few	O
+days	O
+after	O
+pravastatin	O
+discontinuation	O
+.	O
+
+A	O
+previously	O
+unknown	O
+hypothyroidism	B
+,	O
+probably	O
+due	O
+to	O
+chronic	O
+autoimmune	B
+thyroiditis	I
+,	O
+was	O
+evidenced	O
+.	O
+
+Muscle	O
+biopsy	O
+(	O
+left	O
+gastrocnemius	O
+)	O
+revealed	O
+a	O
+perimysial	O
+and	O
+endomysial	O
+inflammatory	O
+infiltrate	O
+with	O
+a	O
+prevalence	O
+of	O
+CD4	O
++	O
+lymphocytes	O
+.	O
+
+While	O
+lovastatin	O
+and	O
+simvastatin	O
+have	O
+been	O
+associated	O
+with	O
+toxic	O
+myopathy	B
+,	O
+pravastatin	O
+-	O
+associated	O
+myopathy	B
+could	O
+represent	O
+a	O
+distinct	O
+,	O
+inflammatory	O
+entity	O
+.	O
+
+Reversal	O
+of	O
+ammonia	O
+coma	B
+in	O
+rats	O
+by	O
+L	O
+-	O
+dopa	O
+:	O
+a	O
+peripheral	O
+effect	O
+.	O
+
+Ammonia	O
+coma	B
+was	O
+produced	O
+in	O
+rats	O
+within	O
+10	O
+to	O
+15	O
+minutes	O
+of	O
+an	O
+intraperitonealinjection	O
+of	O
+1	O
+.	O
+7	O
+mmol	O
+NH4CL	O
+.	O
+
+This	O
+coma	B
+was	O
+prevented	O
+with	O
+1	O
+.	O
+68	O
+mmol	O
+L	O
+-	O
+dopa	O
+given	O
+by	O
+gastric	O
+intubation	O
+15	O
+minutes	O
+before	O
+the	O
+ammonium	O
+salt	O
+injection	O
+.	O
+
+The	O
+effect	O
+of	O
+L	O
+-	O
+dopa	O
+was	O
+correlated	O
+with	O
+a	O
+decrease	O
+in	O
+blood	O
+and	O
+brain	O
+ammonia	O
+,	O
+an	O
+increase	O
+in	O
+brain	O
+dopamine	O
+,	O
+and	O
+an	O
+increase	O
+in	O
+renal	O
+excretion	O
+of	O
+ammonia	O
+and	O
+urea	O
+.	O
+
+Intraventricular	O
+infusion	O
+of	O
+dopamine	O
+sufficient	O
+to	O
+raise	O
+the	O
+brain	O
+dopamine	O
+to	O
+the	O
+same	O
+extent	O
+did	O
+not	O
+prevent	O
+the	O
+ammonia	O
+coma	B
+nor	O
+affect	O
+the	O
+blood	O
+and	O
+brain	O
+ammonia	O
+concentrations	O
+.	O
+
+Bilateral	O
+nephrectomy	O
+eliminated	O
+the	O
+beneficial	O
+effect	O
+of	O
+L	O
+-	O
+dopa	O
+on	O
+blood	O
+and	O
+brain	O
+ammonia	O
+and	O
+the	O
+ammonia	O
+coma	B
+was	O
+not	O
+prevented	O
+.	O
+
+Thus	O
+,	O
+the	O
+reduction	O
+in	O
+blood	O
+and	O
+brain	O
+ammonia	O
+and	O
+the	O
+prevention	O
+of	O
+ammonia	O
+coma	B
+after	O
+L	O
+-	O
+dopa	O
+,	O
+can	O
+be	O
+accounted	O
+for	O
+by	O
+the	O
+peripheral	O
+effect	O
+of	O
+dopamine	O
+on	O
+renal	O
+function	O
+rather	O
+than	O
+its	O
+central	O
+action	O
+.	O
+
+These	O
+results	O
+provide	O
+a	O
+reasonable	O
+explanation	O
+for	O
+the	O
+beneficial	O
+effects	O
+observed	O
+in	O
+some	O
+encephalopathic	B
+patients	O
+receiving	O
+L	O
+-	O
+dopa	O
+.	O
+
+Etoposide	O
+-	O
+related	O
+myocardial	B
+infarction	I
+.	O
+
+The	O
+occurrence	O
+of	O
+a	O
+myocardial	B
+infarction	I
+is	O
+reported	O
+after	O
+chemotherapy	O
+containing	O
+etoposide	O
+,	O
+in	O
+a	O
+man	O
+with	O
+no	O
+risk	O
+factors	O
+for	O
+coronary	B
+heart	I
+disease	I
+.	O
+
+Possible	O
+causal	O
+mechanisms	O
+are	O
+discussed	O
+.	O
+
+Halogenated	O
+anesthetics	O
+form	O
+liver	O
+adducts	O
+and	O
+antigens	O
+that	O
+cross	O
+-	O
+react	O
+with	O
+halothane	O
+-	O
+induced	O
+antibodies	O
+.	O
+
+Two	O
+halogenated	O
+anesthetics	O
+,	O
+enflurane	O
+and	O
+isoflurane	O
+,	O
+have	O
+been	O
+associated	O
+with	O
+an	O
+allergic	O
+-	O
+type	O
+hepatic	B
+injury	I
+both	O
+alone	O
+and	O
+following	O
+previous	O
+exposure	O
+to	O
+halothane	O
+.	O
+
+Halothane	O
+hepatitis	B
+appears	O
+to	O
+involve	O
+an	O
+aberrant	O
+immune	O
+response	O
+.	O
+
+An	O
+antibody	O
+response	O
+to	O
+a	O
+protein	O
+-	O
+bound	O
+biotransformation	O
+product	O
+(	O
+trifluoroacetyl	O
+adduct	O
+)	O
+has	O
+been	O
+detected	O
+on	O
+halothane	O
+hepatitis	B
+patients	O
+.	O
+
+This	O
+study	O
+was	O
+performed	O
+to	O
+determine	O
+cross	O
+-	O
+reactivity	O
+between	O
+enflurane	O
+and	O
+isoflurane	O
+with	O
+the	O
+hypersensitivity	B
+induced	O
+by	O
+halothane	O
+.	O
+
+The	O
+subcellular	O
+and	O
+lobular	O
+production	O
+of	O
+hepatic	O
+neoantigens	O
+recognized	O
+by	O
+halothane	O
+-	O
+induced	O
+antibodies	O
+following	O
+enflurane	O
+and	O
+isoflurane	O
+,	O
+and	O
+the	O
+biochemical	O
+nature	O
+of	O
+these	O
+neoantigens	O
+was	O
+investigated	O
+in	O
+two	O
+animal	O
+models	O
+.	O
+
+Enflurane	O
+administration	O
+resulted	O
+in	O
+neoantigens	O
+detected	O
+in	O
+both	O
+the	O
+microsomal	O
+and	O
+cytosolic	O
+fraction	O
+of	O
+liver	O
+homogenates	O
+and	O
+in	O
+the	O
+centrilobular	O
+region	O
+of	O
+the	O
+liver	O
+.	O
+
+In	O
+the	O
+same	O
+liver	O
+,	O
+biochemical	O
+analysis	O
+detected	O
+fluorinated	O
+liver	O
+adducts	O
+that	O
+were	O
+up	O
+to	O
+20	O
+-	O
+fold	O
+greater	O
+in	O
+guinea	O
+pigs	O
+than	O
+in	O
+rats	O
+.	O
+
+This	O
+supports	O
+and	O
+extends	O
+previous	O
+evidence	O
+for	O
+a	O
+mechanism	O
+by	O
+which	O
+enflurane	O
+and	O
+/	O
+or	O
+isoflurane	O
+could	O
+produce	O
+a	O
+hypersensitivity	B
+condition	O
+similar	O
+to	O
+that	O
+of	O
+halothane	O
+hepatitis	B
+either	O
+alone	O
+or	O
+subsequent	O
+to	O
+halothane	O
+administration	O
+.	O
+
+The	O
+guinea	O
+pig	O
+would	O
+appear	O
+to	O
+be	O
+a	O
+useful	O
+model	O
+for	O
+further	O
+investigations	O
+of	O
+the	O
+immunological	O
+response	O
+to	O
+these	O
+antigens	O
+.	O
+
+Cholinergic	O
+toxicity	B
+resulting	O
+from	O
+ocular	O
+instillation	O
+of	O
+echothiophate	O
+iodide	O
+eye	O
+drops	O
+.	O
+
+A	O
+patient	O
+developed	O
+a	O
+severe	O
+cholinergic	O
+syndrome	O
+from	O
+the	O
+use	O
+of	O
+echothiophate	O
+iodide	O
+ophthalmic	O
+drops	O
+,	O
+presented	O
+with	O
+profound	O
+muscle	B
+weakness	I
+and	O
+was	O
+initially	O
+given	O
+the	O
+diagnosis	O
+of	O
+myasthenia	B
+gravis	I
+.	O
+
+Red	O
+blood	O
+cell	O
+and	O
+serum	O
+cholinesterase	O
+levels	O
+were	O
+severely	O
+depressed	O
+and	O
+symptoms	O
+resolved	O
+spontaneously	O
+following	O
+discontinuation	O
+of	O
+the	O
+eye	O
+drops	O
+.	O
+
+Seizure	B
+after	O
+flumazenil	O
+administration	O
+in	O
+a	O
+pediatric	O
+patient	O
+.	O
+
+Flumazenil	O
+is	O
+a	O
+benzodiazepine	O
+receptor	O
+antagonist	O
+used	O
+to	O
+reverse	O
+sedation	O
+and	O
+respiratory	B
+depression	I
+induced	O
+by	O
+benzodiazepines	O
+.	O
+
+Seizures	B
+and	O
+cardiac	B
+arrhythmias	I
+have	O
+complicated	O
+its	O
+use	O
+in	O
+adult	O
+patients	O
+.	O
+
+Overdose	B
+patients	O
+who	O
+have	O
+coingested	O
+tricyclic	O
+antidepressants	O
+have	O
+a	O
+higher	O
+risk	O
+of	O
+these	O
+complications	O
+.	O
+
+Little	O
+information	O
+exists	O
+concerning	O
+adverse	O
+effects	O
+of	O
+flumazenil	O
+in	O
+children	O
+.	O
+
+We	O
+report	O
+the	O
+occurrence	O
+of	O
+a	O
+generalized	O
+tonic	B
+-	I
+clonic	I
+seizure	I
+in	O
+a	O
+pediatric	O
+patient	O
+following	O
+the	O
+administration	O
+of	O
+flumazenil	O
+.	O
+
+Phase	O
+I	O
+trial	O
+of	O
+13	O
+-	O
+cis	O
+-	O
+retinoic	O
+acid	O
+in	O
+children	O
+with	O
+neuroblastoma	B
+following	O
+bone	O
+marrow	O
+transplantation	O
+.	O
+
+PURPOSE	O
+:	O
+Treatment	O
+of	O
+neuroblastoma	B
+cell	O
+lines	O
+with	O
+13	O
+-	O
+cis	O
+-	O
+retinoic	O
+acid	O
+(	O
+cis	O
+-	O
+RA	O
+)	O
+can	O
+cause	O
+sustained	O
+inhibition	O
+of	O
+proliferation	O
+.	O
+
+Since	O
+cis	O
+-	O
+RA	O
+has	O
+demonstrated	O
+clinical	O
+responses	O
+in	O
+neuroblastoma	B
+patients	O
+,	O
+it	O
+may	O
+be	O
+effective	O
+in	O
+preventing	O
+relapse	O
+after	O
+cytotoxic	O
+therapy	O
+.	O
+
+This	O
+phase	O
+I	O
+trial	O
+was	O
+designed	O
+to	O
+determine	O
+the	O
+maximal	O
+-	O
+tolerated	O
+dosage	O
+(	O
+MTD	O
+)	O
+,	O
+toxicities	B
+,	O
+and	O
+pharmacokinetics	O
+of	O
+cis	O
+-	O
+RA	O
+administered	O
+on	O
+an	O
+intermittent	O
+schedule	O
+in	O
+children	O
+with	O
+neuroblastoma	B
+following	O
+bone	O
+marrow	O
+transplantation	O
+(	O
+BMT	O
+)	O
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+Fifty	O
+-	O
+one	O
+assessable	O
+patients	O
+,	O
+2	O
+to	O
+12	O
+years	O
+of	O
+age	O
+,	O
+were	O
+treated	O
+with	O
+oral	O
+cis	O
+-	O
+RA	O
+administered	O
+in	O
+two	O
+equally	O
+divided	O
+doses	O
+daily	O
+for	O
+2	O
+weeks	O
+,	O
+followed	O
+by	O
+a	O
+2	O
+-	O
+week	O
+rest	O
+period	O
+,	O
+for	O
+up	O
+to	O
+12	O
+courses	O
+.	O
+
+The	O
+dose	O
+was	O
+escalated	O
+from	O
+100	O
+to	O
+200	O
+mg	O
+/	O
+m2	O
+/	O
+d	O
+until	O
+dose	O
+-	O
+limiting	O
+toxicity	B
+(	O
+DLT	O
+)	O
+was	O
+observed	O
+.	O
+
+A	O
+single	O
+intrapatient	O
+dose	O
+escalation	O
+was	O
+permitted	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+MTD	O
+of	O
+cis	O
+-	O
+RA	O
+was	O
+160	O
+mg	O
+/	O
+m2	O
+/	O
+d	O
+.	O
+
+Dose	O
+-	O
+limiting	O
+toxicities	B
+in	O
+six	O
+of	O
+nine	O
+patients	O
+at	O
+200	O
+mg	O
+/	O
+m2	O
+/	O
+d	O
+included	O
+hypercalcemia	B
+(	O
+n	O
+=	O
+3	O
+)	O
+,	O
+rash	B
+(	O
+n	O
+=	O
+2	O
+)	O
+,	O
+and	O
+anemia	B
+/	O
+thrombocytopenia	B
+/	O
+emesis	B
+/	O
+rash	B
+(	O
+n	O
+=	O
+1	O
+)	O
+.	O
+
+All	O
+toxicities	B
+resolved	O
+after	O
+cis	O
+-	O
+RA	O
+was	O
+discontinued	O
+.	O
+
+Three	O
+complete	O
+responses	O
+were	O
+observed	O
+in	O
+marrow	O
+metastases	B
+.	O
+
+Serum	O
+levels	O
+of	O
+7	O
+.	O
+4	O
++	O
+/	O
+-	O
+3	O
+.	O
+0	O
+mumol	O
+/	O
+L	O
+(	O
+peak	O
+)	O
+and	O
+4	O
+.	O
+0	O
++	O
+/	O
+-	O
+2	O
+.	O
+8	O
+mumol	O
+/	O
+L	O
+(	O
+trough	O
+)	O
+at	O
+the	O
+MTD	O
+were	O
+maintained	O
+during	O
+14	O
+days	O
+of	O
+therapy	O
+.	O
+
+The	O
+DLT	O
+correlated	O
+with	O
+serum	O
+levels	O
+>	O
+or	O
+=	O
+10	O
+mumol	O
+/	O
+L	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+MTD	O
+of	O
+cis	O
+-	O
+RA	O
+given	O
+on	O
+this	O
+intermittent	O
+schedule	O
+was	O
+160	O
+mg	O
+/	O
+m2	O
+/	O
+d	O
+.	O
+
+Serum	O
+levels	O
+known	O
+to	O
+be	O
+effective	O
+against	O
+neuroblastoma	B
+in	O
+vitro	O
+were	O
+achieved	O
+at	O
+this	O
+dose	O
+.	O
+
+The	O
+DLT	O
+included	O
+hypercalcemia	B
+,	O
+and	O
+may	O
+be	O
+predicted	O
+by	O
+serum	O
+cis	O
+-	O
+RA	O
+levels	O
+.	O
+
+Monitoring	O
+of	O
+serum	O
+calcium	O
+and	O
+cis	O
+-	O
+RA	O
+levels	O
+is	O
+indicated	O
+in	O
+future	O
+trials	O
+.	O
+
+Time	O
+dependence	O
+of	O
+plasma	O
+malondialdehyde	O
+,	O
+oxypurines	O
+,	O
+and	O
+nucleosides	O
+during	O
+incomplete	O
+cerebral	B
+ischemia	I
+in	O
+the	O
+rat	O
+.	O
+
+Incomplete	O
+cerebral	B
+ischemia	I
+(	O
+30	O
+min	O
+)	O
+was	O
+induced	O
+in	O
+the	O
+rat	O
+by	O
+bilaterally	O
+clamping	O
+the	O
+common	O
+carotid	O
+arteries	O
+.	O
+
+Peripheral	O
+venous	O
+blood	O
+samples	O
+were	O
+withdrawn	O
+from	O
+the	O
+femoral	O
+vein	O
+four	O
+times	O
+(	O
+once	O
+every	O
+5	O
+min	O
+)	O
+before	O
+ischemia	B
+(	O
+0	O
+time	O
+)	O
+and	O
+5	O
+,	O
+15	O
+,	O
+and	O
+30	O
+min	O
+after	O
+ischemia	B
+.	O
+
+Plasma	O
+extracts	O
+were	O
+analyzed	O
+by	O
+a	O
+highly	O
+sensitive	O
+high	O
+-	O
+performance	O
+liquid	O
+chromatographic	O
+method	O
+for	O
+the	O
+direct	O
+determination	O
+of	O
+malondialdehyde	O
+,	O
+oxypurines	O
+,	O
+and	O
+nucleosides	O
+.	O
+
+During	O
+ischemia	B
+,	O
+a	O
+time	O
+-	O
+dependent	O
+increase	O
+of	O
+plasma	O
+oxypurines	O
+and	O
+nucleosides	O
+was	O
+observed	O
+.	O
+
+Plasma	O
+malondialdehyde	O
+,	O
+which	O
+was	O
+present	O
+in	O
+minimal	O
+amount	O
+at	O
+zero	O
+time	O
+(	O
+0	O
+.	O
+058	O
+mumol	O
+/	O
+liter	O
+plasma	O
+;	O
+SD	O
+0	O
+.	O
+015	O
+)	O
+,	O
+increased	O
+after	O
+5	O
+min	O
+of	O
+ischemia	B
+,	O
+resulting	O
+in	O
+a	O
+fivefold	O
+increase	O
+after	O
+30	O
+min	O
+of	O
+carotid	O
+occlusion	O
+(	O
+0	O
+.	O
+298	O
+mumol	O
+/	O
+liter	O
+plasma	O
+;	O
+SD	O
+0	O
+.	O
+078	O
+)	O
+.	O
+
+Increased	O
+plasma	O
+malondialdehyde	O
+was	O
+also	O
+recorded	O
+in	O
+two	O
+other	O
+groups	O
+of	O
+animals	O
+subjected	O
+to	O
+the	O
+same	O
+experimental	O
+model	O
+,	O
+one	O
+receiving	O
+20	O
+mg	O
+/	O
+kg	O
+b	O
+.	O
+w	O
+.	O
+of	O
+the	O
+cyclooxygenase	O
+inhibitor	O
+acetylsalicylate	O
+intravenously	O
+immediately	O
+before	O
+ischemia	B
+,	O
+the	O
+other	O
+receiving	O
+650	O
+micrograms	O
+/	O
+kg	O
+b	O
+.	O
+w	O
+.	O
+of	O
+the	O
+hypotensive	B
+drug	O
+nitroprusside	O
+at	O
+a	O
+flow	O
+rate	O
+of	O
+103	O
+microliters	O
+/	O
+min	O
+intravenously	O
+during	O
+ischemia	B
+,	O
+although	O
+in	O
+this	O
+latter	O
+group	O
+malondialdehyde	O
+was	O
+significantly	O
+higher	O
+.	O
+
+The	O
+present	O
+data	O
+indicate	O
+that	O
+the	O
+determination	O
+of	O
+malondialdehyde	O
+,	O
+oxypurines	O
+,	O
+and	O
+nucleosides	O
+in	O
+peripheral	O
+blood	O
+,	O
+may	O
+be	O
+used	O
+to	O
+monitor	O
+the	O
+metabolic	O
+alterations	O
+of	O
+tissues	O
+occurring	O
+during	O
+ischemic	B
+phenomena	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Acute	O
+renal	B
+toxicity	I
+of	O
+doxorubicin	O
+(	O
+adriamycin	O
+)	O
+-	O
+loaded	O
+cyanoacrylate	O
+nanoparticles	O
+.	O
+
+Acute	O
+doxorubicin	O
+-	O
+loaded	O
+nanoparticle	O
+(	O
+DXNP	O
+)	O
+renal	B
+toxicity	I
+was	O
+explored	O
+in	O
+both	O
+normal	O
+rats	O
+and	O
+rats	O
+with	O
+experimental	O
+glomerulonephritis	B
+.	O
+
+In	O
+normal	O
+rats	O
+,	O
+2	O
+/	O
+6	O
+rats	O
+given	O
+free	O
+doxorubicin	O
+(	O
+DX	O
+)	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+died	O
+within	O
+one	O
+week	O
+,	O
+whereas	O
+all	O
+control	O
+animals	O
+and	O
+all	O
+rats	O
+having	O
+received	O
+free	O
+NP	O
+or	O
+DXNP	O
+survived	O
+.	O
+
+A	O
+3	O
+times	O
+higher	O
+proteinuria	B
+appeared	O
+in	O
+animals	O
+treated	O
+with	O
+DXNP	O
+than	O
+in	O
+those	O
+treated	O
+with	O
+DX	O
+.	O
+
+Free	O
+NP	O
+did	O
+not	O
+provoke	O
+any	O
+proteinuria	B
+.	O
+
+Two	O
+hr	O
+post	O
+-	O
+injection	O
+,	O
+DXNP	O
+was	O
+2	O
+.	O
+7	O
+times	O
+more	O
+concentrated	O
+in	O
+kidneys	O
+than	O
+free	O
+DX	O
+(	O
+p	O
+<	O
+0	O
+.	O
+025	O
+)	O
+.	O
+
+In	O
+rats	O
+with	O
+immune	O
+experimental	O
+glomerulonephritis	B
+,	O
+5	O
+/	O
+6	O
+rats	O
+given	O
+DX	O
+died	O
+within	O
+7	O
+days	O
+,	O
+in	O
+contrast	O
+to	O
+animals	O
+treated	O
+by	O
+DXNP	O
+,	O
+NP	O
+,	O
+or	O
+untreated	O
+,	O
+which	O
+all	O
+survived	O
+.	O
+
+Proteinuria	B
+appeared	O
+in	O
+all	O
+series	O
+,	O
+but	O
+was	O
+2	O
+-	O
+5	O
+times	O
+more	O
+intense	O
+(	O
+p	O
+>	O
+0	O
+.	O
+001	O
+)	O
+and	O
+prolonged	O
+after	O
+doxorubicin	O
+treatment	O
+(	O
+400	O
+-	O
+700	O
+mg	O
+/	O
+day	O
+)	O
+,	O
+without	O
+significant	O
+difference	O
+between	O
+DXNP	O
+and	O
+DX	O
+.	O
+
+Rats	O
+treated	O
+by	O
+unloaded	O
+NP	O
+behaved	O
+as	O
+controls	O
+.	O
+
+These	O
+results	O
+demonstrate	O
+that	O
+,	O
+in	O
+these	O
+experimental	O
+conditions	O
+,	O
+DXNP	O
+killed	O
+less	O
+animals	O
+than	O
+free	O
+DX	O
+,	O
+despite	O
+of	O
+an	O
+enhanced	O
+renal	B
+toxicity	I
+of	O
+the	O
+former	O
+.	O
+
+Both	O
+effects	O
+(	O
+better	O
+survival	O
+and	O
+nephrosis	B
+)	O
+are	O
+most	O
+probably	O
+related	O
+to	O
+an	O
+enhanced	O
+capture	O
+of	O
+DXNP	O
+by	O
+cells	O
+of	O
+the	O
+mononuclear	O
+phagocyte	O
+system	O
+,	O
+including	O
+mesangial	O
+cells	O
+.	O
+
+Prostaglandin	O
+E2	O
+-	O
+induced	O
+bladder	B
+hyperactivity	I
+in	O
+normal	O
+,	O
+conscious	O
+rats	O
+:	O
+involvement	O
+of	O
+tachykinins	O
+?	O
+
+In	O
+normal	O
+conscious	O
+rats	O
+investigated	O
+by	O
+continuous	O
+cystometry	O
+,	O
+intravesically	O
+instilled	O
+prostaglandin	O
+(	O
+PG	O
+)	O
+E2	O
+facilitated	O
+micturition	O
+and	O
+increased	O
+basal	O
+intravesical	O
+pressure	O
+.	O
+
+The	O
+effect	O
+was	O
+attenuated	O
+by	O
+both	O
+the	O
+NK1	O
+receptor	O
+selective	O
+antagonist	O
+RP	O
+67	O
+,	O
+580	O
+and	O
+the	O
+NK2	O
+receptor	O
+selective	O
+antagonist	O
+SR	O
+48	O
+,	O
+968	O
+,	O
+given	O
+intra	O
+-	O
+arterially	O
+,	O
+suggesting	O
+that	O
+it	O
+was	O
+mediated	O
+by	O
+stimulation	O
+of	O
+both	O
+NK1	O
+and	O
+NK2	O
+receptors	O
+.	O
+
+Intra	O
+-	O
+arterially	O
+given	O
+PGE2	O
+produced	O
+a	O
+distinct	O
+increase	O
+in	O
+bladder	O
+pressure	O
+before	O
+initiating	O
+a	O
+micturition	O
+reflex	O
+,	O
+indicating	O
+that	O
+the	O
+PG	O
+had	O
+a	O
+direct	O
+contractant	O
+effect	O
+on	O
+the	O
+detrusor	O
+smooth	O
+muscle	O
+.	O
+
+The	O
+effect	O
+of	O
+intra	O
+-	O
+arterial	O
+PGE2	O
+could	O
+not	O
+be	O
+blocked	O
+by	O
+intra	O
+-	O
+arterial	O
+RP	O
+67	O
+,	O
+580	O
+or	O
+SR	O
+48	O
+,	O
+968	O
+,	O
+which	O
+opens	O
+the	O
+possibility	O
+that	O
+the	O
+micturition	O
+reflex	O
+elicited	O
+by	O
+intra	O
+-	O
+arterial	O
+PGE2	O
+was	O
+mediated	O
+by	O
+pathways	O
+other	O
+than	O
+the	O
+reflex	O
+initiated	O
+when	O
+the	O
+PG	O
+was	O
+given	O
+intravesically	O
+.	O
+
+The	O
+present	O
+results	O
+thus	O
+suggest	O
+that	O
+intra	O
+-	O
+arterial	O
+PGE2	O
+,	O
+given	O
+near	O
+the	O
+bladder	O
+,	O
+may	O
+initiate	O
+micturition	O
+in	O
+the	O
+normal	O
+rat	O
+chiefly	O
+by	O
+directly	O
+contracting	O
+the	O
+smooth	O
+muscle	O
+of	O
+the	O
+detrusor	O
+.	O
+
+However	O
+,	O
+when	O
+given	O
+intravesically	O
+,	O
+PGE2	O
+may	O
+stimulate	O
+micturition	O
+by	O
+releasing	O
+tachykinins	O
+from	O
+nerves	O
+in	O
+and	O
+/	O
+or	O
+immediately	O
+below	O
+the	O
+urothelium	O
+.	O
+
+These	O
+tachykinins	O
+,	O
+in	O
+turn	O
+,	O
+initiate	O
+a	O
+micturition	O
+reflex	O
+by	O
+stimulating	O
+NK1	O
+and	O
+NK2	O
+receptors	O
+.	O
+
+Prostanoids	O
+may	O
+,	O
+via	O
+release	O
+of	O
+tachykinins	O
+,	O
+contribute	O
+to	O
+both	O
+urge	O
+and	O
+bladder	B
+hyperactivity	I
+seen	O
+in	O
+inflammatory	O
+conditions	O
+of	O
+the	O
+lower	O
+urinary	O
+tract	O
+.	O
+
+Refractory	O
+cardiogenic	B
+shock	I
+and	O
+complete	O
+heart	B
+block	I
+after	O
+verapamil	O
+SR	O
+and	O
+metoprolol	O
+treatment	O
+.	O
+
+A	O
+case	O
+report	O
+.	O
+
+A	O
+seventy	O
+-	O
+eight	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+presented	O
+with	O
+complete	O
+heart	B
+block	I
+and	O
+refractory	O
+hypotension	B
+two	O
+days	O
+after	O
+a	O
+therapeutic	O
+dose	O
+of	O
+sustained	O
+-	O
+release	O
+verapamil	O
+with	O
+concomitant	O
+use	O
+of	O
+metoprolol	O
+.	O
+
+The	O
+patient	O
+continued	O
+to	O
+remain	O
+hypotensive	B
+with	O
+complete	O
+heart	B
+block	I
+,	O
+even	O
+with	O
+multiple	O
+uses	O
+of	O
+intravenous	O
+atropine	O
+as	O
+well	O
+as	O
+high	O
+doses	O
+of	O
+pressor	O
+agents	O
+such	O
+as	O
+dopamine	O
+and	O
+dobutamine	O
+.	O
+
+However	O
+,	O
+shortly	O
+after	O
+the	O
+use	O
+of	O
+intravenous	O
+calcium	O
+chloride	O
+,	O
+the	O
+refractory	O
+hypotension	B
+and	O
+complete	O
+heart	B
+block	I
+resolved	O
+.	O
+
+Protective	O
+effect	O
+of	O
+misoprostol	O
+on	O
+indomethacin	O
+induced	O
+renal	B
+dysfunction	I
+in	O
+elderly	O
+patients	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+evaluate	O
+the	O
+possible	O
+protective	O
+effects	O
+of	O
+misoprostol	O
+on	O
+renal	O
+function	O
+in	O
+hospitalized	O
+elderly	O
+patients	O
+treated	O
+with	O
+indomethacin	O
+.	O
+
+METHODS	O
+:	O
+Forty	O
+-	O
+five	O
+hospitalized	O
+elderly	O
+patients	O
+(	O
+>	O
+65	O
+years	O
+old	O
+)	O
+who	O
+required	O
+therapy	O
+with	O
+nonsteroidal	O
+antiinflammatory	O
+drugs	O
+(	O
+NSAID	O
+)	O
+were	O
+randomly	O
+assigned	O
+to	O
+receive	O
+either	O
+indomethacin	O
+,	O
+150	O
+mg	O
+/	O
+day	O
+(	O
+Group	O
+A	O
+)	O
+,	O
+or	O
+indomethacin	O
+150	O
+mg	O
+/	O
+day	O
+plus	O
+misoprostol	O
+at	O
+0	O
+.	O
+6	O
+mg	O
+/	O
+day	O
+(	O
+Group	O
+B	O
+)	O
+.	O
+
+Laboratory	O
+variables	O
+of	O
+renal	O
+function	O
+[	O
+serum	O
+creatinine	O
+,	O
+blood	O
+urea	O
+nitrogen	O
+(	O
+BUN	O
+)	O
+and	O
+electrolytes	O
+]	O
+were	O
+evaluated	O
+before	O
+initiation	O
+of	O
+therapy	O
+and	O
+every	O
+2	O
+days	O
+,	O
+until	O
+termination	O
+of	O
+the	O
+study	O
+(	O
+a	O
+period	O
+of	O
+at	O
+least	O
+6	O
+days	O
+)	O
+.	O
+
+Response	O
+to	O
+treatment	O
+was	O
+estimated	O
+by	O
+the	O
+visual	O
+analog	O
+scale	O
+for	O
+severity	O
+of	O
+pain	B
+.	O
+
+RESULTS	O
+:	O
+Forty	O
+-	O
+two	O
+patients	O
+completed	O
+the	O
+study	O
+,	O
+22	O
+in	O
+Group	O
+A	O
+and	O
+20	O
+in	O
+Group	O
+B	O
+.	O
+
+BUN	O
+and	O
+creatinine	O
+increased	O
+by	O
+>	O
+50	O
+%	O
+of	O
+baseline	O
+levels	O
+in	O
+54	O
+and	O
+45	O
+%	O
+of	O
+Group	O
+A	O
+patients	O
+,	O
+respectively	O
+,	O
+compared	O
+to	O
+only	O
+20	O
+and	O
+10	O
+%	O
+of	O
+Group	O
+B	O
+patients	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Potassium	O
+(	O
+K	O
+)	O
+increment	O
+of	O
+0	O
+.	O
+6	O
+mEq	O
+/	O
+l	O
+or	O
+more	O
+was	O
+observed	O
+in	O
+50	O
+%	O
+of	O
+Group	O
+A	O
+,	O
+but	O
+in	O
+only	O
+15	O
+%	O
+of	O
+Group	O
+B	O
+patients	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+mean	O
+increments	O
+in	O
+BUN	O
+,	O
+creatinine	O
+,	O
+and	O
+K	O
+were	O
+reduced	O
+by	O
+63	O
+,	O
+80	O
+,	O
+and	O
+42	O
+%	O
+,	O
+respectively	O
+,	O
+in	O
+Group	O
+B	O
+patients	O
+compared	O
+to	O
+Group	O
+A	O
+.	O
+Response	O
+to	O
+treatment	O
+did	O
+not	O
+differ	O
+significantly	O
+between	O
+the	O
+2	O
+groups	O
+.	O
+
+CONCLUSION	O
+:	O
+Hospitalized	O
+elderly	O
+patients	O
+are	O
+at	O
+risk	O
+for	O
+developing	O
+indomethacin	O
+related	O
+renal	B
+dysfunction	I
+.	O
+
+Addition	O
+of	O
+misoprostol	O
+can	O
+minimize	O
+this	O
+renal	B
+impairment	I
+without	O
+affecting	O
+pain	B
+control	O
+.	O
+
+Cognitive	B
+deterioration	I
+from	O
+long	O
+-	O
+term	O
+abuse	O
+of	O
+dextromethorphan	O
+:	O
+a	O
+case	O
+report	O
+.	O
+
+Dextromethorphan	O
+(	O
+DM	O
+)	O
+,	O
+the	O
+dextrorotatory	O
+isomer	O
+of	O
+3	O
+-	O
+hydroxy	O
+-	O
+N	O
+-	O
+methylmorphinan	O
+,	O
+is	O
+the	O
+main	O
+ingredient	O
+in	O
+a	O
+number	O
+of	O
+widely	O
+available	O
+,	O
+over	O
+-	O
+the	O
+-	O
+counter	O
+antitussives	O
+.	O
+
+Initial	O
+studies	O
+(	O
+Bornstein	O
+1968	O
+)	O
+showed	O
+that	O
+it	O
+possessed	O
+no	O
+respiratory	O
+suppressant	O
+effects	O
+and	O
+no	O
+addiction	O
+liability	O
+.	O
+
+Subsequently	O
+,	O
+however	O
+,	O
+several	O
+articles	O
+reporting	O
+abuse	O
+of	O
+this	O
+drug	O
+have	O
+appeared	O
+in	O
+the	O
+literature	O
+.	O
+
+The	O
+drug	O
+is	O
+known	O
+to	O
+cause	O
+a	O
+variety	O
+of	O
+acute	O
+toxic	O
+effects	O
+,	O
+ranging	O
+from	O
+nausea	B
+,	O
+restlessness	B
+,	O
+insomnia	B
+,	O
+ataxia	B
+,	O
+slurred	O
+speech	O
+and	O
+nystagmus	B
+to	O
+mood	O
+changes	O
+,	O
+perceptual	O
+alterations	O
+,	O
+inattention	O
+,	O
+disorientation	O
+and	O
+aggressive	B
+behavior	I
+(	O
+Rammer	O
+et	O
+al	O
+1988	O
+;	O
+Katona	O
+and	O
+Watson	O
+1986	O
+;	O
+Isbell	O
+and	O
+Fraser	O
+1953	O
+;	O
+Devlin	O
+et	O
+al	O
+1985	O
+;	O
+McCarthy	O
+1971	O
+;	O
+Dodds	O
+and	O
+Revai	O
+1967	O
+;	O
+Degkwitz	O
+1964	O
+;	O
+Hildebrand	O
+et	O
+al	O
+1989	O
+)	O
+.	O
+
+There	O
+have	O
+also	O
+been	O
+two	O
+reported	O
+fatalities	O
+from	O
+DM	O
+overdoses	O
+(	O
+Fleming	O
+1986	O
+)	O
+.	O
+
+However	O
+,	O
+there	O
+are	O
+no	O
+reports	O
+describing	O
+the	O
+effects	O
+of	O
+chronic	O
+abuse	O
+.	O
+
+This	O
+report	O
+describes	O
+a	O
+case	O
+of	O
+cognitive	B
+deterioration	I
+resulting	O
+from	O
+prolonged	O
+use	O
+of	O
+DM	O
+.	O
+
+Effects	O
+of	O
+ouabain	O
+on	O
+myocardial	O
+oxygen	O
+supply	O
+and	O
+demand	O
+in	O
+patients	O
+with	O
+chronic	O
+coronary	B
+artery	I
+disease	I
+.	O
+
+A	O
+hemodynamic	O
+,	O
+volumetric	O
+,	O
+and	O
+metabolic	O
+study	O
+in	O
+patients	O
+without	O
+heart	B
+failure	I
+.	O
+
+The	O
+effects	O
+of	O
+digitalis	O
+glycosides	O
+on	O
+myocardial	O
+oxygen	O
+supply	O
+and	O
+demand	O
+are	O
+of	O
+particular	O
+interest	O
+in	O
+the	O
+presence	O
+of	O
+obstructive	O
+coronary	B
+artery	I
+disease	I
+,	O
+but	O
+have	O
+not	O
+been	O
+measured	O
+previously	O
+in	O
+man	O
+.	O
+
+We	O
+assessed	O
+the	O
+effects	O
+of	O
+ouabain	O
+(	O
+0	O
+.	O
+015	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+)	O
+on	O
+hemodynamic	O
+,	O
+volumetric	O
+,	O
+and	O
+metabolic	O
+parameters	O
+in	O
+11	O
+patients	O
+with	O
+severe	O
+chronic	O
+coronary	B
+artery	I
+disease	I
+without	O
+clinical	O
+congestive	B
+heart	I
+failure	I
+.	O
+
+Because	O
+the	O
+protocol	O
+was	O
+long	O
+and	O
+involved	O
+interventions	O
+which	O
+might	O
+affect	O
+the	O
+determinations	O
+,	O
+we	O
+also	O
+studied	O
+in	O
+nine	O
+patients	O
+using	O
+an	O
+identical	O
+protocol	O
+except	O
+that	O
+ouabain	O
+administration	O
+was	O
+omitted	O
+.	O
+
+Left	O
+ventricular	O
+end	O
+-	O
+diastolic	O
+pressure	O
+and	O
+left	O
+ventricular	O
+end	O
+-	O
+diastolic	O
+volume	O
+fell	O
+in	O
+each	O
+patient	O
+given	O
+ouabain	O
+,	O
+even	O
+though	O
+they	O
+were	O
+initially	O
+elevated	O
+in	O
+only	O
+two	O
+patients	O
+.	O
+
+Left	O
+ventricular	O
+end	O
+-	O
+diastolic	O
+pressure	O
+fell	O
+from	O
+11	O
+.	O
+5	O
++	O
+/	O
+-	O
+1	O
+.	O
+4	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SE	O
+)	O
+to	O
+5	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+9	O
+mm	O
+Hg	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+and	O
+left	O
+ventricular	O
+end	O
+-	O
+diastolic	O
+volume	O
+fell	O
+from	O
+100	O
++	O
+/	O
+-	O
+17	O
+to	O
+82	O
++	O
+/	O
+-	O
+12	O
+ml	O
+/	O
+m2	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+1	O
+h	O
+after	O
+ouabain	O
+infusion	O
+was	O
+completed	O
+.	O
+
+The	O
+maximum	O
+velocity	O
+of	O
+contractile	O
+element	O
+shortening	O
+increased	O
+from	O
+1	O
+.	O
+68	O
++	O
+/	O
+-	O
+0	O
+.	O
+11	O
+ml	O
+/	O
+s	O
+to	O
+2	O
+.	O
+18	O
++	O
+/	O
+-	O
+0	O
+.	O
+21	O
+muscle	O
+-	O
+lengths	O
+/	O
+s	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+and	O
+is	O
+consistent	O
+with	O
+an	O
+increase	O
+in	O
+contractility	O
+.	O
+
+No	O
+significant	O
+change	O
+in	O
+these	O
+parameters	O
+occurred	O
+in	O
+the	O
+control	O
+patients	O
+.	O
+
+No	O
+significant	O
+change	O
+in	O
+myocardial	O
+oxygen	O
+consumption	O
+occurred	O
+after	O
+ouabain	O
+administration	O
+but	O
+this	O
+may	O
+be	O
+related	O
+to	O
+a	O
+greater	O
+decrease	O
+in	O
+mean	O
+arterial	O
+pressure	O
+in	O
+the	O
+ouabain	O
+patients	O
+than	O
+in	O
+the	O
+control	O
+patients	O
+.	O
+
+We	O
+conclude	O
+that	O
+in	O
+patients	O
+with	O
+chronic	O
+coronary	B
+artery	I
+disease	I
+who	O
+are	O
+not	O
+in	O
+clinical	O
+congestive	B
+heart	I
+failure	I
+left	B
+ventricular	I
+end	I
+-	I
+diastolic	I
+volume	I
+falls	I
+after	O
+ouabain	O
+administration	O
+even	O
+when	O
+it	O
+is	O
+initially	O
+normal	O
+.	O
+
+Though	O
+this	O
+fall	O
+would	O
+be	O
+associated	O
+with	O
+a	O
+decrease	O
+in	O
+wall	O
+tension	O
+,	O
+and	O
+,	O
+therefore	O
+,	O
+of	O
+myocardial	O
+oxygen	O
+consumption	O
+,	O
+it	O
+may	O
+not	O
+be	O
+of	O
+sufficient	O
+magnitude	O
+to	O
+prevent	O
+a	O
+net	O
+increase	O
+in	O
+myocardial	O
+oxygen	O
+consumption	O
+.	O
+
+Nevertheless	O
+,	O
+compensatory	O
+mechanisms	O
+prevent	O
+a	O
+deterioration	O
+of	O
+resting	O
+myocardial	O
+metabolism	O
+.	O
+
+Dexamethasone	O
+-	O
+induced	O
+ocular	B
+hypertension	I
+in	O
+perfusion	O
+-	O
+cultured	O
+human	O
+eyes	O
+.	O
+
+PURPOSE	O
+:	O
+Glucocorticoid	O
+administration	O
+can	O
+lead	O
+to	O
+the	O
+development	O
+of	O
+ocular	B
+hypertension	I
+and	O
+corticosteroid	B
+glaucoma	I
+in	O
+a	O
+subset	O
+of	O
+the	O
+population	O
+through	O
+a	O
+decrease	O
+in	O
+the	O
+aqueous	O
+humor	O
+outflow	O
+facility	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+whether	O
+glucocorticoid	O
+treatment	O
+can	O
+directly	O
+affect	O
+the	O
+outflow	O
+facility	O
+of	O
+isolated	O
+,	O
+perfusion	O
+-	O
+cultured	O
+human	O
+eyes	O
+.	O
+
+METHODS	O
+:	O
+The	O
+anterior	O
+segments	O
+of	O
+human	O
+donor	O
+eyes	O
+from	O
+regional	O
+eye	O
+banks	O
+were	O
+placed	O
+in	O
+a	O
+constant	O
+flow	O
+,	O
+variable	O
+pressure	O
+perfusion	O
+culture	O
+system	O
+.	O
+
+Paired	O
+eyes	O
+were	O
+perfused	O
+in	O
+serum	O
+-	O
+free	O
+media	O
+with	O
+or	O
+without	O
+10	O
+(	O
+-	O
+7	O
+)	O
+M	O
+dexamethasone	O
+for	O
+12	O
+days	O
+.	O
+
+Intraocular	O
+pressure	O
+was	O
+monitored	O
+daily	O
+.	O
+
+After	O
+incubation	O
+,	O
+the	O
+eyes	O
+were	O
+morphologically	O
+characterized	O
+by	O
+light	O
+microscopy	O
+,	O
+transmission	O
+and	O
+scanning	O
+electron	O
+microscopy	O
+,	O
+and	O
+scanning	O
+laser	O
+confocal	O
+microscopy	O
+.	O
+
+RESULTS	O
+:	O
+A	O
+significant	O
+increase	O
+in	O
+intraocular	O
+pressure	O
+developed	O
+in	O
+13	O
+of	O
+the	O
+44	O
+pairs	O
+of	O
+eyes	O
+perfused	O
+with	O
+dexamethasone	O
+with	O
+an	O
+average	O
+pressure	O
+rise	O
+of	O
+17	O
+.	O
+5	O
++	O
+/	O
+-	O
+3	O
+.	O
+8	O
+mm	O
+Hg	O
+after	O
+12	O
+days	O
+of	O
+dexamethasone	O
+exposure	O
+.	O
+
+The	O
+contralateral	O
+control	O
+eyes	O
+,	O
+which	O
+did	O
+not	O
+receive	O
+dexamethasone	O
+,	O
+maintained	O
+a	O
+stable	O
+intraocular	O
+pressure	O
+during	O
+the	O
+same	O
+period	O
+.	O
+
+The	O
+outflow	O
+pathway	O
+of	O
+the	O
+untreated	O
+eyes	O
+appeared	O
+morphologically	O
+normal	O
+.	O
+
+In	O
+contrast	O
+,	O
+the	O
+dexamethasone	O
+-	O
+treated	O
+hypertensive	B
+eyes	I
+had	O
+thickened	O
+trabecular	O
+beams	O
+,	O
+decreased	O
+intertrabecular	O
+spaces	O
+,	O
+thickened	O
+juxtacanalicular	O
+tissue	O
+,	O
+activated	O
+trabecular	O
+meshwork	O
+cells	O
+,	O
+and	O
+increased	O
+amounts	O
+of	O
+amorphogranular	O
+extracellular	O
+material	O
+,	O
+especially	O
+in	O
+the	O
+juxtacanalicular	O
+tissue	O
+and	O
+beneath	O
+the	O
+endothelial	O
+lining	O
+of	O
+the	O
+canal	O
+of	O
+Schlemm	O
+.	O
+
+The	O
+dexamethasone	O
+-	O
+treated	O
+nonresponder	O
+eyes	O
+appeared	O
+to	O
+be	O
+morphologically	O
+similar	O
+to	O
+the	O
+untreated	O
+eyes	O
+,	O
+although	O
+several	O
+subtle	O
+dexamethasone	O
+-	O
+induced	O
+morphologic	O
+changes	O
+were	O
+evident	O
+.	O
+
+CONCLUSION	O
+:	O
+Dexamethasone	O
+treatment	O
+of	O
+isolated	O
+,	O
+perfusion	O
+-	O
+cultured	O
+human	O
+eyes	O
+led	O
+to	O
+the	O
+generation	O
+of	O
+ocular	B
+hypertension	I
+in	O
+approximately	O
+30	O
+%	O
+of	O
+the	O
+dexamethasone	O
+-	O
+treated	O
+eyes	O
+.	O
+
+Steroid	O
+treatment	O
+resulted	O
+in	O
+morphologic	O
+changes	O
+in	O
+the	O
+trabecular	O
+meshwork	O
+similar	O
+to	O
+those	O
+reported	O
+for	O
+corticosteroid	B
+glaucoma	I
+and	O
+open	B
+angle	I
+glaucoma	I
+.	O
+
+This	O
+system	O
+may	O
+provide	O
+an	O
+acute	O
+model	O
+in	O
+which	O
+to	O
+study	O
+the	O
+pathogenic	O
+mechanisms	O
+involved	O
+in	O
+steroid	B
+glaucoma	I
+and	O
+primary	B
+open	I
+angle	I
+glaucoma	I
+.	O
+
+Auditory	O
+disturbance	O
+associated	O
+with	O
+interscalene	O
+brachial	O
+plexus	O
+block	O
+.	O
+
+We	O
+performed	O
+an	O
+audiometric	O
+study	O
+in	O
+20	O
+patients	O
+who	O
+underwent	O
+surgery	O
+of	O
+the	O
+shoulder	O
+region	O
+under	O
+an	O
+interscalene	O
+brachial	O
+plexus	O
+block	O
+(	O
+IBPB	O
+)	O
+.	O
+
+Bupivacaine	O
+0	O
+.	O
+75	O
+%	O
+with	O
+adrenaline	O
+was	O
+given	O
+followed	O
+by	O
+a	O
+24	O
+-	O
+hr	O
+continuous	O
+infusion	O
+of	O
+0	O
+.	O
+25	O
+%	O
+bupivacaine	O
+.	O
+
+Three	O
+audiometric	O
+threshold	O
+measurements	O
+(	O
+0	O
+.	O
+25	O
+-	O
+18	O
+kHz	O
+)	O
+were	O
+made	O
+:	O
+the	O
+first	O
+before	O
+IBPB	O
+,	O
+the	O
+second	O
+2	O
+-	O
+6	O
+h	O
+after	O
+surgery	O
+and	O
+the	O
+third	O
+on	O
+the	O
+first	O
+day	O
+after	O
+operation	O
+.	O
+
+In	O
+four	O
+patients	O
+hearing	B
+impairment	I
+on	O
+the	O
+side	O
+of	O
+the	O
+block	O
+was	O
+demonstrated	O
+after	O
+operation	O
+,	O
+in	O
+three	O
+measurements	O
+on	O
+the	O
+day	O
+of	O
+surgery	O
+and	O
+in	O
+one	O
+on	O
+the	O
+following	O
+day	O
+.	O
+
+The	O
+frequencies	O
+at	O
+which	O
+the	O
+impairment	O
+occurred	O
+varied	O
+between	O
+patients	O
+;	O
+in	O
+one	O
+only	O
+low	O
+frequencies	O
+(	O
+0	O
+.	O
+25	O
+-	O
+0	O
+.	O
+5	O
+kHz	O
+)	O
+were	O
+involved	O
+.	O
+
+The	O
+maximum	O
+change	O
+in	O
+threshold	O
+was	O
+35	O
+dB	O
+at	O
+6	O
+kHz	O
+measured	O
+at	O
+the	O
+end	O
+of	O
+the	O
+continuous	O
+infusion	O
+of	O
+bupivacaine	O
+.	O
+
+This	O
+patient	O
+had	O
+hearing	O
+threshold	O
+changes	O
+(	O
+15	O
+-	O
+20	O
+dB	O
+)	O
+at	O
+6	O
+-	O
+10	O
+kHz	O
+on	O
+the	O
+opposite	O
+side	O
+also	O
+.	O
+
+IBPB	O
+may	O
+cause	O
+transient	O
+auditory	B
+dysfunction	I
+in	O
+the	O
+ipsilateral	O
+ear	O
+,	O
+possibly	O
+via	O
+an	O
+effect	O
+on	O
+sympathetic	O
+innervation	O
+.	O
+
+The	O
+safety	O
+and	O
+efficacy	O
+of	O
+combination	O
+N	O
+-	O
+butyl	O
+-	O
+deoxynojirimycin	O
+(	O
+SC	O
+-	O
+48334	O
+)	O
+and	O
+zidovudine	O
+in	O
+patients	O
+with	O
+HIV	B
+-	I
+1	I
+infection	I
+and	O
+200	O
+-	O
+500	O
+CD4	O
+cells	O
+/	O
+mm3	O
+.	O
+
+We	O
+conducted	O
+a	O
+double	O
+-	O
+blind	O
+,	O
+randomized	O
+phase	O
+II	O
+study	O
+to	O
+evaluate	O
+the	O
+safety	O
+and	O
+activity	O
+of	O
+combination	O
+therapy	O
+with	O
+N	O
+-	O
+butyl	O
+-	O
+deoxynojirimycin	O
+(	O
+SC	O
+-	O
+48334	O
+)	O
+(	O
+an	O
+alpha	O
+-	O
+glucosidase	O
+I	O
+inhibitor	O
+)	O
+and	O
+zidovudine	O
+versus	O
+zidovudine	O
+alone	O
+.	O
+
+Patients	O
+with	O
+200	O
+to	O
+500	O
+CD4	O
+cells	O
+/	O
+mm3	O
+who	O
+tolerated	O
+<	O
+or	O
+=	O
+12	O
+weeks	O
+of	O
+prior	O
+zidovudine	O
+therapy	O
+received	O
+SC	O
+-	O
+48334	O
+(	O
+1000	O
+mg	O
+every	O
+8	O
+h	O
+)	O
+and	O
+zidovudine	O
+(	O
+100	O
+mg	O
+every	O
+8	O
+h	O
+)	O
+or	O
+zidovudine	O
+and	O
+placebo	O
+.	O
+
+Sixty	O
+patients	O
+received	O
+combination	O
+therapy	O
+and	O
+58	O
+,	O
+zidovudine	O
+and	O
+placebo	O
+.	O
+
+Twenty	O
+-	O
+three	O
+patients	O
+(	O
+38	O
+%	O
+)	O
+and	O
+15	O
+(	O
+26	O
+%	O
+)	O
+,	O
+in	O
+the	O
+combination	O
+and	O
+zidovudine	O
+groups	O
+,	O
+respectively	O
+,	O
+discontinued	O
+therapy	O
+(	O
+p	O
+=	O
+0	O
+.	O
+15	O
+)	O
+.	O
+
+The	O
+mean	O
+SC	O
+-	O
+48334	O
+steady	O
+-	O
+state	O
+trough	O
+level	O
+(	O
+4	O
+.	O
+04	O
++	O
+/	O
+-	O
+0	O
+.	O
+99	O
+micrograms	O
+/	O
+ml	O
+)	O
+was	O
+below	O
+the	O
+in	O
+vitro	O
+inhibitory	O
+concentration	O
+for	O
+human	O
+immunodeficiency	B
+virus	O
+(	O
+HIV	O
+)	O
+.	O
+
+The	O
+mean	O
+increase	O
+in	O
+CD4	O
+cells	O
+at	O
+week	O
+4	O
+was	O
+73	O
+.	O
+8	O
+cells	O
+/	O
+mm3	O
+and	O
+52	O
+.	O
+4	O
+cells	O
+/	O
+mm3	O
+for	O
+the	O
+combination	O
+and	O
+zidovudine	O
+groups	O
+,	O
+respectively	O
+(	O
+p	O
+>	O
+0	O
+.	O
+36	O
+)	O
+.	O
+
+For	O
+patients	O
+with	O
+prior	O
+zidovudine	O
+therapy	O
+,	O
+the	O
+mean	O
+change	O
+in	O
+CD4	O
+cells	O
+in	O
+the	O
+combination	O
+and	O
+zidovudine	O
+groups	O
+was	O
+63	O
+.	O
+7	O
+cells	O
+/	O
+mm3	O
+and	O
+4	O
+.	O
+9	O
+cells	O
+/	O
+mm3	O
+at	O
+week	O
+8	O
+and	O
+6	O
+.	O
+8	O
+cells	O
+/	O
+mm3	O
+and	O
+-	O
+45	O
+.	O
+1	O
+cells	O
+/	O
+mm3	O
+at	O
+week	O
+16	O
+,	O
+respectively	O
+.	O
+
+The	O
+number	O
+of	O
+patients	O
+with	O
+suppression	O
+of	O
+HIV	O
+p24	O
+antigenemia	O
+in	O
+the	O
+combination	O
+and	O
+zidovudine	O
+groups	O
+was	O
+six	O
+(	O
+40	O
+%	O
+)	O
+and	O
+two	O
+(	O
+11	O
+%	O
+)	O
+at	O
+week	O
+4	O
+(	O
+p	O
+=	O
+0	O
+.	O
+10	O
+)	O
+and	O
+five	O
+(	O
+45	O
+%	O
+)	O
+and	O
+two	O
+(	O
+14	O
+%	O
+)	O
+at	O
+week	O
+24	O
+(	O
+p	O
+=	O
+0	O
+.	O
+08	O
+)	O
+,	O
+respectively	O
+.	O
+
+Diarrhea	B
+,	O
+flatulence	B
+,	O
+abdominal	B
+pain	I
+,	O
+and	O
+weight	B
+loss	I
+were	O
+common	O
+for	O
+combination	O
+recipients	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Prolonged	O
+paralysis	B
+due	O
+to	O
+nondepolarizing	O
+neuromuscular	O
+blocking	O
+agents	O
+and	O
+corticosteroids	O
+.	O
+
+The	O
+long	O
+-	O
+term	O
+use	O
+of	O
+nondepolarizing	O
+neuromuscular	O
+blocking	O
+agents	O
+(	O
+ND	O
+-	O
+NMBA	O
+)	O
+has	O
+recently	O
+been	O
+implicated	O
+as	O
+a	O
+cause	O
+of	O
+prolonged	O
+muscle	B
+weakness	I
+,	O
+although	O
+the	O
+site	O
+of	O
+the	O
+lesion	O
+and	O
+the	O
+predisposing	O
+factors	O
+have	O
+been	O
+unclear	O
+.	O
+
+We	O
+report	O
+3	O
+patients	O
+(	O
+age	O
+37	O
+-	O
+52	O
+years	O
+)	O
+with	O
+acute	O
+respiratory	B
+insufficiency	I
+who	O
+developed	O
+prolonged	O
+weakness	B
+following	O
+the	O
+discontinuation	O
+of	O
+ND	O
+-	O
+NMBAs	O
+.	O
+
+Two	O
+patients	O
+also	O
+received	O
+intravenous	O
+corticosteroids	O
+.	O
+
+Renal	O
+function	O
+was	O
+normal	O
+but	O
+hepatic	O
+function	O
+was	O
+impaired	O
+in	O
+all	O
+patients	O
+,	O
+and	O
+all	O
+had	O
+acidosis	B
+.	O
+
+Electrophysiologic	O
+studies	O
+revealed	O
+low	O
+amplitude	O
+compound	O
+motor	O
+action	O
+potentials	O
+,	O
+normal	O
+sensory	O
+studies	O
+,	O
+and	O
+fibrillations	O
+.	O
+
+Repetitive	O
+stimulation	O
+at	O
+2	O
+Hz	O
+showed	O
+a	O
+decremental	O
+response	O
+in	O
+2	O
+patients	O
+.	O
+
+The	O
+serum	O
+vecuronium	O
+level	O
+measured	O
+in	O
+1	O
+patient	O
+14	O
+days	O
+after	O
+the	O
+drug	O
+had	O
+been	O
+discontinued	O
+was	O
+172	O
+ng	O
+/	O
+mL	O
+.	O
+
+A	O
+muscle	O
+biopsy	O
+in	O
+this	O
+patient	O
+showed	O
+loss	B
+of	I
+thick	I
+,	I
+myosin	I
+filaments	I
+.	O
+
+The	O
+weakness	B
+in	O
+these	O
+patients	O
+is	O
+due	O
+to	O
+pathology	B
+at	I
+both	I
+the	I
+neuromuscular	I
+junction	I
+(	O
+most	O
+likely	O
+due	O
+to	O
+ND	O
+-	O
+NMBA	O
+)	O
+and	O
+muscle	O
+(	O
+most	O
+likely	O
+due	O
+to	O
+corticosteroids	O
+)	O
+.	O
+
+Hepatic	B
+dysfunction	I
+and	O
+acidosis	B
+are	O
+contributing	O
+risk	O
+factors	O
+.	O
+
+Failure	O
+of	O
+ancrod	O
+in	O
+the	O
+treatment	O
+of	O
+heparin	O
+-	O
+induced	O
+arterial	O
+thrombosis	B
+.	O
+
+The	O
+morbidity	O
+and	O
+mortality	O
+associated	O
+with	O
+heparin	O
+-	O
+induced	O
+thrombosis	B
+remain	O
+high	O
+despite	O
+numerous	O
+empirical	O
+therapies	O
+.	O
+
+Ancrod	O
+has	O
+been	O
+used	O
+successfully	O
+for	O
+prophylaxis	O
+against	O
+development	O
+of	O
+thrombosis	B
+in	O
+patients	O
+with	O
+heparin	O
+induced	O
+platelet	B
+aggregation	I
+who	O
+require	O
+brief	O
+reexposure	O
+to	O
+heparin	O
+,	O
+but	O
+its	O
+success	O
+in	O
+patients	O
+who	O
+have	O
+developed	O
+the	O
+thrombosis	B
+syndrome	O
+is	O
+not	O
+well	O
+defined	O
+.	O
+
+The	O
+authors	O
+present	O
+a	O
+case	O
+of	O
+failure	O
+of	O
+ancrod	O
+treatment	O
+in	O
+a	O
+patient	O
+with	O
+heparin	O
+-	O
+induced	O
+thrombosis	B
+.	O
+
+Water	B
+intoxication	I
+associated	O
+with	O
+oxytocin	O
+administration	O
+during	O
+saline	O
+-	O
+induced	O
+abortion	B
+.	O
+
+Four	O
+cases	O
+of	O
+water	B
+intoxication	I
+in	O
+connection	O
+with	O
+oxytocin	O
+administration	O
+during	O
+saline	O
+-	O
+induced	O
+abortions	B
+are	O
+described	O
+.	O
+
+The	O
+mechanism	O
+of	O
+water	B
+intoxication	I
+is	O
+discussed	O
+in	O
+regard	O
+to	O
+these	O
+cases	O
+.	O
+
+Oxytocin	O
+administration	O
+during	O
+midtrimester	O
+-	O
+induced	O
+abortions	B
+is	O
+advocated	O
+only	O
+if	O
+it	O
+can	O
+be	O
+carried	O
+out	O
+under	O
+careful	O
+observations	O
+of	O
+an	O
+alert	O
+nursing	O
+staff	O
+,	O
+aware	O
+of	O
+the	O
+symptoms	O
+of	O
+water	B
+intoxication	I
+and	O
+instructed	O
+to	O
+watch	O
+the	O
+diuresis	O
+and	O
+report	O
+such	O
+early	O
+signs	O
+of	O
+the	O
+syndrome	O
+as	O
+asthenia	B
+,	O
+muscular	O
+irritability	B
+,	O
+or	O
+headaches	B
+.	O
+
+The	O
+oxytocin	O
+should	O
+be	O
+given	O
+only	O
+in	O
+Ringers	O
+lactate	O
+or	O
+,	O
+alternately	O
+,	O
+in	O
+Ringers	O
+lactate	O
+and	O
+a	O
+5	O
+per	O
+cent	O
+dextrose	O
+and	O
+water	O
+solutions	O
+.	O
+
+The	O
+urinary	O
+output	O
+should	O
+be	O
+monitored	O
+and	O
+the	O
+oxytocin	O
+administration	O
+discontinued	O
+and	O
+the	O
+serum	O
+electrolytes	O
+checked	O
+if	O
+the	O
+urinary	O
+output	O
+decreases	O
+.	O
+
+The	O
+oxytocin	O
+should	O
+not	O
+be	O
+administered	O
+in	O
+excess	O
+of	O
+36	O
+hours	O
+.	O
+
+If	O
+the	O
+patient	O
+has	O
+not	O
+aborted	O
+by	O
+then	O
+the	O
+oxytocin	O
+should	O
+be	O
+discontinued	O
+for	O
+10	O
+to	O
+12	O
+hours	O
+in	O
+order	O
+to	O
+perform	O
+electrolyte	O
+determinations	O
+and	O
+correct	O
+any	O
+electrolyte	O
+imbalance	O
+.	O
+
+Light	O
+chain	O
+proteinuria	B
+and	O
+cellular	O
+mediated	O
+immunity	O
+in	O
+rifampin	O
+treated	O
+patients	O
+with	O
+tuberculosis	B
+.	O
+
+Light	O
+chain	O
+proteinuria	B
+was	O
+found	O
+in	O
+9	O
+of	O
+17	O
+tuberculosis	B
+patients	O
+treated	O
+with	O
+rifampin	O
+.	O
+
+Concomitant	O
+assay	O
+of	O
+cellular	O
+mediated	O
+immunity	O
+in	O
+these	O
+patients	O
+using	O
+skin	O
+test	O
+antigen	O
+and	O
+a	O
+lymphokine	O
+in	O
+vitro	O
+test	O
+provided	O
+results	O
+that	O
+were	O
+different	O
+.	O
+
+Response	O
+to	O
+Varidase	O
+skin	O
+test	O
+antigen	O
+was	O
+negative	O
+for	O
+all	O
+eight	O
+tuberculosis	B
+patients	O
+tested	O
+,	O
+but	O
+there	O
+occurred	O
+a	O
+hyper	O
+-	O
+responsiveness	O
+of	O
+the	O
+lymphocytes	O
+of	O
+these	O
+eight	O
+patients	O
+to	O
+phytomitogen	O
+(	O
+PHA	O
+-	O
+P	O
+)	O
+.	O
+as	O
+well	O
+as	O
+of	O
+those	O
+of	O
+seven	O
+other	O
+tuberculous	B
+patients	O
+.	O
+
+This	O
+last	O
+finding	O
+may	O
+be	O
+related	O
+to	O
+time	O
+of	O
+testing	O
+and	O
+/	O
+or	O
+endogenous	O
+serum	O
+binding	O
+of	O
+rifampin	O
+which	O
+could	O
+have	O
+inhibited	O
+mitogen	O
+activity	O
+for	O
+the	O
+lymphocyte	O
+.	O
+
+KF17837	O
+:	O
+a	O
+novel	O
+selective	O
+adenosine	O
+A2A	O
+receptor	O
+antagonist	O
+with	O
+anticataleptic	O
+activity	O
+.	O
+
+KF17837	O
+is	O
+a	O
+novel	O
+selective	O
+adenosine	O
+A2A	O
+receptor	O
+antagonist	O
+.	O
+
+Oral	O
+administration	O
+of	O
+KF17837	O
+(	O
+2	O
+.	O
+5	O
+,	O
+10	O
+.	O
+0	O
+and	O
+30	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+)	O
+significantly	O
+ameliorated	O
+the	O
+cataleptic	B
+responses	O
+induced	O
+by	O
+intracerebroventricular	O
+administration	O
+of	O
+an	O
+adenosine	O
+A2A	O
+receptor	O
+agonist	O
+,	O
+CGS	O
+21680	O
+(	O
+10	O
+micrograms	O
+)	O
+,	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+.	O
+
+KF17837	O
+also	O
+reduced	O
+the	O
+catalepsy	B
+induced	O
+by	O
+haloperidol	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+and	O
+by	O
+reserpine	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+These	O
+anticataleptic	O
+effects	O
+were	O
+exhibited	O
+dose	O
+dependently	O
+at	O
+doses	O
+from	O
+0	O
+.	O
+625	O
+and	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+,	O
+respectively	O
+.	O
+
+Moreover	O
+,	O
+KF17837	O
+(	O
+0	O
+.	O
+625	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+)	O
+potentiated	O
+the	O
+anticataleptic	O
+effects	O
+of	O
+a	O
+subthreshold	O
+dose	O
+of	O
+L	O
+-	O
+3	O
+,	O
+4	O
+-	O
+dihydroxyphenylalanine	O
+(	O
+L	O
+-	O
+DOPA	O
+;	O
+25	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+plus	O
+benserazide	O
+(	O
+6	O
+.	O
+25	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+These	O
+results	O
+suggested	O
+that	O
+KF17837	O
+is	O
+a	O
+centrally	O
+active	O
+adenosine	O
+A2A	O
+receptor	O
+antagonist	O
+and	O
+that	O
+the	O
+dopaminergic	O
+function	O
+of	O
+the	O
+nigrostriatal	O
+pathway	O
+is	O
+potentiated	O
+by	O
+adenosine	O
+A2A	O
+receptor	O
+antagonists	O
+.	O
+
+Furthermore	O
+,	O
+KF17837	O
+may	O
+be	O
+a	O
+useful	O
+drug	O
+in	O
+the	O
+treatment	O
+of	O
+parkinsonism	B
+.	O
+
+Effect	O
+of	O
+nondopaminergic	O
+drugs	O
+on	O
+L	O
+-	O
+dopa	O
+-	O
+induced	O
+dyskinesias	B
+in	O
+MPTP	O
+-	O
+treated	O
+monkeys	O
+.	O
+
+A	O
+group	O
+of	O
+four	O
+monkeys	O
+was	O
+rendered	O
+parkinsonian	B
+with	O
+the	O
+toxin	O
+MPTP	O
+.	O
+
+They	O
+were	O
+then	O
+treated	O
+chronically	O
+with	O
+L	O
+-	O
+DOPA	O
+/	O
+benserazide	O
+50	O
+/	O
+12	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+given	O
+orally	O
+daily	O
+for	O
+2	O
+months	O
+.	O
+
+This	O
+dose	O
+produced	O
+a	O
+striking	O
+antiparkinsonian	O
+effect	O
+,	O
+but	O
+all	O
+animals	O
+manifested	O
+dyskinesia	B
+.	O
+
+A	O
+series	O
+of	O
+agents	O
+acting	O
+primarily	O
+on	O
+neurotransmitters	O
+other	O
+than	O
+dopamine	O
+were	O
+then	O
+tested	O
+in	O
+combination	O
+with	O
+L	O
+-	O
+DOPA	O
+to	O
+see	O
+if	O
+the	O
+dyskinetic	B
+movements	O
+would	O
+be	O
+modified	O
+.	O
+
+Several	O
+drugs	O
+,	O
+including	O
+clonidine	O
+,	O
+physostigmine	O
+,	O
+methysergide	O
+,	O
+5	O
+-	O
+MDOT	O
+,	O
+propranolol	O
+,	O
+and	O
+MK	O
+-	O
+801	O
+,	O
+markedly	O
+reduced	O
+the	O
+dyskinetic	B
+movements	O
+but	O
+at	O
+the	O
+cost	O
+of	O
+a	O
+return	O
+of	O
+parkinsonian	B
+symptomatology	O
+.	O
+
+However	O
+,	O
+yohimbine	O
+and	O
+meperidine	O
+reduced	O
+predominantly	O
+the	O
+dyskinetic	B
+movements	O
+.	O
+
+Baclofen	O
+was	O
+also	O
+useful	O
+in	O
+one	O
+monkey	O
+against	O
+a	O
+more	O
+dystonic	B
+form	O
+of	O
+dyskinesia	B
+.	O
+
+Atropine	O
+converted	O
+the	O
+dystonic	B
+movements	O
+into	O
+chorea	B
+.	O
+
+Hallucinations	B
+and	O
+ifosfamide	O
+-	O
+induced	O
+neurotoxicity	B
+.	O
+
+BACKGROUND	O
+:	O
+Hallucinations	B
+as	O
+a	O
+symptom	O
+of	O
+central	O
+neurotoxicity	B
+are	O
+a	O
+known	O
+but	O
+poorly	O
+described	O
+side	O
+effect	O
+of	O
+ifosfamide	O
+.	O
+
+Most	O
+cases	O
+of	O
+ifosfamide	O
+-	O
+induced	O
+hallucinations	B
+have	O
+been	O
+reported	O
+with	O
+other	O
+mental	O
+status	O
+changes	O
+.	O
+
+METHODS	O
+:	O
+The	O
+authors	O
+interviewed	O
+six	O
+persons	O
+with	O
+ifosfamide	O
+-	O
+induced	O
+hallucinations	B
+in	O
+the	O
+presence	O
+of	O
+a	O
+clear	O
+sensorium	O
+.	O
+
+All	O
+patients	O
+were	O
+receiving	O
+high	O
+-	O
+dose	O
+ifosfamide	O
+as	O
+part	O
+of	O
+their	O
+bone	O
+marrow	O
+transplant	O
+procedure	O
+.	O
+
+RESULTS	O
+:	O
+Hallucinations	B
+occurred	O
+only	O
+when	O
+the	O
+patient	O
+'	O
+s	O
+eyes	O
+were	O
+closed	O
+and	O
+,	O
+in	O
+all	O
+but	O
+one	O
+case	O
+,	O
+were	O
+reported	O
+as	O
+disturbing	O
+or	O
+frightening	O
+.	O
+
+Underreporting	O
+of	O
+these	O
+hallucinations	B
+by	O
+patients	O
+is	O
+likely	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Hallucinations	B
+may	O
+be	O
+the	O
+sole	O
+or	O
+first	O
+manifestation	O
+of	O
+neurotoxicity	B
+.	O
+
+The	O
+incidence	O
+may	O
+be	O
+dose	O
+and	O
+infusion	O
+-	O
+time	O
+related	O
+.	O
+
+The	O
+clinician	O
+should	O
+be	O
+alerted	O
+for	O
+possible	O
+ifosfamide	O
+-	O
+induced	O
+hallucinations	B
+,	O
+which	O
+may	O
+occur	O
+without	O
+other	O
+signs	O
+of	O
+neurotoxicity	B
+.	O
+
+"	O
+Eyes	O
+-	O
+closed	O
+"	O
+hallucinatory	B
+experiences	O
+appear	O
+to	O
+be	O
+an	O
+unusual	O
+feature	O
+of	O
+this	O
+presentation	O
+.	O
+
+Patients	O
+anxious	O
+about	O
+this	O
+experience	O
+respond	O
+well	O
+to	O
+support	O
+and	O
+education	O
+about	O
+this	O
+occurrence	O
+.	O
+
+Optimal	O
+pharmacologic	O
+management	O
+of	O
+disturbed	O
+patients	O
+is	O
+unclear	O
+.	O
+
+If	O
+agitation	B
+becomes	O
+marked	O
+,	O
+high	O
+-	O
+potency	O
+neuroleptics	O
+(	O
+i	O
+.	O
+e	O
+.	O
+,	O
+haloperidol	O
+)	O
+may	O
+be	O
+effective	O
+.	O
+
+Photodistributed	O
+nifedipine	O
+-	O
+induced	O
+facial	O
+telangiectasia	B
+.	O
+
+Five	O
+months	O
+after	O
+starting	O
+nifedipine	O
+(	O
+Adalat	O
+)	O
+,	O
+two	O
+patients	O
+developed	O
+photodistributed	O
+facial	O
+telangiectasia	B
+,	O
+which	O
+became	O
+more	O
+noticeable	O
+with	O
+time	O
+.	O
+
+Neither	O
+patient	O
+complained	O
+of	O
+photosensitivity	O
+or	O
+flushing	B
+.	O
+
+Both	O
+patients	O
+reported	O
+a	O
+significant	O
+cosmetic	O
+improvement	O
+after	O
+discontinuing	O
+the	O
+drug	O
+.	O
+
+One	O
+commenced	O
+the	O
+closely	O
+related	O
+drug	O
+amlodipine	O
+3	O
+years	O
+later	O
+,	O
+with	O
+recurrence	O
+of	O
+telangiectasia	B
+.	O
+
+The	O
+photodistribution	O
+of	O
+the	O
+telangiectasia	B
+suggests	O
+a	O
+significant	O
+drug	O
+/	O
+light	O
+interaction	O
+.	O
+
+Penicillamine	O
+-	O
+induced	O
+rapidly	O
+progressive	O
+glomerulonephritis	B
+in	O
+a	O
+patient	O
+with	O
+rheumatoid	B
+arthritis	I
+.	O
+
+A	O
+67	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+rheumatoid	B
+arthritis	I
+presented	O
+rapidly	O
+progressive	O
+glomerulonephritis	B
+(	O
+RPGN	B
+)	O
+after	O
+5	O
+months	O
+of	O
+D	O
+-	O
+penicillamine	O
+(	O
+250	O
+mg	O
+/	O
+day	O
+)	O
+treatment	O
+.	O
+
+Light	O
+microscopy	O
+study	O
+showed	O
+severe	O
+glomerulonephritis	B
+with	O
+crescent	O
+formation	O
+in	O
+60	O
+%	O
+of	O
+the	O
+glomeruli	O
+and	O
+infiltration	O
+of	O
+inflammatory	O
+cells	O
+in	O
+the	O
+wall	O
+of	O
+an	O
+arteriole	O
+.	O
+
+Immunofluorescence	O
+revealed	O
+scanty	O
+granular	O
+IgG	O
+,	O
+IgA	O
+and	O
+C3	O
+deposits	O
+along	O
+the	O
+capillary	O
+walls	O
+and	O
+mesangium	O
+.	O
+
+The	O
+patient	O
+was	O
+treated	O
+with	O
+steroid	O
+pulse	O
+,	O
+plasmapheresis	O
+,	O
+cyclophosphamide	O
+and	O
+antiplatelet	O
+agents	O
+.	O
+
+A	O
+complete	O
+recovery	O
+of	O
+renal	O
+function	O
+was	O
+achieved	O
+in	O
+a	O
+few	O
+weeks	O
+.	O
+
+This	O
+new	O
+case	O
+of	O
+RPGN	B
+in	O
+the	O
+course	O
+of	O
+D	O
+-	O
+penicillamine	O
+treatment	O
+emphasizes	O
+the	O
+need	O
+for	O
+frequent	O
+monitoring	O
+of	O
+renal	O
+function	O
+and	O
+evaluation	O
+of	O
+urinary	O
+sediment	O
+and	O
+proteinuria	B
+in	O
+these	O
+patients	O
+.	O
+
+The	O
+prompt	O
+discontinuation	O
+of	O
+D	O
+-	O
+penicillamine	O
+and	O
+vigorous	O
+treatment	O
+measures	O
+could	O
+allow	O
+for	O
+a	O
+good	O
+prognosis	O
+as	O
+in	O
+this	O
+case	O
+.	O
+
+A	O
+case	O
+of	O
+polymyositis	B
+in	O
+a	O
+patient	O
+with	O
+primary	B
+biliary	I
+cirrhosis	I
+treated	O
+with	O
+D	O
+-	O
+penicillamine	O
+.	O
+
+Although	O
+D	O
+-	O
+penicillamine	O
+has	O
+been	O
+used	O
+for	O
+many	O
+rheumatologic	B
+diseases	I
+,	O
+toxicity	B
+limits	O
+its	O
+usefulness	O
+in	O
+many	O
+patients	O
+.	O
+
+Polymyositis	B
+/	O
+dermatomyositis	B
+can	O
+develop	O
+as	O
+one	O
+of	O
+the	O
+autoimmune	O
+complications	O
+of	O
+D	O
+-	O
+penicillamine	O
+treatment	O
+,	O
+but	O
+its	O
+exact	O
+pathogenesis	O
+remains	O
+unclear	O
+.	O
+
+We	O
+report	O
+a	O
+patient	O
+with	O
+primary	B
+biliary	I
+cirrhosis	I
+,	O
+who	O
+developed	O
+polymyositis	B
+while	O
+receiving	O
+D	O
+-	O
+penicillamine	O
+therapy	O
+.	O
+
+We	O
+described	O
+the	O
+special	O
+clinical	O
+course	O
+of	O
+the	O
+patient	O
+.	O
+
+Patients	O
+receiving	O
+D	O
+-	O
+penicillamine	O
+therapy	O
+should	O
+be	O
+followed	O
+carefully	O
+for	O
+the	O
+development	O
+of	O
+autoimmune	O
+complications	O
+like	O
+polymyositis	B
+/	O
+dermatomyositis	B
+.	O
+
+Hyperalgesia	B
+and	O
+myoclonus	B
+in	O
+terminal	O
+cancer	B
+patients	O
+treated	O
+with	O
+continuous	O
+intravenous	O
+morphine	O
+.	O
+
+Eight	O
+cancer	B
+patients	O
+in	O
+the	O
+terminal	O
+stages	O
+of	O
+the	O
+disease	O
+treated	O
+with	O
+high	O
+doses	O
+of	O
+intravenous	O
+morphine	O
+developed	O
+hyperalgesia	B
+.	O
+
+All	O
+cases	O
+were	O
+retrospectively	O
+sampled	O
+from	O
+three	O
+different	O
+hospitals	O
+in	O
+Copenhagen	O
+.	O
+
+Five	O
+patients	O
+developed	O
+universal	O
+hyperalgesia	B
+and	O
+hyperesthesia	B
+which	O
+in	O
+2	O
+cases	O
+were	O
+accompanied	O
+by	O
+myoclonus	B
+.	O
+
+In	O
+3	O
+patients	O
+a	O
+pre	O
+-	O
+existing	O
+neuralgia	B
+increased	O
+to	O
+excruciating	O
+intensity	O
+and	O
+in	O
+2	O
+of	O
+these	O
+cases	O
+myoclonus	B
+occurred	O
+simultaneously	O
+.	O
+
+Although	O
+only	O
+few	O
+clinical	O
+descriptions	O
+of	O
+the	O
+relationship	O
+between	O
+hyperalgesia	B
+/	O
+myoclonus	B
+and	O
+high	O
+doses	O
+of	O
+morphine	O
+are	O
+available	O
+,	O
+experimental	O
+support	O
+from	O
+animal	O
+studies	O
+indicates	O
+that	O
+morphine	O
+,	O
+or	O
+its	O
+metabolites	O
+,	O
+plays	O
+a	O
+causative	O
+role	O
+for	O
+the	O
+observed	O
+behavioural	O
+syndrome	O
+.	O
+
+The	O
+possible	O
+mechanisms	O
+are	O
+discussed	O
+and	O
+treatment	O
+proposals	O
+given	O
+suggesting	O
+the	O
+use	O
+of	O
+more	O
+efficacious	O
+opioids	O
+with	O
+less	O
+excitatory	O
+potency	O
+in	O
+these	O
+situations	O
+.	O
+
+Liposomal	O
+daunorubicin	O
+in	O
+advanced	O
+Kaposi	B
+'	I
+s	I
+sarcoma	I
+:	O
+a	O
+phase	O
+II	O
+study	O
+.	O
+
+We	O
+report	O
+a	O
+non	O
+-	O
+randomized	O
+Phase	O
+II	O
+clinical	O
+trial	O
+to	O
+assess	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+liposomal	O
+daunorubicin	O
+(	O
+DaunoXome	O
+)	O
+in	O
+the	O
+treatment	O
+of	O
+AIDS	B
+related	O
+Kaposi	B
+'	I
+s	I
+sarcoma	I
+.	O
+
+Eleven	O
+homosexual	O
+men	O
+with	O
+advanced	O
+Kaposi	B
+'	I
+s	I
+sarcoma	I
+were	O
+entered	O
+in	O
+the	O
+trial	O
+.	O
+
+Changes	O
+in	O
+size	O
+,	O
+colour	O
+and	O
+associated	O
+oedema	B
+of	O
+selected	O
+'	O
+target	O
+'	O
+lesions	O
+were	O
+measured	O
+.	O
+
+Clinical	O
+,	O
+biochemical	O
+and	O
+haematological	O
+toxicities	B
+were	O
+assessed	O
+.	O
+
+Ten	O
+subjects	O
+were	O
+evaluated	O
+.	O
+
+A	O
+partial	O
+response	O
+was	O
+achieved	O
+in	O
+four	O
+,	O
+of	O
+whom	O
+two	O
+subsequently	O
+relapsed	O
+.	O
+
+Stabilization	O
+of	O
+Kaposi	B
+'	I
+s	I
+sarcoma	I
+occurred	O
+in	O
+the	O
+remaining	O
+six	O
+,	O
+maintained	O
+until	O
+the	O
+end	O
+of	O
+the	O
+trial	O
+period	O
+in	O
+four	O
+.	O
+
+The	O
+drug	O
+was	O
+generally	O
+well	O
+tolerated	O
+,	O
+with	O
+few	O
+mild	O
+symptoms	O
+of	O
+toxicity	B
+.	O
+
+The	O
+main	O
+problem	O
+encountered	O
+was	O
+haematological	O
+toxicity	B
+,	O
+with	O
+three	O
+subjects	O
+experiencing	O
+severe	O
+neutropenia	B
+(	O
+neutrophil	O
+count	O
+<	O
+0	O
+.	O
+5	O
+x	O
+10	O
+(	O
+9	O
+)	O
+/	O
+l	O
+)	O
+.	O
+
+There	O
+was	O
+no	O
+evidence	O
+of	O
+cardiotoxicity	B
+.	O
+
+In	O
+this	O
+small	O
+patient	O
+sample	O
+,	O
+liposomal	O
+daunorubicin	O
+was	O
+an	O
+effective	O
+and	O
+well	O
+tolerated	O
+agent	O
+in	O
+the	O
+treatment	O
+of	O
+Kaposi	B
+'	I
+s	I
+sarcoma	I
+.	O
+
+Long	O
+-	O
+term	O
+effects	O
+of	O
+vincristine	O
+on	O
+the	O
+peripheral	O
+nervous	O
+system	O
+.	O
+
+Forty	O
+patients	O
+with	O
+Non	B
+-	I
+Hodgkin	I
+'	I
+s	I
+Lymphoma	I
+treated	O
+with	O
+vincristine	O
+between	O
+1984	O
+and	O
+1990	O
+(	O
+cumulative	O
+dose	O
+12	O
+mg	O
+in	O
+18	O
+-	O
+24	O
+weeks	O
+)	O
+were	O
+investigated	O
+in	O
+order	O
+to	O
+evaluate	O
+the	O
+long	O
+term	O
+effects	O
+of	O
+vincristine	O
+on	O
+the	O
+peripheral	O
+nervous	O
+system	O
+.	O
+
+The	O
+patients	O
+were	O
+interviewed	O
+with	O
+emphasis	O
+on	O
+neuropathic	B
+symptoms	I
+.	O
+
+Physical	O
+and	O
+quantitative	O
+sensory	O
+examination	O
+with	O
+determination	O
+of	O
+vibratory	O
+perception	O
+and	O
+thermal	O
+discrimination	O
+thresholds	O
+were	O
+performed	O
+,	O
+four	O
+to	O
+77	O
+months	O
+(	O
+median	O
+34	O
+months	O
+)	O
+after	O
+vincristine	O
+treatment	O
+.	O
+
+Twenty	O
+-	O
+seven	O
+patients	O
+reported	O
+neuropathic	B
+symptoms	I
+.	O
+
+In	O
+13	O
+of	O
+these	O
+27	O
+patients	O
+symptoms	O
+were	O
+still	O
+present	O
+at	O
+the	O
+time	O
+of	O
+examination	O
+.	O
+
+In	O
+these	O
+patients	O
+sensory	O
+signs	O
+and	O
+symptoms	O
+predominated	O
+.	O
+
+In	O
+the	O
+other	O
+14	O
+patients	O
+symptoms	O
+had	O
+been	O
+present	O
+in	O
+the	O
+past	O
+.	O
+
+Symptoms	O
+persisted	O
+maximally	O
+40	O
+months	O
+since	O
+cessation	O
+of	O
+therapy	O
+.	O
+
+There	O
+was	O
+no	O
+age	O
+difference	O
+between	O
+patients	O
+with	O
+and	O
+without	O
+complaints	O
+at	O
+the	O
+time	O
+of	O
+examination	O
+.	O
+
+Normal	O
+reflexes	O
+were	O
+found	O
+in	O
+two	O
+third	O
+of	O
+patients	O
+.	O
+
+Neuropathic	O
+complaints	O
+were	O
+not	O
+very	O
+troublesome	O
+on	O
+the	O
+long	O
+term	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+with	O
+the	O
+above	O
+mentioned	O
+vincristine	O
+dose	O
+schedule	O
+signs	O
+and	O
+symptoms	O
+of	O
+vincristine	O
+neuropathy	B
+are	O
+reversible	O
+for	O
+a	O
+great	O
+deal	O
+and	O
+prognosis	O
+is	O
+fairly	O
+good	O
+.	O
+
+Hepatic	O
+adenomas	B
+and	O
+focal	B
+nodular	I
+hyperplasia	I
+of	O
+the	O
+liver	O
+in	O
+young	O
+women	O
+on	O
+oral	O
+contraceptives	O
+:	O
+case	O
+reports	O
+.	O
+
+Two	O
+cases	O
+of	O
+hepatic	O
+adenoma	B
+and	O
+one	O
+of	O
+focal	B
+nodular	I
+hyperplasia	I
+presumably	O
+associated	O
+with	O
+the	O
+use	O
+of	O
+oral	O
+contraceptives	O
+,	O
+are	O
+reported	O
+.	O
+
+Special	O
+reference	O
+is	O
+made	O
+to	O
+their	O
+clinical	O
+presentation	O
+,	O
+which	O
+may	O
+be	O
+totally	O
+asymptomatic	O
+.	O
+
+Liver	O
+-	O
+function	O
+tests	O
+are	O
+of	O
+little	O
+diagnostic	O
+value	O
+,	O
+but	O
+valuable	O
+information	O
+may	O
+be	O
+obtained	O
+from	O
+both	O
+liver	O
+scanning	O
+and	O
+hepatic	O
+angiography	O
+.	O
+
+Histologic	O
+differences	O
+and	O
+clinical	O
+similarities	O
+between	O
+hepatic	O
+adenoma	B
+and	O
+focal	B
+nodular	I
+hyperplasia	I
+of	O
+the	O
+liver	O
+are	O
+discussed	O
+.	O
+
+Loss	O
+of	O
+glutamate	O
+decarboxylase	O
+mRNA	O
+-	O
+containing	O
+neurons	O
+in	O
+the	O
+rat	O
+dentate	O
+gyrus	O
+following	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+.	O
+
+In	O
+situ	O
+hybridization	O
+methods	O
+were	O
+used	O
+to	O
+determine	O
+if	O
+glutamic	O
+acid	O
+decarboxylase	O
+(	O
+GAD	O
+)	O
+mRNA	O
+-	O
+containing	O
+neurons	O
+within	O
+the	O
+hilus	O
+of	O
+the	O
+dentate	O
+gyrus	O
+are	O
+vulnerable	O
+to	O
+seizure	B
+-	O
+induced	O
+damage	O
+in	O
+a	O
+model	O
+of	O
+chronic	O
+seizures	B
+.	O
+
+Sprague	O
+-	O
+Dawley	O
+rats	O
+were	O
+injected	O
+intraperitoneally	O
+with	O
+pilocarpine	O
+,	O
+and	O
+the	O
+hippocampal	O
+formation	O
+was	O
+studied	O
+histologically	O
+at	O
+1	O
+,	O
+2	O
+,	O
+4	O
+,	O
+and	O
+8	O
+week	O
+intervals	O
+after	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+.	O
+
+In	O
+situ	O
+hybridization	O
+histochemistry	O
+,	O
+using	O
+a	O
+digoxigenin	O
+-	O
+labeled	O
+GAD	O
+cRNA	O
+probe	O
+,	O
+demonstrated	O
+a	O
+substantial	O
+decrease	O
+in	O
+the	O
+number	O
+of	O
+GAD	O
+mRNA	O
+-	O
+containing	O
+neurons	O
+in	O
+the	O
+hilus	O
+of	O
+the	O
+dentate	O
+gyrus	O
+in	O
+the	O
+pilocarpine	O
+-	O
+treated	O
+rats	O
+as	O
+compared	O
+to	O
+controls	O
+at	O
+all	O
+time	O
+intervals	O
+.	O
+
+Additional	O
+neuronanatomical	O
+studies	O
+,	O
+including	O
+cresyl	O
+violet	O
+staining	O
+,	O
+neuronal	B
+degeneration	I
+methods	O
+,	O
+and	O
+histochemical	O
+localization	O
+of	O
+glial	O
+fibrillary	O
+acidic	O
+protein	O
+,	O
+suggested	O
+that	O
+the	O
+decrease	O
+in	O
+the	O
+number	O
+of	O
+GAD	O
+mRNA	O
+-	O
+containing	O
+neurons	O
+was	O
+related	O
+to	O
+neuronal	B
+loss	I
+rather	O
+than	O
+to	O
+a	O
+decrease	O
+in	O
+GAD	O
+mRNA	O
+levels	O
+.	O
+
+The	O
+loss	O
+of	O
+GAD	O
+mRNA	O
+-	O
+containing	O
+neurons	O
+in	O
+the	O
+hilus	O
+contrasted	O
+with	O
+the	O
+relative	O
+preservation	O
+of	O
+labeled	O
+putative	O
+basket	O
+cells	O
+along	O
+the	O
+inner	O
+margin	O
+of	O
+the	O
+granule	O
+cell	O
+layer	O
+.	O
+
+Quantitative	O
+analyses	O
+of	O
+labeled	O
+neurons	O
+in	O
+three	O
+regions	O
+of	O
+the	O
+dentate	O
+gyrus	O
+in	O
+the	O
+1	O
+and	O
+2	O
+week	O
+groups	O
+showed	O
+statistically	O
+significant	O
+decreases	O
+in	O
+the	O
+mean	O
+number	O
+of	O
+GAD	O
+mRNA	O
+-	O
+containing	O
+neurons	O
+in	O
+the	O
+hilus	O
+of	O
+both	O
+groups	O
+of	O
+experimental	O
+animals	O
+.	O
+
+No	O
+significant	O
+differences	O
+were	O
+found	O
+in	O
+the	O
+molecular	O
+layer	O
+or	O
+the	O
+granule	O
+cell	O
+layer	O
+,	O
+which	O
+included	O
+labeled	O
+neurons	O
+along	O
+the	O
+lower	O
+margin	O
+of	O
+the	O
+granule	O
+cell	O
+layer	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+,	O
+in	O
+this	O
+model	O
+,	O
+a	O
+subpopulation	O
+of	O
+GAD	O
+mRNA	O
+-	O
+containing	O
+neurons	O
+within	O
+the	O
+dentate	O
+gyrus	O
+is	O
+selectively	O
+vulnerable	O
+to	O
+seizure	B
+-	O
+induced	O
+damage	O
+.	O
+
+Such	O
+differential	O
+vulnerability	O
+appears	O
+to	O
+be	O
+another	O
+indication	O
+of	O
+the	O
+heterogeneity	O
+of	O
+GABA	O
+neurons	O
+.	O
+
+Effects	O
+of	O
+deliberate	O
+hypotension	B
+induced	O
+by	O
+labetalol	O
+with	O
+isoflurane	O
+on	O
+neuropsychological	O
+function	O
+.	O
+
+The	O
+effect	O
+of	O
+deliberate	O
+hypotension	B
+on	O
+brain	O
+function	O
+measured	O
+by	O
+neuropsychological	O
+tests	O
+was	O
+studied	O
+in	O
+41	O
+adult	O
+patients	O
+.	O
+
+Twenty	O
+-	O
+four	O
+patients	O
+were	O
+anaesthetized	O
+for	O
+middle	O
+-	O
+ear	O
+surgery	O
+with	O
+deliberate	O
+hypotension	B
+induced	O
+by	O
+labetalol	O
+with	O
+isoflurane	O
+(	O
+hypotensive	B
+group	O
+)	O
+.	O
+
+Seventeen	O
+patients	O
+without	O
+hypotension	B
+served	O
+as	O
+a	O
+control	O
+group	O
+.	O
+
+The	O
+mean	O
+arterial	O
+pressure	O
+was	O
+77	O
++	O
+/	O
+-	O
+2	O
+mmHg	O
+(	O
+10	O
+.	O
+3	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+kPa	O
+)	O
+before	O
+hypotension	B
+and	O
+50	O
++	O
+/	O
+-	O
+0	O
+mmHg	O
+(	O
+6	O
+.	O
+7	O
++	O
+/	O
+-	O
+0	O
+.	O
+0	O
+kPa	O
+)	O
+during	O
+hypotension	B
+in	O
+the	O
+hypotensive	B
+group	O
+,	O
+and	O
+86	O
++	O
+/	O
+-	O
+2	O
+mmHg	O
+(	O
+11	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+kPa	O
+)	O
+during	O
+anaesthesia	O
+in	O
+the	O
+control	O
+group	O
+.	O
+
+The	O
+following	O
+psychological	O
+tests	O
+were	O
+performed	O
+:	O
+four	O
+subtests	O
+of	O
+the	O
+Wechsler	O
+Adult	O
+Intelligence	O
+Scale	O
+(	O
+similarities	O
+,	O
+digit	O
+span	O
+,	O
+vocabulary	O
+and	O
+digit	O
+symbol	O
+)	O
+,	O
+Trail	O
+-	O
+Making	O
+tests	O
+A	O
+and	O
+B	O
+,	O
+Zung	O
+tests	O
+(	O
+self	O
+-	O
+rating	O
+anxiety	B
+scale	O
+and	O
+self	O
+-	O
+rating	O
+depression	B
+scale	O
+)	O
+and	O
+two	O
+-	O
+part	O
+memory	O
+test	O
+battery	O
+with	O
+immediate	O
+and	O
+delayed	O
+recall	O
+.	O
+
+The	O
+tests	O
+were	O
+performed	O
+preoperatively	O
+and	O
+2	O
+days	O
+postoperatively	O
+.	O
+
+There	O
+were	O
+no	O
+statistically	O
+significant	O
+differences	O
+between	O
+the	O
+groups	O
+in	O
+any	O
+of	O
+the	O
+tests	O
+in	O
+the	O
+changes	O
+from	O
+preoperative	O
+value	O
+to	O
+postoperative	O
+value	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+hypotension	B
+induced	O
+by	O
+labetalol	O
+with	O
+isoflurane	O
+has	O
+no	O
+significant	O
+harmful	O
+effects	O
+on	O
+mental	O
+functions	O
+compared	O
+to	O
+normotensive	O
+anaesthesia	O
+.	O
+
+Apparent	O
+cure	O
+of	O
+rheumatoid	B
+arthritis	I
+by	O
+bone	O
+marrow	O
+transplantation	O
+.	O
+
+We	O
+describe	O
+the	O
+induction	O
+of	O
+sustained	O
+remissions	O
+and	O
+possible	O
+cure	O
+of	O
+severe	O
+erosive	O
+rheumatoid	B
+arthritis	I
+(	O
+RA	B
+)	O
+by	O
+bone	O
+marrow	O
+transplantation	O
+(	O
+BMT	O
+)	O
+in	O
+2	O
+patients	O
+.	O
+
+BMT	O
+was	O
+used	O
+to	O
+treat	O
+severe	O
+aplastic	B
+anemia	I
+which	O
+was	O
+caused	O
+by	O
+gold	O
+in	O
+one	O
+case	O
+and	O
+D	O
+-	O
+penicillamine	O
+in	O
+the	O
+other	O
+.	O
+
+In	O
+the	O
+8	O
+and	O
+6	O
+years	O
+since	O
+the	O
+transplants	O
+(	O
+representing	O
+8	O
+and	O
+4	O
+years	O
+since	O
+cessation	O
+of	O
+all	O
+immunosuppressive	O
+therapy	O
+,	O
+respectively	O
+)	O
+,	O
+the	O
+RA	B
+in	O
+each	O
+case	O
+has	O
+been	O
+completely	O
+quiescent	O
+.	O
+
+Although	O
+short	O
+term	O
+remission	O
+of	O
+severe	O
+RA	B
+following	O
+BMT	O
+has	O
+been	O
+reported	O
+,	O
+these	O
+are	O
+the	O
+first	O
+cases	O
+for	O
+which	O
+prolonged	O
+followup	O
+has	O
+been	O
+available	O
+.	O
+
+This	O
+experience	O
+raises	O
+the	O
+question	O
+of	O
+the	O
+role	O
+of	O
+BMT	O
+itself	O
+as	O
+a	O
+therapeutic	O
+option	O
+for	O
+patients	O
+with	O
+uncontrolled	O
+destructive	O
+synovitis	B
+.	O
+
+Seizures	B
+induced	O
+by	O
+combined	O
+levomepromazine	O
+-	O
+fluvoxamine	O
+treatment	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+combined	O
+levomepromazine	O
+-	O
+fluvoxamine	O
+treatment	O
+-	O
+induced	O
+seizures	B
+.	O
+
+It	O
+seems	O
+that	O
+combined	O
+treatment	O
+of	O
+fluvoxamine	O
+with	O
+phenothiazines	O
+may	O
+possess	O
+proconvulsive	O
+activity	O
+.	O
+
+Case	O
+report	O
+:	O
+pentamidine	O
+and	O
+polymorphic	O
+ventricular	B
+tachycardia	I
+revisited	O
+.	O
+
+Pentamidine	O
+isethionate	O
+has	O
+been	O
+associated	O
+with	O
+ventricular	B
+tachyarrhythmias	I
+,	O
+including	O
+torsade	B
+de	I
+pointes	I
+.	O
+
+This	O
+article	O
+reports	O
+two	O
+cases	O
+of	O
+this	O
+complication	O
+and	O
+reviews	O
+all	O
+reported	O
+cases	O
+to	O
+date	O
+.	O
+
+Pentamidine	O
+-	O
+induced	O
+torsade	B
+de	I
+pointes	I
+may	O
+be	O
+related	O
+to	O
+serum	O
+magnesium	O
+levels	O
+and	O
+hypomagnesemia	B
+may	O
+synergistically	O
+induce	O
+torsade	O
+.	O
+
+Torsade	B
+de	I
+pointes	I
+occurred	O
+after	O
+an	O
+average	O
+of	O
+10	O
+days	O
+of	O
+treatment	O
+with	O
+pentamidine	O
+.	O
+
+In	O
+these	O
+patients	O
+,	O
+no	O
+other	O
+acute	O
+side	O
+effects	O
+of	O
+pentamidine	O
+were	O
+observed	O
+.	O
+
+Torsade	B
+de	I
+pointes	I
+can	O
+be	O
+treated	O
+when	O
+recognized	O
+early	O
+,	O
+possibly	O
+without	O
+discontinuation	O
+of	O
+pentamidine	O
+.	O
+
+When	O
+QTc	B
+interval	I
+prolongation	I
+is	O
+observed	O
+,	O
+early	O
+magnesium	O
+supplementation	O
+is	O
+advocated	O
+.	O
+
+Efficacy	O
+and	O
+tolerability	O
+of	O
+lovastatin	O
+in	O
+3390	O
+women	O
+with	O
+moderate	O
+hypercholesterolemia	B
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+evaluate	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+lovastatin	O
+in	O
+women	O
+with	O
+moderate	O
+hypercholesterolemia	B
+.	O
+
+DESIGN	O
+:	O
+The	O
+Expanded	O
+Clinical	O
+Evaluation	O
+of	O
+Lovastatin	O
+(	O
+EXCEL	O
+)	O
+Study	O
+,	O
+a	O
+multicenter	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+diet	O
+-	O
+and	O
+placebo	O
+-	O
+controlled	O
+trial	O
+,	O
+in	O
+which	O
+participants	O
+were	O
+randomly	O
+assigned	O
+to	O
+receive	O
+placebo	O
+or	O
+lovastatin	O
+at	O
+doses	O
+of	O
+20	O
+or	O
+40	O
+mg	O
+once	O
+daily	O
+,	O
+or	O
+20	O
+or	O
+40	O
+mg	O
+twice	O
+daily	O
+for	O
+48	O
+weeks	O
+.	O
+
+SETTING	O
+:	O
+Ambulatory	O
+patients	O
+recruited	O
+by	O
+362	O
+participating	O
+centers	O
+throughout	O
+the	O
+United	O
+States	O
+.	O
+
+PATIENTS	O
+:	O
+Women	O
+(	O
+n	O
+=	O
+3390	O
+)	O
+from	O
+the	O
+total	O
+cohort	O
+of	O
+8245	O
+volunteers	O
+.	O
+
+MEASUREMENTS	O
+:	O
+Plasma	O
+total	O
+,	O
+low	O
+-	O
+density	O
+lipoprotein	O
+(	O
+LDL	O
+)	O
+,	O
+and	O
+high	O
+-	O
+density	O
+lipoprotein	O
+(	O
+HDL	O
+)	O
+cholesterol	O
+,	O
+and	O
+triglycerides	O
+;	O
+and	O
+laboratory	O
+and	O
+clinical	O
+evidence	O
+of	O
+adverse	O
+events	O
+monitored	O
+periodically	O
+throughout	O
+the	O
+study	O
+.	O
+
+RESULTS	O
+:	O
+Among	O
+women	O
+,	O
+lovastatin	O
+(	O
+20	O
+to	O
+80	O
+mg	O
+/	O
+d	O
+)	O
+produced	O
+sustained	O
+(	O
+12	O
+-	O
+to	O
+48	O
+-	O
+week	O
+)	O
+,	O
+dose	O
+-	O
+related	O
+changes	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+:	O
+decreases	O
+in	O
+LDL	O
+cholesterol	O
+(	O
+24	O
+%	O
+to	O
+40	O
+%	O
+)	O
+and	O
+triglycerides	O
+(	O
+9	O
+%	O
+to	O
+18	O
+%	O
+)	O
+,	O
+and	O
+increases	O
+in	O
+HDL	O
+cholesterol	O
+(	O
+6	O
+.	O
+7	O
+%	O
+to	O
+8	O
+.	O
+6	O
+%	O
+)	O
+.	O
+
+Depending	O
+on	O
+the	O
+dose	O
+,	O
+from	O
+82	O
+%	O
+to	O
+95	O
+%	O
+of	O
+lovastatin	O
+-	O
+treated	O
+women	O
+achieved	O
+the	O
+National	O
+Cholesterol	O
+Education	O
+Program	O
+goal	O
+of	O
+LDL	O
+cholesterol	O
+levels	O
+less	O
+than	O
+4	O
+.	O
+14	O
+mmol	O
+/	O
+L	O
+(	O
+160	O
+mg	O
+/	O
+dL	O
+)	O
+,	O
+and	O
+40	O
+%	O
+to	O
+87	O
+%	O
+achieved	O
+the	O
+goal	O
+of	O
+3	O
+.	O
+36	O
+mmol	O
+/	O
+L	O
+(	O
+130	O
+mg	O
+/	O
+dL	O
+)	O
+.	O
+
+Successive	O
+transaminase	O
+elevations	O
+greater	O
+than	O
+three	O
+times	O
+the	O
+upper	O
+limit	O
+of	O
+normal	O
+occurred	O
+in	O
+0	O
+.	O
+1	O
+%	O
+of	O
+women	O
+and	O
+were	O
+dose	O
+dependent	O
+above	O
+the	O
+20	O
+-	O
+mg	O
+dose	O
+.	O
+
+Myopathy	B
+,	O
+defined	O
+as	O
+muscle	O
+symptoms	O
+with	O
+creatine	O
+kinase	O
+elevations	O
+greater	O
+than	O
+10	O
+times	O
+the	O
+upper	O
+limit	O
+of	O
+normal	O
+,	O
+was	O
+rare	O
+and	O
+associated	O
+with	O
+the	O
+highest	O
+recommended	O
+daily	O
+dose	O
+of	O
+lovastatin	O
+(	O
+80	O
+mg	O
+)	O
+.	O
+
+Estrogen	O
+-	O
+replacement	O
+therapy	O
+appeared	O
+to	O
+have	O
+no	O
+effect	O
+on	O
+either	O
+the	O
+efficacy	O
+or	O
+safety	O
+profile	O
+of	O
+lovastatin	O
+.	O
+
+CONCLUSION	O
+:	O
+Lovastatin	O
+is	O
+highly	O
+effective	O
+and	O
+generally	O
+well	O
+tolerated	O
+as	O
+therapy	O
+for	O
+primary	O
+hypercholesterolemia	B
+in	O
+women	O
+.	O
+
+Tetany	B
+and	O
+rhabdomyolysis	B
+due	O
+to	O
+surreptitious	O
+furosemide	O
+-	O
+-	O
+importance	O
+of	O
+magnesium	O
+supplementation	O
+.	O
+
+Diuretics	O
+may	O
+induce	O
+hypokalemia	B
+,	O
+hypocalcemia	B
+and	O
+hypomagnesemia	B
+.	O
+
+While	O
+severe	O
+hypokalemia	B
+may	O
+cause	O
+muscle	B
+weakness	I
+,	O
+severe	O
+hypomagnesemia	B
+is	O
+associated	O
+with	O
+muscle	B
+spasms	I
+and	O
+tetany	B
+which	O
+cannot	O
+be	O
+corrected	O
+by	O
+potassium	O
+and	O
+calcium	O
+supplementation	O
+alone	O
+(	O
+1	O
+,	O
+2	O
+)	O
+.	O
+
+Surreptitious	O
+diuretic	O
+ingestion	O
+has	O
+been	O
+described	O
+,	O
+mainly	O
+in	O
+women	O
+who	O
+are	O
+concerned	O
+that	O
+they	O
+are	O
+obese	B
+or	O
+edematous	B
+.	O
+
+Symptomatic	O
+hypokalemia	B
+has	O
+been	O
+reported	O
+in	O
+such	O
+patients	O
+(	O
+3	O
+-	O
+7	O
+)	O
+and	O
+in	O
+one	O
+case	O
+hypocalcemia	B
+was	O
+observed	O
+(	O
+8	O
+)	O
+,	O
+but	O
+the	O
+effects	O
+of	O
+magnesium	O
+depletion	O
+were	O
+not	O
+noted	O
+in	O
+these	O
+patients	O
+.	O
+
+Ciprofloxacin	O
+-	O
+induced	O
+nephrotoxicity	B
+in	O
+patients	O
+with	O
+cancer	B
+.	O
+
+Nephrotoxicity	B
+associated	O
+with	O
+ciprofloxacin	O
+is	O
+uncommon	O
+.	O
+
+Five	O
+patients	O
+with	O
+cancer	B
+who	O
+developed	O
+acute	B
+renal	I
+failure	I
+that	O
+followed	O
+treatment	O
+with	O
+ciprofloxacin	O
+are	O
+described	O
+and	O
+an	O
+additional	O
+15	O
+cases	O
+reported	O
+in	O
+the	O
+literature	O
+are	O
+reviewed	O
+.	O
+
+Other	O
+than	O
+elevation	O
+of	O
+serum	O
+creatinine	O
+levels	O
+,	O
+characteristic	O
+clinical	O
+manifestations	O
+and	O
+abnormal	O
+laboratory	O
+findings	O
+are	O
+not	O
+frequently	O
+present	O
+.	O
+
+Allergic	O
+interstitial	B
+nephritis	I
+is	O
+believed	O
+to	O
+be	O
+the	O
+underlying	O
+pathological	O
+-	O
+process	O
+.	O
+
+Definitive	O
+diagnosis	O
+requires	O
+performance	O
+of	O
+renal	O
+biopsy	O
+,	O
+although	O
+this	O
+is	O
+not	O
+always	O
+feasible	O
+.	O
+
+An	O
+improvement	O
+in	O
+renal	O
+function	O
+that	O
+followed	O
+the	O
+discontinuation	O
+of	O
+the	O
+offending	O
+antibiotic	O
+supports	O
+the	O
+presumptive	O
+diagnosis	O
+of	O
+ciprofloxacin	O
+-	O
+induced	O
+acute	B
+renal	I
+failure	I
+.	O
+
+Venous	B
+complications	I
+of	O
+midazolam	O
+versus	O
+diazepam	O
+.	O
+
+Although	O
+some	O
+studies	O
+have	O
+suggested	O
+fewer	O
+venous	B
+complications	I
+are	O
+associated	O
+with	O
+midazolam	O
+than	O
+with	O
+diazepam	O
+for	O
+endoscopic	O
+procedures	O
+,	O
+this	O
+variable	O
+has	O
+not	O
+been	O
+well	O
+documented	O
+.	O
+
+We	O
+prospectively	O
+evaluated	O
+the	O
+incidence	O
+of	O
+venous	B
+complications	I
+after	O
+intravenous	O
+injection	O
+of	O
+diazepam	O
+or	O
+midazolam	O
+in	O
+122	O
+consecutive	O
+patients	O
+undergoing	O
+colonoscopy	O
+and	O
+esophagogastroduodenoscopy	O
+.	O
+
+Overall	O
+,	O
+venous	B
+complications	I
+were	O
+more	O
+frequent	O
+with	O
+diazepam	O
+(	O
+22	O
+of	O
+62	O
+patients	O
+)	O
+than	O
+with	O
+midazolam	O
+(	O
+4	O
+of	O
+60	O
+patients	O
+)	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+A	O
+palpable	O
+venous	O
+cord	O
+was	O
+present	O
+in	O
+23	O
+%	O
+(	O
+14	O
+of	O
+62	O
+)	O
+of	O
+patients	O
+in	O
+the	O
+diazepam	O
+group	O
+,	O
+compared	O
+with	O
+2	O
+%	O
+(	O
+1	O
+of	O
+60	O
+patients	O
+)	O
+in	O
+the	O
+midazolam	O
+group	O
+(	O
+p	O
+<	O
+0	O
+.	O
+002	O
+)	O
+.	O
+
+Pain	B
+at	O
+the	O
+injection	O
+site	O
+occurred	O
+in	O
+35	O
+%	O
+(	O
+22	O
+of	O
+62	O
+)	O
+of	O
+patients	O
+in	O
+the	O
+diazepam	O
+group	O
+compared	O
+with	O
+7	O
+%	O
+(	O
+4	O
+of	O
+60	O
+patients	O
+)	O
+in	O
+the	O
+midazolam	O
+group	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Swelling	B
+and	O
+warmth	O
+at	O
+the	O
+injection	O
+site	O
+were	O
+not	O
+significantly	O
+different	O
+between	O
+the	O
+two	O
+groups	O
+.	O
+
+Smoking	O
+,	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drug	O
+use	O
+,	O
+intravenous	O
+catheter	O
+site	O
+,	O
+dwell	O
+time	O
+of	O
+the	O
+needle	O
+,	O
+alcohol	O
+use	O
+,	O
+and	O
+pain	B
+during	O
+the	O
+injection	O
+had	O
+no	O
+effect	O
+on	O
+the	O
+incidence	O
+of	O
+venous	B
+complications	I
+.	O
+
+Clarithromycin	O
+-	O
+associated	O
+visual	B
+hallucinations	I
+in	O
+a	O
+patient	O
+with	O
+chronic	B
+renal	I
+failure	I
+on	O
+continuous	O
+ambulatory	O
+peritoneal	O
+dialysis	O
+.	O
+
+Visual	B
+hallucinations	I
+are	O
+a	O
+rare	O
+event	O
+in	O
+chronic	B
+renal	I
+failure	I
+and	O
+not	O
+related	O
+to	O
+uremia	B
+per	O
+se	O
+.	O
+
+Unreported	O
+in	O
+the	O
+literature	O
+is	O
+visual	B
+hallucinations	I
+occurring	O
+in	O
+association	O
+with	O
+the	O
+new	O
+macrolide	O
+antibiotic	O
+,	O
+clarithromycin	O
+.	O
+
+We	O
+describe	O
+such	O
+a	O
+case	O
+in	O
+a	O
+patient	O
+with	O
+end	B
+-	I
+stage	I
+renal	I
+disease	I
+(	O
+ESRD	B
+)	O
+maintained	O
+on	O
+continuous	O
+ambulatory	O
+peritoneal	O
+dialysis	O
+(	O
+CAPD	O
+)	O
+.	O
+
+The	O
+combination	O
+of	O
+a	O
+relatively	O
+high	O
+dose	O
+of	O
+clarithromycin	O
+in	O
+face	O
+of	O
+chronic	B
+renal	I
+failure	I
+in	O
+a	O
+functionally	O
+anephric	O
+patient	O
+,	O
+with	O
+underlying	O
+aluminum	O
+intoxication	O
+,	O
+may	O
+have	O
+facilitated	O
+the	O
+appearance	O
+of	O
+this	O
+neurotoxic	B
+side	O
+effect	O
+.	O
+
+It	O
+is	O
+important	O
+to	O
+understand	O
+the	O
+pharmacokinetics	O
+of	O
+medications	O
+in	O
+face	O
+of	O
+chronic	B
+renal	I
+failure	I
+,	O
+the	O
+possibility	O
+of	O
+drug	O
+interactions	O
+,	O
+and	O
+how	O
+these	O
+factors	O
+should	O
+help	O
+guide	O
+medication	O
+therapy	O
+in	O
+the	O
+ESRD	B
+patient	O
+.	O
+
+Changes	O
+in	O
+peroxisomes	O
+in	O
+preneoplastic	O
+liver	O
+and	O
+hepatoma	B
+of	O
+mice	O
+induced	O
+by	O
+alpha	O
+-	O
+benzene	O
+hexachloride	O
+.	O
+
+Peroxisomes	O
+in	O
+hepatomas	B
+and	O
+hyperplastic	O
+preneoplastic	O
+liver	B
+lesions	I
+induced	O
+in	O
+mice	O
+by	O
+500	O
+ppm	O
+alpha	O
+-	O
+benzene	O
+hexachloride	O
+were	O
+examined	O
+histochemically	O
+and	O
+electron	O
+microscopically	O
+.	O
+
+Although	O
+most	O
+of	O
+the	O
+hepatomas	B
+were	O
+well	O
+-	O
+differentiated	O
+tumors	B
+and	O
+contained	O
+a	O
+considerable	O
+number	O
+of	O
+peroxisomes	O
+,	O
+the	O
+tumor	B
+cells	O
+did	O
+not	O
+respond	O
+to	O
+ethyl	O
+-	O
+alpha	O
+-	O
+p	O
+-	O
+chlorophenoxyisobutyrate	O
+with	O
+proliferation	O
+of	O
+peroxisomes	O
+.	O
+
+At	O
+the	O
+16th	O
+week	O
+of	O
+carcinogen	O
+feeding	O
+,	O
+hyperplastic	O
+nodules	O
+appeared	O
+and	O
+advanced	O
+to	O
+further	O
+stages	O
+.	O
+
+A	O
+majority	O
+of	O
+the	O
+nodules	O
+showed	O
+a	O
+considerable	O
+number	O
+of	O
+peroxisomes	O
+and	O
+the	O
+inductive	O
+proliferation	O
+of	O
+peroxisomes	O
+.	O
+
+Within	O
+the	O
+nodules	O
+,	O
+foci	O
+of	O
+proliferation	O
+of	O
+the	O
+cells	O
+that	O
+showed	O
+no	O
+inducibility	O
+of	O
+proliferation	O
+of	O
+peroxisomes	O
+appeared	O
+.	O
+
+These	O
+cells	O
+proliferated	O
+further	O
+,	O
+replacing	O
+the	O
+most	O
+part	O
+of	O
+the	O
+nodules	O
+,	O
+and	O
+with	O
+this	O
+process	O
+hepatomas	B
+appeared	O
+to	O
+have	O
+been	O
+formed	O
+.	O
+
+No	O
+abnormal	O
+matrical	O
+inclusions	O
+of	O
+peroxisomes	O
+were	O
+formed	O
+in	O
+the	O
+cells	O
+of	O
+hyperplastic	O
+nodules	O
+by	O
+ethyl	O
+-	O
+alpha	O
+-	O
+p	O
+-	O
+chlorophenoxyisobutyrate	O
+unlike	O
+in	O
+the	O
+case	O
+of	O
+rats	O
+.	O
+
+Contribution	O
+of	O
+the	O
+sympathetic	O
+nervous	O
+system	O
+to	O
+salt	O
+-	O
+sensitivity	O
+in	O
+lifetime	O
+captopril	O
+-	O
+treated	O
+spontaneously	O
+hypertensive	B
+rats	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+test	O
+the	O
+hypothesis	O
+that	O
+,	O
+in	O
+lifetime	O
+captopril	O
+-	O
+treated	O
+spontaneously	O
+hypertensive	B
+rats	O
+(	O
+SHR	O
+)	O
+,	O
+the	O
+sympathetic	O
+nervous	O
+system	O
+contributes	O
+importantly	O
+to	O
+the	O
+hypertensive	B
+effect	O
+of	O
+dietary	O
+sodium	O
+chloride	O
+supplementation	O
+.	O
+
+METHODS	O
+:	O
+Male	O
+SHR	O
+(	O
+aged	O
+6	O
+weeks	O
+)	O
+that	O
+had	O
+been	O
+treated	O
+from	O
+conception	O
+onward	O
+with	O
+either	O
+captopril	O
+or	O
+vehicle	O
+remained	O
+on	O
+a	O
+basal	O
+sodium	O
+chloride	O
+diet	O
+or	O
+were	O
+fed	O
+a	O
+high	O
+sodium	O
+chloride	O
+diet	O
+.	O
+
+After	O
+2	O
+weeks	O
+,	O
+the	O
+rats	O
+were	O
+subjected	O
+to	O
+ganglionic	O
+blockade	O
+and	O
+2	O
+days	O
+later	O
+,	O
+an	O
+infusion	O
+of	O
+clonidine	O
+.	O
+
+RESULTS	O
+:	O
+Lifetime	O
+captopril	O
+treatment	O
+significantly	O
+lowered	O
+mean	O
+arterial	O
+pressure	O
+in	O
+both	O
+groups	O
+.	O
+
+Intravenous	O
+infusion	O
+of	O
+the	O
+ganglionic	O
+blocker	O
+hexamethonium	O
+resulted	O
+in	O
+a	O
+rapid	O
+decline	O
+in	O
+MAP	O
+that	O
+eliminated	O
+the	O
+dietary	O
+sodium	O
+chloride	O
+-	O
+induced	O
+increase	B
+in	I
+MAP	I
+in	O
+both	O
+groups	O
+.	O
+
+Infusion	O
+of	O
+the	O
+central	O
+nervous	O
+system	O
+alpha2	O
+-	O
+adrenergic	O
+receptor	O
+agonist	O
+clonidine	O
+also	O
+resulted	O
+in	O
+a	O
+greater	O
+reduction	O
+in	O
+MAP	O
+in	O
+both	O
+groups	O
+of	O
+SHR	O
+that	O
+were	O
+fed	O
+the	O
+high	O
+(	O
+compared	O
+with	O
+the	O
+basal	O
+)	O
+sodium	O
+chloride	O
+diet	O
+.	O
+
+CONCLUSIONS	O
+:	O
+In	O
+both	O
+lifetime	O
+captopril	O
+-	O
+treated	O
+and	O
+control	O
+SHR	O
+,	O
+the	O
+sympathetic	O
+nervous	O
+system	O
+contributes	O
+to	O
+the	O
+pressor	O
+effects	O
+of	O
+a	O
+high	O
+sodium	O
+chloride	O
+diet	O
+.	O
+
+Angioedema	B
+associated	O
+with	O
+droperidol	O
+administration	O
+.	O
+
+Angioedema	B
+,	O
+also	O
+known	O
+as	O
+angioneurotic	B
+edema	I
+or	O
+Quincke	B
+'	I
+s	I
+disease	I
+,	O
+is	O
+a	O
+well	O
+-	O
+demarcated	O
+,	O
+localized	O
+edema	B
+involving	O
+the	O
+subcutaneous	O
+tissues	O
+that	O
+may	O
+cause	O
+upper	B
+-	I
+airway	I
+obstruction	I
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+previously	O
+healthy	O
+19	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+no	O
+known	O
+drug	B
+allergies	I
+in	O
+whom	O
+angioedema	B
+with	O
+significant	O
+tongue	B
+swelling	I
+and	O
+protrusion	O
+developed	O
+within	O
+10	O
+minutes	O
+of	O
+the	O
+administration	O
+of	O
+a	O
+single	O
+IV	O
+dose	O
+of	O
+droperidol	O
+.	O
+
+Late	O
+cardiotoxicity	B
+after	O
+treatment	O
+for	O
+a	O
+malignant	O
+bone	B
+tumor	I
+.	O
+
+Cardiac	O
+function	O
+was	O
+assessed	O
+in	O
+long	O
+-	O
+term	O
+survivors	O
+of	O
+malignant	O
+bone	B
+tumors	I
+who	O
+were	O
+treated	O
+according	O
+to	O
+Rosen	O
+'	O
+s	O
+T5	O
+or	O
+T10	O
+protocol	O
+,	O
+both	O
+including	O
+doxorubicin	O
+.	O
+
+Thirty	O
+-	O
+one	O
+patients	O
+,	O
+age	O
+10	O
+-	O
+45	O
+years	O
+(	O
+median	O
+age	O
+17	O
+.	O
+8	O
+years	O
+)	O
+were	O
+evaluated	O
+2	O
+.	O
+3	O
+-	O
+14	O
+.	O
+1	O
+years	O
+(	O
+median	O
+8	O
+.	O
+9	O
+years	O
+)	O
+following	O
+completion	O
+of	O
+treatment	O
+.	O
+
+Cumulative	O
+doses	O
+of	O
+doxorubicin	O
+were	O
+225	O
+-	O
+550	O
+mg	O
+/	O
+m2	O
+(	O
+median	O
+dose	O
+360	O
+)	O
+.	O
+
+The	O
+evaluation	O
+consisted	O
+of	O
+a	O
+history	O
+,	O
+physical	O
+examination	O
+,	O
+electrocardiogram	O
+(	O
+ECG	O
+)	O
+,	O
+signal	O
+averaged	O
+ECG	O
+,	O
+24	O
+-	O
+hour	O
+ambulatory	O
+ECG	O
+,	O
+echocardiography	O
+and	O
+radionuclide	O
+angiography	O
+.	O
+
+Eighteen	O
+of	O
+31	O
+(	O
+58	O
+%	O
+)	O
+patients	O
+showed	O
+cardiac	B
+toxicity	I
+,	O
+defined	O
+as	O
+having	O
+one	O
+or	O
+more	O
+of	O
+the	O
+following	O
+abnormalities	O
+:	O
+late	O
+potentials	O
+,	O
+complex	O
+ventricular	B
+arrhythmias	I
+,	O
+left	O
+ventricular	B
+dilation	I
+,	O
+decreased	O
+shortening	O
+fraction	O
+,	O
+or	O
+decreased	O
+ejection	O
+fraction	O
+.	O
+
+The	O
+incidence	O
+of	O
+cardiac	B
+abnormalities	I
+increased	O
+with	O
+length	O
+of	O
+follow	O
+-	O
+up	O
+(	O
+P	O
+<	O
+or	O
+=	O
+.	O
+05	O
+)	O
+.	O
+
+No	O
+correlation	O
+could	O
+be	O
+demonstrated	O
+between	O
+cumulative	O
+dose	O
+of	O
+doxorubicin	O
+and	O
+cardiac	O
+status	O
+,	O
+except	O
+for	O
+heart	O
+rate	O
+variability	O
+.	O
+
+When	O
+adjusted	O
+to	O
+body	O
+surface	O
+area	O
+,	O
+the	O
+left	O
+ventricular	O
+posterior	O
+wall	O
+thickness	O
+(	O
+LVPW	O
+index	O
+)	O
+was	O
+decreased	O
+in	O
+all	O
+patients	O
+.	O
+
+The	O
+incidence	O
+of	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B
+is	O
+high	O
+and	O
+increases	O
+with	O
+follow	O
+-	O
+up	O
+,	O
+irrespective	O
+of	O
+cumulative	O
+dose	O
+.	O
+
+Life	O
+-	O
+long	O
+cardiac	O
+follow	O
+-	O
+up	O
+in	O
+these	O
+patients	O
+is	O
+warranted	O
+.	O
+
+The	O
+results	O
+of	O
+our	O
+study	O
+suggest	O
+that	O
+heart	O
+rate	O
+variability	O
+and	O
+LVPW	O
+index	O
+could	O
+be	O
+sensitive	O
+indicators	O
+for	O
+cardiotoxicity	B
+.	O
+
+Acute	O
+blood	O
+pressure	O
+elevations	O
+with	O
+caffeine	O
+in	O
+men	O
+with	O
+borderline	O
+systemic	O
+hypertension	B
+.	O
+
+Whether	O
+the	O
+vasoconstrictive	O
+actions	O
+of	O
+caffeine	O
+are	O
+enhanced	O
+in	O
+hypertensive	B
+persons	O
+has	O
+not	O
+been	O
+demonstrated	O
+.	O
+
+Thus	O
+,	O
+caffeine	O
+(	O
+3	O
+.	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+versus	O
+placebo	O
+was	O
+tested	O
+in	O
+48	O
+healthy	O
+men	O
+(	O
+aged	O
+20	O
+to	O
+35	O
+years	O
+)	O
+selected	O
+after	O
+screening	O
+on	O
+2	O
+separate	O
+occasions	O
+.	O
+
+Borderline	O
+hypertensive	B
+men	O
+(	O
+n	O
+=	O
+24	O
+)	O
+were	O
+selected	O
+with	O
+screening	O
+systolic	O
+blood	O
+pressure	O
+(	O
+BP	O
+)	O
+of	O
+140	O
+to	O
+160	O
+mm	O
+Hg	O
+and	O
+/	O
+or	O
+diastolic	O
+BP	O
+90	O
+to	O
+99	O
+mm	O
+Hg	O
+.	O
+
+Low	O
+-	O
+risk	O
+controls	O
+(	O
+n	O
+=	O
+24	O
+)	O
+reported	O
+no	O
+parental	O
+history	O
+of	O
+hypertension	B
+and	O
+had	O
+screening	O
+BP	O
+<	O
+130	O
+/	O
+85	O
+mm	O
+Hg	O
+.	O
+
+Participants	O
+were	O
+then	O
+tested	O
+on	O
+2	O
+occasions	O
+after	O
+12	O
+-	O
+hour	O
+abstinence	O
+from	O
+caffeine	O
+in	O
+each	O
+of	O
+2	O
+protocols	O
+;	O
+this	O
+required	O
+a	O
+total	O
+of	O
+4	O
+laboratory	O
+visits	O
+.	O
+
+Caffeine	O
+-	O
+induced	O
+changes	O
+in	O
+diastolic	O
+BP	O
+were	O
+2	O
+to	O
+3	O
+times	O
+larger	O
+in	O
+borderline	O
+subjects	O
+than	O
+in	O
+controls	O
+(	O
++	O
+8	O
+.	O
+4	O
+vs	O
++	O
+3	O
+.	O
+8	O
+mm	O
+Hg	O
+,	O
+p	O
+<	O
+0	O
+.	O
+0001	O
+)	O
+,	O
+and	O
+were	O
+attributable	O
+to	O
+larger	O
+changes	O
+in	O
+impedance	O
+-	O
+derived	O
+measures	O
+of	O
+systemic	O
+vascular	O
+resistance	O
+(	O
++	O
+135	O
+vs	O
++	O
+45	O
+dynes	O
+.	O
+s	O
+.	O
+cm	O
+-	O
+5	O
+,	O
+p	O
+<	O
+0	O
+.	O
+004	O
+)	O
+.	O
+
+These	O
+findings	O
+were	O
+consistent	O
+and	O
+reached	O
+significance	O
+in	O
+both	O
+protocols	O
+.	O
+
+The	O
+percentage	O
+of	O
+borderline	O
+subjects	O
+in	O
+whom	O
+diastolic	O
+BP	O
+changes	O
+exceeded	O
+the	O
+median	O
+control	O
+response	O
+was	O
+96	O
+%	O
+.	O
+
+Consequently	O
+,	O
+whereas	O
+all	O
+participants	O
+exhibited	O
+normotensive	O
+levels	O
+during	O
+the	O
+resting	O
+predrug	O
+baseline	O
+,	O
+33	O
+%	O
+of	O
+borderline	O
+subjects	O
+achieved	O
+hypertensive	B
+BP	O
+levels	O
+after	O
+caffeine	O
+ingestion	O
+.	O
+
+Thus	O
+,	O
+in	O
+borderline	O
+hypertensive	B
+men	O
+,	O
+exaggerated	O
+responses	O
+to	O
+caffeine	O
+were	O
+:	O
+selective	O
+for	O
+diastolic	O
+BP	O
+,	O
+consistent	O
+with	O
+greater	O
+vasoconstriction	O
+,	O
+replicated	O
+in	O
+2	O
+protocols	O
+,	O
+and	O
+representative	O
+of	O
+nearly	O
+all	O
+borderline	O
+hypertensives	B
+.	O
+
+We	O
+suspect	O
+that	O
+the	O
+potential	O
+for	O
+caffeine	O
+to	O
+stabilize	O
+high	O
+resistance	O
+states	O
+in	O
+susceptible	O
+persons	O
+suggests	O
+that	O
+its	O
+use	O
+may	O
+facilitate	O
+their	O
+disease	O
+progression	O
+,	O
+as	O
+well	O
+as	O
+hinder	O
+accurate	O
+diagnosis	O
+and	O
+treatment	O
+.	O
+
+Absence	O
+of	O
+effect	O
+of	O
+sertraline	O
+on	O
+time	O
+-	O
+based	O
+sensitization	O
+of	O
+cognitive	B
+impairment	I
+with	O
+haloperidol	O
+.	O
+
+This	O
+double	O
+-	O
+blind	O
+,	O
+randomized	O
+,	O
+placebo	O
+-	O
+controlled	O
+study	O
+evaluated	O
+the	O
+effects	O
+of	O
+haloperidol	O
+alone	O
+and	O
+haloperidol	O
+plus	O
+sertraline	O
+on	O
+cognitive	O
+and	O
+psychomotor	O
+function	O
+in	O
+24	O
+healthy	O
+male	O
+subjects	O
+.	O
+
+METHOD	O
+:	O
+All	O
+subjects	O
+received	O
+placebo	O
+on	O
+Day	O
+1	O
+and	O
+haloperidol	O
+2	O
+mg	O
+on	O
+Days	O
+2	O
+and	O
+25	O
+.	O
+
+From	O
+Days	O
+9	O
+to	O
+25	O
+,	O
+subjects	O
+were	O
+randomly	O
+assigned	O
+to	O
+either	O
+sertraline	O
+(	O
+12	O
+subjects	O
+)	O
+or	O
+placebo	O
+(	O
+12	O
+subjects	O
+)	O
+;	O
+the	O
+sertraline	O
+dose	O
+was	O
+titrated	O
+from	O
+50	O
+to	O
+200	O
+mg	O
+/	O
+day	O
+from	O
+Days	O
+9	O
+to	O
+16	O
+,	O
+and	O
+remained	O
+at	O
+200	O
+mg	O
+/	O
+day	O
+for	O
+the	O
+final	O
+10	O
+days	O
+of	O
+the	O
+drug	O
+administration	O
+period	O
+.	O
+
+Cognitive	O
+function	O
+testing	O
+was	O
+performed	O
+before	O
+dosing	O
+and	O
+over	O
+a	O
+24	O
+-	O
+hour	O
+period	O
+after	O
+dosing	O
+on	O
+Days	O
+1	O
+,	O
+2	O
+,	O
+and	O
+25	O
+.	O
+
+RESULTS	O
+:	O
+Impairment	B
+of	I
+cognitive	I
+function	I
+was	O
+observed	O
+6	O
+to	O
+8	O
+hours	O
+after	O
+administration	O
+of	O
+haloperidol	O
+on	O
+Day	O
+2	O
+but	O
+was	O
+not	O
+evident	O
+23	O
+hours	O
+after	O
+dosing	O
+.	O
+
+When	O
+single	O
+-	O
+dose	O
+haloperidol	O
+was	O
+given	O
+again	O
+25	O
+days	O
+later	O
+,	O
+greater	O
+impairment	O
+with	O
+earlier	O
+onset	O
+was	O
+noted	O
+in	O
+several	O
+tests	O
+in	O
+both	O
+treatment	O
+groups	O
+,	O
+suggesting	O
+enhancement	O
+of	O
+this	O
+effect	O
+.	O
+
+There	O
+was	O
+no	O
+indication	O
+that	O
+sertraline	O
+exacerbated	O
+the	O
+impairment	O
+produced	O
+by	O
+haloperidol	O
+since	O
+an	O
+equivalent	O
+effect	O
+also	O
+occurred	O
+in	O
+the	O
+placebo	O
+group	O
+.	O
+
+Three	O
+subjects	O
+(	O
+2	O
+on	O
+sertraline	O
+and	O
+1	O
+on	O
+placebo	O
+)	O
+withdrew	O
+from	O
+the	O
+study	O
+because	O
+of	O
+side	O
+effects	O
+.	O
+
+Ten	O
+subjects	O
+in	O
+each	O
+group	O
+reported	O
+side	O
+effects	O
+related	O
+to	O
+treatment	O
+.	O
+
+The	O
+side	O
+effect	O
+profiles	O
+of	O
+sertraline	O
+and	O
+of	O
+placebo	O
+were	O
+similar	O
+.	O
+
+CONCLUSION	O
+:	O
+Haloperidol	O
+produced	O
+a	O
+clear	O
+profile	O
+of	O
+cognitive	B
+impairment	I
+that	O
+was	O
+not	O
+worsened	O
+by	O
+concomitant	O
+sertraline	O
+administration	O
+.	O
+
+Coexistence	O
+of	O
+cerebral	B
+venous	I
+sinus	I
+and	I
+internal	I
+carotid	I
+artery	I
+thrombosis	I
+associated	O
+with	O
+exogenous	O
+sex	O
+hormones	O
+.	O
+
+A	O
+case	O
+report	O
+.	O
+
+A	O
+forty	O
+-	O
+six	O
+year	O
+-	O
+old	O
+premenopausal	O
+woman	O
+developed	O
+headache	B
+,	O
+nausea	B
+and	O
+vomiting	B
+,	O
+left	O
+hemiparesis	B
+and	O
+seizure	B
+two	O
+days	O
+after	O
+parenteral	O
+use	O
+of	O
+progesterone	O
+and	O
+estradiol	O
+.	O
+
+Diabetes	B
+mellitus	I
+(	O
+DM	B
+)	O
+was	O
+found	O
+during	O
+admission	O
+.	O
+
+Computed	O
+tomography	O
+showed	O
+a	O
+hemorrhagic	B
+infarct	I
+in	O
+the	O
+right	O
+frontal	O
+lobe	O
+and	O
+increased	O
+density	O
+in	O
+the	O
+superior	O
+sagittal	O
+sinus	O
+(	O
+SSS	O
+)	O
+.	O
+
+Left	O
+carotid	O
+angiography	O
+found	O
+occlusion	B
+of	I
+the	I
+left	I
+internal	I
+carotid	I
+artery	I
+(	O
+ICA	O
+)	O
+.	O
+
+Right	O
+carotid	O
+angiograms	O
+failed	O
+to	O
+show	O
+the	O
+SSS	O
+and	O
+inferior	O
+sagittal	O
+sinus	O
+,	O
+suggestive	O
+of	O
+venous	B
+sinus	I
+thrombosis	I
+.	O
+
+Coexistence	O
+of	O
+the	O
+cerebral	B
+artery	I
+and	I
+the	I
+venous	I
+sinus	I
+occlusion	I
+has	O
+been	O
+described	O
+infrequently	O
+.	O
+
+In	O
+this	O
+case	O
+,	O
+the	O
+authors	O
+postulate	O
+that	O
+the	O
+use	O
+of	O
+estradiol	O
+and	O
+progesterone	O
+and	O
+the	O
+underlying	O
+DM	B
+increased	O
+vascular	O
+thrombogenicity	O
+,	O
+which	O
+provided	O
+a	O
+common	O
+denominator	O
+for	O
+thrombosis	B
+of	I
+both	I
+the	I
+ICA	I
+and	I
+the	I
+venous	I
+sinus	I
+.	O
+
+Chemotherapy	O
+of	O
+advanced	O
+inoperable	O
+non	B
+-	I
+small	I
+cell	I
+lung	I
+cancer	I
+with	O
+paclitaxel	O
+:	O
+a	O
+phase	O
+II	O
+trial	O
+.	O
+
+Paclitaxel	O
+(	O
+Taxol	O
+;	O
+Bristol	O
+-	O
+Myers	O
+Squibb	O
+Company	O
+,	O
+Princeton	O
+,	O
+NJ	O
+)	O
+has	O
+demonstrated	O
+significant	O
+antineoplastic	O
+activity	O
+against	O
+different	O
+tumor	B
+types	O
+,	O
+notably	O
+ovarian	B
+and	I
+breast	I
+carcinoma	I
+.	O
+
+Two	O
+phase	O
+II	O
+trials	O
+of	O
+24	O
+-	O
+hour	O
+paclitaxel	O
+infusions	O
+in	O
+chemotherapy	O
+-	O
+naive	O
+patients	O
+with	O
+stage	O
+IIIB	O
+or	O
+IV	O
+non	B
+-	I
+small	I
+cell	I
+lung	I
+cancer	I
+(	O
+NSCLC	B
+)	O
+reported	O
+response	O
+rates	O
+of	O
+21	O
+%	O
+and	O
+24	O
+%	O
+.	O
+
+Leukopenia	B
+was	O
+dose	O
+limiting	O
+:	O
+as	O
+many	O
+as	O
+62	O
+.	O
+5	O
+%	O
+of	O
+patients	O
+experienced	O
+grade	O
+4	O
+leukopenia	B
+.	O
+
+We	O
+investigated	O
+the	O
+efficacy	O
+and	O
+toxicity	B
+of	O
+a	O
+3	O
+-	O
+hour	O
+paclitaxel	O
+infusion	O
+in	O
+a	O
+phase	O
+II	O
+trial	O
+in	O
+patients	O
+with	O
+inoperable	O
+stage	O
+IIIB	O
+or	O
+IV	O
+NSCLC	B
+.	O
+
+The	O
+58	O
+patients	O
+treated	O
+(	O
+41	O
+men	O
+and	O
+17	O
+women	O
+)	O
+had	O
+a	O
+median	O
+age	O
+of	O
+59	O
+years	O
+(	O
+age	O
+range	O
+,	O
+25	O
+to	O
+75	O
+)	O
+and	O
+a	O
+performance	O
+status	O
+of	O
+0	O
+through	O
+2	O
+.	O
+
+Most	O
+patients	O
+(	O
+72	O
+.	O
+4	O
+%	O
+)	O
+had	O
+stage	O
+IV	O
+NSCLC	B
+.	O
+
+Paclitaxel	O
+225	O
+mg	O
+/	O
+m2	O
+was	O
+infused	O
+over	O
+3	O
+hours	O
+every	O
+3	O
+weeks	O
+with	O
+standard	O
+prophylactic	O
+premedication	O
+.	O
+
+Of	O
+50	O
+patients	O
+evaluable	O
+for	O
+response	O
+,	O
+12	O
+(	O
+24	O
+%	O
+)	O
+had	O
+partial	O
+remission	O
+,	O
+26	O
+(	O
+52	O
+%	O
+)	O
+had	O
+no	O
+change	O
+,	O
+and	O
+12	O
+had	O
+disease	O
+progression	O
+(	O
+24	O
+%	O
+)	O
+.	O
+
+Hematologic	O
+toxicities	B
+were	O
+mild	O
+:	O
+only	O
+one	O
+patient	O
+(	O
+2	O
+%	O
+)	O
+developed	O
+grade	O
+3	O
+or	O
+4	O
+neutropenia	B
+,	O
+while	O
+29	O
+%	O
+had	O
+grade	O
+1	O
+or	O
+2	O
+.	O
+
+Grade	O
+1	O
+or	O
+2	O
+polyneuropathy	B
+affected	O
+56	O
+%	O
+of	O
+patients	O
+while	O
+only	O
+one	O
+(	O
+2	O
+%	O
+)	O
+experienced	O
+severe	O
+polyneuropathy	B
+.	O
+
+Similarly	O
+,	O
+grade	O
+1	O
+or	O
+2	O
+myalgia	B
+/	O
+arthralgia	B
+was	O
+observed	O
+in	O
+63	O
+.	O
+2	O
+%	O
+of	O
+patients	O
+,	O
+but	O
+only	O
+14	O
+.	O
+3	O
+%	O
+experienced	O
+grade	O
+3	O
+or	O
+4	O
+.	O
+
+Nausea	B
+and	O
+vomiting	B
+were	O
+infrequent	O
+,	O
+with	O
+14	O
+%	O
+of	O
+patients	O
+experiencing	O
+grade	O
+1	O
+or	O
+2	O
+and	O
+only	O
+2	O
+%	O
+experiencing	O
+grade	O
+3	O
+or	O
+4	O
+.	O
+
+Paclitaxel	O
+is	O
+thus	O
+an	O
+active	O
+single	O
+agent	O
+in	O
+this	O
+patient	O
+population	O
+,	O
+with	O
+a	O
+3	O
+-	O
+hour	O
+infusion	O
+proving	O
+comparably	O
+effective	O
+to	O
+a	O
+24	O
+-	O
+hour	O
+infusion	O
+and	O
+superior	O
+in	O
+terms	O
+of	O
+the	O
+incidence	O
+of	O
+hematologic	O
+and	O
+nonhematologic	O
+toxicity	B
+.	O
+
+Further	O
+phase	O
+II	O
+studies	O
+with	O
+paclitaxel	O
+combined	O
+with	O
+other	O
+drugs	O
+active	O
+against	O
+NSCLC	B
+are	O
+indicated	O
+,	O
+and	O
+phase	O
+III	O
+studies	O
+comparing	O
+paclitaxel	O
+with	O
+standard	O
+chemotherapy	O
+remain	O
+to	O
+be	O
+completed	O
+.	O
+
+Paclitaxel	O
+combined	O
+with	O
+carboplatin	O
+in	O
+the	O
+first	O
+-	O
+line	O
+treatment	O
+of	O
+advanced	O
+ovarian	B
+cancer	I
+.	O
+
+In	O
+a	O
+phase	O
+I	O
+study	O
+to	O
+determine	O
+the	O
+maximum	O
+tolerated	O
+dose	O
+of	O
+paclitaxel	O
+(	O
+Taxol	O
+;	O
+Bristol	O
+-	O
+Myers	O
+Squibb	O
+Company	O
+,	O
+Princeton	O
+,	O
+NJ	O
+)	O
+given	O
+as	O
+a	O
+3	O
+-	O
+hour	O
+infusion	O
+in	O
+combination	O
+with	O
+carboplatin	O
+administered	O
+every	O
+21	O
+days	O
+to	O
+women	O
+with	O
+advanced	O
+ovarian	B
+cancer	I
+,	O
+paclitaxel	O
+doses	O
+were	O
+escalated	O
+as	O
+follows	O
+:	O
+level	O
+1	O
+,	O
+135	O
+mg	O
+/	O
+m2	O
+;	O
+level	O
+2	O
+,	O
+160	O
+mg	O
+/	O
+m2	O
+;	O
+level	O
+3	O
+,	O
+185	O
+mg	O
+/	O
+m2	O
+;	O
+and	O
+level	O
+4	O
+,	O
+210	O
+mg	O
+/	O
+m2	O
+.	O
+
+The	O
+fixed	O
+dose	O
+of	O
+carboplatin	O
+at	O
+levels	O
+1	O
+through	O
+4	O
+was	O
+given	O
+to	O
+achieve	O
+an	O
+area	O
+under	O
+the	O
+concentration	O
+-	O
+time	O
+curve	O
+(	O
+AUC	O
+)	O
+of	O
+5	O
+using	O
+the	O
+Calvert	O
+formula	O
+.	O
+
+In	O
+levels	O
+5	O
+and	O
+6	O
+the	O
+carboplatin	O
+dose	O
+was	O
+targeted	O
+at	O
+AUCs	O
+of	O
+6	O
+and	O
+7	O
+.	O
+5	O
+,	O
+respectively	O
+,	O
+combined	O
+with	O
+a	O
+fixed	O
+paclitaxel	O
+dose	O
+of	O
+185	O
+mg	O
+/	O
+m2	O
+.	O
+
+To	O
+date	O
+,	O
+30	O
+previously	O
+untreated	O
+patients	O
+,	O
+all	O
+with	O
+a	O
+good	O
+performance	O
+status	O
+(	O
+Eastern	O
+Cooperative	O
+Oncology	O
+Group	O
+0	O
+to	O
+2	O
+)	O
+have	O
+been	O
+entered	O
+into	O
+this	O
+ongoing	O
+study	O
+.	O
+
+The	O
+dose	O
+-	O
+limiting	O
+toxicity	B
+of	O
+the	O
+combination	O
+was	O
+myelosuppression	B
+(	O
+leukopenia	B
+,	O
+granulocytopenia	B
+,	O
+and	O
+thrombocytopenia	B
+)	O
+.	O
+
+Neurotoxicity	B
+was	O
+largely	O
+moderate	O
+.	O
+
+So	O
+far	O
+,	O
+14	O
+patients	O
+are	O
+evaluable	O
+for	O
+response	O
+;	O
+of	O
+these	O
+,	O
+eight	O
+(	O
+57	O
+%	O
+)	O
+showed	O
+objective	O
+(	O
+complete	O
+or	O
+partial	O
+)	O
+response	O
+and	O
+disease	O
+stabilized	O
+in	O
+six	O
+patients	O
+.	O
+
+No	O
+patient	O
+had	O
+disease	O
+progression	O
+.	O
+
+We	O
+conclude	O
+that	O
+the	O
+combination	O
+of	O
+paclitaxel	O
+185	O
+mg	O
+/	O
+m2	O
+administered	O
+as	O
+a	O
+3	O
+-	O
+hour	O
+infusion	O
+followed	O
+immediately	O
+by	O
+a	O
+1	O
+-	O
+hour	O
+infusion	O
+of	O
+carboplatin	O
+at	O
+an	O
+AUC	O
+of	O
+6	O
+can	O
+be	O
+administered	O
+safely	O
+in	O
+a	O
+21	O
+-	O
+day	O
+schedule	O
+in	O
+the	O
+outpatient	O
+setting	O
+.	O
+
+The	O
+recommended	O
+dose	O
+for	O
+phase	O
+III	O
+studies	O
+is	O
+paclitaxel	O
+185	O
+mg	O
+/	O
+m2	O
+and	O
+carboplatin	O
+AUC	O
+6	O
+.	O
+
+Effects	O
+of	O
+acute	O
+steroid	O
+administration	O
+on	O
+ventilatory	O
+and	O
+peripheral	O
+muscles	O
+in	O
+rats	O
+.	O
+
+Occasional	O
+case	O
+reports	O
+have	O
+shown	O
+that	O
+acute	O
+myopathy	B
+may	O
+occur	O
+in	O
+patients	O
+treated	O
+with	O
+massive	O
+doses	O
+of	O
+corticosteroids	O
+.	O
+
+The	O
+mechanism	O
+of	O
+this	O
+myopathy	B
+is	O
+poorly	O
+understood	O
+.	O
+
+Therefore	O
+,	O
+60	O
+male	O
+rats	O
+were	O
+randomly	O
+assigned	O
+to	O
+receive	O
+daily	O
+injection	O
+of	O
+saline	O
+(	O
+C	O
+)	O
+,	O
+methylprednisolone	O
+(	O
+M	O
+)	O
+,	O
+or	O
+triamcinolone	O
+(	O
+T	O
+)	O
+80	O
+mg	O
+/	O
+kg	O
+/	O
+d	O
+for	O
+5	O
+d	O
+.	O
+
+Nutritional	O
+intake	O
+,	O
+measured	O
+daily	O
+in	O
+15	O
+animals	O
+,	O
+showed	O
+a	O
+significant	O
+reduction	B
+of	I
+food	I
+intake	I
+in	O
+the	O
+steroid	O
+-	O
+treated	O
+groups	O
+(	O
+-	O
+50	O
+and	O
+-	O
+79	O
+%	O
+in	O
+M	O
+and	O
+T	O
+,	O
+respectively	O
+)	O
+.	O
+
+This	O
+was	O
+associated	O
+with	O
+a	O
+similar	O
+loss	B
+in	I
+body	I
+weight	I
+.	O
+
+In	O
+the	O
+45	O
+remaining	O
+animals	O
+,	O
+diaphragm	O
+contractility	O
+and	O
+histopathologic	O
+features	O
+of	O
+several	O
+muscles	O
+were	O
+studied	O
+.	O
+
+Weights	O
+of	O
+respiratory	O
+and	O
+peripheral	O
+muscles	O
+were	O
+similarly	O
+decreased	O
+after	O
+steroid	O
+treatment	O
+.	O
+
+Maximal	O
+twitches	O
+of	O
+the	O
+diaphragm	O
+were	O
+lower	O
+in	O
+the	O
+C	O
+group	O
+(	O
+653	O
++	O
+/	O
+-	O
+174	O
+g	O
+/	O
+cm	O
+(	O
+2	O
+)	O
+)	O
+than	O
+in	O
+the	O
+M	O
+group	O
+(	O
+837	O
++	O
+/	O
+-	O
+171	O
+g	O
+/	O
+cm	O
+(	O
+2	O
+)	O
+;	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+and	O
+the	O
+T	O
+group	O
+(	O
+765	O
++	O
+/	O
+-	O
+145	O
+g	O
+/	O
+cm	O
+(	O
+2	O
+)	O
+,	O
+NS	O
+)	O
+.	O
+
+Half	O
+-	O
+relaxation	O
+time	O
+was	O
+prolonged	O
+in	O
+both	O
+steroid	O
+groups	O
+,	O
+and	O
+time	O
+to	O
+peak	O
+tension	O
+was	O
+longer	O
+with	O
+M	O
+,	O
+whereas	O
+tetanic	B
+tensions	O
+were	O
+similar	O
+.	O
+
+Steroid	O
+treatment	O
+also	O
+induced	O
+a	O
+leftward	O
+shift	O
+of	O
+the	O
+force	O
+-	O
+frequency	O
+curve	O
+at	O
+25	O
+and	O
+50	O
+Hz	O
+when	O
+compared	O
+with	O
+saline	O
+treatment	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+ATPase	O
+staining	O
+of	O
+the	O
+diaphragm	O
+,	O
+scalenus	O
+medius	O
+,	O
+and	O
+gastrocnemius	O
+showed	O
+type	O
+IIb	O
+fiber	O
+atrophy	B
+in	O
+the	O
+steroid	O
+groups	O
+and	O
+also	O
+diaphragmatic	O
+type	O
+IIa	O
+atrophy	B
+with	O
+T	O
+,	O
+whereas	O
+histologic	O
+examinations	O
+revealed	O
+a	O
+normal	O
+muscular	O
+pattern	O
+with	O
+absence	O
+of	O
+necrosis	B
+.	O
+
+Finally	O
+,	O
+a	O
+pair	O
+-	O
+fed	O
+(	O
+PF	O
+)	O
+study	O
+,	O
+performed	O
+in	O
+18	O
+rats	O
+(	O
+C	O
+,	O
+T	O
+,	O
+and	O
+PF	O
+)	O
+,	O
+showed	O
+that	O
+muscle	B
+atrophy	I
+was	O
+considerably	O
+less	O
+pronounced	O
+in	O
+PF	O
+animals	O
+than	O
+in	O
+T	O
+-	O
+treated	O
+animals	O
+.	O
+
+We	O
+conclude	O
+that	O
+(	O
+1	O
+)	O
+short	O
+-	O
+term	O
+treatment	O
+with	O
+massive	O
+doses	O
+of	O
+steroids	O
+induced	O
+severe	O
+respiratory	O
+and	O
+limb	O
+muscle	O
+wasting	O
+;	O
+(	O
+2	O
+)	O
+both	O
+types	O
+of	O
+steroids	O
+induced	O
+predominantly	O
+type	O
+IIb	O
+atrophy	B
+,	O
+resulting	O
+in	O
+the	O
+expected	O
+alterations	O
+in	O
+diaphragm	O
+contractile	O
+properties	O
+;	O
+(	O
+3	O
+)	O
+neither	O
+steroid	O
+caused	O
+muscle	O
+necrosis	B
+;	O
+(	O
+4	O
+)	O
+type	O
+IIb	O
+atrophy	B
+was	O
+not	O
+caused	O
+by	O
+acute	O
+nutritional	O
+deprivation	O
+alone	O
+.	O
+
+Continuous	O
+subcutaneous	O
+administration	O
+of	O
+mesna	O
+to	O
+prevent	O
+ifosfamide	O
+-	O
+induced	O
+hemorrhagic	B
+cystitis	I
+.	O
+
+Hemorrhagic	B
+cystitis	I
+is	O
+a	O
+major	O
+potential	O
+toxicity	B
+of	O
+ifosfamide	O
+that	O
+can	O
+be	O
+prevented	O
+by	O
+administering	O
+mesna	O
+along	O
+with	O
+the	O
+cytotoxic	O
+agent	O
+.	O
+
+Mesna	O
+is	O
+generally	O
+administered	O
+by	O
+the	O
+intravenous	O
+route	O
+,	O
+although	O
+experience	O
+with	O
+oral	O
+delivery	O
+of	O
+the	O
+drug	O
+has	O
+increased	O
+.	O
+
+The	O
+continuous	O
+subcutaneous	O
+administration	O
+of	O
+mesna	O
+has	O
+the	O
+advantage	O
+of	O
+not	O
+requiring	O
+intravenous	O
+access	O
+.	O
+
+In	O
+addition	O
+,	O
+subcutaneous	O
+delivery	O
+of	O
+the	O
+neutralizing	O
+agent	O
+will	O
+not	O
+be	O
+associated	O
+with	O
+the	O
+risk	O
+of	O
+inadequate	O
+urinary	O
+mesna	O
+concentrations	O
+,	O
+such	O
+as	O
+in	O
+a	O
+patient	O
+taking	O
+oral	O
+mesna	O
+who	O
+experiences	O
+severe	O
+ifosfamide	O
+-	O
+induced	O
+emesis	B
+and	O
+is	O
+unable	O
+to	O
+absorb	O
+the	O
+drug	O
+.	O
+
+Limited	O
+clinical	O
+experience	O
+with	O
+continuous	O
+subcutaneous	O
+mesna	O
+administration	O
+suggests	O
+it	O
+is	O
+a	O
+safe	O
+,	O
+practical	O
+,	O
+and	O
+economic	O
+method	O
+of	O
+drug	O
+delivery	O
+that	O
+permits	O
+ifosfamide	O
+to	O
+be	O
+administered	O
+successfully	O
+in	O
+the	O
+outpatient	O
+setting	O
+.	O
+
+Leg	B
+and	I
+back	I
+pain	I
+after	O
+spinal	O
+anaesthesia	O
+involving	O
+hyperbaric	O
+5	O
+%	O
+lignocaine	O
+.	O
+
+Fifty	O
+-	O
+four	O
+patients	O
+,	O
+aged	O
+27	O
+-	O
+90	O
+years	O
+,	O
+who	O
+were	O
+given	O
+lignocaine	O
+5	O
+%	O
+in	O
+6	O
+.	O
+8	O
+%	O
+glucose	O
+solution	O
+for	O
+spinal	O
+anaesthesia	O
+were	O
+studied	O
+.	O
+
+Thirteen	O
+of	O
+these	O
+patients	O
+experienced	O
+pain	B
+in	I
+the	I
+legs	I
+and	I
+/	I
+or	I
+back	I
+after	O
+recovery	O
+from	O
+anaesthesia	O
+.	O
+
+The	O
+patients	O
+affected	O
+were	O
+younger	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+and	O
+the	O
+site	O
+of	O
+the	O
+dural	O
+puncture	O
+was	O
+higher	O
+(	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+than	O
+those	O
+individuals	O
+without	O
+pain	B
+.	O
+
+Five	O
+of	O
+the	O
+13	O
+patients	O
+(	O
+38	O
+%	O
+)	O
+with	O
+pain	B
+and	O
+seven	O
+of	O
+the	O
+41	O
+patients	O
+(	O
+17	O
+%	O
+)	O
+without	O
+pain	B
+admitted	O
+to	O
+a	O
+high	O
+alcohol	O
+intake	O
+,	O
+which	O
+might	O
+be	O
+a	O
+contributing	O
+factor	O
+.	O
+
+Leg	B
+and	I
+/	I
+or	I
+back	I
+pain	I
+is	O
+associated	O
+with	O
+the	O
+intrathecal	O
+use	O
+of	O
+hyperbaric	O
+5	O
+%	O
+lignocaine	O
+.	O
+
+The	O
+use	O
+of	O
+serum	O
+cholinesterase	O
+in	O
+succinylcholine	O
+apnoea	B
+.	O
+
+Fifteen	O
+patients	O
+demonstrating	O
+unexpected	O
+prolonged	O
+apnoea	B
+lasting	O
+several	O
+hours	O
+after	O
+succinylcholine	O
+have	O
+been	O
+treated	O
+by	O
+a	O
+new	O
+preparation	O
+of	O
+human	O
+serum	O
+cholinesterase	O
+.	O
+
+Adequate	O
+spontaneous	O
+respiration	O
+was	O
+re	O
+-	O
+established	O
+in	O
+an	O
+average	O
+period	O
+of	O
+ten	O
+minutes	O
+after	O
+the	O
+injection	O
+.	O
+
+In	O
+12	O
+patients	O
+biochemical	O
+genetic	O
+examinations	O
+confirmed	O
+the	O
+presence	O
+of	O
+an	O
+atypical	O
+serum	O
+cholinesterase	O
+.	O
+
+In	O
+three	O
+patients	O
+none	O
+of	O
+the	O
+usual	O
+variants	O
+were	O
+found	O
+.	O
+
+It	O
+is	O
+therefore	O
+supposed	O
+that	O
+other	O
+unknown	O
+variants	O
+of	O
+serum	O
+cholinesterase	O
+exist	O
+which	O
+cannot	O
+hydrolyze	O
+succinylcholine	O
+.	O
+
+The	O
+use	O
+of	O
+serum	O
+cholinesterase	O
+in	O
+succinylcholine	O
+apnoea	B
+provided	O
+considerable	O
+relief	O
+to	O
+both	O
+patient	O
+and	O
+anaesthetist	O
+.	O
+
+Increased	O
+sulfation	O
+and	O
+decreased	O
+7alpha	O
+-	O
+hydroxylation	O
+of	O
+deoxycholic	O
+acid	O
+in	O
+ethinyl	O
+estradiol	O
+-	O
+induced	O
+cholestasis	B
+in	O
+rats	O
+.	O
+
+Deoxycholic	O
+acid	O
+conjugation	O
+,	O
+transport	O
+capacity	O
+,	O
+and	O
+metabolism	O
+were	O
+compared	O
+in	O
+control	O
+and	O
+ethinyl	O
+estradiol	O
+-	O
+treated	O
+rats	O
+.	O
+
+Control	O
+rats	O
+were	O
+found	O
+to	O
+have	O
+a	O
+lower	O
+capacity	O
+to	O
+transport	O
+deoxycholic	O
+acid	O
+than	O
+taurodeoxycholic	O
+acid	O
+,	O
+and	O
+both	O
+were	O
+decreased	O
+by	O
+ethinyl	O
+estradiol	O
+treatment	O
+.	O
+
+During	O
+[	O
+24	O
+-	O
+14C	O
+]	O
+sodium	O
+deoxycholate	O
+infusion	O
+,	O
+[	O
+14C	O
+]	O
+biliary	O
+bile	O
+acid	O
+secretion	O
+increased	O
+,	O
+but	O
+bile	O
+flow	O
+did	O
+not	O
+change	O
+significantly	O
+in	O
+either	O
+control	O
+or	O
+ethinyl	O
+estradiol	O
+-	O
+treated	O
+rats	O
+.	O
+
+Ethinyl	O
+estradiol	O
+-	O
+treated	O
+animals	O
+excreted	O
+significantly	O
+less	O
+14C	O
+as	O
+taurocholic	O
+acid	O
+than	O
+did	O
+control	O
+animals	O
+,	O
+consistent	O
+with	O
+an	O
+impairment	O
+of	O
+7alpha	O
+-	O
+hydroxylation	O
+of	O
+taurodeoxycholic	O
+acid	O
+.	O
+
+Ethinyl	O
+estradiol	O
+treatment	O
+did	O
+not	O
+impair	O
+conjugation	O
+of	O
+deoxycholic	O
+acid	O
+,	O
+but	O
+did	O
+result	O
+in	O
+an	O
+increase	O
+in	O
+sulfation	O
+of	O
+taurodeoxycholic	O
+acid	O
+from	O
+1	O
+.	O
+5	O
+%	O
+in	O
+controls	O
+to	O
+nearly	O
+4	O
+.	O
+0	O
+%	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+These	O
+results	O
+are	O
+consistent	O
+with	O
+the	O
+hypothesis	O
+that	O
+the	O
+rat	O
+has	O
+a	O
+poorer	O
+tolerance	O
+for	O
+deoxycholic	O
+acid	O
+than	O
+do	O
+certain	O
+other	O
+species	O
+.	O
+
+Furthermore	O
+,	O
+the	O
+rat	O
+converts	O
+deoxycholic	O
+acid	O
+,	O
+a	O
+poor	O
+choleretic	O
+,	O
+to	O
+taurocholic	O
+acid	O
+,	O
+a	O
+good	O
+choleretic	O
+.	O
+
+When	O
+this	O
+conversion	O
+is	O
+impaired	O
+with	O
+ethinyl	O
+estradiol	O
+treatment	O
+,	O
+sulfation	O
+may	O
+be	O
+an	O
+important	O
+alternate	O
+pathway	O
+for	O
+excretion	O
+of	O
+this	O
+potentially	O
+harmful	O
+bile	O
+acid	O
+.	O
+
+Influence	O
+of	O
+diet	O
+free	O
+of	O
+NAD	O
+-	O
+precursors	O
+on	O
+acetaminophen	O
+hepatotoxicity	B
+in	O
+mice	O
+.	O
+
+Recently	O
+,	O
+we	O
+demonstrated	O
+the	O
+hepatoprotective	O
+effects	O
+of	O
+nicotinic	O
+acid	O
+amide	O
+,	O
+a	O
+selective	O
+inhibitor	O
+of	O
+poly	O
+(	O
+ADP	O
+-	O
+ribose	O
+)	O
+polymerase	O
+(	O
+PARP	O
+;	O
+EC	O
+2	O
+.	O
+4	O
+.	O
+2	O
+.	O
+30	O
+)	O
+on	O
+mice	O
+suffering	O
+from	O
+acetaminophen	O
+(	O
+AAP	O
+)	O
+-	O
+hepatitis	B
+,	O
+suggesting	O
+that	O
+the	O
+AAP	O
+-	O
+induced	O
+liver	B
+injury	I
+involves	O
+a	O
+step	O
+which	O
+depends	O
+on	O
+adenoribosylation	O
+.	O
+
+The	O
+present	O
+study	O
+investigates	O
+the	O
+effects	O
+of	O
+a	O
+diet	O
+free	O
+of	O
+precursors	O
+of	O
+NAD	O
+,	O
+the	O
+substrate	O
+on	O
+which	O
+PARP	O
+acts	O
+,	O
+in	O
+female	O
+NMRI	O
+mice	O
+with	O
+AAP	O
+hepatitis	B
+and	O
+evaluates	O
+the	O
+influence	O
+of	O
+simultaneous	O
+ethanol	O
+consumption	O
+in	O
+these	O
+animals	O
+.	O
+
+Liver	B
+injuries	I
+were	O
+quantified	O
+as	O
+serum	O
+activities	O
+of	O
+glutamate	O
+-	O
+oxaloacetate	O
+transaminase	O
+(	O
+GOT	O
+)	O
+and	O
+glutamate	O
+-	O
+pyruvate	O
+transaminase	O
+(	O
+GPT	O
+)	O
+.	O
+
+While	O
+AAP	O
+caused	O
+a	O
+117	O
+-	O
+fold	O
+elevation	O
+of	O
+serum	O
+transaminase	O
+activities	O
+in	O
+mice	O
+kept	O
+on	O
+a	O
+standard	O
+laboratory	O
+diet	O
+,	O
+which	O
+was	O
+significantly	O
+exacerbated	O
+by	O
+ethanol	O
+and	O
+inhibited	O
+by	O
+nicotinic	O
+acid	O
+amide	O
+(	O
+NAA	O
+)	O
+,	O
+adverse	O
+effects	O
+were	O
+noted	O
+in	O
+animals	O
+fed	O
+a	O
+diet	O
+free	O
+of	O
+precursors	O
+of	O
+NAD	O
+.	O
+
+In	O
+these	O
+animals	O
+,	O
+only	O
+minor	O
+increases	O
+of	O
+serum	O
+transaminase	O
+activities	O
+were	O
+measured	O
+in	O
+the	O
+presence	O
+of	O
+AAP	O
+,	O
+and	O
+unlike	O
+the	O
+exacerbation	O
+caused	O
+by	O
+ethanol	O
+in	O
+mice	O
+on	O
+a	O
+standard	O
+diet	O
+,	O
+the	O
+liver	B
+damage	I
+was	O
+inhibited	O
+by	O
+50	O
+%	O
+by	O
+ethanol	O
+.	O
+
+A	O
+further	O
+64	O
+%	O
+reduction	O
+of	O
+hepatitis	B
+was	O
+observed	O
+,	O
+when	O
+NAA	O
+was	O
+given	O
+to	O
+ethanol	O
+/	O
+AAP	O
+-	O
+mice	O
+.	O
+
+Our	O
+results	O
+provide	O
+evidence	O
+that	O
+the	O
+AAP	O
+-	O
+induced	O
+hepatitis	B
+and	O
+its	O
+exacerbation	O
+by	O
+ethanol	O
+can	O
+either	O
+be	O
+reduced	O
+by	O
+end	O
+-	O
+product	O
+inhibition	O
+of	O
+PARP	O
+by	O
+NAA	O
+or	O
+by	O
+dietary	O
+depletion	O
+of	O
+the	O
+enzyme	O
+'	O
+s	O
+substrate	O
+NAD	O
+.	O
+
+We	O
+see	O
+the	O
+main	O
+application	O
+of	O
+NAA	O
+as	O
+for	O
+the	O
+combinational	O
+use	O
+in	O
+pharmaceutical	O
+preparations	O
+of	O
+acetaminophen	O
+in	O
+order	O
+to	O
+avoid	O
+hepatic	B
+damage	I
+in	O
+patients	O
+treated	O
+with	O
+this	O
+widely	O
+used	O
+analgesic	O
+.	O
+
+Nightmares	O
+and	O
+hallucinations	B
+after	O
+long	O
+-	O
+term	O
+intake	O
+of	O
+tramadol	O
+combined	O
+with	O
+antidepressants	O
+.	O
+
+Tramadol	O
+is	O
+a	O
+weak	O
+opioid	O
+with	O
+effects	O
+on	O
+adrenergic	O
+and	O
+serotonergic	O
+neurotransmission	O
+that	O
+is	O
+used	O
+to	O
+treat	O
+cancer	B
+pain	B
+and	O
+chronic	O
+non	O
+malignant	O
+pain	B
+.	O
+
+This	O
+drug	O
+was	O
+initiated	O
+in	O
+association	O
+with	O
+paroxetine	O
+and	O
+dosulepine	O
+hydrochloride	O
+in	O
+a	O
+tetraparetic	B
+patient	O
+with	O
+chronic	B
+pain	I
+.	O
+
+Fifty	O
+-	O
+six	O
+days	O
+after	O
+initiation	O
+of	O
+the	O
+treatment	O
+the	O
+patient	O
+presented	O
+hallucinations	B
+that	O
+only	O
+stopped	O
+after	O
+the	O
+withdrawal	O
+of	O
+psycho	O
+-	O
+active	O
+drugs	O
+and	O
+tramadol	O
+.	O
+
+The	O
+case	O
+report	O
+questions	O
+the	O
+long	O
+term	O
+use	O
+of	O
+pain	B
+killers	O
+combined	O
+with	O
+psycho	O
+-	O
+active	O
+drugs	O
+in	O
+chronic	O
+non	O
+malignant	O
+pain	B
+,	O
+especially	O
+if	O
+pain	B
+is	O
+under	O
+control	O
+.	O
+
+Effect	O
+of	O
+calcium	O
+chloride	O
+and	O
+4	O
+-	O
+aminopyridine	O
+therapy	O
+on	O
+desipramine	O
+toxicity	B
+in	O
+rats	O
+.	O
+
+BACKGROUND	O
+:	O
+Hypotension	B
+is	O
+a	O
+major	O
+contributor	O
+to	O
+mortality	O
+in	O
+tricyclic	O
+antidepressant	O
+overdose	B
+.	O
+
+Recent	O
+data	O
+suggest	O
+that	O
+tricyclic	O
+antidepressants	O
+inhibit	O
+calcium	O
+influx	O
+in	O
+some	O
+tissues	O
+.	O
+
+This	O
+study	O
+addressed	O
+the	O
+potential	O
+role	O
+of	O
+calcium	O
+channel	O
+blockade	O
+in	O
+tricyclic	O
+antidepressant	O
+-	O
+induced	O
+hypotension	B
+.	O
+
+METHODS	O
+:	O
+Two	O
+interventions	O
+were	O
+studied	O
+that	O
+have	O
+been	O
+shown	O
+previously	O
+to	O
+improve	O
+blood	O
+pressure	O
+with	O
+calcium	O
+channel	O
+blocker	O
+overdose	B
+.	O
+
+CaCl2	O
+and	O
+4	O
+-	O
+aminopyridine	O
+.	O
+
+Anesthetized	O
+rats	O
+received	O
+the	O
+tricyclic	O
+antidepressant	O
+desipramine	O
+IP	O
+to	O
+produce	O
+hypotension	B
+,	O
+QRS	O
+prolongation	O
+,	O
+and	O
+bradycardia	B
+.	O
+
+Fifteen	O
+min	O
+later	O
+,	O
+animals	O
+received	O
+CaCl2	O
+,	O
+NaHCO3	O
+,	O
+or	O
+saline	O
+.	O
+
+In	O
+a	O
+second	O
+experiment	O
+,	O
+rats	O
+received	O
+tricyclic	O
+antidepressant	O
+desipramine	O
+IP	O
+followed	O
+in	O
+15	O
+min	O
+by	O
+4	O
+-	O
+aminopyridine	O
+or	O
+saline	O
+.	O
+
+RESULTS	O
+:	O
+NaHCO3	O
+briefly	O
+(	O
+5	O
+min	O
+)	O
+reversed	O
+hypotension	B
+and	O
+QRS	O
+prolongation	O
+.	O
+
+CaCl2	O
+and	O
+4	O
+-	O
+aminopyridine	O
+failed	O
+to	O
+improve	O
+blood	O
+pressure	O
+.	O
+
+The	O
+incidence	O
+of	O
+ventricular	B
+arrhythmias	I
+(	O
+p	O
+=	O
+0	O
+.	O
+004	O
+)	O
+and	O
+seizures	B
+(	O
+p	O
+=	O
+0	O
+.	O
+03	O
+)	O
+in	O
+the	O
+CaCl2	O
+group	O
+was	O
+higher	O
+than	O
+the	O
+other	O
+groups	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+administration	O
+of	O
+CaCl2	O
+or	O
+4	O
+-	O
+aminopyridine	O
+did	O
+not	O
+reverse	O
+tricyclic	O
+antidepressant	O
+-	O
+induced	O
+hypotension	B
+in	O
+rats	O
+.	O
+
+CaCl2	O
+therapy	O
+may	O
+possibly	O
+worsen	O
+both	O
+cardiovascular	B
+and	I
+central	I
+nervous	I
+system	I
+toxicity	I
+.	O
+
+These	O
+findings	O
+do	O
+not	O
+support	O
+a	O
+role	O
+for	O
+calcium	O
+channel	O
+inhibition	O
+in	O
+the	O
+pathogenesis	O
+of	O
+tricyclic	O
+antidepressant	O
+-	O
+induced	O
+hypotension	B
+.	O
+
+Valsartan	O
+,	O
+a	O
+new	O
+angiotensin	O
+II	O
+antagonist	O
+for	O
+the	O
+treatment	O
+of	O
+essential	O
+hypertension	B
+:	O
+a	O
+comparative	O
+study	O
+of	O
+the	O
+efficacy	O
+and	O
+safety	O
+against	O
+amlodipine	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+compare	O
+the	O
+antihypertensive	O
+efficacy	O
+of	O
+a	O
+new	O
+angiotensin	O
+II	O
+antagonist	O
+,	O
+valsartan	O
+,	O
+with	O
+a	O
+reference	O
+therapy	O
+,	O
+amlodipine	O
+.	O
+
+METHODS	O
+:	O
+One	O
+hundred	O
+sixty	O
+-	O
+eight	O
+adult	O
+outpatients	O
+with	O
+mild	O
+to	O
+moderate	O
+hypertension	B
+were	O
+randomly	O
+allocated	O
+in	O
+double	O
+-	O
+blind	O
+fashion	O
+and	O
+equal	O
+number	O
+to	O
+receive	O
+80	O
+mg	O
+valsartan	O
+or	O
+5	O
+mg	O
+amlodipine	O
+for	O
+12	O
+weeks	O
+.	O
+
+After	O
+8	O
+weeks	O
+of	O
+therapy	O
+,	O
+in	O
+patients	O
+whose	O
+blood	O
+pressure	O
+remained	O
+uncontrolled	O
+,	O
+5	O
+mg	O
+amlodipine	O
+was	O
+added	O
+to	O
+the	O
+initial	O
+therapy	O
+.	O
+
+Patients	O
+were	O
+assessed	O
+at	O
+4	O
+,	O
+8	O
+,	O
+and	O
+12	O
+weeks	O
+.	O
+
+The	O
+primary	O
+efficacy	O
+variable	O
+was	O
+change	O
+from	O
+baseline	O
+in	O
+mean	O
+sitting	O
+diastolic	O
+blood	O
+pressure	O
+at	O
+8	O
+weeks	O
+.	O
+
+Secondary	O
+variables	O
+included	O
+change	O
+in	O
+sitting	O
+systolic	O
+blood	O
+pressure	O
+and	O
+responder	O
+rates	O
+.	O
+
+RESULTS	O
+:	O
+Both	O
+valsartan	O
+and	O
+amlodipine	O
+were	O
+effective	O
+at	O
+lowering	O
+blood	O
+pressure	O
+at	O
+4	O
+,	O
+8	O
+,	O
+and	O
+12	O
+weeks	O
+.	O
+
+Similar	O
+decreases	O
+were	O
+observed	O
+in	O
+both	O
+groups	O
+,	O
+with	O
+no	O
+statistically	O
+significant	O
+differences	O
+between	O
+the	O
+groups	O
+for	O
+any	O
+variable	O
+analyzed	O
+.	O
+
+For	O
+the	O
+primary	O
+variable	O
+the	O
+difference	O
+was	O
+0	O
+.	O
+5	O
+mm	O
+Hg	O
+in	O
+favor	O
+of	O
+valsartan	O
+(	O
+p	O
+=	O
+0	O
+.	O
+68	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+-	O
+2	O
+.	O
+7	O
+to	O
+1	O
+.	O
+7	O
+)	O
+.	O
+
+Responder	O
+rates	O
+at	O
+8	O
+weeks	O
+were	O
+66	O
+.	O
+7	O
+%	O
+for	O
+valsartan	O
+and	O
+60	O
+.	O
+2	O
+%	O
+for	O
+amlodipine	O
+(	O
+p	O
+=	O
+0	O
+.	O
+39	O
+)	O
+.	O
+
+Both	O
+treatments	O
+were	O
+well	O
+tolerated	O
+.	O
+
+The	O
+incidence	O
+of	O
+drug	O
+-	O
+related	O
+dependent	O
+edema	B
+was	O
+somewhat	O
+higher	O
+in	O
+the	O
+amlodipine	O
+group	O
+,	O
+particularly	O
+at	O
+a	O
+dose	O
+of	O
+10	O
+mg	O
+per	O
+day	O
+(	O
+2	O
+.	O
+4	O
+%	O
+for	O
+80	O
+mg	O
+valsartan	O
+;	O
+3	O
+.	O
+6	O
+%	O
+for	O
+5	O
+mg	O
+amlodipine	O
+;	O
+0	O
+%	O
+for	O
+valsartan	O
+plus	O
+5	O
+mg	O
+amlodipine	O
+;	O
+14	O
+.	O
+3	O
+%	O
+for	O
+10	O
+mg	O
+amlodipine	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+data	O
+show	O
+that	O
+valsartan	O
+is	O
+at	O
+least	O
+as	O
+effective	O
+as	O
+amlodipine	O
+in	O
+the	O
+treatment	O
+of	O
+mild	O
+to	O
+moderate	O
+hypertension	B
+.	O
+
+The	O
+results	O
+also	O
+show	O
+valsartan	O
+to	O
+be	O
+well	O
+tolerated	O
+and	O
+suggest	O
+that	O
+it	O
+is	O
+not	O
+associated	O
+with	O
+side	O
+effects	O
+characteristic	O
+of	O
+this	O
+comparator	O
+class	O
+,	O
+dihydropyridine	O
+calcium	O
+antagonists	O
+.	O
+
+A	O
+measure	O
+of	O
+pupillary	B
+oscillation	I
+as	O
+a	O
+marker	O
+of	O
+cocaine	O
+-	O
+induced	O
+paranoia	B
+.	O
+
+Cocaine	O
+-	O
+induced	O
+paranoia	B
+(	O
+CIP	B
+)	O
+remains	O
+an	O
+important	O
+drug	O
+-	O
+induced	O
+model	O
+of	O
+idiopathic	O
+paranoia	B
+for	O
+which	O
+no	O
+psychophysiologic	O
+marker	O
+has	O
+yet	O
+emerged	O
+.	O
+
+Measures	O
+of	O
+pupillary	B
+oscillation	I
+were	O
+able	O
+to	O
+significantly	O
+distinguish	O
+a	O
+group	O
+of	O
+abstinent	O
+crack	O
+cocaine	O
+abusers	O
+endorsing	O
+past	O
+CIP	B
+(	O
+n	O
+=	O
+32	O
+)	O
+from	O
+another	O
+group	O
+of	O
+crack	O
+addicts	O
+who	O
+denied	O
+past	O
+CIP	B
+(	O
+n	O
+=	O
+29	O
+)	O
+.	O
+
+Serotonin	B
+syndrome	I
+from	O
+venlafaxine	O
+-	O
+tranylcypromine	O
+interaction	O
+.	O
+
+Excessive	O
+stimulation	O
+of	O
+serotonin	O
+5HT1A	O
+receptors	O
+causes	O
+a	O
+syndrome	O
+of	O
+serotonin	O
+excess	O
+that	O
+consists	O
+of	O
+shivering	O
+,	O
+muscle	B
+rigidity	I
+,	O
+salivation	B
+,	O
+confusion	B
+,	O
+agitation	B
+and	O
+hyperthermia	B
+.	O
+
+The	O
+most	O
+common	O
+cause	O
+of	O
+this	O
+syndrome	O
+is	O
+an	O
+interaction	O
+between	O
+a	O
+monoamine	O
+oxidase	O
+inhibitor	O
+(	O
+MAOI	O
+)	O
+and	O
+a	O
+specific	O
+serotonin	O
+reuptake	O
+inhibitor	O
+.	O
+
+Venlafaxine	O
+is	O
+a	O
+new	O
+antidepressant	O
+agent	O
+that	O
+inhibits	O
+the	O
+reuptake	O
+of	O
+serotonin	O
+and	O
+norepinephrine	O
+.	O
+
+We	O
+report	O
+a	O
+venlafaxine	O
+-	O
+MAOI	O
+interaction	O
+that	O
+resulted	O
+in	O
+the	O
+serotonin	B
+syndrome	I
+in	O
+a	O
+23	O
+-	O
+y	O
+-	O
+old	O
+male	O
+who	O
+was	O
+taking	O
+tranylcypromine	O
+for	O
+depression	B
+.	O
+
+He	O
+had	O
+been	O
+well	O
+until	O
+the	O
+morning	O
+of	O
+presentation	O
+when	O
+he	O
+took	O
+1	O
+/	O
+2	O
+tab	O
+of	O
+venlafaxine	O
+.	O
+
+Within	O
+2	O
+h	O
+he	O
+became	O
+confused	O
+with	O
+jerking	O
+movements	O
+of	O
+his	O
+extremities	O
+,	O
+tremors	B
+and	O
+rigidity	B
+.	O
+
+He	O
+was	O
+brought	O
+directly	O
+to	O
+a	O
+hospital	O
+where	O
+he	O
+was	O
+found	O
+to	O
+be	O
+agitated	O
+and	O
+confused	O
+with	O
+shivering	O
+,	O
+myoclonic	B
+jerks	I
+,	O
+rigidity	B
+,	O
+salivation	B
+and	O
+diaphoresis	O
+.	O
+
+His	O
+pupils	O
+were	O
+7	O
+mm	O
+and	O
+sluggishly	O
+reactive	O
+to	O
+light	O
+.	O
+
+Vital	O
+signs	O
+were	O
+:	O
+blood	O
+pressure	O
+120	O
+/	O
+67	O
+mm	O
+Hg	O
+,	O
+heart	O
+rate	O
+127	O
+/	O
+min	O
+,	O
+respiratory	O
+rate	O
+28	O
+/	O
+min	O
+,	O
+and	O
+temperature	O
+97	O
+F	O
+.	O
+
+After	O
+180	O
+mg	O
+of	O
+diazepam	O
+i	O
+.	O
+v	O
+.	O
+he	O
+remained	O
+tremulous	O
+with	O
+muscle	B
+rigidity	I
+and	O
+clenched	O
+jaws	O
+.	O
+
+He	O
+was	O
+intubated	O
+for	O
+airway	O
+protection	O
+and	O
+because	O
+of	O
+hypoventilation	B
+,	O
+and	O
+was	O
+paralyzed	B
+to	O
+control	O
+muscle	B
+rigidity	I
+.	O
+
+His	O
+subsequent	O
+course	O
+was	O
+remarkable	O
+for	O
+non	O
+-	O
+immune	O
+thrombocytopenia	B
+which	O
+resolved	O
+.	O
+
+The	O
+patient	O
+'	O
+s	O
+maximal	O
+temperature	O
+was	O
+101	O
+.	O
+2	O
+F	O
+and	O
+his	O
+CPK	O
+remained	O
+<	O
+500	O
+units	O
+/	O
+L	O
+with	O
+no	O
+other	O
+evidence	O
+of	O
+rhabdomyolysis	B
+.	O
+
+His	O
+mental	O
+status	O
+normalized	O
+and	O
+he	O
+was	O
+transferred	O
+to	O
+a	O
+psychiatry	O
+ward	O
+.	O
+
+This	O
+patient	O
+survived	O
+without	O
+sequelae	O
+due	O
+to	O
+the	O
+aggressive	O
+sedation	O
+and	O
+neuromuscular	O
+paralysis	B
+.	O
+
+Cyclophosphamide	O
+associated	O
+bladder	B
+cancer	I
+-	O
+-	O
+a	O
+highly	O
+aggressive	O
+disease	O
+:	O
+analysis	O
+of	O
+12	O
+cases	O
+.	O
+
+PURPOSE	O
+:	O
+We	O
+gained	O
+knowledge	O
+of	O
+the	O
+etiology	O
+,	O
+treatment	O
+and	O
+prevention	O
+of	O
+cyclophosphamide	O
+associated	O
+urothelial	B
+cancer	I
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+The	O
+medical	O
+records	O
+of	O
+6	O
+men	O
+and	O
+6	O
+women	O
+(	O
+mean	O
+age	O
+55	O
+years	O
+)	O
+with	O
+cyclophosphamide	O
+associated	O
+bladder	B
+cancer	I
+were	O
+reviewed	O
+.	O
+
+RESULTS	O
+:	O
+All	O
+tumors	B
+were	O
+grade	O
+3	O
+or	O
+4	O
+transitional	O
+cell	O
+carcinoma	B
+.	O
+
+Of	O
+the	O
+5	O
+patients	O
+initially	O
+treated	O
+with	O
+endoscopic	O
+resection	O
+alone	O
+only	O
+1	O
+is	O
+alive	O
+without	O
+disease	O
+.	O
+
+Of	O
+the	O
+6	O
+patients	O
+who	O
+underwent	O
+early	O
+cystectomy	O
+4	O
+were	O
+alive	O
+at	O
+24	O
+to	O
+111	O
+months	O
+.	O
+
+The	O
+remaining	O
+patient	O
+with	O
+extensive	O
+cancer	B
+underwent	O
+partial	O
+cystectomy	O
+for	O
+palliation	O
+and	O
+died	O
+3	O
+months	O
+later	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Cyclophosphamide	O
+associated	O
+bladder	B
+tumor	I
+is	O
+an	O
+aggressive	O
+disease	O
+.	O
+
+However	O
+,	O
+long	O
+-	O
+term	O
+survival	O
+is	O
+possible	O
+when	O
+radical	O
+cystectomy	O
+is	O
+performed	O
+for	O
+bladder	B
+tumors	I
+with	O
+any	O
+sign	O
+of	O
+invasion	O
+and	O
+for	O
+recurrent	O
+high	O
+grade	O
+disease	O
+,	O
+even	O
+when	O
+noninvasive	O
+.	O
+
+A	O
+phase	O
+I	O
+clinical	O
+study	O
+of	O
+the	O
+antipurine	O
+antifolate	O
+lometrexol	O
+(	O
+DDATHF	O
+)	O
+given	O
+with	O
+oral	O
+folic	O
+acid	O
+.	O
+
+Lometrexol	O
+is	O
+an	O
+antifolate	O
+which	O
+inhibits	O
+glycinamide	O
+ribonucleotide	O
+formyltransferase	O
+(	O
+GARFT	O
+)	O
+,	O
+an	O
+enzyme	O
+essential	O
+for	O
+de	O
+novo	O
+purine	O
+synthesis	O
+.	O
+
+Extensive	O
+experimental	O
+and	O
+limited	O
+clinical	O
+data	O
+have	O
+shown	O
+that	O
+lometrexol	O
+has	O
+activity	O
+against	O
+tumours	B
+which	O
+are	O
+refractory	O
+to	O
+other	O
+drugs	O
+,	O
+notably	O
+methotrexate	O
+.	O
+
+However	O
+,	O
+the	O
+initial	O
+clinical	O
+development	O
+of	O
+lometrexol	O
+was	O
+curtailed	O
+because	O
+of	O
+severe	O
+and	O
+cumulative	O
+antiproliferative	O
+toxicities	B
+.	O
+
+Preclinical	O
+murine	O
+studies	O
+demonstrated	O
+that	O
+the	O
+toxicity	B
+of	O
+lometrexol	O
+can	O
+be	O
+prevented	O
+by	O
+low	O
+dose	O
+folic	O
+acid	O
+administration	O
+,	O
+i	O
+.	O
+e	O
+.	O
+for	O
+7	O
+days	O
+prior	O
+to	O
+and	O
+7	O
+days	O
+following	O
+a	O
+single	O
+bolus	O
+dose	O
+.	O
+
+This	O
+observation	O
+prompted	O
+a	O
+Phase	O
+I	O
+clinical	O
+study	O
+of	O
+lometrexol	O
+given	O
+with	O
+folic	O
+acid	O
+supplementation	O
+which	O
+has	O
+confirmed	O
+that	O
+the	O
+toxicity	B
+of	O
+lometrexol	O
+can	O
+be	O
+markedly	O
+reduced	O
+by	O
+folic	O
+acid	O
+supplementation	O
+.	O
+
+Thrombocytopenia	B
+and	O
+mucositis	B
+were	O
+the	O
+major	O
+toxicities	B
+.	O
+
+There	O
+was	O
+no	O
+clear	O
+relationship	O
+between	O
+clinical	O
+toxicity	B
+and	O
+the	O
+extent	O
+of	O
+plasma	O
+folate	O
+elevation	O
+.	O
+
+Associated	O
+studies	O
+demonstrated	O
+that	O
+lometrexol	O
+plasma	O
+pharmacokinetics	O
+were	O
+not	O
+altered	O
+by	O
+folic	O
+acid	O
+administration	O
+indicating	O
+that	O
+supplementation	O
+is	O
+unlikely	O
+to	O
+reduce	O
+toxicity	B
+by	O
+enhancing	O
+lometrexol	O
+plasma	O
+clearance	O
+.	O
+
+The	O
+work	O
+described	O
+in	O
+this	O
+report	O
+has	O
+identified	O
+for	O
+the	O
+first	O
+time	O
+a	O
+clinically	O
+acceptable	O
+schedule	O
+for	O
+the	O
+administration	O
+of	O
+a	O
+GARFT	O
+inhibitor	O
+.	O
+
+This	O
+information	O
+will	O
+facilitate	O
+the	O
+future	O
+evaluation	O
+of	O
+this	O
+class	O
+of	O
+compounds	O
+in	O
+cancer	B
+therapy	O
+.	O
+
+Fatal	O
+excited	O
+delirium	B
+following	O
+cocaine	O
+use	O
+:	O
+epidemiologic	O
+findings	O
+provide	O
+new	O
+evidence	O
+for	O
+mechanisms	O
+of	O
+cocaine	O
+toxicity	B
+.	O
+
+We	O
+describe	O
+an	O
+outbreak	O
+of	O
+deaths	O
+from	O
+cocaine	O
+-	O
+induced	O
+excited	O
+delirium	B
+(	O
+EDDs	B
+)	O
+in	O
+Dade	O
+County	O
+,	O
+Florida	O
+between	O
+1979	O
+and	O
+1990	O
+.	O
+
+From	O
+a	O
+registry	O
+of	O
+all	O
+cocaine	O
+-	O
+related	O
+deaths	O
+in	O
+Dade	O
+County	O
+,	O
+Florida	O
+,	O
+from	O
+1969	O
+-	O
+1990	O
+,	O
+58	O
+EDDs	B
+were	O
+compared	O
+with	O
+125	O
+victims	O
+of	O
+accidental	O
+cocaine	O
+overdose	B
+without	O
+excited	O
+delirium	B
+.	O
+
+Compared	O
+with	O
+controls	O
+,	O
+EDDs	B
+were	O
+more	O
+frequently	O
+black	O
+,	O
+male	O
+,	O
+and	O
+younger	O
+.	O
+
+They	O
+were	O
+less	O
+likely	O
+to	O
+have	O
+a	O
+low	O
+body	O
+mass	O
+index	O
+,	O
+and	O
+more	O
+likely	O
+to	O
+have	O
+died	O
+in	O
+police	O
+custody	O
+,	O
+to	O
+have	O
+received	O
+medical	O
+treatment	O
+immediately	O
+before	O
+death	O
+,	O
+to	O
+have	O
+survived	O
+for	O
+a	O
+longer	O
+period	O
+,	O
+to	O
+have	O
+developed	O
+hyperthermia	B
+,	O
+and	O
+to	O
+have	O
+died	O
+in	O
+summer	O
+months	O
+.	O
+
+EDDs	B
+had	O
+concentrations	O
+of	O
+cocaine	O
+and	O
+benzoylecgonine	O
+in	O
+autopsy	O
+blood	O
+that	O
+were	O
+similar	O
+to	O
+those	O
+for	O
+controls	O
+.	O
+
+The	O
+epidemiologic	O
+findings	O
+are	O
+most	O
+consistent	O
+with	O
+the	O
+hypothesis	O
+that	O
+chronic	O
+cocaine	O
+use	O
+disrupts	O
+dopaminergic	O
+function	O
+and	O
+,	O
+when	O
+coupled	O
+with	O
+recent	O
+cocaine	O
+use	O
+,	O
+may	O
+precipitate	O
+agitation	B
+,	O
+delirium	B
+,	O
+aberrant	O
+thermoregulation	O
+,	O
+rhabdomyolysis	B
+,	O
+and	O
+sudden	B
+death	I
+.	O
+
+Pemoline	O
+induced	O
+acute	O
+choreoathetosis	B
+:	O
+case	O
+report	O
+and	O
+review	O
+of	O
+the	O
+literature	O
+.	O
+
+BACKGROUND	O
+:	O
+Pemoline	O
+is	O
+an	O
+oxazolidine	O
+derivative	O
+that	O
+is	O
+structurally	O
+different	O
+from	O
+amphetamines	O
+and	O
+used	O
+in	O
+the	O
+treatment	O
+of	O
+attention	B
+deficit	I
+disorder	I
+.	O
+
+Pemoline	O
+has	O
+not	O
+been	O
+commonly	O
+associated	O
+in	O
+the	O
+literature	O
+as	O
+a	O
+cause	O
+of	O
+acute	O
+movement	B
+disorders	I
+.	O
+
+The	O
+following	O
+case	O
+describes	O
+two	O
+children	O
+acutely	O
+poisoned	O
+with	O
+pemoline	O
+who	O
+experienced	O
+profound	O
+choreoathetosis	B
+.	O
+
+CASE	O
+REPORT	O
+:	O
+Two	O
+,	O
+3	O
+-	O
+year	O
+-	O
+old	O
+male	O
+,	O
+identical	O
+twin	O
+siblings	O
+presented	O
+to	O
+the	O
+emergency	O
+department	O
+after	O
+found	O
+playing	O
+with	O
+a	O
+an	O
+empty	O
+bottle	O
+of	O
+pemoline	O
+originally	O
+containing	O
+59	O
+tablets	O
+.	O
+
+The	O
+children	O
+had	O
+a	O
+medical	O
+history	O
+significant	O
+for	O
+attention	B
+deficit	I
+disorder	I
+previously	O
+treated	O
+with	O
+methylphenidate	O
+without	O
+success	O
+.	O
+
+This	O
+was	O
+their	O
+first	O
+day	O
+of	O
+pemoline	O
+therapy	O
+.	O
+
+The	O
+choreoathetoid	B
+movements	O
+began	O
+45	O
+min	O
+to	O
+1	O
+h	O
+after	O
+ingestion	O
+.	O
+
+The	O
+children	O
+gave	O
+no	O
+history	O
+of	O
+prior	O
+movement	B
+disorders	I
+and	O
+there	O
+was	O
+no	O
+family	O
+history	O
+of	O
+movement	B
+disorders	I
+.	O
+
+The	O
+children	O
+received	O
+gastrointestinal	O
+decontamination	O
+and	O
+high	O
+doses	O
+of	O
+intravenous	O
+benzodiazepines	O
+in	O
+an	O
+attempt	O
+to	O
+control	O
+the	O
+choreoathetoid	B
+movements	O
+.	O
+
+Despite	O
+treatment	O
+,	O
+the	O
+children	O
+continued	O
+to	O
+have	O
+choreoathetosis	B
+for	O
+approximately	O
+24	O
+hours	O
+.	O
+
+Forty	O
+-	O
+eight	O
+hours	O
+after	O
+admission	O
+,	O
+the	O
+children	O
+appeared	O
+to	O
+be	O
+at	O
+their	O
+baseline	O
+and	O
+were	O
+discharged	O
+home	O
+.	O
+
+CONCLUSION	O
+:	O
+Pemoline	O
+associated	O
+movement	B
+disorder	I
+has	O
+been	O
+rarely	O
+reported	O
+in	O
+the	O
+acute	O
+toxicology	O
+literature	O
+.	O
+
+The	O
+possibility	O
+of	O
+choreoathetoid	B
+movements	O
+should	O
+be	O
+considered	O
+in	O
+patients	O
+presenting	O
+after	O
+pemoline	O
+overdose	B
+.	O
+
+Effect	O
+of	O
+myopic	O
+excimer	O
+laser	O
+photorefractive	O
+keratectomy	O
+on	O
+the	O
+electrophysiologic	O
+function	O
+of	O
+the	O
+retina	O
+and	O
+optic	O
+nerve	O
+.	O
+
+PURPOSE	O
+:	O
+To	O
+assess	O
+by	O
+electrophysiologic	O
+testing	O
+the	O
+effect	O
+of	O
+photorefractive	O
+keratectomy	O
+(	O
+PRK	O
+)	O
+on	O
+the	O
+retina	O
+and	O
+optic	O
+nerve	O
+.	O
+
+SETTING	O
+:	O
+Eye	O
+Clinic	O
+,	O
+S	O
+.	O
+
+Salvatore	O
+Hospital	O
+,	O
+L	O
+'	O
+Aquila	O
+University	O
+,	O
+Italy	O
+.	O
+
+METHODS	O
+:	O
+Standard	O
+pattern	O
+electroretinograms	O
+(	O
+P	O
+-	O
+ERGs	O
+)	O
+and	O
+standard	O
+pattern	O
+visual	O
+evoked	O
+potentials	O
+(	O
+P	O
+-	O
+VEPs	O
+)	O
+were	O
+done	O
+in	O
+25	O
+eyes	O
+of	O
+25	O
+patients	O
+who	O
+had	O
+myopic	O
+PRK	O
+for	O
+an	O
+attempted	O
+correction	O
+between	O
+5	O
+.	O
+00	O
+and	O
+15	O
+.	O
+00	O
+diopters	O
+(	O
+D	O
+)	O
+(	O
+mean	O
+8	O
+.	O
+00	O
+D	O
+)	O
+.	O
+
+Testing	O
+was	O
+done	O
+preoperatively	O
+and	O
+3	O
+,	O
+6	O
+,	O
+12	O
+,	O
+and	O
+18	O
+months	O
+postoperatively	O
+.	O
+
+The	O
+contralateral	O
+eyes	O
+served	O
+as	O
+controls	O
+.	O
+
+During	O
+the	O
+follow	O
+-	O
+up	O
+,	O
+3	O
+patients	O
+(	O
+12	O
+%	O
+)	O
+developed	O
+steroid	O
+-	O
+induced	O
+elevated	B
+intraocular	I
+pressure	I
+(	O
+IOP	O
+)	O
+that	O
+resolved	O
+after	O
+corticosteroid	O
+therapy	O
+was	O
+discontinued	O
+.	O
+
+RESULTS	O
+:	O
+No	O
+statistically	O
+significant	O
+differences	O
+were	O
+seen	O
+between	O
+treated	O
+and	O
+control	O
+eyes	O
+nor	O
+between	O
+treated	O
+eyes	O
+preoperatively	O
+and	O
+postoperatively	O
+.	O
+
+CONCLUSION	O
+:	O
+Myopic	O
+excimer	O
+laser	O
+PRK	O
+did	O
+not	O
+seem	O
+to	O
+affect	O
+the	O
+posterior	O
+segment	O
+.	O
+
+The	O
+transient	O
+steroid	O
+-	O
+induced	O
+IOP	B
+rise	I
+did	O
+not	O
+seem	O
+to	O
+cause	O
+functional	O
+impairment	O
+.	O
+
+Neutrophil	O
+superoxide	O
+and	O
+hydrogen	O
+peroxide	O
+production	O
+in	O
+patients	O
+with	O
+acute	B
+liver	I
+failure	I
+.	O
+
+Defects	O
+in	O
+superoxide	O
+and	O
+hydrogen	O
+peroxide	O
+production	O
+may	O
+be	O
+implicated	O
+in	O
+the	O
+high	O
+incidence	O
+of	O
+bacterial	B
+infections	I
+in	O
+patients	O
+with	O
+acute	B
+liver	I
+failure	I
+(	O
+ALF	B
+)	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+oxygen	O
+radical	O
+production	O
+in	O
+patients	O
+with	O
+ALF	B
+due	O
+to	O
+paracetamol	O
+overdose	B
+was	O
+compared	O
+with	O
+that	O
+of	O
+healthy	O
+volunteers	O
+.	O
+
+Neutrophils	O
+from	O
+14	O
+ALF	B
+patients	O
+were	O
+stimulated	O
+via	O
+the	O
+complement	O
+receptors	O
+using	O
+zymosan	O
+opsonized	O
+with	O
+ALF	B
+or	O
+control	O
+serum	O
+.	O
+
+Superoxide	O
+and	O
+hydrogen	O
+peroxide	O
+production	O
+by	O
+ALF	B
+neutrophils	O
+stimulated	O
+with	O
+zymosan	O
+opsonized	O
+with	O
+ALF	B
+serum	O
+was	O
+significantly	O
+reduced	O
+compared	O
+with	O
+the	O
+control	O
+subjects	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+This	O
+defect	O
+persisted	O
+when	O
+zymosan	O
+opsonized	O
+by	O
+control	O
+serum	O
+was	O
+used	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Superoxide	O
+and	O
+hydrogen	O
+peroxide	O
+production	O
+in	O
+neutrophils	O
+stimulated	O
+with	O
+formyl	O
+-	O
+methionyl	O
+-	O
+leucyl	O
+-	O
+phenylalanine	O
+(	O
+fMLP	O
+)	O
+from	O
+a	O
+further	O
+18	O
+ALF	B
+patients	O
+was	O
+unaffected	O
+compared	O
+with	O
+control	O
+neutrophils	O
+.	O
+
+Serum	O
+C3	O
+complement	O
+levels	O
+were	O
+significantly	O
+reduced	O
+in	O
+ALF	B
+patients	O
+compared	O
+with	O
+control	O
+subjects	O
+(	O
+P	O
+<	O
+0	O
+.	O
+0005	O
+)	O
+.	O
+
+These	O
+results	O
+demonstrate	O
+a	O
+neutrophil	O
+defect	O
+in	O
+ALF	B
+due	O
+to	O
+paracetamol	O
+overdose	B
+,	O
+that	O
+is	O
+complement	O
+dependent	O
+but	O
+independent	O
+of	O
+serum	O
+complement	O
+,	O
+possibly	O
+connected	O
+to	O
+the	O
+complement	O
+receptor	O
+.	O
+
+Cholesteryl	O
+hemisuccinate	O
+treatment	O
+protects	O
+rodents	O
+from	O
+the	O
+toxic	O
+effects	O
+of	O
+acetaminophen	O
+,	O
+adriamycin	O
+,	O
+carbon	O
+tetrachloride	O
+,	O
+chloroform	O
+and	O
+galactosamine	O
+.	O
+
+In	O
+addition	O
+to	O
+its	O
+use	O
+as	O
+a	O
+stabilizer	O
+/	O
+rigidifier	O
+of	O
+membranes	O
+,	O
+cholesteryl	O
+hemisuccinate	O
+,	O
+tris	O
+salt	O
+(	O
+CS	O
+)	O
+administration	O
+has	O
+also	O
+been	O
+shown	O
+to	O
+protect	O
+rats	O
+from	O
+the	O
+hepatotoxic	B
+effects	O
+of	O
+carbon	O
+tetrachloride	O
+(	O
+CCl4	O
+)	O
+.	O
+
+To	O
+further	O
+our	O
+understanding	O
+of	O
+the	O
+mechanism	O
+of	O
+CS	O
+cytoprotection	O
+,	O
+we	O
+examined	O
+in	O
+rats	O
+and	O
+mice	O
+the	O
+protective	O
+abilities	O
+of	O
+CS	O
+and	O
+the	O
+non	O
+-	O
+hydrolyzable	O
+ether	O
+form	O
+of	O
+CS	O
+,	O
+gamma	O
+-	O
+cholesteryloxybutyric	O
+acid	O
+,	O
+tris	O
+salt	O
+(	O
+CSE	O
+)	O
+against	O
+acetaminophen	O
+-	O
+,	O
+adriamycin	O
+-	O
+,	O
+carbon	O
+tetrachloride	O
+-	O
+,	O
+chloroform	O
+-	O
+and	O
+galactosamine	O
+-	O
+induced	O
+toxicity	B
+.	O
+
+The	O
+results	O
+of	O
+these	O
+studies	O
+demonstrated	O
+that	O
+CS	O
+-	O
+mediated	O
+protection	O
+is	O
+not	O
+selective	O
+for	O
+a	O
+particular	O
+species	O
+,	O
+organ	O
+system	O
+or	O
+toxic	O
+chemical	O
+.	O
+
+A	O
+24	O
+-	O
+h	O
+pretreatment	O
+of	O
+both	O
+rats	O
+and	O
+mice	O
+with	O
+a	O
+single	O
+dose	O
+of	O
+CS	O
+(	O
+100mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+,	O
+resulted	O
+in	O
+significant	O
+protection	O
+against	O
+the	O
+hepatotoxic	B
+effects	O
+of	O
+CCl4	O
+,	O
+CHCl3	O
+,	O
+acetaminophen	O
+and	O
+galactosamine	O
+and	O
+against	O
+the	O
+lethal	O
+(	O
+and	O
+presumably	O
+cardiotoxic	B
+)	O
+effect	O
+of	O
+adriamycin	O
+administration	O
+.	O
+
+Maximal	O
+CS	O
+-	O
+mediated	O
+protection	O
+was	O
+observed	O
+in	O
+experimental	O
+animals	O
+pretreated	O
+24	O
+h	O
+prior	O
+to	O
+the	O
+toxic	O
+insult	O
+.	O
+
+These	O
+data	O
+suggest	O
+that	O
+CS	O
+intervenes	O
+in	O
+a	O
+critical	O
+cellular	O
+event	O
+that	O
+is	O
+an	O
+important	O
+common	O
+pathway	O
+to	O
+toxic	O
+cell	O
+death	O
+.	O
+
+The	O
+mechanism	O
+of	O
+CS	O
+protection	O
+does	O
+not	O
+appear	O
+to	O
+be	O
+dependent	O
+on	O
+the	O
+inhibition	O
+of	O
+chemical	O
+bioactivation	O
+to	O
+a	O
+toxic	O
+reactive	O
+intermediate	O
+(	O
+in	O
+light	O
+of	O
+the	O
+protection	O
+observed	O
+against	O
+galactosamine	O
+hepatotoxicity	B
+)	O
+.	O
+
+However	O
+,	O
+based	O
+on	O
+the	O
+data	O
+presented	O
+,	O
+we	O
+can	O
+not	O
+exclude	O
+the	O
+possibility	O
+that	O
+CS	O
+administration	O
+inhibits	O
+chemical	O
+bioactivation	O
+.	O
+
+Our	O
+findings	O
+do	O
+suggest	O
+that	O
+CS	O
+-	O
+mediated	O
+protection	O
+is	O
+dependent	O
+on	O
+the	O
+action	O
+of	O
+the	O
+intact	O
+anionic	O
+CS	O
+molecule	O
+(	O
+non	O
+-	O
+hydrolyzable	O
+CSE	O
+was	O
+as	O
+protective	O
+as	O
+CS	O
+)	O
+,	O
+whose	O
+mechanism	O
+has	O
+yet	O
+to	O
+be	O
+defined	O
+.	O
+
+A	O
+murine	O
+model	O
+of	O
+adenomyosis	B
+:	O
+the	O
+effects	O
+of	O
+hyperprolactinemia	B
+induced	O
+by	O
+fluoxetine	O
+hydrochloride	O
+,	O
+a	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitor	O
+,	O
+on	O
+adenomyosis	B
+induction	O
+in	O
+Wistar	O
+albino	O
+rats	O
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+investigate	O
+whether	O
+fluoxetine	O
+given	O
+to	O
+castrated	O
+and	O
+noncastrated	O
+rats	O
+caused	O
+hyperprolactinemia	B
+and	O
+its	O
+effects	O
+with	O
+respect	O
+to	O
+adenomyosis	B
+.	O
+
+DESIGN	O
+:	O
+Fluoxetine	O
+,	O
+a	O
+serotonin	O
+reuptake	O
+inhibitor	O
+,	O
+was	O
+given	O
+to	O
+Wistar	O
+Albino	O
+rats	O
+for	O
+98	O
+days	O
+to	O
+produce	O
+hyperprolactinemia	B
+.	O
+
+The	O
+drug	O
+was	O
+given	O
+to	O
+two	O
+groups	O
+consisting	O
+of	O
+castrated	O
+and	O
+noncastrated	O
+rats	O
+and	O
+compared	O
+to	O
+two	O
+groups	O
+of	O
+castrated	O
+and	O
+noncastrated	O
+controls	O
+.	O
+
+Prolactin	O
+levels	O
+were	O
+measured	O
+and	O
+the	O
+uteri	O
+of	O
+the	O
+rats	O
+were	O
+removed	O
+for	O
+histopathological	O
+analysis	O
+at	O
+the	O
+end	O
+of	O
+98	O
+days	O
+.	O
+
+SETTING	O
+:	O
+Marmara	O
+University	O
+School	O
+of	O
+Medicine	O
+,	O
+Department	O
+of	O
+Histology	O
+and	O
+Embryology	O
+,	O
+Zeynep	O
+Kamil	O
+Women	O
+and	O
+Children	O
+'	O
+s	O
+Hospital	O
+.	O
+
+MAIN	O
+OUTCOME	O
+MEASURES	O
+:	O
+Serum	O
+prolactin	O
+levels	O
+,	O
+uterine	O
+histopathology	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+prolactin	O
+levels	O
+of	O
+castrated	O
+and	O
+noncastrated	O
+groups	O
+treated	O
+with	O
+fluoxetine	O
+were	O
+statistically	O
+significantly	O
+higher	O
+when	O
+compared	O
+to	O
+their	O
+respective	O
+control	O
+groups	O
+.	O
+
+Histological	O
+studies	O
+revealed	O
+11	O
+cases	O
+of	O
+adenomyosis	B
+,	O
+all	O
+within	O
+the	O
+noncastrated	O
+group	O
+receiving	O
+fluoxetine	O
+.	O
+
+CONCLUSION	O
+:	O
+It	O
+was	O
+suggested	O
+that	O
+high	O
+serum	O
+prolactin	O
+levels	O
+cause	O
+degeneration	O
+of	O
+myometrial	O
+cells	O
+in	O
+the	O
+presence	O
+of	O
+ovarian	O
+steroids	O
+that	O
+results	O
+in	O
+a	O
+myometrial	O
+invasion	O
+by	O
+endometrial	O
+stroma	O
+.	O
+
+This	O
+invasion	O
+eventually	O
+progresses	O
+to	O
+adenomyosis	B
+.	O
+
+Postinfarction	O
+ventricular	B
+septal	I
+defect	I
+associated	O
+with	O
+long	O
+-	O
+term	O
+steroid	O
+therapy	O
+.	O
+
+Two	O
+cases	O
+of	O
+postinfarction	O
+ventricular	B
+septal	I
+rupture	I
+in	O
+patients	O
+on	O
+long	O
+-	O
+term	O
+steroid	O
+therapy	O
+are	O
+presented	O
+and	O
+the	O
+favourable	O
+outcome	O
+in	O
+both	O
+cases	O
+described	O
+.	O
+
+A	O
+possible	O
+association	O
+between	O
+steroid	O
+therapy	O
+and	O
+subsequent	O
+postinfarction	O
+septal	B
+rupture	I
+is	O
+discussed	O
+.	O
+
+Neuroactive	O
+steroids	O
+protect	O
+against	O
+pilocarpine	O
+-	O
+and	O
+kainic	O
+acid	O
+-	O
+induced	O
+limbic	O
+seizures	B
+and	O
+status	B
+epilepticus	I
+in	O
+mice	O
+.	O
+
+Several	O
+structurally	O
+related	O
+metabolites	O
+of	O
+progesterone	O
+(	O
+3	O
+alpha	O
+-	O
+hydroxy	O
+pregnane	O
+-	O
+20	O
+-	O
+ones	O
+)	O
+and	O
+deoxycorticosterone	O
+(	O
+3	O
+alpha	O
+-	O
+hydroxy	O
+pregnane	O
+-	O
+21	O
+-	O
+diol	O
+-	O
+20	O
+-	O
+ones	O
+)	O
+and	O
+their	O
+3	O
+beta	O
+-	O
+epimers	O
+were	O
+evaluated	O
+for	O
+protective	O
+activity	O
+against	O
+pilocarpine	O
+-	O
+,	O
+kainic	O
+acid	O
+-	O
+and	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+-	O
+induced	O
+seizures	B
+in	O
+mice	O
+.	O
+
+Steroids	O
+with	O
+the	O
+3	O
+-	O
+hydroxy	O
+group	O
+in	O
+the	O
+alpha	O
+-	O
+position	O
+and	O
+5	O
+-	O
+H	O
+in	O
+the	O
+alpha	O
+-	O
+or	O
+beta	O
+-	O
+configurations	O
+were	O
+highly	O
+effective	O
+in	O
+protecting	O
+against	O
+pilocarpine	O
+(	O
+416	O
+mg	O
+/	O
+kg	O
+,	O
+s	O
+.	O
+c	O
+.	O
+)	O
+-	O
+induced	O
+limbic	O
+motor	O
+seizures	B
+and	O
+status	B
+epilepticus	I
+(	O
+ED50	O
+values	O
+,	O
+7	O
+.	O
+0	O
+-	O
+18	O
+.	O
+7	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+The	O
+corresponding	O
+epimers	O
+with	O
+the	O
+3	O
+-	O
+hydroxy	O
+group	O
+in	O
+the	O
+beta	O
+-	O
+position	O
+were	O
+also	O
+effective	O
+but	O
+less	O
+potent	O
+(	O
+ED50	O
+values	O
+,	O
+33	O
+.	O
+8	O
+-	O
+63	O
+.	O
+5	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+Although	O
+the	O
+neuroactive	O
+steroids	O
+were	O
+considerably	O
+less	O
+potent	O
+than	O
+the	O
+benzodiazepine	O
+clonazepam	O
+in	O
+protecting	O
+against	O
+pilocarpine	O
+seizures	B
+,	O
+steroids	O
+with	O
+the	O
+5	O
+alpha	O
+,	O
+3	O
+alpha	O
+-	O
+configuration	O
+had	O
+comparable	O
+or	O
+higher	O
+protective	O
+index	O
+values	O
+(	O
+TD50	O
+for	O
+motor	O
+impairment	O
+divided	O
+by	O
+ED50	O
+for	O
+seizure	B
+protection	O
+)	O
+than	O
+clonazepam	O
+,	O
+indicating	O
+that	O
+some	O
+neuroactive	O
+steroids	O
+may	O
+have	O
+lower	O
+relative	O
+toxicity	B
+.	O
+
+Steroids	O
+with	O
+the	O
+5	O
+alpha	O
+,	O
+3	O
+alpha	O
+-	O
+or	O
+5	O
+beta	O
+,	O
+3	O
+alpha	O
+-	O
+configurations	O
+also	O
+produced	O
+a	O
+dose	O
+-	O
+dependent	O
+delay	O
+in	O
+the	O
+onset	O
+of	O
+limbic	O
+seizures	B
+induced	O
+by	O
+kainic	O
+acid	O
+(	O
+32	O
+mg	O
+/	O
+kg	O
+,	O
+s	O
+.	O
+c	O
+.	O
+)	O
+,	O
+but	O
+did	O
+not	O
+completely	O
+protect	O
+against	O
+the	O
+seizures	B
+.	O
+
+However	O
+,	O
+when	O
+a	O
+second	O
+dose	O
+of	O
+the	O
+steroid	O
+was	O
+administered	O
+1	O
+hr	O
+after	O
+the	O
+first	O
+dose	O
+,	O
+complete	O
+protection	O
+from	O
+the	O
+kainic	O
+acid	O
+-	O
+induced	O
+limbic	O
+seizures	B
+and	O
+status	B
+epilepticus	I
+was	O
+obtained	O
+.	O
+
+The	O
+steroids	O
+also	O
+caused	O
+a	O
+dose	O
+-	O
+dependent	O
+delay	O
+in	O
+NMDA	O
+(	O
+257	O
+mg	O
+/	O
+kg	O
+,	O
+s	O
+.	O
+c	O
+.	O
+)	O
+-	O
+induced	O
+lethality	O
+,	O
+but	O
+did	O
+not	O
+completely	O
+protect	O
+against	O
+NMDA	O
+seizures	B
+or	O
+lethality	O
+.	O
+
+We	O
+conclude	O
+that	O
+neuroactive	O
+steroids	O
+are	O
+highly	O
+effective	O
+in	O
+protecting	O
+against	O
+pilocarpine	O
+-	O
+and	O
+kainic	O
+acid	O
+-	O
+induced	O
+seizures	B
+and	O
+status	B
+epilepticus	I
+in	O
+mice	O
+,	O
+and	O
+may	O
+be	O
+of	O
+utility	O
+in	O
+the	O
+treatment	O
+of	O
+some	O
+forms	O
+of	O
+status	B
+epilepticus	I
+in	O
+humans	O
+.	O
+
+Hepatic	O
+and	O
+extrahepatic	O
+angiotensinogen	O
+gene	O
+expression	O
+in	O
+rats	O
+with	O
+acute	O
+nephrotic	B
+syndrome	I
+.	O
+
+Plasma	O
+concentration	O
+and	O
+urine	O
+excretion	O
+of	O
+the	O
+renin	O
+-	O
+angiotensin	O
+system	O
+proteins	O
+are	O
+altered	O
+in	O
+rats	O
+with	O
+nephrotic	B
+syndrome	I
+(	O
+NS	B
+)	O
+.	O
+
+In	O
+this	O
+work	O
+the	O
+messenger	O
+ribonucleic	O
+acid	O
+(	O
+mRNA	O
+)	O
+levels	O
+of	O
+angiotensinogen	O
+(	O
+Ao	O
+)	O
+were	O
+analyzed	O
+with	O
+the	O
+slot	O
+-	O
+blot	O
+hybridization	O
+technique	O
+in	O
+liver	O
+and	O
+other	O
+extrahepatic	O
+tissues	O
+:	O
+kidney	O
+,	O
+heart	O
+,	O
+brain	O
+,	O
+and	O
+adrenal	O
+gland	O
+from	O
+control	O
+,	O
+nephrotic	B
+,	O
+and	O
+pair	O
+-	O
+fed	O
+(	O
+PF	O
+)	O
+rats	O
+.	O
+
+NS	B
+was	O
+induced	O
+by	O
+a	O
+single	O
+injection	O
+of	O
+puromycin	O
+amino	O
+-	O
+nucleoside	O
+(	O
+PAN	O
+)	O
+.	O
+
+Although	O
+a	O
+great	O
+urinary	O
+excretion	O
+and	O
+half	O
+-	O
+normal	O
+plasma	O
+levels	O
+of	O
+Ao	O
+were	O
+observed	O
+on	O
+day	O
+6	O
+after	O
+PAN	O
+injection	O
+,	O
+when	O
+NS	B
+was	O
+clearly	O
+established	O
+,	O
+hepatic	O
+Ao	O
+mRNA	O
+levels	O
+did	O
+not	O
+change	O
+.	O
+
+Furthermore	O
+,	O
+the	O
+Ao	O
+mRNA	O
+levels	O
+did	O
+not	O
+change	O
+in	O
+any	O
+of	O
+the	O
+extrahepatic	O
+tissues	O
+studied	O
+on	O
+day	O
+6	O
+,	O
+nor	O
+did	O
+its	O
+hepatic	O
+levels	O
+at	O
+days	O
+1	O
+,	O
+3	O
+,	O
+5	O
+,	O
+or	O
+7	O
+after	O
+PAN	O
+injection	O
+.	O
+
+These	O
+data	O
+suggest	O
+that	O
+the	O
+hepatic	O
+and	O
+extrahepatic	O
+Ao	O
+mRNA	O
+levels	O
+are	O
+unaltered	O
+during	O
+the	O
+development	O
+of	O
+the	O
+acute	O
+NS	B
+induced	O
+by	O
+PAN	O
+.	O
+
+Neuroleptic	B
+malignant	I
+syndrome	I
+with	O
+risperidone	O
+.	O
+
+Neuroleptic	B
+malignant	I
+syndrome	I
+is	O
+thought	O
+to	O
+be	O
+a	O
+result	O
+of	O
+dopamine	O
+D2	O
+receptor	O
+blockade	O
+in	O
+the	O
+striatum	O
+of	O
+the	O
+basal	O
+ganglia	O
+.	O
+
+Risperidone	O
+,	O
+a	O
+benzisoxazole	O
+derivative	O
+antipsychotic	O
+,	O
+has	O
+high	O
+serotonin	O
+5	O
+-	O
+HT2	O
+receptor	O
+blockade	O
+and	O
+dose	O
+-	O
+related	O
+D2	O
+receptor	O
+blockade	O
+.	O
+
+The	O
+high	O
+ratio	O
+is	O
+believed	O
+to	O
+impart	O
+the	O
+low	O
+frequency	O
+of	O
+extrapyramidal	B
+symptoms	I
+with	O
+risperidone	O
+at	O
+low	O
+dosages	O
+.	O
+
+With	O
+this	O
+low	O
+frequency	O
+of	O
+extrapyramidal	B
+symptoms	I
+,	O
+it	O
+was	O
+thought	O
+the	O
+frequency	O
+of	O
+neuroleptic	B
+malignant	I
+syndrome	I
+might	O
+also	O
+be	O
+lowered	O
+.	O
+
+A	O
+73	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+developed	O
+neuroleptic	B
+malignant	I
+syndrome	I
+after	O
+monotherapy	O
+with	O
+risperidone	O
+.	O
+
+The	O
+syndrome	O
+reversed	O
+after	O
+discontinuing	O
+risperidone	O
+and	O
+starting	O
+treatment	O
+with	O
+dantrolene	O
+and	O
+bromocriptine	O
+.	O
+
+It	O
+appears	O
+that	O
+the	O
+protection	O
+from	O
+extrapyramidal	O
+side	O
+effects	O
+observed	O
+with	O
+risperidone	O
+does	O
+not	O
+ensure	O
+protection	O
+from	O
+neuroleptic	B
+malignant	I
+syndrome	I
+.	O
+
+The	O
+attenuating	O
+effect	O
+of	O
+carteolol	O
+hydrochloride	O
+,	O
+a	O
+beta	O
+-	O
+adrenoceptor	O
+antagonist	O
+,	O
+on	O
+neuroleptic	O
+-	O
+induced	O
+catalepsy	B
+in	O
+rats	O
+.	O
+
+It	O
+is	O
+known	O
+that	O
+beta	O
+-	O
+adrenoceptor	O
+antagonists	O
+are	O
+effective	O
+in	O
+the	O
+treatment	O
+of	O
+akathisia	B
+,	O
+one	O
+of	O
+the	O
+extrapyramidal	O
+side	O
+effects	O
+that	O
+occur	O
+during	O
+neuroleptic	O
+treatment	O
+.	O
+
+Neuroleptic	O
+-	O
+induced	O
+catalepsy	B
+,	O
+a	O
+model	O
+of	O
+neuroleptic	O
+-	O
+induced	O
+extrapyramidal	O
+side	O
+effects	O
+,	O
+was	O
+considered	O
+suitable	O
+as	O
+a	O
+model	O
+for	O
+predicting	O
+neuroleptic	O
+-	O
+induced	O
+akathisia	B
+in	O
+humans	O
+,	O
+although	O
+neuroleptic	O
+-	O
+induced	O
+catalepsy	B
+was	O
+not	O
+considered	O
+a	O
+specific	O
+test	O
+for	O
+neuroleptic	O
+-	O
+induced	O
+akathisia	B
+.	O
+
+Therefore	O
+,	O
+the	O
+effects	O
+of	O
+carteolol	O
+,	O
+a	O
+beta	O
+-	O
+adrenoceptor	O
+antagonist	O
+,	O
+on	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+in	O
+rats	O
+were	O
+behaviorally	O
+studied	O
+and	O
+compared	O
+with	O
+those	O
+of	O
+propranolol	O
+and	O
+biperiden	O
+,	O
+a	O
+muscarinic	O
+receptor	O
+antagonist	O
+.	O
+
+Carteolol	O
+,	O
+as	O
+well	O
+as	O
+propranolol	O
+and	O
+biperiden	O
+,	O
+inhibited	O
+the	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+.	O
+
+The	O
+inhibitory	O
+effect	O
+of	O
+carteolol	O
+was	O
+almost	O
+comparable	O
+to	O
+that	O
+of	O
+propranolol	O
+,	O
+but	O
+was	O
+weaker	O
+than	O
+that	O
+of	O
+biperiden	O
+.	O
+
+Carteolol	O
+did	O
+not	O
+evoke	O
+postsynaptic	O
+dopamine	O
+receptor	O
+-	O
+stimulating	O
+behavioral	O
+signs	O
+such	O
+as	O
+stereotypy	O
+and	O
+hyperlocomotion	B
+in	O
+rats	O
+.	O
+
+Carteolol	O
+did	O
+not	O
+antagonize	O
+the	O
+inhibitory	O
+effects	O
+of	O
+haloperidol	O
+on	O
+apomorphine	O
+-	O
+induced	O
+stereotypy	O
+and	O
+locomotor	O
+activity	O
+in	O
+rats	O
+.	O
+
+In	O
+addition	O
+,	O
+carteolol	O
+did	O
+not	O
+evoke	O
+5	O
+-	O
+HT1A	O
+receptor	O
+-	O
+stimulating	O
+behavioral	O
+signs	O
+such	O
+as	O
+flat	O
+body	O
+posture	O
+and	O
+forepaw	O
+treading	O
+and	O
+did	O
+not	O
+inhibit	O
+5	O
+-	O
+hydroxytryptophan	O
+-	O
+induced	O
+head	O
+twitch	O
+in	O
+rats	O
+.	O
+
+Finally	O
+,	O
+carteolol	O
+did	O
+not	O
+inhibit	O
+physostigmine	O
+-	O
+induced	O
+lethality	O
+in	O
+rats	O
+.	O
+
+These	O
+results	O
+strongly	O
+suggest	O
+that	O
+carteolol	O
+improves	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+via	O
+its	O
+beta	O
+-	O
+adrenoceptor	O
+antagonistic	O
+activity	O
+and	O
+is	O
+expected	O
+to	O
+be	O
+effective	O
+in	O
+the	O
+treatment	O
+of	O
+akathisia	B
+without	O
+attenuating	O
+neuroleptic	O
+-	O
+induced	O
+antipsychotic	O
+effects	O
+due	O
+to	O
+its	O
+postsynaptic	O
+dopamine	O
+receptor	O
+antagonistic	O
+activity	O
+.	O
+
+Granulosa	B
+cell	I
+tumor	I
+of	I
+the	I
+ovary	I
+associated	O
+with	O
+antecedent	O
+tamoxifen	O
+use	O
+.	O
+
+BACKGROUND	O
+:	O
+Increased	O
+attention	O
+has	O
+been	O
+focused	O
+recently	O
+on	O
+the	O
+estrogenic	O
+effects	O
+of	O
+tamoxifen	O
+.	O
+
+Review	O
+of	O
+the	O
+literature	O
+reveals	O
+an	O
+association	O
+between	O
+tamoxifen	O
+use	O
+and	O
+gynecologic	O
+tumors	B
+.	O
+
+CASE	O
+:	O
+A	O
+52	O
+-	O
+year	O
+-	O
+old	O
+postmenopausal	O
+woman	O
+was	O
+treated	O
+with	O
+tamoxifen	O
+for	O
+stage	O
+II	O
+estrogen	O
+receptor	O
+-	O
+positive	O
+breast	B
+carcinoma	I
+.	O
+
+Her	O
+aspartate	O
+transaminase	O
+and	O
+alanine	O
+transaminase	O
+levels	O
+increase	O
+markedly	O
+after	O
+6	O
+months	O
+of	O
+tamoxifen	O
+use	O
+.	O
+
+After	O
+an	O
+additional	O
+17	O
+months	O
+of	O
+elevated	O
+serum	O
+transaminases	O
+,	O
+the	O
+patient	O
+was	O
+found	O
+to	O
+have	O
+a	O
+stage	O
+Ic	O
+granulosa	B
+cell	I
+tumor	I
+of	I
+the	I
+ovary	I
+.	O
+
+CONCLUSION	O
+:	O
+Patients	O
+with	O
+tamoxifen	O
+-	O
+induced	O
+liver	B
+dysfunction	I
+may	O
+be	O
+at	O
+increased	O
+risk	O
+for	O
+granulosa	B
+cell	I
+tumors	I
+because	O
+of	O
+alterations	O
+in	O
+tamoxifen	O
+metabolism	O
+.	O
+
+Lifetime	O
+treatment	O
+of	O
+mice	O
+with	O
+azidothymidine	O
+(	O
+AZT	O
+)	O
+produces	O
+myelodysplasia	B
+.	O
+
+AZT	O
+has	O
+induced	O
+a	O
+macrocytic	B
+anemia	I
+in	O
+AIDS	B
+patients	O
+on	O
+long	O
+term	O
+AZT	O
+therapy	O
+.	O
+
+It	O
+is	O
+generally	O
+assumed	O
+that	O
+DNA	O
+elongation	O
+is	O
+stopped	O
+by	O
+the	O
+insertion	O
+of	O
+AZT	O
+into	O
+the	O
+chain	O
+in	O
+place	O
+of	O
+thymidine	O
+thus	O
+preventing	O
+the	O
+phosphate	O
+hydroxyl	O
+linkages	O
+and	O
+therefore	O
+suppresses	O
+hemopoietic	O
+progenitor	O
+cell	O
+proliferation	O
+in	O
+an	O
+early	O
+stage	O
+of	O
+differentiation	O
+.	O
+
+CBA	O
+/	O
+Ca	O
+male	O
+mice	O
+started	O
+on	O
+AZT	O
+0	O
+.	O
+75	O
+mg	O
+/	O
+ml	O
+H2O	O
+at	O
+84	O
+days	O
+of	O
+age	O
+and	O
+kept	O
+on	O
+it	O
+for	O
+687	O
+days	O
+when	O
+dosage	O
+reduced	O
+to	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+ml	O
+H2O	O
+for	O
+a	O
+group	O
+,	O
+another	O
+group	O
+removed	O
+from	O
+AZT	O
+to	O
+see	O
+recovery	O
+,	O
+and	O
+third	O
+group	O
+remained	O
+on	O
+0	O
+.	O
+75	O
+mg	O
+.	O
+
+At	O
+687	O
+days	O
+mice	O
+that	O
+had	O
+been	O
+on	O
+0	O
+.	O
+75	O
+mg	O
+had	O
+average	O
+platelet	O
+counts	O
+of	O
+2	O
+.	O
+5	O
+x	O
+10	O
+(	O
+6	O
+)	O
+.	O
+
+Histological	O
+examination	O
+on	O
+9	O
+of	O
+10	O
+mice	O
+with	O
+such	O
+thrombocytopenia	B
+showed	O
+changes	O
+compatible	O
+with	O
+myelodysplastic	B
+syndrome	I
+(	O
+MDS	B
+)	O
+.	O
+
+A	O
+variety	O
+of	O
+histological	O
+patterns	O
+was	O
+observed	O
+.	O
+
+There	O
+were	O
+two	O
+cases	O
+of	O
+hypocellular	O
+myelodysplasia	B
+,	O
+two	O
+cases	O
+of	O
+hypersegmented	O
+myelodysplastic	B
+granulocytosis	O
+,	O
+two	O
+cases	O
+of	O
+hypercellular	O
+marrow	O
+with	O
+abnormal	O
+megakaryocytes	O
+with	O
+bizarre	O
+nuclei	O
+,	O
+one	O
+case	O
+of	O
+megakaryocytic	O
+myelosis	O
+associated	O
+with	O
+a	O
+hyperplastic	B
+marrow	I
+,	O
+dysmyelopoiesis	B
+and	O
+a	O
+hypocellular	B
+marrow	I
+and	O
+two	O
+cases	O
+of	O
+myelodysplasia	B
+with	O
+dyserythropoiesis	B
+,	O
+hemosiderosis	B
+and	O
+a	O
+hypocellular	B
+marrow	I
+.	O
+
+Above	O
+mentioned	O
+AZT	O
+incorporation	O
+may	O
+have	O
+induced	O
+an	O
+ineffective	O
+hemopoiesis	O
+in	O
+the	O
+primitive	O
+hemopoietic	O
+progenitor	O
+cells	O
+,	O
+which	O
+is	O
+known	O
+to	O
+be	O
+seen	O
+commonly	O
+in	O
+the	O
+myelodysplastic	B
+syndrome	I
+.	O
+
+Biphasic	O
+response	O
+of	O
+the	O
+SA	O
+node	O
+of	O
+the	O
+dog	O
+heart	O
+in	O
+vivo	O
+to	O
+selective	O
+administration	O
+of	O
+ketamine	O
+.	O
+
+Effect	O
+of	O
+ketamine	O
+on	O
+the	O
+SA	O
+node	O
+of	O
+the	O
+dog	O
+heart	O
+was	O
+studied	O
+in	O
+vivo	O
+using	O
+a	O
+selective	O
+perfusion	O
+technique	O
+of	O
+the	O
+SA	O
+node	O
+artery	O
+.	O
+
+Injections	O
+of	O
+ketamine	O
+in	O
+doses	O
+from	O
+100	O
+microgram	O
+to	O
+3	O
+mg	O
+into	O
+the	O
+artery	O
+produced	O
+a	O
+depression	B
+of	O
+the	O
+SA	O
+nodal	O
+activity	O
+by	O
+a	O
+direct	O
+action	O
+.	O
+
+This	O
+depression	B
+was	O
+followed	O
+by	O
+the	O
+sudden	O
+appearance	O
+of	O
+a	O
+stimulatory	O
+phase	O
+.	O
+
+Bilateral	O
+vagotomy	O
+and	O
+sympathectomy	O
+or	O
+prior	O
+administration	O
+of	O
+a	O
+ganglion	O
+blocker	O
+failed	O
+to	O
+inhibit	O
+the	O
+occurrence	O
+of	O
+the	O
+ketamine	O
+-	O
+induced	O
+tachycardia	B
+,	O
+while	O
+it	O
+was	O
+completely	O
+abolished	O
+in	O
+the	O
+reserpinized	O
+dogs	O
+or	O
+by	O
+a	O
+prior	O
+injection	O
+of	O
+a	O
+beta	O
+-	O
+blocking	O
+agent	O
+into	O
+the	O
+SA	O
+node	O
+artery	O
+.	O
+
+This	O
+may	O
+indicate	O
+that	O
+an	O
+activation	O
+of	O
+the	O
+peripheral	O
+adrenergic	O
+mechanism	O
+plays	O
+an	O
+important	O
+role	O
+in	O
+the	O
+induction	O
+of	O
+the	O
+excitatory	O
+effect	O
+of	O
+ketamine	O
+injected	O
+in	O
+the	O
+SA	O
+node	O
+artery	O
+.	O
+
+Over	O
+expression	O
+of	O
+vascular	O
+endothelial	O
+growth	O
+factor	O
+and	O
+its	O
+receptor	O
+during	O
+the	O
+development	O
+of	O
+estrogen	O
+-	O
+induced	O
+rat	O
+pituitary	B
+tumors	I
+may	O
+mediate	O
+estrogen	O
+-	O
+initiated	O
+tumor	B
+angiogenesis	O
+.	O
+
+Estrogens	O
+,	O
+which	O
+have	O
+been	O
+associated	O
+with	O
+several	O
+types	O
+of	O
+human	O
+and	O
+animal	O
+cancers	B
+,	O
+can	O
+induce	O
+tumor	B
+angiogenesis	O
+in	O
+the	O
+pituitary	O
+of	O
+Fischer	O
+344	O
+rats	O
+.	O
+
+The	O
+mechanistic	O
+details	O
+of	O
+tumor	B
+angiogenesis	O
+induction	O
+,	O
+during	O
+estrogen	O
+carcinogenesis	B
+,	O
+are	O
+still	O
+unknown	O
+.	O
+
+To	O
+elucidate	O
+the	O
+role	O
+of	O
+estrogen	O
+in	O
+the	O
+regulation	O
+of	O
+tumor	B
+angiogenesis	O
+in	O
+the	O
+pituitary	O
+of	O
+female	O
+rats	O
+,	O
+the	O
+density	O
+of	O
+blood	O
+vessels	O
+was	O
+analysed	O
+using	O
+factor	O
+VIII	O
+related	O
+antigen	O
+(	O
+FVIIIRAg	O
+)	O
+immunohistochemistry	O
+and	O
+the	O
+expression	O
+of	O
+vascular	O
+endothelial	O
+growth	O
+factor	O
+/	O
+vascular	O
+permeability	O
+factor	O
+(	O
+VEGF	O
+/	O
+VPF	O
+)	O
+was	O
+examined	O
+by	O
+Western	O
+blot	O
+and	O
+immunohistochemical	O
+analysis	O
+.	O
+
+The	O
+expression	O
+of	O
+VEGF	O
+receptor	O
+(	O
+VEGFR	O
+-	O
+2	O
+/	O
+Flk	O
+-	O
+1	O
+/	O
+KDR	O
+)	O
+was	O
+also	O
+examined	O
+by	O
+immunohistochemistry	O
+.	O
+
+The	O
+results	O
+demonstrated	O
+that	O
+17beta	O
+-	O
+estradiol	O
+(	O
+E2	O
+)	O
+induces	O
+neovascularization	O
+,	O
+as	O
+well	O
+as	O
+the	O
+growth	O
+and	O
+enlargement	O
+of	O
+blood	O
+vessels	O
+after	O
+7	O
+days	O
+of	O
+exposure	O
+.	O
+
+The	O
+high	O
+tumor	B
+angiogenic	O
+potential	O
+was	O
+associated	O
+with	O
+an	O
+elevated	O
+VEGF	O
+/	O
+VPF	O
+protein	O
+expression	O
+in	O
+the	O
+E2	O
+exposed	O
+pituitary	O
+of	O
+ovariectomized	O
+(	O
+OVEX	O
+)	O
+rats	O
+.	O
+
+VEGF	O
+/	O
+VPF	O
+and	O
+FVIIIRAg	O
+immunohistochemistry	O
+and	O
+endothelial	O
+specific	O
+lectin	O
+(	O
+UEA1	O
+)	O
+binding	O
+studies	O
+,	O
+indicate	O
+that	O
+the	O
+elevation	O
+of	O
+VEGF	O
+protein	O
+expression	O
+initially	O
+occurred	O
+in	O
+both	O
+blood	O
+vessels	O
+and	O
+non	O
+-	O
+endothelial	O
+cells	O
+.	O
+
+After	O
+15	O
+days	O
+of	O
+E2	O
+exposure	O
+,	O
+VEGF	O
+/	O
+VPF	O
+protein	O
+expression	O
+,	O
+in	O
+the	O
+non	O
+-	O
+endothelial	O
+cell	O
+population	O
+,	O
+sharply	O
+declined	O
+and	O
+was	O
+restricted	O
+to	O
+the	O
+blood	O
+vessels	O
+.	O
+
+The	O
+function	O
+of	O
+non	O
+-	O
+endothelial	O
+-	O
+derived	O
+VEGF	O
+is	O
+not	O
+clear	O
+.	O
+
+Furthermore	O
+,	O
+immunohistochemical	O
+studies	O
+demonstrated	O
+that	O
+VEGFR	O
+-	O
+2	O
+(	O
+flk	O
+-	O
+1	O
+/	O
+KDR	O
+)	O
+,	O
+expression	O
+was	O
+elevated	O
+significantly	O
+in	O
+the	O
+endothelial	O
+cells	O
+of	O
+microblood	O
+vessels	O
+after	O
+7	O
+days	O
+of	O
+E2	O
+exposure	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+over	O
+expression	O
+of	O
+VEGF	O
+and	O
+its	O
+receptor	O
+(	O
+VEGFR	O
+-	O
+2	O
+)	O
+may	O
+play	O
+an	O
+important	O
+role	O
+in	O
+the	O
+initial	O
+step	O
+of	O
+the	O
+regulation	O
+of	O
+estrogen	O
+induced	O
+tumor	B
+angiogenesis	O
+in	O
+the	O
+rat	O
+pituitary	O
+.	O
+
+Persistent	O
+nephrogenic	B
+diabetes	I
+insipidus	I
+following	O
+lithium	O
+therapy	O
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+patient	O
+who	O
+developed	O
+severe	O
+hypernatraemic	O
+dehydration	B
+following	O
+a	O
+head	B
+injury	I
+.	O
+
+Ten	O
+years	O
+previously	O
+he	O
+had	O
+been	O
+diagnosed	O
+to	O
+have	O
+lithium	O
+-	O
+induced	O
+nephrogenic	B
+diabetes	I
+insipidus	I
+,	O
+and	O
+lithium	O
+therapy	O
+had	O
+been	O
+discontinued	O
+.	O
+
+He	O
+remained	O
+thirsty	O
+and	O
+polyuric	B
+despite	O
+cessation	O
+of	O
+lithium	O
+and	O
+investigations	O
+on	O
+admission	O
+showed	O
+him	O
+to	O
+have	O
+normal	O
+osmoregulated	O
+thirst	O
+and	O
+vasopressin	O
+secretion	O
+,	O
+with	O
+clear	O
+evidence	O
+of	O
+nephrogenic	B
+diabetes	I
+insipidus	I
+.	O
+
+Lithium	O
+induced	O
+nephrogenic	B
+diabetes	I
+insipidus	I
+is	O
+considered	O
+to	O
+be	O
+reversible	O
+on	O
+cessation	O
+of	O
+therapy	O
+but	O
+polyuria	B
+persisted	O
+in	O
+this	O
+patient	O
+for	O
+ten	O
+years	O
+after	O
+lithium	O
+was	O
+stopped	O
+.	O
+
+We	O
+discuss	O
+the	O
+possible	O
+renal	O
+mechanisms	O
+and	O
+the	O
+implications	O
+for	O
+management	O
+of	O
+patients	O
+with	O
+lithium	O
+-	O
+induced	O
+nephrogenic	B
+diabetes	I
+insipidus	I
+.	O
+
+Effects	O
+of	O
+NIK	O
+-	O
+247	O
+on	O
+cholinesterase	O
+and	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+.	O
+
+The	O
+effects	O
+of	O
+NIK	O
+-	O
+247	O
+on	O
+cholinesterase	O
+,	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+and	O
+spontaneous	O
+movement	O
+were	O
+examined	O
+and	O
+compared	O
+with	O
+those	O
+of	O
+the	O
+well	O
+-	O
+known	O
+cholinesterase	O
+inhibitors	O
+tacrine	O
+and	O
+E	O
+-	O
+2020	O
+.	O
+
+NIK	O
+-	O
+247	O
+,	O
+tacrine	O
+and	O
+E	O
+-	O
+2020	O
+all	O
+strongly	O
+inhibited	O
+acetylcholinesterase	O
+(	O
+AChE	O
+)	O
+in	O
+human	O
+red	O
+blood	O
+cells	O
+(	O
+IC50s	O
+=	O
+1	O
+.	O
+0	O
+x	O
+10	O
+(	O
+-	O
+6	O
+)	O
+,	O
+2	O
+.	O
+9	O
+x	O
+10	O
+(	O
+-	O
+7	O
+)	O
+and	O
+3	O
+.	O
+7	O
+x	O
+10	O
+(	O
+-	O
+8	O
+)	O
+M	O
+,	O
+respectively	O
+)	O
+.	O
+
+In	O
+addition	O
+,	O
+NIK	O
+-	O
+247	O
+and	O
+tacrine	O
+,	O
+but	O
+not	O
+E	O
+-	O
+2020	O
+,	O
+strongly	O
+inhibited	O
+butyrylcholinestrase	O
+(	O
+BuChE	O
+)	O
+in	O
+human	O
+serum	O
+.	O
+
+All	O
+three	O
+drugs	O
+produced	O
+mixed	O
+inhibition	O
+of	O
+AChE	O
+activity	O
+.	O
+
+Moreover	O
+,	O
+the	O
+inhibitory	O
+effect	O
+of	O
+NIK	O
+-	O
+247	O
+on	O
+AChE	O
+was	O
+reversible	O
+.	O
+
+All	O
+compounds	O
+at	O
+0	O
+.	O
+1	O
+-	O
+1	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+significantly	O
+improved	O
+the	O
+amnesia	B
+induced	O
+by	O
+scopolamine	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+in	O
+rats	O
+performing	O
+a	O
+passive	O
+avoidance	O
+task	O
+.	O
+
+The	O
+three	O
+compounds	O
+at	O
+1	O
+and	O
+3	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+did	O
+not	O
+significantly	O
+decrease	O
+spontaneous	O
+movement	O
+by	O
+rats	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+NIK	O
+-	O
+247	O
+at	O
+a	O
+low	O
+dose	O
+(	O
+0	O
+.	O
+1	O
+-	O
+1	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+)	O
+improves	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+but	O
+does	O
+not	O
+affect	O
+spontaneous	O
+movement	O
+.	O
+
+The	O
+findings	O
+suggest	O
+that	O
+NIK	O
+-	O
+247	O
+may	O
+be	O
+a	O
+useful	O
+drug	O
+for	O
+the	O
+treatment	O
+of	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+.	O
+
+Potential	O
+therapeutic	O
+use	O
+of	O
+the	O
+selective	O
+dopamine	O
+D1	O
+receptor	O
+agonist	O
+,	O
+A	O
+-	O
+86929	O
+:	O
+an	O
+acute	O
+study	O
+in	O
+parkinsonian	B
+levodopa	O
+-	O
+primed	O
+monkeys	O
+.	O
+
+The	O
+clinical	O
+utility	O
+of	O
+dopamine	O
+(	O
+DA	O
+)	O
+D1	O
+receptor	O
+agonists	O
+in	O
+the	O
+treatment	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+is	O
+still	O
+unclear	O
+.	O
+
+The	O
+therapeutic	O
+use	O
+of	O
+selective	O
+DA	O
+D1	O
+receptor	O
+agonists	O
+such	O
+as	O
+SKF	O
+-	O
+82958	O
+(	O
+6	O
+-	O
+chloro	O
+-	O
+7	O
+,	O
+8	O
+-	O
+dihydroxy	O
+-	O
+3	O
+-	O
+allyl	O
+-	O
+1	O
+-	O
+phenyl	O
+-	O
+2	O
+,	O
+3	O
+,	O
+4	O
+,	O
+5	O
+-	O
+tetrahydro	O
+-	O
+1H	O
+-	O
+3	O
+-	O
+benzaze	O
+pine	O
+hydrobromide	O
+)	O
+and	O
+A	O
+-	O
+77636	O
+(	O
+[	O
+1R	O
+,	O
+3S	O
+]	O
+3	O
+-	O
+[	O
+1	O
+'	O
+-	O
+admantyl	O
+]	O
+-	O
+1	O
+-	O
+aminomethyl	O
+-	O
+3	O
+,	O
+4	O
+-	O
+dihydro	O
+-	O
+5	O
+,	O
+6	O
+-	O
+dihydroxy	O
+-	O
+1H	O
+-	O
+2	O
+-	O
+benzo	O
+pyran	O
+hydrochloride	O
+)	O
+seems	O
+limited	O
+because	O
+of	O
+their	O
+duration	O
+of	O
+action	O
+,	O
+which	O
+is	O
+too	O
+short	O
+for	O
+SKF	O
+-	O
+82958	O
+(	O
+<	O
+1	O
+hr	O
+)	O
+and	O
+too	O
+long	O
+for	O
+A	O
+-	O
+77636	O
+(	O
+>	O
+20	O
+hr	O
+,	O
+leading	O
+to	O
+behavioral	O
+tolerance	O
+)	O
+.	O
+
+We	O
+therefore	O
+conducted	O
+the	O
+present	O
+acute	O
+dose	O
+-	O
+response	O
+study	O
+in	O
+four	O
+1	O
+-	O
+methyl	O
+-	O
+4	O
+-	O
+phenyl	O
+-	O
+1	O
+,	O
+2	O
+,	O
+3	O
+,	O
+6	O
+-	O
+tetrahydropyridine	O
+(	O
+MPTP	O
+)	O
+-	O
+exposed	O
+cynomolgus	O
+monkeys	O
+primed	O
+to	O
+exhibit	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+to	O
+evaluate	O
+the	O
+locomotor	O
+and	O
+dyskinetic	B
+effects	O
+on	O
+challenge	O
+with	O
+four	O
+doses	O
+(	O
+from	O
+0	O
+.	O
+03	O
+to	O
+1	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+)	O
+of	O
+A	O
+-	O
+86929	O
+(	O
+[	O
+-	O
+]	O
+-	O
+[	O
+5aR	O
+,	O
+11bS	O
+]	O
+-	O
+4	O
+,	O
+5	O
+,	O
+5a	O
+,	O
+6	O
+,	O
+7	O
+,	O
+11b	O
+-	O
+hexahydro	O
+-	O
+2	O
+-	O
+propyl	O
+-	O
+3	O
+-	O
+thia	O
+-	O
+5	O
+-	O
++	O
++	O
++	O
+azacyclopent	O
+-	O
+1	O
+-	O
+ena	O
+[	O
+c	O
+]	O
+phenathrene	O
+-	O
+9	O
+-	O
+10	O
+-	O
+diol	O
+)	O
+,	O
+a	O
+selective	O
+and	O
+full	O
+DA	O
+D1	O
+-	O
+like	O
+receptor	O
+agonist	O
+with	O
+an	O
+intermediate	O
+duration	O
+of	O
+action	O
+.	O
+
+Levodopa	O
+and	O
+the	O
+DA	O
+D2	O
+-	O
+like	O
+receptor	O
+agonist	O
+,	O
+LY	O
+-	O
+171555	O
+(	O
+[	O
+4aR	O
+-	O
+trans	O
+]	O
+-	O
+4	O
+,	O
+4a	O
+,	O
+5	O
+,	O
+6	O
+,	O
+7	O
+,	O
+8	O
+,	O
+8a	O
+,	O
+9	O
+-	O
+o	O
+-	O
+dihydro	O
+-	O
+5n	O
+-	O
+propyl	O
+-	O
+2H	O
+-	O
+pyrazo	O
+lo	O
+-	O
+3	O
+-	O
+4	O
+-	O
+quinoline	O
+hydrochloride	O
+)	O
+were	O
+also	O
+used	O
+for	O
+comparison	O
+.	O
+
+Acute	O
+administration	O
+of	O
+A	O
+-	O
+86929	O
+was	O
+as	O
+efficacious	O
+in	O
+alleviating	O
+MPTP	O
+-	O
+induced	O
+parkinsonism	B
+as	O
+levodopa	O
+and	O
+LY	O
+-	O
+171555	O
+,	O
+but	O
+was	O
+less	O
+likely	O
+to	O
+reproduce	O
+the	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+in	O
+these	O
+animals	O
+than	O
+with	O
+either	O
+LY	O
+-	O
+171555	O
+or	O
+subsequent	O
+challenge	O
+of	O
+levodopa	O
+.	O
+
+Selective	O
+stimulation	O
+of	O
+the	O
+DA	O
+D1	O
+receptor	O
+may	O
+provide	O
+better	O
+integration	O
+of	O
+neural	O
+inputs	O
+transmitted	O
+to	O
+the	O
+internal	O
+segment	O
+of	O
+the	O
+globus	O
+pallidus	O
+(	O
+referred	O
+to	O
+as	O
+the	O
+basal	O
+ganglia	O
+output	O
+)	O
+compared	O
+with	O
+levodopa	O
+and	O
+selective	O
+DA	O
+D2	O
+receptor	O
+agonist	O
+.	O
+
+Potent	O
+DA	O
+D1	O
+receptor	O
+agents	O
+with	O
+an	O
+intermediate	O
+duration	O
+of	O
+efficacy	O
+such	O
+as	O
+A	O
+-	O
+86929	O
+(	O
+approximately	O
+4	O
+hr	O
+at	O
+higher	O
+doses	O
+tested	O
+)	O
+are	O
+potential	O
+therapeutic	O
+tools	O
+in	O
+PD	B
+and	O
+merit	O
+further	O
+attention	O
+.	O
+
+Neuropeptide	O
+-	O
+Y	O
+immunoreactivity	O
+in	O
+the	O
+pilocarpine	O
+model	O
+of	O
+temporal	B
+lobe	I
+epilepsy	I
+.	O
+
+Neuropeptide	O
+-	O
+Y	O
+(	O
+NPY	O
+)	O
+is	O
+expressed	O
+by	O
+granule	O
+cells	O
+and	O
+mossy	O
+fibres	O
+of	O
+the	O
+hippocampal	O
+dentate	O
+gyrus	O
+during	O
+experimental	O
+temporal	B
+lobe	I
+epilepsy	I
+(	O
+TLE	B
+)	O
+.	O
+
+This	O
+expression	O
+may	O
+represent	O
+an	O
+endogenous	O
+damping	O
+mechanism	O
+since	O
+NPY	O
+has	O
+been	O
+shown	O
+to	O
+block	O
+seizure	B
+-	O
+like	O
+events	O
+following	O
+high	O
+-	O
+frequency	O
+stimulation	O
+in	O
+hippocampal	O
+slices	O
+.	O
+
+The	O
+pilocarpine	O
+(	O
+PILO	O
+)	O
+model	O
+of	O
+epilepsy	B
+is	O
+characterized	O
+by	O
+an	O
+acute	O
+period	O
+of	O
+status	B
+epilepticus	I
+followed	O
+by	O
+spontaneous	O
+recurrent	O
+seizures	B
+and	O
+related	O
+brain	B
+damage	I
+.	O
+
+We	O
+report	O
+peroxidase	O
+-	O
+antiperoxidase	O
+immunostaining	O
+for	O
+NPY	O
+in	O
+several	O
+brain	O
+regions	O
+in	O
+this	O
+model	O
+.	O
+
+PILO	O
+-	O
+injected	O
+animals	O
+exhibited	O
+NPY	O
+immunoreactivity	O
+in	O
+the	O
+region	O
+of	O
+the	O
+mossy	O
+fibre	O
+terminals	O
+,	O
+in	O
+the	O
+dentate	O
+gyrus	O
+inner	O
+molecular	O
+layer	O
+and	O
+,	O
+in	O
+a	O
+few	O
+cases	O
+,	O
+within	O
+presumed	O
+granule	O
+cells	O
+.	O
+
+NPY	O
+immunoreactivity	O
+was	O
+also	O
+dramatically	O
+changed	O
+in	O
+the	O
+entorhinal	O
+cortex	O
+,	O
+amygdala	O
+and	O
+sensorimotor	O
+areas	O
+.	O
+
+In	O
+addition	O
+,	O
+PILO	O
+injected	O
+animals	O
+exhibited	O
+a	O
+reduction	O
+in	O
+the	O
+number	O
+of	O
+NPY	O
+-	O
+immunoreactive	O
+interneurons	O
+compared	O
+with	O
+controls	O
+.	O
+
+The	O
+results	O
+demonstrate	O
+that	O
+changes	O
+in	O
+NPY	O
+expression	O
+,	O
+including	O
+expression	O
+in	O
+the	O
+granule	O
+cells	O
+and	O
+mossy	O
+fibres	O
+and	O
+the	O
+loss	O
+of	O
+vulnerable	O
+NPY	O
+neurons	O
+,	O
+are	O
+present	O
+in	O
+the	O
+PILO	O
+model	O
+of	O
+TLE	B
+.	O
+
+However	O
+,	O
+the	O
+significance	O
+of	O
+this	O
+changed	O
+synthesis	O
+of	O
+NPY	O
+remains	O
+to	O
+be	O
+determined	O
+.	O
+
+Posteroventral	O
+medial	O
+pallidotomy	O
+in	O
+advanced	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+BACKGROUND	O
+:	O
+Posteroventral	O
+medial	O
+pallidotomy	O
+sometimes	O
+produces	O
+striking	O
+improvement	O
+in	O
+patients	O
+with	O
+advanced	O
+Parkinson	B
+'	I
+s	I
+disease	I
+,	O
+but	O
+the	O
+studies	O
+to	O
+date	O
+have	O
+involved	O
+small	O
+numbers	O
+of	O
+patients	O
+and	O
+short	O
+-	O
+term	O
+follow	O
+-	O
+up	O
+.	O
+
+METHODS	O
+:	O
+Forty	O
+patients	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+underwent	O
+serial	O
+,	O
+detailed	O
+assessments	O
+both	O
+after	O
+drug	O
+withdrawal	O
+(	O
+"	O
+off	O
+"	O
+period	O
+)	O
+and	O
+while	O
+taking	O
+their	O
+optimal	O
+medical	O
+regimens	O
+(	O
+"	O
+on	O
+"	O
+period	O
+)	O
+.	O
+
+All	O
+patients	O
+were	O
+examined	O
+preoperatively	O
+and	O
+39	O
+were	O
+examined	O
+at	O
+six	O
+months	O
+;	O
+27	O
+of	O
+the	O
+patients	O
+were	O
+also	O
+examined	O
+at	O
+one	O
+year	O
+,	O
+and	O
+11	O
+at	O
+two	O
+years	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+percent	O
+improvements	O
+at	O
+six	O
+months	O
+were	O
+as	O
+follows	O
+:	O
+off	O
+-	O
+period	O
+score	O
+for	O
+overall	O
+motor	O
+function	O
+,	O
+28	O
+percent	O
+(	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+19	O
+to	O
+38	O
+percent	O
+)	O
+,	O
+with	O
+most	O
+of	O
+the	O
+improvement	O
+in	O
+the	O
+contralateral	O
+limbs	O
+;	O
+off	O
+-	O
+period	O
+score	O
+for	O
+activities	O
+of	O
+daily	O
+living	O
+,	O
+29	O
+percent	O
+(	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+19	O
+to	O
+39	O
+percent	O
+)	O
+;	O
+on	O
+-	O
+period	O
+score	O
+for	O
+contralateral	O
+dyskinesias	B
+,	O
+82	O
+percent	O
+(	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+72	O
+to	O
+91	O
+percent	O
+)	O
+;	O
+and	O
+on	O
+-	O
+period	O
+score	O
+for	O
+ipsilateral	O
+dyskinesias	B
+,	O
+44	O
+percent	O
+(	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+29	O
+to	O
+59	O
+percent	O
+)	O
+.	O
+
+The	O
+improvements	O
+in	O
+dyskinesias	B
+and	O
+the	O
+total	O
+scores	O
+for	O
+off	O
+-	O
+period	O
+parkinsonism	B
+,	O
+contralateral	O
+bradykinesia	B
+,	O
+and	O
+rigidity	B
+were	O
+sustained	O
+in	O
+the	O
+11	O
+patients	O
+examined	O
+at	O
+two	O
+years	O
+.	O
+
+The	O
+improvement	O
+in	O
+ipsilateral	O
+dyskinesias	B
+was	O
+lost	O
+after	O
+one	O
+year	O
+,	O
+and	O
+the	O
+improvements	O
+in	O
+postural	O
+stability	O
+and	O
+gait	O
+lasted	O
+only	O
+three	O
+to	O
+six	O
+months	O
+.	O
+
+Approximately	O
+half	O
+the	O
+patients	O
+who	O
+had	O
+been	O
+dependent	O
+on	O
+assistance	O
+in	O
+activities	O
+of	O
+daily	O
+living	O
+in	O
+the	O
+off	O
+period	O
+before	O
+surgery	O
+became	O
+independent	O
+after	O
+surgery	O
+.	O
+
+The	O
+complications	O
+of	O
+surgery	O
+were	O
+generally	O
+well	O
+tolerated	O
+,	O
+and	O
+there	O
+were	O
+no	O
+significant	O
+changes	O
+in	O
+the	O
+use	O
+of	O
+medication	O
+.	O
+
+CONCLUSIONS	O
+:	O
+In	O
+late	O
+-	O
+stage	O
+Parkinson	B
+'	I
+s	I
+disease	I
+,	O
+pallidotomy	O
+significantly	O
+reduces	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+and	O
+off	O
+-	O
+period	O
+disability	O
+.	O
+
+Much	O
+of	O
+the	O
+benefit	O
+is	O
+sustained	O
+at	O
+two	O
+years	O
+,	O
+although	O
+some	O
+improvements	O
+,	O
+such	O
+as	O
+those	O
+on	O
+the	O
+ipsilateral	O
+side	O
+and	O
+in	O
+axial	O
+symptoms	O
+,	O
+wane	O
+within	O
+the	O
+first	O
+year	O
+.	O
+
+The	O
+on	O
+-	O
+period	O
+symptoms	O
+that	O
+are	O
+resistant	O
+to	O
+dopaminergic	O
+therapy	O
+do	O
+not	O
+respond	O
+to	O
+pallidotomy	O
+.	O
+
+Clarithromycin	O
+-	O
+induced	O
+ventricular	B
+tachycardia	I
+.	O
+
+Clarithromycin	O
+is	O
+a	O
+relatively	O
+new	O
+macrolide	O
+antibiotic	O
+that	O
+offers	O
+twice	O
+-	O
+daily	O
+dosing	O
+.	O
+
+It	O
+differs	O
+from	O
+erythromycin	O
+only	O
+in	O
+the	O
+methylation	O
+of	O
+the	O
+hydroxyl	O
+group	O
+at	O
+position	O
+6	O
+.	O
+
+Although	O
+the	O
+side	O
+-	O
+effect	O
+profile	O
+of	O
+erythromycin	O
+is	O
+established	O
+,	O
+including	O
+gastroenteritis	B
+and	O
+interactions	O
+with	O
+other	O
+drugs	O
+subject	O
+to	O
+hepatic	O
+mixed	O
+-	O
+function	O
+oxidase	O
+metabolism	O
+,	O
+experience	O
+with	O
+the	O
+newer	O
+macrolides	O
+is	O
+still	O
+being	O
+recorded	O
+.	O
+
+Cardiotoxicity	B
+has	O
+been	O
+demonstrated	O
+after	O
+both	O
+intravenous	O
+and	O
+oral	O
+administration	O
+of	O
+erythromycin	O
+but	O
+has	O
+never	O
+been	O
+reported	O
+with	O
+the	O
+newer	O
+macrolides	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+ventricular	B
+dysrhythmias	I
+that	O
+occurred	O
+after	O
+six	O
+therapeutic	O
+doses	O
+of	O
+clarithromycin	O
+.	O
+
+The	O
+dysrhythmias	B
+resolved	O
+after	O
+discontinuation	O
+of	O
+the	O
+drug	O
+.	O
+
+Effect	O
+of	O
+glyceryl	O
+trinitrate	O
+on	O
+the	O
+sphincter	B
+of	I
+Oddi	I
+spasm	I
+evoked	O
+by	O
+prostigmine	O
+-	O
+morphine	O
+administration	O
+.	O
+
+OBJECTIVE	O
+:	O
+In	O
+this	O
+study	O
+the	O
+effect	O
+of	O
+glyceryl	O
+trinitrate	O
+on	O
+the	O
+prostigmine	O
+-	O
+morphine	O
+-	O
+induced	O
+sphincter	B
+of	I
+Oddi	I
+spasm	I
+was	O
+evaluated	O
+in	O
+nine	O
+female	O
+patients	O
+with	O
+sphincter	B
+of	I
+Oddi	I
+dyskinesia	I
+.	O
+
+METHOD	O
+:	O
+Sphincter	B
+of	I
+Oddi	I
+spasm	I
+was	O
+induced	O
+by	O
+prostigmine	O
+-	O
+morphine	O
+administration	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+prostigmine	O
+intramuscularly	O
+and	O
+10	O
+mg	O
+morphine	O
+subcutaneously	O
+)	O
+and	O
+visualized	O
+by	O
+quantitative	O
+hepatobiliary	O
+scintigraphy	O
+.	O
+
+The	O
+entire	O
+procedure	O
+was	O
+repeated	O
+during	O
+glyceryl	O
+trinitrate	O
+infusion	O
+(	O
+Nitrolingual	O
+1	O
+microg	O
+/	O
+kg	O
+/	O
+min	O
+for	O
+120	O
+min	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+Prostigmine	O
+-	O
+morphine	O
+provocation	O
+caused	O
+significant	O
+increases	O
+in	O
+the	O
+time	O
+to	O
+peak	O
+activity	O
+(	O
+Tmax	O
+)	O
+over	O
+the	O
+hepatic	O
+hilum	O
+(	O
+HH	O
+:	O
+34	O
+.	O
+33	O
++	O
+/	O
+-	O
+5	O
+.	O
+05	O
+vs	O
+.	O
+22	O
+.	O
+77	O
++	O
+/	O
+-	O
+3	O
+.	O
+26	O
+)	O
+and	O
+the	O
+common	O
+bile	O
+duct	O
+(	O
+CBD	O
+:	O
+60	O
+.	O
+44	O
++	O
+/	O
+-	O
+5	O
+.	O
+99	O
+vs	O
+.	O
+40	O
+.	O
+0	O
++	O
+/	O
+-	O
+2	O
+.	O
+88	O
+)	O
+and	O
+in	O
+the	O
+half	O
+-	O
+time	O
+of	O
+excretion	O
+(	O
+T1	O
+/	O
+2	O
+)	O
+over	O
+the	O
+liver	O
+parenchyma	O
+(	O
+LP	O
+:	O
+120	O
+.	O
+04	O
++	O
+/	O
+-	O
+16	O
+.	O
+01	O
+vs	O
+.	O
+27	O
+.	O
+37	O
++	O
+/	O
+-	O
+2	O
+.	O
+19	O
+)	O
+,	O
+HH	O
+(	O
+117	O
+.	O
+61	O
++	O
+/	O
+-	O
+14	O
+.	O
+71	O
+vs	O
+.	O
+31	O
+.	O
+85	O
++	O
+/	O
+-	O
+3	O
+.	O
+99	O
+)	O
+and	O
+CBD	O
+(	O
+158	O
+.	O
+11	O
++	O
+/	O
+-	O
+9	O
+.	O
+18	O
+vs	O
+.	O
+40	O
+.	O
+1	O
++	O
+/	O
+-	O
+6	O
+.	O
+24	O
+)	O
+,	O
+indicating	O
+a	O
+complete	O
+spasm	B
+at	O
+the	O
+level	O
+of	O
+the	O
+sphincter	O
+of	O
+Oddi	O
+.	O
+
+Glyceryl	O
+trinitrate	O
+infusion	O
+completely	O
+normalized	O
+the	O
+prostigmine	O
+-	O
+morphine	O
+-	O
+induced	O
+alterations	O
+in	O
+these	O
+quantitative	O
+parameters	O
+(	O
+TmaX	O
+over	O
+the	O
+LP	O
+:	O
+11	O
+.	O
+33	O
++	O
+/	O
+-	O
+1	O
+.	O
+13	O
+;	O
+over	O
+the	O
+HH	O
+:	O
+18	O
+.	O
+88	O
++	O
+/	O
+-	O
+1	O
+.	O
+48	O
+;	O
+and	O
+over	O
+the	O
+CBD	O
+:	O
+36	O
+.	O
+22	O
++	O
+/	O
+-	O
+1	O
+.	O
+92	O
+;	O
+and	O
+T1	O
+/	O
+2	O
+over	O
+the	O
+LP	O
+:	O
+28	O
+.	O
+21	O
++	O
+/	O
+-	O
+1	O
+.	O
+83	O
+;	O
+over	O
+the	O
+HH	O
+:	O
+33	O
+.	O
+42	O
++	O
+/	O
+-	O
+3	O
+.	O
+10	O
+;	O
+and	O
+over	O
+the	O
+CBD	O
+:	O
+41	O
+.	O
+66	O
++	O
+/	O
+-	O
+6	O
+.	O
+33	O
+)	O
+,	O
+suggesting	O
+an	O
+effective	O
+sphincter	O
+-	O
+relaxing	O
+effect	O
+of	O
+glyceryl	O
+trinitrate	O
+.	O
+
+CONCLUSION	O
+:	O
+These	O
+results	O
+provide	O
+the	O
+first	O
+evidence	O
+of	O
+the	O
+effectiveness	O
+of	O
+glyceryl	O
+trinitrate	O
+on	O
+the	O
+morphine	O
+-	O
+induced	O
+sphincter	B
+of	I
+Oddi	I
+spasm	I
+in	O
+humans	O
+.	O
+
+Since	O
+glyceryl	O
+trinitrate	O
+is	O
+able	O
+to	O
+overcome	O
+even	O
+the	O
+drastic	O
+effect	O
+of	O
+morphine	O
+,	O
+it	O
+might	O
+be	O
+of	O
+relevance	O
+in	O
+the	O
+treatment	O
+of	O
+sphincter	B
+of	I
+Oddi	I
+dyskinesia	I
+.	O
+
+Immunopathology	O
+of	O
+penicillamine	O
+-	O
+induced	O
+glomerular	B
+disease	I
+.	O
+
+Four	O
+patients	O
+with	O
+rheumatoid	B
+arthritis	I
+developed	O
+heavy	O
+proteinuria	B
+after	O
+five	O
+to	O
+12	O
+months	O
+of	O
+treatment	O
+with	O
+D	O
+-	O
+penicillamine	O
+.	O
+
+Light	O
+microscopy	O
+of	O
+renal	O
+biopsy	O
+samples	O
+showed	O
+minimal	O
+glomerular	O
+capillary	O
+wall	O
+thickening	O
+and	O
+mesangial	O
+matrix	O
+increase	O
+,	O
+or	O
+no	O
+departure	O
+from	O
+normal	O
+.	O
+
+Electron	O
+microscopy	O
+,	O
+however	O
+,	O
+revealed	O
+subepithelial	O
+electron	O
+-	O
+dense	O
+deposits	O
+,	O
+fusion	O
+of	O
+epithelial	O
+cell	O
+foot	O
+processes	O
+,	O
+and	O
+evidence	O
+of	O
+mesangial	O
+cell	O
+hyperactivity	O
+.	O
+
+Immunofluorescence	O
+microscopy	O
+demonstrated	O
+granular	O
+capillary	O
+wall	O
+deposits	O
+of	O
+IgG	O
+and	O
+C3	O
+.	O
+
+The	O
+findings	O
+were	O
+similar	O
+to	O
+those	O
+in	O
+early	O
+membranous	B
+glomerulonephritis	I
+,	O
+differences	O
+being	O
+observed	O
+however	O
+in	O
+the	O
+results	O
+of	O
+staining	O
+for	O
+the	O
+early	O
+-	O
+acting	O
+complement	O
+components	O
+C1q	O
+and	O
+C4	O
+.	O
+
+It	O
+is	O
+tentatively	O
+concluded	O
+that	O
+complement	O
+was	O
+activated	O
+by	O
+the	O
+classical	O
+pathway	O
+.	O
+
+Experimental	O
+cranial	O
+pain	B
+elicited	O
+by	O
+capsaicin	O
+:	O
+a	O
+PET	O
+study	O
+.	O
+
+Using	O
+a	O
+positron	O
+emission	O
+tomography	O
+(	O
+PET	O
+)	O
+study	O
+it	O
+was	O
+shown	O
+recently	O
+that	O
+in	O
+migraine	B
+without	O
+aura	O
+certain	O
+areas	O
+in	O
+the	O
+brain	O
+stem	O
+were	O
+activated	O
+during	O
+the	O
+headache	B
+state	O
+,	O
+but	O
+not	O
+in	O
+the	O
+headache	B
+free	O
+interval	O
+.	O
+
+It	O
+was	O
+suggested	O
+that	O
+this	O
+brain	O
+stem	O
+activation	O
+is	O
+inherent	O
+to	O
+the	O
+migraine	B
+attack	O
+itself	O
+and	O
+represents	O
+the	O
+so	O
+called	O
+'	O
+migraine	B
+generator	O
+'	O
+.	O
+
+To	O
+test	O
+this	O
+hypothesis	O
+we	O
+performed	O
+an	O
+experimental	O
+pain	B
+study	O
+in	O
+seven	O
+healthy	O
+volunteers	O
+,	O
+using	O
+the	O
+same	O
+positioning	O
+in	O
+the	O
+PET	O
+scanner	O
+as	O
+in	O
+the	O
+migraine	B
+patients	O
+.	O
+
+A	O
+small	O
+amount	O
+of	O
+capsaicin	O
+was	O
+administered	O
+subcutaneously	O
+in	O
+the	O
+right	O
+forehead	O
+to	O
+evoke	O
+a	O
+burning	O
+painful	B
+sensation	O
+in	O
+the	O
+first	O
+division	O
+of	O
+the	O
+trigeminal	O
+nerve	O
+.	O
+
+Increases	O
+of	O
+regional	O
+cerebral	O
+blood	O
+flow	O
+(	O
+rCBF	O
+)	O
+were	O
+found	O
+bilaterally	O
+in	O
+the	O
+insula	O
+,	O
+in	O
+the	O
+anterior	O
+cingulate	O
+cortex	O
+,	O
+the	O
+cavernous	O
+sinus	O
+and	O
+the	O
+cerebellum	O
+.	O
+
+Using	O
+the	O
+same	O
+stereotactic	O
+space	O
+limits	O
+as	O
+in	O
+the	O
+above	O
+mentioned	O
+migraine	B
+study	O
+no	O
+brain	O
+stem	O
+activation	O
+was	O
+found	O
+in	O
+the	O
+acute	O
+pain	B
+state	O
+compared	O
+to	O
+the	O
+pain	B
+free	O
+state	O
+.	O
+
+The	O
+increase	O
+of	O
+activation	O
+in	O
+the	O
+region	O
+of	O
+the	O
+cavernous	O
+sinus	O
+however	O
+,	O
+suggests	O
+that	O
+this	O
+structure	O
+is	O
+more	O
+likely	O
+to	O
+be	O
+involved	O
+in	O
+trigeminal	O
+transmitted	O
+pain	B
+as	O
+such	O
+,	O
+rather	O
+than	O
+in	O
+a	O
+specific	O
+type	O
+of	O
+headache	B
+as	O
+was	O
+suggested	O
+for	O
+cluster	B
+headache	I
+.	O
+
+Value	O
+of	O
+methylprednisolone	O
+in	O
+prevention	O
+of	O
+the	O
+arthralgia	B
+-	O
+myalgia	B
+syndrome	O
+associated	O
+with	O
+the	O
+total	O
+dose	O
+infusion	O
+of	O
+iron	O
+dextran	O
+:	O
+a	O
+double	O
+blind	O
+randomized	O
+trial	O
+.	O
+
+The	O
+safety	O
+and	O
+efficacy	O
+of	O
+total	O
+dose	O
+infusion	O
+(	O
+TDI	O
+)	O
+of	O
+iron	O
+dextran	O
+has	O
+been	O
+well	O
+documented	O
+.	O
+
+In	O
+40	O
+%	O
+of	O
+treated	O
+patients	O
+,	O
+an	O
+arthralgia	B
+-	O
+myalgia	B
+syndrome	O
+develops	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+prospective	O
+study	O
+was	O
+to	O
+investigate	O
+whether	O
+intravenous	O
+(	O
+i	O
+.	O
+v	O
+.	O
+)	O
+administration	O
+of	O
+methylprednisolone	O
+(	O
+MP	O
+)	O
+prevents	O
+this	O
+complication	O
+.	O
+
+Sixty	O
+-	O
+five	O
+patients	O
+,	O
+34	O
+women	O
+and	O
+31	O
+men	O
+,	O
+ages	O
+36	O
+to	O
+80	O
+years	O
+,	O
+received	O
+either	O
+normal	O
+saline	O
+before	O
+and	O
+after	O
+TDI	O
+(	O
+group	O
+1	O
+)	O
+,	O
+125	O
+mg	O
+i	O
+.	O
+v	O
+.	O
+MP	O
+before	O
+and	O
+saline	O
+after	O
+TDI	O
+(	O
+group	O
+2	O
+)	O
+,	O
+or	O
+125	O
+mg	O
+i	O
+.	O
+v	O
+.	O
+MP	O
+before	O
+and	O
+after	O
+TDI	O
+(	O
+group	O
+3	O
+)	O
+.	O
+
+Patients	O
+were	O
+observed	O
+for	O
+72	O
+hours	O
+and	O
+reactions	O
+were	O
+recorded	O
+and	O
+graded	O
+according	O
+to	O
+severity	O
+.	O
+
+Fifty	O
+-	O
+eight	O
+percent	O
+of	O
+group	O
+1	O
+patients	O
+,	O
+33	O
+%	O
+of	O
+group	O
+2	O
+,	O
+and	O
+26	O
+%	O
+of	O
+group	O
+3	O
+had	O
+reactions	O
+to	O
+TDI	O
+.	O
+
+The	O
+severity	O
+of	O
+reactions	O
+(	O
+minimal	O
+,	O
+mild	O
+,	O
+and	O
+moderate	O
+,	O
+respectively	O
+)	O
+was	O
+as	O
+follows	O
+:	O
+group	O
+1	O
+-	O
+-	O
+6	O
+,	O
+6	O
+,	O
+and	O
+2	O
+;	O
+group	O
+2	O
+-	O
+-	O
+1	O
+,	O
+5	O
+,	O
+and	O
+0	O
+;	O
+group	O
+3	O
+-	O
+-	O
+5	O
+,	O
+1	O
+,	O
+and	O
+0	O
+.	O
+
+Data	O
+were	O
+analyzed	O
+by	O
+the	O
+two	O
+-	O
+sided	O
+Fisher	O
+'	O
+s	O
+exact	O
+test	O
+using	O
+95	O
+%	O
+confidence	O
+intervals	O
+with	O
+the	O
+approximation	O
+of	O
+Woolf	O
+.	O
+
+These	O
+data	O
+demonstrate	O
+that	O
+administration	O
+of	O
+MP	O
+before	O
+and	O
+after	O
+TDI	O
+reduces	O
+the	O
+frequency	O
+and	O
+severity	O
+of	O
+the	O
+arthralgia	B
+-	O
+myalgia	B
+syndrome	O
+.	O
+
+We	O
+conclude	O
+that	O
+125	O
+mg	O
+i	O
+.	O
+v	O
+.	O
+MP	O
+should	O
+be	O
+given	O
+routinely	O
+before	O
+and	O
+after	O
+TDI	O
+of	O
+iron	O
+dextran	O
+.	O
+
+Prolongation	B
+of	I
+the	I
+QT	I
+interval	I
+related	O
+to	O
+cisapride	O
+-	O
+diltiazem	O
+interaction	O
+.	O
+
+Cisapride	O
+,	O
+a	O
+cytochrome	O
+P450	O
+3A4	O
+(	O
+CYP3A4	O
+)	O
+substrate	O
+,	O
+is	O
+widely	O
+prescribed	O
+for	O
+the	O
+treatment	O
+of	O
+gastrointestinal	B
+motility	I
+disorders	I
+.	O
+
+Prolongation	B
+of	I
+QT	I
+interval	I
+,	O
+torsades	B
+de	I
+pointes	I
+,	O
+and	O
+sudden	B
+cardiac	I
+death	I
+have	O
+been	O
+reported	O
+after	O
+concomitant	O
+administration	O
+with	O
+erythromycin	O
+or	O
+azole	O
+antifungal	O
+agents	O
+,	O
+but	O
+not	O
+with	O
+other	O
+CYP3A4	O
+inhibitors	O
+.	O
+
+A	O
+possible	O
+drug	O
+interaction	O
+occurred	O
+in	O
+a	O
+45	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+who	O
+was	O
+taking	O
+cisapride	O
+for	O
+gastroesophageal	B
+reflux	I
+disorder	I
+and	O
+diltiazem	O
+,	O
+an	O
+agent	O
+that	O
+has	O
+inhibitory	O
+effect	O
+on	O
+CYP3A4	O
+,	O
+for	O
+hypertension	B
+.	O
+
+The	O
+patient	O
+was	O
+in	O
+near	O
+syncope	B
+and	O
+had	O
+QT	B
+-	I
+interval	I
+prolongation	I
+.	O
+
+After	O
+discontinuing	O
+cisapride	O
+,	O
+the	O
+QT	O
+interval	O
+returned	O
+to	O
+normal	O
+and	O
+symptoms	O
+did	O
+not	O
+recur	O
+.	O
+
+We	O
+suggest	O
+that	O
+caution	O
+be	O
+taken	O
+when	O
+cisapride	O
+is	O
+prescribed	O
+with	O
+any	O
+potent	O
+inhibitor	O
+of	O
+CYP3A4	O
+,	O
+including	O
+diltiazem	O
+.	O
+
+Cortical	O
+motor	O
+overactivation	O
+in	O
+parkinsonian	B
+patients	O
+with	O
+L	O
+-	O
+dopa	O
+-	O
+induced	O
+peak	O
+-	O
+dose	O
+dyskinesia	B
+.	O
+
+We	O
+have	O
+studied	O
+the	O
+regional	O
+cerebral	O
+blood	O
+flow	O
+(	O
+rCBF	O
+)	O
+changes	O
+induced	O
+by	O
+the	O
+execution	O
+of	O
+a	O
+finger	O
+-	O
+to	O
+-	O
+thumb	O
+opposition	O
+motor	O
+task	O
+in	O
+the	O
+supplementary	O
+and	O
+primary	O
+motor	O
+cortex	O
+of	O
+two	O
+groups	O
+of	O
+parkinsonian	B
+patients	O
+on	O
+L	O
+-	O
+dopa	O
+medication	O
+,	O
+the	O
+first	O
+one	O
+without	O
+L	O
+-	O
+dopa	O
+induced	O
+dyskinesia	B
+(	O
+n	O
+=	O
+23	O
+)	O
+and	O
+the	O
+other	O
+with	O
+moderate	O
+peak	O
+-	O
+dose	O
+dyskinesia	B
+(	O
+n	O
+=	O
+15	O
+)	O
+,	O
+and	O
+of	O
+a	O
+group	O
+of	O
+14	O
+normal	O
+subjects	O
+.	O
+
+Single	O
+photon	O
+emission	O
+tomography	O
+with	O
+i	O
+.	O
+v	O
+.	O
+133Xe	O
+was	O
+used	O
+to	O
+measure	O
+the	O
+rCBF	O
+changes	O
+.	O
+
+The	O
+dyskinetic	B
+parkinsonian	B
+patients	O
+exhibited	O
+a	O
+pattern	O
+of	O
+response	O
+which	O
+was	O
+markedly	O
+different	O
+from	O
+those	O
+of	O
+the	O
+normal	O
+subjects	O
+and	O
+non	O
+-	O
+dyskinetic	B
+parkinsonian	B
+patients	O
+,	O
+with	O
+a	O
+significant	O
+overactivation	O
+in	O
+the	O
+supplementary	O
+motor	O
+area	O
+and	O
+the	O
+ipsi	O
+-	O
+and	O
+contralateral	O
+primary	O
+motor	O
+areas	O
+.	O
+
+These	O
+results	O
+are	O
+compatible	O
+with	O
+the	O
+hypothesis	O
+that	O
+an	O
+hyperkinetic	B
+abnormal	B
+involuntary	I
+movement	I
+,	O
+like	O
+L	O
+-	O
+dopa	O
+-	O
+induced	O
+peak	O
+dose	O
+dyskinesia	B
+,	O
+is	O
+due	O
+to	O
+a	O
+disinhibition	O
+of	O
+the	O
+primary	O
+and	O
+associated	O
+motor	O
+cortex	O
+secondary	O
+to	O
+an	O
+excessive	O
+outflow	O
+of	O
+the	O
+pallidothalamocortical	O
+motor	O
+loop	O
+.	O
+
+Open	O
+-	O
+label	O
+assessment	O
+of	O
+levofloxacin	O
+for	O
+the	O
+treatment	O
+of	O
+acute	O
+bacterial	O
+sinusitis	B
+in	O
+adults	O
+.	O
+
+PURPOSE	O
+:	O
+To	O
+evaluate	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+levofloxacin	O
+(	O
+500	O
+mg	O
+orally	O
+once	O
+daily	O
+for	O
+10	O
+to	O
+14	O
+days	O
+)	O
+in	O
+treating	O
+adult	O
+outpatients	O
+with	O
+acute	O
+bacterial	O
+sinusitis	B
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+A	O
+total	O
+of	O
+329	O
+patients	O
+enrolled	O
+in	O
+the	O
+study	O
+at	O
+24	O
+centers	O
+.	O
+
+All	O
+patients	O
+had	O
+a	O
+pre	O
+-	O
+therapy	O
+Gram	O
+'	O
+s	O
+stain	O
+and	O
+culture	O
+of	O
+sinus	O
+exudate	O
+obtained	O
+by	O
+antral	O
+puncture	O
+or	O
+nasal	O
+endoscopy	O
+.	O
+
+Clinical	O
+response	O
+was	O
+assessed	O
+on	O
+the	O
+basis	O
+of	O
+signs	O
+and	O
+symptoms	O
+and	O
+sinus	O
+radiograph	O
+or	O
+computed	O
+tomography	O
+results	O
+.	O
+
+Microbiologic	O
+cure	O
+rates	O
+were	O
+determined	O
+on	O
+the	O
+basis	O
+of	O
+presumed	O
+plus	O
+documented	O
+eradication	O
+of	O
+the	O
+pre	O
+-	O
+therapy	O
+pathogen	O
+(	O
+s	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+most	O
+common	O
+pathogens	O
+were	O
+Haemophilus	O
+influenzae	O
+,	O
+Streptococcus	O
+pneumoniae	O
+,	O
+Staphylococcus	O
+aureus	O
+,	O
+and	O
+Moraxella	O
+catarrhalis	O
+.	O
+
+Of	O
+300	O
+clinically	O
+evaluable	O
+patients	O
+,	O
+175	O
+(	O
+58	O
+%	O
+)	O
+were	O
+cured	O
+and	O
+90	O
+(	O
+30	O
+%	O
+)	O
+were	O
+improved	O
+at	O
+the	O
+post	O
+-	O
+therapy	O
+evaluation	O
+,	O
+resulting	O
+in	O
+a	O
+clinical	O
+success	O
+rate	O
+of	O
+88	O
+%	O
+.	O
+
+Thirty	O
+-	O
+five	O
+patients	O
+(	O
+12	O
+%	O
+)	O
+clinically	O
+failed	O
+treatment	O
+.	O
+
+The	O
+microbiologic	O
+eradication	O
+rate	O
+(	O
+presumed	O
+plus	O
+documented	O
+)	O
+among	O
+138	O
+microbiologically	O
+evaluable	O
+patients	O
+was	O
+92	O
+%	O
+.	O
+
+Microbiologic	O
+eradication	O
+rates	O
+(	O
+presumed	O
+plus	O
+documented	O
+)	O
+of	O
+the	O
+most	O
+common	O
+pathogens	O
+ranged	O
+from	O
+93	O
+%	O
+(	O
+M	O
+.	O
+catarrhalis	O
+)	O
+to	O
+100	O
+%	O
+(	O
+S	O
+.	O
+pneumoniae	O
+)	O
+at	O
+the	O
+post	O
+-	O
+therapy	O
+visit	O
+.	O
+
+All	O
+but	O
+one	O
+of	O
+the	O
+265	O
+patients	O
+who	O
+were	O
+cured	O
+or	O
+improved	O
+at	O
+post	O
+-	O
+therapy	O
+returned	O
+for	O
+a	O
+long	O
+-	O
+term	O
+follow	O
+-	O
+up	O
+visit	O
+;	O
+243	O
+(	O
+92	O
+%	O
+)	O
+remained	O
+well	O
+4	O
+to	O
+6	O
+weeks	O
+after	O
+therapy	O
+;	O
+and	O
+21	O
+(	O
+8	O
+%	O
+)	O
+had	O
+a	O
+relapse	O
+of	O
+symptoms	O
+.	O
+
+Adverse	O
+events	O
+considered	O
+to	O
+be	O
+related	O
+to	O
+levofloxacin	O
+administration	O
+were	O
+reported	O
+by	O
+29	O
+patients	O
+(	O
+9	O
+%	O
+)	O
+.	O
+
+The	O
+most	O
+common	O
+drug	O
+-	O
+related	O
+adverse	O
+events	O
+were	O
+diarrhea	B
+,	O
+flatulence	B
+,	O
+and	O
+nausea	B
+;	O
+most	O
+adverse	O
+events	O
+were	O
+mild	O
+to	O
+moderate	O
+in	O
+severity	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+results	O
+of	O
+this	O
+study	O
+indicate	O
+that	O
+levofloxacin	O
+500	O
+mg	O
+once	O
+daily	O
+is	O
+an	O
+effective	O
+and	O
+safe	O
+treatment	O
+for	O
+acute	O
+bacterial	O
+sinusitis	B
+.	O
+
+Iatrogenic	O
+risks	O
+of	O
+endometrial	B
+carcinoma	I
+after	O
+treatment	O
+for	O
+breast	B
+cancer	I
+in	O
+a	O
+large	O
+French	O
+case	O
+-	O
+control	O
+study	O
+.	O
+
+F	O
+d	O
+ration	O
+Nationale	O
+des	O
+Centres	O
+de	O
+Lutte	O
+Contre	O
+le	O
+Cancer	O
+(	O
+FNCLCC	O
+)	O
+.	O
+
+Since	O
+tamoxifen	O
+is	O
+widely	O
+used	O
+in	O
+breast	B
+cancer	I
+treatment	O
+and	O
+has	O
+been	O
+proposed	O
+for	O
+the	O
+prevention	O
+of	O
+breast	B
+cancer	I
+,	O
+its	O
+endometrial	O
+iatrogenic	O
+effects	O
+must	O
+be	O
+carefully	O
+examined	O
+.	O
+
+We	O
+have	O
+investigated	O
+the	O
+association	O
+between	O
+endometrial	B
+cancer	I
+and	O
+tamoxifen	O
+use	O
+or	O
+other	O
+treatments	O
+in	O
+women	O
+treated	O
+for	O
+breast	B
+cancer	I
+in	O
+a	O
+case	O
+-	O
+control	O
+study	O
+.	O
+
+Cases	O
+of	O
+endometrial	B
+cancer	I
+diagnosed	O
+after	O
+breast	B
+cancer	I
+(	O
+n	O
+=	O
+135	O
+)	O
+and	O
+467	O
+controls	O
+matched	O
+for	O
+age	O
+,	O
+year	O
+of	O
+diagnosis	O
+of	O
+breast	B
+cancer	I
+and	O
+hospital	O
+and	O
+survival	O
+time	O
+with	O
+an	O
+intact	O
+uterus	O
+were	O
+included	O
+.	O
+
+Women	O
+who	O
+had	O
+received	O
+tamoxifen	O
+were	O
+significantly	O
+more	O
+likely	O
+to	O
+have	O
+endometrial	B
+cancer	I
+diagnosed	O
+than	O
+those	O
+who	O
+had	O
+not	O
+(	O
+crude	O
+relative	O
+risk	O
+=	O
+4	O
+.	O
+9	O
+,	O
+p	O
+=	O
+0	O
+.	O
+0001	O
+)	O
+.	O
+
+Univariate	O
+and	O
+adjusted	O
+analyses	O
+showed	O
+that	O
+the	O
+risk	O
+increased	O
+with	O
+the	O
+length	O
+of	O
+treatment	O
+(	O
+p	O
+=	O
+0	O
+.	O
+0001	O
+)	O
+or	O
+the	O
+cumulative	O
+dose	O
+of	O
+tamoxifen	O
+received	O
+(	O
+p	O
+=	O
+0	O
+.	O
+0001	O
+)	O
+,	O
+irrespective	O
+of	O
+the	O
+daily	O
+dose	O
+.	O
+
+Women	O
+who	O
+had	O
+undergone	O
+pelvic	O
+radiotherapy	O
+also	O
+had	O
+a	O
+higher	O
+risk	O
+(	O
+crude	O
+relative	O
+risk	O
+=	O
+7	O
+.	O
+8	O
+,	O
+p	O
+=	O
+0	O
+.	O
+0001	O
+)	O
+.	O
+
+After	O
+adjusting	O
+for	O
+confounding	O
+factors	O
+,	O
+the	O
+risk	O
+was	O
+higher	O
+for	O
+tamoxifen	O
+users	O
+(	O
+p	O
+=	O
+0	O
+.	O
+0012	O
+)	O
+,	O
+treatment	O
+for	O
+more	O
+than	O
+3	O
+years	O
+(	O
+all	O
+p	O
+<	O
+0	O
+.	O
+03	O
+)	O
+and	O
+pelvic	O
+radiotherapy	O
+(	O
+p	O
+=	O
+0	O
+.	O
+012	O
+)	O
+.	O
+
+Women	O
+who	O
+had	O
+endometrial	B
+cancer	I
+and	O
+had	O
+received	O
+tamoxifen	O
+had	O
+more	O
+advanced	B
+disease	I
+and	O
+poorer	O
+prognosis	O
+than	O
+those	O
+with	O
+endometrial	B
+cancer	I
+who	O
+had	O
+not	O
+received	O
+this	O
+treatment	O
+.	O
+
+Our	O
+results	O
+suggest	O
+a	O
+causal	O
+role	O
+of	O
+tamoxifen	O
+in	O
+endometrial	B
+cancer	I
+,	O
+particularly	O
+when	O
+used	O
+as	O
+currently	O
+proposed	O
+for	O
+breast	B
+cancer	I
+prevention	O
+.	O
+
+Pelvic	O
+radiotherapy	O
+may	O
+be	O
+an	O
+additional	O
+iatrogenic	O
+factor	O
+for	O
+women	O
+with	O
+breast	B
+cancer	I
+.	O
+
+Endometrial	B
+cancers	I
+diagnosed	O
+in	O
+women	O
+treated	O
+with	O
+tamoxifen	O
+have	O
+poorer	O
+prognosis	O
+.	O
+
+Women	O
+who	O
+receive	O
+tamoxifen	O
+for	O
+breast	B
+cancer	I
+should	O
+be	O
+offered	O
+gynaecological	O
+surveillance	O
+during	O
+and	O
+after	O
+treatment	O
+.	O
+
+A	O
+long	O
+-	O
+term	O
+evaluation	O
+of	O
+the	O
+risk	O
+-	O
+benefit	O
+ratio	O
+of	O
+tamoxifen	O
+as	O
+a	O
+preventive	O
+treatment	O
+for	O
+breast	B
+cancer	I
+is	O
+clearly	O
+warranted	O
+.	O
+
+Contribution	O
+of	O
+the	O
+glycine	O
+site	O
+of	O
+NMDA	O
+receptors	O
+in	O
+rostral	O
+and	O
+intermediate	O
+-	O
+caudal	O
+parts	O
+of	O
+the	O
+striatum	O
+to	O
+the	O
+regulation	O
+of	O
+muscle	O
+tone	O
+in	O
+rats	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+assess	O
+the	O
+contribution	O
+of	O
+the	O
+glycine	O
+site	O
+of	O
+NMDA	O
+receptors	O
+in	O
+the	O
+striatum	O
+to	O
+the	O
+regulation	O
+of	O
+muscle	O
+tone	O
+.	O
+
+Muscle	O
+tone	O
+was	O
+examined	O
+using	O
+a	O
+combined	O
+mechanoand	O
+electromyographic	O
+method	O
+,	O
+which	O
+measured	O
+simultaneously	O
+the	O
+muscle	O
+resistance	O
+(	O
+MMG	O
+)	O
+of	O
+the	O
+rat	O
+'	O
+s	O
+hind	O
+foot	O
+to	O
+passive	O
+extension	O
+and	O
+flexion	O
+in	O
+the	O
+ankle	O
+joint	O
+and	O
+the	O
+electromyographic	O
+activity	O
+(	O
+EMG	O
+)	O
+of	O
+the	O
+antagonistic	O
+muscles	O
+of	O
+that	O
+joint	O
+:	O
+gastrocnemius	O
+and	O
+tibialis	O
+anterior	O
+.	O
+
+Muscle	B
+rigidity	I
+was	O
+induced	O
+by	O
+haloperidol	O
+(	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+5	O
+,	O
+7	O
+-	O
+dichlorokynurenic	O
+acid	O
+(	O
+5	O
+,	O
+7	O
+-	O
+DCKA	O
+)	O
+,	O
+a	O
+selective	O
+glycine	O
+site	O
+antagonist	O
+,	O
+injected	O
+in	O
+doses	O
+of	O
+2	O
+.	O
+5	O
+and	O
+4	O
+.	O
+5	O
+microg	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+bilaterally	O
+,	O
+into	O
+the	O
+rostral	O
+region	O
+of	O
+the	O
+striatum	O
+,	O
+decreased	O
+both	O
+the	O
+haloperidol	O
+-	O
+induced	O
+muscle	B
+rigidity	I
+(	O
+MMG	O
+)	O
+and	O
+the	O
+enhanced	O
+electromyographic	O
+activity	O
+(	O
+EMG	O
+)	O
+.	O
+
+5	O
+,	O
+7	O
+-	O
+DCKA	O
+injected	O
+bilaterally	O
+in	O
+a	O
+dose	O
+of	O
+4	O
+.	O
+5	O
+microg	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+into	O
+the	O
+intermediate	O
+-	O
+caudal	O
+region	O
+of	O
+the	O
+striatum	O
+of	O
+rats	O
+not	O
+pretreated	O
+with	O
+haloperidol	O
+had	O
+no	O
+effect	O
+on	O
+the	O
+muscle	O
+tone	O
+.	O
+
+The	O
+present	O
+results	O
+suggest	O
+that	O
+blockade	O
+of	O
+the	O
+glycine	O
+site	O
+of	O
+NMDA	O
+receptors	O
+in	O
+the	O
+rostral	O
+part	O
+of	O
+the	O
+striatum	O
+may	O
+be	O
+mainly	O
+responsible	O
+for	O
+the	O
+antiparkinsonian	O
+action	O
+of	O
+this	O
+drug	O
+.	O
+
+Carboplatin	O
+toxic	O
+effects	O
+on	O
+the	O
+peripheral	O
+nervous	O
+system	O
+of	O
+the	O
+rat	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+most	O
+striking	O
+of	O
+carboplatin	O
+'	O
+s	O
+advantages	O
+(	O
+CBDCA	O
+)	O
+over	O
+cisplatin	O
+(	O
+CDDP	O
+)	O
+is	O
+its	O
+markedly	O
+reduced	O
+rate	O
+of	O
+neurotoxic	B
+effects	O
+.	O
+
+However	O
+,	O
+the	O
+use	O
+of	O
+CBDCA	O
+higher	O
+-	O
+intensity	O
+schedules	O
+and	O
+the	O
+association	O
+with	O
+other	O
+neurotoxic	B
+drugs	O
+in	O
+polychemotherapy	O
+may	O
+cause	O
+some	O
+concern	O
+about	O
+its	O
+safety	O
+with	O
+respect	O
+to	O
+peripheral	B
+nervous	I
+system	I
+damage	I
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+Two	O
+different	O
+schedules	O
+of	O
+CBDCA	O
+administration	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+and	O
+15	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+twice	O
+a	O
+week	O
+for	O
+nine	O
+times	O
+)	O
+were	O
+evaluated	O
+in	O
+Wistar	O
+rats	O
+.	O
+
+Neurotoxicity	B
+was	O
+assessed	O
+for	O
+behavioral	O
+(	O
+tail	O
+-	O
+flick	O
+test	O
+)	O
+,	O
+neurophysiological	O
+(	O
+nerve	O
+conduction	O
+velocity	O
+in	O
+the	O
+tail	O
+nerve	O
+)	O
+,	O
+morphological	O
+,	O
+morphometrical	O
+and	O
+analytical	O
+effects	O
+.	O
+
+RESULTS	O
+:	O
+CBDCA	O
+administration	O
+induced	O
+dose	O
+-	O
+dependent	O
+peripheral	B
+neurotoxicity	I
+.	O
+
+Pain	B
+perception	O
+and	O
+nerve	O
+conduction	O
+velocity	O
+in	O
+the	O
+tail	O
+were	O
+significantly	O
+impaired	O
+,	O
+particularly	O
+after	O
+the	O
+high	O
+-	O
+dose	O
+treatment	O
+.	O
+
+The	O
+dorsal	O
+root	O
+ganglia	O
+sensory	O
+neurons	O
+and	O
+,	O
+to	O
+a	O
+lesser	O
+extent	O
+,	O
+satellite	O
+cells	O
+showed	O
+the	O
+same	O
+changes	O
+as	O
+those	O
+induced	O
+by	O
+CDDP	O
+,	O
+mainly	O
+affecting	O
+the	O
+nucleus	O
+and	O
+nucleolus	O
+of	O
+ganglionic	O
+sensory	O
+neurons	O
+.	O
+
+Moreover	O
+,	O
+significant	O
+amounts	O
+of	O
+platinum	O
+were	O
+detected	O
+in	O
+the	O
+dorsal	O
+root	O
+ganglia	O
+and	O
+kidney	O
+after	O
+CBDCA	O
+treatment	O
+.	O
+
+CONCLUSIONS	O
+:	O
+CBDCA	O
+is	O
+neurotoxic	B
+in	O
+our	O
+model	O
+,	O
+and	O
+the	O
+type	O
+of	O
+pathological	O
+changes	O
+it	O
+induces	O
+are	O
+so	O
+closely	O
+similar	O
+to	O
+those	O
+caused	O
+by	O
+CDDP	O
+that	O
+it	O
+is	O
+probable	O
+that	O
+neurotoxicity	B
+is	O
+induced	O
+in	O
+the	O
+two	O
+drugs	O
+by	O
+the	O
+same	O
+mechanism	O
+.	O
+
+This	O
+model	O
+can	O
+be	O
+used	O
+alone	O
+or	O
+in	O
+combination	O
+with	O
+other	O
+drugs	O
+to	O
+explore	O
+the	O
+effect	O
+of	O
+CBDCA	O
+on	O
+the	O
+peripheral	O
+nervous	O
+system	O
+.	O
+
+Effects	O
+of	O
+cisapride	O
+on	O
+symptoms	O
+and	O
+postcibal	O
+small	O
+-	O
+bowel	O
+motor	O
+function	O
+in	O
+patients	O
+with	O
+irritable	B
+bowel	I
+syndrome	I
+.	O
+
+BACKGROUND	O
+:	O
+Irritable	B
+bowel	I
+syndrome	I
+is	O
+a	O
+common	O
+cause	O
+of	O
+abdominal	B
+pain	I
+and	O
+discomfort	O
+and	O
+may	O
+be	O
+related	O
+to	O
+disordered	B
+gastrointestinal	I
+motility	I
+.	O
+
+Our	O
+aim	O
+was	O
+to	O
+assess	O
+the	O
+effects	O
+of	O
+long	O
+-	O
+term	O
+treatment	O
+with	O
+a	O
+prokinetic	O
+agent	O
+,	O
+cisapride	O
+,	O
+on	O
+postprandial	O
+jejunal	O
+motility	O
+and	O
+symptoms	O
+in	O
+the	O
+irritable	B
+bowel	I
+syndrome	I
+(	O
+IBS	B
+)	O
+.	O
+
+METHODS	O
+:	O
+Thirty	O
+-	O
+eight	O
+patients	O
+with	O
+IBS	B
+(	O
+constipation	B
+-	O
+predominant	O
+,	O
+n	O
+=	O
+17	O
+;	O
+diarrhoea	B
+-	O
+predominant	O
+,	O
+n	O
+=	O
+21	O
+)	O
+underwent	O
+24	O
+-	O
+h	O
+ambulatory	O
+jejunal	O
+manometry	O
+before	O
+and	O
+after	O
+12	O
+week	O
+'	O
+s	O
+treatment	O
+[	O
+cisapride	O
+,	O
+5	O
+mg	O
+three	O
+times	O
+daily	O
+(	O
+n	O
+=	O
+19	O
+)	O
+or	O
+placebo	O
+(	O
+n	O
+=	O
+19	O
+)	O
+]	O
+.	O
+
+RESULTS	O
+:	O
+In	O
+diarrhoea	B
+-	O
+predominant	O
+patients	O
+significant	O
+differences	O
+in	O
+contraction	O
+characteristics	O
+were	O
+observed	O
+between	O
+the	O
+cisapride	O
+and	O
+placebo	O
+groups	O
+.	O
+
+In	O
+cisapride	O
+-	O
+treated	O
+diarrhoea	B
+-	O
+predominant	O
+patients	O
+the	O
+mean	O
+contraction	O
+amplitude	O
+was	O
+higher	O
+(	O
+29	O
+.	O
+3	O
++	O
+/	O
+-	O
+3	O
+.	O
+2	O
+versus	O
+24	O
+.	O
+9	O
++	O
+/	O
+-	O
+2	O
+.	O
+6	O
+mm	O
+Hg	O
+,	O
+cisapride	O
+versus	O
+placebo	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+;	O
+pretreatment	O
+,	O
+25	O
+.	O
+7	O
++	O
+/	O
+-	O
+6	O
+.	O
+0	O
+mm	O
+Hg	O
+)	O
+,	O
+the	O
+mean	O
+contraction	O
+duration	O
+longer	O
+(	O
+3	O
+.	O
+4	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+versus	O
+3	O
+.	O
+0	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+sec	O
+,	O
+cisapride	O
+versus	O
+placebo	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+;	O
+pretreatment	O
+,	O
+3	O
+.	O
+1	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+sec	O
+)	O
+,	O
+and	O
+the	O
+mean	O
+contraction	O
+frequency	O
+lower	O
+(	O
+2	O
+.	O
+0	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+versus	O
+2	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+4	O
+cont	O
+.	O
+/	O
+min	O
+,	O
+cisapride	O
+versus	O
+placebo	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+;	O
+pretreatment	O
+,	O
+2	O
+.	O
+5	O
++	O
+/	O
+-	O
+1	O
+.	O
+1	O
+cont	O
+.	O
+/	O
+min	O
+]	O
+than	O
+patients	O
+treated	O
+with	O
+placebo	O
+.	O
+
+No	O
+significant	O
+differences	O
+in	O
+jejunal	O
+motility	O
+were	O
+found	O
+in	O
+the	O
+constipation	B
+-	O
+predominant	O
+IBS	B
+group	O
+.	O
+
+Symptoms	O
+were	O
+assessed	O
+by	O
+using	O
+a	O
+visual	O
+analogue	O
+scale	O
+before	O
+and	O
+after	O
+treatment	O
+.	O
+
+Symptom	O
+scores	O
+relating	O
+to	O
+the	O
+severity	O
+of	O
+constipation	B
+were	O
+lower	O
+in	O
+cisapride	O
+-	O
+treated	O
+constipation	B
+-	O
+predominant	O
+IBS	B
+patients	O
+[	O
+score	O
+,	O
+54	O
++	O
+/	O
+-	O
+5	O
+versus	O
+67	O
++	O
+/	O
+-	O
+14	O
+mm	O
+,	O
+cisapride	O
+versus	O
+placebo	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+;	O
+pretreatment	O
+,	O
+62	O
++	O
+/	O
+-	O
+19	O
+mm	O
+]	O
+.	O
+
+Diarrhoea	B
+-	O
+predominant	O
+IBS	B
+patients	O
+had	O
+a	O
+higher	O
+pain	B
+score	O
+after	O
+cisapride	O
+therapy	O
+[	O
+score	O
+,	O
+55	O
++	O
+/	O
+-	O
+15	O
+versus	O
+34	O
++	O
+/	O
+-	O
+12	O
+mm	O
+,	O
+cisapride	O
+versus	O
+placebo	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+;	O
+pretreatment	O
+,	O
+67	O
++	O
+/	O
+-	O
+19	O
+mm	O
+]	O
+.	O
+
+CONCLUSION	O
+:	O
+Cisapride	O
+affects	O
+jejunal	O
+contraction	O
+characteristics	O
+and	O
+some	O
+symptoms	O
+in	O
+IBS	B
+.	O
+
+Prevention	O
+of	O
+breast	B
+cancer	I
+with	O
+tamoxifen	O
+:	O
+preliminary	O
+findings	O
+from	O
+the	O
+Italian	O
+randomised	O
+trial	O
+among	O
+hysterectomised	O
+women	O
+.	O
+
+Italian	O
+Tamoxifen	O
+Prevention	O
+Study	O
+.	O
+
+BACKGROUND	O
+:	O
+Tamoxifen	O
+is	O
+a	O
+candidate	O
+chemopreventive	O
+agent	O
+in	O
+breast	B
+cancer	I
+,	O
+although	O
+the	O
+drug	O
+may	O
+be	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+endometrial	B
+cancer	I
+.	O
+
+Therefore	O
+we	O
+did	O
+a	O
+trial	O
+in	O
+hysterectomised	O
+women	O
+of	O
+tamoxifen	O
+as	O
+a	O
+chemopreventive	O
+.	O
+
+METHODS	O
+:	O
+In	O
+October	O
+,	O
+1992	O
+,	O
+we	O
+started	O
+a	O
+double	O
+-	O
+blind	O
+placebo	O
+-	O
+controlled	O
+,	O
+randomised	O
+trial	O
+of	O
+tamoxifen	O
+in	O
+women	O
+(	O
+mainly	O
+in	O
+Italy	O
+)	O
+who	O
+did	O
+not	O
+have	O
+breast	B
+cancer	I
+and	O
+who	O
+had	O
+had	O
+a	O
+hysterectomy	O
+.	O
+
+Women	O
+were	O
+randomised	O
+to	O
+receive	O
+tamoxifen	O
+20	O
+mg	O
+per	O
+day	O
+or	O
+placebo	O
+,	O
+both	O
+orally	O
+for	O
+5	O
+years	O
+.	O
+
+The	O
+original	O
+plan	O
+was	O
+to	O
+follow	O
+the	O
+intervention	O
+phase	O
+by	O
+5	O
+years	O
+'	O
+follow	O
+-	O
+up	O
+.	O
+
+In	O
+June	O
+,	O
+1997	O
+,	O
+the	O
+trialists	O
+and	O
+the	O
+data	O
+-	O
+monitoring	O
+committee	O
+decided	O
+to	O
+end	O
+recruitment	O
+primarily	O
+because	O
+of	O
+the	O
+number	O
+of	O
+women	O
+dropping	O
+out	O
+of	O
+the	O
+study	O
+.	O
+
+Recruitment	O
+ended	O
+on	O
+July	O
+11	O
+,	O
+1997	O
+,	O
+and	O
+the	O
+study	O
+will	O
+continue	O
+as	O
+planned	O
+.	O
+
+The	O
+primary	O
+endpoints	O
+are	O
+the	O
+occurrence	O
+of	O
+and	O
+deaths	O
+from	O
+breast	B
+cancer	I
+.	O
+
+This	O
+preliminary	O
+interim	O
+analysis	O
+is	O
+based	O
+on	O
+intention	O
+-	O
+to	O
+-	O
+treat	O
+.	O
+
+FINDINGS	O
+:	O
+5408	O
+women	O
+were	O
+randomised	O
+;	O
+participating	O
+women	O
+have	O
+a	O
+median	O
+follow	O
+-	O
+up	O
+of	O
+46	O
+months	O
+for	O
+major	O
+endpoints	O
+.	O
+
+41	O
+cases	O
+of	O
+breast	B
+cancer	I
+occurred	O
+so	O
+far	O
+;	O
+there	O
+have	O
+been	O
+no	O
+deaths	O
+from	O
+breast	B
+cancer	I
+.	O
+
+There	O
+is	O
+no	O
+difference	O
+in	O
+breast	B
+-	I
+cancer	I
+frequency	O
+between	O
+the	O
+placebo	O
+(	O
+22	O
+cases	O
+)	O
+and	O
+tamoxifen	O
+(	O
+19	O
+)	O
+arms	O
+.	O
+
+There	O
+is	O
+a	O
+statistically	O
+significant	O
+reduction	O
+of	O
+breast	B
+cancer	I
+among	O
+women	O
+receiving	O
+tamoxifen	O
+who	O
+also	O
+used	O
+hormone	O
+-	O
+replacement	O
+therapy	O
+during	O
+the	O
+trial	O
+:	O
+among	O
+390	O
+women	O
+on	O
+such	O
+therapy	O
+and	O
+allocated	O
+to	O
+placebo	O
+,	O
+we	O
+found	O
+eight	O
+cases	O
+of	O
+breast	B
+cancer	I
+compared	O
+with	O
+one	O
+case	O
+among	O
+362	O
+women	O
+allocated	O
+to	O
+tamoxifen	O
+.	O
+
+Compared	O
+with	O
+the	O
+placebo	O
+group	O
+,	O
+there	O
+was	O
+a	O
+significantly	O
+increased	O
+risk	O
+of	O
+vascular	B
+events	I
+and	O
+hypertriglyceridaemia	B
+among	O
+women	O
+on	O
+tamoxifen	O
+.	O
+
+INTERPRETATION	O
+:	O
+Although	O
+this	O
+preliminary	O
+analysis	O
+has	O
+low	O
+power	O
+,	O
+in	O
+this	O
+cohort	O
+of	O
+women	O
+at	O
+low	O
+-	O
+to	O
+-	O
+normal	O
+risk	O
+of	O
+breast	B
+cancer	I
+,	O
+the	O
+postulated	O
+protective	O
+effects	O
+of	O
+tamoxifen	O
+are	O
+not	O
+yet	O
+apparent	O
+.	O
+
+Women	O
+using	O
+hormone	O
+-	O
+replacement	O
+therapy	O
+appear	O
+to	O
+have	O
+benefited	O
+from	O
+use	O
+of	O
+tamoxifen	O
+.	O
+
+There	O
+were	O
+no	O
+deaths	O
+from	O
+breast	B
+cancer	I
+recorded	O
+in	O
+women	O
+in	O
+the	O
+study	O
+.	O
+
+It	O
+is	O
+essential	O
+to	O
+continue	O
+follow	O
+-	O
+up	O
+to	O
+quantify	O
+the	O
+long	O
+-	O
+term	O
+risks	O
+and	O
+benefits	O
+of	O
+tamoxifen	O
+therapy	O
+.	O
+
+Epileptogenic	O
+activity	O
+of	O
+folic	O
+acid	O
+after	O
+drug	O
+induces	O
+SLE	B
+(	O
+folic	O
+acid	O
+and	O
+epilepsy	B
+)	O
+
+OBJECTIVE	O
+:	O
+To	O
+study	O
+the	O
+effect	O
+of	O
+folic	O
+acid	O
+-	O
+containing	O
+multivitamin	O
+supplementation	O
+in	O
+epileptic	B
+women	O
+before	O
+and	O
+during	O
+pregnancy	O
+in	O
+order	O
+to	O
+determine	O
+the	O
+rate	O
+of	O
+structural	O
+birth	B
+defects	I
+and	O
+epilepsy	B
+-	O
+related	O
+side	O
+effects	O
+.	O
+
+STUDY	O
+DESIGN	O
+:	O
+First	O
+a	O
+randomised	O
+trial	O
+,	O
+later	O
+periconception	O
+care	O
+including	O
+in	O
+total	O
+12225	O
+females	O
+.	O
+
+RESULTS	O
+:	O
+Of	O
+60	O
+epileptic	B
+women	O
+with	O
+periconceptional	O
+folic	O
+acid	O
+(	O
+0	O
+.	O
+8	O
+mg	O
+)	O
+-	O
+containing	O
+multivitamin	O
+supplementation	O
+,	O
+no	O
+one	O
+developed	O
+epilepsy	B
+-	O
+related	O
+side	O
+effects	O
+during	O
+the	O
+periconception	O
+period	O
+.	O
+
+One	O
+epileptic	B
+woman	O
+delivered	O
+a	O
+newborn	O
+with	O
+cleft	B
+lip	I
+and	I
+palate	I
+.	O
+
+Another	O
+patient	O
+exhibited	O
+with	O
+a	O
+cluster	O
+of	O
+seizures	B
+after	O
+the	O
+periconception	O
+period	O
+using	O
+another	O
+multivitamin	O
+.	O
+
+This	O
+22	O
+-	O
+year	O
+-	O
+old	O
+epileptic	B
+woman	O
+was	O
+treated	O
+continuously	O
+by	O
+carbamazepine	O
+and	O
+a	O
+folic	O
+acid	O
+(	O
+1	O
+mg	O
+)	O
+-	O
+containing	O
+multivitamin	O
+from	O
+the	O
+20th	O
+week	O
+of	O
+gestation	O
+.	O
+
+She	O
+developed	O
+status	B
+epilepticus	I
+and	O
+later	O
+symptoms	O
+of	O
+systemic	B
+lupus	I
+erythematodes	I
+.	O
+
+Her	O
+pregnancy	O
+ended	O
+with	O
+stillbirth	B
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+epileptic	B
+pregnant	O
+patient	O
+'	O
+s	O
+autoimmune	B
+disease	I
+(	O
+probably	O
+drug	O
+-	O
+induced	O
+lupus	B
+)	O
+could	O
+damage	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+,	O
+therefore	O
+the	O
+therapeutic	O
+dose	O
+(	O
+>	O
+or	O
+=	O
+1	O
+mg	O
+)	O
+of	O
+folic	O
+acid	O
+triggered	O
+a	O
+cluster	O
+of	O
+seizures	B
+.	O
+
+Physiological	O
+dose	O
+(	O
+<	O
+1	O
+mg	O
+)	O
+of	O
+folic	O
+acid	O
+both	O
+in	O
+healthy	O
+and	O
+60	O
+epileptic	B
+women	O
+,	O
+all	O
+without	O
+any	O
+autoimmune	B
+disease	I
+,	O
+did	O
+not	O
+increase	O
+the	O
+risk	O
+for	O
+epileptic	B
+seizures	I
+.	O
+
+Stroke	B
+and	O
+cocaine	O
+or	O
+amphetamine	O
+use	O
+.	O
+
+The	O
+association	O
+of	O
+cocaine	O
+and	O
+amphetamine	O
+use	O
+with	O
+hemorrhagic	O
+and	O
+ischemic	B
+stroke	B
+is	O
+based	O
+almost	O
+solely	O
+on	O
+data	O
+from	O
+case	O
+series	O
+.	O
+
+The	O
+limited	O
+number	O
+of	O
+epidemiologic	O
+studies	O
+of	O
+stroke	B
+and	O
+use	O
+of	O
+cocaine	O
+and	O
+/	O
+or	O
+amphetamine	O
+have	O
+been	O
+done	O
+in	O
+settings	O
+that	O
+serve	O
+mostly	O
+the	O
+poor	O
+and	O
+/	O
+or	O
+minorities	O
+.	O
+
+This	O
+case	O
+-	O
+control	O
+study	O
+was	O
+conducted	O
+in	O
+the	O
+defined	O
+population	O
+comprising	O
+members	O
+of	O
+Kaiser	O
+Permanente	O
+of	O
+Northern	O
+and	O
+Southern	O
+California	O
+.	O
+
+We	O
+attempted	O
+to	O
+identify	O
+all	O
+incident	O
+strokes	B
+in	O
+women	O
+ages	O
+15	O
+-	O
+44	O
+years	O
+during	O
+a	O
+3	O
+-	O
+year	O
+period	O
+using	O
+hospital	O
+admission	O
+and	O
+discharge	O
+records	O
+,	O
+emergency	O
+department	O
+logs	O
+,	O
+and	O
+payment	O
+requests	O
+for	O
+out	O
+-	O
+of	O
+-	O
+plan	O
+hospitalizations	O
+.	O
+
+We	O
+selected	O
+controls	O
+,	O
+matched	O
+on	O
+age	O
+and	O
+facility	O
+of	O
+usual	O
+care	O
+,	O
+at	O
+random	O
+from	O
+healthy	O
+members	O
+of	O
+the	O
+health	O
+plan	O
+.	O
+
+We	O
+obtained	O
+information	O
+in	O
+face	O
+-	O
+to	O
+-	O
+face	O
+interviews	O
+.	O
+
+There	O
+were	O
+347	O
+confirmed	O
+stroke	B
+cases	O
+and	O
+1	O
+,	O
+021	O
+controls	O
+.	O
+
+The	O
+univariate	O
+matched	O
+odds	O
+ratio	O
+for	O
+stroke	B
+in	O
+women	O
+who	O
+admitted	O
+to	O
+using	O
+cocaine	O
+and	O
+/	O
+or	O
+amphetamine	O
+was	O
+8	O
+.	O
+5	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+=	O
+3	O
+.	O
+6	O
+-	O
+20	O
+.	O
+0	O
+)	O
+.	O
+
+After	O
+further	O
+adjustment	O
+for	O
+potential	O
+confounders	O
+,	O
+the	O
+odds	O
+ratio	O
+in	O
+women	O
+who	O
+reported	O
+using	O
+cocaine	O
+and	O
+/	O
+or	O
+amphetamine	O
+was	O
+7	O
+.	O
+0	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+=	O
+2	O
+.	O
+8	O
+-	O
+17	O
+.	O
+9	O
+)	O
+.	O
+
+The	O
+use	O
+of	O
+cocaine	O
+and	O
+/	O
+or	O
+amphetamine	O
+is	O
+a	O
+strong	O
+risk	O
+factor	O
+for	O
+stroke	B
+in	O
+this	O
+socioeconomically	O
+heterogeneous	O
+,	O
+insured	O
+urban	O
+population	O
+.	O
+
+Acute	B
+renal	I
+failure	I
+subsequent	O
+to	O
+the	O
+administration	O
+of	O
+rifampicin	O
+.	O
+
+A	O
+follow	O
+-	O
+up	O
+study	O
+of	O
+cases	O
+reported	O
+earlier	O
+.	O
+
+A	O
+clinical	O
+presentation	O
+is	O
+made	O
+of	O
+a	O
+2	O
+-	O
+3	O
+year	O
+follow	O
+-	O
+up	O
+of	O
+six	O
+cases	O
+of	O
+acute	B
+renal	I
+failure	I
+that	O
+have	O
+been	O
+reported	O
+earlier	O
+.	O
+
+The	O
+patients	O
+had	O
+developed	O
+transient	O
+renal	B
+failure	I
+after	O
+the	O
+intermittent	O
+administration	O
+of	O
+rifampicin	O
+.	O
+
+The	O
+stage	O
+of	O
+olig	O
+-	O
+anuria	B
+lasted	O
+for	O
+1	O
+-	O
+3	O
+weeks	O
+,	O
+and	O
+five	O
+of	O
+the	O
+patients	O
+were	O
+treated	O
+by	O
+hemodialysis	O
+.	O
+
+Two	O
+of	O
+the	O
+patients	O
+died	O
+due	O
+to	O
+unrelated	O
+causes	O
+during	O
+the	O
+follow	O
+-	O
+up	O
+period	O
+.	O
+
+The	O
+four	O
+patients	O
+re	O
+-	O
+examined	O
+were	O
+clinically	O
+cured	O
+.	O
+
+Pathologic	O
+findings	O
+by	O
+light	O
+microscopy	O
+and	O
+immunofluorescence	O
+at	O
+biopsy	O
+were	O
+scarce	O
+.	O
+
+Nothing	O
+abnormal	O
+was	O
+seen	O
+by	O
+electron	O
+microscopy	O
+in	O
+two	O
+of	O
+the	O
+cases	O
+studied	O
+.	O
+
+Renal	O
+function	O
+was	O
+normal	O
+.	O
+
+In	O
+three	O
+cases	O
+the	O
+excretion	O
+at	O
+131I	O
+-	O
+hippuran	O
+renography	O
+was	O
+slightly	O
+slowed	O
+.	O
+
+Although	O
+in	O
+the	O
+acute	O
+stage	O
+the	O
+renal	B
+lesions	I
+histologically	O
+appeared	O
+toxic	O
+,	O
+evidence	O
+suggestive	O
+of	O
+an	O
+immunological	O
+mechanism	O
+cannot	O
+be	O
+excluded	O
+.	O
+
+Chronic	O
+effects	O
+of	O
+a	O
+novel	O
+synthetic	O
+anthracycline	O
+derivative	O
+(	O
+SM	O
+-	O
+5887	O
+)	O
+on	O
+normal	O
+heart	O
+and	O
+doxorubicin	O
+-	O
+induced	O
+cardiomyopathy	B
+in	O
+beagle	O
+dogs	O
+.	O
+
+This	O
+study	O
+was	O
+designed	O
+to	O
+investigate	O
+the	O
+chronic	O
+cardiotoxic	B
+potential	O
+of	O
+SM	O
+-	O
+5887	O
+and	O
+a	O
+possible	O
+deteriorating	O
+effect	O
+of	O
+SM	O
+-	O
+5887	O
+on	O
+low	O
+-	O
+grade	O
+cardiotoxicity	B
+pre	O
+-	O
+induced	O
+by	O
+doxorubicin	O
+in	O
+beagle	O
+dogs	O
+.	O
+
+In	O
+the	O
+chronic	O
+treatment	O
+,	O
+beagle	O
+dogs	O
+of	O
+each	O
+sex	O
+were	O
+given	O
+intravenously	O
+once	O
+every	O
+3	O
+weeks	O
+,	O
+either	O
+a	O
+sublethal	O
+dose	O
+of	O
+doxorubicin	O
+(	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+or	O
+SM	O
+-	O
+5887	O
+(	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+The	O
+experiment	O
+was	O
+terminated	O
+3	O
+weeks	O
+after	O
+the	O
+ninth	O
+dosing	O
+.	O
+
+Animals	O
+which	O
+received	O
+over	O
+six	O
+courses	O
+of	O
+doxorubicin	O
+demonstrated	O
+the	O
+electrocardiogram	O
+(	O
+ECG	O
+)	O
+changes	O
+,	O
+decrease	O
+of	O
+blood	O
+pressure	O
+and	O
+high	O
+-	O
+grade	O
+histopathological	O
+cardiomyopathy	B
+,	O
+while	O
+animals	O
+which	O
+were	O
+terminally	O
+sacrificed	O
+after	O
+the	O
+SM	O
+-	O
+5887	O
+administration	O
+did	O
+not	O
+show	O
+any	O
+changes	O
+in	O
+ECG	O
+,	O
+blood	O
+pressure	O
+and	O
+histopathological	O
+examinations	O
+.	O
+
+To	O
+examine	O
+a	O
+possibly	O
+deteriorating	O
+cardiotoxic	B
+effect	O
+of	O
+SM	O
+-	O
+5887	O
+,	O
+low	O
+-	O
+grade	O
+cardiomyopathy	B
+was	O
+induced	O
+in	O
+dogs	O
+by	O
+four	O
+courses	O
+of	O
+doxorubicin	O
+(	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+Nine	O
+weeks	O
+after	O
+pre	O
+-	O
+treatment	O
+,	O
+dogs	O
+were	O
+given	O
+four	O
+courses	O
+of	O
+either	O
+doxorubicin	O
+(	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+or	O
+SM	O
+-	O
+5887	O
+(	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+once	O
+every	O
+3	O
+weeks	O
+.	O
+
+The	O
+low	O
+-	O
+grade	O
+cardiotoxic	B
+changes	O
+were	O
+enhanced	O
+by	O
+the	O
+additional	O
+doxorubicin	O
+treatment	O
+.	O
+
+On	O
+the	O
+contrary	O
+,	O
+the	O
+SM	O
+-	O
+5887	O
+treatment	O
+did	O
+not	O
+progress	O
+the	O
+grade	O
+of	O
+cardiomyopathy	B
+.	O
+
+In	O
+conclusion	O
+,	O
+SM	O
+-	O
+5887	O
+does	O
+not	O
+have	O
+any	O
+potential	O
+of	O
+chronic	O
+cardiotoxicity	B
+and	O
+deteriorating	O
+effect	O
+on	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B
+in	O
+dogs	O
+.	O
+
+Risk	O
+for	O
+valvular	B
+heart	I
+disease	I
+among	O
+users	O
+of	O
+fenfluramine	O
+and	O
+dexfenfluramine	O
+who	O
+underwent	O
+echocardiography	O
+before	O
+use	O
+of	O
+medication	O
+.	O
+
+BACKGROUND	O
+:	O
+Because	O
+uncontrolled	O
+echocardiographic	O
+surveys	O
+suggested	O
+that	O
+up	O
+to	O
+30	O
+%	O
+to	O
+38	O
+%	O
+of	O
+users	O
+of	O
+fenfluramine	O
+and	O
+dexfenfluramine	O
+had	O
+valvular	B
+disease	I
+,	O
+these	O
+drugs	O
+were	O
+withdrawn	O
+from	O
+the	O
+market	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+determine	O
+the	O
+risk	O
+for	O
+new	O
+or	O
+worsening	O
+valvular	B
+abnormalities	I
+among	O
+users	O
+of	O
+fenfluramine	O
+or	O
+dexfenfluramine	O
+who	O
+underwent	O
+echocardiography	O
+before	O
+they	O
+began	O
+to	O
+take	O
+these	O
+medications	O
+.	O
+
+DESIGN	O
+:	O
+Cohort	O
+study	O
+.	O
+
+SETTING	O
+:	O
+Academic	O
+primary	O
+care	O
+practices	O
+.	O
+
+PATIENTS	O
+:	O
+46	O
+patients	O
+who	O
+used	O
+fenfluramine	O
+or	O
+dexfenfluramine	O
+for	O
+14	O
+days	O
+or	O
+more	O
+and	O
+had	O
+echocardiograms	O
+obtained	O
+before	O
+therapy	O
+.	O
+
+MEASUREMENTS	O
+:	O
+Follow	O
+-	O
+up	O
+echocardiography	O
+.	O
+
+The	O
+primary	O
+outcome	O
+was	O
+new	O
+or	O
+worsening	O
+valvulopathy	B
+,	O
+defined	O
+as	O
+progression	O
+of	O
+either	O
+aortic	B
+or	I
+mitral	I
+regurgitation	I
+by	O
+at	O
+least	O
+one	O
+degree	O
+of	O
+severity	O
+and	O
+disease	O
+that	O
+met	O
+U	O
+.	O
+S	O
+.	O
+
+Food	O
+and	O
+Drug	O
+Administration	O
+criteria	O
+(	O
+at	O
+least	O
+mild	O
+aortic	B
+regurgitation	I
+or	O
+moderate	O
+mitral	B
+regurgitation	I
+)	O
+.	O
+
+RESULTS	O
+:	O
+Two	O
+patients	O
+(	O
+4	O
+.	O
+3	O
+%	O
+[	O
+95	O
+%	O
+CI	O
+,	O
+0	O
+.	O
+6	O
+%	O
+to	O
+14	O
+.	O
+8	O
+%	O
+]	O
+)	O
+receiving	O
+fenfluramine	O
+-	O
+phentermine	O
+developed	O
+valvular	B
+heart	I
+disease	I
+.	O
+
+One	O
+had	O
+baseline	O
+bicuspid	B
+aortic	I
+valve	I
+and	O
+mild	O
+aortic	B
+regurgitation	I
+that	O
+progressed	O
+to	O
+moderate	O
+regurgitation	O
+.	O
+
+The	O
+second	O
+patient	O
+developed	O
+new	O
+moderate	O
+aortic	B
+insufficiency	I
+.	O
+
+CONCLUSION	O
+:	O
+Users	O
+of	O
+diet	O
+medications	O
+are	O
+at	O
+risk	O
+for	O
+valvular	B
+heart	I
+disease	I
+.	O
+
+However	O
+,	O
+the	O
+incidence	O
+may	O
+be	O
+lower	O
+than	O
+that	O
+reported	O
+previously	O
+.	O
+
+Therapeutic	O
+drug	O
+monitoring	O
+of	O
+tobramycin	O
+:	O
+once	O
+-	O
+daily	O
+versus	O
+twice	O
+-	O
+daily	O
+dosage	O
+schedules	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+evaluate	O
+the	O
+effect	O
+of	O
+dosage	O
+regimen	O
+(	O
+once	O
+-	O
+daily	O
+vs	O
+.	O
+twice	O
+-	O
+daily	O
+)	O
+of	O
+tobramicyn	O
+on	O
+steady	O
+-	O
+state	O
+serum	O
+concentrations	O
+and	O
+toxicity	B
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+Patients	O
+undergoing	O
+treatment	O
+with	O
+i	O
+.	O
+v	O
+.	O
+tobramycin	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+)	O
+were	O
+randomised	O
+to	O
+two	O
+groups	O
+.	O
+
+Group	O
+OD	O
+(	O
+n	O
+=	O
+22	O
+)	O
+received	O
+a	O
+once	O
+-	O
+daily	O
+dose	O
+of	O
+tobramycin	O
+and	O
+group	O
+TD	O
+(	O
+n	O
+=	O
+21	O
+)	O
+received	O
+the	O
+same	O
+dose	O
+divided	O
+into	O
+two	O
+doses	O
+daily	O
+.	O
+
+Tobramycin	O
+serum	O
+concentrations	O
+(	O
+peak	O
+and	O
+trough	O
+)	O
+were	O
+measured	O
+by	O
+enzyme	O
+multiplied	O
+immunoassay	O
+.	O
+
+The	O
+renal	O
+and	O
+auditory	O
+functions	O
+of	O
+the	O
+patients	O
+were	O
+monitored	O
+before	O
+,	O
+during	O
+and	O
+immediately	O
+after	O
+treatment	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+two	O
+groups	O
+were	O
+comparable	O
+with	O
+respect	O
+to	O
+sex	O
+,	O
+age	O
+,	O
+body	O
+weight	O
+and	O
+renal	O
+function	O
+.	O
+
+No	O
+statistically	O
+significant	O
+differences	O
+were	O
+found	O
+in	O
+mean	O
+daily	O
+dose	O
+,	O
+duration	O
+of	O
+treatment	O
+,	O
+or	O
+cumulative	O
+dose	O
+.	O
+
+Trough	O
+concentrations	O
+were	O
+<	O
+2	O
+g	O
+/	O
+ml	O
+in	O
+the	O
+two	O
+groups	O
+(	O
+100	O
+%	O
+)	O
+.	O
+
+Peak	O
+concentrations	O
+were	O
+>	O
+6	O
+microg	O
+/	O
+ml	O
+in	O
+100	O
+%	O
+of	O
+the	O
+OD	O
+group	O
+and	O
+in	O
+67	O
+%	O
+of	O
+the	O
+TD	O
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+Mean	O
+peak	O
+concentrations	O
+were	O
+markedly	O
+different	O
+:	O
+11	O
+.	O
+00	O
++	O
+/	O
+-	O
+2	O
+.	O
+89	O
+microg	O
+/	O
+ml	O
+in	O
+OD	O
+vs	O
+.	O
+6	O
+.	O
+53	O
++	O
+/	O
+-	O
+1	O
+.	O
+45	O
+microg	O
+/	O
+ml	O
+in	O
+TD	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+The	O
+pharmacokinetics	O
+parameters	O
+were	O
+:	O
+Ke	O
+,	O
+(	O
+0	O
+.	O
+15	O
++	O
+/	O
+-	O
+0	O
+.	O
+03	O
+/	O
+h	O
+in	O
+OD	O
+vs	O
+.	O
+0	O
+.	O
+24	O
++	O
+/	O
+-	O
+0	O
+.	O
+06	O
+/	O
+h	O
+in	O
+TD	O
+)	O
+,	O
+t1	O
+/	O
+2	O
+,	O
+(	O
+4	O
+.	O
+95	O
++	O
+/	O
+-	O
+1	O
+.	O
+41	O
+h	O
+in	O
+OD	O
+vs	O
+.	O
+3	O
+.	O
+07	O
++	O
+/	O
+-	O
+0	O
+.	O
+71	O
+h	O
+in	O
+TD	O
+)	O
+,	O
+Vd	O
+(	O
+0	O
+.	O
+35	O
++	O
+/	O
+-	O
+0	O
+.	O
+11	O
+l	O
+/	O
+kg	O
+in	O
+OD	O
+vs	O
+.	O
+0	O
+.	O
+33	O
++	O
+/	O
+-	O
+0	O
+.	O
+09	O
+l	O
+/	O
+kg	O
+in	O
+TD	O
+)	O
+,	O
+Cl	O
+(	O
+0	O
+.	O
+86	O
++	O
+/	O
+-	O
+0	O
+.	O
+29	O
+ml	O
+/	O
+min	O
+/	O
+kg	O
+in	O
+OD	O
+vs	O
+.	O
+1	O
+.	O
+28	O
++	O
+/	O
+-	O
+0	O
+.	O
+33	O
+ml	O
+/	O
+min	O
+/	O
+kg	O
+in	O
+TD	O
+)	O
+.	O
+
+Increased	O
+serum	O
+creatinine	O
+was	O
+observed	O
+in	O
+73	O
+%	O
+of	O
+patients	O
+in	O
+OD	O
+versus	O
+57	O
+%	O
+of	O
+patients	O
+in	O
+TD	O
+,	O
+without	O
+evidence	O
+of	O
+nephrotoxicity	B
+.	O
+
+In	O
+TD	O
+group	O
+,	O
+three	O
+patients	O
+developed	O
+decreased	B
+auditory	I
+function	I
+,	O
+of	O
+which	O
+one	O
+presented	O
+with	O
+an	O
+auditory	B
+loss	I
+of	O
+-	O
+30	O
+dB	O
+,	O
+whereas	O
+in	O
+the	O
+OD	O
+group	O
+only	O
+one	O
+patient	O
+presented	O
+decreased	B
+auditory	I
+function	I
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+small	O
+study	O
+suggests	O
+that	O
+a	O
+once	O
+-	O
+daily	O
+dosing	O
+regimen	O
+of	O
+tobramycin	O
+is	O
+at	O
+least	O
+as	O
+effective	O
+as	O
+and	O
+is	O
+no	O
+more	O
+and	O
+possibly	O
+less	O
+toxic	O
+than	O
+the	O
+twice	O
+-	O
+daily	O
+regimen	O
+.	O
+
+Using	O
+a	O
+single	O
+-	O
+dose	O
+therapy	O
+,	O
+peak	O
+concentration	O
+determination	O
+is	O
+not	O
+necessary	O
+,	O
+only	O
+trough	O
+samples	O
+should	O
+be	O
+monitored	O
+to	O
+ensure	O
+levels	O
+below	O
+2	O
+microg	O
+/	O
+ml	O
+.	O
+
+Enhanced	O
+bradycardia	B
+induced	O
+by	O
+beta	O
+-	O
+adrenoceptor	O
+antagonists	O
+in	O
+rats	O
+pretreated	O
+with	O
+isoniazid	O
+.	O
+
+High	O
+doses	O
+of	O
+isoniazid	O
+increase	O
+hypotension	B
+induced	O
+by	O
+vasodilators	O
+and	O
+change	O
+the	O
+accompanying	O
+reflex	O
+tachycardia	B
+to	O
+bradycardia	B
+,	O
+an	O
+interaction	O
+attributed	O
+to	O
+decreased	O
+synthesis	O
+of	O
+brain	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+(	O
+GABA	O
+)	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+the	O
+possible	O
+enhancement	O
+by	O
+isoniazid	O
+of	O
+bradycardia	B
+induced	O
+by	O
+beta	O
+-	O
+adrenoceptor	O
+antagonists	O
+was	O
+determined	O
+in	O
+rats	O
+anaesthetised	O
+with	O
+chloralose	O
+-	O
+urethane	O
+.	O
+
+Isoniazid	O
+significantly	O
+increased	O
+bradycardia	B
+after	O
+propranolol	O
+,	O
+pindolol	O
+,	O
+labetalol	O
+and	O
+atenolol	O
+,	O
+as	O
+well	O
+as	O
+after	O
+clonidine	O
+,	O
+but	O
+not	O
+after	O
+hexamethonium	O
+or	O
+carbachol	O
+.	O
+
+Enhancement	O
+was	O
+not	O
+observed	O
+in	O
+rats	O
+pretreated	O
+with	O
+methylatropine	O
+or	O
+previously	O
+vagotomised	O
+.	O
+
+These	O
+results	O
+are	O
+compatible	O
+with	O
+interference	O
+by	O
+isoniazid	O
+with	O
+GABAergic	O
+inhibition	O
+of	O
+cardiac	O
+parasympathetic	O
+tone	O
+.	O
+
+Such	O
+interference	O
+could	O
+be	O
+exerted	O
+centrally	O
+,	O
+possibly	O
+at	O
+the	O
+nucleus	O
+ambiguus	O
+,	O
+or	O
+peripherally	O
+at	O
+the	O
+sinus	O
+node	O
+.	O
+
+Structural	B
+and	I
+functional	I
+impairment	I
+of	I
+mitochondria	I
+in	O
+adriamycin	O
+-	O
+induced	O
+cardiomyopathy	B
+in	O
+mice	O
+:	O
+suppression	O
+of	O
+cytochrome	O
+c	O
+oxidase	O
+II	O
+gene	O
+expression	O
+.	O
+
+The	O
+use	O
+of	O
+adriamycin	O
+(	O
+ADR	O
+)	O
+in	O
+cancer	B
+chemotherapy	O
+has	O
+been	O
+limited	O
+due	O
+to	O
+its	O
+cumulative	O
+cardiovascular	B
+toxicity	I
+.	O
+
+Earlier	O
+observations	O
+that	O
+ADR	O
+interacts	O
+with	O
+mitochondrial	O
+cytochrome	O
+c	O
+oxidase	O
+(	O
+COX	O
+)	O
+and	O
+suppresses	O
+its	O
+enzyme	O
+activity	O
+led	O
+us	O
+to	O
+investigate	O
+ADR	O
+'	O
+s	O
+action	O
+on	O
+the	O
+cardiovascular	O
+functions	O
+and	O
+heart	O
+mitochondrial	O
+morphology	O
+in	O
+Balb	O
+-	O
+c	O
+mice	O
+i	O
+.	O
+p	O
+.	O
+treated	O
+with	O
+ADR	O
+for	O
+several	O
+weeks	O
+.	O
+
+At	O
+various	O
+times	O
+during	O
+treatment	O
+,	O
+the	O
+animals	O
+were	O
+assessed	O
+for	O
+cardiovascular	O
+functions	O
+by	O
+electrocardiography	O
+and	O
+for	O
+heart	O
+tissue	O
+damage	O
+by	O
+electron	O
+microscopy	O
+.	O
+
+In	O
+parallel	O
+,	O
+total	O
+RNA	O
+was	O
+extracted	O
+from	O
+samples	O
+of	O
+dissected	O
+heart	O
+and	O
+analyzed	O
+by	O
+Northern	O
+blot	O
+hybridization	O
+to	O
+determine	O
+the	O
+steady	O
+-	O
+state	O
+level	O
+of	O
+three	O
+RNA	O
+transcripts	O
+encoded	O
+by	O
+the	O
+COXII	O
+,	O
+COXIII	O
+,	O
+and	O
+COXIV	O
+genes	O
+.	O
+
+Similarly	O
+,	O
+samples	O
+obtained	O
+from	O
+the	O
+liver	O
+of	O
+the	O
+same	O
+animals	O
+were	O
+analyzed	O
+for	O
+comparative	O
+studies	O
+.	O
+
+Our	O
+results	O
+indicated	O
+that	O
+1	O
+)	O
+treatment	O
+of	O
+mice	O
+with	O
+ADR	O
+caused	O
+cardiovascular	B
+arrhythmias	I
+characterized	O
+by	O
+bradycardia	B
+,	O
+extension	O
+of	O
+ventricular	O
+depolarization	O
+time	O
+(	O
+tQRS	O
+)	O
+,	O
+and	O
+failure	O
+of	O
+QRS	O
+at	O
+high	O
+concentrations	O
+(	O
+10	O
+-	O
+14	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+cumulative	O
+dose	O
+)	O
+;	O
+2	O
+)	O
+the	O
+heart	O
+mitochondria	O
+underwent	O
+swelling	B
+,	O
+fusion	O
+,	O
+dissolution	O
+,	O
+and	O
+/	O
+or	O
+disruption	O
+of	O
+mitochondrial	O
+cristae	O
+after	O
+several	O
+weeks	O
+of	O
+treatment	O
+.	O
+
+Such	O
+abnormalities	O
+were	O
+not	O
+observed	O
+in	O
+the	O
+mitochondria	O
+of	O
+liver	O
+tissue	O
+;	O
+and	O
+3	O
+)	O
+among	O
+the	O
+three	O
+genes	O
+of	O
+COX	O
+enzyme	O
+examined	O
+,	O
+only	O
+COXII	O
+gene	O
+expression	O
+was	O
+suppressed	O
+by	O
+ADR	O
+treatment	O
+,	O
+mainly	O
+after	O
+8	O
+weeks	O
+in	O
+both	O
+heart	O
+and	O
+liver	O
+.	O
+
+Knowing	O
+that	O
+heart	O
+mitochondria	O
+represent	O
+almost	O
+40	O
+%	O
+of	O
+heart	O
+muscle	O
+by	O
+weight	O
+,	O
+we	O
+conclude	O
+that	O
+the	O
+deteriorating	O
+effects	O
+of	O
+ADR	O
+on	O
+cardiovascular	O
+function	O
+involve	O
+mitochondrial	B
+structural	I
+and	I
+functional	I
+impairment	I
+.	O
+
diff --git a/data/BC5CDR-disease/test.tsv b/data/BC5CDR-disease/test.tsv
new file mode 100644
index 0000000..54acf01
--- /dev/null
+++ b/data/BC5CDR-disease/test.tsv
@@ -0,0 +1,129547 @@
+Torsade	B
+de	I
+pointes	I
+ventricular	B
+tachycardia	I
+during	O
+low	O
+dose	O
+intermittent	O
+dobutamine	O
+treatment	O
+in	O
+a	O
+patient	O
+with	O
+dilated	B
+cardiomyopathy	I
+and	O
+congestive	B
+heart	I
+failure	I
+.	O
+
+The	O
+authors	O
+describe	O
+the	O
+case	O
+of	O
+a	O
+56	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+chronic	O
+,	O
+severe	O
+heart	B
+failure	I
+secondary	O
+to	O
+dilated	B
+cardiomyopathy	I
+and	O
+absence	O
+of	O
+significant	O
+ventricular	B
+arrhythmias	I
+who	O
+developed	O
+QT	B
+prolongation	I
+and	O
+torsade	B
+de	I
+pointes	I
+ventricular	B
+tachycardia	I
+during	O
+one	O
+cycle	O
+of	O
+intermittent	O
+low	O
+dose	O
+(	O
+2	O
+.	O
+5	O
+mcg	O
+/	O
+kg	O
+per	O
+min	O
+)	O
+dobutamine	O
+.	O
+
+This	O
+report	O
+of	O
+torsade	B
+de	I
+pointes	I
+ventricular	B
+tachycardia	I
+during	O
+intermittent	O
+dobutamine	O
+supports	O
+the	O
+hypothesis	O
+that	O
+unpredictable	O
+fatal	O
+arrhythmias	B
+may	O
+occur	O
+even	O
+with	O
+low	O
+doses	O
+and	O
+in	O
+patients	O
+with	O
+no	O
+history	O
+of	O
+significant	O
+rhythm	O
+disturbances	O
+.	O
+
+The	O
+mechanisms	O
+of	O
+proarrhythmic	O
+effects	O
+of	O
+Dubutamine	O
+are	O
+discussed	O
+.	O
+
+Positive	O
+skin	O
+tests	O
+in	O
+late	O
+reactions	O
+to	O
+radiographic	O
+contrast	O
+media	O
+.	O
+
+In	O
+the	O
+last	O
+few	O
+years	O
+delayed	O
+reactions	O
+several	O
+hours	O
+after	O
+the	O
+injection	O
+of	O
+radiographic	O
+and	O
+contrast	O
+materials	O
+(	O
+PRC	O
+)	O
+have	O
+been	O
+described	O
+with	O
+increasing	O
+frequency	O
+.	O
+
+The	O
+authors	O
+report	O
+two	O
+observations	O
+on	O
+patients	O
+with	O
+delayed	O
+reactions	O
+in	O
+whom	O
+intradermoreactions	O
+(	O
+IDR	O
+)	O
+and	O
+patch	O
+tests	O
+to	O
+a	O
+series	O
+of	O
+ionic	O
+and	O
+non	O
+ionic	O
+PRC	O
+were	O
+studied	O
+.	O
+
+After	O
+angiography	O
+by	O
+the	O
+venous	O
+route	O
+in	O
+patient	O
+n	O
+degree	O
+1	O
+a	O
+biphasic	O
+reaction	O
+with	O
+an	O
+immediate	O
+reaction	O
+(	O
+dyspnea	B
+,	O
+loss	B
+of	I
+consciousness	I
+)	O
+and	O
+delayed	O
+macro	B
+-	I
+papular	I
+rash	I
+appeared	O
+,	O
+whilst	O
+patient	O
+n	O
+degree	O
+2	O
+developed	O
+a	O
+generalised	O
+sensation	O
+of	O
+heat	O
+,	O
+persistent	O
+pain	B
+at	O
+the	O
+site	O
+of	O
+injection	O
+immediately	O
+and	O
+a	O
+generalised	O
+macro	O
+-	O
+papular	O
+reaction	O
+after	O
+24	O
+hours	O
+.	O
+
+The	O
+skin	O
+tests	O
+revealed	O
+positive	O
+delayed	O
+reactions	O
+of	O
+24	O
+hours	O
+and	O
+48	O
+hours	O
+by	O
+IDR	O
+and	O
+patch	O
+tests	O
+to	O
+only	O
+some	O
+PRC	O
+with	O
+common	O
+chains	O
+in	O
+their	O
+structures	O
+.	O
+
+The	O
+positive	O
+skin	O
+tests	O
+are	O
+in	O
+favour	O
+of	O
+immunological	O
+reactions	O
+and	O
+may	O
+help	O
+in	O
+diagnosis	O
+of	O
+allergy	B
+in	O
+the	O
+patients	O
+.	O
+
+Risk	O
+of	O
+transient	O
+hyperammonemic	B
+encephalopathy	I
+in	O
+cancer	B
+patients	O
+who	O
+received	O
+continuous	O
+infusion	O
+of	O
+5	O
+-	O
+fluorouracil	O
+with	O
+the	O
+complication	O
+of	O
+dehydration	B
+and	O
+infection	B
+.	O
+
+From	O
+1986	O
+to	O
+1998	O
+,	O
+29	O
+cancer	B
+patients	O
+who	O
+had	O
+32	O
+episodes	O
+of	O
+transient	O
+hyperammonemic	B
+encephalopathy	I
+related	O
+to	O
+continuous	O
+infusion	O
+of	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+were	O
+identified	O
+.	O
+
+None	O
+of	O
+the	O
+patients	O
+had	O
+decompensated	O
+liver	B
+disease	I
+.	O
+
+Onset	O
+of	O
+hyperammonemic	B
+encephalopathy	I
+varied	O
+from	O
+0	O
+.	O
+5	O
+to	O
+5	O
+days	O
+(	O
+mean	O
+:	O
+2	O
+.	O
+6	O
++	O
+/	O
+-	O
+1	O
+.	O
+3	O
+days	O
+)	O
+after	O
+the	O
+initiation	O
+of	O
+chemotherapy	O
+.	O
+
+Plasma	O
+ammonium	O
+level	O
+ranged	O
+from	O
+248	O
+to	O
+2387	O
+microg	O
+%	O
+(	O
+mean	O
+:	O
+626	O
++	O
+/	O
+-	O
+431	O
+microg	O
+%	O
+)	O
+.	O
+
+Among	O
+the	O
+32	O
+episodes	O
+,	O
+26	O
+(	O
+81	O
+%	O
+)	O
+had	O
+various	O
+degrees	O
+of	O
+azotemia	B
+,	O
+18	O
+(	O
+56	O
+%	O
+)	O
+occurred	O
+during	O
+bacterial	B
+infections	I
+and	O
+14	O
+(	O
+44	O
+%	O
+)	O
+without	O
+infection	B
+occurred	O
+during	O
+periods	O
+of	O
+dehydration	B
+.	O
+
+Higher	O
+plasma	O
+ammonium	O
+levels	O
+and	O
+more	O
+rapid	O
+onset	O
+of	O
+hyperammonemia	B
+were	O
+seen	O
+in	O
+18	O
+patients	O
+with	O
+bacterial	B
+infections	I
+(	O
+p	O
+=	O
+0	O
+.	O
+003	O
+and	O
+0	O
+.	O
+0006	O
+,	O
+respectively	O
+)	O
+and	O
+in	O
+nine	O
+patients	O
+receiving	O
+high	O
+daily	O
+doses	O
+(	O
+2600	O
+or	O
+1800	O
+mg	O
+/	O
+m2	O
+)	O
+of	O
+5	O
+-	O
+FU	O
+(	O
+p	O
+=	O
+0	O
+.	O
+0001	O
+and	O
+<	O
+0	O
+.	O
+0001	O
+,	O
+respectively	O
+)	O
+.	O
+
+In	O
+25	O
+out	O
+of	O
+32	O
+episodes	O
+(	O
+78	O
+%	O
+)	O
+,	O
+plasma	O
+ammonium	O
+levels	O
+and	O
+mental	O
+status	O
+returned	O
+to	O
+normal	O
+within	O
+2	O
+days	O
+after	O
+adequate	O
+management	O
+.	O
+
+In	O
+conclusion	O
+,	O
+hyperammonemic	B
+encephalopathy	I
+can	O
+occur	O
+in	O
+patients	O
+receiving	O
+continuous	O
+infusion	O
+of	O
+5	O
+-	O
+FU	O
+.	O
+
+Azotemia	B
+,	O
+body	O
+fluid	O
+insufficiency	O
+and	O
+bacterial	B
+infections	I
+were	O
+frequently	O
+found	O
+in	O
+these	O
+patients	O
+.	O
+
+It	O
+is	O
+therefore	O
+important	O
+to	O
+recognize	O
+this	O
+condition	O
+in	O
+patients	O
+receiving	O
+continuous	O
+infusion	O
+of	O
+5	O
+-	O
+FU	O
+.	O
+
+The	O
+effects	O
+of	O
+quinine	O
+and	O
+4	O
+-	O
+aminopyridine	O
+on	O
+conditioned	O
+place	O
+preference	O
+and	O
+changes	O
+in	O
+motor	O
+activity	O
+induced	O
+by	O
+morphine	O
+in	O
+rats	O
+.	O
+
+1	O
+.	O
+
+The	O
+effects	O
+of	O
+two	O
+unselective	O
+potassium	O
+(	O
+K	O
+(	O
++	O
+)	O
+-	O
+)	O
+channel	O
+blockers	O
+,	O
+quinine	O
+(	O
+12	O
+.	O
+5	O
+,	O
+25	O
+and	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+4	O
+-	O
+aminopyridine	O
+(	O
+1	O
+and	O
+2	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+on	O
+conditioned	O
+place	O
+preference	O
+and	O
+biphasic	O
+changes	O
+in	O
+motor	O
+activity	O
+induced	O
+by	O
+morphine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+were	O
+tested	O
+in	O
+Wistar	O
+rats	O
+.	O
+
+Quinine	O
+is	O
+known	O
+to	O
+block	O
+voltage	O
+-	O
+,	O
+calcium	O
+-	O
+and	O
+ATP	O
+-	O
+sensitive	O
+K	O
+(	O
++	O
+)	O
+-	O
+channels	O
+while	O
+4	O
+-	O
+aminopyridine	O
+is	O
+known	O
+to	O
+block	O
+voltage	O
+-	O
+sensitive	O
+K	O
+(	O
++	O
+)	O
+-	O
+channels	O
+.	O
+
+2	O
+.	O
+
+In	O
+the	O
+counterbalanced	O
+method	O
+,	O
+quinine	O
+attenuated	O
+morphine	O
+-	O
+induced	O
+place	O
+preference	O
+,	O
+whereas	O
+4	O
+-	O
+aminopyridine	O
+was	O
+ineffective	O
+.	O
+
+In	O
+the	O
+motor	O
+activity	O
+test	O
+measured	O
+with	O
+an	O
+Animex	O
+-	O
+activity	O
+meter	O
+neither	O
+of	O
+the	O
+K	O
+(	O
++	O
+)	O
+-	O
+channel	O
+blockers	O
+affected	O
+morphine	O
+-	O
+induced	O
+hypoactivity	B
+,	O
+but	O
+both	O
+K	O
+(	O
++	O
+)	O
+-	O
+channel	O
+blockers	O
+prevented	O
+morphine	O
+-	O
+induced	O
+secondary	O
+hyperactivity	B
+.	O
+
+3	O
+.	O
+
+These	O
+results	O
+suggest	O
+the	O
+involvement	O
+of	O
+quinine	O
+-	O
+sensitive	O
+but	O
+not	O
+4	O
+-	O
+aminopyridine	O
+-	O
+sensitive	O
+K	O
+(	O
++	O
+)	O
+-	O
+channels	O
+in	O
+morphine	O
+reward	O
+.	O
+
+It	O
+is	O
+also	O
+suggested	O
+that	O
+the	O
+blockade	O
+of	O
+K	O
+(	O
++	O
+)	O
+-	O
+channels	O
+sensitive	O
+to	O
+these	O
+blockers	O
+is	O
+not	O
+sufficient	O
+to	O
+prevent	O
+morphine	O
+-	O
+induced	O
+hypoactivity	B
+whereas	O
+morphine	O
+-	O
+induced	O
+hyperactivity	B
+seems	O
+to	O
+be	O
+connected	O
+to	O
+both	O
+quinine	O
+-	O
+and	O
+4	O
+-	O
+aminopyridine	O
+-	O
+sensitive	O
+K	O
+(	O
++	O
+)	O
+-	O
+channels	O
+.	O
+
+Nociceptin	O
+/	O
+orphanin	O
+FQ	O
+and	O
+nocistatin	O
+on	O
+learning	B
+and	I
+memory	I
+impairment	I
+induced	O
+by	O
+scopolamine	O
+in	O
+mice	O
+.	O
+
+1	O
+.	O
+
+Nociceptin	O
+,	O
+also	O
+known	O
+as	O
+orphanin	O
+FQ	O
+,	O
+is	O
+an	O
+endogenous	O
+ligand	O
+for	O
+the	O
+orphan	O
+opioid	O
+receptor	O
+-	O
+like	O
+receptor	O
+1	O
+(	O
+ORL1	O
+)	O
+and	O
+involves	O
+in	O
+various	O
+functions	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+nocistatin	O
+is	O
+recently	O
+isolated	O
+from	O
+the	O
+same	O
+precursor	O
+as	O
+nociceptin	O
+and	O
+blocks	O
+nociceptin	O
+-	O
+induced	O
+allodynia	B
+and	O
+hyperalgesia	B
+.	O
+
+2	O
+.	O
+
+Although	O
+ORL1	O
+receptors	O
+which	O
+display	O
+a	O
+high	O
+degree	O
+of	O
+sequence	O
+homology	O
+with	O
+classical	O
+opioid	O
+receptors	O
+are	O
+abundant	O
+in	O
+the	O
+hippocampus	O
+,	O
+little	O
+is	O
+known	O
+regarding	O
+their	O
+role	O
+in	O
+learning	O
+and	O
+memory	O
+.	O
+
+3	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+investigate	O
+whether	O
+nociceptin	O
+/	O
+orphanin	O
+FQ	O
+and	O
+nocistatin	O
+could	O
+modulate	O
+impairment	B
+of	I
+learning	I
+and	I
+memory	I
+induced	O
+by	O
+scopolamine	O
+,	O
+a	O
+muscarinic	O
+cholinergic	O
+receptor	O
+antagonist	O
+,	O
+using	O
+spontaneous	O
+alternation	O
+of	O
+Y	O
+-	O
+maze	O
+and	O
+step	O
+-	O
+down	O
+type	O
+passive	O
+avoidance	O
+tasks	O
+in	O
+mice	O
+.	O
+
+4	O
+.	O
+
+While	O
+nocistatin	O
+(	O
+0	O
+.	O
+5	O
+-	O
+5	O
+.	O
+0	O
+nmol	O
+mouse	O
+-	O
+1	O
+,	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+administered	O
+30	O
+min	O
+before	O
+spontaneous	O
+alternation	O
+performance	O
+or	O
+the	O
+training	O
+session	O
+of	O
+the	O
+passive	O
+avoidance	O
+task	O
+,	O
+had	O
+no	O
+effect	O
+on	O
+spontaneous	O
+alternation	O
+or	O
+passive	O
+avoidance	O
+behaviours	O
+,	O
+a	O
+lower	O
+per	O
+cent	O
+alternation	O
+and	O
+shorter	O
+median	O
+step	O
+-	O
+down	O
+latency	O
+in	O
+the	O
+retention	O
+test	O
+were	O
+obtained	O
+in	O
+nociceptin	O
+(	O
+1	O
+.	O
+5	O
+and	O
+/	O
+or	O
+5	O
+.	O
+0	O
+nmol	O
+mouse	O
+-	O
+1	O
+,	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+-	O
+treated	O
+normal	O
+mice	O
+.	O
+
+5	O
+.	O
+
+Administration	O
+of	O
+nocistatin	O
+(	O
+1	O
+.	O
+5	O
+and	O
+/	O
+or	O
+5	O
+.	O
+0	O
+nmol	O
+mouse	O
+-	O
+1	O
+,	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+30	O
+min	O
+before	O
+spontaneous	O
+alternation	O
+performance	O
+or	O
+the	O
+training	O
+session	O
+of	O
+the	O
+passive	O
+avoidance	O
+task	O
+,	O
+attenuated	O
+the	O
+scopolamine	O
+-	O
+induced	O
+impairment	O
+of	O
+spontaneous	O
+alternation	O
+and	O
+passive	O
+avoidance	O
+behaviours	O
+.	O
+
+6	O
+.	O
+
+These	O
+results	O
+indicated	O
+that	O
+nocistatin	O
+,	O
+a	O
+new	O
+biologically	O
+active	O
+peptide	O
+,	O
+ameliorates	O
+impairments	O
+of	O
+spontaneous	O
+alternation	O
+and	O
+passive	O
+avoidance	O
+induced	O
+by	O
+scopolamine	O
+,	O
+and	O
+suggested	O
+that	O
+these	O
+peptides	O
+play	O
+opposite	O
+roles	O
+in	O
+learning	O
+and	O
+memory	O
+.	O
+
+Meloxicam	O
+-	O
+induced	O
+liver	B
+toxicity	I
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+female	O
+patient	O
+with	O
+rheumatoid	B
+arthritis	I
+who	O
+developed	O
+acute	O
+cytolytic	O
+hepatitis	B
+due	O
+to	O
+meloxicam	O
+.	O
+
+Recently	O
+introduced	O
+in	O
+Belgium	O
+,	O
+meloxicam	O
+is	O
+the	O
+first	O
+nonsteroidal	O
+antiinflammatory	O
+drug	O
+with	O
+selective	O
+action	O
+on	O
+the	O
+inducible	O
+form	O
+of	O
+cyclooxygenase	O
+2	O
+.	O
+
+The	O
+acute	O
+cytolytic	O
+hepatitis	B
+occurred	O
+rapidly	O
+after	O
+meloxicam	O
+administration	O
+and	O
+was	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+antinuclear	O
+antibodies	O
+suggesting	O
+a	O
+hypersensitivity	B
+mechanism	O
+.	O
+
+This	O
+first	O
+case	O
+of	O
+meloxicam	O
+related	O
+liver	B
+toxicity	I
+demonstrates	O
+the	O
+potential	O
+of	O
+this	O
+drug	O
+to	O
+induce	O
+hepatic	B
+damage	I
+.	O
+
+Induction	O
+of	O
+apoptosis	O
+by	O
+remoxipride	O
+metabolites	O
+in	O
+HL60	O
+and	O
+CD34	O
++	O
+/	O
+CD19	O
+-	O
+human	O
+bone	O
+marrow	O
+progenitor	O
+cells	O
+:	O
+potential	O
+relevance	O
+to	O
+remoxipride	O
+-	O
+induced	O
+aplastic	B
+anemia	I
+.	O
+
+The	O
+antipsychotic	O
+agent	O
+,	O
+remoxipride	O
+[	O
+(	O
+S	O
+)	O
+-	O
+(	O
+-	O
+)	O
+-	O
+3	O
+-	O
+bromo	O
+-	O
+N	O
+-	O
+[	O
+(	O
+1	O
+-	O
+ethyl	O
+-	O
+2	O
+-	O
+pyrrolidinyl	O
+)	O
+methyl	O
+]	O
+-	O
+2	O
+,	O
+6	O
+-	O
+dimethoxybenz	O
+amide	O
+]	O
+has	O
+been	O
+associated	O
+with	O
+acquired	O
+aplastic	B
+anemia	I
+.	O
+
+We	O
+have	O
+examined	O
+the	O
+ability	O
+of	O
+remoxipride	O
+,	O
+three	O
+pyrrolidine	O
+ring	O
+metabolites	O
+and	O
+five	O
+aromatic	O
+ring	O
+metabolites	O
+of	O
+the	O
+parent	O
+compound	O
+to	O
+induce	O
+apoptosis	O
+in	O
+HL60	O
+cells	O
+and	O
+human	O
+bone	O
+marrow	O
+progenitor	O
+(	O
+HBMP	O
+)	O
+cells	O
+.	O
+
+Cells	O
+were	O
+treated	O
+for	O
+0	O
+-	O
+24	O
+h	O
+with	O
+each	O
+compound	O
+(	O
+0	O
+-	O
+200	O
+microM	O
+)	O
+.	O
+
+Apoptosis	O
+was	O
+assessed	O
+by	O
+fluorescence	O
+microscopy	O
+in	O
+Hoechst	O
+33342	O
+-	O
+and	O
+propidium	O
+iodide	O
+stained	O
+cell	O
+samples	O
+.	O
+
+Results	O
+were	O
+confirmed	O
+by	O
+determination	O
+of	O
+internucleosomal	O
+DNA	O
+fragmentation	O
+using	O
+gel	O
+electrophoresis	O
+for	O
+HL60	O
+cell	O
+samples	O
+and	O
+terminal	O
+deoxynucleotidyl	O
+transferase	O
+assay	O
+in	O
+HBMP	O
+cells	O
+.	O
+
+The	O
+catechol	O
+and	O
+hydroquinone	O
+metabolites	O
+,	O
+NCQ436	O
+and	O
+NCQ344	O
+,	O
+induced	O
+apoptosis	O
+in	O
+HL60	O
+and	O
+HBMP	O
+cells	O
+in	O
+a	O
+time	O
+-	O
+and	O
+concentration	O
+dependent	O
+manner	O
+,	O
+while	O
+the	O
+phenols	O
+,	O
+NCR181	O
+,	O
+FLA873	O
+,	O
+and	O
+FLA797	O
+,	O
+and	O
+the	O
+derivatives	O
+formed	O
+by	O
+oxidation	O
+of	O
+the	O
+pyrrolidine	O
+ring	O
+,	O
+FLA838	O
+,	O
+NCM001	O
+,	O
+and	O
+NCL118	O
+,	O
+had	O
+no	O
+effect	O
+.	O
+
+No	O
+necrosis	B
+was	O
+observed	O
+in	O
+cells	O
+treated	O
+with	O
+NCQ436	O
+but	O
+NCQ344	O
+had	O
+a	O
+biphasic	O
+effect	O
+in	O
+both	O
+cell	O
+types	O
+,	O
+inducing	O
+apoptosis	O
+at	O
+lower	O
+concentrations	O
+and	O
+necrosis	B
+at	O
+higher	O
+concentrations	O
+.	O
+
+These	O
+data	O
+show	O
+that	O
+the	O
+catechol	O
+and	O
+hydroquinone	O
+metabolites	O
+of	O
+remoxipride	O
+have	O
+direct	O
+toxic	O
+effects	O
+in	O
+HL60	O
+and	O
+HBMP	O
+cells	O
+,	O
+leading	O
+to	O
+apoptosis	O
+,	O
+while	O
+the	O
+phenol	O
+metabolites	O
+were	O
+inactive	O
+.	O
+
+Similarly	O
+,	O
+benzene	O
+-	O
+derived	O
+catechol	O
+and	O
+hydroquinone	O
+,	O
+but	O
+not	O
+phenol	O
+,	O
+induce	O
+apoptosis	O
+in	O
+HBMP	O
+cells	O
+[	O
+Moran	O
+et	O
+al	O
+.	O
+,	O
+Mol	O
+.	O
+Pharmacol	O
+.	O
+,	O
+50	O
+(	O
+1996	O
+)	O
+610	O
+-	O
+615	O
+]	O
+.	O
+
+We	O
+propose	O
+that	O
+remoxipride	O
+and	O
+benzene	O
+may	O
+induce	O
+aplastic	B
+anemia	I
+via	O
+production	O
+of	O
+similar	O
+reactive	O
+metabolites	O
+and	O
+that	O
+the	O
+ability	O
+of	O
+NCQ436	O
+and	O
+NCQ344	O
+to	O
+induce	O
+apoptosis	O
+in	O
+HBMP	O
+cells	O
+may	O
+contribute	O
+to	O
+the	O
+mechanism	O
+underlying	O
+acquired	O
+aplastic	B
+anemia	I
+that	O
+has	O
+been	O
+associated	O
+with	O
+remoxipride	O
+.	O
+
+Synthesis	O
+and	O
+preliminary	O
+pharmacological	O
+investigations	O
+of	O
+1	O
+-	O
+(	O
+1	O
+,	O
+2	O
+-	O
+dihydro	O
+-	O
+2	O
+-	O
+acenaphthylenyl	O
+)	O
+piperazine	O
+derivatives	O
+as	O
+potential	O
+atypical	O
+antipsychotic	O
+agents	O
+in	O
+mice	O
+.	O
+
+In	O
+research	O
+towards	O
+the	O
+development	O
+of	O
+new	O
+atypical	O
+antipsychotic	O
+agents	O
+,	O
+one	O
+strategy	O
+is	O
+that	O
+the	O
+dopaminergic	O
+system	O
+can	O
+be	O
+modulated	O
+through	O
+manipulation	O
+of	O
+the	O
+serotonergic	O
+system	O
+.	O
+
+The	O
+synthesis	O
+and	O
+preliminary	O
+pharmacological	O
+evaluation	O
+of	O
+a	O
+series	O
+of	O
+potential	O
+atypical	O
+antipsychotic	O
+agents	O
+based	O
+on	O
+the	O
+structure	O
+of	O
+1	O
+-	O
+(	O
+1	O
+,	O
+2	O
+-	O
+dihydro	O
+-	O
+2	O
+-	O
+acenaphthylenyl	O
+)	O
+piperazine	O
+(	O
+7	O
+)	O
+is	O
+described	O
+.	O
+
+Compound	O
+7e	O
+,	O
+5	O
+-	O
+{	O
+2	O
+-	O
+[	O
+4	O
+-	O
+(	O
+1	O
+,	O
+2	O
+-	O
+dihydro	O
+-	O
+2	O
+-	O
+acenaphthylenyl	O
+)	O
+piperazinyl	O
+]	O
+ethyl	O
+}	O
+-	O
+2	O
+,	O
+3	O
+-	O
+dihy	O
+dro	O
+-	O
+1H	O
+-	O
+indol	O
+-	O
+2	O
+-	O
+one	O
+,	O
+from	O
+this	O
+series	O
+showed	O
+significant	O
+affinities	O
+at	O
+the	O
+5	O
+-	O
+HT1A	O
+and	O
+5	O
+-	O
+HT2A	O
+receptors	O
+and	O
+moderate	O
+affinity	O
+at	O
+the	O
+D2	O
+receptor	O
+.	O
+
+7e	O
+exhibits	O
+a	O
+high	O
+reversal	O
+of	O
+catalepsy	B
+induced	O
+by	O
+haloperidol	O
+indicating	O
+its	O
+atypical	O
+antipsychotic	O
+nature	O
+.	O
+
+Sub	O
+-	O
+chronic	O
+inhibition	O
+of	O
+nitric	O
+-	O
+oxide	O
+synthesis	O
+modifies	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+and	O
+the	O
+number	O
+of	O
+NADPH	O
+-	O
+diaphorase	O
+neurons	O
+in	O
+mice	O
+.	O
+
+RATIONALE	O
+:	O
+NG	O
+-	O
+nitro	O
+-	O
+L	O
+-	O
+arginine	O
+(	O
+L	O
+-	O
+NOARG	O
+)	O
+,	O
+an	O
+inhibitor	O
+of	O
+nitric	O
+-	O
+oxide	O
+synthase	O
+(	O
+NOS	O
+)	O
+,	O
+induces	O
+catalepsy	B
+in	O
+mice	O
+.	O
+
+This	O
+effect	O
+undergoes	O
+rapid	O
+tolerance	O
+,	O
+showing	O
+a	O
+significant	O
+decrease	O
+after	O
+2	O
+days	O
+of	O
+sub	O
+-	O
+chronic	O
+L	O
+-	O
+NOARG	O
+treatment	O
+.	O
+
+Nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+has	O
+been	O
+shown	O
+to	O
+influence	O
+dopaminergic	O
+neurotransmission	O
+in	O
+the	O
+striatum	O
+.	O
+
+Neuroleptic	O
+drugs	O
+such	O
+as	O
+haloperidol	O
+,	O
+which	O
+block	O
+dopamine	O
+receptors	O
+,	O
+also	O
+cause	O
+catalepsy	B
+in	O
+rodents	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+investigate	O
+the	O
+effects	O
+of	O
+subchronic	O
+L	O
+-	O
+NOARG	O
+treatment	O
+in	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+and	O
+the	O
+number	O
+of	O
+NOS	O
+neurons	O
+in	O
+areas	O
+related	O
+to	O
+motor	O
+control	O
+.	O
+
+METHODS	O
+:	O
+Male	O
+albino	O
+Swiss	O
+mice	O
+were	O
+treated	O
+sub	O
+-	O
+chronically	O
+(	O
+twice	O
+a	O
+day	O
+for	O
+4	O
+days	O
+)	O
+with	O
+L	O
+-	O
+NOARG	O
+(	O
+40	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+or	O
+haloperidol	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+Catalepsy	B
+was	O
+evaluated	O
+at	O
+the	O
+beginning	O
+and	O
+the	O
+end	O
+of	O
+the	O
+treatments	O
+.	O
+
+Reduced	O
+nicotinamide	O
+adenine	O
+dinucleotide	O
+phosphate	O
+-	O
+diaphorase	O
+(	O
+NADPH	O
+-	O
+d	O
+)	O
+histochemistry	O
+was	O
+also	O
+employed	O
+to	O
+visualize	O
+NOS	O
+as	O
+an	O
+index	O
+of	O
+enzyme	O
+expression	O
+in	O
+mice	O
+brain	O
+regions	O
+related	O
+to	O
+motor	O
+control	O
+.	O
+
+RESULTS	O
+:	O
+L	O
+-	O
+NOARG	O
+sub	O
+-	O
+chronic	O
+administration	O
+produced	O
+tolerance	O
+of	O
+L	O
+-	O
+NOARG	O
+and	O
+of	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+.	O
+
+It	O
+also	O
+induced	O
+an	O
+increase	O
+in	O
+the	O
+number	O
+of	O
+NADPH	O
+-	O
+d	O
+-	O
+positive	O
+cells	O
+in	O
+the	O
+dorsal	O
+part	O
+of	O
+the	O
+caudate	O
+and	O
+accumbens	O
+nuclei	O
+compared	O
+with	O
+haloperidol	O
+and	O
+in	O
+the	O
+pedunculopontine	O
+tegmental	O
+nucleus	O
+compared	O
+with	O
+saline	O
+.	O
+
+In	O
+contrast	O
+,	O
+there	O
+was	O
+a	O
+decrease	O
+in	O
+NADPH	O
+-	O
+d	O
+neuron	O
+number	O
+in	O
+the	O
+substantia	O
+nigra	O
+,	O
+pars	O
+compacta	O
+in	O
+both	O
+haloperidol	O
+-	O
+treated	O
+and	O
+L	O
+-	O
+NOARG	O
+-	O
+treated	O
+animals	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+results	O
+give	O
+further	O
+support	O
+to	O
+the	O
+hypothesis	O
+that	O
+NO	O
+plays	O
+a	O
+role	O
+in	O
+motor	O
+behavior	O
+control	O
+and	O
+suggest	O
+that	O
+it	O
+may	O
+take	O
+part	O
+in	O
+the	O
+synaptic	O
+changes	O
+produced	O
+by	O
+antipsychotic	O
+treatment	O
+.	O
+
+Prolonged	O
+left	B
+ventricular	I
+dysfunction	I
+occurs	O
+in	O
+patients	O
+with	O
+coronary	B
+artery	I
+disease	I
+after	O
+both	O
+dobutamine	O
+and	O
+exercise	O
+induced	O
+myocardial	B
+ischaemia	I
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+determine	O
+whether	O
+pharmacological	O
+stress	O
+leads	O
+to	O
+prolonged	O
+but	O
+reversible	O
+left	B
+ventricular	I
+dysfunction	I
+in	O
+patients	O
+with	O
+coronary	B
+artery	I
+disease	I
+,	O
+similar	O
+to	O
+that	O
+seen	O
+after	O
+exercise	O
+.	O
+
+DESIGN	O
+:	O
+A	O
+randomised	O
+crossover	O
+study	O
+of	O
+recovery	O
+time	O
+of	O
+systolic	O
+and	O
+diastolic	O
+left	O
+ventricular	O
+function	O
+after	O
+exercise	O
+and	O
+dobutamine	O
+induced	O
+ischaemia	B
+.	O
+
+SUBJECTS	O
+:	O
+10	O
+patients	O
+with	O
+stable	B
+angina	I
+,	O
+angiographically	O
+proven	O
+coronary	B
+artery	I
+disease	I
+,	O
+and	O
+normal	O
+left	O
+ventricular	O
+function	O
+.	O
+
+INTERVENTIONS	O
+:	O
+Treadmill	O
+exercise	O
+and	O
+dobutamine	O
+stress	O
+were	O
+performed	O
+on	O
+different	O
+days	O
+.	O
+
+Quantitative	O
+assessment	O
+of	O
+systolic	O
+and	O
+diastolic	O
+left	O
+ventricular	O
+function	O
+was	O
+performed	O
+using	O
+transthoracic	O
+echocardiography	O
+at	O
+baseline	O
+and	O
+at	O
+regular	O
+intervals	O
+after	O
+each	O
+test	O
+.	O
+
+RESULTS	O
+:	O
+Both	O
+forms	O
+of	O
+stress	O
+led	O
+to	O
+prolonged	O
+but	O
+reversible	O
+systolic	O
+and	O
+diastolic	O
+dysfunction	O
+.	O
+
+There	O
+was	O
+no	O
+difference	O
+in	O
+the	O
+maximum	O
+double	O
+product	O
+(	O
+p	O
+=	O
+0	O
+.	O
+53	O
+)	O
+or	O
+ST	O
+depression	B
+(	O
+p	O
+=	O
+0	O
+.	O
+63	O
+)	O
+with	O
+either	O
+form	O
+of	O
+stress	O
+.	O
+
+After	O
+exercise	O
+,	O
+ejection	O
+fraction	O
+was	O
+reduced	O
+at	O
+15	O
+and	O
+30	O
+minutes	O
+compared	O
+with	O
+baseline	O
+(	O
+mean	O
+(	O
+SEM	O
+)	O
+,	O
+-	O
+5	O
+.	O
+6	O
+(	O
+1	O
+.	O
+5	O
+)	O
+%	O
+,	O
+p	O
+<	O
+0	O
+.	O
+05	O
+;	O
+and	O
+-	O
+6	O
+.	O
+1	O
+(	O
+2	O
+.	O
+2	O
+)	O
+%	O
+,	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+,	O
+and	O
+at	O
+30	O
+and	O
+45	O
+minutes	O
+after	O
+dobutamine	O
+(	O
+-	O
+10	O
+.	O
+8	O
+(	O
+1	O
+.	O
+8	O
+)	O
+%	O
+and	O
+-	O
+5	O
+.	O
+5	O
+(	O
+1	O
+.	O
+8	O
+)	O
+%	O
+,	O
+both	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+Regional	O
+analysis	O
+showed	O
+a	O
+reduction	O
+in	O
+the	O
+worst	O
+affected	O
+segment	O
+15	O
+and	O
+30	O
+minutes	O
+after	O
+exercise	O
+(	O
+-	O
+27	O
+.	O
+9	O
+(	O
+7	O
+.	O
+2	O
+)	O
+%	O
+and	O
+-	O
+28	O
+.	O
+6	O
+(	O
+5	O
+.	O
+7	O
+)	O
+%	O
+,	O
+both	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+,	O
+and	O
+at	O
+30	O
+minutes	O
+after	O
+dobutamine	O
+(	O
+-	O
+32	O
+(	O
+5	O
+.	O
+3	O
+)	O
+%	O
+,	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+The	O
+isovolumic	O
+relaxation	O
+period	O
+was	O
+prolonged	O
+45	O
+minutes	O
+after	O
+each	O
+form	O
+of	O
+stress	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+In	O
+patients	O
+with	O
+coronary	B
+artery	I
+disease	I
+,	O
+dobutamine	O
+induced	O
+ischaemia	B
+results	O
+in	O
+prolonged	O
+reversible	O
+left	B
+ventricular	I
+dysfunction	I
+,	O
+presumed	O
+to	O
+be	O
+myocardial	B
+stunning	I
+,	O
+similar	O
+to	O
+that	O
+seen	O
+after	O
+exercise	O
+.	O
+
+Dobutamine	O
+induced	O
+ischaemia	B
+could	O
+therefore	O
+be	O
+used	O
+to	O
+study	O
+the	O
+pathophysiology	O
+of	O
+this	O
+phenomenon	O
+further	O
+in	O
+patients	O
+with	O
+coronary	B
+artery	I
+disease	I
+.	O
+
+Anorexigens	O
+and	O
+pulmonary	B
+hypertension	I
+in	O
+the	O
+United	O
+States	O
+:	O
+results	O
+from	O
+the	O
+surveillance	O
+of	O
+North	O
+American	O
+pulmonary	B
+hypertension	I
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+use	O
+of	O
+appetite	O
+suppressants	O
+in	O
+Europe	O
+has	O
+been	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+primary	B
+pulmonary	I
+hypertension	I
+(	O
+PPH	B
+)	O
+.	O
+
+Recently	O
+,	O
+fenfluramine	O
+appetite	O
+suppressants	O
+became	O
+widely	O
+used	O
+in	O
+the	O
+United	O
+States	O
+but	O
+were	O
+withdrawn	O
+in	O
+September	O
+1997	O
+because	O
+of	O
+concerns	O
+over	O
+adverse	O
+effects	O
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+We	O
+conducted	O
+a	O
+prospective	O
+surveillance	O
+study	O
+on	O
+patients	O
+diagnosed	O
+with	O
+pulmonary	B
+hypertension	I
+at	O
+12	O
+large	O
+referral	O
+centers	O
+in	O
+North	O
+America	O
+.	O
+
+Data	O
+collected	O
+on	O
+patients	O
+seen	O
+from	O
+September	O
+1	O
+,	O
+1996	O
+,	O
+to	O
+December	O
+31	O
+,	O
+1997	O
+,	O
+included	O
+the	O
+cause	O
+of	O
+the	O
+pulmonary	B
+hypertension	I
+and	O
+its	O
+severity	O
+.	O
+
+Patients	O
+with	O
+no	O
+identifiable	O
+cause	O
+of	O
+pulmonary	B
+hypertension	I
+were	O
+classed	O
+as	O
+PPH	B
+.	O
+
+A	O
+history	O
+of	O
+drug	O
+exposure	O
+also	O
+was	O
+taken	O
+with	O
+special	O
+attention	O
+on	O
+the	O
+use	O
+of	O
+antidepressants	O
+,	O
+anorexigens	O
+,	O
+and	O
+amphetamines	O
+.	O
+
+RESULTS	O
+:	O
+Five	O
+hundred	O
+seventy	O
+-	O
+nine	O
+patients	O
+were	O
+studied	O
+,	O
+205	O
+with	O
+PPH	B
+and	O
+374	O
+with	O
+pulmonary	B
+hypertension	I
+from	O
+other	O
+causes	O
+(	O
+secondary	O
+pulmonary	B
+hypertension	I
+[	O
+SPH	O
+]	O
+)	O
+.	O
+
+The	O
+use	O
+of	O
+anorexigens	O
+was	O
+common	O
+in	O
+both	O
+groups	O
+.	O
+
+However	O
+,	O
+of	O
+the	O
+medications	O
+surveyed	O
+,	O
+only	O
+the	O
+fenfluramines	O
+had	O
+a	O
+significant	O
+preferential	O
+association	O
+with	O
+PPH	B
+as	O
+compared	O
+with	O
+SPH	O
+(	O
+adjusted	O
+odds	O
+ratio	O
+for	O
+use	O
+>	O
+6	O
+months	O
+,	O
+7	O
+.	O
+5	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+1	O
+.	O
+7	O
+to	O
+32	O
+.	O
+4	O
+)	O
+.	O
+
+The	O
+association	O
+was	O
+stronger	O
+with	O
+longer	O
+duration	O
+of	O
+use	O
+when	O
+compared	O
+to	O
+shorter	O
+duration	O
+of	O
+use	O
+and	O
+was	O
+more	O
+pronounced	O
+in	O
+recent	O
+users	O
+than	O
+in	O
+remote	O
+users	O
+.	O
+
+An	O
+unexpectedly	O
+high	O
+(	O
+11	O
+.	O
+4	O
+%	O
+)	O
+number	O
+of	O
+patients	O
+with	O
+SPH	O
+had	O
+used	O
+anorexigens	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+magnitude	O
+of	O
+the	O
+association	O
+with	O
+PPH	B
+,	O
+the	O
+increase	O
+of	O
+association	O
+with	O
+increasing	O
+duration	O
+of	O
+use	O
+,	O
+and	O
+the	O
+specificity	O
+for	O
+fenfluramines	O
+are	O
+consistent	O
+with	O
+previous	O
+studies	O
+indicating	O
+that	O
+fenfluramines	O
+are	O
+causally	O
+related	O
+to	O
+PPH	B
+.	O
+
+The	O
+high	O
+prevalence	O
+of	O
+anorexigen	O
+use	O
+in	O
+patients	O
+with	O
+SPH	O
+also	O
+raises	O
+the	O
+possibility	O
+that	O
+these	O
+drugs	O
+precipitate	O
+pulmonary	B
+hypertension	I
+in	O
+patients	O
+with	O
+underlying	O
+conditions	O
+associated	O
+with	O
+SPH	O
+.	O
+
+Clinical	O
+aspects	O
+of	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+and	O
+thrombosis	B
+and	O
+other	O
+side	O
+effects	O
+of	O
+heparin	O
+therapy	O
+.	O
+
+Heparin	O
+,	O
+first	O
+used	O
+to	O
+prevent	O
+the	O
+clotting	O
+of	O
+blood	O
+in	O
+vitro	O
+,	O
+has	O
+been	O
+clinically	O
+used	O
+to	O
+treat	O
+thrombosis	B
+for	O
+more	O
+than	O
+50	O
+years	O
+.	O
+
+Although	O
+several	O
+new	O
+anticoagulant	O
+drugs	O
+are	O
+in	O
+development	O
+,	O
+heparin	O
+remains	O
+the	O
+anticoagulant	O
+of	O
+choice	O
+to	O
+treat	O
+acute	O
+thrombotic	B
+episodes	O
+.	O
+
+The	O
+clinical	O
+effects	O
+of	O
+heparin	O
+are	O
+meritorious	O
+,	O
+but	O
+side	O
+effects	O
+do	O
+exist	O
+.	O
+
+Bleeding	B
+is	O
+the	O
+primary	O
+untoward	O
+effect	O
+of	O
+heparin	O
+.	O
+
+Major	O
+bleeding	B
+is	O
+of	O
+primary	O
+concern	O
+in	O
+patients	O
+receiving	O
+heparin	O
+therapy	O
+.	O
+
+However	O
+,	O
+additional	O
+important	O
+untoward	O
+effects	O
+of	O
+heparin	O
+therapy	O
+include	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+,	O
+heparin	O
+-	O
+associated	O
+osteoporosis	B
+,	O
+eosinophilia	B
+,	O
+skin	B
+reactions	I
+,	O
+allergic	B
+reactions	I
+other	O
+than	O
+thrombocytopenia	B
+,	O
+alopecia	B
+,	O
+transaminasemia	O
+,	O
+hyperkalemia	B
+,	O
+hypoaldosteronism	B
+,	O
+and	O
+priapism	B
+.	O
+
+These	O
+side	O
+effects	O
+are	O
+relatively	O
+rare	O
+in	O
+a	O
+given	O
+individual	O
+,	O
+but	O
+given	O
+the	O
+extremely	O
+widespread	O
+use	O
+of	O
+heparin	O
+,	O
+some	O
+are	O
+quite	O
+common	O
+,	O
+particularly	O
+HITT	B
+and	O
+osteoporosis	B
+.	O
+
+Although	O
+reasonable	O
+incidences	O
+of	O
+many	O
+of	O
+these	O
+side	O
+effects	O
+can	O
+be	O
+"	O
+softly	O
+"	O
+deduced	O
+from	O
+current	O
+reports	O
+dealing	O
+with	O
+unfractionated	O
+heparin	O
+,	O
+at	O
+present	O
+the	O
+incidences	O
+of	O
+these	O
+side	O
+effects	O
+with	O
+newer	O
+low	O
+molecular	O
+weight	O
+heparins	O
+appear	O
+to	O
+be	O
+much	O
+less	O
+common	O
+.	O
+
+However	O
+,	O
+only	O
+longer	O
+experience	O
+will	O
+more	O
+clearly	O
+define	O
+the	O
+incidence	O
+of	O
+each	O
+side	O
+effect	O
+with	O
+low	O
+molecular	O
+weight	O
+preparations	O
+.	O
+
+A	O
+case	O
+of	O
+bilateral	O
+optic	B
+neuropathy	I
+in	O
+a	O
+patient	O
+on	O
+tacrolimus	O
+(	O
+FK506	O
+)	O
+therapy	O
+after	O
+liver	O
+transplantation	O
+.	O
+
+PURPOSE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+bilateral	O
+optic	B
+neuropathy	I
+in	O
+a	O
+patient	O
+receiving	O
+tacrolimus	O
+(	O
+FK	O
+506	O
+,	O
+Prograf	O
+;	O
+Fujisawa	O
+USA	O
+,	O
+Inc	O
+,	O
+Deerfield	O
+,	O
+Illinois	O
+)	O
+for	O
+immunosuppression	O
+after	O
+orthotropic	O
+liver	O
+transplantation	O
+.	O
+
+METHOD	O
+:	O
+Case	O
+report	O
+.	O
+
+In	O
+a	O
+58	O
+-	O
+year	O
+-	O
+old	O
+man	O
+receiving	O
+tacrolimus	O
+after	O
+orthotropic	O
+liver	O
+transplantation	O
+,	O
+serial	O
+neuro	O
+-	O
+ophthalmologic	O
+examinations	O
+and	O
+laboratory	O
+studies	O
+were	O
+performed	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+patient	O
+had	O
+episodic	O
+deterioration	O
+of	O
+vision	O
+in	O
+both	O
+eyes	O
+,	O
+with	O
+clinical	O
+features	O
+resembling	O
+ischemic	B
+optic	I
+neuropathies	I
+.	O
+
+Deterioration	B
+of	I
+vision	I
+occurred	O
+despite	O
+discontinuation	O
+of	O
+the	O
+tacrolimus	O
+.	O
+
+CONCLUSION	O
+:	O
+Tacrolimus	O
+and	O
+other	O
+immunosuppressive	O
+agents	O
+may	O
+be	O
+associated	O
+with	O
+optic	B
+nerve	I
+toxicity	I
+.	O
+
+Hypercalcemia	B
+,	O
+arrhythmia	B
+,	O
+and	O
+mood	O
+stabilizers	O
+.	O
+
+Recent	O
+findings	O
+in	O
+a	O
+bipolar	B
+patient	O
+receiving	O
+maintenance	O
+lithium	O
+therapy	O
+who	O
+developed	O
+hypercalcemia	B
+and	O
+severe	O
+bradyarrhythmia	B
+prompted	O
+the	O
+authors	O
+to	O
+conduct	O
+a	O
+retrospective	O
+study	O
+of	O
+bipolar	B
+patients	O
+with	O
+lithium	O
+-	O
+associated	O
+hypercalcemia	B
+.	O
+
+A	O
+printout	O
+of	O
+all	O
+cases	O
+of	O
+hypercalcemia	B
+that	O
+presented	O
+during	O
+a	O
+1	O
+-	O
+year	O
+period	O
+was	O
+generated	O
+.	O
+
+After	O
+eliminating	O
+spurious	O
+hypercalcemias	B
+or	O
+those	O
+associated	O
+with	O
+intravenous	O
+fluids	O
+,	O
+the	O
+authors	O
+identified	O
+18	O
+non	O
+-	O
+lithium	O
+-	O
+treated	O
+patients	O
+with	O
+hypercalcemias	B
+related	O
+to	O
+malignancies	B
+and	O
+other	O
+medical	O
+conditions	O
+(	O
+group	O
+A	O
+)	O
+and	O
+12	O
+patients	O
+with	O
+lithium	O
+-	O
+associated	O
+hypercalcemia	B
+(	O
+group	O
+B	O
+)	O
+.	O
+
+Patients	O
+in	O
+group	O
+B	O
+were	O
+not	O
+comparable	O
+to	O
+those	O
+in	O
+group	O
+A	O
+,	O
+as	O
+the	O
+latter	O
+were	O
+medically	O
+compromised	O
+and	O
+were	O
+receiving	O
+multiple	O
+pharmacotherapies	O
+.	O
+
+Thus	O
+,	O
+two	O
+control	O
+groups	O
+were	O
+generated	O
+:	O
+group	O
+C1	O
+,	O
+which	O
+included	O
+age	O
+-	O
+and	O
+sex	O
+-	O
+comparable	O
+lithium	O
+-	O
+treated	O
+bipolar	B
+normocalcemic	O
+patients	O
+,	O
+and	O
+group	O
+C2	O
+,	O
+which	O
+included	O
+bipolar	B
+normocalcemic	O
+patients	O
+treated	O
+with	O
+anticonvulsant	O
+mood	O
+stabilizers	O
+.	O
+
+The	O
+electrocardiographic	O
+(	O
+ECG	O
+)	O
+findings	O
+for	O
+patients	O
+in	O
+group	O
+B	O
+were	O
+compared	O
+with	O
+those	O
+of	O
+patients	O
+in	O
+groups	O
+C1	O
+and	O
+C2	O
+.	O
+
+It	O
+was	O
+found	O
+that	O
+these	O
+groups	O
+did	O
+not	O
+differ	O
+in	O
+their	O
+overall	O
+frequency	O
+of	O
+ECG	O
+abnormalities	O
+;	O
+however	O
+,	O
+there	O
+were	O
+significant	O
+differences	O
+in	O
+the	O
+frequency	O
+of	O
+conduction	O
+defects	O
+.	O
+
+Patients	O
+with	O
+hypercalcemia	B
+resulting	O
+from	O
+medical	O
+diseases	O
+and	O
+bipolar	B
+patients	O
+with	O
+lithium	O
+-	O
+associated	O
+hypercalcemia	B
+had	O
+significantly	O
+higher	O
+frequencies	O
+of	O
+conduction	O
+defects	O
+.	O
+
+Patients	O
+in	O
+group	O
+A	O
+had	O
+significant	O
+mortality	O
+at	O
+2	O
+-	O
+year	O
+follow	O
+-	O
+up	O
+(	O
+28	O
+%	O
+)	O
+,	O
+in	O
+contrast	O
+to	O
+zero	O
+mortality	O
+in	O
+the	O
+other	O
+three	O
+groups	O
+.	O
+
+The	O
+clinical	O
+implications	O
+of	O
+these	O
+findings	O
+are	O
+discussed	O
+.	O
+
+Attenuation	O
+of	O
+nephrotoxicity	B
+by	O
+a	O
+novel	O
+lipid	O
+nanosphere	O
+(	O
+NS	O
+-	O
+718	O
+)	O
+incorporating	O
+amphotericin	O
+B	O
+.	O
+
+NS	O
+-	O
+718	O
+,	O
+a	O
+lipid	O
+nanosphere	O
+incorporating	O
+amphotericin	O
+B	O
+,	O
+is	O
+effective	O
+against	O
+pathogenic	O
+fungi	O
+and	O
+has	O
+low	O
+toxicity	B
+.	O
+
+We	O
+compared	O
+the	O
+toxicity	B
+of	O
+NS	O
+-	O
+718	O
+with	O
+that	O
+of	O
+Fungizone	O
+(	O
+amphotericin	O
+B	O
+-	O
+sodium	O
+deoxycholate	O
+;	O
+D	O
+-	O
+AmB	O
+)	O
+in	O
+vitro	O
+using	O
+renal	O
+cell	O
+cultures	O
+and	O
+in	O
+vivo	O
+by	O
+biochemical	O
+analysis	O
+,	O
+histopathological	O
+study	O
+of	O
+the	O
+kidney	O
+and	O
+pharmacokinetic	O
+study	O
+of	O
+amphotericin	O
+B	O
+following	O
+intravenous	O
+infusion	O
+of	O
+the	O
+formulation	O
+in	O
+rats	O
+.	O
+
+Incubation	O
+with	O
+NS	O
+-	O
+718	O
+resulted	O
+in	O
+significantly	O
+less	O
+damage	O
+of	O
+cultured	O
+human	O
+renal	O
+proximal	O
+tubular	O
+epithelial	O
+cells	O
+compared	O
+with	O
+D	O
+-	O
+AmB	O
+.	O
+
+Serum	O
+blood	O
+urea	O
+and	O
+creatinine	O
+concentrations	O
+increased	O
+significantly	O
+in	O
+rats	O
+given	O
+an	O
+iv	O
+infusion	O
+of	O
+D	O
+-	O
+AmB	O
+3	O
+mg	O
+/	O
+kg	O
+but	O
+not	O
+in	O
+those	O
+given	O
+the	O
+same	O
+dose	O
+of	O
+NS	O
+-	O
+718	O
+.	O
+
+Histopathological	O
+examination	O
+of	O
+the	O
+kidney	O
+showed	O
+tubular	B
+necrosis	I
+in	O
+D	O
+-	O
+AmB	O
+-	O
+treated	O
+rats	O
+but	O
+no	O
+change	O
+in	O
+NS	O
+-	O
+718	O
+-	O
+treated	O
+rats	O
+.	O
+
+Amphotericin	O
+B	O
+concentrations	O
+in	O
+the	O
+kidney	O
+in	O
+NS	O
+-	O
+718	O
+-	O
+treated	O
+rats	O
+were	O
+higher	O
+than	O
+those	O
+in	O
+D	O
+-	O
+AmB	O
+-	O
+treated	O
+rats	O
+.	O
+
+Our	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+results	O
+suggest	O
+that	O
+incorporation	O
+of	O
+amphotericin	O
+B	O
+into	O
+lipid	O
+nanospheres	O
+of	O
+NS	O
+-	O
+718	O
+attenuates	O
+the	O
+nephrotoxicity	B
+of	O
+amphotericin	O
+B	O
+.	O
+
+Patterns	O
+of	O
+sulfadiazine	O
+acute	B
+nephrotoxicity	I
+.	O
+
+Sulfadiazine	O
+acute	B
+nephrotoxicity	I
+is	O
+reviving	O
+specially	O
+because	O
+of	O
+its	O
+use	O
+in	O
+toxoplasmosis	B
+in	O
+HIV	O
+-	O
+positive	O
+patients	O
+.	O
+
+We	O
+report	O
+4	O
+cases	O
+,	O
+one	O
+of	O
+them	O
+in	O
+a	O
+previously	O
+healthy	O
+person	O
+.	O
+
+Under	O
+treatment	O
+with	O
+sulfadiazine	O
+they	O
+developed	O
+oliguria	B
+,	O
+abdominal	B
+pain	I
+,	O
+renal	B
+failure	I
+and	O
+showed	O
+multiple	O
+radiolucent	O
+renal	B
+calculi	I
+in	O
+echography	O
+.	O
+
+All	O
+patients	O
+recovered	O
+their	O
+previous	O
+normal	O
+renal	O
+function	O
+after	O
+adequate	O
+hydration	O
+and	O
+alcalinization	O
+.	O
+
+A	O
+nephrostomy	O
+tube	O
+had	O
+to	O
+be	O
+placed	O
+in	O
+one	O
+of	O
+the	O
+patients	O
+for	O
+ureteral	B
+lithiasis	I
+in	O
+a	O
+single	O
+functional	O
+kidney	O
+.	O
+
+None	O
+of	O
+them	O
+needed	O
+dialysis	O
+or	O
+a	O
+renal	O
+biopsy	O
+because	O
+of	O
+a	O
+typical	O
+benign	O
+course	O
+.	O
+
+Treatment	O
+with	O
+sulfadiazine	O
+requires	O
+exquisite	O
+control	O
+of	O
+renal	O
+function	O
+,	O
+an	O
+increase	O
+in	O
+water	O
+ingestion	O
+and	O
+possibly	O
+the	O
+alcalinization	O
+of	O
+the	O
+urine	O
+.	O
+
+We	O
+communicate	O
+a	O
+case	O
+in	O
+a	O
+previously	O
+healthy	O
+person	O
+,	O
+a	O
+fact	O
+not	O
+found	O
+in	O
+the	O
+recent	O
+literature	O
+.	O
+
+Probably	O
+many	O
+more	O
+cases	O
+are	O
+not	O
+detected	O
+.	O
+
+We	O
+think	O
+that	O
+a	O
+prospective	O
+study	O
+would	O
+be	O
+useful	O
+.	O
+
+Downbeat	B
+nystagmus	I
+associated	O
+with	O
+intravenous	O
+patient	O
+-	O
+controlled	O
+administration	O
+of	O
+morphine	O
+.	O
+
+IMPLICATIONS	O
+:	O
+This	O
+case	O
+documents	O
+a	O
+patient	O
+who	O
+developed	O
+dizziness	B
+with	O
+downbeating	B
+nystagmus	I
+while	O
+receiving	O
+a	O
+relatively	O
+large	O
+dose	O
+of	O
+IV	O
+patient	O
+-	O
+controlled	O
+analgesia	O
+morphine	O
+.	O
+
+Although	O
+there	O
+have	O
+been	O
+case	O
+reports	O
+of	O
+epidural	O
+morphine	O
+with	O
+these	O
+symptoms	O
+and	O
+signs	O
+,	O
+this	O
+has	O
+not	O
+been	O
+previously	O
+documented	O
+with	O
+IV	O
+or	O
+patient	O
+-	O
+controlled	O
+analgesia	O
+morphine	O
+.	O
+
+Hemodynamic	O
+and	O
+antiadrenergic	O
+effects	O
+of	O
+dronedarone	O
+and	O
+amiodarone	O
+in	O
+animals	O
+with	O
+a	O
+healed	O
+myocardial	B
+infarction	I
+.	O
+
+The	O
+hemodynamic	O
+and	O
+antiadrenergic	O
+effects	O
+of	O
+dronedarone	O
+,	O
+a	O
+noniodinated	O
+compound	O
+structurally	O
+related	O
+to	O
+amiodarone	O
+,	O
+were	O
+compared	O
+with	O
+those	O
+of	O
+amiodarone	O
+after	O
+prolonged	O
+oral	O
+administration	O
+,	O
+both	O
+at	O
+rest	O
+and	O
+during	O
+sympathetic	O
+stimulation	O
+in	O
+conscious	O
+dogs	O
+with	O
+a	O
+healed	O
+myocardial	B
+infarction	I
+.	O
+
+All	O
+dogs	O
+(	O
+n	O
+=	O
+6	O
+)	O
+randomly	O
+received	O
+orally	O
+dronedarone	O
+(	O
+10	O
+and	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+amiodarone	O
+(	O
+10	O
+and	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+and	O
+placebo	O
+twice	O
+daily	O
+for	O
+7	O
+days	O
+,	O
+with	O
+a	O
+3	O
+-	O
+week	O
+washout	O
+between	O
+consecutive	O
+treatments	O
+.	O
+
+Heart	O
+rate	O
+(	O
+HR	O
+)	O
+,	O
+mean	O
+arterial	O
+pressure	O
+(	O
+MBP	O
+)	O
+,	O
+positive	O
+rate	O
+of	O
+increase	O
+of	O
+left	O
+ventricular	O
+pressure	O
+(	O
++	O
+LVdP	O
+/	O
+dt	O
+)	O
+,	O
+echocardiographically	O
+assessed	O
+left	O
+ventricular	O
+ejection	O
+fraction	O
+(	O
+LVEF	O
+)	O
+,	O
+and	O
+fractional	O
+shortening	O
+(	O
+FS	O
+)	O
+,	O
+as	O
+well	O
+as	O
+chronotropic	O
+response	O
+to	O
+isoproterenol	O
+and	O
+exercise	O
+-	O
+induced	O
+sympathetic	O
+stimulation	O
+were	O
+evaluated	O
+under	O
+baseline	O
+and	O
+posttreatment	O
+conditions	O
+.	O
+
+Resting	O
+values	O
+of	O
+LVEF	O
+,	O
+FS	O
+,	O
++	O
+LVdP	O
+/	O
+dt	O
+,	O
+and	O
+MBP	O
+remained	O
+unchanged	O
+whatever	O
+the	O
+drug	O
+and	O
+the	O
+dosing	O
+regimen	O
+,	O
+whereas	O
+resting	O
+HR	O
+was	O
+significantly	O
+and	O
+dose	O
+-	O
+dependently	O
+lowered	O
+after	O
+dronedarone	O
+and	O
+to	O
+a	O
+lesser	O
+extent	O
+after	O
+amiodarone	O
+.	O
+
+Both	O
+dronedarone	O
+and	O
+amiodarone	O
+significantly	O
+reduced	O
+the	O
+exercise	O
+-	O
+induced	O
+tachycardia	B
+and	O
+,	O
+at	O
+the	O
+highest	O
+dose	O
+,	O
+decreased	O
+the	O
+isoproterenol	O
+-	O
+induced	O
+tachycardia	B
+.	O
+
+Thus	O
+,	O
+dronedarone	O
+and	O
+amiodarone	O
+displayed	O
+a	O
+similar	O
+level	O
+of	O
+antiadrenergic	O
+effect	O
+and	O
+did	O
+not	O
+impair	O
+the	O
+resting	O
+left	O
+ventricular	O
+function	O
+.	O
+
+Consequently	O
+,	O
+dronedarone	O
+might	O
+be	O
+particularly	O
+suitable	O
+for	O
+the	O
+treatment	O
+and	O
+prevention	O
+of	O
+various	O
+clinical	O
+arrhythmias	B
+,	O
+without	O
+compromising	O
+the	O
+left	O
+ventricular	O
+function	O
+.	O
+
+Phase	O
+2	O
+trial	O
+of	O
+liposomal	O
+doxorubicin	O
+(	O
+40	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+)	O
+in	O
+platinum	O
+/	O
+paclitaxel	O
+-	O
+refractory	O
+ovarian	B
+and	I
+fallopian	I
+tube	I
+cancers	I
+and	O
+primary	O
+carcinoma	B
+of	I
+the	I
+peritoneum	I
+.	O
+
+BACKGROUND	O
+:	O
+Several	O
+studies	O
+have	O
+demonstrated	O
+liposomal	O
+doxorubicin	O
+(	O
+Doxil	O
+)	O
+to	O
+be	O
+an	O
+active	O
+antineoplastic	O
+agent	O
+in	O
+platinum	O
+-	O
+resistant	O
+ovarian	B
+cancer	I
+,	O
+with	O
+dose	O
+limiting	O
+toxicity	B
+of	O
+the	O
+standard	O
+dosing	O
+regimen	O
+(	O
+50	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+q	O
+4	O
+weeks	O
+)	O
+being	O
+severe	O
+erythrodysesthesia	B
+(	O
+"	O
+hand	B
+-	I
+foot	I
+syndrome	I
+"	O
+)	O
+and	O
+stomatitis	B
+.	O
+
+We	O
+wished	O
+to	O
+develop	O
+a	O
+more	O
+tolerable	O
+liposomal	O
+doxorubicin	O
+treatment	O
+regimen	O
+and	O
+document	O
+its	O
+level	O
+of	O
+activity	O
+in	O
+a	O
+well	O
+-	O
+defined	O
+patient	O
+population	O
+with	O
+platinum	O
+/	O
+paclitaxel	O
+-	O
+refractory	O
+disease	O
+.	O
+
+METHODS	O
+AND	O
+MATERIALS	O
+:	O
+Patients	O
+with	O
+ovarian	B
+or	I
+fallopian	I
+tube	I
+cancers	I
+or	O
+primary	O
+peritoneal	B
+carcinoma	I
+with	O
+platinum	O
+/	O
+paclitaxel	O
+-	O
+refractory	O
+disease	O
+(	O
+stable	O
+or	O
+progressive	O
+disease	O
+following	O
+treatment	O
+with	O
+these	O
+agents	O
+or	O
+previous	O
+objective	O
+response	O
+<	O
+3	O
+months	O
+in	O
+duration	O
+)	O
+were	O
+treated	O
+with	O
+liposomal	O
+doxorubicin	O
+at	O
+a	O
+dose	O
+of	O
+40	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+q	O
+4	O
+weeks	O
+.	O
+
+RESULTS	O
+:	O
+A	O
+total	O
+of	O
+49	O
+patients	O
+(	O
+median	O
+age	O
+:	O
+60	O
+;	O
+range	O
+41	O
+-	O
+81	O
+)	O
+entered	O
+this	O
+phase	O
+2	O
+trial	O
+.	O
+
+The	O
+median	O
+number	O
+of	O
+prior	O
+regimens	O
+was	O
+2	O
+(	O
+range	O
+:	O
+1	O
+-	O
+6	O
+)	O
+.	O
+
+Six	O
+(	O
+12	O
+%	O
+)	O
+and	O
+4	O
+(	O
+8	O
+%	O
+)	O
+patients	O
+experienced	O
+grade	O
+2	O
+hand	B
+-	I
+foot	I
+syndrome	I
+and	O
+stomatitis	B
+,	O
+respectively	O
+(	O
+no	O
+episodes	O
+of	O
+grade	O
+3	O
+)	O
+.	O
+
+One	O
+patient	O
+developed	O
+grade	O
+3	O
+diarrhea	B
+requiring	O
+hospitalization	O
+for	O
+hydration	O
+.	O
+
+Six	O
+(	O
+12	O
+%	O
+)	O
+individuals	O
+required	O
+dose	O
+reductions	O
+.	O
+
+The	O
+median	O
+number	O
+of	O
+courses	O
+of	O
+liposomal	O
+doxorubicin	O
+administered	O
+on	O
+this	O
+protocol	O
+was	O
+2	O
+(	O
+range	O
+:	O
+1	O
+-	O
+12	O
+)	O
+.	O
+
+Four	O
+of	O
+44	O
+patients	O
+(	O
+9	O
+%	O
+)	O
+evaluable	O
+for	O
+response	O
+exhibited	O
+objective	O
+and	O
+subjective	O
+evidence	O
+of	O
+an	O
+antineoplastic	O
+effect	O
+of	O
+therapy	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+modified	O
+liposomal	O
+doxorubicin	O
+regimen	O
+results	O
+in	O
+less	O
+toxicity	B
+(	O
+stomatitis	B
+,	O
+hand	B
+-	I
+foot	I
+syndrome	I
+)	O
+than	O
+the	O
+standard	O
+FDA	O
+-	O
+approved	O
+dose	O
+schedule	O
+.	O
+
+Definite	O
+,	O
+although	O
+limited	O
+,	O
+antineoplastic	O
+activity	O
+is	O
+observed	O
+in	O
+patients	O
+with	O
+well	O
+-	O
+defined	O
+platinum	O
+-	O
+and	O
+paclitaxel	O
+-	O
+refractory	O
+ovarian	B
+cancer	I
+.	O
+
+Efficacy	O
+of	O
+olanzapine	O
+in	O
+acute	O
+bipolar	B
+mania	I
+:	O
+a	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+study	O
+.	O
+
+The	O
+Olanzipine	O
+HGGW	O
+Study	O
+Group	O
+.	O
+
+BACKGROUND	O
+:	O
+We	O
+compared	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+olanzapine	O
+vs	O
+placebo	O
+for	O
+the	O
+treatment	O
+of	O
+acute	O
+bipolar	B
+mania	I
+.	O
+
+METHODS	O
+:	O
+Four	O
+-	O
+week	O
+,	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+parallel	O
+study	O
+.	O
+
+A	O
+total	O
+of	O
+115	O
+patients	O
+with	O
+a	O
+DSM	O
+-	O
+IV	O
+diagnosis	O
+of	O
+bipolar	B
+disorder	I
+,	O
+manic	B
+or	O
+mixed	O
+,	O
+were	O
+randomized	O
+to	O
+olanzapine	O
+,	O
+5	O
+to	O
+20	O
+mg	O
+/	O
+d	O
+(	O
+n	O
+=	O
+55	O
+)	O
+,	O
+or	O
+placebo	O
+(	O
+n	O
+=	O
+60	O
+)	O
+.	O
+
+The	O
+primary	O
+efficacy	O
+measure	O
+was	O
+the	O
+Young	O
+-	O
+Mania	B
+Rating	O
+Scale	O
+(	O
+Y	O
+-	O
+MRS	O
+)	O
+total	O
+score	O
+.	O
+
+Response	O
+and	O
+euthymia	O
+were	O
+defined	O
+,	O
+a	O
+priori	O
+,	O
+as	O
+at	O
+least	O
+a	O
+50	O
+%	O
+improvement	O
+from	O
+baseline	O
+to	O
+end	O
+point	O
+and	O
+as	O
+a	O
+score	O
+of	O
+no	O
+less	O
+than	O
+12	O
+at	O
+end	O
+point	O
+in	O
+the	O
+Y	O
+-	O
+MRS	O
+total	O
+score	O
+,	O
+respectively	O
+.	O
+
+Safety	O
+was	O
+assessed	O
+using	O
+adverse	O
+events	O
+,	O
+Extrapyramidal	B
+Symptom	I
+(	O
+EPS	B
+)	O
+rating	O
+scales	O
+,	O
+laboratory	O
+values	O
+,	O
+electrocardiograms	O
+,	O
+vital	O
+signs	O
+,	O
+and	O
+weight	O
+change	O
+.	O
+
+RESULTS	O
+:	O
+Olanzapine	O
+-	O
+treated	O
+patients	O
+demonstrated	O
+a	O
+statistically	O
+significant	O
+greater	O
+mean	O
+(	O
++	O
+/	O
+-	O
+SD	O
+)	O
+improvement	O
+in	O
+Y	O
+-	O
+MRS	O
+total	O
+score	O
+than	O
+placebo	O
+-	O
+treated	O
+patients	O
+(	O
+-	O
+14	O
+.	O
+8	O
++	O
+/	O
+-	O
+12	O
+.	O
+5	O
+and	O
+-	O
+8	O
+.	O
+1	O
++	O
+/	O
+-	O
+12	O
+.	O
+7	O
+,	O
+respectively	O
+;	O
+P	O
+<	O
+.	O
+001	O
+)	O
+,	O
+which	O
+was	O
+evident	O
+at	O
+the	O
+first	O
+postbaseline	O
+observation	O
+1	O
+week	O
+after	O
+randomization	O
+and	O
+was	O
+maintained	O
+throughout	O
+the	O
+study	O
+(	O
+last	O
+observation	O
+carried	O
+forward	O
+)	O
+.	O
+
+Olanzapine	O
+-	O
+treated	O
+patients	O
+demonstrated	O
+a	O
+higher	O
+rate	O
+of	O
+response	O
+(	O
+65	O
+%	O
+vs	O
+43	O
+%	O
+,	O
+respectively	O
+;	O
+P	O
+=	O
+.	O
+02	O
+)	O
+and	O
+euthymia	O
+(	O
+61	O
+%	O
+vs	O
+36	O
+%	O
+,	O
+respectively	O
+;	O
+P	O
+=	O
+.	O
+01	O
+)	O
+than	O
+placebo	O
+-	O
+treated	O
+patients	O
+.	O
+
+There	O
+were	O
+no	O
+statistically	O
+significant	O
+differences	O
+in	O
+EPSs	B
+between	O
+groups	O
+.	O
+
+However	O
+,	O
+olanzapine	O
+-	O
+treated	O
+patients	O
+had	O
+a	O
+statistically	O
+significant	O
+greater	O
+mean	O
+(	O
++	O
+/	O
+-	O
+SD	O
+)	O
+weight	B
+gain	I
+than	O
+placebo	O
+-	O
+treated	O
+patients	O
+(	O
+2	O
+.	O
+1	O
++	O
+/	O
+-	O
+2	O
+.	O
+8	O
+vs	O
+0	O
+.	O
+45	O
++	O
+/	O
+-	O
+2	O
+.	O
+3	O
+kg	O
+,	O
+respectively	O
+)	O
+and	O
+also	O
+experienced	O
+more	O
+treatment	O
+-	O
+emergent	O
+somnolence	B
+(	O
+21	O
+patients	O
+[	O
+38	O
+.	O
+2	O
+%	O
+]	O
+vs	O
+5	O
+[	O
+8	O
+.	O
+3	O
+%	O
+]	O
+,	O
+respectively	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+Olanzapine	O
+demonstrated	O
+greater	O
+efficacy	O
+than	O
+placebo	O
+in	O
+the	O
+treatment	O
+of	O
+acute	O
+bipolar	B
+mania	I
+and	O
+was	O
+generally	O
+well	O
+tolerated	O
+.	O
+
+The	O
+effect	O
+of	O
+pupil	B
+dilation	I
+with	O
+tropicamide	O
+on	O
+vision	O
+and	O
+driving	O
+simulator	O
+performance	O
+.	O
+
+PURPOSE	O
+:	O
+To	O
+assess	O
+the	O
+effect	O
+of	O
+pupil	B
+dilation	I
+on	O
+vision	O
+and	O
+driving	O
+ability	O
+.	O
+
+METHODS	O
+:	O
+A	O
+series	O
+of	O
+tests	O
+on	O
+various	O
+parameters	O
+of	O
+visual	O
+function	O
+and	O
+driving	O
+simulator	O
+performance	O
+were	O
+performed	O
+on	O
+12	O
+healthy	O
+drivers	O
+,	O
+before	O
+and	O
+after	O
+pupil	B
+dilation	I
+using	O
+guttae	O
+tropicamide	O
+1	O
+%	O
+.	O
+
+A	O
+driving	O
+simulator	O
+(	O
+Transport	O
+Research	O
+Laboratory	O
+)	O
+was	O
+used	O
+to	O
+measure	O
+reaction	O
+time	O
+(	O
+RT	O
+)	O
+,	O
+speed	O
+maintenance	O
+and	O
+steering	O
+accuracy	O
+.	O
+
+Tests	O
+of	O
+basic	O
+visual	O
+function	O
+included	O
+high	O
+-	O
+and	O
+low	O
+-	O
+contrast	O
+visual	O
+acuity	O
+(	O
+HCVA	O
+and	O
+LCVA	O
+)	O
+,	O
+Pelli	O
+-	O
+Robson	O
+contrast	O
+threshold	O
+(	O
+CT	O
+)	O
+and	O
+Goldmann	O
+perimetry	O
+(	O
+FIELDS	O
+)	O
+.	O
+
+Useful	O
+Field	O
+of	O
+View	O
+(	O
+UFOV	O
+-	O
+-	O
+a	O
+test	O
+of	O
+visual	O
+attention	O
+)	O
+was	O
+also	O
+undertaken	O
+.	O
+
+The	O
+mean	O
+differences	O
+in	O
+the	O
+pre	O
+-	O
+and	O
+post	O
+-	O
+dilatation	O
+measurements	O
+were	O
+tested	O
+for	O
+statistical	O
+significance	O
+at	O
+the	O
+95	O
+%	O
+level	O
+using	O
+one	O
+-	O
+tail	O
+paired	O
+t	O
+-	O
+tests	O
+.	O
+
+RESULTS	O
+:	O
+Pupillary	B
+dilation	I
+resulted	O
+in	O
+a	O
+statistically	O
+significant	O
+deterioration	O
+in	O
+CT	O
+and	O
+HCVA	O
+only	O
+.	O
+
+Five	O
+of	O
+12	O
+drivers	O
+also	O
+exhibited	O
+deterioration	O
+in	O
+LCVA	O
+,	O
+CT	O
+and	O
+RT	O
+.	O
+
+Little	O
+evidence	O
+emerged	O
+for	O
+deterioration	O
+in	O
+FIELDS	O
+and	O
+UFOV	O
+.	O
+
+Also	O
+,	O
+7	O
+of	O
+12	O
+drivers	O
+appeared	O
+to	O
+adjust	O
+their	O
+driving	O
+behaviour	O
+by	O
+reducing	O
+their	O
+speed	O
+on	O
+the	O
+driving	O
+simulator	O
+,	O
+leading	O
+to	O
+improved	O
+steering	O
+accuracy	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Pupillary	B
+dilation	I
+may	O
+lead	O
+to	O
+a	O
+decrease	O
+in	O
+vision	O
+and	O
+daylight	O
+driving	O
+performance	O
+in	O
+young	O
+people	O
+.	O
+
+A	O
+larger	O
+study	O
+,	O
+including	O
+a	O
+broader	O
+spectrum	O
+of	O
+subjects	O
+,	O
+is	O
+warranted	O
+before	O
+guidelines	O
+can	O
+be	O
+recommended	O
+.	O
+
+A	O
+case	O
+of	O
+isotretinoin	B
+embryopathy	I
+with	O
+bilateral	O
+anotia	B
+and	O
+Taussig	B
+-	I
+Bing	I
+malformation	I
+.	O
+
+We	O
+report	O
+a	O
+newborn	O
+infant	O
+with	O
+multiple	O
+congenital	O
+anomalies	O
+(	O
+anotia	B
+and	O
+Taussig	B
+-	I
+Bing	I
+malformation	I
+)	O
+due	O
+to	O
+exposure	O
+to	O
+isotretinoin	O
+within	O
+the	O
+first	O
+trimester	O
+.	O
+
+In	O
+this	O
+paper	O
+we	O
+aim	O
+to	O
+draw	O
+to	O
+the	O
+fact	O
+that	O
+caution	O
+is	O
+needed	O
+when	O
+prescribing	O
+vitamin	O
+A	O
+-	O
+containing	O
+drugs	O
+to	O
+women	O
+of	O
+childbearing	O
+years	O
+.	O
+
+Effect	O
+of	O
+methoxamine	O
+on	O
+maximum	O
+urethral	O
+pressure	O
+in	O
+women	O
+with	O
+genuine	O
+stress	B
+incontinence	I
+:	O
+a	O
+placebo	O
+-	O
+controlled	O
+,	O
+double	O
+-	O
+blind	O
+crossover	O
+study	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+evaluate	O
+the	O
+potential	O
+role	O
+for	O
+a	O
+selective	O
+alpha1	O
+-	O
+adrenoceptor	O
+agonist	O
+in	O
+the	O
+treatment	O
+of	O
+urinary	B
+stress	I
+incontinence	I
+.	O
+
+A	O
+randomised	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+,	O
+crossover	O
+study	O
+design	O
+was	O
+employed	O
+.	O
+
+Half	O
+log	O
+incremental	O
+doses	O
+of	O
+intravenous	O
+methoxamine	O
+or	O
+placebo	O
+(	O
+saline	O
+)	O
+were	O
+administered	O
+to	O
+a	O
+group	O
+of	O
+women	O
+with	O
+genuine	O
+stress	B
+incontinence	I
+while	O
+measuring	O
+maximum	O
+urethral	O
+pressure	O
+(	O
+MUP	O
+)	O
+,	O
+blood	O
+pressure	O
+,	O
+heart	O
+rate	O
+,	O
+and	O
+symptomatic	O
+side	O
+effects	O
+.	O
+
+Methoxamine	O
+evoked	O
+non	O
+-	O
+significant	O
+increases	O
+in	O
+MUP	O
+and	O
+diastolic	O
+blood	O
+pressure	O
+but	O
+caused	O
+a	B
+significant	I
+rise	I
+in	I
+systolic	I
+blood	I
+pressure	I
+and	O
+significant	O
+fall	O
+in	O
+heart	O
+rate	O
+at	O
+maximum	O
+dosage	O
+.	O
+
+Systemic	O
+side	O
+effects	O
+including	O
+piloerection	O
+,	O
+headache	B
+,	O
+and	O
+cold	O
+extremities	O
+were	O
+experienced	O
+in	O
+all	O
+subjects	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+the	O
+clinical	O
+usefulness	O
+of	O
+direct	O
+,	O
+peripherally	O
+acting	O
+sub	O
+-	O
+type	O
+-	O
+selective	O
+alpha1	O
+-	O
+adrenoceptor	O
+agonists	O
+in	O
+the	O
+medical	O
+treatment	O
+of	O
+stress	B
+incontinence	I
+may	O
+be	O
+limited	O
+by	O
+associated	O
+piloerection	O
+and	O
+cardiovascular	O
+side	O
+effects	O
+.	O
+
+Hyperglycemic	B
+effect	O
+of	O
+amino	O
+compounds	O
+structurally	O
+related	O
+to	O
+caproate	O
+in	O
+rats	O
+.	O
+
+The	O
+chronic	O
+feeding	O
+of	O
+small	O
+amounts	O
+(	O
+0	O
+.	O
+3	O
+-	O
+3	O
+%	O
+of	O
+diet	O
+weight	O
+)	O
+of	O
+certain	O
+amino	O
+derivatives	O
+of	O
+caproate	O
+resulted	O
+in	O
+hyperglycemia	B
+,	O
+an	O
+elevated	O
+glucose	O
+tolerance	O
+curve	O
+and	O
+,	O
+occasionally	O
+,	O
+glucosuria	B
+.	O
+
+Effective	O
+compounds	O
+included	O
+norleucine	O
+,	O
+norvaline	O
+,	O
+glutamate	O
+,	O
+epsilon	O
+-	O
+aminocaproate	O
+,	O
+methionine	O
+,	O
+and	O
+leucine	O
+.	O
+
+Toleration	O
+of	O
+high	O
+doses	O
+of	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitors	O
+in	O
+patients	O
+with	O
+chronic	O
+heart	B
+failure	I
+:	O
+results	O
+from	O
+the	O
+ATLAS	O
+trial	O
+.	O
+
+The	O
+Assessment	O
+of	O
+Treatment	O
+with	O
+Lisinopril	O
+and	O
+Survival	O
+.	O
+
+BACKGROUND	O
+:	O
+Treatment	O
+with	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+inhibitors	O
+reduces	O
+mortality	O
+and	O
+morbidity	O
+in	O
+patients	O
+with	O
+chronic	O
+heart	B
+failure	I
+(	O
+CHF	B
+)	O
+,	O
+but	O
+most	O
+affected	O
+patients	O
+are	O
+not	O
+receiving	O
+these	O
+agents	O
+or	O
+are	O
+being	O
+treated	O
+with	O
+doses	O
+lower	O
+than	O
+those	O
+found	O
+to	O
+be	O
+efficacious	O
+in	O
+trials	O
+,	O
+primarily	O
+because	O
+of	O
+concerns	O
+about	O
+the	O
+safety	O
+and	O
+tolerability	O
+of	O
+these	O
+agents	O
+,	O
+especially	O
+at	O
+the	O
+recommended	O
+doses	O
+.	O
+
+The	O
+present	O
+study	O
+examines	O
+the	O
+safety	O
+and	O
+tolerability	O
+of	O
+high	O
+-	O
+compared	O
+with	O
+low	O
+-	O
+dose	O
+lisinopril	O
+in	O
+CHF	B
+.	O
+
+METHODS	O
+:	O
+The	O
+Assessment	O
+of	O
+Lisinopril	O
+and	O
+Survival	O
+study	O
+was	O
+a	O
+multicenter	O
+,	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+trial	O
+in	O
+which	O
+patients	O
+with	O
+or	O
+without	O
+previous	O
+ACE	O
+inhibitor	O
+treatment	O
+were	O
+stabilized	O
+receiving	O
+medium	O
+-	O
+dose	O
+lisinopril	O
+(	O
+12	O
+.	O
+5	O
+or	O
+15	O
+.	O
+0	O
+mg	O
+once	O
+daily	O
+[	O
+OD	O
+]	O
+)	O
+for	O
+2	O
+to	O
+4	O
+weeks	O
+and	O
+then	O
+randomized	O
+to	O
+high	O
+-	O
+(	O
+35	O
+.	O
+0	O
+or	O
+32	O
+.	O
+5	O
+mg	O
+OD	O
+)	O
+or	O
+low	O
+-	O
+dose	O
+(	O
+5	O
+.	O
+0	O
+or	O
+2	O
+.	O
+5	O
+mg	O
+OD	O
+)	O
+groups	O
+.	O
+
+Patients	O
+with	O
+New	O
+York	O
+Heart	O
+Association	O
+classes	O
+II	O
+to	O
+IV	O
+CHF	B
+and	O
+left	O
+ventricular	O
+ejection	O
+fractions	O
+of	O
+no	O
+greater	O
+than	O
+0	O
+.	O
+30	O
+(	O
+n	O
+=	O
+3164	O
+)	O
+were	O
+randomized	O
+and	O
+followed	O
+up	O
+for	O
+a	O
+median	O
+of	O
+46	O
+months	O
+.	O
+
+We	O
+examined	O
+the	O
+occurrence	O
+of	O
+adverse	O
+events	O
+and	O
+the	O
+need	O
+for	O
+discontinuation	O
+and	O
+dose	O
+reduction	O
+during	O
+treatment	O
+,	O
+with	O
+a	O
+focus	O
+on	O
+hypotension	B
+and	O
+renal	B
+dysfunction	I
+.	O
+
+RESULTS	O
+:	O
+Of	O
+405	O
+patients	O
+not	O
+previously	O
+receiving	O
+an	O
+ACE	O
+inhibitor	O
+,	O
+doses	O
+in	O
+only	O
+4	O
+.	O
+2	O
+%	O
+could	O
+not	O
+be	O
+titrated	O
+to	O
+the	O
+medium	O
+doses	O
+required	O
+for	O
+randomization	O
+because	O
+of	O
+symptoms	O
+possibly	O
+related	O
+to	O
+hypotension	B
+(	O
+2	O
+.	O
+0	O
+%	O
+)	O
+or	O
+because	O
+of	O
+renal	B
+dysfunction	I
+or	O
+hyperkalemia	B
+(	O
+2	O
+.	O
+3	O
+%	O
+)	O
+.	O
+
+Doses	O
+in	O
+more	O
+than	O
+90	O
+%	O
+of	O
+randomized	O
+patients	O
+in	O
+the	O
+high	O
+-	O
+and	O
+low	O
+-	O
+dose	O
+groups	O
+were	O
+titrated	O
+to	O
+their	O
+assigned	O
+target	O
+,	O
+and	O
+the	O
+mean	O
+doses	O
+of	O
+blinded	O
+medication	O
+in	O
+both	O
+groups	O
+remained	O
+similar	O
+throughout	O
+the	O
+study	O
+.	O
+
+Withdrawals	O
+occurred	O
+in	O
+27	O
+.	O
+1	O
+%	O
+of	O
+the	O
+high	O
+-	O
+and	O
+30	O
+.	O
+7	O
+%	O
+of	O
+the	O
+low	O
+-	O
+dose	O
+groups	O
+.	O
+
+Subgroups	O
+presumed	O
+to	O
+be	O
+at	O
+higher	O
+risk	O
+for	O
+ACE	O
+inhibitor	O
+intolerance	O
+(	O
+blood	O
+pressure	O
+,	O
+<	O
+120	O
+mm	O
+Hg	O
+;	O
+creatinine	O
+,	O
+>	O
+or	O
+=	O
+132	O
+.	O
+6	O
+micromol	O
+/	O
+L	O
+[	O
+>	O
+or	O
+=	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+dL	O
+]	O
+;	O
+age	O
+,	O
+>	O
+or	O
+=	O
+70	O
+years	O
+;	O
+and	O
+patients	O
+with	O
+diabetes	B
+)	O
+generally	O
+tolerated	O
+the	O
+high	O
+-	O
+dose	O
+strategy	O
+.	O
+
+CONCLUSIONS	O
+:	O
+These	O
+findings	O
+demonstrate	O
+that	O
+ACE	O
+inhibitor	O
+therapy	O
+in	O
+most	O
+patients	O
+with	O
+CHF	B
+can	O
+be	O
+successfully	O
+titrated	O
+to	O
+and	O
+maintained	O
+at	O
+high	O
+doses	O
+,	O
+and	O
+that	O
+more	O
+aggressive	O
+use	O
+of	O
+these	O
+agents	O
+is	O
+warranted	O
+.	O
+
+Cocaine	O
+,	O
+ethanol	O
+,	O
+and	O
+cocaethylene	O
+cardiotoxity	B
+in	O
+an	O
+animal	O
+model	O
+of	O
+cocaine	B
+and	I
+ethanol	I
+abuse	I
+.	O
+
+OBJECTIVES	O
+:	O
+Simultaneous	O
+abuse	B
+of	I
+cocaine	I
+and	I
+ethanol	I
+affects	O
+12	O
+million	O
+Americans	O
+annually	O
+.	O
+
+In	O
+combination	O
+,	O
+these	O
+substances	O
+are	O
+substantially	O
+more	O
+toxic	O
+than	O
+either	O
+drug	O
+alone	O
+.	O
+
+Their	O
+combined	O
+cardiac	B
+toxicity	I
+may	O
+be	O
+due	O
+to	O
+independent	O
+effects	O
+of	O
+each	O
+drug	O
+;	O
+however	O
+,	O
+they	O
+may	O
+also	O
+be	O
+due	O
+to	O
+cocaethylene	O
+(	O
+CE	O
+)	O
+,	O
+a	O
+cocaine	O
+metabolite	O
+formed	O
+only	O
+in	O
+the	O
+presence	O
+of	O
+ethanol	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+delineate	O
+the	O
+role	O
+of	O
+CE	O
+in	O
+the	O
+combined	O
+cardiotoxicity	B
+of	O
+cocaine	O
+and	O
+ethanol	O
+in	O
+a	O
+model	O
+simulating	O
+their	O
+abuse	O
+.	O
+
+METHODS	O
+:	O
+Twenty	O
+-	O
+three	O
+dogs	O
+were	O
+randomized	O
+to	O
+receive	O
+either	O
+1	O
+)	O
+three	O
+intravenous	O
+(	O
+IV	O
+)	O
+boluses	O
+of	O
+cocaine	O
+7	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+with	O
+ethanol	O
+(	O
+1	O
+g	O
+/	O
+kg	O
+)	O
+as	O
+an	O
+IV	O
+infusion	O
+(	O
+C	O
++	O
+E	O
+,	O
+n	O
+=	O
+8	O
+)	O
+,	O
+2	O
+)	O
+three	O
+cocaine	O
+boluses	O
+only	O
+(	O
+C	O
+,	O
+n	O
+=	O
+6	O
+)	O
+,	O
+3	O
+)	O
+ethanol	O
+infusion	O
+only	O
+(	O
+E	O
+,	O
+n	O
+=	O
+5	O
+)	O
+,	O
+or	O
+4	O
+)	O
+placebo	O
+boluses	O
+and	O
+infusion	O
+(	O
+n	O
+=	O
+4	O
+)	O
+.	O
+
+Hemodynamic	O
+measurements	O
+,	O
+electrocardiograms	O
+,	O
+and	O
+serum	O
+drug	O
+concentrations	O
+were	O
+obtained	O
+at	O
+baseline	O
+,	O
+and	O
+then	O
+at	O
+fixed	O
+time	O
+intervals	O
+after	O
+each	O
+drug	O
+was	O
+administered	O
+.	O
+
+RESULTS	O
+:	O
+Two	O
+of	O
+eight	O
+dogs	O
+in	O
+the	O
+C	O
++	O
+E	O
+group	O
+experienced	O
+cardiovascular	B
+collapse	I
+.	O
+
+The	O
+most	O
+dramatic	O
+hemodynamic	O
+changes	O
+occurred	O
+after	O
+each	O
+cocaine	O
+bolus	O
+in	O
+the	O
+C	O
++	O
+E	O
+and	O
+C	O
+only	O
+groups	O
+;	O
+however	O
+,	O
+persistent	O
+hemodynamic	O
+changes	O
+occurred	O
+in	O
+the	O
+C	O
++	O
+E	O
+group	O
+.	O
+
+Peak	O
+CE	O
+levels	O
+were	O
+associated	O
+with	O
+a	O
+45	O
+%	O
+(	O
+SD	O
++	O
+/	O
+-	O
+22	O
+%	O
+,	O
+95	O
+%	O
+CI	O
+=	O
+22	O
+%	O
+to	O
+69	O
+%	O
+)	O
+decrease	B
+in	I
+cardiac	I
+output	I
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+,	O
+a	O
+56	O
+%	O
+(	O
+SD	O
++	O
+/	O
+-	O
+23	O
+%	O
+,	O
+95	O
+%	O
+CI	O
+=	O
+32	O
+%	O
+to	O
+80	O
+%	O
+)	O
+decrease	O
+in	O
+dP	O
+/	O
+dt	O
+(	O
+max	O
+)	O
+(	O
+p	O
+<	O
+.	O
+006	O
+)	O
+,	O
+and	O
+a	O
+23	O
+%	O
+(	O
+SD	O
++	O
+/	O
+-	O
+15	O
+%	O
+,	O
+95	O
+%	O
+CI	O
+=	O
+7	O
+%	O
+to	O
+49	O
+%	O
+)	O
+decrease	O
+in	O
+SVO	O
+(	O
+2	O
+)	O
+(	O
+p	O
+<	O
+0	O
+.	O
+025	O
+)	O
+.	O
+
+Ventricular	B
+arrhythmias	I
+were	O
+primarily	O
+observed	O
+in	O
+the	O
+C	O
++	O
+E	O
+group	O
+,	O
+in	O
+which	O
+four	O
+of	O
+eight	O
+dogs	O
+experienced	O
+ventricular	B
+tachycardia	I
+.	O
+
+CONCLUSIONS	O
+:	O
+Cocaine	O
+and	O
+ethanol	O
+in	O
+combination	O
+were	O
+more	O
+toxic	O
+than	O
+either	O
+substance	O
+alone	O
+.	O
+
+Co	O
+-	O
+administration	O
+resulted	O
+in	O
+prolonged	O
+cardiac	B
+toxicity	I
+and	O
+was	O
+dysrhythmogenic	O
+.	O
+
+Peak	O
+serum	O
+cocaethylene	O
+concentrations	O
+were	O
+associated	O
+with	O
+prolonged	O
+myocardial	B
+depression	I
+.	O
+
+Worsening	O
+of	O
+Parkinsonism	B
+after	O
+the	O
+use	O
+of	O
+veralipride	O
+for	O
+treatment	O
+of	O
+menopause	O
+:	O
+case	O
+report	O
+.	O
+
+We	O
+describe	O
+a	O
+female	O
+patient	O
+with	O
+stable	O
+Parkinson	B
+'	I
+s	I
+disease	I
+who	O
+has	O
+shown	O
+a	O
+marked	O
+worsening	O
+of	O
+her	O
+motor	O
+functions	O
+following	O
+therapy	O
+of	O
+menopause	O
+related	O
+symptoms	O
+with	O
+veralipride	O
+,	O
+as	O
+well	O
+as	O
+the	O
+improvement	O
+of	O
+her	O
+symptoms	O
+back	O
+to	O
+baseline	O
+after	O
+discontinuation	O
+of	O
+the	O
+drug	O
+.	O
+
+We	O
+emphasize	O
+the	O
+anti	O
+-	O
+dopaminergic	O
+effect	O
+of	O
+veralipride	O
+.	O
+
+Viracept	O
+and	O
+irregular	B
+heartbeat	I
+warning	O
+.	O
+
+A	O
+group	O
+of	O
+doctors	O
+in	O
+Boston	O
+warn	O
+that	O
+the	O
+protease	O
+inhibitor	O
+Viracept	O
+may	O
+cause	O
+an	O
+irregular	B
+heart	I
+beat	I
+,	O
+known	O
+as	O
+bradycardia	B
+,	O
+in	O
+people	O
+with	O
+HIV	O
+.	O
+
+Bradycardia	B
+occurred	O
+in	O
+a	O
+45	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+who	O
+was	O
+Viracept	O
+in	O
+combination	O
+with	O
+other	O
+anti	O
+-	O
+HIV	O
+drugs	O
+.	O
+
+The	O
+symptoms	O
+ceased	O
+after	O
+switching	O
+to	O
+another	O
+drug	O
+combination	O
+.	O
+
+Frequency	O
+of	O
+appearance	O
+of	O
+myeloperoxidase	O
+-	O
+antineutrophil	O
+cytoplasmic	O
+antibody	O
+(	O
+MPO	O
+-	O
+ANCA	O
+)	O
+in	O
+Graves	B
+'	I
+disease	I
+patients	O
+treated	O
+with	O
+propylthiouracil	O
+and	O
+the	O
+relationship	O
+between	O
+MPO	O
+-	O
+ANCA	O
+and	O
+clinical	O
+manifestations	O
+.	O
+
+OBJECTIVE	O
+:	O
+Myeloperoxidase	O
+antineutrophil	O
+cytoplasmic	O
+antibody	O
+(	O
+MPO	O
+-	O
+ANCA	O
+)	O
+-	O
+positive	O
+vasculitis	B
+has	O
+been	O
+reported	O
+in	O
+patients	O
+with	O
+Graves	B
+'	I
+disease	I
+who	O
+were	O
+treated	O
+with	O
+propylthiouracil	O
+(	O
+PTU	O
+)	O
+.	O
+
+The	O
+appearance	O
+of	O
+MPO	O
+-	O
+ANCA	O
+in	O
+these	O
+cases	O
+was	O
+suspected	O
+of	O
+being	O
+related	O
+to	O
+PTU	O
+because	O
+the	O
+titres	O
+of	O
+MPO	O
+-	O
+ANCA	O
+decreased	O
+when	O
+PTU	O
+was	O
+stopped	O
+.	O
+
+Nevertheless	O
+,	O
+there	O
+have	O
+been	O
+no	O
+studies	O
+on	O
+the	O
+temporal	O
+relationship	O
+between	O
+the	O
+appearance	O
+of	O
+MPO	O
+-	O
+ANCA	O
+and	O
+vasculitis	B
+during	O
+PTU	O
+therapy	O
+,	O
+or	O
+on	O
+the	O
+incidence	O
+of	O
+MPO	O
+-	O
+ANCA	O
+in	O
+untreated	O
+Graves	B
+'	I
+disease	I
+patients	O
+.	O
+
+Therefore	O
+,	O
+we	O
+sought	O
+to	O
+address	O
+these	O
+parameters	O
+in	O
+patients	O
+with	O
+Graves	B
+'	I
+disease	I
+.	O
+
+PATIENTS	O
+:	O
+We	O
+investigated	O
+102	O
+untreated	O
+patients	O
+with	O
+hyperthyroidism	B
+due	O
+to	O
+Graves	B
+'	I
+disease	I
+for	O
+the	O
+presence	O
+of	O
+MPO	O
+-	O
+ANCA	O
+,	O
+and	O
+for	O
+the	O
+development	O
+vasculitis	B
+after	O
+starting	O
+PTU	O
+therapy	O
+.	O
+
+Twenty	O
+-	O
+nine	O
+of	O
+them	O
+were	O
+later	O
+excluded	O
+because	O
+of	O
+adverse	O
+effects	O
+of	O
+PTU	O
+or	O
+because	O
+the	O
+observation	O
+period	O
+was	O
+less	O
+than	O
+3	O
+months	O
+.	O
+
+The	O
+remaining	O
+73	O
+patients	O
+(	O
+55	O
+women	O
+and	O
+18	O
+men	O
+)	O
+,	O
+all	O
+of	O
+whom	O
+were	O
+examined	O
+for	O
+more	O
+than	O
+3	O
+months	O
+,	O
+were	O
+adopted	O
+as	O
+the	O
+subjects	O
+of	O
+the	O
+investigation	O
+.	O
+
+The	O
+median	O
+observation	O
+period	O
+was	O
+23	O
+.	O
+6	O
+months	O
+(	O
+range	O
+:	O
+3	O
+-	O
+37	O
+months	O
+)	O
+.	O
+
+MEASUREMENTS	O
+:	O
+MPO	O
+-	O
+ANCA	O
+was	O
+measured	O
+at	O
+intervals	O
+of	O
+2	O
+-	O
+6	O
+months	O
+.	O
+
+RESULTS	O
+:	O
+Before	O
+treatment	O
+,	O
+the	O
+MPO	O
+-	O
+ANCA	O
+titres	O
+of	O
+all	O
+102	O
+untreated	O
+Graves	B
+'	I
+disease	I
+patients	O
+were	O
+within	O
+the	O
+reference	O
+range	O
+(	O
+below	O
+10	O
+U	O
+/	O
+ml	O
+)	O
+.	O
+
+Three	O
+(	O
+4	O
+.	O
+1	O
+%	O
+)	O
+of	O
+the	O
+73	O
+patients	O
+were	O
+positive	O
+for	O
+MPO	O
+-	O
+ANCA	O
+at	O
+13	O
+,	O
+16	O
+and	O
+17	O
+months	O
+,	O
+respectively	O
+,	O
+after	O
+the	O
+start	O
+of	O
+PTU	O
+therapy	O
+.	O
+
+In	O
+two	O
+of	O
+them	O
+,	O
+the	O
+MPO	O
+-	O
+ANCA	O
+titres	O
+transiently	O
+increased	O
+to	O
+12	O
+.	O
+8	O
+and	O
+15	O
+.	O
+0	O
+U	O
+/	O
+ml	O
+,	O
+respectively	O
+,	O
+despite	O
+continued	O
+PTU	O
+therapy	O
+,	O
+but	O
+no	O
+vasculitic	B
+disorders	I
+developed	O
+.	O
+
+In	O
+the	O
+third	O
+patient	O
+,	O
+the	O
+MPO	O
+-	O
+ANCA	O
+titre	O
+increased	O
+to	O
+204	O
+U	O
+/	O
+ml	O
+and	O
+she	O
+developed	O
+a	O
+higher	O
+fever	B
+,	O
+oral	B
+ulcers	I
+and	O
+polyarthralgia	B
+,	O
+but	O
+the	O
+symptoms	O
+resolved	O
+2	O
+weeks	O
+after	O
+stopping	O
+PTU	O
+therapy	O
+,	O
+and	O
+the	O
+MPO	O
+-	O
+ANCA	O
+titre	O
+decreased	O
+to	O
+20	O
+.	O
+7	O
+U	O
+/	O
+ml	O
+by	O
+4	O
+months	O
+after	O
+discontinuing	O
+PTU	O
+.	O
+
+CONCLUSIONS	O
+:	O
+PTU	O
+therapy	O
+may	O
+be	O
+related	O
+to	O
+the	O
+appearance	O
+of	O
+MPO	O
+-	O
+ANCA	O
+,	O
+but	O
+MPO	O
+-	O
+ANCA	O
+does	O
+not	O
+appear	O
+to	O
+be	O
+closely	O
+related	O
+to	O
+vasculitis	B
+.	O
+
+Prevalence	O
+of	O
+heart	B
+disease	I
+in	O
+asymptomatic	O
+chronic	O
+cocaine	O
+users	O
+.	O
+
+To	O
+determine	O
+the	O
+prevalence	O
+of	O
+heart	B
+disease	I
+in	O
+outpatient	O
+young	O
+asymptomatic	O
+chronic	O
+cocaine	O
+users	O
+,	O
+35	O
+cocaine	O
+users	O
+and	O
+32	O
+age	O
+-	O
+matched	O
+controls	O
+underwent	O
+resting	O
+and	O
+exercise	O
+electrocardiography	O
+(	O
+ECG	O
+)	O
+and	O
+Doppler	O
+echocardiography	O
+.	O
+
+Findings	O
+consistent	O
+with	O
+coronary	B
+artery	I
+disease	I
+were	O
+detected	O
+in	O
+12	O
+(	O
+34	O
+%	O
+)	O
+patients	O
+and	O
+3	O
+(	O
+9	O
+%	O
+)	O
+controls	O
+(	O
+p	O
+=	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+Decreased	O
+left	O
+ventricular	O
+systolic	O
+function	O
+was	O
+demonstrated	O
+in	O
+5	O
+(	O
+14	O
+%	O
+)	O
+patients	O
+,	O
+but	O
+in	O
+none	O
+of	O
+the	O
+controls	O
+(	O
+p	O
+=	O
+0	O
+.	O
+055	O
+)	O
+.	O
+
+Finally	O
+,	O
+resting	O
+and	O
+peak	O
+exercise	O
+abnormal	B
+left	I
+ventricular	I
+filling	I
+was	O
+detected	O
+in	O
+38	O
+and	O
+35	O
+%	O
+of	O
+patients	O
+as	O
+compared	O
+to	O
+19	O
+and	O
+9	O
+%	O
+of	O
+controls	O
+,	O
+respectively	O
+(	O
+p	O
+=	O
+0	O
+.	O
+11	O
+and	O
+0	O
+.	O
+02	O
+,	O
+respectively	O
+)	O
+.	O
+
+We	O
+conclude	O
+that	O
+coronary	B
+artery	I
+or	I
+myocardial	I
+disease	I
+is	O
+common	O
+(	O
+38	O
+%	O
+)	O
+in	O
+young	O
+asymptomatic	O
+chronic	O
+cocaine	O
+users	O
+.	O
+
+Therefore	O
+,	O
+screening	O
+ECG	O
+and	O
+echocardiography	O
+may	O
+be	O
+warranted	O
+in	O
+these	O
+patients	O
+.	O
+
+Cardioprotective	O
+effects	O
+of	O
+Picrorrhiza	O
+kurroa	O
+against	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	O
+stress	O
+in	O
+rats	O
+.	O
+
+The	O
+cardioprotective	O
+effect	O
+of	O
+the	O
+ethanol	O
+extract	O
+of	O
+Picrorrhiza	O
+kurroa	O
+rhizomes	O
+and	O
+roots	O
+(	O
+PK	O
+)	O
+on	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+in	O
+rats	O
+with	O
+respect	O
+to	O
+lipid	O
+metabolism	O
+in	O
+serum	O
+and	O
+heart	O
+tissue	O
+has	O
+been	O
+investigated	O
+.	O
+
+Oral	O
+pre	O
+-	O
+treatment	O
+with	O
+PK	O
+(	O
+80	O
+mg	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+day	O
+(	O
+-	O
+1	O
+)	O
+for	O
+15	O
+days	O
+)	O
+significantly	O
+prevented	O
+the	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+and	O
+maintained	O
+the	O
+rats	O
+at	O
+near	O
+normal	O
+status	O
+.	O
+
+Phase	O
+2	O
+early	O
+afterdepolarization	O
+as	O
+a	O
+trigger	O
+of	O
+polymorphic	O
+ventricular	B
+tachycardia	I
+in	O
+acquired	O
+long	B
+-	I
+QT	I
+syndrome	I
+:	O
+direct	O
+evidence	O
+from	O
+intracellular	O
+recordings	O
+in	O
+the	O
+intact	O
+left	O
+ventricular	O
+wall	O
+.	O
+
+BACKGROUND	O
+:	O
+This	O
+study	O
+examined	O
+the	O
+role	O
+of	O
+phase	O
+2	O
+early	O
+afterdepolarization	O
+(	O
+EAD	O
+)	O
+in	O
+producing	O
+a	O
+trigger	O
+to	O
+initiate	O
+torsade	B
+de	I
+pointes	I
+(	O
+TdP	B
+)	O
+with	O
+QT	B
+prolongation	I
+induced	O
+by	O
+dl	O
+-	O
+sotalol	O
+and	O
+azimilide	O
+.	O
+
+The	O
+contribution	O
+of	O
+transmural	O
+dispersion	O
+of	O
+repolarization	O
+(	O
+TDR	O
+)	O
+to	O
+transmural	O
+propagation	O
+of	O
+EAD	O
+and	O
+the	O
+maintenance	O
+of	O
+TdP	B
+was	O
+also	O
+evaluated	O
+.	O
+
+METHODS	O
+AND	O
+RESULTS	O
+:	O
+Transmembrane	O
+action	O
+potentials	O
+from	O
+epicardium	O
+,	O
+midmyocardium	O
+,	O
+and	O
+endocardium	O
+were	O
+recorded	O
+simultaneously	O
+,	O
+together	O
+with	O
+a	O
+transmural	O
+ECG	O
+,	O
+in	O
+arterially	O
+perfused	O
+canine	O
+and	O
+rabbit	O
+left	O
+ventricular	O
+preparations	O
+.	O
+
+dl	O
+-	O
+Sotalol	O
+preferentially	O
+prolonged	O
+action	O
+potential	O
+duration	O
+(	O
+APD	O
+)	O
+in	O
+M	O
+cells	O
+dose	O
+-	O
+dependently	O
+(	O
+1	O
+to	O
+100	O
+micromol	O
+/	O
+L	O
+)	O
+,	O
+leading	O
+to	O
+QT	B
+prolongation	I
+and	O
+an	O
+increase	O
+in	O
+TDR	O
+.	O
+
+Azimilide	O
+,	O
+however	O
+,	O
+significantly	O
+prolonged	O
+APD	O
+and	O
+QT	O
+interval	O
+at	O
+concentrations	O
+from	O
+0	O
+.	O
+1	O
+to	O
+10	O
+micromol	O
+/	O
+L	O
+but	O
+shortened	O
+them	O
+at	O
+30	O
+micromol	O
+/	O
+L	O
+.	O
+
+Unlike	O
+dl	O
+-	O
+sotalol	O
+,	O
+azimilide	O
+(	O
+>	O
+3	O
+micromol	O
+/	O
+L	O
+)	O
+increased	O
+epicardial	O
+APD	O
+markedly	O
+,	O
+causing	O
+a	O
+diminished	O
+TDR	O
+.	O
+
+Although	O
+both	O
+dl	O
+-	O
+sotalol	O
+and	O
+azimilide	O
+rarely	O
+induced	O
+EADs	O
+in	O
+canine	O
+left	O
+ventricles	O
+,	O
+they	O
+produced	O
+frequent	O
+EADs	O
+in	O
+rabbits	O
+,	O
+in	O
+which	O
+more	O
+pronounced	O
+QT	B
+prolongation	I
+was	O
+seen	O
+.	O
+
+An	O
+increase	O
+in	O
+TDR	O
+by	O
+dl	O
+-	O
+sotalol	O
+facilitated	O
+transmural	O
+propagation	O
+of	O
+EADs	O
+that	O
+initiated	O
+multiple	O
+episodes	O
+of	O
+spontaneous	O
+TdP	B
+in	O
+3	O
+of	O
+6	O
+rabbit	O
+left	O
+ventricles	O
+.	O
+
+Of	O
+note	O
+,	O
+although	O
+azimilide	O
+(	O
+3	O
+to	O
+10	O
+micromol	O
+/	O
+L	O
+)	O
+increased	O
+APD	O
+more	O
+than	O
+dl	O
+-	O
+sotalol	O
+,	O
+its	O
+EADs	O
+often	O
+failed	O
+to	O
+propagate	O
+transmurally	O
+,	O
+probably	O
+because	O
+of	O
+a	O
+diminished	O
+TDR	O
+.	O
+
+CONCLUSIONS	O
+:	O
+This	O
+study	O
+provides	O
+the	O
+first	O
+direct	O
+evidence	O
+from	O
+intracellular	O
+action	O
+potential	O
+recordings	O
+that	O
+phase	O
+2	O
+EAD	O
+can	O
+be	O
+generated	O
+from	O
+intact	O
+ventricular	O
+wall	O
+and	O
+produce	O
+a	O
+trigger	O
+to	O
+initiate	O
+the	O
+onset	O
+of	O
+TdP	B
+under	O
+QT	B
+prolongation	I
+.	O
+
+A	O
+pilot	O
+study	O
+to	O
+assess	O
+the	O
+safety	O
+of	O
+dobutamine	O
+stress	O
+echocardiography	O
+in	O
+the	O
+emergency	O
+department	O
+evaluation	O
+of	O
+cocaine	O
+-	O
+associated	O
+chest	B
+pain	I
+.	O
+
+STUDY	O
+OBJECTIVE	O
+:	O
+Chest	B
+pain	I
+in	O
+the	O
+setting	O
+of	O
+cocaine	O
+use	O
+poses	O
+a	O
+diagnostic	O
+dilemma	O
+.	O
+
+Dobutamine	O
+stress	O
+echocardiography	O
+(	O
+DSE	O
+)	O
+is	O
+a	O
+widely	O
+available	O
+and	O
+sensitive	O
+test	O
+for	O
+evaluating	O
+cardiac	O
+ischemia	B
+.	O
+
+Because	O
+of	O
+the	O
+theoretical	O
+concern	O
+regarding	O
+administration	O
+of	O
+dobutamine	O
+in	O
+the	O
+setting	O
+of	O
+cocaine	O
+use	O
+,	O
+we	O
+conducted	O
+a	O
+pilot	O
+study	O
+to	O
+assess	O
+the	O
+safety	O
+of	O
+DSE	O
+in	O
+emergency	O
+department	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B
+pain	I
+.	O
+
+METHODS	O
+:	O
+A	O
+prospective	O
+case	O
+series	O
+was	O
+conducted	O
+in	O
+the	O
+intensive	O
+diagnostic	O
+and	O
+treatment	O
+unit	O
+in	O
+the	O
+ED	O
+of	O
+an	O
+urban	O
+tertiary	O
+-	O
+care	O
+teaching	O
+hospital	O
+.	O
+
+Patients	O
+were	O
+eligible	O
+for	O
+DSE	O
+if	O
+they	O
+had	O
+used	O
+cocaine	O
+within	O
+24	O
+hours	O
+preceding	O
+the	O
+onset	O
+of	O
+chest	B
+pain	I
+and	O
+had	O
+a	O
+normal	O
+ECG	O
+and	O
+tropinin	O
+I	O
+level	O
+.	O
+
+Patients	O
+exhibiting	O
+signs	O
+of	O
+continuing	O
+cocaine	O
+toxicity	B
+were	O
+excluded	O
+from	O
+the	O
+study	O
+.	O
+
+All	O
+patients	O
+were	O
+admitted	O
+to	O
+the	O
+hospital	O
+for	O
+serial	O
+testing	O
+after	O
+the	O
+DSE	O
+testing	O
+in	O
+the	O
+intensive	O
+diagnostic	O
+and	O
+treatment	O
+unit	O
+.	O
+
+RESULTS	O
+:	O
+Twenty	O
+-	O
+four	O
+patients	O
+were	O
+enrolled	O
+.	O
+
+Two	O
+patients	O
+had	O
+inadequate	O
+resting	O
+images	O
+,	O
+one	O
+DSE	O
+was	O
+terminated	O
+because	O
+of	O
+inferior	O
+hypokinesis	B
+,	O
+another	O
+DSE	O
+was	O
+terminated	O
+because	O
+of	O
+a	O
+rate	O
+-	O
+related	O
+atrial	O
+conduction	O
+deficit	O
+,	O
+and	O
+1	O
+patient	O
+did	O
+not	O
+reach	O
+the	O
+target	O
+heart	O
+rate	O
+.	O
+
+Thus	O
+,	O
+19	O
+patients	O
+completed	O
+a	O
+DSE	O
+and	O
+reached	O
+their	O
+target	O
+heart	O
+rates	O
+.	O
+
+None	O
+of	O
+the	O
+patients	O
+experienced	O
+signs	O
+of	O
+exaggerated	O
+adrenergic	O
+response	O
+,	O
+which	O
+was	O
+defined	O
+as	O
+a	O
+systolic	O
+blood	O
+pressure	O
+of	O
+greater	O
+than	O
+200	O
+mm	O
+Hg	O
+or	O
+the	O
+occurrence	O
+of	O
+tachydysrhythmias	B
+(	O
+excluding	O
+sinus	B
+tachycardia	I
+)	O
+.	O
+
+Further	O
+suggesting	O
+lack	O
+of	O
+exaggerated	O
+adrenergic	O
+response	O
+,	O
+13	O
+(	O
+65	O
+%	O
+)	O
+of	O
+20	O
+patients	O
+required	O
+supplemental	O
+atropine	O
+to	O
+reach	O
+their	O
+target	O
+heart	O
+rates	O
+.	O
+
+CONCLUSION	O
+:	O
+No	O
+exaggerated	O
+adrenergic	O
+response	O
+was	O
+detected	O
+when	O
+dobutamine	O
+was	O
+administered	O
+to	O
+patients	O
+with	O
+cocaine	O
+-	O
+related	O
+chest	B
+pain	I
+.	O
+
+Prenatal	O
+cocaine	O
+exposure	O
+and	O
+cranial	O
+sonographic	O
+findings	O
+in	O
+preterm	B
+infants	I
+.	O
+
+PURPOSE	O
+:	O
+Prenatal	O
+cocaine	O
+exposure	O
+has	O
+been	O
+linked	O
+with	O
+subependymal	O
+hemorrhage	B
+and	O
+the	O
+formation	O
+of	O
+cysts	B
+that	O
+are	O
+detectable	O
+on	O
+cranial	O
+sonography	O
+in	O
+neonates	O
+born	O
+at	O
+term	O
+.	O
+
+We	O
+sought	O
+to	O
+determine	O
+if	O
+prenatal	O
+cocaine	O
+exposure	O
+increases	O
+the	O
+incidence	O
+of	O
+subependymal	B
+cysts	I
+in	O
+preterm	B
+infants	I
+.	O
+
+METHODS	O
+:	O
+We	O
+retrospectively	O
+reviewed	O
+the	O
+medical	O
+records	O
+and	O
+cranial	O
+sonograms	O
+obtained	O
+during	O
+a	O
+1	O
+-	O
+year	O
+period	O
+on	O
+122	O
+premature	B
+(	I
+<	I
+36	I
+weeks	I
+of	I
+gestation	I
+)	I
+infants	I
+.	O
+
+Infants	O
+were	O
+categorized	O
+into	O
+1	O
+of	O
+2	O
+groups	O
+:	O
+those	O
+exposed	O
+to	O
+cocaine	O
+and	O
+those	O
+not	O
+exposed	O
+to	O
+cocaine	O
+.	O
+
+Infants	O
+were	O
+assigned	O
+to	O
+the	O
+cocaine	O
+-	O
+exposed	O
+group	O
+if	O
+there	O
+was	O
+a	O
+maternal	O
+history	O
+of	O
+cocaine	B
+abuse	I
+during	O
+pregnancy	O
+or	O
+if	O
+maternal	O
+or	O
+neonatal	O
+urine	O
+toxicology	O
+results	O
+were	O
+positive	O
+at	O
+the	O
+time	O
+of	O
+delivery	O
+.	O
+
+RESULTS	O
+:	O
+Five	O
+of	O
+the	O
+122	O
+infants	O
+were	O
+excluded	O
+from	O
+the	O
+study	O
+because	O
+of	O
+insufficient	O
+medical	O
+and	O
+drug	O
+histories	O
+.	O
+
+The	O
+incidence	O
+of	O
+subependymal	B
+cysts	I
+in	O
+the	O
+117	O
+remaining	O
+infants	O
+was	O
+14	O
+%	O
+(	O
+16	O
+of	O
+117	O
+)	O
+.	O
+
+The	O
+incidence	O
+of	O
+subependymal	B
+cysts	I
+in	O
+infants	O
+exposed	O
+to	O
+cocaine	O
+prenatally	O
+was	O
+44	O
+%	O
+(	O
+8	O
+of	O
+18	O
+)	O
+compared	O
+with	O
+8	O
+%	O
+(	O
+8	O
+of	O
+99	O
+)	O
+in	O
+the	O
+unexposed	O
+group	O
+(	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+We	O
+found	O
+an	O
+increased	O
+incidence	O
+of	O
+subependymal	B
+cyst	I
+formation	O
+in	O
+preterm	B
+infants	I
+who	O
+were	O
+exposed	O
+to	O
+cocaine	O
+prenatally	O
+.	O
+
+This	O
+result	O
+is	O
+consistent	O
+with	O
+results	O
+of	O
+similar	O
+studies	O
+in	O
+term	O
+infants	O
+.	O
+
+Thalidomide	O
+neuropathy	B
+in	O
+patients	O
+treated	O
+for	O
+metastatic	O
+prostate	B
+cancer	I
+.	O
+
+We	O
+prospectively	O
+evaluated	O
+thalidomide	O
+-	O
+induced	O
+neuropathy	B
+using	O
+electrodiagnostic	O
+studies	O
+.	O
+
+Sixty	O
+-	O
+seven	O
+men	O
+with	O
+metastatic	O
+androgen	O
+-	O
+independent	O
+prostate	B
+cancer	I
+in	O
+an	O
+open	O
+-	O
+label	O
+trial	O
+of	O
+oral	O
+thalidomide	O
+underwent	O
+neurologic	O
+examinations	O
+and	O
+nerve	O
+conduction	O
+studies	O
+(	O
+NCS	O
+)	O
+prior	O
+to	O
+and	O
+at	O
+3	O
+-	O
+month	O
+intervals	O
+during	O
+treatment	O
+.	O
+
+NCS	O
+included	O
+recording	O
+of	O
+sensory	O
+nerve	O
+action	O
+potentials	O
+(	O
+SNAPs	O
+)	O
+from	O
+median	O
+,	O
+radial	O
+,	O
+ulnar	O
+,	O
+and	O
+sural	O
+nerves	O
+.	O
+
+SNAP	O
+amplitudes	O
+for	O
+each	O
+nerve	O
+were	O
+expressed	O
+as	O
+the	O
+percentage	O
+of	O
+its	O
+baseline	O
+,	O
+and	O
+the	O
+mean	O
+of	O
+the	O
+four	O
+was	O
+termed	O
+the	O
+SNAP	O
+index	O
+.	O
+
+A	O
+40	O
+%	O
+decline	O
+in	O
+the	O
+SNAP	O
+index	O
+was	O
+considered	O
+clinically	O
+significant	O
+.	O
+
+Thalidomide	O
+was	O
+discontinued	O
+in	O
+55	O
+patients	O
+for	O
+lack	O
+of	O
+therapeutic	O
+response	O
+.	O
+
+Of	O
+67	O
+patients	O
+initially	O
+enrolled	O
+,	O
+24	O
+remained	O
+on	O
+thalidomide	O
+for	O
+3	O
+months	O
+,	O
+8	O
+remained	O
+at	O
+6	O
+months	O
+,	O
+and	O
+3	O
+remained	O
+at	O
+9	O
+months	O
+.	O
+
+Six	O
+patients	O
+developed	O
+neuropathy	B
+.	O
+
+Clinical	O
+symptoms	O
+and	O
+a	O
+decline	O
+in	O
+the	O
+SNAP	O
+index	O
+occurred	O
+concurrently	O
+.	O
+
+Older	O
+age	O
+and	O
+cumulative	O
+dose	O
+were	O
+possible	O
+contributing	O
+factors	O
+.	O
+
+Neuropathy	B
+may	O
+thus	O
+be	O
+a	O
+common	O
+complication	O
+of	O
+thalidomide	O
+in	O
+older	O
+patients	O
+.	O
+
+The	O
+SNAP	O
+index	O
+can	O
+be	O
+used	O
+to	O
+monitor	O
+peripheral	B
+neuropathy	I
+,	O
+but	O
+not	O
+for	O
+early	O
+detection	O
+.	O
+
+Overexpression	O
+of	O
+copper	O
+/	O
+zinc	O
+-	O
+superoxide	O
+dismutase	O
+protects	O
+from	O
+kanamycin	O
+-	O
+induced	O
+hearing	B
+loss	I
+.	O
+
+The	O
+participation	O
+of	O
+reactive	O
+oxygen	O
+species	O
+in	O
+aminoglycoside	O
+-	O
+induced	O
+ototoxicity	B
+has	O
+been	O
+deduced	O
+from	O
+observations	O
+that	O
+aminoglycoside	O
+-	O
+iron	O
+complexes	O
+catalyze	O
+the	O
+formation	O
+of	O
+superoxide	O
+radicals	O
+in	O
+vitro	O
+and	O
+that	O
+antioxidants	O
+attenuate	O
+ototoxicity	B
+in	O
+vivo	O
+.	O
+
+We	O
+therefore	O
+hypothesized	O
+that	O
+overexpression	O
+of	O
+Cu	O
+/	O
+Zn	O
+-	O
+superoxide	O
+dismutase	O
+(	O
+h	O
+-	O
+SOD1	O
+)	O
+should	O
+protect	O
+transgenic	O
+mice	O
+from	O
+ototoxicity	B
+.	O
+
+Immunocytochemistry	O
+confirmed	O
+expression	O
+of	O
+h	O
+-	O
+SOD1	O
+in	O
+inner	O
+ear	O
+tissues	O
+of	O
+transgenic	O
+C57BL	O
+/	O
+6	O
+-	O
+TgN	O
+[	O
+SOD1	O
+]	O
+3Cje	O
+mice	O
+.	O
+
+Transgenic	O
+and	O
+nontransgenic	O
+littermates	O
+received	O
+kanamycin	O
+(	O
+400	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+/	O
+day	O
+)	O
+for	O
+10	O
+days	O
+beginning	O
+on	O
+day	O
+10	O
+after	O
+birth	O
+.	O
+
+Auditory	O
+thresholds	O
+were	O
+tested	O
+by	O
+evoked	O
+auditory	O
+brain	O
+stem	O
+responses	O
+at	O
+1	O
+month	O
+after	O
+birth	O
+.	O
+
+In	O
+nontransgenic	O
+animals	O
+,	O
+the	O
+threshold	O
+in	O
+the	O
+kanamycin	O
+-	O
+treated	O
+group	O
+was	O
+45	O
+-	O
+50	O
+dB	O
+higher	O
+than	O
+in	O
+saline	O
+-	O
+injected	O
+controls	O
+.	O
+
+In	O
+the	O
+transgenic	O
+group	O
+,	O
+kanamycin	O
+increased	O
+the	O
+threshold	O
+by	O
+only	O
+15	O
+dB	O
+over	O
+the	O
+respective	O
+controls	O
+.	O
+
+The	O
+effects	O
+were	O
+similar	O
+at	O
+12	O
+and	O
+24	O
+kHz	O
+.	O
+
+The	O
+protection	O
+by	O
+overexpression	O
+of	O
+superoxide	O
+dismutase	O
+supports	O
+the	O
+hypothesis	O
+that	O
+oxidant	O
+stress	O
+plays	O
+a	O
+significant	O
+role	O
+in	O
+aminoglycoside	O
+-	O
+induced	O
+ototoxicity	B
+.	O
+
+The	O
+results	O
+also	O
+suggest	O
+transgenic	O
+animals	O
+as	O
+suitable	O
+models	O
+to	O
+investigate	O
+the	O
+underlying	O
+mechanisms	O
+and	O
+possible	O
+strategies	O
+for	O
+prevention	O
+.	O
+
+Fatty	B
+liver	I
+induced	O
+by	O
+tetracycline	O
+in	O
+the	O
+rat	O
+.	O
+
+Dose	O
+-	O
+response	O
+relationships	O
+and	O
+effect	O
+of	O
+sex	O
+.	O
+
+Dose	O
+-	O
+response	O
+relationships	O
+,	O
+biochemical	O
+mechanisms	O
+,	O
+and	O
+sex	O
+differences	O
+in	O
+the	O
+experimental	O
+fatty	B
+liver	I
+induced	O
+by	O
+tetracycline	O
+were	O
+studied	O
+in	O
+the	O
+intact	O
+rat	O
+and	O
+with	O
+the	O
+isolated	O
+perfused	O
+rat	O
+liver	O
+in	O
+vitro	O
+.	O
+
+In	O
+the	O
+intact	O
+male	O
+and	O
+female	O
+rat	O
+,	O
+no	O
+direct	O
+relationship	O
+was	O
+observed	O
+between	O
+dose	O
+of	O
+tetracycline	O
+and	O
+hepatic	O
+accumulation	O
+of	O
+triglyceride	O
+.	O
+
+With	O
+provision	O
+of	O
+adequate	O
+oleic	O
+acid	O
+as	O
+a	O
+substrate	O
+for	O
+the	O
+isolated	O
+perfused	O
+liver	O
+,	O
+a	O
+direct	O
+relationship	O
+was	O
+observed	O
+between	O
+dose	O
+of	O
+tetracycline	O
+and	O
+both	O
+accumulation	O
+of	O
+triglyceride	O
+in	O
+the	O
+liver	O
+and	O
+depression	B
+of	O
+output	O
+of	O
+triglyceride	O
+by	O
+livers	O
+from	O
+male	O
+and	O
+female	O
+rats	O
+.	O
+
+Marked	O
+differences	O
+were	O
+observed	O
+between	O
+female	O
+and	O
+male	O
+rats	O
+with	O
+regard	O
+to	O
+base	O
+line	O
+(	O
+control	O
+)	O
+hepatic	O
+concentration	O
+of	O
+triglyceride	O
+and	O
+output	O
+of	O
+triglyceride	O
+.	O
+
+Accumulation	O
+of	O
+hepatic	O
+triglyceride	O
+,	O
+as	O
+a	O
+per	O
+cent	O
+of	O
+control	O
+values	O
+,	O
+in	O
+response	O
+to	O
+graded	O
+doses	O
+of	O
+tetracycline	O
+,	O
+did	O
+not	O
+differ	O
+significantly	O
+between	O
+male	O
+,	O
+female	O
+and	O
+pregnant	O
+rat	O
+livers	O
+.	O
+
+However	O
+,	O
+livers	O
+from	O
+female	O
+,	O
+and	O
+especially	O
+pregnant	O
+female	O
+rats	O
+,	O
+were	O
+strikingly	O
+resistant	O
+to	O
+the	O
+effects	O
+of	O
+tetracycline	O
+on	O
+depression	B
+of	O
+output	O
+of	O
+triglyceride	O
+under	O
+these	O
+experimental	O
+conditions	O
+.	O
+
+These	O
+differences	O
+between	O
+the	O
+sexes	O
+could	O
+not	O
+be	O
+related	O
+to	O
+altered	O
+disposition	O
+of	O
+tetracycline	O
+or	O
+altered	O
+uptake	O
+of	O
+oleic	O
+acid	O
+.	O
+
+Depressed	O
+hepatic	O
+secretion	O
+of	O
+triglyceride	O
+accounted	O
+only	O
+for	O
+30	O
+to	O
+50	O
+%	O
+of	O
+accumulated	O
+hepatic	O
+triglyceride	O
+,	O
+indicating	O
+that	O
+additional	O
+mechanisms	O
+must	O
+be	O
+involved	O
+in	O
+the	O
+production	O
+of	O
+the	O
+triglyceride	O
+-	O
+rich	O
+fatty	B
+liver	I
+in	O
+response	O
+to	O
+tetracycline	O
+.	O
+
+Prednisone	O
+induces	O
+anxiety	B
+and	O
+glial	O
+cerebral	O
+changes	O
+in	O
+rats	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+assess	O
+whether	O
+prednisone	O
+(	O
+PDN	O
+)	O
+produces	O
+anxiety	B
+and	O
+/	O
+or	O
+cerebral	O
+glial	O
+changes	O
+in	O
+rats	O
+.	O
+
+METHODS	O
+:	O
+Male	O
+Wistar	O
+rats	O
+were	O
+studied	O
+and	O
+3	O
+groups	O
+were	O
+formed	O
+(	O
+8	O
+rats	O
+per	O
+group	O
+)	O
+.	O
+
+The	O
+moderate	O
+-	O
+dose	O
+group	O
+received	O
+5	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+PDN	O
+released	O
+from	O
+a	O
+subcutaneous	O
+implant	O
+.	O
+
+In	O
+the	O
+high	O
+-	O
+dose	O
+group	O
+,	O
+implants	O
+containing	O
+PDN	O
+equivalent	O
+to	O
+60	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+were	O
+applied	O
+.	O
+
+In	O
+the	O
+control	O
+group	O
+implants	O
+contained	O
+no	O
+PDN	O
+.	O
+
+Anxiety	B
+was	O
+assessed	O
+using	O
+an	O
+open	O
+field	O
+and	O
+elevated	O
+plus	O
+-	O
+maze	O
+devices	O
+.	O
+
+The	O
+number	O
+of	O
+cells	O
+and	O
+cytoplasmic	O
+transformation	O
+of	O
+astrocytes	O
+and	O
+microglia	O
+cells	O
+were	O
+assessed	O
+by	O
+immunohistochemical	O
+analyses	O
+.	O
+
+RESULTS	O
+:	O
+Anxiety	B
+was	O
+documented	O
+in	O
+both	O
+groups	O
+of	O
+PDN	O
+treated	O
+rats	O
+compared	O
+with	O
+controls	O
+.	O
+
+The	O
+magnitude	O
+of	O
+transformation	O
+of	O
+the	O
+microglia	O
+assessed	O
+by	O
+the	O
+number	O
+of	O
+intersections	O
+was	O
+significantly	O
+higher	O
+in	O
+the	O
+PDN	O
+groups	O
+than	O
+in	O
+controls	O
+in	O
+the	O
+prefrontal	O
+cortex	O
+(	O
+moderate	O
+-	O
+dose	O
+,	O
+24	O
+.	O
+1	O
+;	O
+high	O
+-	O
+dose	O
+,	O
+23	O
+.	O
+6	O
+;	O
+controls	O
+18	O
+.	O
+7	O
+;	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+and	O
+striatum	O
+(	O
+moderate	O
+-	O
+dose	O
+25	O
+.	O
+6	O
+;	O
+high	O
+-	O
+dose	O
+26	O
+.	O
+3	O
+;	O
+controls	O
+18	O
+.	O
+9	O
+;	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+,	O
+but	O
+not	O
+in	O
+hippocampus	O
+.	O
+
+The	O
+number	O
+of	O
+stained	O
+microglia	O
+cells	O
+was	O
+significantly	O
+higher	O
+in	O
+the	O
+PDN	O
+treated	O
+groups	O
+in	O
+the	O
+prefrontal	O
+cortex	O
+than	O
+in	O
+controls	O
+(	O
+moderate	O
+-	O
+dose	O
+,	O
+29	O
+.	O
+1	O
+;	O
+high	O
+-	O
+dose	O
+,	O
+28	O
+.	O
+4	O
+;	O
+control	O
+,	O
+17	O
+.	O
+7	O
+cells	O
+per	O
+field	O
+;	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+Stained	O
+microglia	O
+cells	O
+were	O
+significantly	O
+more	O
+numerous	O
+striatum	O
+and	O
+hippocampus	O
+in	O
+the	O
+high	O
+-	O
+dose	O
+group	O
+compared	O
+to	O
+controls	O
+.	O
+
+CONCLUSION	O
+:	O
+Subacute	O
+exposure	O
+to	O
+PDN	O
+induced	O
+anxiety	B
+and	O
+reactivity	O
+of	O
+microglia	O
+.	O
+
+The	O
+relevance	O
+of	O
+these	O
+features	O
+for	O
+patients	O
+using	O
+PDN	O
+remains	O
+to	O
+be	O
+elucidated	O
+.	O
+
+Phase	O
+II	O
+study	O
+of	O
+carboplatin	O
+and	O
+liposomal	O
+doxorubicin	O
+in	O
+patients	O
+with	O
+recurrent	O
+squamous	B
+cell	I
+carcinoma	I
+of	I
+the	I
+cervix	I
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+activity	O
+of	O
+the	O
+combination	O
+of	O
+carboplatin	O
+and	O
+liposomal	O
+doxorubicin	O
+was	O
+tested	O
+in	O
+a	O
+Phase	O
+II	O
+study	O
+of	O
+patients	O
+with	O
+recurrent	O
+cervical	B
+carcinoma	I
+.	O
+
+METHODS	O
+:	O
+The	O
+combination	O
+of	O
+carboplatin	O
+(	O
+area	O
+under	O
+the	O
+concentration	O
+curve	O
+[	O
+AUC	O
+]	O
+,	O
+5	O
+)	O
+and	O
+liposomal	O
+doxorubicin	O
+(	O
+Doxil	O
+;	O
+starting	O
+dose	O
+,	O
+40	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+)	O
+was	O
+administered	O
+intravenously	O
+every	O
+28	O
+days	O
+to	O
+37	O
+patients	O
+with	O
+recurrent	O
+squamous	B
+cell	I
+cervical	I
+carcinoma	I
+to	O
+determine	O
+antitumor	O
+activity	O
+and	O
+toxicity	B
+profile	O
+.	O
+
+RESULTS	O
+:	O
+Twenty	O
+-	O
+nine	O
+patients	O
+were	O
+assessable	O
+for	O
+response	O
+,	O
+and	O
+35	O
+patients	O
+were	O
+assessable	O
+for	O
+toxicity	B
+.	O
+
+The	O
+overall	O
+response	O
+rate	O
+was	O
+38	O
+%	O
+,	O
+the	O
+median	O
+time	O
+to	O
+response	O
+was	O
+10	O
+weeks	O
+,	O
+the	O
+median	O
+duration	O
+of	O
+response	O
+was	O
+26	O
+weeks	O
+,	O
+and	O
+the	O
+median	O
+survival	O
+was	O
+37	O
+weeks	O
+.	O
+
+The	O
+main	O
+toxic	O
+effect	O
+was	O
+myelosuppression	B
+,	O
+with	O
+Grade	O
+3	O
+and	O
+4	O
+neutropenia	B
+in	O
+16	O
+patients	O
+,	O
+anemia	B
+in	O
+12	O
+patients	O
+,	O
+thrombocytopenia	B
+in	O
+11	O
+patients	O
+,	O
+and	O
+neutropenic	B
+fever	I
+in	O
+3	O
+patients	O
+.	O
+
+Four	O
+patients	O
+had	O
+five	O
+infusion	O
+-	O
+related	O
+reactions	O
+during	O
+the	O
+infusion	O
+of	O
+liposomal	O
+doxorubicin	O
+,	O
+leading	O
+to	O
+treatment	O
+discontinuation	O
+in	O
+three	O
+patients	O
+.	O
+
+Grade	O
+>	O
+or	O
+=	O
+2	O
+nonhematologic	O
+toxicity	B
+included	O
+nausea	B
+in	O
+17	O
+patients	O
+,	O
+emesis	B
+in	O
+14	O
+patients	O
+,	O
+fatigue	B
+in	O
+9	O
+patients	O
+,	O
+mucositis	B
+and	O
+/	O
+or	O
+stomatitis	B
+in	O
+8	O
+patients	O
+,	O
+constipation	B
+in	O
+6	O
+patients	O
+,	O
+weight	B
+loss	I
+in	O
+5	O
+patients	O
+,	O
+hand	B
+-	I
+foot	I
+syndrome	I
+in	O
+2	O
+patients	O
+,	O
+and	O
+skin	B
+reactions	I
+in	O
+3	O
+patients	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+combination	O
+of	O
+carboplatin	O
+and	O
+liposomal	O
+doxorubicin	O
+has	O
+modest	O
+activity	O
+in	O
+patients	O
+with	O
+recurrent	O
+cervical	B
+carcinoma	I
+.	O
+
+Antimicrobial	O
+-	O
+induced	O
+mania	B
+(	O
+antibiomania	B
+)	O
+:	O
+a	O
+review	O
+of	O
+spontaneous	O
+reports	O
+.	O
+
+The	O
+authors	O
+reviewed	O
+reported	O
+cases	O
+of	O
+antibiotic	O
+-	O
+induced	O
+manic	B
+episodes	O
+by	O
+means	O
+of	O
+a	O
+MEDLINE	O
+and	O
+PsychLit	O
+search	O
+for	O
+reports	O
+of	O
+antibiotic	O
+-	O
+induced	O
+mania	B
+.	O
+
+Unpublished	O
+reports	O
+were	O
+requested	O
+from	O
+the	O
+World	O
+Health	O
+Organization	O
+(	O
+WHO	O
+)	O
+and	O
+the	O
+Food	O
+and	O
+Drug	O
+Administration	O
+(	O
+FDA	O
+)	O
+.	O
+
+Twenty	O
+-	O
+one	O
+reports	O
+of	O
+antimicrobial	O
+-	O
+induced	O
+mania	B
+were	O
+found	O
+in	O
+the	O
+literature	O
+.	O
+
+There	O
+were	O
+6	O
+cases	O
+implicating	O
+clarithromycin	O
+,	O
+13	O
+implicating	O
+isoniazid	O
+,	O
+and	O
+1	O
+case	O
+each	O
+implicating	O
+erythromycin	O
+and	O
+amoxicillin	O
+.	O
+
+The	O
+WHO	O
+reported	O
+82	O
+cases	O
+.	O
+
+Of	O
+these	O
+,	O
+clarithromycin	O
+was	O
+implicated	O
+in	O
+23	O
+(	O
+27	O
+.	O
+6	O
+%	O
+)	O
+cases	O
+,	O
+ciprofloxacin	O
+in	O
+12	O
+(	O
+14	O
+.	O
+4	O
+%	O
+)	O
+cases	O
+,	O
+and	O
+ofloxacin	O
+in	O
+10	O
+(	O
+12	O
+%	O
+)	O
+cases	O
+.	O
+
+Cotrimoxazole	O
+,	O
+metronidazole	O
+,	O
+and	O
+erythromycin	O
+were	O
+involved	O
+in	O
+15	O
+reported	O
+manic	B
+episodes	O
+.	O
+
+Cases	O
+reported	O
+by	O
+the	O
+FDA	O
+showed	O
+clarithromycin	O
+and	O
+ciprofloxacin	O
+to	O
+be	O
+the	O
+most	O
+frequently	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+mania	B
+.	O
+
+Statistical	O
+analysis	O
+of	O
+the	O
+data	O
+would	O
+not	O
+have	O
+demonstrated	O
+a	O
+significant	O
+statistical	O
+correlative	O
+risk	O
+and	O
+was	O
+therefore	O
+not	O
+undertaken	O
+.	O
+
+Patients	O
+have	O
+an	O
+increased	O
+risk	O
+of	O
+developing	O
+mania	B
+while	O
+being	O
+treated	O
+with	O
+antimicrobials	O
+.	O
+
+Although	O
+this	O
+is	O
+not	O
+a	O
+statistically	O
+significant	O
+risk	O
+,	O
+physicians	O
+must	O
+be	O
+aware	O
+of	O
+the	O
+effect	O
+and	O
+reversibility	O
+.	O
+
+Further	O
+research	O
+clearly	O
+is	O
+required	O
+to	O
+determine	O
+the	O
+incidence	O
+of	O
+antimicrobial	O
+-	O
+induced	O
+mania	B
+,	O
+the	O
+relative	O
+risk	O
+factors	O
+of	O
+developing	O
+an	O
+antimicrobial	O
+-	O
+induced	O
+manic	B
+episode	O
+among	O
+various	O
+demographic	O
+populations	O
+,	O
+and	O
+the	O
+incidence	O
+of	O
+patients	O
+who	O
+continue	O
+to	O
+have	O
+persistent	O
+affective	O
+disorders	O
+once	O
+the	O
+initial	O
+episode	O
+,	O
+which	O
+occurs	O
+while	O
+the	O
+patient	O
+is	O
+taking	O
+antibiotics	O
+,	O
+subsides	O
+.	O
+
+The	O
+authors	O
+elected	O
+to	O
+name	O
+this	O
+syndrome	O
+"	O
+antibiomania	B
+.	O
+"	O
+
+Levodopa	O
+-	O
+induced	O
+ocular	B
+dyskinesias	I
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+Levodopa	O
+-	O
+induced	O
+ocular	B
+dyskinesias	I
+are	O
+very	O
+uncommon	O
+.	O
+
+Usually	O
+they	O
+occur	O
+simultaneously	O
+with	O
+limb	O
+peak	O
+-	O
+dose	O
+choreatic	B
+dyskinesias	I
+.	O
+
+We	O
+report	O
+on	O
+a	O
+patient	O
+with	O
+leftward	O
+and	O
+upward	O
+deviations	O
+of	O
+gaze	O
+during	O
+the	O
+peak	O
+effect	O
+of	O
+levodopa	O
+,	O
+and	O
+hypothesize	O
+that	O
+a	O
+severe	O
+dopaminergic	O
+denervation	O
+in	O
+the	O
+caudate	O
+nucleus	O
+is	O
+needed	O
+for	O
+the	O
+appearance	O
+of	O
+these	O
+levodopa	O
+-	O
+induce	O
+ocular	B
+dyskinesias	I
+.	O
+
+A	O
+comparison	O
+of	O
+glyceryl	O
+trinitrate	O
+with	O
+diclofenac	O
+for	O
+the	O
+treatment	O
+of	O
+primary	O
+dysmenorrhea	B
+:	O
+an	O
+open	O
+,	O
+randomized	O
+,	O
+cross	O
+-	O
+over	O
+trial	O
+.	O
+
+Primary	O
+dysmenorrhea	B
+is	O
+a	O
+syndrome	O
+characterized	O
+by	O
+painful	O
+uterine	O
+contractility	O
+caused	O
+by	O
+a	O
+hypersecretion	O
+of	O
+endometrial	O
+prostaglandins	O
+;	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+are	O
+the	O
+first	O
+choice	O
+for	O
+its	O
+treatment	O
+.	O
+
+However	O
+,	O
+in	O
+vivo	O
+and	O
+in	O
+vitro	O
+studies	O
+have	O
+demonstrated	O
+that	O
+myometrial	O
+cells	O
+are	O
+also	O
+targets	O
+of	O
+the	O
+relaxant	O
+effects	O
+of	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+efficacy	O
+of	O
+glyceryl	O
+trinitrate	O
+(	O
+GTN	O
+)	O
+,	O
+an	O
+NO	O
+donor	O
+,	O
+in	O
+the	O
+resolution	O
+of	O
+primary	O
+dysmenorrhea	B
+in	O
+comparison	O
+with	O
+diclofenac	O
+(	O
+DCF	O
+)	O
+.	O
+
+A	O
+total	O
+of	O
+24	O
+patients	O
+with	O
+the	O
+diagnosis	O
+of	O
+severe	O
+primary	O
+dysmenorrhea	B
+were	O
+studied	O
+during	O
+two	O
+consecutive	O
+menstrual	O
+cycles	O
+.	O
+
+In	O
+an	O
+open	O
+,	O
+cross	O
+-	O
+over	O
+,	O
+controlled	O
+design	O
+,	O
+patients	O
+were	O
+randomized	O
+to	O
+receive	O
+either	O
+DCF	O
+per	O
+os	O
+or	O
+GTN	O
+patches	O
+the	O
+first	O
+days	O
+of	O
+menses	O
+,	O
+when	O
+menstrual	O
+cramps	O
+became	O
+unendurable	O
+.	O
+
+In	O
+the	O
+subsequent	O
+cycle	O
+the	O
+other	O
+treatment	O
+was	O
+used	O
+.	O
+
+Patients	O
+received	O
+up	O
+to	O
+3	O
+doses	O
+/	O
+day	O
+of	O
+50	O
+mg	O
+DCF	O
+or	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+24	O
+h	O
+transdermal	O
+GTN	O
+for	O
+the	O
+first	O
+3	O
+days	O
+of	O
+the	O
+cycle	O
+,	O
+according	O
+to	O
+their	O
+needs	O
+.	O
+
+The	O
+participants	O
+recorded	O
+menstrual	O
+symptoms	O
+and	O
+possible	O
+side	O
+-	O
+effects	O
+at	O
+different	O
+times	O
+(	O
+0	O
+,	O
+30	O
+,	O
+60	O
+,	O
+120	O
+minutes	O
+)	O
+after	O
+the	O
+first	O
+dose	O
+of	O
+medication	O
+on	O
+the	O
+first	O
+day	O
+of	O
+the	O
+cycle	O
+,	O
+with	O
+both	O
+drugs	O
+.	O
+
+The	O
+difference	O
+in	O
+pain	B
+intensity	O
+score	O
+(	O
+DPI	O
+)	O
+was	O
+the	O
+main	O
+outcome	O
+variable	O
+.	O
+
+Both	O
+treatments	O
+significantly	O
+reduced	O
+DPI	O
+by	O
+the	O
+30th	O
+minute	O
+(	O
+GTN	O
+,	O
+-	O
+12	O
+.	O
+8	O
++	O
+/	O
+-	O
+17	O
+.	O
+9	O
+;	O
+DCF	O
+,	O
+-	O
+18	O
+.	O
+9	O
++	O
+/	O
+-	O
+16	O
+.	O
+6	O
+)	O
+.	O
+
+However	O
+,	O
+DCF	O
+continued	O
+to	O
+be	O
+effective	O
+in	O
+reducing	O
+pelvic	B
+pain	I
+for	O
+two	O
+hours	O
+,	O
+whereas	O
+GTN	O
+scores	O
+remained	O
+more	O
+or	O
+less	O
+stable	O
+after	O
+30	O
+min	O
+and	O
+significantly	O
+higher	O
+than	O
+those	O
+for	O
+DFC	O
+(	O
+after	O
+one	O
+hour	O
+:	O
+GTN	O
+,	O
+-	O
+12	O
+.	O
+8	O
++	O
+/	O
+-	O
+17	O
+.	O
+9	O
+;	O
+DFC	O
+,	O
+-	O
+18	O
+.	O
+9	O
++	O
+/	O
+-	O
+16	O
+.	O
+6	O
+and	O
+after	O
+two	O
+hours	O
+:	O
+GTN	O
+,	O
+-	O
+23	O
+.	O
+7	O
++	O
+/	O
+-	O
+20	O
+.	O
+5	O
+;	O
+DFC	O
+,	O
+-	O
+59	O
+.	O
+7	O
++	O
+/	O
+-	O
+17	O
+.	O
+9	O
+,	O
+p	O
+=	O
+0	O
+.	O
+0001	O
+)	O
+.	O
+
+Low	B
+back	I
+pain	I
+was	O
+also	O
+relieved	O
+by	O
+both	O
+drugs	O
+.	O
+
+Headache	B
+was	O
+significantly	O
+increased	O
+by	O
+GTN	O
+but	O
+not	O
+by	O
+DCF	O
+.	O
+
+Eight	O
+patients	O
+stopped	O
+using	O
+GTN	O
+because	O
+headache	B
+-	O
+-	O
+attributed	O
+to	O
+its	O
+use	O
+-	O
+-	O
+became	O
+intolerable	O
+.	O
+
+These	O
+findings	O
+indicate	O
+that	O
+GTN	O
+has	O
+a	O
+reduced	O
+efficacy	O
+and	O
+tolerability	O
+by	O
+comparison	O
+with	O
+DCF	O
+in	O
+the	O
+treatment	O
+of	O
+primary	O
+dysmenorrhea	B
+.	O
+
+Temocapril	O
+,	O
+a	O
+long	O
+-	O
+acting	O
+non	O
+-	O
+SH	O
+group	O
+angiotensin	O
+converting	O
+enzyme	O
+inhibitor	O
+,	O
+modulates	O
+glomerular	B
+injury	I
+in	O
+chronic	O
+puromycin	O
+aminonucleoside	O
+nephrosis	B
+.	O
+
+The	O
+purpose	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+determine	O
+whether	O
+chronic	O
+administration	O
+of	O
+temocapril	O
+,	O
+a	O
+long	O
+-	O
+acting	O
+non	O
+-	O
+SH	O
+group	O
+angiotensin	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+inhibitor	O
+,	O
+reduced	O
+proteinuria	B
+,	O
+inhibited	O
+glomerular	O
+hypertrophy	B
+and	O
+prevented	O
+glomerulosclerosis	B
+in	O
+chronic	O
+puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+)	O
+-	O
+induced	O
+nephrotic	B
+rats	O
+.	O
+
+Nephrosis	B
+was	O
+induced	O
+by	O
+injection	O
+of	O
+PAN	O
+(	O
+15mg	O
+/	O
+100g	O
+body	O
+weight	O
+)	O
+in	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+(	O
+SD	O
+)	O
+rats	O
+.	O
+
+Four	O
+groups	O
+were	O
+used	O
+,	O
+i	O
+)	O
+the	O
+PAN	O
+group	O
+(	O
+14	O
+)	O
+,	O
+ii	O
+)	O
+PAN	O
+/	O
+temocapril	O
+(	O
+13	O
+)	O
+,	O
+iii	O
+)	O
+temocapril	O
+(	O
+14	O
+)	O
+and	O
+iv	O
+)	O
+untreated	O
+controls	O
+(	O
+15	O
+)	O
+.	O
+
+Temocapril	O
+(	O
+8	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+)	O
+was	O
+administered	O
+to	O
+the	O
+rats	O
+which	O
+were	O
+killed	O
+at	O
+weeks	O
+4	O
+,	O
+14	O
+or	O
+20	O
+.	O
+
+At	O
+each	O
+time	O
+point	O
+,	O
+systolic	O
+blood	O
+pressure	O
+(	O
+BP	O
+)	O
+,	O
+urinary	O
+protein	O
+excretion	O
+and	O
+renal	O
+histopathological	O
+findings	O
+were	O
+evaluated	O
+,	O
+and	O
+morphometric	O
+image	O
+analysis	O
+was	O
+done	O
+.	O
+
+Systolic	O
+BP	O
+in	O
+the	O
+PAN	O
+group	O
+was	O
+significantly	O
+high	O
+at	O
+4	O
+,	O
+14	O
+and	O
+20	O
+weeks	O
+,	O
+but	O
+was	O
+normal	O
+in	O
+the	O
+PAN	O
+/	O
+temocapril	O
+group	O
+.	O
+
+Urinary	O
+protein	O
+excretion	O
+in	O
+the	O
+PAN	O
+group	O
+increased	O
+significantly	O
+,	O
+peaking	O
+at	O
+8	O
+days	O
+,	O
+then	O
+decreased	O
+at	O
+4	O
+weeks	O
+,	O
+but	O
+rose	O
+again	O
+significantly	O
+at	O
+14	O
+and	O
+20	O
+weeks	O
+.	O
+
+Temocapril	O
+did	O
+not	O
+attenuate	O
+proteinuria	B
+at	O
+8	O
+days	O
+,	O
+but	O
+it	O
+did	O
+markedly	O
+lower	O
+it	O
+from	O
+weeks	O
+4	O
+to	O
+20	O
+.	O
+
+The	O
+glomerulosclerosis	B
+index	O
+(	O
+GSI	O
+)	O
+was	O
+6	O
+.	O
+21	O
+%	O
+at	O
+4	O
+weeks	O
+and	O
+respectively	O
+25	O
+.	O
+35	O
+%	O
+and	O
+30	O
+.	O
+49	O
+%	O
+at	O
+14	O
+and	O
+20	O
+weeks	O
+in	O
+the	O
+PAN	O
+group	O
+.	O
+
+There	O
+was	O
+a	O
+significant	O
+correlation	O
+between	O
+urinary	O
+protein	O
+excretion	O
+and	O
+GSI	O
+(	O
+r	O
+=	O
+0	O
+.	O
+808	O
+,	O
+p	O
+<	O
+0	O
+.	O
+0001	O
+)	O
+.	O
+
+The	O
+ratio	O
+of	O
+glomerular	O
+tuft	O
+area	O
+to	O
+the	O
+area	O
+of	O
+Bowman	O
+'	O
+s	O
+capsules	O
+(	O
+GT	O
+/	O
+BC	O
+)	O
+in	O
+the	O
+PAN	O
+group	O
+was	O
+significantly	O
+increased	O
+,	O
+but	O
+it	O
+was	O
+significantly	O
+lower	O
+in	O
+the	O
+PAN	O
+/	O
+temocapril	O
+group	O
+.	O
+
+It	O
+appears	O
+that	O
+temocapril	O
+was	O
+effective	O
+in	O
+retarding	O
+renal	O
+progression	O
+and	O
+protected	O
+renal	O
+function	O
+in	O
+PAN	O
+neprotic	B
+rats	O
+.	O
+
+Pulmonary	B
+hypertension	I
+after	O
+ibuprofen	O
+prophylaxis	O
+in	O
+very	O
+preterm	O
+infants	O
+.	O
+
+We	O
+report	O
+three	O
+cases	O
+of	O
+severe	O
+hypoxaemia	B
+after	O
+ibuprofen	O
+administration	O
+during	O
+a	O
+randomised	O
+controlled	O
+trial	O
+of	O
+prophylactic	O
+treatment	O
+of	O
+patent	B
+ductus	I
+arteriosus	I
+with	O
+ibuprofen	O
+in	O
+premature	O
+infants	O
+born	O
+at	O
+less	O
+than	O
+28	O
+weeks	O
+of	O
+gestation	O
+.	O
+
+Echocardiography	O
+showed	O
+severely	O
+decreased	O
+pulmonary	O
+blood	O
+flow	O
+.	O
+
+Hypoxaemia	B
+resolved	O
+quickly	O
+on	O
+inhaled	O
+nitric	O
+oxide	O
+therapy	O
+.	O
+
+We	O
+suggest	O
+that	O
+investigators	O
+involved	O
+in	O
+similar	O
+trials	O
+pay	O
+close	O
+attention	O
+to	O
+pulmonary	O
+pressure	O
+if	O
+hypoxaemia	B
+occurs	O
+after	O
+prophylactic	O
+administration	O
+of	O
+ibuprofen	O
+.	O
+
+Hyponatremia	B
+and	O
+syndrome	B
+of	I
+inappropriate	I
+anti	I
+-	I
+diuretic	I
+hormone	I
+reported	O
+with	O
+the	O
+use	O
+of	O
+Vincristine	O
+:	O
+an	O
+over	O
+-	O
+representation	O
+of	O
+Asians	O
+?	O
+
+PURPOSE	O
+:	O
+This	O
+retrospective	O
+study	O
+used	O
+a	O
+pharmaceutical	O
+company	O
+'	O
+s	O
+global	O
+safety	O
+database	O
+to	O
+determine	O
+the	O
+reporting	O
+rate	O
+of	O
+hyponatremia	B
+and	O
+/	O
+or	O
+syndrome	B
+of	I
+inappropriate	I
+secretion	I
+of	I
+anti	I
+-	I
+diuretic	I
+hormone	I
+(	O
+SIADH	B
+)	O
+among	O
+vincristine	O
+-	O
+treated	O
+patients	O
+and	O
+to	O
+explore	O
+the	O
+possibility	O
+of	O
+at	O
+-	O
+risk	O
+population	O
+subgroups	O
+.	O
+
+METHOD	O
+:	O
+We	O
+searched	O
+the	O
+Eli	O
+Lilly	O
+and	O
+Company	O
+'	O
+s	O
+computerized	O
+adverse	O
+event	O
+database	O
+for	O
+all	O
+reported	O
+cases	O
+of	O
+hyponatremia	B
+and	O
+/	O
+or	O
+SIADH	B
+as	O
+of	O
+1	O
+November	O
+1999	O
+that	O
+had	O
+been	O
+reported	O
+during	O
+the	O
+use	O
+of	O
+vincristine	O
+.	O
+
+RESULTS	O
+:	O
+A	O
+total	O
+of	O
+76	O
+cases	O
+of	O
+hyponatremia	B
+and	O
+/	O
+or	O
+SIADH	B
+associated	O
+with	O
+vincristine	O
+use	O
+were	O
+identified	O
+.	O
+
+The	O
+overall	O
+reporting	O
+rate	O
+was	O
+estimated	O
+to	O
+be	O
+1	O
+.	O
+3	O
+/	O
+100	O
+,	O
+000	O
+treated	O
+patients	O
+.	O
+
+The	O
+average	O
+age	O
+of	O
+patients	O
+was	O
+35	O
+.	O
+6	O
++	O
+/	O
+-	O
+28	O
+.	O
+3	O
+years	O
+,	O
+and	O
+62	O
+%	O
+were	O
+males	O
+.	O
+
+Approximately	O
+75	O
+%	O
+of	O
+the	O
+patients	O
+were	O
+receiving	O
+treatment	O
+for	O
+leukemia	B
+or	O
+lymphoma	B
+.	O
+
+Among	O
+the	O
+39	O
+reports	O
+that	O
+included	O
+information	O
+on	O
+race	O
+,	O
+the	O
+racial	O
+distribution	O
+was	O
+:	O
+1	O
+Black	O
+,	O
+3	O
+Caucasian	O
+,	O
+and	O
+35	O
+Asian	O
+.	O
+
+CONCLUSION	O
+:	O
+Our	O
+data	O
+suggest	O
+that	O
+Asian	O
+patients	O
+may	O
+be	O
+at	O
+increased	O
+risk	O
+of	O
+hyponatremia	B
+and	O
+/	O
+or	O
+SIADH	B
+associated	O
+with	O
+vincristine	O
+use	O
+.	O
+
+Although	O
+the	O
+overall	O
+reported	O
+rate	O
+of	O
+SIADH	B
+associated	O
+with	O
+vincristine	O
+is	O
+very	O
+low	O
+,	O
+physicians	O
+caring	O
+for	O
+Asian	O
+oncology	O
+patients	O
+should	O
+be	O
+aware	O
+of	O
+this	O
+potential	O
+serious	O
+but	O
+reversible	O
+adverse	O
+event	O
+.	O
+
+Delayed	O
+toxicity	B
+of	O
+cyclophosphamide	O
+on	O
+the	O
+bladder	O
+of	O
+DBA	O
+/	O
+2	O
+and	O
+C57BL	O
+/	O
+6	O
+female	O
+mouse	O
+.	O
+
+The	O
+present	O
+study	O
+describes	O
+the	O
+delayed	O
+development	O
+of	O
+a	O
+severe	O
+bladder	O
+pathology	O
+in	O
+a	O
+susceptible	O
+strain	O
+of	O
+mice	O
+(	O
+DBA	O
+/	O
+2	O
+)	O
+but	O
+not	O
+in	O
+a	O
+resistant	O
+strain	O
+(	O
+C57BL	O
+/	O
+6	O
+)	O
+when	O
+both	O
+were	O
+treated	O
+with	O
+a	O
+single	O
+300	O
+mg	O
+/	O
+kg	O
+dose	O
+of	O
+cyclophosphamide	O
+(	O
+CY	O
+)	O
+.	O
+
+Inbred	O
+DBA	O
+/	O
+2	O
+and	O
+C57BL	O
+/	O
+6	O
+female	O
+mice	O
+were	O
+injected	O
+with	O
+CY	O
+,	O
+and	O
+the	O
+effect	O
+of	O
+the	O
+drug	O
+on	O
+the	O
+bladder	O
+was	O
+assessed	O
+during	O
+100	O
+days	O
+by	O
+light	O
+microscopy	O
+using	O
+different	O
+staining	O
+procedures	O
+,	O
+and	O
+after	O
+30	O
+days	O
+by	O
+conventional	O
+electron	O
+microscopy	O
+.	O
+
+Early	O
+CY	O
+toxicity	B
+caused	O
+a	O
+typical	O
+haemorrhagic	B
+cystitis	B
+in	O
+both	O
+strains	O
+that	O
+was	O
+completely	O
+repaired	O
+in	O
+about	O
+7	O
+-	O
+10	O
+days	O
+.	O
+
+After	O
+30	O
+days	O
+of	O
+CY	O
+injection	O
+ulcerous	O
+and	O
+non	O
+-	O
+ulcerous	O
+forms	O
+of	O
+chronic	O
+cystitis	B
+appeared	O
+in	O
+86	O
+%	O
+of	O
+DBA	O
+/	O
+2	O
+mice	O
+but	O
+only	O
+in	O
+4	O
+%	O
+of	O
+C57BL	O
+/	O
+6	O
+mice	O
+.	O
+
+Delayed	O
+cystitis	B
+was	O
+characterized	O
+by	O
+infiltration	O
+and	O
+transepithelial	O
+passage	O
+into	O
+the	O
+lumen	O
+of	O
+inflammatory	O
+cells	O
+and	O
+by	O
+frequent	O
+exfoliation	O
+of	O
+the	O
+urothelium	O
+.	O
+
+Mast	O
+cells	O
+appeared	O
+in	O
+the	O
+connective	O
+and	O
+muscular	O
+layers	O
+of	O
+the	O
+bladder	O
+at	O
+a	O
+much	O
+higher	O
+number	O
+in	O
+DBA	O
+/	O
+2	O
+mice	O
+than	O
+in	O
+C57BL	O
+/	O
+6	O
+mice	O
+or	O
+untreated	O
+controls	O
+.	O
+
+Electron	O
+microscopy	O
+disclosed	O
+the	O
+absence	O
+of	O
+the	O
+typical	O
+discoidal	O
+vesicles	O
+normally	O
+present	O
+in	O
+the	O
+cytoplasm	O
+of	O
+surface	O
+cells	O
+.	O
+
+Instead	O
+,	O
+numerous	O
+abnormal	O
+vesicles	O
+containing	O
+one	O
+or	O
+several	O
+dark	O
+granules	O
+were	O
+observed	O
+in	O
+the	O
+cytoplasm	O
+of	O
+cells	O
+from	O
+all	O
+the	O
+epithelial	O
+layers	O
+.	O
+
+Delayed	O
+cystitis	B
+still	O
+persisted	O
+in	O
+DBA	O
+/	O
+2	O
+mice	O
+100	O
+days	O
+after	O
+treatment	O
+.	O
+
+These	O
+results	O
+indicate	O
+that	O
+delayed	O
+toxicity	B
+of	O
+CY	O
+in	O
+female	O
+DBA	O
+/	O
+2	O
+mice	O
+causes	O
+a	O
+bladder	O
+pathology	O
+that	O
+is	O
+not	O
+observed	O
+in	O
+C57BL	O
+/	O
+6	O
+mice	O
+.	O
+
+This	O
+pathology	O
+resembles	O
+interstitial	B
+cystitis	I
+in	O
+humans	O
+and	O
+could	O
+perhaps	O
+be	O
+used	O
+as	O
+an	O
+animal	O
+model	O
+for	O
+studies	O
+on	O
+the	O
+disease	O
+.	O
+
+High	O
+-	O
+dose	O
+5	O
+-	O
+fluorouracil	O
+/	O
+folinic	O
+acid	O
+in	O
+combination	O
+with	O
+three	O
+-	O
+weekly	O
+mitomycin	O
+C	O
+in	O
+the	O
+treatment	O
+of	O
+advanced	O
+gastric	B
+cancer	I
+.	O
+
+A	O
+phase	O
+II	O
+study	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+24	O
+-	O
+hour	O
+continuous	O
+infusion	O
+of	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+and	O
+folinic	O
+acid	O
+(	O
+FA	O
+)	O
+as	O
+part	O
+of	O
+several	O
+new	O
+multidrug	O
+chemotherapy	O
+regimens	O
+in	O
+advanced	O
+gastric	B
+cancer	I
+(	O
+AGC	B
+)	O
+has	O
+shown	O
+to	O
+be	O
+effective	O
+,	O
+with	O
+low	O
+toxicity	B
+.	O
+
+In	O
+a	O
+previous	O
+phase	O
+II	O
+study	O
+with	O
+3	O
+-	O
+weekly	O
+bolus	O
+5	O
+-	O
+FU	O
+,	O
+FA	O
+and	O
+mitomycin	O
+C	O
+(	O
+MMC	O
+)	O
+we	O
+found	O
+a	O
+low	O
+toxicity	B
+rate	O
+and	O
+response	O
+rates	O
+comparable	O
+to	O
+those	O
+of	O
+regimens	O
+such	O
+as	O
+ELF	O
+,	O
+FAM	O
+or	O
+FAMTX	O
+,	O
+and	O
+a	O
+promising	O
+median	O
+overall	O
+survival	O
+.	O
+
+In	O
+order	O
+to	O
+improve	O
+this	O
+MMC	O
+-	O
+dependent	O
+schedule	O
+we	O
+initiated	O
+a	O
+phase	O
+II	O
+study	O
+with	O
+high	O
+-	O
+dose	O
+5	O
+-	O
+FU	O
+/	O
+FA	O
+and	O
+3	O
+-	O
+weekly	O
+bolus	O
+MMC	O
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+From	O
+February	O
+,	O
+1998	O
+to	O
+September	O
+,	O
+2000	O
+we	O
+recruited	O
+33	O
+patients	O
+with	O
+AGC	B
+to	O
+receive	O
+weekly	O
+24	O
+-	O
+hour	O
+5	O
+-	O
+FU	O
+2	O
+,	O
+600	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+preceded	O
+by	O
+2	O
+-	O
+hour	O
+FA	O
+500	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+for	O
+6	O
+weeks	O
+,	O
+followed	O
+by	O
+a	O
+2	O
+-	O
+week	O
+rest	O
+period	O
+.	O
+
+Bolus	O
+MMC	O
+10	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+was	O
+added	O
+in	O
+3	O
+-	O
+weekly	O
+intervals	O
+.	O
+
+Treatment	O
+given	O
+on	O
+an	O
+outpatient	O
+basis	O
+,	O
+using	O
+portable	O
+pump	O
+systems	O
+,	O
+was	O
+repeated	O
+on	O
+day	O
+57	O
+.	O
+
+Patients	O
+'	O
+characteristics	O
+were	O
+:	O
+male	O
+/	O
+female	O
+ratio	O
+20	O
+/	O
+13	O
+;	O
+median	O
+age	O
+57	O
+(	O
+27	O
+-	O
+75	O
+)	O
+years	O
+;	O
+median	O
+WHO	O
+status	O
+1	O
+(	O
+0	O
+-	O
+2	O
+)	O
+.	O
+
+18	O
+patients	O
+had	O
+a	O
+primary	O
+AGC	B
+,	O
+and	O
+15	O
+showed	O
+a	O
+relapsed	O
+AGC	B
+.	O
+
+Median	O
+follow	O
+-	O
+up	O
+was	O
+11	O
+.	O
+8	O
+months	O
+(	O
+range	O
+of	O
+those	O
+surviving	O
+:	O
+2	O
+.	O
+7	O
+-	O
+11	O
+.	O
+8	O
+months	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+32	O
+patients	O
+were	O
+evaluable	O
+for	O
+response	O
+-	O
+complete	O
+remission	O
+9	O
+.	O
+1	O
+%	O
+(	O
+n	O
+=	O
+3	O
+)	O
+,	O
+partial	O
+remission	O
+45	O
+.	O
+5	O
+%	O
+(	O
+n	O
+=	O
+15	O
+)	O
+,	O
+no	O
+change	O
+27	O
+.	O
+3	O
+%	O
+(	O
+n	O
+=	O
+9	O
+)	O
+,	O
+progressive	O
+disease	O
+15	O
+.	O
+1	O
+%	O
+(	O
+n	O
+=	O
+5	O
+)	O
+.	O
+
+Median	O
+overall	O
+survival	O
+time	O
+was	O
+10	O
+.	O
+2	O
+months	O
+[	O
+95	O
+%	O
+confidence	O
+interval	O
+(	O
+CI	O
+)	O
+:	O
+8	O
+.	O
+7	O
+-	O
+11	O
+.	O
+6	O
+]	O
+,	O
+and	O
+median	O
+progression	O
+-	O
+free	O
+survival	O
+time	O
+was	O
+7	O
+.	O
+6	O
+months	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+4	O
+.	O
+4	O
+-	O
+10	O
+.	O
+9	O
+)	O
+.	O
+
+The	O
+worst	O
+toxicities	B
+(	O
+%	O
+)	O
+observed	O
+were	O
+(	O
+CTC	O
+-	O
+NCI	O
+1	O
+/	O
+2	O
+/	O
+3	O
+)	O
+:	O
+leukopenia	B
+45	O
+.	O
+5	O
+/	O
+18	O
+.	O
+2	O
+/	O
+6	O
+.	O
+1	O
+,	O
+thrombocytopenia	B
+33	O
+.	O
+3	O
+/	O
+9	O
+.	O
+1	O
+/	O
+6	O
+.	O
+1	O
+,	O
+vomitus	B
+24	O
+.	O
+2	O
+/	O
+9	O
+.	O
+1	O
+/	O
+0	O
+,	O
+diarrhea	B
+36	O
+.	O
+4	O
+/	O
+6	O
+.	O
+1	O
+/	O
+3	O
+.	O
+0	O
+,	O
+stomatitis	B
+18	O
+.	O
+2	O
+/	O
+9	O
+.	O
+1	O
+/	O
+0	O
+,	O
+hand	B
+-	I
+foot	I
+syndrome	I
+12	O
+.	O
+1	O
+/	O
+0	O
+/	O
+0	O
+.	O
+
+Two	O
+patients	O
+developed	O
+hemolytic	B
+-	I
+uremic	I
+syndrome	I
+(	O
+HUS	B
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+High	O
+-	O
+dose	O
+5	O
+-	O
+FU	O
+/	O
+FA	O
+/	O
+MMC	O
+is	O
+an	O
+effective	O
+and	O
+well	O
+-	O
+tolerated	O
+outpatient	O
+regimen	O
+for	O
+AGC	B
+(	O
+objective	O
+response	O
+rate	O
+54	O
+.	O
+6	O
+%	O
+)	O
+.	O
+
+It	O
+may	O
+serve	O
+as	O
+an	O
+alternative	O
+to	O
+cisplatin	O
+-	O
+containing	O
+regimens	O
+;	O
+however	O
+,	O
+it	O
+has	O
+to	O
+be	O
+considered	O
+that	O
+possibly	O
+HUS	B
+may	O
+occur	O
+.	O
+
+Persistent	O
+sterile	O
+leukocyturia	B
+is	O
+associated	O
+with	O
+impaired	B
+renal	I
+function	I
+in	O
+human	B
+immunodeficiency	I
+virus	I
+type	I
+1	I
+-	I
+infected	I
+children	O
+treated	O
+with	O
+indinavir	O
+.	O
+
+BACKGROUND	O
+:	O
+Prolonged	O
+administration	O
+of	O
+indinavir	O
+is	O
+associated	O
+with	O
+the	O
+occurrence	O
+of	O
+a	O
+variety	O
+of	O
+renal	O
+complications	O
+in	O
+adults	O
+.	O
+
+These	O
+well	O
+-	O
+documented	O
+side	O
+effects	O
+have	O
+restricted	O
+the	O
+use	O
+of	O
+this	O
+potent	O
+protease	O
+inhibitor	O
+in	O
+children	O
+.	O
+
+DESIGN	O
+:	O
+A	O
+prospective	O
+study	O
+to	O
+monitor	O
+indinavir	O
+-	O
+related	O
+nephrotoxicity	B
+in	O
+a	O
+cohort	O
+of	O
+30	O
+human	B
+immunodeficiency	I
+virus	I
+type	I
+1	I
+-	I
+infected	I
+children	O
+treated	O
+with	O
+indinavir	O
+.	O
+
+METHODS	O
+:	O
+Urinary	O
+pH	O
+,	O
+albumin	O
+,	O
+creatinine	O
+,	O
+the	O
+presence	O
+of	O
+erythrocytes	O
+,	O
+leukocytes	O
+,	O
+bacteria	O
+and	O
+crystals	O
+,	O
+and	O
+culture	O
+were	O
+analyzed	O
+every	O
+3	O
+months	O
+for	O
+96	O
+weeks	O
+.	O
+
+Serum	O
+creatinine	O
+levels	O
+were	O
+routinely	O
+determined	O
+at	O
+the	O
+same	O
+time	O
+points	O
+.	O
+
+Steady	O
+-	O
+state	O
+pharmacokinetics	O
+of	O
+indinavir	O
+were	O
+done	O
+at	O
+week	O
+4	O
+after	O
+the	O
+initiation	O
+of	O
+indinavir	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+cumulative	O
+incidence	O
+of	O
+persistent	O
+sterile	O
+leukocyturia	B
+(	O
+>	O
+or	O
+=	O
+75	O
+cells	O
+/	O
+micro	O
+L	O
+in	O
+at	O
+least	O
+2	O
+consecutive	O
+visits	O
+)	O
+after	O
+96	O
+weeks	O
+was	O
+53	O
+%	O
+.	O
+
+Persistent	O
+sterile	O
+leukocyturia	B
+was	O
+frequently	O
+associated	O
+with	O
+a	O
+mild	O
+increase	O
+in	O
+the	O
+urine	O
+albumin	O
+/	O
+creatinine	O
+ratio	O
+and	O
+by	O
+microscopic	O
+hematuria	B
+.	O
+
+The	O
+cumulative	O
+incidence	O
+of	O
+serum	O
+creatinine	O
+levels	O
+>	O
+50	O
+%	O
+above	O
+normal	O
+was	O
+33	O
+%	O
+after	O
+96	O
+weeks	O
+.	O
+
+Children	O
+with	O
+persistent	O
+sterile	O
+leukocyturia	B
+more	O
+frequently	O
+had	O
+serum	O
+creatinine	O
+levels	O
+of	O
+50	O
+%	O
+above	O
+normal	O
+than	O
+those	O
+children	O
+without	O
+persistent	O
+sterile	O
+leukocyturia	B
+.	O
+
+In	O
+children	O
+younger	O
+than	O
+5	O
+.	O
+6	O
+years	O
+,	O
+persistent	O
+sterile	O
+leukocyturia	B
+was	O
+significantly	O
+more	O
+frequent	O
+than	O
+in	O
+older	O
+children	O
+.	O
+
+A	O
+higher	O
+cumulative	O
+incidence	O
+of	O
+persistent	O
+leukocyturia	B
+was	O
+found	O
+in	O
+children	O
+with	O
+an	O
+area	O
+under	O
+the	O
+curve	O
+>	O
+19	O
+mg	O
+/	O
+L	O
+x	O
+h	O
+or	O
+a	O
+peak	O
+serum	O
+level	O
+of	O
+indinavir	O
+>	O
+12	O
+mg	O
+/	O
+L	O
+.	O
+
+In	O
+4	O
+children	O
+,	O
+indinavir	O
+was	O
+discontinued	O
+because	O
+of	O
+nephrotoxicity	B
+.	O
+
+Subsequently	O
+,	O
+the	O
+serum	O
+creatinine	O
+levels	O
+decreased	O
+,	O
+the	O
+urine	O
+albumin	O
+/	O
+creatinine	O
+ratios	O
+returned	O
+to	O
+zero	O
+,	O
+and	O
+the	O
+leukocyturia	B
+disappeared	O
+within	O
+3	O
+months	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Children	O
+treated	O
+with	O
+indinavir	O
+have	O
+a	O
+high	O
+cumulative	O
+incidence	O
+of	O
+persistent	O
+sterile	O
+leukocyturia	B
+.	O
+
+Children	O
+with	O
+persistent	O
+sterile	O
+leukocyturia	B
+more	O
+frequently	O
+had	O
+an	O
+increase	O
+in	O
+serum	O
+creatinine	O
+levels	O
+of	O
+>	O
+50	O
+%	O
+above	O
+normal	O
+.	O
+
+Younger	O
+children	O
+have	O
+an	O
+additional	O
+risk	O
+for	O
+renal	O
+complications	O
+.	O
+
+The	O
+impairment	B
+of	I
+the	I
+renal	I
+function	I
+in	O
+these	O
+children	O
+occurred	O
+in	O
+the	O
+absence	O
+of	O
+clinical	O
+symptoms	O
+of	O
+nephrolithiasis	B
+.	O
+
+Indinavir	O
+-	O
+associated	O
+nephrotoxicity	B
+must	O
+be	O
+monitored	O
+closely	O
+,	O
+especially	O
+in	O
+children	O
+with	O
+risk	O
+factors	O
+such	O
+as	O
+persistent	O
+sterile	O
+leukocyturia	B
+,	O
+age	O
+<	O
+5	O
+.	O
+6	O
+years	O
+,	O
+an	O
+area	O
+under	O
+the	O
+curve	O
+of	O
+indinavir	O
+>	O
+19	O
+mg	O
+/	O
+L	O
+x	O
+h	O
+,	O
+and	O
+a	O
+C	O
+(	O
+max	O
+)	O
+>	O
+12	O
+mg	O
+/	O
+L	O
+.	O
+
+Utility	O
+of	O
+troponin	O
+I	O
+in	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B
+pain	I
+.	O
+
+Baseline	O
+electrocardiogram	O
+abnormalities	O
+and	O
+market	O
+elevations	O
+not	O
+associated	O
+with	O
+myocardial	B
+necrosis	I
+make	O
+accurate	O
+diagnosis	O
+of	O
+myocardial	B
+infarction	I
+(	O
+MI	B
+)	O
+difficult	O
+in	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B
+pain	I
+.	O
+
+Troponin	O
+sampling	O
+may	O
+offer	O
+greater	O
+diagnostic	O
+utility	O
+in	O
+these	O
+patients	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+assess	O
+outcomes	O
+based	O
+on	O
+troponin	O
+positivity	O
+in	O
+patients	O
+with	O
+cocaine	O
+chest	B
+pain	I
+admitted	O
+for	O
+exclusion	O
+of	O
+MI	B
+.	O
+
+METHODS	O
+:	O
+Outcomes	O
+were	O
+examined	O
+in	O
+patients	O
+admitted	O
+for	O
+possible	O
+MI	B
+after	O
+cocaine	O
+use	O
+.	O
+
+All	O
+patients	O
+underwent	O
+a	O
+rapid	O
+rule	O
+-	O
+in	O
+protocol	O
+that	O
+included	O
+serial	O
+sampling	O
+of	O
+creatine	O
+kinase	O
+(	O
+CK	O
+)	O
+,	O
+CK	O
+-	O
+MB	O
+,	O
+and	O
+cardiac	O
+troponin	O
+I	O
+(	O
+cTnI	O
+)	O
+over	O
+eight	O
+hours	O
+.	O
+
+Outcomes	O
+included	O
+CK	O
+-	O
+MB	O
+MI	B
+(	O
+CK	O
+-	O
+MB	O
+>	O
+or	O
+=	O
+8	O
+ng	O
+/	O
+mL	O
+with	O
+a	O
+relative	O
+index	O
+[	O
+(	O
+CK	O
+-	O
+MB	O
+x	O
+100	O
+)	O
+/	O
+total	O
+CK	O
+]	O
+>	O
+or	O
+=	O
+4	O
+,	O
+cardiac	B
+death	I
+,	O
+and	O
+significant	O
+coronary	B
+disease	I
+(	O
+>	O
+or	O
+=	O
+50	O
+%	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+Of	O
+the	O
+246	O
+admitted	O
+patients	O
+,	O
+34	O
+(	O
+14	O
+%	O
+)	O
+met	O
+CK	O
+-	O
+MB	O
+criteria	O
+for	O
+MI	B
+and	O
+38	O
+(	O
+16	O
+%	O
+)	O
+had	O
+cTnI	O
+elevations	O
+.	O
+
+Angiography	O
+was	O
+performed	O
+in	O
+29	O
+of	O
+38	O
+patients	O
+who	O
+were	O
+cTnI	O
+-	O
+positive	O
+,	O
+with	O
+significant	O
+disease	O
+present	O
+in	O
+25	O
+(	O
+86	O
+%	O
+)	O
+.	O
+
+Three	O
+of	O
+the	O
+four	O
+patients	O
+without	O
+significant	O
+disease	O
+who	O
+had	O
+cTnI	O
+elevations	O
+met	O
+CK	O
+-	O
+MB	O
+criteria	O
+for	O
+MI	B
+,	O
+and	O
+the	O
+other	O
+had	O
+a	O
+peak	O
+CK	O
+-	O
+MB	O
+level	O
+of	O
+13	O
+ng	O
+/	O
+mL	O
+.	O
+
+Sensitivities	O
+,	O
+specificities	O
+,	O
+and	O
+positive	O
+and	O
+negative	O
+likelihood	O
+ratios	O
+for	O
+predicting	O
+cardiac	B
+death	I
+or	O
+significant	O
+disease	O
+were	O
+high	O
+for	O
+both	O
+CK	O
+-	O
+MB	O
+MI	B
+and	O
+cTnI	O
+and	O
+were	O
+not	O
+significantly	O
+different	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Most	O
+patients	O
+with	O
+cTnI	O
+elevations	O
+meet	O
+CK	O
+-	O
+MB	O
+criteria	O
+for	O
+MI	B
+,	O
+as	O
+well	O
+as	O
+have	O
+a	O
+high	O
+incidence	O
+of	O
+underlying	O
+significant	O
+disease	O
+.	O
+
+Troponin	O
+appears	O
+to	O
+have	O
+an	O
+equivalent	O
+diagnostic	O
+accuracy	O
+compared	O
+with	O
+CK	O
+-	O
+MB	O
+for	O
+diagnosing	O
+necrosis	B
+in	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B
+pain	I
+and	O
+suspected	O
+MI	B
+.	O
+
+Acute	O
+interstitial	B
+nephritis	I
+due	O
+to	O
+nicergoline	O
+(	O
+Sermion	O
+)	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+acute	O
+interstitial	B
+nephritis	I
+(	O
+AIN	B
+)	O
+due	O
+to	O
+nicergoline	O
+(	O
+Sermion	O
+)	O
+.	O
+
+A	O
+50	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+admitted	O
+to	O
+our	O
+hospital	O
+for	O
+fever	B
+and	O
+acute	B
+renal	I
+failure	I
+.	O
+
+Before	O
+admission	O
+,	O
+he	O
+had	O
+been	O
+taking	O
+nicergoline	O
+and	O
+bendazac	O
+lysine	O
+due	O
+to	O
+retinal	B
+vein	I
+occlusion	I
+at	O
+ophthalmologic	O
+department	O
+.	O
+
+Thereafter	O
+,	O
+he	O
+experienced	O
+intermittent	O
+fever	B
+and	O
+skin	B
+rash	I
+.	O
+
+On	O
+admission	O
+,	O
+clinical	O
+symptoms	O
+(	O
+i	O
+.	O
+e	O
+.	O
+arthralgia	B
+and	O
+fever	B
+)	O
+and	O
+laboratory	O
+findings	O
+(	O
+i	O
+.	O
+e	O
+.	O
+eosinophilia	B
+and	O
+renal	B
+failure	I
+)	O
+suggested	O
+AIN	B
+,	O
+and	O
+which	O
+was	O
+confirmed	O
+by	O
+pathologic	O
+findings	O
+on	O
+renal	O
+biopsy	O
+.	O
+
+A	O
+lymphocyte	O
+transformation	O
+test	O
+demonstrated	O
+a	O
+positive	O
+result	O
+against	O
+nicergoline	O
+.	O
+
+Treatment	O
+was	O
+consisted	O
+of	O
+withdrawal	O
+of	O
+nicergoline	O
+and	O
+intravenous	O
+methylprednisolone	O
+,	O
+and	O
+his	O
+renal	O
+function	O
+was	O
+completely	O
+recovered	O
+.	O
+
+To	O
+our	O
+knowledge	O
+,	O
+this	O
+is	O
+the	O
+first	O
+report	O
+of	O
+nicergoline	O
+-	O
+associated	O
+AIN	B
+.	O
+
+Neuroleptic	B
+malignant	I
+syndrome	I
+complicated	O
+by	O
+massive	O
+intestinal	O
+bleeding	B
+in	O
+a	O
+patient	O
+with	O
+chronic	B
+renal	I
+failure	I
+.	O
+
+A	O
+patient	O
+with	O
+chronic	B
+renal	I
+failure	I
+(	O
+CRF	B
+)	O
+developed	O
+neuroleptic	B
+malignant	I
+syndrome	I
+(	O
+NMS	B
+)	O
+after	O
+administration	O
+of	O
+risperidone	O
+and	O
+levomepromazine	O
+.	O
+
+In	O
+addition	O
+to	O
+the	O
+typical	O
+symptoms	O
+of	O
+NMS	B
+,	O
+massive	O
+intestinal	O
+bleeding	B
+was	O
+observed	O
+during	O
+the	O
+episode	O
+.	O
+
+This	O
+report	O
+suggests	O
+that	O
+NMS	B
+in	O
+a	O
+patient	O
+with	O
+CRF	B
+may	O
+be	O
+complicated	O
+by	O
+intestinal	O
+bleeding	B
+and	O
+needs	O
+special	O
+caution	O
+for	O
+this	O
+complication	O
+.	O
+
+Blood	O
+brain	O
+barrier	O
+in	O
+right	O
+-	O
+and	O
+left	O
+-	O
+pawed	O
+female	O
+rats	O
+assessed	O
+by	O
+a	O
+new	O
+staining	O
+method	O
+.	O
+
+The	O
+asymmetrical	O
+breakdown	O
+of	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+(	O
+BBB	O
+)	O
+was	O
+studied	O
+in	O
+female	O
+rats	O
+.	O
+
+Paw	O
+preference	O
+was	O
+assessed	O
+by	O
+a	O
+food	O
+reaching	O
+test	O
+.	O
+
+Adrenaline	O
+-	O
+induced	O
+hypertension	B
+was	O
+used	O
+to	O
+destroy	O
+the	O
+BBB	O
+,	O
+which	O
+was	O
+evaluated	O
+using	O
+triphenyltetrazolium	O
+(	O
+TTC	O
+)	O
+staining	O
+of	O
+the	O
+brain	O
+slices	O
+just	O
+after	O
+giving	O
+adrenaline	O
+for	O
+30	O
+s	O
+.	O
+
+In	O
+normal	O
+rats	O
+,	O
+the	O
+whole	O
+brain	O
+sections	O
+exhibited	O
+complete	O
+staining	O
+with	O
+TTC	O
+.	O
+
+After	O
+adrenaline	O
+infusion	O
+for	O
+30	O
+s	O
+,	O
+there	O
+were	O
+large	O
+unstained	O
+areas	O
+in	O
+the	O
+left	O
+brain	O
+in	O
+right	O
+-	O
+pawed	O
+animals	O
+,	O
+and	O
+vice	O
+versa	O
+in	O
+left	O
+-	O
+pawed	O
+animals	O
+.	O
+
+Similar	O
+results	O
+were	O
+obtained	O
+in	O
+seizure	B
+-	O
+induced	O
+breakdown	O
+of	O
+BBB	O
+.	O
+
+These	O
+results	O
+were	O
+explained	O
+by	O
+an	O
+asymmetric	O
+cerebral	O
+blood	O
+flow	O
+depending	O
+upon	O
+the	O
+paw	O
+preference	O
+in	O
+rats	O
+.	O
+
+It	O
+was	O
+suggested	O
+that	O
+this	O
+new	O
+method	O
+and	O
+the	O
+results	O
+are	O
+consistent	O
+with	O
+contralateral	O
+motor	O
+control	O
+that	O
+may	O
+be	O
+important	O
+in	O
+determining	O
+the	O
+dominant	O
+cerebral	O
+hemisphere	O
+in	O
+animals	O
+.	O
+
+Carvedilol	O
+protects	O
+against	O
+doxorubicin	O
+-	O
+induced	O
+mitochondrial	O
+cardiomyopathy	B
+.	O
+
+Several	O
+cytopathic	O
+mechanisms	O
+have	O
+been	O
+suggested	O
+to	O
+mediate	O
+the	O
+dose	O
+-	O
+limiting	O
+cumulative	O
+and	O
+irreversible	O
+cardiomyopathy	B
+caused	O
+by	O
+doxorubicin	O
+.	O
+
+Recent	O
+evidence	O
+indicates	O
+that	O
+oxidative	O
+stress	O
+and	O
+mitochondrial	B
+dysfunction	I
+are	O
+key	O
+factors	O
+in	O
+the	O
+pathogenic	O
+process	O
+.	O
+
+The	O
+objective	O
+of	O
+this	O
+investigation	O
+was	O
+to	O
+test	O
+the	O
+hypothesis	O
+that	O
+carvedilol	O
+,	O
+a	O
+nonselective	O
+beta	O
+-	O
+adrenergic	O
+receptor	O
+antagonist	O
+with	O
+potent	O
+antioxidant	O
+properties	O
+,	O
+protects	O
+against	O
+the	O
+cardiac	O
+and	O
+hepatic	O
+mitochondrial	O
+bioenergetic	O
+dysfunction	O
+associated	O
+with	O
+subchronic	O
+doxorubicin	O
+toxicity	B
+.	O
+
+Heart	O
+and	O
+liver	O
+mitochondria	O
+were	O
+isolated	O
+from	O
+rats	O
+treated	O
+for	O
+7	O
+weeks	O
+with	O
+doxorubicin	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+sc	O
+/	O
+week	O
+)	O
+,	O
+carvedilol	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+ip	O
+/	O
+week	O
+)	O
+,	O
+or	O
+the	O
+combination	O
+of	O
+the	O
+two	O
+drugs	O
+.	O
+
+Heart	O
+mitochondria	O
+isolated	O
+from	O
+doxorubicin	O
+-	O
+treated	O
+rats	O
+exhibited	O
+depressed	O
+rates	O
+for	O
+state	O
+3	O
+respiration	O
+(	O
+336	O
++	O
+/	O
+-	O
+26	O
+versus	O
+425	O
++	O
+/	O
+-	O
+53	O
+natom	O
+O	O
+/	O
+min	O
+/	O
+mg	O
+protein	O
+)	O
+and	O
+a	O
+lower	O
+respiratory	O
+control	O
+ratio	O
+(	O
+RCR	O
+)	O
+(	O
+4	O
+.	O
+3	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+versus	O
+5	O
+.	O
+8	O
++	O
+/	O
+-	O
+0	O
+.	O
+4	O
+)	O
+compared	O
+with	O
+cardiac	O
+mitochondria	O
+isolated	O
+from	O
+saline	O
+-	O
+treated	O
+rats	O
+.	O
+
+Mitochondrial	O
+calcium	O
+-	O
+loading	O
+capacity	O
+and	O
+the	O
+activity	O
+of	O
+NADH	O
+-	O
+dehydrogenase	O
+were	O
+also	O
+suppressed	O
+in	O
+cardiac	O
+mitochondria	O
+from	O
+doxorubicin	O
+-	O
+treated	O
+rats	O
+.	O
+
+Doxorubicin	O
+treatment	O
+also	O
+caused	O
+a	O
+decrease	O
+in	O
+RCR	O
+for	O
+liver	O
+mitochondria	O
+(	O
+3	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+9	O
+versus	O
+5	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+for	O
+control	O
+rats	O
+)	O
+and	O
+inhibition	O
+of	O
+hepatic	O
+cytochrome	O
+oxidase	O
+activity	O
+.	O
+
+Coadministration	O
+of	O
+carvedilol	O
+decreased	O
+the	O
+extent	O
+of	O
+cellular	O
+vacuolization	O
+in	O
+cardiac	O
+myocytes	O
+and	O
+prevented	O
+the	O
+inhibitory	O
+effect	O
+of	O
+doxorubicin	O
+on	O
+mitochondrial	O
+respiration	O
+in	O
+both	O
+heart	O
+and	O
+liver	O
+.	O
+
+Carvedilol	O
+also	O
+prevented	O
+the	O
+decrease	O
+in	O
+mitochondrial	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+loading	O
+capacity	O
+and	O
+the	O
+inhibition	O
+of	O
+the	O
+respiratory	O
+complexes	O
+of	O
+heart	O
+mitochondria	O
+caused	O
+by	O
+doxorubicin	O
+.	O
+
+Carvedilol	O
+by	O
+itself	O
+did	O
+not	O
+affect	O
+any	O
+of	O
+the	O
+parameters	O
+measured	O
+for	O
+heart	O
+or	O
+liver	O
+mitochondria	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+this	O
+protection	O
+by	O
+carvedilol	O
+against	O
+both	O
+the	O
+structural	O
+and	O
+functional	O
+cardiac	O
+tissue	O
+damage	O
+may	O
+afford	O
+significant	O
+clinical	O
+advantage	O
+in	O
+minimizing	O
+the	O
+dose	O
+-	O
+limiting	O
+mitochondrial	B
+dysfunction	I
+and	O
+cardiomyopathy	B
+that	O
+accompanies	O
+long	O
+-	O
+term	O
+doxorubicin	O
+therapy	O
+in	O
+cancer	B
+patients	O
+.	O
+
+Cocaine	O
+-	O
+induced	O
+hyperactivity	B
+is	O
+more	O
+influenced	O
+by	O
+adenosine	O
+receptor	O
+agonists	O
+than	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B
+.	O
+
+The	O
+influence	O
+of	O
+adenosine	O
+receptor	O
+agonists	O
+and	O
+antagonists	O
+on	O
+cocaine	O
+-	O
+and	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B
+was	O
+examined	O
+in	O
+mice	O
+.	O
+
+All	O
+adenosine	O
+receptor	O
+agonists	O
+significantly	O
+decreased	B
+the	I
+locomotor	I
+activity	I
+in	O
+mice	O
+,	O
+and	O
+the	O
+effects	O
+were	O
+dose	O
+-	O
+dependent	O
+.	O
+
+It	O
+seems	O
+that	O
+adenosine	O
+A1	O
+and	O
+A2	O
+receptors	O
+might	O
+be	O
+involved	O
+in	O
+this	O
+reaction	O
+.	O
+
+Moreover	O
+,	O
+all	O
+adenosine	O
+receptor	O
+agonists	O
+:	O
+2	O
+-	O
+p	O
+-	O
+(	O
+2	O
+-	O
+carboxyethyl	O
+)	O
+phenethylamino	O
+-	O
+5	O
+'	O
+-	O
+N	O
+-	O
+ethylcarboxamidoadenosine	O
+(	O
+CGS	O
+21680	O
+)	O
+,	O
+A2A	O
+receptor	O
+agonist	O
+,	O
+N6	O
+-	O
+cyclopentyladenosine	O
+(	O
+CPA	O
+)	O
+,	O
+A1	O
+receptor	O
+agonist	O
+,	O
+and	O
+5	O
+'	O
+-	O
+N	O
+-	O
+ethylcarboxamidoadenosine	O
+(	O
+NECA	O
+)	O
+,	O
+A2	O
+/	O
+A1	O
+receptor	O
+agonist	O
+significantly	O
+and	O
+dose	O
+-	O
+dependently	O
+decreased	O
+cocaine	O
+-	O
+induced	O
+locomotor	O
+activity	O
+.	O
+
+CPA	O
+reduced	O
+cocaine	O
+action	O
+at	O
+the	O
+doses	O
+which	O
+,	O
+given	O
+alone	O
+,	O
+did	O
+not	O
+influence	O
+motility	O
+,	O
+while	O
+CGS	O
+21680	O
+and	O
+NECA	O
+decreased	O
+the	O
+action	O
+of	O
+cocaine	O
+at	O
+the	O
+doses	O
+which	O
+,	O
+given	O
+alone	O
+,	O
+decreased	O
+locomotor	O
+activity	O
+in	O
+animals	O
+.	O
+
+These	O
+results	O
+suggest	O
+the	O
+involvement	O
+of	O
+both	O
+adenosine	O
+receptors	O
+in	O
+the	O
+action	O
+of	O
+cocaine	O
+although	O
+agonists	O
+of	O
+A1	O
+receptors	O
+seem	O
+to	O
+have	O
+stronger	O
+influence	O
+on	O
+it	O
+.	O
+
+The	O
+selective	O
+blockade	O
+of	O
+A2	O
+adenosine	O
+receptor	O
+by	O
+DMPX	O
+(	O
+3	O
+,	O
+7	O
+-	O
+dimethyl	O
+-	O
+1	O
+-	O
+propargylxanthine	O
+)	O
+significantly	O
+enhanced	O
+cocaine	O
+-	O
+induced	O
+locomotor	O
+activity	O
+of	O
+animals	O
+.	O
+
+Caffeine	O
+had	O
+similar	O
+action	O
+but	O
+the	O
+effect	O
+was	O
+not	O
+significant	O
+.	O
+
+CPT	O
+(	O
+8	O
+-	O
+cyclopentyltheophylline	O
+)	O
+-	O
+-	O
+A1	O
+receptor	O
+antagonist	O
+,	O
+did	O
+not	O
+show	O
+any	O
+influence	O
+in	O
+this	O
+test	O
+.	O
+
+Similarly	O
+,	O
+all	O
+adenosine	O
+receptor	O
+agonists	O
+decreased	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B
+,	O
+but	O
+at	O
+the	O
+higher	O
+doses	O
+than	O
+those	O
+which	O
+were	O
+active	O
+in	O
+cocaine	O
+-	O
+induced	O
+hyperactivity	B
+.	O
+
+The	O
+selective	O
+blockade	O
+of	O
+A2	O
+adenosine	O
+receptors	O
+(	O
+DMPX	O
+)	O
+and	O
+non	O
+-	O
+selective	O
+blockade	O
+of	O
+adenosine	O
+receptors	O
+(	O
+caffeine	O
+)	O
+significantly	O
+increased	O
+the	O
+action	O
+of	O
+amphetamine	O
+in	O
+the	O
+locomotor	O
+activity	O
+test	O
+.	O
+
+Our	O
+results	O
+have	O
+shown	O
+that	O
+all	O
+adenosine	O
+receptor	O
+agonists	O
+(	O
+A1	O
+and	O
+A2	O
+)	O
+reduce	O
+cocaine	O
+-	O
+and	O
+amphetamine	O
+-	O
+induced	O
+locomotor	O
+activity	O
+and	O
+indicate	O
+that	O
+cocaine	O
+-	O
+induced	O
+hyperactivity	B
+is	O
+more	O
+influenced	O
+by	O
+adenosine	O
+receptor	O
+agonists	O
+(	O
+particularly	O
+A1	O
+receptors	O
+)	O
+than	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B
+.	O
+
+Amiodarone	O
+and	O
+the	O
+risk	O
+of	O
+bradyarrhythmia	B
+requiring	O
+permanent	O
+pacemaker	O
+in	O
+elderly	O
+patients	O
+with	O
+atrial	B
+fibrillation	I
+and	O
+prior	O
+myocardial	B
+infarction	I
+.	O
+
+OBJECTIVES	O
+:	O
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+whether	O
+the	O
+use	O
+of	O
+amiodarone	O
+in	O
+patients	O
+with	O
+atrial	B
+fibrillation	I
+(	O
+AF	B
+)	O
+increases	O
+the	O
+risk	O
+of	O
+bradyarrhythmia	B
+requiring	O
+a	O
+permanent	O
+pacemaker	O
+.	O
+
+BACKGROUND	O
+:	O
+Reports	O
+of	O
+severe	O
+bradyarrhythmia	B
+during	O
+amiodarone	O
+therapy	O
+are	O
+infrequent	O
+and	O
+limited	O
+to	O
+studies	O
+assessing	O
+the	O
+therapy	O
+'	O
+s	O
+use	O
+in	O
+the	O
+management	O
+of	O
+patients	O
+with	O
+ventricular	B
+arrhythmias	I
+.	O
+
+METHODS	O
+:	O
+A	O
+study	O
+cohort	O
+of	O
+8	O
+,	O
+770	O
+patients	O
+age	O
+>	O
+or	O
+=	O
+65	O
+years	O
+with	O
+a	O
+new	O
+diagnosis	O
+of	O
+AF	B
+was	O
+identified	O
+from	O
+a	O
+provincewide	O
+database	O
+of	O
+Quebec	O
+residents	O
+with	O
+a	O
+myocardial	B
+infarction	I
+(	O
+MI	B
+)	O
+between	O
+1991	O
+and	O
+1999	O
+.	O
+
+Using	O
+a	O
+nested	O
+case	O
+-	O
+control	O
+design	O
+,	O
+477	O
+cases	O
+of	O
+bradyarrhythmia	B
+requiring	O
+a	O
+permanent	O
+pacemaker	O
+were	O
+matched	O
+(	O
+1	O
+:	O
+4	O
+)	O
+to	O
+1	O
+,	O
+908	O
+controls	O
+.	O
+
+Multivariable	O
+logistic	O
+regression	O
+was	O
+used	O
+to	O
+estimate	O
+the	O
+odds	O
+ratio	O
+(	O
+OR	O
+)	O
+of	O
+pacemaker	O
+insertion	O
+associated	O
+with	O
+amiodarone	O
+use	O
+,	O
+controlling	O
+for	O
+baseline	O
+risk	O
+factors	O
+and	O
+exposure	O
+to	O
+sotalol	O
+,	O
+Class	O
+I	O
+antiarrhythmic	O
+agents	O
+,	O
+beta	O
+-	O
+blockers	O
+,	O
+calcium	O
+channel	O
+blockers	O
+,	O
+and	O
+digoxin	O
+.	O
+
+RESULTS	O
+:	O
+amiodarone	O
+use	O
+was	O
+associated	O
+with	O
+an	O
+increased	O
+risk	O
+of	O
+pacemaker	O
+insertion	O
+(	O
+OR	O
+:	O
+2	O
+.	O
+14	O
+,	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+:	O
+1	O
+.	O
+30	O
+to	O
+3	O
+.	O
+54	O
+)	O
+.	O
+
+This	O
+effect	O
+was	O
+modified	O
+by	O
+gender	O
+,	O
+with	O
+a	O
+greater	O
+risk	O
+in	O
+women	O
+versus	O
+men	O
+(	O
+OR	O
+:	O
+3	O
+.	O
+86	O
+,	O
+95	O
+%	O
+CI	O
+:	O
+1	O
+.	O
+70	O
+to	O
+8	O
+.	O
+75	O
+vs	O
+.	O
+OR	O
+:	O
+1	O
+.	O
+52	O
+,	O
+95	O
+%	O
+CI	O
+:	O
+0	O
+.	O
+80	O
+to	O
+2	O
+.	O
+89	O
+)	O
+.	O
+
+Digoxin	O
+was	O
+the	O
+only	O
+other	O
+medication	O
+associated	O
+with	O
+an	O
+increased	O
+risk	O
+of	O
+pacemaker	O
+insertion	O
+(	O
+OR	O
+:	O
+1	O
+.	O
+78	O
+,	O
+95	O
+%	O
+CI	O
+:	O
+1	O
+.	O
+37	O
+to	O
+2	O
+.	O
+31	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+This	O
+study	O
+suggests	O
+that	O
+the	O
+use	O
+of	O
+amiodarone	O
+in	O
+elderly	O
+patients	O
+with	O
+AF	B
+and	O
+a	O
+previous	O
+MI	B
+increases	O
+the	O
+risk	O
+of	O
+bradyarrhythmia	B
+requiring	O
+a	O
+permanent	O
+pacemaker	O
+.	O
+
+The	O
+finding	O
+of	O
+an	O
+augmented	O
+risk	O
+of	O
+pacemaker	O
+insertion	O
+in	O
+elderly	O
+women	O
+receiving	O
+amiodarone	O
+requires	O
+further	O
+investigation	O
+.	O
+
+Indomethacin	O
+-	O
+induced	O
+morphologic	O
+changes	O
+in	O
+the	O
+rat	O
+urinary	O
+bladder	O
+epithelium	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+evaluate	O
+the	O
+morphologic	O
+changes	O
+in	O
+rat	O
+urothelium	O
+induced	O
+by	O
+indomethacin	O
+.	O
+
+Nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drug	O
+-	O
+induced	O
+cystitis	B
+is	O
+a	O
+poorly	O
+recognized	O
+and	O
+under	O
+-	O
+reported	O
+condition	O
+.	O
+
+In	O
+addition	O
+to	O
+tiaprofenic	O
+acid	O
+,	O
+indomethacin	O
+has	O
+been	O
+reported	O
+to	O
+be	O
+associated	O
+with	O
+this	O
+condition	O
+.	O
+
+METHODS	O
+:	O
+Three	O
+groups	O
+were	O
+established	O
+:	O
+a	O
+control	O
+group	O
+(	O
+n	O
+=	O
+10	O
+)	O
+,	O
+a	O
+high	O
+-	O
+dose	O
+group	O
+(	O
+n	O
+=	O
+10	O
+)	O
+,	O
+treated	O
+with	O
+one	O
+intraperitoneal	O
+injection	O
+of	O
+indomethacin	O
+20	O
+mg	O
+/	O
+kg	O
+,	O
+and	O
+a	O
+therapeutic	O
+dose	O
+group	O
+(	O
+n	O
+=	O
+10	O
+)	O
+in	O
+which	O
+oral	O
+indomethacin	O
+was	O
+administered	O
+3	O
+.	O
+25	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+daily	O
+for	O
+3	O
+weeks	O
+.	O
+
+The	O
+animals	O
+were	O
+then	O
+killed	O
+and	O
+the	O
+bladders	O
+removed	O
+for	O
+light	O
+and	O
+electron	O
+microscopic	O
+studies	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+light	O
+microscopic	O
+findings	O
+showed	O
+some	O
+focal	O
+epithelial	O
+degeneration	O
+that	O
+was	O
+more	O
+prominent	O
+in	O
+the	O
+high	O
+-	O
+dose	O
+group	O
+.	O
+
+When	O
+compared	O
+with	O
+the	O
+control	O
+group	O
+,	O
+both	O
+indomethacin	O
+groups	O
+revealed	O
+statistically	O
+increased	O
+numbers	O
+of	O
+mast	O
+cells	O
+in	O
+the	O
+mucosa	O
+(	O
+P	O
+<	O
+0	O
+.	O
+0001	O
+)	O
+and	O
+penetration	O
+of	O
+lanthanum	O
+nitrate	O
+through	O
+intercellular	O
+areas	O
+of	O
+the	O
+epithelium	O
+.	O
+
+Furthermore	O
+,	O
+the	O
+difference	O
+in	O
+mast	O
+cell	O
+counts	O
+between	O
+the	O
+high	O
+and	O
+therapeutic	O
+dose	O
+groups	O
+was	O
+also	O
+statistically	O
+significant	O
+(	O
+P	O
+<	O
+0	O
+.	O
+0001	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Indomethacin	O
+resulted	O
+in	O
+histopathologic	O
+findings	O
+typical	O
+of	O
+interstitial	B
+cystitis	I
+,	O
+such	O
+as	O
+leaky	O
+bladder	O
+epithelium	O
+and	O
+mucosal	O
+mastocytosis	B
+.	O
+
+The	O
+true	O
+incidence	O
+of	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drug	O
+-	O
+induced	O
+cystitis	B
+in	O
+humans	O
+must	O
+be	O
+clarified	O
+by	O
+prospective	O
+clinical	O
+trials	O
+.	O
+
+An	O
+open	O
+-	O
+label	O
+phase	O
+II	O
+study	O
+of	O
+low	O
+-	O
+dose	O
+thalidomide	O
+in	O
+androgen	O
+-	O
+independent	O
+prostate	B
+cancer	I
+.	O
+
+The	O
+antiangiogenic	O
+effects	O
+of	O
+thalidomide	O
+have	O
+been	O
+assessed	O
+in	O
+clinical	O
+trials	O
+in	O
+patients	O
+with	O
+various	O
+solid	O
+and	O
+haematological	B
+malignancies	I
+.	O
+
+Thalidomide	O
+blocks	O
+the	O
+activity	O
+of	O
+angiogenic	O
+agents	O
+including	O
+bFGF	O
+,	O
+VEGF	O
+and	O
+IL	O
+-	O
+6	O
+.	O
+
+We	O
+undertook	O
+an	O
+open	O
+-	O
+label	O
+study	O
+using	O
+thalidomide	O
+100	O
+mg	O
+once	O
+daily	O
+for	O
+up	O
+to	O
+6	O
+months	O
+in	O
+20	O
+men	O
+with	O
+androgen	O
+-	O
+independent	O
+prostate	B
+cancer	I
+.	O
+
+The	O
+mean	O
+time	O
+of	O
+study	O
+was	O
+109	O
+days	O
+(	O
+median	O
+107	O
+,	O
+range	O
+4	O
+-	O
+184	O
+days	O
+)	O
+.	O
+
+Patients	O
+underwent	O
+regular	O
+measurement	O
+of	O
+prostate	O
+-	O
+specific	O
+antigen	O
+(	O
+PSA	O
+)	O
+,	O
+urea	O
+and	O
+electrolytes	O
+,	O
+serum	O
+bFGF	O
+and	O
+VEGF	O
+.	O
+
+Three	O
+men	O
+(	O
+15	O
+%	O
+)	O
+showed	O
+a	O
+decline	O
+in	O
+serum	O
+PSA	O
+of	O
+at	O
+least	O
+50	O
+%	O
+,	O
+sustained	O
+throughout	O
+treatment	O
+.	O
+
+Of	O
+16	O
+men	O
+treated	O
+for	O
+at	O
+least	O
+2	O
+months	O
+,	O
+six	O
+(	O
+37	O
+.	O
+5	O
+%	O
+)	O
+showed	O
+a	O
+fall	O
+in	O
+absolute	O
+PSA	O
+by	O
+a	O
+median	O
+of	O
+48	O
+%	O
+.	O
+
+Increasing	O
+levels	O
+of	O
+serum	O
+bFGF	O
+and	O
+VEGF	O
+were	O
+associated	O
+with	O
+progressive	O
+disease	O
+;	O
+five	O
+of	O
+six	O
+men	O
+who	O
+demonstrated	O
+a	O
+fall	O
+in	O
+PSA	O
+also	O
+showed	O
+a	O
+decline	O
+in	O
+bFGF	O
+and	O
+VEGF	O
+levels	O
+,	O
+and	O
+three	O
+of	O
+four	O
+men	O
+with	O
+a	O
+rising	O
+PSA	O
+showed	O
+an	O
+increase	O
+in	O
+both	O
+growth	O
+factors	O
+.	O
+
+Adverse	O
+effects	O
+included	O
+constipation	B
+,	O
+morning	O
+drowsiness	B
+,	O
+dizziness	B
+and	O
+rash	B
+,	O
+and	O
+resulted	O
+in	O
+withdrawal	O
+from	O
+the	O
+study	O
+by	O
+three	O
+men	O
+.	O
+
+Evidence	O
+of	O
+peripheral	B
+sensory	I
+neuropathy	I
+was	O
+found	O
+in	O
+nine	O
+of	O
+13	O
+men	O
+before	O
+treatment	O
+.	O
+
+In	O
+the	O
+seven	O
+men	O
+who	O
+completed	O
+six	O
+months	O
+on	O
+thalidomide	O
+,	O
+subclinical	O
+evidence	O
+of	O
+peripheral	B
+neuropathy	I
+was	O
+found	O
+in	O
+four	O
+before	O
+treatment	O
+,	O
+but	O
+in	O
+all	O
+seven	O
+at	O
+repeat	O
+testing	O
+.	O
+
+The	O
+findings	O
+indicate	O
+that	O
+thalidomide	O
+may	O
+be	O
+an	O
+option	O
+for	O
+patients	O
+who	O
+have	O
+failed	O
+other	O
+forms	O
+of	O
+therapy	O
+,	O
+provided	O
+close	O
+follow	O
+-	O
+up	O
+is	O
+maintained	O
+for	O
+development	O
+of	O
+peripheral	B
+neuropathy	I
+.	O
+
+Central	B
+nervous	I
+system	I
+toxicity	I
+following	O
+the	O
+administration	O
+of	O
+levobupivacaine	O
+for	O
+lumbar	O
+plexus	O
+block	O
+:	O
+A	O
+report	O
+of	O
+two	O
+cases	O
+.	O
+
+BACKGROUND	O
+AND	O
+OBJECTIVES	O
+:	O
+Central	B
+nervous	I
+system	I
+and	I
+cardiac	I
+toxicity	I
+following	O
+the	O
+administration	O
+of	O
+local	O
+anesthetics	O
+is	O
+a	O
+recognized	O
+complication	O
+of	O
+regional	O
+anesthesia	O
+.	O
+
+Levobupivacaine	O
+,	O
+the	O
+pure	O
+S	O
+(	O
+-	O
+)	O
+enantiomer	O
+of	O
+bupivacaine	O
+,	O
+was	O
+developed	O
+to	O
+improve	O
+the	O
+cardiac	O
+safety	O
+profile	O
+of	O
+bupivacaine	O
+.	O
+
+We	O
+describe	O
+2	O
+cases	O
+of	O
+grand	B
+mal	I
+seizures	I
+following	O
+accidental	O
+intravascular	O
+injection	O
+of	O
+levobupivacaine	O
+.	O
+
+CASE	O
+REPORT	O
+:	O
+Two	O
+patients	O
+presenting	O
+for	O
+elective	O
+orthopedic	O
+surgery	O
+of	O
+the	O
+lower	O
+limb	O
+underwent	O
+blockade	O
+of	O
+the	O
+lumbar	O
+plexus	O
+via	O
+the	O
+posterior	O
+approach	O
+.	O
+
+Immediately	O
+after	O
+the	O
+administration	O
+of	O
+levobupivacaine	O
+0	O
+.	O
+5	O
+%	O
+with	O
+epinephrine	O
+2	O
+.	O
+5	O
+microgram	O
+/	O
+mL	O
+,	O
+the	O
+patients	O
+developed	O
+grand	B
+mal	I
+seizures	I
+,	O
+despite	O
+negative	O
+aspiration	O
+for	O
+blood	O
+and	O
+no	O
+clinical	O
+signs	O
+of	O
+intravenous	O
+epinephrine	O
+administration	O
+.	O
+
+The	O
+seizures	B
+were	O
+successfully	O
+treated	O
+with	O
+sodium	O
+thiopental	O
+in	O
+addition	O
+to	O
+succinylcholine	O
+in	O
+1	O
+patient	O
+.	O
+
+Neither	O
+patient	O
+developed	O
+signs	O
+of	O
+cardiovascular	B
+toxicity	I
+.	O
+
+Both	O
+patients	O
+were	O
+treated	O
+preoperatively	O
+with	O
+beta	O
+-	O
+adrenergic	O
+antagonist	O
+medications	O
+,	O
+which	O
+may	O
+have	O
+masked	O
+the	O
+cardiovascular	O
+signs	O
+of	O
+the	O
+unintentional	O
+intravascular	O
+administration	O
+of	O
+levobupivacaine	O
+with	O
+epinephrine	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Although	O
+levobupivacaine	O
+may	O
+have	O
+a	O
+safer	O
+cardiac	B
+toxicity	I
+profile	O
+than	O
+racemic	O
+bupivacaine	O
+,	O
+if	O
+adequate	O
+amounts	O
+of	O
+levobupivacaine	O
+reach	O
+the	O
+circulation	O
+,	O
+it	O
+will	O
+result	O
+in	O
+convulsions	B
+.	O
+
+Plasma	O
+concentrations	O
+sufficient	O
+to	O
+result	O
+in	O
+central	B
+nervous	I
+system	I
+toxicity	I
+did	O
+not	O
+produce	O
+manifestations	O
+of	O
+cardiac	B
+toxicity	I
+in	O
+these	O
+2	O
+patients	O
+.	O
+
+Amiodarone	O
+-	O
+induced	O
+torsade	B
+de	I
+pointes	I
+during	O
+bladder	O
+irrigation	O
+:	O
+an	O
+unusual	O
+presentation	O
+-	O
+-	O
+a	O
+case	O
+report	O
+.	O
+
+The	O
+authors	O
+present	O
+a	O
+case	O
+of	O
+early	O
+(	O
+within	O
+4	O
+days	O
+)	O
+development	O
+of	O
+torsade	B
+de	I
+pointes	I
+(	O
+TdP	B
+)	O
+associated	O
+with	O
+oral	O
+amiodarone	O
+therapy	O
+.	O
+
+Consistent	O
+with	O
+other	O
+reports	O
+this	O
+case	O
+of	O
+TdP	B
+occurred	O
+in	O
+the	O
+context	O
+of	O
+multiple	O
+exacerbating	O
+factors	O
+including	O
+hypokalemia	B
+and	O
+digoxin	O
+excess	O
+.	O
+
+Transient	O
+prolongation	O
+of	O
+the	O
+QT	O
+during	O
+bladder	O
+irrigation	O
+prompted	O
+the	O
+episode	O
+of	O
+TdP	B
+.	O
+
+It	O
+is	O
+well	O
+known	O
+that	O
+bradycardia	B
+exacerbates	O
+acquired	O
+TdP	B
+.	O
+
+The	O
+authors	O
+speculate	O
+that	O
+the	O
+increased	O
+vagal	O
+tone	O
+during	O
+bladder	O
+irrigation	O
+,	O
+a	O
+vagal	O
+maneuver	O
+,	O
+in	O
+the	O
+context	O
+of	O
+amiodarone	O
+therapy	O
+resulted	O
+in	O
+amiodarone	O
+-	O
+induced	O
+proarrhythmia	B
+.	O
+
+In	O
+the	O
+absence	O
+of	O
+amiodarone	O
+therapy	O
+,	O
+a	O
+second	O
+bladder	O
+irrigation	O
+did	O
+not	O
+induce	O
+TdP	B
+despite	O
+hypokalemia	B
+and	O
+hypomagnesemia	B
+.	O
+
+Anaesthetic	O
+complications	O
+associated	O
+with	O
+myotonia	B
+congenita	I
+:	O
+case	O
+study	O
+and	O
+comparison	O
+with	O
+other	O
+myotonic	B
+disorders	I
+.	O
+
+Myotonia	B
+congenita	I
+(	O
+MC	B
+)	O
+is	O
+caused	O
+by	O
+a	O
+defect	O
+in	O
+the	O
+skeletal	O
+muscle	O
+chloride	O
+channel	O
+function	O
+,	O
+which	O
+may	O
+cause	O
+sustained	B
+membrane	I
+depolarisation	I
+.	O
+
+We	O
+describe	O
+a	O
+previously	O
+healthy	O
+32	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+who	O
+developed	O
+a	O
+life	O
+-	O
+threatening	O
+muscle	B
+spasm	I
+and	O
+secondary	O
+ventilation	O
+difficulties	O
+following	O
+a	O
+preoperative	O
+injection	O
+of	O
+suxamethonium	O
+.	O
+
+The	O
+muscle	B
+spasms	I
+disappeared	O
+spontaneously	O
+and	O
+the	O
+surgery	O
+proceeded	O
+without	O
+further	O
+problems	O
+.	O
+
+When	O
+subsequently	O
+questioned	O
+,	O
+she	O
+reported	O
+minor	O
+symptoms	O
+suggesting	O
+a	O
+myotonic	B
+condition	I
+.	O
+
+Myotonia	B
+was	O
+found	O
+on	O
+clinical	O
+examination	O
+and	O
+EMG	O
+.	O
+
+The	O
+diagnosis	O
+MC	B
+was	O
+confirmed	O
+genetically	O
+.	O
+
+Neither	O
+the	O
+patient	O
+nor	O
+the	O
+anaesthetist	O
+were	O
+aware	O
+of	O
+the	O
+diagnosis	O
+before	O
+this	O
+potentially	O
+lethal	O
+complication	O
+occurred	O
+.	O
+
+We	O
+give	O
+a	O
+brief	O
+overview	O
+of	O
+ion	B
+channel	I
+disorders	I
+including	O
+malignant	B
+hyperthermia	I
+and	O
+their	O
+anaesthetic	O
+considerations	O
+.	O
+
+Respiratory	O
+pattern	O
+in	O
+a	O
+rat	O
+model	O
+of	O
+epilepsy	B
+.	O
+
+PURPOSE	O
+:	O
+Apnea	B
+is	O
+known	O
+to	O
+occur	O
+during	O
+seizures	B
+,	O
+but	O
+systematic	O
+studies	O
+of	O
+ictal	O
+respiratory	O
+changes	O
+in	O
+adults	O
+are	O
+few	O
+.	O
+
+Data	O
+regarding	O
+respiratory	O
+pattern	O
+defects	O
+during	O
+interictal	O
+periods	O
+also	O
+are	O
+scarce	O
+.	O
+
+Here	O
+we	O
+sought	O
+to	O
+generate	O
+information	O
+with	O
+regard	O
+to	O
+the	O
+interictal	O
+period	O
+in	O
+animals	O
+with	O
+pilocarpine	O
+-	O
+induced	O
+epilepsy	B
+.	O
+
+METHODS	O
+:	O
+Twelve	O
+rats	O
+(	O
+six	O
+chronically	O
+epileptic	B
+animals	O
+and	O
+six	O
+controls	O
+)	O
+were	O
+anesthetized	O
+,	O
+given	O
+tracheotomies	O
+,	O
+and	O
+subjected	O
+to	O
+hyperventilation	B
+or	O
+hypoventilation	O
+conditions	O
+.	O
+
+Breathing	O
+movements	O
+caused	O
+changes	O
+in	O
+thoracic	O
+volume	O
+and	O
+forced	O
+air	O
+to	O
+flow	O
+tidally	O
+through	O
+a	O
+pneumotachograph	O
+.	O
+
+This	O
+flow	O
+was	O
+measured	O
+by	O
+using	O
+a	O
+differential	O
+pressure	O
+transducer	O
+,	O
+passed	O
+through	O
+a	O
+polygraph	O
+,	O
+and	O
+from	O
+this	O
+to	O
+a	O
+computer	O
+with	O
+custom	O
+software	O
+that	O
+derived	O
+ventilation	O
+(	O
+VE	O
+)	O
+,	O
+tidal	O
+volume	O
+(	O
+VT	O
+)	O
+,	O
+inspiratory	O
+time	O
+(	O
+TI	O
+)	O
+,	O
+expiratory	O
+time	O
+(	O
+TE	O
+)	O
+,	O
+breathing	O
+frequency	O
+(	O
+f	O
+)	O
+,	O
+and	O
+mean	O
+inspiratory	O
+flow	O
+(	O
+VT	O
+/	O
+TI	O
+)	O
+on	O
+a	O
+breath	O
+-	O
+by	O
+-	O
+breath	O
+basis	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+hyperventilation	B
+maneuver	O
+caused	O
+a	O
+decrease	O
+in	O
+spontaneous	O
+ventilation	O
+in	O
+pilocarpine	O
+-	O
+treated	O
+and	O
+control	O
+rats	O
+.	O
+
+Although	O
+VE	O
+had	O
+a	O
+similar	O
+decrease	O
+in	O
+both	O
+groups	O
+,	O
+in	O
+the	O
+epileptic	B
+group	O
+,	O
+the	O
+decrease	O
+in	O
+VE	O
+was	O
+due	O
+to	O
+a	O
+significant	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+increase	O
+in	O
+TE	O
+peak	O
+in	O
+relation	O
+to	O
+that	O
+of	O
+the	O
+control	O
+animals	O
+.	O
+
+The	O
+hypoventilation	O
+maneuver	O
+led	O
+to	O
+an	O
+increase	O
+in	O
+the	O
+arterial	O
+Paco2	O
+,	O
+followed	O
+by	O
+an	O
+increase	O
+in	O
+VE	O
+.	O
+
+In	O
+the	O
+epileptic	B
+group	O
+,	O
+the	O
+increase	O
+in	O
+VE	O
+was	O
+mediated	O
+by	O
+a	O
+significant	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+decrease	O
+in	O
+TE	O
+peak	O
+compared	O
+with	O
+the	O
+control	O
+group	O
+.	O
+
+Systemic	O
+application	O
+of	O
+KCN	O
+,	O
+to	O
+evaluate	O
+the	O
+effects	O
+of	O
+peripheral	O
+chemoreception	O
+activation	O
+on	O
+ventilation	O
+,	O
+led	O
+to	O
+a	O
+similar	O
+increase	O
+in	O
+VE	O
+for	O
+both	O
+groups	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+data	O
+indicate	O
+that	O
+pilocarpine	O
+-	O
+treated	O
+animals	O
+have	O
+an	O
+altered	O
+ability	O
+to	O
+react	O
+to	O
+(	O
+or	O
+compensate	O
+for	O
+)	O
+blood	O
+gas	O
+changes	O
+with	O
+changes	O
+in	O
+ventilation	O
+and	O
+suggest	O
+that	O
+it	O
+is	O
+centrally	O
+determined	O
+.	O
+
+We	O
+speculate	O
+on	O
+the	O
+possible	O
+relation	O
+of	O
+the	O
+current	O
+findings	O
+on	O
+treating	O
+different	O
+epilepsy	B
+-	O
+associated	O
+conditions	O
+.	O
+
+Fatal	O
+myeloencephalopathy	B
+due	O
+to	O
+intrathecal	O
+vincristine	O
+administration	O
+.	O
+
+Vincristine	O
+was	O
+accidentally	O
+given	O
+intrathecally	O
+to	O
+a	O
+child	O
+with	O
+leukaemia	B
+,	O
+producing	O
+sensory	B
+and	I
+motor	I
+dysfunction	I
+followed	O
+by	O
+encephalopathy	B
+and	O
+death	O
+.	O
+
+Separate	O
+times	O
+for	O
+administering	O
+vincristine	O
+and	O
+intrathecal	O
+therapy	O
+is	O
+recommended	O
+.	O
+
+Progesterone	O
+potentiation	O
+of	O
+bupivacaine	O
+arrhythmogenicity	O
+in	O
+pentobarbital	O
+-	O
+anesthetized	O
+rats	O
+and	O
+beating	O
+rat	O
+heart	O
+cell	O
+cultures	O
+.	O
+
+The	O
+effects	O
+of	O
+progesterone	O
+treatment	O
+on	O
+bupivacaine	O
+arrhythmogenicity	O
+in	O
+beating	O
+rat	O
+heart	O
+myocyte	O
+cultures	O
+and	O
+on	O
+anesthetized	O
+rats	O
+were	O
+determined	O
+.	O
+
+After	O
+determining	O
+the	O
+bupivacaine	O
+AD50	O
+(	O
+the	O
+concentration	O
+of	O
+bupivacaine	O
+that	O
+caused	O
+50	O
+%	O
+of	O
+all	O
+beating	O
+rat	O
+heart	O
+myocyte	O
+cultures	O
+to	O
+become	O
+arrhythmic	B
+)	O
+,	O
+we	O
+determined	O
+the	O
+effect	O
+of	O
+1	O
+-	O
+hour	O
+progesterone	O
+HCl	O
+exposure	O
+on	O
+myocyte	O
+contractile	O
+rhythm	O
+.	O
+
+Each	O
+concentration	O
+of	O
+progesterone	O
+(	O
+6	O
+.	O
+25	O
+,	O
+12	O
+.	O
+5	O
+,	O
+25	O
+,	O
+and	O
+50	O
+micrograms	O
+/	O
+ml	O
+)	O
+caused	O
+a	O
+significant	O
+and	O
+concentration	O
+-	O
+dependent	O
+reduction	O
+in	O
+the	O
+AD50	O
+for	O
+bupivacaine	O
+.	O
+
+Estradiol	O
+treatment	O
+also	O
+increased	O
+the	O
+arrhythmogenicity	O
+of	O
+bupivacaine	O
+in	O
+myocyte	O
+cultures	O
+,	O
+but	O
+was	O
+only	O
+one	O
+fourth	O
+as	O
+potent	O
+as	O
+progesterone	O
+.	O
+
+Neither	O
+progesterone	O
+nor	O
+estradiol	O
+effects	O
+on	O
+bupivacaine	O
+arrhythmogenicity	O
+were	O
+potentiated	O
+by	O
+epinephrine	O
+.	O
+
+Chronic	O
+progesterone	O
+pretreatment	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+for	O
+21	O
+days	O
+)	O
+caused	O
+a	O
+significant	O
+increase	O
+in	O
+bupivacaine	O
+arrhythmogenicity	O
+in	O
+intact	O
+pentobarbital	O
+-	O
+anesthetized	O
+rats	O
+.	O
+
+There	O
+was	O
+a	O
+significant	O
+decrease	O
+in	O
+the	O
+time	O
+to	O
+onset	O
+of	O
+arrhythmia	B
+as	O
+compared	O
+with	O
+control	O
+nonprogesterone	O
+-	O
+treated	O
+rats	O
+(	O
+6	O
+.	O
+2	O
++	O
+/	O
+-	O
+1	O
+.	O
+3	O
+vs	O
+.	O
+30	O
+.	O
+8	O
++	O
+/	O
+-	O
+2	O
+.	O
+5	O
+min	O
+,	O
+mean	O
++	O
+/	O
+-	O
+SE	O
+)	O
+.	O
+
+The	O
+results	O
+of	O
+this	O
+study	O
+indicate	O
+that	O
+progesterone	O
+can	O
+potentiate	O
+bupivacaine	O
+arrhythmogenicity	O
+both	O
+in	O
+vivo	O
+and	O
+in	O
+vitro	O
+.	O
+
+Potentiation	O
+of	O
+bupivacaine	O
+arrhythmia	B
+in	O
+myocyte	O
+cultures	O
+suggests	O
+that	O
+this	O
+effect	O
+is	O
+at	O
+least	O
+partly	O
+mediated	O
+at	O
+the	O
+myocyte	O
+level	O
+.	O
+
+Increased	O
+serum	O
+soluble	O
+Fas	O
+in	O
+patients	O
+with	O
+acute	B
+liver	I
+failure	I
+due	O
+to	O
+paracetamol	O
+overdose	B
+.	O
+
+BACKGROUND	O
+/	O
+AIMS	O
+:	O
+Experimental	O
+studies	O
+have	O
+suggested	O
+that	O
+apoptosis	O
+via	O
+the	O
+Fas	O
+/	O
+Fas	O
+Ligand	O
+signaling	O
+system	O
+may	O
+play	O
+an	O
+important	O
+role	O
+in	O
+the	O
+development	O
+of	O
+acute	B
+liver	I
+failure	I
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+soluble	O
+form	O
+of	O
+Fas	O
+in	O
+patients	O
+with	O
+acute	B
+liver	I
+failure	I
+.	O
+
+METHODOLOGY	O
+:	O
+Serum	O
+levels	O
+of	O
+sFas	O
+(	O
+soluble	O
+Fas	O
+)	O
+were	O
+measured	O
+by	O
+ELISA	O
+in	O
+24	O
+patients	O
+with	O
+acute	B
+liver	I
+failure	I
+and	O
+10	O
+normal	O
+control	O
+subjects	O
+.	O
+
+Serum	O
+levels	O
+of	O
+tumor	B
+necrosis	B
+factor	O
+-	O
+alpha	O
+and	O
+interferon	O
+-	O
+gamma	O
+were	O
+also	O
+determined	O
+by	O
+ELISA	O
+.	O
+
+RESULTS	O
+:	O
+Serum	O
+sFas	O
+was	O
+significantly	O
+increased	O
+in	O
+patients	O
+with	O
+acute	B
+liver	I
+failure	I
+(	O
+median	O
+,	O
+26	O
+.	O
+8	O
+U	O
+/	O
+mL	O
+;	O
+range	O
+,	O
+6	O
+.	O
+9	O
+-	O
+52	O
+.	O
+7	O
+U	O
+/	O
+mL	O
+)	O
+compared	O
+to	O
+the	O
+normal	O
+controls	O
+(	O
+median	O
+,	O
+8	O
+.	O
+6	O
+U	O
+/	O
+mL	O
+;	O
+range	O
+,	O
+6	O
+.	O
+5	O
+-	O
+12	O
+.	O
+0	O
+U	O
+/	O
+mL	O
+,	O
+P	O
+<	O
+0	O
+.	O
+0001	O
+)	O
+.	O
+
+Levels	O
+were	O
+significantly	O
+greater	O
+in	O
+patients	O
+with	O
+acute	B
+liver	I
+failure	I
+due	O
+to	O
+paracetamol	O
+overdose	B
+(	O
+median	O
+,	O
+28	O
+.	O
+7	O
+U	O
+/	O
+mL	O
+;	O
+range	O
+,	O
+12	O
+.	O
+8	O
+-	O
+52	O
+.	O
+7	O
+U	O
+/	O
+mL	O
+,	O
+n	O
+=	O
+17	O
+)	O
+than	O
+those	O
+due	O
+to	O
+non	O
+-	O
+A	O
+to	O
+E	O
+hepatitis	B
+(	O
+median	O
+,	O
+12	O
+.	O
+5	O
+U	O
+/	O
+mL	O
+;	O
+range	O
+,	O
+6	O
+.	O
+9	O
+-	O
+46	O
+.	O
+0	O
+U	O
+/	O
+mL	O
+,	O
+n	O
+=	O
+7	O
+,	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+There	O
+was	O
+no	O
+relationship	O
+of	O
+sFas	O
+to	O
+eventual	O
+outcome	O
+in	O
+the	O
+patients	O
+.	O
+
+A	O
+significant	O
+correlation	O
+was	O
+observed	O
+between	O
+serum	O
+sFas	O
+levels	O
+and	O
+aspartate	O
+aminotransferase	O
+(	O
+r	O
+=	O
+0	O
+.	O
+613	O
+,	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+increased	O
+concentration	O
+of	O
+sFas	O
+in	O
+serum	O
+of	O
+patients	O
+with	O
+acute	B
+liver	I
+failure	I
+may	O
+reflect	O
+activation	O
+of	O
+Fas	O
+-	O
+mediated	O
+apoptosis	O
+in	O
+the	O
+liver	O
+and	O
+this	O
+together	O
+with	O
+increased	O
+tumor	B
+necrosis	B
+factor	O
+-	O
+alpha	O
+may	O
+be	O
+an	O
+important	O
+factor	O
+in	O
+liver	O
+cell	O
+loss	O
+.	O
+
+Bilateral	O
+subthalamic	O
+nucleus	O
+stimulation	O
+for	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+High	O
+frequency	O
+stimulation	O
+of	O
+the	O
+subthalamic	O
+nucleus	O
+(	O
+STN	O
+)	O
+is	O
+known	O
+to	O
+ameliorate	O
+the	O
+signs	O
+and	O
+symptoms	O
+of	O
+advanced	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+AIM	O
+:	O
+We	O
+studied	O
+the	O
+effect	O
+of	O
+high	O
+frequency	O
+STN	O
+stimulation	O
+in	O
+23	O
+patients	O
+.	O
+
+METHOD	O
+:	O
+Twenty	O
+-	O
+three	O
+patients	O
+suffering	O
+from	O
+severe	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+Stages	O
+III	O
+-	O
+V	O
+on	O
+Hoehn	O
+and	O
+Yahr	O
+scale	O
+)	O
+and	O
+,	O
+particularly	O
+bradykinesia	B
+,	O
+rigidity	B
+,	O
+and	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+underwent	O
+bilateral	O
+implantation	O
+of	O
+electrodes	O
+in	O
+the	O
+STN	O
+.	O
+
+Preoperative	O
+and	O
+postoperative	O
+assessments	O
+of	O
+these	O
+patients	O
+at	O
+1	O
+,	O
+3	O
+,	O
+6	O
+and	O
+12	O
+months	O
+follow	O
+-	O
+up	O
+,	O
+in	O
+"	O
+on	O
+"	O
+and	O
+"	O
+off	O
+"	O
+drug	O
+conditions	O
+,	O
+was	O
+carried	O
+out	O
+using	O
+Unified	O
+Parkinson	B
+'	I
+s	I
+Disease	I
+Rating	O
+Scale	O
+,	O
+Hoehn	O
+and	O
+Yahr	O
+staging	O
+,	O
+England	O
+activities	O
+of	O
+daily	O
+living	O
+score	O
+and	O
+video	O
+recordings	O
+.	O
+
+RESULTS	O
+:	O
+After	O
+one	O
+year	O
+of	O
+electrical	O
+stimulation	O
+of	O
+the	O
+STN	O
+,	O
+the	O
+patients	O
+'	O
+scores	O
+for	O
+activities	O
+of	O
+daily	O
+living	O
+and	O
+motor	O
+examination	O
+scores	O
+(	O
+Unified	O
+Parkinson	B
+'	I
+s	I
+Disease	I
+Rating	O
+Scale	O
+parts	O
+II	O
+and	O
+III	O
+)	O
+off	O
+medication	O
+improved	O
+by	O
+62	O
+%	O
+and	O
+61	O
+%	O
+respectively	O
+(	O
+p	O
+<	O
+0	O
+.	O
+0005	O
+)	O
+.	O
+
+The	O
+subscores	O
+for	O
+the	O
+akinesia	B
+,	O
+rigidity	B
+,	O
+tremor	B
+and	O
+gait	O
+also	O
+improved	O
+.	O
+
+(	O
+p	O
+<	O
+0	O
+.	O
+0005	O
+)	O
+.	O
+
+The	O
+average	O
+levodopa	O
+dose	O
+decreased	O
+from	O
+813	O
+mg	O
+to	O
+359	O
+mg	O
+.	O
+
+The	O
+cognitive	O
+functions	O
+remained	O
+unchanged	O
+.	O
+
+Two	O
+patients	O
+developed	O
+device	O
+-	O
+related	O
+complications	O
+and	O
+two	O
+patients	O
+experienced	O
+abnormal	O
+weight	O
+gain	O
+.	O
+
+CONCLUSION	O
+:	O
+Bilateral	O
+subthalamic	O
+nucleus	O
+stimulation	O
+is	O
+an	O
+effective	O
+treatment	O
+for	O
+advanced	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+It	O
+reduces	O
+the	O
+severity	O
+of	O
+"	O
+off	O
+"	O
+phase	O
+symptoms	O
+,	O
+improves	O
+the	O
+axial	O
+symptoms	O
+and	O
+reduces	O
+levodopa	O
+requirements	O
+.	O
+
+The	O
+reduction	O
+in	O
+the	O
+levodopa	O
+dose	O
+is	O
+useful	O
+in	O
+controlling	O
+drug	B
+-	I
+induced	I
+dyskinesias	I
+.	O
+
+Acute	B
+renal	I
+failure	I
+occurring	O
+during	O
+intravenous	O
+desferrioxamine	O
+therapy	O
+:	O
+recovery	O
+after	O
+haemodialysis	O
+.	O
+
+A	O
+patient	O
+with	O
+transfusion	O
+-	O
+dependent	O
+thalassemia	B
+was	O
+undergoing	O
+home	O
+intravenous	O
+desferrioxamine	O
+(	O
+DFX	O
+)	O
+treatment	O
+by	O
+means	O
+of	O
+a	O
+totally	O
+implanted	O
+system	O
+because	O
+of	O
+his	O
+poor	O
+compliance	O
+with	O
+the	O
+nightly	O
+subcutaneous	O
+therapy	O
+.	O
+
+Due	O
+to	O
+an	O
+accidental	O
+malfunctioning	O
+of	O
+the	O
+infusion	O
+pump	O
+,	O
+the	O
+patient	O
+was	O
+inadvertently	O
+administered	O
+a	O
+toxic	O
+dosage	O
+of	O
+the	O
+drug	O
+which	O
+caused	O
+renal	B
+insufficiency	I
+.	O
+
+Given	O
+the	O
+progressive	O
+deterioration	O
+of	O
+the	O
+symptoms	O
+and	O
+of	O
+the	O
+laboratory	O
+values	O
+,	O
+despite	O
+adequate	O
+medical	O
+treatment	O
+,	O
+a	O
+decision	O
+was	O
+made	O
+to	O
+introduce	O
+haemodialytical	O
+therapy	O
+in	O
+order	O
+to	O
+remove	O
+the	O
+drug	O
+and	O
+therapy	O
+reduce	O
+the	O
+nephrotoxicity	B
+.	O
+
+From	O
+the	O
+results	O
+obtained	O
+,	O
+haemodialysis	O
+can	O
+therefore	O
+be	O
+suggested	O
+as	O
+a	O
+useful	O
+therapy	O
+in	O
+rare	O
+cases	O
+of	O
+progressive	O
+acute	B
+renal	I
+failure	I
+caused	O
+by	O
+desferrioxamine	O
+.	O
+
+Ocular	O
+motility	O
+changes	O
+after	O
+subtenon	O
+carboplatin	O
+chemotherapy	O
+for	O
+retinoblastoma	B
+.	O
+
+BACKGROUND	O
+:	O
+Focal	O
+subtenon	O
+carboplatin	O
+injections	O
+have	O
+recently	O
+been	O
+used	O
+as	O
+a	O
+presumably	O
+toxicity	B
+-	O
+free	O
+adjunct	O
+to	O
+systemic	O
+chemotherapy	O
+for	O
+intraocular	O
+retinoblastoma	B
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+our	O
+clinical	O
+experience	O
+with	O
+abnormal	B
+ocular	I
+motility	I
+in	O
+patients	O
+treated	O
+with	O
+subtenon	O
+carboplatin	O
+chemotherapy	O
+.	O
+
+METHODS	O
+:	O
+We	O
+noted	O
+abnormal	B
+ocular	I
+motility	I
+in	O
+10	O
+consecutive	O
+patients	O
+with	O
+retinoblastoma	B
+who	O
+had	O
+received	O
+subtenon	O
+carboplatin	O
+.	O
+
+During	O
+ocular	O
+manipulation	O
+under	O
+general	O
+anesthesia	O
+,	O
+we	O
+assessed	O
+their	O
+eyes	O
+by	O
+forced	O
+duction	O
+testing	O
+,	O
+comparing	O
+ocular	O
+motility	O
+after	O
+tumor	B
+control	O
+with	O
+ocular	O
+motility	O
+at	O
+diagnosis	O
+.	O
+
+Eyes	O
+subsequently	O
+enucleated	O
+because	O
+of	O
+treatment	O
+failure	O
+(	O
+n	O
+=	O
+4	O
+)	O
+were	O
+examined	O
+histologically	O
+.	O
+
+RESULTS	O
+:	O
+Limitation	O
+of	O
+ocular	O
+motility	O
+was	O
+detected	O
+in	O
+all	O
+12	O
+eyes	O
+of	O
+10	O
+patients	O
+treated	O
+for	O
+intraocular	O
+retinoblastoma	B
+with	O
+1	O
+to	O
+6	O
+injections	O
+of	O
+subtenon	O
+carboplatin	O
+as	O
+part	O
+of	O
+multimodality	O
+therapy	O
+.	O
+
+Histopathological	O
+examination	O
+revealed	O
+many	O
+lipophages	O
+in	O
+the	O
+periorbital	O
+fat	O
+surrounding	O
+the	O
+optic	O
+nerve	O
+in	O
+1	O
+eye	O
+,	O
+indicative	O
+of	O
+phagocytosis	O
+of	O
+previously	O
+existing	O
+fat	O
+cells	O
+and	O
+suggesting	O
+prior	O
+fat	O
+necrosis	B
+.	O
+
+The	O
+enucleations	O
+were	O
+technically	O
+difficult	O
+and	O
+hazardous	O
+for	O
+globe	O
+rupture	B
+because	O
+of	O
+extensive	O
+orbital	O
+soft	O
+tissue	O
+adhesions	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Subtenon	O
+carboplatin	O
+chemotherapy	O
+is	O
+associated	O
+with	O
+significant	O
+fibrosis	B
+of	O
+orbital	O
+soft	O
+tissues	O
+,	O
+leading	O
+to	O
+mechanical	O
+restriction	O
+of	O
+eye	O
+movements	O
+and	O
+making	O
+subsequent	O
+enucleation	O
+difficult	O
+.	O
+
+Subtenon	O
+carboplatin	O
+is	O
+not	O
+free	O
+of	O
+toxicity	B
+,	O
+and	O
+its	O
+use	O
+is	O
+best	O
+restricted	O
+to	O
+specific	O
+indications	O
+.	O
+
+Ethambutol	O
+and	O
+optic	B
+neuropathy	I
+.	O
+
+PURPOSE	O
+:	O
+To	O
+demonstrate	O
+the	O
+association	O
+between	O
+ethambutol	O
+and	O
+optic	B
+neuropathy	I
+.	O
+
+METHOD	O
+:	O
+Thirteen	O
+patients	O
+who	O
+developed	O
+optic	B
+neuropathy	I
+after	O
+being	O
+treated	O
+with	O
+ethambutol	O
+for	O
+tuberculosis	B
+of	I
+the	I
+lung	I
+or	I
+lymph	I
+node	I
+at	O
+Siriraj	O
+Hospital	O
+between	O
+1997	O
+and	O
+2001	O
+were	O
+retrospectively	O
+reviewed	O
+.	O
+
+The	O
+clinical	O
+characteristics	O
+and	O
+initial	O
+and	O
+final	O
+visual	O
+acuity	O
+were	O
+analyzed	O
+to	O
+determine	O
+visual	O
+outcome	O
+.	O
+
+RESULTS	O
+:	O
+All	O
+patients	O
+had	O
+optic	B
+neuropathy	I
+between	O
+1	O
+to	O
+6	O
+months	O
+(	O
+mean	O
+=	O
+2	O
+.	O
+9	O
+months	O
+)	O
+after	O
+starting	O
+ethambutol	O
+therapy	O
+at	O
+a	O
+dosage	O
+ranging	O
+from	O
+13	O
+to	O
+20	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+(	O
+mean	O
+=	O
+17	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+)	O
+.	O
+
+Seven	O
+(	O
+54	O
+%	O
+)	O
+of	O
+the	O
+13	O
+patients	O
+experienced	O
+visual	O
+recovery	O
+after	O
+stopping	O
+the	O
+drug	O
+.	O
+
+Of	O
+6	O
+patients	O
+with	O
+irreversible	O
+visual	B
+impairment	I
+,	O
+4	O
+patients	O
+had	O
+diabetes	B
+mellitus	I
+,	O
+glaucoma	B
+and	O
+a	O
+history	O
+of	O
+heavy	O
+smoking	O
+.	O
+
+CONCLUSION	O
+:	O
+Early	O
+recognition	O
+of	O
+optic	B
+neuropathy	I
+should	O
+be	O
+considered	O
+in	O
+patients	O
+with	O
+ethambutol	O
+therapy	O
+.	O
+
+A	O
+low	O
+dose	O
+and	O
+prompt	O
+discontinuation	O
+of	O
+the	O
+drug	O
+is	O
+recommended	O
+particularly	O
+in	O
+individuals	O
+with	O
+diabetes	B
+mellitus	I
+,	O
+glaucoma	B
+or	O
+who	O
+are	O
+heavy	O
+smokers	O
+.	O
+
+Treatment	O
+of	O
+compensatory	O
+gustatory	B
+hyperhidrosis	I
+with	O
+topical	O
+glycopyrrolate	O
+.	O
+
+Gustatory	B
+hyperhidrosis	I
+is	O
+facial	O
+sweating	B
+usually	O
+associated	O
+with	O
+the	O
+eating	O
+of	O
+hot	O
+spicy	O
+food	O
+or	O
+even	O
+smelling	O
+this	O
+food	O
+.	O
+
+Current	O
+options	O
+of	O
+treatment	O
+include	O
+oral	O
+anticholinergic	O
+drugs	O
+,	O
+the	O
+topical	O
+application	O
+of	O
+anticholinergics	O
+or	O
+aluminum	O
+chloride	O
+,	O
+and	O
+the	O
+injection	O
+of	O
+botulinum	O
+toxin	O
+.	O
+
+Thirteen	O
+patients	O
+have	O
+been	O
+treated	O
+to	O
+date	O
+with	O
+1	O
+.	O
+5	O
+%	O
+or	O
+2	O
+%	O
+topical	O
+glycopyrrolate	O
+.	O
+
+All	O
+patients	O
+had	O
+gustatory	B
+hyperhidrosis	I
+,	O
+which	O
+interfered	O
+with	O
+their	O
+social	O
+activities	O
+,	O
+after	O
+transthroacic	O
+endoscopic	O
+sympathectomy	O
+,	O
+and	O
+which	O
+was	O
+associated	O
+with	O
+compensatory	O
+focal	O
+hyperhidrosis	B
+.	O
+
+After	O
+applying	O
+topical	O
+glycopyrrolate	O
+,	O
+the	O
+subjective	O
+effect	O
+was	O
+excellent	O
+(	O
+no	O
+sweating	B
+after	O
+eating	O
+hot	O
+spicy	O
+food	O
+)	O
+in	O
+10	O
+patients	O
+(	O
+77	O
+%	O
+)	O
+,	O
+and	O
+fair	O
+(	O
+clearly	O
+reduced	O
+sweating	B
+)	O
+in	O
+3	O
+patients	O
+(	O
+23	O
+%	O
+)	O
+.	O
+
+All	O
+had	O
+reported	O
+incidents	O
+of	O
+being	O
+very	O
+embarrassed	O
+whilst	O
+eating	O
+hot	O
+spicy	O
+foods	O
+.	O
+
+Adverse	O
+effects	O
+included	O
+a	O
+mildly	O
+dry	B
+mouth	I
+and	O
+a	O
+sore	B
+throat	I
+in	O
+2	O
+patients	O
+(	O
+2	O
+%	O
+glycopyrrolate	O
+)	O
+,	O
+a	O
+light	O
+headache	B
+in	O
+1	O
+patient	O
+(	O
+1	O
+.	O
+5	O
+%	O
+glycopyrrolate	O
+)	O
+.	O
+
+The	O
+topical	O
+application	O
+of	O
+a	O
+glycopyrrolate	O
+pad	O
+appeared	O
+to	O
+be	O
+safe	O
+,	O
+efficacious	O
+,	O
+well	O
+tolerated	O
+,	O
+and	O
+a	O
+convenient	O
+method	O
+of	O
+treatment	O
+for	O
+moderate	O
+to	O
+severe	O
+symptoms	O
+of	O
+gustatory	B
+hyperhidrosis	I
+in	O
+post	O
+transthoracic	O
+endoscopic	O
+sympathectomy	O
+or	O
+sympathicotomy	O
+patients	O
+,	O
+with	O
+few	O
+side	O
+effects	O
+.	O
+
+Neuroleptic	O
+-	O
+associated	O
+hyperprolactinemia	B
+.	O
+
+Can	O
+it	O
+be	O
+treated	O
+with	O
+bromocriptine	O
+?	O
+
+Six	O
+stable	O
+psychiatric	O
+outpatients	O
+with	O
+hyperprolactinemia	B
+and	O
+amenorrhea	B
+/	O
+oligomenorrhea	B
+associated	O
+with	O
+their	O
+neuroleptic	O
+medications	O
+were	O
+treated	O
+with	O
+bromocriptine	O
+.	O
+
+Daily	O
+dosages	O
+of	O
+5	O
+-	O
+10	O
+mg	O
+corrected	O
+the	O
+hyperprolactinemia	B
+and	O
+restored	O
+menstruation	O
+in	O
+four	O
+of	O
+the	O
+six	O
+patients	O
+.	O
+
+One	O
+woman	O
+,	O
+however	O
+,	O
+developed	O
+worsened	O
+psychiatric	B
+symptoms	I
+while	O
+taking	O
+bromocriptine	O
+,	O
+and	O
+it	O
+was	O
+discontinued	O
+.	O
+
+Thus	O
+,	O
+three	O
+of	O
+six	O
+patients	O
+had	O
+their	O
+menstrual	O
+irregularity	O
+successfully	O
+corrected	O
+with	O
+bromocriptine	O
+.	O
+
+This	O
+suggests	O
+that	O
+bromocriptine	O
+should	O
+be	O
+further	O
+evaluated	O
+as	O
+potential	O
+therapy	O
+for	O
+neuroleptic	O
+-	O
+associated	O
+hyperprolactinemia	B
+and	O
+amenorrhea	B
+/	O
+galactorrhea	B
+.	O
+
+Ethacrynic	O
+acid	O
+-	O
+induced	O
+convulsions	B
+and	O
+brain	O
+neurotransmitters	O
+in	O
+mice	O
+.	O
+
+Intracerebroventricular	O
+injection	O
+of	O
+ethacrynic	O
+acid	O
+(	O
+50	O
+%	O
+convulsive	B
+dose	O
+;	O
+50	O
+micrograms	O
+/	O
+mouse	O
+)	O
+accelerated	O
+the	O
+synthesis	O
+/	O
+turnover	O
+of	O
+5	O
+-	O
+hydroxytryptamine	O
+(	O
+5	O
+-	O
+HT	O
+)	O
+but	O
+suppressed	O
+the	O
+synthesis	O
+of	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+and	O
+acetylcholine	O
+in	O
+mouse	O
+brain	O
+.	O
+
+These	O
+effects	O
+were	O
+completely	O
+antagonized	O
+by	O
+pretreatment	O
+with	O
+a	O
+glutamate	O
+/	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+antagonist	O
+,	O
+aminophosphonovaleric	O
+acid	O
+.	O
+
+In	O
+ethacrynic	O
+acid	O
+-	O
+induced	O
+convulsions	B
+,	O
+these	O
+neurotransmitter	O
+systems	O
+may	O
+be	O
+differentially	O
+modulated	O
+,	O
+probably	O
+through	O
+activation	O
+of	O
+glutaminergic	O
+neurons	O
+in	O
+the	O
+brain	O
+.	O
+
+Pharmacology	O
+of	O
+gamma	O
+-	O
+aminobutyric	O
+acidA	O
+receptor	O
+complex	O
+after	O
+the	O
+in	O
+vivo	O
+administration	O
+of	O
+the	O
+anxioselective	O
+and	O
+anticonvulsant	O
+beta	O
+-	O
+carboline	O
+derivative	O
+abecarnil	O
+.	O
+
+In	O
+rodents	O
+,	O
+the	O
+effect	O
+of	O
+the	O
+beta	O
+-	O
+carboline	O
+derivative	O
+isopropyl	O
+-	O
+6	O
+-	O
+benzyloxy	O
+-	O
+4	O
+-	O
+methoxymethyl	O
+-	O
+beta	O
+-	O
+carboline	O
+-	O
+3	O
+-	O
+carboxylate	O
+(	O
+abecarrnil	O
+)	O
+,	O
+a	O
+new	O
+ligand	O
+for	O
+benzodiazepine	O
+receptors	O
+possessing	O
+anxiolytic	O
+and	O
+anticonvulsant	O
+properties	O
+,	O
+was	O
+evaluated	O
+on	O
+the	O
+function	O
+of	O
+central	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+(	O
+GABA	O
+)	O
+A	O
+receptor	O
+complex	O
+,	O
+both	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+.	O
+
+Added	O
+in	O
+vitro	O
+to	O
+rat	O
+cortical	O
+membrane	O
+preparation	O
+,	O
+abecarnil	O
+increased	O
+[	O
+3H	O
+]	O
+GABA	O
+binding	O
+,	O
+enhanced	O
+muscimol	O
+-	O
+stimulated	O
+36Cl	O
+-	O
+uptake	O
+and	O
+reduced	O
+the	O
+binding	O
+of	O
+t	O
+-	O
+[	O
+35S	O
+]	O
+butylbicyclophosphorothionate	O
+(	O
+[	O
+35S	O
+]	O
+TBPS	O
+)	O
+.	O
+
+These	O
+effects	O
+were	O
+similar	O
+to	O
+those	O
+induced	O
+by	O
+diazepam	O
+,	O
+whereas	O
+the	O
+partial	O
+agonist	O
+Ro	O
+16	O
+-	O
+6028	O
+(	O
+tert	O
+-	O
+butyl	O
+-	O
+(	O
+S	O
+)	O
+-	O
+8	O
+-	O
+bromo	O
+-	O
+11	O
+,	O
+12	O
+,	O
+13	O
+,	O
+13a	O
+-	O
+tetrahydro	O
+-	O
+9	O
+-	O
+oxo	O
+-	O
+9H	O
+-	O
+imidazo	O
+[	O
+1	O
+,	O
+5	O
+-	O
+a	O
+]	O
+-	O
+pyrrolo	O
+-	O
+[	O
+2	O
+,	O
+1	O
+-	O
+c	O
+]	O
+[	O
+1	O
+,	O
+4	O
+]	O
+benzodiazepine	O
+-	O
+1	O
+-	O
+carboxylate	O
+)	O
+showed	O
+very	O
+weak	O
+efficacy	O
+in	O
+these	O
+biochemical	O
+tests	O
+.	O
+
+After	O
+i	O
+.	O
+p	O
+.	O
+injection	O
+to	O
+rats	O
+,	O
+abecarnil	O
+and	O
+diazepam	O
+decreased	O
+in	O
+a	O
+time	O
+-	O
+dependent	O
+and	O
+dose	O
+-	O
+related	O
+(	O
+0	O
+.	O
+25	O
+-	O
+20	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+manner	O
+[	O
+35S	O
+]	O
+TBPS	O
+binding	O
+measured	O
+ex	O
+vivo	O
+in	O
+the	O
+cerebral	O
+cortex	O
+.	O
+
+Moreover	O
+,	O
+both	O
+drugs	O
+at	O
+the	O
+dose	O
+of	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+antagonized	O
+completely	O
+the	O
+convulsant	O
+activity	O
+and	O
+the	O
+increase	O
+of	O
+[	O
+35S	O
+]	O
+TBPS	O
+binding	O
+induced	O
+by	O
+isoniazide	O
+(	O
+350	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+as	O
+well	O
+as	O
+the	O
+increase	O
+of	O
+[	O
+35S	O
+]	O
+TBPS	O
+binding	O
+induced	O
+by	O
+foot	O
+-	O
+shock	O
+stress	O
+.	O
+
+To	O
+better	O
+correlate	O
+the	O
+biochemical	O
+and	O
+the	O
+pharmacological	O
+effects	O
+,	O
+we	O
+studied	O
+the	O
+action	O
+of	O
+abecarnil	O
+on	O
+[	O
+35S	O
+]	O
+TBPS	O
+binding	O
+,	O
+exploratory	O
+motility	O
+and	O
+on	O
+isoniazid	O
+-	O
+induced	O
+biochemical	O
+and	O
+pharmacological	O
+effects	O
+in	O
+mice	O
+.	O
+
+In	O
+these	O
+animals	O
+,	O
+abecarnil	O
+produced	O
+a	O
+paralleled	O
+dose	O
+-	O
+dependent	O
+(	O
+0	O
+.	O
+05	O
+-	O
+1	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+reduction	O
+of	O
+both	O
+motor	O
+behavior	O
+and	O
+cortical	O
+[	O
+35S	O
+]	O
+TBPS	O
+binding	O
+.	O
+
+Moreover	O
+,	O
+0	O
+.	O
+05	O
+mg	O
+/	O
+kg	O
+of	O
+this	O
+beta	O
+-	O
+carboline	O
+reduced	O
+markedly	O
+the	O
+increase	O
+of	O
+[	O
+35S	O
+]	O
+TBPS	O
+binding	O
+and	O
+the	O
+convulsions	B
+induced	O
+by	O
+isoniazid	O
+(	O
+200	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Recurrent	O
+myocardial	B
+infarction	I
+in	O
+a	O
+postpartum	O
+patient	O
+receiving	O
+bromocriptine	O
+.	O
+
+Myocardial	B
+infarction	I
+in	O
+puerperium	O
+is	O
+infrequently	O
+reported	O
+.	O
+
+Spasm	B
+,	O
+coronary	O
+dissection	O
+,	O
+or	O
+atheromatous	O
+etiology	O
+has	O
+been	O
+described	O
+.	O
+
+Bromocriptine	O
+has	O
+been	O
+implicated	O
+in	O
+several	O
+previous	O
+case	O
+reports	O
+of	O
+myocardial	B
+infarction	I
+in	O
+the	O
+puerperium	O
+.	O
+
+Our	O
+case	O
+(	O
+including	O
+an	O
+inadvertent	O
+rechallenge	O
+)	O
+suggests	O
+such	O
+a	O
+relationship	O
+.	O
+
+Although	O
+generally	O
+regarded	O
+as	O
+"	O
+safe	O
+,	O
+"	O
+possible	O
+serious	O
+cardiac	O
+effects	O
+of	O
+bromocriptine	O
+should	O
+be	O
+acknowledged	O
+.	O
+
+Asterixis	B
+induced	O
+by	O
+carbamazepine	O
+therapy	O
+.	O
+
+There	O
+are	O
+very	O
+few	O
+reports	O
+about	O
+asterixis	B
+as	O
+a	O
+side	O
+effect	O
+of	O
+treatment	O
+with	O
+psychopharmacologic	O
+agents	O
+.	O
+
+In	O
+this	O
+report	O
+we	O
+present	O
+four	O
+patients	O
+treated	O
+with	O
+a	O
+combination	O
+of	O
+different	O
+psychotropic	O
+drugs	O
+,	O
+in	O
+whom	O
+asterixis	B
+was	O
+triggered	O
+either	O
+by	O
+adding	O
+carbamazepine	O
+(	O
+CBZ	O
+)	O
+to	O
+a	O
+treatment	O
+regimen	O
+,	O
+or	O
+by	O
+increasing	O
+its	O
+dosage	O
+.	O
+
+Neither	O
+dosage	O
+nor	O
+serum	O
+levels	O
+of	O
+CBZ	O
+were	O
+in	O
+a	O
+higher	O
+range	O
+.	O
+
+We	O
+consider	O
+asterixis	B
+to	O
+be	O
+an	O
+easily	O
+overlooked	O
+sign	O
+of	O
+neurotoxicity	B
+,	O
+which	O
+may	O
+occur	O
+even	O
+at	O
+low	O
+or	O
+moderate	O
+dosage	O
+levels	O
+,	O
+if	O
+certain	O
+drugs	O
+as	O
+lithium	O
+or	O
+clozapine	O
+are	O
+used	O
+in	O
+combination	O
+with	O
+CBZ	O
+.	O
+
+Pharmacodynamics	O
+of	O
+the	O
+hypotensive	B
+effect	O
+of	O
+levodopa	O
+in	O
+parkinsonian	B
+patients	O
+.	O
+
+Blood	O
+pressure	O
+effects	O
+of	O
+i	O
+.	O
+v	O
+.	O
+levodopa	O
+were	O
+examined	O
+in	O
+parkinsonian	B
+patients	O
+with	O
+stable	O
+and	O
+fluctuating	O
+responses	O
+to	O
+levodopa	O
+.	O
+
+The	O
+magnitude	O
+of	O
+the	O
+hypotensive	B
+effect	O
+of	O
+levodopa	O
+was	O
+concentration	O
+dependent	O
+and	O
+was	O
+fit	O
+to	O
+an	O
+Emax	O
+model	O
+in	O
+fluctuating	O
+responders	O
+.	O
+
+Stable	O
+responders	O
+demonstrated	O
+a	O
+small	O
+hypotensive	B
+response	O
+.	O
+
+Baseline	O
+blood	O
+pressures	O
+were	O
+higher	O
+in	O
+fluctuating	O
+patients	O
+;	O
+a	O
+higher	O
+baseline	O
+blood	O
+pressure	O
+correlated	O
+with	O
+greater	O
+hypotensive	B
+effects	O
+.	O
+
+Antiparkinsonian	O
+effects	O
+of	O
+levodopa	O
+temporally	O
+correlated	O
+with	O
+blood	O
+pressure	O
+changes	O
+.	O
+
+Phenylalanine	O
+,	O
+a	O
+large	O
+neutral	O
+amino	O
+acid	O
+(	O
+LNAA	O
+)	O
+competing	O
+with	O
+levodopa	O
+for	O
+transport	O
+across	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+,	O
+reduced	O
+the	O
+hypotensive	B
+and	O
+antiparkinsonian	O
+effects	O
+of	O
+levodopa	O
+.	O
+
+We	O
+conclude	O
+that	O
+levodopa	O
+has	O
+a	O
+central	O
+hypotensive	B
+action	O
+that	O
+parallels	O
+the	O
+motor	O
+effects	O
+in	O
+fluctuating	O
+patients	O
+.	O
+
+The	O
+hypotensive	B
+effect	O
+appears	O
+to	O
+be	O
+related	O
+to	O
+the	O
+higher	O
+baseline	O
+blood	O
+pressure	O
+we	O
+observed	O
+in	O
+fluctuating	O
+patients	O
+relative	O
+to	O
+stable	O
+patients	O
+.	O
+
+Syndrome	B
+of	I
+inappropriate	I
+secretion	I
+of	I
+antidiuretic	I
+hormone	I
+after	O
+infusional	O
+vincristine	O
+.	O
+
+A	O
+77	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+refractory	O
+multiple	B
+myeloma	I
+was	O
+treated	O
+with	O
+a	O
+4	O
+-	O
+day	O
+continuous	O
+intravenous	O
+infusion	O
+of	O
+vincristine	O
+and	O
+doxorubicin	O
+and	O
+4	O
+days	O
+of	O
+oral	O
+dexamethasone	O
+.	O
+
+Nine	O
+days	O
+after	O
+her	O
+second	O
+cycle	O
+she	O
+presented	O
+with	O
+lethargy	B
+and	O
+weakness	B
+associated	O
+with	O
+hyponatremia	B
+.	O
+
+Evaluation	O
+revealed	O
+the	O
+syndrome	B
+of	I
+inappropriate	I
+secretion	I
+of	I
+antidiuretic	I
+hormone	I
+,	O
+which	O
+was	O
+attributed	O
+to	O
+the	O
+vincristine	O
+infusion	O
+.	O
+
+After	O
+normal	O
+serum	O
+sodium	O
+levels	O
+returned	O
+,	O
+further	O
+doxorubicin	O
+and	O
+dexamethasone	O
+chemotherapy	O
+without	O
+vincristine	O
+did	O
+not	O
+produce	O
+this	O
+complication	O
+.	O
+
+Heart	B
+failure	I
+:	O
+to	O
+digitalise	O
+or	O
+not	O
+?	O
+
+The	O
+view	O
+against	O
+.	O
+
+Despite	O
+extensive	O
+clinical	O
+experience	O
+the	O
+role	O
+of	O
+digoxin	O
+is	O
+still	O
+not	O
+well	O
+defined	O
+.	O
+
+In	O
+patients	O
+with	O
+atrial	B
+fibrillation	I
+digoxin	O
+is	O
+beneficial	O
+for	O
+ventricular	O
+rate	O
+control	O
+.	O
+
+For	O
+patients	O
+in	O
+sinus	O
+rhythm	O
+and	O
+heart	B
+failure	I
+the	O
+situation	O
+is	O
+less	O
+clear	O
+.	O
+
+Digoxin	O
+has	O
+a	O
+narrow	O
+therapeutic	O
+:	O
+toxic	O
+ratio	O
+and	O
+concentrations	O
+are	O
+affected	O
+by	O
+a	O
+number	O
+of	O
+drugs	O
+.	O
+
+Also	O
+,	O
+digoxin	O
+has	O
+undesirable	O
+effects	O
+such	O
+as	O
+increasing	O
+peripheral	O
+resistance	O
+and	O
+myocardial	O
+demands	O
+,	O
+and	O
+causing	O
+arrhythmias	B
+.	O
+
+There	O
+is	O
+a	O
+paucity	O
+of	O
+data	O
+from	O
+well	O
+-	O
+designed	O
+trials	O
+.	O
+
+The	O
+trials	O
+that	O
+are	O
+available	O
+are	O
+generally	O
+small	O
+with	O
+limitations	O
+in	O
+design	O
+and	O
+these	O
+show	O
+variation	O
+in	O
+patient	O
+benefit	O
+.	O
+
+More	O
+convincing	O
+evidence	O
+is	O
+required	O
+showing	O
+that	O
+digoxin	O
+improves	O
+symptoms	O
+or	O
+exercise	O
+capacity	O
+.	O
+
+Furthermore	O
+,	O
+no	O
+trial	O
+has	O
+had	O
+sufficient	O
+power	O
+to	O
+evaluate	O
+mortality	O
+.	O
+
+Pooled	O
+analysis	O
+of	O
+the	O
+effects	O
+of	O
+other	O
+inotropic	O
+drugs	O
+shows	O
+an	O
+excess	O
+mortality	O
+and	O
+there	O
+is	O
+a	O
+possibility	O
+that	O
+digoxin	O
+may	O
+increase	O
+mortality	O
+after	O
+myocardial	B
+infarction	I
+(	O
+MI	B
+)	O
+.	O
+
+Angiotensin	O
+-	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+inhibitors	O
+should	O
+be	O
+used	O
+first	O
+as	O
+they	O
+are	O
+safer	O
+,	O
+do	O
+not	O
+require	O
+blood	O
+level	O
+monitoring	O
+,	O
+modify	O
+progression	O
+of	O
+disease	O
+,	O
+relieve	O
+symptoms	O
+,	O
+improve	O
+exercise	O
+tolerance	O
+and	O
+reduce	O
+mortality	O
+.	O
+
+Caution	O
+should	O
+be	O
+exercised	O
+in	O
+using	O
+digoxin	O
+until	O
+large	O
+mortality	O
+trials	O
+are	O
+completed	O
+showing	O
+either	O
+benefit	O
+or	O
+harm	O
+.	O
+
+Until	O
+then	O
+digoxin	O
+should	O
+be	O
+considered	O
+a	O
+third	O
+-	O
+line	O
+therapy	O
+.	O
+
+Isradipine	O
+treatment	O
+for	O
+hypertension	B
+in	O
+general	O
+practice	O
+in	O
+Hong	O
+Kong	O
+.	O
+
+A	O
+6	O
+-	O
+week	O
+open	O
+study	O
+of	O
+the	O
+introduction	O
+of	O
+isradipine	O
+treatment	O
+was	O
+conducted	O
+in	O
+general	O
+practice	O
+in	O
+Hong	O
+Kong	O
+.	O
+
+303	O
+Chinese	O
+patients	O
+with	O
+mild	O
+to	O
+moderate	O
+hypertension	B
+entered	O
+the	O
+study	O
+.	O
+
+Side	O
+effects	O
+were	O
+reported	O
+in	O
+21	O
+%	O
+of	O
+patients	O
+and	O
+caused	O
+withdrawal	O
+from	O
+the	O
+study	O
+in	O
+3	O
+patients	O
+.	O
+
+The	O
+main	O
+side	O
+-	O
+effects	O
+were	O
+headache	B
+,	O
+dizziness	B
+,	O
+palpitation	B
+and	O
+flushing	B
+and	O
+these	O
+were	O
+not	O
+more	O
+frequent	O
+than	O
+reported	O
+in	O
+other	O
+studies	O
+with	O
+isradipine	O
+or	O
+with	O
+placebo	O
+.	O
+
+Supine	O
+blood	O
+pressure	O
+was	O
+reduced	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+from	O
+170	O
++	O
+/	O
+-	O
+20	O
+/	O
+102	O
++	O
+/	O
+-	O
+6	O
+mmHg	O
+to	O
+153	O
++	O
+/	O
+-	O
+19	O
+/	O
+92	O
++	O
+/	O
+-	O
+8	O
+,	O
+147	O
++	O
+/	O
+-	O
+18	O
+/	O
+88	O
++	O
+/	O
+-	O
+7	O
+and	O
+144	O
++	O
+/	O
+-	O
+14	O
+/	O
+87	O
++	O
+/	O
+-	O
+6	O
+mmHg	O
+at	O
+2	O
+,	O
+4	O
+and	O
+6	O
+weeks	O
+respectively	O
+in	O
+evaluable	O
+patients	O
+.	O
+
+Similar	O
+reductions	O
+occurred	O
+in	O
+standing	O
+blood	O
+pressure	O
+and	O
+there	O
+was	O
+no	O
+evidence	O
+of	O
+postural	B
+hypotension	I
+.	O
+
+Normalization	O
+and	O
+responder	O
+rates	O
+at	O
+6	O
+weeks	O
+were	O
+86	O
+%	O
+and	O
+69	O
+%	O
+respectively	O
+.	O
+
+Dosage	O
+was	O
+increased	O
+from	O
+2	O
+.	O
+5	O
+mg	O
+b	O
+.	O
+d	O
+.	O
+to	O
+5	O
+mg	O
+b	O
+.	O
+d	O
+.	O
+at	O
+4	O
+weeks	O
+in	O
+patients	O
+with	O
+diastolic	O
+blood	O
+pressure	O
+greater	O
+than	O
+90	O
+mmHg	O
+and	O
+their	O
+further	O
+response	O
+was	O
+greater	O
+than	O
+those	O
+remaining	O
+on	O
+2	O
+.	O
+5	O
+mg	O
+b	O
+.	O
+d	O
+.	O
+
+Pharmacological	O
+characteristics	O
+and	O
+side	O
+effects	O
+of	O
+a	O
+new	O
+galenic	O
+formulation	O
+of	O
+propofol	O
+without	O
+soyabean	O
+oil	O
+.	O
+
+We	O
+compared	O
+the	O
+pharmacokinetics	O
+,	O
+pharmacodynamics	O
+and	O
+safety	O
+profile	O
+of	O
+a	O
+new	O
+galenic	O
+formulation	O
+of	O
+propofol	O
+(	O
+AM149	O
+1	O
+%	O
+)	O
+,	O
+which	O
+does	O
+not	O
+contain	O
+soyabean	O
+oil	O
+,	O
+with	O
+a	O
+standard	O
+formulation	O
+of	O
+propofol	O
+(	O
+Disoprivan	O
+1	O
+%	O
+)	O
+.	O
+
+In	O
+a	O
+randomised	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+cross	O
+-	O
+over	O
+study	O
+,	O
+30	O
+healthy	O
+volunteers	O
+received	O
+a	O
+single	O
+intravenous	O
+bolus	O
+injection	O
+of	O
+2	O
+.	O
+5	O
+mg	O
+.	O
+kg	O
+-	O
+1	O
+propofol	O
+.	O
+
+Plasma	O
+propofol	O
+levels	O
+were	O
+measured	O
+for	O
+48	O
+h	O
+following	O
+drug	O
+administration	O
+and	O
+evaluated	O
+according	O
+to	O
+a	O
+three	O
+-	O
+compartment	O
+model	O
+.	O
+
+The	O
+pharmacodynamic	O
+parameters	O
+assessed	O
+included	O
+induction	O
+and	O
+emergence	O
+times	O
+,	O
+respiratory	O
+and	O
+cardiovascular	O
+effects	O
+,	O
+and	O
+pain	B
+on	O
+injection	O
+.	O
+
+Patients	O
+were	O
+monitored	O
+for	O
+side	O
+effects	O
+over	O
+48	O
+h	O
+.	O
+
+Owing	O
+to	O
+a	O
+high	O
+incidence	O
+of	O
+thrombophlebitis	B
+,	O
+the	O
+study	O
+was	O
+terminated	O
+prematurely	O
+and	O
+only	O
+the	O
+data	O
+of	O
+the	O
+two	O
+parallel	O
+treatment	O
+groups	O
+(	O
+15	O
+patients	O
+in	O
+each	O
+group	O
+)	O
+were	O
+analysed	O
+.	O
+
+Plasma	O
+concentrations	O
+did	O
+not	O
+differ	O
+significantly	O
+between	O
+the	O
+two	O
+formulations	O
+.	O
+
+Anaesthesia	O
+induction	O
+and	O
+emergence	O
+times	O
+,	O
+respiratory	O
+and	O
+cardiovascular	O
+variables	O
+showed	O
+no	O
+significant	O
+differences	O
+between	O
+the	O
+two	O
+treatment	O
+groups	O
+.	O
+
+Pain	B
+on	O
+injection	O
+(	O
+80	O
+vs	O
+.	O
+20	O
+%	O
+,	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+and	O
+thrombophlebitis	B
+(	O
+93	O
+.	O
+3	O
+vs	O
+.	O
+6	O
+.	O
+6	O
+%	O
+,	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+occurred	O
+more	O
+frequently	O
+with	O
+AM149	O
+than	O
+with	O
+Disoprivan	O
+.	O
+
+Although	O
+both	O
+formulations	O
+had	O
+similar	O
+pharmacokinetic	O
+and	O
+pharmacodynamic	O
+profiles	O
+the	O
+new	O
+formulation	O
+is	O
+not	O
+suitable	O
+for	O
+clinical	O
+use	O
+due	O
+to	O
+the	O
+high	O
+incidence	O
+of	O
+thrombophlebitis	B
+produced	O
+.	O
+
+Pure	B
+red	I
+cell	I
+aplasia	I
+,	O
+toxic	B
+dermatitis	I
+and	O
+lymphadenopathy	B
+in	O
+a	O
+patient	O
+taking	O
+diphenylhydantoin	O
+.	O
+
+A	O
+patient	O
+taking	O
+diphenylhydantoin	O
+for	O
+3	O
+weeks	O
+developed	O
+a	O
+generalized	O
+skin	B
+rash	I
+,	O
+lymphadenopathy	B
+and	O
+pure	B
+red	I
+cell	I
+aplasia	I
+.	O
+
+After	O
+withdrawal	O
+of	O
+the	O
+pharmacon	O
+all	O
+symptoms	O
+disappeared	O
+spontaneously	O
+.	O
+
+Skin	B
+rash	I
+is	O
+a	O
+well	O
+-	O
+known	O
+complication	O
+of	O
+diphenylhydantoin	O
+treatment	O
+as	O
+is	O
+benign	O
+and	O
+malignant	O
+lymphadenopathy	B
+.	O
+
+Pure	B
+red	I
+cell	I
+aplasia	I
+associated	O
+with	O
+diphenylhydantoin	O
+medication	O
+has	O
+been	O
+reported	O
+in	O
+3	O
+patients	O
+.	O
+
+The	O
+exact	O
+mechanism	O
+by	O
+which	O
+diphenylhydantoin	O
+exerts	O
+its	O
+toxic	O
+effects	O
+is	O
+not	O
+known	O
+.	O
+
+In	O
+this	O
+patient	O
+the	O
+time	O
+relation	O
+between	O
+the	O
+ingestion	O
+of	O
+diphenylhydantoin	O
+and	O
+the	O
+occurrence	O
+of	O
+the	O
+skin	B
+rash	I
+,	O
+lymphadenopathy	B
+and	O
+pure	B
+red	I
+cell	I
+aplasia	I
+is	O
+very	O
+suggestive	O
+of	O
+a	O
+direct	O
+connection	O
+.	O
+
+Vinorelbine	O
+-	O
+related	O
+cardiac	O
+events	O
+:	O
+a	O
+meta	O
+-	O
+analysis	O
+of	O
+randomized	O
+clinical	O
+trials	O
+.	O
+
+Several	O
+cases	O
+of	O
+cardiac	O
+adverse	O
+reactions	O
+related	O
+to	O
+vinorelbine	O
+(	O
+VNR	O
+)	O
+have	O
+been	O
+reported	O
+in	O
+the	O
+literature	O
+.	O
+
+In	O
+order	O
+to	O
+quantify	O
+the	O
+incidence	O
+of	O
+these	O
+cardiac	O
+events	O
+,	O
+we	O
+performed	O
+a	O
+meta	O
+-	O
+analysis	O
+of	O
+clinical	O
+trials	O
+comparing	O
+VNR	O
+with	O
+other	O
+chemotherapeutic	O
+agents	O
+in	O
+the	O
+treatment	O
+of	O
+various	O
+malignancies	B
+.	O
+
+Randomized	O
+clinical	O
+trials	O
+comparing	O
+VNR	O
+with	O
+other	O
+drugs	O
+in	O
+the	O
+treatment	O
+of	O
+cancer	B
+were	O
+searched	O
+in	O
+Medline	O
+,	O
+Embase	O
+,	O
+Evidence	O
+-	O
+based	O
+Medicine	O
+Reviews	O
+databases	O
+and	O
+the	O
+Cochrane	O
+library	O
+from	O
+1987	O
+to	O
+2002	O
+.	O
+
+Outcomes	O
+of	O
+interest	O
+were	O
+severe	O
+cardiac	O
+events	O
+,	O
+toxic	O
+deaths	O
+and	O
+cardiac	O
+event	O
+-	O
+related	O
+deaths	O
+reported	O
+in	O
+each	O
+publication	O
+.	O
+
+We	O
+found	O
+19	O
+trials	O
+,	O
+involving	O
+2441	O
+patients	O
+treated	O
+by	O
+VNR	O
+and	O
+2050	O
+control	O
+patients	O
+.	O
+
+The	O
+incidence	O
+of	O
+cardiac	O
+events	O
+with	O
+VNR	O
+was	O
+1	O
+.	O
+19	O
+%	O
+[	O
+95	O
+%	O
+confidence	O
+interval	O
+(	O
+CI	O
+)	O
+(	O
+0	O
+.	O
+75	O
+;	O
+1	O
+.	O
+67	O
+)	O
+]	O
+.	O
+
+There	O
+was	O
+no	O
+difference	O
+in	O
+the	O
+risk	O
+of	O
+cardiac	O
+events	O
+between	O
+VNR	O
+and	O
+other	O
+drugs	O
+[	O
+odds	O
+ratio	O
+:	O
+0	O
+.	O
+92	O
+,	O
+95	O
+%	O
+CI	O
+(	O
+0	O
+.	O
+54	O
+;	O
+1	O
+.	O
+55	O
+)	O
+]	O
+.	O
+
+The	O
+risk	O
+of	O
+VNR	O
+cardiac	O
+events	O
+was	O
+similar	O
+to	O
+vindesine	O
+(	O
+VDS	O
+)	O
+and	O
+other	O
+cardiotoxic	B
+drugs	O
+[	O
+fluorouracil	O
+,	O
+anthracyclines	O
+,	O
+gemcitabine	O
+(	O
+GEM	O
+)	O
+em	O
+leader	O
+]	O
+.	O
+
+Even	O
+if	O
+it	O
+did	O
+not	O
+reach	O
+statistical	O
+significance	O
+because	O
+of	O
+a	O
+few	O
+number	O
+of	O
+cases	O
+,	O
+the	O
+risk	O
+was	O
+lower	O
+in	O
+trials	O
+excluding	O
+patients	O
+with	O
+cardiac	O
+history	O
+,	O
+and	O
+seemed	O
+to	O
+be	O
+higher	O
+in	O
+trials	O
+including	O
+patients	O
+with	O
+pre	O
+-	O
+existing	O
+cardiac	B
+diseases	I
+.	O
+
+Vinorelbine	O
+-	O
+related	O
+cardiac	O
+events	O
+concern	O
+about	O
+1	O
+%	O
+of	O
+treated	O
+patients	O
+in	O
+clinical	O
+trials	O
+.	O
+
+However	O
+,	O
+the	O
+risk	O
+associated	O
+with	O
+VNR	O
+seems	O
+to	O
+be	O
+similar	O
+to	O
+that	O
+of	O
+other	O
+chemotherapeutic	O
+agents	O
+in	O
+the	O
+same	O
+indications	O
+.	O
+
+MRI	O
+findings	O
+of	O
+hypoxic	O
+cortical	O
+laminar	O
+necrosis	B
+in	O
+a	O
+child	O
+with	O
+hemolytic	B
+anemia	I
+crisis	O
+.	O
+
+We	O
+present	O
+magnetic	O
+resonance	O
+imaging	O
+findings	O
+of	O
+a	O
+5	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+who	O
+had	O
+a	O
+rapidly	O
+installing	O
+hemolytic	B
+anemia	I
+crisis	O
+induced	O
+by	O
+trimethoprim	O
+-	O
+sulfomethoxazole	O
+,	O
+resulting	O
+in	O
+cerebral	B
+anoxia	I
+leading	O
+to	O
+permanent	O
+damage	O
+.	O
+
+Magnetic	O
+Resonance	O
+imaging	O
+revealed	O
+cortical	O
+laminar	O
+necrosis	B
+in	O
+arterial	O
+border	O
+zones	O
+in	O
+both	O
+cerebral	O
+hemispheres	O
+,	O
+ischemic	O
+changes	O
+in	O
+subcortical	O
+white	O
+matter	O
+of	O
+left	O
+cerebral	O
+hemisphere	O
+,	O
+and	O
+in	O
+the	O
+left	O
+putamen	O
+.	O
+
+Although	O
+cortical	O
+laminar	O
+necrosis	B
+is	O
+a	O
+classic	O
+entity	O
+in	O
+adulthood	O
+related	O
+to	O
+conditions	O
+of	O
+energy	O
+depletions	O
+,	O
+there	O
+are	O
+few	O
+reports	O
+available	O
+in	O
+children	O
+.	O
+
+A	O
+wide	O
+review	O
+of	O
+the	O
+literature	O
+is	O
+also	O
+presented	O
+.	O
+
+The	O
+natural	O
+history	O
+of	O
+Vigabatrin	O
+associated	O
+visual	B
+field	I
+defects	I
+in	O
+patients	O
+electing	O
+to	O
+continue	O
+their	O
+medication	O
+.	O
+
+PURPOSE	O
+:	O
+To	O
+determine	O
+the	O
+natural	O
+history	O
+of	O
+visual	B
+field	I
+defects	I
+in	O
+a	O
+group	O
+of	O
+patients	O
+known	O
+to	O
+have	O
+Vigabatrin	O
+-	O
+associated	O
+changes	O
+who	O
+elected	O
+to	O
+continue	O
+the	O
+medication	O
+because	O
+of	O
+good	O
+seizure	B
+control	O
+.	O
+
+METHODS	O
+:	O
+All	O
+patients	O
+taking	O
+Vigabatrin	O
+alone	O
+or	O
+in	O
+combination	O
+with	O
+other	O
+antiepileptic	O
+drugs	O
+for	O
+at	O
+least	O
+5	O
+years	O
+(	O
+range	O
+5	O
+-	O
+12	O
+years	O
+)	O
+were	O
+entered	O
+into	O
+a	O
+visual	O
+surveillance	O
+programme	O
+.	O
+
+Patients	O
+were	O
+followed	O
+up	O
+at	O
+6	O
+-	O
+monthly	O
+intervals	O
+for	O
+not	O
+less	O
+than	O
+18	O
+months	O
+(	O
+range	O
+18	O
+-	O
+43	O
+months	O
+)	O
+.	O
+
+In	O
+all	O
+,	O
+16	O
+patients	O
+with	O
+unequivocal	O
+defects	O
+continued	O
+the	O
+medication	O
+.	O
+
+Following	O
+already	O
+published	O
+methodology	O
+(	O
+Eye	O
+2002	O
+;	O
+16	O
+;	O
+567	O
+-	O
+571	O
+)	O
+monocular	O
+mean	O
+radial	O
+degrees	O
+(	O
+MRDs	O
+)	O
+to	O
+the	O
+I	O
+/	O
+4e	O
+isopter	O
+on	O
+Goldmann	O
+perimetry	O
+was	O
+calculated	O
+for	O
+the	O
+right	O
+eye	O
+at	O
+the	O
+time	O
+of	O
+discovery	O
+of	O
+a	O
+visual	B
+field	I
+defect	I
+and	O
+again	O
+after	O
+not	O
+less	O
+than	O
+18	O
+months	O
+follow	O
+-	O
+up	O
+.	O
+
+RESULTS	O
+:	O
+Mean	O
+right	O
+eye	O
+MRD	O
+at	O
+presentation	O
+was	O
+36	O
+.	O
+98	O
+degrees	O
+(	O
+range	O
+22	O
+.	O
+25	O
+-	O
+51	O
+.	O
+0	O
+)	O
+,	O
+compared	O
+to	O
+38	O
+.	O
+40	O
+degrees	O
+(	O
+range	O
+22	O
+.	O
+5	O
+-	O
+49	O
+.	O
+75	O
+)	O
+after	O
+follow	O
+-	O
+up	O
+;	O
+P	O
+=	O
+0	O
+.	O
+338	O
+unpaired	O
+t	O
+-	O
+test	O
+.	O
+
+Only	O
+one	O
+patient	O
+demonstrated	O
+a	O
+deterioration	B
+in	I
+visual	I
+field	I
+during	O
+the	O
+study	O
+period	O
+and	O
+discontinued	O
+treatment	O
+.	O
+
+CONCLUSION	O
+:	O
+Established	O
+visual	B
+field	I
+defects	I
+presumed	O
+to	O
+be	O
+due	O
+to	O
+Vigabatrin	O
+therapy	O
+did	O
+not	O
+usually	O
+progress	O
+in	O
+spite	O
+of	O
+continuing	O
+use	O
+of	O
+the	O
+medication	O
+.	O
+
+These	O
+data	O
+give	O
+support	O
+to	O
+the	O
+hypothesis	O
+that	O
+the	O
+pathogenesis	O
+of	O
+Vigabatrin	O
+-	O
+associated	O
+visual	B
+field	I
+defects	I
+may	O
+be	O
+an	O
+idiosyncratic	O
+adverse	O
+drug	O
+reaction	O
+rather	O
+than	O
+dose	O
+-	O
+dependent	O
+toxicity	B
+.	O
+
+Induction	O
+of	O
+rosaceiform	O
+dermatitis	B
+during	O
+treatment	O
+of	O
+facial	B
+inflammatory	I
+dermatoses	I
+with	O
+tacrolimus	O
+ointment	O
+.	O
+
+BACKGROUND	O
+:	O
+Tacrolimus	O
+ointment	O
+is	O
+increasingly	O
+used	O
+for	O
+anti	O
+-	O
+inflammatory	O
+treatment	O
+of	O
+sensitive	O
+areas	O
+such	O
+as	O
+the	O
+face	O
+,	O
+and	O
+recent	O
+observations	O
+indicate	O
+that	O
+the	O
+treatment	O
+is	O
+effective	O
+in	O
+steroid	O
+-	O
+aggravated	O
+rosacea	B
+and	O
+perioral	B
+dermatitis	I
+.	O
+
+We	O
+report	O
+on	O
+rosaceiform	O
+dermatitis	B
+as	O
+a	O
+complication	O
+of	O
+treatment	O
+with	O
+tacrolimus	O
+ointment	O
+.	O
+
+OBSERVATIONS	O
+:	O
+Six	O
+adult	O
+patients	O
+with	O
+inflammatory	B
+facial	I
+dermatoses	I
+were	O
+treated	O
+with	O
+tacrolimus	O
+ointment	O
+because	O
+of	O
+the	O
+ineffectiveness	O
+of	O
+standard	O
+treatments	O
+.	O
+
+Within	O
+2	O
+to	O
+3	O
+weeks	O
+of	O
+initially	O
+effective	O
+and	O
+well	O
+-	O
+tolerated	O
+treatment	O
+,	O
+3	O
+patients	O
+with	O
+a	O
+history	O
+of	O
+rosacea	B
+and	O
+1	O
+with	O
+a	O
+history	O
+of	O
+acne	B
+experienced	O
+sudden	O
+worsening	O
+with	O
+pustular	O
+rosaceiform	O
+lesions	O
+.	O
+
+Biopsy	O
+revealed	O
+an	O
+abundance	O
+of	O
+Demodex	O
+mites	O
+in	O
+2	O
+of	O
+these	O
+patients	O
+.	O
+
+In	O
+1	O
+patient	O
+with	O
+eyelid	O
+eczema	B
+,	O
+rosaceiform	O
+periocular	B
+dermatitis	I
+gradually	O
+appeared	O
+after	O
+3	O
+weeks	O
+of	O
+treatment	O
+.	O
+
+In	O
+1	O
+patient	O
+with	O
+atopic	B
+dermatitis	I
+,	O
+telangiectatic	O
+and	O
+papular	B
+rosacea	I
+insidiously	O
+appeared	O
+after	O
+5	O
+months	O
+of	O
+treatment	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Our	O
+observations	O
+suggest	O
+that	O
+the	O
+spectrum	O
+of	O
+rosaceiform	O
+dermatitis	B
+as	O
+a	O
+complication	O
+of	O
+treatment	O
+with	O
+tacrolimus	O
+ointment	O
+is	O
+heterogeneous	O
+.	O
+
+A	O
+variety	O
+of	O
+factors	O
+,	O
+such	O
+as	O
+vasoactive	O
+properties	O
+of	O
+tacrolimus	O
+,	O
+proliferation	O
+of	O
+Demodex	O
+due	O
+to	O
+local	O
+immunosuppression	O
+,	O
+and	O
+the	O
+occlusive	O
+properties	O
+of	O
+the	O
+ointment	O
+,	O
+may	O
+be	O
+involved	O
+in	O
+the	O
+observed	O
+phenomena	O
+.	O
+
+Future	O
+studies	O
+are	O
+needed	O
+to	O
+identify	O
+individual	O
+risk	O
+factors	O
+.	O
+
+Intravascular	O
+hemolysis	B
+and	O
+acute	B
+renal	I
+failure	I
+following	O
+intermittent	O
+rifampin	O
+therapy	O
+.	O
+
+Renal	B
+failure	I
+is	O
+a	O
+rare	O
+complication	O
+associated	O
+with	O
+the	O
+use	O
+of	O
+rifampin	O
+.	O
+
+Intravascular	O
+hemolysis	B
+leading	O
+to	O
+acute	B
+renal	I
+failure	I
+following	O
+rifampin	O
+therapy	O
+is	O
+extremely	O
+rare	O
+.	O
+
+Two	O
+patients	O
+with	O
+leprosy	B
+who	O
+developed	O
+hemolysis	B
+and	O
+acute	B
+renal	I
+failure	I
+following	O
+rifampin	O
+are	O
+reported	O
+.	O
+
+Structural	O
+abnormalities	O
+in	O
+the	O
+brains	O
+of	O
+human	O
+subjects	O
+who	O
+use	O
+methamphetamine	O
+.	O
+
+We	O
+visualize	O
+,	O
+for	O
+the	O
+first	O
+time	O
+,	O
+the	O
+profile	O
+of	O
+structural	B
+deficits	I
+in	I
+the	I
+human	I
+brain	I
+associated	O
+with	O
+chronic	O
+methamphetamine	O
+(	O
+MA	O
+)	O
+abuse	O
+.	O
+
+Studies	O
+of	O
+human	O
+subjects	O
+who	O
+have	O
+used	O
+MA	O
+chronically	O
+have	O
+revealed	O
+deficits	O
+in	O
+dopaminergic	O
+and	O
+serotonergic	O
+systems	O
+and	O
+cerebral	O
+metabolic	B
+abnormalities	I
+.	O
+
+Using	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+and	O
+new	O
+computational	O
+brain	O
+-	O
+mapping	O
+techniques	O
+,	O
+we	O
+determined	O
+the	O
+pattern	O
+of	O
+structural	O
+brain	O
+alterations	O
+associated	O
+with	O
+chronic	O
+MA	O
+abuse	O
+in	O
+human	O
+subjects	O
+and	O
+related	O
+these	O
+deficits	O
+to	O
+cognitive	B
+impairment	I
+.	O
+
+We	O
+used	O
+high	O
+-	O
+resolution	O
+MRI	O
+and	O
+surface	O
+-	O
+based	O
+computational	O
+image	O
+analyses	O
+to	O
+map	O
+regional	O
+abnormalities	B
+in	I
+the	I
+cortex	I
+,	I
+hippocampus	I
+,	I
+white	I
+matter	I
+,	I
+and	I
+ventricles	I
+in	O
+22	O
+human	O
+subjects	O
+who	O
+used	O
+MA	O
+and	O
+21	O
+age	O
+-	O
+matched	O
+,	O
+healthy	O
+controls	O
+.	O
+
+Cortical	O
+maps	O
+revealed	O
+severe	O
+gray	O
+-	O
+matter	O
+deficits	O
+in	O
+the	O
+cingulate	O
+,	O
+limbic	O
+,	O
+and	O
+paralimbic	O
+cortices	O
+of	O
+MA	O
+abusers	O
+(	O
+averaging	O
+11	O
+.	O
+3	O
+%	O
+below	O
+control	O
+;	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+On	O
+average	O
+,	O
+MA	O
+abusers	O
+had	O
+7	O
+.	O
+8	O
+%	O
+smaller	O
+hippocampal	O
+volumes	O
+than	O
+control	O
+subjects	O
+(	O
+p	O
+<	O
+0	O
+.	O
+01	O
+;	O
+left	O
+,	O
+p	O
+=	O
+0	O
+.	O
+01	O
+;	O
+right	O
+,	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+and	O
+significant	O
+white	O
+-	O
+matter	O
+hypertrophy	B
+(	O
+7	O
+.	O
+0	O
+%	O
+;	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+Hippocampal	O
+deficits	O
+were	O
+mapped	O
+and	O
+correlated	O
+with	O
+memory	O
+performance	O
+on	O
+a	O
+word	O
+-	O
+recall	O
+test	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+MRI	O
+-	O
+based	O
+maps	O
+suggest	O
+that	O
+chronic	O
+methamphetamine	O
+abuse	O
+causes	O
+a	O
+selective	O
+pattern	O
+of	O
+cerebral	O
+deterioration	O
+that	O
+contributes	O
+to	O
+impaired	B
+memory	I
+performance	I
+.	O
+
+MA	O
+may	O
+selectively	O
+damage	O
+the	O
+medial	O
+temporal	O
+lobe	O
+and	O
+,	O
+consistent	O
+with	O
+metabolic	O
+studies	O
+,	O
+the	O
+cingulate	O
+-	O
+limbic	O
+cortex	O
+,	O
+inducing	O
+neuroadaptation	O
+,	O
+neuropil	O
+reduction	O
+,	O
+or	O
+cell	O
+death	O
+.	O
+
+Prominent	O
+white	O
+-	O
+matter	O
+hypertrophy	B
+may	O
+result	O
+from	O
+altered	O
+myelination	O
+and	O
+adaptive	O
+glial	O
+changes	O
+,	O
+including	O
+gliosis	B
+secondary	O
+to	O
+neuronal	B
+damage	I
+.	O
+
+These	O
+brain	O
+substrates	O
+may	O
+help	O
+account	O
+for	O
+the	O
+symptoms	O
+of	O
+MA	O
+abuse	O
+,	O
+providing	O
+therapeutic	O
+targets	O
+for	O
+drug	O
+-	O
+induced	O
+brain	B
+injury	I
+.	O
+
+Disruption	O
+of	O
+hepatic	O
+lipid	O
+homeostasis	O
+in	O
+mice	O
+after	O
+amiodarone	O
+treatment	O
+is	O
+associated	O
+with	O
+peroxisome	O
+proliferator	O
+-	O
+activated	O
+receptor	O
+-	O
+alpha	O
+target	O
+gene	O
+activation	O
+.	O
+
+Amiodarone	O
+,	O
+an	O
+efficacious	O
+and	O
+widely	O
+used	O
+antiarrhythmic	O
+agent	O
+,	O
+has	O
+been	O
+reported	O
+to	O
+cause	O
+hepatotoxicity	B
+in	O
+some	O
+patients	O
+.	O
+
+To	O
+gain	O
+insight	O
+into	O
+the	O
+mechanism	O
+of	O
+this	O
+unwanted	O
+effect	O
+,	O
+mice	O
+were	O
+administered	O
+various	O
+doses	O
+of	O
+amiodarone	O
+and	O
+examined	O
+for	O
+changes	O
+in	O
+hepatic	O
+histology	O
+and	O
+gene	O
+regulation	O
+.	O
+
+Amiodarone	O
+induced	O
+hepatomegaly	B
+,	O
+hepatocyte	O
+microvesicular	O
+lipid	O
+accumulation	O
+,	O
+and	O
+a	O
+significant	O
+decrease	O
+in	O
+serum	O
+triglycerides	O
+and	O
+glucose	O
+.	O
+
+Northern	O
+blot	O
+analysis	O
+of	O
+hepatic	O
+RNA	O
+revealed	O
+a	O
+dose	O
+-	O
+dependent	O
+increase	O
+in	O
+the	O
+expression	O
+of	O
+a	O
+number	O
+of	O
+genes	O
+critical	O
+for	O
+fatty	O
+acid	O
+oxidation	O
+,	O
+lipoprotein	O
+assembly	O
+,	O
+and	O
+lipid	O
+transport	O
+.	O
+
+Many	O
+of	O
+these	O
+genes	O
+are	O
+regulated	O
+by	O
+the	O
+peroxisome	O
+proliferator	O
+-	O
+activated	O
+receptor	O
+-	O
+alpha	O
+(	O
+PPARalpha	O
+)	O
+,	O
+a	O
+ligand	O
+-	O
+activated	O
+nuclear	O
+hormone	O
+receptor	O
+transcription	O
+factor	O
+.	O
+
+The	O
+absence	O
+of	O
+induction	O
+of	O
+these	O
+genes	O
+as	O
+well	O
+as	O
+hepatomegaly	B
+in	O
+PPARalpha	O
+knockout	O
+[	O
+PPARalpha	O
+-	O
+/	O
+-	O
+]	O
+mice	O
+indicated	O
+that	O
+the	O
+effects	O
+of	O
+amiodarone	O
+were	O
+dependent	O
+upon	O
+the	O
+presence	O
+of	O
+a	O
+functional	O
+PPARalpha	O
+gene	O
+.	O
+
+Compared	O
+to	O
+wild	O
+-	O
+type	O
+mice	O
+,	O
+treatment	O
+of	O
+PPARalpha	O
+-	O
+/	O
+-	O
+mice	O
+with	O
+amiodarone	O
+resulted	O
+in	O
+an	O
+increased	O
+rate	O
+and	O
+extent	O
+of	O
+total	O
+body	O
+weight	B
+loss	I
+.	O
+
+The	O
+inability	O
+of	O
+amiodarone	O
+to	O
+directly	O
+activate	O
+either	O
+human	O
+or	O
+mouse	O
+PPARalpha	O
+transiently	O
+expressed	O
+in	O
+human	O
+HepG2	O
+hepatoma	B
+cells	O
+indicates	O
+that	O
+the	O
+effects	O
+of	O
+amiodarone	O
+on	O
+the	O
+function	O
+of	O
+this	O
+receptor	O
+were	O
+indirect	O
+.	O
+
+Based	O
+upon	O
+these	O
+results	O
+,	O
+we	O
+conclude	O
+that	O
+amiodarone	O
+disrupts	O
+hepatic	O
+lipid	O
+homeostasis	O
+and	O
+that	O
+the	O
+increased	O
+expression	O
+of	O
+PPARalpha	O
+target	O
+genes	O
+is	O
+secondary	O
+to	O
+this	O
+toxic	O
+effect	O
+.	O
+
+These	O
+results	O
+provide	O
+important	O
+new	O
+mechanistic	O
+information	O
+regarding	O
+the	O
+hepatotoxic	B
+effects	O
+of	O
+amiodarone	O
+and	O
+indicate	O
+that	O
+PPARalpha	O
+protects	O
+against	O
+amiodarone	O
+-	O
+induced	O
+hepatotoxicity	B
+.	O
+
+Safety	O
+and	O
+compliance	O
+with	O
+once	O
+-	O
+daily	O
+niacin	O
+extended	O
+-	O
+release	O
+/	O
+lovastatin	O
+as	O
+initial	O
+therapy	O
+in	O
+the	O
+Impact	O
+of	O
+Medical	O
+Subspecialty	O
+on	O
+Patient	O
+Compliance	O
+to	O
+Treatment	O
+(	O
+IMPACT	O
+)	O
+study	O
+.	O
+
+Niacin	O
+extended	O
+-	O
+release	O
+/	O
+lovastatin	O
+is	O
+a	O
+new	O
+combination	O
+product	O
+approved	O
+for	O
+treatment	O
+of	O
+primary	O
+hypercholesterolemia	B
+and	O
+mixed	O
+dyslipidemia	B
+.	O
+
+This	O
+open	O
+-	O
+labeled	O
+,	O
+multicenter	O
+study	O
+evaluated	O
+the	O
+safety	O
+of	O
+bedtime	O
+niacin	O
+extended	O
+-	O
+release	O
+/	O
+lovastatin	O
+when	O
+dosed	O
+as	O
+initial	O
+therapy	O
+and	O
+patient	O
+compliance	O
+to	O
+treatment	O
+in	O
+various	O
+clinical	O
+practice	O
+settings	O
+.	O
+
+A	O
+total	O
+of	O
+4	O
+,	O
+499	O
+patients	O
+with	O
+dyslipidemia	B
+requiring	O
+drug	O
+intervention	O
+was	O
+enrolled	O
+at	O
+1	O
+,	O
+081	O
+sites	O
+.	O
+
+Patients	O
+were	O
+treated	O
+with	O
+1	O
+tablet	O
+(	O
+500	O
+mg	O
+of	O
+niacin	O
+extended	O
+-	O
+release	O
+/	O
+20	O
+mg	O
+of	O
+lovastatin	O
+)	O
+once	O
+nightly	O
+for	O
+4	O
+weeks	O
+and	O
+then	O
+2	O
+tablets	O
+for	O
+8	O
+weeks	O
+.	O
+
+Patients	O
+also	O
+received	O
+dietary	O
+counseling	O
+,	O
+educational	O
+materials	O
+,	O
+and	O
+reminders	O
+to	O
+call	O
+a	O
+toll	O
+-	O
+free	O
+number	O
+that	O
+provided	O
+further	O
+education	O
+about	O
+dyslipidemia	B
+and	O
+niacin	O
+extended	O
+-	O
+release	O
+/	O
+lovastatin	O
+.	O
+
+Primary	O
+end	O
+points	O
+were	O
+study	O
+compliance	O
+,	O
+increases	O
+in	O
+liver	O
+transaminases	O
+to	O
+>	O
+3	O
+times	O
+the	O
+upper	O
+limit	O
+of	O
+normal	O
+,	O
+and	O
+clinical	O
+myopathy	B
+.	O
+
+Final	O
+study	O
+status	O
+was	O
+available	O
+for	O
+4	O
+,	O
+217	O
+patients	O
+(	O
+94	O
+%	O
+)	O
+.	O
+
+Compliance	O
+to	O
+niacin	O
+extended	O
+-	O
+release	O
+/	O
+lovastatin	O
+was	O
+77	O
+%	O
+,	O
+with	O
+3	O
+,	O
+245	O
+patients	O
+completing	O
+the	O
+study	O
+.	O
+
+Patients	O
+in	O
+the	O
+southeast	O
+and	O
+those	O
+enrolled	O
+by	O
+endocrinologists	O
+had	O
+the	O
+lowest	O
+compliance	O
+and	O
+highest	O
+adverse	O
+event	O
+rates	O
+.	O
+
+Flushing	B
+was	O
+the	O
+most	O
+common	O
+adverse	O
+event	O
+,	O
+reported	O
+by	O
+18	O
+%	O
+of	O
+patients	O
+and	O
+leading	O
+to	O
+discontinuation	O
+by	O
+6	O
+%	O
+.	O
+
+Incidence	O
+of	O
+increased	O
+aspartate	O
+aminotransferase	O
+and	O
+/	O
+or	O
+alanine	O
+aminotransferase	O
+>	O
+3	O
+times	O
+the	O
+upper	O
+limit	O
+of	O
+normal	O
+was	O
+<	O
+0	O
+.	O
+3	O
+%	O
+.	O
+
+An	O
+increase	O
+of	O
+creatine	O
+phosphokinase	O
+to	O
+>	O
+5	O
+times	O
+the	O
+upper	O
+limit	O
+of	O
+normal	O
+occurred	O
+in	O
+0	O
+.	O
+24	O
+%	O
+of	O
+patients	O
+,	O
+and	O
+no	O
+cases	O
+of	O
+drug	O
+-	O
+induced	O
+myopathy	B
+were	O
+observed	O
+.	O
+
+Niacin	O
+extended	O
+-	O
+release	O
+/	O
+lovastatin	O
+1	O
+,	O
+000	O
+/	O
+40	O
+mg	O
+,	O
+dosed	O
+as	O
+initial	O
+therapy	O
+,	O
+was	O
+associated	O
+with	O
+good	O
+compliance	O
+and	O
+safety	O
+and	O
+had	O
+very	O
+low	O
+incidences	O
+of	O
+increased	O
+liver	O
+and	O
+muscle	O
+enzymes	O
+.	O
+
+Protective	O
+effect	O
+of	O
+Terminalia	O
+chebula	O
+against	O
+experimental	O
+myocardial	B
+injury	I
+induced	O
+by	O
+isoproterenol	O
+.	O
+
+Cardioprotective	O
+effect	O
+of	O
+ethanolic	O
+extract	O
+of	O
+Terminalia	O
+chebula	O
+fruits	O
+(	O
+500	O
+mg	O
+/	O
+kg	O
+body	O
+wt	O
+)	O
+was	O
+examined	O
+in	O
+isoproterenol	O
+(	O
+200	O
+mg	O
+/	O
+kg	O
+body	O
+wt	O
+)	O
+induced	O
+myocardial	B
+damage	I
+in	O
+rats	O
+.	O
+
+In	O
+isoproterenol	O
+administered	O
+rats	O
+,	O
+the	O
+level	O
+of	O
+lipid	O
+peroxides	O
+increased	O
+significantly	O
+in	O
+the	O
+serum	O
+and	O
+heart	O
+.	O
+
+A	O
+significant	O
+decrease	O
+was	O
+observed	O
+in	O
+the	O
+activity	O
+of	O
+the	O
+myocardial	O
+marker	O
+enzymes	O
+with	O
+a	O
+concomitant	O
+increase	O
+in	O
+their	O
+activity	O
+in	O
+serum	O
+.	O
+
+Histopathological	O
+examination	O
+was	O
+carried	O
+out	O
+to	O
+confirm	O
+the	O
+myocardial	O
+necrosis	B
+.	O
+
+T	O
+.	O
+chebula	O
+extract	O
+pretreatment	O
+was	O
+found	O
+to	O
+ameliorate	O
+the	O
+effect	O
+of	O
+isoproterenol	O
+on	O
+lipid	O
+peroxide	O
+formation	O
+and	O
+retained	O
+the	O
+activities	O
+of	O
+the	O
+diagnostic	O
+marker	O
+enzymes	O
+.	O
+
+A	O
+case	O
+of	O
+postoperative	O
+anxiety	B
+due	O
+to	O
+low	O
+dose	O
+droperidol	O
+used	O
+with	O
+patient	O
+-	O
+controlled	O
+analgesia	O
+.	O
+
+A	O
+multiparous	O
+woman	O
+in	O
+good	O
+psychological	O
+health	O
+underwent	O
+urgent	O
+caesarean	O
+section	O
+in	O
+labour	O
+.	O
+
+Postoperatively	O
+,	O
+she	O
+was	O
+given	O
+a	O
+patient	O
+-	O
+controlled	O
+analgesia	O
+device	O
+delivering	O
+boluses	O
+of	O
+diamorphine	O
+0	O
+.	O
+5	O
+mg	O
+and	O
+droperidol	O
+0	O
+.	O
+025	O
+mg	O
+.	O
+
+Whilst	O
+using	O
+the	O
+device	O
+she	O
+gradually	O
+became	O
+anxious	O
+,	O
+the	O
+feeling	O
+worsening	O
+after	O
+each	O
+bolus	O
+.	O
+
+The	O
+diagnosis	O
+of	O
+droperidol	O
+-	O
+induced	O
+psychological	B
+disturbance	I
+was	O
+not	O
+made	O
+straight	O
+away	O
+although	O
+on	O
+subsequent	O
+close	O
+questioning	O
+the	O
+patient	O
+gave	O
+a	O
+very	O
+clear	O
+history	O
+.	O
+
+After	O
+she	O
+had	O
+received	O
+a	O
+total	O
+of	O
+only	O
+0	O
+.	O
+9	O
+mg	O
+droperidol	O
+,	O
+a	O
+syringe	O
+containing	O
+diamorphine	O
+only	O
+was	O
+substituted	O
+and	O
+her	O
+unease	O
+resolved	O
+completely	O
+.	O
+
+We	O
+feel	O
+that	O
+,	O
+although	O
+the	O
+dramatic	O
+extrapyramidal	O
+side	O
+effects	O
+of	O
+dopaminergic	O
+antiemetics	O
+are	O
+well	O
+known	O
+,	O
+more	O
+subtle	O
+manifestations	O
+may	O
+easily	O
+be	O
+overlooked	O
+.	O
+
+Accurate	O
+patient	O
+history	O
+contributes	O
+to	O
+differentiating	O
+diabetes	B
+insipidus	I
+:	O
+a	O
+case	O
+study	O
+.	O
+
+This	O
+case	O
+study	O
+highlights	O
+the	O
+important	O
+contribution	O
+of	O
+nursing	O
+in	O
+obtaining	O
+an	O
+accurate	O
+health	O
+history	O
+.	O
+
+The	O
+case	O
+discussed	O
+herein	O
+initially	O
+appeared	O
+to	O
+be	O
+neurogenic	B
+diabetes	I
+insipidus	I
+(	O
+DI	B
+)	O
+secondary	O
+to	O
+a	O
+traumatic	B
+brain	I
+injury	I
+.	O
+
+The	O
+nursing	O
+staff	O
+,	O
+by	O
+reviewing	O
+the	O
+patient	O
+'	O
+s	O
+health	O
+history	O
+with	O
+his	O
+family	O
+,	O
+discovered	O
+a	O
+history	O
+of	O
+polydipsia	B
+and	O
+long	O
+-	O
+standing	O
+lithium	O
+use	O
+.	O
+
+Lithium	O
+is	O
+implicated	O
+in	O
+drug	O
+-	O
+induced	O
+nephrogenic	B
+DI	I
+,	O
+and	O
+because	O
+the	O
+patient	O
+had	O
+not	O
+received	O
+lithium	O
+since	O
+being	O
+admitted	O
+to	O
+the	O
+hospital	O
+,	O
+his	O
+treatment	O
+changed	O
+to	O
+focus	O
+on	O
+nephrogenic	B
+DI	I
+.	O
+
+By	O
+combining	O
+information	O
+from	O
+the	O
+patient	O
+history	O
+,	O
+the	O
+physical	O
+examination	O
+,	O
+and	O
+radiologic	O
+and	O
+laboratory	O
+studies	O
+,	O
+the	O
+critical	O
+care	O
+team	O
+demonstrated	O
+that	O
+the	O
+patient	O
+had	O
+been	O
+self	O
+-	O
+treating	O
+his	O
+lithium	O
+-	O
+induced	O
+nephrogenic	B
+DI	I
+and	O
+developed	O
+neurogenic	B
+DI	I
+secondary	O
+to	O
+brain	B
+trauma	I
+.	O
+
+Thus	O
+successful	O
+treatment	O
+required	O
+that	O
+nephrogenic	O
+and	O
+neurogenic	B
+DI	I
+be	O
+treated	O
+concomitantly	O
+.	O
+
+Factors	O
+contributing	O
+to	O
+ribavirin	O
+-	O
+induced	O
+anemia	B
+.	O
+
+BACKGROUND	O
+AND	O
+AIM	O
+:	O
+Interferon	O
+and	O
+ribavirin	O
+combination	O
+therapy	O
+for	O
+chronic	B
+hepatitis	I
+C	I
+produces	O
+hemolytic	B
+anemia	I
+.	O
+
+This	O
+study	O
+was	O
+conducted	O
+to	O
+identify	O
+the	O
+factors	O
+contributing	O
+to	O
+ribavirin	O
+-	O
+induced	O
+anemia	B
+.	O
+
+METHODS	O
+:	O
+Eighty	O
+-	O
+eight	O
+patients	O
+with	O
+chronic	B
+hepatitis	I
+C	I
+who	O
+received	O
+interferon	O
+-	O
+alpha	O
+-	O
+2b	O
+at	O
+a	O
+dose	O
+of	O
+6	O
+MU	O
+administered	O
+intramuscularly	O
+for	O
+24	O
+weeks	O
+in	O
+combination	O
+with	O
+ribavirin	O
+administered	O
+orally	O
+at	O
+a	O
+dose	O
+of	O
+600	O
+mg	O
+or	O
+800	O
+mg	O
+participated	O
+in	O
+the	O
+study	O
+.	O
+
+A	O
+hemoglobin	O
+concentration	O
+of	O
+<	O
+10	O
+g	O
+/	O
+dL	O
+was	O
+defined	O
+as	O
+ribavirin	O
+-	O
+induced	O
+anemia	B
+.	O
+
+RESULTS	O
+:	O
+Ribavirin	O
+-	O
+induced	O
+anemia	B
+occurred	O
+in	O
+18	O
+(	O
+20	O
+.	O
+5	O
+%	O
+)	O
+patients	O
+during	O
+treatment	O
+.	O
+
+A	O
+2	O
+g	O
+/	O
+dL	O
+decrease	O
+in	O
+hemoglobin	O
+concentrations	O
+in	O
+patients	O
+with	O
+anemia	B
+was	O
+observed	O
+at	O
+week	O
+2	O
+after	O
+the	O
+start	O
+of	O
+treatment	O
+.	O
+
+The	O
+hemoglobin	O
+concentration	O
+in	O
+patients	O
+with	O
+>	O
+or	O
+=	O
+2	O
+g	O
+/	O
+dL	O
+decrease	O
+at	O
+week	O
+2	O
+was	O
+observed	O
+to	O
+be	O
+significantly	O
+lower	O
+even	O
+after	O
+week	O
+2	O
+than	O
+in	O
+patients	O
+with	O
+<	O
+2	O
+g	O
+/	O
+dL	O
+decrease	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+A	O
+significant	O
+relationship	O
+was	O
+observed	O
+between	O
+the	O
+rate	O
+of	O
+reduction	O
+of	O
+hemoglobin	O
+concentrations	O
+at	O
+week	O
+2	O
+and	O
+the	O
+severity	O
+of	O
+anemia	B
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+Such	O
+factors	O
+as	O
+sex	O
+(	O
+female	O
+)	O
+,	O
+age	O
+(	O
+>	O
+or	O
+=	O
+60	O
+years	O
+old	O
+)	O
+,	O
+and	O
+the	O
+ribavirin	O
+dose	O
+by	O
+body	O
+weight	O
+(	O
+12	O
+mg	O
+/	O
+kg	O
+or	O
+more	O
+)	O
+were	O
+significant	O
+by	O
+univariate	O
+analysis	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Careful	O
+administration	O
+is	O
+necessary	O
+in	O
+patients	O
+>	O
+or	O
+=	O
+60	O
+years	O
+old	O
+,	O
+in	O
+female	O
+patients	O
+,	O
+and	O
+in	O
+patients	O
+receiving	O
+a	O
+ribavirin	O
+dose	O
+of	O
+12	O
+mg	O
+/	O
+kg	O
+or	O
+more	O
+.	O
+
+Patients	O
+who	O
+experience	O
+a	O
+fall	O
+in	O
+hemoglobin	O
+concentrations	O
+of	O
+2	O
+g	O
+/	O
+dL	O
+or	O
+more	O
+at	O
+week	O
+2	O
+after	O
+the	O
+start	O
+of	O
+treatment	O
+should	O
+be	O
+monitored	O
+with	O
+particular	O
+care	O
+.	O
+
+Zidovudine	O
+-	O
+induced	O
+hepatitis	B
+.	O
+
+A	O
+case	O
+of	O
+acute	O
+hepatitis	B
+induced	O
+by	O
+zidovudine	O
+in	O
+a	O
+38	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+with	O
+AIDS	B
+is	O
+presented	O
+.	O
+
+The	O
+mechanism	O
+whereby	O
+the	O
+hepatitis	B
+was	O
+induced	O
+is	O
+not	O
+known	O
+.	O
+
+However	O
+,	O
+the	O
+patient	O
+tolerated	O
+well	O
+an	O
+alternative	O
+reverse	O
+transcriptase	O
+inhibitor	O
+,	O
+2	O
+'	O
+3	O
+'	O
+dideoxyinosine	O
+.	O
+
+Physicians	O
+caring	O
+for	O
+patients	O
+with	O
+AIDS	B
+should	O
+be	O
+aware	O
+of	O
+this	O
+hitherto	O
+rarely	O
+reported	O
+complication	O
+.	O
+
+Oxidative	O
+damage	O
+precedes	O
+nitrative	O
+damage	O
+in	O
+adriamycin	O
+-	O
+induced	O
+cardiac	O
+mitochondrial	B
+injury	I
+.	O
+
+The	O
+purpose	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+determine	O
+if	O
+elevated	O
+reactive	O
+oxygen	O
+(	O
+ROS	O
+)	O
+/	O
+nitrogen	O
+species	O
+(	O
+RNS	O
+)	O
+reported	O
+to	O
+be	O
+present	O
+in	O
+adriamycin	O
+(	O
+ADR	O
+)	O
+-	O
+induced	O
+cardiotoxicity	B
+actually	O
+resulted	O
+in	O
+cardiomyocyte	O
+oxidative	O
+/	O
+nitrative	O
+damage	O
+,	O
+and	O
+to	O
+quantitatively	O
+determine	O
+the	O
+time	O
+course	O
+and	O
+subcellular	O
+localization	O
+of	O
+these	O
+postulated	O
+damage	O
+products	O
+using	O
+an	O
+in	O
+vivo	O
+approach	O
+.	O
+
+B6C3	O
+mice	O
+were	O
+treated	O
+with	O
+a	O
+single	O
+dose	O
+of	O
+20	O
+mg	O
+/	O
+kg	O
+ADR	O
+.	O
+
+Ultrastructural	O
+damage	O
+and	O
+levels	O
+of	O
+4	O
+-	O
+hydroxy	O
+-	O
+2	O
+-	O
+nonenal	O
+(	O
+4HNE	O
+)	O
+-	O
+protein	O
+adducts	O
+and	O
+3	O
+-	O
+nitrotyrosine	O
+(	O
+3NT	O
+)	O
+were	O
+analyzed	O
+.	O
+
+Quantitative	O
+ultrastructural	O
+damage	O
+using	O
+computerized	O
+image	O
+techniques	O
+showed	O
+cardiomyocyte	O
+injury	O
+as	O
+early	O
+as	O
+3	O
+hours	O
+,	O
+with	O
+mitochondria	O
+being	O
+the	O
+most	O
+extensively	O
+and	O
+progressively	O
+injured	O
+subcellular	O
+organelle	O
+.	O
+
+Analysis	O
+of	O
+4HNE	O
+protein	O
+adducts	O
+by	O
+immunogold	O
+electron	O
+microscopy	O
+showed	O
+appearance	O
+of	O
+4HNE	O
+protein	O
+adducts	O
+in	O
+mitochondria	O
+as	O
+early	O
+as	O
+3	O
+hours	O
+,	O
+with	O
+a	O
+peak	O
+at	O
+6	O
+hours	O
+and	O
+subsequent	O
+decline	O
+at	O
+24	O
+hours	O
+.	O
+
+3NT	O
+levels	O
+were	O
+significantly	O
+increased	O
+in	O
+all	O
+subcellular	O
+compartments	O
+at	O
+6	O
+hours	O
+and	O
+subsequently	O
+declined	O
+at	O
+24	O
+hours	O
+.	O
+
+Our	O
+data	O
+showed	O
+ADR	O
+induced	O
+4HNE	O
+-	O
+protein	O
+adducts	O
+in	O
+mitochondria	O
+at	O
+the	O
+same	O
+time	O
+point	O
+as	O
+when	O
+mitochondrial	B
+injury	I
+initially	O
+appeared	O
+.	O
+
+These	O
+results	O
+document	O
+for	O
+the	O
+first	O
+time	O
+in	O
+vivo	O
+that	O
+mitochondrial	B
+oxidative	I
+damage	I
+precedes	O
+nitrative	O
+damage	O
+.	O
+
+The	O
+progressive	O
+nature	O
+of	O
+mitochondrial	B
+injury	I
+suggests	O
+that	O
+mitochondria	O
+,	O
+not	O
+other	O
+subcellular	O
+organelles	O
+,	O
+are	O
+the	O
+major	O
+site	O
+of	O
+intracellular	O
+injury	O
+.	O
+
+Sotalol	O
+-	O
+induced	O
+coronary	B
+spasm	I
+in	O
+a	O
+patient	O
+with	O
+dilated	B
+cardiomyopathy	I
+associated	O
+with	O
+sustained	O
+ventricular	B
+tachycardia	I
+.	O
+
+A	O
+54	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+severe	O
+left	O
+ventricular	B
+dysfunction	I
+due	O
+to	O
+dilated	B
+cardiomyopathy	I
+was	O
+referred	O
+to	O
+our	O
+hospital	O
+for	O
+symptomatic	O
+incessant	O
+sustained	O
+ventricular	B
+tachycardia	I
+(	O
+VT	B
+)	O
+.	O
+
+After	O
+the	O
+administration	O
+of	O
+nifekalant	O
+hydrochloride	O
+,	O
+sustained	O
+VT	B
+was	O
+terminated	O
+.	O
+
+An	O
+alternate	O
+class	O
+III	O
+agent	O
+,	O
+sotalol	O
+,	O
+was	O
+also	O
+effective	O
+for	O
+the	O
+prevention	O
+of	O
+VT	B
+.	O
+
+However	O
+,	O
+one	O
+month	O
+after	O
+switching	O
+over	O
+nifekalant	O
+to	O
+sotalol	O
+,	O
+a	O
+short	O
+duration	O
+of	O
+ST	O
+elevation	O
+was	O
+documented	O
+in	O
+ECG	O
+monitoring	O
+at	O
+almost	O
+the	O
+same	O
+time	O
+for	O
+three	O
+consecutive	O
+days	O
+.	O
+
+ST	O
+elevation	O
+with	O
+chest	O
+discomfort	O
+disappeared	O
+since	O
+he	O
+began	O
+taking	O
+long	O
+-	O
+acting	O
+diltiazem	O
+.	O
+
+Coronary	B
+vasospasm	I
+may	O
+be	O
+induced	O
+by	O
+the	O
+non	O
+-	O
+selective	O
+beta	O
+-	O
+blocking	O
+properties	O
+of	O
+sotalol	O
+.	O
+
+Effects	O
+of	O
+the	O
+antidepressant	O
+trazodone	O
+,	O
+a	O
+5	O
+-	O
+HT	O
+2A	O
+/	O
+2C	O
+receptor	O
+antagonist	O
+,	O
+on	O
+dopamine	O
+-	O
+dependent	O
+behaviors	O
+in	O
+rats	O
+.	O
+
+RATIONALE	O
+:	O
+5	O
+-	O
+Hydroxytryptamine	O
+,	O
+via	O
+stimulation	O
+of	O
+5	O
+-	O
+HT	O
+2C	O
+receptors	O
+,	O
+exerts	O
+a	O
+tonic	O
+inhibitory	O
+influence	O
+on	O
+dopaminergic	O
+neurotransmission	O
+,	O
+whereas	O
+activation	O
+of	O
+5	O
+-	O
+HT	O
+2A	O
+receptors	O
+enhances	O
+stimulated	O
+DAergic	O
+neurotransmission	O
+.	O
+
+The	O
+antidepressant	O
+trazodone	O
+is	O
+a	O
+5	O
+-	O
+HT	O
+2A	O
+/	O
+2C	O
+receptor	O
+antagonist	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+evaluate	O
+the	O
+effect	O
+of	O
+trazodone	O
+treatment	O
+on	O
+behaviors	O
+dependent	O
+on	O
+the	O
+functional	O
+status	O
+of	O
+the	O
+nigrostriatal	O
+DAergic	O
+system	O
+.	O
+
+METHODS	O
+:	O
+The	O
+effect	O
+of	O
+pretreatment	O
+with	O
+trazodone	O
+on	O
+dexamphetamine	O
+-	O
+and	O
+apomorphine	O
+-	O
+induced	O
+oral	B
+stereotypies	I
+,	O
+on	O
+catalepsy	B
+induced	O
+by	O
+haloperidol	O
+and	O
+apomorphine	O
+(	O
+0	O
+.	O
+05	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+,	O
+on	O
+ergometrine	O
+-	O
+induced	O
+wet	O
+dog	O
+shake	O
+(	O
+WDS	O
+)	O
+behavior	O
+and	O
+fluoxetine	O
+-	O
+induced	O
+penile	O
+erections	O
+was	O
+studied	O
+in	O
+rats	O
+.	O
+
+We	O
+also	O
+investigated	O
+whether	O
+trazodone	O
+induces	O
+catalepsy	B
+in	O
+rats	O
+.	O
+
+RESULTS	O
+:	O
+Trazodone	O
+at	O
+2	O
+.	O
+5	O
+-	O
+20	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+did	O
+not	O
+induce	O
+catalepsy	B
+,	O
+and	O
+did	O
+not	O
+antagonize	O
+apomorphine	O
+(	O
+1	O
+.	O
+5	O
+and	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+stereotypy	O
+and	O
+apomorphine	O
+(	O
+0	O
+.	O
+05	O
+mg	O
+/	O
+kg	O
+)	O
+-	O
+induced	O
+catalepsy	B
+.	O
+
+However	O
+,	O
+pretreatment	O
+with	O
+5	O
+,	O
+10	O
+and	O
+20	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+trazodone	O
+enhanced	O
+dexamphetamine	O
+stereotypy	O
+,	O
+and	O
+antagonized	O
+haloperidol	O
+catalepsy	B
+,	O
+ergometrine	O
+-	O
+induced	O
+WDS	O
+behavior	O
+and	O
+fluoxetine	O
+-	O
+induced	O
+penile	O
+erections	O
+.	O
+
+Trazodone	O
+at	O
+30	O
+,	O
+40	O
+and	O
+50	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+induced	O
+catalepsy	B
+and	O
+antagonized	O
+apomorphine	O
+and	O
+dexamphetamine	O
+stereotypies	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Our	O
+results	O
+indicate	O
+that	O
+trazodone	O
+at	O
+2	O
+.	O
+5	O
+-	O
+20	O
+mg	O
+/	O
+kg	O
+does	O
+not	O
+block	O
+pre	O
+-	O
+and	O
+postsynaptic	O
+striatal	O
+D2	O
+DA	O
+receptors	O
+,	O
+while	O
+at	O
+30	O
+,	O
+40	O
+and	O
+50	O
+mg	O
+/	O
+kg	O
+it	O
+blocks	O
+postsynaptic	O
+striatal	O
+D2	O
+DA	O
+receptors	O
+.	O
+
+Furthermore	O
+,	O
+at	O
+5	O
+,	O
+10	O
+and	O
+20	O
+mg	O
+/	O
+kg	O
+,	O
+trazodone	O
+blocks	O
+5	O
+-	O
+HT	O
+2A	O
+and	O
+5	O
+-	O
+HT	O
+2C	O
+receptors	O
+.	O
+
+We	O
+suggest	O
+that	O
+trazodone	O
+(	O
+5	O
+,	O
+10	O
+and	O
+20	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+by	O
+blocking	O
+the	O
+5	O
+-	O
+HT	O
+2C	O
+receptors	O
+,	O
+releases	O
+the	O
+nigrostriatal	O
+DAergic	O
+neurons	O
+from	O
+tonic	O
+inhibition	O
+caused	O
+by	O
+5	O
+-	O
+HT	O
+,	O
+and	O
+thereby	O
+potentiates	O
+dexamphetamine	O
+stereotypy	O
+and	O
+antagonizes	O
+haloperidol	O
+catalepsy	B
+.	O
+
+Swallowing	B
+abnormalities	I
+and	O
+dyskinesia	B
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+Gastrointestinal	B
+abnormalities	I
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+have	O
+been	O
+known	O
+for	O
+almost	O
+two	O
+centuries	O
+,	O
+but	O
+many	O
+aspects	O
+concerning	O
+their	O
+pathophysiology	O
+have	O
+not	O
+been	O
+completely	O
+clarified	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+characterize	O
+the	O
+oropharyngeal	O
+dynamics	O
+in	O
+PD	B
+patients	O
+with	O
+and	O
+without	O
+levodopa	O
+-	O
+induced	O
+dyskinesia	B
+.	O
+
+Fifteen	O
+dyskinetic	B
+,	O
+12	O
+nondyskinetic	O
+patients	O
+,	O
+and	O
+a	O
+control	O
+group	O
+were	O
+included	O
+.	O
+
+Patients	O
+were	O
+asked	O
+about	O
+dysphagia	B
+and	O
+evaluated	O
+with	O
+the	O
+Unified	O
+Parkinson	B
+'	I
+s	I
+Disease	I
+Rating	O
+Scale	O
+Parts	O
+II	O
+and	O
+III	O
+and	O
+the	O
+Hoehn	O
+and	O
+Yahr	O
+scale	O
+.	O
+
+Deglutition	O
+was	O
+assessed	O
+using	O
+modified	O
+barium	O
+swallow	O
+with	O
+videofluoroscopy	O
+.	O
+
+Nondyskinetic	O
+patients	O
+,	O
+but	O
+not	O
+the	O
+dyskinetic	B
+ones	O
+,	O
+showed	O
+less	O
+oropharyngeal	O
+swallowing	O
+efficiency	O
+(	O
+OPSE	O
+)	O
+for	O
+liquid	O
+food	O
+than	O
+controls	O
+(	O
+Dunnett	O
+,	O
+P	O
+=	O
+0	O
+.	O
+02	O
+)	O
+.	O
+
+Dyskinetic	B
+patients	O
+tended	O
+to	O
+have	O
+a	O
+greater	O
+OPSE	O
+than	O
+nondyskinetic	O
+(	O
+Dunnett	O
+,	O
+P	O
+=	O
+0	O
+.	O
+06	O
+)	O
+.	O
+
+Patients	O
+who	O
+were	O
+using	O
+a	O
+higher	O
+dose	O
+of	O
+levodopa	O
+had	O
+a	O
+greater	O
+OPSE	O
+and	O
+a	O
+trend	O
+toward	O
+a	O
+smaller	O
+oral	O
+transit	O
+time	O
+(	O
+Pearson	O
+'	O
+s	O
+correlation	O
+,	O
+P	O
+=	O
+0	O
+.	O
+01	O
+and	O
+0	O
+.	O
+08	O
+,	O
+respectively	O
+)	O
+.	O
+
+Neither	O
+the	O
+report	O
+of	O
+dysphagia	B
+nor	O
+any	O
+of	O
+the	O
+PD	B
+severity	O
+parameters	O
+correlated	O
+to	O
+the	O
+videofluoroscopic	O
+variables	O
+.	O
+
+In	O
+the	O
+current	O
+study	O
+,	O
+dyskinetic	B
+patients	O
+performed	O
+better	O
+in	O
+swallowing	O
+function	O
+,	O
+which	O
+could	O
+be	O
+explained	O
+on	O
+the	O
+basis	O
+of	O
+a	O
+greater	O
+levodopa	O
+dose	O
+.	O
+
+Our	O
+results	O
+suggest	O
+a	O
+role	O
+for	O
+levodopa	O
+in	O
+the	O
+oral	O
+phase	O
+of	O
+deglutition	O
+and	O
+confirm	O
+that	O
+dysphagia	B
+is	O
+not	O
+a	O
+good	O
+predictor	O
+of	O
+deglutition	O
+alterations	O
+in	O
+PD	B
+.	O
+
+Inhibition	O
+of	O
+nuclear	O
+factor	O
+-	O
+kappaB	O
+activation	O
+attenuates	O
+tubulointerstitial	B
+nephritis	I
+induced	O
+by	O
+gentamicin	O
+.	O
+
+BACKGROUND	O
+:	O
+Animals	O
+treated	O
+with	O
+gentamicin	O
+can	O
+show	O
+residual	O
+areas	O
+of	O
+interstitial	O
+fibrosis	B
+in	O
+the	O
+renal	O
+cortex	O
+.	O
+
+This	O
+study	O
+investigated	O
+the	O
+expression	O
+of	O
+nuclear	O
+factor	O
+-	O
+kappaB	O
+(	O
+NF	O
+-	O
+kappaB	O
+)	O
+,	O
+mitogen	O
+-	O
+activated	O
+protein	O
+(	O
+MAP	O
+)	O
+kinases	O
+and	O
+macrophages	O
+in	O
+the	O
+renal	O
+cortex	O
+and	O
+structural	O
+and	O
+functional	O
+renal	O
+changes	O
+of	O
+rats	O
+treated	O
+with	O
+gentamicin	O
+or	O
+gentamicin	O
++	O
+pyrrolidine	O
+dithiocarbamate	O
+(	O
+PDTC	O
+)	O
+,	O
+an	O
+NF	O
+-	O
+kappaB	O
+inhibitor	O
+.	O
+
+METHODS	O
+:	O
+38	O
+female	O
+Wistar	O
+rats	O
+were	O
+injected	O
+with	O
+gentamicin	O
+,	O
+40	O
+mg	O
+/	O
+kg	O
+,	O
+twice	O
+a	O
+day	O
+for	O
+9	O
+days	O
+,	O
+38	O
+with	O
+gentamicin	O
++	O
+PDTC	O
+,	O
+and	O
+28	O
+with	O
+0	O
+.	O
+15	O
+M	O
+NaCl	O
+solution	O
+.	O
+
+The	O
+animals	O
+were	O
+killed	O
+5	O
+and	O
+30	O
+days	O
+after	O
+these	O
+injections	O
+and	O
+the	O
+kidneys	O
+were	O
+removed	O
+for	O
+histological	O
+and	O
+immunohistochemical	O
+studies	O
+.	O
+
+The	O
+results	O
+of	O
+the	O
+immunohistochemical	O
+studies	O
+were	O
+scored	O
+according	O
+to	O
+the	O
+extent	O
+of	O
+staining	O
+.	O
+
+The	O
+fractional	O
+interstitial	O
+area	O
+was	O
+determined	O
+by	O
+morphometry	O
+.	O
+
+RESULTS	O
+:	O
+Gentamicin	O
+-	O
+treated	O
+rats	O
+presented	O
+a	O
+transitory	O
+increase	O
+in	O
+plasma	O
+creatinine	O
+levels	O
+.	O
+
+Increased	O
+ED	O
+-	O
+1	O
+,	O
+MAP	O
+kinases	O
+and	O
+NF	O
+-	O
+kappaB	O
+staining	O
+were	O
+also	O
+observed	O
+in	O
+the	O
+renal	O
+cortex	O
+from	O
+all	O
+gentamicin	O
+-	O
+treated	O
+rats	O
+compared	O
+to	O
+control	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+animals	O
+killed	O
+on	O
+day	O
+30	O
+also	O
+presented	O
+fibrosis	B
+in	O
+the	O
+renal	O
+cortex	O
+despite	O
+the	O
+recovery	O
+of	O
+renal	O
+function	O
+.	O
+
+Treatment	O
+with	O
+PDTC	O
+reduced	O
+the	O
+functional	O
+and	O
+structural	O
+changes	O
+induced	O
+by	O
+gentamicin	O
+.	O
+
+CONCLUSIONS	O
+:	O
+These	O
+data	O
+show	O
+that	O
+inhibition	O
+of	O
+NF	O
+-	O
+kappaB	O
+activation	O
+attenuates	O
+tubulointerstitial	B
+nephritis	I
+induced	O
+by	O
+gentamicin	O
+.	O
+
+Glucose	O
+metabolism	O
+in	O
+patients	O
+with	O
+schizophrenia	B
+treated	O
+with	O
+atypical	O
+antipsychotic	O
+agents	O
+:	O
+a	O
+frequently	O
+sampled	O
+intravenous	O
+glucose	O
+tolerance	O
+test	O
+and	O
+minimal	O
+model	O
+analysis	O
+.	O
+
+BACKGROUND	O
+:	O
+While	O
+the	O
+incidence	O
+of	O
+new	O
+-	O
+onset	O
+diabetes	B
+mellitus	I
+may	O
+be	O
+increasing	O
+in	O
+patients	O
+with	O
+schizophrenia	B
+treated	O
+with	O
+certain	O
+atypical	O
+antipsychotic	O
+agents	O
+,	O
+it	O
+remains	O
+unclear	O
+whether	O
+atypical	O
+agents	O
+are	O
+directly	O
+affecting	O
+glucose	O
+metabolism	O
+or	O
+simply	O
+increasing	O
+known	O
+risk	O
+factors	O
+for	O
+diabetes	B
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+study	O
+the	O
+2	O
+drugs	O
+most	O
+clearly	O
+implicated	O
+(	O
+clozapine	O
+and	O
+olanzapine	O
+)	O
+and	O
+risperidone	O
+using	O
+a	O
+frequently	O
+sampled	O
+intravenous	O
+glucose	O
+tolerance	O
+test	O
+.	O
+
+DESIGN	O
+:	O
+A	O
+cross	O
+-	O
+sectional	O
+design	O
+in	O
+stable	O
+,	O
+treated	O
+patients	O
+with	O
+schizophrenia	B
+evaluated	O
+using	O
+a	O
+frequently	O
+sampled	O
+intravenous	O
+glucose	O
+tolerance	O
+test	O
+and	O
+the	O
+Bergman	O
+minimal	O
+model	O
+analysis	O
+.	O
+
+SETTING	O
+:	O
+Subjects	O
+were	O
+recruited	O
+from	O
+an	O
+urban	O
+community	O
+mental	O
+health	O
+clinic	O
+and	O
+were	O
+studied	O
+at	O
+a	O
+general	O
+clinical	O
+research	O
+center	O
+.	O
+
+Patients	O
+Fifty	O
+subjects	O
+signed	O
+informed	O
+consent	O
+and	O
+41	O
+underwent	O
+the	O
+frequently	O
+sampled	O
+intravenous	O
+glucose	O
+tolerance	O
+test	O
+.	O
+
+Thirty	O
+-	O
+six	O
+nonobese	O
+subjects	O
+with	O
+schizophrenia	B
+or	O
+schizoaffective	B
+disorder	I
+,	O
+matched	O
+by	O
+body	O
+mass	O
+index	O
+and	O
+treated	O
+with	O
+either	O
+clozapine	O
+,	O
+olanzapine	O
+,	O
+or	O
+risperidone	O
+,	O
+were	O
+included	O
+in	O
+the	O
+analysis	O
+.	O
+
+MAIN	O
+OUTCOME	O
+MEASURES	O
+:	O
+Fasting	O
+plasma	O
+glucose	O
+and	O
+fasting	O
+serum	O
+insulin	O
+levels	O
+,	O
+insulin	B
+sensitivity	I
+index	O
+,	O
+homeostasis	O
+model	O
+assessment	O
+of	O
+insulin	B
+resistance	I
+,	O
+and	O
+glucose	O
+effectiveness	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+duration	O
+of	O
+treatment	O
+with	O
+the	O
+identified	O
+atypical	O
+antipsychotic	O
+agent	O
+was	O
+68	O
+.	O
+3	O
++	O
+/	O
+-	O
+28	O
+.	O
+9	O
+months	O
+(	O
+clozapine	O
+)	O
+,	O
+29	O
+.	O
+5	O
++	O
+/	O
+-	O
+17	O
+.	O
+5	O
+months	O
+(	O
+olanzapine	O
+)	O
+,	O
+and	O
+40	O
+.	O
+9	O
++	O
+/	O
+-	O
+33	O
+.	O
+7	O
+(	O
+risperidone	O
+)	O
+.	O
+
+Fasting	O
+serum	O
+insulin	O
+concentrations	O
+differed	O
+among	O
+groups	O
+(	O
+F	O
+(	O
+33	O
+)	O
+=	O
+3	O
+.	O
+35	O
+;	O
+P	O
+=	O
+.	O
+047	O
+)	O
+(	O
+clozapine	O
+>	O
+olanzapine	O
+>	O
+risperidone	O
+)	O
+with	O
+significant	O
+differences	O
+between	O
+clozapine	O
+and	O
+risperidone	O
+(	O
+t	O
+(	O
+33	O
+)	O
+=	O
+2	O
+.	O
+32	O
+;	O
+P	O
+=	O
+.	O
+03	O
+)	O
+and	O
+olanzapine	O
+and	O
+risperidone	O
+(	O
+t	O
+(	O
+33	O
+)	O
+=	O
+2	O
+.	O
+15	O
+;	O
+P	O
+=	O
+.	O
+04	O
+)	O
+.	O
+
+There	O
+was	O
+a	O
+significant	O
+difference	O
+in	O
+insulin	B
+sensitivity	I
+index	O
+among	O
+groups	O
+(	O
+F	O
+(	O
+33	O
+)	O
+=	O
+10	O
+.	O
+66	O
+;	O
+P	O
+<	O
+.	O
+001	O
+)	O
+(	O
+clozapine	O
+<	O
+olanzapine	O
+<	O
+risperidone	O
+)	O
+,	O
+with	O
+subjects	O
+who	O
+received	O
+clozapine	O
+and	O
+olanzapine	O
+exhibiting	O
+significant	O
+insulin	B
+resistance	I
+compared	O
+with	O
+subjects	O
+who	O
+were	O
+treated	O
+with	O
+risperidone	O
+(	O
+clozapine	O
+vs	O
+risperidone	O
+,	O
+t	O
+(	O
+33	O
+)	O
+=	O
+-	O
+4	O
+.	O
+29	O
+;	O
+P	O
+<	O
+.	O
+001	O
+;	O
+olanzapine	O
+vs	O
+risperidone	O
+,	O
+t	O
+(	O
+33	O
+)	O
+=	O
+-	O
+3	O
+.	O
+62	O
+;	O
+P	O
+=	O
+.	O
+001	O
+[	O
+P	O
+<	O
+.	O
+001	O
+]	O
+)	O
+.	O
+
+The	O
+homeostasis	O
+model	O
+assessment	O
+of	O
+insulin	B
+resistance	I
+also	O
+differed	O
+significantly	O
+among	O
+groups	O
+(	O
+F	O
+(	O
+33	O
+)	O
+=	O
+4	O
+.	O
+92	O
+;	O
+P	O
+=	O
+.	O
+01	O
+)	O
+(	O
+clozapine	O
+>	O
+olanzapine	O
+>	O
+risperidone	O
+)	O
+(	O
+clozapine	O
+vs	O
+risperidone	O
+,	O
+t	O
+(	O
+33	O
+)	O
+=	O
+2	O
+.	O
+94	O
+;	O
+P	O
+=	O
+.	O
+006	O
+;	O
+olanzapine	O
+vs	O
+risperidone	O
+,	O
+t	O
+(	O
+33	O
+)	O
+=	O
+2	O
+.	O
+42	O
+;	O
+P	O
+=	O
+.	O
+02	O
+)	O
+.	O
+
+There	O
+was	O
+a	O
+significant	O
+difference	O
+among	O
+groups	O
+in	O
+glucose	O
+effectiveness	O
+(	O
+F	O
+(	O
+30	O
+)	O
+=	O
+4	O
+.	O
+18	O
+;	O
+P	O
+=	O
+.	O
+02	O
+)	O
+(	O
+clozapine	O
+<	O
+olanzapine	O
+<	O
+risperidone	O
+)	O
+with	O
+significant	O
+differences	O
+between	O
+clozapine	O
+and	O
+risperidone	O
+(	O
+t	O
+(	O
+30	O
+)	O
+=	O
+-	O
+2	O
+.	O
+59	O
+;	O
+P	O
+=	O
+.	O
+02	O
+)	O
+and	O
+olanzapine	O
+and	O
+risperidone	O
+(	O
+t	O
+(	O
+30	O
+)	O
+=	O
+-	O
+2	O
+.	O
+34	O
+,	O
+P	O
+=	O
+.	O
+03	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Both	O
+nonobese	O
+clozapine	O
+-	O
+and	O
+olanzapine	O
+-	O
+treated	O
+groups	O
+displayed	O
+significant	O
+insulin	B
+resistance	I
+and	O
+impairment	O
+of	O
+glucose	O
+effectiveness	O
+compared	O
+with	O
+risperidone	O
+-	O
+treated	O
+subjects	O
+.	O
+
+Patients	O
+taking	O
+clozapine	O
+and	O
+olanzapine	O
+must	O
+be	O
+examined	O
+for	O
+insulin	B
+resistance	I
+and	O
+its	O
+consequences	O
+.	O
+
+Thoracic	B
+hematomyelia	I
+secondary	O
+to	O
+coumadin	O
+anticoagulant	O
+therapy	O
+:	O
+a	O
+case	O
+report	O
+.	O
+
+A	O
+case	O
+of	O
+thoracic	B
+hematomyelia	I
+secondary	O
+to	O
+anticoagulant	O
+therapy	O
+is	O
+presented	O
+.	O
+
+Clinical	O
+features	O
+,	O
+similar	O
+to	O
+2	O
+other	O
+previously	O
+reported	O
+cases	O
+,	O
+are	O
+discussed	O
+.	O
+
+A	O
+high	O
+index	O
+of	O
+suspicion	O
+may	O
+lead	O
+to	O
+a	O
+quick	O
+diagnostic	O
+procedure	O
+and	O
+successful	O
+decompressive	O
+surgery	O
+.	O
+
+Mania	B
+associated	O
+with	O
+fluoxetine	O
+treatment	O
+in	O
+adolescents	O
+.	O
+
+Fluoxetine	O
+,	O
+a	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitor	O
+,	O
+is	O
+gaining	O
+increased	O
+acceptance	O
+in	O
+the	O
+treatment	O
+of	O
+adolescent	O
+depression	B
+.	O
+
+Generally	O
+safe	O
+and	O
+well	O
+tolerated	O
+by	O
+adults	O
+,	O
+fluoxetine	O
+has	O
+been	O
+reported	O
+to	O
+induce	O
+mania	B
+.	O
+
+The	O
+cases	O
+of	O
+five	O
+depressed	B
+adolescents	O
+,	O
+14	O
+-	O
+16	O
+years	O
+of	O
+age	O
+,	O
+who	O
+developed	O
+mania	B
+during	O
+pharmacotherapy	O
+with	O
+fluoxetine	O
+,	O
+are	O
+reported	O
+here	O
+.	O
+
+Apparent	O
+risk	O
+factors	O
+for	O
+the	O
+development	O
+of	O
+mania	B
+or	O
+hypomania	B
+during	O
+fluoxetine	O
+pharmacotherapy	O
+in	O
+this	O
+population	O
+were	O
+the	O
+combination	O
+of	O
+attention	B
+-	I
+deficit	I
+hyperactivity	I
+disorder	I
+and	O
+affective	O
+instability	O
+;	O
+major	O
+depression	B
+with	O
+psychotic	B
+features	O
+;	O
+a	O
+family	O
+history	O
+of	O
+affective	B
+disorder	I
+,	O
+especially	O
+bipolar	B
+disorder	I
+;	O
+and	O
+a	O
+diagnosis	O
+of	O
+bipolar	B
+disorder	I
+.	O
+
+Further	O
+study	O
+is	O
+needed	O
+to	O
+determine	O
+the	O
+optimal	O
+dosage	O
+and	O
+to	O
+identify	O
+risk	O
+factors	O
+that	O
+increase	O
+individual	O
+vulnerability	O
+to	O
+fluoxetine	O
+induced	O
+mania	B
+in	O
+adolescents	O
+.	O
+
+Acute	B
+renal	I
+insufficiency	I
+after	O
+high	O
+-	O
+dose	O
+melphalan	O
+in	O
+patients	O
+with	O
+primary	B
+systemic	I
+amyloidosis	I
+during	O
+stem	O
+cell	O
+transplantation	O
+.	O
+
+BACKGROUND	O
+:	O
+Patients	O
+with	O
+primary	B
+systemic	I
+amyloidosis	I
+(	O
+AL	B
+)	O
+have	O
+a	O
+poor	O
+prognosis	O
+.	O
+
+Median	O
+survival	O
+time	O
+from	O
+standard	O
+treatments	O
+is	O
+only	O
+17	O
+months	O
+.	O
+
+High	O
+-	O
+dose	O
+intravenous	O
+melphalan	O
+followed	O
+by	O
+peripheral	O
+blood	O
+stem	O
+cell	O
+transplant	O
+(	O
+PBSCT	O
+)	O
+appears	O
+to	O
+be	O
+the	O
+most	O
+promising	O
+therapy	O
+,	O
+but	O
+treatment	O
+mortality	O
+can	O
+be	O
+high	O
+.	O
+
+The	O
+authors	O
+have	O
+noted	O
+the	O
+development	O
+of	O
+acute	B
+renal	I
+insufficiency	I
+immediately	O
+after	O
+melphalan	O
+conditioning	O
+.	O
+
+This	O
+study	O
+was	O
+undertaken	O
+to	O
+further	O
+examine	O
+its	O
+risk	O
+factors	O
+and	O
+impact	O
+on	O
+posttransplant	O
+mortality	O
+.	O
+
+METHODS	O
+:	O
+Consecutive	O
+AL	B
+patients	O
+who	O
+underwent	O
+PBSCT	O
+were	O
+studied	O
+retrospectively	O
+.	O
+
+Acute	B
+renal	I
+insufficiency	I
+(	O
+ARI	B
+)	O
+after	O
+high	O
+-	O
+dose	O
+melphalan	O
+was	O
+defined	O
+by	O
+a	O
+minimum	O
+increase	O
+of	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+dL	O
+(	O
+44	O
+micromol	O
+/	O
+L	O
+)	O
+in	O
+the	O
+serum	O
+creatinine	O
+level	O
+that	O
+is	O
+greater	O
+than	O
+50	O
+%	O
+of	O
+baseline	O
+immediately	O
+after	O
+conditioning	O
+.	O
+
+Urine	O
+sediment	O
+score	O
+was	O
+the	O
+sum	O
+of	O
+the	O
+individual	O
+types	O
+of	O
+sediment	O
+identified	O
+on	O
+urine	O
+microscopy	O
+.	O
+
+RESULTS	O
+:	O
+Of	O
+the	O
+80	O
+patients	O
+studied	O
+,	O
+ARI	B
+developed	O
+in	O
+18	O
+.	O
+8	O
+%	O
+of	O
+the	O
+patients	O
+after	O
+high	O
+-	O
+dose	O
+melphalan	O
+.	O
+
+Univariate	O
+analysis	O
+identified	O
+age	O
+,	O
+hypoalbuminemia	B
+,	O
+heavy	O
+proteinuria	B
+,	O
+diuretic	O
+use	O
+,	O
+and	O
+urine	O
+sediment	O
+score	O
+(	O
+>	O
+3	O
+)	O
+as	O
+risk	O
+factors	O
+.	O
+
+Age	O
+and	O
+urine	O
+sediment	O
+score	O
+remained	O
+independently	O
+significant	O
+risk	O
+factors	O
+in	O
+the	O
+multivariate	O
+analysis	O
+.	O
+
+Patients	O
+who	O
+had	O
+ARI	B
+after	O
+high	O
+-	O
+dose	O
+melphalan	O
+underwent	O
+dialysis	O
+more	O
+often	O
+(	O
+P	O
+=	O
+0	O
+.	O
+007	O
+)	O
+,	O
+and	O
+had	O
+a	O
+worse	O
+1	O
+-	O
+year	O
+survival	O
+(	O
+P	O
+=	O
+0	O
+.	O
+03	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+timing	O
+of	O
+renal	B
+injury	I
+strongly	O
+suggests	O
+melphalan	O
+as	O
+the	O
+causative	O
+agent	O
+.	O
+
+Ongoing	O
+tubular	B
+injury	I
+may	O
+be	O
+a	O
+prerequisite	O
+for	O
+renal	B
+injury	I
+by	O
+melphalan	O
+as	O
+evidenced	O
+by	O
+the	O
+active	O
+urinary	O
+sediment	O
+.	O
+
+Development	O
+of	O
+ARI	B
+adversely	O
+affected	O
+the	O
+outcome	O
+after	O
+PBSCT	O
+.	O
+
+Effective	O
+preventive	O
+measures	O
+may	O
+help	O
+decrease	O
+the	O
+treatment	O
+mortality	O
+of	O
+PBSCT	O
+in	O
+AL	B
+patients	O
+.	O
+
+Focal	O
+cerebral	B
+ischemia	I
+in	O
+rats	O
+:	O
+effect	O
+of	O
+phenylephrine	O
+-	O
+induced	O
+hypertension	B
+during	O
+reperfusion	O
+.	O
+
+After	O
+180	O
+min	O
+of	O
+temporary	O
+middle	B
+cerebral	I
+artery	I
+occlusion	I
+in	O
+spontaneously	O
+hypertensive	B
+rats	O
+,	O
+the	O
+effect	O
+of	O
+phenylephrine	O
+-	O
+induced	O
+hypertension	B
+on	O
+ischemic	B
+brain	I
+injury	I
+and	O
+blood	O
+-	O
+brain	O
+barrier	O
+permeability	O
+was	O
+determined	O
+.	O
+
+Blood	O
+pressure	O
+was	O
+manipulated	O
+by	O
+one	O
+of	O
+the	O
+following	O
+schedules	O
+during	O
+120	O
+min	O
+of	O
+reperfusion	O
+:	O
+Control	O
+,	O
+normotensive	O
+reperfusion	O
+;	O
+90	O
+/	O
+hypertension	B
+(	O
+90	O
+/	O
+HTN	B
+)	O
+,	O
+blood	O
+pressure	O
+was	O
+increased	O
+by	O
+35	O
+mm	O
+Hg	O
+during	O
+the	O
+initial	O
+90	O
+min	O
+of	O
+reperfusion	O
+only	O
+;	O
+15	O
+/	O
+hypertension	B
+(	O
+15	O
+/	O
+HTN	B
+)	O
+,	O
+normotensive	O
+reperfusion	O
+for	O
+30	O
+min	O
+followed	O
+by	O
+15	O
+min	O
+of	O
+hypertension	B
+and	O
+75	O
+min	O
+of	O
+normotension	O
+.	O
+
+Part	O
+A	O
+,	O
+for	O
+eight	O
+rats	O
+in	O
+each	O
+group	O
+brain	B
+injury	I
+was	O
+evaluated	O
+by	O
+staining	O
+tissue	O
+using	O
+2	O
+,	O
+3	O
+,	O
+5	O
+-	O
+triphenyltetrazolium	O
+chloride	O
+and	O
+edema	B
+was	O
+evaluated	O
+by	O
+microgravimetry	O
+.	O
+
+Part	O
+B	O
+,	O
+for	O
+eight	O
+different	O
+rats	O
+in	O
+each	O
+group	O
+blood	O
+-	O
+brain	O
+barrier	O
+permeability	O
+was	O
+evaluated	O
+by	O
+measuring	O
+the	O
+amount	O
+and	O
+extent	O
+of	O
+extravasation	O
+of	O
+Evans	O
+Blue	O
+dye	O
+.	O
+
+Brain	B
+injury	I
+(	O
+percentage	O
+of	O
+the	O
+ischemic	B
+hemisphere	I
+)	O
+was	O
+less	O
+in	O
+the	O
+15	O
+/	O
+HTN	B
+group	O
+(	O
+16	O
++	O
+/	O
+-	O
+6	O
+,	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+)	O
+versus	O
+the	O
+90	O
+/	O
+HTN	B
+group	O
+(	O
+30	O
++	O
+/	O
+-	O
+6	O
+)	O
+,	O
+which	O
+was	O
+in	O
+turn	O
+less	O
+than	O
+the	O
+control	O
+group	O
+(	O
+42	O
++	O
+/	O
+-	O
+5	O
+)	O
+.	O
+
+Specific	O
+gravity	O
+was	O
+greater	O
+in	O
+the	O
+15	O
+/	O
+HTN	B
+group	O
+(	O
+1	O
+.	O
+043	O
++	O
+/	O
+-	O
+0	O
+.	O
+002	O
+)	O
+versus	O
+the	O
+90	O
+/	O
+HTN	B
+(	O
+1	O
+.	O
+036	O
++	O
+/	O
+-	O
+0	O
+.	O
+003	O
+)	O
+and	O
+control	O
+(	O
+1	O
+.	O
+037	O
++	O
+/	O
+-	O
+0	O
+.	O
+003	O
+)	O
+groups	O
+.	O
+
+Evans	O
+Blue	O
+(	O
+mug	O
+g	O
+-	O
+1	O
+of	O
+brain	O
+tissue	O
+)	O
+was	O
+greater	O
+in	O
+the	O
+90	O
+/	O
+HTN	B
+group	O
+(	O
+24	O
+.	O
+4	O
++	O
+/	O
+-	O
+6	O
+.	O
+0	O
+)	O
+versus	O
+the	O
+control	O
+group	O
+(	O
+12	O
+.	O
+3	O
++	O
+/	O
+-	O
+4	O
+.	O
+1	O
+)	O
+,	O
+which	O
+was	O
+in	O
+turn	O
+greater	O
+than	O
+the	O
+15	O
+/	O
+HTN	B
+group	O
+(	O
+7	O
+.	O
+3	O
++	O
+/	O
+-	O
+3	O
+.	O
+2	O
+)	O
+.	O
+
+This	O
+study	O
+supports	O
+a	O
+hypothesis	O
+that	O
+during	O
+reperfusion	O
+,	O
+a	O
+short	O
+interval	O
+of	O
+hypertension	B
+decreases	O
+brain	B
+injury	I
+and	O
+edema	B
+;	O
+and	O
+that	O
+sustained	O
+hypertension	B
+increases	O
+the	O
+risk	O
+of	O
+vasogenic	B
+edema	I
+.	O
+
+People	O
+aged	O
+over	O
+75	O
+in	O
+atrial	B
+fibrillation	I
+on	O
+warfarin	O
+:	O
+the	O
+rate	O
+of	O
+major	O
+hemorrhage	B
+and	O
+stroke	B
+in	O
+more	O
+than	O
+500	O
+patient	O
+-	O
+years	O
+of	O
+follow	O
+-	O
+up	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+determine	O
+the	O
+incidence	O
+of	O
+major	O
+hemorrhage	B
+and	O
+stroke	B
+in	O
+people	O
+aged	O
+76	O
+and	O
+older	O
+with	O
+atrial	B
+fibrillation	I
+on	O
+adjusted	O
+-	O
+dose	O
+warfarin	O
+who	O
+had	O
+been	O
+recently	O
+been	O
+admitted	O
+to	O
+hospital	O
+.	O
+
+DESIGN	O
+:	O
+A	O
+retrospective	O
+observational	O
+cohort	O
+study	O
+.	O
+
+SETTING	O
+:	O
+A	O
+major	O
+healthcare	O
+network	O
+involving	O
+four	O
+tertiary	O
+hospitals	O
+.	O
+
+PARTICIPANTS	O
+:	O
+Two	O
+hundred	O
+thirty	O
+-	O
+five	O
+patients	O
+aged	O
+76	O
+and	O
+older	O
+admitted	O
+to	O
+a	O
+major	O
+healthcare	O
+network	O
+between	O
+July	O
+1	O
+,	O
+2001	O
+,	O
+and	O
+June	O
+30	O
+,	O
+2002	O
+,	O
+with	O
+atrial	B
+fibrillation	I
+on	O
+warfarin	O
+were	O
+enrolled	O
+.	O
+
+MEASUREMENTS	O
+:	O
+Information	O
+regarding	O
+major	O
+bleeding	B
+episodes	O
+,	O
+strokes	B
+,	O
+and	O
+warfarin	O
+use	O
+was	O
+obtained	O
+from	O
+patients	O
+,	O
+relatives	O
+,	O
+primary	O
+physicians	O
+,	O
+and	O
+medical	O
+records	O
+.	O
+
+RESULTS	O
+:	O
+Two	O
+hundred	O
+twenty	O
+-	O
+eight	O
+patients	O
+(	O
+42	O
+%	O
+men	O
+)	O
+with	O
+a	O
+mean	O
+age	O
+of	O
+81	O
+.	O
+1	O
+(	O
+range	O
+76	O
+-	O
+94	O
+)	O
+were	O
+included	O
+in	O
+the	O
+analysis	O
+.	O
+
+Total	O
+follow	O
+-	O
+up	O
+on	O
+warfarin	O
+was	O
+530	O
+years	O
+(	O
+mean	O
+28	O
+months	O
+)	O
+.	O
+
+There	O
+were	O
+53	O
+major	O
+hemorrhages	B
+,	O
+for	O
+an	O
+annual	O
+rate	O
+of	O
+10	O
+.	O
+0	O
+%	O
+,	O
+including	O
+24	O
+(	O
+45	O
+.	O
+3	O
+%	O
+)	O
+life	O
+-	O
+threatening	O
+and	O
+five	O
+(	O
+9	O
+.	O
+4	O
+%	O
+)	O
+fatal	O
+bleeds	O
+.	O
+
+The	O
+annual	O
+stroke	B
+rate	O
+after	O
+initiation	O
+of	O
+warfarin	O
+was	O
+2	O
+.	O
+6	O
+%	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+rate	O
+of	O
+major	O
+hemorrhage	B
+was	O
+high	O
+in	O
+this	O
+old	O
+,	O
+frail	O
+group	O
+,	O
+but	O
+excluding	O
+fatalities	O
+,	O
+resulted	O
+in	O
+no	O
+long	O
+-	O
+term	O
+sequelae	O
+,	O
+and	O
+the	O
+stroke	B
+rate	O
+on	O
+warfarin	O
+was	O
+low	O
+,	O
+demonstrating	O
+how	O
+effective	O
+warfarin	O
+treatment	O
+is	O
+.	O
+
+Safety	O
+of	O
+celecoxib	O
+in	O
+patients	O
+with	O
+adverse	O
+skin	B
+reactions	I
+to	O
+acetaminophen	O
+(	O
+paracetamol	O
+)	O
+and	O
+nimesulide	O
+associated	O
+or	O
+not	O
+with	O
+common	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+.	O
+
+BACKGROUND	O
+:	O
+Acetaminophen	O
+(	O
+paracetamol	O
+-	O
+-	O
+P	O
+)	O
+and	O
+Nimesulide	O
+(	O
+N	O
+)	O
+are	O
+widely	O
+used	O
+analgesic	O
+-	O
+antipyretic	O
+/	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+.	O
+
+The	O
+rate	O
+of	O
+adverse	O
+hypersensitivity	B
+reactions	O
+to	O
+these	O
+agents	O
+is	O
+generally	O
+low	O
+.	O
+
+On	O
+the	O
+contrary	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+(	O
+NSAIDs	O
+)	O
+are	O
+commonly	O
+involved	O
+in	O
+such	O
+reactions	O
+.	O
+
+Celecoxib	O
+(	O
+CE	O
+)	O
+is	O
+a	O
+novel	O
+drug	O
+,	O
+with	O
+high	O
+selectivity	O
+and	O
+affinity	O
+for	O
+COX	O
+-	O
+2	O
+enzyme	O
+.	O
+
+OBJECTIVE	O
+:	O
+We	O
+evaluated	O
+the	O
+tolerability	O
+of	O
+CE	O
+in	O
+a	O
+group	O
+of	O
+patients	O
+with	O
+documented	O
+history	O
+of	O
+adverse	O
+cutaneous	B
+reactions	I
+to	O
+P	O
+and	O
+N	O
+associated	O
+or	O
+not	O
+to	O
+classic	O
+NSAIDs	O
+.	O
+
+METHODS	O
+:	O
+We	O
+studied	O
+9	O
+patients	O
+with	O
+hypersensitivity	B
+to	O
+P	O
+and	O
+N	O
+with	O
+or	O
+without	O
+associated	O
+reactions	O
+to	O
+classic	O
+NSAIDs	O
+.	O
+
+The	O
+diagnosis	O
+of	O
+P	O
+and	O
+N	O
+-	O
+induced	O
+skin	B
+reactions	I
+was	O
+based	O
+in	O
+vivo	O
+challenge	O
+.	O
+
+The	O
+placebo	O
+was	O
+blindly	O
+administered	O
+at	O
+the	O
+beginning	O
+of	O
+each	O
+challenge	O
+.	O
+
+After	O
+three	O
+days	O
+,	O
+a	O
+cumulative	O
+dosage	O
+of	O
+200	O
+mg	O
+of	O
+CE	O
+in	O
+refracted	O
+doses	O
+were	O
+given	O
+.	O
+
+After	O
+2	O
+-	O
+3	O
+days	O
+,	O
+a	O
+single	O
+dose	O
+of	O
+200	O
+mg	O
+was	O
+administered	O
+.	O
+
+All	O
+patients	O
+were	O
+observed	O
+for	O
+6	O
+hours	O
+after	O
+each	O
+challenge	O
+,	O
+and	O
+controlled	O
+again	O
+after	O
+24	O
+hours	O
+to	O
+exclude	O
+delayed	O
+reactions	O
+.	O
+
+The	O
+challenge	O
+was	O
+considered	O
+positive	O
+if	O
+one	O
+or	O
+more	O
+of	O
+the	O
+following	O
+appeared	O
+:	O
+erythema	B
+,	O
+rush	O
+or	O
+urticaria	B
+-	O
+angioedema	B
+.	O
+
+RESULTS	O
+:	O
+No	O
+reaction	O
+was	O
+observed	O
+with	O
+placebo	O
+and	O
+eight	O
+patients	O
+(	O
+88	O
+.	O
+8	O
+%	O
+)	O
+tolerated	O
+CE	O
+.	O
+
+Only	O
+one	O
+patient	O
+developed	O
+a	O
+moderate	O
+angioedema	B
+of	O
+the	O
+lips	O
+.	O
+
+CONCLUSION	O
+:	O
+Only	O
+one	O
+hypersensitivity	B
+reaction	O
+to	O
+CE	O
+was	O
+documented	O
+among	O
+9	O
+P	O
+and	O
+N	O
+-	O
+highly	O
+NSAIDs	O
+intolerant	O
+patients	O
+.	O
+
+Thus	O
+,	O
+we	O
+conclude	O
+that	O
+CE	O
+is	O
+a	O
+reasonably	O
+safe	O
+alternative	O
+to	O
+be	O
+used	O
+in	O
+subjects	O
+who	O
+do	O
+not	O
+tolerate	O
+P	O
+and	O
+N	O
+.	O
+
+Case	O
+-	O
+control	O
+study	O
+of	O
+regular	O
+analgesic	O
+and	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+use	O
+and	O
+end	B
+-	I
+stage	I
+renal	I
+disease	I
+.	O
+
+BACKGROUND	O
+:	O
+Studies	O
+on	O
+the	O
+association	O
+between	O
+the	O
+long	O
+-	O
+term	O
+use	O
+of	O
+aspirin	O
+and	O
+other	O
+analgesic	O
+and	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+(	O
+NSAIDs	O
+)	O
+and	O
+end	B
+-	I
+stage	I
+renal	I
+disease	I
+(	O
+ESRD	B
+)	O
+have	O
+given	O
+conflicting	O
+results	O
+.	O
+
+In	O
+order	O
+to	O
+examine	O
+this	O
+association	O
+,	O
+a	O
+case	O
+-	O
+control	O
+study	O
+with	O
+incident	O
+cases	O
+of	O
+ESRD	B
+was	O
+carried	O
+out	O
+.	O
+
+METHODS	O
+:	O
+The	O
+cases	O
+were	O
+all	O
+patients	O
+entering	O
+the	O
+local	O
+dialysis	O
+program	O
+because	O
+of	O
+ESRD	B
+in	O
+the	O
+study	O
+area	O
+between	O
+June	O
+1	O
+,	O
+1995	O
+and	O
+November	O
+30	O
+,	O
+1997	O
+.	O
+
+They	O
+were	O
+classified	O
+according	O
+to	O
+the	O
+underlying	O
+disease	O
+,	O
+which	O
+had	O
+presumably	O
+led	O
+them	O
+to	O
+ESRD	B
+.	O
+
+Controls	O
+were	O
+patients	O
+admitted	O
+to	O
+the	O
+same	O
+hospitals	O
+from	O
+where	O
+the	O
+cases	O
+arose	O
+,	O
+also	O
+matched	O
+by	O
+age	O
+and	O
+sex	O
+.	O
+
+Odds	O
+ratios	O
+were	O
+calculated	O
+using	O
+a	O
+conditional	O
+logistic	O
+model	O
+,	O
+including	O
+potential	O
+confounding	O
+factors	O
+,	O
+both	O
+for	O
+the	O
+whole	O
+study	O
+population	O
+and	O
+for	O
+the	O
+various	O
+underlying	O
+diseases	O
+.	O
+
+RESULTS	O
+:	O
+Five	O
+hundred	O
+and	O
+eighty	O
+-	O
+three	O
+cases	O
+and	O
+1190	O
+controls	O
+were	O
+included	O
+in	O
+the	O
+analysis	O
+.	O
+
+Long	O
+-	O
+term	O
+use	O
+of	O
+any	O
+analgesic	O
+was	O
+associated	O
+with	O
+an	O
+overall	O
+odds	O
+ratio	O
+of	O
+1	O
+.	O
+22	O
+(	O
+95	O
+%	O
+CI	O
+,	O
+0	O
+.	O
+89	O
+-	O
+1	O
+.	O
+66	O
+)	O
+.	O
+
+For	O
+specific	O
+groups	O
+of	O
+drugs	O
+,	O
+the	O
+risks	O
+were	O
+1	O
+.	O
+56	O
+(	O
+1	O
+.	O
+05	O
+-	O
+2	O
+.	O
+30	O
+)	O
+for	O
+aspirin	O
+,	O
+1	O
+.	O
+03	O
+(	O
+0	O
+.	O
+60	O
+-	O
+1	O
+.	O
+76	O
+)	O
+for	O
+pyrazolones	O
+,	O
+0	O
+.	O
+80	O
+(	O
+0	O
+.	O
+39	O
+-	O
+1	O
+.	O
+63	O
+)	O
+for	O
+paracetamol	O
+,	O
+and	O
+0	O
+.	O
+94	O
+(	O
+0	O
+.	O
+57	O
+-	O
+1	O
+.	O
+56	O
+)	O
+for	O
+nonaspirin	O
+NSAIDs	O
+.	O
+
+The	O
+risk	O
+of	O
+ESRD	B
+associated	O
+with	O
+aspirin	O
+was	O
+related	O
+to	O
+the	O
+cumulated	O
+dose	O
+and	O
+duration	O
+of	O
+use	O
+,	O
+and	O
+it	O
+was	O
+particularly	O
+high	O
+among	O
+the	O
+subset	O
+of	O
+patients	O
+with	O
+vascular	O
+nephropathy	B
+as	O
+underlying	O
+disease	O
+[	O
+2	O
+.	O
+35	O
+(	O
+1	O
+.	O
+17	O
+-	O
+4	O
+.	O
+72	O
+)	O
+]	O
+.	O
+
+CONCLUSION	O
+:	O
+Our	O
+data	O
+indicate	O
+that	O
+long	O
+-	O
+term	O
+use	O
+of	O
+nonaspirin	O
+analgesic	O
+drugs	O
+and	O
+NSAIDs	O
+is	O
+not	O
+associated	O
+with	O
+an	O
+increased	O
+risk	O
+of	O
+ESRD	B
+.	O
+
+However	O
+,	O
+the	O
+chronic	O
+use	O
+of	O
+aspirin	O
+may	O
+increase	O
+the	O
+risk	O
+of	O
+ESRD	B
+.	O
+
+Two	O
+cases	O
+of	O
+amisulpride	O
+overdose	B
+:	O
+a	O
+cause	O
+for	O
+prolonged	B
+QT	I
+syndrome	I
+.	O
+
+Two	O
+cases	O
+of	O
+deliberate	O
+self	O
+-	O
+poisoning	B
+with	O
+5	O
+g	O
+and	O
+3	O
+.	O
+6	O
+g	O
+of	O
+amisulpride	O
+,	O
+respectively	O
+,	O
+are	O
+reported	O
+.	O
+
+In	O
+both	O
+cases	O
+,	O
+QT	B
+prolongation	I
+and	O
+hypocalcaemia	B
+were	O
+noted	O
+.	O
+
+The	O
+QT	B
+prolongation	I
+appeared	O
+to	O
+respond	O
+to	O
+administration	O
+of	O
+i	O
+.	O
+v	O
+.	O
+calcium	O
+gluconate	O
+.	O
+
+Growth	O
+-	O
+associated	O
+protein	O
+43	O
+expression	O
+in	O
+hippocampal	O
+molecular	O
+layer	O
+of	O
+chronic	O
+epileptic	B
+rats	O
+treated	O
+with	O
+cycloheximide	O
+.	O
+
+PURPOSE	O
+:	O
+GAP43	O
+has	O
+been	O
+thought	O
+to	O
+be	O
+linked	O
+with	O
+mossy	O
+fiber	O
+sprouting	O
+(	O
+MFS	O
+)	O
+in	O
+various	O
+experimental	O
+models	O
+of	O
+epilepsy	B
+.	O
+
+To	O
+investigate	O
+how	O
+GAP43	O
+expression	O
+(	O
+GAP43	O
+-	O
+ir	O
+)	O
+correlates	O
+with	O
+MFS	O
+,	O
+we	O
+assessed	O
+the	O
+intensity	O
+(	O
+densitometry	O
+)	O
+and	O
+extension	O
+(	O
+width	O
+)	O
+of	O
+GAP43	O
+-	O
+ir	O
+in	O
+the	O
+inner	O
+molecular	O
+layer	O
+of	O
+the	O
+dentate	O
+gyrus	O
+(	O
+IML	O
+)	O
+of	O
+rats	O
+subject	O
+to	O
+status	B
+epilepticus	I
+induced	O
+by	O
+pilocarpine	O
+(	O
+Pilo	O
+)	O
+,	O
+previously	O
+injected	O
+or	O
+not	O
+with	O
+cycloheximide	O
+(	O
+CHX	O
+)	O
+,	O
+which	O
+has	O
+been	O
+shown	O
+to	O
+inhibit	O
+MFS	O
+.	O
+
+METHODS	O
+:	O
+CHX	O
+was	O
+injected	O
+before	O
+the	O
+Pilo	O
+injection	O
+in	O
+adult	O
+Wistar	O
+rats	O
+.	O
+
+The	O
+Pilo	O
+group	O
+was	O
+injected	O
+with	O
+the	O
+same	O
+drugs	O
+,	O
+except	O
+for	O
+CHX	O
+.	O
+
+Animals	O
+were	O
+killed	O
+between	O
+30	O
+and	O
+60	O
+days	O
+later	O
+,	O
+and	O
+brain	O
+sections	O
+were	O
+processed	O
+for	O
+GAP43	O
+immunohistochemistry	O
+.	O
+
+RESULTS	O
+:	O
+Densitometry	O
+showed	O
+no	O
+significant	O
+difference	O
+regarding	O
+GAP43	O
+-	O
+ir	O
+in	O
+the	O
+IML	O
+between	O
+Pilo	O
+,	O
+CHX	O
++	O
+Pilo	O
+,	O
+and	O
+control	O
+groups	O
+.	O
+
+However	O
+,	O
+the	O
+results	O
+of	O
+the	O
+width	O
+of	O
+the	O
+GAP43	O
+-	O
+ir	O
+band	O
+in	O
+the	O
+IML	O
+showed	O
+that	O
+CHX	O
++	O
+Pilo	O
+and	O
+control	O
+animals	O
+had	O
+a	O
+significantly	O
+larger	O
+band	O
+(	O
+p	O
+=	O
+0	O
+.	O
+03	O
+)	O
+as	O
+compared	O
+with	O
+that	O
+in	O
+the	O
+Pilo	O
+group	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Our	O
+current	O
+finding	O
+that	O
+animals	O
+in	O
+the	O
+CHX	O
++	O
+Pilo	O
+group	O
+have	O
+a	O
+GAP43	O
+-	O
+ir	O
+band	O
+in	O
+the	O
+IML	O
+,	O
+similar	O
+to	O
+that	O
+of	O
+controls	O
+,	O
+reinforces	O
+prior	O
+data	O
+on	O
+the	O
+blockade	O
+of	O
+MFS	O
+in	O
+these	O
+animals	O
+.	O
+
+The	O
+change	O
+in	O
+GAP43	O
+-	O
+ir	O
+present	O
+in	O
+Pilo	O
+-	O
+treated	O
+animals	O
+was	O
+a	O
+thinning	O
+of	O
+the	O
+band	O
+to	O
+a	O
+very	O
+narrow	O
+layer	O
+just	O
+above	O
+the	O
+granule	O
+cell	O
+layer	O
+that	O
+is	O
+likely	O
+to	O
+be	O
+associated	O
+with	O
+the	O
+loss	O
+of	O
+hilar	O
+cell	O
+projections	O
+that	O
+express	O
+GAP	O
+-	O
+43	O
+.	O
+
+Nicotine	O
+antagonizes	O
+caffeine	O
+-	O
+but	O
+not	O
+pentylenetetrazole	O
+-	O
+induced	O
+anxiogenic	O
+effect	O
+in	O
+mice	O
+.	O
+
+RATIONALE	O
+:	O
+Nicotine	O
+and	O
+caffeine	O
+are	O
+widely	O
+consumed	O
+licit	O
+psychoactive	O
+drugs	O
+worldwide	O
+.	O
+
+Epidemiological	O
+studies	O
+showed	O
+that	O
+they	O
+were	O
+generally	O
+used	O
+concurrently	O
+.	O
+
+Although	O
+some	O
+studies	O
+in	O
+experimental	O
+animals	O
+indicate	O
+clear	O
+pharmacological	O
+interactions	O
+between	O
+them	O
+,	O
+no	O
+studies	O
+have	O
+shown	O
+a	O
+specific	O
+interaction	O
+on	O
+anxiety	B
+responses	O
+.	O
+
+OBJECTIVES	O
+:	O
+The	O
+present	O
+study	O
+investigates	O
+the	O
+effects	O
+of	O
+nicotine	O
+on	O
+anxiety	B
+induced	O
+by	O
+caffeine	O
+and	O
+another	O
+anxiogenic	O
+drug	O
+,	O
+pentylenetetrazole	O
+,	O
+in	O
+mice	O
+.	O
+
+The	O
+elevated	O
+plus	O
+-	O
+maze	O
+(	O
+EPM	O
+)	O
+test	O
+was	O
+used	O
+to	O
+evaluate	O
+the	O
+effects	O
+of	O
+drugs	O
+on	O
+anxiety	B
+.	O
+
+METHODS	O
+:	O
+Adult	O
+male	O
+Swiss	O
+Webster	O
+mice	O
+(	O
+25	O
+-	O
+32	O
+g	O
+)	O
+were	O
+given	O
+nicotine	O
+(	O
+0	O
+.	O
+05	O
+-	O
+0	O
+.	O
+25	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+or	O
+saline	O
+10	O
+min	O
+before	O
+caffeine	O
+(	O
+70	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+or	O
+pentylenetetrazole	O
+(	O
+15	O
+and	O
+30	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+injections	O
+.	O
+
+After	O
+15	O
+min	O
+,	O
+mice	O
+were	O
+evaluated	O
+for	O
+their	O
+open	O
+-	O
+and	O
+closed	O
+-	O
+arm	O
+time	O
+and	O
+entries	O
+on	O
+the	O
+EPM	O
+for	O
+a	O
+10	O
+-	O
+min	O
+session	O
+.	O
+
+Locomotor	O
+activity	O
+was	O
+recorded	O
+for	O
+individual	O
+groups	O
+by	O
+using	O
+the	O
+same	O
+treatment	O
+protocol	O
+with	O
+the	O
+EPM	O
+test	O
+.	O
+
+RESULTS	O
+:	O
+Nicotine	O
+(	O
+0	O
+.	O
+05	O
+-	O
+0	O
+.	O
+25	O
+mg	O
+/	O
+kg	O
+)	O
+itself	O
+did	O
+not	O
+produce	O
+any	O
+significant	O
+effect	O
+in	O
+the	O
+EPM	O
+test	O
+,	O
+whereas	O
+caffeine	O
+(	O
+70	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+pentylenetetrazole	O
+(	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+produced	O
+an	O
+anxiogenic	O
+effect	O
+,	O
+apparent	O
+with	O
+decreases	O
+in	O
+open	O
+-	O
+arm	O
+time	O
+and	O
+entry	O
+.	O
+
+Nicotine	O
+(	O
+0	O
+.	O
+25	O
+mg	O
+/	O
+kg	O
+)	O
+pretreatment	O
+blocked	O
+the	O
+caffeine	O
+-	O
+but	O
+not	O
+pentylenetetrazole	O
+-	O
+induced	O
+anxiety	B
+.	O
+
+Administration	O
+of	O
+each	O
+drug	O
+and	O
+their	O
+combinations	O
+did	O
+not	O
+produce	O
+any	O
+effect	O
+on	O
+locomotor	O
+activity	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Our	O
+results	O
+suggest	O
+that	O
+the	O
+antagonistic	O
+effect	O
+of	O
+nicotine	O
+on	O
+caffeine	O
+-	O
+induced	O
+anxiety	B
+is	O
+specific	O
+to	O
+caffeine	O
+,	O
+instead	O
+of	O
+a	O
+non	O
+-	O
+specific	O
+anxiolytic	O
+effect	O
+.	O
+
+Thus	O
+,	O
+it	O
+may	O
+extend	O
+the	O
+current	O
+findings	O
+on	O
+the	O
+interaction	O
+between	O
+nicotine	O
+and	O
+caffeine	O
+.	O
+
+Long	O
+term	O
+hormone	O
+therapy	O
+for	O
+perimenopausal	O
+and	O
+postmenopausal	O
+women	O
+.	O
+
+BACKGROUND	O
+:	O
+Hormone	O
+therapy	O
+(	O
+HT	O
+)	O
+is	O
+widely	O
+used	O
+for	O
+controlling	O
+menopausal	B
+symptoms	I
+.	O
+
+It	O
+has	O
+also	O
+been	O
+used	O
+for	O
+the	O
+management	O
+and	O
+prevention	O
+of	O
+cardiovascular	B
+disease	I
+,	O
+osteoporosis	B
+and	O
+dementia	B
+in	O
+older	O
+women	O
+but	O
+the	O
+evidence	O
+supporting	O
+its	O
+use	O
+for	O
+these	O
+indications	O
+is	O
+largely	O
+observational	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+assess	O
+the	O
+effect	O
+of	O
+long	O
+-	O
+term	O
+HT	O
+on	O
+mortality	O
+,	O
+heart	B
+disease	I
+,	O
+venous	B
+thromboembolism	I
+,	O
+stroke	B
+,	O
+transient	B
+ischaemic	I
+attacks	I
+,	O
+breast	B
+cancer	I
+,	O
+colorectal	B
+cancer	I
+,	O
+ovarian	B
+cancer	I
+,	O
+endometrial	B
+cancer	I
+,	O
+gallbladder	B
+disease	I
+,	O
+cognitive	O
+function	O
+,	O
+dementia	B
+,	O
+fractures	B
+and	O
+quality	O
+of	O
+life	O
+.	O
+
+SEARCH	O
+STRATEGY	O
+:	O
+We	O
+searched	O
+the	O
+following	O
+databases	O
+up	O
+to	O
+November	O
+2004	O
+:	O
+the	O
+Cochrane	O
+Menstrual	O
+Disorders	O
+and	O
+Subfertility	O
+Group	O
+Trials	O
+Register	O
+,	O
+Cochrane	O
+Central	O
+Register	O
+of	O
+Controlled	O
+Trials	O
+(	O
+CENTRAL	O
+)	O
+,	O
+MEDLINE	O
+,	O
+EMBASE	O
+,	O
+Biological	O
+Abstracts	O
+.	O
+
+Relevant	O
+non	O
+-	O
+indexed	O
+journals	O
+and	O
+conference	O
+abstracts	O
+were	O
+also	O
+searched	O
+.	O
+
+SELECTION	O
+CRITERIA	O
+:	O
+Randomised	O
+double	O
+-	O
+blind	O
+trials	O
+of	O
+HT	O
+(	O
+oestrogens	O
+with	O
+or	O
+without	O
+progestogens	O
+)	O
+versus	O
+placebo	O
+,	O
+taken	O
+for	O
+at	O
+least	O
+one	O
+year	O
+by	O
+perimenopausal	O
+or	O
+postmenopausal	O
+women	O
+.	O
+
+DATA	O
+COLLECTION	O
+AND	O
+ANALYSIS	O
+:	O
+Fifteen	O
+RCTs	O
+were	O
+included	O
+.	O
+
+Trials	O
+were	O
+assessed	O
+for	O
+quality	O
+and	O
+two	O
+review	O
+authors	O
+extracted	O
+data	O
+independently	O
+.	O
+
+They	O
+calculated	O
+risk	O
+ratios	O
+for	O
+dichotomous	O
+outcomes	O
+and	O
+weighted	O
+mean	O
+differences	O
+for	O
+continuous	O
+outcomes	O
+.	O
+
+Clinical	O
+heterogeneity	O
+precluded	O
+meta	O
+-	O
+analysis	O
+for	O
+most	O
+outcomes	O
+.	O
+
+MAIN	O
+RESULTS	O
+:	O
+All	O
+the	O
+statistically	O
+significant	O
+results	O
+were	O
+derived	O
+from	O
+the	O
+two	O
+biggest	O
+trials	O
+.	O
+
+In	O
+relatively	O
+healthy	O
+women	O
+,	O
+combined	O
+continuous	O
+HT	O
+significantly	O
+increased	O
+the	O
+risk	O
+of	O
+venous	B
+thromboembolism	I
+or	O
+coronary	O
+event	O
+(	O
+after	O
+one	O
+year	O
+'	O
+s	O
+use	O
+)	O
+,	O
+stroke	B
+(	O
+after	O
+3	O
+years	O
+)	O
+,	O
+breast	B
+cancer	I
+(	O
+after	O
+5	O
+years	O
+)	O
+and	O
+gallbladder	B
+disease	I
+.	O
+
+Long	O
+-	O
+term	O
+oestrogen	O
+-	O
+only	O
+HT	O
+also	O
+significantly	O
+increased	O
+the	O
+risk	O
+of	O
+stroke	B
+and	O
+gallbladder	B
+disease	I
+.	O
+
+Overall	O
+,	O
+the	O
+only	O
+statistically	O
+significant	O
+benefits	O
+of	O
+HT	O
+were	O
+a	O
+decreased	O
+incidence	O
+of	O
+fractures	B
+and	O
+colon	B
+cancer	I
+with	O
+long	O
+-	O
+term	O
+use	O
+.	O
+
+Among	O
+relatively	O
+healthy	O
+women	O
+over	O
+65	O
+years	O
+taking	O
+continuous	O
+combined	O
+HT	O
+,	O
+there	O
+was	O
+a	O
+statistically	O
+significant	O
+increase	O
+in	O
+the	O
+incidence	O
+of	O
+dementia	B
+.	O
+
+Among	O
+women	O
+with	O
+cardiovascular	B
+disease	I
+,	O
+long	O
+-	O
+term	O
+use	O
+of	O
+combined	O
+continuous	O
+HT	O
+significantly	O
+increased	O
+the	O
+risk	O
+of	O
+venous	B
+thromboembolism	I
+.	O
+
+No	O
+trials	O
+focussed	O
+specifically	O
+on	O
+younger	O
+women	O
+.	O
+
+However	O
+,	O
+one	O
+trial	O
+analysed	O
+subgroups	O
+of	O
+2839	O
+relatively	O
+healthy	O
+50	O
+to	O
+59	O
+year	O
+-	O
+old	O
+women	O
+taking	O
+combined	O
+continuous	O
+HT	O
+and	O
+1637	O
+taking	O
+oestrogen	O
+-	O
+only	O
+HT	O
+,	O
+versus	O
+similar	O
+-	O
+sized	O
+placebo	O
+groups	O
+.	O
+
+The	O
+only	O
+significantly	O
+increased	O
+risk	O
+reported	O
+was	O
+for	O
+venous	B
+thromboembolism	I
+in	O
+women	O
+taking	O
+combined	O
+continuous	O
+HT	O
+;	O
+their	O
+absolute	O
+risk	O
+remained	O
+very	O
+low	O
+.	O
+
+AUTHORS	O
+'	O
+CONCLUSIONS	O
+:	O
+HT	O
+is	O
+not	O
+indicated	O
+for	O
+the	O
+routine	O
+management	O
+of	O
+chronic	B
+disease	I
+.	O
+
+We	O
+need	O
+more	O
+evidence	O
+on	O
+the	O
+safety	O
+of	O
+HT	O
+for	O
+menopausal	O
+symptom	O
+control	O
+,	O
+though	O
+short	O
+-	O
+term	O
+use	O
+appears	O
+to	O
+be	O
+relatively	O
+safe	O
+for	O
+healthy	O
+younger	O
+women	O
+.	O
+
+Drug	B
+-	I
+induced	I
+liver	I
+injury	I
+:	O
+an	O
+analysis	O
+of	O
+461	O
+incidences	O
+submitted	O
+to	O
+the	O
+Spanish	O
+registry	O
+over	O
+a	O
+10	O
+-	O
+year	O
+period	O
+.	O
+
+BACKGROUND	O
+&	O
+AIMS	O
+:	O
+Progress	O
+in	O
+the	O
+understanding	O
+of	O
+susceptibility	O
+factors	O
+to	O
+drug	B
+-	I
+induced	I
+liver	I
+injury	I
+(	O
+DILI	B
+)	O
+and	O
+outcome	O
+predictability	O
+are	O
+hampered	O
+by	O
+the	O
+lack	O
+of	O
+systematic	O
+programs	O
+to	O
+detect	O
+bona	O
+fide	O
+cases	O
+.	O
+
+METHODS	O
+:	O
+A	O
+cooperative	O
+network	O
+was	O
+created	O
+in	O
+1994	O
+in	O
+Spain	O
+to	O
+identify	O
+all	O
+suspicions	O
+of	O
+DILI	B
+following	O
+a	O
+prospective	O
+structured	O
+report	O
+form	O
+.	O
+
+The	O
+liver	B
+damage	I
+was	O
+characterized	O
+according	O
+to	O
+hepatocellular	O
+,	O
+cholestatic	B
+,	O
+and	O
+mixed	O
+laboratory	O
+criteria	O
+and	O
+to	O
+histologic	O
+criteria	O
+when	O
+available	O
+.	O
+
+Further	O
+evaluation	O
+of	O
+causality	O
+assessment	O
+was	O
+centrally	O
+performed	O
+.	O
+
+RESULTS	O
+:	O
+Since	O
+April	O
+1994	O
+to	O
+August	O
+2004	O
+,	O
+461	O
+out	O
+of	O
+570	O
+submitted	O
+cases	O
+,	O
+involving	O
+505	O
+drugs	O
+,	O
+were	O
+deemed	O
+to	O
+be	O
+related	O
+to	O
+DILI	B
+.	O
+
+The	O
+antiinfective	O
+group	O
+of	O
+drugs	O
+was	O
+the	O
+more	O
+frequently	O
+incriminated	O
+,	O
+amoxicillin	O
+-	O
+clavulanate	O
+accounting	O
+for	O
+the	O
+12	O
+.	O
+8	O
+%	O
+of	O
+the	O
+whole	O
+series	O
+.	O
+
+The	O
+hepatocellular	O
+pattern	O
+of	O
+damage	O
+was	O
+the	O
+most	O
+common	O
+(	O
+58	O
+%	O
+)	O
+,	O
+was	O
+inversely	O
+correlated	O
+with	O
+age	O
+(	O
+P	O
+<	O
+.	O
+0001	O
+)	O
+,	O
+and	O
+had	O
+the	O
+worst	O
+outcome	O
+(	O
+Cox	O
+regression	O
+,	O
+P	O
+<	O
+.	O
+034	O
+)	O
+.	O
+
+Indeed	O
+,	O
+the	O
+incidence	O
+of	O
+liver	O
+transplantation	O
+and	O
+death	O
+in	O
+this	O
+group	O
+was	O
+11	O
+.	O
+7	O
+%	O
+if	O
+patients	O
+had	O
+jaundice	B
+at	O
+presentation	O
+,	O
+whereas	O
+the	O
+corresponding	O
+figure	O
+was	O
+3	O
+.	O
+8	O
+%	O
+in	O
+nonjaundiced	O
+patients	O
+(	O
+P	O
+<	O
+.	O
+04	O
+)	O
+.	O
+
+Factors	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+fulminant	B
+hepatic	I
+failure	I
+were	O
+female	O
+sex	O
+(	O
+OR	O
+=	O
+25	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+4	O
+.	O
+1	O
+-	O
+151	O
+;	O
+P	O
+<	O
+.	O
+0001	O
+)	O
+,	O
+hepatocellular	O
+damage	O
+(	O
+OR	O
+=	O
+7	O
+.	O
+9	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+1	O
+.	O
+6	O
+-	O
+37	O
+;	O
+P	O
+<	O
+.	O
+009	O
+)	O
+,	O
+and	O
+higher	O
+baseline	O
+plasma	O
+bilirubin	O
+value	O
+(	O
+OR	O
+=	O
+1	O
+.	O
+15	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+1	O
+.	O
+09	O
+-	O
+1	O
+.	O
+22	O
+;	O
+P	O
+<	O
+.	O
+0001	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Patients	O
+with	O
+drug	O
+-	O
+induced	O
+hepatocellular	O
+jaundice	B
+have	O
+11	O
+.	O
+7	O
+%	O
+chance	O
+of	O
+progressing	O
+to	O
+death	O
+or	O
+transplantation	O
+.	O
+
+Amoxicillin	O
+-	O
+clavulanate	O
+stands	O
+out	O
+as	O
+the	O
+most	O
+common	O
+drug	O
+related	O
+to	O
+DILI	B
+.	O
+
+Morphological	O
+evaluation	O
+of	O
+the	O
+effect	O
+of	O
+d	O
+-	O
+ribose	O
+on	O
+adriamycin	O
+-	O
+evoked	O
+cardiotoxicity	B
+in	O
+rats	O
+.	O
+
+The	O
+influence	O
+of	O
+d	O
+-	O
+ribose	O
+on	O
+adriamycin	O
+-	O
+induced	O
+myocardiopathy	B
+in	O
+rats	O
+was	O
+studied	O
+.	O
+
+Adriamycin	O
+in	O
+the	O
+cumulative	O
+dose	O
+of	O
+25	O
+mg	O
+/	O
+kg	O
+evoked	O
+fully	O
+developed	O
+cardiac	B
+toxicity	I
+.	O
+
+D	O
+-	O
+ribose	O
+in	O
+the	O
+multiple	O
+doses	O
+of	O
+200	O
+mg	O
+/	O
+kg	O
+did	O
+not	O
+influence	O
+ADR	O
+cardiotoxicity	B
+.	O
+
+In	O
+vivo	O
+evidences	O
+suggesting	O
+the	O
+role	O
+of	O
+oxidative	O
+stress	O
+in	O
+pathogenesis	O
+of	O
+vancomycin	O
+-	O
+induced	O
+nephrotoxicity	B
+:	O
+protection	O
+by	O
+erdosteine	O
+.	O
+
+The	O
+aims	O
+of	O
+this	O
+study	O
+were	O
+to	O
+examine	O
+vancomycin	O
+(	O
+VCM	O
+)	O
+-	O
+induced	O
+oxidative	O
+stress	O
+that	O
+promotes	O
+production	O
+of	O
+reactive	O
+oxygen	O
+species	O
+(	O
+ROS	O
+)	O
+and	O
+to	O
+investigate	O
+the	O
+role	O
+of	O
+erdosteine	O
+,	O
+an	O
+expectorant	O
+agent	O
+,	O
+which	O
+has	O
+also	O
+antioxidant	O
+properties	O
+,	O
+on	O
+kidney	O
+tissue	O
+against	O
+the	O
+possible	O
+VCM	O
+-	O
+induced	O
+renal	B
+impairment	I
+in	O
+rats	O
+.	O
+
+Rats	O
+were	O
+divided	O
+into	O
+three	O
+groups	O
+:	O
+sham	O
+,	O
+VCM	O
+and	O
+VCM	O
+plus	O
+erdosteine	O
+.	O
+
+VCM	O
+was	O
+administrated	O
+intraperitoneally	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+with	O
+200mgkg	O
+(	O
+-	O
+1	O
+)	O
+twice	O
+daily	O
+for	O
+7	O
+days	O
+.	O
+
+Erdosteine	O
+was	O
+administered	O
+orally	O
+.	O
+
+VCM	O
+administration	O
+to	O
+control	O
+rats	O
+significantly	O
+increased	O
+renal	O
+malondialdehyde	O
+(	O
+MDA	O
+)	O
+and	O
+urinary	O
+N	O
+-	O
+acetyl	O
+-	O
+beta	O
+-	O
+d	O
+-	O
+glucosaminidase	O
+(	O
+NAG	O
+,	O
+a	O
+marker	O
+of	O
+renal	B
+tubular	I
+injury	I
+)	O
+excretion	O
+but	O
+decreased	O
+superoxide	O
+dismutase	O
+(	O
+SOD	O
+)	O
+and	O
+catalase	O
+(	O
+CAT	O
+)	O
+activities	O
+.	O
+
+Erdosteine	O
+administration	O
+with	O
+VCM	O
+injections	O
+caused	O
+significantly	O
+decreased	O
+renal	O
+MDA	O
+and	O
+urinary	O
+NAG	O
+excretion	O
+,	O
+and	O
+increased	O
+SOD	O
+activity	O
+,	O
+but	O
+not	O
+CAT	O
+activity	O
+in	O
+renal	O
+tissue	O
+when	O
+compared	O
+with	O
+VCM	O
+alone	O
+.	O
+
+Erdosteine	O
+showed	O
+histopathological	O
+protection	O
+against	O
+VCM	O
+-	O
+induced	O
+nephrotoxicity	B
+.	O
+
+There	O
+were	O
+a	O
+significant	O
+dilatation	O
+of	O
+tubular	O
+lumens	O
+,	O
+extensive	O
+epithelial	O
+cell	O
+vacuolization	O
+,	O
+atrophy	B
+,	O
+desquamation	B
+,	O
+and	O
+necrosis	B
+in	O
+VCM	O
+-	O
+treated	O
+rats	O
+more	O
+than	O
+those	O
+of	O
+the	O
+control	O
+and	O
+the	O
+erdosteine	O
+groups	O
+.	O
+
+Erdosteine	O
+caused	O
+a	O
+marked	O
+reduction	O
+in	O
+the	O
+extent	O
+of	O
+tubular	O
+damage	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+oxidative	O
+tubular	O
+damage	O
+plays	O
+an	O
+important	O
+role	O
+in	O
+the	O
+VCM	O
+-	O
+induced	O
+nephrotoxicity	B
+and	O
+the	O
+modulation	O
+of	O
+oxidative	O
+stress	O
+with	O
+erdosteine	O
+reduces	O
+the	O
+VCM	O
+-	O
+induced	O
+kidney	B
+damage	I
+both	O
+at	O
+the	O
+biochemical	O
+and	O
+histological	O
+levels	O
+.	O
+
+Gemfibrozil	O
+-	O
+lovastatin	O
+therapy	O
+for	O
+primary	O
+hyperlipoproteinemias	B
+.	O
+
+The	O
+specific	O
+aim	O
+of	O
+this	O
+retrospective	O
+,	O
+observational	O
+study	O
+was	O
+to	O
+assess	O
+safety	O
+and	O
+efficacy	O
+of	O
+long	O
+-	O
+term	O
+(	O
+21	O
+months	O
+/	O
+patient	O
+)	O
+,	O
+open	O
+-	O
+label	O
+,	O
+gemfibrozil	O
+-	O
+lovastatin	O
+treatment	O
+in	O
+80	O
+patients	O
+with	O
+primary	O
+mixed	O
+hyperlipidemia	B
+(	O
+68	O
+%	O
+of	O
+whom	O
+had	O
+atherosclerotic	B
+vascular	I
+disease	I
+)	O
+.	O
+
+Because	O
+ideal	O
+lipid	O
+targets	O
+were	O
+not	O
+reached	O
+(	O
+low	O
+-	O
+density	O
+lipoprotein	O
+(	O
+LDL	O
+)	O
+cholesterol	O
+less	O
+than	O
+130	O
+mg	O
+/	O
+dl	O
+,	O
+high	O
+-	O
+density	O
+lipoprotein	O
+(	O
+HDL	O
+)	O
+cholesterol	O
+greater	O
+than	O
+35	O
+mg	O
+/	O
+dl	O
+,	O
+or	O
+total	O
+cholesterol	O
+/	O
+HDL	O
+cholesterol	O
+less	O
+than	O
+4	O
+.	O
+5	O
+mg	O
+/	O
+dl	O
+)	O
+with	O
+diet	O
+plus	O
+a	O
+single	O
+drug	O
+,	O
+gemfibrozil	O
+(	O
+1	O
+.	O
+2	O
+g	O
+/	O
+day	O
+)	O
+-	O
+lovastatin	O
+(	O
+primarily	O
+20	O
+or	O
+40	O
+mg	O
+)	O
+treatment	O
+was	O
+given	O
+.	O
+
+Follow	O
+-	O
+up	O
+visits	O
+were	O
+scheduled	O
+with	O
+2	O
+-	O
+drug	O
+therapy	O
+every	O
+6	O
+to	O
+8	O
+weeks	O
+,	O
+an	O
+average	O
+of	O
+10	O
+.	O
+3	O
+visits	O
+per	O
+patient	O
+,	O
+with	O
+741	O
+batteries	O
+of	O
+6	O
+liver	O
+function	O
+tests	O
+and	O
+714	O
+creatine	O
+phosphokinase	O
+levels	O
+measured	O
+.	O
+
+Only	O
+1	O
+of	O
+the	O
+4	O
+,	O
+446	O
+liver	O
+function	O
+tests	O
+(	O
+0	O
+.	O
+02	O
+%	O
+)	O
+,	O
+a	O
+gamma	O
+glutamyl	O
+transferase	O
+,	O
+was	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+3	O
+times	O
+the	O
+upper	O
+normal	O
+limit	O
+.	O
+
+Of	O
+the	O
+714	O
+creatine	O
+phosphokinase	O
+levels	O
+,	O
+9	O
+%	O
+were	O
+high	O
+;	O
+only	O
+1	O
+(	O
+0	O
+.	O
+1	O
+%	O
+)	O
+was	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+3	O
+times	O
+the	O
+upper	O
+normal	O
+limit	O
+.	O
+
+With	O
+2	O
+-	O
+drug	O
+therapy	O
+,	O
+mean	O
+total	O
+cholesterol	O
+decreased	O
+22	O
+%	O
+from	O
+255	O
+to	O
+200	O
+mg	O
+/	O
+dl	O
+,	O
+triglyceride	O
+levels	O
+decreased	O
+35	O
+%	O
+from	O
+236	O
+to	O
+154	O
+mg	O
+/	O
+dl	O
+,	O
+LDL	O
+cholesterol	O
+decreased	O
+26	O
+%	O
+from	O
+176	O
+to	O
+131	O
+mg	O
+/	O
+dl	O
+,	O
+and	O
+the	O
+total	O
+cholesterol	O
+/	O
+HDL	O
+cholesterol	O
+ratio	O
+decreased	O
+24	O
+%	O
+from	O
+7	O
+.	O
+1	O
+to	O
+5	O
+.	O
+4	O
+,	O
+all	O
+p	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+0	O
+.	O
+0001	O
+.	O
+
+Myositis	B
+,	O
+attributable	O
+to	O
+the	O
+drug	O
+combination	O
+and	O
+symptomatic	O
+enough	O
+to	O
+discontinue	O
+it	O
+,	O
+occurred	O
+in	O
+3	O
+%	O
+of	O
+patients	O
+,	O
+and	O
+in	O
+1	O
+%	O
+with	O
+concurrent	O
+high	O
+creatine	O
+phosphokinase	O
+(	O
+769	O
+U	O
+/	O
+liter	O
+)	O
+;	O
+no	O
+patients	O
+had	O
+rhabdomyolysis	B
+or	O
+myoglobinuria	B
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Does	O
+domperidone	O
+potentiate	O
+mirtazapine	O
+-	O
+associated	O
+restless	B
+legs	I
+syndrome	I
+?	O
+
+There	O
+is	O
+now	O
+evidence	O
+to	O
+suggest	O
+a	O
+central	O
+role	O
+for	O
+the	O
+dopaminergic	O
+system	O
+in	O
+restless	B
+legs	I
+syndrome	I
+(	O
+RLS	B
+)	O
+.	O
+
+For	O
+example	O
+,	O
+the	O
+symptoms	O
+of	O
+RLS	B
+can	O
+be	O
+dramatically	O
+improved	O
+by	O
+levodopa	O
+and	O
+dopamine	O
+agonists	O
+,	O
+whereas	O
+central	O
+dopamine	O
+D2	O
+receptor	O
+antagonists	O
+can	O
+induce	O
+or	O
+aggravate	O
+RLS	B
+symptoms	O
+.	O
+
+To	O
+our	O
+knowledge	O
+,	O
+there	O
+is	O
+no	O
+previous	O
+report	O
+regarding	O
+whether	O
+domperidone	O
+,	O
+a	O
+peripheral	O
+dopamine	O
+D2	O
+receptor	O
+antagonist	O
+,	O
+can	O
+also	O
+induce	O
+or	O
+aggravate	O
+symptoms	O
+of	O
+RLS	B
+.	O
+
+Mirtazapine	O
+,	O
+the	O
+first	O
+noradrenergic	O
+and	O
+specific	O
+serotonergic	O
+antidepressant	O
+(	O
+NaSSA	O
+)	O
+,	O
+has	O
+been	O
+associated	O
+with	O
+RLS	B
+in	O
+several	O
+recent	O
+publications	O
+.	O
+
+The	O
+authors	O
+report	O
+here	O
+a	O
+depressed	O
+patient	O
+comorbid	O
+with	O
+postprandial	B
+dyspepsia	I
+who	O
+developed	O
+RLS	B
+after	O
+mirtazapine	O
+had	O
+been	O
+added	O
+to	O
+his	O
+domperidone	O
+therapy	O
+.	O
+
+Our	O
+patient	O
+started	O
+to	O
+have	O
+symptoms	O
+of	O
+RLS	B
+only	O
+after	O
+he	O
+had	O
+been	O
+treated	O
+with	O
+mirtazapine	O
+,	O
+and	O
+his	O
+RLS	B
+symptoms	O
+resolved	O
+completely	O
+upon	O
+discontinuation	O
+of	O
+his	O
+mirtazapine	O
+.	O
+
+Such	O
+a	O
+temporal	O
+relationship	O
+between	O
+the	O
+use	O
+of	O
+mirtazapine	O
+and	O
+the	O
+symptoms	O
+of	O
+RLS	B
+in	O
+our	O
+patient	O
+did	O
+not	O
+support	O
+a	O
+potentiating	O
+effect	O
+of	O
+domperione	O
+on	O
+mirtazapine	O
+-	O
+associated	O
+RLS	B
+.	O
+
+However	O
+,	O
+physicians	O
+should	O
+be	O
+aware	O
+of	O
+the	O
+possibility	O
+that	O
+mirtazapine	O
+can	O
+be	O
+associated	O
+with	O
+RLS	B
+in	O
+some	O
+individuals	O
+,	O
+especially	O
+those	O
+receiving	O
+concomitant	O
+dopamine	O
+D2	O
+receptor	O
+antagonists	O
+.	O
+
+Antiandrogenic	O
+therapy	O
+can	O
+cause	O
+coronary	B
+arterial	I
+disease	I
+.	O
+
+AIM	O
+:	O
+To	O
+study	O
+the	O
+change	O
+of	O
+lipid	O
+metabolism	O
+by	O
+antiandrogen	O
+therapy	O
+in	O
+patients	O
+with	O
+prostate	B
+cancer	I
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+We	O
+studied	O
+with	O
+a	O
+2	O
+.	O
+5	O
+years	O
+follow	O
+-	O
+up	O
+the	O
+changes	O
+in	O
+plasma	O
+cholesterols	O
+(	O
+C	O
+)	O
+,	O
+triglycerides	O
+(	O
+TG	O
+)	O
+,	O
+lipoproteins	O
+(	O
+LP	O
+)	O
+,	O
+and	O
+apolipoproteins	O
+(	O
+Apo	O
+)	O
+B	O
+-	O
+100	O
+,	O
+A	O
+-	O
+I	O
+,	O
+and	O
+A	O
+-	O
+II	O
+pro	O
+fi	O
+les	O
+in	O
+24	O
+patients	O
+of	O
+mean	O
+age	O
+60	O
+years	O
+with	O
+low	O
+risk	O
+prostate	B
+cancer	I
+(	O
+stage	O
+:	O
+T1cN0M0	O
+,	O
+Gleason	O
+score	O
+:	O
+2	O
+-	O
+5	O
+)	O
+during	O
+treatment	O
+with	O
+cyproterone	O
+acetate	O
+(	O
+CPA	O
+)	O
+without	O
+surgical	O
+management	O
+or	O
+radiation	O
+therapy	O
+.	O
+
+RESULTS	O
+:	O
+Significant	O
+decreases	O
+of	O
+HDL	O
+-	O
+C	O
+,	O
+Apo	O
+A	O
+-	O
+I	O
+and	O
+Apo	O
+A	O
+-	O
+II	O
+and	O
+an	O
+increase	O
+of	O
+triglyceride	O
+levels	O
+in	O
+VLDL	O
+were	O
+induced	O
+by	O
+CPA	O
+.	O
+
+After	O
+a	O
+period	O
+of	O
+2	O
+.	O
+5	O
+years	O
+on	O
+CPA	O
+treatment	O
+,	O
+four	O
+patients	O
+out	O
+of	O
+twenty	O
+-	O
+four	O
+were	O
+found	O
+to	O
+be	O
+affected	O
+by	O
+coronary	B
+heart	I
+disease	I
+.	O
+
+CONCLUSIONS	O
+:	O
+Ischaemic	O
+coronary	B
+arteriosclerosis	I
+with	O
+an	O
+incidence	O
+rate	O
+of	O
+16	O
+.	O
+6	O
+%	O
+as	O
+caused	O
+by	O
+prolonged	O
+CPA	O
+therapy	O
+is	O
+mediated	O
+through	O
+changes	O
+in	O
+HDL	O
+cholesterol	O
+,	O
+Apo	O
+A	O
+-	O
+I	O
+and	O
+Apo	O
+A	O
+-	O
+II	O
+pro	O
+fi	O
+les	O
+,	O
+other	O
+than	O
+the	O
+well	O
+-	O
+known	O
+hyperglyceridemic	B
+effect	I
+caused	O
+by	O
+estrogen	O
+.	O
+
+5	O
+-	O
+Fluorouracil	O
+cardiotoxicity	B
+induced	O
+by	O
+alpha	O
+-	O
+fluoro	O
+-	O
+beta	O
+-	O
+alanine	O
+.	O
+
+Cardiotoxicity	B
+is	O
+a	O
+rare	O
+complication	O
+occurring	O
+during	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+treatment	O
+for	O
+malignancies	B
+.	O
+
+We	O
+herein	O
+report	O
+the	O
+case	O
+of	O
+a	O
+70	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+5	O
+-	O
+FU	O
+-	O
+induced	O
+cardiotoxicity	B
+,	O
+in	O
+whom	O
+a	O
+high	O
+serum	O
+level	O
+of	O
+alpha	O
+-	O
+fluoro	O
+-	O
+beta	O
+-	O
+alanine	O
+(	O
+FBAL	O
+)	O
+was	O
+observed	O
+.	O
+
+The	O
+patient	O
+,	O
+who	O
+had	O
+unresectable	O
+colon	B
+cancer	I
+metastases	O
+to	O
+the	O
+liver	O
+and	O
+lung	O
+,	O
+was	O
+referred	O
+to	O
+us	O
+for	O
+chemotherapy	O
+from	O
+an	O
+affiliated	O
+hospital	O
+;	O
+he	O
+had	O
+no	O
+cardiac	O
+history	O
+.	O
+
+After	O
+admission	O
+,	O
+the	O
+patient	O
+received	O
+a	O
+continuous	O
+intravenous	O
+infusion	O
+of	O
+5	O
+-	O
+FU	O
+(	O
+1000	O
+mg	O
+/	O
+day	O
+)	O
+,	O
+during	O
+which	O
+precordial	B
+pain	I
+with	O
+right	B
+bundle	I
+branch	I
+block	I
+occurred	O
+concomitantly	O
+with	O
+a	O
+high	O
+serum	O
+FBAL	O
+concentration	O
+of	O
+1955	O
+ng	O
+/	O
+ml	O
+.	O
+
+Both	O
+the	O
+precordial	B
+pain	I
+and	O
+the	O
+electrocardiographic	O
+changes	O
+disappeared	O
+spontaneously	O
+after	O
+the	O
+discontinuation	O
+of	O
+5	O
+-	O
+FU	O
+.	O
+
+As	O
+the	O
+precordial	B
+pain	I
+in	O
+this	O
+patient	O
+was	O
+considered	O
+to	O
+have	O
+been	O
+due	O
+to	O
+5	O
+-	O
+FU	O
+-	O
+induced	O
+cardiotoxicity	B
+,	O
+the	O
+administration	O
+of	O
+5	O
+-	O
+FU	O
+was	O
+abandoned	O
+.	O
+
+Instead	O
+,	O
+oral	O
+administration	O
+of	O
+S	O
+-	O
+1	O
+(	O
+a	O
+derivative	O
+of	O
+5	O
+-	O
+FU	O
+)	O
+,	O
+at	O
+200	O
+mg	O
+/	O
+day	O
+twice	O
+a	O
+week	O
+,	O
+was	O
+instituted	O
+,	O
+because	O
+S	O
+-	O
+1	O
+has	O
+a	O
+strong	O
+inhibitory	O
+effect	O
+on	O
+dihydropyrimidine	O
+dehydrogenase	O
+,	O
+which	O
+catalyzes	O
+the	O
+degradative	O
+of	O
+5	O
+-	O
+FU	O
+into	O
+FBAL	O
+.	O
+
+The	O
+serum	O
+FBAL	O
+concentration	O
+subsequently	O
+decreased	O
+to	O
+352	O
+ng	O
+/	O
+ml	O
+,	O
+the	O
+same	O
+as	O
+the	O
+value	O
+measured	O
+on	O
+the	O
+first	O
+day	O
+of	O
+S	O
+-	O
+1	O
+administration	O
+.	O
+
+Thereafter	O
+,	O
+no	O
+cardiac	B
+symptoms	I
+were	O
+observed	O
+.	O
+
+The	O
+patient	O
+achieved	O
+a	O
+partial	O
+response	O
+6	O
+months	O
+after	O
+the	O
+initiation	O
+of	O
+the	O
+S	O
+-	O
+1	O
+treatment	O
+.	O
+
+The	O
+experience	O
+of	O
+this	O
+case	O
+,	O
+together	O
+with	O
+a	O
+review	O
+of	O
+the	O
+literature	O
+,	O
+suggests	O
+that	O
+FBAL	O
+is	O
+related	O
+to	O
+5	O
+-	O
+FU	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+S	O
+-	O
+1	O
+may	O
+be	O
+administered	O
+safely	O
+to	O
+patients	O
+with	O
+5	O
+-	O
+FU	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+Hepatocellular	B
+carcinoma	I
+in	O
+Fanconi	B
+'	I
+s	I
+anemia	I
+treated	O
+with	O
+androgen	O
+and	O
+corticosteroid	O
+.	O
+
+The	O
+case	O
+of	O
+an	O
+11	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+is	O
+reported	O
+who	O
+was	O
+known	O
+to	O
+have	O
+Fanconi	B
+'	I
+s	I
+anemia	I
+for	O
+3	O
+years	O
+and	O
+was	O
+treated	O
+with	O
+androgens	O
+,	O
+corticosteroids	O
+and	O
+transfusions	O
+.	O
+
+Two	O
+weeks	O
+before	O
+his	O
+death	O
+he	O
+was	O
+readmitted	O
+because	O
+of	O
+aplastic	O
+crisis	O
+with	O
+septicemia	B
+and	O
+marked	O
+abnormalities	O
+in	O
+liver	O
+function	O
+and	O
+died	O
+of	O
+hemorrhagic	B
+bronchopneumonia	I
+.	O
+
+At	O
+autopsy	O
+peliosis	B
+and	O
+multiple	O
+hepatic	B
+tumors	I
+were	O
+found	O
+which	O
+histologically	O
+proved	O
+to	O
+be	O
+well	O
+-	O
+differentiated	O
+hepatocellular	B
+carcinoma	I
+.	O
+
+This	O
+case	O
+contributes	O
+to	O
+the	O
+previous	O
+observations	O
+that	O
+non	O
+-	O
+metastasizing	O
+hepatic	B
+neoplasms	I
+and	O
+peliosis	B
+can	O
+develop	O
+in	O
+patients	O
+with	O
+androgen	O
+-	O
+and	O
+corticosteroid	O
+-	O
+treated	O
+Fanconi	B
+'	I
+s	I
+anemia	I
+.	O
+
+The	O
+influence	O
+of	O
+the	O
+time	O
+interval	O
+between	O
+monoHER	O
+and	O
+doxorubicin	O
+administration	O
+on	O
+the	O
+protection	O
+against	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B
+in	O
+mice	O
+.	O
+
+PURPOSE	O
+:	O
+Despite	O
+its	O
+well	O
+-	O
+known	O
+cardiotoxicity	B
+,	O
+the	O
+anthracyclin	O
+doxorubicin	O
+(	O
+DOX	O
+)	O
+continues	O
+to	O
+be	O
+an	O
+effective	O
+and	O
+widely	O
+used	O
+chemotherapeutic	O
+agent	O
+.	O
+
+DOX	O
+-	O
+induced	O
+cardiac	B
+damage	I
+presumably	O
+results	O
+from	O
+the	O
+formation	O
+of	O
+free	O
+radicals	O
+by	O
+DOX	O
+.	O
+
+Reactive	O
+oxygen	O
+species	O
+particularly	O
+affect	O
+the	O
+cardiac	O
+myocytes	O
+because	O
+these	O
+cells	O
+seem	O
+to	O
+have	O
+a	O
+relatively	O
+poor	O
+antioxidant	O
+defense	O
+system	O
+.	O
+
+The	O
+semisynthetic	O
+flavonoid	O
+monohydroxyethylrutoside	O
+(	O
+monoHER	O
+)	O
+showed	O
+cardioprotection	O
+against	O
+DOX	O
+-	O
+induced	O
+cardiotoxicity	B
+through	O
+its	O
+radical	O
+scavenging	O
+and	O
+iron	O
+chelating	O
+properties	O
+.	O
+
+Because	O
+of	O
+the	O
+relatively	O
+short	O
+final	O
+half	O
+-	O
+life	O
+of	O
+monoHER	O
+(	O
+about	O
+30	O
+min	O
+)	O
+,	O
+it	O
+is	O
+expected	O
+that	O
+the	O
+time	O
+interval	O
+between	O
+monoHER	O
+and	O
+DOX	O
+might	O
+be	O
+of	O
+influence	O
+on	O
+the	O
+cardioprotective	O
+effect	O
+of	O
+monoHER	O
+.	O
+
+Therefore	O
+,	O
+the	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+investigate	O
+this	O
+possible	O
+effect	O
+.	O
+
+METHODS	O
+:	O
+Six	O
+groups	O
+of	O
+6	O
+BALB	O
+/	O
+c	O
+mice	O
+were	O
+treated	O
+with	O
+saline	O
+,	O
+DOX	O
+alone	O
+or	O
+DOX	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+preceded	O
+by	O
+monoHER	O
+(	O
+500	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+with	O
+an	O
+interval	O
+of	O
+10	O
+,	O
+30	O
+,	O
+60	O
+or	O
+120	O
+min	O
+.	O
+
+After	O
+a	O
+6	O
+-	O
+week	O
+treatment	O
+period	O
+and	O
+additional	O
+observation	O
+for	O
+2	O
+weeks	O
+,	O
+the	O
+mice	O
+were	O
+sacrificed	O
+.	O
+
+Their	O
+cardiac	O
+tissues	O
+were	O
+processed	O
+for	O
+light	O
+microscopy	O
+,	O
+after	O
+which	O
+cardiomyocyte	B
+damage	I
+was	O
+evaluated	O
+according	O
+to	O
+Billingham	O
+(	O
+in	O
+Cancer	B
+Treat	O
+Rep	O
+62	O
+(	O
+6	O
+)	O
+:	O
+865	O
+-	O
+872	O
+,	O
+1978	O
+)	O
+.	O
+
+Microscopic	O
+evaluation	O
+revealed	O
+that	O
+treatment	O
+with	O
+DOX	O
+alone	O
+induced	O
+significant	O
+cardiac	B
+damage	I
+in	O
+comparison	O
+to	O
+the	O
+saline	O
+control	O
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+number	O
+of	O
+damaged	O
+cardiomyocytes	O
+was	O
+9	O
+.	O
+6	O
+-	O
+fold	O
+(	O
+95	O
+%	O
+CI	O
+4	O
+.	O
+4	O
+-	O
+21	O
+.	O
+0	O
+)	O
+higher	O
+in	O
+mice	O
+treated	O
+with	O
+DOX	O
+alone	O
+than	O
+that	O
+in	O
+animals	O
+of	O
+the	O
+control	O
+group	O
+.	O
+
+The	O
+ratio	O
+of	O
+aberrant	O
+cardiomyocytes	O
+in	O
+mice	O
+treated	O
+with	O
+DOX	O
+preceded	O
+by	O
+monoHER	O
+and	O
+those	O
+in	O
+mice	O
+treated	O
+with	O
+saline	O
+ranged	O
+from	O
+1	O
+.	O
+6	O
+to	O
+2	O
+.	O
+8	O
+(	O
+mean	O
+2	O
+.	O
+2	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+2	O
+-	O
+4	O
+.	O
+1	O
+,	O
+P	O
+=	O
+0	O
+.	O
+019	O
+)	O
+.	O
+
+The	O
+mean	O
+protective	O
+effect	O
+by	O
+adding	O
+monoHER	O
+before	O
+DOX	O
+led	O
+to	O
+a	O
+significant	O
+4	O
+.	O
+4	O
+-	O
+fold	O
+reduction	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+,	O
+95	O
+%	O
+CI	O
+2	O
+.	O
+3	O
+-	O
+8	O
+.	O
+2	O
+)	O
+of	O
+abnormal	O
+cardiomyocytes	O
+.	O
+
+This	O
+protective	O
+effect	O
+did	O
+not	O
+depend	O
+on	O
+the	O
+time	O
+interval	O
+between	O
+monoHER	O
+and	O
+DOX	O
+administration	O
+(	O
+P	O
+=	O
+0	O
+.	O
+345	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+results	O
+indicate	O
+that	O
+in	O
+an	O
+outpatient	O
+clinical	O
+setting	O
+monoHER	O
+may	O
+be	O
+administered	O
+shortly	O
+before	O
+DOX	O
+.	O
+
+Clinical	O
+evaluation	O
+of	O
+adverse	O
+effects	O
+during	O
+bepridil	O
+administration	O
+for	O
+atrial	B
+fibrillation	I
+and	I
+flutter	I
+.	O
+
+BACKGROUND	O
+:	O
+Bepridil	O
+hydrochloride	O
+(	O
+Bpd	O
+)	O
+has	O
+attracted	O
+attention	O
+as	O
+an	O
+effective	O
+drug	O
+for	O
+atrial	B
+fibrillation	I
+(	O
+AF	B
+)	O
+and	O
+atrial	B
+flutter	I
+(	O
+AFL	B
+)	O
+.	O
+
+However	O
+,	O
+serious	O
+adverse	O
+effects	O
+,	O
+including	O
+torsade	B
+de	I
+pointes	I
+(	O
+Tdp	B
+)	O
+,	O
+have	O
+been	O
+reported	O
+.	O
+
+METHODS	O
+AND	O
+RESULTS	O
+:	O
+Adverse	O
+effects	O
+of	O
+Bpd	O
+requiring	O
+discontinuation	O
+of	O
+treatment	O
+were	O
+evaluated	O
+.	O
+
+Bpd	O
+was	O
+administered	O
+to	O
+459	O
+patients	O
+(	O
+361	O
+males	O
+,	O
+63	O
++	O
+/	O
+-	O
+12	O
+years	O
+old	O
+)	O
+comprising	O
+378	O
+AF	B
+and	O
+81	O
+AFL	B
+cases	O
+.	O
+
+Mean	O
+left	O
+ventricular	O
+ejection	O
+fraction	O
+and	O
+atrial	O
+dimension	O
+(	O
+LAD	O
+)	O
+were	O
+66	O
++	O
+/	O
+-	O
+11	O
+%	O
+and	O
+40	O
++	O
+/	O
+-	O
+6	O
+mm	O
+,	O
+respectively	O
+.	O
+
+Adverse	O
+effects	O
+were	O
+observed	O
+in	O
+19	O
+patients	O
+(	O
+4	O
+%	O
+)	O
+during	O
+an	O
+average	O
+follow	O
+-	O
+up	O
+of	O
+20	O
+months	O
+.	O
+
+There	O
+was	O
+marked	O
+QT	B
+prolongation	I
+greater	O
+than	O
+0	O
+.	O
+55	O
+s	O
+in	O
+13	O
+patients	O
+,	O
+bradycardia	B
+less	O
+than	O
+40	O
+beats	O
+/	O
+min	O
+in	O
+6	O
+patients	O
+,	O
+dizziness	B
+and	O
+general	O
+fatigue	B
+in	O
+1	O
+patient	O
+each	O
+.	O
+
+In	O
+4	O
+of	O
+13	O
+patients	O
+with	O
+QT	B
+prolongation	I
+,	O
+Tdp	B
+occurred	O
+.	O
+
+The	O
+major	O
+triggering	O
+factors	O
+of	O
+Tdp	B
+were	O
+hypokalemia	B
+and	O
+sudden	O
+decrease	O
+in	O
+heart	O
+rate	O
+.	O
+
+There	O
+were	O
+no	O
+differences	O
+in	O
+the	O
+clinical	O
+backgrounds	O
+of	O
+the	O
+patients	O
+with	O
+and	O
+without	O
+Tdp	B
+other	O
+than	O
+LAD	O
+and	O
+age	O
+,	O
+which	O
+were	O
+larger	O
+and	O
+older	O
+in	O
+the	O
+patients	O
+with	O
+Tdp	B
+.	O
+
+CONCLUSION	O
+:	O
+Careful	O
+observation	O
+of	O
+serum	O
+potassium	O
+concentration	O
+and	O
+the	O
+ECG	O
+should	O
+always	O
+be	O
+done	O
+during	O
+Bpd	O
+administration	O
+,	O
+particularly	O
+in	O
+elderly	O
+patients	O
+.	O
+
+Enhanced	O
+isoproterenol	O
+-	O
+induced	O
+cardiac	B
+hypertrophy	I
+in	O
+transgenic	O
+rats	O
+with	O
+low	O
+brain	O
+angiotensinogen	O
+.	O
+
+We	O
+have	O
+previously	O
+shown	O
+that	O
+a	O
+permanent	O
+deficiency	O
+in	O
+the	O
+brain	O
+renin	O
+-	O
+angiotensin	O
+system	O
+(	O
+RAS	O
+)	O
+may	O
+increase	O
+the	O
+sensitivity	O
+of	O
+the	O
+baroreflex	O
+control	O
+of	O
+heart	O
+rate	O
+.	O
+
+In	O
+this	O
+study	O
+we	O
+aimed	O
+at	O
+studying	O
+the	O
+involvement	O
+of	O
+the	O
+brain	O
+RAS	O
+in	O
+the	O
+cardiac	O
+reactivity	O
+to	O
+the	O
+beta	O
+-	O
+adrenoceptor	O
+(	O
+beta	O
+-	O
+AR	O
+)	O
+agonist	O
+isoproterenol	O
+(	O
+Iso	O
+)	O
+.	O
+
+Transgenic	O
+rats	O
+with	O
+low	O
+brain	O
+angiotensinogen	O
+(	O
+TGR	O
+)	O
+were	O
+used	O
+.	O
+
+In	O
+isolated	O
+hearts	O
+,	O
+Iso	O
+induced	O
+a	O
+significantly	O
+greater	O
+increase	O
+in	O
+left	O
+ventricular	O
+(	O
+LV	O
+)	O
+pressure	O
+and	O
+maximal	O
+contraction	O
+(	O
++	O
+dP	O
+/	O
+dt	O
+(	O
+max	O
+)	O
+)	O
+in	O
+the	O
+TGR	O
+than	O
+in	O
+the	O
+Sprague	O
+-	O
+Dawley	O
+(	O
+SD	O
+)	O
+rats	O
+.	O
+
+LV	B
+hypertrophy	I
+induced	O
+by	O
+Iso	O
+treatment	O
+was	O
+significantly	O
+higher	O
+in	O
+TGR	O
+than	O
+in	O
+SD	O
+rats	O
+(	O
+in	O
+g	O
+LV	O
+wt	O
+/	O
+100	O
+g	O
+body	O
+wt	O
+,	O
+0	O
+.	O
+28	O
++	O
+/	O
+-	O
+0	O
+.	O
+004	O
+vs	O
+.	O
+0	O
+.	O
+24	O
++	O
+/	O
+-	O
+0	O
+.	O
+004	O
+,	O
+respectively	O
+)	O
+.	O
+
+The	O
+greater	O
+LV	B
+hypertrophy	I
+in	O
+TGR	O
+rats	O
+was	O
+associated	O
+with	O
+more	O
+pronounced	O
+downregulation	O
+of	O
+beta	O
+-	O
+AR	O
+and	O
+upregulation	O
+of	O
+LV	O
+beta	O
+-	O
+AR	O
+kinase	O
+-	O
+1	O
+mRNA	O
+levels	O
+compared	O
+with	O
+those	O
+in	O
+SD	O
+rats	O
+.	O
+
+The	O
+decrease	O
+in	O
+the	O
+heart	O
+rate	O
+(	O
+HR	O
+)	O
+induced	O
+by	O
+the	O
+beta	O
+-	O
+AR	O
+antagonist	O
+metoprolol	O
+in	O
+conscious	O
+rats	O
+was	O
+significantly	O
+attenuated	O
+in	O
+TGR	O
+compared	O
+with	O
+SD	O
+rats	O
+(	O
+-	O
+9	O
+.	O
+9	O
++	O
+/	O
+-	O
+1	O
+.	O
+7	O
+%	O
+vs	O
+.	O
+-	O
+18	O
+.	O
+1	O
++	O
+/	O
+-	O
+1	O
+.	O
+5	O
+%	O
+)	O
+,	O
+whereas	O
+the	O
+effect	O
+of	O
+parasympathetic	O
+blockade	O
+by	O
+atropine	O
+on	O
+HR	O
+was	O
+similar	O
+in	O
+both	O
+strains	O
+.	O
+
+These	O
+results	O
+indicate	O
+that	O
+TGR	O
+are	O
+more	O
+sensitive	O
+to	O
+beta	O
+-	O
+AR	O
+agonist	O
+-	O
+induced	O
+cardiac	B
+inotropic	I
+response	O
+and	O
+hypertrophy	B
+,	O
+possibly	O
+due	O
+to	O
+chronically	O
+low	O
+sympathetic	O
+outflow	O
+directed	O
+to	O
+the	O
+heart	O
+.	O
+
+Drug	O
+-	O
+induced	O
+long	B
+QT	I
+syndrome	I
+in	O
+injection	O
+drug	O
+users	O
+receiving	O
+methadone	O
+:	O
+high	O
+frequency	O
+in	O
+hospitalized	O
+patients	O
+and	O
+risk	O
+factors	O
+.	O
+
+BACKGROUND	O
+:	O
+Drug	O
+-	O
+induced	O
+long	B
+QT	I
+syndrome	I
+is	O
+a	O
+serious	O
+adverse	O
+drug	O
+reaction	O
+.	O
+
+Methadone	O
+prolongs	O
+the	O
+QT	O
+interval	O
+in	O
+vitro	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+.	O
+
+In	O
+the	O
+inpatient	O
+setting	O
+,	O
+the	O
+frequency	O
+of	O
+QT	B
+interval	I
+prolongation	I
+with	O
+methadone	O
+treatment	O
+,	O
+its	O
+dose	O
+dependence	O
+,	O
+and	O
+the	O
+importance	O
+of	O
+cofactors	O
+such	O
+as	O
+drug	O
+-	O
+drug	O
+interactions	O
+remain	O
+unknown	O
+.	O
+
+METHODS	O
+:	O
+We	O
+performed	O
+a	O
+systematic	O
+,	O
+retrospective	O
+study	O
+comparing	O
+active	O
+or	O
+former	O
+intravenous	O
+drug	O
+users	O
+receiving	O
+methadone	O
+and	O
+those	O
+not	O
+receiving	O
+methadone	O
+among	O
+all	O
+patients	O
+hospitalized	O
+over	O
+a	O
+5	O
+-	O
+year	O
+period	O
+in	O
+a	O
+tertiary	O
+care	O
+hospital	O
+.	O
+
+A	O
+total	O
+of	O
+167	O
+patients	O
+receiving	O
+methadone	O
+fulfilled	O
+the	O
+inclusion	O
+criteria	O
+and	O
+were	O
+compared	O
+with	O
+a	O
+control	O
+group	O
+of	O
+80	O
+injection	O
+drug	O
+users	O
+not	O
+receiving	O
+methadone	O
+.	O
+
+In	O
+addition	O
+to	O
+methadone	O
+dose	O
+,	O
+15	O
+demographic	O
+,	O
+biological	O
+,	O
+and	O
+pharmacological	O
+variables	O
+were	O
+considered	O
+as	O
+potential	O
+risk	O
+factors	O
+for	O
+QT	B
+prolongation	I
+.	O
+
+RESULTS	O
+:	O
+Among	O
+167	O
+methadone	O
+maintenance	O
+patients	O
+,	O
+the	O
+prevalence	O
+of	O
+QTc	O
+prolongation	O
+to	O
+0	O
+.	O
+50	O
+second	O
+(	O
+(	O
+1	O
+/	O
+2	O
+)	O
+)	O
+or	O
+longer	O
+was	O
+16	O
+.	O
+2	O
+%	O
+compared	O
+with	O
+0	O
+%	O
+in	O
+80	O
+control	O
+subjects	O
+.	O
+
+Six	O
+patients	O
+(	O
+3	O
+.	O
+6	O
+%	O
+)	O
+in	O
+the	O
+methadone	O
+group	O
+presented	O
+torsades	B
+de	I
+pointes	I
+.	O
+
+QTc	O
+length	O
+was	O
+weakly	O
+but	O
+significantly	O
+associated	O
+with	O
+methadone	O
+daily	O
+dose	O
+(	O
+Spearman	O
+rank	O
+correlation	O
+coefficient	O
+,	O
+0	O
+.	O
+20	O
+;	O
+P	O
+<	O
+.	O
+01	O
+)	O
+.	O
+
+Multivariate	O
+regression	O
+analysis	O
+allowed	O
+attribution	O
+of	O
+31	O
+.	O
+8	O
+%	O
+of	O
+QTc	O
+variability	O
+to	O
+methadone	O
+dose	O
+,	O
+cytochrome	O
+P	O
+-	O
+450	O
+3A4	O
+drug	O
+-	O
+drug	O
+interactions	O
+,	O
+hypokalemia	B
+,	O
+and	O
+altered	O
+liver	O
+function	O
+.	O
+
+CONCLUSIONS	O
+:	O
+QT	B
+interval	I
+prolongation	I
+in	O
+methadone	O
+maintenance	O
+patients	O
+hospitalized	O
+in	O
+a	O
+tertiary	O
+care	O
+center	O
+is	O
+a	O
+frequent	O
+finding	O
+.	O
+
+Methadone	O
+dose	O
+,	O
+presence	O
+of	O
+cytochrome	O
+P	O
+-	O
+450	O
+3A4	O
+inhibitors	O
+,	O
+potassium	O
+level	O
+,	O
+and	O
+liver	O
+function	O
+contribute	O
+to	O
+QT	B
+prolongation	I
+.	O
+
+Long	B
+QT	I
+syndrome	I
+can	O
+occur	O
+with	O
+low	O
+doses	O
+of	O
+methadone	O
+.	O
+
+Mechanisms	O
+of	O
+hypertension	B
+induced	O
+by	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+deficiency	O
+:	O
+focus	O
+on	O
+venous	O
+function	O
+.	O
+
+Loss	O
+of	O
+endothelial	O
+cell	O
+-	O
+derived	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+in	O
+hypertension	B
+is	O
+a	O
+hallmark	O
+of	O
+arterial	B
+dysfunction	I
+.	O
+
+Experimental	O
+hypertension	B
+created	O
+by	O
+the	O
+removal	O
+of	O
+NO	O
+,	O
+however	O
+,	O
+involves	O
+mechanisms	O
+in	O
+addition	O
+to	O
+decreased	O
+arterial	O
+vasodilator	O
+activity	O
+.	O
+
+These	O
+include	O
+augmented	O
+endothelin	O
+-	O
+1	O
+(	O
+ET	O
+-	O
+1	O
+)	O
+release	O
+,	O
+increased	O
+sympathetic	O
+nervous	O
+system	O
+activity	O
+,	O
+and	O
+elevated	O
+tissue	O
+oxidative	O
+stress	O
+.	O
+
+We	O
+hypothesized	O
+that	O
+increased	O
+venous	O
+smooth	O
+muscle	O
+(	O
+venomotor	O
+)	O
+tone	O
+plays	O
+a	O
+role	O
+in	O
+Nomega	O
+-	O
+nitro	O
+-	O
+L	O
+-	O
+arginine	O
+(	O
+LNNA	O
+)	O
+hypertension	B
+through	O
+these	O
+mechanisms	O
+.	O
+
+Rats	O
+were	O
+treated	O
+with	O
+the	O
+NO	O
+synthase	O
+inhibitor	O
+LNNA	O
+(	O
+0	O
+.	O
+5	O
+g	O
+/	O
+L	O
+in	O
+drinking	O
+water	O
+)	O
+for	O
+2	O
+weeks	O
+.	O
+
+Mean	O
+arterial	O
+pressure	O
+of	O
+conscious	O
+rats	O
+was	O
+119	O
++	O
+/	O
+-	O
+2	O
+mm	O
+Hg	O
+in	O
+control	O
+and	O
+194	O
++	O
+/	O
+-	O
+5	O
+mm	O
+Hg	O
+in	O
+LNNA	O
+rats	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Carotid	O
+arteries	O
+and	O
+vena	O
+cava	O
+were	O
+removed	O
+for	O
+measurement	O
+of	O
+isometric	O
+contraction	O
+.	O
+
+Maximal	O
+contraction	O
+to	O
+norepinephrine	O
+was	O
+modestly	O
+reduced	O
+in	O
+arteries	O
+from	O
+LNNA	O
+compared	O
+with	O
+control	O
+rats	O
+whereas	O
+the	O
+maximum	O
+contraction	O
+to	O
+ET	O
+-	O
+1	O
+was	O
+significantly	O
+reduced	O
+(	O
+54	O
+%	O
+control	O
+)	O
+.	O
+
+Maximum	O
+contraction	O
+of	O
+vena	O
+cava	O
+to	O
+norepinephrine	O
+(	O
+37	O
+%	O
+control	O
+)	O
+also	O
+was	O
+reduced	O
+but	O
+no	O
+change	O
+in	O
+response	O
+to	O
+ET	O
+-	O
+1	O
+was	O
+observed	O
+.	O
+
+Mean	O
+circulatory	O
+filling	O
+pressure	O
+,	O
+an	O
+in	O
+vivo	O
+measure	O
+of	O
+venomotor	O
+tone	O
+,	O
+was	O
+not	O
+elevated	O
+in	O
+LNNA	O
+hypertension	B
+at	O
+1	O
+or	O
+2	O
+weeks	O
+after	O
+LNNA	O
+.	O
+
+The	O
+superoxide	O
+scavenger	O
+tempol	O
+(	O
+30	O
+,	O
+100	O
+,	O
+and	O
+300	O
+micromol	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+,	O
+IV	O
+)	O
+did	O
+not	O
+change	O
+arterial	O
+pressure	O
+in	O
+control	O
+rats	O
+but	O
+caused	O
+a	O
+dose	O
+-	O
+dependent	O
+decrease	O
+in	O
+LNNA	O
+rats	O
+(	O
+-	O
+18	O
++	O
+/	O
+-	O
+8	O
+,	O
+-	O
+26	O
++	O
+/	O
+-	O
+15	O
+,	O
+and	O
+-	O
+54	O
++	O
+/	O
+-	O
+11	O
+mm	O
+Hg	O
+)	O
+.	O
+
+Similarly	O
+,	O
+ganglionic	O
+blockade	O
+with	O
+hexamethonium	O
+caused	O
+a	O
+significantly	O
+greater	O
+fall	O
+in	O
+LNNA	O
+hypertensive	B
+rats	O
+(	O
+76	O
++	O
+/	O
+-	O
+9	O
+mm	O
+Hg	O
+)	O
+compared	O
+with	O
+control	O
+rats	O
+(	O
+35	O
++	O
+/	O
+-	O
+10	O
+mm	O
+Hg	O
+)	O
+.	O
+
+Carotid	O
+arteries	O
+,	O
+vena	O
+cava	O
+,	O
+and	O
+sympathetic	O
+ganglia	O
+from	O
+LNNA	O
+rats	O
+had	O
+higher	O
+basal	O
+levels	O
+of	O
+superoxide	O
+compared	O
+with	O
+those	O
+from	O
+control	O
+rats	O
+.	O
+
+These	O
+data	O
+suggest	O
+that	O
+while	O
+NO	O
+deficiency	O
+increases	O
+oxidative	O
+stress	O
+and	O
+sympathetic	O
+activity	O
+in	O
+both	O
+arterial	O
+and	O
+venous	O
+vessels	O
+,	O
+the	O
+impact	O
+on	O
+veins	O
+does	O
+not	O
+make	O
+a	O
+major	O
+contribution	O
+to	O
+this	O
+form	O
+of	O
+hypertension	B
+.	O
+
+Association	O
+of	O
+DRD2	O
+polymorphisms	O
+and	O
+chlorpromazine	O
+-	O
+induced	O
+extrapyramidal	B
+syndrome	I
+in	O
+Chinese	O
+schizophrenic	B
+patients	O
+.	O
+
+AIM	O
+:	O
+Extrapyramidal	B
+syndrome	I
+(	O
+EPS	B
+)	O
+is	O
+most	O
+commonly	O
+affected	O
+by	O
+typical	O
+antipsychotic	O
+drugs	O
+that	O
+have	O
+a	O
+high	O
+affinity	O
+with	O
+the	O
+D2	O
+receptor	O
+.	O
+
+Recently	O
+,	O
+many	O
+research	O
+groups	O
+have	O
+reported	O
+on	O
+the	O
+positive	O
+relationship	O
+between	O
+the	O
+genetic	O
+variations	O
+in	O
+the	O
+DRD2	O
+gene	O
+and	O
+the	O
+therapeutic	O
+response	O
+in	O
+schizophrenia	B
+patients	O
+as	O
+a	O
+result	O
+of	O
+the	O
+role	O
+of	O
+variations	O
+in	O
+the	O
+receptor	O
+in	O
+modulating	O
+receptor	O
+expression	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+evaluate	O
+the	O
+role	O
+DRD2	O
+plays	O
+in	O
+chlorpromazine	O
+-	O
+induced	O
+EPS	B
+in	O
+schizophrenic	B
+patients	O
+.	O
+
+METHODS	O
+:	O
+We	O
+identified	O
+seven	O
+SNP	O
+(	O
+single	O
+nucleotide	O
+polymorphism	O
+)	O
+(	O
+-	O
+141Cins	O
+>	O
+del	O
+,	O
+TaqIB	O
+,	O
+TaqID	O
+,	O
+Ser311Cys	O
+,	O
+rs6275	O
+,	O
+rs6277	O
+and	O
+TaqIA	O
+)	O
+in	O
+the	O
+DRD2	O
+gene	O
+in	O
+146	O
+schizophrenic	B
+inpatients	O
+(	O
+59	O
+with	O
+EPS	B
+and	O
+87	O
+without	O
+EPS	B
+according	O
+to	O
+the	O
+Simpson	O
+-	O
+Angus	O
+Scale	O
+)	O
+treated	O
+with	O
+chlorpromazine	O
+after	O
+8	O
+weeks	O
+.	O
+
+The	O
+alleles	O
+of	O
+all	O
+loci	O
+were	O
+determined	O
+by	O
+PCR	O
+(	O
+polymerase	O
+chain	O
+reaction	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+Polymorphisms	O
+TaqID	O
+,	O
+Ser311Cys	O
+and	O
+rs6277	O
+were	O
+not	O
+polymorphic	O
+in	O
+the	O
+population	O
+recruited	O
+in	O
+the	O
+present	O
+study	O
+.	O
+
+No	O
+statistical	O
+significance	O
+was	O
+found	O
+in	O
+the	O
+allele	O
+distribution	O
+of	O
+-	O
+141Cins	O
+>	O
+del	O
+,	O
+TaqIB	O
+,	O
+rs6275	O
+and	O
+TaqIA	O
+or	O
+in	O
+the	O
+estimated	O
+haplotypes	O
+(	O
+constituted	O
+by	O
+TaqIB	O
+,	O
+rs6275	O
+and	O
+TaqIA	O
+)	O
+in	O
+linkage	O
+disequilibrium	O
+between	O
+the	O
+two	O
+groups	O
+.	O
+
+CONCLUSION	O
+:	O
+Our	O
+results	O
+did	O
+not	O
+lend	O
+strong	O
+support	O
+to	O
+the	O
+view	O
+that	O
+the	O
+genetic	O
+variation	O
+of	O
+the	O
+DRD2	O
+gene	O
+plays	O
+a	O
+major	O
+role	O
+in	O
+the	O
+individually	O
+variable	O
+adverse	O
+effect	O
+induced	O
+by	O
+chlorpromazine	O
+,	O
+at	O
+least	O
+in	O
+Chinese	O
+patients	O
+with	O
+schizophrenia	B
+.	O
+
+Our	O
+results	O
+confirmed	O
+a	O
+previous	O
+study	O
+on	O
+the	O
+relationship	O
+between	O
+DRD2	O
+and	O
+EPS	B
+in	O
+Caucasians	O
+.	O
+
+Physical	O
+training	O
+decreases	O
+susceptibility	O
+to	O
+subsequent	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+in	O
+the	O
+rat	O
+.	O
+
+Regular	O
+motor	O
+activity	O
+has	O
+many	O
+benefits	O
+for	O
+mental	O
+and	O
+physical	O
+condition	O
+but	O
+its	O
+implications	O
+for	O
+epilepsy	B
+are	O
+still	O
+controversial	O
+.	O
+
+In	O
+order	O
+to	O
+elucidate	O
+this	O
+problem	O
+,	O
+we	O
+have	O
+studied	O
+the	O
+effect	O
+of	O
+long	O
+-	O
+term	O
+physical	O
+activity	O
+on	O
+susceptibility	O
+to	O
+subsequent	O
+seizures	B
+.	O
+
+Male	O
+Wistar	O
+rats	O
+were	O
+subjected	O
+to	O
+repeated	O
+training	O
+sessions	O
+in	O
+a	O
+treadmill	O
+and	O
+swimming	O
+pool	O
+.	O
+
+Thereafter	O
+,	O
+seizures	B
+were	O
+induced	O
+by	O
+pilocarpine	O
+injections	O
+in	O
+trained	O
+and	O
+non	O
+-	O
+trained	O
+control	O
+groups	O
+.	O
+
+During	O
+the	O
+acute	O
+period	O
+of	O
+status	B
+epilepticus	I
+,	O
+we	O
+measured	O
+:	O
+(	O
+1	O
+)	O
+the	O
+latency	O
+of	O
+the	O
+first	O
+motor	O
+sign	O
+,	O
+(	O
+2	O
+)	O
+the	O
+intensity	O
+of	O
+seizures	B
+,	O
+(	O
+3	O
+)	O
+the	O
+time	O
+when	O
+it	O
+occurred	O
+within	O
+the	O
+6	O
+-	O
+h	O
+observation	O
+period	O
+,	O
+and	O
+(	O
+4	O
+)	O
+the	O
+time	O
+when	O
+the	O
+acute	O
+period	O
+ended	O
+.	O
+
+All	O
+these	O
+behavioral	O
+parameters	O
+showed	O
+statistically	O
+significant	O
+changes	O
+suggesting	O
+that	O
+regular	O
+physical	O
+exercises	O
+decrease	O
+susceptibility	O
+to	O
+subsequently	O
+induced	O
+seizures	B
+and	O
+ameliorate	O
+the	O
+course	O
+of	O
+experimentally	O
+induced	O
+status	B
+epilepticus	I
+.	O
+
+Tonic	O
+dopaminergic	O
+stimulation	O
+impairs	B
+associative	I
+learning	I
+in	O
+healthy	O
+subjects	O
+.	O
+
+Endogenous	O
+dopamine	O
+plays	O
+a	O
+central	O
+role	O
+in	O
+salience	O
+coding	O
+during	O
+associative	O
+learning	O
+.	O
+
+Administration	O
+of	O
+the	O
+dopamine	O
+precursor	O
+levodopa	O
+enhances	O
+learning	O
+in	O
+healthy	O
+subjects	O
+and	O
+stroke	B
+patients	O
+.	O
+
+Because	O
+levodopa	O
+increases	O
+both	O
+phasic	O
+and	O
+tonic	O
+dopaminergic	O
+neurotransmission	O
+,	O
+the	O
+critical	O
+mechanism	O
+mediating	O
+the	O
+enhancement	O
+of	O
+learning	O
+is	O
+unresolved	O
+.	O
+
+We	O
+here	O
+probed	O
+how	O
+selective	O
+tonic	O
+dopaminergic	O
+stimulation	O
+affects	O
+associative	O
+learning	O
+.	O
+
+Forty	O
+healthy	O
+subjects	O
+were	O
+trained	O
+in	O
+a	O
+novel	O
+vocabulary	O
+of	O
+45	O
+concrete	O
+nouns	O
+over	O
+the	O
+course	O
+of	O
+5	O
+consecutive	O
+training	O
+days	O
+in	O
+a	O
+prospective	O
+,	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+design	O
+.	O
+
+Subjects	O
+received	O
+the	O
+tonically	O
+stimulating	O
+dopamine	O
+-	O
+receptor	O
+agonist	O
+pergolide	O
+(	O
+0	O
+.	O
+1	O
+mg	O
+)	O
+vs	O
+placebo	O
+120	O
+min	O
+before	O
+training	O
+on	O
+each	O
+training	O
+day	O
+.	O
+
+The	O
+dopamine	O
+agonist	O
+significantly	O
+impaired	B
+novel	I
+word	I
+learning	I
+compared	O
+to	O
+placebo	O
+.	O
+
+This	O
+learning	O
+decrement	O
+persisted	O
+up	O
+to	O
+the	O
+last	O
+follow	O
+-	O
+up	O
+4	O
+weeks	O
+post	O
+-	O
+training	O
+.	O
+
+Subjects	O
+treated	O
+with	O
+pergolide	O
+also	O
+showed	O
+restricted	O
+emotional	O
+responses	O
+compared	O
+to	O
+the	O
+PLACEBO	O
+group	O
+.	O
+
+The	O
+extent	O
+of	O
+'	O
+flattened	O
+'	O
+affect	O
+with	O
+pergolide	O
+was	O
+related	O
+to	O
+the	O
+degree	O
+of	O
+learning	O
+inhibition	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+tonic	O
+occupation	O
+of	O
+dopamine	O
+receptors	O
+impairs	O
+learning	O
+by	O
+competition	O
+with	O
+phasic	O
+dopamine	O
+signals	O
+.	O
+
+Thus	O
+,	O
+phasic	O
+signaling	O
+seems	O
+to	O
+be	O
+the	O
+critical	O
+mechanism	O
+by	O
+which	O
+dopamine	O
+enhances	O
+associative	O
+learning	O
+in	O
+healthy	O
+subjects	O
+and	O
+stroke	B
+patients	O
+.	O
+
+Minocycline	O
+-	O
+induced	O
+vasculitis	B
+fulfilling	O
+the	O
+criteria	O
+of	O
+polyarteritis	B
+nodosa	I
+.	O
+
+A	O
+47	O
+-	O
+year	O
+-	O
+old	O
+man	O
+who	O
+had	O
+been	O
+taking	O
+minocycline	O
+for	O
+palmoplantar	B
+pustulosis	I
+developed	O
+fever	B
+,	O
+myalgias	B
+,	O
+polyneuropathy	B
+,	O
+and	O
+testicular	B
+pain	I
+,	O
+with	O
+elevated	O
+C	O
+-	O
+reactive	O
+protein	O
+(	O
+CRP	O
+)	O
+.	O
+
+Neither	O
+myeloperoxidase	O
+-	O
+nor	O
+proteinase	O
+-	O
+3	O
+-	O
+antineutrophil	O
+cytoplasmic	O
+antibody	O
+was	O
+positive	O
+.	O
+
+These	O
+manifestations	O
+met	O
+the	O
+American	O
+College	O
+of	O
+Rheumatology	O
+1990	O
+criteria	O
+for	O
+the	O
+classification	O
+of	O
+polyarteritis	B
+nodosa	I
+.	O
+
+Stopping	O
+minocycline	O
+led	O
+to	O
+amelioration	O
+of	O
+symptoms	O
+and	O
+normalization	O
+of	O
+CRP	O
+level	O
+.	O
+
+To	O
+our	O
+knowledge	O
+,	O
+this	O
+is	O
+the	O
+second	O
+case	O
+of	O
+minocycline	O
+-	O
+induced	O
+vasculitis	B
+satisfying	O
+the	O
+criteria	O
+.	O
+
+Differential	O
+diagnosis	O
+for	O
+drug	O
+-	O
+induced	O
+disease	O
+is	O
+invaluable	O
+even	O
+for	O
+patients	O
+with	O
+classical	O
+polyarteritis	B
+nodosa	I
+.	O
+
+Intramuscular	O
+hepatitis	B
+B	I
+immune	O
+globulin	O
+combined	O
+with	O
+lamivudine	O
+in	O
+prevention	O
+of	O
+hepatitis	B
+B	I
+recurrence	O
+after	O
+liver	O
+transplantation	O
+.	O
+
+BACKGROUND	O
+:	O
+Combined	O
+hepatitis	B
+B	I
+immune	O
+globulin	O
+(	O
+HBIg	O
+)	O
+and	O
+lamivudine	O
+in	O
+prophylaxis	O
+of	O
+the	O
+recurrence	O
+of	O
+hepatitis	B
+B	I
+after	O
+liver	O
+transplantation	O
+has	O
+significantly	O
+improved	O
+the	O
+survival	O
+of	O
+HBsAg	O
+positive	O
+patients	O
+.	O
+
+This	O
+study	O
+was	O
+undertaken	O
+to	O
+evaluate	O
+the	O
+outcomes	O
+of	O
+liver	O
+transplantation	O
+for	O
+patients	O
+with	O
+hepatitis	B
+B	I
+virus	O
+(	O
+HBV	O
+)	O
+.	O
+
+METHODS	O
+:	O
+A	O
+retrospective	O
+chart	O
+analysis	O
+and	O
+a	O
+review	O
+of	O
+the	O
+organ	O
+transplant	O
+database	O
+identified	O
+51	O
+patients	O
+(	O
+43	O
+men	O
+and	O
+8	O
+women	O
+)	O
+transplanted	O
+for	O
+benign	O
+HBV	O
+-	O
+related	O
+cirrhotic	B
+diseases	I
+between	O
+June	O
+2002	O
+and	O
+December	O
+2004	O
+who	O
+had	O
+survived	O
+more	O
+than	O
+3	O
+months	O
+.	O
+
+HBIg	O
+was	O
+administered	O
+intravenously	O
+during	O
+the	O
+first	O
+week	O
+and	O
+intramuscularly	O
+thereafter	O
+.	O
+
+RESULTS	O
+:	O
+At	O
+a	O
+median	O
+follow	O
+-	O
+up	O
+of	O
+14	O
+.	O
+1	O
+months	O
+,	O
+the	O
+overall	O
+recurrence	O
+rate	O
+in	O
+the	O
+51	O
+patients	O
+was	O
+3	O
+.	O
+9	O
+%	O
+(	O
+2	O
+/	O
+51	O
+)	O
+.	O
+
+The	O
+overall	O
+patient	O
+survival	O
+was	O
+88	O
+.	O
+3	O
+%	O
+,	O
+and	O
+82	O
+.	O
+4	O
+%	O
+after	O
+1	O
+and	O
+2	O
+years	O
+,	O
+respectively	O
+.	O
+
+A	O
+daily	O
+oral	O
+dose	O
+of	O
+100	O
+mg	O
+lamivudine	O
+for	O
+2	O
+weeks	O
+before	O
+transplantation	O
+for	O
+10	O
+patients	O
+enabled	O
+57	O
+.	O
+1	O
+%	O
+(	O
+4	O
+/	O
+7	O
+)	O
+and	O
+62	O
+.	O
+5	O
+%	O
+(	O
+5	O
+/	O
+8	O
+)	O
+of	O
+HBV	O
+-	O
+DNA	O
+and	O
+HBeAg	O
+positive	O
+patients	O
+respectively	O
+to	O
+convert	O
+to	O
+be	O
+negative	O
+.	O
+
+Intramuscular	O
+HBIg	O
+was	O
+well	O
+tolerated	O
+in	O
+all	O
+patients	O
+.	O
+
+CONCLUSION	O
+:	O
+Lamivudine	O
+combined	O
+with	O
+intramuscular	O
+HBIg	O
+can	O
+effectively	O
+prevent	O
+allograft	O
+from	O
+the	O
+recurrence	O
+of	O
+HBV	O
+after	O
+liver	O
+transplantation	O
+.	O
+
+Anticonvulsant	O
+effect	O
+of	O
+eslicarbazepine	O
+acetate	O
+(	O
+BIA	O
+2	O
+-	O
+093	O
+)	O
+on	O
+seizures	B
+induced	O
+by	O
+microperfusion	O
+of	O
+picrotoxin	O
+in	O
+the	O
+hippocampus	O
+of	O
+freely	O
+moving	O
+rats	O
+.	O
+
+Eslicarbazepine	O
+acetate	O
+(	O
+BIA	O
+2	O
+-	O
+093	O
+,	O
+S	O
+-	O
+(	O
+-	O
+)	O
+-	O
+10	O
+-	O
+acetoxy	O
+-	O
+10	O
+,	O
+11	O
+-	O
+dihydro	O
+-	O
+5H	O
+-	O
+dibenzo	O
+/	O
+b	O
+,	O
+f	O
+/	O
+azepine	O
+-	O
+5	O
+-	O
+carboxamide	O
+)	O
+is	O
+a	O
+novel	O
+antiepileptic	O
+drug	O
+,	O
+now	O
+in	O
+Phase	O
+III	O
+clinical	O
+trials	O
+,	O
+designed	O
+with	O
+the	O
+aim	O
+of	O
+improving	O
+efficacy	O
+and	O
+safety	O
+in	O
+comparison	O
+with	O
+the	O
+structurally	O
+related	O
+drugs	O
+carbamazepine	O
+(	O
+CBZ	O
+)	O
+and	O
+oxcarbazepine	O
+(	O
+OXC	O
+)	O
+.	O
+
+We	O
+have	O
+studied	O
+the	O
+effects	O
+of	O
+oral	O
+treatment	O
+with	O
+eslicarbazepine	O
+acetate	O
+on	O
+a	O
+whole	O
+-	O
+animal	O
+model	O
+in	O
+which	O
+partial	O
+seizures	B
+can	O
+be	O
+elicited	O
+repeatedly	O
+on	O
+different	O
+days	O
+without	O
+changes	O
+in	O
+threshold	O
+or	O
+seizure	B
+patterns	O
+.	O
+
+In	O
+the	O
+animals	O
+treated	O
+with	O
+threshold	O
+doses	O
+of	O
+picrotoxin	O
+,	O
+the	O
+average	O
+number	O
+of	O
+seizures	B
+was	O
+2	O
+.	O
+3	O
++	O
+/	O
+-	O
+1	O
+.	O
+2	O
+,	O
+and	O
+average	O
+seizure	B
+duration	O
+was	O
+39	O
+.	O
+5	O
++	O
+/	O
+-	O
+8	O
+.	O
+4s	O
+.	O
+
+Pre	O
+-	O
+treatment	O
+with	O
+a	O
+dose	O
+of	O
+30	O
+mg	O
+/	O
+kg	O
+2h	O
+before	O
+picrotoxin	O
+microperfusion	O
+prevented	O
+seizures	B
+in	O
+the	O
+75	O
+%	O
+of	O
+the	O
+rats	O
+.	O
+
+Lower	O
+doses	O
+(	O
+3	O
+and	O
+10mg	O
+/	O
+kg	O
+)	O
+did	O
+not	O
+suppress	O
+seizures	B
+,	O
+however	O
+,	O
+after	O
+administration	O
+of	O
+10mg	O
+/	O
+kg	O
+,	O
+significant	O
+reductions	O
+in	O
+seizures	B
+duration	O
+(	O
+24	O
+.	O
+3	O
++	O
+/	O
+-	O
+6	O
+.	O
+8s	O
+)	O
+and	O
+seizure	B
+number	O
+(	O
+1	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+34	O
+)	O
+were	O
+found	O
+.	O
+
+No	O
+adverse	O
+effects	O
+of	O
+eslicarbazepine	O
+acetate	O
+were	O
+observed	O
+in	O
+the	O
+behavioral	O
+/	O
+EEG	O
+patterns	O
+studied	O
+,	O
+including	O
+sleep	O
+/	O
+wakefulness	O
+cycle	O
+,	O
+at	O
+the	O
+doses	O
+studied	O
+.	O
+
+Acute	B
+renal	I
+failure	I
+associated	O
+with	O
+prolonged	O
+intake	O
+of	O
+slimming	O
+pills	O
+containing	O
+anthraquinones	O
+.	O
+
+Chinese	O
+herbal	O
+medicine	O
+preparations	O
+are	O
+widely	O
+available	O
+and	O
+often	O
+regarded	O
+by	O
+the	O
+public	O
+as	O
+natural	O
+and	O
+safe	O
+remedies	O
+for	O
+a	O
+variety	O
+of	O
+medical	O
+conditions	O
+.	O
+
+Nephropathy	B
+caused	O
+by	O
+Chinese	O
+herbs	O
+has	O
+previously	O
+been	O
+reported	O
+,	O
+usually	O
+involving	O
+the	O
+use	O
+of	O
+aristolochic	O
+acids	O
+.	O
+
+We	O
+report	O
+a	O
+23	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+who	O
+developed	O
+acute	B
+renal	I
+failure	I
+following	O
+prolonged	O
+use	O
+of	O
+a	O
+proprietary	O
+Chinese	O
+herbal	O
+slimming	O
+pill	O
+that	O
+contained	O
+anthraquinone	O
+derivatives	O
+,	O
+extracted	O
+from	O
+Rhizoma	O
+Rhei	O
+(	O
+rhubarb	O
+)	O
+.	O
+
+The	O
+renal	B
+injury	I
+was	O
+probably	O
+aggravated	O
+by	O
+the	O
+concomitant	O
+intake	O
+of	O
+a	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drug	O
+,	O
+diclofenac	O
+.	O
+
+Renal	O
+pathology	O
+was	O
+that	O
+of	O
+hypocellular	O
+interstitial	O
+fibrosis	B
+.	O
+
+Spontaneous	O
+renal	O
+recovery	O
+occurred	O
+upon	O
+cessation	O
+of	O
+the	O
+slimming	O
+pills	O
+,	O
+but	O
+mild	O
+interstitial	O
+fibrosis	B
+and	O
+tubular	O
+atrophy	B
+was	O
+still	O
+evident	O
+histologically	O
+4	O
+months	O
+later	O
+.	O
+
+Although	O
+a	O
+causal	O
+relationship	O
+between	O
+the	O
+use	O
+of	O
+an	O
+anthraquinone	O
+-	O
+containing	O
+herbal	O
+agent	O
+and	O
+renal	B
+injury	I
+remains	O
+to	O
+be	O
+proven	O
+,	O
+phytotherapy	O
+-	O
+associated	O
+interstitial	O
+nephropathy	B
+should	O
+be	O
+considered	O
+in	O
+patients	O
+who	O
+present	O
+with	O
+unexplained	O
+renal	B
+failure	I
+.	O
+
+Chloroacetaldehyde	O
+as	O
+a	O
+sulfhydryl	O
+reagent	O
+:	O
+the	O
+role	O
+of	O
+critical	O
+thiol	O
+groups	O
+in	O
+ifosfamide	O
+nephropathy	B
+.	O
+
+Chloroacetaldehyde	O
+(	O
+CAA	O
+)	O
+is	O
+a	O
+metabolite	O
+of	O
+the	O
+alkylating	O
+agent	O
+ifosfamide	O
+(	O
+IFO	O
+)	O
+and	O
+putatively	O
+responsible	O
+for	O
+renal	B
+damage	I
+following	O
+anti	O
+-	O
+tumor	B
+therapy	O
+with	O
+IFO	O
+.	O
+
+Depletion	O
+of	O
+sulfhydryl	O
+(	O
+SH	O
+)	O
+groups	O
+has	O
+been	O
+reported	O
+from	O
+cell	O
+culture	O
+,	O
+animal	O
+and	O
+clinical	O
+studies	O
+.	O
+
+In	O
+this	O
+work	O
+the	O
+effect	O
+of	O
+CAA	O
+on	O
+human	O
+proximal	O
+tubule	O
+cells	O
+in	O
+primary	O
+culture	O
+(	O
+hRPTEC	O
+)	O
+was	O
+investigated	O
+.	O
+
+Toxicity	B
+of	O
+CAA	O
+was	O
+determined	O
+by	O
+protein	O
+content	O
+,	O
+cell	O
+number	O
+,	O
+LDH	O
+release	O
+,	O
+trypan	O
+blue	O
+exclusion	O
+assay	O
+and	O
+caspase	O
+-	O
+3	O
+activity	O
+.	O
+
+Free	O
+thiols	O
+were	O
+measured	O
+by	O
+the	O
+method	O
+of	O
+Ellman	O
+.	O
+
+CAA	O
+reduced	O
+hRPTEC	O
+cell	O
+number	O
+and	O
+protein	O
+,	O
+induced	O
+a	O
+loss	O
+in	O
+free	O
+intracellular	O
+thiols	O
+and	O
+an	O
+increase	O
+in	O
+necrosis	B
+markers	O
+.	O
+
+CAA	O
+but	O
+not	O
+acrolein	O
+inhibited	O
+the	O
+cysteine	O
+proteases	O
+caspase	O
+-	O
+3	O
+,	O
+caspase	O
+-	O
+8	O
+and	O
+cathepsin	O
+B	O
+.	O
+
+Caspase	O
+activation	O
+by	O
+cisplatin	O
+was	O
+inhibited	O
+by	O
+CAA	O
+.	O
+
+In	O
+cells	O
+stained	O
+with	O
+fluorescent	O
+dyes	O
+targeting	O
+lysosomes	O
+,	O
+CAA	O
+induced	O
+an	O
+increase	O
+in	O
+lysosomal	O
+size	O
+and	O
+lysosomal	O
+leakage	O
+.	O
+
+The	O
+effects	O
+of	O
+CAA	O
+on	O
+cysteine	O
+protease	O
+activities	O
+and	O
+thiols	O
+could	O
+be	O
+reproduced	O
+in	O
+cell	O
+lysate	O
+.	O
+
+Acidification	O
+,	O
+which	O
+slowed	O
+the	O
+reaction	O
+of	O
+CAA	O
+with	O
+thiol	O
+donors	O
+,	O
+could	O
+also	O
+attenuate	O
+effects	O
+of	O
+CAA	O
+on	O
+necrosis	B
+markers	O
+,	O
+thiol	O
+depletion	O
+and	O
+cysteine	O
+protease	O
+inhibition	O
+in	O
+living	O
+cells	O
+.	O
+
+Thus	O
+,	O
+CAA	O
+directly	O
+reacts	O
+with	O
+cellular	O
+protein	O
+and	O
+non	O
+-	O
+protein	O
+thiols	O
+,	O
+mediating	O
+its	O
+toxicity	B
+on	O
+hRPTEC	O
+.	O
+
+This	O
+effect	O
+can	O
+be	O
+reduced	O
+by	O
+acidification	O
+.	O
+
+Therefore	O
+,	O
+urinary	O
+acidification	O
+could	O
+be	O
+an	O
+option	O
+to	O
+prevent	O
+IFO	O
+nephropathy	B
+in	O
+patients	O
+.	O
+
+Stereological	O
+methods	O
+reveal	O
+the	O
+robust	O
+size	O
+and	O
+stability	O
+of	O
+ectopic	O
+hilar	O
+granule	O
+cells	O
+after	O
+pilocarpine	O
+-	O
+induced	O
+status	B
+epilepticus	I
+in	O
+the	O
+adult	O
+rat	O
+.	O
+
+Following	O
+status	B
+epilepticus	I
+in	O
+the	O
+rat	O
+,	O
+dentate	O
+granule	O
+cell	O
+neurogenesis	O
+increases	O
+greatly	O
+,	O
+and	O
+many	O
+of	O
+the	O
+new	O
+neurons	O
+appear	O
+to	O
+develop	O
+ectopically	O
+,	O
+in	O
+the	O
+hilar	O
+region	O
+of	O
+the	O
+hippocampal	O
+formation	O
+.	O
+
+It	O
+has	O
+been	O
+suggested	O
+that	O
+the	O
+ectopic	O
+hilar	O
+granule	O
+cells	O
+could	O
+contribute	O
+to	O
+the	O
+spontaneous	O
+seizures	B
+that	O
+ultimately	O
+develop	O
+after	O
+status	B
+epilepticus	I
+.	O
+
+However	O
+,	O
+the	O
+population	O
+has	O
+never	O
+been	O
+quantified	O
+,	O
+so	O
+it	O
+is	O
+unclear	O
+whether	O
+it	O
+is	O
+substantial	O
+enough	O
+to	O
+have	O
+a	O
+strong	O
+influence	O
+on	O
+epileptogenesis	O
+.	O
+
+To	O
+quantify	O
+this	O
+population	O
+,	O
+the	O
+total	O
+number	O
+of	O
+ectopic	O
+hilar	O
+granule	O
+cells	O
+was	O
+estimated	O
+using	O
+unbiased	O
+stereology	O
+at	O
+different	O
+times	O
+after	O
+pilocarpine	O
+-	O
+induced	O
+status	B
+epilepticus	I
+.	O
+
+The	O
+number	O
+of	O
+hilar	O
+neurons	O
+immunoreactive	O
+for	O
+Prox	O
+-	O
+1	O
+,	O
+a	O
+granule	O
+-	O
+cell	O
+-	O
+specific	O
+marker	O
+,	O
+was	O
+estimated	O
+using	O
+the	O
+optical	O
+fractionator	O
+method	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+the	O
+size	O
+of	O
+the	O
+hilar	O
+ectopic	O
+granule	O
+cell	O
+population	O
+after	O
+status	B
+epilepticus	I
+is	O
+substantial	O
+,	O
+and	O
+stable	O
+over	O
+time	O
+.	O
+
+Interestingly	O
+,	O
+the	O
+size	O
+of	O
+the	O
+population	O
+appears	O
+to	O
+be	O
+correlated	O
+with	O
+the	O
+frequency	O
+of	O
+behavioral	O
+seizures	B
+,	O
+because	O
+animals	O
+with	O
+more	O
+ectopic	O
+granule	O
+cells	O
+in	O
+the	O
+hilus	O
+have	O
+more	O
+frequent	O
+behavioral	O
+seizures	B
+.	O
+
+The	O
+hilar	O
+ectopic	O
+granule	O
+cell	O
+population	O
+does	O
+not	O
+appear	O
+to	O
+vary	O
+systematically	O
+across	O
+the	O
+septotemporal	O
+axis	O
+,	O
+although	O
+it	O
+is	O
+associated	O
+with	O
+an	O
+increase	O
+in	O
+volume	O
+of	O
+the	O
+hilus	O
+.	O
+
+The	O
+results	O
+provide	O
+new	O
+insight	O
+into	O
+the	O
+potential	O
+role	O
+of	O
+ectopic	O
+hilar	O
+granule	O
+cells	O
+in	O
+the	O
+pilocarpine	O
+model	O
+of	O
+temporal	B
+lobe	I
+epilepsy	I
+.	O
+
+A	O
+prospective	O
+,	O
+open	O
+-	O
+label	O
+trial	O
+of	O
+galantamine	O
+in	O
+autistic	B
+disorder	I
+.	O
+
+OBJECTIVE	O
+:	O
+Post	O
+-	O
+mortem	O
+studies	O
+have	O
+reported	O
+abnormalities	O
+of	O
+the	O
+cholinergic	O
+system	O
+in	O
+autism	B
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+assess	O
+the	O
+use	O
+of	O
+galantamine	O
+,	O
+an	O
+acetylcholinesterase	O
+inhibitor	O
+and	O
+nicotinic	O
+receptor	O
+modulator	O
+,	O
+in	O
+the	O
+treatment	O
+of	O
+interfering	O
+behaviors	O
+in	O
+children	O
+with	O
+autism	B
+.	O
+
+METHODS	O
+:	O
+Thirteen	O
+medication	O
+-	O
+free	O
+children	O
+with	O
+autism	B
+(	O
+mean	O
+age	O
+,	O
+8	O
+.	O
+8	O
++	O
+/	O
+-	O
+3	O
+.	O
+5	O
+years	O
+)	O
+participated	O
+in	O
+a	O
+12	O
+-	O
+week	O
+,	O
+open	O
+-	O
+label	O
+trial	O
+of	O
+galantamine	O
+.	O
+
+Patients	O
+were	O
+rated	O
+monthly	O
+by	O
+parents	O
+on	O
+the	O
+Aberrant	O
+Behavior	O
+Checklist	O
+(	O
+ABC	O
+)	O
+and	O
+the	O
+Conners	O
+'	O
+Parent	O
+Rating	O
+Scale	O
+-	O
+Revised	O
+,	O
+and	O
+by	O
+a	O
+physician	O
+using	O
+the	O
+Children	O
+'	O
+s	O
+Psychiatric	O
+Rating	O
+Scale	O
+and	O
+the	O
+Clinical	O
+Global	O
+Impressions	O
+scale	O
+.	O
+
+RESULTS	O
+:	O
+Patients	O
+showed	O
+a	O
+significant	O
+reduction	O
+in	O
+parent	O
+-	O
+rated	O
+irritability	B
+and	O
+social	O
+withdrawal	O
+on	O
+the	O
+ABC	O
+as	O
+well	O
+as	O
+significant	O
+improvements	O
+in	O
+emotional	O
+lability	O
+and	O
+inattention	O
+on	O
+the	O
+Conners	O
+'	O
+Parent	O
+Rating	O
+Scale	O
+-	O
+-	O
+Revised	O
+.	O
+
+Similarly	O
+,	O
+clinician	O
+ratings	O
+showed	O
+reductions	O
+in	O
+the	O
+anger	O
+subscale	O
+of	O
+the	O
+Children	O
+'	O
+s	O
+Psychiatric	O
+Rating	O
+Scale	O
+.	O
+
+Eight	O
+of	O
+13	O
+participants	O
+were	O
+rated	O
+as	O
+responders	O
+on	O
+the	O
+basis	O
+of	O
+their	O
+improvement	O
+scores	O
+on	O
+the	O
+Clinical	O
+Global	O
+Impressions	O
+scale	O
+.	O
+
+Overall	O
+,	O
+galantamine	O
+was	O
+well	O
+-	O
+tolerated	O
+,	O
+with	O
+no	O
+significant	O
+adverse	O
+effects	O
+apart	O
+from	O
+headaches	B
+in	O
+one	O
+patient	O
+.	O
+
+CONCLUSION	O
+:	O
+In	O
+this	O
+open	O
+trial	O
+,	O
+galantamine	O
+was	O
+well	O
+-	O
+tolerated	O
+and	O
+appeared	O
+to	O
+be	O
+beneficial	O
+for	O
+the	O
+treatment	O
+of	O
+interfering	O
+behaviors	O
+in	O
+children	O
+with	O
+autism	B
+,	O
+particularly	O
+aggression	B
+,	O
+behavioral	B
+dyscontrol	I
+,	O
+and	O
+inattention	B
+.	O
+
+Further	O
+controlled	O
+trials	O
+are	O
+warranted	O
+.	O
+
+Randomized	O
+comparison	O
+of	O
+olanzapine	O
+versus	O
+risperidone	O
+for	O
+the	O
+treatment	O
+of	O
+first	O
+-	O
+episode	O
+schizophrenia	B
+:	O
+4	O
+-	O
+month	O
+outcomes	O
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+authors	O
+compared	O
+4	O
+-	O
+month	O
+treatment	O
+outcomes	O
+for	O
+olanzapine	O
+versus	O
+risperidone	O
+in	O
+patients	O
+with	O
+first	O
+-	O
+episode	O
+schizophrenia	B
+spectrum	O
+disorders	O
+.	O
+
+METHOD	O
+:	O
+One	O
+hundred	O
+twelve	O
+subjects	O
+(	O
+70	O
+%	O
+male	O
+;	O
+mean	O
+age	O
+=	O
+23	O
+.	O
+3	O
+years	O
+[	O
+SD	O
+=	O
+5	O
+.	O
+1	O
+]	O
+)	O
+with	O
+first	O
+-	O
+episode	O
+schizophrenia	B
+(	O
+75	O
+%	O
+)	O
+,	O
+schizophreniform	B
+disorder	I
+(	O
+17	O
+%	O
+)	O
+,	O
+or	O
+schizoaffective	B
+disorder	I
+(	O
+8	O
+%	O
+)	O
+were	O
+randomly	O
+assigned	O
+to	O
+treatment	O
+with	O
+olanzapine	O
+(	O
+2	O
+.	O
+5	O
+-	O
+20	O
+mg	O
+/	O
+day	O
+)	O
+or	O
+risperidone	O
+(	O
+1	O
+-	O
+6	O
+mg	O
+/	O
+day	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+Response	O
+rates	O
+did	O
+not	O
+significantly	O
+differ	O
+between	O
+olanzapine	O
+(	O
+43	O
+.	O
+7	O
+%	O
+,	O
+95	O
+%	O
+CI	O
+=	O
+28	O
+.	O
+8	O
+%	O
+-	O
+58	O
+.	O
+6	O
+%	O
+)	O
+and	O
+risperidone	O
+(	O
+54	O
+.	O
+3	O
+%	O
+,	O
+95	O
+%	O
+CI	O
+=	O
+39	O
+.	O
+9	O
+%	O
+-	O
+68	O
+.	O
+7	O
+%	O
+)	O
+.	O
+
+Among	O
+those	O
+responding	O
+to	O
+treatment	O
+,	O
+more	O
+subjects	O
+in	O
+the	O
+olanzapine	O
+group	O
+(	O
+40	O
+.	O
+9	O
+%	O
+,	O
+95	O
+%	O
+CI	O
+=	O
+16	O
+.	O
+8	O
+%	O
+-	O
+65	O
+.	O
+0	O
+%	O
+)	O
+than	O
+in	O
+the	O
+risperidone	O
+group	O
+(	O
+18	O
+.	O
+9	O
+%	O
+,	O
+95	O
+%	O
+CI	O
+=	O
+0	O
+%	O
+-	O
+39	O
+.	O
+2	O
+%	O
+)	O
+had	O
+subsequent	O
+ratings	O
+not	O
+meeting	O
+response	O
+criteria	O
+.	O
+
+Negative	O
+symptom	O
+outcomes	O
+and	O
+measures	O
+of	O
+parkinsonism	B
+and	O
+akathisia	B
+did	O
+not	O
+differ	O
+between	O
+medications	O
+.	O
+
+Extrapyramidal	B
+symptom	I
+severity	O
+scores	O
+were	O
+1	O
+.	O
+4	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+1	O
+.	O
+2	O
+-	O
+1	O
+.	O
+6	O
+)	O
+with	O
+risperidone	O
+and	O
+1	O
+.	O
+2	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+1	O
+.	O
+0	O
+-	O
+1	O
+.	O
+4	O
+)	O
+with	O
+olanzapine	O
+.	O
+
+Significantly	O
+more	O
+weight	B
+gain	I
+occurred	O
+with	O
+olanzapine	O
+than	O
+with	O
+risperidone	O
+:	O
+the	O
+increase	O
+in	O
+weight	O
+at	O
+4	O
+months	O
+relative	O
+to	O
+baseline	O
+weight	O
+was	O
+17	O
+.	O
+3	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+14	O
+.	O
+2	O
+%	O
+-	O
+20	O
+.	O
+5	O
+%	O
+)	O
+with	O
+olanzapine	O
+and	O
+11	O
+.	O
+3	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+8	O
+.	O
+4	O
+%	O
+-	O
+14	O
+.	O
+3	O
+%	O
+)	O
+with	O
+risperidone	O
+.	O
+
+Body	O
+mass	O
+index	O
+at	O
+baseline	O
+and	O
+at	O
+4	O
+months	O
+was	O
+24	O
+.	O
+3	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+22	O
+.	O
+8	O
+-	O
+25	O
+.	O
+7	O
+)	O
+versus	O
+28	O
+.	O
+2	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+26	O
+.	O
+7	O
+-	O
+29	O
+.	O
+7	O
+)	O
+with	O
+olanzapine	O
+and	O
+23	O
+.	O
+9	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+22	O
+.	O
+5	O
+-	O
+25	O
+.	O
+3	O
+)	O
+versus	O
+26	O
+.	O
+7	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+25	O
+.	O
+2	O
+-	O
+28	O
+.	O
+2	O
+)	O
+with	O
+risperidone	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Clinical	O
+outcomes	O
+with	O
+risperidone	O
+were	O
+equal	O
+to	O
+those	O
+with	O
+olanzapine	O
+,	O
+and	O
+response	O
+may	O
+be	O
+more	O
+stable	O
+.	O
+
+Olanzapine	O
+may	O
+have	O
+an	O
+advantage	O
+for	O
+motor	O
+side	O
+effects	O
+.	O
+
+Both	O
+medications	O
+caused	O
+substantial	O
+rapid	O
+weight	B
+gain	I
+,	O
+but	O
+weight	B
+gain	I
+was	O
+greater	O
+with	O
+olanzapine	O
+.	O
+
+Early	O
+paracentral	O
+visual	B
+field	I
+loss	I
+in	O
+patients	O
+taking	O
+hydroxychloroquine	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+review	O
+the	O
+natural	O
+history	O
+and	O
+ocular	O
+and	O
+systemic	O
+adverse	O
+effects	O
+of	O
+patients	O
+taking	O
+hydroxychloroquine	O
+sulfate	O
+who	O
+attended	O
+an	O
+ophthalmic	O
+screening	O
+program	O
+.	O
+
+DESIGN	O
+:	O
+Retrospective	O
+study	O
+.	O
+
+RESULTS	O
+:	O
+Records	O
+of	O
+262	O
+patients	O
+who	O
+were	O
+taking	O
+hydroxychloroquine	O
+and	O
+screened	O
+in	O
+the	O
+Department	O
+of	O
+Ophthalmology	O
+were	O
+reviewed	O
+.	O
+
+Of	O
+the	O
+262	O
+patients	O
+,	O
+14	O
+(	O
+18	O
+%	O
+)	O
+of	O
+76	O
+who	O
+had	O
+stopped	O
+treatment	O
+at	O
+the	O
+time	O
+of	O
+the	O
+study	O
+experienced	O
+documented	O
+adverse	O
+effects	O
+.	O
+
+Systemic	O
+adverse	O
+effects	O
+occurred	O
+in	O
+8	O
+patients	O
+(	O
+10	O
+.	O
+5	O
+%	O
+)	O
+and	O
+ocular	O
+adverse	O
+effects	O
+,	O
+in	O
+5	O
+(	O
+6	O
+.	O
+5	O
+%	O
+)	O
+.	O
+
+Thirty	O
+-	O
+five	O
+patients	O
+(	O
+13	O
+.	O
+4	O
+%	O
+)	O
+had	O
+visual	B
+field	I
+abnormalities	I
+,	O
+which	O
+were	O
+attributed	O
+to	O
+hydroxychloroquine	O
+treatment	O
+in	O
+4	O
+patients	O
+(	O
+1	O
+.	O
+5	O
+%	O
+)	O
+.	O
+
+Three	O
+of	O
+the	O
+4	O
+patients	O
+were	O
+taking	O
+less	O
+than	O
+6	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+and	O
+all	O
+patients	O
+had	O
+normal	O
+renal	O
+and	O
+liver	O
+function	O
+test	O
+results	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+current	O
+study	O
+used	O
+a	O
+protocol	O
+of	O
+visual	O
+acuity	O
+and	O
+color	O
+vision	O
+assessment	O
+,	O
+funduscopy	O
+,	O
+and	O
+Humphrey	O
+10	O
+-	O
+2	O
+visual	O
+field	O
+testing	O
+and	O
+shows	O
+that	O
+visual	B
+field	I
+defects	I
+appeared	O
+before	O
+any	O
+corresponding	O
+changes	O
+in	O
+any	O
+other	O
+tested	O
+clinical	O
+parameters	O
+;	O
+the	O
+defects	O
+were	O
+reproducible	O
+and	O
+the	O
+test	O
+parameters	O
+were	O
+reliable	O
+.	O
+
+Patients	O
+taking	O
+hydroxychloroquine	O
+can	O
+demonstrate	O
+a	O
+toxic	O
+reaction	O
+in	O
+the	O
+retina	O
+despite	O
+the	O
+absence	O
+of	O
+known	O
+risk	O
+factors	O
+.	O
+
+Screening	O
+,	O
+including	O
+Humphrey	O
+10	O
+-	O
+2	O
+visual	O
+field	O
+assessment	O
+,	O
+is	O
+recommended	O
+2	O
+years	O
+after	O
+the	O
+initial	O
+baseline	O
+and	O
+yearly	O
+thereafter	O
+.	O
+
+Peri	O
+-	O
+operative	O
+atrioventricular	B
+block	I
+as	O
+a	O
+result	O
+of	O
+chemotherapy	O
+with	O
+epirubicin	O
+and	O
+paclitaxel	O
+.	O
+
+A	O
+47	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+presented	O
+for	O
+mastectomy	O
+and	O
+immediate	O
+latissimus	O
+dorsi	O
+flap	O
+reconstruction	O
+having	O
+been	O
+diagnosed	O
+with	O
+carcinoma	B
+of	I
+the	I
+breast	I
+6	O
+months	O
+previously	O
+.	O
+
+In	O
+the	O
+preceding	O
+months	O
+she	O
+had	O
+received	O
+neo	O
+-	O
+adjuvant	O
+chemotherapy	O
+with	O
+epirubicin	O
+,	O
+paclitaxel	O
+(	O
+Taxol	O
+)	O
+and	O
+cyclophosphamide	O
+.	O
+
+This	O
+had	O
+been	O
+apparently	O
+uncomplicated	O
+and	O
+she	O
+had	O
+maintained	O
+a	O
+remarkably	O
+high	O
+level	O
+of	O
+physical	O
+activity	O
+.	O
+
+She	O
+was	O
+found	O
+to	O
+be	O
+bradycardic	B
+at	O
+pre	O
+-	O
+operative	O
+assessment	O
+but	O
+had	O
+no	O
+cardiac	O
+symptoms	O
+.	O
+
+Second	O
+degree	O
+Mobitz	O
+type	O
+II	O
+atrioventricular	B
+block	I
+was	O
+diagnosed	O
+on	O
+electrocardiogram	O
+,	O
+and	O
+temporary	O
+transvenous	O
+ventricular	O
+pacing	O
+instituted	O
+in	O
+the	O
+peri	O
+-	O
+operative	O
+period	O
+.	O
+
+We	O
+discuss	O
+how	O
+evidence	O
+-	O
+based	O
+guidelines	O
+would	O
+not	O
+have	O
+been	O
+helpful	O
+in	O
+this	O
+case	O
+,	O
+and	O
+how	O
+chemotherapy	O
+can	O
+exhibit	O
+substantial	O
+cardiotoxicity	B
+that	O
+may	O
+develop	O
+over	O
+many	O
+years	O
+.	O
+
+We	O
+suggest	O
+that	O
+patients	O
+who	O
+have	O
+received	O
+chemotherapy	O
+at	O
+any	O
+time	O
+should	O
+have	O
+a	O
+pre	O
+-	O
+operative	O
+electrocardiogram	O
+even	O
+if	O
+they	O
+are	O
+asymptomatic	O
+.	O
+
+Risks	O
+and	O
+benefits	O
+of	O
+COX	O
+-	O
+2	O
+inhibitors	O
+vs	O
+non	O
+-	O
+selective	O
+NSAIDs	O
+:	O
+does	O
+their	O
+cardiovascular	O
+risk	O
+exceed	O
+their	O
+gastrointestinal	O
+benefit	O
+?	O
+
+A	O
+retrospective	O
+cohort	O
+study	O
+.	O
+
+OBJECTIVES	O
+:	O
+The	O
+risk	O
+of	O
+acute	B
+myocardial	I
+infarction	I
+(	O
+AMI	B
+)	O
+with	O
+COX	O
+-	O
+2	O
+inhibitors	O
+may	O
+offset	O
+their	O
+gastrointestinal	O
+(	O
+GI	O
+)	O
+benefit	O
+compared	O
+with	O
+non	O
+-	O
+selective	O
+(	O
+NS	O
+)	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+(	O
+NSAIDs	O
+)	O
+.	O
+
+We	O
+aimed	O
+to	O
+compare	O
+the	O
+risks	O
+of	O
+hospitalization	O
+for	O
+AMI	B
+and	O
+GI	B
+bleeding	I
+among	O
+elderly	O
+patients	O
+using	O
+COX	O
+-	O
+2	O
+inhibitors	O
+,	O
+NS	O
+-	O
+NSAIDs	O
+and	O
+acetaminophen	O
+.	O
+
+METHODS	O
+:	O
+We	O
+conducted	O
+a	O
+retrospective	O
+cohort	O
+study	O
+using	O
+administrative	O
+data	O
+of	O
+patients	O
+>	O
+or	O
+=	O
+65	O
+years	O
+of	O
+age	O
+who	O
+filled	O
+a	O
+prescription	O
+for	O
+NSAID	O
+or	O
+acetaminophen	O
+during	O
+1999	O
+-	O
+2002	O
+.	O
+
+Outcomes	O
+were	O
+compared	O
+using	O
+Cox	O
+regression	O
+models	O
+with	O
+time	O
+-	O
+dependent	O
+exposures	O
+.	O
+
+RESULTS	O
+:	O
+Person	O
+-	O
+years	O
+of	O
+exposure	O
+among	O
+non	O
+-	O
+users	O
+of	O
+aspirin	O
+were	O
+:	O
+75	O
+,	O
+761	O
+to	O
+acetaminophen	O
+,	O
+42	O
+,	O
+671	O
+to	O
+rofecoxib	O
+65	O
+,	O
+860	O
+to	O
+celecoxib	O
+,	O
+and	O
+37	O
+,	O
+495	O
+to	O
+NS	O
+-	O
+NSAIDs	O
+.	O
+
+Among	O
+users	O
+of	O
+aspirin	O
+,	O
+they	O
+were	O
+:	O
+14	O
+,	O
+671	O
+to	O
+rofecoxib	O
+,	O
+22	O
+,	O
+875	O
+to	O
+celecoxib	O
+,	O
+9	O
+,	O
+832	O
+to	O
+NS	O
+-	O
+NSAIDs	O
+and	O
+38	O
+,	O
+048	O
+to	O
+acetaminophen	O
+.	O
+
+Among	O
+non	O
+-	O
+users	O
+of	O
+aspirin	O
+,	O
+the	O
+adjusted	O
+hazard	O
+ratios	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+)	O
+of	O
+hospitalization	O
+for	O
+AMI	B
+/	O
+GI	O
+vs	O
+the	O
+acetaminophen	O
+(	O
+with	O
+no	O
+aspirin	O
+)	O
+group	O
+were	O
+:	O
+rofecoxib	O
+1	O
+.	O
+27	O
+(	O
+1	O
+.	O
+13	O
+,	O
+1	O
+.	O
+42	O
+)	O
+,	O
+celecoxib	O
+0	O
+.	O
+93	O
+(	O
+0	O
+.	O
+83	O
+,	O
+1	O
+.	O
+03	O
+)	O
+,	O
+naproxen	O
+1	O
+.	O
+59	O
+(	O
+1	O
+.	O
+31	O
+,	O
+1	O
+.	O
+93	O
+)	O
+,	O
+diclofenac	O
+1	O
+.	O
+17	O
+(	O
+0	O
+.	O
+99	O
+,	O
+1	O
+.	O
+38	O
+)	O
+and	O
+ibuprofen	O
+1	O
+.	O
+05	O
+(	O
+0	O
+.	O
+74	O
+,	O
+1	O
+.	O
+51	O
+)	O
+.	O
+
+Among	O
+users	O
+of	O
+aspirin	O
+,	O
+they	O
+were	O
+:	O
+rofecoxib	O
+1	O
+.	O
+73	O
+(	O
+1	O
+.	O
+52	O
+,	O
+1	O
+.	O
+98	O
+)	O
+,	O
+celecoxib	O
+1	O
+.	O
+34	O
+(	O
+1	O
+.	O
+19	O
+,	O
+1	O
+.	O
+52	O
+)	O
+,	O
+ibuprofen	O
+1	O
+.	O
+51	O
+(	O
+0	O
+.	O
+95	O
+,	O
+2	O
+.	O
+41	O
+)	O
+,	O
+diclofenac	O
+1	O
+.	O
+69	O
+(	O
+1	O
+.	O
+35	O
+,	O
+2	O
+.	O
+10	O
+)	O
+,	O
+naproxen	O
+1	O
+.	O
+35	O
+(	O
+0	O
+.	O
+97	O
+,	O
+1	O
+.	O
+88	O
+)	O
+and	O
+acetaminophen	O
+1	O
+.	O
+29	O
+(	O
+1	O
+.	O
+17	O
+,	O
+1	O
+.	O
+42	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+Among	O
+non	O
+-	O
+users	O
+of	O
+aspirin	O
+,	O
+naproxen	O
+seemed	O
+to	O
+carry	O
+the	O
+highest	O
+risk	O
+for	O
+AMI	B
+/	O
+GI	B
+bleeding	I
+.	O
+
+The	O
+AMI	B
+/	O
+GI	O
+toxicity	B
+of	O
+celecoxib	O
+was	O
+similar	O
+to	O
+that	O
+of	O
+acetaminophen	O
+and	O
+seemed	O
+to	O
+be	O
+better	O
+than	O
+those	O
+of	O
+rofecoxib	O
+and	O
+NS	O
+-	O
+NSAIDs	O
+.	O
+
+Among	O
+users	O
+of	O
+aspirin	O
+,	O
+both	O
+celecoxib	O
+and	O
+naproxen	O
+seemed	O
+to	O
+be	O
+the	O
+least	O
+toxic	O
+.	O
+
+Quinine	O
+-	O
+induced	O
+arrhythmia	B
+in	O
+a	O
+patient	O
+with	O
+severe	B
+malaria	I
+.	O
+
+It	O
+was	O
+reported	O
+that	O
+there	O
+was	O
+a	O
+case	O
+of	O
+severe	B
+malaria	I
+patient	O
+with	O
+jaundice	B
+who	O
+presented	O
+with	O
+arrhythmia	B
+(	O
+premature	B
+ventricular	I
+contraction	I
+)	O
+while	O
+getting	O
+quinine	O
+infusion	O
+was	O
+reported	O
+.	O
+
+A	O
+man	O
+,	O
+25	O
+years	O
+old	O
+,	O
+was	O
+admitted	O
+to	O
+hospital	O
+with	O
+high	O
+fever	B
+,	O
+chill	B
+,	O
+vomiting	B
+,	O
+jaundice	B
+.	O
+
+The	O
+patient	O
+was	O
+fully	O
+conscious	O
+,	O
+blood	O
+pressure	O
+120	O
+/	O
+80	O
+mmHg	O
+,	O
+pulse	O
+rate	O
+100	O
+x	O
+/	O
+minute	O
+,	O
+regular	O
+.	O
+
+On	O
+admission	O
+,	O
+laboratory	O
+examination	O
+showed	O
+Plasmodium	O
+falciparum	O
+(	O
++	O
++	O
++	O
++	O
+)	O
+,	O
+total	O
+bilirubin	O
+8	O
+.	O
+25	O
+mg	O
+/	O
+dL	O
+,	O
+conjugated	O
+bilirubin	O
+4	O
+.	O
+36	O
+mg	O
+/	O
+dL	O
+,	O
+unconjugated	O
+bilirubin	O
+3	O
+.	O
+89	O
+mg	O
+/	O
+dL	O
+,	O
+potassium	O
+3	O
+.	O
+52	O
+meq	O
+/	O
+L	O
+Patient	O
+was	O
+diagnosed	O
+as	O
+severe	B
+malaria	I
+with	O
+jaundice	B
+and	O
+got	O
+quinine	O
+infusion	O
+in	O
+dextrose	O
+5	O
+%	O
+500	O
+mg	O
+/	O
+8	O
+hour	O
+.	O
+
+On	O
+the	O
+second	O
+day	O
+the	O
+patient	O
+had	O
+vomitus	B
+,	O
+diarrhea	B
+,	O
+tinnitus	B
+,	O
+loss	B
+of	I
+hearing	I
+.	O
+
+After	O
+30	O
+hours	O
+of	O
+quinine	O
+infusion	O
+the	O
+patient	O
+felt	O
+palpitation	B
+and	O
+electrocardiography	O
+(	O
+ECG	O
+)	O
+recording	O
+showed	O
+premature	B
+ventricular	I
+contraction	I
+(	O
+PVC	B
+)	O
+>	O
+5	O
+x	O
+/	O
+minute	O
+,	O
+trigemini	O
+,	O
+constant	O
+type	O
+-	O
+-	O
+sinoatrial	B
+block	I
+,	O
+positive	O
+U	O
+wave	O
+.	O
+
+He	O
+was	O
+treated	O
+with	O
+lidocaine	O
+50	O
+mg	O
+intravenously	O
+followed	O
+by	O
+infusion	O
+1500	O
+mg	O
+in	O
+dextrose	O
+5	O
+%	O
+/	O
+24	O
+hour	O
+and	O
+potassium	O
+aspartate	O
+tablet	O
+.	O
+
+Quinine	O
+infusion	O
+was	O
+discontinued	O
+and	O
+changed	O
+with	O
+sulfate	O
+quinine	O
+tablets	O
+.	O
+
+Three	O
+hours	O
+later	O
+the	O
+patient	O
+felt	O
+better	O
+,	O
+the	O
+frequency	O
+of	O
+PVC	B
+reduced	O
+to	O
+4	O
+-	O
+5	O
+x	O
+/	O
+minute	O
+and	O
+on	O
+the	O
+third	O
+day	O
+ECG	O
+was	O
+normal	O
+,	O
+potassium	O
+level	O
+was	O
+3	O
+.	O
+34	O
+meq	O
+/	O
+L	O
+.	O
+
+He	O
+was	O
+discharged	O
+on	O
+7th	O
+day	O
+in	O
+good	O
+condition	O
+.	O
+
+Quinine	O
+,	O
+like	O
+quinidine	O
+,	O
+is	O
+a	O
+chincona	O
+alkaloid	O
+that	O
+has	O
+anti	O
+-	O
+arrhythmic	B
+property	O
+,	O
+although	O
+it	O
+also	O
+pro	O
+-	O
+arrhythmic	B
+that	O
+can	O
+cause	O
+various	O
+arrhythmias	B
+,	O
+including	O
+severe	O
+arrhythmia	B
+such	O
+as	O
+multiple	O
+PVC	B
+.	O
+
+Administration	O
+of	O
+parenteral	O
+quinine	O
+must	O
+be	O
+done	O
+carefully	O
+and	O
+with	O
+good	O
+observation	O
+because	O
+of	O
+its	O
+pro	O
+-	O
+arrhythmic	B
+effect	O
+,	O
+especially	O
+in	O
+older	O
+patients	O
+who	O
+have	O
+heart	B
+diseases	I
+or	O
+patients	O
+with	O
+electrolyte	B
+disorder	I
+(	O
+hypokalemia	B
+)	O
+which	O
+frequently	O
+occurs	O
+due	O
+to	O
+vomiting	B
+and	O
+or	O
+diarrhea	B
+in	O
+malaria	B
+cases	O
+.	O
+
+Penicillamine	O
+-	O
+related	O
+lichenoid	B
+dermatitis	I
+and	O
+utility	O
+of	O
+zinc	O
+acetate	O
+in	O
+a	O
+Wilson	B
+disease	I
+patient	O
+with	O
+hepatic	O
+presentation	O
+,	O
+anxiety	B
+and	O
+SPECT	O
+abnormalities	O
+.	O
+
+Wilson	B
+'	I
+s	I
+disease	I
+is	O
+an	O
+autosomal	O
+recessive	O
+disorder	O
+of	O
+hepatic	O
+copper	O
+metabolism	O
+with	O
+consequent	O
+copper	O
+accumulation	O
+and	O
+toxicity	B
+in	O
+many	O
+tissues	O
+and	O
+consequent	O
+hepatic	B
+,	I
+neurologic	I
+and	I
+psychiatric	I
+disorders	I
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+Wilson	B
+'	I
+s	I
+disease	I
+with	O
+chronic	B
+liver	I
+disease	I
+;	O
+moreover	O
+,	O
+in	O
+our	O
+patient	O
+,	O
+presenting	O
+also	O
+with	O
+high	O
+levels	O
+of	O
+state	O
+anxiety	B
+without	O
+depression	B
+,	O
+99mTc	O
+-	O
+ECD	O
+-	O
+SPECT	O
+showed	O
+cortical	O
+hypoperfusion	O
+in	O
+frontal	O
+lobes	O
+,	O
+more	O
+marked	O
+on	O
+the	O
+left	O
+frontal	O
+lobe	O
+.	O
+
+During	O
+the	O
+follow	O
+-	O
+up	O
+of	O
+our	O
+patient	O
+,	O
+penicillamine	O
+was	O
+interrupted	O
+after	O
+the	O
+appearance	O
+of	O
+a	O
+lichenoid	B
+dermatitis	I
+,	O
+and	O
+zinc	O
+acetate	O
+permitted	O
+to	O
+continue	O
+the	O
+successful	O
+treatment	O
+of	O
+the	O
+patient	O
+without	O
+side	O
+-	O
+effects	O
+.	O
+
+In	O
+our	O
+case	O
+the	O
+therapy	O
+with	O
+zinc	O
+acetate	O
+represented	O
+an	O
+effective	O
+treatment	O
+for	O
+a	O
+Wilson	B
+'	I
+s	I
+disease	I
+patient	O
+in	O
+which	O
+penicillamine	O
+-	O
+related	O
+side	O
+effects	O
+appeared	O
+.	O
+
+The	O
+safety	O
+of	O
+the	O
+zinc	O
+acetate	O
+allowed	O
+us	O
+to	O
+avoid	O
+other	O
+potentially	O
+toxic	O
+chelating	O
+drugs	O
+;	O
+this	O
+observation	O
+is	O
+in	O
+line	O
+with	O
+the	O
+growing	O
+evidence	O
+on	O
+the	O
+efficacy	O
+of	O
+the	O
+drug	O
+in	O
+the	O
+treatment	O
+of	O
+Wilson	B
+'	I
+s	I
+disease	I
+.	O
+
+Since	O
+most	O
+of	O
+Wilson	B
+'	I
+s	I
+disease	I
+penicillamine	O
+-	O
+treated	O
+patients	O
+do	O
+not	O
+seem	O
+to	O
+develop	O
+this	O
+skin	B
+lesion	I
+,	O
+it	O
+could	O
+be	O
+conceivable	O
+that	O
+a	O
+specific	O
+genetic	O
+factor	O
+is	O
+involved	O
+in	O
+drug	O
+response	O
+.	O
+
+Further	O
+studies	O
+are	O
+needed	O
+for	O
+a	O
+better	O
+clarification	O
+of	O
+Wilson	B
+'	I
+s	I
+disease	I
+therapy	O
+,	O
+and	O
+in	O
+particular	O
+to	O
+differentiate	O
+specific	O
+therapies	O
+for	O
+different	O
+Wilson	B
+'	I
+s	I
+disease	I
+phenotypes	O
+.	O
+
+A	O
+dramatic	O
+drop	B
+in	I
+blood	I
+pressure	I
+following	O
+prehospital	O
+GTN	O
+administration	O
+.	O
+
+A	O
+male	O
+in	O
+his	O
+sixties	O
+with	O
+no	O
+history	O
+of	O
+cardiac	O
+chest	B
+pain	I
+awoke	O
+with	O
+chest	B
+pain	I
+following	O
+an	O
+afternoon	O
+sleep	O
+.	O
+
+The	O
+patient	O
+did	O
+not	O
+self	O
+medicate	O
+.	O
+
+The	O
+patient	O
+'	O
+s	O
+observations	O
+were	O
+within	O
+normal	O
+limits	O
+,	O
+he	O
+was	O
+administered	O
+oxygen	O
+via	O
+a	O
+face	O
+mask	O
+and	O
+glyceryl	O
+trinitrate	O
+(	O
+GTN	O
+)	O
+.	O
+
+Several	O
+minutes	O
+after	O
+the	O
+GTN	O
+the	O
+patient	O
+experienced	O
+a	O
+sudden	O
+drop	B
+in	I
+blood	I
+pressure	I
+and	O
+heart	O
+rate	O
+,	O
+this	O
+was	O
+rectified	O
+by	O
+atropine	O
+sulphate	O
+and	O
+a	O
+fluid	O
+challenge	O
+.	O
+
+There	O
+was	O
+no	O
+further	O
+deterioration	O
+in	O
+the	O
+patient	O
+'	O
+s	O
+condition	O
+during	O
+transport	O
+to	O
+hospital	O
+.	O
+
+There	O
+are	O
+very	O
+few	O
+documented	O
+case	O
+like	O
+this	O
+in	O
+the	O
+prehospital	O
+scientific	O
+literature	O
+.	O
+
+The	O
+cause	O
+appears	O
+to	O
+be	O
+the	O
+Bezold	O
+-	O
+Jarish	O
+reflex	O
+,	O
+stimulation	O
+of	O
+the	O
+ventricular	O
+walls	O
+which	O
+in	O
+turn	O
+decreases	O
+sympathetic	O
+outflow	O
+from	O
+the	O
+vasomotor	O
+centre	O
+.	O
+
+Prehospital	O
+care	O
+providers	O
+who	O
+are	O
+managing	O
+any	O
+patient	O
+with	O
+a	O
+syncopal	B
+episode	I
+that	O
+fails	O
+to	O
+recover	O
+within	O
+a	O
+reasonable	O
+time	O
+frame	O
+should	O
+consider	O
+the	O
+Bezold	O
+-	O
+Jarisch	O
+reflex	O
+as	O
+the	O
+cause	O
+and	O
+manage	O
+the	O
+patient	O
+accordingly	O
+.	O
+
+Chronic	O
+lesion	O
+of	O
+rostral	O
+ventrolateral	O
+medulla	O
+in	O
+spontaneously	O
+hypertensive	B
+rats	O
+.	O
+
+We	O
+studied	O
+the	O
+effects	O
+of	O
+chronic	O
+selective	O
+neuronal	O
+lesion	O
+of	O
+rostral	O
+ventrolateral	O
+medulla	O
+on	O
+mean	O
+arterial	O
+pressure	O
+,	O
+heart	O
+rate	O
+,	O
+and	O
+neurogenic	O
+tone	O
+in	O
+conscious	O
+,	O
+unrestrained	O
+spontaneously	O
+hypertensive	B
+rats	O
+.	O
+
+The	O
+lesions	O
+were	O
+placed	O
+via	O
+bilateral	O
+microinjections	O
+of	O
+30	O
+nmol	O
+/	O
+200	O
+nl	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartic	O
+acid	O
+.	O
+
+The	O
+restimulation	O
+of	O
+this	O
+area	O
+with	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartic	O
+acid	O
+15	O
+days	O
+postlesion	O
+failed	O
+to	O
+produce	O
+a	O
+pressor	O
+response	O
+.	O
+
+One	O
+day	O
+postlesion	O
+,	O
+the	O
+resting	O
+mean	O
+arterial	O
+pressure	O
+was	O
+significantly	O
+decreased	O
+in	O
+lesioned	O
+rats	O
+when	O
+compared	O
+with	O
+sham	O
+rats	O
+(	O
+100	O
++	O
+/	O
+-	O
+7	O
+versus	O
+173	O
++	O
+/	O
+-	O
+4	O
+mm	O
+Hg	O
+,	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Fifteen	O
+days	O
+later	O
+,	O
+the	O
+lesioned	O
+group	O
+still	O
+showed	O
+values	O
+significantly	O
+lower	O
+than	O
+the	O
+sham	O
+group	O
+(	O
+150	O
++	O
+/	O
+-	O
+6	O
+versus	O
+167	O
++	O
+/	O
+-	O
+5	O
+mm	O
+Hg	O
+,	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+No	O
+significant	O
+heart	O
+rate	O
+differences	O
+were	O
+observed	O
+between	O
+the	O
+sham	O
+and	O
+lesioned	O
+groups	O
+.	O
+
+The	O
+ganglionic	O
+blocker	O
+trimethaphan	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+caused	O
+similar	O
+reductions	O
+in	O
+mean	O
+arterial	O
+pressure	O
+in	O
+both	O
+lesioned	O
+and	O
+sham	O
+groups	O
+.	O
+
+The	O
+trimethaphan	O
+-	O
+induced	O
+hypotension	B
+was	O
+accompanied	O
+by	O
+a	O
+significant	O
+bradycardia	B
+in	O
+lesioned	O
+rats	O
+(	O
+-	O
+32	O
++	O
+/	O
+-	O
+13	O
+beats	O
+per	O
+minute	O
+)	O
+but	O
+a	O
+tachycardia	B
+in	O
+sham	O
+rats	O
+(	O
++	O
+33	O
++	O
+/	O
+-	O
+12	O
+beats	O
+per	O
+minute	O
+)	O
+1	O
+day	O
+postlesion	O
+.	O
+
+Therefore	O
+,	O
+rostral	O
+ventrolateral	O
+medulla	O
+neurons	O
+appear	O
+to	O
+play	O
+a	O
+significant	O
+role	O
+in	O
+maintaining	O
+hypertension	B
+in	O
+conscious	O
+spontaneously	O
+hypertensive	B
+rats	O
+.	O
+
+Spinal	O
+or	O
+suprabulbar	O
+structures	O
+could	O
+be	O
+responsible	O
+for	O
+the	O
+gradual	O
+recovery	O
+of	O
+the	O
+hypertension	B
+in	O
+the	O
+lesioned	O
+rats	O
+.	O
+
+Acute	B
+encephalopathy	I
+and	O
+cerebral	B
+vasospasm	I
+after	O
+multiagent	O
+chemotherapy	O
+including	O
+PEG	O
+-	O
+asparaginase	O
+and	O
+intrathecal	O
+cytarabine	O
+for	O
+the	O
+treatment	O
+of	O
+acute	B
+lymphoblastic	I
+leukemia	I
+.	O
+
+A	O
+7	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+with	O
+an	O
+unusual	O
+reaction	O
+to	O
+induction	O
+chemotherapy	O
+for	O
+precursor	O
+B	O
+-	O
+cell	O
+acute	B
+lymphoblastic	I
+leukemia	I
+(	O
+ALL	B
+)	O
+is	O
+described	O
+.	O
+
+The	O
+patient	O
+developed	O
+acute	B
+encephalopathy	I
+evidenced	O
+by	O
+behavioral	O
+changes	O
+,	O
+aphasia	B
+,	O
+incontinence	B
+,	O
+visual	B
+hallucinations	I
+,	O
+and	O
+right	O
+-	O
+sided	O
+weakness	B
+with	O
+diffuse	O
+cerebral	B
+vasospasm	I
+on	O
+magnetic	O
+resonance	O
+angiography	O
+after	O
+the	O
+administration	O
+of	O
+intrathecal	O
+cytarabine	O
+.	O
+
+Vincristine	O
+,	O
+dexamethasone	O
+,	O
+and	O
+polyethylene	O
+glycol	O
+-	O
+asparaginase	O
+were	O
+also	O
+administered	O
+before	O
+the	O
+episode	O
+as	O
+part	O
+of	O
+induction	O
+therapy	O
+.	O
+
+Neurologic	O
+status	O
+returned	O
+to	O
+baseline	O
+within	O
+10	O
+days	O
+of	O
+the	O
+acute	O
+event	O
+,	O
+and	O
+magnetic	O
+resonance	O
+angiography	O
+findings	O
+returned	O
+to	O
+normal	O
+4	O
+months	O
+later	O
+.	O
+
+Comparison	O
+of	O
+valsartan	O
+/	O
+hydrochlorothiazide	O
+combination	O
+therapy	O
+at	O
+doses	O
+up	O
+to	O
+320	O
+/	O
+25	O
+mg	O
+versus	O
+monotherapy	O
+:	O
+a	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+study	O
+followed	O
+by	O
+long	O
+-	O
+term	O
+combination	O
+therapy	O
+in	O
+hypertensive	B
+adults	O
+.	O
+
+BACKGROUND	O
+:	O
+One	O
+third	O
+of	O
+patients	O
+treated	O
+for	O
+hypertension	B
+attain	O
+adequate	O
+blood	O
+pressure	O
+(	O
+BP	O
+)	O
+control	O
+,	O
+and	O
+multidrug	O
+regimens	O
+are	O
+often	O
+required	O
+.	O
+
+Given	O
+the	O
+lifelong	O
+nature	O
+of	O
+hypertension	B
+,	O
+there	O
+is	O
+a	O
+need	O
+to	O
+evaluate	O
+the	O
+long	O
+-	O
+term	O
+efficacy	O
+and	O
+tolerability	O
+of	O
+higher	O
+doses	O
+of	O
+combination	O
+anti	O
+-	O
+hypertensive	B
+therapies	O
+.	O
+
+OBJECTIVE	O
+:	O
+This	O
+study	O
+investigated	O
+the	O
+efficacy	O
+and	O
+tolerability	O
+of	O
+valsartan	O
+(	O
+VAL	O
+)	O
+or	O
+hydrochlorothiazide	O
+(	O
+HCTZ	O
+)	O
+-	O
+monotherapy	O
+and	O
+higher	O
+-	O
+dose	O
+combinations	O
+in	O
+patients	O
+with	O
+essential	B
+hypertension	I
+.	O
+
+METHODS	O
+:	O
+The	O
+first	O
+part	O
+of	O
+this	O
+study	O
+was	O
+an	O
+8	O
+-	O
+week	O
+,	O
+multicenter	O
+,	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+controlled	O
+,	O
+parallel	O
+-	O
+group	O
+trial	O
+.	O
+
+Patients	O
+with	O
+essential	B
+hypertension	I
+(	O
+mean	O
+sitting	O
+diastolic	O
+BP	O
+[	O
+MSDBP	O
+]	O
+,	O
+>	O
+or	O
+=	O
+95	O
+mm	O
+Hg	O
+and	O
+<	O
+110	O
+mm	O
+Hg	O
+)	O
+were	O
+randomized	O
+to	O
+1	O
+of	O
+8	O
+treatment	O
+groups	O
+:	O
+VAL	O
+160	O
+or	O
+320	O
+mg	O
+;	O
+HCTZ	O
+12	O
+.	O
+5	O
+or	O
+25	O
+mg	O
+;	O
+VAL	O
+/	O
+HCTZ	O
+160	O
+/	O
+12	O
+.	O
+5	O
+,	O
+320	O
+/	O
+12	O
+.	O
+5	O
+,	O
+or	O
+320	O
+/	O
+25	O
+mg	O
+;	O
+or	O
+placebo	O
+.	O
+
+Mean	O
+changes	O
+in	O
+MSDBP	O
+and	O
+mean	O
+sitting	O
+systolic	O
+BP	O
+(	O
+MSSBP	O
+)	O
+were	O
+analyzed	O
+at	O
+the	O
+8	O
+-	O
+week	O
+core	O
+study	O
+end	O
+point	O
+.	O
+
+VAL	O
+/	O
+HCTZ	O
+320	O
+/	O
+12	O
+.	O
+5	O
+and	O
+320	O
+/	O
+25	O
+mg	O
+were	O
+further	O
+investigated	O
+in	O
+a	O
+54	O
+-	O
+week	O
+,	O
+open	O
+-	O
+label	O
+extension	O
+.	O
+
+Response	O
+was	O
+defined	O
+as	O
+MSDBP	O
+<	O
+90	O
+mm	O
+Hg	O
+or	O
+a	O
+>	O
+or	O
+=	O
+10	O
+mm	O
+Hg	O
+decrease	O
+compared	O
+to	O
+baseline	O
+.	O
+
+Control	O
+was	O
+defined	O
+as	O
+MSDBP	O
+<	O
+90	O
+mm	O
+Hg	O
+compared	O
+with	O
+baseline	O
+.	O
+
+Tolerability	O
+was	O
+assessed	O
+by	O
+monitoring	O
+adverse	O
+events	O
+at	O
+randomization	O
+and	O
+all	O
+subsequent	O
+study	O
+visits	O
+and	O
+regular	O
+evaluation	O
+of	O
+hematology	O
+and	O
+blood	O
+chemistry	O
+.	O
+
+RESULTS	O
+:	O
+A	O
+total	O
+of	O
+1346	O
+patients	O
+were	O
+randomized	O
+into	O
+the	O
+8	O
+-	O
+week	O
+core	O
+study	O
+(	O
+734	O
+men	O
+,	O
+612	O
+women	O
+;	O
+924	O
+white	O
+,	O
+291	O
+black	O
+,	O
+23	O
+Asian	O
+,	O
+108	O
+other	O
+;	O
+mean	O
+age	O
+,	O
+52	O
+.	O
+7	O
+years	O
+;	O
+mean	O
+weight	O
+,	O
+92	O
+.	O
+6	O
+kg	O
+)	O
+.	O
+
+All	O
+active	O
+treatments	O
+were	O
+associated	O
+with	O
+significantly	O
+reduced	O
+MSSBP	O
+and	O
+MSDBP	O
+during	O
+the	O
+core	O
+8	O
+-	O
+week	O
+study	O
+,	O
+with	O
+each	O
+monotherapy	O
+significantly	O
+contributing	O
+to	O
+the	O
+overall	O
+effect	O
+of	O
+combination	O
+therapy	O
+(	O
+VAL	O
+and	O
+HCTZ	O
+,	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Each	O
+combination	O
+was	O
+associated	O
+with	O
+significantly	O
+greater	O
+reductions	O
+in	O
+MSSBP	O
+and	O
+MSDBP	O
+compared	O
+with	O
+the	O
+monotherapies	O
+and	O
+placebo	O
+(	O
+all	O
+,	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+The	O
+mean	O
+reduction	O
+in	O
+MSSBP	O
+/	O
+MSDBP	O
+with	O
+VAL	O
+/	O
+HCTZ	O
+320	O
+/	O
+25	O
+mg	O
+was	O
+24	O
+.	O
+7	O
+/	O
+16	O
+.	O
+6	O
+mm	O
+Hg	O
+,	O
+compared	O
+with	O
+5	O
+.	O
+9	O
+/	O
+7	O
+.	O
+0	O
+mm	O
+Hg	O
+with	O
+placebo	O
+.	O
+
+The	O
+reduction	O
+in	O
+MSSBP	O
+was	O
+significantly	O
+greater	O
+with	O
+VAL	O
+/	O
+HCTZ	O
+320	O
+/	O
+25	O
+mg	O
+compared	O
+with	O
+VAL	O
+/	O
+HCTZ	O
+160	O
+/	O
+12	O
+.	O
+5	O
+mg	O
+(	O
+P	O
+<	O
+0	O
+.	O
+002	O
+)	O
+.	O
+
+Rates	O
+of	O
+response	O
+and	O
+BP	O
+control	O
+were	O
+significantly	O
+higher	O
+in	O
+the	O
+groups	O
+that	O
+received	O
+combination	O
+treatment	O
+compared	O
+with	O
+those	O
+that	O
+received	O
+monotherapy	O
+.	O
+
+The	O
+incidence	O
+of	O
+hypokalemia	B
+was	O
+lower	O
+with	O
+VAL	O
+/	O
+HCTZ	O
+combinations	O
+(	O
+1	O
+.	O
+8	O
+%	O
+-	O
+6	O
+.	O
+1	O
+%	O
+)	O
+than	O
+with	O
+HCTZ	O
+monotherapies	O
+(	O
+7	O
+.	O
+1	O
+%	O
+-	O
+13	O
+.	O
+3	O
+%	O
+)	O
+.	O
+
+The	O
+majority	O
+of	O
+adverse	O
+events	O
+in	O
+the	O
+core	O
+study	O
+were	O
+of	O
+mild	O
+to	O
+moderate	O
+severity	O
+.	O
+
+The	O
+efficacy	O
+and	O
+tolerability	O
+of	O
+VAL	O
+/	O
+HCTZ	O
+combinations	O
+were	O
+maintained	O
+during	O
+the	O
+extension	O
+(	O
+797	O
+patients	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+In	O
+this	O
+study	O
+population	O
+,	O
+combination	O
+therapies	O
+with	O
+VAL	O
+/	O
+HCTZ	O
+were	O
+associated	O
+with	O
+significantly	O
+greater	O
+BP	O
+reductions	O
+compared	O
+with	O
+either	O
+monotherapy	O
+,	O
+were	O
+well	O
+tolerated	O
+,	O
+and	O
+were	O
+associated	O
+with	O
+less	O
+hypokalemia	B
+than	O
+HCTZ	O
+alone	O
+.	O
+
+Succimer	O
+chelation	O
+improves	O
+learning	O
+,	O
+attention	O
+,	O
+and	O
+arousal	O
+regulation	O
+in	O
+lead	O
+-	O
+exposed	O
+rats	O
+but	O
+produces	O
+lasting	O
+cognitive	B
+impairment	I
+in	O
+the	O
+absence	O
+of	O
+lead	O
+exposure	O
+.	O
+
+BACKGROUND	O
+:	O
+There	O
+is	O
+growing	O
+pressure	O
+for	O
+clinicians	O
+to	O
+prescribe	O
+chelation	O
+therapy	O
+at	O
+only	O
+slightly	O
+elevated	O
+blood	O
+lead	O
+levels	O
+.	O
+
+However	O
+,	O
+very	O
+few	O
+studies	O
+have	O
+evaluated	O
+whether	O
+chelation	O
+improves	O
+cognitive	O
+outcomes	O
+in	O
+Pb	O
+-	O
+exposed	O
+children	O
+,	O
+or	O
+whether	O
+these	O
+agents	O
+have	O
+adverse	O
+effects	O
+that	O
+may	O
+affect	O
+brain	O
+development	O
+in	O
+the	O
+absence	O
+of	O
+Pb	O
+exposure	O
+.	O
+
+OBJECTIVES	O
+:	O
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+answer	O
+these	O
+questions	O
+,	O
+using	O
+a	O
+rodent	O
+model	O
+of	O
+early	O
+childhood	O
+Pb	O
+exposure	O
+and	O
+treatment	O
+with	O
+succimer	O
+,	O
+a	O
+widely	O
+used	O
+chelating	O
+agent	O
+for	O
+the	O
+treatment	O
+of	O
+Pb	B
+poisoning	I
+.	O
+
+RESULTS	O
+:	O
+Pb	O
+exposure	O
+produced	O
+lasting	O
+impairments	B
+in	I
+learning	I
+,	I
+attention	I
+,	I
+inhibitory	I
+control	I
+,	I
+and	I
+arousal	I
+regulation	I
+,	O
+paralleling	O
+the	O
+areas	O
+of	O
+dysfunction	O
+seen	O
+in	O
+Pb	O
+-	O
+exposed	O
+children	O
+.	O
+
+Succimer	O
+treatment	O
+of	O
+the	O
+Pb	O
+-	O
+exposed	O
+rats	O
+significantly	O
+improved	O
+learning	O
+,	O
+attention	O
+,	O
+and	O
+arousal	O
+regulation	O
+,	O
+although	O
+the	O
+efficacy	O
+of	O
+the	O
+treatment	O
+varied	O
+as	O
+a	O
+function	O
+of	O
+the	O
+Pb	O
+exposure	O
+level	O
+and	O
+the	O
+specific	O
+functional	O
+deficit	O
+.	O
+
+In	O
+contrast	O
+,	O
+succimer	O
+treatment	O
+of	O
+rats	O
+not	O
+previously	O
+exposed	O
+to	O
+Pb	O
+produced	O
+lasting	O
+and	O
+pervasive	O
+cognitive	B
+and	I
+affective	I
+dysfunction	I
+comparable	O
+in	O
+magnitude	O
+to	O
+that	O
+produced	O
+by	O
+the	O
+higher	O
+Pb	O
+exposure	O
+regimen	O
+.	O
+
+CONCLUSIONS	O
+:	O
+These	O
+are	O
+the	O
+first	O
+data	O
+,	O
+to	O
+our	O
+knowledge	O
+,	O
+to	O
+show	O
+that	O
+treatment	O
+with	O
+any	O
+chelating	O
+agent	O
+can	O
+alleviate	O
+cognitive	B
+deficits	I
+due	O
+to	O
+Pb	O
+exposure	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+it	O
+may	O
+be	O
+possible	O
+to	O
+identify	O
+a	O
+succimer	O
+treatment	O
+protocol	O
+that	O
+improves	O
+cognitive	O
+outcomes	O
+in	O
+Pb	O
+-	O
+exposed	O
+children	O
+.	O
+
+However	O
+,	O
+they	O
+also	O
+suggest	O
+that	O
+succimer	O
+treatment	O
+should	O
+be	O
+strongly	O
+discouraged	O
+for	O
+children	O
+who	O
+do	O
+not	O
+have	O
+elevated	O
+tissue	O
+levels	O
+of	O
+Pb	O
+or	O
+other	O
+heavy	O
+metals	O
+.	O
+
+Caffeine	O
+challenge	O
+test	O
+in	O
+panic	B
+disorder	I
+and	O
+depression	B
+with	O
+panic	B
+attacks	I
+.	O
+
+Our	O
+aim	O
+was	O
+to	O
+observe	O
+if	O
+patients	O
+with	O
+panic	B
+disorder	I
+(	O
+PD	B
+)	O
+and	O
+patients	O
+with	O
+major	B
+depression	I
+with	O
+panic	B
+attacks	I
+(	O
+MDP	B
+)	O
+(	O
+Diagnostic	O
+and	O
+Statistical	O
+Manual	O
+of	O
+Mental	B
+Disorders	I
+,	O
+Fourth	O
+Edition	O
+criteria	O
+)	O
+respond	O
+in	O
+a	O
+similar	O
+way	O
+to	O
+the	O
+induction	O
+of	O
+panic	B
+attacks	I
+by	O
+an	O
+oral	O
+caffeine	O
+challenge	O
+test	O
+.	O
+
+We	O
+randomly	O
+selected	O
+29	O
+patients	O
+with	O
+PD	B
+,	O
+27	O
+with	O
+MDP	B
+,	O
+25	O
+with	O
+major	B
+depression	I
+without	O
+panic	B
+attacks	I
+(	O
+MD	B
+)	O
+,	O
+and	O
+28	O
+healthy	O
+volunteers	O
+.	O
+
+The	O
+patients	O
+had	O
+no	O
+psychotropic	O
+drug	O
+for	O
+at	O
+least	O
+a	O
+4	O
+-	O
+week	O
+period	O
+.	O
+
+In	O
+a	O
+randomized	O
+double	O
+-	O
+blind	O
+experiment	O
+performed	O
+in	O
+2	O
+occasions	O
+7	O
+days	O
+apart	O
+,	O
+480	O
+mg	O
+caffeine	O
+and	O
+a	O
+caffeine	O
+-	O
+free	O
+(	O
+placebo	O
+)	O
+solution	O
+were	O
+administered	O
+in	O
+a	O
+coffee	O
+form	O
+and	O
+anxiety	B
+scales	O
+were	O
+applied	O
+before	O
+and	O
+after	O
+each	O
+test	O
+.	O
+
+A	O
+total	O
+of	O
+58	O
+.	O
+6	O
+%	O
+(	O
+n	O
+=	O
+17	O
+)	O
+of	O
+patients	O
+with	O
+PD	B
+,	O
+44	O
+.	O
+4	O
+%	O
+(	O
+n	O
+=	O
+12	O
+)	O
+of	O
+patients	O
+with	O
+MDP	B
+,	O
+12	O
+.	O
+0	O
+%	O
+(	O
+n	O
+=	O
+3	O
+)	O
+of	O
+patients	O
+with	O
+MD	B
+,	O
+and	O
+7	O
+.	O
+1	O
+%	O
+(	O
+n	O
+=	O
+2	O
+)	O
+of	O
+control	O
+subjects	O
+had	O
+a	O
+panic	B
+attack	I
+after	O
+the	O
+480	O
+-	O
+mg	O
+caffeine	O
+challenge	O
+test	O
+(	O
+chi	O
+(	O
+2	O
+)	O
+(	O
+3	O
+)	O
+=	O
+16	O
+.	O
+22	O
+,	O
+P	O
+=	O
+.	O
+001	O
+)	O
+.	O
+
+The	O
+patients	O
+with	O
+PD	B
+and	O
+MDP	B
+were	O
+more	O
+sensitive	O
+to	O
+caffeine	O
+than	O
+were	O
+patients	O
+with	O
+MD	B
+and	O
+healthy	O
+volunteers	O
+.	O
+
+No	O
+panic	B
+attack	I
+was	O
+observed	O
+after	O
+the	O
+caffeine	O
+-	O
+free	O
+solution	O
+intake	O
+.	O
+
+The	O
+patients	O
+with	O
+MD	B
+had	O
+a	O
+lower	O
+heart	O
+rate	O
+response	O
+to	O
+the	O
+test	O
+than	O
+all	O
+the	O
+other	O
+groups	O
+(	O
+2	O
+-	O
+way	O
+analysis	O
+of	O
+variance	O
+,	O
+group	O
+by	O
+time	O
+interaction	O
+with	O
+Greenhouse	O
+-	O
+Geisser	O
+correction	O
+:	O
+F	O
+(	O
+3	O
+,	O
+762	O
+)	O
+=	O
+2	O
+.	O
+85	O
+,	O
+P	O
+=	O
+.	O
+026	O
+)	O
+.	O
+
+Our	O
+data	O
+suggest	O
+that	O
+there	O
+is	O
+an	O
+association	O
+between	O
+panic	B
+attacks	I
+,	O
+no	O
+matter	O
+if	O
+associated	O
+with	O
+PD	B
+or	O
+MDP	B
+,	O
+and	O
+hyperreactivity	O
+to	O
+an	O
+oral	O
+caffeine	O
+challenge	O
+test	O
+.	O
+
+Mitral	O
+annuloplasty	O
+as	O
+a	O
+ventricular	O
+restoration	O
+method	O
+for	O
+the	O
+failing	B
+left	I
+ventricle	I
+:	O
+a	O
+pilot	O
+study	O
+.	O
+
+BACKGROUND	O
+AND	O
+AIM	O
+OF	O
+THE	O
+STUDY	O
+:	O
+Undersized	O
+mitral	O
+annuloplasty	O
+(	O
+MAP	O
+)	O
+is	O
+effective	O
+in	O
+patients	O
+with	O
+dilated	B
+cardiomyopathy	I
+and	O
+functional	O
+mitral	B
+regurgitation	I
+(	O
+MR	B
+)	O
+since	O
+,	O
+as	O
+well	O
+as	O
+addressing	O
+the	O
+MR	B
+,	O
+the	O
+MAP	O
+may	O
+also	O
+reshape	O
+the	O
+dilated	O
+left	O
+ventricular	O
+(	O
+LV	O
+)	O
+base	O
+.	O
+
+However	O
+,	O
+the	O
+direct	O
+benefits	O
+of	O
+this	O
+possible	O
+reshaping	O
+on	O
+LV	O
+function	O
+in	O
+the	O
+absence	O
+of	O
+underlying	O
+MR	B
+remain	O
+incompletely	O
+understood	O
+.	O
+
+The	O
+study	O
+aim	O
+was	O
+to	O
+identify	O
+these	O
+benefits	O
+in	O
+a	O
+canine	O
+model	O
+of	O
+acute	O
+heart	B
+failure	I
+.	O
+
+METHODS	O
+:	O
+Six	O
+dogs	O
+underwent	O
+MAP	O
+with	O
+a	O
+prosthetic	O
+band	O
+on	O
+the	O
+posterior	O
+mitral	O
+annulus	O
+,	O
+using	O
+four	O
+mattress	O
+sutures	O
+.	O
+
+The	O
+sutures	O
+were	O
+passed	O
+individually	O
+through	O
+four	O
+tourniquets	O
+and	O
+exteriorized	O
+untied	O
+via	O
+the	O
+left	O
+atriotomy	O
+.	O
+
+Sonomicrometry	O
+crystals	O
+were	O
+implanted	O
+around	O
+the	O
+mitral	O
+annulus	O
+and	O
+left	O
+ventricle	O
+to	O
+measure	O
+geometry	O
+and	O
+regional	O
+function	O
+.	O
+
+Acute	O
+heart	B
+failure	I
+was	O
+induced	O
+by	O
+propranolol	O
+and	O
+volume	O
+loading	O
+after	O
+weaning	O
+from	O
+cardiopulmonary	O
+bypass	O
+;	O
+an	O
+absence	O
+of	O
+MR	B
+was	O
+confirmed	O
+by	O
+echocardiography	O
+.	O
+
+MAP	O
+was	O
+accomplished	O
+by	O
+cinching	O
+the	O
+tourniquets	O
+.	O
+
+Data	O
+were	O
+acquired	O
+at	O
+baseline	O
+,	O
+after	O
+induction	O
+of	O
+acute	O
+heart	B
+failure	I
+,	O
+and	O
+after	O
+MAP	O
+.	O
+
+RESULTS	O
+:	O
+MAP	O
+decreased	O
+mitral	O
+annular	O
+dimensions	O
+in	O
+both	O
+commissure	O
+-	O
+commissure	O
+and	O
+septal	O
+-	O
+lateral	O
+directions	O
+.	O
+
+Concomitantly	O
+,	O
+the	O
+diastolic	O
+diameter	O
+of	O
+the	O
+LV	O
+base	O
+and	O
+LV	O
+sphericity	O
+decreased	O
+(	O
+i	O
+.	O
+e	O
+.	O
+,	O
+improved	O
+)	O
+from	O
+37	O
+.	O
+4	O
++	O
+/	O
+-	O
+9	O
+.	O
+3	O
+to	O
+35	O
+.	O
+9	O
++	O
+/	O
+-	O
+10	O
+mm	O
+(	O
+p	O
+=	O
+0	O
+.	O
+063	O
+)	O
+,	O
+and	O
+from	O
+67	O
+.	O
+9	O
++	O
+/	O
+-	O
+18	O
+.	O
+6	O
+%	O
+to	O
+65	O
+.	O
+3	O
++	O
+/	O
+-	O
+18	O
+.	O
+9	O
+%	O
+(	O
+p	O
+=	O
+0	O
+.	O
+016	O
+)	O
+,	O
+respectively	O
+.	O
+
+Decreases	O
+were	O
+evident	O
+in	O
+both	O
+LV	O
+end	O
+-	O
+diastolic	O
+pressure	O
+(	O
+from	O
+17	O
++	O
+/	O
+-	O
+7	O
+to	O
+15	O
++	O
+/	O
+-	O
+6	O
+mmHg	O
+,	O
+p	O
+=	O
+0	O
+.	O
+0480	O
+and	O
+Tau	O
+(	O
+from	O
+48	O
++	O
+/	O
+-	O
+8	O
+to	O
+45	O
++	O
+/	O
+-	O
+8	O
+ms	O
+,	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+,	O
+while	O
+fractional	O
+shortening	O
+at	O
+the	O
+LV	O
+base	O
+increased	O
+from	O
+7	O
+.	O
+7	O
++	O
+/	O
+-	O
+4	O
+.	O
+5	O
+%	O
+to	O
+9	O
+.	O
+4	O
++	O
+/	O
+-	O
+4	O
+.	O
+5	O
+%	O
+(	O
+p	O
+=	O
+0	O
+.	O
+045	O
+)	O
+.	O
+
+After	O
+MAP	O
+,	O
+increases	O
+were	O
+identified	O
+in	O
+both	O
+cardiac	O
+output	O
+(	O
+from	O
+1	O
+.	O
+54	O
++	O
+/	O
+-	O
+0	O
+.	O
+57	O
+to	O
+1	O
+.	O
+65	O
++	O
+/	O
+-	O
+0	O
+.	O
+57	O
+1	O
+/	O
+min	O
+)	O
+and	O
+Emax	O
+(	O
+from	O
+1	O
+.	O
+86	O
++	O
+/	O
+-	O
+0	O
+.	O
+9	O
+to	O
+2	O
+.	O
+41	O
++	O
+/	O
+-	O
+1	O
+.	O
+31	O
+mmHg	O
+/	O
+ml	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+data	O
+acquired	O
+suggest	O
+that	O
+isolated	O
+MAP	O
+may	O
+have	O
+certain	O
+benefits	O
+on	O
+LV	O
+dimension	O
+/	O
+function	O
+in	O
+acute	O
+heart	B
+failure	I
+,	O
+even	O
+in	O
+the	O
+absence	O
+of	O
+MR	B
+.	O
+
+However	O
+,	O
+further	O
+investigations	O
+are	O
+warranted	O
+in	O
+a	O
+model	O
+of	O
+chronic	O
+heart	B
+failure	I
+.	O
+
+Piperacillin	O
+/	O
+tazobactam	O
+-	O
+induced	O
+seizure	B
+rapidly	O
+reversed	O
+by	O
+high	O
+flux	O
+hemodialysis	O
+in	O
+a	O
+patient	O
+on	O
+peritoneal	O
+dialysis	O
+.	O
+
+Despite	O
+popular	O
+use	O
+of	O
+piperacillin	O
+,	O
+the	O
+dire	O
+neurotoxicity	B
+associated	O
+with	O
+piperacillin	O
+still	O
+goes	O
+unrecognized	O
+,	O
+leading	O
+to	O
+a	O
+delay	O
+in	O
+appropriate	O
+management	O
+.	O
+
+We	O
+report	O
+a	O
+57	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+end	B
+-	I
+stage	I
+renal	I
+disease	I
+receiving	O
+continuous	O
+ambulatory	O
+peritoneal	O
+dialysis	O
+(	O
+CAPD	O
+)	O
+,	O
+who	O
+developed	O
+slurred	O
+speech	O
+,	O
+tremor	B
+,	O
+bizarre	O
+behavior	O
+,	O
+progressive	O
+mental	O
+confusion	B
+,	O
+and	O
+2	O
+episodes	O
+of	O
+generalized	O
+tonic	B
+-	I
+clonic	I
+seizure	I
+(	O
+GTCS	B
+)	O
+after	O
+5	O
+doses	O
+of	O
+piperacillin	O
+/	O
+tazobactam	O
+(	O
+2	O
+g	O
+/	O
+250	O
+mg	O
+)	O
+were	O
+given	O
+for	O
+bronchiectasis	B
+with	O
+secondary	B
+infection	I
+.	O
+
+The	O
+laboratory	O
+data	O
+revealed	O
+normal	O
+plasma	O
+electrolyte	O
+and	O
+ammonia	O
+levels	O
+but	O
+leukocytosis	B
+.	O
+
+Neurologic	O
+examinations	O
+showed	O
+dysarthria	B
+and	O
+bilateral	O
+Babinski	O
+sign	O
+.	O
+
+Computed	O
+tomography	O
+of	O
+brain	O
+and	O
+electroencephalogram	O
+were	O
+unremarkable	O
+.	O
+
+Despite	O
+the	O
+use	O
+of	O
+antiepileptic	O
+agents	O
+,	O
+another	O
+GTCS	B
+episode	O
+recurred	O
+after	O
+the	O
+sixth	O
+dose	O
+of	O
+piperacillin	O
+/	O
+tazobactam	O
+.	O
+
+Brain	O
+magnetic	O
+resonance	O
+imaging	O
+did	O
+not	O
+demonstrate	O
+acute	O
+infarction	B
+and	O
+organic	B
+brain	I
+lesions	I
+.	O
+
+Initiation	O
+of	O
+high	O
+-	O
+flux	O
+hemodialysis	O
+rapidly	O
+reversed	O
+the	O
+neurologic	O
+symptoms	O
+within	O
+4	O
+hours	O
+.	O
+
+Piperacillin	O
+-	O
+induced	O
+encephalopathy	B
+should	O
+be	O
+considered	O
+in	O
+any	O
+uremic	B
+patients	O
+with	O
+unexplained	O
+neurological	O
+manifestations	O
+.	O
+
+CAPD	O
+is	O
+inefficient	O
+in	O
+removing	O
+piperacillin	O
+,	O
+whereas	O
+hemodialysis	O
+can	O
+rapidly	O
+terminate	O
+the	O
+piperacillin	O
+-	O
+induced	O
+encephalopathy	B
+.	O
+
+Frequency	O
+of	O
+transient	O
+ipsilateral	O
+vocal	B
+cord	I
+paralysis	I
+in	O
+patients	O
+undergoing	O
+carotid	O
+endarterectomy	O
+under	O
+local	O
+anesthesia	O
+.	O
+
+BACKGROUND	O
+:	O
+Especially	O
+because	O
+of	O
+improvements	O
+in	O
+clinical	O
+neurologic	O
+monitoring	O
+,	O
+carotid	O
+endarterectomy	O
+done	O
+under	O
+local	O
+anesthesia	O
+has	O
+become	O
+the	O
+technique	O
+of	O
+choice	O
+in	O
+several	O
+centers	O
+.	O
+
+Temporary	O
+ipsilateral	O
+vocal	B
+nerve	I
+palsies	I
+due	O
+to	O
+local	O
+anesthetics	O
+have	O
+been	O
+described	O
+,	O
+however	O
+.	O
+
+Such	O
+complications	O
+are	O
+most	O
+important	O
+in	O
+situations	O
+where	O
+there	O
+is	O
+a	O
+pre	O
+-	O
+existing	O
+contralateral	O
+paralysis	B
+.	O
+
+We	O
+therefore	O
+examined	O
+the	O
+effect	O
+of	O
+local	O
+anesthesia	O
+on	O
+vocal	O
+cord	O
+function	O
+to	O
+better	O
+understand	O
+its	O
+possible	O
+consequences	O
+.	O
+
+METHODS	O
+:	O
+This	O
+prospective	O
+study	O
+included	O
+28	O
+patients	O
+undergoing	O
+carotid	O
+endarterectomy	O
+under	O
+local	O
+anesthesia	O
+.	O
+
+Vocal	O
+cord	O
+function	O
+was	O
+evaluated	O
+before	O
+,	O
+during	O
+,	O
+and	O
+after	O
+surgery	O
+(	O
+postoperative	O
+day	O
+1	O
+)	O
+using	O
+flexible	O
+laryngoscopy	O
+.	O
+
+Anesthesia	O
+was	O
+performed	O
+by	O
+injecting	O
+20	O
+to	O
+40	O
+mL	O
+of	O
+a	O
+mixture	O
+of	O
+long	O
+-	O
+acting	O
+(	O
+ropivacaine	O
+)	O
+and	O
+short	O
+-	O
+acting	O
+(	O
+prilocaine	O
+)	O
+anesthetic	O
+.	O
+
+RESULTS	O
+:	O
+All	O
+patients	O
+had	O
+normal	O
+vocal	O
+cord	O
+function	O
+preoperatively	O
+.	O
+
+Twelve	O
+patients	O
+(	O
+43	O
+%	O
+)	O
+were	O
+found	O
+to	O
+have	O
+intraoperative	O
+ipsilateral	O
+vocal	B
+cord	I
+paralysis	I
+.	O
+
+It	O
+resolved	O
+in	O
+all	O
+cases	O
+<	O
+or	O
+=	O
+24	O
+hours	O
+.	O
+
+There	O
+were	O
+no	O
+significant	O
+differences	O
+in	O
+operating	O
+time	O
+or	O
+volume	O
+or	O
+frequency	O
+of	O
+anesthetic	O
+administration	O
+in	O
+patients	O
+with	O
+temporary	O
+vocal	B
+cord	I
+paralysis	I
+compared	O
+with	O
+those	O
+without	O
+.	O
+
+CONCLUSION	O
+:	O
+Local	O
+anesthesia	O
+led	O
+to	O
+temporary	O
+ipsilateral	O
+vocal	B
+cord	I
+paralysis	I
+in	O
+almost	O
+half	O
+of	O
+these	O
+patients	O
+.	O
+
+Because	O
+pre	O
+-	O
+existing	O
+paralysis	B
+is	O
+of	O
+a	O
+relevant	O
+frequency	O
+(	O
+up	O
+to	O
+3	O
+%	O
+)	O
+,	O
+a	O
+preoperative	O
+evaluation	O
+of	O
+vocal	O
+cord	O
+function	O
+before	O
+carotid	O
+endarterectomy	O
+under	O
+local	O
+anesthesia	O
+is	O
+recommended	O
+to	O
+avoid	O
+intraoperative	O
+bilateral	O
+paralysis	B
+.	O
+
+In	O
+patients	O
+with	O
+preoperative	O
+contralateral	O
+vocal	B
+cord	I
+paralysis	I
+,	O
+surgery	O
+under	O
+general	O
+anesthesia	O
+should	O
+be	O
+considered	O
+.	O
+
+Impaired	B
+fear	I
+recognition	I
+in	O
+regular	O
+recreational	O
+cocaine	O
+users	O
+.	O
+
+INTRODUCTION	O
+:	O
+The	O
+ability	O
+to	O
+read	O
+facial	O
+expressions	O
+is	O
+essential	O
+for	O
+normal	O
+human	O
+social	O
+interaction	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+conduct	O
+the	O
+first	O
+investigation	O
+of	O
+facial	O
+expression	O
+recognition	O
+performance	O
+in	O
+recreational	O
+cocaine	O
+users	O
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+Three	O
+groups	O
+,	O
+comprised	O
+of	O
+21	O
+cocaine	O
+naive	O
+participants	O
+(	O
+CN	O
+)	O
+,	O
+30	O
+occasional	O
+cocaine	O
+(	O
+OC	O
+)	O
+,	O
+and	O
+48	O
+regular	O
+recreational	O
+cocaine	O
+(	O
+RC	O
+)	O
+users	O
+,	O
+were	O
+compared	O
+.	O
+
+An	O
+emotional	O
+facial	O
+expression	O
+(	O
+EFE	O
+)	O
+task	O
+consisting	O
+of	O
+a	O
+male	O
+and	O
+female	O
+face	O
+expressing	O
+six	O
+basic	O
+emotions	O
+(	O
+happiness	O
+,	O
+surprise	O
+,	O
+sadness	O
+,	O
+anger	O
+,	O
+fear	O
+,	O
+and	O
+disgust	O
+)	O
+was	O
+administered	O
+.	O
+
+Mean	O
+percent	O
+accuracy	O
+and	O
+latencies	O
+for	O
+correct	O
+responses	O
+across	O
+eight	O
+presentations	O
+of	O
+each	O
+basic	O
+emotion	O
+were	O
+derived	O
+.	O
+
+Participants	O
+were	O
+also	O
+assessed	O
+with	O
+the	O
+"	O
+Eyes	O
+task	O
+"	O
+to	O
+investigate	O
+their	O
+ability	O
+to	O
+recognize	O
+more	O
+complex	O
+emotional	O
+states	O
+and	O
+the	O
+Symptom	O
+CheckList	O
+-	O
+90	O
+-	O
+Revised	O
+to	O
+measure	O
+psychopathology	O
+.	O
+
+RESULTS	O
+:	O
+There	O
+were	O
+no	O
+group	O
+differences	O
+in	O
+psychopathology	O
+or	O
+"	O
+eyes	O
+task	O
+"	O
+performance	O
+,	O
+but	O
+the	O
+RC	O
+group	O
+,	O
+who	O
+otherwise	O
+had	O
+similar	O
+illicit	O
+substance	O
+use	O
+histories	O
+to	O
+the	O
+OC	O
+group	O
+,	O
+exhibited	O
+impaired	B
+fear	I
+recognition	I
+accuracy	O
+compared	O
+to	O
+the	O
+OC	O
+and	O
+CN	O
+groups	O
+.	O
+
+The	O
+RC	O
+group	O
+also	O
+correctly	O
+identified	O
+anger	O
+,	O
+fear	O
+,	O
+happiness	O
+,	O
+and	O
+surprise	O
+,	O
+more	O
+slowly	O
+than	O
+CN	O
+,	O
+but	O
+not	O
+OC	O
+participants	O
+.	O
+
+The	O
+OC	O
+group	O
+was	O
+slower	O
+than	O
+CN	O
+when	O
+correctly	O
+identifying	O
+disgust	O
+.	O
+
+The	O
+selective	O
+deficit	B
+in	I
+fear	I
+recognition	I
+accuracy	O
+manifested	O
+by	O
+the	O
+RC	O
+group	O
+cannot	O
+be	O
+explained	O
+by	O
+the	O
+subacute	O
+effects	O
+of	O
+cocaine	O
+,	O
+or	O
+ecstasy	O
+,	O
+because	O
+recent	O
+and	O
+less	O
+recent	O
+users	O
+of	O
+these	O
+drugs	O
+within	O
+this	O
+group	O
+were	O
+similarly	O
+impaired	O
+.	O
+
+Possible	O
+parallels	O
+between	O
+RC	O
+users	O
+and	O
+psychopaths	B
+with	O
+respect	O
+to	O
+impaired	B
+fear	I
+recognition	I
+,	O
+amygdala	B
+dysfunction	I
+,	O
+and	O
+etiology	O
+are	O
+discussed	O
+.	O
+
+Damage	B
+of	I
+substantia	I
+nigra	I
+pars	I
+reticulata	I
+during	O
+pilocarpine	O
+-	O
+induced	O
+status	B
+epilepticus	I
+in	O
+the	O
+rat	O
+:	O
+immunohistochemical	O
+study	O
+of	O
+neurons	O
+,	O
+astrocytes	O
+and	O
+serum	O
+-	O
+protein	O
+extravasation	O
+.	O
+
+The	O
+substantia	O
+nigra	O
+has	O
+a	O
+gating	O
+function	O
+controlling	O
+the	O
+spread	O
+of	O
+epileptic	B
+seizure	I
+activity	O
+.	O
+
+Additionally	O
+,	O
+in	O
+models	O
+of	O
+prolonged	B
+status	I
+epilepticus	I
+the	O
+pars	O
+reticulata	O
+of	O
+substantia	O
+nigra	O
+(	O
+SNR	O
+)	O
+suffers	O
+from	O
+a	O
+massive	O
+lesion	O
+which	O
+may	O
+arise	O
+from	O
+a	O
+massive	O
+metabolic	B
+derangement	I
+and	O
+hyperexcitation	O
+developing	O
+in	O
+the	O
+activated	O
+SNR	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+status	B
+epilepticus	I
+was	O
+induced	O
+by	O
+systemic	O
+injection	O
+of	O
+pilocarpine	O
+in	O
+rats	O
+.	O
+
+The	O
+neuropathology	O
+of	O
+SNR	O
+was	O
+investigated	O
+using	O
+immunohistochemical	O
+techniques	O
+with	O
+the	O
+major	O
+emphasis	O
+on	O
+the	O
+time	O
+-	O
+course	O
+of	O
+changes	O
+in	O
+neurons	O
+and	O
+astrocytes	O
+.	O
+
+Animals	O
+surviving	O
+20	O
+,	O
+30	O
+,	O
+40	O
+,	O
+60	O
+min	O
+,	O
+2	O
+,	O
+3	O
+,	O
+6	O
+hours	O
+,	O
+1	O
+,	O
+2	O
+,	O
+and	O
+3	O
+days	O
+after	O
+induction	O
+of	O
+status	B
+epilepticus	I
+were	O
+perfusion	O
+-	O
+fixed	O
+,	O
+and	O
+brains	O
+processed	O
+for	O
+immunohistochemical	O
+staining	O
+of	O
+SNR	O
+.	O
+
+Nissl	O
+-	O
+staining	O
+and	O
+antibodies	O
+against	O
+the	O
+neuron	O
+-	O
+specific	O
+calcium	O
+-	O
+binding	O
+protein	O
+,	O
+parvalbumin	O
+,	O
+served	O
+to	O
+detect	O
+neuronal	B
+damage	I
+in	O
+SNR	O
+.	O
+
+Antibodies	O
+against	O
+the	O
+astroglia	O
+-	O
+specific	O
+cytoskeletal	O
+protein	O
+,	O
+glial	O
+fibrillary	O
+acidic	O
+protein	O
+(	O
+GFAP	O
+)	O
+,	O
+and	O
+against	O
+the	O
+glial	O
+calcium	O
+-	O
+binding	O
+protein	O
+,	O
+S	O
+-	O
+100	O
+protein	O
+,	O
+were	O
+used	O
+to	O
+assess	O
+the	O
+status	O
+of	O
+astrocytes	O
+.	O
+
+Immunohistochemical	O
+staining	O
+for	O
+serum	O
+-	O
+albumin	O
+and	O
+immunoglobulins	O
+in	O
+brain	O
+tissue	O
+was	O
+taken	O
+as	O
+indicator	O
+of	O
+blood	O
+-	O
+brain	O
+barrier	O
+disturbances	O
+and	O
+vasogenic	B
+edema	I
+formation	O
+.	O
+
+Immunohistochemical	O
+staining	O
+indicated	O
+loss	O
+of	O
+GFAP	O
+-	O
+staining	O
+already	O
+at	O
+30	O
+min	O
+after	O
+induction	O
+of	O
+seizures	B
+in	O
+an	O
+oval	O
+focus	O
+situated	O
+in	O
+the	O
+center	O
+of	O
+SNR	O
+while	O
+sparing	O
+medial	O
+and	O
+lateral	O
+aspects	O
+.	O
+
+At	O
+1	O
+h	O
+there	O
+was	O
+additional	O
+vacuolation	O
+in	O
+S	O
+-	O
+100	O
+protein	O
+staining	O
+.	O
+
+By	O
+2	O
+hours	O
+,	O
+parvalbumin	O
+-	O
+staining	O
+changed	O
+in	O
+the	O
+central	O
+SNR	O
+indicating	O
+neuronal	B
+damage	I
+,	O
+and	O
+Nissl	O
+-	O
+staining	O
+visualized	O
+some	O
+neuronal	O
+distortion	O
+.	O
+
+Staining	O
+for	O
+serum	O
+-	O
+proteins	O
+occurred	O
+in	O
+a	O
+patchy	O
+manner	O
+throughout	O
+the	O
+forebrain	O
+during	O
+the	O
+first	O
+hours	O
+.	O
+
+By	O
+6	O
+h	O
+,	O
+vasogenic	B
+edema	I
+covered	O
+the	O
+lesioned	B
+SNR	I
+.	O
+
+By	O
+24	O
+h	O
+,	O
+glial	O
+and	O
+neuronal	O
+markers	O
+indicated	O
+a	O
+massive	O
+lesion	O
+in	O
+the	O
+center	O
+of	O
+SNR	O
+.	O
+
+By	O
+48	O
+-	O
+72	O
+h	O
+,	O
+astrocytes	O
+surrounding	O
+the	O
+lesion	O
+increased	O
+in	O
+size	O
+,	O
+and	O
+polymorphic	O
+phagocytotic	O
+cells	O
+invaded	O
+the	O
+damaged	O
+area	O
+.	O
+
+In	O
+a	O
+further	O
+group	O
+of	O
+animals	O
+surviving	O
+1	O
+to	O
+5	O
+days	O
+,	O
+conventional	O
+paraffin	O
+-	O
+sections	O
+confirmed	O
+the	O
+neuronal	O
+and	O
+glial	O
+damage	B
+of	I
+SNR	I
+.	O
+
+Additional	O
+pathology	O
+of	O
+similar	O
+quality	O
+was	O
+found	O
+in	O
+the	O
+globus	O
+pallidus	O
+.	O
+
+Since	O
+astrocytes	O
+were	O
+always	O
+damaged	O
+in	O
+parallel	O
+with	O
+neurons	O
+in	O
+SNR	O
+it	O
+is	O
+proposed	O
+that	O
+the	O
+anatomical	O
+and	O
+functional	O
+interrelationship	O
+between	O
+neurons	O
+and	O
+astrocytes	O
+is	O
+particularly	O
+tight	O
+in	O
+SNR	O
+.	O
+
+Both	O
+cell	O
+elements	O
+may	O
+suffer	O
+in	O
+common	O
+from	O
+metabolic	O
+disturbance	O
+and	O
+neurotransmitter	B
+dysfunction	I
+as	O
+occur	O
+during	O
+massive	O
+status	B
+epilepticus	I
+.	O
+
+Neuroprotective	O
+effects	O
+of	O
+melatonin	O
+upon	O
+the	O
+offspring	O
+cerebellar	O
+cortex	O
+in	O
+the	O
+rat	O
+model	O
+of	O
+BCNU	O
+-	O
+induced	O
+cortical	B
+dysplasia	I
+.	O
+
+Cortical	B
+dysplasia	I
+is	O
+a	O
+malformation	O
+characterized	O
+by	O
+defects	O
+in	O
+proliferation	O
+,	O
+migration	O
+and	O
+maturation	O
+.	O
+
+This	O
+study	O
+was	O
+designed	O
+to	O
+evaluate	O
+the	O
+alterations	O
+in	O
+offspring	O
+rat	O
+cerebellum	O
+induced	O
+by	O
+maternal	O
+exposure	O
+to	O
+carmustine	O
+-	O
+[	O
+1	O
+,	O
+3	O
+-	O
+bis	O
+(	O
+2	O
+-	O
+chloroethyl	O
+)	O
+-	O
+1	O
+-	O
+nitrosoure	O
+]	O
+(	O
+BCNU	O
+)	O
+and	O
+to	O
+investigate	O
+the	O
+effects	O
+of	O
+exogenous	O
+melatonin	O
+upon	O
+cerebellar	O
+BCNU	O
+-	O
+induced	O
+cortical	B
+dysplasia	I
+,	O
+using	O
+histological	O
+and	O
+biochemical	O
+analyses	O
+.	O
+
+Pregnant	O
+Wistar	O
+rats	O
+were	O
+assigned	O
+to	O
+five	O
+groups	O
+:	O
+intact	O
+-	O
+control	O
+,	O
+saline	O
+-	O
+control	O
+,	O
+melatonin	O
+-	O
+treated	O
+,	O
+BCNU	O
+-	O
+exposed	O
+and	O
+BCNU	O
+-	O
+exposed	O
+plus	O
+melatonin	O
+.	O
+
+Rats	O
+were	O
+exposed	O
+to	O
+BCNU	O
+on	O
+embryonic	O
+day	O
+15	O
+and	O
+melatonin	O
+was	O
+given	O
+until	O
+delivery	O
+.	O
+
+Immuno	O
+/	O
+histochemistry	O
+and	O
+electron	O
+microscopy	O
+were	O
+carried	O
+out	O
+on	O
+the	O
+offspring	O
+cerebellum	O
+,	O
+and	O
+levels	O
+of	O
+malondialdehyde	O
+and	O
+superoxide	O
+dismutase	O
+were	O
+determined	O
+.	O
+
+Histopathologically	O
+,	O
+typical	O
+findings	O
+were	O
+observed	O
+in	O
+the	O
+cerebella	O
+from	O
+the	O
+control	O
+groups	O
+,	O
+but	O
+the	O
+findings	O
+consistent	O
+with	O
+early	O
+embryonic	O
+development	O
+were	O
+noted	O
+in	O
+BCNU	O
+-	O
+exposed	O
+cortical	B
+dysplasia	I
+group	O
+.	O
+
+There	O
+was	O
+a	O
+marked	O
+increase	O
+in	O
+the	O
+number	O
+of	O
+TUNEL	O
+positive	O
+cells	O
+and	O
+nestin	O
+positive	O
+cells	O
+in	O
+BCNU	O
+-	O
+exposed	O
+group	O
+,	O
+but	O
+a	O
+decreased	O
+immunoreactivity	O
+to	O
+glial	O
+fibrillary	O
+acidic	O
+protein	O
+,	O
+synaptophysin	O
+and	O
+transforming	O
+growth	O
+factor	O
+beta1	O
+was	O
+observed	O
+,	O
+indicating	O
+a	O
+delayed	O
+maturation	O
+,	O
+and	O
+melatonin	O
+significantly	O
+reversed	O
+these	O
+changes	O
+.	O
+
+Malondialdehyde	O
+level	O
+in	O
+BCNU	O
+-	O
+exposed	O
+group	O
+was	O
+higher	O
+than	O
+those	O
+in	O
+control	O
+groups	O
+and	O
+melatonin	O
+decreased	O
+malondialdehyde	O
+levels	O
+in	O
+BCNU	O
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+,	O
+while	O
+there	O
+were	O
+no	O
+significant	O
+differences	O
+in	O
+the	O
+superoxide	O
+dismutase	O
+levels	O
+between	O
+these	O
+groups	O
+.	O
+
+These	O
+data	O
+suggest	O
+that	O
+exposure	O
+of	O
+animals	O
+to	O
+BCNU	O
+during	O
+pregnancy	O
+leads	O
+to	O
+delayed	O
+maturation	O
+of	O
+offspring	O
+cerebellum	O
+and	O
+melatonin	O
+protects	O
+the	O
+cerebellum	O
+against	O
+the	O
+effects	O
+of	O
+BCNU	O
+.	O
+
+Reduced	O
+cardiotoxicity	B
+of	O
+doxorubicin	O
+given	O
+in	O
+the	O
+form	O
+of	O
+N	O
+-	O
+(	O
+2	O
+-	O
+hydroxypropyl	O
+)	O
+methacrylamide	O
+conjugates	O
+:	O
+and	O
+experimental	O
+study	O
+in	O
+the	O
+rat	O
+.	O
+
+A	O
+rat	O
+model	O
+was	O
+used	O
+to	O
+evaluate	O
+the	O
+general	O
+acute	O
+toxicity	B
+and	O
+the	O
+late	O
+cardiotoxicity	B
+of	O
+4	O
+mg	O
+/	O
+kg	O
+doxorubicin	O
+(	O
+DOX	O
+)	O
+given	O
+either	O
+as	O
+free	O
+drug	O
+or	O
+in	O
+the	O
+form	O
+of	O
+three	O
+N	O
+-	O
+(	O
+2	O
+-	O
+hydroxypropyl	O
+)	O
+methacrylamide	O
+(	O
+HPMA	O
+)	O
+copolymer	O
+conjugates	O
+.	O
+
+In	O
+these	O
+HPMA	O
+copolymers	O
+,	O
+DOX	O
+was	O
+covalently	O
+bound	O
+via	O
+peptide	O
+linkages	O
+that	O
+were	O
+either	O
+non	O
+-	O
+biodegradable	O
+(	O
+Gly	O
+-	O
+Gly	O
+)	O
+or	O
+degradable	O
+by	O
+lysosomal	O
+proteinases	O
+(	O
+Gly	O
+-	O
+Phe	O
+-	O
+Leu	O
+-	O
+Gly	O
+)	O
+.	O
+
+In	O
+addition	O
+,	O
+one	O
+biodegradable	O
+conjugate	O
+containing	O
+galactosamine	O
+was	O
+used	O
+;	O
+this	O
+residue	O
+was	O
+targeted	O
+to	O
+the	O
+liver	O
+.	O
+
+Over	O
+the	O
+first	O
+3	O
+weeks	O
+after	O
+the	O
+i	O
+.	O
+v	O
+.	O
+administration	O
+of	O
+free	O
+and	O
+polymer	O
+-	O
+bound	O
+DOX	O
+,	O
+all	O
+animals	O
+showed	O
+a	O
+transient	O
+reduction	O
+in	O
+body	O
+weight	O
+.	O
+
+However	O
+,	O
+the	O
+maximal	O
+reduction	O
+in	O
+body	O
+weight	O
+seen	O
+in	O
+animals	O
+that	O
+received	O
+polymer	O
+-	O
+bound	O
+DOX	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+significantly	O
+lower	O
+than	O
+that	O
+observed	O
+in	O
+those	O
+that	O
+received	O
+free	O
+DOX	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+)	O
+or	O
+a	O
+mixture	O
+of	O
+the	O
+unmodified	O
+parent	O
+HPMA	O
+copolymer	O
+and	O
+free	O
+DOX	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+;	O
+P	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+Throughout	O
+the	O
+study	O
+(	O
+20	O
+weeks	O
+)	O
+,	O
+deaths	O
+related	O
+to	O
+cardiotoxicity	B
+were	O
+observed	O
+only	O
+in	O
+animals	O
+that	O
+received	O
+either	O
+free	O
+DOX	O
+or	O
+the	O
+mixture	O
+of	O
+HPMA	O
+copolymer	O
+and	O
+free	O
+DOX	O
+;	O
+in	O
+these	O
+cases	O
+,	O
+histological	O
+investigations	O
+revealed	O
+marked	O
+changes	O
+in	O
+the	O
+heart	O
+that	O
+were	O
+consistent	O
+with	O
+DOX	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+Sequential	O
+measurements	O
+of	O
+cardiac	O
+output	O
+in	O
+surviving	O
+animals	O
+that	O
+received	O
+either	O
+free	O
+DOX	O
+or	O
+the	O
+mixture	O
+of	O
+HPMA	O
+copolymer	O
+and	O
+free	O
+DOX	O
+showed	O
+a	O
+reduction	O
+of	O
+approximately	O
+30	O
+%	O
+in	O
+function	O
+beginning	O
+at	O
+the	O
+4th	O
+week	O
+after	O
+drug	O
+administration	O
+.	O
+
+The	O
+heart	O
+rate	O
+in	O
+these	O
+animals	O
+was	O
+approximately	O
+12	O
+%	O
+lower	O
+than	O
+that	O
+measured	O
+in	O
+age	O
+-	O
+matched	O
+control	O
+rats	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Animals	O
+that	O
+were	O
+given	O
+the	O
+HPMA	O
+copolymer	O
+conjugates	O
+containing	O
+DOX	O
+exhibited	O
+no	O
+significant	O
+change	O
+in	O
+cardiac	O
+output	O
+throughout	O
+the	O
+study	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+In	O
+addition	O
+,	O
+no	O
+significant	O
+histological	O
+change	O
+was	O
+observed	O
+in	O
+the	O
+heart	O
+of	O
+animals	O
+that	O
+received	O
+DOX	O
+in	O
+the	O
+form	O
+of	O
+HPMA	O
+copolymer	O
+conjugates	O
+and	O
+were	O
+killed	O
+at	O
+the	O
+end	O
+of	O
+the	O
+study	O
+.	O
+
+However	O
+,	O
+these	O
+animals	O
+had	O
+shown	O
+a	O
+significant	O
+increase	O
+in	O
+heart	O
+rate	O
+beginning	O
+at	O
+8	O
+weeks	O
+after	O
+drug	O
+administration	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+400	O
+WORDS	O
+)	O
+
+Corneal	B
+ulcers	I
+associated	O
+with	O
+aerosolized	O
+crack	O
+cocaine	O
+use	O
+.	O
+
+PURPOSE	O
+:	O
+We	O
+report	O
+4	O
+cases	O
+of	O
+corneal	B
+ulcers	I
+associated	O
+with	O
+drug	B
+abuse	I
+.	O
+
+The	O
+pathogenesis	O
+of	O
+these	O
+ulcers	B
+and	O
+management	O
+of	O
+these	O
+patients	O
+are	O
+also	O
+reviewed	O
+.	O
+
+METHODS	O
+:	O
+Review	O
+of	O
+all	O
+cases	O
+of	O
+corneal	B
+ulcers	I
+associated	O
+with	O
+drug	B
+abuse	I
+seen	O
+at	O
+our	O
+institution	O
+from	O
+July	O
+2006	O
+to	O
+December	O
+2006	O
+.	O
+
+RESULTS	O
+:	O
+Four	O
+patients	O
+with	O
+corneal	B
+ulcers	I
+associated	O
+with	O
+crack	O
+cocaine	O
+use	O
+were	O
+reviewed	O
+.	O
+
+All	O
+corneal	B
+ulcers	I
+were	O
+cultured	O
+,	O
+and	O
+the	O
+patients	O
+were	O
+admitted	O
+to	O
+the	O
+hospital	O
+for	O
+intensive	O
+topical	O
+antibiotic	O
+treatment	O
+.	O
+
+Each	O
+patient	O
+received	O
+comprehensive	O
+health	O
+care	O
+,	O
+including	O
+medical	O
+and	O
+substance	B
+abuse	I
+consultations	O
+.	O
+
+Streptococcal	O
+organisms	O
+were	O
+found	O
+in	O
+3	O
+cases	O
+and	O
+Capnocytophaga	O
+and	O
+Brevibacterium	O
+casei	O
+in	O
+1	O
+patient	O
+.	O
+
+The	O
+infections	B
+responded	O
+to	O
+antibiotic	O
+treatment	O
+.	O
+
+Two	O
+patients	O
+needed	O
+a	O
+lateral	O
+tarsorrhaphy	O
+for	O
+persistent	O
+epithelial	B
+defects	I
+.	O
+
+CONCLUSIONS	O
+:	O
+Aerosolized	O
+crack	O
+cocaine	O
+use	O
+can	O
+be	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+corneal	B
+ulcers	I
+.	O
+
+Drug	B
+abuse	I
+provides	O
+additional	O
+challenges	O
+for	O
+management	O
+.	O
+
+Not	O
+only	O
+treatment	O
+of	O
+their	O
+infections	B
+but	O
+also	O
+the	O
+overall	O
+poor	O
+health	O
+of	O
+the	O
+patients	O
+and	O
+increased	O
+risk	O
+of	O
+noncompliance	O
+need	O
+to	O
+be	O
+addressed	O
+.	O
+
+Comprehensive	O
+care	O
+may	O
+provide	O
+the	O
+patient	O
+the	O
+opportunity	O
+to	O
+discontinue	O
+their	O
+substance	B
+abuse	I
+,	O
+improve	O
+their	O
+overall	O
+health	O
+,	O
+and	O
+prevent	O
+future	O
+corneal	O
+complications	O
+.	O
+
+Topical	O
+0	O
+.	O
+025	O
+%	O
+capsaicin	O
+in	O
+chronic	O
+post	B
+-	I
+herpetic	I
+neuralgia	I
+:	O
+efficacy	O
+,	O
+predictors	O
+of	O
+response	O
+and	O
+long	O
+-	O
+term	O
+course	O
+.	O
+
+In	O
+order	O
+to	O
+evaluate	O
+the	O
+efficacy	O
+,	O
+time	O
+-	O
+course	O
+of	O
+action	O
+and	O
+predictors	O
+of	O
+response	O
+to	O
+topical	O
+capsaicin	O
+,	O
+39	O
+patients	O
+with	O
+chronic	O
+post	B
+-	I
+herpetic	I
+neuralgia	I
+(	O
+PHN	B
+)	O
+,	O
+median	O
+duration	O
+24	O
+months	O
+,	O
+were	O
+treated	O
+with	O
+0	O
+.	O
+025	O
+%	O
+capsaicin	O
+cream	O
+for	O
+8	O
+weeks	O
+.	O
+
+During	O
+therapy	O
+the	O
+patients	O
+rated	O
+their	O
+pain	B
+on	O
+a	O
+visual	O
+analogue	O
+scale	O
+(	O
+VAS	O
+)	O
+and	O
+a	O
+verbal	O
+outcome	O
+scale	O
+.	O
+
+A	O
+follow	O
+-	O
+up	O
+investigation	O
+was	O
+performed	O
+10	O
+-	O
+12	O
+months	O
+after	O
+study	O
+onset	O
+on	O
+the	O
+patients	O
+who	O
+had	O
+improved	O
+.	O
+
+Nineteen	O
+patients	O
+(	O
+48	O
+.	O
+7	O
+%	O
+)	O
+substantially	O
+improved	O
+after	O
+the	O
+8	O
+-	O
+week	O
+trial	O
+;	O
+5	O
+(	O
+12	O
+.	O
+8	O
+%	O
+)	O
+discontinued	O
+therapy	O
+due	O
+to	O
+side	O
+-	O
+effects	O
+such	O
+as	O
+intolerable	O
+capsaicin	O
+-	O
+induced	O
+burning	O
+sensations	O
+(	O
+4	O
+)	O
+or	O
+mastitis	B
+(	O
+1	O
+)	O
+;	O
+15	O
+(	O
+38	O
+.	O
+5	O
+%	O
+)	O
+reported	O
+no	O
+benefit	O
+.	O
+
+The	O
+decrease	O
+in	O
+VAS	O
+ratings	O
+was	O
+significant	O
+after	O
+2	O
+weeks	O
+of	O
+continuous	O
+application	O
+.	O
+
+Of	O
+the	O
+responders	O
+72	O
+.	O
+2	O
+%	O
+were	O
+still	O
+improved	O
+at	O
+the	O
+follow	O
+-	O
+up	O
+;	O
+only	O
+one	O
+-	O
+third	O
+of	O
+them	O
+had	O
+continued	O
+application	O
+irregularly	O
+.	O
+
+Treatment	O
+effect	O
+was	O
+not	O
+dependent	O
+on	O
+patient	O
+'	O
+s	O
+age	O
+,	O
+duration	O
+or	O
+localization	O
+of	O
+PHN	B
+(	O
+trigeminal	O
+involvement	O
+was	O
+excluded	O
+)	O
+,	O
+sensory	B
+disturbance	I
+or	O
+pain	B
+character	O
+.	O
+
+Treatment	O
+response	O
+was	O
+not	O
+correlated	O
+with	O
+the	O
+incidence	O
+,	O
+time	O
+-	O
+course	O
+or	O
+severity	O
+of	O
+capsaicin	O
+-	O
+induced	O
+burning	O
+.	O
+
+If	O
+confirmed	O
+in	O
+controlled	O
+trials	O
+,	O
+the	O
+long	O
+-	O
+term	O
+results	O
+of	O
+this	O
+open	O
+,	O
+non	O
+-	O
+randomized	O
+study	O
+might	O
+indicate	O
+that	O
+the	O
+analgesic	O
+effect	O
+of	O
+capsaicin	O
+in	O
+PHN	B
+is	O
+mediated	O
+by	O
+both	O
+interference	O
+with	O
+neuropeptide	O
+metabolism	O
+and	O
+morphological	O
+changes	O
+(	O
+perhaps	O
+degeneration	O
+)	O
+of	O
+nociceptive	O
+afferents	O
+.	O
+
+Myo	O
+-	O
+inositol	O
+-	O
+1	O
+-	O
+phosphate	O
+(	O
+MIP	O
+)	O
+synthase	O
+inhibition	O
+:	O
+in	O
+-	O
+vivo	O
+study	O
+in	O
+rats	O
+.	O
+
+Lithium	O
+and	O
+valproate	O
+are	O
+the	O
+prototypic	O
+mood	O
+stabilizers	O
+and	O
+have	O
+diverse	O
+structures	O
+and	O
+targets	O
+.	O
+
+Both	O
+drugs	O
+influence	O
+inositol	O
+metabolism	O
+.	O
+
+Lithium	O
+inhibits	O
+IMPase	O
+and	O
+valproate	O
+inhibits	O
+MIP	O
+synthase	O
+.	O
+
+This	O
+study	O
+shows	O
+that	O
+MIP	O
+synthase	O
+inhibition	O
+does	O
+not	O
+replicate	O
+or	O
+augment	O
+the	O
+effects	O
+of	O
+lithium	O
+in	O
+the	O
+inositol	O
+sensitive	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+model	O
+.	O
+
+This	O
+lack	O
+of	O
+effects	O
+may	O
+stem	O
+from	O
+the	O
+low	O
+contribution	O
+of	O
+de	O
+-	O
+novo	O
+synthesis	O
+to	O
+cellular	O
+inositol	O
+supply	O
+or	O
+to	O
+the	O
+inhibition	O
+of	O
+the	O
+de	O
+-	O
+novo	O
+synthesis	O
+by	O
+lithium	O
+itself	O
+.	O
+
+Non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+-	O
+associated	O
+acute	O
+interstitial	B
+nephritis	I
+with	O
+granular	O
+tubular	O
+basement	O
+membrane	O
+deposits	O
+.	O
+
+Acute	B
+tubulo	I
+-	I
+interstitial	I
+nephritis	I
+(	O
+ATIN	B
+)	O
+is	O
+an	O
+important	O
+cause	O
+of	O
+acute	B
+renal	I
+failure	I
+resulting	O
+from	O
+a	O
+variety	O
+of	O
+insults	O
+,	O
+including	O
+immune	O
+complex	O
+-	O
+mediated	O
+tubulo	B
+-	I
+interstitial	I
+injury	I
+,	O
+but	O
+drugs	O
+such	O
+as	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+(	O
+NSAIDs	O
+)	O
+are	O
+a	O
+far	O
+more	O
+frequent	O
+cause	O
+.	O
+
+Overall	O
+,	O
+as	O
+an	O
+entity	O
+,	O
+ATIN	B
+remains	O
+under	O
+-	O
+diagnosed	O
+,	O
+as	O
+symptoms	O
+resolve	O
+spontaneously	O
+if	O
+the	O
+medication	O
+is	O
+stopped	O
+.	O
+
+We	O
+report	O
+on	O
+a	O
+14	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+who	O
+developed	O
+acute	B
+renal	I
+failure	I
+2	O
+weeks	O
+after	O
+aortic	O
+valve	O
+surgery	O
+.	O
+
+He	O
+was	O
+put	O
+on	O
+aspirin	O
+following	O
+surgery	O
+and	O
+took	O
+ibuprofen	O
+for	O
+fever	B
+for	O
+nearly	O
+a	O
+week	O
+prior	O
+to	O
+presentation	O
+.	O
+
+He	O
+then	O
+presented	O
+to	O
+the	O
+emergency	O
+department	O
+feeling	O
+quite	O
+ill	O
+and	O
+was	O
+found	O
+to	O
+have	O
+a	O
+blood	O
+urea	O
+nitrogen	O
+(	O
+BUN	O
+)	O
+concentration	O
+of	O
+of	O
+147	O
+mg	O
+/	O
+dl	O
+,	O
+creatinine	O
+of	O
+15	O
+.	O
+3	O
+mg	O
+/	O
+dl	O
+and	O
+serum	O
+potassium	O
+of	O
+8	O
+.	O
+7	O
+mEq	O
+/	O
+l	O
+.	O
+
+Dialysis	O
+was	O
+immediately	O
+initiated	O
+.	O
+
+A	O
+kidney	O
+biopsy	O
+showed	O
+inflammatory	O
+infiltrate	O
+consistent	O
+with	O
+ATIN	B
+.	O
+
+However	O
+,	O
+in	O
+the	O
+tubular	O
+basement	O
+membrane	O
+(	O
+TBM	O
+)	O
+,	O
+very	O
+intense	O
+granular	O
+deposits	O
+of	O
+polyclonal	O
+IgG	O
+and	O
+C3	O
+were	O
+noted	O
+.	O
+
+He	O
+needed	O
+dialysis	O
+for	O
+2	O
+weeks	O
+and	O
+was	O
+treated	O
+successfully	O
+with	O
+steroids	O
+for	O
+6	O
+months	O
+.	O
+
+His	O
+renal	O
+recovery	O
+and	O
+disappearance	O
+of	O
+proteinuria	B
+took	O
+a	O
+year	O
+.	O
+
+In	O
+conclusion	O
+,	O
+this	O
+is	O
+a	O
+first	O
+report	O
+of	O
+NSAIDs	O
+-	O
+associated	O
+ATIN	B
+,	O
+showing	O
+deposits	O
+of	O
+granular	O
+immune	O
+complex	O
+present	O
+only	O
+in	O
+the	O
+TBM	O
+and	O
+not	O
+in	O
+the	O
+glomeruli	O
+.	O
+
+Rifampicin	O
+-	O
+associated	O
+segmental	O
+necrotizing	O
+glomerulonephritis	B
+in	O
+staphylococcal	B
+endocarditis	I
+.	O
+
+Segmental	O
+necrotising	O
+glomerulonephritis	B
+has	O
+been	O
+reported	O
+as	O
+complication	O
+of	O
+rifampicin	O
+therapy	O
+in	O
+patients	O
+receiving	O
+treatment	O
+for	O
+tuberculosis	B
+.	O
+
+Changing	O
+epidemiology	O
+of	O
+infections	B
+such	O
+as	O
+infective	B
+endocarditis	I
+(	O
+IE	B
+)	O
+has	O
+led	O
+to	O
+an	O
+increase	O
+in	O
+the	O
+use	O
+of	O
+rifampicin	O
+for	O
+Staphylococcal	B
+infections	I
+.	O
+
+We	O
+describe	O
+a	O
+case	O
+of	O
+a	O
+patient	O
+with	O
+Staphylococcal	B
+IE	I
+who	O
+developed	O
+acute	B
+renal	I
+failure	I
+secondary	O
+to	O
+a	O
+segmental	O
+necrotising	O
+glomerulonephritis	B
+while	O
+being	O
+treated	O
+with	O
+rifampicin	O
+,	O
+and	O
+review	O
+the	O
+literature	O
+regarding	O
+this	O
+complication	O
+of	O
+rifampicin	O
+therapy	O
+.	O
+
+Rate	O
+of	O
+YMDD	O
+motif	O
+mutants	O
+in	O
+lamivudine	O
+-	O
+untreated	O
+Iranian	O
+patients	O
+with	O
+chronic	B
+hepatitis	I
+B	I
+virus	I
+infection	I
+.	O
+
+BACKGROUND	O
+:	O
+Lamivudine	O
+is	O
+used	O
+for	O
+the	O
+treatment	O
+of	O
+chronic	B
+hepatitis	I
+B	I
+patients	O
+.	O
+
+Recent	O
+studies	O
+show	O
+that	O
+the	O
+YMDD	O
+motif	O
+mutants	O
+(	O
+resistant	O
+hepatitis	B
+B	I
+virus	O
+)	O
+occur	O
+as	O
+natural	O
+genome	O
+variability	O
+in	O
+lamivudine	O
+-	O
+untreated	O
+chronic	B
+hepatitis	I
+B	I
+patients	O
+.	O
+
+In	O
+this	O
+study	O
+we	O
+aimed	O
+to	O
+determine	O
+the	O
+rate	O
+of	O
+YMDD	O
+motif	O
+mutants	O
+in	O
+lamivudine	O
+-	O
+untreated	O
+chronic	B
+hepatitis	I
+B	I
+patients	O
+in	O
+Iran	O
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+A	O
+total	O
+of	O
+77	O
+chronic	B
+hepatitis	I
+B	I
+patients	O
+who	O
+had	O
+not	O
+been	O
+treated	O
+with	O
+lamivudine	O
+were	O
+included	O
+in	O
+the	O
+study	O
+.	O
+
+Serum	O
+samples	O
+from	O
+patients	O
+were	O
+tested	O
+by	O
+polymerase	O
+chain	O
+reaction	O
+-	O
+restriction	O
+fragment	O
+length	O
+polymorphism	O
+(	O
+PCR	O
+-	O
+RFLP	O
+)	O
+for	O
+detection	O
+of	O
+YMDD	O
+motif	O
+mutants	O
+.	O
+
+All	O
+patients	O
+were	O
+also	O
+tested	O
+for	O
+liver	O
+enzymes	O
+,	O
+anti	O
+-	O
+HCV	O
+,	O
+HBeAg	O
+,	O
+and	O
+anti	O
+-	O
+HBe	O
+.	O
+
+RESULTS	O
+:	O
+Of	O
+the	O
+77	O
+patients	O
+enrolled	O
+in	O
+the	O
+study	O
+,	O
+73	O
+%	O
+were	O
+male	O
+and	O
+27	O
+%	O
+were	O
+female	O
+.	O
+
+Mean	O
+ALT	O
+and	O
+AST	O
+levels	O
+were	O
+124	O
+.	O
+4	O
++	O
+/	O
+-	O
+73	O
+.	O
+4	O
+and	O
+103	O
+.	O
+1	O
++	O
+/	O
+-	O
+81	O
+IU	O
+/	O
+l	O
+,	O
+respectively	O
+.	O
+
+HBeAg	O
+was	O
+positive	O
+in	O
+40	O
+%	O
+and	O
+anti	O
+-	O
+HBe	O
+in	O
+60	O
+%	O
+of	O
+the	O
+patients	O
+.	O
+
+Anti	O
+-	O
+HCV	O
+was	O
+negative	O
+in	O
+all	O
+of	O
+them	O
+.	O
+
+YMDD	O
+motif	O
+mutants	O
+were	O
+not	O
+detected	O
+in	O
+any	O
+of	O
+the	O
+patients	O
+despite	O
+the	O
+liver	O
+enzyme	O
+levels	O
+and	O
+the	O
+presence	O
+of	O
+HBeAg	O
+or	O
+anti	O
+-	O
+HBe	O
+.	O
+
+CONCLUSION	O
+:	O
+Although	O
+the	O
+natural	O
+occurrence	O
+of	O
+YMDD	O
+motif	O
+mutants	O
+in	O
+lamivudine	O
+-	O
+untreated	O
+patients	O
+with	O
+chronic	B
+hepatitis	I
+B	I
+has	O
+been	O
+reported	O
+,	O
+these	O
+mutants	O
+were	O
+not	O
+detected	O
+in	O
+Iranian	O
+lamivudine	O
+-	O
+untreated	O
+chronic	B
+hepatitis	I
+B	I
+patients	O
+.	O
+
+Branch	O
+retinal	B
+vein	I
+occlusion	I
+and	O
+fluoxetine	O
+.	O
+
+A	O
+case	O
+of	O
+branch	O
+retinal	B
+vein	I
+occlusion	I
+associated	O
+with	O
+fluoxetine	O
+-	O
+induced	O
+secondary	O
+hypertension	B
+is	O
+described	O
+.	O
+
+Although	O
+an	O
+infrequent	O
+complication	O
+of	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitor	O
+therapy	O
+,	O
+it	O
+is	O
+important	O
+that	O
+ophthalmologists	O
+are	O
+aware	O
+that	O
+these	O
+agents	O
+can	O
+cause	O
+hypertension	B
+because	O
+this	O
+class	O
+of	O
+drugs	O
+is	O
+widely	O
+prescribed	O
+.	O
+
+The	O
+differential	O
+effects	O
+of	O
+bupivacaine	O
+and	O
+lidocaine	O
+on	O
+prostaglandin	O
+E2	O
+release	O
+,	O
+cyclooxygenase	O
+gene	O
+expression	O
+and	O
+pain	B
+in	O
+a	O
+clinical	O
+pain	B
+model	O
+.	O
+
+BACKGROUND	O
+:	O
+In	O
+addition	O
+to	O
+blocking	O
+nociceptive	O
+input	O
+from	O
+surgical	O
+sites	O
+,	O
+long	O
+-	O
+acting	O
+local	O
+anesthetics	O
+might	O
+directly	O
+modulate	O
+inflammation	B
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+we	O
+describe	O
+the	O
+proinflammatory	O
+effects	O
+of	O
+bupivacaine	O
+on	O
+local	O
+prostaglandin	O
+E2	O
+(	O
+PGE2	O
+)	O
+production	O
+and	O
+cyclooxygenase	O
+(	O
+COX	O
+)	O
+gene	O
+expression	O
+that	O
+increases	O
+postoperative	B
+pain	I
+in	O
+human	O
+subjects	O
+.	O
+
+METHODS	O
+:	O
+Subjects	O
+(	O
+n	O
+=	O
+114	O
+)	O
+undergoing	O
+extraction	O
+of	O
+impacted	O
+third	O
+molars	O
+received	O
+either	O
+2	O
+%	O
+lidocaine	O
+or	O
+0	O
+.	O
+5	O
+%	O
+bupivacaine	O
+before	O
+surgery	O
+and	O
+either	O
+rofecoxib	O
+50	O
+mg	O
+or	O
+placebo	O
+orally	O
+90	O
+min	O
+before	O
+surgery	O
+and	O
+for	O
+the	O
+following	O
+48	O
+h	O
+.	O
+
+Oral	O
+mucosal	O
+biopsies	O
+were	O
+taken	O
+before	O
+surgery	O
+and	O
+48	O
+h	O
+after	O
+surgery	O
+.	O
+
+After	O
+extraction	O
+,	O
+a	O
+microdialysis	O
+probe	O
+was	O
+placed	O
+at	O
+the	O
+surgical	O
+site	O
+for	O
+PGE2	O
+and	O
+thromboxane	O
+B2	O
+(	O
+TXB2	O
+)	O
+measurements	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+bupivacaine	O
+/	O
+rofecoxib	O
+group	O
+reported	O
+significantly	O
+less	O
+pain	B
+,	O
+as	O
+assessed	O
+by	O
+a	O
+visual	O
+analog	O
+scale	O
+,	O
+compared	O
+with	O
+the	O
+other	O
+three	O
+treatment	O
+groups	O
+over	O
+the	O
+first	O
+4	O
+h	O
+.	O
+
+However	O
+,	O
+the	O
+bupivacaine	O
+/	O
+placebo	O
+group	O
+reported	O
+significantly	O
+more	O
+pain	B
+at	O
+24	O
+h	O
+and	O
+PGE2	O
+levels	O
+during	O
+the	O
+first	O
+4	O
+h	O
+were	O
+significantly	O
+higher	O
+than	O
+the	O
+other	O
+three	O
+treatment	O
+groups	O
+.	O
+
+Moreover	O
+,	O
+bupivacaine	O
+significantly	O
+increased	O
+COX	O
+-	O
+2	O
+gene	O
+expression	O
+at	O
+48	O
+h	O
+as	O
+compared	O
+with	O
+the	O
+lidocaine	O
+/	O
+placebo	O
+group	O
+.	O
+
+Thromboxane	O
+levels	O
+were	O
+not	O
+significantly	O
+affected	O
+by	O
+any	O
+of	O
+the	O
+treatments	O
+,	O
+indicating	O
+that	O
+the	O
+effects	O
+seen	O
+were	O
+attributable	O
+to	O
+inhibition	O
+of	O
+COX	O
+-	O
+2	O
+,	O
+but	O
+not	O
+COX	O
+-	O
+1	O
+.	O
+
+CONCLUSIONS	O
+:	O
+These	O
+results	O
+suggest	O
+that	O
+bupivacaine	O
+stimulates	O
+COX	O
+-	O
+2	O
+gene	O
+expression	O
+after	O
+tissue	B
+injury	I
+,	O
+which	O
+is	O
+associated	O
+with	O
+higher	O
+PGE2	O
+production	O
+and	O
+pain	B
+after	O
+the	O
+local	O
+anesthetic	O
+effect	O
+dissipates	O
+.	O
+
+p75NTR	O
+expression	O
+in	O
+rat	O
+urinary	O
+bladder	O
+sensory	O
+neurons	O
+and	O
+spinal	O
+cord	O
+with	O
+cyclophosphamide	O
+-	O
+induced	O
+cystitis	B
+.	O
+
+A	O
+role	O
+for	O
+nerve	O
+growth	O
+factor	O
+(	O
+NGF	O
+)	O
+in	O
+contributing	O
+to	O
+increased	O
+voiding	O
+frequency	O
+and	O
+altered	O
+sensation	O
+from	O
+the	O
+urinary	O
+bladder	O
+has	O
+been	O
+suggested	O
+.	O
+
+Previous	O
+studies	O
+have	O
+examined	O
+the	O
+expression	O
+and	O
+regulation	O
+of	O
+tyrosine	O
+kinase	O
+receptors	O
+(	O
+Trks	O
+)	O
+in	O
+micturition	O
+reflexes	O
+with	O
+urinary	B
+bladder	I
+inflammation	I
+.	O
+
+The	O
+present	O
+studies	O
+examine	O
+the	O
+expression	O
+and	O
+regulation	O
+of	O
+another	O
+receptor	O
+known	O
+to	O
+bind	O
+NGF	O
+,	O
+p75	O
+(	O
+NTR	O
+)	O
+,	O
+after	O
+various	O
+durations	O
+of	O
+bladder	B
+inflammation	I
+induced	O
+by	O
+cyclophosphamide	O
+(	O
+CYP	O
+)	O
+.	O
+
+CYP	O
+-	O
+induced	O
+cystitis	B
+increased	O
+(	O
+P	O
+<	O
+or	O
+=	O
+0	O
+.	O
+001	O
+)	O
+p75	O
+(	O
+NTR	O
+)	O
+expression	O
+in	O
+the	O
+superficial	O
+lateral	O
+and	O
+medial	O
+dorsal	O
+horn	O
+in	O
+L1	O
+-	O
+L2	O
+and	O
+L6	O
+-	O
+S1	O
+spinal	O
+segments	O
+.	O
+
+The	O
+number	O
+of	O
+p75	O
+(	O
+NTR	O
+)	O
+-	O
+immunoreactive	O
+(	O
+-	O
+IR	O
+)	O
+cells	O
+in	O
+the	O
+lumbosacral	O
+dorsal	O
+root	O
+ganglia	O
+(	O
+DRG	O
+)	O
+also	O
+increased	O
+(	O
+P	O
+<	O
+or	O
+=	O
+0	O
+.	O
+05	O
+)	O
+with	O
+CYP	O
+-	O
+induced	O
+cystitis	B
+(	O
+acute	O
+,	O
+intermediate	O
+,	O
+and	O
+chronic	O
+)	O
+.	O
+
+Quantitative	O
+,	O
+real	O
+-	O
+time	O
+polymerase	O
+chain	O
+reaction	O
+also	O
+demonstrated	O
+significant	O
+increases	O
+(	O
+P	O
+<	O
+or	O
+=	O
+0	O
+.	O
+01	O
+)	O
+in	O
+p75	O
+(	O
+NTR	O
+)	O
+mRNA	O
+in	O
+DRG	O
+with	O
+intermediate	O
+and	O
+chronic	O
+CYP	O
+-	O
+induced	O
+cystitis	B
+.	O
+
+Retrograde	O
+dye	O
+-	O
+tracing	O
+techniques	O
+with	O
+Fastblue	O
+were	O
+used	O
+to	O
+identify	O
+presumptive	O
+bladder	O
+afferent	O
+cells	O
+in	O
+the	O
+lumbosacral	O
+DRG	O
+.	O
+
+In	O
+bladder	O
+afferent	O
+cells	O
+in	O
+DRG	O
+,	O
+p75	O
+(	O
+NTR	O
+)	O
+-	O
+IR	O
+was	O
+also	O
+increased	O
+(	O
+P	O
+<	O
+or	O
+=	O
+0	O
+.	O
+01	O
+)	O
+with	O
+cystitis	B
+.	O
+
+In	O
+addition	O
+to	O
+increases	O
+in	O
+p75	O
+(	O
+NTR	O
+)	O
+-	O
+IR	O
+in	O
+DRG	O
+cell	O
+bodies	O
+,	O
+increases	O
+(	O
+P	O
+<	O
+or	O
+=	O
+0	O
+.	O
+001	O
+)	O
+in	O
+pericellular	O
+(	O
+encircling	O
+DRG	O
+cells	O
+)	O
+p75	O
+(	O
+NTR	O
+)	O
+-	O
+IR	O
+in	O
+DRG	O
+also	O
+increased	O
+.	O
+
+Confocal	O
+analyses	O
+demonstrated	O
+that	O
+pericellular	O
+p75	O
+(	O
+NTR	O
+)	O
+-	O
+IR	O
+was	O
+not	O
+colocalized	O
+with	O
+the	O
+glial	O
+marker	O
+,	O
+glial	O
+fibrillary	O
+acidic	O
+protein	O
+(	O
+GFAP	O
+)	O
+.	O
+
+These	O
+studies	O
+demonstrate	O
+that	O
+p75	O
+(	O
+NTR	O
+)	O
+expression	O
+in	O
+micturition	O
+reflexes	O
+is	O
+present	O
+constitutively	O
+and	O
+modified	O
+by	O
+bladder	B
+inflammation	I
+.	O
+
+The	O
+functional	O
+significance	O
+of	O
+p75	O
+(	O
+NTR	O
+)	O
+expression	O
+in	O
+micturition	O
+reflexes	O
+remains	O
+to	O
+be	O
+determined	O
+.	O
+
+Azathioprine	O
+-	O
+induced	O
+suicidal	O
+erythrocyte	O
+death	O
+.	O
+
+BACKGROUND	O
+:	O
+Azathioprine	O
+is	O
+widely	O
+used	O
+as	O
+an	O
+immunosuppressive	O
+drug	O
+.	O
+
+The	O
+side	O
+effects	O
+of	O
+azathioprine	O
+include	O
+anemia	B
+,	O
+which	O
+has	O
+been	O
+attributed	O
+to	O
+bone	O
+marrow	O
+suppression	O
+.	O
+
+Alternatively	O
+,	O
+anemia	B
+could	O
+result	O
+from	O
+accelerated	O
+suicidal	O
+erythrocyte	O
+death	O
+or	O
+eryptosis	O
+,	O
+which	O
+is	O
+characterized	O
+by	O
+exposure	O
+of	O
+phosphatidylserine	O
+(	O
+PS	O
+)	O
+at	O
+the	O
+erythrocyte	O
+surface	O
+and	O
+by	O
+cell	O
+shrinkage	O
+.	O
+
+METHODS	O
+:	O
+The	O
+present	O
+experiments	O
+explored	O
+whether	O
+azathioprine	O
+influences	O
+eryptosis	O
+.	O
+
+According	O
+to	O
+annexin	O
+V	O
+binding	O
+,	O
+erythrocytes	O
+from	O
+patients	O
+indeed	O
+showed	O
+a	O
+significant	O
+increase	O
+of	O
+PS	O
+exposure	O
+within	O
+1	O
+week	O
+of	O
+treatment	O
+with	O
+azathioprine	O
+.	O
+
+In	O
+a	O
+second	O
+series	O
+,	O
+cytosolic	O
+Ca2	O
++	O
+activity	O
+(	O
+Fluo3	O
+fluorescence	O
+)	O
+,	O
+cell	O
+volume	O
+(	O
+forward	O
+scatter	O
+)	O
+,	O
+and	O
+PS	O
+-	O
+exposure	O
+(	O
+annexin	O
+V	O
+binding	O
+)	O
+were	O
+determined	O
+by	O
+FACS	O
+analysis	O
+in	O
+erythrocytes	O
+from	O
+healthy	O
+volunteers	O
+.	O
+
+RESULTS	O
+:	O
+Exposure	O
+to	O
+azathioprine	O
+(	O
+>	O
+or	O
+=	O
+2	O
+microg	O
+/	O
+mL	O
+)	O
+for	O
+48	O
+hours	O
+increased	O
+cytosolic	O
+Ca2	O
++	O
+activity	O
+and	O
+annexin	O
+V	O
+binding	O
+and	O
+decreased	O
+forward	O
+scatter	O
+.	O
+
+The	O
+effect	O
+of	O
+azathioprine	O
+on	O
+both	O
+annexin	O
+V	O
+binding	O
+and	O
+forward	O
+scatter	O
+was	O
+significantly	O
+blunted	O
+in	O
+the	O
+nominal	O
+absence	O
+of	O
+extracellular	O
+Ca2	O
++	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Azathioprine	O
+triggers	O
+suicidal	O
+erythrocyte	O
+death	O
+,	O
+an	O
+effect	O
+presumably	O
+contributing	O
+to	O
+azathioprine	O
+-	O
+induced	O
+anemia	B
+.	O
+
+Levetiracetam	O
+as	O
+an	O
+adjunct	O
+to	O
+phenobarbital	O
+treatment	O
+in	O
+cats	O
+with	O
+suspected	O
+idiopathic	B
+epilepsy	I
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+assess	O
+pharmacokinetics	O
+,	O
+efficacy	O
+,	O
+and	O
+tolerability	O
+of	O
+oral	O
+levetiracetam	O
+administered	O
+as	O
+an	O
+adjunct	O
+to	O
+phenobarbital	O
+treatment	O
+in	O
+cats	O
+with	O
+poorly	O
+controlled	O
+suspected	O
+idiopathic	B
+epilepsy	I
+.	O
+
+DESIGN	O
+-	O
+Open	O
+-	O
+label	O
+,	O
+noncomparative	O
+clinical	O
+trial	O
+.	O
+
+ANIMALS	O
+:	O
+12	O
+cats	O
+suspected	O
+to	O
+have	O
+idiopathic	B
+epilepsy	I
+that	O
+was	O
+poorly	O
+controlled	O
+with	O
+phenobarbital	O
+or	O
+that	O
+had	O
+unacceptable	O
+adverse	O
+effects	O
+when	O
+treated	O
+with	O
+phenobarbital	O
+.	O
+
+PROCEDURES	O
+:	O
+Cats	O
+were	O
+treated	O
+with	O
+levetiracetam	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+[	O
+9	O
+.	O
+1	O
+mg	O
+/	O
+lb	O
+]	O
+,	O
+PO	O
+,	O
+q	O
+8	O
+h	O
+)	O
+.	O
+
+After	O
+a	O
+minimum	O
+of	O
+1	O
+week	O
+of	O
+treatment	O
+,	O
+serum	O
+levetiracetam	O
+concentrations	O
+were	O
+measured	O
+before	O
+and	O
+2	O
+,	O
+4	O
+,	O
+and	O
+6	O
+hours	O
+after	O
+drug	O
+administration	O
+,	O
+and	O
+maximum	O
+and	O
+minimum	O
+serum	O
+concentrations	O
+and	O
+elimination	O
+half	O
+-	O
+life	O
+were	O
+calculated	O
+.	O
+
+Seizure	B
+frequencies	O
+before	O
+and	O
+after	O
+initiation	O
+of	O
+levetiracetam	O
+treatment	O
+were	O
+compared	O
+,	O
+and	O
+adverse	O
+effects	O
+were	O
+recorded	O
+.	O
+
+RESULTS	O
+:	O
+Median	O
+maximum	O
+serum	O
+levetiracetam	O
+concentration	O
+was	O
+25	O
+.	O
+5	O
+microg	O
+/	O
+mL	O
+,	O
+median	O
+minimum	O
+serum	O
+levetiracetam	O
+concentration	O
+was	O
+8	O
+.	O
+3	O
+microg	O
+/	O
+mL	O
+,	O
+and	O
+median	O
+elimination	O
+half	O
+-	O
+life	O
+was	O
+2	O
+.	O
+9	O
+hours	O
+.	O
+
+Median	O
+seizure	B
+frequency	O
+prior	O
+to	O
+treatment	O
+with	O
+levetiracetam	O
+(	O
+2	O
+.	O
+1	O
+seizures	B
+/	O
+mo	O
+)	O
+was	O
+significantly	O
+higher	O
+than	O
+median	O
+seizure	B
+frequency	O
+after	O
+initiation	O
+of	O
+levetiracetam	O
+treatment	O
+(	O
+0	O
+.	O
+42	O
+seizures	B
+/	O
+mo	O
+)	O
+,	O
+and	O
+7	O
+of	O
+10	O
+cats	O
+were	O
+classified	O
+as	O
+having	O
+responded	O
+to	O
+levetiracetam	O
+treatment	O
+(	O
+ie	O
+,	O
+reduction	O
+in	O
+seizure	B
+frequency	O
+of	O
+>	O
+or	O
+=	O
+50	O
+%	O
+)	O
+.	O
+
+Two	O
+cats	O
+had	O
+transient	O
+lethargy	B
+and	O
+inappetence	B
+.	O
+
+CONCLUSIONS	O
+AND	O
+CLINICAL	O
+RELEVANCE	O
+:	O
+Results	O
+suggested	O
+that	O
+levetiracetam	O
+is	O
+well	O
+tolerated	O
+in	O
+cats	O
+and	O
+may	O
+be	O
+useful	O
+as	O
+an	O
+adjunct	O
+to	O
+phenobarbital	O
+treatment	O
+in	O
+cats	O
+with	O
+idiopathic	B
+epilepsy	I
+.	O
+
+Serotonin	O
+reuptake	O
+inhibitors	O
+,	O
+paranoia	B
+,	O
+and	O
+the	O
+ventral	O
+basal	O
+ganglia	O
+.	O
+
+Antidepressants	O
+have	O
+previously	O
+been	O
+associated	O
+with	O
+paranoid	B
+reactions	O
+in	O
+psychiatric	O
+patients	O
+.	O
+
+Five	O
+cases	O
+of	O
+paranoid	B
+exacerbation	O
+with	O
+the	O
+serotonin	O
+reuptake	O
+inhibitors	O
+fluoxetine	O
+and	O
+amitriptyline	O
+are	O
+reported	O
+here	O
+.	O
+
+Elements	O
+common	O
+to	O
+these	O
+cases	O
+included	O
+a	O
+history	O
+of	O
+paranoid	B
+symptomatology	O
+and	O
+the	O
+concomitant	O
+occurrence	O
+of	O
+depressive	B
+and	I
+psychotic	I
+symptoms	I
+.	O
+
+Complicated	O
+depressive	B
+disorders	I
+(	O
+including	O
+atypicality	O
+of	O
+course	O
+and	O
+symptomatology	O
+,	O
+chronicity	O
+,	O
+psychosis	B
+,	O
+bipolarity	O
+,	O
+and	O
+secondary	O
+onset	O
+in	O
+the	O
+course	O
+of	O
+a	O
+primary	O
+psychosis	B
+)	O
+may	O
+present	O
+particular	O
+vulnerability	O
+to	O
+paranoid	B
+exacerbations	O
+associated	O
+with	O
+serotonin	O
+reuptake	O
+inhibitors	O
+.	O
+
+Although	O
+the	O
+pharmacology	O
+and	O
+neurobiology	O
+of	O
+paranoia	B
+remain	O
+cryptic	O
+,	O
+several	O
+mechanisms	O
+,	O
+including	O
+5HT3	O
+receptor	O
+-	O
+mediated	O
+dopamine	O
+release	O
+,	O
+beta	O
+-	O
+noradrenergic	O
+receptor	O
+downregulation	O
+,	O
+or	O
+GABAB	O
+receptor	O
+upregulation	O
+acting	O
+in	O
+the	O
+vicinity	O
+of	O
+the	O
+ventral	O
+basal	O
+ganglia	O
+(	O
+possibly	O
+in	O
+lateral	O
+orbitofrontal	O
+or	O
+anterior	O
+cingulate	O
+circuits	O
+)	O
+,	O
+might	O
+apply	O
+to	O
+this	O
+phenomenon	O
+.	O
+
+These	O
+cases	O
+call	O
+attention	O
+to	O
+possible	O
+paranoid	B
+exacerbations	O
+with	O
+serotonin	O
+reuptake	O
+blockers	O
+in	O
+select	O
+patients	O
+and	O
+raise	O
+neurobiological	O
+considerations	O
+regarding	O
+paranoia	B
+.	O
+
+Clinical	O
+comparison	O
+of	O
+cardiorespiratory	O
+effects	O
+during	O
+unilateral	O
+and	O
+conventional	O
+spinal	O
+anaesthesia	O
+.	O
+
+BACKGROUND	O
+:	O
+Spinal	O
+anaesthesia	O
+is	O
+widely	O
+employed	O
+in	O
+clinical	O
+practice	O
+but	O
+has	O
+the	O
+main	O
+drawback	O
+of	O
+post	O
+-	O
+spinal	O
+block	O
+hypotension	B
+.	O
+
+Efforts	O
+must	O
+therefore	O
+continue	O
+to	O
+be	O
+made	O
+to	O
+obviate	O
+this	O
+setback	O
+OBJECTIVE	O
+:	O
+To	O
+evaluate	O
+the	O
+cardiovascular	O
+and	O
+respiratory	O
+changes	O
+during	O
+unilateral	O
+and	O
+conventional	O
+spinal	O
+anaesthesia	O
+.	O
+
+METHODS	O
+:	O
+With	O
+ethical	O
+approval	O
+,	O
+we	O
+studied	O
+74	O
+American	O
+Society	O
+of	O
+Anesthesiologists	O
+(	O
+ASA	O
+)	O
+,	O
+physical	O
+status	O
+class	O
+1	O
+and	O
+2	O
+patients	O
+scheduled	O
+for	O
+elective	O
+unilateral	O
+lower	O
+limb	O
+surgery	O
+.	O
+
+Patients	O
+were	O
+randomly	O
+allocated	O
+into	O
+one	O
+of	O
+two	O
+groups	O
+:	O
+lateral	O
+and	O
+conventional	O
+spinal	O
+anaesthesia	O
+groups	O
+.	O
+
+In	O
+the	O
+lateral	O
+position	O
+with	O
+operative	O
+side	O
+down	O
+,	O
+patients	O
+recived	O
+10	O
+mg	O
+(	O
+2mls	O
+)	O
+of	O
+0	O
+.	O
+5	O
+%	O
+hyperbaric	O
+bupivacaine	O
+through	O
+a	O
+25	O
+-	O
+gauge	O
+spinal	O
+needle	O
+.	O
+
+Patients	O
+in	O
+the	O
+unilateral	O
+group	O
+were	O
+maintained	O
+in	O
+the	O
+lateral	O
+position	O
+for	O
+15	O
+minutes	O
+following	O
+spinal	O
+injection	O
+while	O
+those	O
+in	O
+the	O
+conventional	O
+group	O
+were	O
+turned	O
+supine	O
+immediately	O
+after	O
+injection	O
+.	O
+
+Blood	O
+pressure	O
+,	O
+heart	O
+rate	O
+,	O
+respiratory	O
+rate	O
+and	O
+oxygen	O
+saturation	O
+were	O
+monitored	O
+over	O
+1	O
+hour	O
+.	O
+
+RESULTS	O
+:	O
+Three	O
+patients	O
+(	O
+8	O
+.	O
+1	O
+%	O
+)	O
+in	O
+the	O
+unilateral	O
+group	O
+and	O
+5	O
+(	O
+13	O
+.	O
+5	O
+%	O
+)	O
+in	O
+the	O
+conventional	O
+group	O
+developed	O
+hypotension	B
+,	O
+P	O
+=	O
+0	O
+.	O
+71	O
+.	O
+
+Four	O
+(	O
+10	O
+.	O
+8	O
+%	O
+)	O
+patients	O
+in	O
+the	O
+conventional	O
+group	O
+and	O
+1	O
+(	O
+2	O
+.	O
+7	O
+%	O
+)	O
+in	O
+the	O
+unilateral	O
+group	O
+,	O
+P	O
+=	O
+0	O
+.	O
+17	O
+required	O
+epinephrine	O
+infusion	O
+to	O
+treat	O
+hypotension	B
+.	O
+
+Patients	O
+in	O
+the	O
+conventional	O
+group	O
+had	O
+statistically	O
+significant	O
+greater	O
+fall	O
+in	O
+the	O
+systolic	O
+blood	O
+pressures	O
+at	O
+15	O
+,	O
+30	O
+and	O
+45	O
+minutes	O
+when	O
+compared	O
+to	O
+the	O
+baseline	O
+(	O
+P	O
+=	O
+0	O
+.	O
+003	O
+,	O
+0	O
+.	O
+001	O
+and	O
+0	O
+.	O
+004	O
+)	O
+.	O
+
+The	O
+mean	O
+respiratory	O
+rate	O
+and	O
+oxygen	O
+saturations	O
+in	O
+the	O
+two	O
+groups	O
+were	O
+similar	O
+.	O
+
+CONCLUSION	O
+:	O
+Compared	O
+to	O
+conventional	O
+spinal	O
+anaesthesia	O
+,	O
+unilateral	O
+spinal	O
+anaesthesia	O
+was	O
+associated	O
+with	O
+fewer	O
+cardiovascular	O
+perturbations	O
+.	O
+
+Also	O
+,	O
+the	O
+type	O
+of	O
+spinal	O
+block	O
+instituted	O
+affected	O
+neither	O
+the	O
+respiratory	O
+rate	O
+nor	O
+the	O
+arterial	O
+oxygen	O
+saturation	O
+.	O
+
+Spectrum	O
+of	O
+adverse	O
+events	O
+after	O
+generic	O
+HAART	O
+in	O
+southern	O
+Indian	O
+HIV	B
+-	I
+infected	I
+patients	O
+.	O
+
+To	O
+determine	O
+the	O
+incidence	O
+of	O
+clinically	O
+significant	O
+adverse	O
+events	O
+after	O
+long	O
+-	O
+term	O
+,	O
+fixed	O
+-	O
+dose	O
+,	O
+generic	O
+highly	O
+active	O
+antiretroviral	O
+therapy	O
+(	O
+HAART	O
+)	O
+use	O
+among	O
+HIV	B
+-	I
+infected	I
+individuals	O
+in	O
+South	O
+India	O
+,	O
+we	O
+examined	O
+the	O
+experiences	O
+of	O
+3154	O
+HIV	B
+-	I
+infected	I
+individuals	O
+who	O
+received	O
+a	O
+minimum	O
+of	O
+3	O
+months	O
+of	O
+generic	O
+HAART	O
+between	O
+February	O
+1996	O
+and	O
+December	O
+2006	O
+at	O
+a	O
+tertiary	O
+HIV	O
+care	O
+referral	O
+center	O
+in	O
+South	O
+India	O
+.	O
+
+The	O
+most	O
+common	O
+regimens	O
+were	O
+3TC	O
++	O
+d4T	O
++	O
+nevirapine	O
+(	O
+NVP	O
+)	O
+(	O
+54	O
+.	O
+8	O
+%	O
+)	O
+,	O
+zidovudine	O
+(	O
+AZT	O
+)	O
++	O
+3TC	O
++	O
+NVP	O
+(	O
+14	O
+.	O
+5	O
+%	O
+)	O
+,	O
+3TC	O
++	O
+d4T	O
++	O
+efavirenz	O
+(	O
+EFV	O
+)	O
+(	O
+20	O
+.	O
+1	O
+%	O
+)	O
+,	O
+and	O
+AZT	O
++	O
+3TC	O
++	O
+EFV	O
+(	O
+5	O
+.	O
+4	O
+%	O
+)	O
+.	O
+
+The	O
+most	O
+common	O
+adverse	O
+events	O
+and	O
+median	O
+CD4	O
+at	O
+time	O
+of	O
+event	O
+were	O
+rash	B
+(	O
+15	O
+.	O
+2	O
+%	O
+;	O
+CD4	O
+,	O
+285	O
+cells	O
+/	O
+microL	O
+)	O
+and	O
+peripheral	B
+neuropathy	I
+(	O
+9	O
+.	O
+0	O
+%	O
+and	O
+348	O
+cells	O
+/	O
+microL	O
+)	O
+.	O
+
+Clinically	O
+significant	O
+anemia	B
+(	O
+hemoglobin	O
+<	O
+7	O
+g	O
+/	O
+dL	O
+)	O
+was	O
+observed	O
+in	O
+5	O
+.	O
+4	O
+%	O
+of	O
+patients	O
+(	O
+CD4	O
+,	O
+165	O
+cells	O
+/	O
+microL	O
+)	O
+and	O
+hepatitis	B
+(	O
+clinical	O
+jaundice	B
+with	O
+alanine	O
+aminotransferase	O
+>	O
+5	O
+times	O
+upper	O
+limits	O
+of	O
+normal	O
+)	O
+in	O
+3	O
+.	O
+5	O
+%	O
+of	O
+patients	O
+(	O
+CD4	O
+,	O
+260	O
+cells	O
+/	O
+microL	O
+)	O
+.	O
+
+Women	O
+were	O
+significantly	O
+more	O
+likely	O
+to	O
+experience	O
+lactic	B
+acidosis	I
+,	O
+while	O
+men	O
+were	O
+significantly	O
+more	O
+likely	O
+to	O
+experience	O
+immune	B
+reconstitution	I
+syndrome	I
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Among	O
+the	O
+patients	O
+with	O
+1	O
+year	O
+of	O
+follow	O
+-	O
+up	O
+,	O
+NVP	O
+therapy	O
+was	O
+significantly	O
+associated	O
+with	O
+developing	O
+rash	B
+and	O
+d4T	O
+therapy	O
+with	O
+developing	O
+peripheral	B
+neuropathy	I
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Anemia	B
+and	O
+hepatitis	B
+often	O
+occur	O
+within	O
+12	O
+weeks	O
+of	O
+initiating	O
+generic	O
+HAART	O
+.	O
+
+Frequent	O
+and	O
+early	O
+monitoring	O
+for	O
+these	O
+toxicities	B
+is	O
+warranted	O
+in	O
+developing	O
+countries	O
+where	O
+generic	O
+HAART	O
+is	O
+increasingly	O
+available	O
+.	O
+
+Thalidomide	O
+and	O
+sensory	B
+neurotoxicity	I
+:	O
+a	O
+neurophysiological	O
+study	O
+.	O
+
+BACKGROUND	O
+:	O
+Recent	O
+studies	O
+confirmed	O
+a	O
+high	O
+incidence	O
+of	O
+sensory	B
+axonal	I
+neuropathy	I
+in	O
+patients	O
+treated	O
+with	O
+different	O
+doses	O
+of	O
+thalidomide	O
+.	O
+
+The	O
+study	O
+'	O
+s	O
+aims	O
+were	O
+to	O
+measure	O
+variations	O
+in	O
+sural	O
+nerve	O
+sensory	O
+action	O
+potential	O
+(	O
+SAP	O
+)	O
+amplitude	O
+in	O
+patients	O
+with	O
+refractory	O
+cutaneous	B
+lupus	I
+erythematosus	I
+(	O
+CLE	B
+)	O
+treated	O
+with	O
+thalidomide	O
+and	O
+use	O
+these	O
+findings	O
+to	O
+identify	O
+the	O
+neurotoxic	B
+potential	O
+of	O
+thalidomide	O
+and	O
+the	O
+recovery	O
+capacity	O
+of	O
+sensory	O
+fibres	O
+after	O
+discontinuation	O
+of	O
+treatment	O
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+Clinical	O
+and	O
+electrophysiological	O
+data	O
+in	O
+12	O
+female	O
+patients	O
+with	O
+CLE	B
+during	O
+treatment	O
+with	O
+thalidomide	O
+and	O
+up	O
+to	O
+47	O
+months	O
+after	O
+discontinuation	O
+of	O
+treatment	O
+were	O
+analysed	O
+.	O
+
+Sural	O
+nerve	O
+SAP	O
+amplitude	O
+reduction	O
+>	O
+or	O
+=	O
+40	O
+%	O
+was	O
+the	O
+criteria	O
+for	O
+discontinuing	O
+therapy	O
+.	O
+
+RESULTS	O
+:	O
+During	O
+treatment	O
+,	O
+11	O
+patients	O
+showed	O
+a	O
+reduction	O
+in	O
+sural	O
+nerve	O
+SAP	O
+amplitude	O
+compared	O
+to	O
+baseline	O
+values	O
+(	O
+9	O
+with	O
+a	O
+reduction	O
+>	O
+or	O
+=	O
+50	O
+%	O
+and	O
+2	O
+<	O
+50	O
+%	O
+)	O
+.	O
+
+One	O
+patient	O
+showed	O
+no	O
+changes	O
+in	O
+SAP	O
+amplitude	O
+.	O
+
+Five	O
+patients	O
+complained	O
+of	O
+paresthesias	B
+and	O
+leg	O
+cramps	B
+.	O
+
+After	O
+thalidomide	O
+treatment	O
+,	O
+sural	O
+SAP	O
+amplitude	O
+recovered	O
+in	O
+3	O
+patients	O
+.	O
+
+At	O
+detection	O
+of	O
+reduction	O
+in	O
+sural	O
+nerve	O
+SAP	O
+amplitude	O
+,	O
+the	O
+median	O
+thalidomide	O
+cumulative	O
+dose	O
+was	O
+21	O
+.	O
+4	O
+g	O
+.	O
+
+The	O
+threshold	O
+neurotoxic	B
+dosage	O
+is	O
+lower	O
+than	O
+previously	O
+reported	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Sural	O
+nerve	O
+SAP	O
+amplitude	O
+reduction	O
+is	O
+a	O
+reliable	O
+and	O
+sensitive	O
+marker	O
+of	O
+degeneration	O
+and	O
+recovery	O
+of	O
+sensory	O
+fibres	O
+.	O
+
+This	O
+electrophysiological	O
+parameter	O
+provides	O
+information	O
+about	O
+subclinical	O
+neurotoxic	B
+potential	O
+of	O
+thalidomide	O
+but	O
+is	O
+not	O
+helpful	O
+in	O
+predicting	O
+the	O
+appearance	O
+of	O
+sensory	O
+symptoms	O
+.	O
+
+Five	O
+cases	O
+of	O
+encephalitis	B
+during	O
+treatment	O
+of	O
+loiasis	B
+with	O
+diethylcarbamazine	O
+.	O
+
+Five	O
+cases	O
+of	O
+encephalitis	B
+following	O
+treatment	O
+with	O
+diethylcarbamazine	O
+(	O
+DEC	O
+)	O
+were	O
+observed	O
+in	O
+Congolese	O
+patients	O
+with	O
+Loa	O
+loa	O
+filariasis	B
+.	O
+
+Two	O
+cases	O
+had	O
+a	O
+fatal	O
+outcome	O
+and	O
+one	O
+resulted	O
+in	O
+severe	O
+sequelae	O
+.	O
+
+The	O
+notable	O
+fact	O
+was	O
+that	O
+this	O
+complication	O
+occurred	O
+in	O
+three	O
+patients	O
+hospitalized	O
+before	O
+treatment	O
+began	O
+,	O
+with	O
+whom	O
+particularly	O
+strict	O
+therapeutic	O
+precautions	O
+were	O
+taken	O
+,	O
+i	O
+.	O
+e	O
+.	O
+,	O
+initial	O
+dose	O
+less	O
+than	O
+10	O
+mg	O
+of	O
+DEC	O
+,	O
+very	O
+gradual	O
+dose	O
+increases	O
+,	O
+and	O
+associated	O
+anti	O
+-	O
+allergic	O
+treatment	O
+.	O
+
+This	O
+type	O
+of	O
+drug	O
+-	O
+induced	O
+complication	O
+may	O
+not	O
+be	O
+that	O
+uncommon	O
+in	O
+highly	O
+endemic	O
+regions	O
+.	O
+
+It	O
+occurs	O
+primarily	O
+,	O
+but	O
+not	O
+exclusively	O
+,	O
+in	O
+subjects	O
+presenting	O
+with	O
+a	O
+high	O
+microfilarial	O
+load	O
+.	O
+
+The	O
+relationship	O
+between	O
+the	O
+occurrence	O
+of	O
+encephalitis	B
+and	O
+the	O
+decrease	O
+in	O
+microfilaremia	B
+is	O
+evident	O
+.	O
+
+The	O
+pathophysiological	O
+mechanisms	O
+are	O
+discussed	O
+in	O
+the	O
+light	O
+of	O
+these	O
+observations	O
+and	O
+the	O
+few	O
+other	O
+comments	O
+on	O
+this	O
+subject	O
+published	O
+in	O
+the	O
+literature	O
+.	O
+
+Amiodarone	O
+-	O
+related	O
+pulmonary	B
+mass	I
+and	O
+unique	O
+membranous	B
+glomerulonephritis	I
+in	O
+a	O
+patient	O
+with	O
+valvular	B
+heart	I
+disease	I
+:	O
+Diagnostic	O
+pitfall	O
+and	O
+new	O
+findings	O
+.	O
+
+Amiodarone	O
+is	O
+an	O
+anti	O
+-	O
+arrhythmic	B
+drug	O
+for	O
+life	O
+-	O
+threatening	O
+tachycardia	B
+,	O
+but	O
+various	O
+adverse	O
+effects	O
+have	O
+been	O
+reported	O
+.	O
+
+Reported	O
+herein	O
+is	O
+an	O
+autopsy	O
+case	O
+of	O
+valvular	B
+heart	I
+disease	I
+,	O
+in	O
+a	O
+patient	O
+who	O
+developed	O
+a	O
+lung	B
+mass	I
+(	O
+1	O
+.	O
+5	O
+cm	O
+in	O
+diameter	O
+)	O
+and	O
+proteinuria	B
+(	O
+2	O
+.	O
+76	O
+g	O
+/	O
+day	O
+)	O
+after	O
+treatment	O
+with	O
+amiodarone	O
+for	O
+a	O
+long	O
+time	O
+.	O
+
+The	O
+lung	B
+mass	I
+was	O
+highly	O
+suspected	O
+to	O
+be	O
+lung	B
+cancer	I
+on	O
+CT	O
+and	O
+positron	O
+emission	O
+tomography	O
+,	O
+but	O
+histologically	O
+the	O
+lesion	O
+was	O
+composed	O
+of	O
+lymphoplasmacytic	O
+infiltrates	O
+in	O
+alveolar	O
+walls	O
+and	O
+intra	O
+-	O
+alveolar	O
+accumulation	O
+of	O
+foamy	O
+macrophages	O
+containing	O
+characteristic	O
+myelinoid	O
+bodies	O
+,	O
+indicating	O
+that	O
+it	O
+was	O
+an	O
+amiodarone	O
+-	O
+related	O
+lesion	O
+.	O
+
+In	O
+addition	O
+,	O
+the	O
+lung	O
+tissue	O
+had	O
+unevenly	O
+distributed	O
+hemosiderin	B
+deposition	O
+,	O
+and	O
+abnormally	O
+tortuous	O
+capillaries	O
+were	O
+seen	O
+in	O
+the	O
+mass	O
+and	O
+in	O
+heavily	O
+hemosiderotic	B
+lung	O
+portions	O
+outside	O
+the	O
+mass	O
+.	O
+
+In	O
+the	O
+kidneys	O
+,	O
+glomeruli	O
+had	O
+membrane	O
+spikes	O
+,	O
+prominent	O
+swelling	O
+of	O
+podocytes	O
+and	O
+subepithelial	O
+deposits	O
+,	O
+which	O
+were	O
+sometimes	O
+large	O
+and	O
+hump	O
+-	O
+like	O
+.	O
+
+Autoimmune	B
+diseases	I
+,	O
+viral	B
+hepatitis	I
+,	O
+malignant	O
+neoplasms	B
+or	O
+other	O
+diseases	O
+with	O
+a	O
+known	O
+relationship	O
+to	O
+membranous	B
+glomerulonephritis	I
+were	O
+not	O
+found	O
+.	O
+
+The	O
+present	O
+case	O
+highlights	O
+the	O
+possibility	O
+that	O
+differential	O
+diagnosis	O
+between	O
+an	O
+amiodarone	O
+-	O
+related	O
+pulmonary	B
+lesion	I
+and	O
+a	O
+neoplasm	B
+can	O
+be	O
+very	O
+difficult	O
+radiologically	O
+,	O
+and	O
+suggests	O
+that	O
+membranous	B
+glomerulonephritis	I
+might	O
+be	O
+another	O
+possible	O
+complication	O
+of	O
+amiodarone	O
+treatment	O
+.	O
+
+Risk	O
+of	O
+coronary	B
+artery	I
+disease	I
+associated	O
+with	O
+initial	O
+sulphonylurea	O
+treatment	O
+of	O
+patients	O
+with	O
+type	B
+2	I
+diabetes	I
+:	O
+a	O
+matched	O
+case	O
+-	O
+control	O
+study	O
+.	O
+
+AIMS	O
+:	O
+This	O
+study	O
+sought	O
+to	O
+assess	O
+the	O
+risk	O
+of	O
+developing	O
+coronary	B
+artery	I
+disease	I
+(	O
+CAD	B
+)	O
+associated	O
+with	O
+initial	O
+treatment	O
+of	O
+type	B
+2	I
+diabetes	I
+with	O
+different	O
+sulphonylureas	O
+.	O
+
+METHODS	O
+:	O
+In	O
+type	B
+2	I
+diabetic	I
+patients	O
+,	O
+cases	O
+who	O
+developed	O
+CAD	B
+were	O
+compared	O
+retrospectively	O
+with	O
+controls	O
+that	O
+did	O
+not	O
+.	O
+
+The	O
+20	O
+-	O
+year	O
+risk	O
+of	O
+CAD	B
+at	O
+diagnosis	O
+of	O
+diabetes	B
+,	O
+using	O
+the	O
+UKPDS	O
+risk	O
+engine	O
+,	O
+was	O
+used	O
+to	O
+match	O
+cases	O
+with	O
+controls	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+76	O
+cases	O
+of	O
+CAD	B
+were	O
+compared	O
+with	O
+152	O
+controls	O
+.	O
+
+The	O
+hazard	O
+of	O
+developing	O
+CAD	B
+(	O
+95	O
+%	O
+CI	O
+)	O
+associated	O
+with	O
+initial	O
+treatment	O
+increased	O
+by	O
+2	O
+.	O
+4	O
+-	O
+fold	O
+(	O
+1	O
+.	O
+3	O
+-	O
+4	O
+.	O
+3	O
+,	O
+P	O
+=	O
+0	O
+.	O
+004	O
+)	O
+with	O
+glibenclamide	O
+;	O
+2	O
+-	O
+fold	O
+(	O
+0	O
+.	O
+9	O
+-	O
+4	O
+.	O
+6	O
+,	O
+P	O
+=	O
+0	O
+.	O
+099	O
+)	O
+with	O
+glipizide	O
+;	O
+2	O
+.	O
+9	O
+-	O
+fold	O
+(	O
+1	O
+.	O
+6	O
+-	O
+5	O
+.	O
+1	O
+,	O
+P	O
+=	O
+0	O
+.	O
+000	O
+)	O
+with	O
+either	O
+,	O
+and	O
+was	O
+unchanged	O
+with	O
+metformin	O
+.	O
+
+The	O
+hazard	O
+decreased	O
+0	O
+.	O
+3	O
+-	O
+fold	O
+(	O
+0	O
+.	O
+7	O
+-	O
+1	O
+.	O
+7	O
+,	O
+P	O
+=	O
+0	O
+.	O
+385	O
+)	O
+with	O
+glimepiride	O
+,	O
+0	O
+.	O
+4	O
+-	O
+fold	O
+(	O
+0	O
+.	O
+7	O
+-	O
+1	O
+.	O
+3	O
+,	O
+P	O
+=	O
+0	O
+.	O
+192	O
+)	O
+with	O
+gliclazide	O
+,	O
+and	O
+0	O
+.	O
+4	O
+-	O
+fold	O
+(	O
+0	O
+.	O
+7	O
+-	O
+1	O
+.	O
+1	O
+,	O
+P	O
+=	O
+0	O
+.	O
+09	O
+)	O
+with	O
+either	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Initiating	O
+treatment	O
+of	O
+type	B
+2	I
+diabetes	I
+with	O
+glibenclamide	O
+or	O
+glipizide	O
+is	O
+associated	O
+with	O
+increased	O
+risk	O
+of	O
+CAD	B
+in	O
+comparison	O
+to	O
+gliclazide	O
+or	O
+glimepiride	O
+.	O
+
+If	O
+confirmed	O
+,	O
+this	O
+may	O
+be	O
+important	O
+because	O
+most	O
+Indian	O
+patients	O
+receive	O
+the	O
+cheaper	O
+older	O
+sulphonylureas	O
+,	O
+and	O
+present	O
+guidelines	O
+do	O
+not	O
+distinguish	O
+between	O
+individual	O
+agents	O
+.	O
+
+Reduced	O
+progression	O
+of	O
+adriamycin	O
+nephropathy	B
+in	O
+spontaneously	O
+hypertensive	B
+rats	O
+treated	O
+by	O
+losartan	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+antihypertensive	O
+effects	O
+of	O
+angiotensin	O
+II	O
+type	O
+-	O
+1	O
+receptor	O
+blocker	O
+,	O
+losartan	O
+,	O
+and	O
+its	O
+potential	O
+in	O
+slowing	O
+down	O
+renal	B
+disease	I
+progression	O
+in	O
+spontaneously	O
+hypertensive	B
+rats	O
+(	O
+SHR	O
+)	O
+with	O
+adriamycin	O
+(	O
+ADR	O
+)	O
+nephropathy	B
+.	O
+
+METHODS	O
+:	O
+Six	O
+-	O
+month	O
+-	O
+old	O
+female	O
+SHR	O
+were	O
+randomly	O
+selected	O
+in	O
+six	O
+groups	O
+.	O
+
+Two	O
+control	O
+groups	O
+(	O
+SH	O
+(	O
+6	O
+)	O
+,	O
+SH	O
+(	O
+12	O
+)	O
+)	O
+received	O
+vehicle	O
+.	O
+
+Groups	O
+ADR	O
+(	O
+6	O
+)	O
+,	O
+ADR	O
++	O
+LOS	O
+(	O
+6	O
+)	O
+and	O
+ADR	O
+(	O
+12	O
+)	O
+,	O
+and	O
+ADR	O
++	O
+LOS	O
+(	O
+12	O
+)	O
+received	O
+ADR	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+/	O
+b	O
+.	O
+w	O
+.	O
+i	O
+.	O
+v	O
+.	O
+)	O
+twice	O
+in	O
+a	O
+3	O
+-	O
+week	O
+interval	O
+.	O
+
+Group	O
+ADR	O
++	O
+LOS	O
+(	O
+6	O
+)	O
+received	O
+losartan	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+/	O
+b	O
+.	O
+w	O
+.	O
+/	O
+day	O
+by	O
+gavages	O
+)	O
+for	O
+6	O
+weeks	O
+and	O
+group	O
+ADR	O
++	O
+LOS	O
+(	O
+12	O
+)	O
+for	O
+12	O
+weeks	O
+after	O
+second	O
+injection	O
+of	O
+ADR	O
+.	O
+
+Animals	O
+were	O
+killed	O
+after	O
+6	O
+or	O
+12	O
+weeks	O
+,	O
+respectively	O
+.	O
+
+Haemodynamic	O
+measurements	O
+were	O
+performed	O
+on	O
+anaesthetized	O
+animals	O
+,	O
+blood	O
+and	O
+urine	O
+samples	O
+were	O
+taken	O
+for	O
+biochemical	O
+analysis	O
+and	O
+the	O
+left	O
+kidney	O
+was	O
+processed	O
+for	O
+morphological	O
+studies	O
+.	O
+
+RESULTS	O
+:	O
+Short	O
+-	O
+term	O
+losartan	O
+treatment	O
+,	O
+besides	O
+antihypertensive	O
+effect	O
+,	O
+improved	O
+glomerular	O
+filtration	O
+rate	O
+and	O
+ameliorated	O
+glomerulosclerosis	B
+resulting	O
+in	O
+decreased	O
+proteinuria	B
+.	O
+
+Prolonged	O
+treatment	O
+with	O
+losartan	O
+showed	O
+further	O
+reduction	O
+of	O
+glomerulosclerosis	B
+associated	O
+with	O
+reduced	O
+progression	O
+of	O
+tubular	O
+atrophy	B
+and	O
+interstitial	B
+fibrosis	I
+,	O
+thus	O
+preventing	O
+heavy	O
+proteinuria	B
+and	O
+chronic	B
+renal	I
+failure	I
+.	O
+
+Losartan	O
+reduced	O
+uraemia	B
+and	O
+increased	O
+urea	O
+clearance	O
+in	O
+advanced	O
+ADR	O
+nephropathy	B
+in	O
+SHR	O
+.	O
+
+Histological	O
+examination	O
+showed	O
+that	O
+losartan	O
+could	O
+prevent	O
+tubular	O
+atrophy	B
+,	O
+interstitial	O
+infiltration	O
+and	O
+fibrosis	B
+in	O
+ADR	O
+nephropathy	B
+.	O
+
+CONCLUSION	O
+:	O
+Losartan	O
+reduces	O
+the	O
+rate	O
+of	O
+progression	O
+of	O
+ADR	O
+-	O
+induced	O
+focal	B
+segmental	I
+glomerulosclerosis	I
+to	O
+end	B
+-	I
+stage	I
+renal	I
+disease	I
+in	O
+SHR	O
+.	O
+
+The	O
+risks	O
+of	O
+aprotinin	O
+and	O
+tranexamic	O
+acid	O
+in	O
+cardiac	O
+surgery	O
+:	O
+a	O
+one	O
+-	O
+year	O
+follow	O
+-	O
+up	O
+of	O
+1188	O
+consecutive	O
+patients	O
+.	O
+
+BACKGROUND	O
+:	O
+Our	O
+aim	O
+was	O
+to	O
+investigate	O
+postoperative	O
+complications	O
+and	O
+mortality	O
+after	O
+administration	O
+of	O
+aprotinin	O
+compared	O
+to	O
+tranexamic	O
+acid	O
+in	O
+an	O
+unselected	O
+,	O
+consecutive	O
+cohort	O
+.	O
+
+METHODS	O
+:	O
+Perioperative	O
+data	O
+from	O
+consecutive	O
+cardiac	O
+surgery	O
+patients	O
+were	O
+prospectively	O
+collected	O
+between	O
+September	O
+2005	O
+and	O
+June	O
+2006	O
+in	O
+a	O
+university	O
+-	O
+affiliated	O
+clinic	O
+(	O
+n	O
+=	O
+1188	O
+)	O
+.	O
+
+During	O
+the	O
+first	O
+5	O
+mo	O
+,	O
+596	O
+patients	O
+received	O
+aprotinin	O
+(	O
+Group	O
+A	O
+)	O
+;	O
+in	O
+the	O
+next	O
+5	O
+mo	O
+,	O
+592	O
+patients	O
+were	O
+treated	O
+with	O
+tranexamic	O
+acid	O
+(	O
+Group	O
+T	O
+)	O
+.	O
+
+Except	O
+for	O
+antifibrinolytic	O
+therapy	O
+,	O
+the	O
+anesthetic	O
+and	O
+surgical	O
+protocols	O
+remained	O
+unchanged	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+pre	O
+-	O
+and	O
+intraoperative	O
+variables	O
+were	O
+comparable	O
+between	O
+the	O
+treatment	O
+groups	O
+.	O
+
+Postoperatively	O
+,	O
+a	O
+significantly	O
+higher	O
+incidence	O
+of	O
+seizures	B
+was	O
+found	O
+in	O
+Group	O
+T	O
+(	O
+4	O
+.	O
+6	O
+%	O
+vs	O
+1	O
+.	O
+2	O
+%	O
+,	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+This	O
+difference	O
+was	O
+also	O
+significant	O
+in	O
+the	O
+primary	O
+valve	O
+surgery	O
+and	O
+the	O
+high	O
+risk	O
+surgery	O
+subgroups	O
+(	O
+7	O
+.	O
+9	O
+%	O
+vs	O
+1	O
+.	O
+2	O
+%	O
+,	O
+P	O
+=	O
+0	O
+.	O
+003	O
+;	O
+7	O
+.	O
+3	O
+%	O
+vs	O
+2	O
+.	O
+4	O
+%	O
+,	O
+P	O
+=	O
+0	O
+.	O
+035	O
+,	O
+respectively	O
+)	O
+.	O
+
+Persistent	O
+atrial	O
+fibrillation	O
+(	O
+7	O
+.	O
+9	O
+%	O
+vs	O
+2	O
+.	O
+3	O
+%	O
+,	O
+P	O
+=	O
+0	O
+.	O
+020	O
+)	O
+and	O
+renal	B
+failure	I
+(	O
+9	O
+.	O
+7	O
+%	O
+vs	O
+1	O
+.	O
+7	O
+%	O
+,	O
+P	O
+=	O
+0	O
+.	O
+002	O
+)	O
+were	O
+also	O
+more	O
+common	O
+in	O
+Group	O
+T	O
+,	O
+in	O
+the	O
+primary	O
+valve	O
+surgery	O
+subgroup	O
+.	O
+
+On	O
+the	O
+contrary	O
+,	O
+among	O
+primary	O
+coronary	O
+artery	O
+bypass	O
+surgery	O
+patients	O
+,	O
+there	O
+were	O
+more	O
+acute	O
+myocardial	B
+infarctions	I
+and	O
+renal	B
+dysfunction	I
+in	O
+Group	O
+A	O
+(	O
+5	O
+.	O
+8	O
+%	O
+vs	O
+2	O
+.	O
+0	O
+%	O
+,	O
+P	O
+=	O
+0	O
+.	O
+027	O
+;	O
+22	O
+.	O
+5	O
+%	O
+vs	O
+15	O
+.	O
+2	O
+%	O
+,	O
+P	O
+=	O
+0	O
+.	O
+036	O
+,	O
+respectively	O
+)	O
+.	O
+
+The	O
+1	O
+-	O
+yr	O
+mortality	O
+was	O
+significantly	O
+higher	O
+after	O
+aprotinin	O
+treatment	O
+in	O
+the	O
+high	O
+risk	O
+surgery	O
+group	O
+(	O
+17	O
+.	O
+7	O
+%	O
+vs	O
+9	O
+.	O
+8	O
+%	O
+,	O
+P	O
+=	O
+0	O
+.	O
+034	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+Both	O
+antifibrinolytic	O
+drugs	O
+bear	O
+the	O
+risk	O
+of	O
+adverse	O
+outcome	O
+depending	O
+on	O
+the	O
+type	O
+of	O
+cardiac	O
+surgery	O
+.	O
+
+Administration	O
+of	O
+aprotinin	O
+should	O
+be	O
+avoided	O
+in	O
+coronary	O
+artery	O
+bypass	O
+graft	O
+and	O
+high	O
+risk	O
+patients	O
+,	O
+whereas	O
+administration	O
+of	O
+tranexamic	O
+acid	O
+is	O
+not	O
+recommended	O
+in	O
+valve	O
+surgery	O
+.	O
+
+Delirium	B
+in	O
+an	O
+elderly	O
+woman	O
+possibly	O
+associated	O
+with	O
+administration	O
+of	O
+misoprostol	O
+.	O
+
+Misoprostol	O
+has	O
+been	O
+associated	O
+with	O
+adverse	O
+reactions	O
+,	O
+including	O
+gastrointestinal	O
+symptoms	O
+,	O
+gynecologic	O
+problems	O
+,	O
+and	O
+headache	B
+.	O
+
+Changes	O
+in	O
+mental	O
+status	O
+,	O
+however	O
+,	O
+have	O
+not	O
+been	O
+reported	O
+.	O
+
+We	O
+present	O
+a	O
+case	O
+in	O
+which	O
+an	O
+89	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+in	O
+a	O
+long	O
+-	O
+term	O
+care	O
+facility	O
+became	O
+confused	O
+after	O
+the	O
+initiation	O
+of	O
+misoprostol	O
+therapy	O
+.	O
+
+The	O
+patient	O
+'	O
+s	O
+change	O
+in	O
+mental	O
+status	O
+was	O
+first	O
+reported	O
+nine	O
+days	O
+after	O
+the	O
+initiation	O
+of	O
+therapy	O
+.	O
+
+Her	O
+delirium	B
+significantly	O
+improved	O
+after	O
+misoprostol	O
+was	O
+discontinued	O
+and	O
+her	O
+mental	O
+status	O
+returned	O
+to	O
+normal	O
+within	O
+a	O
+week	O
+.	O
+
+Because	O
+no	O
+other	O
+factors	O
+related	O
+to	O
+this	O
+patient	O
+changed	O
+significantly	O
+,	O
+the	O
+delirium	B
+experienced	O
+by	O
+this	O
+patient	O
+possibly	O
+resulted	O
+from	O
+misoprostol	O
+therapy	O
+.	O
+
+The	O
+biological	O
+properties	O
+of	O
+the	O
+optical	O
+isomers	O
+of	O
+propranolol	O
+and	O
+their	O
+effects	O
+on	O
+cardiac	B
+arrhythmias	I
+.	O
+
+1	O
+.	O
+
+The	O
+optical	O
+isomers	O
+of	O
+propranolol	O
+have	O
+been	O
+compared	O
+for	O
+their	O
+beta	O
+-	O
+blocking	O
+and	O
+antiarrhythmic	O
+activities	O
+.	O
+2	O
+.	O
+
+In	O
+blocking	O
+the	O
+positive	O
+inotropic	O
+and	O
+chronotropic	O
+responses	O
+to	O
+isoprenaline	O
+,	O
+(	O
++	O
+)	O
+-	O
+propranolol	O
+had	O
+less	O
+than	O
+one	O
+hundredth	O
+the	O
+potency	O
+of	O
+(	O
+-	O
+)	O
+-	O
+propranolol	O
+.	O
+
+At	O
+dose	O
+levels	O
+of	O
+(	O
++	O
+)	O
+-	O
+propranolol	O
+which	O
+attenuated	O
+the	O
+responses	O
+to	O
+isoprenaline	O
+,	O
+there	O
+was	O
+a	O
+significant	O
+prolongation	O
+of	O
+the	O
+PR	O
+interval	O
+of	O
+the	O
+electrocardiogram	O
+.	O
+3	O
+.	O
+
+The	O
+metabolic	O
+responses	O
+to	O
+isoprenaline	O
+in	O
+dogs	O
+(	O
+an	O
+increase	O
+in	O
+circulating	O
+glucose	O
+,	O
+lactate	O
+and	O
+free	O
+fatty	O
+acids	O
+)	O
+were	O
+all	O
+blocked	O
+by	O
+(	O
+-	O
+)	O
+-	O
+propranolol	O
+.	O
+
+(	O
++	O
+)	O
+-	O
+Propranolol	O
+had	O
+no	O
+effect	O
+on	O
+fatty	O
+acid	O
+mobilization	O
+but	O
+significantly	O
+reduced	O
+the	O
+increments	O
+in	O
+both	O
+lactate	O
+and	O
+glucose	O
+.	O
+4	O
+.	O
+
+Both	O
+isomers	O
+of	O
+propranolol	O
+possessed	O
+similar	O
+depressant	O
+potency	O
+on	O
+isolated	O
+atrial	O
+muscle	O
+taken	O
+from	O
+guinea	O
+-	O
+pigs	O
+.	O
+5	O
+.	O
+
+The	O
+isomers	O
+of	O
+propranolol	O
+exhibited	O
+similar	O
+local	O
+anaesthetic	O
+potencies	O
+on	O
+an	O
+isolated	O
+frog	O
+nerve	O
+preparation	O
+at	O
+a	O
+level	O
+approximately	O
+three	O
+times	O
+that	O
+of	O
+procaine	O
+.	O
+
+The	O
+racemic	O
+compound	O
+was	O
+significantly	O
+less	O
+potent	O
+than	O
+either	O
+isomer	O
+.	O
+6	O
+.	O
+
+Both	O
+isomers	O
+of	O
+propranolol	O
+were	O
+capable	O
+of	O
+preventing	O
+adrenaline	O
+-	O
+induced	O
+cardiac	B
+arrhythmias	I
+in	O
+cats	O
+anaesthetized	O
+with	O
+halothane	O
+,	O
+but	O
+the	O
+mean	O
+dose	O
+of	O
+(	O
+-	O
+)	O
+-	O
+propranolol	O
+was	O
+0	O
+.	O
+09	O
++	O
+/	O
+-	O
+0	O
+.	O
+02	O
+mg	O
+/	O
+kg	O
+whereas	O
+that	O
+of	O
+(	O
++	O
+)	O
+-	O
+propranolol	O
+was	O
+4	O
+.	O
+2	O
++	O
+/	O
+-	O
+1	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+.	O
+
+At	O
+the	O
+effective	O
+dose	O
+level	O
+of	O
+(	O
++	O
+)	O
+-	O
+propranolol	O
+there	O
+was	O
+a	O
+significant	O
+prolongation	O
+of	O
+the	O
+PR	O
+interval	O
+of	O
+the	O
+electrocardiogram	O
+.	O
+
+Blockade	O
+of	O
+arrhythmias	B
+with	O
+both	O
+isomers	O
+was	O
+surmountable	O
+by	O
+increasing	O
+the	O
+dose	O
+of	O
+adrenaline	O
+.	O
+7	O
+.	O
+
+Both	O
+isomers	O
+of	O
+propranolol	O
+were	O
+also	O
+capable	O
+of	O
+reversing	O
+ventricular	B
+tachycardia	I
+caused	O
+by	O
+ouabain	O
+in	O
+anaesthetized	O
+cats	O
+and	O
+dogs	O
+.	O
+
+The	O
+dose	O
+of	O
+(	O
+-	O
+)	O
+-	O
+propranolol	O
+was	O
+significantly	O
+smaller	O
+than	O
+that	O
+of	O
+(	O
++	O
+)	O
+-	O
+propranolol	O
+in	O
+both	O
+species	O
+but	O
+much	O
+higher	O
+than	O
+that	O
+required	O
+to	O
+produce	O
+evidence	O
+of	O
+beta	O
+-	O
+blockade	O
+.	O
+8	O
+.	O
+
+The	O
+implications	O
+of	O
+these	O
+results	O
+are	O
+discussed	O
+.	O
+
+Topotecan	O
+in	O
+combination	O
+with	O
+radiotherapy	O
+in	O
+unresectable	O
+glioblastoma	B
+:	O
+a	O
+phase	O
+2	O
+study	O
+.	O
+
+Improving	O
+glioblastoma	B
+multiforme	I
+(	O
+GBM	B
+)	O
+treatment	O
+with	O
+radio	O
+-	O
+chemotherapy	O
+remains	O
+a	O
+challenge	O
+.	O
+
+Topotecan	O
+is	O
+an	O
+attractive	O
+option	O
+as	O
+it	O
+exhibits	O
+growth	O
+inhibition	O
+of	O
+human	O
+glioma	B
+as	O
+well	O
+as	O
+brain	O
+penetration	O
+.	O
+
+The	O
+present	O
+study	O
+assessed	O
+the	O
+combination	O
+of	O
+radiotherapy	O
+(	O
+60	O
+Gy	O
+/	O
+30	O
+fractions	O
+/	O
+40	O
+days	O
+)	O
+and	O
+topotecan	O
+(	O
+0	O
+.	O
+9	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+/	O
+day	O
+on	O
+days	O
+1	O
+-	O
+5	O
+on	O
+weeks	O
+1	O
+,	O
+3	O
+and	O
+5	O
+)	O
+in	O
+50	O
+adults	O
+with	O
+histologically	O
+proven	O
+and	O
+untreated	O
+GBM	B
+.	O
+
+The	O
+incidence	O
+of	O
+non	O
+-	O
+hematological	O
+toxicities	B
+was	O
+low	O
+and	O
+grade	O
+3	O
+-	O
+4	O
+hematological	O
+toxicities	B
+were	O
+reported	O
+in	O
+20	O
+patients	O
+(	O
+mainly	O
+lymphopenia	B
+and	O
+neutropenia	B
+)	O
+.	O
+
+Partial	O
+response	O
+and	O
+stabilization	O
+rates	O
+were	O
+2	O
+%	O
+and	O
+32	O
+%	O
+,	O
+respectively	O
+,	O
+with	O
+an	O
+overall	O
+time	O
+to	O
+progression	O
+of	O
+12	O
+weeks	O
+.	O
+
+One	O
+-	O
+year	O
+overall	O
+survival	O
+(	O
+OS	O
+)	O
+rate	O
+was	O
+42	O
+%	O
+,	O
+with	O
+a	O
+median	O
+OS	O
+of	O
+40	O
+weeks	O
+.	O
+
+Topotecan	O
+in	O
+combination	O
+with	O
+radiotherapy	O
+was	O
+well	O
+tolerated	O
+.	O
+
+However	O
+,	O
+while	O
+response	O
+and	O
+stabilization	O
+concerned	O
+one	O
+-	O
+third	O
+of	O
+the	O
+patients	O
+,	O
+the	O
+study	O
+did	O
+not	O
+show	O
+increased	O
+benefits	O
+in	O
+terms	O
+of	O
+survival	O
+in	O
+patients	O
+with	O
+unresectable	O
+GBM	B
+.	O
+
+Long	O
+-	O
+term	O
+lithium	O
+therapy	O
+leading	O
+to	O
+hyperparathyroidism	B
+:	O
+a	O
+case	O
+report	O
+.	O
+
+PURPOSE	O
+:	O
+This	O
+paper	O
+reviews	O
+the	O
+effect	O
+of	O
+chronic	O
+lithium	O
+therapy	O
+on	O
+serum	O
+calcium	O
+level	O
+and	O
+parathyroid	O
+glands	O
+,	O
+its	O
+pathogenesis	O
+,	O
+and	O
+treatment	O
+options	O
+.	O
+
+We	O
+examined	O
+the	O
+case	O
+of	O
+a	O
+lithium	O
+-	O
+treated	O
+patient	O
+who	O
+had	O
+recurrent	O
+hypercalcemia	B
+to	O
+better	O
+understand	O
+the	O
+disease	O
+process	O
+.	O
+
+CONCLUSION	O
+:	O
+Primary	B
+hyperparathyroidism	I
+is	O
+a	O
+rare	O
+but	O
+potentially	O
+life	O
+-	O
+threatening	O
+side	O
+effect	O
+of	O
+long	O
+-	O
+term	O
+lithium	O
+therapy	O
+.	O
+
+Careful	O
+patient	O
+selection	O
+and	O
+long	O
+-	O
+term	O
+follow	O
+-	O
+up	O
+can	O
+reduce	O
+morbidity	O
+.	O
+
+PRACTICAL	O
+IMPLICATIONS	O
+:	O
+As	O
+much	O
+as	O
+15	O
+%	O
+of	O
+lithium	O
+-	O
+treated	O
+patients	O
+become	O
+hypercalcemic	B
+.	O
+
+By	O
+routinely	O
+monitoring	O
+serum	O
+calcium	O
+levels	O
+,	O
+healthcare	O
+providers	O
+can	O
+improve	O
+the	O
+quality	O
+of	O
+life	O
+of	O
+this	O
+patient	O
+group	O
+.	O
+
+Comparison	O
+of	O
+laryngeal	O
+mask	O
+with	O
+endotracheal	O
+tube	O
+for	O
+anesthesia	O
+in	O
+endoscopic	O
+sinus	O
+surgery	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+compare	O
+surgical	O
+conditions	O
+,	O
+including	O
+the	O
+amount	O
+of	O
+intraoperative	O
+bleeding	B
+as	O
+well	O
+as	O
+intraoperative	O
+blood	O
+pressure	O
+,	O
+during	O
+functional	O
+endoscopic	O
+sinus	O
+surgery	O
+(	O
+FESS	O
+)	O
+using	O
+flexible	O
+reinforced	O
+laryngeal	O
+mask	O
+airway	O
+(	O
+FRLMA	O
+)	O
+versus	O
+endotracheal	O
+tube	O
+(	O
+ETT	O
+)	O
+in	O
+maintaining	O
+controlled	O
+hypotension	B
+anesthesia	O
+induced	O
+by	O
+propofol	O
+-	O
+remifentanil	O
+total	O
+i	O
+.	O
+v	O
+.	O
+anesthesia	O
+(	O
+TIVA	O
+)	O
+.	O
+
+METHODS	O
+:	O
+Sixty	O
+normotensive	O
+American	O
+Society	O
+of	O
+Anesthesiologists	O
+I	O
+-	O
+II	O
+adult	O
+patients	O
+undergoing	O
+FESS	O
+under	O
+controlled	O
+hypotension	B
+anesthesia	O
+caused	O
+by	O
+propofol	O
+-	O
+remifentanil	O
+-	O
+TIVA	O
+were	O
+randomly	O
+assigned	O
+into	O
+two	O
+groups	O
+:	O
+group	O
+I	O
+,	O
+FRLMA	O
+;	O
+group	O
+II	O
+,	O
+ETT	O
+.	O
+
+Hemorrhage	B
+was	O
+measured	O
+and	O
+the	O
+visibility	O
+of	O
+the	O
+operative	O
+field	O
+was	O
+evaluated	O
+according	O
+to	O
+a	O
+six	O
+-	O
+point	O
+scale	O
+.	O
+
+RESULTS	O
+:	O
+Controlled	O
+hypotension	B
+was	O
+achieved	O
+within	O
+a	O
+shorter	O
+period	O
+using	O
+laryngeal	O
+mask	O
+using	O
+lower	O
+rates	O
+of	O
+remifentanil	O
+infusion	O
+and	O
+lower	O
+total	O
+dose	O
+of	O
+remifentanil	O
+.	O
+
+CONCLUSION	O
+:	O
+In	O
+summary	O
+,	O
+our	O
+results	O
+indicate	O
+that	O
+airway	O
+management	O
+using	O
+FRLMA	O
+during	O
+controlled	O
+hypotension	B
+anesthesia	O
+provided	O
+better	O
+surgical	O
+conditions	O
+in	O
+terms	O
+of	O
+quality	O
+of	O
+operative	O
+field	O
+and	O
+blood	O
+loss	O
+and	O
+allowed	O
+for	O
+convenient	O
+induced	O
+hypotension	B
+with	O
+low	O
+doses	O
+of	O
+remifentanil	O
+during	O
+TIVA	O
+in	O
+patients	O
+undergoing	O
+FESS	O
+.	O
+
+Nonalcoholic	B
+fatty	I
+liver	I
+disease	I
+during	O
+valproate	O
+therapy	O
+.	O
+
+Valproic	O
+acid	O
+(	O
+VPA	O
+)	O
+is	O
+effective	O
+for	O
+the	O
+treatment	O
+of	O
+many	O
+types	O
+of	O
+epilepsy	B
+,	O
+but	O
+its	O
+use	O
+can	O
+be	O
+associated	O
+with	O
+an	O
+increase	O
+in	O
+body	O
+weight	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+nonalcoholic	B
+fatty	I
+liver	I
+disease	I
+(	O
+NAFLD	B
+)	O
+arising	O
+in	O
+a	O
+child	O
+who	O
+developed	O
+obesity	B
+during	O
+VPA	O
+treatment	O
+.	O
+
+Laboratory	O
+data	O
+revealed	O
+hyperinsulinemia	B
+with	O
+insulin	B
+resistance	I
+.	O
+
+After	O
+the	O
+withdrawal	O
+of	O
+VPA	O
+therapy	O
+,	O
+our	O
+patient	O
+showed	O
+a	O
+significant	O
+weight	B
+loss	I
+,	O
+a	O
+decrease	O
+of	O
+body	O
+mass	O
+index	O
+,	O
+and	O
+normalization	O
+of	O
+metabolic	O
+and	O
+endocrine	O
+parameters	O
+;	O
+moreover	O
+,	O
+ultrasound	O
+measurements	O
+showed	O
+a	O
+complete	O
+normalization	O
+.	O
+
+The	O
+present	O
+case	O
+suggests	O
+that	O
+obesity	B
+,	O
+hyperinsulinemia	B
+,	O
+insulin	B
+resistance	I
+,	O
+and	O
+long	O
+-	O
+term	O
+treatment	O
+with	O
+VPA	O
+may	O
+be	O
+all	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+NAFLD	B
+;	O
+this	O
+side	O
+effect	O
+is	O
+reversible	O
+after	O
+VPA	O
+withdrawal	O
+.	O
+
+Carbimazole	O
+induced	O
+ANCA	B
+positive	I
+vasculitis	I
+.	O
+
+Anti	O
+-	O
+thyroid	O
+drugs	O
+,	O
+like	O
+carbimazole	O
+and	O
+propylthiouracil	O
+(	O
+PTU	O
+)	O
+are	O
+commonly	O
+prescribed	O
+for	O
+the	O
+treatment	O
+of	O
+hyperthyroidism	B
+.	O
+
+One	O
+should	O
+be	O
+aware	O
+of	O
+the	O
+side	O
+effects	O
+of	O
+antithyroid	O
+medications	O
+.	O
+
+Antineutrophil	B
+cytoplasmic	I
+antibody	I
+(	I
+ANCA	I
+)	I
+-	I
+-	I
+associated	I
+vasculitis	I
+is	O
+a	O
+potentially	O
+life	O
+-	O
+threatening	O
+adverse	O
+effect	O
+of	O
+antithyroidmedications	O
+.	O
+
+We	O
+report	O
+a	O
+patient	O
+with	O
+Graves	B
+'	I
+disease	I
+who	O
+developed	O
+ANCA	O
+positive	O
+carbimazole	O
+induced	O
+vasculitis	B
+.	O
+
+The	O
+episode	O
+was	O
+characterized	O
+by	O
+a	O
+vasculitic	B
+skin	B
+rash	I
+associated	O
+with	O
+large	O
+joint	O
+arthritis	B
+,	O
+pyrexia	B
+and	O
+parotiditis	B
+but	O
+no	O
+renal	O
+or	O
+pulmonary	O
+involvement	O
+.	O
+
+He	O
+was	O
+referred	O
+to	O
+us	O
+for	O
+neurological	O
+evaluation	O
+because	O
+he	O
+had	O
+difficulty	O
+in	O
+getting	O
+up	O
+from	O
+squatting	O
+position	O
+and	O
+was	O
+suspected	O
+to	O
+have	O
+myositis	B
+.	O
+
+Carbimazole	O
+and	O
+methimazole	O
+have	O
+a	O
+lower	O
+incidence	O
+of	O
+reported	O
+ANCA	O
+positive	O
+side	O
+effects	O
+than	O
+PUT	O
+.	O
+
+To	O
+the	O
+best	O
+of	O
+our	O
+knowledge	O
+this	O
+is	O
+the	O
+first	O
+ANCA	O
+positive	O
+carbimazole	O
+induced	O
+vasculitis	B
+case	O
+reported	O
+from	O
+India	O
+.	O
+
+Aspirin	O
+for	O
+the	O
+primary	O
+prevention	O
+of	O
+cardiovascular	O
+events	O
+:	O
+an	O
+update	O
+of	O
+the	O
+evidence	O
+for	O
+the	O
+U	O
+.	O
+S	O
+.	O
+
+Preventive	O
+Services	O
+Task	O
+Force	O
+.	O
+
+BACKGROUND	O
+:	O
+Coronary	B
+heart	I
+disease	I
+and	O
+cerebrovascular	B
+disease	I
+are	O
+leading	O
+causes	O
+of	O
+death	O
+in	O
+the	O
+United	O
+States	O
+.	O
+
+In	O
+2002	O
+,	O
+the	O
+U	O
+.	O
+S	O
+.	O
+
+Preventive	O
+Services	O
+Task	O
+Force	O
+(	O
+USPSTF	O
+)	O
+strongly	O
+recommended	O
+that	O
+clinicians	O
+discuss	O
+aspirin	O
+with	O
+adults	O
+who	O
+are	O
+at	O
+increased	O
+risk	O
+for	O
+coronary	B
+heart	I
+disease	I
+.	O
+
+PURPOSE	O
+:	O
+To	O
+determine	O
+the	O
+benefits	O
+and	O
+harms	O
+of	O
+taking	O
+aspirin	O
+for	O
+the	O
+primary	O
+prevention	O
+of	O
+myocardial	B
+infarctions	I
+,	O
+strokes	B
+,	O
+and	O
+death	O
+.	O
+
+DATA	O
+SOURCES	O
+:	O
+MEDLINE	O
+and	O
+Cochrane	O
+Library	O
+(	O
+search	O
+dates	O
+,	O
+1	O
+January	O
+2001	O
+to	O
+28	O
+August	O
+2008	O
+)	O
+,	O
+recent	O
+systematic	O
+reviews	O
+,	O
+reference	O
+lists	O
+of	O
+retrieved	O
+articles	O
+,	O
+and	O
+suggestions	O
+from	O
+experts	O
+.	O
+
+STUDY	O
+SELECTION	O
+:	O
+English	O
+-	O
+language	O
+randomized	O
+,	O
+controlled	O
+trials	O
+(	O
+RCTs	O
+)	O
+;	O
+case	O
+-	O
+control	O
+studies	O
+;	O
+meta	O
+-	O
+analyses	O
+;	O
+and	O
+systematic	O
+reviews	O
+of	O
+aspirin	O
+versus	O
+control	O
+for	O
+the	O
+primary	O
+prevention	O
+of	O
+cardiovascular	B
+disease	I
+(	O
+CVD	B
+)	O
+were	O
+selected	O
+to	O
+answer	O
+the	O
+following	O
+questions	O
+:	O
+Does	O
+aspirin	O
+decrease	O
+coronary	O
+heart	O
+events	O
+,	O
+strokes	B
+,	O
+death	O
+from	O
+coronary	O
+heart	O
+events	O
+or	O
+stroke	B
+,	O
+or	O
+all	O
+-	O
+cause	O
+mortality	O
+in	O
+adults	O
+without	O
+known	O
+CVD	B
+?	O
+
+Does	O
+aspirin	O
+increase	O
+gastrointestinal	B
+bleeding	I
+or	O
+hemorrhagic	B
+strokes	I
+?	O
+
+DATA	O
+EXTRACTION	O
+:	O
+All	O
+studies	O
+were	O
+reviewed	O
+,	O
+abstracted	O
+,	O
+and	O
+rated	O
+for	O
+quality	O
+by	O
+using	O
+predefined	O
+USPSTF	O
+criteria	O
+.	O
+
+DATA	O
+SYNTHESIS	O
+:	O
+New	O
+evidence	O
+from	O
+1	O
+good	O
+-	O
+quality	O
+RCT	O
+,	O
+1	O
+good	O
+-	O
+quality	O
+meta	O
+-	O
+analysis	O
+,	O
+and	O
+2	O
+fair	O
+-	O
+quality	O
+subanalyses	O
+of	O
+RCTs	O
+demonstrates	O
+that	O
+aspirin	O
+use	O
+reduces	O
+the	O
+number	O
+of	O
+CVD	B
+events	O
+in	O
+patients	O
+without	O
+known	O
+CVD	B
+.	O
+
+Men	O
+in	O
+these	O
+studies	O
+experienced	O
+fewer	O
+myocardial	B
+infarctions	I
+and	O
+women	O
+experienced	O
+fewer	O
+ischemic	O
+strokes	B
+.	O
+
+Aspirin	O
+does	O
+not	O
+seem	O
+to	O
+affect	O
+CVD	B
+mortality	O
+or	O
+all	O
+-	O
+cause	O
+mortality	O
+in	O
+either	O
+men	O
+or	O
+women	O
+.	O
+
+The	O
+use	O
+of	O
+aspirin	O
+for	O
+primary	O
+prevention	O
+increases	O
+the	O
+risk	O
+for	O
+major	O
+bleeding	B
+events	O
+,	O
+primarily	O
+gastrointestinal	B
+bleeding	I
+events	O
+,	O
+in	O
+both	O
+men	O
+and	O
+women	O
+.	O
+
+Men	O
+have	O
+an	O
+increased	O
+risk	O
+for	O
+hemorrhagic	B
+strokes	I
+with	O
+aspirin	O
+use	O
+.	O
+
+A	O
+new	O
+RCT	O
+and	O
+meta	O
+-	O
+analysis	O
+suggest	O
+that	O
+the	O
+risk	O
+for	O
+hemorrhagic	B
+strokes	I
+in	O
+women	O
+is	O
+not	O
+statistically	O
+significantly	O
+increased	O
+.	O
+
+LIMITATIONS	O
+:	O
+New	O
+evidence	O
+on	O
+aspirin	O
+for	O
+the	O
+primary	O
+prevention	O
+of	O
+CVD	B
+is	O
+limited	O
+.	O
+
+The	O
+dose	O
+of	O
+aspirin	O
+used	O
+in	O
+the	O
+RCTs	O
+varied	O
+,	O
+which	O
+prevented	O
+the	O
+estimation	O
+of	O
+the	O
+most	O
+appropriate	O
+dose	O
+for	O
+primary	O
+prevention	O
+.	O
+
+Several	O
+of	O
+the	O
+RCTs	O
+were	O
+conducted	O
+within	O
+populations	O
+of	O
+health	O
+professionals	O
+,	O
+which	O
+potentially	O
+limits	O
+generalizability	O
+.	O
+
+CONCLUSION	O
+:	O
+Aspirin	O
+reduces	O
+the	O
+risk	O
+for	O
+myocardial	B
+infarction	I
+in	O
+men	O
+and	O
+strokes	B
+in	O
+women	O
+.	O
+
+Aspirin	O
+use	O
+increases	O
+the	O
+risk	O
+for	O
+serious	O
+bleeding	B
+events	O
+.	O
+
+Reducing	O
+harm	O
+associated	O
+with	O
+anticoagulation	O
+:	O
+practical	O
+considerations	O
+of	O
+argatroban	O
+therapy	O
+in	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+.	O
+
+Argatroban	O
+is	O
+a	O
+hepatically	O
+metabolized	O
+,	O
+direct	O
+thrombin	O
+inhibitor	O
+used	O
+for	O
+prophylaxis	O
+or	O
+treatment	O
+of	O
+thrombosis	B
+in	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+(	O
+HIT	B
+)	O
+and	O
+for	O
+patients	O
+with	O
+or	O
+at	O
+risk	O
+of	O
+HIT	B
+undergoing	O
+percutaneous	O
+coronary	O
+intervention	O
+(	O
+PCI	O
+)	O
+.	O
+
+The	O
+objective	O
+of	O
+this	O
+review	O
+is	O
+to	O
+summarize	O
+practical	O
+considerations	O
+of	O
+argatroban	O
+therapy	O
+in	O
+HIT	B
+.	O
+
+The	O
+US	O
+FDA	O
+-	O
+recommended	O
+argatroban	O
+dose	O
+in	O
+HIT	B
+is	O
+2	O
+microg	O
+/	O
+kg	O
+/	O
+min	O
+(	O
+reduced	O
+in	O
+patients	O
+with	O
+hepatic	B
+impairment	I
+and	O
+in	O
+paediatric	O
+patients	O
+)	O
+,	O
+adjusted	O
+to	O
+achieve	O
+activated	O
+partial	O
+thromboplastin	O
+times	O
+(	O
+aPTTs	O
+)	O
+1	O
+.	O
+5	O
+-	O
+3	O
+times	O
+baseline	O
+(	O
+not	O
+>	O
+100	O
+seconds	O
+)	O
+.	O
+
+Contemporary	O
+experiences	O
+indicate	O
+that	O
+reduced	O
+doses	O
+are	O
+also	O
+needed	O
+in	O
+patients	O
+with	O
+conditions	O
+associated	O
+with	O
+hepatic	O
+hypoperfusion	O
+,	O
+e	O
+.	O
+g	O
+.	O
+heart	B
+failure	I
+,	O
+yet	O
+are	O
+unnecessary	O
+for	O
+renal	B
+dysfunction	I
+,	O
+adult	O
+age	O
+,	O
+sex	O
+,	O
+race	O
+/	O
+ethnicity	O
+or	O
+obesity	B
+.	O
+
+Argatroban	O
+0	O
+.	O
+5	O
+-	O
+1	O
+.	O
+2	O
+microg	O
+/	O
+kg	O
+/	O
+min	O
+typically	O
+supports	O
+therapeutic	O
+aPTTs	O
+.	O
+
+The	O
+FDA	O
+-	O
+recommended	O
+dose	O
+during	O
+PCI	O
+is	O
+25	O
+microg	O
+/	O
+kg	O
+/	O
+min	O
+(	O
+350	O
+microg	O
+/	O
+kg	O
+initial	O
+bolus	O
+)	O
+,	O
+adjusted	O
+to	O
+achieve	O
+activated	O
+clotting	O
+times	O
+(	O
+ACTs	O
+)	O
+of	O
+300	O
+-	O
+450	O
+sec	O
+.	O
+
+For	O
+PCI	O
+,	O
+argatroban	O
+has	O
+not	O
+been	O
+investigated	O
+in	O
+hepatically	O
+impaired	O
+patients	O
+;	O
+dose	O
+adjustment	O
+is	O
+unnecessary	O
+for	O
+adult	O
+age	O
+,	O
+sex	O
+,	O
+race	O
+/	O
+ethnicity	O
+or	O
+obesity	B
+,	O
+and	O
+lesser	O
+doses	O
+may	O
+be	O
+adequate	O
+with	O
+concurrent	O
+glycoprotein	O
+IIb	O
+/	O
+IIIa	O
+inhibition	O
+.	O
+
+Argatroban	O
+prolongs	O
+the	O
+International	O
+Normalized	O
+Ratio	O
+,	O
+and	O
+published	O
+approaches	O
+for	O
+monitoring	O
+the	O
+argatroban	O
+-	O
+to	O
+-	O
+warfarin	O
+transition	O
+should	O
+be	O
+followed	O
+.	O
+
+Major	O
+bleeding	B
+with	O
+argatroban	O
+is	O
+0	O
+-	O
+10	O
+%	O
+in	O
+the	O
+non	O
+-	O
+interventional	O
+setting	O
+and	O
+0	O
+-	O
+5	O
+.	O
+8	O
+%	O
+periprocedurally	O
+.	O
+
+Argatroban	O
+has	O
+no	O
+specific	O
+antidote	O
+,	O
+and	O
+if	O
+excessive	O
+anticoagulation	O
+occurs	O
+,	O
+argatroban	O
+infusion	O
+should	O
+be	O
+stopped	O
+or	O
+reduced	O
+.	O
+
+Improved	O
+familiarity	O
+of	O
+healthcare	O
+professionals	O
+with	O
+argatroban	O
+therapy	O
+in	O
+HIT	B
+,	O
+including	O
+in	O
+special	O
+populations	O
+and	O
+during	O
+PCI	O
+,	O
+may	O
+facilitate	O
+reduction	O
+of	O
+harm	O
+associated	O
+with	O
+HIT	B
+(	O
+e	O
+.	O
+g	O
+.	O
+fewer	O
+thromboses	O
+)	O
+or	O
+its	O
+treatment	O
+(	O
+e	O
+.	O
+g	O
+.	O
+fewer	O
+argatroban	O
+medication	O
+errors	O
+)	O
+.	O
+
+Rhabdomyolysis	B
+and	O
+brain	O
+ischemic	B
+stroke	I
+in	O
+a	O
+heroin	O
+-	O
+dependent	O
+male	O
+under	O
+methadone	O
+maintenance	O
+therapy	O
+.	O
+
+OBJECTIVE	O
+:	O
+There	O
+are	O
+several	O
+complications	O
+associated	O
+with	O
+heroin	B
+abuse	I
+,	O
+some	O
+of	O
+which	O
+are	O
+life	O
+-	O
+threatening	O
+.	O
+
+Methadone	O
+may	O
+aggravate	O
+this	O
+problem	O
+.	O
+
+METHOD	O
+:	O
+A	O
+clinical	O
+case	O
+description	O
+.	O
+
+RESULTS	O
+:	O
+A	O
+33	O
+-	O
+year	O
+-	O
+old	O
+man	O
+presented	O
+with	O
+rhabdomyolysis	B
+and	O
+cerebral	O
+ischemic	B
+stroke	I
+after	O
+intravenous	O
+heroin	O
+.	O
+
+He	O
+had	O
+used	O
+heroin	O
+since	O
+age	O
+20	O
+,	O
+and	O
+had	O
+used	O
+150	O
+mg	O
+methadone	O
+daily	O
+for	O
+6	O
+months	O
+.	O
+
+He	O
+was	O
+found	O
+unconsciousness	B
+at	O
+home	O
+and	O
+was	O
+sent	O
+to	O
+our	O
+hospital	O
+.	O
+
+In	O
+the	O
+ER	O
+,	O
+his	O
+opiate	O
+level	O
+was	O
+4497	O
+ng	O
+/	O
+ml	O
+.	O
+
+In	O
+the	O
+ICU	O
+,	O
+we	O
+found	O
+rhabdomyolysis	B
+,	O
+acute	B
+renal	I
+failure	I
+and	O
+acute	O
+respiratory	B
+failure	I
+.	O
+
+After	O
+transfer	O
+to	O
+an	O
+internal	O
+ward	O
+,	O
+we	O
+noted	O
+aphasia	B
+and	O
+weakness	B
+of	O
+his	O
+left	O
+limbs	O
+.	O
+
+After	O
+MRI	O
+,	O
+we	O
+found	O
+cerebral	B
+ischemic	I
+infarction	I
+.	O
+
+CONCLUSION	O
+:	O
+Those	O
+using	O
+methadone	O
+and	O
+heroin	O
+simultaneously	O
+may	O
+increase	O
+risk	O
+of	O
+rhabdomyolysis	B
+and	O
+ischemic	B
+stroke	I
+.	O
+
+Patients	O
+under	O
+methadone	O
+maintenance	O
+therapy	O
+should	O
+be	O
+warned	O
+regarding	O
+these	O
+serious	O
+adverse	O
+events	O
+.	O
+
+Hypotheses	O
+of	O
+heroin	O
+-	O
+related	O
+rhabdomyolysis	B
+and	O
+stroke	B
+in	O
+heroin	O
+abusers	O
+are	O
+discussed	O
+.	O
+
+Increased	O
+vulnerability	O
+to	O
+6	O
+-	O
+hydroxydopamine	O
+lesion	O
+and	O
+reduced	O
+development	O
+of	O
+dyskinesias	B
+in	O
+mice	O
+lacking	O
+CB1	O
+cannabinoid	O
+receptors	O
+.	O
+
+Motor	O
+impairment	O
+,	O
+dopamine	O
+(	O
+DA	O
+)	O
+neuronal	O
+activity	O
+and	O
+proenkephalin	O
+(	O
+PENK	O
+)	O
+gene	O
+expression	O
+in	O
+the	O
+caudate	O
+-	O
+putamen	O
+(	O
+CPu	O
+)	O
+were	O
+measured	O
+in	O
+6	O
+-	O
+OHDA	O
+-	O
+lesioned	O
+and	O
+treated	O
+(	O
+L	O
+-	O
+DOPA	O
++	O
+benserazide	O
+)	O
+CB1	O
+KO	O
+and	O
+WT	O
+mice	O
+.	O
+
+A	O
+lesion	O
+induced	O
+by	O
+6	O
+-	O
+OHDA	O
+produced	O
+more	O
+severe	O
+motor	O
+deterioration	O
+in	O
+CB1	O
+KO	O
+mice	O
+accompanied	O
+by	O
+more	O
+loss	O
+of	O
+DA	O
+neurons	O
+and	O
+increased	O
+PENK	O
+gene	O
+expression	O
+in	O
+the	O
+CPu	O
+.	O
+
+Oxidative	O
+/	O
+nitrosative	O
+and	O
+neuroinflammatory	O
+parameters	O
+were	O
+estimated	O
+in	O
+the	O
+CPu	O
+and	O
+cingulate	O
+cortex	O
+(	O
+Cg	O
+)	O
+.	O
+
+CB1	O
+KO	O
+mice	O
+exhibited	O
+higher	O
+MDA	O
+levels	O
+and	O
+iNOS	O
+protein	O
+expression	O
+in	O
+the	O
+CPu	O
+and	O
+Cg	O
+compared	O
+to	O
+WT	O
+mice	O
+.	O
+
+Treatment	O
+with	O
+L	O
+-	O
+DOPA	O
++	O
+benserazide	O
+(	O
+12	O
+weeks	O
+)	O
+resulted	O
+in	O
+less	O
+severe	O
+dyskinesias	B
+in	O
+CB1	O
+KO	O
+than	O
+in	O
+WT	O
+mice	O
+.	O
+
+The	O
+results	O
+revealed	O
+that	O
+the	O
+lack	O
+of	O
+cannabinoid	O
+CB1	O
+receptors	O
+increased	O
+the	O
+severity	O
+of	O
+motor	O
+impairment	O
+and	O
+DA	O
+lesion	O
+,	O
+and	O
+reduced	O
+L	O
+-	O
+DOPA	O
+-	O
+induced	O
+dyskinesias	B
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+activation	O
+of	O
+CB1	O
+receptors	O
+offers	O
+neuroprotection	O
+against	O
+dopaminergic	O
+lesion	O
+and	O
+the	O
+development	O
+of	O
+L	O
+-	O
+DOPA	O
+-	O
+induced	O
+dyskinesias	B
+.	O
+
+Hepatocellular	O
+oxidant	O
+stress	O
+following	O
+intestinal	O
+ischemia	B
+-	O
+reperfusion	B
+injury	I
+.	O
+
+Reperfusion	O
+of	O
+ischemic	B
+intestine	O
+results	O
+in	O
+acute	O
+liver	B
+dysfunction	I
+characterized	O
+by	O
+hepatocellular	O
+enzyme	O
+release	O
+into	O
+plasma	O
+,	O
+reduction	O
+in	O
+bile	O
+flow	O
+rate	O
+,	O
+and	O
+neutrophil	O
+sequestration	O
+within	O
+the	O
+liver	O
+.	O
+
+The	O
+pathophysiology	O
+underlying	O
+this	O
+acute	O
+hepatic	B
+injury	I
+is	O
+unknown	O
+.	O
+
+This	O
+study	O
+was	O
+undertaken	O
+to	O
+determine	O
+whether	O
+oxidants	O
+are	O
+associated	O
+with	O
+the	O
+hepatic	B
+injury	I
+and	O
+to	O
+determine	O
+the	O
+relative	O
+value	O
+of	O
+several	O
+indirect	O
+methods	O
+of	O
+assessing	O
+oxidant	O
+exposure	O
+in	O
+vivo	O
+.	O
+
+Rats	O
+were	O
+subjected	O
+to	O
+a	O
+standardized	O
+intestinal	O
+ischemia	B
+-	O
+reperfusion	B
+injury	I
+.	O
+
+Hepatic	O
+tissue	O
+was	O
+assayed	O
+for	O
+lipid	O
+peroxidation	O
+products	O
+and	O
+oxidized	O
+and	O
+reduced	O
+glutathione	O
+.	O
+
+There	O
+was	O
+no	O
+change	O
+in	O
+hepatic	O
+tissue	O
+total	O
+glutathione	O
+following	O
+intestinal	O
+ischemia	B
+-	O
+reperfusion	B
+injury	I
+.	O
+
+Oxidized	O
+glutathione	O
+(	O
+GSSG	O
+)	O
+increased	O
+significantly	O
+following	O
+30	O
+and	O
+60	O
+min	O
+of	O
+reperfusion	O
+.	O
+
+There	O
+was	O
+no	O
+increase	O
+in	O
+any	O
+of	O
+the	O
+products	O
+of	O
+lipid	O
+peroxidation	O
+associated	O
+with	O
+this	O
+injury	O
+.	O
+
+An	O
+increase	O
+in	O
+GSSG	O
+within	O
+hepatic	O
+tissue	O
+during	O
+intestinal	O
+reperfusion	O
+suggests	O
+exposure	O
+of	O
+hepatocytes	O
+to	O
+an	O
+oxidant	O
+stress	O
+.	O
+
+The	O
+lack	O
+of	O
+a	O
+significant	O
+increase	O
+in	O
+products	O
+of	O
+lipid	O
+peroxidation	O
+suggests	O
+that	O
+the	O
+oxidant	O
+stress	O
+is	O
+of	O
+insufficient	O
+magnitude	O
+to	O
+result	O
+in	O
+irreversible	O
+injury	O
+to	O
+hepatocyte	O
+cell	O
+membranes	O
+.	O
+
+These	O
+data	O
+also	O
+suggest	O
+that	O
+the	O
+measurement	O
+of	O
+tissue	O
+GSSG	O
+may	O
+be	O
+a	O
+more	O
+sensitive	O
+indicator	O
+of	O
+oxidant	O
+stress	O
+than	O
+measurement	O
+of	O
+products	O
+of	O
+lipid	O
+peroxidation	O
+.	O
+
+Animal	O
+model	O
+of	O
+mania	B
+induced	O
+by	O
+ouabain	O
+:	O
+Evidence	O
+of	O
+oxidative	O
+stress	O
+in	O
+submitochondrial	O
+particles	O
+of	O
+the	O
+rat	O
+brain	O
+.	O
+
+The	O
+intracerebroventricular	O
+(	O
+ICV	O
+)	O
+administration	O
+of	O
+ouabain	O
+(	O
+a	O
+Na	O
+(	O
++	O
+)	O
+/	O
+K	O
+(	O
++	O
+)	O
+-	O
+ATPase	O
+inhibitor	O
+)	O
+in	O
+rats	O
+has	O
+been	O
+suggested	O
+to	O
+mimic	O
+some	O
+symptoms	O
+of	O
+human	O
+bipolar	B
+mania	I
+.	O
+
+Clinical	O
+studies	O
+have	O
+shown	O
+that	O
+bipolar	B
+disorder	I
+may	O
+be	O
+related	O
+to	O
+mitochondrial	B
+dysfunction	I
+.	O
+
+Herein	O
+,	O
+we	O
+investigated	O
+the	O
+behavioral	O
+and	O
+biochemical	O
+effects	O
+induced	O
+by	O
+the	O
+ICV	O
+administration	O
+of	O
+ouabain	O
+in	O
+rats	O
+.	O
+
+To	O
+achieve	O
+this	O
+aim	O
+,	O
+the	O
+effects	O
+of	O
+ouabain	O
+injection	O
+immediately	O
+after	O
+and	O
+7	O
+days	O
+following	O
+a	O
+single	O
+ICV	O
+administration	O
+(	O
+at	O
+concentrations	O
+of	O
+10	O
+(	O
+-	O
+2	O
+)	O
+and	O
+10	O
+(	O
+-	O
+3	O
+)	O
+M	O
+)	O
+on	O
+locomotion	O
+was	O
+measured	O
+using	O
+the	O
+open	O
+-	O
+field	O
+test	O
+.	O
+
+Additionally	O
+,	O
+thiobarbituric	O
+acid	O
+reactive	O
+substances	O
+(	O
+TBARSs	O
+)	O
+and	O
+superoxide	O
+production	O
+were	O
+measured	O
+in	O
+submitochondrial	O
+particles	O
+of	O
+the	O
+prefrontal	O
+cortex	O
+,	O
+hippocampus	O
+,	O
+striatum	O
+and	O
+amygdala	O
+.	O
+
+Our	O
+findings	O
+demonstrated	O
+that	O
+ouabain	O
+at	O
+10	O
+(	O
+-	O
+2	O
+)	O
+and	O
+10	O
+(	O
+-	O
+3	O
+)	O
+M	O
+induced	O
+hyperlocomotion	B
+in	O
+rats	O
+,	O
+and	O
+this	O
+response	O
+remained	O
+up	O
+to	O
+7	O
+days	O
+following	O
+a	O
+single	O
+ICV	O
+injection	O
+.	O
+
+In	O
+addition	O
+,	O
+we	O
+observed	O
+that	O
+the	O
+persistent	O
+increase	O
+in	O
+the	O
+rat	O
+spontaneous	O
+locomotion	O
+is	O
+associated	O
+with	O
+increased	O
+TBARS	O
+levels	O
+and	O
+superoxide	O
+generation	O
+in	O
+submitochondrial	O
+particles	O
+in	O
+the	O
+prefrontal	O
+cortex	O
+,	O
+striatum	O
+and	O
+amygdala	O
+.	O
+
+In	O
+conclusion	O
+,	O
+ouabain	O
+-	O
+induced	O
+mania	B
+-	O
+like	O
+behavior	O
+may	O
+provide	O
+a	O
+useful	O
+animal	O
+model	O
+to	O
+test	O
+the	O
+hypothesis	O
+of	O
+the	O
+involvement	O
+of	O
+oxidative	O
+stress	O
+in	O
+bipolar	B
+disorder	I
+.	O
+
+Intraoperative	O
+dialysis	O
+during	O
+liver	O
+transplantation	O
+with	O
+citrate	O
+dialysate	O
+.	O
+
+Liver	O
+transplantation	O
+for	O
+acutely	O
+ill	O
+patients	O
+with	O
+fulminant	B
+liver	I
+failure	I
+carries	O
+high	O
+intraoperative	O
+and	O
+immediate	O
+postoperative	O
+risks	O
+.	O
+
+These	O
+are	O
+increased	O
+with	O
+the	O
+presence	O
+of	O
+concomitant	O
+acute	B
+kidney	I
+injury	I
+(	O
+AKI	B
+)	O
+and	O
+intraoperative	O
+dialysis	O
+is	O
+sometimes	O
+required	O
+to	O
+allow	O
+the	O
+transplant	O
+to	O
+proceed	O
+.	O
+
+The	O
+derangements	O
+in	O
+the	O
+procoagulant	O
+and	O
+anticoagulant	O
+pathways	O
+during	O
+fulminant	B
+liver	I
+failure	I
+can	O
+lead	O
+to	O
+difficulties	O
+with	O
+anticoagulation	O
+during	O
+dialysis	O
+,	O
+especially	O
+when	O
+continued	O
+in	O
+the	O
+operating	O
+room	O
+.	O
+
+Systemic	O
+anticoagulation	O
+is	O
+unsafe	O
+and	O
+regional	O
+citrate	O
+anticoagulation	O
+in	O
+the	O
+absence	O
+of	O
+a	O
+functional	O
+liver	O
+carries	O
+the	O
+risk	O
+of	O
+citrate	O
+toxicity	B
+.	O
+
+Citrate	O
+dialysate	O
+,	O
+a	O
+new	O
+dialysate	O
+with	O
+citric	O
+acid	O
+can	O
+be	O
+used	O
+for	O
+anticoagulation	O
+in	O
+patients	O
+who	O
+cannot	O
+tolerate	O
+heparin	O
+or	O
+regional	O
+citrate	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+a	O
+40	O
+-	O
+year	O
+-	O
+old	O
+female	O
+with	O
+acetaminophen	O
+-	O
+induced	O
+fulminant	B
+liver	I
+failure	I
+with	O
+associated	O
+AKI	B
+who	O
+underwent	O
+intraoperative	O
+dialytic	O
+support	O
+during	O
+liver	O
+transplantation	O
+anticoagulated	O
+with	O
+citrate	O
+dialysate	O
+during	O
+the	O
+entire	O
+procedure	O
+.	O
+
+The	O
+patient	O
+tolerated	O
+the	O
+procedure	O
+well	O
+without	O
+any	O
+signs	O
+of	O
+citrate	O
+toxicity	B
+and	O
+maintained	O
+adequate	O
+anticoagulation	O
+for	O
+patency	O
+of	O
+the	O
+dialysis	O
+circuit	O
+.	O
+
+Citrate	O
+dialysate	O
+is	O
+a	O
+safe	O
+alternative	O
+for	O
+intradialytic	O
+support	O
+of	O
+liver	O
+transplantation	O
+in	O
+fulminant	B
+liver	I
+failure	I
+.	O
+
+Delirium	B
+in	O
+a	O
+patient	O
+with	O
+toxic	O
+flecainide	O
+plasma	O
+concentrations	O
+:	O
+the	O
+role	O
+of	O
+a	O
+pharmacokinetic	O
+drug	O
+interaction	O
+with	O
+paroxetine	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+describe	O
+a	O
+case	O
+of	O
+flecainide	O
+-	O
+induced	O
+delirium	B
+associated	O
+with	O
+a	O
+pharmacokinetic	O
+drug	O
+interaction	O
+with	O
+paroxetine	O
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+69	O
+-	O
+year	O
+-	O
+old	O
+white	O
+female	O
+presented	O
+to	O
+the	O
+emergency	O
+department	O
+with	O
+a	O
+history	O
+of	O
+confusion	B
+and	O
+paranoia	B
+over	O
+the	O
+past	O
+several	O
+days	O
+.	O
+
+On	O
+admission	O
+the	O
+patient	O
+was	O
+taking	O
+carvedilol	O
+12	O
+mg	O
+twice	O
+daily	O
+,	O
+warfarin	O
+2	O
+mg	O
+/	O
+day	O
+,	O
+folic	O
+acid	O
+1	O
+mg	O
+/	O
+day	O
+,	O
+levothyroxine	O
+100	O
+microg	O
+/	O
+day	O
+,	O
+pantoprazole	O
+40	O
+mg	O
+/	O
+day	O
+,	O
+paroxetine	O
+40	O
+mg	O
+/	O
+day	O
+,	O
+and	O
+flecainide	O
+100	O
+mg	O
+twice	O
+daily	O
+.	O
+
+Flecainide	O
+had	O
+been	O
+started	O
+2	O
+weeks	O
+prior	O
+for	O
+atrial	B
+fibrillation	I
+.	O
+
+Laboratory	O
+test	O
+findings	O
+on	O
+admission	O
+were	O
+notable	O
+only	O
+for	O
+a	O
+flecainide	O
+plasma	O
+concentration	O
+of	O
+1360	O
+microg	O
+/	O
+L	O
+(	O
+reference	O
+range	O
+200	O
+-	O
+1000	O
+)	O
+.	O
+
+A	O
+metabolic	O
+drug	O
+interaction	O
+between	O
+flecainide	O
+and	O
+paroxetine	O
+,	O
+which	O
+the	O
+patient	O
+had	O
+been	O
+taking	O
+for	O
+more	O
+than	O
+5	O
+years	O
+,	O
+was	O
+considered	O
+.	O
+
+Paroxetine	O
+was	O
+discontinued	O
+and	O
+the	O
+dose	O
+of	O
+flecainide	O
+was	O
+reduced	O
+to	O
+50	O
+mg	O
+twice	O
+daily	O
+.	O
+
+Her	O
+delirium	B
+resolved	O
+3	O
+days	O
+later	O
+.	O
+
+DISCUSSION	O
+:	O
+Flecainide	O
+and	O
+pharmacologically	O
+similar	O
+agents	O
+that	O
+interact	O
+with	O
+sodium	O
+channels	O
+may	O
+cause	O
+delirium	B
+in	O
+susceptible	O
+patients	O
+.	O
+
+A	O
+MEDLINE	O
+search	O
+(	O
+1966	O
+-	O
+January	O
+2009	O
+)	O
+revealed	O
+one	O
+in	O
+vivo	O
+pharmacokinetic	O
+study	O
+on	O
+the	O
+interaction	O
+between	O
+flecainide	O
+,	O
+a	O
+CYP2D6	O
+substrate	O
+,	O
+and	O
+paroxetine	O
+,	O
+a	O
+CYP2D6	O
+inhibitor	O
+,	O
+as	O
+well	O
+as	O
+3	O
+case	O
+reports	O
+of	O
+flecainide	O
+-	O
+induced	O
+delirium	B
+.	O
+
+According	O
+to	O
+the	O
+Naranjo	O
+probability	O
+scale	O
+,	O
+flecainide	O
+was	O
+the	O
+probable	O
+cause	O
+of	O
+the	O
+patient	O
+'	O
+s	O
+delirium	B
+;	O
+the	O
+Horn	O
+Drug	O
+Interaction	O
+Probability	O
+Scale	O
+indicates	O
+a	O
+possible	O
+pharmacokinetic	O
+drug	O
+interaction	O
+between	O
+flecainide	O
+and	O
+paroxetine	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Supratherapeutic	O
+flecainide	O
+plasma	O
+concentrations	O
+may	O
+cause	O
+delirium	B
+.	O
+
+Because	O
+toxicity	B
+may	O
+occur	O
+when	O
+flecainide	O
+is	O
+prescribed	O
+with	O
+paroxetine	O
+and	O
+other	O
+potent	O
+CYP2D6	O
+inhibitors	O
+,	O
+flecainide	O
+plasma	O
+concentrations	O
+should	O
+be	O
+monitored	O
+closely	O
+with	O
+commencement	O
+of	O
+CYP2D6	O
+inhibitors	O
+.	O
+
+Efficacy	O
+of	O
+everolimus	O
+(	O
+RAD001	O
+)	O
+in	O
+patients	O
+with	O
+advanced	O
+NSCLC	B
+previously	O
+treated	O
+with	O
+chemotherapy	O
+alone	O
+or	O
+with	O
+chemotherapy	O
+and	O
+EGFR	O
+inhibitors	O
+.	O
+
+BACKGROUND	O
+:	O
+Treatment	O
+options	O
+are	O
+scarce	O
+in	O
+pretreated	O
+advanced	O
+non	B
+-	I
+small	I
+-	I
+cell	I
+lung	I
+cancer	I
+(	O
+NSCLC	B
+)	O
+patients	O
+.	O
+
+RAD001	O
+,	O
+an	O
+oral	O
+inhibitor	O
+of	O
+the	O
+mammalian	O
+target	O
+of	O
+rapamycin	O
+(	O
+mTOR	O
+)	O
+,	O
+has	O
+shown	O
+phase	O
+I	O
+efficacy	O
+in	O
+NSCLC	B
+.	O
+
+METHODS	O
+:	O
+Stage	O
+IIIb	O
+or	O
+IV	O
+NSCLC	B
+patients	O
+,	O
+with	O
+two	O
+or	O
+fewer	O
+prior	O
+chemotherapy	O
+regimens	O
+,	O
+one	O
+platinum	O
+based	O
+(	O
+stratum	O
+1	O
+)	O
+or	O
+both	O
+chemotherapy	O
+and	O
+epidermal	O
+growth	O
+factor	O
+receptor	O
+tyrosine	O
+kinase	O
+inhibitors	O
+(	O
+stratum	O
+2	O
+)	O
+,	O
+received	O
+RAD001	O
+10	O
+mg	O
+/	O
+day	O
+until	O
+progression	O
+or	O
+unacceptable	O
+toxicity	B
+.	O
+
+Primary	O
+objective	O
+was	O
+overall	O
+response	O
+rate	O
+(	O
+ORR	O
+)	O
+.	O
+
+Analyses	O
+of	O
+markers	O
+associated	O
+with	O
+the	O
+mTOR	O
+pathway	O
+were	O
+carried	O
+out	O
+on	O
+archival	O
+tumor	B
+from	O
+a	O
+subgroup	O
+using	O
+immunohistochemistry	O
+(	O
+IHC	O
+)	O
+and	O
+direct	O
+mutation	O
+sequencing	O
+.	O
+
+RESULTS	O
+:	O
+Eighty	O
+-	O
+five	O
+patients	O
+were	O
+enrolled	O
+,	O
+42	O
+in	O
+stratum	O
+1	O
+and	O
+43	O
+in	O
+stratum	O
+.	O
+
+ORR	O
+was	O
+4	O
+.	O
+7	O
+%	O
+(	O
+7	O
+.	O
+1	O
+%	O
+stratum	O
+1	O
+;	O
+2	O
+.	O
+3	O
+%	O
+stratum	O
+2	O
+)	O
+.	O
+
+Overall	O
+disease	O
+control	O
+rate	O
+was	O
+47	O
+.	O
+1	O
+%	O
+.	O
+
+Median	O
+progression	O
+-	O
+free	O
+survivals	O
+(	O
+PFSs	O
+)	O
+were	O
+2	O
+.	O
+6	O
+(	O
+stratum	O
+1	O
+)	O
+and	O
+2	O
+.	O
+7	O
+months	O
+(	O
+stratum	O
+2	O
+)	O
+.	O
+
+Common	O
+>	O
+or	O
+=	O
+grade	O
+3	O
+events	O
+were	O
+fatigue	B
+,	O
+dyspnea	B
+,	O
+stomatitis	B
+,	O
+anemia	B
+,	O
+and	O
+thrombocytopenia	B
+.	O
+
+Pneumonitis	B
+,	O
+probably	O
+or	O
+possibly	O
+related	O
+,	O
+mainly	O
+grade	O
+1	O
+/	O
+2	O
+,	O
+occurred	O
+in	O
+25	O
+%	O
+.	O
+
+Cox	O
+regression	O
+analysis	O
+of	O
+IHC	O
+scores	O
+found	O
+that	O
+only	O
+phospho	O
+AKT	O
+(	O
+pAKT	O
+)	O
+was	O
+a	O
+significant	O
+independent	O
+predictor	O
+of	O
+worse	O
+PFS	O
+.	O
+
+CONCLUSIONS	O
+:	O
+RAD001	O
+10	O
+mg	O
+/	O
+day	O
+was	O
+well	O
+tolerated	O
+,	O
+showing	O
+modest	O
+clinical	O
+activity	O
+in	O
+pretreated	O
+NSCLC	B
+.	O
+
+Evaluation	O
+of	O
+RAD001	O
+plus	O
+standard	O
+therapy	O
+for	O
+metastatic	O
+NSCLC	B
+continues	O
+.	O
+
+Posttransplant	O
+anemia	B
+:	O
+the	O
+role	O
+of	O
+sirolimus	O
+.	O
+
+Posttransplant	O
+anemia	B
+is	O
+a	O
+common	O
+problem	O
+that	O
+may	O
+hinder	O
+patients	O
+'	O
+quality	O
+of	O
+life	O
+.	O
+
+It	O
+occurs	O
+in	O
+12	O
+to	O
+76	O
+%	O
+of	O
+patients	O
+,	O
+and	O
+is	O
+most	O
+common	O
+in	O
+the	O
+immediate	O
+posttransplant	O
+period	O
+.	O
+
+A	O
+variety	O
+of	O
+factors	O
+have	O
+been	O
+identified	O
+that	O
+increase	O
+the	O
+risk	O
+of	O
+posttransplant	O
+anemia	B
+,	O
+of	O
+which	O
+the	O
+level	O
+of	O
+renal	O
+function	O
+is	O
+most	O
+important	O
+.	O
+
+Sirolimus	O
+,	O
+a	O
+mammalian	O
+target	O
+of	O
+rapamycin	O
+inhibitor	O
+,	O
+has	O
+been	O
+implicated	O
+as	O
+playing	O
+a	O
+special	O
+role	O
+in	O
+posttransplant	O
+anemia	B
+.	O
+
+This	O
+review	O
+considers	O
+anemia	B
+associated	O
+with	O
+sirolimus	O
+,	O
+including	O
+its	O
+presentation	O
+,	O
+mechanisms	O
+,	O
+and	O
+management	O
+.	O
+
+Coronary	O
+computerized	O
+tomography	O
+angiography	O
+for	O
+rapid	O
+discharge	O
+of	O
+low	O
+-	O
+risk	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B
+pain	I
+.	O
+
+BACKGROUND	O
+:	O
+Most	O
+patients	O
+presenting	O
+to	O
+emergency	O
+departments	O
+(	O
+EDs	O
+)	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B
+pain	I
+are	O
+admitted	O
+for	O
+at	O
+least	O
+12	O
+hours	O
+and	O
+receive	O
+a	O
+"	O
+rule	O
+out	O
+acute	B
+coronary	I
+syndrome	I
+"	O
+protocol	O
+,	O
+often	O
+with	O
+noninvasive	O
+testing	O
+prior	O
+to	O
+discharge	O
+.	O
+
+In	O
+patients	O
+without	O
+cocaine	O
+use	O
+,	O
+coronary	O
+computerized	O
+tomography	O
+angiography	O
+(	O
+CTA	O
+)	O
+has	O
+been	O
+shown	O
+to	O
+be	O
+useful	O
+for	O
+identifying	O
+a	O
+group	O
+of	O
+patients	O
+at	O
+low	O
+risk	O
+for	O
+cardiac	O
+events	O
+who	O
+can	O
+be	O
+safely	O
+discharged	O
+.	O
+
+It	O
+is	O
+unclear	O
+whether	O
+a	O
+coronary	O
+CTA	O
+strategy	O
+would	O
+be	O
+efficacious	O
+in	O
+cocaine	O
+-	O
+associated	O
+chest	B
+pain	I
+,	O
+as	O
+coronary	B
+vasospasm	I
+may	O
+account	O
+for	O
+some	O
+of	O
+the	O
+ischemia	B
+.	O
+
+We	O
+studied	O
+whether	O
+a	O
+negative	O
+coronary	O
+CTA	O
+in	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B
+pain	I
+could	O
+identify	O
+a	O
+subset	O
+safe	O
+for	O
+discharge	O
+.	O
+
+METHODS	O
+:	O
+We	O
+prospectively	O
+evaluated	O
+the	O
+safety	O
+of	O
+coronary	O
+CTA	O
+for	O
+low	O
+-	O
+risk	O
+patients	O
+who	O
+presented	O
+to	O
+the	O
+ED	O
+with	O
+cocaineassociated	O
+chest	B
+pain	I
+(	O
+self	O
+-	O
+reported	O
+or	O
+positive	O
+urine	O
+test	O
+)	O
+.	O
+
+Consecutive	O
+patients	O
+received	O
+either	O
+immediate	O
+coronary	O
+CTA	O
+in	O
+the	O
+ED	O
+(	O
+without	O
+serial	O
+markers	O
+)	O
+or	O
+underwent	O
+coronary	O
+CTA	O
+after	O
+a	O
+brief	O
+observation	O
+period	O
+with	O
+serial	O
+cardiac	O
+marker	O
+measurements	O
+.	O
+
+Patients	O
+with	O
+negative	O
+coronary	O
+CTA	O
+(	O
+maximal	O
+stenosis	B
+less	O
+than	O
+50	O
+%	O
+)	O
+were	O
+discharged	O
+.	O
+
+The	O
+main	O
+outcome	O
+was	O
+30	O
+-	O
+day	O
+cardiovascular	O
+death	O
+or	O
+myocardial	B
+infarction	I
+.	O
+
+RESULTS	O
+:	O
+A	O
+total	O
+of	O
+59	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B
+pain	I
+were	O
+evaluated	O
+.	O
+
+Patients	O
+had	O
+a	O
+mean	O
+age	O
+of	O
+45	O
+.	O
+6	O
++	O
+/	O
+-	O
+6	O
+.	O
+6	O
+yrs	O
+and	O
+were	O
+86	O
+%	O
+black	O
+,	O
+66	O
+%	O
+male	O
+.	O
+
+Seventy	O
+-	O
+nine	O
+percent	O
+had	O
+a	O
+normal	O
+or	O
+nonspecific	O
+ECG	O
+and	O
+85	O
+%	O
+had	O
+a	O
+TIMI	O
+score	O
+<	O
+2	O
+.	O
+
+Twenty	O
+patients	O
+received	O
+coronary	O
+CTA	O
+immediately	O
+in	O
+the	O
+ED	O
+,	O
+18	O
+of	O
+whom	O
+were	O
+discharged	O
+following	O
+CTA	O
+(	O
+90	O
+%	O
+)	O
+.	O
+
+Thirty	O
+-	O
+nine	O
+received	O
+coronary	O
+CTA	O
+after	O
+a	O
+brief	O
+observation	O
+period	O
+,	O
+with	O
+37	O
+discharged	O
+home	O
+following	O
+CTA	O
+(	O
+95	O
+%	O
+)	O
+.	O
+
+Six	O
+patients	O
+had	O
+coronary	B
+stenosis	I
+>	O
+or	O
+=	O
+50	O
+%	O
+.	O
+
+During	O
+the	O
+30	O
+-	O
+day	O
+follow	O
+-	O
+up	O
+period	O
+,	O
+no	O
+patients	O
+died	O
+of	O
+a	O
+cardiovascular	O
+event	O
+(	O
+0	O
+%	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+0	O
+-	O
+6	O
+.	O
+1	O
+%	O
+)	O
+and	O
+no	O
+patient	O
+sustained	O
+a	O
+nonfatal	O
+myocardial	B
+infarction	I
+(	O
+0	O
+%	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+0	O
+-	O
+6	O
+.	O
+1	O
+%	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Although	O
+cocaine	O
+-	O
+associated	O
+myocardial	B
+ischemia	I
+can	O
+result	O
+from	O
+coronary	O
+vasoconstriction	O
+,	O
+patients	O
+with	O
+cocaine	O
+associated	O
+chest	B
+pain	I
+,	O
+a	O
+non	O
+-	O
+ischemic	B
+ECG	O
+,	O
+and	O
+a	O
+TIMI	O
+risk	O
+score	O
+<	O
+2	O
+may	O
+be	O
+safely	O
+discharged	O
+from	O
+the	O
+ED	O
+after	O
+a	O
+negative	O
+coronary	O
+CTA	O
+with	O
+a	O
+low	O
+risk	O
+of	O
+30	O
+-	O
+day	O
+adverse	O
+events	O
+.	O
+
+Bilateral	O
+haemorrhagic	B
+infarction	I
+of	I
+the	I
+globus	I
+pallidus	I
+after	O
+cocaine	O
+and	O
+alcohol	O
+intoxication	O
+.	O
+
+Cocaine	O
+is	O
+a	O
+risk	O
+factor	O
+for	O
+both	O
+ischemic	B
+and	I
+haemorrhagic	I
+stroke	I
+.	O
+
+We	O
+present	O
+the	O
+case	O
+of	O
+a	O
+31	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+bilateral	O
+ischemia	B
+of	I
+the	I
+globus	I
+pallidus	I
+after	O
+excessive	O
+alcohol	O
+and	O
+intranasal	O
+cocaine	O
+use	O
+.	O
+
+Drug	O
+-	O
+related	O
+globus	B
+pallidus	I
+infarctions	I
+are	O
+most	O
+often	O
+associated	O
+with	O
+heroin	O
+.	O
+
+Bilateral	O
+basal	B
+ganglia	I
+infarcts	I
+after	O
+the	O
+use	O
+of	O
+cocaine	O
+,	O
+without	O
+concurrent	O
+heroin	O
+use	O
+,	O
+have	O
+never	O
+been	O
+reported	O
+.	O
+
+In	O
+our	O
+patient	O
+,	O
+transient	O
+cardiac	B
+arrhythmia	I
+or	O
+respiratory	B
+dysfunction	I
+related	O
+to	O
+cocaine	O
+and	O
+/	O
+or	O
+ethanol	O
+use	O
+were	O
+the	O
+most	O
+likely	O
+causes	O
+of	O
+cerebral	B
+hypoperfusion	I
+.	O
+
+Late	O
+fulminant	O
+posterior	B
+reversible	I
+encephalopathy	I
+syndrome	I
+after	O
+liver	O
+transplant	O
+.	O
+
+OBJECTIVES	O
+:	O
+Posterior	B
+leukoencephalopathy	I
+due	O
+to	O
+calcineurin	O
+-	O
+inhibitor	O
+-	O
+related	O
+neurotoxicity	B
+is	O
+a	O
+rare	O
+but	O
+severe	O
+complication	O
+that	O
+results	O
+from	O
+treatment	O
+with	O
+immunosuppressive	O
+agents	O
+(	O
+primarily	O
+those	O
+administered	O
+after	O
+a	O
+liver	O
+or	O
+kidney	O
+transplant	O
+)	O
+.	O
+
+The	O
+pathophysiologic	O
+mechanisms	O
+of	O
+that	O
+disorder	O
+remain	O
+unknown	O
+.	O
+
+CASE	O
+:	O
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+46	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+who	O
+received	O
+a	O
+liver	O
+transplant	O
+in	O
+our	O
+center	O
+as	O
+treatment	O
+for	O
+alcoholic	B
+cirrhosis	I
+and	O
+in	O
+whom	O
+either	O
+a	O
+fulminant	O
+course	O
+of	O
+posterior	B
+leukoencephalopathy	I
+or	O
+posterior	B
+reversible	I
+encephalopathy	I
+syndrome	I
+developed	O
+110	O
+days	O
+after	O
+transplant	O
+.	O
+
+After	O
+an	O
+initially	O
+uneventful	O
+course	O
+after	O
+the	O
+transplant	O
+,	O
+the	O
+patient	O
+rapidly	O
+fell	O
+into	O
+deep	O
+coma	O
+.	O
+
+RESULTS	O
+:	O
+Cerebral	O
+MRI	O
+scan	O
+showed	O
+typical	O
+signs	O
+of	O
+enhancement	O
+in	O
+the	O
+pontine	O
+and	O
+posterior	O
+regions	O
+.	O
+
+Switching	O
+the	O
+immunosuppressive	O
+regimen	O
+from	O
+tacrolimus	O
+to	O
+cyclosporine	O
+did	O
+not	O
+improve	O
+the	O
+clinical	O
+situation	O
+.	O
+
+The	O
+termination	O
+of	O
+treatment	O
+with	O
+any	O
+calcineurin	O
+inhibitor	O
+resulted	O
+in	O
+a	O
+complete	O
+resolution	O
+of	O
+that	O
+complication	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Posterior	B
+reversible	I
+encephalopathy	I
+syndrome	I
+after	O
+liver	O
+transplant	O
+is	O
+rare	O
+.	O
+
+We	O
+recommend	O
+a	O
+complete	O
+cessation	O
+of	O
+any	O
+calcineurin	O
+inhibitor	O
+rather	O
+than	O
+a	O
+dose	O
+reduction	O
+.	O
+
+Prolonged	O
+hypothermia	B
+as	O
+a	O
+bridge	O
+to	O
+recovery	O
+for	O
+cerebral	B
+edema	I
+and	O
+intracranial	B
+hypertension	I
+associated	O
+with	O
+fulminant	B
+hepatic	I
+failure	I
+.	O
+
+BACKGROUND	O
+:	O
+To	O
+review	O
+evidence	O
+-	O
+based	O
+treatment	O
+options	O
+in	O
+patients	O
+with	O
+cerebral	B
+edema	I
+complicating	O
+fulminant	B
+hepatic	I
+failure	I
+(	O
+FHF	B
+)	O
+and	O
+discuss	O
+the	O
+potential	O
+applications	O
+of	O
+hypothermia	B
+.	O
+
+METHOD	O
+:	O
+Case	O
+-	O
+based	O
+observations	O
+from	O
+a	O
+medical	O
+intensive	O
+care	O
+unit	O
+(	O
+MICU	O
+)	O
+in	O
+a	O
+tertiary	O
+care	O
+facility	O
+in	O
+a	O
+27	O
+-	O
+year	O
+-	O
+old	O
+female	O
+with	O
+FHF	B
+from	O
+acetaminophen	O
+and	O
+resultant	O
+cerebral	B
+edema	I
+.	O
+
+RESULTS	O
+:	O
+Our	O
+patient	O
+was	O
+admitted	O
+to	O
+the	O
+MICU	O
+after	O
+being	O
+found	O
+unresponsive	O
+with	O
+presumed	O
+toxicity	B
+from	O
+acetaminophen	O
+which	O
+was	O
+ingested	O
+over	O
+a	O
+2	O
+-	O
+day	O
+period	O
+.	O
+
+The	O
+patient	O
+had	O
+depressed	O
+of	O
+mental	O
+status	O
+lasting	O
+at	O
+least	O
+24	O
+h	O
+prior	O
+to	O
+admission	O
+.	O
+
+Initial	O
+evaluation	O
+confirmed	O
+FHF	B
+from	O
+acetaminophen	O
+and	O
+cerebral	B
+edema	I
+.	O
+
+The	O
+patient	O
+was	O
+treated	O
+with	O
+hyperosmolar	O
+therapy	O
+,	O
+hyperventilation	B
+,	O
+sedation	O
+,	O
+and	O
+chemical	O
+paralysis	B
+.	O
+
+Her	O
+intracranial	O
+pressure	O
+remained	O
+elevated	O
+despite	O
+maximal	O
+medical	O
+therapy	O
+.	O
+
+We	O
+then	O
+initiated	O
+therapeutic	O
+hypothermia	B
+which	O
+was	O
+continued	O
+for	O
+5	O
+days	O
+.	O
+
+At	O
+re	O
+-	O
+warming	O
+,	O
+patient	O
+had	O
+resolution	O
+of	O
+her	O
+cerebral	B
+edema	I
+and	O
+intracranial	B
+hypertension	I
+.	O
+
+At	O
+discharge	O
+,	O
+she	O
+had	O
+complete	O
+recovery	O
+of	O
+neurological	O
+and	O
+hepatic	O
+functions	O
+.	O
+
+CONCLUSION	O
+:	O
+In	O
+patients	O
+with	O
+FHF	B
+and	O
+cerebral	B
+edema	I
+from	O
+acetaminophen	O
+overdose	B
+,	O
+prolonged	O
+therapeutic	O
+hypothermia	B
+could	O
+potentially	O
+be	O
+used	O
+as	O
+a	O
+life	O
+saving	O
+therapy	O
+and	O
+a	O
+bridge	O
+to	O
+hepatic	O
+and	O
+neurological	O
+recovery	O
+.	O
+
+A	O
+clinical	O
+trial	O
+of	O
+hypothermia	B
+in	O
+patients	O
+with	O
+this	O
+condition	O
+is	O
+warranted	O
+.	O
+
+Binasal	B
+visual	I
+field	I
+defects	I
+are	O
+not	O
+specific	O
+to	O
+vigabatrin	O
+.	O
+
+This	O
+study	O
+investigated	O
+the	O
+visual	B
+defects	I
+associated	O
+with	O
+the	O
+antiepileptic	O
+drug	O
+vigabatrin	O
+(	O
+VGB	O
+)	O
+.	O
+
+Two	O
+hundred	O
+four	O
+people	O
+with	O
+epilepsy	B
+were	O
+grouped	O
+on	O
+the	O
+basis	O
+of	O
+antiepileptic	O
+drug	O
+therapy	O
+(	O
+current	O
+,	O
+previous	O
+,	O
+or	O
+no	O
+exposure	O
+to	O
+VGB	O
+)	O
+.	O
+
+Groups	O
+were	O
+matched	O
+with	O
+respect	O
+to	O
+age	O
+,	O
+gender	O
+,	O
+and	O
+seizure	B
+frequency	O
+.	O
+
+All	O
+patients	O
+underwent	O
+objective	O
+assessment	O
+of	O
+electrophysiological	O
+function	O
+(	O
+wide	O
+-	O
+field	O
+multifocal	O
+electroretinography	O
+)	O
+and	O
+conventional	O
+visual	O
+field	O
+testing	O
+(	O
+static	O
+perimetry	O
+)	O
+.	O
+
+Bilateral	O
+visual	O
+field	O
+constriction	O
+was	O
+observed	O
+in	O
+59	O
+%	O
+of	O
+patients	O
+currently	O
+taking	O
+VGB	O
+,	O
+43	O
+%	O
+of	O
+patients	O
+who	O
+previously	O
+took	O
+VGB	O
+,	O
+and	O
+24	O
+%	O
+of	O
+patients	O
+with	O
+no	O
+exposure	O
+to	O
+VGB	O
+.	O
+
+Assessment	O
+of	O
+retinal	O
+function	O
+revealed	O
+abnormal	O
+responses	O
+in	O
+48	O
+%	O
+of	O
+current	O
+VGB	O
+users	O
+and	O
+22	O
+%	O
+of	O
+prior	O
+VGB	O
+users	O
+,	O
+but	O
+in	O
+none	O
+of	O
+the	O
+patients	O
+without	O
+previous	O
+exposure	O
+to	O
+VGB	O
+.	O
+
+Bilateral	B
+visual	I
+field	I
+abnormalities	I
+are	O
+common	O
+in	O
+the	O
+treated	O
+epilepsy	B
+population	O
+,	O
+irrespective	O
+of	O
+drug	O
+history	O
+.	O
+
+Assessment	O
+by	O
+conventional	O
+static	O
+perimetry	O
+may	O
+neither	O
+be	O
+sufficiently	O
+sensitive	O
+nor	O
+specific	O
+to	O
+reliably	O
+identify	O
+retinal	B
+toxicity	I
+associated	O
+with	O
+VGB	O
+.	O
+
+Smoking	O
+of	O
+crack	O
+cocaine	O
+as	O
+a	O
+risk	O
+factor	O
+for	O
+HIV	B
+infection	I
+among	O
+people	O
+who	O
+use	O
+injection	O
+drugs	O
+.	O
+
+BACKGROUND	O
+:	O
+Little	O
+is	O
+known	O
+about	O
+the	O
+possible	O
+role	O
+that	O
+smoking	O
+crack	O
+cocaine	O
+has	O
+on	O
+the	O
+incidence	O
+of	O
+HIV	B
+infection	I
+.	O
+
+Given	O
+the	O
+increasing	O
+use	O
+of	O
+crack	O
+cocaine	O
+,	O
+we	O
+sought	O
+to	O
+examine	O
+whether	O
+use	O
+of	O
+this	O
+illicit	O
+drug	O
+has	O
+become	O
+a	O
+risk	O
+factor	O
+for	O
+HIV	B
+infection	I
+.	O
+
+METHODS	O
+:	O
+We	O
+included	O
+data	O
+from	O
+people	O
+participating	O
+in	O
+the	O
+Vancouver	O
+Injection	O
+Drug	O
+Users	O
+Study	O
+who	O
+reported	O
+injecting	O
+illicit	O
+drugs	O
+at	O
+least	O
+once	O
+in	O
+the	O
+month	O
+before	O
+enrolment	O
+,	O
+lived	O
+in	O
+the	O
+greater	O
+Vancouver	O
+area	O
+,	O
+were	O
+HIV	O
+-	O
+negative	O
+at	O
+enrolment	O
+and	O
+completed	O
+at	O
+least	O
+1	O
+follow	O
+-	O
+up	O
+study	O
+visit	O
+.	O
+
+To	O
+determine	O
+whether	O
+the	O
+risk	O
+of	O
+HIV	B
+seroconversion	I
+among	O
+daily	O
+smokers	O
+of	O
+crack	O
+cocaine	O
+changed	O
+over	O
+time	O
+,	O
+we	O
+used	O
+Cox	O
+proportional	O
+hazards	O
+regression	O
+and	O
+divided	O
+the	O
+study	O
+into	O
+3	O
+periods	O
+:	O
+May	O
+1	O
+,	O
+1996	O
+-	O
+Nov	O
+.	O
+
+30	O
+,	O
+1999	O
+(	O
+period	O
+1	O
+)	O
+,	O
+Dec	O
+.	O
+
+1	O
+,	O
+1999	O
+-	O
+Nov	O
+.	O
+
+30	O
+,	O
+2002	O
+(	O
+period	O
+2	O
+)	O
+,	O
+and	O
+Dec	O
+.	O
+
+1	O
+,	O
+2002	O
+-	O
+Dec	O
+.	O
+
+30	O
+,	O
+2005	O
+(	O
+period	O
+3	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+Overall	O
+,	O
+1048	O
+eligible	O
+injection	O
+drug	O
+users	O
+were	O
+included	O
+in	O
+our	O
+study	O
+.	O
+
+Of	O
+these	O
+,	O
+137	O
+acquired	O
+HIV	B
+infection	I
+during	O
+follow	O
+-	O
+up	O
+.	O
+
+The	O
+mean	O
+proportion	O
+of	O
+participants	O
+who	O
+reported	O
+daily	O
+smoking	O
+of	O
+crack	O
+cocaine	O
+increased	O
+from	O
+11	O
+.	O
+6	O
+%	O
+in	O
+period	O
+1	O
+to	O
+39	O
+.	O
+7	O
+%	O
+in	O
+period	O
+3	O
+.	O
+
+After	O
+adjusting	O
+for	O
+potential	O
+confounders	O
+,	O
+we	O
+found	O
+that	O
+the	O
+risk	O
+of	O
+HIV	B
+seroconversion	I
+among	O
+participants	O
+who	O
+were	O
+daily	O
+smokers	O
+of	O
+crack	O
+cocaine	O
+increased	O
+over	O
+time	O
+(	O
+period	O
+1	O
+:	O
+hazard	O
+ratio	O
+[	O
+HR	O
+]	O
+1	O
+.	O
+03	O
+,	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+0	O
+.	O
+57	O
+-	O
+1	O
+.	O
+85	O
+;	O
+period	O
+2	O
+:	O
+HR	O
+1	O
+.	O
+68	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+01	O
+-	O
+2	O
+.	O
+80	O
+;	O
+and	O
+period	O
+3	O
+:	O
+HR	O
+2	O
+.	O
+74	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+06	O
+-	O
+7	O
+.	O
+11	O
+)	O
+.	O
+
+INTERPRETATION	O
+:	O
+Smoking	O
+of	O
+crack	O
+cocaine	O
+was	O
+found	O
+to	O
+be	O
+an	O
+independent	O
+risk	O
+factor	O
+for	O
+HIV	B
+seroconversion	I
+among	O
+people	O
+who	O
+were	O
+injection	O
+drug	O
+users	O
+.	O
+
+This	O
+finding	O
+points	O
+to	O
+the	O
+urgent	O
+need	O
+for	O
+evidence	O
+-	O
+based	O
+public	O
+health	O
+initiatives	O
+targeted	O
+at	O
+people	O
+who	O
+smoke	O
+crack	O
+cocaine	O
+.	O
+
+Fluoxetine	O
+improves	O
+the	O
+memory	B
+deficits	I
+caused	O
+by	O
+the	O
+chemotherapy	O
+agent	O
+5	O
+-	O
+fluorouracil	O
+.	O
+
+Cancer	B
+patients	O
+who	O
+have	O
+been	O
+treated	O
+with	O
+systemic	O
+adjuvant	O
+chemotherapy	O
+have	O
+described	O
+experiencing	O
+deteriorations	O
+in	O
+cognition	O
+.	O
+
+A	O
+widely	O
+used	O
+chemotherapeutic	O
+agent	O
+,	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+,	O
+readily	O
+crosses	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+and	O
+so	O
+could	O
+have	O
+a	O
+direct	O
+effect	O
+on	O
+brain	O
+function	O
+.	O
+
+In	O
+particular	O
+this	O
+anti	O
+mitotic	O
+drug	O
+could	O
+reduce	O
+cell	O
+proliferation	O
+in	O
+the	O
+neurogenic	O
+regions	O
+of	O
+the	O
+adult	O
+brain	O
+.	O
+
+In	O
+contrast	O
+reports	O
+indicate	O
+that	O
+hippocampal	O
+dependent	O
+neurogenesis	O
+and	O
+cognition	O
+are	O
+enhanced	O
+by	O
+the	O
+SSRI	O
+antidepressant	O
+Fluoxetine	O
+.	O
+
+In	O
+this	O
+investigation	O
+the	O
+behavioural	O
+effects	O
+of	O
+chronic	O
+(	O
+two	O
+week	O
+)	O
+treatment	O
+with	O
+5	O
+-	O
+FU	O
+and	O
+(	O
+three	O
+weeks	O
+)	O
+with	O
+Fluoxetine	O
+either	O
+separately	O
+or	O
+in	O
+combination	O
+with	O
+5	O
+-	O
+FU	O
+were	O
+tested	O
+on	O
+adult	O
+Lister	O
+hooded	O
+rats	O
+.	O
+
+Behavioural	O
+effects	O
+were	O
+tested	O
+using	O
+a	O
+context	O
+dependent	O
+conditioned	O
+emotional	O
+response	O
+test	O
+(	O
+CER	O
+)	O
+which	O
+showed	O
+that	O
+animals	O
+treated	O
+with	O
+5	O
+-	O
+FU	O
+had	O
+a	O
+significant	O
+reduction	O
+in	O
+freezing	O
+time	O
+compared	O
+to	O
+controls	O
+.	O
+
+A	O
+separate	O
+group	O
+of	O
+animals	O
+was	O
+tested	O
+using	O
+a	O
+hippocampal	O
+dependent	O
+spatial	O
+working	O
+memory	O
+test	O
+,	O
+the	O
+object	O
+location	O
+recognition	O
+test	O
+(	O
+OLR	O
+)	O
+.	O
+
+Animals	O
+treated	O
+only	O
+with	O
+5	O
+-	O
+FU	O
+showed	O
+significant	O
+deficits	O
+in	O
+their	O
+ability	O
+to	O
+carry	O
+out	O
+the	O
+OLR	O
+task	O
+but	O
+co	O
+administration	O
+of	O
+Fluoxetine	O
+improved	O
+their	O
+performance	O
+.	O
+
+5	O
+-	O
+FU	O
+chemotherapy	O
+caused	O
+a	O
+significant	O
+reduction	O
+in	O
+the	O
+number	O
+of	O
+proliferating	O
+cells	O
+in	O
+the	O
+sub	O
+granular	O
+zone	O
+of	O
+the	O
+dentate	O
+gyrus	O
+compared	O
+to	O
+controls	O
+.	O
+
+This	O
+reduction	O
+was	O
+eliminated	O
+when	O
+Fluoxetine	O
+was	O
+co	O
+administered	O
+with	O
+5	O
+-	O
+FU	O
+.	O
+
+Fluoxetine	O
+on	O
+its	O
+own	O
+had	O
+no	O
+effect	O
+on	O
+proliferating	O
+cell	O
+number	O
+or	O
+behaviour	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+5	O
+-	O
+FU	O
+can	O
+negatively	O
+affect	O
+both	O
+cell	O
+proliferation	O
+and	O
+hippocampal	O
+dependent	O
+working	O
+memory	O
+and	O
+that	O
+these	O
+deficits	O
+can	O
+be	O
+reversed	O
+by	O
+the	O
+simultaneous	O
+administration	O
+of	O
+the	O
+antidepressant	O
+Fluoxetine	O
+.	O
+
+Liver	O
+-	O
+specific	O
+ablation	O
+of	O
+integrin	O
+-	O
+linked	O
+kinase	O
+in	O
+mice	O
+results	O
+in	O
+enhanced	O
+and	O
+prolonged	O
+cell	O
+proliferation	O
+and	O
+hepatomegaly	B
+after	O
+phenobarbital	O
+administration	O
+.	O
+
+We	O
+have	O
+recently	O
+demonstrated	O
+that	O
+disruption	O
+of	O
+extracellular	O
+matrix	O
+(	O
+ECM	O
+)	O
+/	O
+integrin	O
+signaling	O
+via	O
+elimination	O
+of	O
+integrin	O
+-	O
+linked	O
+kinase	O
+(	O
+ILK	O
+)	O
+in	O
+hepatocytes	O
+interferes	O
+with	O
+signals	O
+leading	O
+to	O
+termination	O
+of	O
+liver	O
+regeneration	O
+.	O
+
+This	O
+study	O
+investigates	O
+the	O
+role	O
+of	O
+ILK	O
+in	O
+liver	O
+enlargement	O
+induced	O
+by	O
+phenobarbital	O
+(	O
+PB	O
+)	O
+.	O
+
+Wild	O
+-	O
+type	O
+(	O
+WT	O
+)	O
+and	O
+ILK	O
+:	O
+liver	O
+-	O
+/	O
+-	O
+mice	O
+were	O
+given	O
+PB	O
+(	O
+0	O
+.	O
+1	O
+%	O
+in	O
+drinking	O
+water	O
+)	O
+for	O
+10	O
+days	O
+.	O
+
+Livers	O
+were	O
+harvested	O
+on	O
+2	O
+,	O
+5	O
+,	O
+and	O
+10	O
+days	O
+during	O
+PB	O
+administration	O
+.	O
+
+In	O
+the	O
+hepatocyte	O
+-	O
+specific	O
+ILK	O
+/	O
+liver	O
+-	O
+/	O
+-	O
+mice	O
+,	O
+the	O
+liver	O
+:	O
+body	O
+weight	O
+ratio	O
+was	O
+more	O
+than	O
+double	O
+as	O
+compared	O
+to	O
+0	O
+h	O
+at	O
+day	O
+2	O
+(	O
+2	O
+.	O
+5	O
+times	O
+)	O
+,	O
+while	O
+at	O
+days	O
+5	O
+and	O
+10	O
+,	O
+it	O
+was	O
+enlarged	O
+three	O
+times	O
+.	O
+
+In	O
+the	O
+WT	O
+mice	O
+,	O
+the	O
+increase	O
+was	O
+as	O
+expected	O
+from	O
+previous	O
+literature	O
+(	O
+1	O
+.	O
+8	O
+times	O
+)	O
+and	O
+seems	O
+to	O
+have	O
+leveled	O
+off	O
+after	O
+day	O
+2	O
+.	O
+
+There	O
+were	O
+slightly	O
+increased	O
+proliferating	O
+cell	O
+nuclear	O
+antigen	O
+-	O
+positive	O
+cells	O
+in	O
+the	O
+ILK	O
+/	O
+liver	O
+-	O
+/	O
+-	O
+animals	O
+at	O
+day	O
+2	O
+as	O
+compared	O
+to	O
+WT	O
+after	O
+PB	O
+administration	O
+.	O
+
+In	O
+the	O
+WT	O
+animals	O
+,	O
+the	O
+proliferative	O
+response	O
+had	O
+come	O
+back	O
+to	O
+normal	O
+by	O
+days	O
+5	O
+and	O
+10	O
+.	O
+
+Hepatocytes	O
+of	O
+the	O
+ILK	O
+/	O
+liver	O
+-	O
+/	O
+-	O
+mice	O
+continued	O
+to	O
+proliferate	O
+up	O
+until	O
+day	O
+10	O
+.	O
+
+ILK	O
+/	O
+liver	O
+-	O
+/	O
+-	O
+mice	O
+also	O
+showed	O
+increased	O
+expression	O
+of	O
+key	O
+genes	O
+involved	O
+in	O
+hepatocyte	O
+proliferation	O
+at	O
+different	O
+time	O
+points	O
+during	O
+PB	O
+administration	O
+.	O
+
+In	O
+summary	O
+,	O
+ECM	O
+proteins	O
+communicate	O
+with	O
+the	O
+signaling	O
+machinery	O
+of	O
+dividing	O
+cells	O
+via	O
+ILK	O
+to	O
+regulate	O
+hepatocyte	O
+proliferation	O
+and	O
+termination	O
+of	O
+the	O
+proliferative	O
+response	O
+.	O
+
+Lack	O
+of	O
+ILK	O
+in	O
+the	O
+hepatocytes	O
+imparts	O
+prolonged	O
+proliferative	O
+response	O
+not	O
+only	O
+to	O
+stimuli	O
+related	O
+to	O
+liver	O
+regeneration	O
+but	O
+also	O
+to	O
+xenobiotic	O
+chemical	O
+mitogens	O
+,	O
+such	O
+as	O
+PB	O
+.	O
+
+Decreased	O
+Expression	O
+of	O
+Na	O
+/	O
+K	O
+-	O
+ATPase	O
+,	O
+NHE3	O
+,	O
+NBC1	O
+,	O
+AQP1	O
+and	O
+OAT	O
+in	O
+Gentamicin	O
+-	O
+induced	O
+Nephropathy	B
+.	O
+
+The	O
+present	O
+study	O
+was	O
+aimed	O
+to	O
+determine	O
+whether	O
+there	O
+is	O
+an	O
+altered	O
+regulation	O
+of	O
+tubular	O
+transporters	O
+in	O
+gentamicin	O
+-	O
+induced	O
+nephropathy	B
+.	O
+
+Sprague	O
+-	O
+Dawley	O
+male	O
+rats	O
+(	O
+200	O
+~	O
+250	O
+g	O
+)	O
+were	O
+subcutaneously	O
+injected	O
+with	O
+gentamicin	O
+(	O
+100	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+)	O
+for	O
+7	O
+days	O
+,	O
+and	O
+the	O
+expression	O
+of	O
+tubular	O
+transporters	O
+was	O
+determined	O
+by	O
+immunoblotting	O
+and	O
+immunohistochemistry	O
+.	O
+
+The	O
+mRNA	O
+and	O
+protein	O
+expression	O
+of	O
+OAT	O
+was	O
+also	O
+determined	O
+.	O
+
+Gentamicin	O
+-	O
+treated	O
+rats	O
+exhibited	O
+significantly	O
+decreased	O
+creatinine	O
+clearance	O
+along	O
+with	O
+increased	O
+plasma	O
+creatinine	O
+levels	O
+.	O
+
+Accordingly	O
+,	O
+the	O
+fractional	O
+excretion	O
+of	O
+sodium	O
+increased	O
+.	O
+
+Urine	O
+volume	O
+was	O
+increased	O
+,	O
+while	O
+urine	O
+osmolality	O
+and	O
+free	O
+water	O
+reabsorption	O
+were	O
+decreased	O
+.	O
+
+Immunoblotting	O
+and	O
+immunohistochemistry	O
+revealed	O
+decreased	O
+expression	O
+of	O
+Na	O
+(	O
++	O
+)	O
+/	O
+K	O
+(	O
++	O
+)	O
+-	O
+ATPase	O
+,	O
+NHE3	O
+,	O
+NBC1	O
+,	O
+and	O
+AQP1	O
+in	O
+the	O
+kidney	O
+of	O
+gentamicin	O
+-	O
+treated	O
+rats	O
+.	O
+
+The	O
+expression	O
+of	O
+OAT1	O
+and	O
+OAT3	O
+was	O
+also	O
+decreased	O
+.	O
+
+Gentamicin	O
+-	O
+induced	O
+nephropathy	B
+may	O
+at	O
+least	O
+in	O
+part	O
+be	O
+causally	O
+related	O
+with	O
+a	O
+decreased	O
+expression	O
+of	O
+Na	O
+(	O
++	O
+)	O
+/	O
+K	O
+(	O
++	O
+)	O
+-	O
+ATPase	O
+,	O
+NHE3	O
+,	O
+NBC1	O
+,	O
+AQP1	O
+and	O
+OAT	O
+.	O
+
+Acute	B
+renal	I
+failure	I
+after	O
+high	O
+-	O
+dose	O
+methotrexate	O
+therapy	O
+in	O
+a	O
+patient	O
+with	O
+ileostomy	O
+.	O
+
+High	O
+-	O
+dose	O
+methotrexate	O
+(	O
+HD	O
+-	O
+MTX	O
+)	O
+is	O
+an	O
+important	O
+treatment	O
+for	O
+Burkitt	B
+lymphoma	I
+,	O
+but	O
+can	O
+cause	O
+hepatic	B
+and	I
+renal	I
+toxicity	I
+when	O
+its	O
+clearance	O
+is	O
+delayed	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+acute	B
+renal	I
+failure	I
+after	O
+HD	O
+-	O
+MTX	O
+therapy	O
+in	O
+a	O
+patient	O
+with	O
+ileostomy	O
+,	O
+The	O
+patient	O
+was	O
+a	O
+3	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+who	O
+had	O
+received	O
+a	O
+living	O
+-	O
+related	O
+liver	O
+transplantation	O
+for	O
+congenital	O
+biliary	B
+atresia	I
+.	O
+
+At	O
+day	O
+833	O
+after	O
+the	O
+transplantation	O
+,	O
+he	O
+was	O
+diagnosed	O
+with	O
+PTLD	B
+(	O
+post	B
+-	I
+transplantation	I
+lymphoproliferative	I
+disorder	I
+,	O
+Burkitt	B
+-	I
+type	I
+malignant	I
+lymphoma	I
+)	O
+.	O
+
+During	O
+induction	O
+therapy	O
+,	O
+he	O
+suffered	O
+ileal	O
+perforation	O
+and	O
+ileostomy	O
+was	O
+performed	O
+.	O
+
+Subsequent	O
+HD	O
+-	O
+MTX	O
+therapy	O
+caused	O
+acute	B
+renal	I
+failure	I
+that	O
+required	O
+continuous	O
+hemodialysis	O
+.	O
+
+We	O
+supposed	O
+that	O
+intravascular	O
+hypovolemia	B
+due	O
+to	O
+substantial	O
+drainage	O
+from	O
+the	O
+ileostoma	O
+caused	O
+acute	B
+prerenal	I
+failure	I
+.	O
+
+After	O
+recovery	O
+of	O
+his	O
+renal	O
+function	O
+,	O
+we	O
+could	O
+safely	O
+treat	O
+the	O
+patient	O
+with	O
+HD	O
+-	O
+MTX	O
+therapy	O
+by	O
+controlling	O
+drainage	O
+from	O
+ileostoma	O
+with	O
+total	O
+parenteral	O
+nutrition	O
+.	O
+
+Longitudinal	O
+association	O
+of	O
+alcohol	O
+use	O
+with	O
+HIV	B
+disease	I
+progression	O
+and	O
+psychological	O
+health	O
+of	O
+women	O
+with	O
+HIV	O
+.	O
+
+We	O
+evaluated	O
+the	O
+association	O
+of	O
+alcohol	O
+consumption	O
+and	O
+depression	B
+,	O
+and	O
+their	O
+effects	O
+on	O
+HIV	B
+disease	I
+progression	O
+among	O
+women	O
+with	O
+HIV	O
+.	O
+
+The	O
+study	O
+included	O
+871	O
+women	O
+with	O
+HIV	O
+who	O
+were	O
+recruited	O
+from	O
+1993	O
+-	O
+1995	O
+in	O
+four	O
+US	O
+cities	O
+.	O
+
+The	O
+participants	O
+had	O
+physical	O
+examination	O
+,	O
+medical	O
+record	O
+extraction	O
+,	O
+and	O
+venipuncture	O
+,	O
+CD4	O
++	O
+T	O
+-	O
+cell	O
+counts	O
+determination	O
+,	O
+measurement	O
+of	O
+depression	B
+symptoms	O
+(	O
+using	O
+the	O
+self	O
+-	O
+report	O
+Center	O
+for	O
+Epidemiological	O
+Studies	O
+-	O
+Depression	B
+Scale	O
+)	O
+,	O
+and	O
+alcohol	O
+use	O
+assessment	O
+at	O
+enrollment	O
+,	O
+and	O
+semiannually	O
+until	O
+March	O
+2000	O
+.	O
+
+Multilevel	O
+random	O
+coefficient	O
+ordinal	O
+models	O
+as	O
+well	O
+as	O
+multilevel	O
+models	O
+with	O
+joint	O
+responses	O
+were	O
+used	O
+in	O
+the	O
+analysis	O
+.	O
+
+There	O
+was	O
+no	O
+significant	O
+association	O
+between	O
+level	O
+of	O
+alcohol	O
+use	O
+and	O
+CD4	O
++	O
+T	O
+-	O
+cell	O
+counts	O
+.	O
+
+When	O
+participants	O
+were	O
+stratified	O
+by	O
+antiretroviral	O
+therapy	O
+(	O
+ART	O
+)	O
+use	O
+,	O
+the	O
+association	O
+between	O
+alcohol	O
+and	O
+CD4	O
++	O
+T	O
+-	O
+cell	O
+did	O
+not	O
+reach	O
+statistical	O
+significance	O
+.	O
+
+The	O
+association	O
+between	O
+alcohol	O
+consumption	O
+and	O
+depression	B
+was	O
+significant	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Depression	B
+had	O
+a	O
+significant	O
+negative	O
+effect	O
+on	O
+CD4	O
++	O
+T	O
+-	O
+cell	O
+counts	O
+over	O
+time	O
+regardless	O
+of	O
+ART	O
+use	O
+.	O
+
+Our	O
+findings	O
+suggest	O
+that	O
+alcohol	O
+consumption	O
+has	O
+a	O
+direct	O
+association	O
+with	O
+depression	B
+.	O
+
+Moreover	O
+,	O
+depression	B
+is	O
+associated	O
+with	O
+HIV	B
+disease	I
+progression	O
+.	O
+
+Our	O
+findings	O
+have	O
+implications	O
+for	O
+the	O
+provision	O
+of	O
+alcohol	O
+use	O
+interventions	O
+and	O
+psychological	O
+resources	O
+to	O
+improve	O
+the	O
+health	O
+of	O
+women	O
+with	O
+HIV	O
+.	O
+
+Chemokine	O
+CCL2	O
+and	O
+its	O
+receptor	O
+CCR2	O
+are	O
+increased	O
+in	O
+the	O
+hippocampus	O
+following	O
+pilocarpine	O
+-	O
+induced	O
+status	B
+epilepticus	I
+.	O
+
+BACKGROUND	O
+:	O
+Neuroinflammation	B
+occurs	O
+after	O
+seizures	B
+and	O
+is	O
+implicated	O
+in	O
+epileptogenesis	O
+.	O
+
+CCR2	O
+is	O
+a	O
+chemokine	O
+receptor	O
+for	O
+CCL2	O
+and	O
+their	O
+interaction	O
+mediates	O
+monocyte	O
+infiltration	O
+in	O
+the	O
+neuroinflammatory	B
+cascade	O
+triggered	O
+in	O
+different	O
+brain	O
+pathologies	O
+.	O
+
+In	O
+this	O
+work	O
+CCR2	O
+and	O
+CCL2	O
+expression	O
+were	O
+examined	O
+following	O
+status	B
+epilepticus	I
+(	O
+SE	B
+)	O
+induced	O
+by	O
+pilocarpine	O
+injection	O
+.	O
+
+METHODS	O
+:	O
+SE	B
+was	O
+induced	O
+by	O
+pilocarpine	O
+injection	O
+.	O
+
+Control	O
+rats	O
+were	O
+injected	O
+with	O
+saline	O
+instead	O
+of	O
+pilocarpine	O
+.	O
+
+Five	O
+days	O
+after	O
+SE	B
+,	O
+CCR2	O
+staining	O
+in	O
+neurons	O
+and	O
+glial	O
+cells	O
+was	O
+examined	O
+using	O
+imunohistochemical	O
+analyses	O
+.	O
+
+The	O
+number	O
+of	O
+CCR2	O
+positive	O
+cells	O
+was	O
+determined	O
+using	O
+stereology	O
+probes	O
+in	O
+the	O
+hippocampus	O
+.	O
+
+CCL2	O
+expression	O
+in	O
+the	O
+hippocampus	O
+was	O
+examined	O
+by	O
+molecular	O
+assay	O
+.	O
+
+RESULTS	O
+:	O
+Increased	O
+CCR2	O
+was	O
+observed	O
+in	O
+the	O
+hippocampus	O
+after	O
+SE	B
+.	O
+
+Seizures	B
+also	O
+resulted	O
+in	O
+alterations	O
+to	O
+the	O
+cell	O
+types	O
+expressing	O
+CCR2	O
+.	O
+
+Increased	O
+numbers	O
+of	O
+neurons	O
+that	O
+expressed	O
+CCR2	O
+was	O
+observed	O
+following	O
+SE	B
+.	O
+
+Microglial	O
+cells	O
+were	O
+more	O
+closely	O
+apposed	O
+to	O
+the	O
+CCR2	O
+-	O
+labeled	O
+cells	O
+in	O
+SE	B
+rats	O
+.	O
+
+In	O
+addition	O
+,	O
+rats	O
+that	O
+experienced	O
+SE	B
+exhibited	O
+CCR2	O
+-	O
+labeling	O
+in	O
+populations	O
+of	O
+hypertrophied	B
+astrocytes	O
+,	O
+especially	O
+in	O
+CA1	O
+and	O
+dentate	O
+gyrus	O
+.	O
+
+These	O
+CCR2	O
++	O
+astroctytes	O
+were	O
+not	O
+observed	O
+in	O
+control	O
+rats	O
+.	O
+
+Examination	O
+of	O
+CCL2	O
+expression	O
+showed	O
+that	O
+it	O
+was	O
+elevated	O
+in	O
+the	O
+hippocampus	O
+following	O
+SE	B
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+data	O
+show	O
+that	O
+CCR2	O
+and	O
+CCL2	O
+are	O
+up	O
+-	O
+regulated	O
+in	O
+the	O
+hippocampus	O
+after	O
+pilocarpine	O
+-	O
+induced	O
+SE	B
+.	O
+
+Seizures	B
+also	O
+result	O
+in	O
+changes	O
+to	O
+CCR2	O
+receptor	O
+expression	O
+in	O
+neurons	O
+and	O
+astrocytes	O
+.	O
+
+These	O
+changes	O
+might	O
+be	O
+involved	O
+in	O
+detrimental	O
+neuroplasticity	O
+and	O
+neuroinflammatory	B
+changes	O
+that	O
+occur	O
+following	O
+seizures	B
+.	O
+
+Metallothionein	O
+induction	O
+reduces	O
+caspase	O
+-	O
+3	O
+activity	O
+and	O
+TNFalpha	O
+levels	O
+with	O
+preservation	O
+of	O
+cognitive	O
+function	O
+and	O
+intact	O
+hippocampal	O
+neurons	O
+in	O
+carmustine	O
+-	O
+treated	O
+rats	O
+.	O
+
+Hippocampal	O
+integrity	O
+is	O
+essential	O
+for	O
+cognitive	O
+functions	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+induction	O
+of	O
+metallothionein	O
+(	O
+MT	O
+)	O
+by	O
+ZnSO	O
+(	O
+4	O
+)	O
+and	O
+its	O
+role	O
+in	O
+neuroprotection	O
+has	O
+been	O
+documented	O
+.	O
+
+The	O
+present	O
+study	O
+aimed	O
+to	O
+explore	O
+the	O
+effect	O
+of	O
+MT	O
+induction	O
+on	O
+carmustine	O
+(	O
+BCNU	O
+)	O
+-	O
+induced	O
+hippocampal	O
+cognitive	B
+dysfunction	I
+in	O
+rats	O
+.	O
+
+A	O
+total	O
+of	O
+60	O
+male	O
+Wistar	O
+albino	O
+rats	O
+were	O
+randomly	O
+divided	O
+into	O
+four	O
+groups	O
+(	O
+15	O
+/	O
+group	O
+)	O
+:	O
+The	O
+control	O
+group	O
+injected	O
+with	O
+single	O
+doses	O
+of	O
+normal	O
+saline	O
+(	O
+i	O
+.	O
+c	O
+.	O
+v	O
+)	O
+followed	O
+24	O
+h	O
+later	O
+by	O
+BCNU	O
+solvent	O
+(	O
+i	O
+.	O
+v	O
+)	O
+.	O
+
+The	O
+second	O
+group	O
+administered	O
+ZnSO	O
+(	O
+4	O
+)	O
+(	O
+0	O
+.	O
+1	O
+micromol	O
+/	O
+10	O
+microl	O
+normal	O
+saline	O
+,	O
+i	O
+.	O
+c	O
+.	O
+v	O
+,	O
+once	O
+)	O
+then	O
+BCNU	O
+solvent	O
+(	O
+i	O
+.	O
+v	O
+)	O
+after	O
+24	O
+h	O
+.	O
+
+Third	O
+group	O
+received	O
+BCNU	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+v	O
+,	O
+once	O
+)	O
+24	O
+h	O
+after	O
+injection	O
+with	O
+normal	O
+saline	O
+(	O
+i	O
+.	O
+c	O
+.	O
+v	O
+)	O
+.	O
+
+Fourth	O
+group	O
+received	O
+a	O
+single	O
+dose	O
+of	O
+ZnSO	O
+(	O
+4	O
+)	O
+(	O
+0	O
+.	O
+1	O
+micromol	O
+/	O
+10	O
+microl	O
+normal	O
+saline	O
+,	O
+i	O
+.	O
+c	O
+.	O
+v	O
+)	O
+then	O
+BCNU	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+v	O
+,	O
+once	O
+)	O
+after	O
+24	O
+h	O
+.	O
+
+The	O
+obtained	O
+data	O
+revealed	O
+that	O
+BCNU	O
+administration	O
+resulted	O
+in	O
+deterioration	B
+of	I
+learning	I
+and	I
+short	I
+-	I
+term	I
+memory	I
+(	O
+STM	O
+)	O
+,	O
+as	O
+measured	O
+by	O
+using	O
+radial	O
+arm	O
+water	O
+maze	O
+,	O
+accompanied	O
+with	O
+decreased	O
+hippocampal	O
+glutathione	O
+reductase	O
+(	O
+GR	O
+)	O
+activity	O
+and	O
+reduced	O
+glutathione	O
+(	O
+GSH	O
+)	O
+content	O
+.	O
+
+Also	O
+,	O
+BCNU	O
+administration	O
+increased	O
+serum	O
+tumor	B
+necrosis	B
+factor	O
+-	O
+alpha	O
+(	O
+TNFalpha	O
+)	O
+,	O
+hippocampal	O
+MT	O
+and	O
+malondialdehyde	O
+(	O
+MDA	O
+)	O
+contents	O
+as	O
+well	O
+as	O
+caspase	O
+-	O
+3	O
+activity	O
+in	O
+addition	O
+to	O
+histological	O
+alterations	O
+.	O
+
+ZnSO	O
+(	O
+4	O
+)	O
+pretreatment	O
+counteracted	O
+BCNU	O
+-	O
+induced	O
+inhibition	O
+of	O
+GR	O
+and	O
+depletion	O
+of	O
+GSH	O
+and	O
+resulted	O
+in	O
+significant	O
+reduction	O
+in	O
+the	O
+levels	O
+of	O
+MDA	O
+and	O
+TNFalpha	O
+as	O
+well	O
+as	O
+the	O
+activity	O
+of	O
+caspase	O
+-	O
+3	O
+.	O
+
+The	O
+histological	O
+features	O
+were	O
+improved	O
+in	O
+hippocampus	O
+of	O
+rats	O
+treated	O
+with	O
+ZnSO	O
+(	O
+4	O
+)	O
++	O
+BCNU	O
+compared	O
+to	O
+only	O
+BCNU	O
+-	O
+treated	O
+animals	O
+.	O
+
+In	O
+conclusion	O
+,	O
+MT	O
+induction	O
+halts	O
+BCNU	O
+-	O
+induced	O
+hippocampal	O
+toxicity	B
+as	O
+it	O
+prevented	O
+GR	O
+inhibition	O
+and	O
+GSH	O
+depletion	O
+and	O
+counteracted	O
+the	O
+increased	O
+levels	O
+of	O
+TNFalpha	O
+,	O
+MDA	O
+and	O
+caspase	O
+-	O
+3	O
+activity	O
+with	O
+subsequent	O
+preservation	O
+of	O
+cognition	O
+.	O
+
+Fatal	O
+carbamazepine	O
+induced	O
+fulminant	B
+eosinophilic	I
+(	O
+hypersensitivity	B
+)	O
+myocarditis	B
+:	O
+emphasis	O
+on	O
+anatomical	O
+and	O
+histological	O
+characteristics	O
+,	O
+mechanisms	O
+and	O
+genetics	O
+of	O
+drug	B
+hypersensitivity	I
+and	O
+differential	O
+diagnosis	O
+.	O
+
+The	O
+most	O
+severe	O
+adverse	O
+reactions	O
+to	O
+carbamazepine	O
+have	O
+been	O
+observed	O
+in	O
+the	O
+haemopoietic	O
+system	O
+,	O
+the	O
+liver	O
+and	O
+the	O
+cardiovascular	O
+system	O
+.	O
+
+A	O
+frequently	O
+fatal	O
+,	O
+although	O
+exceptionally	O
+rare	O
+side	O
+effect	O
+of	O
+carbamazepine	O
+is	O
+necrotizing	O
+eosinophilic	O
+(	O
+hypersensitivity	B
+)	O
+myocarditis	B
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+hypersensitivity	B
+myocarditis	B
+secondary	O
+to	O
+administration	O
+of	O
+carbamazepine	O
+.	O
+
+Acute	O
+hypersensitivity	B
+myocarditis	B
+was	O
+not	O
+suspected	O
+clinically	O
+,	O
+and	O
+the	O
+diagnosis	O
+was	O
+made	O
+post	O
+-	O
+mortem	O
+.	O
+
+Histology	O
+revealed	O
+diffuse	O
+infiltration	O
+of	O
+the	O
+myocardium	O
+by	O
+eosinophils	O
+and	O
+lymphocytes	O
+with	O
+myocyte	O
+damage	O
+.	O
+
+Clinically	O
+,	O
+death	O
+was	O
+due	O
+to	O
+cardiogenic	B
+shock	I
+.	O
+
+To	O
+best	O
+of	O
+our	O
+knowledge	O
+this	O
+is	O
+the	O
+second	O
+case	O
+of	O
+fatal	O
+carbamazepine	O
+induced	O
+myocarditis	B
+reported	O
+in	O
+English	O
+literature	O
+.	O
+
+Neuropsychiatric	O
+behaviors	O
+in	O
+the	O
+MPTP	O
+marmoset	O
+model	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+OBJECTIVES	O
+:	O
+Neuropsychiatric	O
+symptoms	O
+are	O
+increasingly	O
+recognised	O
+as	O
+a	O
+significant	O
+problem	O
+in	O
+patients	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+.	O
+
+These	O
+symptoms	O
+may	O
+be	O
+due	O
+to	O
+'	O
+sensitisation	O
+'	O
+following	O
+repeated	O
+levodopa	O
+treatment	O
+or	O
+a	O
+direct	O
+effect	O
+of	O
+dopamine	O
+on	O
+the	O
+disease	O
+state	O
+.	O
+
+The	O
+levodopa	O
+-	O
+treated	O
+MPTP	O
+-	O
+lesioned	O
+marmoset	O
+was	O
+used	O
+as	O
+a	O
+model	O
+of	O
+neuropsychiatric	B
+symptoms	I
+in	O
+PD	B
+patients	O
+.	O
+
+Here	O
+we	O
+compare	O
+the	O
+time	O
+course	O
+of	O
+levodopa	O
+-	O
+induced	O
+motor	O
+fluctuations	O
+and	O
+neuropsychiatric	B
+-	I
+like	I
+behaviors	I
+to	O
+determine	O
+the	O
+relationship	O
+between	O
+duration	O
+of	O
+treatment	O
+and	O
+onset	O
+of	O
+symptoms	O
+.	O
+
+METHODS	O
+:	O
+Marmosets	O
+were	O
+administered	O
+1	O
+-	O
+methyl	O
+-	O
+4	O
+-	O
+phenyl	O
+-	O
+1	O
+,	O
+2	O
+,	O
+3	O
+,	O
+6	O
+-	O
+tetrahydropyridine	O
+(	O
+2	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+for	O
+five	O
+days	O
+,	O
+resulting	O
+in	O
+stable	O
+parkinsonism	B
+.	O
+
+Levodopa	O
+(	O
+15	O
+mg	O
+/	O
+kg	O
+and	O
+benserazide	O
+,	O
+3	O
+.	O
+75	O
+mg	O
+/	O
+kg	O
+)	O
+p	O
+.	O
+o	O
+.	O
+
+b	O
+.	O
+i	O
+.	O
+d	O
+,	O
+was	O
+administered	O
+for	O
+30	O
+days	O
+.	O
+
+Animals	O
+were	O
+evaluated	O
+for	O
+parkinsonian	B
+disability	I
+,	O
+dyskinesia	B
+and	O
+on	O
+-	O
+time	O
+(	O
+motor	O
+fluctuations	O
+)	O
+and	O
+neuropsychiatric	B
+-	I
+like	I
+behaviors	I
+on	O
+Day	O
+0	O
+(	O
+prior	O
+to	O
+levodopa	O
+)	O
+and	O
+on	O
+Days	O
+1	O
+,	O
+7	O
+,	O
+13	O
+,	O
+27	O
+and	O
+30	O
+of	O
+treatment	O
+using	O
+post	O
+hoc	O
+DVD	O
+analysis	O
+by	O
+a	O
+trained	O
+rater	O
+,	O
+blind	O
+to	O
+the	O
+treatment	O
+day	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+neuropsychiatric	B
+-	I
+like	I
+behavior	I
+rating	O
+scale	O
+demonstrated	O
+high	O
+interrater	O
+reliability	O
+between	O
+three	O
+trained	O
+raters	O
+of	O
+differing	O
+professional	O
+backgrounds	O
+.	O
+
+As	O
+anticipated	O
+,	O
+animals	O
+exhibited	O
+a	O
+progressive	O
+increase	O
+in	O
+levodopa	O
+-	O
+induced	O
+motor	O
+fluctuations	O
+,	O
+dyskinesia	B
+and	O
+wearing	O
+-	O
+off	O
+,	O
+that	O
+correlated	O
+with	O
+the	O
+duration	O
+of	O
+levodopa	O
+therapy	O
+.	O
+
+In	O
+contrast	O
+,	O
+levodopa	O
+-	O
+induced	O
+neuropsychiatric	B
+-	I
+like	I
+behaviors	I
+were	O
+present	O
+on	O
+Day	O
+1	O
+of	O
+levodopa	O
+treatment	O
+and	O
+their	O
+severity	O
+did	O
+not	O
+correlate	O
+with	O
+duration	O
+of	O
+treatment	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+data	O
+suggest	O
+that	O
+neuropsychiatric	B
+disorders	I
+in	O
+PD	B
+are	O
+more	O
+likely	O
+an	O
+interaction	O
+between	O
+levodopa	O
+and	O
+the	O
+disease	O
+state	O
+than	O
+a	O
+consequence	O
+of	O
+sensitisation	O
+to	O
+repeated	O
+dopaminergic	O
+therapy	O
+.	O
+
+Contrast	O
+medium	O
+nephrotoxicity	B
+after	O
+renal	O
+artery	O
+and	O
+coronary	O
+angioplasty	O
+.	O
+
+BACKGROUND	O
+:	O
+Renal	B
+dysfunction	I
+induced	O
+by	O
+iodinated	O
+contrast	O
+medium	O
+(	O
+CM	O
+)	O
+administration	O
+can	O
+minimize	O
+the	O
+benefit	O
+of	O
+the	O
+interventional	O
+procedure	O
+in	O
+patients	O
+undergoing	O
+renal	O
+angioplasty	O
+(	O
+PTRA	O
+)	O
+.	O
+
+PURPOSE	O
+:	O
+To	O
+compare	O
+the	O
+susceptibility	O
+to	O
+nephrotoxic	B
+effect	O
+of	O
+CM	O
+in	O
+patients	O
+undergoing	O
+PTRA	O
+with	O
+that	O
+of	O
+patients	O
+submitted	O
+to	O
+percutaneous	O
+coronary	O
+intervention	O
+(	O
+PCI	O
+)	O
+.	O
+
+MATERIAL	O
+AND	O
+METHODS	O
+:	O
+A	O
+total	O
+of	O
+33	O
+patients	O
+successfully	O
+treated	O
+with	O
+PTRA	O
+(	O
+PTRA	O
+group	O
+,	O
+mean	O
+age	O
+70	O
++	O
+/	O
+-	O
+12	O
+years	O
+,	O
+23	O
+female	O
+,	O
+basal	O
+creatinine	O
+1	O
+.	O
+46	O
++	O
+/	O
+-	O
+0	O
+.	O
+79	O
+,	O
+range	O
+0	O
+.	O
+7	O
+-	O
+4	O
+.	O
+9	O
+mg	O
+/	O
+dl	O
+)	O
+were	O
+compared	O
+with	O
+33	O
+patients	O
+undergoing	O
+successful	O
+PCI	O
+(	O
+PCI	O
+group	O
+)	O
+,	O
+matched	O
+for	O
+basal	O
+creatinine	O
+(	O
+1	O
+.	O
+44	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+,	O
+range	O
+0	O
+.	O
+7	O
+-	O
+3	O
+.	O
+4	O
+mg	O
+/	O
+dl	O
+)	O
+,	O
+gender	O
+,	O
+and	O
+age	O
+.	O
+
+In	O
+both	O
+groups	O
+postprocedural	O
+(	O
+48	O
+h	O
+)	O
+serum	O
+creatinine	O
+was	O
+measured	O
+.	O
+
+RESULTS	O
+:	O
+Postprocedural	O
+creatinine	O
+level	O
+decreased	O
+nonsignificantly	O
+in	O
+the	O
+PTRA	O
+group	O
+(	O
+1	O
+.	O
+46	O
++	O
+/	O
+-	O
+0	O
+.	O
+8	O
+vs	O
+.	O
+1	O
+.	O
+34	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+dl	O
+,	O
+P	O
+=	O
+NS	O
+)	O
+and	O
+increased	O
+significantly	O
+in	O
+the	O
+PCI	O
+group	O
+(	O
+1	O
+.	O
+44	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+vs	O
+.	O
+1	O
+.	O
+57	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+mg	O
+/	O
+dl	O
+,	O
+P	O
+<	O
+0	O
+.	O
+02	O
+)	O
+.	O
+
+Changes	O
+in	O
+serum	O
+creatinine	O
+after	O
+intervention	O
+(	O
+after	O
+-	O
+before	O
+)	O
+were	O
+significantly	O
+different	O
+between	O
+the	O
+PTRA	O
+and	O
+PCI	O
+groups	O
+(	O
+-	O
+0	O
+.	O
+12	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+vs	O
+.	O
+0	O
+.	O
+13	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+,	O
+P	O
+=	O
+0	O
+.	O
+014	O
+)	O
+.	O
+
+This	O
+difference	O
+was	O
+not	O
+related	O
+to	O
+either	O
+a	O
+different	O
+clinical	O
+risk	O
+profile	O
+or	O
+to	O
+the	O
+volume	O
+of	O
+CM	O
+administered	O
+.	O
+
+CONCLUSION	O
+:	O
+In	O
+this	O
+preliminary	O
+study	O
+patients	O
+submitted	O
+to	O
+PTRA	O
+showed	O
+a	O
+lower	O
+susceptibility	O
+to	O
+renal	B
+damage	I
+induced	O
+by	O
+CM	O
+administration	O
+than	O
+PCI	O
+patients	O
+.	O
+
+The	O
+effectiveness	O
+of	O
+PTRA	O
+on	O
+renal	O
+function	O
+seems	O
+to	O
+be	O
+barely	O
+influenced	O
+by	O
+CM	O
+toxicity	B
+.	O
+
+Diphenhydramine	O
+prevents	O
+the	O
+haemodynamic	O
+changes	O
+of	O
+cimetidine	O
+in	O
+ICU	O
+patients	O
+.	O
+
+Cimetidine	O
+,	O
+a	O
+histamine	O
+2	O
+(	O
+H2	O
+)	O
+antagonist	O
+,	O
+produces	O
+a	O
+decrease	O
+in	O
+arterial	O
+pressure	O
+due	O
+to	O
+vasodilatation	O
+,	O
+especially	O
+in	O
+critically	O
+ill	O
+patients	O
+.	O
+
+This	O
+may	O
+be	O
+because	O
+cimetidine	O
+acts	O
+as	O
+a	O
+histamine	O
+agonist	O
+.	O
+
+We	O
+,	O
+therefore	O
+,	O
+investigated	O
+the	O
+effects	O
+of	O
+the	O
+histamine	O
+1	O
+(	O
+H1	O
+)	O
+receptor	O
+antagonist	O
+,	O
+diphenhydramine	O
+,	O
+on	O
+the	O
+haemodynamic	O
+changes	O
+observed	O
+after	O
+cimetidine	O
+in	O
+ICU	O
+patients	O
+.	O
+
+Each	O
+patient	O
+was	O
+studied	O
+on	O
+two	O
+separate	O
+days	O
+.	O
+
+In	O
+a	O
+random	O
+fashion	O
+,	O
+they	O
+received	O
+cimetidine	O
+200	O
+mg	O
+iv	O
+on	O
+one	O
+day	O
+,	O
+and	O
+on	O
+the	O
+other	O
+,	O
+a	O
+pretreatment	O
+of	O
+diphenhydramine	O
+40	O
+mg	O
+iv	O
+with	O
+cimetidine	O
+200	O
+mg	O
+iv	O
+.	O
+
+In	O
+the	O
+non	O
+-	O
+pretreatment	O
+group	O
+,	O
+mean	O
+arterial	O
+pressure	O
+(	O
+MAP	O
+)	O
+decreased	O
+from	O
+107	O
+.	O
+4	O
++	O
+/	O
+-	O
+8	O
+.	O
+4	O
+mmHg	O
+to	O
+86	O
+.	O
+7	O
++	O
+/	O
+-	O
+11	O
+.	O
+4	O
+mmHg	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+two	O
+minutes	O
+after	O
+cimetidine	O
+.	O
+
+Also	O
+,	O
+systemic	O
+vascular	O
+resistance	O
+(	O
+SVR	O
+)	O
+decreased	O
+during	O
+the	O
+eight	O
+-	O
+minute	O
+observation	O
+period	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+In	O
+contrast	O
+,	O
+in	O
+the	O
+pretreatment	O
+group	O
+,	O
+little	O
+haemodynamic	O
+change	O
+was	O
+seen	O
+.	O
+
+We	O
+conclude	O
+that	O
+an	O
+H1	O
+antagonist	O
+may	O
+be	O
+useful	O
+in	O
+preventing	O
+hypotension	B
+caused	O
+by	O
+iv	O
+cimetidine	O
+,	O
+since	O
+the	O
+vasodilating	O
+activity	O
+of	O
+cimetidine	O
+is	O
+mediated	O
+,	O
+in	O
+part	O
+,	O
+through	O
+the	O
+H1	O
+receptor	O
+.	O
+
+Medical	O
+and	O
+psychiatric	O
+outcomes	O
+for	O
+patients	O
+transplanted	O
+for	O
+acetaminophen	O
+-	O
+induced	O
+acute	B
+liver	I
+failure	I
+:	O
+a	O
+case	O
+-	O
+control	O
+study	O
+.	O
+
+BACKGROUND	O
+:	O
+Acetaminophen	O
+-	O
+induced	O
+hepatotoxicity	B
+is	O
+the	O
+most	O
+common	O
+cause	O
+of	O
+acute	B
+liver	I
+failure	I
+(	O
+ALF	B
+)	O
+in	O
+the	O
+UK	O
+.	O
+
+Patients	O
+often	O
+consume	O
+the	O
+drug	O
+with	O
+suicidal	O
+intent	O
+or	O
+with	O
+a	O
+background	O
+of	O
+substance	O
+dependence	O
+.	O
+
+AIMS	O
+AND	O
+METHODS	O
+:	O
+We	O
+compared	O
+the	O
+severity	O
+of	O
+pretransplant	O
+illness	O
+,	O
+psychiatric	O
+co	O
+-	O
+morbidity	O
+,	O
+medical	O
+and	O
+psychosocial	O
+outcomes	O
+of	O
+all	O
+patients	O
+who	O
+had	O
+undergone	O
+liver	O
+transplantation	O
+(	O
+LT	O
+)	O
+emergently	O
+between	O
+1999	O
+-	O
+2004	O
+for	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B
+(	O
+n	O
+=	O
+36	O
+)	O
+with	O
+age	O
+-	O
+and	O
+sex	O
+-	O
+matched	O
+patients	O
+undergoing	O
+emergent	O
+LT	O
+for	O
+non	O
+-	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B
+(	O
+n	O
+=	O
+35	O
+)	O
+and	O
+elective	O
+LT	O
+for	O
+chronic	B
+liver	I
+disease	I
+(	O
+CLD	B
+,	O
+n	O
+=	O
+34	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+Acetaminophen	O
+-	O
+induced	O
+ALF	B
+patients	O
+undergoing	O
+LT	O
+had	O
+a	O
+greater	O
+severity	O
+of	O
+pre	O
+-	O
+LT	O
+illness	O
+reflected	O
+by	O
+higher	O
+Acute	O
+Physiology	O
+and	O
+Chronic	O
+Health	O
+Evaluation	O
+II	O
+scores	O
+and	O
+requirement	O
+for	O
+organ	O
+support	O
+compared	O
+with	O
+the	O
+other	O
+two	O
+groups	O
+.	O
+
+Twenty	O
+(	O
+56	O
+%	O
+)	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B
+patients	O
+had	O
+a	O
+formal	O
+psychiatric	O
+diagnosis	O
+before	O
+LT	O
+(	O
+non	O
+-	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B
+=	O
+0	O
+/	O
+35	O
+,	O
+CLD	B
+=	O
+2	O
+/	O
+34	O
+;	O
+P	O
+<	O
+0	O
+.	O
+01	O
+for	O
+all	O
+)	O
+and	O
+nine	O
+(	O
+25	O
+%	O
+)	O
+had	O
+a	O
+previous	O
+suicide	O
+attempt	O
+.	O
+
+During	O
+follow	O
+-	O
+up	O
+(	O
+median	O
+5	O
+years	O
+)	O
+,	O
+there	O
+were	O
+no	O
+significant	O
+differences	O
+in	O
+rejection	O
+(	O
+acute	O
+and	O
+chronic	O
+)	O
+,	O
+graft	O
+failure	O
+or	O
+survival	O
+between	O
+the	O
+groups	O
+(	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B
+1	O
+year	O
+87	O
+%	O
+,	O
+5	O
+years	O
+75	O
+%	O
+;	O
+non	O
+-	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B
+88	O
+%	O
+,	O
+78	O
+%	O
+;	O
+CLD	B
+93	O
+%	O
+,	O
+82	O
+%	O
+:	O
+P	O
+>	O
+0	O
+.	O
+6	O
+log	O
+rank	O
+)	O
+.	O
+
+Two	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B
+patients	O
+reattempted	O
+suicide	O
+post	O
+-	O
+LT	O
+(	O
+one	O
+died	O
+8	O
+years	O
+post	O
+-	O
+LT	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Despite	O
+a	O
+high	O
+prevalence	O
+of	O
+psychiatric	O
+disturbance	O
+,	O
+outcomes	O
+for	O
+patients	O
+transplanted	O
+emergently	O
+for	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B
+were	O
+comparable	O
+to	O
+those	O
+transplanted	O
+for	O
+non	O
+-	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B
+and	O
+electively	O
+for	O
+CLD	B
+.	O
+
+Multidisciplinary	O
+approaches	O
+with	O
+long	O
+-	O
+term	O
+psychiatric	O
+follow	O
+-	O
+up	O
+may	O
+contribute	O
+to	O
+low	O
+post	O
+-	O
+transplant	O
+suicide	O
+rates	O
+seen	O
+and	O
+low	O
+rates	O
+of	O
+graft	O
+loss	O
+because	O
+of	O
+non	O
+-	O
+compliance	O
+.	O
+
+Antithrombotic	O
+drug	O
+use	O
+,	O
+cerebral	B
+microbleeds	I
+,	O
+and	O
+intracerebral	B
+hemorrhage	I
+:	O
+a	O
+systematic	O
+review	O
+of	O
+published	O
+and	O
+unpublished	O
+studies	O
+.	O
+
+BACKGROUND	O
+AND	O
+PURPOSE	O
+:	O
+Cerebral	B
+microbleeds	I
+(	O
+MB	B
+)	O
+are	O
+potential	O
+risk	O
+factors	O
+for	O
+intracerebral	B
+hemorrhage	I
+(	O
+ICH	B
+)	O
+,	O
+but	O
+it	O
+is	O
+unclear	O
+if	O
+they	O
+are	O
+a	O
+contraindication	O
+to	O
+using	O
+antithrombotic	O
+drugs	O
+.	O
+
+Insights	O
+could	O
+be	O
+gained	O
+by	O
+pooling	O
+data	O
+on	O
+MB	B
+frequency	O
+stratified	O
+by	O
+antithrombotic	O
+use	O
+in	O
+cohorts	O
+with	O
+ICH	B
+and	O
+ischemic	B
+stroke	I
+(	O
+IS	B
+)	O
+/	O
+transient	B
+ischemic	I
+attack	I
+(	O
+TIA	B
+)	O
+.	O
+
+METHODS	O
+:	O
+We	O
+performed	O
+a	O
+systematic	O
+review	O
+of	O
+published	O
+and	O
+unpublished	O
+data	O
+from	O
+cohorts	O
+with	O
+stroke	B
+or	O
+TIA	B
+to	O
+compare	O
+the	O
+presence	O
+of	O
+MB	B
+in	O
+:	O
+(	O
+1	O
+)	O
+antithrombotic	O
+users	O
+vs	O
+nonantithrombotic	O
+users	O
+with	O
+ICH	B
+;	O
+(	O
+2	O
+)	O
+antithrombotic	O
+users	O
+vs	O
+nonusers	O
+with	O
+IS	B
+/	O
+TIA	B
+;	O
+and	O
+(	O
+3	O
+)	O
+ICH	B
+vs	O
+ischemic	B
+events	O
+stratified	O
+by	O
+antithrombotic	O
+use	O
+.	O
+
+We	O
+also	O
+analyzed	O
+published	O
+and	O
+unpublished	O
+follow	O
+-	O
+up	O
+data	O
+to	O
+determine	O
+the	O
+risk	O
+of	O
+ICH	B
+in	O
+antithrombotic	O
+users	O
+with	O
+MB	B
+.	O
+
+RESULTS	O
+:	O
+In	O
+a	O
+pooled	O
+analysis	O
+of	O
+1460	O
+ICH	B
+and	O
+3817	O
+IS	B
+/	O
+TIA	B
+,	O
+MB	B
+were	O
+more	O
+frequent	O
+in	O
+ICH	B
+vs	O
+IS	B
+/	O
+TIA	B
+in	O
+all	O
+treatment	O
+groups	O
+,	O
+but	O
+the	O
+excess	O
+increased	O
+from	O
+2	O
+.	O
+8	O
+(	O
+odds	O
+ratio	O
+;	O
+range	O
+,	O
+2	O
+.	O
+3	O
+-	O
+3	O
+.	O
+5	O
+)	O
+in	O
+nonantithrombotic	O
+users	O
+to	O
+5	O
+.	O
+7	O
+(	O
+range	O
+,	O
+3	O
+.	O
+4	O
+-	O
+9	O
+.	O
+7	O
+)	O
+in	O
+antiplatelet	O
+users	O
+and	O
+8	O
+.	O
+0	O
+(	O
+range	O
+,	O
+3	O
+.	O
+5	O
+-	O
+17	O
+.	O
+8	O
+)	O
+in	O
+warfarin	O
+users	O
+(	O
+P	O
+difference	O
+=	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+There	O
+was	O
+also	O
+an	O
+excess	O
+of	O
+MB	B
+in	O
+warfarin	O
+users	O
+vs	O
+nonusers	O
+with	O
+ICH	B
+(	O
+OR	O
+,	O
+2	O
+.	O
+7	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+6	O
+-	O
+4	O
+.	O
+4	O
+;	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+but	O
+none	O
+in	O
+warfarin	O
+users	O
+with	O
+IS	B
+/	O
+TIA	B
+(	O
+OR	O
+,	O
+1	O
+.	O
+3	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+0	O
+.	O
+9	O
+-	O
+1	O
+.	O
+7	O
+;	O
+P	O
+=	O
+0	O
+.	O
+33	O
+;	O
+P	O
+difference	O
+=	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+There	O
+was	O
+a	O
+smaller	O
+excess	O
+of	O
+MB	B
+in	O
+antiplatelet	O
+users	O
+vs	O
+nonusers	O
+with	O
+ICH	B
+(	O
+OR	O
+,	O
+1	O
+.	O
+7	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+3	O
+-	O
+2	O
+.	O
+3	O
+;	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+,	O
+but	O
+findings	O
+were	O
+similar	O
+for	O
+antiplatelet	O
+users	O
+with	O
+IS	B
+/	O
+TIA	B
+(	O
+OR	O
+,	O
+1	O
+.	O
+4	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+2	O
+-	O
+1	O
+.	O
+7	O
+;	O
+P	O
+<	O
+0	O
+.	O
+001	O
+;	O
+P	O
+difference	O
+=	O
+0	O
+.	O
+25	O
+)	O
+.	O
+
+In	O
+pooled	O
+follow	O
+-	O
+up	O
+data	O
+for	O
+768	O
+antithrombotic	O
+users	O
+,	O
+presence	O
+of	O
+MB	B
+at	O
+baseline	O
+was	O
+associated	O
+with	O
+a	O
+substantially	O
+increased	O
+risk	O
+of	O
+subsequent	O
+ICH	B
+(	O
+OR	O
+,	O
+12	O
+.	O
+1	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+3	O
+.	O
+4	O
+-	O
+42	O
+.	O
+5	O
+;	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+excess	O
+of	O
+MB	B
+in	O
+warfarin	O
+users	O
+with	O
+ICH	B
+compared	O
+to	O
+other	O
+groups	O
+suggests	O
+that	O
+MB	B
+increase	O
+the	O
+risk	O
+of	O
+warfarin	O
+-	O
+associated	O
+ICH	B
+.	O
+
+Limited	O
+prospective	O
+data	O
+corroborate	O
+these	O
+findings	O
+,	O
+but	O
+larger	O
+prospective	O
+studies	O
+are	O
+urgently	O
+required	O
+.	O
+
+Studies	O
+of	O
+synergy	O
+between	O
+morphine	O
+and	O
+a	O
+novel	O
+sodium	O
+channel	O
+blocker	O
+,	O
+CNSB002	O
+,	O
+in	O
+rat	O
+models	O
+of	O
+inflammatory	O
+and	O
+neuropathic	B
+pain	I
+.	O
+
+OBJECTIVE	O
+:	O
+This	O
+study	O
+determined	O
+the	O
+antihyperalgesic	O
+effect	O
+of	O
+CNSB002	O
+,	O
+a	O
+sodium	O
+channel	O
+blocker	O
+with	O
+antioxidant	O
+properties	O
+given	O
+alone	O
+and	O
+in	O
+combinations	O
+with	O
+morphine	O
+in	O
+rat	O
+models	O
+of	O
+inflammatory	O
+and	O
+neuropathic	B
+pain	I
+.	O
+
+DESIGN	O
+:	O
+Dose	O
+response	O
+curves	O
+for	O
+nonsedating	O
+doses	O
+of	O
+morphine	O
+and	O
+CNSB002	O
+given	O
+intraperitoneally	O
+alone	O
+and	O
+together	O
+in	O
+combinations	O
+were	O
+constructed	O
+for	O
+antihyperalgesic	O
+effect	O
+using	O
+paw	O
+withdrawal	O
+from	O
+noxious	O
+heat	O
+in	O
+two	O
+rat	O
+pain	B
+models	O
+:	O
+carrageenan	O
+-	O
+induced	O
+paw	O
+inflammation	B
+and	O
+streptozotocin	O
+(	O
+STZ	O
+)	O
+-	O
+induced	O
+diabetic	B
+neuropathy	I
+.	O
+
+RESULTS	O
+:	O
+The	O
+maximum	O
+nonsedating	O
+doses	O
+were	O
+:	O
+morphine	O
+,	O
+3	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+;	O
+CNSB002	O
+10	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+;	O
+5	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+CNSB002	O
+with	O
+morphine	O
+3	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+in	O
+combination	O
+.	O
+
+The	O
+doses	O
+calculated	O
+to	O
+cause	O
+50	O
+%	O
+reversal	O
+of	O
+hyperalgesia	B
+(	O
+ED50	O
+)	O
+were	O
+7	O
+.	O
+54	O
+(	O
+1	O
+.	O
+81	O
+)	O
+and	O
+4	O
+.	O
+83	O
+(	O
+1	O
+.	O
+54	O
+)	O
+in	O
+the	O
+carrageenan	O
+model	O
+and	O
+44	O
+.	O
+18	O
+(	O
+1	O
+.	O
+37	O
+)	O
+and	O
+9	O
+.	O
+14	O
+(	O
+1	O
+.	O
+24	O
+)	O
+in	O
+the	O
+STZ	O
+-	O
+induced	O
+neuropathy	B
+model	O
+for	O
+CNSB002	O
+and	O
+morphine	O
+,	O
+respectively	O
+(	O
+mg	O
+/	O
+kg	O
+;	O
+mean	O
+,	O
+SEM	O
+)	O
+.	O
+
+These	O
+values	O
+were	O
+greater	O
+than	O
+the	O
+maximum	O
+nonsedating	O
+doses	O
+.	O
+
+The	O
+ED50	O
+values	O
+for	O
+morphine	O
+when	O
+given	O
+in	O
+combination	O
+with	O
+CNSB002	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+were	O
+less	O
+than	O
+the	O
+maximum	O
+nonsedating	O
+dose	O
+:	O
+0	O
+.	O
+56	O
+(	O
+1	O
+.	O
+55	O
+)	O
+in	O
+the	O
+carrageenan	O
+model	O
+and	O
+1	O
+.	O
+37	O
+(	O
+1	O
+.	O
+23	O
+)	O
+in	O
+the	O
+neuropathy	B
+model	O
+(	O
+mg	O
+/	O
+kg	O
+;	O
+mean	O
+,	O
+SEM	O
+)	O
+.	O
+
+The	O
+antinociception	O
+after	O
+morphine	O
+(	O
+3	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+increased	O
+by	O
+co	O
+-	O
+administration	O
+with	O
+CNSB002	O
+from	O
+28	O
+.	O
+0	O
+and	O
+31	O
+.	O
+7	O
+%	O
+to	O
+114	O
+.	O
+6	O
+and	O
+56	O
+.	O
+9	O
+%	O
+reversal	O
+of	O
+hyperalgesia	B
+in	O
+the	O
+inflammatory	O
+and	O
+neuropathic	B
+models	O
+,	O
+respectively	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+;	O
+one	O
+-	O
+way	O
+analysis	O
+of	O
+variance	O
+-	O
+significantly	O
+greater	O
+than	O
+either	O
+drug	O
+given	O
+alone	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+maximum	O
+antihyperalgesic	O
+effect	O
+achievable	O
+with	O
+nonsedating	O
+doses	O
+of	O
+morphine	O
+may	O
+be	O
+increased	O
+significantly	O
+when	O
+the	O
+drug	O
+is	O
+used	O
+in	O
+combination	O
+with	O
+CNSB002	O
+.	O
+
+Heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+:	O
+a	O
+practical	O
+review	O
+.	O
+
+Heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+(	O
+HIT	B
+)	O
+remains	O
+under	O
+-	O
+recognized	O
+despite	O
+its	O
+potentially	O
+devastating	O
+outcomes	O
+.	O
+
+It	O
+begins	O
+when	O
+heparin	O
+exposure	O
+stimulates	O
+the	O
+formation	O
+of	O
+heparin	O
+-	O
+platelet	O
+factor	O
+4	O
+antibodies	O
+,	O
+which	O
+in	O
+turn	O
+triggers	O
+the	O
+release	O
+of	O
+procoagulant	O
+platelet	O
+particles	O
+.	O
+
+Thrombosis	B
+and	O
+thrombocytopenia	B
+that	O
+follow	O
+comprise	O
+the	O
+2	O
+hallmark	O
+traits	O
+of	O
+HIT	B
+,	O
+with	O
+the	O
+former	O
+largely	O
+responsible	O
+for	O
+significant	O
+vascular	O
+complications	O
+.	O
+
+The	O
+prevalence	O
+of	O
+HIT	B
+varies	O
+among	O
+several	O
+subgroups	O
+,	O
+with	O
+greater	O
+incidence	O
+in	O
+surgical	O
+as	O
+compared	O
+with	O
+medical	O
+populations	O
+.	O
+
+HIT	B
+must	O
+be	O
+acknowledged	O
+for	O
+its	O
+intense	O
+predilection	O
+for	O
+thrombosis	B
+and	O
+suspected	O
+whenever	O
+thrombosis	B
+occurs	O
+after	O
+heparin	O
+exposure	O
+.	O
+
+Early	O
+recognition	O
+that	O
+incorporates	O
+the	O
+clinical	O
+and	O
+serologic	O
+clues	O
+is	O
+paramount	O
+to	O
+timely	O
+institution	O
+of	O
+treatment	O
+,	O
+as	O
+its	O
+delay	O
+may	O
+result	O
+in	O
+catastrophic	O
+outcomes	O
+.	O
+
+The	O
+treatment	O
+of	O
+HIT	B
+mandates	O
+an	O
+immediate	O
+cessation	O
+of	O
+all	O
+heparin	O
+exposure	O
+and	O
+the	O
+institution	O
+of	O
+an	O
+antithrombotic	O
+therapy	O
+,	O
+most	O
+commonly	O
+using	O
+a	O
+direct	O
+thrombin	O
+inhibitor	O
+.	O
+
+Current	O
+"	O
+diagnostic	O
+"	O
+tests	O
+,	O
+which	O
+primarily	O
+include	O
+functional	O
+and	O
+antigenic	O
+assays	O
+,	O
+have	O
+more	O
+of	O
+a	O
+confirmatory	O
+than	O
+diagnostic	O
+role	O
+in	O
+the	O
+management	O
+of	O
+HIT	B
+.	O
+
+Special	O
+attention	O
+must	O
+be	O
+paid	O
+to	O
+cardiac	O
+patients	O
+who	O
+are	O
+often	O
+exposed	O
+to	O
+heparin	O
+multiple	O
+times	O
+during	O
+their	O
+course	O
+of	O
+treatment	O
+.	O
+
+Direct	O
+thrombin	O
+inhibitors	O
+are	O
+appropriate	O
+,	O
+evidence	O
+-	O
+based	O
+alternatives	O
+to	O
+heparin	O
+in	O
+patients	O
+with	O
+a	O
+history	O
+of	O
+HIT	B
+,	O
+who	O
+need	O
+to	O
+undergo	O
+percutaneous	O
+coronary	O
+intervention	O
+.	O
+
+As	O
+heparin	O
+remains	O
+one	O
+of	O
+the	O
+most	O
+frequently	O
+used	O
+medications	O
+today	O
+with	O
+potential	O
+for	O
+HIT	B
+with	O
+every	O
+heparin	O
+exposure	O
+,	O
+a	O
+close	O
+vigilance	O
+of	O
+platelet	O
+counts	O
+must	O
+be	O
+practiced	O
+whenever	O
+heparin	O
+is	O
+initiated	O
+.	O
+
+Abductor	O
+paralysis	B
+after	O
+botox	O
+injection	O
+for	O
+adductor	B
+spasmodic	I
+dysphonia	I
+.	O
+
+OBJECTIVES	O
+/	O
+HYPOTHESIS	O
+:	O
+Botulinum	O
+toxin	O
+(	O
+Botox	O
+)	O
+injections	O
+into	O
+the	O
+thyroarytenoid	O
+muscles	O
+are	O
+the	O
+current	O
+standard	O
+of	O
+care	O
+for	O
+adductor	B
+spasmodic	I
+dysphonia	I
+(	O
+ADSD	B
+)	O
+.	O
+
+Reported	O
+adverse	O
+effects	O
+include	O
+a	O
+period	O
+of	O
+breathiness	O
+,	O
+throat	B
+pain	I
+,	O
+and	O
+difficulty	O
+with	O
+swallowing	O
+liquids	O
+.	O
+
+Here	O
+we	O
+report	O
+multiple	O
+cases	O
+of	O
+bilateral	O
+abductor	O
+paralysis	B
+following	O
+Botox	O
+injections	O
+for	O
+ADSD	B
+,	O
+a	O
+complication	O
+previously	O
+unreported	O
+.	O
+
+STUDY	O
+DESIGN	O
+:	O
+Retrospective	O
+case	O
+series	O
+.	O
+
+METHODS	O
+:	O
+Patients	O
+that	O
+received	O
+Botox	O
+injections	O
+for	O
+spasmodic	B
+dysphonia	I
+between	O
+January	O
+2000	O
+and	O
+October	O
+2009	O
+were	O
+evaluated	O
+.	O
+
+Patients	O
+with	O
+ADSD	B
+were	O
+identified	O
+.	O
+
+The	O
+number	O
+of	O
+treatments	O
+received	O
+and	O
+adverse	O
+effects	O
+were	O
+noted	O
+.	O
+
+For	O
+patients	O
+with	O
+bilateral	O
+abductor	O
+paralysis	B
+,	O
+age	O
+,	O
+sex	O
+,	O
+paralytic	O
+Botox	O
+dose	O
+,	O
+prior	O
+Botox	O
+dose	O
+,	O
+and	O
+course	O
+following	O
+paralysis	B
+were	O
+noted	O
+.	O
+
+RESULTS	O
+:	O
+From	O
+a	O
+database	O
+of	O
+452	O
+patients	O
+receiving	O
+Botox	O
+,	O
+352	O
+patients	O
+had	O
+been	O
+diagnosed	O
+with	O
+ADSD	B
+.	O
+
+Of	O
+these	O
+352	O
+patients	O
+,	O
+eight	O
+patients	O
+suffered	O
+bilateral	O
+abductor	O
+paralysis	B
+,	O
+and	O
+two	O
+suffered	O
+this	O
+complication	O
+twice	O
+.	O
+
+All	O
+affected	O
+patients	O
+were	O
+females	O
+over	O
+the	O
+age	O
+of	O
+50	O
+years	O
+.	O
+
+Most	O
+patients	O
+had	O
+received	O
+treatments	O
+prior	O
+to	O
+abductor	O
+paralysis	B
+and	O
+continued	O
+receiving	O
+after	O
+paralysis	B
+.	O
+
+Seven	O
+patients	O
+recovered	O
+after	O
+a	O
+brief	O
+period	O
+of	O
+activity	O
+restrictions	O
+,	O
+and	O
+one	O
+underwent	O
+a	O
+tracheotomy	O
+.	O
+
+The	O
+incidence	O
+of	O
+abductor	O
+paralysis	B
+after	O
+Botox	O
+injection	O
+for	O
+ADSD	B
+was	O
+0	O
+.	O
+34	O
+%	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Bilateral	O
+abductor	O
+paralysis	B
+is	O
+a	O
+rare	O
+complication	O
+of	O
+Botox	O
+injections	O
+for	O
+ADSD	B
+,	O
+causing	O
+difficulty	O
+with	O
+breathing	O
+upon	O
+exertion	O
+.	O
+
+The	O
+likely	O
+mechanism	O
+of	O
+paralysis	B
+is	O
+diffusion	O
+of	O
+Botox	O
+around	O
+the	O
+muscular	O
+process	O
+of	O
+the	O
+arytenoid	O
+to	O
+the	O
+posterior	O
+cricoarytenoid	O
+muscles	O
+.	O
+
+The	O
+paralysis	B
+is	O
+temporary	O
+,	O
+and	O
+watchful	O
+waiting	O
+with	O
+restriction	O
+of	O
+activity	O
+is	O
+the	O
+recommended	O
+management	O
+.	O
+
+Mitochondrial	B
+impairment	I
+contributes	O
+to	O
+cocaine	O
+-	O
+induced	O
+cardiac	B
+dysfunction	I
+:	O
+Prevention	O
+by	O
+the	O
+targeted	O
+antioxidant	O
+MitoQ	O
+.	O
+
+The	O
+goal	O
+of	O
+this	O
+study	O
+was	O
+to	O
+assess	O
+mitochondrial	O
+function	O
+and	O
+ROS	O
+production	O
+in	O
+an	O
+experimental	O
+model	O
+of	O
+cocaine	O
+-	O
+induced	O
+cardiac	B
+dysfunction	I
+.	O
+
+We	O
+hypothesized	O
+that	O
+cocaine	B
+abuse	I
+may	O
+lead	O
+to	O
+altered	O
+mitochondrial	O
+function	O
+that	O
+in	O
+turn	O
+may	O
+cause	O
+left	B
+ventricular	I
+dysfunction	I
+.	O
+
+Seven	O
+days	O
+of	O
+cocaine	O
+administration	O
+to	O
+rats	O
+led	O
+to	O
+an	O
+increased	O
+oxygen	O
+consumption	O
+detected	O
+in	O
+cardiac	O
+fibers	O
+,	O
+specifically	O
+through	O
+complex	O
+I	O
+and	O
+complex	O
+III	O
+.	O
+
+ROS	O
+levels	O
+were	O
+increased	O
+,	O
+specifically	O
+in	O
+interfibrillar	O
+mitochondria	O
+.	O
+
+In	O
+parallel	O
+there	O
+was	O
+a	O
+decrease	O
+in	O
+ATP	O
+synthesis	O
+,	O
+whereas	O
+no	O
+difference	O
+was	O
+observed	O
+in	O
+subsarcolemmal	O
+mitochondria	O
+.	O
+
+This	O
+uncoupling	O
+effect	O
+on	O
+oxidative	O
+phosphorylation	O
+was	O
+not	O
+detectable	O
+after	O
+short	O
+-	O
+term	O
+exposure	O
+to	O
+cocaine	O
+,	O
+suggesting	O
+that	O
+these	O
+mitochondrial	B
+abnormalities	I
+were	O
+a	O
+late	O
+rather	O
+than	O
+a	O
+primary	O
+event	O
+in	O
+the	O
+pathological	O
+response	O
+to	O
+cocaine	O
+.	O
+
+MitoQ	O
+,	O
+a	O
+mitochondrial	O
+-	O
+targeted	O
+antioxidant	O
+,	O
+was	O
+shown	O
+to	O
+completely	O
+prevent	O
+these	O
+mitochondrial	B
+abnormalities	I
+as	O
+well	O
+as	O
+cardiac	B
+dysfunction	I
+characterized	O
+here	O
+by	O
+a	O
+diastolic	B
+dysfunction	I
+studied	O
+with	O
+a	O
+conductance	O
+catheter	O
+to	O
+obtain	O
+pressure	O
+-	O
+volume	O
+data	O
+.	O
+
+Taken	O
+together	O
+,	O
+these	O
+results	O
+extend	O
+previous	O
+studies	O
+and	O
+demonstrate	O
+that	O
+cocaine	O
+-	O
+induced	O
+cardiac	B
+dysfunction	I
+may	O
+be	O
+due	O
+to	O
+a	O
+mitochondrial	B
+defect	I
+.	O
+
+Trimethoprim	O
+-	O
+induced	O
+immune	O
+hemolytic	B
+anemia	I
+in	O
+a	O
+pediatric	O
+oncology	O
+patient	O
+presenting	O
+as	O
+an	O
+acute	O
+hemolytic	O
+transfusion	O
+reaction	O
+.	O
+
+A	O
+10	O
+-	O
+year	O
+-	O
+old	O
+male	O
+with	O
+acute	B
+leukemia	I
+presented	O
+with	O
+post	O
+-	O
+chemotherapy	O
+anemia	B
+.	O
+
+During	O
+red	O
+cell	O
+transfusion	O
+,	O
+he	O
+developed	O
+hemoglobinuria	B
+.	O
+
+Transfusion	O
+reaction	O
+workup	O
+was	O
+negative	O
+.	O
+
+Drug	O
+-	O
+induced	O
+immune	O
+hemolytic	B
+anemia	I
+was	O
+suspected	O
+because	O
+of	O
+positive	O
+direct	O
+antiglobulin	O
+test	O
+,	O
+negative	O
+eluate	O
+,	O
+and	O
+microspherocytes	O
+on	O
+smear	O
+pre	O
+-	O
+and	O
+post	O
+-	O
+transfusion	O
+.	O
+
+Drug	O
+studies	O
+using	O
+the	O
+indirect	O
+antiglobulin	O
+test	O
+were	O
+strongly	O
+positive	O
+with	O
+trimethoprim	O
+and	O
+trimethoprim	O
+-	O
+sulfamethoxazole	O
+but	O
+negative	O
+with	O
+sulfamethoxazole	O
+.	O
+
+The	O
+patient	O
+recovered	O
+after	O
+discontinuing	O
+the	O
+drug	O
+,	O
+with	O
+no	O
+recurrence	O
+in	O
+2	O
+years	O
+.	O
+
+Other	O
+causes	O
+of	O
+anemia	B
+should	O
+be	O
+considered	O
+in	O
+patients	O
+with	O
+worse	O
+-	O
+than	O
+-	O
+expected	O
+anemia	B
+after	O
+chemotherapy	O
+.	O
+
+Furthermore	O
+,	O
+hemolysis	B
+during	O
+transfusion	O
+is	O
+not	O
+always	O
+a	O
+transfusion	O
+reaction	O
+.	O
+
+Verapamil	O
+stimulation	O
+test	O
+in	O
+hyperprolactinemia	B
+:	O
+loss	O
+of	O
+prolactin	O
+response	O
+in	O
+anatomic	O
+or	O
+functional	O
+stalk	O
+effect	O
+.	O
+
+AIM	O
+:	O
+Verapamil	O
+stimulation	O
+test	O
+was	O
+previously	O
+investigated	O
+as	O
+a	O
+tool	O
+for	O
+differential	O
+diagnosis	O
+of	O
+hyperprolactinemia	B
+,	O
+but	O
+with	O
+conflicting	O
+results	O
+.	O
+
+Macroprolactinemia	B
+was	O
+never	O
+considered	O
+in	O
+those	O
+previous	O
+studies	O
+.	O
+
+Here	O
+,	O
+we	O
+aimed	O
+to	O
+re	O
+-	O
+investigate	O
+the	O
+diagnostic	O
+value	O
+of	O
+verapamil	O
+in	O
+a	O
+population	O
+who	O
+were	O
+all	O
+screened	O
+for	O
+macroprolactinemia	B
+.	O
+
+Prolactin	O
+responses	O
+to	O
+verapamil	O
+in	O
+65	O
+female	O
+patients	O
+(	O
+age	O
+:	O
+29	O
+.	O
+9	O
++	O
+/	O
+-	O
+8	O
+.	O
+1	O
+years	O
+)	O
+with	O
+hyperprolactinemia	B
+were	O
+tested	O
+in	O
+a	O
+descriptive	O
+,	O
+matched	O
+case	O
+-	O
+control	O
+study	O
+.	O
+
+METHODS	O
+:	O
+Verapamil	O
+80	O
+mg	O
+,	O
+p	O
+.	O
+o	O
+.	O
+was	O
+administered	O
+,	O
+and	O
+then	O
+PRL	O
+levels	O
+were	O
+measured	O
+at	O
+8th	O
+and	O
+16th	O
+hours	O
+,	O
+by	O
+immunometric	O
+chemiluminescence	O
+.	O
+
+Verapamil	O
+responsiveness	O
+was	O
+determined	O
+by	O
+peak	O
+percent	O
+change	O
+in	O
+basal	O
+prolactin	O
+levels	O
+(	O
+PRL	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+Verapamil	O
+significantly	O
+increased	O
+PRL	O
+levels	O
+in	O
+healthy	O
+controls	O
+(	O
+N	O
+.	O
+8	O
+,	O
+PRL	O
+:	O
+183	O
+%	O
+)	O
+,	O
+macroprolactinoma	B
+(	O
+N	O
+.	O
+8	O
+,	O
+PRL	O
+:	O
+7	O
+%	O
+)	O
+,	O
+microprolactinoma	B
+(	O
+N	O
+.	O
+19	O
+,	O
+PRL	O
+:	O
+21	O
+%	O
+)	O
+,	O
+macroprolactinemia	B
+(	O
+N	O
+.	O
+23	O
+,	O
+PRL	O
+:	O
+126	O
+%	O
+)	O
+,	O
+but	O
+not	O
+in	O
+pseudoprolactinoma	B
+(	O
+N	O
+.	O
+8	O
+,	O
+PRL	O
+:	O
+0	O
+.	O
+8	O
+%	O
+)	O
+,	O
+and	O
+risperidone	O
+-	O
+induced	O
+hyperprolactinemia	B
+(	O
+N	O
+.	O
+7	O
+,	O
+PRL	O
+:	O
+3	O
+%	O
+)	O
+.	O
+
+ROC	O
+curve	O
+analysis	O
+revealed	O
+that	O
+unresponsiveness	O
+to	O
+verapamil	O
+defined	O
+as	O
+PRL	O
+<	O
+7	O
+%	O
+,	O
+discriminated	O
+anatomical	O
+or	O
+functional	O
+stalk	O
+effect	O
+(	O
+sensitivity	O
+:	O
+74	O
+%	O
+,	O
+specificity	O
+:	O
+73	O
+%	O
+,	O
+AUC	O
+:	O
+0	O
+.	O
+855	O
++	O
+/	O
+-	O
+0	O
+.	O
+04	O
+,	O
+P	O
+<	O
+0	O
+.	O
+001	O
+,	O
+CI	O
+:	O
+0	O
+.	O
+768	O
+-	O
+0	O
+.	O
+942	O
+)	O
+associated	O
+with	O
+pseudoprolactinoma	B
+or	O
+risperidone	O
+-	O
+induced	O
+hyperprolactinemia	B
+,	O
+respectively	O
+.	O
+
+CONCLUSION	O
+:	O
+Verapamil	O
+responsiveness	O
+is	O
+not	O
+a	O
+reliable	O
+finding	O
+for	O
+the	O
+differential	O
+diagnosis	O
+of	O
+hyperprolactinemia	B
+.	O
+
+However	O
+,	O
+verapamil	O
+unresponsiveness	O
+discriminates	O
+stalk	O
+effect	O
+(	O
+i	O
+.	O
+e	O
+.	O
+,	O
+anatomically	O
+or	O
+functionally	O
+inhibited	O
+dopaminergic	O
+tonus	O
+)	O
+from	O
+other	O
+causes	O
+of	O
+hyperprolactinemia	B
+with	O
+varying	O
+degrees	O
+of	O
+responsiveness	O
+.	O
+
+Blockade	O
+of	O
+endothelial	O
+-	O
+mesenchymal	O
+transition	O
+by	O
+a	O
+Smad3	O
+inhibitor	O
+delays	O
+the	O
+early	O
+development	O
+of	O
+streptozotocin	O
+-	O
+induced	O
+diabetic	B
+nephropathy	I
+.	O
+
+OBJECTIVE	O
+:	O
+A	O
+multicenter	O
+,	O
+controlled	O
+trial	O
+showed	O
+that	O
+early	O
+blockade	O
+of	O
+the	O
+renin	O
+-	O
+angiotensin	O
+system	O
+in	O
+patients	O
+with	O
+type	B
+1	I
+diabetes	I
+and	O
+normoalbuminuria	O
+did	O
+not	O
+retard	O
+the	O
+progression	O
+of	O
+nephropathy	B
+,	O
+suggesting	O
+that	O
+other	O
+mechanism	O
+(	O
+s	O
+)	O
+are	O
+involved	O
+in	O
+the	O
+pathogenesis	O
+of	O
+early	O
+diabetic	B
+nephropathy	I
+(	O
+diabetic	B
+nephropathy	I
+)	O
+.	O
+
+We	O
+have	O
+previously	O
+demonstrated	O
+that	O
+endothelial	O
+-	O
+mesenchymal	O
+-	O
+transition	O
+(	O
+EndoMT	O
+)	O
+contributes	O
+to	O
+the	O
+early	O
+development	O
+of	O
+renal	O
+interstitial	O
+fibrosis	B
+independently	O
+of	O
+microalbuminuria	O
+in	O
+mice	O
+with	O
+streptozotocin	O
+(	O
+STZ	O
+)	O
+-	O
+induced	O
+diabetes	B
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+we	O
+hypothesized	O
+that	O
+blocking	O
+EndoMT	O
+reduces	O
+the	O
+early	O
+development	O
+of	O
+diabetic	B
+nephropathy	I
+.	O
+
+RESEARCH	O
+DESIGN	O
+AND	O
+METHODS	O
+:	O
+EndoMT	O
+was	O
+induced	O
+in	O
+a	O
+mouse	O
+pancreatic	O
+microvascular	O
+endothelial	O
+cell	O
+line	O
+(	O
+MMEC	O
+)	O
+in	O
+the	O
+presence	O
+of	O
+advanced	O
+glycation	O
+end	O
+products	O
+(	O
+AGEs	O
+)	O
+and	O
+in	O
+the	O
+endothelial	O
+lineage	O
+-	O
+traceble	O
+mouse	O
+line	O
+Tie2	O
+-	O
+Cre	O
+;	O
+Loxp	O
+-	O
+EGFP	O
+by	O
+administration	O
+of	O
+AGEs	O
+,	O
+with	O
+nonglycated	O
+mouse	O
+albumin	O
+serving	O
+as	O
+a	O
+control	O
+.	O
+
+Phosphorylated	O
+Smad3	O
+was	O
+detected	O
+by	O
+immunoprecipitation	O
+/	O
+Western	O
+blotting	O
+and	O
+confocal	O
+microscopy	O
+.	O
+
+Blocking	O
+studies	O
+using	O
+receptor	O
+for	O
+AGE	O
+siRNA	O
+and	O
+a	O
+specific	O
+inhibitor	O
+of	O
+Smad3	O
+(	O
+SIS3	O
+)	O
+were	O
+performed	O
+in	O
+MMECs	O
+and	O
+in	O
+STZ	O
+-	O
+induced	O
+diabetic	B
+nephropathy	I
+in	O
+Tie2	O
+-	O
+Cre	O
+;	O
+Loxp	O
+-	O
+EGFP	O
+mice	O
+.	O
+
+RESULTS	O
+:	O
+Confocal	O
+microscopy	O
+and	O
+real	O
+-	O
+time	O
+PCR	O
+demonstrated	O
+that	O
+AGEs	O
+induced	O
+EndoMT	O
+in	O
+MMECs	O
+and	O
+in	O
+Tie2	O
+-	O
+Cre	O
+;	O
+Loxp	O
+-	O
+EGFP	O
+mice	O
+.	O
+
+Immunoprecipitation	O
+/	O
+Western	O
+blotting	O
+showed	O
+that	O
+Smad3	O
+was	O
+activated	O
+by	O
+AGEs	O
+but	O
+was	O
+inhibited	O
+by	O
+SIS3	O
+in	O
+MMECs	O
+and	O
+in	O
+STZ	O
+-	O
+induced	O
+diabetic	B
+nephropathy	I
+.	O
+
+Confocal	O
+microscopy	O
+and	O
+real	O
+-	O
+time	O
+PCR	O
+further	O
+demonstrated	O
+that	O
+SIS3	O
+abrogated	O
+EndoMT	O
+,	O
+reduced	O
+renal	O
+fibrosis	B
+,	O
+and	O
+retarded	O
+progression	O
+of	O
+nephropathy	B
+.	O
+
+CONCLUSIONS	O
+:	O
+EndoMT	O
+is	O
+a	O
+novel	O
+pathway	O
+leading	O
+to	O
+early	O
+development	O
+of	O
+diabetic	B
+nephropathy	I
+.	O
+
+Blockade	O
+of	O
+EndoMT	O
+by	O
+SIS3	O
+may	O
+provide	O
+a	O
+new	O
+strategy	O
+to	O
+retard	O
+the	O
+progression	O
+of	O
+diabetic	B
+nephropathy	I
+and	O
+other	O
+diabetes	B
+complications	I
+.	O
+
+Cytostatic	O
+and	O
+anti	O
+-	O
+angiogenic	O
+effects	O
+of	O
+temsirolimus	O
+in	O
+refractory	O
+mantle	B
+cell	I
+lymphoma	I
+.	O
+
+Mantle	B
+cell	I
+lymphoma	I
+(	O
+MCL	B
+)	O
+is	O
+a	O
+rare	O
+and	O
+aggressive	O
+type	O
+of	O
+B	B
+-	I
+cell	I
+non	I
+-	I
+Hodgkin	I
+'	I
+s	I
+lymphoma	I
+.	O
+
+Patients	O
+become	O
+progressively	O
+refractory	O
+to	O
+conventional	O
+chemotherapy	O
+,	O
+and	O
+their	O
+prognosis	O
+is	O
+poor	O
+.	O
+
+However	O
+,	O
+a	O
+38	O
+%	O
+remission	O
+rate	O
+has	O
+been	O
+recently	O
+reported	O
+in	O
+refractory	O
+MCL	B
+treated	O
+with	O
+temsirolimus	O
+,	O
+a	O
+mTOR	O
+inhibitor	O
+.	O
+Here	O
+we	O
+had	O
+the	O
+opportunity	O
+to	O
+study	O
+a	O
+case	O
+of	O
+refractory	O
+MCL	B
+who	O
+had	O
+tumor	B
+regression	O
+two	O
+months	O
+after	O
+temsirolimus	O
+treatment	O
+,	O
+and	O
+a	O
+progression	O
+-	O
+free	O
+survival	O
+of	O
+10	O
+months	O
+.	O
+
+In	O
+this	O
+case	O
+,	O
+lymph	O
+node	O
+biopsies	O
+were	O
+performed	O
+before	O
+and	O
+six	O
+months	O
+after	O
+temsirolimus	O
+therapy	O
+.	O
+
+Comparison	O
+of	O
+the	O
+two	O
+biopsies	O
+showed	O
+that	O
+temsirolimus	O
+inhibited	O
+tumor	B
+cell	O
+proliferation	O
+through	O
+cell	O
+cycle	O
+arrest	O
+,	O
+but	O
+did	O
+not	O
+induce	O
+any	O
+change	O
+in	O
+the	O
+number	O
+of	O
+apoptotic	O
+tumor	B
+cells	O
+.	O
+
+Apart	O
+from	O
+this	O
+cytostatic	O
+effect	O
+,	O
+temsirolimus	O
+had	O
+an	O
+antiangiogenic	O
+effect	O
+with	O
+decrease	O
+of	O
+tumor	B
+microvessel	O
+density	O
+and	O
+of	O
+VEGF	O
+expression	O
+.	O
+
+Moreover	O
+,	O
+numerous	O
+patchy	O
+,	O
+well	O
+-	O
+limited	O
+fibrotic	O
+areas	O
+,	O
+compatible	O
+with	O
+post	O
+-	O
+necrotic	B
+tissue	O
+repair	O
+,	O
+were	O
+found	O
+after	O
+6	O
+-	O
+month	O
+temsirolimus	O
+therapy	O
+.	O
+
+Thus	O
+,	O
+temsirolimus	O
+reduced	O
+tumor	B
+burden	O
+through	O
+associated	O
+cytostatic	O
+and	O
+anti	O
+-	O
+angiogenic	O
+effects	O
+.	O
+This	O
+dual	O
+effect	O
+of	O
+temsirolimus	O
+on	O
+tumor	B
+tissue	O
+could	O
+contribute	O
+to	O
+its	O
+recently	O
+reported	O
+efficiency	O
+in	O
+refractory	O
+MCL	B
+resistant	O
+to	O
+conventional	O
+chemotherapy	O
+.	O
+
+Acute	B
+renal	I
+failure	I
+due	O
+to	O
+rifampicin	O
+.	O
+
+A	O
+23	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+with	O
+bacteriologically	O
+proven	O
+pulmonary	B
+tuberculosis	I
+was	O
+treated	O
+with	O
+the	O
+various	O
+regimens	O
+of	O
+antituberculosis	O
+drugs	O
+for	O
+nearly	O
+15	O
+months	O
+.	O
+
+Rifampicin	O
+was	O
+administered	O
+thrice	O
+as	O
+one	O
+of	O
+the	O
+3	O
+-	O
+4	O
+drug	O
+regimen	O
+and	O
+each	O
+time	O
+he	O
+developed	O
+untoward	O
+side	O
+effects	O
+like	O
+nausea	B
+,	O
+vomiting	B
+and	O
+fever	B
+with	O
+chills	O
+and	O
+rigors	O
+.	O
+
+The	O
+last	O
+such	O
+episode	O
+was	O
+of	O
+acute	O
+renal	O
+failure	O
+at	O
+which	O
+stage	O
+the	O
+patient	O
+was	O
+seen	O
+by	O
+the	O
+authors	O
+of	O
+this	O
+report	O
+.	O
+
+The	O
+patient	O
+,	O
+however	O
+,	O
+made	O
+a	O
+full	O
+recovery	O
+.	O
+
+Syncope	B
+caused	O
+by	O
+hyperkalemia	B
+during	O
+use	O
+of	O
+a	O
+combined	O
+therapy	O
+with	O
+the	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitor	O
+and	O
+spironolactone	O
+.	O
+
+A	O
+76	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+a	O
+history	O
+of	O
+coronary	O
+artery	O
+bypass	O
+grafting	O
+and	O
+prior	O
+myocardial	B
+infarction	I
+was	O
+transferred	O
+to	O
+the	O
+emergency	O
+room	O
+with	O
+loss	B
+of	I
+consciousness	I
+due	O
+to	O
+marked	O
+bradycardia	B
+caused	O
+by	O
+hyperkalemia	B
+.	O
+
+The	O
+concentration	O
+of	O
+serum	O
+potassium	O
+was	O
+high	O
+,	O
+and	O
+normal	O
+sinus	O
+rhythm	O
+was	O
+restored	O
+after	O
+correction	O
+of	O
+the	O
+serum	O
+potassium	O
+level	O
+.	O
+
+The	O
+cause	O
+of	O
+hyperkalemia	B
+was	O
+considered	O
+to	O
+be	O
+several	O
+doses	O
+of	O
+spiranolactone	O
+,	O
+an	O
+aldosterone	O
+antagonist	O
+,	O
+in	O
+addition	O
+to	O
+the	O
+long	O
+-	O
+term	O
+intake	O
+of	O
+ramipril	O
+,	O
+an	O
+ACE	O
+inhibitor	O
+.	O
+
+This	O
+case	O
+is	O
+a	O
+good	O
+example	O
+of	O
+electrolyte	O
+imbalance	O
+causing	O
+acute	O
+life	O
+-	O
+threatening	O
+cardiac	O
+events	O
+.	O
+
+Clinicians	O
+should	O
+be	O
+alert	O
+to	O
+the	O
+possibility	O
+of	O
+hyperkalemia	B
+,	O
+especially	O
+in	O
+elderly	O
+patients	O
+using	O
+ACE	O
+/	O
+ARB	O
+in	O
+combination	O
+with	O
+potassium	O
+sparing	O
+agents	O
+and	O
+who	O
+have	O
+mild	O
+renal	B
+disturbance	I
+.	O
+
+Diffuse	O
+skeletal	O
+pain	B
+after	O
+administration	O
+of	O
+alendronate	O
+.	O
+
+BACKGROUND	O
+:	O
+Osteoporosis	B
+is	O
+caused	O
+by	O
+bone	O
+resorption	O
+in	O
+excess	O
+of	O
+bone	O
+formation	O
+,	O
+and	O
+bisphosphonates	O
+,	O
+are	O
+used	O
+to	O
+inhibit	O
+bone	O
+resorption	O
+.	O
+
+Alendronate	O
+,	O
+a	O
+biphosphonate	O
+,	O
+is	O
+effective	O
+for	O
+both	O
+the	O
+treatment	O
+and	O
+prevention	O
+of	O
+osteoporosis	B
+in	O
+postmenopausal	O
+women	O
+.	O
+
+Side	O
+effects	O
+are	O
+relatively	O
+few	O
+and	O
+prominently	O
+gastrointestinal	O
+.	O
+
+Musculoskeletal	B
+pain	I
+may	O
+be	O
+an	O
+important	O
+side	O
+effect	O
+in	O
+these	O
+patients	O
+.	O
+
+We	O
+presented	O
+a	O
+patient	O
+admitted	O
+to	O
+our	O
+out	O
+-	O
+patient	O
+clinic	O
+with	O
+diffuse	O
+skeletal	O
+pain	B
+after	O
+three	O
+consecutive	O
+administration	O
+of	O
+alendronate	O
+.	O
+
+CONCLUSION	O
+:	O
+We	O
+conclude	O
+that	O
+patients	O
+with	O
+osteoporosis	B
+can	O
+report	O
+pain	B
+,	O
+and	O
+bisphosphonate	O
+-	O
+related	O
+pain	B
+should	O
+also	O
+be	O
+considered	O
+before	O
+ascribing	O
+this	O
+complaint	O
+to	O
+osteoporosis	B
+.	O
+
+Cerebrospinal	O
+fluid	O
+penetration	O
+of	O
+high	O
+-	O
+dose	O
+daptomycin	O
+in	O
+suspected	O
+Staphylococcus	O
+aureus	O
+meningitis	B
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+methicillin	O
+-	O
+sensitive	O
+Staphylococcus	O
+aureus	O
+(	O
+MSSA	O
+)	O
+bacteremia	B
+with	O
+suspected	O
+MSSA	O
+meningitis	B
+treated	O
+with	O
+high	O
+-	O
+dose	O
+daptomycin	O
+assessed	O
+with	O
+concurrent	O
+serum	O
+and	O
+cerebrospinal	O
+fluid	O
+(	O
+CSF	O
+)	O
+concentrations	O
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+54	O
+-	O
+year	O
+-	O
+old	O
+male	O
+presented	O
+to	O
+the	O
+emergency	O
+department	O
+with	O
+generalized	O
+weakness	B
+and	O
+presumed	O
+health	O
+-	O
+care	O
+-	O
+associated	O
+pneumonia	B
+shown	O
+on	O
+chest	O
+radiograph	O
+.	O
+
+Treatment	O
+was	O
+empirically	O
+initiated	O
+with	O
+vancomycin	O
+,	O
+levofloxacin	O
+,	O
+and	O
+piperacillin	O
+/	O
+tazobactam	O
+.	O
+
+Blood	O
+cultures	O
+revealed	O
+S	O
+.	O
+aureus	O
+susceptible	O
+to	O
+oxacillin	O
+.	O
+
+Empiric	O
+antibiotic	O
+treatment	O
+was	O
+narrowed	O
+to	O
+nafcillin	O
+on	O
+day	O
+4	O
+.	O
+
+On	O
+day	O
+8	O
+,	O
+the	O
+patient	O
+developed	O
+acute	B
+renal	I
+failure	I
+(	O
+serum	O
+creatinine	O
+1	O
+.	O
+9	O
+mg	O
+/	O
+dL	O
+,	O
+increased	O
+from	O
+1	O
+.	O
+2	O
+mg	O
+/	O
+dL	O
+the	O
+previous	O
+day	O
+and	O
+0	O
+.	O
+8	O
+mg	O
+/	O
+dL	O
+on	O
+admission	O
+)	O
+.	O
+
+The	O
+patient	O
+'	O
+s	O
+Glasgow	O
+Coma	O
+Score	O
+was	O
+3	O
+,	O
+with	O
+normal	O
+findings	O
+shown	O
+on	O
+computed	O
+tomography	O
+scan	O
+of	O
+the	O
+head	O
+72	O
+hours	O
+following	O
+an	O
+episode	O
+of	O
+cardiac	B
+arrest	I
+on	O
+day	O
+10	O
+.	O
+
+The	O
+patient	O
+experienced	O
+relapsing	O
+MSSA	O
+bacteremia	B
+on	O
+day	O
+9	O
+,	O
+increasing	O
+the	O
+suspicion	O
+for	O
+a	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+infection	B
+.	O
+
+Nafcillin	O
+was	O
+discontinued	O
+and	O
+daptomycin	O
+9	O
+mg	O
+/	O
+kg	O
+daily	O
+was	O
+initiated	O
+for	O
+suspected	O
+meningitis	B
+and	O
+was	O
+continued	O
+until	O
+the	O
+patient	O
+'	O
+s	O
+death	O
+on	O
+day	O
+16	O
+.	O
+
+Daptomycin	O
+serum	O
+and	O
+CSF	O
+trough	O
+concentrations	O
+were	O
+11	O
+.	O
+21	O
+ug	O
+/	O
+mL	O
+and	O
+0	O
+.	O
+52	O
+ug	O
+/	O
+mL	O
+,	O
+respectively	O
+,	O
+prior	O
+to	O
+the	O
+third	O
+dose	O
+.	O
+
+Lumbar	O
+puncture	O
+results	O
+were	O
+inconclusive	O
+and	O
+no	O
+further	O
+blood	O
+cultures	O
+were	O
+positive	O
+for	O
+MSSA	O
+.	O
+
+Creatine	O
+kinase	O
+levels	O
+were	O
+normal	O
+prior	O
+to	O
+daptomycin	O
+therapy	O
+and	O
+were	O
+not	O
+reassessed	O
+.	O
+
+DISCUSSION	O
+:	O
+Daptomycin	O
+was	O
+initiated	O
+in	O
+our	O
+patient	O
+secondary	O
+to	O
+possible	O
+nafcillin	O
+-	O
+induced	O
+acute	O
+interstitial	B
+nephritis	I
+and	O
+relapsing	O
+bacteremia	B
+.	O
+
+At	O
+a	O
+dose	O
+of	O
+9	O
+mg	O
+/	O
+kg	O
+,	O
+resultant	O
+penetration	O
+of	O
+5	O
+%	O
+was	O
+higher	O
+than	O
+in	O
+previous	O
+reports	O
+,	O
+more	O
+consistent	O
+with	O
+inflamed	O
+meninges	O
+.	O
+
+CONCLUSIONS	O
+:	O
+High	O
+-	O
+dose	O
+daptomycin	O
+may	O
+be	O
+an	O
+alternative	O
+option	O
+for	O
+MSSA	O
+bacteremia	B
+with	O
+or	O
+without	O
+a	O
+CNS	O
+source	O
+in	O
+patients	O
+who	O
+have	O
+failed	O
+or	O
+cannot	O
+tolerate	O
+standard	O
+therapy	O
+.	O
+
+Further	O
+clinical	O
+evaluation	O
+in	O
+patients	O
+with	O
+confirmed	O
+meningitis	B
+is	O
+warranted	O
+.	O
+
+The	O
+role	O
+of	O
+nitric	O
+oxide	O
+in	O
+convulsions	B
+induced	O
+by	O
+lindane	O
+in	O
+rats	O
+.	O
+
+Lindane	O
+is	O
+an	O
+organochloride	O
+pesticide	O
+and	O
+scabicide	O
+.	O
+
+It	O
+evokes	O
+convulsions	B
+mainly	O
+trough	O
+the	O
+blockage	O
+of	O
+GABA	O
+(	O
+A	O
+)	O
+receptors	O
+.	O
+
+Nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+,	O
+gaseous	O
+neurotransmitter	O
+,	O
+has	O
+contradictor	O
+role	O
+in	O
+epileptogenesis	O
+due	O
+to	O
+opposite	O
+effects	O
+of	O
+L	O
+-	O
+arginine	O
+,	O
+precursor	O
+of	O
+NO	O
+syntheses	O
+(	O
+NOS	O
+)	O
+,	O
+and	O
+L	O
+-	O
+NAME	O
+(	O
+NOS	O
+inhibitor	O
+)	O
+observed	O
+in	O
+different	O
+epilepsy	B
+models	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+current	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+effects	O
+of	O
+NO	O
+on	O
+the	O
+behavioral	O
+and	O
+EEG	O
+characteristics	O
+of	O
+lindane	O
+-	O
+induced	O
+epilepsy	B
+in	O
+male	O
+Wistar	O
+albino	O
+rats	O
+.	O
+
+The	O
+administration	O
+of	O
+L	O
+-	O
+arginine	O
+(	O
+600	O
+,	O
+800	O
+and	O
+1000	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+in	O
+dose	O
+-	O
+dependent	O
+manner	O
+significantly	O
+increased	O
+convulsion	B
+incidence	O
+and	O
+severity	O
+and	O
+shortened	O
+latency	O
+time	O
+to	O
+first	O
+convulsion	B
+elicited	O
+by	O
+lower	O
+lindane	O
+dose	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+On	O
+the	O
+contrary	O
+,	O
+pretreatment	O
+with	O
+L	O
+-	O
+NAME	O
+(	O
+500	O
+,	O
+700	O
+and	O
+900	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+decreased	O
+convulsion	B
+incidence	O
+and	O
+severity	O
+and	O
+prolonged	O
+latency	O
+time	O
+to	O
+convulsion	B
+following	O
+injection	O
+with	O
+a	O
+convulsive	B
+dose	O
+of	O
+lindane	O
+(	O
+8	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+EEG	O
+analyses	O
+showed	O
+increase	O
+of	O
+number	O
+and	O
+duration	O
+of	O
+ictal	O
+periods	O
+in	O
+EEG	O
+of	O
+rats	O
+receiving	O
+l	O
+-	O
+arginine	O
+prior	O
+to	O
+lindane	O
+and	O
+decrease	O
+of	O
+this	O
+number	O
+in	O
+rats	O
+pretreated	O
+with	O
+L	O
+-	O
+NAME	O
+.	O
+
+These	O
+results	O
+support	O
+the	O
+conclusion	O
+that	O
+NO	O
+plays	O
+a	O
+role	O
+of	O
+endogenous	O
+convulsant	O
+in	O
+rat	O
+model	O
+of	O
+lindane	O
+seizures	B
+.	O
+
+Severe	O
+polyneuropathy	B
+and	O
+motor	O
+loss	O
+after	O
+intrathecal	O
+thiotepa	O
+combination	O
+chemotherapy	O
+:	O
+description	O
+of	O
+two	O
+cases	O
+.	O
+
+Two	O
+cases	O
+of	O
+severe	O
+delayed	O
+neurologic	B
+toxicity	I
+related	O
+to	O
+the	O
+administration	O
+of	O
+intrathecal	O
+(	O
+IT	O
+)	O
+combination	O
+chemotherapy	O
+including	O
+thiotepa	O
+(	O
+TSPA	O
+)	O
+are	O
+presented	O
+.	O
+
+Both	O
+cases	O
+developed	O
+axonal	B
+neuropathy	I
+with	O
+motor	O
+predominance	O
+in	O
+the	O
+lower	O
+extremities	O
+1	O
+and	O
+6	O
+months	O
+after	O
+IT	O
+chemotherapy	O
+was	O
+administered	O
+.	O
+
+Neurologic	B
+toxicities	I
+have	O
+been	O
+described	O
+with	O
+IT	O
+-	O
+methotrexate	O
+,	O
+IT	O
+-	O
+cytosine	O
+arabinoside	O
+and	O
+IT	O
+-	O
+TSPA	O
+.	O
+
+To	O
+our	O
+knowledge	O
+,	O
+however	O
+,	O
+axonal	B
+neuropathy	I
+following	O
+administration	O
+of	O
+these	O
+three	O
+agents	O
+has	O
+not	O
+been	O
+previously	O
+described	O
+.	O
+
+In	O
+spite	O
+of	O
+the	O
+fact	O
+that	O
+TSPA	O
+is	O
+a	O
+useful	O
+IT	O
+agent	O
+,	O
+its	O
+combination	O
+with	O
+MTX	O
+,	O
+ara	O
+-	O
+C	O
+and	O
+radiotherapy	O
+could	O
+cause	O
+severe	O
+neurotoxicity	B
+.	O
+
+This	O
+unexpected	O
+complication	O
+indicates	O
+the	O
+need	O
+for	O
+further	O
+toxicology	O
+research	O
+on	O
+IT	O
+-	O
+TSPA	O
+.	O
+
+Effects	O
+of	O
+cromakalim	O
+and	O
+pinacidil	O
+on	O
+large	O
+epicardial	O
+and	O
+small	O
+coronary	O
+arteries	O
+in	O
+conscious	O
+dogs	O
+.	O
+
+The	O
+effects	O
+of	O
+i	O
+.	O
+v	O
+.	O
+bolus	O
+administration	O
+of	O
+cromakalim	O
+(	O
+1	O
+-	O
+10	O
+micrograms	O
+/	O
+kg	O
+)	O
+and	O
+pinacidil	O
+(	O
+3	O
+-	O
+100	O
+micrograms	O
+/	O
+kg	O
+)	O
+on	O
+large	O
+(	O
+circumflex	O
+artery	O
+)	O
+and	O
+small	O
+coronary	O
+arteries	O
+and	O
+on	O
+systemic	O
+hemodynamics	O
+were	O
+investigated	O
+in	O
+chronically	O
+instrumented	O
+conscious	O
+dogs	O
+and	O
+compared	O
+to	O
+those	O
+of	O
+nitroglycerin	O
+(	O
+0	O
+.	O
+03	O
+-	O
+10	O
+micrograms	O
+/	O
+kg	O
+)	O
+.	O
+
+Nitroglycerin	O
+,	O
+up	O
+to	O
+0	O
+.	O
+3	O
+micrograms	O
+/	O
+kg	O
+,	O
+selectively	O
+increased	O
+circumflex	O
+artery	O
+diameter	O
+(	O
+CxAD	O
+)	O
+without	O
+simultaneously	O
+affecting	O
+any	O
+other	O
+cardiac	O
+or	O
+systemic	O
+hemodynamic	O
+parameter	O
+.	O
+
+In	O
+contrast	O
+,	O
+cromakalim	O
+and	O
+pinacidil	O
+at	O
+all	O
+doses	O
+and	O
+nitroglycerin	O
+at	O
+doses	O
+higher	O
+than	O
+0	O
+.	O
+3	O
+micrograms	O
+/	O
+kg	O
+simultaneously	O
+and	O
+dose	O
+-	O
+dependently	O
+increased	O
+CxAD	O
+,	O
+coronary	O
+blood	O
+flow	O
+and	O
+heart	O
+rate	O
+and	O
+decreased	O
+coronary	O
+vascular	O
+resistance	O
+and	O
+aortic	O
+pressure	O
+.	O
+
+Cromakalim	O
+was	O
+approximately	O
+8	O
+-	O
+to	O
+9	O
+.	O
+5	O
+-	O
+fold	O
+more	O
+potent	O
+than	O
+pinacidil	O
+in	O
+increasing	O
+CxAD	O
+.	O
+
+Vasodilation	O
+of	O
+large	O
+and	O
+small	O
+coronary	O
+vessels	O
+and	O
+hypotension	B
+induced	O
+by	O
+cromakalim	O
+and	O
+pinacidil	O
+were	O
+not	O
+affected	O
+by	O
+prior	O
+combined	O
+beta	O
+adrenergic	O
+and	O
+muscarinic	O
+receptors	O
+blockade	O
+but	O
+drug	O
+-	O
+induced	O
+tachycardia	B
+was	O
+abolished	O
+.	O
+
+When	O
+circumflex	O
+artery	O
+blood	O
+flow	O
+was	O
+maintained	O
+constant	O
+,	O
+the	O
+increases	O
+in	O
+CxAD	O
+induced	O
+by	O
+cromakalim	O
+(	O
+10	O
+micrograms	O
+/	O
+kg	O
+)	O
+,	O
+pinacidil	O
+(	O
+30	O
+micrograms	O
+/	O
+kg	O
+)	O
+and	O
+nitroglycerin	O
+(	O
+10	O
+micrograms	O
+/	O
+kg	O
+)	O
+were	O
+reduced	O
+by	O
+68	O
++	O
+/	O
+-	O
+7	O
+,	O
+54	O
++	O
+/	O
+-	O
+9	O
+and	O
+1	O
++	O
+/	O
+-	O
+1	O
+%	O
+,	O
+respectively	O
+.	O
+
+Thus	O
+,	O
+whereas	O
+nitroglycerin	O
+preferentially	O
+and	O
+flow	O
+-	O
+independently	O
+dilates	O
+large	O
+coronary	O
+arteries	O
+,	O
+cromakalim	O
+and	O
+pinacidil	O
+dilate	O
+both	O
+large	O
+and	O
+small	O
+coronary	O
+arteries	O
+and	O
+this	O
+effect	O
+is	O
+not	O
+dependent	O
+upon	O
+the	O
+simultaneous	O
+beta	O
+adrenoceptors	O
+-	O
+mediated	O
+rise	O
+in	O
+myocardial	O
+metabolic	O
+demand	O
+.	O
+
+Finally	O
+,	O
+two	O
+mechanisms	O
+at	O
+least	O
+,	O
+direct	O
+vasodilation	O
+and	O
+flow	O
+dependency	O
+,	O
+are	O
+involved	O
+in	O
+the	O
+cromakalim	O
+-	O
+and	O
+pinacidil	O
+-	O
+induced	O
+increase	O
+in	O
+CxAD	O
+.	O
+
+Mefenamic	O
+acid	O
+-	O
+induced	O
+neutropenia	B
+and	O
+renal	B
+failure	I
+in	O
+elderly	O
+females	O
+with	O
+hypothyroidism	B
+.	O
+
+We	O
+report	O
+mefenamic	O
+acid	O
+-	O
+induced	O
+non	O
+-	O
+oliguric	O
+renal	B
+failure	I
+and	O
+severe	O
+neutropenia	B
+occurring	O
+simultaneously	O
+in	O
+two	O
+elderly	O
+females	O
+.	O
+
+The	O
+neutropenia	B
+was	O
+due	O
+to	O
+maturation	O
+arrest	O
+of	O
+the	O
+myeloid	O
+series	O
+in	O
+one	O
+patient	O
+.	O
+
+Both	O
+patients	O
+were	O
+also	O
+hypothyroid	B
+,	O
+but	O
+it	O
+is	O
+not	O
+clear	O
+whether	O
+this	O
+was	O
+a	O
+predisposing	O
+factor	O
+to	O
+the	O
+development	O
+of	O
+these	O
+adverse	O
+reactions	O
+.	O
+
+However	O
+,	O
+it	O
+would	O
+seem	O
+prudent	O
+not	O
+to	O
+use	O
+mefenamic	O
+acid	O
+in	O
+hypothyroid	B
+patients	O
+until	O
+the	O
+hypothyroidism	B
+has	O
+been	O
+corrected	O
+.	O
+
+Etiology	O
+of	O
+hypercalcemia	B
+in	O
+hemodialysis	O
+patients	O
+on	O
+calcium	O
+carbonate	O
+therapy	O
+.	O
+
+Fourteen	O
+of	O
+39	O
+dialysis	O
+patients	O
+(	O
+36	O
+%	O
+)	O
+became	O
+hypercalcemic	B
+after	O
+switching	O
+to	O
+calcium	O
+carbonate	O
+as	O
+their	O
+principal	O
+phosphate	O
+binder	O
+.	O
+
+In	O
+order	O
+to	O
+identify	O
+risk	O
+factors	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+hypercalcemia	B
+,	O
+indirect	O
+parameters	O
+of	O
+intestinal	O
+calcium	O
+reabsorption	O
+and	O
+bone	O
+turnover	O
+rate	O
+in	O
+these	O
+14	O
+patients	O
+were	O
+compared	O
+with	O
+results	O
+in	O
+14	O
+eucalcemic	O
+patients	O
+matched	O
+for	O
+age	O
+,	O
+sex	O
+,	O
+length	O
+of	O
+time	O
+on	O
+dialysis	O
+,	O
+and	O
+etiology	O
+of	O
+renal	B
+disease	I
+.	O
+
+In	O
+addition	O
+to	O
+experiencing	O
+hypercalcemic	B
+episodes	O
+with	O
+peak	O
+calcium	O
+values	O
+of	O
+2	O
+.	O
+7	O
+to	O
+3	O
+.	O
+8	O
+mmol	O
+/	O
+L	O
+(	O
+10	O
+.	O
+7	O
+to	O
+15	O
+.	O
+0	O
+mg	O
+/	O
+dL	O
+)	O
+,	O
+patients	O
+in	O
+the	O
+hypercalcemic	B
+group	O
+exhibited	O
+a	O
+significant	O
+increase	O
+in	O
+the	O
+mean	O
+calcium	O
+concentration	O
+obtained	O
+during	O
+6	O
+months	O
+before	O
+the	O
+switch	O
+,	O
+compared	O
+with	O
+the	O
+mean	O
+value	O
+obtained	O
+during	O
+the	O
+7	O
+months	O
+of	O
+observation	O
+after	O
+the	O
+switch	O
+(	O
+2	O
+.	O
+4	O
++	O
+/	O
+-	O
+0	O
+.	O
+03	O
+to	O
+2	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+03	O
+mmol	O
+/	O
+L	O
+[	O
+9	O
+.	O
+7	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+to	O
+10	O
+.	O
+2	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+mg	O
+/	O
+dL	O
+]	O
+,	O
+P	O
+=	O
+0	O
+.	O
+006	O
+)	O
+.	O
+
+In	O
+contrast	O
+,	O
+eucalcemic	O
+patients	O
+exhibited	O
+no	O
+change	O
+in	O
+mean	O
+calcium	O
+values	O
+over	O
+the	O
+same	O
+time	O
+period	O
+(	O
+2	O
+.	O
+3	O
++	O
+/	O
+-	O
+0	O
+.	O
+05	O
+to	O
+2	O
+.	O
+3	O
++	O
+/	O
+-	O
+0	O
+.	O
+05	O
+mmol	O
+/	O
+L	O
+[	O
+9	O
+.	O
+2	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+to	O
+9	O
+.	O
+2	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+mg	O
+/	O
+dL	O
+]	O
+)	O
+.	O
+
+CaCO3	O
+dosage	O
+,	O
+calculated	O
+dietary	O
+calcium	O
+intake	O
+,	O
+and	O
+circulating	O
+levels	O
+of	O
+vitamin	O
+D	O
+metabolites	O
+were	O
+similar	O
+in	O
+both	O
+groups	O
+.	O
+
+Physical	O
+activity	O
+index	O
+and	O
+predialysis	O
+serum	O
+bicarbonate	O
+levels	O
+also	O
+were	O
+similar	O
+in	O
+both	O
+groups	O
+.	O
+
+However	O
+,	O
+there	O
+was	O
+a	O
+significant	O
+difference	O
+in	O
+parameters	O
+reflecting	O
+bone	O
+turnover	O
+rates	O
+between	O
+groups	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Late	O
+-	O
+onset	O
+scleroderma	B
+renal	I
+crisis	I
+induced	O
+by	O
+tacrolimus	O
+and	O
+prednisolone	O
+:	O
+a	O
+case	O
+report	O
+.	O
+
+Scleroderma	B
+renal	I
+crisis	I
+(	O
+SRC	B
+)	O
+is	O
+a	O
+rare	O
+complication	O
+of	O
+systemic	B
+sclerosis	I
+(	O
+SSc	B
+)	O
+but	O
+can	O
+be	O
+severe	O
+enough	O
+to	O
+require	O
+temporary	O
+or	O
+permanent	O
+renal	O
+replacement	O
+therapy	O
+.	O
+
+Moderate	O
+to	O
+high	O
+dose	O
+corticosteroid	O
+use	O
+is	O
+recognized	O
+as	O
+a	O
+major	O
+risk	O
+factor	O
+for	O
+SRC	B
+.	O
+
+Furthermore	O
+,	O
+there	O
+have	O
+been	O
+reports	O
+of	O
+thrombotic	B
+microangiopathy	I
+precipitated	O
+by	O
+cyclosporine	O
+in	O
+patients	O
+with	O
+SSc	B
+.	O
+
+In	O
+this	O
+article	O
+,	O
+we	O
+report	O
+a	O
+patient	O
+with	O
+SRC	B
+induced	O
+by	O
+tacrolimus	O
+and	O
+corticosteroids	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+work	O
+is	O
+to	O
+call	O
+attention	O
+to	O
+the	O
+risk	O
+of	O
+tacrolimus	O
+use	O
+in	O
+patients	O
+with	O
+SSc	B
+.	O
+
+Methyldopa	O
+-	O
+induced	O
+hemolytic	B
+anemia	I
+in	O
+a	O
+15	O
+year	O
+old	O
+presenting	O
+as	O
+near	O
+-	O
+syncope	B
+.	O
+
+Methyldopa	O
+is	O
+an	O
+antihypertensive	O
+medication	O
+which	O
+is	O
+available	O
+generically	O
+and	O
+under	O
+the	O
+trade	O
+name	O
+Aldomet	O
+that	O
+is	O
+widely	O
+prescribed	O
+in	O
+the	O
+adult	O
+population	O
+and	O
+infrequently	O
+used	O
+in	O
+children	O
+.	O
+
+Methyldopa	O
+causes	O
+an	O
+autoimmune	B
+hemolytic	I
+anemia	I
+in	O
+a	O
+small	O
+percentage	O
+of	O
+patients	O
+who	O
+take	O
+the	O
+drug	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+methyldopa	O
+-	O
+induced	O
+hemolytic	B
+anemia	I
+in	O
+a	O
+15	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+who	O
+presented	O
+to	O
+the	O
+emergency	B
+department	I
+with	O
+near	O
+-	O
+syncope	B
+.	O
+
+The	O
+boy	O
+had	O
+been	O
+treated	O
+with	O
+intravenous	O
+methyldopa	O
+during	O
+a	O
+trauma	B
+admission	O
+seven	O
+weeks	O
+prior	O
+to	O
+presentation	O
+.	O
+
+Evaluation	O
+revealed	O
+a	O
+hemoglobin	O
+of	O
+three	O
+grams	O
+,	O
+3	O
++	O
+Coombs	O
+'	O
+test	O
+with	O
+polyspecific	O
+anti	O
+-	O
+human	O
+globulin	O
+and	O
+monospecific	O
+IgG	O
+reagents	O
+,	O
+and	O
+a	O
+warm	O
+reacting	O
+autoantibody	O
+.	O
+
+Transfusion	O
+and	O
+corticosteroid	O
+therapy	O
+resulted	O
+in	O
+a	O
+complete	O
+recovery	O
+of	O
+the	O
+patient	O
+.	O
+
+Emergency	O
+physicians	O
+treating	O
+children	O
+must	O
+be	O
+aware	O
+of	O
+this	O
+syndrome	O
+in	O
+order	O
+to	O
+diagnose	O
+and	O
+treat	O
+it	O
+correctly	O
+.	O
+
+A	O
+brief	O
+review	O
+of	O
+autoimmune	O
+and	O
+drug	O
+-	O
+induced	O
+hemolytic	B
+anemias	I
+is	O
+provided	O
+.	O
+
+The	O
+risk	O
+and	O
+associated	O
+factors	O
+of	O
+methamphetamine	O
+psychosis	B
+in	O
+methamphetamine	O
+-	O
+dependent	O
+patients	O
+in	O
+Malaysia	O
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+risk	O
+of	O
+lifetime	O
+and	O
+current	O
+methamphetamine	O
+-	O
+induced	O
+psychosis	B
+in	O
+patients	O
+with	O
+methamphetamine	O
+dependence	O
+.	O
+
+The	O
+association	O
+between	O
+psychiatric	O
+co	O
+-	O
+morbidity	O
+and	O
+methamphetamine	O
+-	O
+induced	O
+psychosis	B
+was	O
+also	O
+studied	O
+.	O
+
+METHODS	O
+:	O
+This	O
+was	O
+a	O
+cross	O
+-	O
+sectional	O
+study	O
+conducted	O
+concurrently	O
+at	O
+a	O
+teaching	O
+hospital	O
+and	O
+a	O
+drug	O
+rehabilitation	O
+center	O
+in	O
+Malaysia	O
+.	O
+
+Patients	O
+with	O
+the	O
+diagnosis	O
+of	O
+methamphetamine	O
+based	O
+on	O
+DSM	O
+-	O
+IV	O
+were	O
+interviewed	O
+using	O
+the	O
+Mini	O
+International	O
+Neuropsychiatric	O
+Interview	O
+(	O
+M	O
+.	O
+I	O
+.	O
+N	O
+.	O
+I	O
+.	O
+)	O
+for	O
+methamphetamine	O
+-	O
+induced	O
+psychosis	B
+and	O
+other	O
+Axis	O
+I	O
+psychiatric	B
+disorders	I
+.	O
+
+The	O
+information	O
+on	O
+sociodemographic	O
+background	O
+and	O
+drug	O
+use	O
+history	O
+was	O
+obtained	O
+from	O
+interview	O
+or	O
+medical	O
+records	O
+.	O
+
+RESULTS	O
+:	O
+Of	O
+292	O
+subjects	O
+,	O
+47	O
+.	O
+9	O
+%	O
+of	O
+the	O
+subjects	O
+had	O
+a	O
+past	O
+history	O
+of	O
+psychotic	B
+symptoms	I
+and	O
+13	O
+.	O
+0	O
+%	O
+of	O
+the	O
+patients	O
+were	O
+having	O
+current	O
+psychotic	B
+symptoms	I
+.	O
+
+Co	O
+-	O
+morbid	O
+major	O
+depressive	B
+disorder	I
+(	O
+OR	O
+=	O
+7	O
+.	O
+18	O
+,	O
+95	O
+CI	O
+=	O
+2	O
+.	O
+612	O
+-	O
+19	O
+.	O
+708	O
+)	O
+,	O
+bipolar	B
+disorder	I
+(	O
+OR	O
+=	O
+13	O
+.	O
+807	O
+,	O
+95	O
+CI	O
+=	O
+5	O
+.	O
+194	O
+-	O
+36	O
+.	O
+706	O
+)	O
+,	O
+antisocial	B
+personality	I
+disorder	I
+(	O
+OR	O
+=	O
+12	O
+.	O
+619	O
+,	O
+95	O
+CI	O
+=	O
+6	O
+.	O
+702	O
+-	O
+23	O
+.	O
+759	O
+)	O
+and	O
+heavy	O
+methamphetamine	O
+uses	O
+were	O
+significantly	O
+associated	O
+with	O
+lifetime	O
+methamphetamine	O
+-	O
+induced	O
+psychosis	B
+after	O
+adjusted	O
+for	O
+other	O
+factors	O
+.	O
+
+Major	B
+depressive	I
+disorder	I
+(	O
+OR	O
+=	O
+2	O
+.	O
+870	O
+,	O
+CI	O
+=	O
+1	O
+.	O
+154	O
+-	O
+7	O
+.	O
+142	O
+)	O
+and	O
+antisocial	B
+personality	I
+disorder	I
+(	O
+OR	O
+=	O
+3	O
+.	O
+299	O
+,	O
+95	O
+CI	O
+=	O
+1	O
+.	O
+375	O
+-	O
+7	O
+.	O
+914	O
+)	O
+were	O
+the	O
+only	O
+factors	O
+associated	O
+with	O
+current	O
+psychosis	B
+.	O
+
+CONCLUSION	O
+:	O
+There	O
+was	O
+a	O
+high	O
+risk	O
+of	O
+psychosis	B
+in	O
+patients	O
+with	O
+methamphetamine	O
+dependence	O
+.	O
+
+It	O
+was	O
+associated	O
+with	O
+co	O
+-	O
+morbid	O
+affective	B
+disorder	I
+,	O
+antisocial	B
+personality	I
+,	O
+and	O
+heavy	O
+methamphetamine	O
+use	O
+.	O
+
+It	O
+is	O
+recommended	O
+that	O
+all	O
+cases	O
+of	O
+methamphetamine	O
+dependence	O
+should	O
+be	O
+screened	O
+for	O
+psychotic	B
+symptoms	I
+.	O
+
+Cerebellar	O
+sensory	O
+processing	O
+alterations	O
+impact	O
+motor	O
+cortical	O
+plasticity	O
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+:	O
+clues	O
+from	O
+dyskinetic	B
+patients	O
+.	O
+
+The	O
+plasticity	O
+of	O
+primary	O
+motor	O
+cortex	O
+(	O
+M1	O
+)	O
+in	O
+patients	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+and	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+(	O
+LIDs	B
+)	O
+is	O
+severely	O
+impaired	O
+.	O
+
+We	O
+recently	O
+reported	O
+in	O
+young	O
+healthy	O
+subjects	O
+that	O
+inhibitory	O
+cerebellar	O
+stimulation	O
+enhanced	O
+the	O
+sensorimotor	O
+plasticity	O
+of	O
+M1	O
+that	O
+was	O
+induced	O
+by	O
+paired	O
+associative	O
+stimulation	O
+(	O
+PAS	O
+)	O
+.	O
+
+This	O
+study	O
+demonstrates	O
+that	O
+the	O
+deficient	O
+sensorimotor	O
+M1	O
+plasticity	O
+in	O
+16	O
+patients	O
+with	O
+LIDs	B
+could	O
+be	O
+reinstated	O
+by	O
+a	O
+single	O
+session	O
+of	O
+real	O
+inhibitory	O
+cerebellar	O
+stimulation	O
+but	O
+not	O
+sham	O
+stimulation	O
+.	O
+
+This	O
+was	O
+evident	O
+only	O
+when	O
+a	O
+sensory	O
+component	O
+was	O
+involved	O
+in	O
+the	O
+induction	O
+of	O
+plasticity	O
+,	O
+indicating	O
+that	O
+cerebellar	O
+sensory	O
+processing	O
+function	O
+is	O
+involved	O
+in	O
+the	O
+resurgence	O
+of	O
+M1	O
+plasticity	O
+.	O
+
+The	O
+benefit	O
+of	O
+inhibitory	O
+cerebellar	O
+stimulation	O
+on	O
+LIDs	B
+is	O
+known	O
+.	O
+
+To	O
+explore	O
+whether	O
+this	O
+benefit	O
+is	O
+linked	O
+to	O
+the	O
+restoration	O
+of	O
+sensorimotor	O
+plasticity	O
+of	O
+M1	O
+,	O
+we	O
+conducted	O
+an	O
+additional	O
+study	O
+looking	O
+at	O
+changes	O
+in	O
+LIDs	B
+and	O
+PAS	O
+-	O
+induced	O
+plasticity	O
+after	O
+10	O
+sessions	O
+of	O
+either	O
+bilateral	O
+,	O
+real	O
+inhibitory	O
+cerebellar	O
+stimulation	O
+or	O
+sham	O
+stimulation	O
+.	O
+
+Only	O
+real	O
+and	O
+not	O
+sham	O
+stimulation	O
+had	O
+an	O
+antidyskinetic	O
+effect	O
+and	O
+it	O
+was	O
+paralleled	O
+by	O
+a	O
+resurgence	O
+in	O
+the	O
+sensorimotor	O
+plasticity	O
+of	O
+M1	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+alterations	O
+in	O
+cerebellar	O
+sensory	O
+processing	O
+function	O
+,	O
+occurring	O
+secondary	O
+to	O
+abnormal	O
+basal	O
+ganglia	O
+signals	O
+reaching	O
+it	O
+,	O
+may	O
+be	O
+an	O
+important	O
+element	O
+contributing	O
+to	O
+the	O
+maladaptive	O
+sensorimotor	O
+plasticity	O
+of	O
+M1	O
+and	O
+the	O
+emergence	O
+of	O
+abnormal	B
+involuntary	I
+movements	I
+.	O
+
+The	O
+long	O
+-	O
+term	O
+safety	O
+of	O
+danazol	O
+in	O
+women	O
+with	O
+hereditary	B
+angioedema	I
+.	O
+
+Although	O
+the	O
+short	O
+-	O
+term	O
+safety	O
+(	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+6	O
+months	O
+)	O
+of	O
+danazol	O
+has	O
+been	O
+established	O
+in	O
+a	O
+variety	O
+of	O
+settings	O
+,	O
+no	O
+information	O
+exists	O
+as	O
+to	O
+its	O
+long	O
+-	O
+term	O
+safety	O
+.	O
+
+We	O
+therefore	O
+investigated	O
+the	O
+long	O
+-	O
+term	O
+safety	O
+of	O
+danazol	O
+by	O
+performing	O
+a	O
+retrospective	O
+chart	O
+review	O
+of	O
+60	O
+female	O
+patients	O
+with	O
+hereditary	B
+angioedema	I
+treated	O
+with	O
+danazol	O
+for	O
+a	O
+continuous	O
+period	O
+of	O
+6	O
+months	O
+or	O
+longer	O
+.	O
+
+The	O
+mean	O
+age	O
+of	O
+the	O
+patients	O
+was	O
+35	O
+.	O
+2	O
+years	O
+and	O
+the	O
+mean	O
+duration	O
+of	O
+therapy	O
+was	O
+59	O
+.	O
+7	O
+months	O
+.	O
+
+Virtually	O
+all	O
+patients	O
+experienced	O
+one	O
+or	O
+more	O
+adverse	O
+reactions	O
+.	O
+
+Menstrual	B
+abnormalities	I
+(	O
+79	O
+%	O
+)	O
+,	O
+weight	B
+gain	I
+(	O
+60	O
+%	O
+)	O
+,	O
+muscle	B
+cramps	I
+/	O
+myalgias	B
+(	O
+40	O
+%	O
+)	O
+,	O
+and	O
+transaminase	O
+elevations	O
+(	O
+40	O
+%	O
+)	O
+were	O
+the	O
+most	O
+common	O
+adverse	O
+reactions	O
+.	O
+
+The	O
+drug	O
+was	O
+discontinued	O
+due	O
+to	O
+adverse	O
+reactions	O
+in	O
+8	O
+patients	O
+.	O
+
+No	O
+patient	O
+has	O
+died	O
+or	O
+suffered	O
+any	O
+apparent	O
+long	O
+-	O
+term	O
+sequelae	O
+that	O
+were	O
+directly	O
+attributable	O
+to	O
+the	O
+drug	O
+.	O
+
+We	O
+conclude	O
+that	O
+,	O
+despite	O
+a	O
+relatively	O
+high	O
+incidence	O
+of	O
+adverse	O
+reactions	O
+,	O
+danazol	O
+has	O
+proven	O
+to	O
+be	O
+remarkably	O
+safe	O
+over	O
+the	O
+long	O
+-	O
+term	O
+in	O
+this	O
+group	O
+of	O
+patients	O
+.	O
+
+The	O
+function	O
+of	O
+P2X3	O
+receptor	O
+and	O
+NK1	O
+receptor	O
+antagonists	O
+on	O
+cyclophosphamide	O
+-	O
+induced	O
+cystitis	B
+in	O
+rats	O
+.	O
+
+PURPOSE	O
+:	O
+The	O
+purpose	O
+of	O
+the	O
+study	O
+is	O
+to	O
+explore	O
+the	O
+function	O
+of	O
+P2X3	O
+and	O
+NK1	O
+receptors	O
+antagonists	O
+on	O
+cyclophosphamide	O
+(	O
+CYP	O
+)	O
+-	O
+induced	O
+cystitis	B
+in	O
+rats	O
+.	O
+
+METHODS	O
+:	O
+Sixty	O
+female	O
+Sprague	O
+-	O
+Dawley	O
+(	O
+SD	O
+)	O
+rats	O
+were	O
+randomly	O
+divided	O
+into	O
+three	O
+groups	O
+.	O
+
+The	O
+rats	O
+in	O
+the	O
+control	O
+group	O
+were	O
+intraperitoneally	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+injected	O
+with	O
+0	O
+.	O
+9	O
+%	O
+saline	O
+(	O
+4	O
+ml	O
+/	O
+kg	O
+)	O
+;	O
+the	O
+rats	O
+in	O
+the	O
+model	O
+group	O
+were	O
+i	O
+.	O
+p	O
+.	O
+injected	O
+with	O
+CYP	O
+(	O
+150	O
+mg	O
+/	O
+kg	O
+)	O
+;	O
+and	O
+the	O
+rats	O
+in	O
+the	O
+intervention	O
+group	O
+were	O
+i	O
+.	O
+p	O
+.	O
+injected	O
+with	O
+CYP	O
+with	O
+subsequently	O
+perfusion	O
+of	O
+bladder	O
+with	O
+P2X3	O
+and	O
+NK1	O
+receptors	O
+'	O
+antagonists	O
+,	O
+Suramin	O
+and	O
+GR	O
+82334	O
+.	O
+
+Spontaneous	O
+pain	B
+behaviors	O
+following	O
+the	O
+administration	O
+of	O
+CYP	O
+were	O
+observed	O
+.	O
+
+Urodynamic	O
+parameters	O
+,	O
+bladder	O
+pressure	O
+-	O
+volume	O
+curve	O
+,	O
+maximum	O
+voiding	O
+pressure	O
+(	O
+MVP	O
+)	O
+,	O
+and	O
+maximum	O
+cystometric	O
+capacity	O
+(	O
+MCC	O
+)	O
+,	O
+were	O
+recorded	O
+.	O
+
+Pathological	O
+changes	O
+in	O
+bladder	O
+tissue	O
+were	O
+observed	O
+.	O
+
+Immunofluorescence	O
+was	O
+used	O
+to	O
+detect	O
+the	O
+expression	O
+of	O
+P2X3	O
+and	O
+NK1	O
+receptors	O
+in	O
+bladder	O
+.	O
+
+RESULTS	O
+:	O
+Cyclophosphamide	O
+treatment	O
+increased	O
+the	O
+spontaneous	O
+pain	B
+behaviors	O
+scores	O
+.	O
+
+The	O
+incidence	O
+of	O
+bladder	O
+instability	O
+during	O
+urine	O
+storage	O
+period	O
+of	O
+model	O
+group	O
+was	O
+significantly	O
+higher	O
+than	O
+intervention	O
+group	O
+(	O
+X	O
+(	O
+2	O
+)	O
+=	O
+7	O
+.	O
+619	O
+,	O
+P	O
+=	O
+0	O
+.	O
+007	O
+)	O
+and	O
+control	O
+group	O
+(	O
+X	O
+(	O
+2	O
+)	O
+=	O
+13	O
+.	O
+755	O
+,	O
+P	O
+=	O
+0	O
+.	O
+000	O
+)	O
+.	O
+
+MCC	O
+in	O
+the	O
+model	O
+group	O
+was	O
+lower	O
+than	O
+the	O
+control	O
+and	O
+intervention	O
+groups	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+Histological	O
+changes	O
+evident	O
+in	O
+model	O
+and	O
+intervention	O
+groups	O
+rats	O
+'	O
+bladder	O
+included	O
+edema	B
+,	O
+vasodilation	O
+,	O
+and	O
+infiltration	O
+of	O
+inflammatory	O
+cells	O
+.	O
+
+In	O
+model	O
+group	O
+,	O
+the	O
+expression	O
+of	O
+P2X3	O
+receptor	O
+increased	O
+in	O
+urothelium	O
+and	O
+suburothelium	O
+,	O
+and	O
+NK1	O
+receptor	O
+increased	O
+in	O
+suburothelium	O
+,	O
+while	O
+the	O
+expression	O
+of	O
+them	O
+in	O
+intervention	O
+group	O
+was	O
+lower	O
+.	O
+
+CONCLUSIONS	O
+:	O
+In	O
+CYP	O
+-	O
+induced	O
+cystitis	B
+,	O
+the	O
+expression	O
+of	O
+P2X3	O
+and	O
+NK1	O
+receptors	O
+increased	O
+in	O
+urothelium	O
+and	O
+/	O
+or	O
+suburothelium	O
+.	O
+
+Perfusion	O
+of	O
+bladder	O
+with	O
+P2X3	O
+and	O
+NK1	O
+receptors	O
+antagonists	O
+ameliorated	O
+the	O
+bladder	O
+function	O
+.	O
+
+Patient	O
+tolerance	O
+study	O
+of	O
+topical	O
+chlorhexidine	O
+diphosphanilate	O
+:	O
+a	O
+new	O
+topical	O
+agent	O
+for	O
+burns	B
+.	O
+
+Effective	O
+topical	O
+antimicrobial	O
+agents	O
+decrease	O
+infection	B
+and	O
+mortality	O
+in	O
+burn	B
+patients	O
+.	O
+
+Chlorhexidine	O
+phosphanilate	O
+(	O
+CHP	O
+)	O
+,	O
+a	O
+new	O
+broad	O
+-	O
+spectrum	O
+antimicrobial	O
+agent	O
+,	O
+has	O
+been	O
+evaluated	O
+as	O
+a	O
+topical	O
+burn	B
+wound	O
+dressing	O
+in	O
+cream	O
+form	O
+,	O
+but	O
+preliminary	O
+clinical	O
+trials	O
+reported	O
+that	O
+it	O
+was	O
+painful	O
+upon	O
+application	O
+.	O
+
+This	O
+study	O
+compared	O
+various	O
+concentrations	O
+of	O
+CHP	O
+to	O
+determine	O
+if	O
+a	O
+tolerable	O
+concentration	O
+could	O
+be	O
+identified	O
+with	O
+retention	O
+of	O
+antimicrobial	O
+efficacy	O
+.	O
+
+Twenty	O
+-	O
+nine	O
+burn	B
+patients	O
+,	O
+each	O
+with	O
+two	O
+similar	O
+burns	B
+which	O
+could	O
+be	O
+separately	O
+treated	O
+,	O
+were	O
+given	O
+pairs	O
+of	O
+treatments	O
+at	O
+successive	O
+12	O
+-	O
+h	O
+intervals	O
+over	O
+a	O
+3	O
+-	O
+day	O
+period	O
+.	O
+
+One	O
+burn	B
+site	O
+was	O
+treated	O
+with	O
+each	O
+of	O
+four	O
+different	O
+CHP	O
+concentrations	O
+,	O
+from	O
+0	O
+.	O
+25	O
+per	O
+cent	O
+to	O
+2	O
+per	O
+cent	O
+,	O
+their	O
+vehicle	O
+,	O
+and	O
+1	O
+per	O
+cent	O
+silver	O
+sulphadiazine	O
+(	O
+AgSD	O
+)	O
+cream	O
+,	O
+an	O
+antimicrobial	O
+agent	O
+frequently	O
+used	O
+for	O
+topical	O
+treatment	O
+of	O
+burn	B
+wounds	O
+.	O
+
+The	O
+other	O
+site	O
+was	O
+always	O
+treated	O
+with	O
+AgSD	O
+cream	O
+.	O
+
+There	O
+was	O
+a	O
+direct	O
+relationship	O
+between	O
+CHP	O
+concentration	O
+and	O
+patients	O
+'	O
+ratings	O
+of	O
+pain	B
+on	O
+an	O
+analogue	O
+scale	O
+.	O
+
+The	O
+0	O
+.	O
+25	O
+per	O
+cent	O
+CHP	O
+cream	O
+was	O
+closest	O
+to	O
+AgSD	O
+in	O
+pain	B
+tolerance	O
+;	O
+however	O
+,	O
+none	O
+of	O
+the	O
+treatments	O
+differed	O
+statistically	O
+from	O
+AgSD	O
+or	O
+from	O
+each	O
+other	O
+.	O
+
+In	O
+addition	O
+,	O
+ease	O
+of	O
+application	O
+of	O
+CHP	O
+creams	O
+was	O
+less	O
+satisfactory	O
+than	O
+that	O
+of	O
+AgSD	O
+.	O
+
+It	O
+was	O
+concluded	O
+that	O
+formulations	O
+at	O
+or	O
+below	O
+0	O
+.	O
+5	O
+per	O
+cent	O
+CHP	O
+may	O
+prove	O
+acceptable	O
+for	O
+wound	O
+care	O
+,	O
+but	O
+the	O
+vehicle	O
+system	O
+needs	O
+pharmaceutical	O
+improvement	O
+to	O
+render	O
+it	O
+more	O
+tolerable	O
+and	O
+easier	O
+to	O
+use	O
+.	O
+
+Acute	O
+hepatitis	B
+associated	O
+with	O
+clopidogrel	O
+:	O
+a	O
+case	O
+report	O
+and	O
+review	O
+of	O
+the	O
+literature	O
+.	O
+
+Drug	O
+-	O
+induced	O
+hepatotoxicity	B
+is	O
+a	O
+common	O
+cause	O
+of	O
+acute	O
+hepatitis	B
+,	O
+and	O
+the	O
+recognition	O
+of	O
+the	O
+responsible	O
+drug	O
+may	O
+be	O
+difficult	O
+.	O
+
+We	O
+describe	O
+a	O
+case	O
+of	O
+clopidogrel	O
+-	O
+related	O
+acute	O
+hepatitis	B
+.	O
+
+The	O
+diagnosis	O
+is	O
+strongly	O
+suggested	O
+by	O
+an	O
+accurate	O
+medical	O
+history	O
+and	O
+liver	O
+biopsy	O
+.	O
+
+Reports	O
+about	O
+cases	O
+of	O
+hepatotoxicity	B
+due	O
+to	O
+clopidogrel	O
+are	O
+increasing	O
+in	O
+the	O
+last	O
+few	O
+years	O
+,	O
+after	O
+the	O
+increased	O
+use	O
+of	O
+this	O
+drug	O
+.	O
+
+In	O
+conclusion	O
+,	O
+we	O
+believe	O
+that	O
+physicians	O
+should	O
+carefully	O
+consider	O
+the	O
+risk	O
+of	O
+drug	O
+-	O
+induced	O
+hepatic	B
+injury	I
+when	O
+clopidogrel	O
+is	O
+prescribed	O
+.	O
+
+Bortezomib	O
+and	O
+dexamethasone	O
+as	O
+salvage	O
+therapy	O
+in	O
+patients	O
+with	O
+relapsed	O
+/	O
+refractory	O
+multiple	B
+myeloma	I
+:	O
+analysis	O
+of	O
+long	O
+-	O
+term	O
+clinical	O
+outcomes	O
+.	O
+
+Bortezomib	O
+(	O
+bort	O
+)	O
+-	O
+dexamethasone	O
+(	O
+dex	O
+)	O
+is	O
+an	O
+effective	O
+therapy	O
+for	O
+relapsed	O
+/	O
+refractory	O
+(	O
+R	O
+/	O
+R	O
+)	O
+multiple	B
+myeloma	I
+(	O
+MM	B
+)	O
+.	O
+
+This	O
+retrospective	O
+study	O
+investigated	O
+the	O
+combination	O
+of	O
+bort	O
+(	O
+1	O
+.	O
+3	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+on	O
+days	O
+1	O
+,	O
+4	O
+,	O
+8	O
+,	O
+and	O
+11	O
+every	O
+3	O
+weeks	O
+)	O
+and	O
+dex	O
+(	O
+20	O
+mg	O
+on	O
+the	O
+day	O
+of	O
+and	O
+the	O
+day	O
+after	O
+bort	O
+)	O
+as	O
+salvage	O
+treatment	O
+in	O
+85	O
+patients	O
+with	O
+R	O
+/	O
+R	O
+MM	B
+after	O
+prior	O
+autologous	O
+stem	O
+cell	O
+transplantation	O
+or	O
+conventional	O
+chemotherapy	O
+.	O
+
+The	O
+median	O
+number	O
+of	O
+prior	O
+lines	O
+of	O
+therapy	O
+was	O
+2	O
+.	O
+
+Eighty	O
+-	O
+seven	O
+percent	O
+of	O
+the	O
+patients	O
+had	O
+received	O
+immunomodulatory	O
+drugs	O
+included	O
+in	O
+some	O
+line	O
+of	O
+therapy	O
+before	O
+bort	O
+-	O
+dex	O
+.	O
+
+The	O
+median	O
+number	O
+of	O
+bort	O
+-	O
+dex	O
+cycles	O
+was	O
+6	O
+,	O
+up	O
+to	O
+a	O
+maximum	O
+of	O
+12	O
+cycles	O
+.	O
+
+On	O
+an	O
+intention	O
+-	O
+to	O
+-	O
+treat	O
+basis	O
+,	O
+55	O
+%	O
+of	O
+the	O
+patients	O
+achieved	O
+at	O
+least	O
+partial	O
+response	O
+,	O
+including	O
+19	O
+%	O
+CR	O
+and	O
+35	O
+%	O
+achieved	O
+at	O
+least	O
+very	O
+good	O
+partial	O
+response	O
+.	O
+
+Median	O
+durations	O
+of	O
+response	O
+,	O
+time	O
+to	O
+next	O
+therapy	O
+and	O
+treatment	O
+-	O
+free	O
+interval	O
+were	O
+8	O
+,	O
+11	O
+.	O
+2	O
+,	O
+and	O
+5	O
+.	O
+1	O
+months	O
+,	O
+respectively	O
+.	O
+
+The	O
+most	O
+relevant	O
+adverse	O
+event	O
+was	O
+peripheral	B
+neuropathy	I
+,	O
+which	O
+occurred	O
+in	O
+78	O
+%	O
+of	O
+the	O
+patients	O
+(	O
+grade	O
+II	O
+,	O
+38	O
+%	O
+;	O
+grade	O
+III	O
+,	O
+21	O
+%	O
+)	O
+and	O
+led	O
+to	O
+treatment	O
+discontinuation	O
+in	O
+6	O
+%	O
+.	O
+
+With	O
+a	O
+median	O
+follow	O
+up	O
+of	O
+22	O
+months	O
+,	O
+median	O
+time	O
+to	O
+progression	O
+,	O
+progression	O
+-	O
+free	O
+survival	O
+(	O
+PFS	O
+)	O
+and	O
+overall	O
+survival	O
+(	O
+OS	O
+)	O
+were	O
+8	O
+.	O
+9	O
+,	O
+8	O
+.	O
+7	O
+,	O
+and	O
+22	O
+months	O
+,	O
+respectively	O
+.	O
+
+Prolonged	O
+PFS	O
+and	O
+OS	O
+were	O
+observed	O
+in	O
+patients	O
+achieving	O
+CR	O
+and	O
+receiving	O
+bort	O
+-	O
+dex	O
+a	O
+single	O
+line	O
+of	O
+prior	O
+therapy	O
+.	O
+
+Bort	O
+-	O
+dex	O
+was	O
+an	O
+effective	O
+salvage	O
+treatment	O
+for	O
+MM	B
+patients	O
+,	O
+particularly	O
+for	O
+those	O
+in	O
+first	O
+relapse	O
+.	O
+
+Pubertal	O
+exposure	O
+to	O
+Bisphenol	O
+A	O
+increases	O
+anxiety	B
+-	O
+like	O
+behavior	O
+and	O
+decreases	O
+acetylcholinesterase	O
+activity	O
+of	O
+hippocampus	O
+in	O
+adult	O
+male	O
+mice	O
+.	O
+
+The	O
+negative	O
+effects	O
+of	O
+Bisphenol	O
+A	O
+(	O
+BPA	O
+)	O
+on	O
+neurodevelopment	O
+and	O
+behaviors	O
+have	O
+been	O
+well	O
+established	O
+.	O
+
+Acetylcholinesterase	O
+(	O
+AChE	O
+)	O
+is	O
+a	O
+regulatory	O
+enzyme	O
+which	O
+is	O
+involved	O
+in	O
+anxiety	B
+-	O
+like	O
+behavior	O
+.	O
+
+This	O
+study	O
+investigated	O
+behavioral	O
+phenotypes	O
+and	O
+AChE	O
+activity	O
+in	O
+male	O
+mice	O
+following	O
+BPA	O
+exposure	O
+during	O
+puberty	O
+.	O
+
+On	O
+postnatal	O
+day	O
+(	O
+PND	O
+)	O
+35	O
+,	O
+male	O
+mice	O
+were	O
+exposed	O
+to	O
+50mg	O
+BPA	O
+/	O
+kg	O
+diet	O
+per	O
+day	O
+for	O
+a	O
+period	O
+of	O
+35	O
+days	O
+.	O
+
+On	O
+PND71	O
+,	O
+a	O
+behavioral	O
+assay	O
+was	O
+performed	O
+using	O
+the	O
+elevated	O
+plus	O
+maze	O
+(	O
+EPM	O
+)	O
+and	O
+the	O
+light	O
+/	O
+dark	O
+test	O
+.	O
+
+In	O
+addition	O
+,	O
+AChE	O
+activity	O
+was	O
+measured	O
+in	O
+the	O
+prefrontal	O
+cortex	O
+,	O
+hypothalamus	O
+,	O
+cerebellum	O
+and	O
+hippocampus	O
+.	O
+
+Results	O
+from	O
+our	O
+behavioral	O
+phenotyping	O
+indicated	O
+that	O
+anxiety	B
+-	O
+like	O
+behavior	O
+was	O
+increased	O
+in	O
+mice	O
+exposed	O
+to	O
+BPA	O
+.	O
+
+AChE	O
+activity	O
+was	O
+significantly	O
+decreased	O
+in	O
+the	O
+hippocampus	O
+of	O
+mice	O
+with	O
+BPA	O
+compared	O
+to	O
+control	O
+mice	O
+,	O
+whereas	O
+no	O
+difference	O
+was	O
+found	O
+in	O
+the	O
+prefrontal	O
+cortex	O
+,	O
+hypothalamus	O
+and	O
+cerebellum	O
+.	O
+
+Our	O
+findings	O
+showed	O
+that	O
+pubertal	O
+BPA	O
+exposure	O
+increased	O
+anxiety	B
+-	O
+like	O
+behavior	O
+,	O
+which	O
+may	O
+be	O
+associated	O
+with	O
+decreased	O
+AChE	O
+activity	O
+of	O
+the	O
+hippocampus	O
+in	O
+adult	O
+male	O
+mice	O
+.	O
+
+Further	O
+studies	O
+are	O
+necessary	O
+to	O
+investigate	O
+the	O
+cholinergic	O
+signaling	O
+of	O
+the	O
+hippocampus	O
+in	O
+PBE	O
+induced	O
+anxiety	B
+-	O
+like	O
+behaviors	O
+.	O
+
+Biochemical	O
+effects	O
+of	O
+Solidago	O
+virgaurea	O
+extract	O
+on	O
+experimental	O
+cardiotoxicity	B
+.	O
+
+Cardiovascular	B
+diseases	I
+(	O
+CVDs	B
+)	O
+are	O
+the	O
+major	O
+health	O
+problem	O
+of	O
+advanced	O
+as	O
+well	O
+as	O
+developing	O
+countries	O
+of	O
+the	O
+world	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+protective	O
+effect	O
+of	O
+the	O
+Solidago	O
+virgaurea	O
+extract	O
+on	O
+isoproterenol	O
+-	O
+induced	O
+cardiotoxicity	B
+in	O
+rats	O
+.	O
+
+The	O
+subcutaneous	O
+injection	O
+of	O
+isoproterenol	O
+(	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+into	O
+rats	O
+twice	O
+at	O
+an	O
+interval	O
+of	O
+24	O
+h	O
+,	O
+for	O
+two	O
+consecutive	O
+days	O
+,	O
+led	O
+to	O
+a	O
+significant	O
+increase	O
+in	O
+serum	O
+lactate	O
+dehydrogenase	O
+,	O
+creatine	O
+phosphokinase	O
+,	O
+alanine	O
+transaminase	O
+,	O
+aspartate	O
+transaminase	O
+,	O
+and	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+activities	O
+,	O
+total	O
+cholesterol	O
+,	O
+triglycerides	O
+,	O
+free	O
+serum	O
+fatty	O
+acid	O
+,	O
+cardiac	O
+tissue	O
+malondialdehyde	O
+(	O
+MDA	O
+)	O
+,	O
+and	O
+nitric	O
+oxide	O
+levels	O
+and	O
+a	O
+significant	O
+decrease	O
+in	O
+levels	O
+of	O
+glutathione	O
+and	O
+superoxide	O
+dismutase	O
+in	O
+cardiac	O
+tissue	O
+as	O
+compared	O
+to	O
+the	O
+normal	O
+control	O
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Pretreatment	O
+with	O
+S	O
+.	O
+virgaurea	O
+extract	O
+for	O
+5	O
+weeks	O
+at	O
+a	O
+dose	O
+of	O
+250	O
+mg	O
+/	O
+kg	O
+followed	O
+by	O
+isoproterenol	O
+injection	O
+significantly	O
+prevented	O
+the	O
+observed	O
+alterations	O
+.	O
+
+Captopril	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+,	O
+given	O
+orally	O
+)	O
+,	O
+an	O
+inhibitor	O
+of	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+used	O
+as	O
+a	O
+standard	O
+cardioprotective	O
+drug	O
+,	O
+was	O
+used	O
+as	O
+a	O
+positive	O
+control	O
+in	O
+this	O
+study	O
+.	O
+
+The	O
+data	O
+of	O
+the	O
+present	O
+study	O
+suggest	O
+that	O
+S	O
+.	O
+virgaurea	O
+extract	O
+exerts	O
+its	O
+protective	O
+effect	O
+by	O
+decreasing	O
+MDA	O
+level	O
+and	O
+increasing	O
+the	O
+antioxidant	O
+status	O
+in	O
+isoproterenol	O
+-	O
+treated	O
+rats	O
+.	O
+
+The	O
+study	O
+emphasizes	O
+the	O
+beneficial	O
+action	O
+of	O
+S	O
+.	O
+virgaurea	O
+extract	O
+as	O
+a	O
+cardioprotective	O
+agent	O
+.	O
+
+"	O
+Real	O
+-	O
+world	O
+"	O
+data	O
+on	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+lenalidomide	O
+and	O
+dexamethasone	O
+in	O
+patients	O
+with	O
+relapsed	O
+/	O
+refractory	O
+multiple	B
+myeloma	I
+who	O
+were	O
+treated	O
+according	O
+to	O
+the	O
+standard	O
+clinical	O
+practice	O
+:	O
+a	O
+study	O
+of	O
+the	O
+Greek	O
+Myeloma	B
+Study	O
+Group	O
+.	O
+
+Lenalidomide	O
+and	O
+dexamethasone	O
+(	O
+RD	O
+)	O
+is	O
+a	O
+standard	O
+of	O
+care	O
+for	O
+relapsed	O
+/	O
+refractory	O
+multiple	B
+myeloma	I
+(	O
+RRMM	B
+)	O
+,	O
+but	O
+there	O
+is	O
+limited	O
+published	O
+data	O
+on	O
+its	O
+efficacy	O
+and	O
+safety	O
+in	O
+the	O
+"	O
+real	O
+world	O
+"	O
+(	O
+RW	O
+)	O
+,	O
+according	O
+to	O
+the	O
+International	O
+Society	O
+of	O
+Pharmacoeconomics	O
+and	O
+Outcomes	O
+Research	O
+definition	O
+.	O
+
+We	O
+studied	O
+212	O
+RRMM	B
+patients	O
+who	O
+received	O
+RD	O
+in	O
+RW	O
+.	O
+
+Objective	O
+response	O
+(	O
+>	O
+PR	O
+(	O
+partial	O
+response	O
+)	O
+)	O
+rate	O
+was	O
+77	O
+.	O
+4	O
+%	O
+(	O
+complete	O
+response	O
+(	O
+CR	O
+)	O
+,	O
+20	O
+.	O
+2	O
+%	O
+)	O
+.	O
+
+Median	O
+time	O
+to	O
+first	O
+and	O
+best	O
+response	O
+was	O
+2	O
+and	O
+5	O
+months	O
+,	O
+respectively	O
+.	O
+
+Median	O
+time	O
+to	O
+CR	O
+when	O
+RD	O
+was	O
+given	O
+as	O
+2nd	O
+or	O
+>	O
+2	O
+(	O
+nd	O
+)	O
+-	O
+line	O
+treatment	O
+at	O
+4	O
+and	O
+11	O
+months	O
+,	O
+respectively	O
+.	O
+
+Quality	O
+of	O
+response	O
+was	O
+independent	O
+of	O
+previous	O
+lines	O
+of	O
+therapies	O
+or	O
+previous	O
+exposure	O
+to	O
+thalidomide	O
+or	O
+bortezomib	O
+.	O
+
+Median	O
+duration	O
+of	O
+response	O
+was	O
+34	O
+.	O
+4	O
+months	O
+,	O
+and	O
+it	O
+was	O
+higher	O
+in	O
+patients	O
+who	O
+received	O
+RD	O
+until	O
+progression	O
+(	O
+not	O
+reached	O
+versus	O
+19	O
+months	O
+,	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Improvement	O
+of	O
+humoral	O
+immunity	O
+occurred	O
+in	O
+60	O
+%	O
+of	O
+responders	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+and	O
+in	O
+the	O
+majority	O
+of	O
+patients	O
+who	O
+achieved	O
+stable	O
+disease	O
+.	O
+
+Adverse	O
+events	O
+were	O
+reported	O
+in	O
+68	O
+.	O
+9	O
+%	O
+of	O
+patients	O
+(	O
+myelosuppression	B
+in	O
+49	O
+.	O
+4	O
+%	O
+)	O
+and	O
+12	O
+.	O
+7	O
+%	O
+of	O
+patients	O
+needed	O
+hospitalization	O
+.	O
+
+Peripheral	B
+neuropathy	I
+was	O
+observed	O
+only	O
+in	O
+2	O
+.	O
+5	O
+%	O
+of	O
+patients	O
+and	O
+deep	B
+vein	I
+thrombosis	I
+in	O
+5	O
+.	O
+7	O
+%	O
+.	O
+
+Dose	O
+reductions	O
+were	O
+needed	O
+in	O
+31	O
+%	O
+of	O
+patients	O
+and	O
+permanent	O
+discontinuation	O
+in	O
+38	O
+.	O
+9	O
+%	O
+.	O
+
+Median	O
+time	O
+to	O
+treatment	O
+discontinuation	O
+was	O
+16	O
+.	O
+8	O
+months	O
+.	O
+
+Performance	O
+status	O
+(	O
+PS	O
+)	O
+and	O
+initial	O
+lenalidomide	O
+dose	O
+predicted	O
+for	O
+treatment	O
+discontinuation	O
+.	O
+
+Extra	O
+-	O
+medullary	O
+relapses	O
+occurred	O
+in	O
+3	O
+.	O
+8	O
+%	O
+of	O
+patients	O
+.	O
+
+Our	O
+study	O
+confirms	O
+that	O
+RD	O
+is	O
+effective	O
+and	O
+safe	O
+in	O
+RRMM	B
+in	O
+the	O
+RW	O
+;	O
+it	O
+produces	O
+durable	O
+responses	O
+especially	O
+in	O
+patients	O
+who	O
+continue	O
+on	O
+treatment	O
+till	O
+progression	O
+and	O
+improves	O
+humoral	O
+immunity	O
+even	O
+in	O
+patients	O
+with	O
+stable	O
+disease	O
+.	O
+
+The	O
+cytogenetic	O
+action	O
+of	O
+ifosfamide	O
+,	O
+mesna	O
+,	O
+and	O
+their	O
+combination	O
+on	O
+peripheral	O
+rabbit	O
+lymphocytes	O
+:	O
+an	O
+in	O
+vivo	O
+/	O
+in	O
+vitro	O
+cytogenetic	O
+study	O
+.	O
+
+Ifosfamide	O
+(	O
+IFO	O
+)	O
+is	O
+an	O
+alkylating	O
+nitrogen	O
+mustard	O
+,	O
+administrated	O
+as	O
+an	O
+antineoplasmic	O
+agent	O
+.	O
+
+It	O
+is	O
+characterized	O
+by	O
+its	O
+intense	O
+urotoxic	O
+action	O
+,	O
+leading	O
+to	O
+hemorrhagic	B
+cystitis	I
+.	O
+
+This	O
+side	O
+effect	O
+of	O
+IFO	O
+raises	O
+the	O
+requirement	O
+for	O
+the	O
+co	O
+-	O
+administration	O
+with	O
+sodium	O
+2	O
+-	O
+sulfanylethanesulfonate	O
+(	O
+Mesna	O
+)	O
+aiming	O
+to	O
+avoid	O
+or	O
+minimize	O
+this	O
+effect	O
+.	O
+
+IFO	O
+and	O
+Mesna	O
+were	O
+administrated	O
+separately	O
+on	O
+rabbit	O
+'	O
+s	O
+lymphocytes	O
+in	O
+vivo	O
+,	O
+which	O
+were	O
+later	O
+developed	O
+in	O
+vitro	O
+.	O
+
+Cytogenetic	O
+markers	O
+for	O
+sister	O
+chromatid	O
+exchanges	O
+(	O
+SCEs	O
+)	O
+,	O
+proliferation	O
+rate	O
+index	O
+(	O
+PRI	O
+)	O
+and	O
+Mitotic	O
+Index	O
+were	O
+recorded	O
+.	O
+
+Mesna	O
+'	O
+s	O
+action	O
+,	O
+in	O
+conjunction	O
+with	O
+IFO	O
+reduces	O
+the	O
+frequency	O
+of	O
+SCEs	O
+,	O
+in	O
+comparison	O
+with	O
+the	O
+SCEs	O
+recordings	O
+obtained	O
+when	O
+IFO	O
+is	O
+administered	O
+alone	O
+.	O
+
+In	O
+addition	O
+to	O
+this	O
+,	O
+when	O
+high	O
+concentrations	O
+of	O
+Mesna	O
+were	O
+administered	O
+alone	O
+significant	O
+reductions	O
+of	O
+the	O
+PRI	O
+were	O
+noted	O
+,	O
+than	O
+with	O
+IFO	O
+acting	O
+at	O
+the	O
+same	O
+concentration	O
+on	O
+the	O
+lymphocytes	O
+.	O
+
+Mesna	O
+significantly	O
+reduces	O
+IFO	O
+'	O
+s	O
+genotoxicity	B
+,	O
+while	O
+when	O
+administered	O
+in	O
+high	O
+concentrations	O
+it	O
+acts	O
+in	O
+an	O
+inhibitory	O
+fashion	O
+on	O
+the	O
+cytostatic	O
+action	O
+of	O
+the	O
+drug	O
+.	O
+
+Risk	O
+factors	O
+and	O
+predictors	O
+of	O
+levodopa	O
+-	O
+induced	O
+dyskinesia	B
+among	O
+multiethnic	O
+Malaysians	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+Chronic	O
+pulsatile	O
+levodopa	O
+therapy	O
+for	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+leads	O
+to	O
+the	O
+development	O
+of	O
+motor	O
+fluctuations	O
+and	O
+dyskinesia	B
+.	O
+
+We	O
+studied	O
+the	O
+prevalence	O
+and	O
+predictors	O
+of	O
+levodopa	O
+-	O
+induced	O
+dyskinesia	B
+among	O
+multiethnic	O
+Malaysian	O
+patients	O
+with	O
+PD	B
+.	O
+
+METHODS	O
+:	O
+This	O
+is	O
+a	O
+cross	O
+-	O
+sectional	O
+study	O
+involving	O
+95	O
+patients	O
+with	O
+PD	B
+on	O
+uninterrupted	O
+levodopa	O
+therapy	O
+for	O
+at	O
+least	O
+6	O
+months	O
+.	O
+
+The	O
+instrument	O
+used	O
+was	O
+the	O
+UPDRS	O
+questionnaires	O
+.	O
+
+The	O
+predictors	O
+of	O
+dyskinesia	B
+were	O
+determined	O
+using	O
+multivariate	O
+logistic	O
+regression	O
+analysis	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+mean	O
+age	O
+was	O
+65	O
+.	O
+6	O
++	O
+8	O
+.	O
+5	O
+years	O
+.	O
+
+The	O
+mean	O
+onset	O
+age	O
+was	O
+58	O
+.	O
+5	O
++	O
+9	O
+.	O
+8	O
+years	O
+.	O
+
+The	O
+median	O
+disease	O
+duration	O
+was	O
+6	O
+(	O
+7	O
+)	O
+years	O
+.	O
+
+Dyskinesia	B
+was	O
+present	O
+in	O
+44	O
+%	O
+(	O
+n	O
+=	O
+42	O
+)	O
+with	O
+median	O
+levodopa	O
+therapy	O
+of	O
+3	O
+years	O
+.	O
+
+There	O
+were	O
+64	O
+.	O
+3	O
+%	O
+Chinese	O
+,	O
+31	O
+%	O
+Malays	O
+,	O
+and	O
+3	O
+.	O
+7	O
+%	O
+Indians	O
+and	O
+other	O
+ethnic	O
+groups	O
+.	O
+
+Eighty	O
+-	O
+one	O
+percent	O
+of	O
+patients	O
+with	O
+dyskinesia	B
+had	O
+clinical	O
+fluctuations	O
+.	O
+
+Patients	O
+with	O
+dyskinesia	B
+had	O
+lower	O
+onset	O
+age	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+,	O
+longer	O
+duration	O
+of	O
+levodopa	O
+therapy	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+,	O
+longer	O
+disease	O
+duration	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+,	O
+higher	O
+total	O
+daily	O
+levodopa	O
+dose	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+,	O
+and	O
+higher	O
+total	O
+UPDRS	O
+scores	O
+(	O
+p	O
+=	O
+0	O
+.	O
+005	O
+)	O
+than	O
+patients	O
+without	O
+dyskinesia	B
+.	O
+
+The	O
+three	O
+significant	O
+predictors	O
+of	O
+dyskinesia	B
+were	O
+duration	O
+of	O
+levodopa	O
+therapy	O
+,	O
+onset	O
+age	O
+,	O
+and	O
+total	O
+daily	O
+levodopa	O
+dose	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+prevalence	O
+of	O
+levodopa	O
+-	O
+induced	O
+dyskinesia	B
+in	O
+our	O
+patients	O
+was	O
+44	O
+%	O
+.	O
+
+The	O
+most	O
+significant	O
+predictors	O
+were	O
+duration	O
+of	O
+levodopa	O
+therapy	O
+,	O
+total	O
+daily	O
+levodopa	O
+dose	O
+,	O
+and	O
+onset	O
+age	O
+.	O
+
+Dose	O
+-	O
+dependent	O
+neurotoxicity	B
+of	O
+high	O
+-	O
+dose	O
+busulfan	O
+in	O
+children	O
+:	O
+a	O
+clinical	O
+and	O
+pharmacological	O
+study	O
+.	O
+
+Busulfan	O
+is	O
+known	O
+to	O
+be	O
+neurotoxic	B
+in	O
+animals	O
+and	O
+humans	O
+,	O
+but	O
+its	O
+acute	O
+neurotoxicity	B
+remains	O
+poorly	O
+characterized	O
+in	O
+children	O
+.	O
+
+We	O
+report	O
+here	O
+a	O
+retrospective	O
+study	O
+of	O
+123	O
+children	O
+(	O
+median	O
+age	O
+,	O
+6	O
+.	O
+5	O
+years	O
+)	O
+receiving	O
+high	O
+-	O
+dose	O
+busulfan	O
+in	O
+combined	O
+chemotherapy	O
+before	O
+bone	O
+marrow	O
+transplantation	O
+for	O
+malignant	O
+solid	O
+tumors	B
+,	O
+brain	B
+tumors	I
+excluded	O
+.	O
+
+Busulfan	O
+was	O
+given	O
+p	O
+.	O
+o	O
+.	O
+,	O
+every	O
+6	O
+hours	O
+for	O
+16	O
+doses	O
+over	O
+4	O
+days	O
+.	O
+
+Two	O
+total	O
+doses	O
+were	O
+consecutively	O
+used	O
+:	O
+16	O
+mg	O
+/	O
+kg	O
+,	O
+then	O
+600	O
+mg	O
+/	O
+m2	O
+.	O
+
+The	O
+dose	O
+calculation	O
+on	O
+the	O
+basis	O
+of	O
+body	O
+surface	O
+area	O
+results	O
+in	O
+higher	O
+doses	O
+in	O
+young	O
+children	O
+than	O
+in	O
+older	O
+patients	O
+(	O
+16	O
+to	O
+28	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+Ninety	O
+-	O
+six	O
+patients	O
+were	O
+not	O
+given	O
+anticonvulsive	O
+prophylaxis	O
+;	O
+7	O
+(	O
+7	O
+.	O
+5	O
+%	O
+)	O
+developed	O
+seizures	B
+during	O
+the	O
+4	O
+days	O
+of	O
+the	O
+busulfan	O
+course	O
+or	O
+within	O
+24	O
+h	O
+after	O
+the	O
+last	O
+dosing	O
+.	O
+
+When	O
+the	O
+total	O
+busulfan	O
+dose	O
+was	O
+taken	O
+into	O
+account	O
+,	O
+there	O
+was	O
+a	O
+significant	O
+difference	O
+in	O
+terms	O
+of	O
+neurotoxicity	B
+incidence	O
+among	O
+patients	O
+under	O
+16	O
+mg	O
+/	O
+kg	O
+(	O
+1	O
+of	O
+57	O
+,	O
+1	O
+.	O
+7	O
+%	O
+)	O
+and	O
+patients	O
+under	O
+600	O
+mg	O
+/	O
+m2	O
+(	O
+6	O
+of	O
+39	O
+,	O
+15	O
+.	O
+4	O
+%	O
+)	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+02	O
+)	O
+.	O
+
+Twenty	O
+-	O
+seven	O
+patients	O
+were	O
+given	O
+a	O
+600	O
+-	O
+mg	O
+/	O
+m2	O
+busulfan	O
+total	O
+dose	O
+with	O
+continuous	O
+i	O
+.	O
+v	O
+.	O
+infusion	O
+of	O
+clonazepam	O
+;	O
+none	O
+had	O
+any	O
+neurological	B
+symptoms	I
+.	O
+
+Busulfan	O
+levels	O
+were	O
+measured	O
+by	O
+a	O
+gas	O
+chromatographic	O
+-	O
+mass	O
+spectrometry	O
+assay	O
+in	O
+the	O
+plasma	O
+and	O
+cerebrospinal	O
+fluid	O
+of	O
+9	O
+children	O
+without	O
+central	B
+nervous	I
+system	I
+disease	I
+under	O
+600	O
+mg	O
+/	O
+m2	O
+busulfan	O
+with	O
+clonazepam	O
+:	O
+busulfan	O
+cerebrospinal	O
+fluid	O
+:	O
+plasma	O
+ratio	O
+was	O
+1	O
+.	O
+39	O
+.	O
+
+This	O
+was	O
+significantly	O
+different	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+02	O
+)	O
+from	O
+the	O
+cerebrospinal	O
+fluid	O
+:	O
+plasma	O
+ratio	O
+previously	O
+defined	O
+in	O
+children	O
+receiving	O
+a	O
+16	O
+-	O
+mg	O
+/	O
+kg	O
+total	O
+dose	O
+of	O
+busulfan	O
+.	O
+
+This	O
+study	O
+shows	O
+that	O
+busulfan	O
+neurotoxicity	B
+is	O
+dose	O
+-	O
+dependent	O
+in	O
+children	O
+and	O
+efficiently	O
+prevented	O
+by	O
+clonazepam	O
+.	O
+
+A	O
+busulfan	O
+dose	O
+calculated	O
+on	O
+the	O
+basis	O
+of	O
+body	O
+surface	O
+area	O
+,	O
+resulting	O
+in	O
+higher	O
+doses	O
+in	O
+young	O
+children	O
+,	O
+was	O
+followed	O
+by	O
+increased	O
+neurotoxicity	B
+,	O
+close	O
+to	O
+neurotoxicity	B
+incidence	O
+observed	O
+in	O
+adults	O
+.	O
+
+Since	O
+plasma	O
+pharmacokinetic	O
+studies	O
+showed	O
+a	O
+faster	O
+busulfan	O
+clearance	O
+in	O
+children	O
+than	O
+in	O
+adults	O
+,	O
+this	O
+new	O
+dose	O
+may	O
+approximate	O
+more	O
+closely	O
+the	O
+adult	O
+systemic	O
+exposure	O
+obtained	O
+after	O
+the	O
+usual	O
+16	O
+-	O
+mg	O
+/	O
+kg	O
+total	O
+dose	O
+,	O
+with	O
+potential	O
+inferences	O
+in	O
+terms	O
+of	O
+anticancer	O
+or	O
+myeloablative	O
+effects	O
+.	O
+
+The	O
+busulfan	O
+dose	O
+in	O
+children	O
+and	O
+infants	O
+undergoing	O
+bone	O
+marrow	O
+transplantation	O
+should	O
+be	O
+reconsidered	O
+on	O
+the	O
+basis	O
+of	O
+pharmacokinetic	O
+studies	O
+.	O
+
+An	O
+unexpected	O
+diagnosis	O
+in	O
+a	O
+renal	O
+-	O
+transplant	O
+patient	O
+with	O
+proteinuria	B
+treated	O
+with	O
+everolimus	O
+:	O
+AL	B
+amyloidosis	B
+.	O
+
+Proteinuria	B
+is	O
+an	O
+expected	O
+complication	O
+in	O
+transplant	O
+patients	O
+treated	O
+with	O
+mammalian	O
+target	O
+of	O
+rapamycin	O
+inhibitors	O
+(	O
+mTOR	O
+-	O
+i	O
+)	O
+.	O
+
+However	O
+,	O
+clinical	O
+suspicion	O
+should	O
+always	O
+be	O
+supported	O
+by	O
+histological	O
+evidence	O
+in	O
+order	O
+to	O
+investigate	O
+potential	O
+alternate	O
+diagnoses	O
+such	O
+as	O
+acute	O
+or	O
+chronic	O
+rejection	O
+,	O
+interstitial	O
+fibrosis	B
+and	O
+tubular	O
+atrophy	B
+,	O
+or	O
+recurrent	O
+or	O
+de	O
+novo	O
+glomerulopathy	B
+.	O
+
+In	O
+this	O
+case	O
+we	O
+report	O
+the	O
+unexpected	O
+diagnosis	O
+of	O
+amyloidosis	B
+in	O
+a	O
+renal	O
+-	O
+transplant	O
+patient	O
+with	O
+pre	O
+-	O
+transplant	O
+monoclonal	O
+gammapathy	O
+of	O
+undetermined	O
+significance	O
+who	O
+developed	O
+proteinuria	B
+after	O
+conversion	O
+from	O
+tacrolimus	O
+to	O
+everolimus	O
+.	O
+
+Long	O
+-	O
+term	O
+oral	O
+galactose	O
+treatment	O
+prevents	O
+cognitive	B
+deficits	I
+in	O
+male	O
+Wistar	O
+rats	O
+treated	O
+intracerebroventricularly	O
+with	O
+streptozotocin	O
+.	O
+
+Basic	O
+and	O
+clinical	O
+research	O
+has	O
+demonstrated	O
+that	O
+dementia	B
+of	O
+sporadic	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+(	O
+sAD	O
+)	O
+type	O
+is	O
+associated	O
+with	O
+dysfunction	O
+of	O
+the	O
+insulin	O
+-	O
+receptor	O
+(	O
+IR	O
+)	O
+system	O
+followed	O
+by	O
+decreased	O
+glucose	O
+transport	O
+via	O
+glucose	O
+transporter	O
+GLUT4	O
+and	O
+decreased	O
+glucose	O
+metabolism	O
+in	O
+brain	O
+cells	O
+.	O
+
+An	O
+alternative	O
+source	O
+of	O
+energy	O
+is	O
+d	O
+-	O
+galactose	O
+(	O
+the	O
+C	O
+-	O
+4	O
+-	O
+epimer	O
+of	O
+d	O
+-	O
+glucose	O
+)	O
+which	O
+is	O
+transported	O
+into	O
+the	O
+brain	O
+by	O
+insulin	O
+-	O
+independent	O
+GLUT3	O
+transporter	O
+where	O
+it	O
+might	O
+be	O
+metabolized	O
+to	O
+glucose	O
+via	O
+the	O
+Leloir	O
+pathway	O
+.	O
+
+Exclusively	O
+parenteral	O
+daily	O
+injections	O
+of	O
+galactose	O
+induce	O
+memory	B
+deterioration	I
+in	O
+rodents	O
+and	O
+are	O
+used	O
+to	O
+generate	O
+animal	O
+aging	O
+model	O
+,	O
+but	O
+the	O
+effects	O
+of	O
+oral	O
+galactose	O
+treatment	O
+on	O
+cognitive	O
+functions	O
+have	O
+never	O
+been	O
+tested	O
+.	O
+
+We	O
+have	O
+investigated	O
+the	O
+effects	O
+of	O
+continuous	O
+daily	O
+oral	O
+galactose	O
+(	O
+200	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+)	O
+treatment	O
+on	O
+cognitive	B
+deficits	I
+in	O
+streptozotocin	O
+-	O
+induced	O
+(	O
+STZ	O
+-	O
+icv	O
+)	O
+rat	O
+model	O
+of	O
+sAD	O
+,	O
+tested	O
+by	O
+Morris	O
+Water	O
+Maze	O
+and	O
+Passive	O
+Avoidance	O
+test	O
+,	O
+respectively	O
+.	O
+
+One	O
+month	O
+of	O
+oral	O
+galactose	O
+treatment	O
+initiated	O
+immediately	O
+after	O
+the	O
+STZ	O
+-	O
+icv	O
+administration	O
+,	O
+successfully	O
+prevented	O
+development	O
+of	O
+the	O
+STZ	O
+-	O
+icv	O
+-	O
+induced	O
+cognitive	B
+deficits	I
+.	O
+
+Beneficial	O
+effect	O
+of	O
+oral	O
+galactose	O
+was	O
+independent	O
+of	O
+the	O
+rat	O
+age	O
+and	O
+of	O
+the	O
+galactose	O
+dose	O
+ranging	O
+from	O
+100	O
+to	O
+300	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+.	O
+
+Additionally	O
+,	O
+oral	O
+galactose	O
+administration	O
+led	O
+to	O
+the	O
+appearance	O
+of	O
+galactose	O
+in	O
+the	O
+blood	O
+.	O
+
+The	O
+increase	O
+of	O
+galactose	O
+concentration	O
+in	O
+the	O
+cerebrospinal	O
+fluid	O
+was	O
+several	O
+times	O
+lower	O
+after	O
+oral	O
+than	O
+after	O
+parenteral	O
+administration	O
+of	O
+the	O
+same	O
+galactose	O
+dose	O
+.	O
+
+Oral	O
+galactose	O
+exposure	O
+might	O
+have	O
+beneficial	O
+effects	O
+on	O
+learning	O
+and	O
+memory	O
+ability	O
+and	O
+could	O
+be	O
+worth	O
+investigating	O
+for	O
+improvement	O
+of	O
+cognitive	B
+deficits	I
+associated	O
+with	O
+glucose	B
+hypometabolism	I
+in	O
+AD	B
+.	O
+
+An	O
+investigation	O
+of	O
+the	O
+pattern	O
+of	O
+kidney	B
+injury	I
+in	O
+HIV	O
+-	O
+positive	O
+persons	O
+exposed	O
+to	O
+tenofovir	O
+disoproxil	O
+fumarate	O
+:	O
+an	O
+examination	O
+of	O
+a	O
+large	O
+population	O
+database	O
+(	O
+MHRA	O
+database	O
+)	O
+.	O
+
+The	O
+potential	O
+for	O
+tenofovir	O
+to	O
+cause	O
+a	O
+range	O
+of	O
+kidney	O
+syndromes	O
+has	O
+been	O
+established	O
+from	O
+mechanistic	O
+and	O
+randomised	O
+clinical	O
+trials	O
+.	O
+
+However	O
+,	O
+the	O
+exact	O
+pattern	O
+of	O
+kidney	O
+involvement	O
+is	O
+still	O
+uncertain	O
+.	O
+
+We	O
+undertook	O
+a	O
+descriptive	O
+analysis	O
+of	O
+Yellow	O
+Card	O
+records	O
+of	O
+407	O
+HIV	O
+-	O
+positive	O
+persons	O
+taking	O
+tenofovir	O
+disoproxil	O
+fumarate	O
+(	O
+TDF	O
+)	O
+as	O
+part	O
+of	O
+their	O
+antiretroviral	O
+therapy	O
+regimen	O
+and	O
+submitted	O
+to	O
+the	O
+Medicines	O
+and	O
+Healthcare	O
+Products	O
+Regulatory	O
+Agency	O
+(	O
+MHRA	O
+)	O
+with	O
+suspected	O
+kidney	O
+adverse	O
+effects	O
+.	O
+
+Reports	O
+that	O
+satisfy	O
+defined	O
+criteria	O
+were	O
+classified	O
+as	O
+acute	B
+kidney	I
+injury	I
+,	O
+kidney	B
+tubular	I
+dysfunction	I
+and	O
+Fanconi	B
+syndrome	I
+.	O
+
+Of	O
+the	O
+407	O
+Yellow	O
+Card	O
+records	O
+analysed	O
+,	O
+106	O
+satisfied	O
+criteria	O
+for	O
+TDF	O
+-	O
+related	O
+kidney	B
+disease	I
+,	O
+of	O
+which	O
+53	O
+(	O
+50	O
+%	O
+)	O
+had	O
+features	O
+of	O
+kidney	B
+tubular	I
+dysfunction	I
+,	O
+35	O
+(	O
+33	O
+%	O
+)	O
+were	O
+found	O
+to	O
+have	O
+features	O
+of	O
+glomerular	B
+dysfunction	I
+and	O
+18	O
+(	O
+17	O
+%	O
+)	O
+had	O
+Fanconi	B
+syndrome	I
+.	O
+
+The	O
+median	O
+TDF	O
+exposure	O
+was	O
+316	O
+days	O
+(	O
+interquartile	O
+range	O
+120	O
+-	O
+740	O
+)	O
+.	O
+
+The	O
+incidence	O
+of	O
+hospitalisation	O
+for	O
+TDF	O
+kidney	O
+adverse	O
+effects	O
+was	O
+high	O
+,	O
+particularly	O
+amongst	O
+patients	O
+with	O
+features	O
+of	O
+Fanconi	B
+syndrome	I
+.	O
+
+The	O
+pattern	O
+of	O
+kidney	O
+syndromes	O
+in	O
+this	O
+population	O
+series	O
+mirrors	O
+that	O
+reported	O
+in	O
+randomised	O
+clinical	O
+trials	O
+.	O
+
+Cessation	O
+of	O
+TDF	O
+was	O
+associated	O
+with	O
+complete	O
+restoration	O
+of	O
+kidney	O
+function	O
+in	O
+up	O
+half	O
+of	O
+the	O
+patients	O
+in	O
+this	O
+report	O
+.	O
+
+Incidence	O
+of	O
+postoperative	B
+delirium	I
+is	O
+high	O
+even	O
+in	O
+a	O
+population	O
+without	O
+known	O
+risk	O
+factors	O
+.	O
+
+PURPOSE	O
+:	O
+Postoperative	B
+delirium	I
+is	O
+a	O
+recognized	O
+complication	O
+in	O
+populations	O
+at	O
+risk	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+is	O
+to	O
+assess	O
+the	O
+prevalence	O
+of	O
+early	O
+postoperative	B
+delirium	I
+in	O
+a	O
+population	O
+without	O
+known	O
+risk	O
+factors	O
+admitted	O
+to	O
+the	O
+ICU	O
+for	O
+postoperative	O
+monitoring	O
+after	O
+elective	O
+major	O
+surgery	O
+.	O
+
+The	O
+secondary	O
+outcome	O
+investigated	O
+is	O
+to	O
+identify	O
+eventual	O
+independent	O
+risk	O
+factors	O
+among	O
+demographic	O
+data	O
+and	O
+anesthetic	O
+drugs	O
+used	O
+.	O
+
+METHODS	O
+:	O
+An	O
+observational	O
+,	O
+prospective	O
+study	O
+was	O
+conducted	O
+on	O
+a	O
+consecutive	O
+cohort	O
+of	O
+patients	O
+admitted	O
+to	O
+our	O
+ICU	O
+within	O
+and	O
+for	O
+at	O
+least	O
+24	O
+h	O
+after	O
+major	O
+surgical	O
+procedures	O
+.	O
+
+Exclusion	O
+criteria	O
+were	O
+any	O
+preexisting	O
+predisposing	O
+factor	O
+for	O
+delirium	B
+or	O
+other	O
+potentially	O
+confounding	O
+neurological	B
+dysfunctions	I
+.	O
+
+Patients	O
+were	O
+assessed	O
+daily	O
+using	O
+the	O
+confusion	B
+assessment	O
+method	O
+for	O
+the	O
+ICU	O
+scale	O
+for	O
+3	O
+days	O
+after	O
+the	O
+surgical	O
+procedure	O
+.	O
+
+Early	O
+postoperative	B
+delirium	I
+incidence	O
+risk	O
+factors	O
+were	O
+then	O
+assessed	O
+through	O
+three	O
+different	O
+multiple	O
+regression	O
+models	O
+.	O
+
+RESULTS	O
+:	O
+According	O
+to	O
+the	O
+confusion	O
+assessment	O
+method	O
+for	O
+the	O
+ICU	O
+scale	O
+,	O
+28	O
+%	O
+of	O
+patients	O
+were	O
+diagnosed	O
+with	O
+early	O
+postoperative	B
+delirium	I
+.	O
+
+The	O
+use	O
+of	O
+thiopentone	O
+was	O
+significantly	O
+associated	O
+with	O
+an	O
+eight	O
+-	O
+fold	O
+-	O
+higher	O
+risk	O
+for	O
+delirium	B
+compared	O
+to	O
+propofol	O
+(	O
+57	O
+.	O
+1	O
+%	O
+vs	O
+.	O
+7	O
+.	O
+1	O
+%	O
+,	O
+RR	O
+=	O
+8	O
+.	O
+0	O
+,	O
+X2	O
+=	O
+4	O
+.	O
+256	O
+;	O
+df	O
+=	O
+1	O
+;	O
+0	O
+.	O
+05	O
+<	O
+p	O
+<	O
+0	O
+.	O
+02	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+In	O
+this	O
+study	O
+early	O
+postoperative	B
+delirium	I
+was	O
+found	O
+to	O
+be	O
+a	O
+very	O
+common	O
+complication	O
+after	O
+major	O
+surgery	O
+,	O
+even	O
+in	O
+a	O
+population	O
+without	O
+known	O
+risk	O
+factors	O
+.	O
+
+Thiopentone	O
+was	O
+independently	O
+associated	O
+with	O
+an	O
+increase	O
+in	O
+its	O
+relative	O
+risk	O
+.	O
+
+A	O
+single	O
+neurotoxic	B
+dose	O
+of	O
+methamphetamine	O
+induces	O
+a	O
+long	O
+-	O
+lasting	O
+depressive	B
+-	O
+like	O
+behaviour	O
+in	O
+mice	O
+.	O
+
+Methamphetamine	O
+(	O
+METH	O
+)	O
+triggers	O
+a	O
+disruption	O
+of	O
+the	O
+monoaminergic	O
+system	O
+and	O
+METH	O
+abuse	O
+leads	O
+to	O
+negative	O
+emotional	O
+states	O
+including	O
+depressive	B
+symptoms	I
+during	O
+drug	O
+withdrawal	O
+.	O
+
+However	O
+,	O
+it	O
+is	O
+currently	O
+unknown	O
+if	O
+the	O
+acute	O
+toxic	O
+dosage	O
+of	O
+METH	O
+also	O
+causes	O
+a	O
+long	O
+-	O
+lasting	O
+depressive	B
+phenotype	O
+and	O
+persistent	O
+monoaminergic	O
+deficits	O
+.	O
+
+Thus	O
+,	O
+we	O
+now	O
+assessed	O
+the	O
+depressive	B
+-	O
+like	O
+behaviour	O
+in	O
+mice	O
+at	O
+early	O
+and	O
+long	O
+-	O
+term	O
+periods	O
+following	O
+a	O
+single	O
+high	O
+METH	O
+dose	O
+(	O
+30	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+METH	O
+did	O
+not	O
+alter	O
+the	O
+motor	O
+function	O
+and	O
+procedural	O
+memory	O
+of	O
+mice	O
+as	O
+assessed	O
+by	O
+swimming	O
+speed	O
+and	O
+escape	O
+latency	O
+to	O
+find	O
+the	O
+platform	O
+in	O
+a	O
+cued	O
+version	O
+of	O
+the	O
+water	O
+maze	O
+task	O
+.	O
+
+However	O
+,	O
+METH	O
+significantly	O
+increased	O
+the	O
+immobility	O
+time	O
+in	O
+the	O
+tail	O
+suspension	O
+test	O
+at	O
+3	O
+and	O
+49	O
+days	O
+post	O
+-	O
+administration	O
+.	O
+
+This	O
+depressive	B
+-	O
+like	O
+profile	O
+induced	O
+by	O
+METH	O
+was	O
+accompanied	O
+by	O
+a	O
+marked	O
+depletion	O
+of	O
+frontostriatal	O
+dopaminergic	O
+and	O
+serotonergic	O
+neurotransmission	O
+,	O
+indicated	O
+by	O
+a	O
+reduction	O
+in	O
+the	O
+levels	O
+of	O
+dopamine	O
+,	O
+DOPAC	O
+and	O
+HVA	O
+,	O
+tyrosine	O
+hydroxylase	O
+and	O
+serotonin	O
+,	O
+observed	O
+at	O
+both	O
+3	O
+and	O
+49	O
+days	O
+post	O
+-	O
+administration	O
+.	O
+
+In	O
+parallel	O
+,	O
+another	O
+neurochemical	O
+feature	O
+of	O
+depression	B
+-	O
+-	O
+astroglial	O
+dysfunction	O
+-	O
+-	O
+was	O
+unaffected	O
+in	O
+the	O
+cortex	O
+and	O
+the	O
+striatal	O
+levels	O
+of	O
+the	O
+astrocytic	O
+protein	O
+marker	O
+,	O
+glial	O
+fibrillary	O
+acidic	O
+protein	O
+,	O
+were	O
+only	O
+transiently	O
+increased	O
+at	O
+3	O
+days	O
+.	O
+
+These	O
+findings	O
+demonstrate	O
+for	O
+the	O
+first	O
+time	O
+that	O
+a	O
+single	O
+high	O
+dose	O
+of	O
+METH	O
+induces	O
+long	O
+-	O
+lasting	O
+depressive	B
+-	O
+like	O
+behaviour	O
+in	O
+mice	O
+associated	O
+with	O
+a	O
+persistent	O
+disruption	O
+of	O
+frontostriatal	O
+dopaminergic	O
+and	O
+serotonergic	O
+homoeostasis	O
+.	O
+
+Linezolid	O
+-	O
+induced	O
+optic	B
+neuropathy	I
+.	O
+
+Many	O
+systemic	O
+antimicrobials	O
+have	O
+been	O
+implicated	O
+to	O
+cause	O
+ocular	O
+adverse	O
+effects	O
+.	O
+
+This	O
+is	O
+especially	O
+relevant	O
+in	O
+multidrug	O
+therapy	O
+where	O
+more	O
+than	O
+one	O
+drug	O
+can	O
+cause	O
+a	O
+similar	O
+ocular	O
+adverse	O
+effect	O
+.	O
+
+We	O
+describe	O
+a	O
+case	O
+of	O
+progressive	O
+loss	B
+of	I
+vision	I
+associated	O
+with	O
+linezolid	O
+therapy	O
+.	O
+
+A	O
+45	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+who	O
+was	O
+on	O
+treatment	O
+with	O
+multiple	O
+second	O
+-	O
+line	O
+anti	O
+-	O
+tuberculous	O
+drugs	O
+including	O
+linezolid	O
+and	O
+ethambutol	O
+for	O
+extensively	B
+drug	I
+-	I
+resistant	I
+tuberculosis	I
+(	O
+XDR	B
+-	I
+TB	I
+)	O
+presented	O
+to	O
+us	O
+with	O
+painless	O
+progressive	O
+loss	B
+of	I
+vision	I
+in	O
+both	O
+eyes	O
+.	O
+
+Color	O
+vision	O
+was	O
+defective	O
+and	O
+fundus	O
+examination	O
+revealed	O
+optic	B
+disc	I
+edema	I
+in	O
+both	O
+eyes	O
+.	O
+
+Ethambutol	O
+-	O
+induced	O
+toxic	B
+optic	I
+neuropathy	I
+was	O
+suspected	O
+and	O
+tablet	O
+ethambutol	O
+was	O
+withdrawn	O
+.	O
+
+Deterioration	B
+of	I
+vision	I
+occurred	O
+despite	O
+withdrawal	O
+of	O
+ethambutol	O
+.	O
+
+Discontinuation	O
+of	O
+linezolid	O
+resulted	O
+in	O
+marked	O
+improvement	O
+of	O
+vision	O
+.	O
+
+Our	O
+report	O
+emphasizes	O
+the	O
+need	O
+for	O
+monitoring	O
+of	O
+visual	O
+function	O
+in	O
+patients	O
+on	O
+long	O
+-	O
+term	O
+linezolid	O
+treatment	O
+.	O
+
+Resuscitation	O
+with	O
+lipid	O
+,	O
+epinephrine	O
+,	O
+or	O
+both	O
+in	O
+levobupivacaine	O
+-	O
+induced	O
+cardiac	B
+toxicity	I
+in	O
+newborn	O
+piglets	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+optimal	O
+dosing	O
+regimens	O
+of	O
+lipid	O
+emulsion	O
+,	O
+epinephrine	O
+,	O
+or	O
+both	O
+are	O
+not	O
+yet	O
+determined	O
+in	O
+neonates	O
+in	O
+cases	O
+of	O
+local	O
+anaesthetic	O
+systemic	O
+toxicity	B
+(	O
+LAST	O
+)	O
+.	O
+
+METHODS	O
+:	O
+Newborn	O
+piglets	O
+received	O
+levobupivacaine	O
+until	O
+cardiovascular	B
+collapse	I
+occurred	O
+.	O
+
+Standard	O
+cardiopulmonary	O
+resuscitation	O
+was	O
+started	O
+and	O
+electrocardiogram	O
+(	O
+ECG	O
+)	O
+was	O
+monitored	O
+for	O
+ventricular	B
+tachycardia	I
+,	O
+fibrillation	B
+,	O
+or	O
+QRS	O
+prolongation	O
+.	O
+
+Piglets	O
+were	O
+then	O
+randomly	O
+allocated	O
+to	O
+four	O
+groups	O
+:	O
+control	O
+(	O
+saline	O
+)	O
+,	O
+Intralipid	O
+(	O
+)	O
+alone	O
+,	O
+epinephrine	O
+alone	O
+,	O
+or	O
+a	O
+combination	O
+of	O
+Intralipd	O
+plus	O
+epinephrine	O
+.	O
+
+Resuscitation	O
+continued	O
+for	O
+30	O
+min	O
+or	O
+until	O
+there	O
+was	O
+a	O
+return	O
+of	O
+spontaneous	O
+circulation	O
+(	O
+ROSC	O
+)	O
+accompanied	O
+by	O
+a	O
+mean	O
+arterial	O
+pressure	O
+at	O
+or	O
+superior	O
+to	O
+the	O
+baseline	O
+pressure	O
+and	O
+normal	O
+sinus	O
+rhythm	O
+for	O
+a	O
+period	O
+of	O
+30	O
+min	O
+.	O
+
+RESULTS	O
+:	O
+ROSC	O
+was	O
+achieved	O
+in	O
+only	O
+one	O
+of	O
+the	O
+control	O
+piglets	O
+compared	O
+with	O
+most	O
+of	O
+the	O
+treated	O
+piglets	O
+.	O
+
+Mortality	O
+was	O
+not	O
+significantly	O
+different	O
+between	O
+the	O
+three	O
+treatment	O
+groups	O
+,	O
+but	O
+was	O
+significantly	O
+lower	O
+in	O
+all	O
+the	O
+treatment	O
+groups	O
+compared	O
+with	O
+control	O
+.	O
+
+The	O
+number	O
+of	O
+ECG	O
+abnormalities	O
+was	O
+zero	O
+in	O
+the	O
+Intralipid	O
+only	O
+group	O
+,	O
+but	O
+14	O
+and	O
+17	O
+,	O
+respectively	O
+,	O
+in	O
+the	O
+epinephrine	O
+and	O
+epinephrine	O
+plus	O
+lipid	O
+groups	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Lipid	O
+emulsion	O
+with	O
+or	O
+without	O
+epinephrine	O
+,	O
+or	O
+epinephrine	O
+alone	O
+were	O
+equally	O
+effective	O
+in	O
+achieving	O
+a	O
+return	O
+to	O
+spontaneous	O
+circulation	O
+in	O
+this	O
+model	O
+of	O
+LAST	O
+.	O
+
+Epinephrine	O
+alone	O
+or	O
+in	O
+combination	O
+with	O
+lipid	O
+was	O
+associated	O
+with	O
+an	O
+increased	O
+number	O
+of	O
+ECG	O
+abnormalities	O
+compared	O
+with	O
+lipid	O
+emulsion	O
+alone	O
+.	O
+
+Incidence	O
+of	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+type	I
+II	I
+and	O
+postoperative	O
+recovery	O
+of	O
+platelet	O
+count	O
+in	O
+liver	O
+graft	O
+recipients	O
+:	O
+a	O
+retrospective	O
+cohort	O
+analysis	O
+.	O
+
+BACKGROUND	O
+:	O
+Thrombocytopenia	B
+in	O
+patients	O
+with	O
+end	B
+-	I
+stage	I
+liver	I
+disease	I
+is	O
+a	O
+common	O
+disorder	O
+caused	O
+mainly	O
+by	O
+portal	B
+hypertension	I
+,	O
+low	O
+levels	O
+of	O
+thrombopoetin	O
+,	O
+and	O
+endotoxemia	B
+.	O
+
+The	O
+impact	O
+of	O
+immune	O
+-	O
+mediated	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+type	I
+II	I
+(	O
+HIT	B
+type	I
+II	I
+)	O
+as	O
+a	O
+cause	O
+of	O
+thrombocytopenia	B
+after	O
+liver	O
+transplantation	O
+is	O
+not	O
+yet	O
+understood	O
+,	O
+with	O
+few	O
+literature	O
+citations	O
+reporting	O
+contradictory	O
+results	O
+.	O
+
+The	O
+aim	O
+of	O
+our	O
+study	O
+was	O
+to	O
+demonstrate	O
+the	O
+perioperative	O
+course	O
+of	O
+thrombocytopenia	B
+after	O
+liver	O
+transplantation	O
+and	O
+determine	O
+the	O
+occurrence	O
+of	O
+clinical	O
+HIT	B
+type	I
+II	I
+.	O
+
+METHOD	O
+:	O
+We	O
+retrospectively	O
+evaluated	O
+the	O
+medical	O
+records	O
+of	O
+205	O
+consecutive	O
+adult	O
+patients	O
+who	O
+underwent	O
+full	O
+-	O
+size	O
+liver	O
+transplantation	O
+between	O
+January	O
+2006	O
+and	O
+December	O
+2010	O
+due	O
+to	O
+end	B
+-	I
+stage	I
+or	I
+malignant	I
+liver	I
+disease	I
+.	O
+
+Preoperative	O
+platelet	O
+count	O
+,	O
+postoperative	O
+course	O
+of	O
+platelets	O
+,	O
+and	O
+clinical	O
+signs	O
+of	O
+HIT	B
+type	I
+II	I
+were	O
+analyzed	O
+.	O
+
+RESULTS	O
+:	O
+A	O
+total	O
+of	O
+155	O
+(	O
+75	O
+.	O
+6	O
+%	O
+)	O
+of	O
+205	O
+patients	O
+had	O
+thrombocytopenia	B
+before	O
+transplantation	O
+,	O
+significantly	O
+influenced	O
+by	O
+Model	O
+of	O
+End	B
+-	I
+Stage	I
+Liver	I
+Disease	I
+score	O
+and	O
+liver	B
+cirrhosis	I
+.	O
+
+The	O
+platelet	O
+count	O
+exceeded	O
+100	O
+,	O
+000	O
+/	O
+uL	O
+in	O
+most	O
+of	O
+the	O
+patients	O
+(	O
+n	O
+=	O
+193	O
+)	O
+at	O
+a	O
+medium	O
+of	O
+7	O
+d	O
+.	O
+
+Regarding	O
+HIT	B
+II	I
+,	O
+there	O
+were	O
+four	O
+(	O
+1	O
+.	O
+95	O
+%	O
+)	O
+patients	O
+with	O
+a	O
+background	O
+of	O
+HIT	B
+type	I
+II	I
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+incidence	O
+of	O
+HIT	B
+in	O
+patients	O
+with	O
+end	B
+-	I
+stage	I
+hepatic	I
+failure	I
+is	O
+,	O
+with	O
+about	O
+1	O
+.	O
+95	O
+%	O
+,	O
+rare	O
+.	O
+
+For	O
+further	O
+reduction	O
+of	O
+HIT	B
+type	I
+II	I
+,	O
+the	O
+use	O
+of	O
+intravenous	O
+heparin	O
+should	O
+be	O
+avoided	O
+and	O
+the	O
+prophylactic	O
+anticoagulation	O
+should	O
+be	O
+performed	O
+with	O
+low	O
+-	O
+molecular	O
+-	O
+weight	O
+heparin	O
+after	O
+normalization	O
+of	O
+platelet	O
+count	O
+.	O
+
+Takotsubo	B
+syndrome	I
+(	O
+or	O
+apical	B
+ballooning	I
+syndrome	I
+)	O
+secondary	O
+to	O
+Zolmitriptan	O
+.	O
+
+Takotsubo	B
+syndrome	I
+(	O
+TS	B
+)	O
+,	O
+also	O
+known	O
+as	O
+broken	B
+heart	I
+syndrome	I
+,	O
+is	O
+characterized	O
+by	O
+left	O
+ventricle	O
+apical	O
+ballooning	O
+with	O
+elevated	O
+cardiac	O
+biomarkers	O
+and	O
+electrocardiographic	O
+changes	O
+suggestive	O
+of	O
+an	O
+acute	B
+coronary	I
+syndrome	I
+(	O
+ie	O
+,	O
+ST	O
+-	O
+segment	O
+elevation	O
+,	O
+T	O
+wave	O
+inversions	O
+,	O
+and	O
+pathologic	O
+Q	O
+waves	O
+)	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+54	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+medical	O
+history	O
+of	O
+mitral	B
+valve	I
+prolapse	I
+and	O
+migraines	B
+,	O
+who	O
+was	O
+admitted	O
+to	O
+the	O
+hospital	O
+for	O
+substernal	O
+chest	B
+pain	I
+and	O
+electrocardiogram	O
+demonstrated	O
+1	O
+/	O
+2	O
+mm	O
+ST	O
+-	O
+segment	O
+elevation	O
+in	O
+leads	O
+II	O
+,	O
+III	O
+,	O
+aVF	O
+,	O
+V5	O
+,	O
+and	O
+V6	O
+and	O
+positive	O
+troponin	O
+I	O
+.	O
+
+Emergent	O
+coronary	O
+angiogram	O
+revealed	O
+normal	O
+coronary	O
+arteries	O
+with	O
+moderately	O
+reduced	O
+left	O
+ventricular	O
+ejection	O
+fraction	O
+with	O
+wall	O
+motion	O
+abnormalities	O
+consistent	O
+with	O
+TS	B
+.	O
+
+Detailed	O
+history	O
+obtained	O
+retrospectively	O
+revealed	O
+that	O
+the	O
+patient	O
+took	O
+zolmitriptan	O
+sparingly	O
+only	O
+when	O
+she	O
+had	O
+migraines	B
+.	O
+
+But	O
+before	O
+this	O
+event	O
+,	O
+she	O
+was	O
+taking	O
+zolmitriptan	O
+2	O
+-	O
+3	O
+times	O
+daily	O
+for	O
+several	O
+days	O
+because	O
+of	O
+a	O
+persistent	O
+migraine	B
+headache	I
+.	O
+
+She	O
+otherwise	O
+reported	O
+that	O
+she	O
+is	O
+quite	O
+active	O
+,	O
+rides	O
+horses	O
+,	O
+and	O
+does	O
+show	O
+jumping	O
+without	O
+any	O
+limitations	O
+in	O
+her	O
+physical	O
+activity	O
+.	O
+
+There	O
+was	O
+no	O
+evidence	O
+of	O
+any	O
+recent	O
+stress	O
+or	O
+status	B
+migrainosus	I
+.	O
+
+Extensive	O
+literature	O
+search	O
+revealed	O
+multiple	O
+cases	O
+of	O
+coronary	B
+artery	I
+vasospasm	I
+secondary	O
+to	O
+zolmitriptan	O
+,	O
+but	O
+none	O
+of	O
+the	O
+cases	O
+were	O
+associated	O
+with	O
+TS	B
+.	O
+
+Depression	B
+,	O
+impulsiveness	B
+,	O
+sleep	O
+,	O
+and	O
+memory	O
+in	O
+past	O
+and	O
+present	O
+polydrug	O
+users	O
+of	O
+3	O
+,	O
+4	O
+-	O
+methylenedioxymethamphetamine	O
+(	O
+MDMA	O
+,	O
+ecstasy	O
+)	O
+.	O
+
+RATIONALE	O
+:	O
+Ecstasy	O
+(	O
+3	O
+,	O
+4	O
+-	O
+methylenedioxymethamphetamine	O
+,	O
+MDMA	O
+)	O
+is	O
+a	O
+worldwide	O
+recreational	O
+drug	O
+of	O
+abuse	O
+.	O
+
+Unfortunately	O
+,	O
+the	O
+results	O
+from	O
+human	O
+research	O
+investigating	O
+its	O
+psychological	O
+effects	O
+have	O
+been	O
+inconsistent	O
+.	O
+
+OBJECTIVES	O
+:	O
+The	O
+present	O
+study	O
+aimed	O
+to	O
+be	O
+the	O
+largest	O
+to	O
+date	O
+in	O
+sample	O
+size	O
+and	O
+5HT	O
+-	O
+related	O
+behaviors	O
+;	O
+the	O
+first	O
+to	O
+compare	O
+present	O
+ecstasy	O
+users	O
+with	O
+past	O
+users	O
+after	O
+an	O
+abstinence	O
+of	O
+4	O
+or	O
+more	O
+years	O
+,	O
+and	O
+the	O
+first	O
+to	O
+include	O
+robust	O
+controls	O
+for	O
+other	O
+recreational	O
+substances	O
+.	O
+
+METHODS	O
+:	O
+A	O
+sample	O
+of	O
+997	O
+participants	O
+(	O
+52	O
+%	O
+male	O
+)	O
+was	O
+recruited	O
+to	O
+four	O
+control	O
+groups	O
+(	O
+non	O
+-	O
+drug	O
+(	O
+ND	O
+)	O
+,	O
+alcohol	O
+/	O
+nicotine	O
+(	O
+AN	O
+)	O
+,	O
+cannabis	O
+/	O
+alcohol	O
+/	O
+nicotine	O
+(	O
+CAN	O
+)	O
+,	O
+non	O
+-	O
+ecstasy	O
+polydrug	O
+(	O
+PD	O
+)	O
+)	O
+,	O
+and	O
+two	O
+ecstasy	O
+polydrug	O
+groups	O
+(	O
+present	O
+(	O
+MDMA	O
+)	O
+and	O
+past	O
+users	O
+(	O
+EX	O
+-	O
+MDMA	O
+)	O
+.	O
+
+Participants	O
+completed	O
+a	O
+drug	O
+history	O
+questionnaire	O
+,	O
+Beck	O
+Depression	B
+Inventory	O
+,	O
+Barratt	O
+Impulsiveness	B
+Scale	O
+,	O
+Pittsburgh	O
+Sleep	O
+Quality	O
+Index	O
+,	O
+and	O
+Wechsler	O
+Memory	O
+Scale	O
+-	O
+Revised	O
+which	O
+,	O
+in	O
+total	O
+,	O
+provided	O
+13	O
+psychometric	O
+measures	O
+.	O
+
+RESULTS	O
+:	O
+While	O
+the	O
+CAN	O
+and	O
+PD	O
+groups	O
+tended	O
+to	O
+record	O
+greater	O
+deficits	O
+than	O
+the	O
+non	O
+-	O
+drug	O
+controls	O
+,	O
+the	O
+MDMA	O
+and	O
+EX	O
+-	O
+MDMA	O
+groups	O
+recorded	O
+greater	O
+deficits	O
+than	O
+all	O
+the	O
+control	O
+groups	O
+on	O
+ten	O
+of	O
+the	O
+13	O
+psychometric	O
+measures	O
+.	O
+
+Strikingly	O
+,	O
+despite	O
+prolonged	O
+abstinence	O
+(	O
+mean	O
+,	O
+4	O
+.	O
+98	O
+;	O
+range	O
+,	O
+4	O
+-	O
+9	O
+years	O
+)	O
+,	O
+past	O
+ecstasy	O
+users	O
+showed	O
+few	O
+signs	O
+of	O
+recovery	O
+.	O
+
+Compared	O
+with	O
+present	O
+ecstasy	O
+users	O
+,	O
+the	O
+past	O
+users	O
+showed	O
+no	O
+change	O
+for	O
+ten	O
+measures	O
+,	O
+increased	O
+impairment	O
+for	O
+two	O
+measures	O
+,	O
+and	O
+improvement	O
+on	O
+just	O
+one	O
+measure	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Given	O
+this	O
+record	O
+of	O
+impaired	B
+memory	I
+and	O
+clinically	O
+significant	O
+levels	O
+of	O
+depression	B
+,	O
+impulsiveness	B
+,	O
+and	O
+sleep	B
+disturbance	I
+,	O
+the	O
+prognosis	O
+for	O
+the	O
+current	O
+generation	O
+of	O
+ecstasy	O
+users	O
+is	O
+a	O
+major	O
+cause	O
+for	O
+concern	O
+.	O
+
+Association	O
+of	O
+common	O
+genetic	O
+variants	O
+of	O
+HOMER1	O
+gene	O
+with	O
+levodopa	O
+adverse	O
+effects	O
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+patients	O
+.	O
+
+Levodopa	O
+is	O
+the	O
+most	O
+effective	O
+symptomatic	O
+therapy	O
+for	O
+Parkinson	B
+'	I
+s	I
+disease	I
+,	O
+but	O
+its	O
+chronic	O
+use	O
+could	O
+lead	O
+to	O
+chronic	O
+adverse	O
+outcomes	O
+,	O
+such	O
+as	O
+motor	O
+fluctuations	O
+,	O
+dyskinesia	B
+and	O
+visual	B
+hallucinations	I
+.	O
+
+HOMER1	O
+is	O
+a	O
+protein	O
+with	O
+pivotal	O
+function	O
+in	O
+glutamate	O
+transmission	O
+,	O
+which	O
+has	O
+been	O
+related	O
+to	O
+the	O
+pathogenesis	O
+of	O
+these	O
+complications	O
+.	O
+
+This	O
+study	O
+investigates	O
+whether	O
+polymorphisms	O
+in	O
+the	O
+HOMER1	O
+gene	O
+promoter	O
+region	O
+are	O
+associated	O
+with	O
+the	O
+occurrence	O
+of	O
+the	O
+chronic	O
+complications	O
+of	O
+levodopa	O
+therapy	O
+.	O
+
+A	O
+total	O
+of	O
+205	O
+patients	O
+with	O
+idiopathic	B
+Parkinson	I
+'	I
+s	I
+disease	I
+were	O
+investigated	O
+.	O
+
+Patients	O
+were	O
+genotyped	O
+for	O
+rs4704559	O
+,	O
+rs10942891	O
+and	O
+rs4704560	O
+by	O
+allelic	O
+discrimination	O
+with	O
+Taqman	O
+assays	O
+.	O
+
+The	O
+rs4704559	O
+G	O
+allele	O
+was	O
+associated	O
+with	O
+a	O
+lower	O
+prevalence	O
+of	O
+dyskinesia	B
+(	O
+prevalence	O
+ratio	O
+(	O
+PR	O
+)	O
+=	O
+0	O
+.	O
+615	O
+,	O
+95	O
+%	O
+confidence	O
+interval	O
+(	O
+CI	O
+)	O
+0	O
+.	O
+426	O
+-	O
+0	O
+.	O
+887	O
+,	O
+P	O
+=	O
+0	O
+.	O
+009	O
+)	O
+and	O
+visual	B
+hallucinations	I
+(	O
+PR	O
+=	O
+0	O
+.	O
+515	O
+,	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+295	O
+-	O
+0	O
+.	O
+899	O
+,	O
+P	O
+=	O
+0	O
+.	O
+020	O
+)	O
+.	O
+
+Our	O
+data	O
+suggest	O
+that	O
+HOMER1	O
+rs4704559	O
+G	O
+allele	O
+has	O
+a	O
+protective	O
+role	O
+for	O
+the	O
+development	O
+of	O
+levodopa	O
+adverse	O
+effects	O
+.	O
+
+Crocin	O
+improves	O
+lipid	O
+dysregulation	O
+in	O
+subacute	O
+diazinon	O
+exposure	O
+through	O
+ERK1	O
+/	O
+2	O
+pathway	O
+in	O
+rat	O
+liver	O
+.	O
+
+INTRODUCTION	O
+:	O
+Diazinon	O
+Yis	O
+one	O
+of	O
+the	O
+most	O
+broadly	O
+used	O
+organophosphorus	O
+insecticides	O
+in	O
+agriculture	O
+.	O
+
+It	O
+has	O
+been	O
+shown	O
+that	O
+exposure	O
+to	O
+diazinon	O
+may	O
+interfere	O
+with	O
+lipid	O
+metabolism	O
+.	O
+
+Moreover	O
+,	O
+the	O
+hypolipidemic	O
+effect	O
+of	O
+crocin	O
+has	O
+been	O
+established	O
+.	O
+
+Earlier	O
+studies	O
+revealed	O
+the	O
+major	O
+role	O
+of	O
+Extracellular	O
+signal	O
+-	O
+regulated	O
+kinase	O
+(	O
+ERK	O
+)	O
+pathways	O
+in	O
+low	O
+-	O
+density	O
+lipoprotein	O
+receptor	O
+(	O
+LDLr	O
+)	O
+expression	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+evaluate	O
+changes	O
+in	O
+the	O
+regulation	O
+of	O
+lipid	O
+metabolism	O
+,	O
+ERK	O
+and	O
+LDLr	O
+expression	O
+in	O
+the	O
+liver	O
+of	O
+rats	O
+exposed	O
+to	O
+subacute	O
+diazinon	O
+.	O
+
+Furthermore	O
+ameliorating	O
+effect	O
+of	O
+crocin	O
+on	O
+diazinon	O
+induced	O
+disturbed	O
+cholesterol	O
+homeostasis	O
+was	O
+studied	O
+.	O
+
+METHODS	O
+:	O
+24	O
+Rats	O
+were	O
+divided	O
+into	O
+4	O
+groups	O
+and	O
+received	O
+following	O
+treatments	O
+for	O
+4	O
+weeks	O
+;	O
+Corn	O
+oil	O
+(	O
+control	O
+)	O
+,	O
+diazinon	O
+(	O
+15mg	O
+/	O
+kg	O
+per	O
+day	O
+,	O
+orally	O
+)	O
+and	O
+crocin	O
+(	O
+12	O
+.	O
+5	O
+and	O
+25mg	O
+/	O
+kg	O
+per	O
+day	O
+,	O
+intraperitoneally	O
+)	O
+in	O
+combination	O
+with	O
+diazinon	O
+(	O
+15	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+The	O
+levels	O
+of	O
+cholesterol	O
+,	O
+triglyceride	O
+and	O
+LDL	O
+in	O
+blood	O
+of	O
+rats	O
+were	O
+analyzed	O
+.	O
+
+Moreover	O
+mRNA	O
+levels	O
+of	O
+LDLr	O
+and	O
+ERK1	O
+/	O
+2	O
+as	O
+well	O
+as	O
+protein	O
+levels	O
+of	O
+total	O
+and	O
+activated	O
+forms	O
+of	O
+ERK1	O
+/	O
+2	O
+in	O
+rat	O
+liver	O
+were	O
+evaluated	O
+by	O
+Western	O
+blotting	O
+and	O
+quantitative	O
+real	O
+time	O
+polymerase	O
+chain	O
+reaction	O
+analysis	O
+.	O
+
+RESULTS	O
+:	O
+Our	O
+data	O
+showed	O
+that	O
+subacute	O
+exposure	O
+to	O
+diazinon	O
+significantly	O
+increased	O
+concentrations	O
+of	O
+cholesterol	O
+,	O
+triglyceride	O
+and	O
+LDL	O
+.	O
+
+Moreover	O
+diazinon	O
+decreased	O
+ERK1	O
+/	O
+2	O
+protein	O
+phosphorylation	O
+and	O
+LDLr	O
+transcript	O
+.	O
+
+Crocin	O
+reduced	O
+inhibition	O
+of	O
+ERK	O
+activation	O
+and	O
+diazinon	O
+-	O
+induced	O
+hyperlipemia	B
+and	O
+increased	O
+levels	O
+of	O
+LDLr	O
+transcript	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Crocin	O
+may	O
+be	O
+considered	O
+as	O
+a	O
+novel	O
+protective	O
+agent	O
+in	O
+diazinon	O
+-	O
+induced	O
+hyperlipemia	B
+through	O
+modulating	O
+of	O
+ERK	O
+pathway	O
+and	O
+increase	O
+of	O
+LDLr	O
+expression	O
+.	O
+
+GEM	O
+-	O
+P	O
+chemotherapy	O
+is	O
+active	O
+in	O
+the	O
+treatment	O
+of	O
+relapsed	O
+Hodgkin	B
+lymphoma	I
+.	O
+
+Hodgkin	B
+lymphoma	I
+(	O
+HL	B
+)	O
+is	O
+a	O
+relatively	O
+chemosensitive	O
+malignancy	B
+.	O
+
+However	O
+,	O
+for	O
+those	O
+who	O
+relapse	O
+,	O
+high	O
+-	O
+dose	O
+chemotherapy	O
+with	O
+autologous	O
+stem	O
+cell	O
+transplant	O
+is	O
+the	O
+treatment	O
+of	O
+choice	O
+which	O
+relies	O
+on	O
+adequate	O
+disease	O
+control	O
+with	O
+salvage	O
+chemotherapy	O
+.	O
+
+Regimens	O
+commonly	O
+used	O
+often	O
+require	O
+inpatient	O
+administration	O
+and	O
+can	O
+be	O
+difficult	O
+to	O
+deliver	O
+due	O
+to	O
+toxicity	B
+.	O
+
+Gemcitabine	O
+and	O
+cisplatin	O
+have	O
+activity	O
+in	O
+HL	B
+,	O
+non	O
+-	O
+overlapping	O
+toxicity	B
+with	O
+first	O
+-	O
+line	O
+chemotherapeutics	O
+,	O
+and	O
+may	O
+be	O
+delivered	O
+in	O
+an	O
+outpatient	O
+setting	O
+.	O
+
+In	O
+this	O
+retrospective	O
+single	O
+-	O
+centre	O
+analysis	O
+,	O
+patients	O
+with	O
+relapsed	O
+or	O
+refractory	O
+HL	B
+treated	O
+with	O
+gemcitabine	O
+1	O
+,	O
+000	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+day	O
+(	O
+D	O
+)	O
+1	O
+,	O
+D8	O
+and	O
+D15	O
+;	O
+methylprednisolone	O
+1	O
+,	O
+000	O
+mg	O
+D1	O
+-	O
+5	O
+;	O
+and	O
+cisplatin	O
+100	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+D15	O
+,	O
+every	O
+28	O
+days	O
+(	O
+GEM	O
+-	O
+P	O
+)	O
+were	O
+included	O
+.	O
+
+Demographic	O
+,	O
+survival	O
+,	O
+response	O
+and	O
+toxicity	B
+data	O
+were	O
+recorded	O
+.	O
+
+Forty	O
+-	O
+one	O
+eligible	O
+patients	O
+were	O
+identified	O
+:	O
+median	O
+age	O
+27	O
+.	O
+
+One	O
+hundred	O
+and	O
+twenty	O
+-	O
+two	O
+cycles	O
+of	O
+GEM	O
+-	O
+P	O
+were	O
+administered	O
+in	O
+total	O
+(	O
+median	O
+3	O
+cycles	O
+;	O
+range	O
+1	O
+-	O
+6	O
+)	O
+.	O
+
+Twenty	O
+of	O
+41	O
+(	O
+48	O
+%	O
+)	O
+patients	O
+received	O
+GEM	O
+-	O
+P	O
+as	O
+second	O
+-	O
+line	O
+treatment	O
+and	O
+11	O
+/	O
+41	O
+(	O
+27	O
+%	O
+)	O
+as	O
+third	O
+-	O
+line	O
+therapy	O
+.	O
+
+Overall	O
+response	O
+rate	O
+(	O
+ORR	O
+)	O
+to	O
+GEM	O
+-	O
+P	O
+in	O
+the	O
+entire	O
+cohort	O
+was	O
+80	O
+%	O
+(	O
+complete	O
+response	O
+(	O
+CR	O
+)	O
+37	O
+%	O
+,	O
+partial	O
+response	O
+44	O
+%	O
+)	O
+with	O
+14	O
+/	O
+15	O
+CR	O
+confirmed	O
+as	O
+a	O
+metabolic	O
+CR	O
+on	O
+PET	O
+and	O
+ORR	O
+of	O
+85	O
+%	O
+in	O
+the	O
+20	O
+second	O
+-	O
+line	O
+patients	O
+.	O
+
+The	O
+most	O
+common	O
+grade	O
+3	O
+/	O
+4	O
+toxicities	B
+were	O
+haematological	O
+:	O
+neutropenia	B
+54	O
+%	O
+and	O
+thrombocytopenia	B
+51	O
+%	O
+.	O
+
+Median	O
+follow	O
+-	O
+up	O
+from	O
+the	O
+start	O
+of	O
+GEM	O
+-	O
+P	O
+was	O
+4	O
+.	O
+5	O
+years	O
+.	O
+
+Following	O
+GEM	O
+-	O
+P	O
+,	O
+5	O
+-	O
+year	O
+progression	O
+-	O
+free	O
+survival	O
+was	O
+46	O
+%	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+(	O
+CI	O
+)	O
+,	O
+30	O
+-	O
+62	O
+%	O
+)	O
+and	O
+5	O
+-	O
+year	O
+overall	O
+survival	O
+was	O
+59	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+,	O
+43	O
+-	O
+74	O
+%	O
+)	O
+.	O
+
+Fourteen	O
+of	O
+41	O
+patients	O
+proceeded	O
+directly	O
+to	O
+autologous	O
+transplant	O
+.	O
+
+GEM	O
+-	O
+P	O
+is	O
+a	O
+salvage	O
+chemotherapy	O
+with	O
+relatively	O
+high	O
+response	O
+rates	O
+,	O
+leading	O
+to	O
+successful	O
+transplantation	O
+in	O
+appropriate	O
+patients	O
+,	O
+in	O
+the	O
+treatment	O
+of	O
+relapsed	O
+or	O
+refractory	O
+HL	B
+.	O
+
+Basal	O
+functioning	O
+of	O
+the	O
+hypothalamic	O
+-	O
+pituitary	O
+-	O
+adrenal	O
+(	O
+HPA	O
+)	O
+axis	O
+and	O
+psychological	O
+distress	O
+in	O
+recreational	O
+ecstasy	O
+polydrug	O
+users	O
+.	O
+
+RATIONALE	O
+:	O
+Ecstasy	O
+(	O
+MDMA	O
+)	O
+is	O
+a	O
+psychostimulant	O
+drug	O
+which	O
+is	O
+increasingly	O
+associated	O
+with	O
+psychobiological	B
+dysfunction	I
+.	O
+
+While	O
+some	O
+recent	O
+studies	O
+suggest	O
+acute	O
+changes	O
+in	O
+neuroendocrine	O
+function	O
+,	O
+less	O
+is	O
+known	O
+about	O
+long	O
+-	O
+term	O
+changes	O
+in	O
+HPA	O
+functionality	O
+in	O
+recreational	O
+users	O
+.	O
+
+OBJECTIVES	O
+:	O
+The	O
+current	O
+study	O
+is	O
+the	O
+first	O
+to	O
+explore	O
+the	O
+effects	O
+of	O
+ecstasy	O
+-	O
+polydrug	O
+use	O
+on	O
+psychological	O
+distress	O
+and	O
+basal	O
+functioning	O
+of	O
+the	O
+HPA	O
+axis	O
+through	O
+assessing	O
+the	O
+secretion	O
+of	O
+cortisol	O
+across	O
+the	O
+diurnal	O
+period	O
+.	O
+
+METHOD	O
+:	O
+Seventy	O
+-	O
+six	O
+participants	O
+(	O
+21	O
+nonusers	O
+,	O
+29	O
+light	O
+ecstasy	O
+-	O
+polydrug	O
+users	O
+,	O
+26	O
+heavy	O
+ecstasy	O
+-	O
+polydrug	O
+users	O
+)	O
+completed	O
+a	O
+substance	O
+use	O
+inventory	O
+and	O
+measures	O
+of	O
+psychological	O
+distress	O
+at	O
+baseline	O
+,	O
+then	O
+two	O
+consecutive	O
+days	O
+of	O
+cortisol	O
+sampling	O
+(	O
+on	O
+awakening	O
+,	O
+30	O
+min	O
+post	O
+awakening	O
+,	O
+between	O
+1400	O
+and	O
+1600	O
+hours	O
+and	O
+pre	O
+bedtime	O
+)	O
+.	O
+
+On	O
+day	O
+2	O
+,	O
+participants	O
+also	O
+attended	O
+the	O
+laboratory	O
+to	O
+complete	O
+a	O
+20	O
+-	O
+min	O
+multitasking	O
+stressor	O
+.	O
+
+RESULTS	O
+:	O
+Both	O
+user	O
+groups	O
+exhibited	O
+significantly	O
+greater	O
+levels	O
+of	O
+anxiety	B
+and	O
+depression	B
+than	O
+nonusers	O
+.	O
+
+On	O
+day	O
+1	O
+,	O
+all	O
+participants	O
+exhibited	O
+a	O
+typical	O
+cortisol	O
+profile	O
+,	O
+though	O
+light	O
+users	O
+had	O
+significantly	O
+elevated	O
+levels	O
+pre	O
+-	O
+bed	O
+.	O
+
+On	O
+day	O
+2	O
+,	O
+heavy	O
+users	O
+demonstrated	O
+elevated	O
+levels	O
+upon	O
+awakening	O
+and	O
+all	O
+ecstasy	O
+-	O
+polydrug	O
+users	O
+demonstrated	O
+elevated	O
+pre	O
+-	O
+bed	O
+levels	O
+compared	O
+to	O
+non	O
+-	O
+users	O
+.	O
+
+Significant	O
+between	O
+group	O
+differences	O
+were	O
+also	O
+observed	O
+in	O
+afternoon	O
+cortisol	O
+levels	O
+and	O
+in	O
+overall	O
+cortisol	O
+secretion	O
+across	O
+the	O
+day	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+increases	O
+in	O
+anxiety	B
+and	O
+depression	B
+are	O
+in	O
+line	O
+with	O
+previous	O
+observations	O
+in	O
+recreational	O
+ecstasy	O
+-	O
+polydrug	O
+users	O
+.	O
+
+Dysregulated	O
+diurnal	O
+cortisol	O
+may	O
+be	O
+indicative	O
+of	O
+inappropriate	O
+anticipation	O
+of	O
+forthcoming	O
+demands	O
+and	O
+hypersecretion	O
+may	O
+lead	O
+to	O
+the	O
+increased	O
+psychological	O
+and	O
+physical	O
+morbidity	O
+associated	O
+with	O
+heavy	O
+recreational	O
+use	O
+of	O
+ecstasy	O
+.	O
+
+Ifosfamide	O
+related	O
+encephalopathy	B
+:	O
+the	O
+need	O
+for	O
+a	O
+timely	O
+EEG	O
+evaluation	O
+.	O
+
+BACKGROUND	O
+:	O
+Ifosfamide	O
+is	O
+an	O
+alkylating	O
+agent	O
+useful	O
+in	O
+the	O
+treatment	O
+of	O
+a	O
+wide	O
+range	O
+of	O
+cancers	B
+including	O
+sarcomas	B
+,	O
+lymphoma	B
+,	O
+gynecologic	B
+and	I
+testicular	I
+cancers	I
+.	O
+
+Encephalopathy	B
+has	O
+been	O
+reported	O
+in	O
+10	O
+-	O
+40	O
+%	O
+of	O
+patients	O
+receiving	O
+high	O
+-	O
+dose	O
+IV	O
+ifosfamide	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+highlight	O
+the	O
+role	O
+of	O
+electroencephalogram	O
+(	O
+EEG	O
+)	O
+in	O
+the	O
+early	O
+detection	O
+and	O
+management	O
+of	O
+ifosfamide	O
+related	O
+encephalopathy	B
+.	O
+
+METHODS	O
+:	O
+Retrospective	O
+chart	O
+review	O
+including	O
+clinical	O
+data	O
+and	O
+EEG	O
+recordings	O
+was	O
+done	O
+on	O
+five	O
+patients	O
+,	O
+admitted	O
+to	O
+MD	O
+Anderson	O
+Cancer	B
+Center	O
+between	O
+years	O
+2009	O
+and	O
+2012	O
+,	O
+who	O
+developed	O
+ifosfamide	O
+related	O
+acute	O
+encephalopathy	B
+.	O
+
+RESULTS	O
+:	O
+All	O
+five	O
+patients	O
+experienced	O
+symptoms	O
+of	O
+encephalopathy	B
+soon	O
+after	O
+(	O
+within	O
+12	O
+h	O
+-	O
+2	O
+days	O
+)	O
+receiving	O
+ifosfamide	O
+.	O
+
+Two	O
+patients	O
+developed	O
+generalized	O
+convulsions	B
+while	O
+one	O
+patient	O
+developed	O
+continuous	O
+non	B
+-	I
+convulsive	I
+status	I
+epilepticus	I
+(	O
+NCSE	B
+)	O
+that	O
+required	O
+ICU	O
+admission	O
+and	O
+intubation	O
+.	O
+
+Initial	O
+EEG	O
+showed	O
+epileptiform	O
+discharges	O
+in	O
+three	O
+patients	O
+;	O
+run	O
+of	O
+triphasic	O
+waves	O
+in	O
+one	O
+patient	O
+and	O
+moderate	O
+degree	O
+diffuse	O
+generalized	O
+slowing	O
+.	O
+
+Mixed	O
+pattern	O
+with	O
+the	O
+presence	O
+of	O
+both	O
+sharps	O
+and	O
+triphasic	O
+waves	O
+were	O
+also	O
+noted	O
+.	O
+
+Repeat	O
+EEGs	O
+within	O
+24	O
+_	O
+h	O
+of	O
+symptom	O
+onset	O
+showed	O
+marked	O
+improvement	O
+that	O
+was	O
+correlated	O
+with	O
+clinical	O
+improvement	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Severity	O
+of	O
+ifosfamide	O
+related	O
+encephalopathy	B
+correlates	O
+with	O
+EEG	O
+changes	O
+.	O
+
+We	O
+suggest	O
+a	O
+timely	O
+EEG	O
+evaluation	O
+for	O
+patients	O
+receiving	O
+ifosfamide	O
+who	O
+develop	O
+features	O
+of	O
+encephalopathy	B
+.	O
+
+Incidence	O
+of	O
+contrast	O
+-	O
+induced	O
+nephropathy	B
+in	O
+hospitalised	O
+patients	O
+with	O
+cancer	B
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+determine	O
+the	O
+frequency	O
+of	O
+and	O
+possible	O
+factors	O
+related	O
+to	O
+contrast	O
+-	O
+induced	O
+nephropathy	B
+(	O
+CIN	O
+)	O
+in	O
+hospitalised	O
+patients	O
+with	O
+cancer	B
+.	O
+
+METHODS	O
+:	O
+Ninety	O
+adult	O
+patients	O
+were	O
+enrolled	O
+.	O
+
+Patients	O
+with	O
+risk	O
+factors	O
+for	O
+acute	B
+renal	I
+failure	I
+were	O
+excluded	O
+.	O
+
+Blood	O
+samples	O
+were	O
+examined	O
+the	O
+day	O
+before	O
+contrast	O
+-	O
+enhanced	O
+computed	O
+tomography	O
+(	O
+CT	O
+)	O
+and	O
+serially	O
+for	O
+3	O
+days	O
+thereafter	O
+.	O
+
+CIN	O
+was	O
+defined	O
+as	O
+an	O
+increase	O
+in	O
+serum	O
+creatinine	O
+(	O
+Cr	O
+)	O
+of	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+dl	O
+or	O
+more	O
+,	O
+or	O
+elevation	O
+of	O
+Cr	O
+to	O
+25	O
+%	O
+over	O
+baseline	O
+.	O
+
+Relationships	O
+between	O
+CIN	O
+and	O
+possible	O
+risk	O
+factors	O
+were	O
+investigated	O
+.	O
+
+RESULTS	O
+:	O
+CIN	O
+was	O
+detected	O
+in	O
+18	O
+/	O
+90	O
+(	O
+20	O
+%	O
+)	O
+patients	O
+.	O
+
+CIN	O
+developed	O
+in	O
+25	O
+.	O
+5	O
+%	O
+patients	O
+who	O
+underwent	O
+chemotherapy	O
+and	O
+in	O
+11	O
+%	O
+patients	O
+who	O
+did	O
+not	O
+(	O
+P	O
+=	O
+0	O
+.	O
+1	O
+)	O
+.	O
+
+CIN	O
+more	O
+frequently	O
+developed	O
+in	O
+patients	O
+who	O
+had	O
+undergone	O
+CT	O
+within	O
+45	O
+days	O
+after	O
+the	O
+last	O
+chemotherapy	O
+(	O
+P	O
+=	O
+0	O
+.	O
+005	O
+)	O
+;	O
+it	O
+was	O
+also	O
+an	O
+independent	O
+risk	O
+factor	O
+(	O
+P	O
+=	O
+0	O
+.	O
+017	O
+)	O
+.	O
+
+CIN	O
+was	O
+significantly	O
+more	O
+after	O
+treatment	O
+with	O
+bevacizumab	O
+/	O
+irinotecan	O
+(	O
+P	O
+=	O
+0	O
+.	O
+021	O
+)	O
+and	O
+in	O
+patients	O
+with	O
+hypertension	B
+(	O
+P	O
+=	O
+0	O
+.	O
+044	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+incidence	O
+of	O
+CIN	O
+after	O
+CT	O
+in	O
+hospitalised	O
+oncological	O
+patients	O
+was	O
+20	O
+%	O
+.	O
+
+CIN	O
+developed	O
+4	O
+.	O
+5	O
+-	O
+times	O
+more	O
+frequently	O
+in	O
+patients	O
+with	O
+cancer	B
+who	O
+had	O
+undergone	O
+recent	O
+chemotherapy	O
+.	O
+
+Hypertension	B
+and	O
+the	O
+combination	O
+of	O
+bevacizumab	O
+/	O
+irinotecan	O
+may	O
+be	O
+additional	O
+risk	O
+factors	O
+for	O
+CIN	O
+development	O
+.	O
+
+KEY	O
+POINTS	O
+:	O
+.	O
+
+Contrast	O
+-	O
+induced	O
+nephropathy	B
+(	O
+CIN	O
+)	O
+is	O
+a	O
+concern	O
+for	O
+oncological	O
+patients	O
+undergoing	O
+CT	O
+.	O
+
+.	O
+CIN	O
+occurs	O
+more	O
+often	O
+when	O
+CT	O
+is	O
+performed	O
+<	O
+45	O
+days	O
+after	O
+chemotherapy	O
+.	O
+
+.	O
+Hypertension	B
+and	O
+treatment	O
+with	O
+bevacizumab	O
+appear	O
+to	O
+be	O
+additional	O
+risk	O
+factors	O
+.	O
+
+Syndrome	B
+of	I
+inappropriate	I
+antidiuretic	I
+hormone	I
+secretion	O
+associated	O
+with	O
+desvenlafaxine	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+syndrome	B
+of	I
+inappropriate	I
+anti	I
+-	I
+diuretic	I
+hormone	I
+(	O
+SIADH	B
+)	O
+secretion	O
+associated	O
+with	O
+desvenlafaxine	O
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+57	O
+-	O
+year	O
+old	O
+female	O
+with	O
+hyponatraemia	B
+.	O
+
+Her	O
+medications	O
+included	O
+desvenlafaxine	O
+,	O
+and	O
+symptoms	O
+included	O
+nausea	B
+,	O
+anxiety	B
+and	O
+confusion	B
+.	O
+
+The	O
+serum	O
+sodium	O
+at	O
+this	O
+time	O
+was	O
+120	O
+mmol	O
+/	O
+L	O
+,	O
+serum	O
+osmolality	O
+was	O
+263	O
+mosmol	O
+/	O
+kg	O
+,	O
+urine	O
+osmolality	O
+410	O
+mosmol	O
+/	O
+kg	O
+and	O
+urine	O
+sodium	O
+63	O
+mmol	O
+/	O
+L	O
+,	O
+consistent	O
+with	O
+a	O
+diagnosis	O
+of	O
+SIADH	B
+.	O
+
+Desvenlafaxine	O
+was	O
+ceased	O
+and	O
+fluid	O
+restriction	O
+implemented	O
+.	O
+
+After	O
+4	O
+days	O
+the	O
+sodium	O
+increased	O
+to	O
+128	O
+mmol	O
+/	O
+L	O
+and	O
+fluid	O
+restriction	O
+was	O
+relaxed	O
+.	O
+
+During	O
+her	O
+further	O
+3	O
+weeks	O
+inpatient	O
+admission	O
+the	O
+serum	O
+sodium	O
+ranged	O
+from	O
+134	O
+to	O
+137	O
+mmol	O
+/	O
+L	O
+during	O
+treatment	O
+with	O
+mirtazapine	O
+.	O
+
+DISCUSSION	O
+:	O
+SIADH	B
+has	O
+been	O
+widely	O
+reported	O
+with	O
+a	O
+range	O
+of	O
+antidepressants	O
+.	O
+
+This	O
+case	O
+report	O
+suggests	O
+that	O
+desvenlafaxine	O
+might	O
+cause	O
+clinically	O
+significant	O
+hyponatremia	B
+.	O
+
+CONCLUSIONS	O
+:	O
+Clinicians	O
+should	O
+be	O
+aware	O
+of	O
+the	O
+potential	O
+for	O
+antidepressants	O
+to	O
+cause	O
+hyponatremia	B
+,	O
+and	O
+take	O
+appropriate	O
+corrective	O
+action	O
+where	O
+necessary	O
+.	O
+
+Oxidative	O
+stress	O
+on	O
+cardiotoxicity	B
+after	O
+treatment	O
+with	O
+single	O
+and	O
+multiple	O
+doses	O
+of	O
+doxorubicin	O
+.	O
+
+The	O
+mechanism	O
+of	O
+doxorubicin	O
+(	O
+DOX	O
+)	O
+-	O
+induced	O
+cardiotoxicity	B
+remains	O
+controversial	O
+.	O
+
+Wistar	O
+rats	O
+(	O
+n	O
+=	O
+66	O
+)	O
+received	O
+DOX	O
+injections	O
+intraperitoneally	O
+and	O
+were	O
+randomly	O
+assigned	O
+to	O
+2	O
+experimental	O
+protocols	O
+:	O
+(	O
+1	O
+)	O
+rats	O
+were	O
+killed	O
+before	O
+(	O
+-	O
+24	O
+h	O
+,	O
+n	O
+=	O
+8	O
+)	O
+and	O
+24	O
+h	O
+after	O
+(	O
++	O
+24	O
+h	O
+,	O
+n	O
+=	O
+8	O
+)	O
+a	O
+single	O
+dose	O
+of	O
+DOX	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+)	O
+to	O
+determine	O
+the	O
+DOX	O
+acute	O
+effect	O
+and	O
+(	O
+2	O
+)	O
+rats	O
+(	O
+n	O
+=	O
+58	O
+)	O
+received	O
+4	O
+injections	O
+of	O
+DOX	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+/	O
+week	O
+)	O
+and	O
+were	O
+killed	O
+before	O
+the	O
+first	O
+injection	O
+(	O
+M0	O
+)	O
+and	O
+1	O
+week	O
+after	O
+each	O
+injection	O
+(	O
+M1	O
+,	O
+M2	O
+,	O
+M3	O
+,	O
+and	O
+M4	O
+)	O
+to	O
+determine	O
+the	O
+chronological	O
+effects	O
+.	O
+
+Animals	O
+used	O
+at	O
+M0	O
+(	O
+n	O
+=	O
+8	O
+)	O
+were	O
+also	O
+used	O
+at	O
+moment	O
+-	O
+24	O
+h	O
+of	O
+acute	O
+study	O
+.	O
+
+Cardiac	O
+total	O
+antioxidant	O
+performance	O
+(	O
+TAP	O
+)	O
+,	O
+DNA	O
+damage	O
+,	O
+and	O
+morphology	O
+analyses	O
+were	O
+carried	O
+out	O
+at	O
+each	O
+time	O
+point	O
+.	O
+
+Single	O
+dose	O
+of	O
+DOX	O
+was	O
+associated	O
+with	O
+increased	O
+cardiac	B
+disarrangement	I
+,	O
+necrosis	B
+,	O
+and	O
+DNA	O
+damage	O
+(	O
+strand	O
+breaks	O
+(	O
+SBs	O
+)	O
+and	O
+oxidized	O
+pyrimidines	O
+)	O
+and	O
+decreased	O
+TAP	O
+.	O
+
+The	O
+chronological	O
+study	O
+showed	O
+an	O
+effect	O
+of	O
+a	O
+cumulative	O
+dose	O
+on	O
+body	O
+weight	O
+(	O
+R	O
+=	O
+-	O
+0	O
+.	O
+99	O
+,	O
+p	O
+=	O
+0	O
+.	O
+011	O
+)	O
+,	O
+necrosis	B
+(	O
+R	O
+=	O
+1	O
+.	O
+00	O
+,	O
+p	O
+=	O
+0	O
+.	O
+004	O
+)	O
+,	O
+TAP	O
+(	O
+R	O
+=	O
+0	O
+.	O
+95	O
+,	O
+p	O
+=	O
+0	O
+.	O
+049	O
+)	O
+,	O
+and	O
+DNA	O
+SBs	O
+(	O
+R	O
+=	O
+-	O
+0	O
+.	O
+95	O
+,	O
+p	O
+=	O
+0	O
+.	O
+049	O
+)	O
+.	O
+
+DNA	O
+SBs	O
+damage	O
+was	O
+negatively	O
+associated	O
+with	O
+TAP	O
+(	O
+R	O
+=	O
+-	O
+0	O
+.	O
+98	O
+,	O
+p	O
+=	O
+0	O
+.	O
+018	O
+)	O
+,	O
+and	O
+necrosis	B
+(	O
+R	O
+=	O
+-	O
+0	O
+.	O
+97	O
+,	O
+p	O
+=	O
+0	O
+.	O
+027	O
+)	O
+.	O
+
+Our	O
+results	O
+suggest	O
+that	O
+oxidative	O
+damage	O
+is	O
+associated	O
+with	O
+acute	O
+cardiotoxicity	B
+induced	O
+by	O
+a	O
+single	O
+dose	O
+of	O
+DOX	O
+only	O
+.	O
+
+Increased	O
+resistance	O
+to	O
+the	O
+oxidative	O
+stress	O
+is	O
+plausible	O
+for	O
+the	O
+multiple	O
+dose	O
+of	O
+DOX	O
+.	O
+
+Thus	O
+,	O
+different	O
+mechanisms	O
+may	O
+be	O
+involved	O
+in	O
+acute	O
+toxicity	B
+versus	O
+chronic	O
+toxicity	B
+.	O
+
+Tacrolimus	O
+-	O
+related	O
+seizure	B
+after	O
+pediatric	O
+liver	O
+transplantation	O
+-	O
+-	O
+a	O
+single	O
+-	O
+center	O
+experience	O
+.	O
+
+To	O
+identify	O
+the	O
+risk	O
+factors	O
+for	O
+new	O
+-	O
+onset	O
+seizures	B
+after	O
+pediatric	O
+LT	O
+and	O
+to	O
+assess	O
+their	O
+clinical	O
+implications	O
+and	O
+long	O
+-	O
+term	O
+prognosis	O
+.	O
+
+The	O
+clinical	O
+and	O
+laboratory	O
+data	O
+of	O
+27	O
+consecutive	O
+children	O
+who	O
+underwent	O
+LT	O
+from	O
+January	O
+2007	O
+to	O
+December	O
+2010	O
+in	O
+our	O
+center	O
+were	O
+analyzed	O
+retrospectively	O
+.	O
+
+Patients	O
+were	O
+divided	O
+into	O
+seizures	B
+group	O
+and	O
+a	O
+non	O
+-	O
+seizures	B
+group	O
+.	O
+
+Pre	O
+-	O
+operative	O
+,	O
+intra	O
+-	O
+operative	O
+,	O
+and	O
+post	O
+-	O
+operative	O
+data	O
+were	O
+collected	O
+.	O
+
+Seizures	B
+occurred	O
+in	O
+four	O
+children	O
+,	O
+an	O
+incidence	O
+of	O
+14	O
+.	O
+8	O
+%	O
+.	O
+
+All	O
+exhibited	O
+generalized	O
+tonic	B
+-	I
+clonic	I
+seizures	I
+within	O
+the	O
+first	O
+two	O
+wk	O
+after	O
+LT	O
+.	O
+
+Univariate	O
+analysis	O
+showed	O
+that	O
+the	O
+risk	O
+factors	O
+associated	O
+with	O
+seizures	B
+after	O
+pediatric	O
+LT	O
+included	O
+gender	O
+,	O
+pediatric	O
+end	B
+-	I
+stage	I
+liver	I
+disease	I
+score	O
+before	O
+surgery	O
+,	O
+Child	O
+-	O
+Pugh	O
+score	O
+before	O
+surgery	O
+,	O
+serum	O
+total	O
+bilirubin	O
+after	O
+surgery	O
+,	O
+and	O
+trough	O
+TAC	O
+level	O
+.	O
+
+Multivariate	O
+analysis	O
+showed	O
+that	O
+trough	O
+TAC	O
+level	O
+was	O
+the	O
+only	O
+independent	O
+risk	O
+factor	O
+associated	O
+with	O
+the	O
+seizures	B
+.	O
+
+All	O
+children	O
+who	O
+experienced	O
+seizures	B
+survived	O
+with	O
+good	O
+graft	O
+function	O
+and	O
+remained	O
+seizure	B
+-	O
+free	O
+without	O
+anti	O
+-	O
+epileptic	B
+drugs	O
+over	O
+a	O
+mean	O
+follow	O
+-	O
+up	O
+period	O
+of	O
+33	O
+.	O
+7	O
++	O
+14	O
+.	O
+6	O
+months	O
+.	O
+
+High	O
+trough	O
+TAC	O
+level	O
+was	O
+the	O
+predominant	O
+factor	O
+that	O
+contributed	O
+to	O
+seizures	B
+in	O
+the	O
+early	O
+post	O
+-	O
+operative	O
+period	O
+after	O
+pediatric	O
+LT	O
+.	O
+
+High	O
+PELD	O
+and	O
+Child	O
+-	O
+Pugh	O
+scores	O
+before	O
+LT	O
+and	O
+high	O
+post	O
+-	O
+operative	O
+serum	O
+Tbil	O
+may	O
+be	O
+contributory	O
+risk	O
+factors	O
+for	O
+TAC	O
+-	O
+related	O
+seizures	B
+.	O
+
+The	O
+flavonoid	O
+apigenin	O
+delays	O
+forgetting	O
+of	O
+passive	O
+avoidance	O
+conditioning	O
+in	O
+rats	O
+.	O
+
+The	O
+present	O
+experiments	O
+were	O
+performed	O
+to	O
+study	O
+the	O
+effect	O
+of	O
+the	O
+flavonoid	O
+apigenin	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+intraperitoneally	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+,	O
+1	O
+h	O
+before	O
+acquisition	O
+)	O
+,	O
+on	O
+24	O
+h	O
+retention	O
+performance	O
+and	O
+forgetting	O
+of	O
+a	O
+step	O
+-	O
+through	O
+passive	O
+avoidance	O
+task	O
+,	O
+in	O
+young	O
+male	O
+Wistar	O
+rats	O
+.	O
+
+There	O
+were	O
+no	O
+differences	O
+between	O
+saline	O
+-	O
+and	O
+apigenin	O
+-	O
+treated	O
+groups	O
+in	O
+the	O
+24	O
+h	O
+retention	O
+trial	O
+.	O
+
+Furthermore	O
+,	O
+apigenin	O
+did	O
+not	O
+prevent	O
+the	O
+amnesia	B
+induced	O
+by	O
+scopolamine	O
+(	O
+1mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+,	O
+30	O
+min	O
+before	O
+the	O
+acquisition	O
+)	O
+.	O
+
+The	O
+saline	O
+-	O
+and	O
+apigenin	O
+-	O
+treated	O
+rats	O
+that	O
+did	O
+not	O
+step	O
+through	O
+into	O
+the	O
+dark	O
+compartment	O
+during	O
+the	O
+cut	O
+-	O
+off	O
+time	O
+(	O
+540	O
+s	O
+)	O
+were	O
+retested	O
+weekly	O
+for	O
+up	O
+to	O
+eight	O
+weeks	O
+.	O
+
+In	O
+the	O
+saline	O
+treated	O
+group	O
+,	O
+the	O
+first	O
+significant	O
+decline	O
+in	O
+passive	O
+avoidance	O
+response	O
+was	O
+observed	O
+at	O
+four	O
+weeks	O
+,	O
+and	O
+complete	O
+memory	B
+loss	I
+was	O
+found	O
+five	O
+weeks	O
+after	O
+the	O
+acquisition	O
+of	O
+the	O
+passive	O
+avoidance	O
+task	O
+.	O
+
+At	O
+the	O
+end	O
+of	O
+the	O
+experimental	O
+period	O
+,	O
+60	O
+%	O
+of	O
+the	O
+animals	O
+treated	O
+with	O
+apigenin	O
+still	O
+did	O
+not	O
+step	O
+through	O
+.	O
+
+These	O
+data	O
+suggest	O
+that	O
+1	O
+)	O
+apigenin	O
+delays	O
+the	O
+long	O
+-	O
+term	O
+forgetting	O
+but	O
+did	O
+not	O
+modulate	O
+the	O
+24	O
+h	O
+retention	O
+of	O
+fear	O
+memory	O
+and	O
+2	O
+)	O
+the	O
+obtained	O
+beneficial	O
+effect	O
+of	O
+apigenin	O
+on	O
+the	O
+passive	O
+avoidance	O
+conditioning	O
+is	O
+mediated	O
+by	O
+mechanisms	O
+that	O
+do	O
+not	O
+implicate	O
+its	O
+action	O
+on	O
+the	O
+muscarinic	O
+cholinergic	O
+system	O
+.	O
+
+Histamine	O
+antagonists	O
+and	O
+d	O
+-	O
+tubocurarine	O
+-	O
+induced	O
+hypotension	B
+in	O
+cardiac	O
+surgical	O
+patients	O
+.	O
+
+Hemodynamic	O
+effects	O
+and	O
+histamine	O
+release	O
+by	O
+bolus	O
+injection	O
+of	O
+0	O
+.	O
+35	O
+mg	O
+/	O
+kg	O
+of	O
+d	O
+-	O
+tubocurarine	O
+were	O
+studied	O
+in	O
+24	O
+patients	O
+.	O
+
+H1	O
+-	O
+and	O
+H2	O
+-	O
+histamine	O
+antagonists	O
+or	O
+placebo	O
+were	O
+given	O
+before	O
+dosing	O
+with	O
+d	O
+-	O
+tubocurarine	O
+in	O
+a	O
+randomized	O
+double	O
+-	O
+blind	O
+fashion	O
+to	O
+four	O
+groups	O
+:	O
+group	O
+1	O
+-	O
+-	O
+placebo	O
+;	O
+group	O
+2	O
+-	O
+-	O
+cimetidine	O
+,	O
+4	O
+mg	O
+/	O
+kg	O
+,	O
+plus	O
+placebo	O
+;	O
+group	O
+3	O
+-	O
+-	O
+chlorpheniramine	O
+,	O
+0	O
+.	O
+1	O
+mg	O
+/	O
+kg	O
+,	O
+plus	O
+placebo	O
+;	O
+and	O
+group	O
+4	O
+-	O
+-	O
+cimetidine	O
+plus	O
+chlorpheniramine	O
+.	O
+
+Histamine	O
+release	O
+occurred	O
+in	O
+most	O
+patients	O
+,	O
+the	O
+highest	O
+level	O
+2	O
+minutes	O
+after	O
+d	O
+-	O
+tubocurarine	O
+dosing	O
+.	O
+
+Group	O
+1	O
+had	O
+a	O
+moderate	O
+negative	O
+correlation	O
+between	O
+plasma	O
+histamine	O
+change	O
+and	O
+systemic	O
+vascular	O
+resistance	O
+(	O
+r	O
+=	O
+0	O
+.	O
+58	O
+;	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+not	O
+present	O
+in	O
+group	O
+4	O
+.	O
+
+Prior	O
+dosing	O
+with	O
+antagonists	O
+partially	O
+prevented	O
+the	O
+fall	O
+in	O
+systemic	O
+vascular	O
+resistance	O
+.	O
+
+These	O
+data	O
+demonstrate	O
+that	O
+the	O
+hemodynamic	O
+changes	O
+associated	O
+with	O
+d	O
+-	O
+tubocurarine	O
+dosing	O
+are	O
+only	O
+partially	O
+explained	O
+by	O
+histamine	O
+release	O
+.	O
+
+Thus	O
+prior	O
+dosing	O
+with	O
+H1	O
+-	O
+and	O
+H2	O
+-	O
+antagonists	O
+provides	O
+only	O
+partial	O
+protection	O
+.	O
+
+Cholecystokinin	O
+-	O
+octapeptide	O
+restored	O
+morphine	O
+-	O
+induced	O
+hippocampal	O
+long	O
+-	O
+term	O
+potentiation	O
+impairment	O
+in	O
+rats	O
+.	O
+
+Cholecystokinin	O
+-	O
+octapeptide	O
+(	O
+CCK	O
+-	O
+8	O
+)	O
+,	O
+which	O
+is	O
+a	O
+typical	O
+brain	O
+-	O
+gut	O
+peptide	O
+,	O
+exerts	O
+a	O
+wide	O
+range	O
+of	O
+biological	O
+activities	O
+on	O
+the	O
+central	O
+nervous	O
+system	O
+.	O
+
+We	O
+have	O
+previously	O
+reported	O
+that	O
+CCK	O
+-	O
+8	O
+significantly	O
+alleviated	O
+morphine	O
+-	O
+induced	O
+amnesia	B
+and	O
+reversed	O
+spine	O
+density	O
+decreases	O
+in	O
+the	O
+CA1	O
+region	O
+of	O
+the	O
+hippocampus	O
+in	O
+morphine	O
+-	O
+treated	O
+animals	O
+.	O
+
+Here	O
+,	O
+we	O
+investigated	O
+the	O
+effects	O
+of	O
+CCK	O
+-	O
+8	O
+on	O
+long	O
+-	O
+term	O
+potentiation	O
+(	O
+LTP	O
+)	O
+in	O
+the	O
+lateral	O
+perforant	O
+path	O
+(	O
+LPP	O
+)	O
+-	O
+granule	O
+cell	O
+synapse	O
+of	O
+rat	O
+dentate	O
+gyrus	O
+(	O
+DG	O
+)	O
+in	O
+acute	O
+saline	O
+or	O
+morphine	O
+-	O
+treated	O
+rats	O
+.	O
+
+Population	O
+spikes	O
+(	O
+PS	O
+)	O
+,	O
+which	O
+were	O
+evoked	O
+by	O
+stimulation	O
+of	O
+the	O
+LPP	O
+,	O
+were	O
+recorded	O
+in	O
+the	O
+DG	O
+region	O
+.	O
+
+Acute	O
+morphine	O
+(	O
+30mg	O
+/	O
+kg	O
+,	O
+s	O
+.	O
+c	O
+.	O
+)	O
+treatment	O
+significantly	O
+attenuated	O
+hippocampal	O
+LTP	O
+and	O
+CCK	O
+-	O
+8	O
+(	O
+1ug	O
+,	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+restored	O
+the	O
+amplitude	O
+of	O
+PS	O
+that	O
+was	O
+attenuated	O
+by	O
+morphine	O
+injection	O
+.	O
+
+Furthermore	O
+,	O
+microinjection	O
+of	O
+CCK	O
+-	O
+8	O
+(	O
+0	O
+.	O
+1	O
+and	O
+1ug	O
+,	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+also	O
+significantly	O
+augmented	O
+hippocampal	O
+LTP	O
+in	O
+saline	O
+-	O
+treated	O
+(	O
+1ml	O
+/	O
+kg	O
+,	O
+s	O
+.	O
+c	O
+.	O
+)	O
+rats	O
+.	O
+
+Pre	O
+-	O
+treatment	O
+of	O
+the	O
+CCK2	O
+receptor	O
+antagonist	O
+L	O
+-	O
+365	O
+,	O
+260	O
+(	O
+10ug	O
+,	O
+i	O
+.	O
+c	O
+.	O
+v	O
+)	O
+reversed	O
+the	O
+effects	O
+of	O
+CCK	O
+-	O
+8	O
+,	O
+but	O
+the	O
+CCK1	O
+receptor	O
+antagonist	O
+L	O
+-	O
+364	O
+,	O
+718	O
+(	O
+10ug	O
+,	O
+i	O
+.	O
+c	O
+.	O
+v	O
+)	O
+did	O
+not	O
+.	O
+
+The	O
+present	O
+results	O
+demonstrate	O
+that	O
+CCK	O
+-	O
+8	O
+attenuates	O
+the	O
+effect	O
+of	O
+morphine	O
+on	O
+hippocampal	O
+LTP	O
+through	O
+CCK2	O
+receptors	O
+and	O
+suggest	O
+an	O
+ameliorative	O
+function	O
+of	O
+CCK	O
+-	O
+8	O
+on	O
+morphine	O
+-	O
+induced	O
+memory	B
+impairment	I
+.	O
+
+Glial	O
+activation	O
+and	O
+post	O
+-	O
+synaptic	O
+neurotoxicity	B
+:	O
+the	O
+key	O
+events	O
+in	O
+Streptozotocin	O
+(	O
+ICV	O
+)	O
+induced	O
+memory	B
+impairment	I
+in	O
+rats	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+the	O
+role	O
+of	O
+glial	O
+activation	O
+and	O
+post	O
+synaptic	O
+toxicity	B
+in	O
+ICV	O
+Streptozotocin	O
+(	O
+STZ	O
+)	O
+induced	O
+memory	B
+impaired	I
+rats	O
+was	O
+explored	O
+.	O
+
+In	O
+experiment	O
+set	O
+up	O
+1	O
+:	O
+Memory	B
+deficit	I
+was	O
+found	O
+in	O
+Morris	O
+water	O
+maze	O
+test	O
+on	O
+14	O
+-	O
+16	O
+days	O
+after	O
+STZ	O
+(	O
+ICV	O
+;	O
+3mg	O
+/	O
+Kg	O
+)	O
+administration	O
+.	O
+
+STZ	O
+causes	O
+increased	O
+expression	O
+of	O
+GFAP	O
+,	O
+CD11b	O
+and	O
+TNF	O
+-	O
+a	O
+indicating	O
+glial	O
+activation	O
+and	O
+neuroinflammation	B
+.	O
+
+STZ	O
+also	O
+significantly	O
+increased	O
+the	O
+level	O
+of	O
+ROS	O
+,	O
+nitrite	O
+,	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+and	O
+reduced	O
+the	O
+mitochondrial	O
+activity	O
+in	O
+synaptosomal	O
+preparation	O
+illustrating	O
+free	O
+radical	O
+generation	O
+and	O
+excitotoxicity	B
+.	O
+
+Increased	O
+expression	O
+and	O
+activity	O
+of	O
+Caspase	O
+-	O
+3	O
+was	O
+also	O
+observed	O
+in	O
+STZ	O
+treated	O
+rat	O
+which	O
+specify	O
+apoptotic	O
+cell	O
+death	O
+in	O
+hippocampus	O
+and	O
+cortex	O
+.	O
+
+STZ	O
+treatment	O
+showed	O
+decrease	O
+expression	O
+of	O
+post	O
+synaptic	O
+markers	O
+CaMKIIa	O
+and	O
+PSD	O
+-	O
+95	O
+,	O
+while	O
+,	O
+expression	O
+of	O
+pre	O
+synaptic	O
+markers	O
+(	O
+synaptophysin	O
+and	O
+SNAP	O
+-	O
+25	O
+)	O
+remains	O
+unaltered	O
+indicating	O
+selective	O
+post	O
+synaptic	O
+neurotoxicity	B
+.	O
+
+Oral	O
+treatment	O
+with	O
+Memantine	O
+(	O
+10mg	O
+/	O
+kg	O
+)	O
+and	O
+Ibuprofen	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+daily	O
+for	O
+13	O
+days	O
+attenuated	O
+STZ	O
+induced	O
+glial	O
+activation	O
+,	O
+apoptotic	O
+cell	O
+death	O
+and	O
+post	O
+synaptic	O
+neurotoxicity	B
+in	O
+rat	O
+brain	O
+.	O
+
+Further	O
+,	O
+in	O
+experiment	O
+set	O
+up	O
+2	O
+:	O
+where	O
+memory	O
+function	O
+was	O
+not	O
+affected	O
+i	O
+.	O
+e	O
+.	O
+7	O
+-	O
+9	O
+days	O
+after	O
+STZ	O
+treatment	O
+.	O
+
+The	O
+level	O
+of	O
+GFAP	O
+,	O
+CD11b	O
+,	O
+TNF	O
+-	O
+a	O
+,	O
+ROS	O
+and	O
+nitrite	O
+levels	O
+were	O
+increased	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+apoptotic	O
+marker	O
+,	O
+synaptic	O
+markers	O
+,	O
+mitochondrial	O
+activity	O
+and	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+levels	O
+remained	O
+unaffected	O
+.	O
+
+Collective	O
+data	O
+indicates	O
+that	O
+neuroinflammatory	B
+process	O
+and	O
+oxidative	O
+stress	O
+occurs	O
+earlier	O
+to	O
+apoptosis	O
+and	O
+does	O
+not	O
+affect	O
+memory	O
+function	O
+.	O
+
+Present	O
+study	O
+clearly	O
+suggests	O
+that	O
+glial	O
+activation	O
+and	O
+post	O
+synaptic	O
+neurotoxicity	B
+are	O
+the	O
+key	O
+factors	O
+in	O
+STZ	O
+induced	O
+memory	B
+impairment	I
+and	O
+neuronal	O
+cell	O
+death	O
+.	O
+
+Comparison	O
+of	O
+effects	O
+of	O
+isotonic	O
+sodium	O
+chloride	O
+with	O
+diltiazem	O
+in	O
+prevention	O
+of	O
+contrast	O
+-	O
+induced	O
+nephropathy	B
+.	O
+
+INTRODUCTION	O
+AND	O
+OBJECTIVE	O
+:	O
+Contrast	O
+-	O
+induced	O
+nephropathy	B
+(	O
+CIN	O
+)	O
+significantly	O
+increases	O
+the	O
+morbidity	O
+and	O
+mortality	O
+of	O
+patients	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+is	O
+to	O
+investigate	O
+and	O
+compare	O
+the	O
+protective	O
+effects	O
+of	O
+isotonic	O
+sodium	O
+chloride	O
+with	O
+sodium	O
+bicarbonate	O
+infusion	O
+and	O
+isotonic	O
+sodium	O
+chloride	O
+infusion	O
+with	O
+diltiazem	O
+,	O
+a	O
+calcium	O
+channel	O
+blocker	O
+,	O
+in	O
+preventing	O
+CIN	O
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+Our	O
+study	O
+included	O
+patients	O
+who	O
+were	O
+administered	O
+30	O
+-	O
+60	O
+mL	O
+of	O
+iodinated	O
+contrast	O
+agent	O
+for	O
+percutaneous	O
+coronary	O
+angiography	O
+(	O
+PCAG	O
+)	O
+,	O
+all	O
+with	O
+creatinine	O
+values	O
+between	O
+1	O
+.	O
+1	O
+and	O
+3	O
+.	O
+1	O
+mg	O
+/	O
+dL	O
+.	O
+
+Patients	O
+were	O
+divided	O
+into	O
+three	O
+groups	O
+and	O
+each	O
+group	O
+had	O
+20	O
+patients	O
+.	O
+
+The	O
+first	O
+group	O
+of	O
+patients	O
+was	O
+administered	O
+isotonic	O
+sodium	O
+chloride	O
+;	O
+the	O
+second	O
+group	O
+was	O
+administered	O
+a	O
+solution	O
+that	O
+of	O
+5	O
+%	O
+dextrose	O
+and	O
+sodium	O
+bicarbonate	O
+,	O
+while	O
+the	O
+third	O
+group	O
+was	O
+administered	O
+isotonic	O
+sodium	O
+chloride	O
+before	O
+and	O
+after	O
+the	O
+contrast	O
+injection	O
+.	O
+
+The	O
+third	O
+group	O
+received	O
+an	O
+additional	O
+injection	O
+of	O
+diltiazem	O
+the	O
+day	O
+before	O
+and	O
+first	O
+2	O
+days	O
+after	O
+the	O
+contrast	O
+injection	O
+.	O
+
+All	O
+of	O
+the	O
+patients	O
+'	O
+plasma	O
+blood	O
+urea	O
+nitrogen	O
+(	O
+BUN	O
+)	O
+and	O
+creatinine	O
+levels	O
+were	O
+measured	O
+on	O
+the	O
+second	O
+and	O
+seventh	O
+day	O
+after	O
+the	O
+administration	O
+of	O
+intravenous	O
+contrast	O
+material	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+basal	O
+creatinine	O
+levels	O
+were	O
+similar	O
+for	O
+all	O
+three	O
+groups	O
+(	O
+p	O
+>	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Among	O
+a	O
+total	O
+of	O
+60	O
+patients	O
+included	O
+in	O
+the	O
+study	O
+,	O
+16	O
+patients	O
+developed	O
+acute	B
+renal	I
+failure	I
+(	O
+ARF	B
+)	O
+on	O
+the	O
+second	O
+day	O
+after	O
+contrast	O
+material	O
+was	O
+injected	O
+(	O
+26	O
+.	O
+6	O
+%	O
+)	O
+.	O
+
+The	O
+number	O
+of	O
+patients	O
+who	O
+developed	O
+ARF	B
+on	O
+the	O
+second	O
+day	O
+after	O
+the	O
+injection	O
+in	O
+the	O
+first	O
+group	O
+was	O
+five	O
+(	O
+25	O
+%	O
+)	O
+,	O
+in	O
+the	O
+second	O
+group	O
+was	O
+six	O
+(	O
+30	O
+%	O
+)	O
+and	O
+the	O
+third	O
+group	O
+was	O
+five	O
+(	O
+25	O
+%	O
+)	O
+(	O
+p	O
+>	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+There	O
+was	O
+no	O
+significant	O
+difference	O
+between	O
+isotonic	O
+sodium	O
+chloride	O
+,	O
+sodium	O
+bicarbonate	O
+and	O
+isotonic	O
+sodium	O
+chloride	O
+with	O
+diltiazem	O
+application	O
+in	O
+prevention	O
+of	O
+CIN	O
+.	O
+
+Neurocognitive	O
+and	O
+neuroradiologic	O
+central	O
+nervous	O
+system	O
+late	O
+effects	O
+in	O
+children	O
+treated	O
+on	O
+Pediatric	O
+Oncology	O
+Group	O
+(	O
+POG	O
+)	O
+P9605	O
+(	O
+standard	O
+risk	O
+)	O
+and	O
+P9201	O
+(	O
+lesser	O
+risk	O
+)	O
+acute	B
+lymphoblastic	I
+leukemia	I
+protocols	O
+(	O
+ACCL0131	O
+)	O
+:	O
+a	O
+methotrexate	O
+consequence	O
+?	O
+
+A	O
+report	O
+from	O
+the	O
+Children	O
+'	O
+s	O
+Oncology	O
+Group	O
+.	O
+
+Concerns	O
+about	O
+long	O
+-	O
+term	O
+methotrexate	O
+(	O
+MTX	O
+)	O
+neurotoxicity	B
+in	O
+the	O
+1990s	O
+led	O
+to	O
+modifications	O
+in	O
+intrathecal	O
+(	O
+IT	O
+)	O
+therapy	O
+,	O
+leucovorin	O
+rescue	O
+,	O
+and	O
+frequency	O
+of	O
+systemic	O
+MTX	O
+administration	O
+in	O
+children	O
+with	O
+acute	B
+lymphoblastic	I
+leukemia	I
+.	O
+
+In	O
+this	O
+study	O
+,	O
+neurocognitive	O
+outcomes	O
+and	O
+neuroradiologic	O
+evidence	O
+of	O
+leukoencephalopathy	B
+were	O
+compared	O
+in	O
+children	O
+treated	O
+with	O
+intense	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+-	O
+directed	O
+therapy	O
+(	O
+P9605	O
+)	O
+versus	O
+those	O
+receiving	O
+fewer	O
+CNS	O
+-	O
+directed	O
+treatment	O
+days	O
+during	O
+intensive	O
+consolidation	O
+(	O
+P9201	O
+)	O
+.	O
+
+A	O
+total	O
+of	O
+66	O
+children	O
+from	O
+16	O
+Pediatric	O
+Oncology	O
+Group	O
+institutions	O
+with	O
+"	O
+standard	O
+-	O
+risk	O
+"	O
+acute	B
+lymphoblastic	I
+leukemia	I
+,	O
+1	O
+.	O
+00	O
+to	O
+9	O
+.	O
+99	O
+years	O
+at	O
+diagnosis	O
+,	O
+without	O
+evidence	O
+of	O
+CNS	O
+leukemia	B
+at	O
+diagnosis	O
+were	O
+enrolled	O
+on	O
+ACCL0131	O
+:	O
+28	O
+from	O
+P9201	O
+and	O
+38	O
+from	O
+P9605	O
+.	O
+
+Magnetic	O
+resonance	O
+imaging	O
+scans	O
+and	O
+standard	O
+neuropsychological	O
+tests	O
+were	O
+performed	O
+>	O
+2	O
+.	O
+6	O
+years	O
+after	O
+the	O
+end	O
+of	O
+treatment	O
+.	O
+
+Significantly	O
+more	O
+P9605	O
+patients	O
+developed	O
+leukoencephalopathy	B
+compared	O
+with	O
+P9201	O
+patients	O
+(	O
+68	O
+%	O
+,	O
+95	O
+%	O
+confidence	O
+interval	O
+49	O
+%	O
+-	O
+83	O
+%	O
+vs	O
+.	O
+22	O
+%	O
+,	O
+95	O
+%	O
+confidence	O
+interval	O
+5	O
+%	O
+-	O
+44	O
+%	O
+;	O
+P	O
+=	O
+0	O
+.	O
+001	O
+)	O
+identified	O
+as	O
+late	O
+as	O
+7	O
+.	O
+7	O
+years	O
+after	O
+the	O
+end	O
+of	O
+treatment	O
+.	O
+
+Overall	O
+,	O
+40	O
+%	O
+of	O
+patients	O
+scored	O
+<	O
+85	O
+on	O
+either	O
+Verbal	O
+or	O
+Performance	O
+IQ	O
+.	O
+
+Children	O
+on	O
+both	O
+studies	O
+had	O
+significant	O
+attention	B
+problems	I
+,	O
+but	O
+P9605	O
+children	O
+scored	O
+below	O
+average	O
+on	O
+more	O
+neurocognitive	O
+measures	O
+than	O
+those	O
+treated	O
+on	O
+P9201	O
+(	O
+82	O
+%	O
+,	O
+14	O
+/	O
+17	O
+measures	O
+vs	O
+.	O
+24	O
+%	O
+,	O
+4	O
+/	O
+17	O
+measures	O
+)	O
+.	O
+
+This	O
+supports	O
+ongoing	O
+concerns	O
+about	O
+intensive	O
+MTX	O
+exposure	O
+as	O
+a	O
+major	O
+contributor	O
+to	O
+CNS	O
+late	O
+effects	O
+.	O
+
+Tranexamic	O
+acid	O
+overdosage	O
+-	O
+induced	O
+generalized	O
+seizure	B
+in	O
+renal	B
+failure	I
+.	O
+
+We	O
+report	O
+a	O
+45	O
+-	O
+year	O
+-	O
+old	O
+lady	O
+with	O
+chronic	B
+kidney	I
+disease	I
+stage	O
+4	O
+due	O
+to	O
+chronic	O
+tubulointerstial	B
+disease	I
+.	O
+
+She	O
+was	O
+admitted	O
+to	O
+our	O
+center	O
+for	O
+severe	O
+anemia	B
+due	O
+to	O
+menorrhagia	B
+and	O
+deterioration	B
+of	I
+renal	I
+function	I
+.	O
+
+She	O
+was	O
+infused	O
+three	O
+units	O
+of	O
+packed	O
+cells	O
+during	O
+a	O
+session	O
+of	O
+hemodialysis	O
+.	O
+
+Tranexamic	O
+acid	O
+(	O
+TNA	O
+)	O
+1	O
+g	O
+8	O
+-	O
+hourly	O
+was	O
+administered	O
+to	O
+her	O
+to	O
+control	O
+bleeding	B
+per	O
+vaginum	O
+.	O
+
+Two	O
+hours	O
+after	O
+the	O
+sixth	O
+dose	O
+of	O
+TNA	O
+,	O
+she	O
+had	O
+an	O
+episode	O
+of	O
+generalized	O
+tonic	B
+clonic	I
+convulsions	I
+.	O
+
+TNA	O
+was	O
+discontinued	O
+.	O
+
+Investigations	O
+of	O
+the	O
+patient	O
+revealed	O
+no	O
+biochemical	O
+or	O
+structural	O
+central	O
+nervous	B
+system	I
+abnormalities	I
+that	O
+could	O
+have	O
+provoked	O
+the	O
+convulsions	B
+.	O
+
+She	O
+did	O
+not	O
+require	O
+any	O
+further	O
+dialytic	O
+support	O
+.	O
+
+She	O
+had	O
+no	O
+further	O
+episodes	O
+of	O
+convulsion	B
+till	O
+dis	O
+-	O
+charge	O
+and	O
+during	O
+the	O
+two	O
+months	O
+of	O
+follow	O
+-	O
+up	O
+.	O
+
+Thus	O
+,	O
+the	O
+precipitating	O
+cause	O
+of	O
+convulsions	B
+was	O
+believed	O
+to	O
+be	O
+an	O
+overdose	B
+of	O
+TNA	O
+.	O
+
+Pre	O
+-	O
+treatment	O
+of	O
+bupivacaine	O
+-	O
+induced	O
+cardiovascular	B
+depression	I
+using	O
+different	O
+lipid	O
+formulations	O
+of	O
+propofol	O
+.	O
+
+BACKGROUND	O
+:	O
+Pre	O
+-	O
+treatment	O
+with	O
+lipid	O
+emulsions	O
+has	O
+been	O
+shown	O
+to	O
+increase	O
+lethal	O
+doses	O
+of	O
+bupivacaine	O
+,	O
+and	O
+the	O
+lipid	O
+content	O
+of	O
+propofol	O
+may	O
+alleviate	O
+bupivacaine	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+is	O
+to	O
+investigate	O
+the	O
+effects	O
+of	O
+propofol	O
+in	O
+intralipid	O
+or	O
+medialipid	O
+emulsions	O
+on	O
+bupivacaine	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+METHODS	O
+:	O
+Rats	O
+were	O
+anaesthetised	O
+with	O
+ketamine	O
+and	O
+were	O
+given	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+/	O
+min	O
+propofol	O
+in	O
+intralipid	O
+(	O
+Group	O
+P	O
+)	O
+,	O
+propofol	O
+in	O
+medialipid	O
+(	O
+Group	O
+L	O
+)	O
+,	O
+or	O
+saline	O
+(	O
+Group	O
+C	O
+)	O
+over	O
+20	O
+min	O
+.	O
+
+Thereafter	O
+,	O
+2	O
+mg	O
+/	O
+kg	O
+/	O
+min	O
+bupivacaine	O
+0	O
+.	O
+5	O
+%	O
+was	O
+infused	O
+.	O
+
+We	O
+recorded	O
+time	O
+to	O
+first	O
+dysrhythmia	B
+occurrence	O
+,	O
+respective	O
+times	O
+to	O
+25	O
+%	O
+and	O
+50	O
+%	O
+reduction	O
+of	O
+the	O
+heart	O
+rate	O
+(	O
+HR	O
+)	O
+and	O
+mean	O
+arterial	O
+pressure	O
+,	O
+and	O
+time	O
+to	O
+asystole	B
+and	O
+total	O
+amount	O
+of	O
+bupivacaine	O
+consumption	O
+.	O
+
+Blood	O
+and	O
+tissue	O
+samples	O
+were	O
+collected	O
+following	O
+asystole	B
+.	O
+
+RESULTS	O
+:	O
+The	O
+time	O
+to	O
+first	O
+dysrhythmia	B
+occurrence	O
+,	O
+time	O
+to	O
+25	O
+%	O
+and	O
+50	O
+%	O
+reductions	O
+in	O
+HR	O
+,	O
+and	O
+time	O
+to	O
+asystole	B
+were	O
+longer	O
+in	O
+Group	O
+P	O
+than	O
+the	O
+other	O
+groups	O
+.	O
+
+The	O
+cumulative	O
+bupivacaine	O
+dose	O
+given	O
+at	O
+those	O
+time	O
+points	O
+was	O
+higher	O
+in	O
+Group	O
+P	O
+.	O
+Plasma	O
+bupivacaine	O
+levels	O
+were	O
+significantly	O
+lower	O
+in	O
+Group	O
+P	O
+than	O
+in	O
+Group	O
+C	O
+.	O
+Bupivacaine	O
+levels	O
+in	O
+the	O
+brain	O
+and	O
+heart	O
+were	O
+significantly	O
+lower	O
+in	O
+Group	O
+P	O
+and	O
+Group	O
+L	O
+than	O
+in	O
+Group	O
+C	O
+.	O
+
+CONCLUSION	O
+:	O
+We	O
+conclude	O
+that	O
+pre	O
+-	O
+treatment	O
+with	O
+propofol	O
+in	O
+intralipid	O
+,	O
+compared	O
+with	O
+propofol	O
+in	O
+medialipid	O
+or	O
+saline	O
+,	O
+delayed	O
+the	O
+onset	O
+of	O
+bupivacaine	O
+-	O
+induced	O
+cardiotoxic	B
+effects	O
+as	O
+well	O
+as	O
+reduced	O
+plasma	O
+bupivacaine	O
+levels	O
+.	O
+
+Further	O
+studies	O
+are	O
+needed	O
+to	O
+explore	O
+tissue	O
+bupivacaine	O
+levels	O
+of	O
+propofol	O
+in	O
+medialipid	O
+and	O
+adapt	O
+these	O
+results	O
+to	O
+clinical	O
+practice	O
+.	O
+
+Drug	B
+-	I
+Induced	I
+Acute	I
+Liver	I
+Injury	I
+Within	O
+12	O
+Hours	O
+After	O
+Fluvastatin	O
+Therapy	O
+.	O
+
+Although	O
+statins	O
+are	O
+generally	O
+well	O
+-	O
+tolerated	O
+drugs	O
+,	O
+recent	O
+cases	O
+of	O
+drug	B
+-	I
+induced	I
+liver	I
+injury	I
+associated	O
+with	O
+their	O
+use	O
+have	O
+been	O
+reported	O
+.	O
+
+A	O
+52	O
+-	O
+year	O
+-	O
+old	O
+Chinese	O
+man	O
+reported	O
+with	O
+liver	B
+damage	I
+,	O
+which	O
+appeared	O
+12	O
+hours	O
+after	O
+beginning	O
+treatment	O
+with	O
+fluvastatin	O
+.	O
+
+Patient	O
+presented	O
+with	O
+complaints	O
+of	O
+increasing	O
+nausea	B
+,	O
+anorexia	B
+,	O
+and	O
+upper	O
+abdominal	B
+pain	I
+.	O
+
+His	O
+laboratory	O
+values	O
+showed	O
+elevated	O
+creatine	O
+kinase	O
+and	O
+transaminases	O
+.	O
+
+Testing	O
+for	O
+autoantibodies	O
+was	O
+also	O
+negative	O
+.	O
+
+The	O
+liver	O
+biochemistries	O
+eventually	O
+normalized	O
+within	O
+3	O
+weeks	O
+of	O
+stopping	O
+the	O
+fluvastatin	O
+.	O
+
+Therefore	O
+,	O
+when	O
+prescribing	O
+statins	O
+,	O
+the	O
+possibility	O
+of	O
+hepatic	B
+damage	I
+should	O
+be	O
+taken	O
+into	O
+account	O
+.	O
+
+Fluconazole	O
+associated	O
+agranulocytosis	B
+and	O
+thrombocytopenia	B
+.	O
+
+CASE	O
+:	O
+We	O
+describe	O
+a	O
+second	O
+case	O
+of	O
+fluconazole	O
+associated	O
+agranulocytosis	B
+with	O
+thrombocytopenia	B
+and	O
+recovery	O
+upon	O
+discontinuation	O
+of	O
+therapy	O
+.	O
+
+The	O
+patient	O
+began	O
+to	O
+have	O
+changes	O
+in	O
+white	O
+blood	O
+cells	O
+and	O
+platelets	O
+within	O
+48	O
+h	O
+of	O
+administration	O
+of	O
+fluconazole	O
+and	O
+began	O
+to	O
+recover	O
+with	O
+48	O
+h	O
+of	O
+discontinuation	O
+.	O
+
+This	O
+case	O
+highlights	O
+that	O
+drug	O
+-	O
+induced	O
+blood	B
+dyscrasias	I
+can	O
+occur	O
+unexpectedly	O
+as	O
+a	O
+result	O
+of	O
+treatment	O
+with	O
+a	O
+commonly	O
+used	O
+drug	O
+thought	O
+to	O
+be	O
+"	O
+safe	O
+"	O
+.	O
+
+CONCLUSION	O
+:	O
+According	O
+to	O
+Naranjo	O
+'	O
+s	O
+algorithm	O
+the	O
+likelihood	O
+that	O
+our	O
+patient	O
+'	O
+s	O
+agranulocytosis	B
+and	O
+thrombocytopenia	B
+occurred	O
+as	O
+a	O
+result	O
+of	O
+therapy	O
+with	O
+fluconazole	O
+is	O
+probable	O
+,	O
+with	O
+a	O
+total	O
+of	O
+six	O
+points	O
+.	O
+
+We	O
+feel	O
+that	O
+the	O
+weight	O
+of	O
+the	O
+overall	O
+evidence	O
+of	O
+this	O
+evidence	O
+is	O
+strong	O
+.	O
+
+In	O
+particular	O
+the	O
+temporal	O
+relationship	O
+of	O
+bone	B
+marrow	I
+suppression	I
+to	O
+the	O
+initiation	O
+of	O
+fluconazole	O
+and	O
+the	O
+abatement	O
+of	O
+symptoms	O
+that	O
+rapidly	O
+reversed	O
+immediately	O
+following	O
+discontinuation	O
+.	O
+
+Two	O
+-	O
+dimensional	O
+speckle	O
+tracking	O
+echocardiography	O
+combined	O
+with	O
+high	O
+-	O
+sensitive	O
+cardiac	O
+troponin	O
+T	O
+in	O
+early	O
+detection	O
+and	O
+prediction	O
+of	O
+cardiotoxicity	B
+during	O
+epirubicine	O
+-	O
+based	O
+chemotherapy	O
+.	O
+
+AIMS	O
+:	O
+To	O
+investigate	O
+whether	O
+alterations	O
+of	O
+myocardial	B
+strain	I
+and	O
+high	O
+-	O
+sensitive	O
+cardiac	O
+troponin	O
+T	O
+(	O
+cTnT	O
+)	O
+could	O
+predict	O
+future	O
+cardiac	B
+dysfunction	I
+in	O
+patients	O
+after	O
+epirubicin	O
+exposure	O
+.	O
+
+METHODS	O
+:	O
+Seventy	O
+-	O
+five	O
+patients	O
+with	O
+non	B
+-	I
+Hodgkin	I
+lymphoma	I
+treated	O
+with	O
+epirubicin	O
+were	O
+studied	O
+.	O
+
+Blood	O
+collection	O
+and	O
+echocardiography	O
+were	O
+performed	O
+at	O
+baseline	O
+,	O
+1	O
+day	O
+after	O
+the	O
+third	O
+cycle	O
+,	O
+and	O
+1	O
+day	O
+after	O
+completion	O
+of	O
+chemotherapy	O
+.	O
+
+Patients	O
+were	O
+studied	O
+using	O
+echocardiography	O
+during	O
+follow	O
+-	O
+up	O
+.	O
+
+Global	O
+longitudinal	O
+(	O
+GLS	O
+)	O
+,	O
+circumferential	O
+(	O
+GCS	O
+)	O
+,	O
+and	O
+radial	O
+strain	O
+(	O
+GRS	O
+)	O
+were	O
+calculated	O
+using	O
+speckle	O
+tracking	O
+echocardiography	O
+.	O
+
+Left	O
+ventricular	O
+ejection	O
+fraction	O
+was	O
+analysed	O
+by	O
+real	O
+-	O
+time	O
+3D	O
+echocardiography	O
+.	O
+
+Cardiotoxicity	B
+was	O
+defined	O
+as	O
+a	O
+reduction	O
+of	O
+the	O
+LVEF	O
+of	O
+>	O
+5	O
+%	O
+to	O
+<	O
+55	O
+%	O
+with	O
+symptoms	O
+of	O
+heart	B
+failure	I
+or	O
+an	O
+asymptomatic	O
+reduction	O
+of	O
+the	O
+LVEF	O
+of	O
+>	O
+10	O
+%	O
+to	O
+<	O
+55	O
+%	O
+.	O
+
+RESULTS	O
+:	O
+Fourteen	O
+patients	O
+(	O
+18	O
+.	O
+67	O
+%	O
+)	O
+developed	O
+cardiotoxicity	B
+after	O
+treatment	O
+.	O
+
+GLS	O
+(	O
+-	O
+18	O
+.	O
+48	O
++	O
+1	O
+.	O
+72	O
+%	O
+vs	O
+.	O
+-	O
+15	O
+.	O
+96	O
++	O
+1	O
+.	O
+6	O
+%	O
+)	O
+,	O
+GCS	O
+(	O
+-	O
+20	O
+.	O
+93	O
++	O
+2	O
+.	O
+86	O
+%	O
+vs	O
+.	O
+-	O
+19	O
+.	O
+20	O
++	O
+3	O
+.	O
+21	O
+%	O
+)	O
+,	O
+and	O
+GRS	O
+(	O
+39	O
+.	O
+23	O
++	O
+6	O
+.	O
+44	O
+%	O
+vs	O
+.	O
+34	O
+.	O
+98	O
++	O
+6	O
+.	O
+2	O
+%	O
+)	O
+were	O
+markedly	O
+reduced	O
+and	O
+cTnT	O
+was	O
+elevated	O
+from	O
+0	O
+.	O
+0010	O
++	O
+0	O
+.	O
+0020	O
+to	O
+0	O
+.	O
+0073	O
++	O
+0	O
+.	O
+0038	O
+ng	O
+/	O
+mL	O
+(	O
+P	O
+all	O
+<	O
+0	O
+.	O
+01	O
+)	O
+at	O
+the	O
+completion	O
+of	O
+chemotherapy	O
+compared	O
+with	O
+baseline	O
+values	O
+.	O
+
+A	O
+>	O
+15	O
+.	O
+9	O
+%	O
+decrease	O
+in	O
+GLS	O
+[	O
+sensitivity	O
+,	O
+86	O
+%	O
+;	O
+specificity	O
+,	O
+75	O
+%	O
+;	O
+area	O
+under	O
+the	O
+curve	O
+(	O
+AUC	O
+)	O
+=	O
+0	O
+.	O
+815	O
+;	O
+P	O
+=	O
+0	O
+.	O
+001	O
+]	O
+and	O
+a	O
+>	O
+0	O
+.	O
+004	O
+ng	O
+/	O
+mL	O
+elevation	O
+in	O
+cTnT	O
+(	O
+sensitivity	O
+,	O
+79	O
+%	O
+;	O
+specificity	O
+,	O
+64	O
+%	O
+;	O
+AUC	O
+=	O
+0	O
+.	O
+757	O
+;	O
+P	O
+=	O
+0	O
+.	O
+005	O
+)	O
+from	O
+baseline	O
+to	O
+the	O
+third	O
+cycle	O
+of	O
+chemotherapy	O
+predicted	O
+later	O
+cardiotoxicity	B
+.	O
+
+The	O
+decrease	O
+in	O
+GLS	O
+remained	O
+the	O
+only	O
+independent	O
+predictor	O
+of	O
+cardiotoxicity	B
+(	O
+P	O
+=	O
+0	O
+.	O
+000	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+GLS	O
+combined	O
+with	O
+cTnT	O
+may	O
+provide	O
+a	O
+reliable	O
+and	O
+non	O
+-	O
+invasive	O
+method	O
+to	O
+predict	O
+cardiac	B
+dysfunction	I
+in	O
+patients	O
+receiving	O
+anthracycline	O
+-	O
+based	O
+chemotherapy	O
+.	O
+
+Prevention	O
+of	O
+etomidate	O
+-	O
+induced	O
+myoclonus	B
+:	O
+which	O
+is	O
+superior	O
+:	O
+Fentanyl	O
+,	O
+midazolam	O
+,	O
+or	O
+a	O
+combination	O
+?	O
+
+A	O
+Retrospective	O
+comparative	O
+study	O
+.	O
+
+BACKGROUND	O
+:	O
+In	O
+this	O
+retrospective	O
+comparative	O
+study	O
+,	O
+we	O
+aimed	O
+to	O
+compare	O
+the	O
+effectiveness	O
+of	O
+fentanyl	O
+,	O
+midazolam	O
+,	O
+and	O
+a	O
+combination	O
+of	O
+fentanyl	O
+and	O
+midazolam	O
+to	O
+prevent	O
+etomidate	O
+-	O
+induced	O
+myoclonus	B
+.	O
+
+MATERIAL	O
+AND	O
+METHODS	O
+:	O
+This	O
+study	O
+was	O
+performed	O
+based	O
+on	O
+anesthesia	O
+records	O
+.	O
+
+Depending	O
+on	O
+the	O
+drugs	O
+that	O
+would	O
+be	O
+given	O
+before	O
+the	O
+induction	O
+of	O
+anesthesia	O
+with	O
+etomidate	O
+,	O
+the	O
+patients	O
+were	O
+separated	O
+into	O
+4	O
+groups	O
+:	O
+no	O
+pretreatment	O
+(	O
+Group	O
+NP	O
+)	O
+,	O
+fentanyl	O
+1	O
+ug	O
+.	O
+kg	O
+-	O
+1	O
+(	O
+Group	O
+F	O
+)	O
+,	O
+midazolam	O
+0	O
+.	O
+03	O
+mg	O
+.	O
+kg	O
+-	O
+1	O
+(	O
+Group	O
+M	O
+)	O
+,	O
+and	O
+midazolam	O
+0	O
+.	O
+015	O
+mg	O
+.	O
+kg	O
+-	O
+1	O
++	O
+fentanyl	O
+0	O
+.	O
+5	O
+ug	O
+.	O
+kg	O
+-	O
+1	O
+(	O
+Group	O
+FM	O
+)	O
+.	O
+
+Patients	O
+who	O
+received	O
+the	O
+same	O
+anesthetic	O
+procedure	O
+were	O
+selected	O
+:	O
+2	O
+minutes	O
+after	O
+intravenous	O
+injections	O
+of	O
+the	O
+pretreatment	O
+drugs	O
+,	O
+anesthesia	O
+is	O
+induced	O
+with	O
+0	O
+.	O
+3	O
+mg	O
+.	O
+kg	O
+-	O
+1	O
+etomidate	O
+injected	O
+intravenously	O
+over	O
+a	O
+period	O
+of	O
+20	O
+-	O
+30	O
+seconds	O
+.	O
+
+Myoclonic	B
+movements	I
+are	O
+evaluated	O
+,	O
+which	O
+were	O
+observed	O
+and	O
+graded	O
+according	O
+to	O
+clinical	O
+severity	O
+during	O
+the	O
+2	O
+minutes	O
+after	O
+etomidate	O
+injection	O
+.	O
+
+The	O
+severity	O
+of	O
+pain	B
+due	O
+to	O
+etomidate	O
+injection	O
+,	O
+mean	O
+arterial	O
+pressure	O
+,	O
+heart	O
+rate	O
+,	O
+and	O
+adverse	O
+effects	O
+were	O
+also	O
+evaluated	O
+.	O
+
+RESULTS	O
+:	O
+Study	O
+results	O
+showed	O
+that	O
+myoclonus	B
+incidence	O
+was	O
+85	O
+%	O
+,	O
+40	O
+%	O
+,	O
+70	O
+%	O
+,	O
+and	O
+25	O
+%	O
+in	O
+Group	O
+NP	O
+,	O
+Group	O
+F	O
+,	O
+Group	O
+M	O
+,	O
+and	O
+Group	O
+FM	O
+,	O
+respectively	O
+,	O
+and	O
+were	O
+significantly	O
+lower	O
+in	O
+Group	O
+F	O
+and	O
+Group	O
+FM	O
+.	O
+
+CONCLUSIONS	O
+:	O
+We	O
+conclude	O
+that	O
+pretreatment	O
+with	O
+fentanyl	O
+or	O
+combination	O
+of	O
+fentanyl	O
+and	O
+midazolam	O
+was	O
+effective	O
+in	O
+preventing	O
+etomidate	O
+-	O
+induced	O
+myoclonus	B
+.	O
+
+Convulsant	O
+effect	O
+of	O
+lindane	O
+and	O
+regional	O
+brain	O
+concentration	O
+of	O
+GABA	O
+and	O
+dopamine	O
+.	O
+
+Lindane	O
+(	O
+gamma	O
+-	O
+hexachlorocyclohexane	O
+)	O
+is	O
+an	O
+organochlorine	O
+insecticide	O
+with	O
+known	O
+neurotoxic	B
+effects	O
+.	O
+
+Its	O
+mechanism	O
+of	O
+action	O
+is	O
+not	O
+well	O
+understood	O
+although	O
+it	O
+has	O
+been	O
+proposed	O
+that	O
+lindane	O
+acts	O
+as	O
+a	O
+non	O
+-	O
+competitive	O
+antagonist	O
+at	O
+the	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+(	O
+GABA	O
+)	O
+-	O
+A	O
+receptor	O
+.	O
+
+We	O
+studied	O
+the	O
+effect	O
+of	O
+lindane	O
+(	O
+150	O
+mg	O
+/	O
+kg	O
+)	O
+on	O
+the	O
+GABAergic	O
+and	O
+dopaminergic	O
+systems	O
+by	O
+measuring	O
+the	O
+concentration	O
+of	O
+GABA	O
+,	O
+dopamine	O
+and	O
+its	O
+metabolites	O
+in	O
+7	O
+brain	O
+areas	O
+at	O
+the	O
+onset	O
+of	O
+seizures	B
+.	O
+
+All	O
+animals	O
+suffered	O
+tonic	O
+convulsions	B
+at	O
+18	O
+.	O
+3	O
++	O
+/	O
+-	O
+1	O
+.	O
+4	O
+min	O
+after	O
+lindane	O
+administration	O
+.	O
+
+The	O
+concentration	O
+of	O
+GABA	O
+was	O
+only	O
+slightly	O
+but	O
+significantly	O
+decreased	O
+in	O
+the	O
+colliculi	O
+without	O
+modifications	O
+in	O
+the	O
+other	O
+areas	O
+.	O
+
+The	O
+concentration	O
+of	O
+dopamine	O
+was	O
+increased	O
+in	O
+the	O
+mesencephalon	O
+and	O
+that	O
+of	O
+its	O
+metabolite	O
+DOPAC	O
+was	O
+also	O
+increased	O
+in	O
+the	O
+mesencephalon	O
+and	O
+the	O
+striatum	O
+.	O
+
+Cholestatic	B
+presentation	O
+of	O
+yellow	O
+phosphorus	O
+poisoning	B
+.	O
+
+Yellow	O
+phosphorus	O
+,	O
+a	O
+component	O
+of	O
+certain	O
+pesticide	O
+pastes	O
+and	O
+fireworks	O
+,	O
+is	O
+well	O
+known	O
+to	O
+cause	O
+hepatotoxicity	B
+.	O
+
+Poisoning	B
+with	O
+yellow	O
+phosphorus	O
+classically	O
+manifests	O
+with	O
+acute	B
+hepatitis	I
+leading	O
+to	O
+acute	B
+liver	I
+failure	I
+which	O
+may	O
+need	O
+liver	O
+transplantation	O
+.	O
+
+We	O
+present	O
+a	O
+case	O
+of	O
+yellow	O
+phosphorus	O
+poisoning	B
+in	O
+which	O
+a	O
+patient	O
+presented	O
+with	O
+florid	O
+clinical	O
+features	O
+of	O
+cholestasis	B
+highlighting	O
+the	O
+fact	O
+that	O
+cholestasis	B
+can	O
+rarely	O
+be	O
+a	O
+presenting	O
+feature	O
+of	O
+yellow	O
+phosphorus	O
+hepatotoxicity	B
+.	O
+
+Vasovagal	B
+syncope	I
+and	O
+severe	O
+bradycardia	B
+following	O
+intranasal	O
+dexmedetomidine	O
+for	O
+pediatric	O
+procedural	O
+sedation	O
+.	O
+
+We	O
+report	O
+syncope	B
+and	O
+bradycardia	B
+in	O
+an	O
+11	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+following	O
+administration	O
+of	O
+intranasal	O
+dexmedetomidine	O
+for	O
+sedation	O
+for	O
+a	O
+voiding	O
+cystourethrogram	O
+.	O
+
+Following	O
+successful	O
+completion	O
+of	O
+VCUG	O
+and	O
+a	O
+60	O
+-	O
+min	O
+recovery	O
+period	O
+,	O
+the	O
+patient	O
+'	O
+s	O
+level	O
+of	O
+consciousness	O
+and	O
+vital	O
+signs	O
+returned	O
+to	O
+presedation	O
+levels	O
+.	O
+
+Upon	O
+leaving	O
+the	O
+sedation	O
+area	O
+,	O
+the	O
+patient	O
+collapsed	O
+,	O
+with	O
+no	O
+apparent	O
+inciting	O
+event	O
+.	O
+
+The	O
+patient	O
+quickly	O
+regained	O
+consciousness	O
+and	O
+no	O
+injury	O
+occurred	O
+.	O
+
+The	O
+primary	O
+abnormality	O
+found	O
+was	O
+persistent	O
+bradycardia	B
+,	O
+and	O
+she	O
+was	O
+admitted	O
+to	O
+the	O
+hospital	O
+for	O
+telemetric	O
+observation	O
+.	O
+
+The	O
+bradycardia	B
+lasted	O
+~	O
+2	O
+h	O
+,	O
+and	O
+further	O
+cardiac	O
+workup	O
+revealed	O
+no	O
+underlying	O
+abnormality	O
+.	O
+
+Unanticipated	O
+and	O
+previously	O
+unreported	O
+outcomes	O
+may	O
+be	O
+witnessed	O
+as	O
+we	O
+expand	O
+the	O
+use	O
+of	O
+certain	O
+sedatives	O
+to	O
+alternative	O
+routes	O
+of	O
+administration	O
+.	O
+
+Paradoxical	O
+severe	O
+agitation	B
+induced	O
+by	O
+add	O
+-	O
+on	O
+high	O
+-	O
+doses	O
+quetiapine	O
+in	O
+schizo	B
+-	I
+affective	I
+disorder	I
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+35	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+suffering	O
+from	O
+schizo	B
+-	I
+affective	I
+disorder	I
+since	O
+the	O
+age	O
+of	O
+19	O
+years	O
+,	O
+treated	O
+by	O
+a	O
+combination	O
+of	O
+first	O
+-	O
+generation	O
+antipsychotics	O
+,	O
+zuclopenthixol	O
+(	O
+100	O
+mg	O
+/	O
+day	O
+)	O
+and	O
+lithium	O
+(	O
+1200	O
+mg	O
+/	O
+day	O
+)	O
+(	O
+serum	O
+lithium	O
+=	O
+0	O
+.	O
+85	O
+mEq	O
+/	O
+l	O
+)	O
+.	O
+
+This	O
+patient	O
+had	O
+no	O
+associated	O
+personality	B
+disorder	I
+(	O
+particularly	O
+no	O
+antisocial	B
+disorder	I
+)	O
+and	O
+no	O
+substance	B
+abuse	I
+disorder	I
+.	O
+
+Within	O
+the	O
+48	O
+h	O
+following	O
+the	O
+gradual	O
+introduction	O
+of	O
+quetiapine	O
+(	O
+up	O
+to	O
+600	O
+mg	O
+/	O
+day	O
+)	O
+,	O
+the	O
+patient	O
+presented	O
+severe	O
+agitation	B
+without	O
+an	O
+environmental	O
+explanation	O
+,	O
+contrasting	O
+with	O
+the	O
+absence	O
+of	O
+a	O
+history	O
+of	O
+aggressiveness	B
+or	O
+personality	B
+disorder	I
+.	O
+
+The	O
+diagnoses	O
+of	O
+manic	B
+shift	O
+and	O
+akathisia	B
+were	O
+dismissed	O
+.	O
+
+The	O
+withdrawal	O
+and	O
+the	O
+gradual	O
+reintroduction	O
+of	O
+quetiapine	O
+2	O
+weeks	O
+later	O
+,	O
+which	O
+led	O
+to	O
+another	O
+severe	O
+agitation	B
+,	O
+enabled	O
+us	O
+to	O
+attribute	O
+the	O
+agitation	B
+specifically	O
+to	O
+quetiapine	O
+.	O
+
+Antioxidant	O
+effects	O
+of	O
+bovine	O
+lactoferrin	O
+on	O
+dexamethasone	O
+-	O
+induced	O
+hypertension	B
+in	O
+rat	O
+.	O
+
+Dexamethasone	O
+-	O
+(	O
+Dex	O
+-	O
+)	O
+induced	O
+hypertension	B
+is	O
+associated	O
+with	O
+enhanced	O
+oxidative	O
+stress	O
+.	O
+
+Lactoferrin	O
+(	O
+LF	O
+)	O
+is	O
+an	O
+iron	O
+-	O
+binding	O
+glycoprotein	O
+with	O
+antihypertensive	O
+properties	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+investigated	O
+the	O
+effect	O
+of	O
+chronic	O
+administration	O
+of	O
+LF	O
+on	O
+oxidative	O
+stress	O
+and	O
+hypertension	B
+upon	O
+Dex	O
+administration	O
+.	O
+
+Male	O
+Wistar	O
+rats	O
+were	O
+treated	O
+by	O
+Dex	O
+(	O
+30	O
+u	O
+g	O
+/	O
+kg	O
+/	O
+day	O
+subcutaneously	O
+)	O
+or	O
+saline	O
+for	O
+14	O
+days	O
+.	O
+
+Oral	O
+bovine	O
+LF	O
+(	O
+30	O
+,	O
+100	O
+,	O
+300	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+given	O
+from	O
+day	O
+8	O
+to	O
+14	O
+in	O
+a	O
+reversal	O
+study	O
+.	O
+
+In	O
+a	O
+prevention	O
+study	O
+,	O
+rats	O
+received	O
+4	O
+days	O
+of	O
+LF	O
+treatment	O
+followed	O
+by	O
+Dex	O
+and	O
+continued	O
+during	O
+the	O
+test	O
+period	O
+.	O
+
+Systolic	O
+blood	O
+pressure	O
+(	O
+SBP	O
+)	O
+was	O
+measured	O
+using	O
+tail	O
+-	O
+cuff	O
+method	O
+.	O
+
+Thymus	O
+weight	O
+was	O
+used	O
+as	O
+a	O
+marker	O
+of	O
+glucocorticoid	O
+activity	O
+.	O
+
+Plasma	O
+hydrogen	O
+peroxide	O
+(	O
+H2O2	O
+)	O
+concentration	O
+and	O
+ferric	O
+reducing	O
+antioxidant	O
+power	O
+(	O
+FRAP	O
+)	O
+value	O
+were	O
+determined	O
+.	O
+
+Dexamethasone	O
+significantly	O
+increased	O
+SBP	O
+and	O
+plasma	O
+H2O2	O
+level	O
+and	O
+decreased	O
+thymus	O
+and	O
+body	O
+weights	O
+.	O
+
+LF	O
+lowered	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+and	O
+dose	O
+dependently	O
+prevented	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+Dex	O
+-	O
+induced	O
+hypertension	B
+.	O
+
+LF	O
+prevented	O
+body	O
+weight	B
+loss	I
+and	O
+significantly	O
+reduced	O
+the	O
+elevated	O
+plasma	O
+H2O2	O
+and	O
+increased	O
+FRAP	O
+values	O
+.	O
+
+Chronic	O
+administration	O
+of	O
+LF	O
+strongly	O
+reduced	O
+the	O
+blood	O
+pressure	O
+and	O
+production	O
+of	O
+ROS	O
+and	O
+improved	O
+antioxidant	O
+capacity	O
+in	O
+Dex	O
+-	O
+induced	O
+hypertension	B
+,	O
+suggesting	O
+the	O
+role	O
+of	O
+inhibition	O
+of	O
+oxidative	O
+stress	O
+as	O
+another	O
+mechanism	O
+of	O
+antihypertensive	O
+action	O
+of	O
+LF	O
+.	O
+
+The	O
+association	O
+between	O
+tranexamic	O
+acid	O
+and	O
+convulsive	B
+seizures	B
+after	O
+cardiac	O
+surgery	O
+:	O
+a	O
+multivariate	O
+analysis	O
+in	O
+11	O
+529	O
+patients	O
+.	O
+
+Because	O
+of	O
+a	O
+lack	O
+of	O
+contemporary	O
+data	O
+regarding	O
+seizures	B
+after	O
+cardiac	O
+surgery	O
+,	O
+we	O
+undertook	O
+a	O
+retrospective	O
+analysis	O
+of	O
+prospectively	O
+collected	O
+data	O
+from	O
+11	O
+529	O
+patients	O
+in	O
+whom	O
+cardiopulmonary	O
+bypass	O
+was	O
+used	O
+from	O
+January	O
+2004	O
+to	O
+December	O
+2010	O
+.	O
+
+A	O
+convulsive	B
+seizure	B
+was	O
+defined	O
+as	O
+a	O
+transient	O
+episode	O
+of	O
+disturbed	O
+brain	O
+function	O
+characterised	O
+by	O
+abnormal	B
+involuntary	I
+motor	I
+movements	I
+.	O
+
+Multivariate	O
+regression	O
+analysis	O
+was	O
+performed	O
+to	O
+identify	O
+independent	O
+predictors	O
+of	O
+postoperative	O
+seizures	B
+.	O
+
+A	O
+total	O
+of	O
+100	O
+(	O
+0	O
+.	O
+9	O
+%	O
+)	O
+patients	O
+developed	O
+postoperative	O
+convulsive	B
+seizures	B
+.	O
+
+Generalised	B
+and	I
+focal	I
+seizures	I
+were	O
+identified	O
+in	O
+68	O
+and	O
+32	O
+patients	O
+,	O
+respectively	O
+.	O
+
+The	O
+median	O
+(	O
+IQR	O
+[	O
+range	O
+]	O
+)	O
+time	O
+after	O
+surgery	O
+when	O
+the	O
+seizure	B
+occurred	O
+was	O
+7	O
+(	O
+6	O
+-	O
+12	O
+[	O
+1	O
+-	O
+216	O
+]	O
+)	O
+h	O
+and	O
+8	O
+(	O
+6	O
+-	O
+11	O
+[	O
+4	O
+-	O
+18	O
+]	O
+)	O
+h	O
+,	O
+respectively	O
+.	O
+
+Epileptiform	O
+findings	O
+on	O
+electroencephalography	O
+were	O
+seen	O
+in	O
+19	O
+patients	O
+.	O
+
+Independent	O
+predictors	O
+of	O
+postoperative	O
+seizures	B
+included	O
+age	O
+,	O
+female	O
+sex	O
+,	O
+redo	O
+cardiac	O
+surgery	O
+,	O
+calcification	O
+of	O
+ascending	O
+aorta	O
+,	O
+congestive	B
+heart	I
+failure	I
+,	O
+deep	O
+hypothermic	B
+circulatory	O
+arrest	O
+,	O
+duration	O
+of	O
+aortic	O
+cross	O
+-	O
+clamp	O
+and	O
+tranexamic	O
+acid	O
+.	O
+
+When	O
+tested	O
+in	O
+a	O
+multivariate	O
+regression	O
+analysis	O
+,	O
+tranexamic	O
+acid	O
+was	O
+a	O
+strong	O
+independent	O
+predictor	O
+of	O
+seizures	B
+(	O
+OR	O
+14	O
+.	O
+3	O
+,	O
+95	O
+%	O
+CI	O
+5	O
+.	O
+5	O
+-	O
+36	O
+.	O
+7	O
+;	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Patients	O
+with	O
+convulsive	B
+seizures	B
+had	O
+2	O
+.	O
+5	O
+times	O
+higher	O
+in	O
+-	O
+hospital	O
+mortality	O
+rates	O
+and	O
+twice	O
+the	O
+length	O
+of	O
+hospital	O
+stay	O
+compared	O
+with	O
+patients	O
+without	O
+convulsive	B
+seizures	B
+.	O
+
+Mean	O
+(	O
+IQR	O
+[	O
+range	O
+]	O
+)	O
+length	O
+of	O
+stay	O
+in	O
+the	O
+intensive	O
+care	O
+unit	O
+was	O
+115	O
+(	O
+49	O
+-	O
+228	O
+[	O
+32	O
+-	O
+481	O
+]	O
+)	O
+h	O
+in	O
+patients	O
+with	O
+convulsive	B
+seizures	B
+compared	O
+with	O
+26	O
+(	O
+22	O
+-	O
+69	O
+[	O
+14	O
+-	O
+1080	O
+]	O
+)	O
+h	O
+in	O
+patients	O
+without	O
+seizures	B
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Convulsive	B
+seizures	B
+are	O
+a	O
+serious	O
+postoperative	B
+complication	I
+after	O
+cardiac	O
+surgery	O
+.	O
+
+As	O
+tranexamic	O
+acid	O
+is	O
+the	O
+only	O
+modifiable	O
+factor	O
+,	O
+its	O
+administration	O
+,	O
+particularly	O
+in	O
+doses	O
+exceeding	O
+80	O
+mg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+,	O
+should	O
+be	O
+weighed	O
+against	O
+the	O
+risk	O
+of	O
+postoperative	O
+seizures	B
+.	O
+
+Dysfunctional	B
+overnight	I
+memory	I
+consolidation	O
+in	O
+ecstasy	O
+users	O
+.	O
+
+Sleep	O
+plays	O
+an	O
+important	O
+role	O
+in	O
+the	O
+consolidation	O
+and	O
+integration	O
+of	O
+memory	O
+in	O
+a	O
+process	O
+called	O
+overnight	O
+memory	O
+consolidation	O
+.	O
+
+Previous	O
+studies	O
+indicate	O
+that	O
+ecstasy	O
+users	O
+have	O
+marked	O
+and	O
+persistent	O
+neurocognitive	O
+and	O
+sleep	B
+-	I
+related	I
+impairments	I
+.	O
+
+We	O
+extend	O
+past	O
+research	O
+by	O
+examining	O
+overnight	O
+memory	O
+consolidation	O
+among	O
+regular	O
+ecstasy	O
+users	O
+(	O
+n	O
+=	O
+12	O
+)	O
+and	O
+drug	O
+naive	O
+healthy	O
+controls	O
+(	O
+n	O
+=	O
+26	O
+)	O
+.	O
+
+Memory	O
+recall	O
+of	O
+word	O
+pairs	O
+was	O
+evaluated	O
+before	O
+and	O
+after	O
+a	O
+period	O
+of	O
+sleep	O
+,	O
+with	O
+and	O
+without	O
+interference	O
+prior	O
+to	O
+testing	O
+.	O
+
+In	O
+addition	O
+,	O
+we	O
+assessed	O
+neurocognitive	O
+performances	O
+across	O
+tasks	O
+of	O
+learning	O
+,	O
+memory	O
+and	O
+executive	O
+functioning	O
+.	O
+
+Ecstasy	O
+users	O
+demonstrated	O
+impaired	B
+overnight	I
+memory	I
+consolidation	O
+,	O
+a	O
+finding	O
+that	O
+was	O
+more	O
+pronounced	O
+following	O
+associative	O
+interference	O
+.	O
+
+Additionally	O
+,	O
+ecstasy	O
+users	O
+demonstrated	O
+impairments	O
+on	O
+tasks	O
+recruiting	O
+frontostriatal	O
+and	O
+hippocampal	O
+neural	O
+circuitry	O
+,	O
+in	O
+the	O
+domains	O
+of	O
+proactive	O
+interference	O
+memory	O
+,	O
+long	O
+-	O
+term	O
+memory	O
+,	O
+encoding	O
+,	O
+working	O
+memory	O
+and	O
+complex	O
+planning	O
+.	O
+
+We	O
+suggest	O
+that	O
+ecstasy	O
+-	O
+associated	O
+dysfunction	O
+in	O
+fronto	O
+-	O
+temporal	O
+circuitry	O
+may	O
+underlie	O
+overnight	O
+consolidation	O
+memory	B
+impairments	I
+in	O
+regular	O
+ecstasy	O
+users	O
+.	O
+
+Normoammonemic	O
+encephalopathy	B
+:	O
+solely	O
+valproate	O
+induced	O
+or	O
+multiple	O
+mechanisms	O
+?	O
+
+A	O
+77	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+presented	O
+with	O
+subacute	O
+onset	O
+progressive	O
+confusion	B
+,	O
+aggression	B
+,	O
+auditory	B
+hallucinations	I
+and	O
+delusions	B
+.	O
+
+In	O
+the	O
+preceding	O
+months	O
+,	O
+the	O
+patient	O
+had	O
+a	O
+number	O
+of	O
+admissions	O
+with	O
+transient	O
+unilateral	O
+hemiparesis	B
+with	O
+facial	O
+droop	O
+,	O
+and	O
+had	O
+been	O
+started	O
+on	O
+valproate	O
+for	O
+presumed	O
+hemiplegic	B
+migraine	I
+.	O
+
+Valproate	O
+was	O
+withdrawn	O
+soon	O
+after	O
+admission	O
+and	O
+her	O
+cognitive	O
+abilities	O
+have	O
+gradually	O
+improved	O
+over	O
+3	O
+months	O
+of	O
+follow	O
+-	O
+up	O
+.	O
+
+Valproate	O
+levels	O
+taken	O
+prior	O
+to	O
+withdrawal	O
+were	O
+subtherapeutic	O
+and	O
+the	O
+patient	O
+was	O
+normoammonaemic	O
+.	O
+
+EEG	O
+undertaken	O
+during	O
+inpatient	O
+stay	O
+showed	O
+changes	O
+consistent	O
+with	O
+encephalopathy	B
+,	O
+and	O
+low	O
+titre	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+receptor	O
+antibodies	O
+were	O
+present	O
+in	O
+this	O
+patient	O
+.	O
+
+The	O
+possible	O
+aetiologies	O
+of	O
+valproate	O
+-	O
+induced	O
+encephalopathy	B
+and	O
+NMDA	O
+receptor	O
+-	O
+associated	O
+encephalitis	B
+present	O
+a	O
+diagnostic	O
+dilemma	O
+.	O
+
+We	O
+present	O
+a	O
+putative	O
+combinatorial	O
+hypothesis	O
+to	O
+explain	O
+this	O
+patient	O
+'	O
+s	O
+symptoms	O
+.	O
+
+Cerebellar	B
+and	I
+oculomotor	I
+dysfunction	I
+induced	O
+by	O
+rapid	O
+infusion	O
+of	O
+pethidine	O
+.	O
+
+Pethidine	O
+is	O
+an	O
+opioid	O
+that	O
+gains	O
+its	O
+popularity	O
+for	O
+the	O
+effective	O
+pain	B
+control	O
+through	O
+acting	O
+on	O
+the	O
+opioid	O
+-	O
+receptors	O
+.	O
+
+However	O
+,	O
+rapid	O
+pain	B
+relief	O
+sometimes	O
+brings	O
+about	O
+unfavourable	O
+side	O
+effects	O
+that	O
+largely	O
+limit	O
+its	O
+clinical	O
+utility	O
+.	O
+
+Common	O
+side	O
+effects	O
+include	O
+nausea	B
+,	O
+vomiting	B
+and	O
+hypotension	B
+.	O
+
+In	O
+patients	O
+with	O
+impaired	B
+renal	I
+and	I
+liver	I
+function	I
+,	O
+and	O
+those	O
+who	O
+need	O
+long	O
+-	O
+term	O
+pain	B
+control	O
+,	O
+pethidine	O
+may	O
+cause	O
+excitatory	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+effects	O
+through	O
+its	O
+neurotoxic	B
+metabolite	O
+,	O
+norpethidine	O
+,	O
+resulting	O
+in	O
+irritability	B
+and	O
+seizure	B
+attack	O
+.	O
+
+On	O
+the	O
+contrary	O
+,	O
+though	O
+not	O
+clinically	O
+apparent	O
+,	O
+pethidine	O
+potentially	O
+causes	O
+inhibitory	O
+impacts	O
+on	O
+the	O
+CNS	O
+and	O
+impairs	O
+normal	O
+cerebellar	O
+and	O
+oculomotor	O
+function	O
+in	O
+the	O
+short	O
+term	O
+.	O
+
+In	O
+this	O
+case	O
+report	O
+,	O
+we	O
+highlight	O
+opioid	O
+'	O
+s	O
+inhibitory	O
+side	O
+effects	O
+on	O
+the	O
+cerebellar	O
+structure	O
+that	O
+causes	O
+dysmetria	B
+,	O
+dysarthria	B
+,	O
+reduced	O
+smooth	O
+pursuit	O
+gain	O
+and	O
+decreased	O
+saccadic	O
+velocity	O
+.	O
+
+Baboon	B
+syndrome	I
+induced	O
+by	O
+ketoconazole	O
+.	O
+
+A	O
+27	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+presented	O
+with	O
+a	O
+maculopapular	B
+eruption	I
+on	O
+the	O
+flexural	O
+areas	O
+and	O
+buttocks	O
+after	O
+using	O
+oral	O
+ketoconazole	O
+.	O
+
+The	O
+patient	O
+was	O
+diagnosed	O
+with	O
+drug	O
+-	O
+induced	O
+baboon	B
+syndrome	I
+based	O
+on	O
+his	O
+history	O
+,	O
+which	O
+included	O
+prior	O
+sensitivity	O
+to	O
+topical	O
+ketoconazole	O
+,	O
+a	O
+physical	O
+examination	O
+,	O
+and	O
+histopathological	O
+findings	O
+.	O
+
+Baboon	B
+syndrome	I
+is	O
+a	O
+drug	O
+-	O
+or	O
+contact	O
+allergen	O
+-	O
+related	O
+maculopapular	B
+eruption	I
+that	O
+typically	O
+involves	O
+the	O
+flexural	O
+and	O
+gluteal	O
+areas	O
+.	O
+
+To	O
+the	O
+best	O
+of	O
+our	O
+knowledge	O
+,	O
+this	O
+is	O
+the	O
+first	O
+reported	O
+case	O
+of	O
+ketoconazole	O
+-	O
+induced	O
+baboon	B
+syndrome	I
+in	O
+the	O
+English	O
+literature	O
+.	O
+
+A	O
+Case	O
+of	O
+Sudden	B
+Cardiac	I
+Death	I
+due	O
+to	O
+Pilsicainide	O
+-	O
+Induced	O
+Torsades	B
+de	I
+Pointes	I
+.	O
+
+An	O
+84	O
+-	O
+year	O
+-	O
+old	O
+male	O
+received	O
+oral	O
+pilsicainide	O
+,	O
+a	O
+pure	O
+sodium	O
+channel	O
+blocker	O
+with	O
+slow	O
+recovery	O
+kinetics	O
+,	O
+to	O
+convert	O
+his	O
+paroxysmal	O
+atrial	B
+fibrillation	I
+to	O
+a	O
+sinus	O
+rhythm	O
+;	O
+the	O
+patient	O
+developed	O
+sudden	B
+cardiac	I
+death	I
+two	O
+days	O
+later	O
+.	O
+
+The	O
+Holter	O
+electrocardiogram	O
+,	O
+which	O
+was	O
+worn	O
+by	O
+chance	O
+,	O
+revealed	O
+torsade	B
+de	I
+pointes	I
+with	O
+gradually	O
+prolonged	O
+QT	O
+intervals	O
+.	O
+
+This	O
+drug	O
+is	O
+rapidly	O
+absorbed	O
+from	O
+the	O
+gastrointestinal	O
+tract	O
+,	O
+and	O
+most	O
+of	O
+it	O
+is	O
+excreted	O
+from	O
+the	O
+kidney	O
+.	O
+
+Although	O
+the	O
+patient	O
+'	O
+s	O
+renal	O
+function	O
+was	O
+not	O
+highly	O
+impaired	O
+and	O
+the	O
+dose	O
+of	O
+pilsicainide	O
+was	O
+low	O
+,	O
+the	O
+plasma	O
+concentration	O
+of	O
+pilsicainide	O
+may	O
+have	O
+been	O
+high	O
+,	O
+which	O
+can	O
+produce	O
+torsades	B
+de	I
+pointes	I
+in	O
+the	O
+octogenarian	O
+.	O
+
+Although	O
+the	O
+oral	O
+administration	O
+of	O
+class	O
+IC	O
+drugs	O
+,	O
+including	O
+pilsicainide	O
+,	O
+is	O
+effective	O
+to	O
+terminate	O
+atrial	B
+fibrillation	I
+,	O
+careful	O
+consideration	O
+must	O
+be	O
+taken	O
+before	O
+giving	O
+these	O
+drugs	O
+to	O
+octogenarians	O
+.	O
+
+All	O
+-	O
+trans	O
+retinoic	O
+acid	O
+-	O
+induced	O
+inflammatory	O
+myositis	B
+in	O
+a	O
+patient	O
+with	O
+acute	B
+promyelocytic	I
+leukemia	I
+.	O
+
+All	O
+-	O
+trans	O
+retinoic	O
+acid	O
+(	O
+ATRA	O
+)	O
+,	O
+a	O
+component	O
+of	O
+standard	O
+therapy	O
+for	O
+acute	B
+promyelocytic	I
+leukemia	I
+(	O
+APL	B
+)	O
+,	O
+is	O
+associated	O
+with	O
+potentially	O
+serious	O
+but	O
+treatable	O
+adverse	O
+effects	O
+involving	O
+numerous	O
+organ	O
+systems	O
+,	O
+including	O
+rare	O
+skeletal	O
+muscle	O
+involvement	O
+.	O
+
+Only	O
+a	O
+handful	O
+of	O
+cases	O
+of	O
+ATRA	O
+-	O
+induced	O
+myositis	B
+in	O
+children	O
+have	O
+been	O
+reported	O
+,	O
+and	O
+none	O
+in	O
+the	O
+radiology	O
+literature	O
+.	O
+
+We	O
+present	O
+such	O
+a	O
+case	O
+in	O
+a	O
+15	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+with	O
+APL	B
+,	O
+where	O
+recognition	O
+of	O
+imaging	O
+findings	O
+played	O
+a	O
+crucial	O
+role	O
+in	O
+making	O
+the	O
+diagnosis	O
+and	O
+facilitated	O
+prompt	O
+,	O
+effective	O
+treatment	O
+.	O
+
+Tolerability	O
+of	O
+lomustine	O
+in	O
+combination	O
+with	O
+cyclophosphamide	O
+in	O
+dogs	O
+with	O
+lymphoma	B
+.	O
+
+This	O
+retrospective	O
+study	O
+describes	O
+toxicity	B
+associated	O
+with	O
+a	O
+protocol	O
+of	O
+lomustine	O
+(	O
+CCNU	O
+)	O
+and	O
+cyclophosphamide	O
+(	O
+CTX	O
+)	O
+in	O
+dogs	O
+with	O
+lymphoma	B
+.	O
+
+CCNU	O
+was	O
+administered	O
+per	O
+os	O
+(	O
+PO	O
+)	O
+at	O
+a	O
+targeted	O
+dosage	O
+of	O
+60	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+body	O
+surface	O
+area	O
+on	O
+day	O
+0	O
+,	O
+CTX	O
+was	O
+administered	O
+PO	O
+at	O
+a	O
+targeted	O
+dosage	O
+of	O
+250	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+divided	O
+over	O
+days	O
+0	O
+through	O
+4	O
+,	O
+and	O
+all	O
+dogs	O
+received	O
+prophylactic	O
+antibiotics	O
+.	O
+
+Ninety	O
+treatments	O
+were	O
+given	O
+to	O
+the	O
+57	O
+dogs	O
+included	O
+in	O
+the	O
+study	O
+.	O
+
+Neutropenia	B
+was	O
+the	O
+principal	O
+toxic	O
+effect	O
+,	O
+and	O
+the	O
+overall	O
+frequency	O
+of	O
+grade	O
+4	O
+neutropenia	B
+after	O
+the	O
+first	O
+treatment	O
+of	O
+CCNU	O
+/	O
+CTX	O
+was	O
+30	O
+%	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+19	O
+-	O
+43	O
+%	O
+)	O
+.	O
+
+The	O
+mean	O
+body	O
+weight	O
+of	O
+dogs	O
+with	O
+grade	O
+4	O
+neutropenia	B
+(	O
+19	O
+.	O
+7	O
+kg	O
++	O
+13	O
+.	O
+4	O
+kg	O
+)	O
+was	O
+significantly	O
+less	O
+than	O
+the	O
+mean	O
+body	O
+weight	O
+of	O
+dogs	O
+that	O
+did	O
+not	O
+develop	O
+grade	O
+4	O
+neutropenia	B
+(	O
+31	O
+.	O
+7	O
+kg	O
++	O
+12	O
+.	O
+4	O
+kg	O
+;	O
+P	O
+=	O
+.	O
+005	O
+)	O
+.	O
+
+One	O
+dog	O
+(	O
+3	O
+%	O
+)	O
+developed	O
+hematologic	O
+changes	O
+suggestive	O
+of	O
+hepatotoxicity	B
+.	O
+
+No	O
+dogs	O
+had	O
+evidence	O
+of	O
+either	O
+renal	B
+toxicity	I
+or	O
+hemorrhagic	B
+cystitis	I
+.	O
+
+Adverse	O
+gastrointestinal	O
+effects	O
+were	O
+uncommon	O
+.	O
+
+On	O
+the	O
+basis	O
+of	O
+the	O
+findings	O
+reported	O
+herein	O
+,	O
+a	O
+dose	O
+of	O
+60	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+of	O
+CCNU	O
+combined	O
+with	O
+250	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+of	O
+CTX	O
+(	O
+divided	O
+over	O
+5	O
+days	O
+)	O
+q	O
+4	O
+wk	O
+is	O
+tolerable	O
+in	O
+tumor	B
+-	O
+bearing	O
+dogs	O
+.	O
+
+Nelarabine	O
+neurotoxicity	B
+with	O
+concurrent	O
+intrathecal	O
+chemotherapy	O
+:	O
+Case	O
+report	O
+and	O
+review	O
+of	O
+literature	O
+.	O
+
+Severe	O
+nelarabine	O
+neurotoxicity	B
+in	O
+a	O
+patient	O
+who	O
+received	O
+concurrent	O
+intrathecal	O
+(	O
+IT	O
+)	O
+chemotherapy	O
+is	O
+reported	O
+.	O
+
+A	O
+37	O
+-	O
+year	O
+-	O
+old	O
+Caucasian	O
+woman	O
+with	O
+a	O
+history	O
+of	O
+T	B
+-	I
+cell	I
+lymphoblastic	I
+lymphoma	I
+was	O
+admitted	O
+for	O
+relapsed	O
+disease	O
+.	O
+
+She	O
+was	O
+originally	O
+treated	O
+with	O
+induction	O
+chemotherapy	O
+followed	O
+by	O
+an	O
+autologous	O
+transplant	O
+.	O
+
+She	O
+developed	O
+relapsed	O
+disease	O
+10	O
+months	O
+later	O
+with	O
+leukemic	B
+involvement	O
+.	O
+
+She	O
+was	O
+re	O
+-	O
+induced	O
+with	O
+nelarabine	O
+1500	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+on	O
+days	O
+1	O
+,	O
+3	O
+,	O
+and	O
+5	O
+with	O
+1	O
+dose	O
+of	O
+IT	O
+cytarabine	O
+100	O
+mg	O
+on	O
+day	O
+2	O
+as	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+prophylaxis	O
+.	O
+
+At	O
+the	O
+time	O
+of	O
+treatment	O
+,	O
+she	O
+was	O
+on	O
+continuous	O
+renal	O
+replacement	O
+therapy	O
+due	O
+to	O
+sequelae	O
+of	O
+tumor	B
+lysis	I
+syndrome	I
+(	O
+TLS	B
+)	O
+.	O
+
+She	O
+tolerated	O
+therapy	O
+well	O
+,	O
+entered	O
+a	O
+complete	O
+remission	O
+,	O
+and	O
+recovered	O
+her	O
+renal	O
+function	O
+.	O
+
+She	O
+received	O
+a	O
+second	O
+cycle	O
+of	O
+nelarabine	O
+without	O
+additional	O
+IT	O
+prophylaxis	O
+one	O
+month	O
+later	O
+.	O
+
+A	O
+week	O
+after	O
+this	O
+second	O
+cycle	O
+,	O
+she	O
+noted	O
+numbness	O
+in	O
+her	O
+lower	O
+extremities	O
+.	O
+
+Predominantly	O
+sensory	O
+,	O
+though	O
+also	O
+motor	O
+and	O
+autonomic	O
+,	O
+peripheral	B
+neuropathy	I
+started	O
+in	O
+her	O
+feet	O
+,	O
+ascended	O
+proximally	O
+to	O
+the	O
+mid	O
+-	O
+thoracic	O
+region	O
+,	O
+and	O
+eventually	O
+included	O
+her	O
+distal	O
+upper	O
+extremities	O
+.	O
+
+A	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+of	O
+her	O
+spine	O
+demonstrated	O
+changes	O
+from	O
+C2	O
+to	O
+C6	O
+consistent	O
+with	O
+subacute	O
+combined	O
+degeneration	O
+.	O
+
+Nelarabine	O
+was	O
+felt	O
+to	O
+be	O
+the	O
+cause	O
+of	O
+her	O
+symptoms	O
+.	O
+
+Her	O
+neuropathy	B
+stabilized	O
+and	O
+showed	O
+slight	O
+improvement	O
+and	O
+ultimately	O
+received	O
+an	O
+unrelated	O
+,	O
+reduced	O
+-	O
+intensity	O
+allogeneic	O
+transplant	O
+while	O
+in	O
+complete	O
+remission	O
+,	O
+but	O
+relapsed	O
+disease	O
+10	O
+weeks	O
+later	O
+.	O
+
+She	O
+is	O
+currently	O
+being	O
+treated	O
+with	O
+best	O
+supportive	O
+care	O
+.	O
+
+To	O
+our	O
+knowledge	O
+,	O
+this	O
+is	O
+the	O
+first	O
+published	O
+case	O
+report	O
+of	O
+severe	O
+neurotoxicity	B
+caused	O
+by	O
+nelarabine	O
+in	O
+a	O
+patient	O
+who	O
+received	O
+concurrent	O
+IT	O
+chemotherapy	O
+.	O
+
+Valproate	O
+-	O
+induced	O
+hyperammonemic	B
+encephalopathy	B
+in	O
+a	O
+renal	O
+transplanted	O
+patient	O
+.	O
+
+Neurological	B
+complications	I
+after	O
+renal	O
+transplantation	O
+constitute	O
+an	O
+important	O
+cause	O
+of	O
+morbidity	O
+and	O
+mortality	O
+.	O
+
+Their	O
+differential	O
+diagnosis	O
+is	O
+difficult	O
+and	O
+essential	O
+for	O
+subsequent	O
+patient	O
+'	O
+s	O
+management	O
+.	O
+
+Valproate	O
+-	O
+induced	O
+hyperammonemic	B
+encephalopathy	B
+is	O
+an	O
+uncommon	O
+but	O
+serious	O
+effect	O
+of	O
+valproate	O
+treatment	O
+.	O
+
+Here	O
+,	O
+we	O
+describe	O
+the	O
+case	O
+of	O
+a	O
+15	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+who	O
+was	O
+on	O
+a	O
+long	O
+-	O
+term	O
+therapy	O
+with	O
+valproate	O
+due	O
+to	O
+epilepsy	B
+and	O
+revealed	O
+impaired	B
+consciousness	I
+with	O
+hyperammonemia	B
+12	O
+days	O
+after	O
+renal	O
+transplantation	O
+.	O
+
+After	O
+withdraw	O
+of	O
+valproate	O
+,	O
+patients	O
+'	O
+symptoms	O
+resolved	O
+within	O
+24	O
+h	O
+.	O
+
+Clinicians	O
+should	O
+increase	O
+their	O
+awareness	O
+for	O
+potential	O
+complication	O
+of	O
+valproate	O
+,	O
+especially	O
+in	O
+transplanted	O
+patients	O
+.	O
+
+Necrotising	B
+fasciitis	I
+after	O
+bortezomib	O
+and	O
+dexamethasone	O
+-	O
+containing	O
+regimen	O
+in	O
+an	O
+elderly	O
+patient	O
+of	O
+Waldenstrom	B
+macroglobulinaemia	I
+.	O
+
+Bortezomib	O
+and	O
+high	O
+-	O
+dose	O
+dexamethasone	O
+-	O
+containing	O
+regimens	O
+are	O
+considered	O
+to	O
+be	O
+generally	O
+tolerable	O
+with	O
+few	O
+severe	O
+bacterial	B
+infections	I
+in	O
+patients	O
+with	O
+B	O
+-	O
+cell	O
+malignancies	B
+.	O
+
+However	O
+,	O
+information	O
+is	O
+limited	O
+concerning	O
+the	O
+safety	O
+of	O
+the	O
+regimen	O
+in	O
+elderly	O
+patients	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+a	O
+76	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+Waldenstrom	B
+macroglobulinaemia	I
+who	O
+suffered	O
+necrotising	B
+fasciitis	I
+without	O
+neutropenia	B
+after	O
+the	O
+combination	O
+treatment	O
+with	O
+bortezomib	O
+,	O
+high	O
+-	O
+dose	O
+dexamethasone	O
+and	O
+rituximab	O
+.	O
+
+Despite	O
+immediate	O
+intravenous	O
+antimicrobial	O
+therapy	O
+,	O
+he	O
+succumbed	O
+23	O
+h	O
+after	O
+the	O
+onset	O
+.	O
+
+Physicians	O
+should	O
+recognise	O
+the	O
+possibility	O
+of	O
+fatal	O
+bacterial	B
+infections	I
+related	O
+to	O
+bortezomib	O
+plus	O
+high	O
+-	O
+dose	O
+dexamethasone	O
+in	O
+elderly	O
+patients	O
+,	O
+and	O
+we	O
+believe	O
+this	O
+case	O
+warrants	O
+further	O
+investigation	O
+.	O
+
+An	O
+integrated	O
+characterization	O
+of	O
+serological	O
+,	O
+pathological	O
+,	O
+and	O
+functional	O
+events	O
+in	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+Many	O
+efficacious	O
+cancer	B
+treatments	O
+cause	O
+significant	O
+cardiac	O
+morbidity	O
+,	O
+yet	O
+biomarkers	O
+or	O
+functional	O
+indices	O
+of	O
+early	O
+damage	O
+,	O
+which	O
+would	O
+allow	O
+monitoring	O
+and	O
+intervention	O
+,	O
+are	O
+lacking	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+have	O
+utilized	O
+a	O
+rat	O
+model	O
+of	O
+progressive	O
+doxorubicin	O
+(	O
+DOX	O
+)	O
+-	O
+induced	O
+cardiomyopathy	B
+,	O
+applying	O
+multiple	O
+approaches	O
+,	O
+including	O
+cardiac	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+,	O
+to	O
+provide	O
+the	O
+most	O
+comprehensive	O
+characterization	O
+to	O
+date	O
+of	O
+the	O
+timecourse	O
+of	O
+serological	O
+,	O
+pathological	O
+,	O
+and	O
+functional	O
+events	O
+underlying	O
+this	O
+toxicity	B
+.	O
+
+Hannover	O
+Wistar	O
+rats	O
+were	O
+dosed	O
+with	O
+1	O
+.	O
+25	O
+mg	O
+/	O
+kg	O
+DOX	O
+weekly	O
+for	O
+8	O
+weeks	O
+followed	O
+by	O
+a	O
+4	O
+week	O
+off	O
+-	O
+dosing	O
+"	O
+recovery	O
+"	O
+period	O
+.	O
+
+Electron	O
+microscopy	O
+of	O
+the	O
+myocardium	O
+revealed	O
+subcellular	B
+degeneration	I
+and	O
+marked	O
+mitochondrial	O
+changes	O
+after	O
+a	O
+single	O
+dose	O
+.	O
+
+Histopathological	O
+analysis	O
+revealed	O
+progressive	O
+cardiomyocyte	B
+degeneration	I
+,	O
+hypertrophy	B
+/	O
+cytomegaly	O
+,	O
+and	O
+extensive	O
+vacuolation	O
+after	O
+two	O
+doses	O
+.	O
+
+Extensive	O
+replacement	O
+fibrosis	B
+(	O
+quantified	O
+by	O
+Sirius	O
+red	O
+staining	O
+)	O
+developed	O
+during	O
+the	O
+off	O
+-	O
+dosing	O
+period	O
+.	O
+
+Functional	O
+indices	O
+assessed	O
+by	O
+cardiac	O
+MRI	O
+(	O
+including	O
+left	O
+ventricular	O
+ejection	O
+fraction	O
+(	O
+LVEF	O
+)	O
+,	O
+cardiac	O
+output	O
+,	O
+and	O
+E	O
+/	O
+A	O
+ratio	O
+)	O
+declined	O
+progressively	O
+,	O
+reaching	O
+statistical	O
+significance	O
+after	O
+two	O
+doses	O
+and	O
+culminating	O
+in	O
+"	O
+clinical	O
+"	O
+LV	B
+dysfunction	I
+by	O
+12	O
+weeks	O
+.	O
+
+Significant	O
+increases	O
+in	O
+peak	O
+myocardial	O
+contrast	O
+enhancement	O
+and	O
+serological	O
+cardiac	O
+troponin	O
+I	O
+(	O
+cTnI	O
+)	O
+emerged	O
+after	O
+eight	O
+doses	O
+,	O
+importantly	O
+preceding	O
+the	O
+LVEF	O
+decline	O
+to	O
+<	O
+50	O
+%	O
+.	O
+
+Troponin	O
+I	O
+levels	O
+positively	O
+correlated	O
+with	O
+delayed	O
+and	O
+peak	O
+gadolinium	O
+contrast	O
+enhancement	O
+,	O
+histopathological	O
+grading	O
+,	O
+and	O
+diastolic	B
+dysfunction	I
+.	O
+
+In	O
+summary	O
+,	O
+subcellular	O
+cardiomyocyte	B
+degeneration	I
+was	O
+the	O
+earliest	O
+marker	O
+,	O
+followed	O
+by	O
+progressive	O
+functional	O
+decline	O
+and	O
+histopathological	O
+manifestations	O
+.	O
+
+Myocardial	O
+contrast	O
+enhancement	O
+and	O
+elevations	O
+in	O
+cTnI	O
+occurred	O
+later	O
+.	O
+
+However	O
+,	O
+all	O
+indices	O
+predated	O
+"	O
+clinical	O
+"	O
+LV	B
+dysfunction	I
+and	O
+thus	O
+warrant	O
+further	O
+evaluation	O
+as	O
+predictive	O
+biomarkers	O
+.	O
+
+Intradermal	O
+glutamate	O
+and	O
+capsaicin	O
+injections	O
+:	O
+intra	O
+-	O
+and	O
+interindividual	O
+variability	O
+of	O
+provoked	O
+hyperalgesia	B
+and	O
+allodynia	B
+.	O
+
+Intradermal	O
+injections	O
+of	O
+glutamate	O
+and	O
+capsaicin	O
+are	O
+attractive	O
+to	O
+use	O
+in	O
+human	O
+experimental	O
+pain	B
+models	O
+because	O
+hyperalgesia	B
+and	O
+allodynia	B
+mimic	O
+isolated	O
+aspects	O
+of	O
+clinical	O
+pain	B
+disorders	I
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+reproducibility	O
+of	O
+these	O
+models	O
+.	O
+
+Twenty	O
+healthy	O
+male	O
+volunteers	O
+(	O
+mean	O
+age	O
+24	O
+years	O
+;	O
+range	O
+18	O
+-	O
+38	O
+years	O
+)	O
+received	O
+intradermal	O
+injections	O
+of	O
+glutamate	O
+and	O
+capsaicin	O
+in	O
+the	O
+volar	O
+forearm	O
+.	O
+
+Magnitudes	O
+of	O
+secondary	O
+pinprick	O
+hyperalgesia	B
+and	O
+brush	O
+-	O
+evoked	O
+allodynia	B
+were	O
+investigated	O
+using	O
+von	O
+Frey	O
+filaments	O
+(	O
+gauges	O
+10	O
+,	O
+15	O
+,	O
+60	O
+and	O
+100	O
+g	O
+)	O
+and	O
+brush	O
+strokes	O
+.	O
+
+Areas	O
+of	O
+secondary	B
+hyperalgesia	I
+and	O
+allodynia	B
+were	O
+quantified	O
+immediately	O
+after	O
+injection	O
+and	O
+after	O
+15	O
+,	O
+30	O
+and	O
+60	O
+min	O
+.	O
+
+Two	O
+identical	O
+experiments	O
+separated	O
+by	O
+at	O
+least	O
+7	O
+days	O
+were	O
+performed	O
+.	O
+
+Reproducibility	O
+across	O
+and	O
+within	O
+volunteers	O
+(	O
+inter	O
+-	O
+and	O
+intra	O
+-	O
+individual	O
+variation	O
+,	O
+respectively	O
+)	O
+was	O
+assessed	O
+using	O
+intraclass	O
+correlation	O
+coefficient	O
+(	O
+ICC	O
+)	O
+and	O
+coefficient	O
+of	O
+variation	O
+(	O
+CV	O
+)	O
+.	O
+
+Secondary	O
+pinprick	O
+hyperalgesia	B
+was	O
+observed	O
+as	O
+a	O
+marked	O
+increase	O
+in	O
+the	O
+visual	O
+analogue	O
+scale	O
+(	O
+VAS	O
+)	O
+response	O
+to	O
+von	O
+Frey	O
+gauges	O
+60	O
+and	O
+100	O
+g	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+after	O
+glutamate	O
+injection	O
+.	O
+
+For	O
+capsaicin	O
+,	O
+secondary	O
+pinprick	O
+hyperalgesia	B
+was	O
+detected	O
+with	O
+all	O
+von	O
+Frey	O
+gauges	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Glutamate	O
+evoked	O
+reproducible	O
+VAS	O
+response	O
+to	O
+all	O
+von	O
+Frey	O
+gauges	O
+(	O
+ICC	O
+>	O
+0	O
+.	O
+60	O
+)	O
+and	O
+brush	O
+strokes	O
+(	O
+ICC	O
+>	O
+0	O
+.	O
+83	O
+)	O
+.	O
+
+Capsaicin	O
+injection	O
+was	O
+reproducible	O
+for	O
+secondary	B
+hyperalgesia	I
+(	O
+ICC	O
+>	O
+0	O
+.	O
+70	O
+)	O
+and	O
+allodynia	B
+(	O
+ICC	O
+>	O
+0	O
+.	O
+71	O
+)	O
+.	O
+
+Intra	O
+-	O
+individual	O
+variability	O
+was	O
+generally	O
+lower	O
+for	O
+the	O
+VAS	O
+response	O
+to	O
+von	O
+Frey	O
+and	O
+brush	O
+compared	O
+with	O
+areas	O
+of	O
+secondary	B
+hyperalgesia	I
+and	O
+allodynia	B
+.	O
+
+In	O
+conclusion	O
+,	O
+glutamate	O
+and	O
+capsaicin	O
+yield	O
+reproducible	O
+hyperalgesic	B
+and	O
+allodynic	B
+responses	O
+,	O
+and	O
+the	O
+present	O
+model	O
+is	O
+well	O
+suited	O
+for	O
+basic	O
+research	O
+,	O
+as	O
+well	O
+as	O
+for	O
+assessing	O
+the	O
+modulation	O
+of	O
+central	O
+phenomena	O
+.	O
+
+Ocular	O
+-	O
+specific	O
+ER	O
+stress	O
+reduction	O
+rescues	O
+glaucoma	B
+in	O
+murine	O
+glucocorticoid	O
+-	O
+induced	O
+glaucoma	B
+.	O
+
+Administration	O
+of	O
+glucocorticoids	O
+induces	O
+ocular	B
+hypertension	I
+in	O
+some	O
+patients	O
+.	O
+
+If	O
+untreated	O
+,	O
+these	O
+patients	O
+can	O
+develop	O
+a	O
+secondary	O
+glaucoma	B
+that	O
+resembles	O
+primary	B
+open	I
+-	I
+angle	I
+glaucoma	I
+(	O
+POAG	B
+)	O
+.	O
+
+The	O
+underlying	O
+pathology	O
+of	O
+glucocorticoid	O
+-	O
+induced	O
+glaucoma	B
+is	O
+not	O
+fully	O
+understood	O
+,	O
+due	O
+in	O
+part	O
+to	O
+lack	O
+of	O
+an	O
+appropriate	O
+animal	O
+model	O
+.	O
+
+Here	O
+,	O
+we	O
+developed	O
+a	O
+murine	O
+model	O
+of	O
+glucocorticoid	O
+-	O
+induced	O
+glaucoma	B
+that	O
+exhibits	O
+glaucoma	B
+features	O
+that	O
+are	O
+observed	O
+in	O
+patients	O
+.	O
+
+Treatment	O
+of	O
+WT	O
+mice	O
+with	O
+topical	O
+ocular	O
+0	O
+.	O
+1	O
+%	O
+dexamethasone	O
+led	O
+to	O
+elevation	O
+of	O
+intraocular	O
+pressure	O
+(	O
+IOP	O
+)	O
+,	O
+functional	O
+and	O
+structural	O
+loss	O
+of	O
+retinal	B
+ganglion	I
+cells	O
+,	O
+and	O
+axonal	B
+degeneration	I
+,	O
+resembling	O
+glucocorticoid	O
+-	O
+induced	O
+glaucoma	B
+in	O
+human	O
+patients	O
+.	O
+
+Furthermore	O
+,	O
+dexamethasone	O
+-	O
+induced	O
+ocular	B
+hypertension	I
+was	O
+associated	O
+with	O
+chronic	O
+ER	O
+stress	O
+of	O
+the	O
+trabecular	O
+meshwork	O
+(	O
+TM	O
+)	O
+.	O
+
+Similar	O
+to	O
+patients	O
+,	O
+withdrawal	O
+of	O
+dexamethasone	O
+treatment	O
+reduced	O
+elevated	O
+IOP	O
+and	O
+ER	O
+stress	O
+in	O
+this	O
+animal	O
+model	O
+.	O
+
+Dexamethasone	O
+induced	O
+the	O
+transcriptional	O
+factor	O
+CHOP	O
+,	O
+a	O
+marker	O
+for	O
+chronic	O
+ER	O
+stress	O
+,	O
+in	O
+the	O
+anterior	O
+segment	O
+tissues	O
+,	O
+and	O
+Chop	O
+deletion	O
+reduced	O
+ER	O
+stress	O
+in	O
+these	O
+tissues	O
+and	O
+prevented	O
+dexamethasone	O
+-	O
+induced	O
+ocular	B
+hypertension	I
+.	O
+
+Furthermore	O
+,	O
+reduction	O
+of	O
+ER	O
+stress	O
+in	O
+the	O
+TM	O
+with	O
+sodium	O
+4	O
+-	O
+phenylbutyrate	O
+prevented	O
+dexamethasone	O
+-	O
+induced	O
+ocular	B
+hypertension	I
+in	O
+WT	O
+mice	O
+.	O
+
+Our	O
+data	O
+indicate	O
+that	O
+ER	O
+stress	O
+contributes	O
+to	O
+glucocorticoid	O
+-	O
+induced	O
+ocular	B
+hypertension	I
+and	O
+suggest	O
+that	O
+reducing	O
+ER	O
+stress	O
+has	O
+potential	O
+as	O
+a	O
+therapeutic	O
+strategy	O
+for	O
+treating	O
+glucocorticoid	O
+-	O
+induced	O
+glaucoma	B
+.	O
+
+Effects	O
+of	O
+ginsenosides	O
+on	O
+opioid	O
+-	O
+induced	O
+hyperalgesia	B
+in	O
+mice	O
+.	O
+
+Opioid	O
+-	O
+induced	O
+hyperalgesia	B
+(	O
+OIH	B
+)	O
+is	O
+characterized	O
+by	O
+nociceptive	O
+sensitization	O
+caused	O
+by	O
+the	O
+cessation	O
+of	O
+chronic	O
+opioid	O
+use	O
+.	O
+
+OIH	B
+can	O
+limit	O
+the	O
+clinical	O
+use	O
+of	O
+opioid	O
+analgesics	O
+and	O
+complicate	O
+withdrawal	O
+from	O
+opioid	B
+addiction	I
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+investigated	O
+the	O
+effects	O
+of	O
+Re	O
+,	O
+Rg1	O
+,	O
+and	O
+Rb1	O
+ginsenosides	O
+,	O
+the	O
+bioactive	O
+components	O
+of	O
+ginseng	O
+,	O
+on	O
+OIH	B
+.	O
+
+OIH	B
+was	O
+achieved	O
+in	O
+mice	O
+after	O
+subcutaneous	O
+administration	O
+of	O
+morphine	O
+for	O
+7	O
+consecutive	O
+days	O
+three	O
+times	O
+per	O
+day	O
+.	O
+
+During	O
+withdrawal	O
+(	O
+days	O
+8	O
+and	O
+9	O
+)	O
+,	O
+these	O
+mice	O
+were	O
+administered	O
+Re	O
+,	O
+Rg1	O
+,	O
+or	O
+Rb1	O
+intragastrically	O
+two	O
+times	O
+per	O
+day	O
+.	O
+
+On	O
+the	O
+test	O
+day	O
+(	O
+day	O
+10	O
+)	O
+,	O
+mice	O
+were	O
+subjected	O
+to	O
+the	O
+thermal	O
+sensitivity	O
+test	O
+and	O
+the	O
+acetic	O
+acid	O
+-	O
+induced	O
+writhing	O
+test	O
+.	O
+
+Re	O
+(	O
+300	O
+mg	O
+/	O
+kg	O
+)	O
+inhibited	O
+OIH	B
+in	O
+both	O
+the	O
+thermal	O
+sensitivity	O
+test	O
+and	O
+the	O
+acetic	O
+acid	O
+-	O
+induced	O
+writhing	O
+test	O
+.	O
+
+However	O
+,	O
+the	O
+Rg1	O
+and	O
+Rb1	O
+ginsenosides	O
+failed	O
+to	O
+prevent	O
+OIH	B
+in	O
+either	O
+test	O
+.	O
+
+Furthermore	O
+,	O
+Rg1	O
+showed	O
+a	O
+tendency	O
+to	O
+aggravate	O
+OIH	B
+in	O
+the	O
+acetic	O
+acid	O
+-	O
+induced	O
+writhing	O
+test	O
+.	O
+
+Our	O
+data	O
+suggested	O
+that	O
+the	O
+ginsenoside	O
+Re	O
+,	O
+but	O
+not	O
+Rg1	O
+or	O
+Rb1	O
+,	O
+may	O
+contribute	O
+toward	O
+reversal	O
+of	O
+OIH	B
+.	O
+
+A	O
+comparison	O
+of	O
+severe	O
+hemodynamic	O
+disturbances	O
+between	O
+dexmedetomidine	O
+and	O
+propofol	O
+for	O
+sedation	O
+in	O
+neurocritical	O
+care	O
+patients	O
+.	O
+
+OBJECTIVE	O
+:	O
+Dexmedetomidine	O
+and	O
+propofol	O
+are	O
+commonly	O
+used	O
+sedatives	O
+in	O
+neurocritical	O
+care	O
+as	O
+they	O
+allow	O
+for	O
+frequent	O
+neurologic	O
+examinations	O
+.	O
+
+However	O
+,	O
+both	O
+agents	O
+are	O
+associated	O
+with	O
+significant	O
+hemodynamic	O
+side	O
+effects	O
+.	O
+
+The	O
+primary	O
+objective	O
+of	O
+this	O
+study	O
+is	O
+to	O
+compare	O
+the	O
+prevalence	O
+of	O
+severe	O
+hemodynamic	O
+effects	O
+in	O
+neurocritical	O
+care	O
+patients	O
+receiving	O
+dexmedetomidine	O
+and	O
+propofol	O
+.	O
+
+DESIGN	O
+:	O
+Multicenter	O
+,	O
+retrospective	O
+,	O
+propensity	O
+-	O
+matched	O
+cohort	O
+study	O
+.	O
+
+SETTING	O
+:	O
+Neurocritical	O
+care	O
+units	O
+at	O
+two	O
+academic	O
+medical	O
+centers	O
+with	O
+dedicated	O
+neurocritical	O
+care	O
+teams	O
+and	O
+board	O
+-	O
+certified	O
+neurointensivists	O
+.	O
+
+PATIENTS	O
+:	O
+Neurocritical	O
+care	O
+patients	O
+admitted	O
+between	O
+July	O
+2009	O
+and	O
+September	O
+2012	O
+were	O
+evaluated	O
+and	O
+then	O
+matched	O
+1	O
+:	O
+1	O
+based	O
+on	O
+propensity	O
+scoring	O
+of	O
+baseline	O
+characteristics	O
+.	O
+
+INTERVENTIONS	O
+:	O
+Continuous	O
+sedation	O
+with	O
+dexmedetomidine	O
+or	O
+propofol	O
+.	O
+
+MEASUREMENTS	O
+AND	O
+MAIN	O
+RESULTS	O
+:	O
+A	O
+total	O
+of	O
+342	O
+patients	O
+(	O
+105	O
+dexmedetomidine	O
+and	O
+237	O
+propofol	O
+)	O
+were	O
+included	O
+in	O
+the	O
+analysis	O
+,	O
+with	O
+190	O
+matched	O
+(	O
+95	O
+in	O
+each	O
+group	O
+)	O
+by	O
+propensity	O
+score	O
+.	O
+
+The	O
+primary	O
+outcome	O
+of	O
+this	O
+study	O
+was	O
+a	O
+composite	O
+of	O
+severe	O
+hypotension	B
+(	O
+mean	O
+arterial	O
+pressure	O
+<	O
+60	O
+mm	O
+Hg	O
+)	O
+and	O
+bradycardia	B
+(	O
+heart	O
+rate	O
+<	O
+50	O
+beats	O
+/	O
+min	O
+)	O
+during	O
+sedative	O
+infusion	O
+.	O
+
+No	O
+difference	O
+in	O
+the	O
+primary	O
+composite	O
+outcome	O
+in	O
+both	O
+the	O
+unmatched	O
+(	O
+30	O
+%	O
+vs	O
+30	O
+%	O
+,	O
+p	O
+=	O
+0	O
+.	O
+94	O
+)	O
+or	O
+matched	O
+cohorts	O
+(	O
+28	O
+%	O
+vs	O
+34	O
+%	O
+,	O
+p	O
+=	O
+0	O
+.	O
+35	O
+)	O
+could	O
+be	O
+found	O
+.	O
+
+When	O
+analyzed	O
+separately	O
+,	O
+no	O
+differences	O
+could	O
+be	O
+found	O
+in	O
+the	O
+prevalence	O
+of	O
+severe	O
+hypotension	B
+or	O
+bradycardia	B
+in	O
+either	O
+the	O
+unmatched	O
+or	O
+matched	O
+cohorts	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Severe	O
+hypotension	B
+and	O
+bradycardia	B
+occur	O
+at	O
+similar	O
+prevalence	O
+in	O
+neurocritical	O
+care	O
+patients	O
+who	O
+receive	O
+dexmedetomidine	O
+or	O
+propofol	O
+.	O
+
+Providers	O
+should	O
+similarly	O
+consider	O
+the	O
+likelihood	O
+of	O
+hypotension	B
+or	O
+bradycardia	B
+before	O
+starting	O
+either	O
+sedative	O
+.	O
+
+Hydroxytyrosol	O
+ameliorates	O
+oxidative	O
+stress	O
+and	O
+mitochondrial	B
+dysfunction	I
+in	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B
+in	O
+rats	O
+with	O
+breast	B
+cancer	I
+.	O
+
+Oxidative	O
+stress	O
+is	O
+involved	O
+in	O
+several	O
+processes	O
+including	O
+cancer	B
+,	O
+aging	O
+and	O
+cardiovascular	B
+disease	I
+,	O
+and	O
+has	O
+been	O
+shown	O
+to	O
+potentiate	O
+the	O
+therapeutic	O
+effect	O
+of	O
+drugs	O
+such	O
+as	O
+doxorubicin	O
+.	O
+
+Doxorubicin	O
+causes	O
+significant	O
+cardiotoxicity	B
+characterized	O
+by	O
+marked	O
+increases	O
+in	O
+oxidative	O
+stress	O
+and	O
+mitochondrial	B
+dysfunction	I
+.	O
+
+Herein	O
+,	O
+we	O
+investigate	O
+whether	O
+doxorubicin	O
+-	O
+associated	O
+chronic	O
+cardiac	B
+toxicity	I
+can	O
+be	O
+ameliorated	O
+with	O
+the	O
+antioxidant	O
+hydroxytyrosol	O
+in	O
+rats	O
+with	O
+breast	B
+cancer	I
+.	O
+
+Thirty	O
+-	O
+six	O
+rats	O
+bearing	O
+breast	B
+tumors	I
+induced	O
+chemically	O
+were	O
+divided	O
+into	O
+4	O
+groups	O
+:	O
+control	O
+,	O
+hydroxytyrosol	O
+(	O
+0	O
+.	O
+5mg	O
+/	O
+kg	O
+,	O
+5days	O
+/	O
+week	O
+)	O
+,	O
+doxorubicin	O
+(	O
+1mg	O
+/	O
+kg	O
+/	O
+week	O
+)	O
+,	O
+and	O
+doxorubicin	O
+plus	O
+hydroxytyrosol	O
+.	O
+
+Cardiac	B
+disturbances	I
+at	O
+the	O
+cellular	O
+and	O
+mitochondrial	O
+level	O
+,	O
+mitochondrial	O
+electron	O
+transport	O
+chain	O
+complexes	O
+I	O
+-	O
+IV	O
+and	O
+apoptosis	O
+-	O
+inducing	O
+factor	O
+,	O
+and	O
+oxidative	O
+stress	O
+markers	O
+have	O
+been	O
+analyzed	O
+.	O
+
+Hydroxytyrosol	O
+improved	O
+the	O
+cardiac	B
+disturbances	I
+enhanced	O
+by	O
+doxorubicin	O
+by	O
+significantly	O
+reducing	O
+the	O
+percentage	O
+of	O
+altered	O
+mitochondria	O
+and	O
+oxidative	O
+damage	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+hydroxytyrosol	O
+improve	O
+the	O
+mitochondrial	O
+electron	O
+transport	O
+chain	O
+.	O
+
+This	O
+study	O
+demonstrates	O
+that	O
+hydroxytyrosol	O
+protect	O
+rat	O
+heart	B
+damage	I
+provoked	O
+by	O
+doxorubicin	O
+decreasing	O
+oxidative	O
+damage	O
+and	O
+mitochondrial	O
+alterations	O
+.	O
+
+Amiodarone	O
+-	O
+induced	O
+myxoedema	B
+coma	I
+.	O
+
+A	O
+62	O
+-	O
+year	O
+-	O
+old	O
+man	O
+was	O
+found	O
+to	O
+have	O
+bradycardia	B
+,	O
+hypothermia	B
+and	O
+respiratory	B
+failure	I
+3	O
+weeks	O
+after	O
+initiation	O
+of	O
+amiodarone	O
+therapy	O
+for	O
+atrial	B
+fibrillation	I
+.	O
+
+Thyroid	O
+-	O
+stimulating	O
+hormone	O
+was	O
+found	O
+to	O
+be	O
+168	O
+uIU	O
+/	O
+mL	O
+(	O
+nl	O
+.	O
+0	O
+.	O
+3	O
+-	O
+5	O
+uIU	O
+/	O
+mL	O
+)	O
+and	O
+free	O
+thyroxine	O
+(	O
+FT4	O
+)	O
+was	O
+<	O
+0	O
+.	O
+2	O
+ng	O
+/	O
+dL	O
+(	O
+nl	O
+.	O
+0	O
+.	O
+8	O
+-	O
+1	O
+.	O
+8	O
+ng	O
+/	O
+dL	O
+)	O
+.	O
+
+He	O
+received	O
+intravenous	O
+fluids	O
+,	O
+vasopressor	O
+therapy	O
+and	O
+stress	O
+dose	O
+steroids	O
+;	O
+he	O
+was	O
+intubated	O
+and	O
+admitted	O
+to	O
+the	O
+intensive	O
+care	O
+unit	O
+.	O
+
+He	O
+received	O
+500	O
+ug	O
+of	O
+intravenous	O
+levothyroxine	O
+in	O
+the	O
+first	O
+18	O
+h	O
+of	O
+therapy	O
+,	O
+and	O
+150	O
+ug	O
+intravenous	O
+daily	O
+thereafter	O
+.	O
+
+Haemodynamic	O
+improvement	O
+,	O
+along	O
+with	O
+complete	O
+recovery	O
+of	O
+mental	O
+status	O
+,	O
+occurred	O
+after	O
+48	O
+h	O
+.	O
+
+Twelve	O
+hours	O
+after	O
+the	O
+initiation	O
+of	O
+therapy	O
+,	O
+FT4	O
+was	O
+0	O
+.	O
+96	O
+ng	O
+/	O
+dL	O
+.	O
+
+The	O
+patient	O
+was	O
+maintained	O
+on	O
+levothyroxine	O
+175	O
+(	O
+g	O
+POorally	O
+daily	O
+.	O
+
+A	O
+thyroid	O
+ultrasound	O
+showed	O
+diffuse	O
+heterogeneity	O
+.	O
+
+The	O
+24	O
+hour	O
+excretion	O
+of	O
+iodine	O
+was	O
+3657	O
+(	O
+mcg	O
+(	O
+25	O
+-	O
+756	O
+(	O
+mcg	O
+)	O
+.	O
+
+The	O
+only	O
+two	O
+cases	O
+of	O
+amiodarone	O
+-	O
+induced	O
+myxoedema	B
+coma	I
+in	O
+the	O
+literature	O
+report	O
+patient	O
+death	O
+despite	O
+supportive	O
+therapy	O
+and	O
+thyroid	O
+hormone	O
+replacement	O
+.	O
+
+This	O
+case	O
+represents	O
+the	O
+most	O
+thoroughly	O
+investigated	O
+case	O
+of	O
+amiodarone	O
+-	O
+induced	O
+myxoedema	B
+coma	I
+with	O
+a	O
+history	O
+significant	O
+for	O
+subclinical	O
+thyroid	B
+disease	I
+.	O
+
+Use	O
+of	O
+argatroban	O
+and	O
+catheter	O
+-	O
+directed	O
+thrombolysis	B
+with	O
+alteplase	O
+in	O
+an	O
+oncology	O
+patient	O
+with	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+with	O
+thrombosis	B
+.	O
+
+PURPOSE	O
+:	O
+The	O
+case	O
+of	O
+an	O
+oncology	O
+patient	O
+who	O
+developed	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+with	O
+thrombosis	B
+(	O
+HITT	B
+)	O
+and	O
+was	O
+treated	O
+with	O
+argatroban	O
+plus	O
+catheter	O
+-	O
+directed	O
+thrombolysis	B
+(	O
+CDT	O
+)	O
+with	O
+alteplase	O
+is	O
+presented	O
+.	O
+
+SUMMARY	O
+:	O
+A	O
+63	O
+-	O
+year	O
+-	O
+old	O
+Caucasian	O
+man	O
+with	O
+renal	O
+amyloidosis	B
+undergoing	O
+peripheral	O
+blood	O
+stem	O
+cell	O
+collection	O
+for	O
+an	O
+autologous	O
+stem	O
+cell	O
+transplant	O
+developed	O
+extensive	O
+bilateral	O
+upper	B
+-	I
+extremity	I
+deep	I
+venous	I
+thrombosis	I
+(	O
+DVT	B
+)	O
+and	O
+pulmonary	B
+embolism	I
+secondary	O
+to	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+.	O
+
+A	O
+continuous	O
+i	O
+.	O
+v	O
+.	O
+infusion	O
+of	O
+argatroban	O
+was	O
+initiated	O
+,	O
+and	O
+the	O
+patient	O
+was	O
+managed	O
+on	O
+the	O
+general	O
+medical	O
+floor	O
+.	O
+
+After	O
+one	O
+week	O
+of	O
+therapy	O
+,	O
+he	O
+was	O
+transferred	O
+to	O
+the	O
+intensive	O
+care	O
+unit	O
+with	O
+cardiopulmonary	O
+compromise	O
+related	O
+to	O
+superior	B
+vena	I
+cava	I
+(	I
+SVC	I
+)	I
+syndrome	I
+.	O
+
+A	O
+percutaneous	O
+mechanical	O
+thrombectomy	O
+and	O
+CDT	O
+with	O
+alteplase	O
+were	O
+attempted	O
+,	O
+but	O
+the	O
+procedure	O
+was	O
+aborted	O
+due	O
+to	O
+epistaxis	B
+.	O
+
+The	O
+epistaxis	B
+resolved	O
+the	O
+next	O
+day	O
+,	O
+and	O
+the	O
+patient	O
+was	O
+restarted	O
+on	O
+argatroban	O
+.	O
+
+A	O
+second	O
+percutaneous	O
+mechanical	O
+thrombectomy	O
+was	O
+performed	O
+six	O
+days	O
+later	O
+and	O
+resulted	O
+in	O
+partial	O
+revascularization	O
+of	O
+the	O
+SVC	O
+and	O
+central	O
+veins	O
+.	O
+
+Postthrombectomy	O
+continuous	O
+CDT	O
+with	O
+alteplase	O
+was	O
+commenced	O
+while	O
+argatroban	O
+was	O
+withheld	O
+,	O
+and	O
+complete	O
+patency	O
+of	O
+the	O
+SVC	O
+and	O
+central	O
+veins	O
+was	O
+achieved	O
+after	O
+three	O
+days	O
+of	O
+therapy	O
+.	O
+
+Alteplase	O
+was	O
+discontinued	O
+,	O
+and	O
+the	O
+patient	O
+was	O
+reinitiated	O
+on	O
+argatroban	O
+;	O
+ultimately	O
+,	O
+he	O
+was	O
+transitioned	O
+to	O
+warfarin	O
+for	O
+long	O
+-	O
+term	O
+anticoagulation	O
+.	O
+
+Although	O
+the	O
+patient	O
+recovered	O
+,	O
+he	O
+experienced	O
+permanent	O
+vision	B
+and	I
+hearing	I
+loss	I
+,	O
+as	O
+well	O
+as	O
+end	B
+-	I
+stage	I
+renal	I
+disease	I
+.	O
+
+CONCLUSION	O
+:	O
+A	O
+63	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+renal	O
+amyloidosis	B
+and	O
+SVC	B
+syndrome	I
+secondary	O
+to	O
+HITT	B
+was	O
+successfully	O
+treated	O
+with	O
+argatroban	O
+and	O
+CDT	O
+with	O
+alteplase	O
+.	O
+
+Effects	O
+of	O
+dehydroepiandrosterone	O
+in	O
+amphetamine	O
+-	O
+induced	O
+schizophrenia	B
+models	O
+in	O
+mice	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+examine	O
+the	O
+effects	O
+of	O
+dehydroepiandrosterone	O
+(	O
+DHEA	O
+)	O
+on	O
+animal	O
+models	O
+of	O
+schizophrenia	B
+.	O
+
+METHODS	O
+:	O
+Seventy	O
+Swiss	O
+albino	O
+female	O
+mice	O
+(	O
+25	O
+-	O
+35	O
+g	O
+)	O
+were	O
+divided	O
+into	O
+4	O
+groups	O
+:	O
+amphetamine	O
+-	O
+free	O
+(	O
+control	O
+)	O
+,	O
+amphetamine	O
+,	O
+50	O
+,	O
+and	O
+100	O
+mg	O
+/	O
+kg	O
+DHEA	O
+.	O
+
+The	O
+DHEA	O
+was	O
+administered	O
+intraperitoneally	O
+(	O
+ip	O
+)	O
+for	O
+5	O
+days	O
+.	O
+
+Amphetamine	O
+(	O
+3	O
+mg	O
+/	O
+kg	O
+ip	O
+)	O
+induced	O
+hyper	B
+locomotion	O
+,	O
+apomorphine	O
+(	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+subcutaneously	O
+[	O
+sc	O
+]	O
+)	O
+induced	O
+climbing	O
+,	O
+and	O
+haloperidol	O
+(	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+sc	O
+)	O
+induced	O
+catalepsy	B
+tests	O
+were	O
+used	O
+as	O
+animal	O
+models	O
+of	O
+schizophrenia	B
+.	O
+
+The	O
+study	O
+was	O
+conducted	O
+at	O
+the	O
+Animal	O
+Experiment	O
+Laboratories	O
+,	O
+Department	O
+of	O
+Pharmacology	O
+,	O
+Medical	O
+School	O
+,	O
+Eskisehir	O
+Osmangazi	O
+University	O
+,	O
+Eskisehir	O
+,	O
+Turkey	O
+between	O
+March	O
+and	O
+May	O
+2012	O
+.	O
+
+Statistical	O
+analysis	O
+was	O
+carried	O
+out	O
+using	O
+Kruskal	O
+-	O
+Wallis	O
+test	O
+for	O
+hyper	B
+locomotion	O
+,	O
+and	O
+one	O
+-	O
+way	O
+ANOVA	O
+for	O
+climbing	O
+and	O
+catalepsy	B
+tests	O
+.	O
+
+RESULTS	O
+:	O
+In	O
+the	O
+amphetamine	O
+-	O
+induced	O
+locomotion	O
+test	O
+,	O
+there	O
+were	O
+significant	O
+increases	O
+in	O
+all	O
+movements	O
+compared	O
+with	O
+the	O
+amphetamine	O
+-	O
+free	O
+group	O
+.	O
+
+Both	O
+DHEA	O
+50	O
+mg	O
+/	O
+kg	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+,	O
+and	O
+100	O
+mg	O
+/	O
+kg	O
+(	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+significantly	O
+decreased	O
+all	O
+movements	O
+compared	O
+with	O
+the	O
+amphetamine	O
+-	O
+induced	O
+locomotion	O
+group	O
+.	O
+
+There	O
+was	O
+a	O
+significant	O
+difference	O
+between	O
+groups	O
+in	O
+the	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+test	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+There	O
+was	O
+no	O
+significant	O
+difference	O
+between	O
+groups	O
+in	O
+terms	O
+of	O
+total	O
+climbing	O
+time	O
+in	O
+the	O
+apomorphine	O
+-	O
+induced	O
+climbing	O
+test	O
+(	O
+p	O
+>	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+We	O
+observed	O
+that	O
+DHEA	O
+reduced	O
+locomotor	O
+activity	O
+and	O
+increased	O
+catalepsy	B
+at	O
+both	O
+doses	O
+,	O
+while	O
+it	O
+had	O
+no	O
+effect	O
+on	O
+climbing	O
+behavior	O
+.	O
+
+We	O
+suggest	O
+that	O
+DHEA	O
+displays	O
+typical	O
+neuroleptic	O
+-	O
+like	O
+effects	O
+,	O
+and	O
+may	O
+be	O
+used	O
+in	O
+the	O
+treatment	O
+of	O
+schizophrenia	B
+.	O
+
+Availability	O
+of	O
+human	O
+induced	O
+pluripotent	O
+stem	O
+cell	O
+-	O
+derived	O
+cardiomyocytes	O
+in	O
+assessment	O
+of	O
+drug	O
+potential	O
+for	O
+QT	B
+prolongation	I
+.	O
+
+Field	O
+potential	O
+duration	O
+(	O
+FPD	O
+)	O
+in	O
+human	O
+-	O
+induced	O
+pluripotent	O
+stem	O
+cell	O
+-	O
+derived	O
+cardiomyocytes	O
+(	O
+hiPS	O
+-	O
+CMs	O
+)	O
+,	O
+which	O
+can	O
+express	O
+QT	O
+interval	O
+in	O
+an	O
+electrocardiogram	O
+,	O
+is	O
+reported	O
+to	O
+be	O
+a	O
+useful	O
+tool	O
+to	O
+predict	O
+K	O
+(	O
++	O
+)	O
+channel	O
+and	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+channel	O
+blocker	O
+effects	O
+on	O
+QT	O
+interval	O
+.	O
+
+However	O
+,	O
+there	O
+is	O
+no	O
+report	O
+showing	O
+that	O
+this	O
+technique	O
+can	O
+be	O
+used	O
+to	O
+predict	O
+multichannel	O
+blocker	O
+potential	O
+for	O
+QT	B
+prolongation	I
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+is	O
+to	O
+show	O
+that	O
+FPD	O
+from	O
+MEA	O
+(	O
+Multielectrode	O
+array	O
+)	O
+of	O
+hiPS	O
+-	O
+CMs	O
+can	O
+detect	O
+QT	B
+prolongation	I
+induced	O
+by	O
+multichannel	O
+blockers	O
+.	O
+
+hiPS	O
+-	O
+CMs	O
+were	O
+seeded	O
+onto	O
+MEA	O
+and	O
+FPD	O
+was	O
+measured	O
+for	O
+2min	O
+every	O
+10min	O
+for	O
+30min	O
+after	O
+drug	O
+exposure	O
+for	O
+the	O
+vehicle	O
+and	O
+each	O
+drug	O
+concentration	O
+.	O
+
+IKr	O
+and	O
+IKs	O
+blockers	O
+concentration	O
+-	O
+dependently	O
+prolonged	O
+corrected	O
+FPD	O
+(	O
+FPDc	O
+)	O
+,	O
+whereas	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+channel	O
+blockers	O
+concentration	O
+-	O
+dependently	O
+shortened	O
+FPDc	O
+.	O
+
+Also	O
+,	O
+the	O
+multichannel	O
+blockers	O
+Amiodarone	O
+,	O
+Paroxetine	O
+,	O
+Terfenadine	O
+and	O
+Citalopram	O
+prolonged	O
+FPDc	O
+in	O
+a	O
+concentration	O
+dependent	O
+manner	O
+.	O
+
+Finally	O
+,	O
+the	O
+IKr	O
+blockers	O
+,	O
+Terfenadine	O
+and	O
+Citalopram	O
+,	O
+which	O
+are	O
+reported	O
+to	O
+cause	O
+Torsade	B
+de	I
+Pointes	I
+(	O
+TdP	B
+)	O
+in	O
+clinical	O
+practice	O
+,	O
+produced	O
+early	O
+afterdepolarization	O
+(	O
+EAD	O
+)	O
+.	O
+
+hiPS	O
+-	O
+CMs	O
+using	O
+MEA	O
+system	O
+and	O
+FPDc	O
+can	O
+predict	O
+the	O
+effects	O
+of	O
+drug	O
+candidates	O
+on	O
+QT	O
+interval	O
+.	O
+
+This	O
+study	O
+also	O
+shows	O
+that	O
+this	O
+assay	O
+can	O
+help	O
+detect	O
+EAD	O
+for	O
+drugs	O
+with	O
+TdP	B
+potential	O
+.	O
+
+Dermal	O
+developmental	O
+toxicity	B
+of	O
+N	O
+-	O
+phenylimide	O
+herbicides	O
+in	O
+rats	O
+.	O
+
+BACKGROUND	O
+:	O
+S	O
+-	O
+53482	O
+and	O
+S	O
+-	O
+23121	O
+are	O
+N	O
+-	O
+phenylimide	O
+herbicides	O
+and	O
+produced	O
+embryolethality	B
+,	O
+teratogenicity	B
+(	O
+mainly	O
+ventricular	B
+septal	I
+defects	I
+and	O
+wavy	O
+ribs	O
+)	O
+,	O
+and	O
+growth	B
+retardation	I
+in	O
+rats	O
+in	O
+conventional	O
+oral	O
+developmental	O
+toxicity	B
+studies	O
+.	O
+
+Our	O
+objective	O
+in	O
+this	O
+study	O
+was	O
+to	O
+investigate	O
+whether	O
+the	O
+compounds	O
+induce	O
+developmental	O
+toxicity	B
+via	O
+the	O
+dermal	O
+route	O
+,	O
+which	O
+is	O
+more	O
+relevant	O
+to	O
+occupational	O
+exposure	O
+,	O
+hence	O
+better	O
+addressing	O
+human	O
+health	O
+risks	O
+.	O
+
+METHODS	O
+:	O
+S	O
+-	O
+53482	O
+was	O
+administered	O
+dermally	O
+to	O
+rats	O
+at	O
+30	O
+,	O
+100	O
+,	O
+and	O
+300	O
+mg	O
+/	O
+kg	O
+during	O
+organogenesis	O
+,	O
+and	O
+S	O
+-	O
+23121	O
+was	O
+administered	O
+at	O
+200	O
+,	O
+400	O
+,	O
+and	O
+800	O
+mg	O
+/	O
+kg	O
+(	O
+the	O
+maximum	O
+applicable	O
+dose	O
+level	O
+)	O
+.	O
+
+Fetuses	O
+were	O
+obtained	O
+by	O
+a	O
+Cesarean	O
+section	O
+and	O
+examined	O
+for	O
+external	O
+,	O
+visceral	O
+,	O
+and	O
+skeletal	O
+alterations	O
+.	O
+
+RESULTS	O
+:	O
+Dermal	O
+exposure	O
+of	O
+rats	O
+to	O
+S	O
+-	O
+53482	O
+at	O
+300	O
+mg	O
+/	O
+kg	O
+produced	O
+patterns	O
+of	O
+developmental	O
+toxicity	B
+similar	O
+to	O
+those	O
+resulting	O
+from	O
+oral	O
+exposure	O
+.	O
+
+Toxicity	B
+included	O
+embryolethality	B
+,	O
+teratogenicity	B
+,	O
+and	O
+growth	B
+retardation	I
+.	O
+
+Dermal	O
+administration	O
+of	O
+S	O
+-	O
+23121	O
+at	O
+800	O
+mg	O
+/	O
+kg	O
+resulted	O
+in	O
+an	O
+increased	O
+incidence	O
+of	O
+embryonic	B
+death	I
+and	O
+ventricular	B
+septal	I
+defect	I
+,	O
+but	O
+retarded	O
+fetal	O
+growth	O
+was	O
+not	O
+observed	O
+as	O
+it	O
+was	O
+following	O
+oral	O
+exposure	O
+to	O
+S	O
+-	O
+23121	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Based	O
+on	O
+the	O
+results	O
+,	O
+S	O
+-	O
+53482	O
+and	O
+S	O
+-	O
+23121	O
+were	O
+teratogenic	B
+when	O
+administered	O
+dermally	O
+to	O
+pregnant	O
+rats	O
+as	O
+were	O
+the	O
+compounds	O
+administered	O
+orally	O
+.	O
+
+Thus	O
+,	O
+investigation	O
+of	O
+the	O
+mechanism	O
+and	O
+its	O
+human	O
+relevancy	O
+become	O
+more	O
+important	O
+.	O
+
+Rates	O
+of	O
+Renal	B
+Toxicity	I
+in	O
+Cancer	B
+Patients	O
+Receiving	O
+Cisplatin	O
+With	O
+and	O
+Without	O
+Mannitol	O
+.	O
+
+BACKGROUND	O
+:	O
+Cisplatin	O
+is	O
+a	O
+widely	O
+used	O
+antineoplastic	O
+.	O
+
+One	O
+of	O
+the	O
+major	O
+complications	O
+of	O
+cisplatin	O
+use	O
+is	O
+dose	O
+-	O
+limiting	O
+nephrotoxicity	B
+.	O
+
+There	O
+are	O
+many	O
+strategies	O
+to	O
+prevent	O
+this	O
+toxicity	B
+,	O
+including	O
+the	O
+use	O
+of	O
+mannitol	O
+as	O
+a	O
+nephroprotectant	O
+in	O
+combination	O
+with	O
+hydration	O
+.	O
+
+OBJECTIVE	O
+:	O
+We	O
+aimed	O
+to	O
+evaluate	O
+the	O
+rates	O
+of	O
+cisplatin	O
+-	O
+induced	O
+nephrotoxicity	B
+in	O
+cancer	B
+patients	O
+receiving	O
+single	O
+-	O
+agent	O
+cisplatin	O
+with	O
+and	O
+without	O
+mannitol	O
+.	O
+
+METHODS	O
+:	O
+This	O
+single	O
+-	O
+center	O
+retrospective	O
+analysis	O
+was	O
+a	O
+quasi	O
+experiment	O
+created	O
+by	O
+the	O
+national	O
+mannitol	O
+shortage	O
+.	O
+
+Data	O
+were	O
+collected	O
+on	O
+adult	O
+cancer	B
+patients	O
+receiving	O
+single	O
+-	O
+agent	O
+cisplatin	O
+as	O
+an	O
+outpatient	O
+from	O
+January	O
+2011	O
+to	O
+September	O
+2012	O
+.	O
+
+The	O
+primary	O
+outcome	O
+was	O
+acute	B
+kidney	I
+injury	I
+(	O
+AKI	B
+)	O
+.	O
+
+RESULTS	O
+:	O
+We	O
+evaluated	O
+143	O
+patients	O
+who	O
+received	O
+single	O
+-	O
+agent	O
+cisplatin	O
+;	O
+97	O
+.	O
+2	O
+%	O
+of	O
+patients	O
+had	O
+head	B
+and	I
+neck	I
+cancer	I
+as	O
+their	O
+primary	O
+malignancy	B
+.	O
+
+Patients	O
+who	O
+did	O
+not	O
+receive	O
+mannitol	O
+were	O
+more	O
+likely	O
+to	O
+develop	O
+nephrotoxicity	B
+:	O
+odds	O
+ratio	O
+[	O
+OR	O
+]	O
+=	O
+2	O
+.	O
+646	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+1	O
+.	O
+008	O
+,	O
+6	O
+.	O
+944	O
+;	O
+P	O
+=	O
+0	O
+.	O
+048	O
+)	O
+.	O
+
+Patients	O
+who	O
+received	O
+the	O
+100	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+dosing	O
+and	O
+patients	O
+who	O
+had	O
+a	O
+history	O
+of	O
+hypertension	B
+also	O
+had	O
+a	O
+higher	O
+likelihood	O
+of	O
+developing	O
+nephrotoxicity	B
+:	O
+OR	O
+=	O
+11	O
+.	O
+494	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+4	O
+.	O
+149	O
+,	O
+32	O
+.	O
+258	O
+;	O
+P	O
+<	O
+0	O
+.	O
+0001	O
+)	O
+and	O
+OR	O
+=	O
+3	O
+.	O
+219	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+1	O
+.	O
+228	O
+,	O
+8	O
+.	O
+439	O
+;	O
+P	O
+=	O
+0	O
+.	O
+017	O
+)	O
+,	O
+respectively	O
+.	O
+
+CONCLUSIONS	O
+:	O
+When	O
+limited	O
+quantities	O
+of	O
+mannitol	O
+are	O
+available	O
+,	O
+it	O
+should	O
+preferentially	O
+be	O
+given	O
+to	O
+patients	O
+at	O
+particularly	O
+high	O
+risk	O
+of	O
+nephrotoxicity	B
+.	O
+
+Our	O
+analysis	O
+suggests	O
+that	O
+those	O
+patients	O
+receiving	O
+the	O
+dosing	O
+schedule	O
+of	O
+100	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+cisplatin	O
+every	O
+3	O
+weeks	O
+and	O
+those	O
+with	O
+hypertension	B
+are	O
+at	O
+the	O
+greatest	O
+risk	O
+of	O
+nephrotoxicity	B
+and	O
+would	O
+benefit	O
+from	O
+the	O
+addition	O
+of	O
+mannitol	O
+.	O
+
+Metformin	O
+protects	O
+against	O
+seizures	B
+,	O
+learning	B
+and	I
+memory	I
+impairments	I
+and	O
+oxidative	O
+damage	O
+induced	O
+by	O
+pentylenetetrazole	O
+-	O
+induced	O
+kindling	O
+in	O
+mice	O
+.	O
+
+Cognitive	B
+impairment	I
+,	O
+the	O
+most	O
+common	O
+and	O
+severe	O
+comorbidity	O
+of	O
+epilepsy	B
+,	O
+greatly	O
+diminishes	O
+the	O
+quality	O
+of	O
+life	O
+.	O
+
+However	O
+,	O
+current	O
+therapeutic	O
+interventions	O
+for	O
+epilepsy	B
+can	O
+also	O
+cause	O
+untoward	O
+cognitive	O
+effects	O
+.	O
+
+Thus	O
+,	O
+there	O
+is	O
+an	O
+urgent	O
+need	O
+for	O
+new	O
+kinds	O
+of	O
+agents	O
+targeting	O
+both	O
+seizures	B
+and	O
+cognition	B
+deficits	I
+.	O
+
+Oxidative	O
+stress	O
+is	O
+considered	O
+to	O
+play	O
+an	O
+important	O
+role	O
+in	O
+epileptogenesis	O
+and	O
+cognitive	B
+deficits	I
+,	O
+and	O
+antioxidants	O
+have	O
+a	O
+putative	O
+antiepileptic	O
+potential	O
+.	O
+
+Metformin	O
+,	O
+the	O
+most	O
+commonly	O
+prescribed	O
+antidiabetic	O
+oral	O
+drug	O
+,	O
+has	O
+antioxidant	O
+properties	O
+.	O
+
+This	O
+study	O
+was	O
+designed	O
+to	O
+evaluate	O
+the	O
+ameliorative	O
+effects	O
+of	O
+metformin	O
+on	O
+seizures	B
+,	O
+cognitive	B
+impairment	I
+and	O
+brain	O
+oxidative	O
+stress	O
+markers	O
+observed	O
+in	O
+pentylenetetrazole	O
+-	O
+induced	O
+kindling	O
+animals	O
+.	O
+
+Male	O
+C57BL	O
+/	O
+6	O
+mice	O
+were	O
+administered	O
+with	O
+subconvulsive	O
+dose	O
+of	O
+pentylenetetrazole	O
+(	O
+37	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+every	O
+other	O
+day	O
+for	O
+14	O
+injections	O
+.	O
+
+Metformin	O
+was	O
+injected	O
+intraperitoneally	O
+in	O
+dose	O
+of	O
+200mg	O
+/	O
+kg	O
+along	O
+with	O
+alternate	O
+-	O
+day	O
+PTZ	O
+.	O
+
+We	O
+found	O
+that	O
+metformin	O
+suppressed	O
+the	O
+progression	O
+of	O
+kindling	O
+,	O
+ameliorated	O
+the	O
+cognitive	B
+impairment	I
+and	O
+decreased	O
+brain	O
+oxidative	O
+stress	O
+.	O
+
+Thus	O
+the	O
+present	O
+study	O
+concluded	O
+that	O
+metformin	O
+may	O
+be	O
+a	O
+potential	O
+agent	O
+for	O
+the	O
+treatment	O
+of	O
+epilepsy	B
+as	O
+well	O
+as	O
+a	O
+protective	O
+medicine	O
+against	O
+cognitive	B
+impairment	I
+induced	O
+by	O
+seizures	B
+.	O
+
+P53	O
+inhibition	O
+exacerbates	O
+late	O
+-	O
+stage	O
+anthracycline	O
+cardiotoxicity	B
+.	O
+
+AIMS	O
+:	O
+Doxorubicin	O
+(	O
+DOX	O
+)	O
+is	O
+an	O
+effective	O
+anti	O
+-	O
+cancer	B
+therapeutic	O
+,	O
+but	O
+is	O
+associated	O
+with	O
+both	O
+acute	O
+and	O
+late	O
+-	O
+stage	O
+cardiotoxicity	B
+.	O
+
+Children	O
+are	O
+particularly	O
+sensitive	O
+to	O
+DOX	O
+-	O
+induced	O
+heart	B
+failure	I
+.	O
+
+Here	O
+,	O
+the	O
+impact	O
+of	O
+p53	O
+inhibition	O
+on	O
+acute	O
+vs	O
+.	O
+late	O
+-	O
+stage	O
+DOX	O
+cardiotoxicity	B
+was	O
+examined	O
+in	O
+a	O
+juvenile	O
+model	O
+.	O
+
+METHODS	O
+AND	O
+RESULTS	O
+:	O
+Two	O
+-	O
+week	O
+-	O
+old	O
+MHC	O
+-	O
+CB7	O
+mice	O
+(	O
+which	O
+express	O
+dominant	O
+-	O
+interfering	O
+p53	O
+in	O
+cardiomyocytes	O
+)	O
+and	O
+their	O
+non	O
+-	O
+transgenic	O
+(	O
+NON	O
+-	O
+TXG	O
+)	O
+littermates	O
+received	O
+weekly	O
+DOX	O
+injections	O
+for	O
+5	O
+weeks	O
+(	O
+25	O
+mg	O
+/	O
+kg	O
+cumulative	O
+dose	O
+)	O
+.	O
+
+One	O
+week	O
+after	O
+the	O
+last	O
+DOX	O
+treatment	O
+(	O
+acute	O
+stage	O
+)	O
+,	O
+MHC	O
+-	O
+CB7	O
+mice	O
+exhibited	O
+improved	O
+cardiac	O
+function	O
+and	O
+lower	O
+levels	O
+of	O
+cardiomyocyte	O
+apoptosis	O
+when	O
+compared	O
+with	O
+the	O
+NON	O
+-	O
+TXG	O
+mice	O
+.	O
+
+Surprisingly	O
+,	O
+by	O
+13	O
+weeks	O
+following	O
+the	O
+last	O
+DOX	O
+treatment	O
+(	O
+late	O
+stage	O
+)	O
+,	O
+MHC	O
+-	O
+CB7	O
+exhibited	O
+a	O
+progressive	O
+decrease	O
+in	O
+cardiac	O
+function	O
+and	O
+higher	O
+rates	O
+of	O
+cardiomyocyte	O
+apoptosis	O
+when	O
+compared	O
+with	O
+NON	O
+-	O
+TXG	O
+mice	O
+.	O
+
+p53	O
+inhibition	O
+blocked	O
+transient	O
+DOX	O
+-	O
+induced	O
+STAT3	O
+activation	O
+in	O
+MHC	O
+-	O
+CB7	O
+mice	O
+,	O
+which	O
+was	O
+associated	O
+with	O
+enhanced	O
+induction	O
+of	O
+the	O
+DNA	O
+repair	O
+proteins	O
+Ku70	O
+and	O
+Ku80	O
+.	O
+
+Mice	O
+with	O
+cardiomyocyte	O
+-	O
+restricted	O
+deletion	O
+of	O
+STAT3	O
+exhibited	O
+worse	O
+cardiac	O
+function	O
+,	O
+higher	O
+levels	O
+of	O
+cardiomyocyte	O
+apoptosis	O
+,	O
+and	O
+a	O
+greater	O
+induction	O
+of	O
+Ku70	O
+and	O
+Ku80	O
+in	O
+response	O
+to	O
+DOX	O
+treatment	O
+during	O
+the	O
+acute	O
+stage	O
+when	O
+compared	O
+with	O
+control	O
+animals	O
+.	O
+
+CONCLUSION	O
+:	O
+These	O
+data	O
+support	O
+a	O
+model	O
+wherein	O
+a	O
+p53	O
+-	O
+dependent	O
+cardioprotective	O
+pathway	O
+,	O
+mediated	O
+via	O
+STAT3	O
+activation	O
+,	O
+mitigates	O
+DOX	O
+-	O
+induced	O
+myocardial	O
+stress	O
+during	O
+drug	O
+delivery	O
+.	O
+
+Furthermore	O
+,	O
+these	O
+data	O
+suggest	O
+an	O
+explanation	O
+as	O
+to	O
+how	O
+p53	O
+inhibition	O
+can	O
+result	O
+in	O
+cardioprotection	O
+during	O
+drug	O
+treatment	O
+and	O
+,	O
+paradoxically	O
+,	O
+enhanced	O
+cardiotoxicity	B
+long	O
+after	O
+the	O
+cessation	O
+of	O
+drug	O
+treatment	O
+.	O
+
+Metronidazole	O
+-	O
+induced	O
+encephalopathy	B
+:	O
+an	O
+uncommon	O
+scenario	O
+.	O
+
+Metronidazole	O
+can	O
+produce	O
+neurological	O
+complications	O
+although	O
+it	O
+is	O
+not	O
+a	O
+common	O
+scenario	O
+.	O
+
+We	O
+present	O
+a	O
+case	O
+where	O
+a	O
+patient	O
+developed	O
+features	O
+of	O
+encephalopathy	B
+following	O
+prolonged	O
+metronidazole	O
+intake	O
+.	O
+
+Magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+brain	O
+showed	O
+abnormal	O
+signal	O
+intensity	O
+involving	O
+both	O
+dentate	O
+nuclei	O
+of	O
+cerebellum	O
+and	O
+splenium	O
+of	O
+corpus	O
+callosum	O
+.	O
+
+The	O
+diagnosis	O
+of	O
+metronidazole	O
+toxicity	B
+was	O
+made	O
+by	O
+the	O
+MRI	O
+findings	O
+and	O
+supported	O
+clinically	O
+.	O
+
+Aconitine	O
+-	O
+induced	O
+Ca2	O
++	O
+overload	O
+causes	O
+arrhythmia	B
+and	O
+triggers	O
+apoptosis	O
+through	O
+p38	O
+MAPK	O
+signaling	O
+pathway	O
+in	O
+rats	O
+.	O
+
+Aconitine	O
+is	O
+a	O
+major	O
+bioactive	O
+diterpenoid	O
+alkaloid	O
+with	O
+high	O
+content	O
+derived	O
+from	O
+herbal	O
+aconitum	O
+plants	O
+.	O
+
+Emerging	O
+evidence	O
+indicates	O
+that	O
+voltage	O
+-	O
+dependent	O
+Na	O
+(	O
++	O
+)	O
+channels	O
+have	O
+pivotal	O
+roles	O
+in	O
+the	O
+cardiotoxicity	B
+of	O
+aconitine	O
+.	O
+
+However	O
+,	O
+no	O
+reports	O
+are	O
+available	O
+on	O
+the	O
+role	O
+of	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+in	O
+aconitine	O
+poisoning	B
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+explored	O
+the	O
+importance	O
+of	O
+pathological	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+signaling	O
+in	O
+aconitine	O
+poisoning	B
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+.	O
+
+We	O
+found	O
+that	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+overload	O
+lead	O
+to	O
+accelerated	O
+beating	O
+rhythm	O
+in	O
+adult	O
+rat	O
+ventricular	O
+myocytes	O
+and	O
+caused	O
+arrhythmia	B
+in	O
+conscious	O
+freely	O
+moving	O
+rats	O
+.	O
+
+To	O
+investigate	O
+effects	O
+of	O
+aconitine	O
+on	O
+myocardial	B
+injury	I
+,	O
+we	O
+performed	O
+cytotoxicity	B
+assay	O
+in	O
+neonatal	O
+rat	O
+ventricular	O
+myocytes	O
+(	O
+NRVMs	O
+)	O
+,	O
+as	O
+well	O
+as	O
+measured	O
+lactate	O
+dehydrogenase	O
+level	O
+in	O
+the	O
+culture	O
+medium	O
+of	O
+NRVMs	O
+and	O
+activities	O
+of	O
+serum	O
+cardiac	O
+enzymes	O
+in	O
+rats	O
+.	O
+
+The	O
+results	O
+showed	O
+that	O
+aconitine	O
+resulted	O
+in	O
+myocardial	B
+injury	I
+and	O
+reduced	O
+NRVMs	O
+viability	O
+dose	O
+-	O
+dependently	O
+.	O
+
+To	O
+confirm	O
+the	O
+pro	O
+-	O
+apoptotic	O
+effects	O
+,	O
+we	O
+performed	O
+flow	O
+cytometric	O
+detection	O
+,	O
+cardiac	O
+histology	O
+,	O
+transmission	O
+electron	O
+microscopy	O
+and	O
+terminal	O
+deoxynucleotidyl	O
+transferase	O
+-	O
+mediated	O
+dUTP	O
+-	O
+biotin	O
+nick	O
+end	O
+labeling	O
+assay	O
+.	O
+
+The	O
+results	O
+showed	O
+that	O
+aconitine	O
+stimulated	O
+apoptosis	O
+time	O
+-	O
+dependently	O
+.	O
+
+The	O
+expression	O
+analysis	O
+of	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+handling	O
+proteins	O
+demonstrated	O
+that	O
+aconitine	O
+promoted	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+overload	O
+through	O
+the	O
+expression	O
+regulation	O
+of	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+handling	O
+proteins	O
+.	O
+
+The	O
+expression	O
+analysis	O
+of	O
+apoptosis	O
+-	O
+related	O
+proteins	O
+revealed	O
+that	O
+pro	O
+-	O
+apoptotic	O
+protein	O
+expression	O
+was	O
+upregulated	O
+,	O
+and	O
+anti	O
+-	O
+apoptotic	O
+protein	O
+BCL	O
+-	O
+2	O
+expression	O
+was	O
+downregulated	O
+.	O
+
+Furthermore	O
+,	O
+increased	O
+phosphorylation	O
+of	O
+MAPK	O
+family	O
+members	O
+,	O
+especially	O
+the	O
+P	O
+-	O
+P38	O
+/	O
+P38	O
+ratio	O
+was	O
+found	O
+in	O
+cardiac	O
+tissues	O
+.	O
+
+Hence	O
+,	O
+our	O
+results	O
+suggest	O
+that	O
+aconitine	O
+significantly	O
+aggravates	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+overload	O
+and	O
+causes	O
+arrhythmia	B
+and	O
+finally	O
+promotes	O
+apoptotic	O
+development	O
+via	O
+phosphorylation	O
+of	O
+P38	O
+mitogen	O
+-	O
+activated	O
+protein	O
+kinase	O
+.	O
+
+Chronic	O
+treatment	O
+with	O
+metformin	O
+suppresses	O
+toll	O
+-	O
+like	O
+receptor	O
+4	O
+signaling	O
+and	O
+attenuates	O
+left	B
+ventricular	I
+dysfunction	I
+following	O
+myocardial	B
+infarction	I
+.	O
+
+Acute	O
+treatment	O
+with	O
+metformin	O
+has	O
+a	O
+protective	O
+effect	O
+in	O
+myocardial	B
+infarction	I
+by	O
+suppression	O
+of	O
+inflammatory	O
+responses	O
+due	O
+to	O
+activation	O
+of	O
+AMP	O
+-	O
+activated	O
+protein	O
+kinase	O
+(	O
+AMPK	O
+)	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+the	O
+effect	O
+of	O
+chronic	O
+pre	O
+-	O
+treatment	O
+with	O
+metformin	O
+on	O
+cardiac	B
+dysfunction	I
+and	O
+toll	O
+-	O
+like	O
+receptor	O
+4	O
+(	O
+TLR4	O
+)	O
+activities	O
+following	O
+myocardial	B
+infarction	I
+and	O
+their	O
+relation	O
+with	O
+AMPK	O
+were	O
+assessed	O
+.	O
+
+Male	O
+Wistar	O
+rats	O
+were	O
+randomly	O
+assigned	O
+to	O
+one	O
+of	O
+5	O
+groups	O
+(	O
+n	O
+=	O
+6	O
+)	O
+:	O
+normal	O
+control	O
+and	O
+groups	O
+were	O
+injected	O
+isoproterenol	O
+after	O
+chronic	O
+pre	O
+-	O
+treatment	O
+with	O
+0	O
+,	O
+25	O
+,	O
+50	O
+,	O
+or	O
+100mg	O
+/	O
+kg	O
+of	O
+metformin	O
+twice	O
+daily	O
+for	O
+14	O
+days	O
+.	O
+
+Isoproterenol	O
+(	O
+100mg	O
+/	O
+kg	O
+)	O
+was	O
+injected	O
+subcutaneously	O
+on	O
+the	O
+13th	O
+and	O
+14th	O
+days	O
+to	O
+induce	O
+acute	B
+myocardial	I
+infarction	I
+.	O
+
+Isoproterenol	O
+alone	O
+decreased	O
+left	O
+ventricular	O
+systolic	O
+pressure	O
+and	O
+myocardial	O
+contractility	O
+indexed	O
+as	O
+LVdp	O
+/	O
+dtmax	O
+and	O
+LVdp	O
+/	O
+dtmin	O
+.	O
+
+The	O
+left	B
+ventricular	I
+dysfunction	I
+was	O
+significantly	O
+lower	O
+in	O
+the	O
+groups	O
+treated	O
+with	O
+25	O
+and	O
+50mg	O
+/	O
+kg	O
+of	O
+metformin	O
+.	O
+
+Metfromin	O
+markedly	O
+lowered	O
+isoproterenol	O
+-	O
+induced	O
+elevation	O
+in	O
+the	O
+levels	O
+of	O
+TLR4	O
+mRNA	O
+,	O
+myeloid	O
+differentiation	O
+protein	O
+88	O
+(	O
+MyD88	O
+)	O
+,	O
+tumor	B
+necrosis	B
+factor	O
+-	O
+alpha	O
+(	O
+TNF	O
+-	O
+a	O
+)	O
+,	O
+and	O
+interleukin	O
+6	O
+(	O
+IL	O
+-	O
+6	O
+)	O
+in	O
+the	O
+heart	O
+tissues	O
+.	O
+
+Similar	O
+changes	O
+were	O
+also	O
+seen	O
+in	O
+the	O
+serum	O
+levels	O
+of	O
+TNF	O
+-	O
+a	O
+and	O
+IL	O
+-	O
+6	O
+.	O
+
+However	O
+,	O
+the	O
+lower	O
+doses	O
+of	O
+25	O
+and	O
+50mg	O
+/	O
+kg	O
+were	O
+more	O
+effective	O
+than	O
+100mg	O
+/	O
+kg	O
+.	O
+
+Phosphorylated	O
+AMPKa	O
+(	O
+p	O
+-	O
+AMPK	O
+)	O
+in	O
+the	O
+myocardium	O
+was	O
+significantly	O
+elevated	O
+by	O
+25mg	O
+/	O
+kg	O
+of	O
+metformin	O
+,	O
+slightly	O
+by	O
+50mg	O
+/	O
+kg	O
+,	O
+but	O
+not	O
+by	O
+100mg	O
+/	O
+kg	O
+.	O
+
+Chronic	O
+pre	O
+-	O
+treatment	O
+with	O
+metformin	O
+reduces	O
+post	O
+-	O
+myocardial	B
+infarction	I
+cardiac	O
+dysfunction	O
+and	O
+suppresses	O
+inflammatory	O
+responses	O
+,	O
+possibly	O
+through	O
+inhibition	O
+of	O
+TLR4	O
+activities	O
+.	O
+
+This	O
+mechanism	O
+can	O
+be	O
+considered	O
+as	O
+a	O
+target	O
+to	O
+protect	O
+infarcted	O
+myocardium	O
+.	O
+
+Unusual	O
+complications	O
+of	O
+antithyroid	O
+drug	O
+therapy	O
+:	O
+four	O
+case	O
+reports	O
+and	O
+review	O
+of	O
+literature	O
+.	O
+
+Two	O
+cases	O
+of	O
+propylthiouracil	O
+-	O
+associated	O
+acute	O
+hepatitis	B
+,	O
+one	O
+case	O
+of	O
+fatal	O
+methimazole	O
+-	O
+associated	O
+hepatocellular	B
+necrosis	I
+and	O
+one	O
+case	O
+of	O
+propylthiouracil	O
+-	O
+associated	O
+lupus	B
+-	I
+like	I
+syndrome	I
+are	O
+described	O
+.	O
+
+The	O
+literature	O
+related	O
+to	O
+antithyroid	O
+drug	O
+side	O
+effects	O
+and	O
+the	O
+mechanisms	O
+for	O
+their	O
+occurrence	O
+are	O
+reviewed	O
+and	O
+the	O
+efficacy	O
+and	O
+complications	O
+of	O
+thyroidectomy	O
+and	O
+radioiodine	O
+compared	O
+to	O
+those	O
+of	O
+antithyroid	O
+drugs	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+in	O
+most	O
+circumstances	O
+131I	O
+is	O
+the	O
+therapy	O
+of	O
+choice	O
+for	O
+hyperthyroidism	B
+.	O
+
+Neuroleptic	B
+malignant	I
+syndrome	I
+induced	O
+by	O
+combination	O
+therapy	O
+with	O
+tetrabenazine	O
+and	O
+tiapride	O
+in	O
+a	O
+Japanese	O
+patient	O
+with	O
+Huntington	B
+'	I
+s	I
+disease	I
+at	O
+the	O
+terminal	O
+stage	O
+of	O
+recurrent	O
+breast	B
+cancer	I
+.	O
+
+We	O
+herein	O
+describe	O
+the	O
+case	O
+of	O
+an	O
+81	O
+-	O
+year	O
+-	O
+old	O
+Japanese	O
+woman	O
+with	O
+neuroleptic	B
+malignant	I
+syndrome	I
+that	O
+occurred	O
+36	O
+days	O
+after	O
+the	O
+initiation	O
+of	O
+combination	O
+therapy	O
+with	O
+tiapride	O
+(	O
+75	O
+mg	O
+/	O
+day	O
+)	O
+and	O
+tetrabenazine	O
+(	O
+12	O
+.	O
+5	O
+mg	O
+/	O
+day	O
+)	O
+for	O
+Huntington	B
+'	I
+s	I
+disease	I
+.	O
+
+The	O
+patient	O
+had	O
+been	O
+treated	O
+with	O
+tiapride	O
+or	O
+tetrabenazine	O
+alone	O
+without	O
+any	O
+adverse	O
+effects	O
+before	O
+the	O
+administration	O
+of	O
+the	O
+combination	O
+therapy	O
+.	O
+
+She	O
+also	O
+had	O
+advanced	O
+breast	B
+cancer	I
+when	O
+the	O
+combination	O
+therapy	O
+was	O
+initiated	O
+.	O
+
+To	O
+the	O
+best	O
+of	O
+our	O
+knowledge	O
+,	O
+the	O
+occurrence	O
+of	O
+neuroleptic	B
+malignant	I
+syndrome	I
+due	O
+to	O
+combination	O
+therapy	O
+with	O
+tetrabenazine	O
+and	O
+tiapride	O
+has	O
+not	O
+been	O
+previously	O
+reported	O
+.	O
+
+Tetrabenazine	O
+should	O
+be	O
+administered	O
+very	O
+carefully	O
+in	O
+combination	O
+with	O
+other	O
+neuroleptic	O
+drugs	O
+,	O
+particularly	O
+in	O
+patients	O
+with	O
+a	O
+worsening	O
+general	O
+condition	O
+.	O
+
+A	O
+metoprolol	O
+-	O
+terbinafine	O
+combination	O
+induced	O
+bradycardia	B
+.	O
+
+To	O
+report	O
+a	O
+sinus	B
+bradycardia	I
+induced	O
+by	O
+metoprolol	O
+and	O
+terbinafine	O
+drug	O
+-	O
+drug	O
+interaction	O
+and	O
+its	O
+management	O
+.	O
+
+A	O
+63	O
+year	O
+-	O
+old	O
+Caucasian	O
+man	O
+on	O
+metoprolol	O
+200	O
+mg	O
+/	O
+day	O
+for	O
+stable	O
+coronary	B
+artery	I
+disease	I
+was	O
+prescribed	O
+a	O
+90	O
+-	O
+day	O
+course	O
+of	O
+oral	O
+terbinafine	O
+250	O
+mg	O
+/	O
+day	O
+for	O
+onychomycosis	B
+.	O
+
+On	O
+the	O
+49th	O
+day	O
+of	O
+terbinafine	O
+therapy	O
+,	O
+he	O
+was	O
+brought	O
+to	O
+the	O
+emergency	O
+room	O
+for	O
+a	O
+decrease	O
+of	O
+his	O
+global	O
+health	O
+status	O
+,	O
+confusion	B
+and	O
+falls	O
+.	O
+
+The	O
+electrocardiogram	O
+revealed	O
+a	O
+37	O
+beats	O
+/	O
+min	O
+sinus	B
+bradycardia	I
+.	O
+
+A	O
+score	O
+of	O
+7	O
+on	O
+the	O
+Naranjo	O
+adverse	B
+drug	I
+reaction	I
+probability	O
+scale	O
+indicates	O
+a	O
+probable	O
+relationship	O
+between	O
+the	O
+patient	O
+'	O
+s	O
+sinus	B
+bradycardia	I
+and	O
+the	O
+drug	O
+interaction	O
+between	O
+metoprolol	O
+and	O
+terbinafine	O
+.	O
+
+The	O
+heart	O
+rate	O
+ameliorated	O
+first	O
+with	O
+a	O
+decrease	O
+in	O
+the	O
+dose	O
+of	O
+metoprolol	O
+.	O
+
+It	O
+was	O
+subsequently	O
+changed	O
+to	O
+bisoprolol	O
+and	O
+the	O
+heart	O
+rate	O
+remained	O
+normal	O
+.	O
+
+By	O
+inhibiting	O
+the	O
+cytochrome	O
+P450	O
+2D6	O
+,	O
+terbinafine	O
+had	O
+decreased	O
+metoprolol	O
+'	O
+s	O
+clearance	O
+,	O
+leading	O
+in	O
+metoprolol	O
+accumulation	O
+which	O
+has	O
+resulted	O
+in	O
+clinically	O
+significant	O
+sinus	B
+bradycardia	I
+.	O
+
+Optochiasmatic	O
+and	O
+peripheral	B
+neuropathy	I
+due	O
+to	O
+ethambutol	O
+overtreatment	O
+.	O
+
+Ethambutol	O
+is	O
+known	O
+to	O
+cause	O
+optic	B
+neuropathy	I
+and	O
+,	O
+more	O
+rarely	O
+,	O
+axonal	O
+polyneuropathy	B
+.	O
+
+We	O
+characterize	O
+the	O
+clinical	O
+,	O
+neurophysiological	O
+,	O
+and	O
+neuroimaging	O
+findings	O
+in	O
+a	O
+72	O
+-	O
+year	O
+-	O
+old	O
+man	O
+who	O
+developed	O
+visual	B
+loss	I
+and	O
+paresthesias	B
+after	O
+11	O
+weeks	O
+of	O
+exposure	O
+to	O
+a	O
+supratherapeutic	O
+dose	O
+of	O
+ethambutol	O
+.	O
+
+This	O
+case	O
+demonstrates	O
+the	O
+selective	O
+vulnerability	O
+of	O
+the	O
+anterior	O
+visual	O
+pathways	O
+and	O
+peripheral	O
+nerves	O
+to	O
+ethambutol	O
+toxicity	B
+.	O
+
+Testosterone	O
+ameliorates	O
+streptozotocin	O
+-	O
+induced	O
+memory	B
+impairment	I
+in	O
+male	O
+rats	O
+.	O
+
+AIM	O
+:	O
+To	O
+study	O
+the	O
+effects	O
+of	O
+testosterone	O
+on	O
+streptozotocin	O
+(	O
+STZ	O
+)	O
+-	O
+induced	O
+memory	B
+impairment	I
+in	O
+male	O
+rats	O
+.	O
+
+METHODS	O
+:	O
+Adult	O
+male	O
+Wistar	O
+rats	O
+were	O
+intracerebroventricularly	O
+(	O
+icv	O
+)	O
+infused	O
+with	O
+STZ	O
+(	O
+750	O
+ug	O
+)	O
+on	O
+d	O
+1	O
+and	O
+d	O
+3	O
+,	O
+and	O
+a	O
+passive	O
+avoidance	O
+task	O
+was	O
+assessed	O
+2	O
+weeks	O
+after	O
+the	O
+first	O
+injection	O
+of	O
+STZ	O
+.	O
+
+Castration	O
+surgery	O
+was	O
+performed	O
+in	O
+another	O
+group	O
+of	O
+rats	O
+,	O
+and	O
+the	O
+passive	O
+avoidance	O
+task	O
+was	O
+assessed	O
+4	O
+weeks	O
+after	O
+the	O
+operation	O
+.	O
+
+Testosterone	O
+(	O
+1	O
+mg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+d	O
+(	O
+-	O
+1	O
+)	O
+,	O
+sc	O
+)	O
+,	O
+the	O
+androgen	O
+receptor	O
+antagonist	O
+flutamide	O
+(	O
+10	O
+mg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+d	O
+(	O
+-	O
+1	O
+)	O
+,	O
+ip	O
+)	O
+,	O
+the	O
+estrogen	O
+receptor	O
+antagonist	O
+tamoxifen	O
+(	O
+1	O
+mg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+d	O
+(	O
+-	O
+1	O
+)	O
+,	O
+ip	O
+)	O
+or	O
+the	O
+aromatase	O
+inhibitor	O
+letrozole	O
+(	O
+4	O
+mg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+d	O
+(	O
+-	O
+1	O
+)	O
+,	O
+ip	O
+)	O
+were	O
+administered	O
+for	O
+6	O
+d	O
+after	O
+the	O
+first	O
+injection	O
+of	O
+STZ	O
+.	O
+
+RESULTS	O
+:	O
+STZ	O
+administration	O
+and	O
+castration	O
+markedly	O
+decreased	O
+both	O
+STL1	O
+(	O
+the	O
+short	O
+memory	O
+)	O
+and	O
+STL2	O
+(	O
+the	O
+long	O
+memory	O
+)	O
+in	O
+passive	O
+avoidance	O
+tests	O
+.	O
+
+Testosterone	O
+replacement	O
+almost	O
+restored	O
+the	O
+STL1	O
+and	O
+STL2	O
+in	O
+castrated	O
+rats	O
+,	O
+and	O
+significantly	O
+prolonged	O
+the	O
+STL1	O
+and	O
+STL2	O
+in	O
+STZ	O
+-	O
+treated	O
+rats	O
+.	O
+
+Administration	O
+of	O
+flutamide	O
+,	O
+letrozole	O
+or	O
+tamoxifen	O
+significantly	O
+impaired	B
+the	I
+memory	I
+in	O
+intact	O
+rats	O
+,	O
+and	O
+significantly	O
+attenuated	O
+the	O
+testosterone	O
+replacement	O
+in	O
+improving	O
+STZ	O
+-	O
+and	O
+castration	O
+-	O
+induced	O
+memory	B
+impairment	I
+.	O
+
+CONCLUSION	O
+:	O
+Testosterone	O
+administration	O
+ameliorates	O
+STZ	O
+-	O
+and	O
+castration	O
+-	O
+induced	O
+memory	B
+impairment	I
+in	O
+male	O
+Wistar	O
+rats	O
+.	O
+
+Behavioral	O
+and	O
+neurochemical	O
+studies	O
+in	O
+mice	O
+pretreated	O
+with	O
+garcinielliptone	O
+FC	O
+in	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+.	O
+
+Garcinielliptone	O
+FC	O
+(	O
+GFC	O
+)	O
+isolated	O
+from	O
+hexanic	O
+fraction	O
+seed	O
+extract	O
+of	O
+species	O
+Platonia	O
+insignis	O
+Mart	O
+.	O
+
+It	O
+is	O
+widely	O
+used	O
+in	O
+folk	O
+medicine	O
+to	O
+treat	O
+skin	B
+diseases	I
+in	O
+both	O
+humans	O
+and	O
+animals	O
+as	O
+well	O
+as	O
+the	O
+seed	O
+decoction	O
+has	O
+been	O
+used	O
+to	O
+treat	O
+diarrheas	B
+and	O
+inflammatory	B
+diseases	I
+.	O
+
+However	O
+,	O
+there	O
+is	O
+no	O
+research	O
+on	O
+GFC	O
+effects	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+of	O
+rodents	O
+.	O
+
+The	O
+present	O
+study	O
+aimed	O
+to	O
+evaluate	O
+the	O
+GFC	O
+effects	O
+at	O
+doses	O
+of	O
+25	O
+,	O
+50	O
+or	O
+75	O
+mg	O
+/	O
+kg	O
+on	O
+seizure	B
+parameters	O
+to	O
+determine	O
+their	O
+anticonvulsant	O
+activity	O
+and	O
+its	O
+effects	O
+on	O
+amino	O
+acid	O
+(	O
+r	O
+-	O
+aminobutyric	O
+acid	O
+(	O
+GABA	O
+)	O
+,	O
+glutamine	O
+,	O
+aspartate	O
+and	O
+glutathione	O
+)	O
+levels	O
+as	O
+well	O
+as	O
+on	O
+acetylcholinesterase	O
+(	O
+AChE	O
+)	O
+activity	O
+in	O
+mice	O
+hippocampus	O
+after	O
+seizures	B
+.	O
+
+GFC	O
+produced	O
+an	O
+increased	O
+latency	O
+to	O
+first	O
+seizure	B
+,	O
+at	O
+doses	O
+25mg	O
+/	O
+kg	O
+(	O
+20	O
+.	O
+12	O
++	O
+2	O
+.	O
+20	O
+min	O
+)	O
+,	O
+50mg	O
+/	O
+kg	O
+(	O
+20	O
+.	O
+95	O
++	O
+2	O
+.	O
+21	O
+min	O
+)	O
+or	O
+75	O
+mg	O
+/	O
+kg	O
+(	O
+23	O
+.	O
+43	O
++	O
+1	O
+.	O
+99	O
+min	O
+)	O
+when	O
+compared	O
+with	O
+seized	O
+mice	O
+.	O
+
+In	O
+addition	O
+,	O
+GABA	O
+content	O
+of	O
+mice	O
+hippocampus	O
+treated	O
+with	O
+GFC75	O
+plus	O
+P400	O
+showed	O
+an	O
+increase	O
+of	O
+46	O
+.	O
+90	O
+%	O
+when	O
+compared	O
+with	O
+seized	O
+mice	O
+.	O
+
+In	O
+aspartate	O
+,	O
+glutamine	O
+and	O
+glutamate	O
+levels	O
+detected	O
+a	O
+decrease	O
+of	O
+5	O
+.	O
+21	O
+%	O
+,	O
+13	O
+.	O
+55	O
+%	O
+and	O
+21	O
+.	O
+80	O
+%	O
+,	O
+respectively	O
+in	O
+mice	O
+hippocampus	O
+treated	O
+with	O
+GFC75	O
+plus	O
+P400	O
+when	O
+compared	O
+with	O
+seized	O
+mice	O
+.	O
+
+Hippocampus	O
+mice	O
+treated	O
+with	O
+GFC75	O
+plus	O
+P400	O
+showed	O
+an	O
+increase	O
+in	O
+AChE	O
+activity	O
+(	O
+63	O
+.	O
+30	O
+%	O
+)	O
+when	O
+compared	O
+with	O
+seized	O
+mice	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+GFC	O
+can	O
+exert	O
+anticonvulsant	O
+activity	O
+and	O
+reduce	O
+the	O
+frequency	O
+of	O
+installation	O
+of	O
+pilocarpine	O
+-	O
+induced	O
+status	B
+epilepticus	I
+,	O
+as	O
+demonstrated	O
+by	O
+increase	O
+in	O
+latency	O
+to	O
+first	O
+seizure	B
+and	O
+decrease	O
+in	O
+mortality	O
+rate	O
+of	O
+animals	O
+.	O
+
+In	O
+conclusion	O
+,	O
+our	O
+data	O
+suggest	O
+that	O
+GFC	O
+may	O
+influence	O
+in	O
+epileptogenesis	O
+and	O
+promote	O
+anticonvulsant	O
+actions	O
+in	O
+pilocarpine	O
+model	O
+by	O
+modulating	O
+the	O
+GABA	O
+and	O
+glutamate	O
+contents	O
+and	O
+of	O
+AChE	O
+activity	O
+in	O
+seized	O
+mice	O
+hippocampus	O
+.	O
+
+This	O
+compound	O
+may	O
+be	O
+useful	O
+to	O
+produce	O
+neuronal	O
+protection	O
+and	O
+it	O
+can	O
+be	O
+considered	O
+as	O
+an	O
+anticonvulsant	O
+agent	O
+.	O
+
+Standard	O
+operating	O
+procedures	O
+for	O
+antibiotic	O
+therapy	O
+and	O
+the	O
+occurrence	O
+of	O
+acute	B
+kidney	I
+injury	I
+:	O
+a	O
+prospective	O
+,	O
+clinical	O
+,	O
+non	O
+-	O
+interventional	O
+,	O
+observational	O
+study	O
+.	O
+
+INTRODUCTION	O
+:	O
+Acute	B
+kidney	I
+injury	I
+(	O
+AKI	B
+)	O
+occurs	O
+in	O
+7	O
+%	O
+of	O
+hospitalized	O
+and	O
+66	O
+%	O
+of	O
+Intensive	O
+Care	O
+Unit	O
+(	O
+ICU	O
+)	O
+patients	O
+.	O
+
+It	O
+increases	O
+mortality	O
+,	O
+hospital	O
+length	O
+of	O
+stay	O
+,	O
+and	O
+costs	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+investigate	O
+,	O
+whether	O
+there	O
+is	O
+an	O
+association	O
+between	O
+adherence	O
+to	O
+guidelines	O
+(	O
+standard	O
+operating	O
+procedures	O
+(	O
+SOP	O
+)	O
+)	O
+for	O
+potentially	O
+nephrotoxic	B
+antibiotics	O
+and	O
+the	O
+occurrence	O
+of	O
+AKI	B
+.	O
+
+METHODS	O
+:	O
+This	O
+study	O
+was	O
+carried	O
+out	O
+as	O
+a	O
+prospective	O
+,	O
+clinical	O
+,	O
+non	O
+-	O
+interventional	O
+,	O
+observational	O
+study	O
+.	O
+
+Data	O
+collection	O
+was	O
+performed	O
+over	O
+a	O
+total	O
+of	O
+170	O
+days	O
+in	O
+three	O
+ICUs	O
+at	O
+Charite	O
+-	O
+Universitaetsmedizin	O
+Berlin	O
+.	O
+
+A	O
+total	O
+of	O
+675	O
+patients	O
+were	O
+included	O
+;	O
+163	O
+of	O
+these	O
+had	O
+therapy	O
+with	O
+vancomycin	O
+,	O
+gentamicin	O
+,	O
+or	O
+tobramycin	O
+;	O
+were	O
+>	O
+18	O
+years	O
+;	O
+and	O
+treated	O
+in	O
+the	O
+ICU	O
+for	O
+>	O
+24	O
+hours	O
+.	O
+
+Patients	O
+with	O
+an	O
+adherence	O
+to	O
+SOP	O
+>	O
+70	O
+%	O
+were	O
+classified	O
+into	O
+the	O
+high	O
+adherence	O
+group	O
+(	O
+HAG	O
+)	O
+and	O
+patients	O
+with	O
+an	O
+adherence	O
+of	O
+<	O
+70	O
+%	O
+into	O
+the	O
+low	O
+adherence	O
+group	O
+(	O
+LAG	O
+)	O
+.	O
+
+AKI	B
+was	O
+defined	O
+according	O
+to	O
+RIFLE	O
+criteria	O
+.	O
+
+Adherence	O
+to	O
+SOPs	O
+was	O
+evaluated	O
+by	O
+retrospective	O
+expert	O
+audit	O
+.	O
+
+Development	O
+of	O
+AKI	B
+was	O
+compared	O
+between	O
+groups	O
+with	O
+exact	O
+Chi2	O
+-	O
+test	O
+and	O
+multivariate	O
+logistic	O
+regression	O
+analysis	O
+(	O
+two	O
+-	O
+sided	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+LAG	O
+consisted	O
+of	O
+75	O
+patients	O
+(	O
+46	O
+%	O
+)	O
+versus	O
+88	O
+HAG	O
+patients	O
+(	O
+54	O
+%	O
+)	O
+.	O
+
+AKI	B
+occurred	O
+significantly	O
+more	O
+often	O
+in	O
+LAG	O
+with	O
+36	O
+%	O
+versus	O
+21	O
+%	O
+in	O
+HAG	O
+(	O
+P	O
+=	O
+0	O
+.	O
+035	O
+)	O
+.	O
+
+Basic	O
+characteristics	O
+were	O
+comparable	O
+,	O
+except	O
+an	O
+increased	O
+rate	O
+of	O
+soft	O
+tissue	O
+infections	B
+in	O
+LAG	O
+.	O
+
+Multivariate	O
+analysis	O
+revealed	O
+an	O
+odds	O
+ratio	O
+of	O
+2	O
+.	O
+5	O
+-	O
+fold	O
+for	O
+LAG	O
+to	O
+develop	O
+AKI	B
+compared	O
+with	O
+HAG	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+1	O
+.	O
+195	O
+to	O
+5	O
+.	O
+124	O
+,	O
+P	O
+=	O
+0	O
+.	O
+039	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+Low	O
+adherence	O
+to	O
+SOPs	O
+for	O
+potentially	O
+nephrotoxic	B
+antibiotics	O
+was	O
+associated	O
+with	O
+a	O
+higher	O
+occurrence	O
+of	O
+AKI	B
+.	O
+
+TRIAL	O
+REGISTRATION	O
+:	O
+Current	O
+Controlled	O
+Trials	O
+ISRCTN54598675	O
+.	O
+
+Registered	O
+17	O
+August	O
+2007	O
+.	O
+
+Rhabdomyolysis	B
+in	O
+a	O
+hepatitis	B
+C	I
+virus	I
+infected	I
+patient	O
+treated	O
+with	O
+telaprevir	O
+and	O
+simvastatin	O
+.	O
+
+A	O
+46	O
+-	O
+year	O
+old	O
+man	O
+with	O
+a	O
+chronic	O
+hepatitis	B
+C	I
+virus	I
+infection	I
+received	O
+triple	O
+therapy	O
+with	O
+ribavirin	O
+,	O
+pegylated	O
+interferon	O
+and	O
+telaprevir	O
+.	O
+
+The	O
+patient	O
+also	O
+received	O
+simvastatin	O
+.	O
+
+One	O
+month	O
+after	O
+starting	O
+the	O
+antiviral	O
+therapy	O
+,	O
+the	O
+patient	O
+was	O
+admitted	O
+to	O
+the	O
+hospital	O
+because	O
+he	O
+developed	O
+rhabdomyolysis	B
+.	O
+
+At	O
+admission	O
+simvastatin	O
+and	O
+all	O
+antiviral	O
+drugs	O
+were	O
+discontinued	O
+because	O
+toxicity	B
+due	O
+to	O
+a	O
+drug	O
+-	O
+drug	O
+interaction	O
+was	O
+suspected	O
+.	O
+
+The	O
+creatine	O
+kinase	O
+peaked	O
+at	O
+62	O
+,	O
+246	O
+IU	O
+/	O
+L	O
+and	O
+the	O
+patient	O
+was	O
+treated	O
+with	O
+intravenous	O
+normal	O
+saline	O
+.	O
+
+The	O
+patient	O
+'	O
+s	O
+renal	O
+function	O
+remained	O
+unaffected	O
+.	O
+
+Fourteen	O
+days	O
+after	O
+hospitalization	O
+,	O
+creatine	O
+kinase	O
+level	O
+had	O
+returned	O
+to	O
+230	O
+IU	O
+/	O
+L	O
+and	O
+the	O
+patient	O
+was	O
+discharged	O
+.	O
+
+Telaprevir	O
+was	O
+considered	O
+the	O
+probable	O
+causative	O
+agent	O
+of	O
+an	O
+interaction	O
+with	O
+simvastatin	O
+according	O
+to	O
+the	O
+Drug	O
+Interaction	O
+Probability	O
+Scale	O
+.	O
+
+The	O
+interaction	O
+is	O
+due	O
+to	O
+inhibition	O
+of	O
+CYP3A4	O
+-	O
+mediated	O
+simvastatin	O
+clearance	O
+.	O
+
+Simvastatin	O
+plasma	O
+concentration	O
+increased	O
+30	O
+times	O
+in	O
+this	O
+patient	O
+and	O
+statin	O
+induced	O
+muscle	B
+toxicity	I
+is	O
+related	O
+to	O
+the	O
+concentration	O
+of	O
+the	O
+statin	O
+in	O
+blood	O
+.	O
+
+In	O
+conclusion	O
+,	O
+with	O
+this	O
+case	O
+we	O
+illustrate	O
+that	O
+telaprevir	O
+as	O
+well	O
+as	O
+statins	O
+are	O
+susceptible	O
+to	O
+clinical	O
+relevant	O
+drug	O
+-	O
+drug	O
+interactions	O
+.	O
+
+Combination	O
+of	O
+bortezomib	O
+,	O
+thalidomide	O
+,	O
+and	O
+dexamethasone	O
+(	O
+VTD	O
+)	O
+as	O
+a	O
+consolidation	O
+therapy	O
+after	O
+autologous	O
+stem	O
+cell	O
+transplantation	O
+for	O
+symptomatic	O
+multiple	B
+myeloma	I
+in	O
+Japanese	O
+patients	O
+.	O
+
+Consolidation	O
+therapy	O
+for	O
+patients	O
+with	O
+multiple	B
+myeloma	I
+(	O
+MM	B
+)	O
+has	O
+been	O
+widely	O
+adopted	O
+to	O
+improve	O
+treatment	O
+response	O
+following	O
+autologous	O
+stem	O
+cell	O
+transplantation	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+retrospectively	O
+analyzed	O
+the	O
+safety	O
+and	O
+efficacy	O
+of	O
+combination	O
+regimen	O
+of	O
+bortezomib	O
+,	O
+thalidomide	O
+,	O
+and	O
+dexamethasone	O
+(	O
+VTD	O
+)	O
+as	O
+consolidation	O
+therapy	O
+in	O
+24	O
+Japanese	O
+patients	O
+with	O
+newly	O
+diagnosed	O
+MM	B
+.	O
+
+VTD	O
+consisted	O
+of	O
+bortezomib	O
+at	O
+a	O
+dose	O
+of	O
+1	O
+.	O
+3	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+and	O
+dexamethasone	O
+at	O
+a	O
+dose	O
+of	O
+40	O
+mg	O
+/	O
+day	O
+on	O
+days	O
+1	O
+,	O
+8	O
+,	O
+15	O
+,	O
+and	O
+22	O
+of	O
+a	O
+35	O
+-	O
+day	O
+cycle	O
+,	O
+with	O
+daily	O
+oral	O
+thalidomide	O
+at	O
+a	O
+dose	O
+of	O
+100	O
+mg	O
+/	O
+day	O
+.	O
+
+Grade	O
+3	O
+-	O
+4	O
+neutropenia	B
+and	O
+thrombocytopenia	B
+were	O
+documented	O
+in	O
+four	O
+and	O
+three	O
+patients	O
+(	O
+17	O
+and	O
+13	O
+%	O
+)	O
+,	O
+respectively	O
+,	O
+but	O
+drug	O
+dose	O
+reduction	O
+due	O
+to	O
+cytopenia	B
+was	O
+not	O
+required	O
+in	O
+any	O
+case	O
+.	O
+
+Peripheral	B
+neuropathy	I
+was	O
+common	O
+(	O
+63	O
+%	O
+)	O
+,	O
+but	O
+severe	O
+grade	O
+3	O
+-	O
+4	O
+peripheral	B
+neuropathy	I
+was	O
+not	O
+observed	O
+.	O
+
+Very	O
+good	O
+partial	O
+response	O
+or	O
+better	O
+response	O
+(	O
+>	O
+VGPR	O
+)	O
+rates	O
+before	O
+and	O
+after	O
+consolidation	O
+therapy	O
+were	O
+54	O
+and	O
+79	O
+%	O
+,	O
+respectively	O
+.	O
+
+Patients	O
+had	O
+a	O
+significant	O
+probability	O
+of	O
+improving	O
+from	O
+<	O
+VGPR	O
+before	O
+consolidation	O
+therapy	O
+to	O
+>	O
+VGPR	O
+after	O
+consolidation	O
+therapy	O
+(	O
+p	O
+=	O
+0	O
+.	O
+041	O
+)	O
+.	O
+
+The	O
+VTD	O
+regimen	O
+may	O
+be	O
+safe	O
+and	O
+effective	O
+as	O
+a	O
+consolidation	O
+therapy	O
+in	O
+the	O
+treatment	O
+of	O
+MM	O
+in	O
+Japanese	O
+population	O
+.	O
+
+Conversion	O
+to	O
+sirolimus	O
+ameliorates	O
+cyclosporine	O
+-	O
+induced	O
+nephropathy	B
+in	O
+the	O
+rat	O
+:	O
+focus	O
+on	O
+serum	O
+,	O
+urine	O
+,	O
+gene	O
+,	O
+and	O
+protein	O
+renal	O
+expression	O
+biomarkers	O
+.	O
+
+Protocols	O
+of	O
+conversion	O
+from	O
+cyclosporin	O
+A	O
+(	O
+CsA	O
+)	O
+to	O
+sirolimus	O
+(	O
+SRL	O
+)	O
+have	O
+been	O
+widely	O
+used	O
+in	O
+immunotherapy	O
+after	O
+transplantation	O
+to	O
+prevent	O
+CsA	O
+-	O
+induced	O
+nephropathy	B
+,	O
+but	O
+the	O
+molecular	O
+mechanisms	O
+underlying	O
+these	O
+protocols	O
+remain	O
+nuclear	O
+.	O
+
+This	O
+study	O
+aimed	O
+to	O
+identify	O
+the	O
+molecular	O
+pathways	O
+and	O
+putative	O
+biomarkers	O
+of	O
+CsA	O
+-	O
+to	O
+-	O
+SRL	O
+conversion	O
+in	O
+a	O
+rat	O
+model	O
+.	O
+
+Four	O
+animal	O
+groups	O
+(	O
+n	O
+=	O
+6	O
+)	O
+were	O
+tested	O
+during	O
+9	O
+weeks	O
+:	O
+control	O
+,	O
+CsA	O
+,	O
+SRL	O
+,	O
+and	O
+conversion	O
+(	O
+CsA	O
+for	O
+3	O
+weeks	O
+followed	O
+by	O
+SRL	O
+for	O
+6	O
+weeks	O
+)	O
+.	O
+
+Classical	O
+and	O
+emergent	O
+serum	O
+,	O
+urinary	O
+,	O
+and	O
+kidney	O
+tissue	O
+(	O
+gene	O
+and	O
+protein	O
+expression	O
+)	O
+markers	O
+were	O
+assessed	O
+.	O
+
+Renal	B
+lesions	I
+were	O
+analyzed	O
+in	O
+hematoxylin	O
+and	O
+eosin	O
+,	O
+periodic	O
+acid	O
+-	O
+Schiff	O
+,	O
+and	O
+Masson	O
+'	O
+s	O
+trichrome	O
+stains	O
+.	O
+
+SRL	O
+-	O
+treated	O
+rats	O
+presented	O
+proteinuria	B
+and	O
+NGAL	O
+(	O
+serum	O
+and	O
+urinary	O
+)	O
+as	O
+the	O
+best	O
+markers	O
+of	O
+renal	B
+impairment	I
+.	O
+
+Short	O
+CsA	O
+treatment	O
+presented	O
+slight	O
+or	O
+even	O
+absent	O
+kidney	B
+lesions	I
+and	O
+TGF	O
+-	O
+b	O
+,	O
+NF	O
+-	O
+kb	O
+,	O
+mTOR	O
+,	O
+PCNA	O
+,	O
+TP53	O
+,	O
+KIM	O
+-	O
+1	O
+,	O
+and	O
+CTGF	O
+as	O
+relevant	O
+gene	O
+and	O
+protein	O
+changes	O
+.	O
+
+Prolonged	O
+CsA	O
+exposure	O
+aggravated	O
+renal	B
+damage	I
+,	O
+without	O
+clear	O
+changes	O
+on	O
+the	O
+traditional	O
+markers	O
+,	O
+but	O
+with	O
+changes	O
+in	O
+serums	O
+TGF	O
+-	O
+b	O
+and	O
+IL	O
+-	O
+7	O
+,	O
+TBARs	O
+clearance	O
+,	O
+and	O
+kidney	O
+TGF	O
+-	O
+b	O
+and	O
+mTOR	O
+.	O
+
+Conversion	O
+to	O
+SRL	O
+prevented	O
+CsA	O
+-	O
+induced	O
+renal	B
+damage	I
+evolution	O
+(	O
+absent	O
+/	O
+mild	O
+grade	O
+lesions	O
+)	O
+,	O
+while	O
+NGAL	O
+(	O
+serum	O
+versus	O
+urine	O
+)	O
+seems	O
+to	O
+be	O
+a	O
+feasible	O
+biomarker	O
+of	O
+CsA	O
+replacement	O
+to	O
+SRL	O
+.	O
+
+Kinin	O
+B2	O
+receptor	O
+deletion	O
+and	O
+blockage	O
+ameliorates	O
+cisplatin	O
+-	O
+induced	O
+acute	B
+renal	I
+injury	I
+.	O
+
+Cisplatin	O
+treatment	O
+has	O
+been	O
+adopted	O
+in	O
+some	O
+chemotherapies	O
+;	O
+however	O
+,	O
+this	O
+drug	O
+can	O
+induce	O
+acute	B
+kidney	I
+injury	I
+due	O
+its	O
+ability	O
+to	O
+negatively	O
+affect	O
+renal	O
+function	O
+,	O
+augment	O
+serum	O
+levels	O
+of	O
+creatinine	O
+and	O
+urea	O
+,	O
+increase	O
+the	O
+acute	B
+tubular	I
+necrosis	I
+score	O
+and	O
+up	O
+-	O
+regulate	O
+cytokines	O
+(	O
+e	O
+.	O
+g	O
+.	O
+,	O
+IL	O
+-	O
+1b	O
+and	O
+TNF	O
+-	O
+a	O
+)	O
+.	O
+
+The	O
+kinin	O
+B2	O
+receptor	O
+has	O
+been	O
+associated	O
+with	O
+the	O
+inflammation	B
+process	O
+,	O
+as	O
+well	O
+as	O
+the	O
+regulation	O
+of	O
+cytokine	O
+expression	O
+,	O
+and	O
+its	O
+deletion	O
+resulted	O
+in	O
+an	O
+improvement	O
+in	O
+the	O
+diabetic	B
+nephropathy	I
+status	O
+.	O
+
+To	O
+examine	O
+the	O
+role	O
+of	O
+the	O
+kinin	O
+B2	O
+receptor	O
+in	O
+cisplatin	O
+-	O
+induced	O
+acute	B
+kidney	I
+injury	I
+,	O
+kinin	O
+B2	O
+receptor	O
+knockout	O
+mice	O
+were	O
+challenged	O
+with	O
+cisplatin	O
+.	O
+
+Additionally	O
+,	O
+WT	O
+mice	O
+were	O
+treated	O
+with	O
+a	O
+B2	O
+receptor	O
+antagonist	O
+after	O
+cisplatin	O
+administration	O
+.	O
+
+B2	O
+receptor	O
+-	O
+deficient	O
+mice	O
+were	O
+less	O
+sensitive	O
+to	O
+this	O
+drug	O
+than	O
+the	O
+WT	O
+mice	O
+,	O
+as	O
+shown	O
+by	O
+reduced	O
+weight	B
+loss	I
+,	O
+better	O
+preservation	O
+of	O
+kidney	O
+function	O
+,	O
+down	O
+regulation	O
+of	O
+inflammatory	O
+cytokines	O
+and	O
+less	O
+acute	B
+tubular	I
+necrosis	I
+.	O
+
+Moreover	O
+,	O
+treatment	O
+with	O
+the	O
+kinin	O
+B2	O
+receptor	O
+antagonist	O
+effectively	O
+reduced	O
+the	O
+levels	O
+of	O
+serum	O
+creatinine	O
+and	O
+blood	O
+urea	O
+after	O
+cisplatin	O
+administration	O
+.	O
+
+Thus	O
+,	O
+our	O
+data	O
+suggest	O
+that	O
+the	O
+kinin	O
+B2	O
+receptor	O
+is	O
+involved	O
+in	O
+cisplatin	O
+-	O
+induced	O
+acute	B
+kidney	I
+injury	I
+by	O
+mediating	O
+the	O
+necrotic	B
+process	O
+and	O
+the	O
+expression	O
+of	O
+inflammatory	O
+cytokines	O
+,	O
+thus	O
+resulting	O
+in	O
+declined	O
+renal	O
+function	O
+.	O
+
+These	O
+results	O
+highlight	O
+the	O
+kinin	O
+B2	O
+receptor	O
+antagonist	O
+treatment	O
+in	O
+amelioration	O
+of	O
+nephrotoxicity	B
+induced	O
+by	O
+cisplatin	O
+therapy	O
+.	O
+
+Safety	O
+and	O
+efficacy	O
+of	O
+fluocinolone	O
+acetonide	O
+intravitreal	O
+implant	O
+(	O
+0	O
+.	O
+59	O
+mg	O
+)	O
+in	O
+birdshot	B
+retinochoroidopathy	I
+.	O
+
+PURPOSE	O
+:	O
+To	O
+report	O
+the	O
+treatment	O
+outcomes	O
+of	O
+the	O
+fluocinolone	O
+acetonide	O
+intravitreal	O
+implant	O
+(	O
+0	O
+.	O
+59	O
+mg	O
+)	O
+in	O
+patients	O
+with	O
+birdshot	B
+retinochoroidopathy	I
+whose	O
+disease	O
+is	O
+refractory	O
+or	O
+intolerant	O
+to	O
+conventional	O
+immunomodulatory	O
+therapy	O
+.	O
+
+METHODS	O
+:	O
+A	O
+retrospective	O
+case	O
+series	O
+involving	O
+11	O
+birdshot	B
+retinochoroidopathy	I
+patients	O
+(	O
+11	O
+eyes	O
+)	O
+.	O
+
+Eleven	O
+patients	O
+(	O
+11	O
+eyes	O
+)	O
+underwent	O
+surgery	O
+for	O
+fluocinolone	O
+acetonide	O
+implant	O
+(	O
+0	O
+.	O
+59	O
+mg	O
+)	O
+.	O
+
+Treatment	O
+outcomes	O
+of	O
+interest	O
+were	O
+noted	O
+at	O
+baseline	O
+,	O
+before	O
+fluocinolone	O
+acetonide	O
+implant	O
+,	O
+and	O
+then	O
+at	O
+6	O
+months	O
+,	O
+1	O
+year	O
+,	O
+2	O
+years	O
+,	O
+3	O
+years	O
+,	O
+and	O
+beyond	O
+3	O
+years	O
+.	O
+
+Disease	O
+activity	O
+markers	O
+,	O
+including	O
+signs	O
+of	O
+ocular	O
+inflammation	B
+,	O
+evidence	O
+of	O
+retinal	B
+vasculitis	I
+,	O
+Swedish	O
+interactive	O
+threshold	O
+algorithm	O
+-	O
+short	O
+wavelength	O
+automated	O
+perimetry	O
+Humphrey	O
+visual	O
+field	O
+analysis	O
+,	O
+electroretinographic	O
+parameters	O
+,	O
+and	O
+optical	O
+coherence	O
+tomography	O
+were	O
+recorded	O
+.	O
+
+Data	O
+on	O
+occurrence	O
+of	O
+cataract	B
+and	O
+raised	B
+intraocular	I
+pressure	I
+were	O
+collected	O
+in	O
+all	O
+eyes	O
+.	O
+
+RESULTS	O
+:	O
+Intraocular	O
+inflammation	B
+was	O
+present	O
+in	O
+54	O
+.	O
+5	O
+,	O
+9	O
+.	O
+9	O
+,	O
+11	O
+.	O
+1	O
+,	O
+and	O
+0	O
+%	O
+of	O
+patients	O
+at	O
+baseline	O
+,	O
+6	O
+months	O
+,	O
+1	O
+year	O
+,	O
+2	O
+years	O
+,	O
+3	O
+years	O
+,	O
+and	O
+beyond	O
+3	O
+years	O
+after	O
+receiving	O
+the	O
+implant	O
+,	O
+respectively	O
+.	O
+
+Active	O
+vasculitis	B
+was	O
+noted	O
+in	O
+36	O
+.	O
+3	O
+%	O
+patients	O
+at	O
+baseline	O
+and	O
+0	O
+%	O
+at	O
+3	O
+years	O
+of	O
+follow	O
+-	O
+up	O
+.	O
+
+More	O
+than	O
+20	O
+%	O
+(	O
+47	O
+.	O
+61	O
+-	O
+67	O
+.	O
+2	O
+%	O
+)	O
+reduction	O
+in	O
+central	O
+retinal	O
+thickness	O
+was	O
+noted	O
+in	O
+all	O
+patients	O
+with	O
+cystoid	B
+macular	I
+edema	I
+at	O
+6	O
+months	O
+,	O
+1	O
+year	O
+,	O
+2	O
+years	O
+,	O
+and	O
+3	O
+years	O
+postimplant	O
+.	O
+
+At	O
+baseline	O
+,	O
+54	O
+.	O
+5	O
+%	O
+patients	O
+were	O
+on	O
+immunomodulatory	O
+agents	O
+.	O
+
+This	O
+percentage	O
+decreased	O
+to	O
+45	O
+.	O
+45	O
+,	O
+44	O
+.	O
+4	O
+,	O
+and	O
+14	O
+.	O
+28	O
+%	O
+at	O
+1	O
+year	O
+,	O
+2	O
+years	O
+,	O
+and	O
+3	O
+years	O
+postimplant	O
+,	O
+respectively	O
+.	O
+
+Adverse	O
+events	O
+included	O
+increased	B
+intraocular	I
+pressure	I
+(	O
+54	O
+.	O
+5	O
+%	O
+)	O
+and	O
+cataract	B
+formation	O
+(	O
+100	O
+%	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+data	O
+suggest	O
+that	O
+fluocinolone	O
+acetonide	O
+implant	O
+(	O
+0	O
+.	O
+59	O
+mg	O
+)	O
+helps	O
+to	O
+control	O
+inflammation	B
+in	O
+otherwise	O
+treatment	O
+-	O
+refractory	O
+cases	O
+of	O
+birdshot	B
+retinochoroidopathy	I
+.	O
+
+It	O
+is	O
+associated	O
+with	O
+significant	O
+side	O
+effects	O
+of	O
+cataract	B
+and	O
+ocular	B
+hypertension	I
+requiring	O
+treatment	O
+.	O
+
+Optimal	O
+precurarizing	O
+dose	O
+of	O
+rocuronium	O
+to	O
+decrease	O
+fasciculation	B
+and	O
+myalgia	B
+following	O
+succinylcholine	O
+administration	O
+.	O
+
+BACKGROUND	O
+:	O
+Succinylcholine	O
+commonly	O
+produces	O
+frequent	O
+adverse	O
+effects	O
+,	O
+including	O
+muscle	B
+fasciculation	I
+and	O
+myalgia	B
+.	O
+
+The	O
+current	O
+study	O
+identified	O
+the	O
+optimal	O
+dose	O
+of	O
+rocuronium	O
+to	O
+prevent	O
+succinylcholine	O
+-	O
+induced	O
+fasciculation	B
+and	O
+myalgia	B
+and	O
+evaluated	O
+the	O
+influence	O
+of	O
+rocuronium	O
+on	O
+the	O
+speed	O
+of	O
+onset	O
+produced	O
+by	O
+succinylcholine	O
+.	O
+
+METHODS	O
+:	O
+This	O
+randomized	O
+,	O
+double	O
+-	O
+blinded	O
+study	O
+was	O
+conducted	O
+in	O
+100	O
+patients	O
+randomly	O
+allocated	O
+into	O
+five	O
+groups	O
+of	O
+20	O
+patients	O
+each	O
+.	O
+
+Patients	O
+were	O
+randomized	O
+to	O
+receive	O
+0	O
+.	O
+02	O
+,	O
+0	O
+.	O
+03	O
+,	O
+0	O
+.	O
+04	O
+,	O
+0	O
+.	O
+05	O
+and	O
+0	O
+.	O
+06	O
+mg	O
+/	O
+kg	O
+rocuronium	O
+as	O
+a	O
+precurarizing	O
+dose	O
+.	O
+
+Neuromuscular	O
+monitoring	O
+after	O
+each	O
+precurarizing	O
+dose	O
+was	O
+recorded	O
+from	O
+the	O
+adductor	O
+pollicis	O
+muscle	O
+using	O
+acceleromyography	O
+with	O
+train	O
+-	O
+of	O
+-	O
+four	O
+stimulation	O
+of	O
+the	O
+ulnar	O
+nerve	O
+.	O
+
+All	O
+patients	O
+received	O
+succinylcholine	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+at	O
+2	O
+minutes	O
+after	O
+the	O
+precurarization	O
+,	O
+and	O
+were	O
+assessed	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+fasciculations	B
+,	O
+while	O
+myalgia	B
+was	O
+assessed	O
+at	O
+24	O
+hours	O
+after	O
+surgery	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+incidence	O
+and	O
+severity	O
+of	O
+visible	O
+muscle	B
+fasciculation	I
+was	O
+significantly	O
+less	O
+with	O
+increasing	O
+the	O
+amount	O
+of	O
+precurarizing	O
+dose	O
+of	O
+rocuronium	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Those	O
+of	O
+myalgia	B
+tend	O
+to	O
+decrease	O
+according	O
+to	O
+increasing	O
+the	O
+amount	O
+of	O
+precurarizing	O
+dose	O
+of	O
+rocuronium	O
+,	O
+but	O
+there	O
+was	O
+no	O
+significance	O
+(	O
+P	O
+=	O
+0	O
+.	O
+072	O
+)	O
+.	O
+
+The	O
+onset	O
+time	O
+of	O
+succinylcholine	O
+was	O
+significantly	O
+longer	O
+with	O
+increasing	O
+the	O
+amount	O
+of	O
+precurarizing	O
+dose	O
+of	O
+rocuronium	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Precurarization	O
+with	O
+0	O
+.	O
+04	O
+mg	O
+/	O
+kg	O
+rocuronium	O
+was	O
+the	O
+optimal	O
+dose	O
+considering	O
+the	O
+reduction	O
+in	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+fasciculation	B
+and	O
+myalgia	B
+with	O
+acceptable	O
+onset	O
+time	O
+,	O
+and	O
+the	O
+safe	O
+and	O
+effective	O
+precurarization	O
+.	O
+
+Absence	O
+of	O
+PKC	O
+-	O
+alpha	O
+attenuates	O
+lithium	O
+-	O
+induced	O
+nephrogenic	B
+diabetes	I
+insipidus	I
+.	O
+
+Lithium	O
+,	O
+an	O
+effective	O
+antipsychotic	O
+,	O
+induces	O
+nephrogenic	B
+diabetes	I
+insipidus	I
+(	O
+NDI	B
+)	O
+in	O
+40	O
+%	O
+of	O
+patients	O
+.	O
+
+The	O
+decreased	O
+capacity	O
+to	O
+concentrate	O
+urine	O
+is	O
+likely	O
+due	O
+to	O
+lithium	O
+acutely	O
+disrupting	O
+the	O
+cAMP	O
+pathway	O
+and	O
+chronically	O
+reducing	O
+urea	O
+transporter	O
+(	O
+UT	O
+-	O
+A1	O
+)	O
+and	O
+water	O
+channel	O
+(	O
+AQP2	O
+)	O
+expression	O
+in	O
+the	O
+inner	O
+medulla	O
+.	O
+
+Targeting	O
+an	O
+alternative	O
+signaling	O
+pathway	O
+,	O
+such	O
+as	O
+PKC	O
+-	O
+mediated	O
+signaling	O
+,	O
+may	O
+be	O
+an	O
+effective	O
+method	O
+of	O
+treating	O
+lithium	O
+-	O
+induced	O
+polyuria	B
+.	O
+
+PKC	O
+-	O
+alpha	O
+null	O
+mice	O
+(	O
+PKCa	O
+KO	O
+)	O
+and	O
+strain	O
+-	O
+matched	O
+wild	O
+type	O
+(	O
+WT	O
+)	O
+controls	O
+were	O
+treated	O
+with	O
+lithium	O
+for	O
+0	O
+,	O
+3	O
+or	O
+5	O
+days	O
+.	O
+
+WT	O
+mice	O
+had	O
+increased	O
+urine	O
+output	O
+and	O
+lowered	O
+urine	O
+osmolality	O
+after	O
+3	O
+and	O
+5	O
+days	O
+of	O
+treatment	O
+whereas	O
+PKCa	O
+KO	O
+mice	O
+had	O
+no	O
+change	O
+in	O
+urine	O
+output	O
+or	O
+concentration	O
+.	O
+
+Western	O
+blot	O
+analysis	O
+revealed	O
+that	O
+AQP2	O
+expression	O
+in	O
+medullary	O
+tissues	O
+was	O
+lowered	O
+after	O
+3	O
+and	O
+5	O
+days	O
+in	O
+WT	O
+mice	O
+;	O
+however	O
+,	O
+AQP2	O
+was	O
+unchanged	O
+in	O
+PKCa	O
+KO	O
+.	O
+
+Similar	O
+results	O
+were	O
+observed	O
+with	O
+UT	O
+-	O
+A1	O
+expression	O
+.	O
+
+Animals	O
+were	O
+also	O
+treated	O
+with	O
+lithium	O
+for	O
+6	O
+weeks	O
+.	O
+
+Lithium	O
+-	O
+treated	O
+WT	O
+mice	O
+had	O
+19	O
+-	O
+fold	O
+increased	O
+urine	O
+output	O
+whereas	O
+treated	O
+PKCa	O
+KO	O
+animals	O
+had	O
+a	O
+4	O
+-	O
+fold	O
+increase	O
+in	O
+output	O
+.	O
+
+AQP2	O
+and	O
+UT	O
+-	O
+A1	O
+expression	O
+was	O
+lowered	O
+in	O
+6	O
+week	O
+lithium	O
+-	O
+treated	O
+WT	O
+animals	O
+whereas	O
+in	O
+treated	O
+PKCa	O
+KO	O
+mice	O
+,	O
+AQP2	O
+was	O
+only	O
+reduced	O
+by	O
+2	O
+-	O
+fold	O
+and	O
+UT	O
+-	O
+A1	O
+expression	O
+was	O
+unaffected	O
+.	O
+
+Urinary	O
+sodium	O
+,	O
+potassium	O
+and	O
+calcium	O
+were	O
+elevated	O
+in	O
+lithium	O
+-	O
+fed	O
+WT	O
+but	O
+not	O
+in	O
+lithium	O
+-	O
+fed	O
+PKCa	O
+KO	O
+mice	O
+.	O
+
+Our	O
+data	O
+show	O
+that	O
+ablation	O
+of	O
+PKCa	O
+preserves	O
+AQP2	O
+and	O
+UT	O
+-	O
+A1	O
+protein	O
+expression	O
+and	O
+localization	O
+in	O
+lithium	O
+-	O
+induced	O
+NDI	B
+,	O
+and	O
+prevents	O
+the	O
+development	O
+of	O
+the	O
+severe	O
+polyuria	B
+associated	O
+with	O
+lithium	O
+therapy	O
+.	O
+
+Is	O
+Dysguesia	B
+Going	O
+to	O
+be	O
+a	O
+Rare	O
+or	O
+a	O
+Common	O
+Side	O
+-	O
+effect	O
+of	O
+Amlodipine	O
+?	O
+
+A	O
+very	O
+rare	O
+side	O
+-	O
+effect	O
+of	O
+amlodipine	O
+is	O
+dysguesia	B
+.	O
+
+A	O
+review	O
+of	O
+the	O
+literature	O
+produced	O
+only	O
+one	O
+case	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+about	O
+a	O
+female	O
+with	O
+essential	O
+hypertension	B
+on	O
+drug	O
+treatment	O
+with	O
+amlodipine	O
+developed	O
+loss	B
+of	I
+taste	I
+sensation	I
+.	O
+
+Condition	O
+moderately	O
+improved	O
+on	O
+stoppage	O
+of	O
+the	O
+drug	O
+for	O
+25	O
+days	O
+.	O
+
+We	O
+conclude	O
+that	O
+amlodipine	O
+can	O
+cause	O
+dysguesia	B
+.	O
+
+Here	O
+,	O
+we	O
+describe	O
+the	O
+clinical	O
+presentation	O
+and	O
+review	O
+the	O
+relevant	O
+literature	O
+on	O
+amlodipine	O
+and	O
+dysguesia	B
+.	O
+
+Rhabdomyolysis	B
+in	O
+association	O
+with	O
+simvastatin	O
+and	O
+dosage	O
+increment	O
+in	O
+clarithromycin	O
+.	O
+
+Clarithromycin	O
+is	O
+the	O
+most	O
+documented	O
+cytochrome	O
+P450	O
+3A4	O
+(	O
+CYP3A4	O
+)	O
+inhibitor	O
+to	O
+cause	O
+an	O
+adverse	O
+interaction	O
+with	O
+simvastatin	O
+.	O
+
+This	O
+particular	O
+case	O
+is	O
+of	O
+interest	O
+as	O
+rhabdomyolysis	B
+only	O
+occurred	O
+after	O
+an	O
+increase	O
+in	O
+the	O
+dose	O
+of	O
+clarithromycin	O
+.	O
+
+The	O
+patient	O
+developed	O
+raised	O
+cardiac	O
+biomarkers	O
+without	O
+any	O
+obvious	O
+cardiac	O
+issues	O
+,	O
+a	O
+phenomenon	O
+that	O
+has	O
+been	O
+linked	O
+to	O
+rhabdomyolysis	B
+previously	O
+.	O
+
+To	O
+date	O
+,	O
+there	O
+has	O
+been	O
+no	O
+reported	O
+effect	O
+of	O
+rhabdomyolysis	B
+on	O
+the	O
+structure	O
+and	O
+function	O
+of	O
+cardiac	O
+muscle	O
+.	O
+
+Clinicians	O
+need	O
+to	O
+be	O
+aware	O
+of	O
+prescribing	O
+concomitant	O
+medications	O
+that	O
+increase	O
+the	O
+risk	O
+of	O
+myopathy	B
+or	O
+inhibit	O
+the	O
+CYP3A4	O
+enzyme	O
+.	O
+
+Our	O
+case	O
+suggests	O
+that	O
+troponin	O
+elevation	O
+could	O
+be	O
+associated	O
+with	O
+statin	O
+induced	O
+rhabdomyolysis	B
+,	O
+which	O
+may	O
+warrant	O
+further	O
+studies	O
+.	O
+
+Characterization	O
+of	O
+a	O
+novel	O
+BCHE	O
+"	O
+silent	O
+"	O
+allele	O
+:	O
+point	O
+mutation	O
+(	O
+p	O
+.	O
+Val204Asp	O
+)	O
+causes	O
+loss	O
+of	O
+activity	O
+and	O
+prolonged	O
+apnea	B
+with	O
+suxamethonium	O
+.	O
+
+Butyrylcholinesterase	B
+deficiency	I
+is	O
+characterized	O
+by	O
+prolonged	O
+apnea	B
+after	O
+the	O
+use	O
+of	O
+muscle	O
+relaxants	O
+(	O
+suxamethonium	O
+or	O
+mivacurium	O
+)	O
+in	O
+patients	O
+who	O
+have	O
+mutations	O
+in	O
+the	O
+BCHE	O
+gene	O
+.	O
+
+Here	O
+,	O
+we	O
+report	O
+a	O
+case	O
+of	O
+prolonged	O
+neuromuscular	O
+block	O
+after	O
+administration	O
+of	O
+suxamethonium	O
+leading	O
+to	O
+the	O
+discovery	O
+of	O
+a	O
+novel	O
+BCHE	O
+variant	O
+(	O
+c	O
+.	O
+695T	O
+>	O
+A	O
+,	O
+p	O
+.	O
+Val204Asp	O
+)	O
+.	O
+
+Inhibition	O
+studies	O
+,	O
+kinetic	O
+analysis	O
+and	O
+molecular	O
+dynamics	O
+were	O
+undertaken	O
+to	O
+understand	O
+how	O
+this	O
+mutation	O
+disrupts	O
+the	O
+catalytic	O
+triad	O
+and	O
+determines	O
+a	O
+"	O
+silent	O
+"	O
+phenotype	O
+.	O
+
+Low	O
+activity	O
+of	O
+patient	O
+plasma	O
+butyrylcholinesterase	O
+with	O
+butyrylthiocholine	O
+(	O
+BTC	O
+)	O
+and	O
+benzoylcholine	O
+,	O
+and	O
+values	O
+of	O
+dibucaine	O
+and	O
+fluoride	O
+numbers	O
+fit	O
+with	O
+heterozygous	O
+atypical	O
+silent	O
+genotype	O
+.	O
+
+Electrophoretic	O
+analysis	O
+of	O
+plasma	O
+BChE	O
+of	O
+the	O
+proband	O
+and	O
+his	O
+mother	O
+showed	O
+that	O
+patient	O
+has	O
+a	O
+reduced	O
+amount	O
+of	O
+tetrameric	O
+enzyme	O
+in	O
+plasma	O
+and	O
+that	O
+minor	O
+fast	O
+-	O
+moving	O
+BChE	O
+components	O
+:	O
+monomer	O
+,	O
+dimer	O
+,	O
+and	O
+monomer	O
+-	O
+albumin	O
+conjugate	O
+are	O
+missing	O
+.	O
+
+Kinetic	O
+analysis	O
+showed	O
+that	O
+the	O
+p	O
+.	O
+Val204Asp	O
+/	O
+p	O
+.	O
+Asp70Gly	O
+-	O
+p	O
+.	O
+Ala539Thr	O
+BChE	O
+displays	O
+a	O
+pure	O
+Michaelian	O
+behavior	O
+with	O
+BTC	O
+as	O
+the	O
+substrate	O
+.	O
+
+Both	O
+catalytic	O
+parameters	O
+Km	O
+=	O
+265	O
+uM	O
+for	O
+BTC	O
+,	O
+two	O
+times	O
+higher	O
+than	O
+that	O
+of	O
+the	O
+atypical	O
+enzyme	O
+,	O
+and	O
+a	O
+low	O
+Vmax	O
+are	O
+consistent	O
+with	O
+the	O
+absence	O
+of	O
+activity	O
+against	O
+suxamethonium	O
+.	O
+
+Molecular	O
+dynamic	O
+(	O
+MD	O
+)	O
+simulations	O
+showed	O
+that	O
+the	O
+overall	O
+effect	O
+of	O
+the	O
+mutation	O
+p	O
+.	O
+Val204Asp	O
+is	O
+disruption	O
+of	O
+hydrogen	O
+bonding	O
+between	O
+Gln223	O
+and	O
+Glu441	O
+,	O
+leading	O
+Ser198	O
+and	O
+His438	O
+to	O
+move	O
+away	O
+from	O
+each	O
+other	O
+with	O
+subsequent	O
+disruption	O
+of	O
+the	O
+catalytic	O
+triad	O
+functionality	O
+regardless	O
+of	O
+the	O
+type	O
+of	O
+substrate	O
+.	O
+
+MD	O
+also	O
+showed	O
+that	O
+the	O
+enzyme	O
+volume	O
+is	O
+increased	O
+,	O
+suggesting	O
+a	O
+pre	O
+-	O
+denaturation	O
+state	O
+.	O
+
+This	O
+fits	O
+with	O
+the	O
+reduced	O
+concentration	O
+of	O
+p	O
+.	O
+Ala204Asp	O
+/	O
+p	O
+.	O
+Asp70Gly	O
+-	O
+p	O
+.	O
+Ala539Thr	O
+tetrameric	O
+enzyme	O
+in	O
+the	O
+plasma	O
+and	O
+non	O
+-	O
+detectable	O
+fast	O
+moving	O
+-	O
+bands	O
+on	O
+electrophoresis	O
+gels	O
+.	O
+
+Delayed	O
+anemia	B
+after	O
+treatment	O
+with	O
+injectable	O
+artesunate	O
+in	O
+the	O
+Democratic	O
+Republic	O
+of	O
+the	O
+Congo	O
+:	O
+a	O
+manageable	O
+issue	O
+.	O
+
+Cases	O
+of	O
+delayed	O
+hemolytic	B
+anemia	I
+have	O
+been	O
+described	O
+after	O
+treatment	O
+with	O
+injectable	O
+artesunate	O
+,	O
+the	O
+current	O
+World	O
+Health	O
+Organization	O
+(	O
+WHO	O
+)	O
+-	O
+recommended	O
+first	O
+-	O
+line	O
+drug	O
+for	O
+the	O
+treatment	O
+of	O
+severe	O
+malaria	B
+.	O
+
+A	O
+total	O
+of	O
+350	O
+patients	O
+(	O
+215	O
+[	O
+61	O
+.	O
+4	O
+%	O
+]	O
+<	O
+5	O
+years	O
+of	O
+age	O
+and	O
+135	O
+[	O
+38	O
+.	O
+6	O
+%	O
+]	O
+>	O
+5	O
+years	O
+of	O
+age	O
+)	O
+were	O
+followed	O
+-	O
+up	O
+after	O
+treatment	O
+with	O
+injectable	O
+artesunate	O
+for	O
+severe	O
+malaria	B
+in	O
+hospitals	O
+and	O
+health	O
+centers	O
+of	O
+the	O
+Democratic	O
+Republic	O
+of	O
+the	O
+Congo	O
+.	O
+
+Complete	O
+series	O
+of	O
+hemoglobin	O
+(	O
+Hb	O
+)	O
+measurements	O
+were	O
+available	O
+for	O
+201	O
+patients	O
+.	O
+
+A	O
+decrease	O
+in	O
+Hb	O
+levels	O
+between	O
+2	O
+and	O
+5	O
+g	O
+/	O
+dL	O
+was	O
+detected	O
+in	O
+23	O
+(	O
+11	O
+.	O
+4	O
+%	O
+)	O
+patients	O
+during	O
+the	O
+follow	O
+-	O
+up	O
+period	O
+.	O
+
+For	O
+five	O
+patients	O
+,	O
+Hb	O
+levels	O
+decreased	O
+below	O
+5	O
+g	O
+/	O
+dL	O
+during	O
+at	O
+least	O
+one	O
+follow	O
+-	O
+up	O
+visit	O
+.	O
+
+All	O
+cases	O
+of	O
+delayed	O
+anemia	B
+were	O
+clinically	O
+manageable	O
+and	O
+resolved	O
+within	O
+one	O
+month	O
+.	O
+
+Regulation	O
+of	O
+signal	O
+transducer	O
+and	O
+activator	O
+of	O
+transcription	O
+3	O
+and	O
+apoptotic	O
+pathways	O
+by	O
+betaine	O
+attenuates	O
+isoproterenol	O
+-	O
+induced	O
+acute	O
+myocardial	B
+injury	I
+in	O
+rats	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+investigate	O
+the	O
+cardioprotective	O
+effects	O
+of	O
+betaine	O
+on	O
+acute	O
+myocardial	B
+ischemia	I
+induced	O
+experimentally	O
+in	O
+rats	O
+focusing	O
+on	O
+regulation	O
+of	O
+signal	O
+transducer	O
+and	O
+activator	O
+of	O
+transcription	O
+3	O
+(	O
+STAT3	O
+)	O
+and	O
+apoptotic	O
+pathways	O
+as	O
+the	O
+potential	O
+mechanism	O
+underlying	O
+the	O
+drug	O
+effect	O
+.	O
+
+Male	O
+Sprague	O
+Dawley	O
+rats	O
+were	O
+treated	O
+with	O
+betaine	O
+(	O
+100	O
+,	O
+200	O
+,	O
+and	O
+400	O
+mg	O
+/	O
+kg	O
+)	O
+orally	O
+for	O
+40	O
+days	O
+.	O
+
+Acute	O
+myocardial	B
+ischemic	I
+injury	I
+was	O
+induced	O
+in	O
+rats	O
+by	O
+subcutaneous	O
+injection	O
+of	O
+isoproterenol	O
+(	O
+85	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+for	O
+two	O
+consecutive	O
+days	O
+.	O
+
+Serum	O
+cardiac	O
+marker	O
+enzyme	O
+,	O
+histopathological	O
+variables	O
+and	O
+expression	O
+of	O
+protein	O
+levels	O
+were	O
+analyzed	O
+.	O
+
+Oral	O
+administration	O
+of	O
+betaine	O
+(	O
+200	O
+and	O
+400	O
+mg	O
+/	O
+kg	O
+)	O
+significantly	O
+reduced	O
+the	O
+level	O
+of	O
+cardiac	O
+marker	O
+enzyme	O
+in	O
+the	O
+serum	O
+and	O
+prevented	O
+left	O
+ventricular	B
+remodeling	I
+.	O
+
+Western	O
+blot	O
+analysis	O
+showed	O
+that	O
+isoproterenol	O
+-	O
+induced	O
+phosphorylation	O
+of	O
+STAT3	O
+was	O
+maintained	O
+or	O
+further	O
+enhanced	O
+by	O
+betaine	O
+treatment	O
+in	O
+myocardium	O
+.	O
+
+Furthermore	O
+,	O
+betaine	O
+(	O
+200	O
+and	O
+400	O
+mg	O
+/	O
+kg	O
+)	O
+treatment	O
+increased	O
+the	O
+ventricular	O
+expression	O
+of	O
+Bcl	O
+-	O
+2	O
+and	O
+reduced	O
+the	O
+level	O
+of	O
+Bax	O
+,	O
+therefore	O
+causing	O
+a	O
+significant	O
+increase	O
+in	O
+the	O
+ratio	O
+of	O
+Bcl	O
+-	O
+2	O
+/	O
+Bax	O
+.	O
+
+The	O
+protective	O
+role	O
+of	O
+betaine	O
+on	O
+myocardial	B
+damage	I
+was	O
+further	O
+confirmed	O
+by	O
+histopathological	O
+examination	O
+.	O
+
+In	O
+summary	O
+,	O
+our	O
+results	O
+showed	O
+that	O
+betaine	O
+pretreatment	O
+attenuated	O
+isoproterenol	O
+-	O
+induced	O
+acute	O
+myocardial	B
+ischemia	I
+via	O
+the	O
+regulation	O
+of	O
+STAT3	O
+and	O
+apoptotic	O
+pathways	O
+.	O
+
+Quetiapine	O
+-	O
+induced	O
+neutropenia	B
+in	O
+a	O
+bipolar	B
+patient	O
+with	O
+hepatocellular	B
+carcinoma	I
+.	O
+
+OBJECTIVE	O
+:	O
+Quetiapine	O
+is	O
+a	O
+dibenzothiazepine	O
+derivative	O
+,	O
+similar	O
+to	O
+clozapine	O
+,	O
+which	O
+has	O
+the	O
+highest	O
+risk	O
+of	O
+causing	O
+blood	B
+dyscrasias	I
+,	O
+especially	O
+neutropenia	B
+.	O
+
+There	O
+are	O
+some	O
+case	O
+reports	O
+about	O
+this	O
+side	O
+effect	O
+of	O
+quetiapine	O
+,	O
+but	O
+possible	O
+risk	O
+factors	O
+are	O
+seldom	O
+discussed	O
+and	O
+identified	O
+.	O
+
+A	O
+case	O
+of	O
+a	O
+patient	O
+with	O
+hepatocellular	B
+carcinoma	I
+that	O
+developed	O
+neutropenia	B
+after	O
+treatment	O
+with	O
+quetiapine	O
+is	O
+described	O
+here	O
+.	O
+
+CASE	O
+REPORT	O
+:	O
+A	O
+62	O
+-	O
+year	O
+-	O
+old	O
+Taiwanese	O
+widow	O
+with	O
+bipolar	B
+disorder	I
+was	O
+diagnosed	O
+with	O
+hepatocellular	B
+carcinoma	I
+at	O
+age	O
+60	O
+.	O
+
+She	O
+developed	O
+leucopenia	B
+after	O
+being	O
+treated	O
+with	O
+quetiapine	O
+.	O
+
+After	O
+quetiapine	O
+was	O
+discontinued	O
+,	O
+her	O
+white	O
+blood	O
+cell	O
+count	O
+returned	O
+to	O
+normal	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Although	O
+neutropenia	B
+is	O
+not	O
+a	O
+common	O
+side	O
+effect	O
+of	O
+quetiapine	O
+,	O
+physicians	O
+should	O
+be	O
+cautious	O
+about	O
+its	O
+presentation	O
+and	O
+associated	O
+risk	O
+factors	O
+.	O
+
+Hepatic	B
+dysfunction	I
+may	O
+be	O
+one	O
+of	O
+the	O
+possible	O
+risk	O
+factors	O
+,	O
+and	O
+concomitant	O
+fever	B
+may	O
+be	O
+a	O
+diagnostic	O
+marker	O
+for	O
+adverse	O
+reaction	O
+to	O
+quetiapine	O
+.	O
+
+Lateral	O
+antebrachial	O
+cutaneous	O
+neuropathy	B
+after	O
+steroid	O
+injection	O
+at	O
+lateral	O
+epicondyle	O
+.	O
+
+BACKGROUND	O
+AND	O
+OBJECTIVES	O
+:	O
+This	O
+report	O
+aimed	O
+to	O
+present	O
+a	O
+case	O
+of	O
+lateral	O
+antebrachial	O
+cutaneous	O
+neuropathy	B
+(	O
+LACNP	O
+)	O
+that	O
+occurred	O
+after	O
+a	O
+steroid	O
+injection	O
+in	O
+the	O
+lateral	O
+epicondyle	O
+to	O
+treat	O
+lateral	B
+epicondylitis	I
+in	O
+a	O
+40	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+.	O
+
+MATERIAL	O
+AND	O
+METHOD	O
+:	O
+A	O
+40	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+presented	O
+with	O
+decreased	O
+sensation	O
+and	O
+paresthesia	B
+over	O
+her	O
+right	O
+lateral	O
+forearm	O
+;	O
+the	O
+paresthesia	B
+had	O
+occurred	O
+after	O
+a	O
+steroid	O
+injection	O
+in	O
+the	O
+right	O
+lateral	O
+epicondyle	O
+3	O
+months	O
+before	O
+.	O
+
+Her	O
+sensation	O
+of	O
+light	O
+touch	O
+and	O
+pain	B
+was	O
+diminished	O
+over	O
+the	O
+lateral	O
+side	O
+of	O
+the	O
+right	O
+forearm	O
+and	O
+wrist	O
+area	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+sensory	O
+action	O
+potential	O
+amplitude	O
+of	O
+the	O
+right	O
+lateral	O
+antebrachial	O
+cutaneous	O
+nerve	O
+(	O
+LACN	O
+)	O
+(	O
+6	O
+.	O
+2	O
+uV	O
+)	O
+was	O
+lower	O
+than	O
+that	O
+of	O
+the	O
+left	O
+(	O
+13	O
+.	O
+1	O
+uV	O
+)	O
+.	O
+
+The	O
+difference	O
+of	O
+amplitude	O
+between	O
+both	O
+sides	O
+was	O
+significant	O
+because	O
+there	O
+was	O
+more	O
+than	O
+a	O
+50	O
+%	O
+reduction	O
+.	O
+
+She	O
+was	O
+diagnosed	O
+with	O
+right	O
+LACNP	O
+(	O
+mainly	O
+axonal	O
+involvement	O
+)	O
+on	O
+the	O
+basis	O
+of	O
+the	O
+clinical	O
+manifestation	O
+and	O
+the	O
+electrodiagnostic	O
+findings	O
+.	O
+
+Her	O
+symptoms	O
+improved	O
+through	O
+physical	O
+therapy	O
+but	O
+persisted	O
+to	O
+some	O
+degree	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+report	O
+describes	O
+the	O
+case	O
+of	O
+a	O
+woman	O
+with	O
+LACNP	O
+that	O
+developed	O
+after	O
+a	O
+steroid	O
+injection	O
+for	O
+the	O
+treatment	O
+of	O
+lateral	B
+epicondylitis	I
+.	O
+
+An	O
+electrodiagnostic	O
+study	O
+,	O
+including	O
+a	O
+nerve	O
+conduction	O
+study	O
+of	O
+the	O
+LACN	O
+,	O
+was	O
+helpful	O
+to	O
+diagnose	O
+right	O
+LACNP	O
+and	O
+to	O
+find	O
+the	O
+passage	O
+of	O
+the	O
+LACN	O
+on	O
+the	O
+lateral	O
+epicondyle	O
+.	O
+
+Curcumin	O
+prevents	O
+maleate	O
+-	O
+induced	O
+nephrotoxicity	B
+:	O
+relation	O
+to	O
+hemodynamic	O
+alterations	O
+,	O
+oxidative	O
+stress	O
+,	O
+mitochondrial	O
+oxygen	O
+consumption	O
+and	O
+activity	O
+of	O
+respiratory	O
+complex	O
+I	O
+.	O
+
+The	O
+potential	O
+protective	O
+effect	O
+of	O
+the	O
+dietary	O
+antioxidant	O
+curcumin	O
+(	O
+120	O
+mg	O
+/	O
+Kg	O
+/	O
+day	O
+for	O
+6	O
+days	O
+)	O
+against	O
+the	O
+renal	B
+injury	I
+induced	O
+by	O
+maleate	O
+was	O
+evaluated	O
+.	O
+
+Tubular	O
+proteinuria	B
+and	O
+oxidative	O
+stress	O
+were	O
+induced	O
+by	O
+a	O
+single	O
+injection	O
+of	O
+maleate	O
+(	O
+400	O
+mg	O
+/	O
+kg	O
+)	O
+in	O
+rats	O
+.	O
+
+Maleate	O
+-	O
+induced	O
+renal	B
+injury	I
+included	O
+increase	O
+in	O
+renal	O
+vascular	O
+resistance	O
+and	O
+in	O
+the	O
+urinary	O
+excretion	O
+of	O
+total	O
+protein	O
+,	O
+glucose	O
+,	O
+sodium	O
+,	O
+neutrophil	O
+gelatinase	O
+-	O
+associated	O
+lipocalin	O
+(	O
+NGAL	O
+)	O
+and	O
+N	O
+-	O
+acetyl	O
+b	O
+-	O
+D	O
+-	O
+glucosaminidase	O
+(	O
+NAG	O
+)	O
+,	O
+upregulation	O
+of	O
+kidney	B
+injury	I
+molecule	O
+(	O
+KIM	O
+)	O
+-	O
+1	O
+,	O
+decrease	O
+in	O
+renal	O
+blood	O
+flow	O
+and	O
+claudin	O
+-	O
+2	O
+expression	O
+besides	O
+of	O
+necrosis	B
+and	O
+apoptosis	O
+of	O
+tubular	O
+cells	O
+on	O
+24	O
+h	O
+.	O
+
+Oxidative	O
+stress	O
+was	O
+determined	O
+by	O
+measuring	O
+the	O
+oxidation	O
+of	O
+lipids	O
+and	O
+proteins	O
+and	O
+diminution	O
+in	O
+renal	O
+Nrf2	O
+levels	O
+.	O
+
+Studies	O
+were	O
+also	O
+conducted	O
+in	O
+renal	O
+epithelial	O
+LLC	O
+-	O
+PK1	O
+cells	O
+and	O
+in	O
+mitochondria	O
+isolated	O
+from	O
+kidneys	O
+of	O
+all	O
+the	O
+experimental	O
+groups	O
+.	O
+
+Maleate	O
+induced	O
+cell	O
+damage	O
+and	O
+reactive	O
+oxygen	O
+species	O
+(	O
+ROS	O
+)	O
+production	O
+in	O
+LLC	O
+-	O
+PK1	O
+cells	O
+in	O
+culture	O
+.	O
+
+In	O
+addition	O
+,	O
+maleate	O
+treatment	O
+reduced	O
+oxygen	O
+consumption	O
+in	O
+ADP	O
+-	O
+stimulated	O
+mitochondria	O
+and	O
+diminished	O
+respiratory	O
+control	O
+index	O
+when	O
+using	O
+malate	O
+/	O
+glutamate	O
+as	O
+substrate	O
+.	O
+
+The	O
+activities	O
+of	O
+both	O
+complex	O
+I	O
+and	O
+aconitase	O
+were	O
+also	O
+diminished	O
+.	O
+
+All	O
+the	O
+above	O
+-	O
+described	O
+alterations	O
+were	O
+prevented	O
+by	O
+curcumin	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+curcumin	O
+is	O
+able	O
+to	O
+attenuate	O
+in	O
+vivo	O
+maleate	O
+-	O
+induced	O
+nephropathy	B
+and	O
+in	O
+vitro	O
+cell	O
+damage	O
+.	O
+
+The	O
+in	O
+vivo	O
+protection	O
+was	O
+associated	O
+to	O
+the	O
+prevention	O
+of	O
+oxidative	O
+stress	O
+and	O
+preservation	O
+of	O
+mitochondrial	O
+oxygen	O
+consumption	O
+and	O
+activity	O
+of	O
+respiratory	O
+complex	O
+I	O
+,	O
+and	O
+the	O
+in	O
+vitro	O
+protection	O
+was	O
+associated	O
+to	O
+the	O
+prevention	O
+of	O
+ROS	O
+production	O
+.	O
+
+Anticonvulsant	O
+actions	O
+of	O
+MK	O
+-	O
+801	O
+on	O
+the	O
+lithium	O
+-	O
+pilocarpine	O
+model	O
+of	O
+status	B
+epilepticus	I
+in	O
+rats	O
+.	O
+
+MK	O
+-	O
+801	O
+,	O
+a	O
+noncompetitive	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+receptor	O
+antagonist	O
+,	O
+was	O
+tested	O
+for	O
+anticonvulsant	O
+effects	O
+in	O
+rats	O
+using	O
+two	O
+seizure	B
+models	O
+,	O
+coadministration	O
+of	O
+lithium	O
+and	O
+pilocarpine	O
+and	O
+administration	O
+of	O
+a	O
+high	O
+dose	O
+of	O
+pilocarpine	O
+alone	O
+.	O
+
+Three	O
+major	O
+results	O
+are	O
+reported	O
+.	O
+
+First	O
+,	O
+pretreatment	O
+with	O
+MK	O
+-	O
+801	O
+produced	O
+an	O
+effective	O
+and	O
+dose	O
+-	O
+dependent	O
+anticonvulsant	O
+action	O
+with	O
+the	O
+lithium	O
+-	O
+pilocarpine	O
+model	O
+but	O
+not	O
+with	O
+rats	O
+treated	O
+with	O
+pilocarpine	O
+alone	O
+,	O
+suggesting	O
+that	O
+different	O
+biochemical	O
+mechanisms	O
+control	O
+seizures	B
+in	O
+these	O
+two	O
+models	O
+.	O
+
+Second	O
+,	O
+the	O
+anticonvulsant	O
+effect	O
+of	O
+MK	O
+-	O
+801	O
+in	O
+the	O
+lithium	O
+-	O
+pilocarpine	O
+model	O
+only	O
+occurred	O
+after	O
+initial	O
+periods	O
+of	O
+seizure	B
+activity	O
+.	O
+
+This	O
+observation	O
+is	O
+suggested	O
+to	O
+be	O
+an	O
+in	O
+vivo	O
+demonstration	O
+of	O
+the	O
+conclusion	O
+derived	O
+from	O
+in	O
+vitro	O
+experiments	O
+that	O
+MK	O
+-	O
+801	O
+binding	O
+requires	O
+agonist	O
+-	O
+induced	O
+opening	O
+of	O
+the	O
+channel	O
+sites	O
+of	O
+the	O
+NMDA	O
+receptor	O
+.	O
+
+Third	O
+,	O
+although	O
+it	O
+is	O
+relatively	O
+easy	O
+to	O
+block	O
+seizures	B
+induced	O
+by	O
+lithium	O
+and	O
+pilocarpine	O
+by	O
+administration	O
+of	O
+anticonvulsants	O
+prior	O
+to	O
+pilocarpine	O
+,	O
+it	O
+is	O
+more	O
+difficult	O
+to	O
+terminate	O
+ongoing	O
+status	B
+epilepticus	I
+and	O
+block	O
+the	O
+lethality	O
+of	O
+the	O
+seizures	B
+.	O
+
+Administration	O
+of	O
+MK	O
+-	O
+801	O
+30	O
+or	O
+60	O
+min	O
+after	O
+pilocarpine	O
+,	O
+i	O
+.	O
+e	O
+.	O
+,	O
+during	O
+status	B
+epilepticus	I
+,	O
+gradually	O
+reduced	O
+electrical	O
+and	O
+behavioral	O
+seizure	B
+activity	O
+and	O
+greatly	O
+enhanced	O
+the	O
+survival	O
+rate	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+activation	O
+of	O
+NMDA	O
+receptors	O
+plays	O
+an	O
+important	O
+role	O
+in	O
+status	B
+epilepticus	I
+and	O
+brain	B
+damage	I
+in	O
+the	O
+lithium	O
+-	O
+pilocarpine	O
+model	O
+.	O
+
+This	O
+was	O
+further	O
+supported	O
+by	O
+results	O
+showing	O
+that	O
+nonconvulsive	O
+doses	O
+of	O
+NMDA	O
+and	O
+pilocarpine	O
+were	O
+synergistic	O
+,	O
+resulting	O
+in	O
+status	B
+epilepticus	I
+and	O
+subsequent	O
+mortality	O
+.	O
+
+Continuous	O
+infusion	O
+tobramycin	O
+combined	O
+with	O
+carbenicillin	O
+for	O
+infections	B
+in	O
+cancer	B
+patients	O
+.	O
+
+The	O
+cure	O
+rate	O
+of	O
+infections	B
+in	O
+cancer	B
+patients	O
+is	O
+adversely	O
+affected	O
+by	O
+neutropenia	B
+(	O
+less	O
+than	O
+1	O
+,	O
+000	O
+/	O
+mm3	O
+)	O
+.	O
+
+In	O
+particular	O
+,	O
+patients	O
+with	O
+severe	O
+neutropenia	B
+(	O
+less	O
+than	O
+100	O
+/	O
+mm3	O
+)	O
+have	O
+shown	O
+a	O
+poor	O
+response	O
+to	O
+antibiotics	O
+.	O
+
+To	O
+overcome	O
+the	O
+adverse	O
+effects	O
+of	O
+neutropenia	B
+,	O
+tobramycin	O
+was	O
+given	O
+by	O
+continuous	O
+infusion	O
+and	O
+combined	O
+with	O
+intermittent	O
+carbenicillin	O
+.	O
+
+Tobramycin	O
+was	O
+given	O
+to	O
+a	O
+total	O
+daily	O
+dose	O
+of	O
+300	O
+mg	O
+/	O
+m2	O
+and	O
+carbenicillin	O
+was	O
+given	O
+at	O
+a	O
+dose	O
+of	O
+5	O
+gm	O
+every	O
+four	O
+hours	O
+.	O
+
+There	O
+were	O
+125	O
+infectious	O
+episodes	O
+in	O
+116	O
+cancer	B
+patients	O
+receiving	O
+myelosuppressive	O
+chemotherapy	O
+.	O
+
+The	O
+overall	O
+cure	O
+rate	O
+was	O
+70	O
+%	O
+.	O
+
+Pneumonia	B
+was	O
+the	O
+most	O
+common	O
+infection	B
+and	O
+61	O
+%	O
+of	O
+59	O
+episodes	O
+were	O
+cured	O
+.	O
+
+Gram	O
+-	O
+negative	O
+bacilli	O
+were	O
+the	O
+most	O
+common	O
+causative	O
+organisms	O
+and	O
+69	O
+%	O
+of	O
+these	O
+infections	B
+were	O
+cured	O
+.	O
+
+The	O
+most	O
+common	O
+pathogen	O
+was	O
+Klebsiella	O
+pneumoniae	B
+and	O
+this	O
+,	O
+together	O
+with	O
+Escherichia	O
+coli	O
+and	O
+Pseudomonas	O
+aeruginosa	O
+,	O
+accounted	O
+for	O
+74	O
+%	O
+of	O
+all	O
+gram	B
+-	I
+negative	I
+bacillary	I
+infections	I
+.	O
+
+Response	O
+was	O
+not	O
+influenced	O
+by	O
+the	O
+initial	O
+neutrophil	O
+count	O
+,	O
+with	O
+a	O
+62	O
+%	O
+cure	O
+rate	O
+for	O
+39	O
+episodes	O
+associated	O
+with	O
+severe	O
+neutropenia	B
+.	O
+
+However	O
+,	O
+failure	O
+of	O
+the	O
+neutrophil	O
+count	O
+to	O
+increase	O
+during	O
+therapy	O
+adversely	O
+affected	O
+response	O
+.	O
+
+Azotemia	B
+was	O
+the	O
+major	O
+side	O
+effect	O
+recognized	O
+,	O
+and	O
+it	O
+occurred	O
+in	O
+11	O
+%	O
+of	O
+episodes	O
+.	O
+
+Major	O
+azotemia	B
+(	O
+serum	O
+creatinine	O
+greater	O
+than	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+dl	O
+or	O
+BUN	O
+greater	O
+than	O
+50	O
+mg	O
+/	O
+dl	O
+)	O
+occurred	O
+in	O
+only	O
+2	O
+%	O
+.	O
+
+Azotemia	B
+was	O
+not	O
+related	O
+to	O
+duration	O
+of	O
+therapy	O
+or	O
+serum	O
+tobramycin	O
+concentration	O
+.	O
+
+This	O
+antibiotic	O
+regimen	O
+showed	O
+both	O
+therapeutic	O
+efficacy	O
+and	O
+acceptable	O
+renal	B
+toxicity	I
+for	O
+these	O
+patients	O
+.	O
+
+Incidence	O
+of	O
+solid	O
+tumours	B
+among	O
+pesticide	O
+applicators	O
+exposed	O
+to	O
+the	O
+organophosphate	O
+insecticide	O
+diazinon	O
+in	O
+the	O
+Agricultural	O
+Health	O
+Study	O
+:	O
+an	O
+updated	O
+analysis	O
+.	O
+
+OBJECTIVE	O
+:	O
+Diazinon	O
+,	O
+a	O
+common	O
+organophosphate	O
+insecticide	O
+with	O
+genotoxic	O
+properties	O
+,	O
+was	O
+previously	O
+associated	O
+with	O
+lung	B
+cancer	I
+in	O
+the	O
+Agricultural	O
+Health	O
+Study	O
+(	O
+AHS	O
+)	O
+cohort	O
+,	O
+but	O
+few	O
+other	O
+epidemiological	O
+studies	O
+have	O
+examined	O
+diazinon	O
+-	O
+associated	O
+cancer	B
+risk	O
+.	O
+
+We	O
+used	O
+updated	O
+diazinon	O
+exposure	O
+and	O
+cancer	B
+incidence	O
+information	O
+to	O
+evaluate	O
+solid	O
+tumour	B
+risk	O
+in	O
+the	O
+AHS	O
+.	O
+
+METHODS	O
+:	O
+Male	O
+pesticide	O
+applicators	O
+in	O
+Iowa	O
+and	O
+North	O
+Carolina	O
+reported	O
+lifetime	O
+diazinon	O
+use	O
+at	O
+enrolment	O
+(	O
+1993	O
+-	O
+1997	O
+)	O
+and	O
+follow	O
+-	O
+up	O
+(	O
+1998	O
+-	O
+2005	O
+)	O
+;	O
+cancer	B
+incidence	O
+was	O
+assessed	O
+through	O
+2010	O
+(	O
+North	O
+Carolina	O
+)	O
+/	O
+2011	O
+(	O
+Iowa	O
+)	O
+.	O
+
+Among	O
+applicators	O
+with	O
+usage	O
+information	O
+sufficient	O
+to	O
+evaluate	O
+exposure	O
+-	O
+response	O
+patterns	O
+,	O
+we	O
+used	O
+Poisson	O
+regression	O
+to	O
+estimate	O
+adjusted	O
+rate	O
+ratios	O
+(	O
+RRs	O
+)	O
+and	O
+95	O
+%	O
+CI	O
+for	O
+cancer	B
+sites	O
+with	O
+>	O
+10	O
+exposed	O
+cases	O
+for	O
+both	O
+lifetime	O
+(	O
+LT	O
+)	O
+exposure	O
+days	O
+and	O
+intensity	O
+-	O
+weighted	O
+(	O
+IW	O
+)	O
+lifetime	O
+exposure	O
+days	O
+(	O
+accounting	O
+for	O
+factors	O
+impacting	O
+exposure	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+We	O
+observed	O
+elevated	O
+lung	B
+cancer	I
+risks	O
+(	O
+N	O
+=	O
+283	O
+)	O
+among	O
+applicators	O
+with	O
+the	O
+greatest	O
+number	O
+of	O
+LT	O
+(	O
+RR	O
+=	O
+1	O
+.	O
+60	O
+;	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+11	O
+to	O
+2	O
+.	O
+31	O
+;	O
+Ptrend	O
+=	O
+0	O
+.	O
+02	O
+)	O
+and	O
+IW	O
+days	O
+of	O
+diazinon	O
+use	O
+(	O
+RR	O
+=	O
+1	O
+.	O
+41	O
+;	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+98	O
+to	O
+2	O
+.	O
+04	O
+;	O
+Ptrend	O
+=	O
+0	O
+.	O
+08	O
+)	O
+.	O
+
+Kidney	B
+cancer	I
+(	O
+N	O
+=	O
+94	O
+)	O
+risks	O
+were	O
+non	O
+-	O
+significantly	O
+elevated	O
+(	O
+RRLT	O
+days	O
+=	O
+1	O
+.	O
+77	O
+;	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+90	O
+to	O
+3	O
+.	O
+51	O
+;	O
+Ptrend	O
+=	O
+0	O
+.	O
+09	O
+;	O
+RRIW	O
+days	O
+1	O
+.	O
+37	O
+;	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+64	O
+to	O
+2	O
+.	O
+92	O
+;	O
+Ptrend	O
+=	O
+0	O
+.	O
+50	O
+)	O
+,	O
+as	O
+were	O
+risks	O
+for	O
+aggressive	O
+prostate	B
+cancer	I
+(	O
+N	O
+=	O
+656	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Our	O
+updated	O
+evaluation	O
+of	O
+diazinon	O
+provides	O
+additional	O
+evidence	O
+of	O
+an	O
+association	O
+with	O
+lung	B
+cancer	I
+risk	O
+.	O
+
+Newly	O
+identified	O
+links	O
+to	O
+kidney	B
+cancer	I
+and	O
+associations	O
+with	O
+aggressive	O
+prostate	B
+cancer	I
+require	O
+further	O
+evaluation	O
+.	O
+
+Associations	O
+of	O
+Ozone	O
+and	O
+PM2	O
+.	O
+5	O
+Concentrations	O
+With	O
+Parkinson	B
+'	I
+s	I
+Disease	I
+Among	O
+Participants	O
+in	O
+the	O
+Agricultural	O
+Health	O
+Study	O
+.	O
+
+OBJECTIVE	O
+:	O
+This	O
+study	O
+describes	O
+associations	O
+of	O
+ozone	O
+and	O
+fine	O
+particulate	O
+matter	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+observed	O
+among	O
+farmers	O
+in	O
+North	O
+Carolina	O
+and	O
+Iowa	O
+.	O
+
+METHODS	O
+:	O
+We	O
+used	O
+logistic	O
+regression	O
+to	O
+determine	O
+the	O
+associations	O
+of	O
+these	O
+pollutants	O
+with	O
+self	O
+-	O
+reported	O
+,	O
+doctor	O
+-	O
+diagnosed	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+Daily	O
+predicted	O
+pollutant	O
+concentrations	O
+were	O
+used	O
+to	O
+derive	O
+surrogates	O
+of	O
+long	O
+-	O
+term	O
+exposure	O
+and	O
+link	O
+them	O
+to	O
+study	O
+participants	O
+'	O
+geocoded	O
+addresses	O
+.	O
+
+RESULTS	O
+:	O
+We	O
+observed	O
+positive	O
+associations	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+with	O
+ozone	O
+(	O
+odds	O
+ratio	O
+=	O
+1	O
+.	O
+39	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+0	O
+.	O
+98	O
+to	O
+1	O
+.	O
+98	O
+)	O
+and	O
+fine	O
+particulate	O
+matter	O
+(	O
+odds	O
+ratio	O
+=	O
+1	O
+.	O
+34	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+0	O
+.	O
+93	O
+to	O
+1	O
+.	O
+93	O
+)	O
+in	O
+North	O
+Carolina	O
+but	O
+not	O
+in	O
+Iowa	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+plausibility	O
+of	O
+an	O
+effect	O
+of	O
+ambient	O
+concentrations	O
+of	O
+these	O
+pollutants	O
+on	O
+Parkinson	B
+'	I
+s	I
+disease	I
+risk	O
+is	O
+supported	O
+by	O
+experimental	O
+data	O
+demonstrating	O
+damage	O
+to	O
+dopaminergic	O
+neurons	O
+at	O
+relevant	O
+concentrations	O
+.	O
+
+Additional	O
+studies	O
+are	O
+needed	O
+to	O
+address	O
+uncertainties	O
+related	O
+to	O
+confounding	O
+and	O
+to	O
+examine	O
+temporal	O
+aspects	O
+of	O
+the	O
+associations	O
+we	O
+observed	O
+.	O
+
+Low	O
+functional	O
+programming	O
+of	O
+renal	O
+AT2R	O
+mediates	O
+the	O
+developmental	O
+origin	O
+of	O
+glomerulosclerosis	B
+in	O
+adult	O
+offspring	O
+induced	O
+by	O
+prenatal	O
+caffeine	O
+exposure	O
+.	O
+
+UNASSIGNED	O
+:	O
+Our	O
+previous	O
+study	O
+has	O
+indicated	O
+that	O
+prenatal	O
+caffeine	O
+exposure	O
+(	O
+PCE	O
+)	O
+could	O
+induce	O
+intrauterine	B
+growth	I
+retardation	I
+(	O
+IUGR	B
+)	O
+of	O
+offspring	O
+.	O
+
+Recent	O
+research	O
+suggested	O
+that	O
+IUGR	B
+is	O
+a	O
+risk	O
+factor	O
+for	O
+glomerulosclerosis	B
+.	O
+
+However	O
+,	O
+whether	O
+PCE	O
+could	O
+induce	O
+glomerulosclerosis	B
+and	O
+its	O
+underlying	O
+mechanisms	O
+remain	O
+unknown	O
+.	O
+
+This	O
+study	O
+aimed	O
+to	O
+demonstrate	O
+the	O
+induction	O
+to	O
+glomerulosclerosis	B
+in	O
+adult	O
+offspring	O
+by	O
+PCE	O
+and	O
+its	O
+intrauterine	O
+programming	O
+mechanisms	O
+.	O
+
+A	O
+rat	O
+model	O
+of	O
+IUGR	B
+was	O
+established	O
+by	O
+PCE	O
+,	O
+male	O
+fetuses	O
+and	O
+adult	O
+offspring	O
+at	O
+the	O
+age	O
+of	O
+postnatal	O
+week	O
+24	O
+were	O
+euthanized	O
+.	O
+
+The	O
+results	O
+revealed	O
+that	O
+the	O
+adult	O
+offspring	O
+kidneys	O
+in	O
+the	O
+PCE	O
+group	O
+exhibited	O
+glomerulosclerosis	B
+as	O
+well	O
+as	O
+interstitial	B
+fibrosis	I
+,	O
+accompanied	O
+by	O
+elevated	O
+levels	O
+of	O
+serum	O
+creatinine	O
+and	O
+urine	O
+protein	O
+.	O
+
+Renal	O
+angiotensin	O
+II	O
+receptor	O
+type	O
+2	O
+(	O
+AT2R	O
+)	O
+gene	O
+expression	O
+in	O
+adult	O
+offspring	O
+was	O
+reduced	O
+by	O
+PCE	O
+,	O
+whereas	O
+the	O
+renal	O
+angiotensin	O
+II	O
+receptor	O
+type	O
+1a	O
+(	O
+AT1aR	O
+)	O
+/	O
+AT2R	O
+expression	O
+ratio	O
+was	O
+increased	O
+.	O
+
+The	O
+fetal	O
+kidneys	O
+in	O
+the	O
+PCE	O
+group	O
+displayed	O
+an	O
+enlarged	O
+Bowman	O
+'	O
+s	O
+space	O
+and	O
+a	O
+shrunken	O
+glomerular	O
+tuft	O
+,	O
+accompanied	O
+by	O
+a	O
+reduced	O
+cortex	O
+width	O
+and	O
+an	O
+increase	O
+in	O
+the	O
+nephrogenic	O
+zone	O
+/	O
+cortical	O
+zone	O
+ratio	O
+.	O
+
+Observation	O
+by	O
+electronic	O
+microscope	O
+revealed	O
+structural	O
+damage	O
+of	O
+podocytes	O
+;	O
+the	O
+reduced	O
+expression	O
+level	O
+of	O
+podocyte	O
+marker	O
+genes	O
+,	O
+nephrin	O
+and	O
+podocin	O
+,	O
+was	O
+also	O
+detected	O
+by	O
+q	O
+-	O
+PCR	O
+.	O
+
+Moreover	O
+,	O
+AT2R	O
+gene	O
+and	O
+protein	O
+expressions	O
+in	O
+fetal	O
+kidneys	O
+were	O
+inhibited	O
+by	O
+PCE	O
+,	O
+associated	O
+with	O
+the	O
+repression	O
+of	O
+the	O
+gene	O
+expression	O
+of	O
+glial	O
+-	O
+cell	O
+-	O
+line	O
+-	O
+derived	O
+neurotrophic	O
+factor	O
+(	O
+GDNF	O
+)	O
+/	O
+tyrosine	O
+kinase	O
+receptor	O
+(	O
+c	O
+-	O
+Ret	O
+)	O
+signaling	O
+pathway	O
+.	O
+
+These	O
+results	O
+demonstrated	O
+that	O
+PCE	O
+could	O
+induce	O
+dysplasia	B
+of	I
+fetal	I
+kidneys	I
+as	O
+well	O
+as	O
+glomerulosclerosis	B
+of	O
+adult	O
+offspring	O
+,	O
+and	O
+the	O
+low	O
+functional	O
+programming	O
+of	O
+renal	O
+AT2R	O
+might	O
+mediate	O
+the	O
+developmental	O
+origin	O
+of	O
+adult	O
+glomerulosclerosis	B
+.	O
+
+1	O
+,	O
+3	O
+-	O
+Butadiene	O
+,	O
+CML	B
+and	O
+the	O
+t	O
+(	O
+9	O
+:	O
+22	O
+)	O
+translocation	O
+:	O
+A	O
+reality	O
+check	O
+.	O
+
+UNASSIGNED	O
+:	O
+Epidemiological	O
+studies	O
+of	O
+1	O
+,	O
+3	O
+-	O
+butadiene	O
+have	O
+suggest	O
+that	O
+exposures	O
+to	O
+humans	O
+are	O
+associated	O
+with	O
+chronic	B
+myeloid	I
+leukemia	I
+(	O
+CML	B
+)	O
+.	O
+
+CML	B
+has	O
+a	O
+well	O
+-	O
+documented	O
+association	O
+with	O
+ionizing	O
+radiation	O
+,	O
+but	O
+reports	O
+of	O
+associations	O
+with	O
+chemical	O
+exposures	O
+have	O
+been	O
+questioned	O
+.	O
+
+Ionizing	O
+radiation	O
+is	O
+capable	O
+of	O
+inducing	O
+the	O
+requisite	O
+CML	B
+-	O
+associated	O
+t	O
+(	O
+9	O
+:	O
+22	O
+)	O
+translocation	O
+(	O
+Philadelphia	B
+chromosome	I
+)	O
+in	O
+appropriate	O
+cells	O
+in	O
+vitro	O
+but	O
+,	O
+thus	O
+far	O
+,	O
+chemicals	O
+have	O
+not	O
+shown	O
+this	O
+capacity	O
+.	O
+
+We	O
+have	O
+proposed	O
+that	O
+1	O
+,	O
+3	O
+-	O
+butadiene	O
+metabolites	O
+be	O
+so	O
+tested	O
+as	O
+a	O
+reality	O
+check	O
+on	O
+the	O
+epidemiological	O
+reports	O
+.	O
+
+In	O
+order	O
+to	O
+conduct	O
+reliable	O
+testing	O
+in	O
+this	O
+regard	O
+,	O
+it	O
+is	O
+essential	O
+that	O
+a	O
+positive	O
+control	O
+for	O
+induction	O
+be	O
+available	O
+.	O
+
+We	O
+have	O
+used	O
+ionizing	O
+radiation	O
+to	O
+develop	O
+such	O
+a	O
+control	O
+.	O
+
+Results	O
+described	O
+here	O
+demonstrate	O
+that	O
+this	O
+agent	O
+does	O
+in	O
+fact	O
+induce	O
+pathogenic	O
+t	O
+(	O
+9	O
+:	O
+22	O
+)	O
+translocations	O
+in	O
+a	O
+human	O
+myeloid	O
+cell	O
+line	O
+in	O
+vitro	O
+,	O
+but	O
+does	O
+so	O
+at	O
+low	O
+frequencies	O
+.	O
+
+Conditions	O
+that	O
+will	O
+be	O
+required	O
+for	O
+studies	O
+of	O
+1	O
+,	O
+3	O
+-	O
+butadiene	O
+are	O
+discussed	O
+.	O
+
+Cancer	B
+incidence	O
+and	O
+metolachlor	O
+use	O
+in	O
+the	O
+Agricultural	O
+Health	O
+Study	O
+:	O
+An	O
+update	O
+.	O
+
+UNASSIGNED	O
+:	O
+Metolachlor	O
+,	O
+a	O
+widely	O
+used	O
+herbicide	O
+,	O
+is	O
+classified	O
+as	O
+a	O
+Group	O
+C	O
+carcinogen	O
+by	O
+the	O
+U	O
+.	O
+S	O
+.	O
+
+Environmental	O
+Protection	O
+Agency	O
+based	O
+on	O
+increased	O
+liver	B
+neoplasms	I
+in	O
+female	O
+rats	O
+.	O
+
+Epidemiologic	O
+studies	O
+of	O
+the	O
+health	O
+effects	O
+of	O
+metolachlor	O
+have	O
+been	O
+limited	O
+.	O
+
+The	O
+Agricultural	O
+Health	O
+Study	O
+(	O
+AHS	O
+)	O
+is	O
+a	O
+prospective	O
+cohort	O
+study	O
+including	O
+licensed	O
+private	O
+and	O
+commercial	O
+pesticide	O
+applicators	O
+in	O
+Iowa	O
+and	O
+North	O
+Carolina	O
+enrolled	O
+1993	O
+-	O
+1997	O
+.	O
+
+We	O
+evaluated	O
+cancer	B
+incidence	O
+through	O
+2010	O
+/	O
+2011	O
+(	O
+NC	O
+/	O
+IA	O
+)	O
+for	O
+49	O
+,	O
+616	O
+applicators	O
+,	O
+53	O
+%	O
+of	O
+whom	O
+reported	O
+ever	O
+using	O
+metolachlor	O
+.	O
+
+We	O
+used	O
+Poisson	O
+regression	O
+to	O
+evaluate	O
+relations	O
+between	O
+two	O
+metrics	O
+of	O
+metolachlor	O
+use	O
+(	O
+lifetime	O
+days	O
+,	O
+intensity	O
+-	O
+weighted	O
+lifetime	O
+days	O
+)	O
+and	O
+cancer	B
+incidence	O
+.	O
+
+We	O
+saw	O
+no	O
+association	O
+between	O
+metolachlor	O
+use	O
+and	O
+incidence	O
+of	O
+all	O
+cancers	B
+combined	O
+(	O
+n	O
+=	O
+5	O
+,	O
+701	O
+with	O
+a	O
+5	O
+-	O
+year	O
+lag	O
+)	O
+or	O
+most	O
+site	O
+-	O
+specific	O
+cancers	B
+.	O
+
+For	O
+liver	B
+cancer	I
+,	O
+in	O
+analyses	O
+restricted	O
+to	O
+exposed	O
+workers	O
+,	O
+elevations	O
+observed	O
+at	O
+higher	O
+categories	O
+of	O
+use	O
+were	O
+not	O
+statistically	O
+significant	O
+.	O
+
+However	O
+,	O
+trends	O
+for	O
+both	O
+lifetime	O
+and	O
+intensity	O
+-	O
+weighted	O
+lifetime	O
+days	O
+of	O
+metolachor	O
+use	O
+were	O
+positive	O
+and	O
+statistically	O
+significant	O
+with	O
+an	O
+unexposed	O
+reference	O
+group	O
+.	O
+
+A	O
+similar	O
+pattern	O
+was	O
+observed	O
+for	O
+follicular	B
+cell	I
+lymphoma	I
+,	O
+but	O
+no	O
+other	O
+lymphoma	B
+subtypes	O
+.	O
+
+An	O
+earlier	O
+suggestion	O
+of	O
+increased	O
+lung	B
+cancer	I
+risk	O
+at	O
+high	O
+levels	O
+of	O
+metolachlor	O
+use	O
+in	O
+this	O
+cohort	O
+was	O
+not	O
+confirmed	O
+in	O
+this	O
+update	O
+.	O
+
+This	O
+suggestion	O
+of	O
+an	O
+association	O
+between	O
+metolachlor	O
+and	O
+liver	B
+cancer	I
+among	O
+pesticide	O
+applicators	O
+is	O
+a	O
+novel	O
+finding	O
+and	O
+echoes	O
+observation	O
+of	O
+increased	O
+liver	B
+neoplasms	I
+in	O
+some	O
+animal	O
+studies	O
+.	O
+
+However	O
+,	O
+our	O
+findings	O
+for	O
+both	O
+liver	B
+cancer	I
+and	O
+follicular	O
+cell	O
+lymphoma	B
+warrant	O
+follow	O
+-	O
+up	O
+to	O
+better	O
+differentiate	O
+effects	O
+of	O
+metolachlor	O
+use	O
+from	O
+other	O
+factors	O
+.	O
+
+Mechanisms	O
+Underlying	O
+Latent	O
+Disease	O
+Risk	O
+Associated	O
+with	O
+Early	O
+-	O
+Life	O
+Arsenic	O
+Exposure	O
+:	O
+Current	O
+Research	O
+Trends	O
+and	O
+Scientific	O
+Gaps	O
+.	O
+
+BACKGROUND	O
+:	O
+Millions	O
+of	O
+individuals	O
+worldwide	O
+,	O
+particularly	O
+those	O
+living	O
+in	O
+rural	O
+and	O
+developing	O
+areas	O
+,	O
+are	O
+exposed	O
+to	O
+harmful	O
+levels	O
+of	O
+inorganic	O
+arsenic	O
+(	O
+iAs	O
+)	O
+in	O
+their	O
+drinking	O
+water	O
+.	O
+
+Inorganic	O
+As	O
+exposure	O
+during	O
+key	O
+developmental	O
+periods	O
+is	O
+associated	O
+with	O
+a	O
+variety	O
+of	O
+adverse	O
+health	O
+effects	O
+including	O
+those	O
+that	O
+are	O
+evident	O
+in	O
+adulthood	O
+.	O
+
+There	O
+is	O
+considerable	O
+interest	O
+in	O
+identifying	O
+the	O
+molecular	O
+mechanisms	O
+that	O
+relate	O
+early	O
+-	O
+life	O
+iAs	O
+exposure	O
+to	O
+the	O
+development	O
+of	O
+these	O
+latent	O
+diseases	O
+,	O
+particularly	O
+in	O
+relationship	O
+to	O
+cancer	B
+.	O
+
+OBJECTIVES	O
+:	O
+This	O
+work	O
+summarizes	O
+research	O
+on	O
+the	O
+molecular	O
+mechanisms	O
+that	O
+underlie	O
+the	O
+increased	O
+risk	O
+of	O
+cancer	B
+development	O
+in	O
+adulthood	O
+that	O
+is	O
+associated	O
+with	O
+early	O
+-	O
+life	O
+iAs	O
+exposure	O
+.	O
+
+DISCUSSION	O
+:	O
+Epigenetic	O
+reprogramming	O
+that	O
+imparts	O
+functional	O
+changes	O
+in	O
+gene	O
+expression	O
+,	O
+the	O
+development	O
+of	O
+cancer	B
+stem	O
+cells	O
+,	O
+and	O
+immunomodulation	O
+are	O
+plausible	O
+underlying	O
+mechanisms	O
+by	O
+which	O
+early	O
+-	O
+life	O
+iAs	O
+exposure	O
+elicits	O
+latent	O
+carcinogenic	O
+effects	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Evidence	O
+is	O
+mounting	O
+that	O
+relates	O
+early	O
+-	O
+life	O
+iAs	O
+exposure	O
+and	O
+cancer	B
+development	O
+later	O
+in	O
+life	O
+.	O
+
+Future	O
+research	O
+should	O
+include	O
+animal	O
+studies	O
+that	O
+address	O
+mechanistic	O
+hypotheses	O
+and	O
+studies	O
+of	O
+human	O
+populations	O
+that	O
+integrate	O
+early	O
+-	O
+life	O
+exposure	O
+,	O
+molecular	O
+alterations	O
+,	O
+and	O
+latent	O
+disease	O
+outcomes	O
+.	O
+
+Nifedipine	O
+induced	O
+bradycardia	B
+in	O
+a	O
+patient	O
+with	O
+autonomic	B
+neuropathy	I
+.	O
+
+An	O
+80	O
+year	O
+old	O
+diabetic	B
+male	O
+with	O
+evidence	O
+of	O
+peripheral	B
+and	I
+autonomic	I
+neuropathy	I
+was	O
+admitted	O
+with	O
+chest	B
+pain	I
+.	O
+
+He	O
+was	O
+found	O
+to	O
+have	O
+atrial	B
+flutter	I
+at	O
+a	O
+ventricular	O
+rate	O
+of	O
+70	O
+/	O
+min	O
+which	O
+slowed	O
+down	O
+to	O
+30	O
+-	O
+40	O
+/	O
+min	O
+when	O
+nifedipine	O
+(	O
+60	O
+mg	O
+)	O
+in	O
+3	O
+divided	O
+doses	O
+,	O
+during	O
+which	O
+he	O
+was	O
+paced	O
+at	O
+a	O
+rate	O
+of	O
+70	O
+/	O
+min	O
+.	O
+
+This	O
+is	O
+inconsistent	O
+with	O
+the	O
+well	O
+-	O
+established	O
+finding	O
+that	O
+nifedipine	O
+induces	O
+tachycardia	B
+in	O
+normally	O
+innervated	O
+hearts	O
+.	O
+
+However	O
+,	O
+in	O
+hearts	O
+deprived	O
+of	O
+compensatory	O
+sympathetic	O
+drive	O
+,	O
+it	O
+may	O
+lead	O
+to	O
+bradycardia	B
+.	O
+
+The	O
+effect	O
+of	O
+haloperidol	O
+in	O
+cocaine	O
+and	O
+amphetamine	O
+intoxication	O
+.	O
+
+The	O
+effectiveness	O
+of	O
+haloperidol	O
+pretreatment	O
+in	O
+preventing	O
+the	O
+toxic	O
+effects	O
+of	O
+high	O
+doses	O
+of	O
+amphetamine	O
+and	O
+cocaine	O
+was	O
+studied	O
+in	O
+rats	O
+.	O
+
+In	O
+this	O
+model	O
+,	O
+toxic	O
+effects	O
+were	O
+induced	O
+by	O
+intraperitoneal	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+injection	O
+of	O
+amphetamine	O
+75	O
+mg	O
+/	O
+kg	O
+(	O
+100	O
+%	O
+death	O
+rate	O
+)	O
+or	O
+cocaine	O
+70	O
+mg	O
+/	O
+kg	O
+(	O
+82	O
+%	O
+death	O
+rate	O
+)	O
+.	O
+
+Haloperidol	O
+failed	O
+to	O
+prevent	O
+amphetamine	O
+-	O
+induced	O
+seizures	B
+,	O
+but	O
+did	O
+lower	O
+the	O
+mortality	O
+rate	O
+at	O
+most	O
+doses	O
+tested	O
+.	O
+
+Haloperidol	O
+decreased	O
+the	O
+incidence	O
+of	O
+cocaine	O
+-	O
+induced	O
+seizures	B
+at	O
+the	O
+two	O
+highest	O
+doses	O
+,	O
+but	O
+the	O
+lowering	O
+of	O
+the	O
+mortality	O
+rate	O
+did	O
+not	O
+reach	O
+statistical	O
+significance	O
+at	O
+any	O
+dose	O
+.	O
+
+These	O
+data	O
+suggest	O
+a	O
+protective	O
+role	O
+for	O
+the	O
+central	O
+dopamine	O
+blocker	O
+haloperidol	O
+against	O
+death	O
+from	O
+high	O
+-	O
+dose	O
+amphetamine	O
+exposure	O
+without	O
+reducing	O
+the	O
+incidence	O
+of	O
+seizures	B
+.	O
+
+In	O
+contrast	O
+,	O
+haloperidol	O
+demonstrated	O
+an	O
+ability	O
+to	O
+reduce	O
+cocaine	O
+-	O
+induced	O
+seizures	B
+without	O
+significantly	O
+reducing	O
+mortality	O
+.	O
+
+Autoradiographic	O
+evidence	O
+of	O
+estrogen	O
+binding	O
+sites	O
+in	O
+nuclei	O
+of	O
+diethylstilbesterol	O
+induced	O
+hamster	O
+renal	B
+carcinomas	I
+.	O
+
+Estrogen	O
+binding	O
+sites	O
+were	O
+demonstrated	O
+by	O
+autoradiography	O
+in	O
+one	O
+transplantable	O
+and	O
+five	O
+primary	O
+diethylstilbesterol	O
+induced	O
+renal	B
+carcinomas	I
+in	O
+three	O
+hamsters	O
+.	O
+
+Radiolabelling	O
+,	O
+following	O
+the	O
+in	O
+vivo	O
+injection	O
+of	O
+3H	O
+-	O
+17	O
+beta	O
+estradiol	O
+,	O
+was	O
+increased	O
+only	O
+over	O
+the	O
+nuclei	O
+of	O
+tumor	B
+cells	O
+;	O
+stereologic	O
+analysis	O
+revealed	O
+a	O
+4	O
+.	O
+5	O
+-	O
+to	O
+6	O
+.	O
+7	O
+-	O
+times	O
+higher	O
+concentration	O
+of	O
+reduced	O
+silver	O
+grains	O
+over	O
+nuclei	O
+than	O
+cytoplasm	O
+of	O
+these	O
+cells	O
+.	O
+
+Despite	O
+rapid	O
+tubular	O
+excretion	O
+of	O
+estradiol	O
+which	O
+peaked	O
+in	O
+less	O
+than	O
+1	O
+h	O
+,	O
+the	O
+normal	O
+cells	O
+did	O
+not	O
+appear	O
+to	O
+bind	O
+the	O
+ligand	O
+.	O
+
+This	O
+is	O
+the	O
+first	O
+published	O
+report	O
+documenting	O
+the	O
+preferential	O
+in	O
+vivo	O
+binding	O
+of	O
+estrogen	O
+to	O
+nuclei	O
+of	O
+cells	O
+in	O
+estrogen	O
+induced	O
+hamster	O
+renal	B
+carcinomas	I
+.	O
+
+Bradycardia	B
+due	O
+to	O
+biperiden	O
+.	O
+
+In	O
+a	O
+38	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+suffering	O
+from	O
+a	O
+severe	O
+postzosteric	B
+trigeminal	B
+neuralgia	I
+,	O
+intravenous	O
+application	O
+of	O
+10	O
+mg	O
+biperiden	O
+lactate	O
+led	O
+to	O
+a	O
+long	O
+-	O
+lasting	O
+paradoxical	O
+reaction	O
+characterized	O
+by	O
+considerable	O
+bradycardia	B
+,	O
+dysarthria	B
+,	O
+and	O
+dysphagia	B
+.	O
+
+The	O
+heart	O
+rate	O
+was	O
+back	O
+to	O
+normal	O
+within	O
+12	O
+hours	O
+upon	O
+administration	O
+of	O
+orciprenaline	O
+under	O
+cardiac	O
+monitoring	O
+in	O
+an	O
+intensive	O
+care	O
+unit	O
+.	O
+
+Bradycardia	B
+induced	O
+by	O
+biperiden	O
+is	O
+attributed	O
+to	O
+the	O
+speed	O
+of	O
+injection	O
+and	O
+to	O
+a	O
+dose	O
+-	O
+related	O
+dual	O
+effect	O
+of	O
+atropine	O
+-	O
+like	O
+drugs	O
+on	O
+muscarine	O
+receptors	O
+.	O
+
+Deliberate	O
+hypotension	B
+induced	O
+by	O
+labetalol	O
+with	O
+halothane	O
+,	O
+enflurane	O
+or	O
+isoflurane	O
+for	O
+middle	O
+-	O
+ear	O
+surgery	O
+.	O
+
+The	O
+feasibility	O
+of	O
+using	O
+labetalol	O
+,	O
+an	O
+alpha	O
+-	O
+and	O
+beta	O
+-	O
+adrenergic	O
+blocking	O
+agent	O
+,	O
+as	O
+a	O
+hypotensive	B
+agent	O
+in	O
+combination	O
+with	O
+inhalation	O
+anaesthetics	O
+(	O
+halothane	O
+,	O
+enflurane	O
+or	O
+isoflurane	O
+)	O
+was	O
+studied	O
+in	O
+23	O
+adult	O
+patients	O
+undergoing	O
+middle	O
+-	O
+ear	O
+surgery	O
+.	O
+
+The	O
+mean	O
+arterial	O
+pressure	O
+was	O
+decreased	O
+from	O
+86	O
++	O
+/	O
+-	O
+5	O
+(	O
+s	O
+.	O
+e	O
+.	O
+mean	O
+)	O
+mmHg	O
+to	O
+52	O
++	O
+/	O
+-	O
+1	O
+mmHg	O
+(	O
+11	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+to	O
+6	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+kPa	O
+)	O
+for	O
+98	O
++	O
+/	O
+-	O
+10	O
+min	O
+in	O
+the	O
+halothane	O
+(	O
+H	O
+)	O
+group	O
+,	O
+from	O
+79	O
++	O
+/	O
+-	O
+5	O
+to	O
+53	O
++	O
+/	O
+-	O
+1	O
+mmHg	O
+(	O
+10	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+to	O
+7	O
+.	O
+1	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+kPa	O
+)	O
+for	O
+129	O
++	O
+/	O
+-	O
+11	O
+min	O
+in	O
+the	O
+enflurane	O
+(	O
+E	O
+)	O
+group	O
+,	O
+and	O
+from	O
+80	O
++	O
+/	O
+-	O
+4	O
+to	O
+49	O
++	O
+/	O
+-	O
+1	O
+mmHg	O
+(	O
+10	O
+.	O
+7	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+to	O
+6	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+kPa	O
+)	O
+for	O
+135	O
++	O
+/	O
+-	O
+15	O
+min	O
+in	O
+the	O
+isoflurane	O
+(	O
+I	O
+)	O
+group	O
+.	O
+
+The	O
+mean	O
+H	O
+concentration	O
+during	O
+hypotension	B
+in	O
+the	O
+inspiratory	O
+gas	O
+was	O
+0	O
+.	O
+7	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+vol	O
+%	O
+,	O
+the	O
+mean	O
+E	O
+concentration	O
+1	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+vol	O
+%	O
+,	O
+and	O
+the	O
+mean	O
+I	O
+concentration	O
+1	O
+.	O
+0	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+vol	O
+%	O
+.	O
+
+In	O
+addition	O
+,	O
+the	O
+patients	O
+received	O
+fentanyl	O
+and	O
+d	O
+-	O
+tubocurarine	O
+.	O
+
+The	O
+initial	O
+dose	O
+of	O
+labetalol	O
+for	O
+lowering	O
+blood	O
+pressure	O
+was	O
+similar	O
+,	O
+0	O
+.	O
+52	O
+-	O
+0	O
+.	O
+59	O
+mg	O
+/	O
+kg	O
+,	O
+in	O
+all	O
+the	O
+groups	O
+.	O
+
+During	O
+hypotension	B
+,	O
+the	O
+heart	O
+rate	O
+was	O
+stable	O
+without	O
+tachy	B
+-	I
+or	I
+bradycardia	I
+.	O
+
+The	O
+operating	O
+conditions	O
+regarding	O
+bleeding	B
+were	O
+estimated	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+manner	O
+,	O
+and	O
+did	O
+not	O
+differ	O
+significantly	O
+between	O
+the	O
+groups	O
+.	O
+
+During	O
+hypotension	B
+,	O
+the	O
+serum	O
+creatinine	O
+concentration	O
+rose	O
+significantly	O
+in	O
+all	O
+groups	O
+from	O
+the	O
+values	O
+before	O
+hypotension	B
+and	O
+returned	O
+postoperatively	O
+to	O
+the	O
+initial	O
+level	O
+in	O
+the	O
+other	O
+groups	O
+,	O
+except	O
+the	O
+isoflurane	O
+group	O
+.	O
+
+After	O
+hypotension	B
+there	O
+was	O
+no	O
+rebound	O
+phenomenon	O
+in	O
+either	O
+blood	O
+pressure	O
+or	O
+heart	O
+rate	O
+.	O
+
+These	O
+results	O
+indicate	O
+that	O
+labetalol	O
+induces	O
+easily	O
+adjustable	O
+hypotension	B
+without	O
+compensatory	O
+tachycardia	B
+and	O
+rebound	O
+hypertension	B
+.	O
+
+Convulsion	B
+following	O
+intravenous	O
+fluorescein	O
+angiography	O
+.	O
+
+Tonic	B
+-	I
+clonic	I
+seizures	I
+followed	O
+intravenous	O
+fluorescein	O
+injection	O
+for	O
+fundus	O
+angiography	O
+in	O
+a	O
+47	O
+-	O
+year	O
+-	O
+old	O
+male	O
+.	O
+
+Despite	O
+precautions	O
+this	O
+adverse	O
+reaction	O
+recurred	O
+on	O
+re	O
+-	O
+exposure	O
+to	O
+intravenous	O
+fluorescein	O
+.	O
+
+Pharmacology	O
+of	O
+ACC	O
+-	O
+9653	O
+(	O
+phenytoin	O
+prodrug	O
+)	O
+.	O
+
+ACC	O
+-	O
+9653	O
+,	O
+the	O
+disodium	O
+phosphate	O
+ester	O
+of	O
+3	O
+-	O
+hydroxymethyl	O
+-	O
+5	O
+,	O
+5	O
+-	O
+diphenylhydantoin	O
+,	O
+is	O
+a	O
+prodrug	O
+of	O
+phenytoin	O
+with	O
+advantageous	O
+physicochemical	O
+properties	O
+.	O
+
+ACC	O
+-	O
+9653	O
+is	O
+rapidly	O
+converted	O
+enzymatically	O
+to	O
+phenytoin	O
+in	O
+vivo	O
+.	O
+
+ACC	O
+-	O
+9653	O
+and	O
+phenytoin	O
+sodium	O
+have	O
+equivalent	O
+anticonvulsant	O
+activity	O
+against	O
+seizures	B
+induced	O
+by	O
+maximal	O
+electroshock	O
+(	O
+MES	O
+)	O
+in	O
+mice	O
+following	O
+i	O
+.	O
+p	O
+.	O
+,	O
+oral	O
+,	O
+or	O
+i	O
+.	O
+v	O
+.	O
+administration	O
+.	O
+
+The	O
+ED50	O
+doses	O
+were	O
+16	O
+mg	O
+/	O
+kg	O
+for	O
+i	O
+.	O
+v	O
+.	O
+ACC	O
+-	O
+9653	O
+and	O
+8	O
+mg	O
+/	O
+kg	O
+for	O
+i	O
+.	O
+v	O
+.	O
+phenytoin	O
+sodium	O
+.	O
+
+ACC	O
+-	O
+9653	O
+and	O
+phenytoin	O
+sodium	O
+have	O
+similar	O
+antiarrhythmic	O
+activity	O
+against	O
+ouabain	O
+-	O
+induced	O
+ventricular	B
+tachycardia	I
+in	O
+anesthetized	O
+dogs	O
+.	O
+
+The	O
+total	O
+doses	O
+of	O
+ACC	O
+-	O
+9653	O
+or	O
+phenytoin	O
+sodium	O
+necessary	O
+to	O
+convert	O
+the	O
+arrhythmia	B
+to	O
+a	O
+normal	O
+sinus	O
+rhythm	O
+were	O
+24	O
++	O
+/	O
+-	O
+6	O
+and	O
+14	O
++	O
+/	O
+-	O
+3	O
+mg	O
+/	O
+kg	O
+,	O
+respectively	O
+.	O
+
+Only	O
+phenytoin	O
+sodium	O
+displayed	O
+in	O
+vitro	O
+antiarrhythmic	O
+activity	O
+against	O
+strophanthidin	O
+-	O
+induced	O
+arrhythmias	B
+in	O
+guinea	O
+pig	O
+right	O
+atria	O
+.	O
+
+In	O
+anesthetized	O
+dogs	O
+,	O
+a	O
+high	O
+dose	O
+of	O
+ACC	O
+-	O
+9653	O
+(	O
+31	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+infused	O
+over	O
+15	O
+,	O
+20	O
+,	O
+and	O
+30	O
+min	O
+and	O
+the	O
+responses	O
+were	O
+compared	O
+to	O
+an	O
+equimolar	O
+dose	O
+of	O
+phenytoin	O
+sodium	O
+(	O
+21	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+The	O
+ACC	O
+-	O
+9653	O
+and	O
+phenytoin	O
+sodium	O
+treatments	O
+produced	O
+similar	O
+marked	O
+reductions	O
+in	O
+diastolic	O
+blood	O
+pressure	O
+and	O
+contractile	O
+force	O
+(	O
+LVdP	O
+/	O
+dt	O
+)	O
+.	O
+
+The	O
+maximum	O
+effects	O
+of	O
+each	O
+treatment	O
+occurred	O
+at	O
+the	O
+time	O
+of	O
+maximum	O
+phenytoin	O
+sodium	O
+levels	O
+.	O
+
+Acute	O
+toxicity	B
+studies	O
+of	O
+ACC	O
+-	O
+9653	O
+and	O
+phenytoin	O
+sodium	O
+were	O
+carried	O
+out	O
+in	O
+mice	O
+,	O
+rats	O
+,	O
+rabbits	O
+,	O
+and	O
+dogs	O
+by	O
+i	O
+.	O
+v	O
+.	O
+,	O
+i	O
+.	O
+m	O
+.	O
+,	O
+and	O
+i	O
+.	O
+p	O
+.	O
+routes	O
+of	O
+administration	O
+.	O
+
+The	O
+systemic	O
+toxic	O
+signs	O
+of	O
+both	O
+agents	O
+were	O
+similar	O
+and	O
+occurred	O
+at	O
+approximately	O
+equivalent	O
+doses	O
+.	O
+
+Importantly	O
+,	O
+the	O
+local	O
+irritation	O
+of	O
+ACC	O
+-	O
+9653	O
+was	O
+markedly	O
+less	O
+than	O
+phenytoin	O
+sodium	O
+following	O
+i	O
+.	O
+m	O
+.	O
+administration	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Tachyphylaxis	O
+to	O
+systemic	O
+but	O
+not	O
+to	O
+airway	O
+responses	O
+during	O
+prolonged	O
+therapy	O
+with	O
+high	O
+dose	O
+inhaled	O
+salbutamol	O
+in	O
+asthmatics	B
+.	O
+
+High	O
+doses	O
+of	O
+inhaled	O
+salbutamol	O
+produce	O
+substantial	O
+improvements	O
+in	O
+airway	O
+response	O
+in	O
+patients	O
+with	O
+asthma	B
+,	O
+and	O
+are	O
+associated	O
+with	O
+dose	O
+-	O
+dependent	O
+systemic	O
+beta	O
+-	O
+adrenoceptor	O
+responses	O
+.	O
+
+The	O
+purpose	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+investigate	O
+whether	O
+tachyphylaxis	O
+occurs	O
+during	O
+prolonged	O
+treatment	O
+with	O
+high	O
+dose	O
+inhaled	O
+salbutamol	O
+.	O
+
+Twelve	O
+asthmatic	B
+patients	O
+(	O
+FEV1	O
+,	O
+81	O
++	O
+/	O
+-	O
+4	O
+%	O
+predicted	O
+)	O
+,	O
+requiring	O
+only	O
+occasional	O
+inhaled	O
+beta	O
+-	O
+agonists	O
+as	O
+their	O
+sole	O
+therapy	O
+,	O
+were	O
+given	O
+a	O
+14	O
+-	O
+day	O
+treatment	O
+with	O
+high	O
+dose	O
+inhaled	O
+salbutamol	O
+(	O
+HDS	O
+)	O
+,	O
+4	O
+,	O
+000	O
+micrograms	O
+daily	O
+,	O
+low	O
+dose	O
+inhaled	O
+salbutamol	O
+(	O
+LDS	O
+)	O
+,	O
+800	O
+micrograms	O
+daily	O
+,	O
+or	O
+placebo	O
+(	O
+PI	O
+)	O
+by	O
+metered	O
+-	O
+dose	O
+inhaler	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+,	O
+randomized	O
+crossover	O
+design	O
+.	O
+
+During	O
+the	O
+14	O
+-	O
+day	O
+run	O
+-	O
+in	O
+and	O
+during	O
+washout	O
+periods	O
+,	O
+inhaled	O
+beta	O
+-	O
+agonists	O
+were	O
+withheld	O
+and	O
+ipratropium	O
+bromide	O
+was	O
+substituted	O
+for	O
+rescue	O
+purposes	O
+.	O
+
+At	O
+the	O
+end	O
+of	O
+each	O
+14	O
+-	O
+day	O
+treatment	O
+,	O
+a	O
+dose	O
+-	O
+response	O
+curve	O
+(	O
+DRC	O
+)	O
+was	O
+performed	O
+,	O
+and	O
+airway	O
+(	O
+FEV1	O
+,	O
+FEF25	O
+-	O
+75	O
+)	O
+chronotropic	O
+(	O
+HR	O
+)	O
+,	O
+tremor	B
+,	O
+and	O
+metabolic	O
+(	O
+K	O
+,	O
+Glu	O
+)	O
+responses	O
+were	O
+measured	O
+at	O
+each	O
+step	O
+(	O
+from	O
+100	O
+to	O
+4	O
+,	O
+000	O
+micrograms	O
+)	O
+.	O
+
+Treatment	O
+had	O
+no	O
+significant	O
+effect	O
+on	O
+baseline	O
+values	O
+.	O
+
+There	O
+were	O
+dose	O
+-	O
+dependent	O
+increases	O
+in	O
+FEV1	O
+and	O
+FEF25	O
+-	O
+75	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+,	O
+and	O
+pretreatment	O
+with	O
+HDS	O
+did	O
+not	O
+displace	O
+the	O
+DRC	O
+to	O
+the	O
+right	O
+.	O
+
+DRC	O
+for	O
+HR	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+,	O
+K	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+,	O
+and	O
+Glu	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+005	O
+)	O
+were	O
+attenuated	O
+after	O
+treatment	O
+with	O
+HDS	O
+compared	O
+with	O
+PI	O
+.	O
+
+There	O
+were	O
+also	O
+differences	O
+between	O
+HDS	O
+and	O
+LDS	O
+for	O
+HR	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+and	O
+Glu	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+responses	O
+.	O
+
+Frequency	O
+and	O
+severity	O
+of	O
+subjective	O
+adverse	O
+effects	O
+were	O
+also	O
+reduced	O
+after	O
+HDS	O
+:	O
+tremor	B
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+,	O
+palpitations	B
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Phenytoin	O
+induced	O
+fatal	O
+hepatic	B
+injury	I
+.	O
+
+A	O
+61	O
+year	O
+old	O
+female	O
+developed	O
+fatal	O
+hepatic	B
+failure	I
+after	O
+phenytoin	O
+administration	O
+.	O
+
+A	O
+typical	O
+multisystem	O
+clinical	O
+pattern	O
+precedes	O
+the	O
+manifestations	O
+of	O
+hepatic	B
+injury	I
+.	O
+
+The	O
+hematologic	O
+,	O
+biochemical	O
+and	O
+pathologic	O
+features	O
+indicate	O
+a	O
+mixed	O
+hepatocellular	B
+damage	I
+due	O
+to	O
+drug	B
+hypersensitivity	I
+.	O
+
+In	O
+a	O
+patient	O
+receiving	O
+phenytoin	O
+who	O
+presents	O
+a	O
+viral	O
+-	O
+like	O
+illness	O
+,	O
+early	O
+recognition	O
+and	O
+discontinuation	O
+of	O
+the	O
+drug	O
+are	O
+mandatory	O
+.	O
+
+Treatment	O
+of	O
+lethal	O
+pertussis	O
+vaccine	O
+reaction	O
+with	O
+histamine	O
+H1	O
+antagonists	O
+.	O
+
+We	O
+studied	O
+mortality	O
+after	O
+pertussis	B
+immunization	O
+in	O
+the	O
+mouse	O
+.	O
+
+Without	O
+treatment	O
+,	O
+73	O
+of	O
+92	O
+animals	O
+(	O
+80	O
+%	O
+)	O
+died	O
+after	O
+injection	O
+of	O
+bovine	O
+serum	O
+albumin	O
+(	O
+BSA	O
+)	O
+on	O
+day	O
++	O
+7	O
+of	O
+pertussis	B
+immunization	O
+.	O
+
+After	O
+pretreatment	O
+with	O
+3	O
+mg	O
+of	O
+cyproheptadine	O
+,	O
+2	O
+mg	O
+mianserin	O
+,	O
+or	O
+2	O
+mg	O
+chlorpheniramine	O
+,	O
+only	O
+5	O
+of	O
+105	O
+animals	O
+(	O
+5	O
+%	O
+)	O
+died	O
+after	O
+receiving	O
+BSA	O
+on	O
+day	O
++	O
+7	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Blockade	O
+of	O
+histamine	O
+H1	O
+receptors	O
+may	O
+reduce	O
+mortality	O
+in	O
+pertussis	B
+immunization	O
+-	O
+induced	O
+encephalopathy	B
+in	O
+mice	O
+.	O
+
+Support	O
+for	O
+adrenaline	O
+-	O
+hypertension	B
+hypothesis	O
+:	O
+18	O
+hour	O
+pressor	O
+effect	O
+after	O
+6	O
+hours	O
+adrenaline	O
+infusion	O
+.	O
+
+In	O
+a	O
+double	O
+blind	O
+,	O
+crossover	O
+study	O
+6	O
+h	O
+infusions	O
+of	O
+adrenaline	O
+(	O
+15	O
+ng	O
+/	O
+kg	O
+/	O
+min	O
+;	O
+1	O
+ng	O
+=	O
+5	O
+.	O
+458	O
+pmol	O
+)	O
+,	O
+noradrenaline	O
+(	O
+30	O
+ng	O
+/	O
+kg	O
+/	O
+min	O
+;	O
+1	O
+ng	O
+=	O
+5	O
+.	O
+911	O
+pmol	O
+)	O
+,	O
+and	O
+a	O
+5	O
+%	O
+dextrose	O
+solution	O
+(	O
+5	O
+.	O
+4	O
+ml	O
+/	O
+h	O
+)	O
+,	O
+were	O
+given	O
+to	O
+ten	O
+healthy	O
+volunteers	O
+in	O
+random	O
+order	O
+2	O
+weeks	O
+apart	O
+.	O
+
+By	O
+means	O
+of	O
+intra	O
+-	O
+arterial	O
+ambulatory	O
+monitoring	O
+the	O
+haemodynamic	O
+effects	O
+were	O
+followed	O
+for	O
+18	O
+h	O
+after	O
+the	O
+infusions	O
+were	O
+stopped	O
+.	O
+
+Adrenaline	O
+,	O
+but	O
+not	O
+noradrenaline	O
+,	O
+caused	O
+a	O
+delayed	O
+and	O
+protracted	O
+pressor	O
+effect	O
+.	O
+
+Over	O
+the	O
+total	O
+postinfusion	O
+period	O
+systolic	O
+and	O
+diastolic	O
+arterial	O
+pressure	O
+were	O
+6	O
+(	O
+SEM	O
+2	O
+)	O
+%	O
+and	O
+7	O
+(	O
+2	O
+)	O
+%	O
+,	O
+respectively	O
+,	O
+higher	O
+than	O
+after	O
+dextrose	O
+infusion	O
+(	O
+ANOVA	O
+,	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Thus	O
+,	O
+"	O
+stress	O
+"	O
+levels	O
+of	O
+adrenaline	O
+(	O
+230	O
+pg	O
+/	O
+ml	O
+)	O
+for	O
+6	O
+h	O
+cause	O
+a	O
+delayed	O
+and	O
+protracted	O
+pressor	O
+effect	O
+.	O
+
+These	O
+findings	O
+are	O
+strong	O
+support	O
+for	O
+the	O
+adrenaline	O
+-	O
+hypertension	B
+hypothesis	O
+in	O
+man	O
+.	O
+
+Effect	O
+of	O
+alkylxanthines	O
+on	O
+gentamicin	O
+-	O
+induced	O
+acute	B
+renal	I
+failure	I
+in	O
+the	O
+rat	O
+.	O
+
+Adenosine	O
+antagonists	O
+have	O
+been	O
+previously	O
+shown	O
+to	O
+be	O
+of	O
+benefit	O
+in	O
+some	O
+ischaemic	B
+and	O
+nephrotoxic	B
+models	O
+of	O
+acute	B
+renal	I
+failure	I
+(	O
+ARF	B
+)	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+the	O
+effects	O
+of	O
+three	O
+alkylxanthines	O
+with	O
+different	O
+potencies	O
+as	O
+adenosine	O
+antagonists	O
+8	O
+-	O
+phenyltheophylline	O
+,	O
+theophylline	O
+and	O
+enprofylline	O
+,	O
+were	O
+examined	O
+in	O
+rats	O
+developing	O
+acute	B
+renal	I
+failure	I
+after	O
+4	O
+daily	O
+injections	O
+of	O
+gentamicin	O
+(	O
+200	O
+mg	O
+kg	O
+-	O
+1	O
+)	O
+.	O
+
+Renal	O
+function	O
+was	O
+assessed	O
+by	O
+biochemical	O
+(	O
+plasma	O
+urea	O
+and	O
+creatinine	O
+)	O
+,	O
+functional	O
+(	O
+urine	O
+analysis	O
+and	O
+[	O
+3H	O
+]	O
+inulin	O
+and	O
+[	O
+14C	O
+]	O
+p	O
+-	O
+aminohippuric	O
+acid	O
+clearances	O
+)	O
+and	O
+morphological	O
+(	O
+degree	O
+of	O
+necrosis	B
+)	O
+indices	O
+.	O
+
+The	O
+various	O
+drug	O
+treatments	O
+produced	O
+improvements	O
+in	O
+some	O
+,	O
+but	O
+not	O
+all	O
+,	O
+measurements	O
+of	O
+renal	O
+function	O
+.	O
+
+However	O
+,	O
+any	O
+improvement	O
+produced	O
+by	O
+drug	O
+treatment	O
+was	O
+largely	O
+a	O
+result	O
+of	O
+a	O
+beneficial	O
+effect	O
+exerted	O
+by	O
+its	O
+vehicle	O
+(	O
+polyethylene	O
+glycol	O
+and	O
+NaOH	O
+)	O
+.	O
+
+The	O
+lack	O
+of	O
+any	O
+consistent	O
+protective	O
+effect	O
+noted	O
+with	O
+the	O
+alkylxanthines	O
+tested	O
+in	O
+the	O
+present	O
+study	O
+indicates	O
+that	O
+adenosine	O
+plays	O
+little	O
+,	O
+if	O
+any	O
+,	O
+pathophysiological	O
+role	O
+in	O
+gentamicin	O
+-	O
+induced	O
+ARF	B
+.	O
+
+Adverse	O
+ocular	O
+reactions	O
+possibly	O
+associated	O
+with	O
+isotretinoin	O
+.	O
+
+A	O
+total	O
+of	O
+261	O
+adverse	O
+ocular	O
+reactions	O
+occurred	O
+in	O
+237	O
+patients	O
+who	O
+received	O
+isotretinoin	O
+,	O
+a	O
+commonly	O
+used	O
+drug	O
+in	O
+the	O
+treatment	O
+of	O
+severe	O
+cystic	O
+acne	B
+.	O
+
+Blepharoconjunctivitis	B
+,	O
+subjective	O
+complaints	O
+of	O
+dry	B
+eyes	I
+,	O
+blurred	B
+vision	I
+,	O
+contact	O
+lens	O
+intolerance	O
+,	O
+and	O
+photodermatitis	B
+are	O
+reversible	O
+side	O
+effects	O
+.	O
+
+More	O
+serious	O
+ocular	O
+adverse	O
+reactions	O
+include	O
+papilledema	B
+,	O
+pseudotumor	B
+cerebri	I
+,	O
+and	O
+white	O
+or	O
+gray	O
+subepithelial	O
+corneal	B
+opacities	I
+;	O
+all	O
+of	O
+these	O
+are	O
+reversible	O
+if	O
+the	O
+drug	O
+is	O
+discontinued	O
+.	O
+
+Reported	O
+cases	O
+of	O
+decreased	O
+dark	O
+adaptation	O
+are	O
+under	O
+investigation	O
+.	O
+
+Isotretinoin	O
+is	O
+contraindicated	O
+in	O
+pregnancy	O
+because	O
+of	O
+the	O
+many	O
+reported	O
+congenital	B
+abnormalities	I
+after	O
+maternal	O
+use	O
+(	O
+including	O
+microphthalmos	B
+,	O
+orbital	O
+hypertelorism	B
+,	O
+and	O
+optic	B
+nerve	I
+hypoplasia	I
+)	O
+.	O
+
+Procaterol	O
+and	O
+terbutaline	O
+in	O
+bronchial	B
+asthma	I
+.	O
+
+A	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+,	O
+cross	O
+-	O
+over	O
+study	O
+.	O
+
+Procaterol	O
+,	O
+a	O
+new	O
+beta	O
+-	O
+2	O
+adrenoceptor	O
+stimulant	O
+,	O
+was	O
+studied	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+,	O
+cross	O
+-	O
+over	O
+trial	O
+in	O
+patients	O
+with	O
+bronchial	B
+asthma	I
+.	O
+
+Oral	O
+procaterol	O
+50	O
+micrograms	O
+b	O
+.	O
+d	O
+.	O
+,	O
+procaterol	O
+100	O
+micrograms	O
+b	O
+.	O
+d	O
+.	O
+,	O
+and	O
+terbutaline	O
+5	O
+mg	O
+t	O
+.	O
+i	O
+.	O
+d	O
+.	O
+,	O
+were	O
+compared	O
+when	O
+given	O
+randomly	O
+in	O
+1	O
+-	O
+week	O
+treatment	O
+periods	O
+.	O
+
+The	O
+best	O
+clinical	O
+effect	O
+was	O
+found	O
+with	O
+terbutaline	O
+.	O
+
+Both	O
+anti	O
+-	O
+asthmatic	B
+and	O
+tremorgenic	B
+effects	O
+of	O
+procaterol	O
+were	O
+dose	O
+-	O
+related	O
+.	O
+
+Procaterol	O
+appeared	O
+effective	O
+in	O
+the	O
+doses	O
+tested	O
+,	O
+and	O
+a	O
+twice	O
+daily	O
+regimen	O
+would	O
+appear	O
+to	O
+be	O
+suitable	O
+with	O
+this	O
+drug	O
+.	O
+
+Subacute	O
+effects	O
+of	O
+propranolol	O
+and	O
+B	O
+24	O
+/	O
+76	O
+on	O
+isoproterenol	O
+-	O
+induced	O
+rat	O
+heart	B
+hypertrophy	I
+in	O
+correlation	O
+with	O
+blood	O
+pressure	O
+.	O
+
+We	O
+compared	O
+the	O
+potential	O
+beta	O
+-	O
+receptor	O
+blocker	O
+,	O
+B	O
+24	O
+/	O
+76	O
+i	O
+.	O
+e	O
+.	O
+1	O
+-	O
+(	O
+2	O
+,	O
+4	O
+-	O
+dichlorophenoxy	O
+)	O
+-	O
+3	O
+[	O
+2	O
+-	O
+3	O
+,	O
+4	O
+-	O
+dimethoxyphenyl	O
+)	O
+ethanolamino	O
+]	O
+-	O
+prop	O
+an	O
+-	O
+2	O
+-	O
+ol	O
+,	O
+which	O
+is	O
+characterized	O
+by	O
+beta	O
+1	O
+-	O
+adrenoceptor	O
+blocking	O
+and	O
+beta	O
+2	O
+-	O
+adrenoceptor	O
+stimulating	O
+properties	O
+with	O
+propranolol	O
+.	O
+
+The	O
+studies	O
+were	O
+performed	O
+using	O
+an	O
+experimental	O
+model	O
+of	O
+isoproterenol	O
+-	O
+induced	O
+heart	B
+hypertrophy	I
+in	O
+rats	O
+.	O
+
+A	O
+correlation	O
+of	O
+the	O
+blood	O
+pressure	O
+was	O
+neither	O
+found	O
+in	O
+the	O
+development	O
+nor	O
+in	O
+the	O
+attempt	O
+to	O
+suppress	O
+the	O
+development	O
+of	O
+heart	B
+hypertrophy	I
+with	O
+the	O
+two	O
+beta	O
+-	O
+receptor	O
+blockers	O
+.	O
+
+Both	O
+beta	O
+-	O
+blockers	O
+influenced	O
+the	O
+development	O
+of	O
+hypertrophy	B
+to	O
+a	O
+different	O
+,	O
+but	O
+not	O
+reproducible	O
+extent	O
+.	O
+
+It	O
+was	O
+possible	O
+to	O
+suppress	O
+the	O
+increased	O
+ornithine	O
+decarboxylase	O
+activity	O
+with	O
+both	O
+beta	O
+-	O
+blockers	O
+in	O
+hypertrophied	B
+hearts	I
+,	O
+but	O
+there	O
+was	O
+no	O
+effect	O
+on	O
+the	O
+heart	O
+mass	O
+.	O
+
+Neither	O
+propranolol	O
+nor	O
+B	O
+24	O
+/	O
+76	O
+could	O
+stop	O
+the	O
+changes	O
+in	O
+the	O
+characteristic	O
+myosin	O
+isoenzyme	O
+pattern	O
+of	O
+the	O
+hypertrophied	B
+rat	O
+heart	O
+.	O
+
+Thus	O
+,	O
+the	O
+investigations	O
+did	O
+not	O
+provide	O
+any	O
+evidence	O
+that	O
+the	O
+beta	O
+-	O
+receptor	O
+blockers	O
+propranolol	O
+and	O
+B	O
+24	O
+/	O
+76	O
+have	O
+the	O
+potency	O
+to	O
+prevent	O
+isoproterenol	O
+from	O
+producing	O
+heart	B
+hypertrophy	I
+.	O
+
+Increased	O
+anxiogenic	O
+effects	O
+of	O
+caffeine	O
+in	O
+panic	B
+disorders	I
+.	O
+
+The	O
+effects	O
+of	O
+oral	O
+administration	O
+of	O
+caffeine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+on	O
+behavioral	O
+ratings	O
+,	O
+somatic	O
+symptoms	O
+,	O
+blood	O
+pressure	O
+and	O
+plasma	O
+levels	O
+of	O
+3	O
+-	O
+methoxy	O
+-	O
+4	O
+-	O
+hydroxyphenethyleneglycol	O
+(	O
+MHPG	O
+)	O
+and	O
+cortisol	O
+were	O
+determined	O
+in	O
+17	O
+healthy	O
+subjects	O
+and	O
+21	O
+patients	O
+meeting	O
+DSM	O
+-	O
+III	O
+criteria	O
+for	O
+agoraphobia	B
+with	O
+panic	B
+attacks	I
+or	O
+panic	B
+disorder	I
+.	O
+
+Caffeine	O
+produced	O
+significantly	O
+greater	O
+increases	O
+in	O
+subject	O
+-	O
+rated	O
+anxiety	B
+,	O
+nervousness	O
+,	O
+fear	O
+,	O
+nausea	B
+,	O
+palpitations	B
+,	O
+restlessness	B
+,	O
+and	O
+tremors	B
+in	O
+the	O
+patients	O
+compared	O
+with	O
+healthy	O
+subjects	O
+.	O
+
+In	O
+the	O
+patients	O
+,	O
+but	O
+not	O
+the	O
+healthy	O
+subjects	O
+,	O
+these	O
+symptoms	O
+were	O
+significantly	O
+correlated	O
+with	O
+plasma	O
+caffeine	O
+levels	O
+.	O
+
+Seventy	O
+-	O
+one	O
+percent	O
+of	O
+the	O
+patients	O
+reported	O
+that	O
+the	O
+behavioral	O
+effects	O
+of	O
+caffeine	O
+were	O
+similar	O
+to	O
+those	O
+experienced	O
+during	O
+panic	B
+attacks	I
+.	O
+
+Caffeine	O
+did	O
+not	O
+alter	O
+plasma	O
+MHPG	O
+levels	O
+in	O
+either	O
+the	O
+healthy	O
+subjects	O
+or	O
+patients	O
+.	O
+
+Caffeine	O
+increased	O
+plasma	O
+cortisol	O
+levels	O
+equally	O
+in	O
+the	O
+patient	O
+and	O
+healthy	O
+groups	O
+.	O
+
+Because	O
+caffeine	O
+is	O
+an	O
+adenosine	O
+receptor	O
+antagonist	O
+,	O
+these	O
+results	O
+suggest	O
+that	O
+some	O
+panic	B
+disorder	I
+patients	O
+may	O
+have	O
+abnormalities	B
+in	I
+neuronal	I
+systems	I
+involving	O
+adenosine	O
+.	O
+
+Patients	O
+with	O
+anxiety	B
+disorders	I
+may	O
+benefit	O
+by	O
+avoiding	O
+caffeine	O
+-	O
+containing	O
+foods	O
+and	O
+beverages	O
+.	O
+
+Comparison	O
+of	O
+the	O
+effect	O
+of	O
+oxitropium	O
+bromide	O
+and	O
+of	O
+slow	O
+-	O
+release	O
+theophylline	O
+on	O
+nocturnal	O
+asthma	B
+.	O
+
+The	O
+effects	O
+of	O
+a	O
+new	O
+inhaled	O
+antimuscarinic	O
+drug	O
+,	O
+oxitropium	O
+bromide	O
+,	O
+and	O
+of	O
+a	O
+slow	O
+-	O
+release	O
+theophylline	O
+preparation	O
+upon	O
+nocturnal	O
+asthma	B
+were	O
+compared	O
+in	O
+a	O
+placebo	O
+-	O
+controlled	O
+double	O
+-	O
+blind	O
+study	O
+.	O
+
+Two	O
+samples	O
+were	O
+studied	O
+:	O
+12	O
+patients	O
+received	O
+oxitropium	O
+at	O
+600	O
+micrograms	O
+(	O
+6	O
+subjects	O
+)	O
+or	O
+at	O
+400	O
+micrograms	O
+t	O
+.	O
+i	O
+.	O
+d	O
+.	O
+
+(	O
+6	O
+subjects	O
+)	O
+whereas	O
+11	O
+received	O
+theophylline	O
+at	O
+300	O
+mg	O
+b	O
+.	O
+i	O
+.	O
+d	O
+.	O
+
+Morning	O
+dipping	O
+,	O
+assessed	O
+by	O
+the	O
+fall	O
+in	O
+peak	O
+flow	O
+overnight	O
+,	O
+was	O
+significantly	O
+reduced	O
+in	O
+the	O
+periods	O
+when	O
+either	O
+active	O
+drug	O
+was	O
+taken	O
+,	O
+whereas	O
+no	O
+difference	O
+was	O
+noticed	O
+during	O
+the	O
+placebo	O
+administration	O
+.	O
+
+No	O
+significant	O
+difference	O
+was	O
+noticed	O
+between	O
+results	O
+obtained	O
+with	O
+either	O
+active	O
+drug	O
+,	O
+as	O
+well	O
+as	O
+with	O
+either	O
+dosage	O
+of	O
+oxitropium	O
+.	O
+
+No	O
+subject	O
+reported	O
+side	O
+effects	O
+of	O
+oxitropium	O
+,	O
+as	O
+compared	O
+to	O
+three	O
+subjects	O
+reporting	O
+nausea	B
+,	O
+vomiting	B
+and	O
+tremors	B
+after	O
+theophylline	O
+.	O
+
+Oxitropium	O
+proves	O
+to	O
+be	O
+a	O
+valuable	O
+alternative	O
+to	O
+theophylline	O
+in	O
+nocturnal	O
+asthma	B
+,	O
+since	O
+it	O
+is	O
+equally	O
+potent	O
+,	O
+safer	O
+and	O
+does	O
+not	O
+require	O
+the	O
+titration	O
+of	O
+dosage	O
+.	O
+
+Penicillin	O
+anaphylaxis	B
+.	O
+
+A	O
+case	O
+of	O
+oral	O
+penicillin	O
+anaphylaxis	B
+is	O
+described	O
+,	O
+and	O
+the	O
+terminology	O
+,	O
+occurrence	O
+,	O
+clinical	O
+manifestations	O
+,	O
+pathogenesis	O
+,	O
+prevention	O
+,	O
+and	O
+treatment	O
+of	O
+anaphylaxis	B
+are	O
+reviewed	O
+.	O
+
+Emergency	O
+physicians	O
+should	O
+be	O
+aware	O
+of	O
+oral	O
+penicillin	O
+anaphylaxis	B
+in	O
+order	O
+to	O
+prevent	O
+its	O
+occurrence	O
+by	O
+prescribing	O
+the	O
+antibiotic	O
+judiciously	O
+and	O
+knowledgeably	O
+and	O
+to	O
+offer	O
+optimal	O
+medical	O
+therapy	O
+once	O
+this	O
+life	O
+-	O
+threatening	O
+reaction	O
+has	O
+begun	O
+.	O
+
+Reversible	O
+valproic	O
+acid	O
+-	O
+induced	O
+dementia	B
+:	O
+a	O
+case	O
+report	O
+.	O
+
+Reversible	O
+valproic	O
+acid	O
+-	O
+induced	O
+dementia	B
+was	O
+documented	O
+in	O
+a	O
+21	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+epilepsy	B
+who	O
+had	O
+a	O
+3	O
+-	O
+year	O
+history	O
+of	O
+insidious	O
+progressive	O
+decline	O
+in	O
+global	O
+cognitive	O
+abilities	O
+documented	O
+by	O
+serial	O
+neuropsychological	O
+studies	O
+.	O
+
+Repeat	O
+neuropsychological	O
+testing	O
+7	O
+weeks	O
+after	O
+discontinuation	O
+of	O
+the	O
+drug	O
+revealed	O
+dramatic	O
+improvement	O
+in	O
+IQ	O
+,	O
+memory	O
+,	O
+naming	O
+,	O
+and	O
+other	O
+tasks	O
+commensurate	O
+with	O
+clinical	O
+recovery	O
+in	O
+his	O
+intellectual	O
+capacity	O
+.	O
+
+Possible	O
+pathophysiological	O
+mechanisms	O
+which	O
+may	O
+have	O
+been	O
+operative	O
+in	O
+this	O
+case	O
+include	O
+:	O
+a	O
+direct	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+toxic	O
+effect	O
+of	O
+valproic	O
+acid	O
+;	O
+a	O
+paradoxical	O
+epileptogenic	O
+effect	O
+secondary	O
+to	O
+the	O
+drug	O
+;	O
+and	O
+an	O
+indirect	O
+CNS	O
+toxic	O
+effect	O
+mediated	O
+through	O
+valproic	O
+acid	O
+-	O
+induced	O
+hyperammonemia	B
+.	O
+
+Reversal	O
+of	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+of	O
+passive	O
+avoidance	O
+by	O
+pre	O
+-	O
+and	O
+post	O
+-	O
+training	O
+naloxone	O
+.	O
+
+In	O
+a	O
+series	O
+of	O
+five	O
+experiments	O
+,	O
+the	O
+modulating	O
+role	O
+of	O
+naloxone	O
+on	O
+a	O
+scopolamine	O
+-	O
+induced	O
+retention	B
+deficit	I
+in	O
+a	O
+passive	O
+avoidance	O
+paradigm	O
+was	O
+investigated	O
+in	O
+mice	O
+.	O
+
+Scopolamine	O
+,	O
+but	O
+not	O
+methyl	O
+scopolamine	O
+(	O
+1	O
+and	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+induced	O
+an	O
+amnesia	B
+as	O
+measured	O
+by	O
+latency	O
+and	O
+duration	O
+parameters	O
+.	O
+
+Naloxone	O
+(	O
+0	O
+.	O
+3	O
+,	O
+1	O
+,	O
+3	O
+,	O
+and	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+injected	O
+prior	O
+to	O
+training	O
+attenuated	O
+the	O
+retention	B
+deficit	I
+with	O
+a	O
+peak	O
+of	O
+activity	O
+at	O
+3	O
+mg	O
+/	O
+kg	O
+.	O
+
+The	O
+effect	O
+of	O
+naloxone	O
+could	O
+be	O
+antagonized	O
+with	O
+morphine	O
+(	O
+1	O
+,	O
+3	O
+,	O
+and	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+demonstrating	O
+the	O
+opioid	O
+specificity	O
+of	O
+the	O
+naloxone	O
+effect	O
+.	O
+
+Post	O
+-	O
+training	O
+administration	O
+of	O
+naloxone	O
+(	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+as	O
+a	O
+single	O
+or	O
+as	O
+a	O
+split	O
+dose	O
+also	O
+attenuated	O
+the	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+.	O
+
+Control	O
+experiments	O
+indicated	O
+that	O
+neither	O
+an	O
+increase	O
+in	O
+pain	B
+sensitivity	O
+(	O
+pre	O
+-	O
+training	O
+naloxone	O
+)	O
+nor	O
+an	O
+induced	O
+aversive	O
+state	O
+(	O
+post	O
+-	O
+training	O
+naloxone	O
+)	O
+appear	O
+to	O
+be	O
+responsible	O
+for	O
+the	O
+influence	O
+of	O
+naloxone	O
+on	O
+the	O
+scopolamine	O
+-	O
+induced	O
+retention	B
+deficit	I
+.	O
+
+These	O
+results	O
+extend	O
+previous	O
+findings	O
+implicating	O
+a	O
+cholinergic	O
+-	O
+opioid	O
+interaction	O
+in	O
+memory	O
+processes	O
+.	O
+
+A	O
+possible	O
+mechanism	O
+for	O
+this	O
+interaction	O
+involving	O
+the	O
+septo	O
+-	O
+hippocampal	O
+cholinergic	O
+pathway	O
+is	O
+discussed	O
+.	O
+
+Electron	O
+microscopic	O
+investigations	O
+of	O
+the	O
+cyclophosphamide	O
+-	O
+induced	O
+lesions	B
+of	I
+the	I
+urinary	I
+bladder	I
+of	O
+the	O
+rat	O
+and	O
+their	O
+prevention	O
+by	O
+mesna	O
+.	O
+
+Fully	O
+developed	O
+cyclophosphamide	O
+-	O
+induced	O
+cystitis	B
+is	O
+characterized	O
+by	O
+nearly	O
+complete	O
+detachment	O
+of	O
+the	O
+urothelium	O
+,	O
+severe	O
+submucosal	O
+edema	B
+owing	O
+to	O
+damage	O
+to	O
+the	O
+microvascular	O
+bed	O
+and	O
+focal	O
+muscle	O
+necroses	B
+.	O
+
+The	O
+initial	O
+response	O
+to	O
+the	O
+primary	O
+attack	O
+by	O
+the	O
+cyclophosphamide	O
+metabolites	O
+seems	O
+to	O
+be	O
+fragmentation	O
+of	O
+the	O
+luminal	O
+membrane	O
+.	O
+
+This	O
+damages	O
+the	O
+cellular	O
+barrier	O
+against	O
+the	O
+hypertonic	O
+urine	O
+.	O
+
+Subsequent	O
+breaks	O
+in	O
+the	O
+lateral	O
+cell	O
+membranes	O
+of	O
+the	O
+superficial	O
+cells	O
+and	O
+in	O
+all	O
+the	O
+plasma	O
+membranes	O
+of	O
+the	O
+intermediate	O
+and	O
+basal	O
+cells	O
+,	O
+intercellular	O
+and	O
+intracellular	O
+edema	B
+and	O
+disintegration	O
+of	O
+the	O
+desmosomes	O
+and	O
+hemidesmosomes	O
+lead	O
+to	O
+progressive	O
+degeneration	O
+and	O
+detachment	O
+of	O
+the	O
+epithelial	O
+cells	O
+with	O
+exposure	O
+and	O
+splitting	O
+of	O
+the	O
+basal	O
+membrane	O
+.	O
+
+The	O
+morphological	O
+changes	O
+of	O
+the	O
+endothelial	O
+cells	O
+,	O
+which	O
+become	O
+more	O
+pronounced	O
+in	O
+the	O
+later	O
+stages	O
+of	O
+the	O
+experiment	O
+,	O
+the	O
+involvement	O
+of	O
+blood	O
+vessels	O
+regardless	O
+of	O
+their	O
+diameter	O
+and	O
+the	O
+location	O
+-	O
+dependent	O
+extent	O
+of	O
+the	O
+damage	O
+indicate	O
+a	O
+direct	O
+type	O
+of	O
+damage	O
+which	O
+is	O
+preceded	O
+by	O
+a	O
+mediator	O
+-	O
+induced	O
+increase	O
+in	O
+permeability	O
+,	O
+the	O
+morphological	O
+correlate	O
+of	O
+which	O
+is	O
+the	O
+formation	O
+of	O
+gaps	O
+in	O
+the	O
+interendothelial	O
+cell	O
+connections	O
+on	O
+the	O
+venules	O
+.	O
+
+These	O
+changes	O
+can	O
+be	O
+effectively	O
+prevented	O
+by	O
+mesna	O
+.	O
+
+The	O
+only	O
+sign	O
+of	O
+a	O
+possible	O
+involvement	O
+is	O
+the	O
+increase	O
+in	O
+the	O
+number	O
+of	O
+specific	O
+granules	O
+with	O
+a	O
+presumed	O
+lysosomal	O
+function	O
+in	O
+the	O
+superficial	O
+cells	O
+.	O
+
+Increase	O
+in	O
+intragastric	O
+pressure	O
+during	O
+suxamethonium	O
+-	O
+induced	O
+muscle	B
+fasciculations	I
+in	O
+children	O
+:	O
+inhibition	O
+by	O
+alfentanil	O
+.	O
+
+Changes	O
+in	O
+intragastric	O
+pressure	O
+after	O
+the	O
+administration	O
+of	O
+suxamethonium	O
+1	O
+.	O
+5	O
+mg	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+v	O
+.	O
+were	O
+studied	O
+in	O
+32	O
+children	O
+(	O
+mean	O
+age	O
+6	O
+.	O
+9	O
+yr	O
+)	O
+pretreated	O
+with	O
+either	O
+physiological	O
+saline	O
+or	O
+alfentanil	O
+50	O
+micrograms	O
+kg	O
+-	O
+1	O
+.	O
+
+Anaesthesia	O
+was	O
+induced	O
+with	O
+thiopentone	O
+5	O
+mg	O
+kg	O
+-	O
+1	O
+.	O
+
+The	O
+incidence	O
+and	O
+intensity	O
+of	O
+muscle	B
+fasciculations	I
+caused	O
+by	O
+suxamethonium	O
+were	O
+significantly	O
+greater	O
+in	O
+the	O
+control	O
+than	O
+in	O
+the	O
+alfentanil	O
+group	O
+.	O
+
+The	O
+intragastric	O
+pressure	O
+during	O
+muscle	B
+fasciculations	I
+was	O
+significantly	O
+higher	O
+in	O
+the	O
+control	O
+group	O
+(	O
+16	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+(	O
+SEM	O
+)	O
+cm	O
+H2O	O
+)	O
+than	O
+in	O
+the	O
+alfentanil	O
+group	O
+(	O
+7	O
+.	O
+7	O
++	O
+/	O
+-	O
+1	O
+.	O
+5	O
+(	O
+SEM	O
+)	O
+cm	O
+H2O	O
+)	O
+.	O
+
+The	O
+increase	O
+in	O
+intragastric	O
+pressure	O
+was	O
+directly	O
+related	O
+to	O
+the	O
+intensity	O
+of	O
+muscle	B
+fasciculations	I
+(	O
+regression	O
+line	O
+:	O
+y	O
+=	O
+0	O
+.	O
+5	O
++	O
+4	O
+.	O
+78x	O
+with	O
+r	O
+of	O
+0	O
+.	O
+78	O
+)	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+intragastric	O
+pressure	O
+increases	O
+significantly	O
+during	O
+muscle	B
+fasciculations	I
+caused	O
+by	O
+suxamethonium	O
+in	O
+healthy	O
+children	O
+.	O
+
+Alfentanil	O
+50	O
+micrograms	O
+kg	O
+-	O
+1	O
+effectively	O
+inhibits	O
+the	O
+incidence	O
+and	O
+intensity	O
+of	O
+suxamethonium	O
+-	O
+induced	O
+muscle	B
+fasciculations	I
+;	O
+moreover	O
+,	O
+intragastric	O
+pressure	O
+remains	O
+at	O
+its	O
+control	O
+value	O
+.	O
+
+Acute	O
+insulin	O
+treatment	O
+normalizes	O
+the	O
+resistance	O
+to	O
+the	O
+cardiotoxic	B
+effect	O
+of	O
+isoproterenol	O
+in	O
+streptozotocin	O
+diabetic	B
+rats	O
+.	O
+
+A	O
+morphometric	O
+study	O
+of	O
+isoproterenol	O
+induced	O
+myocardial	O
+fibrosis	B
+.	O
+
+The	O
+acute	O
+effect	O
+of	O
+insulin	O
+treatment	O
+on	O
+the	O
+earlier	O
+reported	O
+protective	O
+effect	O
+of	O
+streptozotocin	O
+diabetes	B
+against	O
+the	O
+cardiotoxic	B
+effect	O
+of	O
+high	O
+doses	O
+of	O
+isoproterenol	O
+(	O
+ISO	O
+)	O
+was	O
+investigated	O
+in	O
+rats	O
+.	O
+
+Thirty	O
+to	O
+135	O
+min	O
+after	O
+the	O
+injection	O
+of	O
+crystalline	O
+insulin	O
+,	O
+ISO	O
+was	O
+given	O
+subcutaneously	O
+and	O
+when	O
+ISO	O
+induced	O
+fibrosis	B
+in	O
+the	O
+myocardium	O
+was	O
+morphometrically	O
+analyzed	O
+7	O
+days	O
+later	O
+,	O
+a	O
+highly	O
+significant	O
+correlation	O
+(	O
+r	O
+=	O
+0	O
+.	O
+83	O
+,	O
+2	O
+p	O
+=	O
+0	O
+.	O
+006	O
+)	O
+to	O
+the	O
+slope	O
+of	O
+the	O
+fall	O
+in	O
+blood	O
+glucose	O
+after	O
+insulin	O
+treatment	O
+appeared	O
+.	O
+
+The	O
+myocardial	O
+content	O
+of	O
+catecholamines	O
+was	O
+estimated	O
+in	O
+these	O
+8	O
+day	O
+diabetic	B
+rats	O
+.	O
+
+The	O
+norepinephrine	O
+content	O
+was	O
+significantly	O
+increased	O
+while	O
+epinephrine	O
+remained	O
+unchanged	O
+.	O
+
+An	O
+enhanced	O
+sympathetic	O
+nervous	O
+system	O
+activity	O
+with	O
+a	O
+consequent	O
+down	O
+regulation	O
+of	O
+the	O
+myocardial	O
+beta	O
+-	O
+adrenergic	O
+receptors	O
+could	O
+,	O
+therefore	O
+,	O
+explain	O
+this	O
+catecholamine	O
+resistance	O
+.	O
+
+The	O
+rapid	O
+reversion	O
+after	O
+insulin	O
+treatment	O
+excludes	O
+the	O
+possibility	O
+that	O
+streptozotocin	O
+in	O
+itself	O
+causes	O
+the	O
+ISO	O
+resistance	O
+and	O
+points	O
+towards	O
+a	O
+direct	O
+insulin	O
+effect	O
+on	O
+myocardial	O
+catecholamine	O
+sensitivity	O
+in	O
+diabetic	B
+rats	O
+.	O
+
+The	O
+phenomenon	O
+described	O
+might	O
+elucidate	O
+pathogenetic	O
+mechanisms	O
+behind	O
+toxic	O
+myocardial	O
+cell	O
+degeneration	O
+and	O
+may	O
+possibly	O
+have	O
+relevance	O
+for	O
+acute	O
+cardiovascular	O
+complications	O
+in	O
+diabetic	B
+patients	O
+.	O
+
+Differential	O
+effects	O
+of	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+on	O
+seizures	B
+produced	O
+by	O
+pilocarpine	O
+in	O
+rats	O
+.	O
+
+The	O
+muscarinic	O
+cholinergic	O
+agonist	O
+pilocarpine	O
+induces	O
+in	O
+rats	O
+seizures	B
+and	O
+status	B
+epilepticus	I
+followed	O
+by	O
+widespread	O
+damage	O
+to	O
+the	O
+forebrain	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+investigate	O
+the	O
+effect	O
+of	O
+5	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+,	O
+sodium	O
+salicylate	O
+,	O
+phenylbutazone	O
+,	O
+indomethacin	O
+,	O
+ibuprofen	O
+and	O
+mefenamic	O
+acid	O
+,	O
+on	O
+seizures	B
+produced	O
+by	O
+pilocarpine	O
+.	O
+
+Pretreatment	O
+of	O
+rats	O
+with	O
+sodium	O
+salicylate	O
+,	O
+ED50	O
+103	O
+mg	O
+/	O
+kg	O
+(	O
+60	O
+-	O
+174	O
+)	O
+,	O
+and	O
+phenylbutazone	O
+,	O
+59	O
+mg	O
+/	O
+kg	O
+(	O
+50	O
+-	O
+70	O
+)	O
+converted	O
+the	O
+non	O
+-	O
+convulsant	O
+dose	O
+of	O
+pilocarpine	O
+,	O
+200	O
+mg	O
+/	O
+kg	O
+,	O
+to	O
+a	O
+convulsant	O
+one	O
+.	O
+
+Indomethacin	O
+,	O
+1	O
+-	O
+10	O
+mg	O
+/	O
+kg	O
+,	O
+and	O
+ibuprofen	O
+,	O
+10	O
+-	O
+100	O
+mg	O
+/	O
+kg	O
+,	O
+failed	O
+to	O
+modulate	O
+seizures	B
+produced	O
+by	O
+pilocarpine	O
+.	O
+
+Mefenamic	O
+acid	O
+,	O
+26	O
+(	O
+22	O
+-	O
+30	O
+)	O
+mg	O
+/	O
+kg	O
+,	O
+prevented	O
+seizures	B
+and	O
+protected	O
+rats	O
+from	O
+seizure	B
+-	O
+related	O
+brain	B
+damage	I
+induced	O
+by	O
+pilocarpine	O
+,	O
+380	O
+mg	O
+/	O
+kg	O
+.	O
+
+These	O
+results	O
+indicate	O
+that	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+differentially	O
+modulate	O
+the	O
+threshold	O
+for	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+.	O
+
+Acute	B
+neurologic	I
+dysfunction	I
+after	O
+high	O
+-	O
+dose	O
+etoposide	O
+therapy	O
+for	O
+malignant	B
+glioma	I
+.	O
+
+Etoposide	O
+(	O
+VP	O
+-	O
+16	O
+-	O
+213	O
+)	O
+has	O
+been	O
+used	O
+in	O
+the	O
+treatment	O
+of	O
+many	O
+solid	O
+tumors	B
+and	O
+hematologic	B
+malignancies	I
+.	O
+
+When	O
+used	O
+in	O
+high	O
+doses	O
+and	O
+in	O
+conjunction	O
+with	O
+autologous	O
+bone	O
+marrow	O
+transplantation	O
+,	O
+this	O
+agent	O
+has	O
+activity	O
+against	O
+several	O
+treatment	O
+-	O
+resistant	O
+cancers	B
+including	O
+malignant	B
+glioma	I
+.	O
+
+In	O
+six	O
+of	O
+eight	O
+patients	O
+(	O
+75	O
+%	O
+)	O
+who	O
+we	O
+treated	O
+for	O
+recurrent	O
+or	O
+resistant	O
+glioma	B
+,	O
+sudden	O
+severe	O
+neurologic	B
+deterioration	I
+occurred	O
+.	O
+
+This	O
+developed	O
+a	O
+median	O
+of	O
+9	O
+days	O
+after	O
+initiation	O
+of	O
+high	O
+-	O
+dose	O
+etoposide	O
+therapy	O
+.	O
+
+Significant	O
+clinical	O
+manifestations	O
+have	O
+included	O
+confusion	B
+,	O
+papilledema	B
+,	O
+somnolence	B
+,	O
+exacerbation	O
+of	O
+motor	B
+deficits	I
+,	O
+and	O
+sharp	O
+increase	O
+in	O
+seizure	B
+activity	O
+.	O
+
+These	O
+abnormalities	O
+resolved	O
+rapidly	O
+after	O
+initiation	O
+of	O
+high	O
+-	O
+dose	O
+intravenous	O
+dexamethasone	O
+therapy	O
+.	O
+
+In	O
+all	O
+patients	O
+,	O
+computerized	O
+tomographic	O
+(	O
+CT	O
+)	O
+brain	O
+scans	O
+demonstrated	O
+stability	O
+in	O
+tumor	B
+size	O
+and	O
+peritumor	O
+edema	B
+when	O
+compared	O
+with	O
+pretransplant	O
+scans	O
+.	O
+
+This	O
+complication	O
+appears	O
+to	O
+represent	O
+a	O
+significant	O
+new	O
+toxicity	B
+of	O
+high	O
+-	O
+dose	O
+etoposide	O
+therapy	O
+for	O
+malignant	B
+glioma	I
+.	O
+
+Progressive	O
+bile	B
+duct	I
+injury	I
+after	O
+thiabendazole	O
+administration	O
+.	O
+
+A	O
+27	O
+-	O
+yr	O
+-	O
+old	O
+man	O
+developed	O
+jaundice	B
+2	O
+wk	O
+after	O
+exposure	O
+to	O
+thiabendazole	O
+.	O
+
+Cholestasis	B
+persisted	O
+for	O
+3	O
+yr	O
+,	O
+at	O
+which	O
+time	O
+a	O
+liver	O
+transplant	O
+was	O
+performed	O
+.	O
+
+Two	O
+liver	O
+biopsy	O
+specimens	O
+and	O
+the	O
+hepatectomy	O
+specimen	O
+were	O
+remarkable	O
+for	O
+almost	O
+complete	O
+disappearance	O
+of	O
+interlobular	O
+bile	O
+ducts	O
+.	O
+
+Prominent	O
+fibrosis	B
+and	O
+hepatocellular	O
+regeneration	O
+were	O
+also	O
+present	O
+;	O
+however	O
+,	O
+the	O
+lobular	O
+architecture	O
+was	O
+preserved	O
+.	O
+
+This	O
+case	O
+represents	O
+an	O
+example	O
+of	O
+"	O
+idiosyncratic	O
+"	O
+drug	B
+-	I
+induced	I
+liver	I
+damage	I
+in	O
+which	O
+the	O
+primary	O
+target	O
+of	O
+injury	O
+is	O
+the	O
+bile	O
+duct	O
+.	O
+
+An	O
+autoimmune	O
+pathogenesis	O
+of	O
+the	O
+bile	B
+duct	I
+destruction	I
+is	O
+suggested	O
+.	O
+
+Differential	O
+effects	O
+of	O
+1	O
+,	O
+4	O
+-	O
+dihydropyridine	O
+calcium	O
+channel	O
+blockers	O
+:	O
+therapeutic	O
+implications	O
+.	O
+
+Increasing	O
+recognition	O
+of	O
+the	O
+importance	O
+of	O
+calcium	O
+in	O
+the	O
+pathogenesis	O
+of	O
+cardiovascular	B
+disease	I
+has	O
+stimulated	O
+research	O
+into	O
+the	O
+use	O
+of	O
+calcium	O
+channel	O
+blocking	O
+agents	O
+for	O
+treatment	O
+of	O
+a	O
+variety	O
+of	O
+cardiovascular	B
+diseases	I
+.	O
+
+The	O
+favorable	O
+efficacy	O
+and	O
+tolerability	O
+profiles	O
+of	O
+these	O
+agents	O
+make	O
+them	O
+attractive	O
+therapeutic	O
+modalities	O
+.	O
+
+Clinical	O
+applications	O
+of	O
+calcium	O
+channel	O
+blockers	O
+parallel	O
+their	O
+tissue	O
+selectivity	O
+.	O
+
+In	O
+contrast	O
+to	O
+verapamil	O
+and	O
+diltiazem	O
+,	O
+which	O
+are	O
+roughly	O
+equipotent	O
+in	O
+their	O
+actions	O
+on	O
+the	O
+heart	O
+and	O
+vascular	O
+smooth	O
+muscle	O
+,	O
+the	O
+dihydropyridine	O
+calcium	O
+channel	O
+blockers	O
+are	O
+a	O
+group	O
+of	O
+potent	O
+peripheral	O
+vasodilator	O
+agents	O
+that	O
+exert	O
+minimal	O
+electrophysiologic	O
+effects	O
+on	O
+cardiac	O
+nodal	O
+or	O
+conduction	O
+tissue	O
+.	O
+
+As	O
+the	O
+first	O
+dihydropyridine	O
+available	O
+for	O
+use	O
+in	O
+the	O
+United	O
+States	O
+,	O
+nifedipine	O
+controls	O
+angina	B
+and	O
+hypertension	B
+with	O
+minimal	O
+depression	O
+of	O
+cardiac	O
+function	O
+.	O
+
+Additional	O
+members	O
+of	O
+this	O
+group	O
+of	O
+calcium	O
+channel	O
+blockers	O
+have	O
+been	O
+studied	O
+for	O
+a	O
+variety	O
+of	O
+indications	O
+for	O
+which	O
+they	O
+may	O
+offer	O
+advantages	O
+over	O
+current	O
+therapy	O
+.	O
+
+Once	O
+or	O
+twice	O
+daily	O
+dosage	O
+possible	O
+with	O
+nitrendipine	O
+and	O
+nisoldipine	O
+offers	O
+a	O
+convenient	O
+administration	O
+schedule	O
+,	O
+which	O
+encourages	O
+patient	O
+compliance	O
+in	O
+long	O
+-	O
+term	O
+therapy	O
+of	O
+hypertension	B
+.	O
+
+The	O
+coronary	O
+vasodilating	O
+properties	O
+of	O
+nisoldipine	O
+have	O
+led	O
+to	O
+the	O
+investigation	O
+of	O
+this	O
+agent	O
+for	O
+use	O
+in	O
+angina	B
+.	O
+
+Selectivity	O
+for	O
+the	O
+cerebrovascular	O
+bed	O
+makes	O
+nimodipine	O
+potentially	O
+useful	O
+in	O
+the	O
+treatment	O
+of	O
+subarachnoid	B
+hemorrhage	I
+,	O
+migraine	B
+headache	I
+,	O
+dementia	B
+,	O
+and	O
+stroke	B
+.	O
+
+In	O
+general	O
+,	O
+the	O
+dihydropyridine	O
+calcium	O
+channel	O
+blockers	O
+are	O
+usually	O
+well	O
+tolerated	O
+,	O
+with	O
+headache	B
+,	O
+facial	O
+flushing	B
+,	O
+palpitations	B
+,	O
+edema	B
+,	O
+nausea	B
+,	O
+anorexia	B
+,	O
+and	O
+dizziness	B
+being	O
+the	O
+more	O
+common	O
+adverse	O
+effects	O
+.	O
+
+The	O
+enhancement	O
+of	O
+aminonucleoside	O
+nephrosis	B
+by	O
+the	O
+co	O
+-	O
+administration	O
+of	O
+protamine	O
+.	O
+
+An	O
+experimental	O
+model	O
+of	O
+focal	B
+segmental	I
+glomerular	I
+sclerosis	I
+(	O
+FSGS	B
+)	O
+was	O
+developed	O
+in	O
+rats	O
+by	O
+the	O
+combined	O
+administration	O
+of	O
+puromycin	O
+-	O
+aminonucleoside	O
+(	O
+AMNS	O
+)	O
+and	O
+protamine	O
+sulfate	O
+(	O
+PS	O
+)	O
+.	O
+
+Male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+,	O
+uninephrectomized	O
+three	O
+weeks	O
+before	O
+,	O
+received	O
+daily	O
+injections	O
+of	O
+subcutaneous	O
+AMNS	O
+(	O
+1	O
+mg	O
+/	O
+100	O
+g	O
+body	O
+wt	O
+)	O
+and	O
+intravenous	O
+PS	O
+(	O
+2	O
+separated	O
+doses	O
+of	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+100	O
+g	O
+body	O
+wt	O
+)	O
+for	O
+four	O
+days	O
+.	O
+
+The	O
+series	O
+of	O
+injections	O
+were	O
+repeated	O
+another	O
+three	O
+times	O
+at	O
+10	O
+day	O
+intervals	O
+.	O
+
+The	O
+animals	O
+were	O
+sacrificed	O
+on	O
+days	O
+24	O
+,	O
+52	O
+,	O
+and	O
+80	O
+.	O
+
+They	O
+developed	O
+nephrotic	B
+syndrome	I
+and	O
+finally	O
+renal	B
+failure	I
+.	O
+
+The	O
+time	O
+-	O
+course	O
+curve	O
+of	O
+creatinine	O
+clearance	O
+dropped	O
+and	O
+showed	O
+significant	O
+difference	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+from	O
+that	O
+of	O
+each	O
+control	O
+group	O
+,	O
+such	O
+as	O
+,	O
+AMNS	O
+alone	O
+,	O
+PS	O
+alone	O
+or	O
+saline	O
+injected	O
+.	O
+
+Their	O
+glomeruli	O
+showed	O
+changes	O
+of	O
+progressive	O
+FSGS	B
+.	O
+
+The	O
+ultrastructural	O
+studies	O
+in	O
+the	O
+initial	O
+stage	O
+revealed	O
+significant	O
+lack	O
+of	O
+particles	O
+of	O
+perfused	O
+ruthenium	O
+red	O
+on	O
+the	O
+lamina	O
+rara	O
+externa	O
+and	O
+marked	O
+changes	O
+in	O
+epithelial	O
+cell	O
+cytoplasm	O
+.	O
+
+Therefore	O
+,	O
+it	O
+is	O
+suggested	O
+that	O
+the	O
+administration	O
+of	O
+PS	O
+enhances	O
+the	O
+toxicity	B
+of	O
+AMNS	O
+on	O
+the	O
+glomerulus	O
+and	O
+readily	O
+produces	O
+progressive	O
+FSGS	B
+in	O
+rats	O
+resulting	O
+in	O
+the	O
+end	B
+-	I
+stage	I
+renal	I
+disease	I
+.	O
+
+Theophylline	O
+neurotoxicity	B
+in	O
+pregnant	O
+rats	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+investigation	O
+was	O
+to	O
+determine	O
+whether	O
+the	O
+neurotoxicity	B
+of	O
+theophylline	O
+is	O
+altered	O
+in	O
+advanced	O
+pregnancy	O
+.	O
+
+Sprague	O
+-	O
+Dawley	O
+rats	O
+that	O
+were	O
+20	O
+days	O
+pregnant	O
+and	O
+nonpregnant	O
+rats	O
+of	O
+the	O
+same	O
+age	O
+and	O
+strain	O
+received	O
+infusions	O
+of	O
+aminophylline	O
+until	O
+onset	O
+of	O
+maximal	O
+seizures	B
+which	O
+occurred	O
+after	O
+28	O
+and	O
+30	O
+minutes	O
+respectively	O
+.	O
+
+Theophylline	O
+concentrations	O
+at	O
+this	O
+endpoint	O
+in	O
+serum	O
+(	O
+total	O
+)	O
+and	O
+CSF	O
+were	O
+similar	O
+but	O
+serum	O
+(	O
+free	O
+)	O
+and	O
+brain	O
+concentrations	O
+were	O
+slightly	O
+different	O
+in	O
+pregnant	O
+rats	O
+.	O
+
+Theophylline	O
+serum	O
+protein	O
+binding	O
+determined	O
+by	O
+equilibrium	O
+dialysis	O
+was	O
+lower	O
+in	O
+pregnant	O
+rats	O
+.	O
+
+Fetal	O
+serum	O
+concentrations	O
+at	O
+onset	O
+of	O
+seizures	B
+in	O
+the	O
+mother	O
+were	O
+similar	O
+to	O
+maternal	O
+brain	O
+and	O
+CSF	O
+concentrations	O
+and	O
+correlated	O
+significantly	O
+with	O
+the	O
+former	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+advanced	O
+pregnancy	O
+has	O
+a	O
+negligible	O
+effect	O
+on	O
+the	O
+neurotoxic	B
+response	O
+to	O
+theophylline	O
+in	O
+rats	O
+.	O
+
+Hyperkalemia	B
+induced	O
+by	O
+indomethacin	O
+and	O
+naproxen	O
+and	O
+reversed	O
+by	O
+fludrocortisone	O
+.	O
+
+We	O
+have	O
+described	O
+a	O
+patient	O
+with	O
+severe	O
+rheumatoid	B
+arthritis	I
+and	O
+a	O
+history	O
+of	O
+mefenamic	O
+acid	O
+nephropathy	B
+in	O
+whom	O
+hyperkalemia	B
+and	O
+inappropriate	O
+hypoaldosteronism	B
+were	O
+caused	O
+by	O
+both	O
+indomethacin	O
+and	O
+naproxen	O
+,	O
+without	O
+major	O
+decline	O
+in	O
+renal	O
+function	O
+.	O
+
+It	O
+is	O
+likely	O
+that	O
+preexisting	O
+renal	B
+disease	I
+predisposed	O
+this	O
+patient	O
+to	O
+type	B
+IV	I
+renal	I
+tubular	I
+acidosis	I
+with	O
+prostaglandin	O
+synthetase	O
+inhibitors	O
+.	O
+
+Because	O
+he	O
+was	O
+unable	O
+to	O
+discontinue	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drug	O
+therapy	O
+,	O
+fludrocortisone	O
+was	O
+added	O
+,	O
+correcting	O
+the	O
+hyperkalemia	B
+and	O
+allowing	O
+indomethacin	O
+therapy	O
+to	O
+be	O
+continued	O
+safely	O
+.	O
+
+Hypotension	B
+as	O
+a	O
+manifestation	O
+of	O
+cardiotoxicity	B
+in	O
+three	O
+patients	O
+receiving	O
+cisplatin	O
+and	O
+5	O
+-	O
+fluorouracil	O
+.	O
+
+Cardiac	O
+symptoms	O
+,	O
+including	O
+hypotension	B
+,	O
+developed	O
+in	O
+three	O
+patients	O
+with	O
+advanced	O
+colorectal	B
+carcinoma	I
+while	O
+being	O
+treated	O
+with	O
+cisplatin	O
+(	O
+CDDP	O
+)	O
+and	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+.	O
+
+In	O
+two	O
+patients	O
+,	O
+hypotension	B
+was	O
+associated	O
+with	O
+severe	O
+left	B
+ventricular	I
+dysfunction	I
+.	O
+
+All	O
+three	O
+patients	O
+required	O
+therapy	O
+discontinuation	O
+.	O
+
+Cardiac	O
+enzymes	O
+remained	O
+normal	O
+despite	O
+transient	O
+electrocardiographic	O
+(	O
+EKG	O
+)	O
+changes	O
+.	O
+
+The	O
+presentation	O
+and	O
+cardiac	O
+evaluation	O
+(	O
+hemodynamic	O
+,	O
+echocardiographic	O
+,	O
+and	O
+scintigraphic	O
+)	O
+of	O
+these	O
+patients	O
+suggest	O
+new	O
+manifestations	O
+of	O
+5	O
+-	O
+FU	O
+cardiotoxicity	B
+that	O
+may	O
+be	O
+influenced	O
+by	O
+CDDP	O
+.	O
+
+The	O
+possible	O
+pathophysiologic	O
+mechanisms	O
+are	O
+discussed	O
+.	O
+
+Fatal	O
+aplastic	B
+anemia	I
+in	O
+a	O
+patient	O
+treated	O
+with	O
+carbamazepine	O
+.	O
+
+A	O
+case	O
+of	O
+fatal	O
+aplastic	B
+anemia	I
+due	O
+to	O
+carbamazepine	O
+treatment	O
+in	O
+an	O
+epileptic	B
+woman	O
+is	O
+reported	O
+.	O
+
+Despite	O
+concerns	O
+of	O
+fatal	O
+bone	B
+marrow	I
+toxicity	I
+due	O
+to	O
+carbamazepine	O
+,	O
+this	O
+is	O
+only	O
+the	O
+fourth	O
+documented	O
+and	O
+published	O
+report	O
+.	O
+
+Carbamazepine	O
+is	O
+a	O
+safe	O
+drug	O
+,	O
+but	O
+physicians	O
+and	O
+patients	O
+should	O
+be	O
+aware	O
+of	O
+the	O
+exceedingly	O
+rare	O
+but	O
+potentially	O
+fatal	O
+side	O
+effects	O
+,	O
+better	O
+prevented	O
+by	O
+clinical	O
+than	O
+by	O
+laboratory	O
+monitoring	O
+.	O
+
+Participation	O
+of	O
+a	O
+bulbospinal	O
+serotonergic	O
+pathway	O
+in	O
+the	O
+rat	O
+brain	O
+in	O
+clonidine	O
+-	O
+induced	O
+hypotension	B
+and	O
+bradycardia	B
+.	O
+
+The	O
+effects	O
+of	O
+microinjection	O
+of	O
+clonidine	O
+(	O
+1	O
+-	O
+10	O
+micrograms	O
+in	O
+1	O
+microliter	O
+)	O
+into	O
+a	O
+region	O
+adjacent	O
+to	O
+the	O
+ventrolateral	O
+surface	O
+of	O
+the	O
+medulla	O
+oblongata	O
+on	O
+cardiovascular	O
+function	O
+were	O
+assessed	O
+in	O
+urethane	O
+-	O
+anesthetized	O
+rats	O
+.	O
+
+Intramedullary	O
+administration	O
+of	O
+clonidine	O
+,	O
+but	O
+not	O
+saline	O
+vehicle	O
+,	O
+caused	O
+a	O
+dose	O
+-	O
+dependent	O
+decrease	O
+in	O
+both	O
+the	O
+mean	O
+arterial	O
+pressure	O
+and	O
+the	O
+heart	O
+rate	O
+.	O
+
+The	O
+clonidine	O
+-	O
+induced	O
+hypotension	B
+was	O
+antagonized	O
+by	O
+prior	O
+spinal	O
+transection	O
+,	O
+but	O
+not	O
+bilateral	O
+vagotomy	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+the	O
+clonidine	O
+-	O
+induced	O
+bradycardia	B
+was	O
+antagonized	O
+by	O
+prior	O
+bilateral	O
+vagotomy	O
+,	O
+but	O
+not	O
+spinal	O
+transection	O
+.	O
+
+Furthermore	O
+,	O
+selective	O
+destruction	O
+of	O
+the	O
+spinal	O
+5	O
+-	O
+HT	O
+nerves	O
+,	O
+produced	O
+by	O
+bilateral	O
+spinal	O
+injection	O
+of	O
+5	O
+,	O
+7	O
+-	O
+dihydroxytryptamine	O
+,	O
+reduced	O
+the	O
+magnitude	O
+of	O
+the	O
+vasodepressor	O
+or	O
+the	O
+bradycardiac	B
+responses	O
+to	O
+clonidine	O
+microinjected	O
+into	O
+the	O
+area	O
+near	O
+the	O
+ventrolateral	O
+surface	O
+of	O
+the	O
+medulla	O
+oblongata	O
+in	O
+rats	O
+.	O
+
+The	O
+data	O
+indicate	O
+that	O
+a	O
+bulbospinal	O
+serotonergic	O
+pathway	O
+is	O
+involved	O
+in	O
+development	O
+of	O
+clonidine	O
+-	O
+induced	O
+hypotension	B
+and	O
+bradycardia	B
+.	O
+
+The	O
+induced	O
+hypotension	B
+is	O
+brought	O
+about	O
+by	O
+a	O
+decrease	O
+in	O
+sympathetic	O
+efferent	O
+activity	O
+,	O
+whereas	O
+the	O
+induced	O
+bradycardia	B
+was	O
+due	O
+to	O
+an	O
+increase	O
+in	O
+vagal	O
+efferent	O
+activity	O
+.	O
+
+Hypertension	B
+in	O
+neuroblastoma	B
+induced	O
+by	O
+imipramine	O
+.	O
+
+Hypertension	B
+is	O
+a	O
+well	O
+-	O
+known	O
+finding	O
+in	O
+some	O
+patients	O
+with	O
+neuroblastoma	B
+.	O
+
+However	O
+,	O
+it	O
+has	O
+not	O
+previously	O
+been	O
+described	O
+in	O
+association	O
+with	O
+the	O
+use	O
+of	O
+Imipramine	O
+.	O
+
+We	O
+report	O
+the	O
+occurrence	O
+of	O
+severe	O
+hypertension	B
+(	O
+blood	O
+pressure	O
+190	O
+/	O
+160	O
+)	O
+in	O
+a	O
+4	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+with	O
+neuroblastoma	B
+who	O
+was	O
+given	O
+Imipramine	O
+to	O
+control	O
+a	O
+behavior	B
+disorder	I
+.	O
+
+It	O
+was	O
+determined	O
+later	O
+that	O
+this	O
+patient	O
+'	O
+s	O
+tumor	B
+was	O
+recurring	O
+at	O
+the	O
+time	O
+of	O
+her	O
+hypertensive	B
+episode	O
+.	O
+
+Since	O
+she	O
+had	O
+no	O
+blood	O
+pressure	O
+elevation	O
+at	O
+initial	O
+diagnosis	O
+and	O
+none	O
+following	O
+discontinuation	O
+of	O
+the	O
+Imipramine	O
+(	O
+when	O
+she	O
+was	O
+in	O
+florid	O
+relapse	O
+)	O
+,	O
+we	O
+believe	O
+that	O
+this	O
+drug	O
+rather	O
+than	O
+her	O
+underlying	O
+disease	O
+alone	O
+caused	O
+her	O
+hypertension	B
+.	O
+
+The	O
+mechanism	O
+for	O
+this	O
+reaction	O
+is	O
+believed	O
+to	O
+be	O
+increased	O
+levels	O
+of	O
+vasoactive	O
+catecholamines	O
+due	O
+to	O
+interference	O
+of	O
+their	O
+physiologic	O
+inactivation	O
+by	O
+Imipramine	O
+.	O
+
+From	O
+this	O
+experience	O
+,	O
+we	O
+urge	O
+extreme	O
+caution	O
+in	O
+the	O
+use	O
+of	O
+tricyclic	O
+antidepressants	O
+in	O
+children	O
+with	O
+active	O
+neuroblastoma	B
+.	O
+
+Rechallenge	O
+of	O
+patients	O
+who	O
+developed	O
+oral	B
+candidiasis	I
+or	O
+hoarseness	B
+with	O
+beclomethasone	O
+dipropionate	O
+.	O
+
+Of	O
+158	O
+asthmatic	B
+patients	O
+who	O
+were	O
+placed	O
+on	O
+inhaled	O
+beclomethasone	O
+,	O
+15	O
+(	O
+9	O
+.	O
+5	O
+%	O
+)	O
+developed	O
+either	O
+hoarseness	B
+(	O
+8	O
+)	O
+,	O
+oral	O
+thrush	B
+(	O
+6	O
+)	O
+,	O
+or	O
+both	O
+(	O
+1	O
+)	O
+.	O
+
+When	O
+their	O
+adverse	O
+reactions	O
+subsided	O
+,	O
+seven	O
+of	O
+these	O
+15	O
+patients	O
+were	O
+rechallenged	O
+with	O
+inhaled	O
+beclomethasone	O
+.	O
+
+These	O
+included	O
+five	O
+cases	O
+who	O
+developed	O
+hoarseness	B
+and	O
+three	O
+who	O
+developed	O
+Candidiasis	B
+.	O
+
+One	O
+patient	O
+had	O
+both	O
+.	O
+
+Oral	O
+thrush	B
+did	O
+not	O
+recur	O
+,	O
+but	O
+60	O
+%	O
+(	O
+3	O
+/	O
+5	O
+)	O
+of	O
+patients	O
+with	O
+hoarseness	B
+had	O
+recurrence	O
+.	O
+
+We	O
+conclude	O
+that	O
+patients	O
+may	O
+be	O
+restarted	O
+on	O
+inhaled	O
+beclomethasone	O
+when	O
+clinically	O
+indicated	O
+;	O
+however	O
+,	O
+because	O
+of	O
+the	O
+high	O
+recurrence	O
+rate	O
+,	O
+patients	O
+who	O
+develop	O
+hoarseness	B
+should	O
+not	O
+be	O
+re	O
+-	O
+challenged	O
+.	O
+
+Concomitant	O
+use	O
+of	O
+oral	O
+prednisone	O
+and	O
+topical	O
+beclomethasone	O
+may	O
+increase	O
+the	O
+risk	O
+of	O
+developing	O
+hoarseness	B
+or	O
+candidiasis	B
+.	O
+
+Cyclophosphamide	O
+cardiotoxicity	B
+:	O
+an	O
+analysis	O
+of	O
+dosing	O
+as	O
+a	O
+risk	O
+factor	O
+.	O
+
+Patients	O
+who	O
+undergo	O
+bone	O
+marrow	O
+transplantation	O
+are	O
+generally	O
+immunosuppressed	O
+with	O
+a	O
+dose	O
+of	O
+cyclophosphamide	O
+(	O
+CYA	O
+)	O
+which	O
+is	O
+usually	O
+calculated	O
+based	O
+on	O
+the	O
+patient	O
+'	O
+s	O
+weight	O
+.	O
+
+At	O
+these	O
+high	O
+doses	O
+of	O
+CYA	O
+,	O
+serious	O
+cardiotoxicity	B
+may	O
+occur	O
+,	O
+but	O
+definitive	O
+risk	O
+factors	O
+for	O
+the	O
+development	O
+of	O
+such	O
+cardiotoxicity	B
+have	O
+not	O
+been	O
+described	O
+.	O
+
+Since	O
+chemotherapeutic	O
+agent	O
+toxicity	B
+generally	O
+correlates	O
+with	O
+dose	O
+per	O
+body	O
+surface	O
+area	O
+,	O
+we	O
+retrospectively	O
+calculated	O
+the	O
+dose	O
+of	O
+CYA	O
+in	O
+patients	O
+transplanted	O
+at	O
+our	O
+institution	O
+to	O
+determine	O
+whether	O
+the	O
+incidence	O
+of	O
+CYA	O
+cardiotoxicity	B
+correlated	O
+with	O
+the	O
+dose	O
+per	O
+body	O
+surface	O
+area	O
+.	O
+
+Eighty	O
+patients	O
+who	O
+were	O
+to	O
+receive	O
+CYA	O
+50	O
+mg	O
+/	O
+kg	O
+/	O
+d	O
+for	O
+four	O
+days	O
+as	O
+preparation	O
+for	O
+marrow	O
+grafting	O
+underwent	O
+a	O
+total	O
+of	O
+84	O
+transplants	O
+for	O
+aplastic	B
+anemia	I
+,	O
+Wiskott	B
+-	I
+Aldrich	I
+syndrome	I
+,	O
+or	O
+severe	B
+combined	I
+immunodeficiency	I
+syndrome	I
+.	O
+
+Fourteen	O
+of	O
+84	O
+(	O
+17	O
+%	O
+)	O
+patients	O
+had	O
+symptoms	O
+and	O
+signs	O
+consistent	O
+with	O
+CYA	O
+cardiotoxicity	B
+within	O
+ten	O
+days	O
+of	O
+receiving	O
+1	O
+to	O
+4	O
+doses	O
+of	O
+CYA	O
+.	O
+
+Six	O
+of	O
+the	O
+14	O
+patients	O
+died	O
+with	O
+congestive	B
+heart	I
+failure	I
+.	O
+
+The	O
+dose	O
+of	O
+CYA	O
+per	O
+body	O
+surface	O
+area	O
+was	O
+calculated	O
+for	O
+all	O
+patients	O
+and	O
+the	O
+patients	O
+were	O
+divided	O
+into	O
+two	O
+groups	O
+based	O
+on	O
+daily	O
+CYA	O
+dose	O
+:	O
+Group	O
+1	O
+,	O
+CYA	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+1	O
+.	O
+55	O
+g	O
+/	O
+m2	O
+/	O
+d	O
+;	O
+Group	O
+2	O
+,	O
+CYA	O
+greater	O
+than	O
+1	O
+.	O
+55	O
+g	O
+/	O
+m2	O
+/	O
+d	O
+.	O
+
+Cardiotoxicity	B
+that	O
+was	O
+thought	O
+to	O
+be	O
+related	O
+to	O
+CYA	O
+occurred	O
+in	O
+1	O
+/	O
+32	O
+(	O
+3	O
+%	O
+)	O
+of	O
+patients	O
+in	O
+Group	O
+1	O
+and	O
+in	O
+13	O
+/	O
+52	O
+(	O
+25	O
+%	O
+)	O
+patients	O
+in	O
+Group	O
+2	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+025	O
+)	O
+.	O
+
+Congestive	B
+heart	I
+failure	I
+caused	O
+or	O
+contributed	O
+to	O
+death	O
+in	O
+0	O
+/	O
+32	O
+patients	O
+in	O
+Group	O
+1	O
+v	O
+6	O
+/	O
+52	O
+(	O
+12	O
+%	O
+)	O
+of	O
+patients	O
+in	O
+Group	O
+2	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+25	O
+)	O
+.	O
+
+There	O
+was	O
+no	O
+difference	O
+in	O
+the	O
+rate	O
+of	O
+engraftment	O
+of	O
+evaluable	O
+patients	O
+in	O
+the	O
+two	O
+groups	O
+(	O
+P	O
+greater	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+
+We	O
+conclude	O
+that	O
+the	O
+CYA	O
+cardiotoxicity	B
+correlates	O
+with	O
+CYA	O
+dosage	O
+as	O
+calculated	O
+by	O
+body	O
+surface	O
+area	O
+,	O
+and	O
+that	O
+patients	O
+with	O
+aplastic	B
+anemia	I
+and	O
+immunodeficiencies	B
+can	O
+be	O
+effectively	O
+prepared	O
+for	O
+bone	O
+marrow	O
+grafting	O
+at	O
+a	O
+CYA	O
+dose	O
+of	O
+1	O
+.	O
+55	O
+g	O
+/	O
+m2	O
+/	O
+d	O
+for	O
+four	O
+days	O
+with	O
+a	O
+lower	O
+incidence	O
+of	O
+cardiotoxicity	B
+than	O
+patients	O
+whose	O
+CYA	O
+dosage	O
+is	O
+calculated	O
+based	O
+on	O
+weight	O
+.	O
+
+This	O
+study	O
+reaffirms	O
+the	O
+principle	O
+that	O
+drug	O
+toxicity	B
+correlates	O
+with	O
+dose	O
+per	O
+body	O
+surface	O
+area	O
+.	O
+
+Studies	O
+of	O
+risk	O
+factors	O
+for	O
+aminoglycoside	O
+nephrotoxicity	B
+.	O
+
+The	O
+epidemiology	O
+of	O
+aminoglycoside	O
+-	O
+induced	O
+nephrotoxicity	B
+is	O
+not	O
+fully	O
+understood	O
+.	O
+
+Experimental	O
+studies	O
+in	O
+healthy	O
+human	O
+volunteers	O
+indicate	O
+aminoglycosides	O
+cause	O
+proximal	O
+tubular	O
+damage	O
+in	O
+most	O
+patients	O
+,	O
+but	O
+rarely	O
+,	O
+if	O
+ever	O
+,	O
+cause	O
+glomerular	B
+or	I
+tubular	I
+dysfunction	I
+.	O
+
+Clinical	O
+trials	O
+of	O
+aminoglycosides	O
+in	O
+seriously	O
+ill	O
+patients	O
+indicate	O
+that	O
+the	O
+relative	O
+risk	O
+for	O
+developing	O
+acute	B
+renal	I
+failure	I
+during	O
+therapy	O
+ranges	O
+from	O
+8	O
+to	O
+10	O
+and	O
+that	O
+the	O
+attributable	O
+risk	O
+is	O
+70	O
+%	O
+to	O
+80	O
+%	O
+.	O
+
+Further	O
+analysis	O
+of	O
+these	O
+data	O
+suggests	O
+that	O
+the	O
+duration	O
+of	O
+therapy	O
+,	O
+plasma	O
+aminoglycoside	O
+levels	O
+,	O
+liver	B
+disease	I
+,	O
+advanced	O
+age	O
+,	O
+high	O
+initial	O
+estimated	O
+creatinine	O
+clearance	O
+and	O
+,	O
+possibly	O
+,	O
+female	O
+gender	O
+all	O
+increase	O
+the	O
+risk	O
+for	O
+nephrotoxicity	B
+.	O
+
+Other	O
+causes	O
+of	O
+acute	B
+renal	I
+failure	I
+,	O
+such	O
+as	O
+shock	B
+,	O
+appear	O
+to	O
+have	O
+an	O
+additive	O
+effect	O
+.	O
+
+Predictive	O
+models	O
+have	O
+been	O
+developed	O
+from	O
+these	O
+analyses	O
+that	O
+should	O
+be	O
+useful	O
+for	O
+identifying	O
+patients	O
+at	O
+high	O
+risk	O
+.	O
+
+These	O
+models	O
+may	O
+also	O
+be	O
+useful	O
+in	O
+developing	O
+insights	O
+into	O
+the	O
+pathophysiology	O
+of	O
+aminoglycoside	O
+-	O
+induced	O
+nephrotoxicity	B
+.	O
+
+Central	O
+action	O
+of	O
+narcotic	O
+analgesics	O
+.	O
+
+Part	O
+IV	O
+.	O
+
+Noradrenergic	O
+influences	O
+on	O
+the	O
+activity	O
+of	O
+analgesics	O
+in	O
+rats	O
+.	O
+
+The	O
+effect	O
+of	O
+clonidine	O
+,	O
+naphazoline	O
+and	O
+xylometazoline	O
+on	O
+analgesia	O
+induced	O
+by	O
+morphine	O
+,	O
+codeine	O
+,	O
+fentanyl	O
+and	O
+pentazocine	O
+,	O
+and	O
+on	O
+cataleptic	B
+effect	O
+of	O
+morphine	O
+,	O
+codine	O
+and	O
+fentanyl	O
+was	O
+studied	O
+in	O
+rats	O
+.	O
+
+The	O
+biochemical	O
+assays	O
+on	O
+the	O
+influence	O
+of	O
+four	O
+analgesics	O
+on	O
+the	O
+brain	O
+concentration	O
+and	O
+turnover	O
+of	O
+noradrenaline	O
+(	O
+NA	O
+)	O
+were	O
+also	O
+performed	O
+.	O
+
+It	O
+was	O
+found	O
+that	O
+three	O
+drugs	O
+stimulating	O
+central	O
+NA	O
+receptors	O
+failed	O
+to	O
+affect	O
+the	O
+analgesic	O
+ED50	O
+of	O
+all	O
+antinociceptive	O
+agents	O
+and	O
+they	O
+enhanced	O
+catalepsy	B
+induced	O
+by	O
+morphine	O
+and	O
+fentanyl	O
+.	O
+
+Codeine	O
+catalepsy	B
+was	O
+increased	O
+by	O
+clonidine	O
+and	O
+decreased	O
+by	O
+naphazoline	O
+and	O
+xylometazoline	O
+.	O
+
+The	O
+brain	O
+concentration	O
+of	O
+NA	O
+was	O
+not	O
+changed	O
+by	O
+morphine	O
+and	O
+fentanyl	O
+,	O
+but	O
+one	O
+of	O
+the	O
+doses	O
+of	O
+codeine	O
+(	O
+45	O
+mg	O
+/	O
+kg	O
+)	O
+slightly	O
+enhanced	O
+it	O
+.	O
+
+Pentazocine	O
+dose	O
+-	O
+dependently	O
+decreased	O
+the	O
+brain	O
+level	O
+of	O
+NA	O
+.	O
+
+The	O
+rate	O
+of	O
+NA	O
+turnover	O
+was	O
+not	O
+altered	O
+by	O
+analgesics	O
+except	O
+for	O
+the	O
+higher	O
+dose	O
+of	O
+fentanyl	O
+(	O
+0	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+)	O
+following	O
+which	O
+the	O
+disappearance	O
+of	O
+NA	O
+from	O
+the	O
+brain	O
+was	O
+diminished	O
+.	O
+
+The	O
+results	O
+are	O
+discussed	O
+in	O
+the	O
+light	O
+of	O
+various	O
+and	O
+non	O
+-	O
+uniform	O
+data	O
+from	O
+the	O
+literature	O
+.	O
+
+It	O
+is	O
+suggested	O
+that	O
+in	O
+rats	O
+the	O
+brain	O
+NA	O
+plays	O
+a	O
+less	O
+important	O
+function	O
+than	O
+the	O
+other	O
+monoamines	O
+in	O
+the	O
+behavioural	O
+activity	O
+of	O
+potent	O
+analgesics	O
+.	O
+
+Flurothyl	O
+seizure	B
+thresholds	O
+in	O
+mice	O
+treated	O
+neonatally	O
+with	O
+a	O
+single	O
+injection	O
+of	O
+monosodium	O
+glutamate	O
+(	O
+MSG	O
+)	O
+:	O
+evaluation	O
+of	O
+experimental	O
+parameters	O
+in	O
+flurothyl	O
+seizure	B
+testing	O
+.	O
+
+Monosodium	O
+glutamate	O
+(	O
+MSG	O
+)	O
+administration	O
+to	O
+neonatal	O
+rodents	O
+produces	O
+convulsions	B
+and	O
+results	O
+in	O
+numerous	O
+biochemical	O
+and	O
+behavioral	O
+deficits	O
+.	O
+
+These	O
+studies	O
+were	O
+undertaken	O
+to	O
+determine	O
+if	O
+neonatal	O
+administration	O
+of	O
+MSG	O
+produced	O
+permanent	O
+alterations	O
+in	O
+seizure	B
+susceptibility	O
+,	O
+since	O
+previous	O
+investigations	O
+were	O
+inconclusive	O
+.	O
+
+A	O
+flurothyl	O
+ether	O
+seizure	B
+screening	O
+technique	O
+was	O
+used	O
+to	O
+evaluate	O
+seizure	B
+susceptibility	O
+in	O
+adult	O
+mice	O
+that	O
+received	O
+neonatal	O
+injections	O
+of	O
+MSG	O
+(	O
+4	O
+mg	O
+/	O
+g	O
+and	O
+1	O
+mg	O
+/	O
+g	O
+)	O
+.	O
+
+MSG	O
+treatment	O
+resulted	O
+in	O
+significant	O
+reductions	O
+in	O
+whole	O
+brain	O
+weight	O
+but	O
+did	O
+not	O
+alter	O
+seizure	B
+threshold	O
+.	O
+
+A	O
+naloxone	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+challenge	O
+was	O
+also	O
+ineffective	O
+in	O
+altering	O
+the	O
+seizure	B
+thresholds	O
+of	O
+either	O
+control	O
+of	O
+MSG	O
+-	O
+treated	O
+mice	O
+.	O
+
+Flurothyl	O
+ether	O
+produced	O
+hypothermia	B
+which	O
+was	O
+correlated	O
+with	O
+the	O
+duration	O
+of	O
+flurothyl	O
+exposure	O
+;	O
+however	O
+,	O
+the	O
+relationship	O
+of	O
+hypothermia	B
+to	O
+seizure	B
+induction	O
+was	O
+unclear	O
+.	O
+
+Flurothyl	O
+seizure	B
+testing	O
+proved	O
+to	O
+be	O
+a	O
+rapid	O
+and	O
+reliable	O
+technique	O
+with	O
+which	O
+to	O
+evaluate	O
+seizure	B
+susceptibility	O
+.	O
+
+Susceptibility	O
+to	O
+seizures	B
+produced	O
+by	O
+pilocarpine	O
+in	O
+rats	O
+after	O
+microinjection	O
+of	O
+isoniazid	O
+or	O
+gamma	O
+-	O
+vinyl	O
+-	O
+GABA	O
+into	O
+the	O
+substantia	O
+nigra	O
+.	O
+
+Pilocarpine	O
+,	O
+given	O
+intraperitoneally	O
+to	O
+rats	O
+,	O
+reproduces	O
+the	O
+neuropathological	O
+sequelae	O
+of	O
+temporal	B
+lobe	I
+epilepsy	I
+and	O
+provides	O
+a	O
+relevant	O
+animal	O
+model	O
+for	O
+studying	O
+mechanisms	O
+of	O
+buildup	O
+of	O
+convulsive	B
+activity	O
+and	O
+pathways	O
+operative	O
+in	O
+the	O
+generalization	O
+and	O
+propagation	O
+of	O
+seizures	B
+within	O
+the	O
+forebrain	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+the	O
+effects	O
+of	O
+manipulating	O
+the	O
+activity	O
+of	O
+the	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+(	O
+GABA	O
+)	O
+-	O
+mediated	O
+synaptic	O
+inhibition	O
+within	O
+the	O
+substantia	O
+nigra	O
+on	O
+seizures	B
+produced	O
+by	O
+pilocarpine	O
+in	O
+rats	O
+,	O
+were	O
+investigated	O
+.	O
+
+In	O
+animals	O
+pretreated	O
+with	O
+microinjections	O
+of	O
+isoniazid	O
+,	O
+150	O
+micrograms	O
+,	O
+an	O
+inhibitor	O
+of	O
+activity	O
+of	O
+the	O
+GABA	O
+-	O
+synthesizing	O
+enzyme	O
+,	O
+L	O
+-	O
+glutamic	O
+acid	O
+decarboxylase	O
+,	O
+into	O
+the	O
+substantia	O
+nigra	O
+pars	O
+reticulata	O
+(	O
+SNR	O
+)	O
+,	O
+bilaterally	O
+,	O
+non	O
+-	O
+convulsant	O
+doses	O
+of	O
+pilocarpine	O
+,	O
+100	O
+and	O
+200	O
+mg	O
+/	O
+kg	O
+,	O
+resulted	O
+in	O
+severe	O
+motor	O
+limbic	O
+seizures	B
+and	O
+status	B
+epilepticus	I
+.	O
+
+Electroencephalographic	O
+and	O
+behavioral	O
+monitoring	O
+revealed	O
+a	O
+profound	O
+reduction	O
+of	O
+the	O
+threshold	O
+for	O
+pilocarpine	O
+-	O
+induced	O
+convulsions	B
+.	O
+
+Morphological	O
+analysis	O
+of	O
+frontal	O
+forebrain	O
+sections	O
+with	O
+light	O
+microscopy	O
+revealed	O
+seizure	B
+-	O
+related	O
+damage	O
+to	O
+the	O
+hippocampal	O
+formation	O
+,	O
+thalamus	O
+,	O
+amygdala	O
+,	O
+olfactory	O
+cortex	O
+,	O
+substantia	O
+nigra	O
+and	O
+neocortex	O
+,	O
+which	O
+is	O
+typically	O
+observed	O
+with	O
+pilocarpine	O
+in	O
+doses	O
+exceeding	O
+350	O
+mg	O
+/	O
+kg	O
+.	O
+
+Bilateral	O
+intrastriatal	O
+injections	O
+of	O
+isoniazid	O
+did	O
+not	O
+augment	O
+seizures	B
+produced	O
+by	O
+pilocarpine	O
+,	O
+200	O
+mg	O
+/	O
+kg	O
+.	O
+
+Application	O
+of	O
+an	O
+irreversible	O
+inhibitor	O
+of	O
+GABA	O
+transaminase	O
+,	O
+gamma	O
+-	O
+vinyl	O
+-	O
+GABA	O
+(	O
+D	O
+,	O
+L	O
+-	O
+4	O
+-	O
+amino	O
+-	O
+hex	O
+-	O
+5	O
+-	O
+enoic	O
+acid	O
+)	O
+,	O
+5	O
+micrograms	O
+,	O
+into	O
+the	O
+SNR	O
+,	O
+bilaterally	O
+,	O
+suppressed	O
+the	O
+appearance	O
+of	O
+electrographic	O
+and	O
+behavioral	O
+seizures	B
+produced	O
+by	O
+pilocarpine	O
+,	O
+380	O
+mg	O
+/	O
+kg	O
+.	O
+
+This	O
+treatment	O
+was	O
+also	O
+sufficient	O
+to	O
+protect	O
+animals	O
+from	O
+the	O
+occurrence	O
+of	O
+brain	B
+damage	I
+.	O
+
+Microinjections	O
+of	O
+gamma	O
+-	O
+vinyl	O
+-	O
+GABA	O
+,	O
+5	O
+micrograms	O
+,	O
+into	O
+the	O
+dorsal	O
+striatum	O
+,	O
+bilaterally	O
+,	O
+failed	O
+to	O
+prevent	O
+the	O
+development	O
+of	O
+convulsions	B
+produced	O
+by	O
+pilocarpine	O
+,	O
+380	O
+mg	O
+/	O
+kg	O
+.	O
+
+The	O
+results	O
+demonstrate	O
+that	O
+the	O
+threshold	O
+for	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+in	O
+rats	O
+is	O
+subjected	O
+to	O
+the	O
+regulation	O
+of	O
+the	O
+GABA	O
+-	O
+mediated	O
+synaptic	O
+inhibition	O
+within	O
+the	O
+substantia	O
+nigra	O
+.	O
+
+Human	O
+and	O
+canine	O
+ventricular	O
+vasoactive	O
+intestinal	O
+polypeptide	O
+:	O
+decrease	O
+with	O
+heart	B
+failure	I
+.	O
+
+Vasoactive	O
+intestinal	O
+polypeptide	O
+(	O
+VIP	O
+)	O
+is	O
+a	O
+systemic	O
+and	O
+coronary	O
+vasodilator	O
+that	O
+may	O
+have	O
+positive	O
+inotropic	O
+properties	O
+.	O
+
+Myocardial	O
+levels	O
+of	O
+VIP	O
+were	O
+assayed	O
+before	O
+and	O
+after	O
+the	O
+development	O
+of	O
+heart	B
+failure	I
+in	O
+two	O
+canine	O
+models	O
+.	O
+
+In	O
+the	O
+first	O
+,	O
+cobalt	O
+cardiomyopathy	B
+was	O
+induced	O
+in	O
+eight	O
+dogs	O
+;	O
+VIP	O
+(	O
+by	O
+radioimmunoassay	O
+)	O
+decreased	O
+from	O
+35	O
++	O
+/	O
+-	O
+11	O
+pg	O
+/	O
+mg	O
+protein	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+)	O
+to	O
+5	O
++	O
+/	O
+-	O
+4	O
+pg	O
+/	O
+mg	O
+protein	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+In	O
+six	O
+dogs	O
+with	O
+doxorubicin	O
+-	O
+induced	O
+heart	B
+failure	I
+,	O
+VIP	O
+decreased	O
+from	O
+31	O
++	O
+/	O
+-	O
+7	O
+to	O
+11	O
++	O
+/	O
+-	O
+4	O
+pg	O
+/	O
+mg	O
+protein	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+In	O
+addition	O
+,	O
+VIP	O
+content	O
+of	O
+left	O
+ventricular	O
+muscle	O
+of	O
+resected	O
+failing	O
+hearts	O
+in	O
+10	O
+patients	O
+receiving	O
+a	O
+heart	O
+transplant	O
+was	O
+compared	O
+with	O
+the	O
+papillary	O
+muscles	O
+in	O
+14	O
+patients	O
+(	O
+five	O
+with	O
+rheumatic	B
+disease	I
+,	O
+nine	O
+with	O
+myxomatous	B
+degeneration	I
+)	O
+receiving	O
+mitral	O
+valve	O
+prostheses	O
+.	O
+
+The	O
+lowest	O
+myocardial	O
+VIP	O
+concentration	O
+was	O
+found	O
+in	O
+the	O
+hearts	O
+of	O
+patients	O
+with	O
+coronary	B
+disease	I
+(	O
+one	O
+patient	O
+receiving	O
+a	O
+transplant	O
+and	O
+three	O
+receiving	O
+mitral	O
+prostheses	O
+)	O
+(	O
+6	O
+.	O
+3	O
++	O
+/	O
+-	O
+1	O
+.	O
+9	O
+pg	O
+/	O
+mg	O
+protein	O
+)	O
+.	O
+
+The	O
+other	O
+patients	O
+undergoing	O
+transplantation	O
+had	O
+an	O
+average	O
+ejection	O
+fraction	O
+of	O
+17	O
+%	O
++	O
+/	O
+-	O
+6	O
+%	O
+and	O
+a	O
+VIP	O
+level	O
+of	O
+8	O
+.	O
+8	O
++	O
+/	O
+-	O
+3	O
+.	O
+9	O
+pg	O
+/	O
+mg	O
+protein	O
+.	O
+
+The	O
+hearts	O
+without	O
+coronary	B
+artery	I
+disease	I
+(	O
+average	O
+ejection	O
+fraction	O
+of	O
+this	O
+group	O
+62	O
+%	O
++	O
+/	O
+-	O
+10	O
+%	O
+)	O
+had	O
+a	O
+VIP	O
+concentration	O
+of	O
+14	O
+.	O
+1	O
++	O
+/	O
+-	O
+7	O
+.	O
+9	O
+pg	O
+/	O
+mg	O
+protein	O
+,	O
+and	O
+this	O
+was	O
+greater	O
+than	O
+in	O
+hearts	O
+of	O
+the	O
+patients	O
+with	O
+coronary	B
+disease	I
+and	O
+the	O
+hearts	O
+of	O
+patients	O
+receiving	O
+a	O
+transplant	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Myocardial	O
+catecholamines	O
+were	O
+also	O
+determined	O
+in	O
+14	O
+subjects	O
+;	O
+a	O
+weak	O
+correlation	O
+(	O
+r	O
+=	O
+0	O
+.	O
+57	O
+,	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+between	O
+the	O
+tissue	O
+concentrations	O
+of	O
+VIP	O
+and	O
+norepinephrine	O
+was	O
+noted	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Non	O
+-	O
+invasive	O
+detection	O
+of	O
+coronary	B
+artery	I
+disease	I
+by	O
+body	O
+surface	O
+electrocardiographic	O
+mapping	O
+after	O
+dipyridamole	O
+infusion	O
+.	O
+
+Electrocardiographic	O
+changes	O
+after	O
+dipyridamole	O
+infusion	O
+(	O
+0	O
+.	O
+568	O
+mg	O
+/	O
+kg	O
+/	O
+4	O
+min	O
+)	O
+were	O
+studied	O
+in	O
+41	O
+patients	O
+with	O
+coronary	B
+artery	I
+disease	I
+and	O
+compared	O
+with	O
+those	O
+after	O
+submaximal	O
+treadmill	O
+exercise	O
+by	O
+use	O
+of	O
+the	O
+body	O
+surface	O
+mapping	O
+technique	O
+.	O
+
+Patients	O
+were	O
+divided	O
+into	O
+three	O
+groups	O
+;	O
+19	O
+patients	O
+without	O
+myocardial	B
+infarction	I
+(	O
+non	O
+-	O
+MI	B
+group	O
+)	O
+,	O
+14	O
+with	O
+anterior	B
+infarction	I
+(	O
+ANT	B
+-	I
+MI	I
+)	O
+and	O
+eight	O
+with	O
+inferior	B
+infarction	I
+(	O
+INF	B
+-	I
+MI	I
+)	O
+.	O
+
+Eighty	O
+-	O
+seven	O
+unipolar	O
+electrocardiograms	O
+(	O
+ECGs	O
+)	O
+distributed	O
+over	O
+the	O
+entire	O
+thoracic	O
+surface	O
+were	O
+simultaneously	O
+recorded	O
+.	O
+
+After	O
+dipyridamole	O
+,	O
+ischemic	B
+ST	O
+-	O
+segment	O
+depression	B
+(	O
+0	O
+.	O
+05	O
+mV	O
+or	O
+more	O
+)	O
+was	O
+observed	O
+in	O
+84	O
+%	O
+of	O
+the	O
+non	O
+-	O
+MI	B
+group	O
+,	O
+29	O
+%	O
+of	O
+the	O
+ANT	B
+-	I
+MI	I
+group	O
+,	O
+63	O
+%	O
+of	O
+the	O
+INF	B
+-	I
+MI	I
+group	O
+and	O
+61	O
+%	O
+of	O
+the	O
+total	O
+population	O
+.	O
+
+Exercise	O
+-	O
+induced	O
+ST	O
+depression	B
+was	O
+observed	O
+in	O
+84	O
+%	O
+of	O
+the	O
+non	O
+-	O
+MI	B
+group	O
+,	O
+43	O
+%	O
+of	O
+the	O
+ANT	B
+-	I
+MI	I
+group	O
+,	O
+38	O
+%	O
+of	O
+the	O
+INF	B
+-	I
+MI	I
+group	O
+and	O
+61	O
+%	O
+of	O
+the	O
+total	O
+.	O
+
+For	O
+individual	O
+patients	O
+,	O
+there	O
+were	O
+no	O
+obvious	O
+differences	O
+between	O
+the	O
+body	O
+surface	O
+distribution	O
+of	O
+ST	O
+depression	B
+in	O
+both	O
+tests	O
+.	O
+
+The	O
+increase	O
+in	O
+pressure	O
+rate	O
+product	O
+after	O
+dipyridamole	O
+was	O
+significantly	O
+less	O
+than	O
+that	O
+during	O
+the	O
+treadmill	O
+exercise	O
+.	O
+
+The	O
+data	O
+suggest	O
+that	O
+the	O
+dipyridamole	O
+-	O
+induced	O
+myocardial	B
+ischemia	I
+is	O
+caused	O
+by	O
+the	O
+inhomogenous	O
+distribution	O
+of	O
+myocardial	O
+blood	O
+flow	O
+.	O
+
+We	O
+conclude	O
+that	O
+the	O
+dipyridamole	O
+ECG	O
+test	O
+is	O
+as	O
+useful	O
+as	O
+the	O
+exercise	O
+ECG	O
+test	O
+for	O
+the	O
+assessment	O
+of	O
+coronary	B
+artery	I
+disease	I
+.	O
+
+Bradycardia	B
+after	O
+high	O
+-	O
+dose	O
+intravenous	O
+methylprednisolone	O
+therapy	O
+.	O
+
+In	O
+5	O
+consecutive	O
+patients	O
+with	O
+rheumatoid	B
+arthritis	I
+who	O
+received	O
+intravenous	O
+high	O
+-	O
+dose	O
+methylprednisolone	O
+(	O
+MP	O
+)	O
+therapy	O
+(	O
+1	O
+g	O
+daily	O
+for	O
+2	O
+or	O
+3	O
+consecutive	O
+days	O
+)	O
+,	O
+a	O
+decline	O
+in	O
+pulse	O
+rate	O
+was	O
+observed	O
+,	O
+most	O
+pronounced	O
+on	O
+day	O
+4	O
+.	O
+
+In	O
+one	O
+of	O
+the	O
+5	O
+patients	O
+the	O
+bradycardia	B
+was	O
+associated	O
+with	O
+complaints	O
+of	O
+substernal	O
+pressure	O
+.	O
+
+Reversal	O
+to	O
+normal	O
+heart	O
+rate	O
+was	O
+found	O
+on	O
+day	O
+7	O
+.	O
+
+Electrocardiographic	O
+registrations	O
+showed	O
+sinus	B
+bradycardia	I
+in	O
+all	O
+cases	O
+.	O
+
+No	O
+significant	O
+changes	O
+in	O
+plasma	O
+concentrations	O
+of	O
+electrolytes	O
+were	O
+found	O
+.	O
+
+Careful	O
+observation	O
+of	O
+patients	O
+receiving	O
+high	O
+-	O
+dose	O
+MP	O
+is	O
+recommended	O
+.	O
+
+High	O
+-	O
+dose	O
+MP	O
+may	O
+be	O
+contraindicated	O
+in	O
+patients	O
+with	O
+known	O
+heart	B
+disease	I
+.	O
+
+Two	O
+cases	O
+of	O
+downbeat	B
+nystagmus	I
+and	O
+oscillopsia	B
+associated	O
+with	O
+carbamazepine	O
+.	O
+
+Downbeat	B
+nystagmus	I
+is	O
+often	O
+associated	O
+with	O
+structural	O
+lesions	O
+at	O
+the	O
+craniocervical	O
+junction	O
+,	O
+but	O
+has	O
+occasionally	O
+been	O
+reported	O
+as	O
+a	O
+manifestation	O
+of	O
+metabolic	O
+imbalance	O
+or	O
+drug	O
+intoxication	O
+.	O
+
+We	O
+recorded	O
+the	O
+eye	O
+movements	O
+of	O
+two	O
+patients	O
+with	O
+reversible	O
+downbeat	B
+nystagmus	I
+related	O
+to	O
+carbamazepine	O
+therapy	O
+.	O
+
+The	O
+nystagmus	B
+of	O
+both	O
+patients	O
+resolved	O
+after	O
+reduction	O
+of	O
+the	O
+serum	O
+carbamazepine	O
+levels	O
+.	O
+
+Neuroradiologic	O
+investigations	O
+including	O
+magnetic	O
+resonance	O
+imaging	O
+scans	O
+in	O
+both	O
+patients	O
+showed	O
+no	O
+evidence	O
+of	O
+intracranial	O
+abnormality	O
+.	O
+
+In	O
+patients	O
+with	O
+downbeat	B
+nystagmus	I
+who	O
+are	O
+taking	O
+anticonvulsant	O
+medications	O
+,	O
+consideration	O
+should	O
+be	O
+given	O
+to	O
+reduction	O
+in	O
+dose	O
+before	O
+further	O
+investigation	O
+is	O
+undertaken	O
+.	O
+
+Improvement	O
+by	O
+denopamine	O
+(	O
+TA	O
+-	O
+064	O
+)	O
+of	O
+pentobarbital	O
+-	O
+induced	O
+cardiac	B
+failure	I
+in	O
+the	O
+dog	O
+heart	O
+-	O
+lung	O
+preparation	O
+.	O
+
+The	O
+efficacy	O
+of	O
+denopamine	O
+,	O
+an	O
+orally	O
+active	O
+beta	O
+1	O
+-	O
+adrenoceptor	O
+agonist	O
+,	O
+in	O
+improving	O
+cardiac	B
+failure	I
+was	O
+assessed	O
+in	O
+dog	O
+heart	O
+-	O
+lung	O
+preparations	O
+.	O
+
+Cardiac	O
+functions	O
+depressed	O
+by	O
+pentobarbital	O
+(	O
+118	O
++	O
+/	O
+-	O
+28	O
+mg	O
+;	O
+mean	O
+value	O
++	O
+/	O
+-	O
+SD	O
+)	O
+such	O
+that	O
+cardiac	O
+output	O
+and	O
+maximum	O
+rate	O
+of	O
+rise	O
+of	O
+left	O
+ventricular	O
+pressure	O
+(	O
+LV	O
+dP	O
+/	O
+dt	O
+max	O
+)	O
+had	O
+been	O
+reduced	O
+by	O
+about	O
+35	O
+%	O
+and	O
+26	O
+%	O
+of	O
+the	O
+respective	O
+controls	O
+were	O
+improved	O
+by	O
+denopamine	O
+(	O
+10	O
+-	O
+300	O
+micrograms	O
+)	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+.	O
+
+With	O
+100	O
+micrograms	O
+denopamine	O
+,	O
+almost	O
+complete	O
+restoration	O
+of	O
+cardiac	O
+performance	O
+was	O
+attained	O
+,	O
+associated	O
+with	O
+a	O
+slight	O
+increase	O
+in	O
+heart	O
+rate	O
+.	O
+
+No	O
+arrhythmias	B
+were	O
+induced	O
+by	O
+these	O
+doses	O
+of	O
+denopamine	O
+.	O
+
+The	O
+results	O
+warrant	O
+clinical	O
+trials	O
+of	O
+denopamine	O
+in	O
+the	O
+treatment	O
+of	O
+cardiac	B
+failure	I
+.	O
+
+Clonazepam	O
+monotherapy	O
+for	O
+epilepsy	B
+in	O
+childhood	O
+.	O
+
+Sixty	O
+patients	O
+(	O
+age	O
+-	O
+range	O
+one	O
+month	O
+to	O
+14	O
+years	O
+)	O
+with	O
+other	O
+types	O
+of	O
+epilepsy	B
+than	O
+infantile	B
+spasms	I
+were	O
+treated	O
+with	O
+clonazepam	O
+.	O
+
+Disappearance	O
+of	O
+seizures	B
+and	O
+normalization	O
+of	O
+abnormal	O
+EEG	O
+with	O
+disappearance	O
+of	O
+seizures	B
+were	O
+recognized	O
+in	O
+77	O
+%	O
+and	O
+50	O
+%	O
+,	O
+respectively	O
+.	O
+
+Seizures	B
+disappeared	O
+in	O
+71	O
+%	O
+of	O
+the	O
+patients	O
+with	O
+generalized	O
+seizures	B
+and	O
+89	O
+%	O
+of	O
+partial	O
+seizures	B
+.	O
+
+Improvement	O
+of	O
+abnormal	O
+EEG	O
+was	O
+noticed	O
+in	O
+76	O
+%	O
+of	O
+diffuse	O
+paroxysms	O
+and	O
+in	O
+67	O
+%	O
+of	O
+focal	O
+paroxysms	O
+.	O
+
+In	O
+excellent	O
+cases	O
+,	O
+mean	O
+effective	O
+dosages	O
+were	O
+0	O
+.	O
+086	O
++	O
+/	O
+-	O
+0	O
+.	O
+021	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+in	O
+infants	O
+and	O
+0	O
+.	O
+057	O
++	O
+/	O
+-	O
+0	O
+.	O
+022	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+in	O
+schoolchildren	O
+,	O
+this	O
+difference	O
+was	O
+statistically	O
+significant	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+005	O
+)	O
+.	O
+
+The	O
+incidence	O
+of	O
+side	O
+effects	O
+such	O
+as	O
+drowsiness	B
+and	O
+ataxia	B
+was	O
+only	O
+5	O
+%	O
+.	O
+
+Postmarketing	O
+study	O
+of	O
+timolol	O
+-	O
+hydrochlorothiazide	O
+antihypertensive	O
+therapy	O
+.	O
+
+A	O
+postmarketing	O
+surveillance	O
+study	O
+was	O
+conducted	O
+to	O
+determine	O
+the	O
+safety	O
+and	O
+efficacy	O
+of	O
+a	O
+fixed	O
+-	O
+ratio	O
+combination	O
+containing	O
+10	O
+mg	O
+of	O
+timolol	O
+maleate	O
+and	O
+25	O
+mg	O
+of	O
+hydrochlorothiazide	O
+,	O
+administered	O
+twice	O
+daily	O
+for	O
+one	O
+month	O
+to	O
+hypertensive	B
+patients	O
+.	O
+
+Data	O
+on	O
+9	O
+,	O
+037	O
+patients	O
+were	O
+collected	O
+by	O
+1	O
+,	O
+455	O
+participating	O
+physicians	O
+.	O
+
+Mean	O
+systolic	O
+blood	O
+pressure	O
+decreased	O
+25	O
+mmHg	O
+and	O
+mean	O
+diastolic	O
+blood	O
+pressure	O
+declined	O
+15	O
+mmHg	O
+after	O
+one	O
+month	O
+of	O
+timolol	O
+-	O
+hydrochlorothiazide	O
+therapy	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+01	O
+,	O
+both	O
+comparisons	O
+)	O
+.	O
+
+Age	O
+,	O
+race	O
+,	O
+and	O
+sex	O
+appeared	O
+to	O
+have	O
+no	O
+influence	O
+on	O
+the	O
+decrease	O
+in	O
+blood	O
+pressure	O
+.	O
+
+The	O
+antihypertensive	O
+effect	O
+of	O
+the	O
+drug	O
+was	O
+greater	O
+in	O
+patients	O
+with	O
+more	O
+severe	O
+hypertension	B
+.	O
+
+Overall	O
+,	O
+1	O
+,	O
+453	O
+patients	O
+experienced	O
+a	O
+total	O
+of	O
+2	O
+,	O
+658	O
+adverse	O
+events	O
+,	O
+the	O
+most	O
+common	O
+being	O
+fatigue	B
+,	O
+dizziness	B
+,	O
+and	O
+weakness	B
+.	O
+
+Treatment	O
+in	O
+590	O
+patients	O
+was	O
+discontinued	O
+because	O
+of	O
+adverse	O
+events	O
+.	O
+
+Salicylate	O
+nephropathy	B
+in	O
+the	O
+Gunn	O
+rat	O
+:	O
+potential	O
+role	O
+of	O
+prostaglandins	O
+.	O
+
+We	O
+examined	O
+the	O
+potential	O
+role	O
+of	O
+prostaglandins	O
+in	O
+the	O
+development	O
+of	O
+analgesic	O
+nephropathy	B
+in	O
+the	O
+Gunn	O
+strain	O
+of	O
+rat	O
+.	O
+
+The	O
+homozygous	O
+Gunn	O
+rats	O
+have	O
+unconjugated	O
+hyperbilirubinemia	B
+due	O
+to	O
+the	O
+absence	O
+of	O
+glucuronyl	O
+transferase	O
+,	O
+leading	O
+to	O
+marked	O
+bilirubin	O
+deposition	O
+in	O
+renal	O
+medulla	O
+and	O
+papilla	O
+.	O
+
+These	O
+rats	O
+are	O
+also	O
+highly	O
+susceptible	O
+to	O
+develop	O
+papillary	B
+necrosis	I
+with	O
+analgesic	O
+administration	O
+.	O
+
+We	O
+used	O
+homozygous	O
+(	O
+jj	O
+)	O
+and	O
+phenotypically	O
+normal	O
+heterozygous	O
+(	O
+jJ	O
+)	O
+animals	O
+.	O
+
+Four	O
+groups	O
+of	O
+rats	O
+(	O
+n	O
+=	O
+7	O
+)	O
+were	O
+studied	O
+:	O
+jj	O
+and	O
+jJ	O
+rats	O
+treated	O
+either	O
+with	O
+aspirin	O
+300	O
+mg	O
+/	O
+kg	O
+every	O
+other	O
+day	O
+or	O
+sham	O
+-	O
+treated	O
+.	O
+
+After	O
+one	O
+week	O
+,	O
+slices	O
+of	O
+cortex	O
+,	O
+outer	O
+and	O
+inner	O
+medulla	O
+from	O
+one	O
+kidney	O
+were	O
+incubated	O
+in	O
+buffer	O
+and	O
+prostaglandin	O
+synthesis	O
+was	O
+determined	O
+by	O
+radioimmunoassay	O
+.	O
+
+The	O
+other	O
+kidney	O
+was	O
+examined	O
+histologically	O
+.	O
+
+A	O
+marked	O
+corticomedullary	O
+gradient	O
+of	O
+prostaglandin	O
+synthesis	O
+was	O
+observed	O
+in	O
+all	O
+groups	O
+.	O
+
+PGE2	O
+synthesis	O
+was	O
+significantly	O
+higher	O
+in	O
+outer	O
+medulla	O
+,	O
+but	O
+not	O
+cortex	O
+or	O
+inner	O
+medulla	O
+,	O
+of	O
+jj	O
+(	O
+38	O
++	O
+/	O
+-	O
+6	O
+ng	O
+/	O
+mg	O
+prot	O
+)	O
+than	O
+jJ	O
+rats	O
+(	O
+15	O
++	O
+/	O
+-	O
+3	O
+)	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+Aspirin	O
+treatment	O
+reduced	O
+PGE2	O
+synthesis	O
+in	O
+all	O
+regions	O
+,	O
+but	O
+outer	O
+medullary	O
+PGE2	O
+remained	O
+higher	O
+in	O
+jj	O
+(	O
+18	O
++	O
+/	O
+-	O
+3	O
+)	O
+than	O
+jJ	O
+rats	O
+(	O
+9	O
++	O
+/	O
+-	O
+2	O
+)	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+PGF2	O
+alpha	O
+was	O
+also	O
+significantly	O
+higher	O
+in	O
+the	O
+outer	O
+medulla	O
+of	O
+jj	O
+rats	O
+with	O
+and	O
+without	O
+aspirin	O
+administration	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+changes	O
+in	O
+renal	O
+prostaglandin	O
+synthesis	O
+were	O
+accompanied	O
+by	O
+evidence	O
+of	O
+renal	B
+damage	I
+in	O
+aspirin	O
+-	O
+treated	O
+jj	O
+but	O
+not	O
+jJ	O
+rats	O
+as	O
+evidenced	O
+by	O
+:	O
+increased	O
+incidence	O
+and	O
+severity	O
+of	O
+hematuria	B
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+;	O
+increased	O
+serum	O
+creatinine	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+;	O
+and	O
+increase	O
+in	O
+outer	O
+medullary	O
+histopathologic	O
+lesions	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+005	O
+compared	O
+to	O
+either	O
+sham	O
+-	O
+treated	O
+jj	O
+or	O
+aspirin	O
+-	O
+treated	O
+jJ	O
+)	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+enhanced	O
+prostaglandin	O
+synthesis	O
+contributes	O
+to	O
+maintenance	O
+of	O
+renal	O
+function	O
+and	O
+morphological	O
+integrity	O
+,	O
+and	O
+that	O
+inhibition	O
+of	O
+prostaglandin	O
+synthesis	O
+may	O
+lead	O
+to	O
+pathological	B
+renal	I
+medullary	I
+lesions	I
+and	O
+deterioration	B
+of	I
+renal	I
+function	I
+.	O
+
+Prophylactic	O
+lidocaine	O
+in	O
+the	O
+early	O
+phase	O
+of	O
+suspected	O
+myocardial	B
+infarction	I
+.	O
+
+Four	O
+hundred	O
+two	O
+patients	O
+with	O
+suspected	O
+myocardial	B
+infarction	I
+seen	O
+within	O
+6	O
+hours	O
+of	O
+the	O
+onset	O
+of	O
+symptoms	O
+entered	O
+a	O
+double	O
+-	O
+blind	O
+randomized	O
+trial	O
+of	O
+lidocaine	O
+vs	O
+placebo	O
+.	O
+
+During	O
+the	O
+1	O
+hour	O
+after	O
+administration	O
+of	O
+the	O
+drug	O
+the	O
+incidence	O
+of	O
+ventricular	B
+fibrillation	I
+or	O
+sustained	O
+ventricular	B
+tachycardia	I
+among	O
+the	O
+204	O
+patients	O
+with	O
+acute	O
+myocardial	B
+infarction	I
+was	O
+low	O
+,	O
+1	O
+.	O
+5	O
+%	O
+.	O
+
+Lidocaine	O
+,	O
+given	O
+in	O
+a	O
+300	O
+mg	O
+dose	O
+intramuscularly	O
+followed	O
+by	O
+100	O
+mg	O
+intravenously	O
+,	O
+did	O
+not	O
+prevent	O
+sustained	O
+ventricular	B
+tachycardia	I
+,	O
+although	O
+there	O
+was	O
+a	O
+significant	O
+reduction	O
+in	O
+the	O
+number	O
+of	O
+patients	O
+with	O
+warning	O
+arrhythmias	B
+between	O
+15	O
+and	O
+45	O
+minutes	O
+after	O
+the	O
+administration	O
+of	O
+lidocaine	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+average	O
+plasma	O
+lidocaine	O
+level	O
+10	O
+minutes	O
+after	O
+administration	O
+for	O
+patients	O
+without	O
+a	O
+myocardial	B
+infarction	I
+was	O
+significantly	O
+higher	O
+than	O
+that	O
+for	O
+patients	O
+with	O
+an	O
+acute	O
+infarction	B
+.	O
+
+The	O
+mean	O
+plasma	O
+lidocaine	O
+level	O
+of	O
+patients	O
+on	O
+beta	O
+-	O
+blocking	O
+agents	O
+was	O
+no	O
+different	O
+from	O
+that	O
+in	O
+patients	O
+not	O
+on	O
+beta	O
+blocking	O
+agents	O
+.	O
+
+During	O
+the	O
+1	O
+-	O
+hour	O
+study	O
+period	O
+,	O
+the	O
+incidence	O
+of	O
+central	O
+nervous	O
+system	O
+side	O
+effects	O
+was	O
+significantly	O
+greater	O
+in	O
+the	O
+lidocaine	O
+group	O
+,	O
+hypotension	B
+occurred	O
+in	O
+11	O
+patients	O
+,	O
+nine	O
+of	O
+whom	O
+had	O
+received	O
+lidocaine	O
+,	O
+and	O
+four	O
+patients	O
+died	O
+from	O
+asystole	B
+,	O
+three	O
+of	O
+whom	O
+had	O
+had	O
+lidocaine	O
+.	O
+
+We	O
+cannot	O
+advocate	O
+the	O
+administration	O
+of	O
+lidocaine	O
+prophylactically	O
+in	O
+the	O
+early	O
+hours	O
+of	O
+suspected	O
+myocardial	B
+infarction	I
+.	O
+
+Evidence	O
+for	O
+a	O
+cholinergic	O
+role	O
+in	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+.	O
+
+Experiments	O
+in	O
+mice	O
+tested	O
+previous	O
+evidence	O
+that	O
+activation	O
+of	O
+cholinergic	O
+systems	O
+promotes	O
+catalepsy	B
+and	O
+that	O
+cholinergic	O
+mechanisms	O
+need	O
+to	O
+be	O
+intact	O
+for	O
+full	O
+expression	O
+of	O
+neuroleptic	O
+-	O
+induced	O
+catalepsy	B
+.	O
+
+Large	O
+doses	O
+of	O
+the	O
+cholinomimetic	O
+,	O
+pilocarpine	O
+,	O
+could	O
+induce	O
+catalepsy	B
+when	O
+peripheral	O
+cholinergic	O
+receptors	O
+were	O
+blocked	O
+.	O
+
+Low	O
+doses	O
+of	O
+pilocarpine	O
+caused	O
+a	O
+pronounced	O
+enhancement	O
+of	O
+the	O
+catalepsy	B
+that	O
+was	O
+induced	O
+by	O
+the	O
+dopaminergic	O
+blocker	O
+,	O
+haloperidol	O
+.	O
+
+A	O
+muscarinic	O
+receptor	O
+blocker	O
+,	O
+atropine	O
+,	O
+disrupted	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+.	O
+
+Intracranial	O
+injection	O
+of	O
+an	O
+acetylcholine	O
+-	O
+synthesis	O
+inhibitor	O
+,	O
+hemicholinium	O
+,	O
+prevented	O
+the	O
+catalepsy	B
+that	O
+is	O
+usually	O
+induced	O
+by	O
+haloperidol	O
+.	O
+
+These	O
+findings	O
+suggest	O
+the	O
+hypothesis	O
+that	O
+the	O
+catalepsy	B
+that	O
+is	O
+produced	O
+by	O
+neuroleptics	O
+such	O
+as	O
+haloperidol	O
+is	O
+actually	O
+mediated	O
+by	O
+intrinsic	O
+central	O
+cholinergic	O
+systems	O
+.	O
+
+Alternatively	O
+,	O
+activation	O
+of	O
+central	O
+cholinergic	O
+systems	O
+could	O
+promote	O
+catalepsy	B
+by	O
+suppression	O
+of	O
+dopaminergic	O
+systems	O
+.	O
+
+Cardiovascular	B
+dysfunction	I
+and	O
+hypersensitivity	B
+to	O
+sodium	O
+pentobarbital	O
+induced	O
+by	O
+chronic	O
+barium	O
+chloride	O
+ingestion	O
+.	O
+
+Barium	O
+-	O
+supplemented	O
+Long	O
+-	O
+Evans	O
+hooded	O
+rats	O
+were	O
+characterized	O
+by	O
+a	O
+persistent	O
+hypertension	B
+that	O
+was	O
+evident	O
+after	O
+1	O
+month	O
+of	O
+barium	O
+(	O
+100	O
+micrograms	O
+/	O
+ml	O
+mineral	O
+fortified	O
+water	O
+)	O
+treatment	O
+.	O
+
+Analysis	O
+of	O
+in	O
+vivo	O
+myocardial	O
+excitability	O
+,	O
+contractility	O
+,	O
+and	O
+metabolic	O
+characteristics	O
+at	O
+16	O
+months	O
+revealed	O
+other	O
+significant	O
+barium	O
+-	O
+induced	O
+disturbances	B
+within	I
+the	I
+cardiovascular	I
+system	I
+.	O
+
+The	O
+most	O
+distinctive	O
+aspect	O
+of	O
+the	O
+barium	O
+effect	O
+was	O
+a	O
+demonstrated	O
+hypersensitivity	B
+of	O
+the	O
+cardiovascular	O
+system	O
+to	O
+sodium	O
+pentobarbital	O
+.	O
+
+Under	O
+barbiturate	O
+anesthesia	O
+,	O
+virtually	O
+all	O
+of	O
+the	O
+myocardial	O
+contractile	O
+indices	O
+were	O
+depressed	O
+significantly	O
+in	O
+barium	O
+-	O
+exposed	O
+rats	O
+relative	O
+to	O
+the	O
+corresponding	O
+control	O
+-	O
+fed	O
+rats	O
+.	O
+
+The	O
+lack	O
+of	O
+a	O
+similar	O
+response	O
+to	O
+ketamine	O
+and	O
+xylazine	O
+anesthesia	O
+revealed	O
+that	O
+the	O
+cardiovascular	O
+actions	O
+of	O
+sodium	O
+pentobarbital	O
+in	O
+barium	O
+-	O
+treated	O
+rats	O
+were	O
+linked	O
+specifically	O
+to	O
+this	O
+anesthetic	O
+,	O
+and	O
+were	O
+not	O
+representative	O
+of	O
+a	O
+generalized	O
+anesthetic	O
+response	O
+.	O
+
+Other	O
+myocardial	O
+pathophysiologic	O
+and	O
+metabolic	O
+changes	O
+induced	O
+by	O
+barium	O
+were	O
+manifest	O
+,	O
+irrespective	O
+of	O
+the	O
+anesthetic	O
+employed	O
+.	O
+
+The	O
+contractile	O
+element	O
+shortening	O
+velocity	O
+of	O
+the	O
+cardiac	O
+muscle	O
+fibers	O
+was	O
+significantly	O
+slower	O
+in	O
+both	O
+groups	O
+of	O
+barium	O
+-	O
+treated	O
+rats	O
+relative	O
+to	O
+the	O
+control	O
+groups	O
+,	O
+irrespective	O
+of	O
+the	O
+anesthetic	O
+regimen	O
+.	O
+
+Similarly	O
+,	O
+significant	O
+disturbances	O
+in	O
+myocardial	O
+energy	O
+metabolism	O
+were	O
+detected	O
+in	O
+the	O
+barium	O
+-	O
+exposed	O
+rats	O
+which	O
+were	O
+consistent	O
+with	O
+the	O
+reduced	O
+contractile	O
+element	O
+shortening	O
+velocity	O
+.	O
+
+In	O
+addition	O
+,	O
+the	O
+excitability	O
+of	O
+the	O
+cardiac	O
+conduction	O
+system	O
+was	O
+depressed	O
+preferentially	O
+in	O
+the	O
+atrioventricular	O
+nodal	O
+region	O
+of	O
+hearts	O
+from	O
+barium	O
+-	O
+exposed	O
+rats	O
+.	O
+
+Overall	O
+,	O
+the	O
+altered	O
+cardiac	O
+contractility	O
+and	O
+excitability	O
+characteristics	O
+,	O
+the	O
+myocardial	O
+metabolic	B
+disturbances	I
+,	O
+and	O
+the	O
+hypersensitivity	B
+of	O
+the	O
+cardiovascular	O
+system	O
+to	O
+sodium	O
+pentobarbital	O
+suggest	O
+the	O
+existence	O
+of	O
+a	O
+heretofore	O
+undescribed	O
+cardiomyopathic	B
+disorder	I
+induced	O
+by	O
+chronic	O
+barium	O
+exposure	O
+.	O
+
+These	O
+experimental	O
+findings	O
+represent	O
+the	O
+first	O
+indication	O
+that	O
+life	O
+-	O
+long	O
+barium	O
+ingestion	O
+may	O
+have	O
+significant	O
+adverse	O
+effects	O
+on	O
+the	O
+mammalian	O
+cardiovascular	O
+system	O
+.	O
+
+Propranolol	O
+antagonism	O
+of	O
+phenylpropanolamine	O
+-	O
+induced	O
+hypertension	B
+.	O
+
+Phenylpropanolamine	O
+(	O
+PPA	O
+)	O
+overdose	B
+can	O
+cause	O
+severe	O
+hypertension	B
+,	O
+intracerebral	B
+hemorrhage	I
+,	O
+and	O
+death	O
+.	O
+
+We	O
+studied	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+propranolol	O
+in	O
+the	O
+treatment	O
+of	O
+PPA	O
+-	O
+induced	O
+hypertension	B
+.	O
+
+Subjects	O
+received	O
+propranolol	O
+either	O
+by	O
+mouth	O
+for	O
+48	O
+hours	O
+before	O
+PPA	O
+or	O
+as	O
+a	O
+rapid	O
+intravenous	O
+infusion	O
+after	O
+PPA	O
+.	O
+
+PPA	O
+,	O
+75	O
+mg	O
+alone	O
+,	O
+increased	O
+blood	O
+pressure	O
+(	O
+31	O
++	O
+/	O
+-	O
+14	O
+mm	O
+Hg	O
+systolic	O
+,	O
+20	O
++	O
+/	O
+-	O
+5	O
+mm	O
+Hg	O
+diastolic	O
+)	O
+,	O
+and	O
+propranolol	O
+pretreatment	O
+antagonized	O
+this	O
+increase	O
+(	O
+12	O
++	O
+/	O
+-	O
+10	O
+mm	O
+Hg	O
+systolic	O
+,	O
+10	O
++	O
+/	O
+-	O
+7	O
+mm	O
+Hg	O
+diastolic	O
+)	O
+.	O
+
+Intravenous	O
+propranolol	O
+after	O
+PPA	O
+also	O
+decreased	O
+blood	O
+pressure	O
+.	O
+
+Left	O
+ventricular	O
+function	O
+(	O
+assessed	O
+by	O
+echocardiography	O
+)	O
+showed	O
+that	O
+PPA	O
+increased	O
+the	O
+stroke	B
+volume	O
+30	O
+%	O
+(	O
+from	O
+62	O
+.	O
+5	O
++	O
+/	O
+-	O
+20	O
+.	O
+9	O
+to	O
+80	O
+.	O
+8	O
++	O
+/	O
+-	O
+22	O
+.	O
+4	O
+ml	O
+)	O
+,	O
+the	O
+ejection	O
+fraction	O
+9	O
+%	O
+(	O
+from	O
+64	O
+%	O
++	O
+/	O
+-	O
+10	O
+%	O
+to	O
+70	O
+%	O
++	O
+/	O
+-	O
+7	O
+%	O
+)	O
+,	O
+and	O
+cardiac	O
+output	O
+14	O
+%	O
+(	O
+from	O
+3	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+to	O
+4	O
+.	O
+1	O
++	O
+/	O
+-	O
+1	O
+.	O
+0	O
+L	O
+/	O
+min	O
+)	O
+.	O
+
+Intravenous	O
+propranolol	O
+reversed	O
+these	O
+effects	O
+.	O
+
+Systemic	O
+vascular	O
+resistance	O
+was	O
+increased	O
+by	O
+PPA	O
+28	O
+%	O
+(	O
+from	O
+1710	O
++	O
+/	O
+-	O
+200	O
+to	O
+2190	O
++	O
+/	O
+-	O
+700	O
+dyne	O
+X	O
+sec	O
+/	O
+cm5	O
+)	O
+and	O
+was	O
+further	O
+increased	O
+by	O
+propranolol	O
+22	O
+%	O
+(	O
+to	O
+2660	O
++	O
+/	O
+-	O
+1200	O
+dyne	O
+X	O
+sec	O
+/	O
+cm5	O
+)	O
+.	O
+
+We	O
+conclude	O
+that	O
+PPA	O
+increases	O
+blood	O
+pressure	O
+by	O
+increasing	O
+systemic	O
+vascular	O
+resistance	O
+and	O
+cardiac	O
+output	O
+,	O
+and	O
+that	O
+propranolol	O
+antagonizes	O
+this	O
+increase	O
+by	O
+reversing	O
+the	O
+effect	O
+of	O
+PPA	O
+on	O
+cardiac	O
+output	O
+.	O
+
+That	O
+propranolol	O
+antagonizes	O
+the	O
+pressor	O
+effect	O
+of	O
+PPA	O
+is	O
+in	O
+contrast	O
+to	O
+the	O
+interaction	O
+in	O
+which	O
+propranolol	O
+enhances	O
+the	O
+pressor	O
+effect	O
+of	O
+norepinephrine	O
+.	O
+
+This	O
+is	O
+probably	O
+because	O
+PPA	O
+has	O
+less	O
+beta	O
+2	O
+activity	O
+than	O
+does	O
+norepinephrine	O
+.	O
+
+Mesangial	O
+function	O
+and	O
+glomerular	B
+sclerosis	I
+in	O
+rats	O
+with	O
+aminonucleoside	O
+nephrosis	B
+.	O
+
+The	O
+possible	O
+relationship	O
+between	O
+mesangial	B
+dysfunction	I
+and	O
+development	O
+of	O
+glomerular	B
+sclerosis	I
+was	O
+studied	O
+in	O
+the	O
+puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+)	O
+model	O
+.	O
+
+Five	O
+male	O
+Wistar	O
+rats	O
+received	O
+repeated	O
+subcutaneous	O
+PAN	O
+injections	O
+;	O
+five	O
+controls	O
+received	O
+saline	O
+only	O
+.	O
+
+After	O
+4	O
+weeks	O
+the	O
+PAN	O
+rats	O
+were	O
+severely	O
+proteinuric	B
+(	O
+190	O
++	O
+/	O
+-	O
+80	O
+mg	O
+/	O
+24	O
+hr	O
+)	O
+,	O
+and	O
+all	O
+rats	O
+were	O
+given	O
+colloidal	O
+carbon	O
+(	O
+CC	O
+)	O
+intravenously	O
+.	O
+
+At	O
+5	O
+months	O
+glomerular	B
+sclerosis	I
+was	O
+found	O
+in	O
+7	O
+.	O
+6	O
++	O
+/	O
+-	O
+3	O
+.	O
+4	O
+%	O
+of	O
+the	O
+glomeruli	O
+of	O
+PAN	O
+rats	O
+;	O
+glomeruli	O
+of	O
+the	O
+controls	O
+were	O
+normal	O
+.	O
+
+Glomeruli	O
+of	O
+PAN	O
+rats	O
+contained	O
+significantly	O
+more	O
+CC	O
+than	O
+glomeruli	O
+of	O
+controls	O
+.	O
+
+Glomeruli	O
+with	O
+sclerosis	B
+contained	O
+significantly	O
+more	O
+CC	O
+than	O
+non	O
+-	O
+sclerotic	O
+glomeruli	O
+in	O
+the	O
+same	O
+kidneys	O
+.	O
+
+CC	O
+was	O
+preferentially	O
+localized	O
+within	O
+the	O
+sclerotic	O
+areas	O
+of	O
+the	O
+affected	O
+glomeruli	O
+.	O
+
+Since	O
+mesangial	O
+CC	O
+clearance	O
+from	O
+the	O
+mesangium	O
+did	O
+not	O
+change	O
+during	O
+chronic	O
+PAN	O
+treatment	O
+,	O
+we	O
+conclude	O
+that	O
+this	O
+preferential	O
+CC	O
+localization	O
+within	O
+the	O
+lesions	O
+is	O
+caused	O
+by	O
+an	O
+increased	O
+CC	O
+uptake	O
+shortly	O
+after	O
+injection	O
+in	O
+apparent	O
+vulnerable	O
+areas	O
+where	O
+sclerosis	B
+will	O
+develop	O
+subsequently	O
+.	O
+
+Cluster	O
+analysis	O
+showed	O
+a	O
+random	O
+distribution	O
+of	O
+lesions	O
+in	O
+the	O
+PAN	O
+glomeruli	O
+in	O
+concordance	O
+with	O
+the	O
+random	O
+localization	O
+of	O
+mesangial	O
+areas	O
+with	O
+dysfunction	O
+in	O
+this	O
+model	O
+.	O
+
+Similar	O
+to	O
+the	O
+remnant	O
+kidney	O
+model	O
+in	O
+PAN	O
+nephrosis	B
+the	O
+development	O
+of	O
+glomerular	B
+sclerosis	I
+may	O
+be	O
+related	O
+to	O
+"	O
+mesangial	O
+overloading	O
+.	O
+"	O
+
+Relationship	O
+between	O
+nicotine	O
+-	O
+induced	O
+seizures	B
+and	O
+hippocampal	O
+nicotinic	O
+receptors	O
+.	O
+
+A	O
+controversy	O
+has	O
+existed	O
+for	O
+several	O
+years	O
+concerning	O
+the	O
+physiological	O
+relevance	O
+of	O
+the	O
+nicotinic	O
+receptor	O
+measured	O
+by	O
+alpha	O
+-	O
+bungarotoxin	O
+binding	O
+.	O
+
+Using	O
+mice	O
+derived	O
+from	O
+a	O
+classical	O
+F2	O
+and	O
+backcross	O
+genetic	O
+design	O
+,	O
+a	O
+relationship	O
+between	O
+nicotine	O
+-	O
+induced	O
+seizures	B
+and	O
+alpha	O
+-	O
+bungarotoxin	O
+nicotinic	O
+receptor	O
+concentration	O
+was	O
+found	O
+.	O
+
+Mice	O
+sensitive	O
+to	O
+the	O
+convulsant	O
+effects	O
+of	O
+nicotine	O
+had	O
+greater	O
+alpha	O
+-	O
+bungarotoxin	O
+binding	O
+in	O
+the	O
+hippocampus	O
+than	O
+seizure	B
+insensitive	O
+mice	O
+.	O
+
+The	O
+binding	O
+sites	O
+from	O
+seizure	B
+sensitive	O
+and	O
+resistant	O
+mice	O
+were	O
+equally	O
+affected	O
+by	O
+treatment	O
+with	O
+dithiothreitol	O
+,	O
+trypsin	O
+or	O
+heat	O
+.	O
+
+Thus	O
+it	O
+appears	O
+that	O
+the	O
+difference	O
+between	O
+seizure	B
+sensitive	O
+and	O
+insensitive	O
+animals	O
+may	O
+be	O
+due	O
+to	O
+a	O
+difference	O
+in	O
+hippocampal	O
+nicotinic	O
+receptor	O
+concentration	O
+as	O
+measured	O
+with	O
+alpha	O
+-	O
+bungarotoxin	O
+binding	O
+.	O
+
+The	O
+role	O
+of	O
+p	O
+-	O
+aminophenol	O
+in	O
+acetaminophen	O
+-	O
+induced	O
+nephrotoxicity	B
+:	O
+effect	O
+of	O
+bis	O
+(	O
+p	O
+-	O
+nitrophenyl	O
+)	O
+phosphate	O
+on	O
+acetaminophen	O
+and	O
+p	O
+-	O
+aminophenol	O
+nephrotoxicity	B
+and	O
+metabolism	O
+in	O
+Fischer	O
+344	O
+rats	O
+.	O
+
+Acetaminophen	O
+(	O
+APAP	O
+)	O
+produces	O
+proximal	O
+tubular	B
+necrosis	I
+in	O
+Fischer	O
+344	O
+(	O
+F344	O
+)	O
+rats	O
+.	O
+
+Recently	O
+,	O
+p	O
+-	O
+aminophenol	O
+(	O
+PAP	O
+)	O
+,	O
+a	O
+known	O
+potent	O
+nephrotoxicant	O
+,	O
+was	O
+identified	O
+as	O
+a	O
+metabolite	O
+of	O
+APAP	O
+in	O
+F344	O
+rats	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+if	O
+PAP	O
+formation	O
+is	O
+a	O
+requisite	O
+step	O
+in	O
+APAP	O
+-	O
+induced	O
+nephrotoxicity	B
+.	O
+
+Therefore	O
+,	O
+the	O
+effect	O
+of	O
+bis	O
+(	O
+p	O
+-	O
+nitrophenyl	O
+)	O
+phosphate	O
+(	O
+BNPP	O
+)	O
+,	O
+an	O
+acylamidase	O
+inhibitor	O
+,	O
+on	O
+APAP	O
+and	O
+PAP	O
+nephrotoxicity	B
+and	O
+metabolism	O
+was	O
+determined	O
+.	O
+
+BNPP	O
+(	O
+1	O
+to	O
+8	O
+mM	O
+)	O
+reduced	O
+APAP	O
+deacetylation	O
+and	O
+covalent	O
+binding	O
+in	O
+F344	O
+renal	O
+cortical	O
+homogenates	O
+in	O
+a	O
+concentration	O
+-	O
+dependent	O
+manner	O
+.	O
+
+Pretreatment	O
+of	O
+animals	O
+with	O
+BNPP	O
+prior	O
+to	O
+APAP	O
+or	O
+PAP	O
+administration	O
+resulted	O
+in	O
+marked	O
+reduction	O
+of	O
+APAP	O
+(	O
+900	O
+mg	O
+/	O
+kg	O
+)	O
+nephrotoxicity	B
+but	O
+not	O
+PAP	O
+nephrotoxicity	B
+.	O
+
+This	O
+result	O
+was	O
+not	O
+due	O
+to	O
+altered	O
+disposition	O
+of	O
+either	O
+APAP	O
+or	O
+acetylated	O
+metabolites	O
+in	O
+plasma	O
+or	O
+renal	O
+cortical	O
+and	O
+hepatic	O
+tissue	O
+.	O
+
+Rather	O
+,	O
+BNPP	O
+pretreatment	O
+reduced	O
+the	O
+fraction	O
+of	O
+APAP	O
+excreted	O
+as	O
+PAP	O
+by	O
+64	O
+and	O
+75	O
+%	O
+after	O
+APAP	O
+doses	O
+of	O
+750	O
+and	O
+900	O
+mg	O
+/	O
+kg	O
+.	O
+
+BNPP	O
+did	O
+not	O
+alter	O
+the	O
+excretion	O
+of	O
+APAP	O
+or	O
+any	O
+of	O
+its	O
+non	O
+-	O
+deacetylated	O
+metabolites	O
+nor	O
+did	O
+BNPP	O
+alter	O
+excretion	O
+of	O
+PAP	O
+or	O
+its	O
+metabolites	O
+after	O
+PAP	O
+doses	O
+of	O
+150	O
+and	O
+300	O
+mg	O
+/	O
+kg	O
+.	O
+
+Therefore	O
+,	O
+the	O
+BNPP	O
+-	O
+induced	O
+reduction	O
+in	O
+APAP	O
+-	O
+induced	O
+nephrotoxicity	B
+appears	O
+to	O
+be	O
+due	O
+to	O
+inhibition	O
+of	O
+APAP	O
+deacetylation	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+PAP	O
+formation	O
+,	O
+in	O
+vivo	O
+,	O
+accounts	O
+,	O
+at	O
+least	O
+in	O
+part	O
+,	O
+for	O
+APAP	O
+-	O
+induced	O
+renal	B
+tubular	I
+necrosis	I
+.	O
+
+Morphine	O
+-	O
+induced	O
+seizures	B
+in	O
+newborn	O
+infants	O
+.	O
+
+Two	O
+neonates	O
+suffered	O
+from	O
+generalized	O
+seizures	B
+during	O
+the	O
+course	O
+of	O
+intravenous	O
+morphine	O
+sulfate	O
+for	O
+post	O
+-	O
+operative	O
+analgesia	O
+.	O
+
+They	O
+received	O
+morphine	O
+in	O
+doses	O
+of	O
+32	O
+micrograms	O
+/	O
+kg	O
+/	O
+hr	O
+and	O
+40	O
+micrograms	O
+/	O
+kg	O
+/	O
+hr	O
+larger	O
+than	O
+a	O
+group	O
+of	O
+10	O
+neonates	O
+who	O
+received	O
+6	O
+-	O
+24	O
+micrograms	O
+/	O
+kg	O
+/	O
+hr	O
+and	O
+had	O
+no	O
+seizures	B
+.	O
+
+Plasma	O
+concentrations	O
+of	O
+morphine	O
+in	O
+these	O
+neonates	O
+was	O
+excessive	O
+(	O
+60	O
+and	O
+90	O
+mg	O
+/	O
+ml	O
+)	O
+.	O
+
+Other	O
+known	O
+reasons	O
+for	O
+seizures	B
+were	O
+ruled	O
+out	O
+and	O
+the	O
+convulsions	B
+stopped	O
+a	O
+few	O
+hours	O
+after	O
+cessation	O
+of	O
+morphine	O
+and	O
+did	O
+not	O
+reoccur	O
+in	O
+the	O
+subsequent	O
+8	O
+months	O
+.	O
+
+It	O
+is	O
+suggested	O
+that	O
+post	O
+-	O
+operative	O
+intravenous	O
+morphine	O
+should	O
+not	O
+exceed	O
+20	O
+micrograms	O
+/	O
+kg	O
+/	O
+ml	O
+in	O
+neonates	O
+.	O
+
+Indomethacin	O
+induced	O
+hypotension	B
+in	O
+sodium	O
+and	O
+volume	O
+depleted	O
+rats	O
+.	O
+
+After	O
+a	O
+single	O
+oral	O
+dose	O
+of	O
+4	O
+mg	O
+/	O
+kg	O
+indomethacin	O
+(	O
+IDM	O
+)	O
+to	O
+sodium	O
+and	O
+volume	O
+depleted	O
+rats	O
+plasma	O
+renin	O
+activity	O
+(	O
+PRA	O
+)	O
+and	O
+systolic	O
+blood	O
+pressure	O
+fell	O
+significantly	O
+within	O
+four	O
+hours	O
+.	O
+
+In	O
+sodium	O
+repleted	O
+animals	O
+indomethacin	O
+did	O
+not	O
+change	O
+systolic	O
+blood	O
+pressure	O
+(	O
+BP	O
+)	O
+although	O
+plasma	O
+renin	O
+activity	O
+was	O
+decreased	O
+.	O
+
+Thus	O
+,	O
+indomethacin	O
+by	O
+inhibition	O
+of	O
+prostaglandin	O
+synthesis	O
+may	O
+diminish	O
+the	O
+blood	O
+pressure	O
+maintaining	O
+effect	O
+of	O
+the	O
+stimulated	O
+renin	O
+-	O
+angiotensin	O
+system	O
+in	O
+sodium	O
+and	O
+volume	O
+depletion	O
+.	O
+
+On	O
+the	O
+antiarrhythmic	O
+activity	O
+of	O
+one	O
+N	O
+-	O
+substituted	O
+piperazine	O
+derivative	O
+of	O
+trans	O
+-	O
+2	O
+-	O
+amino	O
+-	O
+3	O
+-	O
+hydroxy	O
+-	O
+1	O
+,	O
+2	O
+,	O
+3	O
+,	O
+4	O
+-	O
+tetrahydroanaphthalene	O
+.	O
+
+The	O
+antiarrhythmic	O
+activity	O
+of	O
+the	O
+compound	O
+N	O
+-	O
+(	O
+trans	O
+-	O
+3	O
+-	O
+hydroxy	O
+-	O
+1	O
+,	O
+2	O
+,	O
+3	O
+,	O
+4	O
+-	O
+tetrahydro	O
+-	O
+2	O
+-	O
+naphthyl	O
+)	O
+-	O
+N	O
+-	O
+(	O
+3	O
+-	O
+oxo	O
+-	O
+3	O
+-	O
+phenyl	O
+-	O
+2	O
+-	O
+methylpropyl	O
+)	O
+-	O
+piperazine	O
+hydrochloride	O
+,	O
+referred	O
+to	O
+as	O
+P11	O
+,	O
+is	O
+studied	O
+on	O
+anaesthesized	O
+cats	O
+and	O
+Wistar	O
+albino	O
+rats	O
+,	O
+as	O
+well	O
+as	O
+on	O
+non	O
+-	O
+anaesthesized	O
+rabbits	O
+.	O
+
+Four	O
+types	O
+of	O
+experimental	O
+arrhythmia	B
+are	O
+used	O
+-	O
+-	O
+with	O
+BaCl2	O
+,	O
+with	O
+chloroform	O
+-	O
+adrenaline	O
+,	O
+with	O
+strophantine	O
+G	O
+and	O
+with	O
+aconitine	O
+.	O
+
+The	O
+compound	O
+P11	O
+is	O
+introduced	O
+in	O
+doses	O
+of	O
+0	O
+.	O
+25	O
+and	O
+0	O
+.	O
+50	O
+mg	O
+/	O
+kg	O
+intravenously	O
+and	O
+10	O
+mg	O
+/	O
+kg	O
+orally	O
+.	O
+
+The	O
+compound	O
+manifests	O
+antiarrhythmic	O
+activity	O
+in	O
+all	O
+models	O
+of	O
+experimental	O
+arrhythmia	B
+used	O
+,	O
+causing	O
+greatest	O
+inhibition	O
+on	O
+the	O
+arrhythmia	B
+induced	O
+by	O
+chloroform	O
+-	O
+adrenaline	O
+(	O
+in	O
+90	O
+per	O
+cent	O
+)	O
+and	O
+with	O
+BaCl2	O
+(	O
+in	O
+84	O
+per	O
+cent	O
+)	O
+.	O
+
+The	O
+results	O
+obtained	O
+are	O
+associated	O
+with	O
+the	O
+beta	O
+-	O
+adrenoblocking	O
+and	O
+with	O
+the	O
+membrane	O
+-	O
+stabilizing	O
+action	O
+of	O
+the	O
+compound	O
+.	O
+
+Recurrent	O
+subarachnoid	B
+hemorrhage	I
+associated	O
+with	O
+aminocaproic	O
+acid	O
+therapy	O
+and	O
+acute	B
+renal	I
+artery	I
+thrombosis	I
+.	O
+
+Case	O
+report	O
+.	O
+
+Epsilon	O
+aminocaproic	O
+acid	O
+(	O
+EACA	O
+)	O
+has	O
+been	O
+used	O
+to	O
+prevent	O
+rebleeding	O
+in	O
+patients	O
+with	O
+subarachnoid	B
+hemorrhage	I
+(	O
+SAH	B
+)	O
+.	O
+
+Although	O
+this	O
+agent	O
+does	O
+decrease	O
+the	O
+frequency	O
+of	O
+rebleeding	O
+,	O
+several	O
+reports	O
+have	O
+described	O
+thrombotic	B
+complications	O
+of	O
+EACA	O
+therapy	O
+.	O
+
+These	O
+complications	O
+have	O
+included	O
+clinical	O
+deterioration	O
+and	O
+intracranial	B
+vascular	I
+thrombosis	I
+in	O
+patients	O
+with	O
+SAH	B
+,	O
+arteriolar	O
+and	O
+capillary	O
+fibrin	O
+thrombi	B
+in	O
+patients	O
+with	O
+fibrinolytic	O
+syndromes	O
+treated	O
+with	O
+EACA	O
+,	O
+or	O
+other	O
+thromboembolic	B
+phenomena	I
+.	O
+
+Since	O
+intravascular	O
+fibrin	O
+thrombi	B
+are	O
+often	O
+observed	O
+in	O
+patients	O
+with	O
+fibrinolytic	O
+disorders	O
+,	O
+EACA	O
+should	O
+not	O
+be	O
+implicated	O
+in	O
+the	O
+pathogenesis	O
+of	O
+fibrin	O
+thrombi	B
+in	O
+patients	O
+with	O
+disseminated	B
+intravascular	I
+coagulation	I
+or	O
+other	O
+"	O
+consumption	B
+coagulopathies	I
+.	O
+"	O
+This	O
+report	O
+describes	O
+subtotal	O
+infarction	B
+of	O
+the	O
+kidney	O
+due	O
+to	O
+thrombosis	B
+of	I
+a	I
+normal	I
+renal	I
+artery	I
+.	O
+
+This	O
+occlusion	O
+occurred	O
+after	O
+EACA	O
+therapy	O
+in	O
+a	O
+patient	O
+with	O
+SAH	B
+and	O
+histopathological	O
+documentation	O
+of	O
+recurrent	O
+SAH	B
+.	O
+
+The	O
+corresponding	O
+clinical	O
+event	O
+was	O
+characterized	O
+by	O
+marked	O
+hypertension	B
+and	O
+abrupt	O
+neurological	O
+deterioration	O
+.	O
+
+Effect	O
+of	O
+vincristine	O
+sulfate	O
+on	O
+Pseudomonas	B
+infections	I
+in	O
+monkeys	O
+.	O
+
+In	O
+rhesus	O
+monkeys	O
+,	O
+intravenous	O
+challenge	O
+with	O
+0	O
+.	O
+6	O
+x	O
+10	O
+(	O
+10	O
+)	O
+to	O
+2	O
+.	O
+2	O
+x	O
+10	O
+(	O
+10	O
+)	O
+Pseudomonas	O
+aeruginosa	O
+organisms	O
+caused	O
+acute	O
+illness	O
+of	O
+4	O
+to	O
+5	O
+days	O
+'	O
+duration	O
+with	O
+spontaneous	O
+recovery	O
+in	O
+13	O
+of	O
+15	O
+monkeys	O
+;	O
+blood	O
+cultures	O
+became	O
+negative	O
+3	O
+to	O
+17	O
+days	O
+after	O
+challenge	O
+.	O
+
+Leukocytosis	B
+was	O
+observed	O
+in	O
+all	O
+monkeys	O
+.	O
+
+Intravenous	O
+or	O
+intratracheal	O
+inoculation	O
+of	O
+2	O
+.	O
+0	O
+to	O
+2	O
+.	O
+5	O
+mg	O
+of	O
+vincristine	O
+sulfate	O
+was	O
+followed	O
+by	O
+leukopenia	B
+in	O
+4	O
+to	O
+5	O
+days	O
+.	O
+
+Intravenous	O
+inoculation	O
+of	O
+4	O
+.	O
+2	O
+x	O
+10	O
+(	O
+10	O
+)	O
+to	O
+7	O
+.	O
+8	O
+x	O
+10	O
+(	O
+10	O
+)	O
+pyocin	O
+type	O
+6	O
+Pseudomonas	O
+organisms	O
+in	O
+monkeys	O
+given	O
+vincristine	O
+sulfate	O
+4	O
+days	O
+previously	O
+resulted	O
+in	O
+fatal	O
+infection	B
+in	O
+11	O
+of	O
+14	O
+monkeys	O
+,	O
+whereas	O
+none	O
+of	O
+four	O
+receiving	O
+Pseudomonas	O
+alone	O
+died	O
+.	O
+
+These	O
+studies	O
+suggest	O
+that	O
+an	O
+antimetabolite	O
+-	O
+induced	O
+leukopenia	B
+predisposes	O
+to	O
+severe	O
+Pseudomonas	O
+sepsis	B
+and	O
+that	O
+such	O
+monkeys	O
+may	O
+serve	O
+as	O
+a	O
+biological	O
+model	O
+for	O
+study	O
+of	O
+comparative	O
+efficacy	O
+of	O
+antimicrobial	O
+agents	O
+.	O
+
+Modification	O
+by	O
+propranolol	O
+of	O
+cardiovascular	O
+effects	O
+of	O
+induced	O
+hypoglycaemia	B
+.	O
+
+The	O
+cardiovascular	O
+effects	O
+of	O
+hypoglycaemia	B
+,	O
+with	O
+and	O
+without	O
+beta	O
+-	O
+blockade	O
+,	O
+were	O
+compared	O
+in	O
+fourteen	O
+healthy	O
+men	O
+.	O
+
+Eight	O
+received	O
+insulin	O
+alone	O
+,	O
+and	O
+eight	O
+,	O
+including	O
+two	O
+of	O
+the	O
+original	O
+insulin	O
+-	O
+only	O
+group	O
+,	O
+were	O
+given	O
+propranolol	O
+and	O
+insulin	O
+.	O
+
+In	O
+the	O
+insulin	O
+-	O
+group	O
+the	O
+period	O
+of	O
+hypoglycaemia	B
+was	O
+associated	O
+with	O
+an	O
+increase	O
+in	O
+heart	O
+-	O
+rate	O
+and	O
+a	O
+fall	O
+in	O
+diastolic	O
+blood	O
+-	O
+pressure	O
+.	O
+
+In	O
+the	O
+propranolol	O
+-	O
+insulin	O
+group	O
+there	O
+was	O
+a	O
+significant	O
+fall	O
+in	O
+heart	O
+-	O
+rate	O
+in	O
+most	O
+subjects	O
+and	O
+an	O
+increase	O
+in	O
+diastolic	O
+pressure	O
+.	O
+
+Typical	O
+S	O
+-	O
+T	O
+/	O
+T	O
+changes	O
+occurred	O
+in	O
+the	O
+insulin	O
+-	O
+group	O
+but	O
+in	O
+none	O
+of	O
+the	O
+propranolol	O
+-	O
+insulin	O
+group	O
+.	O
+
+Hypertension	B
+in	O
+diabetics	B
+prone	O
+to	O
+hypoglycaemia	B
+attacks	O
+should	O
+not	O
+be	O
+treated	O
+with	O
+beta	O
+-	O
+blockers	O
+because	O
+these	O
+drugs	O
+may	O
+cause	O
+a	O
+sharp	O
+rise	O
+in	O
+blood	O
+-	O
+pressure	O
+in	O
+such	O
+patients	O
+.	O
+
+Long	O
+-	O
+term	O
+propranolol	O
+therapy	O
+in	O
+pregnancy	O
+:	O
+maternal	O
+and	O
+fetal	O
+outcome	O
+.	O
+
+Propranolol	O
+,	O
+a	O
+beta	O
+-	O
+adrenergic	O
+blocking	O
+agent	O
+,	O
+has	O
+found	O
+an	O
+important	O
+position	O
+in	O
+the	O
+practice	O
+of	O
+medicine	O
+.	O
+
+Its	O
+use	O
+in	O
+pregnancy	O
+,	O
+however	O
+,	O
+is	O
+an	O
+open	O
+question	O
+as	O
+a	O
+number	O
+of	O
+detrimental	O
+side	O
+effects	O
+have	O
+been	O
+reported	O
+in	O
+the	O
+fetus	O
+and	O
+neonate	O
+.	O
+
+Ten	O
+patients	O
+and	O
+12	O
+pregnancies	O
+are	O
+reported	O
+where	O
+chronic	O
+propranolol	O
+has	O
+been	O
+administered	O
+.	O
+
+Five	O
+patients	O
+with	O
+serial	O
+pregnancies	O
+with	O
+and	O
+without	O
+propranolol	O
+therapy	O
+are	O
+also	O
+examined	O
+.	O
+
+Maternal	O
+,	O
+fetal	O
+,	O
+and	O
+neonatal	O
+complications	O
+are	O
+examined	O
+.	O
+
+An	O
+attempt	O
+is	O
+made	O
+to	O
+differentiate	O
+drug	O
+-	O
+related	O
+complications	O
+from	O
+maternal	O
+disease	O
+-	O
+-	O
+related	O
+complications	O
+.	O
+
+We	O
+conclude	O
+that	O
+previously	O
+reported	O
+hypoglycemia	B
+,	O
+hyperbilirubinemia	B
+,	O
+polycythemia	B
+,	O
+neonatal	B
+apnea	I
+,	O
+and	O
+bradycardia	B
+are	O
+not	O
+invariable	O
+and	O
+cannot	O
+be	O
+statistically	O
+correlated	O
+with	O
+chronic	O
+propranolol	O
+therapy	O
+.	O
+
+Growth	B
+retardation	I
+,	O
+however	O
+,	O
+appears	O
+to	O
+be	O
+significant	O
+in	O
+both	O
+of	O
+our	O
+series	O
+.	O
+
+Central	O
+excitatory	O
+actions	O
+of	O
+flurazepam	O
+.	O
+
+Toxic	O
+actions	O
+of	O
+flurazepam	O
+(	O
+FZP	O
+)	O
+were	O
+studied	O
+in	O
+cats	O
+,	O
+mice	O
+and	O
+rats	O
+.	O
+
+High	O
+doses	O
+caused	O
+an	O
+apparent	O
+central	O
+excitation	O
+,	O
+most	O
+clearly	O
+seen	O
+as	O
+clonic	O
+convulsions	B
+,	O
+superimposed	O
+on	O
+general	O
+depression	B
+.	O
+
+Following	O
+a	O
+lethal	O
+dose	O
+,	O
+death	O
+was	O
+always	O
+associated	O
+with	O
+convulsions	B
+.	O
+
+Comparing	O
+the	O
+relative	O
+sensitivity	O
+to	O
+central	O
+depression	B
+and	O
+excitation	O
+revealed	O
+that	O
+rats	O
+were	O
+least	O
+likely	O
+to	O
+have	O
+convulsions	B
+at	O
+doses	O
+that	O
+did	O
+not	O
+first	O
+cause	O
+loss	B
+of	I
+consciousness	I
+,	O
+while	O
+cats	O
+most	O
+clearly	O
+showed	O
+marked	O
+central	O
+excitatory	O
+actions	O
+.	O
+
+Signs	O
+of	O
+FZP	O
+toxocity	B
+in	O
+cats	O
+included	O
+excessive	O
+salivation	B
+,	O
+extreme	O
+apprehensive	O
+behavior	O
+,	O
+retching	O
+,	O
+muscle	B
+tremors	I
+and	O
+convulsions	B
+.	O
+
+An	O
+interaction	O
+between	O
+FZP	O
+and	O
+pentylenetetrazol	O
+(	O
+PTZ	O
+)	O
+was	O
+shown	O
+by	O
+pretreating	O
+mice	O
+with	O
+FZP	O
+before	O
+PTZ	O
+challenge	O
+.	O
+
+As	O
+a	O
+function	O
+of	O
+dose	O
+,	O
+FZP	O
+first	O
+protected	O
+against	O
+convulsions	B
+and	O
+death	O
+.	O
+
+At	O
+higher	O
+doses	O
+,	O
+however	O
+,	O
+convulsions	B
+again	O
+emerged	O
+.	O
+
+These	O
+doses	O
+of	O
+FZP	O
+were	O
+lower	O
+than	O
+those	O
+that	O
+would	O
+alone	O
+cause	O
+convulsions	B
+.	O
+
+These	O
+results	O
+may	O
+be	O
+relevant	O
+to	O
+the	O
+use	O
+of	O
+FZP	O
+in	O
+clinical	O
+situations	O
+in	O
+which	O
+there	O
+is	O
+increased	O
+neural	O
+excitability	O
+,	O
+such	O
+as	O
+epilepsy	B
+or	O
+sedative	O
+-	O
+hypnotic	O
+drug	O
+withdrawal	O
+.	O
+
+Use	O
+of	O
+propranolol	O
+in	O
+the	O
+treatment	O
+of	O
+idiopathic	B
+orthostatic	I
+hypotension	I
+.	O
+
+Five	O
+patients	O
+with	O
+idiopathic	B
+orthostatic	I
+hypotension	I
+who	O
+had	O
+physiologic	O
+and	O
+biochemical	O
+evidence	O
+of	O
+severe	O
+autonomic	O
+dysfunction	O
+were	O
+included	O
+in	O
+the	O
+study	O
+.	O
+
+They	O
+all	O
+exhibited	O
+markedly	O
+reduced	O
+plasma	O
+catecholamines	O
+and	O
+plasma	O
+renin	O
+activity	O
+in	O
+both	O
+recumbent	O
+and	O
+upright	O
+positions	O
+and	O
+had	O
+marked	O
+hypersensitivity	B
+to	O
+the	O
+pressor	O
+effects	O
+of	O
+infused	O
+norepinephrine	O
+.	O
+
+Treatment	O
+with	O
+propanolol	O
+administered	O
+intravenously	O
+(	O
+1	O
+-	O
+5	O
+mg	O
+)	O
+produced	O
+increases	O
+in	O
+supine	O
+and	O
+upright	O
+blood	O
+pressure	O
+in	O
+4	O
+of	O
+the	O
+5	O
+individuals	O
+with	O
+rises	O
+ranging	O
+from	O
+11	O
+/	O
+6	O
+to	O
+22	O
+/	O
+11	O
+mmHg	O
+.	O
+
+Chronic	O
+oral	O
+administration	O
+of	O
+propranolol	O
+(	O
+40	O
+-	O
+160	O
+mg	O
+/	O
+day	O
+)	O
+also	O
+elevated	O
+the	O
+blood	O
+pressures	O
+of	O
+these	O
+individuals	O
+with	O
+increases	O
+in	O
+the	O
+order	O
+of	O
+20	O
+-	O
+35	O
+/	O
+15	O
+-	O
+25	O
+mmg	O
+being	O
+observed	O
+.	O
+
+In	O
+1	O
+patient	O
+,	O
+marked	O
+hypertension	B
+was	O
+induced	O
+by	O
+propranolol	O
+and	O
+the	O
+drug	O
+had	O
+to	O
+be	O
+withdrawn	O
+.	O
+
+It	O
+otherwise	O
+was	O
+well	O
+tolerated	O
+and	O
+no	O
+important	O
+side	O
+effects	O
+were	O
+observed	O
+.	O
+
+Treatment	O
+has	O
+been	O
+continued	O
+in	O
+3	O
+individuals	O
+for	O
+6	O
+-	O
+13	O
+months	O
+with	O
+persistence	O
+of	O
+the	O
+pressor	O
+effect	O
+,	O
+although	O
+there	O
+appears	O
+to	O
+have	O
+been	O
+some	O
+decrease	O
+in	O
+the	O
+degree	O
+of	O
+response	O
+with	O
+time	O
+.	O
+
+Hemodynamic	O
+measurements	O
+in	O
+1	O
+of	O
+the	O
+patients	O
+demonstrated	O
+an	O
+increase	O
+in	O
+total	O
+peripheral	O
+resistance	O
+and	O
+essentially	O
+no	O
+change	O
+in	O
+cardiac	O
+output	O
+following	O
+propranolol	O
+therapy	O
+.	O
+
+The	O
+studies	O
+suggest	O
+that	O
+propranolol	O
+is	O
+a	O
+useful	O
+drug	O
+in	O
+selected	O
+patients	O
+with	O
+severe	O
+idiopathic	B
+orthostatic	I
+hypotension	I
+.	O
+
+Total	O
+intravenous	O
+anesthesia	O
+with	O
+etomidate	O
+.	O
+
+III	O
+.	O
+
+Some	O
+observations	O
+in	O
+adults	O
+.	O
+
+An	O
+investigation	O
+was	O
+undertaken	O
+to	O
+determine	O
+the	O
+dosage	O
+of	O
+etomidate	O
+required	O
+to	O
+maintain	O
+sleep	O
+in	O
+adults	O
+undergoing	O
+surgery	O
+under	O
+regional	O
+local	O
+anesthesia	O
+.	O
+
+Premedication	O
+of	O
+diazepam	O
+10	O
+mg	O
+and	O
+atropine	O
+0	O
+.	O
+5	O
+mg	O
+was	O
+given	O
+,	O
+and	O
+sleep	O
+was	O
+induced	O
+and	O
+maintained	O
+by	O
+intermittent	O
+intravenous	O
+injections	O
+of	O
+etomidate	O
+0	O
+.	O
+1	O
+/	O
+mg	O
+/	O
+kg	O
+,	O
+given	O
+whenever	O
+the	O
+patient	O
+would	O
+open	O
+his	O
+eyes	O
+on	O
+request	O
+.	O
+
+A	O
+mean	O
+overall	O
+dose	O
+of	O
+etomidate	O
+17	O
+.	O
+4	O
+microgram	O
+/	O
+kg	O
+/	O
+min	O
+.	O
+was	O
+required	O
+to	O
+maintain	O
+sleep	O
+,	O
+but	O
+great	O
+individual	O
+variation	O
+occurred	O
+,	O
+with	O
+older	O
+patients	O
+requiring	O
+less	O
+drug	O
+.	O
+
+The	O
+investigation	O
+was	O
+discontinued	O
+after	O
+18	O
+patients	O
+because	O
+of	O
+the	O
+frequency	O
+and	O
+intensity	O
+of	O
+side	O
+-	O
+effects	O
+,	O
+particularly	O
+pain	B
+and	O
+myoclonia	B
+,	O
+which	O
+caused	O
+the	O
+technique	O
+to	O
+be	O
+abandoned	O
+in	O
+two	O
+cases	O
+.	O
+
+It	O
+is	O
+considered	O
+unlikely	O
+that	O
+etomidate	O
+will	O
+prove	O
+to	O
+be	O
+the	O
+hypnotic	O
+of	O
+choice	O
+for	O
+a	O
+totally	O
+intravenous	O
+anesthetic	O
+technique	O
+in	O
+adults	O
+because	O
+of	O
+the	O
+high	O
+incidence	O
+of	O
+myoclonia	B
+after	O
+prolonged	O
+administration	O
+.	O
+
+In	O
+several	O
+patients	O
+uncontrollable	O
+muscle	O
+movements	O
+persisted	O
+for	O
+many	O
+minutes	O
+after	O
+complete	O
+recovery	O
+of	O
+consciousness	O
+.	O
+
+Evidence	O
+for	O
+cardiac	O
+beta	O
+2	O
+-	O
+adrenoceptors	O
+in	O
+man	O
+.	O
+
+We	O
+compared	O
+the	O
+effects	O
+of	O
+single	O
+doses	O
+of	O
+50	O
+mg	O
+atenolol	O
+(	O
+cardioselective	O
+)	O
+,	O
+40	O
+mg	O
+propranolol	O
+(	O
+nonselective	O
+)	O
+,	O
+and	O
+placebo	O
+on	O
+both	O
+exercise	O
+-	O
+and	O
+isoproterenol	O
+-	O
+induced	O
+tachycardia	B
+in	O
+two	O
+experiments	O
+involving	O
+nine	O
+normal	O
+subjects	O
+.	O
+
+Maximal	O
+exercise	O
+heart	O
+rate	O
+was	O
+reduced	O
+from	O
+187	O
++	O
+/	O
+-	O
+4	O
+(	O
+SEM	O
+)	O
+after	O
+placebo	O
+to	O
+146	O
++	O
+/	O
+-	O
+7	O
+bpm	O
+after	O
+atenolol	O
+and	O
+138	O
++	O
+/	O
+-	O
+6	O
+bpm	O
+after	O
+propranolol	O
+,	O
+but	O
+there	O
+were	O
+no	O
+differences	O
+between	O
+the	O
+drugs	O
+.	O
+
+The	O
+effects	O
+on	O
+isoproterenol	O
+tachycardia	B
+were	O
+determined	O
+before	O
+and	O
+after	O
+atropine	O
+(	O
+0	O
+.	O
+04	O
+mg	O
+/	O
+kg	O
+IV	O
+)	O
+.	O
+
+Isoproterenol	O
+sensitivity	O
+was	O
+determined	O
+as	O
+the	O
+intravenous	O
+dose	O
+that	O
+increased	O
+heart	O
+rate	O
+by	O
+25	O
+bpm	O
+(	O
+CD25	O
+)	O
+and	O
+this	O
+was	O
+increased	O
+from	O
+1	O
+.	O
+8	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+micrograms	O
+after	O
+placebo	O
+to	O
+38	O
+.	O
+9	O
++	O
+/	O
+-	O
+8	O
+.	O
+3	O
+micrograms	O
+after	O
+propranolol	O
+and	O
+8	O
+.	O
+3	O
++	O
+/	O
+-	O
+1	O
+.	O
+7	O
+micrograms	O
+after	O
+atenolol	O
+.	O
+
+The	O
+difference	O
+in	O
+the	O
+effects	O
+of	O
+the	O
+two	O
+was	O
+significant	O
+.	O
+
+After	O
+atropine	O
+the	O
+CD25	O
+was	O
+unchanged	O
+after	O
+placebo	O
+(	O
+2	O
+.	O
+3	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+micrograms	O
+)	O
+and	O
+atenolol	O
+(	O
+7	O
+.	O
+7	O
++	O
+/	O
+-	O
+1	O
+.	O
+3	O
+micrograms	O
+)	O
+;	O
+it	O
+was	O
+reduced	O
+after	O
+propranolol	O
+(	O
+24	O
+.	O
+8	O
++	O
+/	O
+-	O
+5	O
+.	O
+0	O
+micrograms	O
+)	O
+,	O
+but	O
+remained	O
+different	O
+from	O
+atenolol	O
+.	O
+
+This	O
+change	O
+with	O
+propranolol	O
+sensitivity	O
+was	O
+calculated	O
+as	O
+the	O
+apparent	O
+Ka	O
+,	O
+this	O
+was	O
+unchanged	O
+by	O
+atropine	O
+(	O
+11	O
+.	O
+7	O
++	O
+/	O
+-	O
+2	O
+.	O
+1	O
+and	O
+10	O
+.	O
+1	O
++	O
+/	O
+-	O
+2	O
+.	O
+5	O
+ml	O
+/	O
+ng	O
+)	O
+.	O
+
+These	O
+data	O
+are	O
+consistent	O
+with	O
+the	O
+hypothesis	O
+that	O
+exercise	O
+-	O
+induced	O
+tachycardia	B
+results	O
+largely	O
+from	O
+beta	O
+1	O
+-	O
+receptor	O
+activation	O
+that	O
+is	O
+blocked	O
+by	O
+both	O
+cardioselective	O
+and	O
+nonselective	O
+drugs	O
+,	O
+whereas	O
+isoproterenol	O
+activates	O
+both	O
+beta	O
+1	O
+-	O
+and	O
+beta	O
+2	O
+-	O
+receptors	O
+so	O
+that	O
+after	O
+cardioselective	O
+blockade	O
+there	O
+remains	O
+a	O
+beta	O
+2	O
+-	O
+component	O
+that	O
+can	O
+be	O
+blocked	O
+with	O
+a	O
+nonselective	O
+drug	O
+.	O
+
+While	O
+there	O
+appear	O
+to	O
+be	O
+beta	O
+2	O
+-	O
+receptors	O
+in	O
+the	O
+human	O
+heart	O
+,	O
+their	O
+physiologic	O
+or	O
+pathologic	O
+roles	O
+remain	O
+to	O
+be	O
+defined	O
+.	O
+
+Hormones	O
+and	O
+risk	O
+of	O
+breast	B
+cancer	I
+.	O
+
+This	O
+paper	O
+reports	O
+the	O
+results	O
+of	O
+a	O
+study	O
+of	O
+50	O
+menopausal	O
+women	O
+receiving	O
+hormonal	O
+replacement	O
+therapy	O
+.	O
+
+The	O
+majority	O
+(	O
+29	O
+)	O
+had	O
+surgical	O
+menopause	O
+;	O
+their	O
+mean	O
+age	O
+was	O
+45	O
+.	O
+7	O
+years	O
+.	O
+
+It	O
+was	O
+hypothesized	O
+that	O
+progestins	O
+could	O
+equilibrate	O
+the	O
+effects	O
+of	O
+the	O
+estrogenic	O
+stimulation	O
+on	O
+the	O
+mammary	O
+and	O
+endometrial	O
+target	O
+tissues	O
+of	O
+women	O
+on	O
+hormonal	O
+replacement	O
+therapy	O
+.	O
+
+The	O
+treatment	O
+schedule	O
+consisted	O
+of	O
+conjugated	O
+estrogens	O
+(	O
+Premarin	O
+)	O
+1	O
+.	O
+25	O
+mg	O
+/	O
+day	O
+for	O
+21	O
+days	O
+and	O
+Medroxyprogesterone	O
+acetate	O
+10	O
+mg	O
+/	O
+day	O
+for	O
+10	O
+days	O
+in	O
+each	O
+month	O
+.	O
+
+The	O
+mean	O
+treatment	O
+period	O
+was	O
+18	O
+months	O
+.	O
+
+During	O
+the	O
+follow	O
+-	O
+up	O
+period	O
+,	O
+attention	O
+was	O
+paid	O
+to	O
+breast	O
+modifications	O
+as	O
+evidenced	O
+by	O
+symptomatology	O
+,	O
+physical	O
+examination	O
+,	O
+and	O
+plate	O
+thermography	O
+.	O
+
+Mastodynia	B
+was	O
+reported	O
+by	O
+21	O
+patients	O
+,	O
+and	O
+physical	O
+examination	O
+revealed	O
+a	O
+light	O
+increase	O
+in	O
+breast	O
+firmness	O
+in	O
+12	O
+women	O
+and	O
+a	O
+moderate	O
+increase	O
+in	O
+breast	O
+nodularity	O
+in	O
+2	O
+women	O
+.	O
+
+Themography	O
+confirmed	O
+the	O
+existence	O
+of	O
+an	O
+excessive	O
+breast	O
+stimulation	O
+in	O
+1	O
+women	O
+who	O
+complained	O
+of	O
+moderate	O
+mastodynia	B
+and	O
+in	O
+5	O
+of	O
+the	O
+7	O
+women	O
+who	O
+complained	O
+of	O
+severe	O
+mastodynia	B
+.	O
+
+Normalization	O
+was	O
+obtained	O
+by	O
+halving	O
+the	O
+estrogen	O
+dose	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+hormonal	O
+replacement	O
+therapy	O
+can	O
+be	O
+safely	O
+prescribed	O
+if	O
+the	O
+following	O
+criteria	O
+are	O
+satisfied	O
+:	O
+1	O
+)	O
+preliminary	O
+evaluation	O
+of	O
+patients	O
+from	O
+a	O
+clinical	O
+,	O
+metabolic	O
+,	O
+cytologic	O
+,	O
+and	O
+mammographic	O
+perspective	O
+;	O
+2	O
+)	O
+cyclic	O
+treatment	O
+schedule	O
+,	O
+with	O
+a	O
+progestative	O
+phase	O
+of	O
+10	O
+days	O
+;	O
+and	O
+3	O
+)	O
+periodic	O
+complete	O
+follow	O
+-	O
+up	O
+,	O
+with	O
+accurate	O
+thermographic	O
+evaluation	O
+of	O
+the	O
+breast	O
+target	O
+tissues	O
+.	O
+
+Early	O
+infections	B
+in	O
+kidney	O
+,	O
+heart	O
+,	O
+and	O
+liver	O
+transplant	O
+recipients	O
+on	O
+cyclosporine	O
+.	O
+
+Eighty	O
+-	O
+one	O
+renal	O
+,	O
+seventeen	O
+heart	O
+,	O
+and	O
+twenty	O
+-	O
+four	O
+liver	O
+transplant	O
+patients	O
+were	O
+followed	O
+for	O
+infection	B
+.	O
+
+Seventeen	O
+renal	O
+patients	O
+received	O
+azathioprine	O
+(	O
+Aza	O
+)	O
+and	O
+prednisone	O
+as	O
+part	O
+of	O
+a	O
+randomized	O
+trial	O
+of	O
+immunosuppression	O
+with	O
+21	O
+cyclosporine	O
+-	O
+and	O
+-	O
+prednisone	O
+-	O
+treated	O
+renal	O
+transplant	O
+patients	O
+.	O
+
+All	O
+others	O
+received	O
+cyclosporine	O
+and	O
+prednisone	O
+.	O
+
+The	O
+randomized	O
+Aza	O
+patients	O
+had	O
+more	O
+overall	O
+infections	B
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+and	O
+more	O
+nonviral	O
+infections	B
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+02	O
+)	O
+than	O
+the	O
+randomized	O
+cyclosporine	O
+patients	O
+.	O
+
+Heart	O
+and	O
+liver	O
+patients	O
+had	O
+more	O
+infections	B
+than	O
+cyclosporine	O
+renal	O
+patients	O
+but	O
+fewer	O
+infections	B
+than	O
+the	O
+Aza	O
+renal	O
+patients	O
+.	O
+
+There	O
+were	O
+no	O
+infectious	O
+deaths	O
+in	O
+renal	O
+transplant	O
+patients	O
+on	O
+cyclosporine	O
+or	O
+Aza	O
+,	O
+but	O
+infection	B
+played	O
+a	O
+major	O
+role	O
+in	O
+3	O
+out	O
+of	O
+6	O
+cardiac	O
+transplant	O
+deaths	O
+and	O
+in	O
+8	O
+out	O
+of	O
+9	O
+liver	O
+transplant	O
+deaths	O
+.	O
+
+Renal	O
+patients	O
+on	O
+cyclosporine	O
+had	O
+the	O
+fewest	O
+bacteremias	B
+.	O
+
+Analysis	O
+of	O
+site	O
+of	O
+infection	B
+showed	O
+a	O
+preponderance	O
+of	O
+abdominal	B
+infections	I
+in	O
+liver	O
+patients	O
+,	O
+intrathoracic	O
+infections	B
+in	O
+heart	O
+patients	O
+,	O
+and	O
+urinary	B
+tract	I
+infections	I
+in	O
+renal	O
+patients	O
+.	O
+
+Pulmonary	O
+infections	B
+were	O
+less	O
+common	O
+in	O
+cyclosporine	O
+-	O
+treated	O
+renal	O
+patients	O
+than	O
+in	O
+Aza	O
+-	O
+treated	O
+patients	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Aza	O
+patients	O
+had	O
+significantly	O
+more	O
+staphylococcal	B
+infections	I
+than	O
+all	O
+other	O
+transplant	O
+groups	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+005	O
+)	O
+,	O
+and	O
+systemic	O
+fungal	B
+infections	I
+occurred	O
+only	O
+in	O
+the	O
+liver	O
+transplant	O
+group	O
+.	O
+
+Cytomegalovirus	O
+(	O
+CMV	O
+)	O
+shedding	O
+or	O
+serological	O
+rises	O
+in	O
+antibody	O
+titer	O
+,	O
+or	O
+both	O
+occurred	O
+in	O
+78	O
+%	O
+of	O
+cyclosporine	O
+patients	O
+and	O
+76	O
+%	O
+of	O
+Aza	O
+patients	O
+.	O
+
+Of	O
+the	O
+cyclosporine	O
+patients	O
+,	O
+15	O
+%	O
+had	O
+symptoms	O
+related	O
+to	O
+CMV	B
+infection	I
+.	O
+
+Serological	O
+evidence	O
+for	O
+Epstein	B
+Barr	I
+Virus	I
+infection	I
+was	O
+found	O
+in	O
+20	O
+%	O
+of	O
+65	O
+cyclosporine	O
+patients	O
+studied	O
+.	O
+
+Three	O
+had	O
+associated	O
+symptoms	O
+,	O
+and	O
+one	O
+developed	O
+a	O
+lymphoma	B
+.	O
+
+Structure	O
+-	O
+activity	O
+and	O
+dose	O
+-	O
+effect	O
+relationships	O
+of	O
+the	O
+antagonism	O
+of	O
+picrotoxin	O
+-	O
+induced	O
+seizures	B
+by	O
+cholecystokinin	O
+,	O
+fragments	O
+and	O
+analogues	O
+of	O
+cholecystokinin	O
+in	O
+mice	O
+.	O
+
+Intraperitoneal	O
+administration	O
+of	O
+cholecystokinin	O
+octapeptide	O
+sulphate	O
+ester	O
+(	O
+CCK	O
+-	O
+8	O
+-	O
+SE	O
+)	O
+and	O
+nonsulphated	O
+cholecystokinin	O
+octapeptide	O
+(	O
+CCK	O
+-	O
+8	O
+-	O
+NS	O
+)	O
+enhanced	O
+the	O
+latency	O
+of	O
+seizures	B
+induced	O
+by	O
+picrotoxin	O
+in	O
+mice	O
+.	O
+
+Experiments	O
+with	O
+N	O
+-	O
+and	O
+C	O
+-	O
+terminal	O
+fragments	O
+revealed	O
+that	O
+the	O
+C	O
+-	O
+terminal	O
+tetrapeptide	O
+(	O
+CCK	O
+-	O
+5	O
+-	O
+8	O
+)	O
+was	O
+the	O
+active	O
+centre	O
+of	O
+the	O
+CCK	O
+octapeptide	O
+molecule	O
+.	O
+
+The	O
+analogues	O
+CCK	O
+-	O
+8	O
+-	O
+SE	O
+and	O
+CCK	O
+-	O
+8	O
+-	O
+NS	O
+(	O
+dose	O
+range	O
+0	O
+.	O
+2	O
+-	O
+6	O
+.	O
+4	O
+mumol	O
+/	O
+kg	O
+)	O
+and	O
+caerulein	O
+dose	O
+range	O
+0	O
+.	O
+1	O
+-	O
+0	O
+.	O
+8	O
+mumol	O
+/	O
+kg	O
+)	O
+showed	O
+bell	O
+-	O
+shaped	O
+dose	O
+-	O
+effect	O
+curves	O
+,	O
+with	O
+the	O
+greatest	O
+maximum	O
+inhibition	O
+for	O
+CCK	O
+-	O
+8	O
+-	O
+NS	O
+.	O
+
+The	O
+peptide	O
+CCK	O
+-	O
+5	O
+-	O
+8	O
+had	O
+weak	O
+anticonvulsant	O
+activity	O
+in	O
+comparison	O
+to	O
+the	O
+octapeptides	O
+,	O
+3	O
+.	O
+2	O
+mumol	O
+/	O
+kg	O
+and	O
+larger	O
+doses	O
+of	O
+the	O
+reference	O
+drug	O
+,	O
+diazepam	O
+,	O
+totally	O
+prevented	O
+picrotoxin	O
+-	O
+induced	O
+seizures	B
+and	O
+mortality	O
+.	O
+
+The	O
+maximum	O
+effect	O
+of	O
+the	O
+peptides	O
+tested	O
+was	O
+less	O
+than	O
+that	O
+of	O
+diazepam	O
+.	O
+
+Experiments	O
+with	O
+analogues	O
+and	O
+derivatives	O
+of	O
+CCK	O
+-	O
+5	O
+-	O
+8	O
+demonstrated	O
+that	O
+the	O
+effectiveness	O
+of	O
+the	O
+beta	O
+-	O
+alanyl	O
+derivatives	O
+of	O
+CCK	O
+-	O
+5	O
+-	O
+8	O
+were	O
+enhanced	O
+and	O
+that	O
+they	O
+were	O
+equipotent	O
+with	O
+CCK	O
+-	O
+8	O
+-	O
+SE	O
+.	O
+
+Of	O
+the	O
+CCK	O
+-	O
+2	O
+-	O
+8	O
+analogues	O
+,	O
+Ser	O
+(	O
+SO3H	O
+)	O
+7	O
+-	O
+Ac	O
+-	O
+CCK	O
+-	O
+2	O
+-	O
+8	O
+-	O
+SE	O
+and	O
+Thr	O
+(	O
+SO3H	O
+)	O
+7	O
+-	O
+Ac	O
+-	O
+CCK	O
+-	O
+2	O
+-	O
+8	O
+-	O
+SE	O
+and	O
+Hyp	O
+(	O
+SO3H	O
+)	O
+-	O
+Ac	O
+-	O
+CCK	O
+-	O
+2	O
+-	O
+8	O
+-	O
+SE	O
+were	O
+slightly	O
+more	O
+active	O
+than	O
+CCK	O
+-	O
+8	O
+-	O
+SE	O
+.	O
+
+Vasopressin	O
+as	O
+a	O
+possible	O
+contributor	O
+to	O
+hypertension	B
+.	O
+
+The	O
+role	O
+of	O
+vasopressin	O
+as	O
+a	O
+pressor	O
+agent	O
+to	O
+the	O
+hypertensive	B
+process	O
+was	O
+examined	O
+.	O
+
+Vasopressin	O
+plays	O
+a	O
+major	O
+role	O
+in	O
+the	O
+pathogenesis	O
+of	O
+DOCA	O
+-	O
+salt	O
+hypertension	B
+,	O
+since	O
+the	O
+elevation	O
+of	O
+blood	O
+pressure	O
+was	O
+not	O
+substantial	O
+in	O
+the	O
+rats	O
+with	O
+lithium	O
+-	O
+treated	O
+diabetes	B
+insipidus	I
+after	O
+DOCA	O
+-	O
+salt	O
+treatment	O
+.	O
+
+Administration	O
+of	O
+DDAVP	O
+which	O
+has	O
+antidiuretic	O
+action	O
+but	O
+minimal	O
+vasopressor	O
+effect	O
+failed	O
+to	O
+increase	O
+blood	O
+pressure	O
+to	O
+the	O
+levels	O
+observed	O
+after	O
+administration	O
+of	O
+AVP	O
+.	O
+
+Furthermore	O
+,	O
+the	O
+pressor	O
+action	O
+of	O
+vasopressin	O
+appears	O
+to	O
+be	O
+important	O
+in	O
+the	O
+development	O
+of	O
+this	O
+model	O
+of	O
+hypertension	B
+,	O
+since	O
+the	O
+enhanced	O
+pressor	O
+responsiveness	O
+to	O
+the	O
+hormone	O
+was	O
+observed	O
+in	O
+the	O
+initial	O
+stage	O
+of	O
+hypertension	B
+.	O
+
+Increased	O
+secretion	O
+of	O
+vasopressin	O
+from	O
+neurohypophysis	O
+also	O
+promotes	O
+the	O
+function	O
+of	O
+the	O
+hormone	O
+as	O
+a	O
+pathogenetic	O
+factor	O
+in	O
+hypertension	B
+.	O
+
+An	O
+unproportional	O
+release	O
+of	O
+vasopressin	O
+compared	O
+to	O
+plasma	O
+osmolality	O
+may	O
+be	O
+induced	O
+by	O
+the	O
+absence	O
+of	O
+an	O
+adjusting	O
+control	O
+of	O
+angiotensin	O
+II	O
+forming	O
+and	O
+receptor	O
+binding	O
+capacity	O
+for	O
+sodium	O
+balance	O
+in	O
+the	O
+brain	O
+.	O
+
+However	O
+,	O
+the	O
+role	O
+of	O
+vasopressin	O
+remains	O
+to	O
+be	O
+determined	O
+in	O
+human	O
+essential	O
+hypertension	B
+.	O
+
+Toxic	B
+hepatitis	I
+induced	O
+by	O
+disulfiram	O
+in	O
+a	O
+non	O
+-	O
+alcoholic	O
+.	O
+
+A	O
+reversible	O
+toxic	B
+liver	I
+damage	I
+was	O
+observed	O
+in	O
+a	O
+non	O
+-	O
+alcoholic	O
+woman	O
+treated	O
+with	O
+disulfiram	O
+.	O
+
+The	O
+causative	O
+relationship	O
+was	O
+proven	O
+by	O
+challenge	O
+.	O
+
+Atrial	B
+thrombosis	I
+involving	O
+the	O
+heart	O
+of	O
+F	O
+-	O
+344	O
+rats	O
+ingesting	O
+quinacrine	O
+hydrochloride	O
+.	O
+
+Quinacrine	O
+hydrochloride	O
+is	O
+toxic	O
+for	O
+the	O
+heart	O
+of	O
+F	O
+-	O
+344	O
+rats	O
+.	O
+
+Rats	O
+treated	O
+with	O
+500	O
+ppm	O
+quinacrine	O
+hydrochloride	O
+in	O
+the	O
+diet	O
+all	O
+developed	O
+a	O
+high	O
+incidence	O
+of	O
+left	O
+atrial	B
+thrombosis	I
+.	O
+
+The	O
+lesion	O
+was	O
+associated	O
+with	O
+cardiac	B
+hypertrophy	I
+and	O
+dilatation	O
+and	O
+focal	O
+myocardial	B
+degeneration	I
+.	O
+
+Rats	O
+died	O
+from	O
+cardiac	B
+hypertrophy	I
+with	O
+severe	O
+acute	O
+and	O
+chronic	O
+congestion	O
+of	O
+the	O
+lungs	O
+,	O
+liver	O
+,	O
+and	O
+other	O
+organs	O
+.	O
+
+Seventy	O
+percent	O
+of	O
+rats	O
+given	O
+250	O
+ppm	O
+quinacrine	O
+hydrochloride	O
+and	O
+1	O
+,	O
+000	O
+ppm	O
+sodium	O
+nitrite	O
+simultaneously	O
+in	O
+the	O
+diet	O
+had	O
+thrombosis	B
+of	O
+the	O
+atria	O
+of	O
+the	O
+heart	O
+,	O
+while	O
+untreated	O
+control	O
+rats	O
+in	O
+this	O
+laboratory	O
+did	O
+not	O
+have	O
+atrial	B
+thrombosis	I
+.	O
+
+Sodium	O
+nitrite	O
+in	O
+combination	O
+with	O
+quinacrine	O
+hydrochloride	O
+appeared	O
+to	O
+have	O
+no	O
+additional	O
+effect	O
+.	O
+
+Alternating	B
+sinus	I
+rhythm	I
+and	O
+intermittent	O
+sinoatrial	B
+block	I
+induced	O
+by	O
+propranolol	O
+.	O
+
+Alternating	B
+sinus	I
+rhythm	I
+and	O
+intermittent	O
+sinoatrial	B
+(	I
+S	I
+-	I
+A	I
+)	I
+block	I
+was	O
+observed	O
+in	O
+a	O
+57	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+,	O
+under	O
+treatment	O
+for	O
+angina	B
+with	O
+80	O
+mg	O
+propranolol	O
+daily	O
+.	O
+
+The	O
+electrocardiogram	O
+showed	O
+alternation	O
+of	O
+long	O
+and	O
+short	O
+P	O
+-	O
+P	O
+intervals	O
+and	O
+occasional	O
+pauses	O
+.	O
+
+These	O
+pauses	O
+were	O
+always	O
+preceded	O
+by	O
+the	O
+short	O
+P	O
+-	O
+P	O
+intervals	O
+and	O
+were	O
+usually	O
+followed	O
+by	O
+one	O
+or	O
+two	O
+P	O
+-	O
+P	O
+intervals	O
+of	O
+0	O
+.	O
+92	O
+-	O
+0	O
+.	O
+95	O
+s	O
+representing	O
+the	O
+basic	O
+sinus	O
+cycle	O
+.	O
+
+Following	O
+these	O
+basic	O
+sinus	O
+cycles	O
+,	O
+alternating	B
+rhythm	I
+started	O
+with	O
+the	O
+longer	O
+P	O
+-	O
+P	O
+interval	O
+.	O
+
+The	O
+long	O
+P	O
+-	O
+P	O
+intervals	O
+ranged	O
+between	O
+1	O
+.	O
+04	O
+-	O
+1	O
+.	O
+12	O
+s	O
+and	O
+the	O
+short	O
+P	O
+-	O
+P	O
+intervals	O
+between	O
+0	O
+.	O
+80	O
+-	O
+0	O
+.	O
+84	O
+s	O
+,	O
+respectively	O
+.	O
+
+The	O
+duration	O
+of	O
+the	O
+pauses	O
+were	O
+equal	O
+or	O
+almost	O
+equal	O
+to	O
+one	O
+short	O
+plus	O
+one	O
+long	O
+P	O
+-	O
+P	O
+interval	O
+or	O
+to	O
+twice	O
+the	O
+basic	O
+sinus	O
+cycle	O
+.	O
+
+In	O
+one	O
+recording	O
+a	O
+short	O
+period	O
+of	O
+regular	O
+sinus	O
+rhythm	O
+with	O
+intermittent	O
+2	O
+/	O
+1	O
+S	B
+-	I
+A	I
+block	I
+was	O
+observed	O
+.	O
+
+This	O
+short	O
+period	O
+of	O
+sinus	O
+rhythm	O
+was	O
+interrupted	O
+by	O
+sudden	O
+prolongation	O
+of	O
+the	O
+P	O
+-	O
+P	O
+interval	O
+starting	O
+the	O
+alternative	O
+rhythm	O
+.	O
+
+There	O
+were	O
+small	O
+changes	O
+in	O
+the	O
+shape	O
+of	O
+the	O
+P	O
+waves	O
+and	O
+P	O
+-	O
+R	O
+intervals	O
+.	O
+
+S	O
+-	O
+A	O
+conduction	O
+through	O
+two	O
+pathways	O
+,	O
+the	O
+first	O
+with	O
+2	O
+/	O
+1	O
+block	O
+the	O
+second	O
+having	O
+0	O
+.	O
+12	O
+-	O
+0	O
+.	O
+14	O
+s	O
+longer	O
+conduction	O
+time	O
+and	O
+with	O
+occasional	O
+2	O
+/	O
+1	O
+block	O
+was	O
+proposed	O
+for	O
+the	O
+explanation	O
+of	O
+the	O
+alternating	O
+P	O
+-	O
+P	O
+interval	O
+and	O
+other	O
+electrocardiographic	O
+features	O
+seen	O
+.	O
+
+Atropine	O
+1	O
+mg	O
+given	O
+intravenously	O
+resulted	O
+in	O
+shortening	O
+of	O
+all	O
+P	O
+-	O
+P	O
+intervals	O
+without	O
+changing	O
+the	O
+rhythm	O
+.	O
+
+The	O
+abnormal	O
+rhythm	O
+disappeared	O
+with	O
+the	O
+withdrawal	O
+of	O
+propranolol	O
+and	O
+when	O
+the	O
+drug	O
+was	O
+restarted	O
+a	O
+2	O
+/	O
+1	O
+S	B
+-	I
+A	I
+block	I
+was	O
+seen	O
+.	O
+
+This	O
+was	O
+accepted	O
+as	O
+evidence	O
+for	O
+propranolol	O
+being	O
+the	O
+cause	O
+of	O
+this	O
+conduction	B
+disorder	I
+.	O
+
+Antitumor	O
+effect	O
+,	O
+cardiotoxicity	B
+,	O
+and	O
+nephrotoxicity	B
+of	O
+doxorubicin	O
+in	O
+the	O
+IgM	O
+solid	O
+immunocytoma	B
+-	O
+bearing	O
+LOU	O
+/	O
+M	O
+/	O
+WSL	O
+rat	O
+.	O
+
+Antitumor	O
+activity	O
+,	O
+cardiotoxicity	B
+,	O
+and	O
+nephrotoxicity	B
+induced	O
+by	O
+doxorubicin	O
+were	O
+studied	O
+in	O
+LOU	O
+/	O
+M	O
+/	O
+WSL	O
+inbred	O
+rats	O
+each	O
+bearing	O
+a	O
+transplantable	O
+solid	O
+IgM	O
+immunocytoma	B
+.	O
+
+Animals	O
+with	O
+a	O
+tumor	B
+(	O
+diameter	O
+,	O
+15	O
+.	O
+8	O
++	O
+/	O
+-	O
+3	O
+.	O
+3	O
+mm	O
+)	O
+were	O
+treated	O
+with	O
+iv	O
+injections	O
+of	O
+doxorubicin	O
+on	O
+5	O
+consecutive	O
+days	O
+,	O
+followed	O
+by	O
+1	O
+weekly	O
+injection	O
+for	O
+7	O
+weeks	O
+(	O
+dose	O
+range	O
+,	O
+0	O
+.	O
+015	O
+-	O
+4	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+body	O
+wt	O
+)	O
+.	O
+
+Tumor	B
+regression	O
+was	O
+observed	O
+with	O
+0	O
+.	O
+5	O
+mg	O
+doxorubicin	O
+/	O
+kg	O
+.	O
+
+Complete	O
+disappearance	O
+of	O
+the	O
+tumor	B
+was	O
+induced	O
+with	O
+1	O
+.	O
+0	O
+mg	O
+doxorubicin	O
+/	O
+kg	O
+.	O
+
+Histologic	O
+evidence	O
+of	O
+cardiotoxicity	B
+scored	O
+as	O
+grade	O
+III	O
+was	O
+only	O
+observed	O
+at	O
+a	O
+dose	O
+of	O
+1	O
+.	O
+0	O
+mg	O
+doxorubicin	O
+/	O
+kg	O
+.	O
+
+Light	O
+microscopic	O
+evidence	O
+of	O
+renal	B
+damage	I
+was	O
+seen	O
+above	O
+a	O
+dose	O
+of	O
+0	O
+.	O
+5	O
+mg	O
+doxorubicin	O
+/	O
+kg	O
+,	O
+which	O
+resulted	O
+in	O
+albuminuria	B
+and	O
+very	O
+low	O
+serum	O
+albumin	O
+levels	O
+.	O
+
+In	O
+the	O
+group	O
+that	O
+received	O
+1	O
+.	O
+0	O
+mg	O
+doxorubicin	O
+/	O
+kg	O
+,	O
+the	O
+serum	O
+albumin	O
+level	O
+decreased	O
+from	O
+33	O
+.	O
+6	O
++	O
+/	O
+-	O
+4	O
+.	O
+1	O
+to	O
+1	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+g	O
+/	O
+liter	O
+.	O
+
+Ascites	B
+and	O
+hydrothorax	B
+were	O
+observed	O
+simultaneously	O
+.	O
+
+The	O
+same	O
+experiments	O
+were	O
+performed	O
+with	O
+non	O
+-	O
+tumor	B
+-	O
+bearing	O
+rats	O
+,	O
+in	O
+which	O
+no	O
+major	O
+differences	O
+were	O
+observed	O
+.	O
+
+In	O
+conclusion	O
+,	O
+antitumor	O
+activity	O
+,	O
+cardiotoxicity	B
+,	O
+and	O
+nephrotoxicity	B
+were	O
+studied	O
+simultaneously	O
+in	O
+the	O
+same	O
+LOU	O
+/	O
+M	O
+/	O
+WSL	O
+rat	O
+.	O
+
+Albuminuria	B
+due	O
+to	O
+renal	B
+damage	I
+led	O
+to	O
+extremely	O
+low	O
+serum	O
+albumin	O
+levels	O
+,	O
+so	O
+ascites	B
+and	O
+hydrothorax	B
+were	O
+not	O
+necessarily	O
+a	O
+consequence	O
+of	O
+the	O
+observed	O
+cardiomyopathy	B
+.	O
+
+Intraoperative	O
+bradycardia	B
+and	O
+hypotension	B
+associated	O
+with	O
+timolol	O
+and	O
+pilocarpine	O
+eye	O
+drops	O
+.	O
+
+A	O
+69	O
+-	O
+yr	O
+-	O
+old	O
+man	O
+,	O
+who	O
+was	O
+concurrently	O
+being	O
+treated	O
+with	O
+pilocarpine	O
+nitrate	O
+and	O
+timolol	O
+maleate	O
+eye	O
+drops	O
+,	O
+developed	O
+a	O
+bradycardia	B
+and	O
+became	O
+hypotensive	B
+during	O
+halothane	O
+anaesthesia	O
+.	O
+
+Both	O
+timolol	O
+and	O
+pilocarpine	O
+were	O
+subsequently	O
+identified	O
+in	O
+a	O
+24	O
+-	O
+h	O
+collection	O
+of	O
+urine	O
+.	O
+
+Timolol	O
+(	O
+but	O
+not	O
+pilocarpine	O
+)	O
+was	O
+detected	O
+in	O
+a	O
+sample	O
+of	O
+plasma	O
+removed	O
+during	O
+surgery	O
+;	O
+the	O
+plasma	O
+concentration	O
+of	O
+timolol	O
+(	O
+2	O
+.	O
+6	O
+ng	O
+ml	O
+-	O
+1	O
+)	O
+was	O
+consistent	O
+with	O
+partial	O
+beta	O
+-	O
+adrenoceptor	O
+blockade	O
+.	O
+
+It	O
+is	O
+postulated	O
+that	O
+this	O
+action	O
+may	O
+have	O
+been	O
+enhanced	O
+during	O
+halothane	O
+anaesthesia	O
+with	O
+resultant	O
+bradycardia	B
+and	O
+hypotension	B
+.	O
+
+Pilocarpine	O
+may	O
+have	O
+had	O
+a	O
+contributory	O
+effect	O
+.	O
+
+Succinylcholine	O
+apnoea	B
+:	O
+attempted	O
+reversal	O
+with	O
+anticholinesterases	O
+.	O
+
+Anticholinesterases	O
+were	O
+administered	O
+in	O
+an	O
+attempt	O
+to	O
+antagonize	O
+prolonged	O
+neuromuscular	B
+blockade	I
+following	O
+the	O
+administration	O
+of	O
+succinylcholine	O
+in	O
+a	O
+patient	O
+later	O
+found	O
+to	O
+be	O
+homozygous	O
+for	O
+atypical	O
+plasma	O
+cholinesterase	O
+.	O
+
+Edrophonium	O
+10	O
+mg	O
+,	O
+given	O
+74	O
+min	O
+after	O
+succinylcholine	O
+,	O
+when	O
+train	O
+-	O
+of	O
+-	O
+four	O
+stimulation	O
+was	O
+characteristic	O
+of	O
+phase	O
+II	O
+block	O
+,	O
+produced	O
+partial	O
+antagonism	O
+which	O
+was	O
+not	O
+sustained	O
+.	O
+
+Repeated	O
+doses	O
+of	O
+edrophonium	O
+to	O
+70	O
+mg	O
+and	O
+neostigmine	O
+to	O
+2	O
+.	O
+5	O
+mg	O
+did	O
+not	O
+antagonize	O
+or	O
+augment	O
+the	O
+block	O
+.	O
+
+Spontaneous	O
+respiration	O
+recommenced	O
+200	O
+min	O
+after	O
+succinylcholine	O
+administration	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+anticholinesterases	O
+are	O
+only	O
+partially	O
+effective	O
+in	O
+restoring	O
+neuromuscular	O
+function	O
+in	O
+succinylcholine	O
+apnoea	B
+despite	O
+muscle	O
+twitch	O
+activity	O
+typical	O
+of	O
+phase	O
+II	O
+block	O
+.	O
+
+Effect	O
+of	O
+doxorubicin	O
+on	O
+[	O
+omega	O
+-	O
+I	O
+-	O
+131	O
+]	O
+heptadecanoic	O
+acid	O
+myocardial	O
+scintigraphy	O
+and	O
+echocardiography	O
+in	O
+dogs	O
+.	O
+
+The	O
+effects	O
+of	O
+serial	O
+treatment	O
+with	O
+doxorubicin	O
+on	O
+dynamic	O
+myocardial	O
+scintigraphy	O
+with	O
+[	O
+omega	O
+-	O
+I	O
+-	O
+131	O
+]	O
+heptadecanoic	O
+acid	O
+(	O
+I	O
+-	O
+131	O
+HA	O
+)	O
+,	O
+and	O
+on	O
+global	O
+left	O
+-	O
+ventricular	O
+function	O
+determined	O
+echocardiographically	O
+,	O
+were	O
+studied	O
+in	O
+a	O
+group	O
+of	O
+nine	O
+mongrel	O
+dogs	O
+.	O
+
+Total	O
+extractable	O
+myocardial	O
+lipid	O
+was	O
+compared	O
+postmortem	O
+between	O
+a	O
+group	O
+of	O
+control	O
+dogs	O
+and	O
+doxorubicin	O
+-	O
+treated	O
+dogs	O
+.	O
+
+A	O
+significant	O
+and	O
+then	O
+progressive	O
+fall	O
+in	O
+global	O
+LV	O
+function	O
+was	O
+observed	O
+at	O
+a	O
+cumulative	O
+doxorubicin	O
+dose	O
+of	O
+4	O
+mg	O
+/	O
+kg	O
+.	O
+
+A	O
+significant	O
+increase	O
+in	O
+the	O
+myocardial	O
+t1	O
+/	O
+2	O
+of	O
+the	O
+I	O
+-	O
+131	O
+HA	O
+was	O
+observed	O
+only	O
+at	O
+a	O
+higher	O
+cumulative	O
+dose	O
+,	O
+10	O
+mg	O
+/	O
+kg	O
+.	O
+
+No	O
+significant	O
+alteration	O
+in	O
+total	O
+extractable	O
+myocardial	O
+lipids	O
+was	O
+observed	O
+between	O
+control	O
+dogs	O
+and	O
+those	O
+treated	O
+with	O
+doxorubicin	O
+.	O
+
+Our	O
+findings	O
+suggest	O
+that	O
+the	O
+changes	O
+leading	O
+to	O
+an	O
+alteration	O
+of	O
+myocardial	O
+dynamic	O
+imaging	O
+with	O
+I	O
+-	O
+131	O
+HA	O
+are	O
+not	O
+the	O
+initiating	O
+factor	O
+in	O
+doxorubicin	O
+cardiotoxicity	B
+.	O
+
+Hemodynamics	O
+and	O
+myocardial	O
+metabolism	O
+under	O
+deliberate	O
+hypotension	B
+.	O
+
+An	O
+experimental	O
+study	O
+in	O
+dogs	O
+.	O
+
+Coronary	O
+blood	O
+flow	O
+,	O
+cardiac	O
+work	O
+and	O
+metabolism	O
+were	O
+studied	O
+in	O
+dogs	O
+under	O
+sodium	O
+nitroprusside	O
+(	O
+SNP	O
+)	O
+and	O
+trimetaphan	O
+(	O
+TMP	O
+)	O
+deliberate	O
+hypotension	B
+(	O
+20	O
+%	O
+and	O
+40	O
+%	O
+mean	O
+pressure	O
+decrease	O
+from	O
+baseline	O
+)	O
+.	O
+
+Regarding	O
+the	O
+effects	O
+of	O
+drug	O
+-	O
+induced	O
+hypotension	B
+on	O
+coronary	O
+blood	O
+flow	O
+,	O
+aortic	O
+and	O
+coronary	O
+sinus	O
+metabolic	O
+data	O
+(	O
+pH	O
+,	O
+pO2	O
+,	O
+pCO2	O
+)	O
+we	O
+could	O
+confirm	O
+that	O
+nitroprusside	O
+hypotension	B
+could	O
+be	O
+safely	O
+used	O
+to	O
+30	O
+%	O
+mean	O
+blood	O
+pressure	O
+decrease	O
+from	O
+control	O
+,	O
+trimetaphan	O
+hypotension	B
+to	O
+20	O
+%	O
+mean	O
+blood	O
+pressure	O
+decrease	O
+.	O
+
+Cardiac	O
+work	O
+was	O
+significantly	O
+reduced	O
+during	O
+SNP	O
+hypotension	B
+.	O
+
+Myocardial	O
+O2	O
+consumption	O
+and	O
+O2	O
+availability	O
+were	O
+directly	O
+dependent	O
+on	O
+the	O
+coronary	O
+perfusion	O
+.	O
+
+Careful	O
+invasive	O
+monitoring	O
+of	O
+the	O
+blood	O
+pressure	O
+,	O
+blood	O
+gases	O
+and	O
+of	O
+the	O
+ECG	O
+ST	O
+-	O
+T	O
+segment	O
+is	O
+mandatory	O
+.	O
+
+Evidence	O
+for	O
+a	O
+selective	O
+brain	O
+noradrenergic	O
+involvement	O
+in	O
+the	O
+locomotor	O
+stimulant	O
+effects	O
+of	O
+amphetamine	O
+in	O
+the	O
+rat	O
+.	O
+
+Male	O
+rats	O
+received	O
+the	O
+noradrenaline	O
+neurotoxin	O
+DSP4	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+7	O
+days	O
+prior	O
+to	O
+injection	O
+of	O
+D	O
+-	O
+amphetamine	O
+(	O
+10	O
+or	O
+40	O
+mumol	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+The	O
+hyperactivity	B
+induced	O
+by	O
+D	O
+-	O
+amphetamine	O
+(	O
+10	O
+mumol	O
+/	O
+kg	O
+)	O
+was	O
+significantly	O
+reduced	O
+by	O
+DSP4	O
+pretreatment	O
+.	O
+
+However	O
+,	O
+the	O
+increased	O
+rearings	O
+and	O
+the	O
+amphetamine	O
+-	O
+induced	O
+stereotypies	B
+were	O
+not	O
+blocked	O
+by	O
+pretreatment	O
+with	O
+DSP4	O
+.	O
+
+The	O
+reduction	O
+of	O
+amphetamine	O
+hyperactivity	B
+induced	O
+by	O
+DSP4	O
+was	O
+blocked	O
+by	O
+pretreatment	O
+with	O
+the	O
+noradrenaline	O
+-	O
+uptake	O
+blocking	O
+agent	O
+,	O
+desipramine	O
+,	O
+which	O
+prevents	O
+the	O
+neurotoxic	B
+action	O
+of	O
+DSP4	O
+.	O
+
+The	O
+present	O
+results	O
+suggest	O
+a	O
+selective	O
+involvement	O
+of	O
+central	O
+noradrenergic	O
+neurones	O
+in	O
+the	O
+locomotor	O
+stimulant	O
+effect	O
+of	O
+amphetamine	O
+in	O
+the	O
+rat	O
+.	O
+
+Accelerated	B
+junctional	I
+rhythms	I
+during	O
+oral	O
+verapamil	O
+therapy	O
+.	O
+
+This	O
+study	O
+examined	O
+the	O
+frequency	O
+of	O
+atrioventricular	O
+(	O
+AV	O
+)	O
+dissociation	O
+and	O
+accelerated	B
+junctional	I
+rhythms	I
+in	O
+59	O
+patients	O
+receiving	O
+oral	O
+verapamil	O
+.	O
+
+Accelerated	B
+junctional	I
+rhythms	I
+and	O
+AV	O
+dissociation	O
+were	O
+frequent	O
+in	O
+patients	O
+with	O
+supraventricular	B
+tachyarrhythmias	I
+,	O
+particularly	O
+AV	O
+nodal	O
+reentry	O
+.	O
+
+Verapamil	O
+administration	O
+to	O
+these	O
+patients	O
+led	O
+to	O
+an	O
+asymptomatic	O
+increase	O
+in	O
+activity	O
+of	O
+these	O
+junctional	O
+pacemakers	O
+.	O
+
+In	O
+patients	O
+with	O
+various	O
+chest	B
+pain	I
+syndromes	O
+,	O
+verapamil	O
+neither	O
+increased	O
+the	O
+frequency	O
+of	O
+junctional	O
+rhythms	O
+nor	O
+suppressed	O
+their	O
+role	O
+as	O
+escape	O
+rhythms	O
+under	O
+physiologically	O
+appropriate	O
+circumstances	O
+.	O
+
+Interstrain	O
+variation	O
+in	O
+acute	O
+toxic	O
+response	O
+to	O
+caffeine	O
+among	O
+inbred	O
+mice	O
+.	O
+
+Acute	O
+toxic	O
+dosage	O
+-	O
+dependent	O
+behavioral	O
+effects	O
+of	O
+caffeine	O
+were	O
+compared	O
+in	O
+adult	O
+males	O
+from	O
+seven	O
+inbred	O
+mouse	O
+strains	O
+(	O
+A	O
+/	O
+J	O
+,	O
+BALB	O
+/	O
+cJ	O
+,	O
+CBA	O
+/	O
+J	O
+,	O
+C3H	O
+/	O
+HeJ	O
+,	O
+C57BL	O
+/	O
+6J	O
+,	O
+DBA	O
+/	O
+2J	O
+,	O
+SWR	O
+/	O
+J	O
+)	O
+.	O
+
+C57BL	O
+/	O
+6J	O
+,	O
+chosen	O
+as	O
+a	O
+"	O
+prototypic	O
+"	O
+mouse	O
+strain	O
+,	O
+was	O
+used	O
+to	O
+determine	O
+behavioral	O
+responses	O
+to	O
+a	O
+broad	O
+range	O
+(	O
+5	O
+-	O
+500	O
+mg	O
+/	O
+kg	O
+)	O
+of	O
+caffeine	O
+doses	O
+.	O
+
+Five	O
+phenotypic	O
+characteristics	O
+-	O
+-	O
+locomotor	O
+activity	O
+,	O
+righting	O
+ability	O
+,	O
+clonic	B
+seizure	I
+induction	O
+,	O
+stress	O
+-	O
+induced	O
+lethality	O
+,	O
+death	O
+without	O
+external	O
+stress	O
+-	O
+-	O
+were	O
+scored	O
+at	O
+various	O
+caffeine	O
+doses	O
+in	O
+drug	O
+-	O
+naive	O
+animals	O
+under	O
+empirically	O
+optimized	O
+,	O
+rigidly	O
+constant	O
+experimental	O
+conditions	O
+.	O
+
+Mice	O
+(	O
+n	O
+=	O
+12	O
+for	O
+each	O
+point	O
+)	O
+received	O
+single	O
+IP	O
+injections	O
+of	O
+a	O
+fixed	O
+volume	O
+/	O
+g	O
+body	O
+weight	O
+of	O
+physiological	O
+saline	O
+carrier	O
+with	O
+or	O
+without	O
+caffeine	O
+in	O
+doses	O
+ranging	O
+from	O
+125	O
+-	O
+500	O
+mg	O
+/	O
+kg	O
+.	O
+
+Loss	O
+of	O
+righting	O
+ability	O
+was	O
+scored	O
+at	O
+1	O
+,	O
+3	O
+,	O
+5	O
+min	O
+post	O
+dosing	O
+and	O
+at	O
+5	O
+min	O
+intervals	O
+thereafter	O
+for	O
+20	O
+min	O
+.	O
+
+In	O
+the	O
+same	O
+animals	O
+the	O
+occurrence	O
+of	O
+clonic	B
+seizures	I
+was	O
+scored	O
+as	O
+to	O
+time	O
+of	O
+onset	O
+and	O
+severity	O
+for	O
+20	O
+min	O
+after	O
+drug	O
+administration	O
+.	O
+
+When	O
+these	O
+proceeded	O
+to	O
+tonic	B
+seizures	I
+,	O
+death	O
+occurred	O
+in	O
+less	O
+than	O
+20	O
+min	O
+.	O
+
+Animals	O
+surviving	O
+for	O
+20	O
+min	O
+were	O
+immediately	O
+stressed	O
+by	O
+a	O
+swim	O
+test	O
+in	O
+25	O
+degrees	O
+C	O
+water	O
+,	O
+and	O
+death	O
+-	O
+producing	O
+tonic	B
+seizures	I
+were	O
+scored	O
+for	O
+2	O
+min	O
+.	O
+
+In	O
+other	O
+animals	O
+locomotor	O
+activity	O
+was	O
+measured	O
+15	O
+or	O
+60	O
+min	O
+after	O
+caffeine	O
+administration	O
+.	O
+
+By	O
+any	O
+single	O
+behavioral	O
+criterion	O
+or	O
+a	O
+combination	O
+of	O
+these	O
+criteria	O
+,	O
+marked	O
+differences	O
+in	O
+response	O
+to	O
+toxic	O
+caffeine	O
+doses	O
+were	O
+observed	O
+between	O
+strains	O
+.	O
+
+These	O
+results	O
+indicate	O
+that	O
+behavioral	O
+toxicity	B
+testing	O
+of	O
+alkylxanthines	O
+in	O
+a	O
+single	O
+mouse	O
+strain	O
+may	O
+be	O
+misleading	O
+and	O
+suggest	O
+that	O
+toxic	O
+responses	O
+of	O
+the	O
+central	O
+nervous	O
+system	O
+to	O
+this	O
+class	O
+of	O
+compounds	O
+are	O
+genetically	O
+influenced	O
+in	O
+mammals	O
+.	O
+
+Treatment	O
+of	O
+ovarian	B
+cancer	I
+with	O
+a	O
+combination	O
+of	O
+cis	O
+-	O
+platinum	O
+,	O
+adriamycin	O
+,	O
+cyclophosphamide	O
+and	O
+hexamethylmelamine	O
+.	O
+
+During	O
+the	O
+last	O
+2	O
+1	O
+/	O
+2	O
+years	O
+,	O
+38	O
+patients	O
+with	O
+ovarian	B
+cancer	I
+were	O
+treated	O
+with	O
+a	O
+combination	O
+of	O
+cisplatinum	O
+(	O
+CPDD	O
+)	O
+,	O
+50	O
+mg	O
+/	O
+m2	O
+,	O
+adriamycin	O
+,	O
+30	O
+mg	O
+/	O
+m2	O
+,	O
+cyclophosphamide	O
+,	O
+300	O
+mg	O
+/	O
+m2	O
+,	O
+on	O
+day	O
+1	O
+;	O
+and	O
+hexamethylmelamine	O
+(	O
+HMM	O
+)	O
+,	O
+6	O
+mg	O
+/	O
+kg	O
+daily	O
+,	O
+for	O
+14	O
+days	O
+.	O
+
+Each	O
+course	O
+was	O
+repeated	O
+monthly	O
+.	O
+
+2	O
+patients	O
+had	O
+stage	O
+II	O
+,	O
+14	O
+stage	O
+III	O
+and	O
+22	O
+stage	O
+IV	O
+disease	O
+.	O
+
+14	O
+of	O
+the	O
+38	O
+patients	O
+were	O
+previously	O
+treated	O
+with	O
+chemotherapy	O
+,	O
+1	O
+with	O
+radiation	O
+,	O
+6	O
+with	O
+both	O
+chemotherapy	O
+and	O
+radiation	O
+,	O
+and	O
+17	O
+did	O
+not	O
+have	O
+any	O
+treatment	O
+before	O
+CPDD	O
+combination	O
+.	O
+
+31	O
+of	O
+the	O
+38	O
+cases	O
+(	O
+81	O
+.	O
+5	O
+%	O
+)	O
+demonstrated	O
+objective	O
+responses	O
+lasting	O
+for	O
+2	O
+months	O
+or	O
+more	O
+.	O
+
+These	O
+responses	O
+were	O
+partial	O
+in	O
+19	O
+and	O
+complete	O
+in	O
+12	O
+cases	O
+.	O
+
+Hematologic	B
+toxicity	I
+was	O
+moderate	O
+and	O
+with	O
+reversible	O
+anemia	B
+developing	O
+in	O
+71	O
+%	O
+of	O
+patients	O
+.	O
+
+Gastrointestinal	O
+side	O
+effects	O
+from	O
+CPDD	O
+were	O
+universal	O
+.	O
+
+HMM	O
+gastrointestinal	B
+toxicity	I
+necessitated	O
+discontinuation	O
+of	O
+the	O
+drug	O
+in	O
+5	O
+patients	O
+.	O
+
+Severe	O
+nephrotoxicity	B
+was	O
+observed	O
+in	O
+2	O
+patients	O
+but	O
+was	O
+reversible	O
+.	O
+
+There	O
+were	O
+no	O
+drug	O
+-	O
+related	O
+deaths	O
+.	O
+
+Nontraumatic	O
+dissecting	B
+aneurysm	I
+of	O
+the	O
+basilar	O
+artery	O
+.	O
+
+A	O
+case	O
+of	O
+nontraumatic	O
+dissecting	B
+aneurysm	I
+of	O
+the	O
+basilar	O
+artery	O
+in	O
+association	O
+with	O
+hypertension	B
+,	O
+smoke	O
+,	O
+and	O
+oral	O
+contraceptives	O
+is	O
+reported	O
+in	O
+a	O
+young	O
+female	O
+patient	O
+with	O
+a	O
+locked	B
+-	I
+in	I
+syndrome	I
+.	O
+
+A	O
+method	O
+for	O
+the	O
+measurement	O
+of	O
+tremor	B
+,	O
+and	O
+a	O
+comparison	O
+of	O
+the	O
+effects	O
+of	O
+tocolytic	O
+beta	O
+-	O
+mimetics	O
+.	O
+
+A	O
+method	O
+permitting	O
+measurement	O
+of	O
+finger	O
+tremor	B
+as	O
+a	O
+displacement	O
+-	O
+time	O
+curve	O
+is	O
+described	O
+,	O
+using	O
+a	O
+test	O
+system	O
+with	O
+simple	O
+amplitude	O
+calibration	O
+.	O
+
+The	O
+coordinates	O
+of	O
+the	O
+inversion	O
+points	O
+of	O
+the	O
+displacement	O
+-	O
+time	O
+curves	O
+were	O
+transferred	O
+through	O
+graphical	O
+input	O
+equipment	O
+to	O
+punched	O
+tape	O
+.	O
+
+By	O
+means	O
+of	O
+a	O
+computer	O
+program	O
+,	O
+periods	O
+and	O
+amplitudes	O
+of	O
+tremor	B
+oscillations	O
+were	O
+calculated	O
+and	O
+classified	O
+.	O
+
+The	O
+event	O
+frequency	O
+for	O
+each	O
+class	O
+of	O
+periods	O
+and	O
+amplitudes	O
+was	O
+determined	O
+.	O
+
+The	O
+actions	O
+of	O
+fenoterol	O
+-	O
+hydrobromide	O
+,	O
+ritodrin	O
+-	O
+HCl	O
+and	O
+placebo	O
+given	O
+to	O
+10	O
+healthy	O
+subjects	O
+by	O
+intravenous	O
+infusion	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+crossover	O
+study	O
+were	O
+tested	O
+by	O
+this	O
+method	O
+.	O
+
+At	O
+therapeutic	O
+doses	O
+both	O
+substances	O
+raised	O
+the	O
+mean	O
+tremor	B
+amplitude	O
+to	O
+about	O
+three	O
+times	O
+the	O
+control	O
+level	O
+.	O
+
+At	O
+the	O
+same	O
+time	O
+,	O
+the	O
+mean	O
+period	O
+within	O
+each	O
+class	O
+of	O
+amplitudes	O
+shortened	O
+by	O
+10	O
+-	O
+-	O
+20	O
+ms	O
+,	O
+whereas	O
+the	O
+mean	O
+periods	O
+calculated	O
+from	O
+all	O
+oscillations	O
+together	O
+did	O
+not	O
+change	O
+significantly	O
+.	O
+
+After	O
+the	O
+end	O
+of	O
+fenoterol	O
+-	O
+hydrobromide	O
+infusion	O
+,	O
+tremor	B
+amplitudes	O
+decreased	O
+significantly	O
+faster	O
+than	O
+those	O
+following	O
+ritodrin	O
+-	O
+HCl	O
+infusion	O
+.	O
+
+Propylthiouracil	O
+-	O
+induced	O
+hepatic	B
+damage	I
+.	O
+
+Two	O
+cases	O
+of	O
+propylthiouracil	O
+-	O
+induced	O
+liver	B
+damage	I
+have	O
+been	O
+observed	O
+.	O
+
+The	O
+first	O
+case	O
+is	O
+of	O
+an	O
+acute	O
+type	O
+of	O
+damage	O
+,	O
+proven	O
+by	O
+rechallenge	O
+;	O
+the	O
+second	O
+presents	O
+a	O
+clinical	O
+and	O
+histologic	O
+picture	O
+resembling	O
+chronic	B
+active	I
+hepatitis	I
+,	O
+with	O
+spontaneous	O
+remission	O
+.	O
+
+Studies	O
+on	O
+the	O
+bradycardia	B
+induced	O
+by	O
+bepridil	O
+.	O
+
+Bepridil	O
+,	O
+a	O
+novel	O
+active	O
+compound	O
+for	O
+prophylactic	O
+treatment	O
+of	O
+anginal	B
+attacks	I
+,	O
+induced	O
+persistent	O
+bradycardia	B
+and	O
+a	O
+non	O
+-	O
+specific	O
+anti	O
+-	O
+tachycardial	B
+effect	O
+,	O
+the	O
+mechanisms	O
+of	O
+which	O
+were	O
+investigated	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+.	O
+
+In	O
+vitro	O
+perfusion	O
+of	O
+bepridil	O
+in	O
+the	O
+life	O
+-	O
+support	O
+medium	O
+for	O
+isolated	O
+sino	O
+-	O
+atrial	O
+tissue	O
+from	O
+rabbit	O
+heart	O
+,	O
+caused	O
+a	O
+reduction	O
+in	O
+action	O
+potential	O
+(	O
+AP	O
+)	O
+spike	O
+frequency	O
+(	O
+recorded	O
+by	O
+KCl	O
+microelectrodes	O
+)	O
+starting	O
+at	O
+doses	O
+of	O
+5	O
+X	O
+10	O
+(	O
+-	O
+6	O
+)	O
+M	O
+.	O
+
+This	O
+effect	O
+was	O
+dose	O
+-	O
+dependent	O
+up	O
+to	O
+concentrations	O
+of	O
+5	O
+X	O
+10	O
+(	O
+-	O
+5	O
+)	O
+M	O
+,	O
+whereupon	O
+blockade	O
+of	O
+sinus	O
+activity	O
+set	O
+in	O
+.	O
+
+Bepridil	O
+at	O
+a	O
+dose	O
+of	O
+5	O
+X	O
+10	O
+(	O
+-	O
+6	O
+)	O
+M	O
+,	O
+induced	O
+a	O
+concomitant	O
+reduction	O
+in	O
+AP	O
+amplitude	O
+(	O
+falling	O
+from	O
+71	O
++	O
+/	O
+-	O
+8	O
+mV	O
+to	O
+47	O
++	O
+/	O
+-	O
+6	O
+mV	O
+)	O
+,	O
+maximum	O
+systolic	O
+depolarization	O
+velocity	O
+(	O
+phase	O
+0	O
+)	O
+which	O
+fell	O
+from	O
+1	O
+.	O
+85	O
++	O
+/	O
+-	O
+0	O
+.	O
+35	O
+V	O
+/	O
+s	O
+to	O
+0	O
+.	O
+84	O
++	O
+/	O
+-	O
+0	O
+.	O
+28	O
+V	O
+/	O
+s	O
+,	O
+together	O
+with	O
+maximum	O
+diastolic	O
+depolarization	O
+velocity	O
+(	O
+phase	O
+4	O
+)	O
+which	O
+fell	O
+from	O
+38	O
++	O
+/	O
+-	O
+3	O
+mV	O
+/	O
+s	O
+to	O
+24	O
++	O
+/	O
+-	O
+5	O
+mV	O
+/	O
+s	O
+.	O
+
+In	O
+vivo	O
+injection	O
+of	O
+bepridil	O
+at	O
+a	O
+dose	O
+of	O
+5	O
+mg	O
+/	O
+kg	O
+(	O
+i	O
+.	O
+v	O
+.	O
+)	O
+into	O
+6	O
+anaesthetized	O
+dogs	O
+which	O
+had	O
+undergone	O
+ablation	O
+of	O
+all	O
+the	O
+extrinsic	O
+cardiac	O
+afferent	O
+nerve	O
+supply	O
+,	O
+together	O
+with	O
+a	O
+bilateral	O
+medullo	O
+-	O
+adrenalectomy	O
+,	O
+caused	O
+a	O
+marked	O
+reduction	O
+in	O
+heart	O
+rate	O
+which	O
+fell	O
+from	O
+98	O
+.	O
+7	O
++	O
+/	O
+-	O
+4	O
+.	O
+2	O
+beats	O
+/	O
+min	O
+to	O
+76	O
++	O
+/	O
+-	O
+5	O
+.	O
+3	O
+beats	O
+/	O
+min	O
+sustained	O
+for	O
+more	O
+than	O
+45	O
+min	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+bepridil	O
+reduces	O
+heart	O
+rate	O
+by	O
+acting	O
+directly	O
+on	O
+the	O
+sinus	O
+node	O
+.	O
+
+This	O
+effect	O
+,	O
+which	O
+results	O
+in	O
+a	O
+flattening	O
+of	O
+the	O
+phase	O
+0	O
+and	O
+phase	O
+4	O
+slope	O
+,	O
+together	O
+with	O
+a	O
+longer	O
+AP	O
+duration	O
+,	O
+may	O
+be	O
+due	O
+to	O
+an	O
+increase	O
+in	O
+the	O
+time	O
+constants	O
+of	O
+slow	O
+inward	O
+ionic	O
+currents	O
+(	O
+already	O
+demonstrated	O
+elsewhere	O
+)	O
+,	O
+but	O
+also	O
+to	O
+an	O
+increased	O
+time	O
+constant	O
+for	O
+deactivation	O
+of	O
+the	O
+outward	O
+potassium	O
+current	O
+(	O
+Ip	O
+)	O
+.	O
+
+Hepatitis	B
+and	O
+renal	B
+tubular	I
+acidosis	I
+after	O
+anesthesia	O
+with	O
+methoxyflurane	O
+.	O
+
+A	O
+69	O
+-	O
+year	O
+-	O
+old	O
+man	O
+operated	O
+for	O
+acute	B
+cholecystitis	I
+under	O
+methoxyflurane	O
+anesthesia	O
+developed	O
+postoperatively	O
+a	O
+hepatic	B
+insufficiency	I
+syndrome	I
+and	O
+renal	B
+tubular	I
+acidosis	I
+.	O
+
+Massive	O
+bleeding	B
+appeared	O
+during	O
+surgery	O
+which	O
+lasted	O
+for	O
+six	O
+hours	O
+.	O
+
+Postoperative	O
+evolution	O
+under	O
+supportive	O
+therapy	O
+was	O
+favourable	O
+.	O
+
+Complete	O
+recovery	O
+was	O
+confirmed	O
+by	O
+repeated	O
+controls	O
+performed	O
+over	O
+a	O
+period	O
+of	O
+one	O
+year	O
+after	O
+surgery	O
+.	O
+
+Pituitary	O
+response	O
+to	O
+luteinizing	O
+hormone	O
+-	O
+releasing	O
+hormone	O
+during	O
+haloperidol	O
+-	O
+induced	O
+hyperprolactinemia	B
+.	O
+
+The	O
+effects	O
+of	O
+a	O
+6	O
+-	O
+hour	O
+infusion	O
+with	O
+haloperidol	O
+on	O
+serum	O
+prolactin	O
+and	O
+luteinizing	O
+hormone	O
+(	O
+LH	O
+)	O
+levels	O
+was	O
+studied	O
+in	O
+a	O
+group	O
+of	O
+male	O
+subjects	O
+.	O
+
+Five	O
+hours	O
+after	O
+starting	O
+the	O
+infusions	O
+,	O
+a	O
+study	O
+of	O
+the	O
+pituitary	O
+responses	O
+to	O
+LH	O
+-	O
+releasing	O
+hormone	O
+(	O
+LH	O
+-	O
+RH	O
+)	O
+was	O
+carried	O
+out	O
+.	O
+
+Control	O
+patients	O
+received	O
+infusions	O
+of	O
+0	O
+.	O
+9	O
+%	O
+NaCl	O
+solution	O
+.	O
+
+During	O
+the	O
+course	O
+of	O
+haloperidol	O
+infusions	O
+,	O
+significant	O
+hyperprolactinemia	B
+was	O
+found	O
+,	O
+together	O
+with	O
+an	O
+abolished	O
+pituitary	O
+response	O
+to	O
+LH	O
+-	O
+RH	O
+,	O
+as	O
+compared	O
+with	O
+responses	O
+of	O
+control	O
+subjects	O
+.	O
+
+Antirifampicin	O
+antibodies	O
+in	O
+acute	O
+rifampicin	O
+-	O
+associated	O
+renal	B
+failure	I
+.	O
+
+5	O
+patients	O
+with	O
+acute	B
+renal	I
+failure	I
+(	O
+3	O
+with	O
+thrombopenia	B
+and	O
+hemolysis	B
+)	O
+induced	O
+by	O
+the	O
+reintroduction	O
+of	O
+rifampicin	O
+are	O
+described	O
+.	O
+
+No	O
+correlation	O
+was	O
+found	O
+between	O
+the	O
+severity	O
+of	O
+clinical	O
+manifestations	O
+and	O
+the	O
+total	O
+dose	O
+taken	O
+by	O
+the	O
+patients	O
+.	O
+
+In	O
+all	O
+but	O
+1	O
+patient	O
+,	O
+antirifampicin	O
+antibodies	O
+were	O
+detected	O
+.	O
+
+Antibodies	O
+suggested	O
+to	O
+be	O
+of	O
+the	O
+IgM	O
+class	O
+were	O
+detected	O
+in	O
+all	O
+3	O
+patients	O
+with	O
+hematological	B
+disorders	I
+.	O
+
+The	O
+pattern	O
+of	O
+non	O
+-	O
+specific	O
+acute	B
+tubular	I
+necrosis	I
+found	O
+in	O
+the	O
+2	O
+biopsied	O
+patients	O
+,	O
+indistinguishable	O
+from	O
+that	O
+of	O
+ischemic	O
+origin	O
+,	O
+raised	O
+the	O
+possibility	O
+of	O
+a	O
+vascular	O
+-	O
+mediated	O
+damage	O
+.	O
+
+In	O
+3	O
+patients	O
+,	O
+the	O
+possibility	O
+of	O
+a	O
+triggering	O
+immunoallergic	O
+mechanism	O
+is	O
+discussed	O
+.	O
+
+Cardiovascular	O
+effects	O
+of	O
+hypotension	B
+induced	O
+by	O
+adenosine	O
+triphosphate	O
+and	O
+sodium	O
+nitroprusside	O
+on	O
+dogs	O
+with	O
+denervated	O
+hearts	O
+.	O
+
+Adenosine	O
+triphosphate	O
+(	O
+ATP	O
+)	O
+and	O
+sodium	O
+nitroprusside	O
+(	O
+SNP	O
+)	O
+are	O
+administered	O
+to	O
+patients	O
+to	O
+induce	O
+and	O
+control	O
+hypotension	B
+during	O
+anesthesia	O
+.	O
+
+SNP	O
+is	O
+authorized	O
+for	O
+clinical	O
+use	O
+in	O
+USA	O
+and	O
+UK	O
+,	O
+and	O
+ATP	O
+is	O
+clinically	O
+used	O
+in	O
+other	O
+countries	O
+such	O
+as	O
+Japan	O
+.	O
+
+We	O
+investigated	O
+how	O
+these	O
+two	O
+drugs	O
+act	O
+on	O
+the	O
+cardiovascular	O
+systems	O
+of	O
+20	O
+dogs	O
+whose	O
+hearts	O
+had	O
+been	O
+denervated	O
+by	O
+a	O
+procedure	O
+we	O
+had	O
+devised	O
+.	O
+
+ATP	O
+(	O
+10	O
+dogs	O
+)	O
+or	O
+SNP	O
+(	O
+10	O
+dogs	O
+)	O
+was	O
+administered	O
+to	O
+reduce	O
+mean	O
+arterial	O
+pressure	O
+by	O
+30	O
+%	O
+to	O
+70	O
+%	O
+of	O
+control	O
+.	O
+
+Before	O
+,	O
+during	O
+and	O
+after	O
+induced	O
+hypotension	B
+,	O
+we	O
+measured	O
+major	O
+cardiovascular	O
+parameters	O
+.	O
+
+Hypotension	B
+induced	O
+by	O
+ATP	O
+was	O
+accompanied	O
+by	O
+significant	O
+decreases	O
+in	O
+mean	O
+pulmonary	O
+arterial	O
+pressure	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+,	O
+central	O
+venous	O
+pressure	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+,	O
+left	O
+ventricular	O
+end	O
+-	O
+diastolic	O
+pressure	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+,	O
+total	O
+peripheral	O
+resistance	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+,	O
+rate	O
+pressure	O
+product	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+,	O
+total	O
+body	O
+oxygen	O
+consumption	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+,	O
+and	O
+heart	O
+rate	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+;	O
+all	O
+these	O
+variables	O
+returned	O
+normal	O
+within	O
+30	O
+min	O
+after	O
+ATP	O
+was	O
+stopped	O
+.	O
+
+Cardiac	O
+output	O
+did	O
+not	O
+change	O
+.	O
+
+During	O
+hypotension	B
+produced	O
+by	O
+SNP	O
+similar	O
+decreases	O
+were	O
+observed	O
+in	O
+mean	O
+pulmonary	O
+arterial	O
+pressure	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+,	O
+central	O
+venous	O
+pressure	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+,	O
+left	O
+ventricular	O
+end	O
+-	O
+diastolic	O
+pressure	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+,	O
+total	O
+peripheral	O
+resistance	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+,	O
+rate	O
+pressure	O
+product	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+,	O
+and	O
+oxygen	O
+content	O
+difference	O
+between	O
+arterial	O
+and	O
+mixed	O
+venous	O
+blood	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+,	O
+while	O
+heart	O
+rate	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+and	O
+cardiac	O
+output	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+were	O
+increased	O
+.	O
+
+Recoveries	O
+of	O
+heart	O
+rate	O
+and	O
+left	O
+ventricular	O
+end	O
+-	O
+diastolic	O
+pressure	O
+were	O
+not	O
+shown	O
+within	O
+60	O
+min	O
+after	O
+SNP	O
+had	O
+been	O
+stopped	O
+.	O
+
+Both	O
+ATP	O
+and	O
+SNP	O
+should	O
+act	O
+on	O
+the	O
+pacemaker	O
+tissue	O
+of	O
+the	O
+heart	O
+.	O
+
+Comparative	O
+study	O
+:	O
+Endografine	O
+(	O
+diatrizoate	O
+)	O
+,	O
+Vasurix	O
+polyvidone	O
+(	O
+acetrizoate	O
+)	O
+,	O
+Dimer	O
+-	O
+X	O
+(	O
+iocarmate	O
+)	O
+and	O
+Hexabrix	O
+(	O
+ioxaglate	O
+)	O
+in	O
+hysterosalpingography	O
+.	O
+
+Side	O
+effects	O
+of	O
+hysterosalpingography	O
+with	O
+Dimer	O
+-	O
+X	O
+,	O
+Hexabrix	O
+,	O
+Vasurix	O
+polyvidone	O
+and	O
+Endografine	O
+in	O
+142	O
+consecutive	O
+patients	O
+,	O
+receiving	O
+one	O
+of	O
+the	O
+four	O
+tested	O
+media	O
+were	O
+evaluated	O
+from	O
+replies	O
+to	O
+postal	O
+questionnaires	O
+.	O
+
+The	O
+Dimer	O
+-	O
+X	O
+group	O
+had	O
+a	O
+higher	O
+incidence	O
+of	O
+nausea	B
+and	O
+dizziness	B
+.	O
+
+The	O
+Endografine	O
+group	O
+had	O
+a	O
+higher	O
+incidence	O
+of	O
+abdominal	B
+pain	I
+.	O
+
+These	O
+differences	O
+occur	O
+especially	O
+in	O
+the	O
+age	O
+groups	O
+under	O
+30	O
+years	O
+.	O
+
+Hexabrix	O
+and	O
+Vasurix	O
+polyvidone	O
+are	O
+considered	O
+the	O
+best	O
+contrast	O
+media	O
+for	O
+hysterosalpingography	O
+and	O
+perhaps	O
+because	O
+of	O
+its	O
+low	O
+toxicity	B
+Hexabrix	O
+should	O
+be	O
+preferred	O
+.	O
+
+Post	O
+-	O
+suxamethonium	O
+pains	B
+in	O
+Nigerian	O
+surgical	O
+patients	O
+.	O
+
+Contrary	O
+to	O
+an	O
+earlier	O
+report	O
+by	O
+Coxon	O
+,	O
+scoline	O
+pain	B
+occurs	O
+in	O
+African	O
+negroes	O
+.	O
+
+Its	O
+incidence	O
+was	O
+determined	O
+in	O
+a	O
+prospective	O
+study	O
+involving	O
+a	O
+total	O
+of	O
+100	O
+Nigerian	O
+patients	O
+(	O
+50	O
+out	O
+-	O
+patients	O
+and	O
+50	O
+in	O
+-	O
+patients	O
+)	O
+.	O
+
+About	O
+62	O
+%	O
+of	O
+the	O
+out	O
+-	O
+patients	O
+developed	O
+scoline	O
+pain	B
+as	O
+compared	O
+with	O
+about	O
+26	O
+%	O
+among	O
+the	O
+in	O
+-	O
+patients	O
+.	O
+
+The	O
+abolition	O
+of	O
+muscle	O
+fasciculations	B
+(	O
+by	O
+0	O
+.	O
+075mg	O
+/	O
+kg	O
+dose	O
+of	O
+Fazadinium	O
+)	O
+did	O
+not	O
+influence	O
+the	O
+occurrence	O
+of	O
+scoline	O
+pain	B
+.	O
+
+Neither	O
+the	O
+type	O
+of	O
+induction	O
+agent	O
+(	O
+Althesin	O
+or	O
+Thiopentone	O
+)	O
+nor	O
+the	O
+salt	O
+preparation	O
+of	O
+suxamethonium	O
+used	O
+(	O
+chloride	O
+or	O
+bromide	O
+)	O
+,	O
+affected	O
+the	O
+incidence	O
+of	O
+scoline	O
+pain	B
+.	O
+
+Invasive	O
+carcinoma	B
+of	I
+the	I
+renal	I
+pelvis	I
+following	O
+cyclophosphamide	O
+therapy	O
+for	O
+nonmalignant	O
+disease	O
+.	O
+
+A	O
+47	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+right	O
+hydroureteronephrosis	B
+due	O
+to	O
+ureterovesical	O
+junction	O
+obstruction	O
+had	O
+gross	O
+hematuria	B
+after	O
+being	O
+treated	O
+for	O
+five	O
+years	O
+wtih	O
+cyclophosphamide	O
+for	O
+cerebral	B
+vasculitis	I
+.	O
+
+A	O
+right	O
+nephroureterectomy	O
+was	O
+required	O
+for	O
+control	O
+of	O
+bleeding	B
+.	O
+
+The	O
+pathology	O
+specimen	O
+contained	O
+clinically	O
+occult	O
+invasive	O
+carcinoma	B
+of	I
+the	I
+renal	I
+pelvis	I
+.	O
+
+Although	O
+the	O
+ability	O
+of	O
+cyclophosphamide	O
+to	O
+cause	O
+hemorrhagic	B
+cystitis	I
+and	O
+urine	O
+cytologic	O
+abnormalities	O
+indistinguishable	O
+from	O
+high	O
+grade	O
+carcinoma	B
+is	O
+well	O
+known	O
+,	O
+it	O
+is	O
+less	O
+widely	O
+appreciated	O
+that	O
+it	O
+is	O
+also	O
+associated	O
+with	O
+carcinoma	B
+of	I
+the	I
+urinary	I
+tract	I
+.	O
+
+Twenty	O
+carcinomas	B
+of	I
+the	I
+urinary	I
+bladder	I
+and	O
+one	O
+carcinoma	B
+of	I
+the	I
+prostate	I
+have	O
+been	O
+reported	O
+in	O
+association	O
+with	O
+its	O
+use	O
+.	O
+
+The	O
+present	O
+case	O
+is	O
+the	O
+first	O
+carcinoma	B
+of	I
+the	I
+renal	I
+pelvis	I
+reported	O
+in	O
+association	O
+with	O
+cyclophosphamide	O
+treatment	O
+.	O
+
+It	O
+is	O
+the	O
+third	O
+urinary	B
+tract	I
+cancer	I
+reported	O
+in	O
+association	O
+with	O
+cyclophosphamide	O
+treatment	O
+for	O
+nonmalignant	O
+disease	O
+.	O
+
+The	O
+association	O
+of	O
+the	O
+tumor	B
+with	O
+preexisting	O
+hydroureteronephrosis	B
+suggests	O
+that	O
+stasis	O
+prolonged	O
+and	O
+intensified	O
+exposure	O
+of	O
+upper	O
+urinary	O
+tract	O
+epithelium	O
+to	O
+cyclophosphamide	O
+.	O
+
+Patients	O
+who	O
+are	O
+candidates	O
+for	O
+long	O
+-	O
+term	O
+cyclophosphamide	O
+treatment	O
+should	O
+be	O
+routinely	O
+evaluated	O
+for	O
+obstructive	B
+uropathy	I
+.	O
+
+Medial	O
+changes	O
+in	O
+arterial	O
+spasm	B
+induced	O
+by	O
+L	O
+-	O
+norepinephrine	O
+.	O
+
+In	O
+normal	O
+rats	O
+,	O
+the	O
+media	O
+of	O
+small	O
+arteries	O
+(	O
+0	O
+.	O
+4	O
+-	O
+-	O
+0	O
+.	O
+2	O
+mm	O
+in	O
+diameter	O
+)	O
+previously	O
+was	O
+shown	O
+to	O
+contain	O
+intracellular	O
+vacuoles	O
+,	O
+identified	O
+ultrastructurally	O
+as	O
+herniations	O
+of	O
+one	O
+smooth	O
+muscle	O
+cell	O
+into	O
+another	O
+.	O
+
+The	O
+hypothesis	O
+that	O
+intense	O
+vasoconstriction	O
+would	O
+increase	O
+the	O
+number	O
+of	O
+such	O
+vacuoles	O
+has	O
+been	O
+tested	O
+.	O
+
+In	O
+the	O
+media	O
+of	O
+the	O
+saphenous	O
+artery	O
+and	O
+its	O
+distal	O
+branch	O
+,	O
+vasoconstriction	O
+induced	O
+by	O
+L	O
+-	O
+norepinephrine	O
+produced	O
+many	O
+cell	O
+-	O
+to	O
+-	O
+cell	O
+hernias	B
+within	O
+15	O
+minutes	O
+.	O
+
+At	O
+1	O
+day	O
+their	O
+number	O
+was	O
+reduced	O
+to	O
+about	O
+1	O
+/	O
+10	O
+of	O
+the	O
+original	O
+number	O
+.	O
+
+By	O
+7	O
+days	O
+the	O
+vessel	O
+was	O
+almost	O
+restored	O
+to	O
+normal	O
+.	O
+
+Triple	O
+stimulation	O
+over	O
+1	O
+day	O
+induced	O
+more	O
+severe	O
+changes	O
+in	O
+the	O
+media	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+smooth	O
+muscle	O
+cells	O
+are	O
+susceptible	O
+to	O
+damage	O
+in	O
+the	O
+course	O
+of	O
+their	O
+specific	O
+function	O
+.	O
+
+The	O
+experimental	O
+data	O
+are	O
+discussed	O
+in	O
+relation	O
+to	O
+medial	O
+changes	O
+observed	O
+in	O
+other	O
+instances	O
+of	O
+arterial	O
+spasm	B
+.	O
+
+Endothelial	O
+changes	O
+that	O
+developed	O
+in	O
+the	O
+same	O
+experimental	O
+model	O
+were	O
+described	O
+in	O
+a	O
+previous	O
+paper	O
+.	O
+
+Bilateral	O
+retinal	B
+artery	I
+and	I
+choriocapillaris	I
+occlusion	I
+following	O
+the	O
+injection	O
+of	O
+long	O
+-	O
+acting	O
+corticosteroid	O
+suspensions	O
+in	O
+combination	O
+with	O
+other	O
+drugs	O
+:	O
+I	O
+.	O
+
+Clinical	O
+studies	O
+.	O
+
+Two	O
+well	O
+-	O
+documented	O
+cases	O
+of	O
+bilateral	O
+retinal	B
+artery	I
+and	I
+choriocapillaris	I
+occlusions	I
+with	O
+blindness	B
+following	O
+head	O
+and	O
+neck	O
+soft	O
+-	O
+tissue	O
+injection	O
+with	O
+methylprednisolone	O
+acetate	O
+in	O
+combination	O
+with	O
+lidocaine	O
+,	O
+epinephrine	O
+,	O
+or	O
+penicillin	O
+are	O
+reported	O
+.	O
+
+One	O
+case	O
+had	O
+only	O
+a	O
+unilateral	O
+injection	O
+.	O
+
+The	O
+acute	O
+observations	O
+included	O
+hazy	O
+sensorium	O
+,	O
+superior	O
+gaze	O
+palsy	B
+,	O
+pupillary	B
+abnormalities	I
+,	O
+and	O
+conjunctival	O
+hemorrhages	B
+with	O
+edema	B
+.	O
+
+Follow	O
+-	O
+up	O
+changes	O
+showed	O
+marked	O
+visual	B
+loss	I
+,	O
+constricted	O
+visual	O
+fields	O
+,	O
+optic	O
+nerve	O
+pallor	O
+,	O
+vascular	O
+attenuation	O
+,	O
+and	O
+chorioretinal	B
+atrophy	I
+.	O
+
+The	O
+literature	O
+is	O
+reviewed	O
+,	O
+and	O
+possible	O
+causes	O
+are	O
+discussed	O
+.	O
+
+Abnormalities	O
+of	O
+the	O
+pupil	O
+and	O
+visual	O
+-	O
+evoked	O
+potential	O
+in	O
+quinine	O
+amblyopia	B
+.	O
+
+Total	O
+blindness	B
+with	O
+a	O
+transient	O
+tonic	B
+pupillary	I
+response	O
+,	O
+denervation	O
+supersensitivity	O
+,	O
+and	O
+abnormal	O
+visual	O
+-	O
+evoked	O
+potentials	O
+developed	O
+in	O
+a	O
+54	O
+-	O
+year	O
+-	O
+old	O
+man	O
+after	O
+the	O
+use	O
+of	O
+quinine	O
+sulfate	O
+for	O
+leg	B
+cramps	I
+.	O
+
+He	O
+later	O
+recovered	O
+normal	O
+visual	O
+acuity	O
+.	O
+
+A	O
+transient	O
+tonic	B
+pupillary	I
+response	O
+,	O
+denervation	O
+supersensitivity	O
+,	O
+and	O
+abnormal	O
+visual	O
+-	O
+evoked	O
+potentials	O
+in	O
+quinine	O
+toxicity	B
+,	O
+to	O
+our	O
+knowledge	O
+,	O
+have	O
+not	O
+been	O
+previously	O
+reported	O
+.	O
+
+Suxamethonium	O
+-	O
+induced	O
+jaw	B
+stiffness	I
+and	O
+myalgia	B
+associated	O
+with	O
+atypical	O
+cholinesterase	O
+:	O
+case	O
+report	O
+.	O
+
+An	O
+11	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+was	O
+given	O
+halothane	O
+,	O
+nitrous	O
+oxide	O
+and	O
+oxygen	O
+,	O
+pancuronium	O
+0	O
+.	O
+4	O
+mg	O
+and	O
+suxamethonium	O
+100	O
+mg	O
+for	O
+induction	O
+of	O
+anaesthesia	O
+.	O
+
+In	O
+response	O
+to	O
+this	O
+a	O
+marked	O
+jaw	B
+stiffness	I
+occurred	O
+which	O
+lasted	O
+for	O
+two	O
+minutes	O
+and	O
+the	O
+anaesthesia	O
+were	O
+terminated	O
+.	O
+
+Four	O
+hours	O
+of	O
+apnoea	B
+ensued	O
+and	O
+he	O
+suffered	O
+generalized	O
+severe	O
+myalgia	B
+lasting	O
+for	O
+one	O
+week	O
+.	O
+
+He	O
+was	O
+found	O
+to	O
+have	O
+atypical	O
+plasma	O
+cholinesterase	O
+with	O
+a	O
+dibucaine	O
+number	O
+of	O
+12	O
+,	O
+indicating	O
+homozygocity	O
+.	O
+
+This	O
+was	O
+verified	O
+by	O
+study	O
+of	O
+the	O
+family	O
+.	O
+
+The	O
+case	O
+shows	O
+that	O
+prolonged	B
+jaw	I
+rigidity	I
+and	O
+myalgia	B
+may	O
+occur	O
+after	O
+suxamethonium	O
+in	O
+patients	O
+with	O
+atypical	O
+cholinesterase	O
+despite	O
+pretreatment	O
+with	O
+pancuronium	O
+.	O
+
+Indomethacin	O
+-	O
+induced	O
+hyperkalemia	B
+in	O
+three	O
+patients	O
+with	O
+gouty	B
+arthritis	I
+.	O
+
+We	O
+describe	O
+three	O
+patients	O
+in	O
+whom	O
+severe	O
+,	O
+life	O
+-	O
+threatening	O
+hyperkalemia	B
+and	O
+renal	B
+insufficiency	I
+developed	O
+after	O
+treatment	O
+of	O
+acute	O
+gouty	B
+arthritis	I
+with	O
+indomethacin	O
+.	O
+
+This	O
+complication	O
+may	O
+result	O
+from	O
+an	O
+inhibition	O
+of	O
+prostaglandin	O
+synthesis	O
+and	O
+consequent	O
+hyporeninemic	B
+hypoaidosteronism	I
+.	O
+
+Careful	O
+attention	O
+to	O
+renal	O
+function	O
+and	O
+potassium	O
+balance	O
+in	O
+patients	O
+receiving	O
+indomethacin	O
+or	O
+other	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+agents	O
+,	O
+particularly	O
+in	O
+those	O
+patients	O
+with	O
+diabetes	B
+mellitus	I
+or	O
+preexisting	O
+renal	B
+disease	I
+,	O
+will	O
+help	O
+prevent	O
+this	O
+potentially	O
+serious	O
+complication	O
+.	O
+
+Etomidate	O
+:	O
+a	O
+foreshortened	O
+clinical	O
+trial	O
+.	O
+
+A	O
+clinical	O
+evaluation	O
+of	O
+etomidate	O
+for	O
+outpatient	O
+cystoscopy	O
+was	O
+embarked	O
+upon	O
+.	O
+
+Unpremedicated	O
+patients	O
+were	O
+given	O
+fentanyl	O
+1	O
+microgram	O
+/	O
+kg	O
+followed	O
+by	O
+etomidate	O
+0	O
+.	O
+3	O
+mg	O
+/	O
+kg	O
+.	O
+
+Anaesthesia	O
+was	O
+maintained	O
+with	O
+intermittent	O
+etomidate	O
+in	O
+2	O
+-	O
+4	O
+mg	O
+doses	O
+.	O
+
+Patients	O
+were	O
+interviewed	O
+personally	O
+later	O
+the	O
+same	O
+day	O
+,	O
+and	O
+by	O
+questionnaire	O
+three	O
+to	O
+four	O
+weeks	O
+later	O
+.	O
+
+The	O
+trial	O
+was	O
+discontinued	O
+after	O
+20	O
+cases	O
+because	O
+of	O
+an	O
+unacceptable	O
+incidence	O
+of	O
+side	O
+effects	O
+.	O
+
+Venous	O
+pain	B
+occurred	O
+in	O
+68	O
+%	O
+of	O
+patients	O
+and	O
+50	O
+%	O
+had	O
+redness	O
+,	O
+pain	B
+or	O
+swelling	B
+related	O
+to	O
+the	O
+injection	O
+site	O
+,	O
+in	O
+some	O
+cases	O
+lasting	O
+up	O
+to	O
+three	O
+weeks	O
+after	O
+anaesthesia	O
+.	O
+
+Skeletal	O
+movements	O
+occurred	O
+in	O
+50	O
+%	O
+of	O
+patients	O
+;	O
+30	O
+%	O
+experienced	O
+respiratory	B
+upset	I
+,	O
+one	O
+sufficiently	O
+severe	O
+to	O
+necessitate	O
+abandoning	O
+the	O
+technique	O
+.	O
+
+Nausea	B
+and	O
+vomiting	B
+occurred	O
+in	O
+40	O
+%	O
+and	O
+25	O
+%	O
+had	O
+disturbing	O
+emergence	O
+psychoses	B
+.	O
+
+Levodopa	O
+-	O
+induced	O
+dyskinesias	B
+are	O
+improved	O
+by	O
+fluoxetine	O
+.	O
+
+We	O
+evaluated	O
+the	O
+severity	O
+of	O
+motor	B
+disability	I
+and	O
+dyskinesias	B
+in	O
+seven	O
+levodopa	O
+-	O
+responsive	O
+patients	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+after	O
+an	O
+acute	O
+challenge	O
+with	O
+the	O
+mixed	O
+dopamine	O
+agonist	O
+,	O
+apomorphine	O
+,	O
+before	O
+and	O
+after	O
+the	O
+administration	O
+of	O
+fluoxetine	O
+(	O
+20	O
+mg	O
+twice	O
+per	O
+day	O
+)	O
+for	O
+11	O
++	O
+/	O
+-	O
+1	O
+days	O
+.	O
+
+After	O
+fluoxetine	O
+treatment	O
+,	O
+there	O
+was	O
+a	O
+significant	O
+47	O
+%	O
+improvement	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+of	O
+apomorphine	O
+-	O
+induced	O
+dyskinesias	B
+without	O
+modification	O
+of	O
+parkinsonian	B
+motor	B
+disability	I
+.	O
+
+The	O
+dyskinesias	B
+were	O
+reduced	O
+predominantly	O
+in	O
+the	O
+lower	O
+limbs	O
+during	O
+the	O
+onset	O
+and	O
+disappearance	O
+of	O
+dystonic	B
+dyskinesias	I
+(	O
+onset	O
+-	O
+and	O
+end	O
+-	O
+of	O
+-	O
+dose	O
+dyskinesias	B
+)	O
+and	O
+in	O
+the	O
+upper	O
+limbs	O
+during	O
+choreic	B
+mid	I
+-	I
+dose	I
+dyskinesias	I
+.	O
+
+The	O
+results	O
+suggest	O
+that	O
+increased	O
+brain	O
+serotoninergic	O
+transmission	O
+with	O
+fluoxetine	O
+may	O
+reduce	O
+levodopa	O
+-	O
+or	O
+dopamine	O
+agonist	O
+-	O
+induced	O
+dyskinesias	B
+without	O
+aggravating	O
+parkinsonian	B
+motor	B
+disability	I
+.	O
+
+A	O
+large	O
+population	O
+-	O
+based	O
+follow	O
+-	O
+up	O
+study	O
+of	O
+trimethoprim	O
+-	O
+sulfamethoxazole	O
+,	O
+trimethoprim	O
+,	O
+and	O
+cephalexin	O
+for	O
+uncommon	O
+serious	O
+drug	B
+toxicity	I
+.	O
+
+We	O
+conducted	O
+a	O
+population	O
+-	O
+based	O
+45	O
+-	O
+day	O
+follow	O
+-	O
+up	O
+study	O
+of	O
+232	O
+,	O
+390	O
+people	O
+who	O
+were	O
+prescribed	O
+trimethoprim	O
+-	O
+sulfamethoxazole	O
+(	O
+TMP	O
+-	O
+SMZ	O
+)	O
+,	O
+266	O
+,	O
+951	O
+prescribed	O
+trimethoprim	O
+alone	O
+,	O
+and	O
+196	O
+,	O
+397	O
+prescribed	O
+cephalexin	O
+,	O
+to	O
+estimate	O
+the	O
+risk	O
+of	O
+serious	O
+liver	B
+,	I
+blood	I
+,	I
+skin	I
+,	I
+and	I
+renal	I
+disorders	I
+resulting	O
+in	O
+referral	O
+or	O
+hospitalization	O
+associated	O
+with	O
+these	O
+drugs	O
+.	O
+
+The	O
+results	O
+were	O
+based	O
+on	O
+information	O
+recorded	O
+on	O
+office	O
+computers	O
+by	O
+selected	O
+general	O
+practitioners	O
+in	O
+the	O
+United	O
+Kingdom	O
+,	O
+together	O
+with	O
+a	O
+review	O
+of	O
+clinical	O
+records	O
+.	O
+
+The	O
+risk	O
+of	O
+clinically	O
+important	O
+idiopathic	O
+liver	B
+disease	I
+was	O
+similar	O
+for	O
+persons	O
+prescribed	O
+TMP	O
+-	O
+SMZ	O
+(	O
+5	O
+.	O
+2	O
+/	O
+100	O
+,	O
+000	O
+)	O
+and	O
+those	O
+prescribed	O
+trimethoprim	O
+alone	O
+(	O
+3	O
+.	O
+8	O
+/	O
+100	O
+,	O
+000	O
+)	O
+.	O
+
+The	O
+risk	O
+for	O
+those	O
+prescribed	O
+cephalexin	O
+was	O
+somewhat	O
+lower	O
+(	O
+2	O
+.	O
+0	O
+/	O
+100	O
+,	O
+000	O
+)	O
+.	O
+
+Only	O
+five	O
+patients	O
+experienced	O
+blood	O
+disorders	O
+,	O
+one	O
+of	O
+whom	O
+was	O
+exposed	O
+to	O
+TMP	O
+-	O
+SMZ	O
+;	O
+of	O
+seven	O
+with	O
+erythema	B
+multiforme	I
+and	O
+Stevens	B
+-	I
+Johnson	I
+syndrome	I
+,	O
+four	O
+were	O
+exposed	O
+to	O
+TMP	O
+-	O
+SMZ	O
+.	O
+
+The	O
+one	O
+case	O
+of	O
+toxic	B
+epidermal	I
+necrolysis	I
+occurred	O
+in	O
+a	O
+patient	O
+who	O
+took	O
+cephalexin	O
+.	O
+
+Finally	O
+,	O
+only	O
+five	O
+cases	O
+of	O
+acute	O
+parenchymal	O
+renal	B
+disease	I
+occurred	O
+,	O
+none	O
+likely	O
+to	O
+be	O
+caused	O
+by	O
+a	O
+study	O
+drug	O
+.	O
+
+We	O
+conclude	O
+that	O
+the	O
+risk	O
+of	O
+the	O
+serious	O
+diseases	O
+studied	O
+is	O
+small	O
+for	O
+the	O
+three	O
+agents	O
+,	O
+and	O
+compares	O
+reasonably	O
+with	O
+the	O
+risk	O
+for	O
+many	O
+other	O
+antibiotics	O
+.	O
+
+Clinical	O
+safety	O
+of	O
+lidocaine	O
+in	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+myocardial	B
+infarction	I
+.	O
+
+STUDY	O
+OBJECTIVE	O
+:	O
+To	O
+evaluate	O
+the	O
+safety	O
+of	O
+lidocaine	O
+in	O
+the	O
+setting	O
+of	O
+cocaine	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+(	O
+MI	B
+)	O
+.	O
+
+DESIGN	O
+:	O
+A	O
+retrospective	O
+,	O
+multicenter	O
+study	O
+.	O
+
+SETTING	O
+:	O
+Twenty	O
+-	O
+nine	O
+university	O
+,	O
+university	O
+-	O
+affiliated	O
+,	O
+or	O
+community	O
+hospitals	O
+during	O
+a	O
+6	O
+-	O
+year	O
+period	O
+(	O
+total	O
+of	O
+117	O
+cumulative	O
+hospital	O
+-	O
+years	O
+)	O
+.	O
+
+PARTICIPANTS	O
+:	O
+Patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+MI	B
+who	O
+received	O
+lidocaine	O
+in	O
+the	O
+emergency	O
+department	O
+.	O
+
+RESULTS	O
+:	O
+Of	O
+29	O
+patients	O
+who	O
+received	O
+lidocaine	O
+in	O
+the	O
+setting	O
+of	O
+cocaine	O
+-	O
+associated	O
+MI	B
+,	O
+no	O
+patient	O
+died	O
+;	O
+exhibited	O
+bradydysrhythmias	B
+,	O
+ventricular	B
+tachycardia	I
+,	O
+or	O
+ventricular	B
+fibrillation	I
+;	O
+or	O
+experienced	O
+seizures	B
+after	O
+administration	O
+of	O
+lidocaine	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+0	O
+%	O
+to	O
+11	O
+%	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+Despite	O
+theoretical	O
+concerns	O
+that	O
+lidocaine	O
+may	O
+enhance	O
+cocaine	O
+toxicity	B
+,	O
+the	O
+use	O
+of	O
+lidocaine	O
+in	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+MI	B
+was	O
+not	O
+associated	O
+with	O
+significant	O
+cardiovascular	B
+or	I
+central	I
+nervous	I
+system	I
+toxicity	I
+.	O
+
+Experimental	O
+progressive	O
+muscular	B
+dystrophy	I
+and	O
+its	O
+treatment	O
+with	O
+high	O
+doses	O
+anabolizing	O
+agents	O
+.	O
+
+We	O
+are	O
+still	O
+a	O
+long	O
+way	O
+from	O
+discovering	O
+an	O
+unequivocal	O
+pathogenetic	O
+interpretation	O
+of	O
+progressive	O
+muscular	B
+dystrophy	I
+in	O
+man	O
+.	O
+
+Noteworthy	O
+efforts	O
+have	O
+been	O
+made	O
+in	O
+the	O
+experimental	O
+field	O
+;	O
+a	O
+recessive	O
+autosomic	O
+form	O
+found	O
+in	O
+the	O
+mouse	O
+seems	O
+to	O
+bear	O
+the	O
+closest	O
+resemblance	O
+to	O
+the	O
+human	O
+form	O
+from	O
+the	O
+genetic	O
+point	O
+of	O
+view	O
+.	O
+
+Myopathy	B
+due	O
+to	O
+lack	O
+of	O
+vitamin	O
+E	O
+and	O
+myopathy	B
+induced	O
+by	O
+certain	O
+viruses	O
+have	O
+much	O
+in	O
+common	O
+anatomically	O
+and	O
+pathologically	O
+with	O
+the	O
+human	O
+form	O
+.	O
+
+The	O
+authors	O
+induced	O
+myodystrophy	B
+in	O
+the	O
+rat	O
+by	O
+giving	O
+it	O
+a	O
+diet	O
+lacking	O
+in	O
+vitamin	O
+E	O
+.	O
+
+The	O
+pharmacological	O
+characteristics	O
+of	O
+vitamin	O
+E	O
+and	O
+the	O
+degenerative	O
+changes	O
+brought	O
+about	O
+by	O
+its	O
+deficiency	O
+,	O
+especially	O
+in	O
+the	O
+muscles	O
+,	O
+are	O
+illustrated	O
+.	O
+
+It	O
+is	O
+thus	O
+confirmed	O
+that	O
+the	O
+histological	O
+characteristics	O
+of	O
+myopathic	B
+rat	O
+muscle	O
+induced	O
+experimentally	O
+are	O
+extraordinarily	O
+similar	O
+to	O
+those	O
+of	O
+human	O
+myopathy	B
+as	O
+confirmed	O
+during	O
+biopsies	O
+performed	O
+at	O
+the	O
+Orthopaedic	O
+Traumatological	O
+Centre	O
+,	O
+Florence	O
+.	O
+
+The	O
+encouraging	O
+results	O
+obtained	O
+in	O
+various	O
+authoratative	O
+departments	O
+in	O
+myopathic	B
+patients	O
+by	O
+using	O
+anabolizing	O
+steroids	O
+have	O
+encouraged	O
+the	O
+authors	O
+to	O
+investigate	O
+the	O
+beneficial	O
+effects	O
+of	O
+one	O
+anabolizing	O
+agent	O
+(	O
+Dianabol	O
+,	O
+CIBA	O
+)	O
+at	O
+high	O
+doses	O
+in	O
+rats	O
+rendered	O
+myopathic	B
+by	O
+a	O
+diet	O
+deficient	O
+in	O
+vitamin	O
+E	O
+.	O
+
+In	O
+this	O
+way	O
+they	O
+obtained	O
+appreciable	O
+changes	O
+in	O
+body	O
+weight	O
+(	O
+increased	O
+from	O
+50	O
+to	O
+70	O
+g	O
+after	O
+forty	O
+days	O
+at	O
+a	O
+dose	O
+of	O
+5	O
+mg	O
+per	O
+day	O
+of	O
+anabolizing	O
+agent	O
+)	O
+,	O
+but	O
+most	O
+of	O
+all	O
+they	O
+found	O
+histological	O
+changes	O
+due	O
+to	O
+"	O
+regenerative	O
+"	O
+changes	O
+in	O
+the	O
+muscle	O
+tissue	O
+,	O
+which	O
+however	O
+maintained	O
+its	O
+myopathic	B
+characteristics	O
+in	O
+the	O
+control	O
+animals	O
+that	O
+were	O
+not	O
+treated	O
+with	O
+the	O
+anabolizing	O
+agent	O
+.	O
+
+The	O
+authors	O
+conclude	O
+by	O
+affirming	O
+the	O
+undoubted	O
+efficacy	O
+of	O
+the	O
+anabolizing	O
+steroids	O
+in	O
+experimental	O
+myopathic	B
+disease	I
+,	O
+but	O
+they	O
+have	O
+reservations	O
+as	O
+to	O
+the	O
+transfer	O
+of	O
+the	O
+results	O
+into	O
+the	O
+human	O
+field	O
+,	O
+where	O
+high	O
+dosage	O
+cannot	O
+be	O
+carried	O
+out	O
+continuously	O
+because	O
+of	O
+the	O
+effects	O
+of	O
+the	O
+drug	O
+on	O
+virility	O
+;	O
+because	O
+the	O
+tissue	O
+injury	O
+too	O
+often	O
+occurs	O
+at	O
+an	O
+irreversible	O
+stage	O
+vis	O
+-	O
+a	O
+-	O
+vis	O
+the	O
+"	O
+regeneration	O
+"	O
+of	O
+the	O
+muscle	O
+tissue	O
+;	O
+and	O
+finally	O
+because	O
+the	O
+dystrophic	O
+injurious	O
+agent	O
+is	O
+certainly	O
+not	O
+the	O
+lack	O
+of	O
+vitamin	O
+E	O
+but	O
+something	O
+as	O
+yet	O
+unknown	O
+.	O
+
+Paclitaxel	O
+3	O
+-	O
+hour	O
+infusion	O
+given	O
+alone	O
+and	O
+combined	O
+with	O
+carboplatin	O
+:	O
+preliminary	O
+results	O
+of	O
+dose	O
+-	O
+escalation	O
+trials	O
+.	O
+
+Paclitaxel	O
+(	O
+Taxol	O
+;	O
+Bristol	O
+-	O
+Myers	O
+Squibb	O
+Company	O
+,	O
+Princeton	O
+,	O
+NJ	O
+)	O
+by	O
+3	O
+-	O
+hour	O
+infusion	O
+was	O
+combined	O
+with	O
+carboplatin	O
+in	O
+a	O
+phase	O
+I	O
+/	O
+II	O
+study	O
+directed	O
+to	O
+patients	O
+with	O
+non	B
+-	I
+small	I
+cell	I
+lung	I
+cancer	I
+.	O
+
+Carboplatin	O
+was	O
+given	O
+at	O
+a	O
+fixed	O
+target	O
+area	O
+under	O
+the	O
+concentration	O
+-	O
+time	O
+curve	O
+of	O
+6	O
+.	O
+0	O
+by	O
+the	O
+Calvert	O
+formula	O
+,	O
+whereas	O
+paclitaxel	O
+was	O
+escalated	O
+in	O
+patient	O
+cohorts	O
+from	O
+150	O
+mg	O
+/	O
+m2	O
+(	O
+dose	O
+level	O
+I	O
+)	O
+to	O
+175	O
+,	O
+200	O
+,	O
+225	O
+,	O
+and	O
+250	O
+mg	O
+/	O
+m2	O
+.	O
+
+The	O
+225	O
+mg	O
+/	O
+m2	O
+level	O
+was	O
+expanded	O
+for	O
+the	O
+phase	O
+II	O
+study	O
+since	O
+the	O
+highest	O
+level	O
+achieved	O
+(	O
+250	O
+mg	O
+/	O
+m2	O
+)	O
+required	O
+modification	O
+because	O
+of	O
+nonhematologic	O
+toxicities	B
+(	O
+arthralgia	B
+and	O
+sensory	B
+neuropathy	I
+)	O
+.	O
+
+Therapeutic	O
+effects	O
+were	O
+noted	O
+at	O
+all	O
+dose	O
+levels	O
+,	O
+with	O
+objective	O
+responses	O
+in	O
+17	O
+(	O
+two	O
+complete	O
+and	O
+15	O
+partial	O
+regressions	O
+)	O
+of	O
+41	O
+previously	O
+untreated	O
+patients	O
+.	O
+
+Toxicities	B
+were	O
+compared	O
+with	O
+a	O
+cohort	O
+of	O
+patients	O
+in	O
+a	O
+phase	O
+I	O
+trial	O
+of	O
+paclitaxel	O
+alone	O
+at	O
+identical	O
+dose	O
+levels	O
+.	O
+
+Carboplatin	O
+did	O
+not	O
+appear	O
+to	O
+add	O
+to	O
+the	O
+hematologic	B
+toxicities	I
+observed	O
+,	O
+and	O
+the	O
+paclitaxel	O
+/	O
+carboplatin	O
+combination	O
+could	O
+be	O
+dosed	O
+every	O
+3	O
+weeks	O
+.	O
+
+The	O
+dose	O
+-	O
+dependent	O
+effect	O
+of	O
+misoprostol	O
+on	O
+indomethacin	O
+-	O
+induced	O
+renal	B
+dysfunction	I
+in	O
+well	O
+compensated	O
+cirrhosis	B
+.	O
+
+Misoprostol	O
+(	O
+200	O
+micrograms	O
+)	O
+has	O
+been	O
+shown	O
+to	O
+acutely	O
+counteract	O
+the	O
+indomethacin	O
+-	O
+induced	O
+renal	B
+dysfunction	I
+in	O
+well	O
+compensated	O
+cirrhotic	B
+patients	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+if	O
+the	O
+prophylactic	O
+value	O
+of	O
+misoprostol	O
+was	O
+dose	O
+-	O
+dependent	O
+.	O
+
+Parameters	O
+of	O
+renal	O
+hemodynamics	O
+and	O
+tubular	O
+sodium	O
+and	O
+water	O
+handling	O
+were	O
+assessed	O
+by	O
+clearance	O
+techniques	O
+in	O
+26	O
+well	O
+compensated	O
+cirrhotic	B
+patients	O
+before	O
+and	O
+after	O
+an	O
+oral	O
+combination	O
+of	O
+50	O
+mg	O
+of	O
+indomethacin	O
+and	O
+various	O
+doses	O
+of	O
+misoprostol	O
+.	O
+
+The	O
+200	O
+-	O
+micrograms	O
+dose	O
+was	O
+able	O
+to	O
+totally	O
+abolish	O
+the	O
+deleterious	O
+renal	O
+effects	O
+of	O
+indomethacin	O
+,	O
+whereas	O
+the	O
+800	O
+-	O
+micrograms	O
+dose	O
+resulted	O
+in	O
+significant	O
+worsening	O
+of	O
+renal	O
+hemodynamics	O
+and	O
+sodium	O
+retention	O
+.	O
+
+These	O
+changes	O
+were	O
+maximal	O
+in	O
+the	O
+hour	O
+immediately	O
+after	O
+medications	O
+and	O
+slowly	O
+returned	O
+toward	O
+base	O
+-	O
+line	O
+levels	O
+thereafter	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+the	O
+renal	O
+protective	O
+effects	O
+of	O
+misoprostol	O
+is	O
+dose	O
+-	O
+dependent	O
+.	O
+
+However	O
+,	O
+until	O
+this	O
+apparent	O
+ability	O
+of	O
+200	O
+micrograms	O
+of	O
+misoprostol	O
+to	O
+prevent	O
+the	O
+adverse	O
+effects	O
+of	O
+indomethacin	O
+on	O
+renal	O
+function	O
+is	O
+confirmed	O
+with	O
+chronic	O
+frequent	O
+dosing	O
+,	O
+it	O
+would	O
+be	O
+prudent	O
+to	O
+avoid	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+therapy	O
+in	O
+patients	O
+with	O
+cirrhosis	B
+.	O
+
+Increased	O
+frequency	O
+and	O
+severity	O
+of	O
+angio	B
+-	I
+oedema	I
+related	O
+to	O
+long	O
+-	O
+term	O
+therapy	O
+with	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitor	O
+in	O
+two	O
+patients	O
+.	O
+
+Adverse	O
+reactions	O
+to	O
+drugs	O
+are	O
+well	O
+recognized	O
+as	O
+a	O
+cause	O
+of	O
+acute	O
+or	O
+chronic	O
+urticaria	B
+,	O
+and	O
+angio	B
+-	I
+oedema	I
+.	O
+
+Angiotensin	O
+-	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+inhibitors	O
+,	O
+used	O
+to	O
+treat	O
+hypertension	B
+and	O
+congestive	B
+heart	I
+failure	I
+,	O
+were	O
+introduced	O
+in	O
+Europe	O
+in	O
+the	O
+middle	O
+of	O
+the	O
+eighties	O
+,	O
+and	O
+the	O
+use	O
+of	O
+these	O
+drugs	O
+has	O
+increased	O
+progressively	O
+.	O
+
+Soon	O
+after	O
+the	O
+introduction	O
+of	O
+ACE	O
+inhibitors	O
+,	O
+acute	O
+bouts	O
+of	O
+angio	B
+-	I
+oedema	I
+were	O
+reported	O
+in	O
+association	O
+with	O
+the	O
+use	O
+of	O
+these	O
+drugs	O
+.	O
+
+We	O
+wish	O
+to	O
+draw	O
+attention	O
+to	O
+the	O
+possibility	O
+of	O
+adverse	O
+reactions	O
+to	O
+ACE	O
+inhibitors	O
+after	O
+long	O
+-	O
+term	O
+use	O
+and	O
+in	O
+patients	O
+with	O
+pre	O
+-	O
+existing	O
+angio	B
+-	I
+oedema	I
+.	O
+
+Myoclonus	B
+associated	O
+with	O
+lorazepam	O
+therapy	O
+in	O
+very	O
+-	O
+low	O
+-	O
+birth	O
+-	O
+weight	O
+infants	O
+.	O
+
+Lorazepam	O
+is	O
+being	O
+used	O
+with	O
+increasing	O
+frequency	O
+as	O
+a	O
+sedative	O
+in	O
+the	O
+newborn	O
+and	O
+the	O
+young	O
+infant	O
+.	O
+
+Concern	O
+has	O
+been	O
+raised	O
+with	O
+regard	O
+to	O
+the	O
+safety	O
+of	O
+lorazepam	O
+in	O
+this	O
+age	O
+group	O
+,	O
+especially	O
+in	O
+very	O
+-	O
+low	O
+-	O
+birth	O
+-	O
+weight	O
+(	O
+VLBW	O
+;	O
+<	O
+1	O
+,	O
+500	O
+g	O
+)	O
+infants	O
+.	O
+
+Three	O
+young	O
+infants	O
+,	O
+all	O
+of	O
+birth	O
+weight	O
+<	O
+1	O
+,	O
+500	O
+g	O
+,	O
+experienced	O
+myoclonus	B
+following	O
+the	O
+intravenous	O
+administration	O
+of	O
+lorazepam	O
+.	O
+
+The	O
+potential	O
+neurotoxic	B
+effects	O
+of	O
+the	O
+drug	O
+(	O
+and	O
+its	O
+vehicle	O
+)	O
+in	O
+this	O
+population	O
+are	O
+discussed	O
+.	O
+
+Injectable	O
+lorazepam	O
+should	O
+be	O
+used	O
+with	O
+caution	O
+in	O
+VLBW	O
+infants	O
+.	O
+
+Transvenous	O
+right	O
+ventricular	O
+pacing	O
+during	O
+cardiopulmonary	O
+resuscitation	O
+of	O
+pediatric	O
+patients	O
+with	O
+acute	O
+cardiomyopathy	B
+.	O
+
+We	O
+describe	O
+the	O
+cardiopulmonary	O
+resuscitation	O
+efforts	O
+on	O
+five	O
+patients	O
+who	O
+presented	O
+in	O
+acute	O
+circulatory	B
+failure	I
+from	O
+myocardial	B
+dysfunction	I
+.	O
+
+Three	O
+patients	O
+had	O
+acute	O
+viral	O
+myocarditis	B
+,	O
+one	O
+had	O
+a	O
+carbamazepine	O
+-	O
+induced	O
+acute	O
+eosinophilic	B
+myocarditis	I
+,	O
+and	O
+one	O
+had	O
+cardiac	O
+hemosiderosis	O
+resulting	O
+in	O
+acute	O
+cardiogenic	B
+shock	I
+.	O
+
+All	O
+patients	O
+were	O
+continuously	O
+monitored	O
+with	O
+central	O
+venous	O
+and	O
+arterial	O
+catheters	O
+in	O
+addition	O
+to	O
+routine	O
+noninvasive	O
+monitoring	O
+.	O
+
+An	O
+introducer	O
+sheath	O
+,	O
+a	O
+pacemaker	O
+,	O
+and	O
+sterile	O
+pacing	O
+wires	O
+were	O
+made	O
+readily	O
+available	O
+for	O
+the	O
+patients	O
+,	O
+should	O
+the	O
+need	O
+arise	O
+to	O
+terminate	O
+resistant	O
+cardiac	O
+dysrhythmias	B
+.	O
+
+All	O
+patients	O
+developed	O
+cardiocirculatory	O
+arrest	O
+associated	O
+with	O
+extreme	O
+hypotension	B
+and	O
+dysrhythmias	B
+within	O
+the	O
+first	O
+48	O
+hours	O
+of	O
+their	O
+admission	O
+to	O
+the	O
+pediatric	O
+intensive	O
+care	O
+unit	O
+(	O
+PICU	O
+)	O
+.	O
+
+Right	O
+ventricular	O
+pacemaker	O
+wires	O
+were	O
+inserted	O
+in	O
+all	O
+of	O
+them	O
+during	O
+cardiopulmonary	O
+resuscitation	O
+(	O
+CPR	O
+)	O
+.	O
+
+In	O
+four	O
+patients	O
+,	O
+cardiac	O
+pacing	O
+was	O
+used	O
+,	O
+resulting	O
+in	O
+a	O
+temporary	O
+captured	O
+rhythm	O
+and	O
+restoration	O
+of	O
+their	O
+cardiac	O
+output	O
+.	O
+
+These	O
+patients	O
+had	O
+a	O
+second	O
+event	O
+of	O
+cardiac	B
+arrest	I
+,	O
+resulting	O
+in	O
+death	O
+,	O
+within	O
+10	O
+to	O
+60	O
+minutes	O
+.	O
+
+In	O
+one	O
+patient	O
+,	O
+cardiac	O
+pacing	O
+was	O
+not	O
+used	O
+,	O
+because	O
+he	O
+converted	O
+to	O
+normal	O
+sinus	O
+rhythm	O
+by	O
+electrical	O
+defibrillation	O
+within	O
+three	O
+minutes	O
+of	O
+initiating	O
+CPR	O
+.	O
+
+We	O
+conclude	O
+that	O
+cardiac	O
+pacing	O
+during	O
+resuscitative	O
+efforts	O
+in	O
+pediatric	O
+patients	O
+suffering	O
+from	O
+acute	O
+myocardial	B
+dysfunction	I
+may	O
+not	O
+have	O
+long	O
+-	O
+term	O
+value	O
+in	O
+and	O
+of	O
+itself	O
+;	O
+however	O
+,	O
+if	O
+temporary	O
+hemodynamic	O
+stability	O
+is	O
+achieved	O
+by	O
+this	O
+procedure	O
+,	O
+it	O
+may	O
+provide	O
+additional	O
+time	O
+needed	O
+to	O
+institute	O
+other	O
+therapeutic	O
+modalities	O
+.	O
+
+Efficacy	O
+and	O
+safety	O
+of	O
+granisetron	O
+,	O
+a	O
+selective	O
+5	O
+-	O
+hydroxytryptamine	O
+-	O
+3	O
+receptor	O
+antagonist	O
+,	O
+in	O
+the	O
+prevention	O
+of	O
+nausea	B
+and	O
+vomiting	B
+induced	O
+by	O
+high	O
+-	O
+dose	O
+cisplatin	O
+.	O
+
+PURPOSE	O
+:	O
+To	O
+assess	O
+the	O
+antiemetic	O
+effects	O
+and	O
+safety	O
+profile	O
+of	O
+four	O
+different	O
+doses	O
+of	O
+granisetron	O
+(	O
+Kytril	O
+;	O
+SmithKline	O
+Beecham	O
+Pharmaceuticals	O
+,	O
+Philadelphia	O
+,	O
+PA	O
+)	O
+when	O
+administered	O
+as	O
+a	O
+single	O
+intravenous	O
+(	O
+IV	O
+)	O
+dose	O
+for	O
+prophylaxis	O
+of	O
+cisplatin	O
+-	O
+induced	O
+nausea	B
+and	O
+vomiting	B
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+One	O
+hundred	O
+eighty	O
+-	O
+four	O
+chemotherapy	O
+-	O
+naive	O
+patients	O
+receiving	O
+high	O
+-	O
+dose	O
+cisplatin	O
+(	O
+81	O
+to	O
+120	O
+mg	O
+/	O
+m2	O
+)	O
+were	O
+randomized	O
+to	O
+receive	O
+one	O
+of	O
+four	O
+granisetron	O
+doses	O
+(	O
+5	O
+,	O
+10	O
+,	O
+20	O
+,	O
+or	O
+40	O
+micrograms	O
+/	O
+kg	O
+)	O
+administered	O
+before	O
+chemotherapy	O
+.	O
+
+Patients	O
+were	O
+observed	O
+on	O
+an	O
+inpatient	O
+basis	O
+for	O
+18	O
+to	O
+24	O
+hours	O
+,	O
+and	O
+vital	O
+signs	O
+,	O
+nausea	B
+,	O
+vomiting	B
+,	O
+retching	O
+,	O
+and	O
+appetite	O
+were	O
+assessed	O
+.	O
+
+Safety	O
+analyses	O
+included	O
+incidence	O
+of	O
+adverse	O
+experiences	O
+and	O
+laboratory	O
+parameter	O
+changes	O
+.	O
+
+RESULTS	O
+:	O
+After	O
+granisetron	O
+doses	O
+of	O
+5	O
+,	O
+10	O
+,	O
+20	O
+,	O
+and	O
+40	O
+micrograms	O
+/	O
+kg	O
+,	O
+a	O
+major	O
+response	O
+(	O
+<	O
+or	O
+=	O
+two	O
+vomiting	B
+or	O
+retching	O
+episodes	O
+,	O
+and	O
+no	O
+antiemetic	O
+rescue	O
+)	O
+was	O
+recorded	O
+in	O
+23	O
+%	O
+,	O
+57	O
+%	O
+,	O
+58	O
+%	O
+,	O
+and	O
+60	O
+%	O
+of	O
+patients	O
+,	O
+respectively	O
+,	O
+and	O
+a	O
+complete	O
+response	O
+(	O
+no	O
+vomiting	B
+or	O
+retching	O
+,	O
+and	O
+no	O
+antiemetic	O
+rescue	O
+)	O
+in	O
+18	O
+%	O
+,	O
+41	O
+%	O
+,	O
+40	O
+%	O
+,	O
+and	O
+47	O
+%	O
+of	O
+patients	O
+,	O
+respectively	O
+.	O
+
+There	O
+was	O
+a	O
+statistically	O
+longer	O
+time	O
+to	O
+first	O
+episode	O
+of	O
+nausea	B
+(	O
+P	O
+=	O
+.	O
+0015	O
+)	O
+and	O
+vomiting	B
+(	O
+P	O
+=	O
+.	O
+0001	O
+)	O
+,	O
+and	O
+fewer	O
+patients	O
+were	O
+administered	O
+additional	O
+antiemetic	O
+medication	O
+in	O
+the	O
+10	O
+-	O
+micrograms	O
+/	O
+kg	O
+dosing	O
+groups	O
+than	O
+in	O
+the	O
+5	O
+-	O
+micrograms	O
+/	O
+kg	O
+dosing	O
+group	O
+.	O
+
+As	O
+granisetron	O
+dose	O
+increased	O
+,	O
+appetite	O
+return	O
+increased	O
+(	O
+P	O
+=	O
+.	O
+040	O
+)	O
+.	O
+
+Headache	B
+was	O
+the	O
+most	O
+frequently	O
+reported	O
+adverse	O
+event	O
+(	O
+20	O
+%	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+A	O
+single	O
+10	O
+-	O
+,	O
+20	O
+-	O
+,	O
+or	O
+40	O
+-	O
+micrograms	O
+/	O
+kg	O
+dose	O
+of	O
+granisetron	O
+was	O
+effective	O
+in	O
+controlling	O
+vomiting	B
+in	O
+57	O
+%	O
+to	O
+60	O
+%	O
+of	O
+patients	O
+who	O
+received	O
+cisplatin	O
+at	O
+doses	O
+greater	O
+than	O
+81	O
+mg	O
+/	O
+m2	O
+and	O
+totally	O
+prevented	O
+vomiting	B
+in	O
+40	O
+%	O
+to	O
+47	O
+%	O
+of	O
+patients	O
+.	O
+
+There	O
+were	O
+no	O
+statistically	O
+significant	O
+differences	O
+in	O
+efficacy	O
+between	O
+the	O
+10	O
+-	O
+micrograms	O
+/	O
+kg	O
+dose	O
+and	O
+the	O
+20	O
+-	O
+and	O
+40	O
+-	O
+micrograms	O
+/	O
+kg	O
+doses	O
+.	O
+
+Granisetron	O
+was	O
+well	O
+tolerated	O
+at	O
+all	O
+doses	O
+.	O
+
+Adverse	O
+interaction	O
+between	O
+clonidine	O
+and	O
+verapamil	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+two	O
+cases	O
+of	O
+a	O
+possible	O
+adverse	O
+interaction	O
+between	O
+clonidine	O
+and	O
+verapamil	O
+resulting	O
+in	O
+atrioventricular	B
+(	I
+AV	I
+)	I
+block	I
+in	O
+both	O
+patients	O
+and	O
+severe	O
+hypotension	B
+in	O
+one	O
+patient	O
+.	O
+
+CASE	O
+SUMMARIES	O
+:	O
+A	O
+54	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+hyperaldosteronism	B
+was	O
+treated	O
+with	O
+verapamil	O
+480	O
+mg	O
+/	O
+d	O
+and	O
+spironolactone	O
+100	O
+mg	O
+/	O
+d	O
+.	O
+
+After	O
+the	O
+addition	O
+of	O
+a	O
+minimal	O
+dose	O
+of	O
+clonidine	O
+(	O
+0	O
+.	O
+15	O
+mg	O
+bid	O
+)	O
+,	O
+she	O
+developed	O
+complete	O
+AV	B
+block	I
+and	O
+severe	O
+hypotension	B
+,	O
+which	O
+resolved	O
+upon	O
+cessation	O
+of	O
+all	O
+medications	O
+.	O
+
+A	O
+65	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+was	O
+treated	O
+with	O
+extended	O
+-	O
+release	O
+verapamil	O
+240	O
+mg	O
+/	O
+d	O
+.	O
+
+After	O
+the	O
+addition	O
+of	O
+clonidine	O
+0	O
+.	O
+15	O
+mg	O
+bid	O
+she	O
+developed	O
+complete	O
+AV	B
+block	I
+,	O
+which	O
+resolved	O
+after	O
+all	O
+therapy	O
+was	O
+stopped	O
+.	O
+
+DISCUSSION	O
+:	O
+An	O
+adverse	O
+interaction	O
+between	O
+clonidine	O
+and	O
+verapamil	O
+has	O
+not	O
+been	O
+reported	O
+previously	O
+.	O
+
+We	O
+describe	O
+two	O
+such	O
+cases	O
+and	O
+discuss	O
+the	O
+various	O
+mechanisms	O
+that	O
+might	O
+cause	O
+such	O
+an	O
+interaction	O
+.	O
+
+Clinicians	O
+should	O
+be	O
+acquainted	O
+with	O
+this	O
+possibly	O
+fatal	O
+interaction	O
+between	O
+two	O
+commonly	O
+used	O
+antihypertensive	O
+drugs	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Caution	O
+is	O
+recommended	O
+in	O
+combining	O
+clonidine	O
+and	O
+verapamil	O
+therapy	O
+,	O
+even	O
+in	O
+patients	O
+who	O
+do	O
+not	O
+have	O
+sinus	O
+or	O
+AV	O
+node	O
+dysfunction	O
+.	O
+
+The	O
+two	O
+drugs	O
+may	O
+act	O
+synergistically	O
+on	O
+both	O
+the	O
+AV	O
+node	O
+and	O
+the	O
+peripheral	O
+circulation	O
+.	O
+
+Pharmacological	O
+studies	O
+on	O
+a	O
+new	O
+dihydrothienopyridine	O
+calcium	O
+antagonist	O
+,	O
+S	O
+-	O
+312	O
+-	O
+d	O
+.	O
+
+5th	O
+communication	O
+:	O
+anticonvulsant	O
+effects	O
+in	O
+mice	O
+.	O
+
+S	O
+-	O
+312	O
+,	O
+S	O
+-	O
+312	O
+-	O
+d	O
+,	O
+but	O
+not	O
+S	O
+-	O
+312	O
+-	O
+l	O
+,	O
+L	O
+-	O
+type	O
+calcium	O
+channel	O
+antagonists	O
+,	O
+showed	O
+anticonvulsant	O
+effects	O
+on	O
+the	O
+audiogenic	B
+tonic	I
+convulsions	I
+in	O
+DBA	O
+/	O
+2	O
+mice	O
+;	O
+and	O
+their	O
+ED50	O
+values	O
+were	O
+18	O
+.	O
+4	O
+(	O
+12	O
+.	O
+8	O
+-	O
+27	O
+.	O
+1	O
+)	O
+mg	O
+/	O
+kg	O
+,	O
+p	O
+.	O
+o	O
+.	O
+and	O
+15	O
+.	O
+0	O
+(	O
+10	O
+.	O
+2	O
+-	O
+23	O
+.	O
+7	O
+)	O
+mg	O
+/	O
+kg	O
+,	O
+p	O
+.	O
+o	O
+.	O
+,	O
+respectively	O
+,	O
+while	O
+that	O
+of	O
+flunarizine	O
+was	O
+34	O
+.	O
+0	O
+(	O
+26	O
+.	O
+0	O
+-	O
+44	O
+.	O
+8	O
+)	O
+mg	O
+/	O
+kg	O
+,	O
+p	O
+.	O
+o	O
+.	O
+
+Although	O
+moderate	O
+anticonvulsant	O
+effects	O
+of	O
+S	O
+-	O
+312	O
+-	O
+d	O
+in	O
+higher	O
+doses	O
+were	O
+observed	O
+against	O
+the	O
+clonic	O
+convulsions	B
+induced	O
+by	O
+pentylenetetrazole	O
+(	O
+85	O
+mg	O
+/	O
+kg	O
+,	O
+s	O
+.	O
+c	O
+.	O
+)	O
+or	O
+bemegride	O
+(	O
+40	O
+mg	O
+/	O
+kg	O
+,	O
+s	O
+.	O
+c	O
+.	O
+)	O
+,	O
+no	O
+effects	O
+were	O
+observed	O
+in	O
+convulsions	B
+induced	O
+by	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+,	O
+picrotoxin	O
+,	O
+or	O
+electroshock	O
+in	O
+Slc	O
+:	O
+ddY	O
+mice	O
+.	O
+
+S	O
+-	O
+312	O
+-	O
+d	O
+may	O
+be	O
+useful	O
+in	O
+the	O
+therapy	O
+of	O
+certain	O
+types	O
+of	O
+human	O
+epilepsy	B
+.	O
+
+Transmural	O
+myocardial	B
+infarction	I
+with	O
+sumatriptan	O
+.	O
+
+For	O
+sumatriptan	O
+,	O
+tightness	O
+in	O
+the	O
+chest	O
+caused	O
+by	O
+an	O
+unknown	O
+mechanism	O
+has	O
+been	O
+reported	O
+in	O
+3	O
+-	O
+5	O
+%	O
+of	O
+users	O
+.	O
+
+We	O
+describe	O
+a	O
+47	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+an	O
+acute	O
+myocardial	B
+infarction	I
+after	O
+administration	O
+of	O
+sumatriptan	O
+6	O
+mg	O
+subcutaneously	O
+for	O
+cluster	B
+headache	I
+.	O
+
+The	O
+patient	O
+had	O
+no	O
+history	O
+of	O
+underlying	O
+ischaemic	B
+heart	I
+disease	I
+or	O
+Prinzmetal	B
+'	I
+s	I
+angina	I
+.	O
+
+She	O
+recovered	O
+without	O
+complications	O
+.	O
+
+Flumazenil	O
+induces	O
+seizures	B
+and	O
+death	O
+in	O
+mixed	O
+cocaine	O
+-	O
+diazepam	O
+intoxications	O
+.	O
+
+STUDY	O
+HYPOTHESIS	O
+:	O
+Administration	O
+of	O
+the	O
+benzodiazepine	O
+antagonist	O
+flumazenil	O
+may	O
+unmask	O
+seizures	B
+in	O
+mixed	O
+cocaine	O
+-	O
+benzodiazepine	O
+intoxication	O
+.	O
+
+DESIGN	O
+:	O
+Male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+received	O
+100	O
+mg	O
+/	O
+kg	O
+cocaine	O
+IP	O
+alone	O
+,	O
+5	O
+mg	O
+/	O
+kg	O
+diazepam	O
+alone	O
+,	O
+or	O
+a	O
+combination	O
+of	O
+diazepam	O
+and	O
+cocaine	O
+.	O
+
+Three	O
+minutes	O
+later	O
+,	O
+groups	O
+were	O
+challenged	O
+with	O
+vehicle	O
+or	O
+flumazenil	O
+5	O
+or	O
+10	O
+mg	O
+/	O
+kg	O
+IP	O
+.	O
+
+Animal	O
+behavior	O
+,	O
+seizures	B
+(	O
+time	O
+to	O
+and	O
+incidence	O
+)	O
+,	O
+death	O
+(	O
+time	O
+to	O
+and	O
+incidence	O
+)	O
+,	O
+and	O
+cortical	O
+EEG	O
+tracings	O
+were	O
+recorded	O
+.	O
+
+INTERVENTIONS	O
+:	O
+Administration	O
+of	O
+flumazenil	O
+to	O
+animals	O
+after	O
+they	O
+had	O
+received	O
+a	O
+combination	O
+dose	O
+of	O
+cocaine	O
+and	O
+diazepam	O
+.	O
+
+RESULTS	O
+:	O
+In	O
+group	O
+1	O
+,	O
+animals	O
+received	O
+cocaine	O
+followed	O
+by	O
+vehicle	O
+.	O
+
+This	O
+resulted	O
+in	O
+100	O
+%	O
+developing	O
+seizures	B
+and	O
+death	O
+.	O
+
+Group	O
+2	O
+received	O
+diazepam	O
+alone	O
+followed	O
+by	O
+vehicle	O
+.	O
+
+Animals	O
+became	O
+somnolent	O
+and	O
+none	O
+died	O
+.	O
+
+Group	O
+3	O
+received	O
+diazepam	O
+followed	O
+by	O
+5	O
+mg	O
+/	O
+kg	O
+flumazenil	O
+.	O
+
+Animals	O
+became	O
+somnolent	O
+after	O
+diazepam	O
+and	O
+then	O
+active	O
+after	O
+flumazenil	O
+administration	O
+.	O
+
+In	O
+group	O
+4	O
+,	O
+a	O
+combination	O
+of	O
+cocaine	O
+and	O
+diazepam	O
+was	O
+administered	O
+simultaneously	O
+.	O
+
+This	O
+resulted	O
+in	O
+no	O
+overt	O
+or	O
+EEG	O
+-	O
+detectable	O
+seizures	B
+and	O
+a	O
+50	O
+%	O
+incidence	O
+of	O
+death	O
+.	O
+
+Group	O
+5	O
+received	O
+a	O
+similar	O
+combination	O
+of	O
+cocaine	O
+and	O
+diazepam	O
+,	O
+followed	O
+later	O
+by	O
+5	O
+mg	O
+/	O
+kg	O
+flumazenil	O
+.	O
+
+This	O
+resulted	O
+in	O
+an	O
+increased	O
+incidence	O
+of	O
+seizures	B
+,	O
+90	O
+%	O
+(	O
+P	O
+<	O
+.	O
+01	O
+)	O
+,	O
+and	O
+death	O
+,	O
+100	O
+%	O
+(	O
+P	O
+<	O
+or	O
+=	O
+.	O
+01	O
+)	O
+,	O
+compared	O
+with	O
+group	O
+4	O
+.	O
+
+Group	O
+6	O
+received	O
+cocaine	O
+and	O
+diazepam	O
+followed	O
+by	O
+10	O
+mg	O
+/	O
+kg	O
+flumazenil	O
+.	O
+
+This	O
+also	O
+resulted	O
+in	O
+an	O
+increased	O
+incidence	O
+of	O
+seizures	B
+,	O
+90	O
+%	O
+(	O
+P	O
+<	O
+or	O
+=	O
+.	O
+01	O
+)	O
+,	O
+and	O
+death	O
+,	O
+90	O
+%	O
+(	O
+P	O
+<	O
+or	O
+=	O
+.	O
+05	O
+)	O
+,	O
+compared	O
+with	O
+group	O
+4	O
+.	O
+
+CONCLUSION	O
+:	O
+Flumazenil	O
+can	O
+unmask	O
+seizures	B
+and	O
+increase	O
+the	O
+incidence	O
+of	O
+death	O
+in	O
+a	O
+model	O
+of	O
+combined	O
+cocaine	O
+-	O
+diazepam	O
+intoxications	O
+.	O
+
+Mechanisms	O
+for	O
+protective	O
+effects	O
+of	O
+free	O
+radical	O
+scavengers	O
+on	O
+gentamicin	O
+-	O
+mediated	O
+nephropathy	B
+in	O
+rats	O
+.	O
+
+Studies	O
+were	O
+performed	O
+to	O
+examine	O
+the	O
+mechanisms	O
+for	O
+the	O
+protective	O
+effects	O
+of	O
+free	O
+radical	O
+scavengers	O
+on	O
+gentamicin	O
+(	O
+GM	O
+)	O
+-	O
+mediated	O
+nephropathy	B
+.	O
+
+Administration	O
+of	O
+GM	O
+at	O
+40	O
+mg	O
+/	O
+kg	O
+sc	O
+for	O
+13	O
+days	O
+to	O
+rats	O
+induced	O
+a	O
+significant	O
+reduction	O
+in	O
+renal	O
+blood	O
+flow	O
+(	O
+RBF	O
+)	O
+and	O
+inulin	O
+clearance	O
+(	O
+CIn	O
+)	O
+as	O
+well	O
+as	O
+marked	O
+tubular	B
+damage	I
+.	O
+
+A	O
+significant	O
+reduction	O
+in	O
+urinary	O
+guanosine	O
+3	O
+'	O
+,	O
+5	O
+'	O
+-	O
+cyclic	O
+monophosphate	O
+(	O
+cGMP	O
+)	O
+excretion	O
+and	O
+a	O
+significant	O
+increase	O
+in	O
+renal	O
+cortical	O
+renin	O
+and	O
+endothelin	O
+-	O
+1	O
+contents	O
+were	O
+also	O
+observed	O
+in	O
+GM	O
+-	O
+mediated	O
+nephropathy	B
+.	O
+
+Superoxide	O
+dismutase	O
+(	O
+SOD	O
+)	O
+or	O
+dimethylthiourea	O
+(	O
+DMTU	O
+)	O
+significantly	O
+lessened	O
+the	O
+GM	O
+-	O
+induced	O
+decrement	O
+in	O
+CIn	O
+.	O
+
+The	O
+SOD	O
+-	O
+induced	O
+increase	O
+in	O
+glomerular	O
+filtration	O
+rate	O
+was	O
+associated	O
+with	O
+a	O
+marked	O
+improvement	O
+in	O
+RBF	O
+,	O
+an	O
+increase	O
+in	O
+urinary	O
+cGMP	O
+excretion	O
+,	O
+and	O
+a	O
+decrease	O
+in	O
+renal	O
+renin	O
+and	O
+endothelin	O
+-	O
+1	O
+content	O
+.	O
+
+SOD	O
+did	O
+not	O
+attenuate	O
+the	O
+tubular	B
+damage	I
+.	O
+
+In	O
+contrast	O
+,	O
+DMTU	O
+significantly	O
+reduced	O
+the	O
+tubular	B
+damage	I
+and	O
+lipid	O
+peroxidation	O
+,	O
+but	O
+it	O
+did	O
+not	O
+affect	O
+renal	O
+hemodynamics	O
+and	O
+vasoactive	O
+substances	O
+.	O
+
+Neither	O
+SOD	O
+nor	O
+DMTU	O
+affected	O
+the	O
+renal	O
+cortical	O
+GM	O
+content	O
+in	O
+GM	O
+-	O
+treated	O
+rats	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+1	O
+)	O
+both	O
+SOD	O
+and	O
+DMTU	O
+have	O
+protective	O
+effects	O
+on	O
+GM	O
+-	O
+mediated	O
+nephropathy	B
+,	O
+2	O
+)	O
+the	O
+mechanisms	O
+for	O
+the	O
+protective	O
+effects	O
+differ	O
+for	O
+SOD	O
+and	O
+DMTU	O
+,	O
+and	O
+3	O
+)	O
+superoxide	O
+anions	O
+play	O
+a	O
+critical	O
+role	O
+in	O
+GM	O
+-	O
+induced	O
+renal	O
+vasoconstriction	O
+.	O
+
+Cephalothin	O
+-	O
+induced	O
+immune	O
+hemolytic	B
+anemia	I
+.	O
+
+A	O
+patient	O
+with	O
+renal	B
+disease	I
+developed	O
+Coombs	O
+-	O
+positive	O
+hemolytic	B
+anemia	I
+while	O
+receiving	O
+cephalothin	O
+therapy	O
+.	O
+
+An	O
+anti	O
+-	O
+cephalothin	O
+IgG	O
+antibody	O
+was	O
+detected	O
+in	O
+the	O
+patient	O
+'	O
+s	O
+serum	O
+and	O
+in	O
+the	O
+eluates	O
+from	O
+her	O
+erythrocytes	O
+.	O
+
+In	O
+addition	O
+,	O
+nonimmunologic	O
+binding	O
+of	O
+normal	O
+and	O
+patient	O
+'	O
+s	O
+serum	O
+proteins	O
+to	O
+her	O
+own	O
+and	O
+cephalothin	O
+-	O
+coated	O
+normal	O
+red	O
+cells	O
+was	O
+demonstrated	O
+.	O
+
+Skin	O
+tests	O
+and	O
+in	O
+vitro	O
+lymphocyte	O
+stimulation	O
+revealed	O
+that	O
+the	O
+patient	O
+was	O
+sensitized	O
+to	O
+cephalothin	O
+and	O
+also	O
+to	O
+ampicillin	O
+.	O
+
+Careful	O
+investigation	O
+of	O
+drug	O
+-	O
+induced	O
+hemolytic	B
+anemias	I
+reveals	O
+the	O
+complexity	O
+of	O
+the	O
+immune	O
+mechanisms	O
+involved	O
+.	O
+
+Assessment	O
+of	O
+cardiomyocyte	O
+DNA	O
+synthesis	O
+during	O
+hypertrophy	B
+in	O
+adult	O
+mice	O
+.	O
+
+The	O
+ability	O
+of	O
+cardiomyocytes	O
+to	O
+synthesize	O
+DNA	O
+in	O
+response	O
+to	O
+experimentally	O
+induced	O
+cardiac	B
+hypertrophy	I
+was	O
+assessed	O
+in	O
+adult	O
+mice	O
+.	O
+
+Isoproterenol	O
+delivered	O
+by	O
+osmotic	O
+minipump	O
+implantation	O
+in	O
+adult	O
+C3Heb	O
+/	O
+FeJ	O
+mice	O
+resulted	O
+in	O
+a	O
+46	O
+%	O
+increase	O
+in	O
+heart	O
+weight	O
+and	O
+a	O
+19	O
+.	O
+3	O
+%	O
+increase	O
+in	O
+cardiomyocyte	O
+area	O
+.	O
+
+No	O
+DNA	O
+synthesis	O
+,	O
+as	O
+assessed	O
+by	O
+autoradiographic	O
+analysis	O
+of	O
+isolated	O
+cardiomyocytes	O
+,	O
+was	O
+observed	O
+in	O
+control	O
+or	O
+hypertrophic	B
+hearts	I
+.	O
+
+A	O
+survey	O
+of	O
+15	O
+independent	O
+inbred	O
+strains	O
+of	O
+mice	O
+revealed	O
+that	O
+ventricular	O
+cardiomyocyte	O
+nuclear	O
+number	O
+ranged	O
+from	O
+3	O
+to	O
+13	O
+%	O
+mononucleate	O
+,	O
+suggesting	O
+that	O
+cardiomyocyte	O
+terminal	O
+differentiation	O
+is	O
+influenced	O
+directly	O
+or	O
+indirectly	O
+by	O
+genetic	O
+background	O
+.	O
+
+To	O
+determine	O
+whether	O
+the	O
+capacity	O
+for	O
+reactive	O
+DNA	O
+synthesis	O
+was	O
+also	O
+subject	O
+to	O
+genetic	O
+regulation	O
+,	O
+cardiac	B
+hypertrophy	I
+was	O
+induced	O
+in	O
+the	O
+strains	O
+of	O
+mice	O
+comprising	O
+the	O
+extremes	O
+of	O
+the	O
+nuclear	O
+number	O
+survey	O
+.	O
+
+These	O
+data	O
+indicate	O
+that	O
+adult	O
+mouse	O
+atrial	O
+and	O
+ventricular	O
+cardiomyocytes	O
+do	O
+not	O
+synthesize	O
+DNA	O
+in	O
+response	O
+to	O
+isoproterenol	O
+-	O
+induced	O
+cardiac	B
+hypertrophy	I
+.	O
+
+Central	O
+cardiovascular	O
+effects	O
+of	O
+AVP	O
+and	O
+ANP	O
+in	O
+normotensive	O
+and	O
+spontaneously	O
+hypertensive	B
+rats	O
+.	O
+
+The	O
+purpose	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+compare	O
+influence	O
+of	O
+central	O
+arginine	O
+vasopressin	O
+(	O
+AVP	O
+)	O
+and	O
+of	O
+atrial	O
+natriuretic	O
+peptide	O
+(	O
+ANP	O
+)	O
+on	O
+control	O
+of	O
+arterial	O
+blood	O
+pressure	O
+(	O
+MAP	O
+)	O
+and	O
+heart	O
+rate	O
+(	O
+HR	O
+)	O
+in	O
+normotensive	O
+(	O
+WKY	O
+)	O
+and	O
+spontaneously	O
+hypertensive	B
+(	O
+SHR	O
+)	O
+rats	O
+.	O
+
+Three	O
+series	O
+of	O
+experiments	O
+were	O
+performed	O
+on	O
+30	O
+WKY	O
+and	O
+30	O
+SHR	O
+,	O
+chronically	O
+instrumented	O
+with	O
+guide	O
+tubes	O
+in	O
+the	O
+lateral	O
+ventricle	O
+(	O
+LV	O
+)	O
+and	O
+arterial	O
+and	O
+venous	O
+catheters	O
+.	O
+
+MAP	O
+and	O
+HR	O
+were	O
+monitored	O
+before	O
+and	O
+after	O
+i	O
+.	O
+v	O
+.	O
+injections	O
+of	O
+either	O
+vehicle	O
+or	O
+1	O
+,	O
+10	O
+and	O
+50	O
+ng	O
+of	O
+AVP	O
+and	O
+25	O
+,	O
+125	O
+and	O
+500	O
+ng	O
+of	O
+ANP	O
+.	O
+
+Sensitivity	O
+of	O
+cardiac	O
+component	O
+of	O
+baroreflex	O
+(	O
+CCB	O
+)	O
+,	O
+expressed	O
+as	O
+a	O
+slope	O
+of	O
+the	O
+regression	O
+line	O
+was	O
+determined	O
+from	O
+relationships	O
+between	O
+systolic	O
+arterial	O
+pressure	O
+(	O
+SAP	O
+)	O
+and	O
+HR	O
+period	O
+(	O
+HRp	O
+)	O
+during	O
+phenylephrine	O
+(	O
+Phe	O
+)	O
+-	O
+induced	O
+hypertension	B
+and	O
+sodium	O
+nitroprusside	O
+(	O
+SN	O
+)	O
+-	O
+induced	O
+hypotension	B
+.	O
+
+CCB	O
+was	O
+measured	O
+before	O
+and	O
+after	O
+administration	O
+of	O
+either	O
+vehicle	O
+,	O
+AVP	O
+,	O
+ANP	O
+,	O
+or	O
+both	O
+peptides	O
+together	O
+.	O
+
+Increases	O
+of	O
+MAP	O
+occurred	O
+after	O
+LV	O
+administration	O
+of	O
+1	O
+,	O
+10	O
+and	O
+50	O
+ng	O
+of	O
+AVP	O
+in	O
+WKY	O
+and	O
+of	O
+10	O
+and	O
+50	O
+ng	O
+in	O
+SHR	O
+.	O
+
+ANP	O
+did	O
+not	O
+cause	O
+significant	O
+changes	O
+in	O
+MAP	O
+in	O
+both	O
+strains	O
+as	O
+compared	O
+to	O
+vehicle	O
+,	O
+but	O
+it	O
+abolished	O
+AVP	O
+-	O
+induced	O
+MAP	O
+increase	O
+in	O
+WKY	O
+and	O
+SHR	O
+.	O
+
+CCB	O
+was	O
+reduced	O
+in	O
+WKY	O
+and	O
+SHR	O
+after	O
+LV	O
+administration	O
+of	O
+AVP	O
+during	O
+SN	O
+-	O
+induced	O
+hypotension	B
+.	O
+
+In	O
+SHR	O
+but	O
+not	O
+in	O
+WKY	O
+administration	O
+of	O
+ANP	O
+,	O
+AVP	O
+and	O
+ANP	O
++	O
+AVP	O
+decreased	O
+CCB	O
+during	O
+Phe	O
+-	O
+induced	O
+MAP	O
+elevation	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+centrally	O
+applied	O
+AVP	O
+and	O
+ANP	O
+exert	O
+differential	O
+effects	O
+on	O
+blood	O
+pressure	O
+and	O
+baroreflex	O
+control	O
+of	O
+heart	O
+rate	O
+in	O
+WKY	O
+and	O
+SHR	O
+and	O
+suggest	O
+interaction	O
+of	O
+these	O
+two	O
+peptides	O
+in	O
+blood	O
+pressure	O
+regulation	O
+at	O
+the	O
+level	O
+of	O
+central	O
+nervous	O
+system	O
+.	O
+
+Cutaneous	O
+exposure	O
+to	O
+warfarin	O
+-	O
+like	O
+anticoagulant	O
+causing	O
+an	O
+intracerebral	B
+hemorrhage	I
+:	O
+a	O
+case	O
+report	O
+.	O
+
+A	O
+case	O
+of	O
+intercerebral	O
+hematoma	B
+due	O
+to	O
+warfarin	O
+-	O
+induced	O
+coagulopathy	B
+is	O
+presented	O
+.	O
+
+The	O
+39	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+had	O
+spread	O
+a	O
+warfarin	O
+-	O
+type	O
+rat	O
+poison	O
+around	O
+her	O
+house	O
+weekly	O
+using	O
+her	O
+bare	O
+hands	O
+,	O
+with	O
+no	O
+washing	O
+post	O
+application	O
+.	O
+
+Percutaneous	O
+absorption	O
+of	O
+warfarin	O
+causing	O
+coagulopathy	B
+,	O
+reported	O
+three	O
+times	O
+in	O
+the	O
+past	O
+,	O
+is	O
+a	O
+significant	O
+risk	O
+if	O
+protective	O
+measures	O
+,	O
+such	O
+as	O
+gloves	O
+,	O
+are	O
+not	O
+used	O
+.	O
+
+An	O
+adverse	O
+drug	O
+interaction	O
+with	O
+piroxicam	O
+,	O
+which	O
+she	O
+took	O
+occasionally	O
+,	O
+may	O
+have	O
+exacerbated	O
+the	O
+coagulopathy	B
+.	O
+
+Pediatric	O
+heart	O
+transplantation	O
+without	O
+chronic	O
+maintenance	O
+steroids	O
+.	O
+
+From	O
+1986	O
+to	O
+February	O
+1993	O
+,	O
+40	O
+children	O
+aged	O
+2	O
+months	O
+to	O
+18	O
+years	O
+(	O
+average	O
+age	O
+10	O
+.	O
+4	O
++	O
+/	O
+-	O
+5	O
+.	O
+8	O
+years	O
+)	O
+underwent	O
+heart	O
+transplantation	O
+.	O
+
+Indications	O
+for	O
+transplantation	O
+were	O
+idiopathic	B
+cardiomyopathy	I
+(	O
+52	O
+%	O
+)	O
+,	O
+congenital	B
+heart	I
+disease	I
+(	O
+35	O
+%	O
+)	O
+with	O
+and	O
+without	O
+prior	O
+repair	O
+(	O
+71	O
+%	O
+and	O
+29	O
+%	O
+,	O
+respectively	O
+)	O
+,	O
+hypertrophic	B
+cardiomyopathy	I
+(	O
+5	O
+%	O
+)	O
+,	O
+valvular	B
+heart	I
+disease	I
+(	O
+3	O
+%	O
+)	O
+,	O
+and	O
+doxorubicin	O
+cardiomyopathy	B
+(	O
+5	O
+%	O
+)	O
+.	O
+
+Patients	O
+were	O
+managed	O
+with	O
+cyclosporine	O
+and	O
+azathioprine	O
+.	O
+
+No	O
+prophylaxis	O
+with	O
+antilymphocyte	O
+globulin	O
+was	O
+used	O
+.	O
+
+Steroids	O
+were	O
+given	O
+to	O
+39	O
+%	O
+of	O
+patients	O
+for	O
+refractory	O
+rejection	O
+,	O
+but	O
+weaning	O
+was	O
+always	O
+attempted	O
+and	O
+generally	O
+successful	O
+(	O
+64	O
+%	O
+)	O
+.	O
+
+Five	O
+patients	O
+(	O
+14	O
+%	O
+)	O
+received	O
+maintenance	O
+steroids	O
+.	O
+
+Four	O
+patients	O
+died	O
+in	O
+the	O
+perioperative	O
+period	O
+and	O
+one	O
+died	O
+4	O
+months	O
+later	O
+.	O
+
+There	O
+have	O
+been	O
+no	O
+deaths	O
+related	O
+to	O
+rejection	O
+or	O
+infection	B
+.	O
+
+Average	O
+follow	O
+-	O
+up	O
+was	O
+36	O
++	O
+/	O
+-	O
+19	O
+months	O
+(	O
+range	O
+1	O
+to	O
+65	O
+months	O
+)	O
+.	O
+
+Cumulative	O
+survival	O
+is	O
+88	O
+%	O
+at	O
+5	O
+years	O
+.	O
+
+In	O
+patients	O
+less	O
+than	O
+7	O
+years	O
+of	O
+age	O
+,	O
+rejection	O
+was	O
+monitored	O
+noninvasively	O
+.	O
+
+In	O
+the	O
+first	O
+postoperative	O
+month	O
+,	O
+89	O
+%	O
+of	O
+patients	O
+were	O
+treated	O
+for	O
+rejection	O
+.	O
+
+Freedom	O
+from	O
+serious	O
+infections	B
+was	O
+83	O
+%	O
+at	O
+1	O
+month	O
+and	O
+65	O
+%	O
+at	O
+1	O
+year	O
+.	O
+
+Cytomegalovirus	B
+infections	I
+were	O
+treated	O
+successfully	O
+with	O
+ganciclovir	O
+in	O
+11	O
+patients	O
+.	O
+
+No	O
+impairment	O
+of	O
+growth	O
+was	O
+observed	O
+in	O
+children	O
+who	O
+underwent	O
+transplantation	O
+compared	O
+with	O
+a	O
+control	O
+population	O
+.	O
+
+Twenty	O
+-	O
+one	O
+patients	O
+(	O
+60	O
+%	O
+)	O
+have	O
+undergone	O
+annual	O
+catheterizations	O
+and	O
+no	O
+sign	O
+of	O
+graft	O
+atherosclerosis	B
+has	O
+been	O
+observed	O
+.	O
+
+Seizures	B
+occurred	O
+in	O
+five	O
+patients	O
+(	O
+14	O
+%	O
+)	O
+and	O
+hypertension	B
+was	O
+treated	O
+in	O
+10	O
+patients	O
+(	O
+28	O
+%	O
+)	O
+.	O
+
+No	O
+patient	O
+was	O
+disabled	O
+and	O
+no	O
+lymphoproliferative	B
+disorder	I
+was	O
+observed	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Delirium	B
+during	O
+fluoxetine	O
+treatment	O
+.	O
+
+A	O
+case	O
+report	O
+.	O
+
+The	O
+correlation	O
+between	O
+high	O
+serum	O
+tricyclic	O
+antidepressant	O
+concentrations	O
+and	O
+central	O
+nervous	O
+system	O
+side	O
+effects	O
+has	O
+been	O
+well	O
+established	O
+.	O
+
+Only	O
+a	O
+few	O
+reports	O
+exist	O
+,	O
+however	O
+,	O
+on	O
+the	O
+relationship	O
+between	O
+the	O
+serum	O
+concentrations	O
+of	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitors	O
+(	O
+SSRIs	O
+)	O
+and	O
+their	O
+toxic	O
+effects	O
+.	O
+
+In	O
+some	O
+cases	O
+,	O
+a	O
+high	O
+serum	O
+concentration	O
+of	O
+citalopram	O
+(	O
+>	O
+600	O
+nmol	O
+/	O
+L	O
+)	O
+in	O
+elderly	O
+patients	O
+has	O
+been	O
+associated	O
+with	O
+increased	O
+somnolence	B
+and	O
+movement	B
+difficulties	I
+.	O
+
+Widespread	O
+cognitive	B
+disorders	I
+,	O
+such	O
+as	O
+delirium	B
+,	O
+have	O
+not	O
+been	O
+previously	O
+linked	O
+with	O
+high	O
+blood	O
+levels	O
+of	O
+SSRIs	O
+.	O
+
+In	O
+this	O
+report	O
+,	O
+we	O
+describe	O
+a	O
+patient	O
+with	O
+acute	O
+hyperkinetic	B
+delirium	B
+connected	O
+with	O
+a	O
+high	O
+serum	O
+total	O
+fluoxetine	O
+(	O
+fluoxetine	O
+plus	O
+desmethylfluoxetine	O
+)	O
+concentration	O
+.	O
+
+Pulmonary	B
+edema	I
+and	O
+shock	B
+after	O
+high	O
+-	O
+dose	O
+aracytine	O
+-	O
+C	O
+for	O
+lymphoma	B
+;	O
+possible	O
+role	O
+of	O
+TNF	O
+-	O
+alpha	O
+and	O
+PAF	O
+.	O
+
+Four	O
+out	O
+of	O
+23	O
+consecutive	O
+patients	O
+treated	O
+with	O
+high	O
+-	O
+dose	O
+Ara	O
+-	O
+C	O
+for	O
+lymphomas	B
+in	O
+our	O
+institution	O
+developed	O
+a	O
+strikingly	O
+similar	O
+syndrome	O
+during	O
+the	O
+perfusion	O
+.	O
+
+It	O
+was	O
+characterized	O
+by	O
+the	O
+onset	O
+of	O
+fever	B
+,	O
+diarrhea	B
+,	O
+shock	B
+,	O
+pulmonary	B
+edema	I
+,	O
+acute	B
+renal	I
+failure	I
+,	O
+metabolic	B
+acidosis	I
+,	O
+weight	B
+gain	I
+and	O
+leukocytosis	B
+.	O
+
+Thorough	O
+bacteriological	O
+screening	O
+failed	O
+to	O
+provide	O
+evidence	O
+of	O
+infection	B
+.	O
+
+Sequential	O
+biological	O
+assays	O
+of	O
+IL	O
+-	O
+1	O
+,	O
+IL	O
+-	O
+2	O
+,	O
+TNF	O
+and	O
+PAF	O
+were	O
+performed	O
+during	O
+Ara	O
+-	O
+C	O
+infusion	O
+to	O
+ten	O
+patients	O
+,	O
+including	O
+the	O
+four	O
+who	O
+developed	O
+the	O
+syndrome	O
+.	O
+
+TNF	O
+and	O
+PAF	O
+activity	O
+was	O
+found	O
+in	O
+the	O
+serum	O
+of	O
+respectively	O
+two	O
+and	O
+four	O
+of	O
+the	O
+cases	O
+,	O
+but	O
+not	O
+in	O
+the	O
+six	O
+controls	O
+.	O
+
+As	O
+TNF	O
+and	O
+PAF	O
+are	O
+thought	O
+to	O
+be	O
+involved	O
+in	O
+the	O
+development	O
+of	O
+septic	O
+shock	B
+and	O
+adult	B
+respiratory	I
+distress	I
+syndrome	I
+,	O
+we	O
+hypothesize	O
+that	O
+high	O
+-	O
+dose	O
+Ara	O
+-	O
+C	O
+may	O
+be	O
+associated	O
+with	O
+cytokine	O
+release	O
+.	O
+
+Protective	O
+effect	O
+of	O
+clentiazem	O
+against	O
+epinephrine	O
+-	O
+induced	O
+cardiac	B
+injury	I
+in	O
+rats	O
+.	O
+
+We	O
+investigated	O
+the	O
+effects	O
+of	O
+clentiazem	O
+,	O
+a	O
+1	O
+,	O
+5	O
+-	O
+benzothiazepine	O
+calcium	O
+antagonist	O
+,	O
+on	O
+epinephrine	O
+-	O
+induced	O
+cardiomyopathy	B
+in	O
+rats	O
+.	O
+
+With	O
+2	O
+-	O
+week	O
+chronic	O
+epinephrine	O
+infusion	O
+,	O
+16	O
+of	O
+30	O
+rats	O
+died	O
+within	O
+4	O
+days	O
+,	O
+and	O
+severe	O
+ischemic	B
+lesions	I
+and	O
+fibrosis	B
+of	O
+the	O
+left	O
+ventricles	O
+were	O
+observed	O
+.	O
+
+In	O
+epinephrine	O
+-	O
+treated	O
+rats	O
+,	O
+left	O
+atrial	O
+and	O
+left	O
+ventricular	O
+papillary	O
+muscle	O
+contractile	O
+responses	O
+to	O
+isoproterenol	O
+were	O
+reduced	O
+,	O
+but	O
+responses	O
+to	O
+calcium	O
+were	O
+normal	O
+or	O
+enhanced	O
+compared	O
+to	O
+controls	O
+.	O
+
+Left	O
+ventricular	O
+alpha	O
+and	O
+beta	O
+adrenoceptor	O
+densities	O
+were	O
+also	O
+reduced	O
+compared	O
+to	O
+controls	O
+.	O
+
+Treatment	O
+with	O
+clentiazem	O
+prevented	O
+epinephrine	O
+-	O
+induced	O
+death	O
+(	O
+P	O
+<	O
+.	O
+05	O
+)	O
+,	O
+and	O
+attenuated	O
+the	O
+ventricular	O
+ischemic	B
+lesions	I
+and	O
+fibrosis	B
+,	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+.	O
+
+Left	O
+atrial	O
+and	O
+left	O
+ventricular	O
+papillary	O
+muscle	O
+contractile	O
+responses	O
+to	O
+isoproterenol	O
+were	O
+reduced	O
+compared	O
+to	O
+controls	O
+in	O
+groups	O
+treated	O
+with	O
+clentiazem	O
+alone	O
+,	O
+but	O
+combined	O
+with	O
+epinephrine	O
+,	O
+clentiazem	O
+restored	O
+left	O
+atrial	O
+responses	O
+and	O
+enhanced	O
+left	O
+ventricular	O
+papillary	O
+responses	O
+to	O
+isoproterenol	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+clentiazem	O
+did	O
+not	O
+prevent	O
+epinephrine	O
+-	O
+induced	O
+down	O
+-	O
+regulation	O
+of	O
+alpha	O
+and	O
+beta	O
+adrenoceptors	O
+.	O
+
+Interestingly	O
+,	O
+clentiazem	O
+,	O
+infused	O
+alone	O
+,	O
+resulted	O
+in	O
+decreased	O
+adrenergic	O
+receptor	O
+densities	O
+in	O
+the	O
+left	O
+ventricle	O
+.	O
+
+Clentiazem	O
+also	O
+did	O
+not	O
+prevent	O
+the	O
+enhanced	O
+responses	O
+to	O
+calcium	O
+seen	O
+in	O
+the	O
+epinephrine	O
+-	O
+treated	O
+animals	O
+,	O
+although	O
+the	O
+high	O
+dose	O
+of	O
+clentiazem	O
+partially	O
+attenuated	O
+the	O
+maximal	O
+response	O
+to	O
+calcium	O
+compared	O
+to	O
+epinephrine	O
+-	O
+treated	O
+animals	O
+.	O
+
+In	O
+conclusion	O
+,	O
+clentiazem	O
+attenuated	O
+epinephrine	O
+-	O
+induced	O
+cardiac	B
+injury	I
+,	O
+possibly	O
+through	O
+its	O
+effect	O
+on	O
+the	O
+adrenergic	O
+pathway	O
+.	O
+
+Kaliuretic	O
+effect	O
+of	O
+L	O
+-	O
+dopa	O
+treatment	O
+in	O
+parkinsonian	B
+patients	O
+.	O
+
+Hypokalemia	B
+,	O
+sometimes	O
+severe	O
+,	O
+was	O
+observed	O
+in	O
+some	O
+L	O
+-	O
+dopa	O
+-	O
+treated	O
+parkinsonian	B
+patients	O
+.	O
+
+The	O
+influence	O
+of	O
+L	O
+-	O
+dopa	O
+on	O
+the	O
+renal	O
+excretion	O
+of	O
+potassium	O
+was	O
+studied	O
+in	O
+3	O
+patients	O
+with	O
+hypokalemia	B
+and	O
+in	O
+5	O
+normokalemic	O
+patients	O
+by	O
+determination	O
+of	O
+renal	O
+plasma	O
+flow	O
+,	O
+glomerular	O
+filtration	O
+rate	O
+,	O
+plasma	O
+concentration	O
+of	O
+potassium	O
+and	O
+sodium	O
+as	O
+well	O
+as	O
+urinary	O
+excretion	O
+of	O
+potassium	O
+,	O
+sodium	O
+and	O
+aldosterone	O
+.	O
+
+L	O
+-	O
+Dopa	O
+intake	O
+was	O
+found	O
+to	O
+cause	O
+an	O
+increased	O
+excretion	O
+of	O
+potassium	O
+,	O
+and	O
+sometimes	O
+also	O
+of	O
+sodium	O
+,	O
+in	O
+the	O
+hypokalemic	O
+but	O
+not	O
+in	O
+the	O
+normokalemic	O
+patients	O
+.	O
+
+This	O
+effect	O
+on	O
+the	O
+renal	O
+function	O
+could	O
+be	O
+prohibited	O
+by	O
+the	O
+administration	O
+of	O
+a	O
+peripheral	O
+dopa	O
+decarbodylase	O
+inhibitor	O
+.	O
+
+It	O
+is	O
+not	O
+known	O
+why	O
+this	O
+effect	O
+occurred	O
+in	O
+some	O
+individuals	O
+but	O
+not	O
+in	O
+others	O
+,	O
+but	O
+our	O
+results	O
+indicate	O
+a	O
+correlation	O
+between	O
+aldosterone	O
+production	O
+and	O
+this	O
+renal	O
+effect	O
+of	O
+L	O
+-	O
+dopa	O
+.	O
+
+Cocaine	O
+induced	O
+myocardial	B
+ischemia	I
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+myocardial	B
+ischemia	I
+induced	O
+by	O
+cocaine	O
+.	O
+
+The	O
+ischemia	B
+probably	O
+induced	O
+by	O
+coronary	B
+artery	I
+spasm	I
+was	O
+reversed	O
+by	O
+nitroglycerin	O
+and	O
+calcium	O
+blocking	O
+agents	O
+.	O
+
+Doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B
+monitored	O
+by	O
+ECG	O
+in	O
+freely	O
+moving	O
+mice	O
+.	O
+
+A	O
+new	O
+model	O
+to	O
+test	O
+potential	O
+protectors	O
+.	O
+
+In	O
+laboratory	O
+animals	O
+,	O
+histology	O
+is	O
+most	O
+commonly	O
+used	O
+to	O
+study	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+However	O
+,	O
+for	O
+monitoring	O
+during	O
+treatment	O
+,	O
+large	O
+numbers	O
+of	O
+animals	O
+are	O
+needed	O
+.	O
+
+Recently	O
+we	O
+developed	O
+a	O
+new	O
+method	O
+to	O
+measure	O
+ECG	O
+values	O
+in	O
+freely	O
+moving	O
+mice	O
+by	O
+telemetry	O
+.	O
+
+With	O
+this	O
+model	O
+we	O
+investigated	O
+the	O
+effect	O
+of	O
+chronic	O
+doxorubicin	O
+administration	O
+on	O
+the	O
+ECG	O
+of	O
+freely	O
+moving	O
+BALB	O
+/	O
+c	O
+mice	O
+and	O
+the	O
+efficacy	O
+of	O
+ICRF	O
+-	O
+187	O
+as	O
+a	O
+protective	O
+agent	O
+.	O
+
+The	O
+ST	O
+interval	O
+significantly	O
+widened	O
+from	O
+15	O
+.	O
+0	O
++	O
+/	O
+-	O
+1	O
+.	O
+5	O
+to	O
+56	O
+.	O
+8	O
++	O
+/	O
+-	O
+11	O
+.	O
+8	O
+ms	O
+in	O
+week	O
+10	O
+(	O
+7	O
+weekly	O
+doses	O
+of	O
+4	O
+mg	O
+/	O
+kg	O
+doxorubicin	O
+given	O
+i	O
+.	O
+v	O
+.	O
+plus	O
+3	O
+weeks	O
+of	O
+observation	O
+)	O
+.	O
+
+The	O
+ECG	O
+of	O
+the	O
+control	O
+animals	O
+did	O
+not	O
+change	O
+during	O
+the	O
+entire	O
+study	O
+.	O
+
+After	O
+sacrifice	O
+the	O
+hearts	O
+of	O
+doxorubicin	O
+-	O
+treated	O
+animals	O
+were	O
+enlarged	O
+and	O
+the	O
+atria	O
+were	O
+hypertrophic	B
+.	O
+
+As	O
+this	O
+schedule	O
+exerted	O
+more	O
+toxicity	B
+than	O
+needed	O
+to	O
+investigate	O
+protective	O
+agents	O
+,	O
+the	O
+protection	O
+of	O
+ICRF	O
+-	O
+187	O
+was	O
+determined	O
+using	O
+a	O
+dose	O
+schedule	O
+with	O
+lower	O
+general	O
+toxicity	B
+(	O
+6	O
+weekly	O
+doses	O
+of	O
+4	O
+mg	O
+/	O
+kg	O
+doxorubicin	O
+given	O
+i	O
+.	O
+v	O
+.	O
+plus	O
+2	O
+weeks	O
+of	O
+observation	O
+)	O
+.	O
+
+On	O
+this	O
+schedule	O
+,	O
+the	O
+animals	O
+'	O
+hearts	O
+appeared	O
+normal	O
+after	O
+sacrifice	O
+and	O
+ICRF	O
+-	O
+187	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+given	O
+i	O
+.	O
+p	O
+.	O
+1	O
+h	O
+before	O
+doxorubicin	O
+)	O
+provided	O
+almost	O
+full	O
+protection	O
+.	O
+
+These	O
+data	O
+were	O
+confirmed	O
+by	O
+histology	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+this	O
+new	O
+model	O
+is	O
+very	O
+sensitive	O
+and	O
+enables	O
+monitoring	O
+of	O
+the	O
+development	O
+of	O
+cardiotoxicity	B
+with	O
+time	O
+.	O
+
+These	O
+findings	O
+result	O
+in	O
+a	O
+model	O
+that	O
+allows	O
+the	O
+testing	O
+of	O
+protectors	O
+against	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B
+as	O
+demonstrated	O
+by	O
+the	O
+protection	O
+provided	O
+by	O
+ICRF	O
+-	O
+187	O
+.	O
+
+Epinephrine	O
+dysrhythmogenicity	O
+is	O
+not	O
+enhanced	O
+by	O
+subtoxic	O
+bupivacaine	O
+in	O
+dogs	O
+.	O
+
+Since	O
+bupivacaine	O
+and	O
+epinephrine	O
+may	O
+both	O
+precipitate	O
+dysrhythmias	B
+,	O
+circulating	O
+bupivacaine	O
+during	O
+regional	O
+anesthesia	O
+could	O
+potentiate	O
+dysrhythmogenic	O
+effects	O
+of	O
+epinephrine	O
+.	O
+
+We	O
+therefore	O
+examined	O
+whether	O
+bupivacaine	O
+alters	O
+the	O
+dysrhythmogenicity	O
+of	O
+subsequent	O
+administration	O
+of	O
+epinephrine	O
+in	O
+conscious	O
+,	O
+healthy	O
+dogs	O
+and	O
+in	O
+anesthetized	O
+dogs	O
+with	O
+myocardial	B
+infarction	I
+.	O
+
+Forty	O
+-	O
+one	O
+conscious	O
+dogs	O
+received	O
+10	O
+micrograms	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+epinephrine	O
+.	O
+
+Seventeen	O
+animals	O
+responded	O
+with	O
+ventricular	B
+tachycardia	I
+(	O
+VT	B
+)	O
+within	O
+3	O
+min	O
+.	O
+
+After	O
+3	O
+h	O
+,	O
+these	O
+responders	O
+randomly	O
+received	O
+1	O
+or	O
+2	O
+mg	O
+/	O
+kg	O
+bupivacaine	O
+or	O
+saline	O
+over	O
+5	O
+min	O
+,	O
+followed	O
+by	O
+10	O
+micrograms	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+epinephrine	O
+.	O
+
+In	O
+the	O
+bupivacaine	O
+groups	O
+,	O
+epinephrine	O
+caused	O
+fewer	O
+prodysrhythmic	O
+effects	O
+than	O
+without	O
+bupivacaine	O
+.	O
+
+VT	B
+appeared	O
+in	O
+fewer	O
+dogs	O
+and	O
+at	O
+a	O
+later	O
+time	O
+,	O
+and	O
+there	O
+were	O
+more	O
+sinoatrial	O
+beats	O
+and	O
+less	O
+ectopies	O
+.	O
+
+Epinephrine	O
+shortened	O
+QT	O
+less	O
+after	O
+bupivacaine	O
+than	O
+in	O
+control	O
+animals	O
+.	O
+
+One	O
+day	O
+after	O
+experimental	O
+myocardial	B
+infarction	I
+,	O
+six	O
+additional	O
+halothane	O
+-	O
+anesthetized	O
+dogs	O
+received	O
+4	O
+micrograms	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+epinephrine	O
+until	O
+VT	B
+appeared	O
+.	O
+
+After	O
+45	O
+min	O
+,	O
+1	O
+mg	O
+/	O
+kg	O
+bupivacaine	O
+was	O
+injected	O
+over	O
+5	O
+min	O
+,	O
+again	O
+followed	O
+by	O
+4	O
+micrograms	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+epinephrine	O
+.	O
+
+In	O
+these	O
+dogs	O
+,	O
+the	O
+prodysrhythmic	O
+response	O
+to	O
+epinephrine	O
+was	O
+also	O
+mitigated	O
+by	O
+preceding	O
+bupivacaine	O
+.	O
+
+Bupivacaine	O
+antagonizes	O
+epinephrine	O
+dysrhythmogenicity	O
+in	O
+conscious	O
+dogs	O
+susceptible	O
+to	O
+VT	B
+and	O
+in	O
+anesthetized	O
+dogs	O
+with	O
+spontaneous	O
+postinfarct	O
+dysrhythmias	B
+.	O
+
+There	O
+is	O
+no	O
+evidence	O
+that	O
+systemic	O
+subtoxic	O
+bupivacaine	O
+administration	O
+enhances	O
+the	O
+dysrhythmogenicity	O
+of	O
+subsequent	O
+epinephrine	O
+.	O
+
+Milk	B
+-	I
+alkali	I
+syndrome	I
+induced	O
+by	O
+1	O
+,	O
+25	O
+(	O
+OH	O
+)	O
+2D	O
+in	O
+a	O
+patient	O
+with	O
+hypoparathyroidism	B
+.	O
+
+Milk	B
+-	I
+alkali	I
+syndrome	I
+was	O
+first	O
+described	O
+70	O
+years	O
+ago	O
+in	O
+the	O
+context	O
+of	O
+the	O
+treatment	O
+of	O
+peptic	B
+ulcer	I
+disease	I
+with	O
+large	O
+amounts	O
+of	O
+calcium	O
+and	O
+alkali	O
+.	O
+
+Although	O
+with	O
+current	O
+ulcer	B
+therapy	O
+(	O
+H	O
+-	O
+2	O
+blockers	O
+,	O
+omeprazole	O
+,	O
+and	O
+sucralfate	O
+)	O
+,	O
+the	O
+frequency	O
+of	O
+milk	B
+-	I
+alkali	I
+syndrome	I
+has	O
+decreased	O
+significantly	O
+,	O
+the	O
+classic	O
+triad	O
+of	O
+hypercalcemia	B
+,	O
+alkalosis	B
+,	O
+and	O
+renal	B
+impairment	I
+remains	O
+the	O
+hallmark	O
+of	O
+the	O
+syndrome	O
+.	O
+
+Milk	B
+-	I
+alkali	I
+syndrome	I
+can	O
+present	O
+serious	O
+and	O
+occasionally	O
+life	O
+-	O
+threatening	O
+illness	O
+unless	O
+diagnosed	O
+and	O
+treated	O
+appropriately	O
+.	O
+
+This	O
+article	O
+presents	O
+a	O
+patient	O
+with	O
+hypoparathyroidism	B
+who	O
+was	O
+treated	O
+with	O
+calcium	O
+carbonate	O
+and	O
+calcitriol	O
+resulting	O
+in	O
+two	O
+admissions	O
+to	O
+the	O
+hospital	O
+for	O
+milk	B
+-	I
+alkali	I
+syndrome	I
+.	O
+
+The	O
+patient	O
+was	O
+successfully	O
+treated	O
+with	O
+intravenous	O
+pamidronate	O
+on	O
+his	O
+first	O
+admission	O
+and	O
+with	O
+hydrocortisone	O
+on	O
+the	O
+second	O
+.	O
+
+This	O
+illustrates	O
+intravenous	O
+pamidronate	O
+as	O
+a	O
+valuable	O
+therapeutic	O
+tool	O
+when	O
+milk	B
+-	I
+alkali	I
+syndrome	I
+presents	O
+as	O
+hypercalcemic	B
+emergency	I
+.	O
+
+Famotidine	O
+-	O
+associated	O
+delirium	B
+.	O
+
+A	O
+series	O
+of	O
+six	O
+cases	O
+.	O
+
+Famotidine	O
+is	O
+a	O
+histamine	O
+H2	O
+-	O
+receptor	O
+antagonist	O
+used	O
+in	O
+inpatient	O
+settings	O
+for	O
+prevention	O
+of	O
+stress	O
+ulcers	B
+and	O
+is	O
+showing	O
+increasing	O
+popularity	O
+because	O
+of	O
+its	O
+low	O
+cost	O
+.	O
+
+Although	O
+all	O
+of	O
+the	O
+currently	O
+available	O
+H2	O
+-	O
+receptor	O
+antagonists	O
+have	O
+shown	O
+the	O
+propensity	O
+to	O
+cause	O
+delirium	B
+,	O
+only	O
+two	O
+previously	O
+reported	O
+cases	O
+have	O
+been	O
+associated	O
+with	O
+famotidine	O
+.	O
+
+The	O
+authors	O
+report	O
+on	O
+six	O
+cases	O
+of	O
+famotidine	O
+-	O
+associated	O
+delirium	B
+in	O
+hospitalized	O
+patients	O
+who	O
+cleared	O
+completely	O
+upon	O
+removal	O
+of	O
+famotidine	O
+.	O
+
+The	O
+pharmacokinetics	O
+of	O
+famotidine	O
+are	O
+reviewed	O
+,	O
+with	O
+no	O
+change	O
+in	O
+its	O
+metabolism	O
+in	O
+the	O
+elderly	O
+population	O
+seen	O
+.	O
+
+The	O
+implications	O
+of	O
+using	O
+famotidine	O
+in	O
+elderly	O
+persons	O
+are	O
+discussed	O
+.	O
+
+Encephalopathy	B
+during	O
+amitriptyline	O
+therapy	O
+:	O
+are	O
+neuroleptic	B
+malignant	I
+syndrome	I
+and	O
+serotonin	B
+syndrome	I
+spectrum	O
+disorders	O
+?	O
+
+This	O
+report	O
+describes	O
+a	O
+case	O
+of	O
+encephalopathy	B
+developed	O
+in	O
+the	O
+course	O
+of	O
+amitriptyline	O
+therapy	O
+,	O
+during	O
+a	O
+remission	O
+of	O
+unipolar	B
+depression	I
+.	O
+
+This	O
+patient	O
+could	O
+have	O
+been	O
+diagnosed	O
+as	O
+having	O
+either	O
+neuroleptic	B
+malignant	I
+syndrome	I
+(	O
+NMS	B
+)	O
+or	O
+serotonin	B
+syndrome	I
+(	O
+SS	B
+)	O
+.	O
+
+The	O
+major	O
+determinant	O
+of	O
+the	O
+symptoms	O
+may	O
+have	O
+been	O
+dopamine	O
+/	O
+serotonin	O
+imbalance	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+.	O
+
+The	O
+NMS	B
+-	O
+like	O
+encephalopathy	B
+that	O
+develops	O
+in	O
+association	O
+with	O
+the	O
+use	O
+of	O
+antidepressants	O
+indicates	O
+that	O
+NMS	B
+and	O
+SS	B
+are	O
+spectrum	O
+disorders	O
+induced	O
+by	O
+drugs	O
+with	O
+both	O
+antidopaminergic	O
+and	O
+serotonergic	O
+effects	O
+.	O
+
+Genetic	O
+separation	O
+of	O
+tumor	B
+growth	O
+and	O
+hemorrhagic	B
+phenotypes	O
+in	O
+an	O
+estrogen	O
+-	O
+induced	O
+tumor	B
+.	O
+
+Chronic	O
+administration	O
+of	O
+estrogen	O
+to	O
+the	O
+Fischer	O
+344	O
+(	O
+F344	O
+)	O
+rat	O
+induces	O
+growth	O
+of	O
+large	O
+,	O
+hemorrhagic	B
+pituitary	B
+tumors	I
+.	O
+
+Ten	O
+weeks	O
+of	O
+diethylstilbestrol	O
+(	O
+DES	O
+)	O
+treatment	O
+caused	O
+female	O
+F344	O
+rat	O
+pituitaries	O
+to	O
+grow	O
+to	O
+an	O
+average	O
+of	O
+109	O
+.	O
+2	O
++	O
+/	O
+-	O
+6	O
+.	O
+3	O
+mg	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SE	O
+)	O
+versus	O
+11	O
+.	O
+3	O
++	O
+/	O
+-	O
+1	O
+.	O
+4	O
+mg	O
+for	O
+untreated	O
+rats	O
+,	O
+and	O
+to	O
+become	O
+highly	O
+hemorrhagic	B
+.	O
+
+The	O
+same	O
+DES	O
+treatment	O
+produced	O
+no	O
+significant	O
+growth	O
+(	O
+8	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+mg	O
+for	O
+treated	O
+females	O
+versus	O
+8	O
+.	O
+7	O
++	O
+/	O
+-	O
+1	O
+.	O
+1	O
+for	O
+untreated	O
+females	O
+)	O
+or	O
+morphological	O
+changes	O
+in	O
+Brown	O
+Norway	O
+(	O
+BN	O
+)	O
+rat	O
+pituitaries	O
+.	O
+
+An	O
+F1	O
+hybrid	O
+of	O
+F344	O
+and	O
+BN	O
+exhibited	O
+significant	O
+pituitary	O
+growth	O
+after	O
+10	O
+weeks	O
+of	O
+DES	O
+treatment	O
+with	O
+an	O
+average	O
+mass	O
+of	O
+26	O
+.	O
+3	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+mg	O
+compared	O
+with	O
+8	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+9	O
+mg	O
+for	O
+untreated	O
+rats	O
+.	O
+
+Surprisingly	O
+,	O
+the	O
+F1	O
+hybrid	O
+tumors	B
+were	O
+not	O
+hemorrhagic	B
+and	O
+had	O
+hemoglobin	O
+content	O
+and	O
+outward	O
+appearance	O
+identical	O
+to	O
+that	O
+of	O
+BN	O
+.	O
+
+Expression	O
+of	O
+both	O
+growth	O
+and	O
+morphological	O
+changes	O
+is	O
+due	O
+to	O
+multiple	O
+genes	O
+.	O
+
+However	O
+,	O
+while	O
+DES	O
+-	O
+induced	O
+pituitary	O
+growth	O
+exhibited	O
+quantitative	O
+,	O
+additive	O
+inheritance	O
+,	O
+the	O
+hemorrhagic	B
+phenotype	O
+exhibited	O
+recessive	O
+,	O
+epistatic	O
+inheritance	O
+.	O
+
+Only	O
+5	O
+of	O
+the	O
+160	O
+F2	O
+pituitaries	O
+exhibited	O
+the	O
+hemorrhagic	B
+phenotype	O
+;	O
+36	O
+of	O
+the	O
+160	O
+F2	O
+pituitaries	O
+were	O
+in	O
+the	O
+F344	O
+range	O
+of	O
+mass	O
+,	O
+but	O
+31	O
+of	O
+these	O
+were	O
+not	O
+hemorrhagic	B
+,	O
+indicating	O
+that	O
+the	O
+hemorrhagic	B
+phenotype	O
+is	O
+not	O
+merely	O
+a	O
+consequence	O
+of	O
+extensive	O
+growth	O
+.	O
+
+The	O
+hemorrhagic	B
+F2	O
+pituitaries	O
+were	O
+all	O
+among	O
+the	O
+most	O
+massive	O
+,	O
+indicating	O
+that	O
+some	O
+of	O
+the	O
+genes	O
+regulate	O
+both	O
+phenotypes	O
+.	O
+
+Increased	O
+expression	O
+of	O
+neuronal	O
+nitric	O
+oxide	O
+synthase	O
+in	O
+bladder	O
+afferent	O
+pathways	O
+following	O
+chronic	O
+bladder	B
+irritation	I
+.	O
+
+Immunocytochemical	O
+techniques	O
+were	O
+used	O
+to	O
+examine	O
+alterations	O
+in	O
+the	O
+expression	O
+of	O
+neuronal	O
+nitric	O
+oxide	O
+synthase	O
+(	O
+NOS	O
+)	O
+in	O
+bladder	O
+pathways	O
+following	O
+acute	O
+and	O
+chronic	O
+irritation	B
+of	I
+the	I
+urinary	I
+tract	I
+of	O
+the	O
+rat	O
+.	O
+
+Chemical	O
+cystitis	B
+was	O
+induced	O
+by	O
+cyclophosphamide	O
+(	O
+CYP	O
+)	O
+which	O
+is	O
+metabolized	O
+to	O
+acrolein	O
+,	O
+an	O
+irritant	O
+eliminated	O
+in	O
+the	O
+urine	O
+.	O
+
+Injection	O
+of	O
+CYP	O
+(	O
+n	O
+=	O
+10	O
+,	O
+75	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+2	O
+hours	O
+prior	O
+to	O
+perfusion	O
+(	O
+acute	O
+treatment	O
+)	O
+of	O
+the	O
+animals	O
+increased	O
+Fos	O
+-	O
+immunoreactivity	O
+(	O
+IR	O
+)	O
+in	O
+neurons	O
+in	O
+the	O
+dorsal	O
+commissure	O
+,	O
+dorsal	O
+horn	O
+,	O
+and	O
+autonomic	O
+regions	O
+of	O
+spinal	O
+segments	O
+(	O
+L1	O
+-	O
+L2	O
+and	O
+L6	O
+-	O
+S1	O
+)	O
+which	O
+receive	O
+afferent	O
+inputs	O
+from	O
+the	O
+bladder	O
+,	O
+urethra	O
+,	O
+and	O
+ureter	O
+.	O
+
+Fos	O
+-	O
+IR	O
+in	O
+the	O
+spinal	O
+cord	O
+was	O
+not	O
+changed	O
+in	O
+rats	O
+receiving	O
+chronic	O
+CYP	O
+treatment	O
+(	O
+n	O
+=	O
+15	O
+,	O
+75	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+,	O
+every	O
+3rd	O
+day	O
+for	O
+2	O
+weeks	O
+)	O
+.	O
+
+In	O
+control	O
+animals	O
+and	O
+in	O
+animals	O
+treated	O
+acutely	O
+with	O
+CYP	O
+,	O
+only	O
+small	O
+numbers	O
+of	O
+NOS	O
+-	O
+IR	O
+cells	O
+(	O
+0	O
+.	O
+5	O
+-	O
+0	O
+.	O
+7	O
+cell	O
+profiles	O
+/	O
+sections	O
+)	O
+were	O
+detected	O
+in	O
+the	O
+L6	O
+-	O
+S1	O
+dorsal	O
+root	O
+ganglia	O
+(	O
+DRG	O
+)	O
+.	O
+
+Chronic	O
+CYP	O
+administration	O
+significantly	O
+(	O
+P	O
+<	O
+or	O
+=	O
+.	O
+002	O
+)	O
+increased	O
+bladder	O
+weight	O
+by	O
+60	O
+%	O
+and	O
+increased	O
+(	O
+7	O
+-	O
+to	O
+11	O
+-	O
+fold	O
+)	O
+the	O
+numbers	O
+of	O
+NOS	O
+-	O
+immunoreactive	O
+(	O
+IR	O
+)	O
+afferent	O
+neurons	O
+in	O
+the	O
+L6	O
+-	O
+S1	O
+DRG	O
+.	O
+
+A	O
+small	O
+increase	O
+(	O
+1	O
+.	O
+5	O
+-	O
+fold	O
+)	O
+also	O
+occurred	O
+in	O
+the	O
+L1	O
+DRG	O
+,	O
+but	O
+no	O
+change	O
+was	O
+detected	O
+in	O
+the	O
+L2	O
+and	O
+L5	O
+DRG	O
+.	O
+
+Bladder	O
+afferent	O
+cells	O
+in	O
+the	O
+L6	O
+-	O
+S1	O
+DRG	O
+labeled	O
+by	O
+Fluorogold	O
+(	O
+40	O
+microliters	O
+)	O
+injected	O
+into	O
+the	O
+bladder	O
+wall	O
+did	O
+not	O
+exhibit	O
+NOS	O
+-	O
+IR	O
+in	O
+control	O
+animals	O
+;	O
+however	O
+,	O
+following	O
+chronic	O
+CYP	O
+administration	O
+,	O
+a	O
+significant	O
+percentage	O
+of	O
+bladder	O
+afferent	O
+neurons	O
+were	O
+NOS	O
+-	O
+IR	O
+:	O
+L6	O
+(	O
+19	O
+.	O
+8	O
++	O
+/	O
+-	O
+4	O
+.	O
+6	O
+%	O
+)	O
+and	O
+S1	O
+(	O
+25	O
+.	O
+3	O
++	O
+/	O
+-	O
+2	O
+.	O
+9	O
+%	O
+)	O
+.	O
+
+These	O
+results	O
+indicate	O
+that	O
+neuronal	O
+gene	O
+expression	O
+in	O
+visceral	O
+sensory	O
+pathways	O
+can	O
+be	O
+upregulated	O
+by	O
+chemical	O
+irritation	O
+of	O
+afferent	O
+receptors	O
+in	O
+the	O
+urinary	O
+tract	O
+and	O
+/	O
+or	O
+that	O
+pathological	O
+changes	O
+in	O
+the	O
+urinary	O
+tract	O
+can	O
+initiate	O
+chemical	O
+signals	O
+that	O
+alter	O
+the	O
+chemical	O
+properties	O
+of	O
+visceral	O
+afferent	O
+neurons	O
+.	O
+
+Effects	O
+of	O
+a	O
+new	O
+calcium	O
+antagonist	O
+,	O
+CD	O
+-	O
+832	O
+,	O
+on	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+ischemia	I
+in	O
+dogs	O
+with	O
+partial	O
+coronary	B
+stenosis	I
+.	O
+
+Effects	O
+of	O
+CD	O
+-	O
+832	O
+on	O
+isoproterenol	O
+(	O
+ISO	O
+)	O
+-	O
+induced	O
+myocardial	B
+ischemia	I
+were	O
+studied	O
+in	O
+dogs	O
+with	O
+partial	O
+coronary	B
+stenosis	I
+of	O
+the	O
+left	O
+circumflex	O
+coronary	O
+artery	O
+and	O
+findings	O
+were	O
+compared	O
+with	O
+those	O
+for	O
+nifedipine	O
+or	O
+diltiazem	O
+.	O
+
+In	O
+the	O
+presence	O
+of	O
+coronary	B
+artery	I
+stenosis	I
+,	O
+3	O
+-	O
+min	O
+periods	O
+of	O
+intracoronary	O
+ISO	O
+infusion	O
+(	O
+10	O
+ng	O
+/	O
+kg	O
+/	O
+min	O
+)	O
+increased	O
+heart	O
+rate	O
+and	O
+maximal	O
+rate	O
+of	O
+left	O
+ventricular	O
+pressure	O
+rise	O
+,	O
+which	O
+resulted	O
+in	O
+a	O
+decrease	O
+in	O
+percentage	O
+segmental	O
+shortening	O
+and	O
+ST	O
+-	O
+segment	O
+elevation	O
+of	O
+the	O
+epicardial	O
+electrocardiogram	O
+.	O
+
+After	O
+the	O
+control	O
+ISO	O
+infusion	O
+with	O
+stenosis	B
+was	O
+performed	O
+,	O
+equihypotensive	O
+doses	O
+of	O
+CD	O
+-	O
+832	O
+(	O
+3	O
+and	O
+10	O
+micrograms	O
+/	O
+kg	O
+/	O
+min	O
+,	O
+n	O
+=	O
+7	O
+)	O
+,	O
+nifedipine	O
+(	O
+1	O
+and	O
+3	O
+micrograms	O
+/	O
+kg	O
+/	O
+min	O
+,	O
+n	O
+=	O
+9	O
+)	O
+or	O
+diltiazem	O
+(	O
+10	O
+and	O
+30	O
+micrograms	O
+/	O
+kg	O
+/	O
+min	O
+,	O
+n	O
+=	O
+7	O
+)	O
+were	O
+infused	O
+5	O
+min	O
+before	O
+and	O
+during	O
+the	O
+second	O
+and	O
+third	O
+ISO	O
+infusion	O
+.	O
+
+Both	O
+CD	O
+-	O
+832	O
+and	O
+diltiazem	O
+,	O
+but	O
+not	O
+nifedipine	O
+,	O
+significantly	O
+reduced	O
+the	O
+increase	O
+in	O
+heart	O
+rate	O
+induced	O
+by	O
+ISO	O
+infusion	O
+.	O
+
+In	O
+contrast	O
+to	O
+nifedipine	O
+,	O
+CD	O
+-	O
+832	O
+(	O
+10	O
+micrograms	O
+/	O
+kg	O
+/	O
+min	O
+)	O
+prevented	O
+the	O
+decrease	O
+in	O
+percentage	O
+segmental	O
+shortening	O
+from	O
+32	O
++	O
+/	O
+-	O
+12	O
+%	O
+to	O
+115	O
++	O
+/	O
+-	O
+26	O
+%	O
+of	O
+the	O
+control	O
+value	O
+(	O
+P	O
+<	O
+.	O
+01	O
+)	O
+and	O
+ST	O
+-	O
+segment	O
+elevation	O
+from	O
+5	O
+.	O
+6	O
++	O
+/	O
+-	O
+1	O
+.	O
+0	O
+mV	O
+to	O
+1	O
+.	O
+6	O
++	O
+/	O
+-	O
+1	O
+.	O
+3	O
+mV	O
+(	O
+P	O
+<	O
+.	O
+01	O
+)	O
+at	O
+3	O
+min	O
+after	O
+ISO	O
+infusion	O
+with	O
+stenosis	B
+.	O
+
+Diltiazem	O
+(	O
+30	O
+micrograms	O
+/	O
+kg	O
+/	O
+min	O
+)	O
+also	O
+prevented	O
+the	O
+decrease	O
+in	O
+percentage	O
+segmental	O
+shortening	O
+from	O
+34	O
++	O
+/	O
+-	O
+14	O
+%	O
+to	O
+63	O
++	O
+/	O
+-	O
+18	O
+%	O
+of	O
+the	O
+control	O
+value	O
+(	O
+P	O
+<	O
+.	O
+05	O
+)	O
+and	O
+ST	O
+-	O
+segment	O
+elevation	O
+from	O
+4	O
+.	O
+7	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+mV	O
+to	O
+2	O
+.	O
+1	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+mV	O
+(	O
+P	O
+<	O
+.	O
+01	O
+)	O
+at	O
+3	O
+min	O
+after	O
+ISO	O
+infusion	O
+with	O
+stenosis	B
+.	O
+
+These	O
+data	O
+show	O
+that	O
+CD	O
+-	O
+832	O
+improves	O
+myocardial	B
+ischemia	I
+during	O
+ISO	O
+infusion	O
+with	O
+stenosis	B
+and	O
+suggest	O
+that	O
+the	O
+negative	O
+chronotropic	O
+property	O
+of	O
+CD	O
+-	O
+832	O
+plays	O
+a	O
+major	O
+role	O
+in	O
+the	O
+beneficial	O
+effects	O
+of	O
+CD	O
+-	O
+832	O
+.	O
+
+The	O
+effect	O
+of	O
+recombinant	O
+human	O
+insulin	O
+-	O
+like	O
+growth	O
+factor	O
+-	O
+I	O
+on	O
+chronic	O
+puromycin	O
+aminonucleoside	O
+nephropathy	B
+in	O
+rats	O
+.	O
+
+We	O
+recently	O
+demonstrated	O
+that	O
+recombinant	O
+hGH	O
+exacerbates	O
+renal	O
+functional	O
+and	O
+structural	O
+injury	O
+in	O
+chronic	O
+puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+)	O
+nephropathy	B
+,	O
+an	O
+experimental	O
+model	O
+of	O
+glomerular	B
+disease	I
+.	O
+
+Therefore	O
+,	O
+we	O
+examined	O
+whether	O
+recombinant	O
+human	O
+(	O
+rh	O
+)	O
+IGF	O
+-	O
+I	O
+is	O
+a	O
+safer	O
+alternative	O
+for	O
+the	O
+treatment	O
+of	O
+growth	B
+failure	I
+in	O
+rats	O
+with	O
+chronic	O
+PAN	O
+nephropathy	B
+.	O
+
+The	O
+glomerulopathy	B
+was	O
+induced	O
+by	O
+seven	O
+serial	O
+injections	O
+of	O
+PAN	O
+over	O
+12	O
+wk	O
+.	O
+
+Experimental	O
+animals	O
+(	O
+n	O
+=	O
+6	O
+)	O
+received	O
+rhIGF	O
+-	O
+I	O
+,	O
+400	O
+micrograms	O
+/	O
+d	O
+,	O
+whereas	O
+control	O
+rats	O
+(	O
+n	O
+=	O
+6	O
+)	O
+received	O
+the	O
+vehicle	O
+.	O
+
+rhIGF	O
+-	O
+I	O
+improved	O
+weight	O
+gain	O
+by	O
+14	O
+%	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+,	O
+without	O
+altering	O
+hematocrit	O
+or	O
+blood	O
+pressure	O
+in	O
+rats	O
+with	O
+renal	B
+disease	I
+.	O
+
+Urinary	O
+protein	O
+excretion	O
+was	O
+unaltered	O
+by	O
+rhIGF	O
+-	O
+I	O
+treatment	O
+in	O
+rats	O
+with	O
+chronic	O
+PAN	O
+nephropathy	B
+.	O
+
+After	O
+12	O
+wk	O
+,	O
+the	O
+inulin	O
+clearance	O
+was	O
+higher	O
+in	O
+rhIGF	O
+-	O
+I	O
+-	O
+treated	O
+rats	O
+,	O
+0	O
+.	O
+48	O
++	O
+/	O
+-	O
+0	O
+.	O
+08	O
+versus	O
+0	O
+.	O
+24	O
++	O
+/	O
+-	O
+0	O
+.	O
+06	O
+mL	O
+/	O
+min	O
+/	O
+100	O
+g	O
+of	O
+body	O
+weight	O
+in	O
+untreated	O
+PAN	O
+nephropathy	B
+animals	O
+,	O
+p	O
+<	O
+0	O
+.	O
+05	O
+.	O
+
+The	O
+improvement	O
+in	O
+GFR	O
+was	O
+not	O
+associated	O
+with	O
+enhanced	O
+glomerular	B
+hypertrophy	I
+or	O
+increased	O
+segmental	O
+glomerulosclerosis	B
+,	O
+tubulointerstitial	B
+injury	I
+,	O
+or	O
+renal	O
+cortical	O
+malondialdehyde	O
+content	O
+.	O
+
+In	O
+rats	O
+with	O
+PAN	O
+nephropathy	B
+,	O
+administration	O
+of	O
+rhIGF	O
+-	O
+I	O
+increased	O
+IGF	O
+-	O
+I	O
+and	O
+GH	O
+receptor	O
+gene	O
+expression	O
+,	O
+without	O
+altering	O
+the	O
+steady	O
+state	O
+level	O
+of	O
+IGF	O
+-	O
+I	O
+receptor	O
+mRNA	O
+.	O
+
+In	O
+normal	O
+rats	O
+with	O
+intact	O
+kidneys	O
+,	O
+rhIGF	O
+-	O
+I	O
+administration	O
+(	O
+n	O
+=	O
+4	O
+)	O
+did	O
+not	O
+alter	O
+weight	O
+gain	O
+,	O
+blood	O
+pressure	O
+,	O
+proteinuria	B
+,	O
+GFR	O
+,	O
+glomerular	O
+planar	O
+area	O
+,	O
+renal	O
+cortical	O
+malondialdehyde	O
+content	O
+,	O
+or	O
+glomerular	O
+or	O
+tubulointerstitial	B
+damage	I
+,	O
+compared	O
+with	O
+untreated	O
+animals	O
+(	O
+n	O
+=	O
+4	O
+)	O
+.	O
+
+rhIGF	O
+-	O
+I	O
+treatment	O
+reduced	O
+the	O
+steady	O
+state	O
+renal	O
+IGF	O
+-	O
+I	O
+mRNA	O
+level	O
+but	O
+did	O
+not	O
+modify	O
+gene	O
+expression	O
+of	O
+the	O
+IGF	O
+-	O
+I	O
+or	O
+GH	O
+receptors	O
+.	O
+
+We	O
+conclude	O
+that	O
+:	O
+1	O
+)	O
+administration	O
+of	O
+rhIGF	O
+-	O
+I	O
+improves	O
+growth	O
+and	O
+GFR	O
+in	O
+rats	O
+with	O
+chronic	O
+PAN	O
+nephropathy	B
+and	O
+2	O
+)	O
+unlike	O
+rhGH	O
+,	O
+long	O
+-	O
+term	O
+use	O
+of	O
+rhIGF	O
+-	O
+I	O
+does	O
+not	O
+worsen	O
+renal	O
+functional	O
+and	O
+structural	O
+injury	O
+in	O
+this	O
+disease	O
+model	O
+.	O
+
+Nefiracetam	O
+(	O
+DM	O
+-	O
+9384	O
+)	O
+reverses	O
+apomorphine	O
+-	O
+induced	O
+amnesia	B
+of	O
+a	O
+passive	O
+avoidance	O
+response	O
+:	O
+delayed	O
+emergence	O
+of	O
+the	O
+memory	O
+retention	O
+effects	O
+.	O
+
+Nefiracetam	O
+is	O
+a	O
+novel	O
+pyrrolidone	O
+derivative	O
+which	O
+attenuates	O
+scopolamine	O
+-	O
+induced	O
+learning	B
+and	I
+post	I
+-	I
+training	I
+consolidation	I
+deficits	I
+.	O
+
+Given	O
+that	O
+apomorphine	O
+inhibits	O
+passive	O
+avoidance	O
+retention	O
+when	O
+given	O
+during	O
+training	O
+or	O
+in	O
+a	O
+defined	O
+10	O
+-	O
+12h	O
+post	O
+-	O
+training	O
+period	O
+,	O
+we	O
+evaluated	O
+the	O
+ability	O
+of	O
+nefiracetam	O
+to	O
+attenuate	O
+amnesia	B
+induced	O
+by	O
+dopaminergic	O
+agonism	O
+.	O
+
+A	O
+step	O
+-	O
+down	O
+passive	O
+avoidance	O
+paradigm	O
+was	O
+employed	O
+and	O
+nefiracetam	O
+(	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+apomorphine	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+were	O
+given	O
+alone	O
+or	O
+in	O
+combination	O
+during	O
+training	O
+and	O
+at	O
+the	O
+10	O
+-	O
+12h	O
+post	O
+-	O
+training	O
+period	O
+of	O
+consolidation	O
+.	O
+
+Co	O
+-	O
+administration	O
+of	O
+nefiracetam	O
+and	O
+apomorphine	O
+during	O
+training	O
+or	O
+10h	O
+thereafter	O
+produced	O
+no	O
+significant	O
+anti	O
+-	O
+amnesic	O
+effect	O
+.	O
+
+However	O
+,	O
+administration	O
+of	O
+nefiracetam	O
+during	O
+training	O
+completely	O
+reversed	O
+the	O
+amnesia	B
+induced	O
+by	O
+apomorphine	O
+at	O
+the	O
+10h	O
+post	O
+-	O
+training	O
+time	O
+and	O
+the	O
+converse	O
+was	O
+also	O
+true	O
+.	O
+
+These	O
+effects	O
+were	O
+not	O
+mediated	O
+by	O
+a	O
+dopaminergic	O
+mechanism	O
+as	O
+nefiracetam	O
+,	O
+at	O
+millimolar	O
+concentrations	O
+,	O
+failed	O
+to	O
+displace	O
+either	O
+[	O
+3H	O
+]	O
+SCH	O
+23390	O
+or	O
+[	O
+3H	O
+]	O
+spiperone	O
+binding	O
+from	O
+D1	O
+or	O
+D2	O
+dopamine	O
+receptor	O
+subtypes	O
+,	O
+respectively	O
+.	O
+
+It	O
+is	O
+suggested	O
+that	O
+nefiracetam	O
+augments	O
+molecular	O
+processes	O
+in	O
+the	O
+early	O
+stages	O
+of	O
+events	O
+which	O
+ultimately	O
+lead	O
+to	O
+consolidation	O
+of	O
+memory	O
+.	O
+
+Phenytoin	O
+encephalopathy	B
+as	O
+probable	O
+idiosyncratic	O
+reaction	O
+:	O
+case	O
+report	O
+.	O
+
+A	O
+case	O
+of	O
+phenytoin	O
+(	O
+DPH	O
+)	O
+encephalopathy	B
+with	O
+increasing	O
+seizures	B
+and	O
+EEG	O
+and	O
+mental	O
+changes	O
+is	O
+described	O
+.	O
+
+Despite	O
+adequate	O
+oral	O
+dosage	O
+of	O
+DPH	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+/	O
+daily	O
+)	O
+the	O
+plasma	O
+level	O
+was	O
+very	O
+low	O
+(	O
+2	O
+.	O
+8	O
+microgramg	O
+/	O
+ml	O
+)	O
+.	O
+
+The	O
+encephalopathy	B
+was	O
+probably	O
+an	O
+idiosyncratic	O
+and	O
+not	O
+toxic	O
+or	O
+allergic	O
+reaction	O
+.	O
+
+In	O
+fact	O
+the	O
+concentration	O
+of	O
+free	O
+DPH	O
+was	O
+normal	O
+,	O
+the	O
+patient	O
+presented	O
+a	O
+retarded	O
+morbilliform	O
+rash	B
+during	O
+DPH	O
+treatment	O
+,	O
+the	O
+protidogram	O
+was	O
+normal	O
+,	O
+and	O
+an	O
+intradermic	O
+DPH	O
+injection	O
+had	O
+no	O
+local	O
+effect	O
+.	O
+
+The	O
+authors	O
+conclude	O
+that	O
+in	O
+a	O
+patient	O
+starting	O
+DPH	O
+treatment	O
+an	O
+unexpected	O
+increase	O
+in	O
+seizures	B
+,	O
+with	O
+EEG	O
+and	O
+mental	O
+changes	O
+occurring	O
+simultaneously	O
+,	O
+should	O
+alert	O
+the	O
+physician	O
+to	O
+the	O
+possible	O
+need	O
+for	O
+eliminating	O
+DPH	O
+from	O
+the	O
+therapeutic	O
+regimen	O
+,	O
+even	O
+if	O
+plasma	O
+concentrations	O
+are	O
+low	O
+.	O
+
+Prevention	O
+and	O
+treatment	O
+of	O
+endometrial	B
+disease	I
+in	O
+climacteric	O
+women	O
+receiving	O
+oestrogen	O
+therapy	O
+.	O
+
+The	O
+treatment	O
+regimens	O
+are	O
+described	O
+in	O
+74	O
+patients	O
+with	O
+endometrial	B
+disease	I
+among	O
+850	O
+climacteric	O
+women	O
+receiving	O
+oestrogen	O
+therapy	O
+.	O
+
+Cystic	O
+hyperplasia	B
+was	O
+associated	O
+with	O
+unopposed	O
+oestrogen	O
+therapy	O
+without	O
+progestagen	O
+.	O
+
+Two	O
+courses	O
+of	O
+21	O
+days	O
+of	O
+5	O
+mg	O
+norethisterone	O
+daily	O
+caused	O
+reversion	O
+to	O
+normal	O
+in	O
+all	O
+57	O
+cases	O
+of	O
+cystic	O
+hyperplasia	B
+and	O
+6	O
+of	O
+the	O
+8	O
+cases	O
+of	O
+atypical	O
+hyperplasia	B
+.	O
+
+4	O
+cases	O
+of	O
+endometrial	B
+carcinoma	I
+referred	O
+from	O
+elsewhere	O
+demonstrated	O
+the	O
+problems	O
+of	O
+inappropriate	O
+and	O
+unsupervised	O
+unopposed	O
+oestrogen	O
+therapy	O
+and	O
+the	O
+difficulty	O
+in	O
+distinguishing	O
+severe	O
+hyperplasia	B
+from	O
+malignancy	B
+.	O
+
+Cyclical	O
+low	O
+-	O
+dose	O
+oestrogen	O
+therapy	O
+with	O
+7	O
+-	O
+-	O
+13	O
+days	O
+of	O
+progestagen	O
+does	O
+not	O
+seem	O
+to	O
+increase	O
+the	O
+risk	O
+of	O
+endometrial	B
+hyperplasia	I
+or	O
+carcinoma	B
+.	O
+
+Effects	O
+of	O
+exercise	O
+on	O
+the	O
+severity	O
+of	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+.	O
+
+The	O
+effect	O
+of	O
+exercise	O
+on	O
+the	O
+severity	O
+of	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+was	O
+studied	O
+in	O
+male	O
+rats	O
+.	O
+
+Ninety	O
+-	O
+three	O
+rats	O
+were	O
+randomly	O
+divided	O
+into	O
+three	O
+groups	O
+.	O
+
+The	O
+exercise	O
+-	O
+isoproterenol	O
+(	O
+E	O
+-	O
+1	O
+)	O
+and	O
+exercise	O
+control	O
+(	O
+EC	O
+)	O
+groups	O
+exercised	O
+daily	O
+for	O
+thirty	O
+days	O
+on	O
+a	O
+treadmill	O
+at	O
+1	O
+mph	O
+,	O
+2	O
+%	O
+grade	O
+while	O
+animals	O
+of	O
+the	O
+sedentary	O
+-	O
+isoproterenol	O
+(	O
+S	O
+-	O
+I	O
+)	O
+group	O
+remained	O
+sedentary	O
+.	O
+
+Eight	O
+animals	O
+were	O
+assigned	O
+to	O
+the	O
+sedentary	O
+control	O
+(	O
+SC	O
+)	O
+group	O
+which	O
+remained	O
+sedentary	O
+throughout	O
+the	O
+experimental	O
+period	O
+.	O
+
+Forty	O
+-	O
+eight	O
+hours	O
+after	O
+the	O
+final	O
+exercise	O
+period	O
+,	O
+S	O
+-	O
+I	O
+and	O
+E	O
+-	O
+I	O
+animals	O
+received	O
+a	O
+single	O
+subcutaneous	O
+injection	O
+of	O
+isoproterenol	O
+(	O
+250	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+)	O
+.	O
+
+Animals	O
+of	O
+the	O
+S	O
+-	O
+I	O
+group	O
+exhibited	O
+significantly	O
+(	O
+Pp	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+greater	O
+mortality	O
+from	O
+the	O
+effects	O
+of	O
+isoproterenol	O
+than	O
+animals	O
+of	O
+the	O
+E	O
+-	O
+I	O
+group	O
+.	O
+
+Serum	O
+CPK	O
+activity	O
+for	O
+E	O
+-	O
+I	O
+animals	O
+was	O
+significantly	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+greater	O
+than	O
+for	O
+animals	O
+in	O
+the	O
+S	O
+-	O
+I	O
+and	O
+EC	O
+groups	O
+twenty	O
+hours	O
+following	O
+isoproterenol	O
+injection	O
+.	O
+
+No	O
+statistically	O
+significant	O
+differences	O
+were	O
+observed	O
+between	O
+the	O
+two	O
+isoproterenol	O
+treated	O
+groups	O
+for	O
+severity	O
+of	O
+the	O
+induced	O
+lesions	O
+,	O
+changes	O
+in	O
+heart	O
+weight	O
+,	O
+or	O
+heart	O
+weight	O
+to	O
+body	O
+weight	O
+ratios	O
+.	O
+
+The	O
+results	O
+indicated	O
+that	O
+exercise	O
+reduced	O
+the	O
+mortality	O
+associated	O
+with	O
+the	O
+effects	O
+of	O
+large	O
+dosages	O
+of	O
+isoproterenol	O
+but	O
+had	O
+little	O
+on	O
+the	O
+severity	O
+of	O
+the	O
+infarction	B
+.	O
+
+Human	O
+corticotropin	O
+-	O
+releasing	O
+hormone	O
+and	O
+thyrotropin	O
+-	O
+releasing	O
+hormone	O
+modulate	O
+the	O
+hypercapnic	B
+ventilatory	O
+response	O
+in	O
+humans	O
+.	O
+
+Human	O
+corticotropin	O
+-	O
+releasing	O
+hormone	O
+(	O
+hCRH	O
+)	O
+and	O
+thyrotropin	O
+-	O
+releasing	O
+hormone	O
+(	O
+TRH	O
+)	O
+are	O
+known	O
+to	O
+stimulate	O
+ventilation	O
+after	O
+i	O
+.	O
+v	O
+.	O
+administration	O
+in	O
+humans	O
+.	O
+
+In	O
+a	O
+placebo	O
+-	O
+controlled	O
+,	O
+single	O
+-	O
+blind	O
+study	O
+we	O
+aimed	O
+to	O
+clarify	O
+if	O
+both	O
+peptides	O
+act	O
+by	O
+altering	O
+central	O
+chemosensitivity	O
+.	O
+
+Two	O
+subsequent	O
+CO2	O
+-	O
+rebreathing	O
+tests	O
+were	O
+performed	O
+in	O
+healthy	O
+young	O
+volunteers	O
+.	O
+
+During	O
+the	O
+first	O
+test	O
+0	O
+.	O
+9	O
+%	O
+NaCl	O
+was	O
+given	O
+i	O
+.	O
+v	O
+.	O
+;	O
+during	O
+the	O
+second	O
+test	O
+200	O
+micrograms	O
+of	O
+hCRH	O
+(	O
+n	O
+=	O
+12	O
+)	O
+or	O
+400	O
+micrograms	O
+of	O
+TRH	O
+(	O
+n	O
+=	O
+6	O
+)	O
+was	O
+administered	O
+i	O
+.	O
+v	O
+.	O
+Nine	O
+subjects	O
+received	O
+0	O
+.	O
+9	O
+%	O
+NaCl	O
+i	O
+.	O
+v	O
+.	O
+during	O
+both	O
+rebreathing	O
+manoeuvres	O
+.	O
+
+The	O
+CO2	O
+-	O
+response	O
+curves	O
+for	O
+the	O
+two	O
+tests	O
+were	O
+compared	O
+within	O
+the	O
+same	O
+subject	O
+.	O
+
+In	O
+the	O
+hCRH	O
+group	O
+a	O
+marked	O
+parallel	O
+shift	O
+of	O
+the	O
+CO2	O
+-	O
+response	O
+curve	O
+to	O
+the	O
+left	O
+was	O
+observed	O
+after	O
+hCRH	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+The	O
+same	O
+effect	O
+occurred	O
+following	O
+TRH	O
+but	O
+was	O
+less	O
+striking	O
+(	O
+P	O
+=	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+hCRH	O
+and	O
+TRH	O
+caused	O
+a	O
+reduction	O
+in	O
+the	O
+CO2	O
+threshold	O
+.	O
+
+The	O
+CO2	O
+-	O
+response	O
+curves	O
+in	O
+the	O
+control	O
+group	O
+were	O
+nearly	O
+identical	O
+.	O
+
+The	O
+results	O
+indicate	O
+an	O
+additive	O
+effect	O
+of	O
+both	O
+releasing	O
+hormones	O
+on	O
+the	O
+hypercapnic	B
+ventilatory	O
+response	O
+in	O
+humans	O
+,	O
+presumably	O
+independent	O
+of	O
+central	O
+chemosensitivity	O
+.	O
+
+Lamivudine	O
+is	O
+effective	O
+in	O
+suppressing	O
+hepatitis	B
+B	I
+virus	O
+DNA	O
+in	O
+Chinese	O
+hepatitis	O
+B	O
+surface	O
+antigen	O
+carriers	O
+:	O
+a	O
+placebo	O
+-	O
+controlled	O
+trial	O
+.	O
+
+Lamivudine	O
+is	O
+a	O
+novel	O
+2	O
+'	O
+,	O
+3	O
+'	O
+-	O
+dideoxy	O
+cytosine	O
+analogue	O
+that	O
+has	O
+potent	O
+inhibitory	O
+effects	O
+on	O
+hepatitis	B
+B	I
+virus	O
+replication	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+.	O
+
+We	O
+performed	O
+a	O
+single	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+study	O
+to	O
+assess	O
+its	O
+effectiveness	O
+and	O
+safety	O
+in	O
+Chinese	O
+hepatitis	O
+B	O
+surface	O
+antigen	O
+(	O
+HBsAg	O
+)	O
+carriers	O
+.	O
+
+Forty	O
+-	O
+two	O
+Chinese	O
+HBsAg	O
+carriers	O
+were	O
+randomized	O
+to	O
+receive	O
+placebo	O
+(	O
+6	O
+patients	O
+)	O
+or	O
+lamivudine	O
+orally	O
+in	O
+dosages	O
+of	O
+25	O
+mg	O
+,	O
+100	O
+mg	O
+,	O
+or	O
+300	O
+mg	O
+daily	O
+(	O
+12	O
+patients	O
+for	O
+each	O
+dosage	O
+)	O
+.	O
+
+The	O
+drug	O
+was	O
+given	O
+for	O
+4	O
+weeks	O
+.	O
+
+The	O
+patients	O
+were	O
+closely	O
+monitored	O
+clinically	O
+,	O
+biochemically	O
+,	O
+and	O
+serologically	O
+up	O
+to	O
+4	O
+weeks	O
+after	O
+drug	O
+treatment	O
+.	O
+
+All	O
+36	O
+patients	O
+receiving	O
+lamivudine	O
+had	O
+a	O
+decrease	O
+in	O
+hepatitis	B
+B	I
+virus	O
+(	O
+HBV	O
+)	O
+DNA	O
+values	O
+of	O
+>	O
+90	O
+%	O
+(	O
+P	O
+<	O
+.	O
+001	O
+compared	O
+with	O
+placebo	O
+)	O
+.	O
+
+Although	O
+25	O
+mg	O
+of	O
+lamivudine	O
+was	O
+slightly	O
+less	O
+effective	O
+than	O
+100	O
+mg	O
+(	O
+P	O
+=	O
+.	O
+011	O
+)	O
+and	O
+300	O
+mg	O
+(	O
+P	O
+=	O
+.	O
+005	O
+)	O
+,	O
+it	O
+still	O
+induced	O
+94	O
+%	O
+suppression	O
+of	O
+HBV	O
+DNA	O
+after	O
+the	O
+fourth	O
+week	O
+of	O
+therapy	O
+.	O
+
+HBV	O
+DNA	O
+values	O
+returned	O
+to	O
+pretreatment	O
+levels	O
+within	O
+4	O
+weeks	O
+of	O
+cessation	O
+of	O
+therapy	O
+.	O
+
+There	O
+was	O
+no	O
+change	O
+in	O
+the	O
+hepatitis	B
+B	I
+e	O
+antigen	O
+status	O
+or	O
+in	O
+aminotransferase	O
+levels	O
+.	O
+
+No	O
+serious	O
+adverse	O
+events	O
+were	O
+observed	O
+.	O
+
+In	O
+conclusion	O
+,	O
+a	O
+4	O
+-	O
+week	O
+course	O
+of	O
+lamivudine	O
+was	O
+safe	O
+and	O
+effective	O
+in	O
+suppression	O
+of	O
+HBV	O
+DNA	O
+in	O
+Chinese	O
+HBsAg	O
+carriers	O
+.	O
+
+The	O
+suppression	O
+was	O
+>	O
+90	O
+%	O
+but	O
+reversible	O
+.	O
+
+Studies	O
+with	O
+long	O
+-	O
+term	O
+lamivudine	O
+administration	O
+should	O
+be	O
+performed	O
+to	O
+determine	O
+if	O
+prolonged	O
+suppression	O
+of	O
+HBV	O
+DNA	O
+can	O
+be	O
+achieved	O
+.	O
+
+Population	O
+-	O
+based	O
+study	O
+of	O
+risk	O
+of	O
+venous	B
+thromboembolism	I
+associated	O
+with	O
+various	O
+oral	O
+contraceptives	O
+.	O
+
+BACKGROUND	O
+:	O
+Four	O
+studies	O
+published	O
+since	O
+December	O
+,	O
+1995	O
+,	O
+reported	O
+that	O
+the	O
+incidence	O
+of	O
+venous	B
+thromboembolism	I
+(	O
+VTE	B
+)	O
+was	O
+higher	O
+in	O
+women	O
+who	O
+used	O
+oral	O
+contraceptives	O
+(	O
+OCs	O
+)	O
+containing	O
+the	O
+third	O
+-	O
+generation	O
+progestagens	O
+gestodene	O
+or	O
+desogestrel	O
+than	O
+in	O
+users	O
+of	O
+OCs	O
+containing	O
+second	O
+-	O
+generation	O
+progestagens	O
+.	O
+
+However	O
+,	O
+confounding	O
+and	O
+bias	O
+in	O
+the	O
+design	O
+of	O
+these	O
+studies	O
+may	O
+have	O
+affected	O
+the	O
+findings	O
+.	O
+
+The	O
+aim	O
+of	O
+our	O
+study	O
+was	O
+to	O
+re	O
+-	O
+examine	O
+the	O
+association	O
+between	O
+risk	O
+of	O
+VTE	B
+and	O
+OC	O
+use	O
+with	O
+a	O
+different	O
+study	O
+design	O
+and	O
+analysis	O
+to	O
+avoid	O
+some	O
+of	O
+the	O
+bias	O
+and	O
+confounding	O
+of	O
+the	O
+earlier	O
+studies	O
+.	O
+
+METHODS	O
+:	O
+We	O
+used	O
+computer	O
+records	O
+of	O
+patients	O
+from	O
+143	O
+general	O
+practices	O
+in	O
+the	O
+UK	O
+.	O
+
+The	O
+study	O
+was	O
+based	O
+on	O
+the	O
+medical	O
+records	O
+of	O
+about	O
+540	O
+,	O
+000	O
+women	O
+born	O
+between	O
+1941	O
+and	O
+1981	O
+.	O
+
+All	O
+women	O
+who	O
+had	O
+a	O
+recorded	O
+diagnosis	O
+of	O
+deep	B
+-	I
+vein	I
+thrombosis	I
+,	O
+venous	B
+thrombosis	I
+not	O
+otherwise	O
+specified	O
+,	O
+or	O
+pulmonary	O
+embolus	O
+during	O
+the	O
+study	O
+period	O
+,	O
+and	O
+who	O
+had	O
+been	O
+treated	O
+with	O
+an	O
+anticoagulant	O
+were	O
+identified	O
+as	O
+potential	O
+cases	O
+of	O
+VTE	B
+.	O
+
+We	O
+did	O
+a	O
+cohort	O
+analysis	O
+to	O
+estimate	O
+and	O
+compare	O
+incidence	O
+of	O
+VTE	B
+in	O
+users	O
+of	O
+the	O
+main	O
+OC	O
+preparations	O
+,	O
+and	O
+a	O
+nested	O
+case	O
+-	O
+control	O
+study	O
+to	O
+calculate	O
+the	O
+odds	O
+ratios	O
+of	O
+VTE	B
+associated	O
+with	O
+use	O
+of	O
+different	O
+types	O
+of	O
+OC	O
+,	O
+after	O
+adjustment	O
+for	O
+potential	O
+confounding	O
+factors	O
+.	O
+
+In	O
+the	O
+case	O
+-	O
+control	O
+study	O
+,	O
+we	O
+matched	O
+cases	O
+to	O
+controls	O
+by	O
+exact	O
+year	O
+of	O
+birth	O
+,	O
+practice	O
+,	O
+and	O
+current	O
+use	O
+of	O
+OCs	O
+.	O
+
+We	O
+used	O
+a	O
+multiple	O
+logistic	O
+regression	O
+model	O
+that	O
+included	O
+body	O
+-	O
+mass	O
+index	O
+,	O
+number	O
+of	O
+cycles	O
+,	O
+change	O
+in	O
+type	O
+of	O
+OC	O
+prescribed	O
+within	O
+3	O
+months	O
+of	O
+the	O
+event	O
+,	O
+previous	O
+pregnancy	O
+,	O
+and	O
+concurrent	O
+disease	O
+.	O
+
+FINDINGS	O
+:	O
+85	O
+women	O
+met	O
+the	O
+inclusion	O
+criteria	O
+for	O
+VTE	B
+,	O
+two	O
+of	O
+whom	O
+were	O
+users	O
+of	O
+progestagen	O
+-	O
+only	O
+OCs	O
+.	O
+
+Of	O
+the	O
+83	O
+cases	O
+of	O
+VTE	B
+associated	O
+with	O
+use	O
+of	O
+combined	O
+OCs	O
+,	O
+43	O
+were	O
+recorded	O
+as	O
+deep	B
+-	I
+vein	I
+thrombosis	I
+,	O
+35	O
+as	O
+pulmonary	O
+thrombosis	B
+,	O
+and	O
+five	O
+as	O
+venous	B
+thrombosis	I
+not	O
+otherwise	O
+specified	O
+.	O
+
+The	O
+crude	O
+rate	O
+of	O
+VTE	B
+per	O
+10	O
+,	O
+000	O
+woman	O
+-	O
+years	O
+was	O
+4	O
+.	O
+10	O
+in	O
+current	O
+users	O
+of	O
+any	O
+OC	O
+,	O
+3	O
+.	O
+10	O
+in	O
+users	O
+of	O
+second	O
+-	O
+generation	O
+OCs	O
+,	O
+and	O
+4	O
+.	O
+96	O
+in	O
+users	O
+of	O
+third	O
+-	O
+generation	O
+preparations	O
+.	O
+
+After	O
+adjustment	O
+for	O
+age	O
+,	O
+the	O
+rate	O
+ratio	O
+of	O
+VTE	B
+in	O
+users	O
+of	O
+third	O
+-	O
+generation	O
+relative	O
+to	O
+second	O
+-	O
+generation	O
+OCs	O
+was	O
+1	O
+.	O
+68	O
+(	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+04	O
+-	O
+2	O
+.	O
+75	O
+)	O
+.	O
+
+Logistic	O
+regression	O
+showed	O
+no	O
+significant	O
+difference	O
+in	O
+the	O
+risk	O
+of	O
+VTE	B
+between	O
+users	O
+of	O
+third	O
+-	O
+generation	O
+and	O
+second	O
+-	O
+generation	O
+OCs	O
+.	O
+
+Among	O
+users	O
+of	O
+third	O
+-	O
+generation	O
+progestagens	O
+,	O
+the	O
+risk	O
+of	O
+VTE	B
+was	O
+higher	O
+in	O
+users	O
+of	O
+desogestrel	O
+with	O
+20	O
+g	O
+ethinyloestradiol	O
+than	O
+in	O
+users	O
+of	O
+gestodene	O
+or	O
+desogestrel	O
+with	O
+30	O
+g	O
+ethinyloestradiol	O
+.	O
+
+With	O
+all	O
+second	O
+-	O
+generation	O
+OCs	O
+as	O
+the	O
+reference	O
+,	O
+the	O
+odds	O
+ratios	O
+for	O
+VTE	B
+were	O
+3	O
+.	O
+49	O
+(	O
+1	O
+.	O
+21	O
+-	O
+10	O
+.	O
+12	O
+)	O
+for	O
+desogestrel	O
+plus	O
+20	O
+g	O
+ethinyloestradiol	O
+and	O
+1	O
+.	O
+18	O
+(	O
+0	O
+.	O
+66	O
+-	O
+2	O
+.	O
+17	O
+)	O
+for	O
+the	O
+other	O
+third	O
+-	O
+generation	O
+progestagens	O
+.	O
+
+INTERPRETATION	O
+:	O
+The	O
+previously	O
+reported	O
+increase	O
+in	O
+odds	O
+ratio	O
+associated	O
+with	O
+third	O
+-	O
+generation	O
+OCs	O
+when	O
+compared	O
+with	O
+second	O
+-	O
+generation	O
+products	O
+is	O
+likely	O
+to	O
+have	O
+been	O
+the	O
+result	O
+of	O
+residual	O
+confounding	O
+by	O
+age	O
+.	O
+
+The	O
+increased	O
+odds	O
+ratio	O
+associated	O
+with	O
+products	O
+containing	O
+20	O
+micrograms	O
+ethinyloestradiol	O
+and	O
+desogestrel	O
+compared	O
+with	O
+the	O
+30	O
+micrograms	O
+product	O
+is	O
+biologically	O
+implausible	O
+,	O
+and	O
+is	O
+likely	O
+to	O
+be	O
+the	O
+result	O
+of	O
+preferential	O
+prescribing	O
+and	O
+,	O
+thus	O
+,	O
+confounding	O
+.	O
+
+MK	O
+-	O
+801	O
+augments	O
+pilocarpine	O
+-	O
+induced	O
+electrographic	O
+seizure	B
+but	O
+protects	O
+against	O
+brain	B
+damage	I
+in	O
+rats	O
+.	O
+
+1	O
+.	O
+
+The	O
+authors	O
+examined	O
+the	O
+anticonvulsant	O
+effects	O
+of	O
+MK	O
+-	O
+801	O
+on	O
+the	O
+pilocarpine	O
+-	O
+induced	O
+seizure	B
+model	O
+.	O
+
+Intraperitoneal	O
+injection	O
+of	O
+pilocarpine	O
+(	O
+400	O
+mg	O
+/	O
+kg	O
+)	O
+induced	O
+tonic	B
+and	I
+clonic	I
+seizure	I
+.	O
+
+Scopolamine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+pentobarbital	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+prevented	O
+development	O
+of	O
+pilocarpine	O
+-	O
+induced	O
+behavioral	O
+seizure	B
+but	O
+MK	O
+-	O
+801	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+did	O
+not	O
+.	O
+
+2	O
+.	O
+
+An	O
+electrical	O
+seizure	B
+measured	O
+with	O
+hippocampal	O
+EEG	O
+appeared	O
+in	O
+the	O
+pilocarpine	O
+-	O
+treated	O
+group	O
+.	O
+
+Scopolamine	O
+and	O
+pentobarbital	O
+blocked	O
+the	O
+pilocarpine	O
+-	O
+induced	O
+electrographic	O
+seizure	B
+,	O
+MK	O
+-	O
+801	O
+treatment	O
+augmented	O
+the	O
+electrographic	O
+seizure	B
+induced	O
+by	O
+pilocarpine	O
+.	O
+
+3	O
+.	O
+
+Brain	B
+damage	I
+was	O
+assessed	O
+by	O
+examining	O
+the	O
+hippocampus	O
+microscopically	O
+.	O
+
+Pilocarpine	O
+produced	O
+neuronal	B
+death	I
+in	O
+the	O
+hippocampus	O
+,	O
+which	O
+showed	O
+pyknotic	O
+changes	O
+.	O
+
+Pentobarbital	O
+,	O
+scopolamine	O
+and	O
+MK	O
+-	O
+801	O
+protected	O
+the	O
+brain	B
+damage	I
+by	O
+pilocarpine	O
+,	O
+though	O
+in	O
+the	O
+MK	O
+-	O
+801	O
+-	O
+treated	O
+group	O
+,	O
+the	O
+pyramidal	O
+cells	O
+of	O
+hippocampus	O
+appeared	O
+darker	O
+than	O
+normal	O
+.	O
+
+In	O
+all	O
+treatments	O
+,	O
+granule	O
+cells	O
+of	O
+the	O
+dentate	O
+gyrus	O
+were	O
+not	O
+affected	O
+.	O
+
+4	O
+.	O
+
+These	O
+results	O
+indicate	O
+that	O
+status	B
+epilepticus	I
+induced	O
+by	O
+pilocarpine	O
+is	O
+initiated	O
+by	O
+cholinergic	O
+overstimulation	O
+and	O
+propagated	O
+by	O
+glutamatergic	O
+transmission	O
+,	O
+the	O
+elevation	O
+of	O
+which	O
+may	O
+cause	O
+brain	B
+damage	I
+through	O
+an	O
+excitatory	O
+NMDA	O
+receptor	O
+-	O
+mediated	O
+mechanism	O
+.	O
+
+Paclitaxel	O
+,	O
+5	O
+-	O
+fluorouracil	O
+,	O
+and	O
+folinic	O
+acid	O
+in	O
+metastatic	O
+breast	B
+cancer	I
+:	O
+BRE	O
+-	O
+26	O
+,	O
+a	O
+phase	O
+II	O
+trial	O
+.	O
+
+5	O
+-	O
+Fluorouracil	O
+plus	O
+folinic	O
+acid	O
+and	O
+paclitaxel	O
+(	O
+Taxol	O
+;	O
+Bristol	O
+-	O
+Myers	O
+Squibb	O
+Company	O
+,	O
+Princeton	O
+,	O
+NJ	O
+)	O
+are	O
+effective	O
+salvage	O
+therapies	O
+for	O
+metastatic	O
+breast	B
+cancer	I
+patients	O
+.	O
+
+Paclitaxel	O
+and	O
+5	O
+-	O
+fluorouracil	O
+have	O
+additive	O
+cytotoxicity	B
+in	O
+MCF	O
+-	O
+7	O
+cell	O
+lines	O
+.	O
+
+We	O
+performed	O
+a	O
+phase	O
+II	O
+trial	O
+of	O
+paclitaxel	O
+175	O
+mg	O
+/	O
+m2	O
+over	O
+3	O
+hours	O
+on	O
+day	O
+I	O
+followed	O
+by	O
+folinic	O
+acid	O
+300	O
+mg	O
+over	O
+1	O
+hour	O
+before	O
+5	O
+-	O
+fluorouracil	O
+350	O
+mg	O
+/	O
+m2	O
+on	O
+days	O
+1	O
+to	O
+3	O
+every	O
+28	O
+days	O
+(	O
+TFL	O
+)	O
+in	O
+women	O
+with	O
+metastatic	O
+breast	B
+cancer	I
+.	O
+
+Analysis	O
+is	O
+reported	O
+on	O
+37	O
+patients	O
+with	O
+a	O
+minimum	O
+of	O
+6	O
+months	O
+follow	O
+-	O
+up	O
+who	O
+received	O
+a	O
+total	O
+of	O
+192	O
+cycles	O
+of	O
+TFL	O
+:	O
+nine	O
+cycles	O
+(	O
+5	O
+%	O
+)	O
+were	O
+associated	O
+with	O
+grade	O
+3	O
+/	O
+4	O
+neutropenia	B
+requiring	O
+hospitalization	O
+;	O
+seven	O
+(	O
+4	O
+%	O
+)	O
+cycles	O
+in	O
+two	O
+patients	O
+required	O
+granulocyte	O
+colony	O
+-	O
+stimulating	O
+factor	O
+due	O
+to	O
+neutropenia	B
+;	O
+no	O
+patient	O
+required	O
+platelet	O
+transfusions	O
+.	O
+
+Grade	O
+3	O
+/	O
+4	O
+nonhematologic	O
+toxicities	B
+were	O
+uncommon	O
+.	O
+
+Among	O
+the	O
+34	O
+patients	O
+evaluable	O
+for	O
+response	O
+,	O
+there	O
+were	O
+three	O
+complete	O
+responses	O
+(	O
+9	O
+%	O
+)	O
+and	O
+18	O
+partial	O
+responses	O
+(	O
+53	O
+%	O
+)	O
+for	O
+an	O
+overall	O
+response	O
+rate	O
+of	O
+62	O
+%	O
+.	O
+
+Of	O
+the	O
+19	O
+evaluable	O
+patients	O
+with	O
+prior	O
+doxorubicin	O
+exposure	O
+,	O
+11	O
+(	O
+58	O
+%	O
+)	O
+responded	O
+compared	O
+with	O
+nine	O
+of	O
+15	O
+(	O
+60	O
+%	O
+)	O
+without	O
+prior	O
+doxorubicin	O
+.	O
+
+Plasma	O
+paclitaxel	O
+concentrations	O
+were	O
+measured	O
+at	O
+the	O
+completion	O
+of	O
+paclitaxel	O
+infusion	O
+and	O
+at	O
+24	O
+hours	O
+in	O
+19	O
+patients	O
+.	O
+
+TFL	O
+is	O
+an	O
+active	O
+,	O
+well	O
+-	O
+tolerated	O
+regimen	O
+in	O
+metastatic	O
+breast	B
+cancer	I
+.	O
+
+Efficacy	O
+and	O
+proarrhythmia	B
+with	O
+the	O
+use	O
+of	O
+d	O
+,	O
+l	O
+-	O
+sotalol	O
+for	O
+sustained	O
+ventricular	B
+tachyarrhythmias	I
+.	O
+
+This	O
+study	O
+prospectively	O
+evaluated	O
+the	O
+clinical	O
+efficacy	O
+,	O
+the	O
+incidence	O
+of	O
+torsades	B
+de	I
+pointes	I
+,	O
+and	O
+the	O
+presumable	O
+risk	O
+factors	O
+for	O
+torsades	B
+de	I
+pointes	I
+in	O
+patients	O
+treated	O
+with	O
+d	O
+,	O
+l	O
+-	O
+sotalol	O
+for	O
+sustained	O
+ventricular	B
+tachyarrhythmias	I
+.	O
+
+Eighty	O
+-	O
+one	O
+consecutive	O
+patients	O
+(	O
+54	O
+with	O
+coronary	B
+artery	I
+disease	I
+,	O
+and	O
+20	O
+with	O
+dilated	B
+cardiomyopathy	I
+)	O
+with	O
+inducible	O
+sustained	O
+ventricular	B
+tachycardia	I
+or	O
+ventricular	B
+fibrillation	I
+received	O
+oral	O
+d	O
+,	O
+l	O
+-	O
+sotalol	O
+to	O
+prevent	O
+induction	O
+of	O
+the	O
+ventricular	B
+tachyarrhythmia	I
+.	O
+
+During	O
+oral	O
+loading	O
+with	O
+d	O
+,	O
+l	O
+-	O
+sotalol	O
+,	O
+continuous	O
+electrocardiographic	O
+(	O
+ECG	O
+)	O
+monitoring	O
+was	O
+performed	O
+.	O
+
+Those	O
+patients	O
+in	O
+whom	O
+d	O
+,	O
+l	O
+-	O
+sotalol	O
+prevented	O
+induction	O
+of	O
+ventricular	B
+tachycardia	I
+or	O
+ventricular	B
+fibrillation	I
+were	O
+discharged	O
+with	O
+the	O
+drug	O
+and	O
+followed	O
+up	O
+on	O
+an	O
+outpatient	O
+basis	O
+for	O
+21	O
++	O
+/	O
+-	O
+18	O
+months	O
+.	O
+
+Induction	O
+of	O
+the	O
+ventricular	B
+tachyarrhythmia	I
+was	O
+prevented	O
+by	O
+oral	O
+d	O
+,	O
+l	O
+-	O
+sotalol	O
+in	O
+35	O
+(	O
+43	O
+%	O
+)	O
+patients	O
+;	O
+the	O
+ventricular	B
+tachyarrhythmia	I
+remained	O
+inducible	O
+in	O
+40	O
+(	O
+49	O
+%	O
+)	O
+patients	O
+;	O
+and	O
+two	O
+(	O
+2	O
+.	O
+5	O
+%	O
+)	O
+patients	O
+did	O
+not	O
+tolerate	O
+even	O
+40	O
+mg	O
+of	O
+d	O
+,	O
+l	O
+-	O
+sotalol	O
+once	O
+daily	O
+.	O
+
+Four	O
+(	O
+5	O
+%	O
+)	O
+patients	O
+had	O
+from	O
+torsades	B
+de	I
+pointes	I
+during	O
+the	O
+initial	O
+oral	O
+treatment	O
+with	O
+d	O
+,	O
+l	O
+-	O
+sotalol	O
+.	O
+
+Neither	O
+ECG	O
+[	O
+sinus	O
+-	O
+cycle	O
+length	O
+(	O
+SCL	O
+)	O
+,	O
+QT	O
+or	O
+QTc	O
+interval	O
+,	O
+or	O
+U	O
+wave	O
+]	O
+nor	O
+clinical	O
+parameters	O
+identified	O
+patients	O
+at	O
+risk	O
+for	O
+torsades	B
+de	I
+pointes	I
+.	O
+
+However	O
+,	O
+the	O
+oral	O
+dose	O
+of	O
+d	O
+,	O
+l	O
+-	O
+sotalol	O
+was	O
+significantly	O
+lower	O
+in	O
+patients	O
+with	O
+torsades	B
+de	I
+pointes	I
+(	O
+200	O
++	O
+/	O
+-	O
+46	O
+vs	O
+.	O
+328	O
++	O
+/	O
+-	O
+53	O
+mg	O
+/	O
+day	O
+;	O
+p	O
+=	O
+0	O
+.	O
+0017	O
+)	O
+.	O
+
+Risk	O
+factors	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+torsades	B
+de	I
+pointes	I
+were	O
+the	O
+appearance	O
+of	O
+an	O
+U	O
+wave	O
+(	O
+p	O
+=	O
+0	O
+.	O
+049	O
+)	O
+,	O
+female	O
+gender	O
+(	O
+p	O
+=	O
+0	O
+.	O
+015	O
+)	O
+,	O
+and	O
+significant	O
+dose	O
+-	O
+corrected	O
+changes	O
+of	O
+SCL	O
+,	O
+QT	O
+interval	O
+,	O
+and	O
+QTc	O
+interval	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+During	O
+follow	O
+-	O
+up	O
+,	O
+seven	O
+(	O
+20	O
+%	O
+)	O
+patients	O
+had	O
+a	O
+nonfatal	O
+ventricular	B
+tachycardia	I
+recurrence	O
+,	O
+and	O
+two	O
+(	O
+6	O
+%	O
+)	O
+patients	O
+died	O
+suddenly	O
+.	O
+
+One	O
+female	O
+patient	O
+with	O
+stable	O
+cardiac	B
+disease	I
+had	O
+recurrent	O
+torsades	B
+de	I
+pointes	I
+after	O
+2	O
+years	O
+of	O
+successful	O
+treatment	O
+with	O
+d	O
+,	O
+l	O
+-	O
+sotalol	O
+.	O
+
+Torsades	B
+de	I
+pointes	I
+occurred	O
+early	O
+during	O
+treatment	O
+even	O
+with	O
+low	O
+doses	O
+of	O
+oral	O
+d	O
+,	O
+l	O
+-	O
+sotalol	O
+.	O
+
+Pronounced	O
+changes	O
+in	O
+the	O
+surface	O
+ECG	O
+(	O
+cycle	O
+length	O
+,	O
+QT	O
+,	O
+and	O
+QTc	O
+)	O
+in	O
+relation	O
+to	O
+the	O
+dose	O
+of	O
+oral	O
+d	O
+,	O
+l	O
+-	O
+sotalol	O
+might	O
+identify	O
+a	O
+subgroup	O
+of	O
+patients	O
+with	O
+an	O
+increased	O
+risk	O
+for	O
+torsades	B
+de	I
+pointes	I
+.	O
+
+Other	O
+ECG	O
+parameters	O
+before	O
+the	O
+application	O
+of	O
+d	O
+,	O
+l	O
+-	O
+sotalol	O
+did	O
+not	O
+identify	O
+patients	O
+at	O
+increased	O
+risk	O
+for	O
+torsades	B
+de	I
+pointes	I
+.	O
+
+Recurrence	O
+rates	O
+of	O
+ventricular	B
+tachyarrhythmias	I
+are	O
+high	O
+despite	O
+complete	O
+suppression	O
+of	O
+the	O
+arrhythmia	B
+during	O
+programmed	O
+stimulation	O
+.	O
+
+Therefore	O
+programmed	O
+electrical	O
+stimulation	O
+in	O
+the	O
+case	O
+of	O
+d	O
+,	O
+l	O
+-	O
+sotalol	O
+seems	O
+to	O
+be	O
+of	O
+limited	O
+prognostic	O
+value	O
+.	O
+
+Chronic	O
+hyperprolactinemia	B
+and	O
+changes	O
+in	O
+dopamine	O
+neurons	O
+.	O
+
+The	O
+tuberoinfundibular	O
+dopaminergic	O
+(	O
+TIDA	O
+)	O
+system	O
+is	O
+known	O
+to	O
+inhibit	O
+prolactin	O
+(	O
+PRL	O
+)	O
+secretion	O
+.	O
+
+In	O
+young	O
+animals	O
+this	O
+system	O
+responds	O
+to	O
+acute	O
+elevations	O
+in	O
+serum	O
+PRL	O
+by	O
+increasing	O
+its	O
+activity	O
+.	O
+
+However	O
+,	O
+this	O
+responsiveness	O
+is	O
+lost	O
+in	O
+aging	O
+rats	O
+with	O
+chronically	O
+high	O
+serum	O
+PRL	O
+levels	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+induce	O
+hyperprolactinemia	B
+in	O
+rats	O
+for	O
+extended	O
+periods	O
+of	O
+time	O
+and	O
+examine	O
+its	O
+effects	O
+on	O
+dopaminergic	O
+systems	O
+in	O
+the	O
+brain	O
+.	O
+
+Hyperprolactinemia	B
+was	O
+induced	O
+by	O
+treatment	O
+with	O
+haloperidol	O
+,	O
+a	O
+dopamine	O
+receptor	O
+antagonist	O
+,	O
+and	O
+Palkovits	O
+'	O
+microdissection	O
+technique	O
+in	O
+combination	O
+with	O
+high	O
+-	O
+performance	O
+liquid	O
+chromatography	O
+was	O
+used	O
+to	O
+measure	O
+neurotransmitter	O
+concentrations	O
+in	O
+several	O
+areas	O
+of	O
+the	O
+brain	O
+.	O
+
+After	O
+6	O
+months	O
+of	O
+hyperprolactinemia	B
+,	O
+dopamine	O
+(	O
+DA	O
+)	O
+concentrations	O
+in	O
+the	O
+median	O
+eminence	O
+(	O
+ME	O
+)	O
+increased	O
+by	O
+84	O
+%	O
+over	O
+the	O
+control	O
+group	O
+.	O
+
+Nine	O
+months	O
+of	O
+hyperprolactinemia	B
+produced	O
+a	O
+50	O
+%	O
+increase	O
+in	O
+DA	O
+concentrations	O
+in	O
+the	O
+ME	O
+over	O
+the	O
+control	O
+group	O
+.	O
+
+However	O
+,	O
+DA	O
+response	O
+was	O
+lost	O
+if	O
+a	O
+9	O
+-	O
+month	O
+long	O
+haloperidol	O
+-	O
+induced	O
+hyperprolactinemia	B
+was	O
+followed	O
+by	O
+a	O
+1	O
+1	O
+/	O
+2	O
+month	O
+-	O
+long	O
+extremely	O
+high	O
+increase	O
+in	O
+serum	O
+PRL	O
+levels	O
+produced	O
+by	O
+implantation	O
+of	O
+MMQ	O
+cells	O
+under	O
+the	O
+kidney	O
+capsule	O
+.	O
+
+There	O
+was	O
+no	O
+change	O
+in	O
+the	O
+levels	O
+of	O
+DA	O
+,	O
+norepinephrine	O
+(	O
+NE	O
+)	O
+,	O
+serotonin	O
+(	O
+5	O
+-	O
+HT	O
+)	O
+,	O
+or	O
+their	O
+metabolites	O
+in	O
+the	O
+arcuate	O
+nucleus	O
+(	O
+AN	O
+)	O
+,	O
+medial	O
+preoptic	O
+area	O
+(	O
+MPA	O
+)	O
+,	O
+caudate	O
+putamen	O
+(	O
+CP	O
+)	O
+,	O
+substantia	O
+nigra	O
+(	O
+SN	O
+)	O
+,	O
+and	O
+zona	O
+incerta	O
+(	O
+ZI	O
+)	O
+,	O
+except	O
+for	O
+a	O
+decrease	O
+in	O
+5	O
+-	O
+hydroxyindoleacetic	O
+acid	O
+(	O
+5	O
+-	O
+HIAA	O
+)	O
+in	O
+the	O
+AN	O
+after	O
+6	O
+-	O
+months	O
+of	O
+hyperprolactinemia	B
+and	O
+an	O
+increase	O
+in	O
+DA	O
+concentrations	O
+in	O
+the	O
+AN	O
+after	O
+9	O
+-	O
+months	O
+of	O
+hyperprolactinemia	B
+.	O
+
+These	O
+results	O
+demonstrate	O
+that	O
+hyperprolactinemia	B
+specifically	O
+affects	O
+TIDA	O
+neurons	O
+and	O
+these	O
+effects	O
+vary	O
+,	O
+depending	O
+on	O
+the	O
+duration	O
+and	O
+intensity	O
+of	O
+hyperprolactinemia	B
+.	O
+
+The	O
+age	O
+-	O
+related	O
+decrease	O
+in	O
+hypothalamic	O
+dopamine	O
+function	O
+may	O
+be	O
+associated	O
+with	O
+increases	O
+in	O
+PRL	O
+secretion	O
+.	O
+
+Treatment	O
+-	O
+related	O
+disseminated	O
+necrotizing	O
+leukoencephalopathy	B
+with	O
+characteristic	O
+contrast	O
+enhancement	O
+of	O
+the	O
+white	O
+matter	O
+.	O
+
+This	O
+report	O
+describes	O
+unique	O
+contrast	O
+enhancement	O
+of	O
+the	O
+white	O
+matter	O
+on	O
+T1	O
+-	O
+weighted	O
+magnetic	O
+resonance	O
+images	O
+of	O
+two	O
+patients	O
+with	O
+disseminated	O
+necrotizing	O
+leukoencephalopathy	B
+,	O
+which	O
+developed	O
+from	O
+acute	B
+lymphoblastic	I
+leukemia	I
+treated	O
+with	O
+high	O
+-	O
+dose	O
+methotrexate	O
+.	O
+
+In	O
+both	O
+patients	O
+,	O
+the	O
+enhancement	O
+was	O
+more	O
+pronounced	O
+near	O
+the	O
+base	O
+of	O
+the	O
+brain	O
+than	O
+at	O
+the	O
+vertex	O
+.	O
+
+Necropsy	O
+of	O
+the	O
+first	O
+case	O
+revealed	O
+loss	B
+of	I
+myelination	I
+and	O
+necrosis	B
+of	O
+the	O
+white	O
+matter	O
+.	O
+
+Possible	O
+mechanisms	O
+causing	O
+such	O
+a	O
+leukoencephalopathy	B
+are	O
+discussed	O
+.	O
+
+Thrombotic	B
+complications	O
+in	O
+acute	B
+promyelocytic	I
+leukemia	I
+during	O
+all	O
+-	O
+trans	O
+-	O
+retinoic	O
+acid	O
+therapy	O
+.	O
+
+A	O
+case	O
+of	O
+acute	B
+renal	I
+failure	I
+,	O
+due	O
+to	O
+occlusion	B
+of	I
+renal	I
+vessels	I
+in	O
+a	O
+patient	O
+with	O
+acute	B
+promyelocytic	I
+leukemia	I
+(	O
+APL	B
+)	O
+treated	O
+with	O
+all	O
+-	O
+trans	O
+-	O
+retinoic	O
+acid	O
+(	O
+ATRA	O
+)	O
+and	O
+tranexamic	O
+acid	O
+has	O
+been	O
+described	O
+recently	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+acute	B
+renal	I
+failure	I
+in	O
+an	O
+APL	B
+patient	O
+treated	O
+with	O
+ATRA	O
+alone	O
+.	O
+
+This	O
+case	O
+further	O
+supports	O
+the	O
+concern	O
+about	O
+thromboembolic	B
+complications	O
+associated	O
+with	O
+ATRA	O
+therapy	O
+in	O
+APL	B
+patients	O
+.	O
+
+The	O
+patients	O
+,	O
+a	O
+43	O
+-	O
+year	O
+-	O
+old	O
+man	O
+,	O
+presented	O
+all	O
+the	O
+signs	O
+and	O
+symptoms	O
+of	O
+APL	B
+and	O
+was	O
+included	O
+in	O
+a	O
+treatment	O
+protocol	O
+with	O
+ATRA	O
+.	O
+
+After	O
+10	O
+days	O
+of	O
+treatment	O
+,	O
+he	O
+developed	O
+acute	B
+renal	I
+failure	I
+that	O
+was	O
+completely	O
+reversible	O
+after	O
+complete	O
+remission	O
+of	O
+APL	B
+was	O
+achieved	O
+and	O
+therapy	O
+discontinued	O
+.	O
+
+We	O
+conclude	O
+that	O
+ATRA	O
+is	O
+a	O
+valid	O
+therapeutic	O
+choice	O
+for	O
+patients	O
+with	O
+APL	B
+,	O
+although	O
+the	O
+procoagulant	O
+tendency	O
+is	O
+not	O
+completely	O
+corrected	O
+.	O
+
+Thrombotic	B
+events	O
+,	O
+however	O
+,	O
+could	O
+be	O
+avoided	O
+by	O
+using	O
+low	O
+-	O
+dose	O
+heparin	O
+.	O
+
+Pupillary	O
+changes	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+stimulant	O
+-	O
+induced	O
+mania	B
+:	O
+a	O
+case	O
+report	O
+.	O
+
+A	O
+30	O
+-	O
+year	O
+-	O
+old	O
+cocaine	O
+-	O
+dependent	O
+man	O
+who	O
+was	O
+a	O
+subject	O
+in	O
+a	O
+study	O
+evaluating	O
+the	O
+anticraving	O
+efficacy	O
+of	O
+the	O
+stimulant	O
+medication	O
+diethylpropion	O
+(	O
+DEP	O
+)	O
+became	O
+manic	B
+during	O
+his	O
+second	O
+week	O
+on	O
+the	O
+study	O
+drug	O
+.	O
+
+Pupillometric	O
+changes	O
+while	O
+on	O
+DEP	O
+,	O
+especially	O
+changes	O
+in	O
+the	O
+total	O
+power	O
+of	O
+pupillary	B
+oscillation	I
+,	O
+were	O
+dramatically	O
+different	O
+than	O
+those	O
+observed	O
+in	O
+the	O
+eight	O
+other	O
+study	O
+subjects	O
+who	O
+did	O
+not	O
+become	O
+manic	B
+.	O
+
+The	O
+large	O
+changes	O
+in	O
+total	O
+power	O
+of	O
+pupillary	B
+oscillation	I
+occurred	O
+a	O
+few	O
+days	O
+before	O
+the	O
+patient	O
+became	O
+fully	O
+manic	B
+.	O
+
+Such	O
+medication	O
+-	O
+associated	O
+changes	O
+in	O
+the	O
+total	O
+power	O
+of	O
+pupillary	B
+oscillation	I
+might	O
+be	O
+of	O
+utility	O
+in	O
+identifying	O
+persons	O
+at	O
+risk	O
+for	O
+manic	B
+-	O
+like	O
+adverse	O
+effects	O
+during	O
+the	O
+medical	O
+use	O
+of	O
+psychomotor	O
+stimulants	O
+or	O
+sympathomimetic	O
+agents	O
+.	O
+
+Fetal	O
+risks	O
+due	O
+to	O
+warfarin	O
+therapy	O
+during	O
+pregnancy	O
+.	O
+
+Two	O
+mothers	O
+with	O
+heart	O
+valve	O
+prosthesis	O
+were	O
+treated	O
+with	O
+warfarin	O
+during	O
+pregnancy	O
+.	O
+
+In	O
+the	O
+first	O
+case	O
+a	O
+caesarean	O
+section	O
+was	O
+done	O
+one	O
+week	O
+after	O
+replacement	O
+of	O
+warfarin	O
+with	O
+heparin	O
+.	O
+
+The	O
+baby	O
+died	O
+of	O
+cerebral	B
+and	I
+pulmonary	I
+hemorrhage	I
+.	O
+
+The	O
+second	O
+mother	O
+had	O
+a	O
+male	O
+infant	O
+by	O
+caesarean	O
+section	O
+.	O
+
+The	O
+baby	O
+showed	O
+warfarin	O
+-	O
+induced	O
+embryopathy	B
+with	O
+nasal	B
+hypoplasia	I
+and	O
+stippled	B
+epiphyses	I
+(	O
+chondrodysplasia	B
+punctata	I
+)	O
+.	O
+
+Nasal	B
+hypoplasia	I
+with	O
+or	O
+without	O
+stippled	B
+epiphyses	I
+has	O
+now	O
+been	O
+reported	O
+in	O
+11	O
+infants	O
+born	O
+to	O
+mothers	O
+treated	O
+with	O
+warfarin	O
+during	O
+the	O
+first	O
+trimester	O
+,	O
+and	O
+a	O
+causal	O
+association	O
+is	O
+probable	O
+.	O
+
+In	O
+view	O
+of	O
+the	O
+risks	O
+to	O
+both	O
+mother	O
+and	O
+fetus	O
+in	O
+women	O
+with	O
+prosthetic	O
+cardiac	O
+valves	O
+it	O
+is	O
+recommended	O
+that	O
+therapeutic	O
+abortion	O
+be	O
+advised	O
+as	O
+the	O
+first	O
+alternative	O
+.	O
+
+The	O
+negative	O
+mucosal	O
+potential	O
+:	O
+separating	O
+central	O
+and	O
+peripheral	O
+effects	O
+of	O
+NSAIDs	O
+in	O
+man	O
+.	O
+
+OBJECTIVE	O
+:	O
+We	O
+wanted	O
+to	O
+test	O
+whether	O
+assessment	O
+of	O
+both	O
+a	O
+central	O
+pain	B
+-	O
+related	O
+signal	O
+(	O
+chemo	O
+-	O
+somatosensory	O
+evoked	O
+potential	O
+,	O
+CSSEP	O
+)	O
+and	O
+a	O
+concomitantly	O
+recorded	O
+peripheral	O
+signal	O
+(	O
+negative	O
+mucosal	O
+potential	O
+,	O
+NMP	O
+)	O
+allows	O
+for	O
+separation	O
+of	O
+central	O
+and	O
+peripheral	O
+effects	O
+of	O
+NSAIDs	O
+.	O
+
+For	O
+this	O
+purpose	O
+,	O
+experimental	O
+conditions	O
+were	O
+created	O
+in	O
+which	O
+NSAIDs	O
+had	O
+previously	O
+been	O
+observed	O
+to	O
+produce	O
+effects	O
+on	O
+phasic	O
+and	O
+tonic	O
+pain	B
+by	O
+either	O
+central	O
+or	O
+peripheral	O
+mechanisms	O
+.	O
+
+METHODS	O
+:	O
+According	O
+to	O
+a	O
+double	O
+-	O
+blind	O
+,	O
+randomised	O
+,	O
+controlled	O
+,	O
+threefold	O
+cross	O
+-	O
+over	O
+design	O
+,	O
+18	O
+healthy	O
+subjects	O
+(	O
+11	O
+males	O
+,	O
+7	O
+females	O
+;	O
+mean	O
+age	O
+26	O
+years	O
+)	O
+received	O
+either	O
+placebo	O
+,	O
+400	O
+mg	O
+ibuprofen	O
+,	O
+or	O
+800	O
+mg	O
+ibuprofen	O
+.	O
+
+Phasic	O
+pain	B
+was	O
+applied	O
+by	O
+means	O
+of	O
+short	O
+pulses	O
+of	O
+CO2	O
+to	O
+the	O
+nasal	O
+mucosa	O
+(	O
+stimulus	O
+duration	O
+500	O
+ms	O
+,	O
+interval	O
+approximately	O
+60	O
+s	O
+)	O
+,	O
+and	O
+tonic	O
+pain	B
+was	O
+induced	O
+in	O
+the	O
+nasal	O
+cavity	O
+by	O
+means	O
+of	O
+dry	O
+air	O
+of	O
+controlled	O
+temperature	O
+,	O
+humidity	O
+and	O
+flow	O
+rate	O
+(	O
+22	O
+degrees	O
+C	O
+,	O
+0	O
+%	O
+relative	O
+humidity	O
+,	O
+145	O
+ml	O
+.	O
+s	O
+-	O
+1	O
+)	O
+.	O
+
+Both	O
+CSSEPs	O
+as	O
+central	O
+and	O
+NMPs	O
+as	O
+peripheral	O
+correlates	O
+of	O
+pain	B
+were	O
+obtained	O
+in	O
+response	O
+to	O
+the	O
+CO2	O
+stimuli	O
+.	O
+
+Additionally	O
+,	O
+the	O
+subjects	O
+rated	O
+the	O
+intensity	O
+of	O
+both	O
+phasic	O
+and	O
+tonic	O
+pain	B
+by	O
+means	O
+of	O
+visual	O
+analogue	O
+scales	O
+.	O
+
+RESULTS	O
+:	O
+As	O
+described	O
+earlier	O
+,	O
+administration	O
+of	O
+ibuprofen	O
+was	O
+followed	O
+by	O
+a	O
+decrease	O
+in	O
+tonic	O
+pain	B
+but	O
+-	O
+relative	O
+to	O
+placebo	O
+-	O
+an	O
+increase	O
+in	O
+correlates	O
+of	O
+phasic	O
+pain	B
+,	O
+indicating	O
+a	O
+specific	O
+effect	O
+of	O
+ibuprofen	O
+on	O
+the	O
+interaction	O
+between	O
+the	O
+pain	B
+stimuli	O
+under	O
+these	O
+special	O
+experimental	O
+conditions	O
+.	O
+
+Based	O
+on	O
+the	O
+similar	O
+behaviour	O
+of	O
+CSSEP	O
+and	O
+NMP	O
+,	O
+it	O
+was	O
+concluded	O
+that	O
+the	O
+pharmacological	O
+process	O
+underlying	O
+this	O
+phenomenon	O
+was	O
+localised	O
+in	O
+the	O
+periphery	O
+.	O
+
+By	O
+means	O
+of	O
+the	O
+simultaneous	O
+recording	O
+of	O
+interrelated	O
+peripheral	O
+and	O
+central	O
+electrophysiologic	O
+correlates	O
+of	O
+nociception	O
+,	O
+it	O
+was	O
+possible	O
+to	O
+separate	O
+central	O
+and	O
+peripheral	O
+effects	O
+of	O
+an	O
+NSAID	O
+.	O
+
+The	O
+major	O
+advantage	O
+of	O
+this	O
+pain	B
+model	O
+is	O
+the	O
+possibility	O
+of	O
+obtaining	O
+peripheral	O
+pain	B
+-	O
+related	O
+activity	O
+directly	O
+using	O
+a	O
+non	O
+-	O
+invasive	O
+technique	O
+in	O
+humans	O
+.	O
+
+Effect	O
+of	O
+D	O
+-	O
+Glucarates	O
+on	O
+basic	O
+antibiotic	O
+-	O
+induced	O
+renal	B
+damage	I
+in	O
+rats	O
+.	O
+
+Dehydrated	B
+rats	O
+regularly	O
+develop	O
+acute	B
+renal	I
+failure	I
+following	O
+single	O
+injection	O
+of	O
+aminoglycoside	O
+antibiotics	O
+combined	O
+with	O
+dextran	O
+or	O
+of	O
+antibiotics	O
+only	O
+.	O
+
+Oral	O
+administration	O
+of	O
+2	O
+,	O
+5	O
+-	O
+di	O
+-	O
+O	O
+-	O
+acetyl	O
+-	O
+D	O
+-	O
+glucaro	O
+-	O
+1	O
+,	O
+4	O
+-	O
+6	O
+,	O
+3	O
+-	O
+dilactone	O
+protected	O
+rats	O
+against	O
+renal	B
+failure	I
+induced	O
+by	O
+kanamycin	O
+-	O
+dextran	O
+.	O
+
+The	O
+protective	O
+effect	O
+was	O
+prevalent	O
+among	O
+D	O
+-	O
+glucarates	O
+,	O
+and	O
+also	O
+to	O
+other	O
+saccharic	O
+acid	O
+,	O
+hexauronic	O
+acids	O
+and	O
+hexaaldonic	O
+acids	O
+,	O
+although	O
+to	O
+a	O
+lesser	O
+degree	O
+,	O
+but	O
+not	O
+to	O
+a	O
+hexaaldose	O
+,	O
+sugar	O
+alcohols	O
+,	O
+substances	O
+inthe	O
+TCA	O
+cycle	O
+and	O
+other	O
+acidic	O
+compounds	O
+.	O
+
+D	O
+-	O
+Glucarates	O
+were	O
+effective	O
+against	O
+renal	B
+damage	I
+induced	O
+by	O
+peptide	O
+antibiotics	O
+as	O
+well	O
+as	O
+various	O
+aminoglycoside	O
+antibitocis	O
+.	O
+
+Dose	O
+-	O
+responses	O
+were	O
+observed	O
+in	O
+the	O
+protective	O
+effect	O
+of	O
+D	O
+-	O
+Glucarates	O
+.	O
+
+With	O
+a	O
+D	O
+-	O
+glucarate	O
+of	O
+a	O
+fixed	O
+size	O
+of	O
+dose	O
+,	O
+approximately	O
+the	O
+same	O
+degree	O
+of	O
+protection	O
+was	O
+obtained	O
+against	O
+renal	B
+damages	I
+induced	O
+by	O
+different	O
+basic	O
+antibiotics	O
+despite	O
+large	O
+disparities	O
+in	O
+administration	O
+doses	O
+of	O
+different	O
+antibiotics	O
+.	O
+
+D	O
+-	O
+Glucarates	O
+had	O
+the	O
+ability	O
+to	O
+prevent	O
+renal	B
+damage	I
+but	O
+not	O
+to	O
+cure	O
+it	O
+.	O
+
+Rats	O
+excreted	O
+acidic	O
+urine	O
+when	O
+they	O
+were	O
+spared	O
+from	O
+renal	B
+lesions	I
+by	O
+monosaccharides	O
+.	O
+
+The	O
+reduction	O
+effect	O
+of	O
+D	O
+-	O
+glucarates	O
+against	O
+nephrotoxicity	B
+of	O
+basic	O
+antibiotics	O
+was	O
+discussed	O
+.	O
+
+Acute	O
+severe	O
+depression	B
+following	O
+peri	O
+-	O
+operative	O
+ondansetron	O
+.	O
+
+A	O
+41	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+a	O
+strong	O
+history	O
+of	O
+postoperative	B
+nausea	I
+and	I
+vomiting	I
+presented	O
+for	O
+abdominal	O
+hysterectomy	O
+3	O
+months	O
+after	O
+a	O
+previous	O
+anaesthetic	O
+where	O
+ondansetron	O
+prophylaxis	O
+had	O
+been	O
+used	O
+.	O
+
+She	O
+had	O
+developed	O
+a	O
+severe	O
+acute	O
+major	B
+depression	I
+disorder	I
+almost	O
+immediately	O
+thereafter	O
+,	O
+possibly	O
+related	O
+to	O
+the	O
+use	O
+of	O
+a	O
+serotonin	O
+antagonist	O
+.	O
+
+Nine	O
+years	O
+before	O
+she	O
+had	O
+experienced	O
+a	O
+self	O
+-	O
+limited	O
+puerperal	O
+depressive	B
+episode	I
+.	O
+
+Anaesthesia	O
+with	O
+a	O
+propofol	O
+infusion	O
+and	O
+avoidance	O
+of	O
+serotonin	O
+antagonists	O
+provided	O
+a	O
+nausea	B
+-	O
+free	O
+postoperative	O
+course	O
+without	O
+exacerbation	O
+of	O
+the	O
+depression	B
+disorder	I
+.	O
+
+Hypertensive	B
+response	O
+during	O
+dobutamine	O
+stress	O
+echocardiography	O
+.	O
+
+Among	O
+3	O
+,	O
+129	O
+dobutamine	O
+stress	O
+echocardiographic	O
+studies	O
+,	O
+a	O
+hypertensive	B
+response	O
+,	O
+defined	O
+as	O
+systolic	O
+blood	O
+pressure	O
+(	O
+BP	O
+)	O
+>	O
+or	O
+=	O
+220	O
+mm	O
+Hg	O
+and	O
+/	O
+or	O
+diastolic	O
+BP	O
+>	O
+or	O
+=	O
+110	O
+mm	O
+Hg	O
+,	O
+occurred	O
+in	O
+30	O
+patients	O
+(	O
+1	O
+%	O
+)	O
+.	O
+
+Patients	O
+with	O
+this	O
+response	O
+more	O
+often	O
+had	O
+a	O
+history	O
+of	O
+hypertension	B
+and	O
+had	O
+higher	O
+resting	O
+systolic	O
+and	O
+diastolic	O
+BP	O
+before	O
+dobutamine	O
+infusion	O
+.	O
+
+Continuously	O
+nebulized	O
+albuterol	O
+in	O
+severe	O
+exacerbations	O
+of	O
+asthma	B
+in	O
+adults	O
+:	O
+a	O
+case	O
+-	O
+controlled	O
+study	O
+.	O
+
+A	O
+retrospective	O
+,	O
+case	O
+-	O
+controlled	O
+analysis	O
+comparing	O
+patients	O
+admitted	O
+to	O
+a	O
+medical	O
+intensive	O
+care	O
+unit	O
+with	O
+severe	O
+exacerbations	O
+of	O
+asthma	B
+who	O
+received	O
+continuously	O
+nebulized	O
+albuterol	O
+(	O
+CNA	O
+)	O
+versus	O
+intermittent	O
+albuterol	O
+(	O
+INA	O
+)	O
+treatments	O
+is	O
+reported	O
+.	O
+
+Forty	O
+matched	O
+pairs	O
+of	O
+patients	O
+with	O
+asthma	B
+are	O
+compared	O
+.	O
+
+CNA	O
+was	O
+administered	O
+for	O
+a	O
+mean	O
+of	O
+11	O
++	O
+/	O
+-	O
+10	O
+hr	O
+.	O
+
+The	O
+incidence	O
+of	O
+cardiac	B
+dysrhythmias	I
+was	O
+similar	O
+between	O
+groups	O
+.	O
+
+Symptomatic	O
+hypokalemia	B
+did	O
+not	O
+occur	O
+.	O
+
+CNA	O
+patients	O
+had	O
+higher	O
+heart	O
+rates	O
+during	O
+treatment	O
+,	O
+which	O
+may	O
+reflect	O
+severity	O
+of	O
+illness	O
+.	O
+
+The	O
+incidence	O
+of	O
+intubation	O
+was	O
+similar	O
+.	O
+
+We	O
+conclude	O
+that	O
+CNA	O
+and	O
+INA	O
+demonstrated	O
+similar	O
+profiles	O
+with	O
+regard	O
+to	O
+safety	O
+,	O
+morbidity	O
+,	O
+and	O
+mortality	O
+.	O
+
+Paraplegia	B
+following	O
+intrathecal	O
+methotrexate	O
+:	O
+report	O
+of	O
+a	O
+case	O
+and	O
+review	O
+of	O
+the	O
+literature	O
+.	O
+
+A	O
+patient	O
+who	O
+developed	O
+paraplegia	B
+following	O
+the	O
+intrathecal	O
+instillation	O
+of	O
+methotrexate	O
+is	O
+discribed	O
+.	O
+
+The	O
+ten	O
+previously	O
+reported	O
+cases	O
+of	O
+this	O
+unusual	O
+complication	O
+are	O
+reviewed	O
+.	O
+
+The	O
+following	O
+factors	O
+appear	O
+to	O
+predispose	O
+to	O
+the	O
+development	O
+of	O
+this	O
+complication	O
+:	O
+abnormal	O
+cerebrospinal	O
+dynamics	O
+related	O
+to	O
+the	O
+presence	O
+of	O
+central	B
+nervous	I
+system	I
+leukemia	I
+,	O
+and	O
+epidural	O
+cerebrospinal	O
+leakage	O
+;	O
+elevated	O
+cerebrospinal	O
+fluid	O
+methothexate	O
+concentration	O
+related	O
+to	O
+abnormal	O
+cerebrospinal	O
+fluid	O
+dynamics	O
+and	O
+to	O
+inappropriately	O
+high	O
+methotrexate	O
+doses	O
+based	O
+on	O
+body	O
+surface	O
+area	O
+calculations	O
+in	O
+older	O
+children	O
+and	O
+adults	O
+;	O
+the	O
+presence	O
+of	O
+neurotoxic	B
+preservatives	O
+in	O
+commercially	O
+available	O
+methotrexate	O
+preparations	O
+and	O
+diluents	O
+;	O
+and	O
+the	O
+use	O
+of	O
+methotrexate	O
+diluents	O
+of	O
+unphysiologic	O
+pH	O
+,	O
+ionic	O
+content	O
+and	O
+osmolarity	O
+.	O
+
+The	O
+role	O
+of	O
+methotrexate	O
+contaminants	O
+,	O
+local	O
+folate	B
+deficiency	I
+,	O
+and	O
+cranial	O
+irradiation	O
+in	O
+the	O
+pathogenesis	O
+of	O
+intrathecal	O
+methotrexate	O
+toxicity	B
+is	O
+unclear	O
+.	O
+
+The	O
+incidence	O
+of	O
+neurotoxicity	B
+may	O
+be	O
+reduced	O
+by	O
+employing	O
+lower	O
+doses	O
+of	O
+methotrexate	O
+in	O
+the	O
+presence	O
+of	O
+central	B
+nervous	I
+system	I
+leukemia	I
+,	O
+in	O
+older	O
+children	O
+and	O
+adults	O
+,	O
+and	O
+in	O
+the	O
+presence	O
+of	O
+epidural	O
+leakage	O
+.	O
+
+Only	O
+preservative	O
+-	O
+free	O
+methotrexate	O
+in	O
+Elliott	O
+'	O
+s	O
+B	O
+Solution	O
+at	O
+a	O
+concentration	O
+of	O
+not	O
+more	O
+than	O
+1	O
+mg	O
+/	O
+ml	O
+should	O
+be	O
+used	O
+for	O
+intrathecal	O
+administration	O
+.	O
+
+Periodic	O
+monitoring	O
+of	O
+cerebruspinal	O
+fluid	O
+methotrexate	O
+levels	O
+may	O
+be	O
+predictive	O
+of	O
+the	O
+development	O
+of	O
+serious	O
+neurotoxicity	B
+.	O
+
+Hyperosmolar	B
+nonketotic	I
+coma	I
+precipitated	O
+by	O
+lithium	O
+-	O
+induced	O
+nephrogenic	B
+diabetes	I
+insipidus	I
+.	O
+
+A	O
+45	O
+-	O
+year	O
+-	O
+old	O
+man	O
+,	O
+with	O
+a	O
+10	O
+-	O
+year	O
+history	O
+of	O
+manic	B
+depression	I
+treated	O
+with	O
+lithium	O
+,	O
+was	O
+admitted	O
+with	O
+hyperosmolar	B
+,	I
+nonketotic	I
+coma	I
+.	O
+
+He	O
+gave	O
+a	O
+five	O
+-	O
+year	O
+history	O
+of	O
+polyuria	B
+and	O
+polydipsia	B
+,	O
+during	O
+which	O
+time	O
+urinalysis	O
+had	O
+been	O
+negative	O
+for	O
+glucose	O
+.	O
+
+After	O
+recovery	O
+from	O
+hyperglycaemia	B
+,	O
+he	O
+remained	O
+polyuric	B
+despite	O
+normal	O
+blood	O
+glucose	O
+concentrations	O
+;	O
+water	O
+deprivation	O
+testing	O
+indicated	O
+nephrogenic	B
+diabetes	I
+insipidus	I
+,	O
+likely	O
+to	O
+be	O
+lithium	O
+-	O
+induced	O
+.	O
+
+We	O
+hypothesize	O
+that	O
+when	O
+this	O
+man	O
+developed	O
+type	B
+2	I
+diabetes	I
+,	O
+chronic	O
+polyuria	B
+due	O
+to	O
+nephrogenic	B
+diabetes	I
+insipidus	I
+was	O
+sufficient	O
+to	O
+precipitate	O
+hyperosmolar	O
+dehydration	B
+.	O
+
+Effects	O
+of	O
+the	O
+intracoronary	O
+infusion	O
+of	O
+cocaine	O
+on	O
+left	O
+ventricular	O
+systolic	O
+and	O
+diastolic	O
+function	O
+in	O
+humans	O
+.	O
+
+BACKGROUND	O
+:	O
+In	O
+dogs	O
+,	O
+a	O
+large	O
+amount	O
+of	O
+intravenous	O
+cocaine	O
+causes	O
+a	O
+profound	O
+deterioration	B
+of	I
+left	I
+ventricular	I
+(	I
+LV	I
+)	I
+systolic	I
+function	I
+and	O
+an	O
+increase	O
+in	O
+LV	O
+end	O
+-	O
+diastolic	O
+pressure	O
+.	O
+
+This	O
+study	O
+was	O
+done	O
+to	O
+assess	O
+the	O
+influence	O
+of	O
+a	O
+high	O
+intracoronary	O
+cocaine	O
+concentration	O
+on	O
+LV	O
+systolic	O
+and	O
+diastolic	O
+function	O
+in	O
+humans	O
+.	O
+
+METHODS	O
+AND	O
+RESULTS	O
+:	O
+In	O
+20	O
+patients	O
+(	O
+14	O
+men	O
+and	O
+6	O
+women	O
+aged	O
+39	O
+to	O
+72	O
+years	O
+)	O
+referred	O
+for	O
+cardiac	O
+catheterization	O
+for	O
+the	O
+evaluation	O
+of	O
+chest	B
+pain	I
+,	O
+we	O
+measured	O
+heart	O
+rate	O
+,	O
+systemic	O
+arterial	O
+pressure	O
+,	O
+LV	O
+pressure	O
+and	O
+its	O
+first	O
+derivative	O
+(	O
+dP	O
+/	O
+dt	O
+)	O
+,	O
+and	O
+LV	O
+volumes	O
+and	O
+ejection	O
+fraction	O
+before	O
+and	O
+during	O
+the	O
+final	O
+2	O
+to	O
+3	O
+minutes	O
+of	O
+a	O
+15	O
+-	O
+minute	O
+intracoronary	O
+infusion	O
+of	O
+saline	O
+(	O
+n	O
+=	O
+10	O
+,	O
+control	O
+subjects	O
+)	O
+or	O
+cocaine	O
+hydrochloride	O
+1	O
+mg	O
+/	O
+min	O
+(	O
+n	O
+=	O
+10	O
+)	O
+.	O
+
+No	O
+variable	O
+changed	O
+with	O
+saline	O
+.	O
+
+With	O
+cocaine	O
+,	O
+the	O
+drug	O
+concentration	O
+in	O
+blood	O
+obtained	O
+from	O
+the	O
+coronary	O
+sinus	O
+was	O
+3	O
+.	O
+0	O
++	O
+/	O
+-	O
+0	O
+.	O
+4	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+)	O
+mg	O
+/	O
+L	O
+,	O
+similar	O
+in	O
+magnitude	O
+to	O
+the	O
+blood	O
+cocaine	O
+concentration	O
+reported	O
+in	O
+abusers	O
+dying	O
+of	O
+cocaine	O
+intoxication	O
+.	O
+
+Cocaine	O
+induced	O
+no	O
+significant	O
+change	O
+in	O
+heart	O
+rate	O
+,	O
+LV	O
+dP	O
+/	O
+dt	O
+(	O
+positive	O
+or	O
+negative	O
+)	O
+,	O
+or	O
+LV	O
+end	O
+-	O
+diastolic	O
+volume	O
+,	O
+but	O
+it	O
+caused	O
+an	O
+increase	O
+in	O
+systolic	O
+and	O
+mean	O
+arterial	O
+pressures	O
+,	O
+LV	O
+end	O
+-	O
+diastolic	O
+pressure	O
+,	O
+and	O
+LV	O
+end	O
+-	O
+systolic	O
+volume	O
+,	O
+as	O
+well	O
+as	O
+a	O
+decrease	O
+in	O
+LV	O
+ejection	O
+fraction	O
+.	O
+
+CONCLUSIONS	O
+:	O
+In	O
+humans	O
+,	O
+the	O
+intracoronary	O
+infusion	O
+of	O
+cocaine	O
+sufficient	O
+in	O
+amount	O
+to	O
+achieve	O
+a	O
+high	O
+drug	O
+concentration	O
+in	O
+coronary	O
+sinus	O
+blood	O
+causes	O
+a	O
+deterioration	B
+of	I
+LV	I
+systolic	I
+and	I
+diastolic	I
+performance	I
+.	O
+
+Ascending	O
+dose	O
+tolerance	O
+study	O
+of	O
+intramuscular	O
+carbetocin	O
+administered	O
+after	O
+normal	O
+vaginal	O
+birth	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+determine	O
+the	O
+maximum	O
+tolerated	O
+dose	O
+(	O
+MTD	O
+)	O
+of	O
+carbetocin	O
+(	O
+a	O
+long	O
+-	O
+acting	O
+synthetic	O
+analogue	O
+of	O
+oxytocin	O
+)	O
+,	O
+when	O
+administered	O
+immediately	O
+after	O
+vaginal	O
+delivery	O
+at	O
+term	O
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+Carbetocin	O
+was	O
+given	O
+as	O
+an	O
+intramuscular	O
+injection	O
+immediately	O
+after	O
+the	O
+birth	O
+of	O
+the	O
+infant	O
+in	O
+45	O
+healthy	O
+women	O
+with	O
+normal	O
+singleton	O
+pregnancies	O
+who	O
+delivered	O
+vaginally	O
+at	O
+term	O
+.	O
+
+Dosage	O
+groups	O
+of	O
+15	O
+,	O
+30	O
+,	O
+50	O
+,	O
+75	O
+,	O
+100	O
+,	O
+125	O
+,	O
+150	O
+,	O
+175	O
+or	O
+200	O
+microg	O
+carbetocin	O
+were	O
+assigned	O
+to	O
+blocks	O
+of	O
+three	O
+women	O
+according	O
+to	O
+the	O
+continual	O
+reassessment	O
+method	O
+(	O
+CRM	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+All	O
+dosage	O
+groups	O
+consisted	O
+of	O
+three	O
+women	O
+,	O
+except	O
+those	O
+with	O
+100	O
+microg	O
+(	O
+n	O
+=	O
+6	O
+)	O
+and	O
+200	O
+microg	O
+(	O
+n	O
+=	O
+18	O
+)	O
+.	O
+
+Recorded	O
+were	O
+dose	O
+-	O
+limiting	O
+adverse	O
+events	O
+:	O
+hyper	B
+-	I
+or	I
+hypotension	I
+(	O
+three	O
+)	O
+,	O
+severe	O
+abdominal	B
+pain	I
+(	O
+0	O
+)	O
+,	O
+vomiting	B
+(	O
+0	O
+)	O
+and	O
+retained	B
+placenta	I
+(	O
+four	O
+)	O
+.	O
+
+Serious	O
+adverse	O
+events	O
+occurred	O
+in	O
+seven	O
+women	O
+:	O
+six	O
+cases	O
+with	O
+blood	B
+loss	I
+>	O
+or	O
+=	O
+1000	O
+ml	O
+,	O
+four	O
+cases	O
+of	O
+manual	O
+placenta	O
+removal	O
+,	O
+five	O
+cases	O
+of	O
+additional	O
+oxytocics	O
+administration	O
+and	O
+five	O
+cases	O
+of	O
+blood	O
+transfusion	O
+.	O
+
+Maximum	O
+blood	B
+loss	I
+was	O
+greatest	O
+at	O
+the	O
+upper	O
+and	O
+lower	O
+dose	O
+levels	O
+,	O
+and	O
+lowest	O
+in	O
+the	O
+70	O
+-	O
+125	O
+microg	O
+dose	O
+range	O
+.	O
+
+Four	O
+out	O
+of	O
+six	O
+cases	O
+with	O
+blood	B
+loss	I
+>	O
+or	O
+=	O
+1000	O
+ml	O
+occurred	O
+in	O
+the	O
+200	O
+microg	O
+group	O
+.	O
+
+The	O
+majority	O
+of	O
+additional	O
+administration	O
+of	O
+oxytocics	O
+(	O
+4	O
+/	O
+5	O
+)	O
+and	O
+blood	O
+transfusion	O
+(	O
+3	O
+/	O
+5	O
+)	O
+occurred	O
+in	O
+the	O
+dose	O
+groups	O
+of	O
+200	O
+microg	O
+.	O
+
+All	O
+retained	O
+placentae	O
+were	O
+found	O
+in	O
+the	O
+group	O
+of	O
+200	O
+microg	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+MTD	O
+was	O
+calculated	O
+to	O
+be	O
+at	O
+200	O
+microg	O
+carbetocin	O
+.	O
+
+Heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+,	O
+paradoxical	O
+thromboembolism	B
+,	O
+and	O
+other	O
+side	O
+effects	O
+of	O
+heparin	O
+therapy	O
+.	O
+
+Although	O
+several	O
+new	O
+anticoagulant	O
+drugs	O
+are	O
+in	O
+development	O
+,	O
+heparin	O
+remains	O
+the	O
+drug	O
+of	O
+choice	O
+for	O
+most	O
+anticoagulation	O
+needs	O
+.	O
+
+The	O
+clinical	O
+effects	O
+of	O
+heparin	O
+are	O
+meritorious	O
+,	O
+but	O
+side	O
+effects	O
+do	O
+exist	O
+.	O
+
+Important	O
+untoward	O
+effects	O
+of	O
+heparin	O
+therapy	O
+including	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+,	O
+heparin	O
+-	O
+associated	O
+osteoporosis	B
+,	O
+eosinophilia	B
+,	O
+skin	B
+reactions	I
+,	O
+allergic	B
+reactions	I
+other	O
+than	O
+thrombocytopenia	B
+and	O
+alopecia	B
+will	O
+be	O
+discussed	O
+in	O
+this	O
+article	O
+.	O
+
+Nonopaque	O
+crystal	O
+deposition	O
+causing	O
+ureteric	B
+obstruction	I
+in	O
+patients	O
+with	O
+HIV	O
+undergoing	O
+indinavir	O
+therapy	O
+.	O
+
+OBJECTIVE	O
+:	O
+We	O
+describe	O
+the	O
+unique	O
+CT	O
+features	O
+of	O
+ureteric	B
+calculi	I
+in	O
+six	O
+HIV	B
+-	I
+infected	I
+patients	O
+receiving	O
+indinavir	O
+,	O
+the	O
+most	O
+commonly	O
+used	O
+HIV	O
+protease	O
+inhibitor	O
+,	O
+which	O
+is	O
+associated	O
+with	O
+an	O
+increased	O
+incidence	O
+of	O
+urolithiasis	B
+.	O
+
+CONCLUSION	O
+:	O
+Ureteric	B
+obstruction	I
+caused	O
+by	O
+precipitated	O
+indinavir	O
+crystals	O
+may	O
+be	O
+difficult	O
+to	O
+diagnose	O
+with	O
+unenhanced	O
+CT	O
+.	O
+
+The	O
+calculi	O
+are	O
+not	O
+opaque	O
+,	O
+and	O
+secondary	O
+signs	O
+of	O
+obstruction	O
+may	O
+be	O
+absent	O
+or	O
+minimal	O
+and	O
+should	O
+be	O
+sought	O
+carefully	O
+.	O
+
+Images	O
+may	O
+need	O
+to	O
+be	O
+obtained	O
+using	O
+i	O
+.	O
+v	O
+.	O
+contrast	O
+material	O
+to	O
+enable	O
+diagnosis	O
+of	O
+ureteric	B
+stones	I
+or	I
+obstruction	I
+in	O
+patients	O
+with	O
+HIV	B
+infection	I
+who	O
+receive	O
+indinavir	O
+therapy	O
+.	O
+
+Ischemic	B
+colitis	I
+and	O
+sumatriptan	O
+use	O
+.	O
+
+Sumatriptan	O
+succinate	O
+,	O
+a	O
+serotonin	O
+-	O
+1	O
+(	O
+5	O
+-	O
+hydroxytryptamine	O
+-	O
+1	O
+)	O
+receptor	O
+agonist	O
+,	O
+is	O
+an	O
+antimigraine	O
+drug	O
+that	O
+is	O
+reported	O
+to	O
+act	O
+by	O
+selectively	O
+constricting	O
+intracranial	O
+arteries	O
+.	O
+
+Recently	O
+,	O
+vasopressor	O
+responses	O
+that	O
+are	O
+distinct	O
+from	O
+the	O
+cranial	O
+circulation	O
+have	O
+been	O
+demonstrated	O
+to	O
+occur	O
+in	O
+the	O
+systemic	O
+,	O
+pulmonary	O
+,	O
+and	O
+coronary	O
+circulations	O
+.	O
+
+Cases	O
+have	O
+been	O
+published	O
+of	O
+coronary	B
+vasospasm	I
+,	O
+myocardial	B
+ischemia	I
+,	O
+and	O
+myocardial	B
+infarction	I
+occurring	O
+after	O
+sumatriptan	O
+use	O
+.	O
+
+We	O
+report	O
+on	O
+the	O
+development	O
+of	O
+8	O
+serious	O
+cases	O
+of	O
+ischemic	B
+colitis	I
+in	O
+patients	O
+with	O
+migraine	B
+treated	O
+with	O
+sumatriptan	O
+.	O
+
+Pallidotomy	O
+with	O
+the	O
+gamma	O
+knife	O
+:	O
+a	O
+positive	O
+experience	O
+.	O
+
+51	O
+patients	O
+with	O
+medically	O
+refractory	O
+Parkinson	B
+'	I
+s	I
+disease	I
+underwent	O
+stereotactic	O
+posteromedial	O
+pallidotomy	O
+between	O
+August	O
+1993	O
+and	O
+February	O
+1997	O
+for	O
+treatment	O
+of	O
+bradykinesia	B
+,	O
+rigidity	B
+,	O
+and	O
+L	O
+-	O
+DOPA	O
+-	O
+induced	O
+dyskinesias	B
+.	O
+
+In	O
+29	O
+patients	O
+,	O
+the	O
+pallidotomies	O
+were	O
+performed	O
+with	O
+the	O
+Leksell	O
+Gamma	O
+Knife	O
+and	O
+in	O
+22	O
+they	O
+were	O
+performed	O
+with	O
+the	O
+standard	O
+radiofrequency	O
+(	O
+RF	O
+)	O
+method	O
+.	O
+
+Clinical	O
+assessment	O
+as	O
+well	O
+as	O
+blinded	O
+ratings	O
+of	O
+Unified	O
+Parkinson	B
+'	I
+s	I
+Disease	I
+Rating	O
+Scale	O
+(	O
+UPDRS	O
+)	O
+scores	O
+were	O
+carried	O
+out	O
+pre	O
+-	O
+and	O
+postoperatively	O
+.	O
+
+Mean	O
+follow	O
+-	O
+up	O
+time	O
+is	O
+20	O
+.	O
+6	O
+months	O
+(	O
+range	O
+6	O
+-	O
+48	O
+)	O
+and	O
+all	O
+except	O
+4	O
+patients	O
+have	O
+been	O
+followed	O
+more	O
+than	O
+one	O
+year	O
+.	O
+
+85	O
+percent	O
+of	O
+patients	O
+with	O
+dyskinesias	B
+were	O
+relieved	O
+of	O
+symptoms	O
+,	O
+regardless	O
+of	O
+whether	O
+the	O
+pallidotomies	O
+were	O
+performed	O
+with	O
+the	O
+Gamma	O
+Knife	O
+or	O
+radiofrequency	O
+methods	O
+.	O
+
+About	O
+2	O
+/	O
+3	O
+of	O
+the	O
+patients	O
+in	O
+both	O
+Gamma	O
+Knife	O
+and	O
+radiofrequency	O
+groups	O
+showed	O
+improvements	O
+in	O
+bradykinesia	B
+and	O
+rigidity	B
+,	O
+although	O
+when	O
+considered	O
+as	O
+a	O
+group	O
+neither	O
+the	O
+Gamma	O
+Knife	O
+nor	O
+the	O
+radiofrequency	O
+group	O
+showed	O
+statistically	O
+significant	O
+improvements	O
+in	O
+UPDRS	O
+scores	O
+.	O
+
+One	O
+patient	O
+in	O
+the	O
+Gamma	O
+Knife	O
+group	O
+(	O
+3	O
+.	O
+4	O
+%	O
+)	O
+developed	O
+a	O
+homonymous	B
+hemianopsia	I
+9	O
+months	O
+following	O
+treatment	O
+and	O
+5	O
+patients	O
+(	O
+27	O
+.	O
+7	O
+%	O
+)	O
+in	O
+the	O
+radiofrequency	O
+group	O
+became	O
+transiently	O
+confused	O
+postoperatively	O
+.	O
+
+No	O
+other	O
+complications	O
+were	O
+seen	O
+.	O
+
+Gamma	O
+Knife	O
+pallidotomy	O
+is	O
+as	O
+effective	O
+as	O
+radiofrequency	O
+pallidotomy	O
+in	O
+controlling	O
+certain	O
+of	O
+the	O
+symptoms	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+It	O
+may	O
+be	O
+the	O
+only	O
+practical	O
+technique	O
+available	O
+in	O
+certain	O
+patients	O
+,	O
+such	O
+as	O
+those	O
+who	O
+take	O
+anticoagulants	O
+,	O
+have	O
+bleeding	B
+diatheses	O
+or	O
+serious	O
+systemic	O
+medical	O
+illnesses	O
+.	O
+
+It	O
+is	O
+a	O
+viable	O
+option	O
+for	O
+other	O
+patients	O
+as	O
+well	O
+.	O
+
+Centrally	O
+mediated	O
+cardiovascular	O
+effects	O
+of	O
+intracisternal	O
+application	O
+of	O
+carbachol	O
+in	O
+anesthetized	O
+rats	O
+.	O
+
+The	O
+pressor	O
+response	O
+to	O
+the	O
+intracisternal	O
+(	O
+i	O
+.	O
+c	O
+.	O
+)	O
+injection	O
+of	O
+carbachol	O
+(	O
+1	O
+mug	O
+)	O
+in	O
+anesthetized	O
+rats	O
+was	O
+analyzed	O
+.	O
+
+This	O
+response	O
+was	O
+significantly	O
+reduced	O
+by	O
+the	O
+intravenous	O
+(	O
+i	O
+.	O
+v	O
+.	O
+)	O
+injection	O
+of	O
+guanethidine	O
+(	O
+5	O
+mg	O
+)	O
+,	O
+hexamethonium	O
+(	O
+10	O
+mg	O
+)	O
+or	O
+phentolamine	O
+(	O
+5	O
+mg	O
+)	O
+,	O
+and	O
+conversely	O
+,	O
+potentiated	O
+by	O
+i	O
+.	O
+v	O
+.	O
+desmethylimipramine	O
+(	O
+0	O
+.	O
+3	O
+mg	O
+)	O
+,	O
+while	O
+propranolol	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+)	O
+i	O
+.	O
+v	O
+.	O
+selectively	O
+inhibited	O
+the	O
+enlargement	B
+of	I
+pulse	I
+pressure	I
+and	O
+the	O
+tachycardia	B
+following	O
+i	O
+.	O
+c	O
+.	O
+carbachol	O
+(	O
+1	O
+mug	O
+)	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+the	O
+pressor	O
+response	O
+to	O
+i	O
+.	O
+c	O
+.	O
+carbachol	O
+(	O
+1	O
+mug	O
+)	O
+was	O
+almost	O
+completely	O
+blocked	O
+by	O
+i	O
+.	O
+c	O
+.	O
+atropine	O
+(	O
+3	O
+mug	O
+)	O
+or	O
+hexamethonium	O
+(	O
+500	O
+mug	O
+)	O
+,	O
+and	O
+significantly	O
+reduced	O
+by	O
+i	O
+.	O
+c	O
+.	O
+chlorpromazine	O
+(	O
+50	O
+mug	O
+)	O
+but	O
+significantly	O
+potentiated	O
+by	O
+i	O
+.	O
+c	O
+.	O
+desmethylimipramine	O
+(	O
+30	O
+mug	O
+)	O
+.	O
+
+The	O
+pressor	O
+response	O
+to	O
+i	O
+.	O
+c	O
+.	O
+carbachol	O
+(	O
+1	O
+mug	O
+)	O
+remained	O
+unchanged	O
+after	O
+sectioning	O
+of	O
+the	O
+bilateral	O
+cervical	O
+vagal	O
+nerves	O
+but	O
+disappeared	O
+after	O
+sectioning	O
+of	O
+the	O
+spinal	O
+cord	O
+(	O
+C7	O
+-	O
+C8	O
+)	O
+.	O
+
+From	O
+the	O
+above	O
+result	O
+it	O
+is	O
+suggested	O
+that	O
+the	O
+pressor	O
+response	O
+to	O
+i	O
+.	O
+c	O
+.	O
+carbachol	O
+ortral	O
+and	O
+peripheral	O
+adrenergic	O
+mechanisms	O
+,	O
+and	O
+that	O
+the	O
+sympathetic	O
+trunk	O
+is	O
+the	O
+main	O
+pathway	O
+.	O
+
+Neuroleptic	B
+malignant	I
+syndrome	I
+and	O
+methylphenidate	O
+.	O
+
+A	O
+1	O
+-	O
+year	O
+-	O
+old	O
+female	O
+presented	O
+with	O
+neuroleptic	B
+malignant	I
+syndrome	I
+probably	O
+caused	O
+by	O
+methylphenidate	O
+.	O
+
+She	O
+had	O
+defects	O
+in	O
+the	O
+supratentorial	O
+brain	O
+including	O
+the	O
+basal	O
+ganglia	O
+and	O
+the	O
+striatum	O
+(	O
+multicystic	B
+encephalomalacia	I
+)	O
+due	O
+to	O
+severe	O
+perinatal	O
+hypoxic	B
+-	I
+ischemic	I
+encephalopathy	I
+,	O
+which	O
+was	O
+considered	O
+to	O
+be	O
+a	O
+possible	O
+predisposing	O
+factor	O
+causing	O
+neuroleptic	B
+malignant	I
+syndrome	I
+.	O
+
+A	O
+dopaminergic	O
+blockade	O
+mechanism	O
+generally	O
+is	O
+accepted	O
+as	O
+the	O
+pathogenesis	O
+of	O
+this	O
+syndrome	O
+.	O
+
+However	O
+,	O
+methylphenidate	O
+is	O
+a	O
+dopamine	O
+agonist	O
+via	O
+the	O
+inhibition	O
+of	O
+uptake	O
+of	O
+dopamine	O
+,	O
+and	O
+therefore	O
+dopaminergic	O
+systems	O
+in	O
+the	O
+brainstem	O
+(	O
+mainly	O
+the	O
+midbrain	O
+)	O
+and	O
+the	O
+spinal	O
+cord	O
+were	O
+unlikely	O
+to	O
+participate	O
+in	O
+the	O
+onset	O
+of	O
+this	O
+syndrome	O
+.	O
+
+A	O
+relative	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+-	O
+ergic	O
+deficiency	O
+might	O
+occur	O
+because	O
+diazepam	O
+,	O
+a	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+-	O
+mimetic	O
+agent	O
+,	O
+was	O
+strikingly	O
+effective	O
+.	O
+
+This	O
+is	O
+the	O
+first	O
+reported	O
+patient	O
+with	O
+neuroleptic	B
+malignant	I
+syndrome	I
+probably	O
+caused	O
+by	O
+methylphenidate	O
+.	O
+
+Differential	O
+effects	O
+of	O
+17alpha	O
+-	O
+ethinylestradiol	O
+on	O
+the	O
+neutral	O
+and	O
+acidic	O
+pathways	O
+of	O
+bile	O
+salt	O
+synthesis	O
+in	O
+the	O
+rat	O
+.	O
+
+Effects	O
+of	O
+17alpha	O
+-	O
+ethinylestradiol	O
+(	O
+EE	O
+)	O
+on	O
+the	O
+neutral	O
+and	O
+acidic	O
+biosynthetic	O
+pathways	O
+of	O
+bile	O
+salt	O
+(	O
+BS	O
+)	O
+synthesis	O
+were	O
+evaluated	O
+in	O
+rats	O
+with	O
+an	O
+intact	O
+enterohepatic	O
+circulation	O
+and	O
+in	O
+rats	O
+with	O
+long	O
+-	O
+term	O
+bile	O
+diversion	O
+to	O
+induce	O
+BS	O
+synthesis	O
+.	O
+
+For	O
+this	O
+purpose	O
+,	O
+bile	O
+salt	O
+pool	O
+composition	O
+,	O
+synthesis	O
+of	O
+individual	O
+BS	O
+in	O
+vivo	O
+,	O
+hepatic	O
+activities	O
+,	O
+and	O
+expression	O
+levels	O
+of	O
+cholesterol	O
+7alpha	O
+-	O
+hydroxylase	O
+(	O
+CYP7A	O
+)	O
+,	O
+and	O
+sterol	O
+27	O
+-	O
+hydroxylase	O
+(	O
+CYP27	O
+)	O
+,	O
+as	O
+well	O
+as	O
+of	O
+other	O
+enzymes	O
+involved	O
+in	O
+BS	O
+synthesis	O
+,	O
+were	O
+analyzed	O
+in	O
+rats	O
+treated	O
+with	O
+EE	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+,	O
+3	O
+days	O
+)	O
+or	O
+its	O
+vehicle	O
+.	O
+
+BS	O
+pool	O
+size	O
+was	O
+decreased	O
+by	O
+27	O
+%	O
+but	O
+total	O
+BS	O
+synthesis	O
+was	O
+not	O
+affected	O
+by	O
+EE	O
+in	O
+intact	O
+rats	O
+.	O
+
+Synthesis	O
+of	O
+cholate	O
+was	O
+reduced	O
+by	O
+68	O
+%	O
+in	O
+EE	O
+-	O
+treated	O
+rats	O
+,	O
+while	O
+that	O
+of	O
+chenodeoxycholate	O
+was	O
+increased	O
+by	O
+60	O
+%	O
+.	O
+
+The	O
+recently	O
+identified	O
+Delta22	O
+-	O
+isomer	O
+of	O
+beta	O
+-	O
+muricholate	O
+contributed	O
+for	O
+5	O
+.	O
+4	O
+%	O
+and	O
+18	O
+.	O
+3	O
+%	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+to	O
+the	O
+pool	O
+in	O
+control	O
+and	O
+EE	O
+-	O
+treated	O
+rats	O
+,	O
+respectively	O
+,	O
+but	O
+could	O
+not	O
+be	O
+detected	O
+in	O
+bile	O
+after	O
+exhaustion	O
+of	O
+the	O
+pool	O
+.	O
+
+A	O
+clear	O
+reduction	O
+of	O
+BS	O
+synthesis	O
+was	O
+found	O
+in	O
+bile	O
+-	O
+diverted	O
+rats	O
+treated	O
+with	O
+EE	O
+,	O
+yet	O
+biliary	O
+BS	O
+composition	O
+was	O
+only	O
+minimally	O
+affected	O
+.	O
+
+Activity	O
+of	O
+CYP7A	O
+was	O
+decreased	O
+by	O
+EE	O
+in	O
+both	O
+intact	O
+and	O
+bile	O
+-	O
+diverted	O
+rats	O
+,	O
+whereas	O
+the	O
+activity	O
+of	O
+the	O
+CYP27	O
+was	O
+not	O
+affected	O
+.	O
+
+Hepatic	O
+mRNA	O
+levels	O
+of	O
+CYP7A	O
+were	O
+significantly	O
+reduced	O
+by	O
+EE	O
+in	O
+bile	O
+-	O
+diverted	O
+rats	O
+only	O
+;	O
+CYP27	O
+mRNA	O
+levels	O
+were	O
+not	O
+affected	O
+by	O
+EE	O
+.	O
+
+In	O
+addition	O
+,	O
+mRNA	O
+levels	O
+of	O
+sterol	O
+12alpha	O
+-	O
+hydroxylase	O
+and	O
+lithocholate	O
+6beta	O
+-	O
+hydroxylase	O
+were	O
+increased	O
+by	O
+bile	O
+diversion	O
+and	O
+suppressed	O
+by	O
+EE	O
+.	O
+
+This	O
+study	O
+shows	O
+that	O
+17alpha	O
+-	O
+ethinylestradiol	O
+(	O
+EE	O
+)	O
+-	O
+induced	O
+intrahepatic	B
+cholestasis	I
+in	O
+rats	O
+is	O
+associated	O
+with	O
+selective	O
+inhibition	O
+of	O
+the	O
+neutral	O
+pathway	O
+of	O
+bile	O
+salt	O
+(	O
+BS	O
+)	O
+synthesis	O
+.	O
+
+Simultaneous	O
+impairment	O
+of	O
+other	O
+enzymes	O
+in	O
+the	O
+BS	O
+biosynthetic	O
+pathways	O
+may	O
+contribute	O
+to	O
+overall	O
+effects	O
+of	O
+EE	O
+on	O
+BS	O
+synthesis	O
+.	O
+
+Glibenclamide	O
+-	O
+sensitive	O
+hypotension	B
+produced	O
+by	O
+helodermin	O
+assessed	O
+in	O
+the	O
+rat	O
+.	O
+
+The	O
+effects	O
+of	O
+helodermin	O
+,	O
+a	O
+basic	O
+35	O
+-	O
+amino	O
+acid	O
+peptide	O
+isolated	O
+from	O
+the	O
+venom	O
+of	O
+a	O
+lizard	O
+salivary	O
+gland	O
+,	O
+on	O
+arterial	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+were	O
+examined	O
+in	O
+the	O
+rat	O
+,	O
+focusing	O
+on	O
+the	O
+possibility	O
+that	O
+activation	O
+of	O
+ATP	O
+sensitive	O
+K	O
++	O
+(	O
+K	O
+(	O
+ATP	O
+)	O
+)	O
+channels	O
+is	O
+involved	O
+in	O
+the	O
+responses	O
+.	O
+
+The	O
+results	O
+were	O
+also	O
+compared	O
+with	O
+those	O
+of	O
+vasoactive	O
+intestinal	O
+polypeptide	O
+(	O
+VIP	O
+)	O
+.	O
+
+Helodermin	O
+produced	O
+hypotension	B
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+with	O
+approximately	O
+similar	O
+potency	O
+and	O
+duration	O
+to	O
+VIP	O
+.	O
+
+Hypotension	B
+induced	O
+by	O
+both	O
+peptides	O
+was	O
+significantly	O
+attenuated	O
+by	O
+glibenclamide	O
+,	O
+which	O
+abolished	O
+a	O
+levcromakalim	O
+-	O
+produced	O
+decrease	O
+in	O
+arterial	O
+blood	O
+pressure	O
+.	O
+
+Oxyhemoglobin	O
+did	O
+not	O
+affect	O
+helodermin	O
+-	O
+induced	O
+hypotension	B
+,	O
+whereas	O
+it	O
+shortened	O
+the	O
+duration	O
+of	O
+acetylcholine	O
+(	O
+ACh	O
+)	O
+-	O
+produced	O
+hypotension	B
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+helodermin	O
+-	O
+produced	O
+hypotension	B
+is	O
+partly	O
+attributable	O
+to	O
+the	O
+activation	O
+of	O
+glibenclamide	O
+-	O
+sensitive	O
+K	O
++	O
+channels	O
+(	O
+K	O
+(	O
+ATP	O
+)	O
+channels	O
+)	O
+,	O
+which	O
+presumably	O
+exist	O
+on	O
+arterial	O
+smooth	O
+muscle	O
+cells	O
+.	O
+
+EDRF	O
+(	O
+endothelium	O
+-	O
+derived	O
+relaxing	O
+factor	O
+)	O
+/	O
+nitric	O
+oxide	O
+does	O
+not	O
+seem	O
+to	O
+play	O
+an	O
+important	O
+role	O
+in	O
+the	O
+peptide	O
+-	O
+produced	O
+hypotension	B
+.	O
+
+Long	O
+-	O
+term	O
+efficacy	O
+and	O
+adverse	O
+event	O
+of	O
+nifedipine	O
+sustained	O
+-	O
+release	O
+tablets	O
+for	O
+cyclosporin	O
+A	O
+-	O
+induced	O
+hypertension	B
+in	O
+patients	O
+with	O
+psoriasis	B
+.	O
+
+Thirteen	O
+psoriatic	B
+patients	O
+with	O
+hypertension	B
+during	O
+the	O
+course	O
+of	O
+cyclosporin	O
+A	O
+therapy	O
+were	O
+treated	O
+for	O
+25	O
+months	O
+with	O
+a	O
+calcium	O
+channel	O
+blocker	O
+,	O
+sustained	O
+-	O
+release	O
+nifedipine	O
+,	O
+to	O
+study	O
+the	O
+clinical	O
+antihypertensive	O
+effects	O
+and	O
+adverse	O
+events	O
+during	O
+treatment	O
+with	O
+both	O
+drugs	O
+.	O
+
+Seven	O
+of	O
+the	O
+13	O
+patients	O
+had	O
+exhibited	O
+a	O
+subclinical	O
+hypertensive	B
+state	O
+before	O
+cyclosporin	O
+A	O
+therapy	O
+.	O
+
+Both	O
+systolic	O
+and	O
+diastolic	O
+blood	O
+pressures	O
+of	O
+these	O
+13	O
+patients	O
+were	O
+decreased	O
+significantly	O
+after	O
+4	O
+weeks	O
+of	O
+nifedipine	O
+therapy	O
+,	O
+and	O
+blood	O
+pressure	O
+was	O
+maintained	O
+within	O
+the	O
+normal	O
+range	O
+thereafter	O
+for	O
+25	O
+months	O
+.	O
+
+The	O
+adverse	O
+events	O
+during	O
+combined	O
+therapy	O
+with	O
+cyclosporin	O
+A	O
+and	O
+nifedipine	O
+included	O
+an	O
+increase	O
+in	O
+blood	O
+urea	O
+nitrogen	O
+levels	O
+in	O
+9	O
+of	O
+the	O
+13	O
+patients	O
+and	O
+development	O
+of	O
+gingival	B
+hyperplasia	I
+in	O
+2	O
+of	O
+the	O
+13	O
+patients	O
+.	O
+
+Our	O
+findings	O
+indicate	O
+that	O
+sustained	O
+-	O
+release	O
+nifedipine	O
+is	O
+useful	O
+for	O
+hypertensive	B
+psoriatic	B
+patients	O
+under	O
+long	O
+-	O
+term	O
+treatment	O
+with	O
+cyclosporin	O
+A	O
+,	O
+but	O
+that	O
+these	O
+patients	O
+should	O
+be	O
+monitored	O
+for	O
+gingival	B
+hyperplasia	I
+.	O
+
diff --git a/data/BC5CDR-disease/test_modified.tsv b/data/BC5CDR-disease/test_modified.tsv
new file mode 100644
index 0000000..adef417
--- /dev/null
+++ b/data/BC5CDR-disease/test_modified.tsv
@@ -0,0 +1,129546 @@
+Torsade	B-NP
+de	I-NP
+pointes	I-NP
+ventricular	B-NP
+tachycardia	I-NP
+during	O
+low	O
+dose	O
+intermittent	O
+dobutamine	O
+treatment	O
+in	O
+a	O
+patient	O
+with	O
+dilated	B-NP
+cardiomyopathy	I-NP
+and	O
+congestive	B-NP
+heart	I-NP
+failure	I-NP
+.	O
+	
+The	O
+authors	O
+describe	O
+the	O
+case	O
+of	O
+a	O
+56	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+chronic	O
+","	O
+severe	O
+heart	B-NP
+failure	I-NP
+secondary	O
+to	O
+dilated	B-NP
+cardiomyopathy	I-NP
+and	O
+absence	O
+of	O
+significant	O
+ventricular	B-NP
+arrhythmias	I-NP
+who	O
+developed	O
+QT	B-NP
+prolongation	I-NP
+and	O
+torsade	B-NP
+de	I-NP
+pointes	I-NP
+ventricular	B-NP
+tachycardia	I-NP
+during	O
+one	O
+cycle	O
+of	O
+intermittent	O
+low	O
+dose	O
+(	O
+2	O
+.	O
+5	O
+mcg	O
+/	O
+kg	O
+per	O
+min	O
+)	O
+dobutamine	O
+.	O
+	
+This	O
+report	O
+of	O
+torsade	B-NP
+de	I-NP
+pointes	I-NP
+ventricular	B-NP
+tachycardia	I-NP
+during	O
+intermittent	O
+dobutamine	O
+supports	O
+the	O
+hypothesis	O
+that	O
+unpredictable	O
+fatal	O
+arrhythmias	B-NP
+may	O
+occur	O
+even	O
+with	O
+low	O
+doses	O
+and	O
+in	O
+patients	O
+with	O
+no	O
+history	O
+of	O
+significant	O
+rhythm	O
+disturbances	O
+.	O
+	
+The	O
+mechanisms	O
+of	O
+proarrhythmic	O
+effects	O
+of	O
+Dubutamine	O
+are	O
+discussed	O
+.	O
+	
+Positive	O
+skin	O
+tests	O
+in	O
+late	O
+reactions	O
+to	O
+radiographic	O
+contrast	O
+media	O
+.	O
+	
+In	O
+the	O
+last	O
+few	O
+years	O
+delayed	O
+reactions	O
+several	O
+hours	O
+after	O
+the	O
+injection	O
+of	O
+radiographic	O
+and	O
+contrast	O
+materials	O
+(	O
+PRC	O
+)	O
+have	O
+been	O
+described	O
+with	O
+increasing	O
+frequency	O
+.	O
+	
+The	O
+authors	O
+report	O
+two	O
+observations	O
+on	O
+patients	O
+with	O
+delayed	O
+reactions	O
+in	O
+whom	O
+intradermoreactions	O
+(	O
+IDR	O
+)	O
+and	O
+patch	O
+tests	O
+to	O
+a	O
+series	O
+of	O
+ionic	O
+and	O
+non	O
+ionic	O
+PRC	O
+were	O
+studied	O
+.	O
+	
+After	O
+angiography	O
+by	O
+the	O
+venous	O
+route	O
+in	O
+patient	O
+n	O
+degree	O
+1	O
+a	O
+biphasic	O
+reaction	O
+with	O
+an	O
+immediate	O
+reaction	O
+(	O
+dyspnea	B-NP
+","	O
+loss	B-NP
+of	I-NP
+consciousness	I-NP
+)	O
+and	O
+delayed	O
+macro	B-NP
+-	I-NP
+papular	I-NP
+rash	I-NP
+appeared	O
+","	O
+whilst	O
+patient	O
+n	O
+degree	O
+2	O
+developed	O
+a	O
+generalised	O
+sensation	O
+of	O
+heat	O
+","	O
+persistent	O
+pain	B-NP
+at	O
+the	O
+site	O
+of	O
+injection	O
+immediately	O
+and	O
+a	O
+generalised	O
+macro	O
+-	O
+papular	O
+reaction	O
+after	O
+24	O
+hours	O
+.	O
+	
+The	O
+skin	O
+tests	O
+revealed	O
+positive	O
+delayed	O
+reactions	O
+of	O
+24	O
+hours	O
+and	O
+48	O
+hours	O
+by	O
+IDR	O
+and	O
+patch	O
+tests	O
+to	O
+only	O
+some	O
+PRC	O
+with	O
+common	O
+chains	O
+in	O
+their	O
+structures	O
+.	O
+	
+The	O
+positive	O
+skin	O
+tests	O
+are	O
+in	O
+favour	O
+of	O
+immunological	O
+reactions	O
+and	O
+may	O
+help	O
+in	O
+diagnosis	O
+of	O
+allergy	B-NP
+in	O
+the	O
+patients	O
+.	O
+	
+Risk	O
+of	O
+transient	O
+hyperammonemic	B-NP
+encephalopathy	I-NP
+in	O
+cancer	B-NP
+patients	O
+who	O
+received	O
+continuous	O
+infusion	O
+of	O
+5	O
+-	O
+fluorouracil	O
+with	O
+the	O
+complication	O
+of	O
+dehydration	B-NP
+and	O
+infection	B-NP
+.	O
+	
+From	O
+1986	O
+to	O
+1998	O
+","	O
+29	O
+cancer	B-NP
+patients	O
+who	O
+had	O
+32	O
+episodes	O
+of	O
+transient	O
+hyperammonemic	B-NP
+encephalopathy	I-NP
+related	O
+to	O
+continuous	O
+infusion	O
+of	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+were	O
+identified	O
+.	O
+	
+None	O
+of	O
+the	O
+patients	O
+had	O
+decompensated	O
+liver	B-NP
+disease	I-NP
+.	O
+	
+Onset	O
+of	O
+hyperammonemic	B-NP
+encephalopathy	I-NP
+varied	O
+from	O
+0	O
+.	O
+5	O
+to	O
+5	O
+days	O
+(	O
+mean	O
+:	O
+2	O
+.	O
+6	O
++	O
+/	O
+-	O
+1	O
+.	O
+3	O
+days	O
+)	O
+after	O
+the	O
+initiation	O
+of	O
+chemotherapy	O
+.	O
+	
+Plasma	O
+ammonium	O
+level	O
+ranged	O
+from	O
+248	O
+to	O
+2387	O
+microg	O
+%	O
+(	O
+mean	O
+:	O
+626	O
++	O
+/	O
+-	O
+431	O
+microg	O
+%	O
+)	O
+.	O
+	
+Among	O
+the	O
+32	O
+episodes	O
+","	O
+26	O
+(	O
+81	O
+%	O
+)	O
+had	O
+various	O
+degrees	O
+of	O
+azotemia	B-NP
+","	O
+18	O
+(	O
+56	O
+%	O
+)	O
+occurred	O
+during	O
+bacterial	B-NP
+infections	I-NP
+and	O
+14	O
+(	O
+44	O
+%	O
+)	O
+without	O
+infection	B-NP
+occurred	O
+during	O
+periods	O
+of	O
+dehydration	B-NP
+.	O
+	
+Higher	O
+plasma	O
+ammonium	O
+levels	O
+and	O
+more	O
+rapid	O
+onset	O
+of	O
+hyperammonemia	B-NP
+were	O
+seen	O
+in	O
+18	O
+patients	O
+with	O
+bacterial	B-NP
+infections	I-NP
+(	O
+p	O
+=	O
+0	O
+.	O
+3	O
+and	O
+0	O
+.	O
+6	O
+","	O
+respectively	O
+)	O
+and	O
+in	O
+nine	O
+patients	O
+receiving	O
+high	O
+daily	O
+doses	O
+(	O
+2600	O
+or	O
+1800	O
+mg	O
+/	O
+m2	O
+)	O
+of	O
+5	O
+-	O
+FU	O
+(	O
+p	O
+=	O
+0	O
+.	O
+1	O
+and	O
+<	O
+0	O
+.	O
+1	O
+","	O
+respectively	O
+)	O
+.	O
+	
+In	O
+25	O
+out	O
+of	O
+32	O
+episodes	O
+(	O
+78	O
+%	O
+)	O
+","	O
+plasma	O
+ammonium	O
+levels	O
+and	O
+mental	O
+status	O
+returned	O
+to	O
+normal	O
+within	O
+2	O
+days	O
+after	O
+adequate	O
+management	O
+.	O
+	
+In	O
+conclusion	O
+","	O
+hyperammonemic	B-NP
+encephalopathy	I-NP
+can	O
+occur	O
+in	O
+patients	O
+receiving	O
+continuous	O
+infusion	O
+of	O
+5	O
+-	O
+FU	O
+.	O
+	
+Azotemia	B-NP
+","	O
+body	O
+fluid	O
+insufficiency	O
+and	O
+bacterial	B-NP
+infections	I-NP
+were	O
+frequently	O
+found	O
+in	O
+these	O
+patients	O
+.	O
+	
+It	O
+is	O
+therefore	O
+important	O
+to	O
+recognize	O
+this	O
+condition	O
+in	O
+patients	O
+receiving	O
+continuous	O
+infusion	O
+of	O
+5	O
+-	O
+FU	O
+.	O
+	
+The	O
+effects	O
+of	O
+quinine	O
+and	O
+4	O
+-	O
+aminopyridine	O
+on	O
+conditioned	O
+place	O
+preference	O
+and	O
+changes	O
+in	O
+motor	O
+activity	O
+induced	O
+by	O
+morphine	O
+in	O
+rats	O
+.	O
+	
+1	O
+.	O
+	
+The	O
+effects	O
+of	O
+two	O
+unselective	O
+potassium	O
+(	O
+K	O
+(	O
++	O
+)	O
+-	O
+)	O
+channel	O
+blockers	O
+","	O
+quinine	O
+(	O
+12	O
+.	O
+5	O
+","	O
+25	O
+and	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+4	O
+-	O
+aminopyridine	O
+(	O
+1	O
+and	O
+2	O
+mg	O
+/	O
+kg	O
+)	O
+","	O
+on	O
+conditioned	O
+place	O
+preference	O
+and	O
+biphasic	O
+changes	O
+in	O
+motor	O
+activity	O
+induced	O
+by	O
+morphine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+were	O
+tested	O
+in	O
+Wistar	O
+rats	O
+.	O
+	
+Quinine	O
+is	O
+known	O
+to	O
+block	O
+voltage	O
+-	O
+","	O
+calcium	O
+-	O
+and	O
+ATP	O
+-	O
+sensitive	O
+K	O
+(	O
++	O
+)	O
+-	O
+channels	O
+while	O
+4	O
+-	O
+aminopyridine	O
+is	O
+known	O
+to	O
+block	O
+voltage	O
+-	O
+sensitive	O
+K	O
+(	O
++	O
+)	O
+-	O
+channels	O
+.	O
+	
+2	O
+.	O
+	
+In	O
+the	O
+counterbalanced	O
+method	O
+","	O
+quinine	O
+attenuated	O
+morphine	O
+-	O
+induced	O
+place	O
+preference	O
+","	O
+whereas	O
+4	O
+-	O
+aminopyridine	O
+was	O
+ineffective	O
+.	O
+	
+In	O
+the	O
+motor	O
+activity	O
+test	O
+measured	O
+with	O
+an	O
+Animex	O
+-	O
+activity	O
+meter	O
+neither	O
+of	O
+the	O
+K	O
+(	O
++	O
+)	O
+-	O
+channel	O
+blockers	O
+affected	O
+morphine	O
+-	O
+induced	O
+hypoactivity	B-NP
+","	O
+but	O
+both	O
+K	O
+(	O
++	O
+)	O
+-	O
+channel	O
+blockers	O
+prevented	O
+morphine	O
+-	O
+induced	O
+secondary	O
+hyperactivity	B-NP
+.	O
+	
+3	O
+.	O
+	
+These	O
+results	O
+suggest	O
+the	O
+involvement	O
+of	O
+quinine	O
+-	O
+sensitive	O
+but	O
+not	O
+4	O
+-	O
+aminopyridine	O
+-	O
+sensitive	O
+K	O
+(	O
++	O
+)	O
+-	O
+channels	O
+in	O
+morphine	O
+reward	O
+.	O
+	
+It	O
+is	O
+also	O
+suggested	O
+that	O
+the	O
+blockade	O
+of	O
+K	O
+(	O
++	O
+)	O
+-	O
+channels	O
+sensitive	O
+to	O
+these	O
+blockers	O
+is	O
+not	O
+sufficient	O
+to	O
+prevent	O
+morphine	O
+-	O
+induced	O
+hypoactivity	B-NP
+whereas	O
+morphine	O
+-	O
+induced	O
+hyperactivity	B-NP
+seems	O
+to	O
+be	O
+connected	O
+to	O
+both	O
+quinine	O
+-	O
+and	O
+4	O
+-	O
+aminopyridine	O
+-	O
+sensitive	O
+K	O
+(	O
++	O
+)	O
+-	O
+channels	O
+.	O
+	
+Nociceptin	O
+/	O
+orphanin	O
+FQ	O
+and	O
+nocistatin	O
+on	O
+learning	B-NP
+and	I-NP
+memory	I-NP
+impairment	I-NP
+induced	O
+by	O
+scopolamine	O
+in	O
+mice	O
+.	O
+	
+1	O
+.	O
+	
+Nociceptin	O
+","	O
+also	O
+known	O
+as	O
+orphanin	O
+FQ	O
+","	O
+is	O
+an	O
+endogenous	O
+ligand	O
+for	O
+the	O
+orphan	O
+opioid	O
+receptor	O
+-	O
+like	O
+receptor	O
+1	O
+(	O
+ORL1	O
+)	O
+and	O
+involves	O
+in	O
+various	O
+functions	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+.	O
+	
+On	O
+the	O
+other	O
+hand	O
+","	O
+nocistatin	O
+is	O
+recently	O
+isolated	O
+from	O
+the	O
+same	O
+precursor	O
+as	O
+nociceptin	O
+and	O
+blocks	O
+nociceptin	O
+-	O
+induced	O
+allodynia	B-NP
+and	O
+hyperalgesia	B-NP
+.	O
+	
+2	O
+.	O
+	
+Although	O
+ORL1	O
+receptors	O
+which	O
+display	O
+a	O
+high	O
+degree	O
+of	O
+sequence	O
+homology	O
+with	O
+classical	O
+opioid	O
+receptors	O
+are	O
+abundant	O
+in	O
+the	O
+hippocampus	O
+","	O
+little	O
+is	O
+known	O
+regarding	O
+their	O
+role	O
+in	O
+learning	O
+and	O
+memory	O
+.	O
+	
+3	O
+.	O
+	
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+investigate	O
+whether	O
+nociceptin	O
+/	O
+orphanin	O
+FQ	O
+and	O
+nocistatin	O
+could	O
+modulate	O
+impairment	B-NP
+of	I-NP
+learning	I-NP
+and	I-NP
+memory	I-NP
+induced	O
+by	O
+scopolamine	O
+","	O
+a	O
+muscarinic	O
+cholinergic	O
+receptor	O
+antagonist	O
+","	O
+using	O
+spontaneous	O
+alternation	O
+of	O
+Y	O
+-	O
+maze	O
+and	O
+step	O
+-	O
+down	O
+type	O
+passive	O
+avoidance	O
+tasks	O
+in	O
+mice	O
+.	O
+	
+4	O
+.	O
+	
+While	O
+nocistatin	O
+(	O
+0	O
+.	O
+5	O
+-	O
+5	O
+.	O
+0	O
+nmol	O
+mouse	O
+-	O
+1	O
+","	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+administered	O
+30	O
+min	O
+before	O
+spontaneous	O
+alternation	O
+performance	O
+or	O
+the	O
+training	O
+session	O
+of	O
+the	O
+passive	O
+avoidance	O
+task	O
+","	O
+had	O
+no	O
+effect	O
+on	O
+spontaneous	O
+alternation	O
+or	O
+passive	O
+avoidance	O
+behaviours	O
+","	O
+a	O
+lower	O
+per	O
+cent	O
+alternation	O
+and	O
+shorter	O
+median	O
+step	O
+-	O
+down	O
+latency	O
+in	O
+the	O
+retention	O
+test	O
+were	O
+obtained	O
+in	O
+nociceptin	O
+(	O
+1	O
+.	O
+5	O
+and	O
+/	O
+or	O
+5	O
+.	O
+0	O
+nmol	O
+mouse	O
+-	O
+1	O
+","	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+-	O
+treated	O
+normal	O
+mice	O
+.	O
+	
+5	O
+.	O
+	
+Administration	O
+of	O
+nocistatin	O
+(	O
+1	O
+.	O
+5	O
+and	O
+/	O
+or	O
+5	O
+.	O
+0	O
+nmol	O
+mouse	O
+-	O
+1	O
+","	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+30	O
+min	O
+before	O
+spontaneous	O
+alternation	O
+performance	O
+or	O
+the	O
+training	O
+session	O
+of	O
+the	O
+passive	O
+avoidance	O
+task	O
+","	O
+attenuated	O
+the	O
+scopolamine	O
+-	O
+induced	O
+impairment	O
+of	O
+spontaneous	O
+alternation	O
+and	O
+passive	O
+avoidance	O
+behaviours	O
+.	O
+	
+6	O
+.	O
+	
+These	O
+results	O
+indicated	O
+that	O
+nocistatin	O
+","	O
+a	O
+new	O
+biologically	O
+active	O
+peptide	O
+","	O
+ameliorates	O
+impairments	O
+of	O
+spontaneous	O
+alternation	O
+and	O
+passive	O
+avoidance	O
+induced	O
+by	O
+scopolamine	O
+","	O
+and	O
+suggested	O
+that	O
+these	O
+peptides	O
+play	O
+opposite	O
+roles	O
+in	O
+learning	O
+and	O
+memory	O
+.	O
+	
+Meloxicam	O
+-	O
+induced	O
+liver	B-NP
+toxicity	I-NP
+.	O
+	
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+female	O
+patient	O
+with	O
+rheumatoid	B-NP
+arthritis	I-NP
+who	O
+developed	O
+acute	O
+cytolytic	O
+hepatitis	B-NP
+due	O
+to	O
+meloxicam	O
+.	O
+	
+Recently	O
+introduced	O
+in	O
+Belgium	O
+","	O
+meloxicam	O
+is	O
+the	O
+first	O
+nonsteroidal	O
+antiinflammatory	O
+drug	O
+with	O
+selective	O
+action	O
+on	O
+the	O
+inducible	O
+form	O
+of	O
+cyclooxygenase	O
+2	O
+.	O
+	
+The	O
+acute	O
+cytolytic	O
+hepatitis	B-NP
+occurred	O
+rapidly	O
+after	O
+meloxicam	O
+administration	O
+and	O
+was	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+antinuclear	O
+antibodies	O
+suggesting	O
+a	O
+hypersensitivity	B-NP
+mechanism	O
+.	O
+	
+This	O
+first	O
+case	O
+of	O
+meloxicam	O
+related	O
+liver	B-NP
+toxicity	I-NP
+demonstrates	O
+the	O
+potential	O
+of	O
+this	O
+drug	O
+to	O
+induce	O
+hepatic	B-NP
+damage	I-NP
+.	O
+	
+Induction	O
+of	O
+apoptosis	O
+by	O
+remoxipride	O
+metabolites	O
+in	O
+HL60	O
+and	O
+CD34	O
++	O
+/	O
+CD19	O
+-	O
+human	O
+bone	O
+marrow	O
+progenitor	O
+cells	O
+:	O
+potential	O
+relevance	O
+to	O
+remoxipride	O
+-	O
+induced	O
+aplastic	B-NP
+anemia	I-NP
+.	O
+	
+The	O
+antipsychotic	O
+agent	O
+","	O
+remoxipride	O
+[	O
+(	O
+S	O
+)	O
+-	O
+(	O
+-	O
+)	O
+-	O
+3	O
+-	O
+bromo	O
+-	O
+N	O
+-	O
+[	O
+(	O
+1	O
+-	O
+ethyl	O
+-	O
+2	O
+-	O
+pyrrolidinyl	O
+)	O
+methyl	O
+]	O
+-	O
+2	O
+","	O
+6	O
+-	O
+dimethoxybenz	O
+amide	O
+]	O
+has	O
+been	O
+associated	O
+with	O
+acquired	O
+aplastic	B-NP
+anemia	I-NP
+.	O
+	
+We	O
+have	O
+examined	O
+the	O
+ability	O
+of	O
+remoxipride	O
+","	O
+three	O
+pyrrolidine	O
+ring	O
+metabolites	O
+and	O
+five	O
+aromatic	O
+ring	O
+metabolites	O
+of	O
+the	O
+parent	O
+compound	O
+to	O
+induce	O
+apoptosis	O
+in	O
+HL60	O
+cells	O
+and	O
+human	O
+bone	O
+marrow	O
+progenitor	O
+(	O
+HBMP	O
+)	O
+cells	O
+.	O
+	
+Cells	O
+were	O
+treated	O
+for	O
+0	O
+-	O
+24	O
+h	O
+with	O
+each	O
+compound	O
+(	O
+0	O
+-	O
+200	O
+microM	O
+)	O
+.	O
+	
+Apoptosis	O
+was	O
+assessed	O
+by	O
+fluorescence	O
+microscopy	O
+in	O
+Hoechst	O
+33342	O
+-	O
+and	O
+propidium	O
+iodide	O
+stained	O
+cell	O
+samples	O
+.	O
+	
+Results	O
+were	O
+confirmed	O
+by	O
+determination	O
+of	O
+internucleosomal	O
+DNA	O
+fragmentation	O
+using	O
+gel	O
+electrophoresis	O
+for	O
+HL60	O
+cell	O
+samples	O
+and	O
+terminal	O
+deoxynucleotidyl	O
+transferase	O
+assay	O
+in	O
+HBMP	O
+cells	O
+.	O
+	
+The	O
+catechol	O
+and	O
+hydroquinone	O
+metabolites	O
+","	O
+NCQ436	O
+and	O
+NCQ344	O
+","	O
+induced	O
+apoptosis	O
+in	O
+HL60	O
+and	O
+HBMP	O
+cells	O
+in	O
+a	O
+time	O
+-	O
+and	O
+concentration	O
+dependent	O
+manner	O
+","	O
+while	O
+the	O
+phenols	O
+","	O
+NCR181	O
+","	O
+FLA873	O
+","	O
+and	O
+FLA797	O
+","	O
+and	O
+the	O
+derivatives	O
+formed	O
+by	O
+oxidation	O
+of	O
+the	O
+pyrrolidine	O
+ring	O
+","	O
+FLA838	O
+","	O
+NCM001	O
+","	O
+and	O
+NCL118	O
+","	O
+had	O
+no	O
+effect	O
+.	O
+	
+No	O
+necrosis	B-NP
+was	O
+observed	O
+in	O
+cells	O
+treated	O
+with	O
+NCQ436	O
+but	O
+NCQ344	O
+had	O
+a	O
+biphasic	O
+effect	O
+in	O
+both	O
+cell	O
+types	O
+","	O
+inducing	O
+apoptosis	O
+at	O
+lower	O
+concentrations	O
+and	O
+necrosis	B-NP
+at	O
+higher	O
+concentrations	O
+.	O
+	
+These	O
+data	O
+show	O
+that	O
+the	O
+catechol	O
+and	O
+hydroquinone	O
+metabolites	O
+of	O
+remoxipride	O
+have	O
+direct	O
+toxic	O
+effects	O
+in	O
+HL60	O
+and	O
+HBMP	O
+cells	O
+","	O
+leading	O
+to	O
+apoptosis	O
+","	O
+while	O
+the	O
+phenol	O
+metabolites	O
+were	O
+inactive	O
+.	O
+	
+Similarly	O
+","	O
+benzene	O
+-	O
+derived	O
+catechol	O
+and	O
+hydroquinone	O
+","	O
+but	O
+not	O
+phenol	O
+","	O
+induce	O
+apoptosis	O
+in	O
+HBMP	O
+cells	O
+[	O
+Moran	O
+et	O
+al	O
+.	O
+","	O
+Mol	O
+.	O
+Pharmacol	O
+.	O
+","	O
+50	O
+(	O
+1996	O
+)	O
+610	O
+-	O
+615	O
+]	O
+.	O
+	
+We	O
+propose	O
+that	O
+remoxipride	O
+and	O
+benzene	O
+may	O
+induce	O
+aplastic	B-NP
+anemia	I-NP
+via	O
+production	O
+of	O
+similar	O
+reactive	O
+metabolites	O
+and	O
+that	O
+the	O
+ability	O
+of	O
+NCQ436	O
+and	O
+NCQ344	O
+to	O
+induce	O
+apoptosis	O
+in	O
+HBMP	O
+cells	O
+may	O
+contribute	O
+to	O
+the	O
+mechanism	O
+underlying	O
+acquired	O
+aplastic	B-NP
+anemia	I-NP
+that	O
+has	O
+been	O
+associated	O
+with	O
+remoxipride	O
+.	O
+	
+Synthesis	O
+and	O
+preliminary	O
+pharmacological	O
+investigations	O
+of	O
+1	O
+-	O
+(	O
+1	O
+","	O
+2	O
+-	O
+dihydro	O
+-	O
+2	O
+-	O
+acenaphthylenyl	O
+)	O
+piperazine	O
+derivatives	O
+as	O
+potential	O
+atypical	O
+antipsychotic	O
+agents	O
+in	O
+mice	O
+.	O
+	
+In	O
+research	O
+towards	O
+the	O
+development	O
+of	O
+new	O
+atypical	O
+antipsychotic	O
+agents	O
+","	O
+one	O
+strategy	O
+is	O
+that	O
+the	O
+dopaminergic	O
+system	O
+can	O
+be	O
+modulated	O
+through	O
+manipulation	O
+of	O
+the	O
+serotonergic	O
+system	O
+.	O
+	
+The	O
+synthesis	O
+and	O
+preliminary	O
+pharmacological	O
+evaluation	O
+of	O
+a	O
+series	O
+of	O
+potential	O
+atypical	O
+antipsychotic	O
+agents	O
+based	O
+on	O
+the	O
+structure	O
+of	O
+1	O
+-	O
+(	O
+1	O
+","	O
+2	O
+-	O
+dihydro	O
+-	O
+2	O
+-	O
+acenaphthylenyl	O
+)	O
+piperazine	O
+(	O
+7	O
+)	O
+is	O
+described	O
+.	O
+	
+Compound	O
+7e	O
+","	O
+5	O
+-	O
+{	O
+2	O
+-	O
+[	O
+4	O
+-	O
+(	O
+1	O
+","	O
+2	O
+-	O
+dihydro	O
+-	O
+2	O
+-	O
+acenaphthylenyl	O
+)	O
+piperazinyl	O
+]	O
+ethyl	O
+}	O
+-	O
+2	O
+","	O
+3	O
+-	O
+dihy	O
+dro	O
+-	O
+1H	O
+-	O
+indol	O
+-	O
+2	O
+-	O
+one	O
+","	O
+from	O
+this	O
+series	O
+showed	O
+significant	O
+affinities	O
+at	O
+the	O
+5	O
+-	O
+HT1A	O
+and	O
+5	O
+-	O
+HT2A	O
+receptors	O
+and	O
+moderate	O
+affinity	O
+at	O
+the	O
+D2	O
+receptor	O
+.	O
+	
+7e	O
+exhibits	O
+a	O
+high	O
+reversal	O
+of	O
+catalepsy	B-NP
+induced	O
+by	O
+haloperidol	O
+indicating	O
+its	O
+atypical	O
+antipsychotic	O
+nature	O
+.	O
+	
+Sub	O
+-	O
+chronic	O
+inhibition	O
+of	O
+nitric	O
+-	O
+oxide	O
+synthesis	O
+modifies	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B-NP
+and	O
+the	O
+number	O
+of	O
+NADPH	O
+-	O
+diaphorase	O
+neurons	O
+in	O
+mice	O
+.	O
+	
+RATIONALE	O
+:	O
+NG	O
+-	O
+nitro	O
+-	O
+L	O
+-	O
+arginine	O
+(	O
+L	O
+-	O
+NOARG	O
+)	O
+","	O
+an	O
+inhibitor	O
+of	O
+nitric	O
+-	O
+oxide	O
+synthase	O
+(	O
+NOS	O
+)	O
+","	O
+induces	O
+catalepsy	B-NP
+in	O
+mice	O
+.	O
+	
+This	O
+effect	O
+undergoes	O
+rapid	O
+tolerance	O
+","	O
+showing	O
+a	O
+significant	O
+decrease	O
+after	O
+2	O
+days	O
+of	O
+sub	O
+-	O
+chronic	O
+L	O
+-	O
+NOARG	O
+treatment	O
+.	O
+	
+Nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+has	O
+been	O
+shown	O
+to	O
+influence	O
+dopaminergic	O
+neurotransmission	O
+in	O
+the	O
+striatum	O
+.	O
+	
+Neuroleptic	O
+drugs	O
+such	O
+as	O
+haloperidol	O
+","	O
+which	O
+block	O
+dopamine	O
+receptors	O
+","	O
+also	O
+cause	O
+catalepsy	B-NP
+in	O
+rodents	O
+.	O
+	
+OBJECTIVES	O
+:	O
+To	O
+investigate	O
+the	O
+effects	O
+of	O
+subchronic	O
+L	O
+-	O
+NOARG	O
+treatment	O
+in	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B-NP
+and	O
+the	O
+number	O
+of	O
+NOS	O
+neurons	O
+in	O
+areas	O
+related	O
+to	O
+motor	O
+control	O
+.	O
+	
+METHODS	O
+:	O
+Male	O
+albino	O
+Swiss	O
+mice	O
+were	O
+treated	O
+sub	O
+-	O
+chronically	O
+(	O
+twice	O
+a	O
+day	O
+for	O
+4	O
+days	O
+)	O
+with	O
+L	O
+-	O
+NOARG	O
+(	O
+40	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+or	O
+haloperidol	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+	
+Catalepsy	B-NP
+was	O
+evaluated	O
+at	O
+the	O
+beginning	O
+and	O
+the	O
+end	O
+of	O
+the	O
+treatments	O
+.	O
+	
+Reduced	O
+nicotinamide	O
+adenine	O
+dinucleotide	O
+phosphate	O
+-	O
+diaphorase	O
+(	O
+NADPH	O
+-	O
+d	O
+)	O
+histochemistry	O
+was	O
+also	O
+employed	O
+to	O
+visualize	O
+NOS	O
+as	O
+an	O
+index	O
+of	O
+enzyme	O
+expression	O
+in	O
+mice	O
+brain	O
+regions	O
+related	O
+to	O
+motor	O
+control	O
+.	O
+	
+RESULTS	O
+:	O
+L	O
+-	O
+NOARG	O
+sub	O
+-	O
+chronic	O
+administration	O
+produced	O
+tolerance	O
+of	O
+L	O
+-	O
+NOARG	O
+and	O
+of	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B-NP
+.	O
+	
+It	O
+also	O
+induced	O
+an	O
+increase	O
+in	O
+the	O
+number	O
+of	O
+NADPH	O
+-	O
+d	O
+-	O
+positive	O
+cells	O
+in	O
+the	O
+dorsal	O
+part	O
+of	O
+the	O
+caudate	O
+and	O
+accumbens	O
+nuclei	O
+compared	O
+with	O
+haloperidol	O
+and	O
+in	O
+the	O
+pedunculopontine	O
+tegmental	O
+nucleus	O
+compared	O
+with	O
+saline	O
+.	O
+	
+In	O
+contrast	O
+","	O
+there	O
+was	O
+a	O
+decrease	O
+in	O
+NADPH	O
+-	O
+d	O
+neuron	O
+number	O
+in	O
+the	O
+substantia	O
+nigra	O
+","	O
+pars	O
+compacta	O
+in	O
+both	O
+haloperidol	O
+-	O
+treated	O
+and	O
+L	O
+-	O
+NOARG	O
+-	O
+treated	O
+animals	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+results	O
+give	O
+further	O
+support	O
+to	O
+the	O
+hypothesis	O
+that	O
+NO	O
+plays	O
+a	O
+role	O
+in	O
+motor	O
+behavior	O
+control	O
+and	O
+suggest	O
+that	O
+it	O
+may	O
+take	O
+part	O
+in	O
+the	O
+synaptic	O
+changes	O
+produced	O
+by	O
+antipsychotic	O
+treatment	O
+.	O
+	
+Prolonged	O
+left	B-NP
+ventricular	I-NP
+dysfunction	I-NP
+occurs	O
+in	O
+patients	O
+with	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+after	O
+both	O
+dobutamine	O
+and	O
+exercise	O
+induced	O
+myocardial	B-NP
+ischaemia	I-NP
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+determine	O
+whether	O
+pharmacological	O
+stress	O
+leads	O
+to	O
+prolonged	O
+but	O
+reversible	O
+left	B-NP
+ventricular	I-NP
+dysfunction	I-NP
+in	O
+patients	O
+with	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+","	O
+similar	O
+to	O
+that	O
+seen	O
+after	O
+exercise	O
+.	O
+	
+DESIGN	O
+:	O
+A	O
+randomised	O
+crossover	O
+study	O
+of	O
+recovery	O
+time	O
+of	O
+systolic	O
+and	O
+diastolic	O
+left	O
+ventricular	O
+function	O
+after	O
+exercise	O
+and	O
+dobutamine	O
+induced	O
+ischaemia	B-NP
+.	O
+	
+SUBJECTS	O
+:	O
+10	O
+patients	O
+with	O
+stable	B-NP
+angina	I-NP
+","	O
+angiographically	O
+proven	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+","	O
+and	O
+normal	O
+left	O
+ventricular	O
+function	O
+.	O
+	
+INTERVENTIONS	O
+:	O
+Treadmill	O
+exercise	O
+and	O
+dobutamine	O
+stress	O
+were	O
+performed	O
+on	O
+different	O
+days	O
+.	O
+	
+Quantitative	O
+assessment	O
+of	O
+systolic	O
+and	O
+diastolic	O
+left	O
+ventricular	O
+function	O
+was	O
+performed	O
+using	O
+transthoracic	O
+echocardiography	O
+at	O
+baseline	O
+and	O
+at	O
+regular	O
+intervals	O
+after	O
+each	O
+test	O
+.	O
+	
+RESULTS	O
+:	O
+Both	O
+forms	O
+of	O
+stress	O
+led	O
+to	O
+prolonged	O
+but	O
+reversible	O
+systolic	O
+and	O
+diastolic	O
+dysfunction	O
+.	O
+	
+There	O
+was	O
+no	O
+difference	O
+in	O
+the	O
+maximum	O
+double	O
+product	O
+(	O
+p	O
+=	O
+0	O
+.	O
+53	O
+)	O
+or	O
+ST	O
+depression	B-NP
+(	O
+p	O
+=	O
+0	O
+.	O
+63	O
+)	O
+with	O
+either	O
+form	O
+of	O
+stress	O
+.	O
+	
+After	O
+exercise	O
+","	O
+ejection	O
+fraction	O
+was	O
+reduced	O
+at	O
+15	O
+and	O
+30	O
+minutes	O
+compared	O
+with	O
+baseline	O
+(	O
+mean	O
+(	O
+SEM	O
+)	O
+","	O
+-	O
+5	O
+.	O
+6	O
+(	O
+1	O
+.	O
+5	O
+)	O
+%	O
+","	O
+p	O
+<	O
+0	O
+.	O
+5	O
+;	O
+and	O
+-	O
+6	O
+.	O
+1	O
+(	O
+2	O
+.	O
+2	O
+)	O
+%	O
+","	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+","	O
+and	O
+at	O
+30	O
+and	O
+45	O
+minutes	O
+after	O
+dobutamine	O
+(	O
+-	O
+10	O
+.	O
+8	O
+(	O
+1	O
+.	O
+8	O
+)	O
+%	O
+and	O
+-	O
+5	O
+.	O
+5	O
+(	O
+1	O
+.	O
+8	O
+)	O
+%	O
+","	O
+both	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Regional	O
+analysis	O
+showed	O
+a	O
+reduction	O
+in	O
+the	O
+worst	O
+affected	O
+segment	O
+15	O
+and	O
+30	O
+minutes	O
+after	O
+exercise	O
+(	O
+-	O
+27	O
+.	O
+9	O
+(	O
+7	O
+.	O
+2	O
+)	O
+%	O
+and	O
+-	O
+28	O
+.	O
+6	O
+(	O
+5	O
+.	O
+7	O
+)	O
+%	O
+","	O
+both	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+","	O
+and	O
+at	O
+30	O
+minutes	O
+after	O
+dobutamine	O
+(	O
+-	O
+32	O
+(	O
+5	O
+.	O
+3	O
+)	O
+%	O
+","	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+The	O
+isovolumic	O
+relaxation	O
+period	O
+was	O
+prolonged	O
+45	O
+minutes	O
+after	O
+each	O
+form	O
+of	O
+stress	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+In	O
+patients	O
+with	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+","	O
+dobutamine	O
+induced	O
+ischaemia	B-NP
+results	O
+in	O
+prolonged	O
+reversible	O
+left	B-NP
+ventricular	I-NP
+dysfunction	I-NP
+","	O
+presumed	O
+to	O
+be	O
+myocardial	B-NP
+stunning	I-NP
+","	O
+similar	O
+to	O
+that	O
+seen	O
+after	O
+exercise	O
+.	O
+	
+Dobutamine	O
+induced	O
+ischaemia	B-NP
+could	O
+therefore	O
+be	O
+used	O
+to	O
+study	O
+the	O
+pathophysiology	O
+of	O
+this	O
+phenomenon	O
+further	O
+in	O
+patients	O
+with	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+.	O
+	
+Anorexigens	O
+and	O
+pulmonary	B-NP
+hypertension	I-NP
+in	O
+the	O
+United	O
+States	O
+:	O
+results	O
+from	O
+the	O
+surveillance	O
+of	O
+North	O
+American	O
+pulmonary	B-NP
+hypertension	I-NP
+.	O
+	
+BACKGROUND	O
+:	O
+The	O
+use	O
+of	O
+appetite	O
+suppressants	O
+in	O
+Europe	O
+has	O
+been	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+primary	B-NP
+pulmonary	I-NP
+hypertension	I-NP
+(	O
+PPH	B-NP
+)	O
+.	O
+	
+Recently	O
+","	O
+fenfluramine	O
+appetite	O
+suppressants	O
+became	O
+widely	O
+used	O
+in	O
+the	O
+United	O
+States	O
+but	O
+were	O
+withdrawn	O
+in	O
+September	O
+1997	O
+because	O
+of	O
+concerns	O
+over	O
+adverse	O
+effects	O
+.	O
+	
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+We	O
+conducted	O
+a	O
+prospective	O
+surveillance	O
+study	O
+on	O
+patients	O
+diagnosed	O
+with	O
+pulmonary	B-NP
+hypertension	I-NP
+at	O
+12	O
+large	O
+referral	O
+centers	O
+in	O
+North	O
+America	O
+.	O
+	
+Data	O
+collected	O
+on	O
+patients	O
+seen	O
+from	O
+September	O
+1	O
+","	O
+1996	O
+","	O
+to	O
+December	O
+31	O
+","	O
+1997	O
+","	O
+included	O
+the	O
+cause	O
+of	O
+the	O
+pulmonary	B-NP
+hypertension	I-NP
+and	O
+its	O
+severity	O
+.	O
+	
+Patients	O
+with	O
+no	O
+identifiable	O
+cause	O
+of	O
+pulmonary	B-NP
+hypertension	I-NP
+were	O
+classed	O
+as	O
+PPH	B-NP
+.	O
+	
+A	O
+history	O
+of	O
+drug	O
+exposure	O
+also	O
+was	O
+taken	O
+with	O
+special	O
+attention	O
+on	O
+the	O
+use	O
+of	O
+antidepressants	O
+","	O
+anorexigens	O
+","	O
+and	O
+amphetamines	O
+.	O
+	
+RESULTS	O
+:	O
+Five	O
+hundred	O
+seventy	O
+-	O
+nine	O
+patients	O
+were	O
+studied	O
+","	O
+205	O
+with	O
+PPH	B-NP
+and	O
+374	O
+with	O
+pulmonary	B-NP
+hypertension	I-NP
+from	O
+other	O
+causes	O
+(	O
+secondary	O
+pulmonary	B-NP
+hypertension	I-NP
+[	O
+SPH	O
+]	O
+)	O
+.	O
+	
+The	O
+use	O
+of	O
+anorexigens	O
+was	O
+common	O
+in	O
+both	O
+groups	O
+.	O
+	
+However	O
+","	O
+of	O
+the	O
+medications	O
+surveyed	O
+","	O
+only	O
+the	O
+fenfluramines	O
+had	O
+a	O
+significant	O
+preferential	O
+association	O
+with	O
+PPH	B-NP
+as	O
+compared	O
+with	O
+SPH	O
+(	O
+adjusted	O
+odds	O
+ratio	O
+for	O
+use	O
+>	O
+6	O
+months	O
+","	O
+7	O
+.	O
+5	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+","	O
+1	O
+.	O
+7	O
+to	O
+32	O
+.	O
+4	O
+)	O
+.	O
+	
+The	O
+association	O
+was	O
+stronger	O
+with	O
+longer	O
+duration	O
+of	O
+use	O
+when	O
+compared	O
+to	O
+shorter	O
+duration	O
+of	O
+use	O
+and	O
+was	O
+more	O
+pronounced	O
+in	O
+recent	O
+users	O
+than	O
+in	O
+remote	O
+users	O
+.	O
+	
+An	O
+unexpectedly	O
+high	O
+(	O
+11	O
+.	O
+4	O
+%	O
+)	O
+number	O
+of	O
+patients	O
+with	O
+SPH	O
+had	O
+used	O
+anorexigens	O
+.	O
+	
+CONCLUSION	O
+:	O
+The	O
+magnitude	O
+of	O
+the	O
+association	O
+with	O
+PPH	B-NP
+","	O
+the	O
+increase	O
+of	O
+association	O
+with	O
+increasing	O
+duration	O
+of	O
+use	O
+","	O
+and	O
+the	O
+specificity	O
+for	O
+fenfluramines	O
+are	O
+consistent	O
+with	O
+previous	O
+studies	O
+indicating	O
+that	O
+fenfluramines	O
+are	O
+causally	O
+related	O
+to	O
+PPH	B-NP
+.	O
+	
+The	O
+high	O
+prevalence	O
+of	O
+anorexigen	O
+use	O
+in	O
+patients	O
+with	O
+SPH	O
+also	O
+raises	O
+the	O
+possibility	O
+that	O
+these	O
+drugs	O
+precipitate	O
+pulmonary	B-NP
+hypertension	I-NP
+in	O
+patients	O
+with	O
+underlying	O
+conditions	O
+associated	O
+with	O
+SPH	O
+.	O
+	
+Clinical	O
+aspects	O
+of	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+and	O
+thrombosis	B-NP
+and	O
+other	O
+side	O
+effects	O
+of	O
+heparin	O
+therapy	O
+.	O
+	
+Heparin	O
+","	O
+first	O
+used	O
+to	O
+prevent	O
+the	O
+clotting	O
+of	O
+blood	O
+in	O
+vitro	O
+","	O
+has	O
+been	O
+clinically	O
+used	O
+to	O
+treat	O
+thrombosis	B-NP
+for	O
+more	O
+than	O
+50	O
+years	O
+.	O
+	
+Although	O
+several	O
+new	O
+anticoagulant	O
+drugs	O
+are	O
+in	O
+development	O
+","	O
+heparin	O
+remains	O
+the	O
+anticoagulant	O
+of	O
+choice	O
+to	O
+treat	O
+acute	O
+thrombotic	B-NP
+episodes	O
+.	O
+	
+The	O
+clinical	O
+effects	O
+of	O
+heparin	O
+are	O
+meritorious	O
+","	O
+but	O
+side	O
+effects	O
+do	O
+exist	O
+.	O
+	
+Bleeding	B-NP
+is	O
+the	O
+primary	O
+untoward	O
+effect	O
+of	O
+heparin	O
+.	O
+	
+Major	O
+bleeding	B-NP
+is	O
+of	O
+primary	O
+concern	O
+in	O
+patients	O
+receiving	O
+heparin	O
+therapy	O
+.	O
+	
+However	O
+","	O
+additional	O
+important	O
+untoward	O
+effects	O
+of	O
+heparin	O
+therapy	O
+include	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+","	O
+heparin	O
+-	O
+associated	O
+osteoporosis	B-NP
+","	O
+eosinophilia	B-NP
+","	O
+skin	B-NP
+reactions	I-NP
+","	O
+allergic	B-NP
+reactions	I-NP
+other	O
+than	O
+thrombocytopenia	B-NP
+","	O
+alopecia	B-NP
+","	O
+transaminasemia	O
+","	O
+hyperkalemia	B-NP
+","	O
+hypoaldosteronism	B-NP
+","	O
+and	O
+priapism	B-NP
+.	O
+	
+These	O
+side	O
+effects	O
+are	O
+relatively	O
+rare	O
+in	O
+a	O
+given	O
+individual	O
+","	O
+but	O
+given	O
+the	O
+extremely	O
+widespread	O
+use	O
+of	O
+heparin	O
+","	O
+some	O
+are	O
+quite	O
+common	O
+","	O
+particularly	O
+HITT	B-NP
+and	O
+osteoporosis	B-NP
+.	O
+	
+Although	O
+reasonable	O
+incidences	O
+of	O
+many	O
+of	O
+these	O
+side	O
+effects	O
+can	O
+be	O
+"	O
+softly	O
+"	O
+deduced	O
+from	O
+current	O
+reports	O
+dealing	O
+with	O
+unfractionated	O
+heparin	O
+","	O
+at	O
+present	O
+the	O
+incidences	O
+of	O
+these	O
+side	O
+effects	O
+with	O
+newer	O
+low	O
+molecular	O
+weight	O
+heparins	O
+appear	O
+to	O
+be	O
+much	O
+less	O
+common	O
+.	O
+	
+However	O
+","	O
+only	O
+longer	O
+experience	O
+will	O
+more	O
+clearly	O
+define	O
+the	O
+incidence	O
+of	O
+each	O
+side	O
+effect	O
+with	O
+low	O
+molecular	O
+weight	O
+preparations	O
+.	O
+	
+A	O
+case	O
+of	O
+bilateral	O
+optic	B-NP
+neuropathy	I-NP
+in	O
+a	O
+patient	O
+on	O
+tacrolimus	O
+(	O
+FK506	O
+)	O
+therapy	O
+after	O
+liver	O
+transplantation	O
+.	O
+	
+PURPOSE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+bilateral	O
+optic	B-NP
+neuropathy	I-NP
+in	O
+a	O
+patient	O
+receiving	O
+tacrolimus	O
+(	O
+FK	O
+506	O
+","	O
+Prograf	O
+;	O
+Fujisawa	O
+USA	O
+","	O
+Inc	O
+","	O
+Deerfield	O
+","	O
+Illinois	O
+)	O
+for	O
+immunosuppression	O
+after	O
+orthotropic	O
+liver	O
+transplantation	O
+.	O
+	
+METHOD	O
+:	O
+Case	O
+report	O
+.	O
+	
+In	O
+a	O
+58	O
+-	O
+year	O
+-	O
+old	O
+man	O
+receiving	O
+tacrolimus	O
+after	O
+orthotropic	O
+liver	O
+transplantation	O
+","	O
+serial	O
+neuro	O
+-	O
+ophthalmologic	O
+examinations	O
+and	O
+laboratory	O
+studies	O
+were	O
+performed	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+patient	O
+had	O
+episodic	O
+deterioration	O
+of	O
+vision	O
+in	O
+both	O
+eyes	O
+","	O
+with	O
+clinical	O
+features	O
+resembling	O
+ischemic	B-NP
+optic	I-NP
+neuropathies	I-NP
+.	O
+	
+Deterioration	B-NP
+of	I-NP
+vision	I-NP
+occurred	O
+despite	O
+discontinuation	O
+of	O
+the	O
+tacrolimus	O
+.	O
+	
+CONCLUSION	O
+:	O
+Tacrolimus	O
+and	O
+other	O
+immunosuppressive	O
+agents	O
+may	O
+be	O
+associated	O
+with	O
+optic	B-NP
+nerve	I-NP
+toxicity	I-NP
+.	O
+	
+Hypercalcemia	B-NP
+","	O
+arrhythmia	B-NP
+","	O
+and	O
+mood	O
+stabilizers	O
+.	O
+	
+Recent	O
+findings	O
+in	O
+a	O
+bipolar	B-NP
+patient	O
+receiving	O
+maintenance	O
+lithium	O
+therapy	O
+who	O
+developed	O
+hypercalcemia	B-NP
+and	O
+severe	O
+bradyarrhythmia	B-NP
+prompted	O
+the	O
+authors	O
+to	O
+conduct	O
+a	O
+retrospective	O
+study	O
+of	O
+bipolar	B-NP
+patients	O
+with	O
+lithium	O
+-	O
+associated	O
+hypercalcemia	B-NP
+.	O
+	
+A	O
+printout	O
+of	O
+all	O
+cases	O
+of	O
+hypercalcemia	B-NP
+that	O
+presented	O
+during	O
+a	O
+1	O
+-	O
+year	O
+period	O
+was	O
+generated	O
+.	O
+	
+After	O
+eliminating	O
+spurious	O
+hypercalcemias	B-NP
+or	O
+those	O
+associated	O
+with	O
+intravenous	O
+fluids	O
+","	O
+the	O
+authors	O
+identified	O
+18	O
+non	O
+-	O
+lithium	O
+-	O
+treated	O
+patients	O
+with	O
+hypercalcemias	B-NP
+related	O
+to	O
+malignancies	B-NP
+and	O
+other	O
+medical	O
+conditions	O
+(	O
+group	O
+A	O
+)	O
+and	O
+12	O
+patients	O
+with	O
+lithium	O
+-	O
+associated	O
+hypercalcemia	B-NP
+(	O
+group	O
+B	O
+)	O
+.	O
+	
+Patients	O
+in	O
+group	O
+B	O
+were	O
+not	O
+comparable	O
+to	O
+those	O
+in	O
+group	O
+A	O
+","	O
+as	O
+the	O
+latter	O
+were	O
+medically	O
+compromised	O
+and	O
+were	O
+receiving	O
+multiple	O
+pharmacotherapies	O
+.	O
+	
+Thus	O
+","	O
+two	O
+control	O
+groups	O
+were	O
+generated	O
+:	O
+group	O
+C1	O
+","	O
+which	O
+included	O
+age	O
+-	O
+and	O
+sex	O
+-	O
+comparable	O
+lithium	O
+-	O
+treated	O
+bipolar	B-NP
+normocalcemic	O
+patients	O
+","	O
+and	O
+group	O
+C2	O
+","	O
+which	O
+included	O
+bipolar	B-NP
+normocalcemic	O
+patients	O
+treated	O
+with	O
+anticonvulsant	O
+mood	O
+stabilizers	O
+.	O
+	
+The	O
+electrocardiographic	O
+(	O
+ECG	O
+)	O
+findings	O
+for	O
+patients	O
+in	O
+group	O
+B	O
+were	O
+compared	O
+with	O
+those	O
+of	O
+patients	O
+in	O
+groups	O
+C1	O
+and	O
+C2	O
+.	O
+	
+It	O
+was	O
+found	O
+that	O
+these	O
+groups	O
+did	O
+not	O
+differ	O
+in	O
+their	O
+overall	O
+frequency	O
+of	O
+ECG	O
+abnormalities	O
+;	O
+however	O
+","	O
+there	O
+were	O
+significant	O
+differences	O
+in	O
+the	O
+frequency	O
+of	O
+conduction	O
+defects	O
+.	O
+	
+Patients	O
+with	O
+hypercalcemia	B-NP
+resulting	O
+from	O
+medical	O
+diseases	O
+and	O
+bipolar	B-NP
+patients	O
+with	O
+lithium	O
+-	O
+associated	O
+hypercalcemia	B-NP
+had	O
+significantly	O
+higher	O
+frequencies	O
+of	O
+conduction	O
+defects	O
+.	O
+	
+Patients	O
+in	O
+group	O
+A	O
+had	O
+significant	O
+mortality	O
+at	O
+2	O
+-	O
+year	O
+follow	O
+-	O
+up	O
+(	O
+28	O
+%	O
+)	O
+","	O
+in	O
+contrast	O
+to	O
+zero	O
+mortality	O
+in	O
+the	O
+other	O
+three	O
+groups	O
+.	O
+	
+The	O
+clinical	O
+implications	O
+of	O
+these	O
+findings	O
+are	O
+discussed	O
+.	O
+	
+Attenuation	O
+of	O
+nephrotoxicity	B-NP
+by	O
+a	O
+novel	O
+lipid	O
+nanosphere	O
+(	O
+NS	O
+-	O
+718	O
+)	O
+incorporating	O
+amphotericin	O
+B	O
+.	O
+	
+NS	O
+-	O
+718	O
+","	O
+a	O
+lipid	O
+nanosphere	O
+incorporating	O
+amphotericin	O
+B	O
+","	O
+is	O
+effective	O
+against	O
+pathogenic	O
+fungi	O
+and	O
+has	O
+low	O
+toxicity	B-NP
+.	O
+	
+We	O
+compared	O
+the	O
+toxicity	B-NP
+of	O
+NS	O
+-	O
+718	O
+with	O
+that	O
+of	O
+Fungizone	O
+(	O
+amphotericin	O
+B	O
+-	O
+sodium	O
+deoxycholate	O
+;	O
+D	O
+-	O
+AmB	O
+)	O
+in	O
+vitro	O
+using	O
+renal	O
+cell	O
+cultures	O
+and	O
+in	O
+vivo	O
+by	O
+biochemical	O
+analysis	O
+","	O
+histopathological	O
+study	O
+of	O
+the	O
+kidney	O
+and	O
+pharmacokinetic	O
+study	O
+of	O
+amphotericin	O
+B	O
+following	O
+intravenous	O
+infusion	O
+of	O
+the	O
+formulation	O
+in	O
+rats	O
+.	O
+	
+Incubation	O
+with	O
+NS	O
+-	O
+718	O
+resulted	O
+in	O
+significantly	O
+less	O
+damage	O
+of	O
+cultured	O
+human	O
+renal	O
+proximal	O
+tubular	O
+epithelial	O
+cells	O
+compared	O
+with	O
+D	O
+-	O
+AmB	O
+.	O
+	
+Serum	O
+blood	O
+urea	O
+and	O
+creatinine	O
+concentrations	O
+increased	O
+significantly	O
+in	O
+rats	O
+given	O
+an	O
+iv	O
+infusion	O
+of	O
+D	O
+-	O
+AmB	O
+3	O
+mg	O
+/	O
+kg	O
+but	O
+not	O
+in	O
+those	O
+given	O
+the	O
+same	O
+dose	O
+of	O
+NS	O
+-	O
+718	O
+.	O
+	
+Histopathological	O
+examination	O
+of	O
+the	O
+kidney	O
+showed	O
+tubular	B-NP
+necrosis	I-NP
+in	O
+D	O
+-	O
+AmB	O
+-	O
+treated	O
+rats	O
+but	O
+no	O
+change	O
+in	O
+NS	O
+-	O
+718	O
+-	O
+treated	O
+rats	O
+.	O
+	
+Amphotericin	O
+B	O
+concentrations	O
+in	O
+the	O
+kidney	O
+in	O
+NS	O
+-	O
+718	O
+-	O
+treated	O
+rats	O
+were	O
+higher	O
+than	O
+those	O
+in	O
+D	O
+-	O
+AmB	O
+-	O
+treated	O
+rats	O
+.	O
+	
+Our	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+results	O
+suggest	O
+that	O
+incorporation	O
+of	O
+amphotericin	O
+B	O
+into	O
+lipid	O
+nanospheres	O
+of	O
+NS	O
+-	O
+718	O
+attenuates	O
+the	O
+nephrotoxicity	B-NP
+of	O
+amphotericin	O
+B	O
+.	O
+	
+Patterns	O
+of	O
+sulfadiazine	O
+acute	B-NP
+nephrotoxicity	I-NP
+.	O
+	
+Sulfadiazine	O
+acute	B-NP
+nephrotoxicity	I-NP
+is	O
+reviving	O
+specially	O
+because	O
+of	O
+its	O
+use	O
+in	O
+toxoplasmosis	B-NP
+in	O
+HIV	O
+-	O
+positive	O
+patients	O
+.	O
+	
+We	O
+report	O
+4	O
+cases	O
+","	O
+one	O
+of	O
+them	O
+in	O
+a	O
+previously	O
+healthy	O
+person	O
+.	O
+	
+Under	O
+treatment	O
+with	O
+sulfadiazine	O
+they	O
+developed	O
+oliguria	B-NP
+","	O
+abdominal	B-NP
+pain	I-NP
+","	O
+renal	B-NP
+failure	I-NP
+and	O
+showed	O
+multiple	O
+radiolucent	O
+renal	B-NP
+calculi	I-NP
+in	O
+echography	O
+.	O
+	
+All	O
+patients	O
+recovered	O
+their	O
+previous	O
+normal	O
+renal	O
+function	O
+after	O
+adequate	O
+hydration	O
+and	O
+alcalinization	O
+.	O
+	
+A	O
+nephrostomy	O
+tube	O
+had	O
+to	O
+be	O
+placed	O
+in	O
+one	O
+of	O
+the	O
+patients	O
+for	O
+ureteral	B-NP
+lithiasis	I-NP
+in	O
+a	O
+single	O
+functional	O
+kidney	O
+.	O
+	
+None	O
+of	O
+them	O
+needed	O
+dialysis	O
+or	O
+a	O
+renal	O
+biopsy	O
+because	O
+of	O
+a	O
+typical	O
+benign	O
+course	O
+.	O
+	
+Treatment	O
+with	O
+sulfadiazine	O
+requires	O
+exquisite	O
+control	O
+of	O
+renal	O
+function	O
+","	O
+an	O
+increase	O
+in	O
+water	O
+ingestion	O
+and	O
+possibly	O
+the	O
+alcalinization	O
+of	O
+the	O
+urine	O
+.	O
+	
+We	O
+communicate	O
+a	O
+case	O
+in	O
+a	O
+previously	O
+healthy	O
+person	O
+","	O
+a	O
+fact	O
+not	O
+found	O
+in	O
+the	O
+recent	O
+literature	O
+.	O
+	
+Probably	O
+many	O
+more	O
+cases	O
+are	O
+not	O
+detected	O
+.	O
+	
+We	O
+think	O
+that	O
+a	O
+prospective	O
+study	O
+would	O
+be	O
+useful	O
+.	O
+	
+Downbeat	B-NP
+nystagmus	I-NP
+associated	O
+with	O
+intravenous	O
+patient	O
+-	O
+controlled	O
+administration	O
+of	O
+morphine	O
+.	O
+	
+IMPLICATIONS	O
+:	O
+This	O
+case	O
+documents	O
+a	O
+patient	O
+who	O
+developed	O
+dizziness	B-NP
+with	O
+downbeating	B-NP
+nystagmus	I-NP
+while	O
+receiving	O
+a	O
+relatively	O
+large	O
+dose	O
+of	O
+IV	O
+patient	O
+-	O
+controlled	O
+analgesia	O
+morphine	O
+.	O
+	
+Although	O
+there	O
+have	O
+been	O
+case	O
+reports	O
+of	O
+epidural	O
+morphine	O
+with	O
+these	O
+symptoms	O
+and	O
+signs	O
+","	O
+this	O
+has	O
+not	O
+been	O
+previously	O
+documented	O
+with	O
+IV	O
+or	O
+patient	O
+-	O
+controlled	O
+analgesia	O
+morphine	O
+.	O
+	
+Hemodynamic	O
+and	O
+antiadrenergic	O
+effects	O
+of	O
+dronedarone	O
+and	O
+amiodarone	O
+in	O
+animals	O
+with	O
+a	O
+healed	O
+myocardial	B-NP
+infarction	I-NP
+.	O
+	
+The	O
+hemodynamic	O
+and	O
+antiadrenergic	O
+effects	O
+of	O
+dronedarone	O
+","	O
+a	O
+noniodinated	O
+compound	O
+structurally	O
+related	O
+to	O
+amiodarone	O
+","	O
+were	O
+compared	O
+with	O
+those	O
+of	O
+amiodarone	O
+after	O
+prolonged	O
+oral	O
+administration	O
+","	O
+both	O
+at	O
+rest	O
+and	O
+during	O
+sympathetic	O
+stimulation	O
+in	O
+conscious	O
+dogs	O
+with	O
+a	O
+healed	O
+myocardial	B-NP
+infarction	I-NP
+.	O
+	
+All	O
+dogs	O
+(	O
+n	O
+=	O
+6	O
+)	O
+randomly	O
+received	O
+orally	O
+dronedarone	O
+(	O
+10	O
+and	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+","	O
+amiodarone	O
+(	O
+10	O
+and	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+","	O
+and	O
+placebo	O
+twice	O
+daily	O
+for	O
+7	O
+days	O
+","	O
+with	O
+a	O
+3	O
+-	O
+week	O
+washout	O
+between	O
+consecutive	O
+treatments	O
+.	O
+	
+Heart	O
+rate	O
+(	O
+HR	O
+)	O
+","	O
+mean	O
+arterial	O
+pressure	O
+(	O
+MBP	O
+)	O
+","	O
+positive	O
+rate	O
+of	O
+increase	O
+of	O
+left	O
+ventricular	O
+pressure	O
+(	O
++	O
+LVdP	O
+/	O
+dt	O
+)	O
+","	O
+echocardiographically	O
+assessed	O
+left	O
+ventricular	O
+ejection	O
+fraction	O
+(	O
+LVEF	O
+)	O
+","	O
+and	O
+fractional	O
+shortening	O
+(	O
+FS	O
+)	O
+","	O
+as	O
+well	O
+as	O
+chronotropic	O
+response	O
+to	O
+isoproterenol	O
+and	O
+exercise	O
+-	O
+induced	O
+sympathetic	O
+stimulation	O
+were	O
+evaluated	O
+under	O
+baseline	O
+and	O
+posttreatment	O
+conditions	O
+.	O
+	
+Resting	O
+values	O
+of	O
+LVEF	O
+","	O
+FS	O
+","	O
++	O
+LVdP	O
+/	O
+dt	O
+","	O
+and	O
+MBP	O
+remained	O
+unchanged	O
+whatever	O
+the	O
+drug	O
+and	O
+the	O
+dosing	O
+regimen	O
+","	O
+whereas	O
+resting	O
+HR	O
+was	O
+significantly	O
+and	O
+dose	O
+-	O
+dependently	O
+lowered	O
+after	O
+dronedarone	O
+and	O
+to	O
+a	O
+lesser	O
+extent	O
+after	O
+amiodarone	O
+.	O
+	
+Both	O
+dronedarone	O
+and	O
+amiodarone	O
+significantly	O
+reduced	O
+the	O
+exercise	O
+-	O
+induced	O
+tachycardia	B-NP
+and	O
+","	O
+at	O
+the	O
+highest	O
+dose	O
+","	O
+decreased	O
+the	O
+isoproterenol	O
+-	O
+induced	O
+tachycardia	B-NP
+.	O
+	
+Thus	O
+","	O
+dronedarone	O
+and	O
+amiodarone	O
+displayed	O
+a	O
+similar	O
+level	O
+of	O
+antiadrenergic	O
+effect	O
+and	O
+did	O
+not	O
+impair	O
+the	O
+resting	O
+left	O
+ventricular	O
+function	O
+.	O
+	
+Consequently	O
+","	O
+dronedarone	O
+might	O
+be	O
+particularly	O
+suitable	O
+for	O
+the	O
+treatment	O
+and	O
+prevention	O
+of	O
+various	O
+clinical	O
+arrhythmias	B-NP
+","	O
+without	O
+compromising	O
+the	O
+left	O
+ventricular	O
+function	O
+.	O
+	
+Phase	O
+2	O
+trial	O
+of	O
+liposomal	O
+doxorubicin	O
+(	O
+40	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+)	O
+in	O
+platinum	O
+/	O
+paclitaxel	O
+-	O
+refractory	O
+ovarian	B-NP
+and	I-NP
+fallopian	I-NP
+tube	I-NP
+cancers	I-NP
+and	O
+primary	O
+carcinoma	B-NP
+of	I-NP
+the	I-NP
+peritoneum	I-NP
+.	O
+	
+BACKGROUND	O
+:	O
+Several	O
+studies	O
+have	O
+demonstrated	O
+liposomal	O
+doxorubicin	O
+(	O
+Doxil	O
+)	O
+to	O
+be	O
+an	O
+active	O
+antineoplastic	O
+agent	O
+in	O
+platinum	O
+-	O
+resistant	O
+ovarian	B-NP
+cancer	I-NP
+","	O
+with	O
+dose	O
+limiting	O
+toxicity	B-NP
+of	O
+the	O
+standard	O
+dosing	O
+regimen	O
+(	O
+50	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+q	O
+4	O
+weeks	O
+)	O
+being	O
+severe	O
+erythrodysesthesia	B-NP
+(	O
+"	O
+hand	B
+-	I
+foot	I
+syndrome	I
+"	O
+)	O
+and	O
+stomatitis	B-NP
+.	O
+	
+We	O
+wished	O
+to	O
+develop	O
+a	O
+more	O
+tolerable	O
+liposomal	O
+doxorubicin	O
+treatment	O
+regimen	O
+and	O
+document	O
+its	O
+level	O
+of	O
+activity	O
+in	O
+a	O
+well	O
+-	O
+defined	O
+patient	O
+population	O
+with	O
+platinum	O
+/	O
+paclitaxel	O
+-	O
+refractory	O
+disease	O
+.	O
+	
+METHODS	O
+AND	O
+MATERIALS	O
+:	O
+Patients	O
+with	O
+ovarian	B-NP
+or	I-NP
+fallopian	I-NP
+tube	I-NP
+cancers	I-NP
+or	O
+primary	O
+peritoneal	B-NP
+carcinoma	I-NP
+with	O
+platinum	O
+/	O
+paclitaxel	O
+-	O
+refractory	O
+disease	O
+(	O
+stable	O
+or	O
+progressive	O
+disease	O
+following	O
+treatment	O
+with	O
+these	O
+agents	O
+or	O
+previous	O
+objective	O
+response	O
+<	O
+3	O
+months	O
+in	O
+duration	O
+)	O
+were	O
+treated	O
+with	O
+liposomal	O
+doxorubicin	O
+at	O
+a	O
+dose	O
+of	O
+40	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+q	O
+4	O
+weeks	O
+.	O
+	
+RESULTS	O
+:	O
+A	O
+total	O
+of	O
+49	O
+patients	O
+(	O
+median	O
+age	O
+:	O
+60	O
+;	O
+range	O
+41	O
+-	O
+81	O
+)	O
+entered	O
+this	O
+phase	O
+2	O
+trial	O
+.	O
+	
+The	O
+median	O
+number	O
+of	O
+prior	O
+regimens	O
+was	O
+2	O
+(	O
+range	O
+:	O
+1	O
+-	O
+6	O
+)	O
+.	O
+	
+Six	O
+(	O
+12	O
+%	O
+)	O
+and	O
+4	O
+(	O
+8	O
+%	O
+)	O
+patients	O
+experienced	O
+grade	O
+2	O
+hand	B-NP
+-	I-NP
+foot	I-NP
+syndrome	I-NP
+and	O
+stomatitis	B-NP
+","	O
+respectively	O
+(	O
+no	O
+episodes	O
+of	O
+grade	O
+3	O
+)	O
+.	O
+	
+One	O
+patient	O
+developed	O
+grade	O
+3	O
+diarrhea	B-NP
+requiring	O
+hospitalization	O
+for	O
+hydration	O
+.	O
+	
+Six	O
+(	O
+12	O
+%	O
+)	O
+individuals	O
+required	O
+dose	O
+reductions	O
+.	O
+	
+The	O
+median	O
+number	O
+of	O
+courses	O
+of	O
+liposomal	O
+doxorubicin	O
+administered	O
+on	O
+this	O
+protocol	O
+was	O
+2	O
+(	O
+range	O
+:	O
+1	O
+-	O
+12	O
+)	O
+.	O
+	
+Four	O
+of	O
+44	O
+patients	O
+(	O
+9	O
+%	O
+)	O
+evaluable	O
+for	O
+response	O
+exhibited	O
+objective	O
+and	O
+subjective	O
+evidence	O
+of	O
+an	O
+antineoplastic	O
+effect	O
+of	O
+therapy	O
+.	O
+	
+CONCLUSION	O
+:	O
+This	O
+modified	O
+liposomal	O
+doxorubicin	O
+regimen	O
+results	O
+in	O
+less	O
+toxicity	B-NP
+(	O
+stomatitis	B-NP
+","	O
+hand	B-NP
+-	I-NP
+foot	I-NP
+syndrome	I-NP
+)	O
+than	O
+the	O
+standard	O
+FDA	O
+-	O
+approved	O
+dose	O
+schedule	O
+.	O
+	
+Definite	O
+","	O
+although	O
+limited	O
+","	O
+antineoplastic	O
+activity	O
+is	O
+observed	O
+in	O
+patients	O
+with	O
+well	O
+-	O
+defined	O
+platinum	O
+-	O
+and	O
+paclitaxel	O
+-	O
+refractory	O
+ovarian	B-NP
+cancer	I-NP
+.	O
+	
+Efficacy	O
+of	O
+olanzapine	O
+in	O
+acute	O
+bipolar	B-NP
+mania	I-NP
+:	O
+a	O
+double	O
+-	O
+blind	O
+","	O
+placebo	O
+-	O
+controlled	O
+study	O
+.	O
+	
+The	O
+Olanzipine	O
+HGGW	O
+Study	O
+Group	O
+.	O
+	
+BACKGROUND	O
+:	O
+We	O
+compared	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+olanzapine	O
+vs	O
+placebo	O
+for	O
+the	O
+treatment	O
+of	O
+acute	O
+bipolar	B-NP
+mania	I-NP
+.	O
+	
+METHODS	O
+:	O
+Four	O
+-	O
+week	O
+","	O
+randomized	O
+","	O
+double	O
+-	O
+blind	O
+","	O
+parallel	O
+study	O
+.	O
+	
+A	O
+total	O
+of	O
+115	O
+patients	O
+with	O
+a	O
+DSM	O
+-	O
+IV	O
+diagnosis	O
+of	O
+bipolar	B-NP
+disorder	I-NP
+","	O
+manic	B-NP
+or	O
+mixed	O
+","	O
+were	O
+randomized	O
+to	O
+olanzapine	O
+","	O
+5	O
+to	O
+20	O
+mg	O
+/	O
+d	O
+(	O
+n	O
+=	O
+55	O
+)	O
+","	O
+or	O
+placebo	O
+(	O
+n	O
+=	O
+60	O
+)	O
+.	O
+	
+The	O
+primary	O
+efficacy	O
+measure	O
+was	O
+the	O
+Young	O
+-	O
+Mania	B-NP
+Rating	O
+Scale	O
+(	O
+Y	O
+-	O
+MRS	O
+)	O
+total	O
+score	O
+.	O
+	
+Response	O
+and	O
+euthymia	O
+were	O
+defined	O
+","	O
+a	O
+priori	O
+","	O
+as	O
+at	O
+least	O
+a	O
+50	O
+%	O
+improvement	O
+from	O
+baseline	O
+to	O
+end	O
+point	O
+and	O
+as	O
+a	O
+score	O
+of	O
+no	O
+less	O
+than	O
+12	O
+at	O
+end	O
+point	O
+in	O
+the	O
+Y	O
+-	O
+MRS	O
+total	O
+score	O
+","	O
+respectively	O
+.	O
+	
+Safety	O
+was	O
+assessed	O
+using	O
+adverse	O
+events	O
+","	O
+Extrapyramidal	B-NP
+Symptom	I-NP
+(	O
+EPS	B-NP
+)	O
+rating	O
+scales	O
+","	O
+laboratory	O
+values	O
+","	O
+electrocardiograms	O
+","	O
+vital	O
+signs	O
+","	O
+and	O
+weight	O
+change	O
+.	O
+	
+RESULTS	O
+:	O
+Olanzapine	O
+-	O
+treated	O
+patients	O
+demonstrated	O
+a	O
+statistically	O
+significant	O
+greater	O
+mean	O
+(	O
++	O
+/	O
+-	O
+SD	O
+)	O
+improvement	O
+in	O
+Y	O
+-	O
+MRS	O
+total	O
+score	O
+than	O
+placebo	O
+-	O
+treated	O
+patients	O
+(	O
+-	O
+14	O
+.	O
+8	O
++	O
+/	O
+-	O
+12	O
+.	O
+5	O
+and	O
+-	O
+8	O
+.	O
+1	O
++	O
+/	O
+-	O
+12	O
+.	O
+7	O
+","	O
+respectively	O
+;	O
+P	O
+<	O
+.	O
+1	O
+)	O
+","	O
+which	O
+was	O
+evident	O
+at	O
+the	O
+first	O
+postbaseline	O
+observation	O
+1	O
+week	O
+after	O
+randomization	O
+and	O
+was	O
+maintained	O
+throughout	O
+the	O
+study	O
+(	O
+last	O
+observation	O
+carried	O
+forward	O
+)	O
+.	O
+	
+Olanzapine	O
+-	O
+treated	O
+patients	O
+demonstrated	O
+a	O
+higher	O
+rate	O
+of	O
+response	O
+(	O
+65	O
+%	O
+vs	O
+43	O
+%	O
+","	O
+respectively	O
+;	O
+P	O
+=	O
+.	O
+2	O
+)	O
+and	O
+euthymia	O
+(	O
+61	O
+%	O
+vs	O
+36	O
+%	O
+","	O
+respectively	O
+;	O
+P	O
+=	O
+.	O
+1	O
+)	O
+than	O
+placebo	O
+-	O
+treated	O
+patients	O
+.	O
+	
+There	O
+were	O
+no	O
+statistically	O
+significant	O
+differences	O
+in	O
+EPSs	B-NP
+between	O
+groups	O
+.	O
+	
+However	O
+","	O
+olanzapine	O
+-	O
+treated	O
+patients	O
+had	O
+a	O
+statistically	O
+significant	O
+greater	O
+mean	O
+(	O
++	O
+/	O
+-	O
+SD	O
+)	O
+weight	B-NP
+gain	I-NP
+than	O
+placebo	O
+-	O
+treated	O
+patients	O
+(	O
+2	O
+.	O
+1	O
++	O
+/	O
+-	O
+2	O
+.	O
+8	O
+vs	O
+0	O
+.	O
+45	O
++	O
+/	O
+-	O
+2	O
+.	O
+3	O
+kg	O
+","	O
+respectively	O
+)	O
+and	O
+also	O
+experienced	O
+more	O
+treatment	O
+-	O
+emergent	O
+somnolence	B-NP
+(	O
+21	O
+patients	O
+[	O
+38	O
+.	O
+2	O
+%	O
+]	O
+vs	O
+5	O
+[	O
+8	O
+.	O
+3	O
+%	O
+]	O
+","	O
+respectively	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+Olanzapine	O
+demonstrated	O
+greater	O
+efficacy	O
+than	O
+placebo	O
+in	O
+the	O
+treatment	O
+of	O
+acute	O
+bipolar	B-NP
+mania	I-NP
+and	O
+was	O
+generally	O
+well	O
+tolerated	O
+.	O
+	
+The	O
+effect	O
+of	O
+pupil	B-NP
+dilation	I-NP
+with	O
+tropicamide	O
+on	O
+vision	O
+and	O
+driving	O
+simulator	O
+performance	O
+.	O
+	
+PURPOSE	O
+:	O
+To	O
+assess	O
+the	O
+effect	O
+of	O
+pupil	B-NP
+dilation	I-NP
+on	O
+vision	O
+and	O
+driving	O
+ability	O
+.	O
+	
+METHODS	O
+:	O
+A	O
+series	O
+of	O
+tests	O
+on	O
+various	O
+parameters	O
+of	O
+visual	O
+function	O
+and	O
+driving	O
+simulator	O
+performance	O
+were	O
+performed	O
+on	O
+12	O
+healthy	O
+drivers	O
+","	O
+before	O
+and	O
+after	O
+pupil	B-NP
+dilation	I-NP
+using	O
+guttae	O
+tropicamide	O
+1	O
+%	O
+.	O
+	
+A	O
+driving	O
+simulator	O
+(	O
+Transport	O
+Research	O
+Laboratory	O
+)	O
+was	O
+used	O
+to	O
+measure	O
+reaction	O
+time	O
+(	O
+RT	O
+)	O
+","	O
+speed	O
+maintenance	O
+and	O
+steering	O
+accuracy	O
+.	O
+	
+Tests	O
+of	O
+basic	O
+visual	O
+function	O
+included	O
+high	O
+-	O
+and	O
+low	O
+-	O
+contrast	O
+visual	O
+acuity	O
+(	O
+HCVA	O
+and	O
+LCVA	O
+)	O
+","	O
+Pelli	O
+-	O
+Robson	O
+contrast	O
+threshold	O
+(	O
+CT	O
+)	O
+and	O
+Goldmann	O
+perimetry	O
+(	O
+FIELDS	O
+)	O
+.	O
+	
+Useful	O
+Field	O
+of	O
+View	O
+(	O
+UFOV	O
+-	O
+-	O
+a	O
+test	O
+of	O
+visual	O
+attention	O
+)	O
+was	O
+also	O
+undertaken	O
+.	O
+	
+The	O
+mean	O
+differences	O
+in	O
+the	O
+pre	O
+-	O
+and	O
+post	O
+-	O
+dilatation	O
+measurements	O
+were	O
+tested	O
+for	O
+statistical	O
+significance	O
+at	O
+the	O
+95	O
+%	O
+level	O
+using	O
+one	O
+-	O
+tail	O
+paired	O
+t	O
+-	O
+tests	O
+.	O
+	
+RESULTS	O
+:	O
+Pupillary	B-NP
+dilation	I-NP
+resulted	O
+in	O
+a	O
+statistically	O
+significant	O
+deterioration	O
+in	O
+CT	O
+and	O
+HCVA	O
+only	O
+.	O
+	
+Five	O
+of	O
+12	O
+drivers	O
+also	O
+exhibited	O
+deterioration	O
+in	O
+LCVA	O
+","	O
+CT	O
+and	O
+RT	O
+.	O
+	
+Little	O
+evidence	O
+emerged	O
+for	O
+deterioration	O
+in	O
+FIELDS	O
+and	O
+UFOV	O
+.	O
+	
+Also	O
+","	O
+7	O
+of	O
+12	O
+drivers	O
+appeared	O
+to	O
+adjust	O
+their	O
+driving	O
+behaviour	O
+by	O
+reducing	O
+their	O
+speed	O
+on	O
+the	O
+driving	O
+simulator	O
+","	O
+leading	O
+to	O
+improved	O
+steering	O
+accuracy	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Pupillary	B-NP
+dilation	I-NP
+may	O
+lead	O
+to	O
+a	O
+decrease	O
+in	O
+vision	O
+and	O
+daylight	O
+driving	O
+performance	O
+in	O
+young	O
+people	O
+.	O
+	
+A	O
+larger	O
+study	O
+","	O
+including	O
+a	O
+broader	O
+spectrum	O
+of	O
+subjects	O
+","	O
+is	O
+warranted	O
+before	O
+guidelines	O
+can	O
+be	O
+recommended	O
+.	O
+	
+A	O
+case	O
+of	O
+isotretinoin	B-NP
+embryopathy	I-NP
+with	O
+bilateral	O
+anotia	B-NP
+and	O
+Taussig	B-NP
+-	I-NP
+Bing	I-NP
+malformation	I-NP
+.	O
+	
+We	O
+report	O
+a	O
+newborn	O
+infant	O
+with	O
+multiple	O
+congenital	O
+anomalies	O
+(	O
+anotia	B-NP
+and	O
+Taussig	B-NP
+-	I-NP
+Bing	I-NP
+malformation	I-NP
+)	O
+due	O
+to	O
+exposure	O
+to	O
+isotretinoin	O
+within	O
+the	O
+first	O
+trimester	O
+.	O
+	
+In	O
+this	O
+paper	O
+we	O
+aim	O
+to	O
+draw	O
+to	O
+the	O
+fact	O
+that	O
+caution	O
+is	O
+needed	O
+when	O
+prescribing	O
+vitamin	O
+A	O
+-	O
+containing	O
+drugs	O
+to	O
+women	O
+of	O
+childbearing	O
+years	O
+.	O
+	
+Effect	O
+of	O
+methoxamine	O
+on	O
+maximum	O
+urethral	O
+pressure	O
+in	O
+women	O
+with	O
+genuine	O
+stress	B-NP
+incontinence	I-NP
+:	O
+a	O
+placebo	O
+-	O
+controlled	O
+","	O
+double	O
+-	O
+blind	O
+crossover	O
+study	O
+.	O
+	
+The	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+evaluate	O
+the	O
+potential	O
+role	O
+for	O
+a	O
+selective	O
+alpha1	O
+-	O
+adrenoceptor	O
+agonist	O
+in	O
+the	O
+treatment	O
+of	O
+urinary	B-NP
+stress	I-NP
+incontinence	I-NP
+.	O
+	
+A	O
+randomised	O
+","	O
+double	O
+-	O
+blind	O
+","	O
+placebo	O
+-	O
+controlled	O
+","	O
+crossover	O
+study	O
+design	O
+was	O
+employed	O
+.	O
+	
+Half	O
+log	O
+incremental	O
+doses	O
+of	O
+intravenous	O
+methoxamine	O
+or	O
+placebo	O
+(	O
+saline	O
+)	O
+were	O
+administered	O
+to	O
+a	O
+group	O
+of	O
+women	O
+with	O
+genuine	O
+stress	B-NP
+incontinence	I-NP
+while	O
+measuring	O
+maximum	O
+urethral	O
+pressure	O
+(	O
+MUP	O
+)	O
+","	O
+blood	O
+pressure	O
+","	O
+heart	O
+rate	O
+","	O
+and	O
+symptomatic	O
+side	O
+effects	O
+.	O
+	
+Methoxamine	O
+evoked	O
+non	O
+-	O
+significant	O
+increases	O
+in	O
+MUP	O
+and	O
+diastolic	O
+blood	O
+pressure	O
+but	O
+caused	O
+a	B-NP
+significant	I-NP
+rise	I-NP
+in	I-NP
+systolic	I-NP
+blood	I-NP
+pressure	I-NP
+and	O
+significant	O
+fall	O
+in	O
+heart	O
+rate	O
+at	O
+maximum	O
+dosage	O
+.	O
+	
+Systemic	O
+side	O
+effects	O
+including	O
+piloerection	O
+","	O
+headache	B-NP
+","	O
+and	O
+cold	O
+extremities	O
+were	O
+experienced	O
+in	O
+all	O
+subjects	O
+.	O
+	
+The	O
+results	O
+indicate	O
+that	O
+the	O
+clinical	O
+usefulness	O
+of	O
+direct	O
+","	O
+peripherally	O
+acting	O
+sub	O
+-	O
+type	O
+-	O
+selective	O
+alpha1	O
+-	O
+adrenoceptor	O
+agonists	O
+in	O
+the	O
+medical	O
+treatment	O
+of	O
+stress	B-NP
+incontinence	I-NP
+may	O
+be	O
+limited	O
+by	O
+associated	O
+piloerection	O
+and	O
+cardiovascular	O
+side	O
+effects	O
+.	O
+	
+Hyperglycemic	B-NP
+effect	O
+of	O
+amino	O
+compounds	O
+structurally	O
+related	O
+to	O
+caproate	O
+in	O
+rats	O
+.	O
+	
+The	O
+chronic	O
+feeding	O
+of	O
+small	O
+amounts	O
+(	O
+0	O
+.	O
+3	O
+-	O
+3	O
+%	O
+of	O
+diet	O
+weight	O
+)	O
+of	O
+certain	O
+amino	O
+derivatives	O
+of	O
+caproate	O
+resulted	O
+in	O
+hyperglycemia	B-NP
+","	O
+an	O
+elevated	O
+glucose	O
+tolerance	O
+curve	O
+and	O
+","	O
+occasionally	O
+","	O
+glucosuria	B-NP
+.	O
+	
+Effective	O
+compounds	O
+included	O
+norleucine	O
+","	O
+norvaline	O
+","	O
+glutamate	O
+","	O
+epsilon	O
+-	O
+aminocaproate	O
+","	O
+methionine	O
+","	O
+and	O
+leucine	O
+.	O
+	
+Toleration	O
+of	O
+high	O
+doses	O
+of	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitors	O
+in	O
+patients	O
+with	O
+chronic	O
+heart	B-NP
+failure	I-NP
+:	O
+results	O
+from	O
+the	O
+ATLAS	O
+trial	O
+.	O
+	
+The	O
+Assessment	O
+of	O
+Treatment	O
+with	O
+Lisinopril	O
+and	O
+Survival	O
+.	O
+	
+BACKGROUND	O
+:	O
+Treatment	O
+with	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+inhibitors	O
+reduces	O
+mortality	O
+and	O
+morbidity	O
+in	O
+patients	O
+with	O
+chronic	O
+heart	B-NP
+failure	I-NP
+(	O
+CHF	B-NP
+)	O
+","	O
+but	O
+most	O
+affected	O
+patients	O
+are	O
+not	O
+receiving	O
+these	O
+agents	O
+or	O
+are	O
+being	O
+treated	O
+with	O
+doses	O
+lower	O
+than	O
+those	O
+found	O
+to	O
+be	O
+efficacious	O
+in	O
+trials	O
+","	O
+primarily	O
+because	O
+of	O
+concerns	O
+about	O
+the	O
+safety	O
+and	O
+tolerability	O
+of	O
+these	O
+agents	O
+","	O
+especially	O
+at	O
+the	O
+recommended	O
+doses	O
+.	O
+	
+The	O
+present	O
+study	O
+examines	O
+the	O
+safety	O
+and	O
+tolerability	O
+of	O
+high	O
+-	O
+compared	O
+with	O
+low	O
+-	O
+dose	O
+lisinopril	O
+in	O
+CHF	B-NP
+.	O
+	
+METHODS	O
+:	O
+The	O
+Assessment	O
+of	O
+Lisinopril	O
+and	O
+Survival	O
+study	O
+was	O
+a	O
+multicenter	O
+","	O
+randomized	O
+","	O
+double	O
+-	O
+blind	O
+trial	O
+in	O
+which	O
+patients	O
+with	O
+or	O
+without	O
+previous	O
+ACE	O
+inhibitor	O
+treatment	O
+were	O
+stabilized	O
+receiving	O
+medium	O
+-	O
+dose	O
+lisinopril	O
+(	O
+12	O
+.	O
+5	O
+or	O
+15	O
+.	O
+0	O
+mg	O
+once	O
+daily	O
+[	O
+OD	O
+]	O
+)	O
+for	O
+2	O
+to	O
+4	O
+weeks	O
+and	O
+then	O
+randomized	O
+to	O
+high	O
+-	O
+(	O
+35	O
+.	O
+0	O
+or	O
+32	O
+.	O
+5	O
+mg	O
+OD	O
+)	O
+or	O
+low	O
+-	O
+dose	O
+(	O
+5	O
+.	O
+0	O
+or	O
+2	O
+.	O
+5	O
+mg	O
+OD	O
+)	O
+groups	O
+.	O
+	
+Patients	O
+with	O
+New	O
+York	O
+Heart	O
+Association	O
+classes	O
+II	O
+to	O
+IV	O
+CHF	B-NP
+and	O
+left	O
+ventricular	O
+ejection	O
+fractions	O
+of	O
+no	O
+greater	O
+than	O
+0	O
+.	O
+30	O
+(	O
+n	O
+=	O
+3164	O
+)	O
+were	O
+randomized	O
+and	O
+followed	O
+up	O
+for	O
+a	O
+median	O
+of	O
+46	O
+months	O
+.	O
+	
+We	O
+examined	O
+the	O
+occurrence	O
+of	O
+adverse	O
+events	O
+and	O
+the	O
+need	O
+for	O
+discontinuation	O
+and	O
+dose	O
+reduction	O
+during	O
+treatment	O
+","	O
+with	O
+a	O
+focus	O
+on	O
+hypotension	B-NP
+and	O
+renal	B-NP
+dysfunction	I-NP
+.	O
+	
+RESULTS	O
+:	O
+Of	O
+405	O
+patients	O
+not	O
+previously	O
+receiving	O
+an	O
+ACE	O
+inhibitor	O
+","	O
+doses	O
+in	O
+only	O
+4	O
+.	O
+2	O
+%	O
+could	O
+not	O
+be	O
+titrated	O
+to	O
+the	O
+medium	O
+doses	O
+required	O
+for	O
+randomization	O
+because	O
+of	O
+symptoms	O
+possibly	O
+related	O
+to	O
+hypotension	B-NP
+(	O
+2	O
+.	O
+0	O
+%	O
+)	O
+or	O
+because	O
+of	O
+renal	B-NP
+dysfunction	I-NP
+or	O
+hyperkalemia	B-NP
+(	O
+2	O
+.	O
+3	O
+%	O
+)	O
+.	O
+	
+Doses	O
+in	O
+more	O
+than	O
+90	O
+%	O
+of	O
+randomized	O
+patients	O
+in	O
+the	O
+high	O
+-	O
+and	O
+low	O
+-	O
+dose	O
+groups	O
+were	O
+titrated	O
+to	O
+their	O
+assigned	O
+target	O
+","	O
+and	O
+the	O
+mean	O
+doses	O
+of	O
+blinded	O
+medication	O
+in	O
+both	O
+groups	O
+remained	O
+similar	O
+throughout	O
+the	O
+study	O
+.	O
+	
+Withdrawals	O
+occurred	O
+in	O
+27	O
+.	O
+1	O
+%	O
+of	O
+the	O
+high	O
+-	O
+and	O
+30	O
+.	O
+7	O
+%	O
+of	O
+the	O
+low	O
+-	O
+dose	O
+groups	O
+.	O
+	
+Subgroups	O
+presumed	O
+to	O
+be	O
+at	O
+higher	O
+risk	O
+for	O
+ACE	O
+inhibitor	O
+intolerance	O
+(	O
+blood	O
+pressure	O
+","	O
+<	O
+120	O
+mm	O
+Hg	O
+;	O
+creatinine	O
+","	O
+>	O
+or	O
+=	O
+132	O
+.	O
+6	O
+micromol	O
+/	O
+L	O
+[	O
+>	O
+or	O
+=	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+dL	O
+]	O
+;	O
+age	O
+","	O
+>	O
+or	O
+=	O
+70	O
+years	O
+;	O
+and	O
+patients	O
+with	O
+diabetes	B-NP
+)	O
+generally	O
+tolerated	O
+the	O
+high	O
+-	O
+dose	O
+strategy	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+These	O
+findings	O
+demonstrate	O
+that	O
+ACE	O
+inhibitor	O
+therapy	O
+in	O
+most	O
+patients	O
+with	O
+CHF	B-NP
+can	O
+be	O
+successfully	O
+titrated	O
+to	O
+and	O
+maintained	O
+at	O
+high	O
+doses	O
+","	O
+and	O
+that	O
+more	O
+aggressive	O
+use	O
+of	O
+these	O
+agents	O
+is	O
+warranted	O
+.	O
+	
+Cocaine	O
+","	O
+ethanol	O
+","	O
+and	O
+cocaethylene	O
+cardiotoxity	B-NP
+in	O
+an	O
+animal	O
+model	O
+of	O
+cocaine	B-NP
+and	I-NP
+ethanol	I-NP
+abuse	I-NP
+.	O
+	
+OBJECTIVES	O
+:	O
+Simultaneous	O
+abuse	B-NP
+of	I-NP
+cocaine	I-NP
+and	I-NP
+ethanol	I-NP
+affects	O
+12	O
+million	O
+Americans	O
+annually	O
+.	O
+	
+In	O
+combination	O
+","	O
+these	O
+substances	O
+are	O
+substantially	O
+more	O
+toxic	O
+than	O
+either	O
+drug	O
+alone	O
+.	O
+	
+Their	O
+combined	O
+cardiac	B-NP
+toxicity	I-NP
+may	O
+be	O
+due	O
+to	O
+independent	O
+effects	O
+of	O
+each	O
+drug	O
+;	O
+however	O
+","	O
+they	O
+may	O
+also	O
+be	O
+due	O
+to	O
+cocaethylene	O
+(	O
+CE	O
+)	O
+","	O
+a	O
+cocaine	O
+metabolite	O
+formed	O
+only	O
+in	O
+the	O
+presence	O
+of	O
+ethanol	O
+.	O
+	
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+delineate	O
+the	O
+role	O
+of	O
+CE	O
+in	O
+the	O
+combined	O
+cardiotoxicity	B-NP
+of	O
+cocaine	O
+and	O
+ethanol	O
+in	O
+a	O
+model	O
+simulating	O
+their	O
+abuse	O
+.	O
+	
+METHODS	O
+:	O
+Twenty	O
+-	O
+three	O
+dogs	O
+were	O
+randomized	O
+to	O
+receive	O
+either	O
+1	O
+)	O
+three	O
+intravenous	O
+(	O
+IV	O
+)	O
+boluses	O
+of	O
+cocaine	O
+7	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+with	O
+ethanol	O
+(	O
+1	O
+g	O
+/	O
+kg	O
+)	O
+as	O
+an	O
+IV	O
+infusion	O
+(	O
+C	O
++	O
+E	O
+","	O
+n	O
+=	O
+8	O
+)	O
+","	O
+2	O
+)	O
+three	O
+cocaine	O
+boluses	O
+only	O
+(	O
+C	O
+","	O
+n	O
+=	O
+6	O
+)	O
+","	O
+3	O
+)	O
+ethanol	O
+infusion	O
+only	O
+(	O
+E	O
+","	O
+n	O
+=	O
+5	O
+)	O
+","	O
+or	O
+4	O
+)	O
+placebo	O
+boluses	O
+and	O
+infusion	O
+(	O
+n	O
+=	O
+4	O
+)	O
+.	O
+	
+Hemodynamic	O
+measurements	O
+","	O
+electrocardiograms	O
+","	O
+and	O
+serum	O
+drug	O
+concentrations	O
+were	O
+obtained	O
+at	O
+baseline	O
+","	O
+and	O
+then	O
+at	O
+fixed	O
+time	O
+intervals	O
+after	O
+each	O
+drug	O
+was	O
+administered	O
+.	O
+	
+RESULTS	O
+:	O
+Two	O
+of	O
+eight	O
+dogs	O
+in	O
+the	O
+C	O
++	O
+E	O
+group	O
+experienced	O
+cardiovascular	B-NP
+collapse	I-NP
+.	O
+	
+The	O
+most	O
+dramatic	O
+hemodynamic	O
+changes	O
+occurred	O
+after	O
+each	O
+cocaine	O
+bolus	O
+in	O
+the	O
+C	O
++	O
+E	O
+and	O
+C	O
+only	O
+groups	O
+;	O
+however	O
+","	O
+persistent	O
+hemodynamic	O
+changes	O
+occurred	O
+in	O
+the	O
+C	O
++	O
+E	O
+group	O
+.	O
+	
+Peak	O
+CE	O
+levels	O
+were	O
+associated	O
+with	O
+a	O
+45	O
+%	O
+(	O
+SD	O
++	O
+/	O
+-	O
+22	O
+%	O
+","	O
+95	O
+%	O
+CI	O
+=	O
+22	O
+%	O
+to	O
+69	O
+%	O
+)	O
+decrease	B-NP
+in	I-NP
+cardiac	I-NP
+output	I-NP
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+","	O
+a	O
+56	O
+%	O
+(	O
+SD	O
++	O
+/	O
+-	O
+23	O
+%	O
+","	O
+95	O
+%	O
+CI	O
+=	O
+32	O
+%	O
+to	O
+80	O
+%	O
+)	O
+decrease	O
+in	O
+dP	O
+/	O
+dt	O
+(	O
+max	O
+)	O
+(	O
+p	O
+<	O
+.	O
+6	O
+)	O
+","	O
+and	O
+a	O
+23	O
+%	O
+(	O
+SD	O
++	O
+/	O
+-	O
+15	O
+%	O
+","	O
+95	O
+%	O
+CI	O
+=	O
+7	O
+%	O
+to	O
+49	O
+%	O
+)	O
+decrease	O
+in	O
+SVO	O
+(	O
+2	O
+)	O
+(	O
+p	O
+<	O
+0	O
+.	O
+25	O
+)	O
+.	O
+	
+Ventricular	B-NP
+arrhythmias	I-NP
+were	O
+primarily	O
+observed	O
+in	O
+the	O
+C	O
++	O
+E	O
+group	O
+","	O
+in	O
+which	O
+four	O
+of	O
+eight	O
+dogs	O
+experienced	O
+ventricular	B-NP
+tachycardia	I-NP
+.	O
+	
+CONCLUSIONS	O
+:	O
+Cocaine	O
+and	O
+ethanol	O
+in	O
+combination	O
+were	O
+more	O
+toxic	O
+than	O
+either	O
+substance	O
+alone	O
+.	O
+	
+Co	O
+-	O
+administration	O
+resulted	O
+in	O
+prolonged	O
+cardiac	B-NP
+toxicity	I-NP
+and	O
+was	O
+dysrhythmogenic	O
+.	O
+	
+Peak	O
+serum	O
+cocaethylene	O
+concentrations	O
+were	O
+associated	O
+with	O
+prolonged	O
+myocardial	B-NP
+depression	I-NP
+.	O
+	
+Worsening	O
+of	O
+Parkinsonism	B-NP
+after	O
+the	O
+use	O
+of	O
+veralipride	O
+for	O
+treatment	O
+of	O
+menopause	O
+:	O
+case	O
+report	O
+.	O
+	
+We	O
+describe	O
+a	O
+female	O
+patient	O
+with	O
+stable	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+who	O
+has	O
+shown	O
+a	O
+marked	O
+worsening	O
+of	O
+her	O
+motor	O
+functions	O
+following	O
+therapy	O
+of	O
+menopause	O
+related	O
+symptoms	O
+with	O
+veralipride	O
+","	O
+as	O
+well	O
+as	O
+the	O
+improvement	O
+of	O
+her	O
+symptoms	O
+back	O
+to	O
+baseline	O
+after	O
+discontinuation	O
+of	O
+the	O
+drug	O
+.	O
+	
+We	O
+emphasize	O
+the	O
+anti	O
+-	O
+dopaminergic	O
+effect	O
+of	O
+veralipride	O
+.	O
+	
+Viracept	O
+and	O
+irregular	B-NP
+heartbeat	I-NP
+warning	O
+.	O
+	
+A	O
+group	O
+of	O
+doctors	O
+in	O
+Boston	O
+warn	O
+that	O
+the	O
+protease	O
+inhibitor	O
+Viracept	O
+may	O
+cause	O
+an	O
+irregular	B-NP
+heart	I-NP
+beat	I-NP
+","	O
+known	O
+as	O
+bradycardia	B-NP
+","	O
+in	O
+people	O
+with	O
+HIV	O
+.	O
+	
+Bradycardia	B-NP
+occurred	O
+in	O
+a	O
+45	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+who	O
+was	O
+Viracept	O
+in	O
+combination	O
+with	O
+other	O
+anti	O
+-	O
+HIV	O
+drugs	O
+.	O
+	
+The	O
+symptoms	O
+ceased	O
+after	O
+switching	O
+to	O
+another	O
+drug	O
+combination	O
+.	O
+	
+Frequency	O
+of	O
+appearance	O
+of	O
+myeloperoxidase	O
+-	O
+antineutrophil	O
+cytoplasmic	O
+antibody	O
+(	O
+MPO	O
+-	O
+ANCA	O
+)	O
+in	O
+Graves	B-NP
+'	I-NP
+disease	I-NP
+patients	O
+treated	O
+with	O
+propylthiouracil	O
+and	O
+the	O
+relationship	O
+between	O
+MPO	O
+-	O
+ANCA	O
+and	O
+clinical	O
+manifestations	O
+.	O
+	
+OBJECTIVE	O
+:	O
+Myeloperoxidase	O
+antineutrophil	O
+cytoplasmic	O
+antibody	O
+(	O
+MPO	O
+-	O
+ANCA	O
+)	O
+-	O
+positive	O
+vasculitis	B-NP
+has	O
+been	O
+reported	O
+in	O
+patients	O
+with	O
+Graves	B-NP
+'	I-NP
+disease	I-NP
+who	O
+were	O
+treated	O
+with	O
+propylthiouracil	O
+(	O
+PTU	O
+)	O
+.	O
+	
+The	O
+appearance	O
+of	O
+MPO	O
+-	O
+ANCA	O
+in	O
+these	O
+cases	O
+was	O
+suspected	O
+of	O
+being	O
+related	O
+to	O
+PTU	O
+because	O
+the	O
+titres	O
+of	O
+MPO	O
+-	O
+ANCA	O
+decreased	O
+when	O
+PTU	O
+was	O
+stopped	O
+.	O
+	
+Nevertheless	O
+","	O
+there	O
+have	O
+been	O
+no	O
+studies	O
+on	O
+the	O
+temporal	O
+relationship	O
+between	O
+the	O
+appearance	O
+of	O
+MPO	O
+-	O
+ANCA	O
+and	O
+vasculitis	B-NP
+during	O
+PTU	O
+therapy	O
+","	O
+or	O
+on	O
+the	O
+incidence	O
+of	O
+MPO	O
+-	O
+ANCA	O
+in	O
+untreated	O
+Graves	B-NP
+'	I-NP
+disease	I-NP
+patients	O
+.	O
+	
+Therefore	O
+","	O
+we	O
+sought	O
+to	O
+address	O
+these	O
+parameters	O
+in	O
+patients	O
+with	O
+Graves	B-NP
+'	I-NP
+disease	I-NP
+.	O
+	
+PATIENTS	O
+:	O
+We	O
+investigated	O
+102	O
+untreated	O
+patients	O
+with	O
+hyperthyroidism	B-NP
+due	O
+to	O
+Graves	B-NP
+'	I-NP
+disease	I-NP
+for	O
+the	O
+presence	O
+of	O
+MPO	O
+-	O
+ANCA	O
+","	O
+and	O
+for	O
+the	O
+development	O
+vasculitis	B-NP
+after	O
+starting	O
+PTU	O
+therapy	O
+.	O
+	
+Twenty	O
+-	O
+nine	O
+of	O
+them	O
+were	O
+later	O
+excluded	O
+because	O
+of	O
+adverse	O
+effects	O
+of	O
+PTU	O
+or	O
+because	O
+the	O
+observation	O
+period	O
+was	O
+less	O
+than	O
+3	O
+months	O
+.	O
+	
+The	O
+remaining	O
+73	O
+patients	O
+(	O
+55	O
+women	O
+and	O
+18	O
+men	O
+)	O
+","	O
+all	O
+of	O
+whom	O
+were	O
+examined	O
+for	O
+more	O
+than	O
+3	O
+months	O
+","	O
+were	O
+adopted	O
+as	O
+the	O
+subjects	O
+of	O
+the	O
+investigation	O
+.	O
+	
+The	O
+median	O
+observation	O
+period	O
+was	O
+23	O
+.	O
+6	O
+months	O
+(	O
+range	O
+:	O
+3	O
+-	O
+37	O
+months	O
+)	O
+.	O
+	
+MEASUREMENTS	O
+:	O
+MPO	O
+-	O
+ANCA	O
+was	O
+measured	O
+at	O
+intervals	O
+of	O
+2	O
+-	O
+6	O
+months	O
+.	O
+	
+RESULTS	O
+:	O
+Before	O
+treatment	O
+","	O
+the	O
+MPO	O
+-	O
+ANCA	O
+titres	O
+of	O
+all	O
+102	O
+untreated	O
+Graves	B-NP
+'	I-NP
+disease	I-NP
+patients	O
+were	O
+within	O
+the	O
+reference	O
+range	O
+(	O
+below	O
+10	O
+U	O
+/	O
+ml	O
+)	O
+.	O
+	
+Three	O
+(	O
+4	O
+.	O
+1	O
+%	O
+)	O
+of	O
+the	O
+73	O
+patients	O
+were	O
+positive	O
+for	O
+MPO	O
+-	O
+ANCA	O
+at	O
+13	O
+","	O
+16	O
+and	O
+17	O
+months	O
+","	O
+respectively	O
+","	O
+after	O
+the	O
+start	O
+of	O
+PTU	O
+therapy	O
+.	O
+	
+In	O
+two	O
+of	O
+them	O
+","	O
+the	O
+MPO	O
+-	O
+ANCA	O
+titres	O
+transiently	O
+increased	O
+to	O
+12	O
+.	O
+8	O
+and	O
+15	O
+.	O
+0	O
+U	O
+/	O
+ml	O
+","	O
+respectively	O
+","	O
+despite	O
+continued	O
+PTU	O
+therapy	O
+","	O
+but	O
+no	O
+vasculitic	B-NP
+disorders	I-NP
+developed	O
+.	O
+	
+In	O
+the	O
+third	O
+patient	O
+","	O
+the	O
+MPO	O
+-	O
+ANCA	O
+titre	O
+increased	O
+to	O
+204	O
+U	O
+/	O
+ml	O
+and	O
+she	O
+developed	O
+a	O
+higher	O
+fever	B-NP
+","	O
+oral	B-NP
+ulcers	I-NP
+and	O
+polyarthralgia	B-NP
+","	O
+but	O
+the	O
+symptoms	O
+resolved	O
+2	O
+weeks	O
+after	O
+stopping	O
+PTU	O
+therapy	O
+","	O
+and	O
+the	O
+MPO	O
+-	O
+ANCA	O
+titre	O
+decreased	O
+to	O
+20	O
+.	O
+7	O
+U	O
+/	O
+ml	O
+by	O
+4	O
+months	O
+after	O
+discontinuing	O
+PTU	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+PTU	O
+therapy	O
+may	O
+be	O
+related	O
+to	O
+the	O
+appearance	O
+of	O
+MPO	O
+-	O
+ANCA	O
+","	O
+but	O
+MPO	O
+-	O
+ANCA	O
+does	O
+not	O
+appear	O
+to	O
+be	O
+closely	O
+related	O
+to	O
+vasculitis	B-NP
+.	O
+	
+Prevalence	O
+of	O
+heart	B-NP
+disease	I-NP
+in	O
+asymptomatic	O
+chronic	O
+cocaine	O
+users	O
+.	O
+	
+To	O
+determine	O
+the	O
+prevalence	O
+of	O
+heart	B-NP
+disease	I-NP
+in	O
+outpatient	O
+young	O
+asymptomatic	O
+chronic	O
+cocaine	O
+users	O
+","	O
+35	O
+cocaine	O
+users	O
+and	O
+32	O
+age	O
+-	O
+matched	O
+controls	O
+underwent	O
+resting	O
+and	O
+exercise	O
+electrocardiography	O
+(	O
+ECG	O
+)	O
+and	O
+Doppler	O
+echocardiography	O
+.	O
+	
+Findings	O
+consistent	O
+with	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+were	O
+detected	O
+in	O
+12	O
+(	O
+34	O
+%	O
+)	O
+patients	O
+and	O
+3	O
+(	O
+9	O
+%	O
+)	O
+controls	O
+(	O
+p	O
+=	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Decreased	O
+left	O
+ventricular	O
+systolic	O
+function	O
+was	O
+demonstrated	O
+in	O
+5	O
+(	O
+14	O
+%	O
+)	O
+patients	O
+","	O
+but	O
+in	O
+none	O
+of	O
+the	O
+controls	O
+(	O
+p	O
+=	O
+0	O
+.	O
+55	O
+)	O
+.	O
+	
+Finally	O
+","	O
+resting	O
+and	O
+peak	O
+exercise	O
+abnormal	B-NP
+left	I-NP
+ventricular	I-NP
+filling	I-NP
+was	O
+detected	O
+in	O
+38	O
+and	O
+35	O
+%	O
+of	O
+patients	O
+as	O
+compared	O
+to	O
+19	O
+and	O
+9	O
+%	O
+of	O
+controls	O
+","	O
+respectively	O
+(	O
+p	O
+=	O
+0	O
+.	O
+11	O
+and	O
+0	O
+.	O
+2	O
+","	O
+respectively	O
+)	O
+.	O
+	
+We	O
+conclude	O
+that	O
+coronary	B-NP
+artery	I-NP
+or	I-NP
+myocardial	I-NP
+disease	I-NP
+is	O
+common	O
+(	O
+38	O
+%	O
+)	O
+in	O
+young	O
+asymptomatic	O
+chronic	O
+cocaine	O
+users	O
+.	O
+	
+Therefore	O
+","	O
+screening	O
+ECG	O
+and	O
+echocardiography	O
+may	O
+be	O
+warranted	O
+in	O
+these	O
+patients	O
+.	O
+	
+Cardioprotective	O
+effects	O
+of	O
+Picrorrhiza	O
+kurroa	O
+against	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	O
+stress	O
+in	O
+rats	O
+.	O
+	
+The	O
+cardioprotective	O
+effect	O
+of	O
+the	O
+ethanol	O
+extract	O
+of	O
+Picrorrhiza	O
+kurroa	O
+rhizomes	O
+and	O
+roots	O
+(	O
+PK	O
+)	O
+on	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B-NP
+infarction	I-NP
+in	O
+rats	O
+with	O
+respect	O
+to	O
+lipid	O
+metabolism	O
+in	O
+serum	O
+and	O
+heart	O
+tissue	O
+has	O
+been	O
+investigated	O
+.	O
+	
+Oral	O
+pre	O
+-	O
+treatment	O
+with	O
+PK	O
+(	O
+80	O
+mg	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+day	O
+(	O
+-	O
+1	O
+)	O
+for	O
+15	O
+days	O
+)	O
+significantly	O
+prevented	O
+the	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B-NP
+infarction	I-NP
+and	O
+maintained	O
+the	O
+rats	O
+at	O
+near	O
+normal	O
+status	O
+.	O
+	
+Phase	O
+2	O
+early	O
+afterdepolarization	O
+as	O
+a	O
+trigger	O
+of	O
+polymorphic	O
+ventricular	B-NP
+tachycardia	I-NP
+in	O
+acquired	O
+long	B-NP
+-	I-NP
+QT	I-NP
+syndrome	I-NP
+:	O
+direct	O
+evidence	O
+from	O
+intracellular	O
+recordings	O
+in	O
+the	O
+intact	O
+left	O
+ventricular	O
+wall	O
+.	O
+	
+BACKGROUND	O
+:	O
+This	O
+study	O
+examined	O
+the	O
+role	O
+of	O
+phase	O
+2	O
+early	O
+afterdepolarization	O
+(	O
+EAD	O
+)	O
+in	O
+producing	O
+a	O
+trigger	O
+to	O
+initiate	O
+torsade	B-NP
+de	I-NP
+pointes	I-NP
+(	O
+TdP	B-NP
+)	O
+with	O
+QT	B-NP
+prolongation	I-NP
+induced	O
+by	O
+dl	O
+-	O
+sotalol	O
+and	O
+azimilide	O
+.	O
+	
+The	O
+contribution	O
+of	O
+transmural	O
+dispersion	O
+of	O
+repolarization	O
+(	O
+TDR	O
+)	O
+to	O
+transmural	O
+propagation	O
+of	O
+EAD	O
+and	O
+the	O
+maintenance	O
+of	O
+TdP	B-NP
+was	O
+also	O
+evaluated	O
+.	O
+	
+METHODS	O
+AND	O
+RESULTS	O
+:	O
+Transmembrane	O
+action	O
+potentials	O
+from	O
+epicardium	O
+","	O
+midmyocardium	O
+","	O
+and	O
+endocardium	O
+were	O
+recorded	O
+simultaneously	O
+","	O
+together	O
+with	O
+a	O
+transmural	O
+ECG	O
+","	O
+in	O
+arterially	O
+perfused	O
+canine	O
+and	O
+rabbit	O
+left	O
+ventricular	O
+preparations	O
+.	O
+	
+dl	O
+-	O
+Sotalol	O
+preferentially	O
+prolonged	O
+action	O
+potential	O
+duration	O
+(	O
+APD	O
+)	O
+in	O
+M	O
+cells	O
+dose	O
+-	O
+dependently	O
+(	O
+1	O
+to	O
+100	O
+micromol	O
+/	O
+L	O
+)	O
+","	O
+leading	O
+to	O
+QT	B-NP
+prolongation	I-NP
+and	O
+an	O
+increase	O
+in	O
+TDR	O
+.	O
+	
+Azimilide	O
+","	O
+however	O
+","	O
+significantly	O
+prolonged	O
+APD	O
+and	O
+QT	O
+interval	O
+at	O
+concentrations	O
+from	O
+0	O
+.	O
+1	O
+to	O
+10	O
+micromol	O
+/	O
+L	O
+but	O
+shortened	O
+them	O
+at	O
+30	O
+micromol	O
+/	O
+L	O
+.	O
+	
+Unlike	O
+dl	O
+-	O
+sotalol	O
+","	O
+azimilide	O
+(	O
+>	O
+3	O
+micromol	O
+/	O
+L	O
+)	O
+increased	O
+epicardial	O
+APD	O
+markedly	O
+","	O
+causing	O
+a	O
+diminished	O
+TDR	O
+.	O
+	
+Although	O
+both	O
+dl	O
+-	O
+sotalol	O
+and	O
+azimilide	O
+rarely	O
+induced	O
+EADs	O
+in	O
+canine	O
+left	O
+ventricles	O
+","	O
+they	O
+produced	O
+frequent	O
+EADs	O
+in	O
+rabbits	O
+","	O
+in	O
+which	O
+more	O
+pronounced	O
+QT	B-NP
+prolongation	I-NP
+was	O
+seen	O
+.	O
+	
+An	O
+increase	O
+in	O
+TDR	O
+by	O
+dl	O
+-	O
+sotalol	O
+facilitated	O
+transmural	O
+propagation	O
+of	O
+EADs	O
+that	O
+initiated	O
+multiple	O
+episodes	O
+of	O
+spontaneous	O
+TdP	B-NP
+in	O
+3	O
+of	O
+6	O
+rabbit	O
+left	O
+ventricles	O
+.	O
+	
+Of	O
+note	O
+","	O
+although	O
+azimilide	O
+(	O
+3	O
+to	O
+10	O
+micromol	O
+/	O
+L	O
+)	O
+increased	O
+APD	O
+more	O
+than	O
+dl	O
+-	O
+sotalol	O
+","	O
+its	O
+EADs	O
+often	O
+failed	O
+to	O
+propagate	O
+transmurally	O
+","	O
+probably	O
+because	O
+of	O
+a	O
+diminished	O
+TDR	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+This	O
+study	O
+provides	O
+the	O
+first	O
+direct	O
+evidence	O
+from	O
+intracellular	O
+action	O
+potential	O
+recordings	O
+that	O
+phase	O
+2	O
+EAD	O
+can	O
+be	O
+generated	O
+from	O
+intact	O
+ventricular	O
+wall	O
+and	O
+produce	O
+a	O
+trigger	O
+to	O
+initiate	O
+the	O
+onset	O
+of	O
+TdP	B-NP
+under	O
+QT	B-NP
+prolongation	I-NP
+.	O
+	
+A	O
+pilot	O
+study	O
+to	O
+assess	O
+the	O
+safety	O
+of	O
+dobutamine	O
+stress	O
+echocardiography	O
+in	O
+the	O
+emergency	O
+department	O
+evaluation	O
+of	O
+cocaine	O
+-	O
+associated	O
+chest	B-NP
+pain	I-NP
+.	O
+	
+STUDY	O
+OBJECTIVE	O
+:	O
+Chest	B-NP
+pain	I-NP
+in	O
+the	O
+setting	O
+of	O
+cocaine	O
+use	O
+poses	O
+a	O
+diagnostic	O
+dilemma	O
+.	O
+	
+Dobutamine	O
+stress	O
+echocardiography	O
+(	O
+DSE	O
+)	O
+is	O
+a	O
+widely	O
+available	O
+and	O
+sensitive	O
+test	O
+for	O
+evaluating	O
+cardiac	O
+ischemia	B-NP
+.	O
+	
+Because	O
+of	O
+the	O
+theoretical	O
+concern	O
+regarding	O
+administration	O
+of	O
+dobutamine	O
+in	O
+the	O
+setting	O
+of	O
+cocaine	O
+use	O
+","	O
+we	O
+conducted	O
+a	O
+pilot	O
+study	O
+to	O
+assess	O
+the	O
+safety	O
+of	O
+DSE	O
+in	O
+emergency	O
+department	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B-NP
+pain	I-NP
+.	O
+	
+METHODS	O
+:	O
+A	O
+prospective	O
+case	O
+series	O
+was	O
+conducted	O
+in	O
+the	O
+intensive	O
+diagnostic	O
+and	O
+treatment	O
+unit	O
+in	O
+the	O
+ED	O
+of	O
+an	O
+urban	O
+tertiary	O
+-	O
+care	O
+teaching	O
+hospital	O
+.	O
+	
+Patients	O
+were	O
+eligible	O
+for	O
+DSE	O
+if	O
+they	O
+had	O
+used	O
+cocaine	O
+within	O
+24	O
+hours	O
+preceding	O
+the	O
+onset	O
+of	O
+chest	B-NP
+pain	I-NP
+and	O
+had	O
+a	O
+normal	O
+ECG	O
+and	O
+tropinin	O
+I	O
+level	O
+.	O
+	
+Patients	O
+exhibiting	O
+signs	O
+of	O
+continuing	O
+cocaine	O
+toxicity	B-NP
+were	O
+excluded	O
+from	O
+the	O
+study	O
+.	O
+	
+All	O
+patients	O
+were	O
+admitted	O
+to	O
+the	O
+hospital	O
+for	O
+serial	O
+testing	O
+after	O
+the	O
+DSE	O
+testing	O
+in	O
+the	O
+intensive	O
+diagnostic	O
+and	O
+treatment	O
+unit	O
+.	O
+	
+RESULTS	O
+:	O
+Twenty	O
+-	O
+four	O
+patients	O
+were	O
+enrolled	O
+.	O
+	
+Two	O
+patients	O
+had	O
+inadequate	O
+resting	O
+images	O
+","	O
+one	O
+DSE	O
+was	O
+terminated	O
+because	O
+of	O
+inferior	O
+hypokinesis	B-NP
+","	O
+another	O
+DSE	O
+was	O
+terminated	O
+because	O
+of	O
+a	O
+rate	O
+-	O
+related	O
+atrial	O
+conduction	O
+deficit	O
+","	O
+and	O
+1	O
+patient	O
+did	O
+not	O
+reach	O
+the	O
+target	O
+heart	O
+rate	O
+.	O
+	
+Thus	O
+","	O
+19	O
+patients	O
+completed	O
+a	O
+DSE	O
+and	O
+reached	O
+their	O
+target	O
+heart	O
+rates	O
+.	O
+	
+None	O
+of	O
+the	O
+patients	O
+experienced	O
+signs	O
+of	O
+exaggerated	O
+adrenergic	O
+response	O
+","	O
+which	O
+was	O
+defined	O
+as	O
+a	O
+systolic	O
+blood	O
+pressure	O
+of	O
+greater	O
+than	O
+200	O
+mm	O
+Hg	O
+or	O
+the	O
+occurrence	O
+of	O
+tachydysrhythmias	B-NP
+(	O
+excluding	O
+sinus	B-NP
+tachycardia	I-NP
+)	O
+.	O
+	
+Further	O
+suggesting	O
+lack	O
+of	O
+exaggerated	O
+adrenergic	O
+response	O
+","	O
+13	O
+(	O
+65	O
+%	O
+)	O
+of	O
+20	O
+patients	O
+required	O
+supplemental	O
+atropine	O
+to	O
+reach	O
+their	O
+target	O
+heart	O
+rates	O
+.	O
+	
+CONCLUSION	O
+:	O
+No	O
+exaggerated	O
+adrenergic	O
+response	O
+was	O
+detected	O
+when	O
+dobutamine	O
+was	O
+administered	O
+to	O
+patients	O
+with	O
+cocaine	O
+-	O
+related	O
+chest	B-NP
+pain	I-NP
+.	O
+	
+Prenatal	O
+cocaine	O
+exposure	O
+and	O
+cranial	O
+sonographic	O
+findings	O
+in	O
+preterm	B-NP
+infants	I-NP
+.	O
+	
+PURPOSE	O
+:	O
+Prenatal	O
+cocaine	O
+exposure	O
+has	O
+been	O
+linked	O
+with	O
+subependymal	O
+hemorrhage	B-NP
+and	O
+the	O
+formation	O
+of	O
+cysts	B-NP
+that	O
+are	O
+detectable	O
+on	O
+cranial	O
+sonography	O
+in	O
+neonates	O
+born	O
+at	O
+term	O
+.	O
+	
+We	O
+sought	O
+to	O
+determine	O
+if	O
+prenatal	O
+cocaine	O
+exposure	O
+increases	O
+the	O
+incidence	O
+of	O
+subependymal	B-NP
+cysts	I-NP
+in	O
+preterm	B-NP
+infants	I-NP
+.	O
+	
+METHODS	O
+:	O
+We	O
+retrospectively	O
+reviewed	O
+the	O
+medical	O
+records	O
+and	O
+cranial	O
+sonograms	O
+obtained	O
+during	O
+a	O
+1	O
+-	O
+year	O
+period	O
+on	O
+122	O
+premature	B-NP
+(	I-NP
+<	I-NP
+36	I-NP
+weeks	I-NP
+of	I-NP
+gestation	I-NP
+)	I-NP
+infants	I-NP
+.	O
+	
+Infants	O
+were	O
+categorized	O
+into	O
+1	O
+of	O
+2	O
+groups	O
+:	O
+those	O
+exposed	O
+to	O
+cocaine	O
+and	O
+those	O
+not	O
+exposed	O
+to	O
+cocaine	O
+.	O
+	
+Infants	O
+were	O
+assigned	O
+to	O
+the	O
+cocaine	O
+-	O
+exposed	O
+group	O
+if	O
+there	O
+was	O
+a	O
+maternal	O
+history	O
+of	O
+cocaine	B-NP
+abuse	I-NP
+during	O
+pregnancy	O
+or	O
+if	O
+maternal	O
+or	O
+neonatal	O
+urine	O
+toxicology	O
+results	O
+were	O
+positive	O
+at	O
+the	O
+time	O
+of	O
+delivery	O
+.	O
+	
+RESULTS	O
+:	O
+Five	O
+of	O
+the	O
+122	O
+infants	O
+were	O
+excluded	O
+from	O
+the	O
+study	O
+because	O
+of	O
+insufficient	O
+medical	O
+and	O
+drug	O
+histories	O
+.	O
+	
+The	O
+incidence	O
+of	O
+subependymal	B-NP
+cysts	I-NP
+in	O
+the	O
+117	O
+remaining	O
+infants	O
+was	O
+14	O
+%	O
+(	O
+16	O
+of	O
+117	O
+)	O
+.	O
+	
+The	O
+incidence	O
+of	O
+subependymal	B-NP
+cysts	I-NP
+in	O
+infants	O
+exposed	O
+to	O
+cocaine	O
+prenatally	O
+was	O
+44	O
+%	O
+(	O
+8	O
+of	O
+18	O
+)	O
+compared	O
+with	O
+8	O
+%	O
+(	O
+8	O
+of	O
+99	O
+)	O
+in	O
+the	O
+unexposed	O
+group	O
+(	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+We	O
+found	O
+an	O
+increased	O
+incidence	O
+of	O
+subependymal	B-NP
+cyst	I-NP
+formation	O
+in	O
+preterm	B-NP
+infants	I-NP
+who	O
+were	O
+exposed	O
+to	O
+cocaine	O
+prenatally	O
+.	O
+	
+This	O
+result	O
+is	O
+consistent	O
+with	O
+results	O
+of	O
+similar	O
+studies	O
+in	O
+term	O
+infants	O
+.	O
+	
+Thalidomide	O
+neuropathy	B-NP
+in	O
+patients	O
+treated	O
+for	O
+metastatic	O
+prostate	B-NP
+cancer	I-NP
+.	O
+	
+We	O
+prospectively	O
+evaluated	O
+thalidomide	O
+-	O
+induced	O
+neuropathy	B-NP
+using	O
+electrodiagnostic	O
+studies	O
+.	O
+	
+Sixty	O
+-	O
+seven	O
+men	O
+with	O
+metastatic	O
+androgen	O
+-	O
+independent	O
+prostate	B-NP
+cancer	I-NP
+in	O
+an	O
+open	O
+-	O
+label	O
+trial	O
+of	O
+oral	O
+thalidomide	O
+underwent	O
+neurologic	O
+examinations	O
+and	O
+nerve	O
+conduction	O
+studies	O
+(	O
+NCS	O
+)	O
+prior	O
+to	O
+and	O
+at	O
+3	O
+-	O
+month	O
+intervals	O
+during	O
+treatment	O
+.	O
+	
+NCS	O
+included	O
+recording	O
+of	O
+sensory	O
+nerve	O
+action	O
+potentials	O
+(	O
+SNAPs	O
+)	O
+from	O
+median	O
+","	O
+radial	O
+","	O
+ulnar	O
+","	O
+and	O
+sural	O
+nerves	O
+.	O
+	
+SNAP	O
+amplitudes	O
+for	O
+each	O
+nerve	O
+were	O
+expressed	O
+as	O
+the	O
+percentage	O
+of	O
+its	O
+baseline	O
+","	O
+and	O
+the	O
+mean	O
+of	O
+the	O
+four	O
+was	O
+termed	O
+the	O
+SNAP	O
+index	O
+.	O
+	
+A	O
+40	O
+%	O
+decline	O
+in	O
+the	O
+SNAP	O
+index	O
+was	O
+considered	O
+clinically	O
+significant	O
+.	O
+	
+Thalidomide	O
+was	O
+discontinued	O
+in	O
+55	O
+patients	O
+for	O
+lack	O
+of	O
+therapeutic	O
+response	O
+.	O
+	
+Of	O
+67	O
+patients	O
+initially	O
+enrolled	O
+","	O
+24	O
+remained	O
+on	O
+thalidomide	O
+for	O
+3	O
+months	O
+","	O
+8	O
+remained	O
+at	O
+6	O
+months	O
+","	O
+and	O
+3	O
+remained	O
+at	O
+9	O
+months	O
+.	O
+	
+Six	O
+patients	O
+developed	O
+neuropathy	B-NP
+.	O
+	
+Clinical	O
+symptoms	O
+and	O
+a	O
+decline	O
+in	O
+the	O
+SNAP	O
+index	O
+occurred	O
+concurrently	O
+.	O
+	
+Older	O
+age	O
+and	O
+cumulative	O
+dose	O
+were	O
+possible	O
+contributing	O
+factors	O
+.	O
+	
+Neuropathy	B-NP
+may	O
+thus	O
+be	O
+a	O
+common	O
+complication	O
+of	O
+thalidomide	O
+in	O
+older	O
+patients	O
+.	O
+	
+The	O
+SNAP	O
+index	O
+can	O
+be	O
+used	O
+to	O
+monitor	O
+peripheral	B-NP
+neuropathy	I-NP
+","	O
+but	O
+not	O
+for	O
+early	O
+detection	O
+.	O
+	
+Overexpression	O
+of	O
+copper	O
+/	O
+zinc	O
+-	O
+superoxide	O
+dismutase	O
+protects	O
+from	O
+kanamycin	O
+-	O
+induced	O
+hearing	B-NP
+loss	I-NP
+.	O
+	
+The	O
+participation	O
+of	O
+reactive	O
+oxygen	O
+species	O
+in	O
+aminoglycoside	O
+-	O
+induced	O
+ototoxicity	B-NP
+has	O
+been	O
+deduced	O
+from	O
+observations	O
+that	O
+aminoglycoside	O
+-	O
+iron	O
+complexes	O
+catalyze	O
+the	O
+formation	O
+of	O
+superoxide	O
+radicals	O
+in	O
+vitro	O
+and	O
+that	O
+antioxidants	O
+attenuate	O
+ototoxicity	B-NP
+in	O
+vivo	O
+.	O
+	
+We	O
+therefore	O
+hypothesized	O
+that	O
+overexpression	O
+of	O
+Cu	O
+/	O
+Zn	O
+-	O
+superoxide	O
+dismutase	O
+(	O
+h	O
+-	O
+SOD1	O
+)	O
+should	O
+protect	O
+transgenic	O
+mice	O
+from	O
+ototoxicity	B-NP
+.	O
+	
+Immunocytochemistry	O
+confirmed	O
+expression	O
+of	O
+h	O
+-	O
+SOD1	O
+in	O
+inner	O
+ear	O
+tissues	O
+of	O
+transgenic	O
+C57BL	O
+/	O
+6	O
+-	O
+TgN	O
+[	O
+SOD1	O
+]	O
+3Cje	O
+mice	O
+.	O
+	
+Transgenic	O
+and	O
+nontransgenic	O
+littermates	O
+received	O
+kanamycin	O
+(	O
+400	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+/	O
+day	O
+)	O
+for	O
+10	O
+days	O
+beginning	O
+on	O
+day	O
+10	O
+after	O
+birth	O
+.	O
+	
+Auditory	O
+thresholds	O
+were	O
+tested	O
+by	O
+evoked	O
+auditory	O
+brain	O
+stem	O
+responses	O
+at	O
+1	O
+month	O
+after	O
+birth	O
+.	O
+	
+In	O
+nontransgenic	O
+animals	O
+","	O
+the	O
+threshold	O
+in	O
+the	O
+kanamycin	O
+-	O
+treated	O
+group	O
+was	O
+45	O
+-	O
+50	O
+dB	O
+higher	O
+than	O
+in	O
+saline	O
+-	O
+injected	O
+controls	O
+.	O
+	
+In	O
+the	O
+transgenic	O
+group	O
+","	O
+kanamycin	O
+increased	O
+the	O
+threshold	O
+by	O
+only	O
+15	O
+dB	O
+over	O
+the	O
+respective	O
+controls	O
+.	O
+	
+The	O
+effects	O
+were	O
+similar	O
+at	O
+12	O
+and	O
+24	O
+kHz	O
+.	O
+	
+The	O
+protection	O
+by	O
+overexpression	O
+of	O
+superoxide	O
+dismutase	O
+supports	O
+the	O
+hypothesis	O
+that	O
+oxidant	O
+stress	O
+plays	O
+a	O
+significant	O
+role	O
+in	O
+aminoglycoside	O
+-	O
+induced	O
+ototoxicity	B-NP
+.	O
+	
+The	O
+results	O
+also	O
+suggest	O
+transgenic	O
+animals	O
+as	O
+suitable	O
+models	O
+to	O
+investigate	O
+the	O
+underlying	O
+mechanisms	O
+and	O
+possible	O
+strategies	O
+for	O
+prevention	O
+.	O
+	
+Fatty	B-NP
+liver	I-NP
+induced	O
+by	O
+tetracycline	O
+in	O
+the	O
+rat	O
+.	O
+	
+Dose	O
+-	O
+response	O
+relationships	O
+and	O
+effect	O
+of	O
+sex	O
+.	O
+	
+Dose	O
+-	O
+response	O
+relationships	O
+","	O
+biochemical	O
+mechanisms	O
+","	O
+and	O
+sex	O
+differences	O
+in	O
+the	O
+experimental	O
+fatty	B-NP
+liver	I-NP
+induced	O
+by	O
+tetracycline	O
+were	O
+studied	O
+in	O
+the	O
+intact	O
+rat	O
+and	O
+with	O
+the	O
+isolated	O
+perfused	O
+rat	O
+liver	O
+in	O
+vitro	O
+.	O
+	
+In	O
+the	O
+intact	O
+male	O
+and	O
+female	O
+rat	O
+","	O
+no	O
+direct	O
+relationship	O
+was	O
+observed	O
+between	O
+dose	O
+of	O
+tetracycline	O
+and	O
+hepatic	O
+accumulation	O
+of	O
+triglyceride	O
+.	O
+	
+With	O
+provision	O
+of	O
+adequate	O
+oleic	O
+acid	O
+as	O
+a	O
+substrate	O
+for	O
+the	O
+isolated	O
+perfused	O
+liver	O
+","	O
+a	O
+direct	O
+relationship	O
+was	O
+observed	O
+between	O
+dose	O
+of	O
+tetracycline	O
+and	O
+both	O
+accumulation	O
+of	O
+triglyceride	O
+in	O
+the	O
+liver	O
+and	O
+depression	B-NP
+of	O
+output	O
+of	O
+triglyceride	O
+by	O
+livers	O
+from	O
+male	O
+and	O
+female	O
+rats	O
+.	O
+	
+Marked	O
+differences	O
+were	O
+observed	O
+between	O
+female	O
+and	O
+male	O
+rats	O
+with	O
+regard	O
+to	O
+base	O
+line	O
+(	O
+control	O
+)	O
+hepatic	O
+concentration	O
+of	O
+triglyceride	O
+and	O
+output	O
+of	O
+triglyceride	O
+.	O
+	
+Accumulation	O
+of	O
+hepatic	O
+triglyceride	O
+","	O
+as	O
+a	O
+per	O
+cent	O
+of	O
+control	O
+values	O
+","	O
+in	O
+response	O
+to	O
+graded	O
+doses	O
+of	O
+tetracycline	O
+","	O
+did	O
+not	O
+differ	O
+significantly	O
+between	O
+male	O
+","	O
+female	O
+and	O
+pregnant	O
+rat	O
+livers	O
+.	O
+	
+However	O
+","	O
+livers	O
+from	O
+female	O
+","	O
+and	O
+especially	O
+pregnant	O
+female	O
+rats	O
+","	O
+were	O
+strikingly	O
+resistant	O
+to	O
+the	O
+effects	O
+of	O
+tetracycline	O
+on	O
+depression	B-NP
+of	O
+output	O
+of	O
+triglyceride	O
+under	O
+these	O
+experimental	O
+conditions	O
+.	O
+	
+These	O
+differences	O
+between	O
+the	O
+sexes	O
+could	O
+not	O
+be	O
+related	O
+to	O
+altered	O
+disposition	O
+of	O
+tetracycline	O
+or	O
+altered	O
+uptake	O
+of	O
+oleic	O
+acid	O
+.	O
+	
+Depressed	O
+hepatic	O
+secretion	O
+of	O
+triglyceride	O
+accounted	O
+only	O
+for	O
+30	O
+to	O
+50	O
+%	O
+of	O
+accumulated	O
+hepatic	O
+triglyceride	O
+","	O
+indicating	O
+that	O
+additional	O
+mechanisms	O
+must	O
+be	O
+involved	O
+in	O
+the	O
+production	O
+of	O
+the	O
+triglyceride	O
+-	O
+rich	O
+fatty	B-NP
+liver	I-NP
+in	O
+response	O
+to	O
+tetracycline	O
+.	O
+	
+Prednisone	O
+induces	O
+anxiety	B-NP
+and	O
+glial	O
+cerebral	O
+changes	O
+in	O
+rats	O
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+assess	O
+whether	O
+prednisone	O
+(	O
+PDN	O
+)	O
+produces	O
+anxiety	B-NP
+and	O
+/	O
+or	O
+cerebral	O
+glial	O
+changes	O
+in	O
+rats	O
+.	O
+	
+METHODS	O
+:	O
+Male	O
+Wistar	O
+rats	O
+were	O
+studied	O
+and	O
+3	O
+groups	O
+were	O
+formed	O
+(	O
+8	O
+rats	O
+per	O
+group	O
+)	O
+.	O
+	
+The	O
+moderate	O
+-	O
+dose	O
+group	O
+received	O
+5	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+PDN	O
+released	O
+from	O
+a	O
+subcutaneous	O
+implant	O
+.	O
+	
+In	O
+the	O
+high	O
+-	O
+dose	O
+group	O
+","	O
+implants	O
+containing	O
+PDN	O
+equivalent	O
+to	O
+60	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+were	O
+applied	O
+.	O
+	
+In	O
+the	O
+control	O
+group	O
+implants	O
+contained	O
+no	O
+PDN	O
+.	O
+	
+Anxiety	B-NP
+was	O
+assessed	O
+using	O
+an	O
+open	O
+field	O
+and	O
+elevated	O
+plus	O
+-	O
+maze	O
+devices	O
+.	O
+	
+The	O
+number	O
+of	O
+cells	O
+and	O
+cytoplasmic	O
+transformation	O
+of	O
+astrocytes	O
+and	O
+microglia	O
+cells	O
+were	O
+assessed	O
+by	O
+immunohistochemical	O
+analyses	O
+.	O
+	
+RESULTS	O
+:	O
+Anxiety	B-NP
+was	O
+documented	O
+in	O
+both	O
+groups	O
+of	O
+PDN	O
+treated	O
+rats	O
+compared	O
+with	O
+controls	O
+.	O
+	
+The	O
+magnitude	O
+of	O
+transformation	O
+of	O
+the	O
+microglia	O
+assessed	O
+by	O
+the	O
+number	O
+of	O
+intersections	O
+was	O
+significantly	O
+higher	O
+in	O
+the	O
+PDN	O
+groups	O
+than	O
+in	O
+controls	O
+in	O
+the	O
+prefrontal	O
+cortex	O
+(	O
+moderate	O
+-	O
+dose	O
+","	O
+24	O
+.	O
+1	O
+;	O
+high	O
+-	O
+dose	O
+","	O
+23	O
+.	O
+6	O
+;	O
+controls	O
+18	O
+.	O
+7	O
+;	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+and	O
+striatum	O
+(	O
+moderate	O
+-	O
+dose	O
+25	O
+.	O
+6	O
+;	O
+high	O
+-	O
+dose	O
+26	O
+.	O
+3	O
+;	O
+controls	O
+18	O
+.	O
+9	O
+;	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+","	O
+but	O
+not	O
+in	O
+hippocampus	O
+.	O
+	
+The	O
+number	O
+of	O
+stained	O
+microglia	O
+cells	O
+was	O
+significantly	O
+higher	O
+in	O
+the	O
+PDN	O
+treated	O
+groups	O
+in	O
+the	O
+prefrontal	O
+cortex	O
+than	O
+in	O
+controls	O
+(	O
+moderate	O
+-	O
+dose	O
+","	O
+29	O
+.	O
+1	O
+;	O
+high	O
+-	O
+dose	O
+","	O
+28	O
+.	O
+4	O
+;	O
+control	O
+","	O
+17	O
+.	O
+7	O
+cells	O
+per	O
+field	O
+;	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Stained	O
+microglia	O
+cells	O
+were	O
+significantly	O
+more	O
+numerous	O
+striatum	O
+and	O
+hippocampus	O
+in	O
+the	O
+high	O
+-	O
+dose	O
+group	O
+compared	O
+to	O
+controls	O
+.	O
+	
+CONCLUSION	O
+:	O
+Subacute	O
+exposure	O
+to	O
+PDN	O
+induced	O
+anxiety	B-NP
+and	O
+reactivity	O
+of	O
+microglia	O
+.	O
+	
+The	O
+relevance	O
+of	O
+these	O
+features	O
+for	O
+patients	O
+using	O
+PDN	O
+remains	O
+to	O
+be	O
+elucidated	O
+.	O
+	
+Phase	O
+II	O
+study	O
+of	O
+carboplatin	O
+and	O
+liposomal	O
+doxorubicin	O
+in	O
+patients	O
+with	O
+recurrent	O
+squamous	B-NP
+cell	I-NP
+carcinoma	I-NP
+of	I-NP
+the	I-NP
+cervix	I-NP
+.	O
+	
+BACKGROUND	O
+:	O
+The	O
+activity	O
+of	O
+the	O
+combination	O
+of	O
+carboplatin	O
+and	O
+liposomal	O
+doxorubicin	O
+was	O
+tested	O
+in	O
+a	O
+Phase	O
+II	O
+study	O
+of	O
+patients	O
+with	O
+recurrent	O
+cervical	B-NP
+carcinoma	I-NP
+.	O
+	
+METHODS	O
+:	O
+The	O
+combination	O
+of	O
+carboplatin	O
+(	O
+area	O
+under	O
+the	O
+concentration	O
+curve	O
+[	O
+AUC	O
+]	O
+","	O
+5	O
+)	O
+and	O
+liposomal	O
+doxorubicin	O
+(	O
+Doxil	O
+;	O
+starting	O
+dose	O
+","	O
+40	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+)	O
+was	O
+administered	O
+intravenously	O
+every	O
+28	O
+days	O
+to	O
+37	O
+patients	O
+with	O
+recurrent	O
+squamous	B-NP
+cell	I-NP
+cervical	I-NP
+carcinoma	I-NP
+to	O
+determine	O
+antitumor	O
+activity	O
+and	O
+toxicity	B-NP
+profile	O
+.	O
+	
+RESULTS	O
+:	O
+Twenty	O
+-	O
+nine	O
+patients	O
+were	O
+assessable	O
+for	O
+response	O
+","	O
+and	O
+35	O
+patients	O
+were	O
+assessable	O
+for	O
+toxicity	B-NP
+.	O
+	
+The	O
+overall	O
+response	O
+rate	O
+was	O
+38	O
+%	O
+","	O
+the	O
+median	O
+time	O
+to	O
+response	O
+was	O
+10	O
+weeks	O
+","	O
+the	O
+median	O
+duration	O
+of	O
+response	O
+was	O
+26	O
+weeks	O
+","	O
+and	O
+the	O
+median	O
+survival	O
+was	O
+37	O
+weeks	O
+.	O
+	
+The	O
+main	O
+toxic	O
+effect	O
+was	O
+myelosuppression	B-NP
+","	O
+with	O
+Grade	O
+3	O
+and	O
+4	O
+neutropenia	B-NP
+in	O
+16	O
+patients	O
+","	O
+anemia	B-NP
+in	O
+12	O
+patients	O
+","	O
+thrombocytopenia	B-NP
+in	O
+11	O
+patients	O
+","	O
+and	O
+neutropenic	B-NP
+fever	I-NP
+in	O
+3	O
+patients	O
+.	O
+	
+Four	O
+patients	O
+had	O
+five	O
+infusion	O
+-	O
+related	O
+reactions	O
+during	O
+the	O
+infusion	O
+of	O
+liposomal	O
+doxorubicin	O
+","	O
+leading	O
+to	O
+treatment	O
+discontinuation	O
+in	O
+three	O
+patients	O
+.	O
+	
+Grade	O
+>	O
+or	O
+=	O
+2	O
+nonhematologic	O
+toxicity	B-NP
+included	O
+nausea	B-NP
+in	O
+17	O
+patients	O
+","	O
+emesis	B-NP
+in	O
+14	O
+patients	O
+","	O
+fatigue	B-NP
+in	O
+9	O
+patients	O
+","	O
+mucositis	B-NP
+and	O
+/	O
+or	O
+stomatitis	B-NP
+in	O
+8	O
+patients	O
+","	O
+constipation	B-NP
+in	O
+6	O
+patients	O
+","	O
+weight	B-NP
+loss	I-NP
+in	O
+5	O
+patients	O
+","	O
+hand	B-NP
+-	I-NP
+foot	I-NP
+syndrome	I-NP
+in	O
+2	O
+patients	O
+","	O
+and	O
+skin	B-NP
+reactions	I-NP
+in	O
+3	O
+patients	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+combination	O
+of	O
+carboplatin	O
+and	O
+liposomal	O
+doxorubicin	O
+has	O
+modest	O
+activity	O
+in	O
+patients	O
+with	O
+recurrent	O
+cervical	B-NP
+carcinoma	I-NP
+.	O
+	
+Antimicrobial	O
+-	O
+induced	O
+mania	B-NP
+(	O
+antibiomania	B-NP
+)	O
+:	O
+a	O
+review	O
+of	O
+spontaneous	O
+reports	O
+.	O
+	
+The	O
+authors	O
+reviewed	O
+reported	O
+cases	O
+of	O
+antibiotic	O
+-	O
+induced	O
+manic	B-NP
+episodes	O
+by	O
+means	O
+of	O
+a	O
+MEDLINE	O
+and	O
+PsychLit	O
+search	O
+for	O
+reports	O
+of	O
+antibiotic	O
+-	O
+induced	O
+mania	B-NP
+.	O
+	
+Unpublished	O
+reports	O
+were	O
+requested	O
+from	O
+the	O
+World	O
+Health	O
+Organization	O
+(	O
+WHO	O
+)	O
+and	O
+the	O
+Food	O
+and	O
+Drug	O
+Administration	O
+(	O
+FDA	O
+)	O
+.	O
+	
+Twenty	O
+-	O
+one	O
+reports	O
+of	O
+antimicrobial	O
+-	O
+induced	O
+mania	B-NP
+were	O
+found	O
+in	O
+the	O
+literature	O
+.	O
+	
+There	O
+were	O
+6	O
+cases	O
+implicating	O
+clarithromycin	O
+","	O
+13	O
+implicating	O
+isoniazid	O
+","	O
+and	O
+1	O
+case	O
+each	O
+implicating	O
+erythromycin	O
+and	O
+amoxicillin	O
+.	O
+	
+The	O
+WHO	O
+reported	O
+82	O
+cases	O
+.	O
+	
+Of	O
+these	O
+","	O
+clarithromycin	O
+was	O
+implicated	O
+in	O
+23	O
+(	O
+27	O
+.	O
+6	O
+%	O
+)	O
+cases	O
+","	O
+ciprofloxacin	O
+in	O
+12	O
+(	O
+14	O
+.	O
+4	O
+%	O
+)	O
+cases	O
+","	O
+and	O
+ofloxacin	O
+in	O
+10	O
+(	O
+12	O
+%	O
+)	O
+cases	O
+.	O
+	
+Cotrimoxazole	O
+","	O
+metronidazole	O
+","	O
+and	O
+erythromycin	O
+were	O
+involved	O
+in	O
+15	O
+reported	O
+manic	B-NP
+episodes	O
+.	O
+	
+Cases	O
+reported	O
+by	O
+the	O
+FDA	O
+showed	O
+clarithromycin	O
+and	O
+ciprofloxacin	O
+to	O
+be	O
+the	O
+most	O
+frequently	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+mania	B-NP
+.	O
+	
+Statistical	O
+analysis	O
+of	O
+the	O
+data	O
+would	O
+not	O
+have	O
+demonstrated	O
+a	O
+significant	O
+statistical	O
+correlative	O
+risk	O
+and	O
+was	O
+therefore	O
+not	O
+undertaken	O
+.	O
+	
+Patients	O
+have	O
+an	O
+increased	O
+risk	O
+of	O
+developing	O
+mania	B-NP
+while	O
+being	O
+treated	O
+with	O
+antimicrobials	O
+.	O
+	
+Although	O
+this	O
+is	O
+not	O
+a	O
+statistically	O
+significant	O
+risk	O
+","	O
+physicians	O
+must	O
+be	O
+aware	O
+of	O
+the	O
+effect	O
+and	O
+reversibility	O
+.	O
+	
+Further	O
+research	O
+clearly	O
+is	O
+required	O
+to	O
+determine	O
+the	O
+incidence	O
+of	O
+antimicrobial	O
+-	O
+induced	O
+mania	B-NP
+","	O
+the	O
+relative	O
+risk	O
+factors	O
+of	O
+developing	O
+an	O
+antimicrobial	O
+-	O
+induced	O
+manic	B-NP
+episode	O
+among	O
+various	O
+demographic	O
+populations	O
+","	O
+and	O
+the	O
+incidence	O
+of	O
+patients	O
+who	O
+continue	O
+to	O
+have	O
+persistent	O
+affective	O
+disorders	O
+once	O
+the	O
+initial	O
+episode	O
+","	O
+which	O
+occurs	O
+while	O
+the	O
+patient	O
+is	O
+taking	O
+antibiotics	O
+","	O
+subsides	O
+.	O
+	
+The	O
+authors	O
+elected	O
+to	O
+name	O
+this	O
+syndrome	O
+"	O
+antibiomania	B
+.	O
+"	O
+	
+Levodopa	O
+-	O
+induced	O
+ocular	B-NP
+dyskinesias	I-NP
+in	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+Levodopa	O
+-	O
+induced	O
+ocular	B-NP
+dyskinesias	I-NP
+are	O
+very	O
+uncommon	O
+.	O
+	
+Usually	O
+they	O
+occur	O
+simultaneously	O
+with	O
+limb	O
+peak	O
+-	O
+dose	O
+choreatic	B-NP
+dyskinesias	I-NP
+.	O
+	
+We	O
+report	O
+on	O
+a	O
+patient	O
+with	O
+leftward	O
+and	O
+upward	O
+deviations	O
+of	O
+gaze	O
+during	O
+the	O
+peak	O
+effect	O
+of	O
+levodopa	O
+","	O
+and	O
+hypothesize	O
+that	O
+a	O
+severe	O
+dopaminergic	O
+denervation	O
+in	O
+the	O
+caudate	O
+nucleus	O
+is	O
+needed	O
+for	O
+the	O
+appearance	O
+of	O
+these	O
+levodopa	O
+-	O
+induce	O
+ocular	B-NP
+dyskinesias	I-NP
+.	O
+	
+A	O
+comparison	O
+of	O
+glyceryl	O
+trinitrate	O
+with	O
+diclofenac	O
+for	O
+the	O
+treatment	O
+of	O
+primary	O
+dysmenorrhea	B-NP
+:	O
+an	O
+open	O
+","	O
+randomized	O
+","	O
+cross	O
+-	O
+over	O
+trial	O
+.	O
+	
+Primary	O
+dysmenorrhea	B-NP
+is	O
+a	O
+syndrome	O
+characterized	O
+by	O
+painful	O
+uterine	O
+contractility	O
+caused	O
+by	O
+a	O
+hypersecretion	O
+of	O
+endometrial	O
+prostaglandins	O
+;	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+are	O
+the	O
+first	O
+choice	O
+for	O
+its	O
+treatment	O
+.	O
+	
+However	O
+","	O
+in	O
+vivo	O
+and	O
+in	O
+vitro	O
+studies	O
+have	O
+demonstrated	O
+that	O
+myometrial	O
+cells	O
+are	O
+also	O
+targets	O
+of	O
+the	O
+relaxant	O
+effects	O
+of	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+.	O
+	
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+efficacy	O
+of	O
+glyceryl	O
+trinitrate	O
+(	O
+GTN	O
+)	O
+","	O
+an	O
+NO	O
+donor	O
+","	O
+in	O
+the	O
+resolution	O
+of	O
+primary	O
+dysmenorrhea	B-NP
+in	O
+comparison	O
+with	O
+diclofenac	O
+(	O
+DCF	O
+)	O
+.	O
+	
+A	O
+total	O
+of	O
+24	O
+patients	O
+with	O
+the	O
+diagnosis	O
+of	O
+severe	O
+primary	O
+dysmenorrhea	B-NP
+were	O
+studied	O
+during	O
+two	O
+consecutive	O
+menstrual	O
+cycles	O
+.	O
+	
+In	O
+an	O
+open	O
+","	O
+cross	O
+-	O
+over	O
+","	O
+controlled	O
+design	O
+","	O
+patients	O
+were	O
+randomized	O
+to	O
+receive	O
+either	O
+DCF	O
+per	O
+os	O
+or	O
+GTN	O
+patches	O
+the	O
+first	O
+days	O
+of	O
+menses	O
+","	O
+when	O
+menstrual	O
+cramps	O
+became	O
+unendurable	O
+.	O
+	
+In	O
+the	O
+subsequent	O
+cycle	O
+the	O
+other	O
+treatment	O
+was	O
+used	O
+.	O
+	
+Patients	O
+received	O
+up	O
+to	O
+3	O
+doses	O
+/	O
+day	O
+of	O
+50	O
+mg	O
+DCF	O
+or	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+24	O
+h	O
+transdermal	O
+GTN	O
+for	O
+the	O
+first	O
+3	O
+days	O
+of	O
+the	O
+cycle	O
+","	O
+according	O
+to	O
+their	O
+needs	O
+.	O
+	
+The	O
+participants	O
+recorded	O
+menstrual	O
+symptoms	O
+and	O
+possible	O
+side	O
+-	O
+effects	O
+at	O
+different	O
+times	O
+(	O
+0	O
+","	O
+30	O
+","	O
+60	O
+","	O
+120	O
+minutes	O
+)	O
+after	O
+the	O
+first	O
+dose	O
+of	O
+medication	O
+on	O
+the	O
+first	O
+day	O
+of	O
+the	O
+cycle	O
+","	O
+with	O
+both	O
+drugs	O
+.	O
+	
+The	O
+difference	O
+in	O
+pain	B-NP
+intensity	O
+score	O
+(	O
+DPI	O
+)	O
+was	O
+the	O
+main	O
+outcome	O
+variable	O
+.	O
+	
+Both	O
+treatments	O
+significantly	O
+reduced	O
+DPI	O
+by	O
+the	O
+30th	O
+minute	O
+(	O
+GTN	O
+","	O
+-	O
+12	O
+.	O
+8	O
++	O
+/	O
+-	O
+17	O
+.	O
+9	O
+;	O
+DCF	O
+","	O
+-	O
+18	O
+.	O
+9	O
++	O
+/	O
+-	O
+16	O
+.	O
+6	O
+)	O
+.	O
+	
+However	O
+","	O
+DCF	O
+continued	O
+to	O
+be	O
+effective	O
+in	O
+reducing	O
+pelvic	B-NP
+pain	I-NP
+for	O
+two	O
+hours	O
+","	O
+whereas	O
+GTN	O
+scores	O
+remained	O
+more	O
+or	O
+less	O
+stable	O
+after	O
+30	O
+min	O
+and	O
+significantly	O
+higher	O
+than	O
+those	O
+for	O
+DFC	O
+(	O
+after	O
+one	O
+hour	O
+:	O
+GTN	O
+","	O
+-	O
+12	O
+.	O
+8	O
++	O
+/	O
+-	O
+17	O
+.	O
+9	O
+;	O
+DFC	O
+","	O
+-	O
+18	O
+.	O
+9	O
++	O
+/	O
+-	O
+16	O
+.	O
+6	O
+and	O
+after	O
+two	O
+hours	O
+:	O
+GTN	O
+","	O
+-	O
+23	O
+.	O
+7	O
++	O
+/	O
+-	O
+20	O
+.	O
+5	O
+;	O
+DFC	O
+","	O
+-	O
+59	O
+.	O
+7	O
++	O
+/	O
+-	O
+17	O
+.	O
+9	O
+","	O
+p	O
+=	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Low	B-NP
+back	I-NP
+pain	I-NP
+was	O
+also	O
+relieved	O
+by	O
+both	O
+drugs	O
+.	O
+	
+Headache	B-NP
+was	O
+significantly	O
+increased	O
+by	O
+GTN	O
+but	O
+not	O
+by	O
+DCF	O
+.	O
+	
+Eight	O
+patients	O
+stopped	O
+using	O
+GTN	O
+because	O
+headache	B-NP
+-	O
+-	O
+attributed	O
+to	O
+its	O
+use	O
+-	O
+-	O
+became	O
+intolerable	O
+.	O
+	
+These	O
+findings	O
+indicate	O
+that	O
+GTN	O
+has	O
+a	O
+reduced	O
+efficacy	O
+and	O
+tolerability	O
+by	O
+comparison	O
+with	O
+DCF	O
+in	O
+the	O
+treatment	O
+of	O
+primary	O
+dysmenorrhea	B-NP
+.	O
+	
+Temocapril	O
+","	O
+a	O
+long	O
+-	O
+acting	O
+non	O
+-	O
+SH	O
+group	O
+angiotensin	O
+converting	O
+enzyme	O
+inhibitor	O
+","	O
+modulates	O
+glomerular	B-NP
+injury	I-NP
+in	O
+chronic	O
+puromycin	O
+aminonucleoside	O
+nephrosis	B-NP
+.	O
+	
+The	O
+purpose	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+determine	O
+whether	O
+chronic	O
+administration	O
+of	O
+temocapril	O
+","	O
+a	O
+long	O
+-	O
+acting	O
+non	O
+-	O
+SH	O
+group	O
+angiotensin	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+inhibitor	O
+","	O
+reduced	O
+proteinuria	B-NP
+","	O
+inhibited	O
+glomerular	O
+hypertrophy	B-NP
+and	O
+prevented	O
+glomerulosclerosis	B-NP
+in	O
+chronic	O
+puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+)	O
+-	O
+induced	O
+nephrotic	B-NP
+rats	O
+.	O
+	
+Nephrosis	B-NP
+was	O
+induced	O
+by	O
+injection	O
+of	O
+PAN	O
+(	O
+15mg	O
+/	O
+100g	O
+body	O
+weight	O
+)	O
+in	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+(	O
+SD	O
+)	O
+rats	O
+.	O
+	
+Four	O
+groups	O
+were	O
+used	O
+","	O
+i	O
+)	O
+the	O
+PAN	O
+group	O
+(	O
+14	O
+)	O
+","	O
+ii	O
+)	O
+PAN	O
+/	O
+temocapril	O
+(	O
+13	O
+)	O
+","	O
+iii	O
+)	O
+temocapril	O
+(	O
+14	O
+)	O
+and	O
+iv	O
+)	O
+untreated	O
+controls	O
+(	O
+15	O
+)	O
+.	O
+	
+Temocapril	O
+(	O
+8	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+)	O
+was	O
+administered	O
+to	O
+the	O
+rats	O
+which	O
+were	O
+killed	O
+at	O
+weeks	O
+4	O
+","	O
+14	O
+or	O
+20	O
+.	O
+	
+At	O
+each	O
+time	O
+point	O
+","	O
+systolic	O
+blood	O
+pressure	O
+(	O
+BP	O
+)	O
+","	O
+urinary	O
+protein	O
+excretion	O
+and	O
+renal	O
+histopathological	O
+findings	O
+were	O
+evaluated	O
+","	O
+and	O
+morphometric	O
+image	O
+analysis	O
+was	O
+done	O
+.	O
+	
+Systolic	O
+BP	O
+in	O
+the	O
+PAN	O
+group	O
+was	O
+significantly	O
+high	O
+at	O
+4	O
+","	O
+14	O
+and	O
+20	O
+weeks	O
+","	O
+but	O
+was	O
+normal	O
+in	O
+the	O
+PAN	O
+/	O
+temocapril	O
+group	O
+.	O
+	
+Urinary	O
+protein	O
+excretion	O
+in	O
+the	O
+PAN	O
+group	O
+increased	O
+significantly	O
+","	O
+peaking	O
+at	O
+8	O
+days	O
+","	O
+then	O
+decreased	O
+at	O
+4	O
+weeks	O
+","	O
+but	O
+rose	O
+again	O
+significantly	O
+at	O
+14	O
+and	O
+20	O
+weeks	O
+.	O
+	
+Temocapril	O
+did	O
+not	O
+attenuate	O
+proteinuria	B-NP
+at	O
+8	O
+days	O
+","	O
+but	O
+it	O
+did	O
+markedly	O
+lower	O
+it	O
+from	O
+weeks	O
+4	O
+to	O
+20	O
+.	O
+	
+The	O
+glomerulosclerosis	B-NP
+index	O
+(	O
+GSI	O
+)	O
+was	O
+6	O
+.	O
+21	O
+%	O
+at	O
+4	O
+weeks	O
+and	O
+respectively	O
+25	O
+.	O
+35	O
+%	O
+and	O
+30	O
+.	O
+49	O
+%	O
+at	O
+14	O
+and	O
+20	O
+weeks	O
+in	O
+the	O
+PAN	O
+group	O
+.	O
+	
+There	O
+was	O
+a	O
+significant	O
+correlation	O
+between	O
+urinary	O
+protein	O
+excretion	O
+and	O
+GSI	O
+(	O
+r	O
+=	O
+0	O
+.	O
+808	O
+","	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+The	O
+ratio	O
+of	O
+glomerular	O
+tuft	O
+area	O
+to	O
+the	O
+area	O
+of	O
+Bowman	O
+'	O
+s	O
+capsules	O
+(	O
+GT	O
+/	O
+BC	O
+)	O
+in	O
+the	O
+PAN	O
+group	O
+was	O
+significantly	O
+increased	O
+","	O
+but	O
+it	O
+was	O
+significantly	O
+lower	O
+in	O
+the	O
+PAN	O
+/	O
+temocapril	O
+group	O
+.	O
+	
+It	O
+appears	O
+that	O
+temocapril	O
+was	O
+effective	O
+in	O
+retarding	O
+renal	O
+progression	O
+and	O
+protected	O
+renal	O
+function	O
+in	O
+PAN	O
+neprotic	B-NP
+rats	O
+.	O
+	
+Pulmonary	B-NP
+hypertension	I-NP
+after	O
+ibuprofen	O
+prophylaxis	O
+in	O
+very	O
+preterm	O
+infants	O
+.	O
+	
+We	O
+report	O
+three	O
+cases	O
+of	O
+severe	O
+hypoxaemia	B-NP
+after	O
+ibuprofen	O
+administration	O
+during	O
+a	O
+randomised	O
+controlled	O
+trial	O
+of	O
+prophylactic	O
+treatment	O
+of	O
+patent	B-NP
+ductus	I-NP
+arteriosus	I-NP
+with	O
+ibuprofen	O
+in	O
+premature	O
+infants	O
+born	O
+at	O
+less	O
+than	O
+28	O
+weeks	O
+of	O
+gestation	O
+.	O
+	
+Echocardiography	O
+showed	O
+severely	O
+decreased	O
+pulmonary	O
+blood	O
+flow	O
+.	O
+	
+Hypoxaemia	B-NP
+resolved	O
+quickly	O
+on	O
+inhaled	O
+nitric	O
+oxide	O
+therapy	O
+.	O
+	
+We	O
+suggest	O
+that	O
+investigators	O
+involved	O
+in	O
+similar	O
+trials	O
+pay	O
+close	O
+attention	O
+to	O
+pulmonary	O
+pressure	O
+if	O
+hypoxaemia	B-NP
+occurs	O
+after	O
+prophylactic	O
+administration	O
+of	O
+ibuprofen	O
+.	O
+	
+Hyponatremia	B-NP
+and	O
+syndrome	B-NP
+of	I-NP
+inappropriate	I-NP
+anti	I-NP
+-	I-NP
+diuretic	I-NP
+hormone	I-NP
+reported	O
+with	O
+the	O
+use	O
+of	O
+Vincristine	O
+:	O
+an	O
+over	O
+-	O
+representation	O
+of	O
+Asians	O
+?	O
+	
+PURPOSE	O
+:	O
+This	O
+retrospective	O
+study	O
+used	O
+a	O
+pharmaceutical	O
+company	O
+'	O
+s	O
+global	O
+safety	O
+database	O
+to	O
+determine	O
+the	O
+reporting	O
+rate	O
+of	O
+hyponatremia	B-NP
+and	O
+/	O
+or	O
+syndrome	B-NP
+of	I-NP
+inappropriate	I-NP
+secretion	I-NP
+of	I-NP
+anti	I-NP
+-	I-NP
+diuretic	I-NP
+hormone	I-NP
+(	O
+SIADH	B-NP
+)	O
+among	O
+vincristine	O
+-	O
+treated	O
+patients	O
+and	O
+to	O
+explore	O
+the	O
+possibility	O
+of	O
+at	O
+-	O
+risk	O
+population	O
+subgroups	O
+.	O
+	
+METHOD	O
+:	O
+We	O
+searched	O
+the	O
+Eli	O
+Lilly	O
+and	O
+Company	O
+'	O
+s	O
+computerized	O
+adverse	O
+event	O
+database	O
+for	O
+all	O
+reported	O
+cases	O
+of	O
+hyponatremia	B-NP
+and	O
+/	O
+or	O
+SIADH	B-NP
+as	O
+of	O
+1	O
+November	O
+1999	O
+that	O
+had	O
+been	O
+reported	O
+during	O
+the	O
+use	O
+of	O
+vincristine	O
+.	O
+	
+RESULTS	O
+:	O
+A	O
+total	O
+of	O
+76	O
+cases	O
+of	O
+hyponatremia	B-NP
+and	O
+/	O
+or	O
+SIADH	B-NP
+associated	O
+with	O
+vincristine	O
+use	O
+were	O
+identified	O
+.	O
+	
+The	O
+overall	O
+reporting	O
+rate	O
+was	O
+estimated	O
+to	O
+be	O
+1	O
+.	O
+3	O
+/	O
+100	O
+","	O
+0	O
+treated	O
+patients	O
+.	O
+	
+The	O
+average	O
+age	O
+of	O
+patients	O
+was	O
+35	O
+.	O
+6	O
++	O
+/	O
+-	O
+28	O
+.	O
+3	O
+years	O
+","	O
+and	O
+62	O
+%	O
+were	O
+males	O
+.	O
+	
+Approximately	O
+75	O
+%	O
+of	O
+the	O
+patients	O
+were	O
+receiving	O
+treatment	O
+for	O
+leukemia	B-NP
+or	O
+lymphoma	B-NP
+.	O
+	
+Among	O
+the	O
+39	O
+reports	O
+that	O
+included	O
+information	O
+on	O
+race	O
+","	O
+the	O
+racial	O
+distribution	O
+was	O
+:	O
+1	O
+Black	O
+","	O
+3	O
+Caucasian	O
+","	O
+and	O
+35	O
+Asian	O
+.	O
+	
+CONCLUSION	O
+:	O
+Our	O
+data	O
+suggest	O
+that	O
+Asian	O
+patients	O
+may	O
+be	O
+at	O
+increased	O
+risk	O
+of	O
+hyponatremia	B-NP
+and	O
+/	O
+or	O
+SIADH	B-NP
+associated	O
+with	O
+vincristine	O
+use	O
+.	O
+	
+Although	O
+the	O
+overall	O
+reported	O
+rate	O
+of	O
+SIADH	B-NP
+associated	O
+with	O
+vincristine	O
+is	O
+very	O
+low	O
+","	O
+physicians	O
+caring	O
+for	O
+Asian	O
+oncology	O
+patients	O
+should	O
+be	O
+aware	O
+of	O
+this	O
+potential	O
+serious	O
+but	O
+reversible	O
+adverse	O
+event	O
+.	O
+	
+Delayed	O
+toxicity	B-NP
+of	O
+cyclophosphamide	O
+on	O
+the	O
+bladder	O
+of	O
+DBA	O
+/	O
+2	O
+and	O
+C57BL	O
+/	O
+6	O
+female	O
+mouse	O
+.	O
+	
+The	O
+present	O
+study	O
+describes	O
+the	O
+delayed	O
+development	O
+of	O
+a	O
+severe	O
+bladder	O
+pathology	O
+in	O
+a	O
+susceptible	O
+strain	O
+of	O
+mice	O
+(	O
+DBA	O
+/	O
+2	O
+)	O
+but	O
+not	O
+in	O
+a	O
+resistant	O
+strain	O
+(	O
+C57BL	O
+/	O
+6	O
+)	O
+when	O
+both	O
+were	O
+treated	O
+with	O
+a	O
+single	O
+300	O
+mg	O
+/	O
+kg	O
+dose	O
+of	O
+cyclophosphamide	O
+(	O
+CY	O
+)	O
+.	O
+	
+Inbred	O
+DBA	O
+/	O
+2	O
+and	O
+C57BL	O
+/	O
+6	O
+female	O
+mice	O
+were	O
+injected	O
+with	O
+CY	O
+","	O
+and	O
+the	O
+effect	O
+of	O
+the	O
+drug	O
+on	O
+the	O
+bladder	O
+was	O
+assessed	O
+during	O
+100	O
+days	O
+by	O
+light	O
+microscopy	O
+using	O
+different	O
+staining	O
+procedures	O
+","	O
+and	O
+after	O
+30	O
+days	O
+by	O
+conventional	O
+electron	O
+microscopy	O
+.	O
+	
+Early	O
+CY	O
+toxicity	B-NP
+caused	O
+a	O
+typical	O
+haemorrhagic	B-NP
+cystitis	B-NP
+in	O
+both	O
+strains	O
+that	O
+was	O
+completely	O
+repaired	O
+in	O
+about	O
+7	O
+-	O
+10	O
+days	O
+.	O
+	
+After	O
+30	O
+days	O
+of	O
+CY	O
+injection	O
+ulcerous	O
+and	O
+non	O
+-	O
+ulcerous	O
+forms	O
+of	O
+chronic	O
+cystitis	B-NP
+appeared	O
+in	O
+86	O
+%	O
+of	O
+DBA	O
+/	O
+2	O
+mice	O
+but	O
+only	O
+in	O
+4	O
+%	O
+of	O
+C57BL	O
+/	O
+6	O
+mice	O
+.	O
+	
+Delayed	O
+cystitis	B-NP
+was	O
+characterized	O
+by	O
+infiltration	O
+and	O
+transepithelial	O
+passage	O
+into	O
+the	O
+lumen	O
+of	O
+inflammatory	O
+cells	O
+and	O
+by	O
+frequent	O
+exfoliation	O
+of	O
+the	O
+urothelium	O
+.	O
+	
+Mast	O
+cells	O
+appeared	O
+in	O
+the	O
+connective	O
+and	O
+muscular	O
+layers	O
+of	O
+the	O
+bladder	O
+at	O
+a	O
+much	O
+higher	O
+number	O
+in	O
+DBA	O
+/	O
+2	O
+mice	O
+than	O
+in	O
+C57BL	O
+/	O
+6	O
+mice	O
+or	O
+untreated	O
+controls	O
+.	O
+	
+Electron	O
+microscopy	O
+disclosed	O
+the	O
+absence	O
+of	O
+the	O
+typical	O
+discoidal	O
+vesicles	O
+normally	O
+present	O
+in	O
+the	O
+cytoplasm	O
+of	O
+surface	O
+cells	O
+.	O
+	
+Instead	O
+","	O
+numerous	O
+abnormal	O
+vesicles	O
+containing	O
+one	O
+or	O
+several	O
+dark	O
+granules	O
+were	O
+observed	O
+in	O
+the	O
+cytoplasm	O
+of	O
+cells	O
+from	O
+all	O
+the	O
+epithelial	O
+layers	O
+.	O
+	
+Delayed	O
+cystitis	B-NP
+still	O
+persisted	O
+in	O
+DBA	O
+/	O
+2	O
+mice	O
+100	O
+days	O
+after	O
+treatment	O
+.	O
+	
+These	O
+results	O
+indicate	O
+that	O
+delayed	O
+toxicity	B-NP
+of	O
+CY	O
+in	O
+female	O
+DBA	O
+/	O
+2	O
+mice	O
+causes	O
+a	O
+bladder	O
+pathology	O
+that	O
+is	O
+not	O
+observed	O
+in	O
+C57BL	O
+/	O
+6	O
+mice	O
+.	O
+	
+This	O
+pathology	O
+resembles	O
+interstitial	B-NP
+cystitis	I-NP
+in	O
+humans	O
+and	O
+could	O
+perhaps	O
+be	O
+used	O
+as	O
+an	O
+animal	O
+model	O
+for	O
+studies	O
+on	O
+the	O
+disease	O
+.	O
+	
+High	O
+-	O
+dose	O
+5	O
+-	O
+fluorouracil	O
+/	O
+folinic	O
+acid	O
+in	O
+combination	O
+with	O
+three	O
+-	O
+weekly	O
+mitomycin	O
+C	O
+in	O
+the	O
+treatment	O
+of	O
+advanced	O
+gastric	B-NP
+cancer	I-NP
+.	O
+	
+A	O
+phase	O
+II	O
+study	O
+.	O
+	
+BACKGROUND	O
+:	O
+The	O
+24	O
+-	O
+hour	O
+continuous	O
+infusion	O
+of	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+and	O
+folinic	O
+acid	O
+(	O
+FA	O
+)	O
+as	O
+part	O
+of	O
+several	O
+new	O
+multidrug	O
+chemotherapy	O
+regimens	O
+in	O
+advanced	O
+gastric	B-NP
+cancer	I-NP
+(	O
+AGC	B-NP
+)	O
+has	O
+shown	O
+to	O
+be	O
+effective	O
+","	O
+with	O
+low	O
+toxicity	B-NP
+.	O
+	
+In	O
+a	O
+previous	O
+phase	O
+II	O
+study	O
+with	O
+3	O
+-	O
+weekly	O
+bolus	O
+5	O
+-	O
+FU	O
+","	O
+FA	O
+and	O
+mitomycin	O
+C	O
+(	O
+MMC	O
+)	O
+we	O
+found	O
+a	O
+low	O
+toxicity	B-NP
+rate	O
+and	O
+response	O
+rates	O
+comparable	O
+to	O
+those	O
+of	O
+regimens	O
+such	O
+as	O
+ELF	O
+","	O
+FAM	O
+or	O
+FAMTX	O
+","	O
+and	O
+a	O
+promising	O
+median	O
+overall	O
+survival	O
+.	O
+	
+In	O
+order	O
+to	O
+improve	O
+this	O
+MMC	O
+-	O
+dependent	O
+schedule	O
+we	O
+initiated	O
+a	O
+phase	O
+II	O
+study	O
+with	O
+high	O
+-	O
+dose	O
+5	O
+-	O
+FU	O
+/	O
+FA	O
+and	O
+3	O
+-	O
+weekly	O
+bolus	O
+MMC	O
+.	O
+	
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+From	O
+February	O
+","	O
+1998	O
+to	O
+September	O
+","	O
+2000	O
+we	O
+recruited	O
+33	O
+patients	O
+with	O
+AGC	B-NP
+to	O
+receive	O
+weekly	O
+24	O
+-	O
+hour	O
+5	O
+-	O
+FU	O
+2	O
+","	O
+600	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+preceded	O
+by	O
+2	O
+-	O
+hour	O
+FA	O
+500	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+for	O
+6	O
+weeks	O
+","	O
+followed	O
+by	O
+a	O
+2	O
+-	O
+week	O
+rest	O
+period	O
+.	O
+	
+Bolus	O
+MMC	O
+10	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+was	O
+added	O
+in	O
+3	O
+-	O
+weekly	O
+intervals	O
+.	O
+	
+Treatment	O
+given	O
+on	O
+an	O
+outpatient	O
+basis	O
+","	O
+using	O
+portable	O
+pump	O
+systems	O
+","	O
+was	O
+repeated	O
+on	O
+day	O
+57	O
+.	O
+	
+Patients	O
+'	O
+characteristics	O
+were	O
+:	O
+male	O
+/	O
+female	O
+ratio	O
+20	O
+/	O
+13	O
+;	O
+median	O
+age	O
+57	O
+(	O
+27	O
+-	O
+75	O
+)	O
+years	O
+;	O
+median	O
+WHO	O
+status	O
+1	O
+(	O
+0	O
+-	O
+2	O
+)	O
+.	O
+	
+18	O
+patients	O
+had	O
+a	O
+primary	O
+AGC	B-NP
+","	O
+and	O
+15	O
+showed	O
+a	O
+relapsed	O
+AGC	B-NP
+.	O
+	
+Median	O
+follow	O
+-	O
+up	O
+was	O
+11	O
+.	O
+8	O
+months	O
+(	O
+range	O
+of	O
+those	O
+surviving	O
+:	O
+2	O
+.	O
+7	O
+-	O
+11	O
+.	O
+8	O
+months	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+32	O
+patients	O
+were	O
+evaluable	O
+for	O
+response	O
+-	O
+complete	O
+remission	O
+9	O
+.	O
+1	O
+%	O
+(	O
+n	O
+=	O
+3	O
+)	O
+","	O
+partial	O
+remission	O
+45	O
+.	O
+5	O
+%	O
+(	O
+n	O
+=	O
+15	O
+)	O
+","	O
+no	O
+change	O
+27	O
+.	O
+3	O
+%	O
+(	O
+n	O
+=	O
+9	O
+)	O
+","	O
+progressive	O
+disease	O
+15	O
+.	O
+1	O
+%	O
+(	O
+n	O
+=	O
+5	O
+)	O
+.	O
+	
+Median	O
+overall	O
+survival	O
+time	O
+was	O
+10	O
+.	O
+2	O
+months	O
+[	O
+95	O
+%	O
+confidence	O
+interval	O
+(	O
+CI	O
+)	O
+:	O
+8	O
+.	O
+7	O
+-	O
+11	O
+.	O
+6	O
+]	O
+","	O
+and	O
+median	O
+progression	O
+-	O
+free	O
+survival	O
+time	O
+was	O
+7	O
+.	O
+6	O
+months	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+4	O
+.	O
+4	O
+-	O
+10	O
+.	O
+9	O
+)	O
+.	O
+	
+The	O
+worst	O
+toxicities	B-NP
+(	O
+%	O
+)	O
+observed	O
+were	O
+(	O
+CTC	O
+-	O
+NCI	O
+1	O
+/	O
+2	O
+/	O
+3	O
+)	O
+:	O
+leukopenia	B-NP
+45	O
+.	O
+5	O
+/	O
+18	O
+.	O
+2	O
+/	O
+6	O
+.	O
+1	O
+","	O
+thrombocytopenia	B-NP
+33	O
+.	O
+3	O
+/	O
+9	O
+.	O
+1	O
+/	O
+6	O
+.	O
+1	O
+","	O
+vomitus	B-NP
+24	O
+.	O
+2	O
+/	O
+9	O
+.	O
+1	O
+/	O
+0	O
+","	O
+diarrhea	B-NP
+36	O
+.	O
+4	O
+/	O
+6	O
+.	O
+1	O
+/	O
+3	O
+.	O
+0	O
+","	O
+stomatitis	B-NP
+18	O
+.	O
+2	O
+/	O
+9	O
+.	O
+1	O
+/	O
+0	O
+","	O
+hand	B-NP
+-	I-NP
+foot	I-NP
+syndrome	I-NP
+12	O
+.	O
+1	O
+/	O
+0	O
+/	O
+0	O
+.	O
+	
+Two	O
+patients	O
+developed	O
+hemolytic	B-NP
+-	I-NP
+uremic	I-NP
+syndrome	I-NP
+(	O
+HUS	B-NP
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+High	O
+-	O
+dose	O
+5	O
+-	O
+FU	O
+/	O
+FA	O
+/	O
+MMC	O
+is	O
+an	O
+effective	O
+and	O
+well	O
+-	O
+tolerated	O
+outpatient	O
+regimen	O
+for	O
+AGC	B-NP
+(	O
+objective	O
+response	O
+rate	O
+54	O
+.	O
+6	O
+%	O
+)	O
+.	O
+	
+It	O
+may	O
+serve	O
+as	O
+an	O
+alternative	O
+to	O
+cisplatin	O
+-	O
+containing	O
+regimens	O
+;	O
+however	O
+","	O
+it	O
+has	O
+to	O
+be	O
+considered	O
+that	O
+possibly	O
+HUS	B-NP
+may	O
+occur	O
+.	O
+	
+Persistent	O
+sterile	O
+leukocyturia	B-NP
+is	O
+associated	O
+with	O
+impaired	B-NP
+renal	I-NP
+function	I-NP
+in	O
+human	B-NP
+immunodeficiency	I-NP
+virus	I-NP
+type	I-NP
+1	I-NP
+-	I-NP
+infected	I-NP
+children	O
+treated	O
+with	O
+indinavir	O
+.	O
+	
+BACKGROUND	O
+:	O
+Prolonged	O
+administration	O
+of	O
+indinavir	O
+is	O
+associated	O
+with	O
+the	O
+occurrence	O
+of	O
+a	O
+variety	O
+of	O
+renal	O
+complications	O
+in	O
+adults	O
+.	O
+	
+These	O
+well	O
+-	O
+documented	O
+side	O
+effects	O
+have	O
+restricted	O
+the	O
+use	O
+of	O
+this	O
+potent	O
+protease	O
+inhibitor	O
+in	O
+children	O
+.	O
+	
+DESIGN	O
+:	O
+A	O
+prospective	O
+study	O
+to	O
+monitor	O
+indinavir	O
+-	O
+related	O
+nephrotoxicity	B-NP
+in	O
+a	O
+cohort	O
+of	O
+30	O
+human	B-NP
+immunodeficiency	I-NP
+virus	I-NP
+type	I-NP
+1	I-NP
+-	I-NP
+infected	I-NP
+children	O
+treated	O
+with	O
+indinavir	O
+.	O
+	
+METHODS	O
+:	O
+Urinary	O
+pH	O
+","	O
+albumin	O
+","	O
+creatinine	O
+","	O
+the	O
+presence	O
+of	O
+erythrocytes	O
+","	O
+leukocytes	O
+","	O
+bacteria	O
+and	O
+crystals	O
+","	O
+and	O
+culture	O
+were	O
+analyzed	O
+every	O
+3	O
+months	O
+for	O
+96	O
+weeks	O
+.	O
+	
+Serum	O
+creatinine	O
+levels	O
+were	O
+routinely	O
+determined	O
+at	O
+the	O
+same	O
+time	O
+points	O
+.	O
+	
+Steady	O
+-	O
+state	O
+pharmacokinetics	O
+of	O
+indinavir	O
+were	O
+done	O
+at	O
+week	O
+4	O
+after	O
+the	O
+initiation	O
+of	O
+indinavir	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+cumulative	O
+incidence	O
+of	O
+persistent	O
+sterile	O
+leukocyturia	B-NP
+(	O
+>	O
+or	O
+=	O
+75	O
+cells	O
+/	O
+micro	O
+L	O
+in	O
+at	O
+least	O
+2	O
+consecutive	O
+visits	O
+)	O
+after	O
+96	O
+weeks	O
+was	O
+53	O
+%	O
+.	O
+	
+Persistent	O
+sterile	O
+leukocyturia	B-NP
+was	O
+frequently	O
+associated	O
+with	O
+a	O
+mild	O
+increase	O
+in	O
+the	O
+urine	O
+albumin	O
+/	O
+creatinine	O
+ratio	O
+and	O
+by	O
+microscopic	O
+hematuria	B-NP
+.	O
+	
+The	O
+cumulative	O
+incidence	O
+of	O
+serum	O
+creatinine	O
+levels	O
+>	O
+50	O
+%	O
+above	O
+normal	O
+was	O
+33	O
+%	O
+after	O
+96	O
+weeks	O
+.	O
+	
+Children	O
+with	O
+persistent	O
+sterile	O
+leukocyturia	B-NP
+more	O
+frequently	O
+had	O
+serum	O
+creatinine	O
+levels	O
+of	O
+50	O
+%	O
+above	O
+normal	O
+than	O
+those	O
+children	O
+without	O
+persistent	O
+sterile	O
+leukocyturia	B-NP
+.	O
+	
+In	O
+children	O
+younger	O
+than	O
+5	O
+.	O
+6	O
+years	O
+","	O
+persistent	O
+sterile	O
+leukocyturia	B-NP
+was	O
+significantly	O
+more	O
+frequent	O
+than	O
+in	O
+older	O
+children	O
+.	O
+	
+A	O
+higher	O
+cumulative	O
+incidence	O
+of	O
+persistent	O
+leukocyturia	B-NP
+was	O
+found	O
+in	O
+children	O
+with	O
+an	O
+area	O
+under	O
+the	O
+curve	O
+>	O
+19	O
+mg	O
+/	O
+L	O
+x	O
+h	O
+or	O
+a	O
+peak	O
+serum	O
+level	O
+of	O
+indinavir	O
+>	O
+12	O
+mg	O
+/	O
+L	O
+.	O
+	
+In	O
+4	O
+children	O
+","	O
+indinavir	O
+was	O
+discontinued	O
+because	O
+of	O
+nephrotoxicity	B-NP
+.	O
+	
+Subsequently	O
+","	O
+the	O
+serum	O
+creatinine	O
+levels	O
+decreased	O
+","	O
+the	O
+urine	O
+albumin	O
+/	O
+creatinine	O
+ratios	O
+returned	O
+to	O
+zero	O
+","	O
+and	O
+the	O
+leukocyturia	B-NP
+disappeared	O
+within	O
+3	O
+months	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Children	O
+treated	O
+with	O
+indinavir	O
+have	O
+a	O
+high	O
+cumulative	O
+incidence	O
+of	O
+persistent	O
+sterile	O
+leukocyturia	B-NP
+.	O
+	
+Children	O
+with	O
+persistent	O
+sterile	O
+leukocyturia	B-NP
+more	O
+frequently	O
+had	O
+an	O
+increase	O
+in	O
+serum	O
+creatinine	O
+levels	O
+of	O
+>	O
+50	O
+%	O
+above	O
+normal	O
+.	O
+	
+Younger	O
+children	O
+have	O
+an	O
+additional	O
+risk	O
+for	O
+renal	O
+complications	O
+.	O
+	
+The	O
+impairment	B-NP
+of	I-NP
+the	I-NP
+renal	I-NP
+function	I-NP
+in	O
+these	O
+children	O
+occurred	O
+in	O
+the	O
+absence	O
+of	O
+clinical	O
+symptoms	O
+of	O
+nephrolithiasis	B-NP
+.	O
+	
+Indinavir	O
+-	O
+associated	O
+nephrotoxicity	B-NP
+must	O
+be	O
+monitored	O
+closely	O
+","	O
+especially	O
+in	O
+children	O
+with	O
+risk	O
+factors	O
+such	O
+as	O
+persistent	O
+sterile	O
+leukocyturia	B-NP
+","	O
+age	O
+<	O
+5	O
+.	O
+6	O
+years	O
+","	O
+an	O
+area	O
+under	O
+the	O
+curve	O
+of	O
+indinavir	O
+>	O
+19	O
+mg	O
+/	O
+L	O
+x	O
+h	O
+","	O
+and	O
+a	O
+C	O
+(	O
+max	O
+)	O
+>	O
+12	O
+mg	O
+/	O
+L	O
+.	O
+	
+Utility	O
+of	O
+troponin	O
+I	O
+in	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B-NP
+pain	I-NP
+.	O
+	
+Baseline	O
+electrocardiogram	O
+abnormalities	O
+and	O
+market	O
+elevations	O
+not	O
+associated	O
+with	O
+myocardial	B-NP
+necrosis	I-NP
+make	O
+accurate	O
+diagnosis	O
+of	O
+myocardial	B-NP
+infarction	I-NP
+(	O
+MI	B-NP
+)	O
+difficult	O
+in	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B-NP
+pain	I-NP
+.	O
+	
+Troponin	O
+sampling	O
+may	O
+offer	O
+greater	O
+diagnostic	O
+utility	O
+in	O
+these	O
+patients	O
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+assess	O
+outcomes	O
+based	O
+on	O
+troponin	O
+positivity	O
+in	O
+patients	O
+with	O
+cocaine	O
+chest	B-NP
+pain	I-NP
+admitted	O
+for	O
+exclusion	O
+of	O
+MI	B-NP
+.	O
+	
+METHODS	O
+:	O
+Outcomes	O
+were	O
+examined	O
+in	O
+patients	O
+admitted	O
+for	O
+possible	O
+MI	B-NP
+after	O
+cocaine	O
+use	O
+.	O
+	
+All	O
+patients	O
+underwent	O
+a	O
+rapid	O
+rule	O
+-	O
+in	O
+protocol	O
+that	O
+included	O
+serial	O
+sampling	O
+of	O
+creatine	O
+kinase	O
+(	O
+CK	O
+)	O
+","	O
+CK	O
+-	O
+MB	O
+","	O
+and	O
+cardiac	O
+troponin	O
+I	O
+(	O
+cTnI	O
+)	O
+over	O
+eight	O
+hours	O
+.	O
+	
+Outcomes	O
+included	O
+CK	O
+-	O
+MB	O
+MI	B-NP
+(	O
+CK	O
+-	O
+MB	O
+>	O
+or	O
+=	O
+8	O
+ng	O
+/	O
+mL	O
+with	O
+a	O
+relative	O
+index	O
+[	O
+(	O
+CK	O
+-	O
+MB	O
+x	O
+100	O
+)	O
+/	O
+total	O
+CK	O
+]	O
+>	O
+or	O
+=	O
+4	O
+","	O
+cardiac	B-NP
+death	I-NP
+","	O
+and	O
+significant	O
+coronary	B-NP
+disease	I-NP
+(	O
+>	O
+or	O
+=	O
+50	O
+%	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+Of	O
+the	O
+246	O
+admitted	O
+patients	O
+","	O
+34	O
+(	O
+14	O
+%	O
+)	O
+met	O
+CK	O
+-	O
+MB	O
+criteria	O
+for	O
+MI	B-NP
+and	O
+38	O
+(	O
+16	O
+%	O
+)	O
+had	O
+cTnI	O
+elevations	O
+.	O
+	
+Angiography	O
+was	O
+performed	O
+in	O
+29	O
+of	O
+38	O
+patients	O
+who	O
+were	O
+cTnI	O
+-	O
+positive	O
+","	O
+with	O
+significant	O
+disease	O
+present	O
+in	O
+25	O
+(	O
+86	O
+%	O
+)	O
+.	O
+	
+Three	O
+of	O
+the	O
+four	O
+patients	O
+without	O
+significant	O
+disease	O
+who	O
+had	O
+cTnI	O
+elevations	O
+met	O
+CK	O
+-	O
+MB	O
+criteria	O
+for	O
+MI	B-NP
+","	O
+and	O
+the	O
+other	O
+had	O
+a	O
+peak	O
+CK	O
+-	O
+MB	O
+level	O
+of	O
+13	O
+ng	O
+/	O
+mL	O
+.	O
+	
+Sensitivities	O
+","	O
+specificities	O
+","	O
+and	O
+positive	O
+and	O
+negative	O
+likelihood	O
+ratios	O
+for	O
+predicting	O
+cardiac	B-NP
+death	I-NP
+or	O
+significant	O
+disease	O
+were	O
+high	O
+for	O
+both	O
+CK	O
+-	O
+MB	O
+MI	B-NP
+and	O
+cTnI	O
+and	O
+were	O
+not	O
+significantly	O
+different	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Most	O
+patients	O
+with	O
+cTnI	O
+elevations	O
+meet	O
+CK	O
+-	O
+MB	O
+criteria	O
+for	O
+MI	B-NP
+","	O
+as	O
+well	O
+as	O
+have	O
+a	O
+high	O
+incidence	O
+of	O
+underlying	O
+significant	O
+disease	O
+.	O
+	
+Troponin	O
+appears	O
+to	O
+have	O
+an	O
+equivalent	O
+diagnostic	O
+accuracy	O
+compared	O
+with	O
+CK	O
+-	O
+MB	O
+for	O
+diagnosing	O
+necrosis	B-NP
+in	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B-NP
+pain	I-NP
+and	O
+suspected	O
+MI	B-NP
+.	O
+	
+Acute	O
+interstitial	B-NP
+nephritis	I-NP
+due	O
+to	O
+nicergoline	O
+(	O
+Sermion	O
+)	O
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+acute	O
+interstitial	B-NP
+nephritis	I-NP
+(	O
+AIN	B-NP
+)	O
+due	O
+to	O
+nicergoline	O
+(	O
+Sermion	O
+)	O
+.	O
+	
+A	O
+50	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+admitted	O
+to	O
+our	O
+hospital	O
+for	O
+fever	B-NP
+and	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+.	O
+	
+Before	O
+admission	O
+","	O
+he	O
+had	O
+been	O
+taking	O
+nicergoline	O
+and	O
+bendazac	O
+lysine	O
+due	O
+to	O
+retinal	B-NP
+vein	I-NP
+occlusion	I-NP
+at	O
+ophthalmologic	O
+department	O
+.	O
+	
+Thereafter	O
+","	O
+he	O
+experienced	O
+intermittent	O
+fever	B-NP
+and	O
+skin	B-NP
+rash	I-NP
+.	O
+	
+On	O
+admission	O
+","	O
+clinical	O
+symptoms	O
+(	O
+i	O
+.	O
+e	O
+.	O
+arthralgia	B-NP
+and	O
+fever	B-NP
+)	O
+and	O
+laboratory	O
+findings	O
+(	O
+i	O
+.	O
+e	O
+.	O
+eosinophilia	B-NP
+and	O
+renal	B-NP
+failure	I-NP
+)	O
+suggested	O
+AIN	B-NP
+","	O
+and	O
+which	O
+was	O
+confirmed	O
+by	O
+pathologic	O
+findings	O
+on	O
+renal	O
+biopsy	O
+.	O
+	
+A	O
+lymphocyte	O
+transformation	O
+test	O
+demonstrated	O
+a	O
+positive	O
+result	O
+against	O
+nicergoline	O
+.	O
+	
+Treatment	O
+was	O
+consisted	O
+of	O
+withdrawal	O
+of	O
+nicergoline	O
+and	O
+intravenous	O
+methylprednisolone	O
+","	O
+and	O
+his	O
+renal	O
+function	O
+was	O
+completely	O
+recovered	O
+.	O
+	
+To	O
+our	O
+knowledge	O
+","	O
+this	O
+is	O
+the	O
+first	O
+report	O
+of	O
+nicergoline	O
+-	O
+associated	O
+AIN	B-NP
+.	O
+	
+Neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+complicated	O
+by	O
+massive	O
+intestinal	O
+bleeding	B-NP
+in	O
+a	O
+patient	O
+with	O
+chronic	B-NP
+renal	I-NP
+failure	I-NP
+.	O
+	
+A	O
+patient	O
+with	O
+chronic	B-NP
+renal	I-NP
+failure	I-NP
+(	O
+CRF	B-NP
+)	O
+developed	O
+neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+(	O
+NMS	B-NP
+)	O
+after	O
+administration	O
+of	O
+risperidone	O
+and	O
+levomepromazine	O
+.	O
+	
+In	O
+addition	O
+to	O
+the	O
+typical	O
+symptoms	O
+of	O
+NMS	B-NP
+","	O
+massive	O
+intestinal	O
+bleeding	B-NP
+was	O
+observed	O
+during	O
+the	O
+episode	O
+.	O
+	
+This	O
+report	O
+suggests	O
+that	O
+NMS	B-NP
+in	O
+a	O
+patient	O
+with	O
+CRF	B-NP
+may	O
+be	O
+complicated	O
+by	O
+intestinal	O
+bleeding	B-NP
+and	O
+needs	O
+special	O
+caution	O
+for	O
+this	O
+complication	O
+.	O
+	
+Blood	O
+brain	O
+barrier	O
+in	O
+right	O
+-	O
+and	O
+left	O
+-	O
+pawed	O
+female	O
+rats	O
+assessed	O
+by	O
+a	O
+new	O
+staining	O
+method	O
+.	O
+	
+The	O
+asymmetrical	O
+breakdown	O
+of	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+(	O
+BBB	O
+)	O
+was	O
+studied	O
+in	O
+female	O
+rats	O
+.	O
+	
+Paw	O
+preference	O
+was	O
+assessed	O
+by	O
+a	O
+food	O
+reaching	O
+test	O
+.	O
+	
+Adrenaline	O
+-	O
+induced	O
+hypertension	B-NP
+was	O
+used	O
+to	O
+destroy	O
+the	O
+BBB	O
+","	O
+which	O
+was	O
+evaluated	O
+using	O
+triphenyltetrazolium	O
+(	O
+TTC	O
+)	O
+staining	O
+of	O
+the	O
+brain	O
+slices	O
+just	O
+after	O
+giving	O
+adrenaline	O
+for	O
+30	O
+s	O
+.	O
+	
+In	O
+normal	O
+rats	O
+","	O
+the	O
+whole	O
+brain	O
+sections	O
+exhibited	O
+complete	O
+staining	O
+with	O
+TTC	O
+.	O
+	
+After	O
+adrenaline	O
+infusion	O
+for	O
+30	O
+s	O
+","	O
+there	O
+were	O
+large	O
+unstained	O
+areas	O
+in	O
+the	O
+left	O
+brain	O
+in	O
+right	O
+-	O
+pawed	O
+animals	O
+","	O
+and	O
+vice	O
+versa	O
+in	O
+left	O
+-	O
+pawed	O
+animals	O
+.	O
+	
+Similar	O
+results	O
+were	O
+obtained	O
+in	O
+seizure	B-NP
+-	O
+induced	O
+breakdown	O
+of	O
+BBB	O
+.	O
+	
+These	O
+results	O
+were	O
+explained	O
+by	O
+an	O
+asymmetric	O
+cerebral	O
+blood	O
+flow	O
+depending	O
+upon	O
+the	O
+paw	O
+preference	O
+in	O
+rats	O
+.	O
+	
+It	O
+was	O
+suggested	O
+that	O
+this	O
+new	O
+method	O
+and	O
+the	O
+results	O
+are	O
+consistent	O
+with	O
+contralateral	O
+motor	O
+control	O
+that	O
+may	O
+be	O
+important	O
+in	O
+determining	O
+the	O
+dominant	O
+cerebral	O
+hemisphere	O
+in	O
+animals	O
+.	O
+	
+Carvedilol	O
+protects	O
+against	O
+doxorubicin	O
+-	O
+induced	O
+mitochondrial	O
+cardiomyopathy	B-NP
+.	O
+	
+Several	O
+cytopathic	O
+mechanisms	O
+have	O
+been	O
+suggested	O
+to	O
+mediate	O
+the	O
+dose	O
+-	O
+limiting	O
+cumulative	O
+and	O
+irreversible	O
+cardiomyopathy	B-NP
+caused	O
+by	O
+doxorubicin	O
+.	O
+	
+Recent	O
+evidence	O
+indicates	O
+that	O
+oxidative	O
+stress	O
+and	O
+mitochondrial	B-NP
+dysfunction	I-NP
+are	O
+key	O
+factors	O
+in	O
+the	O
+pathogenic	O
+process	O
+.	O
+	
+The	O
+objective	O
+of	O
+this	O
+investigation	O
+was	O
+to	O
+test	O
+the	O
+hypothesis	O
+that	O
+carvedilol	O
+","	O
+a	O
+nonselective	O
+beta	O
+-	O
+adrenergic	O
+receptor	O
+antagonist	O
+with	O
+potent	O
+antioxidant	O
+properties	O
+","	O
+protects	O
+against	O
+the	O
+cardiac	O
+and	O
+hepatic	O
+mitochondrial	O
+bioenergetic	O
+dysfunction	O
+associated	O
+with	O
+subchronic	O
+doxorubicin	O
+toxicity	B-NP
+.	O
+	
+Heart	O
+and	O
+liver	O
+mitochondria	O
+were	O
+isolated	O
+from	O
+rats	O
+treated	O
+for	O
+7	O
+weeks	O
+with	O
+doxorubicin	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+sc	O
+/	O
+week	O
+)	O
+","	O
+carvedilol	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+ip	O
+/	O
+week	O
+)	O
+","	O
+or	O
+the	O
+combination	O
+of	O
+the	O
+two	O
+drugs	O
+.	O
+	
+Heart	O
+mitochondria	O
+isolated	O
+from	O
+doxorubicin	O
+-	O
+treated	O
+rats	O
+exhibited	O
+depressed	O
+rates	O
+for	O
+state	O
+3	O
+respiration	O
+(	O
+336	O
++	O
+/	O
+-	O
+26	O
+versus	O
+425	O
++	O
+/	O
+-	O
+53	O
+natom	O
+O	O
+/	O
+min	O
+/	O
+mg	O
+protein	O
+)	O
+and	O
+a	O
+lower	O
+respiratory	O
+control	O
+ratio	O
+(	O
+RCR	O
+)	O
+(	O
+4	O
+.	O
+3	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+versus	O
+5	O
+.	O
+8	O
++	O
+/	O
+-	O
+0	O
+.	O
+4	O
+)	O
+compared	O
+with	O
+cardiac	O
+mitochondria	O
+isolated	O
+from	O
+saline	O
+-	O
+treated	O
+rats	O
+.	O
+	
+Mitochondrial	O
+calcium	O
+-	O
+loading	O
+capacity	O
+and	O
+the	O
+activity	O
+of	O
+NADH	O
+-	O
+dehydrogenase	O
+were	O
+also	O
+suppressed	O
+in	O
+cardiac	O
+mitochondria	O
+from	O
+doxorubicin	O
+-	O
+treated	O
+rats	O
+.	O
+	
+Doxorubicin	O
+treatment	O
+also	O
+caused	O
+a	O
+decrease	O
+in	O
+RCR	O
+for	O
+liver	O
+mitochondria	O
+(	O
+3	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+9	O
+versus	O
+5	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+for	O
+control	O
+rats	O
+)	O
+and	O
+inhibition	O
+of	O
+hepatic	O
+cytochrome	O
+oxidase	O
+activity	O
+.	O
+	
+Coadministration	O
+of	O
+carvedilol	O
+decreased	O
+the	O
+extent	O
+of	O
+cellular	O
+vacuolization	O
+in	O
+cardiac	O
+myocytes	O
+and	O
+prevented	O
+the	O
+inhibitory	O
+effect	O
+of	O
+doxorubicin	O
+on	O
+mitochondrial	O
+respiration	O
+in	O
+both	O
+heart	O
+and	O
+liver	O
+.	O
+	
+Carvedilol	O
+also	O
+prevented	O
+the	O
+decrease	O
+in	O
+mitochondrial	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+loading	O
+capacity	O
+and	O
+the	O
+inhibition	O
+of	O
+the	O
+respiratory	O
+complexes	O
+of	O
+heart	O
+mitochondria	O
+caused	O
+by	O
+doxorubicin	O
+.	O
+	
+Carvedilol	O
+by	O
+itself	O
+did	O
+not	O
+affect	O
+any	O
+of	O
+the	O
+parameters	O
+measured	O
+for	O
+heart	O
+or	O
+liver	O
+mitochondria	O
+.	O
+	
+It	O
+is	O
+concluded	O
+that	O
+this	O
+protection	O
+by	O
+carvedilol	O
+against	O
+both	O
+the	O
+structural	O
+and	O
+functional	O
+cardiac	O
+tissue	O
+damage	O
+may	O
+afford	O
+significant	O
+clinical	O
+advantage	O
+in	O
+minimizing	O
+the	O
+dose	O
+-	O
+limiting	O
+mitochondrial	B-NP
+dysfunction	I-NP
+and	O
+cardiomyopathy	B-NP
+that	O
+accompanies	O
+long	O
+-	O
+term	O
+doxorubicin	O
+therapy	O
+in	O
+cancer	B-NP
+patients	O
+.	O
+	
+Cocaine	O
+-	O
+induced	O
+hyperactivity	B-NP
+is	O
+more	O
+influenced	O
+by	O
+adenosine	O
+receptor	O
+agonists	O
+than	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B-NP
+.	O
+	
+The	O
+influence	O
+of	O
+adenosine	O
+receptor	O
+agonists	O
+and	O
+antagonists	O
+on	O
+cocaine	O
+-	O
+and	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B-NP
+was	O
+examined	O
+in	O
+mice	O
+.	O
+	
+All	O
+adenosine	O
+receptor	O
+agonists	O
+significantly	O
+decreased	B-NP
+the	I-NP
+locomotor	I-NP
+activity	I-NP
+in	O
+mice	O
+","	O
+and	O
+the	O
+effects	O
+were	O
+dose	O
+-	O
+dependent	O
+.	O
+	
+It	O
+seems	O
+that	O
+adenosine	O
+A1	O
+and	O
+A2	O
+receptors	O
+might	O
+be	O
+involved	O
+in	O
+this	O
+reaction	O
+.	O
+	
+Moreover	O
+","	O
+all	O
+adenosine	O
+receptor	O
+agonists	O
+:	O
+2	O
+-	O
+p	O
+-	O
+(	O
+2	O
+-	O
+carboxyethyl	O
+)	O
+phenethylamino	O
+-	O
+5	O
+'	O
+-	O
+N	O
+-	O
+ethylcarboxamidoadenosine	O
+(	O
+CGS	O
+21680	O
+)	O
+","	O
+A2A	O
+receptor	O
+agonist	O
+","	O
+N6	O
+-	O
+cyclopentyladenosine	O
+(	O
+CPA	O
+)	O
+","	O
+A1	O
+receptor	O
+agonist	O
+","	O
+and	O
+5	O
+'	O
+-	O
+N	O
+-	O
+ethylcarboxamidoadenosine	O
+(	O
+NECA	O
+)	O
+","	O
+A2	O
+/	O
+A1	O
+receptor	O
+agonist	O
+significantly	O
+and	O
+dose	O
+-	O
+dependently	O
+decreased	O
+cocaine	O
+-	O
+induced	O
+locomotor	O
+activity	O
+.	O
+	
+CPA	O
+reduced	O
+cocaine	O
+action	O
+at	O
+the	O
+doses	O
+which	O
+","	O
+given	O
+alone	O
+","	O
+did	O
+not	O
+influence	O
+motility	O
+","	O
+while	O
+CGS	O
+21680	O
+and	O
+NECA	O
+decreased	O
+the	O
+action	O
+of	O
+cocaine	O
+at	O
+the	O
+doses	O
+which	O
+","	O
+given	O
+alone	O
+","	O
+decreased	O
+locomotor	O
+activity	O
+in	O
+animals	O
+.	O
+	
+These	O
+results	O
+suggest	O
+the	O
+involvement	O
+of	O
+both	O
+adenosine	O
+receptors	O
+in	O
+the	O
+action	O
+of	O
+cocaine	O
+although	O
+agonists	O
+of	O
+A1	O
+receptors	O
+seem	O
+to	O
+have	O
+stronger	O
+influence	O
+on	O
+it	O
+.	O
+	
+The	O
+selective	O
+blockade	O
+of	O
+A2	O
+adenosine	O
+receptor	O
+by	O
+DMPX	O
+(	O
+3	O
+","	O
+7	O
+-	O
+dimethyl	O
+-	O
+1	O
+-	O
+propargylxanthine	O
+)	O
+significantly	O
+enhanced	O
+cocaine	O
+-	O
+induced	O
+locomotor	O
+activity	O
+of	O
+animals	O
+.	O
+	
+Caffeine	O
+had	O
+similar	O
+action	O
+but	O
+the	O
+effect	O
+was	O
+not	O
+significant	O
+.	O
+	
+CPT	O
+(	O
+8	O
+-	O
+cyclopentyltheophylline	O
+)	O
+-	O
+-	O
+A1	O
+receptor	O
+antagonist	O
+","	O
+did	O
+not	O
+show	O
+any	O
+influence	O
+in	O
+this	O
+test	O
+.	O
+	
+Similarly	O
+","	O
+all	O
+adenosine	O
+receptor	O
+agonists	O
+decreased	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B-NP
+","	O
+but	O
+at	O
+the	O
+higher	O
+doses	O
+than	O
+those	O
+which	O
+were	O
+active	O
+in	O
+cocaine	O
+-	O
+induced	O
+hyperactivity	B-NP
+.	O
+	
+The	O
+selective	O
+blockade	O
+of	O
+A2	O
+adenosine	O
+receptors	O
+(	O
+DMPX	O
+)	O
+and	O
+non	O
+-	O
+selective	O
+blockade	O
+of	O
+adenosine	O
+receptors	O
+(	O
+caffeine	O
+)	O
+significantly	O
+increased	O
+the	O
+action	O
+of	O
+amphetamine	O
+in	O
+the	O
+locomotor	O
+activity	O
+test	O
+.	O
+	
+Our	O
+results	O
+have	O
+shown	O
+that	O
+all	O
+adenosine	O
+receptor	O
+agonists	O
+(	O
+A1	O
+and	O
+A2	O
+)	O
+reduce	O
+cocaine	O
+-	O
+and	O
+amphetamine	O
+-	O
+induced	O
+locomotor	O
+activity	O
+and	O
+indicate	O
+that	O
+cocaine	O
+-	O
+induced	O
+hyperactivity	B-NP
+is	O
+more	O
+influenced	O
+by	O
+adenosine	O
+receptor	O
+agonists	O
+(	O
+particularly	O
+A1	O
+receptors	O
+)	O
+than	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B-NP
+.	O
+	
+Amiodarone	O
+and	O
+the	O
+risk	O
+of	O
+bradyarrhythmia	B-NP
+requiring	O
+permanent	O
+pacemaker	O
+in	O
+elderly	O
+patients	O
+with	O
+atrial	B-NP
+fibrillation	I-NP
+and	O
+prior	O
+myocardial	B-NP
+infarction	I-NP
+.	O
+	
+OBJECTIVES	O
+:	O
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+whether	O
+the	O
+use	O
+of	O
+amiodarone	O
+in	O
+patients	O
+with	O
+atrial	B-NP
+fibrillation	I-NP
+(	O
+AF	B-NP
+)	O
+increases	O
+the	O
+risk	O
+of	O
+bradyarrhythmia	B-NP
+requiring	O
+a	O
+permanent	O
+pacemaker	O
+.	O
+	
+BACKGROUND	O
+:	O
+Reports	O
+of	O
+severe	O
+bradyarrhythmia	B-NP
+during	O
+amiodarone	O
+therapy	O
+are	O
+infrequent	O
+and	O
+limited	O
+to	O
+studies	O
+assessing	O
+the	O
+therapy	O
+'	O
+s	O
+use	O
+in	O
+the	O
+management	O
+of	O
+patients	O
+with	O
+ventricular	B-NP
+arrhythmias	I-NP
+.	O
+	
+METHODS	O
+:	O
+A	O
+study	O
+cohort	O
+of	O
+8	O
+","	O
+770	O
+patients	O
+age	O
+>	O
+or	O
+=	O
+65	O
+years	O
+with	O
+a	O
+new	O
+diagnosis	O
+of	O
+AF	B-NP
+was	O
+identified	O
+from	O
+a	O
+provincewide	O
+database	O
+of	O
+Quebec	O
+residents	O
+with	O
+a	O
+myocardial	B-NP
+infarction	I-NP
+(	O
+MI	B-NP
+)	O
+between	O
+1991	O
+and	O
+1999	O
+.	O
+	
+Using	O
+a	O
+nested	O
+case	O
+-	O
+control	O
+design	O
+","	O
+477	O
+cases	O
+of	O
+bradyarrhythmia	B-NP
+requiring	O
+a	O
+permanent	O
+pacemaker	O
+were	O
+matched	O
+(	O
+1	O
+:	O
+4	O
+)	O
+to	O
+1	O
+","	O
+908	O
+controls	O
+.	O
+	
+Multivariable	O
+logistic	O
+regression	O
+was	O
+used	O
+to	O
+estimate	O
+the	O
+odds	O
+ratio	O
+(	O
+OR	O
+)	O
+of	O
+pacemaker	O
+insertion	O
+associated	O
+with	O
+amiodarone	O
+use	O
+","	O
+controlling	O
+for	O
+baseline	O
+risk	O
+factors	O
+and	O
+exposure	O
+to	O
+sotalol	O
+","	O
+Class	O
+I	O
+antiarrhythmic	O
+agents	O
+","	O
+beta	O
+-	O
+blockers	O
+","	O
+calcium	O
+channel	O
+blockers	O
+","	O
+and	O
+digoxin	O
+.	O
+	
+RESULTS	O
+:	O
+amiodarone	O
+use	O
+was	O
+associated	O
+with	O
+an	O
+increased	O
+risk	O
+of	O
+pacemaker	O
+insertion	O
+(	O
+OR	O
+:	O
+2	O
+.	O
+14	O
+","	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+:	O
+1	O
+.	O
+30	O
+to	O
+3	O
+.	O
+54	O
+)	O
+.	O
+	
+This	O
+effect	O
+was	O
+modified	O
+by	O
+gender	O
+","	O
+with	O
+a	O
+greater	O
+risk	O
+in	O
+women	O
+versus	O
+men	O
+(	O
+OR	O
+:	O
+3	O
+.	O
+86	O
+","	O
+95	O
+%	O
+CI	O
+:	O
+1	O
+.	O
+70	O
+to	O
+8	O
+.	O
+75	O
+vs	O
+.	O
+OR	O
+:	O
+1	O
+.	O
+52	O
+","	O
+95	O
+%	O
+CI	O
+:	O
+0	O
+.	O
+80	O
+to	O
+2	O
+.	O
+89	O
+)	O
+.	O
+	
+Digoxin	O
+was	O
+the	O
+only	O
+other	O
+medication	O
+associated	O
+with	O
+an	O
+increased	O
+risk	O
+of	O
+pacemaker	O
+insertion	O
+(	O
+OR	O
+:	O
+1	O
+.	O
+78	O
+","	O
+95	O
+%	O
+CI	O
+:	O
+1	O
+.	O
+37	O
+to	O
+2	O
+.	O
+31	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+This	O
+study	O
+suggests	O
+that	O
+the	O
+use	O
+of	O
+amiodarone	O
+in	O
+elderly	O
+patients	O
+with	O
+AF	B-NP
+and	O
+a	O
+previous	O
+MI	B-NP
+increases	O
+the	O
+risk	O
+of	O
+bradyarrhythmia	B-NP
+requiring	O
+a	O
+permanent	O
+pacemaker	O
+.	O
+	
+The	O
+finding	O
+of	O
+an	O
+augmented	O
+risk	O
+of	O
+pacemaker	O
+insertion	O
+in	O
+elderly	O
+women	O
+receiving	O
+amiodarone	O
+requires	O
+further	O
+investigation	O
+.	O
+	
+Indomethacin	O
+-	O
+induced	O
+morphologic	O
+changes	O
+in	O
+the	O
+rat	O
+urinary	O
+bladder	O
+epithelium	O
+.	O
+	
+OBJECTIVES	O
+:	O
+To	O
+evaluate	O
+the	O
+morphologic	O
+changes	O
+in	O
+rat	O
+urothelium	O
+induced	O
+by	O
+indomethacin	O
+.	O
+	
+Nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drug	O
+-	O
+induced	O
+cystitis	B-NP
+is	O
+a	O
+poorly	O
+recognized	O
+and	O
+under	O
+-	O
+reported	O
+condition	O
+.	O
+	
+In	O
+addition	O
+to	O
+tiaprofenic	O
+acid	O
+","	O
+indomethacin	O
+has	O
+been	O
+reported	O
+to	O
+be	O
+associated	O
+with	O
+this	O
+condition	O
+.	O
+	
+METHODS	O
+:	O
+Three	O
+groups	O
+were	O
+established	O
+:	O
+a	O
+control	O
+group	O
+(	O
+n	O
+=	O
+10	O
+)	O
+","	O
+a	O
+high	O
+-	O
+dose	O
+group	O
+(	O
+n	O
+=	O
+10	O
+)	O
+","	O
+treated	O
+with	O
+one	O
+intraperitoneal	O
+injection	O
+of	O
+indomethacin	O
+20	O
+mg	O
+/	O
+kg	O
+","	O
+and	O
+a	O
+therapeutic	O
+dose	O
+group	O
+(	O
+n	O
+=	O
+10	O
+)	O
+in	O
+which	O
+oral	O
+indomethacin	O
+was	O
+administered	O
+3	O
+.	O
+25	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+daily	O
+for	O
+3	O
+weeks	O
+.	O
+	
+The	O
+animals	O
+were	O
+then	O
+killed	O
+and	O
+the	O
+bladders	O
+removed	O
+for	O
+light	O
+and	O
+electron	O
+microscopic	O
+studies	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+light	O
+microscopic	O
+findings	O
+showed	O
+some	O
+focal	O
+epithelial	O
+degeneration	O
+that	O
+was	O
+more	O
+prominent	O
+in	O
+the	O
+high	O
+-	O
+dose	O
+group	O
+.	O
+	
+When	O
+compared	O
+with	O
+the	O
+control	O
+group	O
+","	O
+both	O
+indomethacin	O
+groups	O
+revealed	O
+statistically	O
+increased	O
+numbers	O
+of	O
+mast	O
+cells	O
+in	O
+the	O
+mucosa	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+and	O
+penetration	O
+of	O
+lanthanum	O
+nitrate	O
+through	O
+intercellular	O
+areas	O
+of	O
+the	O
+epithelium	O
+.	O
+	
+Furthermore	O
+","	O
+the	O
+difference	O
+in	O
+mast	O
+cell	O
+counts	O
+between	O
+the	O
+high	O
+and	O
+therapeutic	O
+dose	O
+groups	O
+was	O
+also	O
+statistically	O
+significant	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Indomethacin	O
+resulted	O
+in	O
+histopathologic	O
+findings	O
+typical	O
+of	O
+interstitial	B-NP
+cystitis	I-NP
+","	O
+such	O
+as	O
+leaky	O
+bladder	O
+epithelium	O
+and	O
+mucosal	O
+mastocytosis	B-NP
+.	O
+	
+The	O
+TRUE	O
+incidence	O
+of	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drug	O
+-	O
+induced	O
+cystitis	B-NP
+in	O
+humans	O
+must	O
+be	O
+clarified	O
+by	O
+prospective	O
+clinical	O
+trials	O
+.	O
+	
+An	O
+open	O
+-	O
+label	O
+phase	O
+II	O
+study	O
+of	O
+low	O
+-	O
+dose	O
+thalidomide	O
+in	O
+androgen	O
+-	O
+independent	O
+prostate	B-NP
+cancer	I-NP
+.	O
+	
+The	O
+antiangiogenic	O
+effects	O
+of	O
+thalidomide	O
+have	O
+been	O
+assessed	O
+in	O
+clinical	O
+trials	O
+in	O
+patients	O
+with	O
+various	O
+solid	O
+and	O
+haematological	B-NP
+malignancies	I-NP
+.	O
+	
+Thalidomide	O
+blocks	O
+the	O
+activity	O
+of	O
+angiogenic	O
+agents	O
+including	O
+bFGF	O
+","	O
+VEGF	O
+and	O
+IL	O
+-	O
+6	O
+.	O
+	
+We	O
+undertook	O
+an	O
+open	O
+-	O
+label	O
+study	O
+using	O
+thalidomide	O
+100	O
+mg	O
+once	O
+daily	O
+for	O
+up	O
+to	O
+6	O
+months	O
+in	O
+20	O
+men	O
+with	O
+androgen	O
+-	O
+independent	O
+prostate	B-NP
+cancer	I-NP
+.	O
+	
+The	O
+mean	O
+time	O
+of	O
+study	O
+was	O
+109	O
+days	O
+(	O
+median	O
+107	O
+","	O
+range	O
+4	O
+-	O
+184	O
+days	O
+)	O
+.	O
+	
+Patients	O
+underwent	O
+regular	O
+measurement	O
+of	O
+prostate	O
+-	O
+specific	O
+antigen	O
+(	O
+PSA	O
+)	O
+","	O
+urea	O
+and	O
+electrolytes	O
+","	O
+serum	O
+bFGF	O
+and	O
+VEGF	O
+.	O
+	
+Three	O
+men	O
+(	O
+15	O
+%	O
+)	O
+showed	O
+a	O
+decline	O
+in	O
+serum	O
+PSA	O
+of	O
+at	O
+least	O
+50	O
+%	O
+","	O
+sustained	O
+throughout	O
+treatment	O
+.	O
+	
+Of	O
+16	O
+men	O
+treated	O
+for	O
+at	O
+least	O
+2	O
+months	O
+","	O
+six	O
+(	O
+37	O
+.	O
+5	O
+%	O
+)	O
+showed	O
+a	O
+fall	O
+in	O
+absolute	O
+PSA	O
+by	O
+a	O
+median	O
+of	O
+48	O
+%	O
+.	O
+	
+Increasing	O
+levels	O
+of	O
+serum	O
+bFGF	O
+and	O
+VEGF	O
+were	O
+associated	O
+with	O
+progressive	O
+disease	O
+;	O
+five	O
+of	O
+six	O
+men	O
+who	O
+demonstrated	O
+a	O
+fall	O
+in	O
+PSA	O
+also	O
+showed	O
+a	O
+decline	O
+in	O
+bFGF	O
+and	O
+VEGF	O
+levels	O
+","	O
+and	O
+three	O
+of	O
+four	O
+men	O
+with	O
+a	O
+rising	O
+PSA	O
+showed	O
+an	O
+increase	O
+in	O
+both	O
+growth	O
+factors	O
+.	O
+	
+Adverse	O
+effects	O
+included	O
+constipation	B-NP
+","	O
+morning	O
+drowsiness	B-NP
+","	O
+dizziness	B-NP
+and	O
+rash	B-NP
+","	O
+and	O
+resulted	O
+in	O
+withdrawal	O
+from	O
+the	O
+study	O
+by	O
+three	O
+men	O
+.	O
+	
+Evidence	O
+of	O
+peripheral	B-NP
+sensory	I-NP
+neuropathy	I-NP
+was	O
+found	O
+in	O
+nine	O
+of	O
+13	O
+men	O
+before	O
+treatment	O
+.	O
+	
+In	O
+the	O
+seven	O
+men	O
+who	O
+completed	O
+six	O
+months	O
+on	O
+thalidomide	O
+","	O
+subclinical	O
+evidence	O
+of	O
+peripheral	B-NP
+neuropathy	I-NP
+was	O
+found	O
+in	O
+four	O
+before	O
+treatment	O
+","	O
+but	O
+in	O
+all	O
+seven	O
+at	O
+repeat	O
+testing	O
+.	O
+	
+The	O
+findings	O
+indicate	O
+that	O
+thalidomide	O
+may	O
+be	O
+an	O
+option	O
+for	O
+patients	O
+who	O
+have	O
+failed	O
+other	O
+forms	O
+of	O
+therapy	O
+","	O
+provided	O
+close	O
+follow	O
+-	O
+up	O
+is	O
+maintained	O
+for	O
+development	O
+of	O
+peripheral	B-NP
+neuropathy	I-NP
+.	O
+	
+Central	B-NP
+nervous	I-NP
+system	I-NP
+toxicity	I-NP
+following	O
+the	O
+administration	O
+of	O
+levobupivacaine	O
+for	O
+lumbar	O
+plexus	O
+block	O
+:	O
+A	O
+report	O
+of	O
+two	O
+cases	O
+.	O
+	
+BACKGROUND	O
+AND	O
+OBJECTIVES	O
+:	O
+Central	B-NP
+nervous	I-NP
+system	I-NP
+and	I-NP
+cardiac	I-NP
+toxicity	I-NP
+following	O
+the	O
+administration	O
+of	O
+local	O
+anesthetics	O
+is	O
+a	O
+recognized	O
+complication	O
+of	O
+regional	O
+anesthesia	O
+.	O
+	
+Levobupivacaine	O
+","	O
+the	O
+pure	O
+S	O
+(	O
+-	O
+)	O
+enantiomer	O
+of	O
+bupivacaine	O
+","	O
+was	O
+developed	O
+to	O
+improve	O
+the	O
+cardiac	O
+safety	O
+profile	O
+of	O
+bupivacaine	O
+.	O
+	
+We	O
+describe	O
+2	O
+cases	O
+of	O
+grand	B-NP
+mal	I-NP
+seizures	I-NP
+following	O
+accidental	O
+intravascular	O
+injection	O
+of	O
+levobupivacaine	O
+.	O
+	
+CASE	O
+REPORT	O
+:	O
+Two	O
+patients	O
+presenting	O
+for	O
+elective	O
+orthopedic	O
+surgery	O
+of	O
+the	O
+lower	O
+limb	O
+underwent	O
+blockade	O
+of	O
+the	O
+lumbar	O
+plexus	O
+via	O
+the	O
+posterior	O
+approach	O
+.	O
+	
+Immediately	O
+after	O
+the	O
+administration	O
+of	O
+levobupivacaine	O
+0	O
+.	O
+5	O
+%	O
+with	O
+epinephrine	O
+2	O
+.	O
+5	O
+microgram	O
+/	O
+mL	O
+","	O
+the	O
+patients	O
+developed	O
+grand	B-NP
+mal	I-NP
+seizures	I-NP
+","	O
+despite	O
+negative	O
+aspiration	O
+for	O
+blood	O
+and	O
+no	O
+clinical	O
+signs	O
+of	O
+intravenous	O
+epinephrine	O
+administration	O
+.	O
+	
+The	O
+seizures	B-NP
+were	O
+successfully	O
+treated	O
+with	O
+sodium	O
+thiopental	O
+in	O
+addition	O
+to	O
+succinylcholine	O
+in	O
+1	O
+patient	O
+.	O
+	
+Neither	O
+patient	O
+developed	O
+signs	O
+of	O
+cardiovascular	B-NP
+toxicity	I-NP
+.	O
+	
+Both	O
+patients	O
+were	O
+treated	O
+preoperatively	O
+with	O
+beta	O
+-	O
+adrenergic	O
+antagonist	O
+medications	O
+","	O
+which	O
+may	O
+have	O
+masked	O
+the	O
+cardiovascular	O
+signs	O
+of	O
+the	O
+unintentional	O
+intravascular	O
+administration	O
+of	O
+levobupivacaine	O
+with	O
+epinephrine	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Although	O
+levobupivacaine	O
+may	O
+have	O
+a	O
+safer	O
+cardiac	B-NP
+toxicity	I-NP
+profile	O
+than	O
+racemic	O
+bupivacaine	O
+","	O
+if	O
+adequate	O
+amounts	O
+of	O
+levobupivacaine	O
+reach	O
+the	O
+circulation	O
+","	O
+it	O
+will	O
+result	O
+in	O
+convulsions	B-NP
+.	O
+	
+Plasma	O
+concentrations	O
+sufficient	O
+to	O
+result	O
+in	O
+central	B-NP
+nervous	I-NP
+system	I-NP
+toxicity	I-NP
+did	O
+not	O
+produce	O
+manifestations	O
+of	O
+cardiac	B-NP
+toxicity	I-NP
+in	O
+these	O
+2	O
+patients	O
+.	O
+	
+Amiodarone	O
+-	O
+induced	O
+torsade	B-NP
+de	I-NP
+pointes	I-NP
+during	O
+bladder	O
+irrigation	O
+:	O
+an	O
+unusual	O
+presentation	O
+-	O
+-	O
+a	O
+case	O
+report	O
+.	O
+	
+The	O
+authors	O
+present	O
+a	O
+case	O
+of	O
+early	O
+(	O
+within	O
+4	O
+days	O
+)	O
+development	O
+of	O
+torsade	B-NP
+de	I-NP
+pointes	I-NP
+(	O
+TdP	B-NP
+)	O
+associated	O
+with	O
+oral	O
+amiodarone	O
+therapy	O
+.	O
+	
+Consistent	O
+with	O
+other	O
+reports	O
+this	O
+case	O
+of	O
+TdP	B-NP
+occurred	O
+in	O
+the	O
+context	O
+of	O
+multiple	O
+exacerbating	O
+factors	O
+including	O
+hypokalemia	B-NP
+and	O
+digoxin	O
+excess	O
+.	O
+	
+Transient	O
+prolongation	O
+of	O
+the	O
+QT	O
+during	O
+bladder	O
+irrigation	O
+prompted	O
+the	O
+episode	O
+of	O
+TdP	B-NP
+.	O
+	
+It	O
+is	O
+well	O
+known	O
+that	O
+bradycardia	B-NP
+exacerbates	O
+acquired	O
+TdP	B-NP
+.	O
+	
+The	O
+authors	O
+speculate	O
+that	O
+the	O
+increased	O
+vagal	O
+tone	O
+during	O
+bladder	O
+irrigation	O
+","	O
+a	O
+vagal	O
+maneuver	O
+","	O
+in	O
+the	O
+context	O
+of	O
+amiodarone	O
+therapy	O
+resulted	O
+in	O
+amiodarone	O
+-	O
+induced	O
+proarrhythmia	B-NP
+.	O
+	
+In	O
+the	O
+absence	O
+of	O
+amiodarone	O
+therapy	O
+","	O
+a	O
+second	O
+bladder	O
+irrigation	O
+did	O
+not	O
+induce	O
+TdP	B-NP
+despite	O
+hypokalemia	B-NP
+and	O
+hypomagnesemia	B-NP
+.	O
+	
+Anaesthetic	O
+complications	O
+associated	O
+with	O
+myotonia	B-NP
+congenita	I-NP
+:	O
+case	O
+study	O
+and	O
+comparison	O
+with	O
+other	O
+myotonic	B-NP
+disorders	I-NP
+.	O
+	
+Myotonia	B-NP
+congenita	I-NP
+(	O
+MC	B-NP
+)	O
+is	O
+caused	O
+by	O
+a	O
+defect	O
+in	O
+the	O
+skeletal	O
+muscle	O
+chloride	O
+channel	O
+function	O
+","	O
+which	O
+may	O
+cause	O
+sustained	B-NP
+membrane	I-NP
+depolarisation	I-NP
+.	O
+	
+We	O
+describe	O
+a	O
+previously	O
+healthy	O
+32	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+who	O
+developed	O
+a	O
+life	O
+-	O
+threatening	O
+muscle	B-NP
+spasm	I-NP
+and	O
+secondary	O
+ventilation	O
+difficulties	O
+following	O
+a	O
+preoperative	O
+injection	O
+of	O
+suxamethonium	O
+.	O
+	
+The	O
+muscle	B-NP
+spasms	I-NP
+disappeared	O
+spontaneously	O
+and	O
+the	O
+surgery	O
+proceeded	O
+without	O
+further	O
+problems	O
+.	O
+	
+When	O
+subsequently	O
+questioned	O
+","	O
+she	O
+reported	O
+minor	O
+symptoms	O
+suggesting	O
+a	O
+myotonic	B-NP
+condition	I-NP
+.	O
+	
+Myotonia	B-NP
+was	O
+found	O
+on	O
+clinical	O
+examination	O
+and	O
+EMG	O
+.	O
+	
+The	O
+diagnosis	O
+MC	B-NP
+was	O
+confirmed	O
+genetically	O
+.	O
+	
+Neither	O
+the	O
+patient	O
+nor	O
+the	O
+anaesthetist	O
+were	O
+aware	O
+of	O
+the	O
+diagnosis	O
+before	O
+this	O
+potentially	O
+lethal	O
+complication	O
+occurred	O
+.	O
+	
+We	O
+give	O
+a	O
+brief	O
+overview	O
+of	O
+ion	B-NP
+channel	I-NP
+disorders	I-NP
+including	O
+malignant	B-NP
+hyperthermia	I-NP
+and	O
+their	O
+anaesthetic	O
+considerations	O
+.	O
+	
+Respiratory	O
+pattern	O
+in	O
+a	O
+rat	O
+model	O
+of	O
+epilepsy	B-NP
+.	O
+	
+PURPOSE	O
+:	O
+Apnea	B-NP
+is	O
+known	O
+to	O
+occur	O
+during	O
+seizures	B-NP
+","	O
+but	O
+systematic	O
+studies	O
+of	O
+ictal	O
+respiratory	O
+changes	O
+in	O
+adults	O
+are	O
+few	O
+.	O
+	
+Data	O
+regarding	O
+respiratory	O
+pattern	O
+defects	O
+during	O
+interictal	O
+periods	O
+also	O
+are	O
+scarce	O
+.	O
+	
+Here	O
+we	O
+sought	O
+to	O
+generate	O
+information	O
+with	O
+regard	O
+to	O
+the	O
+interictal	O
+period	O
+in	O
+animals	O
+with	O
+pilocarpine	O
+-	O
+induced	O
+epilepsy	B-NP
+.	O
+	
+METHODS	O
+:	O
+Twelve	O
+rats	O
+(	O
+six	O
+chronically	O
+epileptic	B-NP
+animals	O
+and	O
+six	O
+controls	O
+)	O
+were	O
+anesthetized	O
+","	O
+given	O
+tracheotomies	O
+","	O
+and	O
+subjected	O
+to	O
+hyperventilation	B-NP
+or	O
+hypoventilation	O
+conditions	O
+.	O
+	
+Breathing	O
+movements	O
+caused	O
+changes	O
+in	O
+thoracic	O
+volume	O
+and	O
+forced	O
+air	O
+to	O
+flow	O
+tidally	O
+through	O
+a	O
+pneumotachograph	O
+.	O
+	
+This	O
+flow	O
+was	O
+measured	O
+by	O
+using	O
+a	O
+differential	O
+pressure	O
+transducer	O
+","	O
+passed	O
+through	O
+a	O
+polygraph	O
+","	O
+and	O
+from	O
+this	O
+to	O
+a	O
+computer	O
+with	O
+custom	O
+software	O
+that	O
+derived	O
+ventilation	O
+(	O
+VE	O
+)	O
+","	O
+tidal	O
+volume	O
+(	O
+VT	O
+)	O
+","	O
+inspiratory	O
+time	O
+(	O
+TI	O
+)	O
+","	O
+expiratory	O
+time	O
+(	O
+TE	O
+)	O
+","	O
+breathing	O
+frequency	O
+(	O
+f	O
+)	O
+","	O
+and	O
+mean	O
+inspiratory	O
+flow	O
+(	O
+VT	O
+/	O
+TI	O
+)	O
+on	O
+a	O
+breath	O
+-	O
+by	O
+-	O
+breath	O
+basis	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+hyperventilation	B-NP
+maneuver	O
+caused	O
+a	O
+decrease	O
+in	O
+spontaneous	O
+ventilation	O
+in	O
+pilocarpine	O
+-	O
+treated	O
+and	O
+control	O
+rats	O
+.	O
+	
+Although	O
+VE	O
+had	O
+a	O
+similar	O
+decrease	O
+in	O
+both	O
+groups	O
+","	O
+in	O
+the	O
+epileptic	B-NP
+group	O
+","	O
+the	O
+decrease	O
+in	O
+VE	O
+was	O
+due	O
+to	O
+a	O
+significant	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+increase	O
+in	O
+TE	O
+peak	O
+in	O
+relation	O
+to	O
+that	O
+of	O
+the	O
+control	O
+animals	O
+.	O
+	
+The	O
+hypoventilation	O
+maneuver	O
+led	O
+to	O
+an	O
+increase	O
+in	O
+the	O
+arterial	O
+Paco2	O
+","	O
+followed	O
+by	O
+an	O
+increase	O
+in	O
+VE	O
+.	O
+	
+In	O
+the	O
+epileptic	B-NP
+group	O
+","	O
+the	O
+increase	O
+in	O
+VE	O
+was	O
+mediated	O
+by	O
+a	O
+significant	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+decrease	O
+in	O
+TE	O
+peak	O
+compared	O
+with	O
+the	O
+control	O
+group	O
+.	O
+	
+Systemic	O
+application	O
+of	O
+KCN	O
+","	O
+to	O
+evaluate	O
+the	O
+effects	O
+of	O
+peripheral	O
+chemoreception	O
+activation	O
+on	O
+ventilation	O
+","	O
+led	O
+to	O
+a	O
+similar	O
+increase	O
+in	O
+VE	O
+for	O
+both	O
+groups	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+data	O
+indicate	O
+that	O
+pilocarpine	O
+-	O
+treated	O
+animals	O
+have	O
+an	O
+altered	O
+ability	O
+to	O
+react	O
+to	O
+(	O
+or	O
+compensate	O
+for	O
+)	O
+blood	O
+gas	O
+changes	O
+with	O
+changes	O
+in	O
+ventilation	O
+and	O
+suggest	O
+that	O
+it	O
+is	O
+centrally	O
+determined	O
+.	O
+	
+We	O
+speculate	O
+on	O
+the	O
+possible	O
+relation	O
+of	O
+the	O
+current	O
+findings	O
+on	O
+treating	O
+different	O
+epilepsy	B-NP
+-	O
+associated	O
+conditions	O
+.	O
+	
+Fatal	O
+myeloencephalopathy	B-NP
+due	O
+to	O
+intrathecal	O
+vincristine	O
+administration	O
+.	O
+	
+Vincristine	O
+was	O
+accidentally	O
+given	O
+intrathecally	O
+to	O
+a	O
+child	O
+with	O
+leukaemia	B-NP
+","	O
+producing	O
+sensory	B-NP
+and	I-NP
+motor	I-NP
+dysfunction	I-NP
+followed	O
+by	O
+encephalopathy	B-NP
+and	O
+death	O
+.	O
+	
+Separate	O
+times	O
+for	O
+administering	O
+vincristine	O
+and	O
+intrathecal	O
+therapy	O
+is	O
+recommended	O
+.	O
+	
+Progesterone	O
+potentiation	O
+of	O
+bupivacaine	O
+arrhythmogenicity	O
+in	O
+pentobarbital	O
+-	O
+anesthetized	O
+rats	O
+and	O
+beating	O
+rat	O
+heart	O
+cell	O
+cultures	O
+.	O
+	
+The	O
+effects	O
+of	O
+progesterone	O
+treatment	O
+on	O
+bupivacaine	O
+arrhythmogenicity	O
+in	O
+beating	O
+rat	O
+heart	O
+myocyte	O
+cultures	O
+and	O
+on	O
+anesthetized	O
+rats	O
+were	O
+determined	O
+.	O
+	
+After	O
+determining	O
+the	O
+bupivacaine	O
+AD50	O
+(	O
+the	O
+concentration	O
+of	O
+bupivacaine	O
+that	O
+caused	O
+50	O
+%	O
+of	O
+all	O
+beating	O
+rat	O
+heart	O
+myocyte	O
+cultures	O
+to	O
+become	O
+arrhythmic	B-NP
+)	O
+","	O
+we	O
+determined	O
+the	O
+effect	O
+of	O
+1	O
+-	O
+hour	O
+progesterone	O
+HCl	O
+exposure	O
+on	O
+myocyte	O
+contractile	O
+rhythm	O
+.	O
+	
+Each	O
+concentration	O
+of	O
+progesterone	O
+(	O
+6	O
+.	O
+25	O
+","	O
+12	O
+.	O
+5	O
+","	O
+25	O
+","	O
+and	O
+50	O
+micrograms	O
+/	O
+ml	O
+)	O
+caused	O
+a	O
+significant	O
+and	O
+concentration	O
+-	O
+dependent	O
+reduction	O
+in	O
+the	O
+AD50	O
+for	O
+bupivacaine	O
+.	O
+	
+Estradiol	O
+treatment	O
+also	O
+increased	O
+the	O
+arrhythmogenicity	O
+of	O
+bupivacaine	O
+in	O
+myocyte	O
+cultures	O
+","	O
+but	O
+was	O
+only	O
+one	O
+fourth	O
+as	O
+potent	O
+as	O
+progesterone	O
+.	O
+	
+Neither	O
+progesterone	O
+nor	O
+estradiol	O
+effects	O
+on	O
+bupivacaine	O
+arrhythmogenicity	O
+were	O
+potentiated	O
+by	O
+epinephrine	O
+.	O
+	
+Chronic	O
+progesterone	O
+pretreatment	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+for	O
+21	O
+days	O
+)	O
+caused	O
+a	O
+significant	O
+increase	O
+in	O
+bupivacaine	O
+arrhythmogenicity	O
+in	O
+intact	O
+pentobarbital	O
+-	O
+anesthetized	O
+rats	O
+.	O
+	
+There	O
+was	O
+a	O
+significant	O
+decrease	O
+in	O
+the	O
+time	O
+to	O
+onset	O
+of	O
+arrhythmia	B-NP
+as	O
+compared	O
+with	O
+control	O
+nonprogesterone	O
+-	O
+treated	O
+rats	O
+(	O
+6	O
+.	O
+2	O
++	O
+/	O
+-	O
+1	O
+.	O
+3	O
+vs	O
+.	O
+30	O
+.	O
+8	O
++	O
+/	O
+-	O
+2	O
+.	O
+5	O
+min	O
+","	O
+mean	O
++	O
+/	O
+-	O
+SE	O
+)	O
+.	O
+	
+The	O
+results	O
+of	O
+this	O
+study	O
+indicate	O
+that	O
+progesterone	O
+can	O
+potentiate	O
+bupivacaine	O
+arrhythmogenicity	O
+both	O
+in	O
+vivo	O
+and	O
+in	O
+vitro	O
+.	O
+	
+Potentiation	O
+of	O
+bupivacaine	O
+arrhythmia	B-NP
+in	O
+myocyte	O
+cultures	O
+suggests	O
+that	O
+this	O
+effect	O
+is	O
+at	O
+least	O
+partly	O
+mediated	O
+at	O
+the	O
+myocyte	O
+level	O
+.	O
+	
+Increased	O
+serum	O
+soluble	O
+Fas	O
+in	O
+patients	O
+with	O
+acute	B-NP
+liver	I-NP
+failure	I-NP
+due	O
+to	O
+paracetamol	O
+overdose	B-NP
+.	O
+	
+BACKGROUND	O
+/	O
+AIMS	O
+:	O
+Experimental	O
+studies	O
+have	O
+suggested	O
+that	O
+apoptosis	O
+via	O
+the	O
+Fas	O
+/	O
+Fas	O
+Ligand	O
+signaling	O
+system	O
+may	O
+play	O
+an	O
+important	O
+role	O
+in	O
+the	O
+development	O
+of	O
+acute	B-NP
+liver	I-NP
+failure	I-NP
+.	O
+	
+The	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+soluble	O
+form	O
+of	O
+Fas	O
+in	O
+patients	O
+with	O
+acute	B-NP
+liver	I-NP
+failure	I-NP
+.	O
+	
+METHODOLOGY	O
+:	O
+Serum	O
+levels	O
+of	O
+sFas	O
+(	O
+soluble	O
+Fas	O
+)	O
+were	O
+measured	O
+by	O
+ELISA	O
+in	O
+24	O
+patients	O
+with	O
+acute	B-NP
+liver	I-NP
+failure	I-NP
+and	O
+10	O
+normal	O
+control	O
+subjects	O
+.	O
+	
+Serum	O
+levels	O
+of	O
+tumor	B-NP
+necrosis	B-NP
+factor	O
+-	O
+alpha	O
+and	O
+interferon	O
+-	O
+gamma	O
+were	O
+also	O
+determined	O
+by	O
+ELISA	O
+.	O
+	
+RESULTS	O
+:	O
+Serum	O
+sFas	O
+was	O
+significantly	O
+increased	O
+in	O
+patients	O
+with	O
+acute	B-NP
+liver	I-NP
+failure	I-NP
+(	O
+median	O
+","	O
+26	O
+.	O
+8	O
+U	O
+/	O
+mL	O
+;	O
+range	O
+","	O
+6	O
+.	O
+9	O
+-	O
+52	O
+.	O
+7	O
+U	O
+/	O
+mL	O
+)	O
+compared	O
+to	O
+the	O
+normal	O
+controls	O
+(	O
+median	O
+","	O
+8	O
+.	O
+6	O
+U	O
+/	O
+mL	O
+;	O
+range	O
+","	O
+6	O
+.	O
+5	O
+-	O
+12	O
+.	O
+0	O
+U	O
+/	O
+mL	O
+","	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Levels	O
+were	O
+significantly	O
+greater	O
+in	O
+patients	O
+with	O
+acute	B-NP
+liver	I-NP
+failure	I-NP
+due	O
+to	O
+paracetamol	O
+overdose	B-NP
+(	O
+median	O
+","	O
+28	O
+.	O
+7	O
+U	O
+/	O
+mL	O
+;	O
+range	O
+","	O
+12	O
+.	O
+8	O
+-	O
+52	O
+.	O
+7	O
+U	O
+/	O
+mL	O
+","	O
+n	O
+=	O
+17	O
+)	O
+than	O
+those	O
+due	O
+to	O
+non	O
+-	O
+A	O
+to	O
+E	O
+hepatitis	B-NP
+(	O
+median	O
+","	O
+12	O
+.	O
+5	O
+U	O
+/	O
+mL	O
+;	O
+range	O
+","	O
+6	O
+.	O
+9	O
+-	O
+46	O
+.	O
+0	O
+U	O
+/	O
+mL	O
+","	O
+n	O
+=	O
+7	O
+","	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+There	O
+was	O
+no	O
+relationship	O
+of	O
+sFas	O
+to	O
+eventual	O
+outcome	O
+in	O
+the	O
+patients	O
+.	O
+	
+A	O
+significant	O
+correlation	O
+was	O
+observed	O
+between	O
+serum	O
+sFas	O
+levels	O
+and	O
+aspartate	O
+aminotransferase	O
+(	O
+r	O
+=	O
+0	O
+.	O
+613	O
+","	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+increased	O
+concentration	O
+of	O
+sFas	O
+in	O
+serum	O
+of	O
+patients	O
+with	O
+acute	B-NP
+liver	I-NP
+failure	I-NP
+may	O
+reflect	O
+activation	O
+of	O
+Fas	O
+-	O
+mediated	O
+apoptosis	O
+in	O
+the	O
+liver	O
+and	O
+this	O
+together	O
+with	O
+increased	O
+tumor	B-NP
+necrosis	B-NP
+factor	O
+-	O
+alpha	O
+may	O
+be	O
+an	O
+important	O
+factor	O
+in	O
+liver	O
+cell	O
+loss	O
+.	O
+	
+Bilateral	O
+subthalamic	O
+nucleus	O
+stimulation	O
+for	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+High	O
+frequency	O
+stimulation	O
+of	O
+the	O
+subthalamic	O
+nucleus	O
+(	O
+STN	O
+)	O
+is	O
+known	O
+to	O
+ameliorate	O
+the	O
+signs	O
+and	O
+symptoms	O
+of	O
+advanced	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+AIM	O
+:	O
+We	O
+studied	O
+the	O
+effect	O
+of	O
+high	O
+frequency	O
+STN	O
+stimulation	O
+in	O
+23	O
+patients	O
+.	O
+	
+METHOD	O
+:	O
+Twenty	O
+-	O
+three	O
+patients	O
+suffering	O
+from	O
+severe	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+(	O
+Stages	O
+III	O
+-	O
+V	O
+on	O
+Hoehn	O
+and	O
+Yahr	O
+scale	O
+)	O
+and	O
+","	O
+particularly	O
+bradykinesia	B-NP
+","	O
+rigidity	B-NP
+","	O
+and	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B-NP
+underwent	O
+bilateral	O
+implantation	O
+of	O
+electrodes	O
+in	O
+the	O
+STN	O
+.	O
+	
+Preoperative	O
+and	O
+postoperative	O
+assessments	O
+of	O
+these	O
+patients	O
+at	O
+1	O
+","	O
+3	O
+","	O
+6	O
+and	O
+12	O
+months	O
+follow	O
+-	O
+up	O
+","	O
+in	O
+"	O
+on	O
+"	O
+and	O
+"	O
+off	O
+"	O
+drug	O
+conditions	O
+","	O
+was	O
+carried	O
+out	O
+using	O
+Unified	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+Disease	I-NP
+Rating	O
+Scale	O
+","	O
+Hoehn	O
+and	O
+Yahr	O
+staging	O
+","	O
+England	O
+activities	O
+of	O
+daily	O
+living	O
+score	O
+and	O
+video	O
+recordings	O
+.	O
+	
+RESULTS	O
+:	O
+After	O
+one	O
+year	O
+of	O
+electrical	O
+stimulation	O
+of	O
+the	O
+STN	O
+","	O
+the	O
+patients	O
+'	O
+scores	O
+for	O
+activities	O
+of	O
+daily	O
+living	O
+and	O
+motor	O
+examination	O
+scores	O
+(	O
+Unified	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+Disease	I-NP
+Rating	O
+Scale	O
+parts	O
+II	O
+and	O
+III	O
+)	O
+off	O
+medication	O
+improved	O
+by	O
+62	O
+%	O
+and	O
+61	O
+%	O
+respectively	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+The	O
+subscores	O
+for	O
+the	O
+akinesia	B-NP
+","	O
+rigidity	B-NP
+","	O
+tremor	B-NP
+and	O
+gait	O
+also	O
+improved	O
+.	O
+	
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+The	O
+average	O
+levodopa	O
+dose	O
+decreased	O
+from	O
+813	O
+mg	O
+to	O
+359	O
+mg	O
+.	O
+	
+The	O
+cognitive	O
+functions	O
+remained	O
+unchanged	O
+.	O
+	
+Two	O
+patients	O
+developed	O
+device	O
+-	O
+related	O
+complications	O
+and	O
+two	O
+patients	O
+experienced	O
+abnormal	O
+weight	O
+gain	O
+.	O
+	
+CONCLUSION	O
+:	O
+Bilateral	O
+subthalamic	O
+nucleus	O
+stimulation	O
+is	O
+an	O
+effective	O
+treatment	O
+for	O
+advanced	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+It	O
+reduces	O
+the	O
+severity	O
+of	O
+"	O
+off	O
+"	O
+phase	O
+symptoms	O
+","	O
+improves	O
+the	O
+axial	O
+symptoms	O
+and	O
+reduces	O
+levodopa	O
+requirements	O
+.	O
+	
+The	O
+reduction	O
+in	O
+the	O
+levodopa	O
+dose	O
+is	O
+useful	O
+in	O
+controlling	O
+drug	B-NP
+-	I-NP
+induced	I-NP
+dyskinesias	I-NP
+.	O
+	
+Acute	B-NP
+renal	I-NP
+failure	I-NP
+occurring	O
+during	O
+intravenous	O
+desferrioxamine	O
+therapy	O
+:	O
+recovery	O
+after	O
+haemodialysis	O
+.	O
+	
+A	O
+patient	O
+with	O
+transfusion	O
+-	O
+dependent	O
+thalassemia	B-NP
+was	O
+undergoing	O
+home	O
+intravenous	O
+desferrioxamine	O
+(	O
+DFX	O
+)	O
+treatment	O
+by	O
+means	O
+of	O
+a	O
+totally	O
+implanted	O
+system	O
+because	O
+of	O
+his	O
+poor	O
+compliance	O
+with	O
+the	O
+nightly	O
+subcutaneous	O
+therapy	O
+.	O
+	
+Due	O
+to	O
+an	O
+accidental	O
+malfunctioning	O
+of	O
+the	O
+infusion	O
+pump	O
+","	O
+the	O
+patient	O
+was	O
+inadvertently	O
+administered	O
+a	O
+toxic	O
+dosage	O
+of	O
+the	O
+drug	O
+which	O
+caused	O
+renal	B-NP
+insufficiency	I-NP
+.	O
+	
+Given	O
+the	O
+progressive	O
+deterioration	O
+of	O
+the	O
+symptoms	O
+and	O
+of	O
+the	O
+laboratory	O
+values	O
+","	O
+despite	O
+adequate	O
+medical	O
+treatment	O
+","	O
+a	O
+decision	O
+was	O
+made	O
+to	O
+introduce	O
+haemodialytical	O
+therapy	O
+in	O
+order	O
+to	O
+remove	O
+the	O
+drug	O
+and	O
+therapy	O
+reduce	O
+the	O
+nephrotoxicity	B-NP
+.	O
+	
+From	O
+the	O
+results	O
+obtained	O
+","	O
+haemodialysis	O
+can	O
+therefore	O
+be	O
+suggested	O
+as	O
+a	O
+useful	O
+therapy	O
+in	O
+rare	O
+cases	O
+of	O
+progressive	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+caused	O
+by	O
+desferrioxamine	O
+.	O
+	
+Ocular	O
+motility	O
+changes	O
+after	O
+subtenon	O
+carboplatin	O
+chemotherapy	O
+for	O
+retinoblastoma	B-NP
+.	O
+	
+BACKGROUND	O
+:	O
+Focal	O
+subtenon	O
+carboplatin	O
+injections	O
+have	O
+recently	O
+been	O
+used	O
+as	O
+a	O
+presumably	O
+toxicity	B-NP
+-	O
+free	O
+adjunct	O
+to	O
+systemic	O
+chemotherapy	O
+for	O
+intraocular	O
+retinoblastoma	B-NP
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+report	O
+our	O
+clinical	O
+experience	O
+with	O
+abnormal	B-NP
+ocular	I-NP
+motility	I-NP
+in	O
+patients	O
+treated	O
+with	O
+subtenon	O
+carboplatin	O
+chemotherapy	O
+.	O
+	
+METHODS	O
+:	O
+We	O
+noted	O
+abnormal	B-NP
+ocular	I-NP
+motility	I-NP
+in	O
+10	O
+consecutive	O
+patients	O
+with	O
+retinoblastoma	B-NP
+who	O
+had	O
+received	O
+subtenon	O
+carboplatin	O
+.	O
+	
+During	O
+ocular	O
+manipulation	O
+under	O
+general	O
+anesthesia	O
+","	O
+we	O
+assessed	O
+their	O
+eyes	O
+by	O
+forced	O
+duction	O
+testing	O
+","	O
+comparing	O
+ocular	O
+motility	O
+after	O
+tumor	B-NP
+control	O
+with	O
+ocular	O
+motility	O
+at	O
+diagnosis	O
+.	O
+	
+Eyes	O
+subsequently	O
+enucleated	O
+because	O
+of	O
+treatment	O
+failure	O
+(	O
+n	O
+=	O
+4	O
+)	O
+were	O
+examined	O
+histologically	O
+.	O
+	
+RESULTS	O
+:	O
+Limitation	O
+of	O
+ocular	O
+motility	O
+was	O
+detected	O
+in	O
+all	O
+12	O
+eyes	O
+of	O
+10	O
+patients	O
+treated	O
+for	O
+intraocular	O
+retinoblastoma	B-NP
+with	O
+1	O
+to	O
+6	O
+injections	O
+of	O
+subtenon	O
+carboplatin	O
+as	O
+part	O
+of	O
+multimodality	O
+therapy	O
+.	O
+	
+Histopathological	O
+examination	O
+revealed	O
+many	O
+lipophages	O
+in	O
+the	O
+periorbital	O
+fat	O
+surrounding	O
+the	O
+optic	O
+nerve	O
+in	O
+1	O
+eye	O
+","	O
+indicative	O
+of	O
+phagocytosis	O
+of	O
+previously	O
+existing	O
+fat	O
+cells	O
+and	O
+suggesting	O
+prior	O
+fat	O
+necrosis	B-NP
+.	O
+	
+The	O
+enucleations	O
+were	O
+technically	O
+difficult	O
+and	O
+hazardous	O
+for	O
+globe	O
+rupture	B-NP
+because	O
+of	O
+extensive	O
+orbital	O
+soft	O
+tissue	O
+adhesions	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Subtenon	O
+carboplatin	O
+chemotherapy	O
+is	O
+associated	O
+with	O
+significant	O
+fibrosis	B-NP
+of	O
+orbital	O
+soft	O
+tissues	O
+","	O
+leading	O
+to	O
+mechanical	O
+restriction	O
+of	O
+eye	O
+movements	O
+and	O
+making	O
+subsequent	O
+enucleation	O
+difficult	O
+.	O
+	
+Subtenon	O
+carboplatin	O
+is	O
+not	O
+free	O
+of	O
+toxicity	B-NP
+","	O
+and	O
+its	O
+use	O
+is	O
+best	O
+restricted	O
+to	O
+specific	O
+indications	O
+.	O
+	
+Ethambutol	O
+and	O
+optic	B-NP
+neuropathy	I-NP
+.	O
+	
+PURPOSE	O
+:	O
+To	O
+demonstrate	O
+the	O
+association	O
+between	O
+ethambutol	O
+and	O
+optic	B-NP
+neuropathy	I-NP
+.	O
+	
+METHOD	O
+:	O
+Thirteen	O
+patients	O
+who	O
+developed	O
+optic	B-NP
+neuropathy	I-NP
+after	O
+being	O
+treated	O
+with	O
+ethambutol	O
+for	O
+tuberculosis	B-NP
+of	I-NP
+the	I-NP
+lung	I-NP
+or	I-NP
+lymph	I-NP
+node	I-NP
+at	O
+Siriraj	O
+Hospital	O
+between	O
+1997	O
+and	O
+2001	O
+were	O
+retrospectively	O
+reviewed	O
+.	O
+	
+The	O
+clinical	O
+characteristics	O
+and	O
+initial	O
+and	O
+final	O
+visual	O
+acuity	O
+were	O
+analyzed	O
+to	O
+determine	O
+visual	O
+outcome	O
+.	O
+	
+RESULTS	O
+:	O
+All	O
+patients	O
+had	O
+optic	B-NP
+neuropathy	I-NP
+between	O
+1	O
+to	O
+6	O
+months	O
+(	O
+mean	O
+=	O
+2	O
+.	O
+9	O
+months	O
+)	O
+after	O
+starting	O
+ethambutol	O
+therapy	O
+at	O
+a	O
+dosage	O
+ranging	O
+from	O
+13	O
+to	O
+20	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+(	O
+mean	O
+=	O
+17	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+)	O
+.	O
+	
+Seven	O
+(	O
+54	O
+%	O
+)	O
+of	O
+the	O
+13	O
+patients	O
+experienced	O
+visual	O
+recovery	O
+after	O
+stopping	O
+the	O
+drug	O
+.	O
+	
+Of	O
+6	O
+patients	O
+with	O
+irreversible	O
+visual	B-NP
+impairment	I-NP
+","	O
+4	O
+patients	O
+had	O
+diabetes	B-NP
+mellitus	I-NP
+","	O
+glaucoma	B-NP
+and	O
+a	O
+history	O
+of	O
+heavy	O
+smoking	O
+.	O
+	
+CONCLUSION	O
+:	O
+Early	O
+recognition	O
+of	O
+optic	B-NP
+neuropathy	I-NP
+should	O
+be	O
+considered	O
+in	O
+patients	O
+with	O
+ethambutol	O
+therapy	O
+.	O
+	
+A	O
+low	O
+dose	O
+and	O
+prompt	O
+discontinuation	O
+of	O
+the	O
+drug	O
+is	O
+recommended	O
+particularly	O
+in	O
+individuals	O
+with	O
+diabetes	B-NP
+mellitus	I-NP
+","	O
+glaucoma	B-NP
+or	O
+who	O
+are	O
+heavy	O
+smokers	O
+.	O
+	
+Treatment	O
+of	O
+compensatory	O
+gustatory	B-NP
+hyperhidrosis	I-NP
+with	O
+topical	O
+glycopyrrolate	O
+.	O
+	
+Gustatory	B-NP
+hyperhidrosis	I-NP
+is	O
+facial	O
+sweating	B-NP
+usually	O
+associated	O
+with	O
+the	O
+eating	O
+of	O
+hot	O
+spicy	O
+food	O
+or	O
+even	O
+smelling	O
+this	O
+food	O
+.	O
+	
+Current	O
+options	O
+of	O
+treatment	O
+include	O
+oral	O
+anticholinergic	O
+drugs	O
+","	O
+the	O
+topical	O
+application	O
+of	O
+anticholinergics	O
+or	O
+aluminum	O
+chloride	O
+","	O
+and	O
+the	O
+injection	O
+of	O
+botulinum	O
+toxin	O
+.	O
+	
+Thirteen	O
+patients	O
+have	O
+been	O
+treated	O
+to	O
+date	O
+with	O
+1	O
+.	O
+5	O
+%	O
+or	O
+2	O
+%	O
+topical	O
+glycopyrrolate	O
+.	O
+	
+All	O
+patients	O
+had	O
+gustatory	B-NP
+hyperhidrosis	I-NP
+","	O
+which	O
+interfered	O
+with	O
+their	O
+social	O
+activities	O
+","	O
+after	O
+transthroacic	O
+endoscopic	O
+sympathectomy	O
+","	O
+and	O
+which	O
+was	O
+associated	O
+with	O
+compensatory	O
+focal	O
+hyperhidrosis	B-NP
+.	O
+	
+After	O
+applying	O
+topical	O
+glycopyrrolate	O
+","	O
+the	O
+subjective	O
+effect	O
+was	O
+excellent	O
+(	O
+no	O
+sweating	B-NP
+after	O
+eating	O
+hot	O
+spicy	O
+food	O
+)	O
+in	O
+10	O
+patients	O
+(	O
+77	O
+%	O
+)	O
+","	O
+and	O
+fair	O
+(	O
+clearly	O
+reduced	O
+sweating	B-NP
+)	O
+in	O
+3	O
+patients	O
+(	O
+23	O
+%	O
+)	O
+.	O
+	
+All	O
+had	O
+reported	O
+incidents	O
+of	O
+being	O
+very	O
+embarrassed	O
+whilst	O
+eating	O
+hot	O
+spicy	O
+foods	O
+.	O
+	
+Adverse	O
+effects	O
+included	O
+a	O
+mildly	O
+dry	B-NP
+mouth	I-NP
+and	O
+a	O
+sore	B-NP
+throat	I-NP
+in	O
+2	O
+patients	O
+(	O
+2	O
+%	O
+glycopyrrolate	O
+)	O
+","	O
+a	O
+light	O
+headache	B-NP
+in	O
+1	O
+patient	O
+(	O
+1	O
+.	O
+5	O
+%	O
+glycopyrrolate	O
+)	O
+.	O
+	
+The	O
+topical	O
+application	O
+of	O
+a	O
+glycopyrrolate	O
+pad	O
+appeared	O
+to	O
+be	O
+safe	O
+","	O
+efficacious	O
+","	O
+well	O
+tolerated	O
+","	O
+and	O
+a	O
+convenient	O
+method	O
+of	O
+treatment	O
+for	O
+moderate	O
+to	O
+severe	O
+symptoms	O
+of	O
+gustatory	B-NP
+hyperhidrosis	I-NP
+in	O
+post	O
+transthoracic	O
+endoscopic	O
+sympathectomy	O
+or	O
+sympathicotomy	O
+patients	O
+","	O
+with	O
+few	O
+side	O
+effects	O
+.	O
+	
+Neuroleptic	O
+-	O
+associated	O
+hyperprolactinemia	B-NP
+.	O
+	
+Can	O
+it	O
+be	O
+treated	O
+with	O
+bromocriptine	O
+?	O
+	
+Six	O
+stable	O
+psychiatric	O
+outpatients	O
+with	O
+hyperprolactinemia	B-NP
+and	O
+amenorrhea	B-NP
+/	O
+oligomenorrhea	B-NP
+associated	O
+with	O
+their	O
+neuroleptic	O
+medications	O
+were	O
+treated	O
+with	O
+bromocriptine	O
+.	O
+	
+Daily	O
+dosages	O
+of	O
+5	O
+-	O
+10	O
+mg	O
+corrected	O
+the	O
+hyperprolactinemia	B-NP
+and	O
+restored	O
+menstruation	O
+in	O
+four	O
+of	O
+the	O
+six	O
+patients	O
+.	O
+	
+One	O
+woman	O
+","	O
+however	O
+","	O
+developed	O
+worsened	O
+psychiatric	B-NP
+symptoms	I-NP
+while	O
+taking	O
+bromocriptine	O
+","	O
+and	O
+it	O
+was	O
+discontinued	O
+.	O
+	
+Thus	O
+","	O
+three	O
+of	O
+six	O
+patients	O
+had	O
+their	O
+menstrual	O
+irregularity	O
+successfully	O
+corrected	O
+with	O
+bromocriptine	O
+.	O
+	
+This	O
+suggests	O
+that	O
+bromocriptine	O
+should	O
+be	O
+further	O
+evaluated	O
+as	O
+potential	O
+therapy	O
+for	O
+neuroleptic	O
+-	O
+associated	O
+hyperprolactinemia	B-NP
+and	O
+amenorrhea	B-NP
+/	O
+galactorrhea	B-NP
+.	O
+	
+Ethacrynic	O
+acid	O
+-	O
+induced	O
+convulsions	B-NP
+and	O
+brain	O
+neurotransmitters	O
+in	O
+mice	O
+.	O
+	
+Intracerebroventricular	O
+injection	O
+of	O
+ethacrynic	O
+acid	O
+(	O
+50	O
+%	O
+convulsive	B-NP
+dose	O
+;	O
+50	O
+micrograms	O
+/	O
+mouse	O
+)	O
+accelerated	O
+the	O
+synthesis	O
+/	O
+turnover	O
+of	O
+5	O
+-	O
+hydroxytryptamine	O
+(	O
+5	O
+-	O
+HT	O
+)	O
+but	O
+suppressed	O
+the	O
+synthesis	O
+of	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+and	O
+acetylcholine	O
+in	O
+mouse	O
+brain	O
+.	O
+	
+These	O
+effects	O
+were	O
+completely	O
+antagonized	O
+by	O
+pretreatment	O
+with	O
+a	O
+glutamate	O
+/	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+antagonist	O
+","	O
+aminophosphonovaleric	O
+acid	O
+.	O
+	
+In	O
+ethacrynic	O
+acid	O
+-	O
+induced	O
+convulsions	B-NP
+","	O
+these	O
+neurotransmitter	O
+systems	O
+may	O
+be	O
+differentially	O
+modulated	O
+","	O
+probably	O
+through	O
+activation	O
+of	O
+glutaminergic	O
+neurons	O
+in	O
+the	O
+brain	O
+.	O
+	
+Pharmacology	O
+of	O
+gamma	O
+-	O
+aminobutyric	O
+acidA	O
+receptor	O
+complex	O
+after	O
+the	O
+in	O
+vivo	O
+administration	O
+of	O
+the	O
+anxioselective	O
+and	O
+anticonvulsant	O
+beta	O
+-	O
+carboline	O
+derivative	O
+abecarnil	O
+.	O
+	
+In	O
+rodents	O
+","	O
+the	O
+effect	O
+of	O
+the	O
+beta	O
+-	O
+carboline	O
+derivative	O
+isopropyl	O
+-	O
+6	O
+-	O
+benzyloxy	O
+-	O
+4	O
+-	O
+methoxymethyl	O
+-	O
+beta	O
+-	O
+carboline	O
+-	O
+3	O
+-	O
+carboxylate	O
+(	O
+abecarrnil	O
+)	O
+","	O
+a	O
+new	O
+ligand	O
+for	O
+benzodiazepine	O
+receptors	O
+possessing	O
+anxiolytic	O
+and	O
+anticonvulsant	O
+properties	O
+","	O
+was	O
+evaluated	O
+on	O
+the	O
+function	O
+of	O
+central	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+(	O
+GABA	O
+)	O
+A	O
+receptor	O
+complex	O
+","	O
+both	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+.	O
+	
+Added	O
+in	O
+vitro	O
+to	O
+rat	O
+cortical	O
+membrane	O
+preparation	O
+","	O
+abecarnil	O
+increased	O
+[	O
+3H	O
+]	O
+GABA	O
+binding	O
+","	O
+enhanced	O
+muscimol	O
+-	O
+stimulated	O
+36Cl	O
+-	O
+uptake	O
+and	O
+reduced	O
+the	O
+binding	O
+of	O
+t	O
+-	O
+[	O
+35S	O
+]	O
+butylbicyclophosphorothionate	O
+(	O
+[	O
+35S	O
+]	O
+TBPS	O
+)	O
+.	O
+	
+These	O
+effects	O
+were	O
+similar	O
+to	O
+those	O
+induced	O
+by	O
+diazepam	O
+","	O
+whereas	O
+the	O
+partial	O
+agonist	O
+Ro	O
+16	O
+-	O
+6028	O
+(	O
+tert	O
+-	O
+butyl	O
+-	O
+(	O
+S	O
+)	O
+-	O
+8	O
+-	O
+bromo	O
+-	O
+11	O
+","	O
+12	O
+","	O
+13	O
+","	O
+13a	O
+-	O
+tetrahydro	O
+-	O
+9	O
+-	O
+oxo	O
+-	O
+9H	O
+-	O
+imidazo	O
+[	O
+1	O
+","	O
+5	O
+-	O
+a	O
+]	O
+-	O
+pyrrolo	O
+-	O
+[	O
+2	O
+","	O
+1	O
+-	O
+c	O
+]	O
+[	O
+1	O
+","	O
+4	O
+]	O
+benzodiazepine	O
+-	O
+1	O
+-	O
+carboxylate	O
+)	O
+showed	O
+very	O
+weak	O
+efficacy	O
+in	O
+these	O
+biochemical	O
+tests	O
+.	O
+	
+After	O
+i	O
+.	O
+p	O
+.	O
+injection	O
+to	O
+rats	O
+","	O
+abecarnil	O
+and	O
+diazepam	O
+decreased	O
+in	O
+a	O
+time	O
+-	O
+dependent	O
+and	O
+dose	O
+-	O
+related	O
+(	O
+0	O
+.	O
+25	O
+-	O
+20	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+manner	O
+[	O
+35S	O
+]	O
+TBPS	O
+binding	O
+measured	O
+ex	O
+vivo	O
+in	O
+the	O
+cerebral	O
+cortex	O
+.	O
+	
+Moreover	O
+","	O
+both	O
+drugs	O
+at	O
+the	O
+dose	O
+of	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+antagonized	O
+completely	O
+the	O
+convulsant	O
+activity	O
+and	O
+the	O
+increase	O
+of	O
+[	O
+35S	O
+]	O
+TBPS	O
+binding	O
+induced	O
+by	O
+isoniazide	O
+(	O
+350	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+as	O
+well	O
+as	O
+the	O
+increase	O
+of	O
+[	O
+35S	O
+]	O
+TBPS	O
+binding	O
+induced	O
+by	O
+foot	O
+-	O
+shock	O
+stress	O
+.	O
+	
+To	O
+better	O
+correlate	O
+the	O
+biochemical	O
+and	O
+the	O
+pharmacological	O
+effects	O
+","	O
+we	O
+studied	O
+the	O
+action	O
+of	O
+abecarnil	O
+on	O
+[	O
+35S	O
+]	O
+TBPS	O
+binding	O
+","	O
+exploratory	O
+motility	O
+and	O
+on	O
+isoniazid	O
+-	O
+induced	O
+biochemical	O
+and	O
+pharmacological	O
+effects	O
+in	O
+mice	O
+.	O
+	
+In	O
+these	O
+animals	O
+","	O
+abecarnil	O
+produced	O
+a	O
+paralleled	O
+dose	O
+-	O
+dependent	O
+(	O
+0	O
+.	O
+5	O
+-	O
+1	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+reduction	O
+of	O
+both	O
+motor	O
+behavior	O
+and	O
+cortical	O
+[	O
+35S	O
+]	O
+TBPS	O
+binding	O
+.	O
+	
+Moreover	O
+","	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+of	O
+this	O
+beta	O
+-	O
+carboline	O
+reduced	O
+markedly	O
+the	O
+increase	O
+of	O
+[	O
+35S	O
+]	O
+TBPS	O
+binding	O
+and	O
+the	O
+convulsions	B-NP
+induced	O
+by	O
+isoniazid	O
+(	O
+200	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+	
+Recurrent	O
+myocardial	B-NP
+infarction	I-NP
+in	O
+a	O
+postpartum	O
+patient	O
+receiving	O
+bromocriptine	O
+.	O
+	
+Myocardial	B-NP
+infarction	I-NP
+in	O
+puerperium	O
+is	O
+infrequently	O
+reported	O
+.	O
+	
+Spasm	B-NP
+","	O
+coronary	O
+dissection	O
+","	O
+or	O
+atheromatous	O
+etiology	O
+has	O
+been	O
+described	O
+.	O
+	
+Bromocriptine	O
+has	O
+been	O
+implicated	O
+in	O
+several	O
+previous	O
+case	O
+reports	O
+of	O
+myocardial	B-NP
+infarction	I-NP
+in	O
+the	O
+puerperium	O
+.	O
+	
+Our	O
+case	O
+(	O
+including	O
+an	O
+inadvertent	O
+rechallenge	O
+)	O
+suggests	O
+such	O
+a	O
+relationship	O
+.	O
+	
+Although	O
+generally	O
+regarded	O
+as	O
+"	O
+safe	O
+,	O
+"	O
+possible	O
+serious	O
+cardiac	O
+effects	O
+of	O
+bromocriptine	O
+should	O
+be	O
+acknowledged	O
+.	O
+	
+Asterixis	B-NP
+induced	O
+by	O
+carbamazepine	O
+therapy	O
+.	O
+	
+There	O
+are	O
+very	O
+few	O
+reports	O
+about	O
+asterixis	B-NP
+as	O
+a	O
+side	O
+effect	O
+of	O
+treatment	O
+with	O
+psychopharmacologic	O
+agents	O
+.	O
+	
+In	O
+this	O
+report	O
+we	O
+present	O
+four	O
+patients	O
+treated	O
+with	O
+a	O
+combination	O
+of	O
+different	O
+psychotropic	O
+drugs	O
+","	O
+in	O
+whom	O
+asterixis	B-NP
+was	O
+triggered	O
+either	O
+by	O
+adding	O
+carbamazepine	O
+(	O
+CBZ	O
+)	O
+to	O
+a	O
+treatment	O
+regimen	O
+","	O
+or	O
+by	O
+increasing	O
+its	O
+dosage	O
+.	O
+	
+Neither	O
+dosage	O
+nor	O
+serum	O
+levels	O
+of	O
+CBZ	O
+were	O
+in	O
+a	O
+higher	O
+range	O
+.	O
+	
+We	O
+consider	O
+asterixis	B-NP
+to	O
+be	O
+an	O
+easily	O
+overlooked	O
+sign	O
+of	O
+neurotoxicity	B-NP
+","	O
+which	O
+may	O
+occur	O
+even	O
+at	O
+low	O
+or	O
+moderate	O
+dosage	O
+levels	O
+","	O
+if	O
+certain	O
+drugs	O
+as	O
+lithium	O
+or	O
+clozapine	O
+are	O
+used	O
+in	O
+combination	O
+with	O
+CBZ	O
+.	O
+	
+Pharmacodynamics	O
+of	O
+the	O
+hypotensive	B-NP
+effect	O
+of	O
+levodopa	O
+in	O
+parkinsonian	B-NP
+patients	O
+.	O
+	
+Blood	O
+pressure	O
+effects	O
+of	O
+i	O
+.	O
+v	O
+.	O
+levodopa	O
+were	O
+examined	O
+in	O
+parkinsonian	B-NP
+patients	O
+with	O
+stable	O
+and	O
+fluctuating	O
+responses	O
+to	O
+levodopa	O
+.	O
+	
+The	O
+magnitude	O
+of	O
+the	O
+hypotensive	B-NP
+effect	O
+of	O
+levodopa	O
+was	O
+concentration	O
+dependent	O
+and	O
+was	O
+fit	O
+to	O
+an	O
+Emax	O
+model	O
+in	O
+fluctuating	O
+responders	O
+.	O
+	
+Stable	O
+responders	O
+demonstrated	O
+a	O
+small	O
+hypotensive	B-NP
+response	O
+.	O
+	
+Baseline	O
+blood	O
+pressures	O
+were	O
+higher	O
+in	O
+fluctuating	O
+patients	O
+;	O
+a	O
+higher	O
+baseline	O
+blood	O
+pressure	O
+correlated	O
+with	O
+greater	O
+hypotensive	B-NP
+effects	O
+.	O
+	
+Antiparkinsonian	O
+effects	O
+of	O
+levodopa	O
+temporally	O
+correlated	O
+with	O
+blood	O
+pressure	O
+changes	O
+.	O
+	
+Phenylalanine	O
+","	O
+a	O
+large	O
+neutral	O
+amino	O
+acid	O
+(	O
+LNAA	O
+)	O
+competing	O
+with	O
+levodopa	O
+for	O
+transport	O
+across	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+","	O
+reduced	O
+the	O
+hypotensive	B-NP
+and	O
+antiparkinsonian	O
+effects	O
+of	O
+levodopa	O
+.	O
+	
+We	O
+conclude	O
+that	O
+levodopa	O
+has	O
+a	O
+central	O
+hypotensive	B-NP
+action	O
+that	O
+parallels	O
+the	O
+motor	O
+effects	O
+in	O
+fluctuating	O
+patients	O
+.	O
+	
+The	O
+hypotensive	B-NP
+effect	O
+appears	O
+to	O
+be	O
+related	O
+to	O
+the	O
+higher	O
+baseline	O
+blood	O
+pressure	O
+we	O
+observed	O
+in	O
+fluctuating	O
+patients	O
+relative	O
+to	O
+stable	O
+patients	O
+.	O
+	
+Syndrome	B-NP
+of	I-NP
+inappropriate	I-NP
+secretion	I-NP
+of	I-NP
+antidiuretic	I-NP
+hormone	I-NP
+after	O
+infusional	O
+vincristine	O
+.	O
+	
+A	O
+77	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+refractory	O
+multiple	B-NP
+myeloma	I-NP
+was	O
+treated	O
+with	O
+a	O
+4	O
+-	O
+day	O
+continuous	O
+intravenous	O
+infusion	O
+of	O
+vincristine	O
+and	O
+doxorubicin	O
+and	O
+4	O
+days	O
+of	O
+oral	O
+dexamethasone	O
+.	O
+	
+Nine	O
+days	O
+after	O
+her	O
+second	O
+cycle	O
+she	O
+presented	O
+with	O
+lethargy	B-NP
+and	O
+weakness	B-NP
+associated	O
+with	O
+hyponatremia	B-NP
+.	O
+	
+Evaluation	O
+revealed	O
+the	O
+syndrome	B-NP
+of	I-NP
+inappropriate	I-NP
+secretion	I-NP
+of	I-NP
+antidiuretic	I-NP
+hormone	I-NP
+","	O
+which	O
+was	O
+attributed	O
+to	O
+the	O
+vincristine	O
+infusion	O
+.	O
+	
+After	O
+normal	O
+serum	O
+sodium	O
+levels	O
+returned	O
+","	O
+further	O
+doxorubicin	O
+and	O
+dexamethasone	O
+chemotherapy	O
+without	O
+vincristine	O
+did	O
+not	O
+produce	O
+this	O
+complication	O
+.	O
+	
+Heart	B-NP
+failure	I-NP
+:	O
+to	O
+digitalise	O
+or	O
+not	O
+?	O
+	
+The	O
+view	O
+against	O
+.	O
+	
+Despite	O
+extensive	O
+clinical	O
+experience	O
+the	O
+role	O
+of	O
+digoxin	O
+is	O
+still	O
+not	O
+well	O
+defined	O
+.	O
+	
+In	O
+patients	O
+with	O
+atrial	B-NP
+fibrillation	I-NP
+digoxin	O
+is	O
+beneficial	O
+for	O
+ventricular	O
+rate	O
+control	O
+.	O
+	
+For	O
+patients	O
+in	O
+sinus	O
+rhythm	O
+and	O
+heart	B-NP
+failure	I-NP
+the	O
+situation	O
+is	O
+less	O
+clear	O
+.	O
+	
+Digoxin	O
+has	O
+a	O
+narrow	O
+therapeutic	O
+:	O
+toxic	O
+ratio	O
+and	O
+concentrations	O
+are	O
+affected	O
+by	O
+a	O
+number	O
+of	O
+drugs	O
+.	O
+	
+Also	O
+","	O
+digoxin	O
+has	O
+undesirable	O
+effects	O
+such	O
+as	O
+increasing	O
+peripheral	O
+resistance	O
+and	O
+myocardial	O
+demands	O
+","	O
+and	O
+causing	O
+arrhythmias	B-NP
+.	O
+	
+There	O
+is	O
+a	O
+paucity	O
+of	O
+data	O
+from	O
+well	O
+-	O
+designed	O
+trials	O
+.	O
+	
+The	O
+trials	O
+that	O
+are	O
+available	O
+are	O
+generally	O
+small	O
+with	O
+limitations	O
+in	O
+design	O
+and	O
+these	O
+show	O
+variation	O
+in	O
+patient	O
+benefit	O
+.	O
+	
+More	O
+convincing	O
+evidence	O
+is	O
+required	O
+showing	O
+that	O
+digoxin	O
+improves	O
+symptoms	O
+or	O
+exercise	O
+capacity	O
+.	O
+	
+Furthermore	O
+","	O
+no	O
+trial	O
+has	O
+had	O
+sufficient	O
+power	O
+to	O
+evaluate	O
+mortality	O
+.	O
+	
+Pooled	O
+analysis	O
+of	O
+the	O
+effects	O
+of	O
+other	O
+inotropic	O
+drugs	O
+shows	O
+an	O
+excess	O
+mortality	O
+and	O
+there	O
+is	O
+a	O
+possibility	O
+that	O
+digoxin	O
+may	O
+increase	O
+mortality	O
+after	O
+myocardial	B-NP
+infarction	I-NP
+(	O
+MI	B-NP
+)	O
+.	O
+	
+Angiotensin	O
+-	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+inhibitors	O
+should	O
+be	O
+used	O
+first	O
+as	O
+they	O
+are	O
+safer	O
+","	O
+do	O
+not	O
+require	O
+blood	O
+level	O
+monitoring	O
+","	O
+modify	O
+progression	O
+of	O
+disease	O
+","	O
+relieve	O
+symptoms	O
+","	O
+improve	O
+exercise	O
+tolerance	O
+and	O
+reduce	O
+mortality	O
+.	O
+	
+Caution	O
+should	O
+be	O
+exercised	O
+in	O
+using	O
+digoxin	O
+until	O
+large	O
+mortality	O
+trials	O
+are	O
+completed	O
+showing	O
+either	O
+benefit	O
+or	O
+harm	O
+.	O
+	
+Until	O
+then	O
+digoxin	O
+should	O
+be	O
+considered	O
+a	O
+third	O
+-	O
+line	O
+therapy	O
+.	O
+	
+Isradipine	O
+treatment	O
+for	O
+hypertension	B-NP
+in	O
+general	O
+practice	O
+in	O
+Hong	O
+Kong	O
+.	O
+	
+A	O
+6	O
+-	O
+week	O
+open	O
+study	O
+of	O
+the	O
+introduction	O
+of	O
+isradipine	O
+treatment	O
+was	O
+conducted	O
+in	O
+general	O
+practice	O
+in	O
+Hong	O
+Kong	O
+.	O
+	
+303	O
+Chinese	O
+patients	O
+with	O
+mild	O
+to	O
+moderate	O
+hypertension	B-NP
+entered	O
+the	O
+study	O
+.	O
+	
+Side	O
+effects	O
+were	O
+reported	O
+in	O
+21	O
+%	O
+of	O
+patients	O
+and	O
+caused	O
+withdrawal	O
+from	O
+the	O
+study	O
+in	O
+3	O
+patients	O
+.	O
+	
+The	O
+main	O
+side	O
+-	O
+effects	O
+were	O
+headache	B-NP
+","	O
+dizziness	B-NP
+","	O
+palpitation	B-NP
+and	O
+flushing	B-NP
+and	O
+these	O
+were	O
+not	O
+more	O
+frequent	O
+than	O
+reported	O
+in	O
+other	O
+studies	O
+with	O
+isradipine	O
+or	O
+with	O
+placebo	O
+.	O
+	
+Supine	O
+blood	O
+pressure	O
+was	O
+reduced	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+from	O
+170	O
++	O
+/	O
+-	O
+20	O
+/	O
+102	O
++	O
+/	O
+-	O
+6	O
+mmHg	O
+to	O
+153	O
++	O
+/	O
+-	O
+19	O
+/	O
+92	O
++	O
+/	O
+-	O
+8	O
+","	O
+147	O
++	O
+/	O
+-	O
+18	O
+/	O
+88	O
++	O
+/	O
+-	O
+7	O
+and	O
+144	O
++	O
+/	O
+-	O
+14	O
+/	O
+87	O
++	O
+/	O
+-	O
+6	O
+mmHg	O
+at	O
+2	O
+","	O
+4	O
+and	O
+6	O
+weeks	O
+respectively	O
+in	O
+evaluable	O
+patients	O
+.	O
+	
+Similar	O
+reductions	O
+occurred	O
+in	O
+standing	O
+blood	O
+pressure	O
+and	O
+there	O
+was	O
+no	O
+evidence	O
+of	O
+postural	B-NP
+hypotension	I-NP
+.	O
+	
+Normalization	O
+and	O
+responder	O
+rates	O
+at	O
+6	O
+weeks	O
+were	O
+86	O
+%	O
+and	O
+69	O
+%	O
+respectively	O
+.	O
+	
+Dosage	O
+was	O
+increased	O
+from	O
+2	O
+.	O
+5	O
+mg	O
+b	O
+.	O
+d	O
+.	O
+to	O
+5	O
+mg	O
+b	O
+.	O
+d	O
+.	O
+at	O
+4	O
+weeks	O
+in	O
+patients	O
+with	O
+diastolic	O
+blood	O
+pressure	O
+greater	O
+than	O
+90	O
+mmHg	O
+and	O
+their	O
+further	O
+response	O
+was	O
+greater	O
+than	O
+those	O
+remaining	O
+on	O
+2	O
+.	O
+5	O
+mg	O
+b	O
+.	O
+d	O
+.	O
+	
+Pharmacological	O
+characteristics	O
+and	O
+side	O
+effects	O
+of	O
+a	O
+new	O
+galenic	O
+formulation	O
+of	O
+propofol	O
+without	O
+soyabean	O
+oil	O
+.	O
+	
+We	O
+compared	O
+the	O
+pharmacokinetics	O
+","	O
+pharmacodynamics	O
+and	O
+safety	O
+profile	O
+of	O
+a	O
+new	O
+galenic	O
+formulation	O
+of	O
+propofol	O
+(	O
+AM149	O
+1	O
+%	O
+)	O
+","	O
+which	O
+does	O
+not	O
+contain	O
+soyabean	O
+oil	O
+","	O
+with	O
+a	O
+standard	O
+formulation	O
+of	O
+propofol	O
+(	O
+Disoprivan	O
+1	O
+%	O
+)	O
+.	O
+	
+In	O
+a	O
+randomised	O
+","	O
+double	O
+-	O
+blind	O
+","	O
+cross	O
+-	O
+over	O
+study	O
+","	O
+30	O
+healthy	O
+volunteers	O
+received	O
+a	O
+single	O
+intravenous	O
+bolus	O
+injection	O
+of	O
+2	O
+.	O
+5	O
+mg	O
+.	O
+kg	O
+-	O
+1	O
+propofol	O
+.	O
+	
+Plasma	O
+propofol	O
+levels	O
+were	O
+measured	O
+for	O
+48	O
+h	O
+following	O
+drug	O
+administration	O
+and	O
+evaluated	O
+according	O
+to	O
+a	O
+three	O
+-	O
+compartment	O
+model	O
+.	O
+	
+The	O
+pharmacodynamic	O
+parameters	O
+assessed	O
+included	O
+induction	O
+and	O
+emergence	O
+times	O
+","	O
+respiratory	O
+and	O
+cardiovascular	O
+effects	O
+","	O
+and	O
+pain	B-NP
+on	O
+injection	O
+.	O
+	
+Patients	O
+were	O
+monitored	O
+for	O
+side	O
+effects	O
+over	O
+48	O
+h	O
+.	O
+	
+Owing	O
+to	O
+a	O
+high	O
+incidence	O
+of	O
+thrombophlebitis	B-NP
+","	O
+the	O
+study	O
+was	O
+terminated	O
+prematurely	O
+and	O
+only	O
+the	O
+data	O
+of	O
+the	O
+two	O
+parallel	O
+treatment	O
+groups	O
+(	O
+15	O
+patients	O
+in	O
+each	O
+group	O
+)	O
+were	O
+analysed	O
+.	O
+	
+Plasma	O
+concentrations	O
+did	O
+not	O
+differ	O
+significantly	O
+between	O
+the	O
+two	O
+formulations	O
+.	O
+	
+Anaesthesia	O
+induction	O
+and	O
+emergence	O
+times	O
+","	O
+respiratory	O
+and	O
+cardiovascular	O
+variables	O
+showed	O
+no	O
+significant	O
+differences	O
+between	O
+the	O
+two	O
+treatment	O
+groups	O
+.	O
+	
+Pain	B-NP
+on	O
+injection	O
+(	O
+80	O
+vs	O
+.	O
+20	O
+%	O
+","	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+and	O
+thrombophlebitis	B-NP
+(	O
+93	O
+.	O
+3	O
+vs	O
+.	O
+6	O
+.	O
+6	O
+%	O
+","	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+occurred	O
+more	O
+frequently	O
+with	O
+AM149	O
+than	O
+with	O
+Disoprivan	O
+.	O
+	
+Although	O
+both	O
+formulations	O
+had	O
+similar	O
+pharmacokinetic	O
+and	O
+pharmacodynamic	O
+profiles	O
+the	O
+new	O
+formulation	O
+is	O
+not	O
+suitable	O
+for	O
+clinical	O
+use	O
+due	O
+to	O
+the	O
+high	O
+incidence	O
+of	O
+thrombophlebitis	B-NP
+produced	O
+.	O
+	
+Pure	B-NP
+red	I-NP
+cell	I-NP
+aplasia	I-NP
+","	O
+toxic	B-NP
+dermatitis	I-NP
+and	O
+lymphadenopathy	B-NP
+in	O
+a	O
+patient	O
+taking	O
+diphenylhydantoin	O
+.	O
+	
+A	O
+patient	O
+taking	O
+diphenylhydantoin	O
+for	O
+3	O
+weeks	O
+developed	O
+a	O
+generalized	O
+skin	B-NP
+rash	I-NP
+","	O
+lymphadenopathy	B-NP
+and	O
+pure	B-NP
+red	I-NP
+cell	I-NP
+aplasia	I-NP
+.	O
+	
+After	O
+withdrawal	O
+of	O
+the	O
+pharmacon	O
+all	O
+symptoms	O
+disappeared	O
+spontaneously	O
+.	O
+	
+Skin	B-NP
+rash	I-NP
+is	O
+a	O
+well	O
+-	O
+known	O
+complication	O
+of	O
+diphenylhydantoin	O
+treatment	O
+as	O
+is	O
+benign	O
+and	O
+malignant	O
+lymphadenopathy	B-NP
+.	O
+	
+Pure	B-NP
+red	I-NP
+cell	I-NP
+aplasia	I-NP
+associated	O
+with	O
+diphenylhydantoin	O
+medication	O
+has	O
+been	O
+reported	O
+in	O
+3	O
+patients	O
+.	O
+	
+The	O
+exact	O
+mechanism	O
+by	O
+which	O
+diphenylhydantoin	O
+exerts	O
+its	O
+toxic	O
+effects	O
+is	O
+not	O
+known	O
+.	O
+	
+In	O
+this	O
+patient	O
+the	O
+time	O
+relation	O
+between	O
+the	O
+ingestion	O
+of	O
+diphenylhydantoin	O
+and	O
+the	O
+occurrence	O
+of	O
+the	O
+skin	B-NP
+rash	I-NP
+","	O
+lymphadenopathy	B-NP
+and	O
+pure	B-NP
+red	I-NP
+cell	I-NP
+aplasia	I-NP
+is	O
+very	O
+suggestive	O
+of	O
+a	O
+direct	O
+connection	O
+.	O
+	
+Vinorelbine	O
+-	O
+related	O
+cardiac	O
+events	O
+:	O
+a	O
+meta	O
+-	O
+analysis	O
+of	O
+randomized	O
+clinical	O
+trials	O
+.	O
+	
+Several	O
+cases	O
+of	O
+cardiac	O
+adverse	O
+reactions	O
+related	O
+to	O
+vinorelbine	O
+(	O
+VNR	O
+)	O
+have	O
+been	O
+reported	O
+in	O
+the	O
+literature	O
+.	O
+	
+In	O
+order	O
+to	O
+quantify	O
+the	O
+incidence	O
+of	O
+these	O
+cardiac	O
+events	O
+","	O
+we	O
+performed	O
+a	O
+meta	O
+-	O
+analysis	O
+of	O
+clinical	O
+trials	O
+comparing	O
+VNR	O
+with	O
+other	O
+chemotherapeutic	O
+agents	O
+in	O
+the	O
+treatment	O
+of	O
+various	O
+malignancies	B-NP
+.	O
+	
+Randomized	O
+clinical	O
+trials	O
+comparing	O
+VNR	O
+with	O
+other	O
+drugs	O
+in	O
+the	O
+treatment	O
+of	O
+cancer	B-NP
+were	O
+searched	O
+in	O
+Medline	O
+","	O
+Embase	O
+","	O
+Evidence	O
+-	O
+based	O
+Medicine	O
+Reviews	O
+databases	O
+and	O
+the	O
+Cochrane	O
+library	O
+from	O
+1987	O
+to	O
+2002	O
+.	O
+	
+Outcomes	O
+of	O
+interest	O
+were	O
+severe	O
+cardiac	O
+events	O
+","	O
+toxic	O
+deaths	O
+and	O
+cardiac	O
+event	O
+-	O
+related	O
+deaths	O
+reported	O
+in	O
+each	O
+publication	O
+.	O
+	
+We	O
+found	O
+19	O
+trials	O
+","	O
+involving	O
+2441	O
+patients	O
+treated	O
+by	O
+VNR	O
+and	O
+2050	O
+control	O
+patients	O
+.	O
+	
+The	O
+incidence	O
+of	O
+cardiac	O
+events	O
+with	O
+VNR	O
+was	O
+1	O
+.	O
+19	O
+%	O
+[	O
+95	O
+%	O
+confidence	O
+interval	O
+(	O
+CI	O
+)	O
+(	O
+0	O
+.	O
+75	O
+;	O
+1	O
+.	O
+67	O
+)	O
+]	O
+.	O
+	
+There	O
+was	O
+no	O
+difference	O
+in	O
+the	O
+risk	O
+of	O
+cardiac	O
+events	O
+between	O
+VNR	O
+and	O
+other	O
+drugs	O
+[	O
+odds	O
+ratio	O
+:	O
+0	O
+.	O
+92	O
+","	O
+95	O
+%	O
+CI	O
+(	O
+0	O
+.	O
+54	O
+;	O
+1	O
+.	O
+55	O
+)	O
+]	O
+.	O
+	
+The	O
+risk	O
+of	O
+VNR	O
+cardiac	O
+events	O
+was	O
+similar	O
+to	O
+vindesine	O
+(	O
+VDS	O
+)	O
+and	O
+other	O
+cardiotoxic	B-NP
+drugs	O
+[	O
+fluorouracil	O
+","	O
+anthracyclines	O
+","	O
+gemcitabine	O
+(	O
+GEM	O
+)	O
+em	O
+leader	O
+]	O
+.	O
+	
+Even	O
+if	O
+it	O
+did	O
+not	O
+reach	O
+statistical	O
+significance	O
+because	O
+of	O
+a	O
+few	O
+number	O
+of	O
+cases	O
+","	O
+the	O
+risk	O
+was	O
+lower	O
+in	O
+trials	O
+excluding	O
+patients	O
+with	O
+cardiac	O
+history	O
+","	O
+and	O
+seemed	O
+to	O
+be	O
+higher	O
+in	O
+trials	O
+including	O
+patients	O
+with	O
+pre	O
+-	O
+existing	O
+cardiac	B-NP
+diseases	I-NP
+.	O
+	
+Vinorelbine	O
+-	O
+related	O
+cardiac	O
+events	O
+concern	O
+about	O
+1	O
+%	O
+of	O
+treated	O
+patients	O
+in	O
+clinical	O
+trials	O
+.	O
+	
+However	O
+","	O
+the	O
+risk	O
+associated	O
+with	O
+VNR	O
+seems	O
+to	O
+be	O
+similar	O
+to	O
+that	O
+of	O
+other	O
+chemotherapeutic	O
+agents	O
+in	O
+the	O
+same	O
+indications	O
+.	O
+	
+MRI	O
+findings	O
+of	O
+hypoxic	O
+cortical	O
+laminar	O
+necrosis	B-NP
+in	O
+a	O
+child	O
+with	O
+hemolytic	B-NP
+anemia	I-NP
+crisis	O
+.	O
+	
+We	O
+present	O
+magnetic	O
+resonance	O
+imaging	O
+findings	O
+of	O
+a	O
+5	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+who	O
+had	O
+a	O
+rapidly	O
+installing	O
+hemolytic	B-NP
+anemia	I-NP
+crisis	O
+induced	O
+by	O
+trimethoprim	O
+-	O
+sulfomethoxazole	O
+","	O
+resulting	O
+in	O
+cerebral	B-NP
+anoxia	I-NP
+leading	O
+to	O
+permanent	O
+damage	O
+.	O
+	
+Magnetic	O
+Resonance	O
+imaging	O
+revealed	O
+cortical	O
+laminar	O
+necrosis	B-NP
+in	O
+arterial	O
+border	O
+zones	O
+in	O
+both	O
+cerebral	O
+hemispheres	O
+","	O
+ischemic	O
+changes	O
+in	O
+subcortical	O
+white	O
+matter	O
+of	O
+left	O
+cerebral	O
+hemisphere	O
+","	O
+and	O
+in	O
+the	O
+left	O
+putamen	O
+.	O
+	
+Although	O
+cortical	O
+laminar	O
+necrosis	B-NP
+is	O
+a	O
+classic	O
+entity	O
+in	O
+adulthood	O
+related	O
+to	O
+conditions	O
+of	O
+energy	O
+depletions	O
+","	O
+there	O
+are	O
+few	O
+reports	O
+available	O
+in	O
+children	O
+.	O
+	
+A	O
+wide	O
+review	O
+of	O
+the	O
+literature	O
+is	O
+also	O
+presented	O
+.	O
+	
+The	O
+natural	O
+history	O
+of	O
+Vigabatrin	O
+associated	O
+visual	B-NP
+field	I-NP
+defects	I-NP
+in	O
+patients	O
+electing	O
+to	O
+continue	O
+their	O
+medication	O
+.	O
+	
+PURPOSE	O
+:	O
+To	O
+determine	O
+the	O
+natural	O
+history	O
+of	O
+visual	B-NP
+field	I-NP
+defects	I-NP
+in	O
+a	O
+group	O
+of	O
+patients	O
+known	O
+to	O
+have	O
+Vigabatrin	O
+-	O
+associated	O
+changes	O
+who	O
+elected	O
+to	O
+continue	O
+the	O
+medication	O
+because	O
+of	O
+good	O
+seizure	B-NP
+control	O
+.	O
+	
+METHODS	O
+:	O
+All	O
+patients	O
+taking	O
+Vigabatrin	O
+alone	O
+or	O
+in	O
+combination	O
+with	O
+other	O
+antiepileptic	O
+drugs	O
+for	O
+at	O
+least	O
+5	O
+years	O
+(	O
+range	O
+5	O
+-	O
+12	O
+years	O
+)	O
+were	O
+entered	O
+into	O
+a	O
+visual	O
+surveillance	O
+programme	O
+.	O
+	
+Patients	O
+were	O
+followed	O
+up	O
+at	O
+6	O
+-	O
+monthly	O
+intervals	O
+for	O
+not	O
+less	O
+than	O
+18	O
+months	O
+(	O
+range	O
+18	O
+-	O
+43	O
+months	O
+)	O
+.	O
+	
+In	O
+all	O
+","	O
+16	O
+patients	O
+with	O
+unequivocal	O
+defects	O
+continued	O
+the	O
+medication	O
+.	O
+	
+Following	O
+already	O
+published	O
+methodology	O
+(	O
+Eye	O
+2002	O
+;	O
+16	O
+;	O
+567	O
+-	O
+571	O
+)	O
+monocular	O
+mean	O
+radial	O
+degrees	O
+(	O
+MRDs	O
+)	O
+to	O
+the	O
+I	O
+/	O
+4e	O
+isopter	O
+on	O
+Goldmann	O
+perimetry	O
+was	O
+calculated	O
+for	O
+the	O
+right	O
+eye	O
+at	O
+the	O
+time	O
+of	O
+discovery	O
+of	O
+a	O
+visual	B-NP
+field	I-NP
+defect	I-NP
+and	O
+again	O
+after	O
+not	O
+less	O
+than	O
+18	O
+months	O
+follow	O
+-	O
+up	O
+.	O
+	
+RESULTS	O
+:	O
+Mean	O
+right	O
+eye	O
+MRD	O
+at	O
+presentation	O
+was	O
+36	O
+.	O
+98	O
+degrees	O
+(	O
+range	O
+22	O
+.	O
+25	O
+-	O
+51	O
+.	O
+0	O
+)	O
+","	O
+compared	O
+to	O
+38	O
+.	O
+40	O
+degrees	O
+(	O
+range	O
+22	O
+.	O
+5	O
+-	O
+49	O
+.	O
+75	O
+)	O
+after	O
+follow	O
+-	O
+up	O
+;	O
+P	O
+=	O
+0	O
+.	O
+338	O
+unpaired	O
+t	O
+-	O
+test	O
+.	O
+	
+Only	O
+one	O
+patient	O
+demonstrated	O
+a	O
+deterioration	B-NP
+in	I-NP
+visual	I-NP
+field	I-NP
+during	O
+the	O
+study	O
+period	O
+and	O
+discontinued	O
+treatment	O
+.	O
+	
+CONCLUSION	O
+:	O
+Established	O
+visual	B-NP
+field	I-NP
+defects	I-NP
+presumed	O
+to	O
+be	O
+due	O
+to	O
+Vigabatrin	O
+therapy	O
+did	O
+not	O
+usually	O
+progress	O
+in	O
+spite	O
+of	O
+continuing	O
+use	O
+of	O
+the	O
+medication	O
+.	O
+	
+These	O
+data	O
+give	O
+support	O
+to	O
+the	O
+hypothesis	O
+that	O
+the	O
+pathogenesis	O
+of	O
+Vigabatrin	O
+-	O
+associated	O
+visual	B-NP
+field	I-NP
+defects	I-NP
+may	O
+be	O
+an	O
+idiosyncratic	O
+adverse	O
+drug	O
+reaction	O
+rather	O
+than	O
+dose	O
+-	O
+dependent	O
+toxicity	B-NP
+.	O
+	
+Induction	O
+of	O
+rosaceiform	O
+dermatitis	B-NP
+during	O
+treatment	O
+of	O
+facial	B-NP
+inflammatory	I-NP
+dermatoses	I-NP
+with	O
+tacrolimus	O
+ointment	O
+.	O
+	
+BACKGROUND	O
+:	O
+Tacrolimus	O
+ointment	O
+is	O
+increasingly	O
+used	O
+for	O
+anti	O
+-	O
+inflammatory	O
+treatment	O
+of	O
+sensitive	O
+areas	O
+such	O
+as	O
+the	O
+face	O
+","	O
+and	O
+recent	O
+observations	O
+indicate	O
+that	O
+the	O
+treatment	O
+is	O
+effective	O
+in	O
+steroid	O
+-	O
+aggravated	O
+rosacea	B-NP
+and	O
+perioral	B-NP
+dermatitis	I-NP
+.	O
+	
+We	O
+report	O
+on	O
+rosaceiform	O
+dermatitis	B-NP
+as	O
+a	O
+complication	O
+of	O
+treatment	O
+with	O
+tacrolimus	O
+ointment	O
+.	O
+	
+OBSERVATIONS	O
+:	O
+Six	O
+adult	O
+patients	O
+with	O
+inflammatory	B-NP
+facial	I-NP
+dermatoses	I-NP
+were	O
+treated	O
+with	O
+tacrolimus	O
+ointment	O
+because	O
+of	O
+the	O
+ineffectiveness	O
+of	O
+standard	O
+treatments	O
+.	O
+	
+Within	O
+2	O
+to	O
+3	O
+weeks	O
+of	O
+initially	O
+effective	O
+and	O
+well	O
+-	O
+tolerated	O
+treatment	O
+","	O
+3	O
+patients	O
+with	O
+a	O
+history	O
+of	O
+rosacea	B-NP
+and	O
+1	O
+with	O
+a	O
+history	O
+of	O
+acne	B-NP
+experienced	O
+sudden	O
+worsening	O
+with	O
+pustular	O
+rosaceiform	O
+lesions	O
+.	O
+	
+Biopsy	O
+revealed	O
+an	O
+abundance	O
+of	O
+Demodex	O
+mites	O
+in	O
+2	O
+of	O
+these	O
+patients	O
+.	O
+	
+In	O
+1	O
+patient	O
+with	O
+eyelid	O
+eczema	B-NP
+","	O
+rosaceiform	O
+periocular	B-NP
+dermatitis	I-NP
+gradually	O
+appeared	O
+after	O
+3	O
+weeks	O
+of	O
+treatment	O
+.	O
+	
+In	O
+1	O
+patient	O
+with	O
+atopic	B-NP
+dermatitis	I-NP
+","	O
+telangiectatic	O
+and	O
+papular	B-NP
+rosacea	I-NP
+insidiously	O
+appeared	O
+after	O
+5	O
+months	O
+of	O
+treatment	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Our	O
+observations	O
+suggest	O
+that	O
+the	O
+spectrum	O
+of	O
+rosaceiform	O
+dermatitis	B-NP
+as	O
+a	O
+complication	O
+of	O
+treatment	O
+with	O
+tacrolimus	O
+ointment	O
+is	O
+heterogeneous	O
+.	O
+	
+A	O
+variety	O
+of	O
+factors	O
+","	O
+such	O
+as	O
+vasoactive	O
+properties	O
+of	O
+tacrolimus	O
+","	O
+proliferation	O
+of	O
+Demodex	O
+due	O
+to	O
+local	O
+immunosuppression	O
+","	O
+and	O
+the	O
+occlusive	O
+properties	O
+of	O
+the	O
+ointment	O
+","	O
+may	O
+be	O
+involved	O
+in	O
+the	O
+observed	O
+phenomena	O
+.	O
+	
+Future	O
+studies	O
+are	O
+needed	O
+to	O
+identify	O
+individual	O
+risk	O
+factors	O
+.	O
+	
+Intravascular	O
+hemolysis	B-NP
+and	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+following	O
+intermittent	O
+rifampin	O
+therapy	O
+.	O
+	
+Renal	B-NP
+failure	I-NP
+is	O
+a	O
+rare	O
+complication	O
+associated	O
+with	O
+the	O
+use	O
+of	O
+rifampin	O
+.	O
+	
+Intravascular	O
+hemolysis	B-NP
+leading	O
+to	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+following	O
+rifampin	O
+therapy	O
+is	O
+extremely	O
+rare	O
+.	O
+	
+Two	O
+patients	O
+with	O
+leprosy	B-NP
+who	O
+developed	O
+hemolysis	B-NP
+and	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+following	O
+rifampin	O
+are	O
+reported	O
+.	O
+	
+Structural	O
+abnormalities	O
+in	O
+the	O
+brains	O
+of	O
+human	O
+subjects	O
+who	O
+use	O
+methamphetamine	O
+.	O
+	
+We	O
+visualize	O
+","	O
+for	O
+the	O
+first	O
+time	O
+","	O
+the	O
+profile	O
+of	O
+structural	B-NP
+deficits	I-NP
+in	I-NP
+the	I-NP
+human	I-NP
+brain	I-NP
+associated	O
+with	O
+chronic	O
+methamphetamine	O
+(	O
+MA	O
+)	O
+abuse	O
+.	O
+	
+Studies	O
+of	O
+human	O
+subjects	O
+who	O
+have	O
+used	O
+MA	O
+chronically	O
+have	O
+revealed	O
+deficits	O
+in	O
+dopaminergic	O
+and	O
+serotonergic	O
+systems	O
+and	O
+cerebral	O
+metabolic	B-NP
+abnormalities	I-NP
+.	O
+	
+Using	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+and	O
+new	O
+computational	O
+brain	O
+-	O
+mapping	O
+techniques	O
+","	O
+we	O
+determined	O
+the	O
+pattern	O
+of	O
+structural	O
+brain	O
+alterations	O
+associated	O
+with	O
+chronic	O
+MA	O
+abuse	O
+in	O
+human	O
+subjects	O
+and	O
+related	O
+these	O
+deficits	O
+to	O
+cognitive	B-NP
+impairment	I-NP
+.	O
+	
+We	O
+used	O
+high	O
+-	O
+resolution	O
+MRI	O
+and	O
+surface	O
+-	O
+based	O
+computational	O
+image	O
+analyses	O
+to	O
+map	O
+regional	O
+abnormalities	B-NP
+in	I-NP
+the	I-NP
+cortex	I-NP
+","	I-NP
+hippocampus	I-NP
+","	I-NP
+white	I-NP
+matter	I-NP
+","	I-NP
+and	I-NP
+ventricles	I-NP
+in	O
+22	O
+human	O
+subjects	O
+who	O
+used	O
+MA	O
+and	O
+21	O
+age	O
+-	O
+matched	O
+","	O
+healthy	O
+controls	O
+.	O
+	
+Cortical	O
+maps	O
+revealed	O
+severe	O
+gray	O
+-	O
+matter	O
+deficits	O
+in	O
+the	O
+cingulate	O
+","	O
+limbic	O
+","	O
+and	O
+paralimbic	O
+cortices	O
+of	O
+MA	O
+abusers	O
+(	O
+averaging	O
+11	O
+.	O
+3	O
+%	O
+below	O
+control	O
+;	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+On	O
+average	O
+","	O
+MA	O
+abusers	O
+had	O
+7	O
+.	O
+8	O
+%	O
+smaller	O
+hippocampal	O
+volumes	O
+than	O
+control	O
+subjects	O
+(	O
+p	O
+<	O
+0	O
+.	O
+1	O
+;	O
+left	O
+","	O
+p	O
+=	O
+0	O
+.	O
+1	O
+;	O
+right	O
+","	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+and	O
+significant	O
+white	O
+-	O
+matter	O
+hypertrophy	B-NP
+(	O
+7	O
+.	O
+0	O
+%	O
+;	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Hippocampal	O
+deficits	O
+were	O
+mapped	O
+and	O
+correlated	O
+with	O
+memory	O
+performance	O
+on	O
+a	O
+word	O
+-	O
+recall	O
+test	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+MRI	O
+-	O
+based	O
+maps	O
+suggest	O
+that	O
+chronic	O
+methamphetamine	O
+abuse	O
+causes	O
+a	O
+selective	O
+pattern	O
+of	O
+cerebral	O
+deterioration	O
+that	O
+contributes	O
+to	O
+impaired	B-NP
+memory	I-NP
+performance	I-NP
+.	O
+	
+MA	O
+may	O
+selectively	O
+damage	O
+the	O
+medial	O
+temporal	O
+lobe	O
+and	O
+","	O
+consistent	O
+with	O
+metabolic	O
+studies	O
+","	O
+the	O
+cingulate	O
+-	O
+limbic	O
+cortex	O
+","	O
+inducing	O
+neuroadaptation	O
+","	O
+neuropil	O
+reduction	O
+","	O
+or	O
+cell	O
+death	O
+.	O
+	
+Prominent	O
+white	O
+-	O
+matter	O
+hypertrophy	B-NP
+may	O
+result	O
+from	O
+altered	O
+myelination	O
+and	O
+adaptive	O
+glial	O
+changes	O
+","	O
+including	O
+gliosis	B-NP
+secondary	O
+to	O
+neuronal	B-NP
+damage	I-NP
+.	O
+	
+These	O
+brain	O
+substrates	O
+may	O
+help	O
+account	O
+for	O
+the	O
+symptoms	O
+of	O
+MA	O
+abuse	O
+","	O
+providing	O
+therapeutic	O
+targets	O
+for	O
+drug	O
+-	O
+induced	O
+brain	B-NP
+injury	I-NP
+.	O
+	
+Disruption	O
+of	O
+hepatic	O
+lipid	O
+homeostasis	O
+in	O
+mice	O
+after	O
+amiodarone	O
+treatment	O
+is	O
+associated	O
+with	O
+peroxisome	O
+proliferator	O
+-	O
+activated	O
+receptor	O
+-	O
+alpha	O
+target	O
+gene	O
+activation	O
+.	O
+	
+Amiodarone	O
+","	O
+an	O
+efficacious	O
+and	O
+widely	O
+used	O
+antiarrhythmic	O
+agent	O
+","	O
+has	O
+been	O
+reported	O
+to	O
+cause	O
+hepatotoxicity	B-NP
+in	O
+some	O
+patients	O
+.	O
+	
+To	O
+gain	O
+insight	O
+into	O
+the	O
+mechanism	O
+of	O
+this	O
+unwanted	O
+effect	O
+","	O
+mice	O
+were	O
+administered	O
+various	O
+doses	O
+of	O
+amiodarone	O
+and	O
+examined	O
+for	O
+changes	O
+in	O
+hepatic	O
+histology	O
+and	O
+gene	O
+regulation	O
+.	O
+	
+Amiodarone	O
+induced	O
+hepatomegaly	B-NP
+","	O
+hepatocyte	O
+microvesicular	O
+lipid	O
+accumulation	O
+","	O
+and	O
+a	O
+significant	O
+decrease	O
+in	O
+serum	O
+triglycerides	O
+and	O
+glucose	O
+.	O
+	
+Northern	O
+blot	O
+analysis	O
+of	O
+hepatic	O
+RNA	O
+revealed	O
+a	O
+dose	O
+-	O
+dependent	O
+increase	O
+in	O
+the	O
+expression	O
+of	O
+a	O
+number	O
+of	O
+genes	O
+critical	O
+for	O
+fatty	O
+acid	O
+oxidation	O
+","	O
+lipoprotein	O
+assembly	O
+","	O
+and	O
+lipid	O
+transport	O
+.	O
+	
+Many	O
+of	O
+these	O
+genes	O
+are	O
+regulated	O
+by	O
+the	O
+peroxisome	O
+proliferator	O
+-	O
+activated	O
+receptor	O
+-	O
+alpha	O
+(	O
+PPARalpha	O
+)	O
+","	O
+a	O
+ligand	O
+-	O
+activated	O
+nuclear	O
+hormone	O
+receptor	O
+transcription	O
+factor	O
+.	O
+	
+The	O
+absence	O
+of	O
+induction	O
+of	O
+these	O
+genes	O
+as	O
+well	O
+as	O
+hepatomegaly	B-NP
+in	O
+PPARalpha	O
+knockout	O
+[	O
+PPARalpha	O
+-	O
+/	O
+-	O
+]	O
+mice	O
+indicated	O
+that	O
+the	O
+effects	O
+of	O
+amiodarone	O
+were	O
+dependent	O
+upon	O
+the	O
+presence	O
+of	O
+a	O
+functional	O
+PPARalpha	O
+gene	O
+.	O
+	
+Compared	O
+to	O
+wild	O
+-	O
+type	O
+mice	O
+","	O
+treatment	O
+of	O
+PPARalpha	O
+-	O
+/	O
+-	O
+mice	O
+with	O
+amiodarone	O
+resulted	O
+in	O
+an	O
+increased	O
+rate	O
+and	O
+extent	O
+of	O
+total	O
+body	O
+weight	B-NP
+loss	I-NP
+.	O
+	
+The	O
+inability	O
+of	O
+amiodarone	O
+to	O
+directly	O
+activate	O
+either	O
+human	O
+or	O
+mouse	O
+PPARalpha	O
+transiently	O
+expressed	O
+in	O
+human	O
+HepG2	O
+hepatoma	B-NP
+cells	O
+indicates	O
+that	O
+the	O
+effects	O
+of	O
+amiodarone	O
+on	O
+the	O
+function	O
+of	O
+this	O
+receptor	O
+were	O
+indirect	O
+.	O
+	
+Based	O
+upon	O
+these	O
+results	O
+","	O
+we	O
+conclude	O
+that	O
+amiodarone	O
+disrupts	O
+hepatic	O
+lipid	O
+homeostasis	O
+and	O
+that	O
+the	O
+increased	O
+expression	O
+of	O
+PPARalpha	O
+target	O
+genes	O
+is	O
+secondary	O
+to	O
+this	O
+toxic	O
+effect	O
+.	O
+	
+These	O
+results	O
+provide	O
+important	O
+new	O
+mechanistic	O
+information	O
+regarding	O
+the	O
+hepatotoxic	B-NP
+effects	O
+of	O
+amiodarone	O
+and	O
+indicate	O
+that	O
+PPARalpha	O
+protects	O
+against	O
+amiodarone	O
+-	O
+induced	O
+hepatotoxicity	B-NP
+.	O
+	
+Safety	O
+and	O
+compliance	O
+with	O
+once	O
+-	O
+daily	O
+niacin	O
+extended	O
+-	O
+release	O
+/	O
+lovastatin	O
+as	O
+initial	O
+therapy	O
+in	O
+the	O
+Impact	O
+of	O
+Medical	O
+Subspecialty	O
+on	O
+Patient	O
+Compliance	O
+to	O
+Treatment	O
+(	O
+IMPACT	O
+)	O
+study	O
+.	O
+	
+Niacin	O
+extended	O
+-	O
+release	O
+/	O
+lovastatin	O
+is	O
+a	O
+new	O
+combination	O
+product	O
+approved	O
+for	O
+treatment	O
+of	O
+primary	O
+hypercholesterolemia	B-NP
+and	O
+mixed	O
+dyslipidemia	B-NP
+.	O
+	
+This	O
+open	O
+-	O
+labeled	O
+","	O
+multicenter	O
+study	O
+evaluated	O
+the	O
+safety	O
+of	O
+bedtime	O
+niacin	O
+extended	O
+-	O
+release	O
+/	O
+lovastatin	O
+when	O
+dosed	O
+as	O
+initial	O
+therapy	O
+and	O
+patient	O
+compliance	O
+to	O
+treatment	O
+in	O
+various	O
+clinical	O
+practice	O
+settings	O
+.	O
+	
+A	O
+total	O
+of	O
+4	O
+","	O
+499	O
+patients	O
+with	O
+dyslipidemia	B-NP
+requiring	O
+drug	O
+intervention	O
+was	O
+enrolled	O
+at	O
+1	O
+","	O
+81	O
+sites	O
+.	O
+	
+Patients	O
+were	O
+treated	O
+with	O
+1	O
+tablet	O
+(	O
+500	O
+mg	O
+of	O
+niacin	O
+extended	O
+-	O
+release	O
+/	O
+20	O
+mg	O
+of	O
+lovastatin	O
+)	O
+once	O
+nightly	O
+for	O
+4	O
+weeks	O
+and	O
+then	O
+2	O
+tablets	O
+for	O
+8	O
+weeks	O
+.	O
+	
+Patients	O
+also	O
+received	O
+dietary	O
+counseling	O
+","	O
+educational	O
+materials	O
+","	O
+and	O
+reminders	O
+to	O
+call	O
+a	O
+toll	O
+-	O
+free	O
+number	O
+that	O
+provided	O
+further	O
+education	O
+about	O
+dyslipidemia	B-NP
+and	O
+niacin	O
+extended	O
+-	O
+release	O
+/	O
+lovastatin	O
+.	O
+	
+Primary	O
+end	O
+points	O
+were	O
+study	O
+compliance	O
+","	O
+increases	O
+in	O
+liver	O
+transaminases	O
+to	O
+>	O
+3	O
+times	O
+the	O
+upper	O
+limit	O
+of	O
+normal	O
+","	O
+and	O
+clinical	O
+myopathy	B-NP
+.	O
+	
+Final	O
+study	O
+status	O
+was	O
+available	O
+for	O
+4	O
+","	O
+217	O
+patients	O
+(	O
+94	O
+%	O
+)	O
+.	O
+	
+Compliance	O
+to	O
+niacin	O
+extended	O
+-	O
+release	O
+/	O
+lovastatin	O
+was	O
+77	O
+%	O
+","	O
+with	O
+3	O
+","	O
+245	O
+patients	O
+completing	O
+the	O
+study	O
+.	O
+	
+Patients	O
+in	O
+the	O
+southeast	O
+and	O
+those	O
+enrolled	O
+by	O
+endocrinologists	O
+had	O
+the	O
+lowest	O
+compliance	O
+and	O
+highest	O
+adverse	O
+event	O
+rates	O
+.	O
+	
+Flushing	B-NP
+was	O
+the	O
+most	O
+common	O
+adverse	O
+event	O
+","	O
+reported	O
+by	O
+18	O
+%	O
+of	O
+patients	O
+and	O
+leading	O
+to	O
+discontinuation	O
+by	O
+6	O
+%	O
+.	O
+	
+Incidence	O
+of	O
+increased	O
+aspartate	O
+aminotransferase	O
+and	O
+/	O
+or	O
+alanine	O
+aminotransferase	O
+>	O
+3	O
+times	O
+the	O
+upper	O
+limit	O
+of	O
+normal	O
+was	O
+<	O
+0	O
+.	O
+3	O
+%	O
+.	O
+	
+An	O
+increase	O
+of	O
+creatine	O
+phosphokinase	O
+to	O
+>	O
+5	O
+times	O
+the	O
+upper	O
+limit	O
+of	O
+normal	O
+occurred	O
+in	O
+0	O
+.	O
+24	O
+%	O
+of	O
+patients	O
+","	O
+and	O
+no	O
+cases	O
+of	O
+drug	O
+-	O
+induced	O
+myopathy	B-NP
+were	O
+observed	O
+.	O
+	
+Niacin	O
+extended	O
+-	O
+release	O
+/	O
+lovastatin	O
+1	O
+","	O
+0	O
+/	O
+40	O
+mg	O
+","	O
+dosed	O
+as	O
+initial	O
+therapy	O
+","	O
+was	O
+associated	O
+with	O
+good	O
+compliance	O
+and	O
+safety	O
+and	O
+had	O
+very	O
+low	O
+incidences	O
+of	O
+increased	O
+liver	O
+and	O
+muscle	O
+enzymes	O
+.	O
+	
+Protective	O
+effect	O
+of	O
+Terminalia	O
+chebula	O
+against	O
+experimental	O
+myocardial	B-NP
+injury	I-NP
+induced	O
+by	O
+isoproterenol	O
+.	O
+	
+Cardioprotective	O
+effect	O
+of	O
+ethanolic	O
+extract	O
+of	O
+Terminalia	O
+chebula	O
+fruits	O
+(	O
+500	O
+mg	O
+/	O
+kg	O
+body	O
+wt	O
+)	O
+was	O
+examined	O
+in	O
+isoproterenol	O
+(	O
+200	O
+mg	O
+/	O
+kg	O
+body	O
+wt	O
+)	O
+induced	O
+myocardial	B-NP
+damage	I-NP
+in	O
+rats	O
+.	O
+	
+In	O
+isoproterenol	O
+administered	O
+rats	O
+","	O
+the	O
+level	O
+of	O
+lipid	O
+peroxides	O
+increased	O
+significantly	O
+in	O
+the	O
+serum	O
+and	O
+heart	O
+.	O
+	
+A	O
+significant	O
+decrease	O
+was	O
+observed	O
+in	O
+the	O
+activity	O
+of	O
+the	O
+myocardial	O
+marker	O
+enzymes	O
+with	O
+a	O
+concomitant	O
+increase	O
+in	O
+their	O
+activity	O
+in	O
+serum	O
+.	O
+	
+Histopathological	O
+examination	O
+was	O
+carried	O
+out	O
+to	O
+confirm	O
+the	O
+myocardial	O
+necrosis	B-NP
+.	O
+	
+T	O
+.	O
+chebula	O
+extract	O
+pretreatment	O
+was	O
+found	O
+to	O
+ameliorate	O
+the	O
+effect	O
+of	O
+isoproterenol	O
+on	O
+lipid	O
+peroxide	O
+formation	O
+and	O
+retained	O
+the	O
+activities	O
+of	O
+the	O
+diagnostic	O
+marker	O
+enzymes	O
+.	O
+	
+A	O
+case	O
+of	O
+postoperative	O
+anxiety	B-NP
+due	O
+to	O
+low	O
+dose	O
+droperidol	O
+used	O
+with	O
+patient	O
+-	O
+controlled	O
+analgesia	O
+.	O
+	
+A	O
+multiparous	O
+woman	O
+in	O
+good	O
+psychological	O
+health	O
+underwent	O
+urgent	O
+caesarean	O
+section	O
+in	O
+labour	O
+.	O
+	
+Postoperatively	O
+","	O
+she	O
+was	O
+given	O
+a	O
+patient	O
+-	O
+controlled	O
+analgesia	O
+device	O
+delivering	O
+boluses	O
+of	O
+diamorphine	O
+0	O
+.	O
+5	O
+mg	O
+and	O
+droperidol	O
+0	O
+.	O
+25	O
+mg	O
+.	O
+	
+Whilst	O
+using	O
+the	O
+device	O
+she	O
+gradually	O
+became	O
+anxious	O
+","	O
+the	O
+feeling	O
+worsening	O
+after	O
+each	O
+bolus	O
+.	O
+	
+The	O
+diagnosis	O
+of	O
+droperidol	O
+-	O
+induced	O
+psychological	B-NP
+disturbance	I-NP
+was	O
+not	O
+made	O
+straight	O
+away	O
+although	O
+on	O
+subsequent	O
+close	O
+questioning	O
+the	O
+patient	O
+gave	O
+a	O
+very	O
+clear	O
+history	O
+.	O
+	
+After	O
+she	O
+had	O
+received	O
+a	O
+total	O
+of	O
+only	O
+0	O
+.	O
+9	O
+mg	O
+droperidol	O
+","	O
+a	O
+syringe	O
+containing	O
+diamorphine	O
+only	O
+was	O
+substituted	O
+and	O
+her	O
+unease	O
+resolved	O
+completely	O
+.	O
+	
+We	O
+feel	O
+that	O
+","	O
+although	O
+the	O
+dramatic	O
+extrapyramidal	O
+side	O
+effects	O
+of	O
+dopaminergic	O
+antiemetics	O
+are	O
+well	O
+known	O
+","	O
+more	O
+subtle	O
+manifestations	O
+may	O
+easily	O
+be	O
+overlooked	O
+.	O
+	
+Accurate	O
+patient	O
+history	O
+contributes	O
+to	O
+differentiating	O
+diabetes	B-NP
+insipidus	I-NP
+:	O
+a	O
+case	O
+study	O
+.	O
+	
+This	O
+case	O
+study	O
+highlights	O
+the	O
+important	O
+contribution	O
+of	O
+nursing	O
+in	O
+obtaining	O
+an	O
+accurate	O
+health	O
+history	O
+.	O
+	
+The	O
+case	O
+discussed	O
+herein	O
+initially	O
+appeared	O
+to	O
+be	O
+neurogenic	B-NP
+diabetes	I-NP
+insipidus	I-NP
+(	O
+DI	B-NP
+)	O
+secondary	O
+to	O
+a	O
+traumatic	B-NP
+brain	I-NP
+injury	I-NP
+.	O
+	
+The	O
+nursing	O
+staff	O
+","	O
+by	O
+reviewing	O
+the	O
+patient	O
+'	O
+s	O
+health	O
+history	O
+with	O
+his	O
+family	O
+","	O
+discovered	O
+a	O
+history	O
+of	O
+polydipsia	B-NP
+and	O
+long	O
+-	O
+standing	O
+lithium	O
+use	O
+.	O
+	
+Lithium	O
+is	O
+implicated	O
+in	O
+drug	O
+-	O
+induced	O
+nephrogenic	B-NP
+DI	I-NP
+","	O
+and	O
+because	O
+the	O
+patient	O
+had	O
+not	O
+received	O
+lithium	O
+since	O
+being	O
+admitted	O
+to	O
+the	O
+hospital	O
+","	O
+his	O
+treatment	O
+changed	O
+to	O
+focus	O
+on	O
+nephrogenic	B-NP
+DI	I-NP
+.	O
+	
+By	O
+combining	O
+information	O
+from	O
+the	O
+patient	O
+history	O
+","	O
+the	O
+physical	O
+examination	O
+","	O
+and	O
+radiologic	O
+and	O
+laboratory	O
+studies	O
+","	O
+the	O
+critical	O
+care	O
+team	O
+demonstrated	O
+that	O
+the	O
+patient	O
+had	O
+been	O
+self	O
+-	O
+treating	O
+his	O
+lithium	O
+-	O
+induced	O
+nephrogenic	B-NP
+DI	I-NP
+and	O
+developed	O
+neurogenic	B-NP
+DI	I-NP
+secondary	O
+to	O
+brain	B-NP
+trauma	I-NP
+.	O
+	
+Thus	O
+successful	O
+treatment	O
+required	O
+that	O
+nephrogenic	O
+and	O
+neurogenic	B-NP
+DI	I-NP
+be	O
+treated	O
+concomitantly	O
+.	O
+	
+Factors	O
+contributing	O
+to	O
+ribavirin	O
+-	O
+induced	O
+anemia	B-NP
+.	O
+	
+BACKGROUND	O
+AND	O
+AIM	O
+:	O
+Interferon	O
+and	O
+ribavirin	O
+combination	O
+therapy	O
+for	O
+chronic	B-NP
+hepatitis	I-NP
+C	I-NP
+produces	O
+hemolytic	B-NP
+anemia	I-NP
+.	O
+	
+This	O
+study	O
+was	O
+conducted	O
+to	O
+identify	O
+the	O
+factors	O
+contributing	O
+to	O
+ribavirin	O
+-	O
+induced	O
+anemia	B-NP
+.	O
+	
+METHODS	O
+:	O
+Eighty	O
+-	O
+eight	O
+patients	O
+with	O
+chronic	B-NP
+hepatitis	I-NP
+C	I-NP
+who	O
+received	O
+interferon	O
+-	O
+alpha	O
+-	O
+2b	O
+at	O
+a	O
+dose	O
+of	O
+6	O
+MU	O
+administered	O
+intramuscularly	O
+for	O
+24	O
+weeks	O
+in	O
+combination	O
+with	O
+ribavirin	O
+administered	O
+orally	O
+at	O
+a	O
+dose	O
+of	O
+600	O
+mg	O
+or	O
+800	O
+mg	O
+participated	O
+in	O
+the	O
+study	O
+.	O
+	
+A	O
+hemoglobin	O
+concentration	O
+of	O
+<	O
+10	O
+g	O
+/	O
+dL	O
+was	O
+defined	O
+as	O
+ribavirin	O
+-	O
+induced	O
+anemia	B-NP
+.	O
+	
+RESULTS	O
+:	O
+Ribavirin	O
+-	O
+induced	O
+anemia	B-NP
+occurred	O
+in	O
+18	O
+(	O
+20	O
+.	O
+5	O
+%	O
+)	O
+patients	O
+during	O
+treatment	O
+.	O
+	
+A	O
+2	O
+g	O
+/	O
+dL	O
+decrease	O
+in	O
+hemoglobin	O
+concentrations	O
+in	O
+patients	O
+with	O
+anemia	B-NP
+was	O
+observed	O
+at	O
+week	O
+2	O
+after	O
+the	O
+start	O
+of	O
+treatment	O
+.	O
+	
+The	O
+hemoglobin	O
+concentration	O
+in	O
+patients	O
+with	O
+>	O
+or	O
+=	O
+2	O
+g	O
+/	O
+dL	O
+decrease	O
+at	O
+week	O
+2	O
+was	O
+observed	O
+to	O
+be	O
+significantly	O
+lower	O
+even	O
+after	O
+week	O
+2	O
+than	O
+in	O
+patients	O
+with	O
+<	O
+2	O
+g	O
+/	O
+dL	O
+decrease	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+A	O
+significant	O
+relationship	O
+was	O
+observed	O
+between	O
+the	O
+rate	O
+of	O
+reduction	O
+of	O
+hemoglobin	O
+concentrations	O
+at	O
+week	O
+2	O
+and	O
+the	O
+severity	O
+of	O
+anemia	B-NP
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Such	O
+factors	O
+as	O
+sex	O
+(	O
+female	O
+)	O
+","	O
+age	O
+(	O
+>	O
+or	O
+=	O
+60	O
+years	O
+old	O
+)	O
+","	O
+and	O
+the	O
+ribavirin	O
+dose	O
+by	O
+body	O
+weight	O
+(	O
+12	O
+mg	O
+/	O
+kg	O
+or	O
+more	O
+)	O
+were	O
+significant	O
+by	O
+univariate	O
+analysis	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Careful	O
+administration	O
+is	O
+necessary	O
+in	O
+patients	O
+>	O
+or	O
+=	O
+60	O
+years	O
+old	O
+","	O
+in	O
+female	O
+patients	O
+","	O
+and	O
+in	O
+patients	O
+receiving	O
+a	O
+ribavirin	O
+dose	O
+of	O
+12	O
+mg	O
+/	O
+kg	O
+or	O
+more	O
+.	O
+	
+Patients	O
+who	O
+experience	O
+a	O
+fall	O
+in	O
+hemoglobin	O
+concentrations	O
+of	O
+2	O
+g	O
+/	O
+dL	O
+or	O
+more	O
+at	O
+week	O
+2	O
+after	O
+the	O
+start	O
+of	O
+treatment	O
+should	O
+be	O
+monitored	O
+with	O
+particular	O
+care	O
+.	O
+	
+Zidovudine	O
+-	O
+induced	O
+hepatitis	B-NP
+.	O
+	
+A	O
+case	O
+of	O
+acute	O
+hepatitis	B-NP
+induced	O
+by	O
+zidovudine	O
+in	O
+a	O
+38	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+with	O
+AIDS	B-NP
+is	O
+presented	O
+.	O
+	
+The	O
+mechanism	O
+whereby	O
+the	O
+hepatitis	B-NP
+was	O
+induced	O
+is	O
+not	O
+known	O
+.	O
+	
+However	O
+","	O
+the	O
+patient	O
+tolerated	O
+well	O
+an	O
+alternative	O
+reverse	O
+transcriptase	O
+inhibitor	O
+","	O
+2	O
+'	O
+3	O
+'	O
+dideoxyinosine	O
+.	O
+	
+Physicians	O
+caring	O
+for	O
+patients	O
+with	O
+AIDS	B-NP
+should	O
+be	O
+aware	O
+of	O
+this	O
+hitherto	O
+rarely	O
+reported	O
+complication	O
+.	O
+	
+Oxidative	O
+damage	O
+precedes	O
+nitrative	O
+damage	O
+in	O
+adriamycin	O
+-	O
+induced	O
+cardiac	O
+mitochondrial	B-NP
+injury	I-NP
+.	O
+	
+The	O
+purpose	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+determine	O
+if	O
+elevated	O
+reactive	O
+oxygen	O
+(	O
+ROS	O
+)	O
+/	O
+nitrogen	O
+species	O
+(	O
+RNS	O
+)	O
+reported	O
+to	O
+be	O
+present	O
+in	O
+adriamycin	O
+(	O
+ADR	O
+)	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+actually	O
+resulted	O
+in	O
+cardiomyocyte	O
+oxidative	O
+/	O
+nitrative	O
+damage	O
+","	O
+and	O
+to	O
+quantitatively	O
+determine	O
+the	O
+time	O
+course	O
+and	O
+subcellular	O
+localization	O
+of	O
+these	O
+postulated	O
+damage	O
+products	O
+using	O
+an	O
+in	O
+vivo	O
+approach	O
+.	O
+	
+B6C3	O
+mice	O
+were	O
+treated	O
+with	O
+a	O
+single	O
+dose	O
+of	O
+20	O
+mg	O
+/	O
+kg	O
+ADR	O
+.	O
+	
+Ultrastructural	O
+damage	O
+and	O
+levels	O
+of	O
+4	O
+-	O
+hydroxy	O
+-	O
+2	O
+-	O
+nonenal	O
+(	O
+4HNE	O
+)	O
+-	O
+protein	O
+adducts	O
+and	O
+3	O
+-	O
+nitrotyrosine	O
+(	O
+3NT	O
+)	O
+were	O
+analyzed	O
+.	O
+	
+Quantitative	O
+ultrastructural	O
+damage	O
+using	O
+computerized	O
+image	O
+techniques	O
+showed	O
+cardiomyocyte	O
+injury	O
+as	O
+early	O
+as	O
+3	O
+hours	O
+","	O
+with	O
+mitochondria	O
+being	O
+the	O
+most	O
+extensively	O
+and	O
+progressively	O
+injured	O
+subcellular	O
+organelle	O
+.	O
+	
+Analysis	O
+of	O
+4HNE	O
+protein	O
+adducts	O
+by	O
+immunogold	O
+electron	O
+microscopy	O
+showed	O
+appearance	O
+of	O
+4HNE	O
+protein	O
+adducts	O
+in	O
+mitochondria	O
+as	O
+early	O
+as	O
+3	O
+hours	O
+","	O
+with	O
+a	O
+peak	O
+at	O
+6	O
+hours	O
+and	O
+subsequent	O
+decline	O
+at	O
+24	O
+hours	O
+.	O
+	
+3NT	O
+levels	O
+were	O
+significantly	O
+increased	O
+in	O
+all	O
+subcellular	O
+compartments	O
+at	O
+6	O
+hours	O
+and	O
+subsequently	O
+declined	O
+at	O
+24	O
+hours	O
+.	O
+	
+Our	O
+data	O
+showed	O
+ADR	O
+induced	O
+4HNE	O
+-	O
+protein	O
+adducts	O
+in	O
+mitochondria	O
+at	O
+the	O
+same	O
+time	O
+point	O
+as	O
+when	O
+mitochondrial	B-NP
+injury	I-NP
+initially	O
+appeared	O
+.	O
+	
+These	O
+results	O
+document	O
+for	O
+the	O
+first	O
+time	O
+in	O
+vivo	O
+that	O
+mitochondrial	B-NP
+oxidative	I-NP
+damage	I-NP
+precedes	O
+nitrative	O
+damage	O
+.	O
+	
+The	O
+progressive	O
+nature	O
+of	O
+mitochondrial	B-NP
+injury	I-NP
+suggests	O
+that	O
+mitochondria	O
+","	O
+not	O
+other	O
+subcellular	O
+organelles	O
+","	O
+are	O
+the	O
+major	O
+site	O
+of	O
+intracellular	O
+injury	O
+.	O
+	
+Sotalol	O
+-	O
+induced	O
+coronary	B-NP
+spasm	I-NP
+in	O
+a	O
+patient	O
+with	O
+dilated	B-NP
+cardiomyopathy	I-NP
+associated	O
+with	O
+sustained	O
+ventricular	B-NP
+tachycardia	I-NP
+.	O
+	
+A	O
+54	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+severe	O
+left	O
+ventricular	B-NP
+dysfunction	I-NP
+due	O
+to	O
+dilated	B-NP
+cardiomyopathy	I-NP
+was	O
+referred	O
+to	O
+our	O
+hospital	O
+for	O
+symptomatic	O
+incessant	O
+sustained	O
+ventricular	B-NP
+tachycardia	I-NP
+(	O
+VT	B-NP
+)	O
+.	O
+	
+After	O
+the	O
+administration	O
+of	O
+nifekalant	O
+hydrochloride	O
+","	O
+sustained	O
+VT	B-NP
+was	O
+terminated	O
+.	O
+	
+An	O
+alternate	O
+class	O
+III	O
+agent	O
+","	O
+sotalol	O
+","	O
+was	O
+also	O
+effective	O
+for	O
+the	O
+prevention	O
+of	O
+VT	B-NP
+.	O
+	
+However	O
+","	O
+one	O
+month	O
+after	O
+switching	O
+over	O
+nifekalant	O
+to	O
+sotalol	O
+","	O
+a	O
+short	O
+duration	O
+of	O
+ST	O
+elevation	O
+was	O
+documented	O
+in	O
+ECG	O
+monitoring	O
+at	O
+almost	O
+the	O
+same	O
+time	O
+for	O
+three	O
+consecutive	O
+days	O
+.	O
+	
+ST	O
+elevation	O
+with	O
+chest	O
+discomfort	O
+disappeared	O
+since	O
+he	O
+began	O
+taking	O
+long	O
+-	O
+acting	O
+diltiazem	O
+.	O
+	
+Coronary	B-NP
+vasospasm	I-NP
+may	O
+be	O
+induced	O
+by	O
+the	O
+non	O
+-	O
+selective	O
+beta	O
+-	O
+blocking	O
+properties	O
+of	O
+sotalol	O
+.	O
+	
+Effects	O
+of	O
+the	O
+antidepressant	O
+trazodone	O
+","	O
+a	O
+5	O
+-	O
+HT	O
+2A	O
+/	O
+2C	O
+receptor	O
+antagonist	O
+","	O
+on	O
+dopamine	O
+-	O
+dependent	O
+behaviors	O
+in	O
+rats	O
+.	O
+	
+RATIONALE	O
+:	O
+5	O
+-	O
+Hydroxytryptamine	O
+","	O
+via	O
+stimulation	O
+of	O
+5	O
+-	O
+HT	O
+2C	O
+receptors	O
+","	O
+exerts	O
+a	O
+tonic	O
+inhibitory	O
+influence	O
+on	O
+dopaminergic	O
+neurotransmission	O
+","	O
+whereas	O
+activation	O
+of	O
+5	O
+-	O
+HT	O
+2A	O
+receptors	O
+enhances	O
+stimulated	O
+DAergic	O
+neurotransmission	O
+.	O
+	
+The	O
+antidepressant	O
+trazodone	O
+is	O
+a	O
+5	O
+-	O
+HT	O
+2A	O
+/	O
+2C	O
+receptor	O
+antagonist	O
+.	O
+	
+OBJECTIVES	O
+:	O
+To	O
+evaluate	O
+the	O
+effect	O
+of	O
+trazodone	O
+treatment	O
+on	O
+behaviors	O
+dependent	O
+on	O
+the	O
+functional	O
+status	O
+of	O
+the	O
+nigrostriatal	O
+DAergic	O
+system	O
+.	O
+	
+METHODS	O
+:	O
+The	O
+effect	O
+of	O
+pretreatment	O
+with	O
+trazodone	O
+on	O
+dexamphetamine	O
+-	O
+and	O
+apomorphine	O
+-	O
+induced	O
+oral	B-NP
+stereotypies	I-NP
+","	O
+on	O
+catalepsy	B-NP
+induced	O
+by	O
+haloperidol	O
+and	O
+apomorphine	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+p	O
+.	O
+)	O
+","	O
+on	O
+ergometrine	O
+-	O
+induced	O
+wet	O
+dog	O
+shake	O
+(	O
+WDS	O
+)	O
+behavior	O
+and	O
+fluoxetine	O
+-	O
+induced	O
+penile	O
+erections	O
+was	O
+studied	O
+in	O
+rats	O
+.	O
+	
+We	O
+also	O
+investigated	O
+whether	O
+trazodone	O
+induces	O
+catalepsy	B-NP
+in	O
+rats	O
+.	O
+	
+RESULTS	O
+:	O
+Trazodone	O
+at	O
+2	O
+.	O
+5	O
+-	O
+20	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+did	O
+not	O
+induce	O
+catalepsy	B-NP
+","	O
+and	O
+did	O
+not	O
+antagonize	O
+apomorphine	O
+(	O
+1	O
+.	O
+5	O
+and	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+stereotypy	O
+and	O
+apomorphine	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+-	O
+induced	O
+catalepsy	B-NP
+.	O
+	
+However	O
+","	O
+pretreatment	O
+with	O
+5	O
+","	O
+10	O
+and	O
+20	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+trazodone	O
+enhanced	O
+dexamphetamine	O
+stereotypy	O
+","	O
+and	O
+antagonized	O
+haloperidol	O
+catalepsy	B-NP
+","	O
+ergometrine	O
+-	O
+induced	O
+WDS	O
+behavior	O
+and	O
+fluoxetine	O
+-	O
+induced	O
+penile	O
+erections	O
+.	O
+	
+Trazodone	O
+at	O
+30	O
+","	O
+40	O
+and	O
+50	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+induced	O
+catalepsy	B-NP
+and	O
+antagonized	O
+apomorphine	O
+and	O
+dexamphetamine	O
+stereotypies	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Our	O
+results	O
+indicate	O
+that	O
+trazodone	O
+at	O
+2	O
+.	O
+5	O
+-	O
+20	O
+mg	O
+/	O
+kg	O
+does	O
+not	O
+block	O
+pre	O
+-	O
+and	O
+postsynaptic	O
+striatal	O
+D2	O
+DA	O
+receptors	O
+","	O
+while	O
+at	O
+30	O
+","	O
+40	O
+and	O
+50	O
+mg	O
+/	O
+kg	O
+it	O
+blocks	O
+postsynaptic	O
+striatal	O
+D2	O
+DA	O
+receptors	O
+.	O
+	
+Furthermore	O
+","	O
+at	O
+5	O
+","	O
+10	O
+and	O
+20	O
+mg	O
+/	O
+kg	O
+","	O
+trazodone	O
+blocks	O
+5	O
+-	O
+HT	O
+2A	O
+and	O
+5	O
+-	O
+HT	O
+2C	O
+receptors	O
+.	O
+	
+We	O
+suggest	O
+that	O
+trazodone	O
+(	O
+5	O
+","	O
+10	O
+and	O
+20	O
+mg	O
+/	O
+kg	O
+)	O
+","	O
+by	O
+blocking	O
+the	O
+5	O
+-	O
+HT	O
+2C	O
+receptors	O
+","	O
+releases	O
+the	O
+nigrostriatal	O
+DAergic	O
+neurons	O
+from	O
+tonic	O
+inhibition	O
+caused	O
+by	O
+5	O
+-	O
+HT	O
+","	O
+and	O
+thereby	O
+potentiates	O
+dexamphetamine	O
+stereotypy	O
+and	O
+antagonizes	O
+haloperidol	O
+catalepsy	B-NP
+.	O
+	
+Swallowing	B-NP
+abnormalities	I-NP
+and	O
+dyskinesia	B-NP
+in	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+Gastrointestinal	B-NP
+abnormalities	I-NP
+in	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+(	O
+PD	B-NP
+)	O
+have	O
+been	O
+known	O
+for	O
+almost	O
+two	O
+centuries	O
+","	O
+but	O
+many	O
+aspects	O
+concerning	O
+their	O
+pathophysiology	O
+have	O
+not	O
+been	O
+completely	O
+clarified	O
+.	O
+	
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+characterize	O
+the	O
+oropharyngeal	O
+dynamics	O
+in	O
+PD	B-NP
+patients	O
+with	O
+and	O
+without	O
+levodopa	O
+-	O
+induced	O
+dyskinesia	B-NP
+.	O
+	
+Fifteen	O
+dyskinetic	B-NP
+","	O
+12	O
+nondyskinetic	O
+patients	O
+","	O
+and	O
+a	O
+control	O
+group	O
+were	O
+included	O
+.	O
+	
+Patients	O
+were	O
+asked	O
+about	O
+dysphagia	B-NP
+and	O
+evaluated	O
+with	O
+the	O
+Unified	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+Disease	I-NP
+Rating	O
+Scale	O
+Parts	O
+II	O
+and	O
+III	O
+and	O
+the	O
+Hoehn	O
+and	O
+Yahr	O
+scale	O
+.	O
+	
+Deglutition	O
+was	O
+assessed	O
+using	O
+modified	O
+barium	O
+swallow	O
+with	O
+videofluoroscopy	O
+.	O
+	
+Nondyskinetic	O
+patients	O
+","	O
+but	O
+not	O
+the	O
+dyskinetic	B-NP
+ones	O
+","	O
+showed	O
+less	O
+oropharyngeal	O
+swallowing	O
+efficiency	O
+(	O
+OPSE	O
+)	O
+for	O
+liquid	O
+food	O
+than	O
+controls	O
+(	O
+Dunnett	O
+","	O
+P	O
+=	O
+0	O
+.	O
+2	O
+)	O
+.	O
+	
+Dyskinetic	B-NP
+patients	O
+tended	O
+to	O
+have	O
+a	O
+greater	O
+OPSE	O
+than	O
+nondyskinetic	O
+(	O
+Dunnett	O
+","	O
+P	O
+=	O
+0	O
+.	O
+6	O
+)	O
+.	O
+	
+Patients	O
+who	O
+were	O
+using	O
+a	O
+higher	O
+dose	O
+of	O
+levodopa	O
+had	O
+a	O
+greater	O
+OPSE	O
+and	O
+a	O
+trend	O
+toward	O
+a	O
+smaller	O
+oral	O
+transit	O
+time	O
+(	O
+Pearson	O
+'	O
+s	O
+correlation	O
+","	O
+P	O
+=	O
+0	O
+.	O
+1	O
+and	O
+0	O
+.	O
+8	O
+","	O
+respectively	O
+)	O
+.	O
+	
+Neither	O
+the	O
+report	O
+of	O
+dysphagia	B-NP
+nor	O
+any	O
+of	O
+the	O
+PD	B-NP
+severity	O
+parameters	O
+correlated	O
+to	O
+the	O
+videofluoroscopic	O
+variables	O
+.	O
+	
+In	O
+the	O
+current	O
+study	O
+","	O
+dyskinetic	B-NP
+patients	O
+performed	O
+better	O
+in	O
+swallowing	O
+function	O
+","	O
+which	O
+could	O
+be	O
+explained	O
+on	O
+the	O
+basis	O
+of	O
+a	O
+greater	O
+levodopa	O
+dose	O
+.	O
+	
+Our	O
+results	O
+suggest	O
+a	O
+role	O
+for	O
+levodopa	O
+in	O
+the	O
+oral	O
+phase	O
+of	O
+deglutition	O
+and	O
+confirm	O
+that	O
+dysphagia	B-NP
+is	O
+not	O
+a	O
+good	O
+predictor	O
+of	O
+deglutition	O
+alterations	O
+in	O
+PD	B-NP
+.	O
+	
+Inhibition	O
+of	O
+nuclear	O
+factor	O
+-	O
+kappaB	O
+activation	O
+attenuates	O
+tubulointerstitial	B-NP
+nephritis	I-NP
+induced	O
+by	O
+gentamicin	O
+.	O
+	
+BACKGROUND	O
+:	O
+Animals	O
+treated	O
+with	O
+gentamicin	O
+can	O
+show	O
+residual	O
+areas	O
+of	O
+interstitial	O
+fibrosis	B-NP
+in	O
+the	O
+renal	O
+cortex	O
+.	O
+	
+This	O
+study	O
+investigated	O
+the	O
+expression	O
+of	O
+nuclear	O
+factor	O
+-	O
+kappaB	O
+(	O
+NF	O
+-	O
+kappaB	O
+)	O
+","	O
+mitogen	O
+-	O
+activated	O
+protein	O
+(	O
+MAP	O
+)	O
+kinases	O
+and	O
+macrophages	O
+in	O
+the	O
+renal	O
+cortex	O
+and	O
+structural	O
+and	O
+functional	O
+renal	O
+changes	O
+of	O
+rats	O
+treated	O
+with	O
+gentamicin	O
+or	O
+gentamicin	O
++	O
+pyrrolidine	O
+dithiocarbamate	O
+(	O
+PDTC	O
+)	O
+","	O
+an	O
+NF	O
+-	O
+kappaB	O
+inhibitor	O
+.	O
+	
+METHODS	O
+:	O
+38	O
+female	O
+Wistar	O
+rats	O
+were	O
+injected	O
+with	O
+gentamicin	O
+","	O
+40	O
+mg	O
+/	O
+kg	O
+","	O
+twice	O
+a	O
+day	O
+for	O
+9	O
+days	O
+","	O
+38	O
+with	O
+gentamicin	O
++	O
+PDTC	O
+","	O
+and	O
+28	O
+with	O
+0	O
+.	O
+15	O
+M	O
+NaCl	O
+solution	O
+.	O
+	
+The	O
+animals	O
+were	O
+killed	O
+5	O
+and	O
+30	O
+days	O
+after	O
+these	O
+injections	O
+and	O
+the	O
+kidneys	O
+were	O
+removed	O
+for	O
+histological	O
+and	O
+immunohistochemical	O
+studies	O
+.	O
+	
+The	O
+results	O
+of	O
+the	O
+immunohistochemical	O
+studies	O
+were	O
+scored	O
+according	O
+to	O
+the	O
+extent	O
+of	O
+staining	O
+.	O
+	
+The	O
+fractional	O
+interstitial	O
+area	O
+was	O
+determined	O
+by	O
+morphometry	O
+.	O
+	
+RESULTS	O
+:	O
+Gentamicin	O
+-	O
+treated	O
+rats	O
+presented	O
+a	O
+transitory	O
+increase	O
+in	O
+plasma	O
+creatinine	O
+levels	O
+.	O
+	
+Increased	O
+ED	O
+-	O
+1	O
+","	O
+MAP	O
+kinases	O
+and	O
+NF	O
+-	O
+kappaB	O
+staining	O
+were	O
+also	O
+observed	O
+in	O
+the	O
+renal	O
+cortex	O
+from	O
+all	O
+gentamicin	O
+-	O
+treated	O
+rats	O
+compared	O
+to	O
+control	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+The	O
+animals	O
+killed	O
+on	O
+day	O
+30	O
+also	O
+presented	O
+fibrosis	B-NP
+in	O
+the	O
+renal	O
+cortex	O
+despite	O
+the	O
+recovery	O
+of	O
+renal	O
+function	O
+.	O
+	
+Treatment	O
+with	O
+PDTC	O
+reduced	O
+the	O
+functional	O
+and	O
+structural	O
+changes	O
+induced	O
+by	O
+gentamicin	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+These	O
+data	O
+show	O
+that	O
+inhibition	O
+of	O
+NF	O
+-	O
+kappaB	O
+activation	O
+attenuates	O
+tubulointerstitial	B-NP
+nephritis	I-NP
+induced	O
+by	O
+gentamicin	O
+.	O
+	
+Glucose	O
+metabolism	O
+in	O
+patients	O
+with	O
+schizophrenia	B-NP
+treated	O
+with	O
+atypical	O
+antipsychotic	O
+agents	O
+:	O
+a	O
+frequently	O
+sampled	O
+intravenous	O
+glucose	O
+tolerance	O
+test	O
+and	O
+minimal	O
+model	O
+analysis	O
+.	O
+	
+BACKGROUND	O
+:	O
+While	O
+the	O
+incidence	O
+of	O
+new	O
+-	O
+onset	O
+diabetes	B-NP
+mellitus	I-NP
+may	O
+be	O
+increasing	O
+in	O
+patients	O
+with	O
+schizophrenia	B-NP
+treated	O
+with	O
+certain	O
+atypical	O
+antipsychotic	O
+agents	O
+","	O
+it	O
+remains	O
+unclear	O
+whether	O
+atypical	O
+agents	O
+are	O
+directly	O
+affecting	O
+glucose	O
+metabolism	O
+or	O
+simply	O
+increasing	O
+known	O
+risk	O
+factors	O
+for	O
+diabetes	B-NP
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+study	O
+the	O
+2	O
+drugs	O
+most	O
+clearly	O
+implicated	O
+(	O
+clozapine	O
+and	O
+olanzapine	O
+)	O
+and	O
+risperidone	O
+using	O
+a	O
+frequently	O
+sampled	O
+intravenous	O
+glucose	O
+tolerance	O
+test	O
+.	O
+	
+DESIGN	O
+:	O
+A	O
+cross	O
+-	O
+sectional	O
+design	O
+in	O
+stable	O
+","	O
+treated	O
+patients	O
+with	O
+schizophrenia	B-NP
+evaluated	O
+using	O
+a	O
+frequently	O
+sampled	O
+intravenous	O
+glucose	O
+tolerance	O
+test	O
+and	O
+the	O
+Bergman	O
+minimal	O
+model	O
+analysis	O
+.	O
+	
+SETTING	O
+:	O
+Subjects	O
+were	O
+recruited	O
+from	O
+an	O
+urban	O
+community	O
+mental	O
+health	O
+clinic	O
+and	O
+were	O
+studied	O
+at	O
+a	O
+general	O
+clinical	O
+research	O
+center	O
+.	O
+	
+Patients	O
+Fifty	O
+subjects	O
+signed	O
+informed	O
+consent	O
+and	O
+41	O
+underwent	O
+the	O
+frequently	O
+sampled	O
+intravenous	O
+glucose	O
+tolerance	O
+test	O
+.	O
+	
+Thirty	O
+-	O
+six	O
+nonobese	O
+subjects	O
+with	O
+schizophrenia	B-NP
+or	O
+schizoaffective	B-NP
+disorder	I-NP
+","	O
+matched	O
+by	O
+body	O
+mass	O
+index	O
+and	O
+treated	O
+with	O
+either	O
+clozapine	O
+","	O
+olanzapine	O
+","	O
+or	O
+risperidone	O
+","	O
+were	O
+included	O
+in	O
+the	O
+analysis	O
+.	O
+	
+MAIN	O
+OUTCOME	O
+MEASURES	O
+:	O
+Fasting	O
+plasma	O
+glucose	O
+and	O
+fasting	O
+serum	O
+insulin	O
+levels	O
+","	O
+insulin	B-NP
+sensitivity	I-NP
+index	O
+","	O
+homeostasis	O
+model	O
+assessment	O
+of	O
+insulin	B-NP
+resistance	I-NP
+","	O
+and	O
+glucose	O
+effectiveness	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+duration	O
+of	O
+treatment	O
+with	O
+the	O
+identified	O
+atypical	O
+antipsychotic	O
+agent	O
+was	O
+68	O
+.	O
+3	O
++	O
+/	O
+-	O
+28	O
+.	O
+9	O
+months	O
+(	O
+clozapine	O
+)	O
+","	O
+29	O
+.	O
+5	O
++	O
+/	O
+-	O
+17	O
+.	O
+5	O
+months	O
+(	O
+olanzapine	O
+)	O
+","	O
+and	O
+40	O
+.	O
+9	O
++	O
+/	O
+-	O
+33	O
+.	O
+7	O
+(	O
+risperidone	O
+)	O
+.	O
+	
+Fasting	O
+serum	O
+insulin	O
+concentrations	O
+differed	O
+among	O
+groups	O
+(	O
+F	O
+(	O
+33	O
+)	O
+=	O
+3	O
+.	O
+35	O
+;	O
+P	O
+=	O
+.	O
+47	O
+)	O
+(	O
+clozapine	O
+>	O
+olanzapine	O
+>	O
+risperidone	O
+)	O
+with	O
+significant	O
+differences	O
+between	O
+clozapine	O
+and	O
+risperidone	O
+(	O
+t	O
+(	O
+33	O
+)	O
+=	O
+2	O
+.	O
+32	O
+;	O
+P	O
+=	O
+.	O
+3	O
+)	O
+and	O
+olanzapine	O
+and	O
+risperidone	O
+(	O
+t	O
+(	O
+33	O
+)	O
+=	O
+2	O
+.	O
+15	O
+;	O
+P	O
+=	O
+.	O
+4	O
+)	O
+.	O
+	
+There	O
+was	O
+a	O
+significant	O
+difference	O
+in	O
+insulin	B-NP
+sensitivity	I-NP
+index	O
+among	O
+groups	O
+(	O
+F	O
+(	O
+33	O
+)	O
+=	O
+10	O
+.	O
+66	O
+;	O
+P	O
+<	O
+.	O
+1	O
+)	O
+(	O
+clozapine	O
+<	O
+olanzapine	O
+<	O
+risperidone	O
+)	O
+","	O
+with	O
+subjects	O
+who	O
+received	O
+clozapine	O
+and	O
+olanzapine	O
+exhibiting	O
+significant	O
+insulin	B-NP
+resistance	I-NP
+compared	O
+with	O
+subjects	O
+who	O
+were	O
+treated	O
+with	O
+risperidone	O
+(	O
+clozapine	O
+vs	O
+risperidone	O
+","	O
+t	O
+(	O
+33	O
+)	O
+=	O
+-	O
+4	O
+.	O
+29	O
+;	O
+P	O
+<	O
+.	O
+1	O
+;	O
+olanzapine	O
+vs	O
+risperidone	O
+","	O
+t	O
+(	O
+33	O
+)	O
+=	O
+-	O
+3	O
+.	O
+62	O
+;	O
+P	O
+=	O
+.	O
+1	O
+[	O
+P	O
+<	O
+.	O
+1	O
+]	O
+)	O
+.	O
+	
+The	O
+homeostasis	O
+model	O
+assessment	O
+of	O
+insulin	B-NP
+resistance	I-NP
+also	O
+differed	O
+significantly	O
+among	O
+groups	O
+(	O
+F	O
+(	O
+33	O
+)	O
+=	O
+4	O
+.	O
+92	O
+;	O
+P	O
+=	O
+.	O
+1	O
+)	O
+(	O
+clozapine	O
+>	O
+olanzapine	O
+>	O
+risperidone	O
+)	O
+(	O
+clozapine	O
+vs	O
+risperidone	O
+","	O
+t	O
+(	O
+33	O
+)	O
+=	O
+2	O
+.	O
+94	O
+;	O
+P	O
+=	O
+.	O
+6	O
+;	O
+olanzapine	O
+vs	O
+risperidone	O
+","	O
+t	O
+(	O
+33	O
+)	O
+=	O
+2	O
+.	O
+42	O
+;	O
+P	O
+=	O
+.	O
+2	O
+)	O
+.	O
+	
+There	O
+was	O
+a	O
+significant	O
+difference	O
+among	O
+groups	O
+in	O
+glucose	O
+effectiveness	O
+(	O
+F	O
+(	O
+30	O
+)	O
+=	O
+4	O
+.	O
+18	O
+;	O
+P	O
+=	O
+.	O
+2	O
+)	O
+(	O
+clozapine	O
+<	O
+olanzapine	O
+<	O
+risperidone	O
+)	O
+with	O
+significant	O
+differences	O
+between	O
+clozapine	O
+and	O
+risperidone	O
+(	O
+t	O
+(	O
+30	O
+)	O
+=	O
+-	O
+2	O
+.	O
+59	O
+;	O
+P	O
+=	O
+.	O
+2	O
+)	O
+and	O
+olanzapine	O
+and	O
+risperidone	O
+(	O
+t	O
+(	O
+30	O
+)	O
+=	O
+-	O
+2	O
+.	O
+34	O
+","	O
+P	O
+=	O
+.	O
+3	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Both	O
+nonobese	O
+clozapine	O
+-	O
+and	O
+olanzapine	O
+-	O
+treated	O
+groups	O
+displayed	O
+significant	O
+insulin	B-NP
+resistance	I-NP
+and	O
+impairment	O
+of	O
+glucose	O
+effectiveness	O
+compared	O
+with	O
+risperidone	O
+-	O
+treated	O
+subjects	O
+.	O
+	
+Patients	O
+taking	O
+clozapine	O
+and	O
+olanzapine	O
+must	O
+be	O
+examined	O
+for	O
+insulin	B-NP
+resistance	I-NP
+and	O
+its	O
+consequences	O
+.	O
+	
+Thoracic	B-NP
+hematomyelia	I-NP
+secondary	O
+to	O
+coumadin	O
+anticoagulant	O
+therapy	O
+:	O
+a	O
+case	O
+report	O
+.	O
+	
+A	O
+case	O
+of	O
+thoracic	B-NP
+hematomyelia	I-NP
+secondary	O
+to	O
+anticoagulant	O
+therapy	O
+is	O
+presented	O
+.	O
+	
+Clinical	O
+features	O
+","	O
+similar	O
+to	O
+2	O
+other	O
+previously	O
+reported	O
+cases	O
+","	O
+are	O
+discussed	O
+.	O
+	
+A	O
+high	O
+index	O
+of	O
+suspicion	O
+may	O
+lead	O
+to	O
+a	O
+quick	O
+diagnostic	O
+procedure	O
+and	O
+successful	O
+decompressive	O
+surgery	O
+.	O
+	
+Mania	B-NP
+associated	O
+with	O
+fluoxetine	O
+treatment	O
+in	O
+adolescents	O
+.	O
+	
+Fluoxetine	O
+","	O
+a	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitor	O
+","	O
+is	O
+gaining	O
+increased	O
+acceptance	O
+in	O
+the	O
+treatment	O
+of	O
+adolescent	O
+depression	B-NP
+.	O
+	
+Generally	O
+safe	O
+and	O
+well	O
+tolerated	O
+by	O
+adults	O
+","	O
+fluoxetine	O
+has	O
+been	O
+reported	O
+to	O
+induce	O
+mania	B-NP
+.	O
+	
+The	O
+cases	O
+of	O
+five	O
+depressed	B-NP
+adolescents	O
+","	O
+14	O
+-	O
+16	O
+years	O
+of	O
+age	O
+","	O
+who	O
+developed	O
+mania	B-NP
+during	O
+pharmacotherapy	O
+with	O
+fluoxetine	O
+","	O
+are	O
+reported	O
+here	O
+.	O
+	
+Apparent	O
+risk	O
+factors	O
+for	O
+the	O
+development	O
+of	O
+mania	B-NP
+or	O
+hypomania	B-NP
+during	O
+fluoxetine	O
+pharmacotherapy	O
+in	O
+this	O
+population	O
+were	O
+the	O
+combination	O
+of	O
+attention	B-NP
+-	I-NP
+deficit	I-NP
+hyperactivity	I-NP
+disorder	I-NP
+and	O
+affective	O
+instability	O
+;	O
+major	O
+depression	B-NP
+with	O
+psychotic	B-NP
+features	O
+;	O
+a	O
+family	O
+history	O
+of	O
+affective	B-NP
+disorder	I-NP
+","	O
+especially	O
+bipolar	B-NP
+disorder	I-NP
+;	O
+and	O
+a	O
+diagnosis	O
+of	O
+bipolar	B-NP
+disorder	I-NP
+.	O
+	
+Further	O
+study	O
+is	O
+needed	O
+to	O
+determine	O
+the	O
+optimal	O
+dosage	O
+and	O
+to	O
+identify	O
+risk	O
+factors	O
+that	O
+increase	O
+individual	O
+vulnerability	O
+to	O
+fluoxetine	O
+induced	O
+mania	B-NP
+in	O
+adolescents	O
+.	O
+	
+Acute	B-NP
+renal	I-NP
+insufficiency	I-NP
+after	O
+high	O
+-	O
+dose	O
+melphalan	O
+in	O
+patients	O
+with	O
+primary	B-NP
+systemic	I-NP
+amyloidosis	I-NP
+during	O
+stem	O
+cell	O
+transplantation	O
+.	O
+	
+BACKGROUND	O
+:	O
+Patients	O
+with	O
+primary	B-NP
+systemic	I-NP
+amyloidosis	I-NP
+(	O
+AL	B-NP
+)	O
+have	O
+a	O
+poor	O
+prognosis	O
+.	O
+	
+Median	O
+survival	O
+time	O
+from	O
+standard	O
+treatments	O
+is	O
+only	O
+17	O
+months	O
+.	O
+	
+High	O
+-	O
+dose	O
+intravenous	O
+melphalan	O
+followed	O
+by	O
+peripheral	O
+blood	O
+stem	O
+cell	O
+transplant	O
+(	O
+PBSCT	O
+)	O
+appears	O
+to	O
+be	O
+the	O
+most	O
+promising	O
+therapy	O
+","	O
+but	O
+treatment	O
+mortality	O
+can	O
+be	O
+high	O
+.	O
+	
+The	O
+authors	O
+have	O
+noted	O
+the	O
+development	O
+of	O
+acute	B-NP
+renal	I-NP
+insufficiency	I-NP
+immediately	O
+after	O
+melphalan	O
+conditioning	O
+.	O
+	
+This	O
+study	O
+was	O
+undertaken	O
+to	O
+further	O
+examine	O
+its	O
+risk	O
+factors	O
+and	O
+impact	O
+on	O
+posttransplant	O
+mortality	O
+.	O
+	
+METHODS	O
+:	O
+Consecutive	O
+AL	B-NP
+patients	O
+who	O
+underwent	O
+PBSCT	O
+were	O
+studied	O
+retrospectively	O
+.	O
+	
+Acute	B-NP
+renal	I-NP
+insufficiency	I-NP
+(	O
+ARI	B-NP
+)	O
+after	O
+high	O
+-	O
+dose	O
+melphalan	O
+was	O
+defined	O
+by	O
+a	O
+minimum	O
+increase	O
+of	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+dL	O
+(	O
+44	O
+micromol	O
+/	O
+L	O
+)	O
+in	O
+the	O
+serum	O
+creatinine	O
+level	O
+that	O
+is	O
+greater	O
+than	O
+50	O
+%	O
+of	O
+baseline	O
+immediately	O
+after	O
+conditioning	O
+.	O
+	
+Urine	O
+sediment	O
+score	O
+was	O
+the	O
+sum	O
+of	O
+the	O
+individual	O
+types	O
+of	O
+sediment	O
+identified	O
+on	O
+urine	O
+microscopy	O
+.	O
+	
+RESULTS	O
+:	O
+Of	O
+the	O
+80	O
+patients	O
+studied	O
+","	O
+ARI	B-NP
+developed	O
+in	O
+18	O
+.	O
+8	O
+%	O
+of	O
+the	O
+patients	O
+after	O
+high	O
+-	O
+dose	O
+melphalan	O
+.	O
+	
+Univariate	O
+analysis	O
+identified	O
+age	O
+","	O
+hypoalbuminemia	B-NP
+","	O
+heavy	O
+proteinuria	B-NP
+","	O
+diuretic	O
+use	O
+","	O
+and	O
+urine	O
+sediment	O
+score	O
+(	O
+>	O
+3	O
+)	O
+as	O
+risk	O
+factors	O
+.	O
+	
+Age	O
+and	O
+urine	O
+sediment	O
+score	O
+remained	O
+independently	O
+significant	O
+risk	O
+factors	O
+in	O
+the	O
+multivariate	O
+analysis	O
+.	O
+	
+Patients	O
+who	O
+had	O
+ARI	B-NP
+after	O
+high	O
+-	O
+dose	O
+melphalan	O
+underwent	O
+dialysis	O
+more	O
+often	O
+(	O
+P	O
+=	O
+0	O
+.	O
+7	O
+)	O
+","	O
+and	O
+had	O
+a	O
+worse	O
+1	O
+-	O
+year	O
+survival	O
+(	O
+P	O
+=	O
+0	O
+.	O
+3	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+The	O
+timing	O
+of	O
+renal	B-NP
+injury	I-NP
+strongly	O
+suggests	O
+melphalan	O
+as	O
+the	O
+causative	O
+agent	O
+.	O
+	
+Ongoing	O
+tubular	B-NP
+injury	I-NP
+may	O
+be	O
+a	O
+prerequisite	O
+for	O
+renal	B-NP
+injury	I-NP
+by	O
+melphalan	O
+as	O
+evidenced	O
+by	O
+the	O
+active	O
+urinary	O
+sediment	O
+.	O
+	
+Development	O
+of	O
+ARI	B-NP
+adversely	O
+affected	O
+the	O
+outcome	O
+after	O
+PBSCT	O
+.	O
+	
+Effective	O
+preventive	O
+measures	O
+may	O
+help	O
+decrease	O
+the	O
+treatment	O
+mortality	O
+of	O
+PBSCT	O
+in	O
+AL	B-NP
+patients	O
+.	O
+	
+Focal	O
+cerebral	B-NP
+ischemia	I-NP
+in	O
+rats	O
+:	O
+effect	O
+of	O
+phenylephrine	O
+-	O
+induced	O
+hypertension	B-NP
+during	O
+reperfusion	O
+.	O
+	
+After	O
+180	O
+min	O
+of	O
+temporary	O
+middle	B-NP
+cerebral	I-NP
+artery	I-NP
+occlusion	I-NP
+in	O
+spontaneously	O
+hypertensive	B-NP
+rats	O
+","	O
+the	O
+effect	O
+of	O
+phenylephrine	O
+-	O
+induced	O
+hypertension	B-NP
+on	O
+ischemic	B-NP
+brain	I-NP
+injury	I-NP
+and	O
+blood	O
+-	O
+brain	O
+barrier	O
+permeability	O
+was	O
+determined	O
+.	O
+	
+Blood	O
+pressure	O
+was	O
+manipulated	O
+by	O
+one	O
+of	O
+the	O
+following	O
+schedules	O
+during	O
+120	O
+min	O
+of	O
+reperfusion	O
+:	O
+Control	O
+","	O
+normotensive	O
+reperfusion	O
+;	O
+90	O
+/	O
+hypertension	B-NP
+(	O
+90	O
+/	O
+HTN	B-NP
+)	O
+","	O
+blood	O
+pressure	O
+was	O
+increased	O
+by	O
+35	O
+mm	O
+Hg	O
+during	O
+the	O
+initial	O
+90	O
+min	O
+of	O
+reperfusion	O
+only	O
+;	O
+15	O
+/	O
+hypertension	B-NP
+(	O
+15	O
+/	O
+HTN	B-NP
+)	O
+","	O
+normotensive	O
+reperfusion	O
+for	O
+30	O
+min	O
+followed	O
+by	O
+15	O
+min	O
+of	O
+hypertension	B-NP
+and	O
+75	O
+min	O
+of	O
+normotension	O
+.	O
+	
+Part	O
+A	O
+","	O
+for	O
+eight	O
+rats	O
+in	O
+each	O
+group	O
+brain	B-NP
+injury	I-NP
+was	O
+evaluated	O
+by	O
+staining	O
+tissue	O
+using	O
+2	O
+","	O
+3	O
+","	O
+5	O
+-	O
+triphenyltetrazolium	O
+chloride	O
+and	O
+edema	B-NP
+was	O
+evaluated	O
+by	O
+microgravimetry	O
+.	O
+	
+Part	O
+B	O
+","	O
+for	O
+eight	O
+different	O
+rats	O
+in	O
+each	O
+group	O
+blood	O
+-	O
+brain	O
+barrier	O
+permeability	O
+was	O
+evaluated	O
+by	O
+measuring	O
+the	O
+amount	O
+and	O
+extent	O
+of	O
+extravasation	O
+of	O
+Evans	O
+Blue	O
+dye	O
+.	O
+	
+Brain	B-NP
+injury	I-NP
+(	O
+percentage	O
+of	O
+the	O
+ischemic	B-NP
+hemisphere	I-NP
+)	O
+was	O
+less	O
+in	O
+the	O
+15	O
+/	O
+HTN	B-NP
+group	O
+(	O
+16	O
++	O
+/	O
+-	O
+6	O
+","	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+)	O
+versus	O
+the	O
+90	O
+/	O
+HTN	B-NP
+group	O
+(	O
+30	O
++	O
+/	O
+-	O
+6	O
+)	O
+","	O
+which	O
+was	O
+in	O
+turn	O
+less	O
+than	O
+the	O
+control	O
+group	O
+(	O
+42	O
++	O
+/	O
+-	O
+5	O
+)	O
+.	O
+	
+Specific	O
+gravity	O
+was	O
+greater	O
+in	O
+the	O
+15	O
+/	O
+HTN	B-NP
+group	O
+(	O
+1	O
+.	O
+43	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+)	O
+versus	O
+the	O
+90	O
+/	O
+HTN	B-NP
+(	O
+1	O
+.	O
+36	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+)	O
+and	O
+control	O
+(	O
+1	O
+.	O
+37	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+)	O
+groups	O
+.	O
+	
+Evans	O
+Blue	O
+(	O
+mug	O
+g	O
+-	O
+1	O
+of	O
+brain	O
+tissue	O
+)	O
+was	O
+greater	O
+in	O
+the	O
+90	O
+/	O
+HTN	B-NP
+group	O
+(	O
+24	O
+.	O
+4	O
++	O
+/	O
+-	O
+6	O
+.	O
+0	O
+)	O
+versus	O
+the	O
+control	O
+group	O
+(	O
+12	O
+.	O
+3	O
++	O
+/	O
+-	O
+4	O
+.	O
+1	O
+)	O
+","	O
+which	O
+was	O
+in	O
+turn	O
+greater	O
+than	O
+the	O
+15	O
+/	O
+HTN	B-NP
+group	O
+(	O
+7	O
+.	O
+3	O
++	O
+/	O
+-	O
+3	O
+.	O
+2	O
+)	O
+.	O
+	
+This	O
+study	O
+supports	O
+a	O
+hypothesis	O
+that	O
+during	O
+reperfusion	O
+","	O
+a	O
+short	O
+interval	O
+of	O
+hypertension	B-NP
+decreases	O
+brain	B-NP
+injury	I-NP
+and	O
+edema	B-NP
+;	O
+and	O
+that	O
+sustained	O
+hypertension	B-NP
+increases	O
+the	O
+risk	O
+of	O
+vasogenic	B-NP
+edema	I-NP
+.	O
+	
+People	O
+aged	O
+over	O
+75	O
+in	O
+atrial	B-NP
+fibrillation	I-NP
+on	O
+warfarin	O
+:	O
+the	O
+rate	O
+of	O
+major	O
+hemorrhage	B-NP
+and	O
+stroke	B-NP
+in	O
+more	O
+than	O
+500	O
+patient	O
+-	O
+years	O
+of	O
+follow	O
+-	O
+up	O
+.	O
+	
+OBJECTIVES	O
+:	O
+To	O
+determine	O
+the	O
+incidence	O
+of	O
+major	O
+hemorrhage	B-NP
+and	O
+stroke	B-NP
+in	O
+people	O
+aged	O
+76	O
+and	O
+older	O
+with	O
+atrial	B-NP
+fibrillation	I-NP
+on	O
+adjusted	O
+-	O
+dose	O
+warfarin	O
+who	O
+had	O
+been	O
+recently	O
+been	O
+admitted	O
+to	O
+hospital	O
+.	O
+	
+DESIGN	O
+:	O
+A	O
+retrospective	O
+observational	O
+cohort	O
+study	O
+.	O
+	
+SETTING	O
+:	O
+A	O
+major	O
+healthcare	O
+network	O
+involving	O
+four	O
+tertiary	O
+hospitals	O
+.	O
+	
+PARTICIPANTS	O
+:	O
+Two	O
+hundred	O
+thirty	O
+-	O
+five	O
+patients	O
+aged	O
+76	O
+and	O
+older	O
+admitted	O
+to	O
+a	O
+major	O
+healthcare	O
+network	O
+between	O
+July	O
+1	O
+","	O
+2001	O
+","	O
+and	O
+June	O
+30	O
+","	O
+2002	O
+","	O
+with	O
+atrial	B-NP
+fibrillation	I-NP
+on	O
+warfarin	O
+were	O
+enrolled	O
+.	O
+	
+MEASUREMENTS	O
+:	O
+Information	O
+regarding	O
+major	O
+bleeding	B-NP
+episodes	O
+","	O
+strokes	B-NP
+","	O
+and	O
+warfarin	O
+use	O
+was	O
+obtained	O
+from	O
+patients	O
+","	O
+relatives	O
+","	O
+primary	O
+physicians	O
+","	O
+and	O
+medical	O
+records	O
+.	O
+	
+RESULTS	O
+:	O
+Two	O
+hundred	O
+twenty	O
+-	O
+eight	O
+patients	O
+(	O
+42	O
+%	O
+men	O
+)	O
+with	O
+a	O
+mean	O
+age	O
+of	O
+81	O
+.	O
+1	O
+(	O
+range	O
+76	O
+-	O
+94	O
+)	O
+were	O
+included	O
+in	O
+the	O
+analysis	O
+.	O
+	
+Total	O
+follow	O
+-	O
+up	O
+on	O
+warfarin	O
+was	O
+530	O
+years	O
+(	O
+mean	O
+28	O
+months	O
+)	O
+.	O
+	
+There	O
+were	O
+53	O
+major	O
+hemorrhages	B-NP
+","	O
+for	O
+an	O
+annual	O
+rate	O
+of	O
+10	O
+.	O
+0	O
+%	O
+","	O
+including	O
+24	O
+(	O
+45	O
+.	O
+3	O
+%	O
+)	O
+life	O
+-	O
+threatening	O
+and	O
+five	O
+(	O
+9	O
+.	O
+4	O
+%	O
+)	O
+fatal	O
+bleeds	O
+.	O
+	
+The	O
+annual	O
+stroke	B-NP
+rate	O
+after	O
+initiation	O
+of	O
+warfarin	O
+was	O
+2	O
+.	O
+6	O
+%	O
+.	O
+	
+CONCLUSION	O
+:	O
+The	O
+rate	O
+of	O
+major	O
+hemorrhage	B-NP
+was	O
+high	O
+in	O
+this	O
+old	O
+","	O
+frail	O
+group	O
+","	O
+but	O
+excluding	O
+fatalities	O
+","	O
+resulted	O
+in	O
+no	O
+long	O
+-	O
+term	O
+sequelae	O
+","	O
+and	O
+the	O
+stroke	B-NP
+rate	O
+on	O
+warfarin	O
+was	O
+low	O
+","	O
+demonstrating	O
+how	O
+effective	O
+warfarin	O
+treatment	O
+is	O
+.	O
+	
+Safety	O
+of	O
+celecoxib	O
+in	O
+patients	O
+with	O
+adverse	O
+skin	B-NP
+reactions	I-NP
+to	O
+acetaminophen	O
+(	O
+paracetamol	O
+)	O
+and	O
+nimesulide	O
+associated	O
+or	O
+not	O
+with	O
+common	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+.	O
+	
+BACKGROUND	O
+:	O
+Acetaminophen	O
+(	O
+paracetamol	O
+-	O
+-	O
+P	O
+)	O
+and	O
+Nimesulide	O
+(	O
+N	O
+)	O
+are	O
+widely	O
+used	O
+analgesic	O
+-	O
+antipyretic	O
+/	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+.	O
+	
+The	O
+rate	O
+of	O
+adverse	O
+hypersensitivity	B-NP
+reactions	O
+to	O
+these	O
+agents	O
+is	O
+generally	O
+low	O
+.	O
+	
+On	O
+the	O
+contrary	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+(	O
+NSAIDs	O
+)	O
+are	O
+commonly	O
+involved	O
+in	O
+such	O
+reactions	O
+.	O
+	
+Celecoxib	O
+(	O
+CE	O
+)	O
+is	O
+a	O
+novel	O
+drug	O
+","	O
+with	O
+high	O
+selectivity	O
+and	O
+affinity	O
+for	O
+COX	O
+-	O
+2	O
+enzyme	O
+.	O
+	
+OBJECTIVE	O
+:	O
+We	O
+evaluated	O
+the	O
+tolerability	O
+of	O
+CE	O
+in	O
+a	O
+group	O
+of	O
+patients	O
+with	O
+documented	O
+history	O
+of	O
+adverse	O
+cutaneous	B-NP
+reactions	I-NP
+to	O
+P	O
+and	O
+N	O
+associated	O
+or	O
+not	O
+to	O
+classic	O
+NSAIDs	O
+.	O
+	
+METHODS	O
+:	O
+We	O
+studied	O
+9	O
+patients	O
+with	O
+hypersensitivity	B-NP
+to	O
+P	O
+and	O
+N	O
+with	O
+or	O
+without	O
+associated	O
+reactions	O
+to	O
+classic	O
+NSAIDs	O
+.	O
+	
+The	O
+diagnosis	O
+of	O
+P	O
+and	O
+N	O
+-	O
+induced	O
+skin	B-NP
+reactions	I-NP
+was	O
+based	O
+in	O
+vivo	O
+challenge	O
+.	O
+	
+The	O
+placebo	O
+was	O
+blindly	O
+administered	O
+at	O
+the	O
+beginning	O
+of	O
+each	O
+challenge	O
+.	O
+	
+After	O
+three	O
+days	O
+","	O
+a	O
+cumulative	O
+dosage	O
+of	O
+200	O
+mg	O
+of	O
+CE	O
+in	O
+refracted	O
+doses	O
+were	O
+given	O
+.	O
+	
+After	O
+2	O
+-	O
+3	O
+days	O
+","	O
+a	O
+single	O
+dose	O
+of	O
+200	O
+mg	O
+was	O
+administered	O
+.	O
+	
+All	O
+patients	O
+were	O
+observed	O
+for	O
+6	O
+hours	O
+after	O
+each	O
+challenge	O
+","	O
+and	O
+controlled	O
+again	O
+after	O
+24	O
+hours	O
+to	O
+exclude	O
+delayed	O
+reactions	O
+.	O
+	
+The	O
+challenge	O
+was	O
+considered	O
+positive	O
+if	O
+one	O
+or	O
+more	O
+of	O
+the	O
+following	O
+appeared	O
+:	O
+erythema	B-NP
+","	O
+rush	O
+or	O
+urticaria	B-NP
+-	O
+angioedema	B-NP
+.	O
+	
+RESULTS	O
+:	O
+No	O
+reaction	O
+was	O
+observed	O
+with	O
+placebo	O
+and	O
+eight	O
+patients	O
+(	O
+88	O
+.	O
+8	O
+%	O
+)	O
+tolerated	O
+CE	O
+.	O
+	
+Only	O
+one	O
+patient	O
+developed	O
+a	O
+moderate	O
+angioedema	B-NP
+of	O
+the	O
+lips	O
+.	O
+	
+CONCLUSION	O
+:	O
+Only	O
+one	O
+hypersensitivity	B-NP
+reaction	O
+to	O
+CE	O
+was	O
+documented	O
+among	O
+9	O
+P	O
+and	O
+N	O
+-	O
+highly	O
+NSAIDs	O
+intolerant	O
+patients	O
+.	O
+	
+Thus	O
+","	O
+we	O
+conclude	O
+that	O
+CE	O
+is	O
+a	O
+reasonably	O
+safe	O
+alternative	O
+to	O
+be	O
+used	O
+in	O
+subjects	O
+who	O
+do	O
+not	O
+tolerate	O
+P	O
+and	O
+N	O
+.	O
+	
+Case	O
+-	O
+control	O
+study	O
+of	O
+regular	O
+analgesic	O
+and	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+use	O
+and	O
+end	B-NP
+-	I-NP
+stage	I-NP
+renal	I-NP
+disease	I-NP
+.	O
+	
+BACKGROUND	O
+:	O
+Studies	O
+on	O
+the	O
+association	O
+between	O
+the	O
+long	O
+-	O
+term	O
+use	O
+of	O
+aspirin	O
+and	O
+other	O
+analgesic	O
+and	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+(	O
+NSAIDs	O
+)	O
+and	O
+end	B-NP
+-	I-NP
+stage	I-NP
+renal	I-NP
+disease	I-NP
+(	O
+ESRD	B-NP
+)	O
+have	O
+given	O
+conflicting	O
+results	O
+.	O
+	
+In	O
+order	O
+to	O
+examine	O
+this	O
+association	O
+","	O
+a	O
+case	O
+-	O
+control	O
+study	O
+with	O
+incident	O
+cases	O
+of	O
+ESRD	B-NP
+was	O
+carried	O
+out	O
+.	O
+	
+METHODS	O
+:	O
+The	O
+cases	O
+were	O
+all	O
+patients	O
+entering	O
+the	O
+local	O
+dialysis	O
+program	O
+because	O
+of	O
+ESRD	B-NP
+in	O
+the	O
+study	O
+area	O
+between	O
+June	O
+1	O
+","	O
+1995	O
+and	O
+November	O
+30	O
+","	O
+1997	O
+.	O
+	
+They	O
+were	O
+classified	O
+according	O
+to	O
+the	O
+underlying	O
+disease	O
+","	O
+which	O
+had	O
+presumably	O
+led	O
+them	O
+to	O
+ESRD	B-NP
+.	O
+	
+Controls	O
+were	O
+patients	O
+admitted	O
+to	O
+the	O
+same	O
+hospitals	O
+from	O
+where	O
+the	O
+cases	O
+arose	O
+","	O
+also	O
+matched	O
+by	O
+age	O
+and	O
+sex	O
+.	O
+	
+Odds	O
+ratios	O
+were	O
+calculated	O
+using	O
+a	O
+conditional	O
+logistic	O
+model	O
+","	O
+including	O
+potential	O
+confounding	O
+factors	O
+","	O
+both	O
+for	O
+the	O
+whole	O
+study	O
+population	O
+and	O
+for	O
+the	O
+various	O
+underlying	O
+diseases	O
+.	O
+	
+RESULTS	O
+:	O
+Five	O
+hundred	O
+and	O
+eighty	O
+-	O
+three	O
+cases	O
+and	O
+1190	O
+controls	O
+were	O
+included	O
+in	O
+the	O
+analysis	O
+.	O
+	
+Long	O
+-	O
+term	O
+use	O
+of	O
+any	O
+analgesic	O
+was	O
+associated	O
+with	O
+an	O
+overall	O
+odds	O
+ratio	O
+of	O
+1	O
+.	O
+22	O
+(	O
+95	O
+%	O
+CI	O
+","	O
+0	O
+.	O
+89	O
+-	O
+1	O
+.	O
+66	O
+)	O
+.	O
+	
+For	O
+specific	O
+groups	O
+of	O
+drugs	O
+","	O
+the	O
+risks	O
+were	O
+1	O
+.	O
+56	O
+(	O
+1	O
+.	O
+5	O
+-	O
+2	O
+.	O
+30	O
+)	O
+for	O
+aspirin	O
+","	O
+1	O
+.	O
+3	O
+(	O
+0	O
+.	O
+60	O
+-	O
+1	O
+.	O
+76	O
+)	O
+for	O
+pyrazolones	O
+","	O
+0	O
+.	O
+80	O
+(	O
+0	O
+.	O
+39	O
+-	O
+1	O
+.	O
+63	O
+)	O
+for	O
+paracetamol	O
+","	O
+and	O
+0	O
+.	O
+94	O
+(	O
+0	O
+.	O
+57	O
+-	O
+1	O
+.	O
+56	O
+)	O
+for	O
+nonaspirin	O
+NSAIDs	O
+.	O
+	
+The	O
+risk	O
+of	O
+ESRD	B-NP
+associated	O
+with	O
+aspirin	O
+was	O
+related	O
+to	O
+the	O
+cumulated	O
+dose	O
+and	O
+duration	O
+of	O
+use	O
+","	O
+and	O
+it	O
+was	O
+particularly	O
+high	O
+among	O
+the	O
+subset	O
+of	O
+patients	O
+with	O
+vascular	O
+nephropathy	B-NP
+as	O
+underlying	O
+disease	O
+[	O
+2	O
+.	O
+35	O
+(	O
+1	O
+.	O
+17	O
+-	O
+4	O
+.	O
+72	O
+)	O
+]	O
+.	O
+	
+CONCLUSION	O
+:	O
+Our	O
+data	O
+indicate	O
+that	O
+long	O
+-	O
+term	O
+use	O
+of	O
+nonaspirin	O
+analgesic	O
+drugs	O
+and	O
+NSAIDs	O
+is	O
+not	O
+associated	O
+with	O
+an	O
+increased	O
+risk	O
+of	O
+ESRD	B-NP
+.	O
+	
+However	O
+","	O
+the	O
+chronic	O
+use	O
+of	O
+aspirin	O
+may	O
+increase	O
+the	O
+risk	O
+of	O
+ESRD	B-NP
+.	O
+	
+Two	O
+cases	O
+of	O
+amisulpride	O
+overdose	B-NP
+:	O
+a	O
+cause	O
+for	O
+prolonged	B-NP
+QT	I-NP
+syndrome	I-NP
+.	O
+	
+Two	O
+cases	O
+of	O
+deliberate	O
+self	O
+-	O
+poisoning	B-NP
+with	O
+5	O
+g	O
+and	O
+3	O
+.	O
+6	O
+g	O
+of	O
+amisulpride	O
+","	O
+respectively	O
+","	O
+are	O
+reported	O
+.	O
+	
+In	O
+both	O
+cases	O
+","	O
+QT	B-NP
+prolongation	I-NP
+and	O
+hypocalcaemia	B-NP
+were	O
+noted	O
+.	O
+	
+The	O
+QT	B-NP
+prolongation	I-NP
+appeared	O
+to	O
+respond	O
+to	O
+administration	O
+of	O
+i	O
+.	O
+v	O
+.	O
+calcium	O
+gluconate	O
+.	O
+	
+Growth	O
+-	O
+associated	O
+protein	O
+43	O
+expression	O
+in	O
+hippocampal	O
+molecular	O
+layer	O
+of	O
+chronic	O
+epileptic	B-NP
+rats	O
+treated	O
+with	O
+cycloheximide	O
+.	O
+	
+PURPOSE	O
+:	O
+GAP43	O
+has	O
+been	O
+thought	O
+to	O
+be	O
+linked	O
+with	O
+mossy	O
+fiber	O
+sprouting	O
+(	O
+MFS	O
+)	O
+in	O
+various	O
+experimental	O
+models	O
+of	O
+epilepsy	B-NP
+.	O
+	
+To	O
+investigate	O
+how	O
+GAP43	O
+expression	O
+(	O
+GAP43	O
+-	O
+ir	O
+)	O
+correlates	O
+with	O
+MFS	O
+","	O
+we	O
+assessed	O
+the	O
+intensity	O
+(	O
+densitometry	O
+)	O
+and	O
+extension	O
+(	O
+width	O
+)	O
+of	O
+GAP43	O
+-	O
+ir	O
+in	O
+the	O
+inner	O
+molecular	O
+layer	O
+of	O
+the	O
+dentate	O
+gyrus	O
+(	O
+IML	O
+)	O
+of	O
+rats	O
+subject	O
+to	O
+status	B-NP
+epilepticus	I-NP
+induced	O
+by	O
+pilocarpine	O
+(	O
+Pilo	O
+)	O
+","	O
+previously	O
+injected	O
+or	O
+not	O
+with	O
+cycloheximide	O
+(	O
+CHX	O
+)	O
+","	O
+which	O
+has	O
+been	O
+shown	O
+to	O
+inhibit	O
+MFS	O
+.	O
+	
+METHODS	O
+:	O
+CHX	O
+was	O
+injected	O
+before	O
+the	O
+Pilo	O
+injection	O
+in	O
+adult	O
+Wistar	O
+rats	O
+.	O
+	
+The	O
+Pilo	O
+group	O
+was	O
+injected	O
+with	O
+the	O
+same	O
+drugs	O
+","	O
+except	O
+for	O
+CHX	O
+.	O
+	
+Animals	O
+were	O
+killed	O
+between	O
+30	O
+and	O
+60	O
+days	O
+later	O
+","	O
+and	O
+brain	O
+sections	O
+were	O
+processed	O
+for	O
+GAP43	O
+immunohistochemistry	O
+.	O
+	
+RESULTS	O
+:	O
+Densitometry	O
+showed	O
+no	O
+significant	O
+difference	O
+regarding	O
+GAP43	O
+-	O
+ir	O
+in	O
+the	O
+IML	O
+between	O
+Pilo	O
+","	O
+CHX	O
++	O
+Pilo	O
+","	O
+and	O
+control	O
+groups	O
+.	O
+	
+However	O
+","	O
+the	O
+results	O
+of	O
+the	O
+width	O
+of	O
+the	O
+GAP43	O
+-	O
+ir	O
+band	O
+in	O
+the	O
+IML	O
+showed	O
+that	O
+CHX	O
++	O
+Pilo	O
+and	O
+control	O
+animals	O
+had	O
+a	O
+significantly	O
+larger	O
+band	O
+(	O
+p	O
+=	O
+0	O
+.	O
+3	O
+)	O
+as	O
+compared	O
+with	O
+that	O
+in	O
+the	O
+Pilo	O
+group	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Our	O
+current	O
+finding	O
+that	O
+animals	O
+in	O
+the	O
+CHX	O
++	O
+Pilo	O
+group	O
+have	O
+a	O
+GAP43	O
+-	O
+ir	O
+band	O
+in	O
+the	O
+IML	O
+","	O
+similar	O
+to	O
+that	O
+of	O
+controls	O
+","	O
+reinforces	O
+prior	O
+data	O
+on	O
+the	O
+blockade	O
+of	O
+MFS	O
+in	O
+these	O
+animals	O
+.	O
+	
+The	O
+change	O
+in	O
+GAP43	O
+-	O
+ir	O
+present	O
+in	O
+Pilo	O
+-	O
+treated	O
+animals	O
+was	O
+a	O
+thinning	O
+of	O
+the	O
+band	O
+to	O
+a	O
+very	O
+narrow	O
+layer	O
+just	O
+above	O
+the	O
+granule	O
+cell	O
+layer	O
+that	O
+is	O
+likely	O
+to	O
+be	O
+associated	O
+with	O
+the	O
+loss	O
+of	O
+hilar	O
+cell	O
+projections	O
+that	O
+express	O
+GAP	O
+-	O
+43	O
+.	O
+	
+Nicotine	O
+antagonizes	O
+caffeine	O
+-	O
+but	O
+not	O
+pentylenetetrazole	O
+-	O
+induced	O
+anxiogenic	O
+effect	O
+in	O
+mice	O
+.	O
+	
+RATIONALE	O
+:	O
+Nicotine	O
+and	O
+caffeine	O
+are	O
+widely	O
+consumed	O
+licit	O
+psychoactive	O
+drugs	O
+worldwide	O
+.	O
+	
+Epidemiological	O
+studies	O
+showed	O
+that	O
+they	O
+were	O
+generally	O
+used	O
+concurrently	O
+.	O
+	
+Although	O
+some	O
+studies	O
+in	O
+experimental	O
+animals	O
+indicate	O
+clear	O
+pharmacological	O
+interactions	O
+between	O
+them	O
+","	O
+no	O
+studies	O
+have	O
+shown	O
+a	O
+specific	O
+interaction	O
+on	O
+anxiety	B-NP
+responses	O
+.	O
+	
+OBJECTIVES	O
+:	O
+The	O
+present	O
+study	O
+investigates	O
+the	O
+effects	O
+of	O
+nicotine	O
+on	O
+anxiety	B-NP
+induced	O
+by	O
+caffeine	O
+and	O
+another	O
+anxiogenic	O
+drug	O
+","	O
+pentylenetetrazole	O
+","	O
+in	O
+mice	O
+.	O
+	
+The	O
+elevated	O
+plus	O
+-	O
+maze	O
+(	O
+EPM	O
+)	O
+test	O
+was	O
+used	O
+to	O
+evaluate	O
+the	O
+effects	O
+of	O
+drugs	O
+on	O
+anxiety	B-NP
+.	O
+	
+METHODS	O
+:	O
+Adult	O
+male	O
+Swiss	O
+Webster	O
+mice	O
+(	O
+25	O
+-	O
+32	O
+g	O
+)	O
+were	O
+given	O
+nicotine	O
+(	O
+0	O
+.	O
+5	O
+-	O
+0	O
+.	O
+25	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+or	O
+saline	O
+10	O
+min	O
+before	O
+caffeine	O
+(	O
+70	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+or	O
+pentylenetetrazole	O
+(	O
+15	O
+and	O
+30	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+injections	O
+.	O
+	
+After	O
+15	O
+min	O
+","	O
+mice	O
+were	O
+evaluated	O
+for	O
+their	O
+open	O
+-	O
+and	O
+closed	O
+-	O
+arm	O
+time	O
+and	O
+entries	O
+on	O
+the	O
+EPM	O
+for	O
+a	O
+10	O
+-	O
+min	O
+session	O
+.	O
+	
+Locomotor	O
+activity	O
+was	O
+recorded	O
+for	O
+individual	O
+groups	O
+by	O
+using	O
+the	O
+same	O
+treatment	O
+protocol	O
+with	O
+the	O
+EPM	O
+test	O
+.	O
+	
+RESULTS	O
+:	O
+Nicotine	O
+(	O
+0	O
+.	O
+5	O
+-	O
+0	O
+.	O
+25	O
+mg	O
+/	O
+kg	O
+)	O
+itself	O
+did	O
+not	O
+produce	O
+any	O
+significant	O
+effect	O
+in	O
+the	O
+EPM	O
+test	O
+","	O
+whereas	O
+caffeine	O
+(	O
+70	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+pentylenetetrazole	O
+(	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+produced	O
+an	O
+anxiogenic	O
+effect	O
+","	O
+apparent	O
+with	O
+decreases	O
+in	O
+open	O
+-	O
+arm	O
+time	O
+and	O
+entry	O
+.	O
+	
+Nicotine	O
+(	O
+0	O
+.	O
+25	O
+mg	O
+/	O
+kg	O
+)	O
+pretreatment	O
+blocked	O
+the	O
+caffeine	O
+-	O
+but	O
+not	O
+pentylenetetrazole	O
+-	O
+induced	O
+anxiety	B-NP
+.	O
+	
+Administration	O
+of	O
+each	O
+drug	O
+and	O
+their	O
+combinations	O
+did	O
+not	O
+produce	O
+any	O
+effect	O
+on	O
+locomotor	O
+activity	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Our	O
+results	O
+suggest	O
+that	O
+the	O
+antagonistic	O
+effect	O
+of	O
+nicotine	O
+on	O
+caffeine	O
+-	O
+induced	O
+anxiety	B-NP
+is	O
+specific	O
+to	O
+caffeine	O
+","	O
+instead	O
+of	O
+a	O
+non	O
+-	O
+specific	O
+anxiolytic	O
+effect	O
+.	O
+	
+Thus	O
+","	O
+it	O
+may	O
+extend	O
+the	O
+current	O
+findings	O
+on	O
+the	O
+interaction	O
+between	O
+nicotine	O
+and	O
+caffeine	O
+.	O
+	
+Long	O
+term	O
+hormone	O
+therapy	O
+for	O
+perimenopausal	O
+and	O
+postmenopausal	O
+women	O
+.	O
+	
+BACKGROUND	O
+:	O
+Hormone	O
+therapy	O
+(	O
+HT	O
+)	O
+is	O
+widely	O
+used	O
+for	O
+controlling	O
+menopausal	B-NP
+symptoms	I-NP
+.	O
+	
+It	O
+has	O
+also	O
+been	O
+used	O
+for	O
+the	O
+management	O
+and	O
+prevention	O
+of	O
+cardiovascular	B-NP
+disease	I-NP
+","	O
+osteoporosis	B-NP
+and	O
+dementia	B-NP
+in	O
+older	O
+women	O
+but	O
+the	O
+evidence	O
+supporting	O
+its	O
+use	O
+for	O
+these	O
+indications	O
+is	O
+largely	O
+observational	O
+.	O
+	
+OBJECTIVES	O
+:	O
+To	O
+assess	O
+the	O
+effect	O
+of	O
+long	O
+-	O
+term	O
+HT	O
+on	O
+mortality	O
+","	O
+heart	B-NP
+disease	I-NP
+","	O
+venous	B-NP
+thromboembolism	I-NP
+","	O
+stroke	B-NP
+","	O
+transient	B-NP
+ischaemic	I-NP
+attacks	I-NP
+","	O
+breast	B-NP
+cancer	I-NP
+","	O
+colorectal	B-NP
+cancer	I-NP
+","	O
+ovarian	B-NP
+cancer	I-NP
+","	O
+endometrial	B-NP
+cancer	I-NP
+","	O
+gallbladder	B-NP
+disease	I-NP
+","	O
+cognitive	O
+function	O
+","	O
+dementia	B-NP
+","	O
+fractures	B-NP
+and	O
+quality	O
+of	O
+life	O
+.	O
+	
+SEARCH	O
+STRATEGY	O
+:	O
+We	O
+searched	O
+the	O
+following	O
+databases	O
+up	O
+to	O
+November	O
+2004	O
+:	O
+the	O
+Cochrane	O
+Menstrual	O
+Disorders	O
+and	O
+Subfertility	O
+Group	O
+Trials	O
+Register	O
+","	O
+Cochrane	O
+Central	O
+Register	O
+of	O
+Controlled	O
+Trials	O
+(	O
+CENTRAL	O
+)	O
+","	O
+MEDLINE	O
+","	O
+EMBASE	O
+","	O
+Biological	O
+Abstracts	O
+.	O
+	
+Relevant	O
+non	O
+-	O
+indexed	O
+journals	O
+and	O
+conference	O
+abstracts	O
+were	O
+also	O
+searched	O
+.	O
+	
+SELECTION	O
+CRITERIA	O
+:	O
+Randomised	O
+double	O
+-	O
+blind	O
+trials	O
+of	O
+HT	O
+(	O
+oestrogens	O
+with	O
+or	O
+without	O
+progestogens	O
+)	O
+versus	O
+placebo	O
+","	O
+taken	O
+for	O
+at	O
+least	O
+one	O
+year	O
+by	O
+perimenopausal	O
+or	O
+postmenopausal	O
+women	O
+.	O
+	
+DATA	O
+COLLECTION	O
+AND	O
+ANALYSIS	O
+:	O
+Fifteen	O
+RCTs	O
+were	O
+included	O
+.	O
+	
+Trials	O
+were	O
+assessed	O
+for	O
+quality	O
+and	O
+two	O
+review	O
+authors	O
+extracted	O
+data	O
+independently	O
+.	O
+	
+They	O
+calculated	O
+risk	O
+ratios	O
+for	O
+dichotomous	O
+outcomes	O
+and	O
+weighted	O
+mean	O
+differences	O
+for	O
+continuous	O
+outcomes	O
+.	O
+	
+Clinical	O
+heterogeneity	O
+precluded	O
+meta	O
+-	O
+analysis	O
+for	O
+most	O
+outcomes	O
+.	O
+	
+MAIN	O
+RESULTS	O
+:	O
+All	O
+the	O
+statistically	O
+significant	O
+results	O
+were	O
+derived	O
+from	O
+the	O
+two	O
+biggest	O
+trials	O
+.	O
+	
+In	O
+relatively	O
+healthy	O
+women	O
+","	O
+combined	O
+continuous	O
+HT	O
+significantly	O
+increased	O
+the	O
+risk	O
+of	O
+venous	B-NP
+thromboembolism	I-NP
+or	O
+coronary	O
+event	O
+(	O
+after	O
+one	O
+year	O
+'	O
+s	O
+use	O
+)	O
+","	O
+stroke	B-NP
+(	O
+after	O
+3	O
+years	O
+)	O
+","	O
+breast	B-NP
+cancer	I-NP
+(	O
+after	O
+5	O
+years	O
+)	O
+and	O
+gallbladder	B-NP
+disease	I-NP
+.	O
+	
+Long	O
+-	O
+term	O
+oestrogen	O
+-	O
+only	O
+HT	O
+also	O
+significantly	O
+increased	O
+the	O
+risk	O
+of	O
+stroke	B-NP
+and	O
+gallbladder	B-NP
+disease	I-NP
+.	O
+	
+Overall	O
+","	O
+the	O
+only	O
+statistically	O
+significant	O
+benefits	O
+of	O
+HT	O
+were	O
+a	O
+decreased	O
+incidence	O
+of	O
+fractures	B-NP
+and	O
+colon	B-NP
+cancer	I-NP
+with	O
+long	O
+-	O
+term	O
+use	O
+.	O
+	
+Among	O
+relatively	O
+healthy	O
+women	O
+over	O
+65	O
+years	O
+taking	O
+continuous	O
+combined	O
+HT	O
+","	O
+there	O
+was	O
+a	O
+statistically	O
+significant	O
+increase	O
+in	O
+the	O
+incidence	O
+of	O
+dementia	B-NP
+.	O
+	
+Among	O
+women	O
+with	O
+cardiovascular	B-NP
+disease	I-NP
+","	O
+long	O
+-	O
+term	O
+use	O
+of	O
+combined	O
+continuous	O
+HT	O
+significantly	O
+increased	O
+the	O
+risk	O
+of	O
+venous	B-NP
+thromboembolism	I-NP
+.	O
+	
+No	O
+trials	O
+focussed	O
+specifically	O
+on	O
+younger	O
+women	O
+.	O
+	
+However	O
+","	O
+one	O
+trial	O
+analysed	O
+subgroups	O
+of	O
+2839	O
+relatively	O
+healthy	O
+50	O
+to	O
+59	O
+year	O
+-	O
+old	O
+women	O
+taking	O
+combined	O
+continuous	O
+HT	O
+and	O
+1637	O
+taking	O
+oestrogen	O
+-	O
+only	O
+HT	O
+","	O
+versus	O
+similar	O
+-	O
+sized	O
+placebo	O
+groups	O
+.	O
+	
+The	O
+only	O
+significantly	O
+increased	O
+risk	O
+reported	O
+was	O
+for	O
+venous	B-NP
+thromboembolism	I-NP
+in	O
+women	O
+taking	O
+combined	O
+continuous	O
+HT	O
+;	O
+their	O
+absolute	O
+risk	O
+remained	O
+very	O
+low	O
+.	O
+	
+AUTHORS	O
+'	O
+CONCLUSIONS	O
+:	O
+HT	O
+is	O
+not	O
+indicated	O
+for	O
+the	O
+routine	O
+management	O
+of	O
+chronic	B-NP
+disease	I-NP
+.	O
+	
+We	O
+need	O
+more	O
+evidence	O
+on	O
+the	O
+safety	O
+of	O
+HT	O
+for	O
+menopausal	O
+symptom	O
+control	O
+","	O
+though	O
+short	O
+-	O
+term	O
+use	O
+appears	O
+to	O
+be	O
+relatively	O
+safe	O
+for	O
+healthy	O
+younger	O
+women	O
+.	O
+	
+Drug	B-NP
+-	I-NP
+induced	I-NP
+liver	I-NP
+injury	I-NP
+:	O
+an	O
+analysis	O
+of	O
+461	O
+incidences	O
+submitted	O
+to	O
+the	O
+Spanish	O
+registry	O
+over	O
+a	O
+10	O
+-	O
+year	O
+period	O
+.	O
+	
+BACKGROUND	O
+&	O
+AIMS	O
+:	O
+Progress	O
+in	O
+the	O
+understanding	O
+of	O
+susceptibility	O
+factors	O
+to	O
+drug	B-NP
+-	I-NP
+induced	I-NP
+liver	I-NP
+injury	I-NP
+(	O
+DILI	B-NP
+)	O
+and	O
+outcome	O
+predictability	O
+are	O
+hampered	O
+by	O
+the	O
+lack	O
+of	O
+systematic	O
+programs	O
+to	O
+detect	O
+bona	O
+fide	O
+cases	O
+.	O
+	
+METHODS	O
+:	O
+A	O
+cooperative	O
+network	O
+was	O
+created	O
+in	O
+1994	O
+in	O
+Spain	O
+to	O
+identify	O
+all	O
+suspicions	O
+of	O
+DILI	B-NP
+following	O
+a	O
+prospective	O
+structured	O
+report	O
+form	O
+.	O
+	
+The	O
+liver	B-NP
+damage	I-NP
+was	O
+characterized	O
+according	O
+to	O
+hepatocellular	O
+","	O
+cholestatic	B-NP
+","	O
+and	O
+mixed	O
+laboratory	O
+criteria	O
+and	O
+to	O
+histologic	O
+criteria	O
+when	O
+available	O
+.	O
+	
+Further	O
+evaluation	O
+of	O
+causality	O
+assessment	O
+was	O
+centrally	O
+performed	O
+.	O
+	
+RESULTS	O
+:	O
+Since	O
+April	O
+1994	O
+to	O
+August	O
+2004	O
+","	O
+461	O
+out	O
+of	O
+570	O
+submitted	O
+cases	O
+","	O
+involving	O
+505	O
+drugs	O
+","	O
+were	O
+deemed	O
+to	O
+be	O
+related	O
+to	O
+DILI	B-NP
+.	O
+	
+The	O
+antiinfective	O
+group	O
+of	O
+drugs	O
+was	O
+the	O
+more	O
+frequently	O
+incriminated	O
+","	O
+amoxicillin	O
+-	O
+clavulanate	O
+accounting	O
+for	O
+the	O
+12	O
+.	O
+8	O
+%	O
+of	O
+the	O
+whole	O
+series	O
+.	O
+	
+The	O
+hepatocellular	O
+pattern	O
+of	O
+damage	O
+was	O
+the	O
+most	O
+common	O
+(	O
+58	O
+%	O
+)	O
+","	O
+was	O
+inversely	O
+correlated	O
+with	O
+age	O
+(	O
+P	O
+<	O
+.	O
+1	O
+)	O
+","	O
+and	O
+had	O
+the	O
+worst	O
+outcome	O
+(	O
+Cox	O
+regression	O
+","	O
+P	O
+<	O
+.	O
+34	O
+)	O
+.	O
+	
+Indeed	O
+","	O
+the	O
+incidence	O
+of	O
+liver	O
+transplantation	O
+and	O
+death	O
+in	O
+this	O
+group	O
+was	O
+11	O
+.	O
+7	O
+%	O
+if	O
+patients	O
+had	O
+jaundice	B-NP
+at	O
+presentation	O
+","	O
+whereas	O
+the	O
+corresponding	O
+figure	O
+was	O
+3	O
+.	O
+8	O
+%	O
+in	O
+nonjaundiced	O
+patients	O
+(	O
+P	O
+<	O
+.	O
+4	O
+)	O
+.	O
+	
+Factors	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+fulminant	B-NP
+hepatic	I-NP
+failure	I-NP
+were	O
+female	O
+sex	O
+(	O
+OR	O
+=	O
+25	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+4	O
+.	O
+1	O
+-	O
+151	O
+;	O
+P	O
+<	O
+.	O
+1	O
+)	O
+","	O
+hepatocellular	O
+damage	O
+(	O
+OR	O
+=	O
+7	O
+.	O
+9	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+1	O
+.	O
+6	O
+-	O
+37	O
+;	O
+P	O
+<	O
+.	O
+9	O
+)	O
+","	O
+and	O
+higher	O
+baseline	O
+plasma	O
+bilirubin	O
+value	O
+(	O
+OR	O
+=	O
+1	O
+.	O
+15	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+1	O
+.	O
+9	O
+-	O
+1	O
+.	O
+22	O
+;	O
+P	O
+<	O
+.	O
+1	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Patients	O
+with	O
+drug	O
+-	O
+induced	O
+hepatocellular	O
+jaundice	B-NP
+have	O
+11	O
+.	O
+7	O
+%	O
+chance	O
+of	O
+progressing	O
+to	O
+death	O
+or	O
+transplantation	O
+.	O
+	
+Amoxicillin	O
+-	O
+clavulanate	O
+stands	O
+out	O
+as	O
+the	O
+most	O
+common	O
+drug	O
+related	O
+to	O
+DILI	B-NP
+.	O
+	
+Morphological	O
+evaluation	O
+of	O
+the	O
+effect	O
+of	O
+d	O
+-	O
+ribose	O
+on	O
+adriamycin	O
+-	O
+evoked	O
+cardiotoxicity	B-NP
+in	O
+rats	O
+.	O
+	
+The	O
+influence	O
+of	O
+d	O
+-	O
+ribose	O
+on	O
+adriamycin	O
+-	O
+induced	O
+myocardiopathy	B-NP
+in	O
+rats	O
+was	O
+studied	O
+.	O
+	
+Adriamycin	O
+in	O
+the	O
+cumulative	O
+dose	O
+of	O
+25	O
+mg	O
+/	O
+kg	O
+evoked	O
+fully	O
+developed	O
+cardiac	B-NP
+toxicity	I-NP
+.	O
+	
+D	O
+-	O
+ribose	O
+in	O
+the	O
+multiple	O
+doses	O
+of	O
+200	O
+mg	O
+/	O
+kg	O
+did	O
+not	O
+influence	O
+ADR	O
+cardiotoxicity	B-NP
+.	O
+	
+In	O
+vivo	O
+evidences	O
+suggesting	O
+the	O
+role	O
+of	O
+oxidative	O
+stress	O
+in	O
+pathogenesis	O
+of	O
+vancomycin	O
+-	O
+induced	O
+nephrotoxicity	B-NP
+:	O
+protection	O
+by	O
+erdosteine	O
+.	O
+	
+The	O
+aims	O
+of	O
+this	O
+study	O
+were	O
+to	O
+examine	O
+vancomycin	O
+(	O
+VCM	O
+)	O
+-	O
+induced	O
+oxidative	O
+stress	O
+that	O
+promotes	O
+production	O
+of	O
+reactive	O
+oxygen	O
+species	O
+(	O
+ROS	O
+)	O
+and	O
+to	O
+investigate	O
+the	O
+role	O
+of	O
+erdosteine	O
+","	O
+an	O
+expectorant	O
+agent	O
+","	O
+which	O
+has	O
+also	O
+antioxidant	O
+properties	O
+","	O
+on	O
+kidney	O
+tissue	O
+against	O
+the	O
+possible	O
+VCM	O
+-	O
+induced	O
+renal	B-NP
+impairment	I-NP
+in	O
+rats	O
+.	O
+	
+Rats	O
+were	O
+divided	O
+into	O
+three	O
+groups	O
+:	O
+sham	O
+","	O
+VCM	O
+and	O
+VCM	O
+plus	O
+erdosteine	O
+.	O
+	
+VCM	O
+was	O
+administrated	O
+intraperitoneally	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+with	O
+200mgkg	O
+(	O
+-	O
+1	O
+)	O
+twice	O
+daily	O
+for	O
+7	O
+days	O
+.	O
+	
+Erdosteine	O
+was	O
+administered	O
+orally	O
+.	O
+	
+VCM	O
+administration	O
+to	O
+control	O
+rats	O
+significantly	O
+increased	O
+renal	O
+malondialdehyde	O
+(	O
+MDA	O
+)	O
+and	O
+urinary	O
+N	O
+-	O
+acetyl	O
+-	O
+beta	O
+-	O
+d	O
+-	O
+glucosaminidase	O
+(	O
+NAG	O
+","	O
+a	O
+marker	O
+of	O
+renal	B-NP
+tubular	I-NP
+injury	I-NP
+)	O
+excretion	O
+but	O
+decreased	O
+superoxide	O
+dismutase	O
+(	O
+SOD	O
+)	O
+and	O
+catalase	O
+(	O
+CAT	O
+)	O
+activities	O
+.	O
+	
+Erdosteine	O
+administration	O
+with	O
+VCM	O
+injections	O
+caused	O
+significantly	O
+decreased	O
+renal	O
+MDA	O
+and	O
+urinary	O
+NAG	O
+excretion	O
+","	O
+and	O
+increased	O
+SOD	O
+activity	O
+","	O
+but	O
+not	O
+CAT	O
+activity	O
+in	O
+renal	O
+tissue	O
+when	O
+compared	O
+with	O
+VCM	O
+alone	O
+.	O
+	
+Erdosteine	O
+showed	O
+histopathological	O
+protection	O
+against	O
+VCM	O
+-	O
+induced	O
+nephrotoxicity	B-NP
+.	O
+	
+There	O
+were	O
+a	O
+significant	O
+dilatation	O
+of	O
+tubular	O
+lumens	O
+","	O
+extensive	O
+epithelial	O
+cell	O
+vacuolization	O
+","	O
+atrophy	B-NP
+","	O
+desquamation	B-NP
+","	O
+and	O
+necrosis	B-NP
+in	O
+VCM	O
+-	O
+treated	O
+rats	O
+more	O
+than	O
+those	O
+of	O
+the	O
+control	O
+and	O
+the	O
+erdosteine	O
+groups	O
+.	O
+	
+Erdosteine	O
+caused	O
+a	O
+marked	O
+reduction	O
+in	O
+the	O
+extent	O
+of	O
+tubular	O
+damage	O
+.	O
+	
+It	O
+is	O
+concluded	O
+that	O
+oxidative	O
+tubular	O
+damage	O
+plays	O
+an	O
+important	O
+role	O
+in	O
+the	O
+VCM	O
+-	O
+induced	O
+nephrotoxicity	B-NP
+and	O
+the	O
+modulation	O
+of	O
+oxidative	O
+stress	O
+with	O
+erdosteine	O
+reduces	O
+the	O
+VCM	O
+-	O
+induced	O
+kidney	B-NP
+damage	I-NP
+both	O
+at	O
+the	O
+biochemical	O
+and	O
+histological	O
+levels	O
+.	O
+	
+Gemfibrozil	O
+-	O
+lovastatin	O
+therapy	O
+for	O
+primary	O
+hyperlipoproteinemias	B-NP
+.	O
+	
+The	O
+specific	O
+aim	O
+of	O
+this	O
+retrospective	O
+","	O
+observational	O
+study	O
+was	O
+to	O
+assess	O
+safety	O
+and	O
+efficacy	O
+of	O
+long	O
+-	O
+term	O
+(	O
+21	O
+months	O
+/	O
+patient	O
+)	O
+","	O
+open	O
+-	O
+label	O
+","	O
+gemfibrozil	O
+-	O
+lovastatin	O
+treatment	O
+in	O
+80	O
+patients	O
+with	O
+primary	O
+mixed	O
+hyperlipidemia	B-NP
+(	O
+68	O
+%	O
+of	O
+whom	O
+had	O
+atherosclerotic	B-NP
+vascular	I-NP
+disease	I-NP
+)	O
+.	O
+	
+Because	O
+ideal	O
+lipid	O
+targets	O
+were	O
+not	O
+reached	O
+(	O
+low	O
+-	O
+density	O
+lipoprotein	O
+(	O
+LDL	O
+)	O
+cholesterol	O
+less	O
+than	O
+130	O
+mg	O
+/	O
+dl	O
+","	O
+high	O
+-	O
+density	O
+lipoprotein	O
+(	O
+HDL	O
+)	O
+cholesterol	O
+greater	O
+than	O
+35	O
+mg	O
+/	O
+dl	O
+","	O
+or	O
+total	O
+cholesterol	O
+/	O
+HDL	O
+cholesterol	O
+less	O
+than	O
+4	O
+.	O
+5	O
+mg	O
+/	O
+dl	O
+)	O
+with	O
+diet	O
+plus	O
+a	O
+single	O
+drug	O
+","	O
+gemfibrozil	O
+(	O
+1	O
+.	O
+2	O
+g	O
+/	O
+day	O
+)	O
+-	O
+lovastatin	O
+(	O
+primarily	O
+20	O
+or	O
+40	O
+mg	O
+)	O
+treatment	O
+was	O
+given	O
+.	O
+	
+Follow	O
+-	O
+up	O
+visits	O
+were	O
+scheduled	O
+with	O
+2	O
+-	O
+drug	O
+therapy	O
+every	O
+6	O
+to	O
+8	O
+weeks	O
+","	O
+an	O
+average	O
+of	O
+10	O
+.	O
+3	O
+visits	O
+per	O
+patient	O
+","	O
+with	O
+741	O
+batteries	O
+of	O
+6	O
+liver	O
+function	O
+tests	O
+and	O
+714	O
+creatine	O
+phosphokinase	O
+levels	O
+measured	O
+.	O
+	
+Only	O
+1	O
+of	O
+the	O
+4	O
+","	O
+446	O
+liver	O
+function	O
+tests	O
+(	O
+0	O
+.	O
+2	O
+%	O
+)	O
+","	O
+a	O
+gamma	O
+glutamyl	O
+transferase	O
+","	O
+was	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+3	O
+times	O
+the	O
+upper	O
+normal	O
+limit	O
+.	O
+	
+Of	O
+the	O
+714	O
+creatine	O
+phosphokinase	O
+levels	O
+","	O
+9	O
+%	O
+were	O
+high	O
+;	O
+only	O
+1	O
+(	O
+0	O
+.	O
+1	O
+%	O
+)	O
+was	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+3	O
+times	O
+the	O
+upper	O
+normal	O
+limit	O
+.	O
+	
+With	O
+2	O
+-	O
+drug	O
+therapy	O
+","	O
+mean	O
+total	O
+cholesterol	O
+decreased	O
+22	O
+%	O
+from	O
+255	O
+to	O
+200	O
+mg	O
+/	O
+dl	O
+","	O
+triglyceride	O
+levels	O
+decreased	O
+35	O
+%	O
+from	O
+236	O
+to	O
+154	O
+mg	O
+/	O
+dl	O
+","	O
+LDL	O
+cholesterol	O
+decreased	O
+26	O
+%	O
+from	O
+176	O
+to	O
+131	O
+mg	O
+/	O
+dl	O
+","	O
+and	O
+the	O
+total	O
+cholesterol	O
+/	O
+HDL	O
+cholesterol	O
+ratio	O
+decreased	O
+24	O
+%	O
+from	O
+7	O
+.	O
+1	O
+to	O
+5	O
+.	O
+4	O
+","	O
+all	O
+p	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+0	O
+.	O
+1	O
+.	O
+	
+Myositis	B-NP
+","	O
+attributable	O
+to	O
+the	O
+drug	O
+combination	O
+and	O
+symptomatic	O
+enough	O
+to	O
+discontinue	O
+it	O
+","	O
+occurred	O
+in	O
+3	O
+%	O
+of	O
+patients	O
+","	O
+and	O
+in	O
+1	O
+%	O
+with	O
+concurrent	O
+high	O
+creatine	O
+phosphokinase	O
+(	O
+769	O
+U	O
+/	O
+liter	O
+)	O
+;	O
+no	O
+patients	O
+had	O
+rhabdomyolysis	B-NP
+or	O
+myoglobinuria	B-NP
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+	
+Does	O
+domperidone	O
+potentiate	O
+mirtazapine	O
+-	O
+associated	O
+restless	B-NP
+legs	I-NP
+syndrome	I-NP
+?	O
+	
+There	O
+is	O
+now	O
+evidence	O
+to	O
+suggest	O
+a	O
+central	O
+role	O
+for	O
+the	O
+dopaminergic	O
+system	O
+in	O
+restless	B-NP
+legs	I-NP
+syndrome	I-NP
+(	O
+RLS	B-NP
+)	O
+.	O
+	
+For	O
+example	O
+","	O
+the	O
+symptoms	O
+of	O
+RLS	B-NP
+can	O
+be	O
+dramatically	O
+improved	O
+by	O
+levodopa	O
+and	O
+dopamine	O
+agonists	O
+","	O
+whereas	O
+central	O
+dopamine	O
+D2	O
+receptor	O
+antagonists	O
+can	O
+induce	O
+or	O
+aggravate	O
+RLS	B-NP
+symptoms	O
+.	O
+	
+To	O
+our	O
+knowledge	O
+","	O
+there	O
+is	O
+no	O
+previous	O
+report	O
+regarding	O
+whether	O
+domperidone	O
+","	O
+a	O
+peripheral	O
+dopamine	O
+D2	O
+receptor	O
+antagonist	O
+","	O
+can	O
+also	O
+induce	O
+or	O
+aggravate	O
+symptoms	O
+of	O
+RLS	B-NP
+.	O
+	
+Mirtazapine	O
+","	O
+the	O
+first	O
+noradrenergic	O
+and	O
+specific	O
+serotonergic	O
+antidepressant	O
+(	O
+NaSSA	O
+)	O
+","	O
+has	O
+been	O
+associated	O
+with	O
+RLS	B-NP
+in	O
+several	O
+recent	O
+publications	O
+.	O
+	
+The	O
+authors	O
+report	O
+here	O
+a	O
+depressed	O
+patient	O
+comorbid	O
+with	O
+postprandial	B-NP
+dyspepsia	I-NP
+who	O
+developed	O
+RLS	B-NP
+after	O
+mirtazapine	O
+had	O
+been	O
+added	O
+to	O
+his	O
+domperidone	O
+therapy	O
+.	O
+	
+Our	O
+patient	O
+started	O
+to	O
+have	O
+symptoms	O
+of	O
+RLS	B-NP
+only	O
+after	O
+he	O
+had	O
+been	O
+treated	O
+with	O
+mirtazapine	O
+","	O
+and	O
+his	O
+RLS	B-NP
+symptoms	O
+resolved	O
+completely	O
+upon	O
+discontinuation	O
+of	O
+his	O
+mirtazapine	O
+.	O
+	
+Such	O
+a	O
+temporal	O
+relationship	O
+between	O
+the	O
+use	O
+of	O
+mirtazapine	O
+and	O
+the	O
+symptoms	O
+of	O
+RLS	B-NP
+in	O
+our	O
+patient	O
+did	O
+not	O
+support	O
+a	O
+potentiating	O
+effect	O
+of	O
+domperione	O
+on	O
+mirtazapine	O
+-	O
+associated	O
+RLS	B-NP
+.	O
+	
+However	O
+","	O
+physicians	O
+should	O
+be	O
+aware	O
+of	O
+the	O
+possibility	O
+that	O
+mirtazapine	O
+can	O
+be	O
+associated	O
+with	O
+RLS	B-NP
+in	O
+some	O
+individuals	O
+","	O
+especially	O
+those	O
+receiving	O
+concomitant	O
+dopamine	O
+D2	O
+receptor	O
+antagonists	O
+.	O
+	
+Antiandrogenic	O
+therapy	O
+can	O
+cause	O
+coronary	B-NP
+arterial	I-NP
+disease	I-NP
+.	O
+	
+AIM	O
+:	O
+To	O
+study	O
+the	O
+change	O
+of	O
+lipid	O
+metabolism	O
+by	O
+antiandrogen	O
+therapy	O
+in	O
+patients	O
+with	O
+prostate	B-NP
+cancer	I-NP
+.	O
+	
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+We	O
+studied	O
+with	O
+a	O
+2	O
+.	O
+5	O
+years	O
+follow	O
+-	O
+up	O
+the	O
+changes	O
+in	O
+plasma	O
+cholesterols	O
+(	O
+C	O
+)	O
+","	O
+triglycerides	O
+(	O
+TG	O
+)	O
+","	O
+lipoproteins	O
+(	O
+LP	O
+)	O
+","	O
+and	O
+apolipoproteins	O
+(	O
+Apo	O
+)	O
+B	O
+-	O
+100	O
+","	O
+A	O
+-	O
+I	O
+","	O
+and	O
+A	O
+-	O
+II	O
+pro	O
+fi	O
+les	O
+in	O
+24	O
+patients	O
+of	O
+mean	O
+age	O
+60	O
+years	O
+with	O
+low	O
+risk	O
+prostate	B-NP
+cancer	I-NP
+(	O
+stage	O
+:	O
+T1cN0M0	O
+","	O
+Gleason	O
+score	O
+:	O
+2	O
+-	O
+5	O
+)	O
+during	O
+treatment	O
+with	O
+cyproterone	O
+acetate	O
+(	O
+CPA	O
+)	O
+without	O
+surgical	O
+management	O
+or	O
+radiation	O
+therapy	O
+.	O
+	
+RESULTS	O
+:	O
+Significant	O
+decreases	O
+of	O
+HDL	O
+-	O
+C	O
+","	O
+Apo	O
+A	O
+-	O
+I	O
+and	O
+Apo	O
+A	O
+-	O
+II	O
+and	O
+an	O
+increase	O
+of	O
+triglyceride	O
+levels	O
+in	O
+VLDL	O
+were	O
+induced	O
+by	O
+CPA	O
+.	O
+	
+After	O
+a	O
+period	O
+of	O
+2	O
+.	O
+5	O
+years	O
+on	O
+CPA	O
+treatment	O
+","	O
+four	O
+patients	O
+out	O
+of	O
+twenty	O
+-	O
+four	O
+were	O
+found	O
+to	O
+be	O
+affected	O
+by	O
+coronary	B-NP
+heart	I-NP
+disease	I-NP
+.	O
+	
+CONCLUSIONS	O
+:	O
+Ischaemic	O
+coronary	B-NP
+arteriosclerosis	I-NP
+with	O
+an	O
+incidence	O
+rate	O
+of	O
+16	O
+.	O
+6	O
+%	O
+as	O
+caused	O
+by	O
+prolonged	O
+CPA	O
+therapy	O
+is	O
+mediated	O
+through	O
+changes	O
+in	O
+HDL	O
+cholesterol	O
+","	O
+Apo	O
+A	O
+-	O
+I	O
+and	O
+Apo	O
+A	O
+-	O
+II	O
+pro	O
+fi	O
+les	O
+","	O
+other	O
+than	O
+the	O
+well	O
+-	O
+known	O
+hyperglyceridemic	B-NP
+effect	I-NP
+caused	O
+by	O
+estrogen	O
+.	O
+	
+5	O
+-	O
+Fluorouracil	O
+cardiotoxicity	B-NP
+induced	O
+by	O
+alpha	O
+-	O
+fluoro	O
+-	O
+beta	O
+-	O
+alanine	O
+.	O
+	
+Cardiotoxicity	B-NP
+is	O
+a	O
+rare	O
+complication	O
+occurring	O
+during	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+treatment	O
+for	O
+malignancies	B-NP
+.	O
+	
+We	O
+herein	O
+report	O
+the	O
+case	O
+of	O
+a	O
+70	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+5	O
+-	O
+FU	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+","	O
+in	O
+whom	O
+a	O
+high	O
+serum	O
+level	O
+of	O
+alpha	O
+-	O
+fluoro	O
+-	O
+beta	O
+-	O
+alanine	O
+(	O
+FBAL	O
+)	O
+was	O
+observed	O
+.	O
+	
+The	O
+patient	O
+","	O
+who	O
+had	O
+unresectable	O
+colon	B-NP
+cancer	I-NP
+metastases	O
+to	O
+the	O
+liver	O
+and	O
+lung	O
+","	O
+was	O
+referred	O
+to	O
+us	O
+for	O
+chemotherapy	O
+from	O
+an	O
+affiliated	O
+hospital	O
+;	O
+he	O
+had	O
+no	O
+cardiac	O
+history	O
+.	O
+	
+After	O
+admission	O
+","	O
+the	O
+patient	O
+received	O
+a	O
+continuous	O
+intravenous	O
+infusion	O
+of	O
+5	O
+-	O
+FU	O
+(	O
+1000	O
+mg	O
+/	O
+day	O
+)	O
+","	O
+during	O
+which	O
+precordial	B-NP
+pain	I-NP
+with	O
+right	B-NP
+bundle	I-NP
+branch	I-NP
+block	I-NP
+occurred	O
+concomitantly	O
+with	O
+a	O
+high	O
+serum	O
+FBAL	O
+concentration	O
+of	O
+1955	O
+ng	O
+/	O
+ml	O
+.	O
+	
+Both	O
+the	O
+precordial	B-NP
+pain	I-NP
+and	O
+the	O
+electrocardiographic	O
+changes	O
+disappeared	O
+spontaneously	O
+after	O
+the	O
+discontinuation	O
+of	O
+5	O
+-	O
+FU	O
+.	O
+	
+As	O
+the	O
+precordial	B-NP
+pain	I-NP
+in	O
+this	O
+patient	O
+was	O
+considered	O
+to	O
+have	O
+been	O
+due	O
+to	O
+5	O
+-	O
+FU	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+","	O
+the	O
+administration	O
+of	O
+5	O
+-	O
+FU	O
+was	O
+abandoned	O
+.	O
+	
+Instead	O
+","	O
+oral	O
+administration	O
+of	O
+S	O
+-	O
+1	O
+(	O
+a	O
+derivative	O
+of	O
+5	O
+-	O
+FU	O
+)	O
+","	O
+at	O
+200	O
+mg	O
+/	O
+day	O
+twice	O
+a	O
+week	O
+","	O
+was	O
+instituted	O
+","	O
+because	O
+S	O
+-	O
+1	O
+has	O
+a	O
+strong	O
+inhibitory	O
+effect	O
+on	O
+dihydropyrimidine	O
+dehydrogenase	O
+","	O
+which	O
+catalyzes	O
+the	O
+degradative	O
+of	O
+5	O
+-	O
+FU	O
+into	O
+FBAL	O
+.	O
+	
+The	O
+serum	O
+FBAL	O
+concentration	O
+subsequently	O
+decreased	O
+to	O
+352	O
+ng	O
+/	O
+ml	O
+","	O
+the	O
+same	O
+as	O
+the	O
+value	O
+measured	O
+on	O
+the	O
+first	O
+day	O
+of	O
+S	O
+-	O
+1	O
+administration	O
+.	O
+	
+Thereafter	O
+","	O
+no	O
+cardiac	B-NP
+symptoms	I-NP
+were	O
+observed	O
+.	O
+	
+The	O
+patient	O
+achieved	O
+a	O
+partial	O
+response	O
+6	O
+months	O
+after	O
+the	O
+initiation	O
+of	O
+the	O
+S	O
+-	O
+1	O
+treatment	O
+.	O
+	
+The	O
+experience	O
+of	O
+this	O
+case	O
+","	O
+together	O
+with	O
+a	O
+review	O
+of	O
+the	O
+literature	O
+","	O
+suggests	O
+that	O
+FBAL	O
+is	O
+related	O
+to	O
+5	O
+-	O
+FU	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+.	O
+	
+S	O
+-	O
+1	O
+may	O
+be	O
+administered	O
+safely	O
+to	O
+patients	O
+with	O
+5	O
+-	O
+FU	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+.	O
+	
+Hepatocellular	B-NP
+carcinoma	I-NP
+in	O
+Fanconi	B-NP
+'	I-NP
+s	I-NP
+anemia	I-NP
+treated	O
+with	O
+androgen	O
+and	O
+corticosteroid	O
+.	O
+	
+The	O
+case	O
+of	O
+an	O
+11	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+is	O
+reported	O
+who	O
+was	O
+known	O
+to	O
+have	O
+Fanconi	B-NP
+'	I-NP
+s	I-NP
+anemia	I-NP
+for	O
+3	O
+years	O
+and	O
+was	O
+treated	O
+with	O
+androgens	O
+","	O
+corticosteroids	O
+and	O
+transfusions	O
+.	O
+	
+Two	O
+weeks	O
+before	O
+his	O
+death	O
+he	O
+was	O
+readmitted	O
+because	O
+of	O
+aplastic	O
+crisis	O
+with	O
+septicemia	B-NP
+and	O
+marked	O
+abnormalities	O
+in	O
+liver	O
+function	O
+and	O
+died	O
+of	O
+hemorrhagic	B-NP
+bronchopneumonia	I-NP
+.	O
+	
+At	O
+autopsy	O
+peliosis	B-NP
+and	O
+multiple	O
+hepatic	B-NP
+tumors	I-NP
+were	O
+found	O
+which	O
+histologically	O
+proved	O
+to	O
+be	O
+well	O
+-	O
+differentiated	O
+hepatocellular	B-NP
+carcinoma	I-NP
+.	O
+	
+This	O
+case	O
+contributes	O
+to	O
+the	O
+previous	O
+observations	O
+that	O
+non	O
+-	O
+metastasizing	O
+hepatic	B-NP
+neoplasms	I-NP
+and	O
+peliosis	B-NP
+can	O
+develop	O
+in	O
+patients	O
+with	O
+androgen	O
+-	O
+and	O
+corticosteroid	O
+-	O
+treated	O
+Fanconi	B-NP
+'	I-NP
+s	I-NP
+anemia	I-NP
+.	O
+	
+The	O
+influence	O
+of	O
+the	O
+time	O
+interval	O
+between	O
+monoHER	O
+and	O
+doxorubicin	O
+administration	O
+on	O
+the	O
+protection	O
+against	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+in	O
+mice	O
+.	O
+	
+PURPOSE	O
+:	O
+Despite	O
+its	O
+well	O
+-	O
+known	O
+cardiotoxicity	B-NP
+","	O
+the	O
+anthracyclin	O
+doxorubicin	O
+(	O
+DOX	O
+)	O
+continues	O
+to	O
+be	O
+an	O
+effective	O
+and	O
+widely	O
+used	O
+chemotherapeutic	O
+agent	O
+.	O
+	
+DOX	O
+-	O
+induced	O
+cardiac	B-NP
+damage	I-NP
+presumably	O
+results	O
+from	O
+the	O
+formation	O
+of	O
+free	O
+radicals	O
+by	O
+DOX	O
+.	O
+	
+Reactive	O
+oxygen	O
+species	O
+particularly	O
+affect	O
+the	O
+cardiac	O
+myocytes	O
+because	O
+these	O
+cells	O
+seem	O
+to	O
+have	O
+a	O
+relatively	O
+poor	O
+antioxidant	O
+defense	O
+system	O
+.	O
+	
+The	O
+semisynthetic	O
+flavonoid	O
+monohydroxyethylrutoside	O
+(	O
+monoHER	O
+)	O
+showed	O
+cardioprotection	O
+against	O
+DOX	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+through	O
+its	O
+radical	O
+scavenging	O
+and	O
+iron	O
+chelating	O
+properties	O
+.	O
+	
+Because	O
+of	O
+the	O
+relatively	O
+short	O
+final	O
+half	O
+-	O
+life	O
+of	O
+monoHER	O
+(	O
+about	O
+30	O
+min	O
+)	O
+","	O
+it	O
+is	O
+expected	O
+that	O
+the	O
+time	O
+interval	O
+between	O
+monoHER	O
+and	O
+DOX	O
+might	O
+be	O
+of	O
+influence	O
+on	O
+the	O
+cardioprotective	O
+effect	O
+of	O
+monoHER	O
+.	O
+	
+Therefore	O
+","	O
+the	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+investigate	O
+this	O
+possible	O
+effect	O
+.	O
+	
+METHODS	O
+:	O
+Six	O
+groups	O
+of	O
+6	O
+BALB	O
+/	O
+c	O
+mice	O
+were	O
+treated	O
+with	O
+saline	O
+","	O
+DOX	O
+alone	O
+or	O
+DOX	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+preceded	O
+by	O
+monoHER	O
+(	O
+500	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+with	O
+an	O
+interval	O
+of	O
+10	O
+","	O
+30	O
+","	O
+60	O
+or	O
+120	O
+min	O
+.	O
+	
+After	O
+a	O
+6	O
+-	O
+week	O
+treatment	O
+period	O
+and	O
+additional	O
+observation	O
+for	O
+2	O
+weeks	O
+","	O
+the	O
+mice	O
+were	O
+sacrificed	O
+.	O
+	
+Their	O
+cardiac	O
+tissues	O
+were	O
+processed	O
+for	O
+light	O
+microscopy	O
+","	O
+after	O
+which	O
+cardiomyocyte	B-NP
+damage	I-NP
+was	O
+evaluated	O
+according	O
+to	O
+Billingham	O
+(	O
+in	O
+Cancer	B-NP
+Treat	O
+Rep	O
+62	O
+(	O
+6	O
+)	O
+:	O
+865	O
+-	O
+872	O
+","	O
+1978	O
+)	O
+.	O
+	
+Microscopic	O
+evaluation	O
+revealed	O
+that	O
+treatment	O
+with	O
+DOX	O
+alone	O
+induced	O
+significant	O
+cardiac	B-NP
+damage	I-NP
+in	O
+comparison	O
+to	O
+the	O
+saline	O
+control	O
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+number	O
+of	O
+damaged	O
+cardiomyocytes	O
+was	O
+9	O
+.	O
+6	O
+-	O
+fold	O
+(	O
+95	O
+%	O
+CI	O
+4	O
+.	O
+4	O
+-	O
+21	O
+.	O
+0	O
+)	O
+higher	O
+in	O
+mice	O
+treated	O
+with	O
+DOX	O
+alone	O
+than	O
+that	O
+in	O
+animals	O
+of	O
+the	O
+control	O
+group	O
+.	O
+	
+The	O
+ratio	O
+of	O
+aberrant	O
+cardiomyocytes	O
+in	O
+mice	O
+treated	O
+with	O
+DOX	O
+preceded	O
+by	O
+monoHER	O
+and	O
+those	O
+in	O
+mice	O
+treated	O
+with	O
+saline	O
+ranged	O
+from	O
+1	O
+.	O
+6	O
+to	O
+2	O
+.	O
+8	O
+(	O
+mean	O
+2	O
+.	O
+2	O
+","	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+2	O
+-	O
+4	O
+.	O
+1	O
+","	O
+P	O
+=	O
+0	O
+.	O
+19	O
+)	O
+.	O
+	
+The	O
+mean	O
+protective	O
+effect	O
+by	O
+adding	O
+monoHER	O
+before	O
+DOX	O
+led	O
+to	O
+a	O
+significant	O
+4	O
+.	O
+4	O
+-	O
+fold	O
+reduction	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+","	O
+95	O
+%	O
+CI	O
+2	O
+.	O
+3	O
+-	O
+8	O
+.	O
+2	O
+)	O
+of	O
+abnormal	O
+cardiomyocytes	O
+.	O
+	
+This	O
+protective	O
+effect	O
+did	O
+not	O
+depend	O
+on	O
+the	O
+time	O
+interval	O
+between	O
+monoHER	O
+and	O
+DOX	O
+administration	O
+(	O
+P	O
+=	O
+0	O
+.	O
+345	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+The	O
+results	O
+indicate	O
+that	O
+in	O
+an	O
+outpatient	O
+clinical	O
+setting	O
+monoHER	O
+may	O
+be	O
+administered	O
+shortly	O
+before	O
+DOX	O
+.	O
+	
+Clinical	O
+evaluation	O
+of	O
+adverse	O
+effects	O
+during	O
+bepridil	O
+administration	O
+for	O
+atrial	B-NP
+fibrillation	I-NP
+and	I-NP
+flutter	I-NP
+.	O
+	
+BACKGROUND	O
+:	O
+Bepridil	O
+hydrochloride	O
+(	O
+Bpd	O
+)	O
+has	O
+attracted	O
+attention	O
+as	O
+an	O
+effective	O
+drug	O
+for	O
+atrial	B-NP
+fibrillation	I-NP
+(	O
+AF	B-NP
+)	O
+and	O
+atrial	B-NP
+flutter	I-NP
+(	O
+AFL	B-NP
+)	O
+.	O
+	
+However	O
+","	O
+serious	O
+adverse	O
+effects	O
+","	O
+including	O
+torsade	B-NP
+de	I-NP
+pointes	I-NP
+(	O
+Tdp	B-NP
+)	O
+","	O
+have	O
+been	O
+reported	O
+.	O
+	
+METHODS	O
+AND	O
+RESULTS	O
+:	O
+Adverse	O
+effects	O
+of	O
+Bpd	O
+requiring	O
+discontinuation	O
+of	O
+treatment	O
+were	O
+evaluated	O
+.	O
+	
+Bpd	O
+was	O
+administered	O
+to	O
+459	O
+patients	O
+(	O
+361	O
+males	O
+","	O
+63	O
++	O
+/	O
+-	O
+12	O
+years	O
+old	O
+)	O
+comprising	O
+378	O
+AF	B-NP
+and	O
+81	O
+AFL	B-NP
+cases	O
+.	O
+	
+Mean	O
+left	O
+ventricular	O
+ejection	O
+fraction	O
+and	O
+atrial	O
+dimension	O
+(	O
+LAD	O
+)	O
+were	O
+66	O
++	O
+/	O
+-	O
+11	O
+%	O
+and	O
+40	O
++	O
+/	O
+-	O
+6	O
+mm	O
+","	O
+respectively	O
+.	O
+	
+Adverse	O
+effects	O
+were	O
+observed	O
+in	O
+19	O
+patients	O
+(	O
+4	O
+%	O
+)	O
+during	O
+an	O
+average	O
+follow	O
+-	O
+up	O
+of	O
+20	O
+months	O
+.	O
+	
+There	O
+was	O
+marked	O
+QT	B-NP
+prolongation	I-NP
+greater	O
+than	O
+0	O
+.	O
+55	O
+s	O
+in	O
+13	O
+patients	O
+","	O
+bradycardia	B-NP
+less	O
+than	O
+40	O
+beats	O
+/	O
+min	O
+in	O
+6	O
+patients	O
+","	O
+dizziness	B-NP
+and	O
+general	O
+fatigue	B-NP
+in	O
+1	O
+patient	O
+each	O
+.	O
+	
+In	O
+4	O
+of	O
+13	O
+patients	O
+with	O
+QT	B-NP
+prolongation	I-NP
+","	O
+Tdp	B-NP
+occurred	O
+.	O
+	
+The	O
+major	O
+triggering	O
+factors	O
+of	O
+Tdp	B-NP
+were	O
+hypokalemia	B-NP
+and	O
+sudden	O
+decrease	O
+in	O
+heart	O
+rate	O
+.	O
+	
+There	O
+were	O
+no	O
+differences	O
+in	O
+the	O
+clinical	O
+backgrounds	O
+of	O
+the	O
+patients	O
+with	O
+and	O
+without	O
+Tdp	B-NP
+other	O
+than	O
+LAD	O
+and	O
+age	O
+","	O
+which	O
+were	O
+larger	O
+and	O
+older	O
+in	O
+the	O
+patients	O
+with	O
+Tdp	B-NP
+.	O
+	
+CONCLUSION	O
+:	O
+Careful	O
+observation	O
+of	O
+serum	O
+potassium	O
+concentration	O
+and	O
+the	O
+ECG	O
+should	O
+always	O
+be	O
+done	O
+during	O
+Bpd	O
+administration	O
+","	O
+particularly	O
+in	O
+elderly	O
+patients	O
+.	O
+	
+Enhanced	O
+isoproterenol	O
+-	O
+induced	O
+cardiac	B-NP
+hypertrophy	I-NP
+in	O
+transgenic	O
+rats	O
+with	O
+low	O
+brain	O
+angiotensinogen	O
+.	O
+	
+We	O
+have	O
+previously	O
+shown	O
+that	O
+a	O
+permanent	O
+deficiency	O
+in	O
+the	O
+brain	O
+renin	O
+-	O
+angiotensin	O
+system	O
+(	O
+RAS	O
+)	O
+may	O
+increase	O
+the	O
+sensitivity	O
+of	O
+the	O
+baroreflex	O
+control	O
+of	O
+heart	O
+rate	O
+.	O
+	
+In	O
+this	O
+study	O
+we	O
+aimed	O
+at	O
+studying	O
+the	O
+involvement	O
+of	O
+the	O
+brain	O
+RAS	O
+in	O
+the	O
+cardiac	O
+reactivity	O
+to	O
+the	O
+beta	O
+-	O
+adrenoceptor	O
+(	O
+beta	O
+-	O
+AR	O
+)	O
+agonist	O
+isoproterenol	O
+(	O
+Iso	O
+)	O
+.	O
+	
+Transgenic	O
+rats	O
+with	O
+low	O
+brain	O
+angiotensinogen	O
+(	O
+TGR	O
+)	O
+were	O
+used	O
+.	O
+	
+In	O
+isolated	O
+hearts	O
+","	O
+Iso	O
+induced	O
+a	O
+significantly	O
+greater	O
+increase	O
+in	O
+left	O
+ventricular	O
+(	O
+LV	O
+)	O
+pressure	O
+and	O
+maximal	O
+contraction	O
+(	O
++	O
+dP	O
+/	O
+dt	O
+(	O
+max	O
+)	O
+)	O
+in	O
+the	O
+TGR	O
+than	O
+in	O
+the	O
+Sprague	O
+-	O
+Dawley	O
+(	O
+SD	O
+)	O
+rats	O
+.	O
+	
+LV	B-NP
+hypertrophy	I-NP
+induced	O
+by	O
+Iso	O
+treatment	O
+was	O
+significantly	O
+higher	O
+in	O
+TGR	O
+than	O
+in	O
+SD	O
+rats	O
+(	O
+in	O
+g	O
+LV	O
+wt	O
+/	O
+100	O
+g	O
+body	O
+wt	O
+","	O
+0	O
+.	O
+28	O
++	O
+/	O
+-	O
+0	O
+.	O
+4	O
+vs	O
+.	O
+0	O
+.	O
+24	O
++	O
+/	O
+-	O
+0	O
+.	O
+4	O
+","	O
+respectively	O
+)	O
+.	O
+	
+The	O
+greater	O
+LV	B-NP
+hypertrophy	I-NP
+in	O
+TGR	O
+rats	O
+was	O
+associated	O
+with	O
+more	O
+pronounced	O
+downregulation	O
+of	O
+beta	O
+-	O
+AR	O
+and	O
+upregulation	O
+of	O
+LV	O
+beta	O
+-	O
+AR	O
+kinase	O
+-	O
+1	O
+mRNA	O
+levels	O
+compared	O
+with	O
+those	O
+in	O
+SD	O
+rats	O
+.	O
+	
+The	O
+decrease	O
+in	O
+the	O
+heart	O
+rate	O
+(	O
+HR	O
+)	O
+induced	O
+by	O
+the	O
+beta	O
+-	O
+AR	O
+antagonist	O
+metoprolol	O
+in	O
+conscious	O
+rats	O
+was	O
+significantly	O
+attenuated	O
+in	O
+TGR	O
+compared	O
+with	O
+SD	O
+rats	O
+(	O
+-	O
+9	O
+.	O
+9	O
++	O
+/	O
+-	O
+1	O
+.	O
+7	O
+%	O
+vs	O
+.	O
+-	O
+18	O
+.	O
+1	O
++	O
+/	O
+-	O
+1	O
+.	O
+5	O
+%	O
+)	O
+","	O
+whereas	O
+the	O
+effect	O
+of	O
+parasympathetic	O
+blockade	O
+by	O
+atropine	O
+on	O
+HR	O
+was	O
+similar	O
+in	O
+both	O
+strains	O
+.	O
+	
+These	O
+results	O
+indicate	O
+that	O
+TGR	O
+are	O
+more	O
+sensitive	O
+to	O
+beta	O
+-	O
+AR	O
+agonist	O
+-	O
+induced	O
+cardiac	B-NP
+inotropic	I-NP
+response	O
+and	O
+hypertrophy	B-NP
+","	O
+possibly	O
+due	O
+to	O
+chronically	O
+low	O
+sympathetic	O
+outflow	O
+directed	O
+to	O
+the	O
+heart	O
+.	O
+	
+Drug	O
+-	O
+induced	O
+long	B-NP
+QT	I-NP
+syndrome	I-NP
+in	O
+injection	O
+drug	O
+users	O
+receiving	O
+methadone	O
+:	O
+high	O
+frequency	O
+in	O
+hospitalized	O
+patients	O
+and	O
+risk	O
+factors	O
+.	O
+	
+BACKGROUND	O
+:	O
+Drug	O
+-	O
+induced	O
+long	B-NP
+QT	I-NP
+syndrome	I-NP
+is	O
+a	O
+serious	O
+adverse	O
+drug	O
+reaction	O
+.	O
+	
+Methadone	O
+prolongs	O
+the	O
+QT	O
+interval	O
+in	O
+vitro	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+.	O
+	
+In	O
+the	O
+inpatient	O
+setting	O
+","	O
+the	O
+frequency	O
+of	O
+QT	B-NP
+interval	I-NP
+prolongation	I-NP
+with	O
+methadone	O
+treatment	O
+","	O
+its	O
+dose	O
+dependence	O
+","	O
+and	O
+the	O
+importance	O
+of	O
+cofactors	O
+such	O
+as	O
+drug	O
+-	O
+drug	O
+interactions	O
+remain	O
+unknown	O
+.	O
+	
+METHODS	O
+:	O
+We	O
+performed	O
+a	O
+systematic	O
+","	O
+retrospective	O
+study	O
+comparing	O
+active	O
+or	O
+former	O
+intravenous	O
+drug	O
+users	O
+receiving	O
+methadone	O
+and	O
+those	O
+not	O
+receiving	O
+methadone	O
+among	O
+all	O
+patients	O
+hospitalized	O
+over	O
+a	O
+5	O
+-	O
+year	O
+period	O
+in	O
+a	O
+tertiary	O
+care	O
+hospital	O
+.	O
+	
+A	O
+total	O
+of	O
+167	O
+patients	O
+receiving	O
+methadone	O
+fulfilled	O
+the	O
+inclusion	O
+criteria	O
+and	O
+were	O
+compared	O
+with	O
+a	O
+control	O
+group	O
+of	O
+80	O
+injection	O
+drug	O
+users	O
+not	O
+receiving	O
+methadone	O
+.	O
+	
+In	O
+addition	O
+to	O
+methadone	O
+dose	O
+","	O
+15	O
+demographic	O
+","	O
+biological	O
+","	O
+and	O
+pharmacological	O
+variables	O
+were	O
+considered	O
+as	O
+potential	O
+risk	O
+factors	O
+for	O
+QT	B-NP
+prolongation	I-NP
+.	O
+	
+RESULTS	O
+:	O
+Among	O
+167	O
+methadone	O
+maintenance	O
+patients	O
+","	O
+the	O
+prevalence	O
+of	O
+QTc	O
+prolongation	O
+to	O
+0	O
+.	O
+50	O
+second	O
+(	O
+(	O
+1	O
+/	O
+2	O
+)	O
+)	O
+or	O
+longer	O
+was	O
+16	O
+.	O
+2	O
+%	O
+compared	O
+with	O
+0	O
+%	O
+in	O
+80	O
+control	O
+subjects	O
+.	O
+	
+Six	O
+patients	O
+(	O
+3	O
+.	O
+6	O
+%	O
+)	O
+in	O
+the	O
+methadone	O
+group	O
+presented	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+.	O
+	
+QTc	O
+length	O
+was	O
+weakly	O
+but	O
+significantly	O
+associated	O
+with	O
+methadone	O
+daily	O
+dose	O
+(	O
+Spearman	O
+rank	O
+correlation	O
+coefficient	O
+","	O
+0	O
+.	O
+20	O
+;	O
+P	O
+<	O
+.	O
+1	O
+)	O
+.	O
+	
+Multivariate	O
+regression	O
+analysis	O
+allowed	O
+attribution	O
+of	O
+31	O
+.	O
+8	O
+%	O
+of	O
+QTc	O
+variability	O
+to	O
+methadone	O
+dose	O
+","	O
+cytochrome	O
+P	O
+-	O
+450	O
+3A4	O
+drug	O
+-	O
+drug	O
+interactions	O
+","	O
+hypokalemia	B-NP
+","	O
+and	O
+altered	O
+liver	O
+function	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+QT	B-NP
+interval	I-NP
+prolongation	I-NP
+in	O
+methadone	O
+maintenance	O
+patients	O
+hospitalized	O
+in	O
+a	O
+tertiary	O
+care	O
+center	O
+is	O
+a	O
+frequent	O
+finding	O
+.	O
+	
+Methadone	O
+dose	O
+","	O
+presence	O
+of	O
+cytochrome	O
+P	O
+-	O
+450	O
+3A4	O
+inhibitors	O
+","	O
+potassium	O
+level	O
+","	O
+and	O
+liver	O
+function	O
+contribute	O
+to	O
+QT	B-NP
+prolongation	I-NP
+.	O
+	
+Long	B-NP
+QT	I-NP
+syndrome	I-NP
+can	O
+occur	O
+with	O
+low	O
+doses	O
+of	O
+methadone	O
+.	O
+	
+Mechanisms	O
+of	O
+hypertension	B-NP
+induced	O
+by	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+deficiency	O
+:	O
+focus	O
+on	O
+venous	O
+function	O
+.	O
+	
+Loss	O
+of	O
+endothelial	O
+cell	O
+-	O
+derived	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+in	O
+hypertension	B-NP
+is	O
+a	O
+hallmark	O
+of	O
+arterial	B-NP
+dysfunction	I-NP
+.	O
+	
+Experimental	O
+hypertension	B-NP
+created	O
+by	O
+the	O
+removal	O
+of	O
+NO	O
+","	O
+however	O
+","	O
+involves	O
+mechanisms	O
+in	O
+addition	O
+to	O
+decreased	O
+arterial	O
+vasodilator	O
+activity	O
+.	O
+	
+These	O
+include	O
+augmented	O
+endothelin	O
+-	O
+1	O
+(	O
+ET	O
+-	O
+1	O
+)	O
+release	O
+","	O
+increased	O
+sympathetic	O
+nervous	O
+system	O
+activity	O
+","	O
+and	O
+elevated	O
+tissue	O
+oxidative	O
+stress	O
+.	O
+	
+We	O
+hypothesized	O
+that	O
+increased	O
+venous	O
+smooth	O
+muscle	O
+(	O
+venomotor	O
+)	O
+tone	O
+plays	O
+a	O
+role	O
+in	O
+Nomega	O
+-	O
+nitro	O
+-	O
+L	O
+-	O
+arginine	O
+(	O
+LNNA	O
+)	O
+hypertension	B-NP
+through	O
+these	O
+mechanisms	O
+.	O
+	
+Rats	O
+were	O
+treated	O
+with	O
+the	O
+NO	O
+synthase	O
+inhibitor	O
+LNNA	O
+(	O
+0	O
+.	O
+5	O
+g	O
+/	O
+L	O
+in	O
+drinking	O
+water	O
+)	O
+for	O
+2	O
+weeks	O
+.	O
+	
+Mean	O
+arterial	O
+pressure	O
+of	O
+conscious	O
+rats	O
+was	O
+119	O
++	O
+/	O
+-	O
+2	O
+mm	O
+Hg	O
+in	O
+control	O
+and	O
+194	O
++	O
+/	O
+-	O
+5	O
+mm	O
+Hg	O
+in	O
+LNNA	O
+rats	O
+(	O
+P	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+Carotid	O
+arteries	O
+and	O
+vena	O
+cava	O
+were	O
+removed	O
+for	O
+measurement	O
+of	O
+isometric	O
+contraction	O
+.	O
+	
+Maximal	O
+contraction	O
+to	O
+norepinephrine	O
+was	O
+modestly	O
+reduced	O
+in	O
+arteries	O
+from	O
+LNNA	O
+compared	O
+with	O
+control	O
+rats	O
+whereas	O
+the	O
+maximum	O
+contraction	O
+to	O
+ET	O
+-	O
+1	O
+was	O
+significantly	O
+reduced	O
+(	O
+54	O
+%	O
+control	O
+)	O
+.	O
+	
+Maximum	O
+contraction	O
+of	O
+vena	O
+cava	O
+to	O
+norepinephrine	O
+(	O
+37	O
+%	O
+control	O
+)	O
+also	O
+was	O
+reduced	O
+but	O
+no	O
+change	O
+in	O
+response	O
+to	O
+ET	O
+-	O
+1	O
+was	O
+observed	O
+.	O
+	
+Mean	O
+circulatory	O
+filling	O
+pressure	O
+","	O
+an	O
+in	O
+vivo	O
+measure	O
+of	O
+venomotor	O
+tone	O
+","	O
+was	O
+not	O
+elevated	O
+in	O
+LNNA	O
+hypertension	B-NP
+at	O
+1	O
+or	O
+2	O
+weeks	O
+after	O
+LNNA	O
+.	O
+	
+The	O
+superoxide	O
+scavenger	O
+tempol	O
+(	O
+30	O
+","	O
+100	O
+","	O
+and	O
+300	O
+micromol	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+","	O
+IV	O
+)	O
+did	O
+not	O
+change	O
+arterial	O
+pressure	O
+in	O
+control	O
+rats	O
+but	O
+caused	O
+a	O
+dose	O
+-	O
+dependent	O
+decrease	O
+in	O
+LNNA	O
+rats	O
+(	O
+-	O
+18	O
++	O
+/	O
+-	O
+8	O
+","	O
+-	O
+26	O
++	O
+/	O
+-	O
+15	O
+","	O
+and	O
+-	O
+54	O
++	O
+/	O
+-	O
+11	O
+mm	O
+Hg	O
+)	O
+.	O
+	
+Similarly	O
+","	O
+ganglionic	O
+blockade	O
+with	O
+hexamethonium	O
+caused	O
+a	O
+significantly	O
+greater	O
+fall	O
+in	O
+LNNA	O
+hypertensive	B-NP
+rats	O
+(	O
+76	O
++	O
+/	O
+-	O
+9	O
+mm	O
+Hg	O
+)	O
+compared	O
+with	O
+control	O
+rats	O
+(	O
+35	O
++	O
+/	O
+-	O
+10	O
+mm	O
+Hg	O
+)	O
+.	O
+	
+Carotid	O
+arteries	O
+","	O
+vena	O
+cava	O
+","	O
+and	O
+sympathetic	O
+ganglia	O
+from	O
+LNNA	O
+rats	O
+had	O
+higher	O
+basal	O
+levels	O
+of	O
+superoxide	O
+compared	O
+with	O
+those	O
+from	O
+control	O
+rats	O
+.	O
+	
+These	O
+data	O
+suggest	O
+that	O
+while	O
+NO	O
+deficiency	O
+increases	O
+oxidative	O
+stress	O
+and	O
+sympathetic	O
+activity	O
+in	O
+both	O
+arterial	O
+and	O
+venous	O
+vessels	O
+","	O
+the	O
+impact	O
+on	O
+veins	O
+does	O
+not	O
+make	O
+a	O
+major	O
+contribution	O
+to	O
+this	O
+form	O
+of	O
+hypertension	B-NP
+.	O
+	
+Association	O
+of	O
+DRD2	O
+polymorphisms	O
+and	O
+chlorpromazine	O
+-	O
+induced	O
+extrapyramidal	B-NP
+syndrome	I-NP
+in	O
+Chinese	O
+schizophrenic	B-NP
+patients	O
+.	O
+	
+AIM	O
+:	O
+Extrapyramidal	B-NP
+syndrome	I-NP
+(	O
+EPS	B-NP
+)	O
+is	O
+most	O
+commonly	O
+affected	O
+by	O
+typical	O
+antipsychotic	O
+drugs	O
+that	O
+have	O
+a	O
+high	O
+affinity	O
+with	O
+the	O
+D2	O
+receptor	O
+.	O
+	
+Recently	O
+","	O
+many	O
+research	O
+groups	O
+have	O
+reported	O
+on	O
+the	O
+positive	O
+relationship	O
+between	O
+the	O
+genetic	O
+variations	O
+in	O
+the	O
+DRD2	O
+gene	O
+and	O
+the	O
+therapeutic	O
+response	O
+in	O
+schizophrenia	B-NP
+patients	O
+as	O
+a	O
+result	O
+of	O
+the	O
+role	O
+of	O
+variations	O
+in	O
+the	O
+receptor	O
+in	O
+modulating	O
+receptor	O
+expression	O
+.	O
+	
+In	O
+this	O
+study	O
+","	O
+we	O
+evaluate	O
+the	O
+role	O
+DRD2	O
+plays	O
+in	O
+chlorpromazine	O
+-	O
+induced	O
+EPS	B-NP
+in	O
+schizophrenic	B-NP
+patients	O
+.	O
+	
+METHODS	O
+:	O
+We	O
+identified	O
+seven	O
+SNP	O
+(	O
+single	O
+nucleotide	O
+polymorphism	O
+)	O
+(	O
+-	O
+141Cins	O
+>	O
+del	O
+","	O
+TaqIB	O
+","	O
+TaqID	O
+","	O
+Ser311Cys	O
+","	O
+rs6275	O
+","	O
+rs6277	O
+and	O
+TaqIA	O
+)	O
+in	O
+the	O
+DRD2	O
+gene	O
+in	O
+146	O
+schizophrenic	B-NP
+inpatients	O
+(	O
+59	O
+with	O
+EPS	B-NP
+and	O
+87	O
+without	O
+EPS	B-NP
+according	O
+to	O
+the	O
+Simpson	O
+-	O
+Angus	O
+Scale	O
+)	O
+treated	O
+with	O
+chlorpromazine	O
+after	O
+8	O
+weeks	O
+.	O
+	
+The	O
+alleles	O
+of	O
+all	O
+loci	O
+were	O
+determined	O
+by	O
+PCR	O
+(	O
+polymerase	O
+chain	O
+reaction	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+Polymorphisms	O
+TaqID	O
+","	O
+Ser311Cys	O
+and	O
+rs6277	O
+were	O
+not	O
+polymorphic	O
+in	O
+the	O
+population	O
+recruited	O
+in	O
+the	O
+present	O
+study	O
+.	O
+	
+No	O
+statistical	O
+significance	O
+was	O
+found	O
+in	O
+the	O
+allele	O
+distribution	O
+of	O
+-	O
+141Cins	O
+>	O
+del	O
+","	O
+TaqIB	O
+","	O
+rs6275	O
+and	O
+TaqIA	O
+or	O
+in	O
+the	O
+estimated	O
+haplotypes	O
+(	O
+constituted	O
+by	O
+TaqIB	O
+","	O
+rs6275	O
+and	O
+TaqIA	O
+)	O
+in	O
+linkage	O
+disequilibrium	O
+between	O
+the	O
+two	O
+groups	O
+.	O
+	
+CONCLUSION	O
+:	O
+Our	O
+results	O
+did	O
+not	O
+lend	O
+strong	O
+support	O
+to	O
+the	O
+view	O
+that	O
+the	O
+genetic	O
+variation	O
+of	O
+the	O
+DRD2	O
+gene	O
+plays	O
+a	O
+major	O
+role	O
+in	O
+the	O
+individually	O
+variable	O
+adverse	O
+effect	O
+induced	O
+by	O
+chlorpromazine	O
+","	O
+at	O
+least	O
+in	O
+Chinese	O
+patients	O
+with	O
+schizophrenia	B-NP
+.	O
+	
+Our	O
+results	O
+confirmed	O
+a	O
+previous	O
+study	O
+on	O
+the	O
+relationship	O
+between	O
+DRD2	O
+and	O
+EPS	B-NP
+in	O
+Caucasians	O
+.	O
+	
+Physical	O
+training	O
+decreases	O
+susceptibility	O
+to	O
+subsequent	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B-NP
+in	O
+the	O
+rat	O
+.	O
+	
+Regular	O
+motor	O
+activity	O
+has	O
+many	O
+benefits	O
+for	O
+mental	O
+and	O
+physical	O
+condition	O
+but	O
+its	O
+implications	O
+for	O
+epilepsy	B-NP
+are	O
+still	O
+controversial	O
+.	O
+	
+In	O
+order	O
+to	O
+elucidate	O
+this	O
+problem	O
+","	O
+we	O
+have	O
+studied	O
+the	O
+effect	O
+of	O
+long	O
+-	O
+term	O
+physical	O
+activity	O
+on	O
+susceptibility	O
+to	O
+subsequent	O
+seizures	B-NP
+.	O
+	
+Male	O
+Wistar	O
+rats	O
+were	O
+subjected	O
+to	O
+repeated	O
+training	O
+sessions	O
+in	O
+a	O
+treadmill	O
+and	O
+swimming	O
+pool	O
+.	O
+	
+Thereafter	O
+","	O
+seizures	B-NP
+were	O
+induced	O
+by	O
+pilocarpine	O
+injections	O
+in	O
+trained	O
+and	O
+non	O
+-	O
+trained	O
+control	O
+groups	O
+.	O
+	
+During	O
+the	O
+acute	O
+period	O
+of	O
+status	B-NP
+epilepticus	I-NP
+","	O
+we	O
+measured	O
+:	O
+(	O
+1	O
+)	O
+the	O
+latency	O
+of	O
+the	O
+first	O
+motor	O
+sign	O
+","	O
+(	O
+2	O
+)	O
+the	O
+intensity	O
+of	O
+seizures	B-NP
+","	O
+(	O
+3	O
+)	O
+the	O
+time	O
+when	O
+it	O
+occurred	O
+within	O
+the	O
+6	O
+-	O
+h	O
+observation	O
+period	O
+","	O
+and	O
+(	O
+4	O
+)	O
+the	O
+time	O
+when	O
+the	O
+acute	O
+period	O
+ended	O
+.	O
+	
+All	O
+these	O
+behavioral	O
+parameters	O
+showed	O
+statistically	O
+significant	O
+changes	O
+suggesting	O
+that	O
+regular	O
+physical	O
+exercises	O
+decrease	O
+susceptibility	O
+to	O
+subsequently	O
+induced	O
+seizures	B-NP
+and	O
+ameliorate	O
+the	O
+course	O
+of	O
+experimentally	O
+induced	O
+status	B-NP
+epilepticus	I-NP
+.	O
+	
+Tonic	O
+dopaminergic	O
+stimulation	O
+impairs	B-NP
+associative	I-NP
+learning	I-NP
+in	O
+healthy	O
+subjects	O
+.	O
+	
+Endogenous	O
+dopamine	O
+plays	O
+a	O
+central	O
+role	O
+in	O
+salience	O
+coding	O
+during	O
+associative	O
+learning	O
+.	O
+	
+Administration	O
+of	O
+the	O
+dopamine	O
+precursor	O
+levodopa	O
+enhances	O
+learning	O
+in	O
+healthy	O
+subjects	O
+and	O
+stroke	B-NP
+patients	O
+.	O
+	
+Because	O
+levodopa	O
+increases	O
+both	O
+phasic	O
+and	O
+tonic	O
+dopaminergic	O
+neurotransmission	O
+","	O
+the	O
+critical	O
+mechanism	O
+mediating	O
+the	O
+enhancement	O
+of	O
+learning	O
+is	O
+unresolved	O
+.	O
+	
+We	O
+here	O
+probed	O
+how	O
+selective	O
+tonic	O
+dopaminergic	O
+stimulation	O
+affects	O
+associative	O
+learning	O
+.	O
+	
+Forty	O
+healthy	O
+subjects	O
+were	O
+trained	O
+in	O
+a	O
+novel	O
+vocabulary	O
+of	O
+45	O
+concrete	O
+nouns	O
+over	O
+the	O
+course	O
+of	O
+5	O
+consecutive	O
+training	O
+days	O
+in	O
+a	O
+prospective	O
+","	O
+randomized	O
+","	O
+double	O
+-	O
+blind	O
+","	O
+placebo	O
+-	O
+controlled	O
+design	O
+.	O
+	
+Subjects	O
+received	O
+the	O
+tonically	O
+stimulating	O
+dopamine	O
+-	O
+receptor	O
+agonist	O
+pergolide	O
+(	O
+0	O
+.	O
+1	O
+mg	O
+)	O
+vs	O
+placebo	O
+120	O
+min	O
+before	O
+training	O
+on	O
+each	O
+training	O
+day	O
+.	O
+	
+The	O
+dopamine	O
+agonist	O
+significantly	O
+impaired	B-NP
+novel	I-NP
+word	I-NP
+learning	I-NP
+compared	O
+to	O
+placebo	O
+.	O
+	
+This	O
+learning	O
+decrement	O
+persisted	O
+up	O
+to	O
+the	O
+last	O
+follow	O
+-	O
+up	O
+4	O
+weeks	O
+post	O
+-	O
+training	O
+.	O
+	
+Subjects	O
+treated	O
+with	O
+pergolide	O
+also	O
+showed	O
+restricted	O
+emotional	O
+responses	O
+compared	O
+to	O
+the	O
+PLACEBO	O
+group	O
+.	O
+	
+The	O
+extent	O
+of	O
+'	O
+flattened	O
+'	O
+affect	O
+with	O
+pergolide	O
+was	O
+related	O
+to	O
+the	O
+degree	O
+of	O
+learning	O
+inhibition	O
+.	O
+	
+These	O
+findings	O
+suggest	O
+that	O
+tonic	O
+occupation	O
+of	O
+dopamine	O
+receptors	O
+impairs	O
+learning	O
+by	O
+competition	O
+with	O
+phasic	O
+dopamine	O
+signals	O
+.	O
+	
+Thus	O
+","	O
+phasic	O
+signaling	O
+seems	O
+to	O
+be	O
+the	O
+critical	O
+mechanism	O
+by	O
+which	O
+dopamine	O
+enhances	O
+associative	O
+learning	O
+in	O
+healthy	O
+subjects	O
+and	O
+stroke	B-NP
+patients	O
+.	O
+	
+Minocycline	O
+-	O
+induced	O
+vasculitis	B-NP
+fulfilling	O
+the	O
+criteria	O
+of	O
+polyarteritis	B-NP
+nodosa	I-NP
+.	O
+	
+A	O
+47	O
+-	O
+year	O
+-	O
+old	O
+man	O
+who	O
+had	O
+been	O
+taking	O
+minocycline	O
+for	O
+palmoplantar	B-NP
+pustulosis	I-NP
+developed	O
+fever	B-NP
+","	O
+myalgias	B-NP
+","	O
+polyneuropathy	B-NP
+","	O
+and	O
+testicular	B-NP
+pain	I-NP
+","	O
+with	O
+elevated	O
+C	O
+-	O
+reactive	O
+protein	O
+(	O
+CRP	O
+)	O
+.	O
+	
+Neither	O
+myeloperoxidase	O
+-	O
+nor	O
+proteinase	O
+-	O
+3	O
+-	O
+antineutrophil	O
+cytoplasmic	O
+antibody	O
+was	O
+positive	O
+.	O
+	
+These	O
+manifestations	O
+met	O
+the	O
+American	O
+College	O
+of	O
+Rheumatology	O
+1990	O
+criteria	O
+for	O
+the	O
+classification	O
+of	O
+polyarteritis	B-NP
+nodosa	I-NP
+.	O
+	
+Stopping	O
+minocycline	O
+led	O
+to	O
+amelioration	O
+of	O
+symptoms	O
+and	O
+normalization	O
+of	O
+CRP	O
+level	O
+.	O
+	
+To	O
+our	O
+knowledge	O
+","	O
+this	O
+is	O
+the	O
+second	O
+case	O
+of	O
+minocycline	O
+-	O
+induced	O
+vasculitis	B-NP
+satisfying	O
+the	O
+criteria	O
+.	O
+	
+Differential	O
+diagnosis	O
+for	O
+drug	O
+-	O
+induced	O
+disease	O
+is	O
+invaluable	O
+even	O
+for	O
+patients	O
+with	O
+classical	O
+polyarteritis	B-NP
+nodosa	I-NP
+.	O
+	
+Intramuscular	O
+hepatitis	B-NP
+B	I-NP
+immune	O
+globulin	O
+combined	O
+with	O
+lamivudine	O
+in	O
+prevention	O
+of	O
+hepatitis	B-NP
+B	I-NP
+recurrence	O
+after	O
+liver	O
+transplantation	O
+.	O
+	
+BACKGROUND	O
+:	O
+Combined	O
+hepatitis	B-NP
+B	I-NP
+immune	O
+globulin	O
+(	O
+HBIg	O
+)	O
+and	O
+lamivudine	O
+in	O
+prophylaxis	O
+of	O
+the	O
+recurrence	O
+of	O
+hepatitis	B-NP
+B	I-NP
+after	O
+liver	O
+transplantation	O
+has	O
+significantly	O
+improved	O
+the	O
+survival	O
+of	O
+HBsAg	O
+positive	O
+patients	O
+.	O
+	
+This	O
+study	O
+was	O
+undertaken	O
+to	O
+evaluate	O
+the	O
+outcomes	O
+of	O
+liver	O
+transplantation	O
+for	O
+patients	O
+with	O
+hepatitis	B-NP
+B	I-NP
+virus	O
+(	O
+HBV	O
+)	O
+.	O
+	
+METHODS	O
+:	O
+A	O
+retrospective	O
+chart	O
+analysis	O
+and	O
+a	O
+review	O
+of	O
+the	O
+organ	O
+transplant	O
+database	O
+identified	O
+51	O
+patients	O
+(	O
+43	O
+men	O
+and	O
+8	O
+women	O
+)	O
+transplanted	O
+for	O
+benign	O
+HBV	O
+-	O
+related	O
+cirrhotic	B-NP
+diseases	I-NP
+between	O
+June	O
+2002	O
+and	O
+December	O
+2004	O
+who	O
+had	O
+survived	O
+more	O
+than	O
+3	O
+months	O
+.	O
+	
+HBIg	O
+was	O
+administered	O
+intravenously	O
+during	O
+the	O
+first	O
+week	O
+and	O
+intramuscularly	O
+thereafter	O
+.	O
+	
+RESULTS	O
+:	O
+At	O
+a	O
+median	O
+follow	O
+-	O
+up	O
+of	O
+14	O
+.	O
+1	O
+months	O
+","	O
+the	O
+overall	O
+recurrence	O
+rate	O
+in	O
+the	O
+51	O
+patients	O
+was	O
+3	O
+.	O
+9	O
+%	O
+(	O
+2	O
+/	O
+51	O
+)	O
+.	O
+	
+The	O
+overall	O
+patient	O
+survival	O
+was	O
+88	O
+.	O
+3	O
+%	O
+","	O
+and	O
+82	O
+.	O
+4	O
+%	O
+after	O
+1	O
+and	O
+2	O
+years	O
+","	O
+respectively	O
+.	O
+	
+A	O
+daily	O
+oral	O
+dose	O
+of	O
+100	O
+mg	O
+lamivudine	O
+for	O
+2	O
+weeks	O
+before	O
+transplantation	O
+for	O
+10	O
+patients	O
+enabled	O
+57	O
+.	O
+1	O
+%	O
+(	O
+4	O
+/	O
+7	O
+)	O
+and	O
+62	O
+.	O
+5	O
+%	O
+(	O
+5	O
+/	O
+8	O
+)	O
+of	O
+HBV	O
+-	O
+DNA	O
+and	O
+HBeAg	O
+positive	O
+patients	O
+respectively	O
+to	O
+convert	O
+to	O
+be	O
+negative	O
+.	O
+	
+Intramuscular	O
+HBIg	O
+was	O
+well	O
+tolerated	O
+in	O
+all	O
+patients	O
+.	O
+	
+CONCLUSION	O
+:	O
+Lamivudine	O
+combined	O
+with	O
+intramuscular	O
+HBIg	O
+can	O
+effectively	O
+prevent	O
+allograft	O
+from	O
+the	O
+recurrence	O
+of	O
+HBV	O
+after	O
+liver	O
+transplantation	O
+.	O
+	
+Anticonvulsant	O
+effect	O
+of	O
+eslicarbazepine	O
+acetate	O
+(	O
+BIA	O
+2	O
+-	O
+93	O
+)	O
+on	O
+seizures	B-NP
+induced	O
+by	O
+microperfusion	O
+of	O
+picrotoxin	O
+in	O
+the	O
+hippocampus	O
+of	O
+freely	O
+moving	O
+rats	O
+.	O
+	
+Eslicarbazepine	O
+acetate	O
+(	O
+BIA	O
+2	O
+-	O
+93	O
+","	O
+S	O
+-	O
+(	O
+-	O
+)	O
+-	O
+10	O
+-	O
+acetoxy	O
+-	O
+10	O
+","	O
+11	O
+-	O
+dihydro	O
+-	O
+5H	O
+-	O
+dibenzo	O
+/	O
+b	O
+","	O
+f	O
+/	O
+azepine	O
+-	O
+5	O
+-	O
+carboxamide	O
+)	O
+is	O
+a	O
+novel	O
+antiepileptic	O
+drug	O
+","	O
+now	O
+in	O
+Phase	O
+III	O
+clinical	O
+trials	O
+","	O
+designed	O
+with	O
+the	O
+aim	O
+of	O
+improving	O
+efficacy	O
+and	O
+safety	O
+in	O
+comparison	O
+with	O
+the	O
+structurally	O
+related	O
+drugs	O
+carbamazepine	O
+(	O
+CBZ	O
+)	O
+and	O
+oxcarbazepine	O
+(	O
+OXC	O
+)	O
+.	O
+	
+We	O
+have	O
+studied	O
+the	O
+effects	O
+of	O
+oral	O
+treatment	O
+with	O
+eslicarbazepine	O
+acetate	O
+on	O
+a	O
+whole	O
+-	O
+animal	O
+model	O
+in	O
+which	O
+partial	O
+seizures	B-NP
+can	O
+be	O
+elicited	O
+repeatedly	O
+on	O
+different	O
+days	O
+without	O
+changes	O
+in	O
+threshold	O
+or	O
+seizure	B-NP
+patterns	O
+.	O
+	
+In	O
+the	O
+animals	O
+treated	O
+with	O
+threshold	O
+doses	O
+of	O
+picrotoxin	O
+","	O
+the	O
+average	O
+number	O
+of	O
+seizures	B-NP
+was	O
+2	O
+.	O
+3	O
++	O
+/	O
+-	O
+1	O
+.	O
+2	O
+","	O
+and	O
+average	O
+seizure	B-NP
+duration	O
+was	O
+39	O
+.	O
+5	O
++	O
+/	O
+-	O
+8	O
+.	O
+4s	O
+.	O
+	
+Pre	O
+-	O
+treatment	O
+with	O
+a	O
+dose	O
+of	O
+30	O
+mg	O
+/	O
+kg	O
+2h	O
+before	O
+picrotoxin	O
+microperfusion	O
+prevented	O
+seizures	B-NP
+in	O
+the	O
+75	O
+%	O
+of	O
+the	O
+rats	O
+.	O
+	
+Lower	O
+doses	O
+(	O
+3	O
+and	O
+10mg	O
+/	O
+kg	O
+)	O
+did	O
+not	O
+suppress	O
+seizures	B-NP
+","	O
+however	O
+","	O
+after	O
+administration	O
+of	O
+10mg	O
+/	O
+kg	O
+","	O
+significant	O
+reductions	O
+in	O
+seizures	B-NP
+duration	O
+(	O
+24	O
+.	O
+3	O
++	O
+/	O
+-	O
+6	O
+.	O
+8s	O
+)	O
+and	O
+seizure	B-NP
+number	O
+(	O
+1	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+34	O
+)	O
+were	O
+found	O
+.	O
+	
+No	O
+adverse	O
+effects	O
+of	O
+eslicarbazepine	O
+acetate	O
+were	O
+observed	O
+in	O
+the	O
+behavioral	O
+/	O
+EEG	O
+patterns	O
+studied	O
+","	O
+including	O
+sleep	O
+/	O
+wakefulness	O
+cycle	O
+","	O
+at	O
+the	O
+doses	O
+studied	O
+.	O
+	
+Acute	B-NP
+renal	I-NP
+failure	I-NP
+associated	O
+with	O
+prolonged	O
+intake	O
+of	O
+slimming	O
+pills	O
+containing	O
+anthraquinones	O
+.	O
+	
+Chinese	O
+herbal	O
+medicine	O
+preparations	O
+are	O
+widely	O
+available	O
+and	O
+often	O
+regarded	O
+by	O
+the	O
+public	O
+as	O
+natural	O
+and	O
+safe	O
+remedies	O
+for	O
+a	O
+variety	O
+of	O
+medical	O
+conditions	O
+.	O
+	
+Nephropathy	B-NP
+caused	O
+by	O
+Chinese	O
+herbs	O
+has	O
+previously	O
+been	O
+reported	O
+","	O
+usually	O
+involving	O
+the	O
+use	O
+of	O
+aristolochic	O
+acids	O
+.	O
+	
+We	O
+report	O
+a	O
+23	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+who	O
+developed	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+following	O
+prolonged	O
+use	O
+of	O
+a	O
+proprietary	O
+Chinese	O
+herbal	O
+slimming	O
+pill	O
+that	O
+contained	O
+anthraquinone	O
+derivatives	O
+","	O
+extracted	O
+from	O
+Rhizoma	O
+Rhei	O
+(	O
+rhubarb	O
+)	O
+.	O
+	
+The	O
+renal	B-NP
+injury	I-NP
+was	O
+probably	O
+aggravated	O
+by	O
+the	O
+concomitant	O
+intake	O
+of	O
+a	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drug	O
+","	O
+diclofenac	O
+.	O
+	
+Renal	O
+pathology	O
+was	O
+that	O
+of	O
+hypocellular	O
+interstitial	O
+fibrosis	B-NP
+.	O
+	
+Spontaneous	O
+renal	O
+recovery	O
+occurred	O
+upon	O
+cessation	O
+of	O
+the	O
+slimming	O
+pills	O
+","	O
+but	O
+mild	O
+interstitial	O
+fibrosis	B-NP
+and	O
+tubular	O
+atrophy	B-NP
+was	O
+still	O
+evident	O
+histologically	O
+4	O
+months	O
+later	O
+.	O
+	
+Although	O
+a	O
+causal	O
+relationship	O
+between	O
+the	O
+use	O
+of	O
+an	O
+anthraquinone	O
+-	O
+containing	O
+herbal	O
+agent	O
+and	O
+renal	B-NP
+injury	I-NP
+remains	O
+to	O
+be	O
+proven	O
+","	O
+phytotherapy	O
+-	O
+associated	O
+interstitial	O
+nephropathy	B-NP
+should	O
+be	O
+considered	O
+in	O
+patients	O
+who	O
+present	O
+with	O
+unexplained	O
+renal	B-NP
+failure	I-NP
+.	O
+	
+Chloroacetaldehyde	O
+as	O
+a	O
+sulfhydryl	O
+reagent	O
+:	O
+the	O
+role	O
+of	O
+critical	O
+thiol	O
+groups	O
+in	O
+ifosfamide	O
+nephropathy	B-NP
+.	O
+	
+Chloroacetaldehyde	O
+(	O
+CAA	O
+)	O
+is	O
+a	O
+metabolite	O
+of	O
+the	O
+alkylating	O
+agent	O
+ifosfamide	O
+(	O
+IFO	O
+)	O
+and	O
+putatively	O
+responsible	O
+for	O
+renal	B-NP
+damage	I-NP
+following	O
+anti	O
+-	O
+tumor	B-NP
+therapy	O
+with	O
+IFO	O
+.	O
+	
+Depletion	O
+of	O
+sulfhydryl	O
+(	O
+SH	O
+)	O
+groups	O
+has	O
+been	O
+reported	O
+from	O
+cell	O
+culture	O
+","	O
+animal	O
+and	O
+clinical	O
+studies	O
+.	O
+	
+In	O
+this	O
+work	O
+the	O
+effect	O
+of	O
+CAA	O
+on	O
+human	O
+proximal	O
+tubule	O
+cells	O
+in	O
+primary	O
+culture	O
+(	O
+hRPTEC	O
+)	O
+was	O
+investigated	O
+.	O
+	
+Toxicity	B-NP
+of	O
+CAA	O
+was	O
+determined	O
+by	O
+protein	O
+content	O
+","	O
+cell	O
+number	O
+","	O
+LDH	O
+release	O
+","	O
+trypan	O
+blue	O
+exclusion	O
+assay	O
+and	O
+caspase	O
+-	O
+3	O
+activity	O
+.	O
+	
+Free	O
+thiols	O
+were	O
+measured	O
+by	O
+the	O
+method	O
+of	O
+Ellman	O
+.	O
+	
+CAA	O
+reduced	O
+hRPTEC	O
+cell	O
+number	O
+and	O
+protein	O
+","	O
+induced	O
+a	O
+loss	O
+in	O
+free	O
+intracellular	O
+thiols	O
+and	O
+an	O
+increase	O
+in	O
+necrosis	B-NP
+markers	O
+.	O
+	
+CAA	O
+but	O
+not	O
+acrolein	O
+inhibited	O
+the	O
+cysteine	O
+proteases	O
+caspase	O
+-	O
+3	O
+","	O
+caspase	O
+-	O
+8	O
+and	O
+cathepsin	O
+B	O
+.	O
+	
+Caspase	O
+activation	O
+by	O
+cisplatin	O
+was	O
+inhibited	O
+by	O
+CAA	O
+.	O
+	
+In	O
+cells	O
+stained	O
+with	O
+fluorescent	O
+dyes	O
+targeting	O
+lysosomes	O
+","	O
+CAA	O
+induced	O
+an	O
+increase	O
+in	O
+lysosomal	O
+size	O
+and	O
+lysosomal	O
+leakage	O
+.	O
+	
+The	O
+effects	O
+of	O
+CAA	O
+on	O
+cysteine	O
+protease	O
+activities	O
+and	O
+thiols	O
+could	O
+be	O
+reproduced	O
+in	O
+cell	O
+lysate	O
+.	O
+	
+Acidification	O
+","	O
+which	O
+slowed	O
+the	O
+reaction	O
+of	O
+CAA	O
+with	O
+thiol	O
+donors	O
+","	O
+could	O
+also	O
+attenuate	O
+effects	O
+of	O
+CAA	O
+on	O
+necrosis	B-NP
+markers	O
+","	O
+thiol	O
+depletion	O
+and	O
+cysteine	O
+protease	O
+inhibition	O
+in	O
+living	O
+cells	O
+.	O
+	
+Thus	O
+","	O
+CAA	O
+directly	O
+reacts	O
+with	O
+cellular	O
+protein	O
+and	O
+non	O
+-	O
+protein	O
+thiols	O
+","	O
+mediating	O
+its	O
+toxicity	B-NP
+on	O
+hRPTEC	O
+.	O
+	
+This	O
+effect	O
+can	O
+be	O
+reduced	O
+by	O
+acidification	O
+.	O
+	
+Therefore	O
+","	O
+urinary	O
+acidification	O
+could	O
+be	O
+an	O
+option	O
+to	O
+prevent	O
+IFO	O
+nephropathy	B-NP
+in	O
+patients	O
+.	O
+	
+Stereological	O
+methods	O
+reveal	O
+the	O
+robust	O
+size	O
+and	O
+stability	O
+of	O
+ectopic	O
+hilar	O
+granule	O
+cells	O
+after	O
+pilocarpine	O
+-	O
+induced	O
+status	B-NP
+epilepticus	I-NP
+in	O
+the	O
+adult	O
+rat	O
+.	O
+	
+Following	O
+status	B-NP
+epilepticus	I-NP
+in	O
+the	O
+rat	O
+","	O
+dentate	O
+granule	O
+cell	O
+neurogenesis	O
+increases	O
+greatly	O
+","	O
+and	O
+many	O
+of	O
+the	O
+new	O
+neurons	O
+appear	O
+to	O
+develop	O
+ectopically	O
+","	O
+in	O
+the	O
+hilar	O
+region	O
+of	O
+the	O
+hippocampal	O
+formation	O
+.	O
+	
+It	O
+has	O
+been	O
+suggested	O
+that	O
+the	O
+ectopic	O
+hilar	O
+granule	O
+cells	O
+could	O
+contribute	O
+to	O
+the	O
+spontaneous	O
+seizures	B-NP
+that	O
+ultimately	O
+develop	O
+after	O
+status	B-NP
+epilepticus	I-NP
+.	O
+	
+However	O
+","	O
+the	O
+population	O
+has	O
+never	O
+been	O
+quantified	O
+","	O
+so	O
+it	O
+is	O
+unclear	O
+whether	O
+it	O
+is	O
+substantial	O
+enough	O
+to	O
+have	O
+a	O
+strong	O
+influence	O
+on	O
+epileptogenesis	O
+.	O
+	
+To	O
+quantify	O
+this	O
+population	O
+","	O
+the	O
+total	O
+number	O
+of	O
+ectopic	O
+hilar	O
+granule	O
+cells	O
+was	O
+estimated	O
+using	O
+unbiased	O
+stereology	O
+at	O
+different	O
+times	O
+after	O
+pilocarpine	O
+-	O
+induced	O
+status	B-NP
+epilepticus	I-NP
+.	O
+	
+The	O
+number	O
+of	O
+hilar	O
+neurons	O
+immunoreactive	O
+for	O
+Prox	O
+-	O
+1	O
+","	O
+a	O
+granule	O
+-	O
+cell	O
+-	O
+specific	O
+marker	O
+","	O
+was	O
+estimated	O
+using	O
+the	O
+optical	O
+fractionator	O
+method	O
+.	O
+	
+The	O
+results	O
+indicate	O
+that	O
+the	O
+size	O
+of	O
+the	O
+hilar	O
+ectopic	O
+granule	O
+cell	O
+population	O
+after	O
+status	B-NP
+epilepticus	I-NP
+is	O
+substantial	O
+","	O
+and	O
+stable	O
+over	O
+time	O
+.	O
+	
+Interestingly	O
+","	O
+the	O
+size	O
+of	O
+the	O
+population	O
+appears	O
+to	O
+be	O
+correlated	O
+with	O
+the	O
+frequency	O
+of	O
+behavioral	O
+seizures	B-NP
+","	O
+because	O
+animals	O
+with	O
+more	O
+ectopic	O
+granule	O
+cells	O
+in	O
+the	O
+hilus	O
+have	O
+more	O
+frequent	O
+behavioral	O
+seizures	B-NP
+.	O
+	
+The	O
+hilar	O
+ectopic	O
+granule	O
+cell	O
+population	O
+does	O
+not	O
+appear	O
+to	O
+vary	O
+systematically	O
+across	O
+the	O
+septotemporal	O
+axis	O
+","	O
+although	O
+it	O
+is	O
+associated	O
+with	O
+an	O
+increase	O
+in	O
+volume	O
+of	O
+the	O
+hilus	O
+.	O
+	
+The	O
+results	O
+provide	O
+new	O
+insight	O
+into	O
+the	O
+potential	O
+role	O
+of	O
+ectopic	O
+hilar	O
+granule	O
+cells	O
+in	O
+the	O
+pilocarpine	O
+model	O
+of	O
+temporal	B-NP
+lobe	I-NP
+epilepsy	I-NP
+.	O
+	
+A	O
+prospective	O
+","	O
+open	O
+-	O
+label	O
+trial	O
+of	O
+galantamine	O
+in	O
+autistic	B-NP
+disorder	I-NP
+.	O
+	
+OBJECTIVE	O
+:	O
+Post	O
+-	O
+mortem	O
+studies	O
+have	O
+reported	O
+abnormalities	O
+of	O
+the	O
+cholinergic	O
+system	O
+in	O
+autism	B-NP
+.	O
+	
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+assess	O
+the	O
+use	O
+of	O
+galantamine	O
+","	O
+an	O
+acetylcholinesterase	O
+inhibitor	O
+and	O
+nicotinic	O
+receptor	O
+modulator	O
+","	O
+in	O
+the	O
+treatment	O
+of	O
+interfering	O
+behaviors	O
+in	O
+children	O
+with	O
+autism	B-NP
+.	O
+	
+METHODS	O
+:	O
+Thirteen	O
+medication	O
+-	O
+free	O
+children	O
+with	O
+autism	B-NP
+(	O
+mean	O
+age	O
+","	O
+8	O
+.	O
+8	O
++	O
+/	O
+-	O
+3	O
+.	O
+5	O
+years	O
+)	O
+participated	O
+in	O
+a	O
+12	O
+-	O
+week	O
+","	O
+open	O
+-	O
+label	O
+trial	O
+of	O
+galantamine	O
+.	O
+	
+Patients	O
+were	O
+rated	O
+monthly	O
+by	O
+parents	O
+on	O
+the	O
+Aberrant	O
+Behavior	O
+Checklist	O
+(	O
+ABC	O
+)	O
+and	O
+the	O
+Conners	O
+'	O
+Parent	O
+Rating	O
+Scale	O
+-	O
+Revised	O
+","	O
+and	O
+by	O
+a	O
+physician	O
+using	O
+the	O
+Children	O
+'	O
+s	O
+Psychiatric	O
+Rating	O
+Scale	O
+and	O
+the	O
+Clinical	O
+Global	O
+Impressions	O
+scale	O
+.	O
+	
+RESULTS	O
+:	O
+Patients	O
+showed	O
+a	O
+significant	O
+reduction	O
+in	O
+parent	O
+-	O
+rated	O
+irritability	B-NP
+and	O
+social	O
+withdrawal	O
+on	O
+the	O
+ABC	O
+as	O
+well	O
+as	O
+significant	O
+improvements	O
+in	O
+emotional	O
+lability	O
+and	O
+inattention	O
+on	O
+the	O
+Conners	O
+'	O
+Parent	O
+Rating	O
+Scale	O
+-	O
+-	O
+Revised	O
+.	O
+	
+Similarly	O
+","	O
+clinician	O
+ratings	O
+showed	O
+reductions	O
+in	O
+the	O
+anger	O
+subscale	O
+of	O
+the	O
+Children	O
+'	O
+s	O
+Psychiatric	O
+Rating	O
+Scale	O
+.	O
+	
+Eight	O
+of	O
+13	O
+participants	O
+were	O
+rated	O
+as	O
+responders	O
+on	O
+the	O
+basis	O
+of	O
+their	O
+improvement	O
+scores	O
+on	O
+the	O
+Clinical	O
+Global	O
+Impressions	O
+scale	O
+.	O
+	
+Overall	O
+","	O
+galantamine	O
+was	O
+well	O
+-	O
+tolerated	O
+","	O
+with	O
+no	O
+significant	O
+adverse	O
+effects	O
+apart	O
+from	O
+headaches	B-NP
+in	O
+one	O
+patient	O
+.	O
+	
+CONCLUSION	O
+:	O
+In	O
+this	O
+open	O
+trial	O
+","	O
+galantamine	O
+was	O
+well	O
+-	O
+tolerated	O
+and	O
+appeared	O
+to	O
+be	O
+beneficial	O
+for	O
+the	O
+treatment	O
+of	O
+interfering	O
+behaviors	O
+in	O
+children	O
+with	O
+autism	B-NP
+","	O
+particularly	O
+aggression	B-NP
+","	O
+behavioral	B-NP
+dyscontrol	I-NP
+","	O
+and	O
+inattention	B-NP
+.	O
+	
+Further	O
+controlled	O
+trials	O
+are	O
+warranted	O
+.	O
+	
+Randomized	O
+comparison	O
+of	O
+olanzapine	O
+versus	O
+risperidone	O
+for	O
+the	O
+treatment	O
+of	O
+first	O
+-	O
+episode	O
+schizophrenia	B-NP
+:	O
+4	O
+-	O
+month	O
+outcomes	O
+.	O
+	
+OBJECTIVE	O
+:	O
+The	O
+authors	O
+compared	O
+4	O
+-	O
+month	O
+treatment	O
+outcomes	O
+for	O
+olanzapine	O
+versus	O
+risperidone	O
+in	O
+patients	O
+with	O
+first	O
+-	O
+episode	O
+schizophrenia	B-NP
+spectrum	O
+disorders	O
+.	O
+	
+METHOD	O
+:	O
+One	O
+hundred	O
+twelve	O
+subjects	O
+(	O
+70	O
+%	O
+male	O
+;	O
+mean	O
+age	O
+=	O
+23	O
+.	O
+3	O
+years	O
+[	O
+SD	O
+=	O
+5	O
+.	O
+1	O
+]	O
+)	O
+with	O
+first	O
+-	O
+episode	O
+schizophrenia	B-NP
+(	O
+75	O
+%	O
+)	O
+","	O
+schizophreniform	B-NP
+disorder	I-NP
+(	O
+17	O
+%	O
+)	O
+","	O
+or	O
+schizoaffective	B-NP
+disorder	I-NP
+(	O
+8	O
+%	O
+)	O
+were	O
+randomly	O
+assigned	O
+to	O
+treatment	O
+with	O
+olanzapine	O
+(	O
+2	O
+.	O
+5	O
+-	O
+20	O
+mg	O
+/	O
+day	O
+)	O
+or	O
+risperidone	O
+(	O
+1	O
+-	O
+6	O
+mg	O
+/	O
+day	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+Response	O
+rates	O
+did	O
+not	O
+significantly	O
+differ	O
+between	O
+olanzapine	O
+(	O
+43	O
+.	O
+7	O
+%	O
+","	O
+95	O
+%	O
+CI	O
+=	O
+28	O
+.	O
+8	O
+%	O
+-	O
+58	O
+.	O
+6	O
+%	O
+)	O
+and	O
+risperidone	O
+(	O
+54	O
+.	O
+3	O
+%	O
+","	O
+95	O
+%	O
+CI	O
+=	O
+39	O
+.	O
+9	O
+%	O
+-	O
+68	O
+.	O
+7	O
+%	O
+)	O
+.	O
+	
+Among	O
+those	O
+responding	O
+to	O
+treatment	O
+","	O
+more	O
+subjects	O
+in	O
+the	O
+olanzapine	O
+group	O
+(	O
+40	O
+.	O
+9	O
+%	O
+","	O
+95	O
+%	O
+CI	O
+=	O
+16	O
+.	O
+8	O
+%	O
+-	O
+65	O
+.	O
+0	O
+%	O
+)	O
+than	O
+in	O
+the	O
+risperidone	O
+group	O
+(	O
+18	O
+.	O
+9	O
+%	O
+","	O
+95	O
+%	O
+CI	O
+=	O
+0	O
+%	O
+-	O
+39	O
+.	O
+2	O
+%	O
+)	O
+had	O
+subsequent	O
+ratings	O
+not	O
+meeting	O
+response	O
+criteria	O
+.	O
+	
+Negative	O
+symptom	O
+outcomes	O
+and	O
+measures	O
+of	O
+parkinsonism	B-NP
+and	O
+akathisia	B-NP
+did	O
+not	O
+differ	O
+between	O
+medications	O
+.	O
+	
+Extrapyramidal	B-NP
+symptom	I-NP
+severity	O
+scores	O
+were	O
+1	O
+.	O
+4	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+1	O
+.	O
+2	O
+-	O
+1	O
+.	O
+6	O
+)	O
+with	O
+risperidone	O
+and	O
+1	O
+.	O
+2	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+1	O
+.	O
+0	O
+-	O
+1	O
+.	O
+4	O
+)	O
+with	O
+olanzapine	O
+.	O
+	
+Significantly	O
+more	O
+weight	B-NP
+gain	I-NP
+occurred	O
+with	O
+olanzapine	O
+than	O
+with	O
+risperidone	O
+:	O
+the	O
+increase	O
+in	O
+weight	O
+at	O
+4	O
+months	O
+relative	O
+to	O
+baseline	O
+weight	O
+was	O
+17	O
+.	O
+3	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+14	O
+.	O
+2	O
+%	O
+-	O
+20	O
+.	O
+5	O
+%	O
+)	O
+with	O
+olanzapine	O
+and	O
+11	O
+.	O
+3	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+8	O
+.	O
+4	O
+%	O
+-	O
+14	O
+.	O
+3	O
+%	O
+)	O
+with	O
+risperidone	O
+.	O
+	
+Body	O
+mass	O
+index	O
+at	O
+baseline	O
+and	O
+at	O
+4	O
+months	O
+was	O
+24	O
+.	O
+3	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+22	O
+.	O
+8	O
+-	O
+25	O
+.	O
+7	O
+)	O
+versus	O
+28	O
+.	O
+2	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+26	O
+.	O
+7	O
+-	O
+29	O
+.	O
+7	O
+)	O
+with	O
+olanzapine	O
+and	O
+23	O
+.	O
+9	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+22	O
+.	O
+5	O
+-	O
+25	O
+.	O
+3	O
+)	O
+versus	O
+26	O
+.	O
+7	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+25	O
+.	O
+2	O
+-	O
+28	O
+.	O
+2	O
+)	O
+with	O
+risperidone	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Clinical	O
+outcomes	O
+with	O
+risperidone	O
+were	O
+equal	O
+to	O
+those	O
+with	O
+olanzapine	O
+","	O
+and	O
+response	O
+may	O
+be	O
+more	O
+stable	O
+.	O
+	
+Olanzapine	O
+may	O
+have	O
+an	O
+advantage	O
+for	O
+motor	O
+side	O
+effects	O
+.	O
+	
+Both	O
+medications	O
+caused	O
+substantial	O
+rapid	O
+weight	B-NP
+gain	I-NP
+","	O
+but	O
+weight	B-NP
+gain	I-NP
+was	O
+greater	O
+with	O
+olanzapine	O
+.	O
+	
+Early	O
+paracentral	O
+visual	B-NP
+field	I-NP
+loss	I-NP
+in	O
+patients	O
+taking	O
+hydroxychloroquine	O
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+review	O
+the	O
+natural	O
+history	O
+and	O
+ocular	O
+and	O
+systemic	O
+adverse	O
+effects	O
+of	O
+patients	O
+taking	O
+hydroxychloroquine	O
+sulfate	O
+who	O
+attended	O
+an	O
+ophthalmic	O
+screening	O
+program	O
+.	O
+	
+DESIGN	O
+:	O
+Retrospective	O
+study	O
+.	O
+	
+RESULTS	O
+:	O
+Records	O
+of	O
+262	O
+patients	O
+who	O
+were	O
+taking	O
+hydroxychloroquine	O
+and	O
+screened	O
+in	O
+the	O
+Department	O
+of	O
+Ophthalmology	O
+were	O
+reviewed	O
+.	O
+	
+Of	O
+the	O
+262	O
+patients	O
+","	O
+14	O
+(	O
+18	O
+%	O
+)	O
+of	O
+76	O
+who	O
+had	O
+stopped	O
+treatment	O
+at	O
+the	O
+time	O
+of	O
+the	O
+study	O
+experienced	O
+documented	O
+adverse	O
+effects	O
+.	O
+	
+Systemic	O
+adverse	O
+effects	O
+occurred	O
+in	O
+8	O
+patients	O
+(	O
+10	O
+.	O
+5	O
+%	O
+)	O
+and	O
+ocular	O
+adverse	O
+effects	O
+","	O
+in	O
+5	O
+(	O
+6	O
+.	O
+5	O
+%	O
+)	O
+.	O
+	
+Thirty	O
+-	O
+five	O
+patients	O
+(	O
+13	O
+.	O
+4	O
+%	O
+)	O
+had	O
+visual	B-NP
+field	I-NP
+abnormalities	I-NP
+","	O
+which	O
+were	O
+attributed	O
+to	O
+hydroxychloroquine	O
+treatment	O
+in	O
+4	O
+patients	O
+(	O
+1	O
+.	O
+5	O
+%	O
+)	O
+.	O
+	
+Three	O
+of	O
+the	O
+4	O
+patients	O
+were	O
+taking	O
+less	O
+than	O
+6	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+and	O
+all	O
+patients	O
+had	O
+normal	O
+renal	O
+and	O
+liver	O
+function	O
+test	O
+results	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+current	O
+study	O
+used	O
+a	O
+protocol	O
+of	O
+visual	O
+acuity	O
+and	O
+color	O
+vision	O
+assessment	O
+","	O
+funduscopy	O
+","	O
+and	O
+Humphrey	O
+10	O
+-	O
+2	O
+visual	O
+field	O
+testing	O
+and	O
+shows	O
+that	O
+visual	B-NP
+field	I-NP
+defects	I-NP
+appeared	O
+before	O
+any	O
+corresponding	O
+changes	O
+in	O
+any	O
+other	O
+tested	O
+clinical	O
+parameters	O
+;	O
+the	O
+defects	O
+were	O
+reproducible	O
+and	O
+the	O
+test	O
+parameters	O
+were	O
+reliable	O
+.	O
+	
+Patients	O
+taking	O
+hydroxychloroquine	O
+can	O
+demonstrate	O
+a	O
+toxic	O
+reaction	O
+in	O
+the	O
+retina	O
+despite	O
+the	O
+absence	O
+of	O
+known	O
+risk	O
+factors	O
+.	O
+	
+Screening	O
+","	O
+including	O
+Humphrey	O
+10	O
+-	O
+2	O
+visual	O
+field	O
+assessment	O
+","	O
+is	O
+recommended	O
+2	O
+years	O
+after	O
+the	O
+initial	O
+baseline	O
+and	O
+yearly	O
+thereafter	O
+.	O
+	
+Peri	O
+-	O
+operative	O
+atrioventricular	B-NP
+block	I-NP
+as	O
+a	O
+result	O
+of	O
+chemotherapy	O
+with	O
+epirubicin	O
+and	O
+paclitaxel	O
+.	O
+	
+A	O
+47	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+presented	O
+for	O
+mastectomy	O
+and	O
+immediate	O
+latissimus	O
+dorsi	O
+flap	O
+reconstruction	O
+having	O
+been	O
+diagnosed	O
+with	O
+carcinoma	B-NP
+of	I-NP
+the	I-NP
+breast	I-NP
+6	O
+months	O
+previously	O
+.	O
+	
+In	O
+the	O
+preceding	O
+months	O
+she	O
+had	O
+received	O
+neo	O
+-	O
+adjuvant	O
+chemotherapy	O
+with	O
+epirubicin	O
+","	O
+paclitaxel	O
+(	O
+Taxol	O
+)	O
+and	O
+cyclophosphamide	O
+.	O
+	
+This	O
+had	O
+been	O
+apparently	O
+uncomplicated	O
+and	O
+she	O
+had	O
+maintained	O
+a	O
+remarkably	O
+high	O
+level	O
+of	O
+physical	O
+activity	O
+.	O
+	
+She	O
+was	O
+found	O
+to	O
+be	O
+bradycardic	B-NP
+at	O
+pre	O
+-	O
+operative	O
+assessment	O
+but	O
+had	O
+no	O
+cardiac	O
+symptoms	O
+.	O
+	
+Second	O
+degree	O
+Mobitz	O
+type	O
+II	O
+atrioventricular	B-NP
+block	I-NP
+was	O
+diagnosed	O
+on	O
+electrocardiogram	O
+","	O
+and	O
+temporary	O
+transvenous	O
+ventricular	O
+pacing	O
+instituted	O
+in	O
+the	O
+peri	O
+-	O
+operative	O
+period	O
+.	O
+	
+We	O
+discuss	O
+how	O
+evidence	O
+-	O
+based	O
+guidelines	O
+would	O
+not	O
+have	O
+been	O
+helpful	O
+in	O
+this	O
+case	O
+","	O
+and	O
+how	O
+chemotherapy	O
+can	O
+exhibit	O
+substantial	O
+cardiotoxicity	B-NP
+that	O
+may	O
+develop	O
+over	O
+many	O
+years	O
+.	O
+	
+We	O
+suggest	O
+that	O
+patients	O
+who	O
+have	O
+received	O
+chemotherapy	O
+at	O
+any	O
+time	O
+should	O
+have	O
+a	O
+pre	O
+-	O
+operative	O
+electrocardiogram	O
+even	O
+if	O
+they	O
+are	O
+asymptomatic	O
+.	O
+	
+Risks	O
+and	O
+benefits	O
+of	O
+COX	O
+-	O
+2	O
+inhibitors	O
+vs	O
+non	O
+-	O
+selective	O
+NSAIDs	O
+:	O
+does	O
+their	O
+cardiovascular	O
+risk	O
+exceed	O
+their	O
+gastrointestinal	O
+benefit	O
+?	O
+	
+A	O
+retrospective	O
+cohort	O
+study	O
+.	O
+	
+OBJECTIVES	O
+:	O
+The	O
+risk	O
+of	O
+acute	B-NP
+myocardial	I-NP
+infarction	I-NP
+(	O
+AMI	B-NP
+)	O
+with	O
+COX	O
+-	O
+2	O
+inhibitors	O
+may	O
+offset	O
+their	O
+gastrointestinal	O
+(	O
+GI	O
+)	O
+benefit	O
+compared	O
+with	O
+non	O
+-	O
+selective	O
+(	O
+NS	O
+)	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+(	O
+NSAIDs	O
+)	O
+.	O
+	
+We	O
+aimed	O
+to	O
+compare	O
+the	O
+risks	O
+of	O
+hospitalization	O
+for	O
+AMI	B-NP
+and	O
+GI	B-NP
+bleeding	I-NP
+among	O
+elderly	O
+patients	O
+using	O
+COX	O
+-	O
+2	O
+inhibitors	O
+","	O
+NS	O
+-	O
+NSAIDs	O
+and	O
+acetaminophen	O
+.	O
+	
+METHODS	O
+:	O
+We	O
+conducted	O
+a	O
+retrospective	O
+cohort	O
+study	O
+using	O
+administrative	O
+data	O
+of	O
+patients	O
+>	O
+or	O
+=	O
+65	O
+years	O
+of	O
+age	O
+who	O
+filled	O
+a	O
+prescription	O
+for	O
+NSAID	O
+or	O
+acetaminophen	O
+during	O
+1999	O
+-	O
+2002	O
+.	O
+	
+Outcomes	O
+were	O
+compared	O
+using	O
+Cox	O
+regression	O
+models	O
+with	O
+time	O
+-	O
+dependent	O
+exposures	O
+.	O
+	
+RESULTS	O
+:	O
+Person	O
+-	O
+years	O
+of	O
+exposure	O
+among	O
+non	O
+-	O
+users	O
+of	O
+aspirin	O
+were	O
+:	O
+75	O
+","	O
+761	O
+to	O
+acetaminophen	O
+","	O
+42	O
+","	O
+671	O
+to	O
+rofecoxib	O
+65	O
+","	O
+860	O
+to	O
+celecoxib	O
+","	O
+and	O
+37	O
+","	O
+495	O
+to	O
+NS	O
+-	O
+NSAIDs	O
+.	O
+	
+Among	O
+users	O
+of	O
+aspirin	O
+","	O
+they	O
+were	O
+:	O
+14	O
+","	O
+671	O
+to	O
+rofecoxib	O
+","	O
+22	O
+","	O
+875	O
+to	O
+celecoxib	O
+","	O
+9	O
+","	O
+832	O
+to	O
+NS	O
+-	O
+NSAIDs	O
+and	O
+38	O
+","	O
+48	O
+to	O
+acetaminophen	O
+.	O
+	
+Among	O
+non	O
+-	O
+users	O
+of	O
+aspirin	O
+","	O
+the	O
+adjusted	O
+hazard	O
+ratios	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+)	O
+of	O
+hospitalization	O
+for	O
+AMI	B-NP
+/	O
+GI	O
+vs	O
+the	O
+acetaminophen	O
+(	O
+with	O
+no	O
+aspirin	O
+)	O
+group	O
+were	O
+:	O
+rofecoxib	O
+1	O
+.	O
+27	O
+(	O
+1	O
+.	O
+13	O
+","	O
+1	O
+.	O
+42	O
+)	O
+","	O
+celecoxib	O
+0	O
+.	O
+93	O
+(	O
+0	O
+.	O
+83	O
+","	O
+1	O
+.	O
+3	O
+)	O
+","	O
+naproxen	O
+1	O
+.	O
+59	O
+(	O
+1	O
+.	O
+31	O
+","	O
+1	O
+.	O
+93	O
+)	O
+","	O
+diclofenac	O
+1	O
+.	O
+17	O
+(	O
+0	O
+.	O
+99	O
+","	O
+1	O
+.	O
+38	O
+)	O
+and	O
+ibuprofen	O
+1	O
+.	O
+5	O
+(	O
+0	O
+.	O
+74	O
+","	O
+1	O
+.	O
+51	O
+)	O
+.	O
+	
+Among	O
+users	O
+of	O
+aspirin	O
+","	O
+they	O
+were	O
+:	O
+rofecoxib	O
+1	O
+.	O
+73	O
+(	O
+1	O
+.	O
+52	O
+","	O
+1	O
+.	O
+98	O
+)	O
+","	O
+celecoxib	O
+1	O
+.	O
+34	O
+(	O
+1	O
+.	O
+19	O
+","	O
+1	O
+.	O
+52	O
+)	O
+","	O
+ibuprofen	O
+1	O
+.	O
+51	O
+(	O
+0	O
+.	O
+95	O
+","	O
+2	O
+.	O
+41	O
+)	O
+","	O
+diclofenac	O
+1	O
+.	O
+69	O
+(	O
+1	O
+.	O
+35	O
+","	O
+2	O
+.	O
+10	O
+)	O
+","	O
+naproxen	O
+1	O
+.	O
+35	O
+(	O
+0	O
+.	O
+97	O
+","	O
+1	O
+.	O
+88	O
+)	O
+and	O
+acetaminophen	O
+1	O
+.	O
+29	O
+(	O
+1	O
+.	O
+17	O
+","	O
+1	O
+.	O
+42	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+Among	O
+non	O
+-	O
+users	O
+of	O
+aspirin	O
+","	O
+naproxen	O
+seemed	O
+to	O
+carry	O
+the	O
+highest	O
+risk	O
+for	O
+AMI	B-NP
+/	O
+GI	B-NP
+bleeding	I-NP
+.	O
+	
+The	O
+AMI	B-NP
+/	O
+GI	O
+toxicity	B-NP
+of	O
+celecoxib	O
+was	O
+similar	O
+to	O
+that	O
+of	O
+acetaminophen	O
+and	O
+seemed	O
+to	O
+be	O
+better	O
+than	O
+those	O
+of	O
+rofecoxib	O
+and	O
+NS	O
+-	O
+NSAIDs	O
+.	O
+	
+Among	O
+users	O
+of	O
+aspirin	O
+","	O
+both	O
+celecoxib	O
+and	O
+naproxen	O
+seemed	O
+to	O
+be	O
+the	O
+least	O
+toxic	O
+.	O
+	
+Quinine	O
+-	O
+induced	O
+arrhythmia	B-NP
+in	O
+a	O
+patient	O
+with	O
+severe	B-NP
+malaria	I-NP
+.	O
+	
+It	O
+was	O
+reported	O
+that	O
+there	O
+was	O
+a	O
+case	O
+of	O
+severe	B-NP
+malaria	I-NP
+patient	O
+with	O
+jaundice	B-NP
+who	O
+presented	O
+with	O
+arrhythmia	B-NP
+(	O
+premature	B-NP
+ventricular	I-NP
+contraction	I-NP
+)	O
+while	O
+getting	O
+quinine	O
+infusion	O
+was	O
+reported	O
+.	O
+	
+A	O
+man	O
+","	O
+25	O
+years	O
+old	O
+","	O
+was	O
+admitted	O
+to	O
+hospital	O
+with	O
+high	O
+fever	B-NP
+","	O
+chill	B-NP
+","	O
+vomiting	B-NP
+","	O
+jaundice	B-NP
+.	O
+	
+The	O
+patient	O
+was	O
+fully	O
+conscious	O
+","	O
+blood	O
+pressure	O
+120	O
+/	O
+80	O
+mmHg	O
+","	O
+pulse	O
+rate	O
+100	O
+x	O
+/	O
+minute	O
+","	O
+regular	O
+.	O
+	
+On	O
+admission	O
+","	O
+laboratory	O
+examination	O
+showed	O
+Plasmodium	O
+falciparum	O
+(	O
++	O
++	O
++	O
++	O
+)	O
+","	O
+total	O
+bilirubin	O
+8	O
+.	O
+25	O
+mg	O
+/	O
+dL	O
+","	O
+conjugated	O
+bilirubin	O
+4	O
+.	O
+36	O
+mg	O
+/	O
+dL	O
+","	O
+unconjugated	O
+bilirubin	O
+3	O
+.	O
+89	O
+mg	O
+/	O
+dL	O
+","	O
+potassium	O
+3	O
+.	O
+52	O
+meq	O
+/	O
+L	O
+Patient	O
+was	O
+diagnosed	O
+as	O
+severe	B-NP
+malaria	I-NP
+with	O
+jaundice	B-NP
+and	O
+got	O
+quinine	O
+infusion	O
+in	O
+dextrose	O
+5	O
+%	O
+500	O
+mg	O
+/	O
+8	O
+hour	O
+.	O
+	
+On	O
+the	O
+second	O
+day	O
+the	O
+patient	O
+had	O
+vomitus	B-NP
+","	O
+diarrhea	B-NP
+","	O
+tinnitus	B-NP
+","	O
+loss	B-NP
+of	I-NP
+hearing	I-NP
+.	O
+	
+After	O
+30	O
+hours	O
+of	O
+quinine	O
+infusion	O
+the	O
+patient	O
+felt	O
+palpitation	B-NP
+and	O
+electrocardiography	O
+(	O
+ECG	O
+)	O
+recording	O
+showed	O
+premature	B-NP
+ventricular	I-NP
+contraction	I-NP
+(	O
+PVC	B-NP
+)	O
+>	O
+5	O
+x	O
+/	O
+minute	O
+","	O
+trigemini	O
+","	O
+constant	O
+type	O
+-	O
+-	O
+sinoatrial	B-NP
+block	I-NP
+","	O
+positive	O
+U	O
+wave	O
+.	O
+	
+He	O
+was	O
+treated	O
+with	O
+lidocaine	O
+50	O
+mg	O
+intravenously	O
+followed	O
+by	O
+infusion	O
+1500	O
+mg	O
+in	O
+dextrose	O
+5	O
+%	O
+/	O
+24	O
+hour	O
+and	O
+potassium	O
+aspartate	O
+tablet	O
+.	O
+	
+Quinine	O
+infusion	O
+was	O
+discontinued	O
+and	O
+changed	O
+with	O
+sulfate	O
+quinine	O
+tablets	O
+.	O
+	
+Three	O
+hours	O
+later	O
+the	O
+patient	O
+felt	O
+better	O
+","	O
+the	O
+frequency	O
+of	O
+PVC	B-NP
+reduced	O
+to	O
+4	O
+-	O
+5	O
+x	O
+/	O
+minute	O
+and	O
+on	O
+the	O
+third	O
+day	O
+ECG	O
+was	O
+normal	O
+","	O
+potassium	O
+level	O
+was	O
+3	O
+.	O
+34	O
+meq	O
+/	O
+L	O
+.	O
+	
+He	O
+was	O
+discharged	O
+on	O
+7th	O
+day	O
+in	O
+good	O
+condition	O
+.	O
+	
+Quinine	O
+","	O
+like	O
+quinidine	O
+","	O
+is	O
+a	O
+chincona	O
+alkaloid	O
+that	O
+has	O
+anti	O
+-	O
+arrhythmic	B-NP
+property	O
+","	O
+although	O
+it	O
+also	O
+pro	O
+-	O
+arrhythmic	B-NP
+that	O
+can	O
+cause	O
+various	O
+arrhythmias	B-NP
+","	O
+including	O
+severe	O
+arrhythmia	B-NP
+such	O
+as	O
+multiple	O
+PVC	B-NP
+.	O
+	
+Administration	O
+of	O
+parenteral	O
+quinine	O
+must	O
+be	O
+done	O
+carefully	O
+and	O
+with	O
+good	O
+observation	O
+because	O
+of	O
+its	O
+pro	O
+-	O
+arrhythmic	B-NP
+effect	O
+","	O
+especially	O
+in	O
+older	O
+patients	O
+who	O
+have	O
+heart	B-NP
+diseases	I-NP
+or	O
+patients	O
+with	O
+electrolyte	B-NP
+disorder	I-NP
+(	O
+hypokalemia	B-NP
+)	O
+which	O
+frequently	O
+occurs	O
+due	O
+to	O
+vomiting	B-NP
+and	O
+or	O
+diarrhea	B-NP
+in	O
+malaria	B-NP
+cases	O
+.	O
+	
+Penicillamine	O
+-	O
+related	O
+lichenoid	B-NP
+dermatitis	I-NP
+and	O
+utility	O
+of	O
+zinc	O
+acetate	O
+in	O
+a	O
+Wilson	B-NP
+disease	I-NP
+patient	O
+with	O
+hepatic	O
+presentation	O
+","	O
+anxiety	B-NP
+and	O
+SPECT	O
+abnormalities	O
+.	O
+	
+Wilson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+is	O
+an	O
+autosomal	O
+recessive	O
+disorder	O
+of	O
+hepatic	O
+copper	O
+metabolism	O
+with	O
+consequent	O
+copper	O
+accumulation	O
+and	O
+toxicity	B-NP
+in	O
+many	O
+tissues	O
+and	O
+consequent	O
+hepatic	B-NP
+","	I-NP
+neurologic	I-NP
+and	I-NP
+psychiatric	I-NP
+disorders	I-NP
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+Wilson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+with	O
+chronic	B-NP
+liver	I-NP
+disease	I-NP
+;	O
+moreover	O
+","	O
+in	O
+our	O
+patient	O
+","	O
+presenting	O
+also	O
+with	O
+high	O
+levels	O
+of	O
+state	O
+anxiety	B-NP
+without	O
+depression	B-NP
+","	O
+99mTc	O
+-	O
+ECD	O
+-	O
+SPECT	O
+showed	O
+cortical	O
+hypoperfusion	O
+in	O
+frontal	O
+lobes	O
+","	O
+more	O
+marked	O
+on	O
+the	O
+left	O
+frontal	O
+lobe	O
+.	O
+	
+During	O
+the	O
+follow	O
+-	O
+up	O
+of	O
+our	O
+patient	O
+","	O
+penicillamine	O
+was	O
+interrupted	O
+after	O
+the	O
+appearance	O
+of	O
+a	O
+lichenoid	B-NP
+dermatitis	I-NP
+","	O
+and	O
+zinc	O
+acetate	O
+permitted	O
+to	O
+continue	O
+the	O
+successful	O
+treatment	O
+of	O
+the	O
+patient	O
+without	O
+side	O
+-	O
+effects	O
+.	O
+	
+In	O
+our	O
+case	O
+the	O
+therapy	O
+with	O
+zinc	O
+acetate	O
+represented	O
+an	O
+effective	O
+treatment	O
+for	O
+a	O
+Wilson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+patient	O
+in	O
+which	O
+penicillamine	O
+-	O
+related	O
+side	O
+effects	O
+appeared	O
+.	O
+	
+The	O
+safety	O
+of	O
+the	O
+zinc	O
+acetate	O
+allowed	O
+us	O
+to	O
+avoid	O
+other	O
+potentially	O
+toxic	O
+chelating	O
+drugs	O
+;	O
+this	O
+observation	O
+is	O
+in	O
+line	O
+with	O
+the	O
+growing	O
+evidence	O
+on	O
+the	O
+efficacy	O
+of	O
+the	O
+drug	O
+in	O
+the	O
+treatment	O
+of	O
+Wilson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+Since	O
+most	O
+of	O
+Wilson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+penicillamine	O
+-	O
+treated	O
+patients	O
+do	O
+not	O
+seem	O
+to	O
+develop	O
+this	O
+skin	B-NP
+lesion	I-NP
+","	O
+it	O
+could	O
+be	O
+conceivable	O
+that	O
+a	O
+specific	O
+genetic	O
+factor	O
+is	O
+involved	O
+in	O
+drug	O
+response	O
+.	O
+	
+Further	O
+studies	O
+are	O
+needed	O
+for	O
+a	O
+better	O
+clarification	O
+of	O
+Wilson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+therapy	O
+","	O
+and	O
+in	O
+particular	O
+to	O
+differentiate	O
+specific	O
+therapies	O
+for	O
+different	O
+Wilson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+phenotypes	O
+.	O
+	
+A	O
+dramatic	O
+drop	B-NP
+in	I-NP
+blood	I-NP
+pressure	I-NP
+following	O
+prehospital	O
+GTN	O
+administration	O
+.	O
+	
+A	O
+male	O
+in	O
+his	O
+sixties	O
+with	O
+no	O
+history	O
+of	O
+cardiac	O
+chest	B-NP
+pain	I-NP
+awoke	O
+with	O
+chest	B-NP
+pain	I-NP
+following	O
+an	O
+afternoon	O
+sleep	O
+.	O
+	
+The	O
+patient	O
+did	O
+not	O
+self	O
+medicate	O
+.	O
+	
+The	O
+patient	O
+'	O
+s	O
+observations	O
+were	O
+within	O
+normal	O
+limits	O
+","	O
+he	O
+was	O
+administered	O
+oxygen	O
+via	O
+a	O
+face	O
+mask	O
+and	O
+glyceryl	O
+trinitrate	O
+(	O
+GTN	O
+)	O
+.	O
+	
+Several	O
+minutes	O
+after	O
+the	O
+GTN	O
+the	O
+patient	O
+experienced	O
+a	O
+sudden	O
+drop	B-NP
+in	I-NP
+blood	I-NP
+pressure	I-NP
+and	O
+heart	O
+rate	O
+","	O
+this	O
+was	O
+rectified	O
+by	O
+atropine	O
+sulphate	O
+and	O
+a	O
+fluid	O
+challenge	O
+.	O
+	
+There	O
+was	O
+no	O
+further	O
+deterioration	O
+in	O
+the	O
+patient	O
+'	O
+s	O
+condition	O
+during	O
+transport	O
+to	O
+hospital	O
+.	O
+	
+There	O
+are	O
+very	O
+few	O
+documented	O
+case	O
+like	O
+this	O
+in	O
+the	O
+prehospital	O
+scientific	O
+literature	O
+.	O
+	
+The	O
+cause	O
+appears	O
+to	O
+be	O
+the	O
+Bezold	O
+-	O
+Jarish	O
+reflex	O
+","	O
+stimulation	O
+of	O
+the	O
+ventricular	O
+walls	O
+which	O
+in	O
+turn	O
+decreases	O
+sympathetic	O
+outflow	O
+from	O
+the	O
+vasomotor	O
+centre	O
+.	O
+	
+Prehospital	O
+care	O
+providers	O
+who	O
+are	O
+managing	O
+any	O
+patient	O
+with	O
+a	O
+syncopal	B-NP
+episode	I-NP
+that	O
+fails	O
+to	O
+recover	O
+within	O
+a	O
+reasonable	O
+time	O
+frame	O
+should	O
+consider	O
+the	O
+Bezold	O
+-	O
+Jarisch	O
+reflex	O
+as	O
+the	O
+cause	O
+and	O
+manage	O
+the	O
+patient	O
+accordingly	O
+.	O
+	
+Chronic	O
+lesion	O
+of	O
+rostral	O
+ventrolateral	O
+medulla	O
+in	O
+spontaneously	O
+hypertensive	B-NP
+rats	O
+.	O
+	
+We	O
+studied	O
+the	O
+effects	O
+of	O
+chronic	O
+selective	O
+neuronal	O
+lesion	O
+of	O
+rostral	O
+ventrolateral	O
+medulla	O
+on	O
+mean	O
+arterial	O
+pressure	O
+","	O
+heart	O
+rate	O
+","	O
+and	O
+neurogenic	O
+tone	O
+in	O
+conscious	O
+","	O
+unrestrained	O
+spontaneously	O
+hypertensive	B-NP
+rats	O
+.	O
+	
+The	O
+lesions	O
+were	O
+placed	O
+via	O
+bilateral	O
+microinjections	O
+of	O
+30	O
+nmol	O
+/	O
+200	O
+nl	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartic	O
+acid	O
+.	O
+	
+The	O
+restimulation	O
+of	O
+this	O
+area	O
+with	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartic	O
+acid	O
+15	O
+days	O
+postlesion	O
+failed	O
+to	O
+produce	O
+a	O
+pressor	O
+response	O
+.	O
+	
+One	O
+day	O
+postlesion	O
+","	O
+the	O
+resting	O
+mean	O
+arterial	O
+pressure	O
+was	O
+significantly	O
+decreased	O
+in	O
+lesioned	O
+rats	O
+when	O
+compared	O
+with	O
+sham	O
+rats	O
+(	O
+100	O
++	O
+/	O
+-	O
+7	O
+versus	O
+173	O
++	O
+/	O
+-	O
+4	O
+mm	O
+Hg	O
+","	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+Fifteen	O
+days	O
+later	O
+","	O
+the	O
+lesioned	O
+group	O
+still	O
+showed	O
+values	O
+significantly	O
+lower	O
+than	O
+the	O
+sham	O
+group	O
+(	O
+150	O
++	O
+/	O
+-	O
+6	O
+versus	O
+167	O
++	O
+/	O
+-	O
+5	O
+mm	O
+Hg	O
+","	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+No	O
+significant	O
+heart	O
+rate	O
+differences	O
+were	O
+observed	O
+between	O
+the	O
+sham	O
+and	O
+lesioned	O
+groups	O
+.	O
+	
+The	O
+ganglionic	O
+blocker	O
+trimethaphan	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+caused	O
+similar	O
+reductions	O
+in	O
+mean	O
+arterial	O
+pressure	O
+in	O
+both	O
+lesioned	O
+and	O
+sham	O
+groups	O
+.	O
+	
+The	O
+trimethaphan	O
+-	O
+induced	O
+hypotension	B-NP
+was	O
+accompanied	O
+by	O
+a	O
+significant	O
+bradycardia	B-NP
+in	O
+lesioned	O
+rats	O
+(	O
+-	O
+32	O
++	O
+/	O
+-	O
+13	O
+beats	O
+per	O
+minute	O
+)	O
+but	O
+a	O
+tachycardia	B-NP
+in	O
+sham	O
+rats	O
+(	O
++	O
+33	O
++	O
+/	O
+-	O
+12	O
+beats	O
+per	O
+minute	O
+)	O
+1	O
+day	O
+postlesion	O
+.	O
+	
+Therefore	O
+","	O
+rostral	O
+ventrolateral	O
+medulla	O
+neurons	O
+appear	O
+to	O
+play	O
+a	O
+significant	O
+role	O
+in	O
+maintaining	O
+hypertension	B-NP
+in	O
+conscious	O
+spontaneously	O
+hypertensive	B-NP
+rats	O
+.	O
+	
+Spinal	O
+or	O
+suprabulbar	O
+structures	O
+could	O
+be	O
+responsible	O
+for	O
+the	O
+gradual	O
+recovery	O
+of	O
+the	O
+hypertension	B-NP
+in	O
+the	O
+lesioned	O
+rats	O
+.	O
+	
+Acute	B-NP
+encephalopathy	I-NP
+and	O
+cerebral	B-NP
+vasospasm	I-NP
+after	O
+multiagent	O
+chemotherapy	O
+including	O
+PEG	O
+-	O
+asparaginase	O
+and	O
+intrathecal	O
+cytarabine	O
+for	O
+the	O
+treatment	O
+of	O
+acute	B-NP
+lymphoblastic	I-NP
+leukemia	I-NP
+.	O
+	
+A	O
+7	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+with	O
+an	O
+unusual	O
+reaction	O
+to	O
+induction	O
+chemotherapy	O
+for	O
+precursor	O
+B	O
+-	O
+cell	O
+acute	B-NP
+lymphoblastic	I-NP
+leukemia	I-NP
+(	O
+ALL	B-NP
+)	O
+is	O
+described	O
+.	O
+	
+The	O
+patient	O
+developed	O
+acute	B-NP
+encephalopathy	I-NP
+evidenced	O
+by	O
+behavioral	O
+changes	O
+","	O
+aphasia	B-NP
+","	O
+incontinence	B-NP
+","	O
+visual	B-NP
+hallucinations	I-NP
+","	O
+and	O
+right	O
+-	O
+sided	O
+weakness	B-NP
+with	O
+diffuse	O
+cerebral	B-NP
+vasospasm	I-NP
+on	O
+magnetic	O
+resonance	O
+angiography	O
+after	O
+the	O
+administration	O
+of	O
+intrathecal	O
+cytarabine	O
+.	O
+	
+Vincristine	O
+","	O
+dexamethasone	O
+","	O
+and	O
+polyethylene	O
+glycol	O
+-	O
+asparaginase	O
+were	O
+also	O
+administered	O
+before	O
+the	O
+episode	O
+as	O
+part	O
+of	O
+induction	O
+therapy	O
+.	O
+	
+Neurologic	O
+status	O
+returned	O
+to	O
+baseline	O
+within	O
+10	O
+days	O
+of	O
+the	O
+acute	O
+event	O
+","	O
+and	O
+magnetic	O
+resonance	O
+angiography	O
+findings	O
+returned	O
+to	O
+normal	O
+4	O
+months	O
+later	O
+.	O
+	
+Comparison	O
+of	O
+valsartan	O
+/	O
+hydrochlorothiazide	O
+combination	O
+therapy	O
+at	O
+doses	O
+up	O
+to	O
+320	O
+/	O
+25	O
+mg	O
+versus	O
+monotherapy	O
+:	O
+a	O
+double	O
+-	O
+blind	O
+","	O
+placebo	O
+-	O
+controlled	O
+study	O
+followed	O
+by	O
+long	O
+-	O
+term	O
+combination	O
+therapy	O
+in	O
+hypertensive	B-NP
+adults	O
+.	O
+	
+BACKGROUND	O
+:	O
+One	O
+third	O
+of	O
+patients	O
+treated	O
+for	O
+hypertension	B-NP
+attain	O
+adequate	O
+blood	O
+pressure	O
+(	O
+BP	O
+)	O
+control	O
+","	O
+and	O
+multidrug	O
+regimens	O
+are	O
+often	O
+required	O
+.	O
+	
+Given	O
+the	O
+lifelong	O
+nature	O
+of	O
+hypertension	B-NP
+","	O
+there	O
+is	O
+a	O
+need	O
+to	O
+evaluate	O
+the	O
+long	O
+-	O
+term	O
+efficacy	O
+and	O
+tolerability	O
+of	O
+higher	O
+doses	O
+of	O
+combination	O
+anti	O
+-	O
+hypertensive	B-NP
+therapies	O
+.	O
+	
+OBJECTIVE	O
+:	O
+This	O
+study	O
+investigated	O
+the	O
+efficacy	O
+and	O
+tolerability	O
+of	O
+valsartan	O
+(	O
+VAL	O
+)	O
+or	O
+hydrochlorothiazide	O
+(	O
+HCTZ	O
+)	O
+-	O
+monotherapy	O
+and	O
+higher	O
+-	O
+dose	O
+combinations	O
+in	O
+patients	O
+with	O
+essential	B-NP
+hypertension	I-NP
+.	O
+	
+METHODS	O
+:	O
+The	O
+first	O
+part	O
+of	O
+this	O
+study	O
+was	O
+an	O
+8	O
+-	O
+week	O
+","	O
+multicenter	O
+","	O
+randomized	O
+","	O
+double	O
+-	O
+blind	O
+","	O
+placebo	O
+controlled	O
+","	O
+parallel	O
+-	O
+group	O
+trial	O
+.	O
+	
+Patients	O
+with	O
+essential	B-NP
+hypertension	I-NP
+(	O
+mean	O
+sitting	O
+diastolic	O
+BP	O
+[	O
+MSDBP	O
+]	O
+","	O
+>	O
+or	O
+=	O
+95	O
+mm	O
+Hg	O
+and	O
+<	O
+110	O
+mm	O
+Hg	O
+)	O
+were	O
+randomized	O
+to	O
+1	O
+of	O
+8	O
+treatment	O
+groups	O
+:	O
+VAL	O
+160	O
+or	O
+320	O
+mg	O
+;	O
+HCTZ	O
+12	O
+.	O
+5	O
+or	O
+25	O
+mg	O
+;	O
+VAL	O
+/	O
+HCTZ	O
+160	O
+/	O
+12	O
+.	O
+5	O
+","	O
+320	O
+/	O
+12	O
+.	O
+5	O
+","	O
+or	O
+320	O
+/	O
+25	O
+mg	O
+;	O
+or	O
+placebo	O
+.	O
+	
+Mean	O
+changes	O
+in	O
+MSDBP	O
+and	O
+mean	O
+sitting	O
+systolic	O
+BP	O
+(	O
+MSSBP	O
+)	O
+were	O
+analyzed	O
+at	O
+the	O
+8	O
+-	O
+week	O
+core	O
+study	O
+end	O
+point	O
+.	O
+	
+VAL	O
+/	O
+HCTZ	O
+320	O
+/	O
+12	O
+.	O
+5	O
+and	O
+320	O
+/	O
+25	O
+mg	O
+were	O
+further	O
+investigated	O
+in	O
+a	O
+54	O
+-	O
+week	O
+","	O
+open	O
+-	O
+label	O
+extension	O
+.	O
+	
+Response	O
+was	O
+defined	O
+as	O
+MSDBP	O
+<	O
+90	O
+mm	O
+Hg	O
+or	O
+a	O
+>	O
+or	O
+=	O
+10	O
+mm	O
+Hg	O
+decrease	O
+compared	O
+to	O
+baseline	O
+.	O
+	
+Control	O
+was	O
+defined	O
+as	O
+MSDBP	O
+<	O
+90	O
+mm	O
+Hg	O
+compared	O
+with	O
+baseline	O
+.	O
+	
+Tolerability	O
+was	O
+assessed	O
+by	O
+monitoring	O
+adverse	O
+events	O
+at	O
+randomization	O
+and	O
+all	O
+subsequent	O
+study	O
+visits	O
+and	O
+regular	O
+evaluation	O
+of	O
+hematology	O
+and	O
+blood	O
+chemistry	O
+.	O
+	
+RESULTS	O
+:	O
+A	O
+total	O
+of	O
+1346	O
+patients	O
+were	O
+randomized	O
+into	O
+the	O
+8	O
+-	O
+week	O
+core	O
+study	O
+(	O
+734	O
+men	O
+","	O
+612	O
+women	O
+;	O
+924	O
+white	O
+","	O
+291	O
+black	O
+","	O
+23	O
+Asian	O
+","	O
+108	O
+other	O
+;	O
+mean	O
+age	O
+","	O
+52	O
+.	O
+7	O
+years	O
+;	O
+mean	O
+weight	O
+","	O
+92	O
+.	O
+6	O
+kg	O
+)	O
+.	O
+	
+All	O
+active	O
+treatments	O
+were	O
+associated	O
+with	O
+significantly	O
+reduced	O
+MSSBP	O
+and	O
+MSDBP	O
+during	O
+the	O
+core	O
+8	O
+-	O
+week	O
+study	O
+","	O
+with	O
+each	O
+monotherapy	O
+significantly	O
+contributing	O
+to	O
+the	O
+overall	O
+effect	O
+of	O
+combination	O
+therapy	O
+(	O
+VAL	O
+and	O
+HCTZ	O
+","	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Each	O
+combination	O
+was	O
+associated	O
+with	O
+significantly	O
+greater	O
+reductions	O
+in	O
+MSSBP	O
+and	O
+MSDBP	O
+compared	O
+with	O
+the	O
+monotherapies	O
+and	O
+placebo	O
+(	O
+all	O
+","	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+The	O
+mean	O
+reduction	O
+in	O
+MSSBP	O
+/	O
+MSDBP	O
+with	O
+VAL	O
+/	O
+HCTZ	O
+320	O
+/	O
+25	O
+mg	O
+was	O
+24	O
+.	O
+7	O
+/	O
+16	O
+.	O
+6	O
+mm	O
+Hg	O
+","	O
+compared	O
+with	O
+5	O
+.	O
+9	O
+/	O
+7	O
+.	O
+0	O
+mm	O
+Hg	O
+with	O
+placebo	O
+.	O
+	
+The	O
+reduction	O
+in	O
+MSSBP	O
+was	O
+significantly	O
+greater	O
+with	O
+VAL	O
+/	O
+HCTZ	O
+320	O
+/	O
+25	O
+mg	O
+compared	O
+with	O
+VAL	O
+/	O
+HCTZ	O
+160	O
+/	O
+12	O
+.	O
+5	O
+mg	O
+(	O
+P	O
+<	O
+0	O
+.	O
+2	O
+)	O
+.	O
+	
+Rates	O
+of	O
+response	O
+and	O
+BP	O
+control	O
+were	O
+significantly	O
+higher	O
+in	O
+the	O
+groups	O
+that	O
+received	O
+combination	O
+treatment	O
+compared	O
+with	O
+those	O
+that	O
+received	O
+monotherapy	O
+.	O
+	
+The	O
+incidence	O
+of	O
+hypokalemia	B-NP
+was	O
+lower	O
+with	O
+VAL	O
+/	O
+HCTZ	O
+combinations	O
+(	O
+1	O
+.	O
+8	O
+%	O
+-	O
+6	O
+.	O
+1	O
+%	O
+)	O
+than	O
+with	O
+HCTZ	O
+monotherapies	O
+(	O
+7	O
+.	O
+1	O
+%	O
+-	O
+13	O
+.	O
+3	O
+%	O
+)	O
+.	O
+	
+The	O
+majority	O
+of	O
+adverse	O
+events	O
+in	O
+the	O
+core	O
+study	O
+were	O
+of	O
+mild	O
+to	O
+moderate	O
+severity	O
+.	O
+	
+The	O
+efficacy	O
+and	O
+tolerability	O
+of	O
+VAL	O
+/	O
+HCTZ	O
+combinations	O
+were	O
+maintained	O
+during	O
+the	O
+extension	O
+(	O
+797	O
+patients	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+In	O
+this	O
+study	O
+population	O
+","	O
+combination	O
+therapies	O
+with	O
+VAL	O
+/	O
+HCTZ	O
+were	O
+associated	O
+with	O
+significantly	O
+greater	O
+BP	O
+reductions	O
+compared	O
+with	O
+either	O
+monotherapy	O
+","	O
+were	O
+well	O
+tolerated	O
+","	O
+and	O
+were	O
+associated	O
+with	O
+less	O
+hypokalemia	B-NP
+than	O
+HCTZ	O
+alone	O
+.	O
+	
+Succimer	O
+chelation	O
+improves	O
+learning	O
+","	O
+attention	O
+","	O
+and	O
+arousal	O
+regulation	O
+in	O
+lead	O
+-	O
+exposed	O
+rats	O
+but	O
+produces	O
+lasting	O
+cognitive	B-NP
+impairment	I-NP
+in	O
+the	O
+absence	O
+of	O
+lead	O
+exposure	O
+.	O
+	
+BACKGROUND	O
+:	O
+There	O
+is	O
+growing	O
+pressure	O
+for	O
+clinicians	O
+to	O
+prescribe	O
+chelation	O
+therapy	O
+at	O
+only	O
+slightly	O
+elevated	O
+blood	O
+lead	O
+levels	O
+.	O
+	
+However	O
+","	O
+very	O
+few	O
+studies	O
+have	O
+evaluated	O
+whether	O
+chelation	O
+improves	O
+cognitive	O
+outcomes	O
+in	O
+Pb	O
+-	O
+exposed	O
+children	O
+","	O
+or	O
+whether	O
+these	O
+agents	O
+have	O
+adverse	O
+effects	O
+that	O
+may	O
+affect	O
+brain	O
+development	O
+in	O
+the	O
+absence	O
+of	O
+Pb	O
+exposure	O
+.	O
+	
+OBJECTIVES	O
+:	O
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+answer	O
+these	O
+questions	O
+","	O
+using	O
+a	O
+rodent	O
+model	O
+of	O
+early	O
+childhood	O
+Pb	O
+exposure	O
+and	O
+treatment	O
+with	O
+succimer	O
+","	O
+a	O
+widely	O
+used	O
+chelating	O
+agent	O
+for	O
+the	O
+treatment	O
+of	O
+Pb	B-NP
+poisoning	I-NP
+.	O
+	
+RESULTS	O
+:	O
+Pb	O
+exposure	O
+produced	O
+lasting	O
+impairments	B-NP
+in	I-NP
+learning	I-NP
+","	I-NP
+attention	I-NP
+","	I-NP
+inhibitory	I-NP
+control	I-NP
+","	I-NP
+and	I-NP
+arousal	I-NP
+regulation	I-NP
+","	O
+paralleling	O
+the	O
+areas	O
+of	O
+dysfunction	O
+seen	O
+in	O
+Pb	O
+-	O
+exposed	O
+children	O
+.	O
+	
+Succimer	O
+treatment	O
+of	O
+the	O
+Pb	O
+-	O
+exposed	O
+rats	O
+significantly	O
+improved	O
+learning	O
+","	O
+attention	O
+","	O
+and	O
+arousal	O
+regulation	O
+","	O
+although	O
+the	O
+efficacy	O
+of	O
+the	O
+treatment	O
+varied	O
+as	O
+a	O
+function	O
+of	O
+the	O
+Pb	O
+exposure	O
+level	O
+and	O
+the	O
+specific	O
+functional	O
+deficit	O
+.	O
+	
+In	O
+contrast	O
+","	O
+succimer	O
+treatment	O
+of	O
+rats	O
+not	O
+previously	O
+exposed	O
+to	O
+Pb	O
+produced	O
+lasting	O
+and	O
+pervasive	O
+cognitive	B-NP
+and	I-NP
+affective	I-NP
+dysfunction	I-NP
+comparable	O
+in	O
+magnitude	O
+to	O
+that	O
+produced	O
+by	O
+the	O
+higher	O
+Pb	O
+exposure	O
+regimen	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+These	O
+are	O
+the	O
+first	O
+data	O
+","	O
+to	O
+our	O
+knowledge	O
+","	O
+to	O
+show	O
+that	O
+treatment	O
+with	O
+any	O
+chelating	O
+agent	O
+can	O
+alleviate	O
+cognitive	B-NP
+deficits	I-NP
+due	O
+to	O
+Pb	O
+exposure	O
+.	O
+	
+These	O
+findings	O
+suggest	O
+that	O
+it	O
+may	O
+be	O
+possible	O
+to	O
+identify	O
+a	O
+succimer	O
+treatment	O
+protocol	O
+that	O
+improves	O
+cognitive	O
+outcomes	O
+in	O
+Pb	O
+-	O
+exposed	O
+children	O
+.	O
+	
+However	O
+","	O
+they	O
+also	O
+suggest	O
+that	O
+succimer	O
+treatment	O
+should	O
+be	O
+strongly	O
+discouraged	O
+for	O
+children	O
+who	O
+do	O
+not	O
+have	O
+elevated	O
+tissue	O
+levels	O
+of	O
+Pb	O
+or	O
+other	O
+heavy	O
+metals	O
+.	O
+	
+Caffeine	O
+challenge	O
+test	O
+in	O
+panic	B-NP
+disorder	I-NP
+and	O
+depression	B-NP
+with	O
+panic	B-NP
+attacks	I-NP
+.	O
+	
+Our	O
+aim	O
+was	O
+to	O
+observe	O
+if	O
+patients	O
+with	O
+panic	B-NP
+disorder	I-NP
+(	O
+PD	B-NP
+)	O
+and	O
+patients	O
+with	O
+major	B-NP
+depression	I-NP
+with	O
+panic	B-NP
+attacks	I-NP
+(	O
+MDP	B-NP
+)	O
+(	O
+Diagnostic	O
+and	O
+Statistical	O
+Manual	O
+of	O
+Mental	B-NP
+Disorders	I-NP
+","	O
+Fourth	O
+Edition	O
+criteria	O
+)	O
+respond	O
+in	O
+a	O
+similar	O
+way	O
+to	O
+the	O
+induction	O
+of	O
+panic	B-NP
+attacks	I-NP
+by	O
+an	O
+oral	O
+caffeine	O
+challenge	O
+test	O
+.	O
+	
+We	O
+randomly	O
+selected	O
+29	O
+patients	O
+with	O
+PD	B-NP
+","	O
+27	O
+with	O
+MDP	B-NP
+","	O
+25	O
+with	O
+major	B-NP
+depression	I-NP
+without	O
+panic	B-NP
+attacks	I-NP
+(	O
+MD	B-NP
+)	O
+","	O
+and	O
+28	O
+healthy	O
+volunteers	O
+.	O
+	
+The	O
+patients	O
+had	O
+no	O
+psychotropic	O
+drug	O
+for	O
+at	O
+least	O
+a	O
+4	O
+-	O
+week	O
+period	O
+.	O
+	
+In	O
+a	O
+randomized	O
+double	O
+-	O
+blind	O
+experiment	O
+performed	O
+in	O
+2	O
+occasions	O
+7	O
+days	O
+apart	O
+","	O
+480	O
+mg	O
+caffeine	O
+and	O
+a	O
+caffeine	O
+-	O
+free	O
+(	O
+placebo	O
+)	O
+solution	O
+were	O
+administered	O
+in	O
+a	O
+coffee	O
+form	O
+and	O
+anxiety	B-NP
+scales	O
+were	O
+applied	O
+before	O
+and	O
+after	O
+each	O
+test	O
+.	O
+	
+A	O
+total	O
+of	O
+58	O
+.	O
+6	O
+%	O
+(	O
+n	O
+=	O
+17	O
+)	O
+of	O
+patients	O
+with	O
+PD	B-NP
+","	O
+44	O
+.	O
+4	O
+%	O
+(	O
+n	O
+=	O
+12	O
+)	O
+of	O
+patients	O
+with	O
+MDP	B-NP
+","	O
+12	O
+.	O
+0	O
+%	O
+(	O
+n	O
+=	O
+3	O
+)	O
+of	O
+patients	O
+with	O
+MD	B-NP
+","	O
+and	O
+7	O
+.	O
+1	O
+%	O
+(	O
+n	O
+=	O
+2	O
+)	O
+of	O
+control	O
+subjects	O
+had	O
+a	O
+panic	B-NP
+attack	I-NP
+after	O
+the	O
+480	O
+-	O
+mg	O
+caffeine	O
+challenge	O
+test	O
+(	O
+chi	O
+(	O
+2	O
+)	O
+(	O
+3	O
+)	O
+=	O
+16	O
+.	O
+22	O
+","	O
+P	O
+=	O
+.	O
+1	O
+)	O
+.	O
+	
+The	O
+patients	O
+with	O
+PD	B-NP
+and	O
+MDP	B-NP
+were	O
+more	O
+sensitive	O
+to	O
+caffeine	O
+than	O
+were	O
+patients	O
+with	O
+MD	B-NP
+and	O
+healthy	O
+volunteers	O
+.	O
+	
+No	O
+panic	B-NP
+attack	I-NP
+was	O
+observed	O
+after	O
+the	O
+caffeine	O
+-	O
+free	O
+solution	O
+intake	O
+.	O
+	
+The	O
+patients	O
+with	O
+MD	B-NP
+had	O
+a	O
+lower	O
+heart	O
+rate	O
+response	O
+to	O
+the	O
+test	O
+than	O
+all	O
+the	O
+other	O
+groups	O
+(	O
+2	O
+-	O
+way	O
+analysis	O
+of	O
+variance	O
+","	O
+group	O
+by	O
+time	O
+interaction	O
+with	O
+Greenhouse	O
+-	O
+Geisser	O
+correction	O
+:	O
+F	O
+(	O
+3	O
+","	O
+762	O
+)	O
+=	O
+2	O
+.	O
+85	O
+","	O
+P	O
+=	O
+.	O
+26	O
+)	O
+.	O
+	
+Our	O
+data	O
+suggest	O
+that	O
+there	O
+is	O
+an	O
+association	O
+between	O
+panic	B-NP
+attacks	I-NP
+","	O
+no	O
+matter	O
+if	O
+associated	O
+with	O
+PD	B-NP
+or	O
+MDP	B-NP
+","	O
+and	O
+hyperreactivity	O
+to	O
+an	O
+oral	O
+caffeine	O
+challenge	O
+test	O
+.	O
+	
+Mitral	O
+annuloplasty	O
+as	O
+a	O
+ventricular	O
+restoration	O
+method	O
+for	O
+the	O
+failing	B-NP
+left	I-NP
+ventricle	I-NP
+:	O
+a	O
+pilot	O
+study	O
+.	O
+	
+BACKGROUND	O
+AND	O
+AIM	O
+OF	O
+THE	O
+STUDY	O
+:	O
+Undersized	O
+mitral	O
+annuloplasty	O
+(	O
+MAP	O
+)	O
+is	O
+effective	O
+in	O
+patients	O
+with	O
+dilated	B-NP
+cardiomyopathy	I-NP
+and	O
+functional	O
+mitral	B-NP
+regurgitation	I-NP
+(	O
+MR	B-NP
+)	O
+since	O
+","	O
+as	O
+well	O
+as	O
+addressing	O
+the	O
+MR	B-NP
+","	O
+the	O
+MAP	O
+may	O
+also	O
+reshape	O
+the	O
+dilated	O
+left	O
+ventricular	O
+(	O
+LV	O
+)	O
+base	O
+.	O
+	
+However	O
+","	O
+the	O
+direct	O
+benefits	O
+of	O
+this	O
+possible	O
+reshaping	O
+on	O
+LV	O
+function	O
+in	O
+the	O
+absence	O
+of	O
+underlying	O
+MR	B-NP
+remain	O
+incompletely	O
+understood	O
+.	O
+	
+The	O
+study	O
+aim	O
+was	O
+to	O
+identify	O
+these	O
+benefits	O
+in	O
+a	O
+canine	O
+model	O
+of	O
+acute	O
+heart	B-NP
+failure	I-NP
+.	O
+	
+METHODS	O
+:	O
+Six	O
+dogs	O
+underwent	O
+MAP	O
+with	O
+a	O
+prosthetic	O
+band	O
+on	O
+the	O
+posterior	O
+mitral	O
+annulus	O
+","	O
+using	O
+four	O
+mattress	O
+sutures	O
+.	O
+	
+The	O
+sutures	O
+were	O
+passed	O
+individually	O
+through	O
+four	O
+tourniquets	O
+and	O
+exteriorized	O
+untied	O
+via	O
+the	O
+left	O
+atriotomy	O
+.	O
+	
+Sonomicrometry	O
+crystals	O
+were	O
+implanted	O
+around	O
+the	O
+mitral	O
+annulus	O
+and	O
+left	O
+ventricle	O
+to	O
+measure	O
+geometry	O
+and	O
+regional	O
+function	O
+.	O
+	
+Acute	O
+heart	B-NP
+failure	I-NP
+was	O
+induced	O
+by	O
+propranolol	O
+and	O
+volume	O
+loading	O
+after	O
+weaning	O
+from	O
+cardiopulmonary	O
+bypass	O
+;	O
+an	O
+absence	O
+of	O
+MR	B-NP
+was	O
+confirmed	O
+by	O
+echocardiography	O
+.	O
+	
+MAP	O
+was	O
+accomplished	O
+by	O
+cinching	O
+the	O
+tourniquets	O
+.	O
+	
+Data	O
+were	O
+acquired	O
+at	O
+baseline	O
+","	O
+after	O
+induction	O
+of	O
+acute	O
+heart	B-NP
+failure	I-NP
+","	O
+and	O
+after	O
+MAP	O
+.	O
+	
+RESULTS	O
+:	O
+MAP	O
+decreased	O
+mitral	O
+annular	O
+dimensions	O
+in	O
+both	O
+commissure	O
+-	O
+commissure	O
+and	O
+septal	O
+-	O
+lateral	O
+directions	O
+.	O
+	
+Concomitantly	O
+","	O
+the	O
+diastolic	O
+diameter	O
+of	O
+the	O
+LV	O
+base	O
+and	O
+LV	O
+sphericity	O
+decreased	O
+(	O
+i	O
+.	O
+e	O
+.	O
+","	O
+improved	O
+)	O
+from	O
+37	O
+.	O
+4	O
++	O
+/	O
+-	O
+9	O
+.	O
+3	O
+to	O
+35	O
+.	O
+9	O
++	O
+/	O
+-	O
+10	O
+mm	O
+(	O
+p	O
+=	O
+0	O
+.	O
+63	O
+)	O
+","	O
+and	O
+from	O
+67	O
+.	O
+9	O
++	O
+/	O
+-	O
+18	O
+.	O
+6	O
+%	O
+to	O
+65	O
+.	O
+3	O
++	O
+/	O
+-	O
+18	O
+.	O
+9	O
+%	O
+(	O
+p	O
+=	O
+0	O
+.	O
+16	O
+)	O
+","	O
+respectively	O
+.	O
+	
+Decreases	O
+were	O
+evident	O
+in	O
+both	O
+LV	O
+end	O
+-	O
+diastolic	O
+pressure	O
+(	O
+from	O
+17	O
++	O
+/	O
+-	O
+7	O
+to	O
+15	O
++	O
+/	O
+-	O
+6	O
+mmHg	O
+","	O
+p	O
+=	O
+0	O
+.	O
+480	O
+and	O
+Tau	O
+(	O
+from	O
+48	O
++	O
+/	O
+-	O
+8	O
+to	O
+45	O
++	O
+/	O
+-	O
+8	O
+ms	O
+","	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+","	O
+while	O
+fractional	O
+shortening	O
+at	O
+the	O
+LV	O
+base	O
+increased	O
+from	O
+7	O
+.	O
+7	O
++	O
+/	O
+-	O
+4	O
+.	O
+5	O
+%	O
+to	O
+9	O
+.	O
+4	O
++	O
+/	O
+-	O
+4	O
+.	O
+5	O
+%	O
+(	O
+p	O
+=	O
+0	O
+.	O
+45	O
+)	O
+.	O
+	
+After	O
+MAP	O
+","	O
+increases	O
+were	O
+identified	O
+in	O
+both	O
+cardiac	O
+output	O
+(	O
+from	O
+1	O
+.	O
+54	O
++	O
+/	O
+-	O
+0	O
+.	O
+57	O
+to	O
+1	O
+.	O
+65	O
++	O
+/	O
+-	O
+0	O
+.	O
+57	O
+1	O
+/	O
+min	O
+)	O
+and	O
+Emax	O
+(	O
+from	O
+1	O
+.	O
+86	O
++	O
+/	O
+-	O
+0	O
+.	O
+9	O
+to	O
+2	O
+.	O
+41	O
++	O
+/	O
+-	O
+1	O
+.	O
+31	O
+mmHg	O
+/	O
+ml	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+The	O
+data	O
+acquired	O
+suggest	O
+that	O
+isolated	O
+MAP	O
+may	O
+have	O
+certain	O
+benefits	O
+on	O
+LV	O
+dimension	O
+/	O
+function	O
+in	O
+acute	O
+heart	B-NP
+failure	I-NP
+","	O
+even	O
+in	O
+the	O
+absence	O
+of	O
+MR	B-NP
+.	O
+	
+However	O
+","	O
+further	O
+investigations	O
+are	O
+warranted	O
+in	O
+a	O
+model	O
+of	O
+chronic	O
+heart	B-NP
+failure	I-NP
+.	O
+	
+Piperacillin	O
+/	O
+tazobactam	O
+-	O
+induced	O
+seizure	B-NP
+rapidly	O
+reversed	O
+by	O
+high	O
+flux	O
+hemodialysis	O
+in	O
+a	O
+patient	O
+on	O
+peritoneal	O
+dialysis	O
+.	O
+	
+Despite	O
+popular	O
+use	O
+of	O
+piperacillin	O
+","	O
+the	O
+dire	O
+neurotoxicity	B-NP
+associated	O
+with	O
+piperacillin	O
+still	O
+goes	O
+unrecognized	O
+","	O
+leading	O
+to	O
+a	O
+delay	O
+in	O
+appropriate	O
+management	O
+.	O
+	
+We	O
+report	O
+a	O
+57	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+end	B-NP
+-	I-NP
+stage	I-NP
+renal	I-NP
+disease	I-NP
+receiving	O
+continuous	O
+ambulatory	O
+peritoneal	O
+dialysis	O
+(	O
+CAPD	O
+)	O
+","	O
+who	O
+developed	O
+slurred	O
+speech	O
+","	O
+tremor	B-NP
+","	O
+bizarre	O
+behavior	O
+","	O
+progressive	O
+mental	O
+confusion	B-NP
+","	O
+and	O
+2	O
+episodes	O
+of	O
+generalized	O
+tonic	B-NP
+-	I-NP
+clonic	I-NP
+seizure	I-NP
+(	O
+GTCS	B-NP
+)	O
+after	O
+5	O
+doses	O
+of	O
+piperacillin	O
+/	O
+tazobactam	O
+(	O
+2	O
+g	O
+/	O
+250	O
+mg	O
+)	O
+were	O
+given	O
+for	O
+bronchiectasis	B-NP
+with	O
+secondary	B-NP
+infection	I-NP
+.	O
+	
+The	O
+laboratory	O
+data	O
+revealed	O
+normal	O
+plasma	O
+electrolyte	O
+and	O
+ammonia	O
+levels	O
+but	O
+leukocytosis	B-NP
+.	O
+	
+Neurologic	O
+examinations	O
+showed	O
+dysarthria	B-NP
+and	O
+bilateral	O
+Babinski	O
+sign	O
+.	O
+	
+Computed	O
+tomography	O
+of	O
+brain	O
+and	O
+electroencephalogram	O
+were	O
+unremarkable	O
+.	O
+	
+Despite	O
+the	O
+use	O
+of	O
+antiepileptic	O
+agents	O
+","	O
+another	O
+GTCS	B-NP
+episode	O
+recurred	O
+after	O
+the	O
+sixth	O
+dose	O
+of	O
+piperacillin	O
+/	O
+tazobactam	O
+.	O
+	
+Brain	O
+magnetic	O
+resonance	O
+imaging	O
+did	O
+not	O
+demonstrate	O
+acute	O
+infarction	B-NP
+and	O
+organic	B-NP
+brain	I-NP
+lesions	I-NP
+.	O
+	
+Initiation	O
+of	O
+high	O
+-	O
+flux	O
+hemodialysis	O
+rapidly	O
+reversed	O
+the	O
+neurologic	O
+symptoms	O
+within	O
+4	O
+hours	O
+.	O
+	
+Piperacillin	O
+-	O
+induced	O
+encephalopathy	B-NP
+should	O
+be	O
+considered	O
+in	O
+any	O
+uremic	B-NP
+patients	O
+with	O
+unexplained	O
+neurological	O
+manifestations	O
+.	O
+	
+CAPD	O
+is	O
+inefficient	O
+in	O
+removing	O
+piperacillin	O
+","	O
+whereas	O
+hemodialysis	O
+can	O
+rapidly	O
+terminate	O
+the	O
+piperacillin	O
+-	O
+induced	O
+encephalopathy	B-NP
+.	O
+	
+Frequency	O
+of	O
+transient	O
+ipsilateral	O
+vocal	B-NP
+cord	I-NP
+paralysis	I-NP
+in	O
+patients	O
+undergoing	O
+carotid	O
+endarterectomy	O
+under	O
+local	O
+anesthesia	O
+.	O
+	
+BACKGROUND	O
+:	O
+Especially	O
+because	O
+of	O
+improvements	O
+in	O
+clinical	O
+neurologic	O
+monitoring	O
+","	O
+carotid	O
+endarterectomy	O
+done	O
+under	O
+local	O
+anesthesia	O
+has	O
+become	O
+the	O
+technique	O
+of	O
+choice	O
+in	O
+several	O
+centers	O
+.	O
+	
+Temporary	O
+ipsilateral	O
+vocal	B-NP
+nerve	I-NP
+palsies	I-NP
+due	O
+to	O
+local	O
+anesthetics	O
+have	O
+been	O
+described	O
+","	O
+however	O
+.	O
+	
+Such	O
+complications	O
+are	O
+most	O
+important	O
+in	O
+situations	O
+where	O
+there	O
+is	O
+a	O
+pre	O
+-	O
+existing	O
+contralateral	O
+paralysis	B-NP
+.	O
+	
+We	O
+therefore	O
+examined	O
+the	O
+effect	O
+of	O
+local	O
+anesthesia	O
+on	O
+vocal	O
+cord	O
+function	O
+to	O
+better	O
+understand	O
+its	O
+possible	O
+consequences	O
+.	O
+	
+METHODS	O
+:	O
+This	O
+prospective	O
+study	O
+included	O
+28	O
+patients	O
+undergoing	O
+carotid	O
+endarterectomy	O
+under	O
+local	O
+anesthesia	O
+.	O
+	
+Vocal	O
+cord	O
+function	O
+was	O
+evaluated	O
+before	O
+","	O
+during	O
+","	O
+and	O
+after	O
+surgery	O
+(	O
+postoperative	O
+day	O
+1	O
+)	O
+using	O
+flexible	O
+laryngoscopy	O
+.	O
+	
+Anesthesia	O
+was	O
+performed	O
+by	O
+injecting	O
+20	O
+to	O
+40	O
+mL	O
+of	O
+a	O
+mixture	O
+of	O
+long	O
+-	O
+acting	O
+(	O
+ropivacaine	O
+)	O
+and	O
+short	O
+-	O
+acting	O
+(	O
+prilocaine	O
+)	O
+anesthetic	O
+.	O
+	
+RESULTS	O
+:	O
+All	O
+patients	O
+had	O
+normal	O
+vocal	O
+cord	O
+function	O
+preoperatively	O
+.	O
+	
+Twelve	O
+patients	O
+(	O
+43	O
+%	O
+)	O
+were	O
+found	O
+to	O
+have	O
+intraoperative	O
+ipsilateral	O
+vocal	B-NP
+cord	I-NP
+paralysis	I-NP
+.	O
+	
+It	O
+resolved	O
+in	O
+all	O
+cases	O
+<	O
+or	O
+=	O
+24	O
+hours	O
+.	O
+	
+There	O
+were	O
+no	O
+significant	O
+differences	O
+in	O
+operating	O
+time	O
+or	O
+volume	O
+or	O
+frequency	O
+of	O
+anesthetic	O
+administration	O
+in	O
+patients	O
+with	O
+temporary	O
+vocal	B-NP
+cord	I-NP
+paralysis	I-NP
+compared	O
+with	O
+those	O
+without	O
+.	O
+	
+CONCLUSION	O
+:	O
+Local	O
+anesthesia	O
+led	O
+to	O
+temporary	O
+ipsilateral	O
+vocal	B-NP
+cord	I-NP
+paralysis	I-NP
+in	O
+almost	O
+half	O
+of	O
+these	O
+patients	O
+.	O
+	
+Because	O
+pre	O
+-	O
+existing	O
+paralysis	B-NP
+is	O
+of	O
+a	O
+relevant	O
+frequency	O
+(	O
+up	O
+to	O
+3	O
+%	O
+)	O
+","	O
+a	O
+preoperative	O
+evaluation	O
+of	O
+vocal	O
+cord	O
+function	O
+before	O
+carotid	O
+endarterectomy	O
+under	O
+local	O
+anesthesia	O
+is	O
+recommended	O
+to	O
+avoid	O
+intraoperative	O
+bilateral	O
+paralysis	B-NP
+.	O
+	
+In	O
+patients	O
+with	O
+preoperative	O
+contralateral	O
+vocal	B-NP
+cord	I-NP
+paralysis	I-NP
+","	O
+surgery	O
+under	O
+general	O
+anesthesia	O
+should	O
+be	O
+considered	O
+.	O
+	
+Impaired	B-NP
+fear	I-NP
+recognition	I-NP
+in	O
+regular	O
+recreational	O
+cocaine	O
+users	O
+.	O
+	
+INTRODUCTION	O
+:	O
+The	O
+ability	O
+to	O
+read	O
+facial	O
+expressions	O
+is	O
+essential	O
+for	O
+normal	O
+human	O
+social	O
+interaction	O
+.	O
+	
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+conduct	O
+the	O
+first	O
+investigation	O
+of	O
+facial	O
+expression	O
+recognition	O
+performance	O
+in	O
+recreational	O
+cocaine	O
+users	O
+.	O
+	
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+Three	O
+groups	O
+","	O
+comprised	O
+of	O
+21	O
+cocaine	O
+naive	O
+participants	O
+(	O
+CN	O
+)	O
+","	O
+30	O
+occasional	O
+cocaine	O
+(	O
+OC	O
+)	O
+","	O
+and	O
+48	O
+regular	O
+recreational	O
+cocaine	O
+(	O
+RC	O
+)	O
+users	O
+","	O
+were	O
+compared	O
+.	O
+	
+An	O
+emotional	O
+facial	O
+expression	O
+(	O
+EFE	O
+)	O
+task	O
+consisting	O
+of	O
+a	O
+male	O
+and	O
+female	O
+face	O
+expressing	O
+six	O
+basic	O
+emotions	O
+(	O
+happiness	O
+","	O
+surprise	O
+","	O
+sadness	O
+","	O
+anger	O
+","	O
+fear	O
+","	O
+and	O
+disgust	O
+)	O
+was	O
+administered	O
+.	O
+	
+Mean	O
+percent	O
+accuracy	O
+and	O
+latencies	O
+for	O
+correct	O
+responses	O
+across	O
+eight	O
+presentations	O
+of	O
+each	O
+basic	O
+emotion	O
+were	O
+derived	O
+.	O
+	
+Participants	O
+were	O
+also	O
+assessed	O
+with	O
+the	O
+"	O
+Eyes	O
+task	O
+"	O
+to	O
+investigate	O
+their	O
+ability	O
+to	O
+recognize	O
+more	O
+complex	O
+emotional	O
+states	O
+and	O
+the	O
+Symptom	O
+CheckList	O
+-	O
+90	O
+-	O
+Revised	O
+to	O
+measure	O
+psychopathology	O
+.	O
+	
+RESULTS	O
+:	O
+There	O
+were	O
+no	O
+group	O
+differences	O
+in	O
+psychopathology	O
+or	O
+"	O
+eyes	O
+task	O
+"	O
+performance	O
+","	O
+but	O
+the	O
+RC	O
+group	O
+","	O
+who	O
+otherwise	O
+had	O
+similar	O
+illicit	O
+substance	O
+use	O
+histories	O
+to	O
+the	O
+OC	O
+group	O
+","	O
+exhibited	O
+impaired	B-NP
+fear	I-NP
+recognition	I-NP
+accuracy	O
+compared	O
+to	O
+the	O
+OC	O
+and	O
+CN	O
+groups	O
+.	O
+	
+The	O
+RC	O
+group	O
+also	O
+correctly	O
+identified	O
+anger	O
+","	O
+fear	O
+","	O
+happiness	O
+","	O
+and	O
+surprise	O
+","	O
+more	O
+slowly	O
+than	O
+CN	O
+","	O
+but	O
+not	O
+OC	O
+participants	O
+.	O
+	
+The	O
+OC	O
+group	O
+was	O
+slower	O
+than	O
+CN	O
+when	O
+correctly	O
+identifying	O
+disgust	O
+.	O
+	
+The	O
+selective	O
+deficit	B-NP
+in	I-NP
+fear	I-NP
+recognition	I-NP
+accuracy	O
+manifested	O
+by	O
+the	O
+RC	O
+group	O
+cannot	O
+be	O
+explained	O
+by	O
+the	O
+subacute	O
+effects	O
+of	O
+cocaine	O
+","	O
+or	O
+ecstasy	O
+","	O
+because	O
+recent	O
+and	O
+less	O
+recent	O
+users	O
+of	O
+these	O
+drugs	O
+within	O
+this	O
+group	O
+were	O
+similarly	O
+impaired	O
+.	O
+	
+Possible	O
+parallels	O
+between	O
+RC	O
+users	O
+and	O
+psychopaths	B-NP
+with	O
+respect	O
+to	O
+impaired	B-NP
+fear	I-NP
+recognition	I-NP
+","	O
+amygdala	B-NP
+dysfunction	I-NP
+","	O
+and	O
+etiology	O
+are	O
+discussed	O
+.	O
+	
+Damage	B-NP
+of	I-NP
+substantia	I-NP
+nigra	I-NP
+pars	I-NP
+reticulata	I-NP
+during	O
+pilocarpine	O
+-	O
+induced	O
+status	B-NP
+epilepticus	I-NP
+in	O
+the	O
+rat	O
+:	O
+immunohistochemical	O
+study	O
+of	O
+neurons	O
+","	O
+astrocytes	O
+and	O
+serum	O
+-	O
+protein	O
+extravasation	O
+.	O
+	
+The	O
+substantia	O
+nigra	O
+has	O
+a	O
+gating	O
+function	O
+controlling	O
+the	O
+spread	O
+of	O
+epileptic	B-NP
+seizure	I-NP
+activity	O
+.	O
+	
+Additionally	O
+","	O
+in	O
+models	O
+of	O
+prolonged	B-NP
+status	I-NP
+epilepticus	I-NP
+the	O
+pars	O
+reticulata	O
+of	O
+substantia	O
+nigra	O
+(	O
+SNR	O
+)	O
+suffers	O
+from	O
+a	O
+massive	O
+lesion	O
+which	O
+may	O
+arise	O
+from	O
+a	O
+massive	O
+metabolic	B-NP
+derangement	I-NP
+and	O
+hyperexcitation	O
+developing	O
+in	O
+the	O
+activated	O
+SNR	O
+.	O
+	
+In	O
+this	O
+study	O
+","	O
+status	B-NP
+epilepticus	I-NP
+was	O
+induced	O
+by	O
+systemic	O
+injection	O
+of	O
+pilocarpine	O
+in	O
+rats	O
+.	O
+	
+The	O
+neuropathology	O
+of	O
+SNR	O
+was	O
+investigated	O
+using	O
+immunohistochemical	O
+techniques	O
+with	O
+the	O
+major	O
+emphasis	O
+on	O
+the	O
+time	O
+-	O
+course	O
+of	O
+changes	O
+in	O
+neurons	O
+and	O
+astrocytes	O
+.	O
+	
+Animals	O
+surviving	O
+20	O
+","	O
+30	O
+","	O
+40	O
+","	O
+60	O
+min	O
+","	O
+2	O
+","	O
+3	O
+","	O
+6	O
+hours	O
+","	O
+1	O
+","	O
+2	O
+","	O
+and	O
+3	O
+days	O
+after	O
+induction	O
+of	O
+status	B-NP
+epilepticus	I-NP
+were	O
+perfusion	O
+-	O
+fixed	O
+","	O
+and	O
+brains	O
+processed	O
+for	O
+immunohistochemical	O
+staining	O
+of	O
+SNR	O
+.	O
+	
+Nissl	O
+-	O
+staining	O
+and	O
+antibodies	O
+against	O
+the	O
+neuron	O
+-	O
+specific	O
+calcium	O
+-	O
+binding	O
+protein	O
+","	O
+parvalbumin	O
+","	O
+served	O
+to	O
+detect	O
+neuronal	B-NP
+damage	I-NP
+in	O
+SNR	O
+.	O
+	
+Antibodies	O
+against	O
+the	O
+astroglia	O
+-	O
+specific	O
+cytoskeletal	O
+protein	O
+","	O
+glial	O
+fibrillary	O
+acidic	O
+protein	O
+(	O
+GFAP	O
+)	O
+","	O
+and	O
+against	O
+the	O
+glial	O
+calcium	O
+-	O
+binding	O
+protein	O
+","	O
+S	O
+-	O
+100	O
+protein	O
+","	O
+were	O
+used	O
+to	O
+assess	O
+the	O
+status	O
+of	O
+astrocytes	O
+.	O
+	
+Immunohistochemical	O
+staining	O
+for	O
+serum	O
+-	O
+albumin	O
+and	O
+immunoglobulins	O
+in	O
+brain	O
+tissue	O
+was	O
+taken	O
+as	O
+indicator	O
+of	O
+blood	O
+-	O
+brain	O
+barrier	O
+disturbances	O
+and	O
+vasogenic	B-NP
+edema	I-NP
+formation	O
+.	O
+	
+Immunohistochemical	O
+staining	O
+indicated	O
+loss	O
+of	O
+GFAP	O
+-	O
+staining	O
+already	O
+at	O
+30	O
+min	O
+after	O
+induction	O
+of	O
+seizures	B-NP
+in	O
+an	O
+oval	O
+focus	O
+situated	O
+in	O
+the	O
+center	O
+of	O
+SNR	O
+while	O
+sparing	O
+medial	O
+and	O
+lateral	O
+aspects	O
+.	O
+	
+At	O
+1	O
+h	O
+there	O
+was	O
+additional	O
+vacuolation	O
+in	O
+S	O
+-	O
+100	O
+protein	O
+staining	O
+.	O
+	
+By	O
+2	O
+hours	O
+","	O
+parvalbumin	O
+-	O
+staining	O
+changed	O
+in	O
+the	O
+central	O
+SNR	O
+indicating	O
+neuronal	B-NP
+damage	I-NP
+","	O
+and	O
+Nissl	O
+-	O
+staining	O
+visualized	O
+some	O
+neuronal	O
+distortion	O
+.	O
+	
+Staining	O
+for	O
+serum	O
+-	O
+proteins	O
+occurred	O
+in	O
+a	O
+patchy	O
+manner	O
+throughout	O
+the	O
+forebrain	O
+during	O
+the	O
+first	O
+hours	O
+.	O
+	
+By	O
+6	O
+h	O
+","	O
+vasogenic	B-NP
+edema	I-NP
+covered	O
+the	O
+lesioned	B-NP
+SNR	I-NP
+.	O
+	
+By	O
+24	O
+h	O
+","	O
+glial	O
+and	O
+neuronal	O
+markers	O
+indicated	O
+a	O
+massive	O
+lesion	O
+in	O
+the	O
+center	O
+of	O
+SNR	O
+.	O
+	
+By	O
+48	O
+-	O
+72	O
+h	O
+","	O
+astrocytes	O
+surrounding	O
+the	O
+lesion	O
+increased	O
+in	O
+size	O
+","	O
+and	O
+polymorphic	O
+phagocytotic	O
+cells	O
+invaded	O
+the	O
+damaged	O
+area	O
+.	O
+	
+In	O
+a	O
+further	O
+group	O
+of	O
+animals	O
+surviving	O
+1	O
+to	O
+5	O
+days	O
+","	O
+conventional	O
+paraffin	O
+-	O
+sections	O
+confirmed	O
+the	O
+neuronal	O
+and	O
+glial	O
+damage	B-NP
+of	I-NP
+SNR	I-NP
+.	O
+	
+Additional	O
+pathology	O
+of	O
+similar	O
+quality	O
+was	O
+found	O
+in	O
+the	O
+globus	O
+pallidus	O
+.	O
+	
+Since	O
+astrocytes	O
+were	O
+always	O
+damaged	O
+in	O
+parallel	O
+with	O
+neurons	O
+in	O
+SNR	O
+it	O
+is	O
+proposed	O
+that	O
+the	O
+anatomical	O
+and	O
+functional	O
+interrelationship	O
+between	O
+neurons	O
+and	O
+astrocytes	O
+is	O
+particularly	O
+tight	O
+in	O
+SNR	O
+.	O
+	
+Both	O
+cell	O
+elements	O
+may	O
+suffer	O
+in	O
+common	O
+from	O
+metabolic	O
+disturbance	O
+and	O
+neurotransmitter	B-NP
+dysfunction	I-NP
+as	O
+occur	O
+during	O
+massive	O
+status	B-NP
+epilepticus	I-NP
+.	O
+	
+Neuroprotective	O
+effects	O
+of	O
+melatonin	O
+upon	O
+the	O
+offspring	O
+cerebellar	O
+cortex	O
+in	O
+the	O
+rat	O
+model	O
+of	O
+BCNU	O
+-	O
+induced	O
+cortical	B-NP
+dysplasia	I-NP
+.	O
+	
+Cortical	B-NP
+dysplasia	I-NP
+is	O
+a	O
+malformation	O
+characterized	O
+by	O
+defects	O
+in	O
+proliferation	O
+","	O
+migration	O
+and	O
+maturation	O
+.	O
+	
+This	O
+study	O
+was	O
+designed	O
+to	O
+evaluate	O
+the	O
+alterations	O
+in	O
+offspring	O
+rat	O
+cerebellum	O
+induced	O
+by	O
+maternal	O
+exposure	O
+to	O
+carmustine	O
+-	O
+[	O
+1	O
+","	O
+3	O
+-	O
+bis	O
+(	O
+2	O
+-	O
+chloroethyl	O
+)	O
+-	O
+1	O
+-	O
+nitrosoure	O
+]	O
+(	O
+BCNU	O
+)	O
+and	O
+to	O
+investigate	O
+the	O
+effects	O
+of	O
+exogenous	O
+melatonin	O
+upon	O
+cerebellar	O
+BCNU	O
+-	O
+induced	O
+cortical	B-NP
+dysplasia	I-NP
+","	O
+using	O
+histological	O
+and	O
+biochemical	O
+analyses	O
+.	O
+	
+Pregnant	O
+Wistar	O
+rats	O
+were	O
+assigned	O
+to	O
+five	O
+groups	O
+:	O
+intact	O
+-	O
+control	O
+","	O
+saline	O
+-	O
+control	O
+","	O
+melatonin	O
+-	O
+treated	O
+","	O
+BCNU	O
+-	O
+exposed	O
+and	O
+BCNU	O
+-	O
+exposed	O
+plus	O
+melatonin	O
+.	O
+	
+Rats	O
+were	O
+exposed	O
+to	O
+BCNU	O
+on	O
+embryonic	O
+day	O
+15	O
+and	O
+melatonin	O
+was	O
+given	O
+until	O
+delivery	O
+.	O
+	
+Immuno	O
+/	O
+histochemistry	O
+and	O
+electron	O
+microscopy	O
+were	O
+carried	O
+out	O
+on	O
+the	O
+offspring	O
+cerebellum	O
+","	O
+and	O
+levels	O
+of	O
+malondialdehyde	O
+and	O
+superoxide	O
+dismutase	O
+were	O
+determined	O
+.	O
+	
+Histopathologically	O
+","	O
+typical	O
+findings	O
+were	O
+observed	O
+in	O
+the	O
+cerebella	O
+from	O
+the	O
+control	O
+groups	O
+","	O
+but	O
+the	O
+findings	O
+consistent	O
+with	O
+early	O
+embryonic	O
+development	O
+were	O
+noted	O
+in	O
+BCNU	O
+-	O
+exposed	O
+cortical	B-NP
+dysplasia	I-NP
+group	O
+.	O
+	
+There	O
+was	O
+a	O
+marked	O
+increase	O
+in	O
+the	O
+number	O
+of	O
+TUNEL	O
+positive	O
+cells	O
+and	O
+nestin	O
+positive	O
+cells	O
+in	O
+BCNU	O
+-	O
+exposed	O
+group	O
+","	O
+but	O
+a	O
+decreased	O
+immunoreactivity	O
+to	O
+glial	O
+fibrillary	O
+acidic	O
+protein	O
+","	O
+synaptophysin	O
+and	O
+transforming	O
+growth	O
+factor	O
+beta1	O
+was	O
+observed	O
+","	O
+indicating	O
+a	O
+delayed	O
+maturation	O
+","	O
+and	O
+melatonin	O
+significantly	O
+reversed	O
+these	O
+changes	O
+.	O
+	
+Malondialdehyde	O
+level	O
+in	O
+BCNU	O
+-	O
+exposed	O
+group	O
+was	O
+higher	O
+than	O
+those	O
+in	O
+control	O
+groups	O
+and	O
+melatonin	O
+decreased	O
+malondialdehyde	O
+levels	O
+in	O
+BCNU	O
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+","	O
+while	O
+there	O
+were	O
+no	O
+significant	O
+differences	O
+in	O
+the	O
+superoxide	O
+dismutase	O
+levels	O
+between	O
+these	O
+groups	O
+.	O
+	
+These	O
+data	O
+suggest	O
+that	O
+exposure	O
+of	O
+animals	O
+to	O
+BCNU	O
+during	O
+pregnancy	O
+leads	O
+to	O
+delayed	O
+maturation	O
+of	O
+offspring	O
+cerebellum	O
+and	O
+melatonin	O
+protects	O
+the	O
+cerebellum	O
+against	O
+the	O
+effects	O
+of	O
+BCNU	O
+.	O
+	
+Reduced	O
+cardiotoxicity	B-NP
+of	O
+doxorubicin	O
+given	O
+in	O
+the	O
+form	O
+of	O
+N	O
+-	O
+(	O
+2	O
+-	O
+hydroxypropyl	O
+)	O
+methacrylamide	O
+conjugates	O
+:	O
+and	O
+experimental	O
+study	O
+in	O
+the	O
+rat	O
+.	O
+	
+A	O
+rat	O
+model	O
+was	O
+used	O
+to	O
+evaluate	O
+the	O
+general	O
+acute	O
+toxicity	B-NP
+and	O
+the	O
+late	O
+cardiotoxicity	B-NP
+of	O
+4	O
+mg	O
+/	O
+kg	O
+doxorubicin	O
+(	O
+DOX	O
+)	O
+given	O
+either	O
+as	O
+free	O
+drug	O
+or	O
+in	O
+the	O
+form	O
+of	O
+three	O
+N	O
+-	O
+(	O
+2	O
+-	O
+hydroxypropyl	O
+)	O
+methacrylamide	O
+(	O
+HPMA	O
+)	O
+copolymer	O
+conjugates	O
+.	O
+	
+In	O
+these	O
+HPMA	O
+copolymers	O
+","	O
+DOX	O
+was	O
+covalently	O
+bound	O
+via	O
+peptide	O
+linkages	O
+that	O
+were	O
+either	O
+non	O
+-	O
+biodegradable	O
+(	O
+Gly	O
+-	O
+Gly	O
+)	O
+or	O
+degradable	O
+by	O
+lysosomal	O
+proteinases	O
+(	O
+Gly	O
+-	O
+Phe	O
+-	O
+Leu	O
+-	O
+Gly	O
+)	O
+.	O
+	
+In	O
+addition	O
+","	O
+one	O
+biodegradable	O
+conjugate	O
+containing	O
+galactosamine	O
+was	O
+used	O
+;	O
+this	O
+residue	O
+was	O
+targeted	O
+to	O
+the	O
+liver	O
+.	O
+	
+Over	O
+the	O
+first	O
+3	O
+weeks	O
+after	O
+the	O
+i	O
+.	O
+v	O
+.	O
+administration	O
+of	O
+free	O
+and	O
+polymer	O
+-	O
+bound	O
+DOX	O
+","	O
+all	O
+animals	O
+showed	O
+a	O
+transient	O
+reduction	O
+in	O
+body	O
+weight	O
+.	O
+	
+However	O
+","	O
+the	O
+maximal	O
+reduction	O
+in	O
+body	O
+weight	O
+seen	O
+in	O
+animals	O
+that	O
+received	O
+polymer	O
+-	O
+bound	O
+DOX	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+significantly	O
+lower	O
+than	O
+that	O
+observed	O
+in	O
+those	O
+that	O
+received	O
+free	O
+DOX	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+)	O
+or	O
+a	O
+mixture	O
+of	O
+the	O
+unmodified	O
+parent	O
+HPMA	O
+copolymer	O
+and	O
+free	O
+DOX	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+;	O
+P	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Throughout	O
+the	O
+study	O
+(	O
+20	O
+weeks	O
+)	O
+","	O
+deaths	O
+related	O
+to	O
+cardiotoxicity	B-NP
+were	O
+observed	O
+only	O
+in	O
+animals	O
+that	O
+received	O
+either	O
+free	O
+DOX	O
+or	O
+the	O
+mixture	O
+of	O
+HPMA	O
+copolymer	O
+and	O
+free	O
+DOX	O
+;	O
+in	O
+these	O
+cases	O
+","	O
+histological	O
+investigations	O
+revealed	O
+marked	O
+changes	O
+in	O
+the	O
+heart	O
+that	O
+were	O
+consistent	O
+with	O
+DOX	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+.	O
+	
+Sequential	O
+measurements	O
+of	O
+cardiac	O
+output	O
+in	O
+surviving	O
+animals	O
+that	O
+received	O
+either	O
+free	O
+DOX	O
+or	O
+the	O
+mixture	O
+of	O
+HPMA	O
+copolymer	O
+and	O
+free	O
+DOX	O
+showed	O
+a	O
+reduction	O
+of	O
+approximately	O
+30	O
+%	O
+in	O
+function	O
+beginning	O
+at	O
+the	O
+4th	O
+week	O
+after	O
+drug	O
+administration	O
+.	O
+	
+The	O
+heart	O
+rate	O
+in	O
+these	O
+animals	O
+was	O
+approximately	O
+12	O
+%	O
+lower	O
+than	O
+that	O
+measured	O
+in	O
+age	O
+-	O
+matched	O
+control	O
+rats	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+Animals	O
+that	O
+were	O
+given	O
+the	O
+HPMA	O
+copolymer	O
+conjugates	O
+containing	O
+DOX	O
+exhibited	O
+no	O
+significant	O
+change	O
+in	O
+cardiac	O
+output	O
+throughout	O
+the	O
+study	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+In	O
+addition	O
+","	O
+no	O
+significant	O
+histological	O
+change	O
+was	O
+observed	O
+in	O
+the	O
+heart	O
+of	O
+animals	O
+that	O
+received	O
+DOX	O
+in	O
+the	O
+form	O
+of	O
+HPMA	O
+copolymer	O
+conjugates	O
+and	O
+were	O
+killed	O
+at	O
+the	O
+end	O
+of	O
+the	O
+study	O
+.	O
+	
+However	O
+","	O
+these	O
+animals	O
+had	O
+shown	O
+a	O
+significant	O
+increase	O
+in	O
+heart	O
+rate	O
+beginning	O
+at	O
+8	O
+weeks	O
+after	O
+drug	O
+administration	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+400	O
+WORDS	O
+)	O
+	
+Corneal	B-NP
+ulcers	I-NP
+associated	O
+with	O
+aerosolized	O
+crack	O
+cocaine	O
+use	O
+.	O
+	
+PURPOSE	O
+:	O
+We	O
+report	O
+4	O
+cases	O
+of	O
+corneal	B-NP
+ulcers	I-NP
+associated	O
+with	O
+drug	B-NP
+abuse	I-NP
+.	O
+	
+The	O
+pathogenesis	O
+of	O
+these	O
+ulcers	B-NP
+and	O
+management	O
+of	O
+these	O
+patients	O
+are	O
+also	O
+reviewed	O
+.	O
+	
+METHODS	O
+:	O
+Review	O
+of	O
+all	O
+cases	O
+of	O
+corneal	B-NP
+ulcers	I-NP
+associated	O
+with	O
+drug	B-NP
+abuse	I-NP
+seen	O
+at	O
+our	O
+institution	O
+from	O
+July	O
+2006	O
+to	O
+December	O
+2006	O
+.	O
+	
+RESULTS	O
+:	O
+Four	O
+patients	O
+with	O
+corneal	B-NP
+ulcers	I-NP
+associated	O
+with	O
+crack	O
+cocaine	O
+use	O
+were	O
+reviewed	O
+.	O
+	
+All	O
+corneal	B-NP
+ulcers	I-NP
+were	O
+cultured	O
+","	O
+and	O
+the	O
+patients	O
+were	O
+admitted	O
+to	O
+the	O
+hospital	O
+for	O
+intensive	O
+topical	O
+antibiotic	O
+treatment	O
+.	O
+	
+Each	O
+patient	O
+received	O
+comprehensive	O
+health	O
+care	O
+","	O
+including	O
+medical	O
+and	O
+substance	B-NP
+abuse	I-NP
+consultations	O
+.	O
+	
+Streptococcal	O
+organisms	O
+were	O
+found	O
+in	O
+3	O
+cases	O
+and	O
+Capnocytophaga	O
+and	O
+Brevibacterium	O
+casei	O
+in	O
+1	O
+patient	O
+.	O
+	
+The	O
+infections	B-NP
+responded	O
+to	O
+antibiotic	O
+treatment	O
+.	O
+	
+Two	O
+patients	O
+needed	O
+a	O
+lateral	O
+tarsorrhaphy	O
+for	O
+persistent	O
+epithelial	B-NP
+defects	I-NP
+.	O
+	
+CONCLUSIONS	O
+:	O
+Aerosolized	O
+crack	O
+cocaine	O
+use	O
+can	O
+be	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+corneal	B-NP
+ulcers	I-NP
+.	O
+	
+Drug	B-NP
+abuse	I-NP
+provides	O
+additional	O
+challenges	O
+for	O
+management	O
+.	O
+	
+Not	O
+only	O
+treatment	O
+of	O
+their	O
+infections	B-NP
+but	O
+also	O
+the	O
+overall	O
+poor	O
+health	O
+of	O
+the	O
+patients	O
+and	O
+increased	O
+risk	O
+of	O
+noncompliance	O
+need	O
+to	O
+be	O
+addressed	O
+.	O
+	
+Comprehensive	O
+care	O
+may	O
+provide	O
+the	O
+patient	O
+the	O
+opportunity	O
+to	O
+discontinue	O
+their	O
+substance	B-NP
+abuse	I-NP
+","	O
+improve	O
+their	O
+overall	O
+health	O
+","	O
+and	O
+prevent	O
+future	O
+corneal	O
+complications	O
+.	O
+	
+Topical	O
+0	O
+.	O
+25	O
+%	O
+capsaicin	O
+in	O
+chronic	O
+post	B-NP
+-	I-NP
+herpetic	I-NP
+neuralgia	I-NP
+:	O
+efficacy	O
+","	O
+predictors	O
+of	O
+response	O
+and	O
+long	O
+-	O
+term	O
+course	O
+.	O
+	
+In	O
+order	O
+to	O
+evaluate	O
+the	O
+efficacy	O
+","	O
+time	O
+-	O
+course	O
+of	O
+action	O
+and	O
+predictors	O
+of	O
+response	O
+to	O
+topical	O
+capsaicin	O
+","	O
+39	O
+patients	O
+with	O
+chronic	O
+post	B-NP
+-	I-NP
+herpetic	I-NP
+neuralgia	I-NP
+(	O
+PHN	B-NP
+)	O
+","	O
+median	O
+duration	O
+24	O
+months	O
+","	O
+were	O
+treated	O
+with	O
+0	O
+.	O
+25	O
+%	O
+capsaicin	O
+cream	O
+for	O
+8	O
+weeks	O
+.	O
+	
+During	O
+therapy	O
+the	O
+patients	O
+rated	O
+their	O
+pain	B-NP
+on	O
+a	O
+visual	O
+analogue	O
+scale	O
+(	O
+VAS	O
+)	O
+and	O
+a	O
+verbal	O
+outcome	O
+scale	O
+.	O
+	
+A	O
+follow	O
+-	O
+up	O
+investigation	O
+was	O
+performed	O
+10	O
+-	O
+12	O
+months	O
+after	O
+study	O
+onset	O
+on	O
+the	O
+patients	O
+who	O
+had	O
+improved	O
+.	O
+	
+Nineteen	O
+patients	O
+(	O
+48	O
+.	O
+7	O
+%	O
+)	O
+substantially	O
+improved	O
+after	O
+the	O
+8	O
+-	O
+week	O
+trial	O
+;	O
+5	O
+(	O
+12	O
+.	O
+8	O
+%	O
+)	O
+discontinued	O
+therapy	O
+due	O
+to	O
+side	O
+-	O
+effects	O
+such	O
+as	O
+intolerable	O
+capsaicin	O
+-	O
+induced	O
+burning	O
+sensations	O
+(	O
+4	O
+)	O
+or	O
+mastitis	B-NP
+(	O
+1	O
+)	O
+;	O
+15	O
+(	O
+38	O
+.	O
+5	O
+%	O
+)	O
+reported	O
+no	O
+benefit	O
+.	O
+	
+The	O
+decrease	O
+in	O
+VAS	O
+ratings	O
+was	O
+significant	O
+after	O
+2	O
+weeks	O
+of	O
+continuous	O
+application	O
+.	O
+	
+Of	O
+the	O
+responders	O
+72	O
+.	O
+2	O
+%	O
+were	O
+still	O
+improved	O
+at	O
+the	O
+follow	O
+-	O
+up	O
+;	O
+only	O
+one	O
+-	O
+third	O
+of	O
+them	O
+had	O
+continued	O
+application	O
+irregularly	O
+.	O
+	
+Treatment	O
+effect	O
+was	O
+not	O
+dependent	O
+on	O
+patient	O
+'	O
+s	O
+age	O
+","	O
+duration	O
+or	O
+localization	O
+of	O
+PHN	B-NP
+(	O
+trigeminal	O
+involvement	O
+was	O
+excluded	O
+)	O
+","	O
+sensory	B-NP
+disturbance	I-NP
+or	O
+pain	B-NP
+character	O
+.	O
+	
+Treatment	O
+response	O
+was	O
+not	O
+correlated	O
+with	O
+the	O
+incidence	O
+","	O
+time	O
+-	O
+course	O
+or	O
+severity	O
+of	O
+capsaicin	O
+-	O
+induced	O
+burning	O
+.	O
+	
+If	O
+confirmed	O
+in	O
+controlled	O
+trials	O
+","	O
+the	O
+long	O
+-	O
+term	O
+results	O
+of	O
+this	O
+open	O
+","	O
+non	O
+-	O
+randomized	O
+study	O
+might	O
+indicate	O
+that	O
+the	O
+analgesic	O
+effect	O
+of	O
+capsaicin	O
+in	O
+PHN	B-NP
+is	O
+mediated	O
+by	O
+both	O
+interference	O
+with	O
+neuropeptide	O
+metabolism	O
+and	O
+morphological	O
+changes	O
+(	O
+perhaps	O
+degeneration	O
+)	O
+of	O
+nociceptive	O
+afferents	O
+.	O
+	
+Myo	O
+-	O
+inositol	O
+-	O
+1	O
+-	O
+phosphate	O
+(	O
+MIP	O
+)	O
+synthase	O
+inhibition	O
+:	O
+in	O
+-	O
+vivo	O
+study	O
+in	O
+rats	O
+.	O
+	
+Lithium	O
+and	O
+valproate	O
+are	O
+the	O
+prototypic	O
+mood	O
+stabilizers	O
+and	O
+have	O
+diverse	O
+structures	O
+and	O
+targets	O
+.	O
+	
+Both	O
+drugs	O
+influence	O
+inositol	O
+metabolism	O
+.	O
+	
+Lithium	O
+inhibits	O
+IMPase	O
+and	O
+valproate	O
+inhibits	O
+MIP	O
+synthase	O
+.	O
+	
+This	O
+study	O
+shows	O
+that	O
+MIP	O
+synthase	O
+inhibition	O
+does	O
+not	O
+replicate	O
+or	O
+augment	O
+the	O
+effects	O
+of	O
+lithium	O
+in	O
+the	O
+inositol	O
+sensitive	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B-NP
+model	O
+.	O
+	
+This	O
+lack	O
+of	O
+effects	O
+may	O
+stem	O
+from	O
+the	O
+low	O
+contribution	O
+of	O
+de	O
+-	O
+novo	O
+synthesis	O
+to	O
+cellular	O
+inositol	O
+supply	O
+or	O
+to	O
+the	O
+inhibition	O
+of	O
+the	O
+de	O
+-	O
+novo	O
+synthesis	O
+by	O
+lithium	O
+itself	O
+.	O
+	
+Non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+-	O
+associated	O
+acute	O
+interstitial	B-NP
+nephritis	I-NP
+with	O
+granular	O
+tubular	O
+basement	O
+membrane	O
+deposits	O
+.	O
+	
+Acute	B-NP
+tubulo	I-NP
+-	I-NP
+interstitial	I-NP
+nephritis	I-NP
+(	O
+ATIN	B-NP
+)	O
+is	O
+an	O
+important	O
+cause	O
+of	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+resulting	O
+from	O
+a	O
+variety	O
+of	O
+insults	O
+","	O
+including	O
+immune	O
+complex	O
+-	O
+mediated	O
+tubulo	B-NP
+-	I-NP
+interstitial	I-NP
+injury	I-NP
+","	O
+but	O
+drugs	O
+such	O
+as	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+(	O
+NSAIDs	O
+)	O
+are	O
+a	O
+far	O
+more	O
+frequent	O
+cause	O
+.	O
+	
+Overall	O
+","	O
+as	O
+an	O
+entity	O
+","	O
+ATIN	B-NP
+remains	O
+under	O
+-	O
+diagnosed	O
+","	O
+as	O
+symptoms	O
+resolve	O
+spontaneously	O
+if	O
+the	O
+medication	O
+is	O
+stopped	O
+.	O
+	
+We	O
+report	O
+on	O
+a	O
+14	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+who	O
+developed	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+2	O
+weeks	O
+after	O
+aortic	O
+valve	O
+surgery	O
+.	O
+	
+He	O
+was	O
+put	O
+on	O
+aspirin	O
+following	O
+surgery	O
+and	O
+took	O
+ibuprofen	O
+for	O
+fever	B-NP
+for	O
+nearly	O
+a	O
+week	O
+prior	O
+to	O
+presentation	O
+.	O
+	
+He	O
+then	O
+presented	O
+to	O
+the	O
+emergency	O
+department	O
+feeling	O
+quite	O
+ill	O
+and	O
+was	O
+found	O
+to	O
+have	O
+a	O
+blood	O
+urea	O
+nitrogen	O
+(	O
+BUN	O
+)	O
+concentration	O
+of	O
+of	O
+147	O
+mg	O
+/	O
+dl	O
+","	O
+creatinine	O
+of	O
+15	O
+.	O
+3	O
+mg	O
+/	O
+dl	O
+and	O
+serum	O
+potassium	O
+of	O
+8	O
+.	O
+7	O
+mEq	O
+/	O
+l	O
+.	O
+	
+Dialysis	O
+was	O
+immediately	O
+initiated	O
+.	O
+	
+A	O
+kidney	O
+biopsy	O
+showed	O
+inflammatory	O
+infiltrate	O
+consistent	O
+with	O
+ATIN	B-NP
+.	O
+	
+However	O
+","	O
+in	O
+the	O
+tubular	O
+basement	O
+membrane	O
+(	O
+TBM	O
+)	O
+","	O
+very	O
+intense	O
+granular	O
+deposits	O
+of	O
+polyclonal	O
+IgG	O
+and	O
+C3	O
+were	O
+noted	O
+.	O
+	
+He	O
+needed	O
+dialysis	O
+for	O
+2	O
+weeks	O
+and	O
+was	O
+treated	O
+successfully	O
+with	O
+steroids	O
+for	O
+6	O
+months	O
+.	O
+	
+His	O
+renal	O
+recovery	O
+and	O
+disappearance	O
+of	O
+proteinuria	B-NP
+took	O
+a	O
+year	O
+.	O
+	
+In	O
+conclusion	O
+","	O
+this	O
+is	O
+a	O
+first	O
+report	O
+of	O
+NSAIDs	O
+-	O
+associated	O
+ATIN	B-NP
+","	O
+showing	O
+deposits	O
+of	O
+granular	O
+immune	O
+complex	O
+present	O
+only	O
+in	O
+the	O
+TBM	O
+and	O
+not	O
+in	O
+the	O
+glomeruli	O
+.	O
+	
+Rifampicin	O
+-	O
+associated	O
+segmental	O
+necrotizing	O
+glomerulonephritis	B-NP
+in	O
+staphylococcal	B-NP
+endocarditis	I-NP
+.	O
+	
+Segmental	O
+necrotising	O
+glomerulonephritis	B-NP
+has	O
+been	O
+reported	O
+as	O
+complication	O
+of	O
+rifampicin	O
+therapy	O
+in	O
+patients	O
+receiving	O
+treatment	O
+for	O
+tuberculosis	B-NP
+.	O
+	
+Changing	O
+epidemiology	O
+of	O
+infections	B-NP
+such	O
+as	O
+infective	B-NP
+endocarditis	I-NP
+(	O
+IE	B-NP
+)	O
+has	O
+led	O
+to	O
+an	O
+increase	O
+in	O
+the	O
+use	O
+of	O
+rifampicin	O
+for	O
+Staphylococcal	B-NP
+infections	I-NP
+.	O
+	
+We	O
+describe	O
+a	O
+case	O
+of	O
+a	O
+patient	O
+with	O
+Staphylococcal	B-NP
+IE	I-NP
+who	O
+developed	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+secondary	O
+to	O
+a	O
+segmental	O
+necrotising	O
+glomerulonephritis	B-NP
+while	O
+being	O
+treated	O
+with	O
+rifampicin	O
+","	O
+and	O
+review	O
+the	O
+literature	O
+regarding	O
+this	O
+complication	O
+of	O
+rifampicin	O
+therapy	O
+.	O
+	
+Rate	O
+of	O
+YMDD	O
+motif	O
+mutants	O
+in	O
+lamivudine	O
+-	O
+untreated	O
+Iranian	O
+patients	O
+with	O
+chronic	B-NP
+hepatitis	I-NP
+B	I-NP
+virus	I-NP
+infection	I-NP
+.	O
+	
+BACKGROUND	O
+:	O
+Lamivudine	O
+is	O
+used	O
+for	O
+the	O
+treatment	O
+of	O
+chronic	B-NP
+hepatitis	I-NP
+B	I-NP
+patients	O
+.	O
+	
+Recent	O
+studies	O
+show	O
+that	O
+the	O
+YMDD	O
+motif	O
+mutants	O
+(	O
+resistant	O
+hepatitis	B-NP
+B	I-NP
+virus	O
+)	O
+occur	O
+as	O
+natural	O
+genome	O
+variability	O
+in	O
+lamivudine	O
+-	O
+untreated	O
+chronic	B-NP
+hepatitis	I-NP
+B	I-NP
+patients	O
+.	O
+	
+In	O
+this	O
+study	O
+we	O
+aimed	O
+to	O
+determine	O
+the	O
+rate	O
+of	O
+YMDD	O
+motif	O
+mutants	O
+in	O
+lamivudine	O
+-	O
+untreated	O
+chronic	B-NP
+hepatitis	I-NP
+B	I-NP
+patients	O
+in	O
+Iran	O
+.	O
+	
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+A	O
+total	O
+of	O
+77	O
+chronic	B-NP
+hepatitis	I-NP
+B	I-NP
+patients	O
+who	O
+had	O
+not	O
+been	O
+treated	O
+with	O
+lamivudine	O
+were	O
+included	O
+in	O
+the	O
+study	O
+.	O
+	
+Serum	O
+samples	O
+from	O
+patients	O
+were	O
+tested	O
+by	O
+polymerase	O
+chain	O
+reaction	O
+-	O
+restriction	O
+fragment	O
+length	O
+polymorphism	O
+(	O
+PCR	O
+-	O
+RFLP	O
+)	O
+for	O
+detection	O
+of	O
+YMDD	O
+motif	O
+mutants	O
+.	O
+	
+All	O
+patients	O
+were	O
+also	O
+tested	O
+for	O
+liver	O
+enzymes	O
+","	O
+anti	O
+-	O
+HCV	O
+","	O
+HBeAg	O
+","	O
+and	O
+anti	O
+-	O
+HBe	O
+.	O
+	
+RESULTS	O
+:	O
+Of	O
+the	O
+77	O
+patients	O
+enrolled	O
+in	O
+the	O
+study	O
+","	O
+73	O
+%	O
+were	O
+male	O
+and	O
+27	O
+%	O
+were	O
+female	O
+.	O
+	
+Mean	O
+ALT	O
+and	O
+AST	O
+levels	O
+were	O
+124	O
+.	O
+4	O
++	O
+/	O
+-	O
+73	O
+.	O
+4	O
+and	O
+103	O
+.	O
+1	O
++	O
+/	O
+-	O
+81	O
+IU	O
+/	O
+l	O
+","	O
+respectively	O
+.	O
+	
+HBeAg	O
+was	O
+positive	O
+in	O
+40	O
+%	O
+and	O
+anti	O
+-	O
+HBe	O
+in	O
+60	O
+%	O
+of	O
+the	O
+patients	O
+.	O
+	
+Anti	O
+-	O
+HCV	O
+was	O
+negative	O
+in	O
+all	O
+of	O
+them	O
+.	O
+	
+YMDD	O
+motif	O
+mutants	O
+were	O
+not	O
+detected	O
+in	O
+any	O
+of	O
+the	O
+patients	O
+despite	O
+the	O
+liver	O
+enzyme	O
+levels	O
+and	O
+the	O
+presence	O
+of	O
+HBeAg	O
+or	O
+anti	O
+-	O
+HBe	O
+.	O
+	
+CONCLUSION	O
+:	O
+Although	O
+the	O
+natural	O
+occurrence	O
+of	O
+YMDD	O
+motif	O
+mutants	O
+in	O
+lamivudine	O
+-	O
+untreated	O
+patients	O
+with	O
+chronic	B-NP
+hepatitis	I-NP
+B	I-NP
+has	O
+been	O
+reported	O
+","	O
+these	O
+mutants	O
+were	O
+not	O
+detected	O
+in	O
+Iranian	O
+lamivudine	O
+-	O
+untreated	O
+chronic	B-NP
+hepatitis	I-NP
+B	I-NP
+patients	O
+.	O
+	
+Branch	O
+retinal	B-NP
+vein	I-NP
+occlusion	I-NP
+and	O
+fluoxetine	O
+.	O
+	
+A	O
+case	O
+of	O
+branch	O
+retinal	B-NP
+vein	I-NP
+occlusion	I-NP
+associated	O
+with	O
+fluoxetine	O
+-	O
+induced	O
+secondary	O
+hypertension	B-NP
+is	O
+described	O
+.	O
+	
+Although	O
+an	O
+infrequent	O
+complication	O
+of	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitor	O
+therapy	O
+","	O
+it	O
+is	O
+important	O
+that	O
+ophthalmologists	O
+are	O
+aware	O
+that	O
+these	O
+agents	O
+can	O
+cause	O
+hypertension	B-NP
+because	O
+this	O
+class	O
+of	O
+drugs	O
+is	O
+widely	O
+prescribed	O
+.	O
+	
+The	O
+differential	O
+effects	O
+of	O
+bupivacaine	O
+and	O
+lidocaine	O
+on	O
+prostaglandin	O
+E2	O
+release	O
+","	O
+cyclooxygenase	O
+gene	O
+expression	O
+and	O
+pain	B-NP
+in	O
+a	O
+clinical	O
+pain	B-NP
+model	O
+.	O
+	
+BACKGROUND	O
+:	O
+In	O
+addition	O
+to	O
+blocking	O
+nociceptive	O
+input	O
+from	O
+surgical	O
+sites	O
+","	O
+long	O
+-	O
+acting	O
+local	O
+anesthetics	O
+might	O
+directly	O
+modulate	O
+inflammation	B-NP
+.	O
+	
+In	O
+the	O
+present	O
+study	O
+","	O
+we	O
+describe	O
+the	O
+proinflammatory	O
+effects	O
+of	O
+bupivacaine	O
+on	O
+local	O
+prostaglandin	O
+E2	O
+(	O
+PGE2	O
+)	O
+production	O
+and	O
+cyclooxygenase	O
+(	O
+COX	O
+)	O
+gene	O
+expression	O
+that	O
+increases	O
+postoperative	B-NP
+pain	I-NP
+in	O
+human	O
+subjects	O
+.	O
+	
+METHODS	O
+:	O
+Subjects	O
+(	O
+n	O
+=	O
+114	O
+)	O
+undergoing	O
+extraction	O
+of	O
+impacted	O
+third	O
+molars	O
+received	O
+either	O
+2	O
+%	O
+lidocaine	O
+or	O
+0	O
+.	O
+5	O
+%	O
+bupivacaine	O
+before	O
+surgery	O
+and	O
+either	O
+rofecoxib	O
+50	O
+mg	O
+or	O
+placebo	O
+orally	O
+90	O
+min	O
+before	O
+surgery	O
+and	O
+for	O
+the	O
+following	O
+48	O
+h	O
+.	O
+	
+Oral	O
+mucosal	O
+biopsies	O
+were	O
+taken	O
+before	O
+surgery	O
+and	O
+48	O
+h	O
+after	O
+surgery	O
+.	O
+	
+After	O
+extraction	O
+","	O
+a	O
+microdialysis	O
+probe	O
+was	O
+placed	O
+at	O
+the	O
+surgical	O
+site	O
+for	O
+PGE2	O
+and	O
+thromboxane	O
+B2	O
+(	O
+TXB2	O
+)	O
+measurements	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+bupivacaine	O
+/	O
+rofecoxib	O
+group	O
+reported	O
+significantly	O
+less	O
+pain	B-NP
+","	O
+as	O
+assessed	O
+by	O
+a	O
+visual	O
+analog	O
+scale	O
+","	O
+compared	O
+with	O
+the	O
+other	O
+three	O
+treatment	O
+groups	O
+over	O
+the	O
+first	O
+4	O
+h	O
+.	O
+	
+However	O
+","	O
+the	O
+bupivacaine	O
+/	O
+placebo	O
+group	O
+reported	O
+significantly	O
+more	O
+pain	B-NP
+at	O
+24	O
+h	O
+and	O
+PGE2	O
+levels	O
+during	O
+the	O
+first	O
+4	O
+h	O
+were	O
+significantly	O
+higher	O
+than	O
+the	O
+other	O
+three	O
+treatment	O
+groups	O
+.	O
+	
+Moreover	O
+","	O
+bupivacaine	O
+significantly	O
+increased	O
+COX	O
+-	O
+2	O
+gene	O
+expression	O
+at	O
+48	O
+h	O
+as	O
+compared	O
+with	O
+the	O
+lidocaine	O
+/	O
+placebo	O
+group	O
+.	O
+	
+Thromboxane	O
+levels	O
+were	O
+not	O
+significantly	O
+affected	O
+by	O
+any	O
+of	O
+the	O
+treatments	O
+","	O
+indicating	O
+that	O
+the	O
+effects	O
+seen	O
+were	O
+attributable	O
+to	O
+inhibition	O
+of	O
+COX	O
+-	O
+2	O
+","	O
+but	O
+not	O
+COX	O
+-	O
+1	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+These	O
+results	O
+suggest	O
+that	O
+bupivacaine	O
+stimulates	O
+COX	O
+-	O
+2	O
+gene	O
+expression	O
+after	O
+tissue	B-NP
+injury	I-NP
+","	O
+which	O
+is	O
+associated	O
+with	O
+higher	O
+PGE2	O
+production	O
+and	O
+pain	B-NP
+after	O
+the	O
+local	O
+anesthetic	O
+effect	O
+dissipates	O
+.	O
+	
+p75NTR	O
+expression	O
+in	O
+rat	O
+urinary	O
+bladder	O
+sensory	O
+neurons	O
+and	O
+spinal	O
+cord	O
+with	O
+cyclophosphamide	O
+-	O
+induced	O
+cystitis	B-NP
+.	O
+	
+A	O
+role	O
+for	O
+nerve	O
+growth	O
+factor	O
+(	O
+NGF	O
+)	O
+in	O
+contributing	O
+to	O
+increased	O
+voiding	O
+frequency	O
+and	O
+altered	O
+sensation	O
+from	O
+the	O
+urinary	O
+bladder	O
+has	O
+been	O
+suggested	O
+.	O
+	
+Previous	O
+studies	O
+have	O
+examined	O
+the	O
+expression	O
+and	O
+regulation	O
+of	O
+tyrosine	O
+kinase	O
+receptors	O
+(	O
+Trks	O
+)	O
+in	O
+micturition	O
+reflexes	O
+with	O
+urinary	B-NP
+bladder	I-NP
+inflammation	I-NP
+.	O
+	
+The	O
+present	O
+studies	O
+examine	O
+the	O
+expression	O
+and	O
+regulation	O
+of	O
+another	O
+receptor	O
+known	O
+to	O
+bind	O
+NGF	O
+","	O
+p75	O
+(	O
+NTR	O
+)	O
+","	O
+after	O
+various	O
+durations	O
+of	O
+bladder	B-NP
+inflammation	I-NP
+induced	O
+by	O
+cyclophosphamide	O
+(	O
+CYP	O
+)	O
+.	O
+	
+CYP	O
+-	O
+induced	O
+cystitis	B-NP
+increased	O
+(	O
+P	O
+<	O
+or	O
+=	O
+0	O
+.	O
+1	O
+)	O
+p75	O
+(	O
+NTR	O
+)	O
+expression	O
+in	O
+the	O
+superficial	O
+lateral	O
+and	O
+medial	O
+dorsal	O
+horn	O
+in	O
+L1	O
+-	O
+L2	O
+and	O
+L6	O
+-	O
+S1	O
+spinal	O
+segments	O
+.	O
+	
+The	O
+number	O
+of	O
+p75	O
+(	O
+NTR	O
+)	O
+-	O
+immunoreactive	O
+(	O
+-	O
+IR	O
+)	O
+cells	O
+in	O
+the	O
+lumbosacral	O
+dorsal	O
+root	O
+ganglia	O
+(	O
+DRG	O
+)	O
+also	O
+increased	O
+(	O
+P	O
+<	O
+or	O
+=	O
+0	O
+.	O
+5	O
+)	O
+with	O
+CYP	O
+-	O
+induced	O
+cystitis	B-NP
+(	O
+acute	O
+","	O
+intermediate	O
+","	O
+and	O
+chronic	O
+)	O
+.	O
+	
+Quantitative	O
+","	O
+real	O
+-	O
+time	O
+polymerase	O
+chain	O
+reaction	O
+also	O
+demonstrated	O
+significant	O
+increases	O
+(	O
+P	O
+<	O
+or	O
+=	O
+0	O
+.	O
+1	O
+)	O
+in	O
+p75	O
+(	O
+NTR	O
+)	O
+mRNA	O
+in	O
+DRG	O
+with	O
+intermediate	O
+and	O
+chronic	O
+CYP	O
+-	O
+induced	O
+cystitis	B-NP
+.	O
+	
+Retrograde	O
+dye	O
+-	O
+tracing	O
+techniques	O
+with	O
+Fastblue	O
+were	O
+used	O
+to	O
+identify	O
+presumptive	O
+bladder	O
+afferent	O
+cells	O
+in	O
+the	O
+lumbosacral	O
+DRG	O
+.	O
+	
+In	O
+bladder	O
+afferent	O
+cells	O
+in	O
+DRG	O
+","	O
+p75	O
+(	O
+NTR	O
+)	O
+-	O
+IR	O
+was	O
+also	O
+increased	O
+(	O
+P	O
+<	O
+or	O
+=	O
+0	O
+.	O
+1	O
+)	O
+with	O
+cystitis	B-NP
+.	O
+	
+In	O
+addition	O
+to	O
+increases	O
+in	O
+p75	O
+(	O
+NTR	O
+)	O
+-	O
+IR	O
+in	O
+DRG	O
+cell	O
+bodies	O
+","	O
+increases	O
+(	O
+P	O
+<	O
+or	O
+=	O
+0	O
+.	O
+1	O
+)	O
+in	O
+pericellular	O
+(	O
+encircling	O
+DRG	O
+cells	O
+)	O
+p75	O
+(	O
+NTR	O
+)	O
+-	O
+IR	O
+in	O
+DRG	O
+also	O
+increased	O
+.	O
+	
+Confocal	O
+analyses	O
+demonstrated	O
+that	O
+pericellular	O
+p75	O
+(	O
+NTR	O
+)	O
+-	O
+IR	O
+was	O
+not	O
+colocalized	O
+with	O
+the	O
+glial	O
+marker	O
+","	O
+glial	O
+fibrillary	O
+acidic	O
+protein	O
+(	O
+GFAP	O
+)	O
+.	O
+	
+These	O
+studies	O
+demonstrate	O
+that	O
+p75	O
+(	O
+NTR	O
+)	O
+expression	O
+in	O
+micturition	O
+reflexes	O
+is	O
+present	O
+constitutively	O
+and	O
+modified	O
+by	O
+bladder	B-NP
+inflammation	I-NP
+.	O
+	
+The	O
+functional	O
+significance	O
+of	O
+p75	O
+(	O
+NTR	O
+)	O
+expression	O
+in	O
+micturition	O
+reflexes	O
+remains	O
+to	O
+be	O
+determined	O
+.	O
+	
+Azathioprine	O
+-	O
+induced	O
+suicidal	O
+erythrocyte	O
+death	O
+.	O
+	
+BACKGROUND	O
+:	O
+Azathioprine	O
+is	O
+widely	O
+used	O
+as	O
+an	O
+immunosuppressive	O
+drug	O
+.	O
+	
+The	O
+side	O
+effects	O
+of	O
+azathioprine	O
+include	O
+anemia	B-NP
+","	O
+which	O
+has	O
+been	O
+attributed	O
+to	O
+bone	O
+marrow	O
+suppression	O
+.	O
+	
+Alternatively	O
+","	O
+anemia	B-NP
+could	O
+result	O
+from	O
+accelerated	O
+suicidal	O
+erythrocyte	O
+death	O
+or	O
+eryptosis	O
+","	O
+which	O
+is	O
+characterized	O
+by	O
+exposure	O
+of	O
+phosphatidylserine	O
+(	O
+PS	O
+)	O
+at	O
+the	O
+erythrocyte	O
+surface	O
+and	O
+by	O
+cell	O
+shrinkage	O
+.	O
+	
+METHODS	O
+:	O
+The	O
+present	O
+experiments	O
+explored	O
+whether	O
+azathioprine	O
+influences	O
+eryptosis	O
+.	O
+	
+According	O
+to	O
+annexin	O
+V	O
+binding	O
+","	O
+erythrocytes	O
+from	O
+patients	O
+indeed	O
+showed	O
+a	O
+significant	O
+increase	O
+of	O
+PS	O
+exposure	O
+within	O
+1	O
+week	O
+of	O
+treatment	O
+with	O
+azathioprine	O
+.	O
+	
+In	O
+a	O
+second	O
+series	O
+","	O
+cytosolic	O
+Ca2	O
++	O
+activity	O
+(	O
+Fluo3	O
+fluorescence	O
+)	O
+","	O
+cell	O
+volume	O
+(	O
+forward	O
+scatter	O
+)	O
+","	O
+and	O
+PS	O
+-	O
+exposure	O
+(	O
+annexin	O
+V	O
+binding	O
+)	O
+were	O
+determined	O
+by	O
+FACS	O
+analysis	O
+in	O
+erythrocytes	O
+from	O
+healthy	O
+volunteers	O
+.	O
+	
+RESULTS	O
+:	O
+Exposure	O
+to	O
+azathioprine	O
+(	O
+>	O
+or	O
+=	O
+2	O
+microg	O
+/	O
+mL	O
+)	O
+for	O
+48	O
+hours	O
+increased	O
+cytosolic	O
+Ca2	O
++	O
+activity	O
+and	O
+annexin	O
+V	O
+binding	O
+and	O
+decreased	O
+forward	O
+scatter	O
+.	O
+	
+The	O
+effect	O
+of	O
+azathioprine	O
+on	O
+both	O
+annexin	O
+V	O
+binding	O
+and	O
+forward	O
+scatter	O
+was	O
+significantly	O
+blunted	O
+in	O
+the	O
+nominal	O
+absence	O
+of	O
+extracellular	O
+Ca2	O
++	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Azathioprine	O
+triggers	O
+suicidal	O
+erythrocyte	O
+death	O
+","	O
+an	O
+effect	O
+presumably	O
+contributing	O
+to	O
+azathioprine	O
+-	O
+induced	O
+anemia	B-NP
+.	O
+	
+Levetiracetam	O
+as	O
+an	O
+adjunct	O
+to	O
+phenobarbital	O
+treatment	O
+in	O
+cats	O
+with	O
+suspected	O
+idiopathic	B-NP
+epilepsy	I-NP
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+assess	O
+pharmacokinetics	O
+","	O
+efficacy	O
+","	O
+and	O
+tolerability	O
+of	O
+oral	O
+levetiracetam	O
+administered	O
+as	O
+an	O
+adjunct	O
+to	O
+phenobarbital	O
+treatment	O
+in	O
+cats	O
+with	O
+poorly	O
+controlled	O
+suspected	O
+idiopathic	B-NP
+epilepsy	I-NP
+.	O
+	
+DESIGN	O
+-	O
+Open	O
+-	O
+label	O
+","	O
+noncomparative	O
+clinical	O
+trial	O
+.	O
+	
+ANIMALS	O
+:	O
+12	O
+cats	O
+suspected	O
+to	O
+have	O
+idiopathic	B-NP
+epilepsy	I-NP
+that	O
+was	O
+poorly	O
+controlled	O
+with	O
+phenobarbital	O
+or	O
+that	O
+had	O
+unacceptable	O
+adverse	O
+effects	O
+when	O
+treated	O
+with	O
+phenobarbital	O
+.	O
+	
+PROCEDURES	O
+:	O
+Cats	O
+were	O
+treated	O
+with	O
+levetiracetam	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+[	O
+9	O
+.	O
+1	O
+mg	O
+/	O
+lb	O
+]	O
+","	O
+PO	O
+","	O
+q	O
+8	O
+h	O
+)	O
+.	O
+	
+After	O
+a	O
+minimum	O
+of	O
+1	O
+week	O
+of	O
+treatment	O
+","	O
+serum	O
+levetiracetam	O
+concentrations	O
+were	O
+measured	O
+before	O
+and	O
+2	O
+","	O
+4	O
+","	O
+and	O
+6	O
+hours	O
+after	O
+drug	O
+administration	O
+","	O
+and	O
+maximum	O
+and	O
+minimum	O
+serum	O
+concentrations	O
+and	O
+elimination	O
+half	O
+-	O
+life	O
+were	O
+calculated	O
+.	O
+	
+Seizure	B-NP
+frequencies	O
+before	O
+and	O
+after	O
+initiation	O
+of	O
+levetiracetam	O
+treatment	O
+were	O
+compared	O
+","	O
+and	O
+adverse	O
+effects	O
+were	O
+recorded	O
+.	O
+	
+RESULTS	O
+:	O
+Median	O
+maximum	O
+serum	O
+levetiracetam	O
+concentration	O
+was	O
+25	O
+.	O
+5	O
+microg	O
+/	O
+mL	O
+","	O
+median	O
+minimum	O
+serum	O
+levetiracetam	O
+concentration	O
+was	O
+8	O
+.	O
+3	O
+microg	O
+/	O
+mL	O
+","	O
+and	O
+median	O
+elimination	O
+half	O
+-	O
+life	O
+was	O
+2	O
+.	O
+9	O
+hours	O
+.	O
+	
+Median	O
+seizure	B-NP
+frequency	O
+prior	O
+to	O
+treatment	O
+with	O
+levetiracetam	O
+(	O
+2	O
+.	O
+1	O
+seizures	B-NP
+/	O
+mo	O
+)	O
+was	O
+significantly	O
+higher	O
+than	O
+median	O
+seizure	B-NP
+frequency	O
+after	O
+initiation	O
+of	O
+levetiracetam	O
+treatment	O
+(	O
+0	O
+.	O
+42	O
+seizures	B-NP
+/	O
+mo	O
+)	O
+","	O
+and	O
+7	O
+of	O
+10	O
+cats	O
+were	O
+classified	O
+as	O
+having	O
+responded	O
+to	O
+levetiracetam	O
+treatment	O
+(	O
+ie	O
+","	O
+reduction	O
+in	O
+seizure	B-NP
+frequency	O
+of	O
+>	O
+or	O
+=	O
+50	O
+%	O
+)	O
+.	O
+	
+Two	O
+cats	O
+had	O
+transient	O
+lethargy	B-NP
+and	O
+inappetence	B-NP
+.	O
+	
+CONCLUSIONS	O
+AND	O
+CLINICAL	O
+RELEVANCE	O
+:	O
+Results	O
+suggested	O
+that	O
+levetiracetam	O
+is	O
+well	O
+tolerated	O
+in	O
+cats	O
+and	O
+may	O
+be	O
+useful	O
+as	O
+an	O
+adjunct	O
+to	O
+phenobarbital	O
+treatment	O
+in	O
+cats	O
+with	O
+idiopathic	B-NP
+epilepsy	I-NP
+.	O
+	
+Serotonin	O
+reuptake	O
+inhibitors	O
+","	O
+paranoia	B-NP
+","	O
+and	O
+the	O
+ventral	O
+basal	O
+ganglia	O
+.	O
+	
+Antidepressants	O
+have	O
+previously	O
+been	O
+associated	O
+with	O
+paranoid	B-NP
+reactions	O
+in	O
+psychiatric	O
+patients	O
+.	O
+	
+Five	O
+cases	O
+of	O
+paranoid	B-NP
+exacerbation	O
+with	O
+the	O
+serotonin	O
+reuptake	O
+inhibitors	O
+fluoxetine	O
+and	O
+amitriptyline	O
+are	O
+reported	O
+here	O
+.	O
+	
+Elements	O
+common	O
+to	O
+these	O
+cases	O
+included	O
+a	O
+history	O
+of	O
+paranoid	B-NP
+symptomatology	O
+and	O
+the	O
+concomitant	O
+occurrence	O
+of	O
+depressive	B-NP
+and	I-NP
+psychotic	I-NP
+symptoms	I-NP
+.	O
+	
+Complicated	O
+depressive	B-NP
+disorders	I-NP
+(	O
+including	O
+atypicality	O
+of	O
+course	O
+and	O
+symptomatology	O
+","	O
+chronicity	O
+","	O
+psychosis	B-NP
+","	O
+bipolarity	O
+","	O
+and	O
+secondary	O
+onset	O
+in	O
+the	O
+course	O
+of	O
+a	O
+primary	O
+psychosis	B-NP
+)	O
+may	O
+present	O
+particular	O
+vulnerability	O
+to	O
+paranoid	B-NP
+exacerbations	O
+associated	O
+with	O
+serotonin	O
+reuptake	O
+inhibitors	O
+.	O
+	
+Although	O
+the	O
+pharmacology	O
+and	O
+neurobiology	O
+of	O
+paranoia	B-NP
+remain	O
+cryptic	O
+","	O
+several	O
+mechanisms	O
+","	O
+including	O
+5HT3	O
+receptor	O
+-	O
+mediated	O
+dopamine	O
+release	O
+","	O
+beta	O
+-	O
+noradrenergic	O
+receptor	O
+downregulation	O
+","	O
+or	O
+GABAB	O
+receptor	O
+upregulation	O
+acting	O
+in	O
+the	O
+vicinity	O
+of	O
+the	O
+ventral	O
+basal	O
+ganglia	O
+(	O
+possibly	O
+in	O
+lateral	O
+orbitofrontal	O
+or	O
+anterior	O
+cingulate	O
+circuits	O
+)	O
+","	O
+might	O
+apply	O
+to	O
+this	O
+phenomenon	O
+.	O
+	
+These	O
+cases	O
+call	O
+attention	O
+to	O
+possible	O
+paranoid	B-NP
+exacerbations	O
+with	O
+serotonin	O
+reuptake	O
+blockers	O
+in	O
+select	O
+patients	O
+and	O
+raise	O
+neurobiological	O
+considerations	O
+regarding	O
+paranoia	B-NP
+.	O
+	
+Clinical	O
+comparison	O
+of	O
+cardiorespiratory	O
+effects	O
+during	O
+unilateral	O
+and	O
+conventional	O
+spinal	O
+anaesthesia	O
+.	O
+	
+BACKGROUND	O
+:	O
+Spinal	O
+anaesthesia	O
+is	O
+widely	O
+employed	O
+in	O
+clinical	O
+practice	O
+but	O
+has	O
+the	O
+main	O
+drawback	O
+of	O
+post	O
+-	O
+spinal	O
+block	O
+hypotension	B-NP
+.	O
+	
+Efforts	O
+must	O
+therefore	O
+continue	O
+to	O
+be	O
+made	O
+to	O
+obviate	O
+this	O
+setback	O
+OBJECTIVE	O
+:	O
+To	O
+evaluate	O
+the	O
+cardiovascular	O
+and	O
+respiratory	O
+changes	O
+during	O
+unilateral	O
+and	O
+conventional	O
+spinal	O
+anaesthesia	O
+.	O
+	
+METHODS	O
+:	O
+With	O
+ethical	O
+approval	O
+","	O
+we	O
+studied	O
+74	O
+American	O
+Society	O
+of	O
+Anesthesiologists	O
+(	O
+ASA	O
+)	O
+","	O
+physical	O
+status	O
+class	O
+1	O
+and	O
+2	O
+patients	O
+scheduled	O
+for	O
+elective	O
+unilateral	O
+lower	O
+limb	O
+surgery	O
+.	O
+	
+Patients	O
+were	O
+randomly	O
+allocated	O
+into	O
+one	O
+of	O
+two	O
+groups	O
+:	O
+lateral	O
+and	O
+conventional	O
+spinal	O
+anaesthesia	O
+groups	O
+.	O
+	
+In	O
+the	O
+lateral	O
+position	O
+with	O
+operative	O
+side	O
+down	O
+","	O
+patients	O
+recived	O
+10	O
+mg	O
+(	O
+2mls	O
+)	O
+of	O
+0	O
+.	O
+5	O
+%	O
+hyperbaric	O
+bupivacaine	O
+through	O
+a	O
+25	O
+-	O
+gauge	O
+spinal	O
+needle	O
+.	O
+	
+Patients	O
+in	O
+the	O
+unilateral	O
+group	O
+were	O
+maintained	O
+in	O
+the	O
+lateral	O
+position	O
+for	O
+15	O
+minutes	O
+following	O
+spinal	O
+injection	O
+while	O
+those	O
+in	O
+the	O
+conventional	O
+group	O
+were	O
+turned	O
+supine	O
+immediately	O
+after	O
+injection	O
+.	O
+	
+Blood	O
+pressure	O
+","	O
+heart	O
+rate	O
+","	O
+respiratory	O
+rate	O
+and	O
+oxygen	O
+saturation	O
+were	O
+monitored	O
+over	O
+1	O
+hour	O
+.	O
+	
+RESULTS	O
+:	O
+Three	O
+patients	O
+(	O
+8	O
+.	O
+1	O
+%	O
+)	O
+in	O
+the	O
+unilateral	O
+group	O
+and	O
+5	O
+(	O
+13	O
+.	O
+5	O
+%	O
+)	O
+in	O
+the	O
+conventional	O
+group	O
+developed	O
+hypotension	B-NP
+","	O
+P	O
+=	O
+0	O
+.	O
+71	O
+.	O
+	
+Four	O
+(	O
+10	O
+.	O
+8	O
+%	O
+)	O
+patients	O
+in	O
+the	O
+conventional	O
+group	O
+and	O
+1	O
+(	O
+2	O
+.	O
+7	O
+%	O
+)	O
+in	O
+the	O
+unilateral	O
+group	O
+","	O
+P	O
+=	O
+0	O
+.	O
+17	O
+required	O
+epinephrine	O
+infusion	O
+to	O
+treat	O
+hypotension	B-NP
+.	O
+	
+Patients	O
+in	O
+the	O
+conventional	O
+group	O
+had	O
+statistically	O
+significant	O
+greater	O
+fall	O
+in	O
+the	O
+systolic	O
+blood	O
+pressures	O
+at	O
+15	O
+","	O
+30	O
+and	O
+45	O
+minutes	O
+when	O
+compared	O
+to	O
+the	O
+baseline	O
+(	O
+P	O
+=	O
+0	O
+.	O
+3	O
+","	O
+0	O
+.	O
+1	O
+and	O
+0	O
+.	O
+4	O
+)	O
+.	O
+	
+The	O
+mean	O
+respiratory	O
+rate	O
+and	O
+oxygen	O
+saturations	O
+in	O
+the	O
+two	O
+groups	O
+were	O
+similar	O
+.	O
+	
+CONCLUSION	O
+:	O
+Compared	O
+to	O
+conventional	O
+spinal	O
+anaesthesia	O
+","	O
+unilateral	O
+spinal	O
+anaesthesia	O
+was	O
+associated	O
+with	O
+fewer	O
+cardiovascular	O
+perturbations	O
+.	O
+	
+Also	O
+","	O
+the	O
+type	O
+of	O
+spinal	O
+block	O
+instituted	O
+affected	O
+neither	O
+the	O
+respiratory	O
+rate	O
+nor	O
+the	O
+arterial	O
+oxygen	O
+saturation	O
+.	O
+	
+Spectrum	O
+of	O
+adverse	O
+events	O
+after	O
+generic	O
+HAART	O
+in	O
+southern	O
+Indian	O
+HIV	B-NP
+-	I-NP
+infected	I-NP
+patients	O
+.	O
+	
+To	O
+determine	O
+the	O
+incidence	O
+of	O
+clinically	O
+significant	O
+adverse	O
+events	O
+after	O
+long	O
+-	O
+term	O
+","	O
+fixed	O
+-	O
+dose	O
+","	O
+generic	O
+highly	O
+active	O
+antiretroviral	O
+therapy	O
+(	O
+HAART	O
+)	O
+use	O
+among	O
+HIV	B-NP
+-	I-NP
+infected	I-NP
+individuals	O
+in	O
+South	O
+India	O
+","	O
+we	O
+examined	O
+the	O
+experiences	O
+of	O
+3154	O
+HIV	B-NP
+-	I-NP
+infected	I-NP
+individuals	O
+who	O
+received	O
+a	O
+minimum	O
+of	O
+3	O
+months	O
+of	O
+generic	O
+HAART	O
+between	O
+February	O
+1996	O
+and	O
+December	O
+2006	O
+at	O
+a	O
+tertiary	O
+HIV	O
+care	O
+referral	O
+center	O
+in	O
+South	O
+India	O
+.	O
+	
+The	O
+most	O
+common	O
+regimens	O
+were	O
+3TC	O
++	O
+d4T	O
++	O
+nevirapine	O
+(	O
+NVP	O
+)	O
+(	O
+54	O
+.	O
+8	O
+%	O
+)	O
+","	O
+zidovudine	O
+(	O
+AZT	O
+)	O
++	O
+3TC	O
++	O
+NVP	O
+(	O
+14	O
+.	O
+5	O
+%	O
+)	O
+","	O
+3TC	O
++	O
+d4T	O
++	O
+efavirenz	O
+(	O
+EFV	O
+)	O
+(	O
+20	O
+.	O
+1	O
+%	O
+)	O
+","	O
+and	O
+AZT	O
++	O
+3TC	O
++	O
+EFV	O
+(	O
+5	O
+.	O
+4	O
+%	O
+)	O
+.	O
+	
+The	O
+most	O
+common	O
+adverse	O
+events	O
+and	O
+median	O
+CD4	O
+at	O
+time	O
+of	O
+event	O
+were	O
+rash	B-NP
+(	O
+15	O
+.	O
+2	O
+%	O
+;	O
+CD4	O
+","	O
+285	O
+cells	O
+/	O
+microL	O
+)	O
+and	O
+peripheral	B-NP
+neuropathy	I-NP
+(	O
+9	O
+.	O
+0	O
+%	O
+and	O
+348	O
+cells	O
+/	O
+microL	O
+)	O
+.	O
+	
+Clinically	O
+significant	O
+anemia	B-NP
+(	O
+hemoglobin	O
+<	O
+7	O
+g	O
+/	O
+dL	O
+)	O
+was	O
+observed	O
+in	O
+5	O
+.	O
+4	O
+%	O
+of	O
+patients	O
+(	O
+CD4	O
+","	O
+165	O
+cells	O
+/	O
+microL	O
+)	O
+and	O
+hepatitis	B-NP
+(	O
+clinical	O
+jaundice	B-NP
+with	O
+alanine	O
+aminotransferase	O
+>	O
+5	O
+times	O
+upper	O
+limits	O
+of	O
+normal	O
+)	O
+in	O
+3	O
+.	O
+5	O
+%	O
+of	O
+patients	O
+(	O
+CD4	O
+","	O
+260	O
+cells	O
+/	O
+microL	O
+)	O
+.	O
+	
+Women	O
+were	O
+significantly	O
+more	O
+likely	O
+to	O
+experience	O
+lactic	B-NP
+acidosis	I-NP
+","	O
+while	O
+men	O
+were	O
+significantly	O
+more	O
+likely	O
+to	O
+experience	O
+immune	B-NP
+reconstitution	I-NP
+syndrome	I-NP
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+Among	O
+the	O
+patients	O
+with	O
+1	O
+year	O
+of	O
+follow	O
+-	O
+up	O
+","	O
+NVP	O
+therapy	O
+was	O
+significantly	O
+associated	O
+with	O
+developing	O
+rash	B-NP
+and	O
+d4T	O
+therapy	O
+with	O
+developing	O
+peripheral	B-NP
+neuropathy	I-NP
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+Anemia	B-NP
+and	O
+hepatitis	B-NP
+often	O
+occur	O
+within	O
+12	O
+weeks	O
+of	O
+initiating	O
+generic	O
+HAART	O
+.	O
+	
+Frequent	O
+and	O
+early	O
+monitoring	O
+for	O
+these	O
+toxicities	B-NP
+is	O
+warranted	O
+in	O
+developing	O
+countries	O
+where	O
+generic	O
+HAART	O
+is	O
+increasingly	O
+available	O
+.	O
+	
+Thalidomide	O
+and	O
+sensory	B-NP
+neurotoxicity	I-NP
+:	O
+a	O
+neurophysiological	O
+study	O
+.	O
+	
+BACKGROUND	O
+:	O
+Recent	O
+studies	O
+confirmed	O
+a	O
+high	O
+incidence	O
+of	O
+sensory	B-NP
+axonal	I-NP
+neuropathy	I-NP
+in	O
+patients	O
+treated	O
+with	O
+different	O
+doses	O
+of	O
+thalidomide	O
+.	O
+	
+The	O
+study	O
+'	O
+s	O
+aims	O
+were	O
+to	O
+measure	O
+variations	O
+in	O
+sural	O
+nerve	O
+sensory	O
+action	O
+potential	O
+(	O
+SAP	O
+)	O
+amplitude	O
+in	O
+patients	O
+with	O
+refractory	O
+cutaneous	B-NP
+lupus	I-NP
+erythematosus	I-NP
+(	O
+CLE	B-NP
+)	O
+treated	O
+with	O
+thalidomide	O
+and	O
+use	O
+these	O
+findings	O
+to	O
+identify	O
+the	O
+neurotoxic	B-NP
+potential	O
+of	O
+thalidomide	O
+and	O
+the	O
+recovery	O
+capacity	O
+of	O
+sensory	O
+fibres	O
+after	O
+discontinuation	O
+of	O
+treatment	O
+.	O
+	
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+Clinical	O
+and	O
+electrophysiological	O
+data	O
+in	O
+12	O
+female	O
+patients	O
+with	O
+CLE	B-NP
+during	O
+treatment	O
+with	O
+thalidomide	O
+and	O
+up	O
+to	O
+47	O
+months	O
+after	O
+discontinuation	O
+of	O
+treatment	O
+were	O
+analysed	O
+.	O
+	
+Sural	O
+nerve	O
+SAP	O
+amplitude	O
+reduction	O
+>	O
+or	O
+=	O
+40	O
+%	O
+was	O
+the	O
+criteria	O
+for	O
+discontinuing	O
+therapy	O
+.	O
+	
+RESULTS	O
+:	O
+During	O
+treatment	O
+","	O
+11	O
+patients	O
+showed	O
+a	O
+reduction	O
+in	O
+sural	O
+nerve	O
+SAP	O
+amplitude	O
+compared	O
+to	O
+baseline	O
+values	O
+(	O
+9	O
+with	O
+a	O
+reduction	O
+>	O
+or	O
+=	O
+50	O
+%	O
+and	O
+2	O
+<	O
+50	O
+%	O
+)	O
+.	O
+	
+One	O
+patient	O
+showed	O
+no	O
+changes	O
+in	O
+SAP	O
+amplitude	O
+.	O
+	
+Five	O
+patients	O
+complained	O
+of	O
+paresthesias	B-NP
+and	O
+leg	O
+cramps	B-NP
+.	O
+	
+After	O
+thalidomide	O
+treatment	O
+","	O
+sural	O
+SAP	O
+amplitude	O
+recovered	O
+in	O
+3	O
+patients	O
+.	O
+	
+At	O
+detection	O
+of	O
+reduction	O
+in	O
+sural	O
+nerve	O
+SAP	O
+amplitude	O
+","	O
+the	O
+median	O
+thalidomide	O
+cumulative	O
+dose	O
+was	O
+21	O
+.	O
+4	O
+g	O
+.	O
+	
+The	O
+threshold	O
+neurotoxic	B-NP
+dosage	O
+is	O
+lower	O
+than	O
+previously	O
+reported	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Sural	O
+nerve	O
+SAP	O
+amplitude	O
+reduction	O
+is	O
+a	O
+reliable	O
+and	O
+sensitive	O
+marker	O
+of	O
+degeneration	O
+and	O
+recovery	O
+of	O
+sensory	O
+fibres	O
+.	O
+	
+This	O
+electrophysiological	O
+parameter	O
+provides	O
+information	O
+about	O
+subclinical	O
+neurotoxic	B-NP
+potential	O
+of	O
+thalidomide	O
+but	O
+is	O
+not	O
+helpful	O
+in	O
+predicting	O
+the	O
+appearance	O
+of	O
+sensory	O
+symptoms	O
+.	O
+	
+Five	O
+cases	O
+of	O
+encephalitis	B-NP
+during	O
+treatment	O
+of	O
+loiasis	B-NP
+with	O
+diethylcarbamazine	O
+.	O
+	
+Five	O
+cases	O
+of	O
+encephalitis	B-NP
+following	O
+treatment	O
+with	O
+diethylcarbamazine	O
+(	O
+DEC	O
+)	O
+were	O
+observed	O
+in	O
+Congolese	O
+patients	O
+with	O
+Loa	O
+loa	O
+filariasis	B-NP
+.	O
+	
+Two	O
+cases	O
+had	O
+a	O
+fatal	O
+outcome	O
+and	O
+one	O
+resulted	O
+in	O
+severe	O
+sequelae	O
+.	O
+	
+The	O
+notable	O
+fact	O
+was	O
+that	O
+this	O
+complication	O
+occurred	O
+in	O
+three	O
+patients	O
+hospitalized	O
+before	O
+treatment	O
+began	O
+","	O
+with	O
+whom	O
+particularly	O
+strict	O
+therapeutic	O
+precautions	O
+were	O
+taken	O
+","	O
+i	O
+.	O
+e	O
+.	O
+","	O
+initial	O
+dose	O
+less	O
+than	O
+10	O
+mg	O
+of	O
+DEC	O
+","	O
+very	O
+gradual	O
+dose	O
+increases	O
+","	O
+and	O
+associated	O
+anti	O
+-	O
+allergic	O
+treatment	O
+.	O
+	
+This	O
+type	O
+of	O
+drug	O
+-	O
+induced	O
+complication	O
+may	O
+not	O
+be	O
+that	O
+uncommon	O
+in	O
+highly	O
+endemic	O
+regions	O
+.	O
+	
+It	O
+occurs	O
+primarily	O
+","	O
+but	O
+not	O
+exclusively	O
+","	O
+in	O
+subjects	O
+presenting	O
+with	O
+a	O
+high	O
+microfilarial	O
+load	O
+.	O
+	
+The	O
+relationship	O
+between	O
+the	O
+occurrence	O
+of	O
+encephalitis	B-NP
+and	O
+the	O
+decrease	O
+in	O
+microfilaremia	B-NP
+is	O
+evident	O
+.	O
+	
+The	O
+pathophysiological	O
+mechanisms	O
+are	O
+discussed	O
+in	O
+the	O
+light	O
+of	O
+these	O
+observations	O
+and	O
+the	O
+few	O
+other	O
+comments	O
+on	O
+this	O
+subject	O
+published	O
+in	O
+the	O
+literature	O
+.	O
+	
+Amiodarone	O
+-	O
+related	O
+pulmonary	B-NP
+mass	I-NP
+and	O
+unique	O
+membranous	B-NP
+glomerulonephritis	I-NP
+in	O
+a	O
+patient	O
+with	O
+valvular	B-NP
+heart	I-NP
+disease	I-NP
+:	O
+Diagnostic	O
+pitfall	O
+and	O
+new	O
+findings	O
+.	O
+	
+Amiodarone	O
+is	O
+an	O
+anti	O
+-	O
+arrhythmic	B-NP
+drug	O
+for	O
+life	O
+-	O
+threatening	O
+tachycardia	B-NP
+","	O
+but	O
+various	O
+adverse	O
+effects	O
+have	O
+been	O
+reported	O
+.	O
+	
+Reported	O
+herein	O
+is	O
+an	O
+autopsy	O
+case	O
+of	O
+valvular	B-NP
+heart	I-NP
+disease	I-NP
+","	O
+in	O
+a	O
+patient	O
+who	O
+developed	O
+a	O
+lung	B-NP
+mass	I-NP
+(	O
+1	O
+.	O
+5	O
+cm	O
+in	O
+diameter	O
+)	O
+and	O
+proteinuria	B-NP
+(	O
+2	O
+.	O
+76	O
+g	O
+/	O
+day	O
+)	O
+after	O
+treatment	O
+with	O
+amiodarone	O
+for	O
+a	O
+long	O
+time	O
+.	O
+	
+The	O
+lung	B-NP
+mass	I-NP
+was	O
+highly	O
+suspected	O
+to	O
+be	O
+lung	B-NP
+cancer	I-NP
+on	O
+CT	O
+and	O
+positron	O
+emission	O
+tomography	O
+","	O
+but	O
+histologically	O
+the	O
+lesion	O
+was	O
+composed	O
+of	O
+lymphoplasmacytic	O
+infiltrates	O
+in	O
+alveolar	O
+walls	O
+and	O
+intra	O
+-	O
+alveolar	O
+accumulation	O
+of	O
+foamy	O
+macrophages	O
+containing	O
+characteristic	O
+myelinoid	O
+bodies	O
+","	O
+indicating	O
+that	O
+it	O
+was	O
+an	O
+amiodarone	O
+-	O
+related	O
+lesion	O
+.	O
+	
+In	O
+addition	O
+","	O
+the	O
+lung	O
+tissue	O
+had	O
+unevenly	O
+distributed	O
+hemosiderin	B-NP
+deposition	O
+","	O
+and	O
+abnormally	O
+tortuous	O
+capillaries	O
+were	O
+seen	O
+in	O
+the	O
+mass	O
+and	O
+in	O
+heavily	O
+hemosiderotic	B-NP
+lung	O
+portions	O
+outside	O
+the	O
+mass	O
+.	O
+	
+In	O
+the	O
+kidneys	O
+","	O
+glomeruli	O
+had	O
+membrane	O
+spikes	O
+","	O
+prominent	O
+swelling	O
+of	O
+podocytes	O
+and	O
+subepithelial	O
+deposits	O
+","	O
+which	O
+were	O
+sometimes	O
+large	O
+and	O
+hump	O
+-	O
+like	O
+.	O
+	
+Autoimmune	B-NP
+diseases	I-NP
+","	O
+viral	B-NP
+hepatitis	I-NP
+","	O
+malignant	O
+neoplasms	B-NP
+or	O
+other	O
+diseases	O
+with	O
+a	O
+known	O
+relationship	O
+to	O
+membranous	B-NP
+glomerulonephritis	I-NP
+were	O
+not	O
+found	O
+.	O
+	
+The	O
+present	O
+case	O
+highlights	O
+the	O
+possibility	O
+that	O
+differential	O
+diagnosis	O
+between	O
+an	O
+amiodarone	O
+-	O
+related	O
+pulmonary	B-NP
+lesion	I-NP
+and	O
+a	O
+neoplasm	B-NP
+can	O
+be	O
+very	O
+difficult	O
+radiologically	O
+","	O
+and	O
+suggests	O
+that	O
+membranous	B-NP
+glomerulonephritis	I-NP
+might	O
+be	O
+another	O
+possible	O
+complication	O
+of	O
+amiodarone	O
+treatment	O
+.	O
+	
+Risk	O
+of	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+associated	O
+with	O
+initial	O
+sulphonylurea	O
+treatment	O
+of	O
+patients	O
+with	O
+type	B-NP
+2	I-NP
+diabetes	I-NP
+:	O
+a	O
+matched	O
+case	O
+-	O
+control	O
+study	O
+.	O
+	
+AIMS	O
+:	O
+This	O
+study	O
+sought	O
+to	O
+assess	O
+the	O
+risk	O
+of	O
+developing	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+(	O
+CAD	B-NP
+)	O
+associated	O
+with	O
+initial	O
+treatment	O
+of	O
+type	B-NP
+2	I-NP
+diabetes	I-NP
+with	O
+different	O
+sulphonylureas	O
+.	O
+	
+METHODS	O
+:	O
+In	O
+type	B-NP
+2	I-NP
+diabetic	I-NP
+patients	O
+","	O
+cases	O
+who	O
+developed	O
+CAD	B-NP
+were	O
+compared	O
+retrospectively	O
+with	O
+controls	O
+that	O
+did	O
+not	O
+.	O
+	
+The	O
+20	O
+-	O
+year	O
+risk	O
+of	O
+CAD	B-NP
+at	O
+diagnosis	O
+of	O
+diabetes	B-NP
+","	O
+using	O
+the	O
+UKPDS	O
+risk	O
+engine	O
+","	O
+was	O
+used	O
+to	O
+match	O
+cases	O
+with	O
+controls	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+76	O
+cases	O
+of	O
+CAD	B-NP
+were	O
+compared	O
+with	O
+152	O
+controls	O
+.	O
+	
+The	O
+hazard	O
+of	O
+developing	O
+CAD	B-NP
+(	O
+95	O
+%	O
+CI	O
+)	O
+associated	O
+with	O
+initial	O
+treatment	O
+increased	O
+by	O
+2	O
+.	O
+4	O
+-	O
+fold	O
+(	O
+1	O
+.	O
+3	O
+-	O
+4	O
+.	O
+3	O
+","	O
+P	O
+=	O
+0	O
+.	O
+4	O
+)	O
+with	O
+glibenclamide	O
+;	O
+2	O
+-	O
+fold	O
+(	O
+0	O
+.	O
+9	O
+-	O
+4	O
+.	O
+6	O
+","	O
+P	O
+=	O
+0	O
+.	O
+99	O
+)	O
+with	O
+glipizide	O
+;	O
+2	O
+.	O
+9	O
+-	O
+fold	O
+(	O
+1	O
+.	O
+6	O
+-	O
+5	O
+.	O
+1	O
+","	O
+P	O
+=	O
+0	O
+.	O
+0	O
+)	O
+with	O
+either	O
+","	O
+and	O
+was	O
+unchanged	O
+with	O
+metformin	O
+.	O
+	
+The	O
+hazard	O
+decreased	O
+0	O
+.	O
+3	O
+-	O
+fold	O
+(	O
+0	O
+.	O
+7	O
+-	O
+1	O
+.	O
+7	O
+","	O
+P	O
+=	O
+0	O
+.	O
+385	O
+)	O
+with	O
+glimepiride	O
+","	O
+0	O
+.	O
+4	O
+-	O
+fold	O
+(	O
+0	O
+.	O
+7	O
+-	O
+1	O
+.	O
+3	O
+","	O
+P	O
+=	O
+0	O
+.	O
+192	O
+)	O
+with	O
+gliclazide	O
+","	O
+and	O
+0	O
+.	O
+4	O
+-	O
+fold	O
+(	O
+0	O
+.	O
+7	O
+-	O
+1	O
+.	O
+1	O
+","	O
+P	O
+=	O
+0	O
+.	O
+9	O
+)	O
+with	O
+either	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Initiating	O
+treatment	O
+of	O
+type	B-NP
+2	I-NP
+diabetes	I-NP
+with	O
+glibenclamide	O
+or	O
+glipizide	O
+is	O
+associated	O
+with	O
+increased	O
+risk	O
+of	O
+CAD	B-NP
+in	O
+comparison	O
+to	O
+gliclazide	O
+or	O
+glimepiride	O
+.	O
+	
+If	O
+confirmed	O
+","	O
+this	O
+may	O
+be	O
+important	O
+because	O
+most	O
+Indian	O
+patients	O
+receive	O
+the	O
+cheaper	O
+older	O
+sulphonylureas	O
+","	O
+and	O
+present	O
+guidelines	O
+do	O
+not	O
+distinguish	O
+between	O
+individual	O
+agents	O
+.	O
+	
+Reduced	O
+progression	O
+of	O
+adriamycin	O
+nephropathy	B-NP
+in	O
+spontaneously	O
+hypertensive	B-NP
+rats	O
+treated	O
+by	O
+losartan	O
+.	O
+	
+BACKGROUND	O
+:	O
+The	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+antihypertensive	O
+effects	O
+of	O
+angiotensin	O
+II	O
+type	O
+-	O
+1	O
+receptor	O
+blocker	O
+","	O
+losartan	O
+","	O
+and	O
+its	O
+potential	O
+in	O
+slowing	O
+down	O
+renal	B-NP
+disease	I-NP
+progression	O
+in	O
+spontaneously	O
+hypertensive	B-NP
+rats	O
+(	O
+SHR	O
+)	O
+with	O
+adriamycin	O
+(	O
+ADR	O
+)	O
+nephropathy	B-NP
+.	O
+	
+METHODS	O
+:	O
+Six	O
+-	O
+month	O
+-	O
+old	O
+female	O
+SHR	O
+were	O
+randomly	O
+selected	O
+in	O
+six	O
+groups	O
+.	O
+	
+Two	O
+control	O
+groups	O
+(	O
+SH	O
+(	O
+6	O
+)	O
+","	O
+SH	O
+(	O
+12	O
+)	O
+)	O
+received	O
+vehicle	O
+.	O
+	
+Groups	O
+ADR	O
+(	O
+6	O
+)	O
+","	O
+ADR	O
++	O
+LOS	O
+(	O
+6	O
+)	O
+and	O
+ADR	O
+(	O
+12	O
+)	O
+","	O
+and	O
+ADR	O
++	O
+LOS	O
+(	O
+12	O
+)	O
+received	O
+ADR	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+/	O
+b	O
+.	O
+w	O
+.	O
+i	O
+.	O
+v	O
+.	O
+)	O
+twice	O
+in	O
+a	O
+3	O
+-	O
+week	O
+interval	O
+.	O
+	
+Group	O
+ADR	O
++	O
+LOS	O
+(	O
+6	O
+)	O
+received	O
+losartan	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+/	O
+b	O
+.	O
+w	O
+.	O
+/	O
+day	O
+by	O
+gavages	O
+)	O
+for	O
+6	O
+weeks	O
+and	O
+group	O
+ADR	O
++	O
+LOS	O
+(	O
+12	O
+)	O
+for	O
+12	O
+weeks	O
+after	O
+second	O
+injection	O
+of	O
+ADR	O
+.	O
+	
+Animals	O
+were	O
+killed	O
+after	O
+6	O
+or	O
+12	O
+weeks	O
+","	O
+respectively	O
+.	O
+	
+Haemodynamic	O
+measurements	O
+were	O
+performed	O
+on	O
+anaesthetized	O
+animals	O
+","	O
+blood	O
+and	O
+urine	O
+samples	O
+were	O
+taken	O
+for	O
+biochemical	O
+analysis	O
+and	O
+the	O
+left	O
+kidney	O
+was	O
+processed	O
+for	O
+morphological	O
+studies	O
+.	O
+	
+RESULTS	O
+:	O
+Short	O
+-	O
+term	O
+losartan	O
+treatment	O
+","	O
+besides	O
+antihypertensive	O
+effect	O
+","	O
+improved	O
+glomerular	O
+filtration	O
+rate	O
+and	O
+ameliorated	O
+glomerulosclerosis	B-NP
+resulting	O
+in	O
+decreased	O
+proteinuria	B-NP
+.	O
+	
+Prolonged	O
+treatment	O
+with	O
+losartan	O
+showed	O
+further	O
+reduction	O
+of	O
+glomerulosclerosis	B-NP
+associated	O
+with	O
+reduced	O
+progression	O
+of	O
+tubular	O
+atrophy	B-NP
+and	O
+interstitial	B-NP
+fibrosis	I-NP
+","	O
+thus	O
+preventing	O
+heavy	O
+proteinuria	B-NP
+and	O
+chronic	B-NP
+renal	I-NP
+failure	I-NP
+.	O
+	
+Losartan	O
+reduced	O
+uraemia	B-NP
+and	O
+increased	O
+urea	O
+clearance	O
+in	O
+advanced	O
+ADR	O
+nephropathy	B-NP
+in	O
+SHR	O
+.	O
+	
+Histological	O
+examination	O
+showed	O
+that	O
+losartan	O
+could	O
+prevent	O
+tubular	O
+atrophy	B-NP
+","	O
+interstitial	O
+infiltration	O
+and	O
+fibrosis	B-NP
+in	O
+ADR	O
+nephropathy	B-NP
+.	O
+	
+CONCLUSION	O
+:	O
+Losartan	O
+reduces	O
+the	O
+rate	O
+of	O
+progression	O
+of	O
+ADR	O
+-	O
+induced	O
+focal	B-NP
+segmental	I-NP
+glomerulosclerosis	I-NP
+to	O
+end	B-NP
+-	I-NP
+stage	I-NP
+renal	I-NP
+disease	I-NP
+in	O
+SHR	O
+.	O
+	
+The	O
+risks	O
+of	O
+aprotinin	O
+and	O
+tranexamic	O
+acid	O
+in	O
+cardiac	O
+surgery	O
+:	O
+a	O
+one	O
+-	O
+year	O
+follow	O
+-	O
+up	O
+of	O
+1188	O
+consecutive	O
+patients	O
+.	O
+	
+BACKGROUND	O
+:	O
+Our	O
+aim	O
+was	O
+to	O
+investigate	O
+postoperative	O
+complications	O
+and	O
+mortality	O
+after	O
+administration	O
+of	O
+aprotinin	O
+compared	O
+to	O
+tranexamic	O
+acid	O
+in	O
+an	O
+unselected	O
+","	O
+consecutive	O
+cohort	O
+.	O
+	
+METHODS	O
+:	O
+Perioperative	O
+data	O
+from	O
+consecutive	O
+cardiac	O
+surgery	O
+patients	O
+were	O
+prospectively	O
+collected	O
+between	O
+September	O
+2005	O
+and	O
+June	O
+2006	O
+in	O
+a	O
+university	O
+-	O
+affiliated	O
+clinic	O
+(	O
+n	O
+=	O
+1188	O
+)	O
+.	O
+	
+During	O
+the	O
+first	O
+5	O
+mo	O
+","	O
+596	O
+patients	O
+received	O
+aprotinin	O
+(	O
+Group	O
+A	O
+)	O
+;	O
+in	O
+the	O
+next	O
+5	O
+mo	O
+","	O
+592	O
+patients	O
+were	O
+treated	O
+with	O
+tranexamic	O
+acid	O
+(	O
+Group	O
+T	O
+)	O
+.	O
+	
+Except	O
+for	O
+antifibrinolytic	O
+therapy	O
+","	O
+the	O
+anesthetic	O
+and	O
+surgical	O
+protocols	O
+remained	O
+unchanged	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+pre	O
+-	O
+and	O
+intraoperative	O
+variables	O
+were	O
+comparable	O
+between	O
+the	O
+treatment	O
+groups	O
+.	O
+	
+Postoperatively	O
+","	O
+a	O
+significantly	O
+higher	O
+incidence	O
+of	O
+seizures	B-NP
+was	O
+found	O
+in	O
+Group	O
+T	O
+(	O
+4	O
+.	O
+6	O
+%	O
+vs	O
+1	O
+.	O
+2	O
+%	O
+","	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+This	O
+difference	O
+was	O
+also	O
+significant	O
+in	O
+the	O
+primary	O
+valve	O
+surgery	O
+and	O
+the	O
+high	O
+risk	O
+surgery	O
+subgroups	O
+(	O
+7	O
+.	O
+9	O
+%	O
+vs	O
+1	O
+.	O
+2	O
+%	O
+","	O
+P	O
+=	O
+0	O
+.	O
+3	O
+;	O
+7	O
+.	O
+3	O
+%	O
+vs	O
+2	O
+.	O
+4	O
+%	O
+","	O
+P	O
+=	O
+0	O
+.	O
+35	O
+","	O
+respectively	O
+)	O
+.	O
+	
+Persistent	O
+atrial	O
+fibrillation	O
+(	O
+7	O
+.	O
+9	O
+%	O
+vs	O
+2	O
+.	O
+3	O
+%	O
+","	O
+P	O
+=	O
+0	O
+.	O
+20	O
+)	O
+and	O
+renal	B-NP
+failure	I-NP
+(	O
+9	O
+.	O
+7	O
+%	O
+vs	O
+1	O
+.	O
+7	O
+%	O
+","	O
+P	O
+=	O
+0	O
+.	O
+2	O
+)	O
+were	O
+also	O
+more	O
+common	O
+in	O
+Group	O
+T	O
+","	O
+in	O
+the	O
+primary	O
+valve	O
+surgery	O
+subgroup	O
+.	O
+	
+On	O
+the	O
+contrary	O
+","	O
+among	O
+primary	O
+coronary	O
+artery	O
+bypass	O
+surgery	O
+patients	O
+","	O
+there	O
+were	O
+more	O
+acute	O
+myocardial	B-NP
+infarctions	I-NP
+and	O
+renal	B-NP
+dysfunction	I-NP
+in	O
+Group	O
+A	O
+(	O
+5	O
+.	O
+8	O
+%	O
+vs	O
+2	O
+.	O
+0	O
+%	O
+","	O
+P	O
+=	O
+0	O
+.	O
+27	O
+;	O
+22	O
+.	O
+5	O
+%	O
+vs	O
+15	O
+.	O
+2	O
+%	O
+","	O
+P	O
+=	O
+0	O
+.	O
+36	O
+","	O
+respectively	O
+)	O
+.	O
+	
+The	O
+1	O
+-	O
+yr	O
+mortality	O
+was	O
+significantly	O
+higher	O
+after	O
+aprotinin	O
+treatment	O
+in	O
+the	O
+high	O
+risk	O
+surgery	O
+group	O
+(	O
+17	O
+.	O
+7	O
+%	O
+vs	O
+9	O
+.	O
+8	O
+%	O
+","	O
+P	O
+=	O
+0	O
+.	O
+34	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+Both	O
+antifibrinolytic	O
+drugs	O
+bear	O
+the	O
+risk	O
+of	O
+adverse	O
+outcome	O
+depending	O
+on	O
+the	O
+type	O
+of	O
+cardiac	O
+surgery	O
+.	O
+	
+Administration	O
+of	O
+aprotinin	O
+should	O
+be	O
+avoided	O
+in	O
+coronary	O
+artery	O
+bypass	O
+graft	O
+and	O
+high	O
+risk	O
+patients	O
+","	O
+whereas	O
+administration	O
+of	O
+tranexamic	O
+acid	O
+is	O
+not	O
+recommended	O
+in	O
+valve	O
+surgery	O
+.	O
+	
+Delirium	B-NP
+in	O
+an	O
+elderly	O
+woman	O
+possibly	O
+associated	O
+with	O
+administration	O
+of	O
+misoprostol	O
+.	O
+	
+Misoprostol	O
+has	O
+been	O
+associated	O
+with	O
+adverse	O
+reactions	O
+","	O
+including	O
+gastrointestinal	O
+symptoms	O
+","	O
+gynecologic	O
+problems	O
+","	O
+and	O
+headache	B-NP
+.	O
+	
+Changes	O
+in	O
+mental	O
+status	O
+","	O
+however	O
+","	O
+have	O
+not	O
+been	O
+reported	O
+.	O
+	
+We	O
+present	O
+a	O
+case	O
+in	O
+which	O
+an	O
+89	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+in	O
+a	O
+long	O
+-	O
+term	O
+care	O
+facility	O
+became	O
+confused	O
+after	O
+the	O
+initiation	O
+of	O
+misoprostol	O
+therapy	O
+.	O
+	
+The	O
+patient	O
+'	O
+s	O
+change	O
+in	O
+mental	O
+status	O
+was	O
+first	O
+reported	O
+nine	O
+days	O
+after	O
+the	O
+initiation	O
+of	O
+therapy	O
+.	O
+	
+Her	O
+delirium	B-NP
+significantly	O
+improved	O
+after	O
+misoprostol	O
+was	O
+discontinued	O
+and	O
+her	O
+mental	O
+status	O
+returned	O
+to	O
+normal	O
+within	O
+a	O
+week	O
+.	O
+	
+Because	O
+no	O
+other	O
+factors	O
+related	O
+to	O
+this	O
+patient	O
+changed	O
+significantly	O
+","	O
+the	O
+delirium	B-NP
+experienced	O
+by	O
+this	O
+patient	O
+possibly	O
+resulted	O
+from	O
+misoprostol	O
+therapy	O
+.	O
+	
+The	O
+biological	O
+properties	O
+of	O
+the	O
+optical	O
+isomers	O
+of	O
+propranolol	O
+and	O
+their	O
+effects	O
+on	O
+cardiac	B-NP
+arrhythmias	I-NP
+.	O
+	
+1	O
+.	O
+	
+The	O
+optical	O
+isomers	O
+of	O
+propranolol	O
+have	O
+been	O
+compared	O
+for	O
+their	O
+beta	O
+-	O
+blocking	O
+and	O
+antiarrhythmic	O
+activities	O
+.	O
+2	O
+.	O
+	
+In	O
+blocking	O
+the	O
+positive	O
+inotropic	O
+and	O
+chronotropic	O
+responses	O
+to	O
+isoprenaline	O
+","	O
+(	O
++	O
+)	O
+-	O
+propranolol	O
+had	O
+less	O
+than	O
+one	O
+hundredth	O
+the	O
+potency	O
+of	O
+(	O
+-	O
+)	O
+-	O
+propranolol	O
+.	O
+	
+At	O
+dose	O
+levels	O
+of	O
+(	O
++	O
+)	O
+-	O
+propranolol	O
+which	O
+attenuated	O
+the	O
+responses	O
+to	O
+isoprenaline	O
+","	O
+there	O
+was	O
+a	O
+significant	O
+prolongation	O
+of	O
+the	O
+PR	O
+interval	O
+of	O
+the	O
+electrocardiogram	O
+.	O
+3	O
+.	O
+	
+The	O
+metabolic	O
+responses	O
+to	O
+isoprenaline	O
+in	O
+dogs	O
+(	O
+an	O
+increase	O
+in	O
+circulating	O
+glucose	O
+","	O
+lactate	O
+and	O
+free	O
+fatty	O
+acids	O
+)	O
+were	O
+all	O
+blocked	O
+by	O
+(	O
+-	O
+)	O
+-	O
+propranolol	O
+.	O
+	
+(	O
++	O
+)	O
+-	O
+Propranolol	O
+had	O
+no	O
+effect	O
+on	O
+fatty	O
+acid	O
+mobilization	O
+but	O
+significantly	O
+reduced	O
+the	O
+increments	O
+in	O
+both	O
+lactate	O
+and	O
+glucose	O
+.	O
+4	O
+.	O
+	
+Both	O
+isomers	O
+of	O
+propranolol	O
+possessed	O
+similar	O
+depressant	O
+potency	O
+on	O
+isolated	O
+atrial	O
+muscle	O
+taken	O
+from	O
+guinea	O
+-	O
+pigs	O
+.	O
+5	O
+.	O
+	
+The	O
+isomers	O
+of	O
+propranolol	O
+exhibited	O
+similar	O
+local	O
+anaesthetic	O
+potencies	O
+on	O
+an	O
+isolated	O
+frog	O
+nerve	O
+preparation	O
+at	O
+a	O
+level	O
+approximately	O
+three	O
+times	O
+that	O
+of	O
+procaine	O
+.	O
+	
+The	O
+racemic	O
+compound	O
+was	O
+significantly	O
+less	O
+potent	O
+than	O
+either	O
+isomer	O
+.	O
+6	O
+.	O
+	
+Both	O
+isomers	O
+of	O
+propranolol	O
+were	O
+capable	O
+of	O
+preventing	O
+adrenaline	O
+-	O
+induced	O
+cardiac	B-NP
+arrhythmias	I-NP
+in	O
+cats	O
+anaesthetized	O
+with	O
+halothane	O
+","	O
+but	O
+the	O
+mean	O
+dose	O
+of	O
+(	O
+-	O
+)	O
+-	O
+propranolol	O
+was	O
+0	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+whereas	O
+that	O
+of	O
+(	O
++	O
+)	O
+-	O
+propranolol	O
+was	O
+4	O
+.	O
+2	O
++	O
+/	O
+-	O
+1	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+.	O
+	
+At	O
+the	O
+effective	O
+dose	O
+level	O
+of	O
+(	O
++	O
+)	O
+-	O
+propranolol	O
+there	O
+was	O
+a	O
+significant	O
+prolongation	O
+of	O
+the	O
+PR	O
+interval	O
+of	O
+the	O
+electrocardiogram	O
+.	O
+	
+Blockade	O
+of	O
+arrhythmias	B-NP
+with	O
+both	O
+isomers	O
+was	O
+surmountable	O
+by	O
+increasing	O
+the	O
+dose	O
+of	O
+adrenaline	O
+.	O
+7	O
+.	O
+	
+Both	O
+isomers	O
+of	O
+propranolol	O
+were	O
+also	O
+capable	O
+of	O
+reversing	O
+ventricular	B-NP
+tachycardia	I-NP
+caused	O
+by	O
+ouabain	O
+in	O
+anaesthetized	O
+cats	O
+and	O
+dogs	O
+.	O
+	
+The	O
+dose	O
+of	O
+(	O
+-	O
+)	O
+-	O
+propranolol	O
+was	O
+significantly	O
+smaller	O
+than	O
+that	O
+of	O
+(	O
++	O
+)	O
+-	O
+propranolol	O
+in	O
+both	O
+species	O
+but	O
+much	O
+higher	O
+than	O
+that	O
+required	O
+to	O
+produce	O
+evidence	O
+of	O
+beta	O
+-	O
+blockade	O
+.	O
+8	O
+.	O
+	
+The	O
+implications	O
+of	O
+these	O
+results	O
+are	O
+discussed	O
+.	O
+	
+Topotecan	O
+in	O
+combination	O
+with	O
+radiotherapy	O
+in	O
+unresectable	O
+glioblastoma	B-NP
+:	O
+a	O
+phase	O
+2	O
+study	O
+.	O
+	
+Improving	O
+glioblastoma	B-NP
+multiforme	I-NP
+(	O
+GBM	B-NP
+)	O
+treatment	O
+with	O
+radio	O
+-	O
+chemotherapy	O
+remains	O
+a	O
+challenge	O
+.	O
+	
+Topotecan	O
+is	O
+an	O
+attractive	O
+option	O
+as	O
+it	O
+exhibits	O
+growth	O
+inhibition	O
+of	O
+human	O
+glioma	B-NP
+as	O
+well	O
+as	O
+brain	O
+penetration	O
+.	O
+	
+The	O
+present	O
+study	O
+assessed	O
+the	O
+combination	O
+of	O
+radiotherapy	O
+(	O
+60	O
+Gy	O
+/	O
+30	O
+fractions	O
+/	O
+40	O
+days	O
+)	O
+and	O
+topotecan	O
+(	O
+0	O
+.	O
+9	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+/	O
+day	O
+on	O
+days	O
+1	O
+-	O
+5	O
+on	O
+weeks	O
+1	O
+","	O
+3	O
+and	O
+5	O
+)	O
+in	O
+50	O
+adults	O
+with	O
+histologically	O
+proven	O
+and	O
+untreated	O
+GBM	B-NP
+.	O
+	
+The	O
+incidence	O
+of	O
+non	O
+-	O
+hematological	O
+toxicities	B-NP
+was	O
+low	O
+and	O
+grade	O
+3	O
+-	O
+4	O
+hematological	O
+toxicities	B-NP
+were	O
+reported	O
+in	O
+20	O
+patients	O
+(	O
+mainly	O
+lymphopenia	B-NP
+and	O
+neutropenia	B-NP
+)	O
+.	O
+	
+Partial	O
+response	O
+and	O
+stabilization	O
+rates	O
+were	O
+2	O
+%	O
+and	O
+32	O
+%	O
+","	O
+respectively	O
+","	O
+with	O
+an	O
+overall	O
+time	O
+to	O
+progression	O
+of	O
+12	O
+weeks	O
+.	O
+	
+One	O
+-	O
+year	O
+overall	O
+survival	O
+(	O
+OS	O
+)	O
+rate	O
+was	O
+42	O
+%	O
+","	O
+with	O
+a	O
+median	O
+OS	O
+of	O
+40	O
+weeks	O
+.	O
+	
+Topotecan	O
+in	O
+combination	O
+with	O
+radiotherapy	O
+was	O
+well	O
+tolerated	O
+.	O
+	
+However	O
+","	O
+while	O
+response	O
+and	O
+stabilization	O
+concerned	O
+one	O
+-	O
+third	O
+of	O
+the	O
+patients	O
+","	O
+the	O
+study	O
+did	O
+not	O
+show	O
+increased	O
+benefits	O
+in	O
+terms	O
+of	O
+survival	O
+in	O
+patients	O
+with	O
+unresectable	O
+GBM	B-NP
+.	O
+	
+Long	O
+-	O
+term	O
+lithium	O
+therapy	O
+leading	O
+to	O
+hyperparathyroidism	B-NP
+:	O
+a	O
+case	O
+report	O
+.	O
+	
+PURPOSE	O
+:	O
+This	O
+paper	O
+reviews	O
+the	O
+effect	O
+of	O
+chronic	O
+lithium	O
+therapy	O
+on	O
+serum	O
+calcium	O
+level	O
+and	O
+parathyroid	O
+glands	O
+","	O
+its	O
+pathogenesis	O
+","	O
+and	O
+treatment	O
+options	O
+.	O
+	
+We	O
+examined	O
+the	O
+case	O
+of	O
+a	O
+lithium	O
+-	O
+treated	O
+patient	O
+who	O
+had	O
+recurrent	O
+hypercalcemia	B-NP
+to	O
+better	O
+understand	O
+the	O
+disease	O
+process	O
+.	O
+	
+CONCLUSION	O
+:	O
+Primary	B-NP
+hyperparathyroidism	I-NP
+is	O
+a	O
+rare	O
+but	O
+potentially	O
+life	O
+-	O
+threatening	O
+side	O
+effect	O
+of	O
+long	O
+-	O
+term	O
+lithium	O
+therapy	O
+.	O
+	
+Careful	O
+patient	O
+selection	O
+and	O
+long	O
+-	O
+term	O
+follow	O
+-	O
+up	O
+can	O
+reduce	O
+morbidity	O
+.	O
+	
+PRACTICAL	O
+IMPLICATIONS	O
+:	O
+As	O
+much	O
+as	O
+15	O
+%	O
+of	O
+lithium	O
+-	O
+treated	O
+patients	O
+become	O
+hypercalcemic	B-NP
+.	O
+	
+By	O
+routinely	O
+monitoring	O
+serum	O
+calcium	O
+levels	O
+","	O
+healthcare	O
+providers	O
+can	O
+improve	O
+the	O
+quality	O
+of	O
+life	O
+of	O
+this	O
+patient	O
+group	O
+.	O
+	
+Comparison	O
+of	O
+laryngeal	O
+mask	O
+with	O
+endotracheal	O
+tube	O
+for	O
+anesthesia	O
+in	O
+endoscopic	O
+sinus	O
+surgery	O
+.	O
+	
+BACKGROUND	O
+:	O
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+compare	O
+surgical	O
+conditions	O
+","	O
+including	O
+the	O
+amount	O
+of	O
+intraoperative	O
+bleeding	B-NP
+as	O
+well	O
+as	O
+intraoperative	O
+blood	O
+pressure	O
+","	O
+during	O
+functional	O
+endoscopic	O
+sinus	O
+surgery	O
+(	O
+FESS	O
+)	O
+using	O
+flexible	O
+reinforced	O
+laryngeal	O
+mask	O
+airway	O
+(	O
+FRLMA	O
+)	O
+versus	O
+endotracheal	O
+tube	O
+(	O
+ETT	O
+)	O
+in	O
+maintaining	O
+controlled	O
+hypotension	B-NP
+anesthesia	O
+induced	O
+by	O
+propofol	O
+-	O
+remifentanil	O
+total	O
+i	O
+.	O
+v	O
+.	O
+anesthesia	O
+(	O
+TIVA	O
+)	O
+.	O
+	
+METHODS	O
+:	O
+Sixty	O
+normotensive	O
+American	O
+Society	O
+of	O
+Anesthesiologists	O
+I	O
+-	O
+II	O
+adult	O
+patients	O
+undergoing	O
+FESS	O
+under	O
+controlled	O
+hypotension	B-NP
+anesthesia	O
+caused	O
+by	O
+propofol	O
+-	O
+remifentanil	O
+-	O
+TIVA	O
+were	O
+randomly	O
+assigned	O
+into	O
+two	O
+groups	O
+:	O
+group	O
+I	O
+","	O
+FRLMA	O
+;	O
+group	O
+II	O
+","	O
+ETT	O
+.	O
+	
+Hemorrhage	B-NP
+was	O
+measured	O
+and	O
+the	O
+visibility	O
+of	O
+the	O
+operative	O
+field	O
+was	O
+evaluated	O
+according	O
+to	O
+a	O
+six	O
+-	O
+point	O
+scale	O
+.	O
+	
+RESULTS	O
+:	O
+Controlled	O
+hypotension	B-NP
+was	O
+achieved	O
+within	O
+a	O
+shorter	O
+period	O
+using	O
+laryngeal	O
+mask	O
+using	O
+lower	O
+rates	O
+of	O
+remifentanil	O
+infusion	O
+and	O
+lower	O
+total	O
+dose	O
+of	O
+remifentanil	O
+.	O
+	
+CONCLUSION	O
+:	O
+In	O
+summary	O
+","	O
+our	O
+results	O
+indicate	O
+that	O
+airway	O
+management	O
+using	O
+FRLMA	O
+during	O
+controlled	O
+hypotension	B-NP
+anesthesia	O
+provided	O
+better	O
+surgical	O
+conditions	O
+in	O
+terms	O
+of	O
+quality	O
+of	O
+operative	O
+field	O
+and	O
+blood	O
+loss	O
+and	O
+allowed	O
+for	O
+convenient	O
+induced	O
+hypotension	B-NP
+with	O
+low	O
+doses	O
+of	O
+remifentanil	O
+during	O
+TIVA	O
+in	O
+patients	O
+undergoing	O
+FESS	O
+.	O
+	
+Nonalcoholic	B-NP
+fatty	I-NP
+liver	I-NP
+disease	I-NP
+during	O
+valproate	O
+therapy	O
+.	O
+	
+Valproic	O
+acid	O
+(	O
+VPA	O
+)	O
+is	O
+effective	O
+for	O
+the	O
+treatment	O
+of	O
+many	O
+types	O
+of	O
+epilepsy	B-NP
+","	O
+but	O
+its	O
+use	O
+can	O
+be	O
+associated	O
+with	O
+an	O
+increase	O
+in	O
+body	O
+weight	O
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+nonalcoholic	B-NP
+fatty	I-NP
+liver	I-NP
+disease	I-NP
+(	O
+NAFLD	B-NP
+)	O
+arising	O
+in	O
+a	O
+child	O
+who	O
+developed	O
+obesity	B-NP
+during	O
+VPA	O
+treatment	O
+.	O
+	
+Laboratory	O
+data	O
+revealed	O
+hyperinsulinemia	B-NP
+with	O
+insulin	B-NP
+resistance	I-NP
+.	O
+	
+After	O
+the	O
+withdrawal	O
+of	O
+VPA	O
+therapy	O
+","	O
+our	O
+patient	O
+showed	O
+a	O
+significant	O
+weight	B-NP
+loss	I-NP
+","	O
+a	O
+decrease	O
+of	O
+body	O
+mass	O
+index	O
+","	O
+and	O
+normalization	O
+of	O
+metabolic	O
+and	O
+endocrine	O
+parameters	O
+;	O
+moreover	O
+","	O
+ultrasound	O
+measurements	O
+showed	O
+a	O
+complete	O
+normalization	O
+.	O
+	
+The	O
+present	O
+case	O
+suggests	O
+that	O
+obesity	B-NP
+","	O
+hyperinsulinemia	B-NP
+","	O
+insulin	B-NP
+resistance	I-NP
+","	O
+and	O
+long	O
+-	O
+term	O
+treatment	O
+with	O
+VPA	O
+may	O
+be	O
+all	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+NAFLD	B-NP
+;	O
+this	O
+side	O
+effect	O
+is	O
+reversible	O
+after	O
+VPA	O
+withdrawal	O
+.	O
+	
+Carbimazole	O
+induced	O
+ANCA	B-NP
+positive	I-NP
+vasculitis	I-NP
+.	O
+	
+Anti	O
+-	O
+thyroid	O
+drugs	O
+","	O
+like	O
+carbimazole	O
+and	O
+propylthiouracil	O
+(	O
+PTU	O
+)	O
+are	O
+commonly	O
+prescribed	O
+for	O
+the	O
+treatment	O
+of	O
+hyperthyroidism	B-NP
+.	O
+	
+One	O
+should	O
+be	O
+aware	O
+of	O
+the	O
+side	O
+effects	O
+of	O
+antithyroid	O
+medications	O
+.	O
+	
+Antineutrophil	B-NP
+cytoplasmic	I-NP
+antibody	I-NP
+(	I-NP
+ANCA	I-NP
+)	I-NP
+-	I-NP
+-	I-NP
+associated	I-NP
+vasculitis	I-NP
+is	O
+a	O
+potentially	O
+life	O
+-	O
+threatening	O
+adverse	O
+effect	O
+of	O
+antithyroidmedications	O
+.	O
+	
+We	O
+report	O
+a	O
+patient	O
+with	O
+Graves	B-NP
+'	I-NP
+disease	I-NP
+who	O
+developed	O
+ANCA	O
+positive	O
+carbimazole	O
+induced	O
+vasculitis	B-NP
+.	O
+	
+The	O
+episode	O
+was	O
+characterized	O
+by	O
+a	O
+vasculitic	B-NP
+skin	B-NP
+rash	I-NP
+associated	O
+with	O
+large	O
+joint	O
+arthritis	B-NP
+","	O
+pyrexia	B-NP
+and	O
+parotiditis	B-NP
+but	O
+no	O
+renal	O
+or	O
+pulmonary	O
+involvement	O
+.	O
+	
+He	O
+was	O
+referred	O
+to	O
+us	O
+for	O
+neurological	O
+evaluation	O
+because	O
+he	O
+had	O
+difficulty	O
+in	O
+getting	O
+up	O
+from	O
+squatting	O
+position	O
+and	O
+was	O
+suspected	O
+to	O
+have	O
+myositis	B-NP
+.	O
+	
+Carbimazole	O
+and	O
+methimazole	O
+have	O
+a	O
+lower	O
+incidence	O
+of	O
+reported	O
+ANCA	O
+positive	O
+side	O
+effects	O
+than	O
+PUT	O
+.	O
+	
+To	O
+the	O
+best	O
+of	O
+our	O
+knowledge	O
+this	O
+is	O
+the	O
+first	O
+ANCA	O
+positive	O
+carbimazole	O
+induced	O
+vasculitis	B-NP
+case	O
+reported	O
+from	O
+India	O
+.	O
+	
+Aspirin	O
+for	O
+the	O
+primary	O
+prevention	O
+of	O
+cardiovascular	O
+events	O
+:	O
+an	O
+update	O
+of	O
+the	O
+evidence	O
+for	O
+the	O
+U	O
+.	O
+S	O
+.	O
+	
+Preventive	O
+Services	O
+Task	O
+Force	O
+.	O
+	
+BACKGROUND	O
+:	O
+Coronary	B-NP
+heart	I-NP
+disease	I-NP
+and	O
+cerebrovascular	B-NP
+disease	I-NP
+are	O
+leading	O
+causes	O
+of	O
+death	O
+in	O
+the	O
+United	O
+States	O
+.	O
+	
+In	O
+2002	O
+","	O
+the	O
+U	O
+.	O
+S	O
+.	O
+	
+Preventive	O
+Services	O
+Task	O
+Force	O
+(	O
+USPSTF	O
+)	O
+strongly	O
+recommended	O
+that	O
+clinicians	O
+discuss	O
+aspirin	O
+with	O
+adults	O
+who	O
+are	O
+at	O
+increased	O
+risk	O
+for	O
+coronary	B-NP
+heart	I-NP
+disease	I-NP
+.	O
+	
+PURPOSE	O
+:	O
+To	O
+determine	O
+the	O
+benefits	O
+and	O
+harms	O
+of	O
+taking	O
+aspirin	O
+for	O
+the	O
+primary	O
+prevention	O
+of	O
+myocardial	B-NP
+infarctions	I-NP
+","	O
+strokes	B-NP
+","	O
+and	O
+death	O
+.	O
+	
+DATA	O
+SOURCES	O
+:	O
+MEDLINE	O
+and	O
+Cochrane	O
+Library	O
+(	O
+search	O
+dates	O
+","	O
+1	O
+January	O
+2001	O
+to	O
+28	O
+August	O
+2008	O
+)	O
+","	O
+recent	O
+systematic	O
+reviews	O
+","	O
+reference	O
+lists	O
+of	O
+retrieved	O
+articles	O
+","	O
+and	O
+suggestions	O
+from	O
+experts	O
+.	O
+	
+STUDY	O
+SELECTION	O
+:	O
+English	O
+-	O
+language	O
+randomized	O
+","	O
+controlled	O
+trials	O
+(	O
+RCTs	O
+)	O
+;	O
+case	O
+-	O
+control	O
+studies	O
+;	O
+meta	O
+-	O
+analyses	O
+;	O
+and	O
+systematic	O
+reviews	O
+of	O
+aspirin	O
+versus	O
+control	O
+for	O
+the	O
+primary	O
+prevention	O
+of	O
+cardiovascular	B-NP
+disease	I-NP
+(	O
+CVD	B-NP
+)	O
+were	O
+selected	O
+to	O
+answer	O
+the	O
+following	O
+questions	O
+:	O
+Does	O
+aspirin	O
+decrease	O
+coronary	O
+heart	O
+events	O
+","	O
+strokes	B-NP
+","	O
+death	O
+from	O
+coronary	O
+heart	O
+events	O
+or	O
+stroke	B-NP
+","	O
+or	O
+all	O
+-	O
+cause	O
+mortality	O
+in	O
+adults	O
+without	O
+known	O
+CVD	B-NP
+?	O
+	
+Does	O
+aspirin	O
+increase	O
+gastrointestinal	B-NP
+bleeding	I-NP
+or	O
+hemorrhagic	B-NP
+strokes	I-NP
+?	O
+	
+DATA	O
+EXTRACTION	O
+:	O
+All	O
+studies	O
+were	O
+reviewed	O
+","	O
+abstracted	O
+","	O
+and	O
+rated	O
+for	O
+quality	O
+by	O
+using	O
+predefined	O
+USPSTF	O
+criteria	O
+.	O
+	
+DATA	O
+SYNTHESIS	O
+:	O
+New	O
+evidence	O
+from	O
+1	O
+good	O
+-	O
+quality	O
+RCT	O
+","	O
+1	O
+good	O
+-	O
+quality	O
+meta	O
+-	O
+analysis	O
+","	O
+and	O
+2	O
+fair	O
+-	O
+quality	O
+subanalyses	O
+of	O
+RCTs	O
+demonstrates	O
+that	O
+aspirin	O
+use	O
+reduces	O
+the	O
+number	O
+of	O
+CVD	B-NP
+events	O
+in	O
+patients	O
+without	O
+known	O
+CVD	B-NP
+.	O
+	
+Men	O
+in	O
+these	O
+studies	O
+experienced	O
+fewer	O
+myocardial	B-NP
+infarctions	I-NP
+and	O
+women	O
+experienced	O
+fewer	O
+ischemic	O
+strokes	B-NP
+.	O
+	
+Aspirin	O
+does	O
+not	O
+seem	O
+to	O
+affect	O
+CVD	B-NP
+mortality	O
+or	O
+all	O
+-	O
+cause	O
+mortality	O
+in	O
+either	O
+men	O
+or	O
+women	O
+.	O
+	
+The	O
+use	O
+of	O
+aspirin	O
+for	O
+primary	O
+prevention	O
+increases	O
+the	O
+risk	O
+for	O
+major	O
+bleeding	B-NP
+events	O
+","	O
+primarily	O
+gastrointestinal	B-NP
+bleeding	I-NP
+events	O
+","	O
+in	O
+both	O
+men	O
+and	O
+women	O
+.	O
+	
+Men	O
+have	O
+an	O
+increased	O
+risk	O
+for	O
+hemorrhagic	B-NP
+strokes	I-NP
+with	O
+aspirin	O
+use	O
+.	O
+	
+A	O
+new	O
+RCT	O
+and	O
+meta	O
+-	O
+analysis	O
+suggest	O
+that	O
+the	O
+risk	O
+for	O
+hemorrhagic	B-NP
+strokes	I-NP
+in	O
+women	O
+is	O
+not	O
+statistically	O
+significantly	O
+increased	O
+.	O
+	
+LIMITATIONS	O
+:	O
+New	O
+evidence	O
+on	O
+aspirin	O
+for	O
+the	O
+primary	O
+prevention	O
+of	O
+CVD	B-NP
+is	O
+limited	O
+.	O
+	
+The	O
+dose	O
+of	O
+aspirin	O
+used	O
+in	O
+the	O
+RCTs	O
+varied	O
+","	O
+which	O
+prevented	O
+the	O
+estimation	O
+of	O
+the	O
+most	O
+appropriate	O
+dose	O
+for	O
+primary	O
+prevention	O
+.	O
+	
+Several	O
+of	O
+the	O
+RCTs	O
+were	O
+conducted	O
+within	O
+populations	O
+of	O
+health	O
+professionals	O
+","	O
+which	O
+potentially	O
+limits	O
+generalizability	O
+.	O
+	
+CONCLUSION	O
+:	O
+Aspirin	O
+reduces	O
+the	O
+risk	O
+for	O
+myocardial	B-NP
+infarction	I-NP
+in	O
+men	O
+and	O
+strokes	B-NP
+in	O
+women	O
+.	O
+	
+Aspirin	O
+use	O
+increases	O
+the	O
+risk	O
+for	O
+serious	O
+bleeding	B-NP
+events	O
+.	O
+	
+Reducing	O
+harm	O
+associated	O
+with	O
+anticoagulation	O
+:	O
+practical	O
+considerations	O
+of	O
+argatroban	O
+therapy	O
+in	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+.	O
+	
+Argatroban	O
+is	O
+a	O
+hepatically	O
+metabolized	O
+","	O
+direct	O
+thrombin	O
+inhibitor	O
+used	O
+for	O
+prophylaxis	O
+or	O
+treatment	O
+of	O
+thrombosis	B-NP
+in	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+(	O
+HIT	B-NP
+)	O
+and	O
+for	O
+patients	O
+with	O
+or	O
+at	O
+risk	O
+of	O
+HIT	B-NP
+undergoing	O
+percutaneous	O
+coronary	O
+intervention	O
+(	O
+PCI	O
+)	O
+.	O
+	
+The	O
+objective	O
+of	O
+this	O
+review	O
+is	O
+to	O
+summarize	O
+practical	O
+considerations	O
+of	O
+argatroban	O
+therapy	O
+in	O
+HIT	B-NP
+.	O
+	
+The	O
+US	O
+FDA	O
+-	O
+recommended	O
+argatroban	O
+dose	O
+in	O
+HIT	B-NP
+is	O
+2	O
+microg	O
+/	O
+kg	O
+/	O
+min	O
+(	O
+reduced	O
+in	O
+patients	O
+with	O
+hepatic	B-NP
+impairment	I-NP
+and	O
+in	O
+paediatric	O
+patients	O
+)	O
+","	O
+adjusted	O
+to	O
+achieve	O
+activated	O
+partial	O
+thromboplastin	O
+times	O
+(	O
+aPTTs	O
+)	O
+1	O
+.	O
+5	O
+-	O
+3	O
+times	O
+baseline	O
+(	O
+not	O
+>	O
+100	O
+seconds	O
+)	O
+.	O
+	
+Contemporary	O
+experiences	O
+indicate	O
+that	O
+reduced	O
+doses	O
+are	O
+also	O
+needed	O
+in	O
+patients	O
+with	O
+conditions	O
+associated	O
+with	O
+hepatic	O
+hypoperfusion	O
+","	O
+e	O
+.	O
+g	O
+.	O
+heart	B-NP
+failure	I-NP
+","	O
+yet	O
+are	O
+unnecessary	O
+for	O
+renal	B-NP
+dysfunction	I-NP
+","	O
+adult	O
+age	O
+","	O
+sex	O
+","	O
+race	O
+/	O
+ethnicity	O
+or	O
+obesity	B-NP
+.	O
+	
+Argatroban	O
+0	O
+.	O
+5	O
+-	O
+1	O
+.	O
+2	O
+microg	O
+/	O
+kg	O
+/	O
+min	O
+typically	O
+supports	O
+therapeutic	O
+aPTTs	O
+.	O
+	
+The	O
+FDA	O
+-	O
+recommended	O
+dose	O
+during	O
+PCI	O
+is	O
+25	O
+microg	O
+/	O
+kg	O
+/	O
+min	O
+(	O
+350	O
+microg	O
+/	O
+kg	O
+initial	O
+bolus	O
+)	O
+","	O
+adjusted	O
+to	O
+achieve	O
+activated	O
+clotting	O
+times	O
+(	O
+ACTs	O
+)	O
+of	O
+300	O
+-	O
+450	O
+sec	O
+.	O
+	
+For	O
+PCI	O
+","	O
+argatroban	O
+has	O
+not	O
+been	O
+investigated	O
+in	O
+hepatically	O
+impaired	O
+patients	O
+;	O
+dose	O
+adjustment	O
+is	O
+unnecessary	O
+for	O
+adult	O
+age	O
+","	O
+sex	O
+","	O
+race	O
+/	O
+ethnicity	O
+or	O
+obesity	B-NP
+","	O
+and	O
+lesser	O
+doses	O
+may	O
+be	O
+adequate	O
+with	O
+concurrent	O
+glycoprotein	O
+IIb	O
+/	O
+IIIa	O
+inhibition	O
+.	O
+	
+Argatroban	O
+prolongs	O
+the	O
+International	O
+Normalized	O
+Ratio	O
+","	O
+and	O
+published	O
+approaches	O
+for	O
+monitoring	O
+the	O
+argatroban	O
+-	O
+to	O
+-	O
+warfarin	O
+transition	O
+should	O
+be	O
+followed	O
+.	O
+	
+Major	O
+bleeding	B-NP
+with	O
+argatroban	O
+is	O
+0	O
+-	O
+10	O
+%	O
+in	O
+the	O
+non	O
+-	O
+interventional	O
+setting	O
+and	O
+0	O
+-	O
+5	O
+.	O
+8	O
+%	O
+periprocedurally	O
+.	O
+	
+Argatroban	O
+has	O
+no	O
+specific	O
+antidote	O
+","	O
+and	O
+if	O
+excessive	O
+anticoagulation	O
+occurs	O
+","	O
+argatroban	O
+infusion	O
+should	O
+be	O
+stopped	O
+or	O
+reduced	O
+.	O
+	
+Improved	O
+familiarity	O
+of	O
+healthcare	O
+professionals	O
+with	O
+argatroban	O
+therapy	O
+in	O
+HIT	B-NP
+","	O
+including	O
+in	O
+special	O
+populations	O
+and	O
+during	O
+PCI	O
+","	O
+may	O
+facilitate	O
+reduction	O
+of	O
+harm	O
+associated	O
+with	O
+HIT	B-NP
+(	O
+e	O
+.	O
+g	O
+.	O
+fewer	O
+thromboses	O
+)	O
+or	O
+its	O
+treatment	O
+(	O
+e	O
+.	O
+g	O
+.	O
+fewer	O
+argatroban	O
+medication	O
+errors	O
+)	O
+.	O
+	
+Rhabdomyolysis	B-NP
+and	O
+brain	O
+ischemic	B-NP
+stroke	I-NP
+in	O
+a	O
+heroin	O
+-	O
+dependent	O
+male	O
+under	O
+methadone	O
+maintenance	O
+therapy	O
+.	O
+	
+OBJECTIVE	O
+:	O
+There	O
+are	O
+several	O
+complications	O
+associated	O
+with	O
+heroin	B-NP
+abuse	I-NP
+","	O
+some	O
+of	O
+which	O
+are	O
+life	O
+-	O
+threatening	O
+.	O
+	
+Methadone	O
+may	O
+aggravate	O
+this	O
+problem	O
+.	O
+	
+METHOD	O
+:	O
+A	O
+clinical	O
+case	O
+description	O
+.	O
+	
+RESULTS	O
+:	O
+A	O
+33	O
+-	O
+year	O
+-	O
+old	O
+man	O
+presented	O
+with	O
+rhabdomyolysis	B-NP
+and	O
+cerebral	O
+ischemic	B-NP
+stroke	I-NP
+after	O
+intravenous	O
+heroin	O
+.	O
+	
+He	O
+had	O
+used	O
+heroin	O
+since	O
+age	O
+20	O
+","	O
+and	O
+had	O
+used	O
+150	O
+mg	O
+methadone	O
+daily	O
+for	O
+6	O
+months	O
+.	O
+	
+He	O
+was	O
+found	O
+unconsciousness	B-NP
+at	O
+home	O
+and	O
+was	O
+sent	O
+to	O
+our	O
+hospital	O
+.	O
+	
+In	O
+the	O
+ER	O
+","	O
+his	O
+opiate	O
+level	O
+was	O
+4497	O
+ng	O
+/	O
+ml	O
+.	O
+	
+In	O
+the	O
+ICU	O
+","	O
+we	O
+found	O
+rhabdomyolysis	B-NP
+","	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+and	O
+acute	O
+respiratory	B-NP
+failure	I-NP
+.	O
+	
+After	O
+transfer	O
+to	O
+an	O
+internal	O
+ward	O
+","	O
+we	O
+noted	O
+aphasia	B-NP
+and	O
+weakness	B-NP
+of	O
+his	O
+left	O
+limbs	O
+.	O
+	
+After	O
+MRI	O
+","	O
+we	O
+found	O
+cerebral	B-NP
+ischemic	I-NP
+infarction	I-NP
+.	O
+	
+CONCLUSION	O
+:	O
+Those	O
+using	O
+methadone	O
+and	O
+heroin	O
+simultaneously	O
+may	O
+increase	O
+risk	O
+of	O
+rhabdomyolysis	B-NP
+and	O
+ischemic	B-NP
+stroke	I-NP
+.	O
+	
+Patients	O
+under	O
+methadone	O
+maintenance	O
+therapy	O
+should	O
+be	O
+warned	O
+regarding	O
+these	O
+serious	O
+adverse	O
+events	O
+.	O
+	
+Hypotheses	O
+of	O
+heroin	O
+-	O
+related	O
+rhabdomyolysis	B-NP
+and	O
+stroke	B-NP
+in	O
+heroin	O
+abusers	O
+are	O
+discussed	O
+.	O
+	
+Increased	O
+vulnerability	O
+to	O
+6	O
+-	O
+hydroxydopamine	O
+lesion	O
+and	O
+reduced	O
+development	O
+of	O
+dyskinesias	B-NP
+in	O
+mice	O
+lacking	O
+CB1	O
+cannabinoid	O
+receptors	O
+.	O
+	
+Motor	O
+impairment	O
+","	O
+dopamine	O
+(	O
+DA	O
+)	O
+neuronal	O
+activity	O
+and	O
+proenkephalin	O
+(	O
+PENK	O
+)	O
+gene	O
+expression	O
+in	O
+the	O
+caudate	O
+-	O
+putamen	O
+(	O
+CPu	O
+)	O
+were	O
+measured	O
+in	O
+6	O
+-	O
+OHDA	O
+-	O
+lesioned	O
+and	O
+treated	O
+(	O
+L	O
+-	O
+DOPA	O
++	O
+benserazide	O
+)	O
+CB1	O
+KO	O
+and	O
+WT	O
+mice	O
+.	O
+	
+A	O
+lesion	O
+induced	O
+by	O
+6	O
+-	O
+OHDA	O
+produced	O
+more	O
+severe	O
+motor	O
+deterioration	O
+in	O
+CB1	O
+KO	O
+mice	O
+accompanied	O
+by	O
+more	O
+loss	O
+of	O
+DA	O
+neurons	O
+and	O
+increased	O
+PENK	O
+gene	O
+expression	O
+in	O
+the	O
+CPu	O
+.	O
+	
+Oxidative	O
+/	O
+nitrosative	O
+and	O
+neuroinflammatory	O
+parameters	O
+were	O
+estimated	O
+in	O
+the	O
+CPu	O
+and	O
+cingulate	O
+cortex	O
+(	O
+Cg	O
+)	O
+.	O
+	
+CB1	O
+KO	O
+mice	O
+exhibited	O
+higher	O
+MDA	O
+levels	O
+and	O
+iNOS	O
+protein	O
+expression	O
+in	O
+the	O
+CPu	O
+and	O
+Cg	O
+compared	O
+to	O
+WT	O
+mice	O
+.	O
+	
+Treatment	O
+with	O
+L	O
+-	O
+DOPA	O
++	O
+benserazide	O
+(	O
+12	O
+weeks	O
+)	O
+resulted	O
+in	O
+less	O
+severe	O
+dyskinesias	B-NP
+in	O
+CB1	O
+KO	O
+than	O
+in	O
+WT	O
+mice	O
+.	O
+	
+The	O
+results	O
+revealed	O
+that	O
+the	O
+lack	O
+of	O
+cannabinoid	O
+CB1	O
+receptors	O
+increased	O
+the	O
+severity	O
+of	O
+motor	O
+impairment	O
+and	O
+DA	O
+lesion	O
+","	O
+and	O
+reduced	O
+L	O
+-	O
+DOPA	O
+-	O
+induced	O
+dyskinesias	B-NP
+.	O
+	
+These	O
+results	O
+suggest	O
+that	O
+activation	O
+of	O
+CB1	O
+receptors	O
+offers	O
+neuroprotection	O
+against	O
+dopaminergic	O
+lesion	O
+and	O
+the	O
+development	O
+of	O
+L	O
+-	O
+DOPA	O
+-	O
+induced	O
+dyskinesias	B-NP
+.	O
+	
+Hepatocellular	O
+oxidant	O
+stress	O
+following	O
+intestinal	O
+ischemia	B-NP
+-	O
+reperfusion	B-NP
+injury	I-NP
+.	O
+	
+Reperfusion	O
+of	O
+ischemic	B-NP
+intestine	O
+results	O
+in	O
+acute	O
+liver	B-NP
+dysfunction	I-NP
+characterized	O
+by	O
+hepatocellular	O
+enzyme	O
+release	O
+into	O
+plasma	O
+","	O
+reduction	O
+in	O
+bile	O
+flow	O
+rate	O
+","	O
+and	O
+neutrophil	O
+sequestration	O
+within	O
+the	O
+liver	O
+.	O
+	
+The	O
+pathophysiology	O
+underlying	O
+this	O
+acute	O
+hepatic	B-NP
+injury	I-NP
+is	O
+unknown	O
+.	O
+	
+This	O
+study	O
+was	O
+undertaken	O
+to	O
+determine	O
+whether	O
+oxidants	O
+are	O
+associated	O
+with	O
+the	O
+hepatic	B-NP
+injury	I-NP
+and	O
+to	O
+determine	O
+the	O
+relative	O
+value	O
+of	O
+several	O
+indirect	O
+methods	O
+of	O
+assessing	O
+oxidant	O
+exposure	O
+in	O
+vivo	O
+.	O
+	
+Rats	O
+were	O
+subjected	O
+to	O
+a	O
+standardized	O
+intestinal	O
+ischemia	B-NP
+-	O
+reperfusion	B-NP
+injury	I-NP
+.	O
+	
+Hepatic	O
+tissue	O
+was	O
+assayed	O
+for	O
+lipid	O
+peroxidation	O
+products	O
+and	O
+oxidized	O
+and	O
+reduced	O
+glutathione	O
+.	O
+	
+There	O
+was	O
+no	O
+change	O
+in	O
+hepatic	O
+tissue	O
+total	O
+glutathione	O
+following	O
+intestinal	O
+ischemia	B-NP
+-	O
+reperfusion	B-NP
+injury	I-NP
+.	O
+	
+Oxidized	O
+glutathione	O
+(	O
+GSSG	O
+)	O
+increased	O
+significantly	O
+following	O
+30	O
+and	O
+60	O
+min	O
+of	O
+reperfusion	O
+.	O
+	
+There	O
+was	O
+no	O
+increase	O
+in	O
+any	O
+of	O
+the	O
+products	O
+of	O
+lipid	O
+peroxidation	O
+associated	O
+with	O
+this	O
+injury	O
+.	O
+	
+An	O
+increase	O
+in	O
+GSSG	O
+within	O
+hepatic	O
+tissue	O
+during	O
+intestinal	O
+reperfusion	O
+suggests	O
+exposure	O
+of	O
+hepatocytes	O
+to	O
+an	O
+oxidant	O
+stress	O
+.	O
+	
+The	O
+lack	O
+of	O
+a	O
+significant	O
+increase	O
+in	O
+products	O
+of	O
+lipid	O
+peroxidation	O
+suggests	O
+that	O
+the	O
+oxidant	O
+stress	O
+is	O
+of	O
+insufficient	O
+magnitude	O
+to	O
+result	O
+in	O
+irreversible	O
+injury	O
+to	O
+hepatocyte	O
+cell	O
+membranes	O
+.	O
+	
+These	O
+data	O
+also	O
+suggest	O
+that	O
+the	O
+measurement	O
+of	O
+tissue	O
+GSSG	O
+may	O
+be	O
+a	O
+more	O
+sensitive	O
+indicator	O
+of	O
+oxidant	O
+stress	O
+than	O
+measurement	O
+of	O
+products	O
+of	O
+lipid	O
+peroxidation	O
+.	O
+	
+Animal	O
+model	O
+of	O
+mania	B-NP
+induced	O
+by	O
+ouabain	O
+:	O
+Evidence	O
+of	O
+oxidative	O
+stress	O
+in	O
+submitochondrial	O
+particles	O
+of	O
+the	O
+rat	O
+brain	O
+.	O
+	
+The	O
+intracerebroventricular	O
+(	O
+ICV	O
+)	O
+administration	O
+of	O
+ouabain	O
+(	O
+a	O
+Na	O
+(	O
++	O
+)	O
+/	O
+K	O
+(	O
++	O
+)	O
+-	O
+ATPase	O
+inhibitor	O
+)	O
+in	O
+rats	O
+has	O
+been	O
+suggested	O
+to	O
+mimic	O
+some	O
+symptoms	O
+of	O
+human	O
+bipolar	B-NP
+mania	I-NP
+.	O
+	
+Clinical	O
+studies	O
+have	O
+shown	O
+that	O
+bipolar	B-NP
+disorder	I-NP
+may	O
+be	O
+related	O
+to	O
+mitochondrial	B-NP
+dysfunction	I-NP
+.	O
+	
+Herein	O
+","	O
+we	O
+investigated	O
+the	O
+behavioral	O
+and	O
+biochemical	O
+effects	O
+induced	O
+by	O
+the	O
+ICV	O
+administration	O
+of	O
+ouabain	O
+in	O
+rats	O
+.	O
+	
+To	O
+achieve	O
+this	O
+aim	O
+","	O
+the	O
+effects	O
+of	O
+ouabain	O
+injection	O
+immediately	O
+after	O
+and	O
+7	O
+days	O
+following	O
+a	O
+single	O
+ICV	O
+administration	O
+(	O
+at	O
+concentrations	O
+of	O
+10	O
+(	O
+-	O
+2	O
+)	O
+and	O
+10	O
+(	O
+-	O
+3	O
+)	O
+M	O
+)	O
+on	O
+locomotion	O
+was	O
+measured	O
+using	O
+the	O
+open	O
+-	O
+field	O
+test	O
+.	O
+	
+Additionally	O
+","	O
+thiobarbituric	O
+acid	O
+reactive	O
+substances	O
+(	O
+TBARSs	O
+)	O
+and	O
+superoxide	O
+production	O
+were	O
+measured	O
+in	O
+submitochondrial	O
+particles	O
+of	O
+the	O
+prefrontal	O
+cortex	O
+","	O
+hippocampus	O
+","	O
+striatum	O
+and	O
+amygdala	O
+.	O
+	
+Our	O
+findings	O
+demonstrated	O
+that	O
+ouabain	O
+at	O
+10	O
+(	O
+-	O
+2	O
+)	O
+and	O
+10	O
+(	O
+-	O
+3	O
+)	O
+M	O
+induced	O
+hyperlocomotion	B-NP
+in	O
+rats	O
+","	O
+and	O
+this	O
+response	O
+remained	O
+up	O
+to	O
+7	O
+days	O
+following	O
+a	O
+single	O
+ICV	O
+injection	O
+.	O
+	
+In	O
+addition	O
+","	O
+we	O
+observed	O
+that	O
+the	O
+persistent	O
+increase	O
+in	O
+the	O
+rat	O
+spontaneous	O
+locomotion	O
+is	O
+associated	O
+with	O
+increased	O
+TBARS	O
+levels	O
+and	O
+superoxide	O
+generation	O
+in	O
+submitochondrial	O
+particles	O
+in	O
+the	O
+prefrontal	O
+cortex	O
+","	O
+striatum	O
+and	O
+amygdala	O
+.	O
+	
+In	O
+conclusion	O
+","	O
+ouabain	O
+-	O
+induced	O
+mania	B-NP
+-	O
+like	O
+behavior	O
+may	O
+provide	O
+a	O
+useful	O
+animal	O
+model	O
+to	O
+test	O
+the	O
+hypothesis	O
+of	O
+the	O
+involvement	O
+of	O
+oxidative	O
+stress	O
+in	O
+bipolar	B-NP
+disorder	I-NP
+.	O
+	
+Intraoperative	O
+dialysis	O
+during	O
+liver	O
+transplantation	O
+with	O
+citrate	O
+dialysate	O
+.	O
+	
+Liver	O
+transplantation	O
+for	O
+acutely	O
+ill	O
+patients	O
+with	O
+fulminant	B-NP
+liver	I-NP
+failure	I-NP
+carries	O
+high	O
+intraoperative	O
+and	O
+immediate	O
+postoperative	O
+risks	O
+.	O
+	
+These	O
+are	O
+increased	O
+with	O
+the	O
+presence	O
+of	O
+concomitant	O
+acute	B-NP
+kidney	I-NP
+injury	I-NP
+(	O
+AKI	B-NP
+)	O
+and	O
+intraoperative	O
+dialysis	O
+is	O
+sometimes	O
+required	O
+to	O
+allow	O
+the	O
+transplant	O
+to	O
+proceed	O
+.	O
+	
+The	O
+derangements	O
+in	O
+the	O
+procoagulant	O
+and	O
+anticoagulant	O
+pathways	O
+during	O
+fulminant	B-NP
+liver	I-NP
+failure	I-NP
+can	O
+lead	O
+to	O
+difficulties	O
+with	O
+anticoagulation	O
+during	O
+dialysis	O
+","	O
+especially	O
+when	O
+continued	O
+in	O
+the	O
+operating	O
+room	O
+.	O
+	
+Systemic	O
+anticoagulation	O
+is	O
+unsafe	O
+and	O
+regional	O
+citrate	O
+anticoagulation	O
+in	O
+the	O
+absence	O
+of	O
+a	O
+functional	O
+liver	O
+carries	O
+the	O
+risk	O
+of	O
+citrate	O
+toxicity	B-NP
+.	O
+	
+Citrate	O
+dialysate	O
+","	O
+a	O
+new	O
+dialysate	O
+with	O
+citric	O
+acid	O
+can	O
+be	O
+used	O
+for	O
+anticoagulation	O
+in	O
+patients	O
+who	O
+cannot	O
+tolerate	O
+heparin	O
+or	O
+regional	O
+citrate	O
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+a	O
+40	O
+-	O
+year	O
+-	O
+old	O
+female	O
+with	O
+acetaminophen	O
+-	O
+induced	O
+fulminant	B-NP
+liver	I-NP
+failure	I-NP
+with	O
+associated	O
+AKI	B-NP
+who	O
+underwent	O
+intraoperative	O
+dialytic	O
+support	O
+during	O
+liver	O
+transplantation	O
+anticoagulated	O
+with	O
+citrate	O
+dialysate	O
+during	O
+the	O
+entire	O
+procedure	O
+.	O
+	
+The	O
+patient	O
+tolerated	O
+the	O
+procedure	O
+well	O
+without	O
+any	O
+signs	O
+of	O
+citrate	O
+toxicity	B-NP
+and	O
+maintained	O
+adequate	O
+anticoagulation	O
+for	O
+patency	O
+of	O
+the	O
+dialysis	O
+circuit	O
+.	O
+	
+Citrate	O
+dialysate	O
+is	O
+a	O
+safe	O
+alternative	O
+for	O
+intradialytic	O
+support	O
+of	O
+liver	O
+transplantation	O
+in	O
+fulminant	B-NP
+liver	I-NP
+failure	I-NP
+.	O
+	
+Delirium	B-NP
+in	O
+a	O
+patient	O
+with	O
+toxic	O
+flecainide	O
+plasma	O
+concentrations	O
+:	O
+the	O
+role	O
+of	O
+a	O
+pharmacokinetic	O
+drug	O
+interaction	O
+with	O
+paroxetine	O
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+describe	O
+a	O
+case	O
+of	O
+flecainide	O
+-	O
+induced	O
+delirium	B-NP
+associated	O
+with	O
+a	O
+pharmacokinetic	O
+drug	O
+interaction	O
+with	O
+paroxetine	O
+.	O
+	
+CASE	O
+SUMMARY	O
+:	O
+A	O
+69	O
+-	O
+year	O
+-	O
+old	O
+white	O
+female	O
+presented	O
+to	O
+the	O
+emergency	O
+department	O
+with	O
+a	O
+history	O
+of	O
+confusion	B-NP
+and	O
+paranoia	B-NP
+over	O
+the	O
+past	O
+several	O
+days	O
+.	O
+	
+On	O
+admission	O
+the	O
+patient	O
+was	O
+taking	O
+carvedilol	O
+12	O
+mg	O
+twice	O
+daily	O
+","	O
+warfarin	O
+2	O
+mg	O
+/	O
+day	O
+","	O
+folic	O
+acid	O
+1	O
+mg	O
+/	O
+day	O
+","	O
+levothyroxine	O
+100	O
+microg	O
+/	O
+day	O
+","	O
+pantoprazole	O
+40	O
+mg	O
+/	O
+day	O
+","	O
+paroxetine	O
+40	O
+mg	O
+/	O
+day	O
+","	O
+and	O
+flecainide	O
+100	O
+mg	O
+twice	O
+daily	O
+.	O
+	
+Flecainide	O
+had	O
+been	O
+started	O
+2	O
+weeks	O
+prior	O
+for	O
+atrial	B-NP
+fibrillation	I-NP
+.	O
+	
+Laboratory	O
+test	O
+findings	O
+on	O
+admission	O
+were	O
+notable	O
+only	O
+for	O
+a	O
+flecainide	O
+plasma	O
+concentration	O
+of	O
+1360	O
+microg	O
+/	O
+L	O
+(	O
+reference	O
+range	O
+200	O
+-	O
+1000	O
+)	O
+.	O
+	
+A	O
+metabolic	O
+drug	O
+interaction	O
+between	O
+flecainide	O
+and	O
+paroxetine	O
+","	O
+which	O
+the	O
+patient	O
+had	O
+been	O
+taking	O
+for	O
+more	O
+than	O
+5	O
+years	O
+","	O
+was	O
+considered	O
+.	O
+	
+Paroxetine	O
+was	O
+discontinued	O
+and	O
+the	O
+dose	O
+of	O
+flecainide	O
+was	O
+reduced	O
+to	O
+50	O
+mg	O
+twice	O
+daily	O
+.	O
+	
+Her	O
+delirium	B-NP
+resolved	O
+3	O
+days	O
+later	O
+.	O
+	
+DISCUSSION	O
+:	O
+Flecainide	O
+and	O
+pharmacologically	O
+similar	O
+agents	O
+that	O
+interact	O
+with	O
+sodium	O
+channels	O
+may	O
+cause	O
+delirium	B-NP
+in	O
+susceptible	O
+patients	O
+.	O
+	
+A	O
+MEDLINE	O
+search	O
+(	O
+1966	O
+-	O
+January	O
+2009	O
+)	O
+revealed	O
+one	O
+in	O
+vivo	O
+pharmacokinetic	O
+study	O
+on	O
+the	O
+interaction	O
+between	O
+flecainide	O
+","	O
+a	O
+CYP2D6	O
+substrate	O
+","	O
+and	O
+paroxetine	O
+","	O
+a	O
+CYP2D6	O
+inhibitor	O
+","	O
+as	O
+well	O
+as	O
+3	O
+case	O
+reports	O
+of	O
+flecainide	O
+-	O
+induced	O
+delirium	B-NP
+.	O
+	
+According	O
+to	O
+the	O
+Naranjo	O
+probability	O
+scale	O
+","	O
+flecainide	O
+was	O
+the	O
+probable	O
+cause	O
+of	O
+the	O
+patient	O
+'	O
+s	O
+delirium	B-NP
+;	O
+the	O
+Horn	O
+Drug	O
+Interaction	O
+Probability	O
+Scale	O
+indicates	O
+a	O
+possible	O
+pharmacokinetic	O
+drug	O
+interaction	O
+between	O
+flecainide	O
+and	O
+paroxetine	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Supratherapeutic	O
+flecainide	O
+plasma	O
+concentrations	O
+may	O
+cause	O
+delirium	B-NP
+.	O
+	
+Because	O
+toxicity	B-NP
+may	O
+occur	O
+when	O
+flecainide	O
+is	O
+prescribed	O
+with	O
+paroxetine	O
+and	O
+other	O
+potent	O
+CYP2D6	O
+inhibitors	O
+","	O
+flecainide	O
+plasma	O
+concentrations	O
+should	O
+be	O
+monitored	O
+closely	O
+with	O
+commencement	O
+of	O
+CYP2D6	O
+inhibitors	O
+.	O
+	
+Efficacy	O
+of	O
+everolimus	O
+(	O
+RAD001	O
+)	O
+in	O
+patients	O
+with	O
+advanced	O
+NSCLC	B-NP
+previously	O
+treated	O
+with	O
+chemotherapy	O
+alone	O
+or	O
+with	O
+chemotherapy	O
+and	O
+EGFR	O
+inhibitors	O
+.	O
+	
+BACKGROUND	O
+:	O
+Treatment	O
+options	O
+are	O
+scarce	O
+in	O
+pretreated	O
+advanced	O
+non	B-NP
+-	I-NP
+small	I-NP
+-	I-NP
+cell	I-NP
+lung	I-NP
+cancer	I-NP
+(	O
+NSCLC	B-NP
+)	O
+patients	O
+.	O
+	
+RAD001	O
+","	O
+an	O
+oral	O
+inhibitor	O
+of	O
+the	O
+mammalian	O
+target	O
+of	O
+rapamycin	O
+(	O
+mTOR	O
+)	O
+","	O
+has	O
+shown	O
+phase	O
+I	O
+efficacy	O
+in	O
+NSCLC	B-NP
+.	O
+	
+METHODS	O
+:	O
+Stage	O
+IIIb	O
+or	O
+IV	O
+NSCLC	B-NP
+patients	O
+","	O
+with	O
+two	O
+or	O
+fewer	O
+prior	O
+chemotherapy	O
+regimens	O
+","	O
+one	O
+platinum	O
+based	O
+(	O
+stratum	O
+1	O
+)	O
+or	O
+both	O
+chemotherapy	O
+and	O
+epidermal	O
+growth	O
+factor	O
+receptor	O
+tyrosine	O
+kinase	O
+inhibitors	O
+(	O
+stratum	O
+2	O
+)	O
+","	O
+received	O
+RAD001	O
+10	O
+mg	O
+/	O
+day	O
+until	O
+progression	O
+or	O
+unacceptable	O
+toxicity	B-NP
+.	O
+	
+Primary	O
+objective	O
+was	O
+overall	O
+response	O
+rate	O
+(	O
+ORR	O
+)	O
+.	O
+	
+Analyses	O
+of	O
+markers	O
+associated	O
+with	O
+the	O
+mTOR	O
+pathway	O
+were	O
+carried	O
+out	O
+on	O
+archival	O
+tumor	B-NP
+from	O
+a	O
+subgroup	O
+using	O
+immunohistochemistry	O
+(	O
+IHC	O
+)	O
+and	O
+direct	O
+mutation	O
+sequencing	O
+.	O
+	
+RESULTS	O
+:	O
+Eighty	O
+-	O
+five	O
+patients	O
+were	O
+enrolled	O
+","	O
+42	O
+in	O
+stratum	O
+1	O
+and	O
+43	O
+in	O
+stratum	O
+.	O
+	
+ORR	O
+was	O
+4	O
+.	O
+7	O
+%	O
+(	O
+7	O
+.	O
+1	O
+%	O
+stratum	O
+1	O
+;	O
+2	O
+.	O
+3	O
+%	O
+stratum	O
+2	O
+)	O
+.	O
+	
+Overall	O
+disease	O
+control	O
+rate	O
+was	O
+47	O
+.	O
+1	O
+%	O
+.	O
+	
+Median	O
+progression	O
+-	O
+free	O
+survivals	O
+(	O
+PFSs	O
+)	O
+were	O
+2	O
+.	O
+6	O
+(	O
+stratum	O
+1	O
+)	O
+and	O
+2	O
+.	O
+7	O
+months	O
+(	O
+stratum	O
+2	O
+)	O
+.	O
+	
+Common	O
+>	O
+or	O
+=	O
+grade	O
+3	O
+events	O
+were	O
+fatigue	B-NP
+","	O
+dyspnea	B-NP
+","	O
+stomatitis	B-NP
+","	O
+anemia	B-NP
+","	O
+and	O
+thrombocytopenia	B-NP
+.	O
+	
+Pneumonitis	B-NP
+","	O
+probably	O
+or	O
+possibly	O
+related	O
+","	O
+mainly	O
+grade	O
+1	O
+/	O
+2	O
+","	O
+occurred	O
+in	O
+25	O
+%	O
+.	O
+	
+Cox	O
+regression	O
+analysis	O
+of	O
+IHC	O
+scores	O
+found	O
+that	O
+only	O
+phospho	O
+AKT	O
+(	O
+pAKT	O
+)	O
+was	O
+a	O
+significant	O
+independent	O
+predictor	O
+of	O
+worse	O
+PFS	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+RAD001	O
+10	O
+mg	O
+/	O
+day	O
+was	O
+well	O
+tolerated	O
+","	O
+showing	O
+modest	O
+clinical	O
+activity	O
+in	O
+pretreated	O
+NSCLC	B-NP
+.	O
+	
+Evaluation	O
+of	O
+RAD001	O
+plus	O
+standard	O
+therapy	O
+for	O
+metastatic	O
+NSCLC	B-NP
+continues	O
+.	O
+	
+Posttransplant	O
+anemia	B-NP
+:	O
+the	O
+role	O
+of	O
+sirolimus	O
+.	O
+	
+Posttransplant	O
+anemia	B-NP
+is	O
+a	O
+common	O
+problem	O
+that	O
+may	O
+hinder	O
+patients	O
+'	O
+quality	O
+of	O
+life	O
+.	O
+	
+It	O
+occurs	O
+in	O
+12	O
+to	O
+76	O
+%	O
+of	O
+patients	O
+","	O
+and	O
+is	O
+most	O
+common	O
+in	O
+the	O
+immediate	O
+posttransplant	O
+period	O
+.	O
+	
+A	O
+variety	O
+of	O
+factors	O
+have	O
+been	O
+identified	O
+that	O
+increase	O
+the	O
+risk	O
+of	O
+posttransplant	O
+anemia	B-NP
+","	O
+of	O
+which	O
+the	O
+level	O
+of	O
+renal	O
+function	O
+is	O
+most	O
+important	O
+.	O
+	
+Sirolimus	O
+","	O
+a	O
+mammalian	O
+target	O
+of	O
+rapamycin	O
+inhibitor	O
+","	O
+has	O
+been	O
+implicated	O
+as	O
+playing	O
+a	O
+special	O
+role	O
+in	O
+posttransplant	O
+anemia	B-NP
+.	O
+	
+This	O
+review	O
+considers	O
+anemia	B-NP
+associated	O
+with	O
+sirolimus	O
+","	O
+including	O
+its	O
+presentation	O
+","	O
+mechanisms	O
+","	O
+and	O
+management	O
+.	O
+	
+Coronary	O
+computerized	O
+tomography	O
+angiography	O
+for	O
+rapid	O
+discharge	O
+of	O
+low	O
+-	O
+risk	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B-NP
+pain	I-NP
+.	O
+	
+BACKGROUND	O
+:	O
+Most	O
+patients	O
+presenting	O
+to	O
+emergency	O
+departments	O
+(	O
+EDs	O
+)	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B-NP
+pain	I-NP
+are	O
+admitted	O
+for	O
+at	O
+least	O
+12	O
+hours	O
+and	O
+receive	O
+a	O
+"	O
+rule	O
+out	O
+acute	B
+coronary	I
+syndrome	I
+"	O
+protocol	O
+","	O
+often	O
+with	O
+noninvasive	O
+testing	O
+prior	O
+to	O
+discharge	O
+.	O
+	
+In	O
+patients	O
+without	O
+cocaine	O
+use	O
+","	O
+coronary	O
+computerized	O
+tomography	O
+angiography	O
+(	O
+CTA	O
+)	O
+has	O
+been	O
+shown	O
+to	O
+be	O
+useful	O
+for	O
+identifying	O
+a	O
+group	O
+of	O
+patients	O
+at	O
+low	O
+risk	O
+for	O
+cardiac	O
+events	O
+who	O
+can	O
+be	O
+safely	O
+discharged	O
+.	O
+	
+It	O
+is	O
+unclear	O
+whether	O
+a	O
+coronary	O
+CTA	O
+strategy	O
+would	O
+be	O
+efficacious	O
+in	O
+cocaine	O
+-	O
+associated	O
+chest	B-NP
+pain	I-NP
+","	O
+as	O
+coronary	B-NP
+vasospasm	I-NP
+may	O
+account	O
+for	O
+some	O
+of	O
+the	O
+ischemia	B-NP
+.	O
+	
+We	O
+studied	O
+whether	O
+a	O
+negative	O
+coronary	O
+CTA	O
+in	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B-NP
+pain	I-NP
+could	O
+identify	O
+a	O
+subset	O
+safe	O
+for	O
+discharge	O
+.	O
+	
+METHODS	O
+:	O
+We	O
+prospectively	O
+evaluated	O
+the	O
+safety	O
+of	O
+coronary	O
+CTA	O
+for	O
+low	O
+-	O
+risk	O
+patients	O
+who	O
+presented	O
+to	O
+the	O
+ED	O
+with	O
+cocaineassociated	O
+chest	B-NP
+pain	I-NP
+(	O
+self	O
+-	O
+reported	O
+or	O
+positive	O
+urine	O
+test	O
+)	O
+.	O
+	
+Consecutive	O
+patients	O
+received	O
+either	O
+immediate	O
+coronary	O
+CTA	O
+in	O
+the	O
+ED	O
+(	O
+without	O
+serial	O
+markers	O
+)	O
+or	O
+underwent	O
+coronary	O
+CTA	O
+after	O
+a	O
+brief	O
+observation	O
+period	O
+with	O
+serial	O
+cardiac	O
+marker	O
+measurements	O
+.	O
+	
+Patients	O
+with	O
+negative	O
+coronary	O
+CTA	O
+(	O
+maximal	O
+stenosis	B-NP
+less	O
+than	O
+50	O
+%	O
+)	O
+were	O
+discharged	O
+.	O
+	
+The	O
+main	O
+outcome	O
+was	O
+30	O
+-	O
+day	O
+cardiovascular	O
+death	O
+or	O
+myocardial	B-NP
+infarction	I-NP
+.	O
+	
+RESULTS	O
+:	O
+A	O
+total	O
+of	O
+59	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B-NP
+pain	I-NP
+were	O
+evaluated	O
+.	O
+	
+Patients	O
+had	O
+a	O
+mean	O
+age	O
+of	O
+45	O
+.	O
+6	O
++	O
+/	O
+-	O
+6	O
+.	O
+6	O
+yrs	O
+and	O
+were	O
+86	O
+%	O
+black	O
+","	O
+66	O
+%	O
+male	O
+.	O
+	
+Seventy	O
+-	O
+nine	O
+percent	O
+had	O
+a	O
+normal	O
+or	O
+nonspecific	O
+ECG	O
+and	O
+85	O
+%	O
+had	O
+a	O
+TIMI	O
+score	O
+<	O
+2	O
+.	O
+	
+Twenty	O
+patients	O
+received	O
+coronary	O
+CTA	O
+immediately	O
+in	O
+the	O
+ED	O
+","	O
+18	O
+of	O
+whom	O
+were	O
+discharged	O
+following	O
+CTA	O
+(	O
+90	O
+%	O
+)	O
+.	O
+	
+Thirty	O
+-	O
+nine	O
+received	O
+coronary	O
+CTA	O
+after	O
+a	O
+brief	O
+observation	O
+period	O
+","	O
+with	O
+37	O
+discharged	O
+home	O
+following	O
+CTA	O
+(	O
+95	O
+%	O
+)	O
+.	O
+	
+Six	O
+patients	O
+had	O
+coronary	B-NP
+stenosis	I-NP
+>	O
+or	O
+=	O
+50	O
+%	O
+.	O
+	
+During	O
+the	O
+30	O
+-	O
+day	O
+follow	O
+-	O
+up	O
+period	O
+","	O
+no	O
+patients	O
+died	O
+of	O
+a	O
+cardiovascular	O
+event	O
+(	O
+0	O
+%	O
+;	O
+95	O
+%	O
+CI	O
+","	O
+0	O
+-	O
+6	O
+.	O
+1	O
+%	O
+)	O
+and	O
+no	O
+patient	O
+sustained	O
+a	O
+nonfatal	O
+myocardial	B-NP
+infarction	I-NP
+(	O
+0	O
+%	O
+;	O
+95	O
+%	O
+CI	O
+","	O
+0	O
+-	O
+6	O
+.	O
+1	O
+%	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Although	O
+cocaine	O
+-	O
+associated	O
+myocardial	B-NP
+ischemia	I-NP
+can	O
+result	O
+from	O
+coronary	O
+vasoconstriction	O
+","	O
+patients	O
+with	O
+cocaine	O
+associated	O
+chest	B-NP
+pain	I-NP
+","	O
+a	O
+non	O
+-	O
+ischemic	B-NP
+ECG	O
+","	O
+and	O
+a	O
+TIMI	O
+risk	O
+score	O
+<	O
+2	O
+may	O
+be	O
+safely	O
+discharged	O
+from	O
+the	O
+ED	O
+after	O
+a	O
+negative	O
+coronary	O
+CTA	O
+with	O
+a	O
+low	O
+risk	O
+of	O
+30	O
+-	O
+day	O
+adverse	O
+events	O
+.	O
+	
+Bilateral	O
+haemorrhagic	B-NP
+infarction	I-NP
+of	I-NP
+the	I-NP
+globus	I-NP
+pallidus	I-NP
+after	O
+cocaine	O
+and	O
+alcohol	O
+intoxication	O
+.	O
+	
+Cocaine	O
+is	O
+a	O
+risk	O
+factor	O
+for	O
+both	O
+ischemic	B-NP
+and	I-NP
+haemorrhagic	I-NP
+stroke	I-NP
+.	O
+	
+We	O
+present	O
+the	O
+case	O
+of	O
+a	O
+31	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+bilateral	O
+ischemia	B-NP
+of	I-NP
+the	I-NP
+globus	I-NP
+pallidus	I-NP
+after	O
+excessive	O
+alcohol	O
+and	O
+intranasal	O
+cocaine	O
+use	O
+.	O
+	
+Drug	O
+-	O
+related	O
+globus	B-NP
+pallidus	I-NP
+infarctions	I-NP
+are	O
+most	O
+often	O
+associated	O
+with	O
+heroin	O
+.	O
+	
+Bilateral	O
+basal	B-NP
+ganglia	I-NP
+infarcts	I-NP
+after	O
+the	O
+use	O
+of	O
+cocaine	O
+","	O
+without	O
+concurrent	O
+heroin	O
+use	O
+","	O
+have	O
+never	O
+been	O
+reported	O
+.	O
+	
+In	O
+our	O
+patient	O
+","	O
+transient	O
+cardiac	B-NP
+arrhythmia	I-NP
+or	O
+respiratory	B-NP
+dysfunction	I-NP
+related	O
+to	O
+cocaine	O
+and	O
+/	O
+or	O
+ethanol	O
+use	O
+were	O
+the	O
+most	O
+likely	O
+causes	O
+of	O
+cerebral	B-NP
+hypoperfusion	I-NP
+.	O
+	
+Late	O
+fulminant	O
+posterior	B-NP
+reversible	I-NP
+encephalopathy	I-NP
+syndrome	I-NP
+after	O
+liver	O
+transplant	O
+.	O
+	
+OBJECTIVES	O
+:	O
+Posterior	B-NP
+leukoencephalopathy	I-NP
+due	O
+to	O
+calcineurin	O
+-	O
+inhibitor	O
+-	O
+related	O
+neurotoxicity	B-NP
+is	O
+a	O
+rare	O
+but	O
+severe	O
+complication	O
+that	O
+results	O
+from	O
+treatment	O
+with	O
+immunosuppressive	O
+agents	O
+(	O
+primarily	O
+those	O
+administered	O
+after	O
+a	O
+liver	O
+or	O
+kidney	O
+transplant	O
+)	O
+.	O
+	
+The	O
+pathophysiologic	O
+mechanisms	O
+of	O
+that	O
+disorder	O
+remain	O
+unknown	O
+.	O
+	
+CASE	O
+:	O
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+46	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+who	O
+received	O
+a	O
+liver	O
+transplant	O
+in	O
+our	O
+center	O
+as	O
+treatment	O
+for	O
+alcoholic	B-NP
+cirrhosis	I-NP
+and	O
+in	O
+whom	O
+either	O
+a	O
+fulminant	O
+course	O
+of	O
+posterior	B-NP
+leukoencephalopathy	I-NP
+or	O
+posterior	B-NP
+reversible	I-NP
+encephalopathy	I-NP
+syndrome	I-NP
+developed	O
+110	O
+days	O
+after	O
+transplant	O
+.	O
+	
+After	O
+an	O
+initially	O
+uneventful	O
+course	O
+after	O
+the	O
+transplant	O
+","	O
+the	O
+patient	O
+rapidly	O
+fell	O
+into	O
+deep	O
+coma	O
+.	O
+	
+RESULTS	O
+:	O
+Cerebral	O
+MRI	O
+scan	O
+showed	O
+typical	O
+signs	O
+of	O
+enhancement	O
+in	O
+the	O
+pontine	O
+and	O
+posterior	O
+regions	O
+.	O
+	
+Switching	O
+the	O
+immunosuppressive	O
+regimen	O
+from	O
+tacrolimus	O
+to	O
+cyclosporine	O
+did	O
+not	O
+improve	O
+the	O
+clinical	O
+situation	O
+.	O
+	
+The	O
+termination	O
+of	O
+treatment	O
+with	O
+any	O
+calcineurin	O
+inhibitor	O
+resulted	O
+in	O
+a	O
+complete	O
+resolution	O
+of	O
+that	O
+complication	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Posterior	B-NP
+reversible	I-NP
+encephalopathy	I-NP
+syndrome	I-NP
+after	O
+liver	O
+transplant	O
+is	O
+rare	O
+.	O
+	
+We	O
+recommend	O
+a	O
+complete	O
+cessation	O
+of	O
+any	O
+calcineurin	O
+inhibitor	O
+rather	O
+than	O
+a	O
+dose	O
+reduction	O
+.	O
+	
+Prolonged	O
+hypothermia	B-NP
+as	O
+a	O
+bridge	O
+to	O
+recovery	O
+for	O
+cerebral	B-NP
+edema	I-NP
+and	O
+intracranial	B-NP
+hypertension	I-NP
+associated	O
+with	O
+fulminant	B-NP
+hepatic	I-NP
+failure	I-NP
+.	O
+	
+BACKGROUND	O
+:	O
+To	O
+review	O
+evidence	O
+-	O
+based	O
+treatment	O
+options	O
+in	O
+patients	O
+with	O
+cerebral	B-NP
+edema	I-NP
+complicating	O
+fulminant	B-NP
+hepatic	I-NP
+failure	I-NP
+(	O
+FHF	B-NP
+)	O
+and	O
+discuss	O
+the	O
+potential	O
+applications	O
+of	O
+hypothermia	B-NP
+.	O
+	
+METHOD	O
+:	O
+Case	O
+-	O
+based	O
+observations	O
+from	O
+a	O
+medical	O
+intensive	O
+care	O
+unit	O
+(	O
+MICU	O
+)	O
+in	O
+a	O
+tertiary	O
+care	O
+facility	O
+in	O
+a	O
+27	O
+-	O
+year	O
+-	O
+old	O
+female	O
+with	O
+FHF	B-NP
+from	O
+acetaminophen	O
+and	O
+resultant	O
+cerebral	B-NP
+edema	I-NP
+.	O
+	
+RESULTS	O
+:	O
+Our	O
+patient	O
+was	O
+admitted	O
+to	O
+the	O
+MICU	O
+after	O
+being	O
+found	O
+unresponsive	O
+with	O
+presumed	O
+toxicity	B-NP
+from	O
+acetaminophen	O
+which	O
+was	O
+ingested	O
+over	O
+a	O
+2	O
+-	O
+day	O
+period	O
+.	O
+	
+The	O
+patient	O
+had	O
+depressed	O
+of	O
+mental	O
+status	O
+lasting	O
+at	O
+least	O
+24	O
+h	O
+prior	O
+to	O
+admission	O
+.	O
+	
+Initial	O
+evaluation	O
+confirmed	O
+FHF	B-NP
+from	O
+acetaminophen	O
+and	O
+cerebral	B-NP
+edema	I-NP
+.	O
+	
+The	O
+patient	O
+was	O
+treated	O
+with	O
+hyperosmolar	O
+therapy	O
+","	O
+hyperventilation	B-NP
+","	O
+sedation	O
+","	O
+and	O
+chemical	O
+paralysis	B-NP
+.	O
+	
+Her	O
+intracranial	O
+pressure	O
+remained	O
+elevated	O
+despite	O
+maximal	O
+medical	O
+therapy	O
+.	O
+	
+We	O
+then	O
+initiated	O
+therapeutic	O
+hypothermia	B-NP
+which	O
+was	O
+continued	O
+for	O
+5	O
+days	O
+.	O
+	
+At	O
+re	O
+-	O
+warming	O
+","	O
+patient	O
+had	O
+resolution	O
+of	O
+her	O
+cerebral	B-NP
+edema	I-NP
+and	O
+intracranial	B-NP
+hypertension	I-NP
+.	O
+	
+At	O
+discharge	O
+","	O
+she	O
+had	O
+complete	O
+recovery	O
+of	O
+neurological	O
+and	O
+hepatic	O
+functions	O
+.	O
+	
+CONCLUSION	O
+:	O
+In	O
+patients	O
+with	O
+FHF	B-NP
+and	O
+cerebral	B-NP
+edema	I-NP
+from	O
+acetaminophen	O
+overdose	B-NP
+","	O
+prolonged	O
+therapeutic	O
+hypothermia	B-NP
+could	O
+potentially	O
+be	O
+used	O
+as	O
+a	O
+life	O
+saving	O
+therapy	O
+and	O
+a	O
+bridge	O
+to	O
+hepatic	O
+and	O
+neurological	O
+recovery	O
+.	O
+	
+A	O
+clinical	O
+trial	O
+of	O
+hypothermia	B-NP
+in	O
+patients	O
+with	O
+this	O
+condition	O
+is	O
+warranted	O
+.	O
+	
+Binasal	B-NP
+visual	I-NP
+field	I-NP
+defects	I-NP
+are	O
+not	O
+specific	O
+to	O
+vigabatrin	O
+.	O
+	
+This	O
+study	O
+investigated	O
+the	O
+visual	B-NP
+defects	I-NP
+associated	O
+with	O
+the	O
+antiepileptic	O
+drug	O
+vigabatrin	O
+(	O
+VGB	O
+)	O
+.	O
+	
+Two	O
+hundred	O
+four	O
+people	O
+with	O
+epilepsy	B-NP
+were	O
+grouped	O
+on	O
+the	O
+basis	O
+of	O
+antiepileptic	O
+drug	O
+therapy	O
+(	O
+current	O
+","	O
+previous	O
+","	O
+or	O
+no	O
+exposure	O
+to	O
+VGB	O
+)	O
+.	O
+	
+Groups	O
+were	O
+matched	O
+with	O
+respect	O
+to	O
+age	O
+","	O
+gender	O
+","	O
+and	O
+seizure	B-NP
+frequency	O
+.	O
+	
+All	O
+patients	O
+underwent	O
+objective	O
+assessment	O
+of	O
+electrophysiological	O
+function	O
+(	O
+wide	O
+-	O
+field	O
+multifocal	O
+electroretinography	O
+)	O
+and	O
+conventional	O
+visual	O
+field	O
+testing	O
+(	O
+static	O
+perimetry	O
+)	O
+.	O
+	
+Bilateral	O
+visual	O
+field	O
+constriction	O
+was	O
+observed	O
+in	O
+59	O
+%	O
+of	O
+patients	O
+currently	O
+taking	O
+VGB	O
+","	O
+43	O
+%	O
+of	O
+patients	O
+who	O
+previously	O
+took	O
+VGB	O
+","	O
+and	O
+24	O
+%	O
+of	O
+patients	O
+with	O
+no	O
+exposure	O
+to	O
+VGB	O
+.	O
+	
+Assessment	O
+of	O
+retinal	O
+function	O
+revealed	O
+abnormal	O
+responses	O
+in	O
+48	O
+%	O
+of	O
+current	O
+VGB	O
+users	O
+and	O
+22	O
+%	O
+of	O
+prior	O
+VGB	O
+users	O
+","	O
+but	O
+in	O
+none	O
+of	O
+the	O
+patients	O
+without	O
+previous	O
+exposure	O
+to	O
+VGB	O
+.	O
+	
+Bilateral	B-NP
+visual	I-NP
+field	I-NP
+abnormalities	I-NP
+are	O
+common	O
+in	O
+the	O
+treated	O
+epilepsy	B-NP
+population	O
+","	O
+irrespective	O
+of	O
+drug	O
+history	O
+.	O
+	
+Assessment	O
+by	O
+conventional	O
+static	O
+perimetry	O
+may	O
+neither	O
+be	O
+sufficiently	O
+sensitive	O
+nor	O
+specific	O
+to	O
+reliably	O
+identify	O
+retinal	B-NP
+toxicity	I-NP
+associated	O
+with	O
+VGB	O
+.	O
+	
+Smoking	O
+of	O
+crack	O
+cocaine	O
+as	O
+a	O
+risk	O
+factor	O
+for	O
+HIV	B-NP
+infection	I-NP
+among	O
+people	O
+who	O
+use	O
+injection	O
+drugs	O
+.	O
+	
+BACKGROUND	O
+:	O
+Little	O
+is	O
+known	O
+about	O
+the	O
+possible	O
+role	O
+that	O
+smoking	O
+crack	O
+cocaine	O
+has	O
+on	O
+the	O
+incidence	O
+of	O
+HIV	B-NP
+infection	I-NP
+.	O
+	
+Given	O
+the	O
+increasing	O
+use	O
+of	O
+crack	O
+cocaine	O
+","	O
+we	O
+sought	O
+to	O
+examine	O
+whether	O
+use	O
+of	O
+this	O
+illicit	O
+drug	O
+has	O
+become	O
+a	O
+risk	O
+factor	O
+for	O
+HIV	B-NP
+infection	I-NP
+.	O
+	
+METHODS	O
+:	O
+We	O
+included	O
+data	O
+from	O
+people	O
+participating	O
+in	O
+the	O
+Vancouver	O
+Injection	O
+Drug	O
+Users	O
+Study	O
+who	O
+reported	O
+injecting	O
+illicit	O
+drugs	O
+at	O
+least	O
+once	O
+in	O
+the	O
+month	O
+before	O
+enrolment	O
+","	O
+lived	O
+in	O
+the	O
+greater	O
+Vancouver	O
+area	O
+","	O
+were	O
+HIV	O
+-	O
+negative	O
+at	O
+enrolment	O
+and	O
+completed	O
+at	O
+least	O
+1	O
+follow	O
+-	O
+up	O
+study	O
+visit	O
+.	O
+	
+To	O
+determine	O
+whether	O
+the	O
+risk	O
+of	O
+HIV	B-NP
+seroconversion	I-NP
+among	O
+daily	O
+smokers	O
+of	O
+crack	O
+cocaine	O
+changed	O
+over	O
+time	O
+","	O
+we	O
+used	O
+Cox	O
+proportional	O
+hazards	O
+regression	O
+and	O
+divided	O
+the	O
+study	O
+into	O
+3	O
+periods	O
+:	O
+May	O
+1	O
+","	O
+1996	O
+-	O
+Nov	O
+.	O
+	
+30	O
+","	O
+1999	O
+(	O
+period	O
+1	O
+)	O
+","	O
+Dec	O
+.	O
+	
+1	O
+","	O
+1999	O
+-	O
+Nov	O
+.	O
+	
+30	O
+","	O
+2002	O
+(	O
+period	O
+2	O
+)	O
+","	O
+and	O
+Dec	O
+.	O
+	
+1	O
+","	O
+2002	O
+-	O
+Dec	O
+.	O
+	
+30	O
+","	O
+2005	O
+(	O
+period	O
+3	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+Overall	O
+","	O
+1048	O
+eligible	O
+injection	O
+drug	O
+users	O
+were	O
+included	O
+in	O
+our	O
+study	O
+.	O
+	
+Of	O
+these	O
+","	O
+137	O
+acquired	O
+HIV	B-NP
+infection	I-NP
+during	O
+follow	O
+-	O
+up	O
+.	O
+	
+The	O
+mean	O
+proportion	O
+of	O
+participants	O
+who	O
+reported	O
+daily	O
+smoking	O
+of	O
+crack	O
+cocaine	O
+increased	O
+from	O
+11	O
+.	O
+6	O
+%	O
+in	O
+period	O
+1	O
+to	O
+39	O
+.	O
+7	O
+%	O
+in	O
+period	O
+3	O
+.	O
+	
+After	O
+adjusting	O
+for	O
+potential	O
+confounders	O
+","	O
+we	O
+found	O
+that	O
+the	O
+risk	O
+of	O
+HIV	B-NP
+seroconversion	I-NP
+among	O
+participants	O
+who	O
+were	O
+daily	O
+smokers	O
+of	O
+crack	O
+cocaine	O
+increased	O
+over	O
+time	O
+(	O
+period	O
+1	O
+:	O
+hazard	O
+ratio	O
+[	O
+HR	O
+]	O
+1	O
+.	O
+3	O
+","	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+0	O
+.	O
+57	O
+-	O
+1	O
+.	O
+85	O
+;	O
+period	O
+2	O
+:	O
+HR	O
+1	O
+.	O
+68	O
+","	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+1	O
+-	O
+2	O
+.	O
+80	O
+;	O
+and	O
+period	O
+3	O
+:	O
+HR	O
+2	O
+.	O
+74	O
+","	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+6	O
+-	O
+7	O
+.	O
+11	O
+)	O
+.	O
+	
+INTERPRETATION	O
+:	O
+Smoking	O
+of	O
+crack	O
+cocaine	O
+was	O
+found	O
+to	O
+be	O
+an	O
+independent	O
+risk	O
+factor	O
+for	O
+HIV	B-NP
+seroconversion	I-NP
+among	O
+people	O
+who	O
+were	O
+injection	O
+drug	O
+users	O
+.	O
+	
+This	O
+finding	O
+points	O
+to	O
+the	O
+urgent	O
+need	O
+for	O
+evidence	O
+-	O
+based	O
+public	O
+health	O
+initiatives	O
+targeted	O
+at	O
+people	O
+who	O
+smoke	O
+crack	O
+cocaine	O
+.	O
+	
+Fluoxetine	O
+improves	O
+the	O
+memory	B-NP
+deficits	I-NP
+caused	O
+by	O
+the	O
+chemotherapy	O
+agent	O
+5	O
+-	O
+fluorouracil	O
+.	O
+	
+Cancer	B-NP
+patients	O
+who	O
+have	O
+been	O
+treated	O
+with	O
+systemic	O
+adjuvant	O
+chemotherapy	O
+have	O
+described	O
+experiencing	O
+deteriorations	O
+in	O
+cognition	O
+.	O
+	
+A	O
+widely	O
+used	O
+chemotherapeutic	O
+agent	O
+","	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+","	O
+readily	O
+crosses	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+and	O
+so	O
+could	O
+have	O
+a	O
+direct	O
+effect	O
+on	O
+brain	O
+function	O
+.	O
+	
+In	O
+particular	O
+this	O
+anti	O
+mitotic	O
+drug	O
+could	O
+reduce	O
+cell	O
+proliferation	O
+in	O
+the	O
+neurogenic	O
+regions	O
+of	O
+the	O
+adult	O
+brain	O
+.	O
+	
+In	O
+contrast	O
+reports	O
+indicate	O
+that	O
+hippocampal	O
+dependent	O
+neurogenesis	O
+and	O
+cognition	O
+are	O
+enhanced	O
+by	O
+the	O
+SSRI	O
+antidepressant	O
+Fluoxetine	O
+.	O
+	
+In	O
+this	O
+investigation	O
+the	O
+behavioural	O
+effects	O
+of	O
+chronic	O
+(	O
+two	O
+week	O
+)	O
+treatment	O
+with	O
+5	O
+-	O
+FU	O
+and	O
+(	O
+three	O
+weeks	O
+)	O
+with	O
+Fluoxetine	O
+either	O
+separately	O
+or	O
+in	O
+combination	O
+with	O
+5	O
+-	O
+FU	O
+were	O
+tested	O
+on	O
+adult	O
+Lister	O
+hooded	O
+rats	O
+.	O
+	
+Behavioural	O
+effects	O
+were	O
+tested	O
+using	O
+a	O
+context	O
+dependent	O
+conditioned	O
+emotional	O
+response	O
+test	O
+(	O
+CER	O
+)	O
+which	O
+showed	O
+that	O
+animals	O
+treated	O
+with	O
+5	O
+-	O
+FU	O
+had	O
+a	O
+significant	O
+reduction	O
+in	O
+freezing	O
+time	O
+compared	O
+to	O
+controls	O
+.	O
+	
+A	O
+separate	O
+group	O
+of	O
+animals	O
+was	O
+tested	O
+using	O
+a	O
+hippocampal	O
+dependent	O
+spatial	O
+working	O
+memory	O
+test	O
+","	O
+the	O
+object	O
+location	O
+recognition	O
+test	O
+(	O
+OLR	O
+)	O
+.	O
+	
+Animals	O
+treated	O
+only	O
+with	O
+5	O
+-	O
+FU	O
+showed	O
+significant	O
+deficits	O
+in	O
+their	O
+ability	O
+to	O
+carry	O
+out	O
+the	O
+OLR	O
+task	O
+but	O
+co	O
+administration	O
+of	O
+Fluoxetine	O
+improved	O
+their	O
+performance	O
+.	O
+	
+5	O
+-	O
+FU	O
+chemotherapy	O
+caused	O
+a	O
+significant	O
+reduction	O
+in	O
+the	O
+number	O
+of	O
+proliferating	O
+cells	O
+in	O
+the	O
+sub	O
+granular	O
+zone	O
+of	O
+the	O
+dentate	O
+gyrus	O
+compared	O
+to	O
+controls	O
+.	O
+	
+This	O
+reduction	O
+was	O
+eliminated	O
+when	O
+Fluoxetine	O
+was	O
+co	O
+administered	O
+with	O
+5	O
+-	O
+FU	O
+.	O
+	
+Fluoxetine	O
+on	O
+its	O
+own	O
+had	O
+no	O
+effect	O
+on	O
+proliferating	O
+cell	O
+number	O
+or	O
+behaviour	O
+.	O
+	
+These	O
+findings	O
+suggest	O
+that	O
+5	O
+-	O
+FU	O
+can	O
+negatively	O
+affect	O
+both	O
+cell	O
+proliferation	O
+and	O
+hippocampal	O
+dependent	O
+working	O
+memory	O
+and	O
+that	O
+these	O
+deficits	O
+can	O
+be	O
+reversed	O
+by	O
+the	O
+simultaneous	O
+administration	O
+of	O
+the	O
+antidepressant	O
+Fluoxetine	O
+.	O
+	
+Liver	O
+-	O
+specific	O
+ablation	O
+of	O
+integrin	O
+-	O
+linked	O
+kinase	O
+in	O
+mice	O
+results	O
+in	O
+enhanced	O
+and	O
+prolonged	O
+cell	O
+proliferation	O
+and	O
+hepatomegaly	B-NP
+after	O
+phenobarbital	O
+administration	O
+.	O
+	
+We	O
+have	O
+recently	O
+demonstrated	O
+that	O
+disruption	O
+of	O
+extracellular	O
+matrix	O
+(	O
+ECM	O
+)	O
+/	O
+integrin	O
+signaling	O
+via	O
+elimination	O
+of	O
+integrin	O
+-	O
+linked	O
+kinase	O
+(	O
+ILK	O
+)	O
+in	O
+hepatocytes	O
+interferes	O
+with	O
+signals	O
+leading	O
+to	O
+termination	O
+of	O
+liver	O
+regeneration	O
+.	O
+	
+This	O
+study	O
+investigates	O
+the	O
+role	O
+of	O
+ILK	O
+in	O
+liver	O
+enlargement	O
+induced	O
+by	O
+phenobarbital	O
+(	O
+PB	O
+)	O
+.	O
+	
+Wild	O
+-	O
+type	O
+(	O
+WT	O
+)	O
+and	O
+ILK	O
+:	O
+liver	O
+-	O
+/	O
+-	O
+mice	O
+were	O
+given	O
+PB	O
+(	O
+0	O
+.	O
+1	O
+%	O
+in	O
+drinking	O
+water	O
+)	O
+for	O
+10	O
+days	O
+.	O
+	
+Livers	O
+were	O
+harvested	O
+on	O
+2	O
+","	O
+5	O
+","	O
+and	O
+10	O
+days	O
+during	O
+PB	O
+administration	O
+.	O
+	
+In	O
+the	O
+hepatocyte	O
+-	O
+specific	O
+ILK	O
+/	O
+liver	O
+-	O
+/	O
+-	O
+mice	O
+","	O
+the	O
+liver	O
+:	O
+body	O
+weight	O
+ratio	O
+was	O
+more	O
+than	O
+double	O
+as	O
+compared	O
+to	O
+0	O
+h	O
+at	O
+day	O
+2	O
+(	O
+2	O
+.	O
+5	O
+times	O
+)	O
+","	O
+while	O
+at	O
+days	O
+5	O
+and	O
+10	O
+","	O
+it	O
+was	O
+enlarged	O
+three	O
+times	O
+.	O
+	
+In	O
+the	O
+WT	O
+mice	O
+","	O
+the	O
+increase	O
+was	O
+as	O
+expected	O
+from	O
+previous	O
+literature	O
+(	O
+1	O
+.	O
+8	O
+times	O
+)	O
+and	O
+seems	O
+to	O
+have	O
+leveled	O
+off	O
+after	O
+day	O
+2	O
+.	O
+	
+There	O
+were	O
+slightly	O
+increased	O
+proliferating	O
+cell	O
+nuclear	O
+antigen	O
+-	O
+positive	O
+cells	O
+in	O
+the	O
+ILK	O
+/	O
+liver	O
+-	O
+/	O
+-	O
+animals	O
+at	O
+day	O
+2	O
+as	O
+compared	O
+to	O
+WT	O
+after	O
+PB	O
+administration	O
+.	O
+	
+In	O
+the	O
+WT	O
+animals	O
+","	O
+the	O
+proliferative	O
+response	O
+had	O
+come	O
+back	O
+to	O
+normal	O
+by	O
+days	O
+5	O
+and	O
+10	O
+.	O
+	
+Hepatocytes	O
+of	O
+the	O
+ILK	O
+/	O
+liver	O
+-	O
+/	O
+-	O
+mice	O
+continued	O
+to	O
+proliferate	O
+up	O
+until	O
+day	O
+10	O
+.	O
+	
+ILK	O
+/	O
+liver	O
+-	O
+/	O
+-	O
+mice	O
+also	O
+showed	O
+increased	O
+expression	O
+of	O
+key	O
+genes	O
+involved	O
+in	O
+hepatocyte	O
+proliferation	O
+at	O
+different	O
+time	O
+points	O
+during	O
+PB	O
+administration	O
+.	O
+	
+In	O
+summary	O
+","	O
+ECM	O
+proteins	O
+communicate	O
+with	O
+the	O
+signaling	O
+machinery	O
+of	O
+dividing	O
+cells	O
+via	O
+ILK	O
+to	O
+regulate	O
+hepatocyte	O
+proliferation	O
+and	O
+termination	O
+of	O
+the	O
+proliferative	O
+response	O
+.	O
+	
+Lack	O
+of	O
+ILK	O
+in	O
+the	O
+hepatocytes	O
+imparts	O
+prolonged	O
+proliferative	O
+response	O
+not	O
+only	O
+to	O
+stimuli	O
+related	O
+to	O
+liver	O
+regeneration	O
+but	O
+also	O
+to	O
+xenobiotic	O
+chemical	O
+mitogens	O
+","	O
+such	O
+as	O
+PB	O
+.	O
+	
+Decreased	O
+Expression	O
+of	O
+Na	O
+/	O
+K	O
+-	O
+ATPase	O
+","	O
+NHE3	O
+","	O
+NBC1	O
+","	O
+AQP1	O
+and	O
+OAT	O
+in	O
+Gentamicin	O
+-	O
+induced	O
+Nephropathy	B-NP
+.	O
+	
+The	O
+present	O
+study	O
+was	O
+aimed	O
+to	O
+determine	O
+whether	O
+there	O
+is	O
+an	O
+altered	O
+regulation	O
+of	O
+tubular	O
+transporters	O
+in	O
+gentamicin	O
+-	O
+induced	O
+nephropathy	B-NP
+.	O
+	
+Sprague	O
+-	O
+Dawley	O
+male	O
+rats	O
+(	O
+200	O
+~	O
+250	O
+g	O
+)	O
+were	O
+subcutaneously	O
+injected	O
+with	O
+gentamicin	O
+(	O
+100	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+)	O
+for	O
+7	O
+days	O
+","	O
+and	O
+the	O
+expression	O
+of	O
+tubular	O
+transporters	O
+was	O
+determined	O
+by	O
+immunoblotting	O
+and	O
+immunohistochemistry	O
+.	O
+	
+The	O
+mRNA	O
+and	O
+protein	O
+expression	O
+of	O
+OAT	O
+was	O
+also	O
+determined	O
+.	O
+	
+Gentamicin	O
+-	O
+treated	O
+rats	O
+exhibited	O
+significantly	O
+decreased	O
+creatinine	O
+clearance	O
+along	O
+with	O
+increased	O
+plasma	O
+creatinine	O
+levels	O
+.	O
+	
+Accordingly	O
+","	O
+the	O
+fractional	O
+excretion	O
+of	O
+sodium	O
+increased	O
+.	O
+	
+Urine	O
+volume	O
+was	O
+increased	O
+","	O
+while	O
+urine	O
+osmolality	O
+and	O
+free	O
+water	O
+reabsorption	O
+were	O
+decreased	O
+.	O
+	
+Immunoblotting	O
+and	O
+immunohistochemistry	O
+revealed	O
+decreased	O
+expression	O
+of	O
+Na	O
+(	O
++	O
+)	O
+/	O
+K	O
+(	O
++	O
+)	O
+-	O
+ATPase	O
+","	O
+NHE3	O
+","	O
+NBC1	O
+","	O
+and	O
+AQP1	O
+in	O
+the	O
+kidney	O
+of	O
+gentamicin	O
+-	O
+treated	O
+rats	O
+.	O
+	
+The	O
+expression	O
+of	O
+OAT1	O
+and	O
+OAT3	O
+was	O
+also	O
+decreased	O
+.	O
+	
+Gentamicin	O
+-	O
+induced	O
+nephropathy	B-NP
+may	O
+at	O
+least	O
+in	O
+part	O
+be	O
+causally	O
+related	O
+with	O
+a	O
+decreased	O
+expression	O
+of	O
+Na	O
+(	O
++	O
+)	O
+/	O
+K	O
+(	O
++	O
+)	O
+-	O
+ATPase	O
+","	O
+NHE3	O
+","	O
+NBC1	O
+","	O
+AQP1	O
+and	O
+OAT	O
+.	O
+	
+Acute	B-NP
+renal	I-NP
+failure	I-NP
+after	O
+high	O
+-	O
+dose	O
+methotrexate	O
+therapy	O
+in	O
+a	O
+patient	O
+with	O
+ileostomy	O
+.	O
+	
+High	O
+-	O
+dose	O
+methotrexate	O
+(	O
+HD	O
+-	O
+MTX	O
+)	O
+is	O
+an	O
+important	O
+treatment	O
+for	O
+Burkitt	B-NP
+lymphoma	I-NP
+","	O
+but	O
+can	O
+cause	O
+hepatic	B-NP
+and	I-NP
+renal	I-NP
+toxicity	I-NP
+when	O
+its	O
+clearance	O
+is	O
+delayed	O
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+after	O
+HD	O
+-	O
+MTX	O
+therapy	O
+in	O
+a	O
+patient	O
+with	O
+ileostomy	O
+","	O
+The	O
+patient	O
+was	O
+a	O
+3	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+who	O
+had	O
+received	O
+a	O
+living	O
+-	O
+related	O
+liver	O
+transplantation	O
+for	O
+congenital	O
+biliary	B-NP
+atresia	I-NP
+.	O
+	
+At	O
+day	O
+833	O
+after	O
+the	O
+transplantation	O
+","	O
+he	O
+was	O
+diagnosed	O
+with	O
+PTLD	B-NP
+(	O
+post	B-NP
+-	I-NP
+transplantation	I-NP
+lymphoproliferative	I-NP
+disorder	I-NP
+","	O
+Burkitt	B-NP
+-	I-NP
+type	I-NP
+malignant	I-NP
+lymphoma	I-NP
+)	O
+.	O
+	
+During	O
+induction	O
+therapy	O
+","	O
+he	O
+suffered	O
+ileal	O
+perforation	O
+and	O
+ileostomy	O
+was	O
+performed	O
+.	O
+	
+Subsequent	O
+HD	O
+-	O
+MTX	O
+therapy	O
+caused	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+that	O
+required	O
+continuous	O
+hemodialysis	O
+.	O
+	
+We	O
+supposed	O
+that	O
+intravascular	O
+hypovolemia	B-NP
+due	O
+to	O
+substantial	O
+drainage	O
+from	O
+the	O
+ileostoma	O
+caused	O
+acute	B-NP
+prerenal	I-NP
+failure	I-NP
+.	O
+	
+After	O
+recovery	O
+of	O
+his	O
+renal	O
+function	O
+","	O
+we	O
+could	O
+safely	O
+treat	O
+the	O
+patient	O
+with	O
+HD	O
+-	O
+MTX	O
+therapy	O
+by	O
+controlling	O
+drainage	O
+from	O
+ileostoma	O
+with	O
+total	O
+parenteral	O
+nutrition	O
+.	O
+	
+Longitudinal	O
+association	O
+of	O
+alcohol	O
+use	O
+with	O
+HIV	B-NP
+disease	I-NP
+progression	O
+and	O
+psychological	O
+health	O
+of	O
+women	O
+with	O
+HIV	O
+.	O
+	
+We	O
+evaluated	O
+the	O
+association	O
+of	O
+alcohol	O
+consumption	O
+and	O
+depression	B-NP
+","	O
+and	O
+their	O
+effects	O
+on	O
+HIV	B-NP
+disease	I-NP
+progression	O
+among	O
+women	O
+with	O
+HIV	O
+.	O
+	
+The	O
+study	O
+included	O
+871	O
+women	O
+with	O
+HIV	O
+who	O
+were	O
+recruited	O
+from	O
+1993	O
+-	O
+1995	O
+in	O
+four	O
+US	O
+cities	O
+.	O
+	
+The	O
+participants	O
+had	O
+physical	O
+examination	O
+","	O
+medical	O
+record	O
+extraction	O
+","	O
+and	O
+venipuncture	O
+","	O
+CD4	O
++	O
+T	O
+-	O
+cell	O
+counts	O
+determination	O
+","	O
+measurement	O
+of	O
+depression	B-NP
+symptoms	O
+(	O
+using	O
+the	O
+self	O
+-	O
+report	O
+Center	O
+for	O
+Epidemiological	O
+Studies	O
+-	O
+Depression	B-NP
+Scale	O
+)	O
+","	O
+and	O
+alcohol	O
+use	O
+assessment	O
+at	O
+enrollment	O
+","	O
+and	O
+semiannually	O
+until	O
+March	O
+2000	O
+.	O
+	
+Multilevel	O
+random	O
+coefficient	O
+ordinal	O
+models	O
+as	O
+well	O
+as	O
+multilevel	O
+models	O
+with	O
+joint	O
+responses	O
+were	O
+used	O
+in	O
+the	O
+analysis	O
+.	O
+	
+There	O
+was	O
+no	O
+significant	O
+association	O
+between	O
+level	O
+of	O
+alcohol	O
+use	O
+and	O
+CD4	O
++	O
+T	O
+-	O
+cell	O
+counts	O
+.	O
+	
+When	O
+participants	O
+were	O
+stratified	O
+by	O
+antiretroviral	O
+therapy	O
+(	O
+ART	O
+)	O
+use	O
+","	O
+the	O
+association	O
+between	O
+alcohol	O
+and	O
+CD4	O
++	O
+T	O
+-	O
+cell	O
+did	O
+not	O
+reach	O
+statistical	O
+significance	O
+.	O
+	
+The	O
+association	O
+between	O
+alcohol	O
+consumption	O
+and	O
+depression	B-NP
+was	O
+significant	O
+(	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Depression	B-NP
+had	O
+a	O
+significant	O
+negative	O
+effect	O
+on	O
+CD4	O
++	O
+T	O
+-	O
+cell	O
+counts	O
+over	O
+time	O
+regardless	O
+of	O
+ART	O
+use	O
+.	O
+	
+Our	O
+findings	O
+suggest	O
+that	O
+alcohol	O
+consumption	O
+has	O
+a	O
+direct	O
+association	O
+with	O
+depression	B-NP
+.	O
+	
+Moreover	O
+","	O
+depression	B-NP
+is	O
+associated	O
+with	O
+HIV	B-NP
+disease	I-NP
+progression	O
+.	O
+	
+Our	O
+findings	O
+have	O
+implications	O
+for	O
+the	O
+provision	O
+of	O
+alcohol	O
+use	O
+interventions	O
+and	O
+psychological	O
+resources	O
+to	O
+improve	O
+the	O
+health	O
+of	O
+women	O
+with	O
+HIV	O
+.	O
+	
+Chemokine	O
+CCL2	O
+and	O
+its	O
+receptor	O
+CCR2	O
+are	O
+increased	O
+in	O
+the	O
+hippocampus	O
+following	O
+pilocarpine	O
+-	O
+induced	O
+status	B-NP
+epilepticus	I-NP
+.	O
+	
+BACKGROUND	O
+:	O
+Neuroinflammation	B-NP
+occurs	O
+after	O
+seizures	B-NP
+and	O
+is	O
+implicated	O
+in	O
+epileptogenesis	O
+.	O
+	
+CCR2	O
+is	O
+a	O
+chemokine	O
+receptor	O
+for	O
+CCL2	O
+and	O
+their	O
+interaction	O
+mediates	O
+monocyte	O
+infiltration	O
+in	O
+the	O
+neuroinflammatory	B-NP
+cascade	O
+triggered	O
+in	O
+different	O
+brain	O
+pathologies	O
+.	O
+	
+In	O
+this	O
+work	O
+CCR2	O
+and	O
+CCL2	O
+expression	O
+were	O
+examined	O
+following	O
+status	B-NP
+epilepticus	I-NP
+(	O
+SE	B-NP
+)	O
+induced	O
+by	O
+pilocarpine	O
+injection	O
+.	O
+	
+METHODS	O
+:	O
+SE	B-NP
+was	O
+induced	O
+by	O
+pilocarpine	O
+injection	O
+.	O
+	
+Control	O
+rats	O
+were	O
+injected	O
+with	O
+saline	O
+instead	O
+of	O
+pilocarpine	O
+.	O
+	
+Five	O
+days	O
+after	O
+SE	B-NP
+","	O
+CCR2	O
+staining	O
+in	O
+neurons	O
+and	O
+glial	O
+cells	O
+was	O
+examined	O
+using	O
+imunohistochemical	O
+analyses	O
+.	O
+	
+The	O
+number	O
+of	O
+CCR2	O
+positive	O
+cells	O
+was	O
+determined	O
+using	O
+stereology	O
+probes	O
+in	O
+the	O
+hippocampus	O
+.	O
+	
+CCL2	O
+expression	O
+in	O
+the	O
+hippocampus	O
+was	O
+examined	O
+by	O
+molecular	O
+assay	O
+.	O
+	
+RESULTS	O
+:	O
+Increased	O
+CCR2	O
+was	O
+observed	O
+in	O
+the	O
+hippocampus	O
+after	O
+SE	B-NP
+.	O
+	
+Seizures	B-NP
+also	O
+resulted	O
+in	O
+alterations	O
+to	O
+the	O
+cell	O
+types	O
+expressing	O
+CCR2	O
+.	O
+	
+Increased	O
+numbers	O
+of	O
+neurons	O
+that	O
+expressed	O
+CCR2	O
+was	O
+observed	O
+following	O
+SE	B-NP
+.	O
+	
+Microglial	O
+cells	O
+were	O
+more	O
+closely	O
+apposed	O
+to	O
+the	O
+CCR2	O
+-	O
+labeled	O
+cells	O
+in	O
+SE	B-NP
+rats	O
+.	O
+	
+In	O
+addition	O
+","	O
+rats	O
+that	O
+experienced	O
+SE	B-NP
+exhibited	O
+CCR2	O
+-	O
+labeling	O
+in	O
+populations	O
+of	O
+hypertrophied	B-NP
+astrocytes	O
+","	O
+especially	O
+in	O
+CA1	O
+and	O
+dentate	O
+gyrus	O
+.	O
+	
+These	O
+CCR2	O
++	O
+astroctytes	O
+were	O
+not	O
+observed	O
+in	O
+control	O
+rats	O
+.	O
+	
+Examination	O
+of	O
+CCL2	O
+expression	O
+showed	O
+that	O
+it	O
+was	O
+elevated	O
+in	O
+the	O
+hippocampus	O
+following	O
+SE	B-NP
+.	O
+	
+CONCLUSION	O
+:	O
+The	O
+data	O
+show	O
+that	O
+CCR2	O
+and	O
+CCL2	O
+are	O
+up	O
+-	O
+regulated	O
+in	O
+the	O
+hippocampus	O
+after	O
+pilocarpine	O
+-	O
+induced	O
+SE	B-NP
+.	O
+	
+Seizures	B-NP
+also	O
+result	O
+in	O
+changes	O
+to	O
+CCR2	O
+receptor	O
+expression	O
+in	O
+neurons	O
+and	O
+astrocytes	O
+.	O
+	
+These	O
+changes	O
+might	O
+be	O
+involved	O
+in	O
+detrimental	O
+neuroplasticity	O
+and	O
+neuroinflammatory	B-NP
+changes	O
+that	O
+occur	O
+following	O
+seizures	B-NP
+.	O
+	
+Metallothionein	O
+induction	O
+reduces	O
+caspase	O
+-	O
+3	O
+activity	O
+and	O
+TNFalpha	O
+levels	O
+with	O
+preservation	O
+of	O
+cognitive	O
+function	O
+and	O
+intact	O
+hippocampal	O
+neurons	O
+in	O
+carmustine	O
+-	O
+treated	O
+rats	O
+.	O
+	
+Hippocampal	O
+integrity	O
+is	O
+essential	O
+for	O
+cognitive	O
+functions	O
+.	O
+	
+On	O
+the	O
+other	O
+hand	O
+","	O
+induction	O
+of	O
+metallothionein	O
+(	O
+MT	O
+)	O
+by	O
+ZnSO	O
+(	O
+4	O
+)	O
+and	O
+its	O
+role	O
+in	O
+neuroprotection	O
+has	O
+been	O
+documented	O
+.	O
+	
+The	O
+present	O
+study	O
+aimed	O
+to	O
+explore	O
+the	O
+effect	O
+of	O
+MT	O
+induction	O
+on	O
+carmustine	O
+(	O
+BCNU	O
+)	O
+-	O
+induced	O
+hippocampal	O
+cognitive	B-NP
+dysfunction	I-NP
+in	O
+rats	O
+.	O
+	
+A	O
+total	O
+of	O
+60	O
+male	O
+Wistar	O
+albino	O
+rats	O
+were	O
+randomly	O
+divided	O
+into	O
+four	O
+groups	O
+(	O
+15	O
+/	O
+group	O
+)	O
+:	O
+The	O
+control	O
+group	O
+injected	O
+with	O
+single	O
+doses	O
+of	O
+normal	O
+saline	O
+(	O
+i	O
+.	O
+c	O
+.	O
+v	O
+)	O
+followed	O
+24	O
+h	O
+later	O
+by	O
+BCNU	O
+solvent	O
+(	O
+i	O
+.	O
+v	O
+)	O
+.	O
+	
+The	O
+second	O
+group	O
+administered	O
+ZnSO	O
+(	O
+4	O
+)	O
+(	O
+0	O
+.	O
+1	O
+micromol	O
+/	O
+10	O
+microl	O
+normal	O
+saline	O
+","	O
+i	O
+.	O
+c	O
+.	O
+v	O
+","	O
+once	O
+)	O
+then	O
+BCNU	O
+solvent	O
+(	O
+i	O
+.	O
+v	O
+)	O
+after	O
+24	O
+h	O
+.	O
+	
+Third	O
+group	O
+received	O
+BCNU	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+v	O
+","	O
+once	O
+)	O
+24	O
+h	O
+after	O
+injection	O
+with	O
+normal	O
+saline	O
+(	O
+i	O
+.	O
+c	O
+.	O
+v	O
+)	O
+.	O
+	
+Fourth	O
+group	O
+received	O
+a	O
+single	O
+dose	O
+of	O
+ZnSO	O
+(	O
+4	O
+)	O
+(	O
+0	O
+.	O
+1	O
+micromol	O
+/	O
+10	O
+microl	O
+normal	O
+saline	O
+","	O
+i	O
+.	O
+c	O
+.	O
+v	O
+)	O
+then	O
+BCNU	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+v	O
+","	O
+once	O
+)	O
+after	O
+24	O
+h	O
+.	O
+	
+The	O
+obtained	O
+data	O
+revealed	O
+that	O
+BCNU	O
+administration	O
+resulted	O
+in	O
+deterioration	B-NP
+of	I-NP
+learning	I-NP
+and	I-NP
+short	I-NP
+-	I-NP
+term	I-NP
+memory	I-NP
+(	O
+STM	O
+)	O
+","	O
+as	O
+measured	O
+by	O
+using	O
+radial	O
+arm	O
+water	O
+maze	O
+","	O
+accompanied	O
+with	O
+decreased	O
+hippocampal	O
+glutathione	O
+reductase	O
+(	O
+GR	O
+)	O
+activity	O
+and	O
+reduced	O
+glutathione	O
+(	O
+GSH	O
+)	O
+content	O
+.	O
+	
+Also	O
+","	O
+BCNU	O
+administration	O
+increased	O
+serum	O
+tumor	B-NP
+necrosis	B-NP
+factor	O
+-	O
+alpha	O
+(	O
+TNFalpha	O
+)	O
+","	O
+hippocampal	O
+MT	O
+and	O
+malondialdehyde	O
+(	O
+MDA	O
+)	O
+contents	O
+as	O
+well	O
+as	O
+caspase	O
+-	O
+3	O
+activity	O
+in	O
+addition	O
+to	O
+histological	O
+alterations	O
+.	O
+	
+ZnSO	O
+(	O
+4	O
+)	O
+pretreatment	O
+counteracted	O
+BCNU	O
+-	O
+induced	O
+inhibition	O
+of	O
+GR	O
+and	O
+depletion	O
+of	O
+GSH	O
+and	O
+resulted	O
+in	O
+significant	O
+reduction	O
+in	O
+the	O
+levels	O
+of	O
+MDA	O
+and	O
+TNFalpha	O
+as	O
+well	O
+as	O
+the	O
+activity	O
+of	O
+caspase	O
+-	O
+3	O
+.	O
+	
+The	O
+histological	O
+features	O
+were	O
+improved	O
+in	O
+hippocampus	O
+of	O
+rats	O
+treated	O
+with	O
+ZnSO	O
+(	O
+4	O
+)	O
++	O
+BCNU	O
+compared	O
+to	O
+only	O
+BCNU	O
+-	O
+treated	O
+animals	O
+.	O
+	
+In	O
+conclusion	O
+","	O
+MT	O
+induction	O
+halts	O
+BCNU	O
+-	O
+induced	O
+hippocampal	O
+toxicity	B-NP
+as	O
+it	O
+prevented	O
+GR	O
+inhibition	O
+and	O
+GSH	O
+depletion	O
+and	O
+counteracted	O
+the	O
+increased	O
+levels	O
+of	O
+TNFalpha	O
+","	O
+MDA	O
+and	O
+caspase	O
+-	O
+3	O
+activity	O
+with	O
+subsequent	O
+preservation	O
+of	O
+cognition	O
+.	O
+	
+Fatal	O
+carbamazepine	O
+induced	O
+fulminant	B-NP
+eosinophilic	I-NP
+(	O
+hypersensitivity	B-NP
+)	O
+myocarditis	B-NP
+:	O
+emphasis	O
+on	O
+anatomical	O
+and	O
+histological	O
+characteristics	O
+","	O
+mechanisms	O
+and	O
+genetics	O
+of	O
+drug	B-NP
+hypersensitivity	I-NP
+and	O
+differential	O
+diagnosis	O
+.	O
+	
+The	O
+most	O
+severe	O
+adverse	O
+reactions	O
+to	O
+carbamazepine	O
+have	O
+been	O
+observed	O
+in	O
+the	O
+haemopoietic	O
+system	O
+","	O
+the	O
+liver	O
+and	O
+the	O
+cardiovascular	O
+system	O
+.	O
+	
+A	O
+frequently	O
+fatal	O
+","	O
+although	O
+exceptionally	O
+rare	O
+side	O
+effect	O
+of	O
+carbamazepine	O
+is	O
+necrotizing	O
+eosinophilic	O
+(	O
+hypersensitivity	B-NP
+)	O
+myocarditis	B-NP
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+hypersensitivity	B-NP
+myocarditis	B-NP
+secondary	O
+to	O
+administration	O
+of	O
+carbamazepine	O
+.	O
+	
+Acute	O
+hypersensitivity	B-NP
+myocarditis	B-NP
+was	O
+not	O
+suspected	O
+clinically	O
+","	O
+and	O
+the	O
+diagnosis	O
+was	O
+made	O
+post	O
+-	O
+mortem	O
+.	O
+	
+Histology	O
+revealed	O
+diffuse	O
+infiltration	O
+of	O
+the	O
+myocardium	O
+by	O
+eosinophils	O
+and	O
+lymphocytes	O
+with	O
+myocyte	O
+damage	O
+.	O
+	
+Clinically	O
+","	O
+death	O
+was	O
+due	O
+to	O
+cardiogenic	B-NP
+shock	I-NP
+.	O
+	
+To	O
+best	O
+of	O
+our	O
+knowledge	O
+this	O
+is	O
+the	O
+second	O
+case	O
+of	O
+fatal	O
+carbamazepine	O
+induced	O
+myocarditis	B-NP
+reported	O
+in	O
+English	O
+literature	O
+.	O
+	
+Neuropsychiatric	O
+behaviors	O
+in	O
+the	O
+MPTP	O
+marmoset	O
+model	O
+of	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+OBJECTIVES	O
+:	O
+Neuropsychiatric	O
+symptoms	O
+are	O
+increasingly	O
+recognised	O
+as	O
+a	O
+significant	O
+problem	O
+in	O
+patients	O
+with	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+(	O
+PD	B-NP
+)	O
+.	O
+	
+These	O
+symptoms	O
+may	O
+be	O
+due	O
+to	O
+'	O
+sensitisation	O
+'	O
+following	O
+repeated	O
+levodopa	O
+treatment	O
+or	O
+a	O
+direct	O
+effect	O
+of	O
+dopamine	O
+on	O
+the	O
+disease	O
+state	O
+.	O
+	
+The	O
+levodopa	O
+-	O
+treated	O
+MPTP	O
+-	O
+lesioned	O
+marmoset	O
+was	O
+used	O
+as	O
+a	O
+model	O
+of	O
+neuropsychiatric	B-NP
+symptoms	I-NP
+in	O
+PD	B-NP
+patients	O
+.	O
+	
+Here	O
+we	O
+compare	O
+the	O
+time	O
+course	O
+of	O
+levodopa	O
+-	O
+induced	O
+motor	O
+fluctuations	O
+and	O
+neuropsychiatric	B-NP
+-	I-NP
+like	I-NP
+behaviors	I-NP
+to	O
+determine	O
+the	O
+relationship	O
+between	O
+duration	O
+of	O
+treatment	O
+and	O
+onset	O
+of	O
+symptoms	O
+.	O
+	
+METHODS	O
+:	O
+Marmosets	O
+were	O
+administered	O
+1	O
+-	O
+methyl	O
+-	O
+4	O
+-	O
+phenyl	O
+-	O
+1	O
+","	O
+2	O
+","	O
+3	O
+","	O
+6	O
+-	O
+tetrahydropyridine	O
+(	O
+2	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+for	O
+five	O
+days	O
+","	O
+resulting	O
+in	O
+stable	O
+parkinsonism	B-NP
+.	O
+	
+Levodopa	O
+(	O
+15	O
+mg	O
+/	O
+kg	O
+and	O
+benserazide	O
+","	O
+3	O
+.	O
+75	O
+mg	O
+/	O
+kg	O
+)	O
+p	O
+.	O
+o	O
+.	O
+	
+b	O
+.	O
+i	O
+.	O
+d	O
+","	O
+was	O
+administered	O
+for	O
+30	O
+days	O
+.	O
+	
+Animals	O
+were	O
+evaluated	O
+for	O
+parkinsonian	B-NP
+disability	I-NP
+","	O
+dyskinesia	B-NP
+and	O
+on	O
+-	O
+time	O
+(	O
+motor	O
+fluctuations	O
+)	O
+and	O
+neuropsychiatric	B-NP
+-	I-NP
+like	I-NP
+behaviors	I-NP
+on	O
+Day	O
+0	O
+(	O
+prior	O
+to	O
+levodopa	O
+)	O
+and	O
+on	O
+Days	O
+1	O
+","	O
+7	O
+","	O
+13	O
+","	O
+27	O
+and	O
+30	O
+of	O
+treatment	O
+using	O
+post	O
+hoc	O
+DVD	O
+analysis	O
+by	O
+a	O
+trained	O
+rater	O
+","	O
+blind	O
+to	O
+the	O
+treatment	O
+day	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+neuropsychiatric	B-NP
+-	I-NP
+like	I-NP
+behavior	I-NP
+rating	O
+scale	O
+demonstrated	O
+high	O
+interrater	O
+reliability	O
+between	O
+three	O
+trained	O
+raters	O
+of	O
+differing	O
+professional	O
+backgrounds	O
+.	O
+	
+As	O
+anticipated	O
+","	O
+animals	O
+exhibited	O
+a	O
+progressive	O
+increase	O
+in	O
+levodopa	O
+-	O
+induced	O
+motor	O
+fluctuations	O
+","	O
+dyskinesia	B-NP
+and	O
+wearing	O
+-	O
+off	O
+","	O
+that	O
+correlated	O
+with	O
+the	O
+duration	O
+of	O
+levodopa	O
+therapy	O
+.	O
+	
+In	O
+contrast	O
+","	O
+levodopa	O
+-	O
+induced	O
+neuropsychiatric	B-NP
+-	I-NP
+like	I-NP
+behaviors	I-NP
+were	O
+present	O
+on	O
+Day	O
+1	O
+of	O
+levodopa	O
+treatment	O
+and	O
+their	O
+severity	O
+did	O
+not	O
+correlate	O
+with	O
+duration	O
+of	O
+treatment	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+data	O
+suggest	O
+that	O
+neuropsychiatric	B-NP
+disorders	I-NP
+in	O
+PD	B-NP
+are	O
+more	O
+likely	O
+an	O
+interaction	O
+between	O
+levodopa	O
+and	O
+the	O
+disease	O
+state	O
+than	O
+a	O
+consequence	O
+of	O
+sensitisation	O
+to	O
+repeated	O
+dopaminergic	O
+therapy	O
+.	O
+	
+Contrast	O
+medium	O
+nephrotoxicity	B-NP
+after	O
+renal	O
+artery	O
+and	O
+coronary	O
+angioplasty	O
+.	O
+	
+BACKGROUND	O
+:	O
+Renal	B-NP
+dysfunction	I-NP
+induced	O
+by	O
+iodinated	O
+contrast	O
+medium	O
+(	O
+CM	O
+)	O
+administration	O
+can	O
+minimize	O
+the	O
+benefit	O
+of	O
+the	O
+interventional	O
+procedure	O
+in	O
+patients	O
+undergoing	O
+renal	O
+angioplasty	O
+(	O
+PTRA	O
+)	O
+.	O
+	
+PURPOSE	O
+:	O
+To	O
+compare	O
+the	O
+susceptibility	O
+to	O
+nephrotoxic	B-NP
+effect	O
+of	O
+CM	O
+in	O
+patients	O
+undergoing	O
+PTRA	O
+with	O
+that	O
+of	O
+patients	O
+submitted	O
+to	O
+percutaneous	O
+coronary	O
+intervention	O
+(	O
+PCI	O
+)	O
+.	O
+	
+MATERIAL	O
+AND	O
+METHODS	O
+:	O
+A	O
+total	O
+of	O
+33	O
+patients	O
+successfully	O
+treated	O
+with	O
+PTRA	O
+(	O
+PTRA	O
+group	O
+","	O
+mean	O
+age	O
+70	O
++	O
+/	O
+-	O
+12	O
+years	O
+","	O
+23	O
+female	O
+","	O
+basal	O
+creatinine	O
+1	O
+.	O
+46	O
++	O
+/	O
+-	O
+0	O
+.	O
+79	O
+","	O
+range	O
+0	O
+.	O
+7	O
+-	O
+4	O
+.	O
+9	O
+mg	O
+/	O
+dl	O
+)	O
+were	O
+compared	O
+with	O
+33	O
+patients	O
+undergoing	O
+successful	O
+PCI	O
+(	O
+PCI	O
+group	O
+)	O
+","	O
+matched	O
+for	O
+basal	O
+creatinine	O
+(	O
+1	O
+.	O
+44	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+","	O
+range	O
+0	O
+.	O
+7	O
+-	O
+3	O
+.	O
+4	O
+mg	O
+/	O
+dl	O
+)	O
+","	O
+gender	O
+","	O
+and	O
+age	O
+.	O
+	
+In	O
+both	O
+groups	O
+postprocedural	O
+(	O
+48	O
+h	O
+)	O
+serum	O
+creatinine	O
+was	O
+measured	O
+.	O
+	
+RESULTS	O
+:	O
+Postprocedural	O
+creatinine	O
+level	O
+decreased	O
+nonsignificantly	O
+in	O
+the	O
+PTRA	O
+group	O
+(	O
+1	O
+.	O
+46	O
++	O
+/	O
+-	O
+0	O
+.	O
+8	O
+vs	O
+.	O
+1	O
+.	O
+34	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+dl	O
+","	O
+P	O
+=	O
+NS	O
+)	O
+and	O
+increased	O
+significantly	O
+in	O
+the	O
+PCI	O
+group	O
+(	O
+1	O
+.	O
+44	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+vs	O
+.	O
+1	O
+.	O
+57	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+mg	O
+/	O
+dl	O
+","	O
+P	O
+<	O
+0	O
+.	O
+2	O
+)	O
+.	O
+	
+Changes	O
+in	O
+serum	O
+creatinine	O
+after	O
+intervention	O
+(	O
+after	O
+-	O
+before	O
+)	O
+were	O
+significantly	O
+different	O
+between	O
+the	O
+PTRA	O
+and	O
+PCI	O
+groups	O
+(	O
+-	O
+0	O
+.	O
+12	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+vs	O
+.	O
+0	O
+.	O
+13	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+","	O
+P	O
+=	O
+0	O
+.	O
+14	O
+)	O
+.	O
+	
+This	O
+difference	O
+was	O
+not	O
+related	O
+to	O
+either	O
+a	O
+different	O
+clinical	O
+risk	O
+profile	O
+or	O
+to	O
+the	O
+volume	O
+of	O
+CM	O
+administered	O
+.	O
+	
+CONCLUSION	O
+:	O
+In	O
+this	O
+preliminary	O
+study	O
+patients	O
+submitted	O
+to	O
+PTRA	O
+showed	O
+a	O
+lower	O
+susceptibility	O
+to	O
+renal	B-NP
+damage	I-NP
+induced	O
+by	O
+CM	O
+administration	O
+than	O
+PCI	O
+patients	O
+.	O
+	
+The	O
+effectiveness	O
+of	O
+PTRA	O
+on	O
+renal	O
+function	O
+seems	O
+to	O
+be	O
+barely	O
+influenced	O
+by	O
+CM	O
+toxicity	B-NP
+.	O
+	
+Diphenhydramine	O
+prevents	O
+the	O
+haemodynamic	O
+changes	O
+of	O
+cimetidine	O
+in	O
+ICU	O
+patients	O
+.	O
+	
+Cimetidine	O
+","	O
+a	O
+histamine	O
+2	O
+(	O
+H2	O
+)	O
+antagonist	O
+","	O
+produces	O
+a	O
+decrease	O
+in	O
+arterial	O
+pressure	O
+due	O
+to	O
+vasodilatation	O
+","	O
+especially	O
+in	O
+critically	O
+ill	O
+patients	O
+.	O
+	
+This	O
+may	O
+be	O
+because	O
+cimetidine	O
+acts	O
+as	O
+a	O
+histamine	O
+agonist	O
+.	O
+	
+We	O
+","	O
+therefore	O
+","	O
+investigated	O
+the	O
+effects	O
+of	O
+the	O
+histamine	O
+1	O
+(	O
+H1	O
+)	O
+receptor	O
+antagonist	O
+","	O
+diphenhydramine	O
+","	O
+on	O
+the	O
+haemodynamic	O
+changes	O
+observed	O
+after	O
+cimetidine	O
+in	O
+ICU	O
+patients	O
+.	O
+	
+Each	O
+patient	O
+was	O
+studied	O
+on	O
+two	O
+separate	O
+days	O
+.	O
+	
+In	O
+a	O
+random	O
+fashion	O
+","	O
+they	O
+received	O
+cimetidine	O
+200	O
+mg	O
+iv	O
+on	O
+one	O
+day	O
+","	O
+and	O
+on	O
+the	O
+other	O
+","	O
+a	O
+pretreatment	O
+of	O
+diphenhydramine	O
+40	O
+mg	O
+iv	O
+with	O
+cimetidine	O
+200	O
+mg	O
+iv	O
+.	O
+	
+In	O
+the	O
+non	O
+-	O
+pretreatment	O
+group	O
+","	O
+mean	O
+arterial	O
+pressure	O
+(	O
+MAP	O
+)	O
+decreased	O
+from	O
+107	O
+.	O
+4	O
++	O
+/	O
+-	O
+8	O
+.	O
+4	O
+mmHg	O
+to	O
+86	O
+.	O
+7	O
++	O
+/	O
+-	O
+11	O
+.	O
+4	O
+mmHg	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+two	O
+minutes	O
+after	O
+cimetidine	O
+.	O
+	
+Also	O
+","	O
+systemic	O
+vascular	O
+resistance	O
+(	O
+SVR	O
+)	O
+decreased	O
+during	O
+the	O
+eight	O
+-	O
+minute	O
+observation	O
+period	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+In	O
+contrast	O
+","	O
+in	O
+the	O
+pretreatment	O
+group	O
+","	O
+little	O
+haemodynamic	O
+change	O
+was	O
+seen	O
+.	O
+	
+We	O
+conclude	O
+that	O
+an	O
+H1	O
+antagonist	O
+may	O
+be	O
+useful	O
+in	O
+preventing	O
+hypotension	B-NP
+caused	O
+by	O
+iv	O
+cimetidine	O
+","	O
+since	O
+the	O
+vasodilating	O
+activity	O
+of	O
+cimetidine	O
+is	O
+mediated	O
+","	O
+in	O
+part	O
+","	O
+through	O
+the	O
+H1	O
+receptor	O
+.	O
+	
+Medical	O
+and	O
+psychiatric	O
+outcomes	O
+for	O
+patients	O
+transplanted	O
+for	O
+acetaminophen	O
+-	O
+induced	O
+acute	B-NP
+liver	I-NP
+failure	I-NP
+:	O
+a	O
+case	O
+-	O
+control	O
+study	O
+.	O
+	
+BACKGROUND	O
+:	O
+Acetaminophen	O
+-	O
+induced	O
+hepatotoxicity	B-NP
+is	O
+the	O
+most	O
+common	O
+cause	O
+of	O
+acute	B-NP
+liver	I-NP
+failure	I-NP
+(	O
+ALF	B-NP
+)	O
+in	O
+the	O
+UK	O
+.	O
+	
+Patients	O
+often	O
+consume	O
+the	O
+drug	O
+with	O
+suicidal	O
+intent	O
+or	O
+with	O
+a	O
+background	O
+of	O
+substance	O
+dependence	O
+.	O
+	
+AIMS	O
+AND	O
+METHODS	O
+:	O
+We	O
+compared	O
+the	O
+severity	O
+of	O
+pretransplant	O
+illness	O
+","	O
+psychiatric	O
+co	O
+-	O
+morbidity	O
+","	O
+medical	O
+and	O
+psychosocial	O
+outcomes	O
+of	O
+all	O
+patients	O
+who	O
+had	O
+undergone	O
+liver	O
+transplantation	O
+(	O
+LT	O
+)	O
+emergently	O
+between	O
+1999	O
+-	O
+2004	O
+for	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B-NP
+(	O
+n	O
+=	O
+36	O
+)	O
+with	O
+age	O
+-	O
+and	O
+sex	O
+-	O
+matched	O
+patients	O
+undergoing	O
+emergent	O
+LT	O
+for	O
+non	O
+-	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B-NP
+(	O
+n	O
+=	O
+35	O
+)	O
+and	O
+elective	O
+LT	O
+for	O
+chronic	B-NP
+liver	I-NP
+disease	I-NP
+(	O
+CLD	B-NP
+","	O
+n	O
+=	O
+34	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+Acetaminophen	O
+-	O
+induced	O
+ALF	B-NP
+patients	O
+undergoing	O
+LT	O
+had	O
+a	O
+greater	O
+severity	O
+of	O
+pre	O
+-	O
+LT	O
+illness	O
+reflected	O
+by	O
+higher	O
+Acute	O
+Physiology	O
+and	O
+Chronic	O
+Health	O
+Evaluation	O
+II	O
+scores	O
+and	O
+requirement	O
+for	O
+organ	O
+support	O
+compared	O
+with	O
+the	O
+other	O
+two	O
+groups	O
+.	O
+	
+Twenty	O
+(	O
+56	O
+%	O
+)	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B-NP
+patients	O
+had	O
+a	O
+formal	O
+psychiatric	O
+diagnosis	O
+before	O
+LT	O
+(	O
+non	O
+-	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B-NP
+=	O
+0	O
+/	O
+35	O
+","	O
+CLD	B-NP
+=	O
+2	O
+/	O
+34	O
+;	O
+P	O
+<	O
+0	O
+.	O
+1	O
+for	O
+all	O
+)	O
+and	O
+nine	O
+(	O
+25	O
+%	O
+)	O
+had	O
+a	O
+previous	O
+suicide	O
+attempt	O
+.	O
+	
+During	O
+follow	O
+-	O
+up	O
+(	O
+median	O
+5	O
+years	O
+)	O
+","	O
+there	O
+were	O
+no	O
+significant	O
+differences	O
+in	O
+rejection	O
+(	O
+acute	O
+and	O
+chronic	O
+)	O
+","	O
+graft	O
+failure	O
+or	O
+survival	O
+between	O
+the	O
+groups	O
+(	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B-NP
+1	O
+year	O
+87	O
+%	O
+","	O
+5	O
+years	O
+75	O
+%	O
+;	O
+non	O
+-	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B-NP
+88	O
+%	O
+","	O
+78	O
+%	O
+;	O
+CLD	B-NP
+93	O
+%	O
+","	O
+82	O
+%	O
+:	O
+P	O
+>	O
+0	O
+.	O
+6	O
+log	O
+rank	O
+)	O
+.	O
+	
+Two	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B-NP
+patients	O
+reattempted	O
+suicide	O
+post	O
+-	O
+LT	O
+(	O
+one	O
+died	O
+8	O
+years	O
+post	O
+-	O
+LT	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Despite	O
+a	O
+high	O
+prevalence	O
+of	O
+psychiatric	O
+disturbance	O
+","	O
+outcomes	O
+for	O
+patients	O
+transplanted	O
+emergently	O
+for	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B-NP
+were	O
+comparable	O
+to	O
+those	O
+transplanted	O
+for	O
+non	O
+-	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B-NP
+and	O
+electively	O
+for	O
+CLD	B-NP
+.	O
+	
+Multidisciplinary	O
+approaches	O
+with	O
+long	O
+-	O
+term	O
+psychiatric	O
+follow	O
+-	O
+up	O
+may	O
+contribute	O
+to	O
+low	O
+post	O
+-	O
+transplant	O
+suicide	O
+rates	O
+seen	O
+and	O
+low	O
+rates	O
+of	O
+graft	O
+loss	O
+because	O
+of	O
+non	O
+-	O
+compliance	O
+.	O
+	
+Antithrombotic	O
+drug	O
+use	O
+","	O
+cerebral	B-NP
+microbleeds	I-NP
+","	O
+and	O
+intracerebral	B-NP
+hemorrhage	I-NP
+:	O
+a	O
+systematic	O
+review	O
+of	O
+published	O
+and	O
+unpublished	O
+studies	O
+.	O
+	
+BACKGROUND	O
+AND	O
+PURPOSE	O
+:	O
+Cerebral	B-NP
+microbleeds	I-NP
+(	O
+MB	B-NP
+)	O
+are	O
+potential	O
+risk	O
+factors	O
+for	O
+intracerebral	B-NP
+hemorrhage	I-NP
+(	O
+ICH	B-NP
+)	O
+","	O
+but	O
+it	O
+is	O
+unclear	O
+if	O
+they	O
+are	O
+a	O
+contraindication	O
+to	O
+using	O
+antithrombotic	O
+drugs	O
+.	O
+	
+Insights	O
+could	O
+be	O
+gained	O
+by	O
+pooling	O
+data	O
+on	O
+MB	B-NP
+frequency	O
+stratified	O
+by	O
+antithrombotic	O
+use	O
+in	O
+cohorts	O
+with	O
+ICH	B-NP
+and	O
+ischemic	B-NP
+stroke	I-NP
+(	O
+IS	B-NP
+)	O
+/	O
+transient	B-NP
+ischemic	I-NP
+attack	I-NP
+(	O
+TIA	B-NP
+)	O
+.	O
+	
+METHODS	O
+:	O
+We	O
+performed	O
+a	O
+systematic	O
+review	O
+of	O
+published	O
+and	O
+unpublished	O
+data	O
+from	O
+cohorts	O
+with	O
+stroke	B-NP
+or	O
+TIA	B-NP
+to	O
+compare	O
+the	O
+presence	O
+of	O
+MB	B-NP
+in	O
+:	O
+(	O
+1	O
+)	O
+antithrombotic	O
+users	O
+vs	O
+nonantithrombotic	O
+users	O
+with	O
+ICH	B-NP
+;	O
+(	O
+2	O
+)	O
+antithrombotic	O
+users	O
+vs	O
+nonusers	O
+with	O
+IS	B-NP
+/	O
+TIA	B-NP
+;	O
+and	O
+(	O
+3	O
+)	O
+ICH	B-NP
+vs	O
+ischemic	B-NP
+events	O
+stratified	O
+by	O
+antithrombotic	O
+use	O
+.	O
+	
+We	O
+also	O
+analyzed	O
+published	O
+and	O
+unpublished	O
+follow	O
+-	O
+up	O
+data	O
+to	O
+determine	O
+the	O
+risk	O
+of	O
+ICH	B-NP
+in	O
+antithrombotic	O
+users	O
+with	O
+MB	B-NP
+.	O
+	
+RESULTS	O
+:	O
+In	O
+a	O
+pooled	O
+analysis	O
+of	O
+1460	O
+ICH	B-NP
+and	O
+3817	O
+IS	B-NP
+/	O
+TIA	B-NP
+","	O
+MB	B-NP
+were	O
+more	O
+frequent	O
+in	O
+ICH	B-NP
+vs	O
+IS	B-NP
+/	O
+TIA	B-NP
+in	O
+all	O
+treatment	O
+groups	O
+","	O
+but	O
+the	O
+excess	O
+increased	O
+from	O
+2	O
+.	O
+8	O
+(	O
+odds	O
+ratio	O
+;	O
+range	O
+","	O
+2	O
+.	O
+3	O
+-	O
+3	O
+.	O
+5	O
+)	O
+in	O
+nonantithrombotic	O
+users	O
+to	O
+5	O
+.	O
+7	O
+(	O
+range	O
+","	O
+3	O
+.	O
+4	O
+-	O
+9	O
+.	O
+7	O
+)	O
+in	O
+antiplatelet	O
+users	O
+and	O
+8	O
+.	O
+0	O
+(	O
+range	O
+","	O
+3	O
+.	O
+5	O
+-	O
+17	O
+.	O
+8	O
+)	O
+in	O
+warfarin	O
+users	O
+(	O
+P	O
+difference	O
+=	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+There	O
+was	O
+also	O
+an	O
+excess	O
+of	O
+MB	B-NP
+in	O
+warfarin	O
+users	O
+vs	O
+nonusers	O
+with	O
+ICH	B-NP
+(	O
+OR	O
+","	O
+2	O
+.	O
+7	O
+;	O
+95	O
+%	O
+CI	O
+","	O
+1	O
+.	O
+6	O
+-	O
+4	O
+.	O
+4	O
+;	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+but	O
+none	O
+in	O
+warfarin	O
+users	O
+with	O
+IS	B-NP
+/	O
+TIA	B-NP
+(	O
+OR	O
+","	O
+1	O
+.	O
+3	O
+;	O
+95	O
+%	O
+CI	O
+","	O
+0	O
+.	O
+9	O
+-	O
+1	O
+.	O
+7	O
+;	O
+P	O
+=	O
+0	O
+.	O
+33	O
+;	O
+P	O
+difference	O
+=	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+There	O
+was	O
+a	O
+smaller	O
+excess	O
+of	O
+MB	B-NP
+in	O
+antiplatelet	O
+users	O
+vs	O
+nonusers	O
+with	O
+ICH	B-NP
+(	O
+OR	O
+","	O
+1	O
+.	O
+7	O
+;	O
+95	O
+%	O
+CI	O
+","	O
+1	O
+.	O
+3	O
+-	O
+2	O
+.	O
+3	O
+;	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+","	O
+but	O
+findings	O
+were	O
+similar	O
+for	O
+antiplatelet	O
+users	O
+with	O
+IS	B-NP
+/	O
+TIA	B-NP
+(	O
+OR	O
+","	O
+1	O
+.	O
+4	O
+;	O
+95	O
+%	O
+CI	O
+","	O
+1	O
+.	O
+2	O
+-	O
+1	O
+.	O
+7	O
+;	O
+P	O
+<	O
+0	O
+.	O
+1	O
+;	O
+P	O
+difference	O
+=	O
+0	O
+.	O
+25	O
+)	O
+.	O
+	
+In	O
+pooled	O
+follow	O
+-	O
+up	O
+data	O
+for	O
+768	O
+antithrombotic	O
+users	O
+","	O
+presence	O
+of	O
+MB	B-NP
+at	O
+baseline	O
+was	O
+associated	O
+with	O
+a	O
+substantially	O
+increased	O
+risk	O
+of	O
+subsequent	O
+ICH	B-NP
+(	O
+OR	O
+","	O
+12	O
+.	O
+1	O
+;	O
+95	O
+%	O
+CI	O
+","	O
+3	O
+.	O
+4	O
+-	O
+42	O
+.	O
+5	O
+;	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+excess	O
+of	O
+MB	B-NP
+in	O
+warfarin	O
+users	O
+with	O
+ICH	B-NP
+compared	O
+to	O
+other	O
+groups	O
+suggests	O
+that	O
+MB	B-NP
+increase	O
+the	O
+risk	O
+of	O
+warfarin	O
+-	O
+associated	O
+ICH	B-NP
+.	O
+	
+Limited	O
+prospective	O
+data	O
+corroborate	O
+these	O
+findings	O
+","	O
+but	O
+larger	O
+prospective	O
+studies	O
+are	O
+urgently	O
+required	O
+.	O
+	
+Studies	O
+of	O
+synergy	O
+between	O
+morphine	O
+and	O
+a	O
+novel	O
+sodium	O
+channel	O
+blocker	O
+","	O
+CNSB002	O
+","	O
+in	O
+rat	O
+models	O
+of	O
+inflammatory	O
+and	O
+neuropathic	B-NP
+pain	I-NP
+.	O
+	
+OBJECTIVE	O
+:	O
+This	O
+study	O
+determined	O
+the	O
+antihyperalgesic	O
+effect	O
+of	O
+CNSB002	O
+","	O
+a	O
+sodium	O
+channel	O
+blocker	O
+with	O
+antioxidant	O
+properties	O
+given	O
+alone	O
+and	O
+in	O
+combinations	O
+with	O
+morphine	O
+in	O
+rat	O
+models	O
+of	O
+inflammatory	O
+and	O
+neuropathic	B-NP
+pain	I-NP
+.	O
+	
+DESIGN	O
+:	O
+Dose	O
+response	O
+curves	O
+for	O
+nonsedating	O
+doses	O
+of	O
+morphine	O
+and	O
+CNSB002	O
+given	O
+intraperitoneally	O
+alone	O
+and	O
+together	O
+in	O
+combinations	O
+were	O
+constructed	O
+for	O
+antihyperalgesic	O
+effect	O
+using	O
+paw	O
+withdrawal	O
+from	O
+noxious	O
+heat	O
+in	O
+two	O
+rat	O
+pain	B-NP
+models	O
+:	O
+carrageenan	O
+-	O
+induced	O
+paw	O
+inflammation	B-NP
+and	O
+streptozotocin	O
+(	O
+STZ	O
+)	O
+-	O
+induced	O
+diabetic	B-NP
+neuropathy	I-NP
+.	O
+	
+RESULTS	O
+:	O
+The	O
+maximum	O
+nonsedating	O
+doses	O
+were	O
+:	O
+morphine	O
+","	O
+3	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+;	O
+CNSB002	O
+10	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+;	O
+5	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+CNSB002	O
+with	O
+morphine	O
+3	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+in	O
+combination	O
+.	O
+	
+The	O
+doses	O
+calculated	O
+to	O
+cause	O
+50	O
+%	O
+reversal	O
+of	O
+hyperalgesia	B-NP
+(	O
+ED50	O
+)	O
+were	O
+7	O
+.	O
+54	O
+(	O
+1	O
+.	O
+81	O
+)	O
+and	O
+4	O
+.	O
+83	O
+(	O
+1	O
+.	O
+54	O
+)	O
+in	O
+the	O
+carrageenan	O
+model	O
+and	O
+44	O
+.	O
+18	O
+(	O
+1	O
+.	O
+37	O
+)	O
+and	O
+9	O
+.	O
+14	O
+(	O
+1	O
+.	O
+24	O
+)	O
+in	O
+the	O
+STZ	O
+-	O
+induced	O
+neuropathy	B-NP
+model	O
+for	O
+CNSB002	O
+and	O
+morphine	O
+","	O
+respectively	O
+(	O
+mg	O
+/	O
+kg	O
+;	O
+mean	O
+","	O
+SEM	O
+)	O
+.	O
+	
+These	O
+values	O
+were	O
+greater	O
+than	O
+the	O
+maximum	O
+nonsedating	O
+doses	O
+.	O
+	
+The	O
+ED50	O
+values	O
+for	O
+morphine	O
+when	O
+given	O
+in	O
+combination	O
+with	O
+CNSB002	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+were	O
+less	O
+than	O
+the	O
+maximum	O
+nonsedating	O
+dose	O
+:	O
+0	O
+.	O
+56	O
+(	O
+1	O
+.	O
+55	O
+)	O
+in	O
+the	O
+carrageenan	O
+model	O
+and	O
+1	O
+.	O
+37	O
+(	O
+1	O
+.	O
+23	O
+)	O
+in	O
+the	O
+neuropathy	B-NP
+model	O
+(	O
+mg	O
+/	O
+kg	O
+;	O
+mean	O
+","	O
+SEM	O
+)	O
+.	O
+	
+The	O
+antinociception	O
+after	O
+morphine	O
+(	O
+3	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+increased	O
+by	O
+co	O
+-	O
+administration	O
+with	O
+CNSB002	O
+from	O
+28	O
+.	O
+0	O
+and	O
+31	O
+.	O
+7	O
+%	O
+to	O
+114	O
+.	O
+6	O
+and	O
+56	O
+.	O
+9	O
+%	O
+reversal	O
+of	O
+hyperalgesia	B-NP
+in	O
+the	O
+inflammatory	O
+and	O
+neuropathic	B-NP
+models	O
+","	O
+respectively	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+;	O
+one	O
+-	O
+way	O
+analysis	O
+of	O
+variance	O
+-	O
+significantly	O
+greater	O
+than	O
+either	O
+drug	O
+given	O
+alone	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+maximum	O
+antihyperalgesic	O
+effect	O
+achievable	O
+with	O
+nonsedating	O
+doses	O
+of	O
+morphine	O
+may	O
+be	O
+increased	O
+significantly	O
+when	O
+the	O
+drug	O
+is	O
+used	O
+in	O
+combination	O
+with	O
+CNSB002	O
+.	O
+	
+Heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+:	O
+a	O
+practical	O
+review	O
+.	O
+	
+Heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+(	O
+HIT	B-NP
+)	O
+remains	O
+under	O
+-	O
+recognized	O
+despite	O
+its	O
+potentially	O
+devastating	O
+outcomes	O
+.	O
+	
+It	O
+begins	O
+when	O
+heparin	O
+exposure	O
+stimulates	O
+the	O
+formation	O
+of	O
+heparin	O
+-	O
+platelet	O
+factor	O
+4	O
+antibodies	O
+","	O
+which	O
+in	O
+turn	O
+triggers	O
+the	O
+release	O
+of	O
+procoagulant	O
+platelet	O
+particles	O
+.	O
+	
+Thrombosis	B-NP
+and	O
+thrombocytopenia	B-NP
+that	O
+follow	O
+comprise	O
+the	O
+2	O
+hallmark	O
+traits	O
+of	O
+HIT	B-NP
+","	O
+with	O
+the	O
+former	O
+largely	O
+responsible	O
+for	O
+significant	O
+vascular	O
+complications	O
+.	O
+	
+The	O
+prevalence	O
+of	O
+HIT	B-NP
+varies	O
+among	O
+several	O
+subgroups	O
+","	O
+with	O
+greater	O
+incidence	O
+in	O
+surgical	O
+as	O
+compared	O
+with	O
+medical	O
+populations	O
+.	O
+	
+HIT	B-NP
+must	O
+be	O
+acknowledged	O
+for	O
+its	O
+intense	O
+predilection	O
+for	O
+thrombosis	B-NP
+and	O
+suspected	O
+whenever	O
+thrombosis	B-NP
+occurs	O
+after	O
+heparin	O
+exposure	O
+.	O
+	
+Early	O
+recognition	O
+that	O
+incorporates	O
+the	O
+clinical	O
+and	O
+serologic	O
+clues	O
+is	O
+paramount	O
+to	O
+timely	O
+institution	O
+of	O
+treatment	O
+","	O
+as	O
+its	O
+delay	O
+may	O
+result	O
+in	O
+catastrophic	O
+outcomes	O
+.	O
+	
+The	O
+treatment	O
+of	O
+HIT	B-NP
+mandates	O
+an	O
+immediate	O
+cessation	O
+of	O
+all	O
+heparin	O
+exposure	O
+and	O
+the	O
+institution	O
+of	O
+an	O
+antithrombotic	O
+therapy	O
+","	O
+most	O
+commonly	O
+using	O
+a	O
+direct	O
+thrombin	O
+inhibitor	O
+.	O
+	
+Current	O
+"	O
+diagnostic	O
+"	O
+tests	O
+","	O
+which	O
+primarily	O
+include	O
+functional	O
+and	O
+antigenic	O
+assays	O
+","	O
+have	O
+more	O
+of	O
+a	O
+confirmatory	O
+than	O
+diagnostic	O
+role	O
+in	O
+the	O
+management	O
+of	O
+HIT	B-NP
+.	O
+	
+Special	O
+attention	O
+must	O
+be	O
+paid	O
+to	O
+cardiac	O
+patients	O
+who	O
+are	O
+often	O
+exposed	O
+to	O
+heparin	O
+multiple	O
+times	O
+during	O
+their	O
+course	O
+of	O
+treatment	O
+.	O
+	
+Direct	O
+thrombin	O
+inhibitors	O
+are	O
+appropriate	O
+","	O
+evidence	O
+-	O
+based	O
+alternatives	O
+to	O
+heparin	O
+in	O
+patients	O
+with	O
+a	O
+history	O
+of	O
+HIT	B-NP
+","	O
+who	O
+need	O
+to	O
+undergo	O
+percutaneous	O
+coronary	O
+intervention	O
+.	O
+	
+As	O
+heparin	O
+remains	O
+one	O
+of	O
+the	O
+most	O
+frequently	O
+used	O
+medications	O
+today	O
+with	O
+potential	O
+for	O
+HIT	B-NP
+with	O
+every	O
+heparin	O
+exposure	O
+","	O
+a	O
+close	O
+vigilance	O
+of	O
+platelet	O
+counts	O
+must	O
+be	O
+practiced	O
+whenever	O
+heparin	O
+is	O
+initiated	O
+.	O
+	
+Abductor	O
+paralysis	B-NP
+after	O
+botox	O
+injection	O
+for	O
+adductor	B-NP
+spasmodic	I-NP
+dysphonia	I-NP
+.	O
+	
+OBJECTIVES	O
+/	O
+HYPOTHESIS	O
+:	O
+Botulinum	O
+toxin	O
+(	O
+Botox	O
+)	O
+injections	O
+into	O
+the	O
+thyroarytenoid	O
+muscles	O
+are	O
+the	O
+current	O
+standard	O
+of	O
+care	O
+for	O
+adductor	B-NP
+spasmodic	I-NP
+dysphonia	I-NP
+(	O
+ADSD	B-NP
+)	O
+.	O
+	
+Reported	O
+adverse	O
+effects	O
+include	O
+a	O
+period	O
+of	O
+breathiness	O
+","	O
+throat	B-NP
+pain	I-NP
+","	O
+and	O
+difficulty	O
+with	O
+swallowing	O
+liquids	O
+.	O
+	
+Here	O
+we	O
+report	O
+multiple	O
+cases	O
+of	O
+bilateral	O
+abductor	O
+paralysis	B-NP
+following	O
+Botox	O
+injections	O
+for	O
+ADSD	B-NP
+","	O
+a	O
+complication	O
+previously	O
+unreported	O
+.	O
+	
+STUDY	O
+DESIGN	O
+:	O
+Retrospective	O
+case	O
+series	O
+.	O
+	
+METHODS	O
+:	O
+Patients	O
+that	O
+received	O
+Botox	O
+injections	O
+for	O
+spasmodic	B-NP
+dysphonia	I-NP
+between	O
+January	O
+2000	O
+and	O
+October	O
+2009	O
+were	O
+evaluated	O
+.	O
+	
+Patients	O
+with	O
+ADSD	B-NP
+were	O
+identified	O
+.	O
+	
+The	O
+number	O
+of	O
+treatments	O
+received	O
+and	O
+adverse	O
+effects	O
+were	O
+noted	O
+.	O
+	
+For	O
+patients	O
+with	O
+bilateral	O
+abductor	O
+paralysis	B-NP
+","	O
+age	O
+","	O
+sex	O
+","	O
+paralytic	O
+Botox	O
+dose	O
+","	O
+prior	O
+Botox	O
+dose	O
+","	O
+and	O
+course	O
+following	O
+paralysis	B-NP
+were	O
+noted	O
+.	O
+	
+RESULTS	O
+:	O
+From	O
+a	O
+database	O
+of	O
+452	O
+patients	O
+receiving	O
+Botox	O
+","	O
+352	O
+patients	O
+had	O
+been	O
+diagnosed	O
+with	O
+ADSD	B-NP
+.	O
+	
+Of	O
+these	O
+352	O
+patients	O
+","	O
+eight	O
+patients	O
+suffered	O
+bilateral	O
+abductor	O
+paralysis	B-NP
+","	O
+and	O
+two	O
+suffered	O
+this	O
+complication	O
+twice	O
+.	O
+	
+All	O
+affected	O
+patients	O
+were	O
+females	O
+over	O
+the	O
+age	O
+of	O
+50	O
+years	O
+.	O
+	
+Most	O
+patients	O
+had	O
+received	O
+treatments	O
+prior	O
+to	O
+abductor	O
+paralysis	B-NP
+and	O
+continued	O
+receiving	O
+after	O
+paralysis	B-NP
+.	O
+	
+Seven	O
+patients	O
+recovered	O
+after	O
+a	O
+brief	O
+period	O
+of	O
+activity	O
+restrictions	O
+","	O
+and	O
+one	O
+underwent	O
+a	O
+tracheotomy	O
+.	O
+	
+The	O
+incidence	O
+of	O
+abductor	O
+paralysis	B-NP
+after	O
+Botox	O
+injection	O
+for	O
+ADSD	B-NP
+was	O
+0	O
+.	O
+34	O
+%	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Bilateral	O
+abductor	O
+paralysis	B-NP
+is	O
+a	O
+rare	O
+complication	O
+of	O
+Botox	O
+injections	O
+for	O
+ADSD	B-NP
+","	O
+causing	O
+difficulty	O
+with	O
+breathing	O
+upon	O
+exertion	O
+.	O
+	
+The	O
+likely	O
+mechanism	O
+of	O
+paralysis	B-NP
+is	O
+diffusion	O
+of	O
+Botox	O
+around	O
+the	O
+muscular	O
+process	O
+of	O
+the	O
+arytenoid	O
+to	O
+the	O
+posterior	O
+cricoarytenoid	O
+muscles	O
+.	O
+	
+The	O
+paralysis	B-NP
+is	O
+temporary	O
+","	O
+and	O
+watchful	O
+waiting	O
+with	O
+restriction	O
+of	O
+activity	O
+is	O
+the	O
+recommended	O
+management	O
+.	O
+	
+Mitochondrial	B-NP
+impairment	I-NP
+contributes	O
+to	O
+cocaine	O
+-	O
+induced	O
+cardiac	B-NP
+dysfunction	I-NP
+:	O
+Prevention	O
+by	O
+the	O
+targeted	O
+antioxidant	O
+MitoQ	O
+.	O
+	
+The	O
+goal	O
+of	O
+this	O
+study	O
+was	O
+to	O
+assess	O
+mitochondrial	O
+function	O
+and	O
+ROS	O
+production	O
+in	O
+an	O
+experimental	O
+model	O
+of	O
+cocaine	O
+-	O
+induced	O
+cardiac	B-NP
+dysfunction	I-NP
+.	O
+	
+We	O
+hypothesized	O
+that	O
+cocaine	B-NP
+abuse	I-NP
+may	O
+lead	O
+to	O
+altered	O
+mitochondrial	O
+function	O
+that	O
+in	O
+turn	O
+may	O
+cause	O
+left	B-NP
+ventricular	I-NP
+dysfunction	I-NP
+.	O
+	
+Seven	O
+days	O
+of	O
+cocaine	O
+administration	O
+to	O
+rats	O
+led	O
+to	O
+an	O
+increased	O
+oxygen	O
+consumption	O
+detected	O
+in	O
+cardiac	O
+fibers	O
+","	O
+specifically	O
+through	O
+complex	O
+I	O
+and	O
+complex	O
+III	O
+.	O
+	
+ROS	O
+levels	O
+were	O
+increased	O
+","	O
+specifically	O
+in	O
+interfibrillar	O
+mitochondria	O
+.	O
+	
+In	O
+parallel	O
+there	O
+was	O
+a	O
+decrease	O
+in	O
+ATP	O
+synthesis	O
+","	O
+whereas	O
+no	O
+difference	O
+was	O
+observed	O
+in	O
+subsarcolemmal	O
+mitochondria	O
+.	O
+	
+This	O
+uncoupling	O
+effect	O
+on	O
+oxidative	O
+phosphorylation	O
+was	O
+not	O
+detectable	O
+after	O
+short	O
+-	O
+term	O
+exposure	O
+to	O
+cocaine	O
+","	O
+suggesting	O
+that	O
+these	O
+mitochondrial	B-NP
+abnormalities	I-NP
+were	O
+a	O
+late	O
+rather	O
+than	O
+a	O
+primary	O
+event	O
+in	O
+the	O
+pathological	O
+response	O
+to	O
+cocaine	O
+.	O
+	
+MitoQ	O
+","	O
+a	O
+mitochondrial	O
+-	O
+targeted	O
+antioxidant	O
+","	O
+was	O
+shown	O
+to	O
+completely	O
+prevent	O
+these	O
+mitochondrial	B-NP
+abnormalities	I-NP
+as	O
+well	O
+as	O
+cardiac	B-NP
+dysfunction	I-NP
+characterized	O
+here	O
+by	O
+a	O
+diastolic	B-NP
+dysfunction	I-NP
+studied	O
+with	O
+a	O
+conductance	O
+catheter	O
+to	O
+obtain	O
+pressure	O
+-	O
+volume	O
+data	O
+.	O
+	
+Taken	O
+together	O
+","	O
+these	O
+results	O
+extend	O
+previous	O
+studies	O
+and	O
+demonstrate	O
+that	O
+cocaine	O
+-	O
+induced	O
+cardiac	B-NP
+dysfunction	I-NP
+may	O
+be	O
+due	O
+to	O
+a	O
+mitochondrial	B-NP
+defect	I-NP
+.	O
+	
+Trimethoprim	O
+-	O
+induced	O
+immune	O
+hemolytic	B-NP
+anemia	I-NP
+in	O
+a	O
+pediatric	O
+oncology	O
+patient	O
+presenting	O
+as	O
+an	O
+acute	O
+hemolytic	O
+transfusion	O
+reaction	O
+.	O
+	
+A	O
+10	O
+-	O
+year	O
+-	O
+old	O
+male	O
+with	O
+acute	B-NP
+leukemia	I-NP
+presented	O
+with	O
+post	O
+-	O
+chemotherapy	O
+anemia	B-NP
+.	O
+	
+During	O
+red	O
+cell	O
+transfusion	O
+","	O
+he	O
+developed	O
+hemoglobinuria	B-NP
+.	O
+	
+Transfusion	O
+reaction	O
+workup	O
+was	O
+negative	O
+.	O
+	
+Drug	O
+-	O
+induced	O
+immune	O
+hemolytic	B-NP
+anemia	I-NP
+was	O
+suspected	O
+because	O
+of	O
+positive	O
+direct	O
+antiglobulin	O
+test	O
+","	O
+negative	O
+eluate	O
+","	O
+and	O
+microspherocytes	O
+on	O
+smear	O
+pre	O
+-	O
+and	O
+post	O
+-	O
+transfusion	O
+.	O
+	
+Drug	O
+studies	O
+using	O
+the	O
+indirect	O
+antiglobulin	O
+test	O
+were	O
+strongly	O
+positive	O
+with	O
+trimethoprim	O
+and	O
+trimethoprim	O
+-	O
+sulfamethoxazole	O
+but	O
+negative	O
+with	O
+sulfamethoxazole	O
+.	O
+	
+The	O
+patient	O
+recovered	O
+after	O
+discontinuing	O
+the	O
+drug	O
+","	O
+with	O
+no	O
+recurrence	O
+in	O
+2	O
+years	O
+.	O
+	
+Other	O
+causes	O
+of	O
+anemia	B-NP
+should	O
+be	O
+considered	O
+in	O
+patients	O
+with	O
+worse	O
+-	O
+than	O
+-	O
+expected	O
+anemia	B-NP
+after	O
+chemotherapy	O
+.	O
+	
+Furthermore	O
+","	O
+hemolysis	B-NP
+during	O
+transfusion	O
+is	O
+not	O
+always	O
+a	O
+transfusion	O
+reaction	O
+.	O
+	
+Verapamil	O
+stimulation	O
+test	O
+in	O
+hyperprolactinemia	B-NP
+:	O
+loss	O
+of	O
+prolactin	O
+response	O
+in	O
+anatomic	O
+or	O
+functional	O
+stalk	O
+effect	O
+.	O
+	
+AIM	O
+:	O
+Verapamil	O
+stimulation	O
+test	O
+was	O
+previously	O
+investigated	O
+as	O
+a	O
+tool	O
+for	O
+differential	O
+diagnosis	O
+of	O
+hyperprolactinemia	B-NP
+","	O
+but	O
+with	O
+conflicting	O
+results	O
+.	O
+	
+Macroprolactinemia	B-NP
+was	O
+never	O
+considered	O
+in	O
+those	O
+previous	O
+studies	O
+.	O
+	
+Here	O
+","	O
+we	O
+aimed	O
+to	O
+re	O
+-	O
+investigate	O
+the	O
+diagnostic	O
+value	O
+of	O
+verapamil	O
+in	O
+a	O
+population	O
+who	O
+were	O
+all	O
+screened	O
+for	O
+macroprolactinemia	B-NP
+.	O
+	
+Prolactin	O
+responses	O
+to	O
+verapamil	O
+in	O
+65	O
+female	O
+patients	O
+(	O
+age	O
+:	O
+29	O
+.	O
+9	O
++	O
+/	O
+-	O
+8	O
+.	O
+1	O
+years	O
+)	O
+with	O
+hyperprolactinemia	B-NP
+were	O
+tested	O
+in	O
+a	O
+descriptive	O
+","	O
+matched	O
+case	O
+-	O
+control	O
+study	O
+.	O
+	
+METHODS	O
+:	O
+Verapamil	O
+80	O
+mg	O
+","	O
+p	O
+.	O
+o	O
+.	O
+was	O
+administered	O
+","	O
+and	O
+then	O
+PRL	O
+levels	O
+were	O
+measured	O
+at	O
+8th	O
+and	O
+16th	O
+hours	O
+","	O
+by	O
+immunometric	O
+chemiluminescence	O
+.	O
+	
+Verapamil	O
+responsiveness	O
+was	O
+determined	O
+by	O
+peak	O
+percent	O
+change	O
+in	O
+basal	O
+prolactin	O
+levels	O
+(	O
+PRL	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+Verapamil	O
+significantly	O
+increased	O
+PRL	O
+levels	O
+in	O
+healthy	O
+controls	O
+(	O
+N	O
+.	O
+8	O
+","	O
+PRL	O
+:	O
+183	O
+%	O
+)	O
+","	O
+macroprolactinoma	B-NP
+(	O
+N	O
+.	O
+8	O
+","	O
+PRL	O
+:	O
+7	O
+%	O
+)	O
+","	O
+microprolactinoma	B-NP
+(	O
+N	O
+.	O
+19	O
+","	O
+PRL	O
+:	O
+21	O
+%	O
+)	O
+","	O
+macroprolactinemia	B-NP
+(	O
+N	O
+.	O
+23	O
+","	O
+PRL	O
+:	O
+126	O
+%	O
+)	O
+","	O
+but	O
+not	O
+in	O
+pseudoprolactinoma	B-NP
+(	O
+N	O
+.	O
+8	O
+","	O
+PRL	O
+:	O
+0	O
+.	O
+8	O
+%	O
+)	O
+","	O
+and	O
+risperidone	O
+-	O
+induced	O
+hyperprolactinemia	B-NP
+(	O
+N	O
+.	O
+7	O
+","	O
+PRL	O
+:	O
+3	O
+%	O
+)	O
+.	O
+	
+ROC	O
+curve	O
+analysis	O
+revealed	O
+that	O
+unresponsiveness	O
+to	O
+verapamil	O
+defined	O
+as	O
+PRL	O
+<	O
+7	O
+%	O
+","	O
+discriminated	O
+anatomical	O
+or	O
+functional	O
+stalk	O
+effect	O
+(	O
+sensitivity	O
+:	O
+74	O
+%	O
+","	O
+specificity	O
+:	O
+73	O
+%	O
+","	O
+AUC	O
+:	O
+0	O
+.	O
+855	O
++	O
+/	O
+-	O
+0	O
+.	O
+4	O
+","	O
+P	O
+<	O
+0	O
+.	O
+1	O
+","	O
+CI	O
+:	O
+0	O
+.	O
+768	O
+-	O
+0	O
+.	O
+942	O
+)	O
+associated	O
+with	O
+pseudoprolactinoma	B-NP
+or	O
+risperidone	O
+-	O
+induced	O
+hyperprolactinemia	B-NP
+","	O
+respectively	O
+.	O
+	
+CONCLUSION	O
+:	O
+Verapamil	O
+responsiveness	O
+is	O
+not	O
+a	O
+reliable	O
+finding	O
+for	O
+the	O
+differential	O
+diagnosis	O
+of	O
+hyperprolactinemia	B-NP
+.	O
+	
+However	O
+","	O
+verapamil	O
+unresponsiveness	O
+discriminates	O
+stalk	O
+effect	O
+(	O
+i	O
+.	O
+e	O
+.	O
+","	O
+anatomically	O
+or	O
+functionally	O
+inhibited	O
+dopaminergic	O
+tonus	O
+)	O
+from	O
+other	O
+causes	O
+of	O
+hyperprolactinemia	B-NP
+with	O
+varying	O
+degrees	O
+of	O
+responsiveness	O
+.	O
+	
+Blockade	O
+of	O
+endothelial	O
+-	O
+mesenchymal	O
+transition	O
+by	O
+a	O
+Smad3	O
+inhibitor	O
+delays	O
+the	O
+early	O
+development	O
+of	O
+streptozotocin	O
+-	O
+induced	O
+diabetic	B-NP
+nephropathy	I-NP
+.	O
+	
+OBJECTIVE	O
+:	O
+A	O
+multicenter	O
+","	O
+controlled	O
+trial	O
+showed	O
+that	O
+early	O
+blockade	O
+of	O
+the	O
+renin	O
+-	O
+angiotensin	O
+system	O
+in	O
+patients	O
+with	O
+type	B-NP
+1	I-NP
+diabetes	I-NP
+and	O
+normoalbuminuria	O
+did	O
+not	O
+retard	O
+the	O
+progression	O
+of	O
+nephropathy	B-NP
+","	O
+suggesting	O
+that	O
+other	O
+mechanism	O
+(	O
+s	O
+)	O
+are	O
+involved	O
+in	O
+the	O
+pathogenesis	O
+of	O
+early	O
+diabetic	B-NP
+nephropathy	I-NP
+(	O
+diabetic	B-NP
+nephropathy	I-NP
+)	O
+.	O
+	
+We	O
+have	O
+previously	O
+demonstrated	O
+that	O
+endothelial	O
+-	O
+mesenchymal	O
+-	O
+transition	O
+(	O
+EndoMT	O
+)	O
+contributes	O
+to	O
+the	O
+early	O
+development	O
+of	O
+renal	O
+interstitial	O
+fibrosis	B-NP
+independently	O
+of	O
+microalbuminuria	O
+in	O
+mice	O
+with	O
+streptozotocin	O
+(	O
+STZ	O
+)	O
+-	O
+induced	O
+diabetes	B-NP
+.	O
+	
+In	O
+the	O
+present	O
+study	O
+","	O
+we	O
+hypothesized	O
+that	O
+blocking	O
+EndoMT	O
+reduces	O
+the	O
+early	O
+development	O
+of	O
+diabetic	B-NP
+nephropathy	I-NP
+.	O
+	
+RESEARCH	O
+DESIGN	O
+AND	O
+METHODS	O
+:	O
+EndoMT	O
+was	O
+induced	O
+in	O
+a	O
+mouse	O
+pancreatic	O
+microvascular	O
+endothelial	O
+cell	O
+line	O
+(	O
+MMEC	O
+)	O
+in	O
+the	O
+presence	O
+of	O
+advanced	O
+glycation	O
+end	O
+products	O
+(	O
+AGEs	O
+)	O
+and	O
+in	O
+the	O
+endothelial	O
+lineage	O
+-	O
+traceble	O
+mouse	O
+line	O
+Tie2	O
+-	O
+Cre	O
+;	O
+Loxp	O
+-	O
+EGFP	O
+by	O
+administration	O
+of	O
+AGEs	O
+","	O
+with	O
+nonglycated	O
+mouse	O
+albumin	O
+serving	O
+as	O
+a	O
+control	O
+.	O
+	
+Phosphorylated	O
+Smad3	O
+was	O
+detected	O
+by	O
+immunoprecipitation	O
+/	O
+Western	O
+blotting	O
+and	O
+confocal	O
+microscopy	O
+.	O
+	
+Blocking	O
+studies	O
+using	O
+receptor	O
+for	O
+AGE	O
+siRNA	O
+and	O
+a	O
+specific	O
+inhibitor	O
+of	O
+Smad3	O
+(	O
+SIS3	O
+)	O
+were	O
+performed	O
+in	O
+MMECs	O
+and	O
+in	O
+STZ	O
+-	O
+induced	O
+diabetic	B-NP
+nephropathy	I-NP
+in	O
+Tie2	O
+-	O
+Cre	O
+;	O
+Loxp	O
+-	O
+EGFP	O
+mice	O
+.	O
+	
+RESULTS	O
+:	O
+Confocal	O
+microscopy	O
+and	O
+real	O
+-	O
+time	O
+PCR	O
+demonstrated	O
+that	O
+AGEs	O
+induced	O
+EndoMT	O
+in	O
+MMECs	O
+and	O
+in	O
+Tie2	O
+-	O
+Cre	O
+;	O
+Loxp	O
+-	O
+EGFP	O
+mice	O
+.	O
+	
+Immunoprecipitation	O
+/	O
+Western	O
+blotting	O
+showed	O
+that	O
+Smad3	O
+was	O
+activated	O
+by	O
+AGEs	O
+but	O
+was	O
+inhibited	O
+by	O
+SIS3	O
+in	O
+MMECs	O
+and	O
+in	O
+STZ	O
+-	O
+induced	O
+diabetic	B-NP
+nephropathy	I-NP
+.	O
+	
+Confocal	O
+microscopy	O
+and	O
+real	O
+-	O
+time	O
+PCR	O
+further	O
+demonstrated	O
+that	O
+SIS3	O
+abrogated	O
+EndoMT	O
+","	O
+reduced	O
+renal	O
+fibrosis	B-NP
+","	O
+and	O
+retarded	O
+progression	O
+of	O
+nephropathy	B-NP
+.	O
+	
+CONCLUSIONS	O
+:	O
+EndoMT	O
+is	O
+a	O
+novel	O
+pathway	O
+leading	O
+to	O
+early	O
+development	O
+of	O
+diabetic	B-NP
+nephropathy	I-NP
+.	O
+	
+Blockade	O
+of	O
+EndoMT	O
+by	O
+SIS3	O
+may	O
+provide	O
+a	O
+new	O
+strategy	O
+to	O
+retard	O
+the	O
+progression	O
+of	O
+diabetic	B-NP
+nephropathy	I-NP
+and	O
+other	O
+diabetes	B-NP
+complications	I-NP
+.	O
+	
+Cytostatic	O
+and	O
+anti	O
+-	O
+angiogenic	O
+effects	O
+of	O
+temsirolimus	O
+in	O
+refractory	O
+mantle	B-NP
+cell	I-NP
+lymphoma	I-NP
+.	O
+	
+Mantle	B-NP
+cell	I-NP
+lymphoma	I-NP
+(	O
+MCL	B-NP
+)	O
+is	O
+a	O
+rare	O
+and	O
+aggressive	O
+type	O
+of	O
+B	B-NP
+-	I-NP
+cell	I-NP
+non	I-NP
+-	I-NP
+Hodgkin	I-NP
+'	I-NP
+s	I-NP
+lymphoma	I-NP
+.	O
+	
+Patients	O
+become	O
+progressively	O
+refractory	O
+to	O
+conventional	O
+chemotherapy	O
+","	O
+and	O
+their	O
+prognosis	O
+is	O
+poor	O
+.	O
+	
+However	O
+","	O
+a	O
+38	O
+%	O
+remission	O
+rate	O
+has	O
+been	O
+recently	O
+reported	O
+in	O
+refractory	O
+MCL	B-NP
+treated	O
+with	O
+temsirolimus	O
+","	O
+a	O
+mTOR	O
+inhibitor	O
+.	O
+Here	O
+we	O
+had	O
+the	O
+opportunity	O
+to	O
+study	O
+a	O
+case	O
+of	O
+refractory	O
+MCL	B-NP
+who	O
+had	O
+tumor	B-NP
+regression	O
+two	O
+months	O
+after	O
+temsirolimus	O
+treatment	O
+","	O
+and	O
+a	O
+progression	O
+-	O
+free	O
+survival	O
+of	O
+10	O
+months	O
+.	O
+	
+In	O
+this	O
+case	O
+","	O
+lymph	O
+node	O
+biopsies	O
+were	O
+performed	O
+before	O
+and	O
+six	O
+months	O
+after	O
+temsirolimus	O
+therapy	O
+.	O
+	
+Comparison	O
+of	O
+the	O
+two	O
+biopsies	O
+showed	O
+that	O
+temsirolimus	O
+inhibited	O
+tumor	B-NP
+cell	O
+proliferation	O
+through	O
+cell	O
+cycle	O
+arrest	O
+","	O
+but	O
+did	O
+not	O
+induce	O
+any	O
+change	O
+in	O
+the	O
+number	O
+of	O
+apoptotic	O
+tumor	B-NP
+cells	O
+.	O
+	
+Apart	O
+from	O
+this	O
+cytostatic	O
+effect	O
+","	O
+temsirolimus	O
+had	O
+an	O
+antiangiogenic	O
+effect	O
+with	O
+decrease	O
+of	O
+tumor	B-NP
+microvessel	O
+density	O
+and	O
+of	O
+VEGF	O
+expression	O
+.	O
+	
+Moreover	O
+","	O
+numerous	O
+patchy	O
+","	O
+well	O
+-	O
+limited	O
+fibrotic	O
+areas	O
+","	O
+compatible	O
+with	O
+post	O
+-	O
+necrotic	B-NP
+tissue	O
+repair	O
+","	O
+were	O
+found	O
+after	O
+6	O
+-	O
+month	O
+temsirolimus	O
+therapy	O
+.	O
+	
+Thus	O
+","	O
+temsirolimus	O
+reduced	O
+tumor	B-NP
+burden	O
+through	O
+associated	O
+cytostatic	O
+and	O
+anti	O
+-	O
+angiogenic	O
+effects	O
+.	O
+This	O
+dual	O
+effect	O
+of	O
+temsirolimus	O
+on	O
+tumor	B-NP
+tissue	O
+could	O
+contribute	O
+to	O
+its	O
+recently	O
+reported	O
+efficiency	O
+in	O
+refractory	O
+MCL	B-NP
+resistant	O
+to	O
+conventional	O
+chemotherapy	O
+.	O
+	
+Acute	B-NP
+renal	I-NP
+failure	I-NP
+due	O
+to	O
+rifampicin	O
+.	O
+	
+A	O
+23	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+with	O
+bacteriologically	O
+proven	O
+pulmonary	B-NP
+tuberculosis	I-NP
+was	O
+treated	O
+with	O
+the	O
+various	O
+regimens	O
+of	O
+antituberculosis	O
+drugs	O
+for	O
+nearly	O
+15	O
+months	O
+.	O
+	
+Rifampicin	O
+was	O
+administered	O
+thrice	O
+as	O
+one	O
+of	O
+the	O
+3	O
+-	O
+4	O
+drug	O
+regimen	O
+and	O
+each	O
+time	O
+he	O
+developed	O
+untoward	O
+side	O
+effects	O
+like	O
+nausea	B-NP
+","	O
+vomiting	B-NP
+and	O
+fever	B-NP
+with	O
+chills	O
+and	O
+rigors	O
+.	O
+	
+The	O
+last	O
+such	O
+episode	O
+was	O
+of	O
+acute	O
+renal	O
+failure	O
+at	O
+which	O
+stage	O
+the	O
+patient	O
+was	O
+seen	O
+by	O
+the	O
+authors	O
+of	O
+this	O
+report	O
+.	O
+	
+The	O
+patient	O
+","	O
+however	O
+","	O
+made	O
+a	O
+full	O
+recovery	O
+.	O
+	
+Syncope	B-NP
+caused	O
+by	O
+hyperkalemia	B-NP
+during	O
+use	O
+of	O
+a	O
+combined	O
+therapy	O
+with	O
+the	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitor	O
+and	O
+spironolactone	O
+.	O
+	
+A	O
+76	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+a	O
+history	O
+of	O
+coronary	O
+artery	O
+bypass	O
+grafting	O
+and	O
+prior	O
+myocardial	B-NP
+infarction	I-NP
+was	O
+transferred	O
+to	O
+the	O
+emergency	O
+room	O
+with	O
+loss	B-NP
+of	I-NP
+consciousness	I-NP
+due	O
+to	O
+marked	O
+bradycardia	B-NP
+caused	O
+by	O
+hyperkalemia	B-NP
+.	O
+	
+The	O
+concentration	O
+of	O
+serum	O
+potassium	O
+was	O
+high	O
+","	O
+and	O
+normal	O
+sinus	O
+rhythm	O
+was	O
+restored	O
+after	O
+correction	O
+of	O
+the	O
+serum	O
+potassium	O
+level	O
+.	O
+	
+The	O
+cause	O
+of	O
+hyperkalemia	B-NP
+was	O
+considered	O
+to	O
+be	O
+several	O
+doses	O
+of	O
+spiranolactone	O
+","	O
+an	O
+aldosterone	O
+antagonist	O
+","	O
+in	O
+addition	O
+to	O
+the	O
+long	O
+-	O
+term	O
+intake	O
+of	O
+ramipril	O
+","	O
+an	O
+ACE	O
+inhibitor	O
+.	O
+	
+This	O
+case	O
+is	O
+a	O
+good	O
+example	O
+of	O
+electrolyte	O
+imbalance	O
+causing	O
+acute	O
+life	O
+-	O
+threatening	O
+cardiac	O
+events	O
+.	O
+	
+Clinicians	O
+should	O
+be	O
+alert	O
+to	O
+the	O
+possibility	O
+of	O
+hyperkalemia	B-NP
+","	O
+especially	O
+in	O
+elderly	O
+patients	O
+using	O
+ACE	O
+/	O
+ARB	O
+in	O
+combination	O
+with	O
+potassium	O
+sparing	O
+agents	O
+and	O
+who	O
+have	O
+mild	O
+renal	B-NP
+disturbance	I-NP
+.	O
+	
+Diffuse	O
+skeletal	O
+pain	B-NP
+after	O
+administration	O
+of	O
+alendronate	O
+.	O
+	
+BACKGROUND	O
+:	O
+Osteoporosis	B-NP
+is	O
+caused	O
+by	O
+bone	O
+resorption	O
+in	O
+excess	O
+of	O
+bone	O
+formation	O
+","	O
+and	O
+bisphosphonates	O
+","	O
+are	O
+used	O
+to	O
+inhibit	O
+bone	O
+resorption	O
+.	O
+	
+Alendronate	O
+","	O
+a	O
+biphosphonate	O
+","	O
+is	O
+effective	O
+for	O
+both	O
+the	O
+treatment	O
+and	O
+prevention	O
+of	O
+osteoporosis	B-NP
+in	O
+postmenopausal	O
+women	O
+.	O
+	
+Side	O
+effects	O
+are	O
+relatively	O
+few	O
+and	O
+prominently	O
+gastrointestinal	O
+.	O
+	
+Musculoskeletal	B-NP
+pain	I-NP
+may	O
+be	O
+an	O
+important	O
+side	O
+effect	O
+in	O
+these	O
+patients	O
+.	O
+	
+We	O
+presented	O
+a	O
+patient	O
+admitted	O
+to	O
+our	O
+out	O
+-	O
+patient	O
+clinic	O
+with	O
+diffuse	O
+skeletal	O
+pain	B-NP
+after	O
+three	O
+consecutive	O
+administration	O
+of	O
+alendronate	O
+.	O
+	
+CONCLUSION	O
+:	O
+We	O
+conclude	O
+that	O
+patients	O
+with	O
+osteoporosis	B-NP
+can	O
+report	O
+pain	B-NP
+","	O
+and	O
+bisphosphonate	O
+-	O
+related	O
+pain	B-NP
+should	O
+also	O
+be	O
+considered	O
+before	O
+ascribing	O
+this	O
+complaint	O
+to	O
+osteoporosis	B-NP
+.	O
+	
+Cerebrospinal	O
+fluid	O
+penetration	O
+of	O
+high	O
+-	O
+dose	O
+daptomycin	O
+in	O
+suspected	O
+Staphylococcus	O
+aureus	O
+meningitis	B-NP
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+methicillin	O
+-	O
+sensitive	O
+Staphylococcus	O
+aureus	O
+(	O
+MSSA	O
+)	O
+bacteremia	B-NP
+with	O
+suspected	O
+MSSA	O
+meningitis	B-NP
+treated	O
+with	O
+high	O
+-	O
+dose	O
+daptomycin	O
+assessed	O
+with	O
+concurrent	O
+serum	O
+and	O
+cerebrospinal	O
+fluid	O
+(	O
+CSF	O
+)	O
+concentrations	O
+.	O
+	
+CASE	O
+SUMMARY	O
+:	O
+A	O
+54	O
+-	O
+year	O
+-	O
+old	O
+male	O
+presented	O
+to	O
+the	O
+emergency	O
+department	O
+with	O
+generalized	O
+weakness	B-NP
+and	O
+presumed	O
+health	O
+-	O
+care	O
+-	O
+associated	O
+pneumonia	B-NP
+shown	O
+on	O
+chest	O
+radiograph	O
+.	O
+	
+Treatment	O
+was	O
+empirically	O
+initiated	O
+with	O
+vancomycin	O
+","	O
+levofloxacin	O
+","	O
+and	O
+piperacillin	O
+/	O
+tazobactam	O
+.	O
+	
+Blood	O
+cultures	O
+revealed	O
+S	O
+.	O
+aureus	O
+susceptible	O
+to	O
+oxacillin	O
+.	O
+	
+Empiric	O
+antibiotic	O
+treatment	O
+was	O
+narrowed	O
+to	O
+nafcillin	O
+on	O
+day	O
+4	O
+.	O
+	
+On	O
+day	O
+8	O
+","	O
+the	O
+patient	O
+developed	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+(	O
+serum	O
+creatinine	O
+1	O
+.	O
+9	O
+mg	O
+/	O
+dL	O
+","	O
+increased	O
+from	O
+1	O
+.	O
+2	O
+mg	O
+/	O
+dL	O
+the	O
+previous	O
+day	O
+and	O
+0	O
+.	O
+8	O
+mg	O
+/	O
+dL	O
+on	O
+admission	O
+)	O
+.	O
+	
+The	O
+patient	O
+'	O
+s	O
+Glasgow	O
+Coma	O
+Score	O
+was	O
+3	O
+","	O
+with	O
+normal	O
+findings	O
+shown	O
+on	O
+computed	O
+tomography	O
+scan	O
+of	O
+the	O
+head	O
+72	O
+hours	O
+following	O
+an	O
+episode	O
+of	O
+cardiac	B-NP
+arrest	I-NP
+on	O
+day	O
+10	O
+.	O
+	
+The	O
+patient	O
+experienced	O
+relapsing	O
+MSSA	O
+bacteremia	B-NP
+on	O
+day	O
+9	O
+","	O
+increasing	O
+the	O
+suspicion	O
+for	O
+a	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+infection	B-NP
+.	O
+	
+Nafcillin	O
+was	O
+discontinued	O
+and	O
+daptomycin	O
+9	O
+mg	O
+/	O
+kg	O
+daily	O
+was	O
+initiated	O
+for	O
+suspected	O
+meningitis	B-NP
+and	O
+was	O
+continued	O
+until	O
+the	O
+patient	O
+'	O
+s	O
+death	O
+on	O
+day	O
+16	O
+.	O
+	
+Daptomycin	O
+serum	O
+and	O
+CSF	O
+trough	O
+concentrations	O
+were	O
+11	O
+.	O
+21	O
+ug	O
+/	O
+mL	O
+and	O
+0	O
+.	O
+52	O
+ug	O
+/	O
+mL	O
+","	O
+respectively	O
+","	O
+prior	O
+to	O
+the	O
+third	O
+dose	O
+.	O
+	
+Lumbar	O
+puncture	O
+results	O
+were	O
+inconclusive	O
+and	O
+no	O
+further	O
+blood	O
+cultures	O
+were	O
+positive	O
+for	O
+MSSA	O
+.	O
+	
+Creatine	O
+kinase	O
+levels	O
+were	O
+normal	O
+prior	O
+to	O
+daptomycin	O
+therapy	O
+and	O
+were	O
+not	O
+reassessed	O
+.	O
+	
+DISCUSSION	O
+:	O
+Daptomycin	O
+was	O
+initiated	O
+in	O
+our	O
+patient	O
+secondary	O
+to	O
+possible	O
+nafcillin	O
+-	O
+induced	O
+acute	O
+interstitial	B-NP
+nephritis	I-NP
+and	O
+relapsing	O
+bacteremia	B-NP
+.	O
+	
+At	O
+a	O
+dose	O
+of	O
+9	O
+mg	O
+/	O
+kg	O
+","	O
+resultant	O
+penetration	O
+of	O
+5	O
+%	O
+was	O
+higher	O
+than	O
+in	O
+previous	O
+reports	O
+","	O
+more	O
+consistent	O
+with	O
+inflamed	O
+meninges	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+High	O
+-	O
+dose	O
+daptomycin	O
+may	O
+be	O
+an	O
+alternative	O
+option	O
+for	O
+MSSA	O
+bacteremia	B-NP
+with	O
+or	O
+without	O
+a	O
+CNS	O
+source	O
+in	O
+patients	O
+who	O
+have	O
+failed	O
+or	O
+cannot	O
+tolerate	O
+standard	O
+therapy	O
+.	O
+	
+Further	O
+clinical	O
+evaluation	O
+in	O
+patients	O
+with	O
+confirmed	O
+meningitis	B-NP
+is	O
+warranted	O
+.	O
+	
+The	O
+role	O
+of	O
+nitric	O
+oxide	O
+in	O
+convulsions	B-NP
+induced	O
+by	O
+lindane	O
+in	O
+rats	O
+.	O
+	
+Lindane	O
+is	O
+an	O
+organochloride	O
+pesticide	O
+and	O
+scabicide	O
+.	O
+	
+It	O
+evokes	O
+convulsions	B-NP
+mainly	O
+trough	O
+the	O
+blockage	O
+of	O
+GABA	O
+(	O
+A	O
+)	O
+receptors	O
+.	O
+	
+Nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+","	O
+gaseous	O
+neurotransmitter	O
+","	O
+has	O
+contradictor	O
+role	O
+in	O
+epileptogenesis	O
+due	O
+to	O
+opposite	O
+effects	O
+of	O
+L	O
+-	O
+arginine	O
+","	O
+precursor	O
+of	O
+NO	O
+syntheses	O
+(	O
+NOS	O
+)	O
+","	O
+and	O
+L	O
+-	O
+NAME	O
+(	O
+NOS	O
+inhibitor	O
+)	O
+observed	O
+in	O
+different	O
+epilepsy	B-NP
+models	O
+.	O
+	
+The	O
+aim	O
+of	O
+the	O
+current	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+effects	O
+of	O
+NO	O
+on	O
+the	O
+behavioral	O
+and	O
+EEG	O
+characteristics	O
+of	O
+lindane	O
+-	O
+induced	O
+epilepsy	B-NP
+in	O
+male	O
+Wistar	O
+albino	O
+rats	O
+.	O
+	
+The	O
+administration	O
+of	O
+L	O
+-	O
+arginine	O
+(	O
+600	O
+","	O
+800	O
+and	O
+1000	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+p	O
+.	O
+)	O
+in	O
+dose	O
+-	O
+dependent	O
+manner	O
+significantly	O
+increased	O
+convulsion	B-NP
+incidence	O
+and	O
+severity	O
+and	O
+shortened	O
+latency	O
+time	O
+to	O
+first	O
+convulsion	B-NP
+elicited	O
+by	O
+lower	O
+lindane	O
+dose	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+	
+On	O
+the	O
+contrary	O
+","	O
+pretreatment	O
+with	O
+L	O
+-	O
+NAME	O
+(	O
+500	O
+","	O
+700	O
+and	O
+900	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+p	O
+.	O
+)	O
+decreased	O
+convulsion	B-NP
+incidence	O
+and	O
+severity	O
+and	O
+prolonged	O
+latency	O
+time	O
+to	O
+convulsion	B-NP
+following	O
+injection	O
+with	O
+a	O
+convulsive	B-NP
+dose	O
+of	O
+lindane	O
+(	O
+8	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+	
+EEG	O
+analyses	O
+showed	O
+increase	O
+of	O
+number	O
+and	O
+duration	O
+of	O
+ictal	O
+periods	O
+in	O
+EEG	O
+of	O
+rats	O
+receiving	O
+l	O
+-	O
+arginine	O
+prior	O
+to	O
+lindane	O
+and	O
+decrease	O
+of	O
+this	O
+number	O
+in	O
+rats	O
+pretreated	O
+with	O
+L	O
+-	O
+NAME	O
+.	O
+	
+These	O
+results	O
+support	O
+the	O
+conclusion	O
+that	O
+NO	O
+plays	O
+a	O
+role	O
+of	O
+endogenous	O
+convulsant	O
+in	O
+rat	O
+model	O
+of	O
+lindane	O
+seizures	B-NP
+.	O
+	
+Severe	O
+polyneuropathy	B-NP
+and	O
+motor	O
+loss	O
+after	O
+intrathecal	O
+thiotepa	O
+combination	O
+chemotherapy	O
+:	O
+description	O
+of	O
+two	O
+cases	O
+.	O
+	
+Two	O
+cases	O
+of	O
+severe	O
+delayed	O
+neurologic	B-NP
+toxicity	I-NP
+related	O
+to	O
+the	O
+administration	O
+of	O
+intrathecal	O
+(	O
+IT	O
+)	O
+combination	O
+chemotherapy	O
+including	O
+thiotepa	O
+(	O
+TSPA	O
+)	O
+are	O
+presented	O
+.	O
+	
+Both	O
+cases	O
+developed	O
+axonal	B-NP
+neuropathy	I-NP
+with	O
+motor	O
+predominance	O
+in	O
+the	O
+lower	O
+extremities	O
+1	O
+and	O
+6	O
+months	O
+after	O
+IT	O
+chemotherapy	O
+was	O
+administered	O
+.	O
+	
+Neurologic	B-NP
+toxicities	I-NP
+have	O
+been	O
+described	O
+with	O
+IT	O
+-	O
+methotrexate	O
+","	O
+IT	O
+-	O
+cytosine	O
+arabinoside	O
+and	O
+IT	O
+-	O
+TSPA	O
+.	O
+	
+To	O
+our	O
+knowledge	O
+","	O
+however	O
+","	O
+axonal	B-NP
+neuropathy	I-NP
+following	O
+administration	O
+of	O
+these	O
+three	O
+agents	O
+has	O
+not	O
+been	O
+previously	O
+described	O
+.	O
+	
+In	O
+spite	O
+of	O
+the	O
+fact	O
+that	O
+TSPA	O
+is	O
+a	O
+useful	O
+IT	O
+agent	O
+","	O
+its	O
+combination	O
+with	O
+MTX	O
+","	O
+ara	O
+-	O
+C	O
+and	O
+radiotherapy	O
+could	O
+cause	O
+severe	O
+neurotoxicity	B-NP
+.	O
+	
+This	O
+unexpected	O
+complication	O
+indicates	O
+the	O
+need	O
+for	O
+further	O
+toxicology	O
+research	O
+on	O
+IT	O
+-	O
+TSPA	O
+.	O
+	
+Effects	O
+of	O
+cromakalim	O
+and	O
+pinacidil	O
+on	O
+large	O
+epicardial	O
+and	O
+small	O
+coronary	O
+arteries	O
+in	O
+conscious	O
+dogs	O
+.	O
+	
+The	O
+effects	O
+of	O
+i	O
+.	O
+v	O
+.	O
+bolus	O
+administration	O
+of	O
+cromakalim	O
+(	O
+1	O
+-	O
+10	O
+micrograms	O
+/	O
+kg	O
+)	O
+and	O
+pinacidil	O
+(	O
+3	O
+-	O
+100	O
+micrograms	O
+/	O
+kg	O
+)	O
+on	O
+large	O
+(	O
+circumflex	O
+artery	O
+)	O
+and	O
+small	O
+coronary	O
+arteries	O
+and	O
+on	O
+systemic	O
+hemodynamics	O
+were	O
+investigated	O
+in	O
+chronically	O
+instrumented	O
+conscious	O
+dogs	O
+and	O
+compared	O
+to	O
+those	O
+of	O
+nitroglycerin	O
+(	O
+0	O
+.	O
+3	O
+-	O
+10	O
+micrograms	O
+/	O
+kg	O
+)	O
+.	O
+	
+Nitroglycerin	O
+","	O
+up	O
+to	O
+0	O
+.	O
+3	O
+micrograms	O
+/	O
+kg	O
+","	O
+selectively	O
+increased	O
+circumflex	O
+artery	O
+diameter	O
+(	O
+CxAD	O
+)	O
+without	O
+simultaneously	O
+affecting	O
+any	O
+other	O
+cardiac	O
+or	O
+systemic	O
+hemodynamic	O
+parameter	O
+.	O
+	
+In	O
+contrast	O
+","	O
+cromakalim	O
+and	O
+pinacidil	O
+at	O
+all	O
+doses	O
+and	O
+nitroglycerin	O
+at	O
+doses	O
+higher	O
+than	O
+0	O
+.	O
+3	O
+micrograms	O
+/	O
+kg	O
+simultaneously	O
+and	O
+dose	O
+-	O
+dependently	O
+increased	O
+CxAD	O
+","	O
+coronary	O
+blood	O
+flow	O
+and	O
+heart	O
+rate	O
+and	O
+decreased	O
+coronary	O
+vascular	O
+resistance	O
+and	O
+aortic	O
+pressure	O
+.	O
+	
+Cromakalim	O
+was	O
+approximately	O
+8	O
+-	O
+to	O
+9	O
+.	O
+5	O
+-	O
+fold	O
+more	O
+potent	O
+than	O
+pinacidil	O
+in	O
+increasing	O
+CxAD	O
+.	O
+	
+Vasodilation	O
+of	O
+large	O
+and	O
+small	O
+coronary	O
+vessels	O
+and	O
+hypotension	B-NP
+induced	O
+by	O
+cromakalim	O
+and	O
+pinacidil	O
+were	O
+not	O
+affected	O
+by	O
+prior	O
+combined	O
+beta	O
+adrenergic	O
+and	O
+muscarinic	O
+receptors	O
+blockade	O
+but	O
+drug	O
+-	O
+induced	O
+tachycardia	B-NP
+was	O
+abolished	O
+.	O
+	
+When	O
+circumflex	O
+artery	O
+blood	O
+flow	O
+was	O
+maintained	O
+constant	O
+","	O
+the	O
+increases	O
+in	O
+CxAD	O
+induced	O
+by	O
+cromakalim	O
+(	O
+10	O
+micrograms	O
+/	O
+kg	O
+)	O
+","	O
+pinacidil	O
+(	O
+30	O
+micrograms	O
+/	O
+kg	O
+)	O
+and	O
+nitroglycerin	O
+(	O
+10	O
+micrograms	O
+/	O
+kg	O
+)	O
+were	O
+reduced	O
+by	O
+68	O
++	O
+/	O
+-	O
+7	O
+","	O
+54	O
++	O
+/	O
+-	O
+9	O
+and	O
+1	O
++	O
+/	O
+-	O
+1	O
+%	O
+","	O
+respectively	O
+.	O
+	
+Thus	O
+","	O
+whereas	O
+nitroglycerin	O
+preferentially	O
+and	O
+flow	O
+-	O
+independently	O
+dilates	O
+large	O
+coronary	O
+arteries	O
+","	O
+cromakalim	O
+and	O
+pinacidil	O
+dilate	O
+both	O
+large	O
+and	O
+small	O
+coronary	O
+arteries	O
+and	O
+this	O
+effect	O
+is	O
+not	O
+dependent	O
+upon	O
+the	O
+simultaneous	O
+beta	O
+adrenoceptors	O
+-	O
+mediated	O
+rise	O
+in	O
+myocardial	O
+metabolic	O
+demand	O
+.	O
+	
+Finally	O
+","	O
+two	O
+mechanisms	O
+at	O
+least	O
+","	O
+direct	O
+vasodilation	O
+and	O
+flow	O
+dependency	O
+","	O
+are	O
+involved	O
+in	O
+the	O
+cromakalim	O
+-	O
+and	O
+pinacidil	O
+-	O
+induced	O
+increase	O
+in	O
+CxAD	O
+.	O
+	
+Mefenamic	O
+acid	O
+-	O
+induced	O
+neutropenia	B-NP
+and	O
+renal	B-NP
+failure	I-NP
+in	O
+elderly	O
+females	O
+with	O
+hypothyroidism	B-NP
+.	O
+	
+We	O
+report	O
+mefenamic	O
+acid	O
+-	O
+induced	O
+non	O
+-	O
+oliguric	O
+renal	B-NP
+failure	I-NP
+and	O
+severe	O
+neutropenia	B-NP
+occurring	O
+simultaneously	O
+in	O
+two	O
+elderly	O
+females	O
+.	O
+	
+The	O
+neutropenia	B-NP
+was	O
+due	O
+to	O
+maturation	O
+arrest	O
+of	O
+the	O
+myeloid	O
+series	O
+in	O
+one	O
+patient	O
+.	O
+	
+Both	O
+patients	O
+were	O
+also	O
+hypothyroid	B-NP
+","	O
+but	O
+it	O
+is	O
+not	O
+clear	O
+whether	O
+this	O
+was	O
+a	O
+predisposing	O
+factor	O
+to	O
+the	O
+development	O
+of	O
+these	O
+adverse	O
+reactions	O
+.	O
+	
+However	O
+","	O
+it	O
+would	O
+seem	O
+prudent	O
+not	O
+to	O
+use	O
+mefenamic	O
+acid	O
+in	O
+hypothyroid	B-NP
+patients	O
+until	O
+the	O
+hypothyroidism	B-NP
+has	O
+been	O
+corrected	O
+.	O
+	
+Etiology	O
+of	O
+hypercalcemia	B-NP
+in	O
+hemodialysis	O
+patients	O
+on	O
+calcium	O
+carbonate	O
+therapy	O
+.	O
+	
+Fourteen	O
+of	O
+39	O
+dialysis	O
+patients	O
+(	O
+36	O
+%	O
+)	O
+became	O
+hypercalcemic	B-NP
+after	O
+switching	O
+to	O
+calcium	O
+carbonate	O
+as	O
+their	O
+principal	O
+phosphate	O
+binder	O
+.	O
+	
+In	O
+order	O
+to	O
+identify	O
+risk	O
+factors	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+hypercalcemia	B-NP
+","	O
+indirect	O
+parameters	O
+of	O
+intestinal	O
+calcium	O
+reabsorption	O
+and	O
+bone	O
+turnover	O
+rate	O
+in	O
+these	O
+14	O
+patients	O
+were	O
+compared	O
+with	O
+results	O
+in	O
+14	O
+eucalcemic	O
+patients	O
+matched	O
+for	O
+age	O
+","	O
+sex	O
+","	O
+length	O
+of	O
+time	O
+on	O
+dialysis	O
+","	O
+and	O
+etiology	O
+of	O
+renal	B-NP
+disease	I-NP
+.	O
+	
+In	O
+addition	O
+to	O
+experiencing	O
+hypercalcemic	B-NP
+episodes	O
+with	O
+peak	O
+calcium	O
+values	O
+of	O
+2	O
+.	O
+7	O
+to	O
+3	O
+.	O
+8	O
+mmol	O
+/	O
+L	O
+(	O
+10	O
+.	O
+7	O
+to	O
+15	O
+.	O
+0	O
+mg	O
+/	O
+dL	O
+)	O
+","	O
+patients	O
+in	O
+the	O
+hypercalcemic	B-NP
+group	O
+exhibited	O
+a	O
+significant	O
+increase	O
+in	O
+the	O
+mean	O
+calcium	O
+concentration	O
+obtained	O
+during	O
+6	O
+months	O
+before	O
+the	O
+switch	O
+","	O
+compared	O
+with	O
+the	O
+mean	O
+value	O
+obtained	O
+during	O
+the	O
+7	O
+months	O
+of	O
+observation	O
+after	O
+the	O
+switch	O
+(	O
+2	O
+.	O
+4	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+to	O
+2	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+mmol	O
+/	O
+L	O
+[	O
+9	O
+.	O
+7	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+to	O
+10	O
+.	O
+2	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+mg	O
+/	O
+dL	O
+]	O
+","	O
+P	O
+=	O
+0	O
+.	O
+6	O
+)	O
+.	O
+	
+In	O
+contrast	O
+","	O
+eucalcemic	O
+patients	O
+exhibited	O
+no	O
+change	O
+in	O
+mean	O
+calcium	O
+values	O
+over	O
+the	O
+same	O
+time	O
+period	O
+(	O
+2	O
+.	O
+3	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+to	O
+2	O
+.	O
+3	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+mmol	O
+/	O
+L	O
+[	O
+9	O
+.	O
+2	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+to	O
+9	O
+.	O
+2	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+mg	O
+/	O
+dL	O
+]	O
+)	O
+.	O
+	
+CaCO3	O
+dosage	O
+","	O
+calculated	O
+dietary	O
+calcium	O
+intake	O
+","	O
+and	O
+circulating	O
+levels	O
+of	O
+vitamin	O
+D	O
+metabolites	O
+were	O
+similar	O
+in	O
+both	O
+groups	O
+.	O
+	
+Physical	O
+activity	O
+index	O
+and	O
+predialysis	O
+serum	O
+bicarbonate	O
+levels	O
+also	O
+were	O
+similar	O
+in	O
+both	O
+groups	O
+.	O
+	
+However	O
+","	O
+there	O
+was	O
+a	O
+significant	O
+difference	O
+in	O
+parameters	O
+reflecting	O
+bone	O
+turnover	O
+rates	O
+between	O
+groups	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+	
+Late	O
+-	O
+onset	O
+scleroderma	B-NP
+renal	I-NP
+crisis	I-NP
+induced	O
+by	O
+tacrolimus	O
+and	O
+prednisolone	O
+:	O
+a	O
+case	O
+report	O
+.	O
+	
+Scleroderma	B-NP
+renal	I-NP
+crisis	I-NP
+(	O
+SRC	B-NP
+)	O
+is	O
+a	O
+rare	O
+complication	O
+of	O
+systemic	B-NP
+sclerosis	I-NP
+(	O
+SSc	B-NP
+)	O
+but	O
+can	O
+be	O
+severe	O
+enough	O
+to	O
+require	O
+temporary	O
+or	O
+permanent	O
+renal	O
+replacement	O
+therapy	O
+.	O
+	
+Moderate	O
+to	O
+high	O
+dose	O
+corticosteroid	O
+use	O
+is	O
+recognized	O
+as	O
+a	O
+major	O
+risk	O
+factor	O
+for	O
+SRC	B-NP
+.	O
+	
+Furthermore	O
+","	O
+there	O
+have	O
+been	O
+reports	O
+of	O
+thrombotic	B-NP
+microangiopathy	I-NP
+precipitated	O
+by	O
+cyclosporine	O
+in	O
+patients	O
+with	O
+SSc	B-NP
+.	O
+	
+In	O
+this	O
+article	O
+","	O
+we	O
+report	O
+a	O
+patient	O
+with	O
+SRC	B-NP
+induced	O
+by	O
+tacrolimus	O
+and	O
+corticosteroids	O
+.	O
+	
+The	O
+aim	O
+of	O
+this	O
+work	O
+is	O
+to	O
+call	O
+attention	O
+to	O
+the	O
+risk	O
+of	O
+tacrolimus	O
+use	O
+in	O
+patients	O
+with	O
+SSc	B-NP
+.	O
+	
+Methyldopa	O
+-	O
+induced	O
+hemolytic	B-NP
+anemia	I-NP
+in	O
+a	O
+15	O
+year	O
+old	O
+presenting	O
+as	O
+near	O
+-	O
+syncope	B-NP
+.	O
+	
+Methyldopa	O
+is	O
+an	O
+antihypertensive	O
+medication	O
+which	O
+is	O
+available	O
+generically	O
+and	O
+under	O
+the	O
+trade	O
+name	O
+Aldomet	O
+that	O
+is	O
+widely	O
+prescribed	O
+in	O
+the	O
+adult	O
+population	O
+and	O
+infrequently	O
+used	O
+in	O
+children	O
+.	O
+	
+Methyldopa	O
+causes	O
+an	O
+autoimmune	B-NP
+hemolytic	I-NP
+anemia	I-NP
+in	O
+a	O
+small	O
+percentage	O
+of	O
+patients	O
+who	O
+take	O
+the	O
+drug	O
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+methyldopa	O
+-	O
+induced	O
+hemolytic	B-NP
+anemia	I-NP
+in	O
+a	O
+15	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+who	O
+presented	O
+to	O
+the	O
+emergency	B-NP
+department	I-NP
+with	O
+near	O
+-	O
+syncope	B-NP
+.	O
+	
+The	O
+boy	O
+had	O
+been	O
+treated	O
+with	O
+intravenous	O
+methyldopa	O
+during	O
+a	O
+trauma	B-NP
+admission	O
+seven	O
+weeks	O
+prior	O
+to	O
+presentation	O
+.	O
+	
+Evaluation	O
+revealed	O
+a	O
+hemoglobin	O
+of	O
+three	O
+grams	O
+","	O
+3	O
++	O
+Coombs	O
+'	O
+test	O
+with	O
+polyspecific	O
+anti	O
+-	O
+human	O
+globulin	O
+and	O
+monospecific	O
+IgG	O
+reagents	O
+","	O
+and	O
+a	O
+warm	O
+reacting	O
+autoantibody	O
+.	O
+	
+Transfusion	O
+and	O
+corticosteroid	O
+therapy	O
+resulted	O
+in	O
+a	O
+complete	O
+recovery	O
+of	O
+the	O
+patient	O
+.	O
+	
+Emergency	O
+physicians	O
+treating	O
+children	O
+must	O
+be	O
+aware	O
+of	O
+this	O
+syndrome	O
+in	O
+order	O
+to	O
+diagnose	O
+and	O
+treat	O
+it	O
+correctly	O
+.	O
+	
+A	O
+brief	O
+review	O
+of	O
+autoimmune	O
+and	O
+drug	O
+-	O
+induced	O
+hemolytic	B-NP
+anemias	I-NP
+is	O
+provided	O
+.	O
+	
+The	O
+risk	O
+and	O
+associated	O
+factors	O
+of	O
+methamphetamine	O
+psychosis	B-NP
+in	O
+methamphetamine	O
+-	O
+dependent	O
+patients	O
+in	O
+Malaysia	O
+.	O
+	
+OBJECTIVE	O
+:	O
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+risk	O
+of	O
+lifetime	O
+and	O
+current	O
+methamphetamine	O
+-	O
+induced	O
+psychosis	B-NP
+in	O
+patients	O
+with	O
+methamphetamine	O
+dependence	O
+.	O
+	
+The	O
+association	O
+between	O
+psychiatric	O
+co	O
+-	O
+morbidity	O
+and	O
+methamphetamine	O
+-	O
+induced	O
+psychosis	B-NP
+was	O
+also	O
+studied	O
+.	O
+	
+METHODS	O
+:	O
+This	O
+was	O
+a	O
+cross	O
+-	O
+sectional	O
+study	O
+conducted	O
+concurrently	O
+at	O
+a	O
+teaching	O
+hospital	O
+and	O
+a	O
+drug	O
+rehabilitation	O
+center	O
+in	O
+Malaysia	O
+.	O
+	
+Patients	O
+with	O
+the	O
+diagnosis	O
+of	O
+methamphetamine	O
+based	O
+on	O
+DSM	O
+-	O
+IV	O
+were	O
+interviewed	O
+using	O
+the	O
+Mini	O
+International	O
+Neuropsychiatric	O
+Interview	O
+(	O
+M	O
+.	O
+I	O
+.	O
+N	O
+.	O
+I	O
+.	O
+)	O
+for	O
+methamphetamine	O
+-	O
+induced	O
+psychosis	B-NP
+and	O
+other	O
+Axis	O
+I	O
+psychiatric	B-NP
+disorders	I-NP
+.	O
+	
+The	O
+information	O
+on	O
+sociodemographic	O
+background	O
+and	O
+drug	O
+use	O
+history	O
+was	O
+obtained	O
+from	O
+interview	O
+or	O
+medical	O
+records	O
+.	O
+	
+RESULTS	O
+:	O
+Of	O
+292	O
+subjects	O
+","	O
+47	O
+.	O
+9	O
+%	O
+of	O
+the	O
+subjects	O
+had	O
+a	O
+past	O
+history	O
+of	O
+psychotic	B-NP
+symptoms	I-NP
+and	O
+13	O
+.	O
+0	O
+%	O
+of	O
+the	O
+patients	O
+were	O
+having	O
+current	O
+psychotic	B-NP
+symptoms	I-NP
+.	O
+	
+Co	O
+-	O
+morbid	O
+major	O
+depressive	B-NP
+disorder	I-NP
+(	O
+OR	O
+=	O
+7	O
+.	O
+18	O
+","	O
+95	O
+CI	O
+=	O
+2	O
+.	O
+612	O
+-	O
+19	O
+.	O
+708	O
+)	O
+","	O
+bipolar	B-NP
+disorder	I-NP
+(	O
+OR	O
+=	O
+13	O
+.	O
+807	O
+","	O
+95	O
+CI	O
+=	O
+5	O
+.	O
+194	O
+-	O
+36	O
+.	O
+706	O
+)	O
+","	O
+antisocial	B-NP
+personality	I-NP
+disorder	I-NP
+(	O
+OR	O
+=	O
+12	O
+.	O
+619	O
+","	O
+95	O
+CI	O
+=	O
+6	O
+.	O
+702	O
+-	O
+23	O
+.	O
+759	O
+)	O
+and	O
+heavy	O
+methamphetamine	O
+uses	O
+were	O
+significantly	O
+associated	O
+with	O
+lifetime	O
+methamphetamine	O
+-	O
+induced	O
+psychosis	B-NP
+after	O
+adjusted	O
+for	O
+other	O
+factors	O
+.	O
+	
+Major	B-NP
+depressive	I-NP
+disorder	I-NP
+(	O
+OR	O
+=	O
+2	O
+.	O
+870	O
+","	O
+CI	O
+=	O
+1	O
+.	O
+154	O
+-	O
+7	O
+.	O
+142	O
+)	O
+and	O
+antisocial	B-NP
+personality	I-NP
+disorder	I-NP
+(	O
+OR	O
+=	O
+3	O
+.	O
+299	O
+","	O
+95	O
+CI	O
+=	O
+1	O
+.	O
+375	O
+-	O
+7	O
+.	O
+914	O
+)	O
+were	O
+the	O
+only	O
+factors	O
+associated	O
+with	O
+current	O
+psychosis	B-NP
+.	O
+	
+CONCLUSION	O
+:	O
+There	O
+was	O
+a	O
+high	O
+risk	O
+of	O
+psychosis	B-NP
+in	O
+patients	O
+with	O
+methamphetamine	O
+dependence	O
+.	O
+	
+It	O
+was	O
+associated	O
+with	O
+co	O
+-	O
+morbid	O
+affective	B-NP
+disorder	I-NP
+","	O
+antisocial	B-NP
+personality	I-NP
+","	O
+and	O
+heavy	O
+methamphetamine	O
+use	O
+.	O
+	
+It	O
+is	O
+recommended	O
+that	O
+all	O
+cases	O
+of	O
+methamphetamine	O
+dependence	O
+should	O
+be	O
+screened	O
+for	O
+psychotic	B-NP
+symptoms	I-NP
+.	O
+	
+Cerebellar	O
+sensory	O
+processing	O
+alterations	O
+impact	O
+motor	O
+cortical	O
+plasticity	O
+in	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+:	O
+clues	O
+from	O
+dyskinetic	B-NP
+patients	O
+.	O
+	
+The	O
+plasticity	O
+of	O
+primary	O
+motor	O
+cortex	O
+(	O
+M1	O
+)	O
+in	O
+patients	O
+with	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+(	O
+PD	B-NP
+)	O
+and	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B-NP
+(	O
+LIDs	B-NP
+)	O
+is	O
+severely	O
+impaired	O
+.	O
+	
+We	O
+recently	O
+reported	O
+in	O
+young	O
+healthy	O
+subjects	O
+that	O
+inhibitory	O
+cerebellar	O
+stimulation	O
+enhanced	O
+the	O
+sensorimotor	O
+plasticity	O
+of	O
+M1	O
+that	O
+was	O
+induced	O
+by	O
+paired	O
+associative	O
+stimulation	O
+(	O
+PAS	O
+)	O
+.	O
+	
+This	O
+study	O
+demonstrates	O
+that	O
+the	O
+deficient	O
+sensorimotor	O
+M1	O
+plasticity	O
+in	O
+16	O
+patients	O
+with	O
+LIDs	B-NP
+could	O
+be	O
+reinstated	O
+by	O
+a	O
+single	O
+session	O
+of	O
+real	O
+inhibitory	O
+cerebellar	O
+stimulation	O
+but	O
+not	O
+sham	O
+stimulation	O
+.	O
+	
+This	O
+was	O
+evident	O
+only	O
+when	O
+a	O
+sensory	O
+component	O
+was	O
+involved	O
+in	O
+the	O
+induction	O
+of	O
+plasticity	O
+","	O
+indicating	O
+that	O
+cerebellar	O
+sensory	O
+processing	O
+function	O
+is	O
+involved	O
+in	O
+the	O
+resurgence	O
+of	O
+M1	O
+plasticity	O
+.	O
+	
+The	O
+benefit	O
+of	O
+inhibitory	O
+cerebellar	O
+stimulation	O
+on	O
+LIDs	B-NP
+is	O
+known	O
+.	O
+	
+To	O
+explore	O
+whether	O
+this	O
+benefit	O
+is	O
+linked	O
+to	O
+the	O
+restoration	O
+of	O
+sensorimotor	O
+plasticity	O
+of	O
+M1	O
+","	O
+we	O
+conducted	O
+an	O
+additional	O
+study	O
+looking	O
+at	O
+changes	O
+in	O
+LIDs	B-NP
+and	O
+PAS	O
+-	O
+induced	O
+plasticity	O
+after	O
+10	O
+sessions	O
+of	O
+either	O
+bilateral	O
+","	O
+real	O
+inhibitory	O
+cerebellar	O
+stimulation	O
+or	O
+sham	O
+stimulation	O
+.	O
+	
+Only	O
+real	O
+and	O
+not	O
+sham	O
+stimulation	O
+had	O
+an	O
+antidyskinetic	O
+effect	O
+and	O
+it	O
+was	O
+paralleled	O
+by	O
+a	O
+resurgence	O
+in	O
+the	O
+sensorimotor	O
+plasticity	O
+of	O
+M1	O
+.	O
+	
+These	O
+results	O
+suggest	O
+that	O
+alterations	O
+in	O
+cerebellar	O
+sensory	O
+processing	O
+function	O
+","	O
+occurring	O
+secondary	O
+to	O
+abnormal	O
+basal	O
+ganglia	O
+signals	O
+reaching	O
+it	O
+","	O
+may	O
+be	O
+an	O
+important	O
+element	O
+contributing	O
+to	O
+the	O
+maladaptive	O
+sensorimotor	O
+plasticity	O
+of	O
+M1	O
+and	O
+the	O
+emergence	O
+of	O
+abnormal	B-NP
+involuntary	I-NP
+movements	I-NP
+.	O
+	
+The	O
+long	O
+-	O
+term	O
+safety	O
+of	O
+danazol	O
+in	O
+women	O
+with	O
+hereditary	B-NP
+angioedema	I-NP
+.	O
+	
+Although	O
+the	O
+short	O
+-	O
+term	O
+safety	O
+(	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+6	O
+months	O
+)	O
+of	O
+danazol	O
+has	O
+been	O
+established	O
+in	O
+a	O
+variety	O
+of	O
+settings	O
+","	O
+no	O
+information	O
+exists	O
+as	O
+to	O
+its	O
+long	O
+-	O
+term	O
+safety	O
+.	O
+	
+We	O
+therefore	O
+investigated	O
+the	O
+long	O
+-	O
+term	O
+safety	O
+of	O
+danazol	O
+by	O
+performing	O
+a	O
+retrospective	O
+chart	O
+review	O
+of	O
+60	O
+female	O
+patients	O
+with	O
+hereditary	B-NP
+angioedema	I-NP
+treated	O
+with	O
+danazol	O
+for	O
+a	O
+continuous	O
+period	O
+of	O
+6	O
+months	O
+or	O
+longer	O
+.	O
+	
+The	O
+mean	O
+age	O
+of	O
+the	O
+patients	O
+was	O
+35	O
+.	O
+2	O
+years	O
+and	O
+the	O
+mean	O
+duration	O
+of	O
+therapy	O
+was	O
+59	O
+.	O
+7	O
+months	O
+.	O
+	
+Virtually	O
+all	O
+patients	O
+experienced	O
+one	O
+or	O
+more	O
+adverse	O
+reactions	O
+.	O
+	
+Menstrual	B-NP
+abnormalities	I-NP
+(	O
+79	O
+%	O
+)	O
+","	O
+weight	B-NP
+gain	I-NP
+(	O
+60	O
+%	O
+)	O
+","	O
+muscle	B-NP
+cramps	I-NP
+/	O
+myalgias	B-NP
+(	O
+40	O
+%	O
+)	O
+","	O
+and	O
+transaminase	O
+elevations	O
+(	O
+40	O
+%	O
+)	O
+were	O
+the	O
+most	O
+common	O
+adverse	O
+reactions	O
+.	O
+	
+The	O
+drug	O
+was	O
+discontinued	O
+due	O
+to	O
+adverse	O
+reactions	O
+in	O
+8	O
+patients	O
+.	O
+	
+No	O
+patient	O
+has	O
+died	O
+or	O
+suffered	O
+any	O
+apparent	O
+long	O
+-	O
+term	O
+sequelae	O
+that	O
+were	O
+directly	O
+attributable	O
+to	O
+the	O
+drug	O
+.	O
+	
+We	O
+conclude	O
+that	O
+","	O
+despite	O
+a	O
+relatively	O
+high	O
+incidence	O
+of	O
+adverse	O
+reactions	O
+","	O
+danazol	O
+has	O
+proven	O
+to	O
+be	O
+remarkably	O
+safe	O
+over	O
+the	O
+long	O
+-	O
+term	O
+in	O
+this	O
+group	O
+of	O
+patients	O
+.	O
+	
+The	O
+function	O
+of	O
+P2X3	O
+receptor	O
+and	O
+NK1	O
+receptor	O
+antagonists	O
+on	O
+cyclophosphamide	O
+-	O
+induced	O
+cystitis	B-NP
+in	O
+rats	O
+.	O
+	
+PURPOSE	O
+:	O
+The	O
+purpose	O
+of	O
+the	O
+study	O
+is	O
+to	O
+explore	O
+the	O
+function	O
+of	O
+P2X3	O
+and	O
+NK1	O
+receptors	O
+antagonists	O
+on	O
+cyclophosphamide	O
+(	O
+CYP	O
+)	O
+-	O
+induced	O
+cystitis	B-NP
+in	O
+rats	O
+.	O
+	
+METHODS	O
+:	O
+Sixty	O
+female	O
+Sprague	O
+-	O
+Dawley	O
+(	O
+SD	O
+)	O
+rats	O
+were	O
+randomly	O
+divided	O
+into	O
+three	O
+groups	O
+.	O
+	
+The	O
+rats	O
+in	O
+the	O
+control	O
+group	O
+were	O
+intraperitoneally	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+injected	O
+with	O
+0	O
+.	O
+9	O
+%	O
+saline	O
+(	O
+4	O
+ml	O
+/	O
+kg	O
+)	O
+;	O
+the	O
+rats	O
+in	O
+the	O
+model	O
+group	O
+were	O
+i	O
+.	O
+p	O
+.	O
+injected	O
+with	O
+CYP	O
+(	O
+150	O
+mg	O
+/	O
+kg	O
+)	O
+;	O
+and	O
+the	O
+rats	O
+in	O
+the	O
+intervention	O
+group	O
+were	O
+i	O
+.	O
+p	O
+.	O
+injected	O
+with	O
+CYP	O
+with	O
+subsequently	O
+perfusion	O
+of	O
+bladder	O
+with	O
+P2X3	O
+and	O
+NK1	O
+receptors	O
+'	O
+antagonists	O
+","	O
+Suramin	O
+and	O
+GR	O
+82334	O
+.	O
+	
+Spontaneous	O
+pain	B-NP
+behaviors	O
+following	O
+the	O
+administration	O
+of	O
+CYP	O
+were	O
+observed	O
+.	O
+	
+Urodynamic	O
+parameters	O
+","	O
+bladder	O
+pressure	O
+-	O
+volume	O
+curve	O
+","	O
+maximum	O
+voiding	O
+pressure	O
+(	O
+MVP	O
+)	O
+","	O
+and	O
+maximum	O
+cystometric	O
+capacity	O
+(	O
+MCC	O
+)	O
+","	O
+were	O
+recorded	O
+.	O
+	
+Pathological	O
+changes	O
+in	O
+bladder	O
+tissue	O
+were	O
+observed	O
+.	O
+	
+Immunofluorescence	O
+was	O
+used	O
+to	O
+detect	O
+the	O
+expression	O
+of	O
+P2X3	O
+and	O
+NK1	O
+receptors	O
+in	O
+bladder	O
+.	O
+	
+RESULTS	O
+:	O
+Cyclophosphamide	O
+treatment	O
+increased	O
+the	O
+spontaneous	O
+pain	B-NP
+behaviors	O
+scores	O
+.	O
+	
+The	O
+incidence	O
+of	O
+bladder	O
+instability	O
+during	O
+urine	O
+storage	O
+period	O
+of	O
+model	O
+group	O
+was	O
+significantly	O
+higher	O
+than	O
+intervention	O
+group	O
+(	O
+X	O
+(	O
+2	O
+)	O
+=	O
+7	O
+.	O
+619	O
+","	O
+P	O
+=	O
+0	O
+.	O
+7	O
+)	O
+and	O
+control	O
+group	O
+(	O
+X	O
+(	O
+2	O
+)	O
+=	O
+13	O
+.	O
+755	O
+","	O
+P	O
+=	O
+0	O
+.	O
+0	O
+)	O
+.	O
+	
+MCC	O
+in	O
+the	O
+model	O
+group	O
+was	O
+lower	O
+than	O
+the	O
+control	O
+and	O
+intervention	O
+groups	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Histological	O
+changes	O
+evident	O
+in	O
+model	O
+and	O
+intervention	O
+groups	O
+rats	O
+'	O
+bladder	O
+included	O
+edema	B-NP
+","	O
+vasodilation	O
+","	O
+and	O
+infiltration	O
+of	O
+inflammatory	O
+cells	O
+.	O
+	
+In	O
+model	O
+group	O
+","	O
+the	O
+expression	O
+of	O
+P2X3	O
+receptor	O
+increased	O
+in	O
+urothelium	O
+and	O
+suburothelium	O
+","	O
+and	O
+NK1	O
+receptor	O
+increased	O
+in	O
+suburothelium	O
+","	O
+while	O
+the	O
+expression	O
+of	O
+them	O
+in	O
+intervention	O
+group	O
+was	O
+lower	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+In	O
+CYP	O
+-	O
+induced	O
+cystitis	B-NP
+","	O
+the	O
+expression	O
+of	O
+P2X3	O
+and	O
+NK1	O
+receptors	O
+increased	O
+in	O
+urothelium	O
+and	O
+/	O
+or	O
+suburothelium	O
+.	O
+	
+Perfusion	O
+of	O
+bladder	O
+with	O
+P2X3	O
+and	O
+NK1	O
+receptors	O
+antagonists	O
+ameliorated	O
+the	O
+bladder	O
+function	O
+.	O
+	
+Patient	O
+tolerance	O
+study	O
+of	O
+topical	O
+chlorhexidine	O
+diphosphanilate	O
+:	O
+a	O
+new	O
+topical	O
+agent	O
+for	O
+burns	B-NP
+.	O
+	
+Effective	O
+topical	O
+antimicrobial	O
+agents	O
+decrease	O
+infection	B-NP
+and	O
+mortality	O
+in	O
+burn	B-NP
+patients	O
+.	O
+	
+Chlorhexidine	O
+phosphanilate	O
+(	O
+CHP	O
+)	O
+","	O
+a	O
+new	O
+broad	O
+-	O
+spectrum	O
+antimicrobial	O
+agent	O
+","	O
+has	O
+been	O
+evaluated	O
+as	O
+a	O
+topical	O
+burn	B-NP
+wound	O
+dressing	O
+in	O
+cream	O
+form	O
+","	O
+but	O
+preliminary	O
+clinical	O
+trials	O
+reported	O
+that	O
+it	O
+was	O
+painful	O
+upon	O
+application	O
+.	O
+	
+This	O
+study	O
+compared	O
+various	O
+concentrations	O
+of	O
+CHP	O
+to	O
+determine	O
+if	O
+a	O
+tolerable	O
+concentration	O
+could	O
+be	O
+identified	O
+with	O
+retention	O
+of	O
+antimicrobial	O
+efficacy	O
+.	O
+	
+Twenty	O
+-	O
+nine	O
+burn	B-NP
+patients	O
+","	O
+each	O
+with	O
+two	O
+similar	O
+burns	B-NP
+which	O
+could	O
+be	O
+separately	O
+treated	O
+","	O
+were	O
+given	O
+pairs	O
+of	O
+treatments	O
+at	O
+successive	O
+12	O
+-	O
+h	O
+intervals	O
+over	O
+a	O
+3	O
+-	O
+day	O
+period	O
+.	O
+	
+One	O
+burn	B-NP
+site	O
+was	O
+treated	O
+with	O
+each	O
+of	O
+four	O
+different	O
+CHP	O
+concentrations	O
+","	O
+from	O
+0	O
+.	O
+25	O
+per	O
+cent	O
+to	O
+2	O
+per	O
+cent	O
+","	O
+their	O
+vehicle	O
+","	O
+and	O
+1	O
+per	O
+cent	O
+silver	O
+sulphadiazine	O
+(	O
+AgSD	O
+)	O
+cream	O
+","	O
+an	O
+antimicrobial	O
+agent	O
+frequently	O
+used	O
+for	O
+topical	O
+treatment	O
+of	O
+burn	B-NP
+wounds	O
+.	O
+	
+The	O
+other	O
+site	O
+was	O
+always	O
+treated	O
+with	O
+AgSD	O
+cream	O
+.	O
+	
+There	O
+was	O
+a	O
+direct	O
+relationship	O
+between	O
+CHP	O
+concentration	O
+and	O
+patients	O
+'	O
+ratings	O
+of	O
+pain	B-NP
+on	O
+an	O
+analogue	O
+scale	O
+.	O
+	
+The	O
+0	O
+.	O
+25	O
+per	O
+cent	O
+CHP	O
+cream	O
+was	O
+closest	O
+to	O
+AgSD	O
+in	O
+pain	B-NP
+tolerance	O
+;	O
+however	O
+","	O
+none	O
+of	O
+the	O
+treatments	O
+differed	O
+statistically	O
+from	O
+AgSD	O
+or	O
+from	O
+each	O
+other	O
+.	O
+	
+In	O
+addition	O
+","	O
+ease	O
+of	O
+application	O
+of	O
+CHP	O
+creams	O
+was	O
+less	O
+satisfactory	O
+than	O
+that	O
+of	O
+AgSD	O
+.	O
+	
+It	O
+was	O
+concluded	O
+that	O
+formulations	O
+at	O
+or	O
+below	O
+0	O
+.	O
+5	O
+per	O
+cent	O
+CHP	O
+may	O
+prove	O
+acceptable	O
+for	O
+wound	O
+care	O
+","	O
+but	O
+the	O
+vehicle	O
+system	O
+needs	O
+pharmaceutical	O
+improvement	O
+to	O
+render	O
+it	O
+more	O
+tolerable	O
+and	O
+easier	O
+to	O
+use	O
+.	O
+	
+Acute	O
+hepatitis	B-NP
+associated	O
+with	O
+clopidogrel	O
+:	O
+a	O
+case	O
+report	O
+and	O
+review	O
+of	O
+the	O
+literature	O
+.	O
+	
+Drug	O
+-	O
+induced	O
+hepatotoxicity	B-NP
+is	O
+a	O
+common	O
+cause	O
+of	O
+acute	O
+hepatitis	B-NP
+","	O
+and	O
+the	O
+recognition	O
+of	O
+the	O
+responsible	O
+drug	O
+may	O
+be	O
+difficult	O
+.	O
+	
+We	O
+describe	O
+a	O
+case	O
+of	O
+clopidogrel	O
+-	O
+related	O
+acute	O
+hepatitis	B-NP
+.	O
+	
+The	O
+diagnosis	O
+is	O
+strongly	O
+suggested	O
+by	O
+an	O
+accurate	O
+medical	O
+history	O
+and	O
+liver	O
+biopsy	O
+.	O
+	
+Reports	O
+about	O
+cases	O
+of	O
+hepatotoxicity	B-NP
+due	O
+to	O
+clopidogrel	O
+are	O
+increasing	O
+in	O
+the	O
+last	O
+few	O
+years	O
+","	O
+after	O
+the	O
+increased	O
+use	O
+of	O
+this	O
+drug	O
+.	O
+	
+In	O
+conclusion	O
+","	O
+we	O
+believe	O
+that	O
+physicians	O
+should	O
+carefully	O
+consider	O
+the	O
+risk	O
+of	O
+drug	O
+-	O
+induced	O
+hepatic	B-NP
+injury	I-NP
+when	O
+clopidogrel	O
+is	O
+prescribed	O
+.	O
+	
+Bortezomib	O
+and	O
+dexamethasone	O
+as	O
+salvage	O
+therapy	O
+in	O
+patients	O
+with	O
+relapsed	O
+/	O
+refractory	O
+multiple	B-NP
+myeloma	I-NP
+:	O
+analysis	O
+of	O
+long	O
+-	O
+term	O
+clinical	O
+outcomes	O
+.	O
+	
+Bortezomib	O
+(	O
+bort	O
+)	O
+-	O
+dexamethasone	O
+(	O
+dex	O
+)	O
+is	O
+an	O
+effective	O
+therapy	O
+for	O
+relapsed	O
+/	O
+refractory	O
+(	O
+R	O
+/	O
+R	O
+)	O
+multiple	B-NP
+myeloma	I-NP
+(	O
+MM	B-NP
+)	O
+.	O
+	
+This	O
+retrospective	O
+study	O
+investigated	O
+the	O
+combination	O
+of	O
+bort	O
+(	O
+1	O
+.	O
+3	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+on	O
+days	O
+1	O
+","	O
+4	O
+","	O
+8	O
+","	O
+and	O
+11	O
+every	O
+3	O
+weeks	O
+)	O
+and	O
+dex	O
+(	O
+20	O
+mg	O
+on	O
+the	O
+day	O
+of	O
+and	O
+the	O
+day	O
+after	O
+bort	O
+)	O
+as	O
+salvage	O
+treatment	O
+in	O
+85	O
+patients	O
+with	O
+R	O
+/	O
+R	O
+MM	B-NP
+after	O
+prior	O
+autologous	O
+stem	O
+cell	O
+transplantation	O
+or	O
+conventional	O
+chemotherapy	O
+.	O
+	
+The	O
+median	O
+number	O
+of	O
+prior	O
+lines	O
+of	O
+therapy	O
+was	O
+2	O
+.	O
+	
+Eighty	O
+-	O
+seven	O
+percent	O
+of	O
+the	O
+patients	O
+had	O
+received	O
+immunomodulatory	O
+drugs	O
+included	O
+in	O
+some	O
+line	O
+of	O
+therapy	O
+before	O
+bort	O
+-	O
+dex	O
+.	O
+	
+The	O
+median	O
+number	O
+of	O
+bort	O
+-	O
+dex	O
+cycles	O
+was	O
+6	O
+","	O
+up	O
+to	O
+a	O
+maximum	O
+of	O
+12	O
+cycles	O
+.	O
+	
+On	O
+an	O
+intention	O
+-	O
+to	O
+-	O
+treat	O
+basis	O
+","	O
+55	O
+%	O
+of	O
+the	O
+patients	O
+achieved	O
+at	O
+least	O
+partial	O
+response	O
+","	O
+including	O
+19	O
+%	O
+CR	O
+and	O
+35	O
+%	O
+achieved	O
+at	O
+least	O
+very	O
+good	O
+partial	O
+response	O
+.	O
+	
+Median	O
+durations	O
+of	O
+response	O
+","	O
+time	O
+to	O
+next	O
+therapy	O
+and	O
+treatment	O
+-	O
+free	O
+interval	O
+were	O
+8	O
+","	O
+11	O
+.	O
+2	O
+","	O
+and	O
+5	O
+.	O
+1	O
+months	O
+","	O
+respectively	O
+.	O
+	
+The	O
+most	O
+relevant	O
+adverse	O
+event	O
+was	O
+peripheral	B-NP
+neuropathy	I-NP
+","	O
+which	O
+occurred	O
+in	O
+78	O
+%	O
+of	O
+the	O
+patients	O
+(	O
+grade	O
+II	O
+","	O
+38	O
+%	O
+;	O
+grade	O
+III	O
+","	O
+21	O
+%	O
+)	O
+and	O
+led	O
+to	O
+treatment	O
+discontinuation	O
+in	O
+6	O
+%	O
+.	O
+	
+With	O
+a	O
+median	O
+follow	O
+up	O
+of	O
+22	O
+months	O
+","	O
+median	O
+time	O
+to	O
+progression	O
+","	O
+progression	O
+-	O
+free	O
+survival	O
+(	O
+PFS	O
+)	O
+and	O
+overall	O
+survival	O
+(	O
+OS	O
+)	O
+were	O
+8	O
+.	O
+9	O
+","	O
+8	O
+.	O
+7	O
+","	O
+and	O
+22	O
+months	O
+","	O
+respectively	O
+.	O
+	
+Prolonged	O
+PFS	O
+and	O
+OS	O
+were	O
+observed	O
+in	O
+patients	O
+achieving	O
+CR	O
+and	O
+receiving	O
+bort	O
+-	O
+dex	O
+a	O
+single	O
+line	O
+of	O
+prior	O
+therapy	O
+.	O
+	
+Bort	O
+-	O
+dex	O
+was	O
+an	O
+effective	O
+salvage	O
+treatment	O
+for	O
+MM	B-NP
+patients	O
+","	O
+particularly	O
+for	O
+those	O
+in	O
+first	O
+relapse	O
+.	O
+	
+Pubertal	O
+exposure	O
+to	O
+Bisphenol	O
+A	O
+increases	O
+anxiety	B-NP
+-	O
+like	O
+behavior	O
+and	O
+decreases	O
+acetylcholinesterase	O
+activity	O
+of	O
+hippocampus	O
+in	O
+adult	O
+male	O
+mice	O
+.	O
+	
+The	O
+negative	O
+effects	O
+of	O
+Bisphenol	O
+A	O
+(	O
+BPA	O
+)	O
+on	O
+neurodevelopment	O
+and	O
+behaviors	O
+have	O
+been	O
+well	O
+established	O
+.	O
+	
+Acetylcholinesterase	O
+(	O
+AChE	O
+)	O
+is	O
+a	O
+regulatory	O
+enzyme	O
+which	O
+is	O
+involved	O
+in	O
+anxiety	B-NP
+-	O
+like	O
+behavior	O
+.	O
+	
+This	O
+study	O
+investigated	O
+behavioral	O
+phenotypes	O
+and	O
+AChE	O
+activity	O
+in	O
+male	O
+mice	O
+following	O
+BPA	O
+exposure	O
+during	O
+puberty	O
+.	O
+	
+On	O
+postnatal	O
+day	O
+(	O
+PND	O
+)	O
+35	O
+","	O
+male	O
+mice	O
+were	O
+exposed	O
+to	O
+50mg	O
+BPA	O
+/	O
+kg	O
+diet	O
+per	O
+day	O
+for	O
+a	O
+period	O
+of	O
+35	O
+days	O
+.	O
+	
+On	O
+PND71	O
+","	O
+a	O
+behavioral	O
+assay	O
+was	O
+performed	O
+using	O
+the	O
+elevated	O
+plus	O
+maze	O
+(	O
+EPM	O
+)	O
+and	O
+the	O
+light	O
+/	O
+dark	O
+test	O
+.	O
+	
+In	O
+addition	O
+","	O
+AChE	O
+activity	O
+was	O
+measured	O
+in	O
+the	O
+prefrontal	O
+cortex	O
+","	O
+hypothalamus	O
+","	O
+cerebellum	O
+and	O
+hippocampus	O
+.	O
+	
+Results	O
+from	O
+our	O
+behavioral	O
+phenotyping	O
+indicated	O
+that	O
+anxiety	B-NP
+-	O
+like	O
+behavior	O
+was	O
+increased	O
+in	O
+mice	O
+exposed	O
+to	O
+BPA	O
+.	O
+	
+AChE	O
+activity	O
+was	O
+significantly	O
+decreased	O
+in	O
+the	O
+hippocampus	O
+of	O
+mice	O
+with	O
+BPA	O
+compared	O
+to	O
+control	O
+mice	O
+","	O
+whereas	O
+no	O
+difference	O
+was	O
+found	O
+in	O
+the	O
+prefrontal	O
+cortex	O
+","	O
+hypothalamus	O
+and	O
+cerebellum	O
+.	O
+	
+Our	O
+findings	O
+showed	O
+that	O
+pubertal	O
+BPA	O
+exposure	O
+increased	O
+anxiety	B-NP
+-	O
+like	O
+behavior	O
+","	O
+which	O
+may	O
+be	O
+associated	O
+with	O
+decreased	O
+AChE	O
+activity	O
+of	O
+the	O
+hippocampus	O
+in	O
+adult	O
+male	O
+mice	O
+.	O
+	
+Further	O
+studies	O
+are	O
+necessary	O
+to	O
+investigate	O
+the	O
+cholinergic	O
+signaling	O
+of	O
+the	O
+hippocampus	O
+in	O
+PBE	O
+induced	O
+anxiety	B-NP
+-	O
+like	O
+behaviors	O
+.	O
+	
+Biochemical	O
+effects	O
+of	O
+Solidago	O
+virgaurea	O
+extract	O
+on	O
+experimental	O
+cardiotoxicity	B-NP
+.	O
+	
+Cardiovascular	B-NP
+diseases	I-NP
+(	O
+CVDs	B-NP
+)	O
+are	O
+the	O
+major	O
+health	O
+problem	O
+of	O
+advanced	O
+as	O
+well	O
+as	O
+developing	O
+countries	O
+of	O
+the	O
+world	O
+.	O
+	
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+protective	O
+effect	O
+of	O
+the	O
+Solidago	O
+virgaurea	O
+extract	O
+on	O
+isoproterenol	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+in	O
+rats	O
+.	O
+	
+The	O
+subcutaneous	O
+injection	O
+of	O
+isoproterenol	O
+(	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+into	O
+rats	O
+twice	O
+at	O
+an	O
+interval	O
+of	O
+24	O
+h	O
+","	O
+for	O
+two	O
+consecutive	O
+days	O
+","	O
+led	O
+to	O
+a	O
+significant	O
+increase	O
+in	O
+serum	O
+lactate	O
+dehydrogenase	O
+","	O
+creatine	O
+phosphokinase	O
+","	O
+alanine	O
+transaminase	O
+","	O
+aspartate	O
+transaminase	O
+","	O
+and	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+activities	O
+","	O
+total	O
+cholesterol	O
+","	O
+triglycerides	O
+","	O
+free	O
+serum	O
+fatty	O
+acid	O
+","	O
+cardiac	O
+tissue	O
+malondialdehyde	O
+(	O
+MDA	O
+)	O
+","	O
+and	O
+nitric	O
+oxide	O
+levels	O
+and	O
+a	O
+significant	O
+decrease	O
+in	O
+levels	O
+of	O
+glutathione	O
+and	O
+superoxide	O
+dismutase	O
+in	O
+cardiac	O
+tissue	O
+as	O
+compared	O
+to	O
+the	O
+normal	O
+control	O
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+Pretreatment	O
+with	O
+S	O
+.	O
+virgaurea	O
+extract	O
+for	O
+5	O
+weeks	O
+at	O
+a	O
+dose	O
+of	O
+250	O
+mg	O
+/	O
+kg	O
+followed	O
+by	O
+isoproterenol	O
+injection	O
+significantly	O
+prevented	O
+the	O
+observed	O
+alterations	O
+.	O
+	
+Captopril	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+","	O
+given	O
+orally	O
+)	O
+","	O
+an	O
+inhibitor	O
+of	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+used	O
+as	O
+a	O
+standard	O
+cardioprotective	O
+drug	O
+","	O
+was	O
+used	O
+as	O
+a	O
+positive	O
+control	O
+in	O
+this	O
+study	O
+.	O
+	
+The	O
+data	O
+of	O
+the	O
+present	O
+study	O
+suggest	O
+that	O
+S	O
+.	O
+virgaurea	O
+extract	O
+exerts	O
+its	O
+protective	O
+effect	O
+by	O
+decreasing	O
+MDA	O
+level	O
+and	O
+increasing	O
+the	O
+antioxidant	O
+status	O
+in	O
+isoproterenol	O
+-	O
+treated	O
+rats	O
+.	O
+	
+The	O
+study	O
+emphasizes	O
+the	O
+beneficial	O
+action	O
+of	O
+S	O
+.	O
+virgaurea	O
+extract	O
+as	O
+a	O
+cardioprotective	O
+agent	O
+.	O
+	
+"	O
+Real	O
+-	O
+world	O
+"	O
+data	O
+on	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+lenalidomide	O
+and	O
+dexamethasone	O
+in	O
+patients	O
+with	O
+relapsed	O
+/	O
+refractory	O
+multiple	B-NP
+myeloma	I-NP
+who	O
+were	O
+treated	O
+according	O
+to	O
+the	O
+standard	O
+clinical	O
+practice	O
+:	O
+a	O
+study	O
+of	O
+the	O
+Greek	O
+Myeloma	B-NP
+Study	O
+Group	O
+.	O
+	
+Lenalidomide	O
+and	O
+dexamethasone	O
+(	O
+RD	O
+)	O
+is	O
+a	O
+standard	O
+of	O
+care	O
+for	O
+relapsed	O
+/	O
+refractory	O
+multiple	B-NP
+myeloma	I-NP
+(	O
+RRMM	B-NP
+)	O
+","	O
+but	O
+there	O
+is	O
+limited	O
+published	O
+data	O
+on	O
+its	O
+efficacy	O
+and	O
+safety	O
+in	O
+the	O
+"	O
+real	O
+world	O
+"	O
+(	O
+RW	O
+)	O
+","	O
+according	O
+to	O
+the	O
+International	O
+Society	O
+of	O
+Pharmacoeconomics	O
+and	O
+Outcomes	O
+Research	O
+definition	O
+.	O
+	
+We	O
+studied	O
+212	O
+RRMM	B-NP
+patients	O
+who	O
+received	O
+RD	O
+in	O
+RW	O
+.	O
+	
+Objective	O
+response	O
+(	O
+>	O
+PR	O
+(	O
+partial	O
+response	O
+)	O
+)	O
+rate	O
+was	O
+77	O
+.	O
+4	O
+%	O
+(	O
+complete	O
+response	O
+(	O
+CR	O
+)	O
+","	O
+20	O
+.	O
+2	O
+%	O
+)	O
+.	O
+	
+Median	O
+time	O
+to	O
+first	O
+and	O
+best	O
+response	O
+was	O
+2	O
+and	O
+5	O
+months	O
+","	O
+respectively	O
+.	O
+	
+Median	O
+time	O
+to	O
+CR	O
+when	O
+RD	O
+was	O
+given	O
+as	O
+2nd	O
+or	O
+>	O
+2	O
+(	O
+nd	O
+)	O
+-	O
+line	O
+treatment	O
+at	O
+4	O
+and	O
+11	O
+months	O
+","	O
+respectively	O
+.	O
+	
+Quality	O
+of	O
+response	O
+was	O
+independent	O
+of	O
+previous	O
+lines	O
+of	O
+therapies	O
+or	O
+previous	O
+exposure	O
+to	O
+thalidomide	O
+or	O
+bortezomib	O
+.	O
+	
+Median	O
+duration	O
+of	O
+response	O
+was	O
+34	O
+.	O
+4	O
+months	O
+","	O
+and	O
+it	O
+was	O
+higher	O
+in	O
+patients	O
+who	O
+received	O
+RD	O
+until	O
+progression	O
+(	O
+not	O
+reached	O
+versus	O
+19	O
+months	O
+","	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Improvement	O
+of	O
+humoral	O
+immunity	O
+occurred	O
+in	O
+60	O
+%	O
+of	O
+responders	O
+(	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+and	O
+in	O
+the	O
+majority	O
+of	O
+patients	O
+who	O
+achieved	O
+stable	O
+disease	O
+.	O
+	
+Adverse	O
+events	O
+were	O
+reported	O
+in	O
+68	O
+.	O
+9	O
+%	O
+of	O
+patients	O
+(	O
+myelosuppression	B-NP
+in	O
+49	O
+.	O
+4	O
+%	O
+)	O
+and	O
+12	O
+.	O
+7	O
+%	O
+of	O
+patients	O
+needed	O
+hospitalization	O
+.	O
+	
+Peripheral	B-NP
+neuropathy	I-NP
+was	O
+observed	O
+only	O
+in	O
+2	O
+.	O
+5	O
+%	O
+of	O
+patients	O
+and	O
+deep	B-NP
+vein	I-NP
+thrombosis	I-NP
+in	O
+5	O
+.	O
+7	O
+%	O
+.	O
+	
+Dose	O
+reductions	O
+were	O
+needed	O
+in	O
+31	O
+%	O
+of	O
+patients	O
+and	O
+permanent	O
+discontinuation	O
+in	O
+38	O
+.	O
+9	O
+%	O
+.	O
+	
+Median	O
+time	O
+to	O
+treatment	O
+discontinuation	O
+was	O
+16	O
+.	O
+8	O
+months	O
+.	O
+	
+Performance	O
+status	O
+(	O
+PS	O
+)	O
+and	O
+initial	O
+lenalidomide	O
+dose	O
+predicted	O
+for	O
+treatment	O
+discontinuation	O
+.	O
+	
+Extra	O
+-	O
+medullary	O
+relapses	O
+occurred	O
+in	O
+3	O
+.	O
+8	O
+%	O
+of	O
+patients	O
+.	O
+	
+Our	O
+study	O
+confirms	O
+that	O
+RD	O
+is	O
+effective	O
+and	O
+safe	O
+in	O
+RRMM	B-NP
+in	O
+the	O
+RW	O
+;	O
+it	O
+produces	O
+durable	O
+responses	O
+especially	O
+in	O
+patients	O
+who	O
+continue	O
+on	O
+treatment	O
+till	O
+progression	O
+and	O
+improves	O
+humoral	O
+immunity	O
+even	O
+in	O
+patients	O
+with	O
+stable	O
+disease	O
+.	O
+	
+The	O
+cytogenetic	O
+action	O
+of	O
+ifosfamide	O
+","	O
+mesna	O
+","	O
+and	O
+their	O
+combination	O
+on	O
+peripheral	O
+rabbit	O
+lymphocytes	O
+:	O
+an	O
+in	O
+vivo	O
+/	O
+in	O
+vitro	O
+cytogenetic	O
+study	O
+.	O
+	
+Ifosfamide	O
+(	O
+IFO	O
+)	O
+is	O
+an	O
+alkylating	O
+nitrogen	O
+mustard	O
+","	O
+administrated	O
+as	O
+an	O
+antineoplasmic	O
+agent	O
+.	O
+	
+It	O
+is	O
+characterized	O
+by	O
+its	O
+intense	O
+urotoxic	O
+action	O
+","	O
+leading	O
+to	O
+hemorrhagic	B-NP
+cystitis	I-NP
+.	O
+	
+This	O
+side	O
+effect	O
+of	O
+IFO	O
+raises	O
+the	O
+requirement	O
+for	O
+the	O
+co	O
+-	O
+administration	O
+with	O
+sodium	O
+2	O
+-	O
+sulfanylethanesulfonate	O
+(	O
+Mesna	O
+)	O
+aiming	O
+to	O
+avoid	O
+or	O
+minimize	O
+this	O
+effect	O
+.	O
+	
+IFO	O
+and	O
+Mesna	O
+were	O
+administrated	O
+separately	O
+on	O
+rabbit	O
+'	O
+s	O
+lymphocytes	O
+in	O
+vivo	O
+","	O
+which	O
+were	O
+later	O
+developed	O
+in	O
+vitro	O
+.	O
+	
+Cytogenetic	O
+markers	O
+for	O
+sister	O
+chromatid	O
+exchanges	O
+(	O
+SCEs	O
+)	O
+","	O
+proliferation	O
+rate	O
+index	O
+(	O
+PRI	O
+)	O
+and	O
+Mitotic	O
+Index	O
+were	O
+recorded	O
+.	O
+	
+Mesna	O
+'	O
+s	O
+action	O
+","	O
+in	O
+conjunction	O
+with	O
+IFO	O
+reduces	O
+the	O
+frequency	O
+of	O
+SCEs	O
+","	O
+in	O
+comparison	O
+with	O
+the	O
+SCEs	O
+recordings	O
+obtained	O
+when	O
+IFO	O
+is	O
+administered	O
+alone	O
+.	O
+	
+In	O
+addition	O
+to	O
+this	O
+","	O
+when	O
+high	O
+concentrations	O
+of	O
+Mesna	O
+were	O
+administered	O
+alone	O
+significant	O
+reductions	O
+of	O
+the	O
+PRI	O
+were	O
+noted	O
+","	O
+than	O
+with	O
+IFO	O
+acting	O
+at	O
+the	O
+same	O
+concentration	O
+on	O
+the	O
+lymphocytes	O
+.	O
+	
+Mesna	O
+significantly	O
+reduces	O
+IFO	O
+'	O
+s	O
+genotoxicity	B-NP
+","	O
+while	O
+when	O
+administered	O
+in	O
+high	O
+concentrations	O
+it	O
+acts	O
+in	O
+an	O
+inhibitory	O
+fashion	O
+on	O
+the	O
+cytostatic	O
+action	O
+of	O
+the	O
+drug	O
+.	O
+	
+Risk	O
+factors	O
+and	O
+predictors	O
+of	O
+levodopa	O
+-	O
+induced	O
+dyskinesia	B-NP
+among	O
+multiethnic	O
+Malaysians	O
+with	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+Chronic	O
+pulsatile	O
+levodopa	O
+therapy	O
+for	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+(	O
+PD	B-NP
+)	O
+leads	O
+to	O
+the	O
+development	O
+of	O
+motor	O
+fluctuations	O
+and	O
+dyskinesia	B-NP
+.	O
+	
+We	O
+studied	O
+the	O
+prevalence	O
+and	O
+predictors	O
+of	O
+levodopa	O
+-	O
+induced	O
+dyskinesia	B-NP
+among	O
+multiethnic	O
+Malaysian	O
+patients	O
+with	O
+PD	B-NP
+.	O
+	
+METHODS	O
+:	O
+This	O
+is	O
+a	O
+cross	O
+-	O
+sectional	O
+study	O
+involving	O
+95	O
+patients	O
+with	O
+PD	B-NP
+on	O
+uninterrupted	O
+levodopa	O
+therapy	O
+for	O
+at	O
+least	O
+6	O
+months	O
+.	O
+	
+The	O
+instrument	O
+used	O
+was	O
+the	O
+UPDRS	O
+questionnaires	O
+.	O
+	
+The	O
+predictors	O
+of	O
+dyskinesia	B-NP
+were	O
+determined	O
+using	O
+multivariate	O
+logistic	O
+regression	O
+analysis	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+mean	O
+age	O
+was	O
+65	O
+.	O
+6	O
++	O
+8	O
+.	O
+5	O
+years	O
+.	O
+	
+The	O
+mean	O
+onset	O
+age	O
+was	O
+58	O
+.	O
+5	O
++	O
+9	O
+.	O
+8	O
+years	O
+.	O
+	
+The	O
+median	O
+disease	O
+duration	O
+was	O
+6	O
+(	O
+7	O
+)	O
+years	O
+.	O
+	
+Dyskinesia	B-NP
+was	O
+present	O
+in	O
+44	O
+%	O
+(	O
+n	O
+=	O
+42	O
+)	O
+with	O
+median	O
+levodopa	O
+therapy	O
+of	O
+3	O
+years	O
+.	O
+	
+There	O
+were	O
+64	O
+.	O
+3	O
+%	O
+Chinese	O
+","	O
+31	O
+%	O
+Malays	O
+","	O
+and	O
+3	O
+.	O
+7	O
+%	O
+Indians	O
+and	O
+other	O
+ethnic	O
+groups	O
+.	O
+	
+Eighty	O
+-	O
+one	O
+percent	O
+of	O
+patients	O
+with	O
+dyskinesia	B-NP
+had	O
+clinical	O
+fluctuations	O
+.	O
+	
+Patients	O
+with	O
+dyskinesia	B-NP
+had	O
+lower	O
+onset	O
+age	O
+(	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+","	O
+longer	O
+duration	O
+of	O
+levodopa	O
+therapy	O
+(	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+","	O
+longer	O
+disease	O
+duration	O
+(	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+","	O
+higher	O
+total	O
+daily	O
+levodopa	O
+dose	O
+(	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+","	O
+and	O
+higher	O
+total	O
+UPDRS	O
+scores	O
+(	O
+p	O
+=	O
+0	O
+.	O
+5	O
+)	O
+than	O
+patients	O
+without	O
+dyskinesia	B-NP
+.	O
+	
+The	O
+three	O
+significant	O
+predictors	O
+of	O
+dyskinesia	B-NP
+were	O
+duration	O
+of	O
+levodopa	O
+therapy	O
+","	O
+onset	O
+age	O
+","	O
+and	O
+total	O
+daily	O
+levodopa	O
+dose	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+prevalence	O
+of	O
+levodopa	O
+-	O
+induced	O
+dyskinesia	B-NP
+in	O
+our	O
+patients	O
+was	O
+44	O
+%	O
+.	O
+	
+The	O
+most	O
+significant	O
+predictors	O
+were	O
+duration	O
+of	O
+levodopa	O
+therapy	O
+","	O
+total	O
+daily	O
+levodopa	O
+dose	O
+","	O
+and	O
+onset	O
+age	O
+.	O
+	
+Dose	O
+-	O
+dependent	O
+neurotoxicity	B-NP
+of	O
+high	O
+-	O
+dose	O
+busulfan	O
+in	O
+children	O
+:	O
+a	O
+clinical	O
+and	O
+pharmacological	O
+study	O
+.	O
+	
+Busulfan	O
+is	O
+known	O
+to	O
+be	O
+neurotoxic	B-NP
+in	O
+animals	O
+and	O
+humans	O
+","	O
+but	O
+its	O
+acute	O
+neurotoxicity	B-NP
+remains	O
+poorly	O
+characterized	O
+in	O
+children	O
+.	O
+	
+We	O
+report	O
+here	O
+a	O
+retrospective	O
+study	O
+of	O
+123	O
+children	O
+(	O
+median	O
+age	O
+","	O
+6	O
+.	O
+5	O
+years	O
+)	O
+receiving	O
+high	O
+-	O
+dose	O
+busulfan	O
+in	O
+combined	O
+chemotherapy	O
+before	O
+bone	O
+marrow	O
+transplantation	O
+for	O
+malignant	O
+solid	O
+tumors	B-NP
+","	O
+brain	B-NP
+tumors	I-NP
+excluded	O
+.	O
+	
+Busulfan	O
+was	O
+given	O
+p	O
+.	O
+o	O
+.	O
+","	O
+every	O
+6	O
+hours	O
+for	O
+16	O
+doses	O
+over	O
+4	O
+days	O
+.	O
+	
+Two	O
+total	O
+doses	O
+were	O
+consecutively	O
+used	O
+:	O
+16	O
+mg	O
+/	O
+kg	O
+","	O
+then	O
+600	O
+mg	O
+/	O
+m2	O
+.	O
+	
+The	O
+dose	O
+calculation	O
+on	O
+the	O
+basis	O
+of	O
+body	O
+surface	O
+area	O
+results	O
+in	O
+higher	O
+doses	O
+in	O
+young	O
+children	O
+than	O
+in	O
+older	O
+patients	O
+(	O
+16	O
+to	O
+28	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+	
+Ninety	O
+-	O
+six	O
+patients	O
+were	O
+not	O
+given	O
+anticonvulsive	O
+prophylaxis	O
+;	O
+7	O
+(	O
+7	O
+.	O
+5	O
+%	O
+)	O
+developed	O
+seizures	B-NP
+during	O
+the	O
+4	O
+days	O
+of	O
+the	O
+busulfan	O
+course	O
+or	O
+within	O
+24	O
+h	O
+after	O
+the	O
+last	O
+dosing	O
+.	O
+	
+When	O
+the	O
+total	O
+busulfan	O
+dose	O
+was	O
+taken	O
+into	O
+account	O
+","	O
+there	O
+was	O
+a	O
+significant	O
+difference	O
+in	O
+terms	O
+of	O
+neurotoxicity	B-NP
+incidence	O
+among	O
+patients	O
+under	O
+16	O
+mg	O
+/	O
+kg	O
+(	O
+1	O
+of	O
+57	O
+","	O
+1	O
+.	O
+7	O
+%	O
+)	O
+and	O
+patients	O
+under	O
+600	O
+mg	O
+/	O
+m2	O
+(	O
+6	O
+of	O
+39	O
+","	O
+15	O
+.	O
+4	O
+%	O
+)	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+2	O
+)	O
+.	O
+	
+Twenty	O
+-	O
+seven	O
+patients	O
+were	O
+given	O
+a	O
+600	O
+-	O
+mg	O
+/	O
+m2	O
+busulfan	O
+total	O
+dose	O
+with	O
+continuous	O
+i	O
+.	O
+v	O
+.	O
+infusion	O
+of	O
+clonazepam	O
+;	O
+none	O
+had	O
+any	O
+neurological	B-NP
+symptoms	I-NP
+.	O
+	
+Busulfan	O
+levels	O
+were	O
+measured	O
+by	O
+a	O
+gas	O
+chromatographic	O
+-	O
+mass	O
+spectrometry	O
+assay	O
+in	O
+the	O
+plasma	O
+and	O
+cerebrospinal	O
+fluid	O
+of	O
+9	O
+children	O
+without	O
+central	B-NP
+nervous	I-NP
+system	I-NP
+disease	I-NP
+under	O
+600	O
+mg	O
+/	O
+m2	O
+busulfan	O
+with	O
+clonazepam	O
+:	O
+busulfan	O
+cerebrospinal	O
+fluid	O
+:	O
+plasma	O
+ratio	O
+was	O
+1	O
+.	O
+39	O
+.	O
+	
+This	O
+was	O
+significantly	O
+different	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+2	O
+)	O
+from	O
+the	O
+cerebrospinal	O
+fluid	O
+:	O
+plasma	O
+ratio	O
+previously	O
+defined	O
+in	O
+children	O
+receiving	O
+a	O
+16	O
+-	O
+mg	O
+/	O
+kg	O
+total	O
+dose	O
+of	O
+busulfan	O
+.	O
+	
+This	O
+study	O
+shows	O
+that	O
+busulfan	O
+neurotoxicity	B-NP
+is	O
+dose	O
+-	O
+dependent	O
+in	O
+children	O
+and	O
+efficiently	O
+prevented	O
+by	O
+clonazepam	O
+.	O
+	
+A	O
+busulfan	O
+dose	O
+calculated	O
+on	O
+the	O
+basis	O
+of	O
+body	O
+surface	O
+area	O
+","	O
+resulting	O
+in	O
+higher	O
+doses	O
+in	O
+young	O
+children	O
+","	O
+was	O
+followed	O
+by	O
+increased	O
+neurotoxicity	B-NP
+","	O
+close	O
+to	O
+neurotoxicity	B-NP
+incidence	O
+observed	O
+in	O
+adults	O
+.	O
+	
+Since	O
+plasma	O
+pharmacokinetic	O
+studies	O
+showed	O
+a	O
+faster	O
+busulfan	O
+clearance	O
+in	O
+children	O
+than	O
+in	O
+adults	O
+","	O
+this	O
+new	O
+dose	O
+may	O
+approximate	O
+more	O
+closely	O
+the	O
+adult	O
+systemic	O
+exposure	O
+obtained	O
+after	O
+the	O
+usual	O
+16	O
+-	O
+mg	O
+/	O
+kg	O
+total	O
+dose	O
+","	O
+with	O
+potential	O
+inferences	O
+in	O
+terms	O
+of	O
+anticancer	O
+or	O
+myeloablative	O
+effects	O
+.	O
+	
+The	O
+busulfan	O
+dose	O
+in	O
+children	O
+and	O
+infants	O
+undergoing	O
+bone	O
+marrow	O
+transplantation	O
+should	O
+be	O
+reconsidered	O
+on	O
+the	O
+basis	O
+of	O
+pharmacokinetic	O
+studies	O
+.	O
+	
+An	O
+unexpected	O
+diagnosis	O
+in	O
+a	O
+renal	O
+-	O
+transplant	O
+patient	O
+with	O
+proteinuria	B-NP
+treated	O
+with	O
+everolimus	O
+:	O
+AL	B-NP
+amyloidosis	B-NP
+.	O
+	
+Proteinuria	B-NP
+is	O
+an	O
+expected	O
+complication	O
+in	O
+transplant	O
+patients	O
+treated	O
+with	O
+mammalian	O
+target	O
+of	O
+rapamycin	O
+inhibitors	O
+(	O
+mTOR	O
+-	O
+i	O
+)	O
+.	O
+	
+However	O
+","	O
+clinical	O
+suspicion	O
+should	O
+always	O
+be	O
+supported	O
+by	O
+histological	O
+evidence	O
+in	O
+order	O
+to	O
+investigate	O
+potential	O
+alternate	O
+diagnoses	O
+such	O
+as	O
+acute	O
+or	O
+chronic	O
+rejection	O
+","	O
+interstitial	O
+fibrosis	B-NP
+and	O
+tubular	O
+atrophy	B-NP
+","	O
+or	O
+recurrent	O
+or	O
+de	O
+novo	O
+glomerulopathy	B-NP
+.	O
+	
+In	O
+this	O
+case	O
+we	O
+report	O
+the	O
+unexpected	O
+diagnosis	O
+of	O
+amyloidosis	B-NP
+in	O
+a	O
+renal	O
+-	O
+transplant	O
+patient	O
+with	O
+pre	O
+-	O
+transplant	O
+monoclonal	O
+gammapathy	O
+of	O
+undetermined	O
+significance	O
+who	O
+developed	O
+proteinuria	B-NP
+after	O
+conversion	O
+from	O
+tacrolimus	O
+to	O
+everolimus	O
+.	O
+	
+Long	O
+-	O
+term	O
+oral	O
+galactose	O
+treatment	O
+prevents	O
+cognitive	B-NP
+deficits	I-NP
+in	O
+male	O
+Wistar	O
+rats	O
+treated	O
+intracerebroventricularly	O
+with	O
+streptozotocin	O
+.	O
+	
+Basic	O
+and	O
+clinical	O
+research	O
+has	O
+demonstrated	O
+that	O
+dementia	B-NP
+of	O
+sporadic	O
+Alzheimer	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+(	O
+sAD	O
+)	O
+type	O
+is	O
+associated	O
+with	O
+dysfunction	O
+of	O
+the	O
+insulin	O
+-	O
+receptor	O
+(	O
+IR	O
+)	O
+system	O
+followed	O
+by	O
+decreased	O
+glucose	O
+transport	O
+via	O
+glucose	O
+transporter	O
+GLUT4	O
+and	O
+decreased	O
+glucose	O
+metabolism	O
+in	O
+brain	O
+cells	O
+.	O
+	
+An	O
+alternative	O
+source	O
+of	O
+energy	O
+is	O
+d	O
+-	O
+galactose	O
+(	O
+the	O
+C	O
+-	O
+4	O
+-	O
+epimer	O
+of	O
+d	O
+-	O
+glucose	O
+)	O
+which	O
+is	O
+transported	O
+into	O
+the	O
+brain	O
+by	O
+insulin	O
+-	O
+independent	O
+GLUT3	O
+transporter	O
+where	O
+it	O
+might	O
+be	O
+metabolized	O
+to	O
+glucose	O
+via	O
+the	O
+Leloir	O
+pathway	O
+.	O
+	
+Exclusively	O
+parenteral	O
+daily	O
+injections	O
+of	O
+galactose	O
+induce	O
+memory	B-NP
+deterioration	I-NP
+in	O
+rodents	O
+and	O
+are	O
+used	O
+to	O
+generate	O
+animal	O
+aging	O
+model	O
+","	O
+but	O
+the	O
+effects	O
+of	O
+oral	O
+galactose	O
+treatment	O
+on	O
+cognitive	O
+functions	O
+have	O
+never	O
+been	O
+tested	O
+.	O
+	
+We	O
+have	O
+investigated	O
+the	O
+effects	O
+of	O
+continuous	O
+daily	O
+oral	O
+galactose	O
+(	O
+200	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+)	O
+treatment	O
+on	O
+cognitive	B-NP
+deficits	I-NP
+in	O
+streptozotocin	O
+-	O
+induced	O
+(	O
+STZ	O
+-	O
+icv	O
+)	O
+rat	O
+model	O
+of	O
+sAD	O
+","	O
+tested	O
+by	O
+Morris	O
+Water	O
+Maze	O
+and	O
+Passive	O
+Avoidance	O
+test	O
+","	O
+respectively	O
+.	O
+	
+One	O
+month	O
+of	O
+oral	O
+galactose	O
+treatment	O
+initiated	O
+immediately	O
+after	O
+the	O
+STZ	O
+-	O
+icv	O
+administration	O
+","	O
+successfully	O
+prevented	O
+development	O
+of	O
+the	O
+STZ	O
+-	O
+icv	O
+-	O
+induced	O
+cognitive	B-NP
+deficits	I-NP
+.	O
+	
+Beneficial	O
+effect	O
+of	O
+oral	O
+galactose	O
+was	O
+independent	O
+of	O
+the	O
+rat	O
+age	O
+and	O
+of	O
+the	O
+galactose	O
+dose	O
+ranging	O
+from	O
+100	O
+to	O
+300	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+.	O
+	
+Additionally	O
+","	O
+oral	O
+galactose	O
+administration	O
+led	O
+to	O
+the	O
+appearance	O
+of	O
+galactose	O
+in	O
+the	O
+blood	O
+.	O
+	
+The	O
+increase	O
+of	O
+galactose	O
+concentration	O
+in	O
+the	O
+cerebrospinal	O
+fluid	O
+was	O
+several	O
+times	O
+lower	O
+after	O
+oral	O
+than	O
+after	O
+parenteral	O
+administration	O
+of	O
+the	O
+same	O
+galactose	O
+dose	O
+.	O
+	
+Oral	O
+galactose	O
+exposure	O
+might	O
+have	O
+beneficial	O
+effects	O
+on	O
+learning	O
+and	O
+memory	O
+ability	O
+and	O
+could	O
+be	O
+worth	O
+investigating	O
+for	O
+improvement	O
+of	O
+cognitive	B-NP
+deficits	I-NP
+associated	O
+with	O
+glucose	B-NP
+hypometabolism	I-NP
+in	O
+AD	B-NP
+.	O
+	
+An	O
+investigation	O
+of	O
+the	O
+pattern	O
+of	O
+kidney	B-NP
+injury	I-NP
+in	O
+HIV	O
+-	O
+positive	O
+persons	O
+exposed	O
+to	O
+tenofovir	O
+disoproxil	O
+fumarate	O
+:	O
+an	O
+examination	O
+of	O
+a	O
+large	O
+population	O
+database	O
+(	O
+MHRA	O
+database	O
+)	O
+.	O
+	
+The	O
+potential	O
+for	O
+tenofovir	O
+to	O
+cause	O
+a	O
+range	O
+of	O
+kidney	O
+syndromes	O
+has	O
+been	O
+established	O
+from	O
+mechanistic	O
+and	O
+randomised	O
+clinical	O
+trials	O
+.	O
+	
+However	O
+","	O
+the	O
+exact	O
+pattern	O
+of	O
+kidney	O
+involvement	O
+is	O
+still	O
+uncertain	O
+.	O
+	
+We	O
+undertook	O
+a	O
+descriptive	O
+analysis	O
+of	O
+Yellow	O
+Card	O
+records	O
+of	O
+407	O
+HIV	O
+-	O
+positive	O
+persons	O
+taking	O
+tenofovir	O
+disoproxil	O
+fumarate	O
+(	O
+TDF	O
+)	O
+as	O
+part	O
+of	O
+their	O
+antiretroviral	O
+therapy	O
+regimen	O
+and	O
+submitted	O
+to	O
+the	O
+Medicines	O
+and	O
+Healthcare	O
+Products	O
+Regulatory	O
+Agency	O
+(	O
+MHRA	O
+)	O
+with	O
+suspected	O
+kidney	O
+adverse	O
+effects	O
+.	O
+	
+Reports	O
+that	O
+satisfy	O
+defined	O
+criteria	O
+were	O
+classified	O
+as	O
+acute	B-NP
+kidney	I-NP
+injury	I-NP
+","	O
+kidney	B-NP
+tubular	I-NP
+dysfunction	I-NP
+and	O
+Fanconi	B-NP
+syndrome	I-NP
+.	O
+	
+Of	O
+the	O
+407	O
+Yellow	O
+Card	O
+records	O
+analysed	O
+","	O
+106	O
+satisfied	O
+criteria	O
+for	O
+TDF	O
+-	O
+related	O
+kidney	B-NP
+disease	I-NP
+","	O
+of	O
+which	O
+53	O
+(	O
+50	O
+%	O
+)	O
+had	O
+features	O
+of	O
+kidney	B-NP
+tubular	I-NP
+dysfunction	I-NP
+","	O
+35	O
+(	O
+33	O
+%	O
+)	O
+were	O
+found	O
+to	O
+have	O
+features	O
+of	O
+glomerular	B-NP
+dysfunction	I-NP
+and	O
+18	O
+(	O
+17	O
+%	O
+)	O
+had	O
+Fanconi	B-NP
+syndrome	I-NP
+.	O
+	
+The	O
+median	O
+TDF	O
+exposure	O
+was	O
+316	O
+days	O
+(	O
+interquartile	O
+range	O
+120	O
+-	O
+740	O
+)	O
+.	O
+	
+The	O
+incidence	O
+of	O
+hospitalisation	O
+for	O
+TDF	O
+kidney	O
+adverse	O
+effects	O
+was	O
+high	O
+","	O
+particularly	O
+amongst	O
+patients	O
+with	O
+features	O
+of	O
+Fanconi	B-NP
+syndrome	I-NP
+.	O
+	
+The	O
+pattern	O
+of	O
+kidney	O
+syndromes	O
+in	O
+this	O
+population	O
+series	O
+mirrors	O
+that	O
+reported	O
+in	O
+randomised	O
+clinical	O
+trials	O
+.	O
+	
+Cessation	O
+of	O
+TDF	O
+was	O
+associated	O
+with	O
+complete	O
+restoration	O
+of	O
+kidney	O
+function	O
+in	O
+up	O
+half	O
+of	O
+the	O
+patients	O
+in	O
+this	O
+report	O
+.	O
+	
+Incidence	O
+of	O
+postoperative	B-NP
+delirium	I-NP
+is	O
+high	O
+even	O
+in	O
+a	O
+population	O
+without	O
+known	O
+risk	O
+factors	O
+.	O
+	
+PURPOSE	O
+:	O
+Postoperative	B-NP
+delirium	I-NP
+is	O
+a	O
+recognized	O
+complication	O
+in	O
+populations	O
+at	O
+risk	O
+.	O
+	
+The	O
+aim	O
+of	O
+this	O
+study	O
+is	O
+to	O
+assess	O
+the	O
+prevalence	O
+of	O
+early	O
+postoperative	B-NP
+delirium	I-NP
+in	O
+a	O
+population	O
+without	O
+known	O
+risk	O
+factors	O
+admitted	O
+to	O
+the	O
+ICU	O
+for	O
+postoperative	O
+monitoring	O
+after	O
+elective	O
+major	O
+surgery	O
+.	O
+	
+The	O
+secondary	O
+outcome	O
+investigated	O
+is	O
+to	O
+identify	O
+eventual	O
+independent	O
+risk	O
+factors	O
+among	O
+demographic	O
+data	O
+and	O
+anesthetic	O
+drugs	O
+used	O
+.	O
+	
+METHODS	O
+:	O
+An	O
+observational	O
+","	O
+prospective	O
+study	O
+was	O
+conducted	O
+on	O
+a	O
+consecutive	O
+cohort	O
+of	O
+patients	O
+admitted	O
+to	O
+our	O
+ICU	O
+within	O
+and	O
+for	O
+at	O
+least	O
+24	O
+h	O
+after	O
+major	O
+surgical	O
+procedures	O
+.	O
+	
+Exclusion	O
+criteria	O
+were	O
+any	O
+preexisting	O
+predisposing	O
+factor	O
+for	O
+delirium	B-NP
+or	O
+other	O
+potentially	O
+confounding	O
+neurological	B-NP
+dysfunctions	I-NP
+.	O
+	
+Patients	O
+were	O
+assessed	O
+daily	O
+using	O
+the	O
+confusion	B-NP
+assessment	O
+method	O
+for	O
+the	O
+ICU	O
+scale	O
+for	O
+3	O
+days	O
+after	O
+the	O
+surgical	O
+procedure	O
+.	O
+	
+Early	O
+postoperative	B-NP
+delirium	I-NP
+incidence	O
+risk	O
+factors	O
+were	O
+then	O
+assessed	O
+through	O
+three	O
+different	O
+multiple	O
+regression	O
+models	O
+.	O
+	
+RESULTS	O
+:	O
+According	O
+to	O
+the	O
+confusion	O
+assessment	O
+method	O
+for	O
+the	O
+ICU	O
+scale	O
+","	O
+28	O
+%	O
+of	O
+patients	O
+were	O
+diagnosed	O
+with	O
+early	O
+postoperative	B-NP
+delirium	I-NP
+.	O
+	
+The	O
+use	O
+of	O
+thiopentone	O
+was	O
+significantly	O
+associated	O
+with	O
+an	O
+eight	O
+-	O
+fold	O
+-	O
+higher	O
+risk	O
+for	O
+delirium	B-NP
+compared	O
+to	O
+propofol	O
+(	O
+57	O
+.	O
+1	O
+%	O
+vs	O
+.	O
+7	O
+.	O
+1	O
+%	O
+","	O
+RR	O
+=	O
+8	O
+.	O
+0	O
+","	O
+X2	O
+=	O
+4	O
+.	O
+256	O
+;	O
+df	O
+=	O
+1	O
+;	O
+0	O
+.	O
+5	O
+<	O
+p	O
+<	O
+0	O
+.	O
+2	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+In	O
+this	O
+study	O
+early	O
+postoperative	B-NP
+delirium	I-NP
+was	O
+found	O
+to	O
+be	O
+a	O
+very	O
+common	O
+complication	O
+after	O
+major	O
+surgery	O
+","	O
+even	O
+in	O
+a	O
+population	O
+without	O
+known	O
+risk	O
+factors	O
+.	O
+	
+Thiopentone	O
+was	O
+independently	O
+associated	O
+with	O
+an	O
+increase	O
+in	O
+its	O
+relative	O
+risk	O
+.	O
+	
+A	O
+single	O
+neurotoxic	B-NP
+dose	O
+of	O
+methamphetamine	O
+induces	O
+a	O
+long	O
+-	O
+lasting	O
+depressive	B-NP
+-	O
+like	O
+behaviour	O
+in	O
+mice	O
+.	O
+	
+Methamphetamine	O
+(	O
+METH	O
+)	O
+triggers	O
+a	O
+disruption	O
+of	O
+the	O
+monoaminergic	O
+system	O
+and	O
+METH	O
+abuse	O
+leads	O
+to	O
+negative	O
+emotional	O
+states	O
+including	O
+depressive	B-NP
+symptoms	I-NP
+during	O
+drug	O
+withdrawal	O
+.	O
+	
+However	O
+","	O
+it	O
+is	O
+currently	O
+unknown	O
+if	O
+the	O
+acute	O
+toxic	O
+dosage	O
+of	O
+METH	O
+also	O
+causes	O
+a	O
+long	O
+-	O
+lasting	O
+depressive	B-NP
+phenotype	O
+and	O
+persistent	O
+monoaminergic	O
+deficits	O
+.	O
+	
+Thus	O
+","	O
+we	O
+now	O
+assessed	O
+the	O
+depressive	B-NP
+-	O
+like	O
+behaviour	O
+in	O
+mice	O
+at	O
+early	O
+and	O
+long	O
+-	O
+term	O
+periods	O
+following	O
+a	O
+single	O
+high	O
+METH	O
+dose	O
+(	O
+30	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+	
+METH	O
+did	O
+not	O
+alter	O
+the	O
+motor	O
+function	O
+and	O
+procedural	O
+memory	O
+of	O
+mice	O
+as	O
+assessed	O
+by	O
+swimming	O
+speed	O
+and	O
+escape	O
+latency	O
+to	O
+find	O
+the	O
+platform	O
+in	O
+a	O
+cued	O
+version	O
+of	O
+the	O
+water	O
+maze	O
+task	O
+.	O
+	
+However	O
+","	O
+METH	O
+significantly	O
+increased	O
+the	O
+immobility	O
+time	O
+in	O
+the	O
+tail	O
+suspension	O
+test	O
+at	O
+3	O
+and	O
+49	O
+days	O
+post	O
+-	O
+administration	O
+.	O
+	
+This	O
+depressive	B-NP
+-	O
+like	O
+profile	O
+induced	O
+by	O
+METH	O
+was	O
+accompanied	O
+by	O
+a	O
+marked	O
+depletion	O
+of	O
+frontostriatal	O
+dopaminergic	O
+and	O
+serotonergic	O
+neurotransmission	O
+","	O
+indicated	O
+by	O
+a	O
+reduction	O
+in	O
+the	O
+levels	O
+of	O
+dopamine	O
+","	O
+DOPAC	O
+and	O
+HVA	O
+","	O
+tyrosine	O
+hydroxylase	O
+and	O
+serotonin	O
+","	O
+observed	O
+at	O
+both	O
+3	O
+and	O
+49	O
+days	O
+post	O
+-	O
+administration	O
+.	O
+	
+In	O
+parallel	O
+","	O
+another	O
+neurochemical	O
+feature	O
+of	O
+depression	B-NP
+-	O
+-	O
+astroglial	O
+dysfunction	O
+-	O
+-	O
+was	O
+unaffected	O
+in	O
+the	O
+cortex	O
+and	O
+the	O
+striatal	O
+levels	O
+of	O
+the	O
+astrocytic	O
+protein	O
+marker	O
+","	O
+glial	O
+fibrillary	O
+acidic	O
+protein	O
+","	O
+were	O
+only	O
+transiently	O
+increased	O
+at	O
+3	O
+days	O
+.	O
+	
+These	O
+findings	O
+demonstrate	O
+for	O
+the	O
+first	O
+time	O
+that	O
+a	O
+single	O
+high	O
+dose	O
+of	O
+METH	O
+induces	O
+long	O
+-	O
+lasting	O
+depressive	B-NP
+-	O
+like	O
+behaviour	O
+in	O
+mice	O
+associated	O
+with	O
+a	O
+persistent	O
+disruption	O
+of	O
+frontostriatal	O
+dopaminergic	O
+and	O
+serotonergic	O
+homoeostasis	O
+.	O
+	
+Linezolid	O
+-	O
+induced	O
+optic	B-NP
+neuropathy	I-NP
+.	O
+	
+Many	O
+systemic	O
+antimicrobials	O
+have	O
+been	O
+implicated	O
+to	O
+cause	O
+ocular	O
+adverse	O
+effects	O
+.	O
+	
+This	O
+is	O
+especially	O
+relevant	O
+in	O
+multidrug	O
+therapy	O
+where	O
+more	O
+than	O
+one	O
+drug	O
+can	O
+cause	O
+a	O
+similar	O
+ocular	O
+adverse	O
+effect	O
+.	O
+	
+We	O
+describe	O
+a	O
+case	O
+of	O
+progressive	O
+loss	B-NP
+of	I-NP
+vision	I-NP
+associated	O
+with	O
+linezolid	O
+therapy	O
+.	O
+	
+A	O
+45	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+who	O
+was	O
+on	O
+treatment	O
+with	O
+multiple	O
+second	O
+-	O
+line	O
+anti	O
+-	O
+tuberculous	O
+drugs	O
+including	O
+linezolid	O
+and	O
+ethambutol	O
+for	O
+extensively	B-NP
+drug	I-NP
+-	I-NP
+resistant	I-NP
+tuberculosis	I-NP
+(	O
+XDR	B-NP
+-	I-NP
+TB	I-NP
+)	O
+presented	O
+to	O
+us	O
+with	O
+painless	O
+progressive	O
+loss	B-NP
+of	I-NP
+vision	I-NP
+in	O
+both	O
+eyes	O
+.	O
+	
+Color	O
+vision	O
+was	O
+defective	O
+and	O
+fundus	O
+examination	O
+revealed	O
+optic	B-NP
+disc	I-NP
+edema	I-NP
+in	O
+both	O
+eyes	O
+.	O
+	
+Ethambutol	O
+-	O
+induced	O
+toxic	B-NP
+optic	I-NP
+neuropathy	I-NP
+was	O
+suspected	O
+and	O
+tablet	O
+ethambutol	O
+was	O
+withdrawn	O
+.	O
+	
+Deterioration	B-NP
+of	I-NP
+vision	I-NP
+occurred	O
+despite	O
+withdrawal	O
+of	O
+ethambutol	O
+.	O
+	
+Discontinuation	O
+of	O
+linezolid	O
+resulted	O
+in	O
+marked	O
+improvement	O
+of	O
+vision	O
+.	O
+	
+Our	O
+report	O
+emphasizes	O
+the	O
+need	O
+for	O
+monitoring	O
+of	O
+visual	O
+function	O
+in	O
+patients	O
+on	O
+long	O
+-	O
+term	O
+linezolid	O
+treatment	O
+.	O
+	
+Resuscitation	O
+with	O
+lipid	O
+","	O
+epinephrine	O
+","	O
+or	O
+both	O
+in	O
+levobupivacaine	O
+-	O
+induced	O
+cardiac	B-NP
+toxicity	I-NP
+in	O
+newborn	O
+piglets	O
+.	O
+	
+BACKGROUND	O
+:	O
+The	O
+optimal	O
+dosing	O
+regimens	O
+of	O
+lipid	O
+emulsion	O
+","	O
+epinephrine	O
+","	O
+or	O
+both	O
+are	O
+not	O
+yet	O
+determined	O
+in	O
+neonates	O
+in	O
+cases	O
+of	O
+local	O
+anaesthetic	O
+systemic	O
+toxicity	B-NP
+(	O
+LAST	O
+)	O
+.	O
+	
+METHODS	O
+:	O
+Newborn	O
+piglets	O
+received	O
+levobupivacaine	O
+until	O
+cardiovascular	B-NP
+collapse	I-NP
+occurred	O
+.	O
+	
+Standard	O
+cardiopulmonary	O
+resuscitation	O
+was	O
+started	O
+and	O
+electrocardiogram	O
+(	O
+ECG	O
+)	O
+was	O
+monitored	O
+for	O
+ventricular	B-NP
+tachycardia	I-NP
+","	O
+fibrillation	B-NP
+","	O
+or	O
+QRS	O
+prolongation	O
+.	O
+	
+Piglets	O
+were	O
+then	O
+randomly	O
+allocated	O
+to	O
+four	O
+groups	O
+:	O
+control	O
+(	O
+saline	O
+)	O
+","	O
+Intralipid	O
+(	O
+)	O
+alone	O
+","	O
+epinephrine	O
+alone	O
+","	O
+or	O
+a	O
+combination	O
+of	O
+Intralipd	O
+plus	O
+epinephrine	O
+.	O
+	
+Resuscitation	O
+continued	O
+for	O
+30	O
+min	O
+or	O
+until	O
+there	O
+was	O
+a	O
+return	O
+of	O
+spontaneous	O
+circulation	O
+(	O
+ROSC	O
+)	O
+accompanied	O
+by	O
+a	O
+mean	O
+arterial	O
+pressure	O
+at	O
+or	O
+superior	O
+to	O
+the	O
+baseline	O
+pressure	O
+and	O
+normal	O
+sinus	O
+rhythm	O
+for	O
+a	O
+period	O
+of	O
+30	O
+min	O
+.	O
+	
+RESULTS	O
+:	O
+ROSC	O
+was	O
+achieved	O
+in	O
+only	O
+one	O
+of	O
+the	O
+control	O
+piglets	O
+compared	O
+with	O
+most	O
+of	O
+the	O
+treated	O
+piglets	O
+.	O
+	
+Mortality	O
+was	O
+not	O
+significantly	O
+different	O
+between	O
+the	O
+three	O
+treatment	O
+groups	O
+","	O
+but	O
+was	O
+significantly	O
+lower	O
+in	O
+all	O
+the	O
+treatment	O
+groups	O
+compared	O
+with	O
+control	O
+.	O
+	
+The	O
+number	O
+of	O
+ECG	O
+abnormalities	O
+was	O
+zero	O
+in	O
+the	O
+Intralipid	O
+only	O
+group	O
+","	O
+but	O
+14	O
+and	O
+17	O
+","	O
+respectively	O
+","	O
+in	O
+the	O
+epinephrine	O
+and	O
+epinephrine	O
+plus	O
+lipid	O
+groups	O
+(	O
+P	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Lipid	O
+emulsion	O
+with	O
+or	O
+without	O
+epinephrine	O
+","	O
+or	O
+epinephrine	O
+alone	O
+were	O
+equally	O
+effective	O
+in	O
+achieving	O
+a	O
+return	O
+to	O
+spontaneous	O
+circulation	O
+in	O
+this	O
+model	O
+of	O
+LAST	O
+.	O
+	
+Epinephrine	O
+alone	O
+or	O
+in	O
+combination	O
+with	O
+lipid	O
+was	O
+associated	O
+with	O
+an	O
+increased	O
+number	O
+of	O
+ECG	O
+abnormalities	O
+compared	O
+with	O
+lipid	O
+emulsion	O
+alone	O
+.	O
+	
+Incidence	O
+of	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+type	I-NP
+II	I-NP
+and	O
+postoperative	O
+recovery	O
+of	O
+platelet	O
+count	O
+in	O
+liver	O
+graft	O
+recipients	O
+:	O
+a	O
+retrospective	O
+cohort	O
+analysis	O
+.	O
+	
+BACKGROUND	O
+:	O
+Thrombocytopenia	B-NP
+in	O
+patients	O
+with	O
+end	B-NP
+-	I-NP
+stage	I-NP
+liver	I-NP
+disease	I-NP
+is	O
+a	O
+common	O
+disorder	O
+caused	O
+mainly	O
+by	O
+portal	B-NP
+hypertension	I-NP
+","	O
+low	O
+levels	O
+of	O
+thrombopoetin	O
+","	O
+and	O
+endotoxemia	B-NP
+.	O
+	
+The	O
+impact	O
+of	O
+immune	O
+-	O
+mediated	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+type	I-NP
+II	I-NP
+(	O
+HIT	B-NP
+type	I-NP
+II	I-NP
+)	O
+as	O
+a	O
+cause	O
+of	O
+thrombocytopenia	B-NP
+after	O
+liver	O
+transplantation	O
+is	O
+not	O
+yet	O
+understood	O
+","	O
+with	O
+few	O
+literature	O
+citations	O
+reporting	O
+contradictory	O
+results	O
+.	O
+	
+The	O
+aim	O
+of	O
+our	O
+study	O
+was	O
+to	O
+demonstrate	O
+the	O
+perioperative	O
+course	O
+of	O
+thrombocytopenia	B-NP
+after	O
+liver	O
+transplantation	O
+and	O
+determine	O
+the	O
+occurrence	O
+of	O
+clinical	O
+HIT	B-NP
+type	I-NP
+II	I-NP
+.	O
+	
+METHOD	O
+:	O
+We	O
+retrospectively	O
+evaluated	O
+the	O
+medical	O
+records	O
+of	O
+205	O
+consecutive	O
+adult	O
+patients	O
+who	O
+underwent	O
+full	O
+-	O
+size	O
+liver	O
+transplantation	O
+between	O
+January	O
+2006	O
+and	O
+December	O
+2010	O
+due	O
+to	O
+end	B-NP
+-	I-NP
+stage	I-NP
+or	I-NP
+malignant	I-NP
+liver	I-NP
+disease	I-NP
+.	O
+	
+Preoperative	O
+platelet	O
+count	O
+","	O
+postoperative	O
+course	O
+of	O
+platelets	O
+","	O
+and	O
+clinical	O
+signs	O
+of	O
+HIT	B-NP
+type	I-NP
+II	I-NP
+were	O
+analyzed	O
+.	O
+	
+RESULTS	O
+:	O
+A	O
+total	O
+of	O
+155	O
+(	O
+75	O
+.	O
+6	O
+%	O
+)	O
+of	O
+205	O
+patients	O
+had	O
+thrombocytopenia	B-NP
+before	O
+transplantation	O
+","	O
+significantly	O
+influenced	O
+by	O
+Model	O
+of	O
+End	B-NP
+-	I-NP
+Stage	I-NP
+Liver	I-NP
+Disease	I-NP
+score	O
+and	O
+liver	B-NP
+cirrhosis	I-NP
+.	O
+	
+The	O
+platelet	O
+count	O
+exceeded	O
+100	O
+","	O
+0	O
+/	O
+uL	O
+in	O
+most	O
+of	O
+the	O
+patients	O
+(	O
+n	O
+=	O
+193	O
+)	O
+at	O
+a	O
+medium	O
+of	O
+7	O
+d	O
+.	O
+	
+Regarding	O
+HIT	B-NP
+II	I-NP
+","	O
+there	O
+were	O
+four	O
+(	O
+1	O
+.	O
+95	O
+%	O
+)	O
+patients	O
+with	O
+a	O
+background	O
+of	O
+HIT	B-NP
+type	I-NP
+II	I-NP
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+incidence	O
+of	O
+HIT	B-NP
+in	O
+patients	O
+with	O
+end	B-NP
+-	I-NP
+stage	I-NP
+hepatic	I-NP
+failure	I-NP
+is	O
+","	O
+with	O
+about	O
+1	O
+.	O
+95	O
+%	O
+","	O
+rare	O
+.	O
+	
+For	O
+further	O
+reduction	O
+of	O
+HIT	B-NP
+type	I-NP
+II	I-NP
+","	O
+the	O
+use	O
+of	O
+intravenous	O
+heparin	O
+should	O
+be	O
+avoided	O
+and	O
+the	O
+prophylactic	O
+anticoagulation	O
+should	O
+be	O
+performed	O
+with	O
+low	O
+-	O
+molecular	O
+-	O
+weight	O
+heparin	O
+after	O
+normalization	O
+of	O
+platelet	O
+count	O
+.	O
+	
+Takotsubo	B-NP
+syndrome	I-NP
+(	O
+or	O
+apical	B-NP
+ballooning	I-NP
+syndrome	I-NP
+)	O
+secondary	O
+to	O
+Zolmitriptan	O
+.	O
+	
+Takotsubo	B-NP
+syndrome	I-NP
+(	O
+TS	B-NP
+)	O
+","	O
+also	O
+known	O
+as	O
+broken	B-NP
+heart	I-NP
+syndrome	I-NP
+","	O
+is	O
+characterized	O
+by	O
+left	O
+ventricle	O
+apical	O
+ballooning	O
+with	O
+elevated	O
+cardiac	O
+biomarkers	O
+and	O
+electrocardiographic	O
+changes	O
+suggestive	O
+of	O
+an	O
+acute	B-NP
+coronary	I-NP
+syndrome	I-NP
+(	O
+ie	O
+","	O
+ST	O
+-	O
+segment	O
+elevation	O
+","	O
+T	O
+wave	O
+inversions	O
+","	O
+and	O
+pathologic	O
+Q	O
+waves	O
+)	O
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+54	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+medical	O
+history	O
+of	O
+mitral	B-NP
+valve	I-NP
+prolapse	I-NP
+and	O
+migraines	B-NP
+","	O
+who	O
+was	O
+admitted	O
+to	O
+the	O
+hospital	O
+for	O
+substernal	O
+chest	B-NP
+pain	I-NP
+and	O
+electrocardiogram	O
+demonstrated	O
+1	O
+/	O
+2	O
+mm	O
+ST	O
+-	O
+segment	O
+elevation	O
+in	O
+leads	O
+II	O
+","	O
+III	O
+","	O
+aVF	O
+","	O
+V5	O
+","	O
+and	O
+V6	O
+and	O
+positive	O
+troponin	O
+I	O
+.	O
+	
+Emergent	O
+coronary	O
+angiogram	O
+revealed	O
+normal	O
+coronary	O
+arteries	O
+with	O
+moderately	O
+reduced	O
+left	O
+ventricular	O
+ejection	O
+fraction	O
+with	O
+wall	O
+motion	O
+abnormalities	O
+consistent	O
+with	O
+TS	B-NP
+.	O
+	
+Detailed	O
+history	O
+obtained	O
+retrospectively	O
+revealed	O
+that	O
+the	O
+patient	O
+took	O
+zolmitriptan	O
+sparingly	O
+only	O
+when	O
+she	O
+had	O
+migraines	B-NP
+.	O
+	
+But	O
+before	O
+this	O
+event	O
+","	O
+she	O
+was	O
+taking	O
+zolmitriptan	O
+2	O
+-	O
+3	O
+times	O
+daily	O
+for	O
+several	O
+days	O
+because	O
+of	O
+a	O
+persistent	O
+migraine	B-NP
+headache	I-NP
+.	O
+	
+She	O
+otherwise	O
+reported	O
+that	O
+she	O
+is	O
+quite	O
+active	O
+","	O
+rides	O
+horses	O
+","	O
+and	O
+does	O
+show	O
+jumping	O
+without	O
+any	O
+limitations	O
+in	O
+her	O
+physical	O
+activity	O
+.	O
+	
+There	O
+was	O
+no	O
+evidence	O
+of	O
+any	O
+recent	O
+stress	O
+or	O
+status	B-NP
+migrainosus	I-NP
+.	O
+	
+Extensive	O
+literature	O
+search	O
+revealed	O
+multiple	O
+cases	O
+of	O
+coronary	B-NP
+artery	I-NP
+vasospasm	I-NP
+secondary	O
+to	O
+zolmitriptan	O
+","	O
+but	O
+none	O
+of	O
+the	O
+cases	O
+were	O
+associated	O
+with	O
+TS	B-NP
+.	O
+	
+Depression	B-NP
+","	O
+impulsiveness	B-NP
+","	O
+sleep	O
+","	O
+and	O
+memory	O
+in	O
+past	O
+and	O
+present	O
+polydrug	O
+users	O
+of	O
+3	O
+","	O
+4	O
+-	O
+methylenedioxymethamphetamine	O
+(	O
+MDMA	O
+","	O
+ecstasy	O
+)	O
+.	O
+	
+RATIONALE	O
+:	O
+Ecstasy	O
+(	O
+3	O
+","	O
+4	O
+-	O
+methylenedioxymethamphetamine	O
+","	O
+MDMA	O
+)	O
+is	O
+a	O
+worldwide	O
+recreational	O
+drug	O
+of	O
+abuse	O
+.	O
+	
+Unfortunately	O
+","	O
+the	O
+results	O
+from	O
+human	O
+research	O
+investigating	O
+its	O
+psychological	O
+effects	O
+have	O
+been	O
+inconsistent	O
+.	O
+	
+OBJECTIVES	O
+:	O
+The	O
+present	O
+study	O
+aimed	O
+to	O
+be	O
+the	O
+largest	O
+to	O
+date	O
+in	O
+sample	O
+size	O
+and	O
+5HT	O
+-	O
+related	O
+behaviors	O
+;	O
+the	O
+first	O
+to	O
+compare	O
+present	O
+ecstasy	O
+users	O
+with	O
+past	O
+users	O
+after	O
+an	O
+abstinence	O
+of	O
+4	O
+or	O
+more	O
+years	O
+","	O
+and	O
+the	O
+first	O
+to	O
+include	O
+robust	O
+controls	O
+for	O
+other	O
+recreational	O
+substances	O
+.	O
+	
+METHODS	O
+:	O
+A	O
+sample	O
+of	O
+997	O
+participants	O
+(	O
+52	O
+%	O
+male	O
+)	O
+was	O
+recruited	O
+to	O
+four	O
+control	O
+groups	O
+(	O
+non	O
+-	O
+drug	O
+(	O
+ND	O
+)	O
+","	O
+alcohol	O
+/	O
+nicotine	O
+(	O
+AN	O
+)	O
+","	O
+cannabis	O
+/	O
+alcohol	O
+/	O
+nicotine	O
+(	O
+CAN	O
+)	O
+","	O
+non	O
+-	O
+ecstasy	O
+polydrug	O
+(	O
+PD	O
+)	O
+)	O
+","	O
+and	O
+two	O
+ecstasy	O
+polydrug	O
+groups	O
+(	O
+present	O
+(	O
+MDMA	O
+)	O
+and	O
+past	O
+users	O
+(	O
+EX	O
+-	O
+MDMA	O
+)	O
+.	O
+	
+Participants	O
+completed	O
+a	O
+drug	O
+history	O
+questionnaire	O
+","	O
+Beck	O
+Depression	B-NP
+Inventory	O
+","	O
+Barratt	O
+Impulsiveness	B-NP
+Scale	O
+","	O
+Pittsburgh	O
+Sleep	O
+Quality	O
+Index	O
+","	O
+and	O
+Wechsler	O
+Memory	O
+Scale	O
+-	O
+Revised	O
+which	O
+","	O
+in	O
+total	O
+","	O
+provided	O
+13	O
+psychometric	O
+measures	O
+.	O
+	
+RESULTS	O
+:	O
+While	O
+the	O
+CAN	O
+and	O
+PD	O
+groups	O
+tended	O
+to	O
+record	O
+greater	O
+deficits	O
+than	O
+the	O
+non	O
+-	O
+drug	O
+controls	O
+","	O
+the	O
+MDMA	O
+and	O
+EX	O
+-	O
+MDMA	O
+groups	O
+recorded	O
+greater	O
+deficits	O
+than	O
+all	O
+the	O
+control	O
+groups	O
+on	O
+ten	O
+of	O
+the	O
+13	O
+psychometric	O
+measures	O
+.	O
+	
+Strikingly	O
+","	O
+despite	O
+prolonged	O
+abstinence	O
+(	O
+mean	O
+","	O
+4	O
+.	O
+98	O
+;	O
+range	O
+","	O
+4	O
+-	O
+9	O
+years	O
+)	O
+","	O
+past	O
+ecstasy	O
+users	O
+showed	O
+few	O
+signs	O
+of	O
+recovery	O
+.	O
+	
+Compared	O
+with	O
+present	O
+ecstasy	O
+users	O
+","	O
+the	O
+past	O
+users	O
+showed	O
+no	O
+change	O
+for	O
+ten	O
+measures	O
+","	O
+increased	O
+impairment	O
+for	O
+two	O
+measures	O
+","	O
+and	O
+improvement	O
+on	O
+just	O
+one	O
+measure	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Given	O
+this	O
+record	O
+of	O
+impaired	B-NP
+memory	I-NP
+and	O
+clinically	O
+significant	O
+levels	O
+of	O
+depression	B-NP
+","	O
+impulsiveness	B-NP
+","	O
+and	O
+sleep	B-NP
+disturbance	I-NP
+","	O
+the	O
+prognosis	O
+for	O
+the	O
+current	O
+generation	O
+of	O
+ecstasy	O
+users	O
+is	O
+a	O
+major	O
+cause	O
+for	O
+concern	O
+.	O
+	
+Association	O
+of	O
+common	O
+genetic	O
+variants	O
+of	O
+HOMER1	O
+gene	O
+with	O
+levodopa	O
+adverse	O
+effects	O
+in	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+patients	O
+.	O
+	
+Levodopa	O
+is	O
+the	O
+most	O
+effective	O
+symptomatic	O
+therapy	O
+for	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+","	O
+but	O
+its	O
+chronic	O
+use	O
+could	O
+lead	O
+to	O
+chronic	O
+adverse	O
+outcomes	O
+","	O
+such	O
+as	O
+motor	O
+fluctuations	O
+","	O
+dyskinesia	B-NP
+and	O
+visual	B-NP
+hallucinations	I-NP
+.	O
+	
+HOMER1	O
+is	O
+a	O
+protein	O
+with	O
+pivotal	O
+function	O
+in	O
+glutamate	O
+transmission	O
+","	O
+which	O
+has	O
+been	O
+related	O
+to	O
+the	O
+pathogenesis	O
+of	O
+these	O
+complications	O
+.	O
+	
+This	O
+study	O
+investigates	O
+whether	O
+polymorphisms	O
+in	O
+the	O
+HOMER1	O
+gene	O
+promoter	O
+region	O
+are	O
+associated	O
+with	O
+the	O
+occurrence	O
+of	O
+the	O
+chronic	O
+complications	O
+of	O
+levodopa	O
+therapy	O
+.	O
+	
+A	O
+total	O
+of	O
+205	O
+patients	O
+with	O
+idiopathic	B-NP
+Parkinson	I-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+were	O
+investigated	O
+.	O
+	
+Patients	O
+were	O
+genotyped	O
+for	O
+rs4704559	O
+","	O
+rs10942891	O
+and	O
+rs4704560	O
+by	O
+allelic	O
+discrimination	O
+with	O
+Taqman	O
+assays	O
+.	O
+	
+The	O
+rs4704559	O
+G	O
+allele	O
+was	O
+associated	O
+with	O
+a	O
+lower	O
+prevalence	O
+of	O
+dyskinesia	B-NP
+(	O
+prevalence	O
+ratio	O
+(	O
+PR	O
+)	O
+=	O
+0	O
+.	O
+615	O
+","	O
+95	O
+%	O
+confidence	O
+interval	O
+(	O
+CI	O
+)	O
+0	O
+.	O
+426	O
+-	O
+0	O
+.	O
+887	O
+","	O
+P	O
+=	O
+0	O
+.	O
+9	O
+)	O
+and	O
+visual	B-NP
+hallucinations	I-NP
+(	O
+PR	O
+=	O
+0	O
+.	O
+515	O
+","	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+295	O
+-	O
+0	O
+.	O
+899	O
+","	O
+P	O
+=	O
+0	O
+.	O
+20	O
+)	O
+.	O
+	
+Our	O
+data	O
+suggest	O
+that	O
+HOMER1	O
+rs4704559	O
+G	O
+allele	O
+has	O
+a	O
+protective	O
+role	O
+for	O
+the	O
+development	O
+of	O
+levodopa	O
+adverse	O
+effects	O
+.	O
+	
+Crocin	O
+improves	O
+lipid	O
+dysregulation	O
+in	O
+subacute	O
+diazinon	O
+exposure	O
+through	O
+ERK1	O
+/	O
+2	O
+pathway	O
+in	O
+rat	O
+liver	O
+.	O
+	
+INTRODUCTION	O
+:	O
+Diazinon	O
+Yis	O
+one	O
+of	O
+the	O
+most	O
+broadly	O
+used	O
+organophosphorus	O
+insecticides	O
+in	O
+agriculture	O
+.	O
+	
+It	O
+has	O
+been	O
+shown	O
+that	O
+exposure	O
+to	O
+diazinon	O
+may	O
+interfere	O
+with	O
+lipid	O
+metabolism	O
+.	O
+	
+Moreover	O
+","	O
+the	O
+hypolipidemic	O
+effect	O
+of	O
+crocin	O
+has	O
+been	O
+established	O
+.	O
+	
+Earlier	O
+studies	O
+revealed	O
+the	O
+major	O
+role	O
+of	O
+Extracellular	O
+signal	O
+-	O
+regulated	O
+kinase	O
+(	O
+ERK	O
+)	O
+pathways	O
+in	O
+low	O
+-	O
+density	O
+lipoprotein	O
+receptor	O
+(	O
+LDLr	O
+)	O
+expression	O
+.	O
+	
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+evaluate	O
+changes	O
+in	O
+the	O
+regulation	O
+of	O
+lipid	O
+metabolism	O
+","	O
+ERK	O
+and	O
+LDLr	O
+expression	O
+in	O
+the	O
+liver	O
+of	O
+rats	O
+exposed	O
+to	O
+subacute	O
+diazinon	O
+.	O
+	
+Furthermore	O
+ameliorating	O
+effect	O
+of	O
+crocin	O
+on	O
+diazinon	O
+induced	O
+disturbed	O
+cholesterol	O
+homeostasis	O
+was	O
+studied	O
+.	O
+	
+METHODS	O
+:	O
+24	O
+Rats	O
+were	O
+divided	O
+into	O
+4	O
+groups	O
+and	O
+received	O
+following	O
+treatments	O
+for	O
+4	O
+weeks	O
+;	O
+Corn	O
+oil	O
+(	O
+control	O
+)	O
+","	O
+diazinon	O
+(	O
+15mg	O
+/	O
+kg	O
+per	O
+day	O
+","	O
+orally	O
+)	O
+and	O
+crocin	O
+(	O
+12	O
+.	O
+5	O
+and	O
+25mg	O
+/	O
+kg	O
+per	O
+day	O
+","	O
+intraperitoneally	O
+)	O
+in	O
+combination	O
+with	O
+diazinon	O
+(	O
+15	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+	
+The	O
+levels	O
+of	O
+cholesterol	O
+","	O
+triglyceride	O
+and	O
+LDL	O
+in	O
+blood	O
+of	O
+rats	O
+were	O
+analyzed	O
+.	O
+	
+Moreover	O
+mRNA	O
+levels	O
+of	O
+LDLr	O
+and	O
+ERK1	O
+/	O
+2	O
+as	O
+well	O
+as	O
+protein	O
+levels	O
+of	O
+total	O
+and	O
+activated	O
+forms	O
+of	O
+ERK1	O
+/	O
+2	O
+in	O
+rat	O
+liver	O
+were	O
+evaluated	O
+by	O
+Western	O
+blotting	O
+and	O
+quantitative	O
+real	O
+time	O
+polymerase	O
+chain	O
+reaction	O
+analysis	O
+.	O
+	
+RESULTS	O
+:	O
+Our	O
+data	O
+showed	O
+that	O
+subacute	O
+exposure	O
+to	O
+diazinon	O
+significantly	O
+increased	O
+concentrations	O
+of	O
+cholesterol	O
+","	O
+triglyceride	O
+and	O
+LDL	O
+.	O
+	
+Moreover	O
+diazinon	O
+decreased	O
+ERK1	O
+/	O
+2	O
+protein	O
+phosphorylation	O
+and	O
+LDLr	O
+transcript	O
+.	O
+	
+Crocin	O
+reduced	O
+inhibition	O
+of	O
+ERK	O
+activation	O
+and	O
+diazinon	O
+-	O
+induced	O
+hyperlipemia	B-NP
+and	O
+increased	O
+levels	O
+of	O
+LDLr	O
+transcript	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Crocin	O
+may	O
+be	O
+considered	O
+as	O
+a	O
+novel	O
+protective	O
+agent	O
+in	O
+diazinon	O
+-	O
+induced	O
+hyperlipemia	B-NP
+through	O
+modulating	O
+of	O
+ERK	O
+pathway	O
+and	O
+increase	O
+of	O
+LDLr	O
+expression	O
+.	O
+	
+GEM	O
+-	O
+P	O
+chemotherapy	O
+is	O
+active	O
+in	O
+the	O
+treatment	O
+of	O
+relapsed	O
+Hodgkin	B-NP
+lymphoma	I-NP
+.	O
+	
+Hodgkin	B-NP
+lymphoma	I-NP
+(	O
+HL	B-NP
+)	O
+is	O
+a	O
+relatively	O
+chemosensitive	O
+malignancy	B-NP
+.	O
+	
+However	O
+","	O
+for	O
+those	O
+who	O
+relapse	O
+","	O
+high	O
+-	O
+dose	O
+chemotherapy	O
+with	O
+autologous	O
+stem	O
+cell	O
+transplant	O
+is	O
+the	O
+treatment	O
+of	O
+choice	O
+which	O
+relies	O
+on	O
+adequate	O
+disease	O
+control	O
+with	O
+salvage	O
+chemotherapy	O
+.	O
+	
+Regimens	O
+commonly	O
+used	O
+often	O
+require	O
+inpatient	O
+administration	O
+and	O
+can	O
+be	O
+difficult	O
+to	O
+deliver	O
+due	O
+to	O
+toxicity	B-NP
+.	O
+	
+Gemcitabine	O
+and	O
+cisplatin	O
+have	O
+activity	O
+in	O
+HL	B-NP
+","	O
+non	O
+-	O
+overlapping	O
+toxicity	B-NP
+with	O
+first	O
+-	O
+line	O
+chemotherapeutics	O
+","	O
+and	O
+may	O
+be	O
+delivered	O
+in	O
+an	O
+outpatient	O
+setting	O
+.	O
+	
+In	O
+this	O
+retrospective	O
+single	O
+-	O
+centre	O
+analysis	O
+","	O
+patients	O
+with	O
+relapsed	O
+or	O
+refractory	O
+HL	B-NP
+treated	O
+with	O
+gemcitabine	O
+1	O
+","	O
+0	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+day	O
+(	O
+D	O
+)	O
+1	O
+","	O
+D8	O
+and	O
+D15	O
+;	O
+methylprednisolone	O
+1	O
+","	O
+0	O
+mg	O
+D1	O
+-	O
+5	O
+;	O
+and	O
+cisplatin	O
+100	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+D15	O
+","	O
+every	O
+28	O
+days	O
+(	O
+GEM	O
+-	O
+P	O
+)	O
+were	O
+included	O
+.	O
+	
+Demographic	O
+","	O
+survival	O
+","	O
+response	O
+and	O
+toxicity	B-NP
+data	O
+were	O
+recorded	O
+.	O
+	
+Forty	O
+-	O
+one	O
+eligible	O
+patients	O
+were	O
+identified	O
+:	O
+median	O
+age	O
+27	O
+.	O
+	
+One	O
+hundred	O
+and	O
+twenty	O
+-	O
+two	O
+cycles	O
+of	O
+GEM	O
+-	O
+P	O
+were	O
+administered	O
+in	O
+total	O
+(	O
+median	O
+3	O
+cycles	O
+;	O
+range	O
+1	O
+-	O
+6	O
+)	O
+.	O
+	
+Twenty	O
+of	O
+41	O
+(	O
+48	O
+%	O
+)	O
+patients	O
+received	O
+GEM	O
+-	O
+P	O
+as	O
+second	O
+-	O
+line	O
+treatment	O
+and	O
+11	O
+/	O
+41	O
+(	O
+27	O
+%	O
+)	O
+as	O
+third	O
+-	O
+line	O
+therapy	O
+.	O
+	
+Overall	O
+response	O
+rate	O
+(	O
+ORR	O
+)	O
+to	O
+GEM	O
+-	O
+P	O
+in	O
+the	O
+entire	O
+cohort	O
+was	O
+80	O
+%	O
+(	O
+complete	O
+response	O
+(	O
+CR	O
+)	O
+37	O
+%	O
+","	O
+partial	O
+response	O
+44	O
+%	O
+)	O
+with	O
+14	O
+/	O
+15	O
+CR	O
+confirmed	O
+as	O
+a	O
+metabolic	O
+CR	O
+on	O
+PET	O
+and	O
+ORR	O
+of	O
+85	O
+%	O
+in	O
+the	O
+20	O
+second	O
+-	O
+line	O
+patients	O
+.	O
+	
+The	O
+most	O
+common	O
+grade	O
+3	O
+/	O
+4	O
+toxicities	B-NP
+were	O
+haematological	O
+:	O
+neutropenia	B-NP
+54	O
+%	O
+and	O
+thrombocytopenia	B-NP
+51	O
+%	O
+.	O
+	
+Median	O
+follow	O
+-	O
+up	O
+from	O
+the	O
+start	O
+of	O
+GEM	O
+-	O
+P	O
+was	O
+4	O
+.	O
+5	O
+years	O
+.	O
+	
+Following	O
+GEM	O
+-	O
+P	O
+","	O
+5	O
+-	O
+year	O
+progression	O
+-	O
+free	O
+survival	O
+was	O
+46	O
+%	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+(	O
+CI	O
+)	O
+","	O
+30	O
+-	O
+62	O
+%	O
+)	O
+and	O
+5	O
+-	O
+year	O
+overall	O
+survival	O
+was	O
+59	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+","	O
+43	O
+-	O
+74	O
+%	O
+)	O
+.	O
+	
+Fourteen	O
+of	O
+41	O
+patients	O
+proceeded	O
+directly	O
+to	O
+autologous	O
+transplant	O
+.	O
+	
+GEM	O
+-	O
+P	O
+is	O
+a	O
+salvage	O
+chemotherapy	O
+with	O
+relatively	O
+high	O
+response	O
+rates	O
+","	O
+leading	O
+to	O
+successful	O
+transplantation	O
+in	O
+appropriate	O
+patients	O
+","	O
+in	O
+the	O
+treatment	O
+of	O
+relapsed	O
+or	O
+refractory	O
+HL	B-NP
+.	O
+	
+Basal	O
+functioning	O
+of	O
+the	O
+hypothalamic	O
+-	O
+pituitary	O
+-	O
+adrenal	O
+(	O
+HPA	O
+)	O
+axis	O
+and	O
+psychological	O
+distress	O
+in	O
+recreational	O
+ecstasy	O
+polydrug	O
+users	O
+.	O
+	
+RATIONALE	O
+:	O
+Ecstasy	O
+(	O
+MDMA	O
+)	O
+is	O
+a	O
+psychostimulant	O
+drug	O
+which	O
+is	O
+increasingly	O
+associated	O
+with	O
+psychobiological	B-NP
+dysfunction	I-NP
+.	O
+	
+While	O
+some	O
+recent	O
+studies	O
+suggest	O
+acute	O
+changes	O
+in	O
+neuroendocrine	O
+function	O
+","	O
+less	O
+is	O
+known	O
+about	O
+long	O
+-	O
+term	O
+changes	O
+in	O
+HPA	O
+functionality	O
+in	O
+recreational	O
+users	O
+.	O
+	
+OBJECTIVES	O
+:	O
+The	O
+current	O
+study	O
+is	O
+the	O
+first	O
+to	O
+explore	O
+the	O
+effects	O
+of	O
+ecstasy	O
+-	O
+polydrug	O
+use	O
+on	O
+psychological	O
+distress	O
+and	O
+basal	O
+functioning	O
+of	O
+the	O
+HPA	O
+axis	O
+through	O
+assessing	O
+the	O
+secretion	O
+of	O
+cortisol	O
+across	O
+the	O
+diurnal	O
+period	O
+.	O
+	
+METHOD	O
+:	O
+Seventy	O
+-	O
+six	O
+participants	O
+(	O
+21	O
+nonusers	O
+","	O
+29	O
+light	O
+ecstasy	O
+-	O
+polydrug	O
+users	O
+","	O
+26	O
+heavy	O
+ecstasy	O
+-	O
+polydrug	O
+users	O
+)	O
+completed	O
+a	O
+substance	O
+use	O
+inventory	O
+and	O
+measures	O
+of	O
+psychological	O
+distress	O
+at	O
+baseline	O
+","	O
+then	O
+two	O
+consecutive	O
+days	O
+of	O
+cortisol	O
+sampling	O
+(	O
+on	O
+awakening	O
+","	O
+30	O
+min	O
+post	O
+awakening	O
+","	O
+between	O
+1400	O
+and	O
+1600	O
+hours	O
+and	O
+pre	O
+bedtime	O
+)	O
+.	O
+	
+On	O
+day	O
+2	O
+","	O
+participants	O
+also	O
+attended	O
+the	O
+laboratory	O
+to	O
+complete	O
+a	O
+20	O
+-	O
+min	O
+multitasking	O
+stressor	O
+.	O
+	
+RESULTS	O
+:	O
+Both	O
+user	O
+groups	O
+exhibited	O
+significantly	O
+greater	O
+levels	O
+of	O
+anxiety	B-NP
+and	O
+depression	B-NP
+than	O
+nonusers	O
+.	O
+	
+On	O
+day	O
+1	O
+","	O
+all	O
+participants	O
+exhibited	O
+a	O
+typical	O
+cortisol	O
+profile	O
+","	O
+though	O
+light	O
+users	O
+had	O
+significantly	O
+elevated	O
+levels	O
+pre	O
+-	O
+bed	O
+.	O
+	
+On	O
+day	O
+2	O
+","	O
+heavy	O
+users	O
+demonstrated	O
+elevated	O
+levels	O
+upon	O
+awakening	O
+and	O
+all	O
+ecstasy	O
+-	O
+polydrug	O
+users	O
+demonstrated	O
+elevated	O
+pre	O
+-	O
+bed	O
+levels	O
+compared	O
+to	O
+non	O
+-	O
+users	O
+.	O
+	
+Significant	O
+between	O
+group	O
+differences	O
+were	O
+also	O
+observed	O
+in	O
+afternoon	O
+cortisol	O
+levels	O
+and	O
+in	O
+overall	O
+cortisol	O
+secretion	O
+across	O
+the	O
+day	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+increases	O
+in	O
+anxiety	B-NP
+and	O
+depression	B-NP
+are	O
+in	O
+line	O
+with	O
+previous	O
+observations	O
+in	O
+recreational	O
+ecstasy	O
+-	O
+polydrug	O
+users	O
+.	O
+	
+Dysregulated	O
+diurnal	O
+cortisol	O
+may	O
+be	O
+indicative	O
+of	O
+inappropriate	O
+anticipation	O
+of	O
+forthcoming	O
+demands	O
+and	O
+hypersecretion	O
+may	O
+lead	O
+to	O
+the	O
+increased	O
+psychological	O
+and	O
+physical	O
+morbidity	O
+associated	O
+with	O
+heavy	O
+recreational	O
+use	O
+of	O
+ecstasy	O
+.	O
+	
+Ifosfamide	O
+related	O
+encephalopathy	B-NP
+:	O
+the	O
+need	O
+for	O
+a	O
+timely	O
+EEG	O
+evaluation	O
+.	O
+	
+BACKGROUND	O
+:	O
+Ifosfamide	O
+is	O
+an	O
+alkylating	O
+agent	O
+useful	O
+in	O
+the	O
+treatment	O
+of	O
+a	O
+wide	O
+range	O
+of	O
+cancers	B-NP
+including	O
+sarcomas	B-NP
+","	O
+lymphoma	B-NP
+","	O
+gynecologic	B-NP
+and	I-NP
+testicular	I-NP
+cancers	I-NP
+.	O
+	
+Encephalopathy	B-NP
+has	O
+been	O
+reported	O
+in	O
+10	O
+-	O
+40	O
+%	O
+of	O
+patients	O
+receiving	O
+high	O
+-	O
+dose	O
+IV	O
+ifosfamide	O
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+highlight	O
+the	O
+role	O
+of	O
+electroencephalogram	O
+(	O
+EEG	O
+)	O
+in	O
+the	O
+early	O
+detection	O
+and	O
+management	O
+of	O
+ifosfamide	O
+related	O
+encephalopathy	B-NP
+.	O
+	
+METHODS	O
+:	O
+Retrospective	O
+chart	O
+review	O
+including	O
+clinical	O
+data	O
+and	O
+EEG	O
+recordings	O
+was	O
+done	O
+on	O
+five	O
+patients	O
+","	O
+admitted	O
+to	O
+MD	O
+Anderson	O
+Cancer	B-NP
+Center	O
+between	O
+years	O
+2009	O
+and	O
+2012	O
+","	O
+who	O
+developed	O
+ifosfamide	O
+related	O
+acute	O
+encephalopathy	B-NP
+.	O
+	
+RESULTS	O
+:	O
+All	O
+five	O
+patients	O
+experienced	O
+symptoms	O
+of	O
+encephalopathy	B-NP
+soon	O
+after	O
+(	O
+within	O
+12	O
+h	O
+-	O
+2	O
+days	O
+)	O
+receiving	O
+ifosfamide	O
+.	O
+	
+Two	O
+patients	O
+developed	O
+generalized	O
+convulsions	B-NP
+while	O
+one	O
+patient	O
+developed	O
+continuous	O
+non	B-NP
+-	I-NP
+convulsive	I-NP
+status	I-NP
+epilepticus	I-NP
+(	O
+NCSE	B-NP
+)	O
+that	O
+required	O
+ICU	O
+admission	O
+and	O
+intubation	O
+.	O
+	
+Initial	O
+EEG	O
+showed	O
+epileptiform	O
+discharges	O
+in	O
+three	O
+patients	O
+;	O
+run	O
+of	O
+triphasic	O
+waves	O
+in	O
+one	O
+patient	O
+and	O
+moderate	O
+degree	O
+diffuse	O
+generalized	O
+slowing	O
+.	O
+	
+Mixed	O
+pattern	O
+with	O
+the	O
+presence	O
+of	O
+both	O
+sharps	O
+and	O
+triphasic	O
+waves	O
+were	O
+also	O
+noted	O
+.	O
+	
+Repeat	O
+EEGs	O
+within	O
+24	O
+_	O
+h	O
+of	O
+symptom	O
+onset	O
+showed	O
+marked	O
+improvement	O
+that	O
+was	O
+correlated	O
+with	O
+clinical	O
+improvement	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Severity	O
+of	O
+ifosfamide	O
+related	O
+encephalopathy	B-NP
+correlates	O
+with	O
+EEG	O
+changes	O
+.	O
+	
+We	O
+suggest	O
+a	O
+timely	O
+EEG	O
+evaluation	O
+for	O
+patients	O
+receiving	O
+ifosfamide	O
+who	O
+develop	O
+features	O
+of	O
+encephalopathy	B-NP
+.	O
+	
+Incidence	O
+of	O
+contrast	O
+-	O
+induced	O
+nephropathy	B-NP
+in	O
+hospitalised	O
+patients	O
+with	O
+cancer	B-NP
+.	O
+	
+OBJECTIVES	O
+:	O
+To	O
+determine	O
+the	O
+frequency	O
+of	O
+and	O
+possible	O
+factors	O
+related	O
+to	O
+contrast	O
+-	O
+induced	O
+nephropathy	B-NP
+(	O
+CIN	O
+)	O
+in	O
+hospitalised	O
+patients	O
+with	O
+cancer	B-NP
+.	O
+	
+METHODS	O
+:	O
+Ninety	O
+adult	O
+patients	O
+were	O
+enrolled	O
+.	O
+	
+Patients	O
+with	O
+risk	O
+factors	O
+for	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+were	O
+excluded	O
+.	O
+	
+Blood	O
+samples	O
+were	O
+examined	O
+the	O
+day	O
+before	O
+contrast	O
+-	O
+enhanced	O
+computed	O
+tomography	O
+(	O
+CT	O
+)	O
+and	O
+serially	O
+for	O
+3	O
+days	O
+thereafter	O
+.	O
+	
+CIN	O
+was	O
+defined	O
+as	O
+an	O
+increase	O
+in	O
+serum	O
+creatinine	O
+(	O
+Cr	O
+)	O
+of	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+dl	O
+or	O
+more	O
+","	O
+or	O
+elevation	O
+of	O
+Cr	O
+to	O
+25	O
+%	O
+over	O
+baseline	O
+.	O
+	
+Relationships	O
+between	O
+CIN	O
+and	O
+possible	O
+risk	O
+factors	O
+were	O
+investigated	O
+.	O
+	
+RESULTS	O
+:	O
+CIN	O
+was	O
+detected	O
+in	O
+18	O
+/	O
+90	O
+(	O
+20	O
+%	O
+)	O
+patients	O
+.	O
+	
+CIN	O
+developed	O
+in	O
+25	O
+.	O
+5	O
+%	O
+patients	O
+who	O
+underwent	O
+chemotherapy	O
+and	O
+in	O
+11	O
+%	O
+patients	O
+who	O
+did	O
+not	O
+(	O
+P	O
+=	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+CIN	O
+more	O
+frequently	O
+developed	O
+in	O
+patients	O
+who	O
+had	O
+undergone	O
+CT	O
+within	O
+45	O
+days	O
+after	O
+the	O
+last	O
+chemotherapy	O
+(	O
+P	O
+=	O
+0	O
+.	O
+5	O
+)	O
+;	O
+it	O
+was	O
+also	O
+an	O
+independent	O
+risk	O
+factor	O
+(	O
+P	O
+=	O
+0	O
+.	O
+17	O
+)	O
+.	O
+	
+CIN	O
+was	O
+significantly	O
+more	O
+after	O
+treatment	O
+with	O
+bevacizumab	O
+/	O
+irinotecan	O
+(	O
+P	O
+=	O
+0	O
+.	O
+21	O
+)	O
+and	O
+in	O
+patients	O
+with	O
+hypertension	B-NP
+(	O
+P	O
+=	O
+0	O
+.	O
+44	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+incidence	O
+of	O
+CIN	O
+after	O
+CT	O
+in	O
+hospitalised	O
+oncological	O
+patients	O
+was	O
+20	O
+%	O
+.	O
+	
+CIN	O
+developed	O
+4	O
+.	O
+5	O
+-	O
+times	O
+more	O
+frequently	O
+in	O
+patients	O
+with	O
+cancer	B-NP
+who	O
+had	O
+undergone	O
+recent	O
+chemotherapy	O
+.	O
+	
+Hypertension	B-NP
+and	O
+the	O
+combination	O
+of	O
+bevacizumab	O
+/	O
+irinotecan	O
+may	O
+be	O
+additional	O
+risk	O
+factors	O
+for	O
+CIN	O
+development	O
+.	O
+	
+KEY	O
+POINTS	O
+:	O
+.	O
+	
+Contrast	O
+-	O
+induced	O
+nephropathy	B-NP
+(	O
+CIN	O
+)	O
+is	O
+a	O
+concern	O
+for	O
+oncological	O
+patients	O
+undergoing	O
+CT	O
+.	O
+	
+.	O
+CIN	O
+occurs	O
+more	O
+often	O
+when	O
+CT	O
+is	O
+performed	O
+<	O
+45	O
+days	O
+after	O
+chemotherapy	O
+.	O
+	
+.	O
+Hypertension	B-NP
+and	O
+treatment	O
+with	O
+bevacizumab	O
+appear	O
+to	O
+be	O
+additional	O
+risk	O
+factors	O
+.	O
+	
+Syndrome	B-NP
+of	I-NP
+inappropriate	I-NP
+antidiuretic	I-NP
+hormone	I-NP
+secretion	O
+associated	O
+with	O
+desvenlafaxine	O
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+syndrome	B-NP
+of	I-NP
+inappropriate	I-NP
+anti	I-NP
+-	I-NP
+diuretic	I-NP
+hormone	I-NP
+(	O
+SIADH	B-NP
+)	O
+secretion	O
+associated	O
+with	O
+desvenlafaxine	O
+.	O
+	
+CASE	O
+SUMMARY	O
+:	O
+A	O
+57	O
+-	O
+year	O
+old	O
+female	O
+with	O
+hyponatraemia	B-NP
+.	O
+	
+Her	O
+medications	O
+included	O
+desvenlafaxine	O
+","	O
+and	O
+symptoms	O
+included	O
+nausea	B-NP
+","	O
+anxiety	B-NP
+and	O
+confusion	B-NP
+.	O
+	
+The	O
+serum	O
+sodium	O
+at	O
+this	O
+time	O
+was	O
+120	O
+mmol	O
+/	O
+L	O
+","	O
+serum	O
+osmolality	O
+was	O
+263	O
+mosmol	O
+/	O
+kg	O
+","	O
+urine	O
+osmolality	O
+410	O
+mosmol	O
+/	O
+kg	O
+and	O
+urine	O
+sodium	O
+63	O
+mmol	O
+/	O
+L	O
+","	O
+consistent	O
+with	O
+a	O
+diagnosis	O
+of	O
+SIADH	B-NP
+.	O
+	
+Desvenlafaxine	O
+was	O
+ceased	O
+and	O
+fluid	O
+restriction	O
+implemented	O
+.	O
+	
+After	O
+4	O
+days	O
+the	O
+sodium	O
+increased	O
+to	O
+128	O
+mmol	O
+/	O
+L	O
+and	O
+fluid	O
+restriction	O
+was	O
+relaxed	O
+.	O
+	
+During	O
+her	O
+further	O
+3	O
+weeks	O
+inpatient	O
+admission	O
+the	O
+serum	O
+sodium	O
+ranged	O
+from	O
+134	O
+to	O
+137	O
+mmol	O
+/	O
+L	O
+during	O
+treatment	O
+with	O
+mirtazapine	O
+.	O
+	
+DISCUSSION	O
+:	O
+SIADH	B-NP
+has	O
+been	O
+widely	O
+reported	O
+with	O
+a	O
+range	O
+of	O
+antidepressants	O
+.	O
+	
+This	O
+case	O
+report	O
+suggests	O
+that	O
+desvenlafaxine	O
+might	O
+cause	O
+clinically	O
+significant	O
+hyponatremia	B-NP
+.	O
+	
+CONCLUSIONS	O
+:	O
+Clinicians	O
+should	O
+be	O
+aware	O
+of	O
+the	O
+potential	O
+for	O
+antidepressants	O
+to	O
+cause	O
+hyponatremia	B-NP
+","	O
+and	O
+take	O
+appropriate	O
+corrective	O
+action	O
+where	O
+necessary	O
+.	O
+	
+Oxidative	O
+stress	O
+on	O
+cardiotoxicity	B-NP
+after	O
+treatment	O
+with	O
+single	O
+and	O
+multiple	O
+doses	O
+of	O
+doxorubicin	O
+.	O
+	
+The	O
+mechanism	O
+of	O
+doxorubicin	O
+(	O
+DOX	O
+)	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+remains	O
+controversial	O
+.	O
+	
+Wistar	O
+rats	O
+(	O
+n	O
+=	O
+66	O
+)	O
+received	O
+DOX	O
+injections	O
+intraperitoneally	O
+and	O
+were	O
+randomly	O
+assigned	O
+to	O
+2	O
+experimental	O
+protocols	O
+:	O
+(	O
+1	O
+)	O
+rats	O
+were	O
+killed	O
+before	O
+(	O
+-	O
+24	O
+h	O
+","	O
+n	O
+=	O
+8	O
+)	O
+and	O
+24	O
+h	O
+after	O
+(	O
++	O
+24	O
+h	O
+","	O
+n	O
+=	O
+8	O
+)	O
+a	O
+single	O
+dose	O
+of	O
+DOX	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+)	O
+to	O
+determine	O
+the	O
+DOX	O
+acute	O
+effect	O
+and	O
+(	O
+2	O
+)	O
+rats	O
+(	O
+n	O
+=	O
+58	O
+)	O
+received	O
+4	O
+injections	O
+of	O
+DOX	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+/	O
+week	O
+)	O
+and	O
+were	O
+killed	O
+before	O
+the	O
+first	O
+injection	O
+(	O
+M0	O
+)	O
+and	O
+1	O
+week	O
+after	O
+each	O
+injection	O
+(	O
+M1	O
+","	O
+M2	O
+","	O
+M3	O
+","	O
+and	O
+M4	O
+)	O
+to	O
+determine	O
+the	O
+chronological	O
+effects	O
+.	O
+	
+Animals	O
+used	O
+at	O
+M0	O
+(	O
+n	O
+=	O
+8	O
+)	O
+were	O
+also	O
+used	O
+at	O
+moment	O
+-	O
+24	O
+h	O
+of	O
+acute	O
+study	O
+.	O
+	
+Cardiac	O
+total	O
+antioxidant	O
+performance	O
+(	O
+TAP	O
+)	O
+","	O
+DNA	O
+damage	O
+","	O
+and	O
+morphology	O
+analyses	O
+were	O
+carried	O
+out	O
+at	O
+each	O
+time	O
+point	O
+.	O
+	
+Single	O
+dose	O
+of	O
+DOX	O
+was	O
+associated	O
+with	O
+increased	O
+cardiac	B-NP
+disarrangement	I-NP
+","	O
+necrosis	B-NP
+","	O
+and	O
+DNA	O
+damage	O
+(	O
+strand	O
+breaks	O
+(	O
+SBs	O
+)	O
+and	O
+oxidized	O
+pyrimidines	O
+)	O
+and	O
+decreased	O
+TAP	O
+.	O
+	
+The	O
+chronological	O
+study	O
+showed	O
+an	O
+effect	O
+of	O
+a	O
+cumulative	O
+dose	O
+on	O
+body	O
+weight	O
+(	O
+R	O
+=	O
+-	O
+0	O
+.	O
+99	O
+","	O
+p	O
+=	O
+0	O
+.	O
+11	O
+)	O
+","	O
+necrosis	B-NP
+(	O
+R	O
+=	O
+1	O
+.	O
+0	O
+","	O
+p	O
+=	O
+0	O
+.	O
+4	O
+)	O
+","	O
+TAP	O
+(	O
+R	O
+=	O
+0	O
+.	O
+95	O
+","	O
+p	O
+=	O
+0	O
+.	O
+49	O
+)	O
+","	O
+and	O
+DNA	O
+SBs	O
+(	O
+R	O
+=	O
+-	O
+0	O
+.	O
+95	O
+","	O
+p	O
+=	O
+0	O
+.	O
+49	O
+)	O
+.	O
+	
+DNA	O
+SBs	O
+damage	O
+was	O
+negatively	O
+associated	O
+with	O
+TAP	O
+(	O
+R	O
+=	O
+-	O
+0	O
+.	O
+98	O
+","	O
+p	O
+=	O
+0	O
+.	O
+18	O
+)	O
+","	O
+and	O
+necrosis	B-NP
+(	O
+R	O
+=	O
+-	O
+0	O
+.	O
+97	O
+","	O
+p	O
+=	O
+0	O
+.	O
+27	O
+)	O
+.	O
+	
+Our	O
+results	O
+suggest	O
+that	O
+oxidative	O
+damage	O
+is	O
+associated	O
+with	O
+acute	O
+cardiotoxicity	B-NP
+induced	O
+by	O
+a	O
+single	O
+dose	O
+of	O
+DOX	O
+only	O
+.	O
+	
+Increased	O
+resistance	O
+to	O
+the	O
+oxidative	O
+stress	O
+is	O
+plausible	O
+for	O
+the	O
+multiple	O
+dose	O
+of	O
+DOX	O
+.	O
+	
+Thus	O
+","	O
+different	O
+mechanisms	O
+may	O
+be	O
+involved	O
+in	O
+acute	O
+toxicity	B-NP
+versus	O
+chronic	O
+toxicity	B-NP
+.	O
+	
+Tacrolimus	O
+-	O
+related	O
+seizure	B-NP
+after	O
+pediatric	O
+liver	O
+transplantation	O
+-	O
+-	O
+a	O
+single	O
+-	O
+center	O
+experience	O
+.	O
+	
+To	O
+identify	O
+the	O
+risk	O
+factors	O
+for	O
+new	O
+-	O
+onset	O
+seizures	B-NP
+after	O
+pediatric	O
+LT	O
+and	O
+to	O
+assess	O
+their	O
+clinical	O
+implications	O
+and	O
+long	O
+-	O
+term	O
+prognosis	O
+.	O
+	
+The	O
+clinical	O
+and	O
+laboratory	O
+data	O
+of	O
+27	O
+consecutive	O
+children	O
+who	O
+underwent	O
+LT	O
+from	O
+January	O
+2007	O
+to	O
+December	O
+2010	O
+in	O
+our	O
+center	O
+were	O
+analyzed	O
+retrospectively	O
+.	O
+	
+Patients	O
+were	O
+divided	O
+into	O
+seizures	B-NP
+group	O
+and	O
+a	O
+non	O
+-	O
+seizures	B-NP
+group	O
+.	O
+	
+Pre	O
+-	O
+operative	O
+","	O
+intra	O
+-	O
+operative	O
+","	O
+and	O
+post	O
+-	O
+operative	O
+data	O
+were	O
+collected	O
+.	O
+	
+Seizures	B-NP
+occurred	O
+in	O
+four	O
+children	O
+","	O
+an	O
+incidence	O
+of	O
+14	O
+.	O
+8	O
+%	O
+.	O
+	
+All	O
+exhibited	O
+generalized	O
+tonic	B-NP
+-	I-NP
+clonic	I-NP
+seizures	I-NP
+within	O
+the	O
+first	O
+two	O
+wk	O
+after	O
+LT	O
+.	O
+	
+Univariate	O
+analysis	O
+showed	O
+that	O
+the	O
+risk	O
+factors	O
+associated	O
+with	O
+seizures	B-NP
+after	O
+pediatric	O
+LT	O
+included	O
+gender	O
+","	O
+pediatric	O
+end	B-NP
+-	I-NP
+stage	I-NP
+liver	I-NP
+disease	I-NP
+score	O
+before	O
+surgery	O
+","	O
+Child	O
+-	O
+Pugh	O
+score	O
+before	O
+surgery	O
+","	O
+serum	O
+total	O
+bilirubin	O
+after	O
+surgery	O
+","	O
+and	O
+trough	O
+TAC	O
+level	O
+.	O
+	
+Multivariate	O
+analysis	O
+showed	O
+that	O
+trough	O
+TAC	O
+level	O
+was	O
+the	O
+only	O
+independent	O
+risk	O
+factor	O
+associated	O
+with	O
+the	O
+seizures	B-NP
+.	O
+	
+All	O
+children	O
+who	O
+experienced	O
+seizures	B-NP
+survived	O
+with	O
+good	O
+graft	O
+function	O
+and	O
+remained	O
+seizure	B-NP
+-	O
+free	O
+without	O
+anti	O
+-	O
+epileptic	B-NP
+drugs	O
+over	O
+a	O
+mean	O
+follow	O
+-	O
+up	O
+period	O
+of	O
+33	O
+.	O
+7	O
++	O
+14	O
+.	O
+6	O
+months	O
+.	O
+	
+High	O
+trough	O
+TAC	O
+level	O
+was	O
+the	O
+predominant	O
+factor	O
+that	O
+contributed	O
+to	O
+seizures	B-NP
+in	O
+the	O
+early	O
+post	O
+-	O
+operative	O
+period	O
+after	O
+pediatric	O
+LT	O
+.	O
+	
+High	O
+PELD	O
+and	O
+Child	O
+-	O
+Pugh	O
+scores	O
+before	O
+LT	O
+and	O
+high	O
+post	O
+-	O
+operative	O
+serum	O
+Tbil	O
+may	O
+be	O
+contributory	O
+risk	O
+factors	O
+for	O
+TAC	O
+-	O
+related	O
+seizures	B-NP
+.	O
+	
+The	O
+flavonoid	O
+apigenin	O
+delays	O
+forgetting	O
+of	O
+passive	O
+avoidance	O
+conditioning	O
+in	O
+rats	O
+.	O
+	
+The	O
+present	O
+experiments	O
+were	O
+performed	O
+to	O
+study	O
+the	O
+effect	O
+of	O
+the	O
+flavonoid	O
+apigenin	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+intraperitoneally	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+","	O
+1	O
+h	O
+before	O
+acquisition	O
+)	O
+","	O
+on	O
+24	O
+h	O
+retention	O
+performance	O
+and	O
+forgetting	O
+of	O
+a	O
+step	O
+-	O
+through	O
+passive	O
+avoidance	O
+task	O
+","	O
+in	O
+young	O
+male	O
+Wistar	O
+rats	O
+.	O
+	
+There	O
+were	O
+no	O
+differences	O
+between	O
+saline	O
+-	O
+and	O
+apigenin	O
+-	O
+treated	O
+groups	O
+in	O
+the	O
+24	O
+h	O
+retention	O
+trial	O
+.	O
+	
+Furthermore	O
+","	O
+apigenin	O
+did	O
+not	O
+prevent	O
+the	O
+amnesia	B-NP
+induced	O
+by	O
+scopolamine	O
+(	O
+1mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+p	O
+.	O
+","	O
+30	O
+min	O
+before	O
+the	O
+acquisition	O
+)	O
+.	O
+	
+The	O
+saline	O
+-	O
+and	O
+apigenin	O
+-	O
+treated	O
+rats	O
+that	O
+did	O
+not	O
+step	O
+through	O
+into	O
+the	O
+dark	O
+compartment	O
+during	O
+the	O
+cut	O
+-	O
+off	O
+time	O
+(	O
+540	O
+s	O
+)	O
+were	O
+retested	O
+weekly	O
+for	O
+up	O
+to	O
+eight	O
+weeks	O
+.	O
+	
+In	O
+the	O
+saline	O
+treated	O
+group	O
+","	O
+the	O
+first	O
+significant	O
+decline	O
+in	O
+passive	O
+avoidance	O
+response	O
+was	O
+observed	O
+at	O
+four	O
+weeks	O
+","	O
+and	O
+complete	O
+memory	B-NP
+loss	I-NP
+was	O
+found	O
+five	O
+weeks	O
+after	O
+the	O
+acquisition	O
+of	O
+the	O
+passive	O
+avoidance	O
+task	O
+.	O
+	
+At	O
+the	O
+end	O
+of	O
+the	O
+experimental	O
+period	O
+","	O
+60	O
+%	O
+of	O
+the	O
+animals	O
+treated	O
+with	O
+apigenin	O
+still	O
+did	O
+not	O
+step	O
+through	O
+.	O
+	
+These	O
+data	O
+suggest	O
+that	O
+1	O
+)	O
+apigenin	O
+delays	O
+the	O
+long	O
+-	O
+term	O
+forgetting	O
+but	O
+did	O
+not	O
+modulate	O
+the	O
+24	O
+h	O
+retention	O
+of	O
+fear	O
+memory	O
+and	O
+2	O
+)	O
+the	O
+obtained	O
+beneficial	O
+effect	O
+of	O
+apigenin	O
+on	O
+the	O
+passive	O
+avoidance	O
+conditioning	O
+is	O
+mediated	O
+by	O
+mechanisms	O
+that	O
+do	O
+not	O
+implicate	O
+its	O
+action	O
+on	O
+the	O
+muscarinic	O
+cholinergic	O
+system	O
+.	O
+	
+Histamine	O
+antagonists	O
+and	O
+d	O
+-	O
+tubocurarine	O
+-	O
+induced	O
+hypotension	B-NP
+in	O
+cardiac	O
+surgical	O
+patients	O
+.	O
+	
+Hemodynamic	O
+effects	O
+and	O
+histamine	O
+release	O
+by	O
+bolus	O
+injection	O
+of	O
+0	O
+.	O
+35	O
+mg	O
+/	O
+kg	O
+of	O
+d	O
+-	O
+tubocurarine	O
+were	O
+studied	O
+in	O
+24	O
+patients	O
+.	O
+	
+H1	O
+-	O
+and	O
+H2	O
+-	O
+histamine	O
+antagonists	O
+or	O
+placebo	O
+were	O
+given	O
+before	O
+dosing	O
+with	O
+d	O
+-	O
+tubocurarine	O
+in	O
+a	O
+randomized	O
+double	O
+-	O
+blind	O
+fashion	O
+to	O
+four	O
+groups	O
+:	O
+group	O
+1	O
+-	O
+-	O
+placebo	O
+;	O
+group	O
+2	O
+-	O
+-	O
+cimetidine	O
+","	O
+4	O
+mg	O
+/	O
+kg	O
+","	O
+plus	O
+placebo	O
+;	O
+group	O
+3	O
+-	O
+-	O
+chlorpheniramine	O
+","	O
+0	O
+.	O
+1	O
+mg	O
+/	O
+kg	O
+","	O
+plus	O
+placebo	O
+;	O
+and	O
+group	O
+4	O
+-	O
+-	O
+cimetidine	O
+plus	O
+chlorpheniramine	O
+.	O
+	
+Histamine	O
+release	O
+occurred	O
+in	O
+most	O
+patients	O
+","	O
+the	O
+highest	O
+level	O
+2	O
+minutes	O
+after	O
+d	O
+-	O
+tubocurarine	O
+dosing	O
+.	O
+	
+Group	O
+1	O
+had	O
+a	O
+moderate	O
+negative	O
+correlation	O
+between	O
+plasma	O
+histamine	O
+change	O
+and	O
+systemic	O
+vascular	O
+resistance	O
+(	O
+r	O
+=	O
+0	O
+.	O
+58	O
+;	O
+P	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+not	O
+present	O
+in	O
+group	O
+4	O
+.	O
+	
+Prior	O
+dosing	O
+with	O
+antagonists	O
+partially	O
+prevented	O
+the	O
+fall	O
+in	O
+systemic	O
+vascular	O
+resistance	O
+.	O
+	
+These	O
+data	O
+demonstrate	O
+that	O
+the	O
+hemodynamic	O
+changes	O
+associated	O
+with	O
+d	O
+-	O
+tubocurarine	O
+dosing	O
+are	O
+only	O
+partially	O
+explained	O
+by	O
+histamine	O
+release	O
+.	O
+	
+Thus	O
+prior	O
+dosing	O
+with	O
+H1	O
+-	O
+and	O
+H2	O
+-	O
+antagonists	O
+provides	O
+only	O
+partial	O
+protection	O
+.	O
+	
+Cholecystokinin	O
+-	O
+octapeptide	O
+restored	O
+morphine	O
+-	O
+induced	O
+hippocampal	O
+long	O
+-	O
+term	O
+potentiation	O
+impairment	O
+in	O
+rats	O
+.	O
+	
+Cholecystokinin	O
+-	O
+octapeptide	O
+(	O
+CCK	O
+-	O
+8	O
+)	O
+","	O
+which	O
+is	O
+a	O
+typical	O
+brain	O
+-	O
+gut	O
+peptide	O
+","	O
+exerts	O
+a	O
+wide	O
+range	O
+of	O
+biological	O
+activities	O
+on	O
+the	O
+central	O
+nervous	O
+system	O
+.	O
+	
+We	O
+have	O
+previously	O
+reported	O
+that	O
+CCK	O
+-	O
+8	O
+significantly	O
+alleviated	O
+morphine	O
+-	O
+induced	O
+amnesia	B-NP
+and	O
+reversed	O
+spine	O
+density	O
+decreases	O
+in	O
+the	O
+CA1	O
+region	O
+of	O
+the	O
+hippocampus	O
+in	O
+morphine	O
+-	O
+treated	O
+animals	O
+.	O
+	
+Here	O
+","	O
+we	O
+investigated	O
+the	O
+effects	O
+of	O
+CCK	O
+-	O
+8	O
+on	O
+long	O
+-	O
+term	O
+potentiation	O
+(	O
+LTP	O
+)	O
+in	O
+the	O
+lateral	O
+perforant	O
+path	O
+(	O
+LPP	O
+)	O
+-	O
+granule	O
+cell	O
+synapse	O
+of	O
+rat	O
+dentate	O
+gyrus	O
+(	O
+DG	O
+)	O
+in	O
+acute	O
+saline	O
+or	O
+morphine	O
+-	O
+treated	O
+rats	O
+.	O
+	
+Population	O
+spikes	O
+(	O
+PS	O
+)	O
+","	O
+which	O
+were	O
+evoked	O
+by	O
+stimulation	O
+of	O
+the	O
+LPP	O
+","	O
+were	O
+recorded	O
+in	O
+the	O
+DG	O
+region	O
+.	O
+	
+Acute	O
+morphine	O
+(	O
+30mg	O
+/	O
+kg	O
+","	O
+s	O
+.	O
+c	O
+.	O
+)	O
+treatment	O
+significantly	O
+attenuated	O
+hippocampal	O
+LTP	O
+and	O
+CCK	O
+-	O
+8	O
+(	O
+1ug	O
+","	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+restored	O
+the	O
+amplitude	O
+of	O
+PS	O
+that	O
+was	O
+attenuated	O
+by	O
+morphine	O
+injection	O
+.	O
+	
+Furthermore	O
+","	O
+microinjection	O
+of	O
+CCK	O
+-	O
+8	O
+(	O
+0	O
+.	O
+1	O
+and	O
+1ug	O
+","	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+also	O
+significantly	O
+augmented	O
+hippocampal	O
+LTP	O
+in	O
+saline	O
+-	O
+treated	O
+(	O
+1ml	O
+/	O
+kg	O
+","	O
+s	O
+.	O
+c	O
+.	O
+)	O
+rats	O
+.	O
+	
+Pre	O
+-	O
+treatment	O
+of	O
+the	O
+CCK2	O
+receptor	O
+antagonist	O
+L	O
+-	O
+365	O
+","	O
+260	O
+(	O
+10ug	O
+","	O
+i	O
+.	O
+c	O
+.	O
+v	O
+)	O
+reversed	O
+the	O
+effects	O
+of	O
+CCK	O
+-	O
+8	O
+","	O
+but	O
+the	O
+CCK1	O
+receptor	O
+antagonist	O
+L	O
+-	O
+364	O
+","	O
+718	O
+(	O
+10ug	O
+","	O
+i	O
+.	O
+c	O
+.	O
+v	O
+)	O
+did	O
+not	O
+.	O
+	
+The	O
+present	O
+results	O
+demonstrate	O
+that	O
+CCK	O
+-	O
+8	O
+attenuates	O
+the	O
+effect	O
+of	O
+morphine	O
+on	O
+hippocampal	O
+LTP	O
+through	O
+CCK2	O
+receptors	O
+and	O
+suggest	O
+an	O
+ameliorative	O
+function	O
+of	O
+CCK	O
+-	O
+8	O
+on	O
+morphine	O
+-	O
+induced	O
+memory	B-NP
+impairment	I-NP
+.	O
+	
+Glial	O
+activation	O
+and	O
+post	O
+-	O
+synaptic	O
+neurotoxicity	B-NP
+:	O
+the	O
+key	O
+events	O
+in	O
+Streptozotocin	O
+(	O
+ICV	O
+)	O
+induced	O
+memory	B-NP
+impairment	I-NP
+in	O
+rats	O
+.	O
+	
+In	O
+the	O
+present	O
+study	O
+the	O
+role	O
+of	O
+glial	O
+activation	O
+and	O
+post	O
+synaptic	O
+toxicity	B-NP
+in	O
+ICV	O
+Streptozotocin	O
+(	O
+STZ	O
+)	O
+induced	O
+memory	B-NP
+impaired	I-NP
+rats	O
+was	O
+explored	O
+.	O
+	
+In	O
+experiment	O
+set	O
+up	O
+1	O
+:	O
+Memory	B-NP
+deficit	I-NP
+was	O
+found	O
+in	O
+Morris	O
+water	O
+maze	O
+test	O
+on	O
+14	O
+-	O
+16	O
+days	O
+after	O
+STZ	O
+(	O
+ICV	O
+;	O
+3mg	O
+/	O
+Kg	O
+)	O
+administration	O
+.	O
+	
+STZ	O
+causes	O
+increased	O
+expression	O
+of	O
+GFAP	O
+","	O
+CD11b	O
+and	O
+TNF	O
+-	O
+a	O
+indicating	O
+glial	O
+activation	O
+and	O
+neuroinflammation	B-NP
+.	O
+	
+STZ	O
+also	O
+significantly	O
+increased	O
+the	O
+level	O
+of	O
+ROS	O
+","	O
+nitrite	O
+","	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+and	O
+reduced	O
+the	O
+mitochondrial	O
+activity	O
+in	O
+synaptosomal	O
+preparation	O
+illustrating	O
+free	O
+radical	O
+generation	O
+and	O
+excitotoxicity	B-NP
+.	O
+	
+Increased	O
+expression	O
+and	O
+activity	O
+of	O
+Caspase	O
+-	O
+3	O
+was	O
+also	O
+observed	O
+in	O
+STZ	O
+treated	O
+rat	O
+which	O
+specify	O
+apoptotic	O
+cell	O
+death	O
+in	O
+hippocampus	O
+and	O
+cortex	O
+.	O
+	
+STZ	O
+treatment	O
+showed	O
+decrease	O
+expression	O
+of	O
+post	O
+synaptic	O
+markers	O
+CaMKIIa	O
+and	O
+PSD	O
+-	O
+95	O
+","	O
+while	O
+","	O
+expression	O
+of	O
+pre	O
+synaptic	O
+markers	O
+(	O
+synaptophysin	O
+and	O
+SNAP	O
+-	O
+25	O
+)	O
+remains	O
+unaltered	O
+indicating	O
+selective	O
+post	O
+synaptic	O
+neurotoxicity	B-NP
+.	O
+	
+Oral	O
+treatment	O
+with	O
+Memantine	O
+(	O
+10mg	O
+/	O
+kg	O
+)	O
+and	O
+Ibuprofen	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+daily	O
+for	O
+13	O
+days	O
+attenuated	O
+STZ	O
+induced	O
+glial	O
+activation	O
+","	O
+apoptotic	O
+cell	O
+death	O
+and	O
+post	O
+synaptic	O
+neurotoxicity	B-NP
+in	O
+rat	O
+brain	O
+.	O
+	
+Further	O
+","	O
+in	O
+experiment	O
+set	O
+up	O
+2	O
+:	O
+where	O
+memory	O
+function	O
+was	O
+not	O
+affected	O
+i	O
+.	O
+e	O
+.	O
+7	O
+-	O
+9	O
+days	O
+after	O
+STZ	O
+treatment	O
+.	O
+	
+The	O
+level	O
+of	O
+GFAP	O
+","	O
+CD11b	O
+","	O
+TNF	O
+-	O
+a	O
+","	O
+ROS	O
+and	O
+nitrite	O
+levels	O
+were	O
+increased	O
+.	O
+	
+On	O
+the	O
+other	O
+hand	O
+","	O
+apoptotic	O
+marker	O
+","	O
+synaptic	O
+markers	O
+","	O
+mitochondrial	O
+activity	O
+and	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+levels	O
+remained	O
+unaffected	O
+.	O
+	
+Collective	O
+data	O
+indicates	O
+that	O
+neuroinflammatory	B-NP
+process	O
+and	O
+oxidative	O
+stress	O
+occurs	O
+earlier	O
+to	O
+apoptosis	O
+and	O
+does	O
+not	O
+affect	O
+memory	O
+function	O
+.	O
+	
+Present	O
+study	O
+clearly	O
+suggests	O
+that	O
+glial	O
+activation	O
+and	O
+post	O
+synaptic	O
+neurotoxicity	B-NP
+are	O
+the	O
+key	O
+factors	O
+in	O
+STZ	O
+induced	O
+memory	B-NP
+impairment	I-NP
+and	O
+neuronal	O
+cell	O
+death	O
+.	O
+	
+Comparison	O
+of	O
+effects	O
+of	O
+isotonic	O
+sodium	O
+chloride	O
+with	O
+diltiazem	O
+in	O
+prevention	O
+of	O
+contrast	O
+-	O
+induced	O
+nephropathy	B-NP
+.	O
+	
+INTRODUCTION	O
+AND	O
+OBJECTIVE	O
+:	O
+Contrast	O
+-	O
+induced	O
+nephropathy	B-NP
+(	O
+CIN	O
+)	O
+significantly	O
+increases	O
+the	O
+morbidity	O
+and	O
+mortality	O
+of	O
+patients	O
+.	O
+	
+The	O
+aim	O
+of	O
+this	O
+study	O
+is	O
+to	O
+investigate	O
+and	O
+compare	O
+the	O
+protective	O
+effects	O
+of	O
+isotonic	O
+sodium	O
+chloride	O
+with	O
+sodium	O
+bicarbonate	O
+infusion	O
+and	O
+isotonic	O
+sodium	O
+chloride	O
+infusion	O
+with	O
+diltiazem	O
+","	O
+a	O
+calcium	O
+channel	O
+blocker	O
+","	O
+in	O
+preventing	O
+CIN	O
+.	O
+	
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+Our	O
+study	O
+included	O
+patients	O
+who	O
+were	O
+administered	O
+30	O
+-	O
+60	O
+mL	O
+of	O
+iodinated	O
+contrast	O
+agent	O
+for	O
+percutaneous	O
+coronary	O
+angiography	O
+(	O
+PCAG	O
+)	O
+","	O
+all	O
+with	O
+creatinine	O
+values	O
+between	O
+1	O
+.	O
+1	O
+and	O
+3	O
+.	O
+1	O
+mg	O
+/	O
+dL	O
+.	O
+	
+Patients	O
+were	O
+divided	O
+into	O
+three	O
+groups	O
+and	O
+each	O
+group	O
+had	O
+20	O
+patients	O
+.	O
+	
+The	O
+first	O
+group	O
+of	O
+patients	O
+was	O
+administered	O
+isotonic	O
+sodium	O
+chloride	O
+;	O
+the	O
+second	O
+group	O
+was	O
+administered	O
+a	O
+solution	O
+that	O
+of	O
+5	O
+%	O
+dextrose	O
+and	O
+sodium	O
+bicarbonate	O
+","	O
+while	O
+the	O
+third	O
+group	O
+was	O
+administered	O
+isotonic	O
+sodium	O
+chloride	O
+before	O
+and	O
+after	O
+the	O
+contrast	O
+injection	O
+.	O
+	
+The	O
+third	O
+group	O
+received	O
+an	O
+additional	O
+injection	O
+of	O
+diltiazem	O
+the	O
+day	O
+before	O
+and	O
+first	O
+2	O
+days	O
+after	O
+the	O
+contrast	O
+injection	O
+.	O
+	
+All	O
+of	O
+the	O
+patients	O
+'	O
+plasma	O
+blood	O
+urea	O
+nitrogen	O
+(	O
+BUN	O
+)	O
+and	O
+creatinine	O
+levels	O
+were	O
+measured	O
+on	O
+the	O
+second	O
+and	O
+seventh	O
+day	O
+after	O
+the	O
+administration	O
+of	O
+intravenous	O
+contrast	O
+material	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+basal	O
+creatinine	O
+levels	O
+were	O
+similar	O
+for	O
+all	O
+three	O
+groups	O
+(	O
+p	O
+>	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+Among	O
+a	O
+total	O
+of	O
+60	O
+patients	O
+included	O
+in	O
+the	O
+study	O
+","	O
+16	O
+patients	O
+developed	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+(	O
+ARF	B-NP
+)	O
+on	O
+the	O
+second	O
+day	O
+after	O
+contrast	O
+material	O
+was	O
+injected	O
+(	O
+26	O
+.	O
+6	O
+%	O
+)	O
+.	O
+	
+The	O
+number	O
+of	O
+patients	O
+who	O
+developed	O
+ARF	B-NP
+on	O
+the	O
+second	O
+day	O
+after	O
+the	O
+injection	O
+in	O
+the	O
+first	O
+group	O
+was	O
+five	O
+(	O
+25	O
+%	O
+)	O
+","	O
+in	O
+the	O
+second	O
+group	O
+was	O
+six	O
+(	O
+30	O
+%	O
+)	O
+and	O
+the	O
+third	O
+group	O
+was	O
+five	O
+(	O
+25	O
+%	O
+)	O
+(	O
+p	O
+>	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+There	O
+was	O
+no	O
+significant	O
+difference	O
+between	O
+isotonic	O
+sodium	O
+chloride	O
+","	O
+sodium	O
+bicarbonate	O
+and	O
+isotonic	O
+sodium	O
+chloride	O
+with	O
+diltiazem	O
+application	O
+in	O
+prevention	O
+of	O
+CIN	O
+.	O
+	
+Neurocognitive	O
+and	O
+neuroradiologic	O
+central	O
+nervous	O
+system	O
+late	O
+effects	O
+in	O
+children	O
+treated	O
+on	O
+Pediatric	O
+Oncology	O
+Group	O
+(	O
+POG	O
+)	O
+P9605	O
+(	O
+standard	O
+risk	O
+)	O
+and	O
+P9201	O
+(	O
+lesser	O
+risk	O
+)	O
+acute	B-NP
+lymphoblastic	I-NP
+leukemia	I-NP
+protocols	O
+(	O
+ACCL0131	O
+)	O
+:	O
+a	O
+methotrexate	O
+consequence	O
+?	O
+	
+A	O
+report	O
+from	O
+the	O
+Children	O
+'	O
+s	O
+Oncology	O
+Group	O
+.	O
+	
+Concerns	O
+about	O
+long	O
+-	O
+term	O
+methotrexate	O
+(	O
+MTX	O
+)	O
+neurotoxicity	B-NP
+in	O
+the	O
+1990s	O
+led	O
+to	O
+modifications	O
+in	O
+intrathecal	O
+(	O
+IT	O
+)	O
+therapy	O
+","	O
+leucovorin	O
+rescue	O
+","	O
+and	O
+frequency	O
+of	O
+systemic	O
+MTX	O
+administration	O
+in	O
+children	O
+with	O
+acute	B-NP
+lymphoblastic	I-NP
+leukemia	I-NP
+.	O
+	
+In	O
+this	O
+study	O
+","	O
+neurocognitive	O
+outcomes	O
+and	O
+neuroradiologic	O
+evidence	O
+of	O
+leukoencephalopathy	B-NP
+were	O
+compared	O
+in	O
+children	O
+treated	O
+with	O
+intense	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+-	O
+directed	O
+therapy	O
+(	O
+P9605	O
+)	O
+versus	O
+those	O
+receiving	O
+fewer	O
+CNS	O
+-	O
+directed	O
+treatment	O
+days	O
+during	O
+intensive	O
+consolidation	O
+(	O
+P9201	O
+)	O
+.	O
+	
+A	O
+total	O
+of	O
+66	O
+children	O
+from	O
+16	O
+Pediatric	O
+Oncology	O
+Group	O
+institutions	O
+with	O
+"	O
+standard	O
+-	O
+risk	O
+"	O
+acute	B-NP
+lymphoblastic	I-NP
+leukemia	I-NP
+","	O
+1	O
+.	O
+0	O
+to	O
+9	O
+.	O
+99	O
+years	O
+at	O
+diagnosis	O
+","	O
+without	O
+evidence	O
+of	O
+CNS	O
+leukemia	B-NP
+at	O
+diagnosis	O
+were	O
+enrolled	O
+on	O
+ACCL0131	O
+:	O
+28	O
+from	O
+P9201	O
+and	O
+38	O
+from	O
+P9605	O
+.	O
+	
+Magnetic	O
+resonance	O
+imaging	O
+scans	O
+and	O
+standard	O
+neuropsychological	O
+tests	O
+were	O
+performed	O
+>	O
+2	O
+.	O
+6	O
+years	O
+after	O
+the	O
+end	O
+of	O
+treatment	O
+.	O
+	
+Significantly	O
+more	O
+P9605	O
+patients	O
+developed	O
+leukoencephalopathy	B-NP
+compared	O
+with	O
+P9201	O
+patients	O
+(	O
+68	O
+%	O
+","	O
+95	O
+%	O
+confidence	O
+interval	O
+49	O
+%	O
+-	O
+83	O
+%	O
+vs	O
+.	O
+22	O
+%	O
+","	O
+95	O
+%	O
+confidence	O
+interval	O
+5	O
+%	O
+-	O
+44	O
+%	O
+;	O
+P	O
+=	O
+0	O
+.	O
+1	O
+)	O
+identified	O
+as	O
+late	O
+as	O
+7	O
+.	O
+7	O
+years	O
+after	O
+the	O
+end	O
+of	O
+treatment	O
+.	O
+	
+Overall	O
+","	O
+40	O
+%	O
+of	O
+patients	O
+scored	O
+<	O
+85	O
+on	O
+either	O
+Verbal	O
+or	O
+Performance	O
+IQ	O
+.	O
+	
+Children	O
+on	O
+both	O
+studies	O
+had	O
+significant	O
+attention	B-NP
+problems	I-NP
+","	O
+but	O
+P9605	O
+children	O
+scored	O
+below	O
+average	O
+on	O
+more	O
+neurocognitive	O
+measures	O
+than	O
+those	O
+treated	O
+on	O
+P9201	O
+(	O
+82	O
+%	O
+","	O
+14	O
+/	O
+17	O
+measures	O
+vs	O
+.	O
+24	O
+%	O
+","	O
+4	O
+/	O
+17	O
+measures	O
+)	O
+.	O
+	
+This	O
+supports	O
+ongoing	O
+concerns	O
+about	O
+intensive	O
+MTX	O
+exposure	O
+as	O
+a	O
+major	O
+contributor	O
+to	O
+CNS	O
+late	O
+effects	O
+.	O
+	
+Tranexamic	O
+acid	O
+overdosage	O
+-	O
+induced	O
+generalized	O
+seizure	B-NP
+in	O
+renal	B-NP
+failure	I-NP
+.	O
+	
+We	O
+report	O
+a	O
+45	O
+-	O
+year	O
+-	O
+old	O
+lady	O
+with	O
+chronic	B-NP
+kidney	I-NP
+disease	I-NP
+stage	O
+4	O
+due	O
+to	O
+chronic	O
+tubulointerstial	B-NP
+disease	I-NP
+.	O
+	
+She	O
+was	O
+admitted	O
+to	O
+our	O
+center	O
+for	O
+severe	O
+anemia	B-NP
+due	O
+to	O
+menorrhagia	B-NP
+and	O
+deterioration	B-NP
+of	I-NP
+renal	I-NP
+function	I-NP
+.	O
+	
+She	O
+was	O
+infused	O
+three	O
+units	O
+of	O
+packed	O
+cells	O
+during	O
+a	O
+session	O
+of	O
+hemodialysis	O
+.	O
+	
+Tranexamic	O
+acid	O
+(	O
+TNA	O
+)	O
+1	O
+g	O
+8	O
+-	O
+hourly	O
+was	O
+administered	O
+to	O
+her	O
+to	O
+control	O
+bleeding	B-NP
+per	O
+vaginum	O
+.	O
+	
+Two	O
+hours	O
+after	O
+the	O
+sixth	O
+dose	O
+of	O
+TNA	O
+","	O
+she	O
+had	O
+an	O
+episode	O
+of	O
+generalized	O
+tonic	B-NP
+clonic	I-NP
+convulsions	I-NP
+.	O
+	
+TNA	O
+was	O
+discontinued	O
+.	O
+	
+Investigations	O
+of	O
+the	O
+patient	O
+revealed	O
+no	O
+biochemical	O
+or	O
+structural	O
+central	O
+nervous	B-NP
+system	I-NP
+abnormalities	I-NP
+that	O
+could	O
+have	O
+provoked	O
+the	O
+convulsions	B-NP
+.	O
+	
+She	O
+did	O
+not	O
+require	O
+any	O
+further	O
+dialytic	O
+support	O
+.	O
+	
+She	O
+had	O
+no	O
+further	O
+episodes	O
+of	O
+convulsion	B-NP
+till	O
+dis	O
+-	O
+charge	O
+and	O
+during	O
+the	O
+two	O
+months	O
+of	O
+follow	O
+-	O
+up	O
+.	O
+	
+Thus	O
+","	O
+the	O
+precipitating	O
+cause	O
+of	O
+convulsions	B-NP
+was	O
+believed	O
+to	O
+be	O
+an	O
+overdose	B-NP
+of	O
+TNA	O
+.	O
+	
+Pre	O
+-	O
+treatment	O
+of	O
+bupivacaine	O
+-	O
+induced	O
+cardiovascular	B-NP
+depression	I-NP
+using	O
+different	O
+lipid	O
+formulations	O
+of	O
+propofol	O
+.	O
+	
+BACKGROUND	O
+:	O
+Pre	O
+-	O
+treatment	O
+with	O
+lipid	O
+emulsions	O
+has	O
+been	O
+shown	O
+to	O
+increase	O
+lethal	O
+doses	O
+of	O
+bupivacaine	O
+","	O
+and	O
+the	O
+lipid	O
+content	O
+of	O
+propofol	O
+may	O
+alleviate	O
+bupivacaine	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+.	O
+	
+The	O
+aim	O
+of	O
+this	O
+study	O
+is	O
+to	O
+investigate	O
+the	O
+effects	O
+of	O
+propofol	O
+in	O
+intralipid	O
+or	O
+medialipid	O
+emulsions	O
+on	O
+bupivacaine	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+.	O
+	
+METHODS	O
+:	O
+Rats	O
+were	O
+anaesthetised	O
+with	O
+ketamine	O
+and	O
+were	O
+given	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+/	O
+min	O
+propofol	O
+in	O
+intralipid	O
+(	O
+Group	O
+P	O
+)	O
+","	O
+propofol	O
+in	O
+medialipid	O
+(	O
+Group	O
+L	O
+)	O
+","	O
+or	O
+saline	O
+(	O
+Group	O
+C	O
+)	O
+over	O
+20	O
+min	O
+.	O
+	
+Thereafter	O
+","	O
+2	O
+mg	O
+/	O
+kg	O
+/	O
+min	O
+bupivacaine	O
+0	O
+.	O
+5	O
+%	O
+was	O
+infused	O
+.	O
+	
+We	O
+recorded	O
+time	O
+to	O
+first	O
+dysrhythmia	B-NP
+occurrence	O
+","	O
+respective	O
+times	O
+to	O
+25	O
+%	O
+and	O
+50	O
+%	O
+reduction	O
+of	O
+the	O
+heart	O
+rate	O
+(	O
+HR	O
+)	O
+and	O
+mean	O
+arterial	O
+pressure	O
+","	O
+and	O
+time	O
+to	O
+asystole	B-NP
+and	O
+total	O
+amount	O
+of	O
+bupivacaine	O
+consumption	O
+.	O
+	
+Blood	O
+and	O
+tissue	O
+samples	O
+were	O
+collected	O
+following	O
+asystole	B-NP
+.	O
+	
+RESULTS	O
+:	O
+The	O
+time	O
+to	O
+first	O
+dysrhythmia	B-NP
+occurrence	O
+","	O
+time	O
+to	O
+25	O
+%	O
+and	O
+50	O
+%	O
+reductions	O
+in	O
+HR	O
+","	O
+and	O
+time	O
+to	O
+asystole	B-NP
+were	O
+longer	O
+in	O
+Group	O
+P	O
+than	O
+the	O
+other	O
+groups	O
+.	O
+	
+The	O
+cumulative	O
+bupivacaine	O
+dose	O
+given	O
+at	O
+those	O
+time	O
+points	O
+was	O
+higher	O
+in	O
+Group	O
+P	O
+.	O
+Plasma	O
+bupivacaine	O
+levels	O
+were	O
+significantly	O
+lower	O
+in	O
+Group	O
+P	O
+than	O
+in	O
+Group	O
+C	O
+.	O
+Bupivacaine	O
+levels	O
+in	O
+the	O
+brain	O
+and	O
+heart	O
+were	O
+significantly	O
+lower	O
+in	O
+Group	O
+P	O
+and	O
+Group	O
+L	O
+than	O
+in	O
+Group	O
+C	O
+.	O
+	
+CONCLUSION	O
+:	O
+We	O
+conclude	O
+that	O
+pre	O
+-	O
+treatment	O
+with	O
+propofol	O
+in	O
+intralipid	O
+","	O
+compared	O
+with	O
+propofol	O
+in	O
+medialipid	O
+or	O
+saline	O
+","	O
+delayed	O
+the	O
+onset	O
+of	O
+bupivacaine	O
+-	O
+induced	O
+cardiotoxic	B-NP
+effects	O
+as	O
+well	O
+as	O
+reduced	O
+plasma	O
+bupivacaine	O
+levels	O
+.	O
+	
+Further	O
+studies	O
+are	O
+needed	O
+to	O
+explore	O
+tissue	O
+bupivacaine	O
+levels	O
+of	O
+propofol	O
+in	O
+medialipid	O
+and	O
+adapt	O
+these	O
+results	O
+to	O
+clinical	O
+practice	O
+.	O
+	
+Drug	B-NP
+-	I-NP
+Induced	I-NP
+Acute	I-NP
+Liver	I-NP
+Injury	I-NP
+Within	O
+12	O
+Hours	O
+After	O
+Fluvastatin	O
+Therapy	O
+.	O
+	
+Although	O
+statins	O
+are	O
+generally	O
+well	O
+-	O
+tolerated	O
+drugs	O
+","	O
+recent	O
+cases	O
+of	O
+drug	B-NP
+-	I-NP
+induced	I-NP
+liver	I-NP
+injury	I-NP
+associated	O
+with	O
+their	O
+use	O
+have	O
+been	O
+reported	O
+.	O
+	
+A	O
+52	O
+-	O
+year	O
+-	O
+old	O
+Chinese	O
+man	O
+reported	O
+with	O
+liver	B-NP
+damage	I-NP
+","	O
+which	O
+appeared	O
+12	O
+hours	O
+after	O
+beginning	O
+treatment	O
+with	O
+fluvastatin	O
+.	O
+	
+Patient	O
+presented	O
+with	O
+complaints	O
+of	O
+increasing	O
+nausea	B-NP
+","	O
+anorexia	B-NP
+","	O
+and	O
+upper	O
+abdominal	B-NP
+pain	I-NP
+.	O
+	
+His	O
+laboratory	O
+values	O
+showed	O
+elevated	O
+creatine	O
+kinase	O
+and	O
+transaminases	O
+.	O
+	
+Testing	O
+for	O
+autoantibodies	O
+was	O
+also	O
+negative	O
+.	O
+	
+The	O
+liver	O
+biochemistries	O
+eventually	O
+normalized	O
+within	O
+3	O
+weeks	O
+of	O
+stopping	O
+the	O
+fluvastatin	O
+.	O
+	
+Therefore	O
+","	O
+when	O
+prescribing	O
+statins	O
+","	O
+the	O
+possibility	O
+of	O
+hepatic	B-NP
+damage	I-NP
+should	O
+be	O
+taken	O
+into	O
+account	O
+.	O
+	
+Fluconazole	O
+associated	O
+agranulocytosis	B-NP
+and	O
+thrombocytopenia	B-NP
+.	O
+	
+CASE	O
+:	O
+We	O
+describe	O
+a	O
+second	O
+case	O
+of	O
+fluconazole	O
+associated	O
+agranulocytosis	B-NP
+with	O
+thrombocytopenia	B-NP
+and	O
+recovery	O
+upon	O
+discontinuation	O
+of	O
+therapy	O
+.	O
+	
+The	O
+patient	O
+began	O
+to	O
+have	O
+changes	O
+in	O
+white	O
+blood	O
+cells	O
+and	O
+platelets	O
+within	O
+48	O
+h	O
+of	O
+administration	O
+of	O
+fluconazole	O
+and	O
+began	O
+to	O
+recover	O
+with	O
+48	O
+h	O
+of	O
+discontinuation	O
+.	O
+	
+This	O
+case	O
+highlights	O
+that	O
+drug	O
+-	O
+induced	O
+blood	B-NP
+dyscrasias	I-NP
+can	O
+occur	O
+unexpectedly	O
+as	O
+a	O
+result	O
+of	O
+treatment	O
+with	O
+a	O
+commonly	O
+used	O
+drug	O
+thought	O
+to	O
+be	O
+"	O
+safe	O
+"	O
+.	O
+	
+CONCLUSION	O
+:	O
+According	O
+to	O
+Naranjo	O
+'	O
+s	O
+algorithm	O
+the	O
+likelihood	O
+that	O
+our	O
+patient	O
+'	O
+s	O
+agranulocytosis	B-NP
+and	O
+thrombocytopenia	B-NP
+occurred	O
+as	O
+a	O
+result	O
+of	O
+therapy	O
+with	O
+fluconazole	O
+is	O
+probable	O
+","	O
+with	O
+a	O
+total	O
+of	O
+six	O
+points	O
+.	O
+	
+We	O
+feel	O
+that	O
+the	O
+weight	O
+of	O
+the	O
+overall	O
+evidence	O
+of	O
+this	O
+evidence	O
+is	O
+strong	O
+.	O
+	
+In	O
+particular	O
+the	O
+temporal	O
+relationship	O
+of	O
+bone	B-NP
+marrow	I-NP
+suppression	I-NP
+to	O
+the	O
+initiation	O
+of	O
+fluconazole	O
+and	O
+the	O
+abatement	O
+of	O
+symptoms	O
+that	O
+rapidly	O
+reversed	O
+immediately	O
+following	O
+discontinuation	O
+.	O
+	
+Two	O
+-	O
+dimensional	O
+speckle	O
+tracking	O
+echocardiography	O
+combined	O
+with	O
+high	O
+-	O
+sensitive	O
+cardiac	O
+troponin	O
+T	O
+in	O
+early	O
+detection	O
+and	O
+prediction	O
+of	O
+cardiotoxicity	B-NP
+during	O
+epirubicine	O
+-	O
+based	O
+chemotherapy	O
+.	O
+	
+AIMS	O
+:	O
+To	O
+investigate	O
+whether	O
+alterations	O
+of	O
+myocardial	B-NP
+strain	I-NP
+and	O
+high	O
+-	O
+sensitive	O
+cardiac	O
+troponin	O
+T	O
+(	O
+cTnT	O
+)	O
+could	O
+predict	O
+future	O
+cardiac	B-NP
+dysfunction	I-NP
+in	O
+patients	O
+after	O
+epirubicin	O
+exposure	O
+.	O
+	
+METHODS	O
+:	O
+Seventy	O
+-	O
+five	O
+patients	O
+with	O
+non	B-NP
+-	I-NP
+Hodgkin	I-NP
+lymphoma	I-NP
+treated	O
+with	O
+epirubicin	O
+were	O
+studied	O
+.	O
+	
+Blood	O
+collection	O
+and	O
+echocardiography	O
+were	O
+performed	O
+at	O
+baseline	O
+","	O
+1	O
+day	O
+after	O
+the	O
+third	O
+cycle	O
+","	O
+and	O
+1	O
+day	O
+after	O
+completion	O
+of	O
+chemotherapy	O
+.	O
+	
+Patients	O
+were	O
+studied	O
+using	O
+echocardiography	O
+during	O
+follow	O
+-	O
+up	O
+.	O
+	
+Global	O
+longitudinal	O
+(	O
+GLS	O
+)	O
+","	O
+circumferential	O
+(	O
+GCS	O
+)	O
+","	O
+and	O
+radial	O
+strain	O
+(	O
+GRS	O
+)	O
+were	O
+calculated	O
+using	O
+speckle	O
+tracking	O
+echocardiography	O
+.	O
+	
+Left	O
+ventricular	O
+ejection	O
+fraction	O
+was	O
+analysed	O
+by	O
+real	O
+-	O
+time	O
+3D	O
+echocardiography	O
+.	O
+	
+Cardiotoxicity	B-NP
+was	O
+defined	O
+as	O
+a	O
+reduction	O
+of	O
+the	O
+LVEF	O
+of	O
+>	O
+5	O
+%	O
+to	O
+<	O
+55	O
+%	O
+with	O
+symptoms	O
+of	O
+heart	B-NP
+failure	I-NP
+or	O
+an	O
+asymptomatic	O
+reduction	O
+of	O
+the	O
+LVEF	O
+of	O
+>	O
+10	O
+%	O
+to	O
+<	O
+55	O
+%	O
+.	O
+	
+RESULTS	O
+:	O
+Fourteen	O
+patients	O
+(	O
+18	O
+.	O
+67	O
+%	O
+)	O
+developed	O
+cardiotoxicity	B-NP
+after	O
+treatment	O
+.	O
+	
+GLS	O
+(	O
+-	O
+18	O
+.	O
+48	O
++	O
+1	O
+.	O
+72	O
+%	O
+vs	O
+.	O
+-	O
+15	O
+.	O
+96	O
++	O
+1	O
+.	O
+6	O
+%	O
+)	O
+","	O
+GCS	O
+(	O
+-	O
+20	O
+.	O
+93	O
++	O
+2	O
+.	O
+86	O
+%	O
+vs	O
+.	O
+-	O
+19	O
+.	O
+20	O
++	O
+3	O
+.	O
+21	O
+%	O
+)	O
+","	O
+and	O
+GRS	O
+(	O
+39	O
+.	O
+23	O
++	O
+6	O
+.	O
+44	O
+%	O
+vs	O
+.	O
+34	O
+.	O
+98	O
++	O
+6	O
+.	O
+2	O
+%	O
+)	O
+were	O
+markedly	O
+reduced	O
+and	O
+cTnT	O
+was	O
+elevated	O
+from	O
+0	O
+.	O
+10	O
++	O
+0	O
+.	O
+20	O
+to	O
+0	O
+.	O
+73	O
++	O
+0	O
+.	O
+38	O
+ng	O
+/	O
+mL	O
+(	O
+P	O
+all	O
+<	O
+0	O
+.	O
+1	O
+)	O
+at	O
+the	O
+completion	O
+of	O
+chemotherapy	O
+compared	O
+with	O
+baseline	O
+values	O
+.	O
+	
+A	O
+>	O
+15	O
+.	O
+9	O
+%	O
+decrease	O
+in	O
+GLS	O
+[	O
+sensitivity	O
+","	O
+86	O
+%	O
+;	O
+specificity	O
+","	O
+75	O
+%	O
+;	O
+area	O
+under	O
+the	O
+curve	O
+(	O
+AUC	O
+)	O
+=	O
+0	O
+.	O
+815	O
+;	O
+P	O
+=	O
+0	O
+.	O
+1	O
+]	O
+and	O
+a	O
+>	O
+0	O
+.	O
+4	O
+ng	O
+/	O
+mL	O
+elevation	O
+in	O
+cTnT	O
+(	O
+sensitivity	O
+","	O
+79	O
+%	O
+;	O
+specificity	O
+","	O
+64	O
+%	O
+;	O
+AUC	O
+=	O
+0	O
+.	O
+757	O
+;	O
+P	O
+=	O
+0	O
+.	O
+5	O
+)	O
+from	O
+baseline	O
+to	O
+the	O
+third	O
+cycle	O
+of	O
+chemotherapy	O
+predicted	O
+later	O
+cardiotoxicity	B-NP
+.	O
+	
+The	O
+decrease	O
+in	O
+GLS	O
+remained	O
+the	O
+only	O
+independent	O
+predictor	O
+of	O
+cardiotoxicity	B-NP
+(	O
+P	O
+=	O
+0	O
+.	O
+0	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+GLS	O
+combined	O
+with	O
+cTnT	O
+may	O
+provide	O
+a	O
+reliable	O
+and	O
+non	O
+-	O
+invasive	O
+method	O
+to	O
+predict	O
+cardiac	B-NP
+dysfunction	I-NP
+in	O
+patients	O
+receiving	O
+anthracycline	O
+-	O
+based	O
+chemotherapy	O
+.	O
+	
+Prevention	O
+of	O
+etomidate	O
+-	O
+induced	O
+myoclonus	B-NP
+:	O
+which	O
+is	O
+superior	O
+:	O
+Fentanyl	O
+","	O
+midazolam	O
+","	O
+or	O
+a	O
+combination	O
+?	O
+	
+A	O
+Retrospective	O
+comparative	O
+study	O
+.	O
+	
+BACKGROUND	O
+:	O
+In	O
+this	O
+retrospective	O
+comparative	O
+study	O
+","	O
+we	O
+aimed	O
+to	O
+compare	O
+the	O
+effectiveness	O
+of	O
+fentanyl	O
+","	O
+midazolam	O
+","	O
+and	O
+a	O
+combination	O
+of	O
+fentanyl	O
+and	O
+midazolam	O
+to	O
+prevent	O
+etomidate	O
+-	O
+induced	O
+myoclonus	B-NP
+.	O
+	
+MATERIAL	O
+AND	O
+METHODS	O
+:	O
+This	O
+study	O
+was	O
+performed	O
+based	O
+on	O
+anesthesia	O
+records	O
+.	O
+	
+Depending	O
+on	O
+the	O
+drugs	O
+that	O
+would	O
+be	O
+given	O
+before	O
+the	O
+induction	O
+of	O
+anesthesia	O
+with	O
+etomidate	O
+","	O
+the	O
+patients	O
+were	O
+separated	O
+into	O
+4	O
+groups	O
+:	O
+no	O
+pretreatment	O
+(	O
+Group	O
+NP	O
+)	O
+","	O
+fentanyl	O
+1	O
+ug	O
+.	O
+kg	O
+-	O
+1	O
+(	O
+Group	O
+F	O
+)	O
+","	O
+midazolam	O
+0	O
+.	O
+3	O
+mg	O
+.	O
+kg	O
+-	O
+1	O
+(	O
+Group	O
+M	O
+)	O
+","	O
+and	O
+midazolam	O
+0	O
+.	O
+15	O
+mg	O
+.	O
+kg	O
+-	O
+1	O
++	O
+fentanyl	O
+0	O
+.	O
+5	O
+ug	O
+.	O
+kg	O
+-	O
+1	O
+(	O
+Group	O
+FM	O
+)	O
+.	O
+	
+Patients	O
+who	O
+received	O
+the	O
+same	O
+anesthetic	O
+procedure	O
+were	O
+selected	O
+:	O
+2	O
+minutes	O
+after	O
+intravenous	O
+injections	O
+of	O
+the	O
+pretreatment	O
+drugs	O
+","	O
+anesthesia	O
+is	O
+induced	O
+with	O
+0	O
+.	O
+3	O
+mg	O
+.	O
+kg	O
+-	O
+1	O
+etomidate	O
+injected	O
+intravenously	O
+over	O
+a	O
+period	O
+of	O
+20	O
+-	O
+30	O
+seconds	O
+.	O
+	
+Myoclonic	B-NP
+movements	I-NP
+are	O
+evaluated	O
+","	O
+which	O
+were	O
+observed	O
+and	O
+graded	O
+according	O
+to	O
+clinical	O
+severity	O
+during	O
+the	O
+2	O
+minutes	O
+after	O
+etomidate	O
+injection	O
+.	O
+	
+The	O
+severity	O
+of	O
+pain	B-NP
+due	O
+to	O
+etomidate	O
+injection	O
+","	O
+mean	O
+arterial	O
+pressure	O
+","	O
+heart	O
+rate	O
+","	O
+and	O
+adverse	O
+effects	O
+were	O
+also	O
+evaluated	O
+.	O
+	
+RESULTS	O
+:	O
+Study	O
+results	O
+showed	O
+that	O
+myoclonus	B-NP
+incidence	O
+was	O
+85	O
+%	O
+","	O
+40	O
+%	O
+","	O
+70	O
+%	O
+","	O
+and	O
+25	O
+%	O
+in	O
+Group	O
+NP	O
+","	O
+Group	O
+F	O
+","	O
+Group	O
+M	O
+","	O
+and	O
+Group	O
+FM	O
+","	O
+respectively	O
+","	O
+and	O
+were	O
+significantly	O
+lower	O
+in	O
+Group	O
+F	O
+and	O
+Group	O
+FM	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+We	O
+conclude	O
+that	O
+pretreatment	O
+with	O
+fentanyl	O
+or	O
+combination	O
+of	O
+fentanyl	O
+and	O
+midazolam	O
+was	O
+effective	O
+in	O
+preventing	O
+etomidate	O
+-	O
+induced	O
+myoclonus	B-NP
+.	O
+	
+Convulsant	O
+effect	O
+of	O
+lindane	O
+and	O
+regional	O
+brain	O
+concentration	O
+of	O
+GABA	O
+and	O
+dopamine	O
+.	O
+	
+Lindane	O
+(	O
+gamma	O
+-	O
+hexachlorocyclohexane	O
+)	O
+is	O
+an	O
+organochlorine	O
+insecticide	O
+with	O
+known	O
+neurotoxic	B-NP
+effects	O
+.	O
+	
+Its	O
+mechanism	O
+of	O
+action	O
+is	O
+not	O
+well	O
+understood	O
+although	O
+it	O
+has	O
+been	O
+proposed	O
+that	O
+lindane	O
+acts	O
+as	O
+a	O
+non	O
+-	O
+competitive	O
+antagonist	O
+at	O
+the	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+(	O
+GABA	O
+)	O
+-	O
+A	O
+receptor	O
+.	O
+	
+We	O
+studied	O
+the	O
+effect	O
+of	O
+lindane	O
+(	O
+150	O
+mg	O
+/	O
+kg	O
+)	O
+on	O
+the	O
+GABAergic	O
+and	O
+dopaminergic	O
+systems	O
+by	O
+measuring	O
+the	O
+concentration	O
+of	O
+GABA	O
+","	O
+dopamine	O
+and	O
+its	O
+metabolites	O
+in	O
+7	O
+brain	O
+areas	O
+at	O
+the	O
+onset	O
+of	O
+seizures	B-NP
+.	O
+	
+All	O
+animals	O
+suffered	O
+tonic	O
+convulsions	B-NP
+at	O
+18	O
+.	O
+3	O
++	O
+/	O
+-	O
+1	O
+.	O
+4	O
+min	O
+after	O
+lindane	O
+administration	O
+.	O
+	
+The	O
+concentration	O
+of	O
+GABA	O
+was	O
+only	O
+slightly	O
+but	O
+significantly	O
+decreased	O
+in	O
+the	O
+colliculi	O
+without	O
+modifications	O
+in	O
+the	O
+other	O
+areas	O
+.	O
+	
+The	O
+concentration	O
+of	O
+dopamine	O
+was	O
+increased	O
+in	O
+the	O
+mesencephalon	O
+and	O
+that	O
+of	O
+its	O
+metabolite	O
+DOPAC	O
+was	O
+also	O
+increased	O
+in	O
+the	O
+mesencephalon	O
+and	O
+the	O
+striatum	O
+.	O
+	
+Cholestatic	B-NP
+presentation	O
+of	O
+yellow	O
+phosphorus	O
+poisoning	B-NP
+.	O
+	
+Yellow	O
+phosphorus	O
+","	O
+a	O
+component	O
+of	O
+certain	O
+pesticide	O
+pastes	O
+and	O
+fireworks	O
+","	O
+is	O
+well	O
+known	O
+to	O
+cause	O
+hepatotoxicity	B-NP
+.	O
+	
+Poisoning	B-NP
+with	O
+yellow	O
+phosphorus	O
+classically	O
+manifests	O
+with	O
+acute	B-NP
+hepatitis	I-NP
+leading	O
+to	O
+acute	B-NP
+liver	I-NP
+failure	I-NP
+which	O
+may	O
+need	O
+liver	O
+transplantation	O
+.	O
+	
+We	O
+present	O
+a	O
+case	O
+of	O
+yellow	O
+phosphorus	O
+poisoning	B-NP
+in	O
+which	O
+a	O
+patient	O
+presented	O
+with	O
+florid	O
+clinical	O
+features	O
+of	O
+cholestasis	B-NP
+highlighting	O
+the	O
+fact	O
+that	O
+cholestasis	B-NP
+can	O
+rarely	O
+be	O
+a	O
+presenting	O
+feature	O
+of	O
+yellow	O
+phosphorus	O
+hepatotoxicity	B-NP
+.	O
+	
+Vasovagal	B-NP
+syncope	I-NP
+and	O
+severe	O
+bradycardia	B-NP
+following	O
+intranasal	O
+dexmedetomidine	O
+for	O
+pediatric	O
+procedural	O
+sedation	O
+.	O
+	
+We	O
+report	O
+syncope	B-NP
+and	O
+bradycardia	B-NP
+in	O
+an	O
+11	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+following	O
+administration	O
+of	O
+intranasal	O
+dexmedetomidine	O
+for	O
+sedation	O
+for	O
+a	O
+voiding	O
+cystourethrogram	O
+.	O
+	
+Following	O
+successful	O
+completion	O
+of	O
+VCUG	O
+and	O
+a	O
+60	O
+-	O
+min	O
+recovery	O
+period	O
+","	O
+the	O
+patient	O
+'	O
+s	O
+level	O
+of	O
+consciousness	O
+and	O
+vital	O
+signs	O
+returned	O
+to	O
+presedation	O
+levels	O
+.	O
+	
+Upon	O
+leaving	O
+the	O
+sedation	O
+area	O
+","	O
+the	O
+patient	O
+collapsed	O
+","	O
+with	O
+no	O
+apparent	O
+inciting	O
+event	O
+.	O
+	
+The	O
+patient	O
+quickly	O
+regained	O
+consciousness	O
+and	O
+no	O
+injury	O
+occurred	O
+.	O
+	
+The	O
+primary	O
+abnormality	O
+found	O
+was	O
+persistent	O
+bradycardia	B-NP
+","	O
+and	O
+she	O
+was	O
+admitted	O
+to	O
+the	O
+hospital	O
+for	O
+telemetric	O
+observation	O
+.	O
+	
+The	O
+bradycardia	B-NP
+lasted	O
+~	O
+2	O
+h	O
+","	O
+and	O
+further	O
+cardiac	O
+workup	O
+revealed	O
+no	O
+underlying	O
+abnormality	O
+.	O
+	
+Unanticipated	O
+and	O
+previously	O
+unreported	O
+outcomes	O
+may	O
+be	O
+witnessed	O
+as	O
+we	O
+expand	O
+the	O
+use	O
+of	O
+certain	O
+sedatives	O
+to	O
+alternative	O
+routes	O
+of	O
+administration	O
+.	O
+	
+Paradoxical	O
+severe	O
+agitation	B-NP
+induced	O
+by	O
+add	O
+-	O
+on	O
+high	O
+-	O
+doses	O
+quetiapine	O
+in	O
+schizo	B-NP
+-	I-NP
+affective	I-NP
+disorder	I-NP
+.	O
+	
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+35	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+suffering	O
+from	O
+schizo	B-NP
+-	I-NP
+affective	I-NP
+disorder	I-NP
+since	O
+the	O
+age	O
+of	O
+19	O
+years	O
+","	O
+treated	O
+by	O
+a	O
+combination	O
+of	O
+first	O
+-	O
+generation	O
+antipsychotics	O
+","	O
+zuclopenthixol	O
+(	O
+100	O
+mg	O
+/	O
+day	O
+)	O
+and	O
+lithium	O
+(	O
+1200	O
+mg	O
+/	O
+day	O
+)	O
+(	O
+serum	O
+lithium	O
+=	O
+0	O
+.	O
+85	O
+mEq	O
+/	O
+l	O
+)	O
+.	O
+	
+This	O
+patient	O
+had	O
+no	O
+associated	O
+personality	B-NP
+disorder	I-NP
+(	O
+particularly	O
+no	O
+antisocial	B-NP
+disorder	I-NP
+)	O
+and	O
+no	O
+substance	B-NP
+abuse	I-NP
+disorder	I-NP
+.	O
+	
+Within	O
+the	O
+48	O
+h	O
+following	O
+the	O
+gradual	O
+introduction	O
+of	O
+quetiapine	O
+(	O
+up	O
+to	O
+600	O
+mg	O
+/	O
+day	O
+)	O
+","	O
+the	O
+patient	O
+presented	O
+severe	O
+agitation	B-NP
+without	O
+an	O
+environmental	O
+explanation	O
+","	O
+contrasting	O
+with	O
+the	O
+absence	O
+of	O
+a	O
+history	O
+of	O
+aggressiveness	B-NP
+or	O
+personality	B-NP
+disorder	I-NP
+.	O
+	
+The	O
+diagnoses	O
+of	O
+manic	B-NP
+shift	O
+and	O
+akathisia	B-NP
+were	O
+dismissed	O
+.	O
+	
+The	O
+withdrawal	O
+and	O
+the	O
+gradual	O
+reintroduction	O
+of	O
+quetiapine	O
+2	O
+weeks	O
+later	O
+","	O
+which	O
+led	O
+to	O
+another	O
+severe	O
+agitation	B-NP
+","	O
+enabled	O
+us	O
+to	O
+attribute	O
+the	O
+agitation	B-NP
+specifically	O
+to	O
+quetiapine	O
+.	O
+	
+Antioxidant	O
+effects	O
+of	O
+bovine	O
+lactoferrin	O
+on	O
+dexamethasone	O
+-	O
+induced	O
+hypertension	B-NP
+in	O
+rat	O
+.	O
+	
+Dexamethasone	O
+-	O
+(	O
+Dex	O
+-	O
+)	O
+induced	O
+hypertension	B-NP
+is	O
+associated	O
+with	O
+enhanced	O
+oxidative	O
+stress	O
+.	O
+	
+Lactoferrin	O
+(	O
+LF	O
+)	O
+is	O
+an	O
+iron	O
+-	O
+binding	O
+glycoprotein	O
+with	O
+antihypertensive	O
+properties	O
+.	O
+	
+In	O
+this	O
+study	O
+","	O
+we	O
+investigated	O
+the	O
+effect	O
+of	O
+chronic	O
+administration	O
+of	O
+LF	O
+on	O
+oxidative	O
+stress	O
+and	O
+hypertension	B-NP
+upon	O
+Dex	O
+administration	O
+.	O
+	
+Male	O
+Wistar	O
+rats	O
+were	O
+treated	O
+by	O
+Dex	O
+(	O
+30	O
+u	O
+g	O
+/	O
+kg	O
+/	O
+day	O
+subcutaneously	O
+)	O
+or	O
+saline	O
+for	O
+14	O
+days	O
+.	O
+	
+Oral	O
+bovine	O
+LF	O
+(	O
+30	O
+","	O
+100	O
+","	O
+300	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+given	O
+from	O
+day	O
+8	O
+to	O
+14	O
+in	O
+a	O
+reversal	O
+study	O
+.	O
+	
+In	O
+a	O
+prevention	O
+study	O
+","	O
+rats	O
+received	O
+4	O
+days	O
+of	O
+LF	O
+treatment	O
+followed	O
+by	O
+Dex	O
+and	O
+continued	O
+during	O
+the	O
+test	O
+period	O
+.	O
+	
+Systolic	O
+blood	O
+pressure	O
+(	O
+SBP	O
+)	O
+was	O
+measured	O
+using	O
+tail	O
+-	O
+cuff	O
+method	O
+.	O
+	
+Thymus	O
+weight	O
+was	O
+used	O
+as	O
+a	O
+marker	O
+of	O
+glucocorticoid	O
+activity	O
+.	O
+	
+Plasma	O
+hydrogen	O
+peroxide	O
+(	O
+H2O2	O
+)	O
+concentration	O
+and	O
+ferric	O
+reducing	O
+antioxidant	O
+power	O
+(	O
+FRAP	O
+)	O
+value	O
+were	O
+determined	O
+.	O
+	
+Dexamethasone	O
+significantly	O
+increased	O
+SBP	O
+and	O
+plasma	O
+H2O2	O
+level	O
+and	O
+decreased	O
+thymus	O
+and	O
+body	O
+weights	O
+.	O
+	
+LF	O
+lowered	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+and	O
+dose	O
+dependently	O
+prevented	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+Dex	O
+-	O
+induced	O
+hypertension	B-NP
+.	O
+	
+LF	O
+prevented	O
+body	O
+weight	B-NP
+loss	I-NP
+and	O
+significantly	O
+reduced	O
+the	O
+elevated	O
+plasma	O
+H2O2	O
+and	O
+increased	O
+FRAP	O
+values	O
+.	O
+	
+Chronic	O
+administration	O
+of	O
+LF	O
+strongly	O
+reduced	O
+the	O
+blood	O
+pressure	O
+and	O
+production	O
+of	O
+ROS	O
+and	O
+improved	O
+antioxidant	O
+capacity	O
+in	O
+Dex	O
+-	O
+induced	O
+hypertension	B-NP
+","	O
+suggesting	O
+the	O
+role	O
+of	O
+inhibition	O
+of	O
+oxidative	O
+stress	O
+as	O
+another	O
+mechanism	O
+of	O
+antihypertensive	O
+action	O
+of	O
+LF	O
+.	O
+	
+The	O
+association	O
+between	O
+tranexamic	O
+acid	O
+and	O
+convulsive	B-NP
+seizures	B-NP
+after	O
+cardiac	O
+surgery	O
+:	O
+a	O
+multivariate	O
+analysis	O
+in	O
+11	O
+529	O
+patients	O
+.	O
+	
+Because	O
+of	O
+a	O
+lack	O
+of	O
+contemporary	O
+data	O
+regarding	O
+seizures	B-NP
+after	O
+cardiac	O
+surgery	O
+","	O
+we	O
+undertook	O
+a	O
+retrospective	O
+analysis	O
+of	O
+prospectively	O
+collected	O
+data	O
+from	O
+11	O
+529	O
+patients	O
+in	O
+whom	O
+cardiopulmonary	O
+bypass	O
+was	O
+used	O
+from	O
+January	O
+2004	O
+to	O
+December	O
+2010	O
+.	O
+	
+A	O
+convulsive	B-NP
+seizure	B-NP
+was	O
+defined	O
+as	O
+a	O
+transient	O
+episode	O
+of	O
+disturbed	O
+brain	O
+function	O
+characterised	O
+by	O
+abnormal	B-NP
+involuntary	I-NP
+motor	I-NP
+movements	I-NP
+.	O
+	
+Multivariate	O
+regression	O
+analysis	O
+was	O
+performed	O
+to	O
+identify	O
+independent	O
+predictors	O
+of	O
+postoperative	O
+seizures	B-NP
+.	O
+	
+A	O
+total	O
+of	O
+100	O
+(	O
+0	O
+.	O
+9	O
+%	O
+)	O
+patients	O
+developed	O
+postoperative	O
+convulsive	B-NP
+seizures	B-NP
+.	O
+	
+Generalised	B-NP
+and	I-NP
+focal	I-NP
+seizures	I-NP
+were	O
+identified	O
+in	O
+68	O
+and	O
+32	O
+patients	O
+","	O
+respectively	O
+.	O
+	
+The	O
+median	O
+(	O
+IQR	O
+[	O
+range	O
+]	O
+)	O
+time	O
+after	O
+surgery	O
+when	O
+the	O
+seizure	B-NP
+occurred	O
+was	O
+7	O
+(	O
+6	O
+-	O
+12	O
+[	O
+1	O
+-	O
+216	O
+]	O
+)	O
+h	O
+and	O
+8	O
+(	O
+6	O
+-	O
+11	O
+[	O
+4	O
+-	O
+18	O
+]	O
+)	O
+h	O
+","	O
+respectively	O
+.	O
+	
+Epileptiform	O
+findings	O
+on	O
+electroencephalography	O
+were	O
+seen	O
+in	O
+19	O
+patients	O
+.	O
+	
+Independent	O
+predictors	O
+of	O
+postoperative	O
+seizures	B-NP
+included	O
+age	O
+","	O
+female	O
+sex	O
+","	O
+redo	O
+cardiac	O
+surgery	O
+","	O
+calcification	O
+of	O
+ascending	O
+aorta	O
+","	O
+congestive	B-NP
+heart	I-NP
+failure	I-NP
+","	O
+deep	O
+hypothermic	B-NP
+circulatory	O
+arrest	O
+","	O
+duration	O
+of	O
+aortic	O
+cross	O
+-	O
+clamp	O
+and	O
+tranexamic	O
+acid	O
+.	O
+	
+When	O
+tested	O
+in	O
+a	O
+multivariate	O
+regression	O
+analysis	O
+","	O
+tranexamic	O
+acid	O
+was	O
+a	O
+strong	O
+independent	O
+predictor	O
+of	O
+seizures	B-NP
+(	O
+OR	O
+14	O
+.	O
+3	O
+","	O
+95	O
+%	O
+CI	O
+5	O
+.	O
+5	O
+-	O
+36	O
+.	O
+7	O
+;	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Patients	O
+with	O
+convulsive	B-NP
+seizures	B-NP
+had	O
+2	O
+.	O
+5	O
+times	O
+higher	O
+in	O
+-	O
+hospital	O
+mortality	O
+rates	O
+and	O
+twice	O
+the	O
+length	O
+of	O
+hospital	O
+stay	O
+compared	O
+with	O
+patients	O
+without	O
+convulsive	B-NP
+seizures	B-NP
+.	O
+	
+Mean	O
+(	O
+IQR	O
+[	O
+range	O
+]	O
+)	O
+length	O
+of	O
+stay	O
+in	O
+the	O
+intensive	O
+care	O
+unit	O
+was	O
+115	O
+(	O
+49	O
+-	O
+228	O
+[	O
+32	O
+-	O
+481	O
+]	O
+)	O
+h	O
+in	O
+patients	O
+with	O
+convulsive	B-NP
+seizures	B-NP
+compared	O
+with	O
+26	O
+(	O
+22	O
+-	O
+69	O
+[	O
+14	O
+-	O
+1080	O
+]	O
+)	O
+h	O
+in	O
+patients	O
+without	O
+seizures	B-NP
+(	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Convulsive	B-NP
+seizures	B-NP
+are	O
+a	O
+serious	O
+postoperative	B-NP
+complication	I-NP
+after	O
+cardiac	O
+surgery	O
+.	O
+	
+As	O
+tranexamic	O
+acid	O
+is	O
+the	O
+only	O
+modifiable	O
+factor	O
+","	O
+its	O
+administration	O
+","	O
+particularly	O
+in	O
+doses	O
+exceeding	O
+80	O
+mg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+","	O
+should	O
+be	O
+weighed	O
+against	O
+the	O
+risk	O
+of	O
+postoperative	O
+seizures	B-NP
+.	O
+	
+Dysfunctional	B-NP
+overnight	I-NP
+memory	I-NP
+consolidation	O
+in	O
+ecstasy	O
+users	O
+.	O
+	
+Sleep	O
+plays	O
+an	O
+important	O
+role	O
+in	O
+the	O
+consolidation	O
+and	O
+integration	O
+of	O
+memory	O
+in	O
+a	O
+process	O
+called	O
+overnight	O
+memory	O
+consolidation	O
+.	O
+	
+Previous	O
+studies	O
+indicate	O
+that	O
+ecstasy	O
+users	O
+have	O
+marked	O
+and	O
+persistent	O
+neurocognitive	O
+and	O
+sleep	B-NP
+-	I-NP
+related	I-NP
+impairments	I-NP
+.	O
+	
+We	O
+extend	O
+past	O
+research	O
+by	O
+examining	O
+overnight	O
+memory	O
+consolidation	O
+among	O
+regular	O
+ecstasy	O
+users	O
+(	O
+n	O
+=	O
+12	O
+)	O
+and	O
+drug	O
+naive	O
+healthy	O
+controls	O
+(	O
+n	O
+=	O
+26	O
+)	O
+.	O
+	
+Memory	O
+recall	O
+of	O
+word	O
+pairs	O
+was	O
+evaluated	O
+before	O
+and	O
+after	O
+a	O
+period	O
+of	O
+sleep	O
+","	O
+with	O
+and	O
+without	O
+interference	O
+prior	O
+to	O
+testing	O
+.	O
+	
+In	O
+addition	O
+","	O
+we	O
+assessed	O
+neurocognitive	O
+performances	O
+across	O
+tasks	O
+of	O
+learning	O
+","	O
+memory	O
+and	O
+executive	O
+functioning	O
+.	O
+	
+Ecstasy	O
+users	O
+demonstrated	O
+impaired	B-NP
+overnight	I-NP
+memory	I-NP
+consolidation	O
+","	O
+a	O
+finding	O
+that	O
+was	O
+more	O
+pronounced	O
+following	O
+associative	O
+interference	O
+.	O
+	
+Additionally	O
+","	O
+ecstasy	O
+users	O
+demonstrated	O
+impairments	O
+on	O
+tasks	O
+recruiting	O
+frontostriatal	O
+and	O
+hippocampal	O
+neural	O
+circuitry	O
+","	O
+in	O
+the	O
+domains	O
+of	O
+proactive	O
+interference	O
+memory	O
+","	O
+long	O
+-	O
+term	O
+memory	O
+","	O
+encoding	O
+","	O
+working	O
+memory	O
+and	O
+complex	O
+planning	O
+.	O
+	
+We	O
+suggest	O
+that	O
+ecstasy	O
+-	O
+associated	O
+dysfunction	O
+in	O
+fronto	O
+-	O
+temporal	O
+circuitry	O
+may	O
+underlie	O
+overnight	O
+consolidation	O
+memory	B-NP
+impairments	I-NP
+in	O
+regular	O
+ecstasy	O
+users	O
+.	O
+	
+Normoammonemic	O
+encephalopathy	B-NP
+:	O
+solely	O
+valproate	O
+induced	O
+or	O
+multiple	O
+mechanisms	O
+?	O
+	
+A	O
+77	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+presented	O
+with	O
+subacute	O
+onset	O
+progressive	O
+confusion	B-NP
+","	O
+aggression	B-NP
+","	O
+auditory	B-NP
+hallucinations	I-NP
+and	O
+delusions	B-NP
+.	O
+	
+In	O
+the	O
+preceding	O
+months	O
+","	O
+the	O
+patient	O
+had	O
+a	O
+number	O
+of	O
+admissions	O
+with	O
+transient	O
+unilateral	O
+hemiparesis	B-NP
+with	O
+facial	O
+droop	O
+","	O
+and	O
+had	O
+been	O
+started	O
+on	O
+valproate	O
+for	O
+presumed	O
+hemiplegic	B-NP
+migraine	I-NP
+.	O
+	
+Valproate	O
+was	O
+withdrawn	O
+soon	O
+after	O
+admission	O
+and	O
+her	O
+cognitive	O
+abilities	O
+have	O
+gradually	O
+improved	O
+over	O
+3	O
+months	O
+of	O
+follow	O
+-	O
+up	O
+.	O
+	
+Valproate	O
+levels	O
+taken	O
+prior	O
+to	O
+withdrawal	O
+were	O
+subtherapeutic	O
+and	O
+the	O
+patient	O
+was	O
+normoammonaemic	O
+.	O
+	
+EEG	O
+undertaken	O
+during	O
+inpatient	O
+stay	O
+showed	O
+changes	O
+consistent	O
+with	O
+encephalopathy	B-NP
+","	O
+and	O
+low	O
+titre	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+receptor	O
+antibodies	O
+were	O
+present	O
+in	O
+this	O
+patient	O
+.	O
+	
+The	O
+possible	O
+aetiologies	O
+of	O
+valproate	O
+-	O
+induced	O
+encephalopathy	B-NP
+and	O
+NMDA	O
+receptor	O
+-	O
+associated	O
+encephalitis	B-NP
+present	O
+a	O
+diagnostic	O
+dilemma	O
+.	O
+	
+We	O
+present	O
+a	O
+putative	O
+combinatorial	O
+hypothesis	O
+to	O
+explain	O
+this	O
+patient	O
+'	O
+s	O
+symptoms	O
+.	O
+	
+Cerebellar	B-NP
+and	I-NP
+oculomotor	I-NP
+dysfunction	I-NP
+induced	O
+by	O
+rapid	O
+infusion	O
+of	O
+pethidine	O
+.	O
+	
+Pethidine	O
+is	O
+an	O
+opioid	O
+that	O
+gains	O
+its	O
+popularity	O
+for	O
+the	O
+effective	O
+pain	B-NP
+control	O
+through	O
+acting	O
+on	O
+the	O
+opioid	O
+-	O
+receptors	O
+.	O
+	
+However	O
+","	O
+rapid	O
+pain	B-NP
+relief	O
+sometimes	O
+brings	O
+about	O
+unfavourable	O
+side	O
+effects	O
+that	O
+largely	O
+limit	O
+its	O
+clinical	O
+utility	O
+.	O
+	
+Common	O
+side	O
+effects	O
+include	O
+nausea	B-NP
+","	O
+vomiting	B-NP
+and	O
+hypotension	B-NP
+.	O
+	
+In	O
+patients	O
+with	O
+impaired	B-NP
+renal	I-NP
+and	I-NP
+liver	I-NP
+function	I-NP
+","	O
+and	O
+those	O
+who	O
+need	O
+long	O
+-	O
+term	O
+pain	B-NP
+control	O
+","	O
+pethidine	O
+may	O
+cause	O
+excitatory	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+effects	O
+through	O
+its	O
+neurotoxic	B-NP
+metabolite	O
+","	O
+norpethidine	O
+","	O
+resulting	O
+in	O
+irritability	B-NP
+and	O
+seizure	B-NP
+attack	O
+.	O
+	
+On	O
+the	O
+contrary	O
+","	O
+though	O
+not	O
+clinically	O
+apparent	O
+","	O
+pethidine	O
+potentially	O
+causes	O
+inhibitory	O
+impacts	O
+on	O
+the	O
+CNS	O
+and	O
+impairs	O
+normal	O
+cerebellar	O
+and	O
+oculomotor	O
+function	O
+in	O
+the	O
+short	O
+term	O
+.	O
+	
+In	O
+this	O
+case	O
+report	O
+","	O
+we	O
+highlight	O
+opioid	O
+'	O
+s	O
+inhibitory	O
+side	O
+effects	O
+on	O
+the	O
+cerebellar	O
+structure	O
+that	O
+causes	O
+dysmetria	B-NP
+","	O
+dysarthria	B-NP
+","	O
+reduced	O
+smooth	O
+pursuit	O
+gain	O
+and	O
+decreased	O
+saccadic	O
+velocity	O
+.	O
+	
+Baboon	B-NP
+syndrome	I-NP
+induced	O
+by	O
+ketoconazole	O
+.	O
+	
+A	O
+27	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+presented	O
+with	O
+a	O
+maculopapular	B-NP
+eruption	I-NP
+on	O
+the	O
+flexural	O
+areas	O
+and	O
+buttocks	O
+after	O
+using	O
+oral	O
+ketoconazole	O
+.	O
+	
+The	O
+patient	O
+was	O
+diagnosed	O
+with	O
+drug	O
+-	O
+induced	O
+baboon	B-NP
+syndrome	I-NP
+based	O
+on	O
+his	O
+history	O
+","	O
+which	O
+included	O
+prior	O
+sensitivity	O
+to	O
+topical	O
+ketoconazole	O
+","	O
+a	O
+physical	O
+examination	O
+","	O
+and	O
+histopathological	O
+findings	O
+.	O
+	
+Baboon	B-NP
+syndrome	I-NP
+is	O
+a	O
+drug	O
+-	O
+or	O
+contact	O
+allergen	O
+-	O
+related	O
+maculopapular	B-NP
+eruption	I-NP
+that	O
+typically	O
+involves	O
+the	O
+flexural	O
+and	O
+gluteal	O
+areas	O
+.	O
+	
+To	O
+the	O
+best	O
+of	O
+our	O
+knowledge	O
+","	O
+this	O
+is	O
+the	O
+first	O
+reported	O
+case	O
+of	O
+ketoconazole	O
+-	O
+induced	O
+baboon	B-NP
+syndrome	I-NP
+in	O
+the	O
+English	O
+literature	O
+.	O
+	
+A	O
+Case	O
+of	O
+Sudden	B-NP
+Cardiac	I-NP
+Death	I-NP
+due	O
+to	O
+Pilsicainide	O
+-	O
+Induced	O
+Torsades	B-NP
+de	I-NP
+Pointes	I-NP
+.	O
+	
+An	O
+84	O
+-	O
+year	O
+-	O
+old	O
+male	O
+received	O
+oral	O
+pilsicainide	O
+","	O
+a	O
+pure	O
+sodium	O
+channel	O
+blocker	O
+with	O
+slow	O
+recovery	O
+kinetics	O
+","	O
+to	O
+convert	O
+his	O
+paroxysmal	O
+atrial	B-NP
+fibrillation	I-NP
+to	O
+a	O
+sinus	O
+rhythm	O
+;	O
+the	O
+patient	O
+developed	O
+sudden	B-NP
+cardiac	I-NP
+death	I-NP
+two	O
+days	O
+later	O
+.	O
+	
+The	O
+Holter	O
+electrocardiogram	O
+","	O
+which	O
+was	O
+worn	O
+by	O
+chance	O
+","	O
+revealed	O
+torsade	B-NP
+de	I-NP
+pointes	I-NP
+with	O
+gradually	O
+prolonged	O
+QT	O
+intervals	O
+.	O
+	
+This	O
+drug	O
+is	O
+rapidly	O
+absorbed	O
+from	O
+the	O
+gastrointestinal	O
+tract	O
+","	O
+and	O
+most	O
+of	O
+it	O
+is	O
+excreted	O
+from	O
+the	O
+kidney	O
+.	O
+	
+Although	O
+the	O
+patient	O
+'	O
+s	O
+renal	O
+function	O
+was	O
+not	O
+highly	O
+impaired	O
+and	O
+the	O
+dose	O
+of	O
+pilsicainide	O
+was	O
+low	O
+","	O
+the	O
+plasma	O
+concentration	O
+of	O
+pilsicainide	O
+may	O
+have	O
+been	O
+high	O
+","	O
+which	O
+can	O
+produce	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+in	O
+the	O
+octogenarian	O
+.	O
+	
+Although	O
+the	O
+oral	O
+administration	O
+of	O
+class	O
+IC	O
+drugs	O
+","	O
+including	O
+pilsicainide	O
+","	O
+is	O
+effective	O
+to	O
+terminate	O
+atrial	B-NP
+fibrillation	I-NP
+","	O
+careful	O
+consideration	O
+must	O
+be	O
+taken	O
+before	O
+giving	O
+these	O
+drugs	O
+to	O
+octogenarians	O
+.	O
+	
+All	O
+-	O
+trans	O
+retinoic	O
+acid	O
+-	O
+induced	O
+inflammatory	O
+myositis	B-NP
+in	O
+a	O
+patient	O
+with	O
+acute	B-NP
+promyelocytic	I-NP
+leukemia	I-NP
+.	O
+	
+All	O
+-	O
+trans	O
+retinoic	O
+acid	O
+(	O
+ATRA	O
+)	O
+","	O
+a	O
+component	O
+of	O
+standard	O
+therapy	O
+for	O
+acute	B-NP
+promyelocytic	I-NP
+leukemia	I-NP
+(	O
+APL	B-NP
+)	O
+","	O
+is	O
+associated	O
+with	O
+potentially	O
+serious	O
+but	O
+treatable	O
+adverse	O
+effects	O
+involving	O
+numerous	O
+organ	O
+systems	O
+","	O
+including	O
+rare	O
+skeletal	O
+muscle	O
+involvement	O
+.	O
+	
+Only	O
+a	O
+handful	O
+of	O
+cases	O
+of	O
+ATRA	O
+-	O
+induced	O
+myositis	B-NP
+in	O
+children	O
+have	O
+been	O
+reported	O
+","	O
+and	O
+none	O
+in	O
+the	O
+radiology	O
+literature	O
+.	O
+	
+We	O
+present	O
+such	O
+a	O
+case	O
+in	O
+a	O
+15	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+with	O
+APL	B-NP
+","	O
+where	O
+recognition	O
+of	O
+imaging	O
+findings	O
+played	O
+a	O
+crucial	O
+role	O
+in	O
+making	O
+the	O
+diagnosis	O
+and	O
+facilitated	O
+prompt	O
+","	O
+effective	O
+treatment	O
+.	O
+	
+Tolerability	O
+of	O
+lomustine	O
+in	O
+combination	O
+with	O
+cyclophosphamide	O
+in	O
+dogs	O
+with	O
+lymphoma	B-NP
+.	O
+	
+This	O
+retrospective	O
+study	O
+describes	O
+toxicity	B-NP
+associated	O
+with	O
+a	O
+protocol	O
+of	O
+lomustine	O
+(	O
+CCNU	O
+)	O
+and	O
+cyclophosphamide	O
+(	O
+CTX	O
+)	O
+in	O
+dogs	O
+with	O
+lymphoma	B-NP
+.	O
+	
+CCNU	O
+was	O
+administered	O
+per	O
+os	O
+(	O
+PO	O
+)	O
+at	O
+a	O
+targeted	O
+dosage	O
+of	O
+60	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+body	O
+surface	O
+area	O
+on	O
+day	O
+0	O
+","	O
+CTX	O
+was	O
+administered	O
+PO	O
+at	O
+a	O
+targeted	O
+dosage	O
+of	O
+250	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+divided	O
+over	O
+days	O
+0	O
+through	O
+4	O
+","	O
+and	O
+all	O
+dogs	O
+received	O
+prophylactic	O
+antibiotics	O
+.	O
+	
+Ninety	O
+treatments	O
+were	O
+given	O
+to	O
+the	O
+57	O
+dogs	O
+included	O
+in	O
+the	O
+study	O
+.	O
+	
+Neutropenia	B-NP
+was	O
+the	O
+principal	O
+toxic	O
+effect	O
+","	O
+and	O
+the	O
+overall	O
+frequency	O
+of	O
+grade	O
+4	O
+neutropenia	B-NP
+after	O
+the	O
+first	O
+treatment	O
+of	O
+CCNU	O
+/	O
+CTX	O
+was	O
+30	O
+%	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+","	O
+19	O
+-	O
+43	O
+%	O
+)	O
+.	O
+	
+The	O
+mean	O
+body	O
+weight	O
+of	O
+dogs	O
+with	O
+grade	O
+4	O
+neutropenia	B-NP
+(	O
+19	O
+.	O
+7	O
+kg	O
++	O
+13	O
+.	O
+4	O
+kg	O
+)	O
+was	O
+significantly	O
+less	O
+than	O
+the	O
+mean	O
+body	O
+weight	O
+of	O
+dogs	O
+that	O
+did	O
+not	O
+develop	O
+grade	O
+4	O
+neutropenia	B-NP
+(	O
+31	O
+.	O
+7	O
+kg	O
++	O
+12	O
+.	O
+4	O
+kg	O
+;	O
+P	O
+=	O
+.	O
+5	O
+)	O
+.	O
+	
+One	O
+dog	O
+(	O
+3	O
+%	O
+)	O
+developed	O
+hematologic	O
+changes	O
+suggestive	O
+of	O
+hepatotoxicity	B-NP
+.	O
+	
+No	O
+dogs	O
+had	O
+evidence	O
+of	O
+either	O
+renal	B-NP
+toxicity	I-NP
+or	O
+hemorrhagic	B-NP
+cystitis	I-NP
+.	O
+	
+Adverse	O
+gastrointestinal	O
+effects	O
+were	O
+uncommon	O
+.	O
+	
+On	O
+the	O
+basis	O
+of	O
+the	O
+findings	O
+reported	O
+herein	O
+","	O
+a	O
+dose	O
+of	O
+60	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+of	O
+CCNU	O
+combined	O
+with	O
+250	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+of	O
+CTX	O
+(	O
+divided	O
+over	O
+5	O
+days	O
+)	O
+q	O
+4	O
+wk	O
+is	O
+tolerable	O
+in	O
+tumor	B-NP
+-	O
+bearing	O
+dogs	O
+.	O
+	
+Nelarabine	O
+neurotoxicity	B-NP
+with	O
+concurrent	O
+intrathecal	O
+chemotherapy	O
+:	O
+Case	O
+report	O
+and	O
+review	O
+of	O
+literature	O
+.	O
+	
+Severe	O
+nelarabine	O
+neurotoxicity	B-NP
+in	O
+a	O
+patient	O
+who	O
+received	O
+concurrent	O
+intrathecal	O
+(	O
+IT	O
+)	O
+chemotherapy	O
+is	O
+reported	O
+.	O
+	
+A	O
+37	O
+-	O
+year	O
+-	O
+old	O
+Caucasian	O
+woman	O
+with	O
+a	O
+history	O
+of	O
+T	B-NP
+-	I-NP
+cell	I-NP
+lymphoblastic	I-NP
+lymphoma	I-NP
+was	O
+admitted	O
+for	O
+relapsed	O
+disease	O
+.	O
+	
+She	O
+was	O
+originally	O
+treated	O
+with	O
+induction	O
+chemotherapy	O
+followed	O
+by	O
+an	O
+autologous	O
+transplant	O
+.	O
+	
+She	O
+developed	O
+relapsed	O
+disease	O
+10	O
+months	O
+later	O
+with	O
+leukemic	B-NP
+involvement	O
+.	O
+	
+She	O
+was	O
+re	O
+-	O
+induced	O
+with	O
+nelarabine	O
+1500	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+on	O
+days	O
+1	O
+","	O
+3	O
+","	O
+and	O
+5	O
+with	O
+1	O
+dose	O
+of	O
+IT	O
+cytarabine	O
+100	O
+mg	O
+on	O
+day	O
+2	O
+as	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+prophylaxis	O
+.	O
+	
+At	O
+the	O
+time	O
+of	O
+treatment	O
+","	O
+she	O
+was	O
+on	O
+continuous	O
+renal	O
+replacement	O
+therapy	O
+due	O
+to	O
+sequelae	O
+of	O
+tumor	B-NP
+lysis	I-NP
+syndrome	I-NP
+(	O
+TLS	B-NP
+)	O
+.	O
+	
+She	O
+tolerated	O
+therapy	O
+well	O
+","	O
+entered	O
+a	O
+complete	O
+remission	O
+","	O
+and	O
+recovered	O
+her	O
+renal	O
+function	O
+.	O
+	
+She	O
+received	O
+a	O
+second	O
+cycle	O
+of	O
+nelarabine	O
+without	O
+additional	O
+IT	O
+prophylaxis	O
+one	O
+month	O
+later	O
+.	O
+	
+A	O
+week	O
+after	O
+this	O
+second	O
+cycle	O
+","	O
+she	O
+noted	O
+numbness	O
+in	O
+her	O
+lower	O
+extremities	O
+.	O
+	
+Predominantly	O
+sensory	O
+","	O
+though	O
+also	O
+motor	O
+and	O
+autonomic	O
+","	O
+peripheral	B-NP
+neuropathy	I-NP
+started	O
+in	O
+her	O
+feet	O
+","	O
+ascended	O
+proximally	O
+to	O
+the	O
+mid	O
+-	O
+thoracic	O
+region	O
+","	O
+and	O
+eventually	O
+included	O
+her	O
+distal	O
+upper	O
+extremities	O
+.	O
+	
+A	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+of	O
+her	O
+spine	O
+demonstrated	O
+changes	O
+from	O
+C2	O
+to	O
+C6	O
+consistent	O
+with	O
+subacute	O
+combined	O
+degeneration	O
+.	O
+	
+Nelarabine	O
+was	O
+felt	O
+to	O
+be	O
+the	O
+cause	O
+of	O
+her	O
+symptoms	O
+.	O
+	
+Her	O
+neuropathy	B-NP
+stabilized	O
+and	O
+showed	O
+slight	O
+improvement	O
+and	O
+ultimately	O
+received	O
+an	O
+unrelated	O
+","	O
+reduced	O
+-	O
+intensity	O
+allogeneic	O
+transplant	O
+while	O
+in	O
+complete	O
+remission	O
+","	O
+but	O
+relapsed	O
+disease	O
+10	O
+weeks	O
+later	O
+.	O
+	
+She	O
+is	O
+currently	O
+being	O
+treated	O
+with	O
+best	O
+supportive	O
+care	O
+.	O
+	
+To	O
+our	O
+knowledge	O
+","	O
+this	O
+is	O
+the	O
+first	O
+published	O
+case	O
+report	O
+of	O
+severe	O
+neurotoxicity	B-NP
+caused	O
+by	O
+nelarabine	O
+in	O
+a	O
+patient	O
+who	O
+received	O
+concurrent	O
+IT	O
+chemotherapy	O
+.	O
+	
+Valproate	O
+-	O
+induced	O
+hyperammonemic	B-NP
+encephalopathy	B-NP
+in	O
+a	O
+renal	O
+transplanted	O
+patient	O
+.	O
+	
+Neurological	B-NP
+complications	I-NP
+after	O
+renal	O
+transplantation	O
+constitute	O
+an	O
+important	O
+cause	O
+of	O
+morbidity	O
+and	O
+mortality	O
+.	O
+	
+Their	O
+differential	O
+diagnosis	O
+is	O
+difficult	O
+and	O
+essential	O
+for	O
+subsequent	O
+patient	O
+'	O
+s	O
+management	O
+.	O
+	
+Valproate	O
+-	O
+induced	O
+hyperammonemic	B-NP
+encephalopathy	B-NP
+is	O
+an	O
+uncommon	O
+but	O
+serious	O
+effect	O
+of	O
+valproate	O
+treatment	O
+.	O
+	
+Here	O
+","	O
+we	O
+describe	O
+the	O
+case	O
+of	O
+a	O
+15	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+who	O
+was	O
+on	O
+a	O
+long	O
+-	O
+term	O
+therapy	O
+with	O
+valproate	O
+due	O
+to	O
+epilepsy	B-NP
+and	O
+revealed	O
+impaired	B-NP
+consciousness	I-NP
+with	O
+hyperammonemia	B-NP
+12	O
+days	O
+after	O
+renal	O
+transplantation	O
+.	O
+	
+After	O
+withdraw	O
+of	O
+valproate	O
+","	O
+patients	O
+'	O
+symptoms	O
+resolved	O
+within	O
+24	O
+h	O
+.	O
+	
+Clinicians	O
+should	O
+increase	O
+their	O
+awareness	O
+for	O
+potential	O
+complication	O
+of	O
+valproate	O
+","	O
+especially	O
+in	O
+transplanted	O
+patients	O
+.	O
+	
+Necrotising	B-NP
+fasciitis	I-NP
+after	O
+bortezomib	O
+and	O
+dexamethasone	O
+-	O
+containing	O
+regimen	O
+in	O
+an	O
+elderly	O
+patient	O
+of	O
+Waldenstrom	B-NP
+macroglobulinaemia	I-NP
+.	O
+	
+Bortezomib	O
+and	O
+high	O
+-	O
+dose	O
+dexamethasone	O
+-	O
+containing	O
+regimens	O
+are	O
+considered	O
+to	O
+be	O
+generally	O
+tolerable	O
+with	O
+few	O
+severe	O
+bacterial	B-NP
+infections	I-NP
+in	O
+patients	O
+with	O
+B	O
+-	O
+cell	O
+malignancies	B-NP
+.	O
+	
+However	O
+","	O
+information	O
+is	O
+limited	O
+concerning	O
+the	O
+safety	O
+of	O
+the	O
+regimen	O
+in	O
+elderly	O
+patients	O
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+a	O
+76	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+Waldenstrom	B-NP
+macroglobulinaemia	I-NP
+who	O
+suffered	O
+necrotising	B-NP
+fasciitis	I-NP
+without	O
+neutropenia	B-NP
+after	O
+the	O
+combination	O
+treatment	O
+with	O
+bortezomib	O
+","	O
+high	O
+-	O
+dose	O
+dexamethasone	O
+and	O
+rituximab	O
+.	O
+	
+Despite	O
+immediate	O
+intravenous	O
+antimicrobial	O
+therapy	O
+","	O
+he	O
+succumbed	O
+23	O
+h	O
+after	O
+the	O
+onset	O
+.	O
+	
+Physicians	O
+should	O
+recognise	O
+the	O
+possibility	O
+of	O
+fatal	O
+bacterial	B-NP
+infections	I-NP
+related	O
+to	O
+bortezomib	O
+plus	O
+high	O
+-	O
+dose	O
+dexamethasone	O
+in	O
+elderly	O
+patients	O
+","	O
+and	O
+we	O
+believe	O
+this	O
+case	O
+warrants	O
+further	O
+investigation	O
+.	O
+	
+An	O
+integrated	O
+characterization	O
+of	O
+serological	O
+","	O
+pathological	O
+","	O
+and	O
+functional	O
+events	O
+in	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+.	O
+	
+Many	O
+efficacious	O
+cancer	B-NP
+treatments	O
+cause	O
+significant	O
+cardiac	O
+morbidity	O
+","	O
+yet	O
+biomarkers	O
+or	O
+functional	O
+indices	O
+of	O
+early	O
+damage	O
+","	O
+which	O
+would	O
+allow	O
+monitoring	O
+and	O
+intervention	O
+","	O
+are	O
+lacking	O
+.	O
+	
+In	O
+this	O
+study	O
+","	O
+we	O
+have	O
+utilized	O
+a	O
+rat	O
+model	O
+of	O
+progressive	O
+doxorubicin	O
+(	O
+DOX	O
+)	O
+-	O
+induced	O
+cardiomyopathy	B-NP
+","	O
+applying	O
+multiple	O
+approaches	O
+","	O
+including	O
+cardiac	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+","	O
+to	O
+provide	O
+the	O
+most	O
+comprehensive	O
+characterization	O
+to	O
+date	O
+of	O
+the	O
+timecourse	O
+of	O
+serological	O
+","	O
+pathological	O
+","	O
+and	O
+functional	O
+events	O
+underlying	O
+this	O
+toxicity	B-NP
+.	O
+	
+Hannover	O
+Wistar	O
+rats	O
+were	O
+dosed	O
+with	O
+1	O
+.	O
+25	O
+mg	O
+/	O
+kg	O
+DOX	O
+weekly	O
+for	O
+8	O
+weeks	O
+followed	O
+by	O
+a	O
+4	O
+week	O
+off	O
+-	O
+dosing	O
+"	O
+recovery	O
+"	O
+period	O
+.	O
+	
+Electron	O
+microscopy	O
+of	O
+the	O
+myocardium	O
+revealed	O
+subcellular	B-NP
+degeneration	I-NP
+and	O
+marked	O
+mitochondrial	O
+changes	O
+after	O
+a	O
+single	O
+dose	O
+.	O
+	
+Histopathological	O
+analysis	O
+revealed	O
+progressive	O
+cardiomyocyte	B-NP
+degeneration	I-NP
+","	O
+hypertrophy	B-NP
+/	O
+cytomegaly	O
+","	O
+and	O
+extensive	O
+vacuolation	O
+after	O
+two	O
+doses	O
+.	O
+	
+Extensive	O
+replacement	O
+fibrosis	B-NP
+(	O
+quantified	O
+by	O
+Sirius	O
+red	O
+staining	O
+)	O
+developed	O
+during	O
+the	O
+off	O
+-	O
+dosing	O
+period	O
+.	O
+	
+Functional	O
+indices	O
+assessed	O
+by	O
+cardiac	O
+MRI	O
+(	O
+including	O
+left	O
+ventricular	O
+ejection	O
+fraction	O
+(	O
+LVEF	O
+)	O
+","	O
+cardiac	O
+output	O
+","	O
+and	O
+E	O
+/	O
+A	O
+ratio	O
+)	O
+declined	O
+progressively	O
+","	O
+reaching	O
+statistical	O
+significance	O
+after	O
+two	O
+doses	O
+and	O
+culminating	O
+in	O
+"	O
+clinical	O
+"	O
+LV	B-NP
+dysfunction	I-NP
+by	O
+12	O
+weeks	O
+.	O
+	
+Significant	O
+increases	O
+in	O
+peak	O
+myocardial	O
+contrast	O
+enhancement	O
+and	O
+serological	O
+cardiac	O
+troponin	O
+I	O
+(	O
+cTnI	O
+)	O
+emerged	O
+after	O
+eight	O
+doses	O
+","	O
+importantly	O
+preceding	O
+the	O
+LVEF	O
+decline	O
+to	O
+<	O
+50	O
+%	O
+.	O
+	
+Troponin	O
+I	O
+levels	O
+positively	O
+correlated	O
+with	O
+delayed	O
+and	O
+peak	O
+gadolinium	O
+contrast	O
+enhancement	O
+","	O
+histopathological	O
+grading	O
+","	O
+and	O
+diastolic	B-NP
+dysfunction	I-NP
+.	O
+	
+In	O
+summary	O
+","	O
+subcellular	O
+cardiomyocyte	B-NP
+degeneration	I-NP
+was	O
+the	O
+earliest	O
+marker	O
+","	O
+followed	O
+by	O
+progressive	O
+functional	O
+decline	O
+and	O
+histopathological	O
+manifestations	O
+.	O
+	
+Myocardial	O
+contrast	O
+enhancement	O
+and	O
+elevations	O
+in	O
+cTnI	O
+occurred	O
+later	O
+.	O
+	
+However	O
+","	O
+all	O
+indices	O
+predated	O
+"	O
+clinical	O
+"	O
+LV	B-NP
+dysfunction	I-NP
+and	O
+thus	O
+warrant	O
+further	O
+evaluation	O
+as	O
+predictive	O
+biomarkers	O
+.	O
+	
+Intradermal	O
+glutamate	O
+and	O
+capsaicin	O
+injections	O
+:	O
+intra	O
+-	O
+and	O
+interindividual	O
+variability	O
+of	O
+provoked	O
+hyperalgesia	B-NP
+and	O
+allodynia	B-NP
+.	O
+	
+Intradermal	O
+injections	O
+of	O
+glutamate	O
+and	O
+capsaicin	O
+are	O
+attractive	O
+to	O
+use	O
+in	O
+human	O
+experimental	O
+pain	B-NP
+models	O
+because	O
+hyperalgesia	B-NP
+and	O
+allodynia	B-NP
+mimic	O
+isolated	O
+aspects	O
+of	O
+clinical	O
+pain	B-NP
+disorders	I-NP
+.	O
+	
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+reproducibility	O
+of	O
+these	O
+models	O
+.	O
+	
+Twenty	O
+healthy	O
+male	O
+volunteers	O
+(	O
+mean	O
+age	O
+24	O
+years	O
+;	O
+range	O
+18	O
+-	O
+38	O
+years	O
+)	O
+received	O
+intradermal	O
+injections	O
+of	O
+glutamate	O
+and	O
+capsaicin	O
+in	O
+the	O
+volar	O
+forearm	O
+.	O
+	
+Magnitudes	O
+of	O
+secondary	O
+pinprick	O
+hyperalgesia	B-NP
+and	O
+brush	O
+-	O
+evoked	O
+allodynia	B-NP
+were	O
+investigated	O
+using	O
+von	O
+Frey	O
+filaments	O
+(	O
+gauges	O
+10	O
+","	O
+15	O
+","	O
+60	O
+and	O
+100	O
+g	O
+)	O
+and	O
+brush	O
+strokes	O
+.	O
+	
+Areas	O
+of	O
+secondary	B-NP
+hyperalgesia	I-NP
+and	O
+allodynia	B-NP
+were	O
+quantified	O
+immediately	O
+after	O
+injection	O
+and	O
+after	O
+15	O
+","	O
+30	O
+and	O
+60	O
+min	O
+.	O
+	
+Two	O
+identical	O
+experiments	O
+separated	O
+by	O
+at	O
+least	O
+7	O
+days	O
+were	O
+performed	O
+.	O
+	
+Reproducibility	O
+across	O
+and	O
+within	O
+volunteers	O
+(	O
+inter	O
+-	O
+and	O
+intra	O
+-	O
+individual	O
+variation	O
+","	O
+respectively	O
+)	O
+was	O
+assessed	O
+using	O
+intraclass	O
+correlation	O
+coefficient	O
+(	O
+ICC	O
+)	O
+and	O
+coefficient	O
+of	O
+variation	O
+(	O
+CV	O
+)	O
+.	O
+	
+Secondary	O
+pinprick	O
+hyperalgesia	B-NP
+was	O
+observed	O
+as	O
+a	O
+marked	O
+increase	O
+in	O
+the	O
+visual	O
+analogue	O
+scale	O
+(	O
+VAS	O
+)	O
+response	O
+to	O
+von	O
+Frey	O
+gauges	O
+60	O
+and	O
+100	O
+g	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+after	O
+glutamate	O
+injection	O
+.	O
+	
+For	O
+capsaicin	O
+","	O
+secondary	O
+pinprick	O
+hyperalgesia	B-NP
+was	O
+detected	O
+with	O
+all	O
+von	O
+Frey	O
+gauges	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Glutamate	O
+evoked	O
+reproducible	O
+VAS	O
+response	O
+to	O
+all	O
+von	O
+Frey	O
+gauges	O
+(	O
+ICC	O
+>	O
+0	O
+.	O
+60	O
+)	O
+and	O
+brush	O
+strokes	O
+(	O
+ICC	O
+>	O
+0	O
+.	O
+83	O
+)	O
+.	O
+	
+Capsaicin	O
+injection	O
+was	O
+reproducible	O
+for	O
+secondary	B-NP
+hyperalgesia	I-NP
+(	O
+ICC	O
+>	O
+0	O
+.	O
+70	O
+)	O
+and	O
+allodynia	B-NP
+(	O
+ICC	O
+>	O
+0	O
+.	O
+71	O
+)	O
+.	O
+	
+Intra	O
+-	O
+individual	O
+variability	O
+was	O
+generally	O
+lower	O
+for	O
+the	O
+VAS	O
+response	O
+to	O
+von	O
+Frey	O
+and	O
+brush	O
+compared	O
+with	O
+areas	O
+of	O
+secondary	B-NP
+hyperalgesia	I-NP
+and	O
+allodynia	B-NP
+.	O
+	
+In	O
+conclusion	O
+","	O
+glutamate	O
+and	O
+capsaicin	O
+yield	O
+reproducible	O
+hyperalgesic	B-NP
+and	O
+allodynic	B-NP
+responses	O
+","	O
+and	O
+the	O
+present	O
+model	O
+is	O
+well	O
+suited	O
+for	O
+basic	O
+research	O
+","	O
+as	O
+well	O
+as	O
+for	O
+assessing	O
+the	O
+modulation	O
+of	O
+central	O
+phenomena	O
+.	O
+	
+Ocular	O
+-	O
+specific	O
+ER	O
+stress	O
+reduction	O
+rescues	O
+glaucoma	B-NP
+in	O
+murine	O
+glucocorticoid	O
+-	O
+induced	O
+glaucoma	B-NP
+.	O
+	
+Administration	O
+of	O
+glucocorticoids	O
+induces	O
+ocular	B-NP
+hypertension	I-NP
+in	O
+some	O
+patients	O
+.	O
+	
+If	O
+untreated	O
+","	O
+these	O
+patients	O
+can	O
+develop	O
+a	O
+secondary	O
+glaucoma	B-NP
+that	O
+resembles	O
+primary	B-NP
+open	I-NP
+-	I-NP
+angle	I-NP
+glaucoma	I-NP
+(	O
+POAG	B-NP
+)	O
+.	O
+	
+The	O
+underlying	O
+pathology	O
+of	O
+glucocorticoid	O
+-	O
+induced	O
+glaucoma	B-NP
+is	O
+not	O
+fully	O
+understood	O
+","	O
+due	O
+in	O
+part	O
+to	O
+lack	O
+of	O
+an	O
+appropriate	O
+animal	O
+model	O
+.	O
+	
+Here	O
+","	O
+we	O
+developed	O
+a	O
+murine	O
+model	O
+of	O
+glucocorticoid	O
+-	O
+induced	O
+glaucoma	B-NP
+that	O
+exhibits	O
+glaucoma	B-NP
+features	O
+that	O
+are	O
+observed	O
+in	O
+patients	O
+.	O
+	
+Treatment	O
+of	O
+WT	O
+mice	O
+with	O
+topical	O
+ocular	O
+0	O
+.	O
+1	O
+%	O
+dexamethasone	O
+led	O
+to	O
+elevation	O
+of	O
+intraocular	O
+pressure	O
+(	O
+IOP	O
+)	O
+","	O
+functional	O
+and	O
+structural	O
+loss	O
+of	O
+retinal	B-NP
+ganglion	I-NP
+cells	O
+","	O
+and	O
+axonal	B-NP
+degeneration	I-NP
+","	O
+resembling	O
+glucocorticoid	O
+-	O
+induced	O
+glaucoma	B-NP
+in	O
+human	O
+patients	O
+.	O
+	
+Furthermore	O
+","	O
+dexamethasone	O
+-	O
+induced	O
+ocular	B-NP
+hypertension	I-NP
+was	O
+associated	O
+with	O
+chronic	O
+ER	O
+stress	O
+of	O
+the	O
+trabecular	O
+meshwork	O
+(	O
+TM	O
+)	O
+.	O
+	
+Similar	O
+to	O
+patients	O
+","	O
+withdrawal	O
+of	O
+dexamethasone	O
+treatment	O
+reduced	O
+elevated	O
+IOP	O
+and	O
+ER	O
+stress	O
+in	O
+this	O
+animal	O
+model	O
+.	O
+	
+Dexamethasone	O
+induced	O
+the	O
+transcriptional	O
+factor	O
+CHOP	O
+","	O
+a	O
+marker	O
+for	O
+chronic	O
+ER	O
+stress	O
+","	O
+in	O
+the	O
+anterior	O
+segment	O
+tissues	O
+","	O
+and	O
+Chop	O
+deletion	O
+reduced	O
+ER	O
+stress	O
+in	O
+these	O
+tissues	O
+and	O
+prevented	O
+dexamethasone	O
+-	O
+induced	O
+ocular	B-NP
+hypertension	I-NP
+.	O
+	
+Furthermore	O
+","	O
+reduction	O
+of	O
+ER	O
+stress	O
+in	O
+the	O
+TM	O
+with	O
+sodium	O
+4	O
+-	O
+phenylbutyrate	O
+prevented	O
+dexamethasone	O
+-	O
+induced	O
+ocular	B-NP
+hypertension	I-NP
+in	O
+WT	O
+mice	O
+.	O
+	
+Our	O
+data	O
+indicate	O
+that	O
+ER	O
+stress	O
+contributes	O
+to	O
+glucocorticoid	O
+-	O
+induced	O
+ocular	B-NP
+hypertension	I-NP
+and	O
+suggest	O
+that	O
+reducing	O
+ER	O
+stress	O
+has	O
+potential	O
+as	O
+a	O
+therapeutic	O
+strategy	O
+for	O
+treating	O
+glucocorticoid	O
+-	O
+induced	O
+glaucoma	B-NP
+.	O
+	
+Effects	O
+of	O
+ginsenosides	O
+on	O
+opioid	O
+-	O
+induced	O
+hyperalgesia	B-NP
+in	O
+mice	O
+.	O
+	
+Opioid	O
+-	O
+induced	O
+hyperalgesia	B-NP
+(	O
+OIH	B-NP
+)	O
+is	O
+characterized	O
+by	O
+nociceptive	O
+sensitization	O
+caused	O
+by	O
+the	O
+cessation	O
+of	O
+chronic	O
+opioid	O
+use	O
+.	O
+	
+OIH	B-NP
+can	O
+limit	O
+the	O
+clinical	O
+use	O
+of	O
+opioid	O
+analgesics	O
+and	O
+complicate	O
+withdrawal	O
+from	O
+opioid	B-NP
+addiction	I-NP
+.	O
+	
+In	O
+this	O
+study	O
+","	O
+we	O
+investigated	O
+the	O
+effects	O
+of	O
+Re	O
+","	O
+Rg1	O
+","	O
+and	O
+Rb1	O
+ginsenosides	O
+","	O
+the	O
+bioactive	O
+components	O
+of	O
+ginseng	O
+","	O
+on	O
+OIH	B-NP
+.	O
+	
+OIH	B-NP
+was	O
+achieved	O
+in	O
+mice	O
+after	O
+subcutaneous	O
+administration	O
+of	O
+morphine	O
+for	O
+7	O
+consecutive	O
+days	O
+three	O
+times	O
+per	O
+day	O
+.	O
+	
+During	O
+withdrawal	O
+(	O
+days	O
+8	O
+and	O
+9	O
+)	O
+","	O
+these	O
+mice	O
+were	O
+administered	O
+Re	O
+","	O
+Rg1	O
+","	O
+or	O
+Rb1	O
+intragastrically	O
+two	O
+times	O
+per	O
+day	O
+.	O
+	
+On	O
+the	O
+test	O
+day	O
+(	O
+day	O
+10	O
+)	O
+","	O
+mice	O
+were	O
+subjected	O
+to	O
+the	O
+thermal	O
+sensitivity	O
+test	O
+and	O
+the	O
+acetic	O
+acid	O
+-	O
+induced	O
+writhing	O
+test	O
+.	O
+	
+Re	O
+(	O
+300	O
+mg	O
+/	O
+kg	O
+)	O
+inhibited	O
+OIH	B-NP
+in	O
+both	O
+the	O
+thermal	O
+sensitivity	O
+test	O
+and	O
+the	O
+acetic	O
+acid	O
+-	O
+induced	O
+writhing	O
+test	O
+.	O
+	
+However	O
+","	O
+the	O
+Rg1	O
+and	O
+Rb1	O
+ginsenosides	O
+failed	O
+to	O
+prevent	O
+OIH	B-NP
+in	O
+either	O
+test	O
+.	O
+	
+Furthermore	O
+","	O
+Rg1	O
+showed	O
+a	O
+tendency	O
+to	O
+aggravate	O
+OIH	B-NP
+in	O
+the	O
+acetic	O
+acid	O
+-	O
+induced	O
+writhing	O
+test	O
+.	O
+	
+Our	O
+data	O
+suggested	O
+that	O
+the	O
+ginsenoside	O
+Re	O
+","	O
+but	O
+not	O
+Rg1	O
+or	O
+Rb1	O
+","	O
+may	O
+contribute	O
+toward	O
+reversal	O
+of	O
+OIH	B-NP
+.	O
+	
+A	O
+comparison	O
+of	O
+severe	O
+hemodynamic	O
+disturbances	O
+between	O
+dexmedetomidine	O
+and	O
+propofol	O
+for	O
+sedation	O
+in	O
+neurocritical	O
+care	O
+patients	O
+.	O
+	
+OBJECTIVE	O
+:	O
+Dexmedetomidine	O
+and	O
+propofol	O
+are	O
+commonly	O
+used	O
+sedatives	O
+in	O
+neurocritical	O
+care	O
+as	O
+they	O
+allow	O
+for	O
+frequent	O
+neurologic	O
+examinations	O
+.	O
+	
+However	O
+","	O
+both	O
+agents	O
+are	O
+associated	O
+with	O
+significant	O
+hemodynamic	O
+side	O
+effects	O
+.	O
+	
+The	O
+primary	O
+objective	O
+of	O
+this	O
+study	O
+is	O
+to	O
+compare	O
+the	O
+prevalence	O
+of	O
+severe	O
+hemodynamic	O
+effects	O
+in	O
+neurocritical	O
+care	O
+patients	O
+receiving	O
+dexmedetomidine	O
+and	O
+propofol	O
+.	O
+	
+DESIGN	O
+:	O
+Multicenter	O
+","	O
+retrospective	O
+","	O
+propensity	O
+-	O
+matched	O
+cohort	O
+study	O
+.	O
+	
+SETTING	O
+:	O
+Neurocritical	O
+care	O
+units	O
+at	O
+two	O
+academic	O
+medical	O
+centers	O
+with	O
+dedicated	O
+neurocritical	O
+care	O
+teams	O
+and	O
+board	O
+-	O
+certified	O
+neurointensivists	O
+.	O
+	
+PATIENTS	O
+:	O
+Neurocritical	O
+care	O
+patients	O
+admitted	O
+between	O
+July	O
+2009	O
+and	O
+September	O
+2012	O
+were	O
+evaluated	O
+and	O
+then	O
+matched	O
+1	O
+:	O
+1	O
+based	O
+on	O
+propensity	O
+scoring	O
+of	O
+baseline	O
+characteristics	O
+.	O
+	
+INTERVENTIONS	O
+:	O
+Continuous	O
+sedation	O
+with	O
+dexmedetomidine	O
+or	O
+propofol	O
+.	O
+	
+MEASUREMENTS	O
+AND	O
+MAIN	O
+RESULTS	O
+:	O
+A	O
+total	O
+of	O
+342	O
+patients	O
+(	O
+105	O
+dexmedetomidine	O
+and	O
+237	O
+propofol	O
+)	O
+were	O
+included	O
+in	O
+the	O
+analysis	O
+","	O
+with	O
+190	O
+matched	O
+(	O
+95	O
+in	O
+each	O
+group	O
+)	O
+by	O
+propensity	O
+score	O
+.	O
+	
+The	O
+primary	O
+outcome	O
+of	O
+this	O
+study	O
+was	O
+a	O
+composite	O
+of	O
+severe	O
+hypotension	B-NP
+(	O
+mean	O
+arterial	O
+pressure	O
+<	O
+60	O
+mm	O
+Hg	O
+)	O
+and	O
+bradycardia	B-NP
+(	O
+heart	O
+rate	O
+<	O
+50	O
+beats	O
+/	O
+min	O
+)	O
+during	O
+sedative	O
+infusion	O
+.	O
+	
+No	O
+difference	O
+in	O
+the	O
+primary	O
+composite	O
+outcome	O
+in	O
+both	O
+the	O
+unmatched	O
+(	O
+30	O
+%	O
+vs	O
+30	O
+%	O
+","	O
+p	O
+=	O
+0	O
+.	O
+94	O
+)	O
+or	O
+matched	O
+cohorts	O
+(	O
+28	O
+%	O
+vs	O
+34	O
+%	O
+","	O
+p	O
+=	O
+0	O
+.	O
+35	O
+)	O
+could	O
+be	O
+found	O
+.	O
+	
+When	O
+analyzed	O
+separately	O
+","	O
+no	O
+differences	O
+could	O
+be	O
+found	O
+in	O
+the	O
+prevalence	O
+of	O
+severe	O
+hypotension	B-NP
+or	O
+bradycardia	B-NP
+in	O
+either	O
+the	O
+unmatched	O
+or	O
+matched	O
+cohorts	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Severe	O
+hypotension	B-NP
+and	O
+bradycardia	B-NP
+occur	O
+at	O
+similar	O
+prevalence	O
+in	O
+neurocritical	O
+care	O
+patients	O
+who	O
+receive	O
+dexmedetomidine	O
+or	O
+propofol	O
+.	O
+	
+Providers	O
+should	O
+similarly	O
+consider	O
+the	O
+likelihood	O
+of	O
+hypotension	B-NP
+or	O
+bradycardia	B-NP
+before	O
+starting	O
+either	O
+sedative	O
+.	O
+	
+Hydroxytyrosol	O
+ameliorates	O
+oxidative	O
+stress	O
+and	O
+mitochondrial	B-NP
+dysfunction	I-NP
+in	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+in	O
+rats	O
+with	O
+breast	B-NP
+cancer	I-NP
+.	O
+	
+Oxidative	O
+stress	O
+is	O
+involved	O
+in	O
+several	O
+processes	O
+including	O
+cancer	B-NP
+","	O
+aging	O
+and	O
+cardiovascular	B-NP
+disease	I-NP
+","	O
+and	O
+has	O
+been	O
+shown	O
+to	O
+potentiate	O
+the	O
+therapeutic	O
+effect	O
+of	O
+drugs	O
+such	O
+as	O
+doxorubicin	O
+.	O
+	
+Doxorubicin	O
+causes	O
+significant	O
+cardiotoxicity	B-NP
+characterized	O
+by	O
+marked	O
+increases	O
+in	O
+oxidative	O
+stress	O
+and	O
+mitochondrial	B-NP
+dysfunction	I-NP
+.	O
+	
+Herein	O
+","	O
+we	O
+investigate	O
+whether	O
+doxorubicin	O
+-	O
+associated	O
+chronic	O
+cardiac	B-NP
+toxicity	I-NP
+can	O
+be	O
+ameliorated	O
+with	O
+the	O
+antioxidant	O
+hydroxytyrosol	O
+in	O
+rats	O
+with	O
+breast	B-NP
+cancer	I-NP
+.	O
+	
+Thirty	O
+-	O
+six	O
+rats	O
+bearing	O
+breast	B-NP
+tumors	I-NP
+induced	O
+chemically	O
+were	O
+divided	O
+into	O
+4	O
+groups	O
+:	O
+control	O
+","	O
+hydroxytyrosol	O
+(	O
+0	O
+.	O
+5mg	O
+/	O
+kg	O
+","	O
+5days	O
+/	O
+week	O
+)	O
+","	O
+doxorubicin	O
+(	O
+1mg	O
+/	O
+kg	O
+/	O
+week	O
+)	O
+","	O
+and	O
+doxorubicin	O
+plus	O
+hydroxytyrosol	O
+.	O
+	
+Cardiac	B-NP
+disturbances	I-NP
+at	O
+the	O
+cellular	O
+and	O
+mitochondrial	O
+level	O
+","	O
+mitochondrial	O
+electron	O
+transport	O
+chain	O
+complexes	O
+I	O
+-	O
+IV	O
+and	O
+apoptosis	O
+-	O
+inducing	O
+factor	O
+","	O
+and	O
+oxidative	O
+stress	O
+markers	O
+have	O
+been	O
+analyzed	O
+.	O
+	
+Hydroxytyrosol	O
+improved	O
+the	O
+cardiac	B-NP
+disturbances	I-NP
+enhanced	O
+by	O
+doxorubicin	O
+by	O
+significantly	O
+reducing	O
+the	O
+percentage	O
+of	O
+altered	O
+mitochondria	O
+and	O
+oxidative	O
+damage	O
+.	O
+	
+These	O
+results	O
+suggest	O
+that	O
+hydroxytyrosol	O
+improve	O
+the	O
+mitochondrial	O
+electron	O
+transport	O
+chain	O
+.	O
+	
+This	O
+study	O
+demonstrates	O
+that	O
+hydroxytyrosol	O
+protect	O
+rat	O
+heart	B-NP
+damage	I-NP
+provoked	O
+by	O
+doxorubicin	O
+decreasing	O
+oxidative	O
+damage	O
+and	O
+mitochondrial	O
+alterations	O
+.	O
+	
+Amiodarone	O
+-	O
+induced	O
+myxoedema	B-NP
+coma	I-NP
+.	O
+	
+A	O
+62	O
+-	O
+year	O
+-	O
+old	O
+man	O
+was	O
+found	O
+to	O
+have	O
+bradycardia	B-NP
+","	O
+hypothermia	B-NP
+and	O
+respiratory	B-NP
+failure	I-NP
+3	O
+weeks	O
+after	O
+initiation	O
+of	O
+amiodarone	O
+therapy	O
+for	O
+atrial	B-NP
+fibrillation	I-NP
+.	O
+	
+Thyroid	O
+-	O
+stimulating	O
+hormone	O
+was	O
+found	O
+to	O
+be	O
+168	O
+uIU	O
+/	O
+mL	O
+(	O
+nl	O
+.	O
+0	O
+.	O
+3	O
+-	O
+5	O
+uIU	O
+/	O
+mL	O
+)	O
+and	O
+free	O
+thyroxine	O
+(	O
+FT4	O
+)	O
+was	O
+<	O
+0	O
+.	O
+2	O
+ng	O
+/	O
+dL	O
+(	O
+nl	O
+.	O
+0	O
+.	O
+8	O
+-	O
+1	O
+.	O
+8	O
+ng	O
+/	O
+dL	O
+)	O
+.	O
+	
+He	O
+received	O
+intravenous	O
+fluids	O
+","	O
+vasopressor	O
+therapy	O
+and	O
+stress	O
+dose	O
+steroids	O
+;	O
+he	O
+was	O
+intubated	O
+and	O
+admitted	O
+to	O
+the	O
+intensive	O
+care	O
+unit	O
+.	O
+	
+He	O
+received	O
+500	O
+ug	O
+of	O
+intravenous	O
+levothyroxine	O
+in	O
+the	O
+first	O
+18	O
+h	O
+of	O
+therapy	O
+","	O
+and	O
+150	O
+ug	O
+intravenous	O
+daily	O
+thereafter	O
+.	O
+	
+Haemodynamic	O
+improvement	O
+","	O
+along	O
+with	O
+complete	O
+recovery	O
+of	O
+mental	O
+status	O
+","	O
+occurred	O
+after	O
+48	O
+h	O
+.	O
+	
+Twelve	O
+hours	O
+after	O
+the	O
+initiation	O
+of	O
+therapy	O
+","	O
+FT4	O
+was	O
+0	O
+.	O
+96	O
+ng	O
+/	O
+dL	O
+.	O
+	
+The	O
+patient	O
+was	O
+maintained	O
+on	O
+levothyroxine	O
+175	O
+(	O
+g	O
+POorally	O
+daily	O
+.	O
+	
+A	O
+thyroid	O
+ultrasound	O
+showed	O
+diffuse	O
+heterogeneity	O
+.	O
+	
+The	O
+24	O
+hour	O
+excretion	O
+of	O
+iodine	O
+was	O
+3657	O
+(	O
+mcg	O
+(	O
+25	O
+-	O
+756	O
+(	O
+mcg	O
+)	O
+.	O
+	
+The	O
+only	O
+two	O
+cases	O
+of	O
+amiodarone	O
+-	O
+induced	O
+myxoedema	B-NP
+coma	I-NP
+in	O
+the	O
+literature	O
+report	O
+patient	O
+death	O
+despite	O
+supportive	O
+therapy	O
+and	O
+thyroid	O
+hormone	O
+replacement	O
+.	O
+	
+This	O
+case	O
+represents	O
+the	O
+most	O
+thoroughly	O
+investigated	O
+case	O
+of	O
+amiodarone	O
+-	O
+induced	O
+myxoedema	B-NP
+coma	I-NP
+with	O
+a	O
+history	O
+significant	O
+for	O
+subclinical	O
+thyroid	B-NP
+disease	I-NP
+.	O
+	
+Use	O
+of	O
+argatroban	O
+and	O
+catheter	O
+-	O
+directed	O
+thrombolysis	B-NP
+with	O
+alteplase	O
+in	O
+an	O
+oncology	O
+patient	O
+with	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+with	O
+thrombosis	B-NP
+.	O
+	
+PURPOSE	O
+:	O
+The	O
+case	O
+of	O
+an	O
+oncology	O
+patient	O
+who	O
+developed	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+with	O
+thrombosis	B-NP
+(	O
+HITT	B-NP
+)	O
+and	O
+was	O
+treated	O
+with	O
+argatroban	O
+plus	O
+catheter	O
+-	O
+directed	O
+thrombolysis	B-NP
+(	O
+CDT	O
+)	O
+with	O
+alteplase	O
+is	O
+presented	O
+.	O
+	
+SUMMARY	O
+:	O
+A	O
+63	O
+-	O
+year	O
+-	O
+old	O
+Caucasian	O
+man	O
+with	O
+renal	O
+amyloidosis	B-NP
+undergoing	O
+peripheral	O
+blood	O
+stem	O
+cell	O
+collection	O
+for	O
+an	O
+autologous	O
+stem	O
+cell	O
+transplant	O
+developed	O
+extensive	O
+bilateral	O
+upper	B-NP
+-	I-NP
+extremity	I-NP
+deep	I-NP
+venous	I-NP
+thrombosis	I-NP
+(	O
+DVT	B-NP
+)	O
+and	O
+pulmonary	B-NP
+embolism	I-NP
+secondary	O
+to	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+.	O
+	
+A	O
+continuous	O
+i	O
+.	O
+v	O
+.	O
+infusion	O
+of	O
+argatroban	O
+was	O
+initiated	O
+","	O
+and	O
+the	O
+patient	O
+was	O
+managed	O
+on	O
+the	O
+general	O
+medical	O
+floor	O
+.	O
+	
+After	O
+one	O
+week	O
+of	O
+therapy	O
+","	O
+he	O
+was	O
+transferred	O
+to	O
+the	O
+intensive	O
+care	O
+unit	O
+with	O
+cardiopulmonary	O
+compromise	O
+related	O
+to	O
+superior	B-NP
+vena	I-NP
+cava	I-NP
+(	I-NP
+SVC	I-NP
+)	I-NP
+syndrome	I-NP
+.	O
+	
+A	O
+percutaneous	O
+mechanical	O
+thrombectomy	O
+and	O
+CDT	O
+with	O
+alteplase	O
+were	O
+attempted	O
+","	O
+but	O
+the	O
+procedure	O
+was	O
+aborted	O
+due	O
+to	O
+epistaxis	B-NP
+.	O
+	
+The	O
+epistaxis	B-NP
+resolved	O
+the	O
+next	O
+day	O
+","	O
+and	O
+the	O
+patient	O
+was	O
+restarted	O
+on	O
+argatroban	O
+.	O
+	
+A	O
+second	O
+percutaneous	O
+mechanical	O
+thrombectomy	O
+was	O
+performed	O
+six	O
+days	O
+later	O
+and	O
+resulted	O
+in	O
+partial	O
+revascularization	O
+of	O
+the	O
+SVC	O
+and	O
+central	O
+veins	O
+.	O
+	
+Postthrombectomy	O
+continuous	O
+CDT	O
+with	O
+alteplase	O
+was	O
+commenced	O
+while	O
+argatroban	O
+was	O
+withheld	O
+","	O
+and	O
+complete	O
+patency	O
+of	O
+the	O
+SVC	O
+and	O
+central	O
+veins	O
+was	O
+achieved	O
+after	O
+three	O
+days	O
+of	O
+therapy	O
+.	O
+	
+Alteplase	O
+was	O
+discontinued	O
+","	O
+and	O
+the	O
+patient	O
+was	O
+reinitiated	O
+on	O
+argatroban	O
+;	O
+ultimately	O
+","	O
+he	O
+was	O
+transitioned	O
+to	O
+warfarin	O
+for	O
+long	O
+-	O
+term	O
+anticoagulation	O
+.	O
+	
+Although	O
+the	O
+patient	O
+recovered	O
+","	O
+he	O
+experienced	O
+permanent	O
+vision	B-NP
+and	I-NP
+hearing	I-NP
+loss	I-NP
+","	O
+as	O
+well	O
+as	O
+end	B-NP
+-	I-NP
+stage	I-NP
+renal	I-NP
+disease	I-NP
+.	O
+	
+CONCLUSION	O
+:	O
+A	O
+63	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+renal	O
+amyloidosis	B-NP
+and	O
+SVC	B-NP
+syndrome	I-NP
+secondary	O
+to	O
+HITT	B-NP
+was	O
+successfully	O
+treated	O
+with	O
+argatroban	O
+and	O
+CDT	O
+with	O
+alteplase	O
+.	O
+	
+Effects	O
+of	O
+dehydroepiandrosterone	O
+in	O
+amphetamine	O
+-	O
+induced	O
+schizophrenia	B-NP
+models	O
+in	O
+mice	O
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+examine	O
+the	O
+effects	O
+of	O
+dehydroepiandrosterone	O
+(	O
+DHEA	O
+)	O
+on	O
+animal	O
+models	O
+of	O
+schizophrenia	B-NP
+.	O
+	
+METHODS	O
+:	O
+Seventy	O
+Swiss	O
+albino	O
+female	O
+mice	O
+(	O
+25	O
+-	O
+35	O
+g	O
+)	O
+were	O
+divided	O
+into	O
+4	O
+groups	O
+:	O
+amphetamine	O
+-	O
+free	O
+(	O
+control	O
+)	O
+","	O
+amphetamine	O
+","	O
+50	O
+","	O
+and	O
+100	O
+mg	O
+/	O
+kg	O
+DHEA	O
+.	O
+	
+The	O
+DHEA	O
+was	O
+administered	O
+intraperitoneally	O
+(	O
+ip	O
+)	O
+for	O
+5	O
+days	O
+.	O
+	
+Amphetamine	O
+(	O
+3	O
+mg	O
+/	O
+kg	O
+ip	O
+)	O
+induced	O
+hyper	B-NP
+locomotion	O
+","	O
+apomorphine	O
+(	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+subcutaneously	O
+[	O
+sc	O
+]	O
+)	O
+induced	O
+climbing	O
+","	O
+and	O
+haloperidol	O
+(	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+sc	O
+)	O
+induced	O
+catalepsy	B-NP
+tests	O
+were	O
+used	O
+as	O
+animal	O
+models	O
+of	O
+schizophrenia	B-NP
+.	O
+	
+The	O
+study	O
+was	O
+conducted	O
+at	O
+the	O
+Animal	O
+Experiment	O
+Laboratories	O
+","	O
+Department	O
+of	O
+Pharmacology	O
+","	O
+Medical	O
+School	O
+","	O
+Eskisehir	O
+Osmangazi	O
+University	O
+","	O
+Eskisehir	O
+","	O
+Turkey	O
+between	O
+March	O
+and	O
+May	O
+2012	O
+.	O
+	
+Statistical	O
+analysis	O
+was	O
+carried	O
+out	O
+using	O
+Kruskal	O
+-	O
+Wallis	O
+test	O
+for	O
+hyper	B-NP
+locomotion	O
+","	O
+and	O
+one	O
+-	O
+way	O
+ANOVA	O
+for	O
+climbing	O
+and	O
+catalepsy	B-NP
+tests	O
+.	O
+	
+RESULTS	O
+:	O
+In	O
+the	O
+amphetamine	O
+-	O
+induced	O
+locomotion	O
+test	O
+","	O
+there	O
+were	O
+significant	O
+increases	O
+in	O
+all	O
+movements	O
+compared	O
+with	O
+the	O
+amphetamine	O
+-	O
+free	O
+group	O
+.	O
+	
+Both	O
+DHEA	O
+50	O
+mg	O
+/	O
+kg	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+","	O
+and	O
+100	O
+mg	O
+/	O
+kg	O
+(	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+significantly	O
+decreased	O
+all	O
+movements	O
+compared	O
+with	O
+the	O
+amphetamine	O
+-	O
+induced	O
+locomotion	O
+group	O
+.	O
+	
+There	O
+was	O
+a	O
+significant	O
+difference	O
+between	O
+groups	O
+in	O
+the	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B-NP
+test	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+There	O
+was	O
+no	O
+significant	O
+difference	O
+between	O
+groups	O
+in	O
+terms	O
+of	O
+total	O
+climbing	O
+time	O
+in	O
+the	O
+apomorphine	O
+-	O
+induced	O
+climbing	O
+test	O
+(	O
+p	O
+>	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+We	O
+observed	O
+that	O
+DHEA	O
+reduced	O
+locomotor	O
+activity	O
+and	O
+increased	O
+catalepsy	B-NP
+at	O
+both	O
+doses	O
+","	O
+while	O
+it	O
+had	O
+no	O
+effect	O
+on	O
+climbing	O
+behavior	O
+.	O
+	
+We	O
+suggest	O
+that	O
+DHEA	O
+displays	O
+typical	O
+neuroleptic	O
+-	O
+like	O
+effects	O
+","	O
+and	O
+may	O
+be	O
+used	O
+in	O
+the	O
+treatment	O
+of	O
+schizophrenia	B-NP
+.	O
+	
+Availability	O
+of	O
+human	O
+induced	O
+pluripotent	O
+stem	O
+cell	O
+-	O
+derived	O
+cardiomyocytes	O
+in	O
+assessment	O
+of	O
+drug	O
+potential	O
+for	O
+QT	B-NP
+prolongation	I-NP
+.	O
+	
+Field	O
+potential	O
+duration	O
+(	O
+FPD	O
+)	O
+in	O
+human	O
+-	O
+induced	O
+pluripotent	O
+stem	O
+cell	O
+-	O
+derived	O
+cardiomyocytes	O
+(	O
+hiPS	O
+-	O
+CMs	O
+)	O
+","	O
+which	O
+can	O
+express	O
+QT	O
+interval	O
+in	O
+an	O
+electrocardiogram	O
+","	O
+is	O
+reported	O
+to	O
+be	O
+a	O
+useful	O
+tool	O
+to	O
+predict	O
+K	O
+(	O
++	O
+)	O
+channel	O
+and	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+channel	O
+blocker	O
+effects	O
+on	O
+QT	O
+interval	O
+.	O
+	
+However	O
+","	O
+there	O
+is	O
+no	O
+report	O
+showing	O
+that	O
+this	O
+technique	O
+can	O
+be	O
+used	O
+to	O
+predict	O
+multichannel	O
+blocker	O
+potential	O
+for	O
+QT	B-NP
+prolongation	I-NP
+.	O
+	
+The	O
+aim	O
+of	O
+this	O
+study	O
+is	O
+to	O
+show	O
+that	O
+FPD	O
+from	O
+MEA	O
+(	O
+Multielectrode	O
+array	O
+)	O
+of	O
+hiPS	O
+-	O
+CMs	O
+can	O
+detect	O
+QT	B-NP
+prolongation	I-NP
+induced	O
+by	O
+multichannel	O
+blockers	O
+.	O
+	
+hiPS	O
+-	O
+CMs	O
+were	O
+seeded	O
+onto	O
+MEA	O
+and	O
+FPD	O
+was	O
+measured	O
+for	O
+2min	O
+every	O
+10min	O
+for	O
+30min	O
+after	O
+drug	O
+exposure	O
+for	O
+the	O
+vehicle	O
+and	O
+each	O
+drug	O
+concentration	O
+.	O
+	
+IKr	O
+and	O
+IKs	O
+blockers	O
+concentration	O
+-	O
+dependently	O
+prolonged	O
+corrected	O
+FPD	O
+(	O
+FPDc	O
+)	O
+","	O
+whereas	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+channel	O
+blockers	O
+concentration	O
+-	O
+dependently	O
+shortened	O
+FPDc	O
+.	O
+	
+Also	O
+","	O
+the	O
+multichannel	O
+blockers	O
+Amiodarone	O
+","	O
+Paroxetine	O
+","	O
+Terfenadine	O
+and	O
+Citalopram	O
+prolonged	O
+FPDc	O
+in	O
+a	O
+concentration	O
+dependent	O
+manner	O
+.	O
+	
+Finally	O
+","	O
+the	O
+IKr	O
+blockers	O
+","	O
+Terfenadine	O
+and	O
+Citalopram	O
+","	O
+which	O
+are	O
+reported	O
+to	O
+cause	O
+Torsade	B-NP
+de	I-NP
+Pointes	I-NP
+(	O
+TdP	B-NP
+)	O
+in	O
+clinical	O
+practice	O
+","	O
+produced	O
+early	O
+afterdepolarization	O
+(	O
+EAD	O
+)	O
+.	O
+	
+hiPS	O
+-	O
+CMs	O
+using	O
+MEA	O
+system	O
+and	O
+FPDc	O
+can	O
+predict	O
+the	O
+effects	O
+of	O
+drug	O
+candidates	O
+on	O
+QT	O
+interval	O
+.	O
+	
+This	O
+study	O
+also	O
+shows	O
+that	O
+this	O
+assay	O
+can	O
+help	O
+detect	O
+EAD	O
+for	O
+drugs	O
+with	O
+TdP	B-NP
+potential	O
+.	O
+	
+Dermal	O
+developmental	O
+toxicity	B-NP
+of	O
+N	O
+-	O
+phenylimide	O
+herbicides	O
+in	O
+rats	O
+.	O
+	
+BACKGROUND	O
+:	O
+S	O
+-	O
+53482	O
+and	O
+S	O
+-	O
+23121	O
+are	O
+N	O
+-	O
+phenylimide	O
+herbicides	O
+and	O
+produced	O
+embryolethality	B-NP
+","	O
+teratogenicity	B-NP
+(	O
+mainly	O
+ventricular	B-NP
+septal	I-NP
+defects	I-NP
+and	O
+wavy	O
+ribs	O
+)	O
+","	O
+and	O
+growth	B-NP
+retardation	I-NP
+in	O
+rats	O
+in	O
+conventional	O
+oral	O
+developmental	O
+toxicity	B-NP
+studies	O
+.	O
+	
+Our	O
+objective	O
+in	O
+this	O
+study	O
+was	O
+to	O
+investigate	O
+whether	O
+the	O
+compounds	O
+induce	O
+developmental	O
+toxicity	B-NP
+via	O
+the	O
+dermal	O
+route	O
+","	O
+which	O
+is	O
+more	O
+relevant	O
+to	O
+occupational	O
+exposure	O
+","	O
+hence	O
+better	O
+addressing	O
+human	O
+health	O
+risks	O
+.	O
+	
+METHODS	O
+:	O
+S	O
+-	O
+53482	O
+was	O
+administered	O
+dermally	O
+to	O
+rats	O
+at	O
+30	O
+","	O
+100	O
+","	O
+and	O
+300	O
+mg	O
+/	O
+kg	O
+during	O
+organogenesis	O
+","	O
+and	O
+S	O
+-	O
+23121	O
+was	O
+administered	O
+at	O
+200	O
+","	O
+400	O
+","	O
+and	O
+800	O
+mg	O
+/	O
+kg	O
+(	O
+the	O
+maximum	O
+applicable	O
+dose	O
+level	O
+)	O
+.	O
+	
+Fetuses	O
+were	O
+obtained	O
+by	O
+a	O
+Cesarean	O
+section	O
+and	O
+examined	O
+for	O
+external	O
+","	O
+visceral	O
+","	O
+and	O
+skeletal	O
+alterations	O
+.	O
+	
+RESULTS	O
+:	O
+Dermal	O
+exposure	O
+of	O
+rats	O
+to	O
+S	O
+-	O
+53482	O
+at	O
+300	O
+mg	O
+/	O
+kg	O
+produced	O
+patterns	O
+of	O
+developmental	O
+toxicity	B-NP
+similar	O
+to	O
+those	O
+resulting	O
+from	O
+oral	O
+exposure	O
+.	O
+	
+Toxicity	B-NP
+included	O
+embryolethality	B-NP
+","	O
+teratogenicity	B-NP
+","	O
+and	O
+growth	B-NP
+retardation	I-NP
+.	O
+	
+Dermal	O
+administration	O
+of	O
+S	O
+-	O
+23121	O
+at	O
+800	O
+mg	O
+/	O
+kg	O
+resulted	O
+in	O
+an	O
+increased	O
+incidence	O
+of	O
+embryonic	B-NP
+death	I-NP
+and	O
+ventricular	B-NP
+septal	I-NP
+defect	I-NP
+","	O
+but	O
+retarded	O
+fetal	O
+growth	O
+was	O
+not	O
+observed	O
+as	O
+it	O
+was	O
+following	O
+oral	O
+exposure	O
+to	O
+S	O
+-	O
+23121	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Based	O
+on	O
+the	O
+results	O
+","	O
+S	O
+-	O
+53482	O
+and	O
+S	O
+-	O
+23121	O
+were	O
+teratogenic	B-NP
+when	O
+administered	O
+dermally	O
+to	O
+pregnant	O
+rats	O
+as	O
+were	O
+the	O
+compounds	O
+administered	O
+orally	O
+.	O
+	
+Thus	O
+","	O
+investigation	O
+of	O
+the	O
+mechanism	O
+and	O
+its	O
+human	O
+relevancy	O
+become	O
+more	O
+important	O
+.	O
+	
+Rates	O
+of	O
+Renal	B-NP
+Toxicity	I-NP
+in	O
+Cancer	B-NP
+Patients	O
+Receiving	O
+Cisplatin	O
+With	O
+and	O
+Without	O
+Mannitol	O
+.	O
+	
+BACKGROUND	O
+:	O
+Cisplatin	O
+is	O
+a	O
+widely	O
+used	O
+antineoplastic	O
+.	O
+	
+One	O
+of	O
+the	O
+major	O
+complications	O
+of	O
+cisplatin	O
+use	O
+is	O
+dose	O
+-	O
+limiting	O
+nephrotoxicity	B-NP
+.	O
+	
+There	O
+are	O
+many	O
+strategies	O
+to	O
+prevent	O
+this	O
+toxicity	B-NP
+","	O
+including	O
+the	O
+use	O
+of	O
+mannitol	O
+as	O
+a	O
+nephroprotectant	O
+in	O
+combination	O
+with	O
+hydration	O
+.	O
+	
+OBJECTIVE	O
+:	O
+We	O
+aimed	O
+to	O
+evaluate	O
+the	O
+rates	O
+of	O
+cisplatin	O
+-	O
+induced	O
+nephrotoxicity	B-NP
+in	O
+cancer	B-NP
+patients	O
+receiving	O
+single	O
+-	O
+agent	O
+cisplatin	O
+with	O
+and	O
+without	O
+mannitol	O
+.	O
+	
+METHODS	O
+:	O
+This	O
+single	O
+-	O
+center	O
+retrospective	O
+analysis	O
+was	O
+a	O
+quasi	O
+experiment	O
+created	O
+by	O
+the	O
+national	O
+mannitol	O
+shortage	O
+.	O
+	
+Data	O
+were	O
+collected	O
+on	O
+adult	O
+cancer	B-NP
+patients	O
+receiving	O
+single	O
+-	O
+agent	O
+cisplatin	O
+as	O
+an	O
+outpatient	O
+from	O
+January	O
+2011	O
+to	O
+September	O
+2012	O
+.	O
+	
+The	O
+primary	O
+outcome	O
+was	O
+acute	B-NP
+kidney	I-NP
+injury	I-NP
+(	O
+AKI	B-NP
+)	O
+.	O
+	
+RESULTS	O
+:	O
+We	O
+evaluated	O
+143	O
+patients	O
+who	O
+received	O
+single	O
+-	O
+agent	O
+cisplatin	O
+;	O
+97	O
+.	O
+2	O
+%	O
+of	O
+patients	O
+had	O
+head	B-NP
+and	I-NP
+neck	I-NP
+cancer	I-NP
+as	O
+their	O
+primary	O
+malignancy	B-NP
+.	O
+	
+Patients	O
+who	O
+did	O
+not	O
+receive	O
+mannitol	O
+were	O
+more	O
+likely	O
+to	O
+develop	O
+nephrotoxicity	B-NP
+:	O
+odds	O
+ratio	O
+[	O
+OR	O
+]	O
+=	O
+2	O
+.	O
+646	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+1	O
+.	O
+8	O
+","	O
+6	O
+.	O
+944	O
+;	O
+P	O
+=	O
+0	O
+.	O
+48	O
+)	O
+.	O
+	
+Patients	O
+who	O
+received	O
+the	O
+100	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+dosing	O
+and	O
+patients	O
+who	O
+had	O
+a	O
+history	O
+of	O
+hypertension	B-NP
+also	O
+had	O
+a	O
+higher	O
+likelihood	O
+of	O
+developing	O
+nephrotoxicity	B-NP
+:	O
+OR	O
+=	O
+11	O
+.	O
+494	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+4	O
+.	O
+149	O
+","	O
+32	O
+.	O
+258	O
+;	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+and	O
+OR	O
+=	O
+3	O
+.	O
+219	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+1	O
+.	O
+228	O
+","	O
+8	O
+.	O
+439	O
+;	O
+P	O
+=	O
+0	O
+.	O
+17	O
+)	O
+","	O
+respectively	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+When	O
+limited	O
+quantities	O
+of	O
+mannitol	O
+are	O
+available	O
+","	O
+it	O
+should	O
+preferentially	O
+be	O
+given	O
+to	O
+patients	O
+at	O
+particularly	O
+high	O
+risk	O
+of	O
+nephrotoxicity	B-NP
+.	O
+	
+Our	O
+analysis	O
+suggests	O
+that	O
+those	O
+patients	O
+receiving	O
+the	O
+dosing	O
+schedule	O
+of	O
+100	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+cisplatin	O
+every	O
+3	O
+weeks	O
+and	O
+those	O
+with	O
+hypertension	B-NP
+are	O
+at	O
+the	O
+greatest	O
+risk	O
+of	O
+nephrotoxicity	B-NP
+and	O
+would	O
+benefit	O
+from	O
+the	O
+addition	O
+of	O
+mannitol	O
+.	O
+	
+Metformin	O
+protects	O
+against	O
+seizures	B-NP
+","	O
+learning	B-NP
+and	I-NP
+memory	I-NP
+impairments	I-NP
+and	O
+oxidative	O
+damage	O
+induced	O
+by	O
+pentylenetetrazole	O
+-	O
+induced	O
+kindling	O
+in	O
+mice	O
+.	O
+	
+Cognitive	B-NP
+impairment	I-NP
+","	O
+the	O
+most	O
+common	O
+and	O
+severe	O
+comorbidity	O
+of	O
+epilepsy	B-NP
+","	O
+greatly	O
+diminishes	O
+the	O
+quality	O
+of	O
+life	O
+.	O
+	
+However	O
+","	O
+current	O
+therapeutic	O
+interventions	O
+for	O
+epilepsy	B-NP
+can	O
+also	O
+cause	O
+untoward	O
+cognitive	O
+effects	O
+.	O
+	
+Thus	O
+","	O
+there	O
+is	O
+an	O
+urgent	O
+need	O
+for	O
+new	O
+kinds	O
+of	O
+agents	O
+targeting	O
+both	O
+seizures	B-NP
+and	O
+cognition	B-NP
+deficits	I-NP
+.	O
+	
+Oxidative	O
+stress	O
+is	O
+considered	O
+to	O
+play	O
+an	O
+important	O
+role	O
+in	O
+epileptogenesis	O
+and	O
+cognitive	B-NP
+deficits	I-NP
+","	O
+and	O
+antioxidants	O
+have	O
+a	O
+putative	O
+antiepileptic	O
+potential	O
+.	O
+	
+Metformin	O
+","	O
+the	O
+most	O
+commonly	O
+prescribed	O
+antidiabetic	O
+oral	O
+drug	O
+","	O
+has	O
+antioxidant	O
+properties	O
+.	O
+	
+This	O
+study	O
+was	O
+designed	O
+to	O
+evaluate	O
+the	O
+ameliorative	O
+effects	O
+of	O
+metformin	O
+on	O
+seizures	B-NP
+","	O
+cognitive	B-NP
+impairment	I-NP
+and	O
+brain	O
+oxidative	O
+stress	O
+markers	O
+observed	O
+in	O
+pentylenetetrazole	O
+-	O
+induced	O
+kindling	O
+animals	O
+.	O
+	
+Male	O
+C57BL	O
+/	O
+6	O
+mice	O
+were	O
+administered	O
+with	O
+subconvulsive	O
+dose	O
+of	O
+pentylenetetrazole	O
+(	O
+37	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+p	O
+.	O
+)	O
+every	O
+other	O
+day	O
+for	O
+14	O
+injections	O
+.	O
+	
+Metformin	O
+was	O
+injected	O
+intraperitoneally	O
+in	O
+dose	O
+of	O
+200mg	O
+/	O
+kg	O
+along	O
+with	O
+alternate	O
+-	O
+day	O
+PTZ	O
+.	O
+	
+We	O
+found	O
+that	O
+metformin	O
+suppressed	O
+the	O
+progression	O
+of	O
+kindling	O
+","	O
+ameliorated	O
+the	O
+cognitive	B-NP
+impairment	I-NP
+and	O
+decreased	O
+brain	O
+oxidative	O
+stress	O
+.	O
+	
+Thus	O
+the	O
+present	O
+study	O
+concluded	O
+that	O
+metformin	O
+may	O
+be	O
+a	O
+potential	O
+agent	O
+for	O
+the	O
+treatment	O
+of	O
+epilepsy	B-NP
+as	O
+well	O
+as	O
+a	O
+protective	O
+medicine	O
+against	O
+cognitive	B-NP
+impairment	I-NP
+induced	O
+by	O
+seizures	B-NP
+.	O
+	
+P53	O
+inhibition	O
+exacerbates	O
+late	O
+-	O
+stage	O
+anthracycline	O
+cardiotoxicity	B-NP
+.	O
+	
+AIMS	O
+:	O
+Doxorubicin	O
+(	O
+DOX	O
+)	O
+is	O
+an	O
+effective	O
+anti	O
+-	O
+cancer	B-NP
+therapeutic	O
+","	O
+but	O
+is	O
+associated	O
+with	O
+both	O
+acute	O
+and	O
+late	O
+-	O
+stage	O
+cardiotoxicity	B-NP
+.	O
+	
+Children	O
+are	O
+particularly	O
+sensitive	O
+to	O
+DOX	O
+-	O
+induced	O
+heart	B-NP
+failure	I-NP
+.	O
+	
+Here	O
+","	O
+the	O
+impact	O
+of	O
+p53	O
+inhibition	O
+on	O
+acute	O
+vs	O
+.	O
+late	O
+-	O
+stage	O
+DOX	O
+cardiotoxicity	B-NP
+was	O
+examined	O
+in	O
+a	O
+juvenile	O
+model	O
+.	O
+	
+METHODS	O
+AND	O
+RESULTS	O
+:	O
+Two	O
+-	O
+week	O
+-	O
+old	O
+MHC	O
+-	O
+CB7	O
+mice	O
+(	O
+which	O
+express	O
+dominant	O
+-	O
+interfering	O
+p53	O
+in	O
+cardiomyocytes	O
+)	O
+and	O
+their	O
+non	O
+-	O
+transgenic	O
+(	O
+NON	O
+-	O
+TXG	O
+)	O
+littermates	O
+received	O
+weekly	O
+DOX	O
+injections	O
+for	O
+5	O
+weeks	O
+(	O
+25	O
+mg	O
+/	O
+kg	O
+cumulative	O
+dose	O
+)	O
+.	O
+	
+One	O
+week	O
+after	O
+the	O
+last	O
+DOX	O
+treatment	O
+(	O
+acute	O
+stage	O
+)	O
+","	O
+MHC	O
+-	O
+CB7	O
+mice	O
+exhibited	O
+improved	O
+cardiac	O
+function	O
+and	O
+lower	O
+levels	O
+of	O
+cardiomyocyte	O
+apoptosis	O
+when	O
+compared	O
+with	O
+the	O
+NON	O
+-	O
+TXG	O
+mice	O
+.	O
+	
+Surprisingly	O
+","	O
+by	O
+13	O
+weeks	O
+following	O
+the	O
+last	O
+DOX	O
+treatment	O
+(	O
+late	O
+stage	O
+)	O
+","	O
+MHC	O
+-	O
+CB7	O
+exhibited	O
+a	O
+progressive	O
+decrease	O
+in	O
+cardiac	O
+function	O
+and	O
+higher	O
+rates	O
+of	O
+cardiomyocyte	O
+apoptosis	O
+when	O
+compared	O
+with	O
+NON	O
+-	O
+TXG	O
+mice	O
+.	O
+	
+p53	O
+inhibition	O
+blocked	O
+transient	O
+DOX	O
+-	O
+induced	O
+STAT3	O
+activation	O
+in	O
+MHC	O
+-	O
+CB7	O
+mice	O
+","	O
+which	O
+was	O
+associated	O
+with	O
+enhanced	O
+induction	O
+of	O
+the	O
+DNA	O
+repair	O
+proteins	O
+Ku70	O
+and	O
+Ku80	O
+.	O
+	
+Mice	O
+with	O
+cardiomyocyte	O
+-	O
+restricted	O
+deletion	O
+of	O
+STAT3	O
+exhibited	O
+worse	O
+cardiac	O
+function	O
+","	O
+higher	O
+levels	O
+of	O
+cardiomyocyte	O
+apoptosis	O
+","	O
+and	O
+a	O
+greater	O
+induction	O
+of	O
+Ku70	O
+and	O
+Ku80	O
+in	O
+response	O
+to	O
+DOX	O
+treatment	O
+during	O
+the	O
+acute	O
+stage	O
+when	O
+compared	O
+with	O
+control	O
+animals	O
+.	O
+	
+CONCLUSION	O
+:	O
+These	O
+data	O
+support	O
+a	O
+model	O
+wherein	O
+a	O
+p53	O
+-	O
+dependent	O
+cardioprotective	O
+pathway	O
+","	O
+mediated	O
+via	O
+STAT3	O
+activation	O
+","	O
+mitigates	O
+DOX	O
+-	O
+induced	O
+myocardial	O
+stress	O
+during	O
+drug	O
+delivery	O
+.	O
+	
+Furthermore	O
+","	O
+these	O
+data	O
+suggest	O
+an	O
+explanation	O
+as	O
+to	O
+how	O
+p53	O
+inhibition	O
+can	O
+result	O
+in	O
+cardioprotection	O
+during	O
+drug	O
+treatment	O
+and	O
+","	O
+paradoxically	O
+","	O
+enhanced	O
+cardiotoxicity	B-NP
+long	O
+after	O
+the	O
+cessation	O
+of	O
+drug	O
+treatment	O
+.	O
+	
+Metronidazole	O
+-	O
+induced	O
+encephalopathy	B-NP
+:	O
+an	O
+uncommon	O
+scenario	O
+.	O
+	
+Metronidazole	O
+can	O
+produce	O
+neurological	O
+complications	O
+although	O
+it	O
+is	O
+not	O
+a	O
+common	O
+scenario	O
+.	O
+	
+We	O
+present	O
+a	O
+case	O
+where	O
+a	O
+patient	O
+developed	O
+features	O
+of	O
+encephalopathy	B-NP
+following	O
+prolonged	O
+metronidazole	O
+intake	O
+.	O
+	
+Magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+brain	O
+showed	O
+abnormal	O
+signal	O
+intensity	O
+involving	O
+both	O
+dentate	O
+nuclei	O
+of	O
+cerebellum	O
+and	O
+splenium	O
+of	O
+corpus	O
+callosum	O
+.	O
+	
+The	O
+diagnosis	O
+of	O
+metronidazole	O
+toxicity	B-NP
+was	O
+made	O
+by	O
+the	O
+MRI	O
+findings	O
+and	O
+supported	O
+clinically	O
+.	O
+	
+Aconitine	O
+-	O
+induced	O
+Ca2	O
++	O
+overload	O
+causes	O
+arrhythmia	B-NP
+and	O
+triggers	O
+apoptosis	O
+through	O
+p38	O
+MAPK	O
+signaling	O
+pathway	O
+in	O
+rats	O
+.	O
+	
+Aconitine	O
+is	O
+a	O
+major	O
+bioactive	O
+diterpenoid	O
+alkaloid	O
+with	O
+high	O
+content	O
+derived	O
+from	O
+herbal	O
+aconitum	O
+plants	O
+.	O
+	
+Emerging	O
+evidence	O
+indicates	O
+that	O
+voltage	O
+-	O
+dependent	O
+Na	O
+(	O
++	O
+)	O
+channels	O
+have	O
+pivotal	O
+roles	O
+in	O
+the	O
+cardiotoxicity	B-NP
+of	O
+aconitine	O
+.	O
+	
+However	O
+","	O
+no	O
+reports	O
+are	O
+available	O
+on	O
+the	O
+role	O
+of	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+in	O
+aconitine	O
+poisoning	B-NP
+.	O
+	
+In	O
+this	O
+study	O
+","	O
+we	O
+explored	O
+the	O
+importance	O
+of	O
+pathological	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+signaling	O
+in	O
+aconitine	O
+poisoning	B-NP
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+.	O
+	
+We	O
+found	O
+that	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+overload	O
+lead	O
+to	O
+accelerated	O
+beating	O
+rhythm	O
+in	O
+adult	O
+rat	O
+ventricular	O
+myocytes	O
+and	O
+caused	O
+arrhythmia	B-NP
+in	O
+conscious	O
+freely	O
+moving	O
+rats	O
+.	O
+	
+To	O
+investigate	O
+effects	O
+of	O
+aconitine	O
+on	O
+myocardial	B-NP
+injury	I-NP
+","	O
+we	O
+performed	O
+cytotoxicity	B-NP
+assay	O
+in	O
+neonatal	O
+rat	O
+ventricular	O
+myocytes	O
+(	O
+NRVMs	O
+)	O
+","	O
+as	O
+well	O
+as	O
+measured	O
+lactate	O
+dehydrogenase	O
+level	O
+in	O
+the	O
+culture	O
+medium	O
+of	O
+NRVMs	O
+and	O
+activities	O
+of	O
+serum	O
+cardiac	O
+enzymes	O
+in	O
+rats	O
+.	O
+	
+The	O
+results	O
+showed	O
+that	O
+aconitine	O
+resulted	O
+in	O
+myocardial	B-NP
+injury	I-NP
+and	O
+reduced	O
+NRVMs	O
+viability	O
+dose	O
+-	O
+dependently	O
+.	O
+	
+To	O
+confirm	O
+the	O
+pro	O
+-	O
+apoptotic	O
+effects	O
+","	O
+we	O
+performed	O
+flow	O
+cytometric	O
+detection	O
+","	O
+cardiac	O
+histology	O
+","	O
+transmission	O
+electron	O
+microscopy	O
+and	O
+terminal	O
+deoxynucleotidyl	O
+transferase	O
+-	O
+mediated	O
+dUTP	O
+-	O
+biotin	O
+nick	O
+end	O
+labeling	O
+assay	O
+.	O
+	
+The	O
+results	O
+showed	O
+that	O
+aconitine	O
+stimulated	O
+apoptosis	O
+time	O
+-	O
+dependently	O
+.	O
+	
+The	O
+expression	O
+analysis	O
+of	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+handling	O
+proteins	O
+demonstrated	O
+that	O
+aconitine	O
+promoted	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+overload	O
+through	O
+the	O
+expression	O
+regulation	O
+of	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+handling	O
+proteins	O
+.	O
+	
+The	O
+expression	O
+analysis	O
+of	O
+apoptosis	O
+-	O
+related	O
+proteins	O
+revealed	O
+that	O
+pro	O
+-	O
+apoptotic	O
+protein	O
+expression	O
+was	O
+upregulated	O
+","	O
+and	O
+anti	O
+-	O
+apoptotic	O
+protein	O
+BCL	O
+-	O
+2	O
+expression	O
+was	O
+downregulated	O
+.	O
+	
+Furthermore	O
+","	O
+increased	O
+phosphorylation	O
+of	O
+MAPK	O
+family	O
+members	O
+","	O
+especially	O
+the	O
+P	O
+-	O
+P38	O
+/	O
+P38	O
+ratio	O
+was	O
+found	O
+in	O
+cardiac	O
+tissues	O
+.	O
+	
+Hence	O
+","	O
+our	O
+results	O
+suggest	O
+that	O
+aconitine	O
+significantly	O
+aggravates	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+overload	O
+and	O
+causes	O
+arrhythmia	B-NP
+and	O
+finally	O
+promotes	O
+apoptotic	O
+development	O
+via	O
+phosphorylation	O
+of	O
+P38	O
+mitogen	O
+-	O
+activated	O
+protein	O
+kinase	O
+.	O
+	
+Chronic	O
+treatment	O
+with	O
+metformin	O
+suppresses	O
+toll	O
+-	O
+like	O
+receptor	O
+4	O
+signaling	O
+and	O
+attenuates	O
+left	B-NP
+ventricular	I-NP
+dysfunction	I-NP
+following	O
+myocardial	B-NP
+infarction	I-NP
+.	O
+	
+Acute	O
+treatment	O
+with	O
+metformin	O
+has	O
+a	O
+protective	O
+effect	O
+in	O
+myocardial	B-NP
+infarction	I-NP
+by	O
+suppression	O
+of	O
+inflammatory	O
+responses	O
+due	O
+to	O
+activation	O
+of	O
+AMP	O
+-	O
+activated	O
+protein	O
+kinase	O
+(	O
+AMPK	O
+)	O
+.	O
+	
+In	O
+the	O
+present	O
+study	O
+","	O
+the	O
+effect	O
+of	O
+chronic	O
+pre	O
+-	O
+treatment	O
+with	O
+metformin	O
+on	O
+cardiac	B-NP
+dysfunction	I-NP
+and	O
+toll	O
+-	O
+like	O
+receptor	O
+4	O
+(	O
+TLR4	O
+)	O
+activities	O
+following	O
+myocardial	B-NP
+infarction	I-NP
+and	O
+their	O
+relation	O
+with	O
+AMPK	O
+were	O
+assessed	O
+.	O
+	
+Male	O
+Wistar	O
+rats	O
+were	O
+randomly	O
+assigned	O
+to	O
+one	O
+of	O
+5	O
+groups	O
+(	O
+n	O
+=	O
+6	O
+)	O
+:	O
+normal	O
+control	O
+and	O
+groups	O
+were	O
+injected	O
+isoproterenol	O
+after	O
+chronic	O
+pre	O
+-	O
+treatment	O
+with	O
+0	O
+","	O
+25	O
+","	O
+50	O
+","	O
+or	O
+100mg	O
+/	O
+kg	O
+of	O
+metformin	O
+twice	O
+daily	O
+for	O
+14	O
+days	O
+.	O
+	
+Isoproterenol	O
+(	O
+100mg	O
+/	O
+kg	O
+)	O
+was	O
+injected	O
+subcutaneously	O
+on	O
+the	O
+13th	O
+and	O
+14th	O
+days	O
+to	O
+induce	O
+acute	B-NP
+myocardial	I-NP
+infarction	I-NP
+.	O
+	
+Isoproterenol	O
+alone	O
+decreased	O
+left	O
+ventricular	O
+systolic	O
+pressure	O
+and	O
+myocardial	O
+contractility	O
+indexed	O
+as	O
+LVdp	O
+/	O
+dtmax	O
+and	O
+LVdp	O
+/	O
+dtmin	O
+.	O
+	
+The	O
+left	B-NP
+ventricular	I-NP
+dysfunction	I-NP
+was	O
+significantly	O
+lower	O
+in	O
+the	O
+groups	O
+treated	O
+with	O
+25	O
+and	O
+50mg	O
+/	O
+kg	O
+of	O
+metformin	O
+.	O
+	
+Metfromin	O
+markedly	O
+lowered	O
+isoproterenol	O
+-	O
+induced	O
+elevation	O
+in	O
+the	O
+levels	O
+of	O
+TLR4	O
+mRNA	O
+","	O
+myeloid	O
+differentiation	O
+protein	O
+88	O
+(	O
+MyD88	O
+)	O
+","	O
+tumor	B-NP
+necrosis	B-NP
+factor	O
+-	O
+alpha	O
+(	O
+TNF	O
+-	O
+a	O
+)	O
+","	O
+and	O
+interleukin	O
+6	O
+(	O
+IL	O
+-	O
+6	O
+)	O
+in	O
+the	O
+heart	O
+tissues	O
+.	O
+	
+Similar	O
+changes	O
+were	O
+also	O
+seen	O
+in	O
+the	O
+serum	O
+levels	O
+of	O
+TNF	O
+-	O
+a	O
+and	O
+IL	O
+-	O
+6	O
+.	O
+	
+However	O
+","	O
+the	O
+lower	O
+doses	O
+of	O
+25	O
+and	O
+50mg	O
+/	O
+kg	O
+were	O
+more	O
+effective	O
+than	O
+100mg	O
+/	O
+kg	O
+.	O
+	
+Phosphorylated	O
+AMPKa	O
+(	O
+p	O
+-	O
+AMPK	O
+)	O
+in	O
+the	O
+myocardium	O
+was	O
+significantly	O
+elevated	O
+by	O
+25mg	O
+/	O
+kg	O
+of	O
+metformin	O
+","	O
+slightly	O
+by	O
+50mg	O
+/	O
+kg	O
+","	O
+but	O
+not	O
+by	O
+100mg	O
+/	O
+kg	O
+.	O
+	
+Chronic	O
+pre	O
+-	O
+treatment	O
+with	O
+metformin	O
+reduces	O
+post	O
+-	O
+myocardial	B-NP
+infarction	I-NP
+cardiac	O
+dysfunction	O
+and	O
+suppresses	O
+inflammatory	O
+responses	O
+","	O
+possibly	O
+through	O
+inhibition	O
+of	O
+TLR4	O
+activities	O
+.	O
+	
+This	O
+mechanism	O
+can	O
+be	O
+considered	O
+as	O
+a	O
+target	O
+to	O
+protect	O
+infarcted	O
+myocardium	O
+.	O
+	
+Unusual	O
+complications	O
+of	O
+antithyroid	O
+drug	O
+therapy	O
+:	O
+four	O
+case	O
+reports	O
+and	O
+review	O
+of	O
+literature	O
+.	O
+	
+Two	O
+cases	O
+of	O
+propylthiouracil	O
+-	O
+associated	O
+acute	O
+hepatitis	B-NP
+","	O
+one	O
+case	O
+of	O
+fatal	O
+methimazole	O
+-	O
+associated	O
+hepatocellular	B-NP
+necrosis	I-NP
+and	O
+one	O
+case	O
+of	O
+propylthiouracil	O
+-	O
+associated	O
+lupus	B-NP
+-	I-NP
+like	I-NP
+syndrome	I-NP
+are	O
+described	O
+.	O
+	
+The	O
+literature	O
+related	O
+to	O
+antithyroid	O
+drug	O
+side	O
+effects	O
+and	O
+the	O
+mechanisms	O
+for	O
+their	O
+occurrence	O
+are	O
+reviewed	O
+and	O
+the	O
+efficacy	O
+and	O
+complications	O
+of	O
+thyroidectomy	O
+and	O
+radioiodine	O
+compared	O
+to	O
+those	O
+of	O
+antithyroid	O
+drugs	O
+.	O
+	
+It	O
+is	O
+concluded	O
+that	O
+in	O
+most	O
+circumstances	O
+131I	O
+is	O
+the	O
+therapy	O
+of	O
+choice	O
+for	O
+hyperthyroidism	B-NP
+.	O
+	
+Neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+induced	O
+by	O
+combination	O
+therapy	O
+with	O
+tetrabenazine	O
+and	O
+tiapride	O
+in	O
+a	O
+Japanese	O
+patient	O
+with	O
+Huntington	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+at	O
+the	O
+terminal	O
+stage	O
+of	O
+recurrent	O
+breast	B-NP
+cancer	I-NP
+.	O
+	
+We	O
+herein	O
+describe	O
+the	O
+case	O
+of	O
+an	O
+81	O
+-	O
+year	O
+-	O
+old	O
+Japanese	O
+woman	O
+with	O
+neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+that	O
+occurred	O
+36	O
+days	O
+after	O
+the	O
+initiation	O
+of	O
+combination	O
+therapy	O
+with	O
+tiapride	O
+(	O
+75	O
+mg	O
+/	O
+day	O
+)	O
+and	O
+tetrabenazine	O
+(	O
+12	O
+.	O
+5	O
+mg	O
+/	O
+day	O
+)	O
+for	O
+Huntington	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+The	O
+patient	O
+had	O
+been	O
+treated	O
+with	O
+tiapride	O
+or	O
+tetrabenazine	O
+alone	O
+without	O
+any	O
+adverse	O
+effects	O
+before	O
+the	O
+administration	O
+of	O
+the	O
+combination	O
+therapy	O
+.	O
+	
+She	O
+also	O
+had	O
+advanced	O
+breast	B-NP
+cancer	I-NP
+when	O
+the	O
+combination	O
+therapy	O
+was	O
+initiated	O
+.	O
+	
+To	O
+the	O
+best	O
+of	O
+our	O
+knowledge	O
+","	O
+the	O
+occurrence	O
+of	O
+neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+due	O
+to	O
+combination	O
+therapy	O
+with	O
+tetrabenazine	O
+and	O
+tiapride	O
+has	O
+not	O
+been	O
+previously	O
+reported	O
+.	O
+	
+Tetrabenazine	O
+should	O
+be	O
+administered	O
+very	O
+carefully	O
+in	O
+combination	O
+with	O
+other	O
+neuroleptic	O
+drugs	O
+","	O
+particularly	O
+in	O
+patients	O
+with	O
+a	O
+worsening	O
+general	O
+condition	O
+.	O
+	
+A	O
+metoprolol	O
+-	O
+terbinafine	O
+combination	O
+induced	O
+bradycardia	B-NP
+.	O
+	
+To	O
+report	O
+a	O
+sinus	B-NP
+bradycardia	I-NP
+induced	O
+by	O
+metoprolol	O
+and	O
+terbinafine	O
+drug	O
+-	O
+drug	O
+interaction	O
+and	O
+its	O
+management	O
+.	O
+	
+A	O
+63	O
+year	O
+-	O
+old	O
+Caucasian	O
+man	O
+on	O
+metoprolol	O
+200	O
+mg	O
+/	O
+day	O
+for	O
+stable	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+was	O
+prescribed	O
+a	O
+90	O
+-	O
+day	O
+course	O
+of	O
+oral	O
+terbinafine	O
+250	O
+mg	O
+/	O
+day	O
+for	O
+onychomycosis	B-NP
+.	O
+	
+On	O
+the	O
+49th	O
+day	O
+of	O
+terbinafine	O
+therapy	O
+","	O
+he	O
+was	O
+brought	O
+to	O
+the	O
+emergency	O
+room	O
+for	O
+a	O
+decrease	O
+of	O
+his	O
+global	O
+health	O
+status	O
+","	O
+confusion	B-NP
+and	O
+falls	O
+.	O
+	
+The	O
+electrocardiogram	O
+revealed	O
+a	O
+37	O
+beats	O
+/	O
+min	O
+sinus	B-NP
+bradycardia	I-NP
+.	O
+	
+A	O
+score	O
+of	O
+7	O
+on	O
+the	O
+Naranjo	O
+adverse	B-NP
+drug	I-NP
+reaction	I-NP
+probability	O
+scale	O
+indicates	O
+a	O
+probable	O
+relationship	O
+between	O
+the	O
+patient	O
+'	O
+s	O
+sinus	B-NP
+bradycardia	I-NP
+and	O
+the	O
+drug	O
+interaction	O
+between	O
+metoprolol	O
+and	O
+terbinafine	O
+.	O
+	
+The	O
+heart	O
+rate	O
+ameliorated	O
+first	O
+with	O
+a	O
+decrease	O
+in	O
+the	O
+dose	O
+of	O
+metoprolol	O
+.	O
+	
+It	O
+was	O
+subsequently	O
+changed	O
+to	O
+bisoprolol	O
+and	O
+the	O
+heart	O
+rate	O
+remained	O
+normal	O
+.	O
+	
+By	O
+inhibiting	O
+the	O
+cytochrome	O
+P450	O
+2D6	O
+","	O
+terbinafine	O
+had	O
+decreased	O
+metoprolol	O
+'	O
+s	O
+clearance	O
+","	O
+leading	O
+in	O
+metoprolol	O
+accumulation	O
+which	O
+has	O
+resulted	O
+in	O
+clinically	O
+significant	O
+sinus	B-NP
+bradycardia	I-NP
+.	O
+	
+Optochiasmatic	O
+and	O
+peripheral	B-NP
+neuropathy	I-NP
+due	O
+to	O
+ethambutol	O
+overtreatment	O
+.	O
+	
+Ethambutol	O
+is	O
+known	O
+to	O
+cause	O
+optic	B-NP
+neuropathy	I-NP
+and	O
+","	O
+more	O
+rarely	O
+","	O
+axonal	O
+polyneuropathy	B-NP
+.	O
+	
+We	O
+characterize	O
+the	O
+clinical	O
+","	O
+neurophysiological	O
+","	O
+and	O
+neuroimaging	O
+findings	O
+in	O
+a	O
+72	O
+-	O
+year	O
+-	O
+old	O
+man	O
+who	O
+developed	O
+visual	B-NP
+loss	I-NP
+and	O
+paresthesias	B-NP
+after	O
+11	O
+weeks	O
+of	O
+exposure	O
+to	O
+a	O
+supratherapeutic	O
+dose	O
+of	O
+ethambutol	O
+.	O
+	
+This	O
+case	O
+demonstrates	O
+the	O
+selective	O
+vulnerability	O
+of	O
+the	O
+anterior	O
+visual	O
+pathways	O
+and	O
+peripheral	O
+nerves	O
+to	O
+ethambutol	O
+toxicity	B-NP
+.	O
+	
+Testosterone	O
+ameliorates	O
+streptozotocin	O
+-	O
+induced	O
+memory	B-NP
+impairment	I-NP
+in	O
+male	O
+rats	O
+.	O
+	
+AIM	O
+:	O
+To	O
+study	O
+the	O
+effects	O
+of	O
+testosterone	O
+on	O
+streptozotocin	O
+(	O
+STZ	O
+)	O
+-	O
+induced	O
+memory	B-NP
+impairment	I-NP
+in	O
+male	O
+rats	O
+.	O
+	
+METHODS	O
+:	O
+Adult	O
+male	O
+Wistar	O
+rats	O
+were	O
+intracerebroventricularly	O
+(	O
+icv	O
+)	O
+infused	O
+with	O
+STZ	O
+(	O
+750	O
+ug	O
+)	O
+on	O
+d	O
+1	O
+and	O
+d	O
+3	O
+","	O
+and	O
+a	O
+passive	O
+avoidance	O
+task	O
+was	O
+assessed	O
+2	O
+weeks	O
+after	O
+the	O
+first	O
+injection	O
+of	O
+STZ	O
+.	O
+	
+Castration	O
+surgery	O
+was	O
+performed	O
+in	O
+another	O
+group	O
+of	O
+rats	O
+","	O
+and	O
+the	O
+passive	O
+avoidance	O
+task	O
+was	O
+assessed	O
+4	O
+weeks	O
+after	O
+the	O
+operation	O
+.	O
+	
+Testosterone	O
+(	O
+1	O
+mg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+d	O
+(	O
+-	O
+1	O
+)	O
+","	O
+sc	O
+)	O
+","	O
+the	O
+androgen	O
+receptor	O
+antagonist	O
+flutamide	O
+(	O
+10	O
+mg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+d	O
+(	O
+-	O
+1	O
+)	O
+","	O
+ip	O
+)	O
+","	O
+the	O
+estrogen	O
+receptor	O
+antagonist	O
+tamoxifen	O
+(	O
+1	O
+mg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+d	O
+(	O
+-	O
+1	O
+)	O
+","	O
+ip	O
+)	O
+or	O
+the	O
+aromatase	O
+inhibitor	O
+letrozole	O
+(	O
+4	O
+mg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+d	O
+(	O
+-	O
+1	O
+)	O
+","	O
+ip	O
+)	O
+were	O
+administered	O
+for	O
+6	O
+d	O
+after	O
+the	O
+first	O
+injection	O
+of	O
+STZ	O
+.	O
+	
+RESULTS	O
+:	O
+STZ	O
+administration	O
+and	O
+castration	O
+markedly	O
+decreased	O
+both	O
+STL1	O
+(	O
+the	O
+short	O
+memory	O
+)	O
+and	O
+STL2	O
+(	O
+the	O
+long	O
+memory	O
+)	O
+in	O
+passive	O
+avoidance	O
+tests	O
+.	O
+	
+Testosterone	O
+replacement	O
+almost	O
+restored	O
+the	O
+STL1	O
+and	O
+STL2	O
+in	O
+castrated	O
+rats	O
+","	O
+and	O
+significantly	O
+prolonged	O
+the	O
+STL1	O
+and	O
+STL2	O
+in	O
+STZ	O
+-	O
+treated	O
+rats	O
+.	O
+	
+Administration	O
+of	O
+flutamide	O
+","	O
+letrozole	O
+or	O
+tamoxifen	O
+significantly	O
+impaired	B-NP
+the	I-NP
+memory	I-NP
+in	O
+intact	O
+rats	O
+","	O
+and	O
+significantly	O
+attenuated	O
+the	O
+testosterone	O
+replacement	O
+in	O
+improving	O
+STZ	O
+-	O
+and	O
+castration	O
+-	O
+induced	O
+memory	B-NP
+impairment	I-NP
+.	O
+	
+CONCLUSION	O
+:	O
+Testosterone	O
+administration	O
+ameliorates	O
+STZ	O
+-	O
+and	O
+castration	O
+-	O
+induced	O
+memory	B-NP
+impairment	I-NP
+in	O
+male	O
+Wistar	O
+rats	O
+.	O
+	
+Behavioral	O
+and	O
+neurochemical	O
+studies	O
+in	O
+mice	O
+pretreated	O
+with	O
+garcinielliptone	O
+FC	O
+in	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B-NP
+.	O
+	
+Garcinielliptone	O
+FC	O
+(	O
+GFC	O
+)	O
+isolated	O
+from	O
+hexanic	O
+fraction	O
+seed	O
+extract	O
+of	O
+species	O
+Platonia	O
+insignis	O
+Mart	O
+.	O
+	
+It	O
+is	O
+widely	O
+used	O
+in	O
+folk	O
+medicine	O
+to	O
+treat	O
+skin	B-NP
+diseases	I-NP
+in	O
+both	O
+humans	O
+and	O
+animals	O
+as	O
+well	O
+as	O
+the	O
+seed	O
+decoction	O
+has	O
+been	O
+used	O
+to	O
+treat	O
+diarrheas	B-NP
+and	O
+inflammatory	B-NP
+diseases	I-NP
+.	O
+	
+However	O
+","	O
+there	O
+is	O
+no	O
+research	O
+on	O
+GFC	O
+effects	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+of	O
+rodents	O
+.	O
+	
+The	O
+present	O
+study	O
+aimed	O
+to	O
+evaluate	O
+the	O
+GFC	O
+effects	O
+at	O
+doses	O
+of	O
+25	O
+","	O
+50	O
+or	O
+75	O
+mg	O
+/	O
+kg	O
+on	O
+seizure	B-NP
+parameters	O
+to	O
+determine	O
+their	O
+anticonvulsant	O
+activity	O
+and	O
+its	O
+effects	O
+on	O
+amino	O
+acid	O
+(	O
+r	O
+-	O
+aminobutyric	O
+acid	O
+(	O
+GABA	O
+)	O
+","	O
+glutamine	O
+","	O
+aspartate	O
+and	O
+glutathione	O
+)	O
+levels	O
+as	O
+well	O
+as	O
+on	O
+acetylcholinesterase	O
+(	O
+AChE	O
+)	O
+activity	O
+in	O
+mice	O
+hippocampus	O
+after	O
+seizures	B-NP
+.	O
+	
+GFC	O
+produced	O
+an	O
+increased	O
+latency	O
+to	O
+first	O
+seizure	B-NP
+","	O
+at	O
+doses	O
+25mg	O
+/	O
+kg	O
+(	O
+20	O
+.	O
+12	O
++	O
+2	O
+.	O
+20	O
+min	O
+)	O
+","	O
+50mg	O
+/	O
+kg	O
+(	O
+20	O
+.	O
+95	O
++	O
+2	O
+.	O
+21	O
+min	O
+)	O
+or	O
+75	O
+mg	O
+/	O
+kg	O
+(	O
+23	O
+.	O
+43	O
++	O
+1	O
+.	O
+99	O
+min	O
+)	O
+when	O
+compared	O
+with	O
+seized	O
+mice	O
+.	O
+	
+In	O
+addition	O
+","	O
+GABA	O
+content	O
+of	O
+mice	O
+hippocampus	O
+treated	O
+with	O
+GFC75	O
+plus	O
+P400	O
+showed	O
+an	O
+increase	O
+of	O
+46	O
+.	O
+90	O
+%	O
+when	O
+compared	O
+with	O
+seized	O
+mice	O
+.	O
+	
+In	O
+aspartate	O
+","	O
+glutamine	O
+and	O
+glutamate	O
+levels	O
+detected	O
+a	O
+decrease	O
+of	O
+5	O
+.	O
+21	O
+%	O
+","	O
+13	O
+.	O
+55	O
+%	O
+and	O
+21	O
+.	O
+80	O
+%	O
+","	O
+respectively	O
+in	O
+mice	O
+hippocampus	O
+treated	O
+with	O
+GFC75	O
+plus	O
+P400	O
+when	O
+compared	O
+with	O
+seized	O
+mice	O
+.	O
+	
+Hippocampus	O
+mice	O
+treated	O
+with	O
+GFC75	O
+plus	O
+P400	O
+showed	O
+an	O
+increase	O
+in	O
+AChE	O
+activity	O
+(	O
+63	O
+.	O
+30	O
+%	O
+)	O
+when	O
+compared	O
+with	O
+seized	O
+mice	O
+.	O
+	
+The	O
+results	O
+indicate	O
+that	O
+GFC	O
+can	O
+exert	O
+anticonvulsant	O
+activity	O
+and	O
+reduce	O
+the	O
+frequency	O
+of	O
+installation	O
+of	O
+pilocarpine	O
+-	O
+induced	O
+status	B-NP
+epilepticus	I-NP
+","	O
+as	O
+demonstrated	O
+by	O
+increase	O
+in	O
+latency	O
+to	O
+first	O
+seizure	B-NP
+and	O
+decrease	O
+in	O
+mortality	O
+rate	O
+of	O
+animals	O
+.	O
+	
+In	O
+conclusion	O
+","	O
+our	O
+data	O
+suggest	O
+that	O
+GFC	O
+may	O
+influence	O
+in	O
+epileptogenesis	O
+and	O
+promote	O
+anticonvulsant	O
+actions	O
+in	O
+pilocarpine	O
+model	O
+by	O
+modulating	O
+the	O
+GABA	O
+and	O
+glutamate	O
+contents	O
+and	O
+of	O
+AChE	O
+activity	O
+in	O
+seized	O
+mice	O
+hippocampus	O
+.	O
+	
+This	O
+compound	O
+may	O
+be	O
+useful	O
+to	O
+produce	O
+neuronal	O
+protection	O
+and	O
+it	O
+can	O
+be	O
+considered	O
+as	O
+an	O
+anticonvulsant	O
+agent	O
+.	O
+	
+Standard	O
+operating	O
+procedures	O
+for	O
+antibiotic	O
+therapy	O
+and	O
+the	O
+occurrence	O
+of	O
+acute	B-NP
+kidney	I-NP
+injury	I-NP
+:	O
+a	O
+prospective	O
+","	O
+clinical	O
+","	O
+non	O
+-	O
+interventional	O
+","	O
+observational	O
+study	O
+.	O
+	
+INTRODUCTION	O
+:	O
+Acute	B-NP
+kidney	I-NP
+injury	I-NP
+(	O
+AKI	B-NP
+)	O
+occurs	O
+in	O
+7	O
+%	O
+of	O
+hospitalized	O
+and	O
+66	O
+%	O
+of	O
+Intensive	O
+Care	O
+Unit	O
+(	O
+ICU	O
+)	O
+patients	O
+.	O
+	
+It	O
+increases	O
+mortality	O
+","	O
+hospital	O
+length	O
+of	O
+stay	O
+","	O
+and	O
+costs	O
+.	O
+	
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+investigate	O
+","	O
+whether	O
+there	O
+is	O
+an	O
+association	O
+between	O
+adherence	O
+to	O
+guidelines	O
+(	O
+standard	O
+operating	O
+procedures	O
+(	O
+SOP	O
+)	O
+)	O
+for	O
+potentially	O
+nephrotoxic	B-NP
+antibiotics	O
+and	O
+the	O
+occurrence	O
+of	O
+AKI	B-NP
+.	O
+	
+METHODS	O
+:	O
+This	O
+study	O
+was	O
+carried	O
+out	O
+as	O
+a	O
+prospective	O
+","	O
+clinical	O
+","	O
+non	O
+-	O
+interventional	O
+","	O
+observational	O
+study	O
+.	O
+	
+Data	O
+collection	O
+was	O
+performed	O
+over	O
+a	O
+total	O
+of	O
+170	O
+days	O
+in	O
+three	O
+ICUs	O
+at	O
+Charite	O
+-	O
+Universitaetsmedizin	O
+Berlin	O
+.	O
+	
+A	O
+total	O
+of	O
+675	O
+patients	O
+were	O
+included	O
+;	O
+163	O
+of	O
+these	O
+had	O
+therapy	O
+with	O
+vancomycin	O
+","	O
+gentamicin	O
+","	O
+or	O
+tobramycin	O
+;	O
+were	O
+>	O
+18	O
+years	O
+;	O
+and	O
+treated	O
+in	O
+the	O
+ICU	O
+for	O
+>	O
+24	O
+hours	O
+.	O
+	
+Patients	O
+with	O
+an	O
+adherence	O
+to	O
+SOP	O
+>	O
+70	O
+%	O
+were	O
+classified	O
+into	O
+the	O
+high	O
+adherence	O
+group	O
+(	O
+HAG	O
+)	O
+and	O
+patients	O
+with	O
+an	O
+adherence	O
+of	O
+<	O
+70	O
+%	O
+into	O
+the	O
+low	O
+adherence	O
+group	O
+(	O
+LAG	O
+)	O
+.	O
+	
+AKI	B-NP
+was	O
+defined	O
+according	O
+to	O
+RIFLE	O
+criteria	O
+.	O
+	
+Adherence	O
+to	O
+SOPs	O
+was	O
+evaluated	O
+by	O
+retrospective	O
+expert	O
+audit	O
+.	O
+	
+Development	O
+of	O
+AKI	B-NP
+was	O
+compared	O
+between	O
+groups	O
+with	O
+exact	O
+Chi2	O
+-	O
+test	O
+and	O
+multivariate	O
+logistic	O
+regression	O
+analysis	O
+(	O
+two	O
+-	O
+sided	O
+P	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+LAG	O
+consisted	O
+of	O
+75	O
+patients	O
+(	O
+46	O
+%	O
+)	O
+versus	O
+88	O
+HAG	O
+patients	O
+(	O
+54	O
+%	O
+)	O
+.	O
+	
+AKI	B-NP
+occurred	O
+significantly	O
+more	O
+often	O
+in	O
+LAG	O
+with	O
+36	O
+%	O
+versus	O
+21	O
+%	O
+in	O
+HAG	O
+(	O
+P	O
+=	O
+0	O
+.	O
+35	O
+)	O
+.	O
+	
+Basic	O
+characteristics	O
+were	O
+comparable	O
+","	O
+except	O
+an	O
+increased	O
+rate	O
+of	O
+soft	O
+tissue	O
+infections	B-NP
+in	O
+LAG	O
+.	O
+	
+Multivariate	O
+analysis	O
+revealed	O
+an	O
+odds	O
+ratio	O
+of	O
+2	O
+.	O
+5	O
+-	O
+fold	O
+for	O
+LAG	O
+to	O
+develop	O
+AKI	B-NP
+compared	O
+with	O
+HAG	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+1	O
+.	O
+195	O
+to	O
+5	O
+.	O
+124	O
+","	O
+P	O
+=	O
+0	O
+.	O
+39	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+Low	O
+adherence	O
+to	O
+SOPs	O
+for	O
+potentially	O
+nephrotoxic	B-NP
+antibiotics	O
+was	O
+associated	O
+with	O
+a	O
+higher	O
+occurrence	O
+of	O
+AKI	B-NP
+.	O
+	
+TRIAL	O
+REGISTRATION	O
+:	O
+Current	O
+Controlled	O
+Trials	O
+ISRCTN54598675	O
+.	O
+	
+Registered	O
+17	O
+August	O
+2007	O
+.	O
+	
+Rhabdomyolysis	B-NP
+in	O
+a	O
+hepatitis	B-NP
+C	I-NP
+virus	I-NP
+infected	I-NP
+patient	O
+treated	O
+with	O
+telaprevir	O
+and	O
+simvastatin	O
+.	O
+	
+A	O
+46	O
+-	O
+year	O
+old	O
+man	O
+with	O
+a	O
+chronic	O
+hepatitis	B-NP
+C	I-NP
+virus	I-NP
+infection	I-NP
+received	O
+triple	O
+therapy	O
+with	O
+ribavirin	O
+","	O
+pegylated	O
+interferon	O
+and	O
+telaprevir	O
+.	O
+	
+The	O
+patient	O
+also	O
+received	O
+simvastatin	O
+.	O
+	
+One	O
+month	O
+after	O
+starting	O
+the	O
+antiviral	O
+therapy	O
+","	O
+the	O
+patient	O
+was	O
+admitted	O
+to	O
+the	O
+hospital	O
+because	O
+he	O
+developed	O
+rhabdomyolysis	B-NP
+.	O
+	
+At	O
+admission	O
+simvastatin	O
+and	O
+all	O
+antiviral	O
+drugs	O
+were	O
+discontinued	O
+because	O
+toxicity	B-NP
+due	O
+to	O
+a	O
+drug	O
+-	O
+drug	O
+interaction	O
+was	O
+suspected	O
+.	O
+	
+The	O
+creatine	O
+kinase	O
+peaked	O
+at	O
+62	O
+","	O
+246	O
+IU	O
+/	O
+L	O
+and	O
+the	O
+patient	O
+was	O
+treated	O
+with	O
+intravenous	O
+normal	O
+saline	O
+.	O
+	
+The	O
+patient	O
+'	O
+s	O
+renal	O
+function	O
+remained	O
+unaffected	O
+.	O
+	
+Fourteen	O
+days	O
+after	O
+hospitalization	O
+","	O
+creatine	O
+kinase	O
+level	O
+had	O
+returned	O
+to	O
+230	O
+IU	O
+/	O
+L	O
+and	O
+the	O
+patient	O
+was	O
+discharged	O
+.	O
+	
+Telaprevir	O
+was	O
+considered	O
+the	O
+probable	O
+causative	O
+agent	O
+of	O
+an	O
+interaction	O
+with	O
+simvastatin	O
+according	O
+to	O
+the	O
+Drug	O
+Interaction	O
+Probability	O
+Scale	O
+.	O
+	
+The	O
+interaction	O
+is	O
+due	O
+to	O
+inhibition	O
+of	O
+CYP3A4	O
+-	O
+mediated	O
+simvastatin	O
+clearance	O
+.	O
+	
+Simvastatin	O
+plasma	O
+concentration	O
+increased	O
+30	O
+times	O
+in	O
+this	O
+patient	O
+and	O
+statin	O
+induced	O
+muscle	B-NP
+toxicity	I-NP
+is	O
+related	O
+to	O
+the	O
+concentration	O
+of	O
+the	O
+statin	O
+in	O
+blood	O
+.	O
+	
+In	O
+conclusion	O
+","	O
+with	O
+this	O
+case	O
+we	O
+illustrate	O
+that	O
+telaprevir	O
+as	O
+well	O
+as	O
+statins	O
+are	O
+susceptible	O
+to	O
+clinical	O
+relevant	O
+drug	O
+-	O
+drug	O
+interactions	O
+.	O
+	
+Combination	O
+of	O
+bortezomib	O
+","	O
+thalidomide	O
+","	O
+and	O
+dexamethasone	O
+(	O
+VTD	O
+)	O
+as	O
+a	O
+consolidation	O
+therapy	O
+after	O
+autologous	O
+stem	O
+cell	O
+transplantation	O
+for	O
+symptomatic	O
+multiple	B-NP
+myeloma	I-NP
+in	O
+Japanese	O
+patients	O
+.	O
+	
+Consolidation	O
+therapy	O
+for	O
+patients	O
+with	O
+multiple	B-NP
+myeloma	I-NP
+(	O
+MM	B-NP
+)	O
+has	O
+been	O
+widely	O
+adopted	O
+to	O
+improve	O
+treatment	O
+response	O
+following	O
+autologous	O
+stem	O
+cell	O
+transplantation	O
+.	O
+	
+In	O
+this	O
+study	O
+","	O
+we	O
+retrospectively	O
+analyzed	O
+the	O
+safety	O
+and	O
+efficacy	O
+of	O
+combination	O
+regimen	O
+of	O
+bortezomib	O
+","	O
+thalidomide	O
+","	O
+and	O
+dexamethasone	O
+(	O
+VTD	O
+)	O
+as	O
+consolidation	O
+therapy	O
+in	O
+24	O
+Japanese	O
+patients	O
+with	O
+newly	O
+diagnosed	O
+MM	B-NP
+.	O
+	
+VTD	O
+consisted	O
+of	O
+bortezomib	O
+at	O
+a	O
+dose	O
+of	O
+1	O
+.	O
+3	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+and	O
+dexamethasone	O
+at	O
+a	O
+dose	O
+of	O
+40	O
+mg	O
+/	O
+day	O
+on	O
+days	O
+1	O
+","	O
+8	O
+","	O
+15	O
+","	O
+and	O
+22	O
+of	O
+a	O
+35	O
+-	O
+day	O
+cycle	O
+","	O
+with	O
+daily	O
+oral	O
+thalidomide	O
+at	O
+a	O
+dose	O
+of	O
+100	O
+mg	O
+/	O
+day	O
+.	O
+	
+Grade	O
+3	O
+-	O
+4	O
+neutropenia	B-NP
+and	O
+thrombocytopenia	B-NP
+were	O
+documented	O
+in	O
+four	O
+and	O
+three	O
+patients	O
+(	O
+17	O
+and	O
+13	O
+%	O
+)	O
+","	O
+respectively	O
+","	O
+but	O
+drug	O
+dose	O
+reduction	O
+due	O
+to	O
+cytopenia	B-NP
+was	O
+not	O
+required	O
+in	O
+any	O
+case	O
+.	O
+	
+Peripheral	B-NP
+neuropathy	I-NP
+was	O
+common	O
+(	O
+63	O
+%	O
+)	O
+","	O
+but	O
+severe	O
+grade	O
+3	O
+-	O
+4	O
+peripheral	B-NP
+neuropathy	I-NP
+was	O
+not	O
+observed	O
+.	O
+	
+Very	O
+good	O
+partial	O
+response	O
+or	O
+better	O
+response	O
+(	O
+>	O
+VGPR	O
+)	O
+rates	O
+before	O
+and	O
+after	O
+consolidation	O
+therapy	O
+were	O
+54	O
+and	O
+79	O
+%	O
+","	O
+respectively	O
+.	O
+	
+Patients	O
+had	O
+a	O
+significant	O
+probability	O
+of	O
+improving	O
+from	O
+<	O
+VGPR	O
+before	O
+consolidation	O
+therapy	O
+to	O
+>	O
+VGPR	O
+after	O
+consolidation	O
+therapy	O
+(	O
+p	O
+=	O
+0	O
+.	O
+41	O
+)	O
+.	O
+	
+The	O
+VTD	O
+regimen	O
+may	O
+be	O
+safe	O
+and	O
+effective	O
+as	O
+a	O
+consolidation	O
+therapy	O
+in	O
+the	O
+treatment	O
+of	O
+MM	O
+in	O
+Japanese	O
+population	O
+.	O
+	
+Conversion	O
+to	O
+sirolimus	O
+ameliorates	O
+cyclosporine	O
+-	O
+induced	O
+nephropathy	B-NP
+in	O
+the	O
+rat	O
+:	O
+focus	O
+on	O
+serum	O
+","	O
+urine	O
+","	O
+gene	O
+","	O
+and	O
+protein	O
+renal	O
+expression	O
+biomarkers	O
+.	O
+	
+Protocols	O
+of	O
+conversion	O
+from	O
+cyclosporin	O
+A	O
+(	O
+CsA	O
+)	O
+to	O
+sirolimus	O
+(	O
+SRL	O
+)	O
+have	O
+been	O
+widely	O
+used	O
+in	O
+immunotherapy	O
+after	O
+transplantation	O
+to	O
+prevent	O
+CsA	O
+-	O
+induced	O
+nephropathy	B-NP
+","	O
+but	O
+the	O
+molecular	O
+mechanisms	O
+underlying	O
+these	O
+protocols	O
+remain	O
+nuclear	O
+.	O
+	
+This	O
+study	O
+aimed	O
+to	O
+identify	O
+the	O
+molecular	O
+pathways	O
+and	O
+putative	O
+biomarkers	O
+of	O
+CsA	O
+-	O
+to	O
+-	O
+SRL	O
+conversion	O
+in	O
+a	O
+rat	O
+model	O
+.	O
+	
+Four	O
+animal	O
+groups	O
+(	O
+n	O
+=	O
+6	O
+)	O
+were	O
+tested	O
+during	O
+9	O
+weeks	O
+:	O
+control	O
+","	O
+CsA	O
+","	O
+SRL	O
+","	O
+and	O
+conversion	O
+(	O
+CsA	O
+for	O
+3	O
+weeks	O
+followed	O
+by	O
+SRL	O
+for	O
+6	O
+weeks	O
+)	O
+.	O
+	
+Classical	O
+and	O
+emergent	O
+serum	O
+","	O
+urinary	O
+","	O
+and	O
+kidney	O
+tissue	O
+(	O
+gene	O
+and	O
+protein	O
+expression	O
+)	O
+markers	O
+were	O
+assessed	O
+.	O
+	
+Renal	B-NP
+lesions	I-NP
+were	O
+analyzed	O
+in	O
+hematoxylin	O
+and	O
+eosin	O
+","	O
+periodic	O
+acid	O
+-	O
+Schiff	O
+","	O
+and	O
+Masson	O
+'	O
+s	O
+trichrome	O
+stains	O
+.	O
+	
+SRL	O
+-	O
+treated	O
+rats	O
+presented	O
+proteinuria	B-NP
+and	O
+NGAL	O
+(	O
+serum	O
+and	O
+urinary	O
+)	O
+as	O
+the	O
+best	O
+markers	O
+of	O
+renal	B-NP
+impairment	I-NP
+.	O
+	
+Short	O
+CsA	O
+treatment	O
+presented	O
+slight	O
+or	O
+even	O
+absent	O
+kidney	B-NP
+lesions	I-NP
+and	O
+TGF	O
+-	O
+b	O
+","	O
+NF	O
+-	O
+kb	O
+","	O
+mTOR	O
+","	O
+PCNA	O
+","	O
+TP53	O
+","	O
+KIM	O
+-	O
+1	O
+","	O
+and	O
+CTGF	O
+as	O
+relevant	O
+gene	O
+and	O
+protein	O
+changes	O
+.	O
+	
+Prolonged	O
+CsA	O
+exposure	O
+aggravated	O
+renal	B-NP
+damage	I-NP
+","	O
+without	O
+clear	O
+changes	O
+on	O
+the	O
+traditional	O
+markers	O
+","	O
+but	O
+with	O
+changes	O
+in	O
+serums	O
+TGF	O
+-	O
+b	O
+and	O
+IL	O
+-	O
+7	O
+","	O
+TBARs	O
+clearance	O
+","	O
+and	O
+kidney	O
+TGF	O
+-	O
+b	O
+and	O
+mTOR	O
+.	O
+	
+Conversion	O
+to	O
+SRL	O
+prevented	O
+CsA	O
+-	O
+induced	O
+renal	B-NP
+damage	I-NP
+evolution	O
+(	O
+absent	O
+/	O
+mild	O
+grade	O
+lesions	O
+)	O
+","	O
+while	O
+NGAL	O
+(	O
+serum	O
+versus	O
+urine	O
+)	O
+seems	O
+to	O
+be	O
+a	O
+feasible	O
+biomarker	O
+of	O
+CsA	O
+replacement	O
+to	O
+SRL	O
+.	O
+	
+Kinin	O
+B2	O
+receptor	O
+deletion	O
+and	O
+blockage	O
+ameliorates	O
+cisplatin	O
+-	O
+induced	O
+acute	B-NP
+renal	I-NP
+injury	I-NP
+.	O
+	
+Cisplatin	O
+treatment	O
+has	O
+been	O
+adopted	O
+in	O
+some	O
+chemotherapies	O
+;	O
+however	O
+","	O
+this	O
+drug	O
+can	O
+induce	O
+acute	B-NP
+kidney	I-NP
+injury	I-NP
+due	O
+its	O
+ability	O
+to	O
+negatively	O
+affect	O
+renal	O
+function	O
+","	O
+augment	O
+serum	O
+levels	O
+of	O
+creatinine	O
+and	O
+urea	O
+","	O
+increase	O
+the	O
+acute	B-NP
+tubular	I-NP
+necrosis	I-NP
+score	O
+and	O
+up	O
+-	O
+regulate	O
+cytokines	O
+(	O
+e	O
+.	O
+g	O
+.	O
+","	O
+IL	O
+-	O
+1b	O
+and	O
+TNF	O
+-	O
+a	O
+)	O
+.	O
+	
+The	O
+kinin	O
+B2	O
+receptor	O
+has	O
+been	O
+associated	O
+with	O
+the	O
+inflammation	B-NP
+process	O
+","	O
+as	O
+well	O
+as	O
+the	O
+regulation	O
+of	O
+cytokine	O
+expression	O
+","	O
+and	O
+its	O
+deletion	O
+resulted	O
+in	O
+an	O
+improvement	O
+in	O
+the	O
+diabetic	B-NP
+nephropathy	I-NP
+status	O
+.	O
+	
+To	O
+examine	O
+the	O
+role	O
+of	O
+the	O
+kinin	O
+B2	O
+receptor	O
+in	O
+cisplatin	O
+-	O
+induced	O
+acute	B-NP
+kidney	I-NP
+injury	I-NP
+","	O
+kinin	O
+B2	O
+receptor	O
+knockout	O
+mice	O
+were	O
+challenged	O
+with	O
+cisplatin	O
+.	O
+	
+Additionally	O
+","	O
+WT	O
+mice	O
+were	O
+treated	O
+with	O
+a	O
+B2	O
+receptor	O
+antagonist	O
+after	O
+cisplatin	O
+administration	O
+.	O
+	
+B2	O
+receptor	O
+-	O
+deficient	O
+mice	O
+were	O
+less	O
+sensitive	O
+to	O
+this	O
+drug	O
+than	O
+the	O
+WT	O
+mice	O
+","	O
+as	O
+shown	O
+by	O
+reduced	O
+weight	B-NP
+loss	I-NP
+","	O
+better	O
+preservation	O
+of	O
+kidney	O
+function	O
+","	O
+down	O
+regulation	O
+of	O
+inflammatory	O
+cytokines	O
+and	O
+less	O
+acute	B-NP
+tubular	I-NP
+necrosis	I-NP
+.	O
+	
+Moreover	O
+","	O
+treatment	O
+with	O
+the	O
+kinin	O
+B2	O
+receptor	O
+antagonist	O
+effectively	O
+reduced	O
+the	O
+levels	O
+of	O
+serum	O
+creatinine	O
+and	O
+blood	O
+urea	O
+after	O
+cisplatin	O
+administration	O
+.	O
+	
+Thus	O
+","	O
+our	O
+data	O
+suggest	O
+that	O
+the	O
+kinin	O
+B2	O
+receptor	O
+is	O
+involved	O
+in	O
+cisplatin	O
+-	O
+induced	O
+acute	B-NP
+kidney	I-NP
+injury	I-NP
+by	O
+mediating	O
+the	O
+necrotic	B-NP
+process	O
+and	O
+the	O
+expression	O
+of	O
+inflammatory	O
+cytokines	O
+","	O
+thus	O
+resulting	O
+in	O
+declined	O
+renal	O
+function	O
+.	O
+	
+These	O
+results	O
+highlight	O
+the	O
+kinin	O
+B2	O
+receptor	O
+antagonist	O
+treatment	O
+in	O
+amelioration	O
+of	O
+nephrotoxicity	B-NP
+induced	O
+by	O
+cisplatin	O
+therapy	O
+.	O
+	
+Safety	O
+and	O
+efficacy	O
+of	O
+fluocinolone	O
+acetonide	O
+intravitreal	O
+implant	O
+(	O
+0	O
+.	O
+59	O
+mg	O
+)	O
+in	O
+birdshot	B-NP
+retinochoroidopathy	I-NP
+.	O
+	
+PURPOSE	O
+:	O
+To	O
+report	O
+the	O
+treatment	O
+outcomes	O
+of	O
+the	O
+fluocinolone	O
+acetonide	O
+intravitreal	O
+implant	O
+(	O
+0	O
+.	O
+59	O
+mg	O
+)	O
+in	O
+patients	O
+with	O
+birdshot	B-NP
+retinochoroidopathy	I-NP
+whose	O
+disease	O
+is	O
+refractory	O
+or	O
+intolerant	O
+to	O
+conventional	O
+immunomodulatory	O
+therapy	O
+.	O
+	
+METHODS	O
+:	O
+A	O
+retrospective	O
+case	O
+series	O
+involving	O
+11	O
+birdshot	B-NP
+retinochoroidopathy	I-NP
+patients	O
+(	O
+11	O
+eyes	O
+)	O
+.	O
+	
+Eleven	O
+patients	O
+(	O
+11	O
+eyes	O
+)	O
+underwent	O
+surgery	O
+for	O
+fluocinolone	O
+acetonide	O
+implant	O
+(	O
+0	O
+.	O
+59	O
+mg	O
+)	O
+.	O
+	
+Treatment	O
+outcomes	O
+of	O
+interest	O
+were	O
+noted	O
+at	O
+baseline	O
+","	O
+before	O
+fluocinolone	O
+acetonide	O
+implant	O
+","	O
+and	O
+then	O
+at	O
+6	O
+months	O
+","	O
+1	O
+year	O
+","	O
+2	O
+years	O
+","	O
+3	O
+years	O
+","	O
+and	O
+beyond	O
+3	O
+years	O
+.	O
+	
+Disease	O
+activity	O
+markers	O
+","	O
+including	O
+signs	O
+of	O
+ocular	O
+inflammation	B-NP
+","	O
+evidence	O
+of	O
+retinal	B-NP
+vasculitis	I-NP
+","	O
+Swedish	O
+interactive	O
+threshold	O
+algorithm	O
+-	O
+short	O
+wavelength	O
+automated	O
+perimetry	O
+Humphrey	O
+visual	O
+field	O
+analysis	O
+","	O
+electroretinographic	O
+parameters	O
+","	O
+and	O
+optical	O
+coherence	O
+tomography	O
+were	O
+recorded	O
+.	O
+	
+Data	O
+on	O
+occurrence	O
+of	O
+cataract	B-NP
+and	O
+raised	B-NP
+intraocular	I-NP
+pressure	I-NP
+were	O
+collected	O
+in	O
+all	O
+eyes	O
+.	O
+	
+RESULTS	O
+:	O
+Intraocular	O
+inflammation	B-NP
+was	O
+present	O
+in	O
+54	O
+.	O
+5	O
+","	O
+9	O
+.	O
+9	O
+","	O
+11	O
+.	O
+1	O
+","	O
+and	O
+0	O
+%	O
+of	O
+patients	O
+at	O
+baseline	O
+","	O
+6	O
+months	O
+","	O
+1	O
+year	O
+","	O
+2	O
+years	O
+","	O
+3	O
+years	O
+","	O
+and	O
+beyond	O
+3	O
+years	O
+after	O
+receiving	O
+the	O
+implant	O
+","	O
+respectively	O
+.	O
+	
+Active	O
+vasculitis	B-NP
+was	O
+noted	O
+in	O
+36	O
+.	O
+3	O
+%	O
+patients	O
+at	O
+baseline	O
+and	O
+0	O
+%	O
+at	O
+3	O
+years	O
+of	O
+follow	O
+-	O
+up	O
+.	O
+	
+More	O
+than	O
+20	O
+%	O
+(	O
+47	O
+.	O
+61	O
+-	O
+67	O
+.	O
+2	O
+%	O
+)	O
+reduction	O
+in	O
+central	O
+retinal	O
+thickness	O
+was	O
+noted	O
+in	O
+all	O
+patients	O
+with	O
+cystoid	B-NP
+macular	I-NP
+edema	I-NP
+at	O
+6	O
+months	O
+","	O
+1	O
+year	O
+","	O
+2	O
+years	O
+","	O
+and	O
+3	O
+years	O
+postimplant	O
+.	O
+	
+At	O
+baseline	O
+","	O
+54	O
+.	O
+5	O
+%	O
+patients	O
+were	O
+on	O
+immunomodulatory	O
+agents	O
+.	O
+	
+This	O
+percentage	O
+decreased	O
+to	O
+45	O
+.	O
+45	O
+","	O
+44	O
+.	O
+4	O
+","	O
+and	O
+14	O
+.	O
+28	O
+%	O
+at	O
+1	O
+year	O
+","	O
+2	O
+years	O
+","	O
+and	O
+3	O
+years	O
+postimplant	O
+","	O
+respectively	O
+.	O
+	
+Adverse	O
+events	O
+included	O
+increased	B-NP
+intraocular	I-NP
+pressure	I-NP
+(	O
+54	O
+.	O
+5	O
+%	O
+)	O
+and	O
+cataract	B-NP
+formation	O
+(	O
+100	O
+%	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+The	O
+data	O
+suggest	O
+that	O
+fluocinolone	O
+acetonide	O
+implant	O
+(	O
+0	O
+.	O
+59	O
+mg	O
+)	O
+helps	O
+to	O
+control	O
+inflammation	B-NP
+in	O
+otherwise	O
+treatment	O
+-	O
+refractory	O
+cases	O
+of	O
+birdshot	B-NP
+retinochoroidopathy	I-NP
+.	O
+	
+It	O
+is	O
+associated	O
+with	O
+significant	O
+side	O
+effects	O
+of	O
+cataract	B-NP
+and	O
+ocular	B-NP
+hypertension	I-NP
+requiring	O
+treatment	O
+.	O
+	
+Optimal	O
+precurarizing	O
+dose	O
+of	O
+rocuronium	O
+to	O
+decrease	O
+fasciculation	B-NP
+and	O
+myalgia	B-NP
+following	O
+succinylcholine	O
+administration	O
+.	O
+	
+BACKGROUND	O
+:	O
+Succinylcholine	O
+commonly	O
+produces	O
+frequent	O
+adverse	O
+effects	O
+","	O
+including	O
+muscle	B-NP
+fasciculation	I-NP
+and	O
+myalgia	B-NP
+.	O
+	
+The	O
+current	O
+study	O
+identified	O
+the	O
+optimal	O
+dose	O
+of	O
+rocuronium	O
+to	O
+prevent	O
+succinylcholine	O
+-	O
+induced	O
+fasciculation	B-NP
+and	O
+myalgia	B-NP
+and	O
+evaluated	O
+the	O
+influence	O
+of	O
+rocuronium	O
+on	O
+the	O
+speed	O
+of	O
+onset	O
+produced	O
+by	O
+succinylcholine	O
+.	O
+	
+METHODS	O
+:	O
+This	O
+randomized	O
+","	O
+double	O
+-	O
+blinded	O
+study	O
+was	O
+conducted	O
+in	O
+100	O
+patients	O
+randomly	O
+allocated	O
+into	O
+five	O
+groups	O
+of	O
+20	O
+patients	O
+each	O
+.	O
+	
+Patients	O
+were	O
+randomized	O
+to	O
+receive	O
+0	O
+.	O
+2	O
+","	O
+0	O
+.	O
+3	O
+","	O
+0	O
+.	O
+4	O
+","	O
+0	O
+.	O
+5	O
+and	O
+0	O
+.	O
+6	O
+mg	O
+/	O
+kg	O
+rocuronium	O
+as	O
+a	O
+precurarizing	O
+dose	O
+.	O
+	
+Neuromuscular	O
+monitoring	O
+after	O
+each	O
+precurarizing	O
+dose	O
+was	O
+recorded	O
+from	O
+the	O
+adductor	O
+pollicis	O
+muscle	O
+using	O
+acceleromyography	O
+with	O
+train	O
+-	O
+of	O
+-	O
+four	O
+stimulation	O
+of	O
+the	O
+ulnar	O
+nerve	O
+.	O
+	
+All	O
+patients	O
+received	O
+succinylcholine	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+at	O
+2	O
+minutes	O
+after	O
+the	O
+precurarization	O
+","	O
+and	O
+were	O
+assessed	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+fasciculations	B-NP
+","	O
+while	O
+myalgia	B-NP
+was	O
+assessed	O
+at	O
+24	O
+hours	O
+after	O
+surgery	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+incidence	O
+and	O
+severity	O
+of	O
+visible	O
+muscle	B-NP
+fasciculation	I-NP
+was	O
+significantly	O
+less	O
+with	O
+increasing	O
+the	O
+amount	O
+of	O
+precurarizing	O
+dose	O
+of	O
+rocuronium	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Those	O
+of	O
+myalgia	B-NP
+tend	O
+to	O
+decrease	O
+according	O
+to	O
+increasing	O
+the	O
+amount	O
+of	O
+precurarizing	O
+dose	O
+of	O
+rocuronium	O
+","	O
+but	O
+there	O
+was	O
+no	O
+significance	O
+(	O
+P	O
+=	O
+0	O
+.	O
+72	O
+)	O
+.	O
+	
+The	O
+onset	O
+time	O
+of	O
+succinylcholine	O
+was	O
+significantly	O
+longer	O
+with	O
+increasing	O
+the	O
+amount	O
+of	O
+precurarizing	O
+dose	O
+of	O
+rocuronium	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Precurarization	O
+with	O
+0	O
+.	O
+4	O
+mg	O
+/	O
+kg	O
+rocuronium	O
+was	O
+the	O
+optimal	O
+dose	O
+considering	O
+the	O
+reduction	O
+in	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+fasciculation	B-NP
+and	O
+myalgia	B-NP
+with	O
+acceptable	O
+onset	O
+time	O
+","	O
+and	O
+the	O
+safe	O
+and	O
+effective	O
+precurarization	O
+.	O
+	
+Absence	O
+of	O
+PKC	O
+-	O
+alpha	O
+attenuates	O
+lithium	O
+-	O
+induced	O
+nephrogenic	B-NP
+diabetes	I-NP
+insipidus	I-NP
+.	O
+	
+Lithium	O
+","	O
+an	O
+effective	O
+antipsychotic	O
+","	O
+induces	O
+nephrogenic	B-NP
+diabetes	I-NP
+insipidus	I-NP
+(	O
+NDI	B-NP
+)	O
+in	O
+40	O
+%	O
+of	O
+patients	O
+.	O
+	
+The	O
+decreased	O
+capacity	O
+to	O
+concentrate	O
+urine	O
+is	O
+likely	O
+due	O
+to	O
+lithium	O
+acutely	O
+disrupting	O
+the	O
+cAMP	O
+pathway	O
+and	O
+chronically	O
+reducing	O
+urea	O
+transporter	O
+(	O
+UT	O
+-	O
+A1	O
+)	O
+and	O
+water	O
+channel	O
+(	O
+AQP2	O
+)	O
+expression	O
+in	O
+the	O
+inner	O
+medulla	O
+.	O
+	
+Targeting	O
+an	O
+alternative	O
+signaling	O
+pathway	O
+","	O
+such	O
+as	O
+PKC	O
+-	O
+mediated	O
+signaling	O
+","	O
+may	O
+be	O
+an	O
+effective	O
+method	O
+of	O
+treating	O
+lithium	O
+-	O
+induced	O
+polyuria	B-NP
+.	O
+	
+PKC	O
+-	O
+alpha	O
+null	O
+mice	O
+(	O
+PKCa	O
+KO	O
+)	O
+and	O
+strain	O
+-	O
+matched	O
+wild	O
+type	O
+(	O
+WT	O
+)	O
+controls	O
+were	O
+treated	O
+with	O
+lithium	O
+for	O
+0	O
+","	O
+3	O
+or	O
+5	O
+days	O
+.	O
+	
+WT	O
+mice	O
+had	O
+increased	O
+urine	O
+output	O
+and	O
+lowered	O
+urine	O
+osmolality	O
+after	O
+3	O
+and	O
+5	O
+days	O
+of	O
+treatment	O
+whereas	O
+PKCa	O
+KO	O
+mice	O
+had	O
+no	O
+change	O
+in	O
+urine	O
+output	O
+or	O
+concentration	O
+.	O
+	
+Western	O
+blot	O
+analysis	O
+revealed	O
+that	O
+AQP2	O
+expression	O
+in	O
+medullary	O
+tissues	O
+was	O
+lowered	O
+after	O
+3	O
+and	O
+5	O
+days	O
+in	O
+WT	O
+mice	O
+;	O
+however	O
+","	O
+AQP2	O
+was	O
+unchanged	O
+in	O
+PKCa	O
+KO	O
+.	O
+	
+Similar	O
+results	O
+were	O
+observed	O
+with	O
+UT	O
+-	O
+A1	O
+expression	O
+.	O
+	
+Animals	O
+were	O
+also	O
+treated	O
+with	O
+lithium	O
+for	O
+6	O
+weeks	O
+.	O
+	
+Lithium	O
+-	O
+treated	O
+WT	O
+mice	O
+had	O
+19	O
+-	O
+fold	O
+increased	O
+urine	O
+output	O
+whereas	O
+treated	O
+PKCa	O
+KO	O
+animals	O
+had	O
+a	O
+4	O
+-	O
+fold	O
+increase	O
+in	O
+output	O
+.	O
+	
+AQP2	O
+and	O
+UT	O
+-	O
+A1	O
+expression	O
+was	O
+lowered	O
+in	O
+6	O
+week	O
+lithium	O
+-	O
+treated	O
+WT	O
+animals	O
+whereas	O
+in	O
+treated	O
+PKCa	O
+KO	O
+mice	O
+","	O
+AQP2	O
+was	O
+only	O
+reduced	O
+by	O
+2	O
+-	O
+fold	O
+and	O
+UT	O
+-	O
+A1	O
+expression	O
+was	O
+unaffected	O
+.	O
+	
+Urinary	O
+sodium	O
+","	O
+potassium	O
+and	O
+calcium	O
+were	O
+elevated	O
+in	O
+lithium	O
+-	O
+fed	O
+WT	O
+but	O
+not	O
+in	O
+lithium	O
+-	O
+fed	O
+PKCa	O
+KO	O
+mice	O
+.	O
+	
+Our	O
+data	O
+show	O
+that	O
+ablation	O
+of	O
+PKCa	O
+preserves	O
+AQP2	O
+and	O
+UT	O
+-	O
+A1	O
+protein	O
+expression	O
+and	O
+localization	O
+in	O
+lithium	O
+-	O
+induced	O
+NDI	B-NP
+","	O
+and	O
+prevents	O
+the	O
+development	O
+of	O
+the	O
+severe	O
+polyuria	B-NP
+associated	O
+with	O
+lithium	O
+therapy	O
+.	O
+	
+Is	O
+Dysguesia	B-NP
+Going	O
+to	O
+be	O
+a	O
+Rare	O
+or	O
+a	O
+Common	O
+Side	O
+-	O
+effect	O
+of	O
+Amlodipine	O
+?	O
+	
+A	O
+very	O
+rare	O
+side	O
+-	O
+effect	O
+of	O
+amlodipine	O
+is	O
+dysguesia	B-NP
+.	O
+	
+A	O
+review	O
+of	O
+the	O
+literature	O
+produced	O
+only	O
+one	O
+case	O
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+about	O
+a	O
+female	O
+with	O
+essential	O
+hypertension	B-NP
+on	O
+drug	O
+treatment	O
+with	O
+amlodipine	O
+developed	O
+loss	B-NP
+of	I-NP
+taste	I-NP
+sensation	I-NP
+.	O
+	
+Condition	O
+moderately	O
+improved	O
+on	O
+stoppage	O
+of	O
+the	O
+drug	O
+for	O
+25	O
+days	O
+.	O
+	
+We	O
+conclude	O
+that	O
+amlodipine	O
+can	O
+cause	O
+dysguesia	B-NP
+.	O
+	
+Here	O
+","	O
+we	O
+describe	O
+the	O
+clinical	O
+presentation	O
+and	O
+review	O
+the	O
+relevant	O
+literature	O
+on	O
+amlodipine	O
+and	O
+dysguesia	B-NP
+.	O
+	
+Rhabdomyolysis	B-NP
+in	O
+association	O
+with	O
+simvastatin	O
+and	O
+dosage	O
+increment	O
+in	O
+clarithromycin	O
+.	O
+	
+Clarithromycin	O
+is	O
+the	O
+most	O
+documented	O
+cytochrome	O
+P450	O
+3A4	O
+(	O
+CYP3A4	O
+)	O
+inhibitor	O
+to	O
+cause	O
+an	O
+adverse	O
+interaction	O
+with	O
+simvastatin	O
+.	O
+	
+This	O
+particular	O
+case	O
+is	O
+of	O
+interest	O
+as	O
+rhabdomyolysis	B-NP
+only	O
+occurred	O
+after	O
+an	O
+increase	O
+in	O
+the	O
+dose	O
+of	O
+clarithromycin	O
+.	O
+	
+The	O
+patient	O
+developed	O
+raised	O
+cardiac	O
+biomarkers	O
+without	O
+any	O
+obvious	O
+cardiac	O
+issues	O
+","	O
+a	O
+phenomenon	O
+that	O
+has	O
+been	O
+linked	O
+to	O
+rhabdomyolysis	B-NP
+previously	O
+.	O
+	
+To	O
+date	O
+","	O
+there	O
+has	O
+been	O
+no	O
+reported	O
+effect	O
+of	O
+rhabdomyolysis	B-NP
+on	O
+the	O
+structure	O
+and	O
+function	O
+of	O
+cardiac	O
+muscle	O
+.	O
+	
+Clinicians	O
+need	O
+to	O
+be	O
+aware	O
+of	O
+prescribing	O
+concomitant	O
+medications	O
+that	O
+increase	O
+the	O
+risk	O
+of	O
+myopathy	B-NP
+or	O
+inhibit	O
+the	O
+CYP3A4	O
+enzyme	O
+.	O
+	
+Our	O
+case	O
+suggests	O
+that	O
+troponin	O
+elevation	O
+could	O
+be	O
+associated	O
+with	O
+statin	O
+induced	O
+rhabdomyolysis	B-NP
+","	O
+which	O
+may	O
+warrant	O
+further	O
+studies	O
+.	O
+	
+Characterization	O
+of	O
+a	O
+novel	O
+BCHE	O
+"	O
+silent	O
+"	O
+allele	O
+:	O
+point	O
+mutation	O
+(	O
+p	O
+.	O
+Val204Asp	O
+)	O
+causes	O
+loss	O
+of	O
+activity	O
+and	O
+prolonged	O
+apnea	B-NP
+with	O
+suxamethonium	O
+.	O
+	
+Butyrylcholinesterase	B-NP
+deficiency	I-NP
+is	O
+characterized	O
+by	O
+prolonged	O
+apnea	B-NP
+after	O
+the	O
+use	O
+of	O
+muscle	O
+relaxants	O
+(	O
+suxamethonium	O
+or	O
+mivacurium	O
+)	O
+in	O
+patients	O
+who	O
+have	O
+mutations	O
+in	O
+the	O
+BCHE	O
+gene	O
+.	O
+	
+Here	O
+","	O
+we	O
+report	O
+a	O
+case	O
+of	O
+prolonged	O
+neuromuscular	O
+block	O
+after	O
+administration	O
+of	O
+suxamethonium	O
+leading	O
+to	O
+the	O
+discovery	O
+of	O
+a	O
+novel	O
+BCHE	O
+variant	O
+(	O
+c	O
+.	O
+695T	O
+>	O
+A	O
+","	O
+p	O
+.	O
+Val204Asp	O
+)	O
+.	O
+	
+Inhibition	O
+studies	O
+","	O
+kinetic	O
+analysis	O
+and	O
+molecular	O
+dynamics	O
+were	O
+undertaken	O
+to	O
+understand	O
+how	O
+this	O
+mutation	O
+disrupts	O
+the	O
+catalytic	O
+triad	O
+and	O
+determines	O
+a	O
+"	O
+silent	O
+"	O
+phenotype	O
+.	O
+	
+Low	O
+activity	O
+of	O
+patient	O
+plasma	O
+butyrylcholinesterase	O
+with	O
+butyrylthiocholine	O
+(	O
+BTC	O
+)	O
+and	O
+benzoylcholine	O
+","	O
+and	O
+values	O
+of	O
+dibucaine	O
+and	O
+fluoride	O
+numbers	O
+fit	O
+with	O
+heterozygous	O
+atypical	O
+silent	O
+genotype	O
+.	O
+	
+Electrophoretic	O
+analysis	O
+of	O
+plasma	O
+BChE	O
+of	O
+the	O
+proband	O
+and	O
+his	O
+mother	O
+showed	O
+that	O
+patient	O
+has	O
+a	O
+reduced	O
+amount	O
+of	O
+tetrameric	O
+enzyme	O
+in	O
+plasma	O
+and	O
+that	O
+minor	O
+fast	O
+-	O
+moving	O
+BChE	O
+components	O
+:	O
+monomer	O
+","	O
+dimer	O
+","	O
+and	O
+monomer	O
+-	O
+albumin	O
+conjugate	O
+are	O
+missing	O
+.	O
+	
+Kinetic	O
+analysis	O
+showed	O
+that	O
+the	O
+p	O
+.	O
+Val204Asp	O
+/	O
+p	O
+.	O
+Asp70Gly	O
+-	O
+p	O
+.	O
+Ala539Thr	O
+BChE	O
+displays	O
+a	O
+pure	O
+Michaelian	O
+behavior	O
+with	O
+BTC	O
+as	O
+the	O
+substrate	O
+.	O
+	
+Both	O
+catalytic	O
+parameters	O
+Km	O
+=	O
+265	O
+uM	O
+for	O
+BTC	O
+","	O
+two	O
+times	O
+higher	O
+than	O
+that	O
+of	O
+the	O
+atypical	O
+enzyme	O
+","	O
+and	O
+a	O
+low	O
+Vmax	O
+are	O
+consistent	O
+with	O
+the	O
+absence	O
+of	O
+activity	O
+against	O
+suxamethonium	O
+.	O
+	
+Molecular	O
+dynamic	O
+(	O
+MD	O
+)	O
+simulations	O
+showed	O
+that	O
+the	O
+overall	O
+effect	O
+of	O
+the	O
+mutation	O
+p	O
+.	O
+Val204Asp	O
+is	O
+disruption	O
+of	O
+hydrogen	O
+bonding	O
+between	O
+Gln223	O
+and	O
+Glu441	O
+","	O
+leading	O
+Ser198	O
+and	O
+His438	O
+to	O
+move	O
+away	O
+from	O
+each	O
+other	O
+with	O
+subsequent	O
+disruption	O
+of	O
+the	O
+catalytic	O
+triad	O
+functionality	O
+regardless	O
+of	O
+the	O
+type	O
+of	O
+substrate	O
+.	O
+	
+MD	O
+also	O
+showed	O
+that	O
+the	O
+enzyme	O
+volume	O
+is	O
+increased	O
+","	O
+suggesting	O
+a	O
+pre	O
+-	O
+denaturation	O
+state	O
+.	O
+	
+This	O
+fits	O
+with	O
+the	O
+reduced	O
+concentration	O
+of	O
+p	O
+.	O
+Ala204Asp	O
+/	O
+p	O
+.	O
+Asp70Gly	O
+-	O
+p	O
+.	O
+Ala539Thr	O
+tetrameric	O
+enzyme	O
+in	O
+the	O
+plasma	O
+and	O
+non	O
+-	O
+detectable	O
+fast	O
+moving	O
+-	O
+bands	O
+on	O
+electrophoresis	O
+gels	O
+.	O
+	
+Delayed	O
+anemia	B-NP
+after	O
+treatment	O
+with	O
+injectable	O
+artesunate	O
+in	O
+the	O
+Democratic	O
+Republic	O
+of	O
+the	O
+Congo	O
+:	O
+a	O
+manageable	O
+issue	O
+.	O
+	
+Cases	O
+of	O
+delayed	O
+hemolytic	B-NP
+anemia	I-NP
+have	O
+been	O
+described	O
+after	O
+treatment	O
+with	O
+injectable	O
+artesunate	O
+","	O
+the	O
+current	O
+World	O
+Health	O
+Organization	O
+(	O
+WHO	O
+)	O
+-	O
+recommended	O
+first	O
+-	O
+line	O
+drug	O
+for	O
+the	O
+treatment	O
+of	O
+severe	O
+malaria	B-NP
+.	O
+	
+A	O
+total	O
+of	O
+350	O
+patients	O
+(	O
+215	O
+[	O
+61	O
+.	O
+4	O
+%	O
+]	O
+<	O
+5	O
+years	O
+of	O
+age	O
+and	O
+135	O
+[	O
+38	O
+.	O
+6	O
+%	O
+]	O
+>	O
+5	O
+years	O
+of	O
+age	O
+)	O
+were	O
+followed	O
+-	O
+up	O
+after	O
+treatment	O
+with	O
+injectable	O
+artesunate	O
+for	O
+severe	O
+malaria	B-NP
+in	O
+hospitals	O
+and	O
+health	O
+centers	O
+of	O
+the	O
+Democratic	O
+Republic	O
+of	O
+the	O
+Congo	O
+.	O
+	
+Complete	O
+series	O
+of	O
+hemoglobin	O
+(	O
+Hb	O
+)	O
+measurements	O
+were	O
+available	O
+for	O
+201	O
+patients	O
+.	O
+	
+A	O
+decrease	O
+in	O
+Hb	O
+levels	O
+between	O
+2	O
+and	O
+5	O
+g	O
+/	O
+dL	O
+was	O
+detected	O
+in	O
+23	O
+(	O
+11	O
+.	O
+4	O
+%	O
+)	O
+patients	O
+during	O
+the	O
+follow	O
+-	O
+up	O
+period	O
+.	O
+	
+For	O
+five	O
+patients	O
+","	O
+Hb	O
+levels	O
+decreased	O
+below	O
+5	O
+g	O
+/	O
+dL	O
+during	O
+at	O
+least	O
+one	O
+follow	O
+-	O
+up	O
+visit	O
+.	O
+	
+All	O
+cases	O
+of	O
+delayed	O
+anemia	B-NP
+were	O
+clinically	O
+manageable	O
+and	O
+resolved	O
+within	O
+one	O
+month	O
+.	O
+	
+Regulation	O
+of	O
+signal	O
+transducer	O
+and	O
+activator	O
+of	O
+transcription	O
+3	O
+and	O
+apoptotic	O
+pathways	O
+by	O
+betaine	O
+attenuates	O
+isoproterenol	O
+-	O
+induced	O
+acute	O
+myocardial	B-NP
+injury	I-NP
+in	O
+rats	O
+.	O
+	
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+investigate	O
+the	O
+cardioprotective	O
+effects	O
+of	O
+betaine	O
+on	O
+acute	O
+myocardial	B-NP
+ischemia	I-NP
+induced	O
+experimentally	O
+in	O
+rats	O
+focusing	O
+on	O
+regulation	O
+of	O
+signal	O
+transducer	O
+and	O
+activator	O
+of	O
+transcription	O
+3	O
+(	O
+STAT3	O
+)	O
+and	O
+apoptotic	O
+pathways	O
+as	O
+the	O
+potential	O
+mechanism	O
+underlying	O
+the	O
+drug	O
+effect	O
+.	O
+	
+Male	O
+Sprague	O
+Dawley	O
+rats	O
+were	O
+treated	O
+with	O
+betaine	O
+(	O
+100	O
+","	O
+200	O
+","	O
+and	O
+400	O
+mg	O
+/	O
+kg	O
+)	O
+orally	O
+for	O
+40	O
+days	O
+.	O
+	
+Acute	O
+myocardial	B-NP
+ischemic	I-NP
+injury	I-NP
+was	O
+induced	O
+in	O
+rats	O
+by	O
+subcutaneous	O
+injection	O
+of	O
+isoproterenol	O
+(	O
+85	O
+mg	O
+/	O
+kg	O
+)	O
+","	O
+for	O
+two	O
+consecutive	O
+days	O
+.	O
+	
+Serum	O
+cardiac	O
+marker	O
+enzyme	O
+","	O
+histopathological	O
+variables	O
+and	O
+expression	O
+of	O
+protein	O
+levels	O
+were	O
+analyzed	O
+.	O
+	
+Oral	O
+administration	O
+of	O
+betaine	O
+(	O
+200	O
+and	O
+400	O
+mg	O
+/	O
+kg	O
+)	O
+significantly	O
+reduced	O
+the	O
+level	O
+of	O
+cardiac	O
+marker	O
+enzyme	O
+in	O
+the	O
+serum	O
+and	O
+prevented	O
+left	O
+ventricular	B-NP
+remodeling	I-NP
+.	O
+	
+Western	O
+blot	O
+analysis	O
+showed	O
+that	O
+isoproterenol	O
+-	O
+induced	O
+phosphorylation	O
+of	O
+STAT3	O
+was	O
+maintained	O
+or	O
+further	O
+enhanced	O
+by	O
+betaine	O
+treatment	O
+in	O
+myocardium	O
+.	O
+	
+Furthermore	O
+","	O
+betaine	O
+(	O
+200	O
+and	O
+400	O
+mg	O
+/	O
+kg	O
+)	O
+treatment	O
+increased	O
+the	O
+ventricular	O
+expression	O
+of	O
+Bcl	O
+-	O
+2	O
+and	O
+reduced	O
+the	O
+level	O
+of	O
+Bax	O
+","	O
+therefore	O
+causing	O
+a	O
+significant	O
+increase	O
+in	O
+the	O
+ratio	O
+of	O
+Bcl	O
+-	O
+2	O
+/	O
+Bax	O
+.	O
+	
+The	O
+protective	O
+role	O
+of	O
+betaine	O
+on	O
+myocardial	B-NP
+damage	I-NP
+was	O
+further	O
+confirmed	O
+by	O
+histopathological	O
+examination	O
+.	O
+	
+In	O
+summary	O
+","	O
+our	O
+results	O
+showed	O
+that	O
+betaine	O
+pretreatment	O
+attenuated	O
+isoproterenol	O
+-	O
+induced	O
+acute	O
+myocardial	B-NP
+ischemia	I-NP
+via	O
+the	O
+regulation	O
+of	O
+STAT3	O
+and	O
+apoptotic	O
+pathways	O
+.	O
+	
+Quetiapine	O
+-	O
+induced	O
+neutropenia	B-NP
+in	O
+a	O
+bipolar	B-NP
+patient	O
+with	O
+hepatocellular	B-NP
+carcinoma	I-NP
+.	O
+	
+OBJECTIVE	O
+:	O
+Quetiapine	O
+is	O
+a	O
+dibenzothiazepine	O
+derivative	O
+","	O
+similar	O
+to	O
+clozapine	O
+","	O
+which	O
+has	O
+the	O
+highest	O
+risk	O
+of	O
+causing	O
+blood	B-NP
+dyscrasias	I-NP
+","	O
+especially	O
+neutropenia	B-NP
+.	O
+	
+There	O
+are	O
+some	O
+case	O
+reports	O
+about	O
+this	O
+side	O
+effect	O
+of	O
+quetiapine	O
+","	O
+but	O
+possible	O
+risk	O
+factors	O
+are	O
+seldom	O
+discussed	O
+and	O
+identified	O
+.	O
+	
+A	O
+case	O
+of	O
+a	O
+patient	O
+with	O
+hepatocellular	B-NP
+carcinoma	I-NP
+that	O
+developed	O
+neutropenia	B-NP
+after	O
+treatment	O
+with	O
+quetiapine	O
+is	O
+described	O
+here	O
+.	O
+	
+CASE	O
+REPORT	O
+:	O
+A	O
+62	O
+-	O
+year	O
+-	O
+old	O
+Taiwanese	O
+widow	O
+with	O
+bipolar	B-NP
+disorder	I-NP
+was	O
+diagnosed	O
+with	O
+hepatocellular	B-NP
+carcinoma	I-NP
+at	O
+age	O
+60	O
+.	O
+	
+She	O
+developed	O
+leucopenia	B-NP
+after	O
+being	O
+treated	O
+with	O
+quetiapine	O
+.	O
+	
+After	O
+quetiapine	O
+was	O
+discontinued	O
+","	O
+her	O
+white	O
+blood	O
+cell	O
+count	O
+returned	O
+to	O
+normal	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Although	O
+neutropenia	B-NP
+is	O
+not	O
+a	O
+common	O
+side	O
+effect	O
+of	O
+quetiapine	O
+","	O
+physicians	O
+should	O
+be	O
+cautious	O
+about	O
+its	O
+presentation	O
+and	O
+associated	O
+risk	O
+factors	O
+.	O
+	
+Hepatic	B-NP
+dysfunction	I-NP
+may	O
+be	O
+one	O
+of	O
+the	O
+possible	O
+risk	O
+factors	O
+","	O
+and	O
+concomitant	O
+fever	B-NP
+may	O
+be	O
+a	O
+diagnostic	O
+marker	O
+for	O
+adverse	O
+reaction	O
+to	O
+quetiapine	O
+.	O
+	
+Lateral	O
+antebrachial	O
+cutaneous	O
+neuropathy	B-NP
+after	O
+steroid	O
+injection	O
+at	O
+lateral	O
+epicondyle	O
+.	O
+	
+BACKGROUND	O
+AND	O
+OBJECTIVES	O
+:	O
+This	O
+report	O
+aimed	O
+to	O
+present	O
+a	O
+case	O
+of	O
+lateral	O
+antebrachial	O
+cutaneous	O
+neuropathy	B-NP
+(	O
+LACNP	O
+)	O
+that	O
+occurred	O
+after	O
+a	O
+steroid	O
+injection	O
+in	O
+the	O
+lateral	O
+epicondyle	O
+to	O
+treat	O
+lateral	B-NP
+epicondylitis	I-NP
+in	O
+a	O
+40	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+.	O
+	
+MATERIAL	O
+AND	O
+METHOD	O
+:	O
+A	O
+40	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+presented	O
+with	O
+decreased	O
+sensation	O
+and	O
+paresthesia	B-NP
+over	O
+her	O
+right	O
+lateral	O
+forearm	O
+;	O
+the	O
+paresthesia	B-NP
+had	O
+occurred	O
+after	O
+a	O
+steroid	O
+injection	O
+in	O
+the	O
+right	O
+lateral	O
+epicondyle	O
+3	O
+months	O
+before	O
+.	O
+	
+Her	O
+sensation	O
+of	O
+light	O
+touch	O
+and	O
+pain	B-NP
+was	O
+diminished	O
+over	O
+the	O
+lateral	O
+side	O
+of	O
+the	O
+right	O
+forearm	O
+and	O
+wrist	O
+area	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+sensory	O
+action	O
+potential	O
+amplitude	O
+of	O
+the	O
+right	O
+lateral	O
+antebrachial	O
+cutaneous	O
+nerve	O
+(	O
+LACN	O
+)	O
+(	O
+6	O
+.	O
+2	O
+uV	O
+)	O
+was	O
+lower	O
+than	O
+that	O
+of	O
+the	O
+left	O
+(	O
+13	O
+.	O
+1	O
+uV	O
+)	O
+.	O
+	
+The	O
+difference	O
+of	O
+amplitude	O
+between	O
+both	O
+sides	O
+was	O
+significant	O
+because	O
+there	O
+was	O
+more	O
+than	O
+a	O
+50	O
+%	O
+reduction	O
+.	O
+	
+She	O
+was	O
+diagnosed	O
+with	O
+right	O
+LACNP	O
+(	O
+mainly	O
+axonal	O
+involvement	O
+)	O
+on	O
+the	O
+basis	O
+of	O
+the	O
+clinical	O
+manifestation	O
+and	O
+the	O
+electrodiagnostic	O
+findings	O
+.	O
+	
+Her	O
+symptoms	O
+improved	O
+through	O
+physical	O
+therapy	O
+but	O
+persisted	O
+to	O
+some	O
+degree	O
+.	O
+	
+CONCLUSION	O
+:	O
+This	O
+report	O
+describes	O
+the	O
+case	O
+of	O
+a	O
+woman	O
+with	O
+LACNP	O
+that	O
+developed	O
+after	O
+a	O
+steroid	O
+injection	O
+for	O
+the	O
+treatment	O
+of	O
+lateral	B-NP
+epicondylitis	I-NP
+.	O
+	
+An	O
+electrodiagnostic	O
+study	O
+","	O
+including	O
+a	O
+nerve	O
+conduction	O
+study	O
+of	O
+the	O
+LACN	O
+","	O
+was	O
+helpful	O
+to	O
+diagnose	O
+right	O
+LACNP	O
+and	O
+to	O
+find	O
+the	O
+passage	O
+of	O
+the	O
+LACN	O
+on	O
+the	O
+lateral	O
+epicondyle	O
+.	O
+	
+Curcumin	O
+prevents	O
+maleate	O
+-	O
+induced	O
+nephrotoxicity	B-NP
+:	O
+relation	O
+to	O
+hemodynamic	O
+alterations	O
+","	O
+oxidative	O
+stress	O
+","	O
+mitochondrial	O
+oxygen	O
+consumption	O
+and	O
+activity	O
+of	O
+respiratory	O
+complex	O
+I	O
+.	O
+	
+The	O
+potential	O
+protective	O
+effect	O
+of	O
+the	O
+dietary	O
+antioxidant	O
+curcumin	O
+(	O
+120	O
+mg	O
+/	O
+Kg	O
+/	O
+day	O
+for	O
+6	O
+days	O
+)	O
+against	O
+the	O
+renal	B-NP
+injury	I-NP
+induced	O
+by	O
+maleate	O
+was	O
+evaluated	O
+.	O
+	
+Tubular	O
+proteinuria	B-NP
+and	O
+oxidative	O
+stress	O
+were	O
+induced	O
+by	O
+a	O
+single	O
+injection	O
+of	O
+maleate	O
+(	O
+400	O
+mg	O
+/	O
+kg	O
+)	O
+in	O
+rats	O
+.	O
+	
+Maleate	O
+-	O
+induced	O
+renal	B-NP
+injury	I-NP
+included	O
+increase	O
+in	O
+renal	O
+vascular	O
+resistance	O
+and	O
+in	O
+the	O
+urinary	O
+excretion	O
+of	O
+total	O
+protein	O
+","	O
+glucose	O
+","	O
+sodium	O
+","	O
+neutrophil	O
+gelatinase	O
+-	O
+associated	O
+lipocalin	O
+(	O
+NGAL	O
+)	O
+and	O
+N	O
+-	O
+acetyl	O
+b	O
+-	O
+D	O
+-	O
+glucosaminidase	O
+(	O
+NAG	O
+)	O
+","	O
+upregulation	O
+of	O
+kidney	B-NP
+injury	I-NP
+molecule	O
+(	O
+KIM	O
+)	O
+-	O
+1	O
+","	O
+decrease	O
+in	O
+renal	O
+blood	O
+flow	O
+and	O
+claudin	O
+-	O
+2	O
+expression	O
+besides	O
+of	O
+necrosis	B-NP
+and	O
+apoptosis	O
+of	O
+tubular	O
+cells	O
+on	O
+24	O
+h	O
+.	O
+	
+Oxidative	O
+stress	O
+was	O
+determined	O
+by	O
+measuring	O
+the	O
+oxidation	O
+of	O
+lipids	O
+and	O
+proteins	O
+and	O
+diminution	O
+in	O
+renal	O
+Nrf2	O
+levels	O
+.	O
+	
+Studies	O
+were	O
+also	O
+conducted	O
+in	O
+renal	O
+epithelial	O
+LLC	O
+-	O
+PK1	O
+cells	O
+and	O
+in	O
+mitochondria	O
+isolated	O
+from	O
+kidneys	O
+of	O
+all	O
+the	O
+experimental	O
+groups	O
+.	O
+	
+Maleate	O
+induced	O
+cell	O
+damage	O
+and	O
+reactive	O
+oxygen	O
+species	O
+(	O
+ROS	O
+)	O
+production	O
+in	O
+LLC	O
+-	O
+PK1	O
+cells	O
+in	O
+culture	O
+.	O
+	
+In	O
+addition	O
+","	O
+maleate	O
+treatment	O
+reduced	O
+oxygen	O
+consumption	O
+in	O
+ADP	O
+-	O
+stimulated	O
+mitochondria	O
+and	O
+diminished	O
+respiratory	O
+control	O
+index	O
+when	O
+using	O
+malate	O
+/	O
+glutamate	O
+as	O
+substrate	O
+.	O
+	
+The	O
+activities	O
+of	O
+both	O
+complex	O
+I	O
+and	O
+aconitase	O
+were	O
+also	O
+diminished	O
+.	O
+	
+All	O
+the	O
+above	O
+-	O
+described	O
+alterations	O
+were	O
+prevented	O
+by	O
+curcumin	O
+.	O
+	
+It	O
+is	O
+concluded	O
+that	O
+curcumin	O
+is	O
+able	O
+to	O
+attenuate	O
+in	O
+vivo	O
+maleate	O
+-	O
+induced	O
+nephropathy	B-NP
+and	O
+in	O
+vitro	O
+cell	O
+damage	O
+.	O
+	
+The	O
+in	O
+vivo	O
+protection	O
+was	O
+associated	O
+to	O
+the	O
+prevention	O
+of	O
+oxidative	O
+stress	O
+and	O
+preservation	O
+of	O
+mitochondrial	O
+oxygen	O
+consumption	O
+and	O
+activity	O
+of	O
+respiratory	O
+complex	O
+I	O
+","	O
+and	O
+the	O
+in	O
+vitro	O
+protection	O
+was	O
+associated	O
+to	O
+the	O
+prevention	O
+of	O
+ROS	O
+production	O
+.	O
+	
+Anticonvulsant	O
+actions	O
+of	O
+MK	O
+-	O
+801	O
+on	O
+the	O
+lithium	O
+-	O
+pilocarpine	O
+model	O
+of	O
+status	B-NP
+epilepticus	I-NP
+in	O
+rats	O
+.	O
+	
+MK	O
+-	O
+801	O
+","	O
+a	O
+noncompetitive	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+receptor	O
+antagonist	O
+","	O
+was	O
+tested	O
+for	O
+anticonvulsant	O
+effects	O
+in	O
+rats	O
+using	O
+two	O
+seizure	B-NP
+models	O
+","	O
+coadministration	O
+of	O
+lithium	O
+and	O
+pilocarpine	O
+and	O
+administration	O
+of	O
+a	O
+high	O
+dose	O
+of	O
+pilocarpine	O
+alone	O
+.	O
+	
+Three	O
+major	O
+results	O
+are	O
+reported	O
+.	O
+	
+First	O
+","	O
+pretreatment	O
+with	O
+MK	O
+-	O
+801	O
+produced	O
+an	O
+effective	O
+and	O
+dose	O
+-	O
+dependent	O
+anticonvulsant	O
+action	O
+with	O
+the	O
+lithium	O
+-	O
+pilocarpine	O
+model	O
+but	O
+not	O
+with	O
+rats	O
+treated	O
+with	O
+pilocarpine	O
+alone	O
+","	O
+suggesting	O
+that	O
+different	O
+biochemical	O
+mechanisms	O
+control	O
+seizures	B-NP
+in	O
+these	O
+two	O
+models	O
+.	O
+	
+Second	O
+","	O
+the	O
+anticonvulsant	O
+effect	O
+of	O
+MK	O
+-	O
+801	O
+in	O
+the	O
+lithium	O
+-	O
+pilocarpine	O
+model	O
+only	O
+occurred	O
+after	O
+initial	O
+periods	O
+of	O
+seizure	B-NP
+activity	O
+.	O
+	
+This	O
+observation	O
+is	O
+suggested	O
+to	O
+be	O
+an	O
+in	O
+vivo	O
+demonstration	O
+of	O
+the	O
+conclusion	O
+derived	O
+from	O
+in	O
+vitro	O
+experiments	O
+that	O
+MK	O
+-	O
+801	O
+binding	O
+requires	O
+agonist	O
+-	O
+induced	O
+opening	O
+of	O
+the	O
+channel	O
+sites	O
+of	O
+the	O
+NMDA	O
+receptor	O
+.	O
+	
+Third	O
+","	O
+although	O
+it	O
+is	O
+relatively	O
+easy	O
+to	O
+block	O
+seizures	B-NP
+induced	O
+by	O
+lithium	O
+and	O
+pilocarpine	O
+by	O
+administration	O
+of	O
+anticonvulsants	O
+prior	O
+to	O
+pilocarpine	O
+","	O
+it	O
+is	O
+more	O
+difficult	O
+to	O
+terminate	O
+ongoing	O
+status	B-NP
+epilepticus	I-NP
+and	O
+block	O
+the	O
+lethality	O
+of	O
+the	O
+seizures	B-NP
+.	O
+	
+Administration	O
+of	O
+MK	O
+-	O
+801	O
+30	O
+or	O
+60	O
+min	O
+after	O
+pilocarpine	O
+","	O
+i	O
+.	O
+e	O
+.	O
+","	O
+during	O
+status	B-NP
+epilepticus	I-NP
+","	O
+gradually	O
+reduced	O
+electrical	O
+and	O
+behavioral	O
+seizure	B-NP
+activity	O
+and	O
+greatly	O
+enhanced	O
+the	O
+survival	O
+rate	O
+.	O
+	
+These	O
+results	O
+suggest	O
+that	O
+activation	O
+of	O
+NMDA	O
+receptors	O
+plays	O
+an	O
+important	O
+role	O
+in	O
+status	B-NP
+epilepticus	I-NP
+and	O
+brain	B-NP
+damage	I-NP
+in	O
+the	O
+lithium	O
+-	O
+pilocarpine	O
+model	O
+.	O
+	
+This	O
+was	O
+further	O
+supported	O
+by	O
+results	O
+showing	O
+that	O
+nonconvulsive	O
+doses	O
+of	O
+NMDA	O
+and	O
+pilocarpine	O
+were	O
+synergistic	O
+","	O
+resulting	O
+in	O
+status	B-NP
+epilepticus	I-NP
+and	O
+subsequent	O
+mortality	O
+.	O
+	
+Continuous	O
+infusion	O
+tobramycin	O
+combined	O
+with	O
+carbenicillin	O
+for	O
+infections	B-NP
+in	O
+cancer	B-NP
+patients	O
+.	O
+	
+The	O
+cure	O
+rate	O
+of	O
+infections	B-NP
+in	O
+cancer	B-NP
+patients	O
+is	O
+adversely	O
+affected	O
+by	O
+neutropenia	B-NP
+(	O
+less	O
+than	O
+1	O
+","	O
+0	O
+/	O
+mm3	O
+)	O
+.	O
+	
+In	O
+particular	O
+","	O
+patients	O
+with	O
+severe	O
+neutropenia	B-NP
+(	O
+less	O
+than	O
+100	O
+/	O
+mm3	O
+)	O
+have	O
+shown	O
+a	O
+poor	O
+response	O
+to	O
+antibiotics	O
+.	O
+	
+To	O
+overcome	O
+the	O
+adverse	O
+effects	O
+of	O
+neutropenia	B-NP
+","	O
+tobramycin	O
+was	O
+given	O
+by	O
+continuous	O
+infusion	O
+and	O
+combined	O
+with	O
+intermittent	O
+carbenicillin	O
+.	O
+	
+Tobramycin	O
+was	O
+given	O
+to	O
+a	O
+total	O
+daily	O
+dose	O
+of	O
+300	O
+mg	O
+/	O
+m2	O
+and	O
+carbenicillin	O
+was	O
+given	O
+at	O
+a	O
+dose	O
+of	O
+5	O
+gm	O
+every	O
+four	O
+hours	O
+.	O
+	
+There	O
+were	O
+125	O
+infectious	O
+episodes	O
+in	O
+116	O
+cancer	B-NP
+patients	O
+receiving	O
+myelosuppressive	O
+chemotherapy	O
+.	O
+	
+The	O
+overall	O
+cure	O
+rate	O
+was	O
+70	O
+%	O
+.	O
+	
+Pneumonia	B-NP
+was	O
+the	O
+most	O
+common	O
+infection	B-NP
+and	O
+61	O
+%	O
+of	O
+59	O
+episodes	O
+were	O
+cured	O
+.	O
+	
+Gram	O
+-	O
+negative	O
+bacilli	O
+were	O
+the	O
+most	O
+common	O
+causative	O
+organisms	O
+and	O
+69	O
+%	O
+of	O
+these	O
+infections	B-NP
+were	O
+cured	O
+.	O
+	
+The	O
+most	O
+common	O
+pathogen	O
+was	O
+Klebsiella	O
+pneumoniae	B-NP
+and	O
+this	O
+","	O
+together	O
+with	O
+Escherichia	O
+coli	O
+and	O
+Pseudomonas	O
+aeruginosa	O
+","	O
+accounted	O
+for	O
+74	O
+%	O
+of	O
+all	O
+gram	B-NP
+-	I-NP
+negative	I-NP
+bacillary	I-NP
+infections	I-NP
+.	O
+	
+Response	O
+was	O
+not	O
+influenced	O
+by	O
+the	O
+initial	O
+neutrophil	O
+count	O
+","	O
+with	O
+a	O
+62	O
+%	O
+cure	O
+rate	O
+for	O
+39	O
+episodes	O
+associated	O
+with	O
+severe	O
+neutropenia	B-NP
+.	O
+	
+However	O
+","	O
+failure	O
+of	O
+the	O
+neutrophil	O
+count	O
+to	O
+increase	O
+during	O
+therapy	O
+adversely	O
+affected	O
+response	O
+.	O
+	
+Azotemia	B-NP
+was	O
+the	O
+major	O
+side	O
+effect	O
+recognized	O
+","	O
+and	O
+it	O
+occurred	O
+in	O
+11	O
+%	O
+of	O
+episodes	O
+.	O
+	
+Major	O
+azotemia	B-NP
+(	O
+serum	O
+creatinine	O
+greater	O
+than	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+dl	O
+or	O
+BUN	O
+greater	O
+than	O
+50	O
+mg	O
+/	O
+dl	O
+)	O
+occurred	O
+in	O
+only	O
+2	O
+%	O
+.	O
+	
+Azotemia	B-NP
+was	O
+not	O
+related	O
+to	O
+duration	O
+of	O
+therapy	O
+or	O
+serum	O
+tobramycin	O
+concentration	O
+.	O
+	
+This	O
+antibiotic	O
+regimen	O
+showed	O
+both	O
+therapeutic	O
+efficacy	O
+and	O
+acceptable	O
+renal	B-NP
+toxicity	I-NP
+for	O
+these	O
+patients	O
+.	O
+	
+Incidence	O
+of	O
+solid	O
+tumours	B-NP
+among	O
+pesticide	O
+applicators	O
+exposed	O
+to	O
+the	O
+organophosphate	O
+insecticide	O
+diazinon	O
+in	O
+the	O
+Agricultural	O
+Health	O
+Study	O
+:	O
+an	O
+updated	O
+analysis	O
+.	O
+	
+OBJECTIVE	O
+:	O
+Diazinon	O
+","	O
+a	O
+common	O
+organophosphate	O
+insecticide	O
+with	O
+genotoxic	O
+properties	O
+","	O
+was	O
+previously	O
+associated	O
+with	O
+lung	B-NP
+cancer	I-NP
+in	O
+the	O
+Agricultural	O
+Health	O
+Study	O
+(	O
+AHS	O
+)	O
+cohort	O
+","	O
+but	O
+few	O
+other	O
+epidemiological	O
+studies	O
+have	O
+examined	O
+diazinon	O
+-	O
+associated	O
+cancer	B-NP
+risk	O
+.	O
+	
+We	O
+used	O
+updated	O
+diazinon	O
+exposure	O
+and	O
+cancer	B-NP
+incidence	O
+information	O
+to	O
+evaluate	O
+solid	O
+tumour	B-NP
+risk	O
+in	O
+the	O
+AHS	O
+.	O
+	
+METHODS	O
+:	O
+Male	O
+pesticide	O
+applicators	O
+in	O
+Iowa	O
+and	O
+North	O
+Carolina	O
+reported	O
+lifetime	O
+diazinon	O
+use	O
+at	O
+enrolment	O
+(	O
+1993	O
+-	O
+1997	O
+)	O
+and	O
+follow	O
+-	O
+up	O
+(	O
+1998	O
+-	O
+2005	O
+)	O
+;	O
+cancer	B-NP
+incidence	O
+was	O
+assessed	O
+through	O
+2010	O
+(	O
+North	O
+Carolina	O
+)	O
+/	O
+2011	O
+(	O
+Iowa	O
+)	O
+.	O
+	
+Among	O
+applicators	O
+with	O
+usage	O
+information	O
+sufficient	O
+to	O
+evaluate	O
+exposure	O
+-	O
+response	O
+patterns	O
+","	O
+we	O
+used	O
+Poisson	O
+regression	O
+to	O
+estimate	O
+adjusted	O
+rate	O
+ratios	O
+(	O
+RRs	O
+)	O
+and	O
+95	O
+%	O
+CI	O
+for	O
+cancer	B-NP
+sites	O
+with	O
+>	O
+10	O
+exposed	O
+cases	O
+for	O
+both	O
+lifetime	O
+(	O
+LT	O
+)	O
+exposure	O
+days	O
+and	O
+intensity	O
+-	O
+weighted	O
+(	O
+IW	O
+)	O
+lifetime	O
+exposure	O
+days	O
+(	O
+accounting	O
+for	O
+factors	O
+impacting	O
+exposure	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+We	O
+observed	O
+elevated	O
+lung	B-NP
+cancer	I-NP
+risks	O
+(	O
+N	O
+=	O
+283	O
+)	O
+among	O
+applicators	O
+with	O
+the	O
+greatest	O
+number	O
+of	O
+LT	O
+(	O
+RR	O
+=	O
+1	O
+.	O
+60	O
+;	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+11	O
+to	O
+2	O
+.	O
+31	O
+;	O
+Ptrend	O
+=	O
+0	O
+.	O
+2	O
+)	O
+and	O
+IW	O
+days	O
+of	O
+diazinon	O
+use	O
+(	O
+RR	O
+=	O
+1	O
+.	O
+41	O
+;	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+98	O
+to	O
+2	O
+.	O
+4	O
+;	O
+Ptrend	O
+=	O
+0	O
+.	O
+8	O
+)	O
+.	O
+	
+Kidney	B-NP
+cancer	I-NP
+(	O
+N	O
+=	O
+94	O
+)	O
+risks	O
+were	O
+non	O
+-	O
+significantly	O
+elevated	O
+(	O
+RRLT	O
+days	O
+=	O
+1	O
+.	O
+77	O
+;	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+90	O
+to	O
+3	O
+.	O
+51	O
+;	O
+Ptrend	O
+=	O
+0	O
+.	O
+9	O
+;	O
+RRIW	O
+days	O
+1	O
+.	O
+37	O
+;	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+64	O
+to	O
+2	O
+.	O
+92	O
+;	O
+Ptrend	O
+=	O
+0	O
+.	O
+50	O
+)	O
+","	O
+as	O
+were	O
+risks	O
+for	O
+aggressive	O
+prostate	B-NP
+cancer	I-NP
+(	O
+N	O
+=	O
+656	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Our	O
+updated	O
+evaluation	O
+of	O
+diazinon	O
+provides	O
+additional	O
+evidence	O
+of	O
+an	O
+association	O
+with	O
+lung	B-NP
+cancer	I-NP
+risk	O
+.	O
+	
+Newly	O
+identified	O
+links	O
+to	O
+kidney	B-NP
+cancer	I-NP
+and	O
+associations	O
+with	O
+aggressive	O
+prostate	B-NP
+cancer	I-NP
+require	O
+further	O
+evaluation	O
+.	O
+	
+Associations	O
+of	O
+Ozone	O
+and	O
+PM2	O
+.	O
+5	O
+Concentrations	O
+With	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+Disease	I-NP
+Among	O
+Participants	O
+in	O
+the	O
+Agricultural	O
+Health	O
+Study	O
+.	O
+	
+OBJECTIVE	O
+:	O
+This	O
+study	O
+describes	O
+associations	O
+of	O
+ozone	O
+and	O
+fine	O
+particulate	O
+matter	O
+with	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+observed	O
+among	O
+farmers	O
+in	O
+North	O
+Carolina	O
+and	O
+Iowa	O
+.	O
+	
+METHODS	O
+:	O
+We	O
+used	O
+logistic	O
+regression	O
+to	O
+determine	O
+the	O
+associations	O
+of	O
+these	O
+pollutants	O
+with	O
+self	O
+-	O
+reported	O
+","	O
+doctor	O
+-	O
+diagnosed	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+Daily	O
+predicted	O
+pollutant	O
+concentrations	O
+were	O
+used	O
+to	O
+derive	O
+surrogates	O
+of	O
+long	O
+-	O
+term	O
+exposure	O
+and	O
+link	O
+them	O
+to	O
+study	O
+participants	O
+'	O
+geocoded	O
+addresses	O
+.	O
+	
+RESULTS	O
+:	O
+We	O
+observed	O
+positive	O
+associations	O
+of	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+with	O
+ozone	O
+(	O
+odds	O
+ratio	O
+=	O
+1	O
+.	O
+39	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+0	O
+.	O
+98	O
+to	O
+1	O
+.	O
+98	O
+)	O
+and	O
+fine	O
+particulate	O
+matter	O
+(	O
+odds	O
+ratio	O
+=	O
+1	O
+.	O
+34	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+0	O
+.	O
+93	O
+to	O
+1	O
+.	O
+93	O
+)	O
+in	O
+North	O
+Carolina	O
+but	O
+not	O
+in	O
+Iowa	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+plausibility	O
+of	O
+an	O
+effect	O
+of	O
+ambient	O
+concentrations	O
+of	O
+these	O
+pollutants	O
+on	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+risk	O
+is	O
+supported	O
+by	O
+experimental	O
+data	O
+demonstrating	O
+damage	O
+to	O
+dopaminergic	O
+neurons	O
+at	O
+relevant	O
+concentrations	O
+.	O
+	
+Additional	O
+studies	O
+are	O
+needed	O
+to	O
+address	O
+uncertainties	O
+related	O
+to	O
+confounding	O
+and	O
+to	O
+examine	O
+temporal	O
+aspects	O
+of	O
+the	O
+associations	O
+we	O
+observed	O
+.	O
+	
+Low	O
+functional	O
+programming	O
+of	O
+renal	O
+AT2R	O
+mediates	O
+the	O
+developmental	O
+origin	O
+of	O
+glomerulosclerosis	B-NP
+in	O
+adult	O
+offspring	O
+induced	O
+by	O
+prenatal	O
+caffeine	O
+exposure	O
+.	O
+	
+UNASSIGNED	O
+:	O
+Our	O
+previous	O
+study	O
+has	O
+indicated	O
+that	O
+prenatal	O
+caffeine	O
+exposure	O
+(	O
+PCE	O
+)	O
+could	O
+induce	O
+intrauterine	B-NP
+growth	I-NP
+retardation	I-NP
+(	O
+IUGR	B-NP
+)	O
+of	O
+offspring	O
+.	O
+	
+Recent	O
+research	O
+suggested	O
+that	O
+IUGR	B-NP
+is	O
+a	O
+risk	O
+factor	O
+for	O
+glomerulosclerosis	B-NP
+.	O
+	
+However	O
+","	O
+whether	O
+PCE	O
+could	O
+induce	O
+glomerulosclerosis	B-NP
+and	O
+its	O
+underlying	O
+mechanisms	O
+remain	O
+unknown	O
+.	O
+	
+This	O
+study	O
+aimed	O
+to	O
+demonstrate	O
+the	O
+induction	O
+to	O
+glomerulosclerosis	B-NP
+in	O
+adult	O
+offspring	O
+by	O
+PCE	O
+and	O
+its	O
+intrauterine	O
+programming	O
+mechanisms	O
+.	O
+	
+A	O
+rat	O
+model	O
+of	O
+IUGR	B-NP
+was	O
+established	O
+by	O
+PCE	O
+","	O
+male	O
+fetuses	O
+and	O
+adult	O
+offspring	O
+at	O
+the	O
+age	O
+of	O
+postnatal	O
+week	O
+24	O
+were	O
+euthanized	O
+.	O
+	
+The	O
+results	O
+revealed	O
+that	O
+the	O
+adult	O
+offspring	O
+kidneys	O
+in	O
+the	O
+PCE	O
+group	O
+exhibited	O
+glomerulosclerosis	B-NP
+as	O
+well	O
+as	O
+interstitial	B-NP
+fibrosis	I-NP
+","	O
+accompanied	O
+by	O
+elevated	O
+levels	O
+of	O
+serum	O
+creatinine	O
+and	O
+urine	O
+protein	O
+.	O
+	
+Renal	O
+angiotensin	O
+II	O
+receptor	O
+type	O
+2	O
+(	O
+AT2R	O
+)	O
+gene	O
+expression	O
+in	O
+adult	O
+offspring	O
+was	O
+reduced	O
+by	O
+PCE	O
+","	O
+whereas	O
+the	O
+renal	O
+angiotensin	O
+II	O
+receptor	O
+type	O
+1a	O
+(	O
+AT1aR	O
+)	O
+/	O
+AT2R	O
+expression	O
+ratio	O
+was	O
+increased	O
+.	O
+	
+The	O
+fetal	O
+kidneys	O
+in	O
+the	O
+PCE	O
+group	O
+displayed	O
+an	O
+enlarged	O
+Bowman	O
+'	O
+s	O
+space	O
+and	O
+a	O
+shrunken	O
+glomerular	O
+tuft	O
+","	O
+accompanied	O
+by	O
+a	O
+reduced	O
+cortex	O
+width	O
+and	O
+an	O
+increase	O
+in	O
+the	O
+nephrogenic	O
+zone	O
+/	O
+cortical	O
+zone	O
+ratio	O
+.	O
+	
+Observation	O
+by	O
+electronic	O
+microscope	O
+revealed	O
+structural	O
+damage	O
+of	O
+podocytes	O
+;	O
+the	O
+reduced	O
+expression	O
+level	O
+of	O
+podocyte	O
+marker	O
+genes	O
+","	O
+nephrin	O
+and	O
+podocin	O
+","	O
+was	O
+also	O
+detected	O
+by	O
+q	O
+-	O
+PCR	O
+.	O
+	
+Moreover	O
+","	O
+AT2R	O
+gene	O
+and	O
+protein	O
+expressions	O
+in	O
+fetal	O
+kidneys	O
+were	O
+inhibited	O
+by	O
+PCE	O
+","	O
+associated	O
+with	O
+the	O
+repression	O
+of	O
+the	O
+gene	O
+expression	O
+of	O
+glial	O
+-	O
+cell	O
+-	O
+line	O
+-	O
+derived	O
+neurotrophic	O
+factor	O
+(	O
+GDNF	O
+)	O
+/	O
+tyrosine	O
+kinase	O
+receptor	O
+(	O
+c	O
+-	O
+Ret	O
+)	O
+signaling	O
+pathway	O
+.	O
+	
+These	O
+results	O
+demonstrated	O
+that	O
+PCE	O
+could	O
+induce	O
+dysplasia	B-NP
+of	I-NP
+fetal	I-NP
+kidneys	I-NP
+as	O
+well	O
+as	O
+glomerulosclerosis	B-NP
+of	O
+adult	O
+offspring	O
+","	O
+and	O
+the	O
+low	O
+functional	O
+programming	O
+of	O
+renal	O
+AT2R	O
+might	O
+mediate	O
+the	O
+developmental	O
+origin	O
+of	O
+adult	O
+glomerulosclerosis	B-NP
+.	O
+	
+1	O
+","	O
+3	O
+-	O
+Butadiene	O
+","	O
+CML	B-NP
+and	O
+the	O
+t	O
+(	O
+9	O
+:	O
+22	O
+)	O
+translocation	O
+:	O
+A	O
+reality	O
+check	O
+.	O
+	
+UNASSIGNED	O
+:	O
+Epidemiological	O
+studies	O
+of	O
+1	O
+","	O
+3	O
+-	O
+butadiene	O
+have	O
+suggest	O
+that	O
+exposures	O
+to	O
+humans	O
+are	O
+associated	O
+with	O
+chronic	B-NP
+myeloid	I-NP
+leukemia	I-NP
+(	O
+CML	B-NP
+)	O
+.	O
+	
+CML	B-NP
+has	O
+a	O
+well	O
+-	O
+documented	O
+association	O
+with	O
+ionizing	O
+radiation	O
+","	O
+but	O
+reports	O
+of	O
+associations	O
+with	O
+chemical	O
+exposures	O
+have	O
+been	O
+questioned	O
+.	O
+	
+Ionizing	O
+radiation	O
+is	O
+capable	O
+of	O
+inducing	O
+the	O
+requisite	O
+CML	B-NP
+-	O
+associated	O
+t	O
+(	O
+9	O
+:	O
+22	O
+)	O
+translocation	O
+(	O
+Philadelphia	B-NP
+chromosome	I-NP
+)	O
+in	O
+appropriate	O
+cells	O
+in	O
+vitro	O
+but	O
+","	O
+thus	O
+far	O
+","	O
+chemicals	O
+have	O
+not	O
+shown	O
+this	O
+capacity	O
+.	O
+	
+We	O
+have	O
+proposed	O
+that	O
+1	O
+","	O
+3	O
+-	O
+butadiene	O
+metabolites	O
+be	O
+so	O
+tested	O
+as	O
+a	O
+reality	O
+check	O
+on	O
+the	O
+epidemiological	O
+reports	O
+.	O
+	
+In	O
+order	O
+to	O
+conduct	O
+reliable	O
+testing	O
+in	O
+this	O
+regard	O
+","	O
+it	O
+is	O
+essential	O
+that	O
+a	O
+positive	O
+control	O
+for	O
+induction	O
+be	O
+available	O
+.	O
+	
+We	O
+have	O
+used	O
+ionizing	O
+radiation	O
+to	O
+develop	O
+such	O
+a	O
+control	O
+.	O
+	
+Results	O
+described	O
+here	O
+demonstrate	O
+that	O
+this	O
+agent	O
+does	O
+in	O
+fact	O
+induce	O
+pathogenic	O
+t	O
+(	O
+9	O
+:	O
+22	O
+)	O
+translocations	O
+in	O
+a	O
+human	O
+myeloid	O
+cell	O
+line	O
+in	O
+vitro	O
+","	O
+but	O
+does	O
+so	O
+at	O
+low	O
+frequencies	O
+.	O
+	
+Conditions	O
+that	O
+will	O
+be	O
+required	O
+for	O
+studies	O
+of	O
+1	O
+","	O
+3	O
+-	O
+butadiene	O
+are	O
+discussed	O
+.	O
+	
+Cancer	B-NP
+incidence	O
+and	O
+metolachlor	O
+use	O
+in	O
+the	O
+Agricultural	O
+Health	O
+Study	O
+:	O
+An	O
+update	O
+.	O
+	
+UNASSIGNED	O
+:	O
+Metolachlor	O
+","	O
+a	O
+widely	O
+used	O
+herbicide	O
+","	O
+is	O
+classified	O
+as	O
+a	O
+Group	O
+C	O
+carcinogen	O
+by	O
+the	O
+U	O
+.	O
+S	O
+.	O
+	
+Environmental	O
+Protection	O
+Agency	O
+based	O
+on	O
+increased	O
+liver	B-NP
+neoplasms	I-NP
+in	O
+female	O
+rats	O
+.	O
+	
+Epidemiologic	O
+studies	O
+of	O
+the	O
+health	O
+effects	O
+of	O
+metolachlor	O
+have	O
+been	O
+limited	O
+.	O
+	
+The	O
+Agricultural	O
+Health	O
+Study	O
+(	O
+AHS	O
+)	O
+is	O
+a	O
+prospective	O
+cohort	O
+study	O
+including	O
+licensed	O
+private	O
+and	O
+commercial	O
+pesticide	O
+applicators	O
+in	O
+Iowa	O
+and	O
+North	O
+Carolina	O
+enrolled	O
+1993	O
+-	O
+1997	O
+.	O
+	
+We	O
+evaluated	O
+cancer	B-NP
+incidence	O
+through	O
+2010	O
+/	O
+2011	O
+(	O
+NC	O
+/	O
+IA	O
+)	O
+for	O
+49	O
+","	O
+616	O
+applicators	O
+","	O
+53	O
+%	O
+of	O
+whom	O
+reported	O
+ever	O
+using	O
+metolachlor	O
+.	O
+	
+We	O
+used	O
+Poisson	O
+regression	O
+to	O
+evaluate	O
+relations	O
+between	O
+two	O
+metrics	O
+of	O
+metolachlor	O
+use	O
+(	O
+lifetime	O
+days	O
+","	O
+intensity	O
+-	O
+weighted	O
+lifetime	O
+days	O
+)	O
+and	O
+cancer	B-NP
+incidence	O
+.	O
+	
+We	O
+saw	O
+no	O
+association	O
+between	O
+metolachlor	O
+use	O
+and	O
+incidence	O
+of	O
+all	O
+cancers	B-NP
+combined	O
+(	O
+n	O
+=	O
+5	O
+","	O
+701	O
+with	O
+a	O
+5	O
+-	O
+year	O
+lag	O
+)	O
+or	O
+most	O
+site	O
+-	O
+specific	O
+cancers	B-NP
+.	O
+	
+For	O
+liver	B-NP
+cancer	I-NP
+","	O
+in	O
+analyses	O
+restricted	O
+to	O
+exposed	O
+workers	O
+","	O
+elevations	O
+observed	O
+at	O
+higher	O
+categories	O
+of	O
+use	O
+were	O
+not	O
+statistically	O
+significant	O
+.	O
+	
+However	O
+","	O
+trends	O
+for	O
+both	O
+lifetime	O
+and	O
+intensity	O
+-	O
+weighted	O
+lifetime	O
+days	O
+of	O
+metolachor	O
+use	O
+were	O
+positive	O
+and	O
+statistically	O
+significant	O
+with	O
+an	O
+unexposed	O
+reference	O
+group	O
+.	O
+	
+A	O
+similar	O
+pattern	O
+was	O
+observed	O
+for	O
+follicular	B-NP
+cell	I-NP
+lymphoma	I-NP
+","	O
+but	O
+no	O
+other	O
+lymphoma	B-NP
+subtypes	O
+.	O
+	
+An	O
+earlier	O
+suggestion	O
+of	O
+increased	O
+lung	B-NP
+cancer	I-NP
+risk	O
+at	O
+high	O
+levels	O
+of	O
+metolachlor	O
+use	O
+in	O
+this	O
+cohort	O
+was	O
+not	O
+confirmed	O
+in	O
+this	O
+update	O
+.	O
+	
+This	O
+suggestion	O
+of	O
+an	O
+association	O
+between	O
+metolachlor	O
+and	O
+liver	B-NP
+cancer	I-NP
+among	O
+pesticide	O
+applicators	O
+is	O
+a	O
+novel	O
+finding	O
+and	O
+echoes	O
+observation	O
+of	O
+increased	O
+liver	B-NP
+neoplasms	I-NP
+in	O
+some	O
+animal	O
+studies	O
+.	O
+	
+However	O
+","	O
+our	O
+findings	O
+for	O
+both	O
+liver	B-NP
+cancer	I-NP
+and	O
+follicular	O
+cell	O
+lymphoma	B-NP
+warrant	O
+follow	O
+-	O
+up	O
+to	O
+better	O
+differentiate	O
+effects	O
+of	O
+metolachlor	O
+use	O
+from	O
+other	O
+factors	O
+.	O
+	
+Mechanisms	O
+Underlying	O
+Latent	O
+Disease	O
+Risk	O
+Associated	O
+with	O
+Early	O
+-	O
+Life	O
+Arsenic	O
+Exposure	O
+:	O
+Current	O
+Research	O
+Trends	O
+and	O
+Scientific	O
+Gaps	O
+.	O
+	
+BACKGROUND	O
+:	O
+Millions	O
+of	O
+individuals	O
+worldwide	O
+","	O
+particularly	O
+those	O
+living	O
+in	O
+rural	O
+and	O
+developing	O
+areas	O
+","	O
+are	O
+exposed	O
+to	O
+harmful	O
+levels	O
+of	O
+inorganic	O
+arsenic	O
+(	O
+iAs	O
+)	O
+in	O
+their	O
+drinking	O
+water	O
+.	O
+	
+Inorganic	O
+As	O
+exposure	O
+during	O
+key	O
+developmental	O
+periods	O
+is	O
+associated	O
+with	O
+a	O
+variety	O
+of	O
+adverse	O
+health	O
+effects	O
+including	O
+those	O
+that	O
+are	O
+evident	O
+in	O
+adulthood	O
+.	O
+	
+There	O
+is	O
+considerable	O
+interest	O
+in	O
+identifying	O
+the	O
+molecular	O
+mechanisms	O
+that	O
+relate	O
+early	O
+-	O
+life	O
+iAs	O
+exposure	O
+to	O
+the	O
+development	O
+of	O
+these	O
+latent	O
+diseases	O
+","	O
+particularly	O
+in	O
+relationship	O
+to	O
+cancer	B-NP
+.	O
+	
+OBJECTIVES	O
+:	O
+This	O
+work	O
+summarizes	O
+research	O
+on	O
+the	O
+molecular	O
+mechanisms	O
+that	O
+underlie	O
+the	O
+increased	O
+risk	O
+of	O
+cancer	B-NP
+development	O
+in	O
+adulthood	O
+that	O
+is	O
+associated	O
+with	O
+early	O
+-	O
+life	O
+iAs	O
+exposure	O
+.	O
+	
+DISCUSSION	O
+:	O
+Epigenetic	O
+reprogramming	O
+that	O
+imparts	O
+functional	O
+changes	O
+in	O
+gene	O
+expression	O
+","	O
+the	O
+development	O
+of	O
+cancer	B-NP
+stem	O
+cells	O
+","	O
+and	O
+immunomodulation	O
+are	O
+plausible	O
+underlying	O
+mechanisms	O
+by	O
+which	O
+early	O
+-	O
+life	O
+iAs	O
+exposure	O
+elicits	O
+latent	O
+carcinogenic	O
+effects	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Evidence	O
+is	O
+mounting	O
+that	O
+relates	O
+early	O
+-	O
+life	O
+iAs	O
+exposure	O
+and	O
+cancer	B-NP
+development	O
+later	O
+in	O
+life	O
+.	O
+	
+Future	O
+research	O
+should	O
+include	O
+animal	O
+studies	O
+that	O
+address	O
+mechanistic	O
+hypotheses	O
+and	O
+studies	O
+of	O
+human	O
+populations	O
+that	O
+integrate	O
+early	O
+-	O
+life	O
+exposure	O
+","	O
+molecular	O
+alterations	O
+","	O
+and	O
+latent	O
+disease	O
+outcomes	O
+.	O
+	
+Nifedipine	O
+induced	O
+bradycardia	B-NP
+in	O
+a	O
+patient	O
+with	O
+autonomic	B-NP
+neuropathy	I-NP
+.	O
+	
+An	O
+80	O
+year	O
+old	O
+diabetic	B-NP
+male	O
+with	O
+evidence	O
+of	O
+peripheral	B-NP
+and	I-NP
+autonomic	I-NP
+neuropathy	I-NP
+was	O
+admitted	O
+with	O
+chest	B-NP
+pain	I-NP
+.	O
+	
+He	O
+was	O
+found	O
+to	O
+have	O
+atrial	B-NP
+flutter	I-NP
+at	O
+a	O
+ventricular	O
+rate	O
+of	O
+70	O
+/	O
+min	O
+which	O
+slowed	O
+down	O
+to	O
+30	O
+-	O
+40	O
+/	O
+min	O
+when	O
+nifedipine	O
+(	O
+60	O
+mg	O
+)	O
+in	O
+3	O
+divided	O
+doses	O
+","	O
+during	O
+which	O
+he	O
+was	O
+paced	O
+at	O
+a	O
+rate	O
+of	O
+70	O
+/	O
+min	O
+.	O
+	
+This	O
+is	O
+inconsistent	O
+with	O
+the	O
+well	O
+-	O
+established	O
+finding	O
+that	O
+nifedipine	O
+induces	O
+tachycardia	B-NP
+in	O
+normally	O
+innervated	O
+hearts	O
+.	O
+	
+However	O
+","	O
+in	O
+hearts	O
+deprived	O
+of	O
+compensatory	O
+sympathetic	O
+drive	O
+","	O
+it	O
+may	O
+lead	O
+to	O
+bradycardia	B-NP
+.	O
+	
+The	O
+effect	O
+of	O
+haloperidol	O
+in	O
+cocaine	O
+and	O
+amphetamine	O
+intoxication	O
+.	O
+	
+The	O
+effectiveness	O
+of	O
+haloperidol	O
+pretreatment	O
+in	O
+preventing	O
+the	O
+toxic	O
+effects	O
+of	O
+high	O
+doses	O
+of	O
+amphetamine	O
+and	O
+cocaine	O
+was	O
+studied	O
+in	O
+rats	O
+.	O
+	
+In	O
+this	O
+model	O
+","	O
+toxic	O
+effects	O
+were	O
+induced	O
+by	O
+intraperitoneal	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+injection	O
+of	O
+amphetamine	O
+75	O
+mg	O
+/	O
+kg	O
+(	O
+100	O
+%	O
+death	O
+rate	O
+)	O
+or	O
+cocaine	O
+70	O
+mg	O
+/	O
+kg	O
+(	O
+82	O
+%	O
+death	O
+rate	O
+)	O
+.	O
+	
+Haloperidol	O
+failed	O
+to	O
+prevent	O
+amphetamine	O
+-	O
+induced	O
+seizures	B-NP
+","	O
+but	O
+did	O
+lower	O
+the	O
+mortality	O
+rate	O
+at	O
+most	O
+doses	O
+tested	O
+.	O
+	
+Haloperidol	O
+decreased	O
+the	O
+incidence	O
+of	O
+cocaine	O
+-	O
+induced	O
+seizures	B-NP
+at	O
+the	O
+two	O
+highest	O
+doses	O
+","	O
+but	O
+the	O
+lowering	O
+of	O
+the	O
+mortality	O
+rate	O
+did	O
+not	O
+reach	O
+statistical	O
+significance	O
+at	O
+any	O
+dose	O
+.	O
+	
+These	O
+data	O
+suggest	O
+a	O
+protective	O
+role	O
+for	O
+the	O
+central	O
+dopamine	O
+blocker	O
+haloperidol	O
+against	O
+death	O
+from	O
+high	O
+-	O
+dose	O
+amphetamine	O
+exposure	O
+without	O
+reducing	O
+the	O
+incidence	O
+of	O
+seizures	B-NP
+.	O
+	
+In	O
+contrast	O
+","	O
+haloperidol	O
+demonstrated	O
+an	O
+ability	O
+to	O
+reduce	O
+cocaine	O
+-	O
+induced	O
+seizures	B-NP
+without	O
+significantly	O
+reducing	O
+mortality	O
+.	O
+	
+Autoradiographic	O
+evidence	O
+of	O
+estrogen	O
+binding	O
+sites	O
+in	O
+nuclei	O
+of	O
+diethylstilbesterol	O
+induced	O
+hamster	O
+renal	B-NP
+carcinomas	I-NP
+.	O
+	
+Estrogen	O
+binding	O
+sites	O
+were	O
+demonstrated	O
+by	O
+autoradiography	O
+in	O
+one	O
+transplantable	O
+and	O
+five	O
+primary	O
+diethylstilbesterol	O
+induced	O
+renal	B-NP
+carcinomas	I-NP
+in	O
+three	O
+hamsters	O
+.	O
+	
+Radiolabelling	O
+","	O
+following	O
+the	O
+in	O
+vivo	O
+injection	O
+of	O
+3H	O
+-	O
+17	O
+beta	O
+estradiol	O
+","	O
+was	O
+increased	O
+only	O
+over	O
+the	O
+nuclei	O
+of	O
+tumor	B-NP
+cells	O
+;	O
+stereologic	O
+analysis	O
+revealed	O
+a	O
+4	O
+.	O
+5	O
+-	O
+to	O
+6	O
+.	O
+7	O
+-	O
+times	O
+higher	O
+concentration	O
+of	O
+reduced	O
+silver	O
+grains	O
+over	O
+nuclei	O
+than	O
+cytoplasm	O
+of	O
+these	O
+cells	O
+.	O
+	
+Despite	O
+rapid	O
+tubular	O
+excretion	O
+of	O
+estradiol	O
+which	O
+peaked	O
+in	O
+less	O
+than	O
+1	O
+h	O
+","	O
+the	O
+normal	O
+cells	O
+did	O
+not	O
+appear	O
+to	O
+bind	O
+the	O
+ligand	O
+.	O
+	
+This	O
+is	O
+the	O
+first	O
+published	O
+report	O
+documenting	O
+the	O
+preferential	O
+in	O
+vivo	O
+binding	O
+of	O
+estrogen	O
+to	O
+nuclei	O
+of	O
+cells	O
+in	O
+estrogen	O
+induced	O
+hamster	O
+renal	B-NP
+carcinomas	I-NP
+.	O
+	
+Bradycardia	B-NP
+due	O
+to	O
+biperiden	O
+.	O
+	
+In	O
+a	O
+38	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+suffering	O
+from	O
+a	O
+severe	O
+postzosteric	B-NP
+trigeminal	B-NP
+neuralgia	I-NP
+","	O
+intravenous	O
+application	O
+of	O
+10	O
+mg	O
+biperiden	O
+lactate	O
+led	O
+to	O
+a	O
+long	O
+-	O
+lasting	O
+paradoxical	O
+reaction	O
+characterized	O
+by	O
+considerable	O
+bradycardia	B-NP
+","	O
+dysarthria	B-NP
+","	O
+and	O
+dysphagia	B-NP
+.	O
+	
+The	O
+heart	O
+rate	O
+was	O
+back	O
+to	O
+normal	O
+within	O
+12	O
+hours	O
+upon	O
+administration	O
+of	O
+orciprenaline	O
+under	O
+cardiac	O
+monitoring	O
+in	O
+an	O
+intensive	O
+care	O
+unit	O
+.	O
+	
+Bradycardia	B-NP
+induced	O
+by	O
+biperiden	O
+is	O
+attributed	O
+to	O
+the	O
+speed	O
+of	O
+injection	O
+and	O
+to	O
+a	O
+dose	O
+-	O
+related	O
+dual	O
+effect	O
+of	O
+atropine	O
+-	O
+like	O
+drugs	O
+on	O
+muscarine	O
+receptors	O
+.	O
+	
+Deliberate	O
+hypotension	B-NP
+induced	O
+by	O
+labetalol	O
+with	O
+halothane	O
+","	O
+enflurane	O
+or	O
+isoflurane	O
+for	O
+middle	O
+-	O
+ear	O
+surgery	O
+.	O
+	
+The	O
+feasibility	O
+of	O
+using	O
+labetalol	O
+","	O
+an	O
+alpha	O
+-	O
+and	O
+beta	O
+-	O
+adrenergic	O
+blocking	O
+agent	O
+","	O
+as	O
+a	O
+hypotensive	B-NP
+agent	O
+in	O
+combination	O
+with	O
+inhalation	O
+anaesthetics	O
+(	O
+halothane	O
+","	O
+enflurane	O
+or	O
+isoflurane	O
+)	O
+was	O
+studied	O
+in	O
+23	O
+adult	O
+patients	O
+undergoing	O
+middle	O
+-	O
+ear	O
+surgery	O
+.	O
+	
+The	O
+mean	O
+arterial	O
+pressure	O
+was	O
+decreased	O
+from	O
+86	O
++	O
+/	O
+-	O
+5	O
+(	O
+s	O
+.	O
+e	O
+.	O
+mean	O
+)	O
+mmHg	O
+to	O
+52	O
++	O
+/	O
+-	O
+1	O
+mmHg	O
+(	O
+11	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+to	O
+6	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+kPa	O
+)	O
+for	O
+98	O
++	O
+/	O
+-	O
+10	O
+min	O
+in	O
+the	O
+halothane	O
+(	O
+H	O
+)	O
+group	O
+","	O
+from	O
+79	O
++	O
+/	O
+-	O
+5	O
+to	O
+53	O
++	O
+/	O
+-	O
+1	O
+mmHg	O
+(	O
+10	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+to	O
+7	O
+.	O
+1	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+kPa	O
+)	O
+for	O
+129	O
++	O
+/	O
+-	O
+11	O
+min	O
+in	O
+the	O
+enflurane	O
+(	O
+E	O
+)	O
+group	O
+","	O
+and	O
+from	O
+80	O
++	O
+/	O
+-	O
+4	O
+to	O
+49	O
++	O
+/	O
+-	O
+1	O
+mmHg	O
+(	O
+10	O
+.	O
+7	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+to	O
+6	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+kPa	O
+)	O
+for	O
+135	O
++	O
+/	O
+-	O
+15	O
+min	O
+in	O
+the	O
+isoflurane	O
+(	O
+I	O
+)	O
+group	O
+.	O
+	
+The	O
+mean	O
+H	O
+concentration	O
+during	O
+hypotension	B-NP
+in	O
+the	O
+inspiratory	O
+gas	O
+was	O
+0	O
+.	O
+7	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+vol	O
+%	O
+","	O
+the	O
+mean	O
+E	O
+concentration	O
+1	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+vol	O
+%	O
+","	O
+and	O
+the	O
+mean	O
+I	O
+concentration	O
+1	O
+.	O
+0	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+vol	O
+%	O
+.	O
+	
+In	O
+addition	O
+","	O
+the	O
+patients	O
+received	O
+fentanyl	O
+and	O
+d	O
+-	O
+tubocurarine	O
+.	O
+	
+The	O
+initial	O
+dose	O
+of	O
+labetalol	O
+for	O
+lowering	O
+blood	O
+pressure	O
+was	O
+similar	O
+","	O
+0	O
+.	O
+52	O
+-	O
+0	O
+.	O
+59	O
+mg	O
+/	O
+kg	O
+","	O
+in	O
+all	O
+the	O
+groups	O
+.	O
+	
+During	O
+hypotension	B-NP
+","	O
+the	O
+heart	O
+rate	O
+was	O
+stable	O
+without	O
+tachy	B-NP
+-	I-NP
+or	I-NP
+bradycardia	I-NP
+.	O
+	
+The	O
+operating	O
+conditions	O
+regarding	O
+bleeding	B-NP
+were	O
+estimated	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+manner	O
+","	O
+and	O
+did	O
+not	O
+differ	O
+significantly	O
+between	O
+the	O
+groups	O
+.	O
+	
+During	O
+hypotension	B-NP
+","	O
+the	O
+serum	O
+creatinine	O
+concentration	O
+rose	O
+significantly	O
+in	O
+all	O
+groups	O
+from	O
+the	O
+values	O
+before	O
+hypotension	B-NP
+and	O
+returned	O
+postoperatively	O
+to	O
+the	O
+initial	O
+level	O
+in	O
+the	O
+other	O
+groups	O
+","	O
+except	O
+the	O
+isoflurane	O
+group	O
+.	O
+	
+After	O
+hypotension	B-NP
+there	O
+was	O
+no	O
+rebound	O
+phenomenon	O
+in	O
+either	O
+blood	O
+pressure	O
+or	O
+heart	O
+rate	O
+.	O
+	
+These	O
+results	O
+indicate	O
+that	O
+labetalol	O
+induces	O
+easily	O
+adjustable	O
+hypotension	B-NP
+without	O
+compensatory	O
+tachycardia	B-NP
+and	O
+rebound	O
+hypertension	B-NP
+.	O
+	
+Convulsion	B-NP
+following	O
+intravenous	O
+fluorescein	O
+angiography	O
+.	O
+	
+Tonic	B-NP
+-	I-NP
+clonic	I-NP
+seizures	I-NP
+followed	O
+intravenous	O
+fluorescein	O
+injection	O
+for	O
+fundus	O
+angiography	O
+in	O
+a	O
+47	O
+-	O
+year	O
+-	O
+old	O
+male	O
+.	O
+	
+Despite	O
+precautions	O
+this	O
+adverse	O
+reaction	O
+recurred	O
+on	O
+re	O
+-	O
+exposure	O
+to	O
+intravenous	O
+fluorescein	O
+.	O
+	
+Pharmacology	O
+of	O
+ACC	O
+-	O
+9653	O
+(	O
+phenytoin	O
+prodrug	O
+)	O
+.	O
+	
+ACC	O
+-	O
+9653	O
+","	O
+the	O
+disodium	O
+phosphate	O
+ester	O
+of	O
+3	O
+-	O
+hydroxymethyl	O
+-	O
+5	O
+","	O
+5	O
+-	O
+diphenylhydantoin	O
+","	O
+is	O
+a	O
+prodrug	O
+of	O
+phenytoin	O
+with	O
+advantageous	O
+physicochemical	O
+properties	O
+.	O
+	
+ACC	O
+-	O
+9653	O
+is	O
+rapidly	O
+converted	O
+enzymatically	O
+to	O
+phenytoin	O
+in	O
+vivo	O
+.	O
+	
+ACC	O
+-	O
+9653	O
+and	O
+phenytoin	O
+sodium	O
+have	O
+equivalent	O
+anticonvulsant	O
+activity	O
+against	O
+seizures	B-NP
+induced	O
+by	O
+maximal	O
+electroshock	O
+(	O
+MES	O
+)	O
+in	O
+mice	O
+following	O
+i	O
+.	O
+p	O
+.	O
+","	O
+oral	O
+","	O
+or	O
+i	O
+.	O
+v	O
+.	O
+administration	O
+.	O
+	
+The	O
+ED50	O
+doses	O
+were	O
+16	O
+mg	O
+/	O
+kg	O
+for	O
+i	O
+.	O
+v	O
+.	O
+ACC	O
+-	O
+9653	O
+and	O
+8	O
+mg	O
+/	O
+kg	O
+for	O
+i	O
+.	O
+v	O
+.	O
+phenytoin	O
+sodium	O
+.	O
+	
+ACC	O
+-	O
+9653	O
+and	O
+phenytoin	O
+sodium	O
+have	O
+similar	O
+antiarrhythmic	O
+activity	O
+against	O
+ouabain	O
+-	O
+induced	O
+ventricular	B-NP
+tachycardia	I-NP
+in	O
+anesthetized	O
+dogs	O
+.	O
+	
+The	O
+total	O
+doses	O
+of	O
+ACC	O
+-	O
+9653	O
+or	O
+phenytoin	O
+sodium	O
+necessary	O
+to	O
+convert	O
+the	O
+arrhythmia	B-NP
+to	O
+a	O
+normal	O
+sinus	O
+rhythm	O
+were	O
+24	O
++	O
+/	O
+-	O
+6	O
+and	O
+14	O
++	O
+/	O
+-	O
+3	O
+mg	O
+/	O
+kg	O
+","	O
+respectively	O
+.	O
+	
+Only	O
+phenytoin	O
+sodium	O
+displayed	O
+in	O
+vitro	O
+antiarrhythmic	O
+activity	O
+against	O
+strophanthidin	O
+-	O
+induced	O
+arrhythmias	B-NP
+in	O
+guinea	O
+pig	O
+right	O
+atria	O
+.	O
+	
+In	O
+anesthetized	O
+dogs	O
+","	O
+a	O
+high	O
+dose	O
+of	O
+ACC	O
+-	O
+9653	O
+(	O
+31	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+infused	O
+over	O
+15	O
+","	O
+20	O
+","	O
+and	O
+30	O
+min	O
+and	O
+the	O
+responses	O
+were	O
+compared	O
+to	O
+an	O
+equimolar	O
+dose	O
+of	O
+phenytoin	O
+sodium	O
+(	O
+21	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+	
+The	O
+ACC	O
+-	O
+9653	O
+and	O
+phenytoin	O
+sodium	O
+treatments	O
+produced	O
+similar	O
+marked	O
+reductions	O
+in	O
+diastolic	O
+blood	O
+pressure	O
+and	O
+contractile	O
+force	O
+(	O
+LVdP	O
+/	O
+dt	O
+)	O
+.	O
+	
+The	O
+maximum	O
+effects	O
+of	O
+each	O
+treatment	O
+occurred	O
+at	O
+the	O
+time	O
+of	O
+maximum	O
+phenytoin	O
+sodium	O
+levels	O
+.	O
+	
+Acute	O
+toxicity	B-NP
+studies	O
+of	O
+ACC	O
+-	O
+9653	O
+and	O
+phenytoin	O
+sodium	O
+were	O
+carried	O
+out	O
+in	O
+mice	O
+","	O
+rats	O
+","	O
+rabbits	O
+","	O
+and	O
+dogs	O
+by	O
+i	O
+.	O
+v	O
+.	O
+","	O
+i	O
+.	O
+m	O
+.	O
+","	O
+and	O
+i	O
+.	O
+p	O
+.	O
+routes	O
+of	O
+administration	O
+.	O
+	
+The	O
+systemic	O
+toxic	O
+signs	O
+of	O
+both	O
+agents	O
+were	O
+similar	O
+and	O
+occurred	O
+at	O
+approximately	O
+equivalent	O
+doses	O
+.	O
+	
+Importantly	O
+","	O
+the	O
+local	O
+irritation	O
+of	O
+ACC	O
+-	O
+9653	O
+was	O
+markedly	O
+less	O
+than	O
+phenytoin	O
+sodium	O
+following	O
+i	O
+.	O
+m	O
+.	O
+administration	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+	
+Tachyphylaxis	O
+to	O
+systemic	O
+but	O
+not	O
+to	O
+airway	O
+responses	O
+during	O
+prolonged	O
+therapy	O
+with	O
+high	O
+dose	O
+inhaled	O
+salbutamol	O
+in	O
+asthmatics	B-NP
+.	O
+	
+High	O
+doses	O
+of	O
+inhaled	O
+salbutamol	O
+produce	O
+substantial	O
+improvements	O
+in	O
+airway	O
+response	O
+in	O
+patients	O
+with	O
+asthma	B-NP
+","	O
+and	O
+are	O
+associated	O
+with	O
+dose	O
+-	O
+dependent	O
+systemic	O
+beta	O
+-	O
+adrenoceptor	O
+responses	O
+.	O
+	
+The	O
+purpose	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+investigate	O
+whether	O
+tachyphylaxis	O
+occurs	O
+during	O
+prolonged	O
+treatment	O
+with	O
+high	O
+dose	O
+inhaled	O
+salbutamol	O
+.	O
+	
+Twelve	O
+asthmatic	B-NP
+patients	O
+(	O
+FEV1	O
+","	O
+81	O
++	O
+/	O
+-	O
+4	O
+%	O
+predicted	O
+)	O
+","	O
+requiring	O
+only	O
+occasional	O
+inhaled	O
+beta	O
+-	O
+agonists	O
+as	O
+their	O
+sole	O
+therapy	O
+","	O
+were	O
+given	O
+a	O
+14	O
+-	O
+day	O
+treatment	O
+with	O
+high	O
+dose	O
+inhaled	O
+salbutamol	O
+(	O
+HDS	O
+)	O
+","	O
+4	O
+","	O
+0	O
+micrograms	O
+daily	O
+","	O
+low	O
+dose	O
+inhaled	O
+salbutamol	O
+(	O
+LDS	O
+)	O
+","	O
+800	O
+micrograms	O
+daily	O
+","	O
+or	O
+placebo	O
+(	O
+PI	O
+)	O
+by	O
+metered	O
+-	O
+dose	O
+inhaler	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+","	O
+randomized	O
+crossover	O
+design	O
+.	O
+	
+During	O
+the	O
+14	O
+-	O
+day	O
+run	O
+-	O
+in	O
+and	O
+during	O
+washout	O
+periods	O
+","	O
+inhaled	O
+beta	O
+-	O
+agonists	O
+were	O
+withheld	O
+and	O
+ipratropium	O
+bromide	O
+was	O
+substituted	O
+for	O
+rescue	O
+purposes	O
+.	O
+	
+At	O
+the	O
+end	O
+of	O
+each	O
+14	O
+-	O
+day	O
+treatment	O
+","	O
+a	O
+dose	O
+-	O
+response	O
+curve	O
+(	O
+DRC	O
+)	O
+was	O
+performed	O
+","	O
+and	O
+airway	O
+(	O
+FEV1	O
+","	O
+FEF25	O
+-	O
+75	O
+)	O
+chronotropic	O
+(	O
+HR	O
+)	O
+","	O
+tremor	B-NP
+","	O
+and	O
+metabolic	O
+(	O
+K	O
+","	O
+Glu	O
+)	O
+responses	O
+were	O
+measured	O
+at	O
+each	O
+step	O
+(	O
+from	O
+100	O
+to	O
+4	O
+","	O
+0	O
+micrograms	O
+)	O
+.	O
+	
+Treatment	O
+had	O
+no	O
+significant	O
+effect	O
+on	O
+baseline	O
+values	O
+.	O
+	
+There	O
+were	O
+dose	O
+-	O
+dependent	O
+increases	O
+in	O
+FEV1	O
+and	O
+FEF25	O
+-	O
+75	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+and	O
+pretreatment	O
+with	O
+HDS	O
+did	O
+not	O
+displace	O
+the	O
+DRC	O
+to	O
+the	O
+right	O
+.	O
+	
+DRC	O
+for	O
+HR	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+K	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+and	O
+Glu	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+were	O
+attenuated	O
+after	O
+treatment	O
+with	O
+HDS	O
+compared	O
+with	O
+PI	O
+.	O
+	
+There	O
+were	O
+also	O
+differences	O
+between	O
+HDS	O
+and	O
+LDS	O
+for	O
+HR	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+and	O
+Glu	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+responses	O
+.	O
+	
+Frequency	O
+and	O
+severity	O
+of	O
+subjective	O
+adverse	O
+effects	O
+were	O
+also	O
+reduced	O
+after	O
+HDS	O
+:	O
+tremor	B-NP
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+palpitations	B-NP
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+	
+Phenytoin	O
+induced	O
+fatal	O
+hepatic	B-NP
+injury	I-NP
+.	O
+	
+A	O
+61	O
+year	O
+old	O
+female	O
+developed	O
+fatal	O
+hepatic	B-NP
+failure	I-NP
+after	O
+phenytoin	O
+administration	O
+.	O
+	
+A	O
+typical	O
+multisystem	O
+clinical	O
+pattern	O
+precedes	O
+the	O
+manifestations	O
+of	O
+hepatic	B-NP
+injury	I-NP
+.	O
+	
+The	O
+hematologic	O
+","	O
+biochemical	O
+and	O
+pathologic	O
+features	O
+indicate	O
+a	O
+mixed	O
+hepatocellular	B-NP
+damage	I-NP
+due	O
+to	O
+drug	B-NP
+hypersensitivity	I-NP
+.	O
+	
+In	O
+a	O
+patient	O
+receiving	O
+phenytoin	O
+who	O
+presents	O
+a	O
+viral	O
+-	O
+like	O
+illness	O
+","	O
+early	O
+recognition	O
+and	O
+discontinuation	O
+of	O
+the	O
+drug	O
+are	O
+mandatory	O
+.	O
+	
+Treatment	O
+of	O
+lethal	O
+pertussis	O
+vaccine	O
+reaction	O
+with	O
+histamine	O
+H1	O
+antagonists	O
+.	O
+	
+We	O
+studied	O
+mortality	O
+after	O
+pertussis	B-NP
+immunization	O
+in	O
+the	O
+mouse	O
+.	O
+	
+Without	O
+treatment	O
+","	O
+73	O
+of	O
+92	O
+animals	O
+(	O
+80	O
+%	O
+)	O
+died	O
+after	O
+injection	O
+of	O
+bovine	O
+serum	O
+albumin	O
+(	O
+BSA	O
+)	O
+on	O
+day	O
++	O
+7	O
+of	O
+pertussis	B-NP
+immunization	O
+.	O
+	
+After	O
+pretreatment	O
+with	O
+3	O
+mg	O
+of	O
+cyproheptadine	O
+","	O
+2	O
+mg	O
+mianserin	O
+","	O
+or	O
+2	O
+mg	O
+chlorpheniramine	O
+","	O
+only	O
+5	O
+of	O
+105	O
+animals	O
+(	O
+5	O
+%	O
+)	O
+died	O
+after	O
+receiving	O
+BSA	O
+on	O
+day	O
++	O
+7	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Blockade	O
+of	O
+histamine	O
+H1	O
+receptors	O
+may	O
+reduce	O
+mortality	O
+in	O
+pertussis	B-NP
+immunization	O
+-	O
+induced	O
+encephalopathy	B-NP
+in	O
+mice	O
+.	O
+	
+Support	O
+for	O
+adrenaline	O
+-	O
+hypertension	B-NP
+hypothesis	O
+:	O
+18	O
+hour	O
+pressor	O
+effect	O
+after	O
+6	O
+hours	O
+adrenaline	O
+infusion	O
+.	O
+	
+In	O
+a	O
+double	O
+blind	O
+","	O
+crossover	O
+study	O
+6	O
+h	O
+infusions	O
+of	O
+adrenaline	O
+(	O
+15	O
+ng	O
+/	O
+kg	O
+/	O
+min	O
+;	O
+1	O
+ng	O
+=	O
+5	O
+.	O
+458	O
+pmol	O
+)	O
+","	O
+noradrenaline	O
+(	O
+30	O
+ng	O
+/	O
+kg	O
+/	O
+min	O
+;	O
+1	O
+ng	O
+=	O
+5	O
+.	O
+911	O
+pmol	O
+)	O
+","	O
+and	O
+a	O
+5	O
+%	O
+dextrose	O
+solution	O
+(	O
+5	O
+.	O
+4	O
+ml	O
+/	O
+h	O
+)	O
+","	O
+were	O
+given	O
+to	O
+ten	O
+healthy	O
+volunteers	O
+in	O
+random	O
+order	O
+2	O
+weeks	O
+apart	O
+.	O
+	
+By	O
+means	O
+of	O
+intra	O
+-	O
+arterial	O
+ambulatory	O
+monitoring	O
+the	O
+haemodynamic	O
+effects	O
+were	O
+followed	O
+for	O
+18	O
+h	O
+after	O
+the	O
+infusions	O
+were	O
+stopped	O
+.	O
+	
+Adrenaline	O
+","	O
+but	O
+not	O
+noradrenaline	O
+","	O
+caused	O
+a	O
+delayed	O
+and	O
+protracted	O
+pressor	O
+effect	O
+.	O
+	
+Over	O
+the	O
+total	O
+postinfusion	O
+period	O
+systolic	O
+and	O
+diastolic	O
+arterial	O
+pressure	O
+were	O
+6	O
+(	O
+SEM	O
+2	O
+)	O
+%	O
+and	O
+7	O
+(	O
+2	O
+)	O
+%	O
+","	O
+respectively	O
+","	O
+higher	O
+than	O
+after	O
+dextrose	O
+infusion	O
+(	O
+ANOVA	O
+","	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Thus	O
+","	O
+"	O
+stress	O
+"	O
+levels	O
+of	O
+adrenaline	O
+(	O
+230	O
+pg	O
+/	O
+ml	O
+)	O
+for	O
+6	O
+h	O
+cause	O
+a	O
+delayed	O
+and	O
+protracted	O
+pressor	O
+effect	O
+.	O
+	
+These	O
+findings	O
+are	O
+strong	O
+support	O
+for	O
+the	O
+adrenaline	O
+-	O
+hypertension	B-NP
+hypothesis	O
+in	O
+man	O
+.	O
+	
+Effect	O
+of	O
+alkylxanthines	O
+on	O
+gentamicin	O
+-	O
+induced	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+in	O
+the	O
+rat	O
+.	O
+	
+Adenosine	O
+antagonists	O
+have	O
+been	O
+previously	O
+shown	O
+to	O
+be	O
+of	O
+benefit	O
+in	O
+some	O
+ischaemic	B-NP
+and	O
+nephrotoxic	B-NP
+models	O
+of	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+(	O
+ARF	B-NP
+)	O
+.	O
+	
+In	O
+the	O
+present	O
+study	O
+","	O
+the	O
+effects	O
+of	O
+three	O
+alkylxanthines	O
+with	O
+different	O
+potencies	O
+as	O
+adenosine	O
+antagonists	O
+8	O
+-	O
+phenyltheophylline	O
+","	O
+theophylline	O
+and	O
+enprofylline	O
+","	O
+were	O
+examined	O
+in	O
+rats	O
+developing	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+after	O
+4	O
+daily	O
+injections	O
+of	O
+gentamicin	O
+(	O
+200	O
+mg	O
+kg	O
+-	O
+1	O
+)	O
+.	O
+	
+Renal	O
+function	O
+was	O
+assessed	O
+by	O
+biochemical	O
+(	O
+plasma	O
+urea	O
+and	O
+creatinine	O
+)	O
+","	O
+functional	O
+(	O
+urine	O
+analysis	O
+and	O
+[	O
+3H	O
+]	O
+inulin	O
+and	O
+[	O
+14C	O
+]	O
+p	O
+-	O
+aminohippuric	O
+acid	O
+clearances	O
+)	O
+and	O
+morphological	O
+(	O
+degree	O
+of	O
+necrosis	B-NP
+)	O
+indices	O
+.	O
+	
+The	O
+various	O
+drug	O
+treatments	O
+produced	O
+improvements	O
+in	O
+some	O
+","	O
+but	O
+not	O
+all	O
+","	O
+measurements	O
+of	O
+renal	O
+function	O
+.	O
+	
+However	O
+","	O
+any	O
+improvement	O
+produced	O
+by	O
+drug	O
+treatment	O
+was	O
+largely	O
+a	O
+result	O
+of	O
+a	O
+beneficial	O
+effect	O
+exerted	O
+by	O
+its	O
+vehicle	O
+(	O
+polyethylene	O
+glycol	O
+and	O
+NaOH	O
+)	O
+.	O
+	
+The	O
+lack	O
+of	O
+any	O
+consistent	O
+protective	O
+effect	O
+noted	O
+with	O
+the	O
+alkylxanthines	O
+tested	O
+in	O
+the	O
+present	O
+study	O
+indicates	O
+that	O
+adenosine	O
+plays	O
+little	O
+","	O
+if	O
+any	O
+","	O
+pathophysiological	O
+role	O
+in	O
+gentamicin	O
+-	O
+induced	O
+ARF	B-NP
+.	O
+	
+Adverse	O
+ocular	O
+reactions	O
+possibly	O
+associated	O
+with	O
+isotretinoin	O
+.	O
+	
+A	O
+total	O
+of	O
+261	O
+adverse	O
+ocular	O
+reactions	O
+occurred	O
+in	O
+237	O
+patients	O
+who	O
+received	O
+isotretinoin	O
+","	O
+a	O
+commonly	O
+used	O
+drug	O
+in	O
+the	O
+treatment	O
+of	O
+severe	O
+cystic	O
+acne	B-NP
+.	O
+	
+Blepharoconjunctivitis	B-NP
+","	O
+subjective	O
+complaints	O
+of	O
+dry	B-NP
+eyes	I-NP
+","	O
+blurred	B-NP
+vision	I-NP
+","	O
+contact	O
+lens	O
+intolerance	O
+","	O
+and	O
+photodermatitis	B-NP
+are	O
+reversible	O
+side	O
+effects	O
+.	O
+	
+More	O
+serious	O
+ocular	O
+adverse	O
+reactions	O
+include	O
+papilledema	B-NP
+","	O
+pseudotumor	B-NP
+cerebri	I-NP
+","	O
+and	O
+white	O
+or	O
+gray	O
+subepithelial	O
+corneal	B-NP
+opacities	I-NP
+;	O
+all	O
+of	O
+these	O
+are	O
+reversible	O
+if	O
+the	O
+drug	O
+is	O
+discontinued	O
+.	O
+	
+Reported	O
+cases	O
+of	O
+decreased	O
+dark	O
+adaptation	O
+are	O
+under	O
+investigation	O
+.	O
+	
+Isotretinoin	O
+is	O
+contraindicated	O
+in	O
+pregnancy	O
+because	O
+of	O
+the	O
+many	O
+reported	O
+congenital	B-NP
+abnormalities	I-NP
+after	O
+maternal	O
+use	O
+(	O
+including	O
+microphthalmos	B-NP
+","	O
+orbital	O
+hypertelorism	B-NP
+","	O
+and	O
+optic	B-NP
+nerve	I-NP
+hypoplasia	I-NP
+)	O
+.	O
+	
+Procaterol	O
+and	O
+terbutaline	O
+in	O
+bronchial	B-NP
+asthma	I-NP
+.	O
+	
+A	O
+double	O
+-	O
+blind	O
+","	O
+placebo	O
+-	O
+controlled	O
+","	O
+cross	O
+-	O
+over	O
+study	O
+.	O
+	
+Procaterol	O
+","	O
+a	O
+new	O
+beta	O
+-	O
+2	O
+adrenoceptor	O
+stimulant	O
+","	O
+was	O
+studied	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+","	O
+placebo	O
+-	O
+controlled	O
+","	O
+cross	O
+-	O
+over	O
+trial	O
+in	O
+patients	O
+with	O
+bronchial	B-NP
+asthma	I-NP
+.	O
+	
+Oral	O
+procaterol	O
+50	O
+micrograms	O
+b	O
+.	O
+d	O
+.	O
+","	O
+procaterol	O
+100	O
+micrograms	O
+b	O
+.	O
+d	O
+.	O
+","	O
+and	O
+terbutaline	O
+5	O
+mg	O
+t	O
+.	O
+i	O
+.	O
+d	O
+.	O
+","	O
+were	O
+compared	O
+when	O
+given	O
+randomly	O
+in	O
+1	O
+-	O
+week	O
+treatment	O
+periods	O
+.	O
+	
+The	O
+best	O
+clinical	O
+effect	O
+was	O
+found	O
+with	O
+terbutaline	O
+.	O
+	
+Both	O
+anti	O
+-	O
+asthmatic	B-NP
+and	O
+tremorgenic	B-NP
+effects	O
+of	O
+procaterol	O
+were	O
+dose	O
+-	O
+related	O
+.	O
+	
+Procaterol	O
+appeared	O
+effective	O
+in	O
+the	O
+doses	O
+tested	O
+","	O
+and	O
+a	O
+twice	O
+daily	O
+regimen	O
+would	O
+appear	O
+to	O
+be	O
+suitable	O
+with	O
+this	O
+drug	O
+.	O
+	
+Subacute	O
+effects	O
+of	O
+propranolol	O
+and	O
+B	O
+24	O
+/	O
+76	O
+on	O
+isoproterenol	O
+-	O
+induced	O
+rat	O
+heart	B-NP
+hypertrophy	I-NP
+in	O
+correlation	O
+with	O
+blood	O
+pressure	O
+.	O
+	
+We	O
+compared	O
+the	O
+potential	O
+beta	O
+-	O
+receptor	O
+blocker	O
+","	O
+B	O
+24	O
+/	O
+76	O
+i	O
+.	O
+e	O
+.	O
+1	O
+-	O
+(	O
+2	O
+","	O
+4	O
+-	O
+dichlorophenoxy	O
+)	O
+-	O
+3	O
+[	O
+2	O
+-	O
+3	O
+","	O
+4	O
+-	O
+dimethoxyphenyl	O
+)	O
+ethanolamino	O
+]	O
+-	O
+prop	O
+an	O
+-	O
+2	O
+-	O
+ol	O
+","	O
+which	O
+is	O
+characterized	O
+by	O
+beta	O
+1	O
+-	O
+adrenoceptor	O
+blocking	O
+and	O
+beta	O
+2	O
+-	O
+adrenoceptor	O
+stimulating	O
+properties	O
+with	O
+propranolol	O
+.	O
+	
+The	O
+studies	O
+were	O
+performed	O
+using	O
+an	O
+experimental	O
+model	O
+of	O
+isoproterenol	O
+-	O
+induced	O
+heart	B-NP
+hypertrophy	I-NP
+in	O
+rats	O
+.	O
+	
+A	O
+correlation	O
+of	O
+the	O
+blood	O
+pressure	O
+was	O
+neither	O
+found	O
+in	O
+the	O
+development	O
+nor	O
+in	O
+the	O
+attempt	O
+to	O
+suppress	O
+the	O
+development	O
+of	O
+heart	B-NP
+hypertrophy	I-NP
+with	O
+the	O
+two	O
+beta	O
+-	O
+receptor	O
+blockers	O
+.	O
+	
+Both	O
+beta	O
+-	O
+blockers	O
+influenced	O
+the	O
+development	O
+of	O
+hypertrophy	B-NP
+to	O
+a	O
+different	O
+","	O
+but	O
+not	O
+reproducible	O
+extent	O
+.	O
+	
+It	O
+was	O
+possible	O
+to	O
+suppress	O
+the	O
+increased	O
+ornithine	O
+decarboxylase	O
+activity	O
+with	O
+both	O
+beta	O
+-	O
+blockers	O
+in	O
+hypertrophied	B-NP
+hearts	I-NP
+","	O
+but	O
+there	O
+was	O
+no	O
+effect	O
+on	O
+the	O
+heart	O
+mass	O
+.	O
+	
+Neither	O
+propranolol	O
+nor	O
+B	O
+24	O
+/	O
+76	O
+could	O
+stop	O
+the	O
+changes	O
+in	O
+the	O
+characteristic	O
+myosin	O
+isoenzyme	O
+pattern	O
+of	O
+the	O
+hypertrophied	B-NP
+rat	O
+heart	O
+.	O
+	
+Thus	O
+","	O
+the	O
+investigations	O
+did	O
+not	O
+provide	O
+any	O
+evidence	O
+that	O
+the	O
+beta	O
+-	O
+receptor	O
+blockers	O
+propranolol	O
+and	O
+B	O
+24	O
+/	O
+76	O
+have	O
+the	O
+potency	O
+to	O
+prevent	O
+isoproterenol	O
+from	O
+producing	O
+heart	B-NP
+hypertrophy	I-NP
+.	O
+	
+Increased	O
+anxiogenic	O
+effects	O
+of	O
+caffeine	O
+in	O
+panic	B-NP
+disorders	I-NP
+.	O
+	
+The	O
+effects	O
+of	O
+oral	O
+administration	O
+of	O
+caffeine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+on	O
+behavioral	O
+ratings	O
+","	O
+somatic	O
+symptoms	O
+","	O
+blood	O
+pressure	O
+and	O
+plasma	O
+levels	O
+of	O
+3	O
+-	O
+methoxy	O
+-	O
+4	O
+-	O
+hydroxyphenethyleneglycol	O
+(	O
+MHPG	O
+)	O
+and	O
+cortisol	O
+were	O
+determined	O
+in	O
+17	O
+healthy	O
+subjects	O
+and	O
+21	O
+patients	O
+meeting	O
+DSM	O
+-	O
+III	O
+criteria	O
+for	O
+agoraphobia	B-NP
+with	O
+panic	B-NP
+attacks	I-NP
+or	O
+panic	B-NP
+disorder	I-NP
+.	O
+	
+Caffeine	O
+produced	O
+significantly	O
+greater	O
+increases	O
+in	O
+subject	O
+-	O
+rated	O
+anxiety	B-NP
+","	O
+nervousness	O
+","	O
+fear	O
+","	O
+nausea	B-NP
+","	O
+palpitations	B-NP
+","	O
+restlessness	B-NP
+","	O
+and	O
+tremors	B-NP
+in	O
+the	O
+patients	O
+compared	O
+with	O
+healthy	O
+subjects	O
+.	O
+	
+In	O
+the	O
+patients	O
+","	O
+but	O
+not	O
+the	O
+healthy	O
+subjects	O
+","	O
+these	O
+symptoms	O
+were	O
+significantly	O
+correlated	O
+with	O
+plasma	O
+caffeine	O
+levels	O
+.	O
+	
+Seventy	O
+-	O
+one	O
+percent	O
+of	O
+the	O
+patients	O
+reported	O
+that	O
+the	O
+behavioral	O
+effects	O
+of	O
+caffeine	O
+were	O
+similar	O
+to	O
+those	O
+experienced	O
+during	O
+panic	B-NP
+attacks	I-NP
+.	O
+	
+Caffeine	O
+did	O
+not	O
+alter	O
+plasma	O
+MHPG	O
+levels	O
+in	O
+either	O
+the	O
+healthy	O
+subjects	O
+or	O
+patients	O
+.	O
+	
+Caffeine	O
+increased	O
+plasma	O
+cortisol	O
+levels	O
+equally	O
+in	O
+the	O
+patient	O
+and	O
+healthy	O
+groups	O
+.	O
+	
+Because	O
+caffeine	O
+is	O
+an	O
+adenosine	O
+receptor	O
+antagonist	O
+","	O
+these	O
+results	O
+suggest	O
+that	O
+some	O
+panic	B-NP
+disorder	I-NP
+patients	O
+may	O
+have	O
+abnormalities	B-NP
+in	I-NP
+neuronal	I-NP
+systems	I-NP
+involving	O
+adenosine	O
+.	O
+	
+Patients	O
+with	O
+anxiety	B-NP
+disorders	I-NP
+may	O
+benefit	O
+by	O
+avoiding	O
+caffeine	O
+-	O
+containing	O
+foods	O
+and	O
+beverages	O
+.	O
+	
+Comparison	O
+of	O
+the	O
+effect	O
+of	O
+oxitropium	O
+bromide	O
+and	O
+of	O
+slow	O
+-	O
+release	O
+theophylline	O
+on	O
+nocturnal	O
+asthma	B-NP
+.	O
+	
+The	O
+effects	O
+of	O
+a	O
+new	O
+inhaled	O
+antimuscarinic	O
+drug	O
+","	O
+oxitropium	O
+bromide	O
+","	O
+and	O
+of	O
+a	O
+slow	O
+-	O
+release	O
+theophylline	O
+preparation	O
+upon	O
+nocturnal	O
+asthma	B-NP
+were	O
+compared	O
+in	O
+a	O
+placebo	O
+-	O
+controlled	O
+double	O
+-	O
+blind	O
+study	O
+.	O
+	
+Two	O
+samples	O
+were	O
+studied	O
+:	O
+12	O
+patients	O
+received	O
+oxitropium	O
+at	O
+600	O
+micrograms	O
+(	O
+6	O
+subjects	O
+)	O
+or	O
+at	O
+400	O
+micrograms	O
+t	O
+.	O
+i	O
+.	O
+d	O
+.	O
+	
+(	O
+6	O
+subjects	O
+)	O
+whereas	O
+11	O
+received	O
+theophylline	O
+at	O
+300	O
+mg	O
+b	O
+.	O
+i	O
+.	O
+d	O
+.	O
+	
+Morning	O
+dipping	O
+","	O
+assessed	O
+by	O
+the	O
+fall	O
+in	O
+peak	O
+flow	O
+overnight	O
+","	O
+was	O
+significantly	O
+reduced	O
+in	O
+the	O
+periods	O
+when	O
+either	O
+active	O
+drug	O
+was	O
+taken	O
+","	O
+whereas	O
+no	O
+difference	O
+was	O
+noticed	O
+during	O
+the	O
+placebo	O
+administration	O
+.	O
+	
+No	O
+significant	O
+difference	O
+was	O
+noticed	O
+between	O
+results	O
+obtained	O
+with	O
+either	O
+active	O
+drug	O
+","	O
+as	O
+well	O
+as	O
+with	O
+either	O
+dosage	O
+of	O
+oxitropium	O
+.	O
+	
+No	O
+subject	O
+reported	O
+side	O
+effects	O
+of	O
+oxitropium	O
+","	O
+as	O
+compared	O
+to	O
+three	O
+subjects	O
+reporting	O
+nausea	B-NP
+","	O
+vomiting	B-NP
+and	O
+tremors	B-NP
+after	O
+theophylline	O
+.	O
+	
+Oxitropium	O
+proves	O
+to	O
+be	O
+a	O
+valuable	O
+alternative	O
+to	O
+theophylline	O
+in	O
+nocturnal	O
+asthma	B-NP
+","	O
+since	O
+it	O
+is	O
+equally	O
+potent	O
+","	O
+safer	O
+and	O
+does	O
+not	O
+require	O
+the	O
+titration	O
+of	O
+dosage	O
+.	O
+	
+Penicillin	O
+anaphylaxis	B-NP
+.	O
+	
+A	O
+case	O
+of	O
+oral	O
+penicillin	O
+anaphylaxis	B-NP
+is	O
+described	O
+","	O
+and	O
+the	O
+terminology	O
+","	O
+occurrence	O
+","	O
+clinical	O
+manifestations	O
+","	O
+pathogenesis	O
+","	O
+prevention	O
+","	O
+and	O
+treatment	O
+of	O
+anaphylaxis	B-NP
+are	O
+reviewed	O
+.	O
+	
+Emergency	O
+physicians	O
+should	O
+be	O
+aware	O
+of	O
+oral	O
+penicillin	O
+anaphylaxis	B-NP
+in	O
+order	O
+to	O
+prevent	O
+its	O
+occurrence	O
+by	O
+prescribing	O
+the	O
+antibiotic	O
+judiciously	O
+and	O
+knowledgeably	O
+and	O
+to	O
+offer	O
+optimal	O
+medical	O
+therapy	O
+once	O
+this	O
+life	O
+-	O
+threatening	O
+reaction	O
+has	O
+begun	O
+.	O
+	
+Reversible	O
+valproic	O
+acid	O
+-	O
+induced	O
+dementia	B-NP
+:	O
+a	O
+case	O
+report	O
+.	O
+	
+Reversible	O
+valproic	O
+acid	O
+-	O
+induced	O
+dementia	B-NP
+was	O
+documented	O
+in	O
+a	O
+21	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+epilepsy	B-NP
+who	O
+had	O
+a	O
+3	O
+-	O
+year	O
+history	O
+of	O
+insidious	O
+progressive	O
+decline	O
+in	O
+global	O
+cognitive	O
+abilities	O
+documented	O
+by	O
+serial	O
+neuropsychological	O
+studies	O
+.	O
+	
+Repeat	O
+neuropsychological	O
+testing	O
+7	O
+weeks	O
+after	O
+discontinuation	O
+of	O
+the	O
+drug	O
+revealed	O
+dramatic	O
+improvement	O
+in	O
+IQ	O
+","	O
+memory	O
+","	O
+naming	O
+","	O
+and	O
+other	O
+tasks	O
+commensurate	O
+with	O
+clinical	O
+recovery	O
+in	O
+his	O
+intellectual	O
+capacity	O
+.	O
+	
+Possible	O
+pathophysiological	O
+mechanisms	O
+which	O
+may	O
+have	O
+been	O
+operative	O
+in	O
+this	O
+case	O
+include	O
+:	O
+a	O
+direct	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+toxic	O
+effect	O
+of	O
+valproic	O
+acid	O
+;	O
+a	O
+paradoxical	O
+epileptogenic	O
+effect	O
+secondary	O
+to	O
+the	O
+drug	O
+;	O
+and	O
+an	O
+indirect	O
+CNS	O
+toxic	O
+effect	O
+mediated	O
+through	O
+valproic	O
+acid	O
+-	O
+induced	O
+hyperammonemia	B-NP
+.	O
+	
+Reversal	O
+of	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B-NP
+of	O
+passive	O
+avoidance	O
+by	O
+pre	O
+-	O
+and	O
+post	O
+-	O
+training	O
+naloxone	O
+.	O
+	
+In	O
+a	O
+series	O
+of	O
+five	O
+experiments	O
+","	O
+the	O
+modulating	O
+role	O
+of	O
+naloxone	O
+on	O
+a	O
+scopolamine	O
+-	O
+induced	O
+retention	B-NP
+deficit	I-NP
+in	O
+a	O
+passive	O
+avoidance	O
+paradigm	O
+was	O
+investigated	O
+in	O
+mice	O
+.	O
+	
+Scopolamine	O
+","	O
+but	O
+not	O
+methyl	O
+scopolamine	O
+(	O
+1	O
+and	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+","	O
+induced	O
+an	O
+amnesia	B-NP
+as	O
+measured	O
+by	O
+latency	O
+and	O
+duration	O
+parameters	O
+.	O
+	
+Naloxone	O
+(	O
+0	O
+.	O
+3	O
+","	O
+1	O
+","	O
+3	O
+","	O
+and	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+injected	O
+prior	O
+to	O
+training	O
+attenuated	O
+the	O
+retention	B-NP
+deficit	I-NP
+with	O
+a	O
+peak	O
+of	O
+activity	O
+at	O
+3	O
+mg	O
+/	O
+kg	O
+.	O
+	
+The	O
+effect	O
+of	O
+naloxone	O
+could	O
+be	O
+antagonized	O
+with	O
+morphine	O
+(	O
+1	O
+","	O
+3	O
+","	O
+and	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+","	O
+demonstrating	O
+the	O
+opioid	O
+specificity	O
+of	O
+the	O
+naloxone	O
+effect	O
+.	O
+	
+Post	O
+-	O
+training	O
+administration	O
+of	O
+naloxone	O
+(	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+as	O
+a	O
+single	O
+or	O
+as	O
+a	O
+split	O
+dose	O
+also	O
+attenuated	O
+the	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B-NP
+.	O
+	
+Control	O
+experiments	O
+indicated	O
+that	O
+neither	O
+an	O
+increase	O
+in	O
+pain	B-NP
+sensitivity	O
+(	O
+pre	O
+-	O
+training	O
+naloxone	O
+)	O
+nor	O
+an	O
+induced	O
+aversive	O
+state	O
+(	O
+post	O
+-	O
+training	O
+naloxone	O
+)	O
+appear	O
+to	O
+be	O
+responsible	O
+for	O
+the	O
+influence	O
+of	O
+naloxone	O
+on	O
+the	O
+scopolamine	O
+-	O
+induced	O
+retention	B-NP
+deficit	I-NP
+.	O
+	
+These	O
+results	O
+extend	O
+previous	O
+findings	O
+implicating	O
+a	O
+cholinergic	O
+-	O
+opioid	O
+interaction	O
+in	O
+memory	O
+processes	O
+.	O
+	
+A	O
+possible	O
+mechanism	O
+for	O
+this	O
+interaction	O
+involving	O
+the	O
+septo	O
+-	O
+hippocampal	O
+cholinergic	O
+pathway	O
+is	O
+discussed	O
+.	O
+	
+Electron	O
+microscopic	O
+investigations	O
+of	O
+the	O
+cyclophosphamide	O
+-	O
+induced	O
+lesions	B-NP
+of	I-NP
+the	I-NP
+urinary	I-NP
+bladder	I-NP
+of	O
+the	O
+rat	O
+and	O
+their	O
+prevention	O
+by	O
+mesna	O
+.	O
+	
+Fully	O
+developed	O
+cyclophosphamide	O
+-	O
+induced	O
+cystitis	B-NP
+is	O
+characterized	O
+by	O
+nearly	O
+complete	O
+detachment	O
+of	O
+the	O
+urothelium	O
+","	O
+severe	O
+submucosal	O
+edema	B-NP
+owing	O
+to	O
+damage	O
+to	O
+the	O
+microvascular	O
+bed	O
+and	O
+focal	O
+muscle	O
+necroses	B-NP
+.	O
+	
+The	O
+initial	O
+response	O
+to	O
+the	O
+primary	O
+attack	O
+by	O
+the	O
+cyclophosphamide	O
+metabolites	O
+seems	O
+to	O
+be	O
+fragmentation	O
+of	O
+the	O
+luminal	O
+membrane	O
+.	O
+	
+This	O
+damages	O
+the	O
+cellular	O
+barrier	O
+against	O
+the	O
+hypertonic	O
+urine	O
+.	O
+	
+Subsequent	O
+breaks	O
+in	O
+the	O
+lateral	O
+cell	O
+membranes	O
+of	O
+the	O
+superficial	O
+cells	O
+and	O
+in	O
+all	O
+the	O
+plasma	O
+membranes	O
+of	O
+the	O
+intermediate	O
+and	O
+basal	O
+cells	O
+","	O
+intercellular	O
+and	O
+intracellular	O
+edema	B-NP
+and	O
+disintegration	O
+of	O
+the	O
+desmosomes	O
+and	O
+hemidesmosomes	O
+lead	O
+to	O
+progressive	O
+degeneration	O
+and	O
+detachment	O
+of	O
+the	O
+epithelial	O
+cells	O
+with	O
+exposure	O
+and	O
+splitting	O
+of	O
+the	O
+basal	O
+membrane	O
+.	O
+	
+The	O
+morphological	O
+changes	O
+of	O
+the	O
+endothelial	O
+cells	O
+","	O
+which	O
+become	O
+more	O
+pronounced	O
+in	O
+the	O
+later	O
+stages	O
+of	O
+the	O
+experiment	O
+","	O
+the	O
+involvement	O
+of	O
+blood	O
+vessels	O
+regardless	O
+of	O
+their	O
+diameter	O
+and	O
+the	O
+location	O
+-	O
+dependent	O
+extent	O
+of	O
+the	O
+damage	O
+indicate	O
+a	O
+direct	O
+type	O
+of	O
+damage	O
+which	O
+is	O
+preceded	O
+by	O
+a	O
+mediator	O
+-	O
+induced	O
+increase	O
+in	O
+permeability	O
+","	O
+the	O
+morphological	O
+correlate	O
+of	O
+which	O
+is	O
+the	O
+formation	O
+of	O
+gaps	O
+in	O
+the	O
+interendothelial	O
+cell	O
+connections	O
+on	O
+the	O
+venules	O
+.	O
+	
+These	O
+changes	O
+can	O
+be	O
+effectively	O
+prevented	O
+by	O
+mesna	O
+.	O
+	
+The	O
+only	O
+sign	O
+of	O
+a	O
+possible	O
+involvement	O
+is	O
+the	O
+increase	O
+in	O
+the	O
+number	O
+of	O
+specific	O
+granules	O
+with	O
+a	O
+presumed	O
+lysosomal	O
+function	O
+in	O
+the	O
+superficial	O
+cells	O
+.	O
+	
+Increase	O
+in	O
+intragastric	O
+pressure	O
+during	O
+suxamethonium	O
+-	O
+induced	O
+muscle	B-NP
+fasciculations	I-NP
+in	O
+children	O
+:	O
+inhibition	O
+by	O
+alfentanil	O
+.	O
+	
+Changes	O
+in	O
+intragastric	O
+pressure	O
+after	O
+the	O
+administration	O
+of	O
+suxamethonium	O
+1	O
+.	O
+5	O
+mg	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+v	O
+.	O
+were	O
+studied	O
+in	O
+32	O
+children	O
+(	O
+mean	O
+age	O
+6	O
+.	O
+9	O
+yr	O
+)	O
+pretreated	O
+with	O
+either	O
+physiological	O
+saline	O
+or	O
+alfentanil	O
+50	O
+micrograms	O
+kg	O
+-	O
+1	O
+.	O
+	
+Anaesthesia	O
+was	O
+induced	O
+with	O
+thiopentone	O
+5	O
+mg	O
+kg	O
+-	O
+1	O
+.	O
+	
+The	O
+incidence	O
+and	O
+intensity	O
+of	O
+muscle	B-NP
+fasciculations	I-NP
+caused	O
+by	O
+suxamethonium	O
+were	O
+significantly	O
+greater	O
+in	O
+the	O
+control	O
+than	O
+in	O
+the	O
+alfentanil	O
+group	O
+.	O
+	
+The	O
+intragastric	O
+pressure	O
+during	O
+muscle	B-NP
+fasciculations	I-NP
+was	O
+significantly	O
+higher	O
+in	O
+the	O
+control	O
+group	O
+(	O
+16	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+(	O
+SEM	O
+)	O
+cm	O
+H2O	O
+)	O
+than	O
+in	O
+the	O
+alfentanil	O
+group	O
+(	O
+7	O
+.	O
+7	O
++	O
+/	O
+-	O
+1	O
+.	O
+5	O
+(	O
+SEM	O
+)	O
+cm	O
+H2O	O
+)	O
+.	O
+	
+The	O
+increase	O
+in	O
+intragastric	O
+pressure	O
+was	O
+directly	O
+related	O
+to	O
+the	O
+intensity	O
+of	O
+muscle	B-NP
+fasciculations	I-NP
+(	O
+regression	O
+line	O
+:	O
+y	O
+=	O
+0	O
+.	O
+5	O
++	O
+4	O
+.	O
+78x	O
+with	O
+r	O
+of	O
+0	O
+.	O
+78	O
+)	O
+.	O
+	
+It	O
+is	O
+concluded	O
+that	O
+intragastric	O
+pressure	O
+increases	O
+significantly	O
+during	O
+muscle	B-NP
+fasciculations	I-NP
+caused	O
+by	O
+suxamethonium	O
+in	O
+healthy	O
+children	O
+.	O
+	
+Alfentanil	O
+50	O
+micrograms	O
+kg	O
+-	O
+1	O
+effectively	O
+inhibits	O
+the	O
+incidence	O
+and	O
+intensity	O
+of	O
+suxamethonium	O
+-	O
+induced	O
+muscle	B-NP
+fasciculations	I-NP
+;	O
+moreover	O
+","	O
+intragastric	O
+pressure	O
+remains	O
+at	O
+its	O
+control	O
+value	O
+.	O
+	
+Acute	O
+insulin	O
+treatment	O
+normalizes	O
+the	O
+resistance	O
+to	O
+the	O
+cardiotoxic	B-NP
+effect	O
+of	O
+isoproterenol	O
+in	O
+streptozotocin	O
+diabetic	B-NP
+rats	O
+.	O
+	
+A	O
+morphometric	O
+study	O
+of	O
+isoproterenol	O
+induced	O
+myocardial	O
+fibrosis	B-NP
+.	O
+	
+The	O
+acute	O
+effect	O
+of	O
+insulin	O
+treatment	O
+on	O
+the	O
+earlier	O
+reported	O
+protective	O
+effect	O
+of	O
+streptozotocin	O
+diabetes	B-NP
+against	O
+the	O
+cardiotoxic	B-NP
+effect	O
+of	O
+high	O
+doses	O
+of	O
+isoproterenol	O
+(	O
+ISO	O
+)	O
+was	O
+investigated	O
+in	O
+rats	O
+.	O
+	
+Thirty	O
+to	O
+135	O
+min	O
+after	O
+the	O
+injection	O
+of	O
+crystalline	O
+insulin	O
+","	O
+ISO	O
+was	O
+given	O
+subcutaneously	O
+and	O
+when	O
+ISO	O
+induced	O
+fibrosis	B-NP
+in	O
+the	O
+myocardium	O
+was	O
+morphometrically	O
+analyzed	O
+7	O
+days	O
+later	O
+","	O
+a	O
+highly	O
+significant	O
+correlation	O
+(	O
+r	O
+=	O
+0	O
+.	O
+83	O
+","	O
+2	O
+p	O
+=	O
+0	O
+.	O
+6	O
+)	O
+to	O
+the	O
+slope	O
+of	O
+the	O
+fall	O
+in	O
+blood	O
+glucose	O
+after	O
+insulin	O
+treatment	O
+appeared	O
+.	O
+	
+The	O
+myocardial	O
+content	O
+of	O
+catecholamines	O
+was	O
+estimated	O
+in	O
+these	O
+8	O
+day	O
+diabetic	B-NP
+rats	O
+.	O
+	
+The	O
+norepinephrine	O
+content	O
+was	O
+significantly	O
+increased	O
+while	O
+epinephrine	O
+remained	O
+unchanged	O
+.	O
+	
+An	O
+enhanced	O
+sympathetic	O
+nervous	O
+system	O
+activity	O
+with	O
+a	O
+consequent	O
+down	O
+regulation	O
+of	O
+the	O
+myocardial	O
+beta	O
+-	O
+adrenergic	O
+receptors	O
+could	O
+","	O
+therefore	O
+","	O
+explain	O
+this	O
+catecholamine	O
+resistance	O
+.	O
+	
+The	O
+rapid	O
+reversion	O
+after	O
+insulin	O
+treatment	O
+excludes	O
+the	O
+possibility	O
+that	O
+streptozotocin	O
+in	O
+itself	O
+causes	O
+the	O
+ISO	O
+resistance	O
+and	O
+points	O
+towards	O
+a	O
+direct	O
+insulin	O
+effect	O
+on	O
+myocardial	O
+catecholamine	O
+sensitivity	O
+in	O
+diabetic	B-NP
+rats	O
+.	O
+	
+The	O
+phenomenon	O
+described	O
+might	O
+elucidate	O
+pathogenetic	O
+mechanisms	O
+behind	O
+toxic	O
+myocardial	O
+cell	O
+degeneration	O
+and	O
+may	O
+possibly	O
+have	O
+relevance	O
+for	O
+acute	O
+cardiovascular	O
+complications	O
+in	O
+diabetic	B-NP
+patients	O
+.	O
+	
+Differential	O
+effects	O
+of	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+on	O
+seizures	B-NP
+produced	O
+by	O
+pilocarpine	O
+in	O
+rats	O
+.	O
+	
+The	O
+muscarinic	O
+cholinergic	O
+agonist	O
+pilocarpine	O
+induces	O
+in	O
+rats	O
+seizures	B-NP
+and	O
+status	B-NP
+epilepticus	I-NP
+followed	O
+by	O
+widespread	O
+damage	O
+to	O
+the	O
+forebrain	O
+.	O
+	
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+investigate	O
+the	O
+effect	O
+of	O
+5	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+","	O
+sodium	O
+salicylate	O
+","	O
+phenylbutazone	O
+","	O
+indomethacin	O
+","	O
+ibuprofen	O
+and	O
+mefenamic	O
+acid	O
+","	O
+on	O
+seizures	B-NP
+produced	O
+by	O
+pilocarpine	O
+.	O
+	
+Pretreatment	O
+of	O
+rats	O
+with	O
+sodium	O
+salicylate	O
+","	O
+ED50	O
+103	O
+mg	O
+/	O
+kg	O
+(	O
+60	O
+-	O
+174	O
+)	O
+","	O
+and	O
+phenylbutazone	O
+","	O
+59	O
+mg	O
+/	O
+kg	O
+(	O
+50	O
+-	O
+70	O
+)	O
+converted	O
+the	O
+non	O
+-	O
+convulsant	O
+dose	O
+of	O
+pilocarpine	O
+","	O
+200	O
+mg	O
+/	O
+kg	O
+","	O
+to	O
+a	O
+convulsant	O
+one	O
+.	O
+	
+Indomethacin	O
+","	O
+1	O
+-	O
+10	O
+mg	O
+/	O
+kg	O
+","	O
+and	O
+ibuprofen	O
+","	O
+10	O
+-	O
+100	O
+mg	O
+/	O
+kg	O
+","	O
+failed	O
+to	O
+modulate	O
+seizures	B-NP
+produced	O
+by	O
+pilocarpine	O
+.	O
+	
+Mefenamic	O
+acid	O
+","	O
+26	O
+(	O
+22	O
+-	O
+30	O
+)	O
+mg	O
+/	O
+kg	O
+","	O
+prevented	O
+seizures	B-NP
+and	O
+protected	O
+rats	O
+from	O
+seizure	B-NP
+-	O
+related	O
+brain	B-NP
+damage	I-NP
+induced	O
+by	O
+pilocarpine	O
+","	O
+380	O
+mg	O
+/	O
+kg	O
+.	O
+	
+These	O
+results	O
+indicate	O
+that	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+differentially	O
+modulate	O
+the	O
+threshold	O
+for	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B-NP
+.	O
+	
+Acute	B-NP
+neurologic	I-NP
+dysfunction	I-NP
+after	O
+high	O
+-	O
+dose	O
+etoposide	O
+therapy	O
+for	O
+malignant	B-NP
+glioma	I-NP
+.	O
+	
+Etoposide	O
+(	O
+VP	O
+-	O
+16	O
+-	O
+213	O
+)	O
+has	O
+been	O
+used	O
+in	O
+the	O
+treatment	O
+of	O
+many	O
+solid	O
+tumors	B-NP
+and	O
+hematologic	B-NP
+malignancies	I-NP
+.	O
+	
+When	O
+used	O
+in	O
+high	O
+doses	O
+and	O
+in	O
+conjunction	O
+with	O
+autologous	O
+bone	O
+marrow	O
+transplantation	O
+","	O
+this	O
+agent	O
+has	O
+activity	O
+against	O
+several	O
+treatment	O
+-	O
+resistant	O
+cancers	B-NP
+including	O
+malignant	B-NP
+glioma	I-NP
+.	O
+	
+In	O
+six	O
+of	O
+eight	O
+patients	O
+(	O
+75	O
+%	O
+)	O
+who	O
+we	O
+treated	O
+for	O
+recurrent	O
+or	O
+resistant	O
+glioma	B-NP
+","	O
+sudden	O
+severe	O
+neurologic	B-NP
+deterioration	I-NP
+occurred	O
+.	O
+	
+This	O
+developed	O
+a	O
+median	O
+of	O
+9	O
+days	O
+after	O
+initiation	O
+of	O
+high	O
+-	O
+dose	O
+etoposide	O
+therapy	O
+.	O
+	
+Significant	O
+clinical	O
+manifestations	O
+have	O
+included	O
+confusion	B-NP
+","	O
+papilledema	B-NP
+","	O
+somnolence	B-NP
+","	O
+exacerbation	O
+of	O
+motor	B-NP
+deficits	I-NP
+","	O
+and	O
+sharp	O
+increase	O
+in	O
+seizure	B-NP
+activity	O
+.	O
+	
+These	O
+abnormalities	O
+resolved	O
+rapidly	O
+after	O
+initiation	O
+of	O
+high	O
+-	O
+dose	O
+intravenous	O
+dexamethasone	O
+therapy	O
+.	O
+	
+In	O
+all	O
+patients	O
+","	O
+computerized	O
+tomographic	O
+(	O
+CT	O
+)	O
+brain	O
+scans	O
+demonstrated	O
+stability	O
+in	O
+tumor	B-NP
+size	O
+and	O
+peritumor	O
+edema	B-NP
+when	O
+compared	O
+with	O
+pretransplant	O
+scans	O
+.	O
+	
+This	O
+complication	O
+appears	O
+to	O
+represent	O
+a	O
+significant	O
+new	O
+toxicity	B-NP
+of	O
+high	O
+-	O
+dose	O
+etoposide	O
+therapy	O
+for	O
+malignant	B-NP
+glioma	I-NP
+.	O
+	
+Progressive	O
+bile	B-NP
+duct	I-NP
+injury	I-NP
+after	O
+thiabendazole	O
+administration	O
+.	O
+	
+A	O
+27	O
+-	O
+yr	O
+-	O
+old	O
+man	O
+developed	O
+jaundice	B-NP
+2	O
+wk	O
+after	O
+exposure	O
+to	O
+thiabendazole	O
+.	O
+	
+Cholestasis	B-NP
+persisted	O
+for	O
+3	O
+yr	O
+","	O
+at	O
+which	O
+time	O
+a	O
+liver	O
+transplant	O
+was	O
+performed	O
+.	O
+	
+Two	O
+liver	O
+biopsy	O
+specimens	O
+and	O
+the	O
+hepatectomy	O
+specimen	O
+were	O
+remarkable	O
+for	O
+almost	O
+complete	O
+disappearance	O
+of	O
+interlobular	O
+bile	O
+ducts	O
+.	O
+	
+Prominent	O
+fibrosis	B-NP
+and	O
+hepatocellular	O
+regeneration	O
+were	O
+also	O
+present	O
+;	O
+however	O
+","	O
+the	O
+lobular	O
+architecture	O
+was	O
+preserved	O
+.	O
+	
+This	O
+case	O
+represents	O
+an	O
+example	O
+of	O
+"	O
+idiosyncratic	O
+"	O
+drug	B-NP
+-	I-NP
+induced	I-NP
+liver	I-NP
+damage	I-NP
+in	O
+which	O
+the	O
+primary	O
+target	O
+of	O
+injury	O
+is	O
+the	O
+bile	O
+duct	O
+.	O
+	
+An	O
+autoimmune	O
+pathogenesis	O
+of	O
+the	O
+bile	B-NP
+duct	I-NP
+destruction	I-NP
+is	O
+suggested	O
+.	O
+	
+Differential	O
+effects	O
+of	O
+1	O
+","	O
+4	O
+-	O
+dihydropyridine	O
+calcium	O
+channel	O
+blockers	O
+:	O
+therapeutic	O
+implications	O
+.	O
+	
+Increasing	O
+recognition	O
+of	O
+the	O
+importance	O
+of	O
+calcium	O
+in	O
+the	O
+pathogenesis	O
+of	O
+cardiovascular	B-NP
+disease	I-NP
+has	O
+stimulated	O
+research	O
+into	O
+the	O
+use	O
+of	O
+calcium	O
+channel	O
+blocking	O
+agents	O
+for	O
+treatment	O
+of	O
+a	O
+variety	O
+of	O
+cardiovascular	B-NP
+diseases	I-NP
+.	O
+	
+The	O
+favorable	O
+efficacy	O
+and	O
+tolerability	O
+profiles	O
+of	O
+these	O
+agents	O
+make	O
+them	O
+attractive	O
+therapeutic	O
+modalities	O
+.	O
+	
+Clinical	O
+applications	O
+of	O
+calcium	O
+channel	O
+blockers	O
+parallel	O
+their	O
+tissue	O
+selectivity	O
+.	O
+	
+In	O
+contrast	O
+to	O
+verapamil	O
+and	O
+diltiazem	O
+","	O
+which	O
+are	O
+roughly	O
+equipotent	O
+in	O
+their	O
+actions	O
+on	O
+the	O
+heart	O
+and	O
+vascular	O
+smooth	O
+muscle	O
+","	O
+the	O
+dihydropyridine	O
+calcium	O
+channel	O
+blockers	O
+are	O
+a	O
+group	O
+of	O
+potent	O
+peripheral	O
+vasodilator	O
+agents	O
+that	O
+exert	O
+minimal	O
+electrophysiologic	O
+effects	O
+on	O
+cardiac	O
+nodal	O
+or	O
+conduction	O
+tissue	O
+.	O
+	
+As	O
+the	O
+first	O
+dihydropyridine	O
+available	O
+for	O
+use	O
+in	O
+the	O
+United	O
+States	O
+","	O
+nifedipine	O
+controls	O
+angina	B-NP
+and	O
+hypertension	B-NP
+with	O
+minimal	O
+depression	O
+of	O
+cardiac	O
+function	O
+.	O
+	
+Additional	O
+members	O
+of	O
+this	O
+group	O
+of	O
+calcium	O
+channel	O
+blockers	O
+have	O
+been	O
+studied	O
+for	O
+a	O
+variety	O
+of	O
+indications	O
+for	O
+which	O
+they	O
+may	O
+offer	O
+advantages	O
+over	O
+current	O
+therapy	O
+.	O
+	
+Once	O
+or	O
+twice	O
+daily	O
+dosage	O
+possible	O
+with	O
+nitrendipine	O
+and	O
+nisoldipine	O
+offers	O
+a	O
+convenient	O
+administration	O
+schedule	O
+","	O
+which	O
+encourages	O
+patient	O
+compliance	O
+in	O
+long	O
+-	O
+term	O
+therapy	O
+of	O
+hypertension	B-NP
+.	O
+	
+The	O
+coronary	O
+vasodilating	O
+properties	O
+of	O
+nisoldipine	O
+have	O
+led	O
+to	O
+the	O
+investigation	O
+of	O
+this	O
+agent	O
+for	O
+use	O
+in	O
+angina	B-NP
+.	O
+	
+Selectivity	O
+for	O
+the	O
+cerebrovascular	O
+bed	O
+makes	O
+nimodipine	O
+potentially	O
+useful	O
+in	O
+the	O
+treatment	O
+of	O
+subarachnoid	B-NP
+hemorrhage	I-NP
+","	O
+migraine	B-NP
+headache	I-NP
+","	O
+dementia	B-NP
+","	O
+and	O
+stroke	B-NP
+.	O
+	
+In	O
+general	O
+","	O
+the	O
+dihydropyridine	O
+calcium	O
+channel	O
+blockers	O
+are	O
+usually	O
+well	O
+tolerated	O
+","	O
+with	O
+headache	B-NP
+","	O
+facial	O
+flushing	B-NP
+","	O
+palpitations	B-NP
+","	O
+edema	B-NP
+","	O
+nausea	B-NP
+","	O
+anorexia	B-NP
+","	O
+and	O
+dizziness	B-NP
+being	O
+the	O
+more	O
+common	O
+adverse	O
+effects	O
+.	O
+	
+The	O
+enhancement	O
+of	O
+aminonucleoside	O
+nephrosis	B-NP
+by	O
+the	O
+co	O
+-	O
+administration	O
+of	O
+protamine	O
+.	O
+	
+An	O
+experimental	O
+model	O
+of	O
+focal	B-NP
+segmental	I-NP
+glomerular	I-NP
+sclerosis	I-NP
+(	O
+FSGS	B-NP
+)	O
+was	O
+developed	O
+in	O
+rats	O
+by	O
+the	O
+combined	O
+administration	O
+of	O
+puromycin	O
+-	O
+aminonucleoside	O
+(	O
+AMNS	O
+)	O
+and	O
+protamine	O
+sulfate	O
+(	O
+PS	O
+)	O
+.	O
+	
+Male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+","	O
+uninephrectomized	O
+three	O
+weeks	O
+before	O
+","	O
+received	O
+daily	O
+injections	O
+of	O
+subcutaneous	O
+AMNS	O
+(	O
+1	O
+mg	O
+/	O
+100	O
+g	O
+body	O
+wt	O
+)	O
+and	O
+intravenous	O
+PS	O
+(	O
+2	O
+separated	O
+doses	O
+of	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+100	O
+g	O
+body	O
+wt	O
+)	O
+for	O
+four	O
+days	O
+.	O
+	
+The	O
+series	O
+of	O
+injections	O
+were	O
+repeated	O
+another	O
+three	O
+times	O
+at	O
+10	O
+day	O
+intervals	O
+.	O
+	
+The	O
+animals	O
+were	O
+sacrificed	O
+on	O
+days	O
+24	O
+","	O
+52	O
+","	O
+and	O
+80	O
+.	O
+	
+They	O
+developed	O
+nephrotic	B-NP
+syndrome	I-NP
+and	O
+finally	O
+renal	B-NP
+failure	I-NP
+.	O
+	
+The	O
+time	O
+-	O
+course	O
+curve	O
+of	O
+creatinine	O
+clearance	O
+dropped	O
+and	O
+showed	O
+significant	O
+difference	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+from	O
+that	O
+of	O
+each	O
+control	O
+group	O
+","	O
+such	O
+as	O
+","	O
+AMNS	O
+alone	O
+","	O
+PS	O
+alone	O
+or	O
+saline	O
+injected	O
+.	O
+	
+Their	O
+glomeruli	O
+showed	O
+changes	O
+of	O
+progressive	O
+FSGS	B-NP
+.	O
+	
+The	O
+ultrastructural	O
+studies	O
+in	O
+the	O
+initial	O
+stage	O
+revealed	O
+significant	O
+lack	O
+of	O
+particles	O
+of	O
+perfused	O
+ruthenium	O
+red	O
+on	O
+the	O
+lamina	O
+rara	O
+externa	O
+and	O
+marked	O
+changes	O
+in	O
+epithelial	O
+cell	O
+cytoplasm	O
+.	O
+	
+Therefore	O
+","	O
+it	O
+is	O
+suggested	O
+that	O
+the	O
+administration	O
+of	O
+PS	O
+enhances	O
+the	O
+toxicity	B-NP
+of	O
+AMNS	O
+on	O
+the	O
+glomerulus	O
+and	O
+readily	O
+produces	O
+progressive	O
+FSGS	B-NP
+in	O
+rats	O
+resulting	O
+in	O
+the	O
+end	B-NP
+-	I-NP
+stage	I-NP
+renal	I-NP
+disease	I-NP
+.	O
+	
+Theophylline	O
+neurotoxicity	B-NP
+in	O
+pregnant	O
+rats	O
+.	O
+	
+The	O
+purpose	O
+of	O
+this	O
+investigation	O
+was	O
+to	O
+determine	O
+whether	O
+the	O
+neurotoxicity	B-NP
+of	O
+theophylline	O
+is	O
+altered	O
+in	O
+advanced	O
+pregnancy	O
+.	O
+	
+Sprague	O
+-	O
+Dawley	O
+rats	O
+that	O
+were	O
+20	O
+days	O
+pregnant	O
+and	O
+nonpregnant	O
+rats	O
+of	O
+the	O
+same	O
+age	O
+and	O
+strain	O
+received	O
+infusions	O
+of	O
+aminophylline	O
+until	O
+onset	O
+of	O
+maximal	O
+seizures	B-NP
+which	O
+occurred	O
+after	O
+28	O
+and	O
+30	O
+minutes	O
+respectively	O
+.	O
+	
+Theophylline	O
+concentrations	O
+at	O
+this	O
+endpoint	O
+in	O
+serum	O
+(	O
+total	O
+)	O
+and	O
+CSF	O
+were	O
+similar	O
+but	O
+serum	O
+(	O
+free	O
+)	O
+and	O
+brain	O
+concentrations	O
+were	O
+slightly	O
+different	O
+in	O
+pregnant	O
+rats	O
+.	O
+	
+Theophylline	O
+serum	O
+protein	O
+binding	O
+determined	O
+by	O
+equilibrium	O
+dialysis	O
+was	O
+lower	O
+in	O
+pregnant	O
+rats	O
+.	O
+	
+Fetal	O
+serum	O
+concentrations	O
+at	O
+onset	O
+of	O
+seizures	B-NP
+in	O
+the	O
+mother	O
+were	O
+similar	O
+to	O
+maternal	O
+brain	O
+and	O
+CSF	O
+concentrations	O
+and	O
+correlated	O
+significantly	O
+with	O
+the	O
+former	O
+.	O
+	
+It	O
+is	O
+concluded	O
+that	O
+advanced	O
+pregnancy	O
+has	O
+a	O
+negligible	O
+effect	O
+on	O
+the	O
+neurotoxic	B-NP
+response	O
+to	O
+theophylline	O
+in	O
+rats	O
+.	O
+	
+Hyperkalemia	B-NP
+induced	O
+by	O
+indomethacin	O
+and	O
+naproxen	O
+and	O
+reversed	O
+by	O
+fludrocortisone	O
+.	O
+	
+We	O
+have	O
+described	O
+a	O
+patient	O
+with	O
+severe	O
+rheumatoid	B-NP
+arthritis	I-NP
+and	O
+a	O
+history	O
+of	O
+mefenamic	O
+acid	O
+nephropathy	B-NP
+in	O
+whom	O
+hyperkalemia	B-NP
+and	O
+inappropriate	O
+hypoaldosteronism	B-NP
+were	O
+caused	O
+by	O
+both	O
+indomethacin	O
+and	O
+naproxen	O
+","	O
+without	O
+major	O
+decline	O
+in	O
+renal	O
+function	O
+.	O
+	
+It	O
+is	O
+likely	O
+that	O
+preexisting	O
+renal	B-NP
+disease	I-NP
+predisposed	O
+this	O
+patient	O
+to	O
+type	B-NP
+IV	I-NP
+renal	I-NP
+tubular	I-NP
+acidosis	I-NP
+with	O
+prostaglandin	O
+synthetase	O
+inhibitors	O
+.	O
+	
+Because	O
+he	O
+was	O
+unable	O
+to	O
+discontinue	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drug	O
+therapy	O
+","	O
+fludrocortisone	O
+was	O
+added	O
+","	O
+correcting	O
+the	O
+hyperkalemia	B-NP
+and	O
+allowing	O
+indomethacin	O
+therapy	O
+to	O
+be	O
+continued	O
+safely	O
+.	O
+	
+Hypotension	B-NP
+as	O
+a	O
+manifestation	O
+of	O
+cardiotoxicity	B-NP
+in	O
+three	O
+patients	O
+receiving	O
+cisplatin	O
+and	O
+5	O
+-	O
+fluorouracil	O
+.	O
+	
+Cardiac	O
+symptoms	O
+","	O
+including	O
+hypotension	B-NP
+","	O
+developed	O
+in	O
+three	O
+patients	O
+with	O
+advanced	O
+colorectal	B-NP
+carcinoma	I-NP
+while	O
+being	O
+treated	O
+with	O
+cisplatin	O
+(	O
+CDDP	O
+)	O
+and	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+.	O
+	
+In	O
+two	O
+patients	O
+","	O
+hypotension	B-NP
+was	O
+associated	O
+with	O
+severe	O
+left	B-NP
+ventricular	I-NP
+dysfunction	I-NP
+.	O
+	
+All	O
+three	O
+patients	O
+required	O
+therapy	O
+discontinuation	O
+.	O
+	
+Cardiac	O
+enzymes	O
+remained	O
+normal	O
+despite	O
+transient	O
+electrocardiographic	O
+(	O
+EKG	O
+)	O
+changes	O
+.	O
+	
+The	O
+presentation	O
+and	O
+cardiac	O
+evaluation	O
+(	O
+hemodynamic	O
+","	O
+echocardiographic	O
+","	O
+and	O
+scintigraphic	O
+)	O
+of	O
+these	O
+patients	O
+suggest	O
+new	O
+manifestations	O
+of	O
+5	O
+-	O
+FU	O
+cardiotoxicity	B-NP
+that	O
+may	O
+be	O
+influenced	O
+by	O
+CDDP	O
+.	O
+	
+The	O
+possible	O
+pathophysiologic	O
+mechanisms	O
+are	O
+discussed	O
+.	O
+	
+Fatal	O
+aplastic	B-NP
+anemia	I-NP
+in	O
+a	O
+patient	O
+treated	O
+with	O
+carbamazepine	O
+.	O
+	
+A	O
+case	O
+of	O
+fatal	O
+aplastic	B-NP
+anemia	I-NP
+due	O
+to	O
+carbamazepine	O
+treatment	O
+in	O
+an	O
+epileptic	B-NP
+woman	O
+is	O
+reported	O
+.	O
+	
+Despite	O
+concerns	O
+of	O
+fatal	O
+bone	B-NP
+marrow	I-NP
+toxicity	I-NP
+due	O
+to	O
+carbamazepine	O
+","	O
+this	O
+is	O
+only	O
+the	O
+fourth	O
+documented	O
+and	O
+published	O
+report	O
+.	O
+	
+Carbamazepine	O
+is	O
+a	O
+safe	O
+drug	O
+","	O
+but	O
+physicians	O
+and	O
+patients	O
+should	O
+be	O
+aware	O
+of	O
+the	O
+exceedingly	O
+rare	O
+but	O
+potentially	O
+fatal	O
+side	O
+effects	O
+","	O
+better	O
+prevented	O
+by	O
+clinical	O
+than	O
+by	O
+laboratory	O
+monitoring	O
+.	O
+	
+Participation	O
+of	O
+a	O
+bulbospinal	O
+serotonergic	O
+pathway	O
+in	O
+the	O
+rat	O
+brain	O
+in	O
+clonidine	O
+-	O
+induced	O
+hypotension	B-NP
+and	O
+bradycardia	B-NP
+.	O
+	
+The	O
+effects	O
+of	O
+microinjection	O
+of	O
+clonidine	O
+(	O
+1	O
+-	O
+10	O
+micrograms	O
+in	O
+1	O
+microliter	O
+)	O
+into	O
+a	O
+region	O
+adjacent	O
+to	O
+the	O
+ventrolateral	O
+surface	O
+of	O
+the	O
+medulla	O
+oblongata	O
+on	O
+cardiovascular	O
+function	O
+were	O
+assessed	O
+in	O
+urethane	O
+-	O
+anesthetized	O
+rats	O
+.	O
+	
+Intramedullary	O
+administration	O
+of	O
+clonidine	O
+","	O
+but	O
+not	O
+saline	O
+vehicle	O
+","	O
+caused	O
+a	O
+dose	O
+-	O
+dependent	O
+decrease	O
+in	O
+both	O
+the	O
+mean	O
+arterial	O
+pressure	O
+and	O
+the	O
+heart	O
+rate	O
+.	O
+	
+The	O
+clonidine	O
+-	O
+induced	O
+hypotension	B-NP
+was	O
+antagonized	O
+by	O
+prior	O
+spinal	O
+transection	O
+","	O
+but	O
+not	O
+bilateral	O
+vagotomy	O
+.	O
+	
+On	O
+the	O
+other	O
+hand	O
+","	O
+the	O
+clonidine	O
+-	O
+induced	O
+bradycardia	B-NP
+was	O
+antagonized	O
+by	O
+prior	O
+bilateral	O
+vagotomy	O
+","	O
+but	O
+not	O
+spinal	O
+transection	O
+.	O
+	
+Furthermore	O
+","	O
+selective	O
+destruction	O
+of	O
+the	O
+spinal	O
+5	O
+-	O
+HT	O
+nerves	O
+","	O
+produced	O
+by	O
+bilateral	O
+spinal	O
+injection	O
+of	O
+5	O
+","	O
+7	O
+-	O
+dihydroxytryptamine	O
+","	O
+reduced	O
+the	O
+magnitude	O
+of	O
+the	O
+vasodepressor	O
+or	O
+the	O
+bradycardiac	B-NP
+responses	O
+to	O
+clonidine	O
+microinjected	O
+into	O
+the	O
+area	O
+near	O
+the	O
+ventrolateral	O
+surface	O
+of	O
+the	O
+medulla	O
+oblongata	O
+in	O
+rats	O
+.	O
+	
+The	O
+data	O
+indicate	O
+that	O
+a	O
+bulbospinal	O
+serotonergic	O
+pathway	O
+is	O
+involved	O
+in	O
+development	O
+of	O
+clonidine	O
+-	O
+induced	O
+hypotension	B-NP
+and	O
+bradycardia	B-NP
+.	O
+	
+The	O
+induced	O
+hypotension	B-NP
+is	O
+brought	O
+about	O
+by	O
+a	O
+decrease	O
+in	O
+sympathetic	O
+efferent	O
+activity	O
+","	O
+whereas	O
+the	O
+induced	O
+bradycardia	B-NP
+was	O
+due	O
+to	O
+an	O
+increase	O
+in	O
+vagal	O
+efferent	O
+activity	O
+.	O
+	
+Hypertension	B-NP
+in	O
+neuroblastoma	B-NP
+induced	O
+by	O
+imipramine	O
+.	O
+	
+Hypertension	B-NP
+is	O
+a	O
+well	O
+-	O
+known	O
+finding	O
+in	O
+some	O
+patients	O
+with	O
+neuroblastoma	B-NP
+.	O
+	
+However	O
+","	O
+it	O
+has	O
+not	O
+previously	O
+been	O
+described	O
+in	O
+association	O
+with	O
+the	O
+use	O
+of	O
+Imipramine	O
+.	O
+	
+We	O
+report	O
+the	O
+occurrence	O
+of	O
+severe	O
+hypertension	B-NP
+(	O
+blood	O
+pressure	O
+190	O
+/	O
+160	O
+)	O
+in	O
+a	O
+4	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+with	O
+neuroblastoma	B-NP
+who	O
+was	O
+given	O
+Imipramine	O
+to	O
+control	O
+a	O
+behavior	B-NP
+disorder	I-NP
+.	O
+	
+It	O
+was	O
+determined	O
+later	O
+that	O
+this	O
+patient	O
+'	O
+s	O
+tumor	B-NP
+was	O
+recurring	O
+at	O
+the	O
+time	O
+of	O
+her	O
+hypertensive	B-NP
+episode	O
+.	O
+	
+Since	O
+she	O
+had	O
+no	O
+blood	O
+pressure	O
+elevation	O
+at	O
+initial	O
+diagnosis	O
+and	O
+none	O
+following	O
+discontinuation	O
+of	O
+the	O
+Imipramine	O
+(	O
+when	O
+she	O
+was	O
+in	O
+florid	O
+relapse	O
+)	O
+","	O
+we	O
+believe	O
+that	O
+this	O
+drug	O
+rather	O
+than	O
+her	O
+underlying	O
+disease	O
+alone	O
+caused	O
+her	O
+hypertension	B-NP
+.	O
+	
+The	O
+mechanism	O
+for	O
+this	O
+reaction	O
+is	O
+believed	O
+to	O
+be	O
+increased	O
+levels	O
+of	O
+vasoactive	O
+catecholamines	O
+due	O
+to	O
+interference	O
+of	O
+their	O
+physiologic	O
+inactivation	O
+by	O
+Imipramine	O
+.	O
+	
+From	O
+this	O
+experience	O
+","	O
+we	O
+urge	O
+extreme	O
+caution	O
+in	O
+the	O
+use	O
+of	O
+tricyclic	O
+antidepressants	O
+in	O
+children	O
+with	O
+active	O
+neuroblastoma	B-NP
+.	O
+	
+Rechallenge	O
+of	O
+patients	O
+who	O
+developed	O
+oral	B-NP
+candidiasis	I-NP
+or	O
+hoarseness	B-NP
+with	O
+beclomethasone	O
+dipropionate	O
+.	O
+	
+Of	O
+158	O
+asthmatic	B-NP
+patients	O
+who	O
+were	O
+placed	O
+on	O
+inhaled	O
+beclomethasone	O
+","	O
+15	O
+(	O
+9	O
+.	O
+5	O
+%	O
+)	O
+developed	O
+either	O
+hoarseness	B-NP
+(	O
+8	O
+)	O
+","	O
+oral	O
+thrush	B-NP
+(	O
+6	O
+)	O
+","	O
+or	O
+both	O
+(	O
+1	O
+)	O
+.	O
+	
+When	O
+their	O
+adverse	O
+reactions	O
+subsided	O
+","	O
+seven	O
+of	O
+these	O
+15	O
+patients	O
+were	O
+rechallenged	O
+with	O
+inhaled	O
+beclomethasone	O
+.	O
+	
+These	O
+included	O
+five	O
+cases	O
+who	O
+developed	O
+hoarseness	B-NP
+and	O
+three	O
+who	O
+developed	O
+Candidiasis	B-NP
+.	O
+	
+One	O
+patient	O
+had	O
+both	O
+.	O
+	
+Oral	O
+thrush	B-NP
+did	O
+not	O
+recur	O
+","	O
+but	O
+60	O
+%	O
+(	O
+3	O
+/	O
+5	O
+)	O
+of	O
+patients	O
+with	O
+hoarseness	B-NP
+had	O
+recurrence	O
+.	O
+	
+We	O
+conclude	O
+that	O
+patients	O
+may	O
+be	O
+restarted	O
+on	O
+inhaled	O
+beclomethasone	O
+when	O
+clinically	O
+indicated	O
+;	O
+however	O
+","	O
+because	O
+of	O
+the	O
+high	O
+recurrence	O
+rate	O
+","	O
+patients	O
+who	O
+develop	O
+hoarseness	B-NP
+should	O
+not	O
+be	O
+re	O
+-	O
+challenged	O
+.	O
+	
+Concomitant	O
+use	O
+of	O
+oral	O
+prednisone	O
+and	O
+topical	O
+beclomethasone	O
+may	O
+increase	O
+the	O
+risk	O
+of	O
+developing	O
+hoarseness	B-NP
+or	O
+candidiasis	B-NP
+.	O
+	
+Cyclophosphamide	O
+cardiotoxicity	B-NP
+:	O
+an	O
+analysis	O
+of	O
+dosing	O
+as	O
+a	O
+risk	O
+factor	O
+.	O
+	
+Patients	O
+who	O
+undergo	O
+bone	O
+marrow	O
+transplantation	O
+are	O
+generally	O
+immunosuppressed	O
+with	O
+a	O
+dose	O
+of	O
+cyclophosphamide	O
+(	O
+CYA	O
+)	O
+which	O
+is	O
+usually	O
+calculated	O
+based	O
+on	O
+the	O
+patient	O
+'	O
+s	O
+weight	O
+.	O
+	
+At	O
+these	O
+high	O
+doses	O
+of	O
+CYA	O
+","	O
+serious	O
+cardiotoxicity	B-NP
+may	O
+occur	O
+","	O
+but	O
+definitive	O
+risk	O
+factors	O
+for	O
+the	O
+development	O
+of	O
+such	O
+cardiotoxicity	B-NP
+have	O
+not	O
+been	O
+described	O
+.	O
+	
+Since	O
+chemotherapeutic	O
+agent	O
+toxicity	B-NP
+generally	O
+correlates	O
+with	O
+dose	O
+per	O
+body	O
+surface	O
+area	O
+","	O
+we	O
+retrospectively	O
+calculated	O
+the	O
+dose	O
+of	O
+CYA	O
+in	O
+patients	O
+transplanted	O
+at	O
+our	O
+institution	O
+to	O
+determine	O
+whether	O
+the	O
+incidence	O
+of	O
+CYA	O
+cardiotoxicity	B-NP
+correlated	O
+with	O
+the	O
+dose	O
+per	O
+body	O
+surface	O
+area	O
+.	O
+	
+Eighty	O
+patients	O
+who	O
+were	O
+to	O
+receive	O
+CYA	O
+50	O
+mg	O
+/	O
+kg	O
+/	O
+d	O
+for	O
+four	O
+days	O
+as	O
+preparation	O
+for	O
+marrow	O
+grafting	O
+underwent	O
+a	O
+total	O
+of	O
+84	O
+transplants	O
+for	O
+aplastic	B-NP
+anemia	I-NP
+","	O
+Wiskott	B-NP
+-	I-NP
+Aldrich	I-NP
+syndrome	I-NP
+","	O
+or	O
+severe	B-NP
+combined	I-NP
+immunodeficiency	I-NP
+syndrome	I-NP
+.	O
+	
+Fourteen	O
+of	O
+84	O
+(	O
+17	O
+%	O
+)	O
+patients	O
+had	O
+symptoms	O
+and	O
+signs	O
+consistent	O
+with	O
+CYA	O
+cardiotoxicity	B-NP
+within	O
+ten	O
+days	O
+of	O
+receiving	O
+1	O
+to	O
+4	O
+doses	O
+of	O
+CYA	O
+.	O
+	
+Six	O
+of	O
+the	O
+14	O
+patients	O
+died	O
+with	O
+congestive	B-NP
+heart	I-NP
+failure	I-NP
+.	O
+	
+The	O
+dose	O
+of	O
+CYA	O
+per	O
+body	O
+surface	O
+area	O
+was	O
+calculated	O
+for	O
+all	O
+patients	O
+and	O
+the	O
+patients	O
+were	O
+divided	O
+into	O
+two	O
+groups	O
+based	O
+on	O
+daily	O
+CYA	O
+dose	O
+:	O
+Group	O
+1	O
+","	O
+CYA	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+1	O
+.	O
+55	O
+g	O
+/	O
+m2	O
+/	O
+d	O
+;	O
+Group	O
+2	O
+","	O
+CYA	O
+greater	O
+than	O
+1	O
+.	O
+55	O
+g	O
+/	O
+m2	O
+/	O
+d	O
+.	O
+	
+Cardiotoxicity	B-NP
+that	O
+was	O
+thought	O
+to	O
+be	O
+related	O
+to	O
+CYA	O
+occurred	O
+in	O
+1	O
+/	O
+32	O
+(	O
+3	O
+%	O
+)	O
+of	O
+patients	O
+in	O
+Group	O
+1	O
+and	O
+in	O
+13	O
+/	O
+52	O
+(	O
+25	O
+%	O
+)	O
+patients	O
+in	O
+Group	O
+2	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+25	O
+)	O
+.	O
+	
+Congestive	B-NP
+heart	I-NP
+failure	I-NP
+caused	O
+or	O
+contributed	O
+to	O
+death	O
+in	O
+0	O
+/	O
+32	O
+patients	O
+in	O
+Group	O
+1	O
+v	O
+6	O
+/	O
+52	O
+(	O
+12	O
+%	O
+)	O
+of	O
+patients	O
+in	O
+Group	O
+2	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+25	O
+)	O
+.	O
+	
+There	O
+was	O
+no	O
+difference	O
+in	O
+the	O
+rate	O
+of	O
+engraftment	O
+of	O
+evaluable	O
+patients	O
+in	O
+the	O
+two	O
+groups	O
+(	O
+P	O
+greater	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+We	O
+conclude	O
+that	O
+the	O
+CYA	O
+cardiotoxicity	B-NP
+correlates	O
+with	O
+CYA	O
+dosage	O
+as	O
+calculated	O
+by	O
+body	O
+surface	O
+area	O
+","	O
+and	O
+that	O
+patients	O
+with	O
+aplastic	B-NP
+anemia	I-NP
+and	O
+immunodeficiencies	B-NP
+can	O
+be	O
+effectively	O
+prepared	O
+for	O
+bone	O
+marrow	O
+grafting	O
+at	O
+a	O
+CYA	O
+dose	O
+of	O
+1	O
+.	O
+55	O
+g	O
+/	O
+m2	O
+/	O
+d	O
+for	O
+four	O
+days	O
+with	O
+a	O
+lower	O
+incidence	O
+of	O
+cardiotoxicity	B-NP
+than	O
+patients	O
+whose	O
+CYA	O
+dosage	O
+is	O
+calculated	O
+based	O
+on	O
+weight	O
+.	O
+	
+This	O
+study	O
+reaffirms	O
+the	O
+principle	O
+that	O
+drug	O
+toxicity	B-NP
+correlates	O
+with	O
+dose	O
+per	O
+body	O
+surface	O
+area	O
+.	O
+	
+Studies	O
+of	O
+risk	O
+factors	O
+for	O
+aminoglycoside	O
+nephrotoxicity	B-NP
+.	O
+	
+The	O
+epidemiology	O
+of	O
+aminoglycoside	O
+-	O
+induced	O
+nephrotoxicity	B-NP
+is	O
+not	O
+fully	O
+understood	O
+.	O
+	
+Experimental	O
+studies	O
+in	O
+healthy	O
+human	O
+volunteers	O
+indicate	O
+aminoglycosides	O
+cause	O
+proximal	O
+tubular	O
+damage	O
+in	O
+most	O
+patients	O
+","	O
+but	O
+rarely	O
+","	O
+if	O
+ever	O
+","	O
+cause	O
+glomerular	B-NP
+or	I-NP
+tubular	I-NP
+dysfunction	I-NP
+.	O
+	
+Clinical	O
+trials	O
+of	O
+aminoglycosides	O
+in	O
+seriously	O
+ill	O
+patients	O
+indicate	O
+that	O
+the	O
+relative	O
+risk	O
+for	O
+developing	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+during	O
+therapy	O
+ranges	O
+from	O
+8	O
+to	O
+10	O
+and	O
+that	O
+the	O
+attributable	O
+risk	O
+is	O
+70	O
+%	O
+to	O
+80	O
+%	O
+.	O
+	
+Further	O
+analysis	O
+of	O
+these	O
+data	O
+suggests	O
+that	O
+the	O
+duration	O
+of	O
+therapy	O
+","	O
+plasma	O
+aminoglycoside	O
+levels	O
+","	O
+liver	B-NP
+disease	I-NP
+","	O
+advanced	O
+age	O
+","	O
+high	O
+initial	O
+estimated	O
+creatinine	O
+clearance	O
+and	O
+","	O
+possibly	O
+","	O
+female	O
+gender	O
+all	O
+increase	O
+the	O
+risk	O
+for	O
+nephrotoxicity	B-NP
+.	O
+	
+Other	O
+causes	O
+of	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+","	O
+such	O
+as	O
+shock	B-NP
+","	O
+appear	O
+to	O
+have	O
+an	O
+additive	O
+effect	O
+.	O
+	
+Predictive	O
+models	O
+have	O
+been	O
+developed	O
+from	O
+these	O
+analyses	O
+that	O
+should	O
+be	O
+useful	O
+for	O
+identifying	O
+patients	O
+at	O
+high	O
+risk	O
+.	O
+	
+These	O
+models	O
+may	O
+also	O
+be	O
+useful	O
+in	O
+developing	O
+insights	O
+into	O
+the	O
+pathophysiology	O
+of	O
+aminoglycoside	O
+-	O
+induced	O
+nephrotoxicity	B-NP
+.	O
+	
+Central	O
+action	O
+of	O
+narcotic	O
+analgesics	O
+.	O
+	
+Part	O
+IV	O
+.	O
+	
+Noradrenergic	O
+influences	O
+on	O
+the	O
+activity	O
+of	O
+analgesics	O
+in	O
+rats	O
+.	O
+	
+The	O
+effect	O
+of	O
+clonidine	O
+","	O
+naphazoline	O
+and	O
+xylometazoline	O
+on	O
+analgesia	O
+induced	O
+by	O
+morphine	O
+","	O
+codeine	O
+","	O
+fentanyl	O
+and	O
+pentazocine	O
+","	O
+and	O
+on	O
+cataleptic	B-NP
+effect	O
+of	O
+morphine	O
+","	O
+codine	O
+and	O
+fentanyl	O
+was	O
+studied	O
+in	O
+rats	O
+.	O
+	
+The	O
+biochemical	O
+assays	O
+on	O
+the	O
+influence	O
+of	O
+four	O
+analgesics	O
+on	O
+the	O
+brain	O
+concentration	O
+and	O
+turnover	O
+of	O
+noradrenaline	O
+(	O
+NA	O
+)	O
+were	O
+also	O
+performed	O
+.	O
+	
+It	O
+was	O
+found	O
+that	O
+three	O
+drugs	O
+stimulating	O
+central	O
+NA	O
+receptors	O
+failed	O
+to	O
+affect	O
+the	O
+analgesic	O
+ED50	O
+of	O
+all	O
+antinociceptive	O
+agents	O
+and	O
+they	O
+enhanced	O
+catalepsy	B-NP
+induced	O
+by	O
+morphine	O
+and	O
+fentanyl	O
+.	O
+	
+Codeine	O
+catalepsy	B-NP
+was	O
+increased	O
+by	O
+clonidine	O
+and	O
+decreased	O
+by	O
+naphazoline	O
+and	O
+xylometazoline	O
+.	O
+	
+The	O
+brain	O
+concentration	O
+of	O
+NA	O
+was	O
+not	O
+changed	O
+by	O
+morphine	O
+and	O
+fentanyl	O
+","	O
+but	O
+one	O
+of	O
+the	O
+doses	O
+of	O
+codeine	O
+(	O
+45	O
+mg	O
+/	O
+kg	O
+)	O
+slightly	O
+enhanced	O
+it	O
+.	O
+	
+Pentazocine	O
+dose	O
+-	O
+dependently	O
+decreased	O
+the	O
+brain	O
+level	O
+of	O
+NA	O
+.	O
+	
+The	O
+rate	O
+of	O
+NA	O
+turnover	O
+was	O
+not	O
+altered	O
+by	O
+analgesics	O
+except	O
+for	O
+the	O
+higher	O
+dose	O
+of	O
+fentanyl	O
+(	O
+0	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+)	O
+following	O
+which	O
+the	O
+disappearance	O
+of	O
+NA	O
+from	O
+the	O
+brain	O
+was	O
+diminished	O
+.	O
+	
+The	O
+results	O
+are	O
+discussed	O
+in	O
+the	O
+light	O
+of	O
+various	O
+and	O
+non	O
+-	O
+uniform	O
+data	O
+from	O
+the	O
+literature	O
+.	O
+	
+It	O
+is	O
+suggested	O
+that	O
+in	O
+rats	O
+the	O
+brain	O
+NA	O
+plays	O
+a	O
+less	O
+important	O
+function	O
+than	O
+the	O
+other	O
+monoamines	O
+in	O
+the	O
+behavioural	O
+activity	O
+of	O
+potent	O
+analgesics	O
+.	O
+	
+Flurothyl	O
+seizure	B-NP
+thresholds	O
+in	O
+mice	O
+treated	O
+neonatally	O
+with	O
+a	O
+single	O
+injection	O
+of	O
+monosodium	O
+glutamate	O
+(	O
+MSG	O
+)	O
+:	O
+evaluation	O
+of	O
+experimental	O
+parameters	O
+in	O
+flurothyl	O
+seizure	B-NP
+testing	O
+.	O
+	
+Monosodium	O
+glutamate	O
+(	O
+MSG	O
+)	O
+administration	O
+to	O
+neonatal	O
+rodents	O
+produces	O
+convulsions	B-NP
+and	O
+results	O
+in	O
+numerous	O
+biochemical	O
+and	O
+behavioral	O
+deficits	O
+.	O
+	
+These	O
+studies	O
+were	O
+undertaken	O
+to	O
+determine	O
+if	O
+neonatal	O
+administration	O
+of	O
+MSG	O
+produced	O
+permanent	O
+alterations	O
+in	O
+seizure	B-NP
+susceptibility	O
+","	O
+since	O
+previous	O
+investigations	O
+were	O
+inconclusive	O
+.	O
+	
+A	O
+flurothyl	O
+ether	O
+seizure	B-NP
+screening	O
+technique	O
+was	O
+used	O
+to	O
+evaluate	O
+seizure	B-NP
+susceptibility	O
+in	O
+adult	O
+mice	O
+that	O
+received	O
+neonatal	O
+injections	O
+of	O
+MSG	O
+(	O
+4	O
+mg	O
+/	O
+g	O
+and	O
+1	O
+mg	O
+/	O
+g	O
+)	O
+.	O
+	
+MSG	O
+treatment	O
+resulted	O
+in	O
+significant	O
+reductions	O
+in	O
+whole	O
+brain	O
+weight	O
+but	O
+did	O
+not	O
+alter	O
+seizure	B-NP
+threshold	O
+.	O
+	
+A	O
+naloxone	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+challenge	O
+was	O
+also	O
+ineffective	O
+in	O
+altering	O
+the	O
+seizure	B-NP
+thresholds	O
+of	O
+either	O
+control	O
+of	O
+MSG	O
+-	O
+treated	O
+mice	O
+.	O
+	
+Flurothyl	O
+ether	O
+produced	O
+hypothermia	B-NP
+which	O
+was	O
+correlated	O
+with	O
+the	O
+duration	O
+of	O
+flurothyl	O
+exposure	O
+;	O
+however	O
+","	O
+the	O
+relationship	O
+of	O
+hypothermia	B-NP
+to	O
+seizure	B-NP
+induction	O
+was	O
+unclear	O
+.	O
+	
+Flurothyl	O
+seizure	B-NP
+testing	O
+proved	O
+to	O
+be	O
+a	O
+rapid	O
+and	O
+reliable	O
+technique	O
+with	O
+which	O
+to	O
+evaluate	O
+seizure	B-NP
+susceptibility	O
+.	O
+	
+Susceptibility	O
+to	O
+seizures	B-NP
+produced	O
+by	O
+pilocarpine	O
+in	O
+rats	O
+after	O
+microinjection	O
+of	O
+isoniazid	O
+or	O
+gamma	O
+-	O
+vinyl	O
+-	O
+GABA	O
+into	O
+the	O
+substantia	O
+nigra	O
+.	O
+	
+Pilocarpine	O
+","	O
+given	O
+intraperitoneally	O
+to	O
+rats	O
+","	O
+reproduces	O
+the	O
+neuropathological	O
+sequelae	O
+of	O
+temporal	B-NP
+lobe	I-NP
+epilepsy	I-NP
+and	O
+provides	O
+a	O
+relevant	O
+animal	O
+model	O
+for	O
+studying	O
+mechanisms	O
+of	O
+buildup	O
+of	O
+convulsive	B-NP
+activity	O
+and	O
+pathways	O
+operative	O
+in	O
+the	O
+generalization	O
+and	O
+propagation	O
+of	O
+seizures	B-NP
+within	O
+the	O
+forebrain	O
+.	O
+	
+In	O
+the	O
+present	O
+study	O
+","	O
+the	O
+effects	O
+of	O
+manipulating	O
+the	O
+activity	O
+of	O
+the	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+(	O
+GABA	O
+)	O
+-	O
+mediated	O
+synaptic	O
+inhibition	O
+within	O
+the	O
+substantia	O
+nigra	O
+on	O
+seizures	B-NP
+produced	O
+by	O
+pilocarpine	O
+in	O
+rats	O
+","	O
+were	O
+investigated	O
+.	O
+	
+In	O
+animals	O
+pretreated	O
+with	O
+microinjections	O
+of	O
+isoniazid	O
+","	O
+150	O
+micrograms	O
+","	O
+an	O
+inhibitor	O
+of	O
+activity	O
+of	O
+the	O
+GABA	O
+-	O
+synthesizing	O
+enzyme	O
+","	O
+L	O
+-	O
+glutamic	O
+acid	O
+decarboxylase	O
+","	O
+into	O
+the	O
+substantia	O
+nigra	O
+pars	O
+reticulata	O
+(	O
+SNR	O
+)	O
+","	O
+bilaterally	O
+","	O
+non	O
+-	O
+convulsant	O
+doses	O
+of	O
+pilocarpine	O
+","	O
+100	O
+and	O
+200	O
+mg	O
+/	O
+kg	O
+","	O
+resulted	O
+in	O
+severe	O
+motor	O
+limbic	O
+seizures	B-NP
+and	O
+status	B-NP
+epilepticus	I-NP
+.	O
+	
+Electroencephalographic	O
+and	O
+behavioral	O
+monitoring	O
+revealed	O
+a	O
+profound	O
+reduction	O
+of	O
+the	O
+threshold	O
+for	O
+pilocarpine	O
+-	O
+induced	O
+convulsions	B-NP
+.	O
+	
+Morphological	O
+analysis	O
+of	O
+frontal	O
+forebrain	O
+sections	O
+with	O
+light	O
+microscopy	O
+revealed	O
+seizure	B-NP
+-	O
+related	O
+damage	O
+to	O
+the	O
+hippocampal	O
+formation	O
+","	O
+thalamus	O
+","	O
+amygdala	O
+","	O
+olfactory	O
+cortex	O
+","	O
+substantia	O
+nigra	O
+and	O
+neocortex	O
+","	O
+which	O
+is	O
+typically	O
+observed	O
+with	O
+pilocarpine	O
+in	O
+doses	O
+exceeding	O
+350	O
+mg	O
+/	O
+kg	O
+.	O
+	
+Bilateral	O
+intrastriatal	O
+injections	O
+of	O
+isoniazid	O
+did	O
+not	O
+augment	O
+seizures	B-NP
+produced	O
+by	O
+pilocarpine	O
+","	O
+200	O
+mg	O
+/	O
+kg	O
+.	O
+	
+Application	O
+of	O
+an	O
+irreversible	O
+inhibitor	O
+of	O
+GABA	O
+transaminase	O
+","	O
+gamma	O
+-	O
+vinyl	O
+-	O
+GABA	O
+(	O
+D	O
+","	O
+L	O
+-	O
+4	O
+-	O
+amino	O
+-	O
+hex	O
+-	O
+5	O
+-	O
+enoic	O
+acid	O
+)	O
+","	O
+5	O
+micrograms	O
+","	O
+into	O
+the	O
+SNR	O
+","	O
+bilaterally	O
+","	O
+suppressed	O
+the	O
+appearance	O
+of	O
+electrographic	O
+and	O
+behavioral	O
+seizures	B-NP
+produced	O
+by	O
+pilocarpine	O
+","	O
+380	O
+mg	O
+/	O
+kg	O
+.	O
+	
+This	O
+treatment	O
+was	O
+also	O
+sufficient	O
+to	O
+protect	O
+animals	O
+from	O
+the	O
+occurrence	O
+of	O
+brain	B-NP
+damage	I-NP
+.	O
+	
+Microinjections	O
+of	O
+gamma	O
+-	O
+vinyl	O
+-	O
+GABA	O
+","	O
+5	O
+micrograms	O
+","	O
+into	O
+the	O
+dorsal	O
+striatum	O
+","	O
+bilaterally	O
+","	O
+failed	O
+to	O
+prevent	O
+the	O
+development	O
+of	O
+convulsions	B-NP
+produced	O
+by	O
+pilocarpine	O
+","	O
+380	O
+mg	O
+/	O
+kg	O
+.	O
+	
+The	O
+results	O
+demonstrate	O
+that	O
+the	O
+threshold	O
+for	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B-NP
+in	O
+rats	O
+is	O
+subjected	O
+to	O
+the	O
+regulation	O
+of	O
+the	O
+GABA	O
+-	O
+mediated	O
+synaptic	O
+inhibition	O
+within	O
+the	O
+substantia	O
+nigra	O
+.	O
+	
+Human	O
+and	O
+canine	O
+ventricular	O
+vasoactive	O
+intestinal	O
+polypeptide	O
+:	O
+decrease	O
+with	O
+heart	B-NP
+failure	I-NP
+.	O
+	
+Vasoactive	O
+intestinal	O
+polypeptide	O
+(	O
+VIP	O
+)	O
+is	O
+a	O
+systemic	O
+and	O
+coronary	O
+vasodilator	O
+that	O
+may	O
+have	O
+positive	O
+inotropic	O
+properties	O
+.	O
+	
+Myocardial	O
+levels	O
+of	O
+VIP	O
+were	O
+assayed	O
+before	O
+and	O
+after	O
+the	O
+development	O
+of	O
+heart	B-NP
+failure	I-NP
+in	O
+two	O
+canine	O
+models	O
+.	O
+	
+In	O
+the	O
+first	O
+","	O
+cobalt	O
+cardiomyopathy	B-NP
+was	O
+induced	O
+in	O
+eight	O
+dogs	O
+;	O
+VIP	O
+(	O
+by	O
+radioimmunoassay	O
+)	O
+decreased	O
+from	O
+35	O
++	O
+/	O
+-	O
+11	O
+pg	O
+/	O
+mg	O
+protein	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+)	O
+to	O
+5	O
++	O
+/	O
+-	O
+4	O
+pg	O
+/	O
+mg	O
+protein	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+In	O
+six	O
+dogs	O
+with	O
+doxorubicin	O
+-	O
+induced	O
+heart	B-NP
+failure	I-NP
+","	O
+VIP	O
+decreased	O
+from	O
+31	O
++	O
+/	O
+-	O
+7	O
+to	O
+11	O
++	O
+/	O
+-	O
+4	O
+pg	O
+/	O
+mg	O
+protein	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+In	O
+addition	O
+","	O
+VIP	O
+content	O
+of	O
+left	O
+ventricular	O
+muscle	O
+of	O
+resected	O
+failing	O
+hearts	O
+in	O
+10	O
+patients	O
+receiving	O
+a	O
+heart	O
+transplant	O
+was	O
+compared	O
+with	O
+the	O
+papillary	O
+muscles	O
+in	O
+14	O
+patients	O
+(	O
+five	O
+with	O
+rheumatic	B-NP
+disease	I-NP
+","	O
+nine	O
+with	O
+myxomatous	B-NP
+degeneration	I-NP
+)	O
+receiving	O
+mitral	O
+valve	O
+prostheses	O
+.	O
+	
+The	O
+lowest	O
+myocardial	O
+VIP	O
+concentration	O
+was	O
+found	O
+in	O
+the	O
+hearts	O
+of	O
+patients	O
+with	O
+coronary	B-NP
+disease	I-NP
+(	O
+one	O
+patient	O
+receiving	O
+a	O
+transplant	O
+and	O
+three	O
+receiving	O
+mitral	O
+prostheses	O
+)	O
+(	O
+6	O
+.	O
+3	O
++	O
+/	O
+-	O
+1	O
+.	O
+9	O
+pg	O
+/	O
+mg	O
+protein	O
+)	O
+.	O
+	
+The	O
+other	O
+patients	O
+undergoing	O
+transplantation	O
+had	O
+an	O
+average	O
+ejection	O
+fraction	O
+of	O
+17	O
+%	O
++	O
+/	O
+-	O
+6	O
+%	O
+and	O
+a	O
+VIP	O
+level	O
+of	O
+8	O
+.	O
+8	O
++	O
+/	O
+-	O
+3	O
+.	O
+9	O
+pg	O
+/	O
+mg	O
+protein	O
+.	O
+	
+The	O
+hearts	O
+without	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+(	O
+average	O
+ejection	O
+fraction	O
+of	O
+this	O
+group	O
+62	O
+%	O
++	O
+/	O
+-	O
+10	O
+%	O
+)	O
+had	O
+a	O
+VIP	O
+concentration	O
+of	O
+14	O
+.	O
+1	O
++	O
+/	O
+-	O
+7	O
+.	O
+9	O
+pg	O
+/	O
+mg	O
+protein	O
+","	O
+and	O
+this	O
+was	O
+greater	O
+than	O
+in	O
+hearts	O
+of	O
+the	O
+patients	O
+with	O
+coronary	B-NP
+disease	I-NP
+and	O
+the	O
+hearts	O
+of	O
+patients	O
+receiving	O
+a	O
+transplant	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+Myocardial	O
+catecholamines	O
+were	O
+also	O
+determined	O
+in	O
+14	O
+subjects	O
+;	O
+a	O
+weak	O
+correlation	O
+(	O
+r	O
+=	O
+0	O
+.	O
+57	O
+","	O
+P	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+between	O
+the	O
+tissue	O
+concentrations	O
+of	O
+VIP	O
+and	O
+norepinephrine	O
+was	O
+noted	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+	
+Non	O
+-	O
+invasive	O
+detection	O
+of	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+by	O
+body	O
+surface	O
+electrocardiographic	O
+mapping	O
+after	O
+dipyridamole	O
+infusion	O
+.	O
+	
+Electrocardiographic	O
+changes	O
+after	O
+dipyridamole	O
+infusion	O
+(	O
+0	O
+.	O
+568	O
+mg	O
+/	O
+kg	O
+/	O
+4	O
+min	O
+)	O
+were	O
+studied	O
+in	O
+41	O
+patients	O
+with	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+and	O
+compared	O
+with	O
+those	O
+after	O
+submaximal	O
+treadmill	O
+exercise	O
+by	O
+use	O
+of	O
+the	O
+body	O
+surface	O
+mapping	O
+technique	O
+.	O
+	
+Patients	O
+were	O
+divided	O
+into	O
+three	O
+groups	O
+;	O
+19	O
+patients	O
+without	O
+myocardial	B-NP
+infarction	I-NP
+(	O
+non	O
+-	O
+MI	B-NP
+group	O
+)	O
+","	O
+14	O
+with	O
+anterior	B-NP
+infarction	I-NP
+(	O
+ANT	B-NP
+-	I-NP
+MI	I-NP
+)	O
+and	O
+eight	O
+with	O
+inferior	B-NP
+infarction	I-NP
+(	O
+INF	B-NP
+-	I-NP
+MI	I-NP
+)	O
+.	O
+	
+Eighty	O
+-	O
+seven	O
+unipolar	O
+electrocardiograms	O
+(	O
+ECGs	O
+)	O
+distributed	O
+over	O
+the	O
+entire	O
+thoracic	O
+surface	O
+were	O
+simultaneously	O
+recorded	O
+.	O
+	
+After	O
+dipyridamole	O
+","	O
+ischemic	B-NP
+ST	O
+-	O
+segment	O
+depression	B-NP
+(	O
+0	O
+.	O
+5	O
+mV	O
+or	O
+more	O
+)	O
+was	O
+observed	O
+in	O
+84	O
+%	O
+of	O
+the	O
+non	O
+-	O
+MI	B-NP
+group	O
+","	O
+29	O
+%	O
+of	O
+the	O
+ANT	B-NP
+-	I-NP
+MI	I-NP
+group	O
+","	O
+63	O
+%	O
+of	O
+the	O
+INF	B-NP
+-	I-NP
+MI	I-NP
+group	O
+and	O
+61	O
+%	O
+of	O
+the	O
+total	O
+population	O
+.	O
+	
+Exercise	O
+-	O
+induced	O
+ST	O
+depression	B-NP
+was	O
+observed	O
+in	O
+84	O
+%	O
+of	O
+the	O
+non	O
+-	O
+MI	B-NP
+group	O
+","	O
+43	O
+%	O
+of	O
+the	O
+ANT	B-NP
+-	I-NP
+MI	I-NP
+group	O
+","	O
+38	O
+%	O
+of	O
+the	O
+INF	B-NP
+-	I-NP
+MI	I-NP
+group	O
+and	O
+61	O
+%	O
+of	O
+the	O
+total	O
+.	O
+	
+For	O
+individual	O
+patients	O
+","	O
+there	O
+were	O
+no	O
+obvious	O
+differences	O
+between	O
+the	O
+body	O
+surface	O
+distribution	O
+of	O
+ST	O
+depression	B-NP
+in	O
+both	O
+tests	O
+.	O
+	
+The	O
+increase	O
+in	O
+pressure	O
+rate	O
+product	O
+after	O
+dipyridamole	O
+was	O
+significantly	O
+less	O
+than	O
+that	O
+during	O
+the	O
+treadmill	O
+exercise	O
+.	O
+	
+The	O
+data	O
+suggest	O
+that	O
+the	O
+dipyridamole	O
+-	O
+induced	O
+myocardial	B-NP
+ischemia	I-NP
+is	O
+caused	O
+by	O
+the	O
+inhomogenous	O
+distribution	O
+of	O
+myocardial	O
+blood	O
+flow	O
+.	O
+	
+We	O
+conclude	O
+that	O
+the	O
+dipyridamole	O
+ECG	O
+test	O
+is	O
+as	O
+useful	O
+as	O
+the	O
+exercise	O
+ECG	O
+test	O
+for	O
+the	O
+assessment	O
+of	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+.	O
+	
+Bradycardia	B-NP
+after	O
+high	O
+-	O
+dose	O
+intravenous	O
+methylprednisolone	O
+therapy	O
+.	O
+	
+In	O
+5	O
+consecutive	O
+patients	O
+with	O
+rheumatoid	B-NP
+arthritis	I-NP
+who	O
+received	O
+intravenous	O
+high	O
+-	O
+dose	O
+methylprednisolone	O
+(	O
+MP	O
+)	O
+therapy	O
+(	O
+1	O
+g	O
+daily	O
+for	O
+2	O
+or	O
+3	O
+consecutive	O
+days	O
+)	O
+","	O
+a	O
+decline	O
+in	O
+pulse	O
+rate	O
+was	O
+observed	O
+","	O
+most	O
+pronounced	O
+on	O
+day	O
+4	O
+.	O
+	
+In	O
+one	O
+of	O
+the	O
+5	O
+patients	O
+the	O
+bradycardia	B-NP
+was	O
+associated	O
+with	O
+complaints	O
+of	O
+substernal	O
+pressure	O
+.	O
+	
+Reversal	O
+to	O
+normal	O
+heart	O
+rate	O
+was	O
+found	O
+on	O
+day	O
+7	O
+.	O
+	
+Electrocardiographic	O
+registrations	O
+showed	O
+sinus	B-NP
+bradycardia	I-NP
+in	O
+all	O
+cases	O
+.	O
+	
+No	O
+significant	O
+changes	O
+in	O
+plasma	O
+concentrations	O
+of	O
+electrolytes	O
+were	O
+found	O
+.	O
+	
+Careful	O
+observation	O
+of	O
+patients	O
+receiving	O
+high	O
+-	O
+dose	O
+MP	O
+is	O
+recommended	O
+.	O
+	
+High	O
+-	O
+dose	O
+MP	O
+may	O
+be	O
+contraindicated	O
+in	O
+patients	O
+with	O
+known	O
+heart	B-NP
+disease	I-NP
+.	O
+	
+Two	O
+cases	O
+of	O
+downbeat	B-NP
+nystagmus	I-NP
+and	O
+oscillopsia	B-NP
+associated	O
+with	O
+carbamazepine	O
+.	O
+	
+Downbeat	B-NP
+nystagmus	I-NP
+is	O
+often	O
+associated	O
+with	O
+structural	O
+lesions	O
+at	O
+the	O
+craniocervical	O
+junction	O
+","	O
+but	O
+has	O
+occasionally	O
+been	O
+reported	O
+as	O
+a	O
+manifestation	O
+of	O
+metabolic	O
+imbalance	O
+or	O
+drug	O
+intoxication	O
+.	O
+	
+We	O
+recorded	O
+the	O
+eye	O
+movements	O
+of	O
+two	O
+patients	O
+with	O
+reversible	O
+downbeat	B-NP
+nystagmus	I-NP
+related	O
+to	O
+carbamazepine	O
+therapy	O
+.	O
+	
+The	O
+nystagmus	B-NP
+of	O
+both	O
+patients	O
+resolved	O
+after	O
+reduction	O
+of	O
+the	O
+serum	O
+carbamazepine	O
+levels	O
+.	O
+	
+Neuroradiologic	O
+investigations	O
+including	O
+magnetic	O
+resonance	O
+imaging	O
+scans	O
+in	O
+both	O
+patients	O
+showed	O
+no	O
+evidence	O
+of	O
+intracranial	O
+abnormality	O
+.	O
+	
+In	O
+patients	O
+with	O
+downbeat	B-NP
+nystagmus	I-NP
+who	O
+are	O
+taking	O
+anticonvulsant	O
+medications	O
+","	O
+consideration	O
+should	O
+be	O
+given	O
+to	O
+reduction	O
+in	O
+dose	O
+before	O
+further	O
+investigation	O
+is	O
+undertaken	O
+.	O
+	
+Improvement	O
+by	O
+denopamine	O
+(	O
+TA	O
+-	O
+64	O
+)	O
+of	O
+pentobarbital	O
+-	O
+induced	O
+cardiac	B-NP
+failure	I-NP
+in	O
+the	O
+dog	O
+heart	O
+-	O
+lung	O
+preparation	O
+.	O
+	
+The	O
+efficacy	O
+of	O
+denopamine	O
+","	O
+an	O
+orally	O
+active	O
+beta	O
+1	O
+-	O
+adrenoceptor	O
+agonist	O
+","	O
+in	O
+improving	O
+cardiac	B-NP
+failure	I-NP
+was	O
+assessed	O
+in	O
+dog	O
+heart	O
+-	O
+lung	O
+preparations	O
+.	O
+	
+Cardiac	O
+functions	O
+depressed	O
+by	O
+pentobarbital	O
+(	O
+118	O
++	O
+/	O
+-	O
+28	O
+mg	O
+;	O
+mean	O
+value	O
++	O
+/	O
+-	O
+SD	O
+)	O
+such	O
+that	O
+cardiac	O
+output	O
+and	O
+maximum	O
+rate	O
+of	O
+rise	O
+of	O
+left	O
+ventricular	O
+pressure	O
+(	O
+LV	O
+dP	O
+/	O
+dt	O
+max	O
+)	O
+had	O
+been	O
+reduced	O
+by	O
+about	O
+35	O
+%	O
+and	O
+26	O
+%	O
+of	O
+the	O
+respective	O
+controls	O
+were	O
+improved	O
+by	O
+denopamine	O
+(	O
+10	O
+-	O
+300	O
+micrograms	O
+)	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+.	O
+	
+With	O
+100	O
+micrograms	O
+denopamine	O
+","	O
+almost	O
+complete	O
+restoration	O
+of	O
+cardiac	O
+performance	O
+was	O
+attained	O
+","	O
+associated	O
+with	O
+a	O
+slight	O
+increase	O
+in	O
+heart	O
+rate	O
+.	O
+	
+No	O
+arrhythmias	B-NP
+were	O
+induced	O
+by	O
+these	O
+doses	O
+of	O
+denopamine	O
+.	O
+	
+The	O
+results	O
+warrant	O
+clinical	O
+trials	O
+of	O
+denopamine	O
+in	O
+the	O
+treatment	O
+of	O
+cardiac	B-NP
+failure	I-NP
+.	O
+	
+Clonazepam	O
+monotherapy	O
+for	O
+epilepsy	B-NP
+in	O
+childhood	O
+.	O
+	
+Sixty	O
+patients	O
+(	O
+age	O
+-	O
+range	O
+one	O
+month	O
+to	O
+14	O
+years	O
+)	O
+with	O
+other	O
+types	O
+of	O
+epilepsy	B-NP
+than	O
+infantile	B-NP
+spasms	I-NP
+were	O
+treated	O
+with	O
+clonazepam	O
+.	O
+	
+Disappearance	O
+of	O
+seizures	B-NP
+and	O
+normalization	O
+of	O
+abnormal	O
+EEG	O
+with	O
+disappearance	O
+of	O
+seizures	B-NP
+were	O
+recognized	O
+in	O
+77	O
+%	O
+and	O
+50	O
+%	O
+","	O
+respectively	O
+.	O
+	
+Seizures	B-NP
+disappeared	O
+in	O
+71	O
+%	O
+of	O
+the	O
+patients	O
+with	O
+generalized	O
+seizures	B-NP
+and	O
+89	O
+%	O
+of	O
+partial	O
+seizures	B-NP
+.	O
+	
+Improvement	O
+of	O
+abnormal	O
+EEG	O
+was	O
+noticed	O
+in	O
+76	O
+%	O
+of	O
+diffuse	O
+paroxysms	O
+and	O
+in	O
+67	O
+%	O
+of	O
+focal	O
+paroxysms	O
+.	O
+	
+In	O
+excellent	O
+cases	O
+","	O
+mean	O
+effective	O
+dosages	O
+were	O
+0	O
+.	O
+86	O
++	O
+/	O
+-	O
+0	O
+.	O
+21	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+in	O
+infants	O
+and	O
+0	O
+.	O
+57	O
++	O
+/	O
+-	O
+0	O
+.	O
+22	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+in	O
+schoolchildren	O
+","	O
+this	O
+difference	O
+was	O
+statistically	O
+significant	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+The	O
+incidence	O
+of	O
+side	O
+effects	O
+such	O
+as	O
+drowsiness	B-NP
+and	O
+ataxia	B-NP
+was	O
+only	O
+5	O
+%	O
+.	O
+	
+Postmarketing	O
+study	O
+of	O
+timolol	O
+-	O
+hydrochlorothiazide	O
+antihypertensive	O
+therapy	O
+.	O
+	
+A	O
+postmarketing	O
+surveillance	O
+study	O
+was	O
+conducted	O
+to	O
+determine	O
+the	O
+safety	O
+and	O
+efficacy	O
+of	O
+a	O
+fixed	O
+-	O
+ratio	O
+combination	O
+containing	O
+10	O
+mg	O
+of	O
+timolol	O
+maleate	O
+and	O
+25	O
+mg	O
+of	O
+hydrochlorothiazide	O
+","	O
+administered	O
+twice	O
+daily	O
+for	O
+one	O
+month	O
+to	O
+hypertensive	B-NP
+patients	O
+.	O
+	
+Data	O
+on	O
+9	O
+","	O
+37	O
+patients	O
+were	O
+collected	O
+by	O
+1	O
+","	O
+455	O
+participating	O
+physicians	O
+.	O
+	
+Mean	O
+systolic	O
+blood	O
+pressure	O
+decreased	O
+25	O
+mmHg	O
+and	O
+mean	O
+diastolic	O
+blood	O
+pressure	O
+declined	O
+15	O
+mmHg	O
+after	O
+one	O
+month	O
+of	O
+timolol	O
+-	O
+hydrochlorothiazide	O
+therapy	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+1	O
+","	O
+both	O
+comparisons	O
+)	O
+.	O
+	
+Age	O
+","	O
+race	O
+","	O
+and	O
+sex	O
+appeared	O
+to	O
+have	O
+no	O
+influence	O
+on	O
+the	O
+decrease	O
+in	O
+blood	O
+pressure	O
+.	O
+	
+The	O
+antihypertensive	O
+effect	O
+of	O
+the	O
+drug	O
+was	O
+greater	O
+in	O
+patients	O
+with	O
+more	O
+severe	O
+hypertension	B-NP
+.	O
+	
+Overall	O
+","	O
+1	O
+","	O
+453	O
+patients	O
+experienced	O
+a	O
+total	O
+of	O
+2	O
+","	O
+658	O
+adverse	O
+events	O
+","	O
+the	O
+most	O
+common	O
+being	O
+fatigue	B-NP
+","	O
+dizziness	B-NP
+","	O
+and	O
+weakness	B-NP
+.	O
+	
+Treatment	O
+in	O
+590	O
+patients	O
+was	O
+discontinued	O
+because	O
+of	O
+adverse	O
+events	O
+.	O
+	
+Salicylate	O
+nephropathy	B-NP
+in	O
+the	O
+Gunn	O
+rat	O
+:	O
+potential	O
+role	O
+of	O
+prostaglandins	O
+.	O
+	
+We	O
+examined	O
+the	O
+potential	O
+role	O
+of	O
+prostaglandins	O
+in	O
+the	O
+development	O
+of	O
+analgesic	O
+nephropathy	B-NP
+in	O
+the	O
+Gunn	O
+strain	O
+of	O
+rat	O
+.	O
+	
+The	O
+homozygous	O
+Gunn	O
+rats	O
+have	O
+unconjugated	O
+hyperbilirubinemia	B-NP
+due	O
+to	O
+the	O
+absence	O
+of	O
+glucuronyl	O
+transferase	O
+","	O
+leading	O
+to	O
+marked	O
+bilirubin	O
+deposition	O
+in	O
+renal	O
+medulla	O
+and	O
+papilla	O
+.	O
+	
+These	O
+rats	O
+are	O
+also	O
+highly	O
+susceptible	O
+to	O
+develop	O
+papillary	B-NP
+necrosis	I-NP
+with	O
+analgesic	O
+administration	O
+.	O
+	
+We	O
+used	O
+homozygous	O
+(	O
+jj	O
+)	O
+and	O
+phenotypically	O
+normal	O
+heterozygous	O
+(	O
+jJ	O
+)	O
+animals	O
+.	O
+	
+Four	O
+groups	O
+of	O
+rats	O
+(	O
+n	O
+=	O
+7	O
+)	O
+were	O
+studied	O
+:	O
+jj	O
+and	O
+jJ	O
+rats	O
+treated	O
+either	O
+with	O
+aspirin	O
+300	O
+mg	O
+/	O
+kg	O
+every	O
+other	O
+day	O
+or	O
+sham	O
+-	O
+treated	O
+.	O
+	
+After	O
+one	O
+week	O
+","	O
+slices	O
+of	O
+cortex	O
+","	O
+outer	O
+and	O
+inner	O
+medulla	O
+from	O
+one	O
+kidney	O
+were	O
+incubated	O
+in	O
+buffer	O
+and	O
+prostaglandin	O
+synthesis	O
+was	O
+determined	O
+by	O
+radioimmunoassay	O
+.	O
+	
+The	O
+other	O
+kidney	O
+was	O
+examined	O
+histologically	O
+.	O
+	
+A	O
+marked	O
+corticomedullary	O
+gradient	O
+of	O
+prostaglandin	O
+synthesis	O
+was	O
+observed	O
+in	O
+all	O
+groups	O
+.	O
+	
+PGE2	O
+synthesis	O
+was	O
+significantly	O
+higher	O
+in	O
+outer	O
+medulla	O
+","	O
+but	O
+not	O
+cortex	O
+or	O
+inner	O
+medulla	O
+","	O
+of	O
+jj	O
+(	O
+38	O
++	O
+/	O
+-	O
+6	O
+ng	O
+/	O
+mg	O
+prot	O
+)	O
+than	O
+jJ	O
+rats	O
+(	O
+15	O
++	O
+/	O
+-	O
+3	O
+)	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Aspirin	O
+treatment	O
+reduced	O
+PGE2	O
+synthesis	O
+in	O
+all	O
+regions	O
+","	O
+but	O
+outer	O
+medullary	O
+PGE2	O
+remained	O
+higher	O
+in	O
+jj	O
+(	O
+18	O
++	O
+/	O
+-	O
+3	O
+)	O
+than	O
+jJ	O
+rats	O
+(	O
+9	O
++	O
+/	O
+-	O
+2	O
+)	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+PGF2	O
+alpha	O
+was	O
+also	O
+significantly	O
+higher	O
+in	O
+the	O
+outer	O
+medulla	O
+of	O
+jj	O
+rats	O
+with	O
+and	O
+without	O
+aspirin	O
+administration	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+The	O
+changes	O
+in	O
+renal	O
+prostaglandin	O
+synthesis	O
+were	O
+accompanied	O
+by	O
+evidence	O
+of	O
+renal	B-NP
+damage	I-NP
+in	O
+aspirin	O
+-	O
+treated	O
+jj	O
+but	O
+not	O
+jJ	O
+rats	O
+as	O
+evidenced	O
+by	O
+:	O
+increased	O
+incidence	O
+and	O
+severity	O
+of	O
+hematuria	B-NP
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+;	O
+increased	O
+serum	O
+creatinine	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+;	O
+and	O
+increase	O
+in	O
+outer	O
+medullary	O
+histopathologic	O
+lesions	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+compared	O
+to	O
+either	O
+sham	O
+-	O
+treated	O
+jj	O
+or	O
+aspirin	O
+-	O
+treated	O
+jJ	O
+)	O
+.	O
+	
+These	O
+results	O
+suggest	O
+that	O
+enhanced	O
+prostaglandin	O
+synthesis	O
+contributes	O
+to	O
+maintenance	O
+of	O
+renal	O
+function	O
+and	O
+morphological	O
+integrity	O
+","	O
+and	O
+that	O
+inhibition	O
+of	O
+prostaglandin	O
+synthesis	O
+may	O
+lead	O
+to	O
+pathological	B-NP
+renal	I-NP
+medullary	I-NP
+lesions	I-NP
+and	O
+deterioration	B-NP
+of	I-NP
+renal	I-NP
+function	I-NP
+.	O
+	
+Prophylactic	O
+lidocaine	O
+in	O
+the	O
+early	O
+phase	O
+of	O
+suspected	O
+myocardial	B-NP
+infarction	I-NP
+.	O
+	
+Four	O
+hundred	O
+two	O
+patients	O
+with	O
+suspected	O
+myocardial	B-NP
+infarction	I-NP
+seen	O
+within	O
+6	O
+hours	O
+of	O
+the	O
+onset	O
+of	O
+symptoms	O
+entered	O
+a	O
+double	O
+-	O
+blind	O
+randomized	O
+trial	O
+of	O
+lidocaine	O
+vs	O
+placebo	O
+.	O
+	
+During	O
+the	O
+1	O
+hour	O
+after	O
+administration	O
+of	O
+the	O
+drug	O
+the	O
+incidence	O
+of	O
+ventricular	B-NP
+fibrillation	I-NP
+or	O
+sustained	O
+ventricular	B-NP
+tachycardia	I-NP
+among	O
+the	O
+204	O
+patients	O
+with	O
+acute	O
+myocardial	B-NP
+infarction	I-NP
+was	O
+low	O
+","	O
+1	O
+.	O
+5	O
+%	O
+.	O
+	
+Lidocaine	O
+","	O
+given	O
+in	O
+a	O
+300	O
+mg	O
+dose	O
+intramuscularly	O
+followed	O
+by	O
+100	O
+mg	O
+intravenously	O
+","	O
+did	O
+not	O
+prevent	O
+sustained	O
+ventricular	B-NP
+tachycardia	I-NP
+","	O
+although	O
+there	O
+was	O
+a	O
+significant	O
+reduction	O
+in	O
+the	O
+number	O
+of	O
+patients	O
+with	O
+warning	O
+arrhythmias	B-NP
+between	O
+15	O
+and	O
+45	O
+minutes	O
+after	O
+the	O
+administration	O
+of	O
+lidocaine	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+The	O
+average	O
+plasma	O
+lidocaine	O
+level	O
+10	O
+minutes	O
+after	O
+administration	O
+for	O
+patients	O
+without	O
+a	O
+myocardial	B-NP
+infarction	I-NP
+was	O
+significantly	O
+higher	O
+than	O
+that	O
+for	O
+patients	O
+with	O
+an	O
+acute	O
+infarction	B-NP
+.	O
+	
+The	O
+mean	O
+plasma	O
+lidocaine	O
+level	O
+of	O
+patients	O
+on	O
+beta	O
+-	O
+blocking	O
+agents	O
+was	O
+no	O
+different	O
+from	O
+that	O
+in	O
+patients	O
+not	O
+on	O
+beta	O
+blocking	O
+agents	O
+.	O
+	
+During	O
+the	O
+1	O
+-	O
+hour	O
+study	O
+period	O
+","	O
+the	O
+incidence	O
+of	O
+central	O
+nervous	O
+system	O
+side	O
+effects	O
+was	O
+significantly	O
+greater	O
+in	O
+the	O
+lidocaine	O
+group	O
+","	O
+hypotension	B-NP
+occurred	O
+in	O
+11	O
+patients	O
+","	O
+nine	O
+of	O
+whom	O
+had	O
+received	O
+lidocaine	O
+","	O
+and	O
+four	O
+patients	O
+died	O
+from	O
+asystole	B-NP
+","	O
+three	O
+of	O
+whom	O
+had	O
+had	O
+lidocaine	O
+.	O
+	
+We	O
+cannot	O
+advocate	O
+the	O
+administration	O
+of	O
+lidocaine	O
+prophylactically	O
+in	O
+the	O
+early	O
+hours	O
+of	O
+suspected	O
+myocardial	B-NP
+infarction	I-NP
+.	O
+	
+Evidence	O
+for	O
+a	O
+cholinergic	O
+role	O
+in	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B-NP
+.	O
+	
+Experiments	O
+in	O
+mice	O
+tested	O
+previous	O
+evidence	O
+that	O
+activation	O
+of	O
+cholinergic	O
+systems	O
+promotes	O
+catalepsy	B-NP
+and	O
+that	O
+cholinergic	O
+mechanisms	O
+need	O
+to	O
+be	O
+intact	O
+for	O
+full	O
+expression	O
+of	O
+neuroleptic	O
+-	O
+induced	O
+catalepsy	B-NP
+.	O
+	
+Large	O
+doses	O
+of	O
+the	O
+cholinomimetic	O
+","	O
+pilocarpine	O
+","	O
+could	O
+induce	O
+catalepsy	B-NP
+when	O
+peripheral	O
+cholinergic	O
+receptors	O
+were	O
+blocked	O
+.	O
+	
+Low	O
+doses	O
+of	O
+pilocarpine	O
+caused	O
+a	O
+pronounced	O
+enhancement	O
+of	O
+the	O
+catalepsy	B-NP
+that	O
+was	O
+induced	O
+by	O
+the	O
+dopaminergic	O
+blocker	O
+","	O
+haloperidol	O
+.	O
+	
+A	O
+muscarinic	O
+receptor	O
+blocker	O
+","	O
+atropine	O
+","	O
+disrupted	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B-NP
+.	O
+	
+Intracranial	O
+injection	O
+of	O
+an	O
+acetylcholine	O
+-	O
+synthesis	O
+inhibitor	O
+","	O
+hemicholinium	O
+","	O
+prevented	O
+the	O
+catalepsy	B-NP
+that	O
+is	O
+usually	O
+induced	O
+by	O
+haloperidol	O
+.	O
+	
+These	O
+findings	O
+suggest	O
+the	O
+hypothesis	O
+that	O
+the	O
+catalepsy	B-NP
+that	O
+is	O
+produced	O
+by	O
+neuroleptics	O
+such	O
+as	O
+haloperidol	O
+is	O
+actually	O
+mediated	O
+by	O
+intrinsic	O
+central	O
+cholinergic	O
+systems	O
+.	O
+	
+Alternatively	O
+","	O
+activation	O
+of	O
+central	O
+cholinergic	O
+systems	O
+could	O
+promote	O
+catalepsy	B-NP
+by	O
+suppression	O
+of	O
+dopaminergic	O
+systems	O
+.	O
+	
+Cardiovascular	B-NP
+dysfunction	I-NP
+and	O
+hypersensitivity	B-NP
+to	O
+sodium	O
+pentobarbital	O
+induced	O
+by	O
+chronic	O
+barium	O
+chloride	O
+ingestion	O
+.	O
+	
+Barium	O
+-	O
+supplemented	O
+Long	O
+-	O
+Evans	O
+hooded	O
+rats	O
+were	O
+characterized	O
+by	O
+a	O
+persistent	O
+hypertension	B-NP
+that	O
+was	O
+evident	O
+after	O
+1	O
+month	O
+of	O
+barium	O
+(	O
+100	O
+micrograms	O
+/	O
+ml	O
+mineral	O
+fortified	O
+water	O
+)	O
+treatment	O
+.	O
+	
+Analysis	O
+of	O
+in	O
+vivo	O
+myocardial	O
+excitability	O
+","	O
+contractility	O
+","	O
+and	O
+metabolic	O
+characteristics	O
+at	O
+16	O
+months	O
+revealed	O
+other	O
+significant	O
+barium	O
+-	O
+induced	O
+disturbances	B-NP
+within	I-NP
+the	I-NP
+cardiovascular	I-NP
+system	I-NP
+.	O
+	
+The	O
+most	O
+distinctive	O
+aspect	O
+of	O
+the	O
+barium	O
+effect	O
+was	O
+a	O
+demonstrated	O
+hypersensitivity	B-NP
+of	O
+the	O
+cardiovascular	O
+system	O
+to	O
+sodium	O
+pentobarbital	O
+.	O
+	
+Under	O
+barbiturate	O
+anesthesia	O
+","	O
+virtually	O
+all	O
+of	O
+the	O
+myocardial	O
+contractile	O
+indices	O
+were	O
+depressed	O
+significantly	O
+in	O
+barium	O
+-	O
+exposed	O
+rats	O
+relative	O
+to	O
+the	O
+corresponding	O
+control	O
+-	O
+fed	O
+rats	O
+.	O
+	
+The	O
+lack	O
+of	O
+a	O
+similar	O
+response	O
+to	O
+ketamine	O
+and	O
+xylazine	O
+anesthesia	O
+revealed	O
+that	O
+the	O
+cardiovascular	O
+actions	O
+of	O
+sodium	O
+pentobarbital	O
+in	O
+barium	O
+-	O
+treated	O
+rats	O
+were	O
+linked	O
+specifically	O
+to	O
+this	O
+anesthetic	O
+","	O
+and	O
+were	O
+not	O
+representative	O
+of	O
+a	O
+generalized	O
+anesthetic	O
+response	O
+.	O
+	
+Other	O
+myocardial	O
+pathophysiologic	O
+and	O
+metabolic	O
+changes	O
+induced	O
+by	O
+barium	O
+were	O
+manifest	O
+","	O
+irrespective	O
+of	O
+the	O
+anesthetic	O
+employed	O
+.	O
+	
+The	O
+contractile	O
+element	O
+shortening	O
+velocity	O
+of	O
+the	O
+cardiac	O
+muscle	O
+fibers	O
+was	O
+significantly	O
+slower	O
+in	O
+both	O
+groups	O
+of	O
+barium	O
+-	O
+treated	O
+rats	O
+relative	O
+to	O
+the	O
+control	O
+groups	O
+","	O
+irrespective	O
+of	O
+the	O
+anesthetic	O
+regimen	O
+.	O
+	
+Similarly	O
+","	O
+significant	O
+disturbances	O
+in	O
+myocardial	O
+energy	O
+metabolism	O
+were	O
+detected	O
+in	O
+the	O
+barium	O
+-	O
+exposed	O
+rats	O
+which	O
+were	O
+consistent	O
+with	O
+the	O
+reduced	O
+contractile	O
+element	O
+shortening	O
+velocity	O
+.	O
+	
+In	O
+addition	O
+","	O
+the	O
+excitability	O
+of	O
+the	O
+cardiac	O
+conduction	O
+system	O
+was	O
+depressed	O
+preferentially	O
+in	O
+the	O
+atrioventricular	O
+nodal	O
+region	O
+of	O
+hearts	O
+from	O
+barium	O
+-	O
+exposed	O
+rats	O
+.	O
+	
+Overall	O
+","	O
+the	O
+altered	O
+cardiac	O
+contractility	O
+and	O
+excitability	O
+characteristics	O
+","	O
+the	O
+myocardial	O
+metabolic	B-NP
+disturbances	I-NP
+","	O
+and	O
+the	O
+hypersensitivity	B-NP
+of	O
+the	O
+cardiovascular	O
+system	O
+to	O
+sodium	O
+pentobarbital	O
+suggest	O
+the	O
+existence	O
+of	O
+a	O
+heretofore	O
+undescribed	O
+cardiomyopathic	B-NP
+disorder	I-NP
+induced	O
+by	O
+chronic	O
+barium	O
+exposure	O
+.	O
+	
+These	O
+experimental	O
+findings	O
+represent	O
+the	O
+first	O
+indication	O
+that	O
+life	O
+-	O
+long	O
+barium	O
+ingestion	O
+may	O
+have	O
+significant	O
+adverse	O
+effects	O
+on	O
+the	O
+mammalian	O
+cardiovascular	O
+system	O
+.	O
+	
+Propranolol	O
+antagonism	O
+of	O
+phenylpropanolamine	O
+-	O
+induced	O
+hypertension	B-NP
+.	O
+	
+Phenylpropanolamine	O
+(	O
+PPA	O
+)	O
+overdose	B-NP
+can	O
+cause	O
+severe	O
+hypertension	B-NP
+","	O
+intracerebral	B-NP
+hemorrhage	I-NP
+","	O
+and	O
+death	O
+.	O
+	
+We	O
+studied	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+propranolol	O
+in	O
+the	O
+treatment	O
+of	O
+PPA	O
+-	O
+induced	O
+hypertension	B-NP
+.	O
+	
+Subjects	O
+received	O
+propranolol	O
+either	O
+by	O
+mouth	O
+for	O
+48	O
+hours	O
+before	O
+PPA	O
+or	O
+as	O
+a	O
+rapid	O
+intravenous	O
+infusion	O
+after	O
+PPA	O
+.	O
+	
+PPA	O
+","	O
+75	O
+mg	O
+alone	O
+","	O
+increased	O
+blood	O
+pressure	O
+(	O
+31	O
++	O
+/	O
+-	O
+14	O
+mm	O
+Hg	O
+systolic	O
+","	O
+20	O
++	O
+/	O
+-	O
+5	O
+mm	O
+Hg	O
+diastolic	O
+)	O
+","	O
+and	O
+propranolol	O
+pretreatment	O
+antagonized	O
+this	O
+increase	O
+(	O
+12	O
++	O
+/	O
+-	O
+10	O
+mm	O
+Hg	O
+systolic	O
+","	O
+10	O
++	O
+/	O
+-	O
+7	O
+mm	O
+Hg	O
+diastolic	O
+)	O
+.	O
+	
+Intravenous	O
+propranolol	O
+after	O
+PPA	O
+also	O
+decreased	O
+blood	O
+pressure	O
+.	O
+	
+Left	O
+ventricular	O
+function	O
+(	O
+assessed	O
+by	O
+echocardiography	O
+)	O
+showed	O
+that	O
+PPA	O
+increased	O
+the	O
+stroke	B-NP
+volume	O
+30	O
+%	O
+(	O
+from	O
+62	O
+.	O
+5	O
++	O
+/	O
+-	O
+20	O
+.	O
+9	O
+to	O
+80	O
+.	O
+8	O
++	O
+/	O
+-	O
+22	O
+.	O
+4	O
+ml	O
+)	O
+","	O
+the	O
+ejection	O
+fraction	O
+9	O
+%	O
+(	O
+from	O
+64	O
+%	O
++	O
+/	O
+-	O
+10	O
+%	O
+to	O
+70	O
+%	O
++	O
+/	O
+-	O
+7	O
+%	O
+)	O
+","	O
+and	O
+cardiac	O
+output	O
+14	O
+%	O
+(	O
+from	O
+3	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+to	O
+4	O
+.	O
+1	O
++	O
+/	O
+-	O
+1	O
+.	O
+0	O
+L	O
+/	O
+min	O
+)	O
+.	O
+	
+Intravenous	O
+propranolol	O
+reversed	O
+these	O
+effects	O
+.	O
+	
+Systemic	O
+vascular	O
+resistance	O
+was	O
+increased	O
+by	O
+PPA	O
+28	O
+%	O
+(	O
+from	O
+1710	O
++	O
+/	O
+-	O
+200	O
+to	O
+2190	O
++	O
+/	O
+-	O
+700	O
+dyne	O
+X	O
+sec	O
+/	O
+cm5	O
+)	O
+and	O
+was	O
+further	O
+increased	O
+by	O
+propranolol	O
+22	O
+%	O
+(	O
+to	O
+2660	O
++	O
+/	O
+-	O
+1200	O
+dyne	O
+X	O
+sec	O
+/	O
+cm5	O
+)	O
+.	O
+	
+We	O
+conclude	O
+that	O
+PPA	O
+increases	O
+blood	O
+pressure	O
+by	O
+increasing	O
+systemic	O
+vascular	O
+resistance	O
+and	O
+cardiac	O
+output	O
+","	O
+and	O
+that	O
+propranolol	O
+antagonizes	O
+this	O
+increase	O
+by	O
+reversing	O
+the	O
+effect	O
+of	O
+PPA	O
+on	O
+cardiac	O
+output	O
+.	O
+	
+That	O
+propranolol	O
+antagonizes	O
+the	O
+pressor	O
+effect	O
+of	O
+PPA	O
+is	O
+in	O
+contrast	O
+to	O
+the	O
+interaction	O
+in	O
+which	O
+propranolol	O
+enhances	O
+the	O
+pressor	O
+effect	O
+of	O
+norepinephrine	O
+.	O
+	
+This	O
+is	O
+probably	O
+because	O
+PPA	O
+has	O
+less	O
+beta	O
+2	O
+activity	O
+than	O
+does	O
+norepinephrine	O
+.	O
+	
+Mesangial	O
+function	O
+and	O
+glomerular	B-NP
+sclerosis	I-NP
+in	O
+rats	O
+with	O
+aminonucleoside	O
+nephrosis	B-NP
+.	O
+	
+The	O
+possible	O
+relationship	O
+between	O
+mesangial	B-NP
+dysfunction	I-NP
+and	O
+development	O
+of	O
+glomerular	B-NP
+sclerosis	I-NP
+was	O
+studied	O
+in	O
+the	O
+puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+)	O
+model	O
+.	O
+	
+Five	O
+male	O
+Wistar	O
+rats	O
+received	O
+repeated	O
+subcutaneous	O
+PAN	O
+injections	O
+;	O
+five	O
+controls	O
+received	O
+saline	O
+only	O
+.	O
+	
+After	O
+4	O
+weeks	O
+the	O
+PAN	O
+rats	O
+were	O
+severely	O
+proteinuric	B-NP
+(	O
+190	O
++	O
+/	O
+-	O
+80	O
+mg	O
+/	O
+24	O
+hr	O
+)	O
+","	O
+and	O
+all	O
+rats	O
+were	O
+given	O
+colloidal	O
+carbon	O
+(	O
+CC	O
+)	O
+intravenously	O
+.	O
+	
+At	O
+5	O
+months	O
+glomerular	B-NP
+sclerosis	I-NP
+was	O
+found	O
+in	O
+7	O
+.	O
+6	O
++	O
+/	O
+-	O
+3	O
+.	O
+4	O
+%	O
+of	O
+the	O
+glomeruli	O
+of	O
+PAN	O
+rats	O
+;	O
+glomeruli	O
+of	O
+the	O
+controls	O
+were	O
+normal	O
+.	O
+	
+Glomeruli	O
+of	O
+PAN	O
+rats	O
+contained	O
+significantly	O
+more	O
+CC	O
+than	O
+glomeruli	O
+of	O
+controls	O
+.	O
+	
+Glomeruli	O
+with	O
+sclerosis	B-NP
+contained	O
+significantly	O
+more	O
+CC	O
+than	O
+non	O
+-	O
+sclerotic	O
+glomeruli	O
+in	O
+the	O
+same	O
+kidneys	O
+.	O
+	
+CC	O
+was	O
+preferentially	O
+localized	O
+within	O
+the	O
+sclerotic	O
+areas	O
+of	O
+the	O
+affected	O
+glomeruli	O
+.	O
+	
+Since	O
+mesangial	O
+CC	O
+clearance	O
+from	O
+the	O
+mesangium	O
+did	O
+not	O
+change	O
+during	O
+chronic	O
+PAN	O
+treatment	O
+","	O
+we	O
+conclude	O
+that	O
+this	O
+preferential	O
+CC	O
+localization	O
+within	O
+the	O
+lesions	O
+is	O
+caused	O
+by	O
+an	O
+increased	O
+CC	O
+uptake	O
+shortly	O
+after	O
+injection	O
+in	O
+apparent	O
+vulnerable	O
+areas	O
+where	O
+sclerosis	B-NP
+will	O
+develop	O
+subsequently	O
+.	O
+	
+Cluster	O
+analysis	O
+showed	O
+a	O
+random	O
+distribution	O
+of	O
+lesions	O
+in	O
+the	O
+PAN	O
+glomeruli	O
+in	O
+concordance	O
+with	O
+the	O
+random	O
+localization	O
+of	O
+mesangial	O
+areas	O
+with	O
+dysfunction	O
+in	O
+this	O
+model	O
+.	O
+	
+Similar	O
+to	O
+the	O
+remnant	O
+kidney	O
+model	O
+in	O
+PAN	O
+nephrosis	B-NP
+the	O
+development	O
+of	O
+glomerular	B-NP
+sclerosis	I-NP
+may	O
+be	O
+related	O
+to	O
+"	O
+mesangial	O
+overloading	O
+.	O
+"	O
+	
+Relationship	O
+between	O
+nicotine	O
+-	O
+induced	O
+seizures	B-NP
+and	O
+hippocampal	O
+nicotinic	O
+receptors	O
+.	O
+	
+A	O
+controversy	O
+has	O
+existed	O
+for	O
+several	O
+years	O
+concerning	O
+the	O
+physiological	O
+relevance	O
+of	O
+the	O
+nicotinic	O
+receptor	O
+measured	O
+by	O
+alpha	O
+-	O
+bungarotoxin	O
+binding	O
+.	O
+	
+Using	O
+mice	O
+derived	O
+from	O
+a	O
+classical	O
+F2	O
+and	O
+backcross	O
+genetic	O
+design	O
+","	O
+a	O
+relationship	O
+between	O
+nicotine	O
+-	O
+induced	O
+seizures	B-NP
+and	O
+alpha	O
+-	O
+bungarotoxin	O
+nicotinic	O
+receptor	O
+concentration	O
+was	O
+found	O
+.	O
+	
+Mice	O
+sensitive	O
+to	O
+the	O
+convulsant	O
+effects	O
+of	O
+nicotine	O
+had	O
+greater	O
+alpha	O
+-	O
+bungarotoxin	O
+binding	O
+in	O
+the	O
+hippocampus	O
+than	O
+seizure	B-NP
+insensitive	O
+mice	O
+.	O
+	
+The	O
+binding	O
+sites	O
+from	O
+seizure	B-NP
+sensitive	O
+and	O
+resistant	O
+mice	O
+were	O
+equally	O
+affected	O
+by	O
+treatment	O
+with	O
+dithiothreitol	O
+","	O
+trypsin	O
+or	O
+heat	O
+.	O
+	
+Thus	O
+it	O
+appears	O
+that	O
+the	O
+difference	O
+between	O
+seizure	B-NP
+sensitive	O
+and	O
+insensitive	O
+animals	O
+may	O
+be	O
+due	O
+to	O
+a	O
+difference	O
+in	O
+hippocampal	O
+nicotinic	O
+receptor	O
+concentration	O
+as	O
+measured	O
+with	O
+alpha	O
+-	O
+bungarotoxin	O
+binding	O
+.	O
+	
+The	O
+role	O
+of	O
+p	O
+-	O
+aminophenol	O
+in	O
+acetaminophen	O
+-	O
+induced	O
+nephrotoxicity	B-NP
+:	O
+effect	O
+of	O
+bis	O
+(	O
+p	O
+-	O
+nitrophenyl	O
+)	O
+phosphate	O
+on	O
+acetaminophen	O
+and	O
+p	O
+-	O
+aminophenol	O
+nephrotoxicity	B-NP
+and	O
+metabolism	O
+in	O
+Fischer	O
+344	O
+rats	O
+.	O
+	
+Acetaminophen	O
+(	O
+APAP	O
+)	O
+produces	O
+proximal	O
+tubular	B-NP
+necrosis	I-NP
+in	O
+Fischer	O
+344	O
+(	O
+F344	O
+)	O
+rats	O
+.	O
+	
+Recently	O
+","	O
+p	O
+-	O
+aminophenol	O
+(	O
+PAP	O
+)	O
+","	O
+a	O
+known	O
+potent	O
+nephrotoxicant	O
+","	O
+was	O
+identified	O
+as	O
+a	O
+metabolite	O
+of	O
+APAP	O
+in	O
+F344	O
+rats	O
+.	O
+	
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+if	O
+PAP	O
+formation	O
+is	O
+a	O
+requisite	O
+step	O
+in	O
+APAP	O
+-	O
+induced	O
+nephrotoxicity	B-NP
+.	O
+	
+Therefore	O
+","	O
+the	O
+effect	O
+of	O
+bis	O
+(	O
+p	O
+-	O
+nitrophenyl	O
+)	O
+phosphate	O
+(	O
+BNPP	O
+)	O
+","	O
+an	O
+acylamidase	O
+inhibitor	O
+","	O
+on	O
+APAP	O
+and	O
+PAP	O
+nephrotoxicity	B-NP
+and	O
+metabolism	O
+was	O
+determined	O
+.	O
+	
+BNPP	O
+(	O
+1	O
+to	O
+8	O
+mM	O
+)	O
+reduced	O
+APAP	O
+deacetylation	O
+and	O
+covalent	O
+binding	O
+in	O
+F344	O
+renal	O
+cortical	O
+homogenates	O
+in	O
+a	O
+concentration	O
+-	O
+dependent	O
+manner	O
+.	O
+	
+Pretreatment	O
+of	O
+animals	O
+with	O
+BNPP	O
+prior	O
+to	O
+APAP	O
+or	O
+PAP	O
+administration	O
+resulted	O
+in	O
+marked	O
+reduction	O
+of	O
+APAP	O
+(	O
+900	O
+mg	O
+/	O
+kg	O
+)	O
+nephrotoxicity	B-NP
+but	O
+not	O
+PAP	O
+nephrotoxicity	B-NP
+.	O
+	
+This	O
+result	O
+was	O
+not	O
+due	O
+to	O
+altered	O
+disposition	O
+of	O
+either	O
+APAP	O
+or	O
+acetylated	O
+metabolites	O
+in	O
+plasma	O
+or	O
+renal	O
+cortical	O
+and	O
+hepatic	O
+tissue	O
+.	O
+	
+Rather	O
+","	O
+BNPP	O
+pretreatment	O
+reduced	O
+the	O
+fraction	O
+of	O
+APAP	O
+excreted	O
+as	O
+PAP	O
+by	O
+64	O
+and	O
+75	O
+%	O
+after	O
+APAP	O
+doses	O
+of	O
+750	O
+and	O
+900	O
+mg	O
+/	O
+kg	O
+.	O
+	
+BNPP	O
+did	O
+not	O
+alter	O
+the	O
+excretion	O
+of	O
+APAP	O
+or	O
+any	O
+of	O
+its	O
+non	O
+-	O
+deacetylated	O
+metabolites	O
+nor	O
+did	O
+BNPP	O
+alter	O
+excretion	O
+of	O
+PAP	O
+or	O
+its	O
+metabolites	O
+after	O
+PAP	O
+doses	O
+of	O
+150	O
+and	O
+300	O
+mg	O
+/	O
+kg	O
+.	O
+	
+Therefore	O
+","	O
+the	O
+BNPP	O
+-	O
+induced	O
+reduction	O
+in	O
+APAP	O
+-	O
+induced	O
+nephrotoxicity	B-NP
+appears	O
+to	O
+be	O
+due	O
+to	O
+inhibition	O
+of	O
+APAP	O
+deacetylation	O
+.	O
+	
+It	O
+is	O
+concluded	O
+that	O
+PAP	O
+formation	O
+","	O
+in	O
+vivo	O
+","	O
+accounts	O
+","	O
+at	O
+least	O
+in	O
+part	O
+","	O
+for	O
+APAP	O
+-	O
+induced	O
+renal	B-NP
+tubular	I-NP
+necrosis	I-NP
+.	O
+	
+Morphine	O
+-	O
+induced	O
+seizures	B-NP
+in	O
+newborn	O
+infants	O
+.	O
+	
+Two	O
+neonates	O
+suffered	O
+from	O
+generalized	O
+seizures	B-NP
+during	O
+the	O
+course	O
+of	O
+intravenous	O
+morphine	O
+sulfate	O
+for	O
+post	O
+-	O
+operative	O
+analgesia	O
+.	O
+	
+They	O
+received	O
+morphine	O
+in	O
+doses	O
+of	O
+32	O
+micrograms	O
+/	O
+kg	O
+/	O
+hr	O
+and	O
+40	O
+micrograms	O
+/	O
+kg	O
+/	O
+hr	O
+larger	O
+than	O
+a	O
+group	O
+of	O
+10	O
+neonates	O
+who	O
+received	O
+6	O
+-	O
+24	O
+micrograms	O
+/	O
+kg	O
+/	O
+hr	O
+and	O
+had	O
+no	O
+seizures	B-NP
+.	O
+	
+Plasma	O
+concentrations	O
+of	O
+morphine	O
+in	O
+these	O
+neonates	O
+was	O
+excessive	O
+(	O
+60	O
+and	O
+90	O
+mg	O
+/	O
+ml	O
+)	O
+.	O
+	
+Other	O
+known	O
+reasons	O
+for	O
+seizures	B-NP
+were	O
+ruled	O
+out	O
+and	O
+the	O
+convulsions	B-NP
+stopped	O
+a	O
+few	O
+hours	O
+after	O
+cessation	O
+of	O
+morphine	O
+and	O
+did	O
+not	O
+reoccur	O
+in	O
+the	O
+subsequent	O
+8	O
+months	O
+.	O
+	
+It	O
+is	O
+suggested	O
+that	O
+post	O
+-	O
+operative	O
+intravenous	O
+morphine	O
+should	O
+not	O
+exceed	O
+20	O
+micrograms	O
+/	O
+kg	O
+/	O
+ml	O
+in	O
+neonates	O
+.	O
+	
+Indomethacin	O
+induced	O
+hypotension	B-NP
+in	O
+sodium	O
+and	O
+volume	O
+depleted	O
+rats	O
+.	O
+	
+After	O
+a	O
+single	O
+oral	O
+dose	O
+of	O
+4	O
+mg	O
+/	O
+kg	O
+indomethacin	O
+(	O
+IDM	O
+)	O
+to	O
+sodium	O
+and	O
+volume	O
+depleted	O
+rats	O
+plasma	O
+renin	O
+activity	O
+(	O
+PRA	O
+)	O
+and	O
+systolic	O
+blood	O
+pressure	O
+fell	O
+significantly	O
+within	O
+four	O
+hours	O
+.	O
+	
+In	O
+sodium	O
+repleted	O
+animals	O
+indomethacin	O
+did	O
+not	O
+change	O
+systolic	O
+blood	O
+pressure	O
+(	O
+BP	O
+)	O
+although	O
+plasma	O
+renin	O
+activity	O
+was	O
+decreased	O
+.	O
+	
+Thus	O
+","	O
+indomethacin	O
+by	O
+inhibition	O
+of	O
+prostaglandin	O
+synthesis	O
+may	O
+diminish	O
+the	O
+blood	O
+pressure	O
+maintaining	O
+effect	O
+of	O
+the	O
+stimulated	O
+renin	O
+-	O
+angiotensin	O
+system	O
+in	O
+sodium	O
+and	O
+volume	O
+depletion	O
+.	O
+	
+On	O
+the	O
+antiarrhythmic	O
+activity	O
+of	O
+one	O
+N	O
+-	O
+substituted	O
+piperazine	O
+derivative	O
+of	O
+trans	O
+-	O
+2	O
+-	O
+amino	O
+-	O
+3	O
+-	O
+hydroxy	O
+-	O
+1	O
+","	O
+2	O
+","	O
+3	O
+","	O
+4	O
+-	O
+tetrahydroanaphthalene	O
+.	O
+	
+The	O
+antiarrhythmic	O
+activity	O
+of	O
+the	O
+compound	O
+N	O
+-	O
+(	O
+trans	O
+-	O
+3	O
+-	O
+hydroxy	O
+-	O
+1	O
+","	O
+2	O
+","	O
+3	O
+","	O
+4	O
+-	O
+tetrahydro	O
+-	O
+2	O
+-	O
+naphthyl	O
+)	O
+-	O
+N	O
+-	O
+(	O
+3	O
+-	O
+oxo	O
+-	O
+3	O
+-	O
+phenyl	O
+-	O
+2	O
+-	O
+methylpropyl	O
+)	O
+-	O
+piperazine	O
+hydrochloride	O
+","	O
+referred	O
+to	O
+as	O
+P11	O
+","	O
+is	O
+studied	O
+on	O
+anaesthesized	O
+cats	O
+and	O
+Wistar	O
+albino	O
+rats	O
+","	O
+as	O
+well	O
+as	O
+on	O
+non	O
+-	O
+anaesthesized	O
+rabbits	O
+.	O
+	
+Four	O
+types	O
+of	O
+experimental	O
+arrhythmia	B-NP
+are	O
+used	O
+-	O
+-	O
+with	O
+BaCl2	O
+","	O
+with	O
+chloroform	O
+-	O
+adrenaline	O
+","	O
+with	O
+strophantine	O
+G	O
+and	O
+with	O
+aconitine	O
+.	O
+	
+The	O
+compound	O
+P11	O
+is	O
+introduced	O
+in	O
+doses	O
+of	O
+0	O
+.	O
+25	O
+and	O
+0	O
+.	O
+50	O
+mg	O
+/	O
+kg	O
+intravenously	O
+and	O
+10	O
+mg	O
+/	O
+kg	O
+orally	O
+.	O
+	
+The	O
+compound	O
+manifests	O
+antiarrhythmic	O
+activity	O
+in	O
+all	O
+models	O
+of	O
+experimental	O
+arrhythmia	B-NP
+used	O
+","	O
+causing	O
+greatest	O
+inhibition	O
+on	O
+the	O
+arrhythmia	B-NP
+induced	O
+by	O
+chloroform	O
+-	O
+adrenaline	O
+(	O
+in	O
+90	O
+per	O
+cent	O
+)	O
+and	O
+with	O
+BaCl2	O
+(	O
+in	O
+84	O
+per	O
+cent	O
+)	O
+.	O
+	
+The	O
+results	O
+obtained	O
+are	O
+associated	O
+with	O
+the	O
+beta	O
+-	O
+adrenoblocking	O
+and	O
+with	O
+the	O
+membrane	O
+-	O
+stabilizing	O
+action	O
+of	O
+the	O
+compound	O
+.	O
+	
+Recurrent	O
+subarachnoid	B-NP
+hemorrhage	I-NP
+associated	O
+with	O
+aminocaproic	O
+acid	O
+therapy	O
+and	O
+acute	B-NP
+renal	I-NP
+artery	I-NP
+thrombosis	I-NP
+.	O
+	
+Case	O
+report	O
+.	O
+	
+Epsilon	O
+aminocaproic	O
+acid	O
+(	O
+EACA	O
+)	O
+has	O
+been	O
+used	O
+to	O
+prevent	O
+rebleeding	O
+in	O
+patients	O
+with	O
+subarachnoid	B-NP
+hemorrhage	I-NP
+(	O
+SAH	B-NP
+)	O
+.	O
+	
+Although	O
+this	O
+agent	O
+does	O
+decrease	O
+the	O
+frequency	O
+of	O
+rebleeding	O
+","	O
+several	O
+reports	O
+have	O
+described	O
+thrombotic	B-NP
+complications	O
+of	O
+EACA	O
+therapy	O
+.	O
+	
+These	O
+complications	O
+have	O
+included	O
+clinical	O
+deterioration	O
+and	O
+intracranial	B-NP
+vascular	I-NP
+thrombosis	I-NP
+in	O
+patients	O
+with	O
+SAH	B-NP
+","	O
+arteriolar	O
+and	O
+capillary	O
+fibrin	O
+thrombi	B-NP
+in	O
+patients	O
+with	O
+fibrinolytic	O
+syndromes	O
+treated	O
+with	O
+EACA	O
+","	O
+or	O
+other	O
+thromboembolic	B-NP
+phenomena	I-NP
+.	O
+	
+Since	O
+intravascular	O
+fibrin	O
+thrombi	B-NP
+are	O
+often	O
+observed	O
+in	O
+patients	O
+with	O
+fibrinolytic	O
+disorders	O
+","	O
+EACA	O
+should	O
+not	O
+be	O
+implicated	O
+in	O
+the	O
+pathogenesis	O
+of	O
+fibrin	O
+thrombi	B-NP
+in	O
+patients	O
+with	O
+disseminated	B-NP
+intravascular	I-NP
+coagulation	I-NP
+or	O
+other	O
+"	O
+consumption	B
+coagulopathies	I
+.	O
+"	O
+This	O
+report	O
+describes	O
+subtotal	O
+infarction	B-NP
+of	O
+the	O
+kidney	O
+due	O
+to	O
+thrombosis	B-NP
+of	I-NP
+a	I-NP
+normal	I-NP
+renal	I-NP
+artery	I-NP
+.	O
+	
+This	O
+occlusion	O
+occurred	O
+after	O
+EACA	O
+therapy	O
+in	O
+a	O
+patient	O
+with	O
+SAH	B-NP
+and	O
+histopathological	O
+documentation	O
+of	O
+recurrent	O
+SAH	B-NP
+.	O
+	
+The	O
+corresponding	O
+clinical	O
+event	O
+was	O
+characterized	O
+by	O
+marked	O
+hypertension	B-NP
+and	O
+abrupt	O
+neurological	O
+deterioration	O
+.	O
+	
+Effect	O
+of	O
+vincristine	O
+sulfate	O
+on	O
+Pseudomonas	B-NP
+infections	I-NP
+in	O
+monkeys	O
+.	O
+	
+In	O
+rhesus	O
+monkeys	O
+","	O
+intravenous	O
+challenge	O
+with	O
+0	O
+.	O
+6	O
+x	O
+10	O
+(	O
+10	O
+)	O
+to	O
+2	O
+.	O
+2	O
+x	O
+10	O
+(	O
+10	O
+)	O
+Pseudomonas	O
+aeruginosa	O
+organisms	O
+caused	O
+acute	O
+illness	O
+of	O
+4	O
+to	O
+5	O
+days	O
+'	O
+duration	O
+with	O
+spontaneous	O
+recovery	O
+in	O
+13	O
+of	O
+15	O
+monkeys	O
+;	O
+blood	O
+cultures	O
+became	O
+negative	O
+3	O
+to	O
+17	O
+days	O
+after	O
+challenge	O
+.	O
+	
+Leukocytosis	B-NP
+was	O
+observed	O
+in	O
+all	O
+monkeys	O
+.	O
+	
+Intravenous	O
+or	O
+intratracheal	O
+inoculation	O
+of	O
+2	O
+.	O
+0	O
+to	O
+2	O
+.	O
+5	O
+mg	O
+of	O
+vincristine	O
+sulfate	O
+was	O
+followed	O
+by	O
+leukopenia	B-NP
+in	O
+4	O
+to	O
+5	O
+days	O
+.	O
+	
+Intravenous	O
+inoculation	O
+of	O
+4	O
+.	O
+2	O
+x	O
+10	O
+(	O
+10	O
+)	O
+to	O
+7	O
+.	O
+8	O
+x	O
+10	O
+(	O
+10	O
+)	O
+pyocin	O
+type	O
+6	O
+Pseudomonas	O
+organisms	O
+in	O
+monkeys	O
+given	O
+vincristine	O
+sulfate	O
+4	O
+days	O
+previously	O
+resulted	O
+in	O
+fatal	O
+infection	B-NP
+in	O
+11	O
+of	O
+14	O
+monkeys	O
+","	O
+whereas	O
+none	O
+of	O
+four	O
+receiving	O
+Pseudomonas	O
+alone	O
+died	O
+.	O
+	
+These	O
+studies	O
+suggest	O
+that	O
+an	O
+antimetabolite	O
+-	O
+induced	O
+leukopenia	B-NP
+predisposes	O
+to	O
+severe	O
+Pseudomonas	O
+sepsis	B-NP
+and	O
+that	O
+such	O
+monkeys	O
+may	O
+serve	O
+as	O
+a	O
+biological	O
+model	O
+for	O
+study	O
+of	O
+comparative	O
+efficacy	O
+of	O
+antimicrobial	O
+agents	O
+.	O
+	
+Modification	O
+by	O
+propranolol	O
+of	O
+cardiovascular	O
+effects	O
+of	O
+induced	O
+hypoglycaemia	B-NP
+.	O
+	
+The	O
+cardiovascular	O
+effects	O
+of	O
+hypoglycaemia	B-NP
+","	O
+with	O
+and	O
+without	O
+beta	O
+-	O
+blockade	O
+","	O
+were	O
+compared	O
+in	O
+fourteen	O
+healthy	O
+men	O
+.	O
+	
+Eight	O
+received	O
+insulin	O
+alone	O
+","	O
+and	O
+eight	O
+","	O
+including	O
+two	O
+of	O
+the	O
+original	O
+insulin	O
+-	O
+only	O
+group	O
+","	O
+were	O
+given	O
+propranolol	O
+and	O
+insulin	O
+.	O
+	
+In	O
+the	O
+insulin	O
+-	O
+group	O
+the	O
+period	O
+of	O
+hypoglycaemia	B-NP
+was	O
+associated	O
+with	O
+an	O
+increase	O
+in	O
+heart	O
+-	O
+rate	O
+and	O
+a	O
+fall	O
+in	O
+diastolic	O
+blood	O
+-	O
+pressure	O
+.	O
+	
+In	O
+the	O
+propranolol	O
+-	O
+insulin	O
+group	O
+there	O
+was	O
+a	O
+significant	O
+fall	O
+in	O
+heart	O
+-	O
+rate	O
+in	O
+most	O
+subjects	O
+and	O
+an	O
+increase	O
+in	O
+diastolic	O
+pressure	O
+.	O
+	
+Typical	O
+S	O
+-	O
+T	O
+/	O
+T	O
+changes	O
+occurred	O
+in	O
+the	O
+insulin	O
+-	O
+group	O
+but	O
+in	O
+none	O
+of	O
+the	O
+propranolol	O
+-	O
+insulin	O
+group	O
+.	O
+	
+Hypertension	B-NP
+in	O
+diabetics	B-NP
+prone	O
+to	O
+hypoglycaemia	B-NP
+attacks	O
+should	O
+not	O
+be	O
+treated	O
+with	O
+beta	O
+-	O
+blockers	O
+because	O
+these	O
+drugs	O
+may	O
+cause	O
+a	O
+sharp	O
+rise	O
+in	O
+blood	O
+-	O
+pressure	O
+in	O
+such	O
+patients	O
+.	O
+	
+Long	O
+-	O
+term	O
+propranolol	O
+therapy	O
+in	O
+pregnancy	O
+:	O
+maternal	O
+and	O
+fetal	O
+outcome	O
+.	O
+	
+Propranolol	O
+","	O
+a	O
+beta	O
+-	O
+adrenergic	O
+blocking	O
+agent	O
+","	O
+has	O
+found	O
+an	O
+important	O
+position	O
+in	O
+the	O
+practice	O
+of	O
+medicine	O
+.	O
+	
+Its	O
+use	O
+in	O
+pregnancy	O
+","	O
+however	O
+","	O
+is	O
+an	O
+open	O
+question	O
+as	O
+a	O
+number	O
+of	O
+detrimental	O
+side	O
+effects	O
+have	O
+been	O
+reported	O
+in	O
+the	O
+fetus	O
+and	O
+neonate	O
+.	O
+	
+Ten	O
+patients	O
+and	O
+12	O
+pregnancies	O
+are	O
+reported	O
+where	O
+chronic	O
+propranolol	O
+has	O
+been	O
+administered	O
+.	O
+	
+Five	O
+patients	O
+with	O
+serial	O
+pregnancies	O
+with	O
+and	O
+without	O
+propranolol	O
+therapy	O
+are	O
+also	O
+examined	O
+.	O
+	
+Maternal	O
+","	O
+fetal	O
+","	O
+and	O
+neonatal	O
+complications	O
+are	O
+examined	O
+.	O
+	
+An	O
+attempt	O
+is	O
+made	O
+to	O
+differentiate	O
+drug	O
+-	O
+related	O
+complications	O
+from	O
+maternal	O
+disease	O
+-	O
+-	O
+related	O
+complications	O
+.	O
+	
+We	O
+conclude	O
+that	O
+previously	O
+reported	O
+hypoglycemia	B-NP
+","	O
+hyperbilirubinemia	B-NP
+","	O
+polycythemia	B-NP
+","	O
+neonatal	B-NP
+apnea	I-NP
+","	O
+and	O
+bradycardia	B-NP
+are	O
+not	O
+invariable	O
+and	O
+cannot	O
+be	O
+statistically	O
+correlated	O
+with	O
+chronic	O
+propranolol	O
+therapy	O
+.	O
+	
+Growth	B-NP
+retardation	I-NP
+","	O
+however	O
+","	O
+appears	O
+to	O
+be	O
+significant	O
+in	O
+both	O
+of	O
+our	O
+series	O
+.	O
+	
+Central	O
+excitatory	O
+actions	O
+of	O
+flurazepam	O
+.	O
+	
+Toxic	O
+actions	O
+of	O
+flurazepam	O
+(	O
+FZP	O
+)	O
+were	O
+studied	O
+in	O
+cats	O
+","	O
+mice	O
+and	O
+rats	O
+.	O
+	
+High	O
+doses	O
+caused	O
+an	O
+apparent	O
+central	O
+excitation	O
+","	O
+most	O
+clearly	O
+seen	O
+as	O
+clonic	O
+convulsions	B-NP
+","	O
+superimposed	O
+on	O
+general	O
+depression	B-NP
+.	O
+	
+Following	O
+a	O
+lethal	O
+dose	O
+","	O
+death	O
+was	O
+always	O
+associated	O
+with	O
+convulsions	B-NP
+.	O
+	
+Comparing	O
+the	O
+relative	O
+sensitivity	O
+to	O
+central	O
+depression	B-NP
+and	O
+excitation	O
+revealed	O
+that	O
+rats	O
+were	O
+least	O
+likely	O
+to	O
+have	O
+convulsions	B-NP
+at	O
+doses	O
+that	O
+did	O
+not	O
+first	O
+cause	O
+loss	B-NP
+of	I-NP
+consciousness	I-NP
+","	O
+while	O
+cats	O
+most	O
+clearly	O
+showed	O
+marked	O
+central	O
+excitatory	O
+actions	O
+.	O
+	
+Signs	O
+of	O
+FZP	O
+toxocity	B-NP
+in	O
+cats	O
+included	O
+excessive	O
+salivation	B-NP
+","	O
+extreme	O
+apprehensive	O
+behavior	O
+","	O
+retching	O
+","	O
+muscle	B-NP
+tremors	I-NP
+and	O
+convulsions	B-NP
+.	O
+	
+An	O
+interaction	O
+between	O
+FZP	O
+and	O
+pentylenetetrazol	O
+(	O
+PTZ	O
+)	O
+was	O
+shown	O
+by	O
+pretreating	O
+mice	O
+with	O
+FZP	O
+before	O
+PTZ	O
+challenge	O
+.	O
+	
+As	O
+a	O
+function	O
+of	O
+dose	O
+","	O
+FZP	O
+first	O
+protected	O
+against	O
+convulsions	B-NP
+and	O
+death	O
+.	O
+	
+At	O
+higher	O
+doses	O
+","	O
+however	O
+","	O
+convulsions	B-NP
+again	O
+emerged	O
+.	O
+	
+These	O
+doses	O
+of	O
+FZP	O
+were	O
+lower	O
+than	O
+those	O
+that	O
+would	O
+alone	O
+cause	O
+convulsions	B-NP
+.	O
+	
+These	O
+results	O
+may	O
+be	O
+relevant	O
+to	O
+the	O
+use	O
+of	O
+FZP	O
+in	O
+clinical	O
+situations	O
+in	O
+which	O
+there	O
+is	O
+increased	O
+neural	O
+excitability	O
+","	O
+such	O
+as	O
+epilepsy	B-NP
+or	O
+sedative	O
+-	O
+hypnotic	O
+drug	O
+withdrawal	O
+.	O
+	
+Use	O
+of	O
+propranolol	O
+in	O
+the	O
+treatment	O
+of	O
+idiopathic	B-NP
+orthostatic	I-NP
+hypotension	I-NP
+.	O
+	
+Five	O
+patients	O
+with	O
+idiopathic	B-NP
+orthostatic	I-NP
+hypotension	I-NP
+who	O
+had	O
+physiologic	O
+and	O
+biochemical	O
+evidence	O
+of	O
+severe	O
+autonomic	O
+dysfunction	O
+were	O
+included	O
+in	O
+the	O
+study	O
+.	O
+	
+They	O
+all	O
+exhibited	O
+markedly	O
+reduced	O
+plasma	O
+catecholamines	O
+and	O
+plasma	O
+renin	O
+activity	O
+in	O
+both	O
+recumbent	O
+and	O
+upright	O
+positions	O
+and	O
+had	O
+marked	O
+hypersensitivity	B-NP
+to	O
+the	O
+pressor	O
+effects	O
+of	O
+infused	O
+norepinephrine	O
+.	O
+	
+Treatment	O
+with	O
+propanolol	O
+administered	O
+intravenously	O
+(	O
+1	O
+-	O
+5	O
+mg	O
+)	O
+produced	O
+increases	O
+in	O
+supine	O
+and	O
+upright	O
+blood	O
+pressure	O
+in	O
+4	O
+of	O
+the	O
+5	O
+individuals	O
+with	O
+rises	O
+ranging	O
+from	O
+11	O
+/	O
+6	O
+to	O
+22	O
+/	O
+11	O
+mmHg	O
+.	O
+	
+Chronic	O
+oral	O
+administration	O
+of	O
+propranolol	O
+(	O
+40	O
+-	O
+160	O
+mg	O
+/	O
+day	O
+)	O
+also	O
+elevated	O
+the	O
+blood	O
+pressures	O
+of	O
+these	O
+individuals	O
+with	O
+increases	O
+in	O
+the	O
+order	O
+of	O
+20	O
+-	O
+35	O
+/	O
+15	O
+-	O
+25	O
+mmg	O
+being	O
+observed	O
+.	O
+	
+In	O
+1	O
+patient	O
+","	O
+marked	O
+hypertension	B-NP
+was	O
+induced	O
+by	O
+propranolol	O
+and	O
+the	O
+drug	O
+had	O
+to	O
+be	O
+withdrawn	O
+.	O
+	
+It	O
+otherwise	O
+was	O
+well	O
+tolerated	O
+and	O
+no	O
+important	O
+side	O
+effects	O
+were	O
+observed	O
+.	O
+	
+Treatment	O
+has	O
+been	O
+continued	O
+in	O
+3	O
+individuals	O
+for	O
+6	O
+-	O
+13	O
+months	O
+with	O
+persistence	O
+of	O
+the	O
+pressor	O
+effect	O
+","	O
+although	O
+there	O
+appears	O
+to	O
+have	O
+been	O
+some	O
+decrease	O
+in	O
+the	O
+degree	O
+of	O
+response	O
+with	O
+time	O
+.	O
+	
+Hemodynamic	O
+measurements	O
+in	O
+1	O
+of	O
+the	O
+patients	O
+demonstrated	O
+an	O
+increase	O
+in	O
+total	O
+peripheral	O
+resistance	O
+and	O
+essentially	O
+no	O
+change	O
+in	O
+cardiac	O
+output	O
+following	O
+propranolol	O
+therapy	O
+.	O
+	
+The	O
+studies	O
+suggest	O
+that	O
+propranolol	O
+is	O
+a	O
+useful	O
+drug	O
+in	O
+selected	O
+patients	O
+with	O
+severe	O
+idiopathic	B-NP
+orthostatic	I-NP
+hypotension	I-NP
+.	O
+	
+Total	O
+intravenous	O
+anesthesia	O
+with	O
+etomidate	O
+.	O
+	
+III	O
+.	O
+	
+Some	O
+observations	O
+in	O
+adults	O
+.	O
+	
+An	O
+investigation	O
+was	O
+undertaken	O
+to	O
+determine	O
+the	O
+dosage	O
+of	O
+etomidate	O
+required	O
+to	O
+maintain	O
+sleep	O
+in	O
+adults	O
+undergoing	O
+surgery	O
+under	O
+regional	O
+local	O
+anesthesia	O
+.	O
+	
+Premedication	O
+of	O
+diazepam	O
+10	O
+mg	O
+and	O
+atropine	O
+0	O
+.	O
+5	O
+mg	O
+was	O
+given	O
+","	O
+and	O
+sleep	O
+was	O
+induced	O
+and	O
+maintained	O
+by	O
+intermittent	O
+intravenous	O
+injections	O
+of	O
+etomidate	O
+0	O
+.	O
+1	O
+/	O
+mg	O
+/	O
+kg	O
+","	O
+given	O
+whenever	O
+the	O
+patient	O
+would	O
+open	O
+his	O
+eyes	O
+on	O
+request	O
+.	O
+	
+A	O
+mean	O
+overall	O
+dose	O
+of	O
+etomidate	O
+17	O
+.	O
+4	O
+microgram	O
+/	O
+kg	O
+/	O
+min	O
+.	O
+was	O
+required	O
+to	O
+maintain	O
+sleep	O
+","	O
+but	O
+great	O
+individual	O
+variation	O
+occurred	O
+","	O
+with	O
+older	O
+patients	O
+requiring	O
+less	O
+drug	O
+.	O
+	
+The	O
+investigation	O
+was	O
+discontinued	O
+after	O
+18	O
+patients	O
+because	O
+of	O
+the	O
+frequency	O
+and	O
+intensity	O
+of	O
+side	O
+-	O
+effects	O
+","	O
+particularly	O
+pain	B-NP
+and	O
+myoclonia	B-NP
+","	O
+which	O
+caused	O
+the	O
+technique	O
+to	O
+be	O
+abandoned	O
+in	O
+two	O
+cases	O
+.	O
+	
+It	O
+is	O
+considered	O
+unlikely	O
+that	O
+etomidate	O
+will	O
+prove	O
+to	O
+be	O
+the	O
+hypnotic	O
+of	O
+choice	O
+for	O
+a	O
+totally	O
+intravenous	O
+anesthetic	O
+technique	O
+in	O
+adults	O
+because	O
+of	O
+the	O
+high	O
+incidence	O
+of	O
+myoclonia	B-NP
+after	O
+prolonged	O
+administration	O
+.	O
+	
+In	O
+several	O
+patients	O
+uncontrollable	O
+muscle	O
+movements	O
+persisted	O
+for	O
+many	O
+minutes	O
+after	O
+complete	O
+recovery	O
+of	O
+consciousness	O
+.	O
+	
+Evidence	O
+for	O
+cardiac	O
+beta	O
+2	O
+-	O
+adrenoceptors	O
+in	O
+man	O
+.	O
+	
+We	O
+compared	O
+the	O
+effects	O
+of	O
+single	O
+doses	O
+of	O
+50	O
+mg	O
+atenolol	O
+(	O
+cardioselective	O
+)	O
+","	O
+40	O
+mg	O
+propranolol	O
+(	O
+nonselective	O
+)	O
+","	O
+and	O
+placebo	O
+on	O
+both	O
+exercise	O
+-	O
+and	O
+isoproterenol	O
+-	O
+induced	O
+tachycardia	B-NP
+in	O
+two	O
+experiments	O
+involving	O
+nine	O
+normal	O
+subjects	O
+.	O
+	
+Maximal	O
+exercise	O
+heart	O
+rate	O
+was	O
+reduced	O
+from	O
+187	O
++	O
+/	O
+-	O
+4	O
+(	O
+SEM	O
+)	O
+after	O
+placebo	O
+to	O
+146	O
++	O
+/	O
+-	O
+7	O
+bpm	O
+after	O
+atenolol	O
+and	O
+138	O
++	O
+/	O
+-	O
+6	O
+bpm	O
+after	O
+propranolol	O
+","	O
+but	O
+there	O
+were	O
+no	O
+differences	O
+between	O
+the	O
+drugs	O
+.	O
+	
+The	O
+effects	O
+on	O
+isoproterenol	O
+tachycardia	B-NP
+were	O
+determined	O
+before	O
+and	O
+after	O
+atropine	O
+(	O
+0	O
+.	O
+4	O
+mg	O
+/	O
+kg	O
+IV	O
+)	O
+.	O
+	
+Isoproterenol	O
+sensitivity	O
+was	O
+determined	O
+as	O
+the	O
+intravenous	O
+dose	O
+that	O
+increased	O
+heart	O
+rate	O
+by	O
+25	O
+bpm	O
+(	O
+CD25	O
+)	O
+and	O
+this	O
+was	O
+increased	O
+from	O
+1	O
+.	O
+8	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+micrograms	O
+after	O
+placebo	O
+to	O
+38	O
+.	O
+9	O
++	O
+/	O
+-	O
+8	O
+.	O
+3	O
+micrograms	O
+after	O
+propranolol	O
+and	O
+8	O
+.	O
+3	O
++	O
+/	O
+-	O
+1	O
+.	O
+7	O
+micrograms	O
+after	O
+atenolol	O
+.	O
+	
+The	O
+difference	O
+in	O
+the	O
+effects	O
+of	O
+the	O
+two	O
+was	O
+significant	O
+.	O
+	
+After	O
+atropine	O
+the	O
+CD25	O
+was	O
+unchanged	O
+after	O
+placebo	O
+(	O
+2	O
+.	O
+3	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+micrograms	O
+)	O
+and	O
+atenolol	O
+(	O
+7	O
+.	O
+7	O
++	O
+/	O
+-	O
+1	O
+.	O
+3	O
+micrograms	O
+)	O
+;	O
+it	O
+was	O
+reduced	O
+after	O
+propranolol	O
+(	O
+24	O
+.	O
+8	O
++	O
+/	O
+-	O
+5	O
+.	O
+0	O
+micrograms	O
+)	O
+","	O
+but	O
+remained	O
+different	O
+from	O
+atenolol	O
+.	O
+	
+This	O
+change	O
+with	O
+propranolol	O
+sensitivity	O
+was	O
+calculated	O
+as	O
+the	O
+apparent	O
+Ka	O
+","	O
+this	O
+was	O
+unchanged	O
+by	O
+atropine	O
+(	O
+11	O
+.	O
+7	O
++	O
+/	O
+-	O
+2	O
+.	O
+1	O
+and	O
+10	O
+.	O
+1	O
++	O
+/	O
+-	O
+2	O
+.	O
+5	O
+ml	O
+/	O
+ng	O
+)	O
+.	O
+	
+These	O
+data	O
+are	O
+consistent	O
+with	O
+the	O
+hypothesis	O
+that	O
+exercise	O
+-	O
+induced	O
+tachycardia	B-NP
+results	O
+largely	O
+from	O
+beta	O
+1	O
+-	O
+receptor	O
+activation	O
+that	O
+is	O
+blocked	O
+by	O
+both	O
+cardioselective	O
+and	O
+nonselective	O
+drugs	O
+","	O
+whereas	O
+isoproterenol	O
+activates	O
+both	O
+beta	O
+1	O
+-	O
+and	O
+beta	O
+2	O
+-	O
+receptors	O
+so	O
+that	O
+after	O
+cardioselective	O
+blockade	O
+there	O
+remains	O
+a	O
+beta	O
+2	O
+-	O
+component	O
+that	O
+can	O
+be	O
+blocked	O
+with	O
+a	O
+nonselective	O
+drug	O
+.	O
+	
+While	O
+there	O
+appear	O
+to	O
+be	O
+beta	O
+2	O
+-	O
+receptors	O
+in	O
+the	O
+human	O
+heart	O
+","	O
+their	O
+physiologic	O
+or	O
+pathologic	O
+roles	O
+remain	O
+to	O
+be	O
+defined	O
+.	O
+	
+Hormones	O
+and	O
+risk	O
+of	O
+breast	B-NP
+cancer	I-NP
+.	O
+	
+This	O
+paper	O
+reports	O
+the	O
+results	O
+of	O
+a	O
+study	O
+of	O
+50	O
+menopausal	O
+women	O
+receiving	O
+hormonal	O
+replacement	O
+therapy	O
+.	O
+	
+The	O
+majority	O
+(	O
+29	O
+)	O
+had	O
+surgical	O
+menopause	O
+;	O
+their	O
+mean	O
+age	O
+was	O
+45	O
+.	O
+7	O
+years	O
+.	O
+	
+It	O
+was	O
+hypothesized	O
+that	O
+progestins	O
+could	O
+equilibrate	O
+the	O
+effects	O
+of	O
+the	O
+estrogenic	O
+stimulation	O
+on	O
+the	O
+mammary	O
+and	O
+endometrial	O
+target	O
+tissues	O
+of	O
+women	O
+on	O
+hormonal	O
+replacement	O
+therapy	O
+.	O
+	
+The	O
+treatment	O
+schedule	O
+consisted	O
+of	O
+conjugated	O
+estrogens	O
+(	O
+Premarin	O
+)	O
+1	O
+.	O
+25	O
+mg	O
+/	O
+day	O
+for	O
+21	O
+days	O
+and	O
+Medroxyprogesterone	O
+acetate	O
+10	O
+mg	O
+/	O
+day	O
+for	O
+10	O
+days	O
+in	O
+each	O
+month	O
+.	O
+	
+The	O
+mean	O
+treatment	O
+period	O
+was	O
+18	O
+months	O
+.	O
+	
+During	O
+the	O
+follow	O
+-	O
+up	O
+period	O
+","	O
+attention	O
+was	O
+paid	O
+to	O
+breast	O
+modifications	O
+as	O
+evidenced	O
+by	O
+symptomatology	O
+","	O
+physical	O
+examination	O
+","	O
+and	O
+plate	O
+thermography	O
+.	O
+	
+Mastodynia	B-NP
+was	O
+reported	O
+by	O
+21	O
+patients	O
+","	O
+and	O
+physical	O
+examination	O
+revealed	O
+a	O
+light	O
+increase	O
+in	O
+breast	O
+firmness	O
+in	O
+12	O
+women	O
+and	O
+a	O
+moderate	O
+increase	O
+in	O
+breast	O
+nodularity	O
+in	O
+2	O
+women	O
+.	O
+	
+Themography	O
+confirmed	O
+the	O
+existence	O
+of	O
+an	O
+excessive	O
+breast	O
+stimulation	O
+in	O
+1	O
+women	O
+who	O
+complained	O
+of	O
+moderate	O
+mastodynia	B-NP
+and	O
+in	O
+5	O
+of	O
+the	O
+7	O
+women	O
+who	O
+complained	O
+of	O
+severe	O
+mastodynia	B-NP
+.	O
+	
+Normalization	O
+was	O
+obtained	O
+by	O
+halving	O
+the	O
+estrogen	O
+dose	O
+.	O
+	
+These	O
+results	O
+suggest	O
+that	O
+hormonal	O
+replacement	O
+therapy	O
+can	O
+be	O
+safely	O
+prescribed	O
+if	O
+the	O
+following	O
+criteria	O
+are	O
+satisfied	O
+:	O
+1	O
+)	O
+preliminary	O
+evaluation	O
+of	O
+patients	O
+from	O
+a	O
+clinical	O
+","	O
+metabolic	O
+","	O
+cytologic	O
+","	O
+and	O
+mammographic	O
+perspective	O
+;	O
+2	O
+)	O
+cyclic	O
+treatment	O
+schedule	O
+","	O
+with	O
+a	O
+progestative	O
+phase	O
+of	O
+10	O
+days	O
+;	O
+and	O
+3	O
+)	O
+periodic	O
+complete	O
+follow	O
+-	O
+up	O
+","	O
+with	O
+accurate	O
+thermographic	O
+evaluation	O
+of	O
+the	O
+breast	O
+target	O
+tissues	O
+.	O
+	
+Early	O
+infections	B-NP
+in	O
+kidney	O
+","	O
+heart	O
+","	O
+and	O
+liver	O
+transplant	O
+recipients	O
+on	O
+cyclosporine	O
+.	O
+	
+Eighty	O
+-	O
+one	O
+renal	O
+","	O
+seventeen	O
+heart	O
+","	O
+and	O
+twenty	O
+-	O
+four	O
+liver	O
+transplant	O
+patients	O
+were	O
+followed	O
+for	O
+infection	B-NP
+.	O
+	
+Seventeen	O
+renal	O
+patients	O
+received	O
+azathioprine	O
+(	O
+Aza	O
+)	O
+and	O
+prednisone	O
+as	O
+part	O
+of	O
+a	O
+randomized	O
+trial	O
+of	O
+immunosuppression	O
+with	O
+21	O
+cyclosporine	O
+-	O
+and	O
+-	O
+prednisone	O
+-	O
+treated	O
+renal	O
+transplant	O
+patients	O
+.	O
+	
+All	O
+others	O
+received	O
+cyclosporine	O
+and	O
+prednisone	O
+.	O
+	
+The	O
+randomized	O
+Aza	O
+patients	O
+had	O
+more	O
+overall	O
+infections	B-NP
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+and	O
+more	O
+nonviral	O
+infections	B-NP
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+2	O
+)	O
+than	O
+the	O
+randomized	O
+cyclosporine	O
+patients	O
+.	O
+	
+Heart	O
+and	O
+liver	O
+patients	O
+had	O
+more	O
+infections	B-NP
+than	O
+cyclosporine	O
+renal	O
+patients	O
+but	O
+fewer	O
+infections	B-NP
+than	O
+the	O
+Aza	O
+renal	O
+patients	O
+.	O
+	
+There	O
+were	O
+no	O
+infectious	O
+deaths	O
+in	O
+renal	O
+transplant	O
+patients	O
+on	O
+cyclosporine	O
+or	O
+Aza	O
+","	O
+but	O
+infection	B-NP
+played	O
+a	O
+major	O
+role	O
+in	O
+3	O
+out	O
+of	O
+6	O
+cardiac	O
+transplant	O
+deaths	O
+and	O
+in	O
+8	O
+out	O
+of	O
+9	O
+liver	O
+transplant	O
+deaths	O
+.	O
+	
+Renal	O
+patients	O
+on	O
+cyclosporine	O
+had	O
+the	O
+fewest	O
+bacteremias	B-NP
+.	O
+	
+Analysis	O
+of	O
+site	O
+of	O
+infection	B-NP
+showed	O
+a	O
+preponderance	O
+of	O
+abdominal	B-NP
+infections	I-NP
+in	O
+liver	O
+patients	O
+","	O
+intrathoracic	O
+infections	B-NP
+in	O
+heart	O
+patients	O
+","	O
+and	O
+urinary	B-NP
+tract	I-NP
+infections	I-NP
+in	O
+renal	O
+patients	O
+.	O
+	
+Pulmonary	O
+infections	B-NP
+were	O
+less	O
+common	O
+in	O
+cyclosporine	O
+-	O
+treated	O
+renal	O
+patients	O
+than	O
+in	O
+Aza	O
+-	O
+treated	O
+patients	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+Aza	O
+patients	O
+had	O
+significantly	O
+more	O
+staphylococcal	B-NP
+infections	I-NP
+than	O
+all	O
+other	O
+transplant	O
+groups	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+","	O
+and	O
+systemic	O
+fungal	B-NP
+infections	I-NP
+occurred	O
+only	O
+in	O
+the	O
+liver	O
+transplant	O
+group	O
+.	O
+	
+Cytomegalovirus	O
+(	O
+CMV	O
+)	O
+shedding	O
+or	O
+serological	O
+rises	O
+in	O
+antibody	O
+titer	O
+","	O
+or	O
+both	O
+occurred	O
+in	O
+78	O
+%	O
+of	O
+cyclosporine	O
+patients	O
+and	O
+76	O
+%	O
+of	O
+Aza	O
+patients	O
+.	O
+	
+Of	O
+the	O
+cyclosporine	O
+patients	O
+","	O
+15	O
+%	O
+had	O
+symptoms	O
+related	O
+to	O
+CMV	B-NP
+infection	I-NP
+.	O
+	
+Serological	O
+evidence	O
+for	O
+Epstein	B-NP
+Barr	I-NP
+Virus	I-NP
+infection	I-NP
+was	O
+found	O
+in	O
+20	O
+%	O
+of	O
+65	O
+cyclosporine	O
+patients	O
+studied	O
+.	O
+	
+Three	O
+had	O
+associated	O
+symptoms	O
+","	O
+and	O
+one	O
+developed	O
+a	O
+lymphoma	B-NP
+.	O
+	
+Structure	O
+-	O
+activity	O
+and	O
+dose	O
+-	O
+effect	O
+relationships	O
+of	O
+the	O
+antagonism	O
+of	O
+picrotoxin	O
+-	O
+induced	O
+seizures	B-NP
+by	O
+cholecystokinin	O
+","	O
+fragments	O
+and	O
+analogues	O
+of	O
+cholecystokinin	O
+in	O
+mice	O
+.	O
+	
+Intraperitoneal	O
+administration	O
+of	O
+cholecystokinin	O
+octapeptide	O
+sulphate	O
+ester	O
+(	O
+CCK	O
+-	O
+8	O
+-	O
+SE	O
+)	O
+and	O
+nonsulphated	O
+cholecystokinin	O
+octapeptide	O
+(	O
+CCK	O
+-	O
+8	O
+-	O
+NS	O
+)	O
+enhanced	O
+the	O
+latency	O
+of	O
+seizures	B-NP
+induced	O
+by	O
+picrotoxin	O
+in	O
+mice	O
+.	O
+	
+Experiments	O
+with	O
+N	O
+-	O
+and	O
+C	O
+-	O
+terminal	O
+fragments	O
+revealed	O
+that	O
+the	O
+C	O
+-	O
+terminal	O
+tetrapeptide	O
+(	O
+CCK	O
+-	O
+5	O
+-	O
+8	O
+)	O
+was	O
+the	O
+active	O
+centre	O
+of	O
+the	O
+CCK	O
+octapeptide	O
+molecule	O
+.	O
+	
+The	O
+analogues	O
+CCK	O
+-	O
+8	O
+-	O
+SE	O
+and	O
+CCK	O
+-	O
+8	O
+-	O
+NS	O
+(	O
+dose	O
+range	O
+0	O
+.	O
+2	O
+-	O
+6	O
+.	O
+4	O
+mumol	O
+/	O
+kg	O
+)	O
+and	O
+caerulein	O
+dose	O
+range	O
+0	O
+.	O
+1	O
+-	O
+0	O
+.	O
+8	O
+mumol	O
+/	O
+kg	O
+)	O
+showed	O
+bell	O
+-	O
+shaped	O
+dose	O
+-	O
+effect	O
+curves	O
+","	O
+with	O
+the	O
+greatest	O
+maximum	O
+inhibition	O
+for	O
+CCK	O
+-	O
+8	O
+-	O
+NS	O
+.	O
+	
+The	O
+peptide	O
+CCK	O
+-	O
+5	O
+-	O
+8	O
+had	O
+weak	O
+anticonvulsant	O
+activity	O
+in	O
+comparison	O
+to	O
+the	O
+octapeptides	O
+","	O
+3	O
+.	O
+2	O
+mumol	O
+/	O
+kg	O
+and	O
+larger	O
+doses	O
+of	O
+the	O
+reference	O
+drug	O
+","	O
+diazepam	O
+","	O
+totally	O
+prevented	O
+picrotoxin	O
+-	O
+induced	O
+seizures	B-NP
+and	O
+mortality	O
+.	O
+	
+The	O
+maximum	O
+effect	O
+of	O
+the	O
+peptides	O
+tested	O
+was	O
+less	O
+than	O
+that	O
+of	O
+diazepam	O
+.	O
+	
+Experiments	O
+with	O
+analogues	O
+and	O
+derivatives	O
+of	O
+CCK	O
+-	O
+5	O
+-	O
+8	O
+demonstrated	O
+that	O
+the	O
+effectiveness	O
+of	O
+the	O
+beta	O
+-	O
+alanyl	O
+derivatives	O
+of	O
+CCK	O
+-	O
+5	O
+-	O
+8	O
+were	O
+enhanced	O
+and	O
+that	O
+they	O
+were	O
+equipotent	O
+with	O
+CCK	O
+-	O
+8	O
+-	O
+SE	O
+.	O
+	
+Of	O
+the	O
+CCK	O
+-	O
+2	O
+-	O
+8	O
+analogues	O
+","	O
+Ser	O
+(	O
+SO3H	O
+)	O
+7	O
+-	O
+Ac	O
+-	O
+CCK	O
+-	O
+2	O
+-	O
+8	O
+-	O
+SE	O
+and	O
+Thr	O
+(	O
+SO3H	O
+)	O
+7	O
+-	O
+Ac	O
+-	O
+CCK	O
+-	O
+2	O
+-	O
+8	O
+-	O
+SE	O
+and	O
+Hyp	O
+(	O
+SO3H	O
+)	O
+-	O
+Ac	O
+-	O
+CCK	O
+-	O
+2	O
+-	O
+8	O
+-	O
+SE	O
+were	O
+slightly	O
+more	O
+active	O
+than	O
+CCK	O
+-	O
+8	O
+-	O
+SE	O
+.	O
+	
+Vasopressin	O
+as	O
+a	O
+possible	O
+contributor	O
+to	O
+hypertension	B-NP
+.	O
+	
+The	O
+role	O
+of	O
+vasopressin	O
+as	O
+a	O
+pressor	O
+agent	O
+to	O
+the	O
+hypertensive	B-NP
+process	O
+was	O
+examined	O
+.	O
+	
+Vasopressin	O
+plays	O
+a	O
+major	O
+role	O
+in	O
+the	O
+pathogenesis	O
+of	O
+DOCA	O
+-	O
+salt	O
+hypertension	B-NP
+","	O
+since	O
+the	O
+elevation	O
+of	O
+blood	O
+pressure	O
+was	O
+not	O
+substantial	O
+in	O
+the	O
+rats	O
+with	O
+lithium	O
+-	O
+treated	O
+diabetes	B-NP
+insipidus	I-NP
+after	O
+DOCA	O
+-	O
+salt	O
+treatment	O
+.	O
+	
+Administration	O
+of	O
+DDAVP	O
+which	O
+has	O
+antidiuretic	O
+action	O
+but	O
+minimal	O
+vasopressor	O
+effect	O
+failed	O
+to	O
+increase	O
+blood	O
+pressure	O
+to	O
+the	O
+levels	O
+observed	O
+after	O
+administration	O
+of	O
+AVP	O
+.	O
+	
+Furthermore	O
+","	O
+the	O
+pressor	O
+action	O
+of	O
+vasopressin	O
+appears	O
+to	O
+be	O
+important	O
+in	O
+the	O
+development	O
+of	O
+this	O
+model	O
+of	O
+hypertension	B-NP
+","	O
+since	O
+the	O
+enhanced	O
+pressor	O
+responsiveness	O
+to	O
+the	O
+hormone	O
+was	O
+observed	O
+in	O
+the	O
+initial	O
+stage	O
+of	O
+hypertension	B-NP
+.	O
+	
+Increased	O
+secretion	O
+of	O
+vasopressin	O
+from	O
+neurohypophysis	O
+also	O
+promotes	O
+the	O
+function	O
+of	O
+the	O
+hormone	O
+as	O
+a	O
+pathogenetic	O
+factor	O
+in	O
+hypertension	B-NP
+.	O
+	
+An	O
+unproportional	O
+release	O
+of	O
+vasopressin	O
+compared	O
+to	O
+plasma	O
+osmolality	O
+may	O
+be	O
+induced	O
+by	O
+the	O
+absence	O
+of	O
+an	O
+adjusting	O
+control	O
+of	O
+angiotensin	O
+II	O
+forming	O
+and	O
+receptor	O
+binding	O
+capacity	O
+for	O
+sodium	O
+balance	O
+in	O
+the	O
+brain	O
+.	O
+	
+However	O
+","	O
+the	O
+role	O
+of	O
+vasopressin	O
+remains	O
+to	O
+be	O
+determined	O
+in	O
+human	O
+essential	O
+hypertension	B-NP
+.	O
+	
+Toxic	B-NP
+hepatitis	I-NP
+induced	O
+by	O
+disulfiram	O
+in	O
+a	O
+non	O
+-	O
+alcoholic	O
+.	O
+	
+A	O
+reversible	O
+toxic	B-NP
+liver	I-NP
+damage	I-NP
+was	O
+observed	O
+in	O
+a	O
+non	O
+-	O
+alcoholic	O
+woman	O
+treated	O
+with	O
+disulfiram	O
+.	O
+	
+The	O
+causative	O
+relationship	O
+was	O
+proven	O
+by	O
+challenge	O
+.	O
+	
+Atrial	B-NP
+thrombosis	I-NP
+involving	O
+the	O
+heart	O
+of	O
+F	O
+-	O
+344	O
+rats	O
+ingesting	O
+quinacrine	O
+hydrochloride	O
+.	O
+	
+Quinacrine	O
+hydrochloride	O
+is	O
+toxic	O
+for	O
+the	O
+heart	O
+of	O
+F	O
+-	O
+344	O
+rats	O
+.	O
+	
+Rats	O
+treated	O
+with	O
+500	O
+ppm	O
+quinacrine	O
+hydrochloride	O
+in	O
+the	O
+diet	O
+all	O
+developed	O
+a	O
+high	O
+incidence	O
+of	O
+left	O
+atrial	B-NP
+thrombosis	I-NP
+.	O
+	
+The	O
+lesion	O
+was	O
+associated	O
+with	O
+cardiac	B-NP
+hypertrophy	I-NP
+and	O
+dilatation	O
+and	O
+focal	O
+myocardial	B-NP
+degeneration	I-NP
+.	O
+	
+Rats	O
+died	O
+from	O
+cardiac	B-NP
+hypertrophy	I-NP
+with	O
+severe	O
+acute	O
+and	O
+chronic	O
+congestion	O
+of	O
+the	O
+lungs	O
+","	O
+liver	O
+","	O
+and	O
+other	O
+organs	O
+.	O
+	
+Seventy	O
+percent	O
+of	O
+rats	O
+given	O
+250	O
+ppm	O
+quinacrine	O
+hydrochloride	O
+and	O
+1	O
+","	O
+0	O
+ppm	O
+sodium	O
+nitrite	O
+simultaneously	O
+in	O
+the	O
+diet	O
+had	O
+thrombosis	B-NP
+of	O
+the	O
+atria	O
+of	O
+the	O
+heart	O
+","	O
+while	O
+untreated	O
+control	O
+rats	O
+in	O
+this	O
+laboratory	O
+did	O
+not	O
+have	O
+atrial	B-NP
+thrombosis	I-NP
+.	O
+	
+Sodium	O
+nitrite	O
+in	O
+combination	O
+with	O
+quinacrine	O
+hydrochloride	O
+appeared	O
+to	O
+have	O
+no	O
+additional	O
+effect	O
+.	O
+	
+Alternating	B-NP
+sinus	I-NP
+rhythm	I-NP
+and	O
+intermittent	O
+sinoatrial	B-NP
+block	I-NP
+induced	O
+by	O
+propranolol	O
+.	O
+	
+Alternating	B-NP
+sinus	I-NP
+rhythm	I-NP
+and	O
+intermittent	O
+sinoatrial	B-NP
+(	I-NP
+S	I-NP
+-	I-NP
+A	I-NP
+)	I-NP
+block	I-NP
+was	O
+observed	O
+in	O
+a	O
+57	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+","	O
+under	O
+treatment	O
+for	O
+angina	B-NP
+with	O
+80	O
+mg	O
+propranolol	O
+daily	O
+.	O
+	
+The	O
+electrocardiogram	O
+showed	O
+alternation	O
+of	O
+long	O
+and	O
+short	O
+P	O
+-	O
+P	O
+intervals	O
+and	O
+occasional	O
+pauses	O
+.	O
+	
+These	O
+pauses	O
+were	O
+always	O
+preceded	O
+by	O
+the	O
+short	O
+P	O
+-	O
+P	O
+intervals	O
+and	O
+were	O
+usually	O
+followed	O
+by	O
+one	O
+or	O
+two	O
+P	O
+-	O
+P	O
+intervals	O
+of	O
+0	O
+.	O
+92	O
+-	O
+0	O
+.	O
+95	O
+s	O
+representing	O
+the	O
+basic	O
+sinus	O
+cycle	O
+.	O
+	
+Following	O
+these	O
+basic	O
+sinus	O
+cycles	O
+","	O
+alternating	B-NP
+rhythm	I-NP
+started	O
+with	O
+the	O
+longer	O
+P	O
+-	O
+P	O
+interval	O
+.	O
+	
+The	O
+long	O
+P	O
+-	O
+P	O
+intervals	O
+ranged	O
+between	O
+1	O
+.	O
+4	O
+-	O
+1	O
+.	O
+12	O
+s	O
+and	O
+the	O
+short	O
+P	O
+-	O
+P	O
+intervals	O
+between	O
+0	O
+.	O
+80	O
+-	O
+0	O
+.	O
+84	O
+s	O
+","	O
+respectively	O
+.	O
+	
+The	O
+duration	O
+of	O
+the	O
+pauses	O
+were	O
+equal	O
+or	O
+almost	O
+equal	O
+to	O
+one	O
+short	O
+plus	O
+one	O
+long	O
+P	O
+-	O
+P	O
+interval	O
+or	O
+to	O
+twice	O
+the	O
+basic	O
+sinus	O
+cycle	O
+.	O
+	
+In	O
+one	O
+recording	O
+a	O
+short	O
+period	O
+of	O
+regular	O
+sinus	O
+rhythm	O
+with	O
+intermittent	O
+2	O
+/	O
+1	O
+S	B-NP
+-	I-NP
+A	I-NP
+block	I-NP
+was	O
+observed	O
+.	O
+	
+This	O
+short	O
+period	O
+of	O
+sinus	O
+rhythm	O
+was	O
+interrupted	O
+by	O
+sudden	O
+prolongation	O
+of	O
+the	O
+P	O
+-	O
+P	O
+interval	O
+starting	O
+the	O
+alternative	O
+rhythm	O
+.	O
+	
+There	O
+were	O
+small	O
+changes	O
+in	O
+the	O
+shape	O
+of	O
+the	O
+P	O
+waves	O
+and	O
+P	O
+-	O
+R	O
+intervals	O
+.	O
+	
+S	O
+-	O
+A	O
+conduction	O
+through	O
+two	O
+pathways	O
+","	O
+the	O
+first	O
+with	O
+2	O
+/	O
+1	O
+block	O
+the	O
+second	O
+having	O
+0	O
+.	O
+12	O
+-	O
+0	O
+.	O
+14	O
+s	O
+longer	O
+conduction	O
+time	O
+and	O
+with	O
+occasional	O
+2	O
+/	O
+1	O
+block	O
+was	O
+proposed	O
+for	O
+the	O
+explanation	O
+of	O
+the	O
+alternating	O
+P	O
+-	O
+P	O
+interval	O
+and	O
+other	O
+electrocardiographic	O
+features	O
+seen	O
+.	O
+	
+Atropine	O
+1	O
+mg	O
+given	O
+intravenously	O
+resulted	O
+in	O
+shortening	O
+of	O
+all	O
+P	O
+-	O
+P	O
+intervals	O
+without	O
+changing	O
+the	O
+rhythm	O
+.	O
+	
+The	O
+abnormal	O
+rhythm	O
+disappeared	O
+with	O
+the	O
+withdrawal	O
+of	O
+propranolol	O
+and	O
+when	O
+the	O
+drug	O
+was	O
+restarted	O
+a	O
+2	O
+/	O
+1	O
+S	B-NP
+-	I-NP
+A	I-NP
+block	I-NP
+was	O
+seen	O
+.	O
+	
+This	O
+was	O
+accepted	O
+as	O
+evidence	O
+for	O
+propranolol	O
+being	O
+the	O
+cause	O
+of	O
+this	O
+conduction	B-NP
+disorder	I-NP
+.	O
+	
+Antitumor	O
+effect	O
+","	O
+cardiotoxicity	B-NP
+","	O
+and	O
+nephrotoxicity	B-NP
+of	O
+doxorubicin	O
+in	O
+the	O
+IgM	O
+solid	O
+immunocytoma	B-NP
+-	O
+bearing	O
+LOU	O
+/	O
+M	O
+/	O
+WSL	O
+rat	O
+.	O
+	
+Antitumor	O
+activity	O
+","	O
+cardiotoxicity	B-NP
+","	O
+and	O
+nephrotoxicity	B-NP
+induced	O
+by	O
+doxorubicin	O
+were	O
+studied	O
+in	O
+LOU	O
+/	O
+M	O
+/	O
+WSL	O
+inbred	O
+rats	O
+each	O
+bearing	O
+a	O
+transplantable	O
+solid	O
+IgM	O
+immunocytoma	B-NP
+.	O
+	
+Animals	O
+with	O
+a	O
+tumor	B-NP
+(	O
+diameter	O
+","	O
+15	O
+.	O
+8	O
++	O
+/	O
+-	O
+3	O
+.	O
+3	O
+mm	O
+)	O
+were	O
+treated	O
+with	O
+iv	O
+injections	O
+of	O
+doxorubicin	O
+on	O
+5	O
+consecutive	O
+days	O
+","	O
+followed	O
+by	O
+1	O
+weekly	O
+injection	O
+for	O
+7	O
+weeks	O
+(	O
+dose	O
+range	O
+","	O
+0	O
+.	O
+15	O
+-	O
+4	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+body	O
+wt	O
+)	O
+.	O
+	
+Tumor	B-NP
+regression	O
+was	O
+observed	O
+with	O
+0	O
+.	O
+5	O
+mg	O
+doxorubicin	O
+/	O
+kg	O
+.	O
+	
+Complete	O
+disappearance	O
+of	O
+the	O
+tumor	B-NP
+was	O
+induced	O
+with	O
+1	O
+.	O
+0	O
+mg	O
+doxorubicin	O
+/	O
+kg	O
+.	O
+	
+Histologic	O
+evidence	O
+of	O
+cardiotoxicity	B-NP
+scored	O
+as	O
+grade	O
+III	O
+was	O
+only	O
+observed	O
+at	O
+a	O
+dose	O
+of	O
+1	O
+.	O
+0	O
+mg	O
+doxorubicin	O
+/	O
+kg	O
+.	O
+	
+Light	O
+microscopic	O
+evidence	O
+of	O
+renal	B-NP
+damage	I-NP
+was	O
+seen	O
+above	O
+a	O
+dose	O
+of	O
+0	O
+.	O
+5	O
+mg	O
+doxorubicin	O
+/	O
+kg	O
+","	O
+which	O
+resulted	O
+in	O
+albuminuria	B-NP
+and	O
+very	O
+low	O
+serum	O
+albumin	O
+levels	O
+.	O
+	
+In	O
+the	O
+group	O
+that	O
+received	O
+1	O
+.	O
+0	O
+mg	O
+doxorubicin	O
+/	O
+kg	O
+","	O
+the	O
+serum	O
+albumin	O
+level	O
+decreased	O
+from	O
+33	O
+.	O
+6	O
++	O
+/	O
+-	O
+4	O
+.	O
+1	O
+to	O
+1	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+g	O
+/	O
+liter	O
+.	O
+	
+Ascites	B-NP
+and	O
+hydrothorax	B-NP
+were	O
+observed	O
+simultaneously	O
+.	O
+	
+The	O
+same	O
+experiments	O
+were	O
+performed	O
+with	O
+non	O
+-	O
+tumor	B-NP
+-	O
+bearing	O
+rats	O
+","	O
+in	O
+which	O
+no	O
+major	O
+differences	O
+were	O
+observed	O
+.	O
+	
+In	O
+conclusion	O
+","	O
+antitumor	O
+activity	O
+","	O
+cardiotoxicity	B-NP
+","	O
+and	O
+nephrotoxicity	B-NP
+were	O
+studied	O
+simultaneously	O
+in	O
+the	O
+same	O
+LOU	O
+/	O
+M	O
+/	O
+WSL	O
+rat	O
+.	O
+	
+Albuminuria	B-NP
+due	O
+to	O
+renal	B-NP
+damage	I-NP
+led	O
+to	O
+extremely	O
+low	O
+serum	O
+albumin	O
+levels	O
+","	O
+so	O
+ascites	B-NP
+and	O
+hydrothorax	B-NP
+were	O
+not	O
+necessarily	O
+a	O
+consequence	O
+of	O
+the	O
+observed	O
+cardiomyopathy	B-NP
+.	O
+	
+Intraoperative	O
+bradycardia	B-NP
+and	O
+hypotension	B-NP
+associated	O
+with	O
+timolol	O
+and	O
+pilocarpine	O
+eye	O
+drops	O
+.	O
+	
+A	O
+69	O
+-	O
+yr	O
+-	O
+old	O
+man	O
+","	O
+who	O
+was	O
+concurrently	O
+being	O
+treated	O
+with	O
+pilocarpine	O
+nitrate	O
+and	O
+timolol	O
+maleate	O
+eye	O
+drops	O
+","	O
+developed	O
+a	O
+bradycardia	B-NP
+and	O
+became	O
+hypotensive	B-NP
+during	O
+halothane	O
+anaesthesia	O
+.	O
+	
+Both	O
+timolol	O
+and	O
+pilocarpine	O
+were	O
+subsequently	O
+identified	O
+in	O
+a	O
+24	O
+-	O
+h	O
+collection	O
+of	O
+urine	O
+.	O
+	
+Timolol	O
+(	O
+but	O
+not	O
+pilocarpine	O
+)	O
+was	O
+detected	O
+in	O
+a	O
+sample	O
+of	O
+plasma	O
+removed	O
+during	O
+surgery	O
+;	O
+the	O
+plasma	O
+concentration	O
+of	O
+timolol	O
+(	O
+2	O
+.	O
+6	O
+ng	O
+ml	O
+-	O
+1	O
+)	O
+was	O
+consistent	O
+with	O
+partial	O
+beta	O
+-	O
+adrenoceptor	O
+blockade	O
+.	O
+	
+It	O
+is	O
+postulated	O
+that	O
+this	O
+action	O
+may	O
+have	O
+been	O
+enhanced	O
+during	O
+halothane	O
+anaesthesia	O
+with	O
+resultant	O
+bradycardia	B-NP
+and	O
+hypotension	B-NP
+.	O
+	
+Pilocarpine	O
+may	O
+have	O
+had	O
+a	O
+contributory	O
+effect	O
+.	O
+	
+Succinylcholine	O
+apnoea	B-NP
+:	O
+attempted	O
+reversal	O
+with	O
+anticholinesterases	O
+.	O
+	
+Anticholinesterases	O
+were	O
+administered	O
+in	O
+an	O
+attempt	O
+to	O
+antagonize	O
+prolonged	O
+neuromuscular	B-NP
+blockade	I-NP
+following	O
+the	O
+administration	O
+of	O
+succinylcholine	O
+in	O
+a	O
+patient	O
+later	O
+found	O
+to	O
+be	O
+homozygous	O
+for	O
+atypical	O
+plasma	O
+cholinesterase	O
+.	O
+	
+Edrophonium	O
+10	O
+mg	O
+","	O
+given	O
+74	O
+min	O
+after	O
+succinylcholine	O
+","	O
+when	O
+train	O
+-	O
+of	O
+-	O
+four	O
+stimulation	O
+was	O
+characteristic	O
+of	O
+phase	O
+II	O
+block	O
+","	O
+produced	O
+partial	O
+antagonism	O
+which	O
+was	O
+not	O
+sustained	O
+.	O
+	
+Repeated	O
+doses	O
+of	O
+edrophonium	O
+to	O
+70	O
+mg	O
+and	O
+neostigmine	O
+to	O
+2	O
+.	O
+5	O
+mg	O
+did	O
+not	O
+antagonize	O
+or	O
+augment	O
+the	O
+block	O
+.	O
+	
+Spontaneous	O
+respiration	O
+recommenced	O
+200	O
+min	O
+after	O
+succinylcholine	O
+administration	O
+.	O
+	
+It	O
+is	O
+concluded	O
+that	O
+anticholinesterases	O
+are	O
+only	O
+partially	O
+effective	O
+in	O
+restoring	O
+neuromuscular	O
+function	O
+in	O
+succinylcholine	O
+apnoea	B-NP
+despite	O
+muscle	O
+twitch	O
+activity	O
+typical	O
+of	O
+phase	O
+II	O
+block	O
+.	O
+	
+Effect	O
+of	O
+doxorubicin	O
+on	O
+[	O
+omega	O
+-	O
+I	O
+-	O
+131	O
+]	O
+heptadecanoic	O
+acid	O
+myocardial	O
+scintigraphy	O
+and	O
+echocardiography	O
+in	O
+dogs	O
+.	O
+	
+The	O
+effects	O
+of	O
+serial	O
+treatment	O
+with	O
+doxorubicin	O
+on	O
+dynamic	O
+myocardial	O
+scintigraphy	O
+with	O
+[	O
+omega	O
+-	O
+I	O
+-	O
+131	O
+]	O
+heptadecanoic	O
+acid	O
+(	O
+I	O
+-	O
+131	O
+HA	O
+)	O
+","	O
+and	O
+on	O
+global	O
+left	O
+-	O
+ventricular	O
+function	O
+determined	O
+echocardiographically	O
+","	O
+were	O
+studied	O
+in	O
+a	O
+group	O
+of	O
+nine	O
+mongrel	O
+dogs	O
+.	O
+	
+Total	O
+extractable	O
+myocardial	O
+lipid	O
+was	O
+compared	O
+postmortem	O
+between	O
+a	O
+group	O
+of	O
+control	O
+dogs	O
+and	O
+doxorubicin	O
+-	O
+treated	O
+dogs	O
+.	O
+	
+A	O
+significant	O
+and	O
+then	O
+progressive	O
+fall	O
+in	O
+global	O
+LV	O
+function	O
+was	O
+observed	O
+at	O
+a	O
+cumulative	O
+doxorubicin	O
+dose	O
+of	O
+4	O
+mg	O
+/	O
+kg	O
+.	O
+	
+A	O
+significant	O
+increase	O
+in	O
+the	O
+myocardial	O
+t1	O
+/	O
+2	O
+of	O
+the	O
+I	O
+-	O
+131	O
+HA	O
+was	O
+observed	O
+only	O
+at	O
+a	O
+higher	O
+cumulative	O
+dose	O
+","	O
+10	O
+mg	O
+/	O
+kg	O
+.	O
+	
+No	O
+significant	O
+alteration	O
+in	O
+total	O
+extractable	O
+myocardial	O
+lipids	O
+was	O
+observed	O
+between	O
+control	O
+dogs	O
+and	O
+those	O
+treated	O
+with	O
+doxorubicin	O
+.	O
+	
+Our	O
+findings	O
+suggest	O
+that	O
+the	O
+changes	O
+leading	O
+to	O
+an	O
+alteration	O
+of	O
+myocardial	O
+dynamic	O
+imaging	O
+with	O
+I	O
+-	O
+131	O
+HA	O
+are	O
+not	O
+the	O
+initiating	O
+factor	O
+in	O
+doxorubicin	O
+cardiotoxicity	B-NP
+.	O
+	
+Hemodynamics	O
+and	O
+myocardial	O
+metabolism	O
+under	O
+deliberate	O
+hypotension	B-NP
+.	O
+	
+An	O
+experimental	O
+study	O
+in	O
+dogs	O
+.	O
+	
+Coronary	O
+blood	O
+flow	O
+","	O
+cardiac	O
+work	O
+and	O
+metabolism	O
+were	O
+studied	O
+in	O
+dogs	O
+under	O
+sodium	O
+nitroprusside	O
+(	O
+SNP	O
+)	O
+and	O
+trimetaphan	O
+(	O
+TMP	O
+)	O
+deliberate	O
+hypotension	B-NP
+(	O
+20	O
+%	O
+and	O
+40	O
+%	O
+mean	O
+pressure	O
+decrease	O
+from	O
+baseline	O
+)	O
+.	O
+	
+Regarding	O
+the	O
+effects	O
+of	O
+drug	O
+-	O
+induced	O
+hypotension	B-NP
+on	O
+coronary	O
+blood	O
+flow	O
+","	O
+aortic	O
+and	O
+coronary	O
+sinus	O
+metabolic	O
+data	O
+(	O
+pH	O
+","	O
+pO2	O
+","	O
+pCO2	O
+)	O
+we	O
+could	O
+confirm	O
+that	O
+nitroprusside	O
+hypotension	B-NP
+could	O
+be	O
+safely	O
+used	O
+to	O
+30	O
+%	O
+mean	O
+blood	O
+pressure	O
+decrease	O
+from	O
+control	O
+","	O
+trimetaphan	O
+hypotension	B-NP
+to	O
+20	O
+%	O
+mean	O
+blood	O
+pressure	O
+decrease	O
+.	O
+	
+Cardiac	O
+work	O
+was	O
+significantly	O
+reduced	O
+during	O
+SNP	O
+hypotension	B-NP
+.	O
+	
+Myocardial	O
+O2	O
+consumption	O
+and	O
+O2	O
+availability	O
+were	O
+directly	O
+dependent	O
+on	O
+the	O
+coronary	O
+perfusion	O
+.	O
+	
+Careful	O
+invasive	O
+monitoring	O
+of	O
+the	O
+blood	O
+pressure	O
+","	O
+blood	O
+gases	O
+and	O
+of	O
+the	O
+ECG	O
+ST	O
+-	O
+T	O
+segment	O
+is	O
+mandatory	O
+.	O
+	
+Evidence	O
+for	O
+a	O
+selective	O
+brain	O
+noradrenergic	O
+involvement	O
+in	O
+the	O
+locomotor	O
+stimulant	O
+effects	O
+of	O
+amphetamine	O
+in	O
+the	O
+rat	O
+.	O
+	
+Male	O
+rats	O
+received	O
+the	O
+noradrenaline	O
+neurotoxin	O
+DSP4	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+7	O
+days	O
+prior	O
+to	O
+injection	O
+of	O
+D	O
+-	O
+amphetamine	O
+(	O
+10	O
+or	O
+40	O
+mumol	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+	
+The	O
+hyperactivity	B-NP
+induced	O
+by	O
+D	O
+-	O
+amphetamine	O
+(	O
+10	O
+mumol	O
+/	O
+kg	O
+)	O
+was	O
+significantly	O
+reduced	O
+by	O
+DSP4	O
+pretreatment	O
+.	O
+	
+However	O
+","	O
+the	O
+increased	O
+rearings	O
+and	O
+the	O
+amphetamine	O
+-	O
+induced	O
+stereotypies	B-NP
+were	O
+not	O
+blocked	O
+by	O
+pretreatment	O
+with	O
+DSP4	O
+.	O
+	
+The	O
+reduction	O
+of	O
+amphetamine	O
+hyperactivity	B-NP
+induced	O
+by	O
+DSP4	O
+was	O
+blocked	O
+by	O
+pretreatment	O
+with	O
+the	O
+noradrenaline	O
+-	O
+uptake	O
+blocking	O
+agent	O
+","	O
+desipramine	O
+","	O
+which	O
+prevents	O
+the	O
+neurotoxic	B-NP
+action	O
+of	O
+DSP4	O
+.	O
+	
+The	O
+present	O
+results	O
+suggest	O
+a	O
+selective	O
+involvement	O
+of	O
+central	O
+noradrenergic	O
+neurones	O
+in	O
+the	O
+locomotor	O
+stimulant	O
+effect	O
+of	O
+amphetamine	O
+in	O
+the	O
+rat	O
+.	O
+	
+Accelerated	B-NP
+junctional	I-NP
+rhythms	I-NP
+during	O
+oral	O
+verapamil	O
+therapy	O
+.	O
+	
+This	O
+study	O
+examined	O
+the	O
+frequency	O
+of	O
+atrioventricular	O
+(	O
+AV	O
+)	O
+dissociation	O
+and	O
+accelerated	B-NP
+junctional	I-NP
+rhythms	I-NP
+in	O
+59	O
+patients	O
+receiving	O
+oral	O
+verapamil	O
+.	O
+	
+Accelerated	B-NP
+junctional	I-NP
+rhythms	I-NP
+and	O
+AV	O
+dissociation	O
+were	O
+frequent	O
+in	O
+patients	O
+with	O
+supraventricular	B-NP
+tachyarrhythmias	I-NP
+","	O
+particularly	O
+AV	O
+nodal	O
+reentry	O
+.	O
+	
+Verapamil	O
+administration	O
+to	O
+these	O
+patients	O
+led	O
+to	O
+an	O
+asymptomatic	O
+increase	O
+in	O
+activity	O
+of	O
+these	O
+junctional	O
+pacemakers	O
+.	O
+	
+In	O
+patients	O
+with	O
+various	O
+chest	B-NP
+pain	I-NP
+syndromes	O
+","	O
+verapamil	O
+neither	O
+increased	O
+the	O
+frequency	O
+of	O
+junctional	O
+rhythms	O
+nor	O
+suppressed	O
+their	O
+role	O
+as	O
+escape	O
+rhythms	O
+under	O
+physiologically	O
+appropriate	O
+circumstances	O
+.	O
+	
+Interstrain	O
+variation	O
+in	O
+acute	O
+toxic	O
+response	O
+to	O
+caffeine	O
+among	O
+inbred	O
+mice	O
+.	O
+	
+Acute	O
+toxic	O
+dosage	O
+-	O
+dependent	O
+behavioral	O
+effects	O
+of	O
+caffeine	O
+were	O
+compared	O
+in	O
+adult	O
+males	O
+from	O
+seven	O
+inbred	O
+mouse	O
+strains	O
+(	O
+A	O
+/	O
+J	O
+","	O
+BALB	O
+/	O
+cJ	O
+","	O
+CBA	O
+/	O
+J	O
+","	O
+C3H	O
+/	O
+HeJ	O
+","	O
+C57BL	O
+/	O
+6J	O
+","	O
+DBA	O
+/	O
+2J	O
+","	O
+SWR	O
+/	O
+J	O
+)	O
+.	O
+	
+C57BL	O
+/	O
+6J	O
+","	O
+chosen	O
+as	O
+a	O
+"	O
+prototypic	O
+"	O
+mouse	O
+strain	O
+","	O
+was	O
+used	O
+to	O
+determine	O
+behavioral	O
+responses	O
+to	O
+a	O
+broad	O
+range	O
+(	O
+5	O
+-	O
+500	O
+mg	O
+/	O
+kg	O
+)	O
+of	O
+caffeine	O
+doses	O
+.	O
+	
+Five	O
+phenotypic	O
+characteristics	O
+-	O
+-	O
+locomotor	O
+activity	O
+","	O
+righting	O
+ability	O
+","	O
+clonic	B-NP
+seizure	I-NP
+induction	O
+","	O
+stress	O
+-	O
+induced	O
+lethality	O
+","	O
+death	O
+without	O
+external	O
+stress	O
+-	O
+-	O
+were	O
+scored	O
+at	O
+various	O
+caffeine	O
+doses	O
+in	O
+drug	O
+-	O
+naive	O
+animals	O
+under	O
+empirically	O
+optimized	O
+","	O
+rigidly	O
+constant	O
+experimental	O
+conditions	O
+.	O
+	
+Mice	O
+(	O
+n	O
+=	O
+12	O
+for	O
+each	O
+point	O
+)	O
+received	O
+single	O
+IP	O
+injections	O
+of	O
+a	O
+fixed	O
+volume	O
+/	O
+g	O
+body	O
+weight	O
+of	O
+physiological	O
+saline	O
+carrier	O
+with	O
+or	O
+without	O
+caffeine	O
+in	O
+doses	O
+ranging	O
+from	O
+125	O
+-	O
+500	O
+mg	O
+/	O
+kg	O
+.	O
+	
+Loss	O
+of	O
+righting	O
+ability	O
+was	O
+scored	O
+at	O
+1	O
+","	O
+3	O
+","	O
+5	O
+min	O
+post	O
+dosing	O
+and	O
+at	O
+5	O
+min	O
+intervals	O
+thereafter	O
+for	O
+20	O
+min	O
+.	O
+	
+In	O
+the	O
+same	O
+animals	O
+the	O
+occurrence	O
+of	O
+clonic	B-NP
+seizures	I-NP
+was	O
+scored	O
+as	O
+to	O
+time	O
+of	O
+onset	O
+and	O
+severity	O
+for	O
+20	O
+min	O
+after	O
+drug	O
+administration	O
+.	O
+	
+When	O
+these	O
+proceeded	O
+to	O
+tonic	B-NP
+seizures	I-NP
+","	O
+death	O
+occurred	O
+in	O
+less	O
+than	O
+20	O
+min	O
+.	O
+	
+Animals	O
+surviving	O
+for	O
+20	O
+min	O
+were	O
+immediately	O
+stressed	O
+by	O
+a	O
+swim	O
+test	O
+in	O
+25	O
+degrees	O
+C	O
+water	O
+","	O
+and	O
+death	O
+-	O
+producing	O
+tonic	B-NP
+seizures	I-NP
+were	O
+scored	O
+for	O
+2	O
+min	O
+.	O
+	
+In	O
+other	O
+animals	O
+locomotor	O
+activity	O
+was	O
+measured	O
+15	O
+or	O
+60	O
+min	O
+after	O
+caffeine	O
+administration	O
+.	O
+	
+By	O
+any	O
+single	O
+behavioral	O
+criterion	O
+or	O
+a	O
+combination	O
+of	O
+these	O
+criteria	O
+","	O
+marked	O
+differences	O
+in	O
+response	O
+to	O
+toxic	O
+caffeine	O
+doses	O
+were	O
+observed	O
+between	O
+strains	O
+.	O
+	
+These	O
+results	O
+indicate	O
+that	O
+behavioral	O
+toxicity	B-NP
+testing	O
+of	O
+alkylxanthines	O
+in	O
+a	O
+single	O
+mouse	O
+strain	O
+may	O
+be	O
+misleading	O
+and	O
+suggest	O
+that	O
+toxic	O
+responses	O
+of	O
+the	O
+central	O
+nervous	O
+system	O
+to	O
+this	O
+class	O
+of	O
+compounds	O
+are	O
+genetically	O
+influenced	O
+in	O
+mammals	O
+.	O
+	
+Treatment	O
+of	O
+ovarian	B-NP
+cancer	I-NP
+with	O
+a	O
+combination	O
+of	O
+cis	O
+-	O
+platinum	O
+","	O
+adriamycin	O
+","	O
+cyclophosphamide	O
+and	O
+hexamethylmelamine	O
+.	O
+	
+During	O
+the	O
+last	O
+2	O
+1	O
+/	O
+2	O
+years	O
+","	O
+38	O
+patients	O
+with	O
+ovarian	B-NP
+cancer	I-NP
+were	O
+treated	O
+with	O
+a	O
+combination	O
+of	O
+cisplatinum	O
+(	O
+CPDD	O
+)	O
+","	O
+50	O
+mg	O
+/	O
+m2	O
+","	O
+adriamycin	O
+","	O
+30	O
+mg	O
+/	O
+m2	O
+","	O
+cyclophosphamide	O
+","	O
+300	O
+mg	O
+/	O
+m2	O
+","	O
+on	O
+day	O
+1	O
+;	O
+and	O
+hexamethylmelamine	O
+(	O
+HMM	O
+)	O
+","	O
+6	O
+mg	O
+/	O
+kg	O
+daily	O
+","	O
+for	O
+14	O
+days	O
+.	O
+	
+Each	O
+course	O
+was	O
+repeated	O
+monthly	O
+.	O
+	
+2	O
+patients	O
+had	O
+stage	O
+II	O
+","	O
+14	O
+stage	O
+III	O
+and	O
+22	O
+stage	O
+IV	O
+disease	O
+.	O
+	
+14	O
+of	O
+the	O
+38	O
+patients	O
+were	O
+previously	O
+treated	O
+with	O
+chemotherapy	O
+","	O
+1	O
+with	O
+radiation	O
+","	O
+6	O
+with	O
+both	O
+chemotherapy	O
+and	O
+radiation	O
+","	O
+and	O
+17	O
+did	O
+not	O
+have	O
+any	O
+treatment	O
+before	O
+CPDD	O
+combination	O
+.	O
+	
+31	O
+of	O
+the	O
+38	O
+cases	O
+(	O
+81	O
+.	O
+5	O
+%	O
+)	O
+demonstrated	O
+objective	O
+responses	O
+lasting	O
+for	O
+2	O
+months	O
+or	O
+more	O
+.	O
+	
+These	O
+responses	O
+were	O
+partial	O
+in	O
+19	O
+and	O
+complete	O
+in	O
+12	O
+cases	O
+.	O
+	
+Hematologic	B-NP
+toxicity	I-NP
+was	O
+moderate	O
+and	O
+with	O
+reversible	O
+anemia	B-NP
+developing	O
+in	O
+71	O
+%	O
+of	O
+patients	O
+.	O
+	
+Gastrointestinal	O
+side	O
+effects	O
+from	O
+CPDD	O
+were	O
+universal	O
+.	O
+	
+HMM	O
+gastrointestinal	B-NP
+toxicity	I-NP
+necessitated	O
+discontinuation	O
+of	O
+the	O
+drug	O
+in	O
+5	O
+patients	O
+.	O
+	
+Severe	O
+nephrotoxicity	B-NP
+was	O
+observed	O
+in	O
+2	O
+patients	O
+but	O
+was	O
+reversible	O
+.	O
+	
+There	O
+were	O
+no	O
+drug	O
+-	O
+related	O
+deaths	O
+.	O
+	
+Nontraumatic	O
+dissecting	B-NP
+aneurysm	I-NP
+of	O
+the	O
+basilar	O
+artery	O
+.	O
+	
+A	O
+case	O
+of	O
+nontraumatic	O
+dissecting	B-NP
+aneurysm	I-NP
+of	O
+the	O
+basilar	O
+artery	O
+in	O
+association	O
+with	O
+hypertension	B-NP
+","	O
+smoke	O
+","	O
+and	O
+oral	O
+contraceptives	O
+is	O
+reported	O
+in	O
+a	O
+young	O
+female	O
+patient	O
+with	O
+a	O
+locked	B-NP
+-	I-NP
+in	I-NP
+syndrome	I-NP
+.	O
+	
+A	O
+method	O
+for	O
+the	O
+measurement	O
+of	O
+tremor	B-NP
+","	O
+and	O
+a	O
+comparison	O
+of	O
+the	O
+effects	O
+of	O
+tocolytic	O
+beta	O
+-	O
+mimetics	O
+.	O
+	
+A	O
+method	O
+permitting	O
+measurement	O
+of	O
+finger	O
+tremor	B-NP
+as	O
+a	O
+displacement	O
+-	O
+time	O
+curve	O
+is	O
+described	O
+","	O
+using	O
+a	O
+test	O
+system	O
+with	O
+simple	O
+amplitude	O
+calibration	O
+.	O
+	
+The	O
+coordinates	O
+of	O
+the	O
+inversion	O
+points	O
+of	O
+the	O
+displacement	O
+-	O
+time	O
+curves	O
+were	O
+transferred	O
+through	O
+graphical	O
+input	O
+equipment	O
+to	O
+punched	O
+tape	O
+.	O
+	
+By	O
+means	O
+of	O
+a	O
+computer	O
+program	O
+","	O
+periods	O
+and	O
+amplitudes	O
+of	O
+tremor	B-NP
+oscillations	O
+were	O
+calculated	O
+and	O
+classified	O
+.	O
+	
+The	O
+event	O
+frequency	O
+for	O
+each	O
+class	O
+of	O
+periods	O
+and	O
+amplitudes	O
+was	O
+determined	O
+.	O
+	
+The	O
+actions	O
+of	O
+fenoterol	O
+-	O
+hydrobromide	O
+","	O
+ritodrin	O
+-	O
+HCl	O
+and	O
+placebo	O
+given	O
+to	O
+10	O
+healthy	O
+subjects	O
+by	O
+intravenous	O
+infusion	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+crossover	O
+study	O
+were	O
+tested	O
+by	O
+this	O
+method	O
+.	O
+	
+At	O
+therapeutic	O
+doses	O
+both	O
+substances	O
+raised	O
+the	O
+mean	O
+tremor	B-NP
+amplitude	O
+to	O
+about	O
+three	O
+times	O
+the	O
+control	O
+level	O
+.	O
+	
+At	O
+the	O
+same	O
+time	O
+","	O
+the	O
+mean	O
+period	O
+within	O
+each	O
+class	O
+of	O
+amplitudes	O
+shortened	O
+by	O
+10	O
+-	O
+-	O
+20	O
+ms	O
+","	O
+whereas	O
+the	O
+mean	O
+periods	O
+calculated	O
+from	O
+all	O
+oscillations	O
+together	O
+did	O
+not	O
+change	O
+significantly	O
+.	O
+	
+After	O
+the	O
+end	O
+of	O
+fenoterol	O
+-	O
+hydrobromide	O
+infusion	O
+","	O
+tremor	B-NP
+amplitudes	O
+decreased	O
+significantly	O
+faster	O
+than	O
+those	O
+following	O
+ritodrin	O
+-	O
+HCl	O
+infusion	O
+.	O
+	
+Propylthiouracil	O
+-	O
+induced	O
+hepatic	B-NP
+damage	I-NP
+.	O
+	
+Two	O
+cases	O
+of	O
+propylthiouracil	O
+-	O
+induced	O
+liver	B-NP
+damage	I-NP
+have	O
+been	O
+observed	O
+.	O
+	
+The	O
+first	O
+case	O
+is	O
+of	O
+an	O
+acute	O
+type	O
+of	O
+damage	O
+","	O
+proven	O
+by	O
+rechallenge	O
+;	O
+the	O
+second	O
+presents	O
+a	O
+clinical	O
+and	O
+histologic	O
+picture	O
+resembling	O
+chronic	B-NP
+active	I-NP
+hepatitis	I-NP
+","	O
+with	O
+spontaneous	O
+remission	O
+.	O
+	
+Studies	O
+on	O
+the	O
+bradycardia	B-NP
+induced	O
+by	O
+bepridil	O
+.	O
+	
+Bepridil	O
+","	O
+a	O
+novel	O
+active	O
+compound	O
+for	O
+prophylactic	O
+treatment	O
+of	O
+anginal	B-NP
+attacks	I-NP
+","	O
+induced	O
+persistent	O
+bradycardia	B-NP
+and	O
+a	O
+non	O
+-	O
+specific	O
+anti	O
+-	O
+tachycardial	B-NP
+effect	O
+","	O
+the	O
+mechanisms	O
+of	O
+which	O
+were	O
+investigated	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+.	O
+	
+In	O
+vitro	O
+perfusion	O
+of	O
+bepridil	O
+in	O
+the	O
+life	O
+-	O
+support	O
+medium	O
+for	O
+isolated	O
+sino	O
+-	O
+atrial	O
+tissue	O
+from	O
+rabbit	O
+heart	O
+","	O
+caused	O
+a	O
+reduction	O
+in	O
+action	O
+potential	O
+(	O
+AP	O
+)	O
+spike	O
+frequency	O
+(	O
+recorded	O
+by	O
+KCl	O
+microelectrodes	O
+)	O
+starting	O
+at	O
+doses	O
+of	O
+5	O
+X	O
+10	O
+(	O
+-	O
+6	O
+)	O
+M	O
+.	O
+	
+This	O
+effect	O
+was	O
+dose	O
+-	O
+dependent	O
+up	O
+to	O
+concentrations	O
+of	O
+5	O
+X	O
+10	O
+(	O
+-	O
+5	O
+)	O
+M	O
+","	O
+whereupon	O
+blockade	O
+of	O
+sinus	O
+activity	O
+set	O
+in	O
+.	O
+	
+Bepridil	O
+at	O
+a	O
+dose	O
+of	O
+5	O
+X	O
+10	O
+(	O
+-	O
+6	O
+)	O
+M	O
+","	O
+induced	O
+a	O
+concomitant	O
+reduction	O
+in	O
+AP	O
+amplitude	O
+(	O
+falling	O
+from	O
+71	O
++	O
+/	O
+-	O
+8	O
+mV	O
+to	O
+47	O
++	O
+/	O
+-	O
+6	O
+mV	O
+)	O
+","	O
+maximum	O
+systolic	O
+depolarization	O
+velocity	O
+(	O
+phase	O
+0	O
+)	O
+which	O
+fell	O
+from	O
+1	O
+.	O
+85	O
++	O
+/	O
+-	O
+0	O
+.	O
+35	O
+V	O
+/	O
+s	O
+to	O
+0	O
+.	O
+84	O
++	O
+/	O
+-	O
+0	O
+.	O
+28	O
+V	O
+/	O
+s	O
+","	O
+together	O
+with	O
+maximum	O
+diastolic	O
+depolarization	O
+velocity	O
+(	O
+phase	O
+4	O
+)	O
+which	O
+fell	O
+from	O
+38	O
++	O
+/	O
+-	O
+3	O
+mV	O
+/	O
+s	O
+to	O
+24	O
++	O
+/	O
+-	O
+5	O
+mV	O
+/	O
+s	O
+.	O
+	
+In	O
+vivo	O
+injection	O
+of	O
+bepridil	O
+at	O
+a	O
+dose	O
+of	O
+5	O
+mg	O
+/	O
+kg	O
+(	O
+i	O
+.	O
+v	O
+.	O
+)	O
+into	O
+6	O
+anaesthetized	O
+dogs	O
+which	O
+had	O
+undergone	O
+ablation	O
+of	O
+all	O
+the	O
+extrinsic	O
+cardiac	O
+afferent	O
+nerve	O
+supply	O
+","	O
+together	O
+with	O
+a	O
+bilateral	O
+medullo	O
+-	O
+adrenalectomy	O
+","	O
+caused	O
+a	O
+marked	O
+reduction	O
+in	O
+heart	O
+rate	O
+which	O
+fell	O
+from	O
+98	O
+.	O
+7	O
++	O
+/	O
+-	O
+4	O
+.	O
+2	O
+beats	O
+/	O
+min	O
+to	O
+76	O
++	O
+/	O
+-	O
+5	O
+.	O
+3	O
+beats	O
+/	O
+min	O
+sustained	O
+for	O
+more	O
+than	O
+45	O
+min	O
+.	O
+	
+It	O
+is	O
+concluded	O
+that	O
+bepridil	O
+reduces	O
+heart	O
+rate	O
+by	O
+acting	O
+directly	O
+on	O
+the	O
+sinus	O
+node	O
+.	O
+	
+This	O
+effect	O
+","	O
+which	O
+results	O
+in	O
+a	O
+flattening	O
+of	O
+the	O
+phase	O
+0	O
+and	O
+phase	O
+4	O
+slope	O
+","	O
+together	O
+with	O
+a	O
+longer	O
+AP	O
+duration	O
+","	O
+may	O
+be	O
+due	O
+to	O
+an	O
+increase	O
+in	O
+the	O
+time	O
+constants	O
+of	O
+slow	O
+inward	O
+ionic	O
+currents	O
+(	O
+already	O
+demonstrated	O
+elsewhere	O
+)	O
+","	O
+but	O
+also	O
+to	O
+an	O
+increased	O
+time	O
+constant	O
+for	O
+deactivation	O
+of	O
+the	O
+outward	O
+potassium	O
+current	O
+(	O
+Ip	O
+)	O
+.	O
+	
+Hepatitis	B-NP
+and	O
+renal	B-NP
+tubular	I-NP
+acidosis	I-NP
+after	O
+anesthesia	O
+with	O
+methoxyflurane	O
+.	O
+	
+A	O
+69	O
+-	O
+year	O
+-	O
+old	O
+man	O
+operated	O
+for	O
+acute	B-NP
+cholecystitis	I-NP
+under	O
+methoxyflurane	O
+anesthesia	O
+developed	O
+postoperatively	O
+a	O
+hepatic	B-NP
+insufficiency	I-NP
+syndrome	I-NP
+and	O
+renal	B-NP
+tubular	I-NP
+acidosis	I-NP
+.	O
+	
+Massive	O
+bleeding	B-NP
+appeared	O
+during	O
+surgery	O
+which	O
+lasted	O
+for	O
+six	O
+hours	O
+.	O
+	
+Postoperative	O
+evolution	O
+under	O
+supportive	O
+therapy	O
+was	O
+favourable	O
+.	O
+	
+Complete	O
+recovery	O
+was	O
+confirmed	O
+by	O
+repeated	O
+controls	O
+performed	O
+over	O
+a	O
+period	O
+of	O
+one	O
+year	O
+after	O
+surgery	O
+.	O
+	
+Pituitary	O
+response	O
+to	O
+luteinizing	O
+hormone	O
+-	O
+releasing	O
+hormone	O
+during	O
+haloperidol	O
+-	O
+induced	O
+hyperprolactinemia	B-NP
+.	O
+	
+The	O
+effects	O
+of	O
+a	O
+6	O
+-	O
+hour	O
+infusion	O
+with	O
+haloperidol	O
+on	O
+serum	O
+prolactin	O
+and	O
+luteinizing	O
+hormone	O
+(	O
+LH	O
+)	O
+levels	O
+was	O
+studied	O
+in	O
+a	O
+group	O
+of	O
+male	O
+subjects	O
+.	O
+	
+Five	O
+hours	O
+after	O
+starting	O
+the	O
+infusions	O
+","	O
+a	O
+study	O
+of	O
+the	O
+pituitary	O
+responses	O
+to	O
+LH	O
+-	O
+releasing	O
+hormone	O
+(	O
+LH	O
+-	O
+RH	O
+)	O
+was	O
+carried	O
+out	O
+.	O
+	
+Control	O
+patients	O
+received	O
+infusions	O
+of	O
+0	O
+.	O
+9	O
+%	O
+NaCl	O
+solution	O
+.	O
+	
+During	O
+the	O
+course	O
+of	O
+haloperidol	O
+infusions	O
+","	O
+significant	O
+hyperprolactinemia	B-NP
+was	O
+found	O
+","	O
+together	O
+with	O
+an	O
+abolished	O
+pituitary	O
+response	O
+to	O
+LH	O
+-	O
+RH	O
+","	O
+as	O
+compared	O
+with	O
+responses	O
+of	O
+control	O
+subjects	O
+.	O
+	
+Antirifampicin	O
+antibodies	O
+in	O
+acute	O
+rifampicin	O
+-	O
+associated	O
+renal	B-NP
+failure	I-NP
+.	O
+	
+5	O
+patients	O
+with	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+(	O
+3	O
+with	O
+thrombopenia	B-NP
+and	O
+hemolysis	B-NP
+)	O
+induced	O
+by	O
+the	O
+reintroduction	O
+of	O
+rifampicin	O
+are	O
+described	O
+.	O
+	
+No	O
+correlation	O
+was	O
+found	O
+between	O
+the	O
+severity	O
+of	O
+clinical	O
+manifestations	O
+and	O
+the	O
+total	O
+dose	O
+taken	O
+by	O
+the	O
+patients	O
+.	O
+	
+In	O
+all	O
+but	O
+1	O
+patient	O
+","	O
+antirifampicin	O
+antibodies	O
+were	O
+detected	O
+.	O
+	
+Antibodies	O
+suggested	O
+to	O
+be	O
+of	O
+the	O
+IgM	O
+class	O
+were	O
+detected	O
+in	O
+all	O
+3	O
+patients	O
+with	O
+hematological	B-NP
+disorders	I-NP
+.	O
+	
+The	O
+pattern	O
+of	O
+non	O
+-	O
+specific	O
+acute	B-NP
+tubular	I-NP
+necrosis	I-NP
+found	O
+in	O
+the	O
+2	O
+biopsied	O
+patients	O
+","	O
+indistinguishable	O
+from	O
+that	O
+of	O
+ischemic	O
+origin	O
+","	O
+raised	O
+the	O
+possibility	O
+of	O
+a	O
+vascular	O
+-	O
+mediated	O
+damage	O
+.	O
+	
+In	O
+3	O
+patients	O
+","	O
+the	O
+possibility	O
+of	O
+a	O
+triggering	O
+immunoallergic	O
+mechanism	O
+is	O
+discussed	O
+.	O
+	
+Cardiovascular	O
+effects	O
+of	O
+hypotension	B-NP
+induced	O
+by	O
+adenosine	O
+triphosphate	O
+and	O
+sodium	O
+nitroprusside	O
+on	O
+dogs	O
+with	O
+denervated	O
+hearts	O
+.	O
+	
+Adenosine	O
+triphosphate	O
+(	O
+ATP	O
+)	O
+and	O
+sodium	O
+nitroprusside	O
+(	O
+SNP	O
+)	O
+are	O
+administered	O
+to	O
+patients	O
+to	O
+induce	O
+and	O
+control	O
+hypotension	B-NP
+during	O
+anesthesia	O
+.	O
+	
+SNP	O
+is	O
+authorized	O
+for	O
+clinical	O
+use	O
+in	O
+USA	O
+and	O
+UK	O
+","	O
+and	O
+ATP	O
+is	O
+clinically	O
+used	O
+in	O
+other	O
+countries	O
+such	O
+as	O
+Japan	O
+.	O
+	
+We	O
+investigated	O
+how	O
+these	O
+two	O
+drugs	O
+act	O
+on	O
+the	O
+cardiovascular	O
+systems	O
+of	O
+20	O
+dogs	O
+whose	O
+hearts	O
+had	O
+been	O
+denervated	O
+by	O
+a	O
+procedure	O
+we	O
+had	O
+devised	O
+.	O
+	
+ATP	O
+(	O
+10	O
+dogs	O
+)	O
+or	O
+SNP	O
+(	O
+10	O
+dogs	O
+)	O
+was	O
+administered	O
+to	O
+reduce	O
+mean	O
+arterial	O
+pressure	O
+by	O
+30	O
+%	O
+to	O
+70	O
+%	O
+of	O
+control	O
+.	O
+	
+Before	O
+","	O
+during	O
+and	O
+after	O
+induced	O
+hypotension	B-NP
+","	O
+we	O
+measured	O
+major	O
+cardiovascular	O
+parameters	O
+.	O
+	
+Hypotension	B-NP
+induced	O
+by	O
+ATP	O
+was	O
+accompanied	O
+by	O
+significant	O
+decreases	O
+in	O
+mean	O
+pulmonary	O
+arterial	O
+pressure	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+central	O
+venous	O
+pressure	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+left	O
+ventricular	O
+end	O
+-	O
+diastolic	O
+pressure	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+total	O
+peripheral	O
+resistance	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+rate	O
+pressure	O
+product	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+total	O
+body	O
+oxygen	O
+consumption	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+","	O
+and	O
+heart	O
+rate	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+;	O
+all	O
+these	O
+variables	O
+returned	O
+normal	O
+within	O
+30	O
+min	O
+after	O
+ATP	O
+was	O
+stopped	O
+.	O
+	
+Cardiac	O
+output	O
+did	O
+not	O
+change	O
+.	O
+	
+During	O
+hypotension	B-NP
+produced	O
+by	O
+SNP	O
+similar	O
+decreases	O
+were	O
+observed	O
+in	O
+mean	O
+pulmonary	O
+arterial	O
+pressure	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+central	O
+venous	O
+pressure	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+left	O
+ventricular	O
+end	O
+-	O
+diastolic	O
+pressure	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+total	O
+peripheral	O
+resistance	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+rate	O
+pressure	O
+product	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+and	O
+oxygen	O
+content	O
+difference	O
+between	O
+arterial	O
+and	O
+mixed	O
+venous	O
+blood	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+","	O
+while	O
+heart	O
+rate	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+and	O
+cardiac	O
+output	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+were	O
+increased	O
+.	O
+	
+Recoveries	O
+of	O
+heart	O
+rate	O
+and	O
+left	O
+ventricular	O
+end	O
+-	O
+diastolic	O
+pressure	O
+were	O
+not	O
+shown	O
+within	O
+60	O
+min	O
+after	O
+SNP	O
+had	O
+been	O
+stopped	O
+.	O
+	
+Both	O
+ATP	O
+and	O
+SNP	O
+should	O
+act	O
+on	O
+the	O
+pacemaker	O
+tissue	O
+of	O
+the	O
+heart	O
+.	O
+	
+Comparative	O
+study	O
+:	O
+Endografine	O
+(	O
+diatrizoate	O
+)	O
+","	O
+Vasurix	O
+polyvidone	O
+(	O
+acetrizoate	O
+)	O
+","	O
+Dimer	O
+-	O
+X	O
+(	O
+iocarmate	O
+)	O
+and	O
+Hexabrix	O
+(	O
+ioxaglate	O
+)	O
+in	O
+hysterosalpingography	O
+.	O
+	
+Side	O
+effects	O
+of	O
+hysterosalpingography	O
+with	O
+Dimer	O
+-	O
+X	O
+","	O
+Hexabrix	O
+","	O
+Vasurix	O
+polyvidone	O
+and	O
+Endografine	O
+in	O
+142	O
+consecutive	O
+patients	O
+","	O
+receiving	O
+one	O
+of	O
+the	O
+four	O
+tested	O
+media	O
+were	O
+evaluated	O
+from	O
+replies	O
+to	O
+postal	O
+questionnaires	O
+.	O
+	
+The	O
+Dimer	O
+-	O
+X	O
+group	O
+had	O
+a	O
+higher	O
+incidence	O
+of	O
+nausea	B-NP
+and	O
+dizziness	B-NP
+.	O
+	
+The	O
+Endografine	O
+group	O
+had	O
+a	O
+higher	O
+incidence	O
+of	O
+abdominal	B-NP
+pain	I-NP
+.	O
+	
+These	O
+differences	O
+occur	O
+especially	O
+in	O
+the	O
+age	O
+groups	O
+under	O
+30	O
+years	O
+.	O
+	
+Hexabrix	O
+and	O
+Vasurix	O
+polyvidone	O
+are	O
+considered	O
+the	O
+best	O
+contrast	O
+media	O
+for	O
+hysterosalpingography	O
+and	O
+perhaps	O
+because	O
+of	O
+its	O
+low	O
+toxicity	B-NP
+Hexabrix	O
+should	O
+be	O
+preferred	O
+.	O
+	
+Post	O
+-	O
+suxamethonium	O
+pains	B-NP
+in	O
+Nigerian	O
+surgical	O
+patients	O
+.	O
+	
+Contrary	O
+to	O
+an	O
+earlier	O
+report	O
+by	O
+Coxon	O
+","	O
+scoline	O
+pain	B-NP
+occurs	O
+in	O
+African	O
+negroes	O
+.	O
+	
+Its	O
+incidence	O
+was	O
+determined	O
+in	O
+a	O
+prospective	O
+study	O
+involving	O
+a	O
+total	O
+of	O
+100	O
+Nigerian	O
+patients	O
+(	O
+50	O
+out	O
+-	O
+patients	O
+and	O
+50	O
+in	O
+-	O
+patients	O
+)	O
+.	O
+	
+About	O
+62	O
+%	O
+of	O
+the	O
+out	O
+-	O
+patients	O
+developed	O
+scoline	O
+pain	B-NP
+as	O
+compared	O
+with	O
+about	O
+26	O
+%	O
+among	O
+the	O
+in	O
+-	O
+patients	O
+.	O
+	
+The	O
+abolition	O
+of	O
+muscle	O
+fasciculations	B-NP
+(	O
+by	O
+0	O
+.	O
+075mg	O
+/	O
+kg	O
+dose	O
+of	O
+Fazadinium	O
+)	O
+did	O
+not	O
+influence	O
+the	O
+occurrence	O
+of	O
+scoline	O
+pain	B-NP
+.	O
+	
+Neither	O
+the	O
+type	O
+of	O
+induction	O
+agent	O
+(	O
+Althesin	O
+or	O
+Thiopentone	O
+)	O
+nor	O
+the	O
+salt	O
+preparation	O
+of	O
+suxamethonium	O
+used	O
+(	O
+chloride	O
+or	O
+bromide	O
+)	O
+","	O
+affected	O
+the	O
+incidence	O
+of	O
+scoline	O
+pain	B-NP
+.	O
+	
+Invasive	O
+carcinoma	B-NP
+of	I-NP
+the	I-NP
+renal	I-NP
+pelvis	I-NP
+following	O
+cyclophosphamide	O
+therapy	O
+for	O
+nonmalignant	O
+disease	O
+.	O
+	
+A	O
+47	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+right	O
+hydroureteronephrosis	B-NP
+due	O
+to	O
+ureterovesical	O
+junction	O
+obstruction	O
+had	O
+gross	O
+hematuria	B-NP
+after	O
+being	O
+treated	O
+for	O
+five	O
+years	O
+wtih	O
+cyclophosphamide	O
+for	O
+cerebral	B-NP
+vasculitis	I-NP
+.	O
+	
+A	O
+right	O
+nephroureterectomy	O
+was	O
+required	O
+for	O
+control	O
+of	O
+bleeding	B-NP
+.	O
+	
+The	O
+pathology	O
+specimen	O
+contained	O
+clinically	O
+occult	O
+invasive	O
+carcinoma	B-NP
+of	I-NP
+the	I-NP
+renal	I-NP
+pelvis	I-NP
+.	O
+	
+Although	O
+the	O
+ability	O
+of	O
+cyclophosphamide	O
+to	O
+cause	O
+hemorrhagic	B-NP
+cystitis	I-NP
+and	O
+urine	O
+cytologic	O
+abnormalities	O
+indistinguishable	O
+from	O
+high	O
+grade	O
+carcinoma	B-NP
+is	O
+well	O
+known	O
+","	O
+it	O
+is	O
+less	O
+widely	O
+appreciated	O
+that	O
+it	O
+is	O
+also	O
+associated	O
+with	O
+carcinoma	B-NP
+of	I-NP
+the	I-NP
+urinary	I-NP
+tract	I-NP
+.	O
+	
+Twenty	O
+carcinomas	B-NP
+of	I-NP
+the	I-NP
+urinary	I-NP
+bladder	I-NP
+and	O
+one	O
+carcinoma	B-NP
+of	I-NP
+the	I-NP
+prostate	I-NP
+have	O
+been	O
+reported	O
+in	O
+association	O
+with	O
+its	O
+use	O
+.	O
+	
+The	O
+present	O
+case	O
+is	O
+the	O
+first	O
+carcinoma	B-NP
+of	I-NP
+the	I-NP
+renal	I-NP
+pelvis	I-NP
+reported	O
+in	O
+association	O
+with	O
+cyclophosphamide	O
+treatment	O
+.	O
+	
+It	O
+is	O
+the	O
+third	O
+urinary	B-NP
+tract	I-NP
+cancer	I-NP
+reported	O
+in	O
+association	O
+with	O
+cyclophosphamide	O
+treatment	O
+for	O
+nonmalignant	O
+disease	O
+.	O
+	
+The	O
+association	O
+of	O
+the	O
+tumor	B-NP
+with	O
+preexisting	O
+hydroureteronephrosis	B-NP
+suggests	O
+that	O
+stasis	O
+prolonged	O
+and	O
+intensified	O
+exposure	O
+of	O
+upper	O
+urinary	O
+tract	O
+epithelium	O
+to	O
+cyclophosphamide	O
+.	O
+	
+Patients	O
+who	O
+are	O
+candidates	O
+for	O
+long	O
+-	O
+term	O
+cyclophosphamide	O
+treatment	O
+should	O
+be	O
+routinely	O
+evaluated	O
+for	O
+obstructive	B-NP
+uropathy	I-NP
+.	O
+	
+Medial	O
+changes	O
+in	O
+arterial	O
+spasm	B-NP
+induced	O
+by	O
+L	O
+-	O
+norepinephrine	O
+.	O
+	
+In	O
+normal	O
+rats	O
+","	O
+the	O
+media	O
+of	O
+small	O
+arteries	O
+(	O
+0	O
+.	O
+4	O
+-	O
+-	O
+0	O
+.	O
+2	O
+mm	O
+in	O
+diameter	O
+)	O
+previously	O
+was	O
+shown	O
+to	O
+contain	O
+intracellular	O
+vacuoles	O
+","	O
+identified	O
+ultrastructurally	O
+as	O
+herniations	O
+of	O
+one	O
+smooth	O
+muscle	O
+cell	O
+into	O
+another	O
+.	O
+	
+The	O
+hypothesis	O
+that	O
+intense	O
+vasoconstriction	O
+would	O
+increase	O
+the	O
+number	O
+of	O
+such	O
+vacuoles	O
+has	O
+been	O
+tested	O
+.	O
+	
+In	O
+the	O
+media	O
+of	O
+the	O
+saphenous	O
+artery	O
+and	O
+its	O
+distal	O
+branch	O
+","	O
+vasoconstriction	O
+induced	O
+by	O
+L	O
+-	O
+norepinephrine	O
+produced	O
+many	O
+cell	O
+-	O
+to	O
+-	O
+cell	O
+hernias	B-NP
+within	O
+15	O
+minutes	O
+.	O
+	
+At	O
+1	O
+day	O
+their	O
+number	O
+was	O
+reduced	O
+to	O
+about	O
+1	O
+/	O
+10	O
+of	O
+the	O
+original	O
+number	O
+.	O
+	
+By	O
+7	O
+days	O
+the	O
+vessel	O
+was	O
+almost	O
+restored	O
+to	O
+normal	O
+.	O
+	
+Triple	O
+stimulation	O
+over	O
+1	O
+day	O
+induced	O
+more	O
+severe	O
+changes	O
+in	O
+the	O
+media	O
+.	O
+	
+These	O
+findings	O
+suggest	O
+that	O
+smooth	O
+muscle	O
+cells	O
+are	O
+susceptible	O
+to	O
+damage	O
+in	O
+the	O
+course	O
+of	O
+their	O
+specific	O
+function	O
+.	O
+	
+The	O
+experimental	O
+data	O
+are	O
+discussed	O
+in	O
+relation	O
+to	O
+medial	O
+changes	O
+observed	O
+in	O
+other	O
+instances	O
+of	O
+arterial	O
+spasm	B-NP
+.	O
+	
+Endothelial	O
+changes	O
+that	O
+developed	O
+in	O
+the	O
+same	O
+experimental	O
+model	O
+were	O
+described	O
+in	O
+a	O
+previous	O
+paper	O
+.	O
+	
+Bilateral	O
+retinal	B-NP
+artery	I-NP
+and	I-NP
+choriocapillaris	I-NP
+occlusion	I-NP
+following	O
+the	O
+injection	O
+of	O
+long	O
+-	O
+acting	O
+corticosteroid	O
+suspensions	O
+in	O
+combination	O
+with	O
+other	O
+drugs	O
+:	O
+I	O
+.	O
+	
+Clinical	O
+studies	O
+.	O
+	
+Two	O
+well	O
+-	O
+documented	O
+cases	O
+of	O
+bilateral	O
+retinal	B-NP
+artery	I-NP
+and	I-NP
+choriocapillaris	I-NP
+occlusions	I-NP
+with	O
+blindness	B-NP
+following	O
+head	O
+and	O
+neck	O
+soft	O
+-	O
+tissue	O
+injection	O
+with	O
+methylprednisolone	O
+acetate	O
+in	O
+combination	O
+with	O
+lidocaine	O
+","	O
+epinephrine	O
+","	O
+or	O
+penicillin	O
+are	O
+reported	O
+.	O
+	
+One	O
+case	O
+had	O
+only	O
+a	O
+unilateral	O
+injection	O
+.	O
+	
+The	O
+acute	O
+observations	O
+included	O
+hazy	O
+sensorium	O
+","	O
+superior	O
+gaze	O
+palsy	B-NP
+","	O
+pupillary	B-NP
+abnormalities	I-NP
+","	O
+and	O
+conjunctival	O
+hemorrhages	B-NP
+with	O
+edema	B-NP
+.	O
+	
+Follow	O
+-	O
+up	O
+changes	O
+showed	O
+marked	O
+visual	B-NP
+loss	I-NP
+","	O
+constricted	O
+visual	O
+fields	O
+","	O
+optic	O
+nerve	O
+pallor	O
+","	O
+vascular	O
+attenuation	O
+","	O
+and	O
+chorioretinal	B-NP
+atrophy	I-NP
+.	O
+	
+The	O
+literature	O
+is	O
+reviewed	O
+","	O
+and	O
+possible	O
+causes	O
+are	O
+discussed	O
+.	O
+	
+Abnormalities	O
+of	O
+the	O
+pupil	O
+and	O
+visual	O
+-	O
+evoked	O
+potential	O
+in	O
+quinine	O
+amblyopia	B-NP
+.	O
+	
+Total	O
+blindness	B-NP
+with	O
+a	O
+transient	O
+tonic	B-NP
+pupillary	I-NP
+response	O
+","	O
+denervation	O
+supersensitivity	O
+","	O
+and	O
+abnormal	O
+visual	O
+-	O
+evoked	O
+potentials	O
+developed	O
+in	O
+a	O
+54	O
+-	O
+year	O
+-	O
+old	O
+man	O
+after	O
+the	O
+use	O
+of	O
+quinine	O
+sulfate	O
+for	O
+leg	B-NP
+cramps	I-NP
+.	O
+	
+He	O
+later	O
+recovered	O
+normal	O
+visual	O
+acuity	O
+.	O
+	
+A	O
+transient	O
+tonic	B-NP
+pupillary	I-NP
+response	O
+","	O
+denervation	O
+supersensitivity	O
+","	O
+and	O
+abnormal	O
+visual	O
+-	O
+evoked	O
+potentials	O
+in	O
+quinine	O
+toxicity	B-NP
+","	O
+to	O
+our	O
+knowledge	O
+","	O
+have	O
+not	O
+been	O
+previously	O
+reported	O
+.	O
+	
+Suxamethonium	O
+-	O
+induced	O
+jaw	B-NP
+stiffness	I-NP
+and	O
+myalgia	B-NP
+associated	O
+with	O
+atypical	O
+cholinesterase	O
+:	O
+case	O
+report	O
+.	O
+	
+An	O
+11	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+was	O
+given	O
+halothane	O
+","	O
+nitrous	O
+oxide	O
+and	O
+oxygen	O
+","	O
+pancuronium	O
+0	O
+.	O
+4	O
+mg	O
+and	O
+suxamethonium	O
+100	O
+mg	O
+for	O
+induction	O
+of	O
+anaesthesia	O
+.	O
+	
+In	O
+response	O
+to	O
+this	O
+a	O
+marked	O
+jaw	B-NP
+stiffness	I-NP
+occurred	O
+which	O
+lasted	O
+for	O
+two	O
+minutes	O
+and	O
+the	O
+anaesthesia	O
+were	O
+terminated	O
+.	O
+	
+Four	O
+hours	O
+of	O
+apnoea	B-NP
+ensued	O
+and	O
+he	O
+suffered	O
+generalized	O
+severe	O
+myalgia	B-NP
+lasting	O
+for	O
+one	O
+week	O
+.	O
+	
+He	O
+was	O
+found	O
+to	O
+have	O
+atypical	O
+plasma	O
+cholinesterase	O
+with	O
+a	O
+dibucaine	O
+number	O
+of	O
+12	O
+","	O
+indicating	O
+homozygocity	O
+.	O
+	
+This	O
+was	O
+verified	O
+by	O
+study	O
+of	O
+the	O
+family	O
+.	O
+	
+The	O
+case	O
+shows	O
+that	O
+prolonged	B-NP
+jaw	I-NP
+rigidity	I-NP
+and	O
+myalgia	B-NP
+may	O
+occur	O
+after	O
+suxamethonium	O
+in	O
+patients	O
+with	O
+atypical	O
+cholinesterase	O
+despite	O
+pretreatment	O
+with	O
+pancuronium	O
+.	O
+	
+Indomethacin	O
+-	O
+induced	O
+hyperkalemia	B-NP
+in	O
+three	O
+patients	O
+with	O
+gouty	B-NP
+arthritis	I-NP
+.	O
+	
+We	O
+describe	O
+three	O
+patients	O
+in	O
+whom	O
+severe	O
+","	O
+life	O
+-	O
+threatening	O
+hyperkalemia	B-NP
+and	O
+renal	B-NP
+insufficiency	I-NP
+developed	O
+after	O
+treatment	O
+of	O
+acute	O
+gouty	B-NP
+arthritis	I-NP
+with	O
+indomethacin	O
+.	O
+	
+This	O
+complication	O
+may	O
+result	O
+from	O
+an	O
+inhibition	O
+of	O
+prostaglandin	O
+synthesis	O
+and	O
+consequent	O
+hyporeninemic	B-NP
+hypoaidosteronism	I-NP
+.	O
+	
+Careful	O
+attention	O
+to	O
+renal	O
+function	O
+and	O
+potassium	O
+balance	O
+in	O
+patients	O
+receiving	O
+indomethacin	O
+or	O
+other	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+agents	O
+","	O
+particularly	O
+in	O
+those	O
+patients	O
+with	O
+diabetes	B-NP
+mellitus	I-NP
+or	O
+preexisting	O
+renal	B-NP
+disease	I-NP
+","	O
+will	O
+help	O
+prevent	O
+this	O
+potentially	O
+serious	O
+complication	O
+.	O
+	
+Etomidate	O
+:	O
+a	O
+foreshortened	O
+clinical	O
+trial	O
+.	O
+	
+A	O
+clinical	O
+evaluation	O
+of	O
+etomidate	O
+for	O
+outpatient	O
+cystoscopy	O
+was	O
+embarked	O
+upon	O
+.	O
+	
+Unpremedicated	O
+patients	O
+were	O
+given	O
+fentanyl	O
+1	O
+microgram	O
+/	O
+kg	O
+followed	O
+by	O
+etomidate	O
+0	O
+.	O
+3	O
+mg	O
+/	O
+kg	O
+.	O
+	
+Anaesthesia	O
+was	O
+maintained	O
+with	O
+intermittent	O
+etomidate	O
+in	O
+2	O
+-	O
+4	O
+mg	O
+doses	O
+.	O
+	
+Patients	O
+were	O
+interviewed	O
+personally	O
+later	O
+the	O
+same	O
+day	O
+","	O
+and	O
+by	O
+questionnaire	O
+three	O
+to	O
+four	O
+weeks	O
+later	O
+.	O
+	
+The	O
+trial	O
+was	O
+discontinued	O
+after	O
+20	O
+cases	O
+because	O
+of	O
+an	O
+unacceptable	O
+incidence	O
+of	O
+side	O
+effects	O
+.	O
+	
+Venous	O
+pain	B-NP
+occurred	O
+in	O
+68	O
+%	O
+of	O
+patients	O
+and	O
+50	O
+%	O
+had	O
+redness	O
+","	O
+pain	B-NP
+or	O
+swelling	B-NP
+related	O
+to	O
+the	O
+injection	O
+site	O
+","	O
+in	O
+some	O
+cases	O
+lasting	O
+up	O
+to	O
+three	O
+weeks	O
+after	O
+anaesthesia	O
+.	O
+	
+Skeletal	O
+movements	O
+occurred	O
+in	O
+50	O
+%	O
+of	O
+patients	O
+;	O
+30	O
+%	O
+experienced	O
+respiratory	B-NP
+upset	I-NP
+","	O
+one	O
+sufficiently	O
+severe	O
+to	O
+necessitate	O
+abandoning	O
+the	O
+technique	O
+.	O
+	
+Nausea	B-NP
+and	O
+vomiting	B-NP
+occurred	O
+in	O
+40	O
+%	O
+and	O
+25	O
+%	O
+had	O
+disturbing	O
+emergence	O
+psychoses	B-NP
+.	O
+	
+Levodopa	O
+-	O
+induced	O
+dyskinesias	B-NP
+are	O
+improved	O
+by	O
+fluoxetine	O
+.	O
+	
+We	O
+evaluated	O
+the	O
+severity	O
+of	O
+motor	B-NP
+disability	I-NP
+and	O
+dyskinesias	B-NP
+in	O
+seven	O
+levodopa	O
+-	O
+responsive	O
+patients	O
+with	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+after	O
+an	O
+acute	O
+challenge	O
+with	O
+the	O
+mixed	O
+dopamine	O
+agonist	O
+","	O
+apomorphine	O
+","	O
+before	O
+and	O
+after	O
+the	O
+administration	O
+of	O
+fluoxetine	O
+(	O
+20	O
+mg	O
+twice	O
+per	O
+day	O
+)	O
+for	O
+11	O
++	O
+/	O
+-	O
+1	O
+days	O
+.	O
+	
+After	O
+fluoxetine	O
+treatment	O
+","	O
+there	O
+was	O
+a	O
+significant	O
+47	O
+%	O
+improvement	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+of	O
+apomorphine	O
+-	O
+induced	O
+dyskinesias	B-NP
+without	O
+modification	O
+of	O
+parkinsonian	B-NP
+motor	B-NP
+disability	I-NP
+.	O
+	
+The	O
+dyskinesias	B-NP
+were	O
+reduced	O
+predominantly	O
+in	O
+the	O
+lower	O
+limbs	O
+during	O
+the	O
+onset	O
+and	O
+disappearance	O
+of	O
+dystonic	B-NP
+dyskinesias	I-NP
+(	O
+onset	O
+-	O
+and	O
+end	O
+-	O
+of	O
+-	O
+dose	O
+dyskinesias	B-NP
+)	O
+and	O
+in	O
+the	O
+upper	O
+limbs	O
+during	O
+choreic	B-NP
+mid	I-NP
+-	I-NP
+dose	I-NP
+dyskinesias	I-NP
+.	O
+	
+The	O
+results	O
+suggest	O
+that	O
+increased	O
+brain	O
+serotoninergic	O
+transmission	O
+with	O
+fluoxetine	O
+may	O
+reduce	O
+levodopa	O
+-	O
+or	O
+dopamine	O
+agonist	O
+-	O
+induced	O
+dyskinesias	B-NP
+without	O
+aggravating	O
+parkinsonian	B-NP
+motor	B-NP
+disability	I-NP
+.	O
+	
+A	O
+large	O
+population	O
+-	O
+based	O
+follow	O
+-	O
+up	O
+study	O
+of	O
+trimethoprim	O
+-	O
+sulfamethoxazole	O
+","	O
+trimethoprim	O
+","	O
+and	O
+cephalexin	O
+for	O
+uncommon	O
+serious	O
+drug	B-NP
+toxicity	I-NP
+.	O
+	
+We	O
+conducted	O
+a	O
+population	O
+-	O
+based	O
+45	O
+-	O
+day	O
+follow	O
+-	O
+up	O
+study	O
+of	O
+232	O
+","	O
+390	O
+people	O
+who	O
+were	O
+prescribed	O
+trimethoprim	O
+-	O
+sulfamethoxazole	O
+(	O
+TMP	O
+-	O
+SMZ	O
+)	O
+","	O
+266	O
+","	O
+951	O
+prescribed	O
+trimethoprim	O
+alone	O
+","	O
+and	O
+196	O
+","	O
+397	O
+prescribed	O
+cephalexin	O
+","	O
+to	O
+estimate	O
+the	O
+risk	O
+of	O
+serious	O
+liver	B-NP
+","	I-NP
+blood	I-NP
+","	I-NP
+skin	I-NP
+","	I-NP
+and	I-NP
+renal	I-NP
+disorders	I-NP
+resulting	O
+in	O
+referral	O
+or	O
+hospitalization	O
+associated	O
+with	O
+these	O
+drugs	O
+.	O
+	
+The	O
+results	O
+were	O
+based	O
+on	O
+information	O
+recorded	O
+on	O
+office	O
+computers	O
+by	O
+selected	O
+general	O
+practitioners	O
+in	O
+the	O
+United	O
+Kingdom	O
+","	O
+together	O
+with	O
+a	O
+review	O
+of	O
+clinical	O
+records	O
+.	O
+	
+The	O
+risk	O
+of	O
+clinically	O
+important	O
+idiopathic	O
+liver	B-NP
+disease	I-NP
+was	O
+similar	O
+for	O
+persons	O
+prescribed	O
+TMP	O
+-	O
+SMZ	O
+(	O
+5	O
+.	O
+2	O
+/	O
+100	O
+","	O
+0	O
+)	O
+and	O
+those	O
+prescribed	O
+trimethoprim	O
+alone	O
+(	O
+3	O
+.	O
+8	O
+/	O
+100	O
+","	O
+0	O
+)	O
+.	O
+	
+The	O
+risk	O
+for	O
+those	O
+prescribed	O
+cephalexin	O
+was	O
+somewhat	O
+lower	O
+(	O
+2	O
+.	O
+0	O
+/	O
+100	O
+","	O
+0	O
+)	O
+.	O
+	
+Only	O
+five	O
+patients	O
+experienced	O
+blood	O
+disorders	O
+","	O
+one	O
+of	O
+whom	O
+was	O
+exposed	O
+to	O
+TMP	O
+-	O
+SMZ	O
+;	O
+of	O
+seven	O
+with	O
+erythema	B-NP
+multiforme	I-NP
+and	O
+Stevens	B-NP
+-	I-NP
+Johnson	I-NP
+syndrome	I-NP
+","	O
+four	O
+were	O
+exposed	O
+to	O
+TMP	O
+-	O
+SMZ	O
+.	O
+	
+The	O
+one	O
+case	O
+of	O
+toxic	B-NP
+epidermal	I-NP
+necrolysis	I-NP
+occurred	O
+in	O
+a	O
+patient	O
+who	O
+took	O
+cephalexin	O
+.	O
+	
+Finally	O
+","	O
+only	O
+five	O
+cases	O
+of	O
+acute	O
+parenchymal	O
+renal	B-NP
+disease	I-NP
+occurred	O
+","	O
+none	O
+likely	O
+to	O
+be	O
+caused	O
+by	O
+a	O
+study	O
+drug	O
+.	O
+	
+We	O
+conclude	O
+that	O
+the	O
+risk	O
+of	O
+the	O
+serious	O
+diseases	O
+studied	O
+is	O
+small	O
+for	O
+the	O
+three	O
+agents	O
+","	O
+and	O
+compares	O
+reasonably	O
+with	O
+the	O
+risk	O
+for	O
+many	O
+other	O
+antibiotics	O
+.	O
+	
+Clinical	O
+safety	O
+of	O
+lidocaine	O
+in	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+myocardial	B-NP
+infarction	I-NP
+.	O
+	
+STUDY	O
+OBJECTIVE	O
+:	O
+To	O
+evaluate	O
+the	O
+safety	O
+of	O
+lidocaine	O
+in	O
+the	O
+setting	O
+of	O
+cocaine	O
+-	O
+induced	O
+myocardial	B-NP
+infarction	I-NP
+(	O
+MI	B-NP
+)	O
+.	O
+	
+DESIGN	O
+:	O
+A	O
+retrospective	O
+","	O
+multicenter	O
+study	O
+.	O
+	
+SETTING	O
+:	O
+Twenty	O
+-	O
+nine	O
+university	O
+","	O
+university	O
+-	O
+affiliated	O
+","	O
+or	O
+community	O
+hospitals	O
+during	O
+a	O
+6	O
+-	O
+year	O
+period	O
+(	O
+total	O
+of	O
+117	O
+cumulative	O
+hospital	O
+-	O
+years	O
+)	O
+.	O
+	
+PARTICIPANTS	O
+:	O
+Patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+MI	B-NP
+who	O
+received	O
+lidocaine	O
+in	O
+the	O
+emergency	O
+department	O
+.	O
+	
+RESULTS	O
+:	O
+Of	O
+29	O
+patients	O
+who	O
+received	O
+lidocaine	O
+in	O
+the	O
+setting	O
+of	O
+cocaine	O
+-	O
+associated	O
+MI	B-NP
+","	O
+no	O
+patient	O
+died	O
+;	O
+exhibited	O
+bradydysrhythmias	B-NP
+","	O
+ventricular	B-NP
+tachycardia	I-NP
+","	O
+or	O
+ventricular	B-NP
+fibrillation	I-NP
+;	O
+or	O
+experienced	O
+seizures	B-NP
+after	O
+administration	O
+of	O
+lidocaine	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+","	O
+0	O
+%	O
+to	O
+11	O
+%	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+Despite	O
+theoretical	O
+concerns	O
+that	O
+lidocaine	O
+may	O
+enhance	O
+cocaine	O
+toxicity	B-NP
+","	O
+the	O
+use	O
+of	O
+lidocaine	O
+in	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+MI	B-NP
+was	O
+not	O
+associated	O
+with	O
+significant	O
+cardiovascular	B-NP
+or	I-NP
+central	I-NP
+nervous	I-NP
+system	I-NP
+toxicity	I-NP
+.	O
+	
+Experimental	O
+progressive	O
+muscular	B-NP
+dystrophy	I-NP
+and	O
+its	O
+treatment	O
+with	O
+high	O
+doses	O
+anabolizing	O
+agents	O
+.	O
+	
+We	O
+are	O
+still	O
+a	O
+long	O
+way	O
+from	O
+discovering	O
+an	O
+unequivocal	O
+pathogenetic	O
+interpretation	O
+of	O
+progressive	O
+muscular	B-NP
+dystrophy	I-NP
+in	O
+man	O
+.	O
+	
+Noteworthy	O
+efforts	O
+have	O
+been	O
+made	O
+in	O
+the	O
+experimental	O
+field	O
+;	O
+a	O
+recessive	O
+autosomic	O
+form	O
+found	O
+in	O
+the	O
+mouse	O
+seems	O
+to	O
+bear	O
+the	O
+closest	O
+resemblance	O
+to	O
+the	O
+human	O
+form	O
+from	O
+the	O
+genetic	O
+point	O
+of	O
+view	O
+.	O
+	
+Myopathy	B-NP
+due	O
+to	O
+lack	O
+of	O
+vitamin	O
+E	O
+and	O
+myopathy	B-NP
+induced	O
+by	O
+certain	O
+viruses	O
+have	O
+much	O
+in	O
+common	O
+anatomically	O
+and	O
+pathologically	O
+with	O
+the	O
+human	O
+form	O
+.	O
+	
+The	O
+authors	O
+induced	O
+myodystrophy	B-NP
+in	O
+the	O
+rat	O
+by	O
+giving	O
+it	O
+a	O
+diet	O
+lacking	O
+in	O
+vitamin	O
+E	O
+.	O
+	
+The	O
+pharmacological	O
+characteristics	O
+of	O
+vitamin	O
+E	O
+and	O
+the	O
+degenerative	O
+changes	O
+brought	O
+about	O
+by	O
+its	O
+deficiency	O
+","	O
+especially	O
+in	O
+the	O
+muscles	O
+","	O
+are	O
+illustrated	O
+.	O
+	
+It	O
+is	O
+thus	O
+confirmed	O
+that	O
+the	O
+histological	O
+characteristics	O
+of	O
+myopathic	B-NP
+rat	O
+muscle	O
+induced	O
+experimentally	O
+are	O
+extraordinarily	O
+similar	O
+to	O
+those	O
+of	O
+human	O
+myopathy	B-NP
+as	O
+confirmed	O
+during	O
+biopsies	O
+performed	O
+at	O
+the	O
+Orthopaedic	O
+Traumatological	O
+Centre	O
+","	O
+Florence	O
+.	O
+	
+The	O
+encouraging	O
+results	O
+obtained	O
+in	O
+various	O
+authoratative	O
+departments	O
+in	O
+myopathic	B-NP
+patients	O
+by	O
+using	O
+anabolizing	O
+steroids	O
+have	O
+encouraged	O
+the	O
+authors	O
+to	O
+investigate	O
+the	O
+beneficial	O
+effects	O
+of	O
+one	O
+anabolizing	O
+agent	O
+(	O
+Dianabol	O
+","	O
+CIBA	O
+)	O
+at	O
+high	O
+doses	O
+in	O
+rats	O
+rendered	O
+myopathic	B-NP
+by	O
+a	O
+diet	O
+deficient	O
+in	O
+vitamin	O
+E	O
+.	O
+	
+In	O
+this	O
+way	O
+they	O
+obtained	O
+appreciable	O
+changes	O
+in	O
+body	O
+weight	O
+(	O
+increased	O
+from	O
+50	O
+to	O
+70	O
+g	O
+after	O
+forty	O
+days	O
+at	O
+a	O
+dose	O
+of	O
+5	O
+mg	O
+per	O
+day	O
+of	O
+anabolizing	O
+agent	O
+)	O
+","	O
+but	O
+most	O
+of	O
+all	O
+they	O
+found	O
+histological	O
+changes	O
+due	O
+to	O
+"	O
+regenerative	O
+"	O
+changes	O
+in	O
+the	O
+muscle	O
+tissue	O
+","	O
+which	O
+however	O
+maintained	O
+its	O
+myopathic	B-NP
+characteristics	O
+in	O
+the	O
+control	O
+animals	O
+that	O
+were	O
+not	O
+treated	O
+with	O
+the	O
+anabolizing	O
+agent	O
+.	O
+	
+The	O
+authors	O
+conclude	O
+by	O
+affirming	O
+the	O
+undoubted	O
+efficacy	O
+of	O
+the	O
+anabolizing	O
+steroids	O
+in	O
+experimental	O
+myopathic	B-NP
+disease	I-NP
+","	O
+but	O
+they	O
+have	O
+reservations	O
+as	O
+to	O
+the	O
+transfer	O
+of	O
+the	O
+results	O
+into	O
+the	O
+human	O
+field	O
+","	O
+where	O
+high	O
+dosage	O
+cannot	O
+be	O
+carried	O
+out	O
+continuously	O
+because	O
+of	O
+the	O
+effects	O
+of	O
+the	O
+drug	O
+on	O
+virility	O
+;	O
+because	O
+the	O
+tissue	O
+injury	O
+too	O
+often	O
+occurs	O
+at	O
+an	O
+irreversible	O
+stage	O
+vis	O
+-	O
+a	O
+-	O
+vis	O
+the	O
+"	O
+regeneration	O
+"	O
+of	O
+the	O
+muscle	O
+tissue	O
+;	O
+and	O
+finally	O
+because	O
+the	O
+dystrophic	O
+injurious	O
+agent	O
+is	O
+certainly	O
+not	O
+the	O
+lack	O
+of	O
+vitamin	O
+E	O
+but	O
+something	O
+as	O
+yet	O
+unknown	O
+.	O
+	
+Paclitaxel	O
+3	O
+-	O
+hour	O
+infusion	O
+given	O
+alone	O
+and	O
+combined	O
+with	O
+carboplatin	O
+:	O
+preliminary	O
+results	O
+of	O
+dose	O
+-	O
+escalation	O
+trials	O
+.	O
+	
+Paclitaxel	O
+(	O
+Taxol	O
+;	O
+Bristol	O
+-	O
+Myers	O
+Squibb	O
+Company	O
+","	O
+Princeton	O
+","	O
+NJ	O
+)	O
+by	O
+3	O
+-	O
+hour	O
+infusion	O
+was	O
+combined	O
+with	O
+carboplatin	O
+in	O
+a	O
+phase	O
+I	O
+/	O
+II	O
+study	O
+directed	O
+to	O
+patients	O
+with	O
+non	B-NP
+-	I-NP
+small	I-NP
+cell	I-NP
+lung	I-NP
+cancer	I-NP
+.	O
+	
+Carboplatin	O
+was	O
+given	O
+at	O
+a	O
+fixed	O
+target	O
+area	O
+under	O
+the	O
+concentration	O
+-	O
+time	O
+curve	O
+of	O
+6	O
+.	O
+0	O
+by	O
+the	O
+Calvert	O
+formula	O
+","	O
+whereas	O
+paclitaxel	O
+was	O
+escalated	O
+in	O
+patient	O
+cohorts	O
+from	O
+150	O
+mg	O
+/	O
+m2	O
+(	O
+dose	O
+level	O
+I	O
+)	O
+to	O
+175	O
+","	O
+200	O
+","	O
+225	O
+","	O
+and	O
+250	O
+mg	O
+/	O
+m2	O
+.	O
+	
+The	O
+225	O
+mg	O
+/	O
+m2	O
+level	O
+was	O
+expanded	O
+for	O
+the	O
+phase	O
+II	O
+study	O
+since	O
+the	O
+highest	O
+level	O
+achieved	O
+(	O
+250	O
+mg	O
+/	O
+m2	O
+)	O
+required	O
+modification	O
+because	O
+of	O
+nonhematologic	O
+toxicities	B-NP
+(	O
+arthralgia	B-NP
+and	O
+sensory	B-NP
+neuropathy	I-NP
+)	O
+.	O
+	
+Therapeutic	O
+effects	O
+were	O
+noted	O
+at	O
+all	O
+dose	O
+levels	O
+","	O
+with	O
+objective	O
+responses	O
+in	O
+17	O
+(	O
+two	O
+complete	O
+and	O
+15	O
+partial	O
+regressions	O
+)	O
+of	O
+41	O
+previously	O
+untreated	O
+patients	O
+.	O
+	
+Toxicities	B-NP
+were	O
+compared	O
+with	O
+a	O
+cohort	O
+of	O
+patients	O
+in	O
+a	O
+phase	O
+I	O
+trial	O
+of	O
+paclitaxel	O
+alone	O
+at	O
+identical	O
+dose	O
+levels	O
+.	O
+	
+Carboplatin	O
+did	O
+not	O
+appear	O
+to	O
+add	O
+to	O
+the	O
+hematologic	B-NP
+toxicities	I-NP
+observed	O
+","	O
+and	O
+the	O
+paclitaxel	O
+/	O
+carboplatin	O
+combination	O
+could	O
+be	O
+dosed	O
+every	O
+3	O
+weeks	O
+.	O
+	
+The	O
+dose	O
+-	O
+dependent	O
+effect	O
+of	O
+misoprostol	O
+on	O
+indomethacin	O
+-	O
+induced	O
+renal	B-NP
+dysfunction	I-NP
+in	O
+well	O
+compensated	O
+cirrhosis	B-NP
+.	O
+	
+Misoprostol	O
+(	O
+200	O
+micrograms	O
+)	O
+has	O
+been	O
+shown	O
+to	O
+acutely	O
+counteract	O
+the	O
+indomethacin	O
+-	O
+induced	O
+renal	B-NP
+dysfunction	I-NP
+in	O
+well	O
+compensated	O
+cirrhotic	B-NP
+patients	O
+.	O
+	
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+if	O
+the	O
+prophylactic	O
+value	O
+of	O
+misoprostol	O
+was	O
+dose	O
+-	O
+dependent	O
+.	O
+	
+Parameters	O
+of	O
+renal	O
+hemodynamics	O
+and	O
+tubular	O
+sodium	O
+and	O
+water	O
+handling	O
+were	O
+assessed	O
+by	O
+clearance	O
+techniques	O
+in	O
+26	O
+well	O
+compensated	O
+cirrhotic	B-NP
+patients	O
+before	O
+and	O
+after	O
+an	O
+oral	O
+combination	O
+of	O
+50	O
+mg	O
+of	O
+indomethacin	O
+and	O
+various	O
+doses	O
+of	O
+misoprostol	O
+.	O
+	
+The	O
+200	O
+-	O
+micrograms	O
+dose	O
+was	O
+able	O
+to	O
+totally	O
+abolish	O
+the	O
+deleterious	O
+renal	O
+effects	O
+of	O
+indomethacin	O
+","	O
+whereas	O
+the	O
+800	O
+-	O
+micrograms	O
+dose	O
+resulted	O
+in	O
+significant	O
+worsening	O
+of	O
+renal	O
+hemodynamics	O
+and	O
+sodium	O
+retention	O
+.	O
+	
+These	O
+changes	O
+were	O
+maximal	O
+in	O
+the	O
+hour	O
+immediately	O
+after	O
+medications	O
+and	O
+slowly	O
+returned	O
+toward	O
+base	O
+-	O
+line	O
+levels	O
+thereafter	O
+.	O
+	
+These	O
+results	O
+suggest	O
+that	O
+the	O
+renal	O
+protective	O
+effects	O
+of	O
+misoprostol	O
+is	O
+dose	O
+-	O
+dependent	O
+.	O
+	
+However	O
+","	O
+until	O
+this	O
+apparent	O
+ability	O
+of	O
+200	O
+micrograms	O
+of	O
+misoprostol	O
+to	O
+prevent	O
+the	O
+adverse	O
+effects	O
+of	O
+indomethacin	O
+on	O
+renal	O
+function	O
+is	O
+confirmed	O
+with	O
+chronic	O
+frequent	O
+dosing	O
+","	O
+it	O
+would	O
+be	O
+prudent	O
+to	O
+avoid	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+therapy	O
+in	O
+patients	O
+with	O
+cirrhosis	B-NP
+.	O
+	
+Increased	O
+frequency	O
+and	O
+severity	O
+of	O
+angio	B-NP
+-	I-NP
+oedema	I-NP
+related	O
+to	O
+long	O
+-	O
+term	O
+therapy	O
+with	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitor	O
+in	O
+two	O
+patients	O
+.	O
+	
+Adverse	O
+reactions	O
+to	O
+drugs	O
+are	O
+well	O
+recognized	O
+as	O
+a	O
+cause	O
+of	O
+acute	O
+or	O
+chronic	O
+urticaria	B-NP
+","	O
+and	O
+angio	B-NP
+-	I-NP
+oedema	I-NP
+.	O
+	
+Angiotensin	O
+-	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+inhibitors	O
+","	O
+used	O
+to	O
+treat	O
+hypertension	B-NP
+and	O
+congestive	B-NP
+heart	I-NP
+failure	I-NP
+","	O
+were	O
+introduced	O
+in	O
+Europe	O
+in	O
+the	O
+middle	O
+of	O
+the	O
+eighties	O
+","	O
+and	O
+the	O
+use	O
+of	O
+these	O
+drugs	O
+has	O
+increased	O
+progressively	O
+.	O
+	
+Soon	O
+after	O
+the	O
+introduction	O
+of	O
+ACE	O
+inhibitors	O
+","	O
+acute	O
+bouts	O
+of	O
+angio	B-NP
+-	I-NP
+oedema	I-NP
+were	O
+reported	O
+in	O
+association	O
+with	O
+the	O
+use	O
+of	O
+these	O
+drugs	O
+.	O
+	
+We	O
+wish	O
+to	O
+draw	O
+attention	O
+to	O
+the	O
+possibility	O
+of	O
+adverse	O
+reactions	O
+to	O
+ACE	O
+inhibitors	O
+after	O
+long	O
+-	O
+term	O
+use	O
+and	O
+in	O
+patients	O
+with	O
+pre	O
+-	O
+existing	O
+angio	B-NP
+-	I-NP
+oedema	I-NP
+.	O
+	
+Myoclonus	B-NP
+associated	O
+with	O
+lorazepam	O
+therapy	O
+in	O
+very	O
+-	O
+low	O
+-	O
+birth	O
+-	O
+weight	O
+infants	O
+.	O
+	
+Lorazepam	O
+is	O
+being	O
+used	O
+with	O
+increasing	O
+frequency	O
+as	O
+a	O
+sedative	O
+in	O
+the	O
+newborn	O
+and	O
+the	O
+young	O
+infant	O
+.	O
+	
+Concern	O
+has	O
+been	O
+raised	O
+with	O
+regard	O
+to	O
+the	O
+safety	O
+of	O
+lorazepam	O
+in	O
+this	O
+age	O
+group	O
+","	O
+especially	O
+in	O
+very	O
+-	O
+low	O
+-	O
+birth	O
+-	O
+weight	O
+(	O
+VLBW	O
+;	O
+<	O
+1	O
+","	O
+500	O
+g	O
+)	O
+infants	O
+.	O
+	
+Three	O
+young	O
+infants	O
+","	O
+all	O
+of	O
+birth	O
+weight	O
+<	O
+1	O
+","	O
+500	O
+g	O
+","	O
+experienced	O
+myoclonus	B-NP
+following	O
+the	O
+intravenous	O
+administration	O
+of	O
+lorazepam	O
+.	O
+	
+The	O
+potential	O
+neurotoxic	B-NP
+effects	O
+of	O
+the	O
+drug	O
+(	O
+and	O
+its	O
+vehicle	O
+)	O
+in	O
+this	O
+population	O
+are	O
+discussed	O
+.	O
+	
+Injectable	O
+lorazepam	O
+should	O
+be	O
+used	O
+with	O
+caution	O
+in	O
+VLBW	O
+infants	O
+.	O
+	
+Transvenous	O
+right	O
+ventricular	O
+pacing	O
+during	O
+cardiopulmonary	O
+resuscitation	O
+of	O
+pediatric	O
+patients	O
+with	O
+acute	O
+cardiomyopathy	B-NP
+.	O
+	
+We	O
+describe	O
+the	O
+cardiopulmonary	O
+resuscitation	O
+efforts	O
+on	O
+five	O
+patients	O
+who	O
+presented	O
+in	O
+acute	O
+circulatory	B-NP
+failure	I-NP
+from	O
+myocardial	B-NP
+dysfunction	I-NP
+.	O
+	
+Three	O
+patients	O
+had	O
+acute	O
+viral	O
+myocarditis	B-NP
+","	O
+one	O
+had	O
+a	O
+carbamazepine	O
+-	O
+induced	O
+acute	O
+eosinophilic	B-NP
+myocarditis	I-NP
+","	O
+and	O
+one	O
+had	O
+cardiac	O
+hemosiderosis	O
+resulting	O
+in	O
+acute	O
+cardiogenic	B-NP
+shock	I-NP
+.	O
+	
+All	O
+patients	O
+were	O
+continuously	O
+monitored	O
+with	O
+central	O
+venous	O
+and	O
+arterial	O
+catheters	O
+in	O
+addition	O
+to	O
+routine	O
+noninvasive	O
+monitoring	O
+.	O
+	
+An	O
+introducer	O
+sheath	O
+","	O
+a	O
+pacemaker	O
+","	O
+and	O
+sterile	O
+pacing	O
+wires	O
+were	O
+made	O
+readily	O
+available	O
+for	O
+the	O
+patients	O
+","	O
+should	O
+the	O
+need	O
+arise	O
+to	O
+terminate	O
+resistant	O
+cardiac	O
+dysrhythmias	B-NP
+.	O
+	
+All	O
+patients	O
+developed	O
+cardiocirculatory	O
+arrest	O
+associated	O
+with	O
+extreme	O
+hypotension	B-NP
+and	O
+dysrhythmias	B-NP
+within	O
+the	O
+first	O
+48	O
+hours	O
+of	O
+their	O
+admission	O
+to	O
+the	O
+pediatric	O
+intensive	O
+care	O
+unit	O
+(	O
+PICU	O
+)	O
+.	O
+	
+Right	O
+ventricular	O
+pacemaker	O
+wires	O
+were	O
+inserted	O
+in	O
+all	O
+of	O
+them	O
+during	O
+cardiopulmonary	O
+resuscitation	O
+(	O
+CPR	O
+)	O
+.	O
+	
+In	O
+four	O
+patients	O
+","	O
+cardiac	O
+pacing	O
+was	O
+used	O
+","	O
+resulting	O
+in	O
+a	O
+temporary	O
+captured	O
+rhythm	O
+and	O
+restoration	O
+of	O
+their	O
+cardiac	O
+output	O
+.	O
+	
+These	O
+patients	O
+had	O
+a	O
+second	O
+event	O
+of	O
+cardiac	B-NP
+arrest	I-NP
+","	O
+resulting	O
+in	O
+death	O
+","	O
+within	O
+10	O
+to	O
+60	O
+minutes	O
+.	O
+	
+In	O
+one	O
+patient	O
+","	O
+cardiac	O
+pacing	O
+was	O
+not	O
+used	O
+","	O
+because	O
+he	O
+converted	O
+to	O
+normal	O
+sinus	O
+rhythm	O
+by	O
+electrical	O
+defibrillation	O
+within	O
+three	O
+minutes	O
+of	O
+initiating	O
+CPR	O
+.	O
+	
+We	O
+conclude	O
+that	O
+cardiac	O
+pacing	O
+during	O
+resuscitative	O
+efforts	O
+in	O
+pediatric	O
+patients	O
+suffering	O
+from	O
+acute	O
+myocardial	B-NP
+dysfunction	I-NP
+may	O
+not	O
+have	O
+long	O
+-	O
+term	O
+value	O
+in	O
+and	O
+of	O
+itself	O
+;	O
+however	O
+","	O
+if	O
+temporary	O
+hemodynamic	O
+stability	O
+is	O
+achieved	O
+by	O
+this	O
+procedure	O
+","	O
+it	O
+may	O
+provide	O
+additional	O
+time	O
+needed	O
+to	O
+institute	O
+other	O
+therapeutic	O
+modalities	O
+.	O
+	
+Efficacy	O
+and	O
+safety	O
+of	O
+granisetron	O
+","	O
+a	O
+selective	O
+5	O
+-	O
+hydroxytryptamine	O
+-	O
+3	O
+receptor	O
+antagonist	O
+","	O
+in	O
+the	O
+prevention	O
+of	O
+nausea	B-NP
+and	O
+vomiting	B-NP
+induced	O
+by	O
+high	O
+-	O
+dose	O
+cisplatin	O
+.	O
+	
+PURPOSE	O
+:	O
+To	O
+assess	O
+the	O
+antiemetic	O
+effects	O
+and	O
+safety	O
+profile	O
+of	O
+four	O
+different	O
+doses	O
+of	O
+granisetron	O
+(	O
+Kytril	O
+;	O
+SmithKline	O
+Beecham	O
+Pharmaceuticals	O
+","	O
+Philadelphia	O
+","	O
+PA	O
+)	O
+when	O
+administered	O
+as	O
+a	O
+single	O
+intravenous	O
+(	O
+IV	O
+)	O
+dose	O
+for	O
+prophylaxis	O
+of	O
+cisplatin	O
+-	O
+induced	O
+nausea	B-NP
+and	O
+vomiting	B-NP
+.	O
+	
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+One	O
+hundred	O
+eighty	O
+-	O
+four	O
+chemotherapy	O
+-	O
+naive	O
+patients	O
+receiving	O
+high	O
+-	O
+dose	O
+cisplatin	O
+(	O
+81	O
+to	O
+120	O
+mg	O
+/	O
+m2	O
+)	O
+were	O
+randomized	O
+to	O
+receive	O
+one	O
+of	O
+four	O
+granisetron	O
+doses	O
+(	O
+5	O
+","	O
+10	O
+","	O
+20	O
+","	O
+or	O
+40	O
+micrograms	O
+/	O
+kg	O
+)	O
+administered	O
+before	O
+chemotherapy	O
+.	O
+	
+Patients	O
+were	O
+observed	O
+on	O
+an	O
+inpatient	O
+basis	O
+for	O
+18	O
+to	O
+24	O
+hours	O
+","	O
+and	O
+vital	O
+signs	O
+","	O
+nausea	B-NP
+","	O
+vomiting	B-NP
+","	O
+retching	O
+","	O
+and	O
+appetite	O
+were	O
+assessed	O
+.	O
+	
+Safety	O
+analyses	O
+included	O
+incidence	O
+of	O
+adverse	O
+experiences	O
+and	O
+laboratory	O
+parameter	O
+changes	O
+.	O
+	
+RESULTS	O
+:	O
+After	O
+granisetron	O
+doses	O
+of	O
+5	O
+","	O
+10	O
+","	O
+20	O
+","	O
+and	O
+40	O
+micrograms	O
+/	O
+kg	O
+","	O
+a	O
+major	O
+response	O
+(	O
+<	O
+or	O
+=	O
+two	O
+vomiting	B-NP
+or	O
+retching	O
+episodes	O
+","	O
+and	O
+no	O
+antiemetic	O
+rescue	O
+)	O
+was	O
+recorded	O
+in	O
+23	O
+%	O
+","	O
+57	O
+%	O
+","	O
+58	O
+%	O
+","	O
+and	O
+60	O
+%	O
+of	O
+patients	O
+","	O
+respectively	O
+","	O
+and	O
+a	O
+complete	O
+response	O
+(	O
+no	O
+vomiting	B-NP
+or	O
+retching	O
+","	O
+and	O
+no	O
+antiemetic	O
+rescue	O
+)	O
+in	O
+18	O
+%	O
+","	O
+41	O
+%	O
+","	O
+40	O
+%	O
+","	O
+and	O
+47	O
+%	O
+of	O
+patients	O
+","	O
+respectively	O
+.	O
+	
+There	O
+was	O
+a	O
+statistically	O
+longer	O
+time	O
+to	O
+first	O
+episode	O
+of	O
+nausea	B-NP
+(	O
+P	O
+=	O
+.	O
+15	O
+)	O
+and	O
+vomiting	B-NP
+(	O
+P	O
+=	O
+.	O
+1	O
+)	O
+","	O
+and	O
+fewer	O
+patients	O
+were	O
+administered	O
+additional	O
+antiemetic	O
+medication	O
+in	O
+the	O
+10	O
+-	O
+micrograms	O
+/	O
+kg	O
+dosing	O
+groups	O
+than	O
+in	O
+the	O
+5	O
+-	O
+micrograms	O
+/	O
+kg	O
+dosing	O
+group	O
+.	O
+	
+As	O
+granisetron	O
+dose	O
+increased	O
+","	O
+appetite	O
+return	O
+increased	O
+(	O
+P	O
+=	O
+.	O
+40	O
+)	O
+.	O
+	
+Headache	B-NP
+was	O
+the	O
+most	O
+frequently	O
+reported	O
+adverse	O
+event	O
+(	O
+20	O
+%	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+A	O
+single	O
+10	O
+-	O
+","	O
+20	O
+-	O
+","	O
+or	O
+40	O
+-	O
+micrograms	O
+/	O
+kg	O
+dose	O
+of	O
+granisetron	O
+was	O
+effective	O
+in	O
+controlling	O
+vomiting	B-NP
+in	O
+57	O
+%	O
+to	O
+60	O
+%	O
+of	O
+patients	O
+who	O
+received	O
+cisplatin	O
+at	O
+doses	O
+greater	O
+than	O
+81	O
+mg	O
+/	O
+m2	O
+and	O
+totally	O
+prevented	O
+vomiting	B-NP
+in	O
+40	O
+%	O
+to	O
+47	O
+%	O
+of	O
+patients	O
+.	O
+	
+There	O
+were	O
+no	O
+statistically	O
+significant	O
+differences	O
+in	O
+efficacy	O
+between	O
+the	O
+10	O
+-	O
+micrograms	O
+/	O
+kg	O
+dose	O
+and	O
+the	O
+20	O
+-	O
+and	O
+40	O
+-	O
+micrograms	O
+/	O
+kg	O
+doses	O
+.	O
+	
+Granisetron	O
+was	O
+well	O
+tolerated	O
+at	O
+all	O
+doses	O
+.	O
+	
+Adverse	O
+interaction	O
+between	O
+clonidine	O
+and	O
+verapamil	O
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+report	O
+two	O
+cases	O
+of	O
+a	O
+possible	O
+adverse	O
+interaction	O
+between	O
+clonidine	O
+and	O
+verapamil	O
+resulting	O
+in	O
+atrioventricular	B-NP
+(	I-NP
+AV	I-NP
+)	I-NP
+block	I-NP
+in	O
+both	O
+patients	O
+and	O
+severe	O
+hypotension	B-NP
+in	O
+one	O
+patient	O
+.	O
+	
+CASE	O
+SUMMARIES	O
+:	O
+A	O
+54	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+hyperaldosteronism	B-NP
+was	O
+treated	O
+with	O
+verapamil	O
+480	O
+mg	O
+/	O
+d	O
+and	O
+spironolactone	O
+100	O
+mg	O
+/	O
+d	O
+.	O
+	
+After	O
+the	O
+addition	O
+of	O
+a	O
+minimal	O
+dose	O
+of	O
+clonidine	O
+(	O
+0	O
+.	O
+15	O
+mg	O
+bid	O
+)	O
+","	O
+she	O
+developed	O
+complete	O
+AV	B-NP
+block	I-NP
+and	O
+severe	O
+hypotension	B-NP
+","	O
+which	O
+resolved	O
+upon	O
+cessation	O
+of	O
+all	O
+medications	O
+.	O
+	
+A	O
+65	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+was	O
+treated	O
+with	O
+extended	O
+-	O
+release	O
+verapamil	O
+240	O
+mg	O
+/	O
+d	O
+.	O
+	
+After	O
+the	O
+addition	O
+of	O
+clonidine	O
+0	O
+.	O
+15	O
+mg	O
+bid	O
+she	O
+developed	O
+complete	O
+AV	B-NP
+block	I-NP
+","	O
+which	O
+resolved	O
+after	O
+all	O
+therapy	O
+was	O
+stopped	O
+.	O
+	
+DISCUSSION	O
+:	O
+An	O
+adverse	O
+interaction	O
+between	O
+clonidine	O
+and	O
+verapamil	O
+has	O
+not	O
+been	O
+reported	O
+previously	O
+.	O
+	
+We	O
+describe	O
+two	O
+such	O
+cases	O
+and	O
+discuss	O
+the	O
+various	O
+mechanisms	O
+that	O
+might	O
+cause	O
+such	O
+an	O
+interaction	O
+.	O
+	
+Clinicians	O
+should	O
+be	O
+acquainted	O
+with	O
+this	O
+possibly	O
+fatal	O
+interaction	O
+between	O
+two	O
+commonly	O
+used	O
+antihypertensive	O
+drugs	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Caution	O
+is	O
+recommended	O
+in	O
+combining	O
+clonidine	O
+and	O
+verapamil	O
+therapy	O
+","	O
+even	O
+in	O
+patients	O
+who	O
+do	O
+not	O
+have	O
+sinus	O
+or	O
+AV	O
+node	O
+dysfunction	O
+.	O
+	
+The	O
+two	O
+drugs	O
+may	O
+act	O
+synergistically	O
+on	O
+both	O
+the	O
+AV	O
+node	O
+and	O
+the	O
+peripheral	O
+circulation	O
+.	O
+	
+Pharmacological	O
+studies	O
+on	O
+a	O
+new	O
+dihydrothienopyridine	O
+calcium	O
+antagonist	O
+","	O
+S	O
+-	O
+312	O
+-	O
+d	O
+.	O
+	
+5th	O
+communication	O
+:	O
+anticonvulsant	O
+effects	O
+in	O
+mice	O
+.	O
+	
+S	O
+-	O
+312	O
+","	O
+S	O
+-	O
+312	O
+-	O
+d	O
+","	O
+but	O
+not	O
+S	O
+-	O
+312	O
+-	O
+l	O
+","	O
+L	O
+-	O
+type	O
+calcium	O
+channel	O
+antagonists	O
+","	O
+showed	O
+anticonvulsant	O
+effects	O
+on	O
+the	O
+audiogenic	B-NP
+tonic	I-NP
+convulsions	I-NP
+in	O
+DBA	O
+/	O
+2	O
+mice	O
+;	O
+and	O
+their	O
+ED50	O
+values	O
+were	O
+18	O
+.	O
+4	O
+(	O
+12	O
+.	O
+8	O
+-	O
+27	O
+.	O
+1	O
+)	O
+mg	O
+/	O
+kg	O
+","	O
+p	O
+.	O
+o	O
+.	O
+and	O
+15	O
+.	O
+0	O
+(	O
+10	O
+.	O
+2	O
+-	O
+23	O
+.	O
+7	O
+)	O
+mg	O
+/	O
+kg	O
+","	O
+p	O
+.	O
+o	O
+.	O
+","	O
+respectively	O
+","	O
+while	O
+that	O
+of	O
+flunarizine	O
+was	O
+34	O
+.	O
+0	O
+(	O
+26	O
+.	O
+0	O
+-	O
+44	O
+.	O
+8	O
+)	O
+mg	O
+/	O
+kg	O
+","	O
+p	O
+.	O
+o	O
+.	O
+	
+Although	O
+moderate	O
+anticonvulsant	O
+effects	O
+of	O
+S	O
+-	O
+312	O
+-	O
+d	O
+in	O
+higher	O
+doses	O
+were	O
+observed	O
+against	O
+the	O
+clonic	O
+convulsions	B-NP
+induced	O
+by	O
+pentylenetetrazole	O
+(	O
+85	O
+mg	O
+/	O
+kg	O
+","	O
+s	O
+.	O
+c	O
+.	O
+)	O
+or	O
+bemegride	O
+(	O
+40	O
+mg	O
+/	O
+kg	O
+","	O
+s	O
+.	O
+c	O
+.	O
+)	O
+","	O
+no	O
+effects	O
+were	O
+observed	O
+in	O
+convulsions	B-NP
+induced	O
+by	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+","	O
+picrotoxin	O
+","	O
+or	O
+electroshock	O
+in	O
+Slc	O
+:	O
+ddY	O
+mice	O
+.	O
+	
+S	O
+-	O
+312	O
+-	O
+d	O
+may	O
+be	O
+useful	O
+in	O
+the	O
+therapy	O
+of	O
+certain	O
+types	O
+of	O
+human	O
+epilepsy	B-NP
+.	O
+	
+Transmural	O
+myocardial	B-NP
+infarction	I-NP
+with	O
+sumatriptan	O
+.	O
+	
+For	O
+sumatriptan	O
+","	O
+tightness	O
+in	O
+the	O
+chest	O
+caused	O
+by	O
+an	O
+unknown	O
+mechanism	O
+has	O
+been	O
+reported	O
+in	O
+3	O
+-	O
+5	O
+%	O
+of	O
+users	O
+.	O
+	
+We	O
+describe	O
+a	O
+47	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+an	O
+acute	O
+myocardial	B-NP
+infarction	I-NP
+after	O
+administration	O
+of	O
+sumatriptan	O
+6	O
+mg	O
+subcutaneously	O
+for	O
+cluster	B-NP
+headache	I-NP
+.	O
+	
+The	O
+patient	O
+had	O
+no	O
+history	O
+of	O
+underlying	O
+ischaemic	B-NP
+heart	I-NP
+disease	I-NP
+or	O
+Prinzmetal	B-NP
+'	I-NP
+s	I-NP
+angina	I-NP
+.	O
+	
+She	O
+recovered	O
+without	O
+complications	O
+.	O
+	
+Flumazenil	O
+induces	O
+seizures	B-NP
+and	O
+death	O
+in	O
+mixed	O
+cocaine	O
+-	O
+diazepam	O
+intoxications	O
+.	O
+	
+STUDY	O
+HYPOTHESIS	O
+:	O
+Administration	O
+of	O
+the	O
+benzodiazepine	O
+antagonist	O
+flumazenil	O
+may	O
+unmask	O
+seizures	B-NP
+in	O
+mixed	O
+cocaine	O
+-	O
+benzodiazepine	O
+intoxication	O
+.	O
+	
+DESIGN	O
+:	O
+Male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+received	O
+100	O
+mg	O
+/	O
+kg	O
+cocaine	O
+IP	O
+alone	O
+","	O
+5	O
+mg	O
+/	O
+kg	O
+diazepam	O
+alone	O
+","	O
+or	O
+a	O
+combination	O
+of	O
+diazepam	O
+and	O
+cocaine	O
+.	O
+	
+Three	O
+minutes	O
+later	O
+","	O
+groups	O
+were	O
+challenged	O
+with	O
+vehicle	O
+or	O
+flumazenil	O
+5	O
+or	O
+10	O
+mg	O
+/	O
+kg	O
+IP	O
+.	O
+	
+Animal	O
+behavior	O
+","	O
+seizures	B-NP
+(	O
+time	O
+to	O
+and	O
+incidence	O
+)	O
+","	O
+death	O
+(	O
+time	O
+to	O
+and	O
+incidence	O
+)	O
+","	O
+and	O
+cortical	O
+EEG	O
+tracings	O
+were	O
+recorded	O
+.	O
+	
+INTERVENTIONS	O
+:	O
+Administration	O
+of	O
+flumazenil	O
+to	O
+animals	O
+after	O
+they	O
+had	O
+received	O
+a	O
+combination	O
+dose	O
+of	O
+cocaine	O
+and	O
+diazepam	O
+.	O
+	
+RESULTS	O
+:	O
+In	O
+group	O
+1	O
+","	O
+animals	O
+received	O
+cocaine	O
+followed	O
+by	O
+vehicle	O
+.	O
+	
+This	O
+resulted	O
+in	O
+100	O
+%	O
+developing	O
+seizures	B-NP
+and	O
+death	O
+.	O
+	
+Group	O
+2	O
+received	O
+diazepam	O
+alone	O
+followed	O
+by	O
+vehicle	O
+.	O
+	
+Animals	O
+became	O
+somnolent	O
+and	O
+none	O
+died	O
+.	O
+	
+Group	O
+3	O
+received	O
+diazepam	O
+followed	O
+by	O
+5	O
+mg	O
+/	O
+kg	O
+flumazenil	O
+.	O
+	
+Animals	O
+became	O
+somnolent	O
+after	O
+diazepam	O
+and	O
+then	O
+active	O
+after	O
+flumazenil	O
+administration	O
+.	O
+	
+In	O
+group	O
+4	O
+","	O
+a	O
+combination	O
+of	O
+cocaine	O
+and	O
+diazepam	O
+was	O
+administered	O
+simultaneously	O
+.	O
+	
+This	O
+resulted	O
+in	O
+no	O
+overt	O
+or	O
+EEG	O
+-	O
+detectable	O
+seizures	B-NP
+and	O
+a	O
+50	O
+%	O
+incidence	O
+of	O
+death	O
+.	O
+	
+Group	O
+5	O
+received	O
+a	O
+similar	O
+combination	O
+of	O
+cocaine	O
+and	O
+diazepam	O
+","	O
+followed	O
+later	O
+by	O
+5	O
+mg	O
+/	O
+kg	O
+flumazenil	O
+.	O
+	
+This	O
+resulted	O
+in	O
+an	O
+increased	O
+incidence	O
+of	O
+seizures	B-NP
+","	O
+90	O
+%	O
+(	O
+P	O
+<	O
+.	O
+1	O
+)	O
+","	O
+and	O
+death	O
+","	O
+100	O
+%	O
+(	O
+P	O
+<	O
+or	O
+=	O
+.	O
+1	O
+)	O
+","	O
+compared	O
+with	O
+group	O
+4	O
+.	O
+	
+Group	O
+6	O
+received	O
+cocaine	O
+and	O
+diazepam	O
+followed	O
+by	O
+10	O
+mg	O
+/	O
+kg	O
+flumazenil	O
+.	O
+	
+This	O
+also	O
+resulted	O
+in	O
+an	O
+increased	O
+incidence	O
+of	O
+seizures	B-NP
+","	O
+90	O
+%	O
+(	O
+P	O
+<	O
+or	O
+=	O
+.	O
+1	O
+)	O
+","	O
+and	O
+death	O
+","	O
+90	O
+%	O
+(	O
+P	O
+<	O
+or	O
+=	O
+.	O
+5	O
+)	O
+","	O
+compared	O
+with	O
+group	O
+4	O
+.	O
+	
+CONCLUSION	O
+:	O
+Flumazenil	O
+can	O
+unmask	O
+seizures	B-NP
+and	O
+increase	O
+the	O
+incidence	O
+of	O
+death	O
+in	O
+a	O
+model	O
+of	O
+combined	O
+cocaine	O
+-	O
+diazepam	O
+intoxications	O
+.	O
+	
+Mechanisms	O
+for	O
+protective	O
+effects	O
+of	O
+free	O
+radical	O
+scavengers	O
+on	O
+gentamicin	O
+-	O
+mediated	O
+nephropathy	B-NP
+in	O
+rats	O
+.	O
+	
+Studies	O
+were	O
+performed	O
+to	O
+examine	O
+the	O
+mechanisms	O
+for	O
+the	O
+protective	O
+effects	O
+of	O
+free	O
+radical	O
+scavengers	O
+on	O
+gentamicin	O
+(	O
+GM	O
+)	O
+-	O
+mediated	O
+nephropathy	B-NP
+.	O
+	
+Administration	O
+of	O
+GM	O
+at	O
+40	O
+mg	O
+/	O
+kg	O
+sc	O
+for	O
+13	O
+days	O
+to	O
+rats	O
+induced	O
+a	O
+significant	O
+reduction	O
+in	O
+renal	O
+blood	O
+flow	O
+(	O
+RBF	O
+)	O
+and	O
+inulin	O
+clearance	O
+(	O
+CIn	O
+)	O
+as	O
+well	O
+as	O
+marked	O
+tubular	B-NP
+damage	I-NP
+.	O
+	
+A	O
+significant	O
+reduction	O
+in	O
+urinary	O
+guanosine	O
+3	O
+'	O
+","	O
+5	O
+'	O
+-	O
+cyclic	O
+monophosphate	O
+(	O
+cGMP	O
+)	O
+excretion	O
+and	O
+a	O
+significant	O
+increase	O
+in	O
+renal	O
+cortical	O
+renin	O
+and	O
+endothelin	O
+-	O
+1	O
+contents	O
+were	O
+also	O
+observed	O
+in	O
+GM	O
+-	O
+mediated	O
+nephropathy	B-NP
+.	O
+	
+Superoxide	O
+dismutase	O
+(	O
+SOD	O
+)	O
+or	O
+dimethylthiourea	O
+(	O
+DMTU	O
+)	O
+significantly	O
+lessened	O
+the	O
+GM	O
+-	O
+induced	O
+decrement	O
+in	O
+CIn	O
+.	O
+	
+The	O
+SOD	O
+-	O
+induced	O
+increase	O
+in	O
+glomerular	O
+filtration	O
+rate	O
+was	O
+associated	O
+with	O
+a	O
+marked	O
+improvement	O
+in	O
+RBF	O
+","	O
+an	O
+increase	O
+in	O
+urinary	O
+cGMP	O
+excretion	O
+","	O
+and	O
+a	O
+decrease	O
+in	O
+renal	O
+renin	O
+and	O
+endothelin	O
+-	O
+1	O
+content	O
+.	O
+	
+SOD	O
+did	O
+not	O
+attenuate	O
+the	O
+tubular	B-NP
+damage	I-NP
+.	O
+	
+In	O
+contrast	O
+","	O
+DMTU	O
+significantly	O
+reduced	O
+the	O
+tubular	B-NP
+damage	I-NP
+and	O
+lipid	O
+peroxidation	O
+","	O
+but	O
+it	O
+did	O
+not	O
+affect	O
+renal	O
+hemodynamics	O
+and	O
+vasoactive	O
+substances	O
+.	O
+	
+Neither	O
+SOD	O
+nor	O
+DMTU	O
+affected	O
+the	O
+renal	O
+cortical	O
+GM	O
+content	O
+in	O
+GM	O
+-	O
+treated	O
+rats	O
+.	O
+	
+These	O
+results	O
+suggest	O
+that	O
+1	O
+)	O
+both	O
+SOD	O
+and	O
+DMTU	O
+have	O
+protective	O
+effects	O
+on	O
+GM	O
+-	O
+mediated	O
+nephropathy	B-NP
+","	O
+2	O
+)	O
+the	O
+mechanisms	O
+for	O
+the	O
+protective	O
+effects	O
+differ	O
+for	O
+SOD	O
+and	O
+DMTU	O
+","	O
+and	O
+3	O
+)	O
+superoxide	O
+anions	O
+play	O
+a	O
+critical	O
+role	O
+in	O
+GM	O
+-	O
+induced	O
+renal	O
+vasoconstriction	O
+.	O
+	
+Cephalothin	O
+-	O
+induced	O
+immune	O
+hemolytic	B-NP
+anemia	I-NP
+.	O
+	
+A	O
+patient	O
+with	O
+renal	B-NP
+disease	I-NP
+developed	O
+Coombs	O
+-	O
+positive	O
+hemolytic	B-NP
+anemia	I-NP
+while	O
+receiving	O
+cephalothin	O
+therapy	O
+.	O
+	
+An	O
+anti	O
+-	O
+cephalothin	O
+IgG	O
+antibody	O
+was	O
+detected	O
+in	O
+the	O
+patient	O
+'	O
+s	O
+serum	O
+and	O
+in	O
+the	O
+eluates	O
+from	O
+her	O
+erythrocytes	O
+.	O
+	
+In	O
+addition	O
+","	O
+nonimmunologic	O
+binding	O
+of	O
+normal	O
+and	O
+patient	O
+'	O
+s	O
+serum	O
+proteins	O
+to	O
+her	O
+own	O
+and	O
+cephalothin	O
+-	O
+coated	O
+normal	O
+red	O
+cells	O
+was	O
+demonstrated	O
+.	O
+	
+Skin	O
+tests	O
+and	O
+in	O
+vitro	O
+lymphocyte	O
+stimulation	O
+revealed	O
+that	O
+the	O
+patient	O
+was	O
+sensitized	O
+to	O
+cephalothin	O
+and	O
+also	O
+to	O
+ampicillin	O
+.	O
+	
+Careful	O
+investigation	O
+of	O
+drug	O
+-	O
+induced	O
+hemolytic	B-NP
+anemias	I-NP
+reveals	O
+the	O
+complexity	O
+of	O
+the	O
+immune	O
+mechanisms	O
+involved	O
+.	O
+	
+Assessment	O
+of	O
+cardiomyocyte	O
+DNA	O
+synthesis	O
+during	O
+hypertrophy	B-NP
+in	O
+adult	O
+mice	O
+.	O
+	
+The	O
+ability	O
+of	O
+cardiomyocytes	O
+to	O
+synthesize	O
+DNA	O
+in	O
+response	O
+to	O
+experimentally	O
+induced	O
+cardiac	B-NP
+hypertrophy	I-NP
+was	O
+assessed	O
+in	O
+adult	O
+mice	O
+.	O
+	
+Isoproterenol	O
+delivered	O
+by	O
+osmotic	O
+minipump	O
+implantation	O
+in	O
+adult	O
+C3Heb	O
+/	O
+FeJ	O
+mice	O
+resulted	O
+in	O
+a	O
+46	O
+%	O
+increase	O
+in	O
+heart	O
+weight	O
+and	O
+a	O
+19	O
+.	O
+3	O
+%	O
+increase	O
+in	O
+cardiomyocyte	O
+area	O
+.	O
+	
+No	O
+DNA	O
+synthesis	O
+","	O
+as	O
+assessed	O
+by	O
+autoradiographic	O
+analysis	O
+of	O
+isolated	O
+cardiomyocytes	O
+","	O
+was	O
+observed	O
+in	O
+control	O
+or	O
+hypertrophic	B-NP
+hearts	I-NP
+.	O
+	
+A	O
+survey	O
+of	O
+15	O
+independent	O
+inbred	O
+strains	O
+of	O
+mice	O
+revealed	O
+that	O
+ventricular	O
+cardiomyocyte	O
+nuclear	O
+number	O
+ranged	O
+from	O
+3	O
+to	O
+13	O
+%	O
+mononucleate	O
+","	O
+suggesting	O
+that	O
+cardiomyocyte	O
+terminal	O
+differentiation	O
+is	O
+influenced	O
+directly	O
+or	O
+indirectly	O
+by	O
+genetic	O
+background	O
+.	O
+	
+To	O
+determine	O
+whether	O
+the	O
+capacity	O
+for	O
+reactive	O
+DNA	O
+synthesis	O
+was	O
+also	O
+subject	O
+to	O
+genetic	O
+regulation	O
+","	O
+cardiac	B-NP
+hypertrophy	I-NP
+was	O
+induced	O
+in	O
+the	O
+strains	O
+of	O
+mice	O
+comprising	O
+the	O
+extremes	O
+of	O
+the	O
+nuclear	O
+number	O
+survey	O
+.	O
+	
+These	O
+data	O
+indicate	O
+that	O
+adult	O
+mouse	O
+atrial	O
+and	O
+ventricular	O
+cardiomyocytes	O
+do	O
+not	O
+synthesize	O
+DNA	O
+in	O
+response	O
+to	O
+isoproterenol	O
+-	O
+induced	O
+cardiac	B-NP
+hypertrophy	I-NP
+.	O
+	
+Central	O
+cardiovascular	O
+effects	O
+of	O
+AVP	O
+and	O
+ANP	O
+in	O
+normotensive	O
+and	O
+spontaneously	O
+hypertensive	B-NP
+rats	O
+.	O
+	
+The	O
+purpose	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+compare	O
+influence	O
+of	O
+central	O
+arginine	O
+vasopressin	O
+(	O
+AVP	O
+)	O
+and	O
+of	O
+atrial	O
+natriuretic	O
+peptide	O
+(	O
+ANP	O
+)	O
+on	O
+control	O
+of	O
+arterial	O
+blood	O
+pressure	O
+(	O
+MAP	O
+)	O
+and	O
+heart	O
+rate	O
+(	O
+HR	O
+)	O
+in	O
+normotensive	O
+(	O
+WKY	O
+)	O
+and	O
+spontaneously	O
+hypertensive	B-NP
+(	O
+SHR	O
+)	O
+rats	O
+.	O
+	
+Three	O
+series	O
+of	O
+experiments	O
+were	O
+performed	O
+on	O
+30	O
+WKY	O
+and	O
+30	O
+SHR	O
+","	O
+chronically	O
+instrumented	O
+with	O
+guide	O
+tubes	O
+in	O
+the	O
+lateral	O
+ventricle	O
+(	O
+LV	O
+)	O
+and	O
+arterial	O
+and	O
+venous	O
+catheters	O
+.	O
+	
+MAP	O
+and	O
+HR	O
+were	O
+monitored	O
+before	O
+and	O
+after	O
+i	O
+.	O
+v	O
+.	O
+injections	O
+of	O
+either	O
+vehicle	O
+or	O
+1	O
+","	O
+10	O
+and	O
+50	O
+ng	O
+of	O
+AVP	O
+and	O
+25	O
+","	O
+125	O
+and	O
+500	O
+ng	O
+of	O
+ANP	O
+.	O
+	
+Sensitivity	O
+of	O
+cardiac	O
+component	O
+of	O
+baroreflex	O
+(	O
+CCB	O
+)	O
+","	O
+expressed	O
+as	O
+a	O
+slope	O
+of	O
+the	O
+regression	O
+line	O
+was	O
+determined	O
+from	O
+relationships	O
+between	O
+systolic	O
+arterial	O
+pressure	O
+(	O
+SAP	O
+)	O
+and	O
+HR	O
+period	O
+(	O
+HRp	O
+)	O
+during	O
+phenylephrine	O
+(	O
+Phe	O
+)	O
+-	O
+induced	O
+hypertension	B-NP
+and	O
+sodium	O
+nitroprusside	O
+(	O
+SN	O
+)	O
+-	O
+induced	O
+hypotension	B-NP
+.	O
+	
+CCB	O
+was	O
+measured	O
+before	O
+and	O
+after	O
+administration	O
+of	O
+either	O
+vehicle	O
+","	O
+AVP	O
+","	O
+ANP	O
+","	O
+or	O
+both	O
+peptides	O
+together	O
+.	O
+	
+Increases	O
+of	O
+MAP	O
+occurred	O
+after	O
+LV	O
+administration	O
+of	O
+1	O
+","	O
+10	O
+and	O
+50	O
+ng	O
+of	O
+AVP	O
+in	O
+WKY	O
+and	O
+of	O
+10	O
+and	O
+50	O
+ng	O
+in	O
+SHR	O
+.	O
+	
+ANP	O
+did	O
+not	O
+cause	O
+significant	O
+changes	O
+in	O
+MAP	O
+in	O
+both	O
+strains	O
+as	O
+compared	O
+to	O
+vehicle	O
+","	O
+but	O
+it	O
+abolished	O
+AVP	O
+-	O
+induced	O
+MAP	O
+increase	O
+in	O
+WKY	O
+and	O
+SHR	O
+.	O
+	
+CCB	O
+was	O
+reduced	O
+in	O
+WKY	O
+and	O
+SHR	O
+after	O
+LV	O
+administration	O
+of	O
+AVP	O
+during	O
+SN	O
+-	O
+induced	O
+hypotension	B-NP
+.	O
+	
+In	O
+SHR	O
+but	O
+not	O
+in	O
+WKY	O
+administration	O
+of	O
+ANP	O
+","	O
+AVP	O
+and	O
+ANP	O
++	O
+AVP	O
+decreased	O
+CCB	O
+during	O
+Phe	O
+-	O
+induced	O
+MAP	O
+elevation	O
+.	O
+	
+The	O
+results	O
+indicate	O
+that	O
+centrally	O
+applied	O
+AVP	O
+and	O
+ANP	O
+exert	O
+differential	O
+effects	O
+on	O
+blood	O
+pressure	O
+and	O
+baroreflex	O
+control	O
+of	O
+heart	O
+rate	O
+in	O
+WKY	O
+and	O
+SHR	O
+and	O
+suggest	O
+interaction	O
+of	O
+these	O
+two	O
+peptides	O
+in	O
+blood	O
+pressure	O
+regulation	O
+at	O
+the	O
+level	O
+of	O
+central	O
+nervous	O
+system	O
+.	O
+	
+Cutaneous	O
+exposure	O
+to	O
+warfarin	O
+-	O
+like	O
+anticoagulant	O
+causing	O
+an	O
+intracerebral	B-NP
+hemorrhage	I-NP
+:	O
+a	O
+case	O
+report	O
+.	O
+	
+A	O
+case	O
+of	O
+intercerebral	O
+hematoma	B-NP
+due	O
+to	O
+warfarin	O
+-	O
+induced	O
+coagulopathy	B-NP
+is	O
+presented	O
+.	O
+	
+The	O
+39	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+had	O
+spread	O
+a	O
+warfarin	O
+-	O
+type	O
+rat	O
+poison	O
+around	O
+her	O
+house	O
+weekly	O
+using	O
+her	O
+bare	O
+hands	O
+","	O
+with	O
+no	O
+washing	O
+post	O
+application	O
+.	O
+	
+Percutaneous	O
+absorption	O
+of	O
+warfarin	O
+causing	O
+coagulopathy	B-NP
+","	O
+reported	O
+three	O
+times	O
+in	O
+the	O
+past	O
+","	O
+is	O
+a	O
+significant	O
+risk	O
+if	O
+protective	O
+measures	O
+","	O
+such	O
+as	O
+gloves	O
+","	O
+are	O
+not	O
+used	O
+.	O
+	
+An	O
+adverse	O
+drug	O
+interaction	O
+with	O
+piroxicam	O
+","	O
+which	O
+she	O
+took	O
+occasionally	O
+","	O
+may	O
+have	O
+exacerbated	O
+the	O
+coagulopathy	B-NP
+.	O
+	
+Pediatric	O
+heart	O
+transplantation	O
+without	O
+chronic	O
+maintenance	O
+steroids	O
+.	O
+	
+From	O
+1986	O
+to	O
+February	O
+1993	O
+","	O
+40	O
+children	O
+aged	O
+2	O
+months	O
+to	O
+18	O
+years	O
+(	O
+average	O
+age	O
+10	O
+.	O
+4	O
++	O
+/	O
+-	O
+5	O
+.	O
+8	O
+years	O
+)	O
+underwent	O
+heart	O
+transplantation	O
+.	O
+	
+Indications	O
+for	O
+transplantation	O
+were	O
+idiopathic	B-NP
+cardiomyopathy	I-NP
+(	O
+52	O
+%	O
+)	O
+","	O
+congenital	B-NP
+heart	I-NP
+disease	I-NP
+(	O
+35	O
+%	O
+)	O
+with	O
+and	O
+without	O
+prior	O
+repair	O
+(	O
+71	O
+%	O
+and	O
+29	O
+%	O
+","	O
+respectively	O
+)	O
+","	O
+hypertrophic	B-NP
+cardiomyopathy	I-NP
+(	O
+5	O
+%	O
+)	O
+","	O
+valvular	B-NP
+heart	I-NP
+disease	I-NP
+(	O
+3	O
+%	O
+)	O
+","	O
+and	O
+doxorubicin	O
+cardiomyopathy	B-NP
+(	O
+5	O
+%	O
+)	O
+.	O
+	
+Patients	O
+were	O
+managed	O
+with	O
+cyclosporine	O
+and	O
+azathioprine	O
+.	O
+	
+No	O
+prophylaxis	O
+with	O
+antilymphocyte	O
+globulin	O
+was	O
+used	O
+.	O
+	
+Steroids	O
+were	O
+given	O
+to	O
+39	O
+%	O
+of	O
+patients	O
+for	O
+refractory	O
+rejection	O
+","	O
+but	O
+weaning	O
+was	O
+always	O
+attempted	O
+and	O
+generally	O
+successful	O
+(	O
+64	O
+%	O
+)	O
+.	O
+	
+Five	O
+patients	O
+(	O
+14	O
+%	O
+)	O
+received	O
+maintenance	O
+steroids	O
+.	O
+	
+Four	O
+patients	O
+died	O
+in	O
+the	O
+perioperative	O
+period	O
+and	O
+one	O
+died	O
+4	O
+months	O
+later	O
+.	O
+	
+There	O
+have	O
+been	O
+no	O
+deaths	O
+related	O
+to	O
+rejection	O
+or	O
+infection	B-NP
+.	O
+	
+Average	O
+follow	O
+-	O
+up	O
+was	O
+36	O
++	O
+/	O
+-	O
+19	O
+months	O
+(	O
+range	O
+1	O
+to	O
+65	O
+months	O
+)	O
+.	O
+	
+Cumulative	O
+survival	O
+is	O
+88	O
+%	O
+at	O
+5	O
+years	O
+.	O
+	
+In	O
+patients	O
+less	O
+than	O
+7	O
+years	O
+of	O
+age	O
+","	O
+rejection	O
+was	O
+monitored	O
+noninvasively	O
+.	O
+	
+In	O
+the	O
+first	O
+postoperative	O
+month	O
+","	O
+89	O
+%	O
+of	O
+patients	O
+were	O
+treated	O
+for	O
+rejection	O
+.	O
+	
+Freedom	O
+from	O
+serious	O
+infections	B-NP
+was	O
+83	O
+%	O
+at	O
+1	O
+month	O
+and	O
+65	O
+%	O
+at	O
+1	O
+year	O
+.	O
+	
+Cytomegalovirus	B-NP
+infections	I-NP
+were	O
+treated	O
+successfully	O
+with	O
+ganciclovir	O
+in	O
+11	O
+patients	O
+.	O
+	
+No	O
+impairment	O
+of	O
+growth	O
+was	O
+observed	O
+in	O
+children	O
+who	O
+underwent	O
+transplantation	O
+compared	O
+with	O
+a	O
+control	O
+population	O
+.	O
+	
+Twenty	O
+-	O
+one	O
+patients	O
+(	O
+60	O
+%	O
+)	O
+have	O
+undergone	O
+annual	O
+catheterizations	O
+and	O
+no	O
+sign	O
+of	O
+graft	O
+atherosclerosis	B-NP
+has	O
+been	O
+observed	O
+.	O
+	
+Seizures	B-NP
+occurred	O
+in	O
+five	O
+patients	O
+(	O
+14	O
+%	O
+)	O
+and	O
+hypertension	B-NP
+was	O
+treated	O
+in	O
+10	O
+patients	O
+(	O
+28	O
+%	O
+)	O
+.	O
+	
+No	O
+patient	O
+was	O
+disabled	O
+and	O
+no	O
+lymphoproliferative	B-NP
+disorder	I-NP
+was	O
+observed	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+	
+Delirium	B-NP
+during	O
+fluoxetine	O
+treatment	O
+.	O
+	
+A	O
+case	O
+report	O
+.	O
+	
+The	O
+correlation	O
+between	O
+high	O
+serum	O
+tricyclic	O
+antidepressant	O
+concentrations	O
+and	O
+central	O
+nervous	O
+system	O
+side	O
+effects	O
+has	O
+been	O
+well	O
+established	O
+.	O
+	
+Only	O
+a	O
+few	O
+reports	O
+exist	O
+","	O
+however	O
+","	O
+on	O
+the	O
+relationship	O
+between	O
+the	O
+serum	O
+concentrations	O
+of	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitors	O
+(	O
+SSRIs	O
+)	O
+and	O
+their	O
+toxic	O
+effects	O
+.	O
+	
+In	O
+some	O
+cases	O
+","	O
+a	O
+high	O
+serum	O
+concentration	O
+of	O
+citalopram	O
+(	O
+>	O
+600	O
+nmol	O
+/	O
+L	O
+)	O
+in	O
+elderly	O
+patients	O
+has	O
+been	O
+associated	O
+with	O
+increased	O
+somnolence	B-NP
+and	O
+movement	B-NP
+difficulties	I-NP
+.	O
+	
+Widespread	O
+cognitive	B-NP
+disorders	I-NP
+","	O
+such	O
+as	O
+delirium	B-NP
+","	O
+have	O
+not	O
+been	O
+previously	O
+linked	O
+with	O
+high	O
+blood	O
+levels	O
+of	O
+SSRIs	O
+.	O
+	
+In	O
+this	O
+report	O
+","	O
+we	O
+describe	O
+a	O
+patient	O
+with	O
+acute	O
+hyperkinetic	B-NP
+delirium	B-NP
+connected	O
+with	O
+a	O
+high	O
+serum	O
+total	O
+fluoxetine	O
+(	O
+fluoxetine	O
+plus	O
+desmethylfluoxetine	O
+)	O
+concentration	O
+.	O
+	
+Pulmonary	B-NP
+edema	I-NP
+and	O
+shock	B-NP
+after	O
+high	O
+-	O
+dose	O
+aracytine	O
+-	O
+C	O
+for	O
+lymphoma	B-NP
+;	O
+possible	O
+role	O
+of	O
+TNF	O
+-	O
+alpha	O
+and	O
+PAF	O
+.	O
+	
+Four	O
+out	O
+of	O
+23	O
+consecutive	O
+patients	O
+treated	O
+with	O
+high	O
+-	O
+dose	O
+Ara	O
+-	O
+C	O
+for	O
+lymphomas	B-NP
+in	O
+our	O
+institution	O
+developed	O
+a	O
+strikingly	O
+similar	O
+syndrome	O
+during	O
+the	O
+perfusion	O
+.	O
+	
+It	O
+was	O
+characterized	O
+by	O
+the	O
+onset	O
+of	O
+fever	B-NP
+","	O
+diarrhea	B-NP
+","	O
+shock	B-NP
+","	O
+pulmonary	B-NP
+edema	I-NP
+","	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+","	O
+metabolic	B-NP
+acidosis	I-NP
+","	O
+weight	B-NP
+gain	I-NP
+and	O
+leukocytosis	B-NP
+.	O
+	
+Thorough	O
+bacteriological	O
+screening	O
+failed	O
+to	O
+provide	O
+evidence	O
+of	O
+infection	B-NP
+.	O
+	
+Sequential	O
+biological	O
+assays	O
+of	O
+IL	O
+-	O
+1	O
+","	O
+IL	O
+-	O
+2	O
+","	O
+TNF	O
+and	O
+PAF	O
+were	O
+performed	O
+during	O
+Ara	O
+-	O
+C	O
+infusion	O
+to	O
+ten	O
+patients	O
+","	O
+including	O
+the	O
+four	O
+who	O
+developed	O
+the	O
+syndrome	O
+.	O
+	
+TNF	O
+and	O
+PAF	O
+activity	O
+was	O
+found	O
+in	O
+the	O
+serum	O
+of	O
+respectively	O
+two	O
+and	O
+four	O
+of	O
+the	O
+cases	O
+","	O
+but	O
+not	O
+in	O
+the	O
+six	O
+controls	O
+.	O
+	
+As	O
+TNF	O
+and	O
+PAF	O
+are	O
+thought	O
+to	O
+be	O
+involved	O
+in	O
+the	O
+development	O
+of	O
+septic	O
+shock	B-NP
+and	O
+adult	B-NP
+respiratory	I-NP
+distress	I-NP
+syndrome	I-NP
+","	O
+we	O
+hypothesize	O
+that	O
+high	O
+-	O
+dose	O
+Ara	O
+-	O
+C	O
+may	O
+be	O
+associated	O
+with	O
+cytokine	O
+release	O
+.	O
+	
+Protective	O
+effect	O
+of	O
+clentiazem	O
+against	O
+epinephrine	O
+-	O
+induced	O
+cardiac	B-NP
+injury	I-NP
+in	O
+rats	O
+.	O
+	
+We	O
+investigated	O
+the	O
+effects	O
+of	O
+clentiazem	O
+","	O
+a	O
+1	O
+","	O
+5	O
+-	O
+benzothiazepine	O
+calcium	O
+antagonist	O
+","	O
+on	O
+epinephrine	O
+-	O
+induced	O
+cardiomyopathy	B-NP
+in	O
+rats	O
+.	O
+	
+With	O
+2	O
+-	O
+week	O
+chronic	O
+epinephrine	O
+infusion	O
+","	O
+16	O
+of	O
+30	O
+rats	O
+died	O
+within	O
+4	O
+days	O
+","	O
+and	O
+severe	O
+ischemic	B-NP
+lesions	I-NP
+and	O
+fibrosis	B-NP
+of	O
+the	O
+left	O
+ventricles	O
+were	O
+observed	O
+.	O
+	
+In	O
+epinephrine	O
+-	O
+treated	O
+rats	O
+","	O
+left	O
+atrial	O
+and	O
+left	O
+ventricular	O
+papillary	O
+muscle	O
+contractile	O
+responses	O
+to	O
+isoproterenol	O
+were	O
+reduced	O
+","	O
+but	O
+responses	O
+to	O
+calcium	O
+were	O
+normal	O
+or	O
+enhanced	O
+compared	O
+to	O
+controls	O
+.	O
+	
+Left	O
+ventricular	O
+alpha	O
+and	O
+beta	O
+adrenoceptor	O
+densities	O
+were	O
+also	O
+reduced	O
+compared	O
+to	O
+controls	O
+.	O
+	
+Treatment	O
+with	O
+clentiazem	O
+prevented	O
+epinephrine	O
+-	O
+induced	O
+death	O
+(	O
+P	O
+<	O
+.	O
+5	O
+)	O
+","	O
+and	O
+attenuated	O
+the	O
+ventricular	O
+ischemic	B-NP
+lesions	I-NP
+and	O
+fibrosis	B-NP
+","	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+.	O
+	
+Left	O
+atrial	O
+and	O
+left	O
+ventricular	O
+papillary	O
+muscle	O
+contractile	O
+responses	O
+to	O
+isoproterenol	O
+were	O
+reduced	O
+compared	O
+to	O
+controls	O
+in	O
+groups	O
+treated	O
+with	O
+clentiazem	O
+alone	O
+","	O
+but	O
+combined	O
+with	O
+epinephrine	O
+","	O
+clentiazem	O
+restored	O
+left	O
+atrial	O
+responses	O
+and	O
+enhanced	O
+left	O
+ventricular	O
+papillary	O
+responses	O
+to	O
+isoproterenol	O
+.	O
+	
+On	O
+the	O
+other	O
+hand	O
+clentiazem	O
+did	O
+not	O
+prevent	O
+epinephrine	O
+-	O
+induced	O
+down	O
+-	O
+regulation	O
+of	O
+alpha	O
+and	O
+beta	O
+adrenoceptors	O
+.	O
+	
+Interestingly	O
+","	O
+clentiazem	O
+","	O
+infused	O
+alone	O
+","	O
+resulted	O
+in	O
+decreased	O
+adrenergic	O
+receptor	O
+densities	O
+in	O
+the	O
+left	O
+ventricle	O
+.	O
+	
+Clentiazem	O
+also	O
+did	O
+not	O
+prevent	O
+the	O
+enhanced	O
+responses	O
+to	O
+calcium	O
+seen	O
+in	O
+the	O
+epinephrine	O
+-	O
+treated	O
+animals	O
+","	O
+although	O
+the	O
+high	O
+dose	O
+of	O
+clentiazem	O
+partially	O
+attenuated	O
+the	O
+maximal	O
+response	O
+to	O
+calcium	O
+compared	O
+to	O
+epinephrine	O
+-	O
+treated	O
+animals	O
+.	O
+	
+In	O
+conclusion	O
+","	O
+clentiazem	O
+attenuated	O
+epinephrine	O
+-	O
+induced	O
+cardiac	B-NP
+injury	I-NP
+","	O
+possibly	O
+through	O
+its	O
+effect	O
+on	O
+the	O
+adrenergic	O
+pathway	O
+.	O
+	
+Kaliuretic	O
+effect	O
+of	O
+L	O
+-	O
+dopa	O
+treatment	O
+in	O
+parkinsonian	B-NP
+patients	O
+.	O
+	
+Hypokalemia	B-NP
+","	O
+sometimes	O
+severe	O
+","	O
+was	O
+observed	O
+in	O
+some	O
+L	O
+-	O
+dopa	O
+-	O
+treated	O
+parkinsonian	B-NP
+patients	O
+.	O
+	
+The	O
+influence	O
+of	O
+L	O
+-	O
+dopa	O
+on	O
+the	O
+renal	O
+excretion	O
+of	O
+potassium	O
+was	O
+studied	O
+in	O
+3	O
+patients	O
+with	O
+hypokalemia	B-NP
+and	O
+in	O
+5	O
+normokalemic	O
+patients	O
+by	O
+determination	O
+of	O
+renal	O
+plasma	O
+flow	O
+","	O
+glomerular	O
+filtration	O
+rate	O
+","	O
+plasma	O
+concentration	O
+of	O
+potassium	O
+and	O
+sodium	O
+as	O
+well	O
+as	O
+urinary	O
+excretion	O
+of	O
+potassium	O
+","	O
+sodium	O
+and	O
+aldosterone	O
+.	O
+	
+L	O
+-	O
+Dopa	O
+intake	O
+was	O
+found	O
+to	O
+cause	O
+an	O
+increased	O
+excretion	O
+of	O
+potassium	O
+","	O
+and	O
+sometimes	O
+also	O
+of	O
+sodium	O
+","	O
+in	O
+the	O
+hypokalemic	O
+but	O
+not	O
+in	O
+the	O
+normokalemic	O
+patients	O
+.	O
+	
+This	O
+effect	O
+on	O
+the	O
+renal	O
+function	O
+could	O
+be	O
+prohibited	O
+by	O
+the	O
+administration	O
+of	O
+a	O
+peripheral	O
+dopa	O
+decarbodylase	O
+inhibitor	O
+.	O
+	
+It	O
+is	O
+not	O
+known	O
+why	O
+this	O
+effect	O
+occurred	O
+in	O
+some	O
+individuals	O
+but	O
+not	O
+in	O
+others	O
+","	O
+but	O
+our	O
+results	O
+indicate	O
+a	O
+correlation	O
+between	O
+aldosterone	O
+production	O
+and	O
+this	O
+renal	O
+effect	O
+of	O
+L	O
+-	O
+dopa	O
+.	O
+	
+Cocaine	O
+induced	O
+myocardial	B-NP
+ischemia	I-NP
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+myocardial	B-NP
+ischemia	I-NP
+induced	O
+by	O
+cocaine	O
+.	O
+	
+The	O
+ischemia	B-NP
+probably	O
+induced	O
+by	O
+coronary	B-NP
+artery	I-NP
+spasm	I-NP
+was	O
+reversed	O
+by	O
+nitroglycerin	O
+and	O
+calcium	O
+blocking	O
+agents	O
+.	O
+	
+Doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+monitored	O
+by	O
+ECG	O
+in	O
+freely	O
+moving	O
+mice	O
+.	O
+	
+A	O
+new	O
+model	O
+to	O
+test	O
+potential	O
+protectors	O
+.	O
+	
+In	O
+laboratory	O
+animals	O
+","	O
+histology	O
+is	O
+most	O
+commonly	O
+used	O
+to	O
+study	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+.	O
+	
+However	O
+","	O
+for	O
+monitoring	O
+during	O
+treatment	O
+","	O
+large	O
+numbers	O
+of	O
+animals	O
+are	O
+needed	O
+.	O
+	
+Recently	O
+we	O
+developed	O
+a	O
+new	O
+method	O
+to	O
+measure	O
+ECG	O
+values	O
+in	O
+freely	O
+moving	O
+mice	O
+by	O
+telemetry	O
+.	O
+	
+With	O
+this	O
+model	O
+we	O
+investigated	O
+the	O
+effect	O
+of	O
+chronic	O
+doxorubicin	O
+administration	O
+on	O
+the	O
+ECG	O
+of	O
+freely	O
+moving	O
+BALB	O
+/	O
+c	O
+mice	O
+and	O
+the	O
+efficacy	O
+of	O
+ICRF	O
+-	O
+187	O
+as	O
+a	O
+protective	O
+agent	O
+.	O
+	
+The	O
+ST	O
+interval	O
+significantly	O
+widened	O
+from	O
+15	O
+.	O
+0	O
++	O
+/	O
+-	O
+1	O
+.	O
+5	O
+to	O
+56	O
+.	O
+8	O
++	O
+/	O
+-	O
+11	O
+.	O
+8	O
+ms	O
+in	O
+week	O
+10	O
+(	O
+7	O
+weekly	O
+doses	O
+of	O
+4	O
+mg	O
+/	O
+kg	O
+doxorubicin	O
+given	O
+i	O
+.	O
+v	O
+.	O
+plus	O
+3	O
+weeks	O
+of	O
+observation	O
+)	O
+.	O
+	
+The	O
+ECG	O
+of	O
+the	O
+control	O
+animals	O
+did	O
+not	O
+change	O
+during	O
+the	O
+entire	O
+study	O
+.	O
+	
+After	O
+sacrifice	O
+the	O
+hearts	O
+of	O
+doxorubicin	O
+-	O
+treated	O
+animals	O
+were	O
+enlarged	O
+and	O
+the	O
+atria	O
+were	O
+hypertrophic	B-NP
+.	O
+	
+As	O
+this	O
+schedule	O
+exerted	O
+more	O
+toxicity	B-NP
+than	O
+needed	O
+to	O
+investigate	O
+protective	O
+agents	O
+","	O
+the	O
+protection	O
+of	O
+ICRF	O
+-	O
+187	O
+was	O
+determined	O
+using	O
+a	O
+dose	O
+schedule	O
+with	O
+lower	O
+general	O
+toxicity	B-NP
+(	O
+6	O
+weekly	O
+doses	O
+of	O
+4	O
+mg	O
+/	O
+kg	O
+doxorubicin	O
+given	O
+i	O
+.	O
+v	O
+.	O
+plus	O
+2	O
+weeks	O
+of	O
+observation	O
+)	O
+.	O
+	
+On	O
+this	O
+schedule	O
+","	O
+the	O
+animals	O
+'	O
+hearts	O
+appeared	O
+normal	O
+after	O
+sacrifice	O
+and	O
+ICRF	O
+-	O
+187	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+given	O
+i	O
+.	O
+p	O
+.	O
+1	O
+h	O
+before	O
+doxorubicin	O
+)	O
+provided	O
+almost	O
+full	O
+protection	O
+.	O
+	
+These	O
+data	O
+were	O
+confirmed	O
+by	O
+histology	O
+.	O
+	
+The	O
+results	O
+indicate	O
+that	O
+this	O
+new	O
+model	O
+is	O
+very	O
+sensitive	O
+and	O
+enables	O
+monitoring	O
+of	O
+the	O
+development	O
+of	O
+cardiotoxicity	B-NP
+with	O
+time	O
+.	O
+	
+These	O
+findings	O
+result	O
+in	O
+a	O
+model	O
+that	O
+allows	O
+the	O
+testing	O
+of	O
+protectors	O
+against	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+as	O
+demonstrated	O
+by	O
+the	O
+protection	O
+provided	O
+by	O
+ICRF	O
+-	O
+187	O
+.	O
+	
+Epinephrine	O
+dysrhythmogenicity	O
+is	O
+not	O
+enhanced	O
+by	O
+subtoxic	O
+bupivacaine	O
+in	O
+dogs	O
+.	O
+	
+Since	O
+bupivacaine	O
+and	O
+epinephrine	O
+may	O
+both	O
+precipitate	O
+dysrhythmias	B-NP
+","	O
+circulating	O
+bupivacaine	O
+during	O
+regional	O
+anesthesia	O
+could	O
+potentiate	O
+dysrhythmogenic	O
+effects	O
+of	O
+epinephrine	O
+.	O
+	
+We	O
+therefore	O
+examined	O
+whether	O
+bupivacaine	O
+alters	O
+the	O
+dysrhythmogenicity	O
+of	O
+subsequent	O
+administration	O
+of	O
+epinephrine	O
+in	O
+conscious	O
+","	O
+healthy	O
+dogs	O
+and	O
+in	O
+anesthetized	O
+dogs	O
+with	O
+myocardial	B-NP
+infarction	I-NP
+.	O
+	
+Forty	O
+-	O
+one	O
+conscious	O
+dogs	O
+received	O
+10	O
+micrograms	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+epinephrine	O
+.	O
+	
+Seventeen	O
+animals	O
+responded	O
+with	O
+ventricular	B-NP
+tachycardia	I-NP
+(	O
+VT	B-NP
+)	O
+within	O
+3	O
+min	O
+.	O
+	
+After	O
+3	O
+h	O
+","	O
+these	O
+responders	O
+randomly	O
+received	O
+1	O
+or	O
+2	O
+mg	O
+/	O
+kg	O
+bupivacaine	O
+or	O
+saline	O
+over	O
+5	O
+min	O
+","	O
+followed	O
+by	O
+10	O
+micrograms	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+epinephrine	O
+.	O
+	
+In	O
+the	O
+bupivacaine	O
+groups	O
+","	O
+epinephrine	O
+caused	O
+fewer	O
+prodysrhythmic	O
+effects	O
+than	O
+without	O
+bupivacaine	O
+.	O
+	
+VT	B-NP
+appeared	O
+in	O
+fewer	O
+dogs	O
+and	O
+at	O
+a	O
+later	O
+time	O
+","	O
+and	O
+there	O
+were	O
+more	O
+sinoatrial	O
+beats	O
+and	O
+less	O
+ectopies	O
+.	O
+	
+Epinephrine	O
+shortened	O
+QT	O
+less	O
+after	O
+bupivacaine	O
+than	O
+in	O
+control	O
+animals	O
+.	O
+	
+One	O
+day	O
+after	O
+experimental	O
+myocardial	B-NP
+infarction	I-NP
+","	O
+six	O
+additional	O
+halothane	O
+-	O
+anesthetized	O
+dogs	O
+received	O
+4	O
+micrograms	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+epinephrine	O
+until	O
+VT	B-NP
+appeared	O
+.	O
+	
+After	O
+45	O
+min	O
+","	O
+1	O
+mg	O
+/	O
+kg	O
+bupivacaine	O
+was	O
+injected	O
+over	O
+5	O
+min	O
+","	O
+again	O
+followed	O
+by	O
+4	O
+micrograms	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+epinephrine	O
+.	O
+	
+In	O
+these	O
+dogs	O
+","	O
+the	O
+prodysrhythmic	O
+response	O
+to	O
+epinephrine	O
+was	O
+also	O
+mitigated	O
+by	O
+preceding	O
+bupivacaine	O
+.	O
+	
+Bupivacaine	O
+antagonizes	O
+epinephrine	O
+dysrhythmogenicity	O
+in	O
+conscious	O
+dogs	O
+susceptible	O
+to	O
+VT	B-NP
+and	O
+in	O
+anesthetized	O
+dogs	O
+with	O
+spontaneous	O
+postinfarct	O
+dysrhythmias	B-NP
+.	O
+	
+There	O
+is	O
+no	O
+evidence	O
+that	O
+systemic	O
+subtoxic	O
+bupivacaine	O
+administration	O
+enhances	O
+the	O
+dysrhythmogenicity	O
+of	O
+subsequent	O
+epinephrine	O
+.	O
+	
+Milk	B-NP
+-	I-NP
+alkali	I-NP
+syndrome	I-NP
+induced	O
+by	O
+1	O
+","	O
+25	O
+(	O
+OH	O
+)	O
+2D	O
+in	O
+a	O
+patient	O
+with	O
+hypoparathyroidism	B-NP
+.	O
+	
+Milk	B-NP
+-	I-NP
+alkali	I-NP
+syndrome	I-NP
+was	O
+first	O
+described	O
+70	O
+years	O
+ago	O
+in	O
+the	O
+context	O
+of	O
+the	O
+treatment	O
+of	O
+peptic	B-NP
+ulcer	I-NP
+disease	I-NP
+with	O
+large	O
+amounts	O
+of	O
+calcium	O
+and	O
+alkali	O
+.	O
+	
+Although	O
+with	O
+current	O
+ulcer	B-NP
+therapy	O
+(	O
+H	O
+-	O
+2	O
+blockers	O
+","	O
+omeprazole	O
+","	O
+and	O
+sucralfate	O
+)	O
+","	O
+the	O
+frequency	O
+of	O
+milk	B-NP
+-	I-NP
+alkali	I-NP
+syndrome	I-NP
+has	O
+decreased	O
+significantly	O
+","	O
+the	O
+classic	O
+triad	O
+of	O
+hypercalcemia	B-NP
+","	O
+alkalosis	B-NP
+","	O
+and	O
+renal	B-NP
+impairment	I-NP
+remains	O
+the	O
+hallmark	O
+of	O
+the	O
+syndrome	O
+.	O
+	
+Milk	B-NP
+-	I-NP
+alkali	I-NP
+syndrome	I-NP
+can	O
+present	O
+serious	O
+and	O
+occasionally	O
+life	O
+-	O
+threatening	O
+illness	O
+unless	O
+diagnosed	O
+and	O
+treated	O
+appropriately	O
+.	O
+	
+This	O
+article	O
+presents	O
+a	O
+patient	O
+with	O
+hypoparathyroidism	B-NP
+who	O
+was	O
+treated	O
+with	O
+calcium	O
+carbonate	O
+and	O
+calcitriol	O
+resulting	O
+in	O
+two	O
+admissions	O
+to	O
+the	O
+hospital	O
+for	O
+milk	B-NP
+-	I-NP
+alkali	I-NP
+syndrome	I-NP
+.	O
+	
+The	O
+patient	O
+was	O
+successfully	O
+treated	O
+with	O
+intravenous	O
+pamidronate	O
+on	O
+his	O
+first	O
+admission	O
+and	O
+with	O
+hydrocortisone	O
+on	O
+the	O
+second	O
+.	O
+	
+This	O
+illustrates	O
+intravenous	O
+pamidronate	O
+as	O
+a	O
+valuable	O
+therapeutic	O
+tool	O
+when	O
+milk	B-NP
+-	I-NP
+alkali	I-NP
+syndrome	I-NP
+presents	O
+as	O
+hypercalcemic	B-NP
+emergency	I-NP
+.	O
+	
+Famotidine	O
+-	O
+associated	O
+delirium	B-NP
+.	O
+	
+A	O
+series	O
+of	O
+six	O
+cases	O
+.	O
+	
+Famotidine	O
+is	O
+a	O
+histamine	O
+H2	O
+-	O
+receptor	O
+antagonist	O
+used	O
+in	O
+inpatient	O
+settings	O
+for	O
+prevention	O
+of	O
+stress	O
+ulcers	B-NP
+and	O
+is	O
+showing	O
+increasing	O
+popularity	O
+because	O
+of	O
+its	O
+low	O
+cost	O
+.	O
+	
+Although	O
+all	O
+of	O
+the	O
+currently	O
+available	O
+H2	O
+-	O
+receptor	O
+antagonists	O
+have	O
+shown	O
+the	O
+propensity	O
+to	O
+cause	O
+delirium	B-NP
+","	O
+only	O
+two	O
+previously	O
+reported	O
+cases	O
+have	O
+been	O
+associated	O
+with	O
+famotidine	O
+.	O
+	
+The	O
+authors	O
+report	O
+on	O
+six	O
+cases	O
+of	O
+famotidine	O
+-	O
+associated	O
+delirium	B-NP
+in	O
+hospitalized	O
+patients	O
+who	O
+cleared	O
+completely	O
+upon	O
+removal	O
+of	O
+famotidine	O
+.	O
+	
+The	O
+pharmacokinetics	O
+of	O
+famotidine	O
+are	O
+reviewed	O
+","	O
+with	O
+no	O
+change	O
+in	O
+its	O
+metabolism	O
+in	O
+the	O
+elderly	O
+population	O
+seen	O
+.	O
+	
+The	O
+implications	O
+of	O
+using	O
+famotidine	O
+in	O
+elderly	O
+persons	O
+are	O
+discussed	O
+.	O
+	
+Encephalopathy	B-NP
+during	O
+amitriptyline	O
+therapy	O
+:	O
+are	O
+neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+and	O
+serotonin	B-NP
+syndrome	I-NP
+spectrum	O
+disorders	O
+?	O
+	
+This	O
+report	O
+describes	O
+a	O
+case	O
+of	O
+encephalopathy	B-NP
+developed	O
+in	O
+the	O
+course	O
+of	O
+amitriptyline	O
+therapy	O
+","	O
+during	O
+a	O
+remission	O
+of	O
+unipolar	B-NP
+depression	I-NP
+.	O
+	
+This	O
+patient	O
+could	O
+have	O
+been	O
+diagnosed	O
+as	O
+having	O
+either	O
+neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+(	O
+NMS	B-NP
+)	O
+or	O
+serotonin	B-NP
+syndrome	I-NP
+(	O
+SS	B-NP
+)	O
+.	O
+	
+The	O
+major	O
+determinant	O
+of	O
+the	O
+symptoms	O
+may	O
+have	O
+been	O
+dopamine	O
+/	O
+serotonin	O
+imbalance	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+.	O
+	
+The	O
+NMS	B-NP
+-	O
+like	O
+encephalopathy	B-NP
+that	O
+develops	O
+in	O
+association	O
+with	O
+the	O
+use	O
+of	O
+antidepressants	O
+indicates	O
+that	O
+NMS	B-NP
+and	O
+SS	B-NP
+are	O
+spectrum	O
+disorders	O
+induced	O
+by	O
+drugs	O
+with	O
+both	O
+antidopaminergic	O
+and	O
+serotonergic	O
+effects	O
+.	O
+	
+Genetic	O
+separation	O
+of	O
+tumor	B-NP
+growth	O
+and	O
+hemorrhagic	B-NP
+phenotypes	O
+in	O
+an	O
+estrogen	O
+-	O
+induced	O
+tumor	B-NP
+.	O
+	
+Chronic	O
+administration	O
+of	O
+estrogen	O
+to	O
+the	O
+Fischer	O
+344	O
+(	O
+F344	O
+)	O
+rat	O
+induces	O
+growth	O
+of	O
+large	O
+","	O
+hemorrhagic	B-NP
+pituitary	B-NP
+tumors	I-NP
+.	O
+	
+Ten	O
+weeks	O
+of	O
+diethylstilbestrol	O
+(	O
+DES	O
+)	O
+treatment	O
+caused	O
+female	O
+F344	O
+rat	O
+pituitaries	O
+to	O
+grow	O
+to	O
+an	O
+average	O
+of	O
+109	O
+.	O
+2	O
++	O
+/	O
+-	O
+6	O
+.	O
+3	O
+mg	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SE	O
+)	O
+versus	O
+11	O
+.	O
+3	O
++	O
+/	O
+-	O
+1	O
+.	O
+4	O
+mg	O
+for	O
+untreated	O
+rats	O
+","	O
+and	O
+to	O
+become	O
+highly	O
+hemorrhagic	B-NP
+.	O
+	
+The	O
+same	O
+DES	O
+treatment	O
+produced	O
+no	O
+significant	O
+growth	O
+(	O
+8	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+mg	O
+for	O
+treated	O
+females	O
+versus	O
+8	O
+.	O
+7	O
++	O
+/	O
+-	O
+1	O
+.	O
+1	O
+for	O
+untreated	O
+females	O
+)	O
+or	O
+morphological	O
+changes	O
+in	O
+Brown	O
+Norway	O
+(	O
+BN	O
+)	O
+rat	O
+pituitaries	O
+.	O
+	
+An	O
+F1	O
+hybrid	O
+of	O
+F344	O
+and	O
+BN	O
+exhibited	O
+significant	O
+pituitary	O
+growth	O
+after	O
+10	O
+weeks	O
+of	O
+DES	O
+treatment	O
+with	O
+an	O
+average	O
+mass	O
+of	O
+26	O
+.	O
+3	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+mg	O
+compared	O
+with	O
+8	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+9	O
+mg	O
+for	O
+untreated	O
+rats	O
+.	O
+	
+Surprisingly	O
+","	O
+the	O
+F1	O
+hybrid	O
+tumors	B-NP
+were	O
+not	O
+hemorrhagic	B-NP
+and	O
+had	O
+hemoglobin	O
+content	O
+and	O
+outward	O
+appearance	O
+identical	O
+to	O
+that	O
+of	O
+BN	O
+.	O
+	
+Expression	O
+of	O
+both	O
+growth	O
+and	O
+morphological	O
+changes	O
+is	O
+due	O
+to	O
+multiple	O
+genes	O
+.	O
+	
+However	O
+","	O
+while	O
+DES	O
+-	O
+induced	O
+pituitary	O
+growth	O
+exhibited	O
+quantitative	O
+","	O
+additive	O
+inheritance	O
+","	O
+the	O
+hemorrhagic	B-NP
+phenotype	O
+exhibited	O
+recessive	O
+","	O
+epistatic	O
+inheritance	O
+.	O
+	
+Only	O
+5	O
+of	O
+the	O
+160	O
+F2	O
+pituitaries	O
+exhibited	O
+the	O
+hemorrhagic	B-NP
+phenotype	O
+;	O
+36	O
+of	O
+the	O
+160	O
+F2	O
+pituitaries	O
+were	O
+in	O
+the	O
+F344	O
+range	O
+of	O
+mass	O
+","	O
+but	O
+31	O
+of	O
+these	O
+were	O
+not	O
+hemorrhagic	B-NP
+","	O
+indicating	O
+that	O
+the	O
+hemorrhagic	B-NP
+phenotype	O
+is	O
+not	O
+merely	O
+a	O
+consequence	O
+of	O
+extensive	O
+growth	O
+.	O
+	
+The	O
+hemorrhagic	B-NP
+F2	O
+pituitaries	O
+were	O
+all	O
+among	O
+the	O
+most	O
+massive	O
+","	O
+indicating	O
+that	O
+some	O
+of	O
+the	O
+genes	O
+regulate	O
+both	O
+phenotypes	O
+.	O
+	
+Increased	O
+expression	O
+of	O
+neuronal	O
+nitric	O
+oxide	O
+synthase	O
+in	O
+bladder	O
+afferent	O
+pathways	O
+following	O
+chronic	O
+bladder	B-NP
+irritation	I-NP
+.	O
+	
+Immunocytochemical	O
+techniques	O
+were	O
+used	O
+to	O
+examine	O
+alterations	O
+in	O
+the	O
+expression	O
+of	O
+neuronal	O
+nitric	O
+oxide	O
+synthase	O
+(	O
+NOS	O
+)	O
+in	O
+bladder	O
+pathways	O
+following	O
+acute	O
+and	O
+chronic	O
+irritation	B-NP
+of	I-NP
+the	I-NP
+urinary	I-NP
+tract	I-NP
+of	O
+the	O
+rat	O
+.	O
+	
+Chemical	O
+cystitis	B-NP
+was	O
+induced	O
+by	O
+cyclophosphamide	O
+(	O
+CYP	O
+)	O
+which	O
+is	O
+metabolized	O
+to	O
+acrolein	O
+","	O
+an	O
+irritant	O
+eliminated	O
+in	O
+the	O
+urine	O
+.	O
+	
+Injection	O
+of	O
+CYP	O
+(	O
+n	O
+=	O
+10	O
+","	O
+75	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+p	O
+.	O
+)	O
+2	O
+hours	O
+prior	O
+to	O
+perfusion	O
+(	O
+acute	O
+treatment	O
+)	O
+of	O
+the	O
+animals	O
+increased	O
+Fos	O
+-	O
+immunoreactivity	O
+(	O
+IR	O
+)	O
+in	O
+neurons	O
+in	O
+the	O
+dorsal	O
+commissure	O
+","	O
+dorsal	O
+horn	O
+","	O
+and	O
+autonomic	O
+regions	O
+of	O
+spinal	O
+segments	O
+(	O
+L1	O
+-	O
+L2	O
+and	O
+L6	O
+-	O
+S1	O
+)	O
+which	O
+receive	O
+afferent	O
+inputs	O
+from	O
+the	O
+bladder	O
+","	O
+urethra	O
+","	O
+and	O
+ureter	O
+.	O
+	
+Fos	O
+-	O
+IR	O
+in	O
+the	O
+spinal	O
+cord	O
+was	O
+not	O
+changed	O
+in	O
+rats	O
+receiving	O
+chronic	O
+CYP	O
+treatment	O
+(	O
+n	O
+=	O
+15	O
+","	O
+75	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+p	O
+.	O
+","	O
+every	O
+3rd	O
+day	O
+for	O
+2	O
+weeks	O
+)	O
+.	O
+	
+In	O
+control	O
+animals	O
+and	O
+in	O
+animals	O
+treated	O
+acutely	O
+with	O
+CYP	O
+","	O
+only	O
+small	O
+numbers	O
+of	O
+NOS	O
+-	O
+IR	O
+cells	O
+(	O
+0	O
+.	O
+5	O
+-	O
+0	O
+.	O
+7	O
+cell	O
+profiles	O
+/	O
+sections	O
+)	O
+were	O
+detected	O
+in	O
+the	O
+L6	O
+-	O
+S1	O
+dorsal	O
+root	O
+ganglia	O
+(	O
+DRG	O
+)	O
+.	O
+	
+Chronic	O
+CYP	O
+administration	O
+significantly	O
+(	O
+P	O
+<	O
+or	O
+=	O
+.	O
+2	O
+)	O
+increased	O
+bladder	O
+weight	O
+by	O
+60	O
+%	O
+and	O
+increased	O
+(	O
+7	O
+-	O
+to	O
+11	O
+-	O
+fold	O
+)	O
+the	O
+numbers	O
+of	O
+NOS	O
+-	O
+immunoreactive	O
+(	O
+IR	O
+)	O
+afferent	O
+neurons	O
+in	O
+the	O
+L6	O
+-	O
+S1	O
+DRG	O
+.	O
+	
+A	O
+small	O
+increase	O
+(	O
+1	O
+.	O
+5	O
+-	O
+fold	O
+)	O
+also	O
+occurred	O
+in	O
+the	O
+L1	O
+DRG	O
+","	O
+but	O
+no	O
+change	O
+was	O
+detected	O
+in	O
+the	O
+L2	O
+and	O
+L5	O
+DRG	O
+.	O
+	
+Bladder	O
+afferent	O
+cells	O
+in	O
+the	O
+L6	O
+-	O
+S1	O
+DRG	O
+labeled	O
+by	O
+Fluorogold	O
+(	O
+40	O
+microliters	O
+)	O
+injected	O
+into	O
+the	O
+bladder	O
+wall	O
+did	O
+not	O
+exhibit	O
+NOS	O
+-	O
+IR	O
+in	O
+control	O
+animals	O
+;	O
+however	O
+","	O
+following	O
+chronic	O
+CYP	O
+administration	O
+","	O
+a	O
+significant	O
+percentage	O
+of	O
+bladder	O
+afferent	O
+neurons	O
+were	O
+NOS	O
+-	O
+IR	O
+:	O
+L6	O
+(	O
+19	O
+.	O
+8	O
++	O
+/	O
+-	O
+4	O
+.	O
+6	O
+%	O
+)	O
+and	O
+S1	O
+(	O
+25	O
+.	O
+3	O
++	O
+/	O
+-	O
+2	O
+.	O
+9	O
+%	O
+)	O
+.	O
+	
+These	O
+results	O
+indicate	O
+that	O
+neuronal	O
+gene	O
+expression	O
+in	O
+visceral	O
+sensory	O
+pathways	O
+can	O
+be	O
+upregulated	O
+by	O
+chemical	O
+irritation	O
+of	O
+afferent	O
+receptors	O
+in	O
+the	O
+urinary	O
+tract	O
+and	O
+/	O
+or	O
+that	O
+pathological	O
+changes	O
+in	O
+the	O
+urinary	O
+tract	O
+can	O
+initiate	O
+chemical	O
+signals	O
+that	O
+alter	O
+the	O
+chemical	O
+properties	O
+of	O
+visceral	O
+afferent	O
+neurons	O
+.	O
+	
+Effects	O
+of	O
+a	O
+new	O
+calcium	O
+antagonist	O
+","	O
+CD	O
+-	O
+832	O
+","	O
+on	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B-NP
+ischemia	I-NP
+in	O
+dogs	O
+with	O
+partial	O
+coronary	B-NP
+stenosis	I-NP
+.	O
+	
+Effects	O
+of	O
+CD	O
+-	O
+832	O
+on	O
+isoproterenol	O
+(	O
+ISO	O
+)	O
+-	O
+induced	O
+myocardial	B-NP
+ischemia	I-NP
+were	O
+studied	O
+in	O
+dogs	O
+with	O
+partial	O
+coronary	B-NP
+stenosis	I-NP
+of	O
+the	O
+left	O
+circumflex	O
+coronary	O
+artery	O
+and	O
+findings	O
+were	O
+compared	O
+with	O
+those	O
+for	O
+nifedipine	O
+or	O
+diltiazem	O
+.	O
+	
+In	O
+the	O
+presence	O
+of	O
+coronary	B-NP
+artery	I-NP
+stenosis	I-NP
+","	O
+3	O
+-	O
+min	O
+periods	O
+of	O
+intracoronary	O
+ISO	O
+infusion	O
+(	O
+10	O
+ng	O
+/	O
+kg	O
+/	O
+min	O
+)	O
+increased	O
+heart	O
+rate	O
+and	O
+maximal	O
+rate	O
+of	O
+left	O
+ventricular	O
+pressure	O
+rise	O
+","	O
+which	O
+resulted	O
+in	O
+a	O
+decrease	O
+in	O
+percentage	O
+segmental	O
+shortening	O
+and	O
+ST	O
+-	O
+segment	O
+elevation	O
+of	O
+the	O
+epicardial	O
+electrocardiogram	O
+.	O
+	
+After	O
+the	O
+control	O
+ISO	O
+infusion	O
+with	O
+stenosis	B-NP
+was	O
+performed	O
+","	O
+equihypotensive	O
+doses	O
+of	O
+CD	O
+-	O
+832	O
+(	O
+3	O
+and	O
+10	O
+micrograms	O
+/	O
+kg	O
+/	O
+min	O
+","	O
+n	O
+=	O
+7	O
+)	O
+","	O
+nifedipine	O
+(	O
+1	O
+and	O
+3	O
+micrograms	O
+/	O
+kg	O
+/	O
+min	O
+","	O
+n	O
+=	O
+9	O
+)	O
+or	O
+diltiazem	O
+(	O
+10	O
+and	O
+30	O
+micrograms	O
+/	O
+kg	O
+/	O
+min	O
+","	O
+n	O
+=	O
+7	O
+)	O
+were	O
+infused	O
+5	O
+min	O
+before	O
+and	O
+during	O
+the	O
+second	O
+and	O
+third	O
+ISO	O
+infusion	O
+.	O
+	
+Both	O
+CD	O
+-	O
+832	O
+and	O
+diltiazem	O
+","	O
+but	O
+not	O
+nifedipine	O
+","	O
+significantly	O
+reduced	O
+the	O
+increase	O
+in	O
+heart	O
+rate	O
+induced	O
+by	O
+ISO	O
+infusion	O
+.	O
+	
+In	O
+contrast	O
+to	O
+nifedipine	O
+","	O
+CD	O
+-	O
+832	O
+(	O
+10	O
+micrograms	O
+/	O
+kg	O
+/	O
+min	O
+)	O
+prevented	O
+the	O
+decrease	O
+in	O
+percentage	O
+segmental	O
+shortening	O
+from	O
+32	O
++	O
+/	O
+-	O
+12	O
+%	O
+to	O
+115	O
++	O
+/	O
+-	O
+26	O
+%	O
+of	O
+the	O
+control	O
+value	O
+(	O
+P	O
+<	O
+.	O
+1	O
+)	O
+and	O
+ST	O
+-	O
+segment	O
+elevation	O
+from	O
+5	O
+.	O
+6	O
++	O
+/	O
+-	O
+1	O
+.	O
+0	O
+mV	O
+to	O
+1	O
+.	O
+6	O
++	O
+/	O
+-	O
+1	O
+.	O
+3	O
+mV	O
+(	O
+P	O
+<	O
+.	O
+1	O
+)	O
+at	O
+3	O
+min	O
+after	O
+ISO	O
+infusion	O
+with	O
+stenosis	B-NP
+.	O
+	
+Diltiazem	O
+(	O
+30	O
+micrograms	O
+/	O
+kg	O
+/	O
+min	O
+)	O
+also	O
+prevented	O
+the	O
+decrease	O
+in	O
+percentage	O
+segmental	O
+shortening	O
+from	O
+34	O
++	O
+/	O
+-	O
+14	O
+%	O
+to	O
+63	O
++	O
+/	O
+-	O
+18	O
+%	O
+of	O
+the	O
+control	O
+value	O
+(	O
+P	O
+<	O
+.	O
+5	O
+)	O
+and	O
+ST	O
+-	O
+segment	O
+elevation	O
+from	O
+4	O
+.	O
+7	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+mV	O
+to	O
+2	O
+.	O
+1	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+mV	O
+(	O
+P	O
+<	O
+.	O
+1	O
+)	O
+at	O
+3	O
+min	O
+after	O
+ISO	O
+infusion	O
+with	O
+stenosis	B-NP
+.	O
+	
+These	O
+data	O
+show	O
+that	O
+CD	O
+-	O
+832	O
+improves	O
+myocardial	B-NP
+ischemia	I-NP
+during	O
+ISO	O
+infusion	O
+with	O
+stenosis	B-NP
+and	O
+suggest	O
+that	O
+the	O
+negative	O
+chronotropic	O
+property	O
+of	O
+CD	O
+-	O
+832	O
+plays	O
+a	O
+major	O
+role	O
+in	O
+the	O
+beneficial	O
+effects	O
+of	O
+CD	O
+-	O
+832	O
+.	O
+	
+The	O
+effect	O
+of	O
+recombinant	O
+human	O
+insulin	O
+-	O
+like	O
+growth	O
+factor	O
+-	O
+I	O
+on	O
+chronic	O
+puromycin	O
+aminonucleoside	O
+nephropathy	B-NP
+in	O
+rats	O
+.	O
+	
+We	O
+recently	O
+demonstrated	O
+that	O
+recombinant	O
+hGH	O
+exacerbates	O
+renal	O
+functional	O
+and	O
+structural	O
+injury	O
+in	O
+chronic	O
+puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+)	O
+nephropathy	B-NP
+","	O
+an	O
+experimental	O
+model	O
+of	O
+glomerular	B-NP
+disease	I-NP
+.	O
+	
+Therefore	O
+","	O
+we	O
+examined	O
+whether	O
+recombinant	O
+human	O
+(	O
+rh	O
+)	O
+IGF	O
+-	O
+I	O
+is	O
+a	O
+safer	O
+alternative	O
+for	O
+the	O
+treatment	O
+of	O
+growth	B-NP
+failure	I-NP
+in	O
+rats	O
+with	O
+chronic	O
+PAN	O
+nephropathy	B-NP
+.	O
+	
+The	O
+glomerulopathy	B-NP
+was	O
+induced	O
+by	O
+seven	O
+serial	O
+injections	O
+of	O
+PAN	O
+over	O
+12	O
+wk	O
+.	O
+	
+Experimental	O
+animals	O
+(	O
+n	O
+=	O
+6	O
+)	O
+received	O
+rhIGF	O
+-	O
+I	O
+","	O
+400	O
+micrograms	O
+/	O
+d	O
+","	O
+whereas	O
+control	O
+rats	O
+(	O
+n	O
+=	O
+6	O
+)	O
+received	O
+the	O
+vehicle	O
+.	O
+	
+rhIGF	O
+-	O
+I	O
+improved	O
+weight	O
+gain	O
+by	O
+14	O
+%	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+","	O
+without	O
+altering	O
+hematocrit	O
+or	O
+blood	O
+pressure	O
+in	O
+rats	O
+with	O
+renal	B-NP
+disease	I-NP
+.	O
+	
+Urinary	O
+protein	O
+excretion	O
+was	O
+unaltered	O
+by	O
+rhIGF	O
+-	O
+I	O
+treatment	O
+in	O
+rats	O
+with	O
+chronic	O
+PAN	O
+nephropathy	B-NP
+.	O
+	
+After	O
+12	O
+wk	O
+","	O
+the	O
+inulin	O
+clearance	O
+was	O
+higher	O
+in	O
+rhIGF	O
+-	O
+I	O
+-	O
+treated	O
+rats	O
+","	O
+0	O
+.	O
+48	O
++	O
+/	O
+-	O
+0	O
+.	O
+8	O
+versus	O
+0	O
+.	O
+24	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+mL	O
+/	O
+min	O
+/	O
+100	O
+g	O
+of	O
+body	O
+weight	O
+in	O
+untreated	O
+PAN	O
+nephropathy	B-NP
+animals	O
+","	O
+p	O
+<	O
+0	O
+.	O
+5	O
+.	O
+	
+The	O
+improvement	O
+in	O
+GFR	O
+was	O
+not	O
+associated	O
+with	O
+enhanced	O
+glomerular	B-NP
+hypertrophy	I-NP
+or	O
+increased	O
+segmental	O
+glomerulosclerosis	B-NP
+","	O
+tubulointerstitial	B-NP
+injury	I-NP
+","	O
+or	O
+renal	O
+cortical	O
+malondialdehyde	O
+content	O
+.	O
+	
+In	O
+rats	O
+with	O
+PAN	O
+nephropathy	B-NP
+","	O
+administration	O
+of	O
+rhIGF	O
+-	O
+I	O
+increased	O
+IGF	O
+-	O
+I	O
+and	O
+GH	O
+receptor	O
+gene	O
+expression	O
+","	O
+without	O
+altering	O
+the	O
+steady	O
+state	O
+level	O
+of	O
+IGF	O
+-	O
+I	O
+receptor	O
+mRNA	O
+.	O
+	
+In	O
+normal	O
+rats	O
+with	O
+intact	O
+kidneys	O
+","	O
+rhIGF	O
+-	O
+I	O
+administration	O
+(	O
+n	O
+=	O
+4	O
+)	O
+did	O
+not	O
+alter	O
+weight	O
+gain	O
+","	O
+blood	O
+pressure	O
+","	O
+proteinuria	B-NP
+","	O
+GFR	O
+","	O
+glomerular	O
+planar	O
+area	O
+","	O
+renal	O
+cortical	O
+malondialdehyde	O
+content	O
+","	O
+or	O
+glomerular	O
+or	O
+tubulointerstitial	B-NP
+damage	I-NP
+","	O
+compared	O
+with	O
+untreated	O
+animals	O
+(	O
+n	O
+=	O
+4	O
+)	O
+.	O
+	
+rhIGF	O
+-	O
+I	O
+treatment	O
+reduced	O
+the	O
+steady	O
+state	O
+renal	O
+IGF	O
+-	O
+I	O
+mRNA	O
+level	O
+but	O
+did	O
+not	O
+modify	O
+gene	O
+expression	O
+of	O
+the	O
+IGF	O
+-	O
+I	O
+or	O
+GH	O
+receptors	O
+.	O
+	
+We	O
+conclude	O
+that	O
+:	O
+1	O
+)	O
+administration	O
+of	O
+rhIGF	O
+-	O
+I	O
+improves	O
+growth	O
+and	O
+GFR	O
+in	O
+rats	O
+with	O
+chronic	O
+PAN	O
+nephropathy	B-NP
+and	O
+2	O
+)	O
+unlike	O
+rhGH	O
+","	O
+long	O
+-	O
+term	O
+use	O
+of	O
+rhIGF	O
+-	O
+I	O
+does	O
+not	O
+worsen	O
+renal	O
+functional	O
+and	O
+structural	O
+injury	O
+in	O
+this	O
+disease	O
+model	O
+.	O
+	
+Nefiracetam	O
+(	O
+DM	O
+-	O
+9384	O
+)	O
+reverses	O
+apomorphine	O
+-	O
+induced	O
+amnesia	B-NP
+of	O
+a	O
+passive	O
+avoidance	O
+response	O
+:	O
+delayed	O
+emergence	O
+of	O
+the	O
+memory	O
+retention	O
+effects	O
+.	O
+	
+Nefiracetam	O
+is	O
+a	O
+novel	O
+pyrrolidone	O
+derivative	O
+which	O
+attenuates	O
+scopolamine	O
+-	O
+induced	O
+learning	B-NP
+and	I-NP
+post	I-NP
+-	I-NP
+training	I-NP
+consolidation	I-NP
+deficits	I-NP
+.	O
+	
+Given	O
+that	O
+apomorphine	O
+inhibits	O
+passive	O
+avoidance	O
+retention	O
+when	O
+given	O
+during	O
+training	O
+or	O
+in	O
+a	O
+defined	O
+10	O
+-	O
+12h	O
+post	O
+-	O
+training	O
+period	O
+","	O
+we	O
+evaluated	O
+the	O
+ability	O
+of	O
+nefiracetam	O
+to	O
+attenuate	O
+amnesia	B-NP
+induced	O
+by	O
+dopaminergic	O
+agonism	O
+.	O
+	
+A	O
+step	O
+-	O
+down	O
+passive	O
+avoidance	O
+paradigm	O
+was	O
+employed	O
+and	O
+nefiracetam	O
+(	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+apomorphine	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+were	O
+given	O
+alone	O
+or	O
+in	O
+combination	O
+during	O
+training	O
+and	O
+at	O
+the	O
+10	O
+-	O
+12h	O
+post	O
+-	O
+training	O
+period	O
+of	O
+consolidation	O
+.	O
+	
+Co	O
+-	O
+administration	O
+of	O
+nefiracetam	O
+and	O
+apomorphine	O
+during	O
+training	O
+or	O
+10h	O
+thereafter	O
+produced	O
+no	O
+significant	O
+anti	O
+-	O
+amnesic	O
+effect	O
+.	O
+	
+However	O
+","	O
+administration	O
+of	O
+nefiracetam	O
+during	O
+training	O
+completely	O
+reversed	O
+the	O
+amnesia	B-NP
+induced	O
+by	O
+apomorphine	O
+at	O
+the	O
+10h	O
+post	O
+-	O
+training	O
+time	O
+and	O
+the	O
+converse	O
+was	O
+also	O
+TRUE	O
+.	O
+	
+These	O
+effects	O
+were	O
+not	O
+mediated	O
+by	O
+a	O
+dopaminergic	O
+mechanism	O
+as	O
+nefiracetam	O
+","	O
+at	O
+millimolar	O
+concentrations	O
+","	O
+failed	O
+to	O
+displace	O
+either	O
+[	O
+3H	O
+]	O
+SCH	O
+23390	O
+or	O
+[	O
+3H	O
+]	O
+spiperone	O
+binding	O
+from	O
+D1	O
+or	O
+D2	O
+dopamine	O
+receptor	O
+subtypes	O
+","	O
+respectively	O
+.	O
+	
+It	O
+is	O
+suggested	O
+that	O
+nefiracetam	O
+augments	O
+molecular	O
+processes	O
+in	O
+the	O
+early	O
+stages	O
+of	O
+events	O
+which	O
+ultimately	O
+lead	O
+to	O
+consolidation	O
+of	O
+memory	O
+.	O
+	
+Phenytoin	O
+encephalopathy	B-NP
+as	O
+probable	O
+idiosyncratic	O
+reaction	O
+:	O
+case	O
+report	O
+.	O
+	
+A	O
+case	O
+of	O
+phenytoin	O
+(	O
+DPH	O
+)	O
+encephalopathy	B-NP
+with	O
+increasing	O
+seizures	B-NP
+and	O
+EEG	O
+and	O
+mental	O
+changes	O
+is	O
+described	O
+.	O
+	
+Despite	O
+adequate	O
+oral	O
+dosage	O
+of	O
+DPH	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+/	O
+daily	O
+)	O
+the	O
+plasma	O
+level	O
+was	O
+very	O
+low	O
+(	O
+2	O
+.	O
+8	O
+microgramg	O
+/	O
+ml	O
+)	O
+.	O
+	
+The	O
+encephalopathy	B-NP
+was	O
+probably	O
+an	O
+idiosyncratic	O
+and	O
+not	O
+toxic	O
+or	O
+allergic	O
+reaction	O
+.	O
+	
+In	O
+fact	O
+the	O
+concentration	O
+of	O
+free	O
+DPH	O
+was	O
+normal	O
+","	O
+the	O
+patient	O
+presented	O
+a	O
+retarded	O
+morbilliform	O
+rash	B-NP
+during	O
+DPH	O
+treatment	O
+","	O
+the	O
+protidogram	O
+was	O
+normal	O
+","	O
+and	O
+an	O
+intradermic	O
+DPH	O
+injection	O
+had	O
+no	O
+local	O
+effect	O
+.	O
+	
+The	O
+authors	O
+conclude	O
+that	O
+in	O
+a	O
+patient	O
+starting	O
+DPH	O
+treatment	O
+an	O
+unexpected	O
+increase	O
+in	O
+seizures	B-NP
+","	O
+with	O
+EEG	O
+and	O
+mental	O
+changes	O
+occurring	O
+simultaneously	O
+","	O
+should	O
+alert	O
+the	O
+physician	O
+to	O
+the	O
+possible	O
+need	O
+for	O
+eliminating	O
+DPH	O
+from	O
+the	O
+therapeutic	O
+regimen	O
+","	O
+even	O
+if	O
+plasma	O
+concentrations	O
+are	O
+low	O
+.	O
+	
+Prevention	O
+and	O
+treatment	O
+of	O
+endometrial	B-NP
+disease	I-NP
+in	O
+climacteric	O
+women	O
+receiving	O
+oestrogen	O
+therapy	O
+.	O
+	
+The	O
+treatment	O
+regimens	O
+are	O
+described	O
+in	O
+74	O
+patients	O
+with	O
+endometrial	B-NP
+disease	I-NP
+among	O
+850	O
+climacteric	O
+women	O
+receiving	O
+oestrogen	O
+therapy	O
+.	O
+	
+Cystic	O
+hyperplasia	B-NP
+was	O
+associated	O
+with	O
+unopposed	O
+oestrogen	O
+therapy	O
+without	O
+progestagen	O
+.	O
+	
+Two	O
+courses	O
+of	O
+21	O
+days	O
+of	O
+5	O
+mg	O
+norethisterone	O
+daily	O
+caused	O
+reversion	O
+to	O
+normal	O
+in	O
+all	O
+57	O
+cases	O
+of	O
+cystic	O
+hyperplasia	B-NP
+and	O
+6	O
+of	O
+the	O
+8	O
+cases	O
+of	O
+atypical	O
+hyperplasia	B-NP
+.	O
+	
+4	O
+cases	O
+of	O
+endometrial	B-NP
+carcinoma	I-NP
+referred	O
+from	O
+elsewhere	O
+demonstrated	O
+the	O
+problems	O
+of	O
+inappropriate	O
+and	O
+unsupervised	O
+unopposed	O
+oestrogen	O
+therapy	O
+and	O
+the	O
+difficulty	O
+in	O
+distinguishing	O
+severe	O
+hyperplasia	B-NP
+from	O
+malignancy	B-NP
+.	O
+	
+Cyclical	O
+low	O
+-	O
+dose	O
+oestrogen	O
+therapy	O
+with	O
+7	O
+-	O
+-	O
+13	O
+days	O
+of	O
+progestagen	O
+does	O
+not	O
+seem	O
+to	O
+increase	O
+the	O
+risk	O
+of	O
+endometrial	B-NP
+hyperplasia	I-NP
+or	O
+carcinoma	B-NP
+.	O
+	
+Effects	O
+of	O
+exercise	O
+on	O
+the	O
+severity	O
+of	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B-NP
+infarction	I-NP
+.	O
+	
+The	O
+effect	O
+of	O
+exercise	O
+on	O
+the	O
+severity	O
+of	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B-NP
+infarction	I-NP
+was	O
+studied	O
+in	O
+male	O
+rats	O
+.	O
+	
+Ninety	O
+-	O
+three	O
+rats	O
+were	O
+randomly	O
+divided	O
+into	O
+three	O
+groups	O
+.	O
+	
+The	O
+exercise	O
+-	O
+isoproterenol	O
+(	O
+E	O
+-	O
+1	O
+)	O
+and	O
+exercise	O
+control	O
+(	O
+EC	O
+)	O
+groups	O
+exercised	O
+daily	O
+for	O
+thirty	O
+days	O
+on	O
+a	O
+treadmill	O
+at	O
+1	O
+mph	O
+","	O
+2	O
+%	O
+grade	O
+while	O
+animals	O
+of	O
+the	O
+sedentary	O
+-	O
+isoproterenol	O
+(	O
+S	O
+-	O
+I	O
+)	O
+group	O
+remained	O
+sedentary	O
+.	O
+	
+Eight	O
+animals	O
+were	O
+assigned	O
+to	O
+the	O
+sedentary	O
+control	O
+(	O
+SC	O
+)	O
+group	O
+which	O
+remained	O
+sedentary	O
+throughout	O
+the	O
+experimental	O
+period	O
+.	O
+	
+Forty	O
+-	O
+eight	O
+hours	O
+after	O
+the	O
+final	O
+exercise	O
+period	O
+","	O
+S	O
+-	O
+I	O
+and	O
+E	O
+-	O
+I	O
+animals	O
+received	O
+a	O
+single	O
+subcutaneous	O
+injection	O
+of	O
+isoproterenol	O
+(	O
+250	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+)	O
+.	O
+	
+Animals	O
+of	O
+the	O
+S	O
+-	O
+I	O
+group	O
+exhibited	O
+significantly	O
+(	O
+Pp	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+greater	O
+mortality	O
+from	O
+the	O
+effects	O
+of	O
+isoproterenol	O
+than	O
+animals	O
+of	O
+the	O
+E	O
+-	O
+I	O
+group	O
+.	O
+	
+Serum	O
+CPK	O
+activity	O
+for	O
+E	O
+-	O
+I	O
+animals	O
+was	O
+significantly	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+greater	O
+than	O
+for	O
+animals	O
+in	O
+the	O
+S	O
+-	O
+I	O
+and	O
+EC	O
+groups	O
+twenty	O
+hours	O
+following	O
+isoproterenol	O
+injection	O
+.	O
+	
+No	O
+statistically	O
+significant	O
+differences	O
+were	O
+observed	O
+between	O
+the	O
+two	O
+isoproterenol	O
+treated	O
+groups	O
+for	O
+severity	O
+of	O
+the	O
+induced	O
+lesions	O
+","	O
+changes	O
+in	O
+heart	O
+weight	O
+","	O
+or	O
+heart	O
+weight	O
+to	O
+body	O
+weight	O
+ratios	O
+.	O
+	
+The	O
+results	O
+indicated	O
+that	O
+exercise	O
+reduced	O
+the	O
+mortality	O
+associated	O
+with	O
+the	O
+effects	O
+of	O
+large	O
+dosages	O
+of	O
+isoproterenol	O
+but	O
+had	O
+little	O
+on	O
+the	O
+severity	O
+of	O
+the	O
+infarction	B-NP
+.	O
+	
+Human	O
+corticotropin	O
+-	O
+releasing	O
+hormone	O
+and	O
+thyrotropin	O
+-	O
+releasing	O
+hormone	O
+modulate	O
+the	O
+hypercapnic	B-NP
+ventilatory	O
+response	O
+in	O
+humans	O
+.	O
+	
+Human	O
+corticotropin	O
+-	O
+releasing	O
+hormone	O
+(	O
+hCRH	O
+)	O
+and	O
+thyrotropin	O
+-	O
+releasing	O
+hormone	O
+(	O
+TRH	O
+)	O
+are	O
+known	O
+to	O
+stimulate	O
+ventilation	O
+after	O
+i	O
+.	O
+v	O
+.	O
+administration	O
+in	O
+humans	O
+.	O
+	
+In	O
+a	O
+placebo	O
+-	O
+controlled	O
+","	O
+single	O
+-	O
+blind	O
+study	O
+we	O
+aimed	O
+to	O
+clarify	O
+if	O
+both	O
+peptides	O
+act	O
+by	O
+altering	O
+central	O
+chemosensitivity	O
+.	O
+	
+Two	O
+subsequent	O
+CO2	O
+-	O
+rebreathing	O
+tests	O
+were	O
+performed	O
+in	O
+healthy	O
+young	O
+volunteers	O
+.	O
+	
+During	O
+the	O
+first	O
+test	O
+0	O
+.	O
+9	O
+%	O
+NaCl	O
+was	O
+given	O
+i	O
+.	O
+v	O
+.	O
+;	O
+during	O
+the	O
+second	O
+test	O
+200	O
+micrograms	O
+of	O
+hCRH	O
+(	O
+n	O
+=	O
+12	O
+)	O
+or	O
+400	O
+micrograms	O
+of	O
+TRH	O
+(	O
+n	O
+=	O
+6	O
+)	O
+was	O
+administered	O
+i	O
+.	O
+v	O
+.	O
+Nine	O
+subjects	O
+received	O
+0	O
+.	O
+9	O
+%	O
+NaCl	O
+i	O
+.	O
+v	O
+.	O
+during	O
+both	O
+rebreathing	O
+manoeuvres	O
+.	O
+	
+The	O
+CO2	O
+-	O
+response	O
+curves	O
+for	O
+the	O
+two	O
+tests	O
+were	O
+compared	O
+within	O
+the	O
+same	O
+subject	O
+.	O
+	
+In	O
+the	O
+hCRH	O
+group	O
+a	O
+marked	O
+parallel	O
+shift	O
+of	O
+the	O
+CO2	O
+-	O
+response	O
+curve	O
+to	O
+the	O
+left	O
+was	O
+observed	O
+after	O
+hCRH	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+The	O
+same	O
+effect	O
+occurred	O
+following	O
+TRH	O
+but	O
+was	O
+less	O
+striking	O
+(	O
+P	O
+=	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+hCRH	O
+and	O
+TRH	O
+caused	O
+a	O
+reduction	O
+in	O
+the	O
+CO2	O
+threshold	O
+.	O
+	
+The	O
+CO2	O
+-	O
+response	O
+curves	O
+in	O
+the	O
+control	O
+group	O
+were	O
+nearly	O
+identical	O
+.	O
+	
+The	O
+results	O
+indicate	O
+an	O
+additive	O
+effect	O
+of	O
+both	O
+releasing	O
+hormones	O
+on	O
+the	O
+hypercapnic	B-NP
+ventilatory	O
+response	O
+in	O
+humans	O
+","	O
+presumably	O
+independent	O
+of	O
+central	O
+chemosensitivity	O
+.	O
+	
+Lamivudine	O
+is	O
+effective	O
+in	O
+suppressing	O
+hepatitis	B-NP
+B	I-NP
+virus	O
+DNA	O
+in	O
+Chinese	O
+hepatitis	O
+B	O
+surface	O
+antigen	O
+carriers	O
+:	O
+a	O
+placebo	O
+-	O
+controlled	O
+trial	O
+.	O
+	
+Lamivudine	O
+is	O
+a	O
+novel	O
+2	O
+'	O
+","	O
+3	O
+'	O
+-	O
+dideoxy	O
+cytosine	O
+analogue	O
+that	O
+has	O
+potent	O
+inhibitory	O
+effects	O
+on	O
+hepatitis	B-NP
+B	I-NP
+virus	O
+replication	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+.	O
+	
+We	O
+performed	O
+a	O
+single	O
+-	O
+blind	O
+","	O
+placebo	O
+-	O
+controlled	O
+study	O
+to	O
+assess	O
+its	O
+effectiveness	O
+and	O
+safety	O
+in	O
+Chinese	O
+hepatitis	O
+B	O
+surface	O
+antigen	O
+(	O
+HBsAg	O
+)	O
+carriers	O
+.	O
+	
+Forty	O
+-	O
+two	O
+Chinese	O
+HBsAg	O
+carriers	O
+were	O
+randomized	O
+to	O
+receive	O
+placebo	O
+(	O
+6	O
+patients	O
+)	O
+or	O
+lamivudine	O
+orally	O
+in	O
+dosages	O
+of	O
+25	O
+mg	O
+","	O
+100	O
+mg	O
+","	O
+or	O
+300	O
+mg	O
+daily	O
+(	O
+12	O
+patients	O
+for	O
+each	O
+dosage	O
+)	O
+.	O
+	
+The	O
+drug	O
+was	O
+given	O
+for	O
+4	O
+weeks	O
+.	O
+	
+The	O
+patients	O
+were	O
+closely	O
+monitored	O
+clinically	O
+","	O
+biochemically	O
+","	O
+and	O
+serologically	O
+up	O
+to	O
+4	O
+weeks	O
+after	O
+drug	O
+treatment	O
+.	O
+	
+All	O
+36	O
+patients	O
+receiving	O
+lamivudine	O
+had	O
+a	O
+decrease	O
+in	O
+hepatitis	B-NP
+B	I-NP
+virus	O
+(	O
+HBV	O
+)	O
+DNA	O
+values	O
+of	O
+>	O
+90	O
+%	O
+(	O
+P	O
+<	O
+.	O
+1	O
+compared	O
+with	O
+placebo	O
+)	O
+.	O
+	
+Although	O
+25	O
+mg	O
+of	O
+lamivudine	O
+was	O
+slightly	O
+less	O
+effective	O
+than	O
+100	O
+mg	O
+(	O
+P	O
+=	O
+.	O
+11	O
+)	O
+and	O
+300	O
+mg	O
+(	O
+P	O
+=	O
+.	O
+5	O
+)	O
+","	O
+it	O
+still	O
+induced	O
+94	O
+%	O
+suppression	O
+of	O
+HBV	O
+DNA	O
+after	O
+the	O
+fourth	O
+week	O
+of	O
+therapy	O
+.	O
+	
+HBV	O
+DNA	O
+values	O
+returned	O
+to	O
+pretreatment	O
+levels	O
+within	O
+4	O
+weeks	O
+of	O
+cessation	O
+of	O
+therapy	O
+.	O
+	
+There	O
+was	O
+no	O
+change	O
+in	O
+the	O
+hepatitis	B-NP
+B	I-NP
+e	O
+antigen	O
+status	O
+or	O
+in	O
+aminotransferase	O
+levels	O
+.	O
+	
+No	O
+serious	O
+adverse	O
+events	O
+were	O
+observed	O
+.	O
+	
+In	O
+conclusion	O
+","	O
+a	O
+4	O
+-	O
+week	O
+course	O
+of	O
+lamivudine	O
+was	O
+safe	O
+and	O
+effective	O
+in	O
+suppression	O
+of	O
+HBV	O
+DNA	O
+in	O
+Chinese	O
+HBsAg	O
+carriers	O
+.	O
+	
+The	O
+suppression	O
+was	O
+>	O
+90	O
+%	O
+but	O
+reversible	O
+.	O
+	
+Studies	O
+with	O
+long	O
+-	O
+term	O
+lamivudine	O
+administration	O
+should	O
+be	O
+performed	O
+to	O
+determine	O
+if	O
+prolonged	O
+suppression	O
+of	O
+HBV	O
+DNA	O
+can	O
+be	O
+achieved	O
+.	O
+	
+Population	O
+-	O
+based	O
+study	O
+of	O
+risk	O
+of	O
+venous	B-NP
+thromboembolism	I-NP
+associated	O
+with	O
+various	O
+oral	O
+contraceptives	O
+.	O
+	
+BACKGROUND	O
+:	O
+Four	O
+studies	O
+published	O
+since	O
+December	O
+","	O
+1995	O
+","	O
+reported	O
+that	O
+the	O
+incidence	O
+of	O
+venous	B-NP
+thromboembolism	I-NP
+(	O
+VTE	B-NP
+)	O
+was	O
+higher	O
+in	O
+women	O
+who	O
+used	O
+oral	O
+contraceptives	O
+(	O
+OCs	O
+)	O
+containing	O
+the	O
+third	O
+-	O
+generation	O
+progestagens	O
+gestodene	O
+or	O
+desogestrel	O
+than	O
+in	O
+users	O
+of	O
+OCs	O
+containing	O
+second	O
+-	O
+generation	O
+progestagens	O
+.	O
+	
+However	O
+","	O
+confounding	O
+and	O
+bias	O
+in	O
+the	O
+design	O
+of	O
+these	O
+studies	O
+may	O
+have	O
+affected	O
+the	O
+findings	O
+.	O
+	
+The	O
+aim	O
+of	O
+our	O
+study	O
+was	O
+to	O
+re	O
+-	O
+examine	O
+the	O
+association	O
+between	O
+risk	O
+of	O
+VTE	B-NP
+and	O
+OC	O
+use	O
+with	O
+a	O
+different	O
+study	O
+design	O
+and	O
+analysis	O
+to	O
+avoid	O
+some	O
+of	O
+the	O
+bias	O
+and	O
+confounding	O
+of	O
+the	O
+earlier	O
+studies	O
+.	O
+	
+METHODS	O
+:	O
+We	O
+used	O
+computer	O
+records	O
+of	O
+patients	O
+from	O
+143	O
+general	O
+practices	O
+in	O
+the	O
+UK	O
+.	O
+	
+The	O
+study	O
+was	O
+based	O
+on	O
+the	O
+medical	O
+records	O
+of	O
+about	O
+540	O
+","	O
+0	O
+women	O
+born	O
+between	O
+1941	O
+and	O
+1981	O
+.	O
+	
+All	O
+women	O
+who	O
+had	O
+a	O
+recorded	O
+diagnosis	O
+of	O
+deep	B-NP
+-	I-NP
+vein	I-NP
+thrombosis	I-NP
+","	O
+venous	B-NP
+thrombosis	I-NP
+not	O
+otherwise	O
+specified	O
+","	O
+or	O
+pulmonary	O
+embolus	O
+during	O
+the	O
+study	O
+period	O
+","	O
+and	O
+who	O
+had	O
+been	O
+treated	O
+with	O
+an	O
+anticoagulant	O
+were	O
+identified	O
+as	O
+potential	O
+cases	O
+of	O
+VTE	B-NP
+.	O
+	
+We	O
+did	O
+a	O
+cohort	O
+analysis	O
+to	O
+estimate	O
+and	O
+compare	O
+incidence	O
+of	O
+VTE	B-NP
+in	O
+users	O
+of	O
+the	O
+main	O
+OC	O
+preparations	O
+","	O
+and	O
+a	O
+nested	O
+case	O
+-	O
+control	O
+study	O
+to	O
+calculate	O
+the	O
+odds	O
+ratios	O
+of	O
+VTE	B-NP
+associated	O
+with	O
+use	O
+of	O
+different	O
+types	O
+of	O
+OC	O
+","	O
+after	O
+adjustment	O
+for	O
+potential	O
+confounding	O
+factors	O
+.	O
+	
+In	O
+the	O
+case	O
+-	O
+control	O
+study	O
+","	O
+we	O
+matched	O
+cases	O
+to	O
+controls	O
+by	O
+exact	O
+year	O
+of	O
+birth	O
+","	O
+practice	O
+","	O
+and	O
+current	O
+use	O
+of	O
+OCs	O
+.	O
+	
+We	O
+used	O
+a	O
+multiple	O
+logistic	O
+regression	O
+model	O
+that	O
+included	O
+body	O
+-	O
+mass	O
+index	O
+","	O
+number	O
+of	O
+cycles	O
+","	O
+change	O
+in	O
+type	O
+of	O
+OC	O
+prescribed	O
+within	O
+3	O
+months	O
+of	O
+the	O
+event	O
+","	O
+previous	O
+pregnancy	O
+","	O
+and	O
+concurrent	O
+disease	O
+.	O
+	
+FINDINGS	O
+:	O
+85	O
+women	O
+met	O
+the	O
+inclusion	O
+criteria	O
+for	O
+VTE	B-NP
+","	O
+two	O
+of	O
+whom	O
+were	O
+users	O
+of	O
+progestagen	O
+-	O
+only	O
+OCs	O
+.	O
+	
+Of	O
+the	O
+83	O
+cases	O
+of	O
+VTE	B-NP
+associated	O
+with	O
+use	O
+of	O
+combined	O
+OCs	O
+","	O
+43	O
+were	O
+recorded	O
+as	O
+deep	B-NP
+-	I-NP
+vein	I-NP
+thrombosis	I-NP
+","	O
+35	O
+as	O
+pulmonary	O
+thrombosis	B-NP
+","	O
+and	O
+five	O
+as	O
+venous	B-NP
+thrombosis	I-NP
+not	O
+otherwise	O
+specified	O
+.	O
+	
+The	O
+crude	O
+rate	O
+of	O
+VTE	B-NP
+per	O
+10	O
+","	O
+0	O
+woman	O
+-	O
+years	O
+was	O
+4	O
+.	O
+10	O
+in	O
+current	O
+users	O
+of	O
+any	O
+OC	O
+","	O
+3	O
+.	O
+10	O
+in	O
+users	O
+of	O
+second	O
+-	O
+generation	O
+OCs	O
+","	O
+and	O
+4	O
+.	O
+96	O
+in	O
+users	O
+of	O
+third	O
+-	O
+generation	O
+preparations	O
+.	O
+	
+After	O
+adjustment	O
+for	O
+age	O
+","	O
+the	O
+rate	O
+ratio	O
+of	O
+VTE	B-NP
+in	O
+users	O
+of	O
+third	O
+-	O
+generation	O
+relative	O
+to	O
+second	O
+-	O
+generation	O
+OCs	O
+was	O
+1	O
+.	O
+68	O
+(	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+4	O
+-	O
+2	O
+.	O
+75	O
+)	O
+.	O
+	
+Logistic	O
+regression	O
+showed	O
+no	O
+significant	O
+difference	O
+in	O
+the	O
+risk	O
+of	O
+VTE	B-NP
+between	O
+users	O
+of	O
+third	O
+-	O
+generation	O
+and	O
+second	O
+-	O
+generation	O
+OCs	O
+.	O
+	
+Among	O
+users	O
+of	O
+third	O
+-	O
+generation	O
+progestagens	O
+","	O
+the	O
+risk	O
+of	O
+VTE	B-NP
+was	O
+higher	O
+in	O
+users	O
+of	O
+desogestrel	O
+with	O
+20	O
+g	O
+ethinyloestradiol	O
+than	O
+in	O
+users	O
+of	O
+gestodene	O
+or	O
+desogestrel	O
+with	O
+30	O
+g	O
+ethinyloestradiol	O
+.	O
+	
+With	O
+all	O
+second	O
+-	O
+generation	O
+OCs	O
+as	O
+the	O
+reference	O
+","	O
+the	O
+odds	O
+ratios	O
+for	O
+VTE	B-NP
+were	O
+3	O
+.	O
+49	O
+(	O
+1	O
+.	O
+21	O
+-	O
+10	O
+.	O
+12	O
+)	O
+for	O
+desogestrel	O
+plus	O
+20	O
+g	O
+ethinyloestradiol	O
+and	O
+1	O
+.	O
+18	O
+(	O
+0	O
+.	O
+66	O
+-	O
+2	O
+.	O
+17	O
+)	O
+for	O
+the	O
+other	O
+third	O
+-	O
+generation	O
+progestagens	O
+.	O
+	
+INTERPRETATION	O
+:	O
+The	O
+previously	O
+reported	O
+increase	O
+in	O
+odds	O
+ratio	O
+associated	O
+with	O
+third	O
+-	O
+generation	O
+OCs	O
+when	O
+compared	O
+with	O
+second	O
+-	O
+generation	O
+products	O
+is	O
+likely	O
+to	O
+have	O
+been	O
+the	O
+result	O
+of	O
+residual	O
+confounding	O
+by	O
+age	O
+.	O
+	
+The	O
+increased	O
+odds	O
+ratio	O
+associated	O
+with	O
+products	O
+containing	O
+20	O
+micrograms	O
+ethinyloestradiol	O
+and	O
+desogestrel	O
+compared	O
+with	O
+the	O
+30	O
+micrograms	O
+product	O
+is	O
+biologically	O
+implausible	O
+","	O
+and	O
+is	O
+likely	O
+to	O
+be	O
+the	O
+result	O
+of	O
+preferential	O
+prescribing	O
+and	O
+","	O
+thus	O
+","	O
+confounding	O
+.	O
+	
+MK	O
+-	O
+801	O
+augments	O
+pilocarpine	O
+-	O
+induced	O
+electrographic	O
+seizure	B-NP
+but	O
+protects	O
+against	O
+brain	B-NP
+damage	I-NP
+in	O
+rats	O
+.	O
+	
+1	O
+.	O
+	
+The	O
+authors	O
+examined	O
+the	O
+anticonvulsant	O
+effects	O
+of	O
+MK	O
+-	O
+801	O
+on	O
+the	O
+pilocarpine	O
+-	O
+induced	O
+seizure	B-NP
+model	O
+.	O
+	
+Intraperitoneal	O
+injection	O
+of	O
+pilocarpine	O
+(	O
+400	O
+mg	O
+/	O
+kg	O
+)	O
+induced	O
+tonic	B-NP
+and	I-NP
+clonic	I-NP
+seizure	I-NP
+.	O
+	
+Scopolamine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+pentobarbital	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+prevented	O
+development	O
+of	O
+pilocarpine	O
+-	O
+induced	O
+behavioral	O
+seizure	B-NP
+but	O
+MK	O
+-	O
+801	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+did	O
+not	O
+.	O
+	
+2	O
+.	O
+	
+An	O
+electrical	O
+seizure	B-NP
+measured	O
+with	O
+hippocampal	O
+EEG	O
+appeared	O
+in	O
+the	O
+pilocarpine	O
+-	O
+treated	O
+group	O
+.	O
+	
+Scopolamine	O
+and	O
+pentobarbital	O
+blocked	O
+the	O
+pilocarpine	O
+-	O
+induced	O
+electrographic	O
+seizure	B-NP
+","	O
+MK	O
+-	O
+801	O
+treatment	O
+augmented	O
+the	O
+electrographic	O
+seizure	B-NP
+induced	O
+by	O
+pilocarpine	O
+.	O
+	
+3	O
+.	O
+	
+Brain	B-NP
+damage	I-NP
+was	O
+assessed	O
+by	O
+examining	O
+the	O
+hippocampus	O
+microscopically	O
+.	O
+	
+Pilocarpine	O
+produced	O
+neuronal	B-NP
+death	I-NP
+in	O
+the	O
+hippocampus	O
+","	O
+which	O
+showed	O
+pyknotic	O
+changes	O
+.	O
+	
+Pentobarbital	O
+","	O
+scopolamine	O
+and	O
+MK	O
+-	O
+801	O
+protected	O
+the	O
+brain	B-NP
+damage	I-NP
+by	O
+pilocarpine	O
+","	O
+though	O
+in	O
+the	O
+MK	O
+-	O
+801	O
+-	O
+treated	O
+group	O
+","	O
+the	O
+pyramidal	O
+cells	O
+of	O
+hippocampus	O
+appeared	O
+darker	O
+than	O
+normal	O
+.	O
+	
+In	O
+all	O
+treatments	O
+","	O
+granule	O
+cells	O
+of	O
+the	O
+dentate	O
+gyrus	O
+were	O
+not	O
+affected	O
+.	O
+	
+4	O
+.	O
+	
+These	O
+results	O
+indicate	O
+that	O
+status	B-NP
+epilepticus	I-NP
+induced	O
+by	O
+pilocarpine	O
+is	O
+initiated	O
+by	O
+cholinergic	O
+overstimulation	O
+and	O
+propagated	O
+by	O
+glutamatergic	O
+transmission	O
+","	O
+the	O
+elevation	O
+of	O
+which	O
+may	O
+cause	O
+brain	B-NP
+damage	I-NP
+through	O
+an	O
+excitatory	O
+NMDA	O
+receptor	O
+-	O
+mediated	O
+mechanism	O
+.	O
+	
+Paclitaxel	O
+","	O
+5	O
+-	O
+fluorouracil	O
+","	O
+and	O
+folinic	O
+acid	O
+in	O
+metastatic	O
+breast	B-NP
+cancer	I-NP
+:	O
+BRE	O
+-	O
+26	O
+","	O
+a	O
+phase	O
+II	O
+trial	O
+.	O
+	
+5	O
+-	O
+Fluorouracil	O
+plus	O
+folinic	O
+acid	O
+and	O
+paclitaxel	O
+(	O
+Taxol	O
+;	O
+Bristol	O
+-	O
+Myers	O
+Squibb	O
+Company	O
+","	O
+Princeton	O
+","	O
+NJ	O
+)	O
+are	O
+effective	O
+salvage	O
+therapies	O
+for	O
+metastatic	O
+breast	B-NP
+cancer	I-NP
+patients	O
+.	O
+	
+Paclitaxel	O
+and	O
+5	O
+-	O
+fluorouracil	O
+have	O
+additive	O
+cytotoxicity	B-NP
+in	O
+MCF	O
+-	O
+7	O
+cell	O
+lines	O
+.	O
+	
+We	O
+performed	O
+a	O
+phase	O
+II	O
+trial	O
+of	O
+paclitaxel	O
+175	O
+mg	O
+/	O
+m2	O
+over	O
+3	O
+hours	O
+on	O
+day	O
+I	O
+followed	O
+by	O
+folinic	O
+acid	O
+300	O
+mg	O
+over	O
+1	O
+hour	O
+before	O
+5	O
+-	O
+fluorouracil	O
+350	O
+mg	O
+/	O
+m2	O
+on	O
+days	O
+1	O
+to	O
+3	O
+every	O
+28	O
+days	O
+(	O
+TFL	O
+)	O
+in	O
+women	O
+with	O
+metastatic	O
+breast	B-NP
+cancer	I-NP
+.	O
+	
+Analysis	O
+is	O
+reported	O
+on	O
+37	O
+patients	O
+with	O
+a	O
+minimum	O
+of	O
+6	O
+months	O
+follow	O
+-	O
+up	O
+who	O
+received	O
+a	O
+total	O
+of	O
+192	O
+cycles	O
+of	O
+TFL	O
+:	O
+nine	O
+cycles	O
+(	O
+5	O
+%	O
+)	O
+were	O
+associated	O
+with	O
+grade	O
+3	O
+/	O
+4	O
+neutropenia	B-NP
+requiring	O
+hospitalization	O
+;	O
+seven	O
+(	O
+4	O
+%	O
+)	O
+cycles	O
+in	O
+two	O
+patients	O
+required	O
+granulocyte	O
+colony	O
+-	O
+stimulating	O
+factor	O
+due	O
+to	O
+neutropenia	B-NP
+;	O
+no	O
+patient	O
+required	O
+platelet	O
+transfusions	O
+.	O
+	
+Grade	O
+3	O
+/	O
+4	O
+nonhematologic	O
+toxicities	B-NP
+were	O
+uncommon	O
+.	O
+	
+Among	O
+the	O
+34	O
+patients	O
+evaluable	O
+for	O
+response	O
+","	O
+there	O
+were	O
+three	O
+complete	O
+responses	O
+(	O
+9	O
+%	O
+)	O
+and	O
+18	O
+partial	O
+responses	O
+(	O
+53	O
+%	O
+)	O
+for	O
+an	O
+overall	O
+response	O
+rate	O
+of	O
+62	O
+%	O
+.	O
+	
+Of	O
+the	O
+19	O
+evaluable	O
+patients	O
+with	O
+prior	O
+doxorubicin	O
+exposure	O
+","	O
+11	O
+(	O
+58	O
+%	O
+)	O
+responded	O
+compared	O
+with	O
+nine	O
+of	O
+15	O
+(	O
+60	O
+%	O
+)	O
+without	O
+prior	O
+doxorubicin	O
+.	O
+	
+Plasma	O
+paclitaxel	O
+concentrations	O
+were	O
+measured	O
+at	O
+the	O
+completion	O
+of	O
+paclitaxel	O
+infusion	O
+and	O
+at	O
+24	O
+hours	O
+in	O
+19	O
+patients	O
+.	O
+	
+TFL	O
+is	O
+an	O
+active	O
+","	O
+well	O
+-	O
+tolerated	O
+regimen	O
+in	O
+metastatic	O
+breast	B-NP
+cancer	I-NP
+.	O
+	
+Efficacy	O
+and	O
+proarrhythmia	B-NP
+with	O
+the	O
+use	O
+of	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+for	O
+sustained	O
+ventricular	B-NP
+tachyarrhythmias	I-NP
+.	O
+	
+This	O
+study	O
+prospectively	O
+evaluated	O
+the	O
+clinical	O
+efficacy	O
+","	O
+the	O
+incidence	O
+of	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+","	O
+and	O
+the	O
+presumable	O
+risk	O
+factors	O
+for	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+in	O
+patients	O
+treated	O
+with	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+for	O
+sustained	O
+ventricular	B-NP
+tachyarrhythmias	I-NP
+.	O
+	
+Eighty	O
+-	O
+one	O
+consecutive	O
+patients	O
+(	O
+54	O
+with	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+","	O
+and	O
+20	O
+with	O
+dilated	B-NP
+cardiomyopathy	I-NP
+)	O
+with	O
+inducible	O
+sustained	O
+ventricular	B-NP
+tachycardia	I-NP
+or	O
+ventricular	B-NP
+fibrillation	I-NP
+received	O
+oral	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+to	O
+prevent	O
+induction	O
+of	O
+the	O
+ventricular	B-NP
+tachyarrhythmia	I-NP
+.	O
+	
+During	O
+oral	O
+loading	O
+with	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+","	O
+continuous	O
+electrocardiographic	O
+(	O
+ECG	O
+)	O
+monitoring	O
+was	O
+performed	O
+.	O
+	
+Those	O
+patients	O
+in	O
+whom	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+prevented	O
+induction	O
+of	O
+ventricular	B-NP
+tachycardia	I-NP
+or	O
+ventricular	B-NP
+fibrillation	I-NP
+were	O
+discharged	O
+with	O
+the	O
+drug	O
+and	O
+followed	O
+up	O
+on	O
+an	O
+outpatient	O
+basis	O
+for	O
+21	O
++	O
+/	O
+-	O
+18	O
+months	O
+.	O
+	
+Induction	O
+of	O
+the	O
+ventricular	B-NP
+tachyarrhythmia	I-NP
+was	O
+prevented	O
+by	O
+oral	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+in	O
+35	O
+(	O
+43	O
+%	O
+)	O
+patients	O
+;	O
+the	O
+ventricular	B-NP
+tachyarrhythmia	I-NP
+remained	O
+inducible	O
+in	O
+40	O
+(	O
+49	O
+%	O
+)	O
+patients	O
+;	O
+and	O
+two	O
+(	O
+2	O
+.	O
+5	O
+%	O
+)	O
+patients	O
+did	O
+not	O
+tolerate	O
+even	O
+40	O
+mg	O
+of	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+once	O
+daily	O
+.	O
+	
+Four	O
+(	O
+5	O
+%	O
+)	O
+patients	O
+had	O
+from	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+during	O
+the	O
+initial	O
+oral	O
+treatment	O
+with	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+.	O
+	
+Neither	O
+ECG	O
+[	O
+sinus	O
+-	O
+cycle	O
+length	O
+(	O
+SCL	O
+)	O
+","	O
+QT	O
+or	O
+QTc	O
+interval	O
+","	O
+or	O
+U	O
+wave	O
+]	O
+nor	O
+clinical	O
+parameters	O
+identified	O
+patients	O
+at	O
+risk	O
+for	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+.	O
+	
+However	O
+","	O
+the	O
+oral	O
+dose	O
+of	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+was	O
+significantly	O
+lower	O
+in	O
+patients	O
+with	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+(	O
+200	O
++	O
+/	O
+-	O
+46	O
+vs	O
+.	O
+328	O
++	O
+/	O
+-	O
+53	O
+mg	O
+/	O
+day	O
+;	O
+p	O
+=	O
+0	O
+.	O
+17	O
+)	O
+.	O
+	
+Risk	O
+factors	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+were	O
+the	O
+appearance	O
+of	O
+an	O
+U	O
+wave	O
+(	O
+p	O
+=	O
+0	O
+.	O
+49	O
+)	O
+","	O
+female	O
+gender	O
+(	O
+p	O
+=	O
+0	O
+.	O
+15	O
+)	O
+","	O
+and	O
+significant	O
+dose	O
+-	O
+corrected	O
+changes	O
+of	O
+SCL	O
+","	O
+QT	O
+interval	O
+","	O
+and	O
+QTc	O
+interval	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+During	O
+follow	O
+-	O
+up	O
+","	O
+seven	O
+(	O
+20	O
+%	O
+)	O
+patients	O
+had	O
+a	O
+nonfatal	O
+ventricular	B-NP
+tachycardia	I-NP
+recurrence	O
+","	O
+and	O
+two	O
+(	O
+6	O
+%	O
+)	O
+patients	O
+died	O
+suddenly	O
+.	O
+	
+One	O
+female	O
+patient	O
+with	O
+stable	O
+cardiac	B-NP
+disease	I-NP
+had	O
+recurrent	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+after	O
+2	O
+years	O
+of	O
+successful	O
+treatment	O
+with	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+.	O
+	
+Torsades	B-NP
+de	I-NP
+pointes	I-NP
+occurred	O
+early	O
+during	O
+treatment	O
+even	O
+with	O
+low	O
+doses	O
+of	O
+oral	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+.	O
+	
+Pronounced	O
+changes	O
+in	O
+the	O
+surface	O
+ECG	O
+(	O
+cycle	O
+length	O
+","	O
+QT	O
+","	O
+and	O
+QTc	O
+)	O
+in	O
+relation	O
+to	O
+the	O
+dose	O
+of	O
+oral	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+might	O
+identify	O
+a	O
+subgroup	O
+of	O
+patients	O
+with	O
+an	O
+increased	O
+risk	O
+for	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+.	O
+	
+Other	O
+ECG	O
+parameters	O
+before	O
+the	O
+application	O
+of	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+did	O
+not	O
+identify	O
+patients	O
+at	O
+increased	O
+risk	O
+for	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+.	O
+	
+Recurrence	O
+rates	O
+of	O
+ventricular	B-NP
+tachyarrhythmias	I-NP
+are	O
+high	O
+despite	O
+complete	O
+suppression	O
+of	O
+the	O
+arrhythmia	B-NP
+during	O
+programmed	O
+stimulation	O
+.	O
+	
+Therefore	O
+programmed	O
+electrical	O
+stimulation	O
+in	O
+the	O
+case	O
+of	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+seems	O
+to	O
+be	O
+of	O
+limited	O
+prognostic	O
+value	O
+.	O
+	
+Chronic	O
+hyperprolactinemia	B-NP
+and	O
+changes	O
+in	O
+dopamine	O
+neurons	O
+.	O
+	
+The	O
+tuberoinfundibular	O
+dopaminergic	O
+(	O
+TIDA	O
+)	O
+system	O
+is	O
+known	O
+to	O
+inhibit	O
+prolactin	O
+(	O
+PRL	O
+)	O
+secretion	O
+.	O
+	
+In	O
+young	O
+animals	O
+this	O
+system	O
+responds	O
+to	O
+acute	O
+elevations	O
+in	O
+serum	O
+PRL	O
+by	O
+increasing	O
+its	O
+activity	O
+.	O
+	
+However	O
+","	O
+this	O
+responsiveness	O
+is	O
+lost	O
+in	O
+aging	O
+rats	O
+with	O
+chronically	O
+high	O
+serum	O
+PRL	O
+levels	O
+.	O
+	
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+induce	O
+hyperprolactinemia	B-NP
+in	O
+rats	O
+for	O
+extended	O
+periods	O
+of	O
+time	O
+and	O
+examine	O
+its	O
+effects	O
+on	O
+dopaminergic	O
+systems	O
+in	O
+the	O
+brain	O
+.	O
+	
+Hyperprolactinemia	B-NP
+was	O
+induced	O
+by	O
+treatment	O
+with	O
+haloperidol	O
+","	O
+a	O
+dopamine	O
+receptor	O
+antagonist	O
+","	O
+and	O
+Palkovits	O
+'	O
+microdissection	O
+technique	O
+in	O
+combination	O
+with	O
+high	O
+-	O
+performance	O
+liquid	O
+chromatography	O
+was	O
+used	O
+to	O
+measure	O
+neurotransmitter	O
+concentrations	O
+in	O
+several	O
+areas	O
+of	O
+the	O
+brain	O
+.	O
+	
+After	O
+6	O
+months	O
+of	O
+hyperprolactinemia	B-NP
+","	O
+dopamine	O
+(	O
+DA	O
+)	O
+concentrations	O
+in	O
+the	O
+median	O
+eminence	O
+(	O
+ME	O
+)	O
+increased	O
+by	O
+84	O
+%	O
+over	O
+the	O
+control	O
+group	O
+.	O
+	
+Nine	O
+months	O
+of	O
+hyperprolactinemia	B-NP
+produced	O
+a	O
+50	O
+%	O
+increase	O
+in	O
+DA	O
+concentrations	O
+in	O
+the	O
+ME	O
+over	O
+the	O
+control	O
+group	O
+.	O
+	
+However	O
+","	O
+DA	O
+response	O
+was	O
+lost	O
+if	O
+a	O
+9	O
+-	O
+month	O
+long	O
+haloperidol	O
+-	O
+induced	O
+hyperprolactinemia	B-NP
+was	O
+followed	O
+by	O
+a	O
+1	O
+1	O
+/	O
+2	O
+month	O
+-	O
+long	O
+extremely	O
+high	O
+increase	O
+in	O
+serum	O
+PRL	O
+levels	O
+produced	O
+by	O
+implantation	O
+of	O
+MMQ	O
+cells	O
+under	O
+the	O
+kidney	O
+capsule	O
+.	O
+	
+There	O
+was	O
+no	O
+change	O
+in	O
+the	O
+levels	O
+of	O
+DA	O
+","	O
+norepinephrine	O
+(	O
+NE	O
+)	O
+","	O
+serotonin	O
+(	O
+5	O
+-	O
+HT	O
+)	O
+","	O
+or	O
+their	O
+metabolites	O
+in	O
+the	O
+arcuate	O
+nucleus	O
+(	O
+AN	O
+)	O
+","	O
+medial	O
+preoptic	O
+area	O
+(	O
+MPA	O
+)	O
+","	O
+caudate	O
+putamen	O
+(	O
+CP	O
+)	O
+","	O
+substantia	O
+nigra	O
+(	O
+SN	O
+)	O
+","	O
+and	O
+zona	O
+incerta	O
+(	O
+ZI	O
+)	O
+","	O
+except	O
+for	O
+a	O
+decrease	O
+in	O
+5	O
+-	O
+hydroxyindoleacetic	O
+acid	O
+(	O
+5	O
+-	O
+HIAA	O
+)	O
+in	O
+the	O
+AN	O
+after	O
+6	O
+-	O
+months	O
+of	O
+hyperprolactinemia	B-NP
+and	O
+an	O
+increase	O
+in	O
+DA	O
+concentrations	O
+in	O
+the	O
+AN	O
+after	O
+9	O
+-	O
+months	O
+of	O
+hyperprolactinemia	B-NP
+.	O
+	
+These	O
+results	O
+demonstrate	O
+that	O
+hyperprolactinemia	B-NP
+specifically	O
+affects	O
+TIDA	O
+neurons	O
+and	O
+these	O
+effects	O
+vary	O
+","	O
+depending	O
+on	O
+the	O
+duration	O
+and	O
+intensity	O
+of	O
+hyperprolactinemia	B-NP
+.	O
+	
+The	O
+age	O
+-	O
+related	O
+decrease	O
+in	O
+hypothalamic	O
+dopamine	O
+function	O
+may	O
+be	O
+associated	O
+with	O
+increases	O
+in	O
+PRL	O
+secretion	O
+.	O
+	
+Treatment	O
+-	O
+related	O
+disseminated	O
+necrotizing	O
+leukoencephalopathy	B-NP
+with	O
+characteristic	O
+contrast	O
+enhancement	O
+of	O
+the	O
+white	O
+matter	O
+.	O
+	
+This	O
+report	O
+describes	O
+unique	O
+contrast	O
+enhancement	O
+of	O
+the	O
+white	O
+matter	O
+on	O
+T1	O
+-	O
+weighted	O
+magnetic	O
+resonance	O
+images	O
+of	O
+two	O
+patients	O
+with	O
+disseminated	O
+necrotizing	O
+leukoencephalopathy	B-NP
+","	O
+which	O
+developed	O
+from	O
+acute	B-NP
+lymphoblastic	I-NP
+leukemia	I-NP
+treated	O
+with	O
+high	O
+-	O
+dose	O
+methotrexate	O
+.	O
+	
+In	O
+both	O
+patients	O
+","	O
+the	O
+enhancement	O
+was	O
+more	O
+pronounced	O
+near	O
+the	O
+base	O
+of	O
+the	O
+brain	O
+than	O
+at	O
+the	O
+vertex	O
+.	O
+	
+Necropsy	O
+of	O
+the	O
+first	O
+case	O
+revealed	O
+loss	B-NP
+of	I-NP
+myelination	I-NP
+and	O
+necrosis	B-NP
+of	O
+the	O
+white	O
+matter	O
+.	O
+	
+Possible	O
+mechanisms	O
+causing	O
+such	O
+a	O
+leukoencephalopathy	B-NP
+are	O
+discussed	O
+.	O
+	
+Thrombotic	B-NP
+complications	O
+in	O
+acute	B-NP
+promyelocytic	I-NP
+leukemia	I-NP
+during	O
+all	O
+-	O
+trans	O
+-	O
+retinoic	O
+acid	O
+therapy	O
+.	O
+	
+A	O
+case	O
+of	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+","	O
+due	O
+to	O
+occlusion	B-NP
+of	I-NP
+renal	I-NP
+vessels	I-NP
+in	O
+a	O
+patient	O
+with	O
+acute	B-NP
+promyelocytic	I-NP
+leukemia	I-NP
+(	O
+APL	B-NP
+)	O
+treated	O
+with	O
+all	O
+-	O
+trans	O
+-	O
+retinoic	O
+acid	O
+(	O
+ATRA	O
+)	O
+and	O
+tranexamic	O
+acid	O
+has	O
+been	O
+described	O
+recently	O
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+in	O
+an	O
+APL	B-NP
+patient	O
+treated	O
+with	O
+ATRA	O
+alone	O
+.	O
+	
+This	O
+case	O
+further	O
+supports	O
+the	O
+concern	O
+about	O
+thromboembolic	B-NP
+complications	O
+associated	O
+with	O
+ATRA	O
+therapy	O
+in	O
+APL	B-NP
+patients	O
+.	O
+	
+The	O
+patients	O
+","	O
+a	O
+43	O
+-	O
+year	O
+-	O
+old	O
+man	O
+","	O
+presented	O
+all	O
+the	O
+signs	O
+and	O
+symptoms	O
+of	O
+APL	B-NP
+and	O
+was	O
+included	O
+in	O
+a	O
+treatment	O
+protocol	O
+with	O
+ATRA	O
+.	O
+	
+After	O
+10	O
+days	O
+of	O
+treatment	O
+","	O
+he	O
+developed	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+that	O
+was	O
+completely	O
+reversible	O
+after	O
+complete	O
+remission	O
+of	O
+APL	B-NP
+was	O
+achieved	O
+and	O
+therapy	O
+discontinued	O
+.	O
+	
+We	O
+conclude	O
+that	O
+ATRA	O
+is	O
+a	O
+valid	O
+therapeutic	O
+choice	O
+for	O
+patients	O
+with	O
+APL	B-NP
+","	O
+although	O
+the	O
+procoagulant	O
+tendency	O
+is	O
+not	O
+completely	O
+corrected	O
+.	O
+	
+Thrombotic	B-NP
+events	O
+","	O
+however	O
+","	O
+could	O
+be	O
+avoided	O
+by	O
+using	O
+low	O
+-	O
+dose	O
+heparin	O
+.	O
+	
+Pupillary	O
+changes	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+stimulant	O
+-	O
+induced	O
+mania	B-NP
+:	O
+a	O
+case	O
+report	O
+.	O
+	
+A	O
+30	O
+-	O
+year	O
+-	O
+old	O
+cocaine	O
+-	O
+dependent	O
+man	O
+who	O
+was	O
+a	O
+subject	O
+in	O
+a	O
+study	O
+evaluating	O
+the	O
+anticraving	O
+efficacy	O
+of	O
+the	O
+stimulant	O
+medication	O
+diethylpropion	O
+(	O
+DEP	O
+)	O
+became	O
+manic	B-NP
+during	O
+his	O
+second	O
+week	O
+on	O
+the	O
+study	O
+drug	O
+.	O
+	
+Pupillometric	O
+changes	O
+while	O
+on	O
+DEP	O
+","	O
+especially	O
+changes	O
+in	O
+the	O
+total	O
+power	O
+of	O
+pupillary	B-NP
+oscillation	I-NP
+","	O
+were	O
+dramatically	O
+different	O
+than	O
+those	O
+observed	O
+in	O
+the	O
+eight	O
+other	O
+study	O
+subjects	O
+who	O
+did	O
+not	O
+become	O
+manic	B-NP
+.	O
+	
+The	O
+large	O
+changes	O
+in	O
+total	O
+power	O
+of	O
+pupillary	B-NP
+oscillation	I-NP
+occurred	O
+a	O
+few	O
+days	O
+before	O
+the	O
+patient	O
+became	O
+fully	O
+manic	B-NP
+.	O
+	
+Such	O
+medication	O
+-	O
+associated	O
+changes	O
+in	O
+the	O
+total	O
+power	O
+of	O
+pupillary	B-NP
+oscillation	I-NP
+might	O
+be	O
+of	O
+utility	O
+in	O
+identifying	O
+persons	O
+at	O
+risk	O
+for	O
+manic	B-NP
+-	O
+like	O
+adverse	O
+effects	O
+during	O
+the	O
+medical	O
+use	O
+of	O
+psychomotor	O
+stimulants	O
+or	O
+sympathomimetic	O
+agents	O
+.	O
+	
+Fetal	O
+risks	O
+due	O
+to	O
+warfarin	O
+therapy	O
+during	O
+pregnancy	O
+.	O
+	
+Two	O
+mothers	O
+with	O
+heart	O
+valve	O
+prosthesis	O
+were	O
+treated	O
+with	O
+warfarin	O
+during	O
+pregnancy	O
+.	O
+	
+In	O
+the	O
+first	O
+case	O
+a	O
+caesarean	O
+section	O
+was	O
+done	O
+one	O
+week	O
+after	O
+replacement	O
+of	O
+warfarin	O
+with	O
+heparin	O
+.	O
+	
+The	O
+baby	O
+died	O
+of	O
+cerebral	B-NP
+and	I-NP
+pulmonary	I-NP
+hemorrhage	I-NP
+.	O
+	
+The	O
+second	O
+mother	O
+had	O
+a	O
+male	O
+infant	O
+by	O
+caesarean	O
+section	O
+.	O
+	
+The	O
+baby	O
+showed	O
+warfarin	O
+-	O
+induced	O
+embryopathy	B-NP
+with	O
+nasal	B-NP
+hypoplasia	I-NP
+and	O
+stippled	B-NP
+epiphyses	I-NP
+(	O
+chondrodysplasia	B-NP
+punctata	I-NP
+)	O
+.	O
+	
+Nasal	B-NP
+hypoplasia	I-NP
+with	O
+or	O
+without	O
+stippled	B-NP
+epiphyses	I-NP
+has	O
+now	O
+been	O
+reported	O
+in	O
+11	O
+infants	O
+born	O
+to	O
+mothers	O
+treated	O
+with	O
+warfarin	O
+during	O
+the	O
+first	O
+trimester	O
+","	O
+and	O
+a	O
+causal	O
+association	O
+is	O
+probable	O
+.	O
+	
+In	O
+view	O
+of	O
+the	O
+risks	O
+to	O
+both	O
+mother	O
+and	O
+fetus	O
+in	O
+women	O
+with	O
+prosthetic	O
+cardiac	O
+valves	O
+it	O
+is	O
+recommended	O
+that	O
+therapeutic	O
+abortion	O
+be	O
+advised	O
+as	O
+the	O
+first	O
+alternative	O
+.	O
+	
+The	O
+negative	O
+mucosal	O
+potential	O
+:	O
+separating	O
+central	O
+and	O
+peripheral	O
+effects	O
+of	O
+NSAIDs	O
+in	O
+man	O
+.	O
+	
+OBJECTIVE	O
+:	O
+We	O
+wanted	O
+to	O
+test	O
+whether	O
+assessment	O
+of	O
+both	O
+a	O
+central	O
+pain	B-NP
+-	O
+related	O
+signal	O
+(	O
+chemo	O
+-	O
+somatosensory	O
+evoked	O
+potential	O
+","	O
+CSSEP	O
+)	O
+and	O
+a	O
+concomitantly	O
+recorded	O
+peripheral	O
+signal	O
+(	O
+negative	O
+mucosal	O
+potential	O
+","	O
+NMP	O
+)	O
+allows	O
+for	O
+separation	O
+of	O
+central	O
+and	O
+peripheral	O
+effects	O
+of	O
+NSAIDs	O
+.	O
+	
+For	O
+this	O
+purpose	O
+","	O
+experimental	O
+conditions	O
+were	O
+created	O
+in	O
+which	O
+NSAIDs	O
+had	O
+previously	O
+been	O
+observed	O
+to	O
+produce	O
+effects	O
+on	O
+phasic	O
+and	O
+tonic	O
+pain	B-NP
+by	O
+either	O
+central	O
+or	O
+peripheral	O
+mechanisms	O
+.	O
+	
+METHODS	O
+:	O
+According	O
+to	O
+a	O
+double	O
+-	O
+blind	O
+","	O
+randomised	O
+","	O
+controlled	O
+","	O
+threefold	O
+cross	O
+-	O
+over	O
+design	O
+","	O
+18	O
+healthy	O
+subjects	O
+(	O
+11	O
+males	O
+","	O
+7	O
+females	O
+;	O
+mean	O
+age	O
+26	O
+years	O
+)	O
+received	O
+either	O
+placebo	O
+","	O
+400	O
+mg	O
+ibuprofen	O
+","	O
+or	O
+800	O
+mg	O
+ibuprofen	O
+.	O
+	
+Phasic	O
+pain	B-NP
+was	O
+applied	O
+by	O
+means	O
+of	O
+short	O
+pulses	O
+of	O
+CO2	O
+to	O
+the	O
+nasal	O
+mucosa	O
+(	O
+stimulus	O
+duration	O
+500	O
+ms	O
+","	O
+interval	O
+approximately	O
+60	O
+s	O
+)	O
+","	O
+and	O
+tonic	O
+pain	B-NP
+was	O
+induced	O
+in	O
+the	O
+nasal	O
+cavity	O
+by	O
+means	O
+of	O
+dry	O
+air	O
+of	O
+controlled	O
+temperature	O
+","	O
+humidity	O
+and	O
+flow	O
+rate	O
+(	O
+22	O
+degrees	O
+C	O
+","	O
+0	O
+%	O
+relative	O
+humidity	O
+","	O
+145	O
+ml	O
+.	O
+s	O
+-	O
+1	O
+)	O
+.	O
+	
+Both	O
+CSSEPs	O
+as	O
+central	O
+and	O
+NMPs	O
+as	O
+peripheral	O
+correlates	O
+of	O
+pain	B-NP
+were	O
+obtained	O
+in	O
+response	O
+to	O
+the	O
+CO2	O
+stimuli	O
+.	O
+	
+Additionally	O
+","	O
+the	O
+subjects	O
+rated	O
+the	O
+intensity	O
+of	O
+both	O
+phasic	O
+and	O
+tonic	O
+pain	B-NP
+by	O
+means	O
+of	O
+visual	O
+analogue	O
+scales	O
+.	O
+	
+RESULTS	O
+:	O
+As	O
+described	O
+earlier	O
+","	O
+administration	O
+of	O
+ibuprofen	O
+was	O
+followed	O
+by	O
+a	O
+decrease	O
+in	O
+tonic	O
+pain	B-NP
+but	O
+-	O
+relative	O
+to	O
+placebo	O
+-	O
+an	O
+increase	O
+in	O
+correlates	O
+of	O
+phasic	O
+pain	B-NP
+","	O
+indicating	O
+a	O
+specific	O
+effect	O
+of	O
+ibuprofen	O
+on	O
+the	O
+interaction	O
+between	O
+the	O
+pain	B-NP
+stimuli	O
+under	O
+these	O
+special	O
+experimental	O
+conditions	O
+.	O
+	
+Based	O
+on	O
+the	O
+similar	O
+behaviour	O
+of	O
+CSSEP	O
+and	O
+NMP	O
+","	O
+it	O
+was	O
+concluded	O
+that	O
+the	O
+pharmacological	O
+process	O
+underlying	O
+this	O
+phenomenon	O
+was	O
+localised	O
+in	O
+the	O
+periphery	O
+.	O
+	
+By	O
+means	O
+of	O
+the	O
+simultaneous	O
+recording	O
+of	O
+interrelated	O
+peripheral	O
+and	O
+central	O
+electrophysiologic	O
+correlates	O
+of	O
+nociception	O
+","	O
+it	O
+was	O
+possible	O
+to	O
+separate	O
+central	O
+and	O
+peripheral	O
+effects	O
+of	O
+an	O
+NSAID	O
+.	O
+	
+The	O
+major	O
+advantage	O
+of	O
+this	O
+pain	B-NP
+model	O
+is	O
+the	O
+possibility	O
+of	O
+obtaining	O
+peripheral	O
+pain	B-NP
+-	O
+related	O
+activity	O
+directly	O
+using	O
+a	O
+non	O
+-	O
+invasive	O
+technique	O
+in	O
+humans	O
+.	O
+	
+Effect	O
+of	O
+D	O
+-	O
+Glucarates	O
+on	O
+basic	O
+antibiotic	O
+-	O
+induced	O
+renal	B-NP
+damage	I-NP
+in	O
+rats	O
+.	O
+	
+Dehydrated	B-NP
+rats	O
+regularly	O
+develop	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+following	O
+single	O
+injection	O
+of	O
+aminoglycoside	O
+antibiotics	O
+combined	O
+with	O
+dextran	O
+or	O
+of	O
+antibiotics	O
+only	O
+.	O
+	
+Oral	O
+administration	O
+of	O
+2	O
+","	O
+5	O
+-	O
+di	O
+-	O
+O	O
+-	O
+acetyl	O
+-	O
+D	O
+-	O
+glucaro	O
+-	O
+1	O
+","	O
+4	O
+-	O
+6	O
+","	O
+3	O
+-	O
+dilactone	O
+protected	O
+rats	O
+against	O
+renal	B-NP
+failure	I-NP
+induced	O
+by	O
+kanamycin	O
+-	O
+dextran	O
+.	O
+	
+The	O
+protective	O
+effect	O
+was	O
+prevalent	O
+among	O
+D	O
+-	O
+glucarates	O
+","	O
+and	O
+also	O
+to	O
+other	O
+saccharic	O
+acid	O
+","	O
+hexauronic	O
+acids	O
+and	O
+hexaaldonic	O
+acids	O
+","	O
+although	O
+to	O
+a	O
+lesser	O
+degree	O
+","	O
+but	O
+not	O
+to	O
+a	O
+hexaaldose	O
+","	O
+sugar	O
+alcohols	O
+","	O
+substances	O
+inthe	O
+TCA	O
+cycle	O
+and	O
+other	O
+acidic	O
+compounds	O
+.	O
+	
+D	O
+-	O
+Glucarates	O
+were	O
+effective	O
+against	O
+renal	B-NP
+damage	I-NP
+induced	O
+by	O
+peptide	O
+antibiotics	O
+as	O
+well	O
+as	O
+various	O
+aminoglycoside	O
+antibitocis	O
+.	O
+	
+Dose	O
+-	O
+responses	O
+were	O
+observed	O
+in	O
+the	O
+protective	O
+effect	O
+of	O
+D	O
+-	O
+Glucarates	O
+.	O
+	
+With	O
+a	O
+D	O
+-	O
+glucarate	O
+of	O
+a	O
+fixed	O
+size	O
+of	O
+dose	O
+","	O
+approximately	O
+the	O
+same	O
+degree	O
+of	O
+protection	O
+was	O
+obtained	O
+against	O
+renal	B-NP
+damages	I-NP
+induced	O
+by	O
+different	O
+basic	O
+antibiotics	O
+despite	O
+large	O
+disparities	O
+in	O
+administration	O
+doses	O
+of	O
+different	O
+antibiotics	O
+.	O
+	
+D	O
+-	O
+Glucarates	O
+had	O
+the	O
+ability	O
+to	O
+prevent	O
+renal	B-NP
+damage	I-NP
+but	O
+not	O
+to	O
+cure	O
+it	O
+.	O
+	
+Rats	O
+excreted	O
+acidic	O
+urine	O
+when	O
+they	O
+were	O
+spared	O
+from	O
+renal	B-NP
+lesions	I-NP
+by	O
+monosaccharides	O
+.	O
+	
+The	O
+reduction	O
+effect	O
+of	O
+D	O
+-	O
+glucarates	O
+against	O
+nephrotoxicity	B-NP
+of	O
+basic	O
+antibiotics	O
+was	O
+discussed	O
+.	O
+	
+Acute	O
+severe	O
+depression	B-NP
+following	O
+peri	O
+-	O
+operative	O
+ondansetron	O
+.	O
+	
+A	O
+41	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+a	O
+strong	O
+history	O
+of	O
+postoperative	B-NP
+nausea	I-NP
+and	I-NP
+vomiting	I-NP
+presented	O
+for	O
+abdominal	O
+hysterectomy	O
+3	O
+months	O
+after	O
+a	O
+previous	O
+anaesthetic	O
+where	O
+ondansetron	O
+prophylaxis	O
+had	O
+been	O
+used	O
+.	O
+	
+She	O
+had	O
+developed	O
+a	O
+severe	O
+acute	O
+major	B-NP
+depression	I-NP
+disorder	I-NP
+almost	O
+immediately	O
+thereafter	O
+","	O
+possibly	O
+related	O
+to	O
+the	O
+use	O
+of	O
+a	O
+serotonin	O
+antagonist	O
+.	O
+	
+Nine	O
+years	O
+before	O
+she	O
+had	O
+experienced	O
+a	O
+self	O
+-	O
+limited	O
+puerperal	O
+depressive	B-NP
+episode	I-NP
+.	O
+	
+Anaesthesia	O
+with	O
+a	O
+propofol	O
+infusion	O
+and	O
+avoidance	O
+of	O
+serotonin	O
+antagonists	O
+provided	O
+a	O
+nausea	B-NP
+-	O
+free	O
+postoperative	O
+course	O
+without	O
+exacerbation	O
+of	O
+the	O
+depression	B-NP
+disorder	I-NP
+.	O
+	
+Hypertensive	B-NP
+response	O
+during	O
+dobutamine	O
+stress	O
+echocardiography	O
+.	O
+	
+Among	O
+3	O
+","	O
+129	O
+dobutamine	O
+stress	O
+echocardiographic	O
+studies	O
+","	O
+a	O
+hypertensive	B-NP
+response	O
+","	O
+defined	O
+as	O
+systolic	O
+blood	O
+pressure	O
+(	O
+BP	O
+)	O
+>	O
+or	O
+=	O
+220	O
+mm	O
+Hg	O
+and	O
+/	O
+or	O
+diastolic	O
+BP	O
+>	O
+or	O
+=	O
+110	O
+mm	O
+Hg	O
+","	O
+occurred	O
+in	O
+30	O
+patients	O
+(	O
+1	O
+%	O
+)	O
+.	O
+	
+Patients	O
+with	O
+this	O
+response	O
+more	O
+often	O
+had	O
+a	O
+history	O
+of	O
+hypertension	B-NP
+and	O
+had	O
+higher	O
+resting	O
+systolic	O
+and	O
+diastolic	O
+BP	O
+before	O
+dobutamine	O
+infusion	O
+.	O
+	
+Continuously	O
+nebulized	O
+albuterol	O
+in	O
+severe	O
+exacerbations	O
+of	O
+asthma	B-NP
+in	O
+adults	O
+:	O
+a	O
+case	O
+-	O
+controlled	O
+study	O
+.	O
+	
+A	O
+retrospective	O
+","	O
+case	O
+-	O
+controlled	O
+analysis	O
+comparing	O
+patients	O
+admitted	O
+to	O
+a	O
+medical	O
+intensive	O
+care	O
+unit	O
+with	O
+severe	O
+exacerbations	O
+of	O
+asthma	B-NP
+who	O
+received	O
+continuously	O
+nebulized	O
+albuterol	O
+(	O
+CNA	O
+)	O
+versus	O
+intermittent	O
+albuterol	O
+(	O
+INA	O
+)	O
+treatments	O
+is	O
+reported	O
+.	O
+	
+Forty	O
+matched	O
+pairs	O
+of	O
+patients	O
+with	O
+asthma	B-NP
+are	O
+compared	O
+.	O
+	
+CNA	O
+was	O
+administered	O
+for	O
+a	O
+mean	O
+of	O
+11	O
++	O
+/	O
+-	O
+10	O
+hr	O
+.	O
+	
+The	O
+incidence	O
+of	O
+cardiac	B-NP
+dysrhythmias	I-NP
+was	O
+similar	O
+between	O
+groups	O
+.	O
+	
+Symptomatic	O
+hypokalemia	B-NP
+did	O
+not	O
+occur	O
+.	O
+	
+CNA	O
+patients	O
+had	O
+higher	O
+heart	O
+rates	O
+during	O
+treatment	O
+","	O
+which	O
+may	O
+reflect	O
+severity	O
+of	O
+illness	O
+.	O
+	
+The	O
+incidence	O
+of	O
+intubation	O
+was	O
+similar	O
+.	O
+	
+We	O
+conclude	O
+that	O
+CNA	O
+and	O
+INA	O
+demonstrated	O
+similar	O
+profiles	O
+with	O
+regard	O
+to	O
+safety	O
+","	O
+morbidity	O
+","	O
+and	O
+mortality	O
+.	O
+	
+Paraplegia	B-NP
+following	O
+intrathecal	O
+methotrexate	O
+:	O
+report	O
+of	O
+a	O
+case	O
+and	O
+review	O
+of	O
+the	O
+literature	O
+.	O
+	
+A	O
+patient	O
+who	O
+developed	O
+paraplegia	B-NP
+following	O
+the	O
+intrathecal	O
+instillation	O
+of	O
+methotrexate	O
+is	O
+discribed	O
+.	O
+	
+The	O
+ten	O
+previously	O
+reported	O
+cases	O
+of	O
+this	O
+unusual	O
+complication	O
+are	O
+reviewed	O
+.	O
+	
+The	O
+following	O
+factors	O
+appear	O
+to	O
+predispose	O
+to	O
+the	O
+development	O
+of	O
+this	O
+complication	O
+:	O
+abnormal	O
+cerebrospinal	O
+dynamics	O
+related	O
+to	O
+the	O
+presence	O
+of	O
+central	B-NP
+nervous	I-NP
+system	I-NP
+leukemia	I-NP
+","	O
+and	O
+epidural	O
+cerebrospinal	O
+leakage	O
+;	O
+elevated	O
+cerebrospinal	O
+fluid	O
+methothexate	O
+concentration	O
+related	O
+to	O
+abnormal	O
+cerebrospinal	O
+fluid	O
+dynamics	O
+and	O
+to	O
+inappropriately	O
+high	O
+methotrexate	O
+doses	O
+based	O
+on	O
+body	O
+surface	O
+area	O
+calculations	O
+in	O
+older	O
+children	O
+and	O
+adults	O
+;	O
+the	O
+presence	O
+of	O
+neurotoxic	B-NP
+preservatives	O
+in	O
+commercially	O
+available	O
+methotrexate	O
+preparations	O
+and	O
+diluents	O
+;	O
+and	O
+the	O
+use	O
+of	O
+methotrexate	O
+diluents	O
+of	O
+unphysiologic	O
+pH	O
+","	O
+ionic	O
+content	O
+and	O
+osmolarity	O
+.	O
+	
+The	O
+role	O
+of	O
+methotrexate	O
+contaminants	O
+","	O
+local	O
+folate	B-NP
+deficiency	I-NP
+","	O
+and	O
+cranial	O
+irradiation	O
+in	O
+the	O
+pathogenesis	O
+of	O
+intrathecal	O
+methotrexate	O
+toxicity	B-NP
+is	O
+unclear	O
+.	O
+	
+The	O
+incidence	O
+of	O
+neurotoxicity	B-NP
+may	O
+be	O
+reduced	O
+by	O
+employing	O
+lower	O
+doses	O
+of	O
+methotrexate	O
+in	O
+the	O
+presence	O
+of	O
+central	B-NP
+nervous	I-NP
+system	I-NP
+leukemia	I-NP
+","	O
+in	O
+older	O
+children	O
+and	O
+adults	O
+","	O
+and	O
+in	O
+the	O
+presence	O
+of	O
+epidural	O
+leakage	O
+.	O
+	
+Only	O
+preservative	O
+-	O
+free	O
+methotrexate	O
+in	O
+Elliott	O
+'	O
+s	O
+B	O
+Solution	O
+at	O
+a	O
+concentration	O
+of	O
+not	O
+more	O
+than	O
+1	O
+mg	O
+/	O
+ml	O
+should	O
+be	O
+used	O
+for	O
+intrathecal	O
+administration	O
+.	O
+	
+Periodic	O
+monitoring	O
+of	O
+cerebruspinal	O
+fluid	O
+methotrexate	O
+levels	O
+may	O
+be	O
+predictive	O
+of	O
+the	O
+development	O
+of	O
+serious	O
+neurotoxicity	B-NP
+.	O
+	
+Hyperosmolar	B-NP
+nonketotic	I-NP
+coma	I-NP
+precipitated	O
+by	O
+lithium	O
+-	O
+induced	O
+nephrogenic	B-NP
+diabetes	I-NP
+insipidus	I-NP
+.	O
+	
+A	O
+45	O
+-	O
+year	O
+-	O
+old	O
+man	O
+","	O
+with	O
+a	O
+10	O
+-	O
+year	O
+history	O
+of	O
+manic	B-NP
+depression	I-NP
+treated	O
+with	O
+lithium	O
+","	O
+was	O
+admitted	O
+with	O
+hyperosmolar	B-NP
+","	I-NP
+nonketotic	I-NP
+coma	I-NP
+.	O
+	
+He	O
+gave	O
+a	O
+five	O
+-	O
+year	O
+history	O
+of	O
+polyuria	B-NP
+and	O
+polydipsia	B-NP
+","	O
+during	O
+which	O
+time	O
+urinalysis	O
+had	O
+been	O
+negative	O
+for	O
+glucose	O
+.	O
+	
+After	O
+recovery	O
+from	O
+hyperglycaemia	B-NP
+","	O
+he	O
+remained	O
+polyuric	B-NP
+despite	O
+normal	O
+blood	O
+glucose	O
+concentrations	O
+;	O
+water	O
+deprivation	O
+testing	O
+indicated	O
+nephrogenic	B-NP
+diabetes	I-NP
+insipidus	I-NP
+","	O
+likely	O
+to	O
+be	O
+lithium	O
+-	O
+induced	O
+.	O
+	
+We	O
+hypothesize	O
+that	O
+when	O
+this	O
+man	O
+developed	O
+type	B-NP
+2	I-NP
+diabetes	I-NP
+","	O
+chronic	O
+polyuria	B-NP
+due	O
+to	O
+nephrogenic	B-NP
+diabetes	I-NP
+insipidus	I-NP
+was	O
+sufficient	O
+to	O
+precipitate	O
+hyperosmolar	O
+dehydration	B-NP
+.	O
+	
+Effects	O
+of	O
+the	O
+intracoronary	O
+infusion	O
+of	O
+cocaine	O
+on	O
+left	O
+ventricular	O
+systolic	O
+and	O
+diastolic	O
+function	O
+in	O
+humans	O
+.	O
+	
+BACKGROUND	O
+:	O
+In	O
+dogs	O
+","	O
+a	O
+large	O
+amount	O
+of	O
+intravenous	O
+cocaine	O
+causes	O
+a	O
+profound	O
+deterioration	B-NP
+of	I-NP
+left	I-NP
+ventricular	I-NP
+(	I-NP
+LV	I-NP
+)	I-NP
+systolic	I-NP
+function	I-NP
+and	O
+an	O
+increase	O
+in	O
+LV	O
+end	O
+-	O
+diastolic	O
+pressure	O
+.	O
+	
+This	O
+study	O
+was	O
+done	O
+to	O
+assess	O
+the	O
+influence	O
+of	O
+a	O
+high	O
+intracoronary	O
+cocaine	O
+concentration	O
+on	O
+LV	O
+systolic	O
+and	O
+diastolic	O
+function	O
+in	O
+humans	O
+.	O
+	
+METHODS	O
+AND	O
+RESULTS	O
+:	O
+In	O
+20	O
+patients	O
+(	O
+14	O
+men	O
+and	O
+6	O
+women	O
+aged	O
+39	O
+to	O
+72	O
+years	O
+)	O
+referred	O
+for	O
+cardiac	O
+catheterization	O
+for	O
+the	O
+evaluation	O
+of	O
+chest	B-NP
+pain	I-NP
+","	O
+we	O
+measured	O
+heart	O
+rate	O
+","	O
+systemic	O
+arterial	O
+pressure	O
+","	O
+LV	O
+pressure	O
+and	O
+its	O
+first	O
+derivative	O
+(	O
+dP	O
+/	O
+dt	O
+)	O
+","	O
+and	O
+LV	O
+volumes	O
+and	O
+ejection	O
+fraction	O
+before	O
+and	O
+during	O
+the	O
+final	O
+2	O
+to	O
+3	O
+minutes	O
+of	O
+a	O
+15	O
+-	O
+minute	O
+intracoronary	O
+infusion	O
+of	O
+saline	O
+(	O
+n	O
+=	O
+10	O
+","	O
+control	O
+subjects	O
+)	O
+or	O
+cocaine	O
+hydrochloride	O
+1	O
+mg	O
+/	O
+min	O
+(	O
+n	O
+=	O
+10	O
+)	O
+.	O
+	
+No	O
+variable	O
+changed	O
+with	O
+saline	O
+.	O
+	
+With	O
+cocaine	O
+","	O
+the	O
+drug	O
+concentration	O
+in	O
+blood	O
+obtained	O
+from	O
+the	O
+coronary	O
+sinus	O
+was	O
+3	O
+.	O
+0	O
++	O
+/	O
+-	O
+0	O
+.	O
+4	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+)	O
+mg	O
+/	O
+L	O
+","	O
+similar	O
+in	O
+magnitude	O
+to	O
+the	O
+blood	O
+cocaine	O
+concentration	O
+reported	O
+in	O
+abusers	O
+dying	O
+of	O
+cocaine	O
+intoxication	O
+.	O
+	
+Cocaine	O
+induced	O
+no	O
+significant	O
+change	O
+in	O
+heart	O
+rate	O
+","	O
+LV	O
+dP	O
+/	O
+dt	O
+(	O
+positive	O
+or	O
+negative	O
+)	O
+","	O
+or	O
+LV	O
+end	O
+-	O
+diastolic	O
+volume	O
+","	O
+but	O
+it	O
+caused	O
+an	O
+increase	O
+in	O
+systolic	O
+and	O
+mean	O
+arterial	O
+pressures	O
+","	O
+LV	O
+end	O
+-	O
+diastolic	O
+pressure	O
+","	O
+and	O
+LV	O
+end	O
+-	O
+systolic	O
+volume	O
+","	O
+as	O
+well	O
+as	O
+a	O
+decrease	O
+in	O
+LV	O
+ejection	O
+fraction	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+In	O
+humans	O
+","	O
+the	O
+intracoronary	O
+infusion	O
+of	O
+cocaine	O
+sufficient	O
+in	O
+amount	O
+to	O
+achieve	O
+a	O
+high	O
+drug	O
+concentration	O
+in	O
+coronary	O
+sinus	O
+blood	O
+causes	O
+a	O
+deterioration	B-NP
+of	I-NP
+LV	I-NP
+systolic	I-NP
+and	I-NP
+diastolic	I-NP
+performance	I-NP
+.	O
+	
+Ascending	O
+dose	O
+tolerance	O
+study	O
+of	O
+intramuscular	O
+carbetocin	O
+administered	O
+after	O
+normal	O
+vaginal	O
+birth	O
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+determine	O
+the	O
+maximum	O
+tolerated	O
+dose	O
+(	O
+MTD	O
+)	O
+of	O
+carbetocin	O
+(	O
+a	O
+long	O
+-	O
+acting	O
+synthetic	O
+analogue	O
+of	O
+oxytocin	O
+)	O
+","	O
+when	O
+administered	O
+immediately	O
+after	O
+vaginal	O
+delivery	O
+at	O
+term	O
+.	O
+	
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+Carbetocin	O
+was	O
+given	O
+as	O
+an	O
+intramuscular	O
+injection	O
+immediately	O
+after	O
+the	O
+birth	O
+of	O
+the	O
+infant	O
+in	O
+45	O
+healthy	O
+women	O
+with	O
+normal	O
+singleton	O
+pregnancies	O
+who	O
+delivered	O
+vaginally	O
+at	O
+term	O
+.	O
+	
+Dosage	O
+groups	O
+of	O
+15	O
+","	O
+30	O
+","	O
+50	O
+","	O
+75	O
+","	O
+100	O
+","	O
+125	O
+","	O
+150	O
+","	O
+175	O
+or	O
+200	O
+microg	O
+carbetocin	O
+were	O
+assigned	O
+to	O
+blocks	O
+of	O
+three	O
+women	O
+according	O
+to	O
+the	O
+continual	O
+reassessment	O
+method	O
+(	O
+CRM	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+All	O
+dosage	O
+groups	O
+consisted	O
+of	O
+three	O
+women	O
+","	O
+except	O
+those	O
+with	O
+100	O
+microg	O
+(	O
+n	O
+=	O
+6	O
+)	O
+and	O
+200	O
+microg	O
+(	O
+n	O
+=	O
+18	O
+)	O
+.	O
+	
+Recorded	O
+were	O
+dose	O
+-	O
+limiting	O
+adverse	O
+events	O
+:	O
+hyper	B-NP
+-	I-NP
+or	I-NP
+hypotension	I-NP
+(	O
+three	O
+)	O
+","	O
+severe	O
+abdominal	B-NP
+pain	I-NP
+(	O
+0	O
+)	O
+","	O
+vomiting	B-NP
+(	O
+0	O
+)	O
+and	O
+retained	B-NP
+placenta	I-NP
+(	O
+four	O
+)	O
+.	O
+	
+Serious	O
+adverse	O
+events	O
+occurred	O
+in	O
+seven	O
+women	O
+:	O
+six	O
+cases	O
+with	O
+blood	B-NP
+loss	I-NP
+>	O
+or	O
+=	O
+1000	O
+ml	O
+","	O
+four	O
+cases	O
+of	O
+manual	O
+placenta	O
+removal	O
+","	O
+five	O
+cases	O
+of	O
+additional	O
+oxytocics	O
+administration	O
+and	O
+five	O
+cases	O
+of	O
+blood	O
+transfusion	O
+.	O
+	
+Maximum	O
+blood	B-NP
+loss	I-NP
+was	O
+greatest	O
+at	O
+the	O
+upper	O
+and	O
+lower	O
+dose	O
+levels	O
+","	O
+and	O
+lowest	O
+in	O
+the	O
+70	O
+-	O
+125	O
+microg	O
+dose	O
+range	O
+.	O
+	
+Four	O
+out	O
+of	O
+six	O
+cases	O
+with	O
+blood	B-NP
+loss	I-NP
+>	O
+or	O
+=	O
+1000	O
+ml	O
+occurred	O
+in	O
+the	O
+200	O
+microg	O
+group	O
+.	O
+	
+The	O
+majority	O
+of	O
+additional	O
+administration	O
+of	O
+oxytocics	O
+(	O
+4	O
+/	O
+5	O
+)	O
+and	O
+blood	O
+transfusion	O
+(	O
+3	O
+/	O
+5	O
+)	O
+occurred	O
+in	O
+the	O
+dose	O
+groups	O
+of	O
+200	O
+microg	O
+.	O
+	
+All	O
+retained	O
+placentae	O
+were	O
+found	O
+in	O
+the	O
+group	O
+of	O
+200	O
+microg	O
+.	O
+	
+CONCLUSION	O
+:	O
+The	O
+MTD	O
+was	O
+calculated	O
+to	O
+be	O
+at	O
+200	O
+microg	O
+carbetocin	O
+.	O
+	
+Heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+","	O
+paradoxical	O
+thromboembolism	B-NP
+","	O
+and	O
+other	O
+side	O
+effects	O
+of	O
+heparin	O
+therapy	O
+.	O
+	
+Although	O
+several	O
+new	O
+anticoagulant	O
+drugs	O
+are	O
+in	O
+development	O
+","	O
+heparin	O
+remains	O
+the	O
+drug	O
+of	O
+choice	O
+for	O
+most	O
+anticoagulation	O
+needs	O
+.	O
+	
+The	O
+clinical	O
+effects	O
+of	O
+heparin	O
+are	O
+meritorious	O
+","	O
+but	O
+side	O
+effects	O
+do	O
+exist	O
+.	O
+	
+Important	O
+untoward	O
+effects	O
+of	O
+heparin	O
+therapy	O
+including	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+","	O
+heparin	O
+-	O
+associated	O
+osteoporosis	B-NP
+","	O
+eosinophilia	B-NP
+","	O
+skin	B-NP
+reactions	I-NP
+","	O
+allergic	B-NP
+reactions	I-NP
+other	O
+than	O
+thrombocytopenia	B-NP
+and	O
+alopecia	B-NP
+will	O
+be	O
+discussed	O
+in	O
+this	O
+article	O
+.	O
+	
+Nonopaque	O
+crystal	O
+deposition	O
+causing	O
+ureteric	B-NP
+obstruction	I-NP
+in	O
+patients	O
+with	O
+HIV	O
+undergoing	O
+indinavir	O
+therapy	O
+.	O
+	
+OBJECTIVE	O
+:	O
+We	O
+describe	O
+the	O
+unique	O
+CT	O
+features	O
+of	O
+ureteric	B-NP
+calculi	I-NP
+in	O
+six	O
+HIV	B-NP
+-	I-NP
+infected	I-NP
+patients	O
+receiving	O
+indinavir	O
+","	O
+the	O
+most	O
+commonly	O
+used	O
+HIV	O
+protease	O
+inhibitor	O
+","	O
+which	O
+is	O
+associated	O
+with	O
+an	O
+increased	O
+incidence	O
+of	O
+urolithiasis	B-NP
+.	O
+	
+CONCLUSION	O
+:	O
+Ureteric	B-NP
+obstruction	I-NP
+caused	O
+by	O
+precipitated	O
+indinavir	O
+crystals	O
+may	O
+be	O
+difficult	O
+to	O
+diagnose	O
+with	O
+unenhanced	O
+CT	O
+.	O
+	
+The	O
+calculi	O
+are	O
+not	O
+opaque	O
+","	O
+and	O
+secondary	O
+signs	O
+of	O
+obstruction	O
+may	O
+be	O
+absent	O
+or	O
+minimal	O
+and	O
+should	O
+be	O
+sought	O
+carefully	O
+.	O
+	
+Images	O
+may	O
+need	O
+to	O
+be	O
+obtained	O
+using	O
+i	O
+.	O
+v	O
+.	O
+contrast	O
+material	O
+to	O
+enable	O
+diagnosis	O
+of	O
+ureteric	B-NP
+stones	I-NP
+or	I-NP
+obstruction	I-NP
+in	O
+patients	O
+with	O
+HIV	B-NP
+infection	I-NP
+who	O
+receive	O
+indinavir	O
+therapy	O
+.	O
+	
+Ischemic	B-NP
+colitis	I-NP
+and	O
+sumatriptan	O
+use	O
+.	O
+	
+Sumatriptan	O
+succinate	O
+","	O
+a	O
+serotonin	O
+-	O
+1	O
+(	O
+5	O
+-	O
+hydroxytryptamine	O
+-	O
+1	O
+)	O
+receptor	O
+agonist	O
+","	O
+is	O
+an	O
+antimigraine	O
+drug	O
+that	O
+is	O
+reported	O
+to	O
+act	O
+by	O
+selectively	O
+constricting	O
+intracranial	O
+arteries	O
+.	O
+	
+Recently	O
+","	O
+vasopressor	O
+responses	O
+that	O
+are	O
+distinct	O
+from	O
+the	O
+cranial	O
+circulation	O
+have	O
+been	O
+demonstrated	O
+to	O
+occur	O
+in	O
+the	O
+systemic	O
+","	O
+pulmonary	O
+","	O
+and	O
+coronary	O
+circulations	O
+.	O
+	
+Cases	O
+have	O
+been	O
+published	O
+of	O
+coronary	B-NP
+vasospasm	I-NP
+","	O
+myocardial	B-NP
+ischemia	I-NP
+","	O
+and	O
+myocardial	B-NP
+infarction	I-NP
+occurring	O
+after	O
+sumatriptan	O
+use	O
+.	O
+	
+We	O
+report	O
+on	O
+the	O
+development	O
+of	O
+8	O
+serious	O
+cases	O
+of	O
+ischemic	B-NP
+colitis	I-NP
+in	O
+patients	O
+with	O
+migraine	B-NP
+treated	O
+with	O
+sumatriptan	O
+.	O
+	
+Pallidotomy	O
+with	O
+the	O
+gamma	O
+knife	O
+:	O
+a	O
+positive	O
+experience	O
+.	O
+	
+51	O
+patients	O
+with	O
+medically	O
+refractory	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+underwent	O
+stereotactic	O
+posteromedial	O
+pallidotomy	O
+between	O
+August	O
+1993	O
+and	O
+February	O
+1997	O
+for	O
+treatment	O
+of	O
+bradykinesia	B-NP
+","	O
+rigidity	B-NP
+","	O
+and	O
+L	O
+-	O
+DOPA	O
+-	O
+induced	O
+dyskinesias	B-NP
+.	O
+	
+In	O
+29	O
+patients	O
+","	O
+the	O
+pallidotomies	O
+were	O
+performed	O
+with	O
+the	O
+Leksell	O
+Gamma	O
+Knife	O
+and	O
+in	O
+22	O
+they	O
+were	O
+performed	O
+with	O
+the	O
+standard	O
+radiofrequency	O
+(	O
+RF	O
+)	O
+method	O
+.	O
+	
+Clinical	O
+assessment	O
+as	O
+well	O
+as	O
+blinded	O
+ratings	O
+of	O
+Unified	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+Disease	I-NP
+Rating	O
+Scale	O
+(	O
+UPDRS	O
+)	O
+scores	O
+were	O
+carried	O
+out	O
+pre	O
+-	O
+and	O
+postoperatively	O
+.	O
+	
+Mean	O
+follow	O
+-	O
+up	O
+time	O
+is	O
+20	O
+.	O
+6	O
+months	O
+(	O
+range	O
+6	O
+-	O
+48	O
+)	O
+and	O
+all	O
+except	O
+4	O
+patients	O
+have	O
+been	O
+followed	O
+more	O
+than	O
+one	O
+year	O
+.	O
+	
+85	O
+percent	O
+of	O
+patients	O
+with	O
+dyskinesias	B-NP
+were	O
+relieved	O
+of	O
+symptoms	O
+","	O
+regardless	O
+of	O
+whether	O
+the	O
+pallidotomies	O
+were	O
+performed	O
+with	O
+the	O
+Gamma	O
+Knife	O
+or	O
+radiofrequency	O
+methods	O
+.	O
+	
+About	O
+2	O
+/	O
+3	O
+of	O
+the	O
+patients	O
+in	O
+both	O
+Gamma	O
+Knife	O
+and	O
+radiofrequency	O
+groups	O
+showed	O
+improvements	O
+in	O
+bradykinesia	B-NP
+and	O
+rigidity	B-NP
+","	O
+although	O
+when	O
+considered	O
+as	O
+a	O
+group	O
+neither	O
+the	O
+Gamma	O
+Knife	O
+nor	O
+the	O
+radiofrequency	O
+group	O
+showed	O
+statistically	O
+significant	O
+improvements	O
+in	O
+UPDRS	O
+scores	O
+.	O
+	
+One	O
+patient	O
+in	O
+the	O
+Gamma	O
+Knife	O
+group	O
+(	O
+3	O
+.	O
+4	O
+%	O
+)	O
+developed	O
+a	O
+homonymous	B-NP
+hemianopsia	I-NP
+9	O
+months	O
+following	O
+treatment	O
+and	O
+5	O
+patients	O
+(	O
+27	O
+.	O
+7	O
+%	O
+)	O
+in	O
+the	O
+radiofrequency	O
+group	O
+became	O
+transiently	O
+confused	O
+postoperatively	O
+.	O
+	
+No	O
+other	O
+complications	O
+were	O
+seen	O
+.	O
+	
+Gamma	O
+Knife	O
+pallidotomy	O
+is	O
+as	O
+effective	O
+as	O
+radiofrequency	O
+pallidotomy	O
+in	O
+controlling	O
+certain	O
+of	O
+the	O
+symptoms	O
+of	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+It	O
+may	O
+be	O
+the	O
+only	O
+practical	O
+technique	O
+available	O
+in	O
+certain	O
+patients	O
+","	O
+such	O
+as	O
+those	O
+who	O
+take	O
+anticoagulants	O
+","	O
+have	O
+bleeding	B-NP
+diatheses	O
+or	O
+serious	O
+systemic	O
+medical	O
+illnesses	O
+.	O
+	
+It	O
+is	O
+a	O
+viable	O
+option	O
+for	O
+other	O
+patients	O
+as	O
+well	O
+.	O
+	
+Centrally	O
+mediated	O
+cardiovascular	O
+effects	O
+of	O
+intracisternal	O
+application	O
+of	O
+carbachol	O
+in	O
+anesthetized	O
+rats	O
+.	O
+	
+The	O
+pressor	O
+response	O
+to	O
+the	O
+intracisternal	O
+(	O
+i	O
+.	O
+c	O
+.	O
+)	O
+injection	O
+of	O
+carbachol	O
+(	O
+1	O
+mug	O
+)	O
+in	O
+anesthetized	O
+rats	O
+was	O
+analyzed	O
+.	O
+	
+This	O
+response	O
+was	O
+significantly	O
+reduced	O
+by	O
+the	O
+intravenous	O
+(	O
+i	O
+.	O
+v	O
+.	O
+)	O
+injection	O
+of	O
+guanethidine	O
+(	O
+5	O
+mg	O
+)	O
+","	O
+hexamethonium	O
+(	O
+10	O
+mg	O
+)	O
+or	O
+phentolamine	O
+(	O
+5	O
+mg	O
+)	O
+","	O
+and	O
+conversely	O
+","	O
+potentiated	O
+by	O
+i	O
+.	O
+v	O
+.	O
+desmethylimipramine	O
+(	O
+0	O
+.	O
+3	O
+mg	O
+)	O
+","	O
+while	O
+propranolol	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+)	O
+i	O
+.	O
+v	O
+.	O
+selectively	O
+inhibited	O
+the	O
+enlargement	B-NP
+of	I-NP
+pulse	I-NP
+pressure	I-NP
+and	O
+the	O
+tachycardia	B-NP
+following	O
+i	O
+.	O
+c	O
+.	O
+carbachol	O
+(	O
+1	O
+mug	O
+)	O
+.	O
+	
+On	O
+the	O
+other	O
+hand	O
+","	O
+the	O
+pressor	O
+response	O
+to	O
+i	O
+.	O
+c	O
+.	O
+carbachol	O
+(	O
+1	O
+mug	O
+)	O
+was	O
+almost	O
+completely	O
+blocked	O
+by	O
+i	O
+.	O
+c	O
+.	O
+atropine	O
+(	O
+3	O
+mug	O
+)	O
+or	O
+hexamethonium	O
+(	O
+500	O
+mug	O
+)	O
+","	O
+and	O
+significantly	O
+reduced	O
+by	O
+i	O
+.	O
+c	O
+.	O
+chlorpromazine	O
+(	O
+50	O
+mug	O
+)	O
+but	O
+significantly	O
+potentiated	O
+by	O
+i	O
+.	O
+c	O
+.	O
+desmethylimipramine	O
+(	O
+30	O
+mug	O
+)	O
+.	O
+	
+The	O
+pressor	O
+response	O
+to	O
+i	O
+.	O
+c	O
+.	O
+carbachol	O
+(	O
+1	O
+mug	O
+)	O
+remained	O
+unchanged	O
+after	O
+sectioning	O
+of	O
+the	O
+bilateral	O
+cervical	O
+vagal	O
+nerves	O
+but	O
+disappeared	O
+after	O
+sectioning	O
+of	O
+the	O
+spinal	O
+cord	O
+(	O
+C7	O
+-	O
+C8	O
+)	O
+.	O
+	
+From	O
+the	O
+above	O
+result	O
+it	O
+is	O
+suggested	O
+that	O
+the	O
+pressor	O
+response	O
+to	O
+i	O
+.	O
+c	O
+.	O
+carbachol	O
+ortral	O
+and	O
+peripheral	O
+adrenergic	O
+mechanisms	O
+","	O
+and	O
+that	O
+the	O
+sympathetic	O
+trunk	O
+is	O
+the	O
+main	O
+pathway	O
+.	O
+	
+Neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+and	O
+methylphenidate	O
+.	O
+	
+A	O
+1	O
+-	O
+year	O
+-	O
+old	O
+female	O
+presented	O
+with	O
+neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+probably	O
+caused	O
+by	O
+methylphenidate	O
+.	O
+	
+She	O
+had	O
+defects	O
+in	O
+the	O
+supratentorial	O
+brain	O
+including	O
+the	O
+basal	O
+ganglia	O
+and	O
+the	O
+striatum	O
+(	O
+multicystic	B-NP
+encephalomalacia	I-NP
+)	O
+due	O
+to	O
+severe	O
+perinatal	O
+hypoxic	B-NP
+-	I-NP
+ischemic	I-NP
+encephalopathy	I-NP
+","	O
+which	O
+was	O
+considered	O
+to	O
+be	O
+a	O
+possible	O
+predisposing	O
+factor	O
+causing	O
+neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+.	O
+	
+A	O
+dopaminergic	O
+blockade	O
+mechanism	O
+generally	O
+is	O
+accepted	O
+as	O
+the	O
+pathogenesis	O
+of	O
+this	O
+syndrome	O
+.	O
+	
+However	O
+","	O
+methylphenidate	O
+is	O
+a	O
+dopamine	O
+agonist	O
+via	O
+the	O
+inhibition	O
+of	O
+uptake	O
+of	O
+dopamine	O
+","	O
+and	O
+therefore	O
+dopaminergic	O
+systems	O
+in	O
+the	O
+brainstem	O
+(	O
+mainly	O
+the	O
+midbrain	O
+)	O
+and	O
+the	O
+spinal	O
+cord	O
+were	O
+unlikely	O
+to	O
+participate	O
+in	O
+the	O
+onset	O
+of	O
+this	O
+syndrome	O
+.	O
+	
+A	O
+relative	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+-	O
+ergic	O
+deficiency	O
+might	O
+occur	O
+because	O
+diazepam	O
+","	O
+a	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+-	O
+mimetic	O
+agent	O
+","	O
+was	O
+strikingly	O
+effective	O
+.	O
+	
+This	O
+is	O
+the	O
+first	O
+reported	O
+patient	O
+with	O
+neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+probably	O
+caused	O
+by	O
+methylphenidate	O
+.	O
+	
+Differential	O
+effects	O
+of	O
+17alpha	O
+-	O
+ethinylestradiol	O
+on	O
+the	O
+neutral	O
+and	O
+acidic	O
+pathways	O
+of	O
+bile	O
+salt	O
+synthesis	O
+in	O
+the	O
+rat	O
+.	O
+	
+Effects	O
+of	O
+17alpha	O
+-	O
+ethinylestradiol	O
+(	O
+EE	O
+)	O
+on	O
+the	O
+neutral	O
+and	O
+acidic	O
+biosynthetic	O
+pathways	O
+of	O
+bile	O
+salt	O
+(	O
+BS	O
+)	O
+synthesis	O
+were	O
+evaluated	O
+in	O
+rats	O
+with	O
+an	O
+intact	O
+enterohepatic	O
+circulation	O
+and	O
+in	O
+rats	O
+with	O
+long	O
+-	O
+term	O
+bile	O
+diversion	O
+to	O
+induce	O
+BS	O
+synthesis	O
+.	O
+	
+For	O
+this	O
+purpose	O
+","	O
+bile	O
+salt	O
+pool	O
+composition	O
+","	O
+synthesis	O
+of	O
+individual	O
+BS	O
+in	O
+vivo	O
+","	O
+hepatic	O
+activities	O
+","	O
+and	O
+expression	O
+levels	O
+of	O
+cholesterol	O
+7alpha	O
+-	O
+hydroxylase	O
+(	O
+CYP7A	O
+)	O
+","	O
+and	O
+sterol	O
+27	O
+-	O
+hydroxylase	O
+(	O
+CYP27	O
+)	O
+","	O
+as	O
+well	O
+as	O
+of	O
+other	O
+enzymes	O
+involved	O
+in	O
+BS	O
+synthesis	O
+","	O
+were	O
+analyzed	O
+in	O
+rats	O
+treated	O
+with	O
+EE	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+","	O
+3	O
+days	O
+)	O
+or	O
+its	O
+vehicle	O
+.	O
+	
+BS	O
+pool	O
+size	O
+was	O
+decreased	O
+by	O
+27	O
+%	O
+but	O
+total	O
+BS	O
+synthesis	O
+was	O
+not	O
+affected	O
+by	O
+EE	O
+in	O
+intact	O
+rats	O
+.	O
+	
+Synthesis	O
+of	O
+cholate	O
+was	O
+reduced	O
+by	O
+68	O
+%	O
+in	O
+EE	O
+-	O
+treated	O
+rats	O
+","	O
+while	O
+that	O
+of	O
+chenodeoxycholate	O
+was	O
+increased	O
+by	O
+60	O
+%	O
+.	O
+	
+The	O
+recently	O
+identified	O
+Delta22	O
+-	O
+isomer	O
+of	O
+beta	O
+-	O
+muricholate	O
+contributed	O
+for	O
+5	O
+.	O
+4	O
+%	O
+and	O
+18	O
+.	O
+3	O
+%	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+to	O
+the	O
+pool	O
+in	O
+control	O
+and	O
+EE	O
+-	O
+treated	O
+rats	O
+","	O
+respectively	O
+","	O
+but	O
+could	O
+not	O
+be	O
+detected	O
+in	O
+bile	O
+after	O
+exhaustion	O
+of	O
+the	O
+pool	O
+.	O
+	
+A	O
+clear	O
+reduction	O
+of	O
+BS	O
+synthesis	O
+was	O
+found	O
+in	O
+bile	O
+-	O
+diverted	O
+rats	O
+treated	O
+with	O
+EE	O
+","	O
+yet	O
+biliary	O
+BS	O
+composition	O
+was	O
+only	O
+minimally	O
+affected	O
+.	O
+	
+Activity	O
+of	O
+CYP7A	O
+was	O
+decreased	O
+by	O
+EE	O
+in	O
+both	O
+intact	O
+and	O
+bile	O
+-	O
+diverted	O
+rats	O
+","	O
+whereas	O
+the	O
+activity	O
+of	O
+the	O
+CYP27	O
+was	O
+not	O
+affected	O
+.	O
+	
+Hepatic	O
+mRNA	O
+levels	O
+of	O
+CYP7A	O
+were	O
+significantly	O
+reduced	O
+by	O
+EE	O
+in	O
+bile	O
+-	O
+diverted	O
+rats	O
+only	O
+;	O
+CYP27	O
+mRNA	O
+levels	O
+were	O
+not	O
+affected	O
+by	O
+EE	O
+.	O
+	
+In	O
+addition	O
+","	O
+mRNA	O
+levels	O
+of	O
+sterol	O
+12alpha	O
+-	O
+hydroxylase	O
+and	O
+lithocholate	O
+6beta	O
+-	O
+hydroxylase	O
+were	O
+increased	O
+by	O
+bile	O
+diversion	O
+and	O
+suppressed	O
+by	O
+EE	O
+.	O
+	
+This	O
+study	O
+shows	O
+that	O
+17alpha	O
+-	O
+ethinylestradiol	O
+(	O
+EE	O
+)	O
+-	O
+induced	O
+intrahepatic	B-NP
+cholestasis	I-NP
+in	O
+rats	O
+is	O
+associated	O
+with	O
+selective	O
+inhibition	O
+of	O
+the	O
+neutral	O
+pathway	O
+of	O
+bile	O
+salt	O
+(	O
+BS	O
+)	O
+synthesis	O
+.	O
+	
+Simultaneous	O
+impairment	O
+of	O
+other	O
+enzymes	O
+in	O
+the	O
+BS	O
+biosynthetic	O
+pathways	O
+may	O
+contribute	O
+to	O
+overall	O
+effects	O
+of	O
+EE	O
+on	O
+BS	O
+synthesis	O
+.	O
+	
+Glibenclamide	O
+-	O
+sensitive	O
+hypotension	B-NP
+produced	O
+by	O
+helodermin	O
+assessed	O
+in	O
+the	O
+rat	O
+.	O
+	
+The	O
+effects	O
+of	O
+helodermin	O
+","	O
+a	O
+basic	O
+35	O
+-	O
+amino	O
+acid	O
+peptide	O
+isolated	O
+from	O
+the	O
+venom	O
+of	O
+a	O
+lizard	O
+salivary	O
+gland	O
+","	O
+on	O
+arterial	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+were	O
+examined	O
+in	O
+the	O
+rat	O
+","	O
+focusing	O
+on	O
+the	O
+possibility	O
+that	O
+activation	O
+of	O
+ATP	O
+sensitive	O
+K	O
++	O
+(	O
+K	O
+(	O
+ATP	O
+)	O
+)	O
+channels	O
+is	O
+involved	O
+in	O
+the	O
+responses	O
+.	O
+	
+The	O
+results	O
+were	O
+also	O
+compared	O
+with	O
+those	O
+of	O
+vasoactive	O
+intestinal	O
+polypeptide	O
+(	O
+VIP	O
+)	O
+.	O
+	
+Helodermin	O
+produced	O
+hypotension	B-NP
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+with	O
+approximately	O
+similar	O
+potency	O
+and	O
+duration	O
+to	O
+VIP	O
+.	O
+	
+Hypotension	B-NP
+induced	O
+by	O
+both	O
+peptides	O
+was	O
+significantly	O
+attenuated	O
+by	O
+glibenclamide	O
+","	O
+which	O
+abolished	O
+a	O
+levcromakalim	O
+-	O
+produced	O
+decrease	O
+in	O
+arterial	O
+blood	O
+pressure	O
+.	O
+	
+Oxyhemoglobin	O
+did	O
+not	O
+affect	O
+helodermin	O
+-	O
+induced	O
+hypotension	B-NP
+","	O
+whereas	O
+it	O
+shortened	O
+the	O
+duration	O
+of	O
+acetylcholine	O
+(	O
+ACh	O
+)	O
+-	O
+produced	O
+hypotension	B-NP
+.	O
+	
+These	O
+findings	O
+suggest	O
+that	O
+helodermin	O
+-	O
+produced	O
+hypotension	B-NP
+is	O
+partly	O
+attributable	O
+to	O
+the	O
+activation	O
+of	O
+glibenclamide	O
+-	O
+sensitive	O
+K	O
++	O
+channels	O
+(	O
+K	O
+(	O
+ATP	O
+)	O
+channels	O
+)	O
+","	O
+which	O
+presumably	O
+exist	O
+on	O
+arterial	O
+smooth	O
+muscle	O
+cells	O
+.	O
+	
+EDRF	O
+(	O
+endothelium	O
+-	O
+derived	O
+relaxing	O
+factor	O
+)	O
+/	O
+nitric	O
+oxide	O
+does	O
+not	O
+seem	O
+to	O
+play	O
+an	O
+important	O
+role	O
+in	O
+the	O
+peptide	O
+-	O
+produced	O
+hypotension	B-NP
+.	O
+	
+Long	O
+-	O
+term	O
+efficacy	O
+and	O
+adverse	O
+event	O
+of	O
+nifedipine	O
+sustained	O
+-	O
+release	O
+tablets	O
+for	O
+cyclosporin	O
+A	O
+-	O
+induced	O
+hypertension	B-NP
+in	O
+patients	O
+with	O
+psoriasis	B-NP
+.	O
+	
+Thirteen	O
+psoriatic	B-NP
+patients	O
+with	O
+hypertension	B-NP
+during	O
+the	O
+course	O
+of	O
+cyclosporin	O
+A	O
+therapy	O
+were	O
+treated	O
+for	O
+25	O
+months	O
+with	O
+a	O
+calcium	O
+channel	O
+blocker	O
+","	O
+sustained	O
+-	O
+release	O
+nifedipine	O
+","	O
+to	O
+study	O
+the	O
+clinical	O
+antihypertensive	O
+effects	O
+and	O
+adverse	O
+events	O
+during	O
+treatment	O
+with	O
+both	O
+drugs	O
+.	O
+	
+Seven	O
+of	O
+the	O
+13	O
+patients	O
+had	O
+exhibited	O
+a	O
+subclinical	O
+hypertensive	B-NP
+state	O
+before	O
+cyclosporin	O
+A	O
+therapy	O
+.	O
+	
+Both	O
+systolic	O
+and	O
+diastolic	O
+blood	O
+pressures	O
+of	O
+these	O
+13	O
+patients	O
+were	O
+decreased	O
+significantly	O
+after	O
+4	O
+weeks	O
+of	O
+nifedipine	O
+therapy	O
+","	O
+and	O
+blood	O
+pressure	O
+was	O
+maintained	O
+within	O
+the	O
+normal	O
+range	O
+thereafter	O
+for	O
+25	O
+months	O
+.	O
+	
+The	O
+adverse	O
+events	O
+during	O
+combined	O
+therapy	O
+with	O
+cyclosporin	O
+A	O
+and	O
+nifedipine	O
+included	O
+an	O
+increase	O
+in	O
+blood	O
+urea	O
+nitrogen	O
+levels	O
+in	O
+9	O
+of	O
+the	O
+13	O
+patients	O
+and	O
+development	O
+of	O
+gingival	B-NP
+hyperplasia	I-NP
+in	O
+2	O
+of	O
+the	O
+13	O
+patients	O
+.	O
+	
+Our	O
+findings	O
+indicate	O
+that	O
+sustained	O
+-	O
+release	O
+nifedipine	O
+is	O
+useful	O
+for	O
+hypertensive	B-NP
+psoriatic	B-NP
+patients	O
+under	O
+long	O
+-	O
+term	O
+treatment	O
+with	O
+cyclosporin	O
+A	O
+","	O
+but	O
+that	O
+these	O
+patients	O
+should	O
+be	O
+monitored	O
+for	O
+gingival	B-NP
+hyperplasia	I-NP
+.	O
\ No newline at end of file
diff --git a/data/BC5CDR-disease/tokenized_test.txt b/data/BC5CDR-disease/tokenized_test.txt
new file mode 100644
index 0000000..bbac64b
--- /dev/null
+++ b/data/BC5CDR-disease/tokenized_test.txt
@@ -0,0 +1 @@
+Torsade de pointes ventricular tachycardia during low dose intermittent dobutamine treatment in a patient with dilated cardiomyopathy and congestive heart failure . The authors describe the case of a 56 - year - old woman with chronic , severe heart failure secondary to dilated cardiomyopathy and absence of significant ventricular arrhythmias who developed QT prolongation and torsade de pointes ventricular tachycardia during one cycle of intermittent low dose ( 2 . 5 mcg / kg per min ) dobutamine . This report of torsade de pointes ventricular tachycardia during intermittent dobutamine supports the hypothesis that unpredictable fatal arrhythmias may occur even with low doses and in patients with no history of significant rhythm disturbances . The mechanisms of proarrhythmic effects of Dubutamine are discussed . Positive skin tests in late reactions to radiographic contrast media . In the last few years delayed reactions several hours after the injection of radiographic and contrast materials ( PRC ) have been described with increasing frequency . The authors report two observations on patients with delayed reactions in whom intradermoreactions ( IDR ) and patch tests to a series of ionic and non ionic PRC were studied . After angiography by the venous route in patient n degree 1 a biphasic reaction with an immediate reaction ( dyspnea , loss of consciousness ) and delayed macro - papular rash appeared , whilst patient n degree 2 developed a generalised sensation of heat , persistent pain at the site of injection immediately and a generalised macro - papular reaction after 24 hours . The skin tests revealed positive delayed reactions of 24 hours and 48 hours by IDR and patch tests to only some PRC with common chains in their structures . The positive skin tests are in favour of immunological reactions and may help in diagnosis of allergy in the patients . Risk of transient hyperammonemic encephalopathy in cancer patients who received continuous infusion of 5 - fluorouracil with the complication of dehydration and infection . From 1986 to 1998 , 29 cancer patients who had 32 episodes of transient hyperammonemic encephalopathy related to continuous infusion of 5 - fluorouracil ( 5 - FU ) were identified . None of the patients had decompensated liver disease . Onset of hyperammonemic encephalopathy varied from 0 . 5 to 5 days ( mean : 2 . 6 + / - 1 . 3 days ) after the initiation of chemotherapy . Plasma ammonium level ranged from 248 to 2387 microg % ( mean : 626 + / - 431 microg % ) . Among the 32 episodes , 26 ( 81 % ) had various degrees of azotemia , 18 ( 56 % ) occurred during bacterial infections and 14 ( 44 % ) without infection occurred during periods of dehydration . Higher plasma ammonium levels and more rapid onset of hyperammonemia were seen in 18 patients with bacterial infections ( p = 0 . 003 and 0 . 0006 , respectively ) and in nine patients receiving high daily doses ( 2600 or 1800 mg / m2 ) of 5 - FU ( p = 0 . 0001 and < 0 . 0001 , respectively ) . In 25 out of 32 episodes ( 78 % ) , plasma ammonium levels and mental status returned to normal within 2 days after adequate management . In conclusion , hyperammonemic encephalopathy can occur in patients receiving continuous infusion of 5 - FU . Azotemia , body fluid insufficiency and bacterial infections were frequently found in these patients . It is therefore important to recognize this condition in patients receiving continuous infusion of 5 - FU . The effects of quinine and 4 - aminopyridine on conditioned place preference and changes in motor activity induced by morphine in rats . 1 . The effects of two unselective potassium ( K ( + ) - ) channel blockers , quinine ( 12 . 5 , 25 and 50 mg / kg ) and 4 - aminopyridine ( 1 and 2 mg / kg ) , on conditioned place preference and biphasic changes in motor activity induced by morphine ( 10 mg / kg ) were tested in Wistar rats . Quinine is known to block voltage - , calcium - and ATP - sensitive K ( + ) - channels while 4 - aminopyridine is known to block voltage - sensitive K ( + ) - channels . 2 . In the counterbalanced method , quinine attenuated morphine - induced place preference , whereas 4 - aminopyridine was ineffective . In the motor activity test measured with an Animex - activity meter neither of the K ( + ) - channel blockers affected morphine - induced hypoactivity , but both K ( + ) - channel blockers prevented morphine - induced secondary hyperactivity . 3 . These results suggest the involvement of quinine - sensitive but not 4 - aminopyridine - sensitive K ( + ) - channels in morphine reward . It is also suggested that the blockade of K ( + ) - channels sensitive to these blockers is not sufficient to prevent morphine - induced hypoactivity whereas morphine - induced hyperactivity seems to be connected to both quinine - and 4 - aminopyridine - sensitive K ( + ) - channels . Nociceptin / orphanin FQ and nocistatin on learning and memory impairment induced by scopolamine in mice . 1 . Nociceptin , also known as orphanin FQ , is an endogenous ligand for the orphan opioid receptor - like receptor 1 ( ORL1 ) and involves in various functions in the central nervous system ( CNS ) . On the other hand , nocistatin is recently isolated from the same precursor as nociceptin and blocks nociceptin - induced allodynia and hyperalgesia . 2 . Although ORL1 receptors which display a high degree of sequence homology with classical opioid receptors are abundant in the hippocampus , little is known regarding their role in learning and memory . 3 . The present study was designed to investigate whether nociceptin / orphanin FQ and nocistatin could modulate impairment of learning and memory induced by scopolamine , a muscarinic cholinergic receptor antagonist , using spontaneous alternation of Y - maze and step - down type passive avoidance tasks in mice . 4 . While nocistatin ( 0 . 5 - 5 . 0 nmol mouse - 1 , i . c . v . ) administered 30 min before spontaneous alternation performance or the training session of the passive avoidance task , had no effect on spontaneous alternation or passive avoidance behaviours , a lower per cent alternation and shorter median step - down latency in the retention test were obtained in nociceptin ( 1 . 5 and / or 5 . 0 nmol mouse - 1 , i . c . v . ) - treated normal mice . 5 . Administration of nocistatin ( 1 . 5 and / or 5 . 0 nmol mouse - 1 , i . c . v . ) 30 min before spontaneous alternation performance or the training session of the passive avoidance task , attenuated the scopolamine - induced impairment of spontaneous alternation and passive avoidance behaviours . 6 . These results indicated that nocistatin , a new biologically active peptide , ameliorates impairments of spontaneous alternation and passive avoidance induced by scopolamine , and suggested that these peptides play opposite roles in learning and memory . Meloxicam - induced liver toxicity . We report the case of a female patient with rheumatoid arthritis who developed acute cytolytic hepatitis due to meloxicam . Recently introduced in Belgium , meloxicam is the first nonsteroidal antiinflammatory drug with selective action on the inducible form of cyclooxygenase 2 . The acute cytolytic hepatitis occurred rapidly after meloxicam administration and was associated with the development of antinuclear antibodies suggesting a hypersensitivity mechanism . This first case of meloxicam related liver toxicity demonstrates the potential of this drug to induce hepatic damage . Induction of apoptosis by remoxipride metabolites in HL60 and CD34 + / CD19 - human bone marrow progenitor cells : potential relevance to remoxipride - induced aplastic anemia . The antipsychotic agent , remoxipride [ ( S ) - ( - ) - 3 - bromo - N - [ ( 1 - ethyl - 2 - pyrrolidinyl ) methyl ] - 2 , 6 - dimethoxybenz amide ] has been associated with acquired aplastic anemia . We have examined the ability of remoxipride , three pyrrolidine ring metabolites and five aromatic ring metabolites of the parent compound to induce apoptosis in HL60 cells and human bone marrow progenitor ( HBMP ) cells . Cells were treated for 0 - 24 h with each compound ( 0 - 200 microM ) . Apoptosis was assessed by fluorescence microscopy in Hoechst 33342 - and propidium iodide stained cell samples . Results were confirmed by determination of internucleosomal DNA fragmentation using gel electrophoresis for HL60 cell samples and terminal deoxynucleotidyl transferase assay in HBMP cells . The catechol and hydroquinone metabolites , NCQ436 and NCQ344 , induced apoptosis in HL60 and HBMP cells in a time - and concentration dependent manner , while the phenols , NCR181 , FLA873 , and FLA797 , and the derivatives formed by oxidation of the pyrrolidine ring , FLA838 , NCM001 , and NCL118 , had no effect . No necrosis was observed in cells treated with NCQ436 but NCQ344 had a biphasic effect in both cell types , inducing apoptosis at lower concentrations and necrosis at higher concentrations . These data show that the catechol and hydroquinone metabolites of remoxipride have direct toxic effects in HL60 and HBMP cells , leading to apoptosis , while the phenol metabolites were inactive . Similarly , benzene - derived catechol and hydroquinone , but not phenol , induce apoptosis in HBMP cells [ Moran et al . , Mol . Pharmacol . , 50 ( 1996 ) 610 - 615 ] . We propose that remoxipride and benzene may induce aplastic anemia via production of similar reactive metabolites and that the ability of NCQ436 and NCQ344 to induce apoptosis in HBMP cells may contribute to the mechanism underlying acquired aplastic anemia that has been associated with remoxipride . Synthesis and preliminary pharmacological investigations of 1 - ( 1 , 2 - dihydro - 2 - acenaphthylenyl ) piperazine derivatives as potential atypical antipsychotic agents in mice . In research towards the development of new atypical antipsychotic agents , one strategy is that the dopaminergic system can be modulated through manipulation of the serotonergic system . The synthesis and preliminary pharmacological evaluation of a series of potential atypical antipsychotic agents based on the structure of 1 - ( 1 , 2 - dihydro - 2 - acenaphthylenyl ) piperazine ( 7 ) is described . Compound 7e , 5 - { 2 - [ 4 - ( 1 , 2 - dihydro - 2 - acenaphthylenyl ) piperazinyl ] ethyl } - 2 , 3 - dihy dro - 1H - indol - 2 - one , from this series showed significant affinities at the 5 - HT1A and 5 - HT2A receptors and moderate affinity at the D2 receptor . 7e exhibits a high reversal of catalepsy induced by haloperidol indicating its atypical antipsychotic nature . Sub - chronic inhibition of nitric - oxide synthesis modifies haloperidol - induced catalepsy and the number of NADPH - diaphorase neurons in mice . RATIONALE : NG - nitro - L - arginine ( L - NOARG ) , an inhibitor of nitric - oxide synthase ( NOS ) , induces catalepsy in mice . This effect undergoes rapid tolerance , showing a significant decrease after 2 days of sub - chronic L - NOARG treatment . Nitric oxide ( NO ) has been shown to influence dopaminergic neurotransmission in the striatum . Neuroleptic drugs such as haloperidol , which block dopamine receptors , also cause catalepsy in rodents . OBJECTIVES : To investigate the effects of subchronic L - NOARG treatment in haloperidol - induced catalepsy and the number of NOS neurons in areas related to motor control . METHODS : Male albino Swiss mice were treated sub - chronically ( twice a day for 4 days ) with L - NOARG ( 40 mg / kg i . p . ) or haloperidol ( 1 mg / kg i . p . ) . Catalepsy was evaluated at the beginning and the end of the treatments . Reduced nicotinamide adenine dinucleotide phosphate - diaphorase ( NADPH - d ) histochemistry was also employed to visualize NOS as an index of enzyme expression in mice brain regions related to motor control . RESULTS : L - NOARG sub - chronic administration produced tolerance of L - NOARG and of haloperidol - induced catalepsy . It also induced an increase in the number of NADPH - d - positive cells in the dorsal part of the caudate and accumbens nuclei compared with haloperidol and in the pedunculopontine tegmental nucleus compared with saline . In contrast , there was a decrease in NADPH - d neuron number in the substantia nigra , pars compacta in both haloperidol - treated and L - NOARG - treated animals . CONCLUSIONS : The results give further support to the hypothesis that NO plays a role in motor behavior control and suggest that it may take part in the synaptic changes produced by antipsychotic treatment . Prolonged left ventricular dysfunction occurs in patients with coronary artery disease after both dobutamine and exercise induced myocardial ischaemia . OBJECTIVE : To determine whether pharmacological stress leads to prolonged but reversible left ventricular dysfunction in patients with coronary artery disease , similar to that seen after exercise . DESIGN : A randomised crossover study of recovery time of systolic and diastolic left ventricular function after exercise and dobutamine induced ischaemia . SUBJECTS : 10 patients with stable angina , angiographically proven coronary artery disease , and normal left ventricular function . INTERVENTIONS : Treadmill exercise and dobutamine stress were performed on different days . Quantitative assessment of systolic and diastolic left ventricular function was performed using transthoracic echocardiography at baseline and at regular intervals after each test . RESULTS : Both forms of stress led to prolonged but reversible systolic and diastolic dysfunction . There was no difference in the maximum double product ( p = 0 . 53 ) or ST depression ( p = 0 . 63 ) with either form of stress . After exercise , ejection fraction was reduced at 15 and 30 minutes compared with baseline ( mean ( SEM ) , - 5 . 6 ( 1 . 5 ) % , p < 0 . 05 ; and - 6 . 1 ( 2 . 2 ) % , p < 0 . 01 ) , and at 30 and 45 minutes after dobutamine ( - 10 . 8 ( 1 . 8 ) % and - 5 . 5 ( 1 . 8 ) % , both p < 0 . 01 ) . Regional analysis showed a reduction in the worst affected segment 15 and 30 minutes after exercise ( - 27 . 9 ( 7 . 2 ) % and - 28 . 6 ( 5 . 7 ) % , both p < 0 . 01 ) , and at 30 minutes after dobutamine ( - 32 ( 5 . 3 ) % , p < 0 . 01 ) . The isovolumic relaxation period was prolonged 45 minutes after each form of stress ( p < 0 . 05 ) . CONCLUSIONS : In patients with coronary artery disease , dobutamine induced ischaemia results in prolonged reversible left ventricular dysfunction , presumed to be myocardial stunning , similar to that seen after exercise . Dobutamine induced ischaemia could therefore be used to study the pathophysiology of this phenomenon further in patients with coronary artery disease . Anorexigens and pulmonary hypertension in the United States : results from the surveillance of North American pulmonary hypertension . BACKGROUND : The use of appetite suppressants in Europe has been associated with the development of primary pulmonary hypertension ( PPH ) . Recently , fenfluramine appetite suppressants became widely used in the United States but were withdrawn in September 1997 because of concerns over adverse effects . MATERIALS AND METHODS : We conducted a prospective surveillance study on patients diagnosed with pulmonary hypertension at 12 large referral centers in North America . Data collected on patients seen from September 1 , 1996 , to December 31 , 1997 , included the cause of the pulmonary hypertension and its severity . Patients with no identifiable cause of pulmonary hypertension were classed as PPH . A history of drug exposure also was taken with special attention on the use of antidepressants , anorexigens , and amphetamines . RESULTS : Five hundred seventy - nine patients were studied , 205 with PPH and 374 with pulmonary hypertension from other causes ( secondary pulmonary hypertension [ SPH ] ) . The use of anorexigens was common in both groups . However , of the medications surveyed , only the fenfluramines had a significant preferential association with PPH as compared with SPH ( adjusted odds ratio for use > 6 months , 7 . 5 ; 95 % confidence interval , 1 . 7 to 32 . 4 ) . The association was stronger with longer duration of use when compared to shorter duration of use and was more pronounced in recent users than in remote users . An unexpectedly high ( 11 . 4 % ) number of patients with SPH had used anorexigens . CONCLUSION : The magnitude of the association with PPH , the increase of association with increasing duration of use , and the specificity for fenfluramines are consistent with previous studies indicating that fenfluramines are causally related to PPH . The high prevalence of anorexigen use in patients with SPH also raises the possibility that these drugs precipitate pulmonary hypertension in patients with underlying conditions associated with SPH . Clinical aspects of heparin - induced thrombocytopenia and thrombosis and other side effects of heparin therapy . Heparin , first used to prevent the clotting of blood in vitro , has been clinically used to treat thrombosis for more than 50 years . Although several new anticoagulant drugs are in development , heparin remains the anticoagulant of choice to treat acute thrombotic episodes . The clinical effects of heparin are meritorious , but side effects do exist . Bleeding is the primary untoward effect of heparin . Major bleeding is of primary concern in patients receiving heparin therapy . However , additional important untoward effects of heparin therapy include heparin - induced thrombocytopenia , heparin - associated osteoporosis , eosinophilia , skin reactions , allergic reactions other than thrombocytopenia , alopecia , transaminasemia , hyperkalemia , hypoaldosteronism , and priapism . These side effects are relatively rare in a given individual , but given the extremely widespread use of heparin , some are quite common , particularly HITT and osteoporosis . Although reasonable incidences of many of these side effects can be " softly " deduced from current reports dealing with unfractionated heparin , at present the incidences of these side effects with newer low molecular weight heparins appear to be much less common . However , only longer experience will more clearly define the incidence of each side effect with low molecular weight preparations . A case of bilateral optic neuropathy in a patient on tacrolimus ( FK506 ) therapy after liver transplantation . PURPOSE : To report a case of bilateral optic neuropathy in a patient receiving tacrolimus ( FK 506 , Prograf ; Fujisawa USA , Inc , Deerfield , Illinois ) for immunosuppression after orthotropic liver transplantation . METHOD : Case report . In a 58 - year - old man receiving tacrolimus after orthotropic liver transplantation , serial neuro - ophthalmologic examinations and laboratory studies were performed . RESULTS : The patient had episodic deterioration of vision in both eyes , with clinical features resembling ischemic optic neuropathies . Deterioration of vision occurred despite discontinuation of the tacrolimus . CONCLUSION : Tacrolimus and other immunosuppressive agents may be associated with optic nerve toxicity . Hypercalcemia , arrhythmia , and mood stabilizers . Recent findings in a bipolar patient receiving maintenance lithium therapy who developed hypercalcemia and severe bradyarrhythmia prompted the authors to conduct a retrospective study of bipolar patients with lithium - associated hypercalcemia . A printout of all cases of hypercalcemia that presented during a 1 - year period was generated . After eliminating spurious hypercalcemias or those associated with intravenous fluids , the authors identified 18 non - lithium - treated patients with hypercalcemias related to malignancies and other medical conditions ( group A ) and 12 patients with lithium - associated hypercalcemia ( group B ) . Patients in group B were not comparable to those in group A , as the latter were medically compromised and were receiving multiple pharmacotherapies . Thus , two control groups were generated : group C1 , which included age - and sex - comparable lithium - treated bipolar normocalcemic patients , and group C2 , which included bipolar normocalcemic patients treated with anticonvulsant mood stabilizers . The electrocardiographic ( ECG ) findings for patients in group B were compared with those of patients in groups C1 and C2 . It was found that these groups did not differ in their overall frequency of ECG abnormalities ; however , there were significant differences in the frequency of conduction defects . Patients with hypercalcemia resulting from medical diseases and bipolar patients with lithium - associated hypercalcemia had significantly higher frequencies of conduction defects . Patients in group A had significant mortality at 2 - year follow - up ( 28 % ) , in contrast to zero mortality in the other three groups . The clinical implications of these findings are discussed . Attenuation of nephrotoxicity by a novel lipid nanosphere ( NS - 718 ) incorporating amphotericin B . NS - 718 , a lipid nanosphere incorporating amphotericin B , is effective against pathogenic fungi and has low toxicity . We compared the toxicity of NS - 718 with that of Fungizone ( amphotericin B - sodium deoxycholate ; D - AmB ) in vitro using renal cell cultures and in vivo by biochemical analysis , histopathological study of the kidney and pharmacokinetic study of amphotericin B following intravenous infusion of the formulation in rats . Incubation with NS - 718 resulted in significantly less damage of cultured human renal proximal tubular epithelial cells compared with D - AmB . Serum blood urea and creatinine concentrations increased significantly in rats given an iv infusion of D - AmB 3 mg / kg but not in those given the same dose of NS - 718 . Histopathological examination of the kidney showed tubular necrosis in D - AmB - treated rats but no change in NS - 718 - treated rats . Amphotericin B concentrations in the kidney in NS - 718 - treated rats were higher than those in D - AmB - treated rats . Our in vitro and in vivo results suggest that incorporation of amphotericin B into lipid nanospheres of NS - 718 attenuates the nephrotoxicity of amphotericin B . Patterns of sulfadiazine acute nephrotoxicity . Sulfadiazine acute nephrotoxicity is reviving specially because of its use in toxoplasmosis in HIV - positive patients . We report 4 cases , one of them in a previously healthy person . Under treatment with sulfadiazine they developed oliguria , abdominal pain , renal failure and showed multiple radiolucent renal calculi in echography . All patients recovered their previous normal renal function after adequate hydration and alcalinization . A nephrostomy tube had to be placed in one of the patients for ureteral lithiasis in a single functional kidney . None of them needed dialysis or a renal biopsy because of a typical benign course . Treatment with sulfadiazine requires exquisite control of renal function , an increase in water ingestion and possibly the alcalinization of the urine . We communicate a case in a previously healthy person , a fact not found in the recent literature . Probably many more cases are not detected . We think that a prospective study would be useful . Downbeat nystagmus associated with intravenous patient - controlled administration of morphine . IMPLICATIONS : This case documents a patient who developed dizziness with downbeating nystagmus while receiving a relatively large dose of IV patient - controlled analgesia morphine . Although there have been case reports of epidural morphine with these symptoms and signs , this has not been previously documented with IV or patient - controlled analgesia morphine . Hemodynamic and antiadrenergic effects of dronedarone and amiodarone in animals with a healed myocardial infarction . The hemodynamic and antiadrenergic effects of dronedarone , a noniodinated compound structurally related to amiodarone , were compared with those of amiodarone after prolonged oral administration , both at rest and during sympathetic stimulation in conscious dogs with a healed myocardial infarction . All dogs ( n = 6 ) randomly received orally dronedarone ( 10 and 30 mg / kg ) , amiodarone ( 10 and 30 mg / kg ) , and placebo twice daily for 7 days , with a 3 - week washout between consecutive treatments . Heart rate ( HR ) , mean arterial pressure ( MBP ) , positive rate of increase of left ventricular pressure ( + LVdP / dt ) , echocardiographically assessed left ventricular ejection fraction ( LVEF ) , and fractional shortening ( FS ) , as well as chronotropic response to isoproterenol and exercise - induced sympathetic stimulation were evaluated under baseline and posttreatment conditions . Resting values of LVEF , FS , + LVdP / dt , and MBP remained unchanged whatever the drug and the dosing regimen , whereas resting HR was significantly and dose - dependently lowered after dronedarone and to a lesser extent after amiodarone . Both dronedarone and amiodarone significantly reduced the exercise - induced tachycardia and , at the highest dose , decreased the isoproterenol - induced tachycardia . Thus , dronedarone and amiodarone displayed a similar level of antiadrenergic effect and did not impair the resting left ventricular function . Consequently , dronedarone might be particularly suitable for the treatment and prevention of various clinical arrhythmias , without compromising the left ventricular function . Phase 2 trial of liposomal doxorubicin ( 40 mg / m ( 2 ) ) in platinum / paclitaxel - refractory ovarian and fallopian tube cancers and primary carcinoma of the peritoneum . BACKGROUND : Several studies have demonstrated liposomal doxorubicin ( Doxil ) to be an active antineoplastic agent in platinum - resistant ovarian cancer , with dose limiting toxicity of the standard dosing regimen ( 50 mg / m ( 2 ) q 4 weeks ) being severe erythrodysesthesia ( " hand - foot syndrome " ) and stomatitis . We wished to develop a more tolerable liposomal doxorubicin treatment regimen and document its level of activity in a well - defined patient population with platinum / paclitaxel - refractory disease . METHODS AND MATERIALS : Patients with ovarian or fallopian tube cancers or primary peritoneal carcinoma with platinum / paclitaxel - refractory disease ( stable or progressive disease following treatment with these agents or previous objective response < 3 months in duration ) were treated with liposomal doxorubicin at a dose of 40 mg / m ( 2 ) q 4 weeks . RESULTS : A total of 49 patients ( median age : 60 ; range 41 - 81 ) entered this phase 2 trial . The median number of prior regimens was 2 ( range : 1 - 6 ) . Six ( 12 % ) and 4 ( 8 % ) patients experienced grade 2 hand - foot syndrome and stomatitis , respectively ( no episodes of grade 3 ) . One patient developed grade 3 diarrhea requiring hospitalization for hydration . Six ( 12 % ) individuals required dose reductions . The median number of courses of liposomal doxorubicin administered on this protocol was 2 ( range : 1 - 12 ) . Four of 44 patients ( 9 % ) evaluable for response exhibited objective and subjective evidence of an antineoplastic effect of therapy . CONCLUSION : This modified liposomal doxorubicin regimen results in less toxicity ( stomatitis , hand - foot syndrome ) than the standard FDA - approved dose schedule . Definite , although limited , antineoplastic activity is observed in patients with well - defined platinum - and paclitaxel - refractory ovarian cancer . Efficacy of olanzapine in acute bipolar mania : a double - blind , placebo - controlled study . The Olanzipine HGGW Study Group . BACKGROUND : We compared the efficacy and safety of olanzapine vs placebo for the treatment of acute bipolar mania . METHODS : Four - week , randomized , double - blind , parallel study . A total of 115 patients with a DSM - IV diagnosis of bipolar disorder , manic or mixed , were randomized to olanzapine , 5 to 20 mg / d ( n = 55 ) , or placebo ( n = 60 ) . The primary efficacy measure was the Young - Mania Rating Scale ( Y - MRS ) total score . Response and euthymia were defined , a priori , as at least a 50 % improvement from baseline to end point and as a score of no less than 12 at end point in the Y - MRS total score , respectively . Safety was assessed using adverse events , Extrapyramidal Symptom ( EPS ) rating scales , laboratory values , electrocardiograms , vital signs , and weight change . RESULTS : Olanzapine - treated patients demonstrated a statistically significant greater mean ( + / - SD ) improvement in Y - MRS total score than placebo - treated patients ( - 14 . 8 + / - 12 . 5 and - 8 . 1 + / - 12 . 7 , respectively ; P < . 001 ) , which was evident at the first postbaseline observation 1 week after randomization and was maintained throughout the study ( last observation carried forward ) . Olanzapine - treated patients demonstrated a higher rate of response ( 65 % vs 43 % , respectively ; P = . 02 ) and euthymia ( 61 % vs 36 % , respectively ; P = . 01 ) than placebo - treated patients . There were no statistically significant differences in EPSs between groups . However , olanzapine - treated patients had a statistically significant greater mean ( + / - SD ) weight gain than placebo - treated patients ( 2 . 1 + / - 2 . 8 vs 0 . 45 + / - 2 . 3 kg , respectively ) and also experienced more treatment - emergent somnolence ( 21 patients [ 38 . 2 % ] vs 5 [ 8 . 3 % ] , respectively ) . CONCLUSION : Olanzapine demonstrated greater efficacy than placebo in the treatment of acute bipolar mania and was generally well tolerated . The effect of pupil dilation with tropicamide on vision and driving simulator performance . PURPOSE : To assess the effect of pupil dilation on vision and driving ability . METHODS : A series of tests on various parameters of visual function and driving simulator performance were performed on 12 healthy drivers , before and after pupil dilation using guttae tropicamide 1 % . A driving simulator ( Transport Research Laboratory ) was used to measure reaction time ( RT ) , speed maintenance and steering accuracy . Tests of basic visual function included high - and low - contrast visual acuity ( HCVA and LCVA ) , Pelli - Robson contrast threshold ( CT ) and Goldmann perimetry ( FIELDS ) . Useful Field of View ( UFOV - - a test of visual attention ) was also undertaken . The mean differences in the pre - and post - dilatation measurements were tested for statistical significance at the 95 % level using one - tail paired t - tests . RESULTS : Pupillary dilation resulted in a statistically significant deterioration in CT and HCVA only . Five of 12 drivers also exhibited deterioration in LCVA , CT and RT . Little evidence emerged for deterioration in FIELDS and UFOV . Also , 7 of 12 drivers appeared to adjust their driving behaviour by reducing their speed on the driving simulator , leading to improved steering accuracy . CONCLUSIONS : Pupillary dilation may lead to a decrease in vision and daylight driving performance in young people . A larger study , including a broader spectrum of subjects , is warranted before guidelines can be recommended . A case of isotretinoin embryopathy with bilateral anotia and Taussig - Bing malformation . We report a newborn infant with multiple congenital anomalies ( anotia and Taussig - Bing malformation ) due to exposure to isotretinoin within the first trimester . In this paper we aim to draw to the fact that caution is needed when prescribing vitamin A - containing drugs to women of childbearing years . Effect of methoxamine on maximum urethral pressure in women with genuine stress incontinence : a placebo - controlled , double - blind crossover study . The aim of the study was to evaluate the potential role for a selective alpha1 - adrenoceptor agonist in the treatment of urinary stress incontinence . A randomised , double - blind , placebo - controlled , crossover study design was employed . Half log incremental doses of intravenous methoxamine or placebo ( saline ) were administered to a group of women with genuine stress incontinence while measuring maximum urethral pressure ( MUP ) , blood pressure , heart rate , and symptomatic side effects . Methoxamine evoked non - significant increases in MUP and diastolic blood pressure but caused a significant rise in systolic blood pressure and significant fall in heart rate at maximum dosage . Systemic side effects including piloerection , headache , and cold extremities were experienced in all subjects . The results indicate that the clinical usefulness of direct , peripherally acting sub - type - selective alpha1 - adrenoceptor agonists in the medical treatment of stress incontinence may be limited by associated piloerection and cardiovascular side effects . Hyperglycemic effect of amino compounds structurally related to caproate in rats . The chronic feeding of small amounts ( 0 . 3 - 3 % of diet weight ) of certain amino derivatives of caproate resulted in hyperglycemia , an elevated glucose tolerance curve and , occasionally , glucosuria . Effective compounds included norleucine , norvaline , glutamate , epsilon - aminocaproate , methionine , and leucine . Toleration of high doses of angiotensin - converting enzyme inhibitors in patients with chronic heart failure : results from the ATLAS trial . The Assessment of Treatment with Lisinopril and Survival . BACKGROUND : Treatment with angiotensin - converting enzyme ( ACE ) inhibitors reduces mortality and morbidity in patients with chronic heart failure ( CHF ) , but most affected patients are not receiving these agents or are being treated with doses lower than those found to be efficacious in trials , primarily because of concerns about the safety and tolerability of these agents , especially at the recommended doses . The present study examines the safety and tolerability of high - compared with low - dose lisinopril in CHF . METHODS : The Assessment of Lisinopril and Survival study was a multicenter , randomized , double - blind trial in which patients with or without previous ACE inhibitor treatment were stabilized receiving medium - dose lisinopril ( 12 . 5 or 15 . 0 mg once daily [ OD ] ) for 2 to 4 weeks and then randomized to high - ( 35 . 0 or 32 . 5 mg OD ) or low - dose ( 5 . 0 or 2 . 5 mg OD ) groups . Patients with New York Heart Association classes II to IV CHF and left ventricular ejection fractions of no greater than 0 . 30 ( n = 3164 ) were randomized and followed up for a median of 46 months . We examined the occurrence of adverse events and the need for discontinuation and dose reduction during treatment , with a focus on hypotension and renal dysfunction . RESULTS : Of 405 patients not previously receiving an ACE inhibitor , doses in only 4 . 2 % could not be titrated to the medium doses required for randomization because of symptoms possibly related to hypotension ( 2 . 0 % ) or because of renal dysfunction or hyperkalemia ( 2 . 3 % ) . Doses in more than 90 % of randomized patients in the high - and low - dose groups were titrated to their assigned target , and the mean doses of blinded medication in both groups remained similar throughout the study . Withdrawals occurred in 27 . 1 % of the high - and 30 . 7 % of the low - dose groups . Subgroups presumed to be at higher risk for ACE inhibitor intolerance ( blood pressure , < 120 mm Hg ; creatinine , > or = 132 . 6 micromol / L [ > or = 1 . 5 mg / dL ] ; age , > or = 70 years ; and patients with diabetes ) generally tolerated the high - dose strategy . CONCLUSIONS : These findings demonstrate that ACE inhibitor therapy in most patients with CHF can be successfully titrated to and maintained at high doses , and that more aggressive use of these agents is warranted . Cocaine , ethanol , and cocaethylene cardiotoxity in an animal model of cocaine and ethanol abuse . OBJECTIVES : Simultaneous abuse of cocaine and ethanol affects 12 million Americans annually . In combination , these substances are substantially more toxic than either drug alone . Their combined cardiac toxicity may be due to independent effects of each drug ; however , they may also be due to cocaethylene ( CE ) , a cocaine metabolite formed only in the presence of ethanol . The purpose of this study was to delineate the role of CE in the combined cardiotoxicity of cocaine and ethanol in a model simulating their abuse . METHODS : Twenty - three dogs were randomized to receive either 1 ) three intravenous ( IV ) boluses of cocaine 7 . 5 mg / kg with ethanol ( 1 g / kg ) as an IV infusion ( C + E , n = 8 ) , 2 ) three cocaine boluses only ( C , n = 6 ) , 3 ) ethanol infusion only ( E , n = 5 ) , or 4 ) placebo boluses and infusion ( n = 4 ) . Hemodynamic measurements , electrocardiograms , and serum drug concentrations were obtained at baseline , and then at fixed time intervals after each drug was administered . RESULTS : Two of eight dogs in the C + E group experienced cardiovascular collapse . The most dramatic hemodynamic changes occurred after each cocaine bolus in the C + E and C only groups ; however , persistent hemodynamic changes occurred in the C + E group . Peak CE levels were associated with a 45 % ( SD + / - 22 % , 95 % CI = 22 % to 69 % ) decrease in cardiac output ( p < 0 . 05 ) , a 56 % ( SD + / - 23 % , 95 % CI = 32 % to 80 % ) decrease in dP / dt ( max ) ( p < . 006 ) , and a 23 % ( SD + / - 15 % , 95 % CI = 7 % to 49 % ) decrease in SVO ( 2 ) ( p < 0 . 025 ) . Ventricular arrhythmias were primarily observed in the C + E group , in which four of eight dogs experienced ventricular tachycardia . CONCLUSIONS : Cocaine and ethanol in combination were more toxic than either substance alone . Co - administration resulted in prolonged cardiac toxicity and was dysrhythmogenic . Peak serum cocaethylene concentrations were associated with prolonged myocardial depression . Worsening of Parkinsonism after the use of veralipride for treatment of menopause : case report . We describe a female patient with stable Parkinson ' s disease who has shown a marked worsening of her motor functions following therapy of menopause related symptoms with veralipride , as well as the improvement of her symptoms back to baseline after discontinuation of the drug . We emphasize the anti - dopaminergic effect of veralipride . Viracept and irregular heartbeat warning . A group of doctors in Boston warn that the protease inhibitor Viracept may cause an irregular heart beat , known as bradycardia , in people with HIV . Bradycardia occurred in a 45 - year - old male patient who was Viracept in combination with other anti - HIV drugs . The symptoms ceased after switching to another drug combination . Frequency of appearance of myeloperoxidase - antineutrophil cytoplasmic antibody ( MPO - ANCA ) in Graves ' disease patients treated with propylthiouracil and the relationship between MPO - ANCA and clinical manifestations . OBJECTIVE : Myeloperoxidase antineutrophil cytoplasmic antibody ( MPO - ANCA ) - positive vasculitis has been reported in patients with Graves ' disease who were treated with propylthiouracil ( PTU ) . The appearance of MPO - ANCA in these cases was suspected of being related to PTU because the titres of MPO - ANCA decreased when PTU was stopped . Nevertheless , there have been no studies on the temporal relationship between the appearance of MPO - ANCA and vasculitis during PTU therapy , or on the incidence of MPO - ANCA in untreated Graves ' disease patients . Therefore , we sought to address these parameters in patients with Graves ' disease . PATIENTS : We investigated 102 untreated patients with hyperthyroidism due to Graves ' disease for the presence of MPO - ANCA , and for the development vasculitis after starting PTU therapy . Twenty - nine of them were later excluded because of adverse effects of PTU or because the observation period was less than 3 months . The remaining 73 patients ( 55 women and 18 men ) , all of whom were examined for more than 3 months , were adopted as the subjects of the investigation . The median observation period was 23 . 6 months ( range : 3 - 37 months ) . MEASUREMENTS : MPO - ANCA was measured at intervals of 2 - 6 months . RESULTS : Before treatment , the MPO - ANCA titres of all 102 untreated Graves ' disease patients were within the reference range ( below 10 U / ml ) . Three ( 4 . 1 % ) of the 73 patients were positive for MPO - ANCA at 13 , 16 and 17 months , respectively , after the start of PTU therapy . In two of them , the MPO - ANCA titres transiently increased to 12 . 8 and 15 . 0 U / ml , respectively , despite continued PTU therapy , but no vasculitic disorders developed . In the third patient , the MPO - ANCA titre increased to 204 U / ml and she developed a higher fever , oral ulcers and polyarthralgia , but the symptoms resolved 2 weeks after stopping PTU therapy , and the MPO - ANCA titre decreased to 20 . 7 U / ml by 4 months after discontinuing PTU . CONCLUSIONS : PTU therapy may be related to the appearance of MPO - ANCA , but MPO - ANCA does not appear to be closely related to vasculitis . Prevalence of heart disease in asymptomatic chronic cocaine users . To determine the prevalence of heart disease in outpatient young asymptomatic chronic cocaine users , 35 cocaine users and 32 age - matched controls underwent resting and exercise electrocardiography ( ECG ) and Doppler echocardiography . Findings consistent with coronary artery disease were detected in 12 ( 34 % ) patients and 3 ( 9 % ) controls ( p = 0 . 01 ) . Decreased left ventricular systolic function was demonstrated in 5 ( 14 % ) patients , but in none of the controls ( p = 0 . 055 ) . Finally , resting and peak exercise abnormal left ventricular filling was detected in 38 and 35 % of patients as compared to 19 and 9 % of controls , respectively ( p = 0 . 11 and 0 . 02 , respectively ) . We conclude that coronary artery or myocardial disease is common ( 38 % ) in young asymptomatic chronic cocaine users . Therefore , screening ECG and echocardiography may be warranted in these patients . Cardioprotective effects of Picrorrhiza kurroa against isoproterenol - induced myocardial stress in rats . The cardioprotective effect of the ethanol extract of Picrorrhiza kurroa rhizomes and roots ( PK ) on isoproterenol - induced myocardial infarction in rats with respect to lipid metabolism in serum and heart tissue has been investigated . Oral pre - treatment with PK ( 80 mg kg ( - 1 ) day ( - 1 ) for 15 days ) significantly prevented the isoproterenol - induced myocardial infarction and maintained the rats at near normal status . Phase 2 early afterdepolarization as a trigger of polymorphic ventricular tachycardia in acquired long - QT syndrome : direct evidence from intracellular recordings in the intact left ventricular wall . BACKGROUND : This study examined the role of phase 2 early afterdepolarization ( EAD ) in producing a trigger to initiate torsade de pointes ( TdP ) with QT prolongation induced by dl - sotalol and azimilide . The contribution of transmural dispersion of repolarization ( TDR ) to transmural propagation of EAD and the maintenance of TdP was also evaluated . METHODS AND RESULTS : Transmembrane action potentials from epicardium , midmyocardium , and endocardium were recorded simultaneously , together with a transmural ECG , in arterially perfused canine and rabbit left ventricular preparations . dl - Sotalol preferentially prolonged action potential duration ( APD ) in M cells dose - dependently ( 1 to 100 micromol / L ) , leading to QT prolongation and an increase in TDR . Azimilide , however , significantly prolonged APD and QT interval at concentrations from 0 . 1 to 10 micromol / L but shortened them at 30 micromol / L . Unlike dl - sotalol , azimilide ( > 3 micromol / L ) increased epicardial APD markedly , causing a diminished TDR . Although both dl - sotalol and azimilide rarely induced EADs in canine left ventricles , they produced frequent EADs in rabbits , in which more pronounced QT prolongation was seen . An increase in TDR by dl - sotalol facilitated transmural propagation of EADs that initiated multiple episodes of spontaneous TdP in 3 of 6 rabbit left ventricles . Of note , although azimilide ( 3 to 10 micromol / L ) increased APD more than dl - sotalol , its EADs often failed to propagate transmurally , probably because of a diminished TDR . CONCLUSIONS : This study provides the first direct evidence from intracellular action potential recordings that phase 2 EAD can be generated from intact ventricular wall and produce a trigger to initiate the onset of TdP under QT prolongation . A pilot study to assess the safety of dobutamine stress echocardiography in the emergency department evaluation of cocaine - associated chest pain . STUDY OBJECTIVE : Chest pain in the setting of cocaine use poses a diagnostic dilemma . Dobutamine stress echocardiography ( DSE ) is a widely available and sensitive test for evaluating cardiac ischemia . Because of the theoretical concern regarding administration of dobutamine in the setting of cocaine use , we conducted a pilot study to assess the safety of DSE in emergency department patients with cocaine - associated chest pain . METHODS : A prospective case series was conducted in the intensive diagnostic and treatment unit in the ED of an urban tertiary - care teaching hospital . Patients were eligible for DSE if they had used cocaine within 24 hours preceding the onset of chest pain and had a normal ECG and tropinin I level . Patients exhibiting signs of continuing cocaine toxicity were excluded from the study . All patients were admitted to the hospital for serial testing after the DSE testing in the intensive diagnostic and treatment unit . RESULTS : Twenty - four patients were enrolled . Two patients had inadequate resting images , one DSE was terminated because of inferior hypokinesis , another DSE was terminated because of a rate - related atrial conduction deficit , and 1 patient did not reach the target heart rate . Thus , 19 patients completed a DSE and reached their target heart rates . None of the patients experienced signs of exaggerated adrenergic response , which was defined as a systolic blood pressure of greater than 200 mm Hg or the occurrence of tachydysrhythmias ( excluding sinus tachycardia ) . Further suggesting lack of exaggerated adrenergic response , 13 ( 65 % ) of 20 patients required supplemental atropine to reach their target heart rates . CONCLUSION : No exaggerated adrenergic response was detected when dobutamine was administered to patients with cocaine - related chest pain . Prenatal cocaine exposure and cranial sonographic findings in preterm infants . PURPOSE : Prenatal cocaine exposure has been linked with subependymal hemorrhage and the formation of cysts that are detectable on cranial sonography in neonates born at term . We sought to determine if prenatal cocaine exposure increases the incidence of subependymal cysts in preterm infants . METHODS : We retrospectively reviewed the medical records and cranial sonograms obtained during a 1 - year period on 122 premature ( < 36 weeks of gestation ) infants . Infants were categorized into 1 of 2 groups : those exposed to cocaine and those not exposed to cocaine . Infants were assigned to the cocaine - exposed group if there was a maternal history of cocaine abuse during pregnancy or if maternal or neonatal urine toxicology results were positive at the time of delivery . RESULTS : Five of the 122 infants were excluded from the study because of insufficient medical and drug histories . The incidence of subependymal cysts in the 117 remaining infants was 14 % ( 16 of 117 ) . The incidence of subependymal cysts in infants exposed to cocaine prenatally was 44 % ( 8 of 18 ) compared with 8 % ( 8 of 99 ) in the unexposed group ( p < 0 . 01 ) . CONCLUSIONS : We found an increased incidence of subependymal cyst formation in preterm infants who were exposed to cocaine prenatally . This result is consistent with results of similar studies in term infants . Thalidomide neuropathy in patients treated for metastatic prostate cancer . We prospectively evaluated thalidomide - induced neuropathy using electrodiagnostic studies . Sixty - seven men with metastatic androgen - independent prostate cancer in an open - label trial of oral thalidomide underwent neurologic examinations and nerve conduction studies ( NCS ) prior to and at 3 - month intervals during treatment . NCS included recording of sensory nerve action potentials ( SNAPs ) from median , radial , ulnar , and sural nerves . SNAP amplitudes for each nerve were expressed as the percentage of its baseline , and the mean of the four was termed the SNAP index . A 40 % decline in the SNAP index was considered clinically significant . Thalidomide was discontinued in 55 patients for lack of therapeutic response . Of 67 patients initially enrolled , 24 remained on thalidomide for 3 months , 8 remained at 6 months , and 3 remained at 9 months . Six patients developed neuropathy . Clinical symptoms and a decline in the SNAP index occurred concurrently . Older age and cumulative dose were possible contributing factors . Neuropathy may thus be a common complication of thalidomide in older patients . The SNAP index can be used to monitor peripheral neuropathy , but not for early detection . Overexpression of copper / zinc - superoxide dismutase protects from kanamycin - induced hearing loss . The participation of reactive oxygen species in aminoglycoside - induced ototoxicity has been deduced from observations that aminoglycoside - iron complexes catalyze the formation of superoxide radicals in vitro and that antioxidants attenuate ototoxicity in vivo . We therefore hypothesized that overexpression of Cu / Zn - superoxide dismutase ( h - SOD1 ) should protect transgenic mice from ototoxicity . Immunocytochemistry confirmed expression of h - SOD1 in inner ear tissues of transgenic C57BL / 6 - TgN [ SOD1 ] 3Cje mice . Transgenic and nontransgenic littermates received kanamycin ( 400 mg / kg body weight / day ) for 10 days beginning on day 10 after birth . Auditory thresholds were tested by evoked auditory brain stem responses at 1 month after birth . In nontransgenic animals , the threshold in the kanamycin - treated group was 45 - 50 dB higher than in saline - injected controls . In the transgenic group , kanamycin increased the threshold by only 15 dB over the respective controls . The effects were similar at 12 and 24 kHz . The protection by overexpression of superoxide dismutase supports the hypothesis that oxidant stress plays a significant role in aminoglycoside - induced ototoxicity . The results also suggest transgenic animals as suitable models to investigate the underlying mechanisms and possible strategies for prevention . Fatty liver induced by tetracycline in the rat . Dose - response relationships and effect of sex . Dose - response relationships , biochemical mechanisms , and sex differences in the experimental fatty liver induced by tetracycline were studied in the intact rat and with the isolated perfused rat liver in vitro . In the intact male and female rat , no direct relationship was observed between dose of tetracycline and hepatic accumulation of triglyceride . With provision of adequate oleic acid as a substrate for the isolated perfused liver , a direct relationship was observed between dose of tetracycline and both accumulation of triglyceride in the liver and depression of output of triglyceride by livers from male and female rats . Marked differences were observed between female and male rats with regard to base line ( control ) hepatic concentration of triglyceride and output of triglyceride . Accumulation of hepatic triglyceride , as a per cent of control values , in response to graded doses of tetracycline , did not differ significantly between male , female and pregnant rat livers . However , livers from female , and especially pregnant female rats , were strikingly resistant to the effects of tetracycline on depression of output of triglyceride under these experimental conditions . These differences between the sexes could not be related to altered disposition of tetracycline or altered uptake of oleic acid . Depressed hepatic secretion of triglyceride accounted only for 30 to 50 % of accumulated hepatic triglyceride , indicating that additional mechanisms must be involved in the production of the triglyceride - rich fatty liver in response to tetracycline . Prednisone induces anxiety and glial cerebral changes in rats . OBJECTIVE : To assess whether prednisone ( PDN ) produces anxiety and / or cerebral glial changes in rats . METHODS : Male Wistar rats were studied and 3 groups were formed ( 8 rats per group ) . The moderate - dose group received 5 mg / kg / day PDN released from a subcutaneous implant . In the high - dose group , implants containing PDN equivalent to 60 mg / kg / day were applied . In the control group implants contained no PDN . Anxiety was assessed using an open field and elevated plus - maze devices . The number of cells and cytoplasmic transformation of astrocytes and microglia cells were assessed by immunohistochemical analyses . RESULTS : Anxiety was documented in both groups of PDN treated rats compared with controls . The magnitude of transformation of the microglia assessed by the number of intersections was significantly higher in the PDN groups than in controls in the prefrontal cortex ( moderate - dose , 24 . 1 ; high - dose , 23 . 6 ; controls 18 . 7 ; p < 0 . 01 ) and striatum ( moderate - dose 25 . 6 ; high - dose 26 . 3 ; controls 18 . 9 ; p < 0 . 01 ) , but not in hippocampus . The number of stained microglia cells was significantly higher in the PDN treated groups in the prefrontal cortex than in controls ( moderate - dose , 29 . 1 ; high - dose , 28 . 4 ; control , 17 . 7 cells per field ; p < 0 . 01 ) . Stained microglia cells were significantly more numerous striatum and hippocampus in the high - dose group compared to controls . CONCLUSION : Subacute exposure to PDN induced anxiety and reactivity of microglia . The relevance of these features for patients using PDN remains to be elucidated . Phase II study of carboplatin and liposomal doxorubicin in patients with recurrent squamous cell carcinoma of the cervix . BACKGROUND : The activity of the combination of carboplatin and liposomal doxorubicin was tested in a Phase II study of patients with recurrent cervical carcinoma . METHODS : The combination of carboplatin ( area under the concentration curve [ AUC ] , 5 ) and liposomal doxorubicin ( Doxil ; starting dose , 40 mg / m ( 2 ) ) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile . RESULTS : Twenty - nine patients were assessable for response , and 35 patients were assessable for toxicity . The overall response rate was 38 % , the median time to response was 10 weeks , the median duration of response was 26 weeks , and the median survival was 37 weeks . The main toxic effect was myelosuppression , with Grade 3 and 4 neutropenia in 16 patients , anemia in 12 patients , thrombocytopenia in 11 patients , and neutropenic fever in 3 patients . Four patients had five infusion - related reactions during the infusion of liposomal doxorubicin , leading to treatment discontinuation in three patients . Grade > or = 2 nonhematologic toxicity included nausea in 17 patients , emesis in 14 patients , fatigue in 9 patients , mucositis and / or stomatitis in 8 patients , constipation in 6 patients , weight loss in 5 patients , hand - foot syndrome in 2 patients , and skin reactions in 3 patients . CONCLUSIONS : The combination of carboplatin and liposomal doxorubicin has modest activity in patients with recurrent cervical carcinoma . Antimicrobial - induced mania ( antibiomania ) : a review of spontaneous reports . The authors reviewed reported cases of antibiotic - induced manic episodes by means of a MEDLINE and PsychLit search for reports of antibiotic - induced mania . Unpublished reports were requested from the World Health Organization ( WHO ) and the Food and Drug Administration ( FDA ) . Twenty - one reports of antimicrobial - induced mania were found in the literature . There were 6 cases implicating clarithromycin , 13 implicating isoniazid , and 1 case each implicating erythromycin and amoxicillin . The WHO reported 82 cases . Of these , clarithromycin was implicated in 23 ( 27 . 6 % ) cases , ciprofloxacin in 12 ( 14 . 4 % ) cases , and ofloxacin in 10 ( 12 % ) cases . Cotrimoxazole , metronidazole , and erythromycin were involved in 15 reported manic episodes . Cases reported by the FDA showed clarithromycin and ciprofloxacin to be the most frequently associated with the development of mania . Statistical analysis of the data would not have demonstrated a significant statistical correlative risk and was therefore not undertaken . Patients have an increased risk of developing mania while being treated with antimicrobials . Although this is not a statistically significant risk , physicians must be aware of the effect and reversibility . Further research clearly is required to determine the incidence of antimicrobial - induced mania , the relative risk factors of developing an antimicrobial - induced manic episode among various demographic populations , and the incidence of patients who continue to have persistent affective disorders once the initial episode , which occurs while the patient is taking antibiotics , subsides . The authors elected to name this syndrome " antibiomania . " Levodopa - induced ocular dyskinesias in Parkinson ' s disease . Levodopa - induced ocular dyskinesias are very uncommon . Usually they occur simultaneously with limb peak - dose choreatic dyskinesias . We report on a patient with leftward and upward deviations of gaze during the peak effect of levodopa , and hypothesize that a severe dopaminergic denervation in the caudate nucleus is needed for the appearance of these levodopa - induce ocular dyskinesias . A comparison of glyceryl trinitrate with diclofenac for the treatment of primary dysmenorrhea : an open , randomized , cross - over trial . Primary dysmenorrhea is a syndrome characterized by painful uterine contractility caused by a hypersecretion of endometrial prostaglandins ; non - steroidal anti - inflammatory drugs are the first choice for its treatment . However , in vivo and in vitro studies have demonstrated that myometrial cells are also targets of the relaxant effects of nitric oxide ( NO ) . The aim of the present study was to determine the efficacy of glyceryl trinitrate ( GTN ) , an NO donor , in the resolution of primary dysmenorrhea in comparison with diclofenac ( DCF ) . A total of 24 patients with the diagnosis of severe primary dysmenorrhea were studied during two consecutive menstrual cycles . In an open , cross - over , controlled design , patients were randomized to receive either DCF per os or GTN patches the first days of menses , when menstrual cramps became unendurable . In the subsequent cycle the other treatment was used . Patients received up to 3 doses / day of 50 mg DCF or 2 . 5 mg / 24 h transdermal GTN for the first 3 days of the cycle , according to their needs . The participants recorded menstrual symptoms and possible side - effects at different times ( 0 , 30 , 60 , 120 minutes ) after the first dose of medication on the first day of the cycle , with both drugs . The difference in pain intensity score ( DPI ) was the main outcome variable . Both treatments significantly reduced DPI by the 30th minute ( GTN , - 12 . 8 + / - 17 . 9 ; DCF , - 18 . 9 + / - 16 . 6 ) . However , DCF continued to be effective in reducing pelvic pain for two hours , whereas GTN scores remained more or less stable after 30 min and significantly higher than those for DFC ( after one hour : GTN , - 12 . 8 + / - 17 . 9 ; DFC , - 18 . 9 + / - 16 . 6 and after two hours : GTN , - 23 . 7 + / - 20 . 5 ; DFC , - 59 . 7 + / - 17 . 9 , p = 0 . 0001 ) . Low back pain was also relieved by both drugs . Headache was significantly increased by GTN but not by DCF . Eight patients stopped using GTN because headache - - attributed to its use - - became intolerable . These findings indicate that GTN has a reduced efficacy and tolerability by comparison with DCF in the treatment of primary dysmenorrhea . Temocapril , a long - acting non - SH group angiotensin converting enzyme inhibitor , modulates glomerular injury in chronic puromycin aminonucleoside nephrosis . The purpose of the present study was to determine whether chronic administration of temocapril , a long - acting non - SH group angiotensin converting enzyme ( ACE ) inhibitor , reduced proteinuria , inhibited glomerular hypertrophy and prevented glomerulosclerosis in chronic puromycin aminonucleoside ( PAN ) - induced nephrotic rats . Nephrosis was induced by injection of PAN ( 15mg / 100g body weight ) in male Sprague - Dawley ( SD ) rats . Four groups were used , i ) the PAN group ( 14 ) , ii ) PAN / temocapril ( 13 ) , iii ) temocapril ( 14 ) and iv ) untreated controls ( 15 ) . Temocapril ( 8 mg / kg / day ) was administered to the rats which were killed at weeks 4 , 14 or 20 . At each time point , systolic blood pressure ( BP ) , urinary protein excretion and renal histopathological findings were evaluated , and morphometric image analysis was done . Systolic BP in the PAN group was significantly high at 4 , 14 and 20 weeks , but was normal in the PAN / temocapril group . Urinary protein excretion in the PAN group increased significantly , peaking at 8 days , then decreased at 4 weeks , but rose again significantly at 14 and 20 weeks . Temocapril did not attenuate proteinuria at 8 days , but it did markedly lower it from weeks 4 to 20 . The glomerulosclerosis index ( GSI ) was 6 . 21 % at 4 weeks and respectively 25 . 35 % and 30 . 49 % at 14 and 20 weeks in the PAN group . There was a significant correlation between urinary protein excretion and GSI ( r = 0 . 808 , p < 0 . 0001 ) . The ratio of glomerular tuft area to the area of Bowman ' s capsules ( GT / BC ) in the PAN group was significantly increased , but it was significantly lower in the PAN / temocapril group . It appears that temocapril was effective in retarding renal progression and protected renal function in PAN neprotic rats . Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants . We report three cases of severe hypoxaemia after ibuprofen administration during a randomised controlled trial of prophylactic treatment of patent ductus arteriosus with ibuprofen in premature infants born at less than 28 weeks of gestation . Echocardiography showed severely decreased pulmonary blood flow . Hypoxaemia resolved quickly on inhaled nitric oxide therapy . We suggest that investigators involved in similar trials pay close attention to pulmonary pressure if hypoxaemia occurs after prophylactic administration of ibuprofen . Hyponatremia and syndrome of inappropriate anti - diuretic hormone reported with the use of Vincristine : an over - representation of Asians ? PURPOSE : This retrospective study used a pharmaceutical company ' s global safety database to determine the reporting rate of hyponatremia and / or syndrome of inappropriate secretion of anti - diuretic hormone ( SIADH ) among vincristine - treated patients and to explore the possibility of at - risk population subgroups . METHOD : We searched the Eli Lilly and Company ' s computerized adverse event database for all reported cases of hyponatremia and / or SIADH as of 1 November 1999 that had been reported during the use of vincristine . RESULTS : A total of 76 cases of hyponatremia and / or SIADH associated with vincristine use were identified . The overall reporting rate was estimated to be 1 . 3 / 100 , 000 treated patients . The average age of patients was 35 . 6 + / - 28 . 3 years , and 62 % were males . Approximately 75 % of the patients were receiving treatment for leukemia or lymphoma . Among the 39 reports that included information on race , the racial distribution was : 1 Black , 3 Caucasian , and 35 Asian . CONCLUSION : Our data suggest that Asian patients may be at increased risk of hyponatremia and / or SIADH associated with vincristine use . Although the overall reported rate of SIADH associated with vincristine is very low , physicians caring for Asian oncology patients should be aware of this potential serious but reversible adverse event . Delayed toxicity of cyclophosphamide on the bladder of DBA / 2 and C57BL / 6 female mouse . The present study describes the delayed development of a severe bladder pathology in a susceptible strain of mice ( DBA / 2 ) but not in a resistant strain ( C57BL / 6 ) when both were treated with a single 300 mg / kg dose of cyclophosphamide ( CY ) . Inbred DBA / 2 and C57BL / 6 female mice were injected with CY , and the effect of the drug on the bladder was assessed during 100 days by light microscopy using different staining procedures , and after 30 days by conventional electron microscopy . Early CY toxicity caused a typical haemorrhagic cystitis in both strains that was completely repaired in about 7 - 10 days . After 30 days of CY injection ulcerous and non - ulcerous forms of chronic cystitis appeared in 86 % of DBA / 2 mice but only in 4 % of C57BL / 6 mice . Delayed cystitis was characterized by infiltration and transepithelial passage into the lumen of inflammatory cells and by frequent exfoliation of the urothelium . Mast cells appeared in the connective and muscular layers of the bladder at a much higher number in DBA / 2 mice than in C57BL / 6 mice or untreated controls . Electron microscopy disclosed the absence of the typical discoidal vesicles normally present in the cytoplasm of surface cells . Instead , numerous abnormal vesicles containing one or several dark granules were observed in the cytoplasm of cells from all the epithelial layers . Delayed cystitis still persisted in DBA / 2 mice 100 days after treatment . These results indicate that delayed toxicity of CY in female DBA / 2 mice causes a bladder pathology that is not observed in C57BL / 6 mice . This pathology resembles interstitial cystitis in humans and could perhaps be used as an animal model for studies on the disease . High - dose 5 - fluorouracil / folinic acid in combination with three - weekly mitomycin C in the treatment of advanced gastric cancer . A phase II study . BACKGROUND : The 24 - hour continuous infusion of 5 - fluorouracil ( 5 - FU ) and folinic acid ( FA ) as part of several new multidrug chemotherapy regimens in advanced gastric cancer ( AGC ) has shown to be effective , with low toxicity . In a previous phase II study with 3 - weekly bolus 5 - FU , FA and mitomycin C ( MMC ) we found a low toxicity rate and response rates comparable to those of regimens such as ELF , FAM or FAMTX , and a promising median overall survival . In order to improve this MMC - dependent schedule we initiated a phase II study with high - dose 5 - FU / FA and 3 - weekly bolus MMC . PATIENTS AND METHODS : From February , 1998 to September , 2000 we recruited 33 patients with AGC to receive weekly 24 - hour 5 - FU 2 , 600 mg / m ( 2 ) preceded by 2 - hour FA 500 mg / m ( 2 ) for 6 weeks , followed by a 2 - week rest period . Bolus MMC 10 mg / m ( 2 ) was added in 3 - weekly intervals . Treatment given on an outpatient basis , using portable pump systems , was repeated on day 57 . Patients ' characteristics were : male / female ratio 20 / 13 ; median age 57 ( 27 - 75 ) years ; median WHO status 1 ( 0 - 2 ) . 18 patients had a primary AGC , and 15 showed a relapsed AGC . Median follow - up was 11 . 8 months ( range of those surviving : 2 . 7 - 11 . 8 months ) . RESULTS : 32 patients were evaluable for response - complete remission 9 . 1 % ( n = 3 ) , partial remission 45 . 5 % ( n = 15 ) , no change 27 . 3 % ( n = 9 ) , progressive disease 15 . 1 % ( n = 5 ) . Median overall survival time was 10 . 2 months [ 95 % confidence interval ( CI ) : 8 . 7 - 11 . 6 ] , and median progression - free survival time was 7 . 6 months ( 95 % CI : 4 . 4 - 10 . 9 ) . The worst toxicities ( % ) observed were ( CTC - NCI 1 / 2 / 3 ) : leukopenia 45 . 5 / 18 . 2 / 6 . 1 , thrombocytopenia 33 . 3 / 9 . 1 / 6 . 1 , vomitus 24 . 2 / 9 . 1 / 0 , diarrhea 36 . 4 / 6 . 1 / 3 . 0 , stomatitis 18 . 2 / 9 . 1 / 0 , hand - foot syndrome 12 . 1 / 0 / 0 . Two patients developed hemolytic - uremic syndrome ( HUS ) . CONCLUSIONS : High - dose 5 - FU / FA / MMC is an effective and well - tolerated outpatient regimen for AGC ( objective response rate 54 . 6 % ) . It may serve as an alternative to cisplatin - containing regimens ; however , it has to be considered that possibly HUS may occur . Persistent sterile leukocyturia is associated with impaired renal function in human immunodeficiency virus type 1 - infected children treated with indinavir . BACKGROUND : Prolonged administration of indinavir is associated with the occurrence of a variety of renal complications in adults . These well - documented side effects have restricted the use of this potent protease inhibitor in children . DESIGN : A prospective study to monitor indinavir - related nephrotoxicity in a cohort of 30 human immunodeficiency virus type 1 - infected children treated with indinavir . METHODS : Urinary pH , albumin , creatinine , the presence of erythrocytes , leukocytes , bacteria and crystals , and culture were analyzed every 3 months for 96 weeks . Serum creatinine levels were routinely determined at the same time points . Steady - state pharmacokinetics of indinavir were done at week 4 after the initiation of indinavir . RESULTS : The cumulative incidence of persistent sterile leukocyturia ( > or = 75 cells / micro L in at least 2 consecutive visits ) after 96 weeks was 53 % . Persistent sterile leukocyturia was frequently associated with a mild increase in the urine albumin / creatinine ratio and by microscopic hematuria . The cumulative incidence of serum creatinine levels > 50 % above normal was 33 % after 96 weeks . Children with persistent sterile leukocyturia more frequently had serum creatinine levels of 50 % above normal than those children without persistent sterile leukocyturia . In children younger than 5 . 6 years , persistent sterile leukocyturia was significantly more frequent than in older children . A higher cumulative incidence of persistent leukocyturia was found in children with an area under the curve > 19 mg / L x h or a peak serum level of indinavir > 12 mg / L . In 4 children , indinavir was discontinued because of nephrotoxicity . Subsequently , the serum creatinine levels decreased , the urine albumin / creatinine ratios returned to zero , and the leukocyturia disappeared within 3 months . CONCLUSIONS : Children treated with indinavir have a high cumulative incidence of persistent sterile leukocyturia . Children with persistent sterile leukocyturia more frequently had an increase in serum creatinine levels of > 50 % above normal . Younger children have an additional risk for renal complications . The impairment of the renal function in these children occurred in the absence of clinical symptoms of nephrolithiasis . Indinavir - associated nephrotoxicity must be monitored closely , especially in children with risk factors such as persistent sterile leukocyturia , age < 5 . 6 years , an area under the curve of indinavir > 19 mg / L x h , and a C ( max ) > 12 mg / L . Utility of troponin I in patients with cocaine - associated chest pain . Baseline electrocardiogram abnormalities and market elevations not associated with myocardial necrosis make accurate diagnosis of myocardial infarction ( MI ) difficult in patients with cocaine - associated chest pain . Troponin sampling may offer greater diagnostic utility in these patients . OBJECTIVE : To assess outcomes based on troponin positivity in patients with cocaine chest pain admitted for exclusion of MI . METHODS : Outcomes were examined in patients admitted for possible MI after cocaine use . All patients underwent a rapid rule - in protocol that included serial sampling of creatine kinase ( CK ) , CK - MB , and cardiac troponin I ( cTnI ) over eight hours . Outcomes included CK - MB MI ( CK - MB > or = 8 ng / mL with a relative index [ ( CK - MB x 100 ) / total CK ] > or = 4 , cardiac death , and significant coronary disease ( > or = 50 % ) . RESULTS : Of the 246 admitted patients , 34 ( 14 % ) met CK - MB criteria for MI and 38 ( 16 % ) had cTnI elevations . Angiography was performed in 29 of 38 patients who were cTnI - positive , with significant disease present in 25 ( 86 % ) . Three of the four patients without significant disease who had cTnI elevations met CK - MB criteria for MI , and the other had a peak CK - MB level of 13 ng / mL . Sensitivities , specificities , and positive and negative likelihood ratios for predicting cardiac death or significant disease were high for both CK - MB MI and cTnI and were not significantly different . CONCLUSIONS : Most patients with cTnI elevations meet CK - MB criteria for MI , as well as have a high incidence of underlying significant disease . Troponin appears to have an equivalent diagnostic accuracy compared with CK - MB for diagnosing necrosis in patients with cocaine - associated chest pain and suspected MI . Acute interstitial nephritis due to nicergoline ( Sermion ) . We report a case of acute interstitial nephritis ( AIN ) due to nicergoline ( Sermion ) . A 50 - year - old patient admitted to our hospital for fever and acute renal failure . Before admission , he had been taking nicergoline and bendazac lysine due to retinal vein occlusion at ophthalmologic department . Thereafter , he experienced intermittent fever and skin rash . On admission , clinical symptoms ( i . e . arthralgia and fever ) and laboratory findings ( i . e . eosinophilia and renal failure ) suggested AIN , and which was confirmed by pathologic findings on renal biopsy . A lymphocyte transformation test demonstrated a positive result against nicergoline . Treatment was consisted of withdrawal of nicergoline and intravenous methylprednisolone , and his renal function was completely recovered . To our knowledge , this is the first report of nicergoline - associated AIN . Neuroleptic malignant syndrome complicated by massive intestinal bleeding in a patient with chronic renal failure . A patient with chronic renal failure ( CRF ) developed neuroleptic malignant syndrome ( NMS ) after administration of risperidone and levomepromazine . In addition to the typical symptoms of NMS , massive intestinal bleeding was observed during the episode . This report suggests that NMS in a patient with CRF may be complicated by intestinal bleeding and needs special caution for this complication . Blood brain barrier in right - and left - pawed female rats assessed by a new staining method . The asymmetrical breakdown of the blood - brain barrier ( BBB ) was studied in female rats . Paw preference was assessed by a food reaching test . Adrenaline - induced hypertension was used to destroy the BBB , which was evaluated using triphenyltetrazolium ( TTC ) staining of the brain slices just after giving adrenaline for 30 s . In normal rats , the whole brain sections exhibited complete staining with TTC . After adrenaline infusion for 30 s , there were large unstained areas in the left brain in right - pawed animals , and vice versa in left - pawed animals . Similar results were obtained in seizure - induced breakdown of BBB . These results were explained by an asymmetric cerebral blood flow depending upon the paw preference in rats . It was suggested that this new method and the results are consistent with contralateral motor control that may be important in determining the dominant cerebral hemisphere in animals . Carvedilol protects against doxorubicin - induced mitochondrial cardiomyopathy . Several cytopathic mechanisms have been suggested to mediate the dose - limiting cumulative and irreversible cardiomyopathy caused by doxorubicin . Recent evidence indicates that oxidative stress and mitochondrial dysfunction are key factors in the pathogenic process . The objective of this investigation was to test the hypothesis that carvedilol , a nonselective beta - adrenergic receptor antagonist with potent antioxidant properties , protects against the cardiac and hepatic mitochondrial bioenergetic dysfunction associated with subchronic doxorubicin toxicity . Heart and liver mitochondria were isolated from rats treated for 7 weeks with doxorubicin ( 2 mg / kg sc / week ) , carvedilol ( 1 mg / kg ip / week ) , or the combination of the two drugs . Heart mitochondria isolated from doxorubicin - treated rats exhibited depressed rates for state 3 respiration ( 336 + / - 26 versus 425 + / - 53 natom O / min / mg protein ) and a lower respiratory control ratio ( RCR ) ( 4 . 3 + / - 0 . 6 versus 5 . 8 + / - 0 . 4 ) compared with cardiac mitochondria isolated from saline - treated rats . Mitochondrial calcium - loading capacity and the activity of NADH - dehydrogenase were also suppressed in cardiac mitochondria from doxorubicin - treated rats . Doxorubicin treatment also caused a decrease in RCR for liver mitochondria ( 3 . 9 + / - 0 . 9 versus 5 . 6 + / - 0 . 7 for control rats ) and inhibition of hepatic cytochrome oxidase activity . Coadministration of carvedilol decreased the extent of cellular vacuolization in cardiac myocytes and prevented the inhibitory effect of doxorubicin on mitochondrial respiration in both heart and liver . Carvedilol also prevented the decrease in mitochondrial Ca ( 2 + ) loading capacity and the inhibition of the respiratory complexes of heart mitochondria caused by doxorubicin . Carvedilol by itself did not affect any of the parameters measured for heart or liver mitochondria . It is concluded that this protection by carvedilol against both the structural and functional cardiac tissue damage may afford significant clinical advantage in minimizing the dose - limiting mitochondrial dysfunction and cardiomyopathy that accompanies long - term doxorubicin therapy in cancer patients . Cocaine - induced hyperactivity is more influenced by adenosine receptor agonists than amphetamine - induced hyperactivity . The influence of adenosine receptor agonists and antagonists on cocaine - and amphetamine - induced hyperactivity was examined in mice . All adenosine receptor agonists significantly decreased the locomotor activity in mice , and the effects were dose - dependent . It seems that adenosine A1 and A2 receptors might be involved in this reaction . Moreover , all adenosine receptor agonists : 2 - p - ( 2 - carboxyethyl ) phenethylamino - 5 ' - N - ethylcarboxamidoadenosine ( CGS 21680 ) , A2A receptor agonist , N6 - cyclopentyladenosine ( CPA ) , A1 receptor agonist , and 5 ' - N - ethylcarboxamidoadenosine ( NECA ) , A2 / A1 receptor agonist significantly and dose - dependently decreased cocaine - induced locomotor activity . CPA reduced cocaine action at the doses which , given alone , did not influence motility , while CGS 21680 and NECA decreased the action of cocaine at the doses which , given alone , decreased locomotor activity in animals . These results suggest the involvement of both adenosine receptors in the action of cocaine although agonists of A1 receptors seem to have stronger influence on it . The selective blockade of A2 adenosine receptor by DMPX ( 3 , 7 - dimethyl - 1 - propargylxanthine ) significantly enhanced cocaine - induced locomotor activity of animals . Caffeine had similar action but the effect was not significant . CPT ( 8 - cyclopentyltheophylline ) - - A1 receptor antagonist , did not show any influence in this test . Similarly , all adenosine receptor agonists decreased amphetamine - induced hyperactivity , but at the higher doses than those which were active in cocaine - induced hyperactivity . The selective blockade of A2 adenosine receptors ( DMPX ) and non - selective blockade of adenosine receptors ( caffeine ) significantly increased the action of amphetamine in the locomotor activity test . Our results have shown that all adenosine receptor agonists ( A1 and A2 ) reduce cocaine - and amphetamine - induced locomotor activity and indicate that cocaine - induced hyperactivity is more influenced by adenosine receptor agonists ( particularly A1 receptors ) than amphetamine - induced hyperactivity . Amiodarone and the risk of bradyarrhythmia requiring permanent pacemaker in elderly patients with atrial fibrillation and prior myocardial infarction . OBJECTIVES : The aim of this study was to determine whether the use of amiodarone in patients with atrial fibrillation ( AF ) increases the risk of bradyarrhythmia requiring a permanent pacemaker . BACKGROUND : Reports of severe bradyarrhythmia during amiodarone therapy are infrequent and limited to studies assessing the therapy ' s use in the management of patients with ventricular arrhythmias . METHODS : A study cohort of 8 , 770 patients age > or = 65 years with a new diagnosis of AF was identified from a provincewide database of Quebec residents with a myocardial infarction ( MI ) between 1991 and 1999 . Using a nested case - control design , 477 cases of bradyarrhythmia requiring a permanent pacemaker were matched ( 1 : 4 ) to 1 , 908 controls . Multivariable logistic regression was used to estimate the odds ratio ( OR ) of pacemaker insertion associated with amiodarone use , controlling for baseline risk factors and exposure to sotalol , Class I antiarrhythmic agents , beta - blockers , calcium channel blockers , and digoxin . RESULTS : amiodarone use was associated with an increased risk of pacemaker insertion ( OR : 2 . 14 , 95 % confidence interval [ CI ] : 1 . 30 to 3 . 54 ) . This effect was modified by gender , with a greater risk in women versus men ( OR : 3 . 86 , 95 % CI : 1 . 70 to 8 . 75 vs . OR : 1 . 52 , 95 % CI : 0 . 80 to 2 . 89 ) . Digoxin was the only other medication associated with an increased risk of pacemaker insertion ( OR : 1 . 78 , 95 % CI : 1 . 37 to 2 . 31 ) . CONCLUSIONS : This study suggests that the use of amiodarone in elderly patients with AF and a previous MI increases the risk of bradyarrhythmia requiring a permanent pacemaker . The finding of an augmented risk of pacemaker insertion in elderly women receiving amiodarone requires further investigation . Indomethacin - induced morphologic changes in the rat urinary bladder epithelium . OBJECTIVES : To evaluate the morphologic changes in rat urothelium induced by indomethacin . Nonsteroidal anti - inflammatory drug - induced cystitis is a poorly recognized and under - reported condition . In addition to tiaprofenic acid , indomethacin has been reported to be associated with this condition . METHODS : Three groups were established : a control group ( n = 10 ) , a high - dose group ( n = 10 ) , treated with one intraperitoneal injection of indomethacin 20 mg / kg , and a therapeutic dose group ( n = 10 ) in which oral indomethacin was administered 3 . 25 mg / kg body weight daily for 3 weeks . The animals were then killed and the bladders removed for light and electron microscopic studies . RESULTS : The light microscopic findings showed some focal epithelial degeneration that was more prominent in the high - dose group . When compared with the control group , both indomethacin groups revealed statistically increased numbers of mast cells in the mucosa ( P < 0 . 0001 ) and penetration of lanthanum nitrate through intercellular areas of the epithelium . Furthermore , the difference in mast cell counts between the high and therapeutic dose groups was also statistically significant ( P < 0 . 0001 ) . CONCLUSIONS : Indomethacin resulted in histopathologic findings typical of interstitial cystitis , such as leaky bladder epithelium and mucosal mastocytosis . The true incidence of nonsteroidal anti - inflammatory drug - induced cystitis in humans must be clarified by prospective clinical trials . An open - label phase II study of low - dose thalidomide in androgen - independent prostate cancer . The antiangiogenic effects of thalidomide have been assessed in clinical trials in patients with various solid and haematological malignancies . Thalidomide blocks the activity of angiogenic agents including bFGF , VEGF and IL - 6 . We undertook an open - label study using thalidomide 100 mg once daily for up to 6 months in 20 men with androgen - independent prostate cancer . The mean time of study was 109 days ( median 107 , range 4 - 184 days ) . Patients underwent regular measurement of prostate - specific antigen ( PSA ) , urea and electrolytes , serum bFGF and VEGF . Three men ( 15 % ) showed a decline in serum PSA of at least 50 % , sustained throughout treatment . Of 16 men treated for at least 2 months , six ( 37 . 5 % ) showed a fall in absolute PSA by a median of 48 % . Increasing levels of serum bFGF and VEGF were associated with progressive disease ; five of six men who demonstrated a fall in PSA also showed a decline in bFGF and VEGF levels , and three of four men with a rising PSA showed an increase in both growth factors . Adverse effects included constipation , morning drowsiness , dizziness and rash , and resulted in withdrawal from the study by three men . Evidence of peripheral sensory neuropathy was found in nine of 13 men before treatment . In the seven men who completed six months on thalidomide , subclinical evidence of peripheral neuropathy was found in four before treatment , but in all seven at repeat testing . The findings indicate that thalidomide may be an option for patients who have failed other forms of therapy , provided close follow - up is maintained for development of peripheral neuropathy . Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block : A report of two cases . BACKGROUND AND OBJECTIVES : Central nervous system and cardiac toxicity following the administration of local anesthetics is a recognized complication of regional anesthesia . Levobupivacaine , the pure S ( - ) enantiomer of bupivacaine , was developed to improve the cardiac safety profile of bupivacaine . We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine . CASE REPORT : Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach . Immediately after the administration of levobupivacaine 0 . 5 % with epinephrine 2 . 5 microgram / mL , the patients developed grand mal seizures , despite negative aspiration for blood and no clinical signs of intravenous epinephrine administration . The seizures were successfully treated with sodium thiopental in addition to succinylcholine in 1 patient . Neither patient developed signs of cardiovascular toxicity . Both patients were treated preoperatively with beta - adrenergic antagonist medications , which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with epinephrine . CONCLUSIONS : Although levobupivacaine may have a safer cardiac toxicity profile than racemic bupivacaine , if adequate amounts of levobupivacaine reach the circulation , it will result in convulsions . Plasma concentrations sufficient to result in central nervous system toxicity did not produce manifestations of cardiac toxicity in these 2 patients . Amiodarone - induced torsade de pointes during bladder irrigation : an unusual presentation - - a case report . The authors present a case of early ( within 4 days ) development of torsade de pointes ( TdP ) associated with oral amiodarone therapy . Consistent with other reports this case of TdP occurred in the context of multiple exacerbating factors including hypokalemia and digoxin excess . Transient prolongation of the QT during bladder irrigation prompted the episode of TdP . It is well known that bradycardia exacerbates acquired TdP . The authors speculate that the increased vagal tone during bladder irrigation , a vagal maneuver , in the context of amiodarone therapy resulted in amiodarone - induced proarrhythmia . In the absence of amiodarone therapy , a second bladder irrigation did not induce TdP despite hypokalemia and hypomagnesemia . Anaesthetic complications associated with myotonia congenita : case study and comparison with other myotonic disorders . Myotonia congenita ( MC ) is caused by a defect in the skeletal muscle chloride channel function , which may cause sustained membrane depolarisation . We describe a previously healthy 32 - year - old woman who developed a life - threatening muscle spasm and secondary ventilation difficulties following a preoperative injection of suxamethonium . The muscle spasms disappeared spontaneously and the surgery proceeded without further problems . When subsequently questioned , she reported minor symptoms suggesting a myotonic condition . Myotonia was found on clinical examination and EMG . The diagnosis MC was confirmed genetically . Neither the patient nor the anaesthetist were aware of the diagnosis before this potentially lethal complication occurred . We give a brief overview of ion channel disorders including malignant hyperthermia and their anaesthetic considerations . Respiratory pattern in a rat model of epilepsy . PURPOSE : Apnea is known to occur during seizures , but systematic studies of ictal respiratory changes in adults are few . Data regarding respiratory pattern defects during interictal periods also are scarce . Here we sought to generate information with regard to the interictal period in animals with pilocarpine - induced epilepsy . METHODS : Twelve rats ( six chronically epileptic animals and six controls ) were anesthetized , given tracheotomies , and subjected to hyperventilation or hypoventilation conditions . Breathing movements caused changes in thoracic volume and forced air to flow tidally through a pneumotachograph . This flow was measured by using a differential pressure transducer , passed through a polygraph , and from this to a computer with custom software that derived ventilation ( VE ) , tidal volume ( VT ) , inspiratory time ( TI ) , expiratory time ( TE ) , breathing frequency ( f ) , and mean inspiratory flow ( VT / TI ) on a breath - by - breath basis . RESULTS : The hyperventilation maneuver caused a decrease in spontaneous ventilation in pilocarpine - treated and control rats . Although VE had a similar decrease in both groups , in the epileptic group , the decrease in VE was due to a significant ( p < 0 . 05 ) increase in TE peak in relation to that of the control animals . The hypoventilation maneuver led to an increase in the arterial Paco2 , followed by an increase in VE . In the epileptic group , the increase in VE was mediated by a significant ( p < 0 . 05 ) decrease in TE peak compared with the control group . Systemic application of KCN , to evaluate the effects of peripheral chemoreception activation on ventilation , led to a similar increase in VE for both groups . CONCLUSIONS : The data indicate that pilocarpine - treated animals have an altered ability to react to ( or compensate for ) blood gas changes with changes in ventilation and suggest that it is centrally determined . We speculate on the possible relation of the current findings on treating different epilepsy - associated conditions . Fatal myeloencephalopathy due to intrathecal vincristine administration . Vincristine was accidentally given intrathecally to a child with leukaemia , producing sensory and motor dysfunction followed by encephalopathy and death . Separate times for administering vincristine and intrathecal therapy is recommended . Progesterone potentiation of bupivacaine arrhythmogenicity in pentobarbital - anesthetized rats and beating rat heart cell cultures . The effects of progesterone treatment on bupivacaine arrhythmogenicity in beating rat heart myocyte cultures and on anesthetized rats were determined . After determining the bupivacaine AD50 ( the concentration of bupivacaine that caused 50 % of all beating rat heart myocyte cultures to become arrhythmic ) , we determined the effect of 1 - hour progesterone HCl exposure on myocyte contractile rhythm . Each concentration of progesterone ( 6 . 25 , 12 . 5 , 25 , and 50 micrograms / ml ) caused a significant and concentration - dependent reduction in the AD50 for bupivacaine . Estradiol treatment also increased the arrhythmogenicity of bupivacaine in myocyte cultures , but was only one fourth as potent as progesterone . Neither progesterone nor estradiol effects on bupivacaine arrhythmogenicity were potentiated by epinephrine . Chronic progesterone pretreatment ( 5 mg / kg / day for 21 days ) caused a significant increase in bupivacaine arrhythmogenicity in intact pentobarbital - anesthetized rats . There was a significant decrease in the time to onset of arrhythmia as compared with control nonprogesterone - treated rats ( 6 . 2 + / - 1 . 3 vs . 30 . 8 + / - 2 . 5 min , mean + / - SE ) . The results of this study indicate that progesterone can potentiate bupivacaine arrhythmogenicity both in vivo and in vitro . Potentiation of bupivacaine arrhythmia in myocyte cultures suggests that this effect is at least partly mediated at the myocyte level . Increased serum soluble Fas in patients with acute liver failure due to paracetamol overdose . BACKGROUND / AIMS : Experimental studies have suggested that apoptosis via the Fas / Fas Ligand signaling system may play an important role in the development of acute liver failure . The aim of the study was to investigate the soluble form of Fas in patients with acute liver failure . METHODOLOGY : Serum levels of sFas ( soluble Fas ) were measured by ELISA in 24 patients with acute liver failure and 10 normal control subjects . Serum levels of tumor necrosis factor - alpha and interferon - gamma were also determined by ELISA . RESULTS : Serum sFas was significantly increased in patients with acute liver failure ( median , 26 . 8 U / mL ; range , 6 . 9 - 52 . 7 U / mL ) compared to the normal controls ( median , 8 . 6 U / mL ; range , 6 . 5 - 12 . 0 U / mL , P < 0 . 0001 ) . Levels were significantly greater in patients with acute liver failure due to paracetamol overdose ( median , 28 . 7 U / mL ; range , 12 . 8 - 52 . 7 U / mL , n = 17 ) than those due to non - A to E hepatitis ( median , 12 . 5 U / mL ; range , 6 . 9 - 46 . 0 U / mL , n = 7 , P < 0 . 01 ) . There was no relationship of sFas to eventual outcome in the patients . A significant correlation was observed between serum sFas levels and aspartate aminotransferase ( r = 0 . 613 , P < 0 . 01 ) . CONCLUSIONS : The increased concentration of sFas in serum of patients with acute liver failure may reflect activation of Fas - mediated apoptosis in the liver and this together with increased tumor necrosis factor - alpha may be an important factor in liver cell loss . Bilateral subthalamic nucleus stimulation for Parkinson ' s disease . High frequency stimulation of the subthalamic nucleus ( STN ) is known to ameliorate the signs and symptoms of advanced Parkinson ' s disease . AIM : We studied the effect of high frequency STN stimulation in 23 patients . METHOD : Twenty - three patients suffering from severe Parkinson ' s disease ( Stages III - V on Hoehn and Yahr scale ) and , particularly bradykinesia , rigidity , and levodopa - induced dyskinesias underwent bilateral implantation of electrodes in the STN . Preoperative and postoperative assessments of these patients at 1 , 3 , 6 and 12 months follow - up , in " on " and " off " drug conditions , was carried out using Unified Parkinson ' s Disease Rating Scale , Hoehn and Yahr staging , England activities of daily living score and video recordings . RESULTS : After one year of electrical stimulation of the STN , the patients ' scores for activities of daily living and motor examination scores ( Unified Parkinson ' s Disease Rating Scale parts II and III ) off medication improved by 62 % and 61 % respectively ( p < 0 . 0005 ) . The subscores for the akinesia , rigidity , tremor and gait also improved . ( p < 0 . 0005 ) . The average levodopa dose decreased from 813 mg to 359 mg . The cognitive functions remained unchanged . Two patients developed device - related complications and two patients experienced abnormal weight gain . CONCLUSION : Bilateral subthalamic nucleus stimulation is an effective treatment for advanced Parkinson ' s disease . It reduces the severity of " off " phase symptoms , improves the axial symptoms and reduces levodopa requirements . The reduction in the levodopa dose is useful in controlling drug - induced dyskinesias . Acute renal failure occurring during intravenous desferrioxamine therapy : recovery after haemodialysis . A patient with transfusion - dependent thalassemia was undergoing home intravenous desferrioxamine ( DFX ) treatment by means of a totally implanted system because of his poor compliance with the nightly subcutaneous therapy . Due to an accidental malfunctioning of the infusion pump , the patient was inadvertently administered a toxic dosage of the drug which caused renal insufficiency . Given the progressive deterioration of the symptoms and of the laboratory values , despite adequate medical treatment , a decision was made to introduce haemodialytical therapy in order to remove the drug and therapy reduce the nephrotoxicity . From the results obtained , haemodialysis can therefore be suggested as a useful therapy in rare cases of progressive acute renal failure caused by desferrioxamine . Ocular motility changes after subtenon carboplatin chemotherapy for retinoblastoma . BACKGROUND : Focal subtenon carboplatin injections have recently been used as a presumably toxicity - free adjunct to systemic chemotherapy for intraocular retinoblastoma . OBJECTIVE : To report our clinical experience with abnormal ocular motility in patients treated with subtenon carboplatin chemotherapy . METHODS : We noted abnormal ocular motility in 10 consecutive patients with retinoblastoma who had received subtenon carboplatin . During ocular manipulation under general anesthesia , we assessed their eyes by forced duction testing , comparing ocular motility after tumor control with ocular motility at diagnosis . Eyes subsequently enucleated because of treatment failure ( n = 4 ) were examined histologically . RESULTS : Limitation of ocular motility was detected in all 12 eyes of 10 patients treated for intraocular retinoblastoma with 1 to 6 injections of subtenon carboplatin as part of multimodality therapy . Histopathological examination revealed many lipophages in the periorbital fat surrounding the optic nerve in 1 eye , indicative of phagocytosis of previously existing fat cells and suggesting prior fat necrosis . The enucleations were technically difficult and hazardous for globe rupture because of extensive orbital soft tissue adhesions . CONCLUSIONS : Subtenon carboplatin chemotherapy is associated with significant fibrosis of orbital soft tissues , leading to mechanical restriction of eye movements and making subsequent enucleation difficult . Subtenon carboplatin is not free of toxicity , and its use is best restricted to specific indications . Ethambutol and optic neuropathy . PURPOSE : To demonstrate the association between ethambutol and optic neuropathy . METHOD : Thirteen patients who developed optic neuropathy after being treated with ethambutol for tuberculosis of the lung or lymph node at Siriraj Hospital between 1997 and 2001 were retrospectively reviewed . The clinical characteristics and initial and final visual acuity were analyzed to determine visual outcome . RESULTS : All patients had optic neuropathy between 1 to 6 months ( mean = 2 . 9 months ) after starting ethambutol therapy at a dosage ranging from 13 to 20 mg / kg / day ( mean = 17 mg / kg / day ) . Seven ( 54 % ) of the 13 patients experienced visual recovery after stopping the drug . Of 6 patients with irreversible visual impairment , 4 patients had diabetes mellitus , glaucoma and a history of heavy smoking . CONCLUSION : Early recognition of optic neuropathy should be considered in patients with ethambutol therapy . A low dose and prompt discontinuation of the drug is recommended particularly in individuals with diabetes mellitus , glaucoma or who are heavy smokers . Treatment of compensatory gustatory hyperhidrosis with topical glycopyrrolate . Gustatory hyperhidrosis is facial sweating usually associated with the eating of hot spicy food or even smelling this food . Current options of treatment include oral anticholinergic drugs , the topical application of anticholinergics or aluminum chloride , and the injection of botulinum toxin . Thirteen patients have been treated to date with 1 . 5 % or 2 % topical glycopyrrolate . All patients had gustatory hyperhidrosis , which interfered with their social activities , after transthroacic endoscopic sympathectomy , and which was associated with compensatory focal hyperhidrosis . After applying topical glycopyrrolate , the subjective effect was excellent ( no sweating after eating hot spicy food ) in 10 patients ( 77 % ) , and fair ( clearly reduced sweating ) in 3 patients ( 23 % ) . All had reported incidents of being very embarrassed whilst eating hot spicy foods . Adverse effects included a mildly dry mouth and a sore throat in 2 patients ( 2 % glycopyrrolate ) , a light headache in 1 patient ( 1 . 5 % glycopyrrolate ) . The topical application of a glycopyrrolate pad appeared to be safe , efficacious , well tolerated , and a convenient method of treatment for moderate to severe symptoms of gustatory hyperhidrosis in post transthoracic endoscopic sympathectomy or sympathicotomy patients , with few side effects . Neuroleptic - associated hyperprolactinemia . Can it be treated with bromocriptine ? Six stable psychiatric outpatients with hyperprolactinemia and amenorrhea / oligomenorrhea associated with their neuroleptic medications were treated with bromocriptine . Daily dosages of 5 - 10 mg corrected the hyperprolactinemia and restored menstruation in four of the six patients . One woman , however , developed worsened psychiatric symptoms while taking bromocriptine , and it was discontinued . Thus , three of six patients had their menstrual irregularity successfully corrected with bromocriptine . This suggests that bromocriptine should be further evaluated as potential therapy for neuroleptic - associated hyperprolactinemia and amenorrhea / galactorrhea . Ethacrynic acid - induced convulsions and brain neurotransmitters in mice . Intracerebroventricular injection of ethacrynic acid ( 50 % convulsive dose ; 50 micrograms / mouse ) accelerated the synthesis / turnover of 5 - hydroxytryptamine ( 5 - HT ) but suppressed the synthesis of gamma - aminobutyric acid and acetylcholine in mouse brain . These effects were completely antagonized by pretreatment with a glutamate / N - methyl - D - aspartate antagonist , aminophosphonovaleric acid . In ethacrynic acid - induced convulsions , these neurotransmitter systems may be differentially modulated , probably through activation of glutaminergic neurons in the brain . Pharmacology of gamma - aminobutyric acidA receptor complex after the in vivo administration of the anxioselective and anticonvulsant beta - carboline derivative abecarnil . In rodents , the effect of the beta - carboline derivative isopropyl - 6 - benzyloxy - 4 - methoxymethyl - beta - carboline - 3 - carboxylate ( abecarrnil ) , a new ligand for benzodiazepine receptors possessing anxiolytic and anticonvulsant properties , was evaluated on the function of central gamma - aminobutyric acid ( GABA ) A receptor complex , both in vitro and in vivo . Added in vitro to rat cortical membrane preparation , abecarnil increased [ 3H ] GABA binding , enhanced muscimol - stimulated 36Cl - uptake and reduced the binding of t - [ 35S ] butylbicyclophosphorothionate ( [ 35S ] TBPS ) . These effects were similar to those induced by diazepam , whereas the partial agonist Ro 16 - 6028 ( tert - butyl - ( S ) - 8 - bromo - 11 , 12 , 13 , 13a - tetrahydro - 9 - oxo - 9H - imidazo [ 1 , 5 - a ] - pyrrolo - [ 2 , 1 - c ] [ 1 , 4 ] benzodiazepine - 1 - carboxylate ) showed very weak efficacy in these biochemical tests . After i . p . injection to rats , abecarnil and diazepam decreased in a time - dependent and dose - related ( 0 . 25 - 20 mg / kg i . p . ) manner [ 35S ] TBPS binding measured ex vivo in the cerebral cortex . Moreover , both drugs at the dose of 0 . 5 mg / kg antagonized completely the convulsant activity and the increase of [ 35S ] TBPS binding induced by isoniazide ( 350 mg / kg s . c . ) as well as the increase of [ 35S ] TBPS binding induced by foot - shock stress . To better correlate the biochemical and the pharmacological effects , we studied the action of abecarnil on [ 35S ] TBPS binding , exploratory motility and on isoniazid - induced biochemical and pharmacological effects in mice . In these animals , abecarnil produced a paralleled dose - dependent ( 0 . 05 - 1 mg / kg i . p . ) reduction of both motor behavior and cortical [ 35S ] TBPS binding . Moreover , 0 . 05 mg / kg of this beta - carboline reduced markedly the increase of [ 35S ] TBPS binding and the convulsions induced by isoniazid ( 200 mg / kg s . c . ) . ( ABSTRACT TRUNCATED AT 250 WORDS ) Recurrent myocardial infarction in a postpartum patient receiving bromocriptine . Myocardial infarction in puerperium is infrequently reported . Spasm , coronary dissection , or atheromatous etiology has been described . Bromocriptine has been implicated in several previous case reports of myocardial infarction in the puerperium . Our case ( including an inadvertent rechallenge ) suggests such a relationship . Although generally regarded as " safe , " possible serious cardiac effects of bromocriptine should be acknowledged . Asterixis induced by carbamazepine therapy . There are very few reports about asterixis as a side effect of treatment with psychopharmacologic agents . In this report we present four patients treated with a combination of different psychotropic drugs , in whom asterixis was triggered either by adding carbamazepine ( CBZ ) to a treatment regimen , or by increasing its dosage . Neither dosage nor serum levels of CBZ were in a higher range . We consider asterixis to be an easily overlooked sign of neurotoxicity , which may occur even at low or moderate dosage levels , if certain drugs as lithium or clozapine are used in combination with CBZ . Pharmacodynamics of the hypotensive effect of levodopa in parkinsonian patients . Blood pressure effects of i . v . levodopa were examined in parkinsonian patients with stable and fluctuating responses to levodopa . The magnitude of the hypotensive effect of levodopa was concentration dependent and was fit to an Emax model in fluctuating responders . Stable responders demonstrated a small hypotensive response . Baseline blood pressures were higher in fluctuating patients ; a higher baseline blood pressure correlated with greater hypotensive effects . Antiparkinsonian effects of levodopa temporally correlated with blood pressure changes . Phenylalanine , a large neutral amino acid ( LNAA ) competing with levodopa for transport across the blood - brain barrier , reduced the hypotensive and antiparkinsonian effects of levodopa . We conclude that levodopa has a central hypotensive action that parallels the motor effects in fluctuating patients . The hypotensive effect appears to be related to the higher baseline blood pressure we observed in fluctuating patients relative to stable patients . Syndrome of inappropriate secretion of antidiuretic hormone after infusional vincristine . A 77 - year - old woman with refractory multiple myeloma was treated with a 4 - day continuous intravenous infusion of vincristine and doxorubicin and 4 days of oral dexamethasone . Nine days after her second cycle she presented with lethargy and weakness associated with hyponatremia . Evaluation revealed the syndrome of inappropriate secretion of antidiuretic hormone , which was attributed to the vincristine infusion . After normal serum sodium levels returned , further doxorubicin and dexamethasone chemotherapy without vincristine did not produce this complication . Heart failure : to digitalise or not ? The view against . Despite extensive clinical experience the role of digoxin is still not well defined . In patients with atrial fibrillation digoxin is beneficial for ventricular rate control . For patients in sinus rhythm and heart failure the situation is less clear . Digoxin has a narrow therapeutic : toxic ratio and concentrations are affected by a number of drugs . Also , digoxin has undesirable effects such as increasing peripheral resistance and myocardial demands , and causing arrhythmias . There is a paucity of data from well - designed trials . The trials that are available are generally small with limitations in design and these show variation in patient benefit . More convincing evidence is required showing that digoxin improves symptoms or exercise capacity . Furthermore , no trial has had sufficient power to evaluate mortality . Pooled analysis of the effects of other inotropic drugs shows an excess mortality and there is a possibility that digoxin may increase mortality after myocardial infarction ( MI ) . Angiotensin - converting enzyme ( ACE ) inhibitors should be used first as they are safer , do not require blood level monitoring , modify progression of disease , relieve symptoms , improve exercise tolerance and reduce mortality . Caution should be exercised in using digoxin until large mortality trials are completed showing either benefit or harm . Until then digoxin should be considered a third - line therapy . Isradipine treatment for hypertension in general practice in Hong Kong . A 6 - week open study of the introduction of isradipine treatment was conducted in general practice in Hong Kong . 303 Chinese patients with mild to moderate hypertension entered the study . Side effects were reported in 21 % of patients and caused withdrawal from the study in 3 patients . The main side - effects were headache , dizziness , palpitation and flushing and these were not more frequent than reported in other studies with isradipine or with placebo . Supine blood pressure was reduced ( P less than 0 . 01 ) from 170 + / - 20 / 102 + / - 6 mmHg to 153 + / - 19 / 92 + / - 8 , 147 + / - 18 / 88 + / - 7 and 144 + / - 14 / 87 + / - 6 mmHg at 2 , 4 and 6 weeks respectively in evaluable patients . Similar reductions occurred in standing blood pressure and there was no evidence of postural hypotension . Normalization and responder rates at 6 weeks were 86 % and 69 % respectively . Dosage was increased from 2 . 5 mg b . d . to 5 mg b . d . at 4 weeks in patients with diastolic blood pressure greater than 90 mmHg and their further response was greater than those remaining on 2 . 5 mg b . d . Pharmacological characteristics and side effects of a new galenic formulation of propofol without soyabean oil . We compared the pharmacokinetics , pharmacodynamics and safety profile of a new galenic formulation of propofol ( AM149 1 % ) , which does not contain soyabean oil , with a standard formulation of propofol ( Disoprivan 1 % ) . In a randomised , double - blind , cross - over study , 30 healthy volunteers received a single intravenous bolus injection of 2 . 5 mg . kg - 1 propofol . Plasma propofol levels were measured for 48 h following drug administration and evaluated according to a three - compartment model . The pharmacodynamic parameters assessed included induction and emergence times , respiratory and cardiovascular effects , and pain on injection . Patients were monitored for side effects over 48 h . Owing to a high incidence of thrombophlebitis , the study was terminated prematurely and only the data of the two parallel treatment groups ( 15 patients in each group ) were analysed . Plasma concentrations did not differ significantly between the two formulations . Anaesthesia induction and emergence times , respiratory and cardiovascular variables showed no significant differences between the two treatment groups . Pain on injection ( 80 vs . 20 % , p < 0 . 01 ) and thrombophlebitis ( 93 . 3 vs . 6 . 6 % , p < 0 . 001 ) occurred more frequently with AM149 than with Disoprivan . Although both formulations had similar pharmacokinetic and pharmacodynamic profiles the new formulation is not suitable for clinical use due to the high incidence of thrombophlebitis produced . Pure red cell aplasia , toxic dermatitis and lymphadenopathy in a patient taking diphenylhydantoin . A patient taking diphenylhydantoin for 3 weeks developed a generalized skin rash , lymphadenopathy and pure red cell aplasia . After withdrawal of the pharmacon all symptoms disappeared spontaneously . Skin rash is a well - known complication of diphenylhydantoin treatment as is benign and malignant lymphadenopathy . Pure red cell aplasia associated with diphenylhydantoin medication has been reported in 3 patients . The exact mechanism by which diphenylhydantoin exerts its toxic effects is not known . In this patient the time relation between the ingestion of diphenylhydantoin and the occurrence of the skin rash , lymphadenopathy and pure red cell aplasia is very suggestive of a direct connection . Vinorelbine - related cardiac events : a meta - analysis of randomized clinical trials . Several cases of cardiac adverse reactions related to vinorelbine ( VNR ) have been reported in the literature . In order to quantify the incidence of these cardiac events , we performed a meta - analysis of clinical trials comparing VNR with other chemotherapeutic agents in the treatment of various malignancies . Randomized clinical trials comparing VNR with other drugs in the treatment of cancer were searched in Medline , Embase , Evidence - based Medicine Reviews databases and the Cochrane library from 1987 to 2002 . Outcomes of interest were severe cardiac events , toxic deaths and cardiac event - related deaths reported in each publication . We found 19 trials , involving 2441 patients treated by VNR and 2050 control patients . The incidence of cardiac events with VNR was 1 . 19 % [ 95 % confidence interval ( CI ) ( 0 . 75 ; 1 . 67 ) ] . There was no difference in the risk of cardiac events between VNR and other drugs [ odds ratio : 0 . 92 , 95 % CI ( 0 . 54 ; 1 . 55 ) ] . The risk of VNR cardiac events was similar to vindesine ( VDS ) and other cardiotoxic drugs [ fluorouracil , anthracyclines , gemcitabine ( GEM ) em leader ] . Even if it did not reach statistical significance because of a few number of cases , the risk was lower in trials excluding patients with cardiac history , and seemed to be higher in trials including patients with pre - existing cardiac diseases . Vinorelbine - related cardiac events concern about 1 % of treated patients in clinical trials . However , the risk associated with VNR seems to be similar to that of other chemotherapeutic agents in the same indications . MRI findings of hypoxic cortical laminar necrosis in a child with hemolytic anemia crisis . We present magnetic resonance imaging findings of a 5 - year - old girl who had a rapidly installing hemolytic anemia crisis induced by trimethoprim - sulfomethoxazole , resulting in cerebral anoxia leading to permanent damage . Magnetic Resonance imaging revealed cortical laminar necrosis in arterial border zones in both cerebral hemispheres , ischemic changes in subcortical white matter of left cerebral hemisphere , and in the left putamen . Although cortical laminar necrosis is a classic entity in adulthood related to conditions of energy depletions , there are few reports available in children . A wide review of the literature is also presented . The natural history of Vigabatrin associated visual field defects in patients electing to continue their medication . PURPOSE : To determine the natural history of visual field defects in a group of patients known to have Vigabatrin - associated changes who elected to continue the medication because of good seizure control . METHODS : All patients taking Vigabatrin alone or in combination with other antiepileptic drugs for at least 5 years ( range 5 - 12 years ) were entered into a visual surveillance programme . Patients were followed up at 6 - monthly intervals for not less than 18 months ( range 18 - 43 months ) . In all , 16 patients with unequivocal defects continued the medication . Following already published methodology ( Eye 2002 ; 16 ; 567 - 571 ) monocular mean radial degrees ( MRDs ) to the I / 4e isopter on Goldmann perimetry was calculated for the right eye at the time of discovery of a visual field defect and again after not less than 18 months follow - up . RESULTS : Mean right eye MRD at presentation was 36 . 98 degrees ( range 22 . 25 - 51 . 0 ) , compared to 38 . 40 degrees ( range 22 . 5 - 49 . 75 ) after follow - up ; P = 0 . 338 unpaired t - test . Only one patient demonstrated a deterioration in visual field during the study period and discontinued treatment . CONCLUSION : Established visual field defects presumed to be due to Vigabatrin therapy did not usually progress in spite of continuing use of the medication . These data give support to the hypothesis that the pathogenesis of Vigabatrin - associated visual field defects may be an idiosyncratic adverse drug reaction rather than dose - dependent toxicity . Induction of rosaceiform dermatitis during treatment of facial inflammatory dermatoses with tacrolimus ointment . BACKGROUND : Tacrolimus ointment is increasingly used for anti - inflammatory treatment of sensitive areas such as the face , and recent observations indicate that the treatment is effective in steroid - aggravated rosacea and perioral dermatitis . We report on rosaceiform dermatitis as a complication of treatment with tacrolimus ointment . OBSERVATIONS : Six adult patients with inflammatory facial dermatoses were treated with tacrolimus ointment because of the ineffectiveness of standard treatments . Within 2 to 3 weeks of initially effective and well - tolerated treatment , 3 patients with a history of rosacea and 1 with a history of acne experienced sudden worsening with pustular rosaceiform lesions . Biopsy revealed an abundance of Demodex mites in 2 of these patients . In 1 patient with eyelid eczema , rosaceiform periocular dermatitis gradually appeared after 3 weeks of treatment . In 1 patient with atopic dermatitis , telangiectatic and papular rosacea insidiously appeared after 5 months of treatment . CONCLUSIONS : Our observations suggest that the spectrum of rosaceiform dermatitis as a complication of treatment with tacrolimus ointment is heterogeneous . A variety of factors , such as vasoactive properties of tacrolimus , proliferation of Demodex due to local immunosuppression , and the occlusive properties of the ointment , may be involved in the observed phenomena . Future studies are needed to identify individual risk factors . Intravascular hemolysis and acute renal failure following intermittent rifampin therapy . Renal failure is a rare complication associated with the use of rifampin . Intravascular hemolysis leading to acute renal failure following rifampin therapy is extremely rare . Two patients with leprosy who developed hemolysis and acute renal failure following rifampin are reported . Structural abnormalities in the brains of human subjects who use methamphetamine . We visualize , for the first time , the profile of structural deficits in the human brain associated with chronic methamphetamine ( MA ) abuse . Studies of human subjects who have used MA chronically have revealed deficits in dopaminergic and serotonergic systems and cerebral metabolic abnormalities . Using magnetic resonance imaging ( MRI ) and new computational brain - mapping techniques , we determined the pattern of structural brain alterations associated with chronic MA abuse in human subjects and related these deficits to cognitive impairment . We used high - resolution MRI and surface - based computational image analyses to map regional abnormalities in the cortex , hippocampus , white matter , and ventricles in 22 human subjects who used MA and 21 age - matched , healthy controls . Cortical maps revealed severe gray - matter deficits in the cingulate , limbic , and paralimbic cortices of MA abusers ( averaging 11 . 3 % below control ; p < 0 . 05 ) . On average , MA abusers had 7 . 8 % smaller hippocampal volumes than control subjects ( p < 0 . 01 ; left , p = 0 . 01 ; right , p < 0 . 05 ) and significant white - matter hypertrophy ( 7 . 0 % ; p < 0 . 01 ) . Hippocampal deficits were mapped and correlated with memory performance on a word - recall test ( p < 0 . 05 ) . MRI - based maps suggest that chronic methamphetamine abuse causes a selective pattern of cerebral deterioration that contributes to impaired memory performance . MA may selectively damage the medial temporal lobe and , consistent with metabolic studies , the cingulate - limbic cortex , inducing neuroadaptation , neuropil reduction , or cell death . Prominent white - matter hypertrophy may result from altered myelination and adaptive glial changes , including gliosis secondary to neuronal damage . These brain substrates may help account for the symptoms of MA abuse , providing therapeutic targets for drug - induced brain injury . Disruption of hepatic lipid homeostasis in mice after amiodarone treatment is associated with peroxisome proliferator - activated receptor - alpha target gene activation . Amiodarone , an efficacious and widely used antiarrhythmic agent , has been reported to cause hepatotoxicity in some patients . To gain insight into the mechanism of this unwanted effect , mice were administered various doses of amiodarone and examined for changes in hepatic histology and gene regulation . Amiodarone induced hepatomegaly , hepatocyte microvesicular lipid accumulation , and a significant decrease in serum triglycerides and glucose . Northern blot analysis of hepatic RNA revealed a dose - dependent increase in the expression of a number of genes critical for fatty acid oxidation , lipoprotein assembly , and lipid transport . Many of these genes are regulated by the peroxisome proliferator - activated receptor - alpha ( PPARalpha ) , a ligand - activated nuclear hormone receptor transcription factor . The absence of induction of these genes as well as hepatomegaly in PPARalpha knockout [ PPARalpha - / - ] mice indicated that the effects of amiodarone were dependent upon the presence of a functional PPARalpha gene . Compared to wild - type mice , treatment of PPARalpha - / - mice with amiodarone resulted in an increased rate and extent of total body weight loss . The inability of amiodarone to directly activate either human or mouse PPARalpha transiently expressed in human HepG2 hepatoma cells indicates that the effects of amiodarone on the function of this receptor were indirect . Based upon these results , we conclude that amiodarone disrupts hepatic lipid homeostasis and that the increased expression of PPARalpha target genes is secondary to this toxic effect . These results provide important new mechanistic information regarding the hepatotoxic effects of amiodarone and indicate that PPARalpha protects against amiodarone - induced hepatotoxicity . Safety and compliance with once - daily niacin extended - release / lovastatin as initial therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment ( IMPACT ) study . Niacin extended - release / lovastatin is a new combination product approved for treatment of primary hypercholesterolemia and mixed dyslipidemia . This open - labeled , multicenter study evaluated the safety of bedtime niacin extended - release / lovastatin when dosed as initial therapy and patient compliance to treatment in various clinical practice settings . A total of 4 , 499 patients with dyslipidemia requiring drug intervention was enrolled at 1 , 081 sites . Patients were treated with 1 tablet ( 500 mg of niacin extended - release / 20 mg of lovastatin ) once nightly for 4 weeks and then 2 tablets for 8 weeks . Patients also received dietary counseling , educational materials , and reminders to call a toll - free number that provided further education about dyslipidemia and niacin extended - release / lovastatin . Primary end points were study compliance , increases in liver transaminases to > 3 times the upper limit of normal , and clinical myopathy . Final study status was available for 4 , 217 patients ( 94 % ) . Compliance to niacin extended - release / lovastatin was 77 % , with 3 , 245 patients completing the study . Patients in the southeast and those enrolled by endocrinologists had the lowest compliance and highest adverse event rates . Flushing was the most common adverse event , reported by 18 % of patients and leading to discontinuation by 6 % . Incidence of increased aspartate aminotransferase and / or alanine aminotransferase > 3 times the upper limit of normal was < 0 . 3 % . An increase of creatine phosphokinase to > 5 times the upper limit of normal occurred in 0 . 24 % of patients , and no cases of drug - induced myopathy were observed . Niacin extended - release / lovastatin 1 , 000 / 40 mg , dosed as initial therapy , was associated with good compliance and safety and had very low incidences of increased liver and muscle enzymes . Protective effect of Terminalia chebula against experimental myocardial injury induced by isoproterenol . Cardioprotective effect of ethanolic extract of Terminalia chebula fruits ( 500 mg / kg body wt ) was examined in isoproterenol ( 200 mg / kg body wt ) induced myocardial damage in rats . In isoproterenol administered rats , the level of lipid peroxides increased significantly in the serum and heart . A significant decrease was observed in the activity of the myocardial marker enzymes with a concomitant increase in their activity in serum . Histopathological examination was carried out to confirm the myocardial necrosis . T . chebula extract pretreatment was found to ameliorate the effect of isoproterenol on lipid peroxide formation and retained the activities of the diagnostic marker enzymes . A case of postoperative anxiety due to low dose droperidol used with patient - controlled analgesia . A multiparous woman in good psychological health underwent urgent caesarean section in labour . Postoperatively , she was given a patient - controlled analgesia device delivering boluses of diamorphine 0 . 5 mg and droperidol 0 . 025 mg . Whilst using the device she gradually became anxious , the feeling worsening after each bolus . The diagnosis of droperidol - induced psychological disturbance was not made straight away although on subsequent close questioning the patient gave a very clear history . After she had received a total of only 0 . 9 mg droperidol , a syringe containing diamorphine only was substituted and her unease resolved completely . We feel that , although the dramatic extrapyramidal side effects of dopaminergic antiemetics are well known , more subtle manifestations may easily be overlooked . Accurate patient history contributes to differentiating diabetes insipidus : a case study . This case study highlights the important contribution of nursing in obtaining an accurate health history . The case discussed herein initially appeared to be neurogenic diabetes insipidus ( DI ) secondary to a traumatic brain injury . The nursing staff , by reviewing the patient ' s health history with his family , discovered a history of polydipsia and long - standing lithium use . Lithium is implicated in drug - induced nephrogenic DI , and because the patient had not received lithium since being admitted to the hospital , his treatment changed to focus on nephrogenic DI . By combining information from the patient history , the physical examination , and radiologic and laboratory studies , the critical care team demonstrated that the patient had been self - treating his lithium - induced nephrogenic DI and developed neurogenic DI secondary to brain trauma . Thus successful treatment required that nephrogenic and neurogenic DI be treated concomitantly . Factors contributing to ribavirin - induced anemia . BACKGROUND AND AIM : Interferon and ribavirin combination therapy for chronic hepatitis C produces hemolytic anemia . This study was conducted to identify the factors contributing to ribavirin - induced anemia . METHODS : Eighty - eight patients with chronic hepatitis C who received interferon - alpha - 2b at a dose of 6 MU administered intramuscularly for 24 weeks in combination with ribavirin administered orally at a dose of 600 mg or 800 mg participated in the study . A hemoglobin concentration of < 10 g / dL was defined as ribavirin - induced anemia . RESULTS : Ribavirin - induced anemia occurred in 18 ( 20 . 5 % ) patients during treatment . A 2 g / dL decrease in hemoglobin concentrations in patients with anemia was observed at week 2 after the start of treatment . The hemoglobin concentration in patients with > or = 2 g / dL decrease at week 2 was observed to be significantly lower even after week 2 than in patients with < 2 g / dL decrease ( P < 0 . 01 ) . A significant relationship was observed between the rate of reduction of hemoglobin concentrations at week 2 and the severity of anemia ( P < 0 . 01 ) . Such factors as sex ( female ) , age ( > or = 60 years old ) , and the ribavirin dose by body weight ( 12 mg / kg or more ) were significant by univariate analysis . CONCLUSIONS : Careful administration is necessary in patients > or = 60 years old , in female patients , and in patients receiving a ribavirin dose of 12 mg / kg or more . Patients who experience a fall in hemoglobin concentrations of 2 g / dL or more at week 2 after the start of treatment should be monitored with particular care . Zidovudine - induced hepatitis . A case of acute hepatitis induced by zidovudine in a 38 - year - old patient with AIDS is presented . The mechanism whereby the hepatitis was induced is not known . However , the patient tolerated well an alternative reverse transcriptase inhibitor , 2 ' 3 ' dideoxyinosine . Physicians caring for patients with AIDS should be aware of this hitherto rarely reported complication . Oxidative damage precedes nitrative damage in adriamycin - induced cardiac mitochondrial injury . The purpose of the present study was to determine if elevated reactive oxygen ( ROS ) / nitrogen species ( RNS ) reported to be present in adriamycin ( ADR ) - induced cardiotoxicity actually resulted in cardiomyocyte oxidative / nitrative damage , and to quantitatively determine the time course and subcellular localization of these postulated damage products using an in vivo approach . B6C3 mice were treated with a single dose of 20 mg / kg ADR . Ultrastructural damage and levels of 4 - hydroxy - 2 - nonenal ( 4HNE ) - protein adducts and 3 - nitrotyrosine ( 3NT ) were analyzed . Quantitative ultrastructural damage using computerized image techniques showed cardiomyocyte injury as early as 3 hours , with mitochondria being the most extensively and progressively injured subcellular organelle . Analysis of 4HNE protein adducts by immunogold electron microscopy showed appearance of 4HNE protein adducts in mitochondria as early as 3 hours , with a peak at 6 hours and subsequent decline at 24 hours . 3NT levels were significantly increased in all subcellular compartments at 6 hours and subsequently declined at 24 hours . Our data showed ADR induced 4HNE - protein adducts in mitochondria at the same time point as when mitochondrial injury initially appeared . These results document for the first time in vivo that mitochondrial oxidative damage precedes nitrative damage . The progressive nature of mitochondrial injury suggests that mitochondria , not other subcellular organelles , are the major site of intracellular injury . Sotalol - induced coronary spasm in a patient with dilated cardiomyopathy associated with sustained ventricular tachycardia . A 54 - year - old man with severe left ventricular dysfunction due to dilated cardiomyopathy was referred to our hospital for symptomatic incessant sustained ventricular tachycardia ( VT ) . After the administration of nifekalant hydrochloride , sustained VT was terminated . An alternate class III agent , sotalol , was also effective for the prevention of VT . However , one month after switching over nifekalant to sotalol , a short duration of ST elevation was documented in ECG monitoring at almost the same time for three consecutive days . ST elevation with chest discomfort disappeared since he began taking long - acting diltiazem . Coronary vasospasm may be induced by the non - selective beta - blocking properties of sotalol . Effects of the antidepressant trazodone , a 5 - HT 2A / 2C receptor antagonist , on dopamine - dependent behaviors in rats . RATIONALE : 5 - Hydroxytryptamine , via stimulation of 5 - HT 2C receptors , exerts a tonic inhibitory influence on dopaminergic neurotransmission , whereas activation of 5 - HT 2A receptors enhances stimulated DAergic neurotransmission . The antidepressant trazodone is a 5 - HT 2A / 2C receptor antagonist . OBJECTIVES : To evaluate the effect of trazodone treatment on behaviors dependent on the functional status of the nigrostriatal DAergic system . METHODS : The effect of pretreatment with trazodone on dexamphetamine - and apomorphine - induced oral stereotypies , on catalepsy induced by haloperidol and apomorphine ( 0 . 05 mg / kg , i . p . ) , on ergometrine - induced wet dog shake ( WDS ) behavior and fluoxetine - induced penile erections was studied in rats . We also investigated whether trazodone induces catalepsy in rats . RESULTS : Trazodone at 2 . 5 - 20 mg / kg i . p . did not induce catalepsy , and did not antagonize apomorphine ( 1 . 5 and 3 mg / kg ) stereotypy and apomorphine ( 0 . 05 mg / kg ) - induced catalepsy . However , pretreatment with 5 , 10 and 20 mg / kg i . p . trazodone enhanced dexamphetamine stereotypy , and antagonized haloperidol catalepsy , ergometrine - induced WDS behavior and fluoxetine - induced penile erections . Trazodone at 30 , 40 and 50 mg / kg i . p . induced catalepsy and antagonized apomorphine and dexamphetamine stereotypies . CONCLUSIONS : Our results indicate that trazodone at 2 . 5 - 20 mg / kg does not block pre - and postsynaptic striatal D2 DA receptors , while at 30 , 40 and 50 mg / kg it blocks postsynaptic striatal D2 DA receptors . Furthermore , at 5 , 10 and 20 mg / kg , trazodone blocks 5 - HT 2A and 5 - HT 2C receptors . We suggest that trazodone ( 5 , 10 and 20 mg / kg ) , by blocking the 5 - HT 2C receptors , releases the nigrostriatal DAergic neurons from tonic inhibition caused by 5 - HT , and thereby potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy . Swallowing abnormalities and dyskinesia in Parkinson ' s disease . Gastrointestinal abnormalities in Parkinson ' s disease ( PD ) have been known for almost two centuries , but many aspects concerning their pathophysiology have not been completely clarified . The aim of this study was to characterize the oropharyngeal dynamics in PD patients with and without levodopa - induced dyskinesia . Fifteen dyskinetic , 12 nondyskinetic patients , and a control group were included . Patients were asked about dysphagia and evaluated with the Unified Parkinson ' s Disease Rating Scale Parts II and III and the Hoehn and Yahr scale . Deglutition was assessed using modified barium swallow with videofluoroscopy . Nondyskinetic patients , but not the dyskinetic ones , showed less oropharyngeal swallowing efficiency ( OPSE ) for liquid food than controls ( Dunnett , P = 0 . 02 ) . Dyskinetic patients tended to have a greater OPSE than nondyskinetic ( Dunnett , P = 0 . 06 ) . Patients who were using a higher dose of levodopa had a greater OPSE and a trend toward a smaller oral transit time ( Pearson ' s correlation , P = 0 . 01 and 0 . 08 , respectively ) . Neither the report of dysphagia nor any of the PD severity parameters correlated to the videofluoroscopic variables . In the current study , dyskinetic patients performed better in swallowing function , which could be explained on the basis of a greater levodopa dose . Our results suggest a role for levodopa in the oral phase of deglutition and confirm that dysphagia is not a good predictor of deglutition alterations in PD . Inhibition of nuclear factor - kappaB activation attenuates tubulointerstitial nephritis induced by gentamicin . BACKGROUND : Animals treated with gentamicin can show residual areas of interstitial fibrosis in the renal cortex . This study investigated the expression of nuclear factor - kappaB ( NF - kappaB ) , mitogen - activated protein ( MAP ) kinases and macrophages in the renal cortex and structural and functional renal changes of rats treated with gentamicin or gentamicin + pyrrolidine dithiocarbamate ( PDTC ) , an NF - kappaB inhibitor . METHODS : 38 female Wistar rats were injected with gentamicin , 40 mg / kg , twice a day for 9 days , 38 with gentamicin + PDTC , and 28 with 0 . 15 M NaCl solution . The animals were killed 5 and 30 days after these injections and the kidneys were removed for histological and immunohistochemical studies . The results of the immunohistochemical studies were scored according to the extent of staining . The fractional interstitial area was determined by morphometry . RESULTS : Gentamicin - treated rats presented a transitory increase in plasma creatinine levels . Increased ED - 1 , MAP kinases and NF - kappaB staining were also observed in the renal cortex from all gentamicin - treated rats compared to control ( p < 0 . 05 ) . The animals killed on day 30 also presented fibrosis in the renal cortex despite the recovery of renal function . Treatment with PDTC reduced the functional and structural changes induced by gentamicin . CONCLUSIONS : These data show that inhibition of NF - kappaB activation attenuates tubulointerstitial nephritis induced by gentamicin . Glucose metabolism in patients with schizophrenia treated with atypical antipsychotic agents : a frequently sampled intravenous glucose tolerance test and minimal model analysis . BACKGROUND : While the incidence of new - onset diabetes mellitus may be increasing in patients with schizophrenia treated with certain atypical antipsychotic agents , it remains unclear whether atypical agents are directly affecting glucose metabolism or simply increasing known risk factors for diabetes . OBJECTIVE : To study the 2 drugs most clearly implicated ( clozapine and olanzapine ) and risperidone using a frequently sampled intravenous glucose tolerance test . DESIGN : A cross - sectional design in stable , treated patients with schizophrenia evaluated using a frequently sampled intravenous glucose tolerance test and the Bergman minimal model analysis . SETTING : Subjects were recruited from an urban community mental health clinic and were studied at a general clinical research center . Patients Fifty subjects signed informed consent and 41 underwent the frequently sampled intravenous glucose tolerance test . Thirty - six nonobese subjects with schizophrenia or schizoaffective disorder , matched by body mass index and treated with either clozapine , olanzapine , or risperidone , were included in the analysis . MAIN OUTCOME MEASURES : Fasting plasma glucose and fasting serum insulin levels , insulin sensitivity index , homeostasis model assessment of insulin resistance , and glucose effectiveness . RESULTS : The mean + / - SD duration of treatment with the identified atypical antipsychotic agent was 68 . 3 + / - 28 . 9 months ( clozapine ) , 29 . 5 + / - 17 . 5 months ( olanzapine ) , and 40 . 9 + / - 33 . 7 ( risperidone ) . Fasting serum insulin concentrations differed among groups ( F ( 33 ) = 3 . 35 ; P = . 047 ) ( clozapine > olanzapine > risperidone ) with significant differences between clozapine and risperidone ( t ( 33 ) = 2 . 32 ; P = . 03 ) and olanzapine and risperidone ( t ( 33 ) = 2 . 15 ; P = . 04 ) . There was a significant difference in insulin sensitivity index among groups ( F ( 33 ) = 10 . 66 ; P < . 001 ) ( clozapine < olanzapine < risperidone ) , with subjects who received clozapine and olanzapine exhibiting significant insulin resistance compared with subjects who were treated with risperidone ( clozapine vs risperidone , t ( 33 ) = - 4 . 29 ; P < . 001 ; olanzapine vs risperidone , t ( 33 ) = - 3 . 62 ; P = . 001 [ P < . 001 ] ) . The homeostasis model assessment of insulin resistance also differed significantly among groups ( F ( 33 ) = 4 . 92 ; P = . 01 ) ( clozapine > olanzapine > risperidone ) ( clozapine vs risperidone , t ( 33 ) = 2 . 94 ; P = . 006 ; olanzapine vs risperidone , t ( 33 ) = 2 . 42 ; P = . 02 ) . There was a significant difference among groups in glucose effectiveness ( F ( 30 ) = 4 . 18 ; P = . 02 ) ( clozapine < olanzapine < risperidone ) with significant differences between clozapine and risperidone ( t ( 30 ) = - 2 . 59 ; P = . 02 ) and olanzapine and risperidone ( t ( 30 ) = - 2 . 34 , P = . 03 ) . CONCLUSIONS : Both nonobese clozapine - and olanzapine - treated groups displayed significant insulin resistance and impairment of glucose effectiveness compared with risperidone - treated subjects . Patients taking clozapine and olanzapine must be examined for insulin resistance and its consequences . Thoracic hematomyelia secondary to coumadin anticoagulant therapy : a case report . A case of thoracic hematomyelia secondary to anticoagulant therapy is presented . Clinical features , similar to 2 other previously reported cases , are discussed . A high index of suspicion may lead to a quick diagnostic procedure and successful decompressive surgery . Mania associated with fluoxetine treatment in adolescents . Fluoxetine , a selective serotonin reuptake inhibitor , is gaining increased acceptance in the treatment of adolescent depression . Generally safe and well tolerated by adults , fluoxetine has been reported to induce mania . The cases of five depressed adolescents , 14 - 16 years of age , who developed mania during pharmacotherapy with fluoxetine , are reported here . Apparent risk factors for the development of mania or hypomania during fluoxetine pharmacotherapy in this population were the combination of attention - deficit hyperactivity disorder and affective instability ; major depression with psychotic features ; a family history of affective disorder , especially bipolar disorder ; and a diagnosis of bipolar disorder . Further study is needed to determine the optimal dosage and to identify risk factors that increase individual vulnerability to fluoxetine induced mania in adolescents . Acute renal insufficiency after high - dose melphalan in patients with primary systemic amyloidosis during stem cell transplantation . BACKGROUND : Patients with primary systemic amyloidosis ( AL ) have a poor prognosis . Median survival time from standard treatments is only 17 months . High - dose intravenous melphalan followed by peripheral blood stem cell transplant ( PBSCT ) appears to be the most promising therapy , but treatment mortality can be high . The authors have noted the development of acute renal insufficiency immediately after melphalan conditioning . This study was undertaken to further examine its risk factors and impact on posttransplant mortality . METHODS : Consecutive AL patients who underwent PBSCT were studied retrospectively . Acute renal insufficiency ( ARI ) after high - dose melphalan was defined by a minimum increase of 0 . 5 mg / dL ( 44 micromol / L ) in the serum creatinine level that is greater than 50 % of baseline immediately after conditioning . Urine sediment score was the sum of the individual types of sediment identified on urine microscopy . RESULTS : Of the 80 patients studied , ARI developed in 18 . 8 % of the patients after high - dose melphalan . Univariate analysis identified age , hypoalbuminemia , heavy proteinuria , diuretic use , and urine sediment score ( > 3 ) as risk factors . Age and urine sediment score remained independently significant risk factors in the multivariate analysis . Patients who had ARI after high - dose melphalan underwent dialysis more often ( P = 0 . 007 ) , and had a worse 1 - year survival ( P = 0 . 03 ) . CONCLUSION : The timing of renal injury strongly suggests melphalan as the causative agent . Ongoing tubular injury may be a prerequisite for renal injury by melphalan as evidenced by the active urinary sediment . Development of ARI adversely affected the outcome after PBSCT . Effective preventive measures may help decrease the treatment mortality of PBSCT in AL patients . Focal cerebral ischemia in rats : effect of phenylephrine - induced hypertension during reperfusion . After 180 min of temporary middle cerebral artery occlusion in spontaneously hypertensive rats , the effect of phenylephrine - induced hypertension on ischemic brain injury and blood - brain barrier permeability was determined . Blood pressure was manipulated by one of the following schedules during 120 min of reperfusion : Control , normotensive reperfusion ; 90 / hypertension ( 90 / HTN ) , blood pressure was increased by 35 mm Hg during the initial 90 min of reperfusion only ; 15 / hypertension ( 15 / HTN ) , normotensive reperfusion for 30 min followed by 15 min of hypertension and 75 min of normotension . Part A , for eight rats in each group brain injury was evaluated by staining tissue using 2 , 3 , 5 - triphenyltetrazolium chloride and edema was evaluated by microgravimetry . Part B , for eight different rats in each group blood - brain barrier permeability was evaluated by measuring the amount and extent of extravasation of Evans Blue dye . Brain injury ( percentage of the ischemic hemisphere ) was less in the 15 / HTN group ( 16 + / - 6 , mean + / - SD ) versus the 90 / HTN group ( 30 + / - 6 ) , which was in turn less than the control group ( 42 + / - 5 ) . Specific gravity was greater in the 15 / HTN group ( 1 . 043 + / - 0 . 002 ) versus the 90 / HTN ( 1 . 036 + / - 0 . 003 ) and control ( 1 . 037 + / - 0 . 003 ) groups . Evans Blue ( mug g - 1 of brain tissue ) was greater in the 90 / HTN group ( 24 . 4 + / - 6 . 0 ) versus the control group ( 12 . 3 + / - 4 . 1 ) , which was in turn greater than the 15 / HTN group ( 7 . 3 + / - 3 . 2 ) . This study supports a hypothesis that during reperfusion , a short interval of hypertension decreases brain injury and edema ; and that sustained hypertension increases the risk of vasogenic edema . People aged over 75 in atrial fibrillation on warfarin : the rate of major hemorrhage and stroke in more than 500 patient - years of follow - up . OBJECTIVES : To determine the incidence of major hemorrhage and stroke in people aged 76 and older with atrial fibrillation on adjusted - dose warfarin who had been recently been admitted to hospital . DESIGN : A retrospective observational cohort study . SETTING : A major healthcare network involving four tertiary hospitals . PARTICIPANTS : Two hundred thirty - five patients aged 76 and older admitted to a major healthcare network between July 1 , 2001 , and June 30 , 2002 , with atrial fibrillation on warfarin were enrolled . MEASUREMENTS : Information regarding major bleeding episodes , strokes , and warfarin use was obtained from patients , relatives , primary physicians , and medical records . RESULTS : Two hundred twenty - eight patients ( 42 % men ) with a mean age of 81 . 1 ( range 76 - 94 ) were included in the analysis . Total follow - up on warfarin was 530 years ( mean 28 months ) . There were 53 major hemorrhages , for an annual rate of 10 . 0 % , including 24 ( 45 . 3 % ) life - threatening and five ( 9 . 4 % ) fatal bleeds . The annual stroke rate after initiation of warfarin was 2 . 6 % . CONCLUSION : The rate of major hemorrhage was high in this old , frail group , but excluding fatalities , resulted in no long - term sequelae , and the stroke rate on warfarin was low , demonstrating how effective warfarin treatment is . Safety of celecoxib in patients with adverse skin reactions to acetaminophen ( paracetamol ) and nimesulide associated or not with common non - steroidal anti - inflammatory drugs . BACKGROUND : Acetaminophen ( paracetamol - - P ) and Nimesulide ( N ) are widely used analgesic - antipyretic / anti - inflammatory drugs . The rate of adverse hypersensitivity reactions to these agents is generally low . On the contrary non - steroidal anti - inflammatory drugs ( NSAIDs ) are commonly involved in such reactions . Celecoxib ( CE ) is a novel drug , with high selectivity and affinity for COX - 2 enzyme . OBJECTIVE : We evaluated the tolerability of CE in a group of patients with documented history of adverse cutaneous reactions to P and N associated or not to classic NSAIDs . METHODS : We studied 9 patients with hypersensitivity to P and N with or without associated reactions to classic NSAIDs . The diagnosis of P and N - induced skin reactions was based in vivo challenge . The placebo was blindly administered at the beginning of each challenge . After three days , a cumulative dosage of 200 mg of CE in refracted doses were given . After 2 - 3 days , a single dose of 200 mg was administered . All patients were observed for 6 hours after each challenge , and controlled again after 24 hours to exclude delayed reactions . The challenge was considered positive if one or more of the following appeared : erythema , rush or urticaria - angioedema . RESULTS : No reaction was observed with placebo and eight patients ( 88 . 8 % ) tolerated CE . Only one patient developed a moderate angioedema of the lips . CONCLUSION : Only one hypersensitivity reaction to CE was documented among 9 P and N - highly NSAIDs intolerant patients . Thus , we conclude that CE is a reasonably safe alternative to be used in subjects who do not tolerate P and N . Case - control study of regular analgesic and nonsteroidal anti - inflammatory use and end - stage renal disease . BACKGROUND : Studies on the association between the long - term use of aspirin and other analgesic and nonsteroidal anti - inflammatory drugs ( NSAIDs ) and end - stage renal disease ( ESRD ) have given conflicting results . In order to examine this association , a case - control study with incident cases of ESRD was carried out . METHODS : The cases were all patients entering the local dialysis program because of ESRD in the study area between June 1 , 1995 and November 30 , 1997 . They were classified according to the underlying disease , which had presumably led them to ESRD . Controls were patients admitted to the same hospitals from where the cases arose , also matched by age and sex . Odds ratios were calculated using a conditional logistic model , including potential confounding factors , both for the whole study population and for the various underlying diseases . RESULTS : Five hundred and eighty - three cases and 1190 controls were included in the analysis . Long - term use of any analgesic was associated with an overall odds ratio of 1 . 22 ( 95 % CI , 0 . 89 - 1 . 66 ) . For specific groups of drugs , the risks were 1 . 56 ( 1 . 05 - 2 . 30 ) for aspirin , 1 . 03 ( 0 . 60 - 1 . 76 ) for pyrazolones , 0 . 80 ( 0 . 39 - 1 . 63 ) for paracetamol , and 0 . 94 ( 0 . 57 - 1 . 56 ) for nonaspirin NSAIDs . The risk of ESRD associated with aspirin was related to the cumulated dose and duration of use , and it was particularly high among the subset of patients with vascular nephropathy as underlying disease [ 2 . 35 ( 1 . 17 - 4 . 72 ) ] . CONCLUSION : Our data indicate that long - term use of nonaspirin analgesic drugs and NSAIDs is not associated with an increased risk of ESRD . However , the chronic use of aspirin may increase the risk of ESRD . Two cases of amisulpride overdose : a cause for prolonged QT syndrome . Two cases of deliberate self - poisoning with 5 g and 3 . 6 g of amisulpride , respectively , are reported . In both cases , QT prolongation and hypocalcaemia were noted . The QT prolongation appeared to respond to administration of i . v . calcium gluconate . Growth - associated protein 43 expression in hippocampal molecular layer of chronic epileptic rats treated with cycloheximide . PURPOSE : GAP43 has been thought to be linked with mossy fiber sprouting ( MFS ) in various experimental models of epilepsy . To investigate how GAP43 expression ( GAP43 - ir ) correlates with MFS , we assessed the intensity ( densitometry ) and extension ( width ) of GAP43 - ir in the inner molecular layer of the dentate gyrus ( IML ) of rats subject to status epilepticus induced by pilocarpine ( Pilo ) , previously injected or not with cycloheximide ( CHX ) , which has been shown to inhibit MFS . METHODS : CHX was injected before the Pilo injection in adult Wistar rats . The Pilo group was injected with the same drugs , except for CHX . Animals were killed between 30 and 60 days later , and brain sections were processed for GAP43 immunohistochemistry . RESULTS : Densitometry showed no significant difference regarding GAP43 - ir in the IML between Pilo , CHX + Pilo , and control groups . However , the results of the width of the GAP43 - ir band in the IML showed that CHX + Pilo and control animals had a significantly larger band ( p = 0 . 03 ) as compared with that in the Pilo group . CONCLUSIONS : Our current finding that animals in the CHX + Pilo group have a GAP43 - ir band in the IML , similar to that of controls , reinforces prior data on the blockade of MFS in these animals . The change in GAP43 - ir present in Pilo - treated animals was a thinning of the band to a very narrow layer just above the granule cell layer that is likely to be associated with the loss of hilar cell projections that express GAP - 43 . Nicotine antagonizes caffeine - but not pentylenetetrazole - induced anxiogenic effect in mice . RATIONALE : Nicotine and caffeine are widely consumed licit psychoactive drugs worldwide . Epidemiological studies showed that they were generally used concurrently . Although some studies in experimental animals indicate clear pharmacological interactions between them , no studies have shown a specific interaction on anxiety responses . OBJECTIVES : The present study investigates the effects of nicotine on anxiety induced by caffeine and another anxiogenic drug , pentylenetetrazole , in mice . The elevated plus - maze ( EPM ) test was used to evaluate the effects of drugs on anxiety . METHODS : Adult male Swiss Webster mice ( 25 - 32 g ) were given nicotine ( 0 . 05 - 0 . 25 mg / kg s . c . ) or saline 10 min before caffeine ( 70 mg / kg i . p . ) or pentylenetetrazole ( 15 and 30 mg / kg i . p . ) injections . After 15 min , mice were evaluated for their open - and closed - arm time and entries on the EPM for a 10 - min session . Locomotor activity was recorded for individual groups by using the same treatment protocol with the EPM test . RESULTS : Nicotine ( 0 . 05 - 0 . 25 mg / kg ) itself did not produce any significant effect in the EPM test , whereas caffeine ( 70 mg / kg ) and pentylenetetrazole ( 30 mg / kg ) produced an anxiogenic effect , apparent with decreases in open - arm time and entry . Nicotine ( 0 . 25 mg / kg ) pretreatment blocked the caffeine - but not pentylenetetrazole - induced anxiety . Administration of each drug and their combinations did not produce any effect on locomotor activity . CONCLUSIONS : Our results suggest that the antagonistic effect of nicotine on caffeine - induced anxiety is specific to caffeine , instead of a non - specific anxiolytic effect . Thus , it may extend the current findings on the interaction between nicotine and caffeine . Long term hormone therapy for perimenopausal and postmenopausal women . BACKGROUND : Hormone therapy ( HT ) is widely used for controlling menopausal symptoms . It has also been used for the management and prevention of cardiovascular disease , osteoporosis and dementia in older women but the evidence supporting its use for these indications is largely observational . OBJECTIVES : To assess the effect of long - term HT on mortality , heart disease , venous thromboembolism , stroke , transient ischaemic attacks , breast cancer , colorectal cancer , ovarian cancer , endometrial cancer , gallbladder disease , cognitive function , dementia , fractures and quality of life . SEARCH STRATEGY : We searched the following databases up to November 2004 : the Cochrane Menstrual Disorders and Subfertility Group Trials Register , Cochrane Central Register of Controlled Trials ( CENTRAL ) , MEDLINE , EMBASE , Biological Abstracts . Relevant non - indexed journals and conference abstracts were also searched . SELECTION CRITERIA : Randomised double - blind trials of HT ( oestrogens with or without progestogens ) versus placebo , taken for at least one year by perimenopausal or postmenopausal women . DATA COLLECTION AND ANALYSIS : Fifteen RCTs were included . Trials were assessed for quality and two review authors extracted data independently . They calculated risk ratios for dichotomous outcomes and weighted mean differences for continuous outcomes . Clinical heterogeneity precluded meta - analysis for most outcomes . MAIN RESULTS : All the statistically significant results were derived from the two biggest trials . In relatively healthy women , combined continuous HT significantly increased the risk of venous thromboembolism or coronary event ( after one year ' s use ) , stroke ( after 3 years ) , breast cancer ( after 5 years ) and gallbladder disease . Long - term oestrogen - only HT also significantly increased the risk of stroke and gallbladder disease . Overall , the only statistically significant benefits of HT were a decreased incidence of fractures and colon cancer with long - term use . Among relatively healthy women over 65 years taking continuous combined HT , there was a statistically significant increase in the incidence of dementia . Among women with cardiovascular disease , long - term use of combined continuous HT significantly increased the risk of venous thromboembolism . No trials focussed specifically on younger women . However , one trial analysed subgroups of 2839 relatively healthy 50 to 59 year - old women taking combined continuous HT and 1637 taking oestrogen - only HT , versus similar - sized placebo groups . The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT ; their absolute risk remained very low . AUTHORS ' CONCLUSIONS : HT is not indicated for the routine management of chronic disease . We need more evidence on the safety of HT for menopausal symptom control , though short - term use appears to be relatively safe for healthy younger women . Drug - induced liver injury : an analysis of 461 incidences submitted to the Spanish registry over a 10 - year period . BACKGROUND & AIMS : Progress in the understanding of susceptibility factors to drug - induced liver injury ( DILI ) and outcome predictability are hampered by the lack of systematic programs to detect bona fide cases . METHODS : A cooperative network was created in 1994 in Spain to identify all suspicions of DILI following a prospective structured report form . The liver damage was characterized according to hepatocellular , cholestatic , and mixed laboratory criteria and to histologic criteria when available . Further evaluation of causality assessment was centrally performed . RESULTS : Since April 1994 to August 2004 , 461 out of 570 submitted cases , involving 505 drugs , were deemed to be related to DILI . The antiinfective group of drugs was the more frequently incriminated , amoxicillin - clavulanate accounting for the 12 . 8 % of the whole series . The hepatocellular pattern of damage was the most common ( 58 % ) , was inversely correlated with age ( P < . 0001 ) , and had the worst outcome ( Cox regression , P < . 034 ) . Indeed , the incidence of liver transplantation and death in this group was 11 . 7 % if patients had jaundice at presentation , whereas the corresponding figure was 3 . 8 % in nonjaundiced patients ( P < . 04 ) . Factors associated with the development of fulminant hepatic failure were female sex ( OR = 25 ; 95 % CI : 4 . 1 - 151 ; P < . 0001 ) , hepatocellular damage ( OR = 7 . 9 ; 95 % CI : 1 . 6 - 37 ; P < . 009 ) , and higher baseline plasma bilirubin value ( OR = 1 . 15 ; 95 % CI : 1 . 09 - 1 . 22 ; P < . 0001 ) . CONCLUSIONS : Patients with drug - induced hepatocellular jaundice have 11 . 7 % chance of progressing to death or transplantation . Amoxicillin - clavulanate stands out as the most common drug related to DILI . Morphological evaluation of the effect of d - ribose on adriamycin - evoked cardiotoxicity in rats . The influence of d - ribose on adriamycin - induced myocardiopathy in rats was studied . Adriamycin in the cumulative dose of 25 mg / kg evoked fully developed cardiac toxicity . D - ribose in the multiple doses of 200 mg / kg did not influence ADR cardiotoxicity . In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin - induced nephrotoxicity : protection by erdosteine . The aims of this study were to examine vancomycin ( VCM ) - induced oxidative stress that promotes production of reactive oxygen species ( ROS ) and to investigate the role of erdosteine , an expectorant agent , which has also antioxidant properties , on kidney tissue against the possible VCM - induced renal impairment in rats . Rats were divided into three groups : sham , VCM and VCM plus erdosteine . VCM was administrated intraperitoneally ( i . p . ) with 200mgkg ( - 1 ) twice daily for 7 days . Erdosteine was administered orally . VCM administration to control rats significantly increased renal malondialdehyde ( MDA ) and urinary N - acetyl - beta - d - glucosaminidase ( NAG , a marker of renal tubular injury ) excretion but decreased superoxide dismutase ( SOD ) and catalase ( CAT ) activities . Erdosteine administration with VCM injections caused significantly decreased renal MDA and urinary NAG excretion , and increased SOD activity , but not CAT activity in renal tissue when compared with VCM alone . Erdosteine showed histopathological protection against VCM - induced nephrotoxicity . There were a significant dilatation of tubular lumens , extensive epithelial cell vacuolization , atrophy , desquamation , and necrosis in VCM - treated rats more than those of the control and the erdosteine groups . Erdosteine caused a marked reduction in the extent of tubular damage . It is concluded that oxidative tubular damage plays an important role in the VCM - induced nephrotoxicity and the modulation of oxidative stress with erdosteine reduces the VCM - induced kidney damage both at the biochemical and histological levels . Gemfibrozil - lovastatin therapy for primary hyperlipoproteinemias . The specific aim of this retrospective , observational study was to assess safety and efficacy of long - term ( 21 months / patient ) , open - label , gemfibrozil - lovastatin treatment in 80 patients with primary mixed hyperlipidemia ( 68 % of whom had atherosclerotic vascular disease ) . Because ideal lipid targets were not reached ( low - density lipoprotein ( LDL ) cholesterol less than 130 mg / dl , high - density lipoprotein ( HDL ) cholesterol greater than 35 mg / dl , or total cholesterol / HDL cholesterol less than 4 . 5 mg / dl ) with diet plus a single drug , gemfibrozil ( 1 . 2 g / day ) - lovastatin ( primarily 20 or 40 mg ) treatment was given . Follow - up visits were scheduled with 2 - drug therapy every 6 to 8 weeks , an average of 10 . 3 visits per patient , with 741 batteries of 6 liver function tests and 714 creatine phosphokinase levels measured . Only 1 of the 4 , 446 liver function tests ( 0 . 02 % ) , a gamma glutamyl transferase , was greater than or equal to 3 times the upper normal limit . Of the 714 creatine phosphokinase levels , 9 % were high ; only 1 ( 0 . 1 % ) was greater than or equal to 3 times the upper normal limit . With 2 - drug therapy , mean total cholesterol decreased 22 % from 255 to 200 mg / dl , triglyceride levels decreased 35 % from 236 to 154 mg / dl , LDL cholesterol decreased 26 % from 176 to 131 mg / dl , and the total cholesterol / HDL cholesterol ratio decreased 24 % from 7 . 1 to 5 . 4 , all p less than or equal to 0 . 0001 . Myositis , attributable to the drug combination and symptomatic enough to discontinue it , occurred in 3 % of patients , and in 1 % with concurrent high creatine phosphokinase ( 769 U / liter ) ; no patients had rhabdomyolysis or myoglobinuria . ( ABSTRACT TRUNCATED AT 250 WORDS ) Does domperidone potentiate mirtazapine - associated restless legs syndrome ? There is now evidence to suggest a central role for the dopaminergic system in restless legs syndrome ( RLS ) . For example , the symptoms of RLS can be dramatically improved by levodopa and dopamine agonists , whereas central dopamine D2 receptor antagonists can induce or aggravate RLS symptoms . To our knowledge , there is no previous report regarding whether domperidone , a peripheral dopamine D2 receptor antagonist , can also induce or aggravate symptoms of RLS . Mirtazapine , the first noradrenergic and specific serotonergic antidepressant ( NaSSA ) , has been associated with RLS in several recent publications . The authors report here a depressed patient comorbid with postprandial dyspepsia who developed RLS after mirtazapine had been added to his domperidone therapy . Our patient started to have symptoms of RLS only after he had been treated with mirtazapine , and his RLS symptoms resolved completely upon discontinuation of his mirtazapine . Such a temporal relationship between the use of mirtazapine and the symptoms of RLS in our patient did not support a potentiating effect of domperione on mirtazapine - associated RLS . However , physicians should be aware of the possibility that mirtazapine can be associated with RLS in some individuals , especially those receiving concomitant dopamine D2 receptor antagonists . Antiandrogenic therapy can cause coronary arterial disease . AIM : To study the change of lipid metabolism by antiandrogen therapy in patients with prostate cancer . MATERIALS AND METHODS : We studied with a 2 . 5 years follow - up the changes in plasma cholesterols ( C ) , triglycerides ( TG ) , lipoproteins ( LP ) , and apolipoproteins ( Apo ) B - 100 , A - I , and A - II pro fi les in 24 patients of mean age 60 years with low risk prostate cancer ( stage : T1cN0M0 , Gleason score : 2 - 5 ) during treatment with cyproterone acetate ( CPA ) without surgical management or radiation therapy . RESULTS : Significant decreases of HDL - C , Apo A - I and Apo A - II and an increase of triglyceride levels in VLDL were induced by CPA . After a period of 2 . 5 years on CPA treatment , four patients out of twenty - four were found to be affected by coronary heart disease . CONCLUSIONS : Ischaemic coronary arteriosclerosis with an incidence rate of 16 . 6 % as caused by prolonged CPA therapy is mediated through changes in HDL cholesterol , Apo A - I and Apo A - II pro fi les , other than the well - known hyperglyceridemic effect caused by estrogen . 5 - Fluorouracil cardiotoxicity induced by alpha - fluoro - beta - alanine . Cardiotoxicity is a rare complication occurring during 5 - fluorouracil ( 5 - FU ) treatment for malignancies . We herein report the case of a 70 - year - old man with 5 - FU - induced cardiotoxicity , in whom a high serum level of alpha - fluoro - beta - alanine ( FBAL ) was observed . The patient , who had unresectable colon cancer metastases to the liver and lung , was referred to us for chemotherapy from an affiliated hospital ; he had no cardiac history . After admission , the patient received a continuous intravenous infusion of 5 - FU ( 1000 mg / day ) , during which precordial pain with right bundle branch block occurred concomitantly with a high serum FBAL concentration of 1955 ng / ml . Both the precordial pain and the electrocardiographic changes disappeared spontaneously after the discontinuation of 5 - FU . As the precordial pain in this patient was considered to have been due to 5 - FU - induced cardiotoxicity , the administration of 5 - FU was abandoned . Instead , oral administration of S - 1 ( a derivative of 5 - FU ) , at 200 mg / day twice a week , was instituted , because S - 1 has a strong inhibitory effect on dihydropyrimidine dehydrogenase , which catalyzes the degradative of 5 - FU into FBAL . The serum FBAL concentration subsequently decreased to 352 ng / ml , the same as the value measured on the first day of S - 1 administration . Thereafter , no cardiac symptoms were observed . The patient achieved a partial response 6 months after the initiation of the S - 1 treatment . The experience of this case , together with a review of the literature , suggests that FBAL is related to 5 - FU - induced cardiotoxicity . S - 1 may be administered safely to patients with 5 - FU - induced cardiotoxicity . Hepatocellular carcinoma in Fanconi ' s anemia treated with androgen and corticosteroid . The case of an 11 - year - old boy is reported who was known to have Fanconi ' s anemia for 3 years and was treated with androgens , corticosteroids and transfusions . Two weeks before his death he was readmitted because of aplastic crisis with septicemia and marked abnormalities in liver function and died of hemorrhagic bronchopneumonia . At autopsy peliosis and multiple hepatic tumors were found which histologically proved to be well - differentiated hepatocellular carcinoma . This case contributes to the previous observations that non - metastasizing hepatic neoplasms and peliosis can develop in patients with androgen - and corticosteroid - treated Fanconi ' s anemia . The influence of the time interval between monoHER and doxorubicin administration on the protection against doxorubicin - induced cardiotoxicity in mice . PURPOSE : Despite its well - known cardiotoxicity , the anthracyclin doxorubicin ( DOX ) continues to be an effective and widely used chemotherapeutic agent . DOX - induced cardiac damage presumably results from the formation of free radicals by DOX . Reactive oxygen species particularly affect the cardiac myocytes because these cells seem to have a relatively poor antioxidant defense system . The semisynthetic flavonoid monohydroxyethylrutoside ( monoHER ) showed cardioprotection against DOX - induced cardiotoxicity through its radical scavenging and iron chelating properties . Because of the relatively short final half - life of monoHER ( about 30 min ) , it is expected that the time interval between monoHER and DOX might be of influence on the cardioprotective effect of monoHER . Therefore , the aim of the present study was to investigate this possible effect . METHODS : Six groups of 6 BALB / c mice were treated with saline , DOX alone or DOX ( 4 mg / kg i . v . ) preceded by monoHER ( 500 mg / kg i . p . ) with an interval of 10 , 30 , 60 or 120 min . After a 6 - week treatment period and additional observation for 2 weeks , the mice were sacrificed . Their cardiac tissues were processed for light microscopy , after which cardiomyocyte damage was evaluated according to Billingham ( in Cancer Treat Rep 62 ( 6 ) : 865 - 872 , 1978 ) . Microscopic evaluation revealed that treatment with DOX alone induced significant cardiac damage in comparison to the saline control group ( P < 0 . 001 ) . RESULTS : The number of damaged cardiomyocytes was 9 . 6 - fold ( 95 % CI 4 . 4 - 21 . 0 ) higher in mice treated with DOX alone than that in animals of the control group . The ratio of aberrant cardiomyocytes in mice treated with DOX preceded by monoHER and those in mice treated with saline ranged from 1 . 6 to 2 . 8 ( mean 2 . 2 , 95 % CI 1 . 2 - 4 . 1 , P = 0 . 019 ) . The mean protective effect by adding monoHER before DOX led to a significant 4 . 4 - fold reduction ( P < 0 . 001 , 95 % CI 2 . 3 - 8 . 2 ) of abnormal cardiomyocytes . This protective effect did not depend on the time interval between monoHER and DOX administration ( P = 0 . 345 ) . CONCLUSION : The results indicate that in an outpatient clinical setting monoHER may be administered shortly before DOX . Clinical evaluation of adverse effects during bepridil administration for atrial fibrillation and flutter . BACKGROUND : Bepridil hydrochloride ( Bpd ) has attracted attention as an effective drug for atrial fibrillation ( AF ) and atrial flutter ( AFL ) . However , serious adverse effects , including torsade de pointes ( Tdp ) , have been reported . METHODS AND RESULTS : Adverse effects of Bpd requiring discontinuation of treatment were evaluated . Bpd was administered to 459 patients ( 361 males , 63 + / - 12 years old ) comprising 378 AF and 81 AFL cases . Mean left ventricular ejection fraction and atrial dimension ( LAD ) were 66 + / - 11 % and 40 + / - 6 mm , respectively . Adverse effects were observed in 19 patients ( 4 % ) during an average follow - up of 20 months . There was marked QT prolongation greater than 0 . 55 s in 13 patients , bradycardia less than 40 beats / min in 6 patients , dizziness and general fatigue in 1 patient each . In 4 of 13 patients with QT prolongation , Tdp occurred . The major triggering factors of Tdp were hypokalemia and sudden decrease in heart rate . There were no differences in the clinical backgrounds of the patients with and without Tdp other than LAD and age , which were larger and older in the patients with Tdp . CONCLUSION : Careful observation of serum potassium concentration and the ECG should always be done during Bpd administration , particularly in elderly patients . Enhanced isoproterenol - induced cardiac hypertrophy in transgenic rats with low brain angiotensinogen . We have previously shown that a permanent deficiency in the brain renin - angiotensin system ( RAS ) may increase the sensitivity of the baroreflex control of heart rate . In this study we aimed at studying the involvement of the brain RAS in the cardiac reactivity to the beta - adrenoceptor ( beta - AR ) agonist isoproterenol ( Iso ) . Transgenic rats with low brain angiotensinogen ( TGR ) were used . In isolated hearts , Iso induced a significantly greater increase in left ventricular ( LV ) pressure and maximal contraction ( + dP / dt ( max ) ) in the TGR than in the Sprague - Dawley ( SD ) rats . LV hypertrophy induced by Iso treatment was significantly higher in TGR than in SD rats ( in g LV wt / 100 g body wt , 0 . 28 + / - 0 . 004 vs . 0 . 24 + / - 0 . 004 , respectively ) . The greater LV hypertrophy in TGR rats was associated with more pronounced downregulation of beta - AR and upregulation of LV beta - AR kinase - 1 mRNA levels compared with those in SD rats . The decrease in the heart rate ( HR ) induced by the beta - AR antagonist metoprolol in conscious rats was significantly attenuated in TGR compared with SD rats ( - 9 . 9 + / - 1 . 7 % vs . - 18 . 1 + / - 1 . 5 % ) , whereas the effect of parasympathetic blockade by atropine on HR was similar in both strains . These results indicate that TGR are more sensitive to beta - AR agonist - induced cardiac inotropic response and hypertrophy , possibly due to chronically low sympathetic outflow directed to the heart . Drug - induced long QT syndrome in injection drug users receiving methadone : high frequency in hospitalized patients and risk factors . BACKGROUND : Drug - induced long QT syndrome is a serious adverse drug reaction . Methadone prolongs the QT interval in vitro in a dose - dependent manner . In the inpatient setting , the frequency of QT interval prolongation with methadone treatment , its dose dependence , and the importance of cofactors such as drug - drug interactions remain unknown . METHODS : We performed a systematic , retrospective study comparing active or former intravenous drug users receiving methadone and those not receiving methadone among all patients hospitalized over a 5 - year period in a tertiary care hospital . A total of 167 patients receiving methadone fulfilled the inclusion criteria and were compared with a control group of 80 injection drug users not receiving methadone . In addition to methadone dose , 15 demographic , biological , and pharmacological variables were considered as potential risk factors for QT prolongation . RESULTS : Among 167 methadone maintenance patients , the prevalence of QTc prolongation to 0 . 50 second ( ( 1 / 2 ) ) or longer was 16 . 2 % compared with 0 % in 80 control subjects . Six patients ( 3 . 6 % ) in the methadone group presented torsades de pointes . QTc length was weakly but significantly associated with methadone daily dose ( Spearman rank correlation coefficient , 0 . 20 ; P < . 01 ) . Multivariate regression analysis allowed attribution of 31 . 8 % of QTc variability to methadone dose , cytochrome P - 450 3A4 drug - drug interactions , hypokalemia , and altered liver function . CONCLUSIONS : QT interval prolongation in methadone maintenance patients hospitalized in a tertiary care center is a frequent finding . Methadone dose , presence of cytochrome P - 450 3A4 inhibitors , potassium level , and liver function contribute to QT prolongation . Long QT syndrome can occur with low doses of methadone . Mechanisms of hypertension induced by nitric oxide ( NO ) deficiency : focus on venous function . Loss of endothelial cell - derived nitric oxide ( NO ) in hypertension is a hallmark of arterial dysfunction . Experimental hypertension created by the removal of NO , however , involves mechanisms in addition to decreased arterial vasodilator activity . These include augmented endothelin - 1 ( ET - 1 ) release , increased sympathetic nervous system activity , and elevated tissue oxidative stress . We hypothesized that increased venous smooth muscle ( venomotor ) tone plays a role in Nomega - nitro - L - arginine ( LNNA ) hypertension through these mechanisms . Rats were treated with the NO synthase inhibitor LNNA ( 0 . 5 g / L in drinking water ) for 2 weeks . Mean arterial pressure of conscious rats was 119 + / - 2 mm Hg in control and 194 + / - 5 mm Hg in LNNA rats ( P < 0 . 05 ) . Carotid arteries and vena cava were removed for measurement of isometric contraction . Maximal contraction to norepinephrine was modestly reduced in arteries from LNNA compared with control rats whereas the maximum contraction to ET - 1 was significantly reduced ( 54 % control ) . Maximum contraction of vena cava to norepinephrine ( 37 % control ) also was reduced but no change in response to ET - 1 was observed . Mean circulatory filling pressure , an in vivo measure of venomotor tone , was not elevated in LNNA hypertension at 1 or 2 weeks after LNNA . The superoxide scavenger tempol ( 30 , 100 , and 300 micromol kg ( - 1 ) , IV ) did not change arterial pressure in control rats but caused a dose - dependent decrease in LNNA rats ( - 18 + / - 8 , - 26 + / - 15 , and - 54 + / - 11 mm Hg ) . Similarly , ganglionic blockade with hexamethonium caused a significantly greater fall in LNNA hypertensive rats ( 76 + / - 9 mm Hg ) compared with control rats ( 35 + / - 10 mm Hg ) . Carotid arteries , vena cava , and sympathetic ganglia from LNNA rats had higher basal levels of superoxide compared with those from control rats . These data suggest that while NO deficiency increases oxidative stress and sympathetic activity in both arterial and venous vessels , the impact on veins does not make a major contribution to this form of hypertension . Association of DRD2 polymorphisms and chlorpromazine - induced extrapyramidal syndrome in Chinese schizophrenic patients . AIM : Extrapyramidal syndrome ( EPS ) is most commonly affected by typical antipsychotic drugs that have a high affinity with the D2 receptor . Recently , many research groups have reported on the positive relationship between the genetic variations in the DRD2 gene and the therapeutic response in schizophrenia patients as a result of the role of variations in the receptor in modulating receptor expression . In this study , we evaluate the role DRD2 plays in chlorpromazine - induced EPS in schizophrenic patients . METHODS : We identified seven SNP ( single nucleotide polymorphism ) ( - 141Cins > del , TaqIB , TaqID , Ser311Cys , rs6275 , rs6277 and TaqIA ) in the DRD2 gene in 146 schizophrenic inpatients ( 59 with EPS and 87 without EPS according to the Simpson - Angus Scale ) treated with chlorpromazine after 8 weeks . The alleles of all loci were determined by PCR ( polymerase chain reaction ) . RESULTS : Polymorphisms TaqID , Ser311Cys and rs6277 were not polymorphic in the population recruited in the present study . No statistical significance was found in the allele distribution of - 141Cins > del , TaqIB , rs6275 and TaqIA or in the estimated haplotypes ( constituted by TaqIB , rs6275 and TaqIA ) in linkage disequilibrium between the two groups . CONCLUSION : Our results did not lend strong support to the view that the genetic variation of the DRD2 gene plays a major role in the individually variable adverse effect induced by chlorpromazine , at least in Chinese patients with schizophrenia . Our results confirmed a previous study on the relationship between DRD2 and EPS in Caucasians . Physical training decreases susceptibility to subsequent pilocarpine - induced seizures in the rat . Regular motor activity has many benefits for mental and physical condition but its implications for epilepsy are still controversial . In order to elucidate this problem , we have studied the effect of long - term physical activity on susceptibility to subsequent seizures . Male Wistar rats were subjected to repeated training sessions in a treadmill and swimming pool . Thereafter , seizures were induced by pilocarpine injections in trained and non - trained control groups . During the acute period of status epilepticus , we measured : ( 1 ) the latency of the first motor sign , ( 2 ) the intensity of seizures , ( 3 ) the time when it occurred within the 6 - h observation period , and ( 4 ) the time when the acute period ended . All these behavioral parameters showed statistically significant changes suggesting that regular physical exercises decrease susceptibility to subsequently induced seizures and ameliorate the course of experimentally induced status epilepticus . Tonic dopaminergic stimulation impairs associative learning in healthy subjects . Endogenous dopamine plays a central role in salience coding during associative learning . Administration of the dopamine precursor levodopa enhances learning in healthy subjects and stroke patients . Because levodopa increases both phasic and tonic dopaminergic neurotransmission , the critical mechanism mediating the enhancement of learning is unresolved . We here probed how selective tonic dopaminergic stimulation affects associative learning . Forty healthy subjects were trained in a novel vocabulary of 45 concrete nouns over the course of 5 consecutive training days in a prospective , randomized , double - blind , placebo - controlled design . Subjects received the tonically stimulating dopamine - receptor agonist pergolide ( 0 . 1 mg ) vs placebo 120 min before training on each training day . The dopamine agonist significantly impaired novel word learning compared to placebo . This learning decrement persisted up to the last follow - up 4 weeks post - training . Subjects treated with pergolide also showed restricted emotional responses compared to the PLACEBO group . The extent of ' flattened ' affect with pergolide was related to the degree of learning inhibition . These findings suggest that tonic occupation of dopamine receptors impairs learning by competition with phasic dopamine signals . Thus , phasic signaling seems to be the critical mechanism by which dopamine enhances associative learning in healthy subjects and stroke patients . Minocycline - induced vasculitis fulfilling the criteria of polyarteritis nodosa . A 47 - year - old man who had been taking minocycline for palmoplantar pustulosis developed fever , myalgias , polyneuropathy , and testicular pain , with elevated C - reactive protein ( CRP ) . Neither myeloperoxidase - nor proteinase - 3 - antineutrophil cytoplasmic antibody was positive . These manifestations met the American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa . Stopping minocycline led to amelioration of symptoms and normalization of CRP level . To our knowledge , this is the second case of minocycline - induced vasculitis satisfying the criteria . Differential diagnosis for drug - induced disease is invaluable even for patients with classical polyarteritis nodosa . Intramuscular hepatitis B immune globulin combined with lamivudine in prevention of hepatitis B recurrence after liver transplantation . BACKGROUND : Combined hepatitis B immune globulin ( HBIg ) and lamivudine in prophylaxis of the recurrence of hepatitis B after liver transplantation has significantly improved the survival of HBsAg positive patients . This study was undertaken to evaluate the outcomes of liver transplantation for patients with hepatitis B virus ( HBV ) . METHODS : A retrospective chart analysis and a review of the organ transplant database identified 51 patients ( 43 men and 8 women ) transplanted for benign HBV - related cirrhotic diseases between June 2002 and December 2004 who had survived more than 3 months . HBIg was administered intravenously during the first week and intramuscularly thereafter . RESULTS : At a median follow - up of 14 . 1 months , the overall recurrence rate in the 51 patients was 3 . 9 % ( 2 / 51 ) . The overall patient survival was 88 . 3 % , and 82 . 4 % after 1 and 2 years , respectively . A daily oral dose of 100 mg lamivudine for 2 weeks before transplantation for 10 patients enabled 57 . 1 % ( 4 / 7 ) and 62 . 5 % ( 5 / 8 ) of HBV - DNA and HBeAg positive patients respectively to convert to be negative . Intramuscular HBIg was well tolerated in all patients . CONCLUSION : Lamivudine combined with intramuscular HBIg can effectively prevent allograft from the recurrence of HBV after liver transplantation . Anticonvulsant effect of eslicarbazepine acetate ( BIA 2 - 093 ) on seizures induced by microperfusion of picrotoxin in the hippocampus of freely moving rats . Eslicarbazepine acetate ( BIA 2 - 093 , S - ( - ) - 10 - acetoxy - 10 , 11 - dihydro - 5H - dibenzo / b , f / azepine - 5 - carboxamide ) is a novel antiepileptic drug , now in Phase III clinical trials , designed with the aim of improving efficacy and safety in comparison with the structurally related drugs carbamazepine ( CBZ ) and oxcarbazepine ( OXC ) . We have studied the effects of oral treatment with eslicarbazepine acetate on a whole - animal model in which partial seizures can be elicited repeatedly on different days without changes in threshold or seizure patterns . In the animals treated with threshold doses of picrotoxin , the average number of seizures was 2 . 3 + / - 1 . 2 , and average seizure duration was 39 . 5 + / - 8 . 4s . Pre - treatment with a dose of 30 mg / kg 2h before picrotoxin microperfusion prevented seizures in the 75 % of the rats . Lower doses ( 3 and 10mg / kg ) did not suppress seizures , however , after administration of 10mg / kg , significant reductions in seizures duration ( 24 . 3 + / - 6 . 8s ) and seizure number ( 1 . 6 + / - 0 . 34 ) were found . No adverse effects of eslicarbazepine acetate were observed in the behavioral / EEG patterns studied , including sleep / wakefulness cycle , at the doses studied . Acute renal failure associated with prolonged intake of slimming pills containing anthraquinones . Chinese herbal medicine preparations are widely available and often regarded by the public as natural and safe remedies for a variety of medical conditions . Nephropathy caused by Chinese herbs has previously been reported , usually involving the use of aristolochic acids . We report a 23 - year - old woman who developed acute renal failure following prolonged use of a proprietary Chinese herbal slimming pill that contained anthraquinone derivatives , extracted from Rhizoma Rhei ( rhubarb ) . The renal injury was probably aggravated by the concomitant intake of a non - steroidal anti - inflammatory drug , diclofenac . Renal pathology was that of hypocellular interstitial fibrosis . Spontaneous renal recovery occurred upon cessation of the slimming pills , but mild interstitial fibrosis and tubular atrophy was still evident histologically 4 months later . Although a causal relationship between the use of an anthraquinone - containing herbal agent and renal injury remains to be proven , phytotherapy - associated interstitial nephropathy should be considered in patients who present with unexplained renal failure . Chloroacetaldehyde as a sulfhydryl reagent : the role of critical thiol groups in ifosfamide nephropathy . Chloroacetaldehyde ( CAA ) is a metabolite of the alkylating agent ifosfamide ( IFO ) and putatively responsible for renal damage following anti - tumor therapy with IFO . Depletion of sulfhydryl ( SH ) groups has been reported from cell culture , animal and clinical studies . In this work the effect of CAA on human proximal tubule cells in primary culture ( hRPTEC ) was investigated . Toxicity of CAA was determined by protein content , cell number , LDH release , trypan blue exclusion assay and caspase - 3 activity . Free thiols were measured by the method of Ellman . CAA reduced hRPTEC cell number and protein , induced a loss in free intracellular thiols and an increase in necrosis markers . CAA but not acrolein inhibited the cysteine proteases caspase - 3 , caspase - 8 and cathepsin B . Caspase activation by cisplatin was inhibited by CAA . In cells stained with fluorescent dyes targeting lysosomes , CAA induced an increase in lysosomal size and lysosomal leakage . The effects of CAA on cysteine protease activities and thiols could be reproduced in cell lysate . Acidification , which slowed the reaction of CAA with thiol donors , could also attenuate effects of CAA on necrosis markers , thiol depletion and cysteine protease inhibition in living cells . Thus , CAA directly reacts with cellular protein and non - protein thiols , mediating its toxicity on hRPTEC . This effect can be reduced by acidification . Therefore , urinary acidification could be an option to prevent IFO nephropathy in patients . Stereological methods reveal the robust size and stability of ectopic hilar granule cells after pilocarpine - induced status epilepticus in the adult rat . Following status epilepticus in the rat , dentate granule cell neurogenesis increases greatly , and many of the new neurons appear to develop ectopically , in the hilar region of the hippocampal formation . It has been suggested that the ectopic hilar granule cells could contribute to the spontaneous seizures that ultimately develop after status epilepticus . However , the population has never been quantified , so it is unclear whether it is substantial enough to have a strong influence on epileptogenesis . To quantify this population , the total number of ectopic hilar granule cells was estimated using unbiased stereology at different times after pilocarpine - induced status epilepticus . The number of hilar neurons immunoreactive for Prox - 1 , a granule - cell - specific marker , was estimated using the optical fractionator method . The results indicate that the size of the hilar ectopic granule cell population after status epilepticus is substantial , and stable over time . Interestingly , the size of the population appears to be correlated with the frequency of behavioral seizures , because animals with more ectopic granule cells in the hilus have more frequent behavioral seizures . The hilar ectopic granule cell population does not appear to vary systematically across the septotemporal axis , although it is associated with an increase in volume of the hilus . The results provide new insight into the potential role of ectopic hilar granule cells in the pilocarpine model of temporal lobe epilepsy . A prospective , open - label trial of galantamine in autistic disorder . OBJECTIVE : Post - mortem studies have reported abnormalities of the cholinergic system in autism . The purpose of this study was to assess the use of galantamine , an acetylcholinesterase inhibitor and nicotinic receptor modulator , in the treatment of interfering behaviors in children with autism . METHODS : Thirteen medication - free children with autism ( mean age , 8 . 8 + / - 3 . 5 years ) participated in a 12 - week , open - label trial of galantamine . Patients were rated monthly by parents on the Aberrant Behavior Checklist ( ABC ) and the Conners ' Parent Rating Scale - Revised , and by a physician using the Children ' s Psychiatric Rating Scale and the Clinical Global Impressions scale . RESULTS : Patients showed a significant reduction in parent - rated irritability and social withdrawal on the ABC as well as significant improvements in emotional lability and inattention on the Conners ' Parent Rating Scale - - Revised . Similarly , clinician ratings showed reductions in the anger subscale of the Children ' s Psychiatric Rating Scale . Eight of 13 participants were rated as responders on the basis of their improvement scores on the Clinical Global Impressions scale . Overall , galantamine was well - tolerated , with no significant adverse effects apart from headaches in one patient . CONCLUSION : In this open trial , galantamine was well - tolerated and appeared to be beneficial for the treatment of interfering behaviors in children with autism , particularly aggression , behavioral dyscontrol , and inattention . Further controlled trials are warranted . Randomized comparison of olanzapine versus risperidone for the treatment of first - episode schizophrenia : 4 - month outcomes . OBJECTIVE : The authors compared 4 - month treatment outcomes for olanzapine versus risperidone in patients with first - episode schizophrenia spectrum disorders . METHOD : One hundred twelve subjects ( 70 % male ; mean age = 23 . 3 years [ SD = 5 . 1 ] ) with first - episode schizophrenia ( 75 % ) , schizophreniform disorder ( 17 % ) , or schizoaffective disorder ( 8 % ) were randomly assigned to treatment with olanzapine ( 2 . 5 - 20 mg / day ) or risperidone ( 1 - 6 mg / day ) . RESULTS : Response rates did not significantly differ between olanzapine ( 43 . 7 % , 95 % CI = 28 . 8 % - 58 . 6 % ) and risperidone ( 54 . 3 % , 95 % CI = 39 . 9 % - 68 . 7 % ) . Among those responding to treatment , more subjects in the olanzapine group ( 40 . 9 % , 95 % CI = 16 . 8 % - 65 . 0 % ) than in the risperidone group ( 18 . 9 % , 95 % CI = 0 % - 39 . 2 % ) had subsequent ratings not meeting response criteria . Negative symptom outcomes and measures of parkinsonism and akathisia did not differ between medications . Extrapyramidal symptom severity scores were 1 . 4 ( 95 % CI = 1 . 2 - 1 . 6 ) with risperidone and 1 . 2 ( 95 % CI = 1 . 0 - 1 . 4 ) with olanzapine . Significantly more weight gain occurred with olanzapine than with risperidone : the increase in weight at 4 months relative to baseline weight was 17 . 3 % ( 95 % CI = 14 . 2 % - 20 . 5 % ) with olanzapine and 11 . 3 % ( 95 % CI = 8 . 4 % - 14 . 3 % ) with risperidone . Body mass index at baseline and at 4 months was 24 . 3 ( 95 % CI = 22 . 8 - 25 . 7 ) versus 28 . 2 ( 95 % CI = 26 . 7 - 29 . 7 ) with olanzapine and 23 . 9 ( 95 % CI = 22 . 5 - 25 . 3 ) versus 26 . 7 ( 95 % CI = 25 . 2 - 28 . 2 ) with risperidone . CONCLUSIONS : Clinical outcomes with risperidone were equal to those with olanzapine , and response may be more stable . Olanzapine may have an advantage for motor side effects . Both medications caused substantial rapid weight gain , but weight gain was greater with olanzapine . Early paracentral visual field loss in patients taking hydroxychloroquine . OBJECTIVE : To review the natural history and ocular and systemic adverse effects of patients taking hydroxychloroquine sulfate who attended an ophthalmic screening program . DESIGN : Retrospective study . RESULTS : Records of 262 patients who were taking hydroxychloroquine and screened in the Department of Ophthalmology were reviewed . Of the 262 patients , 14 ( 18 % ) of 76 who had stopped treatment at the time of the study experienced documented adverse effects . Systemic adverse effects occurred in 8 patients ( 10 . 5 % ) and ocular adverse effects , in 5 ( 6 . 5 % ) . Thirty - five patients ( 13 . 4 % ) had visual field abnormalities , which were attributed to hydroxychloroquine treatment in 4 patients ( 1 . 5 % ) . Three of the 4 patients were taking less than 6 . 5 mg / kg per day and all patients had normal renal and liver function test results . CONCLUSIONS : The current study used a protocol of visual acuity and color vision assessment , funduscopy , and Humphrey 10 - 2 visual field testing and shows that visual field defects appeared before any corresponding changes in any other tested clinical parameters ; the defects were reproducible and the test parameters were reliable . Patients taking hydroxychloroquine can demonstrate a toxic reaction in the retina despite the absence of known risk factors . Screening , including Humphrey 10 - 2 visual field assessment , is recommended 2 years after the initial baseline and yearly thereafter . Peri - operative atrioventricular block as a result of chemotherapy with epirubicin and paclitaxel . A 47 - year - old woman presented for mastectomy and immediate latissimus dorsi flap reconstruction having been diagnosed with carcinoma of the breast 6 months previously . In the preceding months she had received neo - adjuvant chemotherapy with epirubicin , paclitaxel ( Taxol ) and cyclophosphamide . This had been apparently uncomplicated and she had maintained a remarkably high level of physical activity . She was found to be bradycardic at pre - operative assessment but had no cardiac symptoms . Second degree Mobitz type II atrioventricular block was diagnosed on electrocardiogram , and temporary transvenous ventricular pacing instituted in the peri - operative period . We discuss how evidence - based guidelines would not have been helpful in this case , and how chemotherapy can exhibit substantial cardiotoxicity that may develop over many years . We suggest that patients who have received chemotherapy at any time should have a pre - operative electrocardiogram even if they are asymptomatic . Risks and benefits of COX - 2 inhibitors vs non - selective NSAIDs : does their cardiovascular risk exceed their gastrointestinal benefit ? A retrospective cohort study . OBJECTIVES : The risk of acute myocardial infarction ( AMI ) with COX - 2 inhibitors may offset their gastrointestinal ( GI ) benefit compared with non - selective ( NS ) non - steroidal anti - inflammatory drugs ( NSAIDs ) . We aimed to compare the risks of hospitalization for AMI and GI bleeding among elderly patients using COX - 2 inhibitors , NS - NSAIDs and acetaminophen . METHODS : We conducted a retrospective cohort study using administrative data of patients > or = 65 years of age who filled a prescription for NSAID or acetaminophen during 1999 - 2002 . Outcomes were compared using Cox regression models with time - dependent exposures . RESULTS : Person - years of exposure among non - users of aspirin were : 75 , 761 to acetaminophen , 42 , 671 to rofecoxib 65 , 860 to celecoxib , and 37 , 495 to NS - NSAIDs . Among users of aspirin , they were : 14 , 671 to rofecoxib , 22 , 875 to celecoxib , 9 , 832 to NS - NSAIDs and 38 , 048 to acetaminophen . Among non - users of aspirin , the adjusted hazard ratios ( 95 % confidence interval ) of hospitalization for AMI / GI vs the acetaminophen ( with no aspirin ) group were : rofecoxib 1 . 27 ( 1 . 13 , 1 . 42 ) , celecoxib 0 . 93 ( 0 . 83 , 1 . 03 ) , naproxen 1 . 59 ( 1 . 31 , 1 . 93 ) , diclofenac 1 . 17 ( 0 . 99 , 1 . 38 ) and ibuprofen 1 . 05 ( 0 . 74 , 1 . 51 ) . Among users of aspirin , they were : rofecoxib 1 . 73 ( 1 . 52 , 1 . 98 ) , celecoxib 1 . 34 ( 1 . 19 , 1 . 52 ) , ibuprofen 1 . 51 ( 0 . 95 , 2 . 41 ) , diclofenac 1 . 69 ( 1 . 35 , 2 . 10 ) , naproxen 1 . 35 ( 0 . 97 , 1 . 88 ) and acetaminophen 1 . 29 ( 1 . 17 , 1 . 42 ) . CONCLUSION : Among non - users of aspirin , naproxen seemed to carry the highest risk for AMI / GI bleeding . The AMI / GI toxicity of celecoxib was similar to that of acetaminophen and seemed to be better than those of rofecoxib and NS - NSAIDs . Among users of aspirin , both celecoxib and naproxen seemed to be the least toxic . Quinine - induced arrhythmia in a patient with severe malaria . It was reported that there was a case of severe malaria patient with jaundice who presented with arrhythmia ( premature ventricular contraction ) while getting quinine infusion was reported . A man , 25 years old , was admitted to hospital with high fever , chill , vomiting , jaundice . The patient was fully conscious , blood pressure 120 / 80 mmHg , pulse rate 100 x / minute , regular . On admission , laboratory examination showed Plasmodium falciparum ( + + + + ) , total bilirubin 8 . 25 mg / dL , conjugated bilirubin 4 . 36 mg / dL , unconjugated bilirubin 3 . 89 mg / dL , potassium 3 . 52 meq / L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in dextrose 5 % 500 mg / 8 hour . On the second day the patient had vomitus , diarrhea , tinnitus , loss of hearing . After 30 hours of quinine infusion the patient felt palpitation and electrocardiography ( ECG ) recording showed premature ventricular contraction ( PVC ) > 5 x / minute , trigemini , constant type - - sinoatrial block , positive U wave . He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in dextrose 5 % / 24 hour and potassium aspartate tablet . Quinine infusion was discontinued and changed with sulfate quinine tablets . Three hours later the patient felt better , the frequency of PVC reduced to 4 - 5 x / minute and on the third day ECG was normal , potassium level was 3 . 34 meq / L . He was discharged on 7th day in good condition . Quinine , like quinidine , is a chincona alkaloid that has anti - arrhythmic property , although it also pro - arrhythmic that can cause various arrhythmias , including severe arrhythmia such as multiple PVC . Administration of parenteral quinine must be done carefully and with good observation because of its pro - arrhythmic effect , especially in older patients who have heart diseases or patients with electrolyte disorder ( hypokalemia ) which frequently occurs due to vomiting and or diarrhea in malaria cases . Penicillamine - related lichenoid dermatitis and utility of zinc acetate in a Wilson disease patient with hepatic presentation , anxiety and SPECT abnormalities . Wilson ' s disease is an autosomal recessive disorder of hepatic copper metabolism with consequent copper accumulation and toxicity in many tissues and consequent hepatic , neurologic and psychiatric disorders . We report a case of Wilson ' s disease with chronic liver disease ; moreover , in our patient , presenting also with high levels of state anxiety without depression , 99mTc - ECD - SPECT showed cortical hypoperfusion in frontal lobes , more marked on the left frontal lobe . During the follow - up of our patient , penicillamine was interrupted after the appearance of a lichenoid dermatitis , and zinc acetate permitted to continue the successful treatment of the patient without side - effects . In our case the therapy with zinc acetate represented an effective treatment for a Wilson ' s disease patient in which penicillamine - related side effects appeared . The safety of the zinc acetate allowed us to avoid other potentially toxic chelating drugs ; this observation is in line with the growing evidence on the efficacy of the drug in the treatment of Wilson ' s disease . Since most of Wilson ' s disease penicillamine - treated patients do not seem to develop this skin lesion , it could be conceivable that a specific genetic factor is involved in drug response . Further studies are needed for a better clarification of Wilson ' s disease therapy , and in particular to differentiate specific therapies for different Wilson ' s disease phenotypes . A dramatic drop in blood pressure following prehospital GTN administration . A male in his sixties with no history of cardiac chest pain awoke with chest pain following an afternoon sleep . The patient did not self medicate . The patient ' s observations were within normal limits , he was administered oxygen via a face mask and glyceryl trinitrate ( GTN ) . Several minutes after the GTN the patient experienced a sudden drop in blood pressure and heart rate , this was rectified by atropine sulphate and a fluid challenge . There was no further deterioration in the patient ' s condition during transport to hospital . There are very few documented case like this in the prehospital scientific literature . The cause appears to be the Bezold - Jarish reflex , stimulation of the ventricular walls which in turn decreases sympathetic outflow from the vasomotor centre . Prehospital care providers who are managing any patient with a syncopal episode that fails to recover within a reasonable time frame should consider the Bezold - Jarisch reflex as the cause and manage the patient accordingly . Chronic lesion of rostral ventrolateral medulla in spontaneously hypertensive rats . We studied the effects of chronic selective neuronal lesion of rostral ventrolateral medulla on mean arterial pressure , heart rate , and neurogenic tone in conscious , unrestrained spontaneously hypertensive rats . The lesions were placed via bilateral microinjections of 30 nmol / 200 nl N - methyl - D - aspartic acid . The restimulation of this area with N - methyl - D - aspartic acid 15 days postlesion failed to produce a pressor response . One day postlesion , the resting mean arterial pressure was significantly decreased in lesioned rats when compared with sham rats ( 100 + / - 7 versus 173 + / - 4 mm Hg , p less than 0 . 05 ) . Fifteen days later , the lesioned group still showed values significantly lower than the sham group ( 150 + / - 6 versus 167 + / - 5 mm Hg , p less than 0 . 05 ) . No significant heart rate differences were observed between the sham and lesioned groups . The ganglionic blocker trimethaphan ( 5 mg / kg i . v . ) caused similar reductions in mean arterial pressure in both lesioned and sham groups . The trimethaphan - induced hypotension was accompanied by a significant bradycardia in lesioned rats ( - 32 + / - 13 beats per minute ) but a tachycardia in sham rats ( + 33 + / - 12 beats per minute ) 1 day postlesion . Therefore , rostral ventrolateral medulla neurons appear to play a significant role in maintaining hypertension in conscious spontaneously hypertensive rats . Spinal or suprabulbar structures could be responsible for the gradual recovery of the hypertension in the lesioned rats . Acute encephalopathy and cerebral vasospasm after multiagent chemotherapy including PEG - asparaginase and intrathecal cytarabine for the treatment of acute lymphoblastic leukemia . A 7 - year - old girl with an unusual reaction to induction chemotherapy for precursor B - cell acute lymphoblastic leukemia ( ALL ) is described . The patient developed acute encephalopathy evidenced by behavioral changes , aphasia , incontinence , visual hallucinations , and right - sided weakness with diffuse cerebral vasospasm on magnetic resonance angiography after the administration of intrathecal cytarabine . Vincristine , dexamethasone , and polyethylene glycol - asparaginase were also administered before the episode as part of induction therapy . Neurologic status returned to baseline within 10 days of the acute event , and magnetic resonance angiography findings returned to normal 4 months later . Comparison of valsartan / hydrochlorothiazide combination therapy at doses up to 320 / 25 mg versus monotherapy : a double - blind , placebo - controlled study followed by long - term combination therapy in hypertensive adults . BACKGROUND : One third of patients treated for hypertension attain adequate blood pressure ( BP ) control , and multidrug regimens are often required . Given the lifelong nature of hypertension , there is a need to evaluate the long - term efficacy and tolerability of higher doses of combination anti - hypertensive therapies . OBJECTIVE : This study investigated the efficacy and tolerability of valsartan ( VAL ) or hydrochlorothiazide ( HCTZ ) - monotherapy and higher - dose combinations in patients with essential hypertension . METHODS : The first part of this study was an 8 - week , multicenter , randomized , double - blind , placebo controlled , parallel - group trial . Patients with essential hypertension ( mean sitting diastolic BP [ MSDBP ] , > or = 95 mm Hg and < 110 mm Hg ) were randomized to 1 of 8 treatment groups : VAL 160 or 320 mg ; HCTZ 12 . 5 or 25 mg ; VAL / HCTZ 160 / 12 . 5 , 320 / 12 . 5 , or 320 / 25 mg ; or placebo . Mean changes in MSDBP and mean sitting systolic BP ( MSSBP ) were analyzed at the 8 - week core study end point . VAL / HCTZ 320 / 12 . 5 and 320 / 25 mg were further investigated in a 54 - week , open - label extension . Response was defined as MSDBP < 90 mm Hg or a > or = 10 mm Hg decrease compared to baseline . Control was defined as MSDBP < 90 mm Hg compared with baseline . Tolerability was assessed by monitoring adverse events at randomization and all subsequent study visits and regular evaluation of hematology and blood chemistry . RESULTS : A total of 1346 patients were randomized into the 8 - week core study ( 734 men , 612 women ; 924 white , 291 black , 23 Asian , 108 other ; mean age , 52 . 7 years ; mean weight , 92 . 6 kg ) . All active treatments were associated with significantly reduced MSSBP and MSDBP during the core 8 - week study , with each monotherapy significantly contributing to the overall effect of combination therapy ( VAL and HCTZ , P < 0 . 001 ) . Each combination was associated with significantly greater reductions in MSSBP and MSDBP compared with the monotherapies and placebo ( all , P < 0 . 001 ) . The mean reduction in MSSBP / MSDBP with VAL / HCTZ 320 / 25 mg was 24 . 7 / 16 . 6 mm Hg , compared with 5 . 9 / 7 . 0 mm Hg with placebo . The reduction in MSSBP was significantly greater with VAL / HCTZ 320 / 25 mg compared with VAL / HCTZ 160 / 12 . 5 mg ( P < 0 . 002 ) . Rates of response and BP control were significantly higher in the groups that received combination treatment compared with those that received monotherapy . The incidence of hypokalemia was lower with VAL / HCTZ combinations ( 1 . 8 % - 6 . 1 % ) than with HCTZ monotherapies ( 7 . 1 % - 13 . 3 % ) . The majority of adverse events in the core study were of mild to moderate severity . The efficacy and tolerability of VAL / HCTZ combinations were maintained during the extension ( 797 patients ) . CONCLUSIONS : In this study population , combination therapies with VAL / HCTZ were associated with significantly greater BP reductions compared with either monotherapy , were well tolerated , and were associated with less hypokalemia than HCTZ alone . Succimer chelation improves learning , attention , and arousal regulation in lead - exposed rats but produces lasting cognitive impairment in the absence of lead exposure . BACKGROUND : There is growing pressure for clinicians to prescribe chelation therapy at only slightly elevated blood lead levels . However , very few studies have evaluated whether chelation improves cognitive outcomes in Pb - exposed children , or whether these agents have adverse effects that may affect brain development in the absence of Pb exposure . OBJECTIVES : The present study was designed to answer these questions , using a rodent model of early childhood Pb exposure and treatment with succimer , a widely used chelating agent for the treatment of Pb poisoning . RESULTS : Pb exposure produced lasting impairments in learning , attention , inhibitory control , and arousal regulation , paralleling the areas of dysfunction seen in Pb - exposed children . Succimer treatment of the Pb - exposed rats significantly improved learning , attention , and arousal regulation , although the efficacy of the treatment varied as a function of the Pb exposure level and the specific functional deficit . In contrast , succimer treatment of rats not previously exposed to Pb produced lasting and pervasive cognitive and affective dysfunction comparable in magnitude to that produced by the higher Pb exposure regimen . CONCLUSIONS : These are the first data , to our knowledge , to show that treatment with any chelating agent can alleviate cognitive deficits due to Pb exposure . These findings suggest that it may be possible to identify a succimer treatment protocol that improves cognitive outcomes in Pb - exposed children . However , they also suggest that succimer treatment should be strongly discouraged for children who do not have elevated tissue levels of Pb or other heavy metals . Caffeine challenge test in panic disorder and depression with panic attacks . Our aim was to observe if patients with panic disorder ( PD ) and patients with major depression with panic attacks ( MDP ) ( Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition criteria ) respond in a similar way to the induction of panic attacks by an oral caffeine challenge test . We randomly selected 29 patients with PD , 27 with MDP , 25 with major depression without panic attacks ( MD ) , and 28 healthy volunteers . The patients had no psychotropic drug for at least a 4 - week period . In a randomized double - blind experiment performed in 2 occasions 7 days apart , 480 mg caffeine and a caffeine - free ( placebo ) solution were administered in a coffee form and anxiety scales were applied before and after each test . A total of 58 . 6 % ( n = 17 ) of patients with PD , 44 . 4 % ( n = 12 ) of patients with MDP , 12 . 0 % ( n = 3 ) of patients with MD , and 7 . 1 % ( n = 2 ) of control subjects had a panic attack after the 480 - mg caffeine challenge test ( chi ( 2 ) ( 3 ) = 16 . 22 , P = . 001 ) . The patients with PD and MDP were more sensitive to caffeine than were patients with MD and healthy volunteers . No panic attack was observed after the caffeine - free solution intake . The patients with MD had a lower heart rate response to the test than all the other groups ( 2 - way analysis of variance , group by time interaction with Greenhouse - Geisser correction : F ( 3 , 762 ) = 2 . 85 , P = . 026 ) . Our data suggest that there is an association between panic attacks , no matter if associated with PD or MDP , and hyperreactivity to an oral caffeine challenge test . Mitral annuloplasty as a ventricular restoration method for the failing left ventricle : a pilot study . BACKGROUND AND AIM OF THE STUDY : Undersized mitral annuloplasty ( MAP ) is effective in patients with dilated cardiomyopathy and functional mitral regurgitation ( MR ) since , as well as addressing the MR , the MAP may also reshape the dilated left ventricular ( LV ) base . However , the direct benefits of this possible reshaping on LV function in the absence of underlying MR remain incompletely understood . The study aim was to identify these benefits in a canine model of acute heart failure . METHODS : Six dogs underwent MAP with a prosthetic band on the posterior mitral annulus , using four mattress sutures . The sutures were passed individually through four tourniquets and exteriorized untied via the left atriotomy . Sonomicrometry crystals were implanted around the mitral annulus and left ventricle to measure geometry and regional function . Acute heart failure was induced by propranolol and volume loading after weaning from cardiopulmonary bypass ; an absence of MR was confirmed by echocardiography . MAP was accomplished by cinching the tourniquets . Data were acquired at baseline , after induction of acute heart failure , and after MAP . RESULTS : MAP decreased mitral annular dimensions in both commissure - commissure and septal - lateral directions . Concomitantly , the diastolic diameter of the LV base and LV sphericity decreased ( i . e . , improved ) from 37 . 4 + / - 9 . 3 to 35 . 9 + / - 10 mm ( p = 0 . 063 ) , and from 67 . 9 + / - 18 . 6 % to 65 . 3 + / - 18 . 9 % ( p = 0 . 016 ) , respectively . Decreases were evident in both LV end - diastolic pressure ( from 17 + / - 7 to 15 + / - 6 mmHg , p = 0 . 0480 and Tau ( from 48 + / - 8 to 45 + / - 8 ms , p < 0 . 01 ) , while fractional shortening at the LV base increased from 7 . 7 + / - 4 . 5 % to 9 . 4 + / - 4 . 5 % ( p = 0 . 045 ) . After MAP , increases were identified in both cardiac output ( from 1 . 54 + / - 0 . 57 to 1 . 65 + / - 0 . 57 1 / min ) and Emax ( from 1 . 86 + / - 0 . 9 to 2 . 41 + / - 1 . 31 mmHg / ml ) . CONCLUSION : The data acquired suggest that isolated MAP may have certain benefits on LV dimension / function in acute heart failure , even in the absence of MR . However , further investigations are warranted in a model of chronic heart failure . Piperacillin / tazobactam - induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis . Despite popular use of piperacillin , the dire neurotoxicity associated with piperacillin still goes unrecognized , leading to a delay in appropriate management . We report a 57 - year - old woman with end - stage renal disease receiving continuous ambulatory peritoneal dialysis ( CAPD ) , who developed slurred speech , tremor , bizarre behavior , progressive mental confusion , and 2 episodes of generalized tonic - clonic seizure ( GTCS ) after 5 doses of piperacillin / tazobactam ( 2 g / 250 mg ) were given for bronchiectasis with secondary infection . The laboratory data revealed normal plasma electrolyte and ammonia levels but leukocytosis . Neurologic examinations showed dysarthria and bilateral Babinski sign . Computed tomography of brain and electroencephalogram were unremarkable . Despite the use of antiepileptic agents , another GTCS episode recurred after the sixth dose of piperacillin / tazobactam . Brain magnetic resonance imaging did not demonstrate acute infarction and organic brain lesions . Initiation of high - flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours . Piperacillin - induced encephalopathy should be considered in any uremic patients with unexplained neurological manifestations . CAPD is inefficient in removing piperacillin , whereas hemodialysis can rapidly terminate the piperacillin - induced encephalopathy . Frequency of transient ipsilateral vocal cord paralysis in patients undergoing carotid endarterectomy under local anesthesia . BACKGROUND : Especially because of improvements in clinical neurologic monitoring , carotid endarterectomy done under local anesthesia has become the technique of choice in several centers . Temporary ipsilateral vocal nerve palsies due to local anesthetics have been described , however . Such complications are most important in situations where there is a pre - existing contralateral paralysis . We therefore examined the effect of local anesthesia on vocal cord function to better understand its possible consequences . METHODS : This prospective study included 28 patients undergoing carotid endarterectomy under local anesthesia . Vocal cord function was evaluated before , during , and after surgery ( postoperative day 1 ) using flexible laryngoscopy . Anesthesia was performed by injecting 20 to 40 mL of a mixture of long - acting ( ropivacaine ) and short - acting ( prilocaine ) anesthetic . RESULTS : All patients had normal vocal cord function preoperatively . Twelve patients ( 43 % ) were found to have intraoperative ipsilateral vocal cord paralysis . It resolved in all cases < or = 24 hours . There were no significant differences in operating time or volume or frequency of anesthetic administration in patients with temporary vocal cord paralysis compared with those without . CONCLUSION : Local anesthesia led to temporary ipsilateral vocal cord paralysis in almost half of these patients . Because pre - existing paralysis is of a relevant frequency ( up to 3 % ) , a preoperative evaluation of vocal cord function before carotid endarterectomy under local anesthesia is recommended to avoid intraoperative bilateral paralysis . In patients with preoperative contralateral vocal cord paralysis , surgery under general anesthesia should be considered . Impaired fear recognition in regular recreational cocaine users . INTRODUCTION : The ability to read facial expressions is essential for normal human social interaction . The aim of the present study was to conduct the first investigation of facial expression recognition performance in recreational cocaine users . MATERIALS AND METHODS : Three groups , comprised of 21 cocaine naive participants ( CN ) , 30 occasional cocaine ( OC ) , and 48 regular recreational cocaine ( RC ) users , were compared . An emotional facial expression ( EFE ) task consisting of a male and female face expressing six basic emotions ( happiness , surprise , sadness , anger , fear , and disgust ) was administered . Mean percent accuracy and latencies for correct responses across eight presentations of each basic emotion were derived . Participants were also assessed with the " Eyes task " to investigate their ability to recognize more complex emotional states and the Symptom CheckList - 90 - Revised to measure psychopathology . RESULTS : There were no group differences in psychopathology or " eyes task " performance , but the RC group , who otherwise had similar illicit substance use histories to the OC group , exhibited impaired fear recognition accuracy compared to the OC and CN groups . The RC group also correctly identified anger , fear , happiness , and surprise , more slowly than CN , but not OC participants . The OC group was slower than CN when correctly identifying disgust . The selective deficit in fear recognition accuracy manifested by the RC group cannot be explained by the subacute effects of cocaine , or ecstasy , because recent and less recent users of these drugs within this group were similarly impaired . Possible parallels between RC users and psychopaths with respect to impaired fear recognition , amygdala dysfunction , and etiology are discussed . Damage of substantia nigra pars reticulata during pilocarpine - induced status epilepticus in the rat : immunohistochemical study of neurons , astrocytes and serum - protein extravasation . The substantia nigra has a gating function controlling the spread of epileptic seizure activity . Additionally , in models of prolonged status epilepticus the pars reticulata of substantia nigra ( SNR ) suffers from a massive lesion which may arise from a massive metabolic derangement and hyperexcitation developing in the activated SNR . In this study , status epilepticus was induced by systemic injection of pilocarpine in rats . The neuropathology of SNR was investigated using immunohistochemical techniques with the major emphasis on the time - course of changes in neurons and astrocytes . Animals surviving 20 , 30 , 40 , 60 min , 2 , 3 , 6 hours , 1 , 2 , and 3 days after induction of status epilepticus were perfusion - fixed , and brains processed for immunohistochemical staining of SNR . Nissl - staining and antibodies against the neuron - specific calcium - binding protein , parvalbumin , served to detect neuronal damage in SNR . Antibodies against the astroglia - specific cytoskeletal protein , glial fibrillary acidic protein ( GFAP ) , and against the glial calcium - binding protein , S - 100 protein , were used to assess the status of astrocytes . Immunohistochemical staining for serum - albumin and immunoglobulins in brain tissue was taken as indicator of blood - brain barrier disturbances and vasogenic edema formation . Immunohistochemical staining indicated loss of GFAP - staining already at 30 min after induction of seizures in an oval focus situated in the center of SNR while sparing medial and lateral aspects . At 1 h there was additional vacuolation in S - 100 protein staining . By 2 hours , parvalbumin - staining changed in the central SNR indicating neuronal damage , and Nissl - staining visualized some neuronal distortion . Staining for serum - proteins occurred in a patchy manner throughout the forebrain during the first hours . By 6 h , vasogenic edema covered the lesioned SNR . By 24 h , glial and neuronal markers indicated a massive lesion in the center of SNR . By 48 - 72 h , astrocytes surrounding the lesion increased in size , and polymorphic phagocytotic cells invaded the damaged area . In a further group of animals surviving 1 to 5 days , conventional paraffin - sections confirmed the neuronal and glial damage of SNR . Additional pathology of similar quality was found in the globus pallidus . Since astrocytes were always damaged in parallel with neurons in SNR it is proposed that the anatomical and functional interrelationship between neurons and astrocytes is particularly tight in SNR . Both cell elements may suffer in common from metabolic disturbance and neurotransmitter dysfunction as occur during massive status epilepticus . Neuroprotective effects of melatonin upon the offspring cerebellar cortex in the rat model of BCNU - induced cortical dysplasia . Cortical dysplasia is a malformation characterized by defects in proliferation , migration and maturation . This study was designed to evaluate the alterations in offspring rat cerebellum induced by maternal exposure to carmustine - [ 1 , 3 - bis ( 2 - chloroethyl ) - 1 - nitrosoure ] ( BCNU ) and to investigate the effects of exogenous melatonin upon cerebellar BCNU - induced cortical dysplasia , using histological and biochemical analyses . Pregnant Wistar rats were assigned to five groups : intact - control , saline - control , melatonin - treated , BCNU - exposed and BCNU - exposed plus melatonin . Rats were exposed to BCNU on embryonic day 15 and melatonin was given until delivery . Immuno / histochemistry and electron microscopy were carried out on the offspring cerebellum , and levels of malondialdehyde and superoxide dismutase were determined . Histopathologically , typical findings were observed in the cerebella from the control groups , but the findings consistent with early embryonic development were noted in BCNU - exposed cortical dysplasia group . There was a marked increase in the number of TUNEL positive cells and nestin positive cells in BCNU - exposed group , but a decreased immunoreactivity to glial fibrillary acidic protein , synaptophysin and transforming growth factor beta1 was observed , indicating a delayed maturation , and melatonin significantly reversed these changes . Malondialdehyde level in BCNU - exposed group was higher than those in control groups and melatonin decreased malondialdehyde levels in BCNU group ( P < 0 . 01 ) , while there were no significant differences in the superoxide dismutase levels between these groups . These data suggest that exposure of animals to BCNU during pregnancy leads to delayed maturation of offspring cerebellum and melatonin protects the cerebellum against the effects of BCNU . Reduced cardiotoxicity of doxorubicin given in the form of N - ( 2 - hydroxypropyl ) methacrylamide conjugates : and experimental study in the rat . A rat model was used to evaluate the general acute toxicity and the late cardiotoxicity of 4 mg / kg doxorubicin ( DOX ) given either as free drug or in the form of three N - ( 2 - hydroxypropyl ) methacrylamide ( HPMA ) copolymer conjugates . In these HPMA copolymers , DOX was covalently bound via peptide linkages that were either non - biodegradable ( Gly - Gly ) or degradable by lysosomal proteinases ( Gly - Phe - Leu - Gly ) . In addition , one biodegradable conjugate containing galactosamine was used ; this residue was targeted to the liver . Over the first 3 weeks after the i . v . administration of free and polymer - bound DOX , all animals showed a transient reduction in body weight . However , the maximal reduction in body weight seen in animals that received polymer - bound DOX ( 4 mg / kg ) was significantly lower than that observed in those that received free DOX ( 4 mg / kg ) or a mixture of the unmodified parent HPMA copolymer and free DOX ( 4 mg / kg ; P less than 0 . 01 ) . Throughout the study ( 20 weeks ) , deaths related to cardiotoxicity were observed only in animals that received either free DOX or the mixture of HPMA copolymer and free DOX ; in these cases , histological investigations revealed marked changes in the heart that were consistent with DOX - induced cardiotoxicity . Sequential measurements of cardiac output in surviving animals that received either free DOX or the mixture of HPMA copolymer and free DOX showed a reduction of approximately 30 % in function beginning at the 4th week after drug administration . The heart rate in these animals was approximately 12 % lower than that measured in age - matched control rats ( P less than 0 . 05 ) . Animals that were given the HPMA copolymer conjugates containing DOX exhibited no significant change in cardiac output throughout the study ( P less than 0 . 05 ) . In addition , no significant histological change was observed in the heart of animals that received DOX in the form of HPMA copolymer conjugates and were killed at the end of the study . However , these animals had shown a significant increase in heart rate beginning at 8 weeks after drug administration ( P less than 0 . 01 ) . ( ABSTRACT TRUNCATED AT 400 WORDS ) Corneal ulcers associated with aerosolized crack cocaine use . PURPOSE : We report 4 cases of corneal ulcers associated with drug abuse . The pathogenesis of these ulcers and management of these patients are also reviewed . METHODS : Review of all cases of corneal ulcers associated with drug abuse seen at our institution from July 2006 to December 2006 . RESULTS : Four patients with corneal ulcers associated with crack cocaine use were reviewed . All corneal ulcers were cultured , and the patients were admitted to the hospital for intensive topical antibiotic treatment . Each patient received comprehensive health care , including medical and substance abuse consultations . Streptococcal organisms were found in 3 cases and Capnocytophaga and Brevibacterium casei in 1 patient . The infections responded to antibiotic treatment . Two patients needed a lateral tarsorrhaphy for persistent epithelial defects . CONCLUSIONS : Aerosolized crack cocaine use can be associated with the development of corneal ulcers . Drug abuse provides additional challenges for management . Not only treatment of their infections but also the overall poor health of the patients and increased risk of noncompliance need to be addressed . Comprehensive care may provide the patient the opportunity to discontinue their substance abuse , improve their overall health , and prevent future corneal complications . Topical 0 . 025 % capsaicin in chronic post - herpetic neuralgia : efficacy , predictors of response and long - term course . In order to evaluate the efficacy , time - course of action and predictors of response to topical capsaicin , 39 patients with chronic post - herpetic neuralgia ( PHN ) , median duration 24 months , were treated with 0 . 025 % capsaicin cream for 8 weeks . During therapy the patients rated their pain on a visual analogue scale ( VAS ) and a verbal outcome scale . A follow - up investigation was performed 10 - 12 months after study onset on the patients who had improved . Nineteen patients ( 48 . 7 % ) substantially improved after the 8 - week trial ; 5 ( 12 . 8 % ) discontinued therapy due to side - effects such as intolerable capsaicin - induced burning sensations ( 4 ) or mastitis ( 1 ) ; 15 ( 38 . 5 % ) reported no benefit . The decrease in VAS ratings was significant after 2 weeks of continuous application . Of the responders 72 . 2 % were still improved at the follow - up ; only one - third of them had continued application irregularly . Treatment effect was not dependent on patient ' s age , duration or localization of PHN ( trigeminal involvement was excluded ) , sensory disturbance or pain character . Treatment response was not correlated with the incidence , time - course or severity of capsaicin - induced burning . If confirmed in controlled trials , the long - term results of this open , non - randomized study might indicate that the analgesic effect of capsaicin in PHN is mediated by both interference with neuropeptide metabolism and morphological changes ( perhaps degeneration ) of nociceptive afferents . Myo - inositol - 1 - phosphate ( MIP ) synthase inhibition : in - vivo study in rats . Lithium and valproate are the prototypic mood stabilizers and have diverse structures and targets . Both drugs influence inositol metabolism . Lithium inhibits IMPase and valproate inhibits MIP synthase . This study shows that MIP synthase inhibition does not replicate or augment the effects of lithium in the inositol sensitive pilocarpine - induced seizures model . This lack of effects may stem from the low contribution of de - novo synthesis to cellular inositol supply or to the inhibition of the de - novo synthesis by lithium itself . Non - steroidal anti - inflammatory drugs - associated acute interstitial nephritis with granular tubular basement membrane deposits . Acute tubulo - interstitial nephritis ( ATIN ) is an important cause of acute renal failure resulting from a variety of insults , including immune complex - mediated tubulo - interstitial injury , but drugs such as non - steroidal anti - inflammatory drugs ( NSAIDs ) are a far more frequent cause . Overall , as an entity , ATIN remains under - diagnosed , as symptoms resolve spontaneously if the medication is stopped . We report on a 14 - year - old boy who developed acute renal failure 2 weeks after aortic valve surgery . He was put on aspirin following surgery and took ibuprofen for fever for nearly a week prior to presentation . He then presented to the emergency department feeling quite ill and was found to have a blood urea nitrogen ( BUN ) concentration of of 147 mg / dl , creatinine of 15 . 3 mg / dl and serum potassium of 8 . 7 mEq / l . Dialysis was immediately initiated . A kidney biopsy showed inflammatory infiltrate consistent with ATIN . However , in the tubular basement membrane ( TBM ) , very intense granular deposits of polyclonal IgG and C3 were noted . He needed dialysis for 2 weeks and was treated successfully with steroids for 6 months . His renal recovery and disappearance of proteinuria took a year . In conclusion , this is a first report of NSAIDs - associated ATIN , showing deposits of granular immune complex present only in the TBM and not in the glomeruli . Rifampicin - associated segmental necrotizing glomerulonephritis in staphylococcal endocarditis . Segmental necrotising glomerulonephritis has been reported as complication of rifampicin therapy in patients receiving treatment for tuberculosis . Changing epidemiology of infections such as infective endocarditis ( IE ) has led to an increase in the use of rifampicin for Staphylococcal infections . We describe a case of a patient with Staphylococcal IE who developed acute renal failure secondary to a segmental necrotising glomerulonephritis while being treated with rifampicin , and review the literature regarding this complication of rifampicin therapy . Rate of YMDD motif mutants in lamivudine - untreated Iranian patients with chronic hepatitis B virus infection . BACKGROUND : Lamivudine is used for the treatment of chronic hepatitis B patients . Recent studies show that the YMDD motif mutants ( resistant hepatitis B virus ) occur as natural genome variability in lamivudine - untreated chronic hepatitis B patients . In this study we aimed to determine the rate of YMDD motif mutants in lamivudine - untreated chronic hepatitis B patients in Iran . PATIENTS AND METHODS : A total of 77 chronic hepatitis B patients who had not been treated with lamivudine were included in the study . Serum samples from patients were tested by polymerase chain reaction - restriction fragment length polymorphism ( PCR - RFLP ) for detection of YMDD motif mutants . All patients were also tested for liver enzymes , anti - HCV , HBeAg , and anti - HBe . RESULTS : Of the 77 patients enrolled in the study , 73 % were male and 27 % were female . Mean ALT and AST levels were 124 . 4 + / - 73 . 4 and 103 . 1 + / - 81 IU / l , respectively . HBeAg was positive in 40 % and anti - HBe in 60 % of the patients . Anti - HCV was negative in all of them . YMDD motif mutants were not detected in any of the patients despite the liver enzyme levels and the presence of HBeAg or anti - HBe . CONCLUSION : Although the natural occurrence of YMDD motif mutants in lamivudine - untreated patients with chronic hepatitis B has been reported , these mutants were not detected in Iranian lamivudine - untreated chronic hepatitis B patients . Branch retinal vein occlusion and fluoxetine . A case of branch retinal vein occlusion associated with fluoxetine - induced secondary hypertension is described . Although an infrequent complication of selective serotonin reuptake inhibitor therapy , it is important that ophthalmologists are aware that these agents can cause hypertension because this class of drugs is widely prescribed . The differential effects of bupivacaine and lidocaine on prostaglandin E2 release , cyclooxygenase gene expression and pain in a clinical pain model . BACKGROUND : In addition to blocking nociceptive input from surgical sites , long - acting local anesthetics might directly modulate inflammation . In the present study , we describe the proinflammatory effects of bupivacaine on local prostaglandin E2 ( PGE2 ) production and cyclooxygenase ( COX ) gene expression that increases postoperative pain in human subjects . METHODS : Subjects ( n = 114 ) undergoing extraction of impacted third molars received either 2 % lidocaine or 0 . 5 % bupivacaine before surgery and either rofecoxib 50 mg or placebo orally 90 min before surgery and for the following 48 h . Oral mucosal biopsies were taken before surgery and 48 h after surgery . After extraction , a microdialysis probe was placed at the surgical site for PGE2 and thromboxane B2 ( TXB2 ) measurements . RESULTS : The bupivacaine / rofecoxib group reported significantly less pain , as assessed by a visual analog scale , compared with the other three treatment groups over the first 4 h . However , the bupivacaine / placebo group reported significantly more pain at 24 h and PGE2 levels during the first 4 h were significantly higher than the other three treatment groups . Moreover , bupivacaine significantly increased COX - 2 gene expression at 48 h as compared with the lidocaine / placebo group . Thromboxane levels were not significantly affected by any of the treatments , indicating that the effects seen were attributable to inhibition of COX - 2 , but not COX - 1 . CONCLUSIONS : These results suggest that bupivacaine stimulates COX - 2 gene expression after tissue injury , which is associated with higher PGE2 production and pain after the local anesthetic effect dissipates . p75NTR expression in rat urinary bladder sensory neurons and spinal cord with cyclophosphamide - induced cystitis . A role for nerve growth factor ( NGF ) in contributing to increased voiding frequency and altered sensation from the urinary bladder has been suggested . Previous studies have examined the expression and regulation of tyrosine kinase receptors ( Trks ) in micturition reflexes with urinary bladder inflammation . The present studies examine the expression and regulation of another receptor known to bind NGF , p75 ( NTR ) , after various durations of bladder inflammation induced by cyclophosphamide ( CYP ) . CYP - induced cystitis increased ( P < or = 0 . 001 ) p75 ( NTR ) expression in the superficial lateral and medial dorsal horn in L1 - L2 and L6 - S1 spinal segments . The number of p75 ( NTR ) - immunoreactive ( - IR ) cells in the lumbosacral dorsal root ganglia ( DRG ) also increased ( P < or = 0 . 05 ) with CYP - induced cystitis ( acute , intermediate , and chronic ) . Quantitative , real - time polymerase chain reaction also demonstrated significant increases ( P < or = 0 . 01 ) in p75 ( NTR ) mRNA in DRG with intermediate and chronic CYP - induced cystitis . Retrograde dye - tracing techniques with Fastblue were used to identify presumptive bladder afferent cells in the lumbosacral DRG . In bladder afferent cells in DRG , p75 ( NTR ) - IR was also increased ( P < or = 0 . 01 ) with cystitis . In addition to increases in p75 ( NTR ) - IR in DRG cell bodies , increases ( P < or = 0 . 001 ) in pericellular ( encircling DRG cells ) p75 ( NTR ) - IR in DRG also increased . Confocal analyses demonstrated that pericellular p75 ( NTR ) - IR was not colocalized with the glial marker , glial fibrillary acidic protein ( GFAP ) . These studies demonstrate that p75 ( NTR ) expression in micturition reflexes is present constitutively and modified by bladder inflammation . The functional significance of p75 ( NTR ) expression in micturition reflexes remains to be determined . Azathioprine - induced suicidal erythrocyte death . BACKGROUND : Azathioprine is widely used as an immunosuppressive drug . The side effects of azathioprine include anemia , which has been attributed to bone marrow suppression . Alternatively , anemia could result from accelerated suicidal erythrocyte death or eryptosis , which is characterized by exposure of phosphatidylserine ( PS ) at the erythrocyte surface and by cell shrinkage . METHODS : The present experiments explored whether azathioprine influences eryptosis . According to annexin V binding , erythrocytes from patients indeed showed a significant increase of PS exposure within 1 week of treatment with azathioprine . In a second series , cytosolic Ca2 + activity ( Fluo3 fluorescence ) , cell volume ( forward scatter ) , and PS - exposure ( annexin V binding ) were determined by FACS analysis in erythrocytes from healthy volunteers . RESULTS : Exposure to azathioprine ( > or = 2 microg / mL ) for 48 hours increased cytosolic Ca2 + activity and annexin V binding and decreased forward scatter . The effect of azathioprine on both annexin V binding and forward scatter was significantly blunted in the nominal absence of extracellular Ca2 + . CONCLUSIONS : Azathioprine triggers suicidal erythrocyte death , an effect presumably contributing to azathioprine - induced anemia . Levetiracetam as an adjunct to phenobarbital treatment in cats with suspected idiopathic epilepsy . OBJECTIVE : To assess pharmacokinetics , efficacy , and tolerability of oral levetiracetam administered as an adjunct to phenobarbital treatment in cats with poorly controlled suspected idiopathic epilepsy . DESIGN - Open - label , noncomparative clinical trial . ANIMALS : 12 cats suspected to have idiopathic epilepsy that was poorly controlled with phenobarbital or that had unacceptable adverse effects when treated with phenobarbital . PROCEDURES : Cats were treated with levetiracetam ( 20 mg / kg [ 9 . 1 mg / lb ] , PO , q 8 h ) . After a minimum of 1 week of treatment , serum levetiracetam concentrations were measured before and 2 , 4 , and 6 hours after drug administration , and maximum and minimum serum concentrations and elimination half - life were calculated . Seizure frequencies before and after initiation of levetiracetam treatment were compared , and adverse effects were recorded . RESULTS : Median maximum serum levetiracetam concentration was 25 . 5 microg / mL , median minimum serum levetiracetam concentration was 8 . 3 microg / mL , and median elimination half - life was 2 . 9 hours . Median seizure frequency prior to treatment with levetiracetam ( 2 . 1 seizures / mo ) was significantly higher than median seizure frequency after initiation of levetiracetam treatment ( 0 . 42 seizures / mo ) , and 7 of 10 cats were classified as having responded to levetiracetam treatment ( ie , reduction in seizure frequency of > or = 50 % ) . Two cats had transient lethargy and inappetence . CONCLUSIONS AND CLINICAL RELEVANCE : Results suggested that levetiracetam is well tolerated in cats and may be useful as an adjunct to phenobarbital treatment in cats with idiopathic epilepsy . Serotonin reuptake inhibitors , paranoia , and the ventral basal ganglia . Antidepressants have previously been associated with paranoid reactions in psychiatric patients . Five cases of paranoid exacerbation with the serotonin reuptake inhibitors fluoxetine and amitriptyline are reported here . Elements common to these cases included a history of paranoid symptomatology and the concomitant occurrence of depressive and psychotic symptoms . Complicated depressive disorders ( including atypicality of course and symptomatology , chronicity , psychosis , bipolarity , and secondary onset in the course of a primary psychosis ) may present particular vulnerability to paranoid exacerbations associated with serotonin reuptake inhibitors . Although the pharmacology and neurobiology of paranoia remain cryptic , several mechanisms , including 5HT3 receptor - mediated dopamine release , beta - noradrenergic receptor downregulation , or GABAB receptor upregulation acting in the vicinity of the ventral basal ganglia ( possibly in lateral orbitofrontal or anterior cingulate circuits ) , might apply to this phenomenon . These cases call attention to possible paranoid exacerbations with serotonin reuptake blockers in select patients and raise neurobiological considerations regarding paranoia . Clinical comparison of cardiorespiratory effects during unilateral and conventional spinal anaesthesia . BACKGROUND : Spinal anaesthesia is widely employed in clinical practice but has the main drawback of post - spinal block hypotension . Efforts must therefore continue to be made to obviate this setback OBJECTIVE : To evaluate the cardiovascular and respiratory changes during unilateral and conventional spinal anaesthesia . METHODS : With ethical approval , we studied 74 American Society of Anesthesiologists ( ASA ) , physical status class 1 and 2 patients scheduled for elective unilateral lower limb surgery . Patients were randomly allocated into one of two groups : lateral and conventional spinal anaesthesia groups . In the lateral position with operative side down , patients recived 10 mg ( 2mls ) of 0 . 5 % hyperbaric bupivacaine through a 25 - gauge spinal needle . Patients in the unilateral group were maintained in the lateral position for 15 minutes following spinal injection while those in the conventional group were turned supine immediately after injection . Blood pressure , heart rate , respiratory rate and oxygen saturation were monitored over 1 hour . RESULTS : Three patients ( 8 . 1 % ) in the unilateral group and 5 ( 13 . 5 % ) in the conventional group developed hypotension , P = 0 . 71 . Four ( 10 . 8 % ) patients in the conventional group and 1 ( 2 . 7 % ) in the unilateral group , P = 0 . 17 required epinephrine infusion to treat hypotension . Patients in the conventional group had statistically significant greater fall in the systolic blood pressures at 15 , 30 and 45 minutes when compared to the baseline ( P = 0 . 003 , 0 . 001 and 0 . 004 ) . The mean respiratory rate and oxygen saturations in the two groups were similar . CONCLUSION : Compared to conventional spinal anaesthesia , unilateral spinal anaesthesia was associated with fewer cardiovascular perturbations . Also , the type of spinal block instituted affected neither the respiratory rate nor the arterial oxygen saturation . Spectrum of adverse events after generic HAART in southern Indian HIV - infected patients . To determine the incidence of clinically significant adverse events after long - term , fixed - dose , generic highly active antiretroviral therapy ( HAART ) use among HIV - infected individuals in South India , we examined the experiences of 3154 HIV - infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India . The most common regimens were 3TC + d4T + nevirapine ( NVP ) ( 54 . 8 % ) , zidovudine ( AZT ) + 3TC + NVP ( 14 . 5 % ) , 3TC + d4T + efavirenz ( EFV ) ( 20 . 1 % ) , and AZT + 3TC + EFV ( 5 . 4 % ) . The most common adverse events and median CD4 at time of event were rash ( 15 . 2 % ; CD4 , 285 cells / microL ) and peripheral neuropathy ( 9 . 0 % and 348 cells / microL ) . Clinically significant anemia ( hemoglobin < 7 g / dL ) was observed in 5 . 4 % of patients ( CD4 , 165 cells / microL ) and hepatitis ( clinical jaundice with alanine aminotransferase > 5 times upper limits of normal ) in 3 . 5 % of patients ( CD4 , 260 cells / microL ) . Women were significantly more likely to experience lactic acidosis , while men were significantly more likely to experience immune reconstitution syndrome ( p < 0 . 05 ) . Among the patients with 1 year of follow - up , NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy ( p < 0 . 05 ) . Anemia and hepatitis often occur within 12 weeks of initiating generic HAART . Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available . Thalidomide and sensory neurotoxicity : a neurophysiological study . BACKGROUND : Recent studies confirmed a high incidence of sensory axonal neuropathy in patients treated with different doses of thalidomide . The study ' s aims were to measure variations in sural nerve sensory action potential ( SAP ) amplitude in patients with refractory cutaneous lupus erythematosus ( CLE ) treated with thalidomide and use these findings to identify the neurotoxic potential of thalidomide and the recovery capacity of sensory fibres after discontinuation of treatment . PATIENTS AND METHODS : Clinical and electrophysiological data in 12 female patients with CLE during treatment with thalidomide and up to 47 months after discontinuation of treatment were analysed . Sural nerve SAP amplitude reduction > or = 40 % was the criteria for discontinuing therapy . RESULTS : During treatment , 11 patients showed a reduction in sural nerve SAP amplitude compared to baseline values ( 9 with a reduction > or = 50 % and 2 < 50 % ) . One patient showed no changes in SAP amplitude . Five patients complained of paresthesias and leg cramps . After thalidomide treatment , sural SAP amplitude recovered in 3 patients . At detection of reduction in sural nerve SAP amplitude , the median thalidomide cumulative dose was 21 . 4 g . The threshold neurotoxic dosage is lower than previously reported . CONCLUSIONS : Sural nerve SAP amplitude reduction is a reliable and sensitive marker of degeneration and recovery of sensory fibres . This electrophysiological parameter provides information about subclinical neurotoxic potential of thalidomide but is not helpful in predicting the appearance of sensory symptoms . Five cases of encephalitis during treatment of loiasis with diethylcarbamazine . Five cases of encephalitis following treatment with diethylcarbamazine ( DEC ) were observed in Congolese patients with Loa loa filariasis . Two cases had a fatal outcome and one resulted in severe sequelae . The notable fact was that this complication occurred in three patients hospitalized before treatment began , with whom particularly strict therapeutic precautions were taken , i . e . , initial dose less than 10 mg of DEC , very gradual dose increases , and associated anti - allergic treatment . This type of drug - induced complication may not be that uncommon in highly endemic regions . It occurs primarily , but not exclusively , in subjects presenting with a high microfilarial load . The relationship between the occurrence of encephalitis and the decrease in microfilaremia is evident . The pathophysiological mechanisms are discussed in the light of these observations and the few other comments on this subject published in the literature . Amiodarone - related pulmonary mass and unique membranous glomerulonephritis in a patient with valvular heart disease : Diagnostic pitfall and new findings . Amiodarone is an anti - arrhythmic drug for life - threatening tachycardia , but various adverse effects have been reported . Reported herein is an autopsy case of valvular heart disease , in a patient who developed a lung mass ( 1 . 5 cm in diameter ) and proteinuria ( 2 . 76 g / day ) after treatment with amiodarone for a long time . The lung mass was highly suspected to be lung cancer on CT and positron emission tomography , but histologically the lesion was composed of lymphoplasmacytic infiltrates in alveolar walls and intra - alveolar accumulation of foamy macrophages containing characteristic myelinoid bodies , indicating that it was an amiodarone - related lesion . In addition , the lung tissue had unevenly distributed hemosiderin deposition , and abnormally tortuous capillaries were seen in the mass and in heavily hemosiderotic lung portions outside the mass . In the kidneys , glomeruli had membrane spikes , prominent swelling of podocytes and subepithelial deposits , which were sometimes large and hump - like . Autoimmune diseases , viral hepatitis , malignant neoplasms or other diseases with a known relationship to membranous glomerulonephritis were not found . The present case highlights the possibility that differential diagnosis between an amiodarone - related pulmonary lesion and a neoplasm can be very difficult radiologically , and suggests that membranous glomerulonephritis might be another possible complication of amiodarone treatment . Risk of coronary artery disease associated with initial sulphonylurea treatment of patients with type 2 diabetes : a matched case - control study . AIMS : This study sought to assess the risk of developing coronary artery disease ( CAD ) associated with initial treatment of type 2 diabetes with different sulphonylureas . METHODS : In type 2 diabetic patients , cases who developed CAD were compared retrospectively with controls that did not . The 20 - year risk of CAD at diagnosis of diabetes , using the UKPDS risk engine , was used to match cases with controls . RESULTS : The 76 cases of CAD were compared with 152 controls . The hazard of developing CAD ( 95 % CI ) associated with initial treatment increased by 2 . 4 - fold ( 1 . 3 - 4 . 3 , P = 0 . 004 ) with glibenclamide ; 2 - fold ( 0 . 9 - 4 . 6 , P = 0 . 099 ) with glipizide ; 2 . 9 - fold ( 1 . 6 - 5 . 1 , P = 0 . 000 ) with either , and was unchanged with metformin . The hazard decreased 0 . 3 - fold ( 0 . 7 - 1 . 7 , P = 0 . 385 ) with glimepiride , 0 . 4 - fold ( 0 . 7 - 1 . 3 , P = 0 . 192 ) with gliclazide , and 0 . 4 - fold ( 0 . 7 - 1 . 1 , P = 0 . 09 ) with either . CONCLUSIONS : Initiating treatment of type 2 diabetes with glibenclamide or glipizide is associated with increased risk of CAD in comparison to gliclazide or glimepiride . If confirmed , this may be important because most Indian patients receive the cheaper older sulphonylureas , and present guidelines do not distinguish between individual agents . Reduced progression of adriamycin nephropathy in spontaneously hypertensive rats treated by losartan . BACKGROUND : The aim of the study was to investigate the antihypertensive effects of angiotensin II type - 1 receptor blocker , losartan , and its potential in slowing down renal disease progression in spontaneously hypertensive rats ( SHR ) with adriamycin ( ADR ) nephropathy . METHODS : Six - month - old female SHR were randomly selected in six groups . Two control groups ( SH ( 6 ) , SH ( 12 ) ) received vehicle . Groups ADR ( 6 ) , ADR + LOS ( 6 ) and ADR ( 12 ) , and ADR + LOS ( 12 ) received ADR ( 2 mg / kg / b . w . i . v . ) twice in a 3 - week interval . Group ADR + LOS ( 6 ) received losartan ( 10 mg / kg / b . w . / day by gavages ) for 6 weeks and group ADR + LOS ( 12 ) for 12 weeks after second injection of ADR . Animals were killed after 6 or 12 weeks , respectively . Haemodynamic measurements were performed on anaesthetized animals , blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies . RESULTS : Short - term losartan treatment , besides antihypertensive effect , improved glomerular filtration rate and ameliorated glomerulosclerosis resulting in decreased proteinuria . Prolonged treatment with losartan showed further reduction of glomerulosclerosis associated with reduced progression of tubular atrophy and interstitial fibrosis , thus preventing heavy proteinuria and chronic renal failure . Losartan reduced uraemia and increased urea clearance in advanced ADR nephropathy in SHR . Histological examination showed that losartan could prevent tubular atrophy , interstitial infiltration and fibrosis in ADR nephropathy . CONCLUSION : Losartan reduces the rate of progression of ADR - induced focal segmental glomerulosclerosis to end - stage renal disease in SHR . The risks of aprotinin and tranexamic acid in cardiac surgery : a one - year follow - up of 1188 consecutive patients . BACKGROUND : Our aim was to investigate postoperative complications and mortality after administration of aprotinin compared to tranexamic acid in an unselected , consecutive cohort . METHODS : Perioperative data from consecutive cardiac surgery patients were prospectively collected between September 2005 and June 2006 in a university - affiliated clinic ( n = 1188 ) . During the first 5 mo , 596 patients received aprotinin ( Group A ) ; in the next 5 mo , 592 patients were treated with tranexamic acid ( Group T ) . Except for antifibrinolytic therapy , the anesthetic and surgical protocols remained unchanged . RESULTS : The pre - and intraoperative variables were comparable between the treatment groups . Postoperatively , a significantly higher incidence of seizures was found in Group T ( 4 . 6 % vs 1 . 2 % , P < 0 . 001 ) . This difference was also significant in the primary valve surgery and the high risk surgery subgroups ( 7 . 9 % vs 1 . 2 % , P = 0 . 003 ; 7 . 3 % vs 2 . 4 % , P = 0 . 035 , respectively ) . Persistent atrial fibrillation ( 7 . 9 % vs 2 . 3 % , P = 0 . 020 ) and renal failure ( 9 . 7 % vs 1 . 7 % , P = 0 . 002 ) were also more common in Group T , in the primary valve surgery subgroup . On the contrary , among primary coronary artery bypass surgery patients , there were more acute myocardial infarctions and renal dysfunction in Group A ( 5 . 8 % vs 2 . 0 % , P = 0 . 027 ; 22 . 5 % vs 15 . 2 % , P = 0 . 036 , respectively ) . The 1 - yr mortality was significantly higher after aprotinin treatment in the high risk surgery group ( 17 . 7 % vs 9 . 8 % , P = 0 . 034 ) . CONCLUSION : Both antifibrinolytic drugs bear the risk of adverse outcome depending on the type of cardiac surgery . Administration of aprotinin should be avoided in coronary artery bypass graft and high risk patients , whereas administration of tranexamic acid is not recommended in valve surgery . Delirium in an elderly woman possibly associated with administration of misoprostol . Misoprostol has been associated with adverse reactions , including gastrointestinal symptoms , gynecologic problems , and headache . Changes in mental status , however , have not been reported . We present a case in which an 89 - year - old woman in a long - term care facility became confused after the initiation of misoprostol therapy . The patient ' s change in mental status was first reported nine days after the initiation of therapy . Her delirium significantly improved after misoprostol was discontinued and her mental status returned to normal within a week . Because no other factors related to this patient changed significantly , the delirium experienced by this patient possibly resulted from misoprostol therapy . The biological properties of the optical isomers of propranolol and their effects on cardiac arrhythmias . 1 . The optical isomers of propranolol have been compared for their beta - blocking and antiarrhythmic activities . 2 . In blocking the positive inotropic and chronotropic responses to isoprenaline , ( + ) - propranolol had less than one hundredth the potency of ( - ) - propranolol . At dose levels of ( + ) - propranolol which attenuated the responses to isoprenaline , there was a significant prolongation of the PR interval of the electrocardiogram . 3 . The metabolic responses to isoprenaline in dogs ( an increase in circulating glucose , lactate and free fatty acids ) were all blocked by ( - ) - propranolol . ( + ) - Propranolol had no effect on fatty acid mobilization but significantly reduced the increments in both lactate and glucose . 4 . Both isomers of propranolol possessed similar depressant potency on isolated atrial muscle taken from guinea - pigs . 5 . The isomers of propranolol exhibited similar local anaesthetic potencies on an isolated frog nerve preparation at a level approximately three times that of procaine . The racemic compound was significantly less potent than either isomer . 6 . Both isomers of propranolol were capable of preventing adrenaline - induced cardiac arrhythmias in cats anaesthetized with halothane , but the mean dose of ( - ) - propranolol was 0 . 09 + / - 0 . 02 mg / kg whereas that of ( + ) - propranolol was 4 . 2 + / - 1 . 2 mg / kg . At the effective dose level of ( + ) - propranolol there was a significant prolongation of the PR interval of the electrocardiogram . Blockade of arrhythmias with both isomers was surmountable by increasing the dose of adrenaline . 7 . Both isomers of propranolol were also capable of reversing ventricular tachycardia caused by ouabain in anaesthetized cats and dogs . The dose of ( - ) - propranolol was significantly smaller than that of ( + ) - propranolol in both species but much higher than that required to produce evidence of beta - blockade . 8 . The implications of these results are discussed . Topotecan in combination with radiotherapy in unresectable glioblastoma : a phase 2 study . Improving glioblastoma multiforme ( GBM ) treatment with radio - chemotherapy remains a challenge . Topotecan is an attractive option as it exhibits growth inhibition of human glioma as well as brain penetration . The present study assessed the combination of radiotherapy ( 60 Gy / 30 fractions / 40 days ) and topotecan ( 0 . 9 mg / m ( 2 ) / day on days 1 - 5 on weeks 1 , 3 and 5 ) in 50 adults with histologically proven and untreated GBM . The incidence of non - hematological toxicities was low and grade 3 - 4 hematological toxicities were reported in 20 patients ( mainly lymphopenia and neutropenia ) . Partial response and stabilization rates were 2 % and 32 % , respectively , with an overall time to progression of 12 weeks . One - year overall survival ( OS ) rate was 42 % , with a median OS of 40 weeks . Topotecan in combination with radiotherapy was well tolerated . However , while response and stabilization concerned one - third of the patients , the study did not show increased benefits in terms of survival in patients with unresectable GBM . Long - term lithium therapy leading to hyperparathyroidism : a case report . PURPOSE : This paper reviews the effect of chronic lithium therapy on serum calcium level and parathyroid glands , its pathogenesis , and treatment options . We examined the case of a lithium - treated patient who had recurrent hypercalcemia to better understand the disease process . CONCLUSION : Primary hyperparathyroidism is a rare but potentially life - threatening side effect of long - term lithium therapy . Careful patient selection and long - term follow - up can reduce morbidity . PRACTICAL IMPLICATIONS : As much as 15 % of lithium - treated patients become hypercalcemic . By routinely monitoring serum calcium levels , healthcare providers can improve the quality of life of this patient group . Comparison of laryngeal mask with endotracheal tube for anesthesia in endoscopic sinus surgery . BACKGROUND : The purpose of this study was to compare surgical conditions , including the amount of intraoperative bleeding as well as intraoperative blood pressure , during functional endoscopic sinus surgery ( FESS ) using flexible reinforced laryngeal mask airway ( FRLMA ) versus endotracheal tube ( ETT ) in maintaining controlled hypotension anesthesia induced by propofol - remifentanil total i . v . anesthesia ( TIVA ) . METHODS : Sixty normotensive American Society of Anesthesiologists I - II adult patients undergoing FESS under controlled hypotension anesthesia caused by propofol - remifentanil - TIVA were randomly assigned into two groups : group I , FRLMA ; group II , ETT . Hemorrhage was measured and the visibility of the operative field was evaluated according to a six - point scale . RESULTS : Controlled hypotension was achieved within a shorter period using laryngeal mask using lower rates of remifentanil infusion and lower total dose of remifentanil . CONCLUSION : In summary , our results indicate that airway management using FRLMA during controlled hypotension anesthesia provided better surgical conditions in terms of quality of operative field and blood loss and allowed for convenient induced hypotension with low doses of remifentanil during TIVA in patients undergoing FESS . Nonalcoholic fatty liver disease during valproate therapy . Valproic acid ( VPA ) is effective for the treatment of many types of epilepsy , but its use can be associated with an increase in body weight . We report a case of nonalcoholic fatty liver disease ( NAFLD ) arising in a child who developed obesity during VPA treatment . Laboratory data revealed hyperinsulinemia with insulin resistance . After the withdrawal of VPA therapy , our patient showed a significant weight loss , a decrease of body mass index , and normalization of metabolic and endocrine parameters ; moreover , ultrasound measurements showed a complete normalization . The present case suggests that obesity , hyperinsulinemia , insulin resistance , and long - term treatment with VPA may be all associated with the development of NAFLD ; this side effect is reversible after VPA withdrawal . Carbimazole induced ANCA positive vasculitis . Anti - thyroid drugs , like carbimazole and propylthiouracil ( PTU ) are commonly prescribed for the treatment of hyperthyroidism . One should be aware of the side effects of antithyroid medications . Antineutrophil cytoplasmic antibody ( ANCA ) - - associated vasculitis is a potentially life - threatening adverse effect of antithyroidmedications . We report a patient with Graves ' disease who developed ANCA positive carbimazole induced vasculitis . The episode was characterized by a vasculitic skin rash associated with large joint arthritis , pyrexia and parotiditis but no renal or pulmonary involvement . He was referred to us for neurological evaluation because he had difficulty in getting up from squatting position and was suspected to have myositis . Carbimazole and methimazole have a lower incidence of reported ANCA positive side effects than PUT . To the best of our knowledge this is the first ANCA positive carbimazole induced vasculitis case reported from India . Aspirin for the primary prevention of cardiovascular events : an update of the evidence for the U . S . Preventive Services Task Force . BACKGROUND : Coronary heart disease and cerebrovascular disease are leading causes of death in the United States . In 2002 , the U . S . Preventive Services Task Force ( USPSTF ) strongly recommended that clinicians discuss aspirin with adults who are at increased risk for coronary heart disease . PURPOSE : To determine the benefits and harms of taking aspirin for the primary prevention of myocardial infarctions , strokes , and death . DATA SOURCES : MEDLINE and Cochrane Library ( search dates , 1 January 2001 to 28 August 2008 ) , recent systematic reviews , reference lists of retrieved articles , and suggestions from experts . STUDY SELECTION : English - language randomized , controlled trials ( RCTs ) ; case - control studies ; meta - analyses ; and systematic reviews of aspirin versus control for the primary prevention of cardiovascular disease ( CVD ) were selected to answer the following questions : Does aspirin decrease coronary heart events , strokes , death from coronary heart events or stroke , or all - cause mortality in adults without known CVD ? Does aspirin increase gastrointestinal bleeding or hemorrhagic strokes ? DATA EXTRACTION : All studies were reviewed , abstracted , and rated for quality by using predefined USPSTF criteria . DATA SYNTHESIS : New evidence from 1 good - quality RCT , 1 good - quality meta - analysis , and 2 fair - quality subanalyses of RCTs demonstrates that aspirin use reduces the number of CVD events in patients without known CVD . Men in these studies experienced fewer myocardial infarctions and women experienced fewer ischemic strokes . Aspirin does not seem to affect CVD mortality or all - cause mortality in either men or women . The use of aspirin for primary prevention increases the risk for major bleeding events , primarily gastrointestinal bleeding events , in both men and women . Men have an increased risk for hemorrhagic strokes with aspirin use . A new RCT and meta - analysis suggest that the risk for hemorrhagic strokes in women is not statistically significantly increased . LIMITATIONS : New evidence on aspirin for the primary prevention of CVD is limited . The dose of aspirin used in the RCTs varied , which prevented the estimation of the most appropriate dose for primary prevention . Several of the RCTs were conducted within populations of health professionals , which potentially limits generalizability . CONCLUSION : Aspirin reduces the risk for myocardial infarction in men and strokes in women . Aspirin use increases the risk for serious bleeding events . Reducing harm associated with anticoagulation : practical considerations of argatroban therapy in heparin - induced thrombocytopenia . Argatroban is a hepatically metabolized , direct thrombin inhibitor used for prophylaxis or treatment of thrombosis in heparin - induced thrombocytopenia ( HIT ) and for patients with or at risk of HIT undergoing percutaneous coronary intervention ( PCI ) . The objective of this review is to summarize practical considerations of argatroban therapy in HIT . The US FDA - recommended argatroban dose in HIT is 2 microg / kg / min ( reduced in patients with hepatic impairment and in paediatric patients ) , adjusted to achieve activated partial thromboplastin times ( aPTTs ) 1 . 5 - 3 times baseline ( not > 100 seconds ) . Contemporary experiences indicate that reduced doses are also needed in patients with conditions associated with hepatic hypoperfusion , e . g . heart failure , yet are unnecessary for renal dysfunction , adult age , sex , race / ethnicity or obesity . Argatroban 0 . 5 - 1 . 2 microg / kg / min typically supports therapeutic aPTTs . The FDA - recommended dose during PCI is 25 microg / kg / min ( 350 microg / kg initial bolus ) , adjusted to achieve activated clotting times ( ACTs ) of 300 - 450 sec . For PCI , argatroban has not been investigated in hepatically impaired patients ; dose adjustment is unnecessary for adult age , sex , race / ethnicity or obesity , and lesser doses may be adequate with concurrent glycoprotein IIb / IIIa inhibition . Argatroban prolongs the International Normalized Ratio , and published approaches for monitoring the argatroban - to - warfarin transition should be followed . Major bleeding with argatroban is 0 - 10 % in the non - interventional setting and 0 - 5 . 8 % periprocedurally . Argatroban has no specific antidote , and if excessive anticoagulation occurs , argatroban infusion should be stopped or reduced . Improved familiarity of healthcare professionals with argatroban therapy in HIT , including in special populations and during PCI , may facilitate reduction of harm associated with HIT ( e . g . fewer thromboses ) or its treatment ( e . g . fewer argatroban medication errors ) . Rhabdomyolysis and brain ischemic stroke in a heroin - dependent male under methadone maintenance therapy . OBJECTIVE : There are several complications associated with heroin abuse , some of which are life - threatening . Methadone may aggravate this problem . METHOD : A clinical case description . RESULTS : A 33 - year - old man presented with rhabdomyolysis and cerebral ischemic stroke after intravenous heroin . He had used heroin since age 20 , and had used 150 mg methadone daily for 6 months . He was found unconsciousness at home and was sent to our hospital . In the ER , his opiate level was 4497 ng / ml . In the ICU , we found rhabdomyolysis , acute renal failure and acute respiratory failure . After transfer to an internal ward , we noted aphasia and weakness of his left limbs . After MRI , we found cerebral ischemic infarction . CONCLUSION : Those using methadone and heroin simultaneously may increase risk of rhabdomyolysis and ischemic stroke . Patients under methadone maintenance therapy should be warned regarding these serious adverse events . Hypotheses of heroin - related rhabdomyolysis and stroke in heroin abusers are discussed . Increased vulnerability to 6 - hydroxydopamine lesion and reduced development of dyskinesias in mice lacking CB1 cannabinoid receptors . Motor impairment , dopamine ( DA ) neuronal activity and proenkephalin ( PENK ) gene expression in the caudate - putamen ( CPu ) were measured in 6 - OHDA - lesioned and treated ( L - DOPA + benserazide ) CB1 KO and WT mice . A lesion induced by 6 - OHDA produced more severe motor deterioration in CB1 KO mice accompanied by more loss of DA neurons and increased PENK gene expression in the CPu . Oxidative / nitrosative and neuroinflammatory parameters were estimated in the CPu and cingulate cortex ( Cg ) . CB1 KO mice exhibited higher MDA levels and iNOS protein expression in the CPu and Cg compared to WT mice . Treatment with L - DOPA + benserazide ( 12 weeks ) resulted in less severe dyskinesias in CB1 KO than in WT mice . The results revealed that the lack of cannabinoid CB1 receptors increased the severity of motor impairment and DA lesion , and reduced L - DOPA - induced dyskinesias . These results suggest that activation of CB1 receptors offers neuroprotection against dopaminergic lesion and the development of L - DOPA - induced dyskinesias . Hepatocellular oxidant stress following intestinal ischemia - reperfusion injury . Reperfusion of ischemic intestine results in acute liver dysfunction characterized by hepatocellular enzyme release into plasma , reduction in bile flow rate , and neutrophil sequestration within the liver . The pathophysiology underlying this acute hepatic injury is unknown . This study was undertaken to determine whether oxidants are associated with the hepatic injury and to determine the relative value of several indirect methods of assessing oxidant exposure in vivo . Rats were subjected to a standardized intestinal ischemia - reperfusion injury . Hepatic tissue was assayed for lipid peroxidation products and oxidized and reduced glutathione . There was no change in hepatic tissue total glutathione following intestinal ischemia - reperfusion injury . Oxidized glutathione ( GSSG ) increased significantly following 30 and 60 min of reperfusion . There was no increase in any of the products of lipid peroxidation associated with this injury . An increase in GSSG within hepatic tissue during intestinal reperfusion suggests exposure of hepatocytes to an oxidant stress . The lack of a significant increase in products of lipid peroxidation suggests that the oxidant stress is of insufficient magnitude to result in irreversible injury to hepatocyte cell membranes . These data also suggest that the measurement of tissue GSSG may be a more sensitive indicator of oxidant stress than measurement of products of lipid peroxidation . Animal model of mania induced by ouabain : Evidence of oxidative stress in submitochondrial particles of the rat brain . The intracerebroventricular ( ICV ) administration of ouabain ( a Na ( + ) / K ( + ) - ATPase inhibitor ) in rats has been suggested to mimic some symptoms of human bipolar mania . Clinical studies have shown that bipolar disorder may be related to mitochondrial dysfunction . Herein , we investigated the behavioral and biochemical effects induced by the ICV administration of ouabain in rats . To achieve this aim , the effects of ouabain injection immediately after and 7 days following a single ICV administration ( at concentrations of 10 ( - 2 ) and 10 ( - 3 ) M ) on locomotion was measured using the open - field test . Additionally , thiobarbituric acid reactive substances ( TBARSs ) and superoxide production were measured in submitochondrial particles of the prefrontal cortex , hippocampus , striatum and amygdala . Our findings demonstrated that ouabain at 10 ( - 2 ) and 10 ( - 3 ) M induced hyperlocomotion in rats , and this response remained up to 7 days following a single ICV injection . In addition , we observed that the persistent increase in the rat spontaneous locomotion is associated with increased TBARS levels and superoxide generation in submitochondrial particles in the prefrontal cortex , striatum and amygdala . In conclusion , ouabain - induced mania - like behavior may provide a useful animal model to test the hypothesis of the involvement of oxidative stress in bipolar disorder . Intraoperative dialysis during liver transplantation with citrate dialysate . Liver transplantation for acutely ill patients with fulminant liver failure carries high intraoperative and immediate postoperative risks . These are increased with the presence of concomitant acute kidney injury ( AKI ) and intraoperative dialysis is sometimes required to allow the transplant to proceed . The derangements in the procoagulant and anticoagulant pathways during fulminant liver failure can lead to difficulties with anticoagulation during dialysis , especially when continued in the operating room . Systemic anticoagulation is unsafe and regional citrate anticoagulation in the absence of a functional liver carries the risk of citrate toxicity . Citrate dialysate , a new dialysate with citric acid can be used for anticoagulation in patients who cannot tolerate heparin or regional citrate . We report a case of a 40 - year - old female with acetaminophen - induced fulminant liver failure with associated AKI who underwent intraoperative dialytic support during liver transplantation anticoagulated with citrate dialysate during the entire procedure . The patient tolerated the procedure well without any signs of citrate toxicity and maintained adequate anticoagulation for patency of the dialysis circuit . Citrate dialysate is a safe alternative for intradialytic support of liver transplantation in fulminant liver failure . Delirium in a patient with toxic flecainide plasma concentrations : the role of a pharmacokinetic drug interaction with paroxetine . OBJECTIVE : To describe a case of flecainide - induced delirium associated with a pharmacokinetic drug interaction with paroxetine . CASE SUMMARY : A 69 - year - old white female presented to the emergency department with a history of confusion and paranoia over the past several days . On admission the patient was taking carvedilol 12 mg twice daily , warfarin 2 mg / day , folic acid 1 mg / day , levothyroxine 100 microg / day , pantoprazole 40 mg / day , paroxetine 40 mg / day , and flecainide 100 mg twice daily . Flecainide had been started 2 weeks prior for atrial fibrillation . Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg / L ( reference range 200 - 1000 ) . A metabolic drug interaction between flecainide and paroxetine , which the patient had been taking for more than 5 years , was considered . Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily . Her delirium resolved 3 days later . DISCUSSION : Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients . A MEDLINE search ( 1966 - January 2009 ) revealed one in vivo pharmacokinetic study on the interaction between flecainide , a CYP2D6 substrate , and paroxetine , a CYP2D6 inhibitor , as well as 3 case reports of flecainide - induced delirium . According to the Naranjo probability scale , flecainide was the probable cause of the patient ' s delirium ; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine . CONCLUSIONS : Supratherapeutic flecainide plasma concentrations may cause delirium . Because toxicity may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors , flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors . Efficacy of everolimus ( RAD001 ) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors . BACKGROUND : Treatment options are scarce in pretreated advanced non - small - cell lung cancer ( NSCLC ) patients . RAD001 , an oral inhibitor of the mammalian target of rapamycin ( mTOR ) , has shown phase I efficacy in NSCLC . METHODS : Stage IIIb or IV NSCLC patients , with two or fewer prior chemotherapy regimens , one platinum based ( stratum 1 ) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors ( stratum 2 ) , received RAD001 10 mg / day until progression or unacceptable toxicity . Primary objective was overall response rate ( ORR ) . Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry ( IHC ) and direct mutation sequencing . RESULTS : Eighty - five patients were enrolled , 42 in stratum 1 and 43 in stratum . ORR was 4 . 7 % ( 7 . 1 % stratum 1 ; 2 . 3 % stratum 2 ) . Overall disease control rate was 47 . 1 % . Median progression - free survivals ( PFSs ) were 2 . 6 ( stratum 1 ) and 2 . 7 months ( stratum 2 ) . Common > or = grade 3 events were fatigue , dyspnea , stomatitis , anemia , and thrombocytopenia . Pneumonitis , probably or possibly related , mainly grade 1 / 2 , occurred in 25 % . Cox regression analysis of IHC scores found that only phospho AKT ( pAKT ) was a significant independent predictor of worse PFS . CONCLUSIONS : RAD001 10 mg / day was well tolerated , showing modest clinical activity in pretreated NSCLC . Evaluation of RAD001 plus standard therapy for metastatic NSCLC continues . Posttransplant anemia : the role of sirolimus . Posttransplant anemia is a common problem that may hinder patients ' quality of life . It occurs in 12 to 76 % of patients , and is most common in the immediate posttransplant period . A variety of factors have been identified that increase the risk of posttransplant anemia , of which the level of renal function is most important . Sirolimus , a mammalian target of rapamycin inhibitor , has been implicated as playing a special role in posttransplant anemia . This review considers anemia associated with sirolimus , including its presentation , mechanisms , and management . Coronary computerized tomography angiography for rapid discharge of low - risk patients with cocaine - associated chest pain . BACKGROUND : Most patients presenting to emergency departments ( EDs ) with cocaine - associated chest pain are admitted for at least 12 hours and receive a " rule out acute coronary syndrome " protocol , often with noninvasive testing prior to discharge . In patients without cocaine use , coronary computerized tomography angiography ( CTA ) has been shown to be useful for identifying a group of patients at low risk for cardiac events who can be safely discharged . It is unclear whether a coronary CTA strategy would be efficacious in cocaine - associated chest pain , as coronary vasospasm may account for some of the ischemia . We studied whether a negative coronary CTA in patients with cocaine - associated chest pain could identify a subset safe for discharge . METHODS : We prospectively evaluated the safety of coronary CTA for low - risk patients who presented to the ED with cocaineassociated chest pain ( self - reported or positive urine test ) . Consecutive patients received either immediate coronary CTA in the ED ( without serial markers ) or underwent coronary CTA after a brief observation period with serial cardiac marker measurements . Patients with negative coronary CTA ( maximal stenosis less than 50 % ) were discharged . The main outcome was 30 - day cardiovascular death or myocardial infarction . RESULTS : A total of 59 patients with cocaine - associated chest pain were evaluated . Patients had a mean age of 45 . 6 + / - 6 . 6 yrs and were 86 % black , 66 % male . Seventy - nine percent had a normal or nonspecific ECG and 85 % had a TIMI score < 2 . Twenty patients received coronary CTA immediately in the ED , 18 of whom were discharged following CTA ( 90 % ) . Thirty - nine received coronary CTA after a brief observation period , with 37 discharged home following CTA ( 95 % ) . Six patients had coronary stenosis > or = 50 % . During the 30 - day follow - up period , no patients died of a cardiovascular event ( 0 % ; 95 % CI , 0 - 6 . 1 % ) and no patient sustained a nonfatal myocardial infarction ( 0 % ; 95 % CI , 0 - 6 . 1 % ) . CONCLUSIONS : Although cocaine - associated myocardial ischemia can result from coronary vasoconstriction , patients with cocaine associated chest pain , a non - ischemic ECG , and a TIMI risk score < 2 may be safely discharged from the ED after a negative coronary CTA with a low risk of 30 - day adverse events . Bilateral haemorrhagic infarction of the globus pallidus after cocaine and alcohol intoxication . Cocaine is a risk factor for both ischemic and haemorrhagic stroke . We present the case of a 31 - year - old man with bilateral ischemia of the globus pallidus after excessive alcohol and intranasal cocaine use . Drug - related globus pallidus infarctions are most often associated with heroin . Bilateral basal ganglia infarcts after the use of cocaine , without concurrent heroin use , have never been reported . In our patient , transient cardiac arrhythmia or respiratory dysfunction related to cocaine and / or ethanol use were the most likely causes of cerebral hypoperfusion . Late fulminant posterior reversible encephalopathy syndrome after liver transplant . OBJECTIVES : Posterior leukoencephalopathy due to calcineurin - inhibitor - related neurotoxicity is a rare but severe complication that results from treatment with immunosuppressive agents ( primarily those administered after a liver or kidney transplant ) . The pathophysiologic mechanisms of that disorder remain unknown . CASE : We report the case of a 46 - year - old woman who received a liver transplant in our center as treatment for alcoholic cirrhosis and in whom either a fulminant course of posterior leukoencephalopathy or posterior reversible encephalopathy syndrome developed 110 days after transplant . After an initially uneventful course after the transplant , the patient rapidly fell into deep coma . RESULTS : Cerebral MRI scan showed typical signs of enhancement in the pontine and posterior regions . Switching the immunosuppressive regimen from tacrolimus to cyclosporine did not improve the clinical situation . The termination of treatment with any calcineurin inhibitor resulted in a complete resolution of that complication . CONCLUSIONS : Posterior reversible encephalopathy syndrome after liver transplant is rare . We recommend a complete cessation of any calcineurin inhibitor rather than a dose reduction . Prolonged hypothermia as a bridge to recovery for cerebral edema and intracranial hypertension associated with fulminant hepatic failure . BACKGROUND : To review evidence - based treatment options in patients with cerebral edema complicating fulminant hepatic failure ( FHF ) and discuss the potential applications of hypothermia . METHOD : Case - based observations from a medical intensive care unit ( MICU ) in a tertiary care facility in a 27 - year - old female with FHF from acetaminophen and resultant cerebral edema . RESULTS : Our patient was admitted to the MICU after being found unresponsive with presumed toxicity from acetaminophen which was ingested over a 2 - day period . The patient had depressed of mental status lasting at least 24 h prior to admission . Initial evaluation confirmed FHF from acetaminophen and cerebral edema . The patient was treated with hyperosmolar therapy , hyperventilation , sedation , and chemical paralysis . Her intracranial pressure remained elevated despite maximal medical therapy . We then initiated therapeutic hypothermia which was continued for 5 days . At re - warming , patient had resolution of her cerebral edema and intracranial hypertension . At discharge , she had complete recovery of neurological and hepatic functions . CONCLUSION : In patients with FHF and cerebral edema from acetaminophen overdose , prolonged therapeutic hypothermia could potentially be used as a life saving therapy and a bridge to hepatic and neurological recovery . A clinical trial of hypothermia in patients with this condition is warranted . Binasal visual field defects are not specific to vigabatrin . This study investigated the visual defects associated with the antiepileptic drug vigabatrin ( VGB ) . Two hundred four people with epilepsy were grouped on the basis of antiepileptic drug therapy ( current , previous , or no exposure to VGB ) . Groups were matched with respect to age , gender , and seizure frequency . All patients underwent objective assessment of electrophysiological function ( wide - field multifocal electroretinography ) and conventional visual field testing ( static perimetry ) . Bilateral visual field constriction was observed in 59 % of patients currently taking VGB , 43 % of patients who previously took VGB , and 24 % of patients with no exposure to VGB . Assessment of retinal function revealed abnormal responses in 48 % of current VGB users and 22 % of prior VGB users , but in none of the patients without previous exposure to VGB . Bilateral visual field abnormalities are common in the treated epilepsy population , irrespective of drug history . Assessment by conventional static perimetry may neither be sufficiently sensitive nor specific to reliably identify retinal toxicity associated with VGB . Smoking of crack cocaine as a risk factor for HIV infection among people who use injection drugs . BACKGROUND : Little is known about the possible role that smoking crack cocaine has on the incidence of HIV infection . Given the increasing use of crack cocaine , we sought to examine whether use of this illicit drug has become a risk factor for HIV infection . METHODS : We included data from people participating in the Vancouver Injection Drug Users Study who reported injecting illicit drugs at least once in the month before enrolment , lived in the greater Vancouver area , were HIV - negative at enrolment and completed at least 1 follow - up study visit . To determine whether the risk of HIV seroconversion among daily smokers of crack cocaine changed over time , we used Cox proportional hazards regression and divided the study into 3 periods : May 1 , 1996 - Nov . 30 , 1999 ( period 1 ) , Dec . 1 , 1999 - Nov . 30 , 2002 ( period 2 ) , and Dec . 1 , 2002 - Dec . 30 , 2005 ( period 3 ) . RESULTS : Overall , 1048 eligible injection drug users were included in our study . Of these , 137 acquired HIV infection during follow - up . The mean proportion of participants who reported daily smoking of crack cocaine increased from 11 . 6 % in period 1 to 39 . 7 % in period 3 . After adjusting for potential confounders , we found that the risk of HIV seroconversion among participants who were daily smokers of crack cocaine increased over time ( period 1 : hazard ratio [ HR ] 1 . 03 , 95 % confidence interval [ CI ] 0 . 57 - 1 . 85 ; period 2 : HR 1 . 68 , 95 % CI 1 . 01 - 2 . 80 ; and period 3 : HR 2 . 74 , 95 % CI 1 . 06 - 7 . 11 ) . INTERPRETATION : Smoking of crack cocaine was found to be an independent risk factor for HIV seroconversion among people who were injection drug users . This finding points to the urgent need for evidence - based public health initiatives targeted at people who smoke crack cocaine . Fluoxetine improves the memory deficits caused by the chemotherapy agent 5 - fluorouracil . Cancer patients who have been treated with systemic adjuvant chemotherapy have described experiencing deteriorations in cognition . A widely used chemotherapeutic agent , 5 - fluorouracil ( 5 - FU ) , readily crosses the blood - brain barrier and so could have a direct effect on brain function . In particular this anti mitotic drug could reduce cell proliferation in the neurogenic regions of the adult brain . In contrast reports indicate that hippocampal dependent neurogenesis and cognition are enhanced by the SSRI antidepressant Fluoxetine . In this investigation the behavioural effects of chronic ( two week ) treatment with 5 - FU and ( three weeks ) with Fluoxetine either separately or in combination with 5 - FU were tested on adult Lister hooded rats . Behavioural effects were tested using a context dependent conditioned emotional response test ( CER ) which showed that animals treated with 5 - FU had a significant reduction in freezing time compared to controls . A separate group of animals was tested using a hippocampal dependent spatial working memory test , the object location recognition test ( OLR ) . Animals treated only with 5 - FU showed significant deficits in their ability to carry out the OLR task but co administration of Fluoxetine improved their performance . 5 - FU chemotherapy caused a significant reduction in the number of proliferating cells in the sub granular zone of the dentate gyrus compared to controls . This reduction was eliminated when Fluoxetine was co administered with 5 - FU . Fluoxetine on its own had no effect on proliferating cell number or behaviour . These findings suggest that 5 - FU can negatively affect both cell proliferation and hippocampal dependent working memory and that these deficits can be reversed by the simultaneous administration of the antidepressant Fluoxetine . Liver - specific ablation of integrin - linked kinase in mice results in enhanced and prolonged cell proliferation and hepatomegaly after phenobarbital administration . We have recently demonstrated that disruption of extracellular matrix ( ECM ) / integrin signaling via elimination of integrin - linked kinase ( ILK ) in hepatocytes interferes with signals leading to termination of liver regeneration . This study investigates the role of ILK in liver enlargement induced by phenobarbital ( PB ) . Wild - type ( WT ) and ILK : liver - / - mice were given PB ( 0 . 1 % in drinking water ) for 10 days . Livers were harvested on 2 , 5 , and 10 days during PB administration . In the hepatocyte - specific ILK / liver - / - mice , the liver : body weight ratio was more than double as compared to 0 h at day 2 ( 2 . 5 times ) , while at days 5 and 10 , it was enlarged three times . In the WT mice , the increase was as expected from previous literature ( 1 . 8 times ) and seems to have leveled off after day 2 . There were slightly increased proliferating cell nuclear antigen - positive cells in the ILK / liver - / - animals at day 2 as compared to WT after PB administration . In the WT animals , the proliferative response had come back to normal by days 5 and 10 . Hepatocytes of the ILK / liver - / - mice continued to proliferate up until day 10 . ILK / liver - / - mice also showed increased expression of key genes involved in hepatocyte proliferation at different time points during PB administration . In summary , ECM proteins communicate with the signaling machinery of dividing cells via ILK to regulate hepatocyte proliferation and termination of the proliferative response . Lack of ILK in the hepatocytes imparts prolonged proliferative response not only to stimuli related to liver regeneration but also to xenobiotic chemical mitogens , such as PB . Decreased Expression of Na / K - ATPase , NHE3 , NBC1 , AQP1 and OAT in Gentamicin - induced Nephropathy . The present study was aimed to determine whether there is an altered regulation of tubular transporters in gentamicin - induced nephropathy . Sprague - Dawley male rats ( 200 ~ 250 g ) were subcutaneously injected with gentamicin ( 100 mg / kg per day ) for 7 days , and the expression of tubular transporters was determined by immunoblotting and immunohistochemistry . The mRNA and protein expression of OAT was also determined . Gentamicin - treated rats exhibited significantly decreased creatinine clearance along with increased plasma creatinine levels . Accordingly , the fractional excretion of sodium increased . Urine volume was increased , while urine osmolality and free water reabsorption were decreased . Immunoblotting and immunohistochemistry revealed decreased expression of Na ( + ) / K ( + ) - ATPase , NHE3 , NBC1 , and AQP1 in the kidney of gentamicin - treated rats . The expression of OAT1 and OAT3 was also decreased . Gentamicin - induced nephropathy may at least in part be causally related with a decreased expression of Na ( + ) / K ( + ) - ATPase , NHE3 , NBC1 , AQP1 and OAT . Acute renal failure after high - dose methotrexate therapy in a patient with ileostomy . High - dose methotrexate ( HD - MTX ) is an important treatment for Burkitt lymphoma , but can cause hepatic and renal toxicity when its clearance is delayed . We report a case of acute renal failure after HD - MTX therapy in a patient with ileostomy , The patient was a 3 - year - old boy who had received a living - related liver transplantation for congenital biliary atresia . At day 833 after the transplantation , he was diagnosed with PTLD ( post - transplantation lymphoproliferative disorder , Burkitt - type malignant lymphoma ) . During induction therapy , he suffered ileal perforation and ileostomy was performed . Subsequent HD - MTX therapy caused acute renal failure that required continuous hemodialysis . We supposed that intravascular hypovolemia due to substantial drainage from the ileostoma caused acute prerenal failure . After recovery of his renal function , we could safely treat the patient with HD - MTX therapy by controlling drainage from ileostoma with total parenteral nutrition . Longitudinal association of alcohol use with HIV disease progression and psychological health of women with HIV . We evaluated the association of alcohol consumption and depression , and their effects on HIV disease progression among women with HIV . The study included 871 women with HIV who were recruited from 1993 - 1995 in four US cities . The participants had physical examination , medical record extraction , and venipuncture , CD4 + T - cell counts determination , measurement of depression symptoms ( using the self - report Center for Epidemiological Studies - Depression Scale ) , and alcohol use assessment at enrollment , and semiannually until March 2000 . Multilevel random coefficient ordinal models as well as multilevel models with joint responses were used in the analysis . There was no significant association between level of alcohol use and CD4 + T - cell counts . When participants were stratified by antiretroviral therapy ( ART ) use , the association between alcohol and CD4 + T - cell did not reach statistical significance . The association between alcohol consumption and depression was significant ( p < 0 . 001 ) . Depression had a significant negative effect on CD4 + T - cell counts over time regardless of ART use . Our findings suggest that alcohol consumption has a direct association with depression . Moreover , depression is associated with HIV disease progression . Our findings have implications for the provision of alcohol use interventions and psychological resources to improve the health of women with HIV . Chemokine CCL2 and its receptor CCR2 are increased in the hippocampus following pilocarpine - induced status epilepticus . BACKGROUND : Neuroinflammation occurs after seizures and is implicated in epileptogenesis . CCR2 is a chemokine receptor for CCL2 and their interaction mediates monocyte infiltration in the neuroinflammatory cascade triggered in different brain pathologies . In this work CCR2 and CCL2 expression were examined following status epilepticus ( SE ) induced by pilocarpine injection . METHODS : SE was induced by pilocarpine injection . Control rats were injected with saline instead of pilocarpine . Five days after SE , CCR2 staining in neurons and glial cells was examined using imunohistochemical analyses . The number of CCR2 positive cells was determined using stereology probes in the hippocampus . CCL2 expression in the hippocampus was examined by molecular assay . RESULTS : Increased CCR2 was observed in the hippocampus after SE . Seizures also resulted in alterations to the cell types expressing CCR2 . Increased numbers of neurons that expressed CCR2 was observed following SE . Microglial cells were more closely apposed to the CCR2 - labeled cells in SE rats . In addition , rats that experienced SE exhibited CCR2 - labeling in populations of hypertrophied astrocytes , especially in CA1 and dentate gyrus . These CCR2 + astroctytes were not observed in control rats . Examination of CCL2 expression showed that it was elevated in the hippocampus following SE . CONCLUSION : The data show that CCR2 and CCL2 are up - regulated in the hippocampus after pilocarpine - induced SE . Seizures also result in changes to CCR2 receptor expression in neurons and astrocytes . These changes might be involved in detrimental neuroplasticity and neuroinflammatory changes that occur following seizures . Metallothionein induction reduces caspase - 3 activity and TNFalpha levels with preservation of cognitive function and intact hippocampal neurons in carmustine - treated rats . Hippocampal integrity is essential for cognitive functions . On the other hand , induction of metallothionein ( MT ) by ZnSO ( 4 ) and its role in neuroprotection has been documented . The present study aimed to explore the effect of MT induction on carmustine ( BCNU ) - induced hippocampal cognitive dysfunction in rats . A total of 60 male Wistar albino rats were randomly divided into four groups ( 15 / group ) : The control group injected with single doses of normal saline ( i . c . v ) followed 24 h later by BCNU solvent ( i . v ) . The second group administered ZnSO ( 4 ) ( 0 . 1 micromol / 10 microl normal saline , i . c . v , once ) then BCNU solvent ( i . v ) after 24 h . Third group received BCNU ( 20 mg / kg , i . v , once ) 24 h after injection with normal saline ( i . c . v ) . Fourth group received a single dose of ZnSO ( 4 ) ( 0 . 1 micromol / 10 microl normal saline , i . c . v ) then BCNU ( 20 mg / kg , i . v , once ) after 24 h . The obtained data revealed that BCNU administration resulted in deterioration of learning and short - term memory ( STM ) , as measured by using radial arm water maze , accompanied with decreased hippocampal glutathione reductase ( GR ) activity and reduced glutathione ( GSH ) content . Also , BCNU administration increased serum tumor necrosis factor - alpha ( TNFalpha ) , hippocampal MT and malondialdehyde ( MDA ) contents as well as caspase - 3 activity in addition to histological alterations . ZnSO ( 4 ) pretreatment counteracted BCNU - induced inhibition of GR and depletion of GSH and resulted in significant reduction in the levels of MDA and TNFalpha as well as the activity of caspase - 3 . The histological features were improved in hippocampus of rats treated with ZnSO ( 4 ) + BCNU compared to only BCNU - treated animals . In conclusion , MT induction halts BCNU - induced hippocampal toxicity as it prevented GR inhibition and GSH depletion and counteracted the increased levels of TNFalpha , MDA and caspase - 3 activity with subsequent preservation of cognition . Fatal carbamazepine induced fulminant eosinophilic ( hypersensitivity ) myocarditis : emphasis on anatomical and histological characteristics , mechanisms and genetics of drug hypersensitivity and differential diagnosis . The most severe adverse reactions to carbamazepine have been observed in the haemopoietic system , the liver and the cardiovascular system . A frequently fatal , although exceptionally rare side effect of carbamazepine is necrotizing eosinophilic ( hypersensitivity ) myocarditis . We report a case of hypersensitivity myocarditis secondary to administration of carbamazepine . Acute hypersensitivity myocarditis was not suspected clinically , and the diagnosis was made post - mortem . Histology revealed diffuse infiltration of the myocardium by eosinophils and lymphocytes with myocyte damage . Clinically , death was due to cardiogenic shock . To best of our knowledge this is the second case of fatal carbamazepine induced myocarditis reported in English literature . Neuropsychiatric behaviors in the MPTP marmoset model of Parkinson ' s disease . OBJECTIVES : Neuropsychiatric symptoms are increasingly recognised as a significant problem in patients with Parkinson ' s disease ( PD ) . These symptoms may be due to ' sensitisation ' following repeated levodopa treatment or a direct effect of dopamine on the disease state . The levodopa - treated MPTP - lesioned marmoset was used as a model of neuropsychiatric symptoms in PD patients . Here we compare the time course of levodopa - induced motor fluctuations and neuropsychiatric - like behaviors to determine the relationship between duration of treatment and onset of symptoms . METHODS : Marmosets were administered 1 - methyl - 4 - phenyl - 1 , 2 , 3 , 6 - tetrahydropyridine ( 2 . 0 mg / kg s . c . ) for five days , resulting in stable parkinsonism . Levodopa ( 15 mg / kg and benserazide , 3 . 75 mg / kg ) p . o . b . i . d , was administered for 30 days . Animals were evaluated for parkinsonian disability , dyskinesia and on - time ( motor fluctuations ) and neuropsychiatric - like behaviors on Day 0 ( prior to levodopa ) and on Days 1 , 7 , 13 , 27 and 30 of treatment using post hoc DVD analysis by a trained rater , blind to the treatment day . RESULTS : The neuropsychiatric - like behavior rating scale demonstrated high interrater reliability between three trained raters of differing professional backgrounds . As anticipated , animals exhibited a progressive increase in levodopa - induced motor fluctuations , dyskinesia and wearing - off , that correlated with the duration of levodopa therapy . In contrast , levodopa - induced neuropsychiatric - like behaviors were present on Day 1 of levodopa treatment and their severity did not correlate with duration of treatment . CONCLUSIONS : The data suggest that neuropsychiatric disorders in PD are more likely an interaction between levodopa and the disease state than a consequence of sensitisation to repeated dopaminergic therapy . Contrast medium nephrotoxicity after renal artery and coronary angioplasty . BACKGROUND : Renal dysfunction induced by iodinated contrast medium ( CM ) administration can minimize the benefit of the interventional procedure in patients undergoing renal angioplasty ( PTRA ) . PURPOSE : To compare the susceptibility to nephrotoxic effect of CM in patients undergoing PTRA with that of patients submitted to percutaneous coronary intervention ( PCI ) . MATERIAL AND METHODS : A total of 33 patients successfully treated with PTRA ( PTRA group , mean age 70 + / - 12 years , 23 female , basal creatinine 1 . 46 + / - 0 . 79 , range 0 . 7 - 4 . 9 mg / dl ) were compared with 33 patients undergoing successful PCI ( PCI group ) , matched for basal creatinine ( 1 . 44 + / - 0 . 6 , range 0 . 7 - 3 . 4 mg / dl ) , gender , and age . In both groups postprocedural ( 48 h ) serum creatinine was measured . RESULTS : Postprocedural creatinine level decreased nonsignificantly in the PTRA group ( 1 . 46 + / - 0 . 8 vs . 1 . 34 + / - 0 . 5 mg / dl , P = NS ) and increased significantly in the PCI group ( 1 . 44 + / - 0 . 6 vs . 1 . 57 + / - 0 . 7 mg / dl , P < 0 . 02 ) . Changes in serum creatinine after intervention ( after - before ) were significantly different between the PTRA and PCI groups ( - 0 . 12 + / - 0 . 5 vs . 0 . 13 + / - 0 . 3 , P = 0 . 014 ) . This difference was not related to either a different clinical risk profile or to the volume of CM administered . CONCLUSION : In this preliminary study patients submitted to PTRA showed a lower susceptibility to renal damage induced by CM administration than PCI patients . The effectiveness of PTRA on renal function seems to be barely influenced by CM toxicity . Diphenhydramine prevents the haemodynamic changes of cimetidine in ICU patients . Cimetidine , a histamine 2 ( H2 ) antagonist , produces a decrease in arterial pressure due to vasodilatation , especially in critically ill patients . This may be because cimetidine acts as a histamine agonist . We , therefore , investigated the effects of the histamine 1 ( H1 ) receptor antagonist , diphenhydramine , on the haemodynamic changes observed after cimetidine in ICU patients . Each patient was studied on two separate days . In a random fashion , they received cimetidine 200 mg iv on one day , and on the other , a pretreatment of diphenhydramine 40 mg iv with cimetidine 200 mg iv . In the non - pretreatment group , mean arterial pressure ( MAP ) decreased from 107 . 4 + / - 8 . 4 mmHg to 86 . 7 + / - 11 . 4 mmHg ( P less than 0 . 01 ) two minutes after cimetidine . Also , systemic vascular resistance ( SVR ) decreased during the eight - minute observation period ( P less than 0 . 01 ) . In contrast , in the pretreatment group , little haemodynamic change was seen . We conclude that an H1 antagonist may be useful in preventing hypotension caused by iv cimetidine , since the vasodilating activity of cimetidine is mediated , in part , through the H1 receptor . Medical and psychiatric outcomes for patients transplanted for acetaminophen - induced acute liver failure : a case - control study . BACKGROUND : Acetaminophen - induced hepatotoxicity is the most common cause of acute liver failure ( ALF ) in the UK . Patients often consume the drug with suicidal intent or with a background of substance dependence . AIMS AND METHODS : We compared the severity of pretransplant illness , psychiatric co - morbidity , medical and psychosocial outcomes of all patients who had undergone liver transplantation ( LT ) emergently between 1999 - 2004 for acetaminophen - induced ALF ( n = 36 ) with age - and sex - matched patients undergoing emergent LT for non - acetaminophen - induced ALF ( n = 35 ) and elective LT for chronic liver disease ( CLD , n = 34 ) . RESULTS : Acetaminophen - induced ALF patients undergoing LT had a greater severity of pre - LT illness reflected by higher Acute Physiology and Chronic Health Evaluation II scores and requirement for organ support compared with the other two groups . Twenty ( 56 % ) acetaminophen - induced ALF patients had a formal psychiatric diagnosis before LT ( non - acetaminophen - induced ALF = 0 / 35 , CLD = 2 / 34 ; P < 0 . 01 for all ) and nine ( 25 % ) had a previous suicide attempt . During follow - up ( median 5 years ) , there were no significant differences in rejection ( acute and chronic ) , graft failure or survival between the groups ( acetaminophen - induced ALF 1 year 87 % , 5 years 75 % ; non - acetaminophen - induced ALF 88 % , 78 % ; CLD 93 % , 82 % : P > 0 . 6 log rank ) . Two acetaminophen - induced ALF patients reattempted suicide post - LT ( one died 8 years post - LT ) . CONCLUSIONS : Despite a high prevalence of psychiatric disturbance , outcomes for patients transplanted emergently for acetaminophen - induced ALF were comparable to those transplanted for non - acetaminophen - induced ALF and electively for CLD . Multidisciplinary approaches with long - term psychiatric follow - up may contribute to low post - transplant suicide rates seen and low rates of graft loss because of non - compliance . Antithrombotic drug use , cerebral microbleeds , and intracerebral hemorrhage : a systematic review of published and unpublished studies . BACKGROUND AND PURPOSE : Cerebral microbleeds ( MB ) are potential risk factors for intracerebral hemorrhage ( ICH ) , but it is unclear if they are a contraindication to using antithrombotic drugs . Insights could be gained by pooling data on MB frequency stratified by antithrombotic use in cohorts with ICH and ischemic stroke ( IS ) / transient ischemic attack ( TIA ) . METHODS : We performed a systematic review of published and unpublished data from cohorts with stroke or TIA to compare the presence of MB in : ( 1 ) antithrombotic users vs nonantithrombotic users with ICH ; ( 2 ) antithrombotic users vs nonusers with IS / TIA ; and ( 3 ) ICH vs ischemic events stratified by antithrombotic use . We also analyzed published and unpublished follow - up data to determine the risk of ICH in antithrombotic users with MB . RESULTS : In a pooled analysis of 1460 ICH and 3817 IS / TIA , MB were more frequent in ICH vs IS / TIA in all treatment groups , but the excess increased from 2 . 8 ( odds ratio ; range , 2 . 3 - 3 . 5 ) in nonantithrombotic users to 5 . 7 ( range , 3 . 4 - 9 . 7 ) in antiplatelet users and 8 . 0 ( range , 3 . 5 - 17 . 8 ) in warfarin users ( P difference = 0 . 01 ) . There was also an excess of MB in warfarin users vs nonusers with ICH ( OR , 2 . 7 ; 95 % CI , 1 . 6 - 4 . 4 ; P < 0 . 001 ) but none in warfarin users with IS / TIA ( OR , 1 . 3 ; 95 % CI , 0 . 9 - 1 . 7 ; P = 0 . 33 ; P difference = 0 . 01 ) . There was a smaller excess of MB in antiplatelet users vs nonusers with ICH ( OR , 1 . 7 ; 95 % CI , 1 . 3 - 2 . 3 ; P < 0 . 001 ) , but findings were similar for antiplatelet users with IS / TIA ( OR , 1 . 4 ; 95 % CI , 1 . 2 - 1 . 7 ; P < 0 . 001 ; P difference = 0 . 25 ) . In pooled follow - up data for 768 antithrombotic users , presence of MB at baseline was associated with a substantially increased risk of subsequent ICH ( OR , 12 . 1 ; 95 % CI , 3 . 4 - 42 . 5 ; P < 0 . 001 ) . CONCLUSIONS : The excess of MB in warfarin users with ICH compared to other groups suggests that MB increase the risk of warfarin - associated ICH . Limited prospective data corroborate these findings , but larger prospective studies are urgently required . Studies of synergy between morphine and a novel sodium channel blocker , CNSB002 , in rat models of inflammatory and neuropathic pain . OBJECTIVE : This study determined the antihyperalgesic effect of CNSB002 , a sodium channel blocker with antioxidant properties given alone and in combinations with morphine in rat models of inflammatory and neuropathic pain . DESIGN : Dose response curves for nonsedating doses of morphine and CNSB002 given intraperitoneally alone and together in combinations were constructed for antihyperalgesic effect using paw withdrawal from noxious heat in two rat pain models : carrageenan - induced paw inflammation and streptozotocin ( STZ ) - induced diabetic neuropathy . RESULTS : The maximum nonsedating doses were : morphine , 3 . 2 mg / kg ; CNSB002 10 . 0 mg / kg ; 5 . 0 mg / kg CNSB002 with morphine 3 . 2 mg / kg in combination . The doses calculated to cause 50 % reversal of hyperalgesia ( ED50 ) were 7 . 54 ( 1 . 81 ) and 4 . 83 ( 1 . 54 ) in the carrageenan model and 44 . 18 ( 1 . 37 ) and 9 . 14 ( 1 . 24 ) in the STZ - induced neuropathy model for CNSB002 and morphine , respectively ( mg / kg ; mean , SEM ) . These values were greater than the maximum nonsedating doses . The ED50 values for morphine when given in combination with CNSB002 ( 5 mg / kg ) were less than the maximum nonsedating dose : 0 . 56 ( 1 . 55 ) in the carrageenan model and 1 . 37 ( 1 . 23 ) in the neuropathy model ( mg / kg ; mean , SEM ) . The antinociception after morphine ( 3 . 2 mg / kg ) was increased by co - administration with CNSB002 from 28 . 0 and 31 . 7 % to 114 . 6 and 56 . 9 % reversal of hyperalgesia in the inflammatory and neuropathic models , respectively ( P < 0 . 01 ; one - way analysis of variance - significantly greater than either drug given alone ) . CONCLUSIONS : The maximum antihyperalgesic effect achievable with nonsedating doses of morphine may be increased significantly when the drug is used in combination with CNSB002 . Heparin - induced thrombocytopenia : a practical review . Heparin - induced thrombocytopenia ( HIT ) remains under - recognized despite its potentially devastating outcomes . It begins when heparin exposure stimulates the formation of heparin - platelet factor 4 antibodies , which in turn triggers the release of procoagulant platelet particles . Thrombosis and thrombocytopenia that follow comprise the 2 hallmark traits of HIT , with the former largely responsible for significant vascular complications . The prevalence of HIT varies among several subgroups , with greater incidence in surgical as compared with medical populations . HIT must be acknowledged for its intense predilection for thrombosis and suspected whenever thrombosis occurs after heparin exposure . Early recognition that incorporates the clinical and serologic clues is paramount to timely institution of treatment , as its delay may result in catastrophic outcomes . The treatment of HIT mandates an immediate cessation of all heparin exposure and the institution of an antithrombotic therapy , most commonly using a direct thrombin inhibitor . Current " diagnostic " tests , which primarily include functional and antigenic assays , have more of a confirmatory than diagnostic role in the management of HIT . Special attention must be paid to cardiac patients who are often exposed to heparin multiple times during their course of treatment . Direct thrombin inhibitors are appropriate , evidence - based alternatives to heparin in patients with a history of HIT , who need to undergo percutaneous coronary intervention . As heparin remains one of the most frequently used medications today with potential for HIT with every heparin exposure , a close vigilance of platelet counts must be practiced whenever heparin is initiated . Abductor paralysis after botox injection for adductor spasmodic dysphonia . OBJECTIVES / HYPOTHESIS : Botulinum toxin ( Botox ) injections into the thyroarytenoid muscles are the current standard of care for adductor spasmodic dysphonia ( ADSD ) . Reported adverse effects include a period of breathiness , throat pain , and difficulty with swallowing liquids . Here we report multiple cases of bilateral abductor paralysis following Botox injections for ADSD , a complication previously unreported . STUDY DESIGN : Retrospective case series . METHODS : Patients that received Botox injections for spasmodic dysphonia between January 2000 and October 2009 were evaluated . Patients with ADSD were identified . The number of treatments received and adverse effects were noted . For patients with bilateral abductor paralysis , age , sex , paralytic Botox dose , prior Botox dose , and course following paralysis were noted . RESULTS : From a database of 452 patients receiving Botox , 352 patients had been diagnosed with ADSD . Of these 352 patients , eight patients suffered bilateral abductor paralysis , and two suffered this complication twice . All affected patients were females over the age of 50 years . Most patients had received treatments prior to abductor paralysis and continued receiving after paralysis . Seven patients recovered after a brief period of activity restrictions , and one underwent a tracheotomy . The incidence of abductor paralysis after Botox injection for ADSD was 0 . 34 % . CONCLUSIONS : Bilateral abductor paralysis is a rare complication of Botox injections for ADSD , causing difficulty with breathing upon exertion . The likely mechanism of paralysis is diffusion of Botox around the muscular process of the arytenoid to the posterior cricoarytenoid muscles . The paralysis is temporary , and watchful waiting with restriction of activity is the recommended management . Mitochondrial impairment contributes to cocaine - induced cardiac dysfunction : Prevention by the targeted antioxidant MitoQ . The goal of this study was to assess mitochondrial function and ROS production in an experimental model of cocaine - induced cardiac dysfunction . We hypothesized that cocaine abuse may lead to altered mitochondrial function that in turn may cause left ventricular dysfunction . Seven days of cocaine administration to rats led to an increased oxygen consumption detected in cardiac fibers , specifically through complex I and complex III . ROS levels were increased , specifically in interfibrillar mitochondria . In parallel there was a decrease in ATP synthesis , whereas no difference was observed in subsarcolemmal mitochondria . This uncoupling effect on oxidative phosphorylation was not detectable after short - term exposure to cocaine , suggesting that these mitochondrial abnormalities were a late rather than a primary event in the pathological response to cocaine . MitoQ , a mitochondrial - targeted antioxidant , was shown to completely prevent these mitochondrial abnormalities as well as cardiac dysfunction characterized here by a diastolic dysfunction studied with a conductance catheter to obtain pressure - volume data . Taken together , these results extend previous studies and demonstrate that cocaine - induced cardiac dysfunction may be due to a mitochondrial defect . Trimethoprim - induced immune hemolytic anemia in a pediatric oncology patient presenting as an acute hemolytic transfusion reaction . A 10 - year - old male with acute leukemia presented with post - chemotherapy anemia . During red cell transfusion , he developed hemoglobinuria . Transfusion reaction workup was negative . Drug - induced immune hemolytic anemia was suspected because of positive direct antiglobulin test , negative eluate , and microspherocytes on smear pre - and post - transfusion . Drug studies using the indirect antiglobulin test were strongly positive with trimethoprim and trimethoprim - sulfamethoxazole but negative with sulfamethoxazole . The patient recovered after discontinuing the drug , with no recurrence in 2 years . Other causes of anemia should be considered in patients with worse - than - expected anemia after chemotherapy . Furthermore , hemolysis during transfusion is not always a transfusion reaction . Verapamil stimulation test in hyperprolactinemia : loss of prolactin response in anatomic or functional stalk effect . AIM : Verapamil stimulation test was previously investigated as a tool for differential diagnosis of hyperprolactinemia , but with conflicting results . Macroprolactinemia was never considered in those previous studies . Here , we aimed to re - investigate the diagnostic value of verapamil in a population who were all screened for macroprolactinemia . Prolactin responses to verapamil in 65 female patients ( age : 29 . 9 + / - 8 . 1 years ) with hyperprolactinemia were tested in a descriptive , matched case - control study . METHODS : Verapamil 80 mg , p . o . was administered , and then PRL levels were measured at 8th and 16th hours , by immunometric chemiluminescence . Verapamil responsiveness was determined by peak percent change in basal prolactin levels ( PRL ) . RESULTS : Verapamil significantly increased PRL levels in healthy controls ( N . 8 , PRL : 183 % ) , macroprolactinoma ( N . 8 , PRL : 7 % ) , microprolactinoma ( N . 19 , PRL : 21 % ) , macroprolactinemia ( N . 23 , PRL : 126 % ) , but not in pseudoprolactinoma ( N . 8 , PRL : 0 . 8 % ) , and risperidone - induced hyperprolactinemia ( N . 7 , PRL : 3 % ) . ROC curve analysis revealed that unresponsiveness to verapamil defined as PRL < 7 % , discriminated anatomical or functional stalk effect ( sensitivity : 74 % , specificity : 73 % , AUC : 0 . 855 + / - 0 . 04 , P < 0 . 001 , CI : 0 . 768 - 0 . 942 ) associated with pseudoprolactinoma or risperidone - induced hyperprolactinemia , respectively . CONCLUSION : Verapamil responsiveness is not a reliable finding for the differential diagnosis of hyperprolactinemia . However , verapamil unresponsiveness discriminates stalk effect ( i . e . , anatomically or functionally inhibited dopaminergic tonus ) from other causes of hyperprolactinemia with varying degrees of responsiveness . Blockade of endothelial - mesenchymal transition by a Smad3 inhibitor delays the early development of streptozotocin - induced diabetic nephropathy . OBJECTIVE : A multicenter , controlled trial showed that early blockade of the renin - angiotensin system in patients with type 1 diabetes and normoalbuminuria did not retard the progression of nephropathy , suggesting that other mechanism ( s ) are involved in the pathogenesis of early diabetic nephropathy ( diabetic nephropathy ) . We have previously demonstrated that endothelial - mesenchymal - transition ( EndoMT ) contributes to the early development of renal interstitial fibrosis independently of microalbuminuria in mice with streptozotocin ( STZ ) - induced diabetes . In the present study , we hypothesized that blocking EndoMT reduces the early development of diabetic nephropathy . RESEARCH DESIGN AND METHODS : EndoMT was induced in a mouse pancreatic microvascular endothelial cell line ( MMEC ) in the presence of advanced glycation end products ( AGEs ) and in the endothelial lineage - traceble mouse line Tie2 - Cre ; Loxp - EGFP by administration of AGEs , with nonglycated mouse albumin serving as a control . Phosphorylated Smad3 was detected by immunoprecipitation / Western blotting and confocal microscopy . Blocking studies using receptor for AGE siRNA and a specific inhibitor of Smad3 ( SIS3 ) were performed in MMECs and in STZ - induced diabetic nephropathy in Tie2 - Cre ; Loxp - EGFP mice . RESULTS : Confocal microscopy and real - time PCR demonstrated that AGEs induced EndoMT in MMECs and in Tie2 - Cre ; Loxp - EGFP mice . Immunoprecipitation / Western blotting showed that Smad3 was activated by AGEs but was inhibited by SIS3 in MMECs and in STZ - induced diabetic nephropathy . Confocal microscopy and real - time PCR further demonstrated that SIS3 abrogated EndoMT , reduced renal fibrosis , and retarded progression of nephropathy . CONCLUSIONS : EndoMT is a novel pathway leading to early development of diabetic nephropathy . Blockade of EndoMT by SIS3 may provide a new strategy to retard the progression of diabetic nephropathy and other diabetes complications . Cytostatic and anti - angiogenic effects of temsirolimus in refractory mantle cell lymphoma . Mantle cell lymphoma ( MCL ) is a rare and aggressive type of B - cell non - Hodgkin ' s lymphoma . Patients become progressively refractory to conventional chemotherapy , and their prognosis is poor . However , a 38 % remission rate has been recently reported in refractory MCL treated with temsirolimus , a mTOR inhibitor . Here we had the opportunity to study a case of refractory MCL who had tumor regression two months after temsirolimus treatment , and a progression - free survival of 10 months . In this case , lymph node biopsies were performed before and six months after temsirolimus therapy . Comparison of the two biopsies showed that temsirolimus inhibited tumor cell proliferation through cell cycle arrest , but did not induce any change in the number of apoptotic tumor cells . Apart from this cytostatic effect , temsirolimus had an antiangiogenic effect with decrease of tumor microvessel density and of VEGF expression . Moreover , numerous patchy , well - limited fibrotic areas , compatible with post - necrotic tissue repair , were found after 6 - month temsirolimus therapy . Thus , temsirolimus reduced tumor burden through associated cytostatic and anti - angiogenic effects . This dual effect of temsirolimus on tumor tissue could contribute to its recently reported efficiency in refractory MCL resistant to conventional chemotherapy . Acute renal failure due to rifampicin . A 23 - year - old male patient with bacteriologically proven pulmonary tuberculosis was treated with the various regimens of antituberculosis drugs for nearly 15 months . Rifampicin was administered thrice as one of the 3 - 4 drug regimen and each time he developed untoward side effects like nausea , vomiting and fever with chills and rigors . The last such episode was of acute renal failure at which stage the patient was seen by the authors of this report . The patient , however , made a full recovery . Syncope caused by hyperkalemia during use of a combined therapy with the angiotensin - converting enzyme inhibitor and spironolactone . A 76 year - old woman with a history of coronary artery bypass grafting and prior myocardial infarction was transferred to the emergency room with loss of consciousness due to marked bradycardia caused by hyperkalemia . The concentration of serum potassium was high , and normal sinus rhythm was restored after correction of the serum potassium level . The cause of hyperkalemia was considered to be several doses of spiranolactone , an aldosterone antagonist , in addition to the long - term intake of ramipril , an ACE inhibitor . This case is a good example of electrolyte imbalance causing acute life - threatening cardiac events . Clinicians should be alert to the possibility of hyperkalemia , especially in elderly patients using ACE / ARB in combination with potassium sparing agents and who have mild renal disturbance . Diffuse skeletal pain after administration of alendronate . BACKGROUND : Osteoporosis is caused by bone resorption in excess of bone formation , and bisphosphonates , are used to inhibit bone resorption . Alendronate , a biphosphonate , is effective for both the treatment and prevention of osteoporosis in postmenopausal women . Side effects are relatively few and prominently gastrointestinal . Musculoskeletal pain may be an important side effect in these patients . We presented a patient admitted to our out - patient clinic with diffuse skeletal pain after three consecutive administration of alendronate . CONCLUSION : We conclude that patients with osteoporosis can report pain , and bisphosphonate - related pain should also be considered before ascribing this complaint to osteoporosis . Cerebrospinal fluid penetration of high - dose daptomycin in suspected Staphylococcus aureus meningitis . OBJECTIVE : To report a case of methicillin - sensitive Staphylococcus aureus ( MSSA ) bacteremia with suspected MSSA meningitis treated with high - dose daptomycin assessed with concurrent serum and cerebrospinal fluid ( CSF ) concentrations . CASE SUMMARY : A 54 - year - old male presented to the emergency department with generalized weakness and presumed health - care - associated pneumonia shown on chest radiograph . Treatment was empirically initiated with vancomycin , levofloxacin , and piperacillin / tazobactam . Blood cultures revealed S . aureus susceptible to oxacillin . Empiric antibiotic treatment was narrowed to nafcillin on day 4 . On day 8 , the patient developed acute renal failure ( serum creatinine 1 . 9 mg / dL , increased from 1 . 2 mg / dL the previous day and 0 . 8 mg / dL on admission ) . The patient ' s Glasgow Coma Score was 3 , with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10 . The patient experienced relapsing MSSA bacteremia on day 9 , increasing the suspicion for a central nervous system ( CNS ) infection . Nafcillin was discontinued and daptomycin 9 mg / kg daily was initiated for suspected meningitis and was continued until the patient ' s death on day 16 . Daptomycin serum and CSF trough concentrations were 11 . 21 ug / mL and 0 . 52 ug / mL , respectively , prior to the third dose . Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA . Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed . DISCUSSION : Daptomycin was initiated in our patient secondary to possible nafcillin - induced acute interstitial nephritis and relapsing bacteremia . At a dose of 9 mg / kg , resultant penetration of 5 % was higher than in previous reports , more consistent with inflamed meninges . CONCLUSIONS : High - dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy . Further clinical evaluation in patients with confirmed meningitis is warranted . The role of nitric oxide in convulsions induced by lindane in rats . Lindane is an organochloride pesticide and scabicide . It evokes convulsions mainly trough the blockage of GABA ( A ) receptors . Nitric oxide ( NO ) , gaseous neurotransmitter , has contradictor role in epileptogenesis due to opposite effects of L - arginine , precursor of NO syntheses ( NOS ) , and L - NAME ( NOS inhibitor ) observed in different epilepsy models . The aim of the current study was to determine the effects of NO on the behavioral and EEG characteristics of lindane - induced epilepsy in male Wistar albino rats . The administration of L - arginine ( 600 , 800 and 1000 mg / kg , i . p . ) in dose - dependent manner significantly increased convulsion incidence and severity and shortened latency time to first convulsion elicited by lower lindane dose ( 4 mg / kg , i . p . ) . On the contrary , pretreatment with L - NAME ( 500 , 700 and 900 mg / kg , i . p . ) decreased convulsion incidence and severity and prolonged latency time to convulsion following injection with a convulsive dose of lindane ( 8 mg / kg , i . p . ) . EEG analyses showed increase of number and duration of ictal periods in EEG of rats receiving l - arginine prior to lindane and decrease of this number in rats pretreated with L - NAME . These results support the conclusion that NO plays a role of endogenous convulsant in rat model of lindane seizures . Severe polyneuropathy and motor loss after intrathecal thiotepa combination chemotherapy : description of two cases . Two cases of severe delayed neurologic toxicity related to the administration of intrathecal ( IT ) combination chemotherapy including thiotepa ( TSPA ) are presented . Both cases developed axonal neuropathy with motor predominance in the lower extremities 1 and 6 months after IT chemotherapy was administered . Neurologic toxicities have been described with IT - methotrexate , IT - cytosine arabinoside and IT - TSPA . To our knowledge , however , axonal neuropathy following administration of these three agents has not been previously described . In spite of the fact that TSPA is a useful IT agent , its combination with MTX , ara - C and radiotherapy could cause severe neurotoxicity . This unexpected complication indicates the need for further toxicology research on IT - TSPA . Effects of cromakalim and pinacidil on large epicardial and small coronary arteries in conscious dogs . The effects of i . v . bolus administration of cromakalim ( 1 - 10 micrograms / kg ) and pinacidil ( 3 - 100 micrograms / kg ) on large ( circumflex artery ) and small coronary arteries and on systemic hemodynamics were investigated in chronically instrumented conscious dogs and compared to those of nitroglycerin ( 0 . 03 - 10 micrograms / kg ) . Nitroglycerin , up to 0 . 3 micrograms / kg , selectively increased circumflex artery diameter ( CxAD ) without simultaneously affecting any other cardiac or systemic hemodynamic parameter . In contrast , cromakalim and pinacidil at all doses and nitroglycerin at doses higher than 0 . 3 micrograms / kg simultaneously and dose - dependently increased CxAD , coronary blood flow and heart rate and decreased coronary vascular resistance and aortic pressure . Cromakalim was approximately 8 - to 9 . 5 - fold more potent than pinacidil in increasing CxAD . Vasodilation of large and small coronary vessels and hypotension induced by cromakalim and pinacidil were not affected by prior combined beta adrenergic and muscarinic receptors blockade but drug - induced tachycardia was abolished . When circumflex artery blood flow was maintained constant , the increases in CxAD induced by cromakalim ( 10 micrograms / kg ) , pinacidil ( 30 micrograms / kg ) and nitroglycerin ( 10 micrograms / kg ) were reduced by 68 + / - 7 , 54 + / - 9 and 1 + / - 1 % , respectively . Thus , whereas nitroglycerin preferentially and flow - independently dilates large coronary arteries , cromakalim and pinacidil dilate both large and small coronary arteries and this effect is not dependent upon the simultaneous beta adrenoceptors - mediated rise in myocardial metabolic demand . Finally , two mechanisms at least , direct vasodilation and flow dependency , are involved in the cromakalim - and pinacidil - induced increase in CxAD . Mefenamic acid - induced neutropenia and renal failure in elderly females with hypothyroidism . We report mefenamic acid - induced non - oliguric renal failure and severe neutropenia occurring simultaneously in two elderly females . The neutropenia was due to maturation arrest of the myeloid series in one patient . Both patients were also hypothyroid , but it is not clear whether this was a predisposing factor to the development of these adverse reactions . However , it would seem prudent not to use mefenamic acid in hypothyroid patients until the hypothyroidism has been corrected . Etiology of hypercalcemia in hemodialysis patients on calcium carbonate therapy . Fourteen of 39 dialysis patients ( 36 % ) became hypercalcemic after switching to calcium carbonate as their principal phosphate binder . In order to identify risk factors associated with the development of hypercalcemia , indirect parameters of intestinal calcium reabsorption and bone turnover rate in these 14 patients were compared with results in 14 eucalcemic patients matched for age , sex , length of time on dialysis , and etiology of renal disease . In addition to experiencing hypercalcemic episodes with peak calcium values of 2 . 7 to 3 . 8 mmol / L ( 10 . 7 to 15 . 0 mg / dL ) , patients in the hypercalcemic group exhibited a significant increase in the mean calcium concentration obtained during 6 months before the switch , compared with the mean value obtained during the 7 months of observation after the switch ( 2 . 4 + / - 0 . 03 to 2 . 5 + / - 0 . 03 mmol / L [ 9 . 7 + / - 0 . 2 to 10 . 2 + / - 0 . 1 mg / dL ] , P = 0 . 006 ) . In contrast , eucalcemic patients exhibited no change in mean calcium values over the same time period ( 2 . 3 + / - 0 . 05 to 2 . 3 + / - 0 . 05 mmol / L [ 9 . 2 + / - 0 . 2 to 9 . 2 + / - 0 . 2 mg / dL ] ) . CaCO3 dosage , calculated dietary calcium intake , and circulating levels of vitamin D metabolites were similar in both groups . Physical activity index and predialysis serum bicarbonate levels also were similar in both groups . However , there was a significant difference in parameters reflecting bone turnover rates between groups . ( ABSTRACT TRUNCATED AT 250 WORDS ) Late - onset scleroderma renal crisis induced by tacrolimus and prednisolone : a case report . Scleroderma renal crisis ( SRC ) is a rare complication of systemic sclerosis ( SSc ) but can be severe enough to require temporary or permanent renal replacement therapy . Moderate to high dose corticosteroid use is recognized as a major risk factor for SRC . Furthermore , there have been reports of thrombotic microangiopathy precipitated by cyclosporine in patients with SSc . In this article , we report a patient with SRC induced by tacrolimus and corticosteroids . The aim of this work is to call attention to the risk of tacrolimus use in patients with SSc . Methyldopa - induced hemolytic anemia in a 15 year old presenting as near - syncope . Methyldopa is an antihypertensive medication which is available generically and under the trade name Aldomet that is widely prescribed in the adult population and infrequently used in children . Methyldopa causes an autoimmune hemolytic anemia in a small percentage of patients who take the drug . We report a case of methyldopa - induced hemolytic anemia in a 15 - year - old boy who presented to the emergency department with near - syncope . The boy had been treated with intravenous methyldopa during a trauma admission seven weeks prior to presentation . Evaluation revealed a hemoglobin of three grams , 3 + Coombs ' test with polyspecific anti - human globulin and monospecific IgG reagents , and a warm reacting autoantibody . Transfusion and corticosteroid therapy resulted in a complete recovery of the patient . Emergency physicians treating children must be aware of this syndrome in order to diagnose and treat it correctly . A brief review of autoimmune and drug - induced hemolytic anemias is provided . The risk and associated factors of methamphetamine psychosis in methamphetamine - dependent patients in Malaysia . OBJECTIVE : The objective of this study was to determine the risk of lifetime and current methamphetamine - induced psychosis in patients with methamphetamine dependence . The association between psychiatric co - morbidity and methamphetamine - induced psychosis was also studied . METHODS : This was a cross - sectional study conducted concurrently at a teaching hospital and a drug rehabilitation center in Malaysia . Patients with the diagnosis of methamphetamine based on DSM - IV were interviewed using the Mini International Neuropsychiatric Interview ( M . I . N . I . ) for methamphetamine - induced psychosis and other Axis I psychiatric disorders . The information on sociodemographic background and drug use history was obtained from interview or medical records . RESULTS : Of 292 subjects , 47 . 9 % of the subjects had a past history of psychotic symptoms and 13 . 0 % of the patients were having current psychotic symptoms . Co - morbid major depressive disorder ( OR = 7 . 18 , 95 CI = 2 . 612 - 19 . 708 ) , bipolar disorder ( OR = 13 . 807 , 95 CI = 5 . 194 - 36 . 706 ) , antisocial personality disorder ( OR = 12 . 619 , 95 CI = 6 . 702 - 23 . 759 ) and heavy methamphetamine uses were significantly associated with lifetime methamphetamine - induced psychosis after adjusted for other factors . Major depressive disorder ( OR = 2 . 870 , CI = 1 . 154 - 7 . 142 ) and antisocial personality disorder ( OR = 3 . 299 , 95 CI = 1 . 375 - 7 . 914 ) were the only factors associated with current psychosis . CONCLUSION : There was a high risk of psychosis in patients with methamphetamine dependence . It was associated with co - morbid affective disorder , antisocial personality , and heavy methamphetamine use . It is recommended that all cases of methamphetamine dependence should be screened for psychotic symptoms . Cerebellar sensory processing alterations impact motor cortical plasticity in Parkinson ' s disease : clues from dyskinetic patients . The plasticity of primary motor cortex ( M1 ) in patients with Parkinson ' s disease ( PD ) and levodopa - induced dyskinesias ( LIDs ) is severely impaired . We recently reported in young healthy subjects that inhibitory cerebellar stimulation enhanced the sensorimotor plasticity of M1 that was induced by paired associative stimulation ( PAS ) . This study demonstrates that the deficient sensorimotor M1 plasticity in 16 patients with LIDs could be reinstated by a single session of real inhibitory cerebellar stimulation but not sham stimulation . This was evident only when a sensory component was involved in the induction of plasticity , indicating that cerebellar sensory processing function is involved in the resurgence of M1 plasticity . The benefit of inhibitory cerebellar stimulation on LIDs is known . To explore whether this benefit is linked to the restoration of sensorimotor plasticity of M1 , we conducted an additional study looking at changes in LIDs and PAS - induced plasticity after 10 sessions of either bilateral , real inhibitory cerebellar stimulation or sham stimulation . Only real and not sham stimulation had an antidyskinetic effect and it was paralleled by a resurgence in the sensorimotor plasticity of M1 . These results suggest that alterations in cerebellar sensory processing function , occurring secondary to abnormal basal ganglia signals reaching it , may be an important element contributing to the maladaptive sensorimotor plasticity of M1 and the emergence of abnormal involuntary movements . The long - term safety of danazol in women with hereditary angioedema . Although the short - term safety ( less than or equal to 6 months ) of danazol has been established in a variety of settings , no information exists as to its long - term safety . We therefore investigated the long - term safety of danazol by performing a retrospective chart review of 60 female patients with hereditary angioedema treated with danazol for a continuous period of 6 months or longer . The mean age of the patients was 35 . 2 years and the mean duration of therapy was 59 . 7 months . Virtually all patients experienced one or more adverse reactions . Menstrual abnormalities ( 79 % ) , weight gain ( 60 % ) , muscle cramps / myalgias ( 40 % ) , and transaminase elevations ( 40 % ) were the most common adverse reactions . The drug was discontinued due to adverse reactions in 8 patients . No patient has died or suffered any apparent long - term sequelae that were directly attributable to the drug . We conclude that , despite a relatively high incidence of adverse reactions , danazol has proven to be remarkably safe over the long - term in this group of patients . The function of P2X3 receptor and NK1 receptor antagonists on cyclophosphamide - induced cystitis in rats . PURPOSE : The purpose of the study is to explore the function of P2X3 and NK1 receptors antagonists on cyclophosphamide ( CYP ) - induced cystitis in rats . METHODS : Sixty female Sprague - Dawley ( SD ) rats were randomly divided into three groups . The rats in the control group were intraperitoneally ( i . p . ) injected with 0 . 9 % saline ( 4 ml / kg ) ; the rats in the model group were i . p . injected with CYP ( 150 mg / kg ) ; and the rats in the intervention group were i . p . injected with CYP with subsequently perfusion of bladder with P2X3 and NK1 receptors ' antagonists , Suramin and GR 82334 . Spontaneous pain behaviors following the administration of CYP were observed . Urodynamic parameters , bladder pressure - volume curve , maximum voiding pressure ( MVP ) , and maximum cystometric capacity ( MCC ) , were recorded . Pathological changes in bladder tissue were observed . Immunofluorescence was used to detect the expression of P2X3 and NK1 receptors in bladder . RESULTS : Cyclophosphamide treatment increased the spontaneous pain behaviors scores . The incidence of bladder instability during urine storage period of model group was significantly higher than intervention group ( X ( 2 ) = 7 . 619 , P = 0 . 007 ) and control group ( X ( 2 ) = 13 . 755 , P = 0 . 000 ) . MCC in the model group was lower than the control and intervention groups ( P < 0 . 01 ) . Histological changes evident in model and intervention groups rats ' bladder included edema , vasodilation , and infiltration of inflammatory cells . In model group , the expression of P2X3 receptor increased in urothelium and suburothelium , and NK1 receptor increased in suburothelium , while the expression of them in intervention group was lower . CONCLUSIONS : In CYP - induced cystitis , the expression of P2X3 and NK1 receptors increased in urothelium and / or suburothelium . Perfusion of bladder with P2X3 and NK1 receptors antagonists ameliorated the bladder function . Patient tolerance study of topical chlorhexidine diphosphanilate : a new topical agent for burns . Effective topical antimicrobial agents decrease infection and mortality in burn patients . Chlorhexidine phosphanilate ( CHP ) , a new broad - spectrum antimicrobial agent , has been evaluated as a topical burn wound dressing in cream form , but preliminary clinical trials reported that it was painful upon application . This study compared various concentrations of CHP to determine if a tolerable concentration could be identified with retention of antimicrobial efficacy . Twenty - nine burn patients , each with two similar burns which could be separately treated , were given pairs of treatments at successive 12 - h intervals over a 3 - day period . One burn site was treated with each of four different CHP concentrations , from 0 . 25 per cent to 2 per cent , their vehicle , and 1 per cent silver sulphadiazine ( AgSD ) cream , an antimicrobial agent frequently used for topical treatment of burn wounds . The other site was always treated with AgSD cream . There was a direct relationship between CHP concentration and patients ' ratings of pain on an analogue scale . The 0 . 25 per cent CHP cream was closest to AgSD in pain tolerance ; however , none of the treatments differed statistically from AgSD or from each other . In addition , ease of application of CHP creams was less satisfactory than that of AgSD . It was concluded that formulations at or below 0 . 5 per cent CHP may prove acceptable for wound care , but the vehicle system needs pharmaceutical improvement to render it more tolerable and easier to use . Acute hepatitis associated with clopidogrel : a case report and review of the literature . Drug - induced hepatotoxicity is a common cause of acute hepatitis , and the recognition of the responsible drug may be difficult . We describe a case of clopidogrel - related acute hepatitis . The diagnosis is strongly suggested by an accurate medical history and liver biopsy . Reports about cases of hepatotoxicity due to clopidogrel are increasing in the last few years , after the increased use of this drug . In conclusion , we believe that physicians should carefully consider the risk of drug - induced hepatic injury when clopidogrel is prescribed . Bortezomib and dexamethasone as salvage therapy in patients with relapsed / refractory multiple myeloma : analysis of long - term clinical outcomes . Bortezomib ( bort ) - dexamethasone ( dex ) is an effective therapy for relapsed / refractory ( R / R ) multiple myeloma ( MM ) . This retrospective study investigated the combination of bort ( 1 . 3 mg / m ( 2 ) on days 1 , 4 , 8 , and 11 every 3 weeks ) and dex ( 20 mg on the day of and the day after bort ) as salvage treatment in 85 patients with R / R MM after prior autologous stem cell transplantation or conventional chemotherapy . The median number of prior lines of therapy was 2 . Eighty - seven percent of the patients had received immunomodulatory drugs included in some line of therapy before bort - dex . The median number of bort - dex cycles was 6 , up to a maximum of 12 cycles . On an intention - to - treat basis , 55 % of the patients achieved at least partial response , including 19 % CR and 35 % achieved at least very good partial response . Median durations of response , time to next therapy and treatment - free interval were 8 , 11 . 2 , and 5 . 1 months , respectively . The most relevant adverse event was peripheral neuropathy , which occurred in 78 % of the patients ( grade II , 38 % ; grade III , 21 % ) and led to treatment discontinuation in 6 % . With a median follow up of 22 months , median time to progression , progression - free survival ( PFS ) and overall survival ( OS ) were 8 . 9 , 8 . 7 , and 22 months , respectively . Prolonged PFS and OS were observed in patients achieving CR and receiving bort - dex a single line of prior therapy . Bort - dex was an effective salvage treatment for MM patients , particularly for those in first relapse . Pubertal exposure to Bisphenol A increases anxiety - like behavior and decreases acetylcholinesterase activity of hippocampus in adult male mice . The negative effects of Bisphenol A ( BPA ) on neurodevelopment and behaviors have been well established . Acetylcholinesterase ( AChE ) is a regulatory enzyme which is involved in anxiety - like behavior . This study investigated behavioral phenotypes and AChE activity in male mice following BPA exposure during puberty . On postnatal day ( PND ) 35 , male mice were exposed to 50mg BPA / kg diet per day for a period of 35 days . On PND71 , a behavioral assay was performed using the elevated plus maze ( EPM ) and the light / dark test . In addition , AChE activity was measured in the prefrontal cortex , hypothalamus , cerebellum and hippocampus . Results from our behavioral phenotyping indicated that anxiety - like behavior was increased in mice exposed to BPA . AChE activity was significantly decreased in the hippocampus of mice with BPA compared to control mice , whereas no difference was found in the prefrontal cortex , hypothalamus and cerebellum . Our findings showed that pubertal BPA exposure increased anxiety - like behavior , which may be associated with decreased AChE activity of the hippocampus in adult male mice . Further studies are necessary to investigate the cholinergic signaling of the hippocampus in PBE induced anxiety - like behaviors . Biochemical effects of Solidago virgaurea extract on experimental cardiotoxicity . Cardiovascular diseases ( CVDs ) are the major health problem of advanced as well as developing countries of the world . The aim of the present study was to investigate the protective effect of the Solidago virgaurea extract on isoproterenol - induced cardiotoxicity in rats . The subcutaneous injection of isoproterenol ( 30 mg / kg ) into rats twice at an interval of 24 h , for two consecutive days , led to a significant increase in serum lactate dehydrogenase , creatine phosphokinase , alanine transaminase , aspartate transaminase , and angiotensin - converting enzyme activities , total cholesterol , triglycerides , free serum fatty acid , cardiac tissue malondialdehyde ( MDA ) , and nitric oxide levels and a significant decrease in levels of glutathione and superoxide dismutase in cardiac tissue as compared to the normal control group ( P < 0 . 05 ) . Pretreatment with S . virgaurea extract for 5 weeks at a dose of 250 mg / kg followed by isoproterenol injection significantly prevented the observed alterations . Captopril ( 50 mg / kg / day , given orally ) , an inhibitor of angiotensin - converting enzyme used as a standard cardioprotective drug , was used as a positive control in this study . The data of the present study suggest that S . virgaurea extract exerts its protective effect by decreasing MDA level and increasing the antioxidant status in isoproterenol - treated rats . The study emphasizes the beneficial action of S . virgaurea extract as a cardioprotective agent . " Real - world " data on the efficacy and safety of lenalidomide and dexamethasone in patients with relapsed / refractory multiple myeloma who were treated according to the standard clinical practice : a study of the Greek Myeloma Study Group . Lenalidomide and dexamethasone ( RD ) is a standard of care for relapsed / refractory multiple myeloma ( RRMM ) , but there is limited published data on its efficacy and safety in the " real world " ( RW ) , according to the International Society of Pharmacoeconomics and Outcomes Research definition . We studied 212 RRMM patients who received RD in RW . Objective response ( > PR ( partial response ) ) rate was 77 . 4 % ( complete response ( CR ) , 20 . 2 % ) . Median time to first and best response was 2 and 5 months , respectively . Median time to CR when RD was given as 2nd or > 2 ( nd ) - line treatment at 4 and 11 months , respectively . Quality of response was independent of previous lines of therapies or previous exposure to thalidomide or bortezomib . Median duration of response was 34 . 4 months , and it was higher in patients who received RD until progression ( not reached versus 19 months , p < 0 . 001 ) . Improvement of humoral immunity occurred in 60 % of responders ( p < 0 . 001 ) and in the majority of patients who achieved stable disease . Adverse events were reported in 68 . 9 % of patients ( myelosuppression in 49 . 4 % ) and 12 . 7 % of patients needed hospitalization . Peripheral neuropathy was observed only in 2 . 5 % of patients and deep vein thrombosis in 5 . 7 % . Dose reductions were needed in 31 % of patients and permanent discontinuation in 38 . 9 % . Median time to treatment discontinuation was 16 . 8 months . Performance status ( PS ) and initial lenalidomide dose predicted for treatment discontinuation . Extra - medullary relapses occurred in 3 . 8 % of patients . Our study confirms that RD is effective and safe in RRMM in the RW ; it produces durable responses especially in patients who continue on treatment till progression and improves humoral immunity even in patients with stable disease . The cytogenetic action of ifosfamide , mesna , and their combination on peripheral rabbit lymphocytes : an in vivo / in vitro cytogenetic study . Ifosfamide ( IFO ) is an alkylating nitrogen mustard , administrated as an antineoplasmic agent . It is characterized by its intense urotoxic action , leading to hemorrhagic cystitis . This side effect of IFO raises the requirement for the co - administration with sodium 2 - sulfanylethanesulfonate ( Mesna ) aiming to avoid or minimize this effect . IFO and Mesna were administrated separately on rabbit ' s lymphocytes in vivo , which were later developed in vitro . Cytogenetic markers for sister chromatid exchanges ( SCEs ) , proliferation rate index ( PRI ) and Mitotic Index were recorded . Mesna ' s action , in conjunction with IFO reduces the frequency of SCEs , in comparison with the SCEs recordings obtained when IFO is administered alone . In addition to this , when high concentrations of Mesna were administered alone significant reductions of the PRI were noted , than with IFO acting at the same concentration on the lymphocytes . Mesna significantly reduces IFO ' s genotoxicity , while when administered in high concentrations it acts in an inhibitory fashion on the cytostatic action of the drug . Risk factors and predictors of levodopa - induced dyskinesia among multiethnic Malaysians with Parkinson ' s disease . Chronic pulsatile levodopa therapy for Parkinson ' s disease ( PD ) leads to the development of motor fluctuations and dyskinesia . We studied the prevalence and predictors of levodopa - induced dyskinesia among multiethnic Malaysian patients with PD . METHODS : This is a cross - sectional study involving 95 patients with PD on uninterrupted levodopa therapy for at least 6 months . The instrument used was the UPDRS questionnaires . The predictors of dyskinesia were determined using multivariate logistic regression analysis . RESULTS : The mean age was 65 . 6 + 8 . 5 years . The mean onset age was 58 . 5 + 9 . 8 years . The median disease duration was 6 ( 7 ) years . Dyskinesia was present in 44 % ( n = 42 ) with median levodopa therapy of 3 years . There were 64 . 3 % Chinese , 31 % Malays , and 3 . 7 % Indians and other ethnic groups . Eighty - one percent of patients with dyskinesia had clinical fluctuations . Patients with dyskinesia had lower onset age ( p < 0 . 001 ) , longer duration of levodopa therapy ( p < 0 . 001 ) , longer disease duration ( p < 0 . 001 ) , higher total daily levodopa dose ( p < 0 . 001 ) , and higher total UPDRS scores ( p = 0 . 005 ) than patients without dyskinesia . The three significant predictors of dyskinesia were duration of levodopa therapy , onset age , and total daily levodopa dose . CONCLUSIONS : The prevalence of levodopa - induced dyskinesia in our patients was 44 % . The most significant predictors were duration of levodopa therapy , total daily levodopa dose , and onset age . Dose - dependent neurotoxicity of high - dose busulfan in children : a clinical and pharmacological study . Busulfan is known to be neurotoxic in animals and humans , but its acute neurotoxicity remains poorly characterized in children . We report here a retrospective study of 123 children ( median age , 6 . 5 years ) receiving high - dose busulfan in combined chemotherapy before bone marrow transplantation for malignant solid tumors , brain tumors excluded . Busulfan was given p . o . , every 6 hours for 16 doses over 4 days . Two total doses were consecutively used : 16 mg / kg , then 600 mg / m2 . The dose calculation on the basis of body surface area results in higher doses in young children than in older patients ( 16 to 28 mg / kg ) . Ninety - six patients were not given anticonvulsive prophylaxis ; 7 ( 7 . 5 % ) developed seizures during the 4 days of the busulfan course or within 24 h after the last dosing . When the total busulfan dose was taken into account , there was a significant difference in terms of neurotoxicity incidence among patients under 16 mg / kg ( 1 of 57 , 1 . 7 % ) and patients under 600 mg / m2 ( 6 of 39 , 15 . 4 % ) ( P less than 0 . 02 ) . Twenty - seven patients were given a 600 - mg / m2 busulfan total dose with continuous i . v . infusion of clonazepam ; none had any neurological symptoms . Busulfan levels were measured by a gas chromatographic - mass spectrometry assay in the plasma and cerebrospinal fluid of 9 children without central nervous system disease under 600 mg / m2 busulfan with clonazepam : busulfan cerebrospinal fluid : plasma ratio was 1 . 39 . This was significantly different ( P less than 0 . 02 ) from the cerebrospinal fluid : plasma ratio previously defined in children receiving a 16 - mg / kg total dose of busulfan . This study shows that busulfan neurotoxicity is dose - dependent in children and efficiently prevented by clonazepam . A busulfan dose calculated on the basis of body surface area , resulting in higher doses in young children , was followed by increased neurotoxicity , close to neurotoxicity incidence observed in adults . Since plasma pharmacokinetic studies showed a faster busulfan clearance in children than in adults , this new dose may approximate more closely the adult systemic exposure obtained after the usual 16 - mg / kg total dose , with potential inferences in terms of anticancer or myeloablative effects . The busulfan dose in children and infants undergoing bone marrow transplantation should be reconsidered on the basis of pharmacokinetic studies . An unexpected diagnosis in a renal - transplant patient with proteinuria treated with everolimus : AL amyloidosis . Proteinuria is an expected complication in transplant patients treated with mammalian target of rapamycin inhibitors ( mTOR - i ) . However , clinical suspicion should always be supported by histological evidence in order to investigate potential alternate diagnoses such as acute or chronic rejection , interstitial fibrosis and tubular atrophy , or recurrent or de novo glomerulopathy . In this case we report the unexpected diagnosis of amyloidosis in a renal - transplant patient with pre - transplant monoclonal gammapathy of undetermined significance who developed proteinuria after conversion from tacrolimus to everolimus . Long - term oral galactose treatment prevents cognitive deficits in male Wistar rats treated intracerebroventricularly with streptozotocin . Basic and clinical research has demonstrated that dementia of sporadic Alzheimer ' s disease ( sAD ) type is associated with dysfunction of the insulin - receptor ( IR ) system followed by decreased glucose transport via glucose transporter GLUT4 and decreased glucose metabolism in brain cells . An alternative source of energy is d - galactose ( the C - 4 - epimer of d - glucose ) which is transported into the brain by insulin - independent GLUT3 transporter where it might be metabolized to glucose via the Leloir pathway . Exclusively parenteral daily injections of galactose induce memory deterioration in rodents and are used to generate animal aging model , but the effects of oral galactose treatment on cognitive functions have never been tested . We have investigated the effects of continuous daily oral galactose ( 200 mg / kg / day ) treatment on cognitive deficits in streptozotocin - induced ( STZ - icv ) rat model of sAD , tested by Morris Water Maze and Passive Avoidance test , respectively . One month of oral galactose treatment initiated immediately after the STZ - icv administration , successfully prevented development of the STZ - icv - induced cognitive deficits . Beneficial effect of oral galactose was independent of the rat age and of the galactose dose ranging from 100 to 300 mg / kg / day . Additionally , oral galactose administration led to the appearance of galactose in the blood . The increase of galactose concentration in the cerebrospinal fluid was several times lower after oral than after parenteral administration of the same galactose dose . Oral galactose exposure might have beneficial effects on learning and memory ability and could be worth investigating for improvement of cognitive deficits associated with glucose hypometabolism in AD . An investigation of the pattern of kidney injury in HIV - positive persons exposed to tenofovir disoproxil fumarate : an examination of a large population database ( MHRA database ) . The potential for tenofovir to cause a range of kidney syndromes has been established from mechanistic and randomised clinical trials . However , the exact pattern of kidney involvement is still uncertain . We undertook a descriptive analysis of Yellow Card records of 407 HIV - positive persons taking tenofovir disoproxil fumarate ( TDF ) as part of their antiretroviral therapy regimen and submitted to the Medicines and Healthcare Products Regulatory Agency ( MHRA ) with suspected kidney adverse effects . Reports that satisfy defined criteria were classified as acute kidney injury , kidney tubular dysfunction and Fanconi syndrome . Of the 407 Yellow Card records analysed , 106 satisfied criteria for TDF - related kidney disease , of which 53 ( 50 % ) had features of kidney tubular dysfunction , 35 ( 33 % ) were found to have features of glomerular dysfunction and 18 ( 17 % ) had Fanconi syndrome . The median TDF exposure was 316 days ( interquartile range 120 - 740 ) . The incidence of hospitalisation for TDF kidney adverse effects was high , particularly amongst patients with features of Fanconi syndrome . The pattern of kidney syndromes in this population series mirrors that reported in randomised clinical trials . Cessation of TDF was associated with complete restoration of kidney function in up half of the patients in this report . Incidence of postoperative delirium is high even in a population without known risk factors . PURPOSE : Postoperative delirium is a recognized complication in populations at risk . The aim of this study is to assess the prevalence of early postoperative delirium in a population without known risk factors admitted to the ICU for postoperative monitoring after elective major surgery . The secondary outcome investigated is to identify eventual independent risk factors among demographic data and anesthetic drugs used . METHODS : An observational , prospective study was conducted on a consecutive cohort of patients admitted to our ICU within and for at least 24 h after major surgical procedures . Exclusion criteria were any preexisting predisposing factor for delirium or other potentially confounding neurological dysfunctions . Patients were assessed daily using the confusion assessment method for the ICU scale for 3 days after the surgical procedure . Early postoperative delirium incidence risk factors were then assessed through three different multiple regression models . RESULTS : According to the confusion assessment method for the ICU scale , 28 % of patients were diagnosed with early postoperative delirium . The use of thiopentone was significantly associated with an eight - fold - higher risk for delirium compared to propofol ( 57 . 1 % vs . 7 . 1 % , RR = 8 . 0 , X2 = 4 . 256 ; df = 1 ; 0 . 05 < p < 0 . 02 ) . CONCLUSION : In this study early postoperative delirium was found to be a very common complication after major surgery , even in a population without known risk factors . Thiopentone was independently associated with an increase in its relative risk . A single neurotoxic dose of methamphetamine induces a long - lasting depressive - like behaviour in mice . Methamphetamine ( METH ) triggers a disruption of the monoaminergic system and METH abuse leads to negative emotional states including depressive symptoms during drug withdrawal . However , it is currently unknown if the acute toxic dosage of METH also causes a long - lasting depressive phenotype and persistent monoaminergic deficits . Thus , we now assessed the depressive - like behaviour in mice at early and long - term periods following a single high METH dose ( 30 mg / kg , i . p . ) . METH did not alter the motor function and procedural memory of mice as assessed by swimming speed and escape latency to find the platform in a cued version of the water maze task . However , METH significantly increased the immobility time in the tail suspension test at 3 and 49 days post - administration . This depressive - like profile induced by METH was accompanied by a marked depletion of frontostriatal dopaminergic and serotonergic neurotransmission , indicated by a reduction in the levels of dopamine , DOPAC and HVA , tyrosine hydroxylase and serotonin , observed at both 3 and 49 days post - administration . In parallel , another neurochemical feature of depression - - astroglial dysfunction - - was unaffected in the cortex and the striatal levels of the astrocytic protein marker , glial fibrillary acidic protein , were only transiently increased at 3 days . These findings demonstrate for the first time that a single high dose of METH induces long - lasting depressive - like behaviour in mice associated with a persistent disruption of frontostriatal dopaminergic and serotonergic homoeostasis . Linezolid - induced optic neuropathy . Many systemic antimicrobials have been implicated to cause ocular adverse effects . This is especially relevant in multidrug therapy where more than one drug can cause a similar ocular adverse effect . We describe a case of progressive loss of vision associated with linezolid therapy . A 45 - year - old male patient who was on treatment with multiple second - line anti - tuberculous drugs including linezolid and ethambutol for extensively drug - resistant tuberculosis ( XDR - TB ) presented to us with painless progressive loss of vision in both eyes . Color vision was defective and fundus examination revealed optic disc edema in both eyes . Ethambutol - induced toxic optic neuropathy was suspected and tablet ethambutol was withdrawn . Deterioration of vision occurred despite withdrawal of ethambutol . Discontinuation of linezolid resulted in marked improvement of vision . Our report emphasizes the need for monitoring of visual function in patients on long - term linezolid treatment . Resuscitation with lipid , epinephrine , or both in levobupivacaine - induced cardiac toxicity in newborn piglets . BACKGROUND : The optimal dosing regimens of lipid emulsion , epinephrine , or both are not yet determined in neonates in cases of local anaesthetic systemic toxicity ( LAST ) . METHODS : Newborn piglets received levobupivacaine until cardiovascular collapse occurred . Standard cardiopulmonary resuscitation was started and electrocardiogram ( ECG ) was monitored for ventricular tachycardia , fibrillation , or QRS prolongation . Piglets were then randomly allocated to four groups : control ( saline ) , Intralipid ( ) alone , epinephrine alone , or a combination of Intralipd plus epinephrine . Resuscitation continued for 30 min or until there was a return of spontaneous circulation ( ROSC ) accompanied by a mean arterial pressure at or superior to the baseline pressure and normal sinus rhythm for a period of 30 min . RESULTS : ROSC was achieved in only one of the control piglets compared with most of the treated piglets . Mortality was not significantly different between the three treatment groups , but was significantly lower in all the treatment groups compared with control . The number of ECG abnormalities was zero in the Intralipid only group , but 14 and 17 , respectively , in the epinephrine and epinephrine plus lipid groups ( P < 0 . 05 ) . CONCLUSIONS : Lipid emulsion with or without epinephrine , or epinephrine alone were equally effective in achieving a return to spontaneous circulation in this model of LAST . Epinephrine alone or in combination with lipid was associated with an increased number of ECG abnormalities compared with lipid emulsion alone . Incidence of heparin - induced thrombocytopenia type II and postoperative recovery of platelet count in liver graft recipients : a retrospective cohort analysis . BACKGROUND : Thrombocytopenia in patients with end - stage liver disease is a common disorder caused mainly by portal hypertension , low levels of thrombopoetin , and endotoxemia . The impact of immune - mediated heparin - induced thrombocytopenia type II ( HIT type II ) as a cause of thrombocytopenia after liver transplantation is not yet understood , with few literature citations reporting contradictory results . The aim of our study was to demonstrate the perioperative course of thrombocytopenia after liver transplantation and determine the occurrence of clinical HIT type II . METHOD : We retrospectively evaluated the medical records of 205 consecutive adult patients who underwent full - size liver transplantation between January 2006 and December 2010 due to end - stage or malignant liver disease . Preoperative platelet count , postoperative course of platelets , and clinical signs of HIT type II were analyzed . RESULTS : A total of 155 ( 75 . 6 % ) of 205 patients had thrombocytopenia before transplantation , significantly influenced by Model of End - Stage Liver Disease score and liver cirrhosis . The platelet count exceeded 100 , 000 / uL in most of the patients ( n = 193 ) at a medium of 7 d . Regarding HIT II , there were four ( 1 . 95 % ) patients with a background of HIT type II . CONCLUSIONS : The incidence of HIT in patients with end - stage hepatic failure is , with about 1 . 95 % , rare . For further reduction of HIT type II , the use of intravenous heparin should be avoided and the prophylactic anticoagulation should be performed with low - molecular - weight heparin after normalization of platelet count . Takotsubo syndrome ( or apical ballooning syndrome ) secondary to Zolmitriptan . Takotsubo syndrome ( TS ) , also known as broken heart syndrome , is characterized by left ventricle apical ballooning with elevated cardiac biomarkers and electrocardiographic changes suggestive of an acute coronary syndrome ( ie , ST - segment elevation , T wave inversions , and pathologic Q waves ) . We report a case of 54 - year - old woman with medical history of mitral valve prolapse and migraines , who was admitted to the hospital for substernal chest pain and electrocardiogram demonstrated 1 / 2 mm ST - segment elevation in leads II , III , aVF , V5 , and V6 and positive troponin I . Emergent coronary angiogram revealed normal coronary arteries with moderately reduced left ventricular ejection fraction with wall motion abnormalities consistent with TS . Detailed history obtained retrospectively revealed that the patient took zolmitriptan sparingly only when she had migraines . But before this event , she was taking zolmitriptan 2 - 3 times daily for several days because of a persistent migraine headache . She otherwise reported that she is quite active , rides horses , and does show jumping without any limitations in her physical activity . There was no evidence of any recent stress or status migrainosus . Extensive literature search revealed multiple cases of coronary artery vasospasm secondary to zolmitriptan , but none of the cases were associated with TS . Depression , impulsiveness , sleep , and memory in past and present polydrug users of 3 , 4 - methylenedioxymethamphetamine ( MDMA , ecstasy ) . RATIONALE : Ecstasy ( 3 , 4 - methylenedioxymethamphetamine , MDMA ) is a worldwide recreational drug of abuse . Unfortunately , the results from human research investigating its psychological effects have been inconsistent . OBJECTIVES : The present study aimed to be the largest to date in sample size and 5HT - related behaviors ; the first to compare present ecstasy users with past users after an abstinence of 4 or more years , and the first to include robust controls for other recreational substances . METHODS : A sample of 997 participants ( 52 % male ) was recruited to four control groups ( non - drug ( ND ) , alcohol / nicotine ( AN ) , cannabis / alcohol / nicotine ( CAN ) , non - ecstasy polydrug ( PD ) ) , and two ecstasy polydrug groups ( present ( MDMA ) and past users ( EX - MDMA ) . Participants completed a drug history questionnaire , Beck Depression Inventory , Barratt Impulsiveness Scale , Pittsburgh Sleep Quality Index , and Wechsler Memory Scale - Revised which , in total , provided 13 psychometric measures . RESULTS : While the CAN and PD groups tended to record greater deficits than the non - drug controls , the MDMA and EX - MDMA groups recorded greater deficits than all the control groups on ten of the 13 psychometric measures . Strikingly , despite prolonged abstinence ( mean , 4 . 98 ; range , 4 - 9 years ) , past ecstasy users showed few signs of recovery . Compared with present ecstasy users , the past users showed no change for ten measures , increased impairment for two measures , and improvement on just one measure . CONCLUSIONS : Given this record of impaired memory and clinically significant levels of depression , impulsiveness , and sleep disturbance , the prognosis for the current generation of ecstasy users is a major cause for concern . Association of common genetic variants of HOMER1 gene with levodopa adverse effects in Parkinson ' s disease patients . Levodopa is the most effective symptomatic therapy for Parkinson ' s disease , but its chronic use could lead to chronic adverse outcomes , such as motor fluctuations , dyskinesia and visual hallucinations . HOMER1 is a protein with pivotal function in glutamate transmission , which has been related to the pathogenesis of these complications . This study investigates whether polymorphisms in the HOMER1 gene promoter region are associated with the occurrence of the chronic complications of levodopa therapy . A total of 205 patients with idiopathic Parkinson ' s disease were investigated . Patients were genotyped for rs4704559 , rs10942891 and rs4704560 by allelic discrimination with Taqman assays . The rs4704559 G allele was associated with a lower prevalence of dyskinesia ( prevalence ratio ( PR ) = 0 . 615 , 95 % confidence interval ( CI ) 0 . 426 - 0 . 887 , P = 0 . 009 ) and visual hallucinations ( PR = 0 . 515 , 95 % CI 0 . 295 - 0 . 899 , P = 0 . 020 ) . Our data suggest that HOMER1 rs4704559 G allele has a protective role for the development of levodopa adverse effects . Crocin improves lipid dysregulation in subacute diazinon exposure through ERK1 / 2 pathway in rat liver . INTRODUCTION : Diazinon Yis one of the most broadly used organophosphorus insecticides in agriculture . It has been shown that exposure to diazinon may interfere with lipid metabolism . Moreover , the hypolipidemic effect of crocin has been established . Earlier studies revealed the major role of Extracellular signal - regulated kinase ( ERK ) pathways in low - density lipoprotein receptor ( LDLr ) expression . The aim of this study was to evaluate changes in the regulation of lipid metabolism , ERK and LDLr expression in the liver of rats exposed to subacute diazinon . Furthermore ameliorating effect of crocin on diazinon induced disturbed cholesterol homeostasis was studied . METHODS : 24 Rats were divided into 4 groups and received following treatments for 4 weeks ; Corn oil ( control ) , diazinon ( 15mg / kg per day , orally ) and crocin ( 12 . 5 and 25mg / kg per day , intraperitoneally ) in combination with diazinon ( 15 mg / kg ) . The levels of cholesterol , triglyceride and LDL in blood of rats were analyzed . Moreover mRNA levels of LDLr and ERK1 / 2 as well as protein levels of total and activated forms of ERK1 / 2 in rat liver were evaluated by Western blotting and quantitative real time polymerase chain reaction analysis . RESULTS : Our data showed that subacute exposure to diazinon significantly increased concentrations of cholesterol , triglyceride and LDL . Moreover diazinon decreased ERK1 / 2 protein phosphorylation and LDLr transcript . Crocin reduced inhibition of ERK activation and diazinon - induced hyperlipemia and increased levels of LDLr transcript . CONCLUSIONS : Crocin may be considered as a novel protective agent in diazinon - induced hyperlipemia through modulating of ERK pathway and increase of LDLr expression . GEM - P chemotherapy is active in the treatment of relapsed Hodgkin lymphoma . Hodgkin lymphoma ( HL ) is a relatively chemosensitive malignancy . However , for those who relapse , high - dose chemotherapy with autologous stem cell transplant is the treatment of choice which relies on adequate disease control with salvage chemotherapy . Regimens commonly used often require inpatient administration and can be difficult to deliver due to toxicity . Gemcitabine and cisplatin have activity in HL , non - overlapping toxicity with first - line chemotherapeutics , and may be delivered in an outpatient setting . In this retrospective single - centre analysis , patients with relapsed or refractory HL treated with gemcitabine 1 , 000 mg / m ( 2 ) day ( D ) 1 , D8 and D15 ; methylprednisolone 1 , 000 mg D1 - 5 ; and cisplatin 100 mg / m ( 2 ) D15 , every 28 days ( GEM - P ) were included . Demographic , survival , response and toxicity data were recorded . Forty - one eligible patients were identified : median age 27 . One hundred and twenty - two cycles of GEM - P were administered in total ( median 3 cycles ; range 1 - 6 ) . Twenty of 41 ( 48 % ) patients received GEM - P as second - line treatment and 11 / 41 ( 27 % ) as third - line therapy . Overall response rate ( ORR ) to GEM - P in the entire cohort was 80 % ( complete response ( CR ) 37 % , partial response 44 % ) with 14 / 15 CR confirmed as a metabolic CR on PET and ORR of 85 % in the 20 second - line patients . The most common grade 3 / 4 toxicities were haematological : neutropenia 54 % and thrombocytopenia 51 % . Median follow - up from the start of GEM - P was 4 . 5 years . Following GEM - P , 5 - year progression - free survival was 46 % ( 95 % confidence interval ( CI ) , 30 - 62 % ) and 5 - year overall survival was 59 % ( 95 % CI , 43 - 74 % ) . Fourteen of 41 patients proceeded directly to autologous transplant . GEM - P is a salvage chemotherapy with relatively high response rates , leading to successful transplantation in appropriate patients , in the treatment of relapsed or refractory HL . Basal functioning of the hypothalamic - pituitary - adrenal ( HPA ) axis and psychological distress in recreational ecstasy polydrug users . RATIONALE : Ecstasy ( MDMA ) is a psychostimulant drug which is increasingly associated with psychobiological dysfunction . While some recent studies suggest acute changes in neuroendocrine function , less is known about long - term changes in HPA functionality in recreational users . OBJECTIVES : The current study is the first to explore the effects of ecstasy - polydrug use on psychological distress and basal functioning of the HPA axis through assessing the secretion of cortisol across the diurnal period . METHOD : Seventy - six participants ( 21 nonusers , 29 light ecstasy - polydrug users , 26 heavy ecstasy - polydrug users ) completed a substance use inventory and measures of psychological distress at baseline , then two consecutive days of cortisol sampling ( on awakening , 30 min post awakening , between 1400 and 1600 hours and pre bedtime ) . On day 2 , participants also attended the laboratory to complete a 20 - min multitasking stressor . RESULTS : Both user groups exhibited significantly greater levels of anxiety and depression than nonusers . On day 1 , all participants exhibited a typical cortisol profile , though light users had significantly elevated levels pre - bed . On day 2 , heavy users demonstrated elevated levels upon awakening and all ecstasy - polydrug users demonstrated elevated pre - bed levels compared to non - users . Significant between group differences were also observed in afternoon cortisol levels and in overall cortisol secretion across the day . CONCLUSIONS : The increases in anxiety and depression are in line with previous observations in recreational ecstasy - polydrug users . Dysregulated diurnal cortisol may be indicative of inappropriate anticipation of forthcoming demands and hypersecretion may lead to the increased psychological and physical morbidity associated with heavy recreational use of ecstasy . Ifosfamide related encephalopathy : the need for a timely EEG evaluation . BACKGROUND : Ifosfamide is an alkylating agent useful in the treatment of a wide range of cancers including sarcomas , lymphoma , gynecologic and testicular cancers . Encephalopathy has been reported in 10 - 40 % of patients receiving high - dose IV ifosfamide . OBJECTIVE : To highlight the role of electroencephalogram ( EEG ) in the early detection and management of ifosfamide related encephalopathy . METHODS : Retrospective chart review including clinical data and EEG recordings was done on five patients , admitted to MD Anderson Cancer Center between years 2009 and 2012 , who developed ifosfamide related acute encephalopathy . RESULTS : All five patients experienced symptoms of encephalopathy soon after ( within 12 h - 2 days ) receiving ifosfamide . Two patients developed generalized convulsions while one patient developed continuous non - convulsive status epilepticus ( NCSE ) that required ICU admission and intubation . Initial EEG showed epileptiform discharges in three patients ; run of triphasic waves in one patient and moderate degree diffuse generalized slowing . Mixed pattern with the presence of both sharps and triphasic waves were also noted . Repeat EEGs within 24 _ h of symptom onset showed marked improvement that was correlated with clinical improvement . CONCLUSIONS : Severity of ifosfamide related encephalopathy correlates with EEG changes . We suggest a timely EEG evaluation for patients receiving ifosfamide who develop features of encephalopathy . Incidence of contrast - induced nephropathy in hospitalised patients with cancer . OBJECTIVES : To determine the frequency of and possible factors related to contrast - induced nephropathy ( CIN ) in hospitalised patients with cancer . METHODS : Ninety adult patients were enrolled . Patients with risk factors for acute renal failure were excluded . Blood samples were examined the day before contrast - enhanced computed tomography ( CT ) and serially for 3 days thereafter . CIN was defined as an increase in serum creatinine ( Cr ) of 0 . 5 mg / dl or more , or elevation of Cr to 25 % over baseline . Relationships between CIN and possible risk factors were investigated . RESULTS : CIN was detected in 18 / 90 ( 20 % ) patients . CIN developed in 25 . 5 % patients who underwent chemotherapy and in 11 % patients who did not ( P = 0 . 1 ) . CIN more frequently developed in patients who had undergone CT within 45 days after the last chemotherapy ( P = 0 . 005 ) ; it was also an independent risk factor ( P = 0 . 017 ) . CIN was significantly more after treatment with bevacizumab / irinotecan ( P = 0 . 021 ) and in patients with hypertension ( P = 0 . 044 ) . CONCLUSIONS : The incidence of CIN after CT in hospitalised oncological patients was 20 % . CIN developed 4 . 5 - times more frequently in patients with cancer who had undergone recent chemotherapy . Hypertension and the combination of bevacizumab / irinotecan may be additional risk factors for CIN development . KEY POINTS : . Contrast - induced nephropathy ( CIN ) is a concern for oncological patients undergoing CT . . CIN occurs more often when CT is performed < 45 days after chemotherapy . . Hypertension and treatment with bevacizumab appear to be additional risk factors . Syndrome of inappropriate antidiuretic hormone secretion associated with desvenlafaxine . OBJECTIVE : To report a case of syndrome of inappropriate anti - diuretic hormone ( SIADH ) secretion associated with desvenlafaxine . CASE SUMMARY : A 57 - year old female with hyponatraemia . Her medications included desvenlafaxine , and symptoms included nausea , anxiety and confusion . The serum sodium at this time was 120 mmol / L , serum osmolality was 263 mosmol / kg , urine osmolality 410 mosmol / kg and urine sodium 63 mmol / L , consistent with a diagnosis of SIADH . Desvenlafaxine was ceased and fluid restriction implemented . After 4 days the sodium increased to 128 mmol / L and fluid restriction was relaxed . During her further 3 weeks inpatient admission the serum sodium ranged from 134 to 137 mmol / L during treatment with mirtazapine . DISCUSSION : SIADH has been widely reported with a range of antidepressants . This case report suggests that desvenlafaxine might cause clinically significant hyponatremia . CONCLUSIONS : Clinicians should be aware of the potential for antidepressants to cause hyponatremia , and take appropriate corrective action where necessary . Oxidative stress on cardiotoxicity after treatment with single and multiple doses of doxorubicin . The mechanism of doxorubicin ( DOX ) - induced cardiotoxicity remains controversial . Wistar rats ( n = 66 ) received DOX injections intraperitoneally and were randomly assigned to 2 experimental protocols : ( 1 ) rats were killed before ( - 24 h , n = 8 ) and 24 h after ( + 24 h , n = 8 ) a single dose of DOX ( 4 mg / kg body weight ) to determine the DOX acute effect and ( 2 ) rats ( n = 58 ) received 4 injections of DOX ( 4 mg / kg body weight / week ) and were killed before the first injection ( M0 ) and 1 week after each injection ( M1 , M2 , M3 , and M4 ) to determine the chronological effects . Animals used at M0 ( n = 8 ) were also used at moment - 24 h of acute study . Cardiac total antioxidant performance ( TAP ) , DNA damage , and morphology analyses were carried out at each time point . Single dose of DOX was associated with increased cardiac disarrangement , necrosis , and DNA damage ( strand breaks ( SBs ) and oxidized pyrimidines ) and decreased TAP . The chronological study showed an effect of a cumulative dose on body weight ( R = - 0 . 99 , p = 0 . 011 ) , necrosis ( R = 1 . 00 , p = 0 . 004 ) , TAP ( R = 0 . 95 , p = 0 . 049 ) , and DNA SBs ( R = - 0 . 95 , p = 0 . 049 ) . DNA SBs damage was negatively associated with TAP ( R = - 0 . 98 , p = 0 . 018 ) , and necrosis ( R = - 0 . 97 , p = 0 . 027 ) . Our results suggest that oxidative damage is associated with acute cardiotoxicity induced by a single dose of DOX only . Increased resistance to the oxidative stress is plausible for the multiple dose of DOX . Thus , different mechanisms may be involved in acute toxicity versus chronic toxicity . Tacrolimus - related seizure after pediatric liver transplantation - - a single - center experience . To identify the risk factors for new - onset seizures after pediatric LT and to assess their clinical implications and long - term prognosis . The clinical and laboratory data of 27 consecutive children who underwent LT from January 2007 to December 2010 in our center were analyzed retrospectively . Patients were divided into seizures group and a non - seizures group . Pre - operative , intra - operative , and post - operative data were collected . Seizures occurred in four children , an incidence of 14 . 8 % . All exhibited generalized tonic - clonic seizures within the first two wk after LT . Univariate analysis showed that the risk factors associated with seizures after pediatric LT included gender , pediatric end - stage liver disease score before surgery , Child - Pugh score before surgery , serum total bilirubin after surgery , and trough TAC level . Multivariate analysis showed that trough TAC level was the only independent risk factor associated with the seizures . All children who experienced seizures survived with good graft function and remained seizure - free without anti - epileptic drugs over a mean follow - up period of 33 . 7 + 14 . 6 months . High trough TAC level was the predominant factor that contributed to seizures in the early post - operative period after pediatric LT . High PELD and Child - Pugh scores before LT and high post - operative serum Tbil may be contributory risk factors for TAC - related seizures . The flavonoid apigenin delays forgetting of passive avoidance conditioning in rats . The present experiments were performed to study the effect of the flavonoid apigenin ( 20 mg / kg intraperitoneally ( i . p . ) , 1 h before acquisition ) , on 24 h retention performance and forgetting of a step - through passive avoidance task , in young male Wistar rats . There were no differences between saline - and apigenin - treated groups in the 24 h retention trial . Furthermore , apigenin did not prevent the amnesia induced by scopolamine ( 1mg / kg , i . p . , 30 min before the acquisition ) . The saline - and apigenin - treated rats that did not step through into the dark compartment during the cut - off time ( 540 s ) were retested weekly for up to eight weeks . In the saline treated group , the first significant decline in passive avoidance response was observed at four weeks , and complete memory loss was found five weeks after the acquisition of the passive avoidance task . At the end of the experimental period , 60 % of the animals treated with apigenin still did not step through . These data suggest that 1 ) apigenin delays the long - term forgetting but did not modulate the 24 h retention of fear memory and 2 ) the obtained beneficial effect of apigenin on the passive avoidance conditioning is mediated by mechanisms that do not implicate its action on the muscarinic cholinergic system . Histamine antagonists and d - tubocurarine - induced hypotension in cardiac surgical patients . Hemodynamic effects and histamine release by bolus injection of 0 . 35 mg / kg of d - tubocurarine were studied in 24 patients . H1 - and H2 - histamine antagonists or placebo were given before dosing with d - tubocurarine in a randomized double - blind fashion to four groups : group 1 - - placebo ; group 2 - - cimetidine , 4 mg / kg , plus placebo ; group 3 - - chlorpheniramine , 0 . 1 mg / kg , plus placebo ; and group 4 - - cimetidine plus chlorpheniramine . Histamine release occurred in most patients , the highest level 2 minutes after d - tubocurarine dosing . Group 1 had a moderate negative correlation between plasma histamine change and systemic vascular resistance ( r = 0 . 58 ; P less than 0 . 05 ) not present in group 4 . Prior dosing with antagonists partially prevented the fall in systemic vascular resistance . These data demonstrate that the hemodynamic changes associated with d - tubocurarine dosing are only partially explained by histamine release . Thus prior dosing with H1 - and H2 - antagonists provides only partial protection . Cholecystokinin - octapeptide restored morphine - induced hippocampal long - term potentiation impairment in rats . Cholecystokinin - octapeptide ( CCK - 8 ) , which is a typical brain - gut peptide , exerts a wide range of biological activities on the central nervous system . We have previously reported that CCK - 8 significantly alleviated morphine - induced amnesia and reversed spine density decreases in the CA1 region of the hippocampus in morphine - treated animals . Here , we investigated the effects of CCK - 8 on long - term potentiation ( LTP ) in the lateral perforant path ( LPP ) - granule cell synapse of rat dentate gyrus ( DG ) in acute saline or morphine - treated rats . Population spikes ( PS ) , which were evoked by stimulation of the LPP , were recorded in the DG region . Acute morphine ( 30mg / kg , s . c . ) treatment significantly attenuated hippocampal LTP and CCK - 8 ( 1ug , i . c . v . ) restored the amplitude of PS that was attenuated by morphine injection . Furthermore , microinjection of CCK - 8 ( 0 . 1 and 1ug , i . c . v . ) also significantly augmented hippocampal LTP in saline - treated ( 1ml / kg , s . c . ) rats . Pre - treatment of the CCK2 receptor antagonist L - 365 , 260 ( 10ug , i . c . v ) reversed the effects of CCK - 8 , but the CCK1 receptor antagonist L - 364 , 718 ( 10ug , i . c . v ) did not . The present results demonstrate that CCK - 8 attenuates the effect of morphine on hippocampal LTP through CCK2 receptors and suggest an ameliorative function of CCK - 8 on morphine - induced memory impairment . Glial activation and post - synaptic neurotoxicity : the key events in Streptozotocin ( ICV ) induced memory impairment in rats . In the present study the role of glial activation and post synaptic toxicity in ICV Streptozotocin ( STZ ) induced memory impaired rats was explored . In experiment set up 1 : Memory deficit was found in Morris water maze test on 14 - 16 days after STZ ( ICV ; 3mg / Kg ) administration . STZ causes increased expression of GFAP , CD11b and TNF - a indicating glial activation and neuroinflammation . STZ also significantly increased the level of ROS , nitrite , Ca ( 2 + ) and reduced the mitochondrial activity in synaptosomal preparation illustrating free radical generation and excitotoxicity . Increased expression and activity of Caspase - 3 was also observed in STZ treated rat which specify apoptotic cell death in hippocampus and cortex . STZ treatment showed decrease expression of post synaptic markers CaMKIIa and PSD - 95 , while , expression of pre synaptic markers ( synaptophysin and SNAP - 25 ) remains unaltered indicating selective post synaptic neurotoxicity . Oral treatment with Memantine ( 10mg / kg ) and Ibuprofen ( 50 mg / kg ) daily for 13 days attenuated STZ induced glial activation , apoptotic cell death and post synaptic neurotoxicity in rat brain . Further , in experiment set up 2 : where memory function was not affected i . e . 7 - 9 days after STZ treatment . The level of GFAP , CD11b , TNF - a , ROS and nitrite levels were increased . On the other hand , apoptotic marker , synaptic markers , mitochondrial activity and Ca ( 2 + ) levels remained unaffected . Collective data indicates that neuroinflammatory process and oxidative stress occurs earlier to apoptosis and does not affect memory function . Present study clearly suggests that glial activation and post synaptic neurotoxicity are the key factors in STZ induced memory impairment and neuronal cell death . Comparison of effects of isotonic sodium chloride with diltiazem in prevention of contrast - induced nephropathy . INTRODUCTION AND OBJECTIVE : Contrast - induced nephropathy ( CIN ) significantly increases the morbidity and mortality of patients . The aim of this study is to investigate and compare the protective effects of isotonic sodium chloride with sodium bicarbonate infusion and isotonic sodium chloride infusion with diltiazem , a calcium channel blocker , in preventing CIN . MATERIALS AND METHODS : Our study included patients who were administered 30 - 60 mL of iodinated contrast agent for percutaneous coronary angiography ( PCAG ) , all with creatinine values between 1 . 1 and 3 . 1 mg / dL . Patients were divided into three groups and each group had 20 patients . The first group of patients was administered isotonic sodium chloride ; the second group was administered a solution that of 5 % dextrose and sodium bicarbonate , while the third group was administered isotonic sodium chloride before and after the contrast injection . The third group received an additional injection of diltiazem the day before and first 2 days after the contrast injection . All of the patients ' plasma blood urea nitrogen ( BUN ) and creatinine levels were measured on the second and seventh day after the administration of intravenous contrast material . RESULTS : The basal creatinine levels were similar for all three groups ( p > 0 . 05 ) . Among a total of 60 patients included in the study , 16 patients developed acute renal failure ( ARF ) on the second day after contrast material was injected ( 26 . 6 % ) . The number of patients who developed ARF on the second day after the injection in the first group was five ( 25 % ) , in the second group was six ( 30 % ) and the third group was five ( 25 % ) ( p > 0 . 05 ) . CONCLUSION : There was no significant difference between isotonic sodium chloride , sodium bicarbonate and isotonic sodium chloride with diltiazem application in prevention of CIN . Neurocognitive and neuroradiologic central nervous system late effects in children treated on Pediatric Oncology Group ( POG ) P9605 ( standard risk ) and P9201 ( lesser risk ) acute lymphoblastic leukemia protocols ( ACCL0131 ) : a methotrexate consequence ? A report from the Children ' s Oncology Group . Concerns about long - term methotrexate ( MTX ) neurotoxicity in the 1990s led to modifications in intrathecal ( IT ) therapy , leucovorin rescue , and frequency of systemic MTX administration in children with acute lymphoblastic leukemia . In this study , neurocognitive outcomes and neuroradiologic evidence of leukoencephalopathy were compared in children treated with intense central nervous system ( CNS ) - directed therapy ( P9605 ) versus those receiving fewer CNS - directed treatment days during intensive consolidation ( P9201 ) . A total of 66 children from 16 Pediatric Oncology Group institutions with " standard - risk " acute lymphoblastic leukemia , 1 . 00 to 9 . 99 years at diagnosis , without evidence of CNS leukemia at diagnosis were enrolled on ACCL0131 : 28 from P9201 and 38 from P9605 . Magnetic resonance imaging scans and standard neuropsychological tests were performed > 2 . 6 years after the end of treatment . Significantly more P9605 patients developed leukoencephalopathy compared with P9201 patients ( 68 % , 95 % confidence interval 49 % - 83 % vs . 22 % , 95 % confidence interval 5 % - 44 % ; P = 0 . 001 ) identified as late as 7 . 7 years after the end of treatment . Overall , 40 % of patients scored < 85 on either Verbal or Performance IQ . Children on both studies had significant attention problems , but P9605 children scored below average on more neurocognitive measures than those treated on P9201 ( 82 % , 14 / 17 measures vs . 24 % , 4 / 17 measures ) . This supports ongoing concerns about intensive MTX exposure as a major contributor to CNS late effects . Tranexamic acid overdosage - induced generalized seizure in renal failure . We report a 45 - year - old lady with chronic kidney disease stage 4 due to chronic tubulointerstial disease . She was admitted to our center for severe anemia due to menorrhagia and deterioration of renal function . She was infused three units of packed cells during a session of hemodialysis . Tranexamic acid ( TNA ) 1 g 8 - hourly was administered to her to control bleeding per vaginum . Two hours after the sixth dose of TNA , she had an episode of generalized tonic clonic convulsions . TNA was discontinued . Investigations of the patient revealed no biochemical or structural central nervous system abnormalities that could have provoked the convulsions . She did not require any further dialytic support . She had no further episodes of convulsion till dis - charge and during the two months of follow - up . Thus , the precipitating cause of convulsions was believed to be an overdose of TNA . Pre - treatment of bupivacaine - induced cardiovascular depression using different lipid formulations of propofol . BACKGROUND : Pre - treatment with lipid emulsions has been shown to increase lethal doses of bupivacaine , and the lipid content of propofol may alleviate bupivacaine - induced cardiotoxicity . The aim of this study is to investigate the effects of propofol in intralipid or medialipid emulsions on bupivacaine - induced cardiotoxicity . METHODS : Rats were anaesthetised with ketamine and were given 0 . 5 mg / kg / min propofol in intralipid ( Group P ) , propofol in medialipid ( Group L ) , or saline ( Group C ) over 20 min . Thereafter , 2 mg / kg / min bupivacaine 0 . 5 % was infused . We recorded time to first dysrhythmia occurrence , respective times to 25 % and 50 % reduction of the heart rate ( HR ) and mean arterial pressure , and time to asystole and total amount of bupivacaine consumption . Blood and tissue samples were collected following asystole . RESULTS : The time to first dysrhythmia occurrence , time to 25 % and 50 % reductions in HR , and time to asystole were longer in Group P than the other groups . The cumulative bupivacaine dose given at those time points was higher in Group P . Plasma bupivacaine levels were significantly lower in Group P than in Group C . Bupivacaine levels in the brain and heart were significantly lower in Group P and Group L than in Group C . CONCLUSION : We conclude that pre - treatment with propofol in intralipid , compared with propofol in medialipid or saline , delayed the onset of bupivacaine - induced cardiotoxic effects as well as reduced plasma bupivacaine levels . Further studies are needed to explore tissue bupivacaine levels of propofol in medialipid and adapt these results to clinical practice . Drug - Induced Acute Liver Injury Within 12 Hours After Fluvastatin Therapy . Although statins are generally well - tolerated drugs , recent cases of drug - induced liver injury associated with their use have been reported . A 52 - year - old Chinese man reported with liver damage , which appeared 12 hours after beginning treatment with fluvastatin . Patient presented with complaints of increasing nausea , anorexia , and upper abdominal pain . His laboratory values showed elevated creatine kinase and transaminases . Testing for autoantibodies was also negative . The liver biochemistries eventually normalized within 3 weeks of stopping the fluvastatin . Therefore , when prescribing statins , the possibility of hepatic damage should be taken into account . Fluconazole associated agranulocytosis and thrombocytopenia . CASE : We describe a second case of fluconazole associated agranulocytosis with thrombocytopenia and recovery upon discontinuation of therapy . The patient began to have changes in white blood cells and platelets within 48 h of administration of fluconazole and began to recover with 48 h of discontinuation . This case highlights that drug - induced blood dyscrasias can occur unexpectedly as a result of treatment with a commonly used drug thought to be " safe " . CONCLUSION : According to Naranjo ' s algorithm the likelihood that our patient ' s agranulocytosis and thrombocytopenia occurred as a result of therapy with fluconazole is probable , with a total of six points . We feel that the weight of the overall evidence of this evidence is strong . In particular the temporal relationship of bone marrow suppression to the initiation of fluconazole and the abatement of symptoms that rapidly reversed immediately following discontinuation . Two - dimensional speckle tracking echocardiography combined with high - sensitive cardiac troponin T in early detection and prediction of cardiotoxicity during epirubicine - based chemotherapy . AIMS : To investigate whether alterations of myocardial strain and high - sensitive cardiac troponin T ( cTnT ) could predict future cardiac dysfunction in patients after epirubicin exposure . METHODS : Seventy - five patients with non - Hodgkin lymphoma treated with epirubicin were studied . Blood collection and echocardiography were performed at baseline , 1 day after the third cycle , and 1 day after completion of chemotherapy . Patients were studied using echocardiography during follow - up . Global longitudinal ( GLS ) , circumferential ( GCS ) , and radial strain ( GRS ) were calculated using speckle tracking echocardiography . Left ventricular ejection fraction was analysed by real - time 3D echocardiography . Cardiotoxicity was defined as a reduction of the LVEF of > 5 % to < 55 % with symptoms of heart failure or an asymptomatic reduction of the LVEF of > 10 % to < 55 % . RESULTS : Fourteen patients ( 18 . 67 % ) developed cardiotoxicity after treatment . GLS ( - 18 . 48 + 1 . 72 % vs . - 15 . 96 + 1 . 6 % ) , GCS ( - 20 . 93 + 2 . 86 % vs . - 19 . 20 + 3 . 21 % ) , and GRS ( 39 . 23 + 6 . 44 % vs . 34 . 98 + 6 . 2 % ) were markedly reduced and cTnT was elevated from 0 . 0010 + 0 . 0020 to 0 . 0073 + 0 . 0038 ng / mL ( P all < 0 . 01 ) at the completion of chemotherapy compared with baseline values . A > 15 . 9 % decrease in GLS [ sensitivity , 86 % ; specificity , 75 % ; area under the curve ( AUC ) = 0 . 815 ; P = 0 . 001 ] and a > 0 . 004 ng / mL elevation in cTnT ( sensitivity , 79 % ; specificity , 64 % ; AUC = 0 . 757 ; P = 0 . 005 ) from baseline to the third cycle of chemotherapy predicted later cardiotoxicity . The decrease in GLS remained the only independent predictor of cardiotoxicity ( P = 0 . 000 ) . CONCLUSIONS : GLS combined with cTnT may provide a reliable and non - invasive method to predict cardiac dysfunction in patients receiving anthracycline - based chemotherapy . Prevention of etomidate - induced myoclonus : which is superior : Fentanyl , midazolam , or a combination ? A Retrospective comparative study . BACKGROUND : In this retrospective comparative study , we aimed to compare the effectiveness of fentanyl , midazolam , and a combination of fentanyl and midazolam to prevent etomidate - induced myoclonus . MATERIAL AND METHODS : This study was performed based on anesthesia records . Depending on the drugs that would be given before the induction of anesthesia with etomidate , the patients were separated into 4 groups : no pretreatment ( Group NP ) , fentanyl 1 ug . kg - 1 ( Group F ) , midazolam 0 . 03 mg . kg - 1 ( Group M ) , and midazolam 0 . 015 mg . kg - 1 + fentanyl 0 . 5 ug . kg - 1 ( Group FM ) . Patients who received the same anesthetic procedure were selected : 2 minutes after intravenous injections of the pretreatment drugs , anesthesia is induced with 0 . 3 mg . kg - 1 etomidate injected intravenously over a period of 20 - 30 seconds . Myoclonic movements are evaluated , which were observed and graded according to clinical severity during the 2 minutes after etomidate injection . The severity of pain due to etomidate injection , mean arterial pressure , heart rate , and adverse effects were also evaluated . RESULTS : Study results showed that myoclonus incidence was 85 % , 40 % , 70 % , and 25 % in Group NP , Group F , Group M , and Group FM , respectively , and were significantly lower in Group F and Group FM . CONCLUSIONS : We conclude that pretreatment with fentanyl or combination of fentanyl and midazolam was effective in preventing etomidate - induced myoclonus . Convulsant effect of lindane and regional brain concentration of GABA and dopamine . Lindane ( gamma - hexachlorocyclohexane ) is an organochlorine insecticide with known neurotoxic effects . Its mechanism of action is not well understood although it has been proposed that lindane acts as a non - competitive antagonist at the gamma - aminobutyric acid ( GABA ) - A receptor . We studied the effect of lindane ( 150 mg / kg ) on the GABAergic and dopaminergic systems by measuring the concentration of GABA , dopamine and its metabolites in 7 brain areas at the onset of seizures . All animals suffered tonic convulsions at 18 . 3 + / - 1 . 4 min after lindane administration . The concentration of GABA was only slightly but significantly decreased in the colliculi without modifications in the other areas . The concentration of dopamine was increased in the mesencephalon and that of its metabolite DOPAC was also increased in the mesencephalon and the striatum . Cholestatic presentation of yellow phosphorus poisoning . Yellow phosphorus , a component of certain pesticide pastes and fireworks , is well known to cause hepatotoxicity . Poisoning with yellow phosphorus classically manifests with acute hepatitis leading to acute liver failure which may need liver transplantation . We present a case of yellow phosphorus poisoning in which a patient presented with florid clinical features of cholestasis highlighting the fact that cholestasis can rarely be a presenting feature of yellow phosphorus hepatotoxicity . Vasovagal syncope and severe bradycardia following intranasal dexmedetomidine for pediatric procedural sedation . We report syncope and bradycardia in an 11 - year - old girl following administration of intranasal dexmedetomidine for sedation for a voiding cystourethrogram . Following successful completion of VCUG and a 60 - min recovery period , the patient ' s level of consciousness and vital signs returned to presedation levels . Upon leaving the sedation area , the patient collapsed , with no apparent inciting event . The patient quickly regained consciousness and no injury occurred . The primary abnormality found was persistent bradycardia , and she was admitted to the hospital for telemetric observation . The bradycardia lasted ~ 2 h , and further cardiac workup revealed no underlying abnormality . Unanticipated and previously unreported outcomes may be witnessed as we expand the use of certain sedatives to alternative routes of administration . Paradoxical severe agitation induced by add - on high - doses quetiapine in schizo - affective disorder . We report the case of a 35 - year - old patient suffering from schizo - affective disorder since the age of 19 years , treated by a combination of first - generation antipsychotics , zuclopenthixol ( 100 mg / day ) and lithium ( 1200 mg / day ) ( serum lithium = 0 . 85 mEq / l ) . This patient had no associated personality disorder ( particularly no antisocial disorder ) and no substance abuse disorder . Within the 48 h following the gradual introduction of quetiapine ( up to 600 mg / day ) , the patient presented severe agitation without an environmental explanation , contrasting with the absence of a history of aggressiveness or personality disorder . The diagnoses of manic shift and akathisia were dismissed . The withdrawal and the gradual reintroduction of quetiapine 2 weeks later , which led to another severe agitation , enabled us to attribute the agitation specifically to quetiapine . Antioxidant effects of bovine lactoferrin on dexamethasone - induced hypertension in rat . Dexamethasone - ( Dex - ) induced hypertension is associated with enhanced oxidative stress . Lactoferrin ( LF ) is an iron - binding glycoprotein with antihypertensive properties . In this study , we investigated the effect of chronic administration of LF on oxidative stress and hypertension upon Dex administration . Male Wistar rats were treated by Dex ( 30 u g / kg / day subcutaneously ) or saline for 14 days . Oral bovine LF ( 30 , 100 , 300 mg / kg ) was given from day 8 to 14 in a reversal study . In a prevention study , rats received 4 days of LF treatment followed by Dex and continued during the test period . Systolic blood pressure ( SBP ) was measured using tail - cuff method . Thymus weight was used as a marker of glucocorticoid activity . Plasma hydrogen peroxide ( H2O2 ) concentration and ferric reducing antioxidant power ( FRAP ) value were determined . Dexamethasone significantly increased SBP and plasma H2O2 level and decreased thymus and body weights . LF lowered ( P < 0 . 01 ) and dose dependently prevented ( P < 0 . 001 ) Dex - induced hypertension . LF prevented body weight loss and significantly reduced the elevated plasma H2O2 and increased FRAP values . Chronic administration of LF strongly reduced the blood pressure and production of ROS and improved antioxidant capacity in Dex - induced hypertension , suggesting the role of inhibition of oxidative stress as another mechanism of antihypertensive action of LF . The association between tranexamic acid and convulsive seizures after cardiac surgery : a multivariate analysis in 11 529 patients . Because of a lack of contemporary data regarding seizures after cardiac surgery , we undertook a retrospective analysis of prospectively collected data from 11 529 patients in whom cardiopulmonary bypass was used from January 2004 to December 2010 . A convulsive seizure was defined as a transient episode of disturbed brain function characterised by abnormal involuntary motor movements . Multivariate regression analysis was performed to identify independent predictors of postoperative seizures . A total of 100 ( 0 . 9 % ) patients developed postoperative convulsive seizures . Generalised and focal seizures were identified in 68 and 32 patients , respectively . The median ( IQR [ range ] ) time after surgery when the seizure occurred was 7 ( 6 - 12 [ 1 - 216 ] ) h and 8 ( 6 - 11 [ 4 - 18 ] ) h , respectively . Epileptiform findings on electroencephalography were seen in 19 patients . Independent predictors of postoperative seizures included age , female sex , redo cardiac surgery , calcification of ascending aorta , congestive heart failure , deep hypothermic circulatory arrest , duration of aortic cross - clamp and tranexamic acid . When tested in a multivariate regression analysis , tranexamic acid was a strong independent predictor of seizures ( OR 14 . 3 , 95 % CI 5 . 5 - 36 . 7 ; p < 0 . 001 ) . Patients with convulsive seizures had 2 . 5 times higher in - hospital mortality rates and twice the length of hospital stay compared with patients without convulsive seizures . Mean ( IQR [ range ] ) length of stay in the intensive care unit was 115 ( 49 - 228 [ 32 - 481 ] ) h in patients with convulsive seizures compared with 26 ( 22 - 69 [ 14 - 1080 ] ) h in patients without seizures ( p < 0 . 001 ) . Convulsive seizures are a serious postoperative complication after cardiac surgery . As tranexamic acid is the only modifiable factor , its administration , particularly in doses exceeding 80 mg . kg ( - 1 ) , should be weighed against the risk of postoperative seizures . Dysfunctional overnight memory consolidation in ecstasy users . Sleep plays an important role in the consolidation and integration of memory in a process called overnight memory consolidation . Previous studies indicate that ecstasy users have marked and persistent neurocognitive and sleep - related impairments . We extend past research by examining overnight memory consolidation among regular ecstasy users ( n = 12 ) and drug naive healthy controls ( n = 26 ) . Memory recall of word pairs was evaluated before and after a period of sleep , with and without interference prior to testing . In addition , we assessed neurocognitive performances across tasks of learning , memory and executive functioning . Ecstasy users demonstrated impaired overnight memory consolidation , a finding that was more pronounced following associative interference . Additionally , ecstasy users demonstrated impairments on tasks recruiting frontostriatal and hippocampal neural circuitry , in the domains of proactive interference memory , long - term memory , encoding , working memory and complex planning . We suggest that ecstasy - associated dysfunction in fronto - temporal circuitry may underlie overnight consolidation memory impairments in regular ecstasy users . Normoammonemic encephalopathy : solely valproate induced or multiple mechanisms ? A 77 - year - old woman presented with subacute onset progressive confusion , aggression , auditory hallucinations and delusions . In the preceding months , the patient had a number of admissions with transient unilateral hemiparesis with facial droop , and had been started on valproate for presumed hemiplegic migraine . Valproate was withdrawn soon after admission and her cognitive abilities have gradually improved over 3 months of follow - up . Valproate levels taken prior to withdrawal were subtherapeutic and the patient was normoammonaemic . EEG undertaken during inpatient stay showed changes consistent with encephalopathy , and low titre N - methyl - D - aspartate ( NMDA ) receptor antibodies were present in this patient . The possible aetiologies of valproate - induced encephalopathy and NMDA receptor - associated encephalitis present a diagnostic dilemma . We present a putative combinatorial hypothesis to explain this patient ' s symptoms . Cerebellar and oculomotor dysfunction induced by rapid infusion of pethidine . Pethidine is an opioid that gains its popularity for the effective pain control through acting on the opioid - receptors . However , rapid pain relief sometimes brings about unfavourable side effects that largely limit its clinical utility . Common side effects include nausea , vomiting and hypotension . In patients with impaired renal and liver function , and those who need long - term pain control , pethidine may cause excitatory central nervous system ( CNS ) effects through its neurotoxic metabolite , norpethidine , resulting in irritability and seizure attack . On the contrary , though not clinically apparent , pethidine potentially causes inhibitory impacts on the CNS and impairs normal cerebellar and oculomotor function in the short term . In this case report , we highlight opioid ' s inhibitory side effects on the cerebellar structure that causes dysmetria , dysarthria , reduced smooth pursuit gain and decreased saccadic velocity . Baboon syndrome induced by ketoconazole . A 27 - year - old male patient presented with a maculopapular eruption on the flexural areas and buttocks after using oral ketoconazole . The patient was diagnosed with drug - induced baboon syndrome based on his history , which included prior sensitivity to topical ketoconazole , a physical examination , and histopathological findings . Baboon syndrome is a drug - or contact allergen - related maculopapular eruption that typically involves the flexural and gluteal areas . To the best of our knowledge , this is the first reported case of ketoconazole - induced baboon syndrome in the English literature . A Case of Sudden Cardiac Death due to Pilsicainide - Induced Torsades de Pointes . An 84 - year - old male received oral pilsicainide , a pure sodium channel blocker with slow recovery kinetics , to convert his paroxysmal atrial fibrillation to a sinus rhythm ; the patient developed sudden cardiac death two days later . The Holter electrocardiogram , which was worn by chance , revealed torsade de pointes with gradually prolonged QT intervals . This drug is rapidly absorbed from the gastrointestinal tract , and most of it is excreted from the kidney . Although the patient ' s renal function was not highly impaired and the dose of pilsicainide was low , the plasma concentration of pilsicainide may have been high , which can produce torsades de pointes in the octogenarian . Although the oral administration of class IC drugs , including pilsicainide , is effective to terminate atrial fibrillation , careful consideration must be taken before giving these drugs to octogenarians . All - trans retinoic acid - induced inflammatory myositis in a patient with acute promyelocytic leukemia . All - trans retinoic acid ( ATRA ) , a component of standard therapy for acute promyelocytic leukemia ( APL ) , is associated with potentially serious but treatable adverse effects involving numerous organ systems , including rare skeletal muscle involvement . Only a handful of cases of ATRA - induced myositis in children have been reported , and none in the radiology literature . We present such a case in a 15 - year - old boy with APL , where recognition of imaging findings played a crucial role in making the diagnosis and facilitated prompt , effective treatment . Tolerability of lomustine in combination with cyclophosphamide in dogs with lymphoma . This retrospective study describes toxicity associated with a protocol of lomustine ( CCNU ) and cyclophosphamide ( CTX ) in dogs with lymphoma . CCNU was administered per os ( PO ) at a targeted dosage of 60 mg / m ( 2 ) body surface area on day 0 , CTX was administered PO at a targeted dosage of 250 mg / m ( 2 ) divided over days 0 through 4 , and all dogs received prophylactic antibiotics . Ninety treatments were given to the 57 dogs included in the study . Neutropenia was the principal toxic effect , and the overall frequency of grade 4 neutropenia after the first treatment of CCNU / CTX was 30 % ( 95 % confidence interval , 19 - 43 % ) . The mean body weight of dogs with grade 4 neutropenia ( 19 . 7 kg + 13 . 4 kg ) was significantly less than the mean body weight of dogs that did not develop grade 4 neutropenia ( 31 . 7 kg + 12 . 4 kg ; P = . 005 ) . One dog ( 3 % ) developed hematologic changes suggestive of hepatotoxicity . No dogs had evidence of either renal toxicity or hemorrhagic cystitis . Adverse gastrointestinal effects were uncommon . On the basis of the findings reported herein , a dose of 60 mg / m ( 2 ) of CCNU combined with 250 mg / m ( 2 ) of CTX ( divided over 5 days ) q 4 wk is tolerable in tumor - bearing dogs . Nelarabine neurotoxicity with concurrent intrathecal chemotherapy : Case report and review of literature . Severe nelarabine neurotoxicity in a patient who received concurrent intrathecal ( IT ) chemotherapy is reported . A 37 - year - old Caucasian woman with a history of T - cell lymphoblastic lymphoma was admitted for relapsed disease . She was originally treated with induction chemotherapy followed by an autologous transplant . She developed relapsed disease 10 months later with leukemic involvement . She was re - induced with nelarabine 1500 mg / m ( 2 ) on days 1 , 3 , and 5 with 1 dose of IT cytarabine 100 mg on day 2 as central nervous system ( CNS ) prophylaxis . At the time of treatment , she was on continuous renal replacement therapy due to sequelae of tumor lysis syndrome ( TLS ) . She tolerated therapy well , entered a complete remission , and recovered her renal function . She received a second cycle of nelarabine without additional IT prophylaxis one month later . A week after this second cycle , she noted numbness in her lower extremities . Predominantly sensory , though also motor and autonomic , peripheral neuropathy started in her feet , ascended proximally to the mid - thoracic region , and eventually included her distal upper extremities . A magnetic resonance imaging ( MRI ) of her spine demonstrated changes from C2 to C6 consistent with subacute combined degeneration . Nelarabine was felt to be the cause of her symptoms . Her neuropathy stabilized and showed slight improvement and ultimately received an unrelated , reduced - intensity allogeneic transplant while in complete remission , but relapsed disease 10 weeks later . She is currently being treated with best supportive care . To our knowledge , this is the first published case report of severe neurotoxicity caused by nelarabine in a patient who received concurrent IT chemotherapy . Valproate - induced hyperammonemic encephalopathy in a renal transplanted patient . Neurological complications after renal transplantation constitute an important cause of morbidity and mortality . Their differential diagnosis is difficult and essential for subsequent patient ' s management . Valproate - induced hyperammonemic encephalopathy is an uncommon but serious effect of valproate treatment . Here , we describe the case of a 15 - year - old girl who was on a long - term therapy with valproate due to epilepsy and revealed impaired consciousness with hyperammonemia 12 days after renal transplantation . After withdraw of valproate , patients ' symptoms resolved within 24 h . Clinicians should increase their awareness for potential complication of valproate , especially in transplanted patients . Necrotising fasciitis after bortezomib and dexamethasone - containing regimen in an elderly patient of Waldenstrom macroglobulinaemia . Bortezomib and high - dose dexamethasone - containing regimens are considered to be generally tolerable with few severe bacterial infections in patients with B - cell malignancies . However , information is limited concerning the safety of the regimen in elderly patients . We report a case of a 76 - year - old man with Waldenstrom macroglobulinaemia who suffered necrotising fasciitis without neutropenia after the combination treatment with bortezomib , high - dose dexamethasone and rituximab . Despite immediate intravenous antimicrobial therapy , he succumbed 23 h after the onset . Physicians should recognise the possibility of fatal bacterial infections related to bortezomib plus high - dose dexamethasone in elderly patients , and we believe this case warrants further investigation . An integrated characterization of serological , pathological , and functional events in doxorubicin - induced cardiotoxicity . Many efficacious cancer treatments cause significant cardiac morbidity , yet biomarkers or functional indices of early damage , which would allow monitoring and intervention , are lacking . In this study , we have utilized a rat model of progressive doxorubicin ( DOX ) - induced cardiomyopathy , applying multiple approaches , including cardiac magnetic resonance imaging ( MRI ) , to provide the most comprehensive characterization to date of the timecourse of serological , pathological , and functional events underlying this toxicity . Hannover Wistar rats were dosed with 1 . 25 mg / kg DOX weekly for 8 weeks followed by a 4 week off - dosing " recovery " period . Electron microscopy of the myocardium revealed subcellular degeneration and marked mitochondrial changes after a single dose . Histopathological analysis revealed progressive cardiomyocyte degeneration , hypertrophy / cytomegaly , and extensive vacuolation after two doses . Extensive replacement fibrosis ( quantified by Sirius red staining ) developed during the off - dosing period . Functional indices assessed by cardiac MRI ( including left ventricular ejection fraction ( LVEF ) , cardiac output , and E / A ratio ) declined progressively , reaching statistical significance after two doses and culminating in " clinical " LV dysfunction by 12 weeks . Significant increases in peak myocardial contrast enhancement and serological cardiac troponin I ( cTnI ) emerged after eight doses , importantly preceding the LVEF decline to < 50 % . Troponin I levels positively correlated with delayed and peak gadolinium contrast enhancement , histopathological grading , and diastolic dysfunction . In summary , subcellular cardiomyocyte degeneration was the earliest marker , followed by progressive functional decline and histopathological manifestations . Myocardial contrast enhancement and elevations in cTnI occurred later . However , all indices predated " clinical " LV dysfunction and thus warrant further evaluation as predictive biomarkers . Intradermal glutamate and capsaicin injections : intra - and interindividual variability of provoked hyperalgesia and allodynia . Intradermal injections of glutamate and capsaicin are attractive to use in human experimental pain models because hyperalgesia and allodynia mimic isolated aspects of clinical pain disorders . The aim of the present study was to investigate the reproducibility of these models . Twenty healthy male volunteers ( mean age 24 years ; range 18 - 38 years ) received intradermal injections of glutamate and capsaicin in the volar forearm . Magnitudes of secondary pinprick hyperalgesia and brush - evoked allodynia were investigated using von Frey filaments ( gauges 10 , 15 , 60 and 100 g ) and brush strokes . Areas of secondary hyperalgesia and allodynia were quantified immediately after injection and after 15 , 30 and 60 min . Two identical experiments separated by at least 7 days were performed . Reproducibility across and within volunteers ( inter - and intra - individual variation , respectively ) was assessed using intraclass correlation coefficient ( ICC ) and coefficient of variation ( CV ) . Secondary pinprick hyperalgesia was observed as a marked increase in the visual analogue scale ( VAS ) response to von Frey gauges 60 and 100 g ( P < 0 . 001 ) after glutamate injection . For capsaicin , secondary pinprick hyperalgesia was detected with all von Frey gauges ( P < 0 . 001 ) . Glutamate evoked reproducible VAS response to all von Frey gauges ( ICC > 0 . 60 ) and brush strokes ( ICC > 0 . 83 ) . Capsaicin injection was reproducible for secondary hyperalgesia ( ICC > 0 . 70 ) and allodynia ( ICC > 0 . 71 ) . Intra - individual variability was generally lower for the VAS response to von Frey and brush compared with areas of secondary hyperalgesia and allodynia . In conclusion , glutamate and capsaicin yield reproducible hyperalgesic and allodynic responses , and the present model is well suited for basic research , as well as for assessing the modulation of central phenomena . Ocular - specific ER stress reduction rescues glaucoma in murine glucocorticoid - induced glaucoma . Administration of glucocorticoids induces ocular hypertension in some patients . If untreated , these patients can develop a secondary glaucoma that resembles primary open - angle glaucoma ( POAG ) . The underlying pathology of glucocorticoid - induced glaucoma is not fully understood , due in part to lack of an appropriate animal model . Here , we developed a murine model of glucocorticoid - induced glaucoma that exhibits glaucoma features that are observed in patients . Treatment of WT mice with topical ocular 0 . 1 % dexamethasone led to elevation of intraocular pressure ( IOP ) , functional and structural loss of retinal ganglion cells , and axonal degeneration , resembling glucocorticoid - induced glaucoma in human patients . Furthermore , dexamethasone - induced ocular hypertension was associated with chronic ER stress of the trabecular meshwork ( TM ) . Similar to patients , withdrawal of dexamethasone treatment reduced elevated IOP and ER stress in this animal model . Dexamethasone induced the transcriptional factor CHOP , a marker for chronic ER stress , in the anterior segment tissues , and Chop deletion reduced ER stress in these tissues and prevented dexamethasone - induced ocular hypertension . Furthermore , reduction of ER stress in the TM with sodium 4 - phenylbutyrate prevented dexamethasone - induced ocular hypertension in WT mice . Our data indicate that ER stress contributes to glucocorticoid - induced ocular hypertension and suggest that reducing ER stress has potential as a therapeutic strategy for treating glucocorticoid - induced glaucoma . Effects of ginsenosides on opioid - induced hyperalgesia in mice . Opioid - induced hyperalgesia ( OIH ) is characterized by nociceptive sensitization caused by the cessation of chronic opioid use . OIH can limit the clinical use of opioid analgesics and complicate withdrawal from opioid addiction . In this study , we investigated the effects of Re , Rg1 , and Rb1 ginsenosides , the bioactive components of ginseng , on OIH . OIH was achieved in mice after subcutaneous administration of morphine for 7 consecutive days three times per day . During withdrawal ( days 8 and 9 ) , these mice were administered Re , Rg1 , or Rb1 intragastrically two times per day . On the test day ( day 10 ) , mice were subjected to the thermal sensitivity test and the acetic acid - induced writhing test . Re ( 300 mg / kg ) inhibited OIH in both the thermal sensitivity test and the acetic acid - induced writhing test . However , the Rg1 and Rb1 ginsenosides failed to prevent OIH in either test . Furthermore , Rg1 showed a tendency to aggravate OIH in the acetic acid - induced writhing test . Our data suggested that the ginsenoside Re , but not Rg1 or Rb1 , may contribute toward reversal of OIH . A comparison of severe hemodynamic disturbances between dexmedetomidine and propofol for sedation in neurocritical care patients . OBJECTIVE : Dexmedetomidine and propofol are commonly used sedatives in neurocritical care as they allow for frequent neurologic examinations . However , both agents are associated with significant hemodynamic side effects . The primary objective of this study is to compare the prevalence of severe hemodynamic effects in neurocritical care patients receiving dexmedetomidine and propofol . DESIGN : Multicenter , retrospective , propensity - matched cohort study . SETTING : Neurocritical care units at two academic medical centers with dedicated neurocritical care teams and board - certified neurointensivists . PATIENTS : Neurocritical care patients admitted between July 2009 and September 2012 were evaluated and then matched 1 : 1 based on propensity scoring of baseline characteristics . INTERVENTIONS : Continuous sedation with dexmedetomidine or propofol . MEASUREMENTS AND MAIN RESULTS : A total of 342 patients ( 105 dexmedetomidine and 237 propofol ) were included in the analysis , with 190 matched ( 95 in each group ) by propensity score . The primary outcome of this study was a composite of severe hypotension ( mean arterial pressure < 60 mm Hg ) and bradycardia ( heart rate < 50 beats / min ) during sedative infusion . No difference in the primary composite outcome in both the unmatched ( 30 % vs 30 % , p = 0 . 94 ) or matched cohorts ( 28 % vs 34 % , p = 0 . 35 ) could be found . When analyzed separately , no differences could be found in the prevalence of severe hypotension or bradycardia in either the unmatched or matched cohorts . CONCLUSIONS : Severe hypotension and bradycardia occur at similar prevalence in neurocritical care patients who receive dexmedetomidine or propofol . Providers should similarly consider the likelihood of hypotension or bradycardia before starting either sedative . Hydroxytyrosol ameliorates oxidative stress and mitochondrial dysfunction in doxorubicin - induced cardiotoxicity in rats with breast cancer . Oxidative stress is involved in several processes including cancer , aging and cardiovascular disease , and has been shown to potentiate the therapeutic effect of drugs such as doxorubicin . Doxorubicin causes significant cardiotoxicity characterized by marked increases in oxidative stress and mitochondrial dysfunction . Herein , we investigate whether doxorubicin - associated chronic cardiac toxicity can be ameliorated with the antioxidant hydroxytyrosol in rats with breast cancer . Thirty - six rats bearing breast tumors induced chemically were divided into 4 groups : control , hydroxytyrosol ( 0 . 5mg / kg , 5days / week ) , doxorubicin ( 1mg / kg / week ) , and doxorubicin plus hydroxytyrosol . Cardiac disturbances at the cellular and mitochondrial level , mitochondrial electron transport chain complexes I - IV and apoptosis - inducing factor , and oxidative stress markers have been analyzed . Hydroxytyrosol improved the cardiac disturbances enhanced by doxorubicin by significantly reducing the percentage of altered mitochondria and oxidative damage . These results suggest that hydroxytyrosol improve the mitochondrial electron transport chain . This study demonstrates that hydroxytyrosol protect rat heart damage provoked by doxorubicin decreasing oxidative damage and mitochondrial alterations . Amiodarone - induced myxoedema coma . A 62 - year - old man was found to have bradycardia , hypothermia and respiratory failure 3 weeks after initiation of amiodarone therapy for atrial fibrillation . Thyroid - stimulating hormone was found to be 168 uIU / mL ( nl . 0 . 3 - 5 uIU / mL ) and free thyroxine ( FT4 ) was < 0 . 2 ng / dL ( nl . 0 . 8 - 1 . 8 ng / dL ) . He received intravenous fluids , vasopressor therapy and stress dose steroids ; he was intubated and admitted to the intensive care unit . He received 500 ug of intravenous levothyroxine in the first 18 h of therapy , and 150 ug intravenous daily thereafter . Haemodynamic improvement , along with complete recovery of mental status , occurred after 48 h . Twelve hours after the initiation of therapy , FT4 was 0 . 96 ng / dL . The patient was maintained on levothyroxine 175 ( g POorally daily . A thyroid ultrasound showed diffuse heterogeneity . The 24 hour excretion of iodine was 3657 ( mcg ( 25 - 756 ( mcg ) . The only two cases of amiodarone - induced myxoedema coma in the literature report patient death despite supportive therapy and thyroid hormone replacement . This case represents the most thoroughly investigated case of amiodarone - induced myxoedema coma with a history significant for subclinical thyroid disease . Use of argatroban and catheter - directed thrombolysis with alteplase in an oncology patient with heparin - induced thrombocytopenia with thrombosis . PURPOSE : The case of an oncology patient who developed heparin - induced thrombocytopenia with thrombosis ( HITT ) and was treated with argatroban plus catheter - directed thrombolysis ( CDT ) with alteplase is presented . SUMMARY : A 63 - year - old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper - extremity deep venous thrombosis ( DVT ) and pulmonary embolism secondary to heparin - induced thrombocytopenia . A continuous i . v . infusion of argatroban was initiated , and the patient was managed on the general medical floor . After one week of therapy , he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava ( SVC ) syndrome . A percutaneous mechanical thrombectomy and CDT with alteplase were attempted , but the procedure was aborted due to epistaxis . The epistaxis resolved the next day , and the patient was restarted on argatroban . A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins . Postthrombectomy continuous CDT with alteplase was commenced while argatroban was withheld , and complete patency of the SVC and central veins was achieved after three days of therapy . Alteplase was discontinued , and the patient was reinitiated on argatroban ; ultimately , he was transitioned to warfarin for long - term anticoagulation . Although the patient recovered , he experienced permanent vision and hearing loss , as well as end - stage renal disease . CONCLUSION : A 63 - year - old man with renal amyloidosis and SVC syndrome secondary to HITT was successfully treated with argatroban and CDT with alteplase . Effects of dehydroepiandrosterone in amphetamine - induced schizophrenia models in mice . OBJECTIVE : To examine the effects of dehydroepiandrosterone ( DHEA ) on animal models of schizophrenia . METHODS : Seventy Swiss albino female mice ( 25 - 35 g ) were divided into 4 groups : amphetamine - free ( control ) , amphetamine , 50 , and 100 mg / kg DHEA . The DHEA was administered intraperitoneally ( ip ) for 5 days . Amphetamine ( 3 mg / kg ip ) induced hyper locomotion , apomorphine ( 1 . 5 mg / kg subcutaneously [ sc ] ) induced climbing , and haloperidol ( 1 . 5 mg / kg sc ) induced catalepsy tests were used as animal models of schizophrenia . The study was conducted at the Animal Experiment Laboratories , Department of Pharmacology , Medical School , Eskisehir Osmangazi University , Eskisehir , Turkey between March and May 2012 . Statistical analysis was carried out using Kruskal - Wallis test for hyper locomotion , and one - way ANOVA for climbing and catalepsy tests . RESULTS : In the amphetamine - induced locomotion test , there were significant increases in all movements compared with the amphetamine - free group . Both DHEA 50 mg / kg ( p < 0 . 05 ) , and 100 mg / kg ( p < 0 . 01 ) significantly decreased all movements compared with the amphetamine - induced locomotion group . There was a significant difference between groups in the haloperidol - induced catalepsy test ( p < 0 . 05 ) . There was no significant difference between groups in terms of total climbing time in the apomorphine - induced climbing test ( p > 0 . 05 ) . CONCLUSION : We observed that DHEA reduced locomotor activity and increased catalepsy at both doses , while it had no effect on climbing behavior . We suggest that DHEA displays typical neuroleptic - like effects , and may be used in the treatment of schizophrenia . Availability of human induced pluripotent stem cell - derived cardiomyocytes in assessment of drug potential for QT prolongation . Field potential duration ( FPD ) in human - induced pluripotent stem cell - derived cardiomyocytes ( hiPS - CMs ) , which can express QT interval in an electrocardiogram , is reported to be a useful tool to predict K ( + ) channel and Ca ( 2 + ) channel blocker effects on QT interval . However , there is no report showing that this technique can be used to predict multichannel blocker potential for QT prolongation . The aim of this study is to show that FPD from MEA ( Multielectrode array ) of hiPS - CMs can detect QT prolongation induced by multichannel blockers . hiPS - CMs were seeded onto MEA and FPD was measured for 2min every 10min for 30min after drug exposure for the vehicle and each drug concentration . IKr and IKs blockers concentration - dependently prolonged corrected FPD ( FPDc ) , whereas Ca ( 2 + ) channel blockers concentration - dependently shortened FPDc . Also , the multichannel blockers Amiodarone , Paroxetine , Terfenadine and Citalopram prolonged FPDc in a concentration dependent manner . Finally , the IKr blockers , Terfenadine and Citalopram , which are reported to cause Torsade de Pointes ( TdP ) in clinical practice , produced early afterdepolarization ( EAD ) . hiPS - CMs using MEA system and FPDc can predict the effects of drug candidates on QT interval . This study also shows that this assay can help detect EAD for drugs with TdP potential . Dermal developmental toxicity of N - phenylimide herbicides in rats . BACKGROUND : S - 53482 and S - 23121 are N - phenylimide herbicides and produced embryolethality , teratogenicity ( mainly ventricular septal defects and wavy ribs ) , and growth retardation in rats in conventional oral developmental toxicity studies . Our objective in this study was to investigate whether the compounds induce developmental toxicity via the dermal route , which is more relevant to occupational exposure , hence better addressing human health risks . METHODS : S - 53482 was administered dermally to rats at 30 , 100 , and 300 mg / kg during organogenesis , and S - 23121 was administered at 200 , 400 , and 800 mg / kg ( the maximum applicable dose level ) . Fetuses were obtained by a Cesarean section and examined for external , visceral , and skeletal alterations . RESULTS : Dermal exposure of rats to S - 53482 at 300 mg / kg produced patterns of developmental toxicity similar to those resulting from oral exposure . Toxicity included embryolethality , teratogenicity , and growth retardation . Dermal administration of S - 23121 at 800 mg / kg resulted in an increased incidence of embryonic death and ventricular septal defect , but retarded fetal growth was not observed as it was following oral exposure to S - 23121 . CONCLUSIONS : Based on the results , S - 53482 and S - 23121 were teratogenic when administered dermally to pregnant rats as were the compounds administered orally . Thus , investigation of the mechanism and its human relevancy become more important . Rates of Renal Toxicity in Cancer Patients Receiving Cisplatin With and Without Mannitol . BACKGROUND : Cisplatin is a widely used antineoplastic . One of the major complications of cisplatin use is dose - limiting nephrotoxicity . There are many strategies to prevent this toxicity , including the use of mannitol as a nephroprotectant in combination with hydration . OBJECTIVE : We aimed to evaluate the rates of cisplatin - induced nephrotoxicity in cancer patients receiving single - agent cisplatin with and without mannitol . METHODS : This single - center retrospective analysis was a quasi experiment created by the national mannitol shortage . Data were collected on adult cancer patients receiving single - agent cisplatin as an outpatient from January 2011 to September 2012 . The primary outcome was acute kidney injury ( AKI ) . RESULTS : We evaluated 143 patients who received single - agent cisplatin ; 97 . 2 % of patients had head and neck cancer as their primary malignancy . Patients who did not receive mannitol were more likely to develop nephrotoxicity : odds ratio [ OR ] = 2 . 646 ( 95 % CI = 1 . 008 , 6 . 944 ; P = 0 . 048 ) . Patients who received the 100 mg / m ( 2 ) dosing and patients who had a history of hypertension also had a higher likelihood of developing nephrotoxicity : OR = 11 . 494 ( 95 % CI = 4 . 149 , 32 . 258 ; P < 0 . 0001 ) and OR = 3 . 219 ( 95 % CI = 1 . 228 , 8 . 439 ; P = 0 . 017 ) , respectively . CONCLUSIONS : When limited quantities of mannitol are available , it should preferentially be given to patients at particularly high risk of nephrotoxicity . Our analysis suggests that those patients receiving the dosing schedule of 100 mg / m ( 2 ) cisplatin every 3 weeks and those with hypertension are at the greatest risk of nephrotoxicity and would benefit from the addition of mannitol . Metformin protects against seizures , learning and memory impairments and oxidative damage induced by pentylenetetrazole - induced kindling in mice . Cognitive impairment , the most common and severe comorbidity of epilepsy , greatly diminishes the quality of life . However , current therapeutic interventions for epilepsy can also cause untoward cognitive effects . Thus , there is an urgent need for new kinds of agents targeting both seizures and cognition deficits . Oxidative stress is considered to play an important role in epileptogenesis and cognitive deficits , and antioxidants have a putative antiepileptic potential . Metformin , the most commonly prescribed antidiabetic oral drug , has antioxidant properties . This study was designed to evaluate the ameliorative effects of metformin on seizures , cognitive impairment and brain oxidative stress markers observed in pentylenetetrazole - induced kindling animals . Male C57BL / 6 mice were administered with subconvulsive dose of pentylenetetrazole ( 37 mg / kg , i . p . ) every other day for 14 injections . Metformin was injected intraperitoneally in dose of 200mg / kg along with alternate - day PTZ . We found that metformin suppressed the progression of kindling , ameliorated the cognitive impairment and decreased brain oxidative stress . Thus the present study concluded that metformin may be a potential agent for the treatment of epilepsy as well as a protective medicine against cognitive impairment induced by seizures . P53 inhibition exacerbates late - stage anthracycline cardiotoxicity . AIMS : Doxorubicin ( DOX ) is an effective anti - cancer therapeutic , but is associated with both acute and late - stage cardiotoxicity . Children are particularly sensitive to DOX - induced heart failure . Here , the impact of p53 inhibition on acute vs . late - stage DOX cardiotoxicity was examined in a juvenile model . METHODS AND RESULTS : Two - week - old MHC - CB7 mice ( which express dominant - interfering p53 in cardiomyocytes ) and their non - transgenic ( NON - TXG ) littermates received weekly DOX injections for 5 weeks ( 25 mg / kg cumulative dose ) . One week after the last DOX treatment ( acute stage ) , MHC - CB7 mice exhibited improved cardiac function and lower levels of cardiomyocyte apoptosis when compared with the NON - TXG mice . Surprisingly , by 13 weeks following the last DOX treatment ( late stage ) , MHC - CB7 exhibited a progressive decrease in cardiac function and higher rates of cardiomyocyte apoptosis when compared with NON - TXG mice . p53 inhibition blocked transient DOX - induced STAT3 activation in MHC - CB7 mice , which was associated with enhanced induction of the DNA repair proteins Ku70 and Ku80 . Mice with cardiomyocyte - restricted deletion of STAT3 exhibited worse cardiac function , higher levels of cardiomyocyte apoptosis , and a greater induction of Ku70 and Ku80 in response to DOX treatment during the acute stage when compared with control animals . CONCLUSION : These data support a model wherein a p53 - dependent cardioprotective pathway , mediated via STAT3 activation , mitigates DOX - induced myocardial stress during drug delivery . Furthermore , these data suggest an explanation as to how p53 inhibition can result in cardioprotection during drug treatment and , paradoxically , enhanced cardiotoxicity long after the cessation of drug treatment . Metronidazole - induced encephalopathy : an uncommon scenario . Metronidazole can produce neurological complications although it is not a common scenario . We present a case where a patient developed features of encephalopathy following prolonged metronidazole intake . Magnetic resonance imaging ( MRI ) brain showed abnormal signal intensity involving both dentate nuclei of cerebellum and splenium of corpus callosum . The diagnosis of metronidazole toxicity was made by the MRI findings and supported clinically . Aconitine - induced Ca2 + overload causes arrhythmia and triggers apoptosis through p38 MAPK signaling pathway in rats . Aconitine is a major bioactive diterpenoid alkaloid with high content derived from herbal aconitum plants . Emerging evidence indicates that voltage - dependent Na ( + ) channels have pivotal roles in the cardiotoxicity of aconitine . However , no reports are available on the role of Ca ( 2 + ) in aconitine poisoning . In this study , we explored the importance of pathological Ca ( 2 + ) signaling in aconitine poisoning in vitro and in vivo . We found that Ca ( 2 + ) overload lead to accelerated beating rhythm in adult rat ventricular myocytes and caused arrhythmia in conscious freely moving rats . To investigate effects of aconitine on myocardial injury , we performed cytotoxicity assay in neonatal rat ventricular myocytes ( NRVMs ) , as well as measured lactate dehydrogenase level in the culture medium of NRVMs and activities of serum cardiac enzymes in rats . The results showed that aconitine resulted in myocardial injury and reduced NRVMs viability dose - dependently . To confirm the pro - apoptotic effects , we performed flow cytometric detection , cardiac histology , transmission electron microscopy and terminal deoxynucleotidyl transferase - mediated dUTP - biotin nick end labeling assay . The results showed that aconitine stimulated apoptosis time - dependently . The expression analysis of Ca ( 2 + ) handling proteins demonstrated that aconitine promoted Ca ( 2 + ) overload through the expression regulation of Ca ( 2 + ) handling proteins . The expression analysis of apoptosis - related proteins revealed that pro - apoptotic protein expression was upregulated , and anti - apoptotic protein BCL - 2 expression was downregulated . Furthermore , increased phosphorylation of MAPK family members , especially the P - P38 / P38 ratio was found in cardiac tissues . Hence , our results suggest that aconitine significantly aggravates Ca ( 2 + ) overload and causes arrhythmia and finally promotes apoptotic development via phosphorylation of P38 mitogen - activated protein kinase . Chronic treatment with metformin suppresses toll - like receptor 4 signaling and attenuates left ventricular dysfunction following myocardial infarction . Acute treatment with metformin has a protective effect in myocardial infarction by suppression of inflammatory responses due to activation of AMP - activated protein kinase ( AMPK ) . In the present study , the effect of chronic pre - treatment with metformin on cardiac dysfunction and toll - like receptor 4 ( TLR4 ) activities following myocardial infarction and their relation with AMPK were assessed . Male Wistar rats were randomly assigned to one of 5 groups ( n = 6 ) : normal control and groups were injected isoproterenol after chronic pre - treatment with 0 , 25 , 50 , or 100mg / kg of metformin twice daily for 14 days . Isoproterenol ( 100mg / kg ) was injected subcutaneously on the 13th and 14th days to induce acute myocardial infarction . Isoproterenol alone decreased left ventricular systolic pressure and myocardial contractility indexed as LVdp / dtmax and LVdp / dtmin . The left ventricular dysfunction was significantly lower in the groups treated with 25 and 50mg / kg of metformin . Metfromin markedly lowered isoproterenol - induced elevation in the levels of TLR4 mRNA , myeloid differentiation protein 88 ( MyD88 ) , tumor necrosis factor - alpha ( TNF - a ) , and interleukin 6 ( IL - 6 ) in the heart tissues . Similar changes were also seen in the serum levels of TNF - a and IL - 6 . However , the lower doses of 25 and 50mg / kg were more effective than 100mg / kg . Phosphorylated AMPKa ( p - AMPK ) in the myocardium was significantly elevated by 25mg / kg of metformin , slightly by 50mg / kg , but not by 100mg / kg . Chronic pre - treatment with metformin reduces post - myocardial infarction cardiac dysfunction and suppresses inflammatory responses , possibly through inhibition of TLR4 activities . This mechanism can be considered as a target to protect infarcted myocardium . Unusual complications of antithyroid drug therapy : four case reports and review of literature . Two cases of propylthiouracil - associated acute hepatitis , one case of fatal methimazole - associated hepatocellular necrosis and one case of propylthiouracil - associated lupus - like syndrome are described . The literature related to antithyroid drug side effects and the mechanisms for their occurrence are reviewed and the efficacy and complications of thyroidectomy and radioiodine compared to those of antithyroid drugs . It is concluded that in most circumstances 131I is the therapy of choice for hyperthyroidism . Neuroleptic malignant syndrome induced by combination therapy with tetrabenazine and tiapride in a Japanese patient with Huntington ' s disease at the terminal stage of recurrent breast cancer . We herein describe the case of an 81 - year - old Japanese woman with neuroleptic malignant syndrome that occurred 36 days after the initiation of combination therapy with tiapride ( 75 mg / day ) and tetrabenazine ( 12 . 5 mg / day ) for Huntington ' s disease . The patient had been treated with tiapride or tetrabenazine alone without any adverse effects before the administration of the combination therapy . She also had advanced breast cancer when the combination therapy was initiated . To the best of our knowledge , the occurrence of neuroleptic malignant syndrome due to combination therapy with tetrabenazine and tiapride has not been previously reported . Tetrabenazine should be administered very carefully in combination with other neuroleptic drugs , particularly in patients with a worsening general condition . A metoprolol - terbinafine combination induced bradycardia . To report a sinus bradycardia induced by metoprolol and terbinafine drug - drug interaction and its management . A 63 year - old Caucasian man on metoprolol 200 mg / day for stable coronary artery disease was prescribed a 90 - day course of oral terbinafine 250 mg / day for onychomycosis . On the 49th day of terbinafine therapy , he was brought to the emergency room for a decrease of his global health status , confusion and falls . The electrocardiogram revealed a 37 beats / min sinus bradycardia . A score of 7 on the Naranjo adverse drug reaction probability scale indicates a probable relationship between the patient ' s sinus bradycardia and the drug interaction between metoprolol and terbinafine . The heart rate ameliorated first with a decrease in the dose of metoprolol . It was subsequently changed to bisoprolol and the heart rate remained normal . By inhibiting the cytochrome P450 2D6 , terbinafine had decreased metoprolol ' s clearance , leading in metoprolol accumulation which has resulted in clinically significant sinus bradycardia . Optochiasmatic and peripheral neuropathy due to ethambutol overtreatment . Ethambutol is known to cause optic neuropathy and , more rarely , axonal polyneuropathy . We characterize the clinical , neurophysiological , and neuroimaging findings in a 72 - year - old man who developed visual loss and paresthesias after 11 weeks of exposure to a supratherapeutic dose of ethambutol . This case demonstrates the selective vulnerability of the anterior visual pathways and peripheral nerves to ethambutol toxicity . Testosterone ameliorates streptozotocin - induced memory impairment in male rats . AIM : To study the effects of testosterone on streptozotocin ( STZ ) - induced memory impairment in male rats . METHODS : Adult male Wistar rats were intracerebroventricularly ( icv ) infused with STZ ( 750 ug ) on d 1 and d 3 , and a passive avoidance task was assessed 2 weeks after the first injection of STZ . Castration surgery was performed in another group of rats , and the passive avoidance task was assessed 4 weeks after the operation . Testosterone ( 1 mg . kg ( - 1 ) . d ( - 1 ) , sc ) , the androgen receptor antagonist flutamide ( 10 mg . kg ( - 1 ) . d ( - 1 ) , ip ) , the estrogen receptor antagonist tamoxifen ( 1 mg . kg ( - 1 ) . d ( - 1 ) , ip ) or the aromatase inhibitor letrozole ( 4 mg . kg ( - 1 ) . d ( - 1 ) , ip ) were administered for 6 d after the first injection of STZ . RESULTS : STZ administration and castration markedly decreased both STL1 ( the short memory ) and STL2 ( the long memory ) in passive avoidance tests . Testosterone replacement almost restored the STL1 and STL2 in castrated rats , and significantly prolonged the STL1 and STL2 in STZ - treated rats . Administration of flutamide , letrozole or tamoxifen significantly impaired the memory in intact rats , and significantly attenuated the testosterone replacement in improving STZ - and castration - induced memory impairment . CONCLUSION : Testosterone administration ameliorates STZ - and castration - induced memory impairment in male Wistar rats . Behavioral and neurochemical studies in mice pretreated with garcinielliptone FC in pilocarpine - induced seizures . Garcinielliptone FC ( GFC ) isolated from hexanic fraction seed extract of species Platonia insignis Mart . It is widely used in folk medicine to treat skin diseases in both humans and animals as well as the seed decoction has been used to treat diarrheas and inflammatory diseases . However , there is no research on GFC effects in the central nervous system of rodents . The present study aimed to evaluate the GFC effects at doses of 25 , 50 or 75 mg / kg on seizure parameters to determine their anticonvulsant activity and its effects on amino acid ( r - aminobutyric acid ( GABA ) , glutamine , aspartate and glutathione ) levels as well as on acetylcholinesterase ( AChE ) activity in mice hippocampus after seizures . GFC produced an increased latency to first seizure , at doses 25mg / kg ( 20 . 12 + 2 . 20 min ) , 50mg / kg ( 20 . 95 + 2 . 21 min ) or 75 mg / kg ( 23 . 43 + 1 . 99 min ) when compared with seized mice . In addition , GABA content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46 . 90 % when compared with seized mice . In aspartate , glutamine and glutamate levels detected a decrease of 5 . 21 % , 13 . 55 % and 21 . 80 % , respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice . Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity ( 63 . 30 % ) when compared with seized mice . The results indicate that GFC can exert anticonvulsant activity and reduce the frequency of installation of pilocarpine - induced status epilepticus , as demonstrated by increase in latency to first seizure and decrease in mortality rate of animals . In conclusion , our data suggest that GFC may influence in epileptogenesis and promote anticonvulsant actions in pilocarpine model by modulating the GABA and glutamate contents and of AChE activity in seized mice hippocampus . This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent . Standard operating procedures for antibiotic therapy and the occurrence of acute kidney injury : a prospective , clinical , non - interventional , observational study . INTRODUCTION : Acute kidney injury ( AKI ) occurs in 7 % of hospitalized and 66 % of Intensive Care Unit ( ICU ) patients . It increases mortality , hospital length of stay , and costs . The aim of this study was to investigate , whether there is an association between adherence to guidelines ( standard operating procedures ( SOP ) ) for potentially nephrotoxic antibiotics and the occurrence of AKI . METHODS : This study was carried out as a prospective , clinical , non - interventional , observational study . Data collection was performed over a total of 170 days in three ICUs at Charite - Universitaetsmedizin Berlin . A total of 675 patients were included ; 163 of these had therapy with vancomycin , gentamicin , or tobramycin ; were > 18 years ; and treated in the ICU for > 24 hours . Patients with an adherence to SOP > 70 % were classified into the high adherence group ( HAG ) and patients with an adherence of < 70 % into the low adherence group ( LAG ) . AKI was defined according to RIFLE criteria . Adherence to SOPs was evaluated by retrospective expert audit . Development of AKI was compared between groups with exact Chi2 - test and multivariate logistic regression analysis ( two - sided P < 0 . 05 ) . RESULTS : LAG consisted of 75 patients ( 46 % ) versus 88 HAG patients ( 54 % ) . AKI occurred significantly more often in LAG with 36 % versus 21 % in HAG ( P = 0 . 035 ) . Basic characteristics were comparable , except an increased rate of soft tissue infections in LAG . Multivariate analysis revealed an odds ratio of 2 . 5 - fold for LAG to develop AKI compared with HAG ( 95 % confidence interval 1 . 195 to 5 . 124 , P = 0 . 039 ) . CONCLUSION : Low adherence to SOPs for potentially nephrotoxic antibiotics was associated with a higher occurrence of AKI . TRIAL REGISTRATION : Current Controlled Trials ISRCTN54598675 . Registered 17 August 2007 . Rhabdomyolysis in a hepatitis C virus infected patient treated with telaprevir and simvastatin . A 46 - year old man with a chronic hepatitis C virus infection received triple therapy with ribavirin , pegylated interferon and telaprevir . The patient also received simvastatin . One month after starting the antiviral therapy , the patient was admitted to the hospital because he developed rhabdomyolysis . At admission simvastatin and all antiviral drugs were discontinued because toxicity due to a drug - drug interaction was suspected . The creatine kinase peaked at 62 , 246 IU / L and the patient was treated with intravenous normal saline . The patient ' s renal function remained unaffected . Fourteen days after hospitalization , creatine kinase level had returned to 230 IU / L and the patient was discharged . Telaprevir was considered the probable causative agent of an interaction with simvastatin according to the Drug Interaction Probability Scale . The interaction is due to inhibition of CYP3A4 - mediated simvastatin clearance . Simvastatin plasma concentration increased 30 times in this patient and statin induced muscle toxicity is related to the concentration of the statin in blood . In conclusion , with this case we illustrate that telaprevir as well as statins are susceptible to clinical relevant drug - drug interactions . Combination of bortezomib , thalidomide , and dexamethasone ( VTD ) as a consolidation therapy after autologous stem cell transplantation for symptomatic multiple myeloma in Japanese patients . Consolidation therapy for patients with multiple myeloma ( MM ) has been widely adopted to improve treatment response following autologous stem cell transplantation . In this study , we retrospectively analyzed the safety and efficacy of combination regimen of bortezomib , thalidomide , and dexamethasone ( VTD ) as consolidation therapy in 24 Japanese patients with newly diagnosed MM . VTD consisted of bortezomib at a dose of 1 . 3 mg / m ( 2 ) and dexamethasone at a dose of 40 mg / day on days 1 , 8 , 15 , and 22 of a 35 - day cycle , with daily oral thalidomide at a dose of 100 mg / day . Grade 3 - 4 neutropenia and thrombocytopenia were documented in four and three patients ( 17 and 13 % ) , respectively , but drug dose reduction due to cytopenia was not required in any case . Peripheral neuropathy was common ( 63 % ) , but severe grade 3 - 4 peripheral neuropathy was not observed . Very good partial response or better response ( > VGPR ) rates before and after consolidation therapy were 54 and 79 % , respectively . Patients had a significant probability of improving from < VGPR before consolidation therapy to > VGPR after consolidation therapy ( p = 0 . 041 ) . The VTD regimen may be safe and effective as a consolidation therapy in the treatment of MM in Japanese population . Conversion to sirolimus ameliorates cyclosporine - induced nephropathy in the rat : focus on serum , urine , gene , and protein renal expression biomarkers . Protocols of conversion from cyclosporin A ( CsA ) to sirolimus ( SRL ) have been widely used in immunotherapy after transplantation to prevent CsA - induced nephropathy , but the molecular mechanisms underlying these protocols remain nuclear . This study aimed to identify the molecular pathways and putative biomarkers of CsA - to - SRL conversion in a rat model . Four animal groups ( n = 6 ) were tested during 9 weeks : control , CsA , SRL , and conversion ( CsA for 3 weeks followed by SRL for 6 weeks ) . Classical and emergent serum , urinary , and kidney tissue ( gene and protein expression ) markers were assessed . Renal lesions were analyzed in hematoxylin and eosin , periodic acid - Schiff , and Masson ' s trichrome stains . SRL - treated rats presented proteinuria and NGAL ( serum and urinary ) as the best markers of renal impairment . Short CsA treatment presented slight or even absent kidney lesions and TGF - b , NF - kb , mTOR , PCNA , TP53 , KIM - 1 , and CTGF as relevant gene and protein changes . Prolonged CsA exposure aggravated renal damage , without clear changes on the traditional markers , but with changes in serums TGF - b and IL - 7 , TBARs clearance , and kidney TGF - b and mTOR . Conversion to SRL prevented CsA - induced renal damage evolution ( absent / mild grade lesions ) , while NGAL ( serum versus urine ) seems to be a feasible biomarker of CsA replacement to SRL . Kinin B2 receptor deletion and blockage ameliorates cisplatin - induced acute renal injury . Cisplatin treatment has been adopted in some chemotherapies ; however , this drug can induce acute kidney injury due its ability to negatively affect renal function , augment serum levels of creatinine and urea , increase the acute tubular necrosis score and up - regulate cytokines ( e . g . , IL - 1b and TNF - a ) . The kinin B2 receptor has been associated with the inflammation process , as well as the regulation of cytokine expression , and its deletion resulted in an improvement in the diabetic nephropathy status . To examine the role of the kinin B2 receptor in cisplatin - induced acute kidney injury , kinin B2 receptor knockout mice were challenged with cisplatin . Additionally , WT mice were treated with a B2 receptor antagonist after cisplatin administration . B2 receptor - deficient mice were less sensitive to this drug than the WT mice , as shown by reduced weight loss , better preservation of kidney function , down regulation of inflammatory cytokines and less acute tubular necrosis . Moreover , treatment with the kinin B2 receptor antagonist effectively reduced the levels of serum creatinine and blood urea after cisplatin administration . Thus , our data suggest that the kinin B2 receptor is involved in cisplatin - induced acute kidney injury by mediating the necrotic process and the expression of inflammatory cytokines , thus resulting in declined renal function . These results highlight the kinin B2 receptor antagonist treatment in amelioration of nephrotoxicity induced by cisplatin therapy . Safety and efficacy of fluocinolone acetonide intravitreal implant ( 0 . 59 mg ) in birdshot retinochoroidopathy . PURPOSE : To report the treatment outcomes of the fluocinolone acetonide intravitreal implant ( 0 . 59 mg ) in patients with birdshot retinochoroidopathy whose disease is refractory or intolerant to conventional immunomodulatory therapy . METHODS : A retrospective case series involving 11 birdshot retinochoroidopathy patients ( 11 eyes ) . Eleven patients ( 11 eyes ) underwent surgery for fluocinolone acetonide implant ( 0 . 59 mg ) . Treatment outcomes of interest were noted at baseline , before fluocinolone acetonide implant , and then at 6 months , 1 year , 2 years , 3 years , and beyond 3 years . Disease activity markers , including signs of ocular inflammation , evidence of retinal vasculitis , Swedish interactive threshold algorithm - short wavelength automated perimetry Humphrey visual field analysis , electroretinographic parameters , and optical coherence tomography were recorded . Data on occurrence of cataract and raised intraocular pressure were collected in all eyes . RESULTS : Intraocular inflammation was present in 54 . 5 , 9 . 9 , 11 . 1 , and 0 % of patients at baseline , 6 months , 1 year , 2 years , 3 years , and beyond 3 years after receiving the implant , respectively . Active vasculitis was noted in 36 . 3 % patients at baseline and 0 % at 3 years of follow - up . More than 20 % ( 47 . 61 - 67 . 2 % ) reduction in central retinal thickness was noted in all patients with cystoid macular edema at 6 months , 1 year , 2 years , and 3 years postimplant . At baseline , 54 . 5 % patients were on immunomodulatory agents . This percentage decreased to 45 . 45 , 44 . 4 , and 14 . 28 % at 1 year , 2 years , and 3 years postimplant , respectively . Adverse events included increased intraocular pressure ( 54 . 5 % ) and cataract formation ( 100 % ) . CONCLUSION : The data suggest that fluocinolone acetonide implant ( 0 . 59 mg ) helps to control inflammation in otherwise treatment - refractory cases of birdshot retinochoroidopathy . It is associated with significant side effects of cataract and ocular hypertension requiring treatment . Optimal precurarizing dose of rocuronium to decrease fasciculation and myalgia following succinylcholine administration . BACKGROUND : Succinylcholine commonly produces frequent adverse effects , including muscle fasciculation and myalgia . The current study identified the optimal dose of rocuronium to prevent succinylcholine - induced fasciculation and myalgia and evaluated the influence of rocuronium on the speed of onset produced by succinylcholine . METHODS : This randomized , double - blinded study was conducted in 100 patients randomly allocated into five groups of 20 patients each . Patients were randomized to receive 0 . 02 , 0 . 03 , 0 . 04 , 0 . 05 and 0 . 06 mg / kg rocuronium as a precurarizing dose . Neuromuscular monitoring after each precurarizing dose was recorded from the adductor pollicis muscle using acceleromyography with train - of - four stimulation of the ulnar nerve . All patients received succinylcholine 1 . 5 mg / kg at 2 minutes after the precurarization , and were assessed the incidence and severity of fasciculations , while myalgia was assessed at 24 hours after surgery . RESULTS : The incidence and severity of visible muscle fasciculation was significantly less with increasing the amount of precurarizing dose of rocuronium ( P < 0 . 001 ) . Those of myalgia tend to decrease according to increasing the amount of precurarizing dose of rocuronium , but there was no significance ( P = 0 . 072 ) . The onset time of succinylcholine was significantly longer with increasing the amount of precurarizing dose of rocuronium ( P < 0 . 001 ) . CONCLUSIONS : Precurarization with 0 . 04 mg / kg rocuronium was the optimal dose considering the reduction in the incidence and severity of fasciculation and myalgia with acceptable onset time , and the safe and effective precurarization . Absence of PKC - alpha attenuates lithium - induced nephrogenic diabetes insipidus . Lithium , an effective antipsychotic , induces nephrogenic diabetes insipidus ( NDI ) in 40 % of patients . The decreased capacity to concentrate urine is likely due to lithium acutely disrupting the cAMP pathway and chronically reducing urea transporter ( UT - A1 ) and water channel ( AQP2 ) expression in the inner medulla . Targeting an alternative signaling pathway , such as PKC - mediated signaling , may be an effective method of treating lithium - induced polyuria . PKC - alpha null mice ( PKCa KO ) and strain - matched wild type ( WT ) controls were treated with lithium for 0 , 3 or 5 days . WT mice had increased urine output and lowered urine osmolality after 3 and 5 days of treatment whereas PKCa KO mice had no change in urine output or concentration . Western blot analysis revealed that AQP2 expression in medullary tissues was lowered after 3 and 5 days in WT mice ; however , AQP2 was unchanged in PKCa KO . Similar results were observed with UT - A1 expression . Animals were also treated with lithium for 6 weeks . Lithium - treated WT mice had 19 - fold increased urine output whereas treated PKCa KO animals had a 4 - fold increase in output . AQP2 and UT - A1 expression was lowered in 6 week lithium - treated WT animals whereas in treated PKCa KO mice , AQP2 was only reduced by 2 - fold and UT - A1 expression was unaffected . Urinary sodium , potassium and calcium were elevated in lithium - fed WT but not in lithium - fed PKCa KO mice . Our data show that ablation of PKCa preserves AQP2 and UT - A1 protein expression and localization in lithium - induced NDI , and prevents the development of the severe polyuria associated with lithium therapy . Is Dysguesia Going to be a Rare or a Common Side - effect of Amlodipine ? A very rare side - effect of amlodipine is dysguesia . A review of the literature produced only one case . We report a case about a female with essential hypertension on drug treatment with amlodipine developed loss of taste sensation . Condition moderately improved on stoppage of the drug for 25 days . We conclude that amlodipine can cause dysguesia . Here , we describe the clinical presentation and review the relevant literature on amlodipine and dysguesia . Rhabdomyolysis in association with simvastatin and dosage increment in clarithromycin . Clarithromycin is the most documented cytochrome P450 3A4 ( CYP3A4 ) inhibitor to cause an adverse interaction with simvastatin . This particular case is of interest as rhabdomyolysis only occurred after an increase in the dose of clarithromycin . The patient developed raised cardiac biomarkers without any obvious cardiac issues , a phenomenon that has been linked to rhabdomyolysis previously . To date , there has been no reported effect of rhabdomyolysis on the structure and function of cardiac muscle . Clinicians need to be aware of prescribing concomitant medications that increase the risk of myopathy or inhibit the CYP3A4 enzyme . Our case suggests that troponin elevation could be associated with statin induced rhabdomyolysis , which may warrant further studies . Characterization of a novel BCHE " silent " allele : point mutation ( p . Val204Asp ) causes loss of activity and prolonged apnea with suxamethonium . Butyrylcholinesterase deficiency is characterized by prolonged apnea after the use of muscle relaxants ( suxamethonium or mivacurium ) in patients who have mutations in the BCHE gene . Here , we report a case of prolonged neuromuscular block after administration of suxamethonium leading to the discovery of a novel BCHE variant ( c . 695T > A , p . Val204Asp ) . Inhibition studies , kinetic analysis and molecular dynamics were undertaken to understand how this mutation disrupts the catalytic triad and determines a " silent " phenotype . Low activity of patient plasma butyrylcholinesterase with butyrylthiocholine ( BTC ) and benzoylcholine , and values of dibucaine and fluoride numbers fit with heterozygous atypical silent genotype . Electrophoretic analysis of plasma BChE of the proband and his mother showed that patient has a reduced amount of tetrameric enzyme in plasma and that minor fast - moving BChE components : monomer , dimer , and monomer - albumin conjugate are missing . Kinetic analysis showed that the p . Val204Asp / p . Asp70Gly - p . Ala539Thr BChE displays a pure Michaelian behavior with BTC as the substrate . Both catalytic parameters Km = 265 uM for BTC , two times higher than that of the atypical enzyme , and a low Vmax are consistent with the absence of activity against suxamethonium . Molecular dynamic ( MD ) simulations showed that the overall effect of the mutation p . Val204Asp is disruption of hydrogen bonding between Gln223 and Glu441 , leading Ser198 and His438 to move away from each other with subsequent disruption of the catalytic triad functionality regardless of the type of substrate . MD also showed that the enzyme volume is increased , suggesting a pre - denaturation state . This fits with the reduced concentration of p . Ala204Asp / p . Asp70Gly - p . Ala539Thr tetrameric enzyme in the plasma and non - detectable fast moving - bands on electrophoresis gels . Delayed anemia after treatment with injectable artesunate in the Democratic Republic of the Congo : a manageable issue . Cases of delayed hemolytic anemia have been described after treatment with injectable artesunate , the current World Health Organization ( WHO ) - recommended first - line drug for the treatment of severe malaria . A total of 350 patients ( 215 [ 61 . 4 % ] < 5 years of age and 135 [ 38 . 6 % ] > 5 years of age ) were followed - up after treatment with injectable artesunate for severe malaria in hospitals and health centers of the Democratic Republic of the Congo . Complete series of hemoglobin ( Hb ) measurements were available for 201 patients . A decrease in Hb levels between 2 and 5 g / dL was detected in 23 ( 11 . 4 % ) patients during the follow - up period . For five patients , Hb levels decreased below 5 g / dL during at least one follow - up visit . All cases of delayed anemia were clinically manageable and resolved within one month . Regulation of signal transducer and activator of transcription 3 and apoptotic pathways by betaine attenuates isoproterenol - induced acute myocardial injury in rats . The present study was designed to investigate the cardioprotective effects of betaine on acute myocardial ischemia induced experimentally in rats focusing on regulation of signal transducer and activator of transcription 3 ( STAT3 ) and apoptotic pathways as the potential mechanism underlying the drug effect . Male Sprague Dawley rats were treated with betaine ( 100 , 200 , and 400 mg / kg ) orally for 40 days . Acute myocardial ischemic injury was induced in rats by subcutaneous injection of isoproterenol ( 85 mg / kg ) , for two consecutive days . Serum cardiac marker enzyme , histopathological variables and expression of protein levels were analyzed . Oral administration of betaine ( 200 and 400 mg / kg ) significantly reduced the level of cardiac marker enzyme in the serum and prevented left ventricular remodeling . Western blot analysis showed that isoproterenol - induced phosphorylation of STAT3 was maintained or further enhanced by betaine treatment in myocardium . Furthermore , betaine ( 200 and 400 mg / kg ) treatment increased the ventricular expression of Bcl - 2 and reduced the level of Bax , therefore causing a significant increase in the ratio of Bcl - 2 / Bax . The protective role of betaine on myocardial damage was further confirmed by histopathological examination . In summary , our results showed that betaine pretreatment attenuated isoproterenol - induced acute myocardial ischemia via the regulation of STAT3 and apoptotic pathways . Quetiapine - induced neutropenia in a bipolar patient with hepatocellular carcinoma . OBJECTIVE : Quetiapine is a dibenzothiazepine derivative , similar to clozapine , which has the highest risk of causing blood dyscrasias , especially neutropenia . There are some case reports about this side effect of quetiapine , but possible risk factors are seldom discussed and identified . A case of a patient with hepatocellular carcinoma that developed neutropenia after treatment with quetiapine is described here . CASE REPORT : A 62 - year - old Taiwanese widow with bipolar disorder was diagnosed with hepatocellular carcinoma at age 60 . She developed leucopenia after being treated with quetiapine . After quetiapine was discontinued , her white blood cell count returned to normal . CONCLUSIONS : Although neutropenia is not a common side effect of quetiapine , physicians should be cautious about its presentation and associated risk factors . Hepatic dysfunction may be one of the possible risk factors , and concomitant fever may be a diagnostic marker for adverse reaction to quetiapine . Lateral antebrachial cutaneous neuropathy after steroid injection at lateral epicondyle . BACKGROUND AND OBJECTIVES : This report aimed to present a case of lateral antebrachial cutaneous neuropathy ( LACNP ) that occurred after a steroid injection in the lateral epicondyle to treat lateral epicondylitis in a 40 - year - old woman . MATERIAL AND METHOD : A 40 - year - old woman presented with decreased sensation and paresthesia over her right lateral forearm ; the paresthesia had occurred after a steroid injection in the right lateral epicondyle 3 months before . Her sensation of light touch and pain was diminished over the lateral side of the right forearm and wrist area . RESULTS : The sensory action potential amplitude of the right lateral antebrachial cutaneous nerve ( LACN ) ( 6 . 2 uV ) was lower than that of the left ( 13 . 1 uV ) . The difference of amplitude between both sides was significant because there was more than a 50 % reduction . She was diagnosed with right LACNP ( mainly axonal involvement ) on the basis of the clinical manifestation and the electrodiagnostic findings . Her symptoms improved through physical therapy but persisted to some degree . CONCLUSION : This report describes the case of a woman with LACNP that developed after a steroid injection for the treatment of lateral epicondylitis . An electrodiagnostic study , including a nerve conduction study of the LACN , was helpful to diagnose right LACNP and to find the passage of the LACN on the lateral epicondyle . Curcumin prevents maleate - induced nephrotoxicity : relation to hemodynamic alterations , oxidative stress , mitochondrial oxygen consumption and activity of respiratory complex I . The potential protective effect of the dietary antioxidant curcumin ( 120 mg / Kg / day for 6 days ) against the renal injury induced by maleate was evaluated . Tubular proteinuria and oxidative stress were induced by a single injection of maleate ( 400 mg / kg ) in rats . Maleate - induced renal injury included increase in renal vascular resistance and in the urinary excretion of total protein , glucose , sodium , neutrophil gelatinase - associated lipocalin ( NGAL ) and N - acetyl b - D - glucosaminidase ( NAG ) , upregulation of kidney injury molecule ( KIM ) - 1 , decrease in renal blood flow and claudin - 2 expression besides of necrosis and apoptosis of tubular cells on 24 h . Oxidative stress was determined by measuring the oxidation of lipids and proteins and diminution in renal Nrf2 levels . Studies were also conducted in renal epithelial LLC - PK1 cells and in mitochondria isolated from kidneys of all the experimental groups . Maleate induced cell damage and reactive oxygen species ( ROS ) production in LLC - PK1 cells in culture . In addition , maleate treatment reduced oxygen consumption in ADP - stimulated mitochondria and diminished respiratory control index when using malate / glutamate as substrate . The activities of both complex I and aconitase were also diminished . All the above - described alterations were prevented by curcumin . It is concluded that curcumin is able to attenuate in vivo maleate - induced nephropathy and in vitro cell damage . The in vivo protection was associated to the prevention of oxidative stress and preservation of mitochondrial oxygen consumption and activity of respiratory complex I , and the in vitro protection was associated to the prevention of ROS production . Anticonvulsant actions of MK - 801 on the lithium - pilocarpine model of status epilepticus in rats . MK - 801 , a noncompetitive N - methyl - D - aspartate ( NMDA ) receptor antagonist , was tested for anticonvulsant effects in rats using two seizure models , coadministration of lithium and pilocarpine and administration of a high dose of pilocarpine alone . Three major results are reported . First , pretreatment with MK - 801 produced an effective and dose - dependent anticonvulsant action with the lithium - pilocarpine model but not with rats treated with pilocarpine alone , suggesting that different biochemical mechanisms control seizures in these two models . Second , the anticonvulsant effect of MK - 801 in the lithium - pilocarpine model only occurred after initial periods of seizure activity . This observation is suggested to be an in vivo demonstration of the conclusion derived from in vitro experiments that MK - 801 binding requires agonist - induced opening of the channel sites of the NMDA receptor . Third , although it is relatively easy to block seizures induced by lithium and pilocarpine by administration of anticonvulsants prior to pilocarpine , it is more difficult to terminate ongoing status epilepticus and block the lethality of the seizures . Administration of MK - 801 30 or 60 min after pilocarpine , i . e . , during status epilepticus , gradually reduced electrical and behavioral seizure activity and greatly enhanced the survival rate . These results suggest that activation of NMDA receptors plays an important role in status epilepticus and brain damage in the lithium - pilocarpine model . This was further supported by results showing that nonconvulsive doses of NMDA and pilocarpine were synergistic , resulting in status epilepticus and subsequent mortality . Continuous infusion tobramycin combined with carbenicillin for infections in cancer patients . The cure rate of infections in cancer patients is adversely affected by neutropenia ( less than 1 , 000 / mm3 ) . In particular , patients with severe neutropenia ( less than 100 / mm3 ) have shown a poor response to antibiotics . To overcome the adverse effects of neutropenia , tobramycin was given by continuous infusion and combined with intermittent carbenicillin . Tobramycin was given to a total daily dose of 300 mg / m2 and carbenicillin was given at a dose of 5 gm every four hours . There were 125 infectious episodes in 116 cancer patients receiving myelosuppressive chemotherapy . The overall cure rate was 70 % . Pneumonia was the most common infection and 61 % of 59 episodes were cured . Gram - negative bacilli were the most common causative organisms and 69 % of these infections were cured . The most common pathogen was Klebsiella pneumoniae and this , together with Escherichia coli and Pseudomonas aeruginosa , accounted for 74 % of all gram - negative bacillary infections . Response was not influenced by the initial neutrophil count , with a 62 % cure rate for 39 episodes associated with severe neutropenia . However , failure of the neutrophil count to increase during therapy adversely affected response . Azotemia was the major side effect recognized , and it occurred in 11 % of episodes . Major azotemia ( serum creatinine greater than 2 . 5 mg / dl or BUN greater than 50 mg / dl ) occurred in only 2 % . Azotemia was not related to duration of therapy or serum tobramycin concentration . This antibiotic regimen showed both therapeutic efficacy and acceptable renal toxicity for these patients . Incidence of solid tumours among pesticide applicators exposed to the organophosphate insecticide diazinon in the Agricultural Health Study : an updated analysis . OBJECTIVE : Diazinon , a common organophosphate insecticide with genotoxic properties , was previously associated with lung cancer in the Agricultural Health Study ( AHS ) cohort , but few other epidemiological studies have examined diazinon - associated cancer risk . We used updated diazinon exposure and cancer incidence information to evaluate solid tumour risk in the AHS . METHODS : Male pesticide applicators in Iowa and North Carolina reported lifetime diazinon use at enrolment ( 1993 - 1997 ) and follow - up ( 1998 - 2005 ) ; cancer incidence was assessed through 2010 ( North Carolina ) / 2011 ( Iowa ) . Among applicators with usage information sufficient to evaluate exposure - response patterns , we used Poisson regression to estimate adjusted rate ratios ( RRs ) and 95 % CI for cancer sites with > 10 exposed cases for both lifetime ( LT ) exposure days and intensity - weighted ( IW ) lifetime exposure days ( accounting for factors impacting exposure ) . RESULTS : We observed elevated lung cancer risks ( N = 283 ) among applicators with the greatest number of LT ( RR = 1 . 60 ; 95 % CI 1 . 11 to 2 . 31 ; Ptrend = 0 . 02 ) and IW days of diazinon use ( RR = 1 . 41 ; 95 % CI 0 . 98 to 2 . 04 ; Ptrend = 0 . 08 ) . Kidney cancer ( N = 94 ) risks were non - significantly elevated ( RRLT days = 1 . 77 ; 95 % CI 0 . 90 to 3 . 51 ; Ptrend = 0 . 09 ; RRIW days 1 . 37 ; 95 % CI 0 . 64 to 2 . 92 ; Ptrend = 0 . 50 ) , as were risks for aggressive prostate cancer ( N = 656 ) . CONCLUSIONS : Our updated evaluation of diazinon provides additional evidence of an association with lung cancer risk . Newly identified links to kidney cancer and associations with aggressive prostate cancer require further evaluation . Associations of Ozone and PM2 . 5 Concentrations With Parkinson ' s Disease Among Participants in the Agricultural Health Study . OBJECTIVE : This study describes associations of ozone and fine particulate matter with Parkinson ' s disease observed among farmers in North Carolina and Iowa . METHODS : We used logistic regression to determine the associations of these pollutants with self - reported , doctor - diagnosed Parkinson ' s disease . Daily predicted pollutant concentrations were used to derive surrogates of long - term exposure and link them to study participants ' geocoded addresses . RESULTS : We observed positive associations of Parkinson ' s disease with ozone ( odds ratio = 1 . 39 ; 95 % CI : 0 . 98 to 1 . 98 ) and fine particulate matter ( odds ratio = 1 . 34 ; 95 % CI : 0 . 93 to 1 . 93 ) in North Carolina but not in Iowa . CONCLUSIONS : The plausibility of an effect of ambient concentrations of these pollutants on Parkinson ' s disease risk is supported by experimental data demonstrating damage to dopaminergic neurons at relevant concentrations . Additional studies are needed to address uncertainties related to confounding and to examine temporal aspects of the associations we observed . Low functional programming of renal AT2R mediates the developmental origin of glomerulosclerosis in adult offspring induced by prenatal caffeine exposure . UNASSIGNED : Our previous study has indicated that prenatal caffeine exposure ( PCE ) could induce intrauterine growth retardation ( IUGR ) of offspring . Recent research suggested that IUGR is a risk factor for glomerulosclerosis . However , whether PCE could induce glomerulosclerosis and its underlying mechanisms remain unknown . This study aimed to demonstrate the induction to glomerulosclerosis in adult offspring by PCE and its intrauterine programming mechanisms . A rat model of IUGR was established by PCE , male fetuses and adult offspring at the age of postnatal week 24 were euthanized . The results revealed that the adult offspring kidneys in the PCE group exhibited glomerulosclerosis as well as interstitial fibrosis , accompanied by elevated levels of serum creatinine and urine protein . Renal angiotensin II receptor type 2 ( AT2R ) gene expression in adult offspring was reduced by PCE , whereas the renal angiotensin II receptor type 1a ( AT1aR ) / AT2R expression ratio was increased . The fetal kidneys in the PCE group displayed an enlarged Bowman ' s space and a shrunken glomerular tuft , accompanied by a reduced cortex width and an increase in the nephrogenic zone / cortical zone ratio . Observation by electronic microscope revealed structural damage of podocytes ; the reduced expression level of podocyte marker genes , nephrin and podocin , was also detected by q - PCR . Moreover , AT2R gene and protein expressions in fetal kidneys were inhibited by PCE , associated with the repression of the gene expression of glial - cell - line - derived neurotrophic factor ( GDNF ) / tyrosine kinase receptor ( c - Ret ) signaling pathway . These results demonstrated that PCE could induce dysplasia of fetal kidneys as well as glomerulosclerosis of adult offspring , and the low functional programming of renal AT2R might mediate the developmental origin of adult glomerulosclerosis . 1 , 3 - Butadiene , CML and the t ( 9 : 22 ) translocation : A reality check . UNASSIGNED : Epidemiological studies of 1 , 3 - butadiene have suggest that exposures to humans are associated with chronic myeloid leukemia ( CML ) . CML has a well - documented association with ionizing radiation , but reports of associations with chemical exposures have been questioned . Ionizing radiation is capable of inducing the requisite CML - associated t ( 9 : 22 ) translocation ( Philadelphia chromosome ) in appropriate cells in vitro but , thus far , chemicals have not shown this capacity . We have proposed that 1 , 3 - butadiene metabolites be so tested as a reality check on the epidemiological reports . In order to conduct reliable testing in this regard , it is essential that a positive control for induction be available . We have used ionizing radiation to develop such a control . Results described here demonstrate that this agent does in fact induce pathogenic t ( 9 : 22 ) translocations in a human myeloid cell line in vitro , but does so at low frequencies . Conditions that will be required for studies of 1 , 3 - butadiene are discussed . Cancer incidence and metolachlor use in the Agricultural Health Study : An update . UNASSIGNED : Metolachlor , a widely used herbicide , is classified as a Group C carcinogen by the U . S . Environmental Protection Agency based on increased liver neoplasms in female rats . Epidemiologic studies of the health effects of metolachlor have been limited . The Agricultural Health Study ( AHS ) is a prospective cohort study including licensed private and commercial pesticide applicators in Iowa and North Carolina enrolled 1993 - 1997 . We evaluated cancer incidence through 2010 / 2011 ( NC / IA ) for 49 , 616 applicators , 53 % of whom reported ever using metolachlor . We used Poisson regression to evaluate relations between two metrics of metolachlor use ( lifetime days , intensity - weighted lifetime days ) and cancer incidence . We saw no association between metolachlor use and incidence of all cancers combined ( n = 5 , 701 with a 5 - year lag ) or most site - specific cancers . For liver cancer , in analyses restricted to exposed workers , elevations observed at higher categories of use were not statistically significant . However , trends for both lifetime and intensity - weighted lifetime days of metolachor use were positive and statistically significant with an unexposed reference group . A similar pattern was observed for follicular cell lymphoma , but no other lymphoma subtypes . An earlier suggestion of increased lung cancer risk at high levels of metolachlor use in this cohort was not confirmed in this update . This suggestion of an association between metolachlor and liver cancer among pesticide applicators is a novel finding and echoes observation of increased liver neoplasms in some animal studies . However , our findings for both liver cancer and follicular cell lymphoma warrant follow - up to better differentiate effects of metolachlor use from other factors . Mechanisms Underlying Latent Disease Risk Associated with Early - Life Arsenic Exposure : Current Research Trends and Scientific Gaps . BACKGROUND : Millions of individuals worldwide , particularly those living in rural and developing areas , are exposed to harmful levels of inorganic arsenic ( iAs ) in their drinking water . Inorganic As exposure during key developmental periods is associated with a variety of adverse health effects including those that are evident in adulthood . There is considerable interest in identifying the molecular mechanisms that relate early - life iAs exposure to the development of these latent diseases , particularly in relationship to cancer . OBJECTIVES : This work summarizes research on the molecular mechanisms that underlie the increased risk of cancer development in adulthood that is associated with early - life iAs exposure . DISCUSSION : Epigenetic reprogramming that imparts functional changes in gene expression , the development of cancer stem cells , and immunomodulation are plausible underlying mechanisms by which early - life iAs exposure elicits latent carcinogenic effects . CONCLUSIONS : Evidence is mounting that relates early - life iAs exposure and cancer development later in life . Future research should include animal studies that address mechanistic hypotheses and studies of human populations that integrate early - life exposure , molecular alterations , and latent disease outcomes . Nifedipine induced bradycardia in a patient with autonomic neuropathy . An 80 year old diabetic male with evidence of peripheral and autonomic neuropathy was admitted with chest pain . He was found to have atrial flutter at a ventricular rate of 70 / min which slowed down to 30 - 40 / min when nifedipine ( 60 mg ) in 3 divided doses , during which he was paced at a rate of 70 / min . This is inconsistent with the well - established finding that nifedipine induces tachycardia in normally innervated hearts . However , in hearts deprived of compensatory sympathetic drive , it may lead to bradycardia . The effect of haloperidol in cocaine and amphetamine intoxication . The effectiveness of haloperidol pretreatment in preventing the toxic effects of high doses of amphetamine and cocaine was studied in rats . In this model , toxic effects were induced by intraperitoneal ( i . p . ) injection of amphetamine 75 mg / kg ( 100 % death rate ) or cocaine 70 mg / kg ( 82 % death rate ) . Haloperidol failed to prevent amphetamine - induced seizures , but did lower the mortality rate at most doses tested . Haloperidol decreased the incidence of cocaine - induced seizures at the two highest doses , but the lowering of the mortality rate did not reach statistical significance at any dose . These data suggest a protective role for the central dopamine blocker haloperidol against death from high - dose amphetamine exposure without reducing the incidence of seizures . In contrast , haloperidol demonstrated an ability to reduce cocaine - induced seizures without significantly reducing mortality . Autoradiographic evidence of estrogen binding sites in nuclei of diethylstilbesterol induced hamster renal carcinomas . Estrogen binding sites were demonstrated by autoradiography in one transplantable and five primary diethylstilbesterol induced renal carcinomas in three hamsters . Radiolabelling , following the in vivo injection of 3H - 17 beta estradiol , was increased only over the nuclei of tumor cells ; stereologic analysis revealed a 4 . 5 - to 6 . 7 - times higher concentration of reduced silver grains over nuclei than cytoplasm of these cells . Despite rapid tubular excretion of estradiol which peaked in less than 1 h , the normal cells did not appear to bind the ligand . This is the first published report documenting the preferential in vivo binding of estrogen to nuclei of cells in estrogen induced hamster renal carcinomas . Bradycardia due to biperiden . In a 38 - year - old male patient suffering from a severe postzosteric trigeminal neuralgia , intravenous application of 10 mg biperiden lactate led to a long - lasting paradoxical reaction characterized by considerable bradycardia , dysarthria , and dysphagia . The heart rate was back to normal within 12 hours upon administration of orciprenaline under cardiac monitoring in an intensive care unit . Bradycardia induced by biperiden is attributed to the speed of injection and to a dose - related dual effect of atropine - like drugs on muscarine receptors . Deliberate hypotension induced by labetalol with halothane , enflurane or isoflurane for middle - ear surgery . The feasibility of using labetalol , an alpha - and beta - adrenergic blocking agent , as a hypotensive agent in combination with inhalation anaesthetics ( halothane , enflurane or isoflurane ) was studied in 23 adult patients undergoing middle - ear surgery . The mean arterial pressure was decreased from 86 + / - 5 ( s . e . mean ) mmHg to 52 + / - 1 mmHg ( 11 . 5 + / - 0 . 7 to 6 . 9 + / - 0 . 1 kPa ) for 98 + / - 10 min in the halothane ( H ) group , from 79 + / - 5 to 53 + / - 1 mmHg ( 10 . 5 + / - 0 . 7 to 7 . 1 + / - 0 . 1 kPa ) for 129 + / - 11 min in the enflurane ( E ) group , and from 80 + / - 4 to 49 + / - 1 mmHg ( 10 . 7 + / - 0 . 5 to 6 . 5 + / - 0 . 1 kPa ) for 135 + / - 15 min in the isoflurane ( I ) group . The mean H concentration during hypotension in the inspiratory gas was 0 . 7 + / - 0 . 1 vol % , the mean E concentration 1 . 6 + / - 0 . 2 vol % , and the mean I concentration 1 . 0 + / - 0 . 1 vol % . In addition , the patients received fentanyl and d - tubocurarine . The initial dose of labetalol for lowering blood pressure was similar , 0 . 52 - 0 . 59 mg / kg , in all the groups . During hypotension , the heart rate was stable without tachy - or bradycardia . The operating conditions regarding bleeding were estimated in a double - blind manner , and did not differ significantly between the groups . During hypotension , the serum creatinine concentration rose significantly in all groups from the values before hypotension and returned postoperatively to the initial level in the other groups , except the isoflurane group . After hypotension there was no rebound phenomenon in either blood pressure or heart rate . These results indicate that labetalol induces easily adjustable hypotension without compensatory tachycardia and rebound hypertension . Convulsion following intravenous fluorescein angiography . Tonic - clonic seizures followed intravenous fluorescein injection for fundus angiography in a 47 - year - old male . Despite precautions this adverse reaction recurred on re - exposure to intravenous fluorescein . Pharmacology of ACC - 9653 ( phenytoin prodrug ) . ACC - 9653 , the disodium phosphate ester of 3 - hydroxymethyl - 5 , 5 - diphenylhydantoin , is a prodrug of phenytoin with advantageous physicochemical properties . ACC - 9653 is rapidly converted enzymatically to phenytoin in vivo . ACC - 9653 and phenytoin sodium have equivalent anticonvulsant activity against seizures induced by maximal electroshock ( MES ) in mice following i . p . , oral , or i . v . administration . The ED50 doses were 16 mg / kg for i . v . ACC - 9653 and 8 mg / kg for i . v . phenytoin sodium . ACC - 9653 and phenytoin sodium have similar antiarrhythmic activity against ouabain - induced ventricular tachycardia in anesthetized dogs . The total doses of ACC - 9653 or phenytoin sodium necessary to convert the arrhythmia to a normal sinus rhythm were 24 + / - 6 and 14 + / - 3 mg / kg , respectively . Only phenytoin sodium displayed in vitro antiarrhythmic activity against strophanthidin - induced arrhythmias in guinea pig right atria . In anesthetized dogs , a high dose of ACC - 9653 ( 31 mg / kg ) was infused over 15 , 20 , and 30 min and the responses were compared to an equimolar dose of phenytoin sodium ( 21 mg / kg ) . The ACC - 9653 and phenytoin sodium treatments produced similar marked reductions in diastolic blood pressure and contractile force ( LVdP / dt ) . The maximum effects of each treatment occurred at the time of maximum phenytoin sodium levels . Acute toxicity studies of ACC - 9653 and phenytoin sodium were carried out in mice , rats , rabbits , and dogs by i . v . , i . m . , and i . p . routes of administration . The systemic toxic signs of both agents were similar and occurred at approximately equivalent doses . Importantly , the local irritation of ACC - 9653 was markedly less than phenytoin sodium following i . m . administration . ( ABSTRACT TRUNCATED AT 250 WORDS ) Tachyphylaxis to systemic but not to airway responses during prolonged therapy with high dose inhaled salbutamol in asthmatics . High doses of inhaled salbutamol produce substantial improvements in airway response in patients with asthma , and are associated with dose - dependent systemic beta - adrenoceptor responses . The purpose of the present study was to investigate whether tachyphylaxis occurs during prolonged treatment with high dose inhaled salbutamol . Twelve asthmatic patients ( FEV1 , 81 + / - 4 % predicted ) , requiring only occasional inhaled beta - agonists as their sole therapy , were given a 14 - day treatment with high dose inhaled salbutamol ( HDS ) , 4 , 000 micrograms daily , low dose inhaled salbutamol ( LDS ) , 800 micrograms daily , or placebo ( PI ) by metered - dose inhaler in a double - blind , randomized crossover design . During the 14 - day run - in and during washout periods , inhaled beta - agonists were withheld and ipratropium bromide was substituted for rescue purposes . At the end of each 14 - day treatment , a dose - response curve ( DRC ) was performed , and airway ( FEV1 , FEF25 - 75 ) chronotropic ( HR ) , tremor , and metabolic ( K , Glu ) responses were measured at each step ( from 100 to 4 , 000 micrograms ) . Treatment had no significant effect on baseline values . There were dose - dependent increases in FEV1 and FEF25 - 75 ( p less than 0 . 001 ) , and pretreatment with HDS did not displace the DRC to the right . DRC for HR ( p less than 0 . 001 ) , K ( p less than 0 . 001 ) , and Glu ( p less than 0 . 005 ) were attenuated after treatment with HDS compared with PI . There were also differences between HDS and LDS for HR ( p less than 0 . 001 ) and Glu ( p less than 0 . 05 ) responses . Frequency and severity of subjective adverse effects were also reduced after HDS : tremor ( p less than 0 . 001 ) , palpitations ( p less than 0 . 001 ) . ( ABSTRACT TRUNCATED AT 250 WORDS ) Phenytoin induced fatal hepatic injury . A 61 year old female developed fatal hepatic failure after phenytoin administration . A typical multisystem clinical pattern precedes the manifestations of hepatic injury . The hematologic , biochemical and pathologic features indicate a mixed hepatocellular damage due to drug hypersensitivity . In a patient receiving phenytoin who presents a viral - like illness , early recognition and discontinuation of the drug are mandatory . Treatment of lethal pertussis vaccine reaction with histamine H1 antagonists . We studied mortality after pertussis immunization in the mouse . Without treatment , 73 of 92 animals ( 80 % ) died after injection of bovine serum albumin ( BSA ) on day + 7 of pertussis immunization . After pretreatment with 3 mg of cyproheptadine , 2 mg mianserin , or 2 mg chlorpheniramine , only 5 of 105 animals ( 5 % ) died after receiving BSA on day + 7 ( p less than 0 . 001 ) . Blockade of histamine H1 receptors may reduce mortality in pertussis immunization - induced encephalopathy in mice . Support for adrenaline - hypertension hypothesis : 18 hour pressor effect after 6 hours adrenaline infusion . In a double blind , crossover study 6 h infusions of adrenaline ( 15 ng / kg / min ; 1 ng = 5 . 458 pmol ) , noradrenaline ( 30 ng / kg / min ; 1 ng = 5 . 911 pmol ) , and a 5 % dextrose solution ( 5 . 4 ml / h ) , were given to ten healthy volunteers in random order 2 weeks apart . By means of intra - arterial ambulatory monitoring the haemodynamic effects were followed for 18 h after the infusions were stopped . Adrenaline , but not noradrenaline , caused a delayed and protracted pressor effect . Over the total postinfusion period systolic and diastolic arterial pressure were 6 ( SEM 2 ) % and 7 ( 2 ) % , respectively , higher than after dextrose infusion ( ANOVA , p less than 0 . 001 ) . Thus , " stress " levels of adrenaline ( 230 pg / ml ) for 6 h cause a delayed and protracted pressor effect . These findings are strong support for the adrenaline - hypertension hypothesis in man . Effect of alkylxanthines on gentamicin - induced acute renal failure in the rat . Adenosine antagonists have been previously shown to be of benefit in some ischaemic and nephrotoxic models of acute renal failure ( ARF ) . In the present study , the effects of three alkylxanthines with different potencies as adenosine antagonists 8 - phenyltheophylline , theophylline and enprofylline , were examined in rats developing acute renal failure after 4 daily injections of gentamicin ( 200 mg kg - 1 ) . Renal function was assessed by biochemical ( plasma urea and creatinine ) , functional ( urine analysis and [ 3H ] inulin and [ 14C ] p - aminohippuric acid clearances ) and morphological ( degree of necrosis ) indices . The various drug treatments produced improvements in some , but not all , measurements of renal function . However , any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle ( polyethylene glycol and NaOH ) . The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that adenosine plays little , if any , pathophysiological role in gentamicin - induced ARF . Adverse ocular reactions possibly associated with isotretinoin . A total of 261 adverse ocular reactions occurred in 237 patients who received isotretinoin , a commonly used drug in the treatment of severe cystic acne . Blepharoconjunctivitis , subjective complaints of dry eyes , blurred vision , contact lens intolerance , and photodermatitis are reversible side effects . More serious ocular adverse reactions include papilledema , pseudotumor cerebri , and white or gray subepithelial corneal opacities ; all of these are reversible if the drug is discontinued . Reported cases of decreased dark adaptation are under investigation . Isotretinoin is contraindicated in pregnancy because of the many reported congenital abnormalities after maternal use ( including microphthalmos , orbital hypertelorism , and optic nerve hypoplasia ) . Procaterol and terbutaline in bronchial asthma . A double - blind , placebo - controlled , cross - over study . Procaterol , a new beta - 2 adrenoceptor stimulant , was studied in a double - blind , placebo - controlled , cross - over trial in patients with bronchial asthma . Oral procaterol 50 micrograms b . d . , procaterol 100 micrograms b . d . , and terbutaline 5 mg t . i . d . , were compared when given randomly in 1 - week treatment periods . The best clinical effect was found with terbutaline . Both anti - asthmatic and tremorgenic effects of procaterol were dose - related . Procaterol appeared effective in the doses tested , and a twice daily regimen would appear to be suitable with this drug . Subacute effects of propranolol and B 24 / 76 on isoproterenol - induced rat heart hypertrophy in correlation with blood pressure . We compared the potential beta - receptor blocker , B 24 / 76 i . e . 1 - ( 2 , 4 - dichlorophenoxy ) - 3 [ 2 - 3 , 4 - dimethoxyphenyl ) ethanolamino ] - prop an - 2 - ol , which is characterized by beta 1 - adrenoceptor blocking and beta 2 - adrenoceptor stimulating properties with propranolol . The studies were performed using an experimental model of isoproterenol - induced heart hypertrophy in rats . A correlation of the blood pressure was neither found in the development nor in the attempt to suppress the development of heart hypertrophy with the two beta - receptor blockers . Both beta - blockers influenced the development of hypertrophy to a different , but not reproducible extent . It was possible to suppress the increased ornithine decarboxylase activity with both beta - blockers in hypertrophied hearts , but there was no effect on the heart mass . Neither propranolol nor B 24 / 76 could stop the changes in the characteristic myosin isoenzyme pattern of the hypertrophied rat heart . Thus , the investigations did not provide any evidence that the beta - receptor blockers propranolol and B 24 / 76 have the potency to prevent isoproterenol from producing heart hypertrophy . Increased anxiogenic effects of caffeine in panic disorders . The effects of oral administration of caffeine ( 10 mg / kg ) on behavioral ratings , somatic symptoms , blood pressure and plasma levels of 3 - methoxy - 4 - hydroxyphenethyleneglycol ( MHPG ) and cortisol were determined in 17 healthy subjects and 21 patients meeting DSM - III criteria for agoraphobia with panic attacks or panic disorder . Caffeine produced significantly greater increases in subject - rated anxiety , nervousness , fear , nausea , palpitations , restlessness , and tremors in the patients compared with healthy subjects . In the patients , but not the healthy subjects , these symptoms were significantly correlated with plasma caffeine levels . Seventy - one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during panic attacks . Caffeine did not alter plasma MHPG levels in either the healthy subjects or patients . Caffeine increased plasma cortisol levels equally in the patient and healthy groups . Because caffeine is an adenosine receptor antagonist , these results suggest that some panic disorder patients may have abnormalities in neuronal systems involving adenosine . Patients with anxiety disorders may benefit by avoiding caffeine - containing foods and beverages . Comparison of the effect of oxitropium bromide and of slow - release theophylline on nocturnal asthma . The effects of a new inhaled antimuscarinic drug , oxitropium bromide , and of a slow - release theophylline preparation upon nocturnal asthma were compared in a placebo - controlled double - blind study . Two samples were studied : 12 patients received oxitropium at 600 micrograms ( 6 subjects ) or at 400 micrograms t . i . d . ( 6 subjects ) whereas 11 received theophylline at 300 mg b . i . d . Morning dipping , assessed by the fall in peak flow overnight , was significantly reduced in the periods when either active drug was taken , whereas no difference was noticed during the placebo administration . No significant difference was noticed between results obtained with either active drug , as well as with either dosage of oxitropium . No subject reported side effects of oxitropium , as compared to three subjects reporting nausea , vomiting and tremors after theophylline . Oxitropium proves to be a valuable alternative to theophylline in nocturnal asthma , since it is equally potent , safer and does not require the titration of dosage . Penicillin anaphylaxis . A case of oral penicillin anaphylaxis is described , and the terminology , occurrence , clinical manifestations , pathogenesis , prevention , and treatment of anaphylaxis are reviewed . Emergency physicians should be aware of oral penicillin anaphylaxis in order to prevent its occurrence by prescribing the antibiotic judiciously and knowledgeably and to offer optimal medical therapy once this life - threatening reaction has begun . Reversible valproic acid - induced dementia : a case report . Reversible valproic acid - induced dementia was documented in a 21 - year - old man with epilepsy who had a 3 - year history of insidious progressive decline in global cognitive abilities documented by serial neuropsychological studies . Repeat neuropsychological testing 7 weeks after discontinuation of the drug revealed dramatic improvement in IQ , memory , naming , and other tasks commensurate with clinical recovery in his intellectual capacity . Possible pathophysiological mechanisms which may have been operative in this case include : a direct central nervous system ( CNS ) toxic effect of valproic acid ; a paradoxical epileptogenic effect secondary to the drug ; and an indirect CNS toxic effect mediated through valproic acid - induced hyperammonemia . Reversal of scopolamine - induced amnesia of passive avoidance by pre - and post - training naloxone . In a series of five experiments , the modulating role of naloxone on a scopolamine - induced retention deficit in a passive avoidance paradigm was investigated in mice . Scopolamine , but not methyl scopolamine ( 1 and 3 mg / kg ) , induced an amnesia as measured by latency and duration parameters . Naloxone ( 0 . 3 , 1 , 3 , and 10 mg / kg ) injected prior to training attenuated the retention deficit with a peak of activity at 3 mg / kg . The effect of naloxone could be antagonized with morphine ( 1 , 3 , and 10 mg / kg ) , demonstrating the opioid specificity of the naloxone effect . Post - training administration of naloxone ( 3 mg / kg ) as a single or as a split dose also attenuated the scopolamine - induced amnesia . Control experiments indicated that neither an increase in pain sensitivity ( pre - training naloxone ) nor an induced aversive state ( post - training naloxone ) appear to be responsible for the influence of naloxone on the scopolamine - induced retention deficit . These results extend previous findings implicating a cholinergic - opioid interaction in memory processes . A possible mechanism for this interaction involving the septo - hippocampal cholinergic pathway is discussed . Electron microscopic investigations of the cyclophosphamide - induced lesions of the urinary bladder of the rat and their prevention by mesna . Fully developed cyclophosphamide - induced cystitis is characterized by nearly complete detachment of the urothelium , severe submucosal edema owing to damage to the microvascular bed and focal muscle necroses . The initial response to the primary attack by the cyclophosphamide metabolites seems to be fragmentation of the luminal membrane . This damages the cellular barrier against the hypertonic urine . Subsequent breaks in the lateral cell membranes of the superficial cells and in all the plasma membranes of the intermediate and basal cells , intercellular and intracellular edema and disintegration of the desmosomes and hemidesmosomes lead to progressive degeneration and detachment of the epithelial cells with exposure and splitting of the basal membrane . The morphological changes of the endothelial cells , which become more pronounced in the later stages of the experiment , the involvement of blood vessels regardless of their diameter and the location - dependent extent of the damage indicate a direct type of damage which is preceded by a mediator - induced increase in permeability , the morphological correlate of which is the formation of gaps in the interendothelial cell connections on the venules . These changes can be effectively prevented by mesna . The only sign of a possible involvement is the increase in the number of specific granules with a presumed lysosomal function in the superficial cells . Increase in intragastric pressure during suxamethonium - induced muscle fasciculations in children : inhibition by alfentanil . Changes in intragastric pressure after the administration of suxamethonium 1 . 5 mg kg - 1 i . v . were studied in 32 children ( mean age 6 . 9 yr ) pretreated with either physiological saline or alfentanil 50 micrograms kg - 1 . Anaesthesia was induced with thiopentone 5 mg kg - 1 . The incidence and intensity of muscle fasciculations caused by suxamethonium were significantly greater in the control than in the alfentanil group . The intragastric pressure during muscle fasciculations was significantly higher in the control group ( 16 + / - 0 . 7 ( SEM ) cm H2O ) than in the alfentanil group ( 7 . 7 + / - 1 . 5 ( SEM ) cm H2O ) . The increase in intragastric pressure was directly related to the intensity of muscle fasciculations ( regression line : y = 0 . 5 + 4 . 78x with r of 0 . 78 ) . It is concluded that intragastric pressure increases significantly during muscle fasciculations caused by suxamethonium in healthy children . Alfentanil 50 micrograms kg - 1 effectively inhibits the incidence and intensity of suxamethonium - induced muscle fasciculations ; moreover , intragastric pressure remains at its control value . Acute insulin treatment normalizes the resistance to the cardiotoxic effect of isoproterenol in streptozotocin diabetic rats . A morphometric study of isoproterenol induced myocardial fibrosis . The acute effect of insulin treatment on the earlier reported protective effect of streptozotocin diabetes against the cardiotoxic effect of high doses of isoproterenol ( ISO ) was investigated in rats . Thirty to 135 min after the injection of crystalline insulin , ISO was given subcutaneously and when ISO induced fibrosis in the myocardium was morphometrically analyzed 7 days later , a highly significant correlation ( r = 0 . 83 , 2 p = 0 . 006 ) to the slope of the fall in blood glucose after insulin treatment appeared . The myocardial content of catecholamines was estimated in these 8 day diabetic rats . The norepinephrine content was significantly increased while epinephrine remained unchanged . An enhanced sympathetic nervous system activity with a consequent down regulation of the myocardial beta - adrenergic receptors could , therefore , explain this catecholamine resistance . The rapid reversion after insulin treatment excludes the possibility that streptozotocin in itself causes the ISO resistance and points towards a direct insulin effect on myocardial catecholamine sensitivity in diabetic rats . The phenomenon described might elucidate pathogenetic mechanisms behind toxic myocardial cell degeneration and may possibly have relevance for acute cardiovascular complications in diabetic patients . Differential effects of non - steroidal anti - inflammatory drugs on seizures produced by pilocarpine in rats . The muscarinic cholinergic agonist pilocarpine induces in rats seizures and status epilepticus followed by widespread damage to the forebrain . The present study was designed to investigate the effect of 5 non - steroidal anti - inflammatory drugs , sodium salicylate , phenylbutazone , indomethacin , ibuprofen and mefenamic acid , on seizures produced by pilocarpine . Pretreatment of rats with sodium salicylate , ED50 103 mg / kg ( 60 - 174 ) , and phenylbutazone , 59 mg / kg ( 50 - 70 ) converted the non - convulsant dose of pilocarpine , 200 mg / kg , to a convulsant one . Indomethacin , 1 - 10 mg / kg , and ibuprofen , 10 - 100 mg / kg , failed to modulate seizures produced by pilocarpine . Mefenamic acid , 26 ( 22 - 30 ) mg / kg , prevented seizures and protected rats from seizure - related brain damage induced by pilocarpine , 380 mg / kg . These results indicate that non - steroidal anti - inflammatory drugs differentially modulate the threshold for pilocarpine - induced seizures . Acute neurologic dysfunction after high - dose etoposide therapy for malignant glioma . Etoposide ( VP - 16 - 213 ) has been used in the treatment of many solid tumors and hematologic malignancies . When used in high doses and in conjunction with autologous bone marrow transplantation , this agent has activity against several treatment - resistant cancers including malignant glioma . In six of eight patients ( 75 % ) who we treated for recurrent or resistant glioma , sudden severe neurologic deterioration occurred . This developed a median of 9 days after initiation of high - dose etoposide therapy . Significant clinical manifestations have included confusion , papilledema , somnolence , exacerbation of motor deficits , and sharp increase in seizure activity . These abnormalities resolved rapidly after initiation of high - dose intravenous dexamethasone therapy . In all patients , computerized tomographic ( CT ) brain scans demonstrated stability in tumor size and peritumor edema when compared with pretransplant scans . This complication appears to represent a significant new toxicity of high - dose etoposide therapy for malignant glioma . Progressive bile duct injury after thiabendazole administration . A 27 - yr - old man developed jaundice 2 wk after exposure to thiabendazole . Cholestasis persisted for 3 yr , at which time a liver transplant was performed . Two liver biopsy specimens and the hepatectomy specimen were remarkable for almost complete disappearance of interlobular bile ducts . Prominent fibrosis and hepatocellular regeneration were also present ; however , the lobular architecture was preserved . This case represents an example of " idiosyncratic " drug - induced liver damage in which the primary target of injury is the bile duct . An autoimmune pathogenesis of the bile duct destruction is suggested . Differential effects of 1 , 4 - dihydropyridine calcium channel blockers : therapeutic implications . Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases . The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities . Clinical applications of calcium channel blockers parallel their tissue selectivity . In contrast to verapamil and diltiazem , which are roughly equipotent in their actions on the heart and vascular smooth muscle , the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue . As the first dihydropyridine available for use in the United States , nifedipine controls angina and hypertension with minimal depression of cardiac function . Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy . Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule , which encourages patient compliance in long - term therapy of hypertension . The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina . Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage , migraine headache , dementia , and stroke . In general , the dihydropyridine calcium channel blockers are usually well tolerated , with headache , facial flushing , palpitations , edema , nausea , anorexia , and dizziness being the more common adverse effects . The enhancement of aminonucleoside nephrosis by the co - administration of protamine . An experimental model of focal segmental glomerular sclerosis ( FSGS ) was developed in rats by the combined administration of puromycin - aminonucleoside ( AMNS ) and protamine sulfate ( PS ) . Male Sprague - Dawley rats , uninephrectomized three weeks before , received daily injections of subcutaneous AMNS ( 1 mg / 100 g body wt ) and intravenous PS ( 2 separated doses of 2 . 5 mg / 100 g body wt ) for four days . The series of injections were repeated another three times at 10 day intervals . The animals were sacrificed on days 24 , 52 , and 80 . They developed nephrotic syndrome and finally renal failure . The time - course curve of creatinine clearance dropped and showed significant difference ( P less than 0 . 01 ) from that of each control group , such as , AMNS alone , PS alone or saline injected . Their glomeruli showed changes of progressive FSGS . The ultrastructural studies in the initial stage revealed significant lack of particles of perfused ruthenium red on the lamina rara externa and marked changes in epithelial cell cytoplasm . Therefore , it is suggested that the administration of PS enhances the toxicity of AMNS on the glomerulus and readily produces progressive FSGS in rats resulting in the end - stage renal disease . Theophylline neurotoxicity in pregnant rats . The purpose of this investigation was to determine whether the neurotoxicity of theophylline is altered in advanced pregnancy . Sprague - Dawley rats that were 20 days pregnant and nonpregnant rats of the same age and strain received infusions of aminophylline until onset of maximal seizures which occurred after 28 and 30 minutes respectively . Theophylline concentrations at this endpoint in serum ( total ) and CSF were similar but serum ( free ) and brain concentrations were slightly different in pregnant rats . Theophylline serum protein binding determined by equilibrium dialysis was lower in pregnant rats . Fetal serum concentrations at onset of seizures in the mother were similar to maternal brain and CSF concentrations and correlated significantly with the former . It is concluded that advanced pregnancy has a negligible effect on the neurotoxic response to theophylline in rats . Hyperkalemia induced by indomethacin and naproxen and reversed by fludrocortisone . We have described a patient with severe rheumatoid arthritis and a history of mefenamic acid nephropathy in whom hyperkalemia and inappropriate hypoaldosteronism were caused by both indomethacin and naproxen , without major decline in renal function . It is likely that preexisting renal disease predisposed this patient to type IV renal tubular acidosis with prostaglandin synthetase inhibitors . Because he was unable to discontinue nonsteroidal anti - inflammatory drug therapy , fludrocortisone was added , correcting the hyperkalemia and allowing indomethacin therapy to be continued safely . Hypotension as a manifestation of cardiotoxicity in three patients receiving cisplatin and 5 - fluorouracil . Cardiac symptoms , including hypotension , developed in three patients with advanced colorectal carcinoma while being treated with cisplatin ( CDDP ) and 5 - fluorouracil ( 5 - FU ) . In two patients , hypotension was associated with severe left ventricular dysfunction . All three patients required therapy discontinuation . Cardiac enzymes remained normal despite transient electrocardiographic ( EKG ) changes . The presentation and cardiac evaluation ( hemodynamic , echocardiographic , and scintigraphic ) of these patients suggest new manifestations of 5 - FU cardiotoxicity that may be influenced by CDDP . The possible pathophysiologic mechanisms are discussed . Fatal aplastic anemia in a patient treated with carbamazepine . A case of fatal aplastic anemia due to carbamazepine treatment in an epileptic woman is reported . Despite concerns of fatal bone marrow toxicity due to carbamazepine , this is only the fourth documented and published report . Carbamazepine is a safe drug , but physicians and patients should be aware of the exceedingly rare but potentially fatal side effects , better prevented by clinical than by laboratory monitoring . Participation of a bulbospinal serotonergic pathway in the rat brain in clonidine - induced hypotension and bradycardia . The effects of microinjection of clonidine ( 1 - 10 micrograms in 1 microliter ) into a region adjacent to the ventrolateral surface of the medulla oblongata on cardiovascular function were assessed in urethane - anesthetized rats . Intramedullary administration of clonidine , but not saline vehicle , caused a dose - dependent decrease in both the mean arterial pressure and the heart rate . The clonidine - induced hypotension was antagonized by prior spinal transection , but not bilateral vagotomy . On the other hand , the clonidine - induced bradycardia was antagonized by prior bilateral vagotomy , but not spinal transection . Furthermore , selective destruction of the spinal 5 - HT nerves , produced by bilateral spinal injection of 5 , 7 - dihydroxytryptamine , reduced the magnitude of the vasodepressor or the bradycardiac responses to clonidine microinjected into the area near the ventrolateral surface of the medulla oblongata in rats . The data indicate that a bulbospinal serotonergic pathway is involved in development of clonidine - induced hypotension and bradycardia . The induced hypotension is brought about by a decrease in sympathetic efferent activity , whereas the induced bradycardia was due to an increase in vagal efferent activity . Hypertension in neuroblastoma induced by imipramine . Hypertension is a well - known finding in some patients with neuroblastoma . However , it has not previously been described in association with the use of Imipramine . We report the occurrence of severe hypertension ( blood pressure 190 / 160 ) in a 4 - year - old girl with neuroblastoma who was given Imipramine to control a behavior disorder . It was determined later that this patient ' s tumor was recurring at the time of her hypertensive episode . Since she had no blood pressure elevation at initial diagnosis and none following discontinuation of the Imipramine ( when she was in florid relapse ) , we believe that this drug rather than her underlying disease alone caused her hypertension . The mechanism for this reaction is believed to be increased levels of vasoactive catecholamines due to interference of their physiologic inactivation by Imipramine . From this experience , we urge extreme caution in the use of tricyclic antidepressants in children with active neuroblastoma . Rechallenge of patients who developed oral candidiasis or hoarseness with beclomethasone dipropionate . Of 158 asthmatic patients who were placed on inhaled beclomethasone , 15 ( 9 . 5 % ) developed either hoarseness ( 8 ) , oral thrush ( 6 ) , or both ( 1 ) . When their adverse reactions subsided , seven of these 15 patients were rechallenged with inhaled beclomethasone . These included five cases who developed hoarseness and three who developed Candidiasis . One patient had both . Oral thrush did not recur , but 60 % ( 3 / 5 ) of patients with hoarseness had recurrence . We conclude that patients may be restarted on inhaled beclomethasone when clinically indicated ; however , because of the high recurrence rate , patients who develop hoarseness should not be re - challenged . Concomitant use of oral prednisone and topical beclomethasone may increase the risk of developing hoarseness or candidiasis . Cyclophosphamide cardiotoxicity : an analysis of dosing as a risk factor . Patients who undergo bone marrow transplantation are generally immunosuppressed with a dose of cyclophosphamide ( CYA ) which is usually calculated based on the patient ' s weight . At these high doses of CYA , serious cardiotoxicity may occur , but definitive risk factors for the development of such cardiotoxicity have not been described . Since chemotherapeutic agent toxicity generally correlates with dose per body surface area , we retrospectively calculated the dose of CYA in patients transplanted at our institution to determine whether the incidence of CYA cardiotoxicity correlated with the dose per body surface area . Eighty patients who were to receive CYA 50 mg / kg / d for four days as preparation for marrow grafting underwent a total of 84 transplants for aplastic anemia , Wiskott - Aldrich syndrome , or severe combined immunodeficiency syndrome . Fourteen of 84 ( 17 % ) patients had symptoms and signs consistent with CYA cardiotoxicity within ten days of receiving 1 to 4 doses of CYA . Six of the 14 patients died with congestive heart failure . The dose of CYA per body surface area was calculated for all patients and the patients were divided into two groups based on daily CYA dose : Group 1 , CYA less than or equal to 1 . 55 g / m2 / d ; Group 2 , CYA greater than 1 . 55 g / m2 / d . Cardiotoxicity that was thought to be related to CYA occurred in 1 / 32 ( 3 % ) of patients in Group 1 and in 13 / 52 ( 25 % ) patients in Group 2 ( P less than 0 . 025 ) . Congestive heart failure caused or contributed to death in 0 / 32 patients in Group 1 v 6 / 52 ( 12 % ) of patients in Group 2 ( P less than 0 . 25 ) . There was no difference in the rate of engraftment of evaluable patients in the two groups ( P greater than 0 . 5 ) . We conclude that the CYA cardiotoxicity correlates with CYA dosage as calculated by body surface area , and that patients with aplastic anemia and immunodeficiencies can be effectively prepared for bone marrow grafting at a CYA dose of 1 . 55 g / m2 / d for four days with a lower incidence of cardiotoxicity than patients whose CYA dosage is calculated based on weight . This study reaffirms the principle that drug toxicity correlates with dose per body surface area . Studies of risk factors for aminoglycoside nephrotoxicity . The epidemiology of aminoglycoside - induced nephrotoxicity is not fully understood . Experimental studies in healthy human volunteers indicate aminoglycosides cause proximal tubular damage in most patients , but rarely , if ever , cause glomerular or tubular dysfunction . Clinical trials of aminoglycosides in seriously ill patients indicate that the relative risk for developing acute renal failure during therapy ranges from 8 to 10 and that the attributable risk is 70 % to 80 % . Further analysis of these data suggests that the duration of therapy , plasma aminoglycoside levels , liver disease , advanced age , high initial estimated creatinine clearance and , possibly , female gender all increase the risk for nephrotoxicity . Other causes of acute renal failure , such as shock , appear to have an additive effect . Predictive models have been developed from these analyses that should be useful for identifying patients at high risk . These models may also be useful in developing insights into the pathophysiology of aminoglycoside - induced nephrotoxicity . Central action of narcotic analgesics . Part IV . Noradrenergic influences on the activity of analgesics in rats . The effect of clonidine , naphazoline and xylometazoline on analgesia induced by morphine , codeine , fentanyl and pentazocine , and on cataleptic effect of morphine , codine and fentanyl was studied in rats . The biochemical assays on the influence of four analgesics on the brain concentration and turnover of noradrenaline ( NA ) were also performed . It was found that three drugs stimulating central NA receptors failed to affect the analgesic ED50 of all antinociceptive agents and they enhanced catalepsy induced by morphine and fentanyl . Codeine catalepsy was increased by clonidine and decreased by naphazoline and xylometazoline . The brain concentration of NA was not changed by morphine and fentanyl , but one of the doses of codeine ( 45 mg / kg ) slightly enhanced it . Pentazocine dose - dependently decreased the brain level of NA . The rate of NA turnover was not altered by analgesics except for the higher dose of fentanyl ( 0 . 2 mg / kg ) following which the disappearance of NA from the brain was diminished . The results are discussed in the light of various and non - uniform data from the literature . It is suggested that in rats the brain NA plays a less important function than the other monoamines in the behavioural activity of potent analgesics . Flurothyl seizure thresholds in mice treated neonatally with a single injection of monosodium glutamate ( MSG ) : evaluation of experimental parameters in flurothyl seizure testing . Monosodium glutamate ( MSG ) administration to neonatal rodents produces convulsions and results in numerous biochemical and behavioral deficits . These studies were undertaken to determine if neonatal administration of MSG produced permanent alterations in seizure susceptibility , since previous investigations were inconclusive . A flurothyl ether seizure screening technique was used to evaluate seizure susceptibility in adult mice that received neonatal injections of MSG ( 4 mg / g and 1 mg / g ) . MSG treatment resulted in significant reductions in whole brain weight but did not alter seizure threshold . A naloxone ( 5 mg / kg ) challenge was also ineffective in altering the seizure thresholds of either control of MSG - treated mice . Flurothyl ether produced hypothermia which was correlated with the duration of flurothyl exposure ; however , the relationship of hypothermia to seizure induction was unclear . Flurothyl seizure testing proved to be a rapid and reliable technique with which to evaluate seizure susceptibility . Susceptibility to seizures produced by pilocarpine in rats after microinjection of isoniazid or gamma - vinyl - GABA into the substantia nigra . Pilocarpine , given intraperitoneally to rats , reproduces the neuropathological sequelae of temporal lobe epilepsy and provides a relevant animal model for studying mechanisms of buildup of convulsive activity and pathways operative in the generalization and propagation of seizures within the forebrain . In the present study , the effects of manipulating the activity of the gamma - aminobutyric acid ( GABA ) - mediated synaptic inhibition within the substantia nigra on seizures produced by pilocarpine in rats , were investigated . In animals pretreated with microinjections of isoniazid , 150 micrograms , an inhibitor of activity of the GABA - synthesizing enzyme , L - glutamic acid decarboxylase , into the substantia nigra pars reticulata ( SNR ) , bilaterally , non - convulsant doses of pilocarpine , 100 and 200 mg / kg , resulted in severe motor limbic seizures and status epilepticus . Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for pilocarpine - induced convulsions . Morphological analysis of frontal forebrain sections with light microscopy revealed seizure - related damage to the hippocampal formation , thalamus , amygdala , olfactory cortex , substantia nigra and neocortex , which is typically observed with pilocarpine in doses exceeding 350 mg / kg . Bilateral intrastriatal injections of isoniazid did not augment seizures produced by pilocarpine , 200 mg / kg . Application of an irreversible inhibitor of GABA transaminase , gamma - vinyl - GABA ( D , L - 4 - amino - hex - 5 - enoic acid ) , 5 micrograms , into the SNR , bilaterally , suppressed the appearance of electrographic and behavioral seizures produced by pilocarpine , 380 mg / kg . This treatment was also sufficient to protect animals from the occurrence of brain damage . Microinjections of gamma - vinyl - GABA , 5 micrograms , into the dorsal striatum , bilaterally , failed to prevent the development of convulsions produced by pilocarpine , 380 mg / kg . The results demonstrate that the threshold for pilocarpine - induced seizures in rats is subjected to the regulation of the GABA - mediated synaptic inhibition within the substantia nigra . Human and canine ventricular vasoactive intestinal polypeptide : decrease with heart failure . Vasoactive intestinal polypeptide ( VIP ) is a systemic and coronary vasodilator that may have positive inotropic properties . Myocardial levels of VIP were assayed before and after the development of heart failure in two canine models . In the first , cobalt cardiomyopathy was induced in eight dogs ; VIP ( by radioimmunoassay ) decreased from 35 + / - 11 pg / mg protein ( mean + / - SD ) to 5 + / - 4 pg / mg protein ( P less than 0 . 05 ) . In six dogs with doxorubicin - induced heart failure , VIP decreased from 31 + / - 7 to 11 + / - 4 pg / mg protein ( P less than 0 . 05 ) . In addition , VIP content of left ventricular muscle of resected failing hearts in 10 patients receiving a heart transplant was compared with the papillary muscles in 14 patients ( five with rheumatic disease , nine with myxomatous degeneration ) receiving mitral valve prostheses . The lowest myocardial VIP concentration was found in the hearts of patients with coronary disease ( one patient receiving a transplant and three receiving mitral prostheses ) ( 6 . 3 + / - 1 . 9 pg / mg protein ) . The other patients undergoing transplantation had an average ejection fraction of 17 % + / - 6 % and a VIP level of 8 . 8 + / - 3 . 9 pg / mg protein . The hearts without coronary artery disease ( average ejection fraction of this group 62 % + / - 10 % ) had a VIP concentration of 14 . 1 + / - 7 . 9 pg / mg protein , and this was greater than in hearts of the patients with coronary disease and the hearts of patients receiving a transplant ( P less than 0 . 05 ) . Myocardial catecholamines were also determined in 14 subjects ; a weak correlation ( r = 0 . 57 , P less than 0 . 05 ) between the tissue concentrations of VIP and norepinephrine was noted . ( ABSTRACT TRUNCATED AT 250 WORDS ) Non - invasive detection of coronary artery disease by body surface electrocardiographic mapping after dipyridamole infusion . Electrocardiographic changes after dipyridamole infusion ( 0 . 568 mg / kg / 4 min ) were studied in 41 patients with coronary artery disease and compared with those after submaximal treadmill exercise by use of the body surface mapping technique . Patients were divided into three groups ; 19 patients without myocardial infarction ( non - MI group ) , 14 with anterior infarction ( ANT - MI ) and eight with inferior infarction ( INF - MI ) . Eighty - seven unipolar electrocardiograms ( ECGs ) distributed over the entire thoracic surface were simultaneously recorded . After dipyridamole , ischemic ST - segment depression ( 0 . 05 mV or more ) was observed in 84 % of the non - MI group , 29 % of the ANT - MI group , 63 % of the INF - MI group and 61 % of the total population . Exercise - induced ST depression was observed in 84 % of the non - MI group , 43 % of the ANT - MI group , 38 % of the INF - MI group and 61 % of the total . For individual patients , there were no obvious differences between the body surface distribution of ST depression in both tests . The increase in pressure rate product after dipyridamole was significantly less than that during the treadmill exercise . The data suggest that the dipyridamole - induced myocardial ischemia is caused by the inhomogenous distribution of myocardial blood flow . We conclude that the dipyridamole ECG test is as useful as the exercise ECG test for the assessment of coronary artery disease . Bradycardia after high - dose intravenous methylprednisolone therapy . In 5 consecutive patients with rheumatoid arthritis who received intravenous high - dose methylprednisolone ( MP ) therapy ( 1 g daily for 2 or 3 consecutive days ) , a decline in pulse rate was observed , most pronounced on day 4 . In one of the 5 patients the bradycardia was associated with complaints of substernal pressure . Reversal to normal heart rate was found on day 7 . Electrocardiographic registrations showed sinus bradycardia in all cases . No significant changes in plasma concentrations of electrolytes were found . Careful observation of patients receiving high - dose MP is recommended . High - dose MP may be contraindicated in patients with known heart disease . Two cases of downbeat nystagmus and oscillopsia associated with carbamazepine . Downbeat nystagmus is often associated with structural lesions at the craniocervical junction , but has occasionally been reported as a manifestation of metabolic imbalance or drug intoxication . We recorded the eye movements of two patients with reversible downbeat nystagmus related to carbamazepine therapy . The nystagmus of both patients resolved after reduction of the serum carbamazepine levels . Neuroradiologic investigations including magnetic resonance imaging scans in both patients showed no evidence of intracranial abnormality . In patients with downbeat nystagmus who are taking anticonvulsant medications , consideration should be given to reduction in dose before further investigation is undertaken . Improvement by denopamine ( TA - 064 ) of pentobarbital - induced cardiac failure in the dog heart - lung preparation . The efficacy of denopamine , an orally active beta 1 - adrenoceptor agonist , in improving cardiac failure was assessed in dog heart - lung preparations . Cardiac functions depressed by pentobarbital ( 118 + / - 28 mg ; mean value + / - SD ) such that cardiac output and maximum rate of rise of left ventricular pressure ( LV dP / dt max ) had been reduced by about 35 % and 26 % of the respective controls were improved by denopamine ( 10 - 300 micrograms ) in a dose - dependent manner . With 100 micrograms denopamine , almost complete restoration of cardiac performance was attained , associated with a slight increase in heart rate . No arrhythmias were induced by these doses of denopamine . The results warrant clinical trials of denopamine in the treatment of cardiac failure . Clonazepam monotherapy for epilepsy in childhood . Sixty patients ( age - range one month to 14 years ) with other types of epilepsy than infantile spasms were treated with clonazepam . Disappearance of seizures and normalization of abnormal EEG with disappearance of seizures were recognized in 77 % and 50 % , respectively . Seizures disappeared in 71 % of the patients with generalized seizures and 89 % of partial seizures . Improvement of abnormal EEG was noticed in 76 % of diffuse paroxysms and in 67 % of focal paroxysms . In excellent cases , mean effective dosages were 0 . 086 + / - 0 . 021 mg / kg / day in infants and 0 . 057 + / - 0 . 022 mg / kg / day in schoolchildren , this difference was statistically significant ( p less than 0 . 005 ) . The incidence of side effects such as drowsiness and ataxia was only 5 % . Postmarketing study of timolol - hydrochlorothiazide antihypertensive therapy . A postmarketing surveillance study was conducted to determine the safety and efficacy of a fixed - ratio combination containing 10 mg of timolol maleate and 25 mg of hydrochlorothiazide , administered twice daily for one month to hypertensive patients . Data on 9 , 037 patients were collected by 1 , 455 participating physicians . Mean systolic blood pressure decreased 25 mmHg and mean diastolic blood pressure declined 15 mmHg after one month of timolol - hydrochlorothiazide therapy ( P less than 0 . 01 , both comparisons ) . Age , race , and sex appeared to have no influence on the decrease in blood pressure . The antihypertensive effect of the drug was greater in patients with more severe hypertension . Overall , 1 , 453 patients experienced a total of 2 , 658 adverse events , the most common being fatigue , dizziness , and weakness . Treatment in 590 patients was discontinued because of adverse events . Salicylate nephropathy in the Gunn rat : potential role of prostaglandins . We examined the potential role of prostaglandins in the development of analgesic nephropathy in the Gunn strain of rat . The homozygous Gunn rats have unconjugated hyperbilirubinemia due to the absence of glucuronyl transferase , leading to marked bilirubin deposition in renal medulla and papilla . These rats are also highly susceptible to develop papillary necrosis with analgesic administration . We used homozygous ( jj ) and phenotypically normal heterozygous ( jJ ) animals . Four groups of rats ( n = 7 ) were studied : jj and jJ rats treated either with aspirin 300 mg / kg every other day or sham - treated . After one week , slices of cortex , outer and inner medulla from one kidney were incubated in buffer and prostaglandin synthesis was determined by radioimmunoassay . The other kidney was examined histologically . A marked corticomedullary gradient of prostaglandin synthesis was observed in all groups . PGE2 synthesis was significantly higher in outer medulla , but not cortex or inner medulla , of jj ( 38 + / - 6 ng / mg prot ) than jJ rats ( 15 + / - 3 ) ( p less than 0 . 01 ) . Aspirin treatment reduced PGE2 synthesis in all regions , but outer medullary PGE2 remained higher in jj ( 18 + / - 3 ) than jJ rats ( 9 + / - 2 ) ( p less than 0 . 05 ) . PGF2 alpha was also significantly higher in the outer medulla of jj rats with and without aspirin administration ( p less than 0 . 05 ) . The changes in renal prostaglandin synthesis were accompanied by evidence of renal damage in aspirin - treated jj but not jJ rats as evidenced by : increased incidence and severity of hematuria ( p less than 0 . 01 ) ; increased serum creatinine ( p less than 0 . 05 ) ; and increase in outer medullary histopathologic lesions ( p less than 0 . 005 compared to either sham - treated jj or aspirin - treated jJ ) . These results suggest that enhanced prostaglandin synthesis contributes to maintenance of renal function and morphological integrity , and that inhibition of prostaglandin synthesis may lead to pathological renal medullary lesions and deterioration of renal function . Prophylactic lidocaine in the early phase of suspected myocardial infarction . Four hundred two patients with suspected myocardial infarction seen within 6 hours of the onset of symptoms entered a double - blind randomized trial of lidocaine vs placebo . During the 1 hour after administration of the drug the incidence of ventricular fibrillation or sustained ventricular tachycardia among the 204 patients with acute myocardial infarction was low , 1 . 5 % . Lidocaine , given in a 300 mg dose intramuscularly followed by 100 mg intravenously , did not prevent sustained ventricular tachycardia , although there was a significant reduction in the number of patients with warning arrhythmias between 15 and 45 minutes after the administration of lidocaine ( p less than 0 . 05 ) . The average plasma lidocaine level 10 minutes after administration for patients without a myocardial infarction was significantly higher than that for patients with an acute infarction . The mean plasma lidocaine level of patients on beta - blocking agents was no different from that in patients not on beta blocking agents . During the 1 - hour study period , the incidence of central nervous system side effects was significantly greater in the lidocaine group , hypotension occurred in 11 patients , nine of whom had received lidocaine , and four patients died from asystole , three of whom had had lidocaine . We cannot advocate the administration of lidocaine prophylactically in the early hours of suspected myocardial infarction . Evidence for a cholinergic role in haloperidol - induced catalepsy . Experiments in mice tested previous evidence that activation of cholinergic systems promotes catalepsy and that cholinergic mechanisms need to be intact for full expression of neuroleptic - induced catalepsy . Large doses of the cholinomimetic , pilocarpine , could induce catalepsy when peripheral cholinergic receptors were blocked . Low doses of pilocarpine caused a pronounced enhancement of the catalepsy that was induced by the dopaminergic blocker , haloperidol . A muscarinic receptor blocker , atropine , disrupted haloperidol - induced catalepsy . Intracranial injection of an acetylcholine - synthesis inhibitor , hemicholinium , prevented the catalepsy that is usually induced by haloperidol . These findings suggest the hypothesis that the catalepsy that is produced by neuroleptics such as haloperidol is actually mediated by intrinsic central cholinergic systems . Alternatively , activation of central cholinergic systems could promote catalepsy by suppression of dopaminergic systems . Cardiovascular dysfunction and hypersensitivity to sodium pentobarbital induced by chronic barium chloride ingestion . Barium - supplemented Long - Evans hooded rats were characterized by a persistent hypertension that was evident after 1 month of barium ( 100 micrograms / ml mineral fortified water ) treatment . Analysis of in vivo myocardial excitability , contractility , and metabolic characteristics at 16 months revealed other significant barium - induced disturbances within the cardiovascular system . The most distinctive aspect of the barium effect was a demonstrated hypersensitivity of the cardiovascular system to sodium pentobarbital . Under barbiturate anesthesia , virtually all of the myocardial contractile indices were depressed significantly in barium - exposed rats relative to the corresponding control - fed rats . The lack of a similar response to ketamine and xylazine anesthesia revealed that the cardiovascular actions of sodium pentobarbital in barium - treated rats were linked specifically to this anesthetic , and were not representative of a generalized anesthetic response . Other myocardial pathophysiologic and metabolic changes induced by barium were manifest , irrespective of the anesthetic employed . The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of barium - treated rats relative to the control groups , irrespective of the anesthetic regimen . Similarly , significant disturbances in myocardial energy metabolism were detected in the barium - exposed rats which were consistent with the reduced contractile element shortening velocity . In addition , the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from barium - exposed rats . Overall , the altered cardiac contractility and excitability characteristics , the myocardial metabolic disturbances , and the hypersensitivity of the cardiovascular system to sodium pentobarbital suggest the existence of a heretofore undescribed cardiomyopathic disorder induced by chronic barium exposure . These experimental findings represent the first indication that life - long barium ingestion may have significant adverse effects on the mammalian cardiovascular system . Propranolol antagonism of phenylpropanolamine - induced hypertension . Phenylpropanolamine ( PPA ) overdose can cause severe hypertension , intracerebral hemorrhage , and death . We studied the efficacy and safety of propranolol in the treatment of PPA - induced hypertension . Subjects received propranolol either by mouth for 48 hours before PPA or as a rapid intravenous infusion after PPA . PPA , 75 mg alone , increased blood pressure ( 31 + / - 14 mm Hg systolic , 20 + / - 5 mm Hg diastolic ) , and propranolol pretreatment antagonized this increase ( 12 + / - 10 mm Hg systolic , 10 + / - 7 mm Hg diastolic ) . Intravenous propranolol after PPA also decreased blood pressure . Left ventricular function ( assessed by echocardiography ) showed that PPA increased the stroke volume 30 % ( from 62 . 5 + / - 20 . 9 to 80 . 8 + / - 22 . 4 ml ) , the ejection fraction 9 % ( from 64 % + / - 10 % to 70 % + / - 7 % ) , and cardiac output 14 % ( from 3 . 6 + / - 0 . 6 to 4 . 1 + / - 1 . 0 L / min ) . Intravenous propranolol reversed these effects . Systemic vascular resistance was increased by PPA 28 % ( from 1710 + / - 200 to 2190 + / - 700 dyne X sec / cm5 ) and was further increased by propranolol 22 % ( to 2660 + / - 1200 dyne X sec / cm5 ) . We conclude that PPA increases blood pressure by increasing systemic vascular resistance and cardiac output , and that propranolol antagonizes this increase by reversing the effect of PPA on cardiac output . That propranolol antagonizes the pressor effect of PPA is in contrast to the interaction in which propranolol enhances the pressor effect of norepinephrine . This is probably because PPA has less beta 2 activity than does norepinephrine . Mesangial function and glomerular sclerosis in rats with aminonucleoside nephrosis . The possible relationship between mesangial dysfunction and development of glomerular sclerosis was studied in the puromycin aminonucleoside ( PAN ) model . Five male Wistar rats received repeated subcutaneous PAN injections ; five controls received saline only . After 4 weeks the PAN rats were severely proteinuric ( 190 + / - 80 mg / 24 hr ) , and all rats were given colloidal carbon ( CC ) intravenously . At 5 months glomerular sclerosis was found in 7 . 6 + / - 3 . 4 % of the glomeruli of PAN rats ; glomeruli of the controls were normal . Glomeruli of PAN rats contained significantly more CC than glomeruli of controls . Glomeruli with sclerosis contained significantly more CC than non - sclerotic glomeruli in the same kidneys . CC was preferentially localized within the sclerotic areas of the affected glomeruli . Since mesangial CC clearance from the mesangium did not change during chronic PAN treatment , we conclude that this preferential CC localization within the lesions is caused by an increased CC uptake shortly after injection in apparent vulnerable areas where sclerosis will develop subsequently . Cluster analysis showed a random distribution of lesions in the PAN glomeruli in concordance with the random localization of mesangial areas with dysfunction in this model . Similar to the remnant kidney model in PAN nephrosis the development of glomerular sclerosis may be related to " mesangial overloading . " Relationship between nicotine - induced seizures and hippocampal nicotinic receptors . A controversy has existed for several years concerning the physiological relevance of the nicotinic receptor measured by alpha - bungarotoxin binding . Using mice derived from a classical F2 and backcross genetic design , a relationship between nicotine - induced seizures and alpha - bungarotoxin nicotinic receptor concentration was found . Mice sensitive to the convulsant effects of nicotine had greater alpha - bungarotoxin binding in the hippocampus than seizure insensitive mice . The binding sites from seizure sensitive and resistant mice were equally affected by treatment with dithiothreitol , trypsin or heat . Thus it appears that the difference between seizure sensitive and insensitive animals may be due to a difference in hippocampal nicotinic receptor concentration as measured with alpha - bungarotoxin binding . The role of p - aminophenol in acetaminophen - induced nephrotoxicity : effect of bis ( p - nitrophenyl ) phosphate on acetaminophen and p - aminophenol nephrotoxicity and metabolism in Fischer 344 rats . Acetaminophen ( APAP ) produces proximal tubular necrosis in Fischer 344 ( F344 ) rats . Recently , p - aminophenol ( PAP ) , a known potent nephrotoxicant , was identified as a metabolite of APAP in F344 rats . The purpose of this study was to determine if PAP formation is a requisite step in APAP - induced nephrotoxicity . Therefore , the effect of bis ( p - nitrophenyl ) phosphate ( BNPP ) , an acylamidase inhibitor , on APAP and PAP nephrotoxicity and metabolism was determined . BNPP ( 1 to 8 mM ) reduced APAP deacetylation and covalent binding in F344 renal cortical homogenates in a concentration - dependent manner . Pretreatment of animals with BNPP prior to APAP or PAP administration resulted in marked reduction of APAP ( 900 mg / kg ) nephrotoxicity but not PAP nephrotoxicity . This result was not due to altered disposition of either APAP or acetylated metabolites in plasma or renal cortical and hepatic tissue . Rather , BNPP pretreatment reduced the fraction of APAP excreted as PAP by 64 and 75 % after APAP doses of 750 and 900 mg / kg . BNPP did not alter the excretion of APAP or any of its non - deacetylated metabolites nor did BNPP alter excretion of PAP or its metabolites after PAP doses of 150 and 300 mg / kg . Therefore , the BNPP - induced reduction in APAP - induced nephrotoxicity appears to be due to inhibition of APAP deacetylation . It is concluded that PAP formation , in vivo , accounts , at least in part , for APAP - induced renal tubular necrosis . Morphine - induced seizures in newborn infants . Two neonates suffered from generalized seizures during the course of intravenous morphine sulfate for post - operative analgesia . They received morphine in doses of 32 micrograms / kg / hr and 40 micrograms / kg / hr larger than a group of 10 neonates who received 6 - 24 micrograms / kg / hr and had no seizures . Plasma concentrations of morphine in these neonates was excessive ( 60 and 90 mg / ml ) . Other known reasons for seizures were ruled out and the convulsions stopped a few hours after cessation of morphine and did not reoccur in the subsequent 8 months . It is suggested that post - operative intravenous morphine should not exceed 20 micrograms / kg / ml in neonates . Indomethacin induced hypotension in sodium and volume depleted rats . After a single oral dose of 4 mg / kg indomethacin ( IDM ) to sodium and volume depleted rats plasma renin activity ( PRA ) and systolic blood pressure fell significantly within four hours . In sodium repleted animals indomethacin did not change systolic blood pressure ( BP ) although plasma renin activity was decreased . Thus , indomethacin by inhibition of prostaglandin synthesis may diminish the blood pressure maintaining effect of the stimulated renin - angiotensin system in sodium and volume depletion . On the antiarrhythmic activity of one N - substituted piperazine derivative of trans - 2 - amino - 3 - hydroxy - 1 , 2 , 3 , 4 - tetrahydroanaphthalene . The antiarrhythmic activity of the compound N - ( trans - 3 - hydroxy - 1 , 2 , 3 , 4 - tetrahydro - 2 - naphthyl ) - N - ( 3 - oxo - 3 - phenyl - 2 - methylpropyl ) - piperazine hydrochloride , referred to as P11 , is studied on anaesthesized cats and Wistar albino rats , as well as on non - anaesthesized rabbits . Four types of experimental arrhythmia are used - - with BaCl2 , with chloroform - adrenaline , with strophantine G and with aconitine . The compound P11 is introduced in doses of 0 . 25 and 0 . 50 mg / kg intravenously and 10 mg / kg orally . The compound manifests antiarrhythmic activity in all models of experimental arrhythmia used , causing greatest inhibition on the arrhythmia induced by chloroform - adrenaline ( in 90 per cent ) and with BaCl2 ( in 84 per cent ) . The results obtained are associated with the beta - adrenoblocking and with the membrane - stabilizing action of the compound . Recurrent subarachnoid hemorrhage associated with aminocaproic acid therapy and acute renal artery thrombosis . Case report . Epsilon aminocaproic acid ( EACA ) has been used to prevent rebleeding in patients with subarachnoid hemorrhage ( SAH ) . Although this agent does decrease the frequency of rebleeding , several reports have described thrombotic complications of EACA therapy . These complications have included clinical deterioration and intracranial vascular thrombosis in patients with SAH , arteriolar and capillary fibrin thrombi in patients with fibrinolytic syndromes treated with EACA , or other thromboembolic phenomena . Since intravascular fibrin thrombi are often observed in patients with fibrinolytic disorders , EACA should not be implicated in the pathogenesis of fibrin thrombi in patients with disseminated intravascular coagulation or other " consumption coagulopathies . " This report describes subtotal infarction of the kidney due to thrombosis of a normal renal artery . This occlusion occurred after EACA therapy in a patient with SAH and histopathological documentation of recurrent SAH . The corresponding clinical event was characterized by marked hypertension and abrupt neurological deterioration . Effect of vincristine sulfate on Pseudomonas infections in monkeys . In rhesus monkeys , intravenous challenge with 0 . 6 x 10 ( 10 ) to 2 . 2 x 10 ( 10 ) Pseudomonas aeruginosa organisms caused acute illness of 4 to 5 days ' duration with spontaneous recovery in 13 of 15 monkeys ; blood cultures became negative 3 to 17 days after challenge . Leukocytosis was observed in all monkeys . Intravenous or intratracheal inoculation of 2 . 0 to 2 . 5 mg of vincristine sulfate was followed by leukopenia in 4 to 5 days . Intravenous inoculation of 4 . 2 x 10 ( 10 ) to 7 . 8 x 10 ( 10 ) pyocin type 6 Pseudomonas organisms in monkeys given vincristine sulfate 4 days previously resulted in fatal infection in 11 of 14 monkeys , whereas none of four receiving Pseudomonas alone died . These studies suggest that an antimetabolite - induced leukopenia predisposes to severe Pseudomonas sepsis and that such monkeys may serve as a biological model for study of comparative efficacy of antimicrobial agents . Modification by propranolol of cardiovascular effects of induced hypoglycaemia . The cardiovascular effects of hypoglycaemia , with and without beta - blockade , were compared in fourteen healthy men . Eight received insulin alone , and eight , including two of the original insulin - only group , were given propranolol and insulin . In the insulin - group the period of hypoglycaemia was associated with an increase in heart - rate and a fall in diastolic blood - pressure . In the propranolol - insulin group there was a significant fall in heart - rate in most subjects and an increase in diastolic pressure . Typical S - T / T changes occurred in the insulin - group but in none of the propranolol - insulin group . Hypertension in diabetics prone to hypoglycaemia attacks should not be treated with beta - blockers because these drugs may cause a sharp rise in blood - pressure in such patients . Long - term propranolol therapy in pregnancy : maternal and fetal outcome . Propranolol , a beta - adrenergic blocking agent , has found an important position in the practice of medicine . Its use in pregnancy , however , is an open question as a number of detrimental side effects have been reported in the fetus and neonate . Ten patients and 12 pregnancies are reported where chronic propranolol has been administered . Five patients with serial pregnancies with and without propranolol therapy are also examined . Maternal , fetal , and neonatal complications are examined . An attempt is made to differentiate drug - related complications from maternal disease - - related complications . We conclude that previously reported hypoglycemia , hyperbilirubinemia , polycythemia , neonatal apnea , and bradycardia are not invariable and cannot be statistically correlated with chronic propranolol therapy . Growth retardation , however , appears to be significant in both of our series . Central excitatory actions of flurazepam . Toxic actions of flurazepam ( FZP ) were studied in cats , mice and rats . High doses caused an apparent central excitation , most clearly seen as clonic convulsions , superimposed on general depression . Following a lethal dose , death was always associated with convulsions . Comparing the relative sensitivity to central depression and excitation revealed that rats were least likely to have convulsions at doses that did not first cause loss of consciousness , while cats most clearly showed marked central excitatory actions . Signs of FZP toxocity in cats included excessive salivation , extreme apprehensive behavior , retching , muscle tremors and convulsions . An interaction between FZP and pentylenetetrazol ( PTZ ) was shown by pretreating mice with FZP before PTZ challenge . As a function of dose , FZP first protected against convulsions and death . At higher doses , however , convulsions again emerged . These doses of FZP were lower than those that would alone cause convulsions . These results may be relevant to the use of FZP in clinical situations in which there is increased neural excitability , such as epilepsy or sedative - hypnotic drug withdrawal . Use of propranolol in the treatment of idiopathic orthostatic hypotension . Five patients with idiopathic orthostatic hypotension who had physiologic and biochemical evidence of severe autonomic dysfunction were included in the study . They all exhibited markedly reduced plasma catecholamines and plasma renin activity in both recumbent and upright positions and had marked hypersensitivity to the pressor effects of infused norepinephrine . Treatment with propanolol administered intravenously ( 1 - 5 mg ) produced increases in supine and upright blood pressure in 4 of the 5 individuals with rises ranging from 11 / 6 to 22 / 11 mmHg . Chronic oral administration of propranolol ( 40 - 160 mg / day ) also elevated the blood pressures of these individuals with increases in the order of 20 - 35 / 15 - 25 mmg being observed . In 1 patient , marked hypertension was induced by propranolol and the drug had to be withdrawn . It otherwise was well tolerated and no important side effects were observed . Treatment has been continued in 3 individuals for 6 - 13 months with persistence of the pressor effect , although there appears to have been some decrease in the degree of response with time . Hemodynamic measurements in 1 of the patients demonstrated an increase in total peripheral resistance and essentially no change in cardiac output following propranolol therapy . The studies suggest that propranolol is a useful drug in selected patients with severe idiopathic orthostatic hypotension . Total intravenous anesthesia with etomidate . III . Some observations in adults . An investigation was undertaken to determine the dosage of etomidate required to maintain sleep in adults undergoing surgery under regional local anesthesia . Premedication of diazepam 10 mg and atropine 0 . 5 mg was given , and sleep was induced and maintained by intermittent intravenous injections of etomidate 0 . 1 / mg / kg , given whenever the patient would open his eyes on request . A mean overall dose of etomidate 17 . 4 microgram / kg / min . was required to maintain sleep , but great individual variation occurred , with older patients requiring less drug . The investigation was discontinued after 18 patients because of the frequency and intensity of side - effects , particularly pain and myoclonia , which caused the technique to be abandoned in two cases . It is considered unlikely that etomidate will prove to be the hypnotic of choice for a totally intravenous anesthetic technique in adults because of the high incidence of myoclonia after prolonged administration . In several patients uncontrollable muscle movements persisted for many minutes after complete recovery of consciousness . Evidence for cardiac beta 2 - adrenoceptors in man . We compared the effects of single doses of 50 mg atenolol ( cardioselective ) , 40 mg propranolol ( nonselective ) , and placebo on both exercise - and isoproterenol - induced tachycardia in two experiments involving nine normal subjects . Maximal exercise heart rate was reduced from 187 + / - 4 ( SEM ) after placebo to 146 + / - 7 bpm after atenolol and 138 + / - 6 bpm after propranolol , but there were no differences between the drugs . The effects on isoproterenol tachycardia were determined before and after atropine ( 0 . 04 mg / kg IV ) . Isoproterenol sensitivity was determined as the intravenous dose that increased heart rate by 25 bpm ( CD25 ) and this was increased from 1 . 8 + / - 0 . 3 micrograms after placebo to 38 . 9 + / - 8 . 3 micrograms after propranolol and 8 . 3 + / - 1 . 7 micrograms after atenolol . The difference in the effects of the two was significant . After atropine the CD25 was unchanged after placebo ( 2 . 3 + / - 0 . 3 micrograms ) and atenolol ( 7 . 7 + / - 1 . 3 micrograms ) ; it was reduced after propranolol ( 24 . 8 + / - 5 . 0 micrograms ) , but remained different from atenolol . This change with propranolol sensitivity was calculated as the apparent Ka , this was unchanged by atropine ( 11 . 7 + / - 2 . 1 and 10 . 1 + / - 2 . 5 ml / ng ) . These data are consistent with the hypothesis that exercise - induced tachycardia results largely from beta 1 - receptor activation that is blocked by both cardioselective and nonselective drugs , whereas isoproterenol activates both beta 1 - and beta 2 - receptors so that after cardioselective blockade there remains a beta 2 - component that can be blocked with a nonselective drug . While there appear to be beta 2 - receptors in the human heart , their physiologic or pathologic roles remain to be defined . Hormones and risk of breast cancer . This paper reports the results of a study of 50 menopausal women receiving hormonal replacement therapy . The majority ( 29 ) had surgical menopause ; their mean age was 45 . 7 years . It was hypothesized that progestins could equilibrate the effects of the estrogenic stimulation on the mammary and endometrial target tissues of women on hormonal replacement therapy . The treatment schedule consisted of conjugated estrogens ( Premarin ) 1 . 25 mg / day for 21 days and Medroxyprogesterone acetate 10 mg / day for 10 days in each month . The mean treatment period was 18 months . During the follow - up period , attention was paid to breast modifications as evidenced by symptomatology , physical examination , and plate thermography . Mastodynia was reported by 21 patients , and physical examination revealed a light increase in breast firmness in 12 women and a moderate increase in breast nodularity in 2 women . Themography confirmed the existence of an excessive breast stimulation in 1 women who complained of moderate mastodynia and in 5 of the 7 women who complained of severe mastodynia . Normalization was obtained by halving the estrogen dose . These results suggest that hormonal replacement therapy can be safely prescribed if the following criteria are satisfied : 1 ) preliminary evaluation of patients from a clinical , metabolic , cytologic , and mammographic perspective ; 2 ) cyclic treatment schedule , with a progestative phase of 10 days ; and 3 ) periodic complete follow - up , with accurate thermographic evaluation of the breast target tissues . Early infections in kidney , heart , and liver transplant recipients on cyclosporine . Eighty - one renal , seventeen heart , and twenty - four liver transplant patients were followed for infection . Seventeen renal patients received azathioprine ( Aza ) and prednisone as part of a randomized trial of immunosuppression with 21 cyclosporine - and - prednisone - treated renal transplant patients . All others received cyclosporine and prednisone . The randomized Aza patients had more overall infections ( P less than 0 . 05 ) and more nonviral infections ( P less than 0 . 02 ) than the randomized cyclosporine patients . Heart and liver patients had more infections than cyclosporine renal patients but fewer infections than the Aza renal patients . There were no infectious deaths in renal transplant patients on cyclosporine or Aza , but infection played a major role in 3 out of 6 cardiac transplant deaths and in 8 out of 9 liver transplant deaths . Renal patients on cyclosporine had the fewest bacteremias . Analysis of site of infection showed a preponderance of abdominal infections in liver patients , intrathoracic infections in heart patients , and urinary tract infections in renal patients . Pulmonary infections were less common in cyclosporine - treated renal patients than in Aza - treated patients ( P less than 0 . 05 ) . Aza patients had significantly more staphylococcal infections than all other transplant groups ( P less than 0 . 005 ) , and systemic fungal infections occurred only in the liver transplant group . Cytomegalovirus ( CMV ) shedding or serological rises in antibody titer , or both occurred in 78 % of cyclosporine patients and 76 % of Aza patients . Of the cyclosporine patients , 15 % had symptoms related to CMV infection . Serological evidence for Epstein Barr Virus infection was found in 20 % of 65 cyclosporine patients studied . Three had associated symptoms , and one developed a lymphoma . Structure - activity and dose - effect relationships of the antagonism of picrotoxin - induced seizures by cholecystokinin , fragments and analogues of cholecystokinin in mice . Intraperitoneal administration of cholecystokinin octapeptide sulphate ester ( CCK - 8 - SE ) and nonsulphated cholecystokinin octapeptide ( CCK - 8 - NS ) enhanced the latency of seizures induced by picrotoxin in mice . Experiments with N - and C - terminal fragments revealed that the C - terminal tetrapeptide ( CCK - 5 - 8 ) was the active centre of the CCK octapeptide molecule . The analogues CCK - 8 - SE and CCK - 8 - NS ( dose range 0 . 2 - 6 . 4 mumol / kg ) and caerulein dose range 0 . 1 - 0 . 8 mumol / kg ) showed bell - shaped dose - effect curves , with the greatest maximum inhibition for CCK - 8 - NS . The peptide CCK - 5 - 8 had weak anticonvulsant activity in comparison to the octapeptides , 3 . 2 mumol / kg and larger doses of the reference drug , diazepam , totally prevented picrotoxin - induced seizures and mortality . The maximum effect of the peptides tested was less than that of diazepam . Experiments with analogues and derivatives of CCK - 5 - 8 demonstrated that the effectiveness of the beta - alanyl derivatives of CCK - 5 - 8 were enhanced and that they were equipotent with CCK - 8 - SE . Of the CCK - 2 - 8 analogues , Ser ( SO3H ) 7 - Ac - CCK - 2 - 8 - SE and Thr ( SO3H ) 7 - Ac - CCK - 2 - 8 - SE and Hyp ( SO3H ) - Ac - CCK - 2 - 8 - SE were slightly more active than CCK - 8 - SE . Vasopressin as a possible contributor to hypertension . The role of vasopressin as a pressor agent to the hypertensive process was examined . Vasopressin plays a major role in the pathogenesis of DOCA - salt hypertension , since the elevation of blood pressure was not substantial in the rats with lithium - treated diabetes insipidus after DOCA - salt treatment . Administration of DDAVP which has antidiuretic action but minimal vasopressor effect failed to increase blood pressure to the levels observed after administration of AVP . Furthermore , the pressor action of vasopressin appears to be important in the development of this model of hypertension , since the enhanced pressor responsiveness to the hormone was observed in the initial stage of hypertension . Increased secretion of vasopressin from neurohypophysis also promotes the function of the hormone as a pathogenetic factor in hypertension . An unproportional release of vasopressin compared to plasma osmolality may be induced by the absence of an adjusting control of angiotensin II forming and receptor binding capacity for sodium balance in the brain . However , the role of vasopressin remains to be determined in human essential hypertension . Toxic hepatitis induced by disulfiram in a non - alcoholic . A reversible toxic liver damage was observed in a non - alcoholic woman treated with disulfiram . The causative relationship was proven by challenge . Atrial thrombosis involving the heart of F - 344 rats ingesting quinacrine hydrochloride . Quinacrine hydrochloride is toxic for the heart of F - 344 rats . Rats treated with 500 ppm quinacrine hydrochloride in the diet all developed a high incidence of left atrial thrombosis . The lesion was associated with cardiac hypertrophy and dilatation and focal myocardial degeneration . Rats died from cardiac hypertrophy with severe acute and chronic congestion of the lungs , liver , and other organs . Seventy percent of rats given 250 ppm quinacrine hydrochloride and 1 , 000 ppm sodium nitrite simultaneously in the diet had thrombosis of the atria of the heart , while untreated control rats in this laboratory did not have atrial thrombosis . Sodium nitrite in combination with quinacrine hydrochloride appeared to have no additional effect . Alternating sinus rhythm and intermittent sinoatrial block induced by propranolol . Alternating sinus rhythm and intermittent sinoatrial ( S - A ) block was observed in a 57 - year - old woman , under treatment for angina with 80 mg propranolol daily . The electrocardiogram showed alternation of long and short P - P intervals and occasional pauses . These pauses were always preceded by the short P - P intervals and were usually followed by one or two P - P intervals of 0 . 92 - 0 . 95 s representing the basic sinus cycle . Following these basic sinus cycles , alternating rhythm started with the longer P - P interval . The long P - P intervals ranged between 1 . 04 - 1 . 12 s and the short P - P intervals between 0 . 80 - 0 . 84 s , respectively . The duration of the pauses were equal or almost equal to one short plus one long P - P interval or to twice the basic sinus cycle . In one recording a short period of regular sinus rhythm with intermittent 2 / 1 S - A block was observed . This short period of sinus rhythm was interrupted by sudden prolongation of the P - P interval starting the alternative rhythm . There were small changes in the shape of the P waves and P - R intervals . S - A conduction through two pathways , the first with 2 / 1 block the second having 0 . 12 - 0 . 14 s longer conduction time and with occasional 2 / 1 block was proposed for the explanation of the alternating P - P interval and other electrocardiographic features seen . Atropine 1 mg given intravenously resulted in shortening of all P - P intervals without changing the rhythm . The abnormal rhythm disappeared with the withdrawal of propranolol and when the drug was restarted a 2 / 1 S - A block was seen . This was accepted as evidence for propranolol being the cause of this conduction disorder . Antitumor effect , cardiotoxicity , and nephrotoxicity of doxorubicin in the IgM solid immunocytoma - bearing LOU / M / WSL rat . Antitumor activity , cardiotoxicity , and nephrotoxicity induced by doxorubicin were studied in LOU / M / WSL inbred rats each bearing a transplantable solid IgM immunocytoma . Animals with a tumor ( diameter , 15 . 8 + / - 3 . 3 mm ) were treated with iv injections of doxorubicin on 5 consecutive days , followed by 1 weekly injection for 7 weeks ( dose range , 0 . 015 - 4 . 0 mg / kg body wt ) . Tumor regression was observed with 0 . 5 mg doxorubicin / kg . Complete disappearance of the tumor was induced with 1 . 0 mg doxorubicin / kg . Histologic evidence of cardiotoxicity scored as grade III was only observed at a dose of 1 . 0 mg doxorubicin / kg . Light microscopic evidence of renal damage was seen above a dose of 0 . 5 mg doxorubicin / kg , which resulted in albuminuria and very low serum albumin levels . In the group that received 1 . 0 mg doxorubicin / kg , the serum albumin level decreased from 33 . 6 + / - 4 . 1 to 1 . 5 + / - 0 . 5 g / liter . Ascites and hydrothorax were observed simultaneously . The same experiments were performed with non - tumor - bearing rats , in which no major differences were observed . In conclusion , antitumor activity , cardiotoxicity , and nephrotoxicity were studied simultaneously in the same LOU / M / WSL rat . Albuminuria due to renal damage led to extremely low serum albumin levels , so ascites and hydrothorax were not necessarily a consequence of the observed cardiomyopathy . Intraoperative bradycardia and hypotension associated with timolol and pilocarpine eye drops . A 69 - yr - old man , who was concurrently being treated with pilocarpine nitrate and timolol maleate eye drops , developed a bradycardia and became hypotensive during halothane anaesthesia . Both timolol and pilocarpine were subsequently identified in a 24 - h collection of urine . Timolol ( but not pilocarpine ) was detected in a sample of plasma removed during surgery ; the plasma concentration of timolol ( 2 . 6 ng ml - 1 ) was consistent with partial beta - adrenoceptor blockade . It is postulated that this action may have been enhanced during halothane anaesthesia with resultant bradycardia and hypotension . Pilocarpine may have had a contributory effect . Succinylcholine apnoea : attempted reversal with anticholinesterases . Anticholinesterases were administered in an attempt to antagonize prolonged neuromuscular blockade following the administration of succinylcholine in a patient later found to be homozygous for atypical plasma cholinesterase . Edrophonium 10 mg , given 74 min after succinylcholine , when train - of - four stimulation was characteristic of phase II block , produced partial antagonism which was not sustained . Repeated doses of edrophonium to 70 mg and neostigmine to 2 . 5 mg did not antagonize or augment the block . Spontaneous respiration recommenced 200 min after succinylcholine administration . It is concluded that anticholinesterases are only partially effective in restoring neuromuscular function in succinylcholine apnoea despite muscle twitch activity typical of phase II block . Effect of doxorubicin on [ omega - I - 131 ] heptadecanoic acid myocardial scintigraphy and echocardiography in dogs . The effects of serial treatment with doxorubicin on dynamic myocardial scintigraphy with [ omega - I - 131 ] heptadecanoic acid ( I - 131 HA ) , and on global left - ventricular function determined echocardiographically , were studied in a group of nine mongrel dogs . Total extractable myocardial lipid was compared postmortem between a group of control dogs and doxorubicin - treated dogs . A significant and then progressive fall in global LV function was observed at a cumulative doxorubicin dose of 4 mg / kg . A significant increase in the myocardial t1 / 2 of the I - 131 HA was observed only at a higher cumulative dose , 10 mg / kg . No significant alteration in total extractable myocardial lipids was observed between control dogs and those treated with doxorubicin . Our findings suggest that the changes leading to an alteration of myocardial dynamic imaging with I - 131 HA are not the initiating factor in doxorubicin cardiotoxicity . Hemodynamics and myocardial metabolism under deliberate hypotension . An experimental study in dogs . Coronary blood flow , cardiac work and metabolism were studied in dogs under sodium nitroprusside ( SNP ) and trimetaphan ( TMP ) deliberate hypotension ( 20 % and 40 % mean pressure decrease from baseline ) . Regarding the effects of drug - induced hypotension on coronary blood flow , aortic and coronary sinus metabolic data ( pH , pO2 , pCO2 ) we could confirm that nitroprusside hypotension could be safely used to 30 % mean blood pressure decrease from control , trimetaphan hypotension to 20 % mean blood pressure decrease . Cardiac work was significantly reduced during SNP hypotension . Myocardial O2 consumption and O2 availability were directly dependent on the coronary perfusion . Careful invasive monitoring of the blood pressure , blood gases and of the ECG ST - T segment is mandatory . Evidence for a selective brain noradrenergic involvement in the locomotor stimulant effects of amphetamine in the rat . Male rats received the noradrenaline neurotoxin DSP4 ( 50 mg / kg ) 7 days prior to injection of D - amphetamine ( 10 or 40 mumol / kg i . p . ) . The hyperactivity induced by D - amphetamine ( 10 mumol / kg ) was significantly reduced by DSP4 pretreatment . However , the increased rearings and the amphetamine - induced stereotypies were not blocked by pretreatment with DSP4 . The reduction of amphetamine hyperactivity induced by DSP4 was blocked by pretreatment with the noradrenaline - uptake blocking agent , desipramine , which prevents the neurotoxic action of DSP4 . The present results suggest a selective involvement of central noradrenergic neurones in the locomotor stimulant effect of amphetamine in the rat . Accelerated junctional rhythms during oral verapamil therapy . This study examined the frequency of atrioventricular ( AV ) dissociation and accelerated junctional rhythms in 59 patients receiving oral verapamil . Accelerated junctional rhythms and AV dissociation were frequent in patients with supraventricular tachyarrhythmias , particularly AV nodal reentry . Verapamil administration to these patients led to an asymptomatic increase in activity of these junctional pacemakers . In patients with various chest pain syndromes , verapamil neither increased the frequency of junctional rhythms nor suppressed their role as escape rhythms under physiologically appropriate circumstances . Interstrain variation in acute toxic response to caffeine among inbred mice . Acute toxic dosage - dependent behavioral effects of caffeine were compared in adult males from seven inbred mouse strains ( A / J , BALB / cJ , CBA / J , C3H / HeJ , C57BL / 6J , DBA / 2J , SWR / J ) . C57BL / 6J , chosen as a " prototypic " mouse strain , was used to determine behavioral responses to a broad range ( 5 - 500 mg / kg ) of caffeine doses . Five phenotypic characteristics - - locomotor activity , righting ability , clonic seizure induction , stress - induced lethality , death without external stress - - were scored at various caffeine doses in drug - naive animals under empirically optimized , rigidly constant experimental conditions . Mice ( n = 12 for each point ) received single IP injections of a fixed volume / g body weight of physiological saline carrier with or without caffeine in doses ranging from 125 - 500 mg / kg . Loss of righting ability was scored at 1 , 3 , 5 min post dosing and at 5 min intervals thereafter for 20 min . In the same animals the occurrence of clonic seizures was scored as to time of onset and severity for 20 min after drug administration . When these proceeded to tonic seizures , death occurred in less than 20 min . Animals surviving for 20 min were immediately stressed by a swim test in 25 degrees C water , and death - producing tonic seizures were scored for 2 min . In other animals locomotor activity was measured 15 or 60 min after caffeine administration . By any single behavioral criterion or a combination of these criteria , marked differences in response to toxic caffeine doses were observed between strains . These results indicate that behavioral toxicity testing of alkylxanthines in a single mouse strain may be misleading and suggest that toxic responses of the central nervous system to this class of compounds are genetically influenced in mammals . Treatment of ovarian cancer with a combination of cis - platinum , adriamycin , cyclophosphamide and hexamethylmelamine . During the last 2 1 / 2 years , 38 patients with ovarian cancer were treated with a combination of cisplatinum ( CPDD ) , 50 mg / m2 , adriamycin , 30 mg / m2 , cyclophosphamide , 300 mg / m2 , on day 1 ; and hexamethylmelamine ( HMM ) , 6 mg / kg daily , for 14 days . Each course was repeated monthly . 2 patients had stage II , 14 stage III and 22 stage IV disease . 14 of the 38 patients were previously treated with chemotherapy , 1 with radiation , 6 with both chemotherapy and radiation , and 17 did not have any treatment before CPDD combination . 31 of the 38 cases ( 81 . 5 % ) demonstrated objective responses lasting for 2 months or more . These responses were partial in 19 and complete in 12 cases . Hematologic toxicity was moderate and with reversible anemia developing in 71 % of patients . Gastrointestinal side effects from CPDD were universal . HMM gastrointestinal toxicity necessitated discontinuation of the drug in 5 patients . Severe nephrotoxicity was observed in 2 patients but was reversible . There were no drug - related deaths . Nontraumatic dissecting aneurysm of the basilar artery . A case of nontraumatic dissecting aneurysm of the basilar artery in association with hypertension , smoke , and oral contraceptives is reported in a young female patient with a locked - in syndrome . A method for the measurement of tremor , and a comparison of the effects of tocolytic beta - mimetics . A method permitting measurement of finger tremor as a displacement - time curve is described , using a test system with simple amplitude calibration . The coordinates of the inversion points of the displacement - time curves were transferred through graphical input equipment to punched tape . By means of a computer program , periods and amplitudes of tremor oscillations were calculated and classified . The event frequency for each class of periods and amplitudes was determined . The actions of fenoterol - hydrobromide , ritodrin - HCl and placebo given to 10 healthy subjects by intravenous infusion in a double - blind crossover study were tested by this method . At therapeutic doses both substances raised the mean tremor amplitude to about three times the control level . At the same time , the mean period within each class of amplitudes shortened by 10 - - 20 ms , whereas the mean periods calculated from all oscillations together did not change significantly . After the end of fenoterol - hydrobromide infusion , tremor amplitudes decreased significantly faster than those following ritodrin - HCl infusion . Propylthiouracil - induced hepatic damage . Two cases of propylthiouracil - induced liver damage have been observed . The first case is of an acute type of damage , proven by rechallenge ; the second presents a clinical and histologic picture resembling chronic active hepatitis , with spontaneous remission . Studies on the bradycardia induced by bepridil . Bepridil , a novel active compound for prophylactic treatment of anginal attacks , induced persistent bradycardia and a non - specific anti - tachycardial effect , the mechanisms of which were investigated in vitro and in vivo . In vitro perfusion of bepridil in the life - support medium for isolated sino - atrial tissue from rabbit heart , caused a reduction in action potential ( AP ) spike frequency ( recorded by KCl microelectrodes ) starting at doses of 5 X 10 ( - 6 ) M . This effect was dose - dependent up to concentrations of 5 X 10 ( - 5 ) M , whereupon blockade of sinus activity set in . Bepridil at a dose of 5 X 10 ( - 6 ) M , induced a concomitant reduction in AP amplitude ( falling from 71 + / - 8 mV to 47 + / - 6 mV ) , maximum systolic depolarization velocity ( phase 0 ) which fell from 1 . 85 + / - 0 . 35 V / s to 0 . 84 + / - 0 . 28 V / s , together with maximum diastolic depolarization velocity ( phase 4 ) which fell from 38 + / - 3 mV / s to 24 + / - 5 mV / s . In vivo injection of bepridil at a dose of 5 mg / kg ( i . v . ) into 6 anaesthetized dogs which had undergone ablation of all the extrinsic cardiac afferent nerve supply , together with a bilateral medullo - adrenalectomy , caused a marked reduction in heart rate which fell from 98 . 7 + / - 4 . 2 beats / min to 76 + / - 5 . 3 beats / min sustained for more than 45 min . It is concluded that bepridil reduces heart rate by acting directly on the sinus node . This effect , which results in a flattening of the phase 0 and phase 4 slope , together with a longer AP duration , may be due to an increase in the time constants of slow inward ionic currents ( already demonstrated elsewhere ) , but also to an increased time constant for deactivation of the outward potassium current ( Ip ) . Hepatitis and renal tubular acidosis after anesthesia with methoxyflurane . A 69 - year - old man operated for acute cholecystitis under methoxyflurane anesthesia developed postoperatively a hepatic insufficiency syndrome and renal tubular acidosis . Massive bleeding appeared during surgery which lasted for six hours . Postoperative evolution under supportive therapy was favourable . Complete recovery was confirmed by repeated controls performed over a period of one year after surgery . Pituitary response to luteinizing hormone - releasing hormone during haloperidol - induced hyperprolactinemia . The effects of a 6 - hour infusion with haloperidol on serum prolactin and luteinizing hormone ( LH ) levels was studied in a group of male subjects . Five hours after starting the infusions , a study of the pituitary responses to LH - releasing hormone ( LH - RH ) was carried out . Control patients received infusions of 0 . 9 % NaCl solution . During the course of haloperidol infusions , significant hyperprolactinemia was found , together with an abolished pituitary response to LH - RH , as compared with responses of control subjects . Antirifampicin antibodies in acute rifampicin - associated renal failure . 5 patients with acute renal failure ( 3 with thrombopenia and hemolysis ) induced by the reintroduction of rifampicin are described . No correlation was found between the severity of clinical manifestations and the total dose taken by the patients . In all but 1 patient , antirifampicin antibodies were detected . Antibodies suggested to be of the IgM class were detected in all 3 patients with hematological disorders . The pattern of non - specific acute tubular necrosis found in the 2 biopsied patients , indistinguishable from that of ischemic origin , raised the possibility of a vascular - mediated damage . In 3 patients , the possibility of a triggering immunoallergic mechanism is discussed . Cardiovascular effects of hypotension induced by adenosine triphosphate and sodium nitroprusside on dogs with denervated hearts . Adenosine triphosphate ( ATP ) and sodium nitroprusside ( SNP ) are administered to patients to induce and control hypotension during anesthesia . SNP is authorized for clinical use in USA and UK , and ATP is clinically used in other countries such as Japan . We investigated how these two drugs act on the cardiovascular systems of 20 dogs whose hearts had been denervated by a procedure we had devised . ATP ( 10 dogs ) or SNP ( 10 dogs ) was administered to reduce mean arterial pressure by 30 % to 70 % of control . Before , during and after induced hypotension , we measured major cardiovascular parameters . Hypotension induced by ATP was accompanied by significant decreases in mean pulmonary arterial pressure ( p less than 0 . 001 ) , central venous pressure ( p less than 0 . 001 ) , left ventricular end - diastolic pressure ( p less than 0 . 001 ) , total peripheral resistance ( p less than 0 . 001 ) , rate pressure product ( p less than 0 . 001 ) , total body oxygen consumption ( p less than 0 . 05 ) , and heart rate ( p less than 0 . 001 ) ; all these variables returned normal within 30 min after ATP was stopped . Cardiac output did not change . During hypotension produced by SNP similar decreases were observed in mean pulmonary arterial pressure ( p less than 0 . 01 ) , central venous pressure ( p less than 0 . 001 ) , left ventricular end - diastolic pressure ( p less than 0 . 01 ) , total peripheral resistance ( p less than 0 . 001 ) , rate pressure product ( p less than 0 . 001 ) , and oxygen content difference between arterial and mixed venous blood ( p less than 0 . 05 ) , while heart rate ( p less than 0 . 001 ) and cardiac output ( p less than 0 . 05 ) were increased . Recoveries of heart rate and left ventricular end - diastolic pressure were not shown within 60 min after SNP had been stopped . Both ATP and SNP should act on the pacemaker tissue of the heart . Comparative study : Endografine ( diatrizoate ) , Vasurix polyvidone ( acetrizoate ) , Dimer - X ( iocarmate ) and Hexabrix ( ioxaglate ) in hysterosalpingography . Side effects of hysterosalpingography with Dimer - X , Hexabrix , Vasurix polyvidone and Endografine in 142 consecutive patients , receiving one of the four tested media were evaluated from replies to postal questionnaires . The Dimer - X group had a higher incidence of nausea and dizziness . The Endografine group had a higher incidence of abdominal pain . These differences occur especially in the age groups under 30 years . Hexabrix and Vasurix polyvidone are considered the best contrast media for hysterosalpingography and perhaps because of its low toxicity Hexabrix should be preferred . Post - suxamethonium pains in Nigerian surgical patients . Contrary to an earlier report by Coxon , scoline pain occurs in African negroes . Its incidence was determined in a prospective study involving a total of 100 Nigerian patients ( 50 out - patients and 50 in - patients ) . About 62 % of the out - patients developed scoline pain as compared with about 26 % among the in - patients . The abolition of muscle fasciculations ( by 0 . 075mg / kg dose of Fazadinium ) did not influence the occurrence of scoline pain . Neither the type of induction agent ( Althesin or Thiopentone ) nor the salt preparation of suxamethonium used ( chloride or bromide ) , affected the incidence of scoline pain . Invasive carcinoma of the renal pelvis following cyclophosphamide therapy for nonmalignant disease . A 47 - year - old woman with right hydroureteronephrosis due to ureterovesical junction obstruction had gross hematuria after being treated for five years wtih cyclophosphamide for cerebral vasculitis . A right nephroureterectomy was required for control of bleeding . The pathology specimen contained clinically occult invasive carcinoma of the renal pelvis . Although the ability of cyclophosphamide to cause hemorrhagic cystitis and urine cytologic abnormalities indistinguishable from high grade carcinoma is well known , it is less widely appreciated that it is also associated with carcinoma of the urinary tract . Twenty carcinomas of the urinary bladder and one carcinoma of the prostate have been reported in association with its use . The present case is the first carcinoma of the renal pelvis reported in association with cyclophosphamide treatment . It is the third urinary tract cancer reported in association with cyclophosphamide treatment for nonmalignant disease . The association of the tumor with preexisting hydroureteronephrosis suggests that stasis prolonged and intensified exposure of upper urinary tract epithelium to cyclophosphamide . Patients who are candidates for long - term cyclophosphamide treatment should be routinely evaluated for obstructive uropathy . Medial changes in arterial spasm induced by L - norepinephrine . In normal rats , the media of small arteries ( 0 . 4 - - 0 . 2 mm in diameter ) previously was shown to contain intracellular vacuoles , identified ultrastructurally as herniations of one smooth muscle cell into another . The hypothesis that intense vasoconstriction would increase the number of such vacuoles has been tested . In the media of the saphenous artery and its distal branch , vasoconstriction induced by L - norepinephrine produced many cell - to - cell hernias within 15 minutes . At 1 day their number was reduced to about 1 / 10 of the original number . By 7 days the vessel was almost restored to normal . Triple stimulation over 1 day induced more severe changes in the media . These findings suggest that smooth muscle cells are susceptible to damage in the course of their specific function . The experimental data are discussed in relation to medial changes observed in other instances of arterial spasm . Endothelial changes that developed in the same experimental model were described in a previous paper . Bilateral retinal artery and choriocapillaris occlusion following the injection of long - acting corticosteroid suspensions in combination with other drugs : I . Clinical studies . Two well - documented cases of bilateral retinal artery and choriocapillaris occlusions with blindness following head and neck soft - tissue injection with methylprednisolone acetate in combination with lidocaine , epinephrine , or penicillin are reported . One case had only a unilateral injection . The acute observations included hazy sensorium , superior gaze palsy , pupillary abnormalities , and conjunctival hemorrhages with edema . Follow - up changes showed marked visual loss , constricted visual fields , optic nerve pallor , vascular attenuation , and chorioretinal atrophy . The literature is reviewed , and possible causes are discussed . Abnormalities of the pupil and visual - evoked potential in quinine amblyopia . Total blindness with a transient tonic pupillary response , denervation supersensitivity , and abnormal visual - evoked potentials developed in a 54 - year - old man after the use of quinine sulfate for leg cramps . He later recovered normal visual acuity . A transient tonic pupillary response , denervation supersensitivity , and abnormal visual - evoked potentials in quinine toxicity , to our knowledge , have not been previously reported . Suxamethonium - induced jaw stiffness and myalgia associated with atypical cholinesterase : case report . An 11 - year - old boy was given halothane , nitrous oxide and oxygen , pancuronium 0 . 4 mg and suxamethonium 100 mg for induction of anaesthesia . In response to this a marked jaw stiffness occurred which lasted for two minutes and the anaesthesia were terminated . Four hours of apnoea ensued and he suffered generalized severe myalgia lasting for one week . He was found to have atypical plasma cholinesterase with a dibucaine number of 12 , indicating homozygocity . This was verified by study of the family . The case shows that prolonged jaw rigidity and myalgia may occur after suxamethonium in patients with atypical cholinesterase despite pretreatment with pancuronium . Indomethacin - induced hyperkalemia in three patients with gouty arthritis . We describe three patients in whom severe , life - threatening hyperkalemia and renal insufficiency developed after treatment of acute gouty arthritis with indomethacin . This complication may result from an inhibition of prostaglandin synthesis and consequent hyporeninemic hypoaidosteronism . Careful attention to renal function and potassium balance in patients receiving indomethacin or other nonsteroidal anti - inflammatory agents , particularly in those patients with diabetes mellitus or preexisting renal disease , will help prevent this potentially serious complication . Etomidate : a foreshortened clinical trial . A clinical evaluation of etomidate for outpatient cystoscopy was embarked upon . Unpremedicated patients were given fentanyl 1 microgram / kg followed by etomidate 0 . 3 mg / kg . Anaesthesia was maintained with intermittent etomidate in 2 - 4 mg doses . Patients were interviewed personally later the same day , and by questionnaire three to four weeks later . The trial was discontinued after 20 cases because of an unacceptable incidence of side effects . Venous pain occurred in 68 % of patients and 50 % had redness , pain or swelling related to the injection site , in some cases lasting up to three weeks after anaesthesia . Skeletal movements occurred in 50 % of patients ; 30 % experienced respiratory upset , one sufficiently severe to necessitate abandoning the technique . Nausea and vomiting occurred in 40 % and 25 % had disturbing emergence psychoses . Levodopa - induced dyskinesias are improved by fluoxetine . We evaluated the severity of motor disability and dyskinesias in seven levodopa - responsive patients with Parkinson ' s disease after an acute challenge with the mixed dopamine agonist , apomorphine , before and after the administration of fluoxetine ( 20 mg twice per day ) for 11 + / - 1 days . After fluoxetine treatment , there was a significant 47 % improvement ( p < 0 . 05 ) of apomorphine - induced dyskinesias without modification of parkinsonian motor disability . The dyskinesias were reduced predominantly in the lower limbs during the onset and disappearance of dystonic dyskinesias ( onset - and end - of - dose dyskinesias ) and in the upper limbs during choreic mid - dose dyskinesias . The results suggest that increased brain serotoninergic transmission with fluoxetine may reduce levodopa - or dopamine agonist - induced dyskinesias without aggravating parkinsonian motor disability . A large population - based follow - up study of trimethoprim - sulfamethoxazole , trimethoprim , and cephalexin for uncommon serious drug toxicity . We conducted a population - based 45 - day follow - up study of 232 , 390 people who were prescribed trimethoprim - sulfamethoxazole ( TMP - SMZ ) , 266 , 951 prescribed trimethoprim alone , and 196 , 397 prescribed cephalexin , to estimate the risk of serious liver , blood , skin , and renal disorders resulting in referral or hospitalization associated with these drugs . The results were based on information recorded on office computers by selected general practitioners in the United Kingdom , together with a review of clinical records . The risk of clinically important idiopathic liver disease was similar for persons prescribed TMP - SMZ ( 5 . 2 / 100 , 000 ) and those prescribed trimethoprim alone ( 3 . 8 / 100 , 000 ) . The risk for those prescribed cephalexin was somewhat lower ( 2 . 0 / 100 , 000 ) . Only five patients experienced blood disorders , one of whom was exposed to TMP - SMZ ; of seven with erythema multiforme and Stevens - Johnson syndrome , four were exposed to TMP - SMZ . The one case of toxic epidermal necrolysis occurred in a patient who took cephalexin . Finally , only five cases of acute parenchymal renal disease occurred , none likely to be caused by a study drug . We conclude that the risk of the serious diseases studied is small for the three agents , and compares reasonably with the risk for many other antibiotics . Clinical safety of lidocaine in patients with cocaine - associated myocardial infarction . STUDY OBJECTIVE : To evaluate the safety of lidocaine in the setting of cocaine - induced myocardial infarction ( MI ) . DESIGN : A retrospective , multicenter study . SETTING : Twenty - nine university , university - affiliated , or community hospitals during a 6 - year period ( total of 117 cumulative hospital - years ) . PARTICIPANTS : Patients with cocaine - associated MI who received lidocaine in the emergency department . RESULTS : Of 29 patients who received lidocaine in the setting of cocaine - associated MI , no patient died ; exhibited bradydysrhythmias , ventricular tachycardia , or ventricular fibrillation ; or experienced seizures after administration of lidocaine ( 95 % confidence interval , 0 % to 11 % ) . CONCLUSION : Despite theoretical concerns that lidocaine may enhance cocaine toxicity , the use of lidocaine in patients with cocaine - associated MI was not associated with significant cardiovascular or central nervous system toxicity . Experimental progressive muscular dystrophy and its treatment with high doses anabolizing agents . We are still a long way from discovering an unequivocal pathogenetic interpretation of progressive muscular dystrophy in man . Noteworthy efforts have been made in the experimental field ; a recessive autosomic form found in the mouse seems to bear the closest resemblance to the human form from the genetic point of view . Myopathy due to lack of vitamin E and myopathy induced by certain viruses have much in common anatomically and pathologically with the human form . The authors induced myodystrophy in the rat by giving it a diet lacking in vitamin E . The pharmacological characteristics of vitamin E and the degenerative changes brought about by its deficiency , especially in the muscles , are illustrated . It is thus confirmed that the histological characteristics of myopathic rat muscle induced experimentally are extraordinarily similar to those of human myopathy as confirmed during biopsies performed at the Orthopaedic Traumatological Centre , Florence . The encouraging results obtained in various authoratative departments in myopathic patients by using anabolizing steroids have encouraged the authors to investigate the beneficial effects of one anabolizing agent ( Dianabol , CIBA ) at high doses in rats rendered myopathic by a diet deficient in vitamin E . In this way they obtained appreciable changes in body weight ( increased from 50 to 70 g after forty days at a dose of 5 mg per day of anabolizing agent ) , but most of all they found histological changes due to " regenerative " changes in the muscle tissue , which however maintained its myopathic characteristics in the control animals that were not treated with the anabolizing agent . The authors conclude by affirming the undoubted efficacy of the anabolizing steroids in experimental myopathic disease , but they have reservations as to the transfer of the results into the human field , where high dosage cannot be carried out continuously because of the effects of the drug on virility ; because the tissue injury too often occurs at an irreversible stage vis - a - vis the " regeneration " of the muscle tissue ; and finally because the dystrophic injurious agent is certainly not the lack of vitamin E but something as yet unknown . Paclitaxel 3 - hour infusion given alone and combined with carboplatin : preliminary results of dose - escalation trials . Paclitaxel ( Taxol ; Bristol - Myers Squibb Company , Princeton , NJ ) by 3 - hour infusion was combined with carboplatin in a phase I / II study directed to patients with non - small cell lung cancer . Carboplatin was given at a fixed target area under the concentration - time curve of 6 . 0 by the Calvert formula , whereas paclitaxel was escalated in patient cohorts from 150 mg / m2 ( dose level I ) to 175 , 200 , 225 , and 250 mg / m2 . The 225 mg / m2 level was expanded for the phase II study since the highest level achieved ( 250 mg / m2 ) required modification because of nonhematologic toxicities ( arthralgia and sensory neuropathy ) . Therapeutic effects were noted at all dose levels , with objective responses in 17 ( two complete and 15 partial regressions ) of 41 previously untreated patients . Toxicities were compared with a cohort of patients in a phase I trial of paclitaxel alone at identical dose levels . Carboplatin did not appear to add to the hematologic toxicities observed , and the paclitaxel / carboplatin combination could be dosed every 3 weeks . The dose - dependent effect of misoprostol on indomethacin - induced renal dysfunction in well compensated cirrhosis . Misoprostol ( 200 micrograms ) has been shown to acutely counteract the indomethacin - induced renal dysfunction in well compensated cirrhotic patients . The aim of this study was to determine if the prophylactic value of misoprostol was dose - dependent . Parameters of renal hemodynamics and tubular sodium and water handling were assessed by clearance techniques in 26 well compensated cirrhotic patients before and after an oral combination of 50 mg of indomethacin and various doses of misoprostol . The 200 - micrograms dose was able to totally abolish the deleterious renal effects of indomethacin , whereas the 800 - micrograms dose resulted in significant worsening of renal hemodynamics and sodium retention . These changes were maximal in the hour immediately after medications and slowly returned toward base - line levels thereafter . These results suggest that the renal protective effects of misoprostol is dose - dependent . However , until this apparent ability of 200 micrograms of misoprostol to prevent the adverse effects of indomethacin on renal function is confirmed with chronic frequent dosing , it would be prudent to avoid nonsteroidal anti - inflammatory therapy in patients with cirrhosis . Increased frequency and severity of angio - oedema related to long - term therapy with angiotensin - converting enzyme inhibitor in two patients . Adverse reactions to drugs are well recognized as a cause of acute or chronic urticaria , and angio - oedema . Angiotensin - converting enzyme ( ACE ) inhibitors , used to treat hypertension and congestive heart failure , were introduced in Europe in the middle of the eighties , and the use of these drugs has increased progressively . Soon after the introduction of ACE inhibitors , acute bouts of angio - oedema were reported in association with the use of these drugs . We wish to draw attention to the possibility of adverse reactions to ACE inhibitors after long - term use and in patients with pre - existing angio - oedema . Myoclonus associated with lorazepam therapy in very - low - birth - weight infants . Lorazepam is being used with increasing frequency as a sedative in the newborn and the young infant . Concern has been raised with regard to the safety of lorazepam in this age group , especially in very - low - birth - weight ( VLBW ; < 1 , 500 g ) infants . Three young infants , all of birth weight < 1 , 500 g , experienced myoclonus following the intravenous administration of lorazepam . The potential neurotoxic effects of the drug ( and its vehicle ) in this population are discussed . Injectable lorazepam should be used with caution in VLBW infants . Transvenous right ventricular pacing during cardiopulmonary resuscitation of pediatric patients with acute cardiomyopathy . We describe the cardiopulmonary resuscitation efforts on five patients who presented in acute circulatory failure from myocardial dysfunction . Three patients had acute viral myocarditis , one had a carbamazepine - induced acute eosinophilic myocarditis , and one had cardiac hemosiderosis resulting in acute cardiogenic shock . All patients were continuously monitored with central venous and arterial catheters in addition to routine noninvasive monitoring . An introducer sheath , a pacemaker , and sterile pacing wires were made readily available for the patients , should the need arise to terminate resistant cardiac dysrhythmias . All patients developed cardiocirculatory arrest associated with extreme hypotension and dysrhythmias within the first 48 hours of their admission to the pediatric intensive care unit ( PICU ) . Right ventricular pacemaker wires were inserted in all of them during cardiopulmonary resuscitation ( CPR ) . In four patients , cardiac pacing was used , resulting in a temporary captured rhythm and restoration of their cardiac output . These patients had a second event of cardiac arrest , resulting in death , within 10 to 60 minutes . In one patient , cardiac pacing was not used , because he converted to normal sinus rhythm by electrical defibrillation within three minutes of initiating CPR . We conclude that cardiac pacing during resuscitative efforts in pediatric patients suffering from acute myocardial dysfunction may not have long - term value in and of itself ; however , if temporary hemodynamic stability is achieved by this procedure , it may provide additional time needed to institute other therapeutic modalities . Efficacy and safety of granisetron , a selective 5 - hydroxytryptamine - 3 receptor antagonist , in the prevention of nausea and vomiting induced by high - dose cisplatin . PURPOSE : To assess the antiemetic effects and safety profile of four different doses of granisetron ( Kytril ; SmithKline Beecham Pharmaceuticals , Philadelphia , PA ) when administered as a single intravenous ( IV ) dose for prophylaxis of cisplatin - induced nausea and vomiting . PATIENTS AND METHODS : One hundred eighty - four chemotherapy - naive patients receiving high - dose cisplatin ( 81 to 120 mg / m2 ) were randomized to receive one of four granisetron doses ( 5 , 10 , 20 , or 40 micrograms / kg ) administered before chemotherapy . Patients were observed on an inpatient basis for 18 to 24 hours , and vital signs , nausea , vomiting , retching , and appetite were assessed . Safety analyses included incidence of adverse experiences and laboratory parameter changes . RESULTS : After granisetron doses of 5 , 10 , 20 , and 40 micrograms / kg , a major response ( < or = two vomiting or retching episodes , and no antiemetic rescue ) was recorded in 23 % , 57 % , 58 % , and 60 % of patients , respectively , and a complete response ( no vomiting or retching , and no antiemetic rescue ) in 18 % , 41 % , 40 % , and 47 % of patients , respectively . There was a statistically longer time to first episode of nausea ( P = . 0015 ) and vomiting ( P = . 0001 ) , and fewer patients were administered additional antiemetic medication in the 10 - micrograms / kg dosing groups than in the 5 - micrograms / kg dosing group . As granisetron dose increased , appetite return increased ( P = . 040 ) . Headache was the most frequently reported adverse event ( 20 % ) . CONCLUSION : A single 10 - , 20 - , or 40 - micrograms / kg dose of granisetron was effective in controlling vomiting in 57 % to 60 % of patients who received cisplatin at doses greater than 81 mg / m2 and totally prevented vomiting in 40 % to 47 % of patients . There were no statistically significant differences in efficacy between the 10 - micrograms / kg dose and the 20 - and 40 - micrograms / kg doses . Granisetron was well tolerated at all doses . Adverse interaction between clonidine and verapamil . OBJECTIVE : To report two cases of a possible adverse interaction between clonidine and verapamil resulting in atrioventricular ( AV ) block in both patients and severe hypotension in one patient . CASE SUMMARIES : A 54 - year - old woman with hyperaldosteronism was treated with verapamil 480 mg / d and spironolactone 100 mg / d . After the addition of a minimal dose of clonidine ( 0 . 15 mg bid ) , she developed complete AV block and severe hypotension , which resolved upon cessation of all medications . A 65 - year - old woman was treated with extended - release verapamil 240 mg / d . After the addition of clonidine 0 . 15 mg bid she developed complete AV block , which resolved after all therapy was stopped . DISCUSSION : An adverse interaction between clonidine and verapamil has not been reported previously . We describe two such cases and discuss the various mechanisms that might cause such an interaction . Clinicians should be acquainted with this possibly fatal interaction between two commonly used antihypertensive drugs . CONCLUSIONS : Caution is recommended in combining clonidine and verapamil therapy , even in patients who do not have sinus or AV node dysfunction . The two drugs may act synergistically on both the AV node and the peripheral circulation . Pharmacological studies on a new dihydrothienopyridine calcium antagonist , S - 312 - d . 5th communication : anticonvulsant effects in mice . S - 312 , S - 312 - d , but not S - 312 - l , L - type calcium channel antagonists , showed anticonvulsant effects on the audiogenic tonic convulsions in DBA / 2 mice ; and their ED50 values were 18 . 4 ( 12 . 8 - 27 . 1 ) mg / kg , p . o . and 15 . 0 ( 10 . 2 - 23 . 7 ) mg / kg , p . o . , respectively , while that of flunarizine was 34 . 0 ( 26 . 0 - 44 . 8 ) mg / kg , p . o . Although moderate anticonvulsant effects of S - 312 - d in higher doses were observed against the clonic convulsions induced by pentylenetetrazole ( 85 mg / kg , s . c . ) or bemegride ( 40 mg / kg , s . c . ) , no effects were observed in convulsions induced by N - methyl - D - aspartate , picrotoxin , or electroshock in Slc : ddY mice . S - 312 - d may be useful in the therapy of certain types of human epilepsy . Transmural myocardial infarction with sumatriptan . For sumatriptan , tightness in the chest caused by an unknown mechanism has been reported in 3 - 5 % of users . We describe a 47 - year - old woman with an acute myocardial infarction after administration of sumatriptan 6 mg subcutaneously for cluster headache . The patient had no history of underlying ischaemic heart disease or Prinzmetal ' s angina . She recovered without complications . Flumazenil induces seizures and death in mixed cocaine - diazepam intoxications . STUDY HYPOTHESIS : Administration of the benzodiazepine antagonist flumazenil may unmask seizures in mixed cocaine - benzodiazepine intoxication . DESIGN : Male Sprague - Dawley rats received 100 mg / kg cocaine IP alone , 5 mg / kg diazepam alone , or a combination of diazepam and cocaine . Three minutes later , groups were challenged with vehicle or flumazenil 5 or 10 mg / kg IP . Animal behavior , seizures ( time to and incidence ) , death ( time to and incidence ) , and cortical EEG tracings were recorded . INTERVENTIONS : Administration of flumazenil to animals after they had received a combination dose of cocaine and diazepam . RESULTS : In group 1 , animals received cocaine followed by vehicle . This resulted in 100 % developing seizures and death . Group 2 received diazepam alone followed by vehicle . Animals became somnolent and none died . Group 3 received diazepam followed by 5 mg / kg flumazenil . Animals became somnolent after diazepam and then active after flumazenil administration . In group 4 , a combination of cocaine and diazepam was administered simultaneously . This resulted in no overt or EEG - detectable seizures and a 50 % incidence of death . Group 5 received a similar combination of cocaine and diazepam , followed later by 5 mg / kg flumazenil . This resulted in an increased incidence of seizures , 90 % ( P < . 01 ) , and death , 100 % ( P < or = . 01 ) , compared with group 4 . Group 6 received cocaine and diazepam followed by 10 mg / kg flumazenil . This also resulted in an increased incidence of seizures , 90 % ( P < or = . 01 ) , and death , 90 % ( P < or = . 05 ) , compared with group 4 . CONCLUSION : Flumazenil can unmask seizures and increase the incidence of death in a model of combined cocaine - diazepam intoxications . Mechanisms for protective effects of free radical scavengers on gentamicin - mediated nephropathy in rats . Studies were performed to examine the mechanisms for the protective effects of free radical scavengers on gentamicin ( GM ) - mediated nephropathy . Administration of GM at 40 mg / kg sc for 13 days to rats induced a significant reduction in renal blood flow ( RBF ) and inulin clearance ( CIn ) as well as marked tubular damage . A significant reduction in urinary guanosine 3 ' , 5 ' - cyclic monophosphate ( cGMP ) excretion and a significant increase in renal cortical renin and endothelin - 1 contents were also observed in GM - mediated nephropathy . Superoxide dismutase ( SOD ) or dimethylthiourea ( DMTU ) significantly lessened the GM - induced decrement in CIn . The SOD - induced increase in glomerular filtration rate was associated with a marked improvement in RBF , an increase in urinary cGMP excretion , and a decrease in renal renin and endothelin - 1 content . SOD did not attenuate the tubular damage . In contrast , DMTU significantly reduced the tubular damage and lipid peroxidation , but it did not affect renal hemodynamics and vasoactive substances . Neither SOD nor DMTU affected the renal cortical GM content in GM - treated rats . These results suggest that 1 ) both SOD and DMTU have protective effects on GM - mediated nephropathy , 2 ) the mechanisms for the protective effects differ for SOD and DMTU , and 3 ) superoxide anions play a critical role in GM - induced renal vasoconstriction . Cephalothin - induced immune hemolytic anemia . A patient with renal disease developed Coombs - positive hemolytic anemia while receiving cephalothin therapy . An anti - cephalothin IgG antibody was detected in the patient ' s serum and in the eluates from her erythrocytes . In addition , nonimmunologic binding of normal and patient ' s serum proteins to her own and cephalothin - coated normal red cells was demonstrated . Skin tests and in vitro lymphocyte stimulation revealed that the patient was sensitized to cephalothin and also to ampicillin . Careful investigation of drug - induced hemolytic anemias reveals the complexity of the immune mechanisms involved . Assessment of cardiomyocyte DNA synthesis during hypertrophy in adult mice . The ability of cardiomyocytes to synthesize DNA in response to experimentally induced cardiac hypertrophy was assessed in adult mice . Isoproterenol delivered by osmotic minipump implantation in adult C3Heb / FeJ mice resulted in a 46 % increase in heart weight and a 19 . 3 % increase in cardiomyocyte area . No DNA synthesis , as assessed by autoradiographic analysis of isolated cardiomyocytes , was observed in control or hypertrophic hearts . A survey of 15 independent inbred strains of mice revealed that ventricular cardiomyocyte nuclear number ranged from 3 to 13 % mononucleate , suggesting that cardiomyocyte terminal differentiation is influenced directly or indirectly by genetic background . To determine whether the capacity for reactive DNA synthesis was also subject to genetic regulation , cardiac hypertrophy was induced in the strains of mice comprising the extremes of the nuclear number survey . These data indicate that adult mouse atrial and ventricular cardiomyocytes do not synthesize DNA in response to isoproterenol - induced cardiac hypertrophy . Central cardiovascular effects of AVP and ANP in normotensive and spontaneously hypertensive rats . The purpose of the present study was to compare influence of central arginine vasopressin ( AVP ) and of atrial natriuretic peptide ( ANP ) on control of arterial blood pressure ( MAP ) and heart rate ( HR ) in normotensive ( WKY ) and spontaneously hypertensive ( SHR ) rats . Three series of experiments were performed on 30 WKY and 30 SHR , chronically instrumented with guide tubes in the lateral ventricle ( LV ) and arterial and venous catheters . MAP and HR were monitored before and after i . v . injections of either vehicle or 1 , 10 and 50 ng of AVP and 25 , 125 and 500 ng of ANP . Sensitivity of cardiac component of baroreflex ( CCB ) , expressed as a slope of the regression line was determined from relationships between systolic arterial pressure ( SAP ) and HR period ( HRp ) during phenylephrine ( Phe ) - induced hypertension and sodium nitroprusside ( SN ) - induced hypotension . CCB was measured before and after administration of either vehicle , AVP , ANP , or both peptides together . Increases of MAP occurred after LV administration of 1 , 10 and 50 ng of AVP in WKY and of 10 and 50 ng in SHR . ANP did not cause significant changes in MAP in both strains as compared to vehicle , but it abolished AVP - induced MAP increase in WKY and SHR . CCB was reduced in WKY and SHR after LV administration of AVP during SN - induced hypotension . In SHR but not in WKY administration of ANP , AVP and ANP + AVP decreased CCB during Phe - induced MAP elevation . The results indicate that centrally applied AVP and ANP exert differential effects on blood pressure and baroreflex control of heart rate in WKY and SHR and suggest interaction of these two peptides in blood pressure regulation at the level of central nervous system . Cutaneous exposure to warfarin - like anticoagulant causing an intracerebral hemorrhage : a case report . A case of intercerebral hematoma due to warfarin - induced coagulopathy is presented . The 39 - year - old woman had spread a warfarin - type rat poison around her house weekly using her bare hands , with no washing post application . Percutaneous absorption of warfarin causing coagulopathy , reported three times in the past , is a significant risk if protective measures , such as gloves , are not used . An adverse drug interaction with piroxicam , which she took occasionally , may have exacerbated the coagulopathy . Pediatric heart transplantation without chronic maintenance steroids . From 1986 to February 1993 , 40 children aged 2 months to 18 years ( average age 10 . 4 + / - 5 . 8 years ) underwent heart transplantation . Indications for transplantation were idiopathic cardiomyopathy ( 52 % ) , congenital heart disease ( 35 % ) with and without prior repair ( 71 % and 29 % , respectively ) , hypertrophic cardiomyopathy ( 5 % ) , valvular heart disease ( 3 % ) , and doxorubicin cardiomyopathy ( 5 % ) . Patients were managed with cyclosporine and azathioprine . No prophylaxis with antilymphocyte globulin was used . Steroids were given to 39 % of patients for refractory rejection , but weaning was always attempted and generally successful ( 64 % ) . Five patients ( 14 % ) received maintenance steroids . Four patients died in the perioperative period and one died 4 months later . There have been no deaths related to rejection or infection . Average follow - up was 36 + / - 19 months ( range 1 to 65 months ) . Cumulative survival is 88 % at 5 years . In patients less than 7 years of age , rejection was monitored noninvasively . In the first postoperative month , 89 % of patients were treated for rejection . Freedom from serious infections was 83 % at 1 month and 65 % at 1 year . Cytomegalovirus infections were treated successfully with ganciclovir in 11 patients . No impairment of growth was observed in children who underwent transplantation compared with a control population . Twenty - one patients ( 60 % ) have undergone annual catheterizations and no sign of graft atherosclerosis has been observed . Seizures occurred in five patients ( 14 % ) and hypertension was treated in 10 patients ( 28 % ) . No patient was disabled and no lymphoproliferative disorder was observed . ( ABSTRACT TRUNCATED AT 250 WORDS ) Delirium during fluoxetine treatment . A case report . The correlation between high serum tricyclic antidepressant concentrations and central nervous system side effects has been well established . Only a few reports exist , however , on the relationship between the serum concentrations of selective serotonin reuptake inhibitors ( SSRIs ) and their toxic effects . In some cases , a high serum concentration of citalopram ( > 600 nmol / L ) in elderly patients has been associated with increased somnolence and movement difficulties . Widespread cognitive disorders , such as delirium , have not been previously linked with high blood levels of SSRIs . In this report , we describe a patient with acute hyperkinetic delirium connected with a high serum total fluoxetine ( fluoxetine plus desmethylfluoxetine ) concentration . Pulmonary edema and shock after high - dose aracytine - C for lymphoma ; possible role of TNF - alpha and PAF . Four out of 23 consecutive patients treated with high - dose Ara - C for lymphomas in our institution developed a strikingly similar syndrome during the perfusion . It was characterized by the onset of fever , diarrhea , shock , pulmonary edema , acute renal failure , metabolic acidosis , weight gain and leukocytosis . Thorough bacteriological screening failed to provide evidence of infection . Sequential biological assays of IL - 1 , IL - 2 , TNF and PAF were performed during Ara - C infusion to ten patients , including the four who developed the syndrome . TNF and PAF activity was found in the serum of respectively two and four of the cases , but not in the six controls . As TNF and PAF are thought to be involved in the development of septic shock and adult respiratory distress syndrome , we hypothesize that high - dose Ara - C may be associated with cytokine release . Protective effect of clentiazem against epinephrine - induced cardiac injury in rats . We investigated the effects of clentiazem , a 1 , 5 - benzothiazepine calcium antagonist , on epinephrine - induced cardiomyopathy in rats . With 2 - week chronic epinephrine infusion , 16 of 30 rats died within 4 days , and severe ischemic lesions and fibrosis of the left ventricles were observed . In epinephrine - treated rats , left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced , but responses to calcium were normal or enhanced compared to controls . Left ventricular alpha and beta adrenoceptor densities were also reduced compared to controls . Treatment with clentiazem prevented epinephrine - induced death ( P < . 05 ) , and attenuated the ventricular ischemic lesions and fibrosis , in a dose - dependent manner . Left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced compared to controls in groups treated with clentiazem alone , but combined with epinephrine , clentiazem restored left atrial responses and enhanced left ventricular papillary responses to isoproterenol . On the other hand clentiazem did not prevent epinephrine - induced down - regulation of alpha and beta adrenoceptors . Interestingly , clentiazem , infused alone , resulted in decreased adrenergic receptor densities in the left ventricle . Clentiazem also did not prevent the enhanced responses to calcium seen in the epinephrine - treated animals , although the high dose of clentiazem partially attenuated the maximal response to calcium compared to epinephrine - treated animals . In conclusion , clentiazem attenuated epinephrine - induced cardiac injury , possibly through its effect on the adrenergic pathway . Kaliuretic effect of L - dopa treatment in parkinsonian patients . Hypokalemia , sometimes severe , was observed in some L - dopa - treated parkinsonian patients . The influence of L - dopa on the renal excretion of potassium was studied in 3 patients with hypokalemia and in 5 normokalemic patients by determination of renal plasma flow , glomerular filtration rate , plasma concentration of potassium and sodium as well as urinary excretion of potassium , sodium and aldosterone . L - Dopa intake was found to cause an increased excretion of potassium , and sometimes also of sodium , in the hypokalemic but not in the normokalemic patients . This effect on the renal function could be prohibited by the administration of a peripheral dopa decarbodylase inhibitor . It is not known why this effect occurred in some individuals but not in others , but our results indicate a correlation between aldosterone production and this renal effect of L - dopa . Cocaine induced myocardial ischemia . We report a case of myocardial ischemia induced by cocaine . The ischemia probably induced by coronary artery spasm was reversed by nitroglycerin and calcium blocking agents . Doxorubicin - induced cardiotoxicity monitored by ECG in freely moving mice . A new model to test potential protectors . In laboratory animals , histology is most commonly used to study doxorubicin - induced cardiotoxicity . However , for monitoring during treatment , large numbers of animals are needed . Recently we developed a new method to measure ECG values in freely moving mice by telemetry . With this model we investigated the effect of chronic doxorubicin administration on the ECG of freely moving BALB / c mice and the efficacy of ICRF - 187 as a protective agent . The ST interval significantly widened from 15 . 0 + / - 1 . 5 to 56 . 8 + / - 11 . 8 ms in week 10 ( 7 weekly doses of 4 mg / kg doxorubicin given i . v . plus 3 weeks of observation ) . The ECG of the control animals did not change during the entire study . After sacrifice the hearts of doxorubicin - treated animals were enlarged and the atria were hypertrophic . As this schedule exerted more toxicity than needed to investigate protective agents , the protection of ICRF - 187 was determined using a dose schedule with lower general toxicity ( 6 weekly doses of 4 mg / kg doxorubicin given i . v . plus 2 weeks of observation ) . On this schedule , the animals ' hearts appeared normal after sacrifice and ICRF - 187 ( 50 mg / kg given i . p . 1 h before doxorubicin ) provided almost full protection . These data were confirmed by histology . The results indicate that this new model is very sensitive and enables monitoring of the development of cardiotoxicity with time . These findings result in a model that allows the testing of protectors against doxorubicin - induced cardiotoxicity as demonstrated by the protection provided by ICRF - 187 . Epinephrine dysrhythmogenicity is not enhanced by subtoxic bupivacaine in dogs . Since bupivacaine and epinephrine may both precipitate dysrhythmias , circulating bupivacaine during regional anesthesia could potentiate dysrhythmogenic effects of epinephrine . We therefore examined whether bupivacaine alters the dysrhythmogenicity of subsequent administration of epinephrine in conscious , healthy dogs and in anesthetized dogs with myocardial infarction . Forty - one conscious dogs received 10 micrograms . kg - 1 . min - 1 epinephrine . Seventeen animals responded with ventricular tachycardia ( VT ) within 3 min . After 3 h , these responders randomly received 1 or 2 mg / kg bupivacaine or saline over 5 min , followed by 10 micrograms . kg - 1 . min - 1 epinephrine . In the bupivacaine groups , epinephrine caused fewer prodysrhythmic effects than without bupivacaine . VT appeared in fewer dogs and at a later time , and there were more sinoatrial beats and less ectopies . Epinephrine shortened QT less after bupivacaine than in control animals . One day after experimental myocardial infarction , six additional halothane - anesthetized dogs received 4 micrograms . kg - 1 . min - 1 epinephrine until VT appeared . After 45 min , 1 mg / kg bupivacaine was injected over 5 min , again followed by 4 micrograms . kg - 1 . min - 1 epinephrine . In these dogs , the prodysrhythmic response to epinephrine was also mitigated by preceding bupivacaine . Bupivacaine antagonizes epinephrine dysrhythmogenicity in conscious dogs susceptible to VT and in anesthetized dogs with spontaneous postinfarct dysrhythmias . There is no evidence that systemic subtoxic bupivacaine administration enhances the dysrhythmogenicity of subsequent epinephrine . Milk - alkali syndrome induced by 1 , 25 ( OH ) 2D in a patient with hypoparathyroidism . Milk - alkali syndrome was first described 70 years ago in the context of the treatment of peptic ulcer disease with large amounts of calcium and alkali . Although with current ulcer therapy ( H - 2 blockers , omeprazole , and sucralfate ) , the frequency of milk - alkali syndrome has decreased significantly , the classic triad of hypercalcemia , alkalosis , and renal impairment remains the hallmark of the syndrome . Milk - alkali syndrome can present serious and occasionally life - threatening illness unless diagnosed and treated appropriately . This article presents a patient with hypoparathyroidism who was treated with calcium carbonate and calcitriol resulting in two admissions to the hospital for milk - alkali syndrome . The patient was successfully treated with intravenous pamidronate on his first admission and with hydrocortisone on the second . This illustrates intravenous pamidronate as a valuable therapeutic tool when milk - alkali syndrome presents as hypercalcemic emergency . Famotidine - associated delirium . A series of six cases . Famotidine is a histamine H2 - receptor antagonist used in inpatient settings for prevention of stress ulcers and is showing increasing popularity because of its low cost . Although all of the currently available H2 - receptor antagonists have shown the propensity to cause delirium , only two previously reported cases have been associated with famotidine . The authors report on six cases of famotidine - associated delirium in hospitalized patients who cleared completely upon removal of famotidine . The pharmacokinetics of famotidine are reviewed , with no change in its metabolism in the elderly population seen . The implications of using famotidine in elderly persons are discussed . Encephalopathy during amitriptyline therapy : are neuroleptic malignant syndrome and serotonin syndrome spectrum disorders ? This report describes a case of encephalopathy developed in the course of amitriptyline therapy , during a remission of unipolar depression . This patient could have been diagnosed as having either neuroleptic malignant syndrome ( NMS ) or serotonin syndrome ( SS ) . The major determinant of the symptoms may have been dopamine / serotonin imbalance in the central nervous system . The NMS - like encephalopathy that develops in association with the use of antidepressants indicates that NMS and SS are spectrum disorders induced by drugs with both antidopaminergic and serotonergic effects . Genetic separation of tumor growth and hemorrhagic phenotypes in an estrogen - induced tumor . Chronic administration of estrogen to the Fischer 344 ( F344 ) rat induces growth of large , hemorrhagic pituitary tumors . Ten weeks of diethylstilbestrol ( DES ) treatment caused female F344 rat pituitaries to grow to an average of 109 . 2 + / - 6 . 3 mg ( mean + / - SE ) versus 11 . 3 + / - 1 . 4 mg for untreated rats , and to become highly hemorrhagic . The same DES treatment produced no significant growth ( 8 . 9 + / - 0 . 5 mg for treated females versus 8 . 7 + / - 1 . 1 for untreated females ) or morphological changes in Brown Norway ( BN ) rat pituitaries . An F1 hybrid of F344 and BN exhibited significant pituitary growth after 10 weeks of DES treatment with an average mass of 26 . 3 + / - 0 . 7 mg compared with 8 . 6 + / - 0 . 9 mg for untreated rats . Surprisingly , the F1 hybrid tumors were not hemorrhagic and had hemoglobin content and outward appearance identical to that of BN . Expression of both growth and morphological changes is due to multiple genes . However , while DES - induced pituitary growth exhibited quantitative , additive inheritance , the hemorrhagic phenotype exhibited recessive , epistatic inheritance . Only 5 of the 160 F2 pituitaries exhibited the hemorrhagic phenotype ; 36 of the 160 F2 pituitaries were in the F344 range of mass , but 31 of these were not hemorrhagic , indicating that the hemorrhagic phenotype is not merely a consequence of extensive growth . The hemorrhagic F2 pituitaries were all among the most massive , indicating that some of the genes regulate both phenotypes . Increased expression of neuronal nitric oxide synthase in bladder afferent pathways following chronic bladder irritation . Immunocytochemical techniques were used to examine alterations in the expression of neuronal nitric oxide synthase ( NOS ) in bladder pathways following acute and chronic irritation of the urinary tract of the rat . Chemical cystitis was induced by cyclophosphamide ( CYP ) which is metabolized to acrolein , an irritant eliminated in the urine . Injection of CYP ( n = 10 , 75 mg / kg , i . p . ) 2 hours prior to perfusion ( acute treatment ) of the animals increased Fos - immunoreactivity ( IR ) in neurons in the dorsal commissure , dorsal horn , and autonomic regions of spinal segments ( L1 - L2 and L6 - S1 ) which receive afferent inputs from the bladder , urethra , and ureter . Fos - IR in the spinal cord was not changed in rats receiving chronic CYP treatment ( n = 15 , 75 mg / kg , i . p . , every 3rd day for 2 weeks ) . In control animals and in animals treated acutely with CYP , only small numbers of NOS - IR cells ( 0 . 5 - 0 . 7 cell profiles / sections ) were detected in the L6 - S1 dorsal root ganglia ( DRG ) . Chronic CYP administration significantly ( P < or = . 002 ) increased bladder weight by 60 % and increased ( 7 - to 11 - fold ) the numbers of NOS - immunoreactive ( IR ) afferent neurons in the L6 - S1 DRG . A small increase ( 1 . 5 - fold ) also occurred in the L1 DRG , but no change was detected in the L2 and L5 DRG . Bladder afferent cells in the L6 - S1 DRG labeled by Fluorogold ( 40 microliters ) injected into the bladder wall did not exhibit NOS - IR in control animals ; however , following chronic CYP administration , a significant percentage of bladder afferent neurons were NOS - IR : L6 ( 19 . 8 + / - 4 . 6 % ) and S1 ( 25 . 3 + / - 2 . 9 % ) . These results indicate that neuronal gene expression in visceral sensory pathways can be upregulated by chemical irritation of afferent receptors in the urinary tract and / or that pathological changes in the urinary tract can initiate chemical signals that alter the chemical properties of visceral afferent neurons . Effects of a new calcium antagonist , CD - 832 , on isoproterenol - induced myocardial ischemia in dogs with partial coronary stenosis . Effects of CD - 832 on isoproterenol ( ISO ) - induced myocardial ischemia were studied in dogs with partial coronary stenosis of the left circumflex coronary artery and findings were compared with those for nifedipine or diltiazem . In the presence of coronary artery stenosis , 3 - min periods of intracoronary ISO infusion ( 10 ng / kg / min ) increased heart rate and maximal rate of left ventricular pressure rise , which resulted in a decrease in percentage segmental shortening and ST - segment elevation of the epicardial electrocardiogram . After the control ISO infusion with stenosis was performed , equihypotensive doses of CD - 832 ( 3 and 10 micrograms / kg / min , n = 7 ) , nifedipine ( 1 and 3 micrograms / kg / min , n = 9 ) or diltiazem ( 10 and 30 micrograms / kg / min , n = 7 ) were infused 5 min before and during the second and third ISO infusion . Both CD - 832 and diltiazem , but not nifedipine , significantly reduced the increase in heart rate induced by ISO infusion . In contrast to nifedipine , CD - 832 ( 10 micrograms / kg / min ) prevented the decrease in percentage segmental shortening from 32 + / - 12 % to 115 + / - 26 % of the control value ( P < . 01 ) and ST - segment elevation from 5 . 6 + / - 1 . 0 mV to 1 . 6 + / - 1 . 3 mV ( P < . 01 ) at 3 min after ISO infusion with stenosis . Diltiazem ( 30 micrograms / kg / min ) also prevented the decrease in percentage segmental shortening from 34 + / - 14 % to 63 + / - 18 % of the control value ( P < . 05 ) and ST - segment elevation from 4 . 7 + / - 0 . 7 mV to 2 . 1 + / - 0 . 7 mV ( P < . 01 ) at 3 min after ISO infusion with stenosis . These data show that CD - 832 improves myocardial ischemia during ISO infusion with stenosis and suggest that the negative chronotropic property of CD - 832 plays a major role in the beneficial effects of CD - 832 . The effect of recombinant human insulin - like growth factor - I on chronic puromycin aminonucleoside nephropathy in rats . We recently demonstrated that recombinant hGH exacerbates renal functional and structural injury in chronic puromycin aminonucleoside ( PAN ) nephropathy , an experimental model of glomerular disease . Therefore , we examined whether recombinant human ( rh ) IGF - I is a safer alternative for the treatment of growth failure in rats with chronic PAN nephropathy . The glomerulopathy was induced by seven serial injections of PAN over 12 wk . Experimental animals ( n = 6 ) received rhIGF - I , 400 micrograms / d , whereas control rats ( n = 6 ) received the vehicle . rhIGF - I improved weight gain by 14 % ( p < 0 . 05 ) , without altering hematocrit or blood pressure in rats with renal disease . Urinary protein excretion was unaltered by rhIGF - I treatment in rats with chronic PAN nephropathy . After 12 wk , the inulin clearance was higher in rhIGF - I - treated rats , 0 . 48 + / - 0 . 08 versus 0 . 24 + / - 0 . 06 mL / min / 100 g of body weight in untreated PAN nephropathy animals , p < 0 . 05 . The improvement in GFR was not associated with enhanced glomerular hypertrophy or increased segmental glomerulosclerosis , tubulointerstitial injury , or renal cortical malondialdehyde content . In rats with PAN nephropathy , administration of rhIGF - I increased IGF - I and GH receptor gene expression , without altering the steady state level of IGF - I receptor mRNA . In normal rats with intact kidneys , rhIGF - I administration ( n = 4 ) did not alter weight gain , blood pressure , proteinuria , GFR , glomerular planar area , renal cortical malondialdehyde content , or glomerular or tubulointerstitial damage , compared with untreated animals ( n = 4 ) . rhIGF - I treatment reduced the steady state renal IGF - I mRNA level but did not modify gene expression of the IGF - I or GH receptors . We conclude that : 1 ) administration of rhIGF - I improves growth and GFR in rats with chronic PAN nephropathy and 2 ) unlike rhGH , long - term use of rhIGF - I does not worsen renal functional and structural injury in this disease model . Nefiracetam ( DM - 9384 ) reverses apomorphine - induced amnesia of a passive avoidance response : delayed emergence of the memory retention effects . Nefiracetam is a novel pyrrolidone derivative which attenuates scopolamine - induced learning and post - training consolidation deficits . Given that apomorphine inhibits passive avoidance retention when given during training or in a defined 10 - 12h post - training period , we evaluated the ability of nefiracetam to attenuate amnesia induced by dopaminergic agonism . A step - down passive avoidance paradigm was employed and nefiracetam ( 3 mg / kg ) and apomorphine ( 0 . 5 mg / kg ) were given alone or in combination during training and at the 10 - 12h post - training period of consolidation . Co - administration of nefiracetam and apomorphine during training or 10h thereafter produced no significant anti - amnesic effect . However , administration of nefiracetam during training completely reversed the amnesia induced by apomorphine at the 10h post - training time and the converse was also true . These effects were not mediated by a dopaminergic mechanism as nefiracetam , at millimolar concentrations , failed to displace either [ 3H ] SCH 23390 or [ 3H ] spiperone binding from D1 or D2 dopamine receptor subtypes , respectively . It is suggested that nefiracetam augments molecular processes in the early stages of events which ultimately lead to consolidation of memory . Phenytoin encephalopathy as probable idiosyncratic reaction : case report . A case of phenytoin ( DPH ) encephalopathy with increasing seizures and EEG and mental changes is described . Despite adequate oral dosage of DPH ( 5 mg / kg / daily ) the plasma level was very low ( 2 . 8 microgramg / ml ) . The encephalopathy was probably an idiosyncratic and not toxic or allergic reaction . In fact the concentration of free DPH was normal , the patient presented a retarded morbilliform rash during DPH treatment , the protidogram was normal , and an intradermic DPH injection had no local effect . The authors conclude that in a patient starting DPH treatment an unexpected increase in seizures , with EEG and mental changes occurring simultaneously , should alert the physician to the possible need for eliminating DPH from the therapeutic regimen , even if plasma concentrations are low . Prevention and treatment of endometrial disease in climacteric women receiving oestrogen therapy . The treatment regimens are described in 74 patients with endometrial disease among 850 climacteric women receiving oestrogen therapy . Cystic hyperplasia was associated with unopposed oestrogen therapy without progestagen . Two courses of 21 days of 5 mg norethisterone daily caused reversion to normal in all 57 cases of cystic hyperplasia and 6 of the 8 cases of atypical hyperplasia . 4 cases of endometrial carcinoma referred from elsewhere demonstrated the problems of inappropriate and unsupervised unopposed oestrogen therapy and the difficulty in distinguishing severe hyperplasia from malignancy . Cyclical low - dose oestrogen therapy with 7 - - 13 days of progestagen does not seem to increase the risk of endometrial hyperplasia or carcinoma . Effects of exercise on the severity of isoproterenol - induced myocardial infarction . The effect of exercise on the severity of isoproterenol - induced myocardial infarction was studied in male rats . Ninety - three rats were randomly divided into three groups . The exercise - isoproterenol ( E - 1 ) and exercise control ( EC ) groups exercised daily for thirty days on a treadmill at 1 mph , 2 % grade while animals of the sedentary - isoproterenol ( S - I ) group remained sedentary . Eight animals were assigned to the sedentary control ( SC ) group which remained sedentary throughout the experimental period . Forty - eight hours after the final exercise period , S - I and E - I animals received a single subcutaneous injection of isoproterenol ( 250 mg / kg body weight ) . Animals of the S - I group exhibited significantly ( Pp less than 0 . 05 ) greater mortality from the effects of isoproterenol than animals of the E - I group . Serum CPK activity for E - I animals was significantly ( p less than 0 . 05 ) greater than for animals in the S - I and EC groups twenty hours following isoproterenol injection . No statistically significant differences were observed between the two isoproterenol treated groups for severity of the induced lesions , changes in heart weight , or heart weight to body weight ratios . The results indicated that exercise reduced the mortality associated with the effects of large dosages of isoproterenol but had little on the severity of the infarction . Human corticotropin - releasing hormone and thyrotropin - releasing hormone modulate the hypercapnic ventilatory response in humans . Human corticotropin - releasing hormone ( hCRH ) and thyrotropin - releasing hormone ( TRH ) are known to stimulate ventilation after i . v . administration in humans . In a placebo - controlled , single - blind study we aimed to clarify if both peptides act by altering central chemosensitivity . Two subsequent CO2 - rebreathing tests were performed in healthy young volunteers . During the first test 0 . 9 % NaCl was given i . v . ; during the second test 200 micrograms of hCRH ( n = 12 ) or 400 micrograms of TRH ( n = 6 ) was administered i . v . Nine subjects received 0 . 9 % NaCl i . v . during both rebreathing manoeuvres . The CO2 - response curves for the two tests were compared within the same subject . In the hCRH group a marked parallel shift of the CO2 - response curve to the left was observed after hCRH ( P < 0 . 01 ) . The same effect occurred following TRH but was less striking ( P = 0 . 05 ) . hCRH and TRH caused a reduction in the CO2 threshold . The CO2 - response curves in the control group were nearly identical . The results indicate an additive effect of both releasing hormones on the hypercapnic ventilatory response in humans , presumably independent of central chemosensitivity . Lamivudine is effective in suppressing hepatitis B virus DNA in Chinese hepatitis B surface antigen carriers : a placebo - controlled trial . Lamivudine is a novel 2 ' , 3 ' - dideoxy cytosine analogue that has potent inhibitory effects on hepatitis B virus replication in vitro and in vivo . We performed a single - blind , placebo - controlled study to assess its effectiveness and safety in Chinese hepatitis B surface antigen ( HBsAg ) carriers . Forty - two Chinese HBsAg carriers were randomized to receive placebo ( 6 patients ) or lamivudine orally in dosages of 25 mg , 100 mg , or 300 mg daily ( 12 patients for each dosage ) . The drug was given for 4 weeks . The patients were closely monitored clinically , biochemically , and serologically up to 4 weeks after drug treatment . All 36 patients receiving lamivudine had a decrease in hepatitis B virus ( HBV ) DNA values of > 90 % ( P < . 001 compared with placebo ) . Although 25 mg of lamivudine was slightly less effective than 100 mg ( P = . 011 ) and 300 mg ( P = . 005 ) , it still induced 94 % suppression of HBV DNA after the fourth week of therapy . HBV DNA values returned to pretreatment levels within 4 weeks of cessation of therapy . There was no change in the hepatitis B e antigen status or in aminotransferase levels . No serious adverse events were observed . In conclusion , a 4 - week course of lamivudine was safe and effective in suppression of HBV DNA in Chinese HBsAg carriers . The suppression was > 90 % but reversible . Studies with long - term lamivudine administration should be performed to determine if prolonged suppression of HBV DNA can be achieved . Population - based study of risk of venous thromboembolism associated with various oral contraceptives . BACKGROUND : Four studies published since December , 1995 , reported that the incidence of venous thromboembolism ( VTE ) was higher in women who used oral contraceptives ( OCs ) containing the third - generation progestagens gestodene or desogestrel than in users of OCs containing second - generation progestagens . However , confounding and bias in the design of these studies may have affected the findings . The aim of our study was to re - examine the association between risk of VTE and OC use with a different study design and analysis to avoid some of the bias and confounding of the earlier studies . METHODS : We used computer records of patients from 143 general practices in the UK . The study was based on the medical records of about 540 , 000 women born between 1941 and 1981 . All women who had a recorded diagnosis of deep - vein thrombosis , venous thrombosis not otherwise specified , or pulmonary embolus during the study period , and who had been treated with an anticoagulant were identified as potential cases of VTE . We did a cohort analysis to estimate and compare incidence of VTE in users of the main OC preparations , and a nested case - control study to calculate the odds ratios of VTE associated with use of different types of OC , after adjustment for potential confounding factors . In the case - control study , we matched cases to controls by exact year of birth , practice , and current use of OCs . We used a multiple logistic regression model that included body - mass index , number of cycles , change in type of OC prescribed within 3 months of the event , previous pregnancy , and concurrent disease . FINDINGS : 85 women met the inclusion criteria for VTE , two of whom were users of progestagen - only OCs . Of the 83 cases of VTE associated with use of combined OCs , 43 were recorded as deep - vein thrombosis , 35 as pulmonary thrombosis , and five as venous thrombosis not otherwise specified . The crude rate of VTE per 10 , 000 woman - years was 4 . 10 in current users of any OC , 3 . 10 in users of second - generation OCs , and 4 . 96 in users of third - generation preparations . After adjustment for age , the rate ratio of VTE in users of third - generation relative to second - generation OCs was 1 . 68 ( 95 % CI 1 . 04 - 2 . 75 ) . Logistic regression showed no significant difference in the risk of VTE between users of third - generation and second - generation OCs . Among users of third - generation progestagens , the risk of VTE was higher in users of desogestrel with 20 g ethinyloestradiol than in users of gestodene or desogestrel with 30 g ethinyloestradiol . With all second - generation OCs as the reference , the odds ratios for VTE were 3 . 49 ( 1 . 21 - 10 . 12 ) for desogestrel plus 20 g ethinyloestradiol and 1 . 18 ( 0 . 66 - 2 . 17 ) for the other third - generation progestagens . INTERPRETATION : The previously reported increase in odds ratio associated with third - generation OCs when compared with second - generation products is likely to have been the result of residual confounding by age . The increased odds ratio associated with products containing 20 micrograms ethinyloestradiol and desogestrel compared with the 30 micrograms product is biologically implausible , and is likely to be the result of preferential prescribing and , thus , confounding . MK - 801 augments pilocarpine - induced electrographic seizure but protects against brain damage in rats . 1 . The authors examined the anticonvulsant effects of MK - 801 on the pilocarpine - induced seizure model . Intraperitoneal injection of pilocarpine ( 400 mg / kg ) induced tonic and clonic seizure . Scopolamine ( 10 mg / kg ) and pentobarbital ( 5 mg / kg ) prevented development of pilocarpine - induced behavioral seizure but MK - 801 ( 0 . 5 mg / kg ) did not . 2 . An electrical seizure measured with hippocampal EEG appeared in the pilocarpine - treated group . Scopolamine and pentobarbital blocked the pilocarpine - induced electrographic seizure , MK - 801 treatment augmented the electrographic seizure induced by pilocarpine . 3 . Brain damage was assessed by examining the hippocampus microscopically . Pilocarpine produced neuronal death in the hippocampus , which showed pyknotic changes . Pentobarbital , scopolamine and MK - 801 protected the brain damage by pilocarpine , though in the MK - 801 - treated group , the pyramidal cells of hippocampus appeared darker than normal . In all treatments , granule cells of the dentate gyrus were not affected . 4 . These results indicate that status epilepticus induced by pilocarpine is initiated by cholinergic overstimulation and propagated by glutamatergic transmission , the elevation of which may cause brain damage through an excitatory NMDA receptor - mediated mechanism . Paclitaxel , 5 - fluorouracil , and folinic acid in metastatic breast cancer : BRE - 26 , a phase II trial . 5 - Fluorouracil plus folinic acid and paclitaxel ( Taxol ; Bristol - Myers Squibb Company , Princeton , NJ ) are effective salvage therapies for metastatic breast cancer patients . Paclitaxel and 5 - fluorouracil have additive cytotoxicity in MCF - 7 cell lines . We performed a phase II trial of paclitaxel 175 mg / m2 over 3 hours on day I followed by folinic acid 300 mg over 1 hour before 5 - fluorouracil 350 mg / m2 on days 1 to 3 every 28 days ( TFL ) in women with metastatic breast cancer . Analysis is reported on 37 patients with a minimum of 6 months follow - up who received a total of 192 cycles of TFL : nine cycles ( 5 % ) were associated with grade 3 / 4 neutropenia requiring hospitalization ; seven ( 4 % ) cycles in two patients required granulocyte colony - stimulating factor due to neutropenia ; no patient required platelet transfusions . Grade 3 / 4 nonhematologic toxicities were uncommon . Among the 34 patients evaluable for response , there were three complete responses ( 9 % ) and 18 partial responses ( 53 % ) for an overall response rate of 62 % . Of the 19 evaluable patients with prior doxorubicin exposure , 11 ( 58 % ) responded compared with nine of 15 ( 60 % ) without prior doxorubicin . Plasma paclitaxel concentrations were measured at the completion of paclitaxel infusion and at 24 hours in 19 patients . TFL is an active , well - tolerated regimen in metastatic breast cancer . Efficacy and proarrhythmia with the use of d , l - sotalol for sustained ventricular tachyarrhythmias . This study prospectively evaluated the clinical efficacy , the incidence of torsades de pointes , and the presumable risk factors for torsades de pointes in patients treated with d , l - sotalol for sustained ventricular tachyarrhythmias . Eighty - one consecutive patients ( 54 with coronary artery disease , and 20 with dilated cardiomyopathy ) with inducible sustained ventricular tachycardia or ventricular fibrillation received oral d , l - sotalol to prevent induction of the ventricular tachyarrhythmia . During oral loading with d , l - sotalol , continuous electrocardiographic ( ECG ) monitoring was performed . Those patients in whom d , l - sotalol prevented induction of ventricular tachycardia or ventricular fibrillation were discharged with the drug and followed up on an outpatient basis for 21 + / - 18 months . Induction of the ventricular tachyarrhythmia was prevented by oral d , l - sotalol in 35 ( 43 % ) patients ; the ventricular tachyarrhythmia remained inducible in 40 ( 49 % ) patients ; and two ( 2 . 5 % ) patients did not tolerate even 40 mg of d , l - sotalol once daily . Four ( 5 % ) patients had from torsades de pointes during the initial oral treatment with d , l - sotalol . Neither ECG [ sinus - cycle length ( SCL ) , QT or QTc interval , or U wave ] nor clinical parameters identified patients at risk for torsades de pointes . However , the oral dose of d , l - sotalol was significantly lower in patients with torsades de pointes ( 200 + / - 46 vs . 328 + / - 53 mg / day ; p = 0 . 0017 ) . Risk factors associated with the development of torsades de pointes were the appearance of an U wave ( p = 0 . 049 ) , female gender ( p = 0 . 015 ) , and significant dose - corrected changes of SCL , QT interval , and QTc interval ( p < 0 . 05 ) . During follow - up , seven ( 20 % ) patients had a nonfatal ventricular tachycardia recurrence , and two ( 6 % ) patients died suddenly . One female patient with stable cardiac disease had recurrent torsades de pointes after 2 years of successful treatment with d , l - sotalol . Torsades de pointes occurred early during treatment even with low doses of oral d , l - sotalol . Pronounced changes in the surface ECG ( cycle length , QT , and QTc ) in relation to the dose of oral d , l - sotalol might identify a subgroup of patients with an increased risk for torsades de pointes . Other ECG parameters before the application of d , l - sotalol did not identify patients at increased risk for torsades de pointes . Recurrence rates of ventricular tachyarrhythmias are high despite complete suppression of the arrhythmia during programmed stimulation . Therefore programmed electrical stimulation in the case of d , l - sotalol seems to be of limited prognostic value . Chronic hyperprolactinemia and changes in dopamine neurons . The tuberoinfundibular dopaminergic ( TIDA ) system is known to inhibit prolactin ( PRL ) secretion . In young animals this system responds to acute elevations in serum PRL by increasing its activity . However , this responsiveness is lost in aging rats with chronically high serum PRL levels . The purpose of this study was to induce hyperprolactinemia in rats for extended periods of time and examine its effects on dopaminergic systems in the brain . Hyperprolactinemia was induced by treatment with haloperidol , a dopamine receptor antagonist , and Palkovits ' microdissection technique in combination with high - performance liquid chromatography was used to measure neurotransmitter concentrations in several areas of the brain . After 6 months of hyperprolactinemia , dopamine ( DA ) concentrations in the median eminence ( ME ) increased by 84 % over the control group . Nine months of hyperprolactinemia produced a 50 % increase in DA concentrations in the ME over the control group . However , DA response was lost if a 9 - month long haloperidol - induced hyperprolactinemia was followed by a 1 1 / 2 month - long extremely high increase in serum PRL levels produced by implantation of MMQ cells under the kidney capsule . There was no change in the levels of DA , norepinephrine ( NE ) , serotonin ( 5 - HT ) , or their metabolites in the arcuate nucleus ( AN ) , medial preoptic area ( MPA ) , caudate putamen ( CP ) , substantia nigra ( SN ) , and zona incerta ( ZI ) , except for a decrease in 5 - hydroxyindoleacetic acid ( 5 - HIAA ) in the AN after 6 - months of hyperprolactinemia and an increase in DA concentrations in the AN after 9 - months of hyperprolactinemia . These results demonstrate that hyperprolactinemia specifically affects TIDA neurons and these effects vary , depending on the duration and intensity of hyperprolactinemia . The age - related decrease in hypothalamic dopamine function may be associated with increases in PRL secretion . Treatment - related disseminated necrotizing leukoencephalopathy with characteristic contrast enhancement of the white matter . This report describes unique contrast enhancement of the white matter on T1 - weighted magnetic resonance images of two patients with disseminated necrotizing leukoencephalopathy , which developed from acute lymphoblastic leukemia treated with high - dose methotrexate . In both patients , the enhancement was more pronounced near the base of the brain than at the vertex . Necropsy of the first case revealed loss of myelination and necrosis of the white matter . Possible mechanisms causing such a leukoencephalopathy are discussed . Thrombotic complications in acute promyelocytic leukemia during all - trans - retinoic acid therapy . A case of acute renal failure , due to occlusion of renal vessels in a patient with acute promyelocytic leukemia ( APL ) treated with all - trans - retinoic acid ( ATRA ) and tranexamic acid has been described recently . We report a case of acute renal failure in an APL patient treated with ATRA alone . This case further supports the concern about thromboembolic complications associated with ATRA therapy in APL patients . The patients , a 43 - year - old man , presented all the signs and symptoms of APL and was included in a treatment protocol with ATRA . After 10 days of treatment , he developed acute renal failure that was completely reversible after complete remission of APL was achieved and therapy discontinued . We conclude that ATRA is a valid therapeutic choice for patients with APL , although the procoagulant tendency is not completely corrected . Thrombotic events , however , could be avoided by using low - dose heparin . Pupillary changes associated with the development of stimulant - induced mania : a case report . A 30 - year - old cocaine - dependent man who was a subject in a study evaluating the anticraving efficacy of the stimulant medication diethylpropion ( DEP ) became manic during his second week on the study drug . Pupillometric changes while on DEP , especially changes in the total power of pupillary oscillation , were dramatically different than those observed in the eight other study subjects who did not become manic . The large changes in total power of pupillary oscillation occurred a few days before the patient became fully manic . Such medication - associated changes in the total power of pupillary oscillation might be of utility in identifying persons at risk for manic - like adverse effects during the medical use of psychomotor stimulants or sympathomimetic agents . Fetal risks due to warfarin therapy during pregnancy . Two mothers with heart valve prosthesis were treated with warfarin during pregnancy . In the first case a caesarean section was done one week after replacement of warfarin with heparin . The baby died of cerebral and pulmonary hemorrhage . The second mother had a male infant by caesarean section . The baby showed warfarin - induced embryopathy with nasal hypoplasia and stippled epiphyses ( chondrodysplasia punctata ) . Nasal hypoplasia with or without stippled epiphyses has now been reported in 11 infants born to mothers treated with warfarin during the first trimester , and a causal association is probable . In view of the risks to both mother and fetus in women with prosthetic cardiac valves it is recommended that therapeutic abortion be advised as the first alternative . The negative mucosal potential : separating central and peripheral effects of NSAIDs in man . OBJECTIVE : We wanted to test whether assessment of both a central pain - related signal ( chemo - somatosensory evoked potential , CSSEP ) and a concomitantly recorded peripheral signal ( negative mucosal potential , NMP ) allows for separation of central and peripheral effects of NSAIDs . For this purpose , experimental conditions were created in which NSAIDs had previously been observed to produce effects on phasic and tonic pain by either central or peripheral mechanisms . METHODS : According to a double - blind , randomised , controlled , threefold cross - over design , 18 healthy subjects ( 11 males , 7 females ; mean age 26 years ) received either placebo , 400 mg ibuprofen , or 800 mg ibuprofen . Phasic pain was applied by means of short pulses of CO2 to the nasal mucosa ( stimulus duration 500 ms , interval approximately 60 s ) , and tonic pain was induced in the nasal cavity by means of dry air of controlled temperature , humidity and flow rate ( 22 degrees C , 0 % relative humidity , 145 ml . s - 1 ) . Both CSSEPs as central and NMPs as peripheral correlates of pain were obtained in response to the CO2 stimuli . Additionally , the subjects rated the intensity of both phasic and tonic pain by means of visual analogue scales . RESULTS : As described earlier , administration of ibuprofen was followed by a decrease in tonic pain but - relative to placebo - an increase in correlates of phasic pain , indicating a specific effect of ibuprofen on the interaction between the pain stimuli under these special experimental conditions . Based on the similar behaviour of CSSEP and NMP , it was concluded that the pharmacological process underlying this phenomenon was localised in the periphery . By means of the simultaneous recording of interrelated peripheral and central electrophysiologic correlates of nociception , it was possible to separate central and peripheral effects of an NSAID . The major advantage of this pain model is the possibility of obtaining peripheral pain - related activity directly using a non - invasive technique in humans . Effect of D - Glucarates on basic antibiotic - induced renal damage in rats . Dehydrated rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only . Oral administration of 2 , 5 - di - O - acetyl - D - glucaro - 1 , 4 - 6 , 3 - dilactone protected rats against renal failure induced by kanamycin - dextran . The protective effect was prevalent among D - glucarates , and also to other saccharic acid , hexauronic acids and hexaaldonic acids , although to a lesser degree , but not to a hexaaldose , sugar alcohols , substances inthe TCA cycle and other acidic compounds . D - Glucarates were effective against renal damage induced by peptide antibiotics as well as various aminoglycoside antibitocis . Dose - responses were observed in the protective effect of D - Glucarates . With a D - glucarate of a fixed size of dose , approximately the same degree of protection was obtained against renal damages induced by different basic antibiotics despite large disparities in administration doses of different antibiotics . D - Glucarates had the ability to prevent renal damage but not to cure it . Rats excreted acidic urine when they were spared from renal lesions by monosaccharides . The reduction effect of D - glucarates against nephrotoxicity of basic antibiotics was discussed . Acute severe depression following peri - operative ondansetron . A 41 - year - old woman with a strong history of postoperative nausea and vomiting presented for abdominal hysterectomy 3 months after a previous anaesthetic where ondansetron prophylaxis had been used . She had developed a severe acute major depression disorder almost immediately thereafter , possibly related to the use of a serotonin antagonist . Nine years before she had experienced a self - limited puerperal depressive episode . Anaesthesia with a propofol infusion and avoidance of serotonin antagonists provided a nausea - free postoperative course without exacerbation of the depression disorder . Hypertensive response during dobutamine stress echocardiography . Among 3 , 129 dobutamine stress echocardiographic studies , a hypertensive response , defined as systolic blood pressure ( BP ) > or = 220 mm Hg and / or diastolic BP > or = 110 mm Hg , occurred in 30 patients ( 1 % ) . Patients with this response more often had a history of hypertension and had higher resting systolic and diastolic BP before dobutamine infusion . Continuously nebulized albuterol in severe exacerbations of asthma in adults : a case - controlled study . A retrospective , case - controlled analysis comparing patients admitted to a medical intensive care unit with severe exacerbations of asthma who received continuously nebulized albuterol ( CNA ) versus intermittent albuterol ( INA ) treatments is reported . Forty matched pairs of patients with asthma are compared . CNA was administered for a mean of 11 + / - 10 hr . The incidence of cardiac dysrhythmias was similar between groups . Symptomatic hypokalemia did not occur . CNA patients had higher heart rates during treatment , which may reflect severity of illness . The incidence of intubation was similar . We conclude that CNA and INA demonstrated similar profiles with regard to safety , morbidity , and mortality . Paraplegia following intrathecal methotrexate : report of a case and review of the literature . A patient who developed paraplegia following the intrathecal instillation of methotrexate is discribed . The ten previously reported cases of this unusual complication are reviewed . The following factors appear to predispose to the development of this complication : abnormal cerebrospinal dynamics related to the presence of central nervous system leukemia , and epidural cerebrospinal leakage ; elevated cerebrospinal fluid methothexate concentration related to abnormal cerebrospinal fluid dynamics and to inappropriately high methotrexate doses based on body surface area calculations in older children and adults ; the presence of neurotoxic preservatives in commercially available methotrexate preparations and diluents ; and the use of methotrexate diluents of unphysiologic pH , ionic content and osmolarity . The role of methotrexate contaminants , local folate deficiency , and cranial irradiation in the pathogenesis of intrathecal methotrexate toxicity is unclear . The incidence of neurotoxicity may be reduced by employing lower doses of methotrexate in the presence of central nervous system leukemia , in older children and adults , and in the presence of epidural leakage . Only preservative - free methotrexate in Elliott ' s B Solution at a concentration of not more than 1 mg / ml should be used for intrathecal administration . Periodic monitoring of cerebruspinal fluid methotrexate levels may be predictive of the development of serious neurotoxicity . Hyperosmolar nonketotic coma precipitated by lithium - induced nephrogenic diabetes insipidus . A 45 - year - old man , with a 10 - year history of manic depression treated with lithium , was admitted with hyperosmolar , nonketotic coma . He gave a five - year history of polyuria and polydipsia , during which time urinalysis had been negative for glucose . After recovery from hyperglycaemia , he remained polyuric despite normal blood glucose concentrations ; water deprivation testing indicated nephrogenic diabetes insipidus , likely to be lithium - induced . We hypothesize that when this man developed type 2 diabetes , chronic polyuria due to nephrogenic diabetes insipidus was sufficient to precipitate hyperosmolar dehydration . Effects of the intracoronary infusion of cocaine on left ventricular systolic and diastolic function in humans . BACKGROUND : In dogs , a large amount of intravenous cocaine causes a profound deterioration of left ventricular ( LV ) systolic function and an increase in LV end - diastolic pressure . This study was done to assess the influence of a high intracoronary cocaine concentration on LV systolic and diastolic function in humans . METHODS AND RESULTS : In 20 patients ( 14 men and 6 women aged 39 to 72 years ) referred for cardiac catheterization for the evaluation of chest pain , we measured heart rate , systemic arterial pressure , LV pressure and its first derivative ( dP / dt ) , and LV volumes and ejection fraction before and during the final 2 to 3 minutes of a 15 - minute intracoronary infusion of saline ( n = 10 , control subjects ) or cocaine hydrochloride 1 mg / min ( n = 10 ) . No variable changed with saline . With cocaine , the drug concentration in blood obtained from the coronary sinus was 3 . 0 + / - 0 . 4 ( mean + / - SD ) mg / L , similar in magnitude to the blood cocaine concentration reported in abusers dying of cocaine intoxication . Cocaine induced no significant change in heart rate , LV dP / dt ( positive or negative ) , or LV end - diastolic volume , but it caused an increase in systolic and mean arterial pressures , LV end - diastolic pressure , and LV end - systolic volume , as well as a decrease in LV ejection fraction . CONCLUSIONS : In humans , the intracoronary infusion of cocaine sufficient in amount to achieve a high drug concentration in coronary sinus blood causes a deterioration of LV systolic and diastolic performance . Ascending dose tolerance study of intramuscular carbetocin administered after normal vaginal birth . OBJECTIVE : To determine the maximum tolerated dose ( MTD ) of carbetocin ( a long - acting synthetic analogue of oxytocin ) , when administered immediately after vaginal delivery at term . MATERIALS AND METHODS : Carbetocin was given as an intramuscular injection immediately after the birth of the infant in 45 healthy women with normal singleton pregnancies who delivered vaginally at term . Dosage groups of 15 , 30 , 50 , 75 , 100 , 125 , 150 , 175 or 200 microg carbetocin were assigned to blocks of three women according to the continual reassessment method ( CRM ) . RESULTS : All dosage groups consisted of three women , except those with 100 microg ( n = 6 ) and 200 microg ( n = 18 ) . Recorded were dose - limiting adverse events : hyper - or hypotension ( three ) , severe abdominal pain ( 0 ) , vomiting ( 0 ) and retained placenta ( four ) . Serious adverse events occurred in seven women : six cases with blood loss > or = 1000 ml , four cases of manual placenta removal , five cases of additional oxytocics administration and five cases of blood transfusion . Maximum blood loss was greatest at the upper and lower dose levels , and lowest in the 70 - 125 microg dose range . Four out of six cases with blood loss > or = 1000 ml occurred in the 200 microg group . The majority of additional administration of oxytocics ( 4 / 5 ) and blood transfusion ( 3 / 5 ) occurred in the dose groups of 200 microg . All retained placentae were found in the group of 200 microg . CONCLUSION : The MTD was calculated to be at 200 microg carbetocin . Heparin - induced thrombocytopenia , paradoxical thromboembolism , and other side effects of heparin therapy . Although several new anticoagulant drugs are in development , heparin remains the drug of choice for most anticoagulation needs . The clinical effects of heparin are meritorious , but side effects do exist . Important untoward effects of heparin therapy including heparin - induced thrombocytopenia , heparin - associated osteoporosis , eosinophilia , skin reactions , allergic reactions other than thrombocytopenia and alopecia will be discussed in this article . Nonopaque crystal deposition causing ureteric obstruction in patients with HIV undergoing indinavir therapy . OBJECTIVE : We describe the unique CT features of ureteric calculi in six HIV - infected patients receiving indinavir , the most commonly used HIV protease inhibitor , which is associated with an increased incidence of urolithiasis . CONCLUSION : Ureteric obstruction caused by precipitated indinavir crystals may be difficult to diagnose with unenhanced CT . The calculi are not opaque , and secondary signs of obstruction may be absent or minimal and should be sought carefully . Images may need to be obtained using i . v . contrast material to enable diagnosis of ureteric stones or obstruction in patients with HIV infection who receive indinavir therapy . Ischemic colitis and sumatriptan use . Sumatriptan succinate , a serotonin - 1 ( 5 - hydroxytryptamine - 1 ) receptor agonist , is an antimigraine drug that is reported to act by selectively constricting intracranial arteries . Recently , vasopressor responses that are distinct from the cranial circulation have been demonstrated to occur in the systemic , pulmonary , and coronary circulations . Cases have been published of coronary vasospasm , myocardial ischemia , and myocardial infarction occurring after sumatriptan use . We report on the development of 8 serious cases of ischemic colitis in patients with migraine treated with sumatriptan . Pallidotomy with the gamma knife : a positive experience . 51 patients with medically refractory Parkinson ' s disease underwent stereotactic posteromedial pallidotomy between August 1993 and February 1997 for treatment of bradykinesia , rigidity , and L - DOPA - induced dyskinesias . In 29 patients , the pallidotomies were performed with the Leksell Gamma Knife and in 22 they were performed with the standard radiofrequency ( RF ) method . Clinical assessment as well as blinded ratings of Unified Parkinson ' s Disease Rating Scale ( UPDRS ) scores were carried out pre - and postoperatively . Mean follow - up time is 20 . 6 months ( range 6 - 48 ) and all except 4 patients have been followed more than one year . 85 percent of patients with dyskinesias were relieved of symptoms , regardless of whether the pallidotomies were performed with the Gamma Knife or radiofrequency methods . About 2 / 3 of the patients in both Gamma Knife and radiofrequency groups showed improvements in bradykinesia and rigidity , although when considered as a group neither the Gamma Knife nor the radiofrequency group showed statistically significant improvements in UPDRS scores . One patient in the Gamma Knife group ( 3 . 4 % ) developed a homonymous hemianopsia 9 months following treatment and 5 patients ( 27 . 7 % ) in the radiofrequency group became transiently confused postoperatively . No other complications were seen . Gamma Knife pallidotomy is as effective as radiofrequency pallidotomy in controlling certain of the symptoms of Parkinson ' s disease . It may be the only practical technique available in certain patients , such as those who take anticoagulants , have bleeding diatheses or serious systemic medical illnesses . It is a viable option for other patients as well . Centrally mediated cardiovascular effects of intracisternal application of carbachol in anesthetized rats . The pressor response to the intracisternal ( i . c . ) injection of carbachol ( 1 mug ) in anesthetized rats was analyzed . This response was significantly reduced by the intravenous ( i . v . ) injection of guanethidine ( 5 mg ) , hexamethonium ( 10 mg ) or phentolamine ( 5 mg ) , and conversely , potentiated by i . v . desmethylimipramine ( 0 . 3 mg ) , while propranolol ( 0 . 5 mg ) i . v . selectively inhibited the enlargement of pulse pressure and the tachycardia following i . c . carbachol ( 1 mug ) . On the other hand , the pressor response to i . c . carbachol ( 1 mug ) was almost completely blocked by i . c . atropine ( 3 mug ) or hexamethonium ( 500 mug ) , and significantly reduced by i . c . chlorpromazine ( 50 mug ) but significantly potentiated by i . c . desmethylimipramine ( 30 mug ) . The pressor response to i . c . carbachol ( 1 mug ) remained unchanged after sectioning of the bilateral cervical vagal nerves but disappeared after sectioning of the spinal cord ( C7 - C8 ) . From the above result it is suggested that the pressor response to i . c . carbachol ortral and peripheral adrenergic mechanisms , and that the sympathetic trunk is the main pathway . Neuroleptic malignant syndrome and methylphenidate . A 1 - year - old female presented with neuroleptic malignant syndrome probably caused by methylphenidate . She had defects in the supratentorial brain including the basal ganglia and the striatum ( multicystic encephalomalacia ) due to severe perinatal hypoxic - ischemic encephalopathy , which was considered to be a possible predisposing factor causing neuroleptic malignant syndrome . A dopaminergic blockade mechanism generally is accepted as the pathogenesis of this syndrome . However , methylphenidate is a dopamine agonist via the inhibition of uptake of dopamine , and therefore dopaminergic systems in the brainstem ( mainly the midbrain ) and the spinal cord were unlikely to participate in the onset of this syndrome . A relative gamma - aminobutyric acid - ergic deficiency might occur because diazepam , a gamma - aminobutyric acid - mimetic agent , was strikingly effective . This is the first reported patient with neuroleptic malignant syndrome probably caused by methylphenidate . Differential effects of 17alpha - ethinylestradiol on the neutral and acidic pathways of bile salt synthesis in the rat . Effects of 17alpha - ethinylestradiol ( EE ) on the neutral and acidic biosynthetic pathways of bile salt ( BS ) synthesis were evaluated in rats with an intact enterohepatic circulation and in rats with long - term bile diversion to induce BS synthesis . For this purpose , bile salt pool composition , synthesis of individual BS in vivo , hepatic activities , and expression levels of cholesterol 7alpha - hydroxylase ( CYP7A ) , and sterol 27 - hydroxylase ( CYP27 ) , as well as of other enzymes involved in BS synthesis , were analyzed in rats treated with EE ( 5 mg / kg , 3 days ) or its vehicle . BS pool size was decreased by 27 % but total BS synthesis was not affected by EE in intact rats . Synthesis of cholate was reduced by 68 % in EE - treated rats , while that of chenodeoxycholate was increased by 60 % . The recently identified Delta22 - isomer of beta - muricholate contributed for 5 . 4 % and 18 . 3 % ( P < 0 . 01 ) to the pool in control and EE - treated rats , respectively , but could not be detected in bile after exhaustion of the pool . A clear reduction of BS synthesis was found in bile - diverted rats treated with EE , yet biliary BS composition was only minimally affected . Activity of CYP7A was decreased by EE in both intact and bile - diverted rats , whereas the activity of the CYP27 was not affected . Hepatic mRNA levels of CYP7A were significantly reduced by EE in bile - diverted rats only ; CYP27 mRNA levels were not affected by EE . In addition , mRNA levels of sterol 12alpha - hydroxylase and lithocholate 6beta - hydroxylase were increased by bile diversion and suppressed by EE . This study shows that 17alpha - ethinylestradiol ( EE ) - induced intrahepatic cholestasis in rats is associated with selective inhibition of the neutral pathway of bile salt ( BS ) synthesis . Simultaneous impairment of other enzymes in the BS biosynthetic pathways may contribute to overall effects of EE on BS synthesis . Glibenclamide - sensitive hypotension produced by helodermin assessed in the rat . The effects of helodermin , a basic 35 - amino acid peptide isolated from the venom of a lizard salivary gland , on arterial blood pressure and heart rate were examined in the rat , focusing on the possibility that activation of ATP sensitive K + ( K ( ATP ) ) channels is involved in the responses . The results were also compared with those of vasoactive intestinal polypeptide ( VIP ) . Helodermin produced hypotension in a dose - dependent manner with approximately similar potency and duration to VIP . Hypotension induced by both peptides was significantly attenuated by glibenclamide , which abolished a levcromakalim - produced decrease in arterial blood pressure . Oxyhemoglobin did not affect helodermin - induced hypotension , whereas it shortened the duration of acetylcholine ( ACh ) - produced hypotension . These findings suggest that helodermin - produced hypotension is partly attributable to the activation of glibenclamide - sensitive K + channels ( K ( ATP ) channels ) , which presumably exist on arterial smooth muscle cells . EDRF ( endothelium - derived relaxing factor ) / nitric oxide does not seem to play an important role in the peptide - produced hypotension . Long - term efficacy and adverse event of nifedipine sustained - release tablets for cyclosporin A - induced hypertension in patients with psoriasis . Thirteen psoriatic patients with hypertension during the course of cyclosporin A therapy were treated for 25 months with a calcium channel blocker , sustained - release nifedipine , to study the clinical antihypertensive effects and adverse events during treatment with both drugs . Seven of the 13 patients had exhibited a subclinical hypertensive state before cyclosporin A therapy . Both systolic and diastolic blood pressures of these 13 patients were decreased significantly after 4 weeks of nifedipine therapy , and blood pressure was maintained within the normal range thereafter for 25 months . The adverse events during combined therapy with cyclosporin A and nifedipine included an increase in blood urea nitrogen levels in 9 of the 13 patients and development of gingival hyperplasia in 2 of the 13 patients . Our findings indicate that sustained - release nifedipine is useful for hypertensive psoriatic patients under long - term treatment with cyclosporin A , but that these patients should be monitored for gingival hyperplasia . 
\ No newline at end of file
diff --git a/data/BC5CDR-disease/train.tsv b/data/BC5CDR-disease/train.tsv
new file mode 100644
index 0000000..c94422e
--- /dev/null
+++ b/data/BC5CDR-disease/train.tsv
@@ -0,0 +1,122730 @@
+Selegiline	O
+-	O
+induced	O
+postural	B
+hypotension	I
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+:	O
+a	O
+longitudinal	O
+study	O
+on	O
+the	O
+effects	O
+of	O
+drug	O
+withdrawal	O
+.	O
+
+OBJECTIVES	O
+:	O
+The	O
+United	O
+Kingdom	O
+Parkinson	B
+'	I
+s	I
+Disease	I
+Research	O
+Group	O
+(	O
+UKPDRG	O
+)	O
+trial	O
+found	O
+an	O
+increased	O
+mortality	O
+in	O
+patients	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+randomized	O
+to	O
+receive	O
+10	O
+mg	O
+selegiline	O
+per	O
+day	O
+and	O
+L	O
+-	O
+dopa	O
+compared	O
+with	O
+those	O
+taking	O
+L	O
+-	O
+dopa	O
+alone	O
+.	O
+
+Recently	O
+,	O
+we	O
+found	O
+that	O
+therapy	O
+with	O
+selegiline	O
+and	O
+L	O
+-	O
+dopa	O
+was	O
+associated	O
+with	O
+selective	O
+systolic	B
+orthostatic	I
+hypotension	I
+which	O
+was	O
+abolished	O
+by	O
+withdrawal	O
+of	O
+selegiline	O
+.	O
+
+This	O
+unwanted	O
+effect	O
+on	O
+postural	O
+blood	O
+pressure	O
+was	O
+not	O
+the	O
+result	O
+of	O
+underlying	O
+autonomic	O
+failure	O
+.	O
+
+The	O
+aims	O
+of	O
+this	O
+study	O
+were	O
+to	O
+confirm	O
+our	O
+previous	O
+findings	O
+in	O
+a	O
+separate	O
+cohort	O
+of	O
+patients	O
+and	O
+to	O
+determine	O
+the	O
+time	O
+course	O
+of	O
+the	O
+cardiovascular	O
+consequences	O
+of	O
+stopping	O
+selegiline	O
+in	O
+the	O
+expectation	O
+that	O
+this	O
+might	O
+shed	O
+light	O
+on	O
+the	O
+mechanisms	O
+by	O
+which	O
+the	O
+drug	O
+causes	O
+orthostatic	B
+hypotension	I
+.	O
+
+METHODS	O
+:	O
+The	O
+cardiovascular	O
+responses	O
+to	O
+standing	O
+and	O
+head	O
+-	O
+up	O
+tilt	O
+were	O
+studied	O
+repeatedly	O
+in	O
+PD	B
+patients	O
+receiving	O
+selegiline	O
+and	O
+as	O
+the	O
+drug	O
+was	O
+withdrawn	O
+.	O
+
+RESULTS	O
+:	O
+Head	O
+-	O
+up	O
+tilt	O
+caused	O
+systolic	B
+orthostatic	I
+hypotension	I
+which	O
+was	O
+marked	O
+in	O
+six	O
+of	O
+20	O
+PD	B
+patients	O
+on	O
+selegiline	O
+,	O
+one	O
+of	O
+whom	O
+lost	O
+consciousness	O
+with	O
+unrecordable	O
+blood	O
+pressures	O
+.	O
+
+A	O
+lesser	O
+degree	O
+of	O
+orthostatic	B
+hypotension	I
+occurred	O
+with	O
+standing	O
+.	O
+
+Orthostatic	B
+hypotension	I
+was	O
+ameliorated	O
+4	O
+days	O
+after	O
+withdrawal	O
+of	O
+selegiline	O
+and	O
+totally	O
+abolished	O
+7	O
+days	O
+after	O
+discontinuation	O
+of	O
+the	O
+drug	O
+.	O
+
+Stopping	O
+selegiline	O
+also	O
+significantly	O
+reduced	B
+the	I
+supine	I
+systolic	I
+and	I
+diastolic	I
+blood	I
+pressures	I
+consistent	O
+with	O
+a	O
+previously	O
+undescribed	O
+supine	O
+pressor	O
+action	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+study	O
+confirms	O
+our	O
+previous	O
+finding	O
+that	O
+selegiline	O
+in	O
+combination	O
+with	O
+L	O
+-	O
+dopa	O
+is	O
+associated	O
+with	O
+selective	O
+orthostatic	B
+hypotension	I
+.	O
+
+The	O
+possibilities	O
+that	O
+these	O
+cardiovascular	O
+findings	O
+might	O
+be	O
+the	O
+result	O
+of	O
+non	O
+-	O
+selective	O
+inhibition	O
+of	O
+monoamine	O
+oxidase	O
+or	O
+of	O
+amphetamine	O
+and	O
+metamphetamine	O
+are	O
+discussed	O
+.	O
+
+Further	O
+studies	O
+on	O
+effects	O
+of	O
+irrigation	O
+solutions	O
+on	O
+rat	O
+bladders	O
+.	O
+
+Further	O
+studies	O
+on	O
+the	O
+effects	O
+of	O
+certain	O
+irrigating	O
+fluids	O
+on	O
+the	O
+rat	O
+bladder	O
+for	O
+18	O
+hours	O
+are	O
+reported	O
+.	O
+
+The	O
+results	O
+have	O
+shown	O
+that	O
+the	O
+degradation	O
+product	O
+p	O
+-	O
+choloroaniline	O
+is	O
+not	O
+a	O
+significant	O
+factor	O
+in	O
+chlorhexidine	O
+-	O
+digluconate	O
+associated	O
+erosive	O
+cystitis	B
+.	O
+
+A	O
+high	O
+percentage	O
+of	O
+kanamycin	O
+-	O
+colistin	O
+and	O
+povidone	O
+-	O
+iodine	O
+irrigations	O
+were	O
+associated	O
+with	O
+erosive	O
+cystitis	B
+and	O
+suggested	O
+a	O
+possible	O
+complication	O
+with	O
+human	O
+usage	O
+.	O
+
+Picloxydine	O
+irrigations	O
+appeared	O
+to	O
+have	O
+a	O
+lower	O
+incidence	O
+of	O
+erosive	O
+cystitis	B
+but	O
+further	O
+studies	O
+would	O
+have	O
+to	O
+be	O
+performed	O
+before	O
+it	O
+could	O
+be	O
+recommended	O
+for	O
+use	O
+in	O
+urological	O
+procedures	O
+.	O
+
+Effects	O
+of	O
+tetrandrine	O
+and	O
+fangchinoline	O
+on	O
+experimental	O
+thrombosis	B
+in	O
+mice	O
+and	O
+human	O
+platelet	B
+aggregation	I
+.	O
+
+Tetrandrine	O
+(	O
+TET	O
+)	O
+and	O
+fangchinoline	O
+(	O
+FAN	O
+)	O
+are	O
+two	O
+naturally	O
+occurring	O
+analogues	O
+with	O
+a	O
+bisbenzylisoquinoline	O
+structure	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+undertaken	O
+to	O
+investigate	O
+the	O
+effects	O
+of	O
+TET	O
+and	O
+FAN	O
+on	O
+the	O
+experimental	O
+thrombosis	B
+induced	O
+by	O
+collagen	O
+plus	O
+epinephrine	O
+(	O
+EP	O
+)	O
+in	O
+mice	O
+,	O
+and	O
+platelet	B
+aggregation	I
+and	O
+blood	B
+coagulation	I
+in	O
+vitro	O
+.	O
+
+In	O
+the	O
+in	O
+vivo	O
+study	O
+,	O
+the	O
+administration	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+of	O
+TET	O
+and	O
+FAN	O
+in	O
+mice	O
+showed	O
+the	O
+inhibition	O
+of	O
+thrombosis	B
+by	O
+55	O
+%	O
+and	O
+35	O
+%	O
+,	O
+respectively	O
+,	O
+while	O
+acetylsalicylic	O
+acid	O
+(	O
+ASA	O
+,	O
+50	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+,	O
+a	O
+positive	O
+control	O
+,	O
+showed	O
+only	O
+30	O
+%	O
+inhibition	O
+.	O
+
+In	O
+the	O
+vitro	O
+human	O
+platelet	B
+aggregations	I
+induced	O
+by	O
+the	O
+agonists	O
+used	O
+in	O
+tests	O
+,	O
+TET	O
+and	O
+FAN	O
+showed	O
+the	O
+inhibitions	O
+dose	O
+dependently	O
+.	O
+
+In	O
+addition	O
+,	O
+neither	O
+TET	O
+nor	O
+FAN	O
+showed	O
+any	O
+anticoagulation	O
+activities	O
+in	O
+the	O
+measurement	O
+of	O
+the	O
+activated	O
+partial	O
+thromboplastin	O
+time	O
+(	O
+APTT	O
+)	O
+,	O
+prothrombin	O
+time	O
+(	O
+PT	O
+)	O
+and	O
+thrombin	O
+time	O
+(	O
+TT	O
+)	O
+using	O
+human	O
+-	O
+citrated	O
+plasma	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+antithrombosis	O
+of	O
+TET	O
+and	O
+FAN	O
+in	O
+mice	O
+may	O
+be	O
+mainly	O
+related	O
+to	O
+the	O
+antiplatelet	O
+aggregation	O
+activities	O
+.	O
+
+Angioedema	B
+due	O
+to	O
+ACE	O
+inhibitors	O
+:	O
+common	O
+and	O
+inadequately	O
+diagnosed	O
+.	O
+
+The	O
+estimated	O
+incidence	O
+of	O
+angioedema	B
+during	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+inhibitor	O
+treatment	O
+is	O
+between	O
+1	O
+and	O
+7	O
+per	O
+thousand	O
+patients	O
+.	O
+
+This	O
+potentially	O
+serious	O
+adverse	O
+effect	O
+is	O
+often	O
+preceded	O
+by	O
+minor	O
+manifestations	O
+that	O
+may	O
+serve	O
+as	O
+a	O
+warning	O
+.	O
+
+Cocaine	O
+-	O
+induced	O
+mood	B
+disorder	I
+:	O
+prevalence	O
+rates	O
+and	O
+psychiatric	B
+symptoms	O
+in	O
+an	O
+outpatient	O
+cocaine	O
+-	O
+dependent	O
+sample	O
+.	O
+
+This	O
+paper	O
+attempts	O
+to	O
+examine	O
+and	O
+compare	O
+prevalence	O
+rates	O
+and	O
+symptom	O
+patterns	O
+of	O
+DSM	O
+substance	O
+-	O
+induced	O
+and	O
+other	O
+mood	B
+disorders	I
+.	O
+
+243	O
+cocaine	O
+-	O
+dependent	O
+outpatients	O
+with	O
+cocaine	O
+-	O
+induced	O
+mood	B
+disorder	I
+(	O
+CIMD	B
+)	O
+,	O
+other	O
+mood	B
+disorders	I
+,	O
+or	O
+no	O
+mood	B
+disorder	I
+were	O
+compared	O
+on	O
+measures	O
+of	O
+psychiatric	B
+symptoms	O
+.	O
+
+The	O
+prevalence	O
+rate	O
+for	O
+CIMD	B
+was	O
+12	O
+%	O
+at	O
+baseline	O
+.	O
+
+Introduction	O
+of	O
+the	O
+DSM	O
+-	O
+IV	O
+diagnosis	O
+of	O
+CIMD	B
+did	O
+not	O
+substantially	O
+affect	O
+rates	O
+of	O
+the	O
+other	O
+depressive	B
+disorders	I
+.	O
+
+Patients	O
+with	O
+CIMD	B
+had	O
+symptom	O
+severity	O
+levels	O
+between	O
+those	O
+of	O
+patients	O
+with	O
+and	O
+without	O
+a	O
+mood	B
+disorder	I
+.	O
+
+These	O
+findings	O
+suggest	O
+some	O
+validity	O
+for	O
+the	O
+new	O
+DSM	O
+-	O
+IV	O
+diagnosis	O
+of	O
+CIMD	B
+,	O
+but	O
+also	O
+suggest	O
+that	O
+it	O
+requires	O
+further	O
+specification	O
+and	O
+replication	O
+.	O
+
+Effect	O
+of	O
+fucoidan	O
+treatment	O
+on	O
+collagenase	O
+-	O
+induced	O
+intracerebral	B
+hemorrhage	I
+in	O
+rats	O
+.	O
+
+Inflammatory	O
+cells	O
+are	O
+postulated	O
+to	O
+mediate	O
+some	O
+of	O
+the	O
+brain	B
+damage	I
+following	O
+ischemic	B
+stroke	I
+.	O
+
+Intracerebral	B
+hemorrhage	I
+is	O
+associated	O
+with	O
+more	O
+inflammation	B
+than	O
+ischemic	B
+stroke	I
+.	O
+
+We	O
+tested	O
+the	O
+sulfated	O
+polysaccharide	O
+fucoidan	O
+,	O
+which	O
+has	O
+been	O
+reported	O
+to	O
+reduce	O
+inflammatory	O
+brain	B
+damage	I
+,	O
+in	O
+a	O
+rat	O
+model	O
+of	O
+intracerebral	B
+hemorrhage	I
+induced	O
+by	O
+injection	O
+of	O
+bacterial	O
+collagenase	O
+into	O
+the	O
+caudate	O
+nucleus	O
+.	O
+
+Rats	O
+were	O
+treated	O
+with	O
+seven	O
+day	O
+intravenous	O
+infusion	O
+of	O
+fucoidan	O
+(	O
+30	O
+micrograms	O
+h	O
+-	O
+1	O
+)	O
+or	O
+vehicle	O
+.	O
+
+The	O
+hematoma	B
+was	O
+assessed	O
+in	O
+vivo	O
+by	O
+magnetic	O
+resonance	O
+imaging	O
+.	O
+
+Motor	O
+behavior	O
+,	O
+passive	O
+avoidance	O
+,	O
+and	O
+skilled	O
+forelimb	O
+function	O
+were	O
+tested	O
+repeatedly	O
+for	O
+six	O
+weeks	O
+.	O
+
+Fucoidan	O
+-	O
+treated	O
+rats	O
+exhibited	O
+evidence	O
+of	O
+impaired	B
+blood	I
+clotting	I
+and	O
+hemodilution	B
+,	O
+had	O
+larger	O
+hematomas	B
+,	O
+and	O
+tended	O
+to	O
+have	O
+less	O
+inflammation	B
+in	O
+the	O
+vicinity	O
+of	O
+the	O
+hematoma	B
+after	O
+three	O
+days	O
+.	O
+
+They	O
+showed	O
+significantly	O
+more	O
+rapid	O
+improvement	O
+of	O
+motor	O
+function	O
+in	O
+the	O
+first	O
+week	O
+following	O
+hemorrhage	B
+and	O
+better	O
+memory	O
+retention	O
+in	O
+the	O
+passive	O
+avoidance	O
+test	O
+.	O
+
+Acute	O
+white	B
+matter	I
+edema	I
+and	O
+eventual	O
+neuronal	B
+loss	I
+in	O
+the	O
+striatum	O
+adjacent	O
+to	O
+the	O
+hematoma	B
+did	O
+not	O
+differ	O
+between	O
+the	O
+two	O
+groups	O
+.	O
+
+Investigation	O
+of	O
+more	O
+specific	O
+anti	O
+-	O
+inflammatory	O
+agents	O
+and	O
+hemodiluting	O
+agents	O
+are	O
+warranted	O
+in	O
+intracerebral	B
+hemorrhage	I
+.	O
+
+Recurarization	O
+in	O
+the	O
+recovery	O
+room	O
+.	O
+
+A	O
+case	O
+of	O
+recurarization	O
+in	O
+the	O
+recovery	O
+room	O
+is	O
+reported	O
+.	O
+
+Accumulation	O
+of	O
+atracurium	O
+in	O
+the	O
+intravenous	O
+line	O
+led	O
+to	O
+recurarization	O
+after	O
+flushing	O
+the	O
+line	O
+in	O
+the	O
+recovery	O
+room	O
+.	O
+
+A	O
+respiratory	B
+arrest	I
+with	O
+severe	O
+desaturation	B
+and	O
+bradycardia	B
+occurred	O
+.	O
+
+Circumstances	O
+leading	O
+to	O
+this	O
+event	O
+and	O
+the	O
+mechanisms	O
+enabling	O
+a	O
+neuromuscular	B
+blockade	I
+to	O
+occur	O
+,	O
+following	O
+the	O
+administration	O
+of	O
+a	O
+small	O
+dose	O
+of	O
+relaxant	O
+,	O
+are	O
+discussed	O
+.	O
+
+The	O
+haemodynamic	O
+effects	O
+of	O
+propofol	O
+in	O
+combination	O
+with	O
+ephedrine	O
+in	O
+elderly	O
+patients	O
+(	O
+ASA	O
+groups	O
+3	O
+and	O
+4	O
+)	O
+.	O
+
+The	O
+marked	O
+vasodilator	O
+and	O
+negative	O
+inotropic	O
+effects	O
+of	O
+propofol	O
+are	O
+disadvantages	O
+in	O
+frail	O
+elderly	O
+patients	O
+.	O
+
+We	O
+investigated	O
+the	O
+safety	O
+and	O
+efficacy	O
+of	O
+adding	O
+different	O
+doses	O
+of	O
+ephedrine	O
+to	O
+propofol	O
+in	O
+order	O
+to	O
+obtund	O
+the	O
+hypotensive	B
+response	O
+.	O
+
+The	O
+haemodynamic	O
+effects	O
+of	O
+adding	O
+15	O
+,	O
+20	O
+or	O
+25	O
+mg	O
+of	O
+ephedrine	O
+to	O
+200	O
+mg	O
+of	O
+propofol	O
+were	O
+compared	O
+to	O
+control	O
+in	O
+40	O
+ASA	O
+3	O
+/	O
+4	O
+patients	O
+over	O
+60	O
+years	O
+presenting	O
+for	O
+genito	O
+-	O
+urinary	O
+surgery	O
+.	O
+
+The	O
+addition	O
+of	O
+ephedrine	O
+to	O
+propofol	O
+appears	O
+to	O
+be	O
+an	O
+effective	O
+method	O
+of	O
+obtunding	O
+the	O
+hypotensive	B
+response	O
+to	O
+propofol	O
+at	O
+all	O
+doses	O
+used	O
+in	O
+this	O
+study	O
+.	O
+
+However	O
+,	O
+marked	O
+tachycardia	B
+associated	O
+with	O
+the	O
+use	O
+of	O
+ephedrine	O
+in	O
+combination	O
+with	O
+propofol	O
+occurred	O
+in	O
+the	O
+majority	O
+of	O
+patients	O
+,	O
+occasionally	O
+reaching	O
+high	O
+levels	O
+in	O
+individual	O
+patients	O
+.	O
+
+Due	O
+to	O
+the	O
+risk	O
+of	O
+this	O
+tachycardia	B
+inducing	O
+myocardial	B
+ischemia	I
+,	O
+we	O
+would	O
+not	O
+recommend	O
+the	O
+use	O
+in	O
+elderly	O
+patients	O
+of	O
+any	O
+of	O
+the	O
+ephedrine	O
+/	O
+propofol	O
+/	O
+mixtures	O
+studied	O
+.	O
+
+Gemcitabine	O
+plus	O
+vinorelbine	O
+in	O
+nonsmall	B
+cell	I
+lung	I
+carcinoma	I
+patients	O
+age	O
+70	O
+years	O
+or	O
+older	O
+or	O
+patients	O
+who	O
+cannot	O
+receive	O
+cisplatin	O
+.	O
+
+Oncopaz	O
+Cooperative	O
+Group	O
+.	O
+
+BACKGROUND	O
+:	O
+Although	O
+the	O
+prevalence	O
+of	O
+nonsmall	B
+cell	I
+lung	I
+carcinoma	I
+(	O
+NSCLC	B
+)	O
+is	O
+high	O
+among	O
+elderly	O
+patients	O
+,	O
+few	O
+data	O
+are	O
+available	O
+regarding	O
+the	O
+efficacy	O
+and	O
+toxicity	B
+of	O
+chemotherapy	O
+in	O
+this	O
+group	O
+of	O
+patients	O
+.	O
+
+Recent	O
+reports	O
+indicate	O
+that	O
+single	O
+agent	O
+therapy	O
+with	O
+vinorelbine	O
+(	O
+VNB	O
+)	O
+or	O
+gemcitabine	O
+(	O
+GEM	O
+)	O
+may	O
+obtain	O
+a	O
+response	O
+rate	O
+of	O
+20	O
+-	O
+30	O
+%	O
+in	O
+elderly	O
+patients	O
+,	O
+with	O
+acceptable	O
+toxicity	B
+and	O
+improvement	O
+in	O
+symptoms	O
+and	O
+quality	O
+of	O
+life	O
+.	O
+
+In	O
+the	O
+current	O
+study	O
+the	O
+efficacy	O
+and	O
+toxicity	B
+of	O
+the	O
+combination	O
+of	O
+GEM	O
+and	O
+VNB	O
+in	O
+elderly	O
+patients	O
+with	O
+advanced	O
+NSCLC	B
+or	O
+those	O
+with	O
+some	O
+contraindication	O
+to	O
+receiving	O
+cisplatin	O
+were	O
+assessed	O
+.	O
+
+METHODS	O
+:	O
+Forty	O
+-	O
+nine	O
+patients	O
+with	O
+advanced	O
+NSCLC	B
+were	O
+included	O
+,	O
+38	O
+of	O
+whom	O
+were	O
+age	O
+>	O
+/	O
+=	O
+70	O
+years	O
+and	O
+11	O
+were	O
+age	O
+<	O
+70	O
+years	O
+but	O
+who	O
+had	O
+some	O
+contraindication	O
+to	O
+receiving	O
+cisplatin	O
+.	O
+
+All	O
+patients	O
+were	O
+evaluable	O
+for	O
+response	O
+and	O
+toxicity	B
+.	O
+
+Treatment	O
+was	O
+comprised	O
+of	O
+VNB	O
+,	O
+25	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+,	O
+plus	O
+GEM	O
+,	O
+1000	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+,	O
+both	O
+on	O
+Days	O
+1	O
+,	O
+8	O
+,	O
+and	O
+15	O
+every	O
+28	O
+days	O
+.	O
+
+Patients	O
+received	O
+a	O
+minimum	O
+of	O
+three	O
+courses	O
+unless	O
+progressive	O
+disease	O
+was	O
+detected	O
+.	O
+
+RESULTS	O
+:	O
+One	O
+hundred	O
+sixty	O
+-	O
+five	O
+courses	O
+were	O
+administered	O
+,	O
+with	O
+a	O
+median	O
+of	O
+3	O
+.	O
+
+6	O
+courses	O
+per	O
+patient	O
+.	O
+
+The	O
+overall	O
+response	O
+rate	O
+was	O
+26	O
+%	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+15	O
+-	O
+41	O
+%	O
+)	O
+.	O
+
+Two	O
+patients	O
+attained	O
+a	O
+complete	O
+response	O
+(	O
+4	O
+%	O
+)	O
+and	O
+11	O
+patients	O
+(	O
+22	O
+%	O
+)	O
+achieved	O
+a	O
+partial	O
+response	O
+.	O
+
+Eastern	O
+Cooperative	O
+Oncology	O
+Group	O
+performance	O
+status	O
+improved	O
+in	O
+35	O
+%	O
+of	O
+those	O
+patients	O
+with	O
+an	O
+initial	O
+value	O
+>	O
+0	O
+,	O
+whereas	O
+relief	O
+of	O
+at	O
+least	O
+1	O
+symptom	O
+without	O
+worsening	O
+of	O
+other	O
+symptoms	O
+was	O
+noted	O
+in	O
+27	O
+patients	O
+(	O
+55	O
+%	O
+)	O
+.	O
+
+The	O
+median	O
+time	O
+to	O
+progression	O
+was	O
+16	O
+weeks	O
+and	O
+the	O
+1	O
+-	O
+year	O
+survival	O
+rate	O
+was	O
+33	O
+%	O
+.	O
+
+Toxicity	B
+was	O
+mild	O
+.	O
+
+Six	O
+patients	O
+(	O
+12	O
+%	O
+)	O
+had	O
+World	O
+Health	O
+Organization	O
+Grade	O
+3	O
+-	O
+4	O
+neutropenia	B
+,	O
+2	O
+patients	O
+(	O
+4	O
+%	O
+)	O
+had	O
+Grade	O
+3	O
+-	O
+4	O
+thrombocytopenia	B
+,	O
+and	O
+2	O
+patients	O
+(	O
+4	O
+%	O
+)	O
+had	O
+Grade	O
+3	O
+neurotoxicity	B
+.	O
+
+Three	O
+patients	O
+with	O
+severe	O
+neutropenia	B
+(	O
+6	O
+%	O
+)	O
+died	O
+of	O
+sepsis	B
+.	O
+
+The	O
+median	O
+age	O
+of	O
+those	O
+patients	O
+developing	O
+Grade	O
+3	O
+-	O
+4	O
+neutropenia	B
+was	O
+significantly	O
+higher	O
+than	O
+that	O
+of	O
+the	O
+remaining	O
+patients	O
+(	O
+75	O
+years	O
+vs	O
+.	O
+72	O
+years	O
+;	O
+P	O
+=	O
+0	O
+.	O
+047	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+combination	O
+of	O
+GEM	O
+and	O
+VNB	O
+is	O
+moderately	O
+active	O
+and	O
+well	O
+tolerated	O
+except	O
+in	O
+patients	O
+age	O
+>	O
+/	O
+=	O
+75	O
+years	O
+.	O
+
+This	O
+age	O
+group	O
+had	O
+an	O
+increased	O
+risk	O
+of	O
+myelosuppression	B
+.	O
+
+Therefore	O
+the	O
+prophylactic	O
+use	O
+of	O
+granulocyte	O
+-	O
+colony	O
+stimulating	O
+factor	O
+should	O
+be	O
+considered	O
+with	O
+this	O
+treatment	O
+.	O
+
+New	O
+chemotherapy	O
+combinations	O
+with	O
+higher	O
+activity	O
+and	O
+lower	O
+toxicity	B
+are	O
+needed	O
+for	O
+elderly	O
+patients	O
+with	O
+advanced	O
+NSCLC	B
+.	O
+
+A	O
+selective	O
+dopamine	O
+D4	O
+receptor	O
+antagonist	O
+,	O
+NRA0160	O
+:	O
+a	O
+preclinical	O
+neuropharmacological	O
+profile	O
+.	O
+
+NRA0160	O
+,	O
+5	O
+-	O
+[	O
+2	O
+-	O
+(	O
+4	O
+-	O
+(	O
+3	O
+-	O
+fluorobenzylidene	O
+)	O
+piperidin	O
+-	O
+1	O
+-	O
+yl	O
+)	O
+ethyl	O
+]	O
+-	O
+4	O
+-	O
+(	O
+4	O
+-	O
+fluorophenyl	O
+)	O
+thiazole	O
+-	O
+2	O
+-	O
+carboxamide	O
+,	O
+has	O
+a	O
+high	O
+affinity	O
+for	O
+human	O
+cloned	O
+dopamine	O
+D4	O
+.	O
+2	O
+,	O
+D4	O
+.	O
+4	O
+and	O
+D4	O
+.	O
+7	O
+receptors	O
+,	O
+with	O
+Ki	O
+values	O
+of	O
+0	O
+.	O
+5	O
+,	O
+0	O
+.	O
+9	O
+and	O
+2	O
+.	O
+7	O
+nM	O
+,	O
+respectively	O
+.	O
+
+NRA0160	O
+is	O
+over	O
+20	O
+,	O
+000fold	O
+more	O
+potent	O
+at	O
+the	O
+dopamine	O
+D4	O
+.	O
+2	O
+receptor	O
+compared	O
+with	O
+the	O
+human	O
+cloned	O
+dopamine	O
+D2L	O
+receptor	O
+.	O
+
+NRA0160	O
+has	O
+negligible	O
+affinity	O
+for	O
+the	O
+human	O
+cloned	O
+dopamine	O
+D3	O
+receptor	O
+(	O
+Ki	O
+=	O
+39	O
+nM	O
+)	O
+,	O
+rat	O
+serotonin	O
+(	O
+5	O
+-	O
+HT	O
+)	O
+2A	O
+receptors	O
+(	O
+Ki	O
+=	O
+180	O
+nM	O
+)	O
+and	O
+rat	O
+alpha1	O
+adrenoceptor	O
+(	O
+Ki	O
+=	O
+237	O
+nM	O
+)	O
+.	O
+
+NRA0160	O
+and	O
+clozapine	O
+antagonized	O
+locomotor	O
+hyperactivity	B
+induced	O
+by	O
+methamphetamine	O
+(	O
+MAP	O
+)	O
+in	O
+mice	O
+.	O
+
+NRA0160	O
+and	O
+clozapine	O
+antagonized	O
+MAP	O
+-	O
+induced	O
+stereotyped	O
+behavior	O
+in	O
+mice	O
+,	O
+although	O
+their	O
+effects	O
+did	O
+not	O
+exceed	O
+50	O
+%	O
+inhibition	O
+,	O
+even	O
+at	O
+the	O
+highest	O
+dose	O
+given	O
+.	O
+
+NRA0160	O
+and	O
+clozapine	O
+significantly	O
+induced	O
+catalepsy	B
+in	O
+rats	O
+,	O
+although	O
+their	O
+effects	O
+did	O
+not	O
+exceed	O
+50	O
+%	O
+induction	O
+even	O
+at	O
+the	O
+highest	O
+dose	O
+given	O
+.	O
+
+NRA0160	O
+and	O
+clozapine	O
+significantly	O
+reversed	O
+the	O
+disruption	O
+of	O
+prepulse	O
+inhibition	O
+(	O
+PPI	O
+)	O
+in	O
+rats	O
+produced	O
+by	O
+apomorphine	O
+.	O
+
+NRA0160	O
+and	O
+clozapine	O
+significantly	O
+shortened	O
+the	O
+phencyclidine	O
+(	O
+PCP	O
+)	O
+-	O
+induced	O
+prolonged	O
+swimming	O
+latency	O
+in	O
+rats	O
+in	O
+a	O
+water	O
+maze	O
+task	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+NRA0160	O
+may	O
+have	O
+unique	O
+antipsychotic	O
+activities	O
+without	O
+the	O
+liability	O
+of	O
+motor	O
+side	O
+effects	O
+typical	O
+of	O
+classical	O
+antipsychotics	O
+.	O
+
+Warfarin	O
+-	O
+induced	O
+artery	B
+calcification	I
+is	O
+accelerated	O
+by	O
+growth	O
+and	O
+vitamin	O
+D	O
+.	O
+
+The	O
+present	O
+studies	O
+demonstrate	O
+that	O
+growth	O
+and	O
+vitamin	O
+D	O
+treatment	O
+enhance	O
+the	O
+extent	O
+of	O
+artery	B
+calcification	I
+in	O
+rats	O
+given	O
+sufficient	O
+doses	O
+of	O
+Warfarin	O
+to	O
+inhibit	O
+gamma	O
+-	O
+carboxylation	O
+of	O
+matrix	O
+Gla	O
+protein	O
+,	O
+a	O
+calcification	B
+inhibitor	O
+known	O
+to	O
+be	O
+expressed	O
+by	O
+smooth	O
+muscle	O
+cells	O
+and	O
+macrophages	O
+in	O
+the	O
+artery	O
+wall	O
+.	O
+
+The	O
+first	O
+series	O
+of	O
+experiments	O
+examined	O
+the	O
+influence	O
+of	O
+age	O
+and	O
+growth	O
+status	O
+on	O
+artery	B
+calcification	I
+in	O
+Warfarin	O
+-	O
+treated	O
+rats	O
+.	O
+
+Treatment	O
+for	O
+2	O
+weeks	O
+with	O
+Warfarin	O
+caused	O
+massive	O
+focal	O
+calcification	B
+of	I
+the	I
+artery	I
+media	O
+in	O
+20	O
+-	O
+day	O
+-	O
+old	O
+rats	O
+and	O
+less	O
+extensive	O
+focal	O
+calcification	B
+in	O
+42	O
+-	O
+day	O
+-	O
+old	O
+rats	O
+.	O
+
+In	O
+contrast	O
+,	O
+no	O
+artery	B
+calcification	I
+could	O
+be	O
+detected	O
+in	O
+10	O
+-	O
+month	O
+-	O
+old	O
+adult	O
+rats	O
+even	O
+after	O
+4	O
+weeks	O
+of	O
+Warfarin	O
+treatment	O
+.	O
+
+To	O
+directly	O
+examine	O
+the	O
+importance	O
+of	O
+growth	O
+to	O
+Warfarin	O
+-	O
+induced	O
+artery	B
+calcification	I
+in	O
+animals	O
+of	O
+the	O
+same	O
+age	O
+,	O
+20	O
+-	O
+day	O
+-	O
+old	O
+rats	O
+were	O
+fed	O
+for	O
+2	O
+weeks	O
+either	O
+an	O
+ad	O
+libitum	O
+diet	O
+or	O
+a	O
+6	O
+-	O
+g	O
+/	O
+d	O
+restricted	O
+diet	O
+that	O
+maintains	O
+weight	O
+but	O
+prevents	O
+growth	O
+.	O
+
+Concurrent	O
+treatment	O
+of	O
+both	O
+dietary	O
+groups	O
+with	O
+Warfarin	O
+produced	O
+massive	O
+focal	O
+calcification	B
+of	I
+the	I
+artery	I
+media	O
+in	O
+the	O
+ad	O
+libitum	O
+-	O
+fed	O
+rats	O
+but	O
+no	O
+detectable	O
+artery	B
+calcification	I
+in	O
+the	O
+restricted	O
+-	O
+diet	O
+,	O
+growth	O
+-	O
+inhibited	O
+group	O
+.	O
+
+Although	O
+the	O
+explanation	O
+for	O
+the	O
+association	O
+between	O
+artery	B
+calcification	I
+and	O
+growth	O
+status	O
+cannot	O
+be	O
+determined	O
+from	O
+the	O
+present	O
+study	O
+,	O
+there	O
+was	O
+a	O
+relationship	O
+between	O
+higher	O
+serum	O
+phosphate	O
+and	O
+susceptibility	O
+to	O
+artery	B
+calcification	I
+,	O
+with	O
+30	O
+%	O
+higher	O
+levels	O
+of	O
+serum	O
+phosphate	O
+in	O
+young	O
+,	O
+ad	O
+libitum	O
+-	O
+fed	O
+rats	O
+compared	O
+with	O
+either	O
+of	O
+the	O
+groups	O
+that	O
+was	O
+resistant	O
+to	O
+Warfarin	O
+-	O
+induced	O
+artery	B
+calcification	I
+,	O
+ie	O
+,	O
+the	O
+10	O
+-	O
+month	O
+-	O
+old	O
+rats	O
+and	O
+the	O
+restricted	O
+-	O
+diet	O
+,	O
+growth	O
+-	O
+inhibited	O
+young	O
+rats	O
+.	O
+
+This	O
+observation	O
+suggests	O
+that	O
+increased	O
+susceptibility	O
+to	O
+Warfarin	O
+-	O
+induced	O
+artery	B
+calcification	I
+could	O
+be	O
+related	O
+to	O
+higher	O
+serum	O
+phosphate	O
+levels	O
+.	O
+
+The	O
+second	O
+set	O
+of	O
+experiments	O
+examined	O
+the	O
+possible	O
+synergy	O
+between	O
+vitamin	O
+D	O
+and	O
+Warfarin	O
+in	O
+artery	B
+calcification	I
+.	O
+
+High	O
+doses	O
+of	O
+vitamin	O
+D	O
+are	O
+known	O
+to	O
+cause	O
+calcification	B
+of	I
+the	I
+artery	I
+media	O
+in	O
+as	O
+little	O
+as	O
+3	O
+to	O
+4	O
+days	O
+.	O
+
+High	O
+doses	O
+of	O
+the	O
+vitamin	O
+K	O
+antagonist	O
+Warfarin	O
+are	O
+also	O
+known	O
+to	O
+cause	O
+calcification	B
+of	I
+the	I
+artery	I
+media	O
+,	O
+but	O
+at	O
+treatment	O
+times	O
+of	O
+2	O
+weeks	O
+or	O
+longer	O
+yet	O
+not	O
+at	O
+1	O
+week	O
+.	O
+
+In	O
+the	O
+current	O
+study	O
+,	O
+we	O
+investigated	O
+the	O
+synergy	O
+between	O
+these	O
+2	O
+treatments	O
+and	O
+found	O
+that	O
+concurrent	O
+Warfarin	O
+administration	O
+dramatically	O
+increased	O
+the	O
+extent	O
+of	O
+calcification	B
+in	O
+the	O
+media	O
+of	O
+vitamin	O
+D	O
+-	O
+treated	O
+rats	O
+at	O
+3	O
+and	O
+4	O
+days	O
+.	O
+
+There	O
+was	O
+a	O
+close	O
+parallel	O
+between	O
+the	O
+effect	O
+of	O
+vitamin	O
+D	O
+dose	O
+on	O
+artery	B
+calcification	I
+and	O
+the	O
+effect	O
+of	O
+vitamin	O
+D	O
+dose	O
+on	O
+the	O
+elevation	O
+of	O
+serum	O
+calcium	O
+,	O
+which	O
+suggests	O
+that	O
+vitamin	O
+D	O
+may	O
+induce	O
+artery	B
+calcification	I
+through	O
+its	O
+effect	O
+on	O
+serum	O
+calcium	O
+.	O
+
+Because	O
+Warfarin	O
+treatment	O
+had	O
+no	O
+effect	O
+on	O
+the	O
+elevation	O
+in	O
+serum	O
+calcium	O
+produced	O
+by	O
+vitamin	O
+D	O
+,	O
+the	O
+synergy	O
+between	O
+Warfarin	O
+and	O
+vitamin	O
+D	O
+is	O
+probably	O
+best	O
+explained	O
+by	O
+the	O
+hypothesis	O
+that	O
+Warfarin	O
+inhibits	O
+the	O
+activity	O
+of	O
+matrix	O
+Gla	O
+protein	O
+as	O
+a	O
+calcification	B
+inhibitor	O
+.	O
+
+High	O
+levels	O
+of	O
+matrix	O
+Gla	O
+protein	O
+are	O
+found	O
+at	O
+sites	O
+of	O
+artery	B
+calcification	I
+in	O
+rats	O
+treated	O
+with	O
+vitamin	O
+D	O
+plus	O
+Warfarin	O
+,	O
+and	O
+chemical	O
+analysis	O
+showed	O
+that	O
+the	O
+protein	O
+that	O
+accumulated	O
+was	O
+indeed	O
+not	O
+gamma	O
+-	O
+carboxylated	O
+.	O
+
+These	O
+observations	O
+indicate	O
+that	O
+although	O
+the	O
+gamma	O
+-	O
+carboxyglutamate	O
+residues	O
+of	O
+matrix	O
+Gla	O
+protein	O
+are	O
+apparently	O
+required	O
+for	O
+its	O
+function	O
+as	O
+a	O
+calcification	B
+inhibitor	O
+,	O
+they	O
+are	O
+not	O
+required	O
+for	O
+its	O
+accumulation	O
+at	O
+calcification	B
+sites	O
+.	O
+
+Test	O
+conditions	O
+influence	O
+the	O
+response	O
+to	O
+a	O
+drug	O
+challenge	O
+in	O
+rodents	O
+.	O
+
+These	O
+studies	O
+were	O
+conducted	O
+to	O
+examine	O
+the	O
+differential	O
+response	O
+to	O
+a	O
+drug	O
+challenge	O
+under	O
+varied	O
+experimental	O
+test	O
+conditions	O
+routinely	O
+employed	O
+to	O
+study	O
+drug	O
+-	O
+induced	O
+behavioral	O
+and	O
+neurophysiological	O
+responses	O
+in	O
+rodents	O
+.	O
+
+Apomorphine	O
+,	O
+a	O
+nonselective	O
+dopamine	O
+agonist	O
+,	O
+was	O
+selected	O
+due	O
+to	O
+its	O
+biphasic	O
+behavioral	O
+effects	O
+,	O
+its	O
+ability	O
+to	O
+induce	O
+hypothermia	B
+,	O
+and	O
+to	O
+produce	O
+distinct	O
+changes	O
+to	O
+dopamine	O
+turnover	O
+in	O
+the	O
+rodent	O
+brain	O
+.	O
+
+From	O
+such	O
+experiments	O
+there	O
+is	O
+evidence	O
+that	O
+characterization	O
+and	O
+detection	O
+of	O
+apomorphine	O
+-	O
+induced	O
+activity	O
+in	O
+rodents	O
+critically	O
+depends	O
+upon	O
+the	O
+test	O
+conditions	O
+employed	O
+.	O
+
+In	O
+rats	O
+,	O
+detection	O
+of	O
+apomorphine	O
+-	O
+induced	O
+hyperactivity	B
+was	O
+facilitated	O
+by	O
+a	O
+period	O
+of	O
+acclimatization	O
+to	O
+the	O
+test	O
+conditions	O
+.	O
+
+Moreover	O
+,	O
+test	O
+conditions	O
+can	O
+impact	O
+upon	O
+other	O
+physiological	O
+responses	O
+to	O
+apomorphine	O
+such	O
+as	O
+drug	O
+-	O
+induced	O
+hypothermia	B
+.	O
+
+In	O
+mice	O
+,	O
+apomorphine	O
+produced	O
+qualitatively	O
+different	O
+responses	O
+under	O
+novel	O
+conditions	O
+when	O
+compared	O
+to	O
+those	O
+behaviors	O
+elicited	O
+in	O
+the	O
+home	O
+test	O
+cage	O
+.	O
+
+Drug	O
+-	O
+induced	O
+gross	O
+activity	O
+counts	O
+were	O
+increased	O
+in	O
+the	O
+novel	O
+exploratory	O
+box	O
+only	O
+,	O
+while	O
+measures	O
+of	O
+stereotypic	O
+behavior	O
+were	O
+similar	O
+in	O
+both	O
+.	O
+
+By	O
+contrast	O
+,	O
+apomorphine	O
+-	O
+induced	O
+locomotion	O
+was	O
+more	O
+prominent	O
+in	O
+the	O
+novel	O
+exploratory	O
+box	O
+.	O
+
+Dopamine	O
+turnover	O
+ratios	O
+(	O
+DOPAC	O
+:	O
+DA	O
+and	O
+HVA	O
+:	O
+DA	O
+)	O
+were	O
+found	O
+to	O
+be	O
+lower	O
+in	O
+those	O
+animals	O
+exposed	O
+to	O
+the	O
+exploratory	O
+box	O
+when	O
+compared	O
+to	O
+their	O
+home	O
+cage	O
+counterparts	O
+.	O
+
+However	O
+,	O
+apomorphine	O
+-	O
+induced	O
+reductions	O
+in	O
+striatal	O
+dopamine	O
+turnover	O
+were	O
+detected	O
+in	O
+both	O
+novel	O
+and	O
+home	O
+cage	O
+environments	O
+.	O
+
+The	O
+implications	O
+of	O
+these	O
+findings	O
+are	O
+discussed	O
+with	O
+particular	O
+emphasis	O
+upon	O
+conducting	O
+psychopharmacological	O
+challenge	O
+tests	O
+in	O
+rodents	O
+.	O
+
+Hemolysis	B
+of	O
+human	O
+erythrocytes	O
+induced	O
+by	O
+tamoxifen	O
+is	O
+related	O
+to	O
+disruption	O
+of	O
+membrane	O
+structure	O
+.	O
+
+Tamoxifen	O
+(	O
+TAM	O
+)	O
+,	O
+the	O
+antiestrogenic	O
+drug	O
+most	O
+widely	O
+prescribed	O
+in	O
+the	O
+chemotherapy	O
+of	O
+breast	B
+cancer	I
+,	O
+induces	O
+changes	O
+in	O
+normal	O
+discoid	O
+shape	O
+of	O
+erythrocytes	O
+and	O
+hemolytic	B
+anemia	I
+.	O
+
+This	O
+work	O
+evaluates	O
+the	O
+effects	O
+of	O
+TAM	O
+on	O
+isolated	O
+human	O
+erythrocytes	O
+,	O
+attempting	O
+to	O
+identify	O
+the	O
+underlying	O
+mechanisms	O
+on	O
+TAM	O
+-	O
+induced	O
+hemolytic	B
+anemia	I
+and	O
+the	O
+involvement	O
+of	O
+biomembranes	O
+in	O
+its	O
+cytostatic	O
+action	O
+mechanisms	O
+.	O
+
+TAM	O
+induces	O
+hemolysis	B
+of	O
+erythrocytes	O
+as	O
+a	O
+function	O
+of	O
+concentration	O
+.	O
+
+The	O
+extension	O
+of	O
+hemolysis	B
+is	O
+variable	O
+with	O
+erythrocyte	O
+samples	O
+,	O
+but	O
+12	O
+.	O
+5	O
+microM	O
+TAM	O
+induces	O
+total	O
+hemolysis	B
+of	O
+all	O
+tested	O
+suspensions	O
+.	O
+
+Despite	O
+inducing	O
+extensive	O
+erythrocyte	O
+lysis	O
+,	O
+TAM	O
+does	O
+not	O
+shift	O
+the	O
+osmotic	O
+fragility	O
+curves	O
+of	O
+erythrocytes	O
+.	O
+
+The	O
+hemolytic	B
+effect	O
+of	O
+TAM	O
+is	O
+prevented	O
+by	O
+low	O
+concentrations	O
+of	O
+alpha	O
+-	O
+tocopherol	O
+(	O
+alpha	O
+-	O
+T	O
+)	O
+and	O
+alpha	O
+-	O
+tocopherol	O
+acetate	O
+(	O
+alpha	O
+-	O
+TAc	O
+)	O
+(	O
+inactivated	O
+functional	O
+hydroxyl	O
+)	O
+indicating	O
+that	O
+TAM	O
+-	O
+induced	O
+hemolysis	B
+is	O
+not	O
+related	O
+to	O
+oxidative	O
+membrane	O
+damage	O
+.	O
+
+This	O
+was	O
+further	O
+evidenced	O
+by	O
+absence	O
+of	O
+oxygen	O
+consumption	O
+and	O
+hemoglobin	O
+oxidation	O
+both	O
+determined	O
+in	O
+parallel	O
+with	O
+TAM	O
+-	O
+induced	O
+hemolysis	B
+.	O
+
+Furthermore	O
+,	O
+it	O
+was	O
+observed	O
+that	O
+TAM	O
+inhibits	O
+the	O
+peroxidation	O
+of	O
+human	O
+erythrocytes	O
+induced	O
+by	O
+AAPH	O
+,	O
+thus	O
+ruling	O
+out	O
+TAM	O
+-	O
+induced	O
+cell	O
+oxidative	O
+stress	O
+.	O
+
+Hemolysis	B
+caused	O
+by	O
+TAM	O
+was	O
+not	O
+preceded	O
+by	O
+the	O
+leakage	O
+of	O
+K	O
+(	O
++	O
+)	O
+from	O
+the	O
+cells	O
+,	O
+also	O
+excluding	O
+a	O
+colloid	O
+-	O
+osmotic	O
+type	O
+mechanism	O
+of	O
+hemolysis	B
+,	O
+according	O
+to	O
+the	O
+effects	O
+on	O
+osmotic	O
+fragility	O
+curves	O
+.	O
+
+However	O
+,	O
+TAM	O
+induces	O
+release	O
+of	O
+peripheral	O
+proteins	O
+of	O
+membrane	O
+-	O
+cytoskeleton	O
+and	O
+cytosol	O
+proteins	O
+essentially	O
+bound	O
+to	O
+band	O
+3	O
+.	O
+
+Either	O
+alpha	O
+-	O
+T	O
+or	O
+alpha	O
+-	O
+TAc	O
+increases	O
+membrane	O
+packing	O
+and	O
+prevents	O
+TAM	O
+partition	O
+into	O
+model	O
+membranes	O
+.	O
+
+These	O
+effects	O
+suggest	O
+that	O
+the	O
+protection	O
+from	O
+hemolysis	B
+by	O
+tocopherols	O
+is	O
+related	O
+to	O
+a	O
+decreased	O
+TAM	O
+incorporation	O
+in	O
+condensed	O
+membranes	O
+and	O
+the	O
+structural	O
+damage	O
+of	O
+the	O
+erythrocyte	O
+membrane	O
+is	O
+consequently	O
+avoided	O
+.	O
+
+Therefore	O
+,	O
+TAM	O
+-	O
+induced	O
+hemolysis	B
+results	O
+from	O
+a	O
+structural	O
+perturbation	O
+of	O
+red	O
+cell	O
+membrane	O
+,	O
+leading	O
+to	O
+changes	O
+in	O
+the	O
+framework	O
+of	O
+the	O
+erythrocyte	O
+membrane	O
+and	O
+its	O
+cytoskeleton	O
+caused	O
+by	O
+its	O
+high	O
+partition	O
+in	O
+the	O
+membrane	O
+.	O
+
+These	O
+defects	O
+explain	O
+the	O
+abnormal	O
+erythrocyte	O
+shape	O
+and	O
+decreased	O
+mechanical	O
+stability	O
+promoted	O
+by	O
+TAM	O
+,	O
+resulting	O
+in	O
+hemolytic	B
+anemia	I
+.	O
+
+Additionally	O
+,	O
+since	O
+membrane	O
+leakage	O
+is	O
+a	O
+final	O
+stage	O
+of	O
+cytotoxicity	O
+,	O
+the	O
+disruption	O
+of	O
+the	O
+structural	O
+characteristics	O
+of	O
+biomembranes	O
+by	O
+TAM	O
+may	O
+contribute	O
+to	O
+the	O
+multiple	O
+mechanisms	O
+of	O
+its	O
+anticancer	O
+action	O
+.	O
+
+Changes	O
+of	O
+sodium	O
+and	O
+ATP	O
+affinities	O
+of	O
+the	O
+cardiac	O
+(	O
+Na	O
+,	O
+K	O
+)	O
+-	O
+ATPase	O
+during	O
+and	O
+after	O
+nitric	O
+oxide	O
+deficient	O
+hypertension	B
+.	O
+
+In	O
+the	O
+cardiovascular	O
+system	O
+,	O
+NO	O
+is	O
+involved	O
+in	O
+the	O
+regulation	O
+of	O
+a	O
+variety	O
+of	O
+functions	O
+.	O
+
+Inhibition	O
+of	O
+NO	O
+synthesis	O
+induces	O
+sustained	O
+hypertension	B
+.	O
+
+In	O
+several	O
+models	O
+of	O
+hypertension	B
+,	O
+elevation	O
+of	O
+intracellular	O
+sodium	O
+level	O
+was	O
+documented	O
+in	O
+cardiac	O
+tissue	O
+.	O
+
+To	O
+assess	O
+the	O
+molecular	O
+basis	O
+of	O
+disturbances	O
+in	O
+transmembraneous	O
+transport	O
+of	O
+Na	O
++	O
+,	O
+we	O
+studied	O
+the	O
+response	O
+of	O
+cardiac	O
+(	O
+Na	O
+,	O
+K	O
+)	O
+-	O
+ATPase	O
+to	O
+NO	O
+-	O
+deficient	O
+hypertension	B
+induced	O
+in	O
+rats	O
+by	O
+NO	O
+-	O
+synthase	O
+inhibition	O
+with	O
+40	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+N	O
+(	O
+G	O
+)	O
+-	O
+nitro	O
+-	O
+L	O
+-	O
+arginine	O
+methyl	O
+ester	O
+(	O
+L	O
+-	O
+NAME	O
+)	O
+for	O
+4	O
+four	O
+weeks	O
+.	O
+
+After	O
+4	O
+-	O
+week	O
+administration	O
+of	O
+L	O
+-	O
+NAME	O
+,	O
+the	O
+systolic	O
+blood	O
+pressure	O
+(	O
+SBP	O
+)	O
+increased	O
+by	O
+36	O
+%	O
+.	O
+
+Two	O
+weeks	O
+after	O
+terminating	O
+the	O
+treatment	O
+,	O
+the	O
+SBP	O
+recovered	O
+to	O
+control	O
+value	O
+.	O
+
+When	O
+activating	O
+the	O
+(	O
+Na	O
+,	O
+K	O
+)	O
+-	O
+ATPase	O
+with	O
+its	O
+substrate	O
+ATP	O
+,	O
+no	O
+changes	O
+in	O
+Km	O
+and	O
+Vmax	O
+values	O
+were	O
+observed	O
+in	O
+NO	O
+-	O
+deficient	O
+rats	O
+.	O
+
+During	O
+activation	O
+with	O
+Na	O
++	O
+,	O
+the	O
+Vmax	O
+remained	O
+unchanged	O
+,	O
+however	O
+the	O
+K	O
+(	O
+Na	O
+)	O
+increased	O
+by	O
+50	O
+%	O
+,	O
+indicating	O
+a	O
+profound	O
+decrease	O
+in	O
+the	O
+affinity	O
+of	O
+the	O
+Na	O
++	O
+-	O
+binding	O
+site	O
+in	O
+NO	O
+-	O
+deficient	O
+rats	O
+.	O
+
+After	O
+recovery	O
+from	O
+hypertension	B
+,	O
+the	O
+activity	O
+of	O
+(	O
+Na	O
+,	O
+K	O
+)	O
+-	O
+ATPase	O
+increased	O
+,	O
+due	O
+to	O
+higher	O
+affinity	O
+of	O
+the	O
+ATP	O
+-	O
+binding	O
+site	O
+,	O
+as	O
+revealed	O
+from	O
+the	O
+lowered	O
+Km	O
+value	O
+for	O
+ATP	O
+.	O
+
+The	O
+K	O
+(	O
+Na	O
+)	O
+value	O
+for	O
+Na	O
++	O
+returned	O
+to	O
+control	O
+value	O
+.	O
+
+Inhibition	O
+of	O
+NO	O
+-	O
+synthase	O
+induced	O
+a	O
+reversible	O
+hypertension	B
+accompanied	O
+by	O
+depressed	B
+Na	O
++	O
+-	O
+extrusion	O
+from	O
+cardiac	O
+cells	O
+as	O
+a	O
+consequence	O
+of	O
+deteriorated	O
+Na	O
++	O
+-	O
+binding	O
+properties	O
+of	O
+the	O
+(	O
+Na	O
+,	O
+K	O
+)	O
+-	O
+ATPase	O
+.	O
+
+After	O
+recovery	O
+of	O
+blood	O
+pressure	O
+to	O
+control	O
+values	O
+,	O
+the	O
+extrusion	O
+of	O
+Na	O
++	O
+from	O
+cardiac	O
+cells	O
+was	O
+normalized	O
+,	O
+as	O
+revealed	O
+by	O
+restoration	O
+of	O
+the	O
+(	O
+Na	O
+,	O
+K	O
+)	O
+-	O
+ATPase	O
+activity	O
+.	O
+
+Effects	O
+of	O
+long	O
+-	O
+term	O
+pretreatment	O
+with	O
+isoproterenol	O
+on	O
+bromocriptine	O
+-	O
+induced	O
+tachycardia	B
+in	O
+conscious	O
+rats	O
+.	O
+
+It	O
+has	O
+been	O
+shown	O
+that	O
+bromocriptine	O
+-	O
+induced	O
+tachycardia	B
+,	O
+which	O
+persisted	O
+after	O
+adrenalectomy	O
+,	O
+is	O
+(	O
+i	O
+)	O
+mediated	O
+by	O
+central	O
+dopamine	O
+D2	O
+receptor	O
+activation	O
+and	O
+(	O
+ii	O
+)	O
+reduced	O
+by	O
+5	O
+-	O
+day	O
+isoproterenol	O
+pretreatment	O
+,	O
+supporting	O
+therefore	O
+the	O
+hypothesis	O
+that	O
+this	O
+effect	O
+is	O
+dependent	O
+on	O
+sympathetic	O
+outflow	O
+to	O
+the	O
+heart	O
+.	O
+
+This	O
+study	O
+was	O
+conducted	O
+to	O
+examine	O
+whether	O
+prolonged	O
+pretreatment	O
+with	O
+isoproterenol	O
+could	O
+abolish	O
+bromocriptine	O
+-	O
+induced	O
+tachycardia	B
+in	O
+conscious	O
+rats	O
+.	O
+
+Isoproterenol	O
+pretreatment	O
+for	O
+15	O
+days	O
+caused	O
+cardiac	B
+hypertrophy	I
+without	O
+affecting	O
+baseline	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+.	O
+
+In	O
+control	O
+rats	O
+,	O
+intravenous	O
+bromocriptine	O
+(	O
+150	O
+microg	O
+/	O
+kg	O
+)	O
+induced	O
+significant	O
+hypotension	B
+and	O
+tachycardia	B
+.	O
+
+Bromocriptine	O
+-	O
+induced	O
+hypotension	B
+was	O
+unaffected	O
+by	O
+isoproterenol	O
+pretreatment	O
+,	O
+while	O
+tachycardia	B
+was	O
+reversed	O
+to	O
+significant	O
+bradycardia	B
+,	O
+an	O
+effect	O
+that	O
+was	O
+partly	O
+reduced	O
+by	O
+i	O
+.	O
+v	O
+.	O
+domperidone	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+Neither	O
+cardiac	O
+vagal	O
+nor	O
+sympathetic	O
+tone	O
+was	O
+altered	O
+by	O
+isoproterenol	O
+pretreatment	O
+.	O
+
+In	O
+isolated	O
+perfused	O
+heart	O
+preparations	O
+from	O
+isoproterenol	O
+-	O
+pretreated	O
+rats	O
+,	O
+the	O
+isoproterenol	O
+-	O
+induced	O
+maximal	O
+increase	O
+in	O
+left	O
+ventricular	O
+systolic	O
+pressure	O
+was	O
+significantly	O
+reduced	O
+,	O
+compared	O
+with	O
+saline	O
+-	O
+pretreated	O
+rats	O
+(	O
+the	O
+EC50	O
+of	O
+the	O
+isoproterenol	O
+-	O
+induced	O
+increase	O
+in	O
+left	O
+ventricular	O
+systolic	O
+pressure	O
+was	O
+enhanced	O
+approximately	O
+22	O
+-	O
+fold	O
+)	O
+.	O
+
+These	O
+results	O
+show	O
+that	O
+15	O
+-	O
+day	O
+isoproterenol	O
+pretreatment	O
+not	O
+only	O
+abolished	O
+but	O
+reversed	O
+bromocriptine	O
+-	O
+induced	O
+tachycardia	B
+to	O
+bradycardia	B
+,	O
+an	O
+effect	O
+that	O
+is	O
+mainly	O
+related	O
+to	O
+further	O
+cardiac	O
+beta	O
+-	O
+adrenoceptor	O
+desensitization	O
+rather	O
+than	O
+to	O
+impairment	O
+of	O
+autonomic	O
+regulation	O
+of	O
+the	O
+heart	O
+.	O
+
+They	O
+suggest	O
+that	O
+,	O
+in	O
+normal	O
+conscious	O
+rats	O
+,	O
+the	O
+central	O
+tachycardia	B
+of	O
+bromocriptine	O
+appears	O
+to	O
+predominate	O
+and	O
+to	O
+mask	O
+the	O
+bradycardia	B
+of	O
+this	O
+agonist	O
+at	O
+peripheral	O
+dopamine	O
+D2	O
+receptors	O
+.	O
+
+A	O
+developmental	O
+analysis	O
+of	O
+clonidine	O
+'	O
+s	O
+effects	O
+on	O
+cardiac	O
+rate	O
+and	O
+ultrasound	O
+production	O
+in	O
+infant	O
+rats	O
+.	O
+
+Under	O
+controlled	O
+conditions	O
+,	O
+infant	O
+rats	O
+emit	O
+ultrasonic	O
+vocalizations	O
+during	O
+extreme	O
+cold	O
+exposure	O
+and	O
+after	O
+administration	O
+of	O
+the	O
+alpha	O
+(	O
+2	O
+)	O
+adrenoceptor	O
+agonist	O
+,	O
+clonidine	O
+.	O
+
+Previous	O
+investigations	O
+have	O
+determined	O
+that	O
+,	O
+in	O
+response	O
+to	O
+clonidine	O
+,	O
+ultrasound	O
+production	O
+increases	O
+through	O
+the	O
+2nd	O
+-	O
+week	O
+postpartum	O
+and	O
+decreases	O
+thereafter	O
+.	O
+
+Given	O
+that	O
+sympathetic	O
+neural	O
+dominance	O
+exhibits	O
+a	O
+similar	O
+developmental	O
+pattern	O
+,	O
+and	O
+given	O
+that	O
+clonidine	O
+induces	O
+sympathetic	O
+withdrawal	O
+and	O
+bradycardia	B
+,	O
+we	O
+hypothesized	O
+that	O
+clonidine	O
+'	O
+s	O
+developmental	O
+effects	O
+on	O
+cardiac	O
+rate	O
+and	O
+ultrasound	O
+production	O
+would	O
+mirror	O
+each	O
+other	O
+.	O
+
+Therefore	O
+,	O
+in	O
+the	O
+present	O
+experiment	O
+,	O
+the	O
+effects	O
+of	O
+clonidine	O
+administration	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+on	O
+cardiac	O
+rate	O
+and	O
+ultrasound	O
+production	O
+were	O
+examined	O
+in	O
+2	O
+-	O
+,	O
+8	O
+-	O
+,	O
+15	O
+-	O
+,	O
+and	O
+20	O
+-	O
+day	O
+-	O
+old	O
+rats	O
+.	O
+
+Age	O
+-	O
+related	O
+changes	O
+in	O
+ultrasound	O
+production	O
+corresponded	O
+with	O
+changes	O
+in	O
+cardiovascular	O
+variables	O
+,	O
+including	O
+baseline	O
+cardiac	O
+rate	O
+and	O
+clonidine	O
+-	O
+induced	O
+bradycardia	B
+.	O
+
+This	O
+experiment	O
+is	O
+discussed	O
+with	O
+regard	O
+to	O
+the	O
+hypothesis	O
+that	O
+ultrasound	O
+production	O
+is	O
+the	O
+acoustic	O
+by	O
+-	O
+product	O
+of	O
+a	O
+physiological	O
+maneuver	O
+that	O
+compensates	O
+for	O
+clonidine	O
+'	O
+s	O
+detrimental	O
+effects	O
+on	O
+cardiovascular	O
+function	O
+.	O
+
+Recurrent	O
+use	O
+of	O
+newer	O
+oral	O
+contraceptives	O
+and	O
+the	O
+risk	O
+of	O
+venous	B
+thromboembolism	I
+.	O
+
+The	O
+epidemiological	O
+studies	O
+that	O
+assessed	O
+the	O
+risk	O
+of	O
+venous	B
+thromboembolism	I
+(	O
+VTE	B
+)	O
+associated	O
+with	O
+newer	O
+oral	O
+contraceptives	O
+(	O
+OC	O
+)	O
+did	O
+not	O
+distinguish	O
+between	O
+patterns	O
+of	O
+OC	O
+use	O
+,	O
+namely	O
+first	O
+-	O
+time	O
+users	O
+,	O
+repeaters	O
+and	O
+switchers	O
+.	O
+
+Data	O
+from	O
+a	O
+Transnational	O
+case	O
+-	O
+control	O
+study	O
+were	O
+used	O
+to	O
+assess	O
+the	O
+risk	O
+of	O
+VTE	B
+for	O
+the	O
+latter	O
+patterns	O
+of	O
+use	O
+,	O
+while	O
+accounting	O
+for	O
+duration	O
+of	O
+use	O
+.	O
+
+Over	O
+the	O
+period	O
+1993	O
+-	O
+1996	O
+,	O
+551	O
+cases	O
+of	O
+VTE	B
+were	O
+identified	O
+in	O
+Germany	O
+and	O
+the	O
+UK	O
+along	O
+with	O
+2066	O
+controls	O
+.	O
+
+Totals	O
+of	O
+128	O
+cases	O
+and	O
+650	O
+controls	O
+were	O
+analysed	O
+for	O
+repeat	O
+use	O
+and	O
+135	O
+cases	O
+and	O
+622	O
+controls	O
+for	O
+switching	O
+patterns	O
+.	O
+
+The	O
+adjusted	O
+rate	O
+ratio	O
+of	O
+VTE	B
+for	O
+repeat	O
+users	O
+of	O
+third	O
+generation	O
+OC	O
+was	O
+0	O
+.	O
+6	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+0	O
+.	O
+3	O
+-	O
+1	O
+.	O
+2	O
+)	O
+relative	O
+to	O
+repeat	O
+users	O
+of	O
+second	O
+generation	O
+pills	O
+,	O
+whereas	O
+it	O
+was	O
+1	O
+.	O
+3	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+0	O
+.	O
+7	O
+-	O
+2	O
+.	O
+4	O
+)	O
+for	O
+switchers	O
+from	O
+second	O
+to	O
+third	O
+generation	O
+pills	O
+relative	O
+to	O
+switchers	O
+from	O
+third	O
+to	O
+second	O
+generation	O
+pills	O
+.	O
+
+We	O
+conclude	O
+that	O
+second	O
+and	O
+third	O
+generation	O
+agents	O
+are	O
+associated	O
+with	O
+equivalent	O
+risks	O
+of	O
+VTE	B
+when	O
+the	O
+same	O
+agent	O
+is	O
+used	O
+repeatedly	O
+after	O
+interruption	O
+periods	O
+or	O
+when	O
+users	O
+are	O
+switched	O
+between	O
+the	O
+two	O
+generations	O
+of	O
+pills	O
+.	O
+
+These	O
+analyses	O
+suggest	O
+that	O
+the	O
+higher	O
+risk	O
+observed	O
+for	O
+the	O
+newer	O
+OC	O
+in	O
+other	O
+studies	O
+may	O
+be	O
+the	O
+result	O
+of	O
+inadequate	O
+comparisons	O
+of	O
+pill	O
+users	O
+with	O
+different	O
+patterns	O
+of	O
+pill	O
+use	O
+.	O
+
+Differential	O
+effects	O
+of	O
+systemically	O
+administered	O
+ketamine	O
+and	O
+lidocaine	O
+on	O
+dynamic	O
+and	O
+static	O
+hyperalgesia	B
+induced	O
+by	O
+intradermal	O
+capsaicin	O
+in	O
+humans	O
+.	O
+
+We	O
+have	O
+examined	O
+the	O
+effect	O
+of	O
+systemic	O
+administration	O
+of	O
+ketamine	O
+and	O
+lidocaine	O
+on	O
+brush	O
+-	O
+evoked	O
+(	O
+dynamic	O
+)	O
+pain	B
+and	O
+punctate	O
+-	O
+evoked	O
+(	O
+static	O
+)	O
+hyperalgesia	B
+induced	O
+by	O
+capsaicin	O
+.	O
+
+In	O
+a	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+,	O
+crossover	O
+study	O
+,	O
+we	O
+studied	O
+12	O
+volunteers	O
+in	O
+three	O
+experiments	O
+.	O
+
+Capsaicin	O
+100	O
+micrograms	O
+was	O
+injected	O
+intradermally	O
+on	O
+the	O
+volar	O
+forearm	O
+followed	O
+by	O
+an	O
+i	O
+.	O
+v	O
+.	O
+infusion	O
+of	O
+ketamine	O
+(	O
+bolus	O
+0	O
+.	O
+1	O
+mg	O
+kg	O
+-	O
+1	O
+over	O
+10	O
+min	O
+followed	O
+by	O
+infusion	O
+of	O
+7	O
+micrograms	O
+kg	O
+-	O
+1	O
+min	O
+-	O
+1	O
+)	O
+,	O
+lidocaine	O
+5	O
+mg	O
+kg	O
+-	O
+1	O
+or	O
+saline	O
+for	O
+50	O
+min	O
+.	O
+
+Infusion	O
+started	O
+15	O
+min	O
+after	O
+injection	O
+of	O
+capsaicin	O
+.	O
+
+The	O
+following	O
+were	O
+measured	O
+:	O
+spontaneous	O
+pain	B
+,	O
+pain	B
+evoked	O
+by	O
+punctate	O
+and	O
+brush	O
+stimuli	O
+(	O
+VAS	O
+)	O
+,	O
+and	O
+areas	O
+of	O
+brush	O
+-	O
+evoked	O
+and	O
+punctate	O
+-	O
+evoked	O
+hyperalgesia	B
+.	O
+
+Ketamine	O
+reduced	O
+both	O
+the	O
+area	O
+of	O
+brush	O
+-	O
+evoked	O
+and	O
+punctate	O
+-	O
+evoked	O
+hyperalgesia	B
+significantly	O
+and	O
+it	O
+tended	O
+to	O
+reduce	O
+brush	O
+-	O
+evoked	O
+pain	B
+.	O
+
+Lidocaine	O
+reduced	O
+the	O
+area	O
+of	O
+punctate	O
+-	O
+evoked	O
+hyperalgesia	B
+significantly	O
+.	O
+
+It	O
+tended	O
+to	O
+reduce	O
+VAS	O
+scores	O
+of	O
+spontaneous	O
+pain	B
+but	O
+had	O
+no	O
+effect	O
+on	O
+evoked	O
+pain	B
+.	O
+
+The	O
+differential	O
+effects	O
+of	O
+ketamine	O
+and	O
+lidocaine	O
+on	O
+static	O
+and	O
+dynamic	O
+hyperalgesia	B
+suggest	O
+that	O
+the	O
+two	O
+types	O
+of	O
+hyperalgesia	B
+are	O
+mediated	O
+by	O
+separate	O
+mechanisms	O
+and	O
+have	O
+a	O
+distinct	O
+pharmacology	O
+.	O
+
+Development	O
+of	O
+apomorphine	O
+-	O
+induced	O
+aggressive	B
+behavior	I
+:	O
+comparison	O
+of	O
+adult	O
+male	O
+and	O
+female	O
+Wistar	O
+rats	O
+.	O
+
+The	O
+development	O
+of	O
+apomorphine	O
+-	O
+induced	O
+(	O
+1	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+once	O
+daily	O
+)	O
+aggressive	B
+behavior	I
+of	O
+adult	O
+male	O
+and	O
+female	O
+Wistar	O
+rats	O
+obtained	O
+from	O
+the	O
+same	O
+breeder	O
+was	O
+studied	O
+in	O
+two	O
+consecutive	O
+sets	O
+.	O
+
+In	O
+male	O
+animals	O
+,	O
+repeated	O
+apomorphine	O
+treatment	O
+induced	O
+a	O
+gradual	O
+development	O
+of	O
+aggressive	B
+behavior	I
+as	O
+evidenced	O
+by	O
+the	O
+increased	O
+intensity	O
+of	O
+aggressiveness	B
+and	O
+shortened	O
+latency	O
+before	O
+the	O
+first	O
+attack	O
+toward	O
+the	O
+opponent	O
+.	O
+
+In	O
+female	O
+rats	O
+,	O
+only	O
+a	O
+weak	O
+tendency	O
+toward	O
+aggressiveness	B
+was	O
+found	O
+.	O
+
+In	O
+conclusion	O
+,	O
+the	O
+present	O
+study	O
+demonstrates	O
+gender	O
+differences	O
+in	O
+the	O
+development	O
+of	O
+the	O
+apomorphine	O
+-	O
+induced	O
+aggressive	B
+behavior	I
+and	O
+indicates	O
+that	O
+the	O
+female	O
+rats	O
+do	O
+not	O
+fill	O
+the	O
+validation	O
+criteria	O
+for	O
+use	O
+in	O
+this	O
+method	O
+.	O
+
+Intracranial	B
+aneurysms	I
+and	O
+cocaine	B
+abuse	I
+:	O
+analysis	O
+of	O
+prognostic	O
+indicators	O
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+outcome	O
+of	O
+subarachnoid	B
+hemorrhage	I
+associated	O
+with	O
+cocaine	B
+abuse	I
+is	O
+reportedly	O
+poor	O
+.	O
+
+However	O
+,	O
+no	O
+study	O
+in	O
+the	O
+literature	O
+has	O
+reported	O
+the	O
+use	O
+of	O
+a	O
+statistical	O
+model	O
+to	O
+analyze	O
+the	O
+variables	O
+that	O
+influence	O
+outcome	O
+.	O
+
+METHODS	O
+:	O
+A	O
+review	O
+of	O
+admissions	O
+during	O
+a	O
+6	O
+-	O
+year	O
+period	O
+revealed	O
+14	O
+patients	O
+with	O
+cocaine	O
+-	O
+related	O
+aneurysms	B
+.	O
+
+This	O
+group	O
+was	O
+compared	O
+with	O
+a	O
+control	O
+group	O
+of	O
+135	O
+patients	O
+with	O
+ruptured	B
+aneurysms	I
+and	O
+no	O
+history	O
+of	O
+cocaine	B
+abuse	I
+.	O
+
+Age	O
+at	O
+presentation	O
+,	O
+time	O
+of	O
+ictus	O
+after	O
+intoxication	O
+,	O
+Hunt	O
+and	O
+Hess	O
+grade	O
+of	O
+subarachnoid	B
+hemorrhage	I
+,	O
+size	O
+of	O
+the	O
+aneurysm	B
+,	O
+location	O
+of	O
+the	O
+aneurysm	B
+,	O
+and	O
+the	O
+Glasgow	O
+Outcome	O
+Scale	O
+score	O
+were	O
+assessed	O
+and	O
+compared	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+patients	O
+in	O
+the	O
+study	O
+group	O
+were	O
+significantly	O
+younger	O
+than	O
+the	O
+patients	O
+in	O
+the	O
+control	O
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+002	O
+)	O
+.	O
+
+In	O
+patients	O
+in	O
+the	O
+study	O
+group	O
+,	O
+all	O
+aneurysms	B
+were	O
+located	O
+in	O
+the	O
+anterior	O
+circulation	O
+.	O
+
+The	O
+majority	O
+of	O
+these	O
+aneurysms	B
+were	O
+smaller	O
+than	O
+those	O
+of	O
+the	O
+control	O
+group	O
+(	O
+8	O
++	O
+/	O
+-	O
+6	O
+.	O
+08	O
+mm	O
+versus	O
+11	O
++	O
+/	O
+-	O
+5	O
+.	O
+4	O
+mm	O
+;	O
+P	O
+=	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+differences	O
+in	O
+mortality	O
+and	O
+morbidity	O
+between	O
+the	O
+two	O
+groups	O
+were	O
+not	O
+significant	O
+.	O
+
+Hunt	O
+and	O
+Hess	O
+grade	O
+(	O
+P	O
+<	O
+0	O
+.	O
+005	O
+)	O
+and	O
+age	O
+(	O
+P	O
+<	O
+0	O
+.	O
+007	O
+)	O
+were	O
+significant	O
+predictors	O
+of	O
+outcome	O
+for	O
+the	O
+patients	O
+with	O
+cocaine	O
+-	O
+related	O
+aneurysms	B
+.	O
+
+CONCLUSION	O
+:	O
+Cocaine	O
+use	O
+predisposed	O
+aneurysmal	B
+rupture	I
+at	O
+a	O
+significantly	O
+earlier	O
+age	O
+and	O
+in	O
+much	O
+smaller	O
+aneurysms	B
+.	O
+
+Contrary	O
+to	O
+the	O
+published	O
+literature	O
+,	O
+this	O
+group	O
+did	O
+reasonably	O
+well	O
+with	O
+aggressive	O
+management	O
+.	O
+
+Effect	O
+of	O
+intravenous	O
+nimodipine	O
+on	O
+blood	O
+pressure	O
+and	O
+outcome	O
+after	O
+acute	B
+stroke	I
+.	O
+
+BACKGROUND	O
+AND	O
+PURPOSE	O
+:	O
+The	O
+Intravenous	O
+Nimodipine	O
+West	O
+European	O
+Stroke	B
+Trial	O
+(	O
+INWEST	O
+)	O
+found	O
+a	O
+correlation	O
+between	O
+nimodipine	O
+-	O
+induced	O
+reduction	B
+in	I
+blood	I
+pressure	I
+(	O
+BP	O
+)	O
+and	O
+an	O
+unfavorable	O
+outcome	O
+in	O
+acute	B
+stroke	I
+.	O
+
+We	O
+sought	O
+to	O
+confirm	O
+this	O
+correlation	O
+with	O
+and	O
+without	O
+adjustment	O
+for	O
+prognostic	O
+variables	O
+and	O
+to	O
+investigate	O
+outcome	O
+in	O
+subgroups	O
+with	O
+increasing	O
+levels	O
+of	O
+BP	B
+reduction	I
+.	O
+
+METHODS	O
+:	O
+Patients	O
+with	O
+a	O
+clinical	O
+diagnosis	O
+of	O
+ischemic	B
+stroke	I
+(	O
+within	O
+24	O
+hours	O
+)	O
+were	O
+consecutively	O
+allocated	O
+to	O
+receive	O
+placebo	O
+(	O
+n	O
+=	O
+100	O
+)	O
+,	O
+1	O
+mg	O
+/	O
+h	O
+(	O
+low	O
+-	O
+dose	O
+)	O
+nimodipine	O
+(	O
+n	O
+=	O
+101	O
+)	O
+,	O
+or	O
+2	O
+mg	O
+/	O
+h	O
+(	O
+high	O
+-	O
+dose	O
+)	O
+nimodipine	O
+(	O
+n	O
+=	O
+94	O
+)	O
+.	O
+
+The	O
+correlation	O
+between	O
+average	O
+BP	O
+change	O
+during	O
+the	O
+first	O
+2	O
+days	O
+and	O
+the	O
+outcome	O
+at	O
+day	O
+21	O
+was	O
+analyzed	O
+.	O
+
+RESULTS	O
+:	O
+Two	O
+hundred	O
+sixty	O
+-	O
+five	O
+patients	O
+were	O
+included	O
+in	O
+this	O
+analysis	O
+(	O
+n	O
+=	O
+92	O
+,	O
+93	O
+,	O
+and	O
+80	O
+for	O
+placebo	O
+,	O
+low	O
+dose	O
+,	O
+and	O
+high	O
+dose	O
+,	O
+respectively	O
+)	O
+.	O
+
+Nimodipine	O
+treatment	O
+resulted	O
+in	O
+a	O
+statistically	O
+significant	O
+reduction	B
+in	I
+systolic	I
+BP	I
+(	O
+SBP	O
+)	O
+and	O
+diastolic	O
+BP	O
+(	O
+DBP	O
+)	O
+from	O
+baseline	O
+compared	O
+with	O
+placebo	O
+during	O
+the	O
+first	O
+few	O
+days	O
+.	O
+
+In	O
+multivariate	O
+analysis	O
+,	O
+a	O
+significant	O
+correlation	O
+between	O
+DBP	B
+reduction	I
+and	O
+worsening	O
+of	O
+the	O
+neurological	O
+score	O
+was	O
+found	O
+for	O
+the	O
+high	O
+-	O
+dose	O
+group	O
+(	O
+beta	O
+=	O
+0	O
+.	O
+49	O
+,	O
+P	O
+=	O
+0	O
+.	O
+048	O
+)	O
+.	O
+
+Patients	O
+with	O
+a	O
+DBP	B
+reduction	I
+of	O
+>	O
+or	O
+=	O
+20	O
+%	O
+in	O
+the	O
+high	O
+-	O
+dose	O
+group	O
+had	O
+a	O
+significantly	O
+increased	O
+adjusted	O
+OR	O
+for	O
+the	O
+compound	O
+outcome	O
+variable	O
+death	B
+or	O
+dependency	O
+(	O
+Barthel	O
+Index	O
+<	O
+60	O
+)	O
+(	O
+n	O
+/	O
+N	O
+=	O
+25	O
+/	O
+26	O
+,	O
+OR	O
+10	O
+.	O
+16	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+02	O
+to	O
+101	O
+.	O
+74	O
+)	O
+and	O
+death	B
+alone	O
+(	O
+n	O
+/	O
+N	O
+=	O
+9	O
+/	O
+26	O
+,	O
+OR	O
+4	O
+.	O
+336	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+131	O
+16	O
+.	O
+619	O
+)	O
+compared	O
+with	O
+all	O
+placebo	O
+patients	O
+(	O
+n	O
+/	O
+N	O
+=	O
+62	O
+/	O
+92	O
+and	O
+14	O
+/	O
+92	O
+,	O
+respectively	O
+)	O
+.	O
+
+There	O
+was	O
+no	O
+correlation	O
+between	O
+SBP	O
+change	O
+and	O
+outcome	O
+.	O
+
+CONCLUSIONS	O
+:	O
+DBP	O
+,	O
+but	O
+not	O
+SBP	O
+,	O
+reduction	O
+was	O
+associated	O
+with	O
+neurological	O
+worsening	O
+after	O
+the	O
+intravenous	O
+administration	O
+of	O
+high	O
+-	O
+dose	O
+nimodipine	O
+after	O
+acute	B
+stroke	I
+.	O
+
+For	O
+low	O
+-	O
+dose	O
+nimodipine	O
+,	O
+the	O
+results	O
+were	O
+not	O
+conclusive	O
+.	O
+
+These	O
+results	O
+do	O
+not	O
+confirm	O
+or	O
+exclude	O
+a	O
+neuroprotective	O
+property	O
+of	O
+nimodipine	O
+.	O
+
+Neonatal	O
+pyridoxine	O
+responsive	O
+convulsions	B
+due	O
+to	O
+isoniazid	O
+therapy	O
+.	O
+
+A	O
+17	O
+-	O
+day	O
+-	O
+old	O
+infant	O
+on	O
+isoniazid	O
+therapy	O
+13	O
+mg	O
+/	O
+kg	O
+daily	O
+from	O
+birth	O
+because	O
+of	O
+maternal	O
+tuberculosis	B
+was	O
+admitted	O
+after	O
+4	O
+days	O
+of	O
+clonic	B
+fits	I
+.	O
+
+No	O
+underlying	O
+infective	O
+or	O
+biochemical	O
+cause	O
+could	O
+be	O
+found	O
+.	O
+
+The	O
+fits	B
+ceased	O
+within	O
+4	O
+hours	O
+of	O
+administering	O
+intramuscular	O
+pyridoxine	O
+,	O
+suggesting	O
+an	O
+aetiology	O
+of	O
+pyridoxine	O
+deficiency	O
+secondary	O
+to	O
+isoniazid	O
+medication	O
+.	O
+
+Ketamine	O
+sedation	O
+for	O
+the	O
+reduction	O
+of	O
+children	O
+'	O
+s	O
+fractures	B
+in	O
+the	O
+emergency	O
+department	O
+.	O
+
+BACKGROUND	O
+:	O
+There	O
+recently	O
+has	O
+been	O
+a	O
+resurgence	O
+in	O
+the	O
+utilization	O
+of	O
+ketamine	O
+,	O
+a	O
+unique	O
+anesthetic	O
+,	O
+for	O
+emergency	O
+-	O
+department	O
+procedures	O
+requiring	O
+sedation	O
+.	O
+
+The	O
+purpose	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+examine	O
+the	O
+safety	O
+and	O
+efficacy	O
+of	O
+ketamine	O
+for	O
+sedation	O
+in	O
+the	O
+treatment	O
+of	O
+children	O
+'	O
+s	O
+fractures	B
+in	O
+the	O
+emergency	O
+department	O
+.	O
+
+METHODS	O
+:	O
+One	O
+hundred	O
+and	O
+fourteen	O
+children	O
+(	O
+average	O
+age	O
+,	O
+5	O
+.	O
+3	O
+years	O
+;	O
+range	O
+,	O
+twelve	O
+months	O
+to	O
+ten	O
+years	O
+and	O
+ten	O
+months	O
+)	O
+who	O
+underwent	O
+closed	O
+reduction	O
+of	O
+an	O
+isolated	O
+fracture	B
+or	O
+dislocation	B
+in	O
+the	O
+emergency	O
+department	O
+at	O
+a	O
+level	O
+-	O
+I	O
+trauma	B
+center	O
+were	O
+prospectively	O
+evaluated	O
+.	O
+
+Ketamine	O
+hydrochloride	O
+was	O
+administered	O
+intravenously	O
+(	O
+at	O
+a	O
+dose	O
+of	O
+two	O
+milligrams	O
+per	O
+kilogram	O
+of	O
+body	O
+weight	O
+)	O
+in	O
+ninety	O
+-	O
+nine	O
+of	O
+the	O
+patients	O
+and	O
+intramuscularly	O
+(	O
+at	O
+a	O
+dose	O
+of	O
+four	O
+milligrams	O
+per	O
+kilogram	O
+of	O
+body	O
+weight	O
+)	O
+in	O
+the	O
+other	O
+fifteen	O
+.	O
+
+A	O
+board	O
+-	O
+certified	O
+emergency	O
+physician	O
+skilled	O
+in	O
+airway	O
+management	O
+supervised	O
+administration	O
+of	O
+the	O
+anesthetic	O
+,	O
+and	O
+the	O
+patients	O
+were	O
+monitored	O
+by	O
+a	O
+registered	O
+nurse	O
+.	O
+
+Any	O
+pain	B
+during	O
+the	O
+reduction	O
+was	O
+rated	O
+by	O
+the	O
+orthopaedic	O
+surgeon	O
+treating	O
+the	O
+patient	O
+according	O
+to	O
+the	O
+Children	O
+'	O
+s	O
+Hospital	O
+of	O
+Eastern	O
+Ontario	O
+Pain	B
+Scale	O
+(	O
+CHEOPS	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+average	O
+time	O
+from	O
+intravenous	O
+administration	O
+of	O
+ketamine	O
+to	O
+manipulation	O
+of	O
+the	O
+fracture	B
+or	O
+dislocation	B
+was	O
+one	O
+minute	O
+and	O
+thirty	O
+-	O
+six	O
+seconds	O
+(	O
+range	O
+,	O
+twenty	O
+seconds	O
+to	O
+five	O
+minutes	O
+)	O
+,	O
+and	O
+the	O
+average	O
+time	O
+from	O
+intramuscular	O
+administration	O
+to	O
+manipulation	O
+was	O
+four	O
+minutes	O
+and	O
+forty	O
+-	O
+two	O
+seconds	O
+(	O
+range	O
+,	O
+sixty	O
+seconds	O
+to	O
+fifteen	O
+minutes	O
+)	O
+.	O
+
+The	O
+average	O
+score	O
+according	O
+to	O
+the	O
+Children	O
+'	O
+s	O
+Hospital	O
+of	O
+Eastern	O
+Ontario	O
+Pain	B
+Scale	O
+was	O
+6	O
+.	O
+4	O
+points	O
+(	O
+range	O
+,	O
+5	O
+to	O
+10	O
+points	O
+)	O
+,	O
+reflecting	O
+minimal	O
+or	O
+no	O
+pain	B
+during	O
+fracture	B
+reduction	O
+.	O
+
+Adequate	O
+fracture	B
+reduction	O
+was	O
+obtained	O
+in	O
+111	O
+of	O
+the	O
+children	O
+.	O
+
+Ninety	O
+-	O
+nine	O
+percent	O
+(	O
+sixty	O
+-	O
+eight	O
+)	O
+of	O
+the	O
+sixty	O
+-	O
+nine	O
+parents	O
+present	O
+during	O
+the	O
+reduction	O
+were	O
+pleased	O
+with	O
+the	O
+sedation	O
+and	O
+would	O
+allow	O
+it	O
+to	O
+be	O
+used	O
+again	O
+in	O
+a	O
+similar	O
+situation	O
+.	O
+
+Patency	O
+of	O
+the	O
+airway	O
+and	O
+independent	O
+respiration	O
+were	O
+maintained	O
+in	O
+all	O
+of	O
+the	O
+patients	O
+.	O
+
+Blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+remained	O
+stable	O
+.	O
+
+Minor	O
+side	O
+effects	O
+included	O
+nausea	B
+(	O
+thirteen	O
+patients	O
+)	O
+,	O
+emesis	B
+(	O
+eight	O
+of	O
+the	O
+thirteen	O
+patients	O
+with	O
+nausea	B
+)	O
+,	O
+clumsiness	B
+(	O
+evident	O
+as	O
+ataxic	B
+movements	I
+in	O
+ten	O
+patients	O
+)	O
+,	O
+and	O
+dysphoric	B
+reaction	I
+(	O
+one	O
+patient	O
+)	O
+.	O
+
+No	O
+long	O
+-	O
+term	O
+sequelae	O
+were	O
+noted	O
+,	O
+and	O
+no	O
+patients	O
+had	O
+hallucinations	B
+or	O
+nightmares	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Ketamine	O
+reliably	O
+,	O
+safely	O
+,	O
+and	O
+quickly	O
+provided	O
+adequate	O
+sedation	O
+to	O
+effectively	O
+facilitate	O
+the	O
+reduction	O
+of	O
+children	O
+'	O
+s	O
+fractures	B
+in	O
+the	O
+emergency	O
+department	O
+at	O
+our	O
+institution	O
+.	O
+
+Ketamine	O
+should	O
+only	O
+be	O
+used	O
+in	O
+an	O
+environment	O
+such	O
+as	O
+the	O
+emergency	O
+department	O
+,	O
+where	O
+proper	O
+one	O
+-	O
+on	O
+-	O
+one	O
+monitoring	O
+is	O
+used	O
+and	O
+board	O
+-	O
+certified	O
+physicians	O
+skilled	O
+in	O
+airway	O
+management	O
+are	O
+directly	O
+involved	O
+in	O
+the	O
+care	O
+of	O
+the	O
+patient	O
+.	O
+
+Cyclosporine	O
+and	O
+tacrolimus	O
+-	O
+associated	O
+thrombotic	B
+microangiopathy	I
+.	O
+
+The	O
+development	O
+of	O
+thrombotic	B
+microangiopathy	I
+(	O
+TMA	B
+)	O
+associated	O
+with	O
+the	O
+use	O
+of	O
+cyclosporine	O
+has	O
+been	O
+well	O
+documented	O
+.	O
+
+Treatments	O
+have	O
+included	O
+discontinuation	O
+or	O
+reduction	O
+of	O
+cyclosporine	O
+dose	O
+with	O
+or	O
+without	O
+concurrent	O
+plasma	O
+exchange	O
+,	O
+plasma	O
+infusion	O
+,	O
+anticoagulation	O
+,	O
+and	O
+intravenous	O
+immunoglobulin	O
+G	O
+infusion	O
+.	O
+
+However	O
+,	O
+for	O
+recipients	O
+of	O
+organ	O
+transplantation	O
+,	O
+removing	O
+the	O
+inciting	O
+agent	O
+is	O
+not	O
+without	O
+the	O
+attendant	O
+risk	O
+of	O
+precipitating	O
+acute	O
+rejection	O
+and	O
+graft	O
+loss	O
+.	O
+
+The	O
+last	O
+decade	O
+has	O
+seen	O
+the	O
+emergence	O
+of	O
+tacrolimus	O
+as	O
+a	O
+potent	O
+immunosuppressive	O
+agent	O
+with	O
+mechanisms	O
+of	O
+action	O
+virtually	O
+identical	O
+to	O
+those	O
+of	O
+cyclosporine	O
+.	O
+
+As	O
+a	O
+result	O
+,	O
+switching	O
+to	O
+tacrolimus	O
+has	O
+been	O
+reported	O
+to	O
+be	O
+a	O
+viable	O
+therapeutic	O
+option	O
+in	O
+the	O
+setting	O
+of	O
+cyclosporine	O
+-	O
+induced	O
+TMA	B
+.	O
+
+With	O
+the	O
+more	O
+widespread	O
+application	O
+of	O
+tacrolimus	O
+in	O
+organ	O
+transplantation	O
+,	O
+tacrolimus	O
+-	O
+associated	O
+TMA	B
+has	O
+also	O
+been	O
+recognized	O
+.	O
+
+However	O
+,	O
+literature	O
+regarding	O
+the	O
+incidence	O
+of	O
+the	O
+recurrence	O
+of	O
+TMA	B
+in	O
+patients	O
+exposed	O
+sequentially	O
+to	O
+cyclosporine	O
+and	O
+tacrolimus	O
+is	O
+limited	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+a	O
+living	O
+donor	O
+renal	O
+transplant	O
+recipient	O
+who	O
+developed	O
+cyclosporine	O
+-	O
+induced	O
+TMA	B
+that	O
+responded	O
+to	O
+the	O
+withdrawal	O
+of	O
+cyclosporine	O
+in	O
+conjunction	O
+with	O
+plasmapheresis	O
+and	O
+fresh	O
+frozen	O
+plasma	O
+replacement	O
+therapy	O
+.	O
+
+Introduction	O
+of	O
+tacrolimus	O
+as	O
+an	O
+alternative	O
+immunosuppressive	O
+agent	O
+resulted	O
+in	O
+the	O
+recurrence	O
+of	O
+TMA	B
+and	O
+the	O
+subsequent	O
+loss	O
+of	O
+the	O
+renal	O
+allograft	O
+.	O
+
+Patients	O
+who	O
+are	O
+switched	O
+from	O
+cyclosporine	O
+to	O
+tacrolimus	O
+or	O
+vice	O
+versa	O
+should	O
+be	O
+closely	O
+monitored	O
+for	O
+the	O
+signs	O
+and	O
+symptoms	O
+of	O
+recurrent	O
+TMA	B
+.	O
+
+Analgesic	O
+effect	O
+of	O
+intravenous	O
+ketamine	O
+in	O
+cancer	B
+patients	O
+on	O
+morphine	O
+therapy	O
+:	O
+a	O
+randomized	O
+,	O
+controlled	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+crossover	O
+,	O
+double	O
+-	O
+dose	O
+study	O
+.	O
+
+Pain	B
+not	O
+responsive	O
+to	O
+morphine	O
+is	O
+often	O
+problematic	O
+.	O
+
+Animal	O
+and	O
+clinical	O
+studies	O
+have	O
+suggested	O
+that	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+antagonists	O
+,	O
+such	O
+as	O
+ketamine	O
+,	O
+may	O
+be	O
+effective	O
+in	O
+improving	O
+opioid	O
+analgesia	O
+in	O
+difficult	O
+pain	B
+syndromes	O
+,	O
+such	O
+as	O
+neuropathic	B
+pain	I
+.	O
+
+A	O
+slow	O
+bolus	O
+of	O
+subhypnotic	O
+doses	O
+of	O
+ketamine	O
+(	O
+0	O
+.	O
+25	O
+mg	O
+/	O
+kg	O
+or	O
+0	O
+.	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+given	O
+to	O
+10	O
+cancer	B
+patients	O
+whose	O
+pain	B
+was	O
+unrelieved	O
+by	O
+morphine	O
+in	O
+a	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+crossover	O
+,	O
+double	O
+-	O
+dose	O
+study	O
+.	O
+
+Pain	B
+intensity	O
+on	O
+a	O
+0	O
+to	O
+10	O
+numerical	O
+scale	O
+;	O
+nausea	B
+and	O
+vomiting	B
+,	O
+drowsiness	O
+,	O
+confusion	B
+,	O
+and	O
+dry	B
+mouth	I
+,	O
+using	O
+a	O
+scale	O
+from	O
+0	O
+to	O
+3	O
+(	O
+not	O
+at	O
+all	O
+,	O
+slight	O
+,	O
+a	O
+lot	O
+,	O
+awful	O
+)	O
+;	O
+Mini	O
+-	O
+Mental	O
+State	O
+Examination	O
+(	O
+MMSE	O
+)	O
+(	O
+0	O
+-	O
+30	O
+)	O
+;	O
+and	O
+arterial	O
+pressure	O
+were	O
+recorded	O
+before	O
+administration	O
+of	O
+drugs	O
+(	O
+T0	O
+)	O
+and	O
+after	O
+30	O
+minutes	O
+(	O
+T30	O
+)	O
+,	O
+60	O
+minutes	O
+(	O
+T60	O
+)	O
+,	O
+120	O
+minutes	O
+(	O
+T120	O
+)	O
+,	O
+and	O
+180	O
+minutes	O
+(	O
+T180	O
+)	O
+.	O
+
+Ketamine	O
+,	O
+but	O
+not	O
+saline	O
+solution	O
+,	O
+significantly	O
+reduced	O
+the	O
+pain	B
+intensity	O
+in	O
+almost	O
+all	O
+the	O
+patients	O
+at	O
+both	O
+doses	O
+.	O
+
+This	O
+effect	O
+was	O
+more	O
+relevant	O
+in	O
+patients	O
+treated	O
+with	O
+higher	O
+doses	O
+.	O
+
+Hallucinations	B
+occurred	O
+in	O
+4	O
+patients	O
+,	O
+and	O
+an	O
+unpleasant	O
+sensation	O
+(	O
+"	O
+empty	O
+head	O
+"	O
+)	O
+was	O
+also	O
+reported	O
+by	O
+2	O
+patients	O
+.	O
+
+These	O
+episodes	O
+reversed	O
+after	O
+the	O
+administration	O
+of	O
+diazepam	O
+1	O
+mg	O
+intravenously	O
+.	O
+
+Significant	O
+increases	O
+in	O
+drowsiness	O
+were	O
+reported	O
+in	O
+patients	O
+treated	O
+with	O
+ketamine	O
+in	O
+both	O
+groups	O
+and	O
+were	O
+more	O
+marked	O
+with	O
+ketamine	O
+0	O
+.	O
+50	O
+mg	O
+/	O
+kg	O
+.	O
+
+A	O
+significant	O
+difference	O
+in	O
+MMSE	O
+was	O
+observed	O
+at	O
+T30	O
+in	O
+patients	O
+who	O
+received	O
+0	O
+.	O
+50	O
+mg	O
+/	O
+kg	O
+of	O
+ketamine	O
+.	O
+
+Ketamine	O
+can	O
+improve	O
+morphine	O
+analgesia	O
+in	O
+difficult	O
+pain	B
+syndromes	O
+,	O
+such	O
+as	O
+neuropathic	B
+pain	I
+.	O
+
+However	O
+,	O
+the	O
+occurrence	O
+of	O
+central	O
+adverse	O
+effects	O
+should	O
+be	O
+taken	O
+into	O
+account	O
+,	O
+especially	O
+when	O
+using	O
+higher	O
+doses	O
+.	O
+
+This	O
+observation	O
+should	O
+be	O
+tested	O
+in	O
+studies	O
+of	O
+prolonged	O
+ketamine	O
+administration	O
+.	O
+
+Paclitaxel	O
+,	O
+cisplatin	O
+,	O
+and	O
+gemcitabine	O
+combination	O
+chemotherapy	O
+within	O
+a	O
+multidisciplinary	O
+therapeutic	O
+approach	O
+in	O
+metastatic	O
+nonsmall	B
+cell	I
+lung	I
+carcinoma	I
+.	O
+
+BACKGROUND	O
+:	O
+Cisplatin	O
+-	O
+based	O
+chemotherapy	O
+combinations	O
+improve	O
+quality	O
+of	O
+life	O
+and	O
+survival	O
+in	O
+advanced	O
+nonsmall	B
+cell	I
+lung	I
+carcinoma	I
+(	O
+NSCLC	B
+)	O
+.	O
+
+The	O
+emergence	O
+of	O
+new	O
+active	O
+drugs	O
+might	O
+translate	O
+into	O
+more	O
+effective	O
+regimens	O
+for	O
+the	O
+treatment	O
+of	O
+this	O
+disease	O
+.	O
+
+METHODS	O
+:	O
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+feasibility	O
+,	O
+response	O
+rate	O
+,	O
+and	O
+toxicity	B
+of	O
+a	O
+paclitaxel	O
+,	O
+cisplatin	O
+,	O
+and	O
+gemcitabine	O
+combination	O
+to	O
+treat	O
+metastatic	O
+NSCLC	B
+.	O
+
+Thirty	O
+-	O
+five	O
+consecutive	O
+chemotherapy	O
+-	O
+naive	O
+patients	O
+with	O
+Stage	O
+IV	O
+NSCLC	B
+and	O
+an	O
+Eastern	O
+Cooperative	O
+Oncology	O
+Group	O
+performance	O
+status	O
+of	O
+0	O
+-	O
+2	O
+were	O
+treated	O
+with	O
+a	O
+combination	O
+of	O
+paclitaxel	O
+(	O
+135	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+given	O
+intravenously	O
+in	O
+3	O
+hours	O
+)	O
+on	O
+Day	O
+1	O
+,	O
+cisplatin	O
+(	O
+120	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+given	O
+intravenously	O
+in	O
+6	O
+hours	O
+)	O
+on	O
+Day	O
+1	O
+,	O
+and	O
+gemcitabine	O
+(	O
+800	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+given	O
+intravenously	O
+in	O
+30	O
+minutes	O
+)	O
+on	O
+Days	O
+1	O
+and	O
+8	O
+,	O
+every	O
+4	O
+weeks	O
+.	O
+
+Although	O
+responding	O
+patients	O
+were	O
+scheduled	O
+to	O
+receive	O
+consolidation	O
+radiotherapy	O
+and	O
+24	O
+patients	O
+received	O
+preplanned	O
+second	O
+-	O
+line	O
+chemotherapy	O
+after	O
+disease	O
+progression	O
+,	O
+the	O
+response	O
+and	O
+toxicity	B
+rates	O
+reported	O
+refer	O
+only	O
+to	O
+the	O
+chemotherapy	O
+regimen	O
+given	O
+.	O
+
+RESULTS	O
+:	O
+All	O
+the	O
+patients	O
+were	O
+examined	O
+for	O
+toxicity	B
+;	O
+34	O
+were	O
+examinable	O
+for	O
+response	O
+.	O
+
+An	O
+objective	O
+response	O
+was	O
+observed	O
+in	O
+73	O
+.	O
+5	O
+%	O
+of	O
+the	O
+patients	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+,	O
+55	O
+.	O
+6	O
+-	O
+87	O
+.	O
+1	O
+%	O
+)	O
+,	O
+including	O
+4	O
+complete	O
+responses	O
+(	O
+11	O
+.	O
+7	O
+%	O
+)	O
+.	O
+
+According	O
+to	O
+intention	O
+-	O
+to	O
+-	O
+treat	O
+,	O
+the	O
+overall	O
+response	O
+rate	O
+was	O
+71	O
+.	O
+4	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+,	O
+53	O
+.	O
+7	O
+-	O
+85	O
+.	O
+4	O
+%	O
+)	O
+.	O
+
+After	O
+154	O
+courses	O
+of	O
+therapy	O
+,	O
+the	O
+median	O
+dose	O
+intensity	O
+was	O
+131	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+for	O
+paclitaxel	O
+(	O
+97	O
+.	O
+3	O
+%	O
+)	O
+,	O
+117	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+for	O
+cisplatin	O
+(	O
+97	O
+.	O
+3	O
+%	O
+)	O
+,	O
+and	O
+1378	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+for	O
+gemcitabine	O
+(	O
+86	O
+.	O
+2	O
+%	O
+)	O
+.	O
+
+World	O
+Health	O
+Organization	O
+Grade	O
+3	O
+-	O
+4	O
+neutropenia	B
+and	O
+thrombocytopenia	B
+occurred	O
+in	O
+39	O
+.	O
+9	O
+%	O
+and	O
+11	O
+.	O
+4	O
+%	O
+of	O
+patients	O
+,	O
+respectively	O
+.	O
+
+There	O
+was	O
+one	O
+treatment	O
+-	O
+related	O
+death	B
+.	O
+
+Nonhematologic	O
+toxicities	B
+were	O
+mild	O
+.	O
+
+After	O
+a	O
+median	O
+follow	O
+-	O
+up	O
+of	O
+22	O
+months	O
+,	O
+the	O
+median	O
+progression	O
+free	O
+survival	O
+rate	O
+was	O
+7	O
+months	O
+,	O
+and	O
+the	O
+median	O
+survival	O
+time	O
+was	O
+16	O
+months	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+combination	O
+of	O
+paclitaxel	O
+,	O
+cisplatin	O
+,	O
+and	O
+gemcitabine	O
+is	O
+well	O
+tolerated	O
+and	O
+shows	O
+high	O
+activity	O
+in	O
+metastatic	O
+NSCLC	B
+.	O
+
+This	O
+treatment	O
+merits	O
+further	O
+comparison	O
+with	O
+other	O
+cisplatin	O
+-	O
+based	O
+regimens	O
+.	O
+
+Serotonergic	O
+antidepressants	O
+and	O
+urinary	B
+incontinence	I
+.	O
+
+Many	O
+new	O
+serotonergic	O
+antidepressants	O
+have	O
+been	O
+introduced	O
+over	O
+the	O
+past	O
+decade	O
+.	O
+
+Although	O
+urinary	B
+incontinence	I
+is	O
+listed	O
+as	O
+one	O
+side	O
+effect	O
+of	O
+these	O
+drugs	O
+in	O
+their	O
+package	O
+inserts	O
+there	O
+is	O
+only	O
+one	O
+report	O
+in	O
+the	O
+literature	O
+.	O
+
+This	O
+concerns	O
+2	O
+male	O
+patients	O
+who	O
+experienced	O
+incontinence	B
+while	O
+taking	O
+venlafaxine	O
+.	O
+
+In	O
+the	O
+present	O
+paper	O
+the	O
+authors	O
+describe	O
+2	O
+female	O
+patients	O
+who	O
+developed	O
+incontinence	B
+secondary	O
+to	O
+the	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitors	O
+paroxetine	O
+and	O
+sertraline	O
+,	O
+as	O
+well	O
+as	O
+a	O
+third	O
+who	O
+developed	O
+this	O
+side	O
+effect	O
+on	O
+venlafaxine	O
+.	O
+
+In	O
+2	O
+of	O
+the	O
+3	O
+cases	O
+the	O
+patients	O
+were	O
+also	O
+taking	O
+lithium	O
+carbonate	O
+and	O
+beta	O
+-	O
+blockers	O
+,	O
+both	O
+of	O
+which	O
+could	O
+have	O
+contributed	O
+to	O
+the	O
+incontinence	B
+.	O
+
+Animal	O
+studies	O
+suggest	O
+that	O
+incontinence	B
+secondary	O
+to	O
+serotonergic	O
+antidepressants	O
+could	O
+be	O
+mediated	O
+by	O
+the	O
+5HT4	O
+receptors	O
+found	O
+on	O
+the	O
+bladder	O
+.	O
+
+Further	O
+research	O
+is	O
+needed	O
+to	O
+delineate	O
+the	O
+frequency	O
+of	O
+this	O
+troubling	O
+side	O
+effect	O
+and	O
+how	O
+best	O
+to	O
+treat	O
+it	O
+.	O
+
+Acute	O
+cocaine	O
+-	O
+induced	O
+seizures	B
+:	O
+differential	O
+sensitivity	O
+of	O
+six	O
+inbred	O
+mouse	O
+strains	O
+.	O
+
+Mature	O
+male	O
+and	O
+female	O
+mice	O
+from	O
+six	O
+inbred	O
+stains	O
+were	O
+tested	O
+for	O
+susceptibility	O
+to	O
+behavioral	O
+seizures	B
+induced	O
+by	O
+a	O
+single	O
+injection	O
+of	O
+cocaine	O
+.	O
+
+Cocaine	O
+was	O
+injected	O
+ip	O
+over	O
+a	O
+range	O
+of	O
+doses	O
+(	O
+50	O
+-	O
+100	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+behavior	O
+was	O
+monitored	O
+for	O
+20	O
+minutes	O
+.	O
+
+Seizure	B
+end	O
+points	O
+included	O
+latency	O
+to	O
+forelimb	O
+or	O
+hindlimb	O
+clonus	O
+,	O
+latency	O
+to	O
+clonic	O
+running	O
+seizure	B
+and	O
+latency	O
+to	O
+jumping	O
+bouncing	O
+seizure	B
+.	O
+
+A	O
+range	O
+of	O
+strain	O
+specific	O
+sensitivities	O
+was	O
+documented	O
+with	O
+A	O
+/	O
+J	O
+and	O
+SJL	O
+mice	O
+being	O
+most	O
+sensitive	O
+and	O
+C57BL	O
+/	O
+6J	O
+most	O
+resistant	O
+.	O
+
+DBA	O
+/	O
+2J	O
+,	O
+BALB	O
+/	O
+cByJ	O
+and	O
+NZW	O
+/	O
+LacJ	O
+strains	O
+exhibited	O
+intermediate	O
+sensitivity	O
+.	O
+
+EEG	O
+recordings	O
+were	O
+made	O
+in	O
+SJL	O
+,	O
+A	O
+/	O
+J	O
+and	O
+C57BL	O
+/	O
+6J	O
+mice	O
+revealing	O
+a	O
+close	O
+correspondence	O
+between	O
+electrical	O
+activity	O
+and	O
+behavior	O
+.	O
+
+Additionally	O
+,	O
+levels	O
+of	O
+cocaine	O
+determined	O
+in	O
+hippocampus	O
+and	O
+cortex	O
+were	O
+not	O
+different	O
+between	O
+sensitive	O
+and	O
+resistant	O
+strains	O
+.	O
+
+Additional	O
+studies	O
+of	O
+these	O
+murine	O
+strains	O
+may	O
+be	O
+useful	O
+for	O
+investigating	O
+genetic	O
+influences	O
+on	O
+cocaine	O
+-	O
+induced	O
+seizures	B
+.	O
+
+Hypotension	B
+following	O
+the	O
+initiation	O
+of	O
+tizanidine	O
+in	O
+a	O
+patient	O
+treated	O
+with	O
+an	O
+angiotensin	O
+converting	O
+enzyme	O
+inhibitor	O
+for	O
+chronic	O
+hypertension	B
+.	O
+
+Centrally	O
+acting	O
+alpha	O
+-	O
+2	O
+adrenergic	O
+agonists	O
+are	O
+one	O
+of	O
+several	O
+pharmacologic	O
+agents	O
+used	O
+in	O
+the	O
+treatment	O
+of	O
+spasticity	B
+related	O
+to	O
+disorders	B
+of	I
+the	I
+central	I
+nervous	I
+system	I
+.	O
+
+In	O
+addition	O
+to	O
+their	O
+effects	O
+on	O
+spasticity	B
+,	O
+certain	O
+adverse	O
+cardiorespiratory	O
+effects	O
+have	O
+been	O
+reported	O
+.	O
+
+Adults	O
+chronically	O
+treated	O
+with	O
+angiotensin	O
+converting	O
+enzyme	O
+inhibitors	O
+may	O
+have	O
+a	O
+limited	O
+ability	O
+to	O
+respond	O
+to	O
+hypotension	B
+when	O
+the	O
+sympathetic	O
+response	O
+is	O
+simultaneously	O
+blocked	O
+.	O
+
+The	O
+authors	O
+present	O
+a	O
+10	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+chronically	O
+treated	O
+with	O
+lisinopril	O
+,	O
+an	O
+angiotensin	O
+converting	O
+enzyme	O
+inhibitor	O
+,	O
+to	O
+control	O
+hypertension	B
+who	O
+developed	O
+hypotension	B
+following	O
+the	O
+addition	O
+of	O
+tizanidine	O
+,	O
+an	O
+alpha	O
+-	O
+2	O
+agonist	O
+,	O
+for	O
+the	O
+treatment	O
+of	O
+spasticity	B
+.	O
+
+The	O
+possible	O
+interaction	O
+of	O
+tizanidine	O
+and	O
+other	O
+antihypertensive	O
+agents	O
+should	O
+be	O
+kept	O
+in	O
+mind	O
+when	O
+prescribing	O
+therapy	O
+to	O
+treat	O
+either	O
+hypertension	B
+or	O
+spasticity	B
+in	O
+such	O
+patients	O
+.	O
+
+Two	O
+mouse	O
+lines	O
+selected	O
+for	O
+differential	O
+sensitivities	O
+to	O
+beta	O
+-	O
+carboline	O
+-	O
+induced	O
+seizures	B
+are	O
+also	O
+differentially	O
+sensitive	O
+to	O
+various	O
+pharmacological	O
+effects	O
+of	O
+other	O
+GABA	O
+(	O
+A	O
+)	O
+receptor	O
+ligands	O
+.	O
+
+Two	O
+mouse	O
+lines	O
+were	O
+selectively	O
+bred	O
+according	O
+to	O
+their	O
+sensitivity	O
+(	O
+BS	O
+line	O
+)	O
+or	O
+resistance	O
+(	O
+BR	O
+line	O
+)	O
+to	O
+seizures	B
+induced	O
+by	O
+a	O
+single	O
+i	O
+.	O
+p	O
+.	O
+injection	O
+of	O
+methyl	O
+beta	O
+-	O
+carboline	O
+-	O
+3	O
+-	O
+carboxylate	O
+(	O
+beta	O
+-	O
+CCM	O
+)	O
+,	O
+an	O
+inverse	O
+agonist	O
+of	O
+the	O
+GABA	O
+(	O
+A	O
+)	O
+receptor	O
+benzodiazepine	O
+site	O
+.	O
+
+Our	O
+aim	O
+was	O
+to	O
+characterize	O
+both	O
+lines	O
+'	O
+sensitivities	O
+to	O
+various	O
+physiological	O
+effects	O
+of	O
+other	O
+ligands	O
+of	O
+the	O
+GABA	O
+(	O
+A	O
+)	O
+receptor	O
+.	O
+
+We	O
+measured	O
+diazepam	O
+-	O
+induced	O
+anxiolysis	O
+with	O
+the	O
+elevated	O
+plus	O
+-	O
+maze	O
+test	O
+,	O
+diazepam	O
+-	O
+induced	O
+sedation	O
+by	O
+recording	O
+the	O
+vigilance	O
+states	O
+,	O
+and	O
+picrotoxin	O
+-	O
+and	O
+pentylenetetrazol	O
+-	O
+induced	O
+seizures	B
+after	O
+i	O
+.	O
+p	O
+.	O
+injections	O
+.	O
+
+Results	O
+presented	O
+here	O
+show	O
+that	O
+the	O
+differential	O
+sensitivities	O
+of	O
+BS	O
+and	O
+BR	O
+lines	O
+to	O
+beta	O
+-	O
+CCM	O
+can	O
+be	O
+extended	O
+to	O
+diazepam	O
+,	O
+picrotoxin	O
+,	O
+and	O
+pentylenetetrazol	O
+,	O
+suggesting	O
+a	O
+genetic	O
+selection	O
+of	O
+a	O
+general	O
+sensitivity	O
+and	O
+resistance	O
+to	O
+several	O
+ligands	O
+of	O
+the	O
+GABA	O
+(	O
+A	O
+)	O
+receptor	O
+.	O
+
+Propylthiouracil	O
+-	O
+induced	O
+perinuclear	O
+-	O
+staining	O
+antineutrophil	O
+cytoplasmic	O
+autoantibody	O
+-	O
+positive	O
+vasculitis	B
+in	O
+conjunction	O
+with	O
+pericarditis	B
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+describe	O
+a	O
+case	O
+of	O
+propylthiouracil	O
+-	O
+induced	O
+vasculitis	B
+manifesting	O
+with	O
+pericarditis	B
+.	O
+
+METHODS	O
+:	O
+We	O
+present	O
+the	O
+first	O
+case	O
+report	O
+of	O
+a	O
+woman	O
+with	O
+hyperthyroidism	B
+treated	O
+with	O
+propylthiouracil	O
+in	O
+whom	O
+a	O
+syndrome	O
+of	O
+pericarditis	B
+,	O
+fever	B
+,	O
+and	O
+glomerulonephritis	B
+developed	O
+.	O
+
+Serologic	O
+testing	O
+and	O
+immunologic	O
+studies	O
+were	O
+done	O
+,	O
+and	O
+a	O
+pericardial	O
+biopsy	O
+was	O
+performed	O
+.	O
+
+RESULTS	O
+:	O
+A	O
+25	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+Graves	B
+'	I
+disease	I
+had	O
+a	O
+febrile	B
+illness	I
+and	O
+evidence	O
+of	O
+pericarditis	B
+,	O
+which	O
+was	O
+confirmed	O
+by	O
+biopsy	O
+.	O
+
+Serologic	O
+evaluation	O
+revealed	O
+the	O
+presence	O
+of	O
+perinuclear	O
+-	O
+staining	O
+antineutrophil	O
+cytoplasmic	O
+autoantibodies	O
+(	O
+pANCA	O
+)	O
+against	O
+myeloperoxidase	O
+(	O
+MPO	O
+)	O
+.	O
+
+Propylthiouracil	O
+therapy	O
+was	O
+withdrawn	O
+,	O
+and	O
+she	O
+was	O
+treated	O
+with	O
+a	O
+1	O
+-	O
+month	O
+course	O
+of	O
+prednisone	O
+,	O
+which	O
+alleviated	O
+her	O
+symptoms	O
+.	O
+
+A	O
+literature	O
+review	O
+revealed	O
+no	O
+prior	O
+reports	O
+of	O
+pericarditis	B
+in	O
+anti	O
+-	O
+MPO	O
+pANCA	O
+-	O
+positive	O
+vasculitis	B
+associated	O
+with	O
+propylthio	O
+-	O
+uracil	O
+therapy	O
+.	O
+
+CONCLUSION	O
+:	O
+Pericarditis	B
+may	O
+be	O
+the	O
+initial	O
+manifestation	O
+of	O
+drug	O
+-	O
+induced	O
+vasculitis	B
+attributable	O
+to	O
+propylthio	O
+-	O
+uracil	O
+therapy	O
+.	O
+
+Repeated	O
+transient	O
+anuria	B
+following	O
+losartan	O
+administration	O
+in	O
+a	O
+patient	O
+with	O
+a	O
+solitary	O
+kidney	O
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+70	O
+-	O
+year	O
+-	O
+old	O
+hypertensive	B
+man	O
+with	O
+a	O
+solitary	O
+kidney	O
+and	O
+chronic	B
+renal	I
+insufficiency	I
+who	O
+developed	O
+two	O
+episodes	O
+of	O
+transient	O
+anuria	B
+after	O
+losartan	O
+administration	O
+.	O
+
+He	O
+was	O
+hospitalized	O
+for	O
+a	O
+myocardial	B
+infarction	I
+with	O
+pulmonary	B
+edema	I
+,	O
+treated	O
+with	O
+high	O
+-	O
+dose	O
+diuretics	O
+.	O
+
+Due	O
+to	O
+severe	O
+systolic	B
+dysfunction	I
+losartan	O
+was	O
+prescribed	O
+.	O
+
+Surprisingly	O
+,	O
+the	O
+first	O
+dose	O
+of	O
+50	O
+mg	O
+of	O
+losartan	O
+resulted	O
+in	O
+a	O
+sudden	O
+anuria	B
+,	O
+which	O
+lasted	O
+eight	O
+hours	O
+despite	O
+high	O
+-	O
+dose	O
+furosemide	O
+and	O
+amine	O
+infusion	O
+.	O
+
+One	O
+week	O
+later	O
+,	O
+by	O
+mistake	O
+,	O
+losartan	O
+was	O
+prescribed	O
+again	O
+and	O
+after	O
+the	O
+second	O
+dose	O
+of	O
+50	O
+mg	O
+,	O
+the	O
+patient	O
+developed	O
+a	O
+second	O
+episode	O
+of	O
+transient	O
+anuria	B
+lasting	O
+10	O
+hours	O
+.	O
+
+During	O
+these	O
+two	O
+episodes	O
+,	O
+his	O
+blood	O
+pressure	O
+diminished	O
+but	O
+no	O
+severe	O
+hypotension	B
+was	O
+noted	O
+.	O
+
+Ultimately	O
+,	O
+an	O
+arteriography	O
+showed	O
+a	O
+70	O
+-	O
+80	O
+%	O
+renal	B
+artery	I
+stenosis	I
+.	O
+
+In	O
+this	O
+patient	O
+,	O
+renal	B
+artery	I
+stenosis	I
+combined	O
+with	O
+heart	B
+failure	I
+and	O
+diuretic	O
+therapy	O
+certainly	O
+resulted	O
+in	O
+a	O
+strong	O
+activation	O
+of	O
+the	O
+renin	O
+-	O
+angiotensin	O
+system	O
+(	O
+RAS	O
+)	O
+.	O
+
+Under	O
+such	O
+conditions	O
+,	O
+angiotensin	O
+II	O
+receptor	O
+blockade	O
+by	O
+losartan	O
+probably	O
+induced	O
+a	O
+critical	O
+fall	O
+in	O
+glomerular	O
+filtration	O
+pressure	O
+.	O
+
+This	O
+case	O
+report	O
+highlights	O
+the	O
+fact	O
+that	O
+the	O
+angiotensin	O
+II	O
+receptor	O
+antagonist	O
+losartan	O
+can	O
+cause	O
+serious	O
+unexpected	O
+complications	O
+in	O
+patients	O
+with	O
+renovascular	B
+disease	I
+and	O
+should	O
+be	O
+used	O
+with	O
+extreme	O
+caution	O
+in	O
+this	O
+setting	O
+.	O
+
+Calcineurin	O
+-	O
+inhibitor	O
+induced	O
+pain	B
+syndrome	O
+(	O
+CIPS	B
+)	O
+:	O
+a	O
+severe	O
+disabling	O
+complication	O
+after	O
+organ	O
+transplantation	O
+.	O
+
+Bone	O
+pain	B
+after	O
+transplantation	O
+is	O
+a	O
+frequent	O
+complication	O
+that	O
+can	O
+be	O
+caused	O
+by	O
+several	O
+diseases	O
+.	O
+
+Treatment	O
+strategies	O
+depend	O
+on	O
+the	O
+correct	O
+diagnosis	O
+of	O
+the	O
+pain	B
+.	O
+
+Nine	O
+patients	O
+with	O
+severe	O
+pain	B
+in	O
+their	O
+feet	O
+,	O
+which	O
+was	O
+registered	O
+after	O
+transplantation	O
+,	O
+were	O
+investigated	O
+.	O
+
+Bone	O
+scans	O
+showed	O
+an	O
+increased	O
+tracer	O
+uptake	O
+of	O
+the	O
+foot	O
+bones	O
+.	O
+
+Magnetic	O
+resonance	O
+imaging	O
+demonstrated	O
+bone	B
+marrow	I
+oedema	I
+in	O
+the	O
+painful	O
+bones	O
+.	O
+
+Pain	B
+was	O
+not	O
+explained	O
+by	O
+other	O
+diseases	O
+causing	O
+foot	O
+pain	B
+,	O
+like	O
+reflex	B
+sympathetic	I
+dystrophy	I
+,	O
+polyneuropathy	B
+,	O
+Morton	B
+'	I
+s	I
+neuralgia	I
+,	O
+gout	B
+,	O
+osteoporosis	B
+,	O
+avascular	B
+necrosis	I
+,	O
+intermittent	B
+claudication	I
+,	O
+orthopaedic	O
+foot	B
+deformities	I
+,	O
+stress	B
+fractures	I
+,	O
+and	O
+hyperparathyroidism	B
+.	O
+
+The	O
+reduction	O
+of	O
+cyclosporine	O
+-	O
+or	O
+tacrolimus	O
+trough	O
+levels	O
+and	O
+the	O
+administration	O
+of	O
+calcium	O
+channel	O
+blockers	O
+led	O
+to	O
+relief	O
+of	O
+pain	B
+.	O
+
+The	O
+Calcineurin	O
+-	O
+inhibitor	O
+Induced	O
+Pain	B
+Syndrome	O
+(	O
+CIPS	B
+)	O
+is	O
+a	O
+rare	O
+but	O
+severe	O
+side	O
+effect	O
+of	O
+cyclosporine	O
+or	O
+tacrolimus	O
+and	O
+is	O
+accurately	O
+diagnosed	O
+by	O
+its	O
+typical	O
+presentation	O
+,	O
+magnetic	O
+resonance	O
+imaging	O
+and	O
+bone	O
+scans	O
+.	O
+
+Incorrect	O
+diagnosis	O
+of	O
+the	O
+syndrome	O
+will	O
+lead	O
+to	O
+a	O
+significant	O
+reduction	O
+of	O
+life	O
+quality	O
+in	O
+patients	O
+suffering	O
+from	O
+CIPS	B
+.	O
+
+Brain	O
+natriuretic	O
+peptide	O
+is	O
+a	O
+predictor	O
+of	O
+anthracycline	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+Anthracyclines	O
+are	O
+effective	O
+antineoplastic	O
+drugs	O
+,	O
+but	O
+they	O
+frequently	O
+cause	O
+dose	O
+-	O
+related	O
+cardiotoxicity	B
+.	O
+
+The	O
+cardiotoxicity	B
+of	O
+conventional	O
+anthracycline	O
+therapy	O
+highlights	O
+a	O
+need	O
+to	O
+search	O
+for	O
+methods	O
+that	O
+are	O
+highly	O
+sensitive	O
+and	O
+capable	O
+of	O
+predicting	O
+cardiac	B
+dysfunction	I
+.	O
+
+We	O
+measured	O
+the	O
+plasma	O
+level	O
+of	O
+brain	O
+natriuretic	O
+peptide	O
+(	O
+BNP	O
+)	O
+to	O
+determine	O
+whether	O
+BNP	O
+might	O
+serve	O
+as	O
+a	O
+simple	O
+diagnostic	O
+indicator	O
+of	O
+anthracycline	O
+-	O
+induced	O
+cardiotoxicity	B
+in	O
+patients	O
+with	O
+acute	B
+leukemia	I
+treated	O
+with	O
+a	O
+daunorubicin	O
+(	O
+DNR	O
+)	O
+-	O
+containing	O
+regimen	O
+.	O
+
+Thirteen	O
+patients	O
+with	O
+acute	B
+leukemia	I
+were	O
+treated	O
+with	O
+a	O
+DNR	O
+-	O
+containing	O
+regimen	O
+.	O
+
+Cardiac	O
+functions	O
+were	O
+evaluated	O
+with	O
+radionuclide	O
+angiography	O
+before	O
+chemotherapies	O
+.	O
+
+The	O
+plasma	O
+levels	O
+of	O
+atrial	O
+natriuretic	O
+peptide	O
+(	O
+ANP	O
+)	O
+and	O
+BNP	O
+were	O
+measured	O
+at	O
+the	O
+time	O
+of	O
+radionuclide	O
+angiography	O
+.	O
+
+Three	O
+patients	O
+developed	O
+congestive	B
+heart	I
+failure	I
+after	O
+the	O
+completion	O
+of	O
+chemotherapy	O
+.	O
+
+Five	O
+patients	O
+were	O
+diagnosed	O
+as	O
+having	O
+subclinical	O
+heart	B
+failure	I
+after	O
+the	O
+completion	O
+of	O
+chemotherapy	O
+.	O
+
+The	O
+plasma	O
+levels	O
+of	O
+BNP	O
+in	O
+all	O
+the	O
+patients	O
+with	O
+clinical	O
+and	O
+subclinical	O
+heart	B
+failure	I
+increased	O
+above	O
+the	O
+normal	O
+limit	O
+(	O
+40	O
+pg	O
+/	O
+ml	O
+)	O
+before	O
+the	O
+detection	O
+of	O
+clinical	O
+or	O
+subclinical	O
+heart	B
+failure	I
+by	O
+radionuclide	O
+angiography	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+BNP	O
+did	O
+not	O
+increase	O
+in	O
+the	O
+patients	O
+without	O
+heart	B
+failure	I
+given	O
+DNR	O
+,	O
+even	O
+at	O
+more	O
+than	O
+700	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+.	O
+
+The	O
+plasma	O
+level	O
+of	O
+ANP	O
+did	O
+not	O
+always	O
+increase	O
+in	O
+all	O
+the	O
+patients	O
+with	O
+clinical	O
+and	O
+subclinical	O
+heart	B
+failure	I
+.	O
+
+These	O
+preliminary	O
+results	O
+suggest	O
+that	O
+BNP	O
+may	O
+be	O
+useful	O
+as	O
+an	O
+early	O
+and	O
+sensitive	O
+indicator	O
+of	O
+anthracycline	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+Nephrotoxicity	B
+of	O
+combined	O
+cephalothin	O
+-	O
+gentamicin	O
+regimen	O
+.	O
+
+Two	O
+patients	O
+developed	O
+acute	B
+tubular	I
+necrosis	I
+,	O
+characterized	O
+clinically	O
+by	O
+acute	O
+oliguric	B
+renal	I
+failure	I
+,	O
+while	O
+they	O
+were	O
+receiving	O
+a	O
+combination	O
+of	O
+cephalothin	O
+sodium	O
+and	O
+gentamicin	O
+sulfate	O
+therapy	O
+.	O
+
+Patients	O
+who	O
+are	O
+given	O
+this	O
+drug	O
+regimen	O
+should	O
+be	O
+observed	O
+very	O
+carefully	O
+for	O
+early	O
+signs	O
+of	O
+nephrotoxicity	B
+.	O
+
+High	O
+doses	O
+of	O
+this	O
+antibiotic	O
+combination	O
+should	O
+be	O
+avoided	O
+especially	O
+in	O
+elderly	O
+patients	O
+.	O
+
+Patients	O
+with	O
+renal	B
+insufficiency	I
+should	O
+not	O
+be	O
+given	O
+this	O
+regimen	O
+.	O
+
+In	O
+vivo	O
+protection	O
+of	O
+dna	O
+damage	O
+associated	O
+apoptotic	O
+and	O
+necrotic	B
+cell	O
+deaths	O
+during	O
+acetaminophen	O
+-	O
+induced	O
+nephrotoxicity	B
+,	O
+amiodarone	O
+-	O
+induced	O
+lung	B
+toxicity	I
+and	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B
+by	O
+a	O
+novel	O
+IH636	O
+grape	O
+seed	O
+proanthocyanidin	O
+extract	O
+.	O
+
+Grape	O
+seed	O
+extract	O
+,	O
+primarily	O
+a	O
+mixture	O
+of	O
+proanthocyanidins	O
+,	O
+has	O
+been	O
+shown	O
+to	O
+modulate	O
+a	O
+wide	O
+-	O
+range	O
+of	O
+biological	O
+,	O
+pharmacological	O
+and	O
+toxicological	O
+effects	O
+which	O
+are	O
+mainly	O
+cytoprotective	O
+.	O
+
+This	O
+study	O
+assessed	O
+the	O
+ability	O
+of	O
+IH636	O
+grape	O
+seed	O
+proanthocyanidin	O
+extract	O
+(	O
+GSPE	O
+)	O
+to	O
+prevent	O
+acetaminophen	O
+(	O
+AAP	O
+)	O
+-	O
+induced	O
+nephrotoxicity	B
+,	O
+amiodarone	O
+(	O
+AMI	O
+)	O
+-	O
+induced	O
+lung	B
+toxicity	I
+,	O
+and	O
+doxorubicin	O
+(	O
+DOX	O
+)	O
+-	O
+induced	O
+cardiotoxicity	B
+in	O
+mice	O
+.	O
+
+Experimental	O
+design	O
+consisted	O
+of	O
+four	O
+groups	O
+:	O
+control	O
+(	O
+vehicle	O
+alone	O
+)	O
+,	O
+GSPE	O
+alone	O
+,	O
+drug	O
+alone	O
+and	O
+GSPE	O
++	O
+drug	O
+.	O
+
+For	O
+the	O
+cytoprotection	O
+study	O
+,	O
+animals	O
+were	O
+orally	O
+gavaged	O
+100	O
+mg	O
+/	O
+Kg	O
+GSPE	O
+for	O
+7	O
+-	O
+10	O
+days	O
+followed	O
+by	O
+i	O
+.	O
+p	O
+.	O
+injections	O
+of	O
+organ	O
+specific	O
+three	O
+drugs	O
+(	O
+AAP	O
+:	O
+500	O
+mg	O
+/	O
+Kg	O
+for	O
+24	O
+h	O
+;	O
+AMI	O
+:	O
+50	O
+mg	O
+/	O
+Kg	O
+/	O
+day	O
+for	O
+four	O
+days	O
+;	O
+DOX	O
+:	O
+20	O
+mg	O
+/	O
+Kg	O
+for	O
+48	O
+h	O
+)	O
+.	O
+
+Parameters	O
+of	O
+study	O
+included	O
+analysis	O
+of	O
+serum	O
+chemistry	O
+(	O
+ALT	O
+,	O
+BUN	O
+and	O
+CPK	O
+)	O
+,	O
+and	O
+orderly	O
+fragmentation	O
+of	O
+genomic	O
+DNA	O
+(	O
+both	O
+endonuclease	O
+-	O
+dependent	O
+and	O
+independent	O
+)	O
+in	O
+addition	O
+to	O
+microscopic	O
+evaluation	O
+of	O
+damage	O
+and	O
+/	O
+or	O
+protection	O
+in	O
+corresponding	O
+PAS	O
+stained	O
+tissues	O
+.	O
+
+Results	O
+indicate	O
+that	O
+GSPE	O
+preexposure	O
+prior	O
+to	O
+AAP	O
+,	O
+AMI	O
+and	O
+DOX	O
+,	O
+provided	O
+near	O
+complete	O
+protection	O
+in	O
+terms	O
+of	O
+serum	O
+chemistry	O
+changes	O
+(	O
+ALT	O
+,	O
+BUN	O
+and	O
+CPK	O
+)	O
+,	O
+and	O
+significantly	O
+reduced	O
+DNA	O
+fragmentation	O
+.	O
+
+Histopathological	O
+examination	O
+of	O
+kidney	O
+,	O
+heart	O
+and	O
+lung	O
+sections	O
+revealed	O
+moderate	O
+to	O
+massive	O
+tissue	B
+damage	I
+with	O
+a	O
+variety	O
+of	O
+morphological	O
+aberrations	O
+by	O
+all	O
+the	O
+three	O
+drugs	O
+in	O
+the	O
+absence	O
+of	O
+GSPE	O
+preexposure	O
+than	O
+in	O
+its	O
+presence	O
+.	O
+
+GSPE	O
++	O
+drug	O
+exposed	O
+tissues	O
+exhibited	O
+minor	O
+residual	O
+damage	O
+or	O
+near	O
+total	O
+recovery	O
+.	O
+
+Additionally	O
+,	O
+histopathological	O
+alterations	O
+mirrored	O
+both	O
+serum	O
+chemistry	O
+changes	O
+and	O
+the	O
+pattern	O
+of	O
+DNA	O
+fragmentation	O
+.	O
+
+Interestingly	O
+,	O
+all	O
+the	O
+drugs	O
+,	O
+such	O
+as	O
+,	O
+AAP	O
+,	O
+AMI	O
+and	O
+DOX	O
+induced	O
+apoptotic	O
+death	O
+in	O
+addition	O
+to	O
+necrosis	B
+in	O
+the	O
+respective	O
+organs	O
+which	O
+was	O
+very	O
+effectively	O
+blocked	O
+by	O
+GSPE	O
+.	O
+
+Since	O
+AAP	O
+,	O
+AMI	O
+and	O
+DOX	O
+undergo	O
+biotransformation	O
+and	O
+are	O
+known	O
+to	O
+produce	O
+damaging	O
+radicals	O
+in	O
+vivo	O
+,	O
+the	O
+protection	O
+by	O
+GSPE	O
+may	O
+be	O
+linked	O
+to	O
+both	O
+inhibition	O
+of	O
+metabolism	O
+and	O
+/	O
+or	O
+detoxification	O
+of	O
+cytotoxic	O
+radicals	O
+.	O
+
+In	O
+addition	O
+,	O
+its	O
+'	O
+presumed	O
+contribution	O
+to	O
+DNA	O
+repair	O
+may	O
+be	O
+another	O
+important	O
+attribute	O
+,	O
+which	O
+played	O
+a	O
+role	O
+in	O
+the	O
+chemoprevention	O
+process	O
+.	O
+
+Additionally	O
+,	O
+this	O
+may	O
+have	O
+been	O
+the	O
+first	O
+report	O
+on	O
+AMI	O
+-	O
+induced	O
+apoptotic	O
+death	O
+in	O
+the	O
+lung	O
+tissue	O
+.	O
+
+Taken	O
+together	O
+,	O
+these	O
+events	O
+undoubtedly	O
+establish	O
+GSPE	O
+'	O
+s	O
+abundant	O
+bioavailability	O
+,	O
+and	O
+the	O
+power	O
+to	O
+defend	O
+multiple	O
+target	O
+organs	O
+from	O
+toxic	O
+assaults	O
+induced	O
+by	O
+structurally	O
+diverse	O
+and	O
+functionally	O
+different	O
+entities	O
+in	O
+vivo	O
+.	O
+
+Antidepressant	O
+-	O
+induced	O
+mania	B
+in	O
+bipolar	B
+patients	O
+:	O
+identification	O
+of	O
+risk	O
+factors	O
+.	O
+
+BACKGROUND	O
+:	O
+Concerns	O
+about	O
+possible	O
+risks	O
+of	O
+switching	O
+to	O
+mania	B
+associated	O
+with	O
+antidepressants	O
+continue	O
+to	O
+interfere	O
+with	O
+the	O
+establishment	O
+of	O
+an	O
+optimal	O
+treatment	O
+paradigm	O
+for	O
+bipolar	B
+depression	I
+.	O
+
+METHOD	O
+:	O
+The	O
+response	O
+of	O
+44	O
+patients	O
+meeting	O
+DSM	O
+-	O
+IV	O
+criteria	O
+for	O
+bipolar	B
+disorder	I
+to	O
+naturalistic	O
+treatment	O
+was	O
+assessed	O
+for	O
+at	O
+least	O
+6	O
+weeks	O
+using	O
+the	O
+Montgomery	O
+-	O
+Asberg	O
+Depression	O
+Rating	O
+Scale	O
+and	O
+the	O
+Bech	O
+-	O
+Rafaelson	O
+Mania	O
+Rating	O
+Scale	O
+.	O
+
+Patients	O
+who	O
+experienced	O
+a	O
+manic	B
+or	O
+hypomanic	B
+switch	O
+were	O
+compared	O
+with	O
+those	O
+who	O
+did	O
+not	O
+on	O
+several	O
+variables	O
+including	O
+age	O
+,	O
+sex	O
+,	O
+diagnosis	O
+(	O
+DSM	B
+-	I
+IV	I
+bipolar	I
+I	I
+vs	O
+.	O
+bipolar	B
+II	I
+)	O
+,	O
+number	O
+of	O
+previous	O
+manic	B
+episodes	O
+,	O
+type	O
+of	O
+antidepressant	O
+therapy	O
+used	O
+(	O
+electroconvulsive	O
+therapy	O
+vs	O
+.	O
+antidepressant	O
+drugs	O
+and	O
+,	O
+more	O
+particularly	O
+,	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitors	O
+[	O
+SSRIs	O
+]	O
+)	O
+,	O
+use	O
+and	O
+type	O
+of	O
+mood	O
+stabilizers	O
+(	O
+lithium	O
+vs	O
+.	O
+anticonvulsants	O
+)	O
+,	O
+and	O
+temperament	O
+of	O
+the	O
+patient	O
+,	O
+assessed	O
+during	O
+a	O
+normothymic	O
+period	O
+using	O
+the	O
+hyperthymia	O
+component	O
+of	O
+the	O
+Semi	O
+-	O
+structured	O
+Affective	O
+Temperament	O
+Interview	O
+.	O
+
+RESULTS	O
+:	O
+Switches	O
+to	O
+hypomania	B
+or	O
+mania	B
+occurred	O
+in	O
+27	O
+%	O
+of	O
+all	O
+patients	O
+(	O
+N	O
+=	O
+12	O
+)	O
+(	O
+and	O
+in	O
+24	O
+%	O
+of	O
+the	O
+subgroup	O
+of	O
+patients	O
+treated	O
+with	O
+SSRIs	O
+[	O
+8	O
+/	O
+33	O
+]	O
+)	O
+;	O
+16	O
+%	O
+(	O
+N	O
+=	O
+7	O
+)	O
+experienced	O
+manic	B
+episodes	O
+,	O
+and	O
+11	O
+%	O
+(	O
+N	O
+=	O
+5	O
+)	O
+experienced	O
+hypomanic	B
+episodes	O
+.	O
+
+Sex	O
+,	O
+age	O
+,	O
+diagnosis	O
+(	O
+bipolar	B
+I	I
+vs	O
+.	O
+bipolar	B
+II	I
+)	O
+,	O
+and	O
+additional	O
+treatment	O
+did	O
+not	O
+affect	O
+the	O
+risk	O
+of	O
+switching	O
+.	O
+
+The	O
+incidence	O
+of	O
+mood	O
+switches	O
+seemed	O
+not	O
+to	O
+differ	O
+between	O
+patients	O
+receiving	O
+an	O
+anticonvulsant	O
+and	O
+those	O
+receiving	O
+no	O
+mood	O
+stabilizer	O
+.	O
+
+In	O
+contrast	O
+,	O
+mood	O
+switches	O
+were	O
+less	O
+frequent	O
+in	O
+patients	O
+receiving	O
+lithium	O
+(	O
+15	O
+%	O
+,	O
+4	O
+/	O
+26	O
+)	O
+than	O
+in	O
+patients	O
+not	O
+treated	O
+with	O
+lithium	O
+(	O
+44	O
+%	O
+,	O
+8	O
+/	O
+18	O
+;	O
+p	O
+=	O
+.	O
+04	O
+)	O
+.	O
+
+The	O
+number	O
+of	O
+previous	O
+manic	B
+episodes	O
+did	O
+not	O
+affect	O
+the	O
+probability	O
+of	O
+switching	O
+,	O
+whereas	O
+a	O
+high	O
+score	O
+on	O
+the	O
+hyperthymia	O
+component	O
+of	O
+the	O
+Semistructured	O
+Affective	O
+Temperament	O
+Interview	O
+was	O
+associated	O
+with	O
+a	O
+greater	O
+risk	O
+of	O
+switching	O
+(	O
+p	O
+=	O
+.	O
+008	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+frequency	O
+of	O
+mood	O
+switching	O
+associated	O
+with	O
+acute	O
+antidepressant	O
+therapy	O
+may	O
+be	O
+reduced	O
+by	O
+lithium	O
+treatment	O
+.	O
+
+Particular	O
+attention	O
+should	O
+be	O
+paid	O
+to	O
+patients	O
+with	O
+a	O
+hyperthymic	O
+temperament	O
+,	O
+who	O
+have	O
+a	O
+greater	O
+risk	O
+of	O
+mood	O
+switches	O
+.	O
+
+Peritubular	O
+capillary	O
+basement	O
+membrane	O
+reduplication	O
+in	O
+allografts	O
+and	O
+native	O
+kidney	B
+disease	I
+:	O
+a	O
+clinicopathologic	O
+study	O
+of	O
+278	O
+consecutive	O
+renal	O
+specimens	O
+.	O
+
+BACKGROUND	O
+:	O
+An	O
+association	O
+has	O
+been	O
+found	O
+between	O
+transplant	B
+glomerulopathy	I
+(	O
+TG	B
+)	O
+and	O
+reduplication	O
+of	O
+peritubular	O
+capillary	O
+basement	O
+membranes	O
+(	O
+PTCR	O
+)	O
+.	O
+
+Although	O
+such	O
+an	O
+association	O
+is	O
+of	O
+practical	O
+and	O
+theoretical	O
+importance	O
+,	O
+only	O
+one	O
+prospective	O
+study	O
+has	O
+tried	O
+to	O
+confirm	O
+it	O
+.	O
+
+METHODS	O
+:	O
+We	O
+examined	O
+278	O
+consecutive	O
+renal	O
+specimens	O
+(	O
+from	O
+135	O
+transplants	O
+and	O
+143	O
+native	O
+kidneys	O
+)	O
+for	O
+ultrastructural	O
+evidence	O
+of	O
+PTCR	O
+.	O
+
+In	O
+addition	O
+to	O
+renal	O
+allografts	O
+with	O
+TG	B
+,	O
+we	O
+also	O
+examined	O
+grafts	O
+with	O
+acute	O
+rejection	O
+,	O
+recurrent	O
+glomerulonephritis	B
+,	O
+chronic	B
+allograft	I
+nephropathy	I
+and	O
+stable	O
+grafts	O
+(	O
+"	O
+protocol	O
+biopsies	O
+"	O
+)	O
+.	O
+
+Native	O
+kidney	O
+specimens	O
+included	O
+a	O
+wide	O
+range	O
+of	O
+glomerulopathies	B
+as	O
+well	O
+as	O
+cases	O
+of	O
+thrombotic	B
+microangiopathy	I
+,	O
+malignant	B
+hypertension	I
+,	O
+acute	O
+interstitial	B
+nephritis	I
+,	O
+and	O
+acute	B
+tubular	I
+necrosis	I
+.	O
+
+RESULTS	O
+:	O
+We	O
+found	O
+PTCR	O
+in	O
+14	O
+of	O
+15	O
+cases	O
+of	O
+TG	B
+,	O
+in	O
+7	O
+transplant	O
+biopsy	O
+specimens	O
+without	O
+TG	B
+,	O
+and	O
+in	O
+13	O
+of	O
+143	O
+native	O
+kidney	O
+biopsy	O
+specimens	O
+.	O
+
+These	O
+13	O
+included	O
+cases	O
+of	O
+malignant	B
+hypertension	I
+,	O
+thrombotic	B
+microangiopathy	I
+,	O
+lupus	B
+nephritis	I
+,	O
+Henoch	B
+-	I
+Schonlein	I
+nephritis	I
+,	O
+crescentic	O
+glomerulonephritis	B
+,	O
+and	O
+cocaine	O
+-	O
+related	O
+acute	B
+renal	I
+failure	I
+.	O
+
+Mild	O
+PTCR	O
+in	O
+allografts	O
+without	O
+TG	B
+did	O
+not	O
+predict	O
+renal	B
+failure	I
+or	O
+significant	O
+proteinuria	B
+after	O
+follow	O
+-	O
+up	O
+periods	O
+of	O
+between	O
+3	O
+months	O
+and	O
+1	O
+year	O
+.	O
+
+CONCLUSIONS	O
+:	O
+We	O
+conclude	O
+that	O
+in	O
+transplants	O
+,	O
+there	O
+is	O
+a	O
+strong	O
+association	O
+between	O
+well	O
+-	O
+developed	O
+PTCR	O
+and	O
+TG	B
+,	O
+while	O
+the	O
+significance	O
+of	O
+mild	O
+PTCR	O
+and	O
+its	O
+predictive	O
+value	O
+in	O
+the	O
+absence	O
+of	O
+TG	B
+is	O
+unclear	O
+.	O
+
+PTCR	O
+also	O
+occurs	O
+in	O
+certain	O
+native	O
+kidney	B
+diseases	I
+,	O
+though	O
+the	O
+association	O
+is	O
+not	O
+as	O
+strong	O
+as	O
+that	O
+for	O
+TG	B
+.	O
+
+We	O
+suggest	O
+that	O
+repeated	O
+endothelial	B
+injury	I
+,	O
+including	O
+immunologic	B
+injury	I
+,	O
+may	O
+be	O
+the	O
+cause	O
+of	O
+this	O
+lesion	O
+both	O
+in	O
+allografts	O
+and	O
+native	O
+kidneys	O
+.	O
+
+Caffeine	O
+-	O
+induced	O
+cardiac	B
+arrhythmia	I
+:	O
+an	O
+unrecognised	O
+danger	O
+of	O
+healthfood	O
+products	O
+.	O
+
+We	O
+describe	O
+a	O
+25	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+pre	O
+-	O
+existing	O
+mitral	B
+valve	I
+prolapse	I
+who	O
+developed	O
+intractable	O
+ventricular	B
+fibrillation	I
+after	O
+consuming	O
+a	O
+"	O
+natural	O
+energy	O
+"	O
+guarana	O
+health	O
+drink	O
+containing	O
+a	O
+high	O
+concentration	O
+of	O
+caffeine	O
+.	O
+
+This	O
+case	O
+highlights	O
+the	O
+need	O
+for	O
+adequate	O
+labelling	O
+and	O
+regulation	O
+of	O
+such	O
+products	O
+.	O
+
+Conformationally	O
+restricted	O
+analogs	O
+of	O
+BD1008	O
+and	O
+an	O
+antisense	O
+oligodeoxynucleotide	O
+targeting	O
+sigma1	O
+receptors	O
+produce	O
+anti	O
+-	O
+cocaine	O
+effects	O
+in	O
+mice	O
+.	O
+
+Cocaine	O
+'	O
+s	O
+ability	O
+to	O
+interact	O
+with	O
+sigma	O
+receptors	O
+suggests	O
+that	O
+these	O
+proteins	O
+mediate	O
+some	O
+of	O
+its	O
+behavioral	O
+effects	O
+.	O
+
+Therefore	O
+,	O
+three	O
+novel	O
+sigma	O
+receptor	O
+ligands	O
+with	O
+antagonist	O
+activity	O
+were	O
+evaluated	O
+in	O
+Swiss	O
+Webster	O
+mice	O
+:	O
+BD1018	O
+(	O
+3S	O
+-	O
+1	O
+-	O
+[	O
+2	O
+-	O
+(	O
+3	O
+,	O
+4	O
+-	O
+dichlorophenyl	O
+)	O
+ethyl	O
+]	O
+-	O
+1	O
+,	O
+4	O
+-	O
+diazabicyclo	O
+[	O
+4	O
+.	O
+3	O
+.	O
+0	O
+]	O
+nonane	O
+)	O
+,	O
+BD1063	O
+(	O
+1	O
+-	O
+[	O
+2	O
+-	O
+(	O
+3	O
+,	O
+4	O
+-	O
+dichlorophenyl	O
+)	O
+ethyl	O
+]	O
+-	O
+4	O
+-	O
+methylpiperazine	O
+)	O
+,	O
+and	O
+LR132	O
+(	O
+1R	O
+,	O
+2S	O
+-	O
+(	O
++	O
+)	O
+-	O
+cis	O
+-	O
+N	O
+-	O
+[	O
+2	O
+-	O
+(	O
+3	O
+,	O
+4	O
+-	O
+dichlorophenyl	O
+)	O
+ethyl	O
+]	O
+-	O
+2	O
+-	O
+(	O
+1	O
+-	O
+pyrrolidinyl	O
+)	O
+cyclohexylamine	O
+)	O
+.	O
+
+Competition	O
+binding	O
+assays	O
+demonstrated	O
+that	O
+all	O
+three	O
+compounds	O
+have	O
+high	O
+affinities	O
+for	O
+sigma1	O
+receptors	O
+.	O
+
+The	O
+three	O
+compounds	O
+vary	O
+in	O
+their	O
+affinities	O
+for	O
+sigma2	O
+receptors	O
+and	O
+exhibit	O
+negligible	O
+affinities	O
+for	O
+dopamine	O
+,	O
+opioid	O
+,	O
+GABA	O
+(	O
+A	O
+)	O
+and	O
+NMDA	O
+receptors	O
+.	O
+
+In	O
+behavioral	O
+studies	O
+,	O
+pre	O
+-	O
+treatment	O
+of	O
+mice	O
+with	O
+BD1018	O
+,	O
+BD1063	O
+,	O
+or	O
+LR132	O
+significantly	O
+attenuated	O
+cocaine	O
+-	O
+induced	O
+convulsions	B
+and	O
+lethality	O
+.	O
+
+Moreover	O
+,	O
+post	O
+-	O
+treatment	O
+with	O
+LR132	O
+prevented	O
+cocaine	O
+-	O
+induced	O
+lethality	O
+in	O
+a	O
+significant	O
+proportion	O
+of	O
+animals	O
+.	O
+
+In	O
+contrast	O
+to	O
+the	O
+protection	O
+provided	O
+by	O
+the	O
+putative	O
+antagonists	O
+,	O
+the	O
+well	O
+-	O
+characterized	O
+sigma	O
+receptor	O
+agonist	O
+di	O
+-	O
+o	O
+-	O
+tolylguanidine	O
+(	O
+DTG	O
+)	O
+and	O
+the	O
+novel	O
+sigma	O
+receptor	O
+agonist	O
+BD1031	O
+(	O
+3R	O
+-	O
+1	O
+-	O
+[	O
+2	O
+-	O
+(	O
+3	O
+,	O
+4	O
+-	O
+dichlorophenyl	O
+)	O
+ethyl	O
+]	O
+-	O
+1	O
+,	O
+4	O
+-	O
+diazabicyclo	O
+[	O
+4	O
+.	O
+3	O
+.	O
+0	O
+]	O
+nonane	O
+)	O
+each	O
+worsened	O
+the	O
+behavioral	O
+toxicity	B
+of	O
+cocaine	O
+.	O
+
+At	O
+doses	O
+where	O
+alone	O
+,	O
+they	O
+produced	O
+no	O
+significant	O
+effects	O
+on	O
+locomotion	O
+,	O
+BD1018	O
+,	O
+BD1063	O
+and	O
+LR132	O
+significantly	O
+attenuated	O
+the	O
+locomotor	O
+stimulatory	O
+effects	O
+of	O
+cocaine	O
+.	O
+
+To	O
+further	O
+validate	O
+the	O
+hypothesis	O
+that	O
+the	O
+anti	O
+-	O
+cocaine	O
+effects	O
+of	O
+the	O
+novel	O
+ligands	O
+involved	O
+antagonism	O
+of	O
+sigma	O
+receptors	O
+,	O
+an	O
+antisense	O
+oligodeoxynucleotide	O
+against	O
+sigma1	O
+receptors	O
+was	O
+also	O
+shown	O
+to	O
+significantly	O
+attenuate	O
+the	O
+convulsive	B
+and	O
+locomotor	O
+stimulatory	O
+effects	O
+of	O
+cocaine	O
+.	O
+
+Together	O
+,	O
+the	O
+data	O
+suggests	O
+that	O
+functional	O
+antagonism	O
+of	O
+sigma	O
+receptors	O
+is	O
+capable	O
+of	O
+attenuating	O
+a	O
+number	O
+of	O
+cocaine	O
+-	O
+induced	O
+behaviors	O
+.	O
+
+Ranitidine	O
+-	O
+induced	O
+acute	O
+interstitial	B
+nephritis	I
+in	O
+a	O
+cadaveric	O
+renal	O
+allograft	O
+.	O
+
+Ranitidine	O
+frequently	O
+is	O
+used	O
+for	O
+preventing	O
+peptic	O
+ulceration	O
+after	O
+renal	O
+transplantation	O
+.	O
+
+This	O
+drug	O
+occasionally	O
+has	O
+been	O
+associated	O
+with	O
+acute	O
+interstitial	B
+nephritis	I
+in	O
+native	O
+kidneys	O
+.	O
+
+There	O
+are	O
+no	O
+similar	O
+reports	O
+with	O
+renal	O
+transplantation	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+ranitidine	O
+-	O
+induced	O
+acute	O
+interstitial	B
+nephritis	I
+in	O
+a	O
+recipient	O
+of	O
+a	O
+cadaveric	O
+renal	O
+allograft	O
+presenting	O
+with	O
+acute	O
+allograft	O
+dysfunction	O
+within	O
+48	O
+hours	O
+of	O
+exposure	O
+to	O
+the	O
+drug	O
+.	O
+
+The	O
+biopsy	O
+specimen	O
+showed	O
+pathognomonic	O
+features	O
+,	O
+including	O
+eosinophilic	O
+infiltration	O
+of	O
+the	O
+interstitial	O
+compartment	O
+.	O
+
+Allograft	O
+function	O
+improved	O
+rapidly	O
+and	O
+returned	O
+to	O
+baseline	O
+after	O
+stopping	O
+the	O
+drug	O
+.	O
+
+Liver	B
+disease	I
+caused	O
+by	O
+propylthiouracil	O
+.	O
+
+This	O
+report	O
+presents	O
+the	O
+clinical	O
+,	O
+laboratory	O
+,	O
+and	O
+light	O
+and	O
+electron	O
+microscopic	O
+observations	O
+on	O
+a	O
+patient	O
+with	O
+chronic	B
+active	I
+(	I
+aggressive	I
+)	I
+hepatitis	I
+caused	O
+by	O
+the	O
+administration	O
+of	O
+propylthiouracil	O
+.	O
+
+This	O
+is	O
+an	O
+addition	O
+to	O
+the	O
+list	O
+of	O
+drugs	O
+that	O
+must	O
+be	O
+considered	O
+in	O
+the	O
+evaluation	O
+of	O
+chronic	O
+liver	B
+disease	I
+.	O
+
+Withdrawal	B
+-	I
+emergent	I
+rabbit	I
+syndrome	I
+during	O
+dose	O
+reduction	O
+of	O
+risperidone	O
+.	O
+
+Rabbit	B
+syndrome	I
+(	O
+RS	B
+)	O
+is	O
+a	O
+rare	O
+extrapyramidal	O
+side	O
+effect	O
+caused	O
+by	O
+prolonged	O
+neuroleptic	O
+medication	O
+.	O
+
+Here	O
+we	O
+present	O
+a	O
+case	O
+of	O
+withdrawal	B
+-	I
+emergent	I
+RS	I
+,	O
+which	O
+is	O
+the	O
+first	O
+of	O
+its	O
+kind	O
+to	O
+be	O
+reported	O
+.	O
+
+The	O
+patient	O
+developed	O
+RS	B
+during	O
+dose	O
+reduction	O
+of	O
+risperidone	O
+.	O
+
+The	O
+symptom	O
+was	O
+treated	O
+successfully	O
+with	O
+trihexyphenidyl	O
+anticholinergic	O
+therapy	O
+.	O
+
+The	O
+underlying	O
+mechanism	O
+of	O
+withdrawal	B
+-	I
+emergent	I
+RS	I
+in	O
+the	O
+present	O
+case	O
+may	O
+have	O
+been	O
+related	O
+to	O
+the	O
+pharmacological	O
+profile	O
+of	O
+risperidone	O
+,	O
+a	O
+serotonin	O
+-	O
+dopamine	O
+antagonist	O
+,	O
+suggesting	O
+the	O
+pathophysiologic	O
+influence	O
+of	O
+the	O
+serotonin	O
+system	O
+in	O
+the	O
+development	O
+of	O
+RS	B
+.	O
+
+Pharmacokinetic	O
+/	O
+pharmacodynamic	O
+assessment	O
+of	O
+the	O
+effects	O
+of	O
+E4031	O
+,	O
+cisapride	O
+,	O
+terfenadine	O
+and	O
+terodiline	O
+on	O
+monophasic	O
+action	O
+potential	O
+duration	O
+in	O
+dog	O
+.	O
+
+1	O
+.	O
+
+Torsades	B
+de	I
+pointes	I
+(	O
+TDP	B
+)	O
+is	O
+a	O
+potentially	O
+fatal	O
+ventricular	B
+tachycardia	I
+associated	O
+with	O
+increases	O
+in	O
+QT	O
+interval	O
+and	O
+monophasic	O
+action	O
+potential	O
+duration	O
+(	O
+MAPD	O
+)	O
+.	O
+
+TDP	B
+is	O
+a	O
+side	O
+-	O
+effect	O
+that	O
+has	O
+led	O
+to	O
+withdrawal	O
+of	O
+several	O
+drugs	O
+from	O
+the	O
+market	O
+(	O
+e	O
+.	O
+g	O
+.	O
+terfenadine	O
+and	O
+terodiline	O
+)	O
+.	O
+
+2	O
+.	O
+
+The	O
+potential	O
+of	O
+compounds	O
+to	O
+cause	O
+TDP	B
+was	O
+evaluated	O
+by	O
+monitoring	O
+their	O
+effects	O
+on	O
+MAPD	O
+in	O
+dog	O
+.	O
+
+Four	O
+compounds	O
+known	O
+to	O
+increase	O
+QT	O
+interval	O
+and	O
+cause	O
+TDP	B
+were	O
+investigated	O
+:	O
+terfenadine	O
+,	O
+terodiline	O
+,	O
+cisapride	O
+and	O
+E4031	O
+.	O
+
+On	O
+the	O
+basis	O
+that	O
+only	O
+free	O
+drug	O
+in	O
+the	O
+systemic	O
+circulation	O
+will	O
+elicit	O
+a	O
+pharmacological	O
+response	O
+target	O
+,	O
+free	O
+concentrations	O
+in	O
+plasma	O
+were	O
+selected	O
+to	O
+mimic	O
+the	O
+free	O
+drug	O
+exposures	O
+in	O
+man	O
+.	O
+
+Infusion	O
+regimens	O
+were	O
+designed	O
+that	O
+rapidly	O
+achieved	O
+and	O
+maintained	O
+target	O
+-	O
+free	O
+concentrations	O
+of	O
+these	O
+drugs	O
+in	O
+plasma	O
+and	O
+data	O
+on	O
+the	O
+relationship	O
+between	O
+free	O
+concentration	O
+and	O
+changes	O
+in	O
+MAPD	O
+were	O
+obtained	O
+for	O
+these	O
+compounds	O
+.	O
+
+3	O
+.	O
+
+These	O
+data	O
+indicate	O
+that	O
+the	O
+free	O
+ED50	O
+in	O
+plasma	O
+for	O
+terfenadine	O
+(	O
+1	O
+.	O
+9	O
+nM	O
+)	O
+,	O
+terodiline	O
+(	O
+76	O
+nM	O
+)	O
+,	O
+cisapride	O
+(	O
+11	O
+nM	O
+)	O
+and	O
+E4031	O
+(	O
+1	O
+.	O
+9	O
+nM	O
+)	O
+closely	O
+correlate	O
+with	O
+the	O
+free	O
+concentration	O
+in	O
+man	O
+causing	O
+QT	O
+effects	O
+.	O
+
+For	O
+compounds	O
+that	O
+have	O
+shown	O
+TDP	B
+in	O
+the	O
+clinic	O
+(	O
+terfenadine	O
+,	O
+terodiline	O
+,	O
+cisapride	O
+)	O
+there	O
+is	O
+little	O
+differentiation	O
+between	O
+the	O
+dog	O
+ED50	O
+and	O
+the	O
+efficacious	O
+free	O
+plasma	O
+concentrations	O
+in	O
+man	O
+(	O
+<	O
+10	O
+-	O
+fold	O
+)	O
+reflecting	O
+their	O
+limited	O
+safety	O
+margins	O
+.	O
+
+These	O
+data	O
+underline	O
+the	O
+need	O
+to	O
+maximize	O
+the	O
+therapeutic	O
+ratio	O
+with	O
+respect	O
+to	O
+TDP	B
+in	O
+potential	O
+development	O
+candidates	O
+and	O
+the	O
+importance	O
+of	O
+using	O
+free	O
+drug	O
+concentrations	O
+in	O
+pharmacokinetic	O
+/	O
+pharmacodynamic	O
+studies	O
+.	O
+
+Bladder	O
+retention	B
+of	I
+urine	I
+as	O
+a	O
+result	O
+of	O
+continuous	O
+intravenous	O
+infusion	O
+of	O
+fentanyl	O
+:	O
+2	O
+case	O
+reports	O
+.	O
+
+Sedation	O
+has	O
+been	O
+commonly	O
+used	O
+in	O
+the	O
+neonate	O
+to	O
+decrease	O
+the	O
+stress	O
+and	O
+pain	B
+from	O
+the	O
+noxious	O
+stimuli	O
+and	O
+invasive	O
+procedures	O
+in	O
+the	O
+neonatal	O
+intensive	O
+care	O
+unit	O
+,	O
+as	O
+well	O
+as	O
+to	O
+facilitate	O
+synchrony	O
+between	O
+ventilator	O
+and	O
+spontaneous	O
+breaths	O
+.	O
+
+Fentanyl	O
+,	O
+an	O
+opioid	O
+analgesic	O
+,	O
+is	O
+frequently	O
+used	O
+in	O
+the	O
+neonatal	O
+intensive	O
+care	O
+unit	O
+setting	O
+for	O
+these	O
+very	O
+purposes	O
+.	O
+
+Various	O
+reported	O
+side	O
+effects	O
+of	O
+fentanyl	O
+administration	O
+include	O
+chest	B
+wall	I
+rigidity	I
+,	O
+hypotension	B
+,	O
+respiratory	B
+depression	I
+,	O
+and	O
+bradycardia	B
+.	O
+
+Here	O
+,	O
+2	O
+cases	O
+of	O
+urinary	B
+bladder	I
+retention	I
+leading	O
+to	O
+renal	O
+pelvocalyceal	O
+dilatation	O
+mimicking	O
+hydronephrosis	B
+as	O
+a	O
+result	O
+of	O
+continuous	O
+infusion	O
+of	O
+fentanyl	O
+are	O
+reported	O
+.	O
+
+Fatal	O
+myeloencephalopathy	B
+due	O
+to	O
+accidental	O
+intrathecal	O
+vincristin	O
+administration	O
+:	O
+a	O
+report	O
+of	O
+two	O
+cases	O
+.	O
+
+We	O
+report	O
+on	O
+two	O
+fatal	O
+cases	O
+of	O
+accidental	O
+intrathecal	O
+vincristine	O
+instillation	O
+in	O
+a	O
+5	O
+-	O
+year	O
+old	O
+girl	O
+with	O
+recurrent	O
+acute	B
+lymphoblastic	I
+leucemia	I
+and	O
+a	O
+57	O
+-	O
+year	O
+old	O
+man	O
+with	O
+lymphoblastic	B
+lymphoma	I
+.	O
+
+The	O
+girl	O
+died	O
+seven	O
+days	O
+,	O
+the	O
+man	O
+four	O
+weeks	O
+after	O
+intrathecal	O
+injection	O
+of	O
+vincristine	O
+.	O
+
+Clinically	O
+,	O
+the	O
+onset	O
+was	O
+characterized	O
+by	O
+the	O
+signs	O
+of	O
+opistothonus	B
+,	I
+sensory	I
+and	I
+motor	I
+dysfunction	I
+and	O
+ascending	O
+paralysis	B
+.	O
+
+Histological	O
+and	O
+immunohistochemical	O
+investigations	O
+(	O
+HE	O
+-	O
+LFB	O
+,	O
+CD	O
+-	O
+68	O
+,	O
+Neurofilament	O
+)	O
+revealed	O
+degeneration	B
+of	I
+myelin	I
+and	I
+axons	I
+as	O
+well	O
+as	O
+pseudocystic	B
+transformation	I
+in	O
+areas	O
+exposed	O
+to	O
+vincristine	O
+,	O
+accompanied	O
+by	O
+secondary	O
+changes	O
+with	O
+numerous	O
+prominent	O
+macrophages	O
+.	O
+
+The	O
+clinical	O
+course	O
+and	O
+histopathological	O
+results	O
+of	O
+the	O
+two	O
+cases	O
+are	O
+presented	O
+.	O
+
+A	O
+review	O
+of	O
+all	O
+reported	O
+cases	O
+in	O
+the	O
+literature	O
+is	O
+given	O
+.	O
+
+A	O
+better	O
+controlled	O
+regimen	O
+for	O
+administering	O
+vincristine	O
+and	O
+intrathecal	O
+chemotherapy	O
+is	O
+recommended	O
+.	O
+
+Palpebral	B
+twitching	I
+in	O
+a	O
+depressed	B
+adolescent	O
+on	O
+citalopram	O
+.	O
+
+Current	O
+estimates	O
+suggest	O
+that	O
+between	O
+0	O
+.	O
+4	O
+%	O
+and	O
+8	O
+.	O
+3	O
+%	O
+of	O
+children	O
+and	O
+adolescents	O
+are	O
+affected	O
+by	O
+major	B
+depression	I
+.	O
+
+We	O
+report	O
+a	O
+favorable	O
+response	O
+to	O
+treatment	O
+with	O
+citalopram	O
+by	O
+a	O
+15	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+with	O
+major	B
+depression	I
+who	O
+exhibited	O
+palpebral	B
+twitching	I
+during	O
+his	O
+first	O
+2	O
+weeks	O
+of	O
+treatment	O
+.	O
+
+This	O
+may	O
+have	O
+been	O
+a	O
+side	O
+effect	O
+of	O
+citalopram	O
+as	O
+it	O
+remitted	O
+with	O
+redistribution	O
+of	O
+doses	O
+.	O
+
+The	O
+3	O
+-	O
+week	O
+sulphasalazine	O
+syndrome	O
+strikes	O
+again	O
+.	O
+
+A	O
+34	O
+-	O
+year	O
+-	O
+old	O
+lady	O
+developed	O
+a	O
+constellation	O
+of	O
+dermatitis	B
+,	O
+fever	B
+,	O
+lymphadenopathy	B
+and	O
+hepatitis	B
+,	O
+beginning	O
+on	O
+the	O
+17th	O
+day	O
+of	O
+a	O
+course	O
+of	O
+oral	O
+sulphasalazine	O
+for	O
+sero	O
+-	O
+negative	O
+rheumatoid	B
+arthritis	I
+.	O
+
+Cervical	O
+and	O
+inguinal	O
+lymph	O
+node	O
+biopsies	O
+showed	O
+the	O
+features	O
+of	O
+severe	O
+necrotising	O
+lymphadenitis	B
+,	O
+associated	O
+with	O
+erythrophagocytosis	O
+and	O
+prominent	O
+eosinophilic	O
+infiltrates	O
+,	O
+without	O
+viral	O
+inclusion	O
+bodies	O
+,	O
+suggestive	O
+of	O
+an	O
+adverse	B
+drug	I
+reaction	I
+.	O
+A	O
+week	O
+later	O
+,	O
+fulminant	O
+drug	B
+-	I
+induced	I
+hepatitis	I
+,	O
+associated	O
+with	O
+the	O
+presence	O
+of	O
+anti	O
+-	O
+nuclear	O
+autoantibodies	O
+(	O
+but	O
+not	O
+with	O
+other	O
+markers	O
+of	O
+autoimmunity	B
+)	O
+,	O
+and	O
+accompanied	O
+by	O
+multi	B
+-	I
+organ	I
+failure	I
+and	O
+sepsis	B
+,	O
+supervened	O
+.	O
+
+She	O
+subsequently	O
+died	O
+some	O
+5	O
+weeks	O
+after	O
+the	O
+commencement	O
+of	O
+her	O
+drug	O
+therapy	O
+.	O
+Post	O
+-	O
+mortem	O
+examination	O
+showed	O
+evidence	O
+of	O
+massive	B
+hepatocellular	I
+necrosis	I
+,	O
+acute	O
+hypersensitivity	O
+myocarditis	B
+,	O
+focal	O
+acute	O
+tubulo	O
+-	O
+interstitial	O
+nephritis	B
+and	O
+extensive	O
+bone	B
+marrow	I
+necrosis	I
+,	O
+with	O
+no	O
+evidence	O
+of	O
+malignancy	B
+.	O
+
+It	O
+is	O
+thought	O
+that	O
+the	O
+clinico	O
+-	O
+pathological	O
+features	O
+and	O
+chronology	O
+of	O
+this	O
+case	O
+bore	O
+the	O
+hallmarks	O
+of	O
+the	O
+so	O
+-	O
+called	O
+"	O
+3	O
+-	O
+week	O
+sulphasalazine	O
+syndrome	O
+"	O
+,	O
+a	O
+rare	O
+,	O
+but	O
+often	O
+fatal	O
+,	O
+immunoallergic	O
+reaction	O
+to	O
+sulphasalazine	O
+.	O
+
+Intravenous	O
+administration	O
+of	O
+prochlorperazine	O
+by	O
+15	O
+-	O
+minute	O
+infusion	O
+versus	O
+2	O
+-	O
+minute	O
+bolus	O
+does	O
+not	O
+affect	O
+the	O
+incidence	O
+of	O
+akathisia	B
+:	O
+a	O
+prospective	O
+,	O
+randomized	O
+,	O
+controlled	O
+trial	O
+.	O
+
+STUDY	O
+OBJECTIVE	O
+:	O
+We	O
+sought	O
+to	O
+compare	O
+the	O
+rate	O
+of	O
+akathisia	B
+after	O
+administration	O
+of	O
+intravenous	O
+prochlorperazine	O
+as	O
+a	O
+2	O
+-	O
+minute	O
+bolus	O
+or	O
+15	O
+-	O
+minute	O
+infusion	O
+.	O
+
+METHODS	O
+:	O
+We	O
+conducted	O
+a	O
+prospective	O
+,	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+study	O
+in	O
+the	O
+emergency	O
+department	O
+of	O
+a	O
+central	O
+-	O
+city	O
+teaching	O
+hospital	O
+.	O
+
+Patients	O
+aged	O
+18	O
+years	O
+or	O
+older	O
+treated	O
+with	O
+prochlorperazine	O
+for	O
+headache	B
+,	O
+nausea	B
+,	O
+or	O
+vomiting	B
+were	O
+eligible	O
+for	O
+inclusion	O
+.	O
+
+Study	O
+participants	O
+were	O
+randomized	O
+to	O
+receive	O
+10	O
+mg	O
+of	O
+prochlorperazine	O
+administered	O
+intravenously	O
+by	O
+means	O
+of	O
+2	O
+-	O
+minute	O
+push	O
+(	O
+bolus	O
+group	O
+)	O
+or	O
+10	O
+mg	O
+diluted	O
+in	O
+50	O
+mL	O
+of	O
+normal	O
+saline	O
+solution	O
+administered	O
+by	O
+means	O
+of	O
+intravenous	O
+infusion	O
+during	O
+a	O
+15	O
+-	O
+minute	O
+period	O
+(	O
+infusion	O
+group	O
+)	O
+.	O
+
+The	O
+main	O
+outcome	O
+was	O
+the	O
+number	O
+of	O
+study	O
+participants	O
+experiencing	O
+akathisia	B
+within	O
+60	O
+minutes	O
+of	O
+administration	O
+.	O
+
+Akathisia	O
+was	O
+defined	O
+as	O
+either	O
+a	O
+spontaneous	O
+report	O
+of	O
+restlessness	O
+or	O
+agitation	B
+or	O
+a	O
+change	O
+of	O
+2	O
+or	O
+more	O
+in	O
+the	O
+patient	O
+-	O
+reported	O
+akathisia	B
+rating	O
+scale	O
+and	O
+a	O
+change	O
+of	O
+at	O
+least	O
+1	O
+in	O
+the	O
+investigator	O
+-	O
+observed	O
+akathisia	B
+rating	O
+scale	O
+.	O
+
+The	O
+intensity	O
+of	O
+headache	B
+and	O
+nausea	B
+was	O
+measured	O
+with	O
+a	O
+100	O
+-	O
+mm	O
+visual	O
+analog	O
+scale	O
+.	O
+
+RESULTS	O
+:	O
+One	O
+hundred	O
+patients	O
+were	O
+enrolled	O
+.	O
+
+One	O
+study	O
+participant	O
+was	O
+excluded	O
+after	O
+protocol	O
+violation	O
+.	O
+
+Seventy	O
+-	O
+three	O
+percent	O
+(	O
+73	O
+/	O
+99	O
+)	O
+of	O
+the	O
+study	O
+participants	O
+were	O
+treated	O
+for	O
+headache	B
+and	O
+70	O
+%	O
+(	O
+70	O
+/	O
+99	O
+)	O
+for	O
+nausea	B
+.	O
+
+In	O
+the	O
+bolus	O
+group	O
+,	O
+26	O
+.	O
+0	O
+%	O
+(	O
+13	O
+/	O
+50	O
+)	O
+had	O
+akathisia	B
+compared	O
+with	O
+32	O
+.	O
+7	O
+%	O
+(	O
+16	O
+/	O
+49	O
+)	O
+in	O
+the	O
+infusion	O
+group	O
+(	O
+Delta	O
+=	O
+-	O
+6	O
+.	O
+7	O
+%	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+-	O
+24	O
+.	O
+6	O
+%	O
+to	O
+11	O
+.	O
+2	O
+%	O
+)	O
+.	O
+
+The	O
+difference	O
+between	O
+the	O
+bolus	O
+and	O
+infusion	O
+groups	O
+in	O
+the	O
+percentage	O
+of	O
+participants	O
+who	O
+saw	O
+a	O
+50	O
+%	O
+reduction	O
+in	O
+their	O
+headache	B
+intensity	O
+within	O
+30	O
+minutes	O
+was	O
+11	O
+.	O
+8	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+-	O
+9	O
+.	O
+6	O
+%	O
+to	O
+33	O
+.	O
+3	O
+%	O
+)	O
+.	O
+
+The	O
+difference	O
+in	O
+the	O
+percentage	O
+of	O
+patients	O
+with	O
+a	O
+50	O
+%	O
+reduction	O
+in	O
+their	O
+nausea	B
+was	O
+12	O
+.	O
+6	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+-	O
+4	O
+.	O
+6	O
+%	O
+to	O
+29	O
+.	O
+8	O
+%	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+A	O
+50	O
+%	O
+reduction	O
+in	O
+the	O
+incidence	O
+of	O
+akathisia	B
+when	O
+prochlorperazine	O
+was	O
+administered	O
+by	O
+means	O
+of	O
+15	O
+-	O
+minute	O
+intravenous	O
+infusion	O
+versus	O
+a	O
+2	O
+-	O
+minute	O
+intravenous	O
+push	O
+was	O
+not	O
+detected	O
+.	O
+
+The	O
+efficacy	O
+of	O
+prochlorperazine	O
+in	O
+the	O
+treatment	O
+of	O
+headache	B
+and	O
+nausea	B
+likewise	O
+did	O
+not	O
+appear	O
+to	O
+be	O
+affected	O
+by	O
+the	O
+rate	O
+of	O
+administration	O
+,	O
+although	O
+no	O
+formal	O
+statistical	O
+comparisons	O
+were	O
+made	O
+.	O
+
+Combined	O
+antiretroviral	O
+therapy	O
+causes	O
+cardiomyopathy	B
+and	O
+elevates	O
+plasma	O
+lactate	O
+in	O
+transgenic	O
+AIDS	B
+mice	O
+.	O
+
+Highly	O
+active	O
+antiretroviral	O
+therapy	O
+(	O
+HAART	O
+)	O
+is	O
+implicated	O
+in	O
+cardiomyopathy	B
+(	O
+CM	B
+)	O
+and	O
+in	O
+elevated	O
+plasma	O
+lactate	O
+(	O
+LA	O
+)	O
+in	O
+AIDS	B
+through	O
+mechanisms	O
+of	O
+mitochondrial	B
+dysfunction	I
+.	O
+
+To	O
+determine	O
+mitochondrial	O
+events	O
+from	O
+HAART	O
+in	O
+vivo	O
+,	O
+8	O
+-	O
+week	O
+-	O
+old	O
+hemizygous	O
+transgenic	O
+AIDS	B
+mice	O
+(	O
+NL4	O
+-	O
+3Delta	O
+gag	O
+/	O
+pol	O
+;	O
+TG	O
+)	O
+and	O
+wild	O
+-	O
+type	O
+FVB	O
+/	O
+n	O
+littermates	O
+were	O
+treated	O
+with	O
+the	O
+HAART	O
+combination	O
+of	O
+zidovudine	O
+,	O
+lamivudine	O
+,	O
+and	O
+indinavir	O
+or	O
+vehicle	O
+control	O
+for	O
+10	O
+days	O
+or	O
+35	O
+days	O
+.	O
+
+At	O
+termination	O
+of	O
+the	O
+experiments	O
+,	O
+mice	O
+underwent	O
+echocardiography	O
+,	O
+quantitation	O
+of	O
+abundance	O
+of	O
+molecular	O
+markers	O
+of	O
+CM	B
+(	O
+ventricular	O
+mRNA	O
+encoding	O
+atrial	O
+natriuretic	O
+factor	O
+[	O
+ANF	O
+]	O
+and	O
+sarcoplasmic	O
+calcium	O
+ATPase	O
+[	O
+SERCA2	O
+]	O
+)	O
+,	O
+and	O
+determination	O
+of	O
+plasma	O
+LA	O
+.	O
+
+Myocardial	O
+histologic	O
+features	O
+were	O
+analyzed	O
+semiquantitatively	O
+and	O
+results	O
+were	O
+confirmed	O
+by	O
+transmission	O
+electron	O
+microscopy	O
+.	O
+
+After	O
+35	O
+days	O
+in	O
+the	O
+TG	O
++	O
+HAART	O
+cohort	O
+,	O
+left	O
+ventricular	O
+mass	O
+increased	O
+160	O
+%	O
+by	O
+echocardiography	O
+.	O
+
+Molecularly	O
+,	O
+ANF	O
+mRNA	O
+increased	O
+250	O
+%	O
+and	O
+SERCA2	O
+mRNA	O
+decreased	O
+57	O
+%	O
+.	O
+
+Biochemically	O
+,	O
+LA	O
+was	O
+elevated	O
+(	O
+8	O
+.	O
+5	O
++	O
+/	O
+-	O
+2	O
+.	O
+0	O
+mM	O
+)	O
+.	O
+
+Pathologically	O
+,	O
+granular	O
+cytoplasmic	O
+changes	O
+were	O
+found	O
+in	O
+cardiac	O
+myocytes	O
+,	O
+indicating	O
+enlarged	O
+,	O
+damaged	O
+mitochondria	O
+.	O
+
+Findings	O
+were	O
+confirmed	O
+ultrastructurally	O
+.	O
+
+No	O
+changes	O
+were	O
+found	O
+in	O
+other	O
+cohorts	O
+.	O
+
+After	O
+10	O
+days	O
+,	O
+only	O
+ANF	O
+was	O
+elevated	O
+,	O
+and	O
+only	O
+in	O
+the	O
+TG	O
++	O
+HAART	O
+cohort	O
+.	O
+
+Results	O
+show	O
+that	O
+cumulative	O
+HAART	O
+caused	O
+mitochondrial	O
+CM	B
+with	O
+elevated	O
+LA	O
+in	O
+AIDS	B
+transgenic	O
+mice	O
+.	O
+
+A	O
+Phase	O
+II	O
+trial	O
+of	O
+cisplatin	O
+plus	O
+WR	O
+-	O
+2721	O
+(	O
+amifostine	O
+)	O
+for	O
+metastatic	O
+breast	B
+carcinoma	I
+:	O
+an	O
+Eastern	O
+Cooperative	O
+Oncology	O
+Group	O
+Study	O
+(	O
+E8188	O
+)	O
+.	O
+
+BACKGROUND	O
+:	O
+Cisplatin	O
+has	O
+minimal	O
+antitumor	O
+activity	O
+when	O
+used	O
+as	O
+second	O
+-	O
+or	O
+third	O
+-	O
+line	O
+treatment	O
+of	O
+metastatic	O
+breast	B
+carcinoma	I
+.	O
+
+Older	O
+reports	O
+suggest	O
+an	O
+objective	O
+response	O
+rate	O
+of	O
+8	O
+%	O
+when	O
+60	O
+-	O
+120	O
+mg	O
+/	O
+m2	O
+of	O
+cisplatin	O
+is	O
+administered	O
+every	O
+3	O
+-	O
+4	O
+weeks	O
+.	O
+
+Although	O
+a	O
+dose	O
+-	O
+response	O
+effect	O
+has	O
+been	O
+observed	O
+with	O
+cisplatin	O
+,	O
+the	O
+dose	O
+-	O
+limiting	O
+toxicities	B
+associated	O
+with	O
+cisplatin	O
+(	O
+e	O
+.	O
+g	O
+.	O
+,	O
+nephrotoxicity	B
+,	O
+ototoxicity	B
+,	O
+and	O
+neurotoxicity	B
+)	O
+have	O
+limited	O
+its	O
+use	O
+as	O
+a	O
+treatment	O
+for	O
+breast	B
+carcinoma	I
+.	O
+
+WR	O
+-	O
+2721	O
+or	O
+amifostine	O
+initially	O
+was	O
+developed	O
+to	O
+protect	O
+military	O
+personnel	O
+in	O
+the	O
+event	O
+of	O
+nuclear	O
+war	O
+.	O
+
+Amifostine	O
+subsequently	O
+was	O
+shown	O
+to	O
+protect	O
+normal	O
+tissues	O
+from	O
+the	O
+toxic	O
+effects	O
+of	O
+alkylating	O
+agents	O
+and	O
+cisplatin	O
+without	O
+decreasing	O
+the	O
+antitumor	O
+effect	O
+of	O
+the	O
+chemotherapy	O
+.	O
+
+Early	O
+trials	O
+of	O
+cisplatin	O
+and	O
+amifostine	O
+also	O
+suggested	O
+that	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+cisplatin	O
+-	O
+induced	O
+nephrotoxicity	B
+,	O
+ototoxicity	B
+,	O
+and	O
+neuropathy	B
+were	O
+reduced	O
+.	O
+
+METHODS	O
+:	O
+A	O
+Phase	O
+II	O
+study	O
+of	O
+the	O
+combination	O
+of	O
+cisplatin	O
+plus	O
+amifostine	O
+was	O
+conducted	O
+in	O
+patients	O
+with	O
+progressive	O
+metastatic	O
+breast	B
+carcinoma	I
+who	O
+had	O
+received	O
+one	O
+,	O
+but	O
+not	O
+more	O
+than	O
+one	O
+,	O
+chemotherapy	O
+regimen	O
+for	O
+metastatic	O
+disease	O
+.	O
+
+Patients	O
+received	O
+amifostine	O
+,	O
+910	O
+mg	O
+/	O
+m2	O
+intravenously	O
+over	O
+15	O
+minutes	O
+.	O
+
+After	O
+completion	O
+of	O
+the	O
+amifostine	O
+infusion	O
+,	O
+cisplatin	O
+120	O
+mg	O
+/	O
+m2	O
+was	O
+administered	O
+over	O
+30	O
+minutes	O
+.	O
+
+Intravenous	O
+hydration	O
+and	O
+mannitol	O
+was	O
+administered	O
+before	O
+and	O
+after	O
+cisplatin	O
+.	O
+
+Treatment	O
+was	O
+administered	O
+every	O
+3	O
+weeks	O
+until	O
+disease	O
+progression	O
+.	O
+
+RESULTS	O
+:	O
+Forty	O
+-	O
+four	O
+patients	O
+were	O
+enrolled	O
+in	O
+the	O
+study	O
+of	O
+which	O
+7	O
+(	O
+16	O
+%	O
+)	O
+were	O
+ineligible	O
+.	O
+
+A	O
+median	O
+of	O
+2	O
+cycles	O
+of	O
+therapy	O
+was	O
+administered	O
+to	O
+the	O
+37	O
+eligible	O
+patients	O
+.	O
+
+Six	O
+partial	O
+responses	O
+were	O
+observed	O
+for	O
+an	O
+overall	O
+response	O
+rate	O
+of	O
+16	O
+%	O
+.	O
+
+Most	O
+patients	O
+(	O
+57	O
+%	O
+)	O
+stopped	O
+treatment	O
+because	O
+of	O
+disease	O
+progression	O
+.	O
+
+Neurologic	B
+toxicity	I
+was	O
+reported	O
+in	O
+52	O
+%	O
+of	O
+patients	O
+.	O
+
+Seven	O
+different	O
+life	O
+-	O
+threatening	O
+toxicities	B
+were	O
+observed	O
+in	O
+patients	O
+while	O
+receiving	O
+treatment	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+combination	O
+of	O
+cisplatin	O
+and	O
+amifostine	O
+in	O
+this	O
+study	O
+resulted	O
+in	O
+an	O
+overall	O
+response	O
+rate	O
+of	O
+16	O
+%	O
+.	O
+
+Neither	O
+a	O
+tumor	B
+-	O
+protective	O
+effect	O
+nor	O
+reduced	O
+toxicity	B
+to	O
+normal	O
+tissues	O
+was	O
+observed	O
+with	O
+the	O
+addition	O
+of	O
+amifostine	O
+to	O
+cisplatin	O
+in	O
+this	O
+trial	O
+.	O
+
+Oral	O
+contraceptives	O
+and	O
+the	O
+risk	O
+of	O
+myocardial	B
+infarction	I
+.	O
+
+BACKGROUND	O
+:	O
+An	O
+association	O
+between	O
+the	O
+use	O
+of	O
+oral	O
+contraceptives	O
+and	O
+the	O
+risk	O
+of	O
+myocardial	B
+infarction	I
+has	O
+been	O
+found	O
+in	O
+some	O
+,	O
+but	O
+not	O
+all	O
+,	O
+studies	O
+.	O
+
+We	O
+investigated	O
+this	O
+association	O
+,	O
+according	O
+to	O
+the	O
+type	O
+of	O
+progestagen	O
+included	O
+in	O
+third	O
+-	O
+generation	O
+(	O
+i	O
+.	O
+e	O
+.	O
+,	O
+desogestrel	O
+or	O
+gestodene	O
+)	O
+and	O
+second	O
+-	O
+generation	O
+(	O
+i	O
+.	O
+e	O
+.	O
+,	O
+levonorgestrel	O
+)	O
+oral	O
+contraceptives	O
+,	O
+the	O
+dose	O
+of	O
+estrogen	O
+,	O
+and	O
+the	O
+presence	O
+or	O
+absence	O
+of	O
+prothrombotic	O
+mutations	O
+METHODS	O
+:	O
+In	O
+a	O
+nationwide	O
+,	O
+population	O
+-	O
+based	O
+,	O
+case	O
+-	O
+control	O
+study	O
+,	O
+we	O
+identified	O
+and	O
+enrolled	O
+248	O
+women	O
+18	O
+through	O
+49	O
+years	O
+of	O
+age	O
+who	O
+had	O
+had	O
+a	O
+first	O
+myocardial	B
+infarction	I
+between	O
+1990	O
+and	O
+1995	O
+and	O
+925	O
+control	O
+women	O
+who	O
+had	O
+not	O
+had	O
+a	O
+myocardial	B
+infarction	I
+and	O
+who	O
+were	O
+matched	O
+for	O
+age	O
+,	O
+calendar	O
+year	O
+of	O
+the	O
+index	O
+event	O
+,	O
+and	O
+area	O
+of	O
+residence	O
+.	O
+
+Subjects	O
+supplied	O
+information	O
+on	O
+oral	O
+-	O
+contraceptive	O
+use	O
+and	O
+major	O
+cardiovascular	O
+risk	O
+factors	O
+.	O
+
+An	O
+analysis	O
+for	O
+factor	O
+V	O
+Leiden	O
+and	O
+the	O
+G20210A	O
+mutation	O
+in	O
+the	O
+prothrombin	O
+gene	O
+was	O
+conducted	O
+in	O
+217	O
+patients	O
+and	O
+763	O
+controls	O
+RESULTS	O
+:	O
+The	O
+odds	O
+ratio	O
+for	O
+myocardial	B
+infarction	I
+among	O
+women	O
+who	O
+used	O
+any	O
+type	O
+of	O
+combined	O
+oral	O
+contraceptive	O
+,	O
+as	O
+compared	O
+with	O
+nonusers	O
+,	O
+was	O
+2	O
+.	O
+0	O
+(	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+1	O
+.	O
+5	O
+to	O
+2	O
+.	O
+8	O
+)	O
+.	O
+
+The	O
+adjusted	O
+odds	O
+ratio	O
+was	O
+2	O
+.	O
+5	O
+(	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+1	O
+.	O
+5	O
+to	O
+4	O
+.	O
+1	O
+)	O
+among	O
+women	O
+who	O
+used	O
+second	O
+-	O
+generation	O
+oral	O
+contraceptives	O
+and	O
+1	O
+.	O
+3	O
+(	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+0	O
+.	O
+7	O
+to	O
+2	O
+.	O
+5	O
+)	O
+among	O
+those	O
+who	O
+used	O
+third	O
+-	O
+generation	O
+oral	O
+contraceptives	O
+.	O
+
+Among	O
+women	O
+who	O
+used	O
+oral	O
+contraceptives	O
+,	O
+the	O
+odds	O
+ratio	O
+was	O
+2	O
+.	O
+1	O
+(	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+1	O
+.	O
+5	O
+to	O
+3	O
+.	O
+0	O
+)	O
+for	O
+those	O
+without	O
+a	O
+prothrombotic	O
+mutation	O
+and	O
+1	O
+.	O
+9	O
+(	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+0	O
+.	O
+6	O
+to	O
+5	O
+.	O
+5	O
+)	O
+for	O
+those	O
+with	O
+a	O
+mutation	O
+CONCLUSIONS	O
+:	O
+The	O
+risk	O
+of	O
+myocardial	B
+infarction	I
+was	O
+increased	O
+among	O
+women	O
+who	O
+used	O
+second	O
+-	O
+generation	O
+oral	O
+contraceptives	O
+.	O
+
+The	O
+results	O
+with	O
+respect	O
+to	O
+the	O
+use	O
+of	O
+third	O
+-	O
+generation	O
+oral	O
+contraceptives	O
+were	O
+inconclusive	O
+but	O
+suggested	O
+that	O
+the	O
+risk	O
+was	O
+lower	O
+than	O
+the	O
+risk	O
+associated	O
+with	O
+second	O
+-	O
+generation	O
+oral	O
+contraceptives	O
+.	O
+
+The	O
+risk	O
+of	O
+myocardial	B
+infarction	I
+was	O
+similar	O
+among	O
+women	O
+who	O
+used	O
+oral	O
+contraceptives	O
+whether	O
+or	O
+not	O
+they	O
+had	O
+a	O
+prothrombotic	O
+mutation	O
+.	O
+
+End	B
+-	I
+stage	I
+renal	I
+disease	I
+(	O
+ESRD	B
+)	O
+after	O
+orthotopic	O
+liver	O
+transplantation	O
+(	O
+OLTX	O
+)	O
+using	O
+calcineurin	O
+-	O
+based	O
+immunotherapy	O
+:	O
+risk	O
+of	O
+development	O
+and	O
+treatment	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+calcineurin	O
+inhibitors	O
+cyclosporine	O
+and	O
+tacrolimus	O
+are	O
+both	O
+known	O
+to	O
+be	O
+nephrotoxic	B
+.	O
+
+Their	O
+use	O
+in	O
+orthotopic	O
+liver	O
+transplantation	O
+(	O
+OLTX	O
+)	O
+has	O
+dramatically	O
+improved	O
+success	O
+rates	O
+.	O
+
+Recently	O
+,	O
+however	O
+,	O
+we	O
+have	O
+had	O
+an	O
+increase	O
+of	O
+patients	O
+who	O
+are	O
+presenting	O
+after	O
+OLTX	O
+with	O
+end	B
+-	I
+stage	I
+renal	I
+disease	I
+(	O
+ESRD	B
+)	O
+.	O
+
+This	O
+retrospective	O
+study	O
+examines	O
+the	O
+incidence	O
+and	O
+treatment	O
+of	O
+ESRD	B
+and	O
+chronic	B
+renal	I
+failure	I
+(	O
+CRF	B
+)	O
+in	O
+OLTX	O
+patients	O
+.	O
+
+METHODS	O
+:	O
+Patients	O
+receiving	O
+an	O
+OLTX	O
+only	O
+from	O
+June	O
+1985	O
+through	O
+December	O
+of	O
+1994	O
+who	O
+survived	O
+6	O
+months	O
+postoperatively	O
+were	O
+studied	O
+(	O
+n	O
+=	O
+834	O
+)	O
+.	O
+
+Our	O
+prospectively	O
+collected	O
+database	O
+was	O
+the	O
+source	O
+of	O
+information	O
+.	O
+
+Patients	O
+were	O
+divided	O
+into	O
+three	O
+groups	O
+:	O
+Controls	O
+,	O
+no	O
+CRF	B
+or	O
+ESRD	B
+,	O
+n	O
+=	O
+748	O
+;	O
+CRF	B
+,	O
+sustained	O
+serum	O
+creatinine	O
+>	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+dl	O
+,	O
+n	O
+=	O
+41	O
+;	O
+and	O
+ESRD	B
+,	O
+n	O
+=	O
+45	O
+.	O
+
+Groups	O
+were	O
+compared	O
+for	O
+preoperative	O
+laboratory	O
+variables	O
+,	O
+diagnosis	O
+,	O
+postoperative	O
+variables	O
+,	O
+survival	O
+,	O
+type	O
+of	O
+ESRD	B
+therapy	O
+,	O
+and	O
+survival	O
+from	O
+onset	O
+of	O
+ESRD	B
+.	O
+
+RESULTS	O
+:	O
+At	O
+13	O
+years	O
+after	O
+OLTX	O
+,	O
+the	O
+incidence	O
+of	O
+severe	O
+renal	B
+dysfunction	I
+was	O
+18	O
+.	O
+1	O
+%	O
+(	O
+CRF	B
+8	O
+.	O
+6	O
+%	O
+and	O
+ESRD	B
+9	O
+.	O
+5	O
+%	O
+)	O
+.	O
+
+Compared	O
+with	O
+control	O
+patients	O
+,	O
+CRF	B
+and	O
+ESRD	B
+patients	O
+had	O
+higher	O
+preoperative	O
+serum	O
+creatinine	O
+levels	O
+,	O
+a	O
+greater	O
+percentage	O
+of	O
+patients	O
+with	O
+hepatorenal	B
+syndrome	I
+,	O
+higher	O
+percentage	O
+requirement	O
+for	O
+dialysis	O
+in	O
+the	O
+first	O
+3	O
+months	O
+postoperatively	O
+,	O
+and	O
+a	O
+higher	O
+1	O
+-	O
+year	O
+serum	O
+creatinine	O
+.	O
+
+Multivariate	O
+stepwise	O
+logistic	O
+regression	O
+analysis	O
+using	O
+preoperative	O
+and	O
+postoperative	O
+variables	O
+identified	O
+that	O
+an	O
+increase	O
+of	O
+serum	O
+creatinine	O
+compared	O
+with	O
+average	O
+at	O
+1	O
+year	O
+,	O
+3	O
+months	O
+,	O
+and	O
+4	O
+weeks	O
+postoperatively	O
+were	O
+independent	O
+risk	O
+factors	O
+for	O
+the	O
+development	O
+of	O
+CRF	B
+or	O
+ESRD	B
+with	O
+odds	O
+ratios	O
+of	O
+2	O
+.	O
+6	O
+,	O
+2	O
+.	O
+2	O
+,	O
+and	O
+1	O
+.	O
+6	O
+,	O
+respectively	O
+.	O
+
+Overall	O
+survival	O
+from	O
+the	O
+time	O
+of	O
+OLTX	O
+was	O
+not	O
+significantly	O
+different	O
+among	O
+groups	O
+,	O
+but	O
+by	O
+year	O
+13	O
+,	O
+the	O
+survival	O
+of	O
+the	O
+patients	O
+who	O
+had	O
+ESRD	B
+was	O
+only	O
+28	O
+.	O
+2	O
+%	O
+compared	O
+with	O
+54	O
+.	O
+6	O
+%	O
+in	O
+the	O
+control	O
+group	O
+.	O
+
+Patients	O
+developing	O
+ESRD	B
+had	O
+a	O
+6	O
+-	O
+year	O
+survival	O
+after	O
+onset	O
+of	O
+ESRD	B
+of	O
+27	O
+%	O
+for	O
+the	O
+patients	O
+receiving	O
+hemodialysis	O
+versus	O
+71	O
+.	O
+4	O
+%	O
+for	O
+the	O
+patients	O
+developing	O
+ESRD	B
+who	O
+subsequently	O
+received	O
+kidney	O
+transplants	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Patients	O
+who	O
+are	O
+more	O
+than	O
+10	O
+years	O
+post	O
+-	O
+OLTX	O
+have	O
+CRF	B
+and	O
+ESRD	B
+at	O
+a	O
+high	O
+rate	O
+.	O
+
+The	O
+development	O
+of	O
+ESRD	B
+decreases	O
+survival	O
+,	O
+particularly	O
+in	O
+those	O
+patients	O
+treated	O
+with	O
+dialysis	O
+only	O
+.	O
+
+Patients	O
+who	O
+develop	O
+ESRD	B
+have	O
+a	O
+higher	O
+preoperative	O
+and	O
+1	O
+-	O
+year	O
+serum	O
+creatinine	O
+and	O
+are	O
+more	O
+likely	O
+to	O
+have	O
+hepatorenal	B
+syndrome	I
+.	O
+
+However	O
+,	O
+an	O
+increase	O
+of	O
+serum	O
+creatinine	O
+at	O
+various	O
+times	O
+postoperatively	O
+is	O
+more	O
+predictive	O
+of	O
+the	O
+development	O
+of	O
+CRF	B
+or	O
+ESRD	B
+.	O
+
+New	O
+strategies	O
+for	O
+long	O
+-	O
+term	O
+immunosuppression	O
+may	O
+be	O
+needed	O
+to	O
+decrease	O
+this	O
+complication	O
+.	O
+
+Epileptic	B
+seizures	I
+following	O
+cortical	O
+application	O
+of	O
+fibrin	O
+sealants	O
+containing	O
+tranexamic	O
+acid	O
+in	O
+rats	O
+.	O
+
+BACKGROUND	O
+:	O
+Fibrin	O
+sealants	O
+(	O
+FS	O
+)	O
+derived	O
+from	O
+human	O
+plasma	O
+are	O
+frequently	O
+used	O
+in	O
+neurosurgery	O
+.	O
+
+In	O
+order	O
+to	O
+increase	O
+clot	O
+stability	O
+,	O
+FS	O
+typically	O
+contain	O
+aprotinin	O
+,	O
+a	O
+natural	O
+fibrinolysis	O
+inhibitor	O
+.	O
+
+Recently	O
+,	O
+synthetic	O
+fibrinolysis	O
+inhibitors	O
+such	O
+as	O
+tranexamic	O
+acid	O
+(	O
+tAMCA	O
+)	O
+have	O
+been	O
+considered	O
+as	O
+substitutes	O
+for	O
+aprotinin	O
+.	O
+
+However	O
+,	O
+tAMCA	O
+has	O
+been	O
+shown	O
+to	O
+cause	O
+epileptic	B
+seizures	I
+.	O
+
+We	O
+wanted	O
+to	O
+study	O
+whether	O
+tAMCA	O
+retains	O
+its	O
+convulsive	B
+action	O
+if	O
+incorporated	O
+into	O
+a	O
+FS	O
+.	O
+
+METHOD	O
+:	O
+FS	O
+containing	O
+aprotinin	O
+or	O
+different	O
+concentrations	O
+of	O
+tAMCA	O
+(	O
+0	O
+.	O
+5	O
+-	O
+47	O
+.	O
+5	O
+mg	O
+/	O
+ml	O
+)	O
+were	O
+applied	O
+to	O
+the	O
+pial	O
+surface	O
+of	O
+the	O
+cortex	O
+of	O
+anaesthetized	O
+rats	O
+.	O
+
+The	O
+response	O
+of	O
+the	O
+animals	O
+was	O
+evaluated	O
+using	O
+electroencephalography	O
+and	O
+by	O
+monitoring	O
+the	O
+clinical	O
+behaviour	O
+during	O
+and	O
+after	O
+recovery	O
+from	O
+anaesthesia	O
+.	O
+
+FINDINGS	O
+:	O
+FS	O
+containing	O
+tAMCA	O
+caused	O
+paroxysmal	O
+brain	O
+activity	O
+which	O
+was	O
+associated	O
+with	O
+distinct	O
+convulsive	B
+behaviours	O
+.	O
+
+The	O
+degree	O
+of	O
+these	O
+seizures	B
+increased	O
+with	O
+increasing	O
+concentration	O
+of	O
+tAMCA	O
+.	O
+
+Thus	O
+,	O
+FS	O
+containing	O
+47	O
+.	O
+5	O
+mg	O
+/	O
+ml	O
+tAMCA	O
+evoked	O
+generalized	B
+seizures	I
+in	O
+all	O
+tested	O
+rats	O
+(	O
+n	O
+=	O
+6	O
+)	O
+while	O
+the	O
+lowest	O
+concentration	O
+of	O
+tAMCA	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+ml	O
+)	O
+only	O
+evoked	O
+brief	O
+episodes	O
+of	O
+jerk	O
+-	O
+correlated	O
+convulsive	B
+potentials	O
+in	O
+1	O
+of	O
+6	O
+rats	O
+.	O
+
+In	O
+contrast	O
+,	O
+FS	O
+containing	O
+aprotinin	O
+did	O
+not	O
+evoke	O
+any	O
+paroxysmal	O
+activity	O
+.	O
+
+INTERPRETATION	O
+:	O
+Tranexamic	O
+acid	O
+retains	O
+its	O
+convulsive	B
+action	O
+within	O
+FS	O
+.	O
+
+Thus	O
+,	O
+use	O
+of	O
+FS	O
+containing	O
+tAMCA	O
+for	O
+surgery	O
+within	O
+or	O
+close	O
+to	O
+the	O
+CNS	O
+may	O
+pose	O
+a	O
+substantial	O
+risk	O
+to	O
+the	O
+patient	O
+.	O
+
+Sequential	O
+observations	O
+of	O
+exencephaly	B
+and	O
+subsequent	O
+morphological	O
+changes	O
+by	O
+mouse	O
+exo	O
+utero	O
+development	O
+system	O
+:	O
+analysis	O
+of	O
+the	O
+mechanism	O
+of	O
+transformation	O
+from	O
+exencephaly	B
+to	O
+anencephaly	B
+.	O
+
+Anencephaly	B
+has	O
+been	O
+suggested	O
+to	O
+develop	O
+from	O
+exencephaly	B
+;	O
+however	O
+,	O
+there	O
+is	O
+little	O
+direct	O
+experimental	O
+evidence	O
+to	O
+support	O
+this	O
+,	O
+and	O
+the	O
+mechanism	O
+of	O
+transformation	O
+remains	O
+unclear	O
+.	O
+
+We	O
+examined	O
+this	O
+theory	O
+using	O
+the	O
+exo	O
+utero	O
+development	O
+system	O
+that	O
+allows	O
+direct	O
+and	O
+sequential	O
+observations	O
+of	O
+mid	O
+-	O
+to	O
+late	O
+-	O
+gestation	O
+mouse	O
+embryos	O
+.	O
+
+We	O
+observed	O
+the	O
+exencephaly	B
+induced	O
+by	O
+5	O
+-	O
+azacytidine	O
+at	O
+embryonic	O
+day	O
+13	O
+.	O
+5	O
+(	O
+E13	O
+.	O
+5	O
+)	O
+,	O
+let	O
+the	O
+embryos	O
+develop	O
+exo	O
+utero	O
+until	O
+E18	O
+.	O
+5	O
+,	O
+and	O
+re	O
+-	O
+observed	O
+the	O
+same	O
+embryos	O
+at	O
+E18	O
+.	O
+5	O
+.	O
+
+We	O
+confirmed	O
+several	O
+cases	O
+of	O
+transformation	O
+from	O
+exencephaly	B
+to	O
+anencephaly	B
+.	O
+
+However	O
+,	O
+in	O
+many	O
+cases	O
+,	O
+the	O
+exencephalic	B
+brain	O
+tissue	O
+was	O
+preserved	O
+with	O
+more	O
+or	O
+less	O
+reduction	O
+during	O
+this	O
+period	O
+.	O
+
+To	O
+analyze	O
+the	O
+transformation	O
+patterns	O
+,	O
+we	O
+classified	O
+the	O
+exencephaly	B
+by	O
+size	O
+and	O
+shape	O
+of	O
+the	O
+exencephalic	B
+tissue	O
+into	O
+several	O
+types	O
+at	O
+E13	O
+.	O
+5	O
+and	O
+E18	O
+.	O
+5	O
+.	O
+
+It	O
+was	O
+found	O
+that	O
+the	O
+transformation	O
+of	O
+exencephalic	B
+tissue	O
+was	O
+not	O
+simply	O
+size	O
+-	O
+dependent	O
+,	O
+and	O
+all	O
+cases	O
+of	O
+anencephaly	B
+at	O
+E18	O
+.	O
+5	O
+resulted	O
+from	O
+embryos	O
+with	O
+a	O
+large	O
+amount	O
+of	O
+exencephalic	B
+tissue	O
+at	O
+E13	O
+.	O
+5	O
+.	O
+
+Microscopic	O
+observation	O
+showed	O
+the	O
+configuration	O
+of	O
+exencephaly	B
+at	O
+E13	O
+.	O
+5	O
+,	O
+frequent	O
+hemorrhaging	B
+and	O
+detachment	O
+of	O
+the	O
+neural	O
+plate	O
+from	O
+surface	O
+ectoderm	O
+in	O
+the	O
+exencephalic	B
+head	O
+at	O
+E15	O
+.	O
+5	O
+,	O
+and	O
+multiple	O
+modes	O
+of	O
+reduction	O
+in	O
+the	O
+exencephalic	B
+tissue	O
+at	O
+E18	O
+.	O
+5	O
+.	O
+
+From	O
+observations	O
+of	O
+the	O
+vasculature	O
+,	O
+altered	O
+distribution	O
+patterns	O
+of	O
+vessels	O
+were	O
+identified	O
+in	O
+the	O
+exencephalic	B
+head	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+overgrowth	O
+of	O
+the	O
+exencephalic	B
+neural	O
+tissue	O
+causes	O
+the	O
+altered	O
+distribution	O
+patterns	O
+of	O
+vessels	O
+,	O
+subsequent	O
+peripheral	O
+circulatory	B
+failure	I
+and	O
+/	O
+or	O
+hemorrhaging	B
+in	O
+various	O
+parts	O
+of	O
+the	O
+exencephalic	B
+head	O
+,	O
+leading	O
+to	O
+the	O
+multiple	O
+modes	O
+of	O
+tissue	O
+reduction	O
+during	O
+transformation	O
+from	O
+exencephaly	B
+to	O
+anencephaly	B
+.	O
+
+99mTc	O
+-	O
+glucarate	O
+for	O
+detection	O
+of	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+in	O
+rats	O
+.	O
+
+Infarct	B
+-	O
+avid	O
+radiopharmaceuticals	O
+are	O
+necessary	O
+for	O
+rapid	O
+and	O
+timely	O
+diagnosis	O
+of	O
+acute	O
+myocardial	B
+infarction	I
+.	O
+
+The	O
+animal	O
+model	O
+used	O
+to	O
+produce	O
+infarction	B
+implies	O
+artery	O
+ligation	O
+but	O
+chemical	O
+induction	O
+can	O
+be	O
+easily	O
+obtained	O
+with	O
+isoproterenol	O
+.	O
+
+A	O
+new	O
+infarct	B
+-	O
+avid	O
+radiopharmaceutical	O
+based	O
+on	O
+glucaric	O
+acid	O
+was	O
+prepared	O
+in	O
+the	O
+hospital	O
+radiopharmacy	O
+of	O
+the	O
+INCMNSZ	O
+.	O
+
+99mTc	O
+-	O
+glucarate	O
+was	O
+easy	O
+to	O
+prepare	O
+,	O
+stable	O
+for	O
+96	O
+h	O
+and	O
+was	O
+used	O
+to	O
+study	O
+its	O
+biodistribution	O
+in	O
+rats	O
+with	O
+isoproterenol	O
+-	O
+induced	O
+acute	O
+myocardial	B
+infarction	I
+.	O
+
+Histological	O
+studies	O
+demonstrated	O
+that	O
+the	O
+rats	O
+developed	O
+an	O
+infarct	B
+18	O
+h	O
+after	O
+isoproterenol	O
+administration	O
+.	O
+
+The	O
+rat	O
+biodistribution	O
+studies	O
+showed	O
+a	O
+rapid	O
+blood	O
+clearance	O
+via	O
+the	O
+kidneys	O
+.	O
+
+Thirty	O
+minutes	O
+after	O
+99mTc	O
+-	O
+glucarate	O
+administration	O
+the	O
+standardised	O
+heart	O
+uptake	O
+value	O
+S	O
+(	O
+h	O
+)	O
+UV	O
+was	O
+4	O
+.	O
+7	O
+in	O
+infarcted	O
+rat	O
+heart	O
+which	O
+is	O
+six	O
+times	O
+more	O
+than	O
+in	O
+normal	O
+rats	O
+.	O
+
+ROIs	O
+drawn	O
+over	O
+the	O
+gamma	O
+camera	O
+images	O
+showed	O
+a	O
+ratio	O
+of	O
+4	O
+.	O
+4	O
+.	O
+
+The	O
+high	O
+image	O
+quality	O
+suggests	O
+that	O
+high	O
+contrast	O
+images	O
+can	O
+be	O
+obtained	O
+in	O
+humans	O
+and	O
+the	O
+96	O
+h	O
+stability	O
+makes	O
+it	O
+an	O
+ideal	O
+agent	O
+to	O
+detect	O
+,	O
+in	O
+patients	O
+,	O
+early	O
+cardiac	B
+infarction	I
+.	O
+
+Bupropion	O
+(	O
+Zyban	O
+)	O
+toxicity	B
+.	O
+
+Bupropion	O
+is	O
+a	O
+monocyclic	O
+antidepressant	O
+structurally	O
+related	O
+to	O
+amphetamine	O
+.	O
+
+Zyban	O
+,	O
+a	O
+sustained	O
+-	O
+release	O
+formulation	O
+of	O
+bupropion	O
+hydrochloride	O
+,	O
+was	O
+recently	O
+released	O
+in	O
+Ireland	O
+,	O
+as	O
+a	O
+smoking	O
+cessation	O
+aid	O
+.	O
+
+In	O
+the	O
+initial	O
+6	O
+months	O
+since	O
+it	O
+'	O
+s	O
+introduction	O
+,	O
+12	O
+overdose	B
+cases	O
+have	O
+been	O
+reported	O
+to	O
+The	O
+National	O
+Poisons	O
+Information	O
+Centre	O
+.	O
+
+8	O
+patients	O
+developed	O
+symptoms	O
+of	O
+toxicity	B
+.	O
+
+Common	O
+features	O
+included	O
+tachycardia	B
+,	O
+drowsiness	O
+,	O
+hallucinations	B
+and	O
+convulsions	B
+.	O
+
+Two	O
+patients	O
+developed	O
+severe	O
+cardiac	B
+arrhythmias	I
+,	O
+including	O
+one	O
+patient	O
+who	O
+was	O
+resuscitated	O
+following	O
+a	O
+cardiac	B
+arrest	I
+.	O
+
+All	O
+patients	O
+recovered	O
+without	O
+sequelae	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+a	O
+31	O
+year	O
+old	O
+female	O
+who	O
+required	O
+admission	O
+to	O
+the	O
+Intensive	O
+Care	O
+Unit	O
+for	O
+ventilation	O
+and	O
+full	O
+supportive	O
+therapy	O
+,	O
+following	O
+ingestion	O
+of	O
+13	O
+.	O
+5g	O
+bupropion	O
+.	O
+
+Recurrent	O
+seizures	B
+were	O
+treated	O
+with	O
+diazepam	O
+and	O
+broad	O
+complex	O
+tachycardia	B
+was	O
+successfully	O
+treated	O
+with	O
+adenosine	O
+.	O
+
+Zyban	O
+caused	O
+significant	O
+neurological	B
+and	I
+cardiovascular	I
+toxicity	I
+in	O
+overdose	B
+.	O
+
+The	O
+potential	O
+toxic	O
+effects	O
+should	O
+be	O
+considered	O
+when	O
+prescribing	O
+it	O
+as	O
+a	O
+smoking	O
+cessation	O
+aid	O
+.	O
+
+GLEPP1	O
+receptor	O
+tyrosine	O
+phosphatase	O
+(	O
+Ptpro	O
+)	O
+in	O
+rat	O
+PAN	O
+nephrosis	B
+.	O
+
+A	O
+marker	O
+of	O
+acute	O
+podocyte	O
+injury	O
+.	O
+
+Glomerular	O
+epithelial	O
+protein	O
+1	O
+(	O
+GLEPP1	O
+)	O
+is	O
+a	O
+podocyte	O
+receptor	O
+membrane	O
+protein	O
+tyrosine	O
+phosphatase	O
+located	O
+on	O
+the	O
+apical	O
+cell	O
+membrane	O
+of	O
+visceral	O
+glomerular	O
+epithelial	O
+cell	O
+and	O
+foot	O
+processes	O
+.	O
+
+This	O
+receptor	O
+plays	O
+a	O
+role	O
+in	O
+regulating	O
+the	O
+structure	O
+and	O
+function	O
+of	O
+podocyte	O
+foot	O
+process	O
+.	O
+
+To	O
+better	O
+understand	O
+the	O
+utility	O
+of	O
+GLEPP1	O
+as	O
+a	O
+marker	O
+of	O
+glomerular	B
+injury	I
+,	O
+the	O
+amount	O
+and	O
+distribution	O
+of	O
+GLEPP1	O
+protein	O
+and	O
+mRNA	O
+were	O
+examined	O
+by	O
+immunohistochemistry	O
+,	O
+Western	O
+blot	O
+and	O
+RNase	O
+protection	O
+assay	O
+in	O
+a	O
+model	O
+of	O
+podocyte	O
+injury	O
+in	O
+the	O
+rat	O
+.	O
+
+Puromycin	O
+aminonucleoside	O
+nephrosis	B
+was	O
+induced	O
+by	O
+single	O
+intraperitoneal	O
+injection	O
+of	O
+puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+,	O
+20	O
+mg	O
+/	O
+100g	O
+BW	O
+)	O
+.	O
+
+Tissues	O
+were	O
+analyzed	O
+at	O
+0	O
+,	O
+5	O
+,	O
+7	O
+,	O
+11	O
+,	O
+21	O
+,	O
+45	O
+,	O
+80	O
+and	O
+126	O
+days	O
+after	O
+PAN	O
+injection	O
+so	O
+as	O
+to	O
+include	O
+both	O
+the	O
+acute	O
+phase	O
+of	O
+proteinuria	B
+associated	O
+with	O
+foot	O
+process	O
+effacement	O
+(	O
+days	O
+5	O
+-	O
+11	O
+)	O
+and	O
+the	O
+chronic	O
+phase	O
+of	O
+proteinuria	B
+associated	O
+with	O
+glomerulosclerosis	B
+(	O
+days	O
+45	O
+-	O
+126	O
+)	O
+.	O
+
+At	O
+day	O
+5	O
+,	O
+GLEPP1	O
+protein	O
+and	O
+mRNA	O
+were	O
+reduced	O
+from	O
+the	O
+normal	O
+range	O
+(	O
+265	O
+.	O
+2	O
++	O
+/	O
+-	O
+79	O
+.	O
+6	O
+x	O
+10	O
+(	O
+6	O
+)	O
+moles	O
+/	O
+glomerulus	O
+and	O
+100	O
+%	O
+)	O
+to	O
+15	O
+%	O
+of	O
+normal	O
+(	O
+41	O
+.	O
+8	O
++	O
+/	O
+-	O
+4	O
+.	O
+8	O
+x	O
+10	O
+(	O
+6	O
+)	O
+moles	O
+/	O
+glomerulus	O
+,	O
+p	O
+<	O
+0	O
+.	O
+005	O
+)	O
+.	O
+
+This	O
+occurred	O
+in	O
+association	O
+with	O
+an	O
+increase	O
+in	O
+urinary	O
+protein	O
+content	O
+from	O
+1	O
+.	O
+8	O
++	O
+/	O
+-	O
+1	O
+to	O
+99	O
+.	O
+0	O
++	O
+/	O
+-	O
+61	O
+mg	O
+/	O
+day	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+In	O
+contrast	O
+,	O
+podocalyxin	O
+did	O
+not	O
+change	O
+significantly	O
+at	O
+this	O
+time	O
+.	O
+
+By	O
+day	O
+11	O
+,	O
+GLEPP1	O
+protein	O
+and	O
+mRNA	O
+had	O
+begun	O
+to	O
+return	O
+towards	O
+baseline	O
+.	O
+
+By	O
+day	O
+45	O
+-	O
+126	O
+,	O
+at	O
+a	O
+time	O
+when	O
+glomerular	O
+scarring	O
+was	O
+present	O
+,	O
+GLEPP1	O
+was	O
+absent	O
+from	O
+glomerulosclerotic	O
+areas	O
+although	O
+the	O
+total	O
+glomerular	O
+content	O
+of	O
+GLEPP1	O
+was	O
+not	O
+different	O
+from	O
+normal	O
+.	O
+
+We	O
+conclude	O
+that	O
+GLEPP1	O
+expression	O
+,	O
+unlike	O
+podocalyxin	O
+,	O
+reflects	O
+podocyte	O
+injury	O
+induced	O
+by	O
+PAN	O
+.	O
+
+GLEPP1	O
+expression	O
+may	O
+be	O
+a	O
+useful	O
+marker	O
+of	O
+podocyte	O
+injury	O
+.	O
+
+Antithymocyte	O
+globulin	O
+in	O
+the	O
+treatment	O
+of	O
+D	O
+-	O
+penicillamine	O
+-	O
+induced	O
+aplastic	B
+anemia	I
+.	O
+
+A	O
+patient	O
+who	O
+received	O
+antithymocyte	O
+globulin	O
+therapy	O
+for	O
+aplastic	B
+anemia	I
+due	O
+to	O
+D	O
+-	O
+penicillamine	O
+therapy	O
+is	O
+described	O
+.	O
+
+Bone	O
+marrow	O
+recovery	O
+and	O
+peripheral	O
+blood	O
+recovery	O
+were	O
+complete	O
+1	O
+month	O
+and	O
+3	O
+months	O
+,	O
+respectively	O
+,	O
+after	O
+treatment	O
+,	O
+and	O
+blood	O
+transfusion	O
+or	O
+other	O
+therapies	O
+were	O
+not	O
+necessary	O
+in	O
+a	O
+follow	O
+-	O
+up	O
+period	O
+of	O
+more	O
+than	O
+2	O
+years	O
+.	O
+
+Use	O
+of	O
+antithymocyte	O
+globulin	O
+may	O
+be	O
+the	O
+optimal	O
+treatment	O
+of	O
+D	O
+-	O
+penicillamine	O
+-	O
+induced	O
+aplastic	B
+anemia	I
+.	O
+
+Metamizol	O
+potentiates	O
+morphine	O
+antinociception	O
+but	O
+not	O
+constipation	B
+after	O
+chronic	O
+treatment	O
+.	O
+
+This	O
+work	O
+evaluates	O
+the	O
+antinociceptive	O
+and	O
+constipating	B
+effects	O
+of	O
+the	O
+combination	O
+of	O
+3	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+morphine	O
+with	O
+177	O
+.	O
+8	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+metamizol	O
+in	O
+acutely	O
+and	O
+chronically	O
+treated	O
+(	O
+once	O
+a	O
+day	O
+for	O
+12	O
+days	O
+)	O
+rats	O
+.	O
+
+On	O
+the	O
+13th	O
+day	O
+,	O
+antinociceptive	O
+effects	O
+were	O
+assessed	O
+using	O
+a	O
+model	O
+of	O
+inflammatory	O
+nociception	O
+,	O
+pain	B
+-	O
+induced	O
+functional	O
+impairment	O
+model	O
+,	O
+and	O
+the	O
+charcoal	O
+meal	O
+test	O
+was	O
+used	O
+to	O
+evaluate	O
+the	O
+intestinal	O
+transit	O
+.	O
+
+Simultaneous	O
+administration	O
+of	O
+morphine	O
+with	O
+metamizol	O
+resulted	O
+in	O
+a	O
+markedly	O
+antinociceptive	O
+potentiation	O
+and	O
+an	O
+increasing	O
+of	O
+the	O
+duration	O
+of	O
+action	O
+after	O
+a	O
+single	O
+(	O
+298	O
++	O
+/	O
+-	O
+7	O
+vs	O
+.	O
+139	O
++	O
+/	O
+-	O
+36	O
+units	O
+area	O
+(	O
+ua	O
+)	O
+;	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+and	O
+repeated	O
+administration	O
+(	O
+280	O
++	O
+/	O
+-	O
+17	O
+vs	O
+.	O
+131	O
++	O
+/	O
+-	O
+22	O
+ua	O
+;	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Antinociceptive	O
+effect	O
+of	O
+morphine	O
+was	O
+reduced	O
+in	O
+chronically	O
+treated	O
+rats	O
+(	O
+39	O
++	O
+/	O
+-	O
+10	O
+vs	O
+.	O
+18	O
++	O
+/	O
+-	O
+5	O
+au	O
+)	O
+while	O
+the	O
+combination	O
+-	O
+induced	O
+antinociception	O
+was	O
+remained	O
+similar	O
+as	O
+an	O
+acute	O
+treatment	O
+(	O
+298	O
++	O
+/	O
+-	O
+7	O
+vs	O
+.	O
+280	O
++	O
+/	O
+-	O
+17	O
+au	O
+)	O
+.	O
+
+Acute	O
+antinociceptive	O
+effects	O
+of	O
+the	O
+combination	O
+were	O
+partially	O
+prevented	O
+by	O
+3	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+naloxone	O
+s	O
+.	O
+c	O
+.	O
+
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+,	O
+suggesting	O
+the	O
+partial	O
+involvement	O
+of	O
+the	O
+opioidergic	O
+system	O
+in	O
+the	O
+synergism	O
+observed	O
+.	O
+
+In	O
+independent	O
+groups	O
+,	O
+morphine	O
+inhibited	O
+the	O
+intestinal	O
+transit	O
+in	O
+48	O
++	O
+/	O
+-	O
+4	O
+%	O
+and	O
+38	O
++	O
+/	O
+-	O
+4	O
+%	O
+after	O
+acute	O
+and	O
+chronic	O
+treatment	O
+,	O
+respectively	O
+,	O
+suggesting	O
+that	O
+tolerance	O
+did	O
+not	O
+develop	O
+to	O
+the	O
+constipating	B
+effects	O
+.	O
+
+The	O
+combination	O
+inhibited	O
+intestinal	O
+transit	O
+similar	O
+to	O
+that	O
+produced	O
+by	O
+morphine	O
+regardless	O
+of	O
+the	O
+time	O
+of	O
+treatment	O
+,	O
+suggesting	O
+that	O
+metamizol	O
+did	O
+not	O
+potentiate	O
+morphine	O
+-	O
+induced	O
+constipation	B
+.	O
+
+These	O
+findings	O
+show	O
+a	O
+significant	O
+interaction	O
+between	O
+morphine	O
+and	O
+metamizol	O
+in	O
+chronically	O
+treated	O
+rats	O
+,	O
+suggesting	O
+that	O
+this	O
+combination	O
+could	O
+be	O
+useful	O
+for	O
+the	O
+treatment	O
+of	O
+chronic	B
+pain	I
+.	O
+
+Ifosfamide	O
+encephalopathy	B
+presenting	O
+with	O
+asterixis	B
+.	O
+
+CNS	O
+toxic	O
+effects	O
+of	O
+the	O
+antineoplastic	O
+agent	O
+ifosfamide	O
+(	O
+IFX	O
+)	O
+are	O
+frequent	O
+and	O
+include	O
+a	O
+variety	O
+of	O
+neurological	O
+symptoms	O
+that	O
+can	O
+limit	O
+drug	O
+use	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+a	O
+51	O
+-	O
+year	O
+-	O
+old	O
+man	O
+who	O
+developed	O
+severe	O
+,	O
+disabling	O
+negative	O
+myoclonus	B
+of	O
+the	O
+upper	O
+and	O
+lower	O
+extremities	O
+after	O
+the	O
+infusion	O
+of	O
+ifosfamide	O
+for	O
+plasmacytoma	B
+.	O
+
+He	O
+was	O
+awake	O
+,	O
+revealed	O
+no	O
+changes	O
+of	O
+mental	O
+status	O
+and	O
+at	O
+rest	O
+there	O
+were	O
+no	O
+further	O
+motor	O
+symptoms	O
+.	O
+
+Cranial	O
+magnetic	O
+resonance	O
+imaging	O
+and	O
+extensive	O
+laboratory	O
+studies	O
+failed	O
+to	O
+reveal	O
+structural	B
+lesions	I
+of	I
+the	I
+brain	I
+and	O
+metabolic	B
+abnormalities	I
+.	O
+
+An	O
+electroencephalogram	O
+showed	O
+continuous	O
+,	O
+generalized	O
+irregular	O
+slowing	O
+with	O
+admixed	O
+periodic	O
+triphasic	O
+waves	O
+indicating	O
+symptomatic	O
+encephalopathy	B
+.	O
+
+The	O
+administration	O
+of	O
+ifosfamide	O
+was	O
+discontinued	O
+and	O
+within	O
+12	O
+h	O
+the	O
+asterixis	B
+resolved	O
+completely	O
+.	O
+
+In	O
+the	O
+patient	O
+described	O
+,	O
+the	O
+presence	O
+of	O
+asterixis	B
+during	O
+infusion	O
+of	O
+ifosfamide	O
+,	O
+normal	O
+laboratory	O
+findings	O
+and	O
+imaging	O
+studies	O
+and	O
+the	O
+resolution	O
+of	O
+symptoms	O
+following	O
+the	O
+discontinuation	O
+of	O
+the	O
+drug	O
+suggest	O
+that	O
+negative	O
+myoclonus	B
+is	O
+associated	O
+with	O
+the	O
+use	O
+of	O
+IFX	O
+.	O
+
+Antagonism	O
+between	O
+interleukin	O
+3	O
+and	O
+erythropoietin	O
+in	O
+mice	O
+with	O
+azidothymidine	O
+-	O
+induced	O
+anemia	B
+and	O
+in	O
+bone	O
+marrow	O
+endothelial	O
+cells	O
+.	O
+
+Azidothymidine	O
+(	O
+AZT	O
+)	O
+-	O
+induced	O
+anemia	B
+in	O
+mice	O
+can	O
+be	O
+reversed	O
+by	O
+the	O
+administration	O
+of	O
+IGF	O
+-	O
+IL	O
+-	O
+3	O
+(	O
+fusion	O
+protein	O
+of	O
+insulin	O
+-	O
+like	O
+growth	O
+factor	O
+II	O
+(	O
+IGF	O
+II	O
+)	O
+and	O
+interleukin	O
+3	O
+)	O
+.	O
+
+Although	O
+interleukin	O
+3	O
+(	O
+IL	O
+-	O
+3	O
+)	O
+and	O
+erythropoietin	O
+(	O
+EPO	O
+)	O
+are	O
+known	O
+to	O
+act	O
+synergistically	O
+on	O
+hematopoietic	O
+cell	O
+proliferation	O
+in	O
+vitro	O
+,	O
+injection	O
+of	O
+IGF	O
+-	O
+IL	O
+-	O
+3	O
+and	O
+EPO	O
+in	O
+AZT	O
+-	O
+treated	O
+mice	O
+resulted	O
+in	O
+a	O
+reduction	O
+of	O
+red	O
+cells	O
+and	O
+an	O
+increase	O
+of	O
+plasma	O
+EPO	O
+levels	O
+as	O
+compared	O
+to	O
+animals	O
+treated	O
+with	O
+IGF	O
+-	O
+IL	O
+-	O
+3	O
+or	O
+EPO	O
+alone	O
+.	O
+
+We	O
+tested	O
+the	O
+hypothesis	O
+that	O
+the	O
+antagonistic	O
+effect	O
+of	O
+IL	O
+-	O
+3	O
+and	O
+EPO	O
+on	O
+erythroid	O
+cells	O
+may	O
+be	O
+mediated	O
+by	O
+endothelial	O
+cells	O
+.	O
+
+Bovine	O
+liver	O
+erythroid	O
+cells	O
+were	O
+cultured	O
+on	O
+monolayers	O
+of	O
+human	O
+bone	O
+marrow	O
+endothelial	O
+cells	O
+previously	O
+treated	O
+with	O
+EPO	O
+and	O
+IGF	O
+-	O
+IL	O
+-	O
+3	O
+.	O
+
+There	O
+was	O
+a	O
+significant	O
+reduction	O
+of	O
+thymidine	O
+incorporation	O
+into	O
+both	O
+erythroid	O
+and	O
+endothelial	O
+cells	O
+in	O
+cultures	O
+pre	O
+-	O
+treated	O
+with	O
+IGF	O
+-	O
+IL	O
+-	O
+3	O
+and	O
+EPO	O
+.	O
+
+Endothelial	O
+cell	O
+culture	O
+supernatants	O
+separated	O
+by	O
+ultrafiltration	O
+and	O
+ultracentrifugation	O
+from	O
+cells	O
+treated	O
+with	O
+EPO	O
+and	O
+IL	O
+-	O
+3	O
+significantly	O
+reduced	O
+thymidine	O
+incorporation	O
+into	O
+erythroid	O
+cells	O
+as	O
+compared	O
+to	O
+identical	O
+fractions	O
+obtained	O
+from	O
+the	O
+media	O
+of	O
+cells	O
+cultured	O
+with	O
+EPO	O
+alone	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+endothelial	O
+cells	O
+treated	O
+simultaneously	O
+with	O
+EPO	O
+and	O
+IL	O
+-	O
+3	O
+have	O
+a	O
+negative	O
+effect	O
+on	O
+erythroid	O
+cell	O
+production	O
+.	O
+
+The	O
+relationship	O
+between	O
+hippocampal	O
+acetylcholine	O
+release	O
+and	O
+cholinergic	O
+convulsant	O
+sensitivity	O
+in	O
+withdrawal	O
+seizure	B
+-	O
+prone	O
+and	O
+withdrawal	O
+seizure	B
+-	O
+resistant	O
+selected	O
+mouse	O
+lines	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+septo	O
+-	O
+hippocampal	O
+cholinergic	O
+pathway	O
+has	O
+been	O
+implicated	O
+in	O
+epileptogenesis	O
+,	O
+and	O
+genetic	O
+factors	O
+influence	O
+the	O
+response	O
+to	O
+cholinergic	O
+agents	O
+,	O
+but	O
+limited	O
+data	O
+are	O
+available	O
+on	O
+cholinergic	O
+involvement	O
+in	O
+alcohol	O
+withdrawal	O
+severity	O
+.	O
+
+Thus	O
+,	O
+the	O
+relationship	O
+between	O
+cholinergic	O
+activity	O
+and	O
+responsiveness	O
+and	O
+alcohol	O
+withdrawal	O
+was	O
+investigated	O
+in	O
+a	O
+genetic	O
+animal	O
+model	O
+of	O
+ethanol	O
+withdrawal	O
+severity	O
+.	O
+
+METHODS	O
+:	O
+Cholinergic	O
+convulsant	O
+sensitivity	O
+was	O
+examined	O
+in	O
+alcohol	O
+-	O
+na	O
+ve	O
+Withdrawal	O
+Seizure	B
+-	O
+Prone	O
+(	O
+WSP	O
+)	O
+and	O
+-	O
+Resistant	O
+(	O
+WSR	O
+)	O
+mice	O
+.	O
+
+Animals	O
+were	O
+administered	O
+nicotine	O
+,	O
+carbachol	O
+,	O
+or	O
+neostigmine	O
+via	O
+timed	O
+tail	O
+vein	O
+infusion	O
+,	O
+and	O
+the	O
+latencies	O
+to	O
+onset	O
+of	O
+tremor	B
+and	O
+clonus	O
+were	O
+recorded	O
+and	O
+converted	O
+to	O
+threshold	O
+dose	O
+.	O
+
+We	O
+also	O
+used	O
+microdialysis	O
+to	O
+measure	O
+basal	O
+and	O
+potassium	O
+-	O
+stimulated	O
+acetylcholine	O
+(	O
+ACh	O
+)	O
+release	O
+in	O
+the	O
+CA1	O
+region	O
+of	O
+the	O
+hippocampus	O
+.	O
+
+Potassium	O
+was	O
+applied	O
+by	O
+reverse	O
+dialysis	O
+twice	O
+,	O
+separated	O
+by	O
+75	O
+min	O
+.	O
+
+Hippocampal	O
+ACh	O
+also	O
+was	O
+measured	O
+during	O
+testing	O
+for	O
+handling	O
+-	O
+induced	O
+convulsions	B
+.	O
+
+RESULTS	O
+:	O
+Sensitivity	O
+to	O
+several	O
+convulsion	B
+endpoints	O
+induced	O
+by	O
+nicotine	O
+,	O
+carbachol	O
+,	O
+and	O
+neostigmine	O
+were	O
+significantly	O
+greater	O
+in	O
+WSR	O
+versus	O
+WSP	O
+mice	O
+.	O
+
+In	O
+microdialysis	O
+experiments	O
+,	O
+the	O
+lines	O
+did	O
+not	O
+differ	O
+in	O
+basal	O
+release	O
+of	O
+ACh	O
+,	O
+and	O
+50	O
+mM	O
+KCl	O
+increased	O
+ACh	O
+output	O
+in	O
+both	O
+lines	O
+of	O
+mice	O
+.	O
+
+However	O
+,	O
+the	O
+increase	O
+in	O
+release	O
+of	O
+ACh	O
+produced	O
+by	O
+the	O
+first	O
+application	O
+of	O
+KCl	O
+was	O
+2	O
+-	O
+fold	O
+higher	O
+in	O
+WSP	O
+versus	O
+WSR	O
+mice	O
+.	O
+
+When	O
+hippocampal	O
+ACh	O
+was	O
+measured	O
+during	O
+testing	O
+for	O
+handling	O
+-	O
+induced	O
+convulsions	B
+,	O
+extracellular	O
+ACh	O
+was	O
+significantly	O
+elevated	O
+(	O
+192	O
+%	O
+)	O
+in	O
+WSP	O
+mice	O
+,	O
+but	O
+was	O
+nonsignificantly	O
+elevated	O
+(	O
+59	O
+%	O
+)	O
+in	O
+WSR	O
+mice	O
+.	O
+
+CONCLUSIONS	O
+:	O
+These	O
+results	O
+suggest	O
+that	O
+differences	O
+in	O
+cholinergic	O
+activity	O
+and	O
+postsynaptic	O
+sensitivity	O
+to	O
+cholinergic	O
+convulsants	B
+may	O
+be	O
+associated	O
+with	O
+ethanol	O
+withdrawal	O
+severity	O
+and	O
+implicate	O
+cholinergic	O
+mechanisms	O
+in	O
+alcohol	O
+withdrawal	O
+.	O
+
+Specifically	O
+,	O
+WSP	O
+mice	O
+may	O
+have	O
+lower	O
+sensitivity	O
+to	O
+cholinergic	O
+convulsants	B
+compared	O
+with	O
+WSR	O
+because	O
+of	O
+postsynaptic	O
+receptor	O
+desensitization	O
+brought	O
+on	O
+by	O
+higher	O
+activity	O
+of	O
+cholinergic	O
+neurons	O
+.	O
+
+Capsaicin	O
+-	O
+induced	O
+muscle	B
+pain	I
+alters	O
+the	O
+excitability	O
+of	O
+the	O
+human	O
+jaw	O
+-	O
+stretch	O
+reflex	O
+.	O
+
+The	O
+pathophysiology	O
+of	O
+painful	O
+temporomandibular	B
+disorders	I
+is	O
+not	O
+fully	O
+understood	O
+,	O
+but	O
+evidence	O
+suggests	O
+that	O
+muscle	B
+pain	I
+modulates	O
+motor	O
+function	O
+in	O
+characteristic	O
+ways	O
+.	O
+
+This	O
+study	O
+tested	O
+the	O
+hypothesis	O
+that	O
+activation	O
+of	O
+nociceptive	B
+muscle	I
+afferent	O
+fibers	O
+would	O
+be	O
+linked	O
+to	O
+an	O
+increased	O
+excitability	O
+of	O
+the	O
+human	O
+jaw	O
+-	O
+stretch	O
+reflex	O
+and	O
+whether	O
+this	O
+process	O
+would	O
+be	O
+sensitive	O
+to	O
+length	O
+and	O
+velocity	O
+of	O
+the	O
+stretch	O
+.	O
+
+Capsaicin	O
+(	O
+10	O
+micro	O
+g	O
+)	O
+was	O
+injected	O
+into	O
+the	O
+masseter	O
+muscle	O
+to	O
+induce	O
+pain	B
+in	O
+11	O
+healthy	O
+volunteers	O
+.	O
+
+Short	O
+-	O
+latency	O
+reflex	O
+responses	O
+were	O
+evoked	O
+in	O
+the	O
+masseter	O
+and	O
+temporalis	O
+muscles	O
+by	O
+a	O
+stretch	O
+device	O
+with	O
+different	O
+velocities	O
+and	O
+displacements	O
+before	O
+,	O
+during	O
+,	O
+and	O
+after	O
+the	O
+pain	B
+.	O
+
+The	O
+normalized	O
+reflex	O
+amplitude	O
+increased	O
+with	O
+an	O
+increase	O
+in	O
+velocity	O
+at	O
+a	O
+given	O
+displacement	O
+,	O
+but	O
+remained	O
+constant	O
+with	O
+different	O
+displacements	O
+at	O
+a	O
+given	O
+velocity	O
+.	O
+
+The	O
+normalized	O
+reflex	O
+amplitude	O
+was	O
+significantly	O
+higher	O
+during	O
+pain	B
+,	O
+but	O
+only	O
+at	O
+faster	O
+stretches	O
+in	O
+the	O
+painful	B
+muscle	I
+.	O
+
+Increased	O
+sensitivity	O
+of	O
+the	O
+fusimotor	O
+system	O
+during	O
+acute	O
+muscle	B
+pain	I
+could	O
+be	O
+one	O
+likely	O
+mechanism	O
+to	O
+explain	O
+the	O
+findings	O
+.	O
+
+Effects	O
+of	O
+5	O
+-	O
+HT1B	O
+receptor	O
+ligands	O
+microinjected	O
+into	O
+the	O
+accumbal	O
+shell	O
+or	O
+core	O
+on	O
+the	O
+cocaine	O
+-	O
+induced	O
+locomotor	B
+hyperactivity	I
+in	O
+rats	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+examine	O
+the	O
+effect	O
+of	O
+5	O
+-	O
+HT1B	O
+receptor	O
+ligands	O
+microinjected	O
+into	O
+the	O
+subregions	O
+of	O
+the	O
+nucleus	O
+accumbens	O
+(	O
+the	O
+shell	O
+and	O
+the	O
+core	O
+)	O
+on	O
+the	O
+locomotor	B
+hyperactivity	I
+induced	O
+by	O
+cocaine	O
+in	O
+rats	O
+.	O
+
+Male	O
+Wistar	O
+rats	O
+were	O
+implanted	O
+bilaterally	O
+with	O
+cannulae	O
+into	O
+the	O
+accumbens	O
+shell	O
+or	O
+core	O
+,	O
+and	O
+then	O
+were	O
+locally	O
+injected	O
+with	O
+GR	O
+55562	O
+(	O
+an	O
+antagonist	O
+of	O
+5	O
+-	O
+HT1B	O
+receptors	O
+)	O
+or	O
+CP	O
+93129	O
+(	O
+an	O
+agonist	O
+of	O
+5	O
+-	O
+HT1B	O
+receptors	O
+)	O
+.	O
+
+Given	O
+alone	O
+to	O
+any	O
+accumbal	O
+subregion	O
+,	O
+GR	O
+55562	O
+(	O
+0	O
+.	O
+1	O
+-	O
+10	O
+microg	O
+/	O
+side	O
+)	O
+or	O
+CP	O
+93129	O
+(	O
+0	O
+.	O
+1	O
+-	O
+10	O
+microg	O
+/	O
+side	O
+)	O
+did	O
+not	O
+change	O
+basal	O
+locomotor	O
+activity	O
+.	O
+
+Systemic	O
+cocaine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+significantly	O
+increased	O
+the	O
+locomotor	O
+activity	O
+of	O
+rats	O
+.	O
+
+GR	O
+55562	O
+(	O
+0	O
+.	O
+1	O
+-	O
+10	O
+microg	O
+/	O
+side	O
+)	O
+,	O
+administered	O
+intra	O
+-	O
+accumbens	O
+shell	O
+prior	O
+to	O
+cocaine	O
+,	O
+dose	O
+-	O
+dependently	O
+attenuated	O
+the	O
+psychostimulant	O
+-	O
+induced	O
+locomotor	B
+hyperactivity	I
+.	O
+
+Such	O
+attenuation	O
+was	O
+not	O
+found	O
+in	O
+animals	O
+which	O
+had	O
+been	O
+injected	O
+with	O
+GR	O
+55562	O
+into	O
+the	O
+accumbens	O
+core	O
+.	O
+
+When	O
+injected	O
+into	O
+the	O
+accumbens	O
+shell	O
+(	O
+but	O
+not	O
+the	O
+core	O
+)	O
+before	O
+cocaine	O
+,	O
+CP	O
+93129	O
+(	O
+0	O
+.	O
+1	O
+-	O
+10	O
+microg	O
+/	O
+side	O
+)	O
+enhanced	O
+the	O
+locomotor	O
+response	O
+to	O
+cocaine	O
+;	O
+the	O
+maximum	O
+effect	O
+being	O
+observed	O
+after	O
+10	O
+microg	O
+/	O
+side	O
+of	O
+the	O
+agonist	O
+.	O
+
+The	O
+later	O
+enhancement	O
+was	O
+attenuated	O
+after	O
+intra	O
+-	O
+accumbens	O
+shell	O
+treatment	O
+with	O
+GR	O
+55562	O
+(	O
+1	O
+microg	O
+/	O
+side	O
+)	O
+.	O
+
+Our	O
+findings	O
+indicate	O
+that	O
+cocaine	O
+induced	O
+hyperlocomotion	B
+is	O
+modified	O
+by	O
+5	O
+-	O
+HT1B	O
+receptor	O
+ligands	O
+microinjected	O
+into	O
+the	O
+accumbens	O
+shell	O
+,	O
+but	O
+not	O
+core	O
+,	O
+this	O
+modification	O
+consisting	O
+in	O
+inhibitory	O
+and	O
+facilitatory	O
+effects	O
+of	O
+the	O
+5	O
+-	O
+HT1B	O
+receptor	O
+antagonist	O
+(	O
+GR	O
+55562	O
+)	O
+and	O
+agonist	O
+(	O
+CP	O
+93129	O
+)	O
+,	O
+respectively	O
+.	O
+
+In	O
+other	O
+words	O
+,	O
+the	O
+present	O
+results	O
+suggest	O
+that	O
+the	O
+accumbal	O
+shell	O
+5	O
+-	O
+HT1B	O
+receptors	O
+play	O
+a	O
+permissive	O
+role	O
+in	O
+the	O
+behavioural	O
+response	O
+to	O
+the	O
+psychostimulant	O
+.	O
+
+Cocaine	O
+related	O
+chest	B
+pain	I
+:	O
+are	O
+we	O
+seeing	O
+the	O
+tip	O
+of	O
+an	O
+iceberg	O
+?	O
+
+The	O
+recreational	O
+use	O
+of	O
+cocaine	O
+is	O
+on	O
+the	O
+increase	O
+.	O
+
+The	O
+emergency	O
+nurse	O
+ought	O
+to	O
+be	O
+familiar	O
+with	O
+some	O
+of	O
+the	O
+cardiovascular	O
+consequences	O
+of	O
+cocaine	O
+use	O
+.	O
+
+In	O
+particular	O
+,	O
+the	O
+tendency	O
+of	O
+cocaine	O
+to	O
+produce	O
+chest	B
+pain	I
+ought	O
+to	O
+be	O
+in	O
+the	O
+mind	O
+of	O
+the	O
+emergency	O
+nurse	O
+when	O
+faced	O
+with	O
+a	O
+young	O
+victim	O
+of	O
+chest	B
+pain	I
+who	O
+is	O
+otherwise	O
+at	O
+low	O
+risk	O
+.	O
+
+The	O
+mechanism	O
+of	O
+chest	B
+pain	I
+related	O
+to	O
+cocaine	O
+use	O
+is	O
+discussed	O
+and	O
+treatment	O
+dilemmas	O
+are	O
+discussed	O
+.	O
+
+Finally	O
+,	O
+moral	O
+issues	O
+relating	O
+to	O
+the	O
+testing	O
+of	O
+potential	O
+cocaine	O
+users	O
+will	O
+be	O
+addressed	O
+.	O
+
+Crossover	O
+comparison	O
+of	O
+efficacy	O
+and	O
+preference	O
+for	O
+rizatriptan	O
+10	O
+mg	O
+versus	O
+ergotamine	O
+/	O
+caffeine	O
+in	O
+migraine	B
+.	O
+
+Rizatriptan	O
+is	O
+a	O
+selective	O
+5	O
+-	O
+HT	O
+(	O
+1B	O
+/	O
+1D	O
+)	O
+receptor	O
+agonist	O
+with	O
+rapid	O
+oral	O
+absorption	O
+and	O
+early	O
+onset	O
+of	O
+action	O
+in	O
+the	O
+acute	O
+treatment	O
+of	O
+migraine	B
+.	O
+
+This	O
+randomized	O
+double	O
+-	O
+blind	O
+crossover	O
+outpatient	O
+study	O
+assessed	O
+the	O
+preference	O
+for	O
+1	O
+rizatriptan	O
+10	O
+mg	O
+tablet	O
+to	O
+2	O
+ergotamine	O
+1	O
+mg	O
+/	O
+caffeine	O
+100	O
+mg	O
+tablets	O
+in	O
+439	O
+patients	O
+treating	O
+a	O
+single	O
+migraine	B
+attack	O
+with	O
+each	O
+therapy	O
+.	O
+
+Of	O
+patients	O
+expressing	O
+a	O
+preference	O
+(	O
+89	O
+.	O
+1	O
+%	O
+)	O
+,	O
+more	O
+than	O
+twice	O
+as	O
+many	O
+preferred	O
+rizatriptan	O
+to	O
+ergotamine	O
+/	O
+caffeine	O
+(	O
+69	O
+.	O
+9	O
+vs	O
+.	O
+30	O
+.	O
+1	O
+%	O
+,	O
+p	O
+<	O
+or	O
+=	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Faster	O
+relief	O
+of	O
+headache	B
+was	O
+the	O
+most	O
+important	O
+reason	O
+for	O
+preference	O
+,	O
+cited	O
+by	O
+67	O
+.	O
+3	O
+%	O
+of	O
+patients	O
+preferring	O
+rizatriptan	O
+and	O
+54	O
+.	O
+2	O
+%	O
+of	O
+patients	O
+who	O
+preferred	O
+ergotamine	O
+/	O
+caffeine	O
+.	O
+
+The	O
+co	O
+-	O
+primary	O
+endpoint	O
+of	O
+being	O
+pain	B
+free	O
+at	O
+2	O
+h	O
+was	O
+also	O
+in	O
+favor	O
+of	O
+rizatriptan	O
+.	O
+
+Forty	O
+-	O
+nine	O
+percent	O
+of	O
+patients	O
+were	O
+pain	B
+free	O
+2	O
+h	O
+after	O
+rizatriptan	O
+,	O
+compared	O
+with	O
+24	O
+.	O
+3	O
+%	O
+treated	O
+with	O
+ergotamine	O
+/	O
+caffeine	O
+(	O
+p	O
+<	O
+or	O
+=	O
+0	O
+.	O
+001	O
+)	O
+,	O
+rizatriptan	O
+being	O
+superior	O
+within	O
+1	O
+h	O
+of	O
+treatment	O
+.	O
+
+Headache	B
+relief	O
+at	O
+2	O
+h	O
+was	O
+75	O
+.	O
+9	O
+%	O
+for	O
+rizatriptan	O
+and	O
+47	O
+.	O
+3	O
+%	O
+for	O
+ergotamine	O
+/	O
+caffeine	O
+(	O
+p	O
+<	O
+or	O
+=	O
+0	O
+.	O
+001	O
+)	O
+,	O
+with	O
+rizatriptan	O
+being	O
+superior	O
+to	O
+ergotamine	O
+/	O
+caffeine	O
+within	O
+30	O
+min	O
+of	O
+dosing	O
+.	O
+
+Almost	O
+36	O
+%	O
+of	O
+patients	O
+taking	O
+rizatriptan	O
+were	O
+pain	B
+free	O
+at	O
+2	O
+h	O
+and	O
+had	O
+no	O
+recurrence	O
+or	O
+need	O
+for	O
+additional	O
+medication	O
+within	O
+24	O
+h	O
+,	O
+compared	O
+to	O
+20	O
+%	O
+of	O
+patients	O
+on	O
+ergotamine	O
+/	O
+caffeine	O
+(	O
+p	O
+<	O
+or	O
+=	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Rizatriptan	O
+was	O
+also	O
+superior	O
+to	O
+ergotamine	O
+/	O
+caffeine	O
+in	O
+the	O
+proportions	O
+of	O
+patients	O
+with	O
+no	O
+nausea	B
+,	O
+vomiting	B
+,	O
+phonophobia	B
+or	O
+photophobia	B
+and	O
+for	O
+patients	O
+with	O
+normal	O
+function	O
+2	O
+h	O
+after	O
+drug	O
+intake	O
+(	O
+p	O
+<	O
+or	O
+=	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+More	O
+patients	O
+were	O
+(	O
+completely	O
+,	O
+very	O
+or	O
+somewhat	O
+)	O
+satisfied	O
+2	O
+h	O
+after	O
+treatment	O
+with	O
+rizatriptan	O
+(	O
+69	O
+.	O
+8	O
+%	O
+)	O
+than	O
+at	O
+2	O
+h	O
+after	O
+treatment	O
+with	O
+ergotamine	O
+/	O
+caffeine	O
+(	O
+38	O
+.	O
+6	O
+%	O
+,	O
+p	O
+<	O
+or	O
+=	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Recurrence	O
+rates	O
+were	O
+31	O
+.	O
+4	O
+%	O
+with	O
+rizatriptan	O
+and	O
+15	O
+.	O
+3	O
+%	O
+with	O
+ergotamine	O
+/	O
+caffeine	O
+.	O
+
+Both	O
+active	O
+treatments	O
+were	O
+well	O
+tolerated	O
+.	O
+
+The	O
+most	O
+common	O
+adverse	O
+events	O
+(	O
+incidence	O
+>	O
+or	O
+=	O
+5	O
+%	O
+in	O
+one	O
+group	O
+)	O
+after	O
+rizatriptan	O
+and	O
+ergotamine	O
+/	O
+caffeine	O
+,	O
+respectively	O
+,	O
+were	O
+dizziness	B
+(	O
+6	O
+.	O
+7	O
+and	O
+5	O
+.	O
+3	O
+%	O
+)	O
+,	O
+nausea	B
+(	O
+4	O
+.	O
+2	O
+and	O
+8	O
+.	O
+5	O
+%	O
+)	O
+and	O
+somnolence	B
+(	O
+5	O
+.	O
+5	O
+and	O
+2	O
+.	O
+3	O
+%	O
+)	O
+.	O
+
+Severe	O
+ocular	B
+and	I
+orbital	I
+toxicity	I
+after	O
+intracarotid	O
+injection	O
+of	O
+carboplatin	O
+for	O
+recurrent	O
+glioblastomas	B
+.	O
+
+BACKGROUND	O
+:	O
+Glioblastoma	B
+is	O
+a	O
+malignant	B
+tumor	I
+that	O
+occurs	O
+in	O
+the	O
+cerebrum	O
+during	O
+adulthood	O
+.	O
+
+With	O
+current	O
+treatment	O
+regimens	O
+including	O
+combined	O
+surgery	O
+,	O
+radiation	O
+and	O
+chemotherapy	O
+,	O
+the	O
+average	O
+life	O
+expectancy	O
+of	O
+the	O
+patients	O
+is	O
+limited	O
+to	O
+approximately	O
+1	O
+year	O
+.	O
+
+Therefore	O
+,	O
+patients	O
+with	O
+glioblastoma	B
+sometimes	O
+have	O
+intracarotid	O
+injection	O
+of	O
+carcinostatics	O
+added	O
+to	O
+the	O
+treatment	O
+regimen	O
+.	O
+
+Generally	O
+,	O
+carboplatin	O
+is	O
+said	O
+to	O
+have	O
+milder	O
+side	O
+effects	O
+than	O
+cisplatin	O
+,	O
+whose	O
+ocular	B
+and	I
+orbital	I
+toxicity	I
+are	O
+well	O
+known	O
+.	O
+
+However	O
+,	O
+we	O
+experienced	O
+a	O
+case	O
+of	O
+severe	O
+ocular	B
+and	I
+orbital	I
+toxicity	I
+after	O
+intracarotid	O
+injection	O
+of	O
+carboplatin	O
+,	O
+which	O
+is	O
+infrequently	O
+reported	O
+.	O
+
+CASE	O
+:	O
+A	O
+58	O
+-	O
+year	O
+-	O
+old	O
+man	O
+received	O
+an	O
+intracarotid	O
+injection	O
+of	O
+carboplatin	O
+for	O
+recurrent	O
+glioblastomas	B
+in	O
+his	O
+left	O
+temporal	O
+lobe	O
+.	O
+
+He	O
+complained	O
+of	O
+pain	B
+and	I
+visual	I
+disturbance	I
+in	I
+the	I
+ipsilateral	I
+eye	I
+30	O
+h	O
+after	O
+the	O
+injection	O
+.	O
+
+Various	O
+ocular	O
+symptoms	O
+and	O
+findings	O
+caused	O
+by	O
+carboplatin	O
+toxicity	B
+were	O
+seen	O
+.	O
+
+RESULTS	O
+:	O
+He	O
+was	O
+treated	O
+with	O
+intravenous	O
+administration	O
+of	O
+corticosteroids	O
+and	O
+glycerin	O
+for	O
+6	O
+days	O
+after	O
+the	O
+injection	O
+.	O
+
+Although	O
+the	O
+intraocular	O
+pressure	O
+elevation	O
+caused	O
+by	O
+secondary	O
+acute	O
+angle	O
+-	O
+closure	O
+glaucoma	B
+decreased	O
+and	O
+ocular	B
+pain	I
+diminished	O
+,	O
+inexorable	O
+papilledema	B
+and	O
+exudative	O
+retinal	B
+detachment	I
+continued	O
+for	O
+3	O
+weeks	O
+.	O
+
+Finally	O
+,	O
+6	O
+weeks	O
+later	O
+,	O
+diffuse	O
+chorioretinal	B
+atrophy	I
+with	O
+optic	B
+atrophy	I
+occurred	O
+and	O
+the	O
+vision	O
+in	O
+his	O
+left	O
+eye	O
+was	O
+lost	O
+.	O
+
+CONCLUSION	O
+:	O
+When	O
+performing	O
+intracarotid	O
+injection	O
+of	O
+carboplatin	O
+,	O
+we	O
+must	O
+be	O
+aware	O
+of	O
+its	O
+potentially	O
+blinding	O
+ocular	B
+toxicity	I
+.	O
+
+It	O
+is	O
+recommended	O
+that	O
+further	O
+studies	O
+and	O
+investigations	O
+are	O
+undertaken	O
+in	O
+the	O
+effort	O
+to	O
+minimize	O
+such	O
+severe	O
+side	O
+effects	O
+.	O
+
+Visual	B
+hallucinations	I
+associated	O
+with	O
+zonisamide	O
+.	O
+
+Zonisamide	O
+is	O
+a	O
+broad	O
+-	O
+spectrum	O
+antiepileptic	O
+drug	O
+used	O
+to	O
+treat	O
+various	O
+types	O
+of	O
+seizures	B
+.	O
+
+Although	O
+visual	B
+hallucinations	I
+have	O
+not	O
+been	O
+reported	O
+as	O
+an	O
+adverse	O
+effect	O
+of	O
+this	O
+agent	O
+,	O
+we	O
+describe	O
+three	O
+patients	O
+who	O
+experienced	O
+complex	O
+visual	B
+hallucinations	I
+and	O
+altered	O
+mental	O
+status	O
+after	O
+zonisamide	O
+treatment	O
+was	O
+begun	O
+or	O
+its	O
+dosage	O
+increased	O
+.	O
+
+All	O
+three	O
+had	O
+been	O
+diagnosed	O
+earlier	O
+with	O
+epilepsy	B
+,	O
+and	O
+their	O
+electroencephalogram	O
+(	O
+EEG	O
+)	O
+findings	O
+were	O
+abnormal	O
+.	O
+
+During	O
+monitoring	O
+,	O
+visual	B
+hallucinations	I
+did	O
+not	O
+correlate	O
+with	O
+EEG	O
+readings	O
+,	O
+nor	O
+did	O
+video	O
+recording	O
+capture	O
+any	O
+of	O
+the	O
+described	O
+events	O
+.	O
+
+None	O
+of	O
+the	O
+patients	O
+had	O
+experienced	O
+visual	B
+hallucinations	I
+before	O
+this	O
+event	O
+.	O
+
+The	O
+only	O
+recent	O
+change	O
+in	O
+their	O
+treatment	O
+was	O
+the	O
+introduction	O
+or	O
+increased	O
+dosage	O
+of	O
+zonisamide	O
+.	O
+
+With	O
+either	O
+discontinuation	O
+or	O
+decreased	O
+dosage	O
+of	O
+the	O
+drug	O
+the	O
+symptoms	O
+disappeared	O
+and	O
+did	O
+not	O
+recur	O
+.	O
+
+Further	O
+observations	O
+and	O
+reports	O
+will	O
+help	O
+clarify	O
+this	O
+adverse	O
+effect	O
+.	O
+
+Until	O
+then	O
+,	O
+clinicians	O
+need	O
+to	O
+be	O
+aware	O
+of	O
+this	O
+possible	O
+complication	O
+associated	O
+with	O
+zonisamide	O
+.	O
+
+Anti	O
+-	O
+epileptic	B
+drugs	O
+-	O
+induced	O
+de	O
+novo	O
+absence	B
+seizures	I
+.	O
+
+The	O
+authors	O
+present	O
+three	O
+patients	O
+with	O
+de	O
+novo	O
+absence	B
+epilepsy	I
+after	O
+administration	O
+of	O
+carbamazepine	O
+and	O
+vigabatrin	O
+.	O
+
+Despite	O
+the	O
+underlying	O
+diseases	O
+,	O
+the	O
+prognosis	O
+for	O
+drug	O
+-	O
+induced	O
+de	O
+novo	O
+absence	B
+seizure	I
+is	O
+good	O
+because	O
+it	O
+subsides	O
+rapidly	O
+after	O
+discontinuing	O
+the	O
+use	O
+of	O
+the	O
+offending	O
+drugs	O
+.	O
+
+The	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+-	O
+transmitted	O
+thalamocortical	O
+circuitry	O
+accounts	O
+for	O
+a	O
+major	O
+part	O
+of	O
+the	O
+underlying	O
+neurophysiology	O
+of	O
+the	O
+absence	B
+epilepsy	I
+.	O
+
+Because	O
+drug	O
+-	O
+induced	O
+de	O
+novo	O
+absence	B
+seizure	I
+is	O
+rare	O
+,	O
+pro	O
+-	O
+absence	O
+drugs	O
+can	O
+only	O
+be	O
+considered	O
+a	O
+promoting	O
+factor	O
+.	O
+
+The	O
+underlying	O
+epileptogenecity	O
+of	O
+the	O
+patients	O
+or	O
+the	O
+synergistic	O
+effects	O
+of	O
+the	O
+accompanying	O
+drugs	O
+is	O
+required	O
+to	O
+trigger	O
+the	O
+de	O
+novo	O
+absence	B
+seizure	I
+.	O
+
+The	O
+possibility	O
+of	O
+drug	O
+-	O
+induced	O
+aggravation	O
+should	O
+be	O
+considered	O
+whenever	O
+an	O
+unexpected	O
+increase	O
+in	O
+seizure	B
+frequency	O
+and	O
+/	O
+or	O
+new	O
+seizure	B
+types	O
+appear	O
+following	O
+a	O
+change	O
+in	O
+drug	O
+treatment	O
+.	O
+
+By	O
+understanding	O
+the	O
+underlying	O
+mechanism	O
+of	O
+absence	B
+epilepsy	I
+,	O
+we	O
+can	O
+avoid	O
+the	O
+inappropriate	O
+use	O
+of	O
+anticonvulsants	O
+in	O
+children	O
+with	O
+epilepsy	B
+and	O
+prevent	O
+drug	O
+-	O
+induced	O
+absence	B
+seizures	I
+.	O
+
+Prenatal	O
+dexamethasone	O
+programs	O
+hypertension	B
+and	O
+renal	B
+injury	I
+in	O
+the	O
+rat	O
+.	O
+
+Dexamethasone	O
+is	O
+frequently	O
+administered	O
+to	O
+the	O
+developing	O
+fetus	O
+to	O
+accelerate	O
+pulmonary	O
+development	O
+.	O
+
+The	O
+purpose	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+determine	O
+if	O
+prenatal	O
+dexamethasone	O
+programmed	O
+a	O
+progressive	O
+increase	B
+in	I
+blood	I
+pressure	I
+and	O
+renal	B
+injury	I
+in	O
+rats	O
+.	O
+
+Pregnant	O
+rats	O
+were	O
+given	O
+either	O
+vehicle	O
+or	O
+2	O
+daily	O
+intraperitoneal	O
+injections	O
+of	O
+dexamethasone	O
+(	O
+0	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+)	O
+on	O
+gestational	O
+days	O
+11	O
+and	O
+12	O
+,	O
+13	O
+and	O
+14	O
+,	O
+15	O
+and	O
+16	O
+,	O
+17	O
+and	O
+18	O
+,	O
+or	O
+19	O
+and	O
+20	O
+.	O
+
+Offspring	O
+of	O
+rats	O
+administered	O
+dexamethasone	O
+on	O
+days	O
+15	O
+and	O
+16	O
+gestation	O
+had	O
+a	O
+20	O
+%	O
+reduction	B
+in	I
+glomerular	I
+number	I
+compared	O
+with	O
+control	O
+at	O
+6	O
+to	O
+9	O
+months	O
+of	O
+age	O
+(	O
+22	O
+527	O
++	O
+/	O
+-	O
+509	O
+versus	O
+28	O
+050	O
++	O
+/	O
+-	O
+561	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+,	O
+which	O
+was	O
+comparable	O
+to	O
+the	O
+percent	O
+reduction	O
+in	O
+glomeruli	O
+measured	O
+at	O
+3	O
+weeks	O
+of	O
+age	O
+.	O
+
+Six	O
+-	O
+to	O
+9	O
+-	O
+month	O
+old	O
+rats	O
+receiving	O
+prenatal	O
+dexamethasone	O
+on	O
+days	O
+17	O
+and	O
+18	O
+of	O
+gestation	O
+had	O
+a	O
+17	O
+%	O
+reduction	O
+in	O
+glomeruli	O
+(	O
+23	O
+380	O
++	O
+/	O
+-	O
+587	O
+)	O
+compared	O
+with	O
+control	O
+rats	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Male	O
+rats	O
+that	O
+received	O
+prenatal	O
+dexamethasone	O
+on	O
+days	O
+15	O
+and	O
+16	O
+,	O
+17	O
+and	O
+18	O
+,	O
+and	O
+13	O
+and	O
+14	O
+of	O
+gestation	O
+had	O
+elevated	B
+blood	I
+pressures	I
+at	O
+6	O
+months	O
+of	O
+age	O
+;	O
+the	O
+latter	O
+group	O
+did	O
+not	O
+have	O
+a	O
+reduction	B
+in	I
+glomerular	I
+number	I
+.	O
+
+Adult	O
+rats	O
+given	O
+dexamethasone	O
+on	O
+days	O
+15	O
+and	O
+16	O
+of	O
+gestation	O
+had	O
+more	O
+glomeruli	O
+with	O
+glomerulosclerosis	B
+than	O
+control	O
+rats	O
+.	O
+
+This	O
+study	O
+shows	O
+that	O
+prenatal	O
+dexamethasone	O
+in	O
+rats	O
+results	O
+in	O
+a	O
+reduction	B
+in	I
+glomerular	I
+number	I
+,	O
+glomerulosclerosis	B
+,	O
+and	O
+hypertension	B
+when	O
+administered	O
+at	O
+specific	O
+points	O
+during	O
+gestation	O
+.	O
+
+Hypertension	B
+was	O
+observed	O
+in	O
+animals	O
+that	O
+had	O
+a	O
+reduction	O
+in	O
+glomeruli	O
+as	O
+well	O
+as	O
+in	O
+a	O
+group	O
+that	O
+did	O
+not	O
+have	O
+a	O
+reduction	B
+in	I
+glomerular	I
+number	I
+,	O
+suggesting	O
+that	O
+a	O
+reduction	B
+in	I
+glomerular	I
+number	I
+is	O
+not	O
+the	O
+sole	O
+cause	O
+for	O
+the	O
+development	O
+of	O
+hypertension	B
+.	O
+
+Kidney	O
+function	O
+and	O
+morphology	O
+after	O
+short	O
+-	O
+term	O
+combination	O
+therapy	O
+with	O
+cyclosporine	O
+A	O
+,	O
+tacrolimus	O
+and	O
+sirolimus	O
+in	O
+the	O
+rat	O
+.	O
+
+BACKGROUND	O
+:	O
+Sirolimus	O
+(	O
+SRL	O
+)	O
+may	O
+supplement	O
+calcineurin	O
+inhibitors	O
+in	O
+clinical	O
+organ	O
+transplantation	O
+.	O
+
+These	O
+are	O
+nephrotoxic	B
+,	O
+but	O
+SRL	O
+seems	O
+to	O
+act	O
+differently	O
+displaying	O
+only	O
+minor	O
+nephrotoxic	B
+effects	O
+,	O
+although	O
+this	O
+question	O
+is	O
+still	O
+open	O
+.	O
+
+In	O
+a	O
+number	O
+of	O
+treatment	O
+protocols	O
+where	O
+SRL	O
+was	O
+combined	O
+with	O
+a	O
+calcineurin	O
+inhibitor	O
+indications	O
+of	O
+a	O
+synergistic	O
+nephrotoxic	B
+effect	O
+were	O
+described	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+examine	O
+further	O
+the	O
+renal	O
+function	O
+,	O
+including	O
+morphological	O
+analysis	O
+of	O
+the	O
+kidneys	O
+of	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+treated	O
+with	O
+either	O
+cyclosporine	O
+A	O
+(	O
+CsA	O
+)	O
+,	O
+tacrolimus	O
+(	O
+FK506	O
+)	O
+or	O
+SRL	O
+as	O
+monotherapies	O
+or	O
+in	O
+different	O
+combinations	O
+.	O
+
+METHODS	O
+:	O
+For	O
+a	O
+period	O
+of	O
+2	O
+weeks	O
+,	O
+CsA	O
+15	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+(	O
+given	O
+orally	O
+)	O
+,	O
+FK506	O
+3	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+(	O
+given	O
+orally	O
+)	O
+or	O
+SRL	O
+0	O
+.	O
+4	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+(	O
+given	O
+intraperitoneally	O
+)	O
+was	O
+administered	O
+once	O
+a	O
+day	O
+as	O
+these	O
+doses	O
+have	O
+earlier	O
+been	O
+found	O
+to	O
+achieve	O
+a	O
+significant	O
+immunosuppressive	O
+effect	O
+in	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+.	O
+
+In	O
+the	O
+'	O
+conscious	O
+catheterized	O
+rat	O
+'	O
+model	O
+,	O
+the	O
+glomerular	O
+filtration	O
+rate	O
+(	O
+GFR	O
+)	O
+was	O
+measured	O
+as	O
+the	O
+clearance	O
+of	O
+Cr	O
+(	O
+EDTA	O
+)	O
+.	O
+
+The	O
+morphological	O
+analysis	O
+of	O
+the	O
+kidneys	O
+included	O
+a	O
+semi	O
+-	O
+quantitative	O
+scoring	O
+system	O
+analysing	O
+the	O
+degree	O
+of	O
+striped	O
+fibrosis	B
+,	O
+subcapsular	O
+fibrosis	B
+and	O
+the	O
+number	O
+of	O
+basophilic	O
+tubules	O
+,	O
+plus	O
+an	O
+additional	O
+stereological	O
+analysis	O
+of	O
+the	O
+total	O
+grade	O
+of	O
+fibrosis	B
+in	O
+the	O
+cortex	O
+stained	O
+with	O
+Sirius	O
+Red	O
+.	O
+
+RESULTS	O
+:	O
+CsA	O
+,	O
+FK506	O
+and	O
+SRL	O
+all	O
+significantly	O
+decreased	O
+the	O
+GFR	O
+.	O
+
+A	O
+further	O
+deterioration	O
+was	O
+seen	O
+when	O
+CsA	O
+was	O
+combined	O
+with	O
+either	O
+FK506	O
+or	O
+SRL	O
+,	O
+whereas	O
+the	O
+GFR	O
+remained	O
+unchanged	O
+in	O
+the	O
+group	O
+treated	O
+with	O
+FK506	O
+plus	O
+SRL	O
+when	O
+compared	O
+with	O
+treatment	O
+with	O
+any	O
+of	O
+the	O
+single	O
+substances	O
+.	O
+
+The	O
+morphological	O
+changes	O
+presented	O
+a	O
+similar	O
+pattern	O
+.	O
+
+The	O
+semi	O
+-	O
+quantitative	O
+scoring	O
+was	O
+significantly	O
+worst	O
+in	O
+the	O
+group	O
+treated	O
+with	O
+CsA	O
+plus	O
+SRL	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+compared	O
+with	O
+controls	O
+)	O
+and	O
+the	O
+analysis	O
+of	O
+the	O
+total	O
+grade	O
+of	O
+fibrosis	B
+also	O
+showed	O
+the	O
+highest	O
+proportion	O
+in	O
+the	O
+same	O
+group	O
+and	O
+was	O
+significantly	O
+different	O
+from	O
+controls	O
+(	O
+P	O
+<	O
+0	O
+.	O
+02	O
+)	O
+.	O
+
+The	O
+FK506	O
+plus	O
+SRL	O
+combination	O
+showed	O
+only	O
+a	O
+marginally	O
+higher	O
+degree	O
+of	O
+fibrosis	B
+as	O
+compared	O
+with	O
+controls	O
+(	O
+P	O
+=	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+rat	O
+study	O
+demonstrated	O
+a	O
+synergistic	O
+nephrotoxic	B
+effect	O
+of	O
+CsA	O
+plus	O
+SRL	O
+,	O
+whereas	O
+FK506	O
+plus	O
+SRL	O
+was	O
+better	O
+tolerated	O
+.	O
+
+Evaluation	O
+of	O
+cardiac	O
+troponin	O
+I	O
+and	O
+T	O
+levels	O
+as	O
+markers	O
+of	O
+myocardial	B
+damage	I
+in	O
+doxorubicin	O
+-	O
+induced	O
+cardiomyopathy	B
+rats	O
+,	O
+and	O
+their	O
+relationship	O
+with	O
+echocardiographic	O
+and	O
+histological	O
+findings	O
+.	O
+
+BACKGROUND	O
+:	O
+Cardiac	O
+troponins	O
+I	O
+(	O
+cTnI	O
+)	O
+and	O
+T	O
+(	O
+cTnT	O
+)	O
+have	O
+been	O
+shown	O
+to	O
+be	O
+highly	O
+sensitive	O
+and	O
+specific	O
+markers	O
+of	O
+myocardial	B
+cell	I
+injury	I
+.	O
+
+We	O
+investigated	O
+the	O
+diagnostic	O
+value	O
+of	O
+cTnI	O
+and	O
+cTnT	O
+for	O
+the	O
+diagnosis	O
+of	O
+myocardial	B
+damage	I
+in	O
+a	O
+rat	O
+model	O
+of	O
+doxorubicin	O
+(	O
+DOX	O
+)	O
+-	O
+induced	O
+cardiomyopathy	B
+,	O
+and	O
+we	O
+examined	O
+the	O
+relationship	O
+between	O
+serial	O
+cTnI	O
+and	O
+cTnT	O
+with	O
+the	O
+development	O
+of	O
+cardiac	B
+disorders	I
+monitored	O
+by	O
+echocardiography	O
+and	O
+histological	O
+examinations	O
+in	O
+this	O
+model	O
+.	O
+
+METHODS	O
+:	O
+Thirty	O
+-	O
+five	O
+Wistar	O
+rats	O
+were	O
+given	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+DOX	O
+,	O
+i	O
+.	O
+v	O
+.	O
+,	O
+weekly	O
+for	O
+up	O
+to	O
+8	O
+weeks	O
+for	O
+a	O
+total	O
+cumulative	O
+dose	O
+of	O
+12	O
+mg	O
+/	O
+kg	O
+BW	O
+.	O
+
+Ten	O
+rats	O
+received	O
+saline	O
+as	O
+a	O
+control	O
+group	O
+.	O
+
+cTnI	O
+was	O
+measured	O
+with	O
+Access	O
+(	O
+R	O
+)	O
+(	O
+ng	O
+/	O
+ml	O
+)	O
+and	O
+a	O
+research	O
+immunoassay	O
+(	O
+pg	O
+/	O
+ml	O
+)	O
+,	O
+and	O
+compared	O
+with	O
+cTnT	O
+,	O
+CK	O
+-	O
+MB	O
+mass	O
+and	O
+CK	O
+.	O
+
+By	O
+using	O
+transthoracic	O
+echocardiography	O
+,	O
+anterior	O
+and	O
+posterior	O
+wall	O
+thickness	O
+,	O
+LV	O
+diameters	O
+and	O
+LV	O
+fractional	O
+shortening	O
+(	O
+FS	O
+)	O
+were	O
+measured	O
+in	O
+all	O
+rats	O
+before	O
+DOX	O
+or	O
+saline	O
+,	O
+and	O
+at	O
+weeks	O
+6	O
+and	O
+9	O
+after	O
+treatment	O
+in	O
+all	O
+surviving	O
+rats	O
+.	O
+
+Histology	O
+was	O
+performed	O
+in	O
+DOX	O
+-	O
+rats	O
+at	O
+6	O
+and	O
+9	O
+weeks	O
+after	O
+the	O
+last	O
+DOX	O
+dose	O
+and	O
+in	O
+all	O
+controls	O
+.	O
+
+RESULTS	O
+:	O
+Eighteen	O
+of	O
+the	O
+DOX	O
+rats	O
+died	O
+prematurely	O
+of	O
+general	O
+toxicity	B
+during	O
+the	O
+9	O
+-	O
+week	O
+period	O
+.	O
+
+End	O
+-	O
+diastolic	O
+(	O
+ED	O
+)	O
+and	O
+end	O
+-	O
+systolic	O
+(	O
+ES	O
+)	O
+LV	O
+diameters	O
+/	O
+BW	O
+significantly	O
+increased	O
+,	O
+whereas	O
+LV	O
+FS	O
+was	O
+decreased	O
+after	O
+9	O
+weeks	O
+in	O
+the	O
+DOX	O
+group	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+These	O
+parameters	O
+remained	O
+unchanged	O
+in	O
+controls	O
+.	O
+
+Histological	O
+evaluation	O
+of	O
+hearts	O
+from	O
+all	O
+rats	O
+given	O
+DOX	O
+revealed	O
+significant	O
+slight	O
+degrees	O
+of	O
+perivascular	O
+and	O
+interstitial	O
+fibrosis	B
+.	O
+
+In	O
+7	O
+of	O
+the	O
+18	O
+rats	O
+,	O
+degeneration	O
+and	O
+myocyte	O
+vacuolisation	O
+were	O
+found	O
+.	O
+
+Only	O
+five	O
+of	O
+the	O
+controls	O
+exhibited	O
+evidence	O
+of	O
+very	O
+slight	O
+perivascular	O
+fibrosis	B
+.	O
+
+A	O
+significant	O
+rise	O
+in	O
+cTnT	O
+was	O
+found	O
+in	O
+DOX	O
+rats	O
+after	O
+cumulative	O
+doses	O
+of	O
+7	O
+.	O
+5	O
+and	O
+12	O
+mg	O
+/	O
+kg	O
+in	O
+comparison	O
+with	O
+baseline	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+cTnT	O
+found	O
+in	O
+rats	O
+after	O
+12	O
+mg	O
+/	O
+kg	O
+were	O
+significantly	O
+greater	O
+than	O
+that	O
+found	O
+after	O
+7	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+DOX	O
+.	O
+
+Maximal	O
+cTnI	O
+(	O
+pg	O
+/	O
+ml	O
+)	O
+and	O
+cTnT	O
+levels	O
+were	O
+significantly	O
+increased	O
+in	O
+DOX	O
+rats	O
+compared	O
+with	O
+controls	O
+(	O
+p	O
+=	O
+0	O
+.	O
+006	O
+,	O
+0	O
+.	O
+007	O
+)	O
+.	O
+
+cTnI	O
+(	O
+ng	O
+/	O
+ml	O
+)	O
+,	O
+CK	O
+-	O
+MB	O
+mass	O
+and	O
+CK	O
+remained	O
+unchanged	O
+in	O
+DOX	O
+rats	O
+compared	O
+with	O
+controls	O
+.	O
+
+All	O
+markers	O
+remained	O
+stable	O
+in	O
+controls	O
+.	O
+
+Analysis	O
+of	O
+data	O
+revealed	O
+a	O
+significant	O
+correlation	O
+between	O
+maximal	O
+cTnT	O
+and	O
+ED	O
+and	O
+ES	O
+LV	O
+diameters	O
+/	O
+BW	O
+(	O
+r	O
+=	O
+0	O
+.	O
+81	O
+and	O
+0	O
+.	O
+65	O
+;	O
+p	O
+<	O
+0	O
+.	O
+0001	O
+)	O
+.	O
+
+A	O
+significant	O
+relationship	O
+was	O
+observed	O
+between	O
+maximal	O
+cTnT	O
+and	O
+the	O
+extent	O
+of	O
+myocardial	O
+morphological	O
+changes	O
+,	O
+and	O
+between	O
+LV	O
+diameters	O
+/	O
+BW	O
+and	O
+histological	O
+findings	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Among	O
+markers	O
+of	O
+ischemic	B
+injury	I
+after	O
+DOX	O
+in	O
+rats	O
+,	O
+cTnT	O
+showed	O
+the	O
+greatest	O
+ability	O
+to	O
+detect	O
+myocardial	B
+damage	I
+assessed	O
+by	O
+echocardiographic	O
+detection	O
+and	O
+histological	O
+changes	O
+.	O
+
+Although	O
+there	O
+was	O
+a	O
+discrepancy	O
+between	O
+the	O
+amount	O
+of	O
+cTnI	O
+and	O
+cTnT	O
+after	O
+DOX	O
+,	O
+probably	O
+due	O
+to	O
+heterogeneity	O
+in	O
+cross	O
+-	O
+reactivities	O
+of	O
+mAbs	O
+to	O
+various	O
+cTnI	O
+and	O
+cTnT	O
+forms	O
+,	O
+it	O
+is	O
+likely	O
+that	O
+cTnT	O
+in	O
+rats	O
+after	O
+DOX	O
+indicates	O
+cell	O
+damage	O
+determined	O
+by	O
+the	O
+magnitude	O
+of	O
+injury	O
+induced	O
+and	O
+that	O
+cTnT	O
+should	O
+be	O
+a	O
+useful	O
+marker	O
+for	O
+the	O
+prediction	O
+of	O
+experimentally	O
+induced	O
+cardiotoxicity	B
+and	O
+possibly	O
+for	O
+cardioprotective	O
+experiments	O
+.	O
+
+Octreotide	O
+-	O
+induced	O
+hypoxemia	B
+and	O
+pulmonary	B
+hypertension	I
+in	O
+premature	O
+neonates	O
+.	O
+
+The	O
+authors	O
+report	O
+2	O
+cases	O
+of	O
+premature	O
+neonates	O
+who	O
+had	O
+enterocutaneous	O
+fistula	B
+complicating	O
+necrotizing	B
+enterocolitis	I
+.	O
+
+Pulmonary	B
+hypertension	I
+developed	O
+after	O
+administration	O
+of	O
+a	O
+somatostatin	O
+analogue	O
+,	O
+octreotide	O
+,	O
+to	O
+enhance	O
+resolution	O
+of	O
+the	O
+fistula	B
+.	O
+
+The	O
+authors	O
+discuss	O
+the	O
+mechanism	O
+of	O
+the	O
+occurrence	O
+of	O
+this	O
+complication	O
+and	O
+recommend	O
+caution	O
+of	O
+its	O
+use	O
+in	O
+high	O
+-	O
+risk	O
+premature	O
+neonates	O
+.	O
+
+The	O
+risk	O
+of	O
+venous	B
+thromboembolism	I
+in	O
+women	O
+prescribed	O
+cyproterone	O
+acetate	O
+in	O
+combination	O
+with	O
+ethinyl	O
+estradiol	O
+:	O
+a	O
+nested	O
+cohort	O
+analysis	O
+and	O
+case	O
+-	O
+control	O
+study	O
+.	O
+
+BACKGROUND	O
+:	O
+Cyproterone	O
+acetate	O
+combined	O
+with	O
+ethinyl	O
+estradiol	O
+(	O
+CPA	O
+/	O
+EE	O
+)	O
+is	O
+licensed	O
+in	O
+the	O
+UK	O
+for	O
+the	O
+treatment	O
+of	O
+women	O
+with	O
+acne	B
+and	O
+hirsutism	B
+and	O
+is	O
+also	O
+a	O
+treatment	O
+option	O
+for	O
+polycystic	B
+ovary	I
+syndrome	I
+(	O
+PCOS	B
+)	O
+.	O
+
+Previous	O
+studies	O
+have	O
+demonstrated	O
+an	O
+increased	O
+risk	O
+of	O
+venous	B
+thromboembolism	I
+(	O
+VTE	B
+)	O
+associated	O
+with	O
+CPA	O
+/	O
+EE	O
+compared	O
+with	O
+conventional	O
+combined	O
+oral	O
+contraceptives	O
+(	O
+COCs	O
+)	O
+.	O
+
+We	O
+believe	O
+the	O
+results	O
+of	O
+those	O
+studies	O
+may	O
+have	O
+been	O
+affected	O
+by	O
+residual	O
+confounding	O
+.	O
+
+METHODS	O
+:	O
+Using	O
+the	O
+General	O
+Practice	O
+Research	O
+Database	O
+we	O
+conducted	O
+a	O
+cohort	O
+analysis	O
+and	O
+case	O
+-	O
+control	O
+study	O
+nested	O
+within	O
+a	O
+population	O
+of	O
+women	O
+aged	O
+between	O
+15	O
+and	O
+39	O
+years	O
+with	O
+acne	B
+,	O
+hirsutism	B
+or	O
+PCOS	B
+to	O
+estimate	O
+the	O
+risk	O
+of	O
+VTE	B
+associated	O
+with	O
+CPA	O
+/	O
+EE	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+age	O
+-	O
+adjusted	O
+incidence	O
+rate	O
+ratio	O
+for	O
+CPA	O
+/	O
+EE	O
+versus	O
+conventional	O
+COCs	O
+was	O
+2	O
+.	O
+20	O
+[	O
+95	O
+%	O
+confidence	O
+interval	O
+(	O
+CI	O
+)	O
+1	O
+.	O
+35	O
+-	O
+3	O
+.	O
+58	O
+]	O
+.	O
+
+Using	O
+as	O
+the	O
+reference	O
+group	O
+women	O
+who	O
+were	O
+not	O
+using	O
+oral	O
+contraception	O
+,	O
+had	O
+no	O
+recent	O
+pregnancy	O
+or	O
+menopausal	O
+symptoms	O
+,	O
+the	O
+case	O
+-	O
+control	O
+analysis	O
+gave	O
+an	O
+adjusted	O
+odds	O
+ratio	O
+(	O
+OR	O
+(	O
+adj	O
+)	O
+)	O
+of	O
+7	O
+.	O
+44	O
+(	O
+95	O
+%	O
+CI	O
+3	O
+.	O
+67	O
+-	O
+15	O
+.	O
+08	O
+)	O
+for	O
+CPA	O
+/	O
+EE	O
+use	O
+compared	O
+with	O
+an	O
+OR	O
+(	O
+adj	O
+)	O
+of	O
+2	O
+.	O
+58	O
+(	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+60	O
+-	O
+4	O
+.	O
+18	O
+)	O
+for	O
+use	O
+of	O
+conventional	O
+COCs	O
+.	O
+
+CONCLUSIONS	O
+:	O
+We	O
+have	O
+demonstrated	O
+an	O
+increased	O
+risk	O
+of	O
+VTE	B
+associated	O
+with	O
+the	O
+use	O
+of	O
+CPA	O
+/	O
+EE	O
+in	O
+women	O
+with	O
+acne	B
+,	O
+hirsutism	B
+or	O
+PCOS	B
+although	O
+residual	O
+confounding	O
+by	O
+indication	O
+cannot	O
+be	O
+excluded	O
+.	O
+
+The	O
+effect	O
+of	O
+treatment	O
+with	O
+gum	O
+Arabic	O
+on	O
+gentamicin	O
+nephrotoxicity	B
+in	O
+rats	O
+:	O
+a	O
+preliminary	O
+study	O
+.	O
+
+In	O
+the	O
+present	O
+work	O
+we	O
+assessed	O
+the	O
+effect	O
+of	O
+treatment	O
+of	O
+rats	O
+with	O
+gum	O
+Arabic	O
+on	O
+acute	B
+renal	I
+failure	I
+induced	O
+by	O
+gentamicin	O
+(	O
+GM	O
+)	O
+nephrotoxicity	B
+.	O
+
+Rats	O
+were	O
+treated	O
+with	O
+the	O
+vehicle	O
+(	O
+2	O
+mL	O
+/	O
+kg	O
+of	O
+distilled	O
+water	O
+and	O
+5	O
+%	O
+w	O
+/	O
+v	O
+cellulose	O
+,	O
+10	O
+days	O
+)	O
+,	O
+gum	O
+Arabic	O
+(	O
+2	O
+mL	O
+/	O
+kg	O
+of	O
+a	O
+10	O
+%	O
+w	O
+/	O
+v	O
+aqueous	O
+suspension	O
+of	O
+gum	O
+Arabic	O
+powder	O
+,	O
+orally	O
+for	O
+10	O
+days	O
+)	O
+,	O
+or	O
+gum	O
+Arabic	O
+concomitantly	O
+with	O
+GM	O
+(	O
+80mg	O
+/	O
+kg	O
+/	O
+day	O
+intramuscularly	O
+,	O
+during	O
+the	O
+last	O
+six	O
+days	O
+of	O
+the	O
+treatment	O
+period	O
+)	O
+.	O
+
+Nephrotoxicity	B
+was	O
+assessed	O
+by	O
+measuring	O
+the	O
+concentrations	O
+of	O
+creatinine	O
+and	O
+urea	O
+in	O
+the	O
+plasma	O
+and	O
+reduced	O
+glutathione	O
+(	O
+GSH	O
+)	O
+in	O
+the	O
+kidney	O
+cortex	O
+,	O
+and	O
+by	O
+light	O
+microscopic	O
+examination	O
+of	O
+kidney	O
+sections	O
+.	O
+
+The	O
+results	O
+indicated	O
+that	O
+concomitant	O
+treatment	O
+with	O
+gum	O
+Arabic	O
+and	O
+GM	O
+significantly	O
+increased	O
+creatinine	O
+and	O
+urea	O
+by	O
+about	O
+183	O
+and	O
+239	O
+%	O
+,	O
+respectively	O
+(	O
+compared	O
+to	O
+432	O
+and	O
+346	O
+%	O
+,	O
+respectively	O
+,	O
+in	O
+rats	O
+treated	O
+with	O
+cellulose	O
+and	O
+GM	O
+)	O
+,	O
+and	O
+decreased	O
+that	O
+of	O
+cortical	O
+GSH	O
+by	O
+21	O
+%	O
+(	O
+compared	O
+to	O
+27	O
+%	O
+in	O
+the	O
+cellulose	O
+plus	O
+GM	O
+group	O
+)	O
+The	O
+GM	O
+-	O
+induced	O
+proximal	O
+tubular	B
+necrosis	I
+appeared	O
+to	O
+be	O
+slightly	O
+less	O
+severe	O
+in	O
+rats	O
+given	O
+GM	O
+together	O
+with	O
+gum	O
+Arabic	O
+than	O
+in	O
+those	O
+given	O
+GM	O
+and	O
+cellulose	O
+.	O
+
+It	O
+could	O
+be	O
+inferred	O
+that	O
+gum	O
+Arabic	O
+treatment	O
+has	O
+induced	O
+a	O
+modest	O
+amelioration	O
+of	O
+some	O
+of	O
+the	O
+histological	O
+and	O
+biochemical	O
+indices	O
+of	O
+GM	O
+nephrotoxicity	B
+.	O
+
+Further	O
+work	O
+is	O
+warranted	O
+on	O
+the	O
+effect	O
+of	O
+the	O
+treatments	O
+on	O
+renal	O
+functional	O
+aspects	O
+in	O
+models	O
+of	O
+chronic	B
+renal	I
+failure	I
+,	O
+and	O
+on	O
+the	O
+mechanism	O
+(	O
+s	O
+)	O
+involved	O
+.	O
+
+Increased	O
+frequency	O
+of	O
+venous	B
+thromboembolism	I
+with	O
+the	O
+combination	O
+of	O
+docetaxel	O
+and	O
+thalidomide	O
+in	O
+patients	O
+with	O
+metastatic	O
+androgen	O
+-	O
+independent	O
+prostate	B
+cancer	I
+.	O
+
+STUDY	O
+OBJECTIVE	O
+:	O
+To	O
+evaluate	O
+the	O
+frequency	O
+of	O
+venous	B
+thromboembolism	I
+(	O
+VTE	B
+)	O
+in	O
+patients	O
+with	O
+advanced	O
+androgen	O
+-	O
+independent	O
+prostate	B
+cancer	I
+who	O
+were	O
+treated	O
+with	O
+docetaxel	O
+alone	O
+or	O
+in	O
+combination	O
+with	O
+thalidomide	O
+.	O
+
+DESIGN	O
+:	O
+Retrospective	O
+analysis	O
+of	O
+a	O
+randomized	O
+phase	O
+II	O
+trial	O
+.	O
+
+SETTING	O
+:	O
+National	O
+Institutes	O
+of	O
+Health	O
+clinical	O
+research	O
+center	O
+.	O
+
+PATIENTS	O
+:	O
+Seventy	O
+men	O
+,	O
+aged	O
+50	O
+-	O
+80	O
+years	O
+,	O
+with	O
+advanced	O
+androgen	O
+-	O
+independent	O
+prostate	B
+cancer	I
+.	O
+
+INTERVENTION	O
+:	O
+Each	O
+patient	O
+received	O
+either	O
+intravenous	O
+docetaxel	O
+30	O
+mg	O
+/	O
+m2	O
+/	O
+week	O
+for	O
+3	O
+consecutive	O
+weeks	O
+,	O
+followed	O
+by	O
+1	O
+week	O
+off	O
+,	O
+or	O
+the	O
+combination	O
+of	O
+continuous	O
+oral	O
+thalidomide	O
+200	O
+mg	O
+every	O
+evening	O
+plus	O
+the	O
+same	O
+docetaxel	O
+regimen	O
+.	O
+
+This	O
+4	O
+-	O
+week	O
+cycle	O
+was	O
+repeated	O
+until	O
+there	O
+was	O
+evidence	O
+of	O
+excessive	O
+toxicity	B
+or	O
+disease	O
+progression	O
+.	O
+
+MEASUREMENTS	O
+AND	O
+MAIN	O
+RESULTS	O
+:	O
+None	O
+of	O
+23	O
+patients	O
+who	O
+received	O
+docetaxel	O
+alone	O
+developed	O
+VTE	B
+,	O
+whereas	O
+9	O
+of	O
+47	O
+patients	O
+(	O
+19	O
+%	O
+)	O
+who	O
+received	O
+docetaxel	O
+plus	O
+thalidomide	O
+developed	O
+VTE	B
+(	O
+p	O
+=	O
+0	O
+.	O
+025	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+addition	O
+of	O
+thalidomide	O
+to	O
+docetaxel	O
+in	O
+the	O
+treatment	O
+of	O
+prostate	B
+cancer	I
+significantly	O
+increases	O
+the	O
+frequency	O
+of	O
+VTE	B
+.	O
+
+Clinicians	O
+should	O
+be	O
+aware	O
+of	O
+this	O
+potential	O
+complication	O
+when	O
+adding	O
+thalidomide	O
+to	O
+chemotherapeutic	O
+regimens	O
+.	O
+
+Ticlopidine	O
+-	O
+induced	O
+cholestatic	B
+hepatitis	I
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+2	O
+cases	O
+of	O
+ticlopidine	O
+-	O
+induced	O
+cholestatic	B
+hepatitis	I
+,	O
+investigate	O
+its	O
+mechanism	O
+,	O
+and	O
+compare	O
+the	O
+observed	O
+main	O
+characteristics	O
+with	O
+those	O
+of	O
+the	O
+published	O
+cases	O
+.	O
+
+CASE	O
+SUMMARIES	O
+:	O
+Two	O
+patients	O
+developed	O
+prolonged	O
+cholestatic	B
+hepatitis	I
+after	O
+receiving	O
+ticlopidine	O
+following	O
+percutaneous	O
+coronary	O
+angioplasty	O
+,	O
+with	O
+complete	O
+remission	O
+during	O
+the	O
+follow	O
+-	O
+up	O
+period	O
+.	O
+
+T	O
+-	O
+cell	O
+stimulation	O
+by	O
+therapeutic	O
+concentration	O
+of	O
+ticlopidine	O
+was	O
+demonstrated	O
+in	O
+vitro	O
+in	O
+the	O
+patients	O
+,	O
+but	O
+not	O
+in	O
+healthy	O
+controls	O
+.	O
+
+DISCUSSION	O
+:	O
+Cholestatic	B
+hepatitis	I
+is	O
+a	O
+rare	O
+complication	O
+of	O
+the	O
+antiplatelet	O
+agent	O
+ticlopidine	O
+;	O
+several	O
+cases	O
+have	O
+been	O
+reported	O
+but	O
+few	O
+in	O
+the	O
+English	O
+literature	O
+.	O
+
+Our	O
+patients	O
+developed	O
+jaundice	B
+following	O
+treatment	O
+with	O
+ticlopidine	O
+and	O
+showed	O
+the	O
+clinical	O
+and	O
+laboratory	O
+characteristics	O
+of	O
+cholestatic	B
+hepatitis	I
+,	O
+which	O
+resolved	O
+after	O
+discontinuation	O
+of	O
+the	O
+drug	O
+.	O
+
+Hepatitis	B
+may	O
+develop	O
+weeks	O
+after	O
+discontinuation	O
+of	O
+the	O
+drug	O
+and	O
+may	O
+run	O
+a	O
+prolonged	O
+course	O
+,	O
+but	O
+complete	O
+remission	O
+was	O
+observed	O
+in	O
+all	O
+reported	O
+cases	O
+.	O
+
+An	O
+objective	O
+causality	O
+assessment	O
+revealed	O
+that	O
+the	O
+adverse	O
+drug	O
+event	O
+was	O
+probably	O
+related	O
+to	O
+the	O
+use	O
+of	O
+ticlopidine	O
+.	O
+
+The	O
+mechanisms	O
+of	O
+this	O
+ticlopidine	O
+-	O
+induced	O
+cholestasis	B
+are	O
+unclear	O
+.	O
+
+Immune	O
+mechanisms	O
+may	O
+be	O
+involved	O
+in	O
+the	O
+drug	O
+'	O
+s	O
+hepatotoxicity	B
+,	O
+as	O
+suggested	O
+by	O
+the	O
+T	O
+-	O
+cell	O
+stimulation	O
+study	O
+reported	O
+here	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Cholestatic	B
+hepatitis	I
+is	O
+a	O
+rare	O
+adverse	O
+effect	O
+of	O
+ticlopidine	O
+that	O
+may	O
+be	O
+immune	O
+mediated	O
+.	O
+
+Patients	O
+receiving	O
+the	O
+drug	O
+should	O
+be	O
+monitored	O
+with	O
+liver	O
+function	O
+tests	O
+along	O
+with	O
+complete	O
+blood	O
+cell	O
+counts	O
+.	O
+
+This	O
+complication	O
+will	O
+be	O
+observed	O
+even	O
+less	O
+often	O
+in	O
+the	O
+future	O
+as	O
+ticlopidine	O
+is	O
+being	O
+replaced	O
+by	O
+the	O
+newer	O
+antiplatelet	O
+agent	O
+clopidogrel	O
+.	O
+
+Epithelial	O
+sodium	O
+channel	O
+(	O
+ENaC	O
+)	O
+subunit	O
+mRNA	O
+and	O
+protein	O
+expression	O
+in	O
+rats	O
+with	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+nephrotic	B
+syndrome	I
+.	O
+
+In	O
+experimental	O
+nephrotic	B
+syndrome	I
+,	O
+urinary	O
+sodium	O
+excretion	O
+is	O
+decreased	O
+during	O
+the	O
+early	O
+phase	O
+of	O
+the	O
+disease	O
+.	O
+
+The	O
+molecular	O
+mechanism	O
+(	O
+s	O
+)	O
+leading	O
+to	O
+salt	O
+retention	O
+has	O
+not	O
+been	O
+completely	O
+elucidated	O
+.	O
+
+The	O
+rate	O
+-	O
+limiting	O
+constituent	O
+of	O
+collecting	O
+duct	O
+sodium	O
+transport	O
+is	O
+the	O
+epithelial	O
+sodium	O
+channel	O
+(	O
+ENaC	O
+)	O
+.	O
+
+We	O
+examined	O
+the	O
+abundance	O
+of	O
+ENaC	O
+subunit	O
+mRNAs	O
+and	O
+proteins	O
+in	O
+puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+)	O
+-	O
+induced	O
+nephrotic	B
+syndrome	I
+.	O
+
+The	O
+time	O
+courses	O
+of	O
+urinary	O
+sodium	O
+excretion	O
+,	O
+plasma	O
+aldosterone	O
+concentration	O
+and	O
+proteinuria	B
+were	O
+studied	O
+in	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+treated	O
+with	O
+a	O
+single	O
+dose	O
+of	O
+either	O
+PAN	O
+or	O
+vehicle	O
+.	O
+
+The	O
+relative	O
+amounts	O
+of	O
+alphaENaC	O
+,	O
+betaENaC	O
+and	O
+gammaENaC	O
+mRNAs	O
+were	O
+determined	O
+in	O
+kidneys	O
+from	O
+these	O
+rats	O
+by	O
+real	O
+-	O
+time	O
+quantitative	O
+TaqMan	O
+PCR	O
+,	O
+and	O
+the	O
+amounts	O
+of	O
+proteins	O
+by	O
+Western	O
+blot	O
+.	O
+
+The	O
+kinetics	O
+of	O
+urinary	O
+sodium	O
+excretion	O
+and	O
+the	O
+appearance	O
+of	O
+proteinuria	B
+were	O
+comparable	O
+with	O
+those	O
+reported	O
+previously	O
+.	O
+
+Sodium	O
+retention	O
+occurred	O
+on	O
+days	O
+2	O
+,	O
+3	O
+and	O
+6	O
+after	O
+PAN	O
+injection	O
+.	O
+
+A	O
+significant	O
+up	O
+-	O
+regulation	O
+of	O
+alphaENaC	O
+and	O
+betaENaC	O
+mRNA	O
+abundance	O
+on	O
+days	O
+1	O
+and	O
+2	O
+preceded	O
+sodium	O
+retention	O
+on	O
+days	O
+2	O
+and	O
+3	O
+.	O
+
+Conversely	O
+,	O
+down	O
+-	O
+regulation	O
+of	O
+alphaENaC	O
+,	O
+betaENaC	O
+and	O
+gammaENaC	O
+mRNA	O
+expression	O
+on	O
+day	O
+3	O
+occurred	O
+in	O
+the	O
+presence	O
+of	O
+high	O
+aldosterone	O
+concentrations	O
+,	O
+and	O
+was	O
+followed	O
+by	O
+a	O
+return	O
+of	O
+sodium	O
+excretion	O
+to	O
+control	O
+values	O
+.	O
+
+The	O
+amounts	O
+of	O
+alphaENaC	O
+,	O
+betaENaC	O
+and	O
+gammaENaC	O
+proteins	O
+were	O
+not	O
+increased	O
+during	O
+PAN	O
+-	O
+induced	O
+sodium	O
+retention	O
+.	O
+
+In	O
+conclusion	O
+,	O
+ENaC	O
+mRNA	O
+expression	O
+,	O
+especially	O
+alphaENaC	O
+,	O
+is	O
+increased	O
+in	O
+the	O
+very	O
+early	O
+phase	O
+of	O
+the	O
+experimental	O
+model	O
+of	O
+PAN	O
+-	O
+induced	O
+nephrotic	B
+syndrome	I
+in	O
+rats	O
+,	O
+but	O
+appears	O
+to	O
+escape	O
+from	O
+the	O
+regulation	O
+by	O
+aldosterone	O
+after	O
+day	O
+3	O
+.	O
+
+Sub	O
+-	O
+chronic	O
+low	O
+dose	O
+gamma	O
+-	O
+vinyl	O
+GABA	O
+(	O
+vigabatrin	O
+)	O
+inhibits	O
+cocaine	O
+-	O
+induced	O
+increases	O
+in	O
+nucleus	O
+accumbens	O
+dopamine	O
+.	O
+
+RATIONALE	O
+:	O
+gamma	O
+-	O
+Vinyl	O
+GABA	O
+(	O
+GVG	O
+)	O
+irreversibly	O
+inhibits	O
+GABA	O
+-	O
+transaminase	O
+.	O
+
+This	O
+non	O
+-	O
+receptor	O
+mediated	O
+inhibition	O
+requires	O
+de	O
+novo	O
+synthesis	O
+for	O
+restoration	O
+of	O
+functional	O
+GABA	O
+catabolism	O
+.	O
+
+OBJECTIVES	O
+:	O
+Given	O
+its	O
+preclinical	O
+success	O
+for	O
+treating	O
+substance	B
+abuse	I
+and	O
+the	O
+increased	O
+risk	O
+of	O
+visual	B
+field	I
+defects	I
+(	O
+VFD	B
+)	O
+associated	O
+with	O
+cumulative	O
+lifetime	O
+exposure	O
+,	O
+we	O
+explored	O
+the	O
+effects	O
+of	O
+sub	O
+-	O
+chronic	O
+low	O
+dose	O
+GVG	O
+on	O
+cocaine	O
+-	O
+induced	O
+increases	O
+in	O
+nucleus	O
+accumbens	O
+(	O
+NAcc	O
+)	O
+dopamine	O
+(	O
+DA	O
+)	O
+.	O
+
+METHODS	O
+:	O
+Using	O
+in	O
+vivo	O
+microdialysis	O
+,	O
+we	O
+compared	O
+acute	O
+exposure	O
+(	O
+450	O
+mg	O
+/	O
+kg	O
+)	O
+to	O
+an	O
+identical	O
+sub	O
+-	O
+chronic	O
+exposure	O
+(	O
+150	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+for	O
+3	O
+days	O
+)	O
+,	O
+followed	O
+by	O
+1	O
+-	O
+or	O
+3	O
+-	O
+day	O
+washout	O
+.	O
+
+Finally	O
+,	O
+we	O
+examined	O
+the	O
+low	O
+dose	O
+of	O
+150	O
+mg	O
+/	O
+kg	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+)	O
+using	O
+a	O
+similar	O
+washout	O
+period	O
+.	O
+
+RESULTS	O
+:	O
+Sub	O
+-	O
+chronic	O
+GVG	O
+exposure	O
+inhibited	O
+the	O
+effect	O
+of	O
+cocaine	O
+for	O
+3	O
+days	O
+,	O
+which	O
+exceeded	O
+in	O
+magnitude	O
+and	O
+duration	O
+the	O
+identical	O
+acute	O
+dose	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Sub	O
+-	O
+chronic	O
+low	O
+dose	O
+GVG	O
+potentiates	O
+and	O
+extends	O
+the	O
+inhibition	O
+of	O
+cocaine	O
+-	O
+induced	O
+increases	O
+in	O
+dopamine	O
+,	O
+effectively	O
+reducing	O
+cumulative	O
+exposures	O
+and	O
+the	O
+risk	O
+for	O
+VFDS	O
+.	O
+
+MR	O
+imaging	O
+with	O
+quantitative	O
+diffusion	O
+mapping	O
+of	O
+tacrolimus	O
+-	O
+induced	O
+neurotoxicity	B
+in	O
+organ	O
+transplant	O
+patients	O
+.	O
+
+Our	O
+objective	O
+was	O
+to	O
+investigate	O
+brain	O
+MR	O
+imaging	O
+findings	O
+and	O
+the	O
+utility	O
+of	O
+diffusion	O
+-	O
+weighted	O
+(	O
+DW	O
+)	O
+imaging	O
+in	O
+organ	O
+transplant	O
+patients	O
+who	O
+developed	O
+neurologic	O
+symptoms	O
+during	O
+tacrolimus	O
+therapy	O
+.	O
+
+Brain	O
+MR	O
+studies	O
+,	O
+including	O
+DW	O
+imaging	O
+,	O
+were	O
+prospectively	O
+performed	O
+in	O
+14	O
+organ	O
+transplant	O
+patients	O
+receiving	O
+tacrolimus	O
+who	O
+developed	O
+neurologic	B
+complications	I
+.	O
+
+In	O
+each	O
+patient	O
+who	O
+had	O
+abnormalities	O
+on	O
+the	O
+initial	O
+MR	O
+study	O
+,	O
+a	O
+follow	O
+-	O
+up	O
+MR	O
+study	O
+was	O
+performed	O
+1	O
+month	O
+later	O
+.	O
+
+Apparent	O
+diffusion	O
+coefficient	O
+(	O
+ADC	O
+)	O
+values	O
+on	O
+the	O
+initial	O
+MR	O
+study	O
+were	O
+correlated	O
+with	O
+reversibility	O
+of	O
+the	O
+lesions	O
+.	O
+
+Of	O
+the	O
+14	O
+patients	O
+,	O
+5	O
+(	O
+35	O
+.	O
+7	O
+%	O
+)	O
+had	O
+white	B
+matter	I
+abnormalities	I
+,	O
+1	O
+(	O
+7	O
+.	O
+1	O
+%	O
+)	O
+had	O
+putaminal	B
+hemorrhage	I
+,	O
+and	O
+8	O
+(	O
+57	O
+.	O
+1	O
+%	O
+)	O
+had	O
+normal	O
+findings	O
+on	O
+initial	O
+MR	O
+images	O
+.	O
+
+Among	O
+the	O
+5	O
+patients	O
+with	O
+white	B
+matter	I
+abnormalities	I
+,	O
+4	O
+patients	O
+(	O
+80	O
+.	O
+0	O
+%	O
+)	O
+showed	O
+higher	O
+than	O
+normal	O
+ADC	O
+values	O
+on	O
+initial	O
+MR	O
+images	O
+,	O
+and	O
+all	O
+showed	O
+complete	O
+resolution	O
+on	O
+follow	O
+-	O
+up	O
+images	O
+.	O
+
+The	O
+remaining	O
+1	O
+patient	O
+(	O
+20	O
+.	O
+0	O
+%	O
+)	O
+showed	O
+lower	O
+than	O
+normal	O
+ADC	O
+value	O
+and	O
+showed	O
+incomplete	O
+resolution	O
+with	O
+cortical	B
+laminar	I
+necrosis	I
+.	O
+
+Diffusion	O
+-	O
+weighted	O
+imaging	O
+may	O
+be	O
+useful	O
+in	O
+predicting	O
+the	O
+outcomes	O
+of	O
+the	O
+lesions	O
+of	O
+tacrolimus	O
+-	O
+induced	O
+neurotoxicity	B
+.	O
+
+L	O
+-	O
+arginine	O
+transport	O
+in	O
+humans	O
+with	O
+cortisol	O
+-	O
+induced	O
+hypertension	B
+.	O
+
+A	O
+deficient	O
+L	O
+-	O
+arginine	O
+-	O
+nitric	O
+oxide	O
+system	O
+is	O
+implicated	O
+in	O
+cortisol	O
+-	O
+induced	O
+hypertension	B
+.	O
+
+We	O
+investigate	O
+whether	O
+abnormalities	O
+in	O
+L	O
+-	O
+arginine	O
+uptake	O
+contribute	O
+to	O
+this	O
+deficiency	O
+.	O
+
+Eight	O
+healthy	O
+men	O
+were	O
+recruited	O
+.	O
+
+Hydrocortisone	O
+acetate	O
+(	O
+50	O
+mg	O
+)	O
+was	O
+given	O
+orally	O
+every	O
+6	O
+hours	O
+for	O
+24	O
+hours	O
+after	O
+a	O
+5	O
+-	O
+day	O
+fixed	O
+-	O
+salt	O
+diet	O
+(	O
+150	O
+mmol	O
+/	O
+d	O
+)	O
+.	O
+
+Crossover	O
+studies	O
+were	O
+performed	O
+2	O
+weeks	O
+apart	O
+.	O
+
+Thirty	O
+milliliters	O
+of	O
+blood	O
+was	O
+obtained	O
+for	O
+isolation	O
+of	O
+peripheral	O
+blood	O
+mononuclear	O
+cells	O
+after	O
+each	O
+treatment	O
+period	O
+.	O
+
+L	O
+-	O
+arginine	O
+uptake	O
+was	O
+assessed	O
+in	O
+mononuclear	O
+cells	O
+incubated	O
+with	O
+L	O
+-	O
+arginine	O
+(	O
+1	O
+to	O
+300	O
+micromol	O
+/	O
+L	O
+)	O
+,	O
+incorporating	O
+100	O
+nmol	O
+/	O
+L	O
+[	O
+3H	O
+]	O
+-	O
+l	O
+-	O
+arginine	O
+for	O
+a	O
+period	O
+of	O
+5	O
+minutes	O
+at	O
+37	O
+degrees	O
+C	O
+.	O
+
+Forearm	O
+[	O
+3H	O
+]	O
+-	O
+L	O
+-	O
+arginine	O
+extraction	O
+was	O
+calculated	O
+after	O
+infusion	O
+of	O
+[	O
+3H	O
+]	O
+-	O
+L	O
+-	O
+arginine	O
+into	O
+the	O
+brachial	O
+artery	O
+at	O
+a	O
+rate	O
+of	O
+100	O
+nCi	O
+/	O
+min	O
+for	O
+80	O
+minutes	O
+.	O
+
+Deep	O
+forearm	O
+venous	O
+samples	O
+were	O
+collected	O
+for	O
+determination	O
+of	O
+L	O
+-	O
+arginine	O
+extraction	O
+.	O
+
+Plasma	O
+cortisol	O
+concentrations	O
+were	O
+significantly	O
+raised	O
+during	O
+the	O
+active	O
+phase	O
+(	O
+323	O
++	O
+/	O
+-	O
+43	O
+to	O
+1082	O
++	O
+/	O
+-	O
+245	O
+mmol	O
+/	O
+L	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Systolic	O
+blood	O
+pressure	O
+was	O
+elevated	O
+by	O
+an	O
+average	O
+of	O
+7	O
+mm	O
+Hg	O
+.	O
+
+Neither	O
+L	O
+-	O
+arginine	O
+transport	O
+into	O
+mononuclear	O
+cells	O
+(	O
+placebo	O
+vs	O
+active	O
+,	O
+26	O
+.	O
+3	O
++	O
+/	O
+-	O
+3	O
+.	O
+6	O
+vs	O
+29	O
+.	O
+0	O
++	O
+/	O
+-	O
+2	O
+.	O
+1	O
+pmol	O
+/	O
+10	O
+000	O
+cells	O
+per	O
+5	O
+minutes	O
+,	O
+respectively	O
+,	O
+at	O
+an	O
+l	O
+-	O
+arginine	O
+concentration	O
+of	O
+300	O
+micromol	O
+/	O
+L	O
+)	O
+nor	O
+L	O
+-	O
+arginine	O
+extraction	O
+in	O
+the	O
+forearm	O
+(	O
+at	O
+80	O
+minutes	O
+,	O
+placebo	O
+vs	O
+active	O
+,	O
+1	O
+868	O
+904	O
++	O
+/	O
+-	O
+434	O
+962	O
+vs	O
+2	O
+013	O
+910	O
++	O
+/	O
+-	O
+770	O
+619	O
+disintegrations	O
+per	O
+minute	O
+)	O
+was	O
+affected	O
+by	O
+cortisol	O
+treatment	O
+;	O
+ie	O
+,	O
+that	O
+L	O
+-	O
+arginine	O
+uptake	O
+is	O
+not	O
+affected	O
+by	O
+short	O
+-	O
+term	O
+cortisol	O
+treatment	O
+.	O
+
+We	O
+conclude	O
+that	O
+cortisol	O
+-	O
+induced	O
+increases	B
+in	I
+blood	I
+pressure	I
+are	O
+not	O
+associated	O
+with	O
+abnormalities	O
+in	O
+the	O
+l	O
+-	O
+arginine	O
+transport	O
+system	O
+.	O
+
+Amount	O
+of	O
+bleeding	B
+and	O
+hematoma	B
+size	O
+in	O
+the	O
+collagenase	O
+-	O
+induced	O
+intracerebral	B
+hemorrhage	I
+rat	O
+model	O
+.	O
+
+The	O
+aggravated	O
+risk	O
+on	O
+intracerebral	B
+hemorrhage	I
+(	O
+ICH	B
+)	O
+with	O
+drugs	O
+used	O
+for	O
+stroke	B
+patients	O
+should	O
+be	O
+estimated	O
+carefully	O
+.	O
+
+We	O
+therefore	O
+established	O
+sensitive	O
+quantification	O
+methods	O
+and	O
+provided	O
+a	O
+rat	O
+ICH	B
+model	O
+for	O
+detection	O
+of	O
+ICH	B
+deterioration	O
+.	O
+
+In	O
+ICH	B
+intrastriatally	O
+induced	O
+by	O
+0	O
+.	O
+014	O
+-	O
+unit	O
+,	O
+0	O
+.	O
+070	O
+-	O
+unit	O
+,	O
+and	O
+0	O
+.	O
+350	O
+-	O
+unit	O
+collagenase	O
+,	O
+the	O
+amount	O
+of	O
+bleeding	B
+was	O
+measured	O
+using	O
+a	O
+hemoglobin	O
+assay	O
+developed	O
+in	O
+the	O
+present	O
+study	O
+and	O
+was	O
+compared	O
+with	O
+the	O
+morphologically	O
+determined	O
+hematoma	B
+volume	O
+.	O
+
+The	O
+blood	O
+amounts	O
+and	O
+hematoma	B
+volumes	O
+were	O
+significantly	O
+correlated	O
+,	O
+and	O
+the	O
+hematoma	B
+induced	O
+by	O
+0	O
+.	O
+014	O
+-	O
+unit	O
+collagenase	O
+was	O
+adequate	O
+to	O
+detect	O
+ICH	B
+deterioration	O
+.	O
+
+In	O
+ICH	B
+induction	O
+using	O
+0	O
+.	O
+014	O
+-	O
+unit	O
+collagenase	O
+,	O
+heparin	O
+enhanced	O
+the	O
+hematoma	B
+volume	O
+3	O
+.	O
+4	O
+-	O
+fold	O
+over	O
+that	O
+seen	O
+in	O
+control	O
+ICH	B
+animals	O
+and	O
+the	O
+bleeding	B
+7	O
+.	O
+6	O
+-	O
+fold	O
+.	O
+
+Data	O
+suggest	O
+that	O
+this	O
+sensitive	O
+hemoglobin	O
+assay	O
+is	O
+useful	O
+for	O
+ICH	B
+detection	O
+,	O
+and	O
+that	O
+a	O
+model	O
+with	O
+a	O
+small	O
+ICH	B
+induced	O
+with	O
+a	O
+low	O
+-	O
+dose	O
+collagenase	O
+should	O
+be	O
+used	O
+for	O
+evaluation	O
+of	O
+drugs	O
+that	O
+may	O
+affect	O
+ICH	B
+.	O
+
+Estradiol	O
+reduces	O
+seizure	B
+-	O
+induced	O
+hippocampal	B
+injury	I
+in	O
+ovariectomized	O
+female	O
+but	O
+not	O
+in	O
+male	O
+rats	O
+.	O
+
+Estrogens	O
+protect	O
+ovariectomized	O
+rats	O
+from	O
+hippocampal	B
+injury	I
+induced	O
+by	O
+kainic	O
+acid	O
+-	O
+induced	O
+status	B
+epilepticus	I
+(	O
+SE	B
+)	O
+.	O
+
+We	O
+compared	O
+the	O
+effects	O
+of	O
+17beta	O
+-	O
+estradiol	O
+in	O
+adult	O
+male	O
+and	O
+ovariectomized	O
+female	O
+rats	O
+subjected	O
+to	O
+lithium	O
+-	O
+pilocarpine	O
+-	O
+induced	O
+SE	B
+.	O
+
+Rats	O
+received	O
+subcutaneous	O
+injections	O
+of	O
+17beta	O
+-	O
+estradiol	O
+(	O
+2	O
+microg	O
+/	O
+rat	O
+)	O
+or	O
+oil	O
+once	O
+daily	O
+for	O
+four	O
+consecutive	O
+days	O
+.	O
+
+SE	B
+was	O
+induced	O
+20	O
+h	O
+following	O
+the	O
+second	O
+injection	O
+and	O
+terminated	O
+3	O
+h	O
+later	O
+.	O
+
+The	O
+extent	O
+of	O
+silver	O
+-	O
+stained	O
+CA3	O
+and	O
+CA1	O
+hippocampal	O
+neurons	O
+was	O
+evaluated	O
+2	O
+days	O
+after	O
+SE	B
+.	O
+
+17beta	O
+-	O
+Estradiol	O
+did	O
+not	O
+alter	O
+the	O
+onset	O
+of	O
+first	O
+clonus	O
+in	O
+ovariectomized	O
+rats	O
+but	O
+accelerated	O
+it	O
+in	O
+males	O
+.	O
+
+17beta	O
+-	O
+Estradiol	O
+reduced	O
+the	O
+argyrophilic	O
+neurons	O
+in	O
+the	O
+CA1	O
+and	O
+CA3	O
+-	O
+C	O
+sectors	O
+of	O
+ovariectomized	O
+rats	O
+.	O
+
+In	O
+males	O
+,	O
+estradiol	O
+increased	O
+the	O
+total	O
+damage	O
+score	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+the	O
+effects	O
+of	O
+estradiol	O
+on	O
+seizure	B
+threshold	O
+and	O
+damage	O
+may	O
+be	O
+altered	O
+by	O
+sex	O
+-	O
+related	O
+differences	O
+in	O
+the	O
+hormonal	O
+environment	O
+.	O
+
+Pseudoacromegaly	B
+induced	O
+by	O
+the	O
+long	O
+-	O
+term	O
+use	O
+of	O
+minoxidil	O
+.	O
+
+Acromegaly	B
+is	O
+an	O
+endocrine	B
+disorder	I
+caused	O
+by	O
+chronic	O
+excessive	O
+growth	O
+hormone	O
+secretion	O
+from	O
+the	O
+anterior	O
+pituitary	O
+gland	O
+.	O
+
+Significant	O
+disfiguring	O
+changes	O
+occur	O
+as	O
+a	O
+result	O
+of	O
+bone	O
+,	O
+cartilage	O
+,	O
+and	O
+soft	O
+tissue	O
+hypertrophy	B
+,	O
+including	O
+the	O
+thickening	O
+of	O
+the	O
+skin	O
+,	O
+coarsening	O
+of	O
+facial	O
+features	O
+,	O
+and	O
+cutis	B
+verticis	I
+gyrata	I
+.	O
+
+Pseudoacromegaly	B
+,	O
+on	O
+the	O
+other	O
+hand	O
+,	O
+is	O
+the	O
+presence	O
+of	O
+similar	O
+acromegaloid	O
+features	O
+in	O
+the	O
+absence	O
+of	O
+elevated	O
+growth	O
+hormone	O
+or	O
+insulin	O
+-	O
+like	O
+growth	O
+factor	O
+levels	O
+.	O
+
+We	O
+present	O
+a	O
+patient	O
+with	O
+pseudoacromegaly	B
+that	O
+resulted	O
+from	O
+the	O
+long	O
+-	O
+term	O
+use	O
+of	O
+minoxidil	O
+at	O
+an	O
+unusually	O
+high	O
+dose	O
+.	O
+
+This	O
+is	O
+the	O
+first	O
+case	O
+report	O
+of	O
+pseudoacromegaly	B
+as	O
+a	O
+side	O
+effect	O
+of	O
+minoxidil	O
+use	O
+.	O
+
+Combined	O
+androgen	O
+blockade	O
+-	O
+induced	O
+anemia	B
+in	O
+prostate	B
+cancer	I
+patients	O
+without	O
+bone	O
+involvement	O
+.	O
+
+BACKGROUND	O
+:	O
+To	O
+determine	O
+the	O
+onset	O
+and	O
+extent	O
+of	O
+combined	O
+androgen	O
+blockade	O
+(	O
+CAB	O
+)	O
+-	O
+induced	O
+anemia	B
+in	O
+prostate	B
+cancer	I
+patients	O
+without	O
+bone	O
+involvement	O
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+Forty	O
+-	O
+two	O
+patients	O
+with	O
+biopsy	O
+-	O
+proven	O
+prostatic	B
+adenocarcinoma	I
+[	O
+26	O
+with	O
+stage	O
+C	O
+(	O
+T3N0M0	O
+)	O
+and	O
+16	O
+with	O
+stage	O
+D1	O
+(	O
+T3N1M0	O
+)	O
+]	O
+were	O
+included	O
+in	O
+this	O
+study	O
+.	O
+
+All	O
+patients	O
+received	O
+CAB	O
+[	O
+leuprolide	O
+acetate	O
+(	O
+LHRH	O
+-	O
+A	O
+)	O
+3	O
+.	O
+75	O
+mg	O
+,	O
+intramuscularly	O
+,	O
+every	O
+28	O
+days	O
+plus	O
+250	O
+mg	O
+flutamide	O
+,	O
+tid	O
+,	O
+per	O
+Os	O
+]	O
+and	O
+were	O
+evaluated	O
+for	O
+anemia	B
+by	O
+physical	O
+examination	O
+and	O
+laboratory	O
+tests	O
+at	O
+baseline	O
+and	O
+4	O
+subsequent	O
+intervals	O
+(	O
+1	O
+,	O
+2	O
+,	O
+3	O
+and	O
+6	O
+months	O
+post	O
+-	O
+CAB	O
+)	O
+.	O
+
+Hb	O
+,	O
+PSA	O
+and	O
+Testosterone	O
+measurements	O
+were	O
+recorded	O
+.	O
+
+Patients	O
+with	O
+stage	O
+D2	O
+-	O
+3	O
+disease	O
+,	O
+abnormal	O
+hemoglobin	O
+level	O
+or	O
+renal	O
+and	O
+liver	O
+function	O
+tests	O
+that	O
+were	O
+higher	O
+than	O
+the	O
+upper	O
+limits	O
+were	O
+excluded	O
+from	O
+the	O
+study	O
+.	O
+
+The	O
+duration	O
+of	O
+the	O
+study	O
+was	O
+six	O
+months	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+mean	O
+hemoglobin	O
+(	O
+Hb	O
+)	O
+levels	O
+were	O
+significantly	O
+declined	O
+in	O
+all	O
+patients	O
+from	O
+baseline	O
+of	O
+14	O
+.	O
+2	O
+g	O
+/	O
+dl	O
+to	O
+14	O
+.	O
+0	O
+g	O
+/	O
+dl	O
+,	O
+13	O
+.	O
+5	O
+g	O
+/	O
+dl	O
+,	O
+13	O
+.	O
+2	O
+g	O
+/	O
+dl	O
+and	O
+12	O
+.	O
+7	O
+g	O
+/	O
+dl	O
+at	O
+1	O
+,	O
+2	O
+,	O
+3	O
+and	O
+6	O
+months	O
+post	O
+-	O
+CAB	O
+,	O
+respectively	O
+.	O
+
+Severe	O
+and	O
+clinically	O
+evident	O
+anemia	B
+of	O
+Hb	O
+<	O
+11	O
+g	O
+/	O
+dl	O
+with	O
+clinical	O
+symptoms	O
+was	O
+detected	O
+in	O
+6	O
+patients	O
+(	O
+14	O
+.	O
+3	O
+%	O
+)	O
+.	O
+
+This	O
+CAB	O
+-	O
+induced	O
+anemia	B
+was	O
+normochromic	O
+and	O
+normocytic	O
+.	O
+
+At	O
+six	O
+months	O
+post	O
+-	O
+CAB	O
+,	O
+patients	O
+with	O
+severe	O
+anemia	B
+had	O
+a	O
+Hb	O
+mean	O
+value	O
+of	O
+10	O
+.	O
+2	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+g	O
+/	O
+dl	O
+(	O
+X	O
++	O
+/	O
+-	O
+SE	O
+)	O
+,	O
+whereas	O
+the	O
+other	O
+patients	O
+had	O
+mild	O
+anemia	B
+with	O
+Hb	O
+mean	O
+value	O
+of	O
+13	O
+.	O
+2	O
++	O
+/	O
+-	O
+0	O
+.	O
+17	O
+(	O
+X	O
++	O
+/	O
+-	O
+SE	O
+)	O
+.	O
+
+The	O
+development	O
+of	O
+severe	O
+anemia	B
+at	O
+6	O
+months	O
+post	O
+-	O
+CAB	O
+was	O
+predictable	O
+by	O
+the	O
+reduction	O
+of	O
+Hb	O
+baseline	O
+value	O
+of	O
+more	O
+than	O
+2	O
+.	O
+5	O
+g	O
+/	O
+dl	O
+after	O
+3	O
+months	O
+of	O
+CAB	O
+(	O
+p	O
+=	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+The	O
+development	O
+of	O
+severe	O
+CAB	O
+-	O
+induced	O
+anemia	B
+in	O
+prostate	B
+cancer	I
+patients	O
+did	O
+not	O
+correlate	O
+with	O
+T	O
+baseline	O
+values	O
+(	O
+T	O
+<	O
+3	O
+ng	O
+/	O
+ml	O
+versus	O
+T	O
+>	O
+or	O
+=	O
+3	O
+ng	O
+/	O
+ml	O
+)	O
+,	O
+with	O
+age	O
+(	O
+<	O
+76	O
+yrs	O
+versus	O
+>	O
+or	O
+=	O
+76	O
+yrs	O
+)	O
+,	O
+and	O
+clinical	O
+stage	O
+(	O
+stage	O
+C	O
+versus	O
+stage	O
+D1	O
+)	O
+.	O
+
+Severe	O
+and	O
+clinically	O
+evident	O
+anemia	B
+was	O
+easily	O
+corrected	O
+by	O
+subcutaneous	O
+injections	O
+(	O
+3	O
+times	O
+/	O
+week	O
+for	O
+1	O
+month	O
+)	O
+of	O
+recombinant	O
+erythropoietin	O
+(	O
+rHuEPO	O
+-	O
+beta	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+Our	O
+data	O
+suggest	O
+that	O
+rHuEPO	O
+-	O
+beta	O
+correctable	O
+CAB	O
+-	O
+induced	O
+anemia	B
+occurs	O
+in	O
+14	O
+.	O
+3	O
+%	O
+of	O
+prostate	B
+cancer	I
+patients	O
+after	O
+6	O
+months	O
+of	O
+therapy	O
+.	O
+
+Delirium	B
+during	O
+clozapine	O
+treatment	O
+:	O
+incidence	O
+and	O
+associated	O
+risk	O
+factors	O
+.	O
+
+BACKGROUND	O
+:	O
+Incidence	O
+and	O
+risk	O
+factors	O
+for	O
+delirium	B
+during	O
+clozapine	O
+treatment	O
+require	O
+further	O
+clarification	O
+.	O
+
+METHODS	O
+:	O
+We	O
+used	O
+computerized	O
+pharmacy	O
+records	O
+to	O
+identify	O
+all	O
+adult	O
+psychiatric	B
+inpatients	O
+treated	O
+with	O
+clozapine	O
+(	O
+1995	O
+-	O
+96	O
+)	O
+,	O
+reviewed	O
+their	O
+medical	O
+records	O
+to	O
+score	O
+incidence	O
+and	O
+severity	O
+of	O
+delirium	B
+,	O
+and	O
+tested	O
+associations	O
+with	O
+potential	O
+risk	O
+factors	O
+.	O
+
+RESULTS	O
+:	O
+Subjects	O
+(	O
+n	O
+=	O
+139	O
+)	O
+were	O
+72	O
+women	O
+and	O
+67	O
+men	O
+,	O
+aged	O
+40	O
+.	O
+8	O
++	O
+/	O
+-	O
+12	O
+.	O
+1	O
+years	O
+,	O
+hospitalized	O
+for	O
+24	O
+.	O
+9	O
++	O
+/	O
+-	O
+23	O
+.	O
+3	O
+days	O
+,	O
+and	O
+given	O
+clozapine	O
+,	O
+gradually	O
+increased	O
+to	O
+an	O
+average	O
+daily	O
+dose	O
+of	O
+282	O
++	O
+/	O
+-	O
+203	O
+mg	O
+(	O
+3	O
+.	O
+45	O
++	O
+/	O
+-	O
+2	O
+.	O
+45	O
+mg	O
+/	O
+kg	O
+)	O
+for	O
+18	O
+.	O
+9	O
++	O
+/	O
+-	O
+16	O
+.	O
+4	O
+days	O
+.	O
+
+Delirium	B
+was	O
+diagnosed	O
+in	O
+14	O
+(	O
+10	O
+.	O
+1	O
+%	O
+incidence	O
+,	O
+or	O
+1	O
+.	O
+48	O
+cases	O
+/	O
+person	O
+-	O
+years	O
+of	O
+exposure	O
+)	O
+;	O
+71	O
+.	O
+4	O
+%	O
+of	O
+cases	O
+were	O
+moderate	O
+or	O
+severe	O
+.	O
+
+Associated	O
+factors	O
+were	O
+co	O
+-	O
+treatment	O
+with	O
+other	O
+centrally	O
+antimuscarinic	O
+agents	O
+,	O
+poor	O
+clinical	O
+outcome	O
+,	O
+older	O
+age	O
+,	O
+and	O
+longer	O
+hospitalization	O
+(	O
+by	O
+17	O
+.	O
+5	O
+days	O
+,	O
+increasing	O
+cost	O
+)	O
+;	O
+sex	O
+,	O
+diagnosis	O
+or	O
+medical	O
+co	O
+-	O
+morbidity	O
+,	O
+and	O
+daily	O
+clozapine	O
+dose	O
+,	O
+which	O
+fell	O
+with	O
+age	O
+,	O
+were	O
+unrelated	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Delirium	B
+was	O
+found	O
+in	O
+10	O
+%	O
+of	O
+clozapine	O
+-	O
+treated	O
+inpatients	O
+,	O
+particularly	O
+in	O
+older	O
+patients	O
+exposed	O
+to	O
+other	O
+central	O
+anticholinergics	O
+.	O
+
+Delirium	B
+was	O
+inconsistently	O
+recognized	O
+clinically	O
+in	O
+milder	O
+cases	O
+and	O
+was	O
+associated	O
+with	O
+increased	O
+length	O
+-	O
+of	O
+-	O
+stay	O
+and	O
+higher	O
+costs	O
+,	O
+and	O
+inferior	O
+clinical	O
+outcome	O
+.	O
+
+Neuroprotective	O
+action	O
+of	O
+MPEP	O
+,	O
+a	O
+selective	O
+mGluR5	O
+antagonist	O
+,	O
+in	O
+methamphetamine	O
+-	O
+induced	O
+dopaminergic	O
+neurotoxicity	B
+is	O
+associated	O
+with	O
+a	O
+decrease	O
+in	O
+dopamine	O
+outflow	O
+and	O
+inhibition	O
+of	O
+hyperthermia	B
+in	O
+rats	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+examine	O
+the	O
+role	O
+of	O
+metabotropic	O
+glutamate	O
+receptor	O
+5	O
+(	O
+mGluR5	O
+)	O
+in	O
+the	O
+toxic	O
+action	O
+of	O
+methamphetamine	O
+on	O
+dopaminergic	O
+neurones	O
+in	O
+rats	O
+.	O
+
+Methamphetamine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+sc	O
+)	O
+,	O
+administered	O
+five	O
+times	O
+,	O
+reduced	O
+the	O
+levels	O
+of	O
+dopamine	O
+and	O
+its	O
+metabolites	O
+in	O
+striatal	O
+tissue	O
+when	O
+measured	O
+72	O
+h	O
+after	O
+the	O
+last	O
+injection	O
+.	O
+
+A	O
+selective	O
+antagonist	O
+of	O
+mGluR5	O
+,	O
+2	O
+-	O
+methyl	O
+-	O
+6	O
+-	O
+(	O
+phenylethynyl	O
+)	O
+pyridine	O
+(	O
+MPEP	O
+;	O
+5	O
+mg	O
+/	O
+kg	O
+ip	O
+)	O
+,	O
+when	O
+administered	O
+five	O
+times	O
+immediately	O
+before	O
+each	O
+methamphetamine	O
+injection	O
+reversed	O
+the	O
+above	O
+-	O
+mentioned	O
+methamphetamine	O
+effects	O
+.	O
+
+A	O
+single	O
+MPEP	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+ip	O
+)	O
+injection	O
+reduced	O
+the	O
+basal	O
+extracellular	O
+dopamine	O
+level	O
+in	O
+the	O
+striatum	O
+,	O
+as	O
+well	O
+as	O
+dopamine	O
+release	O
+stimulated	O
+either	O
+by	O
+methamphetamine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+sc	O
+)	O
+or	O
+by	O
+intrastriatally	O
+administered	O
+veratridine	O
+(	O
+100	O
+microM	O
+)	O
+.	O
+
+Moreover	O
+,	O
+it	O
+transiently	O
+diminished	O
+the	O
+methamphetamine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+sc	O
+)	O
+-	O
+induced	O
+hyperthermia	B
+and	O
+reduced	O
+basal	O
+body	O
+temperature	O
+.	O
+
+MPEP	O
+administered	O
+into	O
+the	O
+striatum	O
+at	O
+high	O
+concentrations	O
+(	O
+500	O
+microM	O
+)	O
+increased	O
+extracellular	O
+dopamine	O
+levels	O
+,	O
+while	O
+lower	O
+concentrations	O
+(	O
+50	O
+-	O
+100	O
+microM	O
+)	O
+were	O
+devoid	O
+of	O
+any	O
+effect	O
+.	O
+
+The	O
+results	O
+of	O
+this	O
+study	O
+suggest	O
+that	O
+the	O
+blockade	O
+of	O
+mGluR5	O
+by	O
+MPEP	O
+may	O
+protect	O
+dopaminergic	O
+neurones	O
+against	O
+methamphetamine	O
+-	O
+induced	O
+toxicity	B
+.	O
+
+Neuroprotection	O
+rendered	O
+by	O
+MPEP	O
+may	O
+be	O
+associated	O
+with	O
+the	O
+reduction	O
+of	O
+the	O
+methamphetamine	O
+-	O
+induced	O
+dopamine	O
+efflux	O
+in	O
+the	O
+striatum	O
+due	O
+to	O
+the	O
+blockade	O
+of	O
+extrastriatal	O
+mGluR5	O
+,	O
+and	O
+with	O
+a	O
+decrease	O
+in	O
+hyperthermia	B
+.	O
+
+Protective	O
+efficacy	O
+of	O
+neuroactive	O
+steroids	O
+against	O
+cocaine	O
+kindled	O
+-	O
+seizures	B
+in	O
+mice	O
+.	O
+
+Neuroactive	O
+steroids	O
+demonstrate	O
+pharmacological	O
+actions	O
+that	O
+have	O
+relevance	O
+for	O
+a	O
+host	O
+of	O
+neurological	B
+and	I
+psychiatric	I
+disorders	I
+.	O
+
+They	O
+offer	O
+protection	O
+against	O
+seizures	B
+in	O
+a	O
+range	O
+of	O
+models	O
+and	O
+seem	O
+to	O
+inhibit	O
+certain	O
+stages	O
+of	O
+drug	B
+dependence	I
+in	O
+preclinical	O
+assessments	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+evaluate	O
+two	O
+endogenous	O
+and	O
+one	O
+synthetic	O
+neuroactive	O
+steroid	O
+that	O
+positively	O
+modulate	O
+the	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+(	O
+GABA	O
+(	O
+A	O
+)	O
+)	O
+receptor	O
+against	O
+the	O
+increase	O
+in	O
+sensitivity	O
+to	O
+the	O
+convulsant	O
+effects	O
+of	O
+cocaine	O
+engendered	O
+by	O
+repeated	O
+cocaine	O
+administration	O
+(	O
+seizure	B
+kindling	O
+)	O
+.	O
+
+Allopregnanolone	O
+(	O
+3alpha	O
+-	O
+hydroxy	O
+-	O
+5alpha	O
+-	O
+pregnan	O
+-	O
+20	O
+-	O
+one	O
+)	O
+,	O
+pregnanolone	O
+(	O
+3alpha	O
+-	O
+hydroxy	O
+-	O
+5beta	O
+-	O
+pregnan	O
+-	O
+20	O
+-	O
+one	O
+)	O
+and	O
+ganaxolone	O
+(	O
+a	O
+synthetic	O
+derivative	O
+of	O
+allopregnanolone	O
+3alpha	O
+-	O
+hydroxy	O
+-	O
+3beta	O
+-	O
+methyl	O
+-	O
+5alpha	O
+-	O
+pregnan	O
+-	O
+20	O
+-	O
+one	O
+)	O
+were	O
+tested	O
+for	O
+their	O
+ability	O
+to	O
+suppress	O
+the	O
+expression	O
+(	O
+anticonvulsant	O
+effect	O
+)	O
+and	O
+development	O
+(	O
+antiepileptogenic	O
+effect	O
+)	O
+of	O
+cocaine	O
+-	O
+kindled	O
+seizures	B
+in	O
+male	O
+,	O
+Swiss	O
+-	O
+Webster	O
+mice	O
+.	O
+
+Kindled	O
+seizures	B
+were	O
+induced	O
+by	O
+daily	O
+administration	O
+of	O
+60	O
+mg	O
+/	O
+kg	O
+cocaine	O
+for	O
+5	O
+days	O
+.	O
+
+All	O
+of	O
+these	O
+positive	O
+GABA	O
+(	O
+A	O
+)	O
+modulators	O
+suppressed	O
+the	O
+expression	O
+of	O
+kindled	O
+seizures	B
+,	O
+whereas	O
+only	O
+allopregnanolone	O
+and	O
+ganaxolone	O
+inhibited	O
+the	O
+development	O
+of	O
+kindling	O
+.	O
+
+Allopregnanolone	O
+and	O
+pregnanolone	O
+,	O
+but	O
+not	O
+ganaxolone	O
+,	O
+also	O
+reduced	O
+cumulative	O
+lethality	O
+associated	O
+with	O
+kindling	O
+.	O
+
+These	O
+findings	O
+demonstrate	O
+that	O
+some	O
+neuroactive	O
+steroids	O
+attenuate	O
+convulsant	O
+and	O
+sensitizing	O
+properties	O
+of	O
+cocaine	O
+and	O
+add	O
+to	O
+a	O
+growing	O
+literature	O
+on	O
+their	O
+potential	O
+use	O
+in	O
+the	O
+modulation	O
+of	O
+effects	O
+of	O
+drugs	O
+of	O
+abuse	O
+.	O
+
+Effect	O
+of	O
+humoral	O
+modulators	O
+of	O
+morphine	O
+-	O
+induced	O
+increase	B
+in	I
+locomotor	I
+activity	I
+of	O
+mice	O
+.	O
+
+The	O
+effect	O
+of	O
+humoral	O
+modulators	O
+on	O
+the	O
+morphine	O
+-	O
+induced	O
+increase	B
+in	I
+locomotor	I
+activity	I
+of	O
+mice	O
+was	O
+studied	O
+.	O
+
+The	O
+subcutaneous	O
+administration	O
+of	O
+10	O
+mg	O
+/	O
+kg	O
+of	O
+morphine	O
+-	O
+HC1	O
+produced	O
+a	O
+marked	O
+increase	B
+in	I
+locomotor	I
+activity	I
+in	O
+mice	O
+.	O
+
+The	O
+morphine	O
+-	O
+induced	O
+hyperactivity	B
+was	O
+potentiated	O
+by	O
+scopolamine	O
+and	O
+attenuated	O
+by	O
+physostigmine	O
+.	O
+
+In	O
+contrast	O
+,	O
+both	O
+methscopolamine	O
+and	O
+neostigmine	O
+,	O
+which	O
+do	O
+not	O
+penetrate	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+,	O
+had	O
+no	O
+effect	O
+on	O
+the	O
+hyperactivity	B
+produced	O
+by	O
+morphine	O
+.	O
+
+Pretreatment	O
+of	O
+mice	O
+with	O
+alpha	O
+-	O
+methyltyrosine	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+,	O
+one	O
+hour	O
+)	O
+,	O
+an	O
+inhibitor	O
+of	O
+tyrosine	O
+hydroxylase	O
+,	O
+significantly	O
+decreased	O
+the	O
+activity	O
+-	O
+increasing	O
+effects	O
+of	O
+morphine	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+pretreatment	O
+with	O
+p	O
+-	O
+chlorophenylalamine	O
+(	O
+3	O
+X	O
+320	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+,	O
+24	O
+hr	O
+)	O
+,	O
+a	O
+serotonin	O
+depletor	O
+,	O
+caused	O
+no	O
+significant	O
+change	O
+in	O
+the	O
+hyperactivity	B
+.	O
+
+The	O
+study	O
+suggests	O
+that	O
+the	O
+activity	O
+-	O
+increasing	O
+effects	O
+of	O
+morphine	O
+are	O
+mediated	O
+by	O
+the	O
+release	O
+of	O
+catecholamines	O
+from	O
+adrenergic	O
+neurons	O
+in	O
+the	O
+brain	O
+.	O
+
+And	O
+the	O
+results	O
+are	O
+consistent	O
+with	O
+the	O
+hypothesis	O
+that	O
+morphine	O
+acts	O
+by	O
+retarding	O
+the	O
+release	O
+of	O
+acetylcholine	O
+at	O
+some	O
+central	O
+cholinergic	O
+synapses	O
+.	O
+
+It	O
+is	O
+also	O
+suggested	O
+from	O
+collected	O
+evidence	O
+that	O
+the	O
+activity	O
+-	O
+increasing	O
+effects	O
+of	O
+morphine	O
+in	O
+mice	O
+are	O
+mediated	O
+by	O
+mechanisms	O
+different	O
+from	O
+those	O
+which	O
+mediate	O
+the	O
+activity	O
+-	O
+increasing	O
+effects	O
+of	O
+morphine	O
+in	O
+rats	O
+.	O
+
+Effects	O
+of	O
+uninephrectomy	O
+and	O
+high	O
+protein	O
+feeding	O
+on	O
+lithium	O
+-	O
+induced	O
+chronic	B
+renal	I
+failure	I
+in	O
+rats	O
+.	O
+
+Rats	O
+with	O
+lithium	O
+-	O
+induced	O
+nephropathy	B
+were	O
+subjected	O
+to	O
+high	O
+protein	O
+(	O
+HP	O
+)	O
+feeding	O
+,	O
+uninephrectomy	O
+(	O
+NX	O
+)	O
+or	O
+a	O
+combination	O
+of	O
+these	O
+,	O
+in	O
+an	O
+attempt	O
+to	O
+induce	O
+glomerular	O
+hyperfiltration	O
+and	O
+further	O
+progression	O
+of	O
+renal	B
+failure	I
+.	O
+
+Newborn	O
+female	O
+Wistar	O
+rats	O
+were	O
+fed	O
+a	O
+lithium	O
+-	O
+containing	O
+diet	O
+(	O
+50	O
+mmol	O
+/	O
+kg	O
+)	O
+for	O
+8	O
+weeks	O
+and	O
+then	O
+randomized	O
+to	O
+normal	O
+diet	O
+,	O
+HP	O
+diet	O
+(	O
+40	O
+vs	O
+.	O
+19	O
+%	O
+)	O
+,	O
+NX	O
+or	O
+HP	O
++	O
+NX	O
+for	O
+another	O
+8	O
+weeks	O
+.	O
+
+Corresponding	O
+non	O
+-	O
+lithium	O
+pretreated	O
+groups	O
+were	O
+generated	O
+.	O
+
+When	O
+comparing	O
+all	O
+lithium	O
+treated	O
+versus	O
+non	O
+-	O
+lithium	O
+-	O
+treated	O
+groups	O
+,	O
+lithium	O
+caused	O
+a	O
+reduction	O
+in	O
+glomerular	O
+filtration	O
+rate	O
+(	O
+GFR	O
+)	O
+without	O
+significant	O
+changes	O
+in	O
+effective	O
+renal	O
+plasma	O
+flow	O
+(	O
+as	O
+determined	O
+by	O
+a	O
+marker	O
+secreted	O
+into	O
+the	O
+proximal	O
+tubules	O
+)	O
+or	O
+lithium	O
+clearance	O
+.	O
+
+Consequently	O
+,	O
+lithium	O
+pretreatment	O
+caused	O
+a	O
+fall	O
+in	O
+filtration	O
+fraction	O
+and	O
+an	O
+increase	O
+in	O
+fractional	O
+Li	O
+excretion	O
+.	O
+
+Lithium	O
+also	O
+caused	O
+proteinuria	B
+and	O
+systolic	O
+hypertension	B
+in	O
+absence	O
+of	O
+glomerulosclerosis	B
+.	O
+
+HP	O
+failed	O
+to	O
+accentuante	O
+progression	O
+of	O
+renal	B
+failure	I
+and	O
+in	O
+fact	O
+tended	O
+to	O
+increase	O
+GFR	O
+and	O
+decrease	O
+plasma	O
+creatinine	O
+levels	O
+in	O
+lithium	O
+pretreated	O
+rats	O
+.	O
+
+NX	O
+caused	O
+an	O
+additive	O
+deterioration	O
+in	O
+GFR	O
+which	O
+,	O
+however	O
+,	O
+was	O
+ameliorated	O
+by	O
+HP	O
+.	O
+
+NX	O
++	O
+HP	O
+caused	O
+a	O
+further	O
+rise	O
+in	O
+blood	O
+pressure	O
+in	O
+Li	O
+-	O
+pretreated	O
+rats	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+Li	O
+-	O
+induced	O
+nephropathy	B
+,	O
+even	O
+when	O
+the	O
+GFR	O
+is	O
+only	O
+modestly	O
+reduced	O
+,	O
+is	O
+associated	O
+with	O
+proteinuria	B
+and	O
+arterial	O
+systolic	O
+hypertension	B
+.	O
+
+In	O
+this	O
+model	O
+of	O
+chronic	B
+renal	I
+failure	I
+the	O
+decline	O
+in	O
+GFR	O
+is	O
+not	O
+accompanied	O
+by	O
+a	O
+corresponding	O
+fall	O
+in	O
+effective	O
+renal	O
+plasma	O
+flow	O
+,	O
+which	O
+may	O
+be	O
+the	O
+functional	O
+expression	O
+of	O
+the	O
+formation	O
+of	O
+nonfiltrating	O
+atubular	O
+glomeruli	O
+.	O
+
+The	O
+fractional	O
+reabsorption	O
+of	O
+tubular	O
+fluid	O
+by	O
+the	O
+proximal	O
+tubules	O
+is	O
+reduced	O
+,	O
+leaving	O
+the	O
+distal	O
+delivery	O
+unchanged	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Treatment	O
+of	O
+Crohn	B
+'	I
+s	I
+disease	I
+with	O
+fusidic	O
+acid	O
+:	O
+an	O
+antibiotic	O
+with	O
+immunosuppressive	O
+properties	O
+similar	O
+to	O
+cyclosporin	O
+.	O
+
+Fusidic	O
+acid	O
+is	O
+an	O
+antibiotic	O
+with	O
+T	O
+-	O
+cell	O
+specific	O
+immunosuppressive	O
+effects	O
+similar	O
+to	O
+those	O
+of	O
+cyclosporin	O
+.	O
+
+Because	O
+of	O
+the	O
+need	O
+for	O
+the	O
+development	O
+of	O
+new	O
+treatments	O
+for	O
+Crohn	B
+'	I
+s	I
+disease	I
+,	O
+a	O
+pilot	O
+study	O
+was	O
+undertaken	O
+to	O
+estimate	O
+the	O
+pharmacodynamics	O
+and	O
+tolerability	O
+of	O
+fusidic	O
+acid	O
+treatment	O
+in	O
+chronic	O
+active	O
+,	O
+therapy	O
+-	O
+resistant	O
+patients	O
+.	O
+
+Eight	O
+Crohn	B
+'	I
+s	I
+disease	I
+patients	O
+were	O
+included	O
+.	O
+
+Fusidic	O
+acid	O
+was	O
+administered	O
+orally	O
+in	O
+a	O
+dose	O
+of	O
+500	O
+mg	O
+t	O
+.	O
+d	O
+.	O
+s	O
+.	O
+and	O
+the	O
+treatment	O
+was	O
+planned	O
+to	O
+last	O
+8	O
+weeks	O
+.	O
+
+The	O
+disease	O
+activity	O
+was	O
+primarily	O
+measured	O
+by	O
+a	O
+modified	O
+individual	O
+grading	O
+score	O
+.	O
+
+Five	O
+of	O
+8	O
+patients	O
+(	O
+63	O
+%	O
+)	O
+improved	O
+during	O
+fusidic	O
+acid	O
+treatment	O
+:	O
+3	O
+at	O
+two	O
+weeks	O
+and	O
+2	O
+after	O
+four	O
+weeks	O
+.	O
+
+There	O
+were	O
+no	O
+serious	O
+clinical	O
+side	O
+effects	O
+,	O
+but	O
+dose	O
+reduction	O
+was	O
+required	O
+in	O
+two	O
+patients	O
+because	O
+of	O
+nausea	B
+.	O
+
+Biochemically	O
+,	O
+an	O
+increase	O
+in	O
+alkaline	O
+phosphatases	O
+was	O
+noted	O
+in	O
+5	O
+of	O
+8	O
+cases	O
+(	O
+63	O
+%	O
+)	O
+,	O
+and	O
+the	O
+greatest	O
+increases	O
+were	O
+seen	O
+in	O
+those	O
+who	O
+had	O
+elevated	O
+levels	O
+prior	O
+to	O
+treatment	O
+.	O
+
+All	O
+reversed	O
+to	O
+pre	O
+-	O
+treatment	O
+levels	O
+after	O
+cessation	O
+of	O
+treatment	O
+.	O
+
+The	O
+results	O
+of	O
+this	O
+pilot	O
+study	O
+suggest	O
+that	O
+fusidic	O
+acid	O
+may	O
+be	O
+of	O
+benefit	O
+in	O
+selected	O
+chronic	O
+active	O
+Crohn	B
+'	I
+s	I
+disease	I
+patients	O
+in	O
+whom	O
+conventional	O
+treatment	O
+is	O
+ineffective	O
+.	O
+
+Because	O
+there	O
+seems	O
+to	O
+exist	O
+a	O
+scientific	O
+rationale	O
+for	O
+the	O
+use	O
+of	O
+fusidic	O
+acid	O
+at	O
+the	O
+cytokine	O
+level	O
+in	O
+inflammatory	B
+bowel	I
+disease	I
+,	O
+we	O
+suggest	O
+that	O
+the	O
+role	O
+of	O
+this	O
+treatment	O
+should	O
+be	O
+further	O
+investigated	O
+.	O
+
+Changes	O
+in	O
+depressive	B
+status	O
+associated	O
+with	O
+topical	O
+beta	O
+-	O
+blockers	O
+.	O
+
+Depression	B
+and	O
+sexual	B
+dysfunction	I
+have	O
+been	O
+related	O
+to	O
+side	O
+effects	O
+of	O
+topical	O
+beta	O
+-	O
+blockers	O
+.	O
+
+We	O
+performed	O
+a	O
+preliminary	O
+study	O
+in	O
+order	O
+to	O
+determine	O
+any	O
+difference	O
+between	O
+a	O
+non	O
+selective	O
+beta	O
+-	O
+blocker	O
+(	O
+timolol	O
+)	O
+and	O
+a	O
+selective	O
+beta	O
+-	O
+blocker	O
+(	O
+betaxolol	O
+)	O
+regarding	O
+CNS	O
+side	O
+effects	O
+.	O
+
+Eight	O
+glaucomatous	B
+patients	O
+chronically	O
+treated	O
+with	O
+timolol	O
+0	O
+.	O
+5	O
+%	O
+/	O
+12h	O
+,	O
+suffering	O
+from	O
+depression	B
+diagnosed	O
+through	O
+DMS	O
+-	O
+III	O
+-	O
+R	O
+criteria	O
+,	O
+were	O
+included	O
+in	O
+the	O
+study	O
+.	O
+
+During	O
+the	O
+six	O
+-	O
+month	O
+follow	O
+up	O
+,	O
+depression	B
+was	O
+quantified	O
+through	O
+the	O
+Beck	O
+and	O
+Zung	O
+-	O
+Conde	O
+scales	O
+every	O
+two	O
+months	O
+.	O
+
+In	O
+a	O
+double	O
+blind	O
+cross	O
+-	O
+over	O
+study	O
+with	O
+control	O
+group	O
+,	O
+the	O
+patients	O
+under	O
+timolol	O
+treatment	O
+presented	O
+higher	O
+depression	B
+values	O
+measured	O
+through	O
+the	O
+Beck	O
+and	O
+the	O
+Zung	O
+-	O
+Conde	O
+scales	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+vs	O
+control	O
+)	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+betaxolol	O
+could	O
+be	O
+less	O
+of	O
+a	O
+depression	B
+-	O
+inducer	O
+than	O
+timolol	O
+in	O
+predisposed	O
+patients	O
+.	O
+
+Protection	O
+against	O
+amphetamine	O
+-	O
+induced	O
+neurotoxicity	B
+toward	O
+striatal	O
+dopamine	O
+neurons	O
+in	O
+rodents	O
+by	O
+LY274614	O
+,	O
+an	O
+excitatory	O
+amino	O
+acid	O
+antagonist	O
+.	O
+
+LY274614	O
+,	O
+3SR	O
+,	O
+4aRS	O
+,	O
+6SR	O
+,	O
+8aRS	O
+-	O
+6	O
+-	O
+[	O
+phosphonomethyl	O
+]	O
+decahydr	O
+oisoquinoline	O
+-	O
+3	O
+-	O
+carboxylic	O
+acid	O
+,	O
+has	O
+been	O
+described	O
+as	O
+a	O
+potent	O
+antagonist	O
+of	O
+the	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+subtype	O
+of	O
+glutamate	O
+receptor	O
+.	O
+
+Here	O
+its	O
+ability	O
+to	O
+antagonize	O
+the	O
+prolonged	O
+depletion	O
+of	O
+dopamine	O
+in	O
+the	O
+striatum	O
+by	O
+amphetamine	O
+in	O
+iprindole	O
+-	O
+treated	O
+rats	O
+is	O
+reported	O
+.	O
+
+A	O
+single	O
+18	O
+.	O
+4	O
+mg	O
+/	O
+kg	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+dose	O
+of	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+amphetamine	O
+hemisulfate	O
+,	O
+given	O
+to	O
+rats	O
+pretreated	O
+with	O
+iprindole	O
+,	O
+resulted	O
+in	O
+persistent	O
+depletion	O
+of	O
+dopamine	O
+in	O
+the	O
+striatum	O
+1	O
+week	O
+later	O
+.	O
+
+This	O
+prolonged	O
+depletion	O
+of	O
+dopamine	O
+in	O
+the	O
+striatum	O
+was	O
+antagonized	O
+by	O
+dizocilpine	O
+(	O
+MK	O
+-	O
+801	O
+,	O
+a	O
+non	O
+-	O
+competitive	O
+antagonist	O
+of	O
+NMDA	O
+receptors	O
+)	O
+or	O
+by	O
+LY274614	O
+(	O
+a	O
+competitive	O
+antagonist	O
+of	O
+NMDA	O
+receptors	O
+)	O
+.	O
+
+The	O
+protective	O
+effect	O
+of	O
+LY274614	O
+was	O
+dose	O
+-	O
+dependent	O
+,	O
+being	O
+maximum	O
+at	O
+10	O
+-	O
+40	O
+mgkg	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+A	O
+10	O
+mg	O
+/	O
+kg	O
+dose	O
+of	O
+LY274614	O
+was	O
+effective	O
+in	O
+antagonizing	O
+the	O
+depletion	O
+of	O
+dopamine	O
+in	O
+the	O
+striatum	O
+,	O
+when	O
+given	O
+as	O
+long	O
+as	O
+8	O
+hr	O
+prior	O
+to	O
+amphetamine	O
+but	O
+not	O
+when	O
+given	O
+24	O
+hr	O
+prior	O
+to	O
+amphetamine	O
+.	O
+
+Depletion	O
+of	O
+dopamine	O
+in	O
+the	O
+striatum	O
+was	O
+also	O
+antagonized	O
+when	O
+LY274614	O
+was	O
+given	O
+after	O
+the	O
+injection	O
+of	O
+amphetamine	O
+;	O
+LY274614	O
+protected	O
+when	O
+given	O
+up	O
+to	O
+4	O
+hr	O
+after	O
+but	O
+not	O
+when	O
+given	O
+8	O
+or	O
+24	O
+hr	O
+after	O
+amphetamine	O
+.	O
+
+The	O
+prolonged	O
+depletion	O
+of	O
+dopamine	O
+in	O
+the	O
+striatum	O
+in	O
+mice	O
+,	O
+given	O
+multiple	O
+injections	O
+of	O
+methamphetamine	O
+,	O
+was	O
+also	O
+antagonized	O
+dose	O
+-	O
+dependently	O
+and	O
+completely	O
+by	O
+LY274614	O
+.	O
+
+The	O
+data	O
+strengthen	O
+the	O
+evidence	O
+that	O
+the	O
+neurotoxic	B
+effect	O
+of	O
+amphetamine	O
+and	O
+related	O
+compounds	O
+toward	O
+nigrostriatal	O
+dopamine	O
+neurons	O
+involves	O
+NMDA	O
+receptors	O
+and	O
+that	O
+LY274614	O
+is	O
+an	O
+NMDA	O
+receptor	O
+antagonist	O
+with	O
+long	O
+-	O
+lasting	O
+in	O
+vivo	O
+effects	O
+in	O
+rats	O
+.	O
+
+Ketoconazole	O
+-	O
+induced	O
+neurologic	B
+sequelae	I
+.	O
+
+A	O
+77	O
+-	O
+y	O
+-	O
+old	O
+patient	O
+developed	O
+weakness	B
+of	I
+extremities	I
+,	O
+legs	B
+paralysis	I
+,	O
+dysarthria	B
+and	O
+tremor	B
+1	O
+h	O
+after	O
+ingestion	O
+of	O
+200	O
+mg	O
+ketoconazole	O
+for	O
+the	O
+first	O
+time	O
+in	O
+his	O
+life	O
+.	O
+
+All	O
+complaints	O
+faded	O
+away	O
+within	O
+24	O
+h	O
+.	O
+
+Few	O
+days	O
+later	O
+,	O
+the	O
+patient	O
+used	O
+another	O
+200	O
+mg	O
+ketoconazole	O
+tablet	O
+,	O
+and	O
+within	O
+an	O
+hour	O
+experienced	O
+a	O
+similar	O
+clinical	O
+picture	O
+,	O
+which	O
+resolved	O
+again	O
+spontaneously	O
+within	O
+hours	O
+.	O
+
+Laboratory	O
+evaluations	O
+,	O
+including	O
+head	O
+CT	O
+scan	O
+,	O
+were	O
+normal	O
+.	O
+
+This	O
+case	O
+illustrates	O
+the	O
+need	O
+for	O
+close	O
+vigilance	O
+in	O
+adverse	B
+drug	I
+reactions	I
+,	O
+particularly	O
+in	O
+the	O
+elderly	O
+.	O
+
+Development	O
+of	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+in	O
+parkinsonian	B
+monkeys	O
+may	O
+depend	O
+upon	O
+rate	O
+of	O
+symptom	O
+onset	O
+and	O
+/	O
+or	O
+duration	O
+of	O
+symptoms	O
+.	O
+
+Levodopa	O
+-	O
+induced	O
+dyskinesias	B
+(	O
+LIDs	B
+)	O
+present	O
+a	O
+major	O
+problem	O
+for	O
+the	O
+long	O
+-	O
+term	O
+management	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+patients	O
+.	O
+
+Due	O
+to	O
+the	O
+interdependence	O
+of	O
+risk	O
+factors	O
+in	O
+clinical	O
+populations	O
+,	O
+it	O
+is	O
+difficult	O
+to	O
+independently	O
+examine	O
+factors	O
+that	O
+may	O
+influence	O
+the	O
+development	O
+of	O
+LIDs	B
+.	O
+
+Using	O
+macaque	O
+monkeys	O
+with	O
+different	O
+types	O
+of	O
+MPTP	O
+-	O
+induced	O
+parkinsonism	B
+,	O
+the	O
+current	O
+study	O
+evaluated	O
+the	O
+degree	O
+to	O
+which	O
+rate	O
+of	O
+symptom	O
+progression	O
+,	O
+symptom	O
+severity	O
+,	O
+and	O
+response	O
+to	O
+and	O
+duration	O
+of	O
+levodopa	O
+therapy	O
+may	O
+be	O
+involved	O
+in	O
+the	O
+development	O
+of	O
+LIDs	B
+.	O
+
+Monkeys	O
+with	O
+acute	O
+(	O
+short	O
+-	O
+term	O
+)	O
+MPTP	O
+exposure	O
+,	O
+rapid	O
+symptom	O
+onset	O
+and	O
+short	O
+symptom	O
+duration	O
+prior	O
+to	O
+initiation	O
+of	O
+levodopa	O
+therapy	O
+developed	O
+dyskinesia	B
+between	O
+11	O
+and	O
+24	O
+days	O
+of	O
+daily	O
+levodopa	O
+administration	O
+.	O
+
+In	O
+contrast	O
+,	O
+monkeys	O
+with	O
+long	O
+-	O
+term	O
+MPTP	O
+exposure	O
+,	O
+slow	O
+symptom	O
+progression	O
+and	O
+/	O
+or	O
+long	O
+symptom	O
+duration	O
+prior	O
+to	O
+initiation	O
+of	O
+levodopa	O
+therapy	O
+were	O
+more	O
+resistant	O
+to	O
+developing	O
+LIDs	B
+(	O
+e	O
+.	O
+g	O
+.	O
+,	O
+dyskinesia	B
+developed	O
+no	O
+sooner	O
+than	O
+146	O
+days	O
+of	O
+chronic	O
+levodopa	O
+administration	O
+)	O
+.	O
+
+All	O
+animals	O
+were	O
+similarly	O
+symptomatic	O
+at	O
+the	O
+start	O
+of	O
+levodopa	O
+treatment	O
+and	O
+had	O
+similar	O
+therapeutic	O
+responses	O
+to	O
+the	O
+drug	O
+.	O
+
+These	O
+data	O
+suggest	O
+distinct	O
+differences	O
+in	O
+the	O
+propensity	O
+to	O
+develop	O
+LIDs	B
+in	O
+monkeys	O
+with	O
+different	O
+rates	O
+of	O
+symptom	O
+progression	O
+or	O
+symptom	O
+durations	O
+prior	O
+to	O
+levodopa	O
+and	O
+demonstrate	O
+the	O
+value	O
+of	O
+these	O
+models	O
+for	O
+further	O
+studying	O
+the	O
+pathophysiology	O
+of	O
+LIDs	B
+.	O
+
+A	O
+diet	O
+promoting	O
+sugar	B
+dependency	I
+causes	O
+behavioral	B
+cross	I
+-	I
+sensitization	I
+to	O
+a	O
+low	O
+dose	O
+of	O
+amphetamine	O
+.	O
+
+Previous	O
+research	O
+in	O
+this	O
+laboratory	O
+has	O
+shown	O
+that	O
+a	O
+diet	O
+of	O
+intermittent	O
+excessive	O
+sugar	O
+consumption	O
+produces	O
+a	O
+state	O
+with	O
+neurochemical	O
+and	O
+behavioral	O
+similarities	O
+to	O
+drug	B
+dependency	I
+.	O
+
+The	O
+present	O
+study	O
+examined	O
+whether	O
+female	O
+rats	O
+on	O
+various	O
+regimens	O
+of	O
+sugar	O
+access	O
+would	O
+show	O
+behavioral	B
+cross	I
+-	I
+sensitization	I
+to	O
+a	O
+low	O
+dose	O
+of	O
+amphetamine	O
+.	O
+
+After	O
+a	O
+30	O
+-	O
+min	O
+baseline	O
+measure	O
+of	O
+locomotor	O
+activity	O
+(	O
+day	O
+0	O
+)	O
+,	O
+animals	O
+were	O
+maintained	O
+on	O
+a	O
+cyclic	O
+diet	O
+of	O
+12	O
+-	O
+h	O
+deprivation	O
+followed	O
+by	O
+12	O
+-	O
+h	O
+access	O
+to	O
+10	O
+%	O
+sucrose	O
+solution	O
+and	O
+chow	O
+pellets	O
+(	O
+12	O
+h	O
+access	O
+starting	O
+4	O
+h	O
+after	O
+onset	O
+of	O
+the	O
+dark	O
+period	O
+)	O
+for	O
+21	O
+days	O
+.	O
+
+Locomotor	O
+activity	O
+was	O
+measured	O
+again	O
+for	O
+30	O
+min	O
+at	O
+the	O
+beginning	O
+of	O
+days	O
+1	O
+and	O
+21	O
+of	O
+sugar	O
+access	O
+.	O
+
+Beginning	O
+on	O
+day	O
+22	O
+,	O
+all	O
+rats	O
+were	O
+maintained	O
+on	O
+ad	O
+libitum	O
+chow	O
+.	O
+
+Nine	O
+days	O
+later	O
+locomotor	O
+activity	O
+was	O
+measured	O
+in	O
+response	O
+to	O
+a	O
+single	O
+low	O
+dose	O
+of	O
+amphetamine	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+The	O
+animals	O
+that	O
+had	O
+experienced	O
+cyclic	O
+sucrose	O
+and	O
+chow	O
+were	O
+hyperactive	B
+in	O
+response	O
+to	O
+amphetamine	O
+compared	O
+with	O
+four	O
+control	O
+groups	O
+(	O
+ad	O
+libitum	O
+10	O
+%	O
+sucrose	O
+and	O
+chow	O
+followed	O
+by	O
+amphetamine	O
+injection	O
+,	O
+cyclic	O
+chow	O
+followed	O
+by	O
+amphetamine	O
+injection	O
+,	O
+ad	O
+libitum	O
+chow	O
+with	O
+amphetamine	O
+,	O
+or	O
+cyclic	O
+10	O
+%	O
+sucrose	O
+and	O
+chow	O
+with	O
+a	O
+saline	O
+injection	O
+)	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+a	O
+diet	O
+comprised	O
+of	O
+alternating	O
+deprivation	O
+and	O
+access	O
+to	O
+a	O
+sugar	O
+solution	O
+and	O
+chow	O
+produces	O
+bingeing	O
+on	O
+sugar	O
+that	O
+leads	O
+to	O
+a	O
+long	O
+lasting	O
+state	O
+of	O
+increased	O
+sensitivity	O
+to	O
+amphetamine	O
+,	O
+possibly	O
+due	O
+to	O
+a	O
+lasting	O
+alteration	O
+in	O
+the	O
+dopamine	O
+system	O
+.	O
+
+Reversible	O
+dilated	B
+cardiomyopathy	I
+related	O
+to	O
+amphotericin	O
+B	O
+therapy	O
+.	O
+
+We	O
+describe	O
+a	O
+patient	O
+who	O
+developed	O
+dilated	B
+cardiomyopathy	I
+and	O
+clinical	O
+congestive	O
+heart	B
+failure	I
+after	O
+2	O
+months	O
+of	O
+therapy	O
+with	O
+amphotericin	O
+B	O
+(	O
+AmB	O
+)	O
+for	O
+disseminated	O
+coccidioidomycosis	B
+.	O
+
+His	O
+echocardiographic	O
+abnormalities	O
+and	O
+heart	B
+failure	I
+resolved	O
+after	O
+posaconazole	O
+was	O
+substituted	O
+for	O
+AmB	O
+.	O
+
+It	O
+is	O
+important	O
+to	O
+recognize	O
+the	O
+rare	O
+and	O
+potentially	O
+reversible	O
+toxicity	B
+of	O
+AmB	O
+.	O
+
+NO	O
+-	O
+induced	O
+migraine	B
+attack	O
+:	O
+strong	O
+increase	O
+in	O
+plasma	O
+calcitonin	O
+gene	O
+-	O
+related	O
+peptide	O
+(	O
+CGRP	O
+)	O
+concentration	O
+and	O
+negative	O
+correlation	O
+with	O
+platelet	O
+serotonin	O
+release	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+investigate	O
+changes	O
+in	O
+the	O
+plasma	O
+calcitonin	O
+gene	O
+-	O
+related	O
+peptide	O
+(	O
+CGRP	O
+)	O
+concentration	O
+and	O
+platelet	O
+serotonin	O
+(	O
+5	O
+-	O
+hydroxytriptamine	O
+,	O
+5	O
+-	O
+HT	O
+)	O
+content	O
+during	O
+the	O
+immediate	O
+headache	B
+and	O
+the	O
+delayed	O
+genuine	O
+migraine	B
+attack	O
+provoked	O
+by	O
+nitroglycerin	O
+.	O
+
+Fifteen	O
+female	O
+migraineurs	B
+(	I
+without	I
+aura	I
+)	I
+and	O
+eight	O
+controls	O
+participated	O
+in	O
+the	O
+study	O
+.	O
+
+Sublingual	O
+nitroglycerin	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+)	O
+was	O
+administered	O
+.	O
+
+Blood	O
+was	O
+collected	O
+from	O
+the	O
+antecubital	O
+vein	O
+four	O
+times	O
+:	O
+60	O
+min	O
+before	O
+and	O
+after	O
+the	O
+nitroglycerin	O
+application	O
+,	O
+and	O
+60	O
+and	O
+120	O
+min	O
+after	O
+the	O
+beginning	O
+of	O
+the	O
+migraine	B
+attack	O
+(	O
+mean	O
+344	O
+and	O
+404	O
+min	O
+;	O
+12	O
+subjects	O
+)	O
+.	O
+
+In	O
+those	O
+subjects	O
+who	O
+had	O
+no	O
+migraine	B
+attack	O
+(	O
+11	O
+subjects	O
+)	O
+a	O
+similar	O
+time	O
+schedule	O
+was	O
+used	O
+.	O
+
+Plasma	O
+CGRP	O
+concentration	O
+increased	O
+significantly	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+during	O
+the	O
+migraine	B
+attack	O
+and	O
+returned	O
+to	O
+baseline	O
+after	O
+the	O
+cessation	O
+of	O
+the	O
+migraine	B
+.	O
+
+In	O
+addition	O
+,	O
+both	O
+change	O
+and	O
+peak	O
+,	O
+showed	O
+significant	O
+positive	O
+correlations	O
+with	O
+migraine	B
+headache	B
+intensity	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+However	O
+,	O
+plasma	O
+CGRP	O
+concentrations	O
+failed	O
+to	O
+change	O
+during	O
+immediate	O
+headache	B
+and	O
+in	O
+the	O
+subjects	O
+with	O
+no	O
+migraine	B
+attack	O
+.	O
+
+Basal	O
+CGRP	O
+concentration	O
+was	O
+significantly	O
+higher	O
+and	O
+platelet	O
+5	O
+-	O
+HT	O
+content	O
+tended	O
+to	O
+be	O
+lower	O
+in	O
+subjects	O
+who	O
+experienced	O
+a	O
+migraine	B
+attack	O
+.	O
+
+Platelet	O
+serotonin	O
+content	O
+decreased	O
+significantly	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+after	O
+nitroglycerin	O
+in	O
+subjects	O
+with	O
+no	O
+migraine	B
+attack	O
+but	O
+no	O
+consistent	O
+change	O
+was	O
+observed	O
+in	O
+patients	O
+with	O
+migraine	B
+attack	O
+.	O
+
+In	O
+conclusion	O
+,	O
+the	O
+fact	O
+that	O
+plasma	O
+CGRP	O
+concentration	O
+correlates	O
+with	O
+the	O
+timing	O
+and	O
+severity	O
+of	O
+a	O
+migraine	B
+headache	B
+suggests	O
+a	O
+direct	O
+relationship	O
+between	O
+CGRP	O
+and	O
+migraine	B
+.	O
+
+In	O
+contrast	O
+,	O
+serotonin	O
+release	O
+from	O
+platelets	O
+does	O
+not	O
+provoke	O
+migraine	B
+,	O
+it	O
+may	O
+even	O
+counteract	O
+the	O
+headache	B
+and	O
+the	O
+concomitant	O
+CGRP	O
+release	O
+in	O
+this	O
+model	O
+.	O
+
+Hyperbaric	O
+oxygen	O
+therapy	O
+for	O
+control	O
+of	O
+intractable	O
+cyclophosphamide	O
+-	O
+induced	O
+hemorrhagic	B
+cystitis	I
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+intractable	O
+hemorrhagic	B
+cystitis	I
+due	O
+to	O
+cyclophosphamide	O
+therapy	O
+for	O
+Wegener	B
+'	I
+s	I
+granulomatosis	I
+.	O
+
+Conservative	O
+treatment	O
+,	O
+including	O
+bladder	O
+irrigation	O
+with	O
+physiological	O
+saline	O
+and	O
+instillation	O
+of	O
+prostaglandin	O
+F2	O
+alpha	O
+,	O
+failed	O
+to	O
+totally	O
+control	O
+hemorrhage	B
+.	O
+
+We	O
+then	O
+used	O
+hyperbaric	O
+oxygen	O
+at	O
+an	O
+absolute	O
+pressure	O
+of	O
+2	O
+atm	O
+,	O
+5	O
+days	O
+a	O
+week	O
+for	O
+8	O
+consecutive	O
+weeks	O
+.	O
+
+The	O
+bleeding	B
+ceased	O
+completely	O
+by	O
+the	O
+end	O
+of	O
+treatment	O
+and	O
+the	O
+patient	O
+remained	O
+free	O
+of	O
+hematuria	B
+thereafter	O
+.	O
+
+No	O
+side	O
+effect	O
+was	O
+noted	O
+during	O
+the	O
+course	O
+of	O
+therapy	O
+.	O
+
+In	O
+future	O
+,	O
+this	O
+form	O
+of	O
+therapy	O
+can	O
+offer	O
+a	O
+safe	O
+alternative	O
+in	O
+the	O
+treatment	O
+of	O
+cyclophosphamide	O
+-	O
+induced	O
+hemorrhagic	B
+cystitis	I
+.	O
+
+Acute	B
+psychosis	I
+due	O
+to	O
+treatment	O
+with	O
+phenytoin	O
+in	O
+a	O
+nonepileptic	O
+patient	O
+.	O
+
+The	O
+development	O
+of	O
+psychosis	B
+related	O
+to	O
+antiepileptic	O
+drug	O
+treatment	O
+is	O
+usually	O
+attributed	O
+to	O
+the	O
+interaction	O
+between	O
+the	O
+epileptic	B
+brain	O
+substratum	O
+and	O
+the	O
+antiepileptic	O
+drugs	O
+.	O
+
+The	O
+case	O
+of	O
+a	O
+nonepileptic	O
+patient	O
+who	O
+developed	O
+psychosis	B
+following	O
+phenytoin	O
+treatment	O
+for	O
+trigeminal	B
+neuralgia	I
+is	O
+described	O
+.	O
+
+This	O
+case	O
+suggests	O
+that	O
+the	O
+psychotic	B
+symptoms	I
+that	O
+occur	O
+following	O
+phenytoin	O
+treatment	O
+in	O
+some	O
+epileptic	B
+patients	O
+may	O
+be	O
+the	O
+direct	O
+result	O
+of	O
+medication	O
+,	O
+unrelated	O
+to	O
+seizures	B
+.	O
+
+Risks	O
+of	O
+the	O
+consumption	O
+of	O
+beverages	O
+containing	O
+quinine	O
+.	O
+
+Although	O
+the	O
+United	O
+States	O
+Food	O
+and	O
+Drug	O
+Administration	O
+banned	O
+its	O
+use	O
+for	O
+nocturnal	B
+leg	I
+cramps	I
+due	O
+to	O
+lack	O
+of	O
+safety	O
+and	O
+efficacy	O
+,	O
+quinine	O
+is	O
+widely	O
+available	O
+in	O
+beverages	O
+including	O
+tonic	O
+water	O
+and	O
+bitter	O
+lemon	O
+.	O
+
+Numerous	O
+anecdotal	O
+reports	O
+suggest	O
+that	O
+products	O
+containing	O
+quinine	O
+may	O
+produce	O
+neurological	B
+complications	I
+,	O
+including	O
+confusion	B
+,	O
+altered	O
+mental	O
+status	O
+,	O
+seizures	B
+,	O
+and	O
+coma	B
+,	O
+particularly	O
+in	O
+older	O
+women	O
+.	O
+
+Psychologists	O
+need	O
+to	O
+inquire	O
+about	O
+consumption	O
+of	O
+quinine	O
+-	O
+containing	O
+beverages	O
+as	O
+part	O
+of	O
+an	O
+evaluation	O
+process	O
+.	O
+
+Transient	O
+platypnea	B
+-	I
+orthodeoxia	I
+-	I
+like	I
+syndrome	I
+induced	O
+by	O
+propafenone	O
+overdose	B
+in	O
+a	O
+young	O
+woman	O
+with	O
+Ebstein	B
+'	I
+s	I
+anomaly	I
+.	O
+
+In	O
+this	O
+report	O
+we	O
+describe	O
+the	O
+case	O
+of	O
+a	O
+37	O
+-	O
+year	O
+-	O
+old	O
+white	O
+woman	O
+with	O
+Ebstein	B
+'	I
+s	I
+anomaly	I
+,	O
+who	O
+developed	O
+a	O
+rare	O
+syndrome	O
+called	O
+platypnea	B
+-	I
+orthodeoxia	I
+,	O
+characterized	O
+by	O
+massive	O
+right	O
+-	O
+to	O
+-	O
+left	O
+interatrial	O
+shunting	O
+with	O
+transient	O
+profound	O
+hypoxia	B
+and	O
+cyanosis	B
+.	O
+
+This	O
+shunt	O
+of	O
+blood	O
+via	O
+a	O
+patent	B
+foramen	I
+ovale	I
+occurred	O
+in	O
+the	O
+presence	O
+of	O
+a	O
+normal	O
+pulmonary	O
+artery	O
+pressure	O
+,	O
+and	O
+was	O
+probably	O
+precipitated	O
+by	O
+a	O
+propafenone	O
+overdose	B
+.	O
+
+This	O
+drug	O
+caused	O
+biventricular	B
+dysfunction	I
+,	O
+due	O
+to	O
+its	O
+negative	O
+inotropic	O
+effect	O
+,	O
+and	O
+hypotension	B
+,	O
+due	O
+to	O
+its	O
+peripheral	O
+vasodilatory	O
+effect	O
+.	O
+
+These	O
+effects	O
+gave	O
+rise	O
+to	O
+an	O
+increase	O
+in	O
+the	O
+right	O
+atrial	O
+pressure	O
+and	O
+a	O
+decrease	O
+in	O
+the	O
+left	O
+one	O
+with	O
+a	O
+consequent	O
+stretching	O
+of	O
+the	O
+foramen	O
+ovale	O
+and	O
+the	O
+creation	O
+of	O
+massive	O
+right	O
+-	O
+to	O
+-	O
+left	O
+shunting	O
+.	O
+
+In	O
+our	O
+case	O
+this	O
+interatrial	O
+shunt	O
+was	O
+very	O
+accurately	O
+detected	O
+at	O
+bubble	O
+contrast	O
+echocardiography	O
+.	O
+
+Noxious	O
+chemical	O
+stimulation	O
+of	O
+rat	O
+facial	O
+mucosa	O
+increases	O
+intracranial	O
+blood	O
+flow	O
+through	O
+a	O
+trigemino	O
+-	O
+parasympathetic	O
+reflex	O
+-	O
+-	O
+an	O
+experimental	O
+model	O
+for	O
+vascular	B
+dysfunctions	I
+in	O
+cluster	B
+headache	I
+.	O
+
+Cluster	B
+headache	I
+is	O
+characterized	O
+by	O
+typical	O
+autonomic	O
+dysfunctions	O
+including	O
+facial	O
+and	O
+intracranial	B
+vascular	I
+disturbances	I
+.	O
+
+Both	O
+the	O
+trigeminal	O
+and	O
+the	O
+cranial	O
+parasympathetic	O
+systems	O
+may	O
+be	O
+involved	O
+in	O
+mediating	O
+these	O
+dysfunctions	O
+.	O
+
+An	O
+experimental	O
+model	O
+was	O
+developed	O
+in	O
+the	O
+rat	O
+to	O
+measure	O
+changes	O
+in	O
+lacrimation	O
+and	O
+intracranial	O
+blood	O
+flow	O
+following	O
+noxious	O
+chemical	O
+stimulation	O
+of	O
+facial	O
+mucosa	O
+.	O
+
+Blood	O
+flow	O
+was	O
+monitored	O
+in	O
+arteries	O
+of	O
+the	O
+exposed	O
+cranial	O
+dura	O
+mater	O
+and	O
+the	O
+parietal	O
+cortex	O
+using	O
+laser	O
+Doppler	O
+flowmetry	O
+.	O
+
+Capsaicin	O
+(	O
+0	O
+.	O
+01	O
+-	O
+1	O
+mm	O
+)	O
+applied	O
+to	O
+oral	O
+or	O
+nasal	O
+mucosa	O
+induced	O
+increases	B
+in	I
+dural	I
+and	I
+cortical	I
+blood	I
+flow	I
+and	O
+provoked	O
+lacrimation	O
+.	O
+
+These	O
+responses	O
+were	O
+blocked	O
+by	O
+systemic	O
+pre	O
+-	O
+administration	O
+of	O
+hexamethonium	O
+chloride	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+The	O
+evoked	O
+increases	B
+in	I
+dural	I
+blood	I
+flow	I
+were	O
+also	O
+abolished	O
+by	O
+topical	O
+pre	O
+-	O
+administration	O
+of	O
+atropine	O
+(	O
+1	O
+mm	O
+)	O
+and	O
+[	O
+Lys1	O
+,	O
+Pro2	O
+,	O
+5	O
+,	O
+Arg3	O
+,	O
+4	O
+,	O
+Tyr6	O
+]	O
+-	O
+VIP	O
+(	O
+0	O
+.	O
+1	O
+mm	O
+)	O
+,	O
+a	O
+vasoactive	O
+intestinal	O
+polypeptide	O
+(	O
+VIP	O
+)	O
+antagonist	O
+,	O
+onto	O
+the	O
+exposed	O
+dura	O
+mater	O
+.	O
+
+We	O
+conclude	O
+that	O
+noxious	O
+stimulation	O
+of	O
+facial	O
+mucosa	O
+increases	O
+intracranial	O
+blood	O
+flow	O
+and	O
+lacrimation	O
+via	O
+a	O
+trigemino	O
+-	O
+parasympathetic	O
+reflex	O
+.	O
+
+The	O
+blood	O
+flow	O
+responses	O
+seem	O
+to	O
+be	O
+mediated	O
+by	O
+the	O
+release	O
+of	O
+acetylcholine	O
+and	O
+VIP	O
+within	O
+the	O
+meninges	O
+.	O
+
+Similar	O
+mechanisms	O
+may	O
+be	O
+involved	O
+in	O
+the	O
+pathogenesis	O
+of	O
+cluster	B
+headache	I
+.	O
+
+Organophosphate	O
+-	O
+induced	O
+convulsions	B
+and	O
+prevention	O
+of	O
+neuropathological	B
+damages	I
+.	O
+
+Such	O
+organophosphorus	O
+(	O
+OP	O
+)	O
+compounds	O
+as	O
+diisopropylfluorophosphate	O
+(	O
+DFP	O
+)	O
+,	O
+sarin	O
+and	O
+soman	O
+are	O
+potent	O
+inhibitors	O
+of	O
+acetylcholinesterases	O
+(	O
+AChEs	O
+)	O
+and	O
+butyrylcholinesterases	O
+(	O
+BChEs	O
+)	O
+.	O
+
+The	O
+acute	O
+toxicity	B
+of	O
+OPs	O
+is	O
+the	O
+result	O
+of	O
+their	O
+irreversible	O
+binding	O
+with	O
+AChEs	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+,	O
+which	O
+elevates	O
+acetylcholine	O
+(	O
+ACh	O
+)	O
+levels	O
+.	O
+
+The	O
+protective	O
+action	O
+of	O
+subcutaneously	O
+(	O
+SC	O
+)	O
+administered	O
+antidotes	O
+or	O
+their	O
+combinations	O
+in	O
+DFP	O
+(	O
+2	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+BW	O
+)	O
+intoxication	O
+was	O
+studied	O
+in	O
+9	O
+-	O
+10	O
+-	O
+weeks	O
+-	O
+old	O
+Han	O
+-	O
+Wistar	O
+male	O
+rats	O
+.	O
+
+The	O
+rats	O
+received	O
+AChE	O
+reactivator	O
+pralidoxime	O
+-	O
+2	O
+-	O
+chloride	O
+(	O
+2PAM	O
+)	O
+(	O
+30	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+BW	O
+)	O
+,	O
+anticonvulsant	O
+diazepam	O
+(	O
+2	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+BW	O
+)	O
+,	O
+A	O
+(	O
+1	O
+)	O
+-	O
+adenosine	O
+receptor	O
+agonist	O
+N	O
+(	O
+6	O
+)	O
+-	O
+cyclopentyl	O
+adenosine	O
+(	O
+CPA	O
+)	O
+(	O
+2	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+BW	O
+)	O
+,	O
+NMDA	O
+-	O
+receptor	O
+antagonist	O
+dizocilpine	O
+maleate	O
+(	O
++	O
+-	O
+MK801	O
+hydrogen	O
+maleate	O
+)	O
+(	O
+2	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+BW	O
+)	O
+or	O
+their	O
+combinations	O
+with	O
+cholinolytic	O
+drug	O
+atropine	O
+sulfate	O
+(	O
+50	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+BW	O
+)	O
+immediately	O
+or	O
+30	O
+min	O
+after	O
+the	O
+single	O
+SC	O
+injection	O
+of	O
+DFP	O
+.	O
+
+The	O
+control	O
+rats	O
+received	O
+atropine	O
+sulfate	O
+,	O
+but	O
+also	O
+saline	O
+and	O
+olive	O
+oil	O
+instead	O
+of	O
+other	O
+antidotes	O
+and	O
+DFP	O
+,	O
+respectively	O
+.	O
+
+All	O
+rats	O
+were	O
+terminated	O
+either	O
+24	O
+h	O
+or	O
+3	O
+weeks	O
+after	O
+the	O
+DFP	O
+injection	O
+.	O
+
+The	O
+rats	O
+treated	O
+with	O
+DFP	O
+-	O
+atropine	O
+showed	O
+severe	O
+typical	O
+OP	O
+-	O
+induced	O
+toxicity	B
+signs	O
+.	O
+
+When	O
+CPA	O
+,	O
+diazepam	O
+or	O
+2PAM	O
+was	O
+given	O
+immediately	O
+after	O
+DFP	O
+-	O
+atropine	O
+,	O
+these	O
+treatments	O
+prevented	O
+,	O
+delayed	O
+or	O
+shortened	O
+the	O
+occurrence	O
+of	O
+serious	O
+signs	O
+of	O
+poisoning	B
+.	O
+
+Atropine	O
+-	O
+MK801	O
+did	O
+not	O
+offer	O
+any	O
+additional	O
+protection	O
+against	O
+DFP	O
+toxicity	B
+.	O
+
+In	O
+conclusion	O
+,	O
+CPA	O
+,	O
+diazepam	O
+and	O
+2PAM	O
+in	O
+combination	O
+with	O
+atropine	O
+prevented	O
+the	O
+occurrence	O
+of	O
+serious	O
+signs	O
+of	O
+poisoning	B
+and	O
+thus	O
+reduced	O
+the	O
+toxicity	B
+of	O
+DFP	O
+in	O
+rat	O
+.	O
+
+A	O
+pyridoxine	O
+-	O
+dependent	O
+behavioral	B
+disorder	I
+unmasked	O
+by	O
+isoniazid	O
+.	O
+
+A	O
+3	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+had	O
+behavioral	B
+deterioration	I
+,	O
+with	O
+hyperkinesis	B
+,	O
+irritability	B
+,	O
+and	O
+sleeping	B
+difficulties	I
+after	O
+the	O
+therapeutic	O
+administration	O
+of	O
+isoniazid	O
+.	O
+
+The	O
+administration	O
+of	O
+pharmacologic	O
+doses	O
+of	O
+pyridoxine	O
+hydrochloride	O
+led	O
+to	O
+a	O
+disappearance	O
+of	O
+symptoms	O
+.	O
+
+After	O
+discontinuing	O
+isoniazid	O
+therapy	O
+a	O
+similar	O
+pattern	O
+of	O
+behavior	O
+was	O
+noted	O
+that	O
+was	O
+controlled	O
+by	O
+pyridoxine	O
+.	O
+
+A	O
+placebo	O
+had	O
+no	O
+effect	O
+,	O
+but	O
+niacinamide	O
+was	O
+as	O
+effective	O
+as	O
+pyridoxine	O
+.	O
+
+Periodic	O
+withdrawal	O
+of	O
+pyridoxine	O
+was	O
+associated	O
+with	O
+return	O
+of	O
+the	O
+hyperkinesis	B
+.	O
+
+The	O
+level	O
+of	O
+pyridoxal	O
+in	O
+the	O
+blood	O
+was	O
+normal	O
+during	O
+the	O
+periods	O
+of	O
+relapse	O
+.	O
+
+Metabolic	O
+studies	O
+suggested	O
+a	O
+block	O
+in	O
+the	O
+kynurenine	O
+pathway	O
+of	O
+tryptophan	O
+metabolism	O
+.	O
+
+The	O
+patient	O
+has	O
+been	O
+followed	O
+for	O
+six	O
+years	O
+and	O
+has	O
+required	O
+pharmacologic	O
+doses	O
+of	O
+pyridoxine	O
+to	O
+control	O
+her	O
+behavior	O
+.	O
+
+Recurrent	O
+excitation	O
+in	O
+the	O
+dentate	O
+gyrus	O
+of	O
+a	O
+murine	O
+model	O
+of	O
+temporal	B
+lobe	I
+epilepsy	I
+.	O
+
+Similar	O
+to	O
+rats	O
+,	O
+systemic	O
+pilocarpine	O
+injection	O
+causes	O
+status	B
+epilepticus	I
+(	O
+SE	B
+)	O
+and	O
+the	O
+eventual	O
+development	O
+of	O
+spontaneous	O
+seizures	B
+and	O
+mossy	O
+fiber	O
+sprouting	O
+in	O
+C57BL	O
+/	O
+6	O
+and	O
+CD1	O
+mice	O
+,	O
+but	O
+the	O
+physiological	O
+correlates	O
+of	O
+these	O
+events	O
+have	O
+not	O
+been	O
+identified	O
+in	O
+mice	O
+.	O
+
+Population	O
+responses	O
+in	O
+granule	O
+cells	O
+of	O
+the	O
+dentate	O
+gyrus	O
+were	O
+examined	O
+in	O
+transverse	O
+slices	O
+of	O
+the	O
+ventral	O
+hippocampus	O
+from	O
+pilocarpine	O
+-	O
+treated	O
+and	O
+untreated	O
+mice	O
+.	O
+
+In	O
+Mg	O
+(	O
+2	O
++	O
+)	O
+-	O
+free	O
+bathing	O
+medium	O
+containing	O
+bicuculline	O
+,	O
+conditions	O
+designed	O
+to	O
+increase	O
+excitability	O
+in	O
+the	O
+slices	O
+,	O
+electrical	O
+stimulation	O
+of	O
+the	O
+hilus	O
+resulted	O
+in	O
+a	O
+single	O
+population	O
+spike	O
+in	O
+granule	O
+cells	O
+from	O
+control	O
+mice	O
+and	O
+pilocarpine	O
+-	O
+treated	O
+mice	O
+that	O
+did	O
+not	O
+experience	O
+SE	B
+.	O
+
+In	O
+SE	B
+survivors	O
+,	O
+similar	O
+stimulation	O
+resulted	O
+in	O
+a	O
+population	O
+spike	O
+followed	O
+,	O
+at	O
+a	O
+variable	O
+latency	O
+,	O
+by	O
+negative	O
+DC	O
+shifts	O
+and	O
+repetitive	O
+afterdischarges	O
+of	O
+3	O
+-	O
+60	O
+s	O
+duration	O
+,	O
+which	O
+were	O
+blocked	O
+by	O
+ionotropic	O
+glutamate	O
+receptor	O
+antagonists	O
+.	O
+
+Focal	O
+glutamate	O
+photostimulation	O
+of	O
+the	O
+granule	O
+cell	O
+layer	O
+at	O
+sites	O
+distant	O
+from	O
+the	O
+recording	O
+pipette	O
+resulted	O
+in	O
+population	O
+responses	O
+of	O
+1	O
+-	O
+30	O
+s	O
+duration	O
+in	O
+slices	O
+from	O
+SE	B
+survivors	O
+but	O
+not	O
+other	O
+groups	O
+.	O
+
+These	O
+data	O
+support	O
+the	O
+hypothesis	O
+that	O
+SE	B
+-	O
+induced	O
+mossy	O
+fiber	O
+sprouting	O
+and	O
+synaptic	O
+reorganization	O
+are	O
+relevant	O
+characteristics	O
+of	O
+seizure	B
+development	O
+in	O
+these	O
+murine	O
+strains	O
+,	O
+resembling	O
+rat	O
+models	O
+of	O
+human	O
+temporal	B
+lobe	I
+epilepsy	I
+.	O
+
+Urinary	B
+bladder	I
+cancer	I
+in	O
+Wegener	B
+'	I
+s	I
+granulomatosis	I
+:	O
+risks	O
+and	O
+relation	O
+to	O
+cyclophosphamide	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+assess	O
+and	O
+characterise	O
+the	O
+risk	O
+of	O
+bladder	B
+cancer	I
+,	O
+and	O
+its	O
+relation	O
+to	O
+cyclophosphamide	O
+,	O
+in	O
+patients	O
+with	O
+Wegener	B
+'	I
+s	I
+granulomatosis	I
+.	O
+
+METHODS	O
+:	O
+In	O
+the	O
+population	O
+based	O
+,	O
+nationwide	O
+Swedish	O
+Inpatient	O
+Register	O
+a	O
+cohort	O
+of	O
+1065	O
+patients	O
+with	O
+Wegener	B
+'	I
+s	I
+granulomatosis	I
+,	O
+1969	O
+-	O
+95	O
+,	O
+was	O
+identified	O
+.	O
+
+Through	O
+linkage	O
+with	O
+the	O
+Swedish	O
+Cancer	B
+Register	O
+,	O
+all	O
+subjects	O
+in	O
+this	O
+cohort	O
+diagnosed	O
+with	O
+bladder	B
+cancer	I
+were	O
+identified	O
+.	O
+
+Nested	O
+within	O
+the	O
+cohort	O
+,	O
+a	O
+matched	O
+case	O
+-	O
+control	O
+study	O
+was	O
+performed	O
+to	O
+estimate	O
+the	O
+association	O
+between	O
+cyclophosphamide	O
+and	O
+bladder	B
+cancer	I
+using	O
+odds	O
+ratios	O
+(	O
+ORs	O
+)	O
+as	O
+relative	O
+risk	O
+.	O
+
+In	O
+the	O
+cohort	O
+the	O
+cumulative	O
+risk	O
+of	O
+bladder	B
+cancer	I
+after	O
+Wegener	B
+'	I
+s	I
+granulomatosis	I
+,	O
+and	O
+the	O
+relative	O
+prevalence	O
+of	O
+a	O
+history	O
+of	O
+bladder	B
+cancer	I
+at	O
+the	O
+time	O
+of	O
+diagnosis	O
+of	O
+Wegener	B
+'	I
+s	I
+granulomatosis	I
+,	O
+were	O
+also	O
+estimated	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+median	O
+cumulative	O
+doses	O
+of	O
+cyclophosphamide	O
+among	O
+cases	O
+(	O
+n	O
+=	O
+11	O
+)	O
+and	O
+controls	O
+(	O
+n	O
+=	O
+25	O
+)	O
+were	O
+113	O
+g	O
+and	O
+25	O
+g	O
+,	O
+respectively	O
+.	O
+
+The	O
+risk	O
+of	O
+bladder	B
+cancer	I
+doubled	O
+for	O
+every	O
+10	O
+g	O
+increment	O
+in	O
+cyclophosphamide	O
+(	O
+OR	O
+=	O
+2	O
+.	O
+0	O
+,	O
+95	O
+%	O
+confidence	O
+interval	O
+(	O
+CI	O
+)	O
+0	O
+.	O
+8	O
+to	O
+4	O
+.	O
+9	O
+)	O
+.	O
+
+Treatment	O
+duration	O
+longer	O
+than	O
+1	O
+year	O
+was	O
+associated	O
+with	O
+an	O
+eightfold	O
+increased	O
+risk	O
+(	O
+OR	O
+=	O
+7	O
+.	O
+7	O
+,	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+9	O
+to	O
+69	O
+)	O
+.	O
+
+The	O
+absolute	O
+risk	O
+for	O
+bladder	B
+cancer	I
+in	O
+the	O
+cohort	O
+reached	O
+10	O
+%	O
+16	O
+years	O
+after	O
+diagnosis	O
+of	O
+Wegener	B
+'	I
+s	I
+granulomatosis	I
+,	O
+and	O
+a	O
+history	O
+of	O
+bladder	B
+cancer	I
+was	O
+(	O
+non	O
+-	O
+significantly	O
+)	O
+twice	O
+as	O
+common	O
+as	O
+expected	O
+at	O
+the	O
+time	O
+of	O
+diagnosis	O
+of	O
+Wegener	B
+'	I
+s	I
+granulomatosis	I
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+results	O
+indicate	O
+a	O
+dose	O
+-	O
+response	O
+relationship	O
+between	O
+cyclophosphamide	O
+and	O
+the	O
+risk	O
+of	O
+bladder	B
+cancer	I
+,	O
+high	O
+cumulative	O
+risks	O
+in	O
+the	O
+entire	O
+cohort	O
+,	O
+and	O
+also	O
+the	O
+possibility	O
+of	O
+risk	O
+factors	O
+operating	O
+even	O
+before	O
+Wegener	B
+'	I
+s	I
+granulomatosis	I
+.	O
+
+Differential	O
+modulation	O
+by	O
+estrogen	O
+of	O
+alpha2	O
+-	O
+adrenergic	O
+and	O
+I1	O
+-	O
+imidazoline	O
+receptor	O
+-	O
+mediated	O
+hypotension	B
+in	O
+female	O
+rats	O
+.	O
+
+We	O
+have	O
+recently	O
+shown	O
+that	O
+estrogen	O
+negatively	O
+modulates	O
+the	O
+hypotensive	B
+effect	O
+of	O
+clonidine	O
+(	O
+mixed	O
+alpha2	O
+-	O
+/	O
+I1	O
+-	O
+receptor	O
+agonist	O
+)	O
+in	O
+female	O
+rats	O
+and	O
+implicates	O
+the	O
+cardiovascular	O
+autonomic	O
+control	O
+in	O
+this	O
+interaction	O
+.	O
+
+The	O
+present	O
+study	O
+investigated	O
+whether	O
+this	O
+effect	O
+of	O
+estrogen	O
+involves	O
+interaction	O
+with	O
+alpha2	O
+-	O
+and	O
+/	O
+or	O
+I1	O
+-	O
+receptors	O
+.	O
+
+Changes	O
+evoked	O
+by	O
+a	O
+single	O
+intraperitoneal	O
+injection	O
+of	O
+rilmenidine	O
+(	O
+600	O
+microg	O
+/	O
+kg	O
+)	O
+or	O
+alpha	O
+-	O
+methyldopa	O
+(	O
+100	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+selective	O
+I1	O
+-	O
+and	O
+alpha2	O
+-	O
+receptor	O
+agonists	O
+,	O
+respectively	O
+,	O
+in	O
+blood	O
+pressure	O
+,	O
+hemodynamic	O
+variability	O
+,	O
+and	O
+locomotor	O
+activity	O
+were	O
+assessed	O
+in	O
+radiotelemetered	O
+sham	O
+-	O
+operated	O
+and	O
+ovariectomized	O
+(	O
+Ovx	O
+)	O
+Sprague	O
+-	O
+Dawley	O
+female	O
+rats	O
+with	O
+or	O
+without	O
+12	O
+-	O
+wk	O
+estrogen	O
+replacement	O
+.	O
+
+Three	O
+time	O
+domain	O
+indexes	O
+of	O
+hemodynamic	O
+variability	O
+were	O
+employed	O
+:	O
+the	O
+standard	O
+deviation	O
+of	O
+mean	O
+arterial	O
+pressure	O
+as	O
+a	O
+measure	O
+of	O
+blood	O
+pressure	O
+variability	O
+and	O
+the	O
+standard	O
+deviation	O
+of	O
+beat	O
+-	O
+to	O
+-	O
+beat	O
+intervals	O
+(	O
+SDRR	O
+)	O
+and	O
+the	O
+root	O
+mean	O
+square	O
+of	O
+successive	O
+differences	O
+in	O
+R	O
+-	O
+wave	O
+-	O
+to	O
+-	O
+R	O
+-	O
+wave	O
+intervals	O
+as	O
+measures	O
+of	O
+heart	O
+rate	O
+variability	O
+.	O
+
+In	O
+sham	O
+-	O
+operated	O
+rats	O
+,	O
+rilmenidine	O
+or	O
+alpha	O
+-	O
+methyldopa	O
+elicited	O
+similar	O
+hypotension	B
+that	O
+lasted	O
+at	O
+least	O
+5	O
+h	O
+and	O
+was	O
+associated	O
+with	O
+reductions	O
+in	O
+standard	O
+deviation	O
+of	O
+mean	O
+arterial	O
+pressure	O
+.	O
+
+SDRR	O
+was	O
+reduced	O
+only	O
+by	O
+alpha	O
+-	O
+methyldopa	O
+.	O
+
+Ovx	O
+significantly	O
+enhanced	O
+the	O
+hypotensive	B
+response	O
+to	O
+alpha	O
+-	O
+methyldopa	O
+,	O
+in	O
+contrast	O
+to	O
+no	O
+effect	O
+on	O
+rilmenidine	O
+hypotension	B
+.	O
+
+The	O
+enhanced	O
+alpha	O
+-	O
+methyldopa	O
+hypotension	B
+in	O
+Ovx	O
+rats	O
+was	O
+paralleled	O
+with	O
+further	O
+reduction	O
+in	O
+SDRR	O
+and	O
+a	B
+reduced	I
+locomotor	I
+activity	I
+.	O
+
+Estrogen	O
+replacement	O
+(	O
+17beta	O
+-	O
+estradiol	O
+subcutaneous	O
+pellet	O
+,	O
+14	O
+.	O
+2	O
+microg	O
+/	O
+day	O
+,	O
+12	O
+wk	O
+)	O
+of	O
+Ovx	O
+rats	O
+restored	O
+the	O
+hemodynamic	O
+and	O
+locomotor	O
+effects	O
+of	O
+alpha	O
+-	O
+methyldopa	O
+to	O
+sham	O
+-	O
+operated	O
+levels	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+estrogen	O
+downregulates	O
+alpha2	O
+-	O
+but	O
+not	O
+I1	O
+-	O
+receptor	O
+-	O
+mediated	O
+hypotension	B
+and	O
+highlight	O
+a	O
+role	O
+for	O
+the	O
+cardiac	O
+autonomic	O
+control	O
+in	O
+alpha	O
+-	O
+methyldopa	O
+-	O
+estrogen	O
+interaction	O
+.	O
+
+Severe	O
+reversible	O
+left	B
+ventricular	I
+systolic	I
+and	I
+diastolic	I
+dysfunction	I
+due	O
+to	O
+accidental	O
+iatrogenic	O
+epinephrine	O
+overdose	B
+.	O
+
+Catecholamine	O
+-	O
+induced	O
+cardiomyopathy	B
+due	O
+to	O
+chronic	O
+excess	O
+of	O
+endogenous	O
+catecholamines	O
+has	O
+been	O
+recognized	O
+for	O
+decades	O
+as	O
+a	O
+clinical	O
+phenomenon	O
+.	O
+
+In	O
+contrast	O
+,	O
+reports	O
+of	O
+myocardial	B
+dysfunction	I
+due	O
+to	O
+acute	O
+iatrogenic	O
+overdose	B
+are	O
+rare	O
+.	O
+
+A	O
+35	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+whose	O
+cervix	O
+uteri	O
+was	O
+inadvertently	O
+injected	O
+with	O
+8	O
+mg	O
+of	O
+epinephrine	O
+developed	O
+myocardial	B
+stunning	I
+that	O
+was	O
+characterized	O
+by	O
+severe	O
+hemodynamic	O
+compromise	O
+,	O
+profound	O
+,	O
+albeit	O
+transient	O
+,	O
+left	B
+ventricular	I
+systolic	I
+and	I
+diastolic	I
+dysfunction	I
+,	O
+and	O
+only	O
+modestly	O
+elevated	O
+biochemical	O
+markers	O
+of	O
+myocardial	B
+necrosis	I
+.	O
+
+Our	O
+case	O
+illustrates	O
+the	O
+serious	O
+consequences	O
+of	O
+medical	O
+errors	O
+that	O
+can	O
+be	O
+avoided	O
+through	O
+improved	O
+medication	O
+labeling	O
+and	O
+staff	O
+supervision	O
+.	O
+
+Cardioprotective	O
+effect	O
+of	O
+tincture	O
+of	O
+Crataegus	O
+on	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+in	O
+rats	O
+.	O
+
+Tincture	O
+of	O
+Crataegus	O
+(	O
+TCR	O
+)	O
+,	O
+an	O
+alcoholic	O
+extract	O
+of	O
+the	O
+berries	O
+of	O
+hawthorn	O
+(	O
+Crataegus	O
+oxycantha	O
+)	O
+,	O
+is	O
+used	O
+in	O
+herbal	O
+and	O
+homeopathic	O
+medicine	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+done	O
+to	O
+investigate	O
+the	O
+protective	O
+effect	O
+of	O
+TCR	O
+on	O
+experimentally	O
+induced	O
+myocardial	B
+infarction	I
+in	O
+rats	O
+.	O
+
+Pretreatment	O
+of	O
+TCR	O
+,	O
+at	O
+a	O
+dose	O
+of	O
+0	O
+.	O
+5	O
+mL	O
+/	O
+100	O
+g	O
+bodyweight	O
+per	O
+day	O
+,	O
+orally	O
+for	O
+30	O
+days	O
+,	O
+prevented	O
+the	O
+increase	O
+in	O
+lipid	O
+peroxidation	O
+and	O
+activity	O
+of	O
+marker	O
+enzymes	O
+observed	O
+in	O
+isoproterenol	O
+-	O
+induced	O
+rats	O
+(	O
+85	O
+mg	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+s	O
+.	O
+c	O
+.	O
+for	O
+2	O
+days	O
+at	O
+an	O
+interval	O
+of	O
+24	O
+h	O
+)	O
+.	O
+
+TCR	O
+prevented	O
+the	O
+isoproterenol	O
+-	O
+induced	O
+decrease	O
+in	O
+antioxidant	O
+enzymes	O
+in	O
+the	O
+heart	O
+and	O
+increased	O
+the	O
+rate	O
+of	O
+ADP	O
+-	O
+stimulated	O
+oxygen	O
+uptake	O
+and	O
+respiratory	O
+coupling	O
+ratio	O
+.	O
+
+TCR	O
+protected	O
+against	O
+pathological	O
+changes	O
+induced	O
+by	O
+isoproterenol	O
+in	O
+rat	O
+heart	O
+.	O
+
+The	O
+results	O
+show	O
+that	O
+pretreatment	O
+with	O
+TCR	O
+may	O
+be	O
+useful	O
+in	O
+preventing	O
+the	O
+damage	O
+induced	O
+by	O
+isoproterenol	O
+in	O
+rat	O
+heart	O
+.	O
+
+Treatment	O
+of	O
+tinnitus	B
+by	O
+intratympanic	O
+instillation	O
+of	O
+lignocaine	O
+(	O
+lidocaine	O
+)	O
+2	O
+per	O
+cent	O
+through	O
+ventilation	O
+tubes	O
+.	O
+
+Idiopathic	B
+subjective	I
+tinnitus	I
+(	O
+IST	B
+)	O
+is	O
+one	O
+of	O
+the	O
+most	O
+obscure	O
+otological	O
+pathologies	O
+.	O
+
+This	O
+paper	O
+presents	O
+the	O
+results	O
+of	O
+treating	O
+IST	B
+by	O
+intratympanic	O
+instillation	O
+of	O
+lignocaine	O
+(	O
+lidocaine	O
+)	O
+2	O
+per	O
+cent	O
+through	O
+a	O
+grommet	O
+,	O
+for	O
+five	O
+weekly	O
+courses	O
+.	O
+
+Fifty	O
+-	O
+two	O
+patients	O
+suffering	O
+from	O
+intractable	O
+tinnitus	B
+entered	O
+this	O
+therapeutic	O
+trial	O
+,	O
+but	O
+only	O
+nine	O
+finished	O
+all	O
+five	O
+courses	O
+.	O
+
+In	O
+one	O
+patient	O
+,	O
+the	O
+tinnitus	B
+was	O
+almost	O
+completely	O
+abolished	O
+,	O
+but	O
+in	O
+all	O
+the	O
+nine	O
+patients	O
+the	O
+decompensated	O
+tinnitus	B
+changed	O
+to	O
+a	O
+compensated	O
+one	O
+.	O
+
+We	O
+suggest	O
+this	O
+mode	O
+of	O
+treatment	O
+for	O
+patients	O
+that	O
+were	O
+previously	O
+treated	O
+by	O
+drugs	O
+,	O
+acupuncture	O
+and	O
+biofeedback	O
+,	O
+with	O
+disappointing	O
+results	O
+.	O
+
+Patients	O
+should	O
+be	O
+warned	O
+about	O
+the	O
+side	O
+effects	O
+of	O
+vertigo	B
+and	O
+vomiting	B
+,	O
+which	O
+subsides	O
+gradually	O
+with	O
+every	O
+new	O
+instillation	O
+,	O
+and	O
+that	O
+the	O
+tinnitus	B
+may	O
+not	O
+disappear	O
+but	O
+will	O
+be	O
+alleviated	O
+,	O
+enabling	O
+them	O
+to	O
+cope	O
+more	O
+easily	O
+with	O
+the	O
+disease	O
+and	O
+lead	O
+a	O
+more	O
+normal	O
+life	O
+.	O
+
+The	O
+alpha3	O
+and	O
+beta4	O
+nicotinic	O
+acetylcholine	O
+receptor	O
+subunits	O
+are	O
+necessary	O
+for	O
+nicotine	O
+-	O
+induced	O
+seizures	B
+and	O
+hypolocomotion	B
+in	O
+mice	O
+.	O
+
+Binding	O
+of	O
+nicotine	O
+to	O
+nicotinic	O
+acetylcholine	O
+receptors	O
+(	O
+nAChRs	O
+)	O
+elicits	O
+a	O
+series	O
+of	O
+dose	O
+-	O
+dependent	O
+behaviors	O
+that	O
+go	O
+from	O
+altered	O
+exploration	O
+,	O
+sedation	O
+,	O
+and	O
+tremors	B
+,	O
+to	O
+seizures	B
+and	O
+death	B
+.	O
+
+nAChRs	O
+are	O
+pentameric	O
+ion	O
+channels	O
+usually	O
+composed	O
+of	O
+alpha	O
+and	O
+beta	O
+subunits	O
+.	O
+
+A	O
+gene	O
+cluster	O
+comprises	O
+the	O
+alpha3	O
+,	O
+alpha5	O
+and	O
+beta4	O
+subunits	O
+,	O
+which	O
+coassemble	O
+to	O
+form	O
+functional	O
+receptors	O
+.	O
+
+We	O
+examined	O
+the	O
+role	O
+of	O
+the	O
+beta4	O
+subunits	O
+in	O
+nicotine	O
+-	O
+induced	O
+seizures	B
+and	O
+hypolocomotion	B
+in	O
+beta4	O
+homozygous	O
+null	O
+(	O
+beta4	O
+-	O
+/	O
+-	O
+)	O
+and	O
+alpha3	O
+heterozygous	O
+(	O
++	O
+/	O
+-	O
+)	O
+mice	O
+.	O
+
+beta4	O
+-	O
+/	O
+-	O
+mice	O
+were	O
+less	O
+sensitive	O
+to	O
+the	O
+effects	O
+of	O
+nicotine	O
+both	O
+at	O
+low	O
+doses	O
+,	O
+measured	O
+as	O
+decreased	O
+exploration	O
+in	O
+an	O
+open	O
+field	O
+,	O
+and	O
+at	O
+high	O
+doses	O
+,	O
+measured	O
+as	O
+sensitivity	O
+to	O
+nicotine	O
+-	O
+induced	O
+seizures	B
+.	O
+
+Using	O
+in	O
+situ	O
+hybridization	O
+probes	O
+for	O
+the	O
+alpha3	O
+and	O
+alpha5	O
+subunits	O
+,	O
+we	O
+showed	O
+that	O
+alpha5	O
+mRNA	O
+levels	O
+are	O
+unchanged	O
+,	O
+whereas	O
+alpha3	O
+mRNA	O
+levels	O
+are	O
+selectively	O
+decreased	O
+in	O
+the	O
+mitral	O
+cell	O
+layer	O
+of	O
+the	O
+olfactory	O
+bulb	O
+,	O
+and	O
+the	O
+inferior	O
+and	O
+the	O
+superior	O
+colliculus	O
+of	O
+beta4	O
+-	O
+/	O
+-	O
+brains	O
+.	O
+
+alpha3	O
++	O
+/	O
+-	O
+mice	O
+were	O
+partially	O
+resistant	O
+to	O
+nicotine	O
+-	O
+induced	O
+seizures	B
+when	O
+compared	O
+to	O
+wild	O
+-	O
+type	O
+littermates	O
+.	O
+
+mRNA	O
+levels	O
+for	O
+the	O
+alpha5	O
+and	O
+the	O
+beta4	O
+subunits	O
+were	O
+unchanged	O
+in	O
+alpha3	O
++	O
+/	O
+-	O
+brains	O
+.	O
+
+Together	O
+,	O
+these	O
+results	O
+suggest	O
+that	O
+the	O
+beta4	O
+and	O
+the	O
+alpha3	O
+subunits	O
+are	O
+mediators	O
+of	O
+nicotine	O
+-	O
+induced	O
+seizures	B
+and	O
+hypolocomotion	B
+.	O
+
+The	O
+effects	O
+of	O
+sevoflurane	O
+on	O
+lidocaine	O
+-	O
+induced	O
+convulsions	B
+.	O
+
+The	O
+influence	O
+of	O
+sevoflurane	O
+on	O
+lidocaine	O
+-	O
+induced	O
+convulsions	B
+was	O
+studied	O
+in	O
+cats	O
+.	O
+
+The	O
+convulsive	B
+threshold	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+)	O
+was	O
+41	O
+.	O
+4	O
++	O
+/	O
+-	O
+6	O
+.	O
+5	O
+mg	O
+.	O
+
+l	O
+(	O
+-	O
+1	O
+)	O
+with	O
+lidocaine	O
+infusion	O
+(	O
+6	O
+mg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+min	O
+(	O
+-	O
+1	O
+)	O
+)	O
+,	O
+increasing	O
+significantly	O
+to	O
+66	O
+.	O
+6	O
++	O
+/	O
+-	O
+10	O
+.	O
+9	O
+mg	O
+.	O
+
+l	O
+(	O
+-	O
+1	O
+)	O
+when	O
+the	O
+end	O
+-	O
+tidal	O
+concentration	O
+of	O
+sevoflurane	O
+was	O
+0	O
+.	O
+8	O
+%	O
+.	O
+
+However	O
+,	O
+the	O
+threshold	O
+(	O
+61	O
+.	O
+6	O
++	O
+/	O
+-	O
+8	O
+.	O
+7	O
+mg	O
+.	O
+l	O
+(	O
+-	O
+1	O
+)	O
+)	O
+during	O
+1	O
+.	O
+6	O
+%	O
+sevoflurane	O
+was	O
+not	O
+significant	O
+from	O
+that	O
+during	O
+0	O
+.	O
+8	O
+%	O
+sevoflurane	O
+,	O
+indicating	O
+a	O
+celling	O
+effect	O
+.	O
+
+There	O
+was	O
+no	O
+significant	O
+difference	O
+in	O
+the	O
+convulsive	B
+threshold	O
+between	O
+sevoflurane	O
+and	O
+enflurane	O
+.	O
+
+The	O
+rise	O
+in	O
+blood	O
+pressure	O
+became	O
+less	O
+marked	O
+when	O
+higher	O
+concentrations	O
+of	O
+sevoflurane	O
+or	O
+enflurane	O
+were	O
+administered	O
+and	O
+the	O
+blood	O
+pressure	O
+at	O
+convulsions	B
+decreased	O
+significantly	O
+in	O
+1	O
+.	O
+6	O
+%	O
+sevoflurane	O
+,	O
+and	O
+in	O
+0	O
+.	O
+8	O
+%	O
+and	O
+1	O
+.	O
+6	O
+%	O
+enflurane	O
+.	O
+
+However	O
+,	O
+there	O
+was	O
+no	O
+significant	O
+difference	O
+in	O
+the	O
+lidocaine	O
+concentrations	O
+measured	O
+when	O
+the	O
+systolic	O
+blood	O
+pressure	O
+became	O
+70	O
+mmHg	O
+.	O
+
+Apamin	O
+,	O
+a	O
+selective	O
+blocker	O
+of	O
+calcium	O
+-	O
+dependent	O
+potassium	O
+channels	O
+,	O
+was	O
+administered	O
+intracerebroventricularly	O
+in	O
+rats	O
+anesthetized	O
+with	O
+0	O
+.	O
+8	O
+%	O
+sevoflurane	O
+to	O
+investigate	O
+the	O
+mechanism	O
+of	O
+the	O
+anticonvulsive	O
+effects	O
+.	O
+
+Apamin	O
+(	O
+10	O
+ng	O
+)	O
+had	O
+a	O
+tendency	O
+to	O
+decrease	O
+the	O
+convulsive	B
+threshold	O
+(	O
+21	O
+.	O
+6	O
++	O
+/	O
+-	O
+2	O
+.	O
+2	O
+to	O
+19	O
+.	O
+9	O
++	O
+/	O
+-	O
+2	O
+.	O
+5	O
+mg	O
+.	O
+l	O
+(	O
+-	O
+1	O
+)	O
+)	O
+but	O
+this	O
+was	O
+not	O
+statistically	O
+significant	O
+.	O
+
+It	O
+is	O
+suggested	O
+that	O
+sevoflurane	O
+reduces	O
+the	O
+convulsive	B
+effect	O
+of	O
+lidocaine	O
+toxicity	B
+but	O
+carries	O
+some	O
+risk	O
+due	O
+to	O
+circulatory	O
+depression	B
+.	O
+
+Cardiac	B
+toxicity	I
+observed	O
+in	O
+association	O
+with	O
+high	O
+-	O
+dose	O
+cyclophosphamide	O
+-	O
+based	O
+chemotherapy	O
+for	O
+metastatic	O
+breast	B
+cancer	I
+.	O
+
+INTRODUCTION	O
+:	O
+Cyclophosphamide	O
+is	O
+an	O
+alkylating	O
+agent	O
+given	O
+frequently	O
+as	O
+a	O
+component	O
+of	O
+many	O
+conditioning	O
+regimens	O
+.	O
+
+In	O
+high	O
+doses	O
+,	O
+its	O
+nonhematological	O
+dose	O
+-	O
+limiting	O
+toxicity	B
+is	O
+cardiomyopathy	B
+.	O
+
+STUDY	O
+DESIGN	O
+:	O
+We	O
+combined	O
+paclitaxel	O
+,	O
+melphalan	O
+and	O
+high	O
+-	O
+dose	O
+cyclophosphamide	O
+,	O
+thiotepa	O
+,	O
+and	O
+carboplatin	O
+in	O
+a	O
+triple	O
+sequential	O
+high	O
+-	O
+dose	O
+regimen	O
+for	O
+patients	O
+with	O
+metastatic	O
+breast	B
+cancer	I
+.	O
+
+Analysis	O
+was	O
+performed	O
+on	O
+61	O
+women	O
+with	O
+chemotherapy	O
+-	O
+responsive	O
+metastatic	O
+breast	B
+cancer	I
+receiving	O
+96	O
+-	O
+h	O
+infusional	O
+cyclophosphamide	O
+as	O
+part	O
+of	O
+a	O
+triple	O
+sequential	O
+high	O
+-	O
+dose	O
+regimen	O
+to	O
+assess	O
+association	O
+between	O
+presence	O
+of	O
+peritransplant	O
+congestive	B
+heart	I
+failure	I
+(	O
+CHF	B
+)	O
+and	O
+the	O
+following	O
+pretreatment	O
+characteristics	O
+:	O
+presence	O
+of	O
+electrocardiogram	O
+(	O
+EKG	O
+)	O
+abnormalities	O
+,	O
+age	O
+,	O
+hypertension	B
+,	O
+prior	O
+cardiac	O
+history	O
+,	O
+smoking	O
+,	O
+diabetes	B
+mellitus	I
+,	O
+prior	O
+use	O
+of	O
+anthracyclines	O
+,	O
+and	O
+left	O
+-	O
+sided	O
+chest	O
+irradiation	O
+.	O
+
+RESULTS	O
+:	O
+Six	O
+of	O
+61	O
+women	O
+(	O
+10	O
+%	O
+)	O
+developed	O
+clinically	O
+reversible	O
+grade	O
+3	O
+CHF	B
+following	O
+infusional	O
+cyclophosphamide	O
+with	O
+a	O
+median	O
+percent	O
+decline	O
+in	O
+ejection	O
+fraction	O
+of	O
+31	O
+%	O
+.	O
+
+Incidence	O
+of	O
+transient	O
+cyclophosphamide	O
+-	O
+related	O
+cardiac	B
+toxicity	I
+(	O
+10	O
+%	O
+)	O
+is	O
+comparable	O
+to	O
+previous	O
+recorded	O
+literature	O
+.	O
+
+Older	O
+age	O
+was	O
+significantly	O
+correlated	O
+with	O
+the	O
+CHF	B
+development	O
+;	O
+with	O
+median	O
+ages	O
+for	O
+the	O
+entire	O
+group	O
+and	O
+for	O
+patients	O
+developing	O
+CHF	B
+of	O
+45	O
+and	O
+59	O
+,	O
+respectively	O
+.	O
+
+No	O
+association	O
+was	O
+found	O
+with	O
+other	O
+pretreatment	O
+characteristics	O
+.	O
+
+CONCLUSIONS	O
+:	O
+As	O
+a	O
+result	O
+of	O
+these	O
+findings	O
+,	O
+oncologists	O
+should	O
+carefully	O
+monitor	O
+fluid	O
+balance	O
+in	O
+older	O
+patients	O
+.	O
+
+Routine	O
+EKG	O
+monitoring	O
+during	O
+infusional	O
+cyclophosphamide	O
+did	O
+not	O
+predict	O
+CHF	B
+development	O
+.	O
+
+Tremor	B
+side	O
+effects	O
+of	O
+salbutamol	O
+,	O
+quantified	O
+by	O
+a	O
+laser	O
+pointer	O
+technique	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+study	O
+tremor	B
+side	O
+effects	O
+of	O
+salbutamol	O
+an	O
+easily	O
+applicable	O
+,	O
+quick	O
+and	O
+low	O
+-	O
+priced	O
+method	O
+is	O
+needed	O
+.	O
+
+A	O
+new	O
+method	O
+using	O
+a	O
+commercially	O
+available	O
+,	O
+pen	O
+-	O
+shaped	O
+laser	O
+pointer	O
+was	O
+developed	O
+.	O
+
+Aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+determine	O
+sensitivity	O
+,	O
+reproducibility	O
+,	O
+reference	O
+values	O
+and	O
+the	O
+agreement	O
+with	O
+a	O
+questionnaire	O
+.	O
+
+METHODS	O
+:	O
+Tremor	B
+was	O
+measured	O
+using	O
+a	O
+laser	O
+pointer	O
+technique	O
+.	O
+
+To	O
+determine	O
+sensitivity	O
+we	O
+assessed	O
+tremor	B
+in	O
+44	O
+patients	O
+with	O
+obstructive	B
+lung	I
+disease	I
+after	O
+administration	O
+of	O
+cumulative	O
+doses	O
+of	O
+salbutamol	O
+.	O
+
+Subjects	O
+were	O
+asked	O
+to	O
+aim	O
+at	O
+the	O
+centre	O
+of	O
+a	O
+target	O
+,	O
+subdivided	O
+in	O
+concentric	O
+circles	O
+,	O
+from	O
+5	O
+m	O
+distance	O
+.	O
+
+The	O
+circle	O
+in	O
+which	O
+the	O
+participant	O
+succeeded	O
+to	O
+aim	O
+was	O
+recorded	O
+in	O
+millimetres	O
+radius	O
+.	O
+
+In	O
+another	O
+series	O
+of	O
+measurements	O
+,	O
+reproducibility	O
+and	O
+reference	O
+values	O
+of	O
+the	O
+tremor	B
+was	O
+assessed	O
+in	O
+65	O
+healthy	O
+subjects	O
+in	O
+three	O
+sessions	O
+,	O
+at	O
+9	O
+a	O
+.	O
+m	O
+.	O
+,	O
+4	O
+p	O
+.	O
+m	O
+.	O
+and	O
+9	O
+a	O
+.	O
+m	O
+.	O
+,	O
+respectively	O
+,	O
+1	O
+week	O
+later	O
+.	O
+
+Postural	O
+tremor	B
+was	O
+measured	O
+with	O
+the	O
+arm	O
+horizontally	O
+outstretched	O
+rest	O
+tremor	B
+with	O
+the	O
+arm	O
+supported	O
+by	O
+an	O
+armrest	O
+and	O
+finally	O
+tremor	B
+was	O
+measured	O
+after	O
+holding	O
+a	O
+2	O
+-	O
+kg	O
+weight	O
+until	O
+exhaustion	O
+.	O
+
+Inter	O
+-	O
+observer	O
+variability	O
+was	O
+measured	O
+in	O
+a	O
+series	O
+of	O
+10	O
+healthy	O
+subjects	O
+.	O
+
+Tremor	B
+was	O
+measured	O
+simultaneously	O
+by	O
+two	O
+independent	O
+observers	O
+.	O
+
+RESULTS	O
+:	O
+Salbutamol	O
+significantly	O
+increased	O
+tremor	B
+severity	O
+in	O
+patients	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+way	O
+.	O
+
+Within	O
+healthy	O
+adults	O
+no	O
+age	O
+-	O
+dependency	O
+could	O
+be	O
+found	O
+(	O
+b	O
+=	O
+0	O
+.	O
+262	O
+mm	O
+/	O
+year	O
+;	O
+P	O
+=	O
+0	O
+.	O
+72	O
+)	O
+.	O
+
+There	O
+was	O
+no	O
+agreement	O
+between	O
+the	O
+questionnaire	O
+and	O
+tremor	B
+severity	O
+(	O
+r	O
+=	O
+0	O
+.	O
+093	O
+;	O
+P	O
+=	O
+0	O
+.	O
+53	O
+)	O
+.	O
+
+Postural	O
+tremor	B
+showed	O
+no	O
+significant	O
+difference	O
+between	O
+the	O
+first	O
+and	O
+third	O
+session	O
+(	O
+P	O
+=	O
+0	O
+.	O
+07	O
+)	O
+.	O
+
+Support	O
+of	O
+the	O
+arm	O
+decreased	O
+tremor	B
+severity	O
+,	O
+exhaustion	O
+increased	O
+tremor	B
+severity	O
+significantly	O
+.	O
+
+A	O
+good	O
+agreement	O
+was	O
+found	O
+between	O
+two	O
+independent	O
+observers	O
+(	O
+interclass	O
+correlation	O
+coefficient	O
+0	O
+.	O
+72	O
+)	O
+.	O
+
+DISCUSSION	O
+:	O
+Quantifying	O
+tremor	B
+by	O
+using	O
+an	O
+inexpensive	O
+laser	O
+pointer	O
+is	O
+,	O
+with	O
+the	O
+exception	O
+of	O
+children	O
+(	O
+<	O
+12	O
+years	O
+)	O
+a	O
+sensitive	O
+and	O
+reproducible	O
+method	O
+.	O
+
+Safety	O
+and	O
+adverse	O
+effects	O
+associated	O
+with	O
+raloxifene	O
+:	O
+multiple	O
+outcomes	O
+of	O
+raloxifene	O
+evaluation	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+examine	O
+the	O
+effect	O
+of	O
+raloxifene	O
+on	O
+major	O
+adverse	O
+events	O
+that	O
+occur	O
+with	O
+postmenopausal	O
+estrogen	O
+therapy	O
+or	O
+tamoxifen	O
+.	O
+
+METHODS	O
+:	O
+The	O
+Multiple	O
+Outcomes	O
+of	O
+Raloxifene	O
+Evaluation	O
+,	O
+a	O
+multicenter	O
+,	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+trial	O
+,	O
+enrolled	O
+7	O
+,	O
+705	O
+postmenopausal	O
+women	O
+with	O
+osteoporosis	B
+.	O
+
+Women	O
+were	O
+randomly	O
+assigned	O
+to	O
+raloxifene	O
+60	O
+mg	O
+/	O
+d	O
+or	O
+120	O
+mg	O
+/	O
+d	O
+or	O
+placebo	O
+.	O
+
+Outcomes	O
+included	O
+venous	B
+thromboembolism	I
+,	O
+cataracts	B
+,	O
+gallbladder	B
+disease	I
+,	O
+and	O
+endometrial	B
+hyperplasia	I
+or	I
+cancer	I
+.	O
+
+RESULTS	O
+:	O
+During	O
+a	O
+mean	O
+follow	O
+-	O
+up	O
+of	O
+3	O
+.	O
+3	O
+years	O
+,	O
+raloxifene	O
+was	O
+associated	O
+with	O
+an	O
+increased	O
+risk	O
+for	O
+venous	B
+thromboembolism	I
+(	O
+relative	O
+risk	O
+[	O
+RR	O
+]	O
+2	O
+.	O
+1	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+1	O
+.	O
+2	O
+-	O
+3	O
+.	O
+8	O
+)	O
+.	O
+
+The	O
+excess	O
+event	O
+rate	O
+was	O
+1	O
+.	O
+8	O
+per	O
+1	O
+,	O
+000	O
+woman	O
+-	O
+years	O
+(	O
+95	O
+%	O
+CI	O
+-	O
+0	O
+.	O
+5	O
+-	O
+4	O
+.	O
+1	O
+)	O
+,	O
+and	O
+the	O
+number	O
+needed	O
+to	O
+treat	O
+to	O
+cause	O
+1	O
+event	O
+was	O
+170	O
+(	O
+95	O
+%	O
+CI	O
+100	O
+-	O
+582	O
+)	O
+over	O
+3	O
+.	O
+3	O
+years	O
+.	O
+
+Risk	O
+in	O
+the	O
+raloxifene	O
+group	O
+was	O
+higher	O
+than	O
+in	O
+the	O
+placebo	O
+group	O
+for	O
+the	O
+first	O
+2	O
+years	O
+,	O
+but	O
+decreased	O
+to	O
+about	O
+the	O
+same	O
+rate	O
+as	O
+in	O
+the	O
+placebo	O
+group	O
+thereafter	O
+.	O
+
+Raloxifene	O
+did	O
+not	O
+increase	O
+risk	O
+for	O
+cataracts	B
+(	O
+RR	O
+0	O
+.	O
+9	O
+;	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+8	O
+-	O
+1	O
+.	O
+1	O
+)	O
+,	O
+gallbladder	B
+disease	I
+(	O
+RR	O
+1	O
+.	O
+0	O
+;	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+7	O
+-	O
+1	O
+.	O
+3	O
+)	O
+,	O
+endometrial	B
+hyperplasia	I
+(	O
+RR	O
+1	O
+.	O
+3	O
+;	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+4	O
+-	O
+5	O
+.	O
+1	O
+)	O
+,	O
+or	O
+endometrial	B
+cancer	I
+(	O
+RR	O
+0	O
+.	O
+9	O
+;	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+3	O
+-	O
+2	O
+.	O
+7	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+Raloxifene	O
+was	O
+associated	O
+with	O
+an	O
+increased	O
+risk	O
+for	O
+venous	B
+thromboembolism	I
+,	O
+but	O
+there	O
+was	O
+no	O
+increased	O
+risk	O
+for	O
+cataracts	B
+,	O
+gallbladder	B
+disease	I
+,	O
+endometrial	B
+hyperplasia	I
+,	O
+or	O
+endometrial	B
+cancer	I
+.	O
+
+LEVEL	O
+OF	O
+EVIDENCE	O
+:	O
+I	O
+
+Optimization	O
+of	O
+levodopa	O
+therapy	O
+.	O
+
+While	O
+there	O
+is	O
+no	O
+single	O
+correct	O
+starting	O
+dose	O
+for	O
+levodopa	O
+therapy	O
+,	O
+many	O
+individuals	O
+can	O
+be	O
+started	O
+on	O
+either	O
+the	O
+25	O
+/	O
+100	O
+or	O
+controlled	O
+-	O
+release	O
+formula	O
+,	O
+following	O
+the	O
+general	O
+rule	O
+not	O
+to	O
+attempt	O
+to	O
+titrate	O
+carbidopa	O
+-	O
+levodopa	O
+to	O
+the	O
+point	O
+of	O
+"	O
+normality	O
+,	O
+"	O
+which	O
+can	O
+lead	O
+to	O
+toxicity	B
+.	O
+
+The	O
+physician	O
+should	O
+also	O
+determine	O
+the	O
+proper	O
+use	O
+of	O
+any	O
+adjunctive	O
+medications	O
+;	O
+such	O
+combined	O
+therapy	O
+has	O
+become	O
+the	O
+standard	O
+approach	O
+to	O
+treatment	O
+.	O
+
+Following	O
+the	O
+initial	O
+period	O
+of	O
+therapy	O
+,	O
+emerging	O
+difficulties	O
+require	O
+a	O
+reassessment	O
+of	O
+therapeutic	O
+approaches	O
+,	O
+such	O
+as	O
+dosage	O
+adjustment	O
+or	O
+introduction	O
+of	O
+a	O
+dopamine	O
+agonist	O
+.	O
+
+Other	O
+possible	O
+adverse	O
+effects	O
+-	O
+-	O
+such	O
+as	O
+gastrointestinal	B
+disorders	I
+,	O
+orthostatic	B
+hypotension	I
+,	O
+levodopa	O
+-	O
+induced	O
+psychosis	B
+,	O
+sleep	B
+disturbances	I
+or	O
+parasomnias	B
+,	O
+or	O
+drug	O
+interactions	O
+-	O
+-	O
+also	O
+require	O
+carefully	O
+monitored	O
+individual	O
+treatment	O
+.	O
+
+Nonpharmacologic	O
+concerns	O
+can	O
+help	O
+the	O
+Parkinson	B
+'	I
+s	I
+disease	I
+patient	O
+achieve	O
+and	O
+maintain	O
+optimal	O
+functioning	O
+,	O
+including	O
+daily	O
+exercise	O
+,	O
+physical	O
+therapy	O
+,	O
+and	O
+involvement	O
+with	O
+support	O
+groups	O
+.	O
+
+Long	O
+term	O
+audiological	O
+evaluation	O
+of	O
+beta	B
+-	I
+thalassemic	I
+patients	O
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+identify	O
+the	O
+incidence	O
+and	O
+to	O
+monitor	O
+the	O
+progression	O
+of	O
+hearing	B
+loss	I
+in	O
+children	O
+and	O
+young	O
+adults	O
+with	O
+beta	B
+-	I
+thalassemia	I
+major	O
+.	O
+
+METHODS	O
+:	O
+One	O
+hundred	O
+and	O
+four	O
+(	O
+104	O
+)	O
+patients	O
+aged	O
+6	O
+-	O
+35	O
+years	O
+(	O
+mean	O
+17	O
+,	O
+2	O
+years	O
+)	O
+participated	O
+in	O
+the	O
+study	O
+.	O
+
+All	O
+patients	O
+were	O
+on	O
+a	O
+regular	O
+transfusion	O
+-	O
+chelation	O
+program	O
+maintaining	O
+a	O
+mean	O
+hemoglobin	O
+level	O
+of	O
+9	O
+.	O
+5	O
+gr	O
+/	O
+dl	O
+.	O
+
+Subjects	O
+were	O
+receiving	O
+desferrioxamine	O
+(	O
+DFO	O
+)	O
+chelation	O
+treatment	O
+with	O
+a	O
+mean	O
+daily	O
+dose	O
+of	O
+50	O
+-	O
+60	O
+mg	O
+/	O
+kg	O
+,	O
+5	O
+-	O
+6	O
+days	O
+a	O
+week	O
+during	O
+the	O
+first	O
+six	O
+years	O
+of	O
+the	O
+study	O
+,	O
+which	O
+was	O
+then	O
+reduced	O
+to	O
+40	O
+-	O
+50	O
+mg	O
+/	O
+kg	O
+for	O
+the	O
+following	O
+eight	O
+years	O
+.	O
+
+Patients	O
+were	O
+followed	O
+for	O
+8	O
+-	O
+14	O
+years	O
+.	O
+
+RESULTS	O
+:	O
+Overall	O
+,	O
+21	O
+out	O
+of	O
+104	O
+patients	O
+(	O
+20	O
+.	O
+2	O
+%	O
+)	O
+presented	O
+with	O
+high	O
+frequency	O
+sensorineural	B
+hearing	I
+loss	I
+(	O
+SNHL	B
+)	O
+,	O
+either	O
+unilateral	O
+or	O
+bilateral	O
+.	O
+
+No	O
+ototoxic	B
+factor	O
+,	O
+other	O
+than	O
+DFO	O
+,	O
+was	O
+present	O
+in	O
+any	O
+of	O
+the	O
+patients	O
+.	O
+
+Patients	O
+with	O
+SNHL	B
+presented	O
+with	O
+relatively	O
+lower	O
+serum	O
+ferritin	O
+levels	O
+than	O
+those	O
+with	O
+normal	O
+hearing	O
+,	O
+however	O
+,	O
+no	O
+statistically	O
+significant	O
+difference	O
+was	O
+observed	O
+.	O
+
+Subjects	O
+with	O
+SNHL	B
+were	O
+submitted	O
+to	O
+DFO	O
+reduction	O
+or	O
+temporary	O
+withdrawal	O
+.	O
+
+Following	O
+intervention	O
+,	O
+7	O
+out	O
+of	O
+21	O
+affected	O
+patients	O
+recovered	O
+,	O
+10	O
+remained	O
+stable	O
+and	O
+4	O
+demonstrated	O
+aggravation	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+findings	O
+are	O
+indicative	O
+of	O
+DFO	O
+'	O
+s	O
+contributing	O
+role	O
+in	O
+the	O
+development	O
+of	O
+hearing	B
+impairment	I
+.	O
+
+Regular	O
+audiologic	O
+evaluation	O
+is	O
+imperative	O
+in	O
+all	O
+thalassemic	B
+patients	O
+so	O
+that	O
+early	O
+changes	O
+may	O
+be	O
+recognized	O
+and	O
+treatment	O
+may	O
+be	O
+judiciously	O
+adjusted	O
+in	O
+order	O
+to	O
+prevent	O
+or	O
+reverse	O
+hearing	B
+impairment	I
+.	O
+
+Individual	O
+differences	O
+in	O
+renal	O
+ACE	O
+activity	O
+in	O
+healthy	O
+rats	O
+predict	O
+susceptibility	O
+to	O
+adriamycin	O
+-	O
+induced	O
+renal	B
+damage	I
+.	O
+
+BACKGROUND	O
+:	O
+In	O
+man	O
+,	O
+differences	O
+in	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+levels	O
+,	O
+related	O
+to	O
+ACE	O
+(	O
+I	O
+/	O
+D	O
+)	O
+genotype	O
+,	O
+are	O
+associated	O
+with	O
+renal	O
+prognosis	O
+.	O
+
+This	O
+raises	O
+the	O
+hypothesis	O
+that	O
+individual	O
+differences	O
+in	O
+renal	O
+ACE	O
+activity	O
+are	O
+involved	O
+in	O
+renal	O
+susceptibility	O
+to	O
+inflicted	O
+damage	O
+.	O
+
+Therefore	O
+,	O
+we	O
+studied	O
+the	O
+predictive	O
+effect	O
+of	O
+renal	O
+ACE	O
+activity	O
+for	O
+the	O
+severity	O
+of	O
+renal	B
+damage	I
+induced	O
+by	O
+a	O
+single	O
+injection	O
+of	O
+adriamycin	O
+in	O
+rats	O
+.	O
+
+METHODS	O
+:	O
+Renal	O
+ACE	O
+activity	O
+(	O
+Hip	O
+-	O
+His	O
+-	O
+Leu	O
+cleavage	O
+by	O
+cortical	O
+homogenates	O
+)	O
+was	O
+determined	O
+by	O
+renal	O
+biopsy	O
+in	O
+27	O
+adult	O
+male	O
+Wistar	O
+rats	O
+.	O
+
+After	O
+1	O
+week	O
+of	O
+recovery	O
+,	O
+proteinuria	B
+was	O
+induced	O
+by	O
+adriamycin	O
+[	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+intravenously	O
+(	O
+i	O
+.	O
+v	O
+.	O
+)	O
+n	O
+=	O
+18	O
+;	O
+controls	O
+,	O
+saline	O
+i	O
+.	O
+v	O
+.	O
+n	O
+=	O
+9	O
+]	O
+.	O
+
+Proteinuria	B
+was	O
+measured	O
+every	O
+2	O
+weeks	O
+.	O
+
+After	O
+12	O
+weeks	O
+,	O
+rats	O
+were	O
+sacrificed	O
+and	O
+their	O
+kidneys	O
+harvested	O
+.	O
+
+RESULTS	O
+:	O
+As	O
+anticipated	O
+,	O
+adriamycin	O
+elicited	O
+nephrotic	B
+range	O
+proteinuria	B
+,	O
+renal	B
+interstitial	I
+damage	I
+and	O
+mild	O
+focal	B
+glomerulosclerosis	I
+.	O
+
+Baseline	O
+renal	O
+ACE	O
+positively	O
+correlated	O
+with	O
+the	O
+relative	O
+rise	O
+in	O
+proteinuria	B
+after	O
+adriamycin	O
+(	O
+r	O
+=	O
+0	O
+.	O
+62	O
+,	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+,	O
+renal	O
+interstitial	O
+alpha	O
+-	O
+smooth	O
+muscle	O
+actin	O
+(	O
+r	O
+=	O
+0	O
+.	O
+49	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+,	O
+interstitial	O
+macrophage	O
+influx	O
+(	O
+r	O
+=	O
+0	O
+.	O
+56	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+,	O
+interstitial	O
+collagen	O
+III	O
+(	O
+r	O
+=	O
+0	O
+.	O
+53	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+,	O
+glomerular	O
+alpha	O
+-	O
+smooth	O
+muscle	O
+actin	O
+(	O
+r	O
+=	O
+0	O
+.	O
+74	O
+,	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+and	O
+glomerular	O
+desmin	O
+(	O
+r	O
+=	O
+0	O
+.	O
+48	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Baseline	O
+renal	O
+ACE	O
+did	O
+not	O
+correlate	O
+with	O
+focal	B
+glomerulosclerosis	I
+(	O
+r	O
+=	O
+0	O
+.	O
+22	O
+,	O
+NS	O
+)	O
+.	O
+
+In	O
+controls	O
+,	O
+no	O
+predictive	O
+values	O
+for	O
+renal	O
+parameters	O
+were	O
+observed	O
+.	O
+
+CONCLUSION	O
+:	O
+Individual	O
+differences	O
+in	O
+renal	O
+ACE	O
+activity	O
+predict	O
+the	O
+severity	O
+of	O
+adriamycin	O
+-	O
+induced	O
+renal	B
+damage	I
+in	O
+this	O
+outbred	O
+rat	O
+strain	O
+.	O
+
+This	O
+supports	O
+the	O
+assumption	O
+that	O
+differences	O
+in	O
+renal	O
+ACE	O
+activity	O
+predispose	O
+to	O
+a	O
+less	O
+favourable	O
+course	O
+of	O
+renal	B
+damage	I
+.	O
+
+Recurrent	O
+acute	O
+interstitial	B
+nephritis	I
+induced	O
+by	O
+azithromycin	O
+.	O
+
+A	O
+14	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+is	O
+reported	O
+with	O
+recurrent	O
+,	O
+azithromycin	O
+-	O
+induced	O
+,	O
+acute	O
+interstitial	B
+nephritis	I
+.	O
+
+The	O
+second	O
+episode	O
+was	O
+more	O
+severe	O
+than	O
+the	O
+first	O
+;	O
+and	O
+although	O
+both	O
+were	O
+treated	O
+with	O
+intensive	O
+corticosteroid	O
+therapy	O
+,	O
+renal	O
+function	O
+remained	O
+impaired	O
+.	O
+
+Although	O
+most	O
+cases	O
+of	O
+antibiotic	O
+induced	O
+acute	O
+interstitial	B
+nephritis	I
+are	O
+benign	O
+and	O
+self	O
+-	O
+limited	O
+,	O
+some	O
+patients	O
+are	O
+at	O
+risk	O
+for	O
+permanent	O
+renal	B
+injury	I
+.	O
+
+Spironolactone	O
+-	O
+induced	O
+renal	B
+insufficiency	I
+and	O
+hyperkalemia	B
+in	O
+patients	O
+with	O
+heart	B
+failure	I
+.	O
+
+BACKGROUND	O
+:	O
+A	O
+previous	O
+randomized	O
+controlled	O
+trial	O
+evaluating	O
+the	O
+use	O
+of	O
+spironolactone	O
+in	O
+heart	B
+failure	I
+patients	O
+reported	O
+a	O
+low	O
+risk	O
+of	O
+hyperkalemia	B
+(	O
+2	O
+%	O
+)	O
+and	O
+renal	B
+insufficiency	I
+(	O
+0	O
+%	O
+)	O
+.	O
+
+Because	O
+treatments	O
+for	O
+heart	B
+failure	I
+have	O
+changed	O
+since	O
+the	O
+benefits	O
+of	O
+spironolactone	O
+were	O
+reported	O
+,	O
+the	O
+prevalence	O
+of	O
+these	O
+complications	O
+may	O
+differ	O
+in	O
+current	O
+clinical	O
+practice	O
+.	O
+
+We	O
+therefore	O
+sought	O
+to	O
+determine	O
+the	O
+prevalence	O
+and	O
+clinical	O
+associations	O
+of	O
+hyperkalemia	B
+and	O
+renal	B
+insufficiency	I
+in	O
+heart	B
+failure	I
+patients	O
+treated	O
+with	O
+spironolactone	O
+.	O
+
+METHODS	O
+:	O
+We	O
+performed	O
+a	O
+case	O
+control	O
+study	O
+of	O
+heart	B
+failure	I
+patients	O
+treated	O
+with	O
+spironolactone	O
+in	O
+our	O
+clinical	O
+practice	O
+.	O
+
+Cases	O
+were	O
+patients	O
+who	O
+developed	O
+hyperkalemia	B
+(	O
+K	O
+(	O
++	O
+)	O
+>	O
+5	O
+.	O
+0	O
+mEq	O
+/	O
+L	O
+)	O
+or	O
+renal	B
+insufficiency	I
+(	O
+Cr	O
+>	O
+or	O
+=	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+dL	O
+)	O
+,	O
+and	O
+they	O
+were	O
+compared	O
+to	O
+2	O
+randomly	O
+selected	O
+controls	O
+per	O
+case	O
+.	O
+
+Clinical	O
+characteristics	O
+,	O
+medications	O
+,	O
+and	O
+serum	O
+chemistries	O
+at	O
+baseline	O
+and	O
+follow	O
+-	O
+up	O
+time	O
+periods	O
+were	O
+compared	O
+.	O
+
+RESULTS	O
+:	O
+Sixty	O
+-	O
+seven	O
+of	O
+926	O
+patients	O
+(	O
+7	O
+.	O
+2	O
+%	O
+)	O
+required	O
+discontinuation	O
+of	O
+spironolactone	O
+due	O
+to	O
+hyperkalemia	B
+(	O
+n	O
+=	O
+33	O
+)	O
+or	O
+renal	B
+failure	I
+(	O
+n	O
+=	O
+34	O
+)	O
+.	O
+
+Patients	O
+who	O
+developed	O
+hyperkalemia	B
+were	O
+older	O
+and	O
+more	O
+likely	O
+to	O
+have	O
+diabetes	B
+,	O
+had	O
+higher	O
+baseline	O
+serum	O
+potassium	O
+levels	O
+and	O
+lower	O
+baseline	O
+potassium	O
+supplement	O
+doses	O
+,	O
+and	O
+were	O
+more	O
+likely	O
+to	O
+be	O
+treated	O
+with	O
+beta	O
+-	O
+blockers	O
+than	O
+controls	O
+(	O
+n	O
+=	O
+134	O
+)	O
+.	O
+
+Patients	O
+who	O
+developed	O
+renal	B
+insufficiency	I
+had	O
+lower	O
+baseline	O
+body	O
+weight	O
+and	O
+higher	O
+baseline	O
+serum	O
+creatinine	O
+,	O
+required	O
+higher	O
+doses	O
+of	O
+loop	O
+diuretics	O
+,	O
+and	O
+were	O
+more	O
+likely	O
+to	O
+be	O
+treated	O
+with	O
+thiazide	O
+diuretics	O
+than	O
+controls	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Spironolactone	O
+-	O
+induced	O
+hyperkalemia	B
+and	O
+renal	B
+insufficiency	I
+are	O
+more	O
+common	O
+in	O
+our	O
+clinical	O
+experience	O
+than	O
+reported	O
+previously	O
+.	O
+
+This	O
+difference	O
+is	O
+explained	O
+by	O
+patient	O
+comorbidities	O
+and	O
+more	O
+frequent	O
+use	O
+of	O
+beta	O
+-	O
+blockers	O
+.	O
+
+Acute	O
+reserpine	O
+and	O
+subchronic	O
+haloperidol	O
+treatments	O
+change	O
+synaptosomal	O
+brain	O
+glutamate	O
+uptake	O
+and	O
+elicit	O
+orofacial	B
+dyskinesia	I
+in	O
+rats	O
+.	O
+
+Reserpine	O
+-	O
+and	O
+haloperidol	O
+-	O
+induced	O
+orofacial	B
+dyskinesia	I
+are	O
+putative	O
+animal	O
+models	O
+of	O
+tardive	B
+dyskinesia	I
+(	O
+TD	B
+)	O
+whose	O
+pathophysiology	O
+has	O
+been	O
+related	O
+to	O
+free	O
+radical	O
+generation	O
+and	O
+oxidative	O
+stress	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+the	O
+authors	O
+induced	O
+orofacial	B
+dyskinesia	I
+by	O
+acute	O
+reserpine	O
+and	O
+subchronic	O
+haloperidol	O
+administration	O
+to	O
+rats	O
+.	O
+
+Reserpine	O
+injection	O
+(	O
+one	O
+dose	O
+of	O
+1	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+every	O
+other	O
+day	O
+for	O
+3	O
+days	O
+caused	O
+a	O
+significant	O
+increase	O
+in	O
+vacuous	O
+chewing	O
+,	O
+tongue	O
+protrusion	O
+and	O
+duration	O
+of	O
+facial	O
+twitching	O
+,	O
+compared	O
+to	O
+the	O
+control	O
+.	O
+
+Haloperidol	O
+administration	O
+(	O
+one	O
+dose	O
+of	O
+12	O
+mg	O
+/	O
+kg	O
+once	O
+a	O
+week	O
+s	O
+.	O
+c	O
+.	O
+)	O
+for	O
+4	O
+weeks	O
+caused	O
+an	O
+increase	O
+in	O
+vacuous	O
+chewing	O
+,	O
+tongue	O
+protrusion	O
+and	O
+duration	O
+of	O
+facial	O
+twitching	O
+observed	O
+in	O
+four	O
+weekly	O
+evaluations	O
+.	O
+
+After	O
+the	O
+treatments	O
+and	O
+behavioral	O
+observation	O
+,	O
+glutamate	O
+uptake	O
+by	O
+segments	O
+of	O
+the	O
+brain	O
+was	O
+analyzed	O
+.	O
+
+A	O
+decreased	O
+glutamate	O
+uptake	O
+was	O
+observed	O
+in	O
+the	O
+subcortical	O
+parts	O
+of	O
+animals	O
+treated	O
+with	O
+reserpine	O
+and	O
+haloperidol	O
+,	O
+compared	O
+to	O
+the	O
+control	O
+.	O
+
+Importantly	O
+,	O
+a	O
+decrease	O
+in	O
+glutamate	O
+uptake	O
+correlates	O
+negatively	O
+with	O
+an	O
+increase	O
+in	O
+the	O
+incidence	O
+of	O
+orofacial	B
+diskinesia	I
+.	O
+
+These	O
+results	O
+indicate	O
+that	O
+early	O
+changes	O
+in	O
+glutamate	O
+transport	O
+may	O
+be	O
+related	O
+to	O
+the	O
+development	O
+of	O
+vacuous	O
+chewing	O
+movements	O
+in	O
+rats	O
+.	O
+
+Ceftriaxone	O
+-	O
+associated	O
+biliary	B
+pseudolithiasis	I
+in	O
+paediatric	O
+surgical	O
+patients	O
+.	O
+
+It	O
+is	O
+well	O
+known	O
+that	O
+ceftriaxone	O
+leads	O
+to	O
+pseudolithiasis	B
+in	O
+some	O
+patients	O
+.	O
+
+Clinical	O
+and	O
+experimental	O
+studies	O
+also	O
+suggest	O
+that	O
+situations	O
+causing	O
+gallbladder	B
+dysfunction	I
+,	O
+such	O
+as	O
+fasting	O
+,	O
+may	O
+have	O
+a	O
+role	O
+for	O
+the	O
+development	O
+of	O
+pseudolithiasis	B
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+prospectively	O
+evaluated	O
+the	O
+incidence	O
+and	O
+clinical	O
+importance	O
+of	O
+pseudolithiasis	B
+in	O
+paediatric	O
+surgical	O
+patients	O
+receiving	O
+ceftriaxone	O
+treatment	O
+,	O
+who	O
+often	O
+had	O
+to	O
+fast	O
+in	O
+the	O
+post	O
+-	O
+operative	O
+period	O
+.	O
+
+Fifty	O
+children	O
+who	O
+were	O
+given	O
+ceftriaxone	O
+were	O
+evaluated	O
+by	O
+serial	O
+abdominal	O
+sonograms	O
+.	O
+
+Of	O
+those	O
+,	O
+13	O
+(	O
+26	O
+%	O
+)	O
+developed	O
+biliary	O
+pathology	O
+.	O
+
+Comparison	O
+of	O
+the	O
+patients	O
+with	O
+or	O
+without	O
+pseudolithiasis	B
+revealed	O
+no	O
+significant	O
+difference	O
+with	O
+respect	O
+to	O
+age	O
+,	O
+sex	O
+,	O
+duration	O
+of	O
+the	O
+treatment	O
+and	O
+starvation	O
+variables	O
+.	O
+
+After	O
+cessation	O
+of	O
+the	O
+treatment	O
+,	O
+pseudolithiasis	B
+resolved	O
+spontaneously	O
+within	O
+a	O
+short	O
+period	O
+.	O
+
+The	O
+incidence	O
+of	O
+pseudolithiasis	B
+is	O
+not	O
+affected	O
+by	O
+fasting	O
+.	O
+
+Coronary	B
+aneurysm	I
+after	O
+implantation	O
+of	O
+a	O
+paclitaxel	O
+-	O
+eluting	O
+stent	O
+.	O
+
+Formation	O
+of	O
+coronary	B
+aneurysm	I
+is	O
+a	O
+rare	O
+complication	O
+of	O
+stenting	O
+with	O
+bare	O
+metal	O
+stents	O
+,	O
+but	O
+based	O
+on	O
+experimental	O
+studies	O
+drug	O
+-	O
+eluting	O
+stents	O
+may	O
+induce	O
+toxic	O
+effects	O
+on	O
+the	O
+vessel	O
+wall	O
+with	O
+incomplete	O
+stent	O
+apposition	O
+,	O
+aneurysm	B
+formation	O
+and	O
+with	O
+the	O
+potential	O
+of	O
+stent	O
+thrombosis	B
+or	O
+vessel	B
+rupture	I
+.	O
+
+We	O
+present	O
+a	O
+43	O
+-	O
+year	O
+-	O
+old	O
+man	O
+who	O
+developed	O
+a	O
+coronary	B
+aneurysm	I
+in	O
+the	O
+right	O
+coronary	O
+artery	O
+6	O
+months	O
+after	O
+receiving	O
+a	O
+paclitaxel	O
+-	O
+eluting	O
+stent	O
+.	O
+
+The	O
+patient	O
+was	O
+asymptomatic	O
+and	O
+the	O
+aneurysm	B
+was	O
+detected	O
+in	O
+a	O
+routine	O
+control	O
+.	O
+
+Angiography	O
+and	O
+intracoronary	O
+ultrasound	O
+demonstrated	O
+lack	O
+of	O
+contact	O
+between	O
+stent	O
+and	O
+vessel	O
+wall	O
+in	O
+a	O
+15	O
+-	O
+mm	O
+long	O
+segment	O
+with	O
+maximal	O
+aneurysm	B
+diameter	O
+of	O
+6	O
+.	O
+0	O
+mm	O
+.	O
+
+The	O
+patient	O
+was	O
+successfully	O
+treated	O
+with	O
+a	O
+graft	O
+stent	O
+.	O
+
+Causes	O
+of	O
+acute	O
+thrombotic	B
+microangiopathy	I
+in	O
+patients	O
+receiving	O
+kidney	O
+transplantation	O
+.	O
+
+OBJECTIVES	O
+:	O
+Thrombotic	B
+microangiopathy	I
+is	O
+a	O
+well	O
+-	O
+known	O
+problem	O
+in	O
+patients	O
+following	O
+renal	O
+transplantation	O
+.	O
+
+In	O
+postrenal	O
+transplantation	O
+,	O
+thrombotic	B
+microangiopathy	I
+is	O
+often	O
+a	O
+reflection	O
+of	O
+hemolytic	B
+uremic	I
+syndrome	I
+.	O
+
+We	O
+aimed	O
+to	O
+determine	O
+the	O
+causes	O
+of	O
+thrombotic	B
+microangiopathy	I
+in	O
+a	O
+population	O
+of	O
+renal	O
+transplantation	O
+recipients	O
+and	O
+discuss	O
+the	O
+literature	O
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+We	O
+investigated	O
+the	O
+causes	O
+of	O
+thrombotic	B
+microangiopathy	I
+during	O
+a	O
+1	O
+-	O
+year	O
+period	O
+,	O
+from	O
+June	O
+2003	O
+to	O
+June	O
+2004	O
+,	O
+at	O
+the	O
+King	O
+Fahad	O
+National	O
+Guard	O
+Hospital	O
+in	O
+Riyadh	O
+,	O
+Saudi	O
+Arabia	O
+,	O
+by	O
+reviewing	O
+the	O
+slides	O
+of	O
+all	O
+transplant	O
+biopsies	O
+(	O
+n	O
+=	O
+25	O
+)	O
+performed	O
+during	O
+this	O
+interval	O
+.	O
+
+Pre	O
+-	O
+and	O
+posttransplant	O
+crossmatching	O
+was	O
+done	O
+when	O
+possible	O
+.	O
+
+RESULTS	O
+:	O
+Five	O
+cases	O
+of	O
+thrombotic	B
+microangiopathy	I
+were	O
+found	O
+.	O
+
+Three	O
+of	O
+these	O
+cases	O
+were	O
+from	O
+the	O
+25	O
+transplantations	O
+performed	O
+at	O
+King	O
+Fahad	O
+National	O
+Guard	O
+Hospital	O
+,	O
+while	O
+the	O
+other	O
+2	O
+transplantations	O
+had	O
+been	O
+performed	O
+abroad	O
+and	O
+were	O
+referred	O
+to	O
+us	O
+for	O
+follow	O
+-	O
+up	O
+.	O
+
+Three	O
+cases	O
+were	O
+related	O
+to	O
+cyclosporine	O
+,	O
+and	O
+1	O
+case	O
+was	O
+secondary	O
+to	O
+both	O
+cyclosporine	O
+and	O
+tacrolimus	O
+.	O
+
+The	O
+fifth	O
+case	O
+had	O
+features	O
+of	O
+thrombotic	B
+microangiopathy	I
+related	O
+to	O
+an	O
+antiphospholipid	B
+syndrome	I
+in	O
+a	O
+patient	O
+with	O
+systemic	B
+lupus	I
+erythematosus	I
+.	O
+
+CONCLUSIONS	O
+:	O
+In	O
+the	O
+literature	O
+,	O
+the	O
+most	O
+-	O
+frequent	O
+cause	O
+of	O
+hemolytic	B
+uremic	I
+syndrome	I
+in	O
+patients	O
+following	O
+renal	O
+transplantation	O
+is	O
+recurrence	O
+of	O
+the	O
+hemolytic	B
+uremic	I
+syndrome	I
+.	O
+
+Other	O
+causes	O
+include	O
+drug	O
+-	O
+related	O
+(	O
+cyclosporine	O
+,	O
+tacrolimus	O
+)	O
+toxicity	B
+,	O
+procoagulant	O
+status	O
+,	O
+and	O
+antibody	O
+-	O
+mediated	O
+rejection	O
+.	O
+
+We	O
+found	O
+that	O
+the	O
+most	O
+-	O
+frequent	O
+cause	O
+of	O
+thrombotic	B
+microangiopathy	I
+was	O
+drug	O
+related	O
+,	O
+secondary	O
+mainly	O
+to	O
+cyclosporine	O
+.	O
+
+In	O
+the	O
+current	O
+study	O
+,	O
+the	O
+frequency	O
+of	O
+thrombotic	B
+microangiopathy	I
+was	O
+similar	O
+to	O
+the	O
+percentage	O
+reported	O
+in	O
+the	O
+literature	O
+(	O
+20	O
+%	O
+)	O
+.	O
+
+Comparison	O
+of	O
+developmental	O
+toxicity	B
+of	O
+selective	O
+and	O
+non	O
+-	O
+selective	O
+cyclooxygenase	O
+-	O
+2	O
+inhibitors	O
+in	O
+CRL	O
+:	O
+(	O
+WI	O
+)	O
+WUBR	O
+Wistar	O
+rats	O
+-	O
+-	O
+DFU	O
+and	O
+piroxicam	O
+study	O
+.	O
+
+BACKGROUND	O
+:	O
+Cyclooxygenase	O
+(	O
+COX	O
+)	O
+inhibitors	O
+are	O
+one	O
+of	O
+the	O
+most	O
+often	O
+ingested	O
+drugs	O
+during	O
+pregnancy	O
+.	O
+
+Unlike	O
+general	O
+toxicity	B
+data	O
+,	O
+their	O
+prenatal	O
+toxic	O
+effects	O
+were	O
+not	O
+extensively	O
+studied	O
+before	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+experiment	O
+was	O
+to	O
+evaluate	O
+the	O
+developmental	O
+toxicity	B
+of	O
+the	O
+non	O
+-	O
+selective	O
+(	O
+piroxicam	O
+)	O
+and	O
+selective	O
+(	O
+DFU	O
+;	O
+5	O
+,	O
+5	O
+-	O
+dimethyl	O
+-	O
+3	O
+-	O
+(	O
+3	O
+-	O
+fluorophenyl	O
+)	O
+-	O
+4	O
+-	O
+(	O
+4	O
+-	O
+methylsulphonyl	O
+)	O
+phenyl	O
+-	O
+2	O
+(	O
+5H	O
+)	O
+-	O
+furanon	O
+)	O
+COX	O
+-	O
+2	O
+inhibitors	O
+.	O
+
+METHODS	O
+:	O
+Drugs	O
+were	O
+separately	O
+,	O
+orally	O
+once	O
+daily	O
+dosed	O
+to	O
+pregnant	O
+rats	O
+from	O
+day	O
+8	O
+to	O
+21	O
+(	O
+GD1	O
+=	O
+plug	O
+day	O
+)	O
+.	O
+
+Doses	O
+were	O
+set	O
+at	O
+0	O
+.	O
+3	O
+,	O
+3	O
+.	O
+0	O
+and	O
+30	O
+.	O
+0mg	O
+/	O
+kg	O
+for	O
+piroxicam	O
+and	O
+0	O
+.	O
+2	O
+,	O
+2	O
+.	O
+0	O
+and	O
+20	O
+.	O
+0mg	O
+/	O
+kg	O
+for	O
+DFU	O
+.	O
+
+Fetuses	O
+were	O
+delivered	O
+on	O
+GD	O
+21	O
+and	O
+routinely	O
+examined	O
+.	O
+
+Comprehensive	O
+clinical	O
+and	O
+developmental	O
+measurements	O
+were	O
+done	O
+.	O
+
+The	O
+pooled	O
+statistical	O
+analysis	O
+for	O
+ventricular	B
+septal	I
+(	I
+VSD	I
+)	I
+and	I
+midline	I
+(	I
+MD	I
+)	I
+defects	I
+was	O
+performed	O
+for	O
+rat	O
+fetuses	O
+exposed	O
+to	O
+piroxicam	O
+,	O
+selective	O
+and	O
+non	O
+-	O
+selective	O
+COX	O
+-	O
+2	O
+inhibitor	O
+based	O
+on	O
+present	O
+and	O
+historic	O
+data	O
+.	O
+
+RESULTS	O
+:	O
+Maternal	O
+toxicity	B
+,	O
+intrauterine	B
+growth	I
+retardation	I
+,	O
+and	O
+increase	B
+of	I
+external	I
+and	I
+skeletal	I
+variations	I
+were	O
+found	O
+in	O
+rats	O
+treated	O
+with	O
+the	O
+highest	O
+dose	O
+of	O
+piroxicam	O
+.	O
+
+Decrease	O
+of	O
+fetal	O
+length	O
+was	O
+the	O
+only	O
+signs	O
+of	O
+the	O
+DFU	O
+developmental	O
+toxicity	B
+observed	O
+in	O
+pups	O
+exposed	O
+to	O
+the	O
+highest	O
+compound	O
+dose	O
+.	O
+
+Lack	O
+of	O
+teratogenicity	O
+was	O
+found	O
+in	O
+piroxicam	O
+and	O
+DFU	O
+-	O
+exposed	O
+groups	O
+.	O
+
+Prenatal	O
+exposure	O
+to	O
+non	O
+-	O
+selective	O
+COX	O
+inhibitors	O
+increases	O
+the	O
+risk	O
+of	O
+VSD	O
+and	O
+MD	O
+when	O
+compared	O
+to	O
+historic	O
+control	O
+but	O
+not	O
+with	O
+selective	O
+COX	O
+-	O
+2	O
+inhibitors	O
+.	O
+
+CONCLUSION	O
+:	O
+Both	O
+selective	O
+and	O
+non	O
+-	O
+selective	O
+COX	O
+-	O
+2	O
+inhibitors	O
+were	O
+toxic	O
+for	O
+rats	O
+fetuses	O
+when	O
+administered	O
+in	O
+the	O
+highest	O
+dose	O
+.	O
+
+Unlike	O
+DFU	O
+,	O
+piroxicam	O
+was	O
+also	O
+highly	O
+toxic	O
+to	O
+the	O
+dams	O
+.	O
+
+Prenatal	O
+exposure	O
+to	O
+selective	O
+COX	O
+-	O
+2	O
+inhibitors	O
+does	O
+not	O
+increase	O
+the	O
+risk	O
+of	O
+ventricular	B
+septal	I
+and	I
+midline	I
+defects	I
+in	O
+rat	O
+when	O
+compared	O
+to	O
+non	O
+-	O
+selective	O
+drugs	O
+and	O
+historic	O
+control	O
+.	O
+
+Lone	O
+atrial	B
+fibrillation	I
+associated	O
+with	O
+creatine	O
+monohydrate	O
+supplementation	O
+.	O
+
+Atrial	B
+fibrillation	I
+in	O
+young	O
+patients	O
+without	O
+structural	O
+heart	B
+disease	I
+is	O
+rare	O
+.	O
+
+Therefore	O
+,	O
+when	O
+the	O
+arrhythmia	B
+is	O
+present	O
+in	O
+this	O
+population	O
+,	O
+reversible	O
+causes	O
+must	O
+be	O
+identified	O
+and	O
+resolved	O
+.	O
+
+Thyroid	B
+disorders	I
+,	O
+illicit	O
+drug	O
+or	O
+stimulant	O
+use	O
+,	O
+and	O
+acute	B
+alcohol	I
+intoxication	I
+are	O
+among	O
+these	O
+causes	O
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+30	O
+-	O
+year	O
+-	O
+old	O
+Caucasian	O
+man	O
+who	O
+came	O
+to	O
+the	O
+emergency	O
+department	O
+in	O
+atrial	B
+fibrillation	I
+with	O
+rapid	O
+ventricular	O
+response	O
+.	O
+
+His	O
+medical	O
+history	O
+was	O
+unremarkable	O
+,	O
+except	O
+for	O
+minor	O
+fractures	B
+of	O
+the	O
+fingers	O
+and	O
+foot	O
+.	O
+
+Thyroid	O
+-	O
+stimulating	O
+hormone	O
+,	O
+magnesium	O
+,	O
+and	O
+potassium	O
+levels	O
+were	O
+within	O
+normal	O
+limits	O
+,	O
+urine	O
+drug	O
+screen	O
+was	O
+negative	O
+,	O
+and	O
+alcohol	O
+use	O
+was	O
+denied	O
+.	O
+
+However	O
+,	O
+when	O
+the	O
+patient	O
+was	O
+questioned	O
+about	O
+use	O
+of	O
+herbal	O
+products	O
+and	O
+supplements	O
+,	O
+the	O
+use	O
+of	O
+creatine	O
+monohydrate	O
+was	O
+revealed	O
+.	O
+
+The	O
+patient	O
+was	O
+admitted	O
+to	O
+the	O
+hospital	O
+,	O
+anticoagulated	O
+with	O
+unfractionated	O
+heparin	O
+,	O
+and	O
+given	O
+intravenous	O
+diltiazem	O
+for	O
+rate	O
+control	O
+and	O
+intravenous	O
+amiodarone	O
+for	O
+rate	O
+and	O
+rhythm	O
+control	O
+.	O
+
+When	O
+discharged	O
+less	O
+than	O
+24	O
+hours	O
+later	O
+,	O
+he	O
+was	O
+receiving	O
+metoprolol	O
+and	O
+aspirin	O
+,	O
+with	O
+follow	O
+-	O
+up	O
+plans	O
+for	O
+echocardiography	O
+and	O
+nuclear	O
+imaging	O
+to	O
+assess	O
+perfusion	O
+.	O
+
+Exogenous	O
+creatine	O
+is	O
+used	O
+by	O
+athletes	O
+to	O
+theoretically	O
+improve	O
+exercise	O
+performance	O
+.	O
+
+Vegetarians	O
+may	O
+also	O
+take	O
+creatine	O
+to	O
+replace	O
+what	O
+they	O
+are	O
+not	O
+consuming	O
+from	O
+meat	O
+,	O
+fish	O
+,	O
+and	O
+other	O
+animal	O
+products	O
+.	O
+
+Previous	O
+anecdotal	O
+reports	O
+have	O
+linked	O
+creatine	O
+to	O
+the	O
+development	O
+of	O
+arrhythmia	B
+.	O
+
+Clinicians	O
+must	O
+be	O
+diligent	O
+when	O
+interviewing	O
+patients	O
+about	O
+their	O
+drug	O
+therapy	O
+histories	O
+and	O
+include	O
+questions	O
+about	O
+their	O
+use	O
+of	O
+herbal	O
+products	O
+and	O
+dietary	O
+supplements	O
+.	O
+
+In	O
+addition	O
+,	O
+it	O
+is	O
+important	O
+to	O
+report	O
+adverse	O
+effects	O
+associated	O
+with	O
+frequently	O
+consumed	O
+supplements	O
+and	O
+herbal	O
+products	O
+to	O
+the	O
+Food	O
+and	O
+Drug	O
+Administration	O
+and	O
+in	O
+the	O
+literature	O
+.	O
+
+Seizures	B
+induced	O
+by	O
+the	O
+cocaine	O
+metabolite	O
+benzoylecgonine	O
+in	O
+rats	O
+.	O
+
+The	O
+half	O
+-	O
+life	O
+(	O
+t1	O
+/	O
+2	O
+)	O
+of	O
+cocaine	O
+is	O
+relatively	O
+short	O
+,	O
+but	O
+some	O
+of	O
+the	O
+consequences	O
+of	O
+its	O
+use	O
+,	O
+such	O
+as	O
+seizures	B
+and	O
+strokes	B
+,	O
+can	O
+occur	O
+hours	O
+after	O
+exposure	O
+.	O
+
+This	O
+led	O
+us	O
+to	O
+hypothesize	O
+that	O
+a	O
+metabolite	O
+of	O
+cocaine	O
+may	O
+be	O
+responsible	O
+for	O
+some	O
+of	O
+those	O
+delayed	O
+sequelae	O
+.	O
+
+We	O
+evaluated	O
+the	O
+potential	O
+of	O
+the	O
+major	O
+metabolite	O
+of	O
+cocaine	O
+,	O
+benzoylecgonine	O
+(	O
+BE	O
+)	O
+,	O
+to	O
+cause	O
+seizures	B
+.	O
+
+Two	O
+separate	O
+equimolar	O
+doses	O
+(	O
+0	O
+.	O
+2	O
+and	O
+0	O
+.	O
+4	O
+mumol	O
+)	O
+of	O
+either	O
+cocaine	O
+or	O
+BE	O
+were	O
+injected	O
+ventricularly	O
+in	O
+unanesthetized	O
+juvenile	O
+rats	O
+.	O
+
+Treated	O
+rats	O
+were	O
+then	O
+evaluated	O
+for	O
+incidence	O
+,	O
+latency	O
+,	O
+and	O
+seizure	B
+pattern	O
+or	O
+for	O
+locomotor	O
+activity	O
+in	O
+animals	O
+without	O
+seizures	B
+.	O
+
+BE	O
+-	O
+Induced	O
+seizures	B
+occurred	O
+more	O
+frequently	O
+and	O
+had	O
+significantly	O
+longer	O
+latencies	O
+than	O
+those	O
+induced	O
+by	O
+equimolar	O
+amounts	O
+of	O
+cocaine	O
+.	O
+
+Whereas	O
+cocaine	O
+-	O
+induced	O
+seizures	B
+were	O
+best	O
+characterized	O
+as	O
+brief	O
+,	O
+generalized	O
+,	O
+and	O
+tonic	O
+and	O
+resulted	O
+in	O
+death	B
+,	O
+those	O
+induced	O
+by	O
+BE	O
+were	O
+prolonged	O
+,	O
+often	O
+multiple	O
+and	O
+mixed	O
+in	O
+type	O
+,	O
+and	O
+rarely	O
+resulted	O
+in	O
+death	B
+.	O
+
+Electrical	O
+recordings	O
+from	O
+the	O
+hippocampus	O
+showed	O
+a	O
+rhythmic	O
+progression	O
+in	O
+EEG	O
+frequency	O
+and	O
+voltage	O
+with	O
+clinical	O
+seizure	B
+expression	O
+.	O
+
+BE	O
+-	O
+Injected	O
+rats	O
+that	O
+did	O
+not	O
+have	O
+seizures	B
+had	O
+significantly	O
+more	O
+locomotor	O
+activity	O
+than	O
+cocaine	O
+-	O
+injected	O
+animals	O
+without	O
+seizures	B
+.	O
+
+The	O
+finding	O
+that	O
+cocaine	O
+-	O
+and	O
+BE	O
+-	O
+induced	O
+seizures	B
+differ	O
+in	O
+several	O
+respects	O
+suggests	O
+more	O
+than	O
+one	O
+mechanism	O
+for	O
+cocaine	O
+-	O
+induced	O
+seizures	B
+and	O
+emphasizes	O
+the	O
+importance	O
+of	O
+a	O
+cocaine	O
+metabolite	O
+,	O
+BE	O
+.	O
+
+The	O
+selective	O
+5	O
+-	O
+HT6	O
+receptor	O
+antagonist	O
+Ro4368554	O
+restores	O
+memory	O
+performance	O
+in	O
+cholinergic	O
+and	O
+serotonergic	O
+models	O
+of	O
+memory	B
+deficiency	I
+in	O
+the	O
+rat	O
+.	O
+
+Antagonists	O
+at	O
+serotonin	O
+type	O
+6	O
+(	O
+5	O
+-	O
+HT	O
+(	O
+6	O
+)	O
+)	O
+receptors	O
+show	O
+activity	O
+in	O
+models	O
+of	O
+learning	O
+and	O
+memory	O
+.	O
+
+Although	O
+the	O
+underlying	O
+mechanism	O
+(	O
+s	O
+)	O
+are	O
+not	O
+well	O
+understood	O
+,	O
+these	O
+effects	O
+may	O
+involve	O
+an	O
+increase	O
+in	O
+acetylcholine	O
+(	O
+ACh	O
+)	O
+levels	O
+.	O
+
+The	O
+present	O
+study	O
+sought	O
+to	O
+characterize	O
+the	O
+cognitive	O
+-	O
+enhancing	O
+effects	O
+of	O
+the	O
+5	O
+-	O
+HT	O
+(	O
+6	O
+)	O
+antagonist	O
+Ro4368554	O
+(	O
+3	O
+-	O
+benzenesulfonyl	O
+-	O
+7	O
+-	O
+(	O
+4	O
+-	O
+methyl	O
+-	O
+piperazin	O
+-	O
+1	O
+-	O
+yl	O
+)	O
+1H	O
+-	O
+indole	O
+)	O
+in	O
+a	O
+rat	O
+object	O
+recognition	O
+task	O
+employing	O
+a	O
+cholinergic	O
+(	O
+scopolamine	O
+pretreatment	O
+)	O
+and	O
+a	O
+serotonergic	O
+-	O
+(	O
+tryptophan	O
+(	O
+TRP	O
+)	O
+depletion	O
+)	O
+deficient	O
+model	O
+,	O
+and	O
+compared	O
+its	O
+pattern	O
+of	O
+action	O
+with	O
+that	O
+of	O
+the	O
+acetylcholinesterase	O
+inhibitor	O
+metrifonate	O
+.	O
+
+Initial	O
+testing	O
+in	O
+a	O
+time	O
+-	O
+dependent	O
+forgetting	O
+task	O
+employing	O
+a	O
+24	O
+-	O
+h	O
+delay	O
+between	O
+training	O
+and	O
+testing	O
+showed	O
+that	O
+metrifonate	O
+improved	O
+object	O
+recognition	O
+(	O
+at	O
+10	O
+and	O
+30	O
+mg	O
+/	O
+kg	O
+,	O
+p	O
+.	O
+o	O
+.	O
+)	O
+,	O
+whereas	O
+Ro4368554	O
+was	O
+inactive	O
+.	O
+
+Both	O
+,	O
+Ro4368554	O
+(	O
+3	O
+and	O
+10	O
+mg	O
+/	O
+kg	O
+,	O
+intraperitoneally	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+)	O
+and	O
+metrifonate	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+,	O
+p	O
+.	O
+o	O
+.	O
+,	O
+respectively	O
+)	O
+reversed	O
+memory	B
+deficits	I
+induced	O
+by	O
+scopolamine	O
+and	O
+TRP	O
+depletion	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+,	O
+and	O
+3	O
+mg	O
+/	O
+kg	O
+,	O
+p	O
+.	O
+o	O
+.	O
+,	O
+respectively	O
+)	O
+.	O
+
+In	O
+conclusion	O
+,	O
+although	O
+Ro4368554	O
+did	O
+not	O
+improve	O
+a	O
+time	O
+-	O
+related	O
+retention	O
+deficit	O
+,	O
+it	O
+reversed	O
+a	O
+cholinergic	O
+and	O
+a	O
+serotonergic	O
+memory	B
+deficit	I
+,	O
+suggesting	O
+that	O
+both	O
+mechanisms	O
+may	O
+be	O
+involved	O
+in	O
+the	O
+facilitation	O
+of	O
+object	O
+memory	O
+by	O
+Ro4368554	O
+and	O
+,	O
+possibly	O
+,	O
+other	O
+5	O
+-	O
+HT	O
+(	O
+6	O
+)	O
+receptor	O
+antagonists	O
+.	O
+
+Evaluation	O
+of	O
+the	O
+anticocaine	O
+monoclonal	O
+antibody	O
+GNC92H2	O
+as	O
+an	O
+immunotherapy	O
+for	O
+cocaine	B
+overdose	I
+.	O
+
+The	O
+illicit	O
+use	O
+of	O
+cocaine	O
+continues	O
+in	O
+epidemic	O
+proportions	O
+and	O
+treatment	O
+for	O
+cocaine	B
+overdose	I
+remains	O
+elusive	O
+.	O
+
+Current	O
+protein	O
+-	O
+based	O
+technology	O
+offers	O
+a	O
+new	O
+therapeutic	O
+venue	O
+by	O
+which	O
+antibodies	O
+bind	O
+the	O
+drug	O
+in	O
+the	O
+blood	O
+stream	O
+,	O
+inactivating	O
+its	O
+toxic	O
+effects	O
+.	O
+
+The	O
+therapeutic	O
+potential	O
+of	O
+the	O
+anticocaine	O
+antibody	O
+GNC92H2	O
+was	O
+examined	O
+using	O
+a	O
+model	O
+of	O
+cocaine	B
+overdose	I
+.	O
+
+Swiss	O
+albino	O
+mice	O
+prepared	O
+with	O
+intrajugular	O
+catheters	O
+were	O
+tested	O
+in	O
+photocell	O
+cages	O
+after	O
+administration	O
+of	O
+93	O
+mg	O
+/	O
+kg	O
+(	O
+LD50	O
+)	O
+of	O
+cocaine	O
+and	O
+GNC92H2	O
+infusions	O
+ranging	O
+from	O
+30	O
+to	O
+190	O
+mg	O
+/	O
+kg	O
+.	O
+
+GNC92H2	O
+was	O
+delivered	O
+30	O
+min	O
+before	O
+,	O
+concomitantly	O
+or	O
+3	O
+min	O
+after	O
+cocaine	O
+treatment	O
+.	O
+
+Significant	O
+blockade	O
+of	O
+cocaine	O
+toxicity	B
+was	O
+observed	O
+with	O
+the	O
+higher	O
+dose	O
+of	O
+GNC92H2	O
+(	O
+190	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+where	O
+premorbid	O
+behaviors	O
+were	O
+reduced	O
+up	O
+to	O
+40	O
+%	O
+,	O
+seizures	B
+up	O
+to	O
+77	O
+%	O
+and	O
+death	B
+by	O
+72	O
+%	O
+.	O
+
+Importantly	O
+,	O
+GNC92H2	O
+prevented	O
+death	B
+even	O
+post	O
+-	O
+cocaine	O
+injection	O
+.	O
+
+The	O
+results	O
+support	O
+the	O
+important	O
+potential	O
+of	O
+GNC92H2	O
+as	O
+a	O
+therapeutic	O
+tool	O
+against	O
+cocaine	B
+overdose	I
+.	O
+
+Electrocardiographic	O
+evidence	O
+of	O
+myocardial	B
+injury	I
+in	O
+psychiatrically	O
+hospitalized	O
+cocaine	O
+abusers	O
+.	O
+
+The	O
+electrocardiograms	O
+(	O
+ECG	O
+)	O
+of	O
+99	O
+cocaine	O
+-	O
+abusing	O
+patients	O
+were	O
+compared	O
+with	O
+the	O
+ECGs	O
+of	O
+50	O
+schizophrenic	B
+controls	O
+.	O
+
+Eleven	O
+of	O
+the	O
+cocaine	O
+abusers	O
+and	O
+none	O
+of	O
+the	O
+controls	O
+had	O
+ECG	O
+evidence	O
+of	O
+significant	O
+myocardial	B
+injury	I
+defined	O
+as	O
+myocardial	B
+infarction	I
+,	O
+ischemia	B
+,	O
+and	O
+bundle	B
+branch	I
+block	I
+.	O
+
+Behavioral	O
+effects	O
+of	O
+urotensin	O
+-	O
+II	O
+centrally	O
+administered	O
+in	O
+mice	O
+.	O
+
+Urotensin	O
+-	O
+II	O
+(	O
+U	O
+-	O
+II	O
+)	O
+receptors	O
+are	O
+widely	O
+distributed	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+.	O
+
+Intracerebroventricular	O
+(	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+injection	O
+of	O
+U	O
+-	O
+II	O
+causes	O
+hypertension	B
+and	O
+bradycardia	B
+and	O
+stimulates	O
+prolactin	O
+and	O
+thyrotropin	O
+secretion	O
+.	O
+
+However	O
+,	O
+the	O
+behavioral	O
+effects	O
+of	O
+centrally	O
+administered	O
+U	O
+-	O
+II	O
+have	O
+received	O
+little	O
+attention	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+we	O
+tested	O
+the	O
+effects	O
+of	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+injections	O
+of	O
+U	O
+-	O
+II	O
+on	O
+behavioral	O
+,	O
+metabolic	O
+,	O
+and	O
+endocrine	O
+responses	O
+in	O
+mice	O
+.	O
+
+Administration	O
+of	O
+graded	O
+doses	O
+of	O
+U	O
+-	O
+II	O
+(	O
+1	O
+-	O
+10	O
+,	O
+000	O
+ng	O
+/	O
+mouse	O
+)	O
+provoked	O
+:	O
+(	O
+1	O
+)	O
+a	O
+dose	O
+-	O
+dependent	O
+reduction	O
+in	O
+the	O
+number	O
+of	O
+head	O
+dips	O
+in	O
+the	O
+hole	O
+-	O
+board	O
+test	O
+;	O
+(	O
+2	O
+)	O
+a	O
+dose	O
+-	O
+dependent	O
+reduction	O
+in	O
+the	O
+number	O
+of	O
+entries	O
+in	O
+the	O
+white	O
+chamber	O
+in	O
+the	O
+black	O
+-	O
+and	O
+-	O
+white	O
+compartment	O
+test	O
+,	O
+and	O
+in	O
+the	O
+number	O
+of	O
+entries	O
+in	O
+the	O
+central	O
+platform	O
+and	O
+open	O
+arms	O
+in	O
+the	O
+plus	O
+-	O
+maze	O
+test	O
+;	O
+and	O
+(	O
+3	O
+)	O
+a	O
+dose	O
+-	O
+dependent	O
+increase	O
+in	O
+the	O
+duration	O
+of	O
+immobility	O
+in	O
+the	O
+forced	O
+-	O
+swimming	O
+test	O
+and	O
+tail	O
+suspension	O
+test	O
+.	O
+
+Intracerebroventricular	O
+injection	O
+of	O
+U	O
+-	O
+II	O
+also	O
+caused	O
+an	O
+increase	O
+in	O
+:	O
+food	O
+intake	O
+at	O
+doses	O
+of	O
+100	O
+and	O
+1	O
+,	O
+000	O
+ng	O
+/	O
+mouse	O
+,	O
+water	O
+intake	O
+at	O
+doses	O
+of	O
+100	O
+-	O
+10	O
+,	O
+000	O
+ng	O
+/	O
+mouse	O
+,	O
+and	O
+horizontal	O
+locomotion	O
+activity	O
+at	O
+a	O
+dose	O
+of	O
+10	O
+,	O
+000	O
+ng	O
+/	O
+mouse	O
+.	O
+
+Whatever	O
+was	O
+the	O
+dose	O
+,	O
+the	O
+central	O
+administration	O
+of	O
+U	O
+-	O
+II	O
+had	O
+no	O
+effect	O
+on	O
+body	O
+temperature	O
+,	O
+nociception	O
+,	O
+apomorphine	O
+-	O
+induced	O
+penile	B
+erection	I
+and	O
+climbing	O
+behavior	O
+,	O
+and	O
+stress	O
+-	O
+induced	O
+plasma	O
+corticosterone	O
+level	O
+.	O
+
+Taken	O
+together	O
+,	O
+the	O
+present	O
+study	O
+demonstrates	O
+that	O
+the	O
+central	O
+injection	O
+of	O
+U	O
+-	O
+II	O
+at	O
+doses	O
+of	O
+1	O
+-	O
+10	O
+,	O
+000	O
+ng	O
+/	O
+mouse	O
+induces	O
+anxiogenic	O
+-	O
+and	O
+depressant	O
+-	O
+like	O
+effects	O
+in	O
+mouse	O
+.	O
+
+These	O
+data	O
+suggest	O
+that	O
+U	O
+-	O
+II	O
+may	O
+be	O
+involved	O
+in	O
+some	O
+aspects	O
+of	O
+psychiatric	B
+disorders	I
+.	O
+
+Learning	O
+of	O
+rats	O
+under	O
+amnesia	B
+caused	O
+by	O
+pentobarbital	O
+.	O
+
+Dissociated	O
+learning	O
+of	O
+rats	O
+in	O
+the	O
+normal	O
+state	O
+and	O
+the	O
+state	O
+of	O
+amnesia	B
+produced	O
+by	O
+pentobarbital	O
+(	O
+15	O
+mg	O
+/	O
+kg	O
+,	O
+ip	O
+)	O
+was	O
+carried	O
+out	O
+.	O
+
+Rats	O
+were	O
+trained	O
+to	O
+approach	O
+a	O
+shelf	O
+where	O
+they	O
+received	O
+food	O
+reinforcement	O
+.	O
+
+In	O
+Group	O
+1	O
+the	O
+rats	O
+were	O
+trained	O
+under	O
+the	O
+influence	O
+of	O
+pentobarbital	O
+to	O
+run	O
+to	O
+the	O
+same	O
+shelf	O
+as	O
+in	O
+the	O
+normal	O
+state	O
+.	O
+
+In	O
+Group	O
+2	O
+the	O
+rats	O
+were	O
+trained	O
+to	O
+approach	O
+different	O
+shelves	O
+in	O
+different	O
+drug	O
+states	O
+.	O
+
+It	O
+was	O
+shown	O
+that	O
+memory	B
+dissociation	I
+occurred	O
+in	O
+both	O
+groups	O
+.	O
+
+Differences	O
+in	O
+the	O
+parameters	O
+of	O
+training	O
+under	O
+the	O
+influence	O
+of	O
+pentobarbital	O
+between	O
+Groups	O
+1	O
+and	O
+2	O
+were	O
+revealed	O
+.	O
+
+These	O
+findings	O
+show	O
+that	O
+the	O
+brain	O
+-	O
+dissociated	O
+state	O
+induced	O
+by	O
+pentobarbital	O
+is	O
+formed	O
+with	O
+the	O
+participation	O
+of	O
+the	O
+mechanisms	O
+of	O
+information	O
+perception	O
+.	O
+
+The	O
+effects	O
+of	O
+short	O
+-	O
+term	O
+raloxifene	O
+therapy	O
+on	O
+fibrinolysis	O
+markers	O
+:	O
+TAFI	O
+,	O
+tPA	O
+,	O
+and	O
+PAI	O
+-	O
+1	O
+.	O
+
+BACKGROUND	O
+:	O
+Markers	O
+of	O
+fibrinolysis	O
+,	O
+thrombin	O
+-	O
+activatable	O
+fibrinolysis	O
+inhibitor	O
+(	O
+TAFI	O
+)	O
+,	O
+tissue	O
+-	O
+type	O
+plasminogen	O
+activator	O
+(	O
+tPA	O
+)	O
+,	O
+and	O
+plasminogen	O
+activator	O
+inhibitor	O
+-	O
+1	O
+(	O
+PAI	O
+-	O
+1	O
+)	O
+levels	O
+were	O
+studied	O
+for	O
+the	O
+evaluation	O
+of	O
+short	O
+-	O
+term	O
+effects	O
+of	O
+raloxifene	O
+administration	O
+in	O
+postmenopausal	O
+women	O
+.	O
+
+METHODS	O
+:	O
+Thirty	O
+-	O
+nine	O
+postmenopausal	O
+women	O
+with	O
+osteopenia	B
+or	O
+osteoporosis	B
+were	O
+included	O
+in	O
+this	O
+prospective	O
+,	O
+controlled	O
+clinical	O
+study	O
+.	O
+
+Twenty	O
+-	O
+five	O
+women	O
+were	O
+given	O
+raloxifene	O
+hydrochloride	O
+(	O
+60	O
+mg	O
+/	O
+day	O
+)	O
+plus	O
+calcium	O
+(	O
+500	O
+mg	O
+/	O
+day	O
+)	O
+.	O
+
+Age	O
+-	O
+matched	O
+controls	O
+(	O
+n	O
+=	O
+14	O
+)	O
+were	O
+given	O
+only	O
+calcium	O
+.	O
+
+Plasma	O
+TAFI	O
+,	O
+tPA	O
+,	O
+and	O
+PAI	O
+-	O
+1	O
+antigen	O
+levels	O
+were	O
+measured	O
+at	O
+baseline	O
+and	O
+after	O
+3	O
+months	O
+of	O
+treatment	O
+by	O
+commercially	O
+available	O
+ELISA	O
+kits	O
+.	O
+
+Variations	O
+of	O
+individuals	O
+were	O
+assessed	O
+by	O
+Wilcoxon	O
+'	O
+s	O
+test	O
+.	O
+
+Relationship	O
+between	O
+those	O
+markers	O
+and	O
+demographic	O
+characteristics	O
+were	O
+investigated	O
+.	O
+
+RESULTS	O
+:	O
+Three	O
+months	O
+of	O
+raloxifene	O
+treatment	O
+was	O
+associated	O
+with	O
+a	O
+significant	O
+decrease	O
+in	O
+the	O
+plasma	O
+TAFI	O
+antigen	O
+concentrations	O
+(	O
+16	O
+%	O
+change	O
+,	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+,	O
+and	O
+a	O
+significant	O
+increase	O
+in	O
+tPA	O
+antigen	O
+concentrations	O
+(	O
+25	O
+%	O
+change	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+A	O
+significant	O
+correlation	O
+was	O
+found	O
+between	O
+baseline	O
+TAFI	O
+antigen	O
+concentrations	O
+and	O
+the	O
+duration	O
+of	O
+amenorrhea	B
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+;	O
+r	O
+=	O
+0	O
+.	O
+33	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+We	O
+suggest	O
+that	O
+the	O
+increased	O
+risk	O
+of	O
+venous	B
+thromboembolism	I
+due	O
+to	O
+raloxifene	O
+treatment	O
+may	O
+be	O
+related	O
+to	O
+increased	O
+tPA	O
+levels	O
+,	O
+but	O
+not	O
+TAFI	O
+levels	O
+.	O
+
+Valproate	O
+-	O
+induced	O
+encephalopathy	B
+.	O
+
+Valproate	O
+-	O
+induced	O
+encephalopathy	B
+is	O
+a	O
+rare	O
+syndrome	O
+that	O
+may	O
+manifest	O
+in	O
+otherwise	O
+normal	O
+epileptic	B
+individuals	O
+.	O
+
+It	O
+may	O
+even	O
+present	O
+in	O
+patients	O
+who	O
+have	O
+tolerated	O
+this	O
+medicine	O
+well	O
+in	O
+the	O
+past	O
+.	O
+
+It	O
+is	O
+usually	O
+but	O
+not	O
+necessarily	O
+associated	O
+with	O
+hyperammonemia	B
+.	O
+
+The	O
+EEG	O
+shows	O
+characteristic	O
+triphasic	O
+waves	O
+in	O
+most	O
+patients	O
+with	O
+this	O
+complication	O
+.	O
+
+A	O
+case	O
+of	O
+valproate	O
+-	O
+induced	O
+encephalopathy	B
+is	O
+presented	O
+.	O
+
+The	O
+problems	O
+in	O
+diagnosing	O
+this	O
+condition	O
+are	O
+subsequently	O
+discussed	O
+.	O
+
+Recurrent	O
+dysphonia	B
+and	O
+acitretin	O
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+woman	O
+complaining	O
+of	O
+dysphonia	B
+while	O
+she	O
+was	O
+treated	O
+by	O
+acitretin	O
+.	O
+
+Her	O
+symptoms	O
+totally	O
+regressed	O
+after	O
+drug	O
+withdrawal	O
+and	O
+reappeared	O
+when	O
+acitretin	O
+was	O
+reintroduced	O
+.	O
+
+To	O
+our	O
+knowledge	O
+,	O
+this	O
+is	O
+the	O
+first	O
+case	O
+of	O
+acitretin	O
+-	O
+induced	O
+dysphonia	B
+.	O
+
+This	O
+effect	O
+may	O
+be	O
+related	O
+to	O
+the	O
+pharmacological	O
+effect	O
+of	O
+this	O
+drug	O
+on	O
+mucous	O
+membranes	O
+.	O
+
+Nitro	O
+-	O
+L	O
+-	O
+arginine	O
+methyl	O
+ester	O
+:	O
+a	O
+potential	O
+protector	O
+against	O
+gentamicin	O
+ototoxicity	B
+.	O
+
+The	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+inhibitor	O
+nitro	O
+-	O
+L	O
+-	O
+arginine	O
+methyl	O
+ester	O
+(	O
+L	O
+-	O
+NAME	O
+)	O
+may	O
+act	O
+as	O
+an	O
+otoprotectant	O
+against	O
+high	B
+-	I
+frequency	I
+hearing	I
+loss	I
+caused	O
+by	O
+gentamicin	O
+,	O
+but	O
+further	O
+studies	O
+are	O
+needed	O
+to	O
+confirm	O
+this	O
+.	O
+Aminoglycoside	O
+antibiotics	O
+are	O
+still	O
+widely	O
+used	O
+by	O
+virtue	O
+of	O
+their	O
+efficacy	O
+and	O
+low	O
+cost	O
+.	O
+
+Their	O
+ototoxicity	B
+is	O
+a	O
+serious	O
+health	O
+problem	O
+and	O
+,	O
+as	O
+their	O
+ototoxic	B
+mechanism	O
+involves	O
+the	O
+production	O
+of	O
+NO	O
+,	O
+we	O
+need	O
+to	O
+assess	O
+the	O
+use	O
+of	O
+NO	O
+inhibitors	O
+for	O
+the	O
+prevention	O
+of	O
+aminoglycoside	O
+-	O
+induced	O
+sensorineural	B
+hearing	I
+loss	I
+.	O
+
+In	O
+this	O
+experimental	O
+study	O
+we	O
+used	O
+30	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+,	O
+27	O
+of	O
+which	O
+had	O
+gentamicin	O
+instilled	O
+into	O
+the	O
+middle	O
+ear	O
+.	O
+
+The	O
+otoprotectant	O
+L	O
+-	O
+NAME	O
+was	O
+administered	O
+topically	O
+to	O
+12	O
+/	O
+27	O
+animals	O
+.	O
+
+Its	O
+effect	O
+was	O
+determined	O
+in	O
+terms	O
+of	O
+attenuation	O
+of	O
+hearing	B
+loss	I
+,	O
+measured	O
+by	O
+shifts	O
+in	O
+the	O
+auditory	O
+brainstem	O
+response	O
+threshold	O
+.	O
+
+L	O
+-	O
+NAME	O
+reduced	O
+gentamicin	O
+-	O
+induced	O
+hearing	B
+loss	I
+in	O
+the	O
+high	O
+-	O
+frequency	O
+range	O
+,	O
+but	O
+gave	O
+no	O
+protection	O
+in	O
+the	O
+middle	O
+or	O
+low	O
+frequencies	O
+.	O
+
+Safety	O
+profile	O
+of	O
+a	O
+nicotine	O
+lozenge	O
+compared	O
+with	O
+that	O
+of	O
+nicotine	O
+gum	O
+in	O
+adult	O
+smokers	O
+with	O
+underlying	O
+medical	O
+conditions	O
+:	O
+a	O
+12	O
+-	O
+week	O
+,	O
+randomized	O
+,	O
+open	O
+-	O
+label	O
+study	O
+.	O
+
+BACKGROUND	O
+:	O
+Nicotine	O
+polacrilex	O
+lozenges	O
+deliver	O
+25	O
+%	O
+to	O
+27	O
+%	O
+more	O
+nicotine	O
+compared	O
+with	O
+equivalent	O
+doses	O
+of	O
+nicotine	O
+polacrilex	O
+gum	O
+.	O
+
+The	O
+increased	O
+nicotine	O
+exposure	O
+from	O
+the	O
+lozenge	O
+has	O
+raised	O
+questions	O
+about	O
+the	O
+relative	O
+safety	O
+of	O
+the	O
+lozenge	O
+and	O
+gum	O
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+compare	O
+the	O
+safety	O
+profiles	O
+of	O
+the	O
+4	O
+-	O
+mg	O
+nicotine	O
+lozenge	O
+and	O
+4	O
+-	O
+mg	O
+nicotine	O
+gum	O
+in	O
+smokers	O
+with	O
+selected	O
+label	O
+-	O
+restricted	O
+diseases	O
+.	O
+
+METHODS	O
+:	O
+This	O
+was	O
+a	O
+multicenter	O
+,	O
+randomized	O
+,	O
+open	O
+-	O
+label	O
+study	O
+in	O
+adult	O
+smokers	O
+with	O
+heart	B
+disease	I
+,	O
+hypertension	B
+not	O
+controlled	O
+by	O
+medication	O
+,	O
+and	O
+/	O
+or	O
+diabetes	B
+mellitus	I
+.	O
+
+Patients	O
+were	O
+randomized	O
+in	O
+a	O
+1	O
+:	O
+1	O
+ratio	O
+to	O
+receive	O
+the	O
+4	O
+-	O
+mg	O
+nicotine	O
+lozenge	O
+or	O
+4	O
+-	O
+mg	O
+nicotine	O
+gum	O
+.	O
+
+Safety	O
+assessments	O
+were	O
+made	O
+at	O
+baseline	O
+and	O
+at	O
+2	O
+,	O
+4	O
+,	O
+6	O
+,	O
+and	O
+12	O
+weeks	O
+after	O
+the	O
+start	O
+of	O
+product	O
+use	O
+.	O
+
+RESULTS	O
+:	O
+Nine	O
+hundred	O
+one	O
+patients	O
+were	O
+randomized	O
+to	O
+treatment	O
+,	O
+447	O
+who	O
+received	O
+the	O
+lozenge	O
+and	O
+454	O
+who	O
+received	O
+the	O
+gum	O
+(	O
+safety	O
+population	O
+)	O
+.	O
+
+The	O
+majority	O
+were	O
+women	O
+(	O
+52	O
+.	O
+7	O
+%	O
+)	O
+.	O
+
+Patients	O
+'	O
+mean	O
+age	O
+was	O
+53	O
+.	O
+9	O
+years	O
+,	O
+their	O
+mean	O
+weight	O
+was	O
+193	O
+.	O
+9	O
+pounds	O
+,	O
+and	O
+they	O
+smoked	O
+a	O
+mean	O
+of	O
+25	O
+.	O
+2	O
+cigarettes	O
+per	O
+day	O
+at	O
+baseline	O
+.	O
+
+Five	O
+hundred	O
+fifty	O
+-	O
+three	O
+patients	O
+,	O
+264	O
+taking	O
+the	O
+lozenge	O
+and	O
+289	O
+taking	O
+the	O
+gum	O
+,	O
+used	O
+the	O
+study	O
+product	O
+for	O
+>	O
+or	O
+=	O
+4	O
+days	O
+per	O
+week	O
+during	O
+the	O
+first	O
+2	O
+weeks	O
+(	O
+evaluable	O
+population	O
+)	O
+.	O
+
+The	O
+nicotine	O
+lozenge	O
+and	O
+nicotine	O
+gum	O
+were	O
+equally	O
+well	O
+tolerated	O
+,	O
+despite	O
+increased	O
+nicotine	O
+exposure	O
+from	O
+the	O
+lozenge	O
+.	O
+
+The	O
+incidence	O
+of	O
+adverse	O
+events	O
+in	O
+the	O
+2	O
+groups	O
+was	O
+similar	O
+during	O
+the	O
+first	O
+2	O
+weeks	O
+of	O
+product	O
+use	O
+(	O
+evaluation	O
+population	O
+:	O
+55	O
+.	O
+3	O
+%	O
+lozenge	O
+,	O
+54	O
+.	O
+7	O
+%	O
+gum	O
+)	O
+,	O
+as	O
+well	O
+as	O
+during	O
+the	O
+entire	O
+study	O
+(	O
+safety	O
+population	O
+:	O
+63	O
+.	O
+8	O
+%	O
+and	O
+58	O
+.	O
+6	O
+%	O
+,	O
+respectively	O
+)	O
+.	O
+
+Stratification	O
+of	O
+patients	O
+by	O
+sex	O
+,	O
+age	O
+,	O
+extent	O
+of	O
+concurrent	O
+smoking	O
+,	O
+extent	O
+of	O
+product	O
+use	O
+,	O
+and	O
+severity	O
+of	O
+adverse	O
+events	O
+revealed	O
+no	O
+clinically	O
+significant	O
+differences	O
+between	O
+the	O
+lozenge	O
+and	O
+gum	O
+.	O
+
+The	O
+most	O
+common	O
+adverse	O
+events	O
+were	O
+nausea	B
+(	O
+17	O
+.	O
+2	O
+%	O
+and	O
+16	O
+.	O
+1	O
+%	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+-	O
+3	O
+.	O
+7	O
+to	O
+6	O
+.	O
+0	O
+)	O
+,	O
+hiccups	B
+(	O
+10	O
+.	O
+7	O
+%	O
+and	O
+6	O
+.	O
+6	O
+%	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+0	O
+.	O
+5	O
+to	O
+7	O
+.	O
+8	O
+)	O
+,	O
+and	O
+headache	B
+(	O
+8	O
+.	O
+7	O
+%	O
+and	O
+9	O
+.	O
+9	O
+%	O
+;	O
+95	O
+%	O
+Cl	O
+,	O
+-	O
+5	O
+.	O
+0	O
+to	O
+2	O
+.	O
+6	O
+)	O
+.	O
+
+Serious	O
+adverse	O
+events	O
+were	O
+reported	O
+in	O
+11	O
+and	O
+13	O
+patients	O
+in	O
+the	O
+respective	O
+groups	O
+.	O
+
+Fewer	O
+than	O
+6	O
+%	O
+of	O
+patients	O
+in	O
+either	O
+group	O
+were	O
+considered	O
+by	O
+the	O
+investigator	O
+to	O
+have	O
+a	O
+worsening	O
+of	O
+their	O
+overall	O
+disease	O
+condition	O
+during	O
+the	O
+study	O
+.	O
+
+The	O
+majority	O
+of	O
+patients	O
+(	O
+>	O
+60	O
+%	O
+)	O
+experienced	O
+no	O
+change	O
+in	O
+their	O
+disease	O
+status	O
+from	O
+baseline	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+4	O
+-	O
+mg	O
+nicotine	O
+lozenge	O
+and	O
+4	O
+-	O
+mg	O
+nicotine	O
+gum	O
+had	O
+comparable	O
+safety	O
+profiles	O
+in	O
+these	O
+patients	O
+with	O
+label	O
+-	O
+restricted	O
+medical	O
+conditions	O
+.	O
+
+Pharmacological	O
+modulation	O
+of	O
+pain	B
+-	O
+related	O
+brain	O
+activity	O
+during	O
+normal	O
+and	O
+central	O
+sensitization	O
+states	O
+in	O
+humans	O
+.	O
+
+Abnormal	O
+processing	O
+of	O
+somatosensory	O
+inputs	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+(	O
+central	O
+sensitization	O
+)	O
+is	O
+the	O
+mechanism	O
+accounting	O
+for	O
+the	O
+enhanced	O
+pain	B
+sensitivity	O
+in	O
+the	O
+skin	O
+surrounding	O
+tissue	B
+injury	I
+(	O
+secondary	B
+hyperalgesia	I
+)	O
+.	O
+
+Secondary	B
+hyperalgesia	I
+shares	O
+clinical	O
+characteristics	O
+with	O
+neurogenic	B
+hyperalgesia	I
+in	O
+patients	O
+with	O
+neuropathic	B
+pain	I
+.	O
+
+Abnormal	O
+brain	O
+responses	O
+to	O
+somatosensory	O
+stimuli	O
+have	O
+been	O
+found	O
+in	O
+patients	O
+with	O
+hyperalgesia	B
+as	O
+well	O
+as	O
+in	O
+normal	O
+subjects	O
+during	O
+experimental	O
+central	O
+sensitization	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+assess	O
+the	O
+effects	O
+of	O
+gabapentin	O
+,	O
+a	O
+drug	O
+effective	O
+in	O
+neuropathic	B
+pain	I
+patients	O
+,	O
+on	O
+brain	O
+processing	O
+of	O
+nociceptive	O
+information	O
+in	O
+normal	O
+and	O
+central	O
+sensitization	O
+states	O
+.	O
+
+Using	O
+functional	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+fMRI	O
+)	O
+in	O
+normal	O
+volunteers	O
+,	O
+we	O
+studied	O
+the	O
+gabapentin	O
+-	O
+induced	O
+modulation	O
+of	O
+brain	O
+activity	O
+in	O
+response	O
+to	O
+nociceptive	O
+mechanical	O
+stimulation	O
+of	O
+normal	O
+skin	O
+and	O
+capsaicin	O
+-	O
+induced	O
+secondary	B
+hyperalgesia	I
+.	O
+
+The	O
+dose	O
+of	O
+gabapentin	O
+was	O
+1	O
+,	O
+800	O
+mg	O
+per	O
+os	O
+,	O
+in	O
+a	O
+single	O
+administration	O
+.	O
+
+We	O
+found	O
+that	O
+(	O
+i	O
+)	O
+gabapentin	O
+reduced	O
+the	O
+activations	O
+in	O
+the	O
+bilateral	O
+operculoinsular	O
+cortex	O
+,	O
+independently	O
+of	O
+the	O
+presence	O
+of	O
+central	O
+sensitization	O
+;	O
+(	O
+ii	O
+)	O
+gabapentin	O
+reduced	O
+the	O
+activation	O
+in	O
+the	O
+brainstem	O
+,	O
+only	O
+during	O
+central	O
+sensitization	O
+;	O
+(	O
+iii	O
+)	O
+gabapentin	O
+suppressed	O
+stimulus	O
+-	O
+induced	O
+deactivations	O
+,	O
+only	O
+during	O
+central	O
+sensitization	O
+;	O
+this	O
+effect	O
+was	O
+more	O
+robust	O
+than	O
+the	O
+effect	O
+on	O
+brain	O
+activation	O
+.	O
+
+The	O
+observed	O
+drug	O
+-	O
+induced	O
+effects	O
+were	O
+not	O
+due	O
+to	O
+changes	O
+in	O
+the	O
+baseline	O
+fMRI	O
+signal	O
+.	O
+
+These	O
+findings	O
+indicate	O
+that	O
+gabapentin	O
+has	O
+a	O
+measurable	O
+antinociceptive	O
+effect	O
+and	O
+a	O
+stronger	O
+antihyperalgesic	O
+effect	O
+most	O
+evident	O
+in	O
+the	O
+brain	O
+areas	O
+undergoing	O
+deactivation	O
+,	O
+thus	O
+supporting	O
+the	O
+concept	O
+that	O
+gabapentin	O
+is	O
+more	O
+effective	O
+in	O
+modulating	O
+nociceptive	O
+transmission	O
+when	O
+central	O
+sensitization	O
+is	O
+present	O
+.	O
+
+Investigation	O
+of	O
+mitochondrial	O
+involvement	O
+in	O
+the	O
+experimental	O
+model	O
+of	O
+epilepsy	B
+induced	O
+by	O
+pilocarpine	O
+.	O
+
+Mitochondrial	B
+abnormalities	I
+have	O
+been	O
+associated	O
+with	O
+several	O
+aspects	O
+of	O
+epileptogenesis	O
+,	O
+such	O
+as	O
+energy	O
+generation	O
+,	O
+control	O
+of	O
+cell	O
+death	B
+,	O
+neurotransmitter	O
+synthesis	O
+,	O
+and	O
+free	O
+radical	O
+(	O
+FR	O
+)	O
+production	O
+.	O
+
+Increased	O
+production	O
+of	O
+FRs	O
+may	O
+cause	O
+mtDNA	O
+damage	O
+leading	O
+to	O
+decreased	O
+activities	O
+of	O
+oxidative	O
+phosphorylation	O
+complexes	O
+containing	O
+mtDNA	O
+-	O
+encoded	O
+subunits	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+investigated	O
+whether	O
+increased	O
+generation	O
+of	O
+FR	O
+during	O
+status	B
+epilepticus	I
+would	O
+be	O
+sufficient	O
+to	O
+provoke	O
+abnormalities	O
+in	O
+mtDNA	O
+and	O
+in	O
+the	O
+expression	O
+and	O
+activity	O
+of	O
+cytochrome	O
+c	O
+oxidase	O
+(	O
+CCO	O
+)	O
+,	O
+complex	O
+IV	O
+of	O
+the	O
+respiratory	O
+chain	O
+,	O
+in	O
+the	O
+chronic	O
+phase	O
+of	O
+the	O
+pilocarpine	O
+model	O
+of	O
+temporal	B
+lobe	I
+epilepsy	I
+.	O
+
+DNA	O
+analysis	O
+revealed	O
+low	O
+amounts	O
+of	O
+a	O
+4	O
+.	O
+8	O
+kb	O
+mtDNA	O
+deletion	O
+but	O
+with	O
+no	O
+differences	O
+in	O
+frequency	O
+or	O
+quantity	O
+in	O
+the	O
+control	O
+and	O
+experimental	O
+groups	O
+.	O
+
+We	O
+did	O
+not	O
+find	O
+abnormalities	O
+in	O
+the	O
+expression	O
+and	O
+distribution	O
+of	O
+an	O
+mtDNA	O
+-	O
+encoded	O
+subunit	O
+of	O
+CCO	O
+(	O
+CCO	O
+-	O
+I	O
+)	O
+or	O
+a	O
+relative	O
+decrease	O
+in	O
+CCO	O
+-	O
+I	O
+when	O
+compared	O
+with	O
+nuclear	O
+-	O
+encoded	O
+subunits	O
+(	O
+CCO	O
+-	O
+IV	O
+and	O
+SDH	O
+-	O
+fp	O
+)	O
+.	O
+
+No	O
+abnormality	O
+in	O
+CCO	O
+activity	O
+was	O
+observed	O
+through	O
+histochemistry	O
+.	O
+
+Although	O
+evidences	O
+of	O
+mitochondrial	B
+abnormalities	I
+were	O
+found	O
+in	O
+previously	O
+published	O
+studies	O
+,	O
+our	O
+results	O
+do	O
+not	O
+suggest	O
+that	O
+the	O
+FRs	O
+,	O
+generated	O
+during	O
+the	O
+acute	O
+phase	O
+,	O
+determined	O
+important	O
+abnormalities	O
+in	O
+mtDNA	O
+,	O
+in	O
+expression	O
+of	O
+CCO	O
+-	O
+I	O
+,	O
+and	O
+in	O
+CCO	O
+activity	O
+.	O
+
+Adverse	O
+effect	O
+of	O
+the	O
+calcium	O
+channel	O
+blocker	O
+nitrendipine	O
+on	O
+nephrosclerosis	B
+in	O
+rats	O
+with	O
+renovascular	B
+hypertension	I
+.	O
+
+The	O
+effect	O
+of	O
+a	O
+6	O
+-	O
+week	O
+treatment	O
+with	O
+the	O
+calcium	O
+channel	O
+blocker	O
+nitrendipine	O
+or	O
+the	O
+angiotensin	O
+converting	O
+enzyme	O
+inhibitor	O
+enalapril	O
+on	O
+blood	O
+pressure	O
+,	O
+albuminuria	B
+,	O
+renal	O
+hemodynamics	O
+,	O
+and	O
+morphology	O
+of	O
+the	O
+nonclipped	O
+kidney	O
+was	O
+studied	O
+in	O
+rats	O
+with	O
+two	O
+-	O
+kidney	O
+,	O
+one	O
+clip	O
+renovascular	B
+hypertension	I
+.	O
+
+Six	O
+weeks	O
+after	O
+clipping	O
+of	O
+one	O
+renal	O
+artery	O
+,	O
+hypertensive	B
+rats	O
+(	O
+178	O
++	O
+/	O
+-	O
+4	O
+mm	O
+Hg	O
+)	O
+were	O
+randomly	O
+assigned	O
+to	O
+three	O
+groups	O
+:	O
+untreated	O
+hypertensive	B
+controls	O
+(	O
+n	O
+=	O
+8	O
+)	O
+,	O
+enalapril	O
+-	O
+treated	O
+(	O
+n	O
+=	O
+8	O
+)	O
+,	O
+or	O
+nitrendipine	O
+-	O
+treated	O
+(	O
+n	O
+=	O
+10	O
+)	O
+.	O
+
+Sham	O
+-	O
+operated	O
+rats	O
+served	O
+as	O
+normotensive	O
+controls	O
+(	O
+128	O
++	O
+/	O
+-	O
+3	O
+mm	O
+Hg	O
+,	O
+n	O
+=	O
+8	O
+)	O
+.	O
+
+After	O
+6	O
+weeks	O
+of	O
+treatment	O
+,	O
+renal	O
+hemodynamics	O
+(	O
+glomerular	O
+filtration	O
+rate	O
+and	O
+renal	O
+plasma	O
+flow	O
+)	O
+were	O
+measured	O
+in	O
+the	O
+anesthetized	O
+rats	O
+.	O
+
+Renal	O
+tissue	O
+was	O
+obtained	O
+for	O
+determination	O
+of	O
+glomerular	O
+size	O
+and	O
+sclerosis	O
+.	O
+
+Enalapril	O
+but	O
+not	O
+nitrendipine	O
+reduced	O
+blood	O
+pressure	O
+significantly	O
+.	O
+
+After	O
+6	O
+weeks	O
+of	O
+therapy	O
+,	O
+glomerular	O
+filtration	O
+rate	O
+was	O
+not	O
+different	O
+among	O
+the	O
+studied	O
+groups	O
+.	O
+
+Renal	O
+plasma	O
+flow	O
+increased	O
+,	O
+but	O
+albumin	O
+excretion	O
+and	O
+glomerulosclerosis	B
+did	O
+not	O
+change	O
+after	O
+enalapril	O
+treatment	O
+.	O
+
+In	O
+contrast	O
+,	O
+in	O
+the	O
+nitrendipine	O
+-	O
+treated	O
+group	O
+albuminuria	B
+increased	O
+from	O
+12	O
+.	O
+8	O
++	O
+/	O
+-	O
+2	O
+progressively	O
+to	O
+163	O
++	O
+/	O
+-	O
+55	O
+compared	O
+with	O
+19	O
+.	O
+2	O
++	O
+/	O
+-	O
+9	O
+mg	O
+/	O
+24	O
+hr	O
+in	O
+the	O
+hypertensive	B
+controls	O
+.	O
+
+Furthermore	O
+,	O
+glomerulosclerosis	B
+index	O
+was	O
+significantly	O
+increased	O
+in	O
+the	O
+nitrendipine	O
+-	O
+treated	O
+group	O
+compared	O
+with	O
+the	O
+hypertensive	B
+controls	O
+(	O
+0	O
+.	O
+38	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+versus	O
+0	O
+.	O
+13	O
++	O
+/	O
+-	O
+0	O
+.	O
+04	O
+)	O
+.	O
+
+In	O
+addition	O
+,	O
+glomerular	O
+size	O
+was	O
+higher	O
+in	O
+the	O
+nitrendipine	O
+-	O
+treated	O
+group	O
+(	O
+14	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+17	O
+10	O
+(	O
+-	O
+3	O
+)	O
+mm2	O
+)	O
+but	O
+lower	O
+in	O
+the	O
+enalapril	O
+-	O
+treated	O
+group	O
+(	O
+11	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+15	O
+10	O
+(	O
+-	O
+3	O
+)	O
+mm2	O
+)	O
+compared	O
+with	O
+the	O
+hypertensive	B
+controls	O
+(	O
+12	O
+.	O
+1	O
++	O
+/	O
+-	O
+0	O
+.	O
+17	O
+10	O
+(	O
+-	O
+3	O
+)	O
+mm2	O
+)	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Ketoconazole	O
+induced	O
+torsades	B
+de	I
+pointes	I
+without	O
+concomitant	O
+use	O
+of	O
+QT	O
+interval	O
+-	O
+prolonging	O
+drug	O
+.	O
+
+Ketoconazole	O
+is	O
+not	O
+known	O
+to	O
+be	O
+proarrhythmic	O
+without	O
+concomitant	O
+use	O
+of	O
+QT	O
+interval	O
+-	O
+prolonging	O
+drugs	O
+.	O
+
+We	O
+report	O
+a	O
+woman	O
+with	O
+coronary	B
+artery	I
+disease	I
+who	O
+developed	O
+a	O
+markedly	O
+prolonged	B
+QT	I
+interval	I
+and	O
+torsades	B
+de	I
+pointes	I
+(	O
+TdP	B
+)	O
+after	O
+taking	O
+ketoconazole	O
+for	O
+treatment	O
+of	O
+fungal	B
+infection	I
+.	O
+
+Her	O
+QT	O
+interval	O
+returned	O
+to	O
+normal	O
+upon	O
+withdrawal	O
+of	O
+ketoconazole	O
+.	O
+
+Genetic	O
+study	O
+did	O
+not	O
+find	O
+any	O
+mutation	O
+in	O
+her	O
+genes	O
+that	O
+encode	O
+cardiac	O
+IKr	O
+channel	O
+proteins	O
+.	O
+
+We	O
+postulate	O
+that	O
+by	O
+virtue	O
+of	O
+its	O
+direct	O
+blocking	O
+action	O
+on	O
+IKr	O
+,	O
+ketoconazole	O
+alone	O
+may	O
+prolong	O
+QT	O
+interval	O
+and	O
+induce	O
+TdP	B
+.	O
+
+This	O
+calls	O
+for	O
+attention	O
+when	O
+ketoconazole	O
+is	O
+administered	O
+to	O
+patients	O
+with	O
+risk	O
+factors	O
+for	O
+acquired	O
+long	B
+QT	I
+syndrome	I
+.	O
+
+Cerebral	B
+vasculitis	I
+following	O
+oral	O
+methylphenidate	O
+intake	O
+in	O
+an	O
+adult	O
+:	O
+a	O
+case	O
+report	O
+.	O
+
+Methylphenidate	O
+is	O
+structurally	O
+and	O
+functionally	O
+similar	O
+to	O
+amphetamine	O
+.	O
+
+Cerebral	B
+vasculitis	I
+associated	O
+with	O
+amphetamine	B
+abuse	I
+is	O
+well	O
+documented	O
+,	O
+and	O
+in	O
+rare	O
+cases	O
+ischaemic	B
+stroke	I
+has	O
+been	O
+reported	O
+after	O
+methylphenidate	O
+intake	O
+in	O
+children	O
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+63	O
+-	O
+year	O
+-	O
+old	O
+female	O
+who	O
+was	O
+treated	O
+with	O
+methylphenidate	O
+due	O
+to	O
+hyperactivity	B
+and	O
+suffered	O
+from	O
+multiple	O
+ischaemic	B
+strokes	I
+.	O
+
+We	O
+consider	O
+drug	O
+-	O
+induced	O
+cerebral	B
+vasculitis	I
+as	O
+the	O
+most	O
+likely	O
+cause	O
+of	O
+recurrent	O
+ischaemic	B
+strokes	I
+in	O
+the	O
+absence	O
+of	O
+any	O
+pathological	O
+findings	O
+during	O
+the	O
+diagnostic	O
+work	O
+-	O
+up	O
+.	O
+
+We	O
+conclude	O
+that	O
+methylphenidate	O
+mediated	O
+vasculitis	B
+should	O
+be	O
+considered	O
+in	O
+patients	O
+with	O
+neurological	O
+symptoms	O
+and	O
+a	O
+history	O
+of	O
+methylphenidate	O
+therapy	O
+.	O
+
+This	O
+potential	O
+side	O
+-	O
+effect	O
+,	O
+though	O
+very	O
+rare	O
+,	O
+represents	O
+one	O
+more	O
+reason	O
+to	O
+be	O
+very	O
+restrictive	O
+in	O
+the	O
+use	O
+of	O
+methylphenidate	O
+.	O
+
+MDMA	O
+polydrug	O
+users	O
+show	O
+process	O
+-	O
+specific	O
+central	O
+executive	O
+impairments	O
+coupled	O
+with	O
+impaired	B
+social	I
+and	I
+emotional	I
+judgement	I
+processes	I
+.	O
+
+In	O
+recent	O
+years	O
+working	O
+memory	B
+deficits	I
+have	O
+been	O
+reported	O
+in	O
+users	O
+of	O
+MDMA	O
+(	O
+3	O
+,	O
+4	O
+-	O
+methylenedioxymethamphetamine	O
+,	O
+ecstasy	O
+)	O
+.	O
+
+The	O
+current	O
+study	O
+aimed	O
+to	O
+assess	O
+the	O
+impact	O
+of	O
+MDMA	O
+use	O
+on	O
+three	O
+separate	O
+central	O
+executive	O
+processes	O
+(	O
+set	O
+shifting	O
+,	O
+inhibition	O
+and	O
+memory	O
+updating	O
+)	O
+and	O
+also	O
+on	O
+"	O
+prefrontal	O
+"	O
+mediated	O
+social	O
+and	O
+emotional	O
+judgement	O
+processes	O
+.	O
+
+Fifteen	O
+polydrug	O
+ecstasy	O
+users	O
+and	O
+15	O
+polydrug	O
+non	O
+-	O
+ecstasy	O
+user	O
+controls	O
+completed	O
+a	O
+general	O
+drug	O
+use	O
+questionnaire	O
+,	O
+the	O
+Brixton	O
+Spatial	O
+Anticipation	O
+task	O
+(	O
+set	O
+shifting	O
+)	O
+,	O
+Backward	O
+Digit	O
+Span	O
+procedure	O
+(	O
+memory	O
+updating	O
+)	O
+,	O
+Inhibition	O
+of	O
+Return	O
+(	O
+inhibition	O
+)	O
+,	O
+an	O
+emotional	O
+intelligence	O
+scale	O
+,	O
+the	O
+Tromso	O
+Social	O
+Intelligence	O
+Scale	O
+and	O
+the	O
+Dysexecutive	O
+Questionnaire	O
+(	O
+DEX	O
+)	O
+.	O
+
+Compared	O
+with	O
+MDMA	O
+-	O
+free	O
+polydrug	O
+controls	O
+,	O
+MDMA	O
+polydrug	O
+users	O
+showed	O
+impairments	O
+in	O
+set	O
+shifting	O
+and	O
+memory	O
+updating	O
+,	O
+and	O
+also	O
+in	O
+social	O
+and	O
+emotional	O
+judgement	O
+processes	O
+.	O
+
+The	O
+latter	O
+two	O
+deficits	O
+remained	O
+significant	O
+after	O
+controlling	O
+for	O
+other	O
+drug	O
+use	O
+.	O
+
+These	O
+data	O
+lend	O
+further	O
+support	O
+to	O
+the	O
+proposal	O
+that	O
+cognitive	O
+processes	O
+mediated	O
+by	O
+the	O
+prefrontal	O
+cortex	O
+may	O
+be	O
+impaired	O
+by	O
+recreational	O
+ecstasy	O
+use	O
+.	O
+
+Phase	O
+II	O
+study	O
+of	O
+the	O
+amsacrine	O
+analogue	O
+CI	O
+-	O
+921	O
+(	O
+NSC	O
+343499	O
+)	O
+in	O
+non	B
+-	I
+small	I
+cell	I
+lung	I
+cancer	I
+.	O
+
+CI	O
+-	O
+921	O
+(	O
+NSC	O
+343499	O
+;	O
+9	O
+-	O
+[	O
+[	O
+2	O
+-	O
+methoxy	O
+-	O
+4	O
+-	O
+[	O
+(	O
+methylsulphonyl	O
+)	O
+amino	O
+]	O
+phenyl	O
+]	O
+amino	O
+]	O
+-	O
+N	O
+,	O
+5	O
+-	O
+dimethyl	O
+-	O
+4	O
+-	O
+acridinecarboxamide	O
+)	O
+is	O
+a	O
+topoisomerase	O
+II	O
+poison	O
+with	O
+high	O
+experimental	O
+antitumour	O
+activity	O
+.	O
+
+It	O
+was	O
+administered	O
+by	O
+15	O
+min	O
+infusion	O
+to	O
+16	O
+evaluable	O
+patients	O
+with	O
+non	B
+-	I
+small	I
+cell	I
+lung	I
+cancer	I
+(	O
+NSCLC	B
+)	O
+(	O
+7	O
+with	O
+no	O
+prior	O
+treatment	O
+,	O
+9	O
+patients	O
+in	O
+relapse	O
+following	O
+surgery	O
+/	O
+radiotherapy	O
+)	O
+at	O
+a	O
+dose	O
+(	O
+648	O
+mg	O
+/	O
+m2	O
+divided	O
+over	O
+3	O
+days	O
+,	O
+repeated	O
+every	O
+3	O
+weeks	O
+)	O
+determined	O
+by	O
+phase	O
+I	O
+trial	O
+.	O
+
+Patients	O
+had	O
+a	O
+median	O
+performance	O
+status	O
+of	O
+1	O
+(	O
+WHO	O
+)	O
+,	O
+and	O
+median	O
+age	O
+of	O
+61	O
+years	O
+.	O
+
+The	O
+histology	O
+comprised	O
+squamous	B
+carcinoma	I
+(	O
+11	O
+)	O
+,	O
+adenocarcinoma	B
+(	O
+1	O
+)	O
+,	O
+mixed	O
+histology	O
+(	O
+2	O
+)	O
+,	O
+bronchio	B
+-	I
+alveolar	I
+carcinoma	I
+(	O
+1	O
+)	O
+and	O
+large	O
+cell	O
+undifferentiated	B
+carcinoma	I
+(	O
+1	O
+)	O
+.	O
+
+Neutropenia	B
+grade	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+3	O
+was	O
+seen	O
+in	O
+15	O
+patients	O
+,	O
+infections	B
+with	O
+recovery	O
+in	O
+3	O
+,	O
+and	O
+grand	O
+mal	O
+seizures	B
+in	O
+1	O
+patient	O
+.	O
+
+Grade	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+2	O
+nausea	B
+and	O
+vomiting	B
+occurred	O
+in	O
+66	O
+%	O
+courses	O
+and	O
+phlebitis	B
+in	O
+the	O
+infusion	O
+arm	O
+in	O
+37	O
+%	O
+.	O
+
+1	O
+patient	O
+with	O
+squamous	B
+cell	I
+carcinoma	I
+achieved	O
+a	O
+partial	O
+response	O
+lasting	O
+5	O
+months	O
+.	O
+
+Further	O
+testing	O
+in	O
+this	O
+and	O
+other	O
+tumour	B
+types	O
+using	O
+multiple	O
+daily	O
+schedules	O
+is	O
+warranted	O
+.	O
+
+Pharmacokinetics	O
+of	O
+desipramine	O
+HCl	O
+when	O
+administered	O
+with	O
+cinacalcet	O
+HCl	O
+.	O
+
+OBJECTIVE	O
+:	O
+In	O
+vitro	O
+work	O
+has	O
+demonstrated	O
+that	O
+cinacalcet	O
+is	O
+a	O
+strong	O
+inhibitor	O
+of	O
+cytochrome	O
+P450	O
+isoenzyme	O
+(	O
+CYP	O
+)	O
+2D6	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+evaluate	O
+the	O
+effect	O
+of	O
+cinacalcet	O
+on	O
+CYP2D6	O
+activity	O
+,	O
+using	O
+desipramine	O
+as	O
+a	O
+probe	O
+substrate	O
+,	O
+in	O
+healthy	O
+subjects	O
+.	O
+
+METHODS	O
+:	O
+Seventeen	O
+subjects	O
+who	O
+were	O
+genotyped	O
+as	O
+CYP2D6	O
+extensive	O
+metabolizers	O
+were	O
+enrolled	O
+in	O
+this	O
+randomized	O
+,	O
+open	O
+-	O
+label	O
+,	O
+crossover	O
+study	O
+to	O
+receive	O
+a	O
+single	O
+oral	O
+dose	O
+of	O
+desipramine	O
+(	O
+50	O
+mg	O
+)	O
+on	O
+two	O
+separate	O
+occasions	O
+,	O
+once	O
+alone	O
+and	O
+once	O
+after	O
+multiple	O
+doses	O
+of	O
+cinacalcet	O
+(	O
+90	O
+mg	O
+for	O
+7	O
+days	O
+)	O
+.	O
+
+Blood	O
+samples	O
+were	O
+obtained	O
+predose	O
+and	O
+up	O
+to	O
+72	O
+h	O
+postdose	O
+.	O
+
+RESULTS	O
+:	O
+Fourteen	O
+subjects	O
+completed	O
+both	O
+treatment	O
+arms	O
+.	O
+
+Relative	O
+to	O
+desipramine	O
+alone	O
+,	O
+mean	O
+AUC	O
+and	O
+C	O
+(	O
+max	O
+)	O
+of	O
+desipramine	O
+increased	O
+3	O
+.	O
+6	O
+-	O
+and	O
+1	O
+.	O
+8	O
+-	O
+fold	O
+when	O
+coadministered	O
+with	O
+cinacalcet	O
+.	O
+
+The	O
+t	O
+(	O
+1	O
+/	O
+2	O
+,	O
+z	O
+)	O
+of	O
+desipramine	O
+was	O
+longer	O
+when	O
+desipramine	O
+was	O
+coadministered	O
+with	O
+cinacalcet	O
+(	O
+21	O
+.	O
+0	O
+versus	O
+43	O
+.	O
+3	O
+hs	O
+)	O
+.	O
+
+The	O
+t	O
+(	O
+max	O
+)	O
+was	O
+similar	O
+between	O
+the	O
+regimens	O
+.	O
+
+Fewer	O
+subjects	O
+reported	O
+adverse	O
+events	O
+following	O
+treatment	O
+with	O
+desipramine	O
+alone	O
+than	O
+when	O
+receiving	O
+desipramine	O
+with	O
+cinacalcet	O
+(	O
+33	O
+versus	O
+86	O
+%	O
+)	O
+,	O
+the	O
+most	O
+frequent	O
+of	O
+which	O
+(	O
+nausea	B
+and	O
+headache	B
+)	O
+have	O
+been	O
+reported	O
+for	O
+patients	O
+treated	O
+with	O
+either	O
+desipramine	O
+or	O
+cinacalcet	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+study	O
+demonstrates	O
+that	O
+cinacalcet	O
+is	O
+a	O
+strong	O
+inhibitor	O
+of	O
+CYP2D6	O
+.	O
+
+These	O
+data	O
+suggest	O
+that	O
+during	O
+concomitant	O
+treatment	O
+with	O
+cinacalcet	O
+,	O
+dose	O
+adjustment	O
+may	O
+be	O
+necessary	O
+for	O
+drugs	O
+that	O
+demonstrate	O
+a	O
+narrow	O
+therapeutic	O
+index	O
+and	O
+are	O
+metabolized	O
+by	O
+CYP2D6	O
+.	O
+
+Case	O
+report	O
+:	O
+acute	O
+unintentional	O
+carbachol	O
+intoxication	O
+.	O
+
+INTRODUCTION	O
+:	O
+Intoxications	O
+with	O
+carbachol	O
+,	O
+a	O
+muscarinic	O
+cholinergic	O
+receptor	O
+agonist	O
+are	O
+rare	O
+.	O
+
+We	O
+report	O
+an	O
+interesting	O
+case	O
+investigating	O
+a	O
+(	O
+near	O
+)	O
+fatal	O
+poisoning	B
+.	O
+
+METHODS	O
+:	O
+The	O
+son	O
+of	O
+an	O
+84	O
+-	O
+year	O
+-	O
+old	O
+male	O
+discovered	O
+a	O
+newspaper	O
+report	O
+stating	O
+clinical	O
+success	O
+with	O
+plant	O
+extracts	O
+in	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+.	O
+
+The	O
+mode	O
+of	O
+action	O
+was	O
+said	O
+to	O
+be	O
+comparable	O
+to	O
+that	O
+of	O
+the	O
+synthetic	O
+compound	O
+'	O
+carbamylcholin	O
+'	O
+;	O
+that	O
+is	O
+,	O
+carbachol	O
+.	O
+
+He	O
+bought	O
+25	O
+g	O
+of	O
+carbachol	O
+as	O
+pure	O
+substance	O
+in	O
+a	O
+pharmacy	O
+,	O
+and	O
+the	O
+father	O
+was	O
+administered	O
+400	O
+to	O
+500	O
+mg	O
+.	O
+
+Carbachol	O
+concentrations	O
+in	O
+serum	O
+and	O
+urine	O
+on	O
+day	O
+1	O
+and	O
+2	O
+of	O
+hospital	O
+admission	O
+were	O
+analysed	O
+by	O
+HPLC	O
+-	O
+mass	O
+spectrometry	O
+.	O
+
+RESULTS	O
+:	O
+Minutes	O
+after	O
+oral	O
+administration	O
+,	O
+the	O
+patient	O
+developed	O
+nausea	B
+,	O
+sweating	O
+and	O
+hypotension	B
+,	O
+and	O
+finally	O
+collapsed	O
+.	O
+
+Bradycardia	B
+,	O
+cholinergic	O
+symptoms	O
+and	O
+asystole	B
+occurred	O
+.	O
+
+Initial	O
+cardiopulmonary	O
+resuscitation	O
+and	O
+immediate	O
+treatment	O
+with	O
+adrenaline	O
+(	O
+epinephrine	O
+)	O
+,	O
+atropine	O
+and	O
+furosemide	O
+was	O
+successful	O
+.	O
+
+On	O
+hospital	O
+admission	O
+,	O
+blood	O
+pressure	O
+of	O
+the	O
+intubated	O
+,	O
+bradyarrhythmic	O
+patient	O
+was	O
+100	O
+/	O
+65	O
+mmHg	O
+.	O
+
+Further	O
+signs	O
+were	O
+hyperhidrosis	B
+,	O
+hypersalivation	B
+,	O
+bronchorrhoea	B
+,	O
+and	O
+severe	O
+miosis	B
+;	O
+the	O
+electrocardiographic	O
+finding	O
+was	O
+atrio	B
+-	I
+ventricular	I
+dissociation	I
+.	O
+
+High	O
+doses	O
+of	O
+atropine	O
+(	O
+up	O
+to	O
+50	O
+mg	O
+per	O
+24	O
+hours	O
+)	O
+,	O
+adrenaline	O
+and	O
+dopamine	O
+were	O
+necessary	O
+.	O
+
+The	O
+patient	O
+was	O
+extubated	O
+1	O
+week	O
+later	O
+.	O
+
+However	O
+,	O
+increased	O
+dyspnoea	B
+and	O
+bronchospasm	B
+necessitated	O
+reintubation	O
+.	O
+
+Respiratory	B
+insufficiency	I
+was	O
+further	O
+worsened	O
+by	O
+Proteus	B
+mirabilis	I
+infection	I
+and	O
+severe	O
+bronchoconstriction	O
+.	O
+
+One	O
+week	O
+later	O
+,	O
+the	O
+patient	O
+was	O
+again	O
+extubated	O
+and	O
+3	O
+days	O
+later	O
+was	O
+transferred	O
+to	O
+a	O
+peripheral	O
+ward	O
+.	O
+
+On	O
+the	O
+next	O
+day	O
+he	O
+died	O
+,	O
+probably	O
+as	O
+a	O
+result	O
+of	O
+heart	B
+failure	I
+.	O
+
+Serum	O
+samples	O
+from	O
+the	O
+first	O
+and	O
+second	O
+days	O
+contained	O
+3	O
+.	O
+6	O
+and	O
+1	O
+.	O
+9	O
+mg	O
+/	O
+l	O
+carbachol	O
+,	O
+respectively	O
+.	O
+
+The	O
+corresponding	O
+urine	O
+concentrations	O
+amounted	O
+to	O
+374	O
+and	O
+554	O
+mg	O
+/	O
+l	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+case	O
+started	O
+with	O
+a	O
+media	O
+report	O
+in	O
+a	O
+popular	O
+newspaper	O
+,	O
+initiated	O
+by	O
+published	O
+,	O
+peer	O
+-	O
+reviewed	O
+research	O
+on	O
+herbals	O
+,	O
+and	O
+involved	O
+human	O
+failure	O
+in	O
+a	O
+case	O
+history	O
+,	O
+medical	O
+examination	O
+and	O
+clinical	O
+treatment	O
+.	O
+
+For	O
+the	O
+first	O
+time	O
+,	O
+an	O
+analytical	O
+method	O
+for	O
+the	O
+determination	O
+of	O
+carbachol	O
+in	O
+plasma	O
+and	O
+urine	O
+has	O
+been	O
+developed	O
+.	O
+
+The	O
+analysed	O
+carbachol	O
+concentration	O
+exceeded	O
+the	O
+supposed	O
+serum	O
+level	O
+resulting	O
+from	O
+a	O
+therapeutic	O
+dose	O
+by	O
+a	O
+factor	O
+of	O
+130	O
+to	O
+260	O
+.	O
+
+Especially	O
+in	O
+old	O
+patients	O
+,	O
+intensivists	O
+should	O
+consider	O
+intoxications	O
+(	O
+with	O
+cholinergics	O
+)	O
+as	O
+a	O
+cause	O
+of	O
+acute	B
+cardiovascular	I
+failure	I
+.	O
+
+Pharmacological	O
+evidence	O
+for	O
+the	O
+potential	O
+of	O
+Daucus	O
+carota	O
+in	O
+the	O
+management	O
+of	O
+cognitive	B
+dysfunctions	I
+.	O
+
+The	O
+present	O
+study	O
+was	O
+aimed	O
+at	O
+investigating	O
+the	O
+effects	O
+of	O
+Daucus	O
+carota	O
+seeds	O
+on	O
+cognitive	O
+functions	O
+,	O
+total	O
+serum	O
+cholesterol	O
+levels	O
+and	O
+brain	O
+cholinesterase	O
+activity	O
+in	O
+mice	O
+.	O
+
+The	O
+ethanolic	O
+extract	O
+of	O
+Daucus	O
+carota	O
+seeds	O
+(	O
+DCE	O
+)	O
+was	O
+administered	O
+orally	O
+in	O
+three	O
+doses	O
+(	O
+100	O
+,	O
+200	O
+,	O
+400	O
+mg	O
+/	O
+kg	O
+)	O
+for	O
+seven	O
+successive	O
+days	O
+to	O
+different	O
+groups	O
+of	O
+young	O
+and	O
+aged	O
+mice	O
+.	O
+
+Elevated	O
+plus	O
+maze	O
+and	O
+passive	O
+avoidance	O
+apparatus	O
+served	O
+as	O
+the	O
+exteroceptive	O
+behavioral	O
+models	O
+for	O
+testing	O
+memory	O
+.	O
+
+Diazepam	O
+-	O
+,	O
+scopolamine	O
+-	O
+and	O
+ageing	O
+-	O
+induced	O
+amnesia	B
+served	O
+as	O
+the	O
+interoceptive	O
+behavioral	O
+models	O
+.	O
+
+DCE	O
+(	O
+200	O
+,	O
+400	O
+mg	O
+/	O
+kg	O
+,	O
+p	O
+.	O
+o	O
+.	O
+)	O
+showed	O
+significant	O
+improvement	O
+in	O
+memory	O
+scores	O
+of	O
+young	O
+and	O
+aged	O
+mice	O
+.	O
+
+The	O
+extent	O
+of	O
+memory	O
+improvement	O
+evoked	O
+by	O
+DCE	O
+was	O
+23	O
+%	O
+at	O
+the	O
+dose	O
+of	O
+200	O
+mg	O
+/	O
+kg	O
+and	O
+35	O
+%	O
+at	O
+the	O
+dose	O
+of	O
+400	O
+mg	O
+/	O
+kg	O
+in	O
+young	O
+mice	O
+using	O
+elevated	O
+plus	O
+maze	O
+.	O
+
+Similarly	O
+,	O
+significant	O
+improvements	O
+in	O
+memory	O
+scores	O
+were	O
+observed	O
+using	O
+passive	O
+avoidance	O
+apparatus	O
+and	O
+aged	O
+mice	O
+.	O
+
+Furthermore	O
+,	O
+DCE	O
+reversed	O
+the	O
+amnesia	B
+induced	O
+by	O
+scopolamine	O
+(	O
+0	O
+.	O
+4	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+and	O
+diazepam	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+Daucus	O
+carota	O
+extract	O
+(	O
+200	O
+,	O
+400	O
+mg	O
+/	O
+kg	O
+,	O
+p	O
+.	O
+o	O
+.	O
+)	O
+reduced	O
+significantly	O
+the	O
+brain	O
+acetylcholinesterase	O
+activity	O
+and	O
+cholesterol	O
+levels	O
+in	O
+young	O
+and	O
+aged	O
+mice	O
+.	O
+
+The	O
+extent	O
+of	O
+inhibition	O
+of	O
+brain	O
+cholinesterase	O
+activity	O
+evoked	O
+by	O
+DCE	O
+at	O
+the	O
+dose	O
+of	O
+400	O
+mg	O
+/	O
+kg	O
+was	O
+22	O
+%	O
+in	O
+young	O
+and	O
+19	O
+%	O
+in	O
+aged	O
+mice	O
+.	O
+
+There	O
+was	O
+a	O
+remarkable	O
+reduction	O
+in	O
+total	O
+cholesterol	O
+level	O
+as	O
+well	O
+,	O
+to	O
+the	O
+extent	O
+of	O
+23	O
+%	O
+in	O
+young	O
+and	O
+21	O
+%	O
+in	O
+aged	O
+animals	O
+with	O
+this	O
+dose	O
+of	O
+DCE	O
+.	O
+
+Therefore	O
+,	O
+DCE	O
+may	O
+prove	O
+to	O
+be	O
+a	O
+useful	O
+remedy	O
+for	O
+the	O
+management	O
+of	O
+cognitive	B
+dysfunctions	I
+on	O
+account	O
+of	O
+its	O
+multifarious	O
+beneficial	O
+effects	O
+such	O
+as	O
+,	O
+memory	O
+improving	O
+property	O
+,	O
+cholesterol	O
+lowering	O
+property	O
+and	O
+anticholinesterase	O
+activity	O
+.	O
+
+Valproic	O
+acid	O
+induced	O
+encephalopathy	B
+-	O
+-	O
+19	O
+new	O
+cases	O
+in	O
+Germany	O
+from	O
+1994	O
+to	O
+2003	O
+-	O
+-	O
+a	O
+side	O
+effect	O
+associated	O
+to	O
+VPA	O
+-	O
+therapy	O
+not	O
+only	O
+in	O
+young	O
+children	O
+.	O
+
+Valproic	O
+acid	O
+(	O
+VPA	O
+)	O
+is	O
+a	O
+broad	O
+-	O
+spectrum	O
+antiepileptic	O
+drug	O
+and	O
+is	O
+usually	O
+well	O
+-	O
+tolerated	O
+.	O
+
+Rare	O
+serious	O
+complications	O
+may	O
+occur	O
+in	O
+some	O
+patients	O
+,	O
+including	O
+haemorrhagic	O
+pancreatitis	B
+,	O
+bone	B
+marrow	I
+suppression	I
+,	O
+VPA	O
+-	O
+induced	O
+hepatotoxicity	B
+and	O
+VPA	O
+-	O
+induced	O
+encephalopathy	B
+.	O
+
+The	O
+typical	O
+signs	O
+of	O
+VPA	O
+-	O
+induced	O
+encephalopathy	B
+are	O
+impaired	B
+consciousness	I
+,	O
+sometimes	O
+marked	O
+EEG	O
+background	O
+slowing	O
+,	O
+increased	O
+seizure	B
+frequency	O
+,	O
+with	O
+or	O
+without	O
+hyperammonemia	B
+.	O
+
+There	O
+is	O
+still	O
+no	O
+proof	O
+of	O
+causative	O
+effect	O
+of	O
+VPA	O
+in	O
+patients	O
+with	O
+encephalopathy	B
+,	O
+but	O
+only	O
+of	O
+an	O
+association	O
+with	O
+an	O
+assumed	O
+causal	O
+relation	O
+.	O
+
+We	O
+report	O
+19	O
+patients	O
+with	O
+VPA	O
+-	O
+associated	O
+encephalopathy	B
+in	O
+Germany	O
+from	O
+the	O
+years	O
+1994	O
+to	O
+2003	O
+,	O
+none	O
+of	O
+whom	O
+had	O
+been	O
+published	O
+previously	O
+.	O
+
+Cerebral	B
+haemorrhage	I
+induced	O
+by	O
+warfarin	O
+-	O
+the	O
+influence	O
+of	O
+drug	O
+-	O
+drug	O
+interactions	O
+.	O
+
+PURPOSE	O
+:	O
+To	O
+evaluate	O
+the	O
+frequency	O
+,	O
+severity	O
+and	O
+preventability	O
+of	O
+warfarin	O
+-	O
+induced	O
+cerebral	B
+haemorrhages	I
+due	O
+to	O
+warfarin	O
+and	O
+warfarin	O
+-	O
+drug	O
+interactions	O
+in	O
+patients	O
+living	O
+in	O
+the	O
+county	O
+of	O
+Osterg	O
+tland	O
+,	O
+Sweden	O
+.	O
+
+METHODS	O
+:	O
+All	O
+patients	O
+with	O
+a	O
+diagnosed	O
+cerebral	B
+haemorrhage	I
+at	O
+three	O
+hospitals	O
+during	O
+the	O
+period	O
+2000	O
+-	O
+2002	O
+were	O
+identified	O
+.	O
+
+Medical	O
+records	O
+were	O
+studied	O
+retrospectively	O
+to	O
+evaluate	O
+whether	O
+warfarin	O
+and	O
+warfarin	O
+-	O
+drug	O
+interactions	O
+could	O
+have	O
+caused	O
+the	O
+cerebral	B
+haemorrhage	I
+.	O
+
+The	O
+proportion	O
+of	O
+possibly	O
+avoidable	O
+cases	O
+due	O
+to	O
+drug	O
+interactions	O
+was	O
+estimated	O
+.	O
+
+RESULTS	O
+:	O
+Among	O
+593	O
+patients	O
+with	O
+cerebral	B
+haemorrhage	I
+,	O
+59	O
+(	O
+10	O
+%	O
+)	O
+were	O
+assessed	O
+as	O
+related	O
+to	O
+warfarin	O
+treatment	O
+.	O
+
+This	O
+imply	O
+an	O
+incidence	O
+of	O
+1	O
+.	O
+7	O
+/	O
+100	O
+,	O
+000	O
+treatment	O
+years	O
+.	O
+
+Of	O
+the	O
+59	O
+cases	O
+,	O
+26	O
+(	O
+44	O
+%	O
+)	O
+had	O
+a	O
+fatal	O
+outcome	O
+,	O
+compared	O
+to	O
+136	O
+(	O
+25	O
+%	O
+)	O
+among	O
+the	O
+non	O
+-	O
+warfarin	O
+patients	O
+(	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+A	O
+warfarin	O
+-	O
+drug	O
+interaction	O
+could	O
+have	O
+contributed	O
+to	O
+the	O
+haemorrhage	B
+in	O
+24	O
+(	O
+41	O
+%	O
+)	O
+of	O
+the	O
+warfarin	O
+patients	O
+and	O
+in	O
+7	O
+of	O
+these	O
+(	O
+12	O
+%	O
+)	O
+the	O
+bleeding	B
+complication	O
+was	O
+considered	O
+being	O
+possible	O
+to	O
+avoid	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Warfarin	O
+-	O
+induced	O
+cerebral	B
+haemorrhages	I
+are	O
+a	O
+major	O
+clinical	O
+problem	O
+with	O
+a	O
+high	O
+fatality	O
+rate	O
+.	O
+
+Almost	O
+half	O
+of	O
+the	O
+cases	O
+was	O
+related	O
+to	O
+a	O
+warfarin	O
+-	O
+drug	O
+interaction	O
+.	O
+
+A	O
+significant	O
+proportion	O
+of	O
+warfarin	O
+-	O
+related	O
+cerebral	B
+haemorrhages	I
+might	O
+have	O
+been	O
+prevented	O
+if	O
+greater	O
+caution	O
+had	O
+been	O
+taken	O
+when	O
+prescribing	O
+drugs	O
+known	O
+to	O
+interact	O
+with	O
+warfarin	O
+.	O
+
+Antipsychotic	O
+-	O
+like	O
+profile	O
+of	O
+thioperamide	O
+,	O
+a	O
+selective	O
+H3	O
+-	O
+receptor	O
+antagonist	O
+in	O
+mice	O
+.	O
+
+Experimental	O
+and	O
+clinical	O
+evidence	O
+points	O
+to	O
+a	O
+role	O
+of	O
+central	O
+histaminergic	O
+system	O
+in	O
+the	O
+pathogenesis	O
+of	O
+schizophrenia	B
+.	O
+
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+study	O
+the	O
+effect	O
+of	O
+histamine	O
+H	O
+(	O
+3	O
+)	O
+-	O
+receptor	O
+ligands	O
+on	O
+neuroleptic	O
+-	O
+induced	O
+catalepsy	B
+,	O
+apomorphine	O
+-	O
+induced	O
+climbing	O
+behavior	O
+and	O
+amphetamine	O
+-	O
+induced	O
+locomotor	O
+activities	O
+in	O
+mice	O
+.	O
+
+Catalepsy	B
+was	O
+induced	O
+by	O
+haloperidol	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+)	O
+,	O
+while	O
+apomorphine	O
+(	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+and	O
+amphetamine	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+were	O
+used	O
+for	O
+studying	O
+climbing	O
+behavior	O
+and	O
+locomotor	O
+activities	O
+,	O
+respectively	O
+.	O
+
+(	O
+R	O
+)	O
+-	O
+alpha	O
+-	O
+methylhistamine	O
+(	O
+RAMH	O
+)	O
+(	O
+5	O
+microg	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+and	O
+thioperamide	O
+(	O
+THP	O
+)	O
+(	O
+15	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+,	O
+per	O
+se	O
+did	O
+not	O
+cause	O
+catalepsy	B
+.	O
+
+Administration	O
+of	O
+THP	O
+(	O
+3	O
+.	O
+75	O
+,	O
+7	O
+.	O
+5	O
+and	O
+15	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+1	O
+h	O
+prior	O
+to	O
+haloperidol	O
+resulted	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+increase	O
+in	O
+the	O
+catalepsy	B
+times	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+However	O
+,	O
+pretreatment	O
+with	O
+RAMH	O
+significantly	O
+reversed	O
+such	O
+an	O
+effect	O
+of	O
+THP	O
+(	O
+15	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+RAMH	O
+per	O
+se	O
+showed	O
+significant	O
+reduction	O
+in	O
+locomotor	O
+time	O
+,	O
+distance	O
+traveled	O
+and	O
+average	O
+speed	O
+but	O
+THP	O
+(	O
+15	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+per	O
+se	O
+had	O
+no	O
+effect	O
+on	O
+these	O
+parameters	O
+.	O
+
+On	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B
+,	O
+THP	O
+(	O
+3	O
+.	O
+75	O
+and	O
+7	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+reduced	O
+locomotor	O
+time	O
+,	O
+distance	O
+traveled	O
+and	O
+average	O
+speed	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Pretreatment	O
+with	O
+RAMH	O
+(	O
+5	O
+microg	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+could	O
+partially	O
+reverse	O
+such	O
+effects	O
+of	O
+THP	O
+(	O
+3	O
+.	O
+75	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+Climbing	O
+behavior	O
+induced	O
+by	O
+apomorphine	O
+was	O
+reduced	O
+in	O
+animals	O
+treated	O
+with	O
+THP	O
+.	O
+
+Such	O
+an	O
+effect	O
+was	O
+,	O
+however	O
+,	O
+reversed	O
+in	O
+presence	O
+of	O
+RAMH	O
+.	O
+
+THP	O
+exhibited	O
+an	O
+antipsychotic	O
+-	O
+like	O
+profile	O
+by	O
+potentiating	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+,	O
+reducing	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B
+and	O
+reducing	O
+apomorphine	O
+-	O
+induced	O
+climbing	O
+in	O
+mice	O
+.	O
+
+Such	O
+effects	O
+of	O
+THP	O
+were	O
+reversed	O
+by	O
+RAMH	O
+indicating	O
+the	O
+involvement	O
+of	O
+histamine	O
+H	O
+(	O
+3	O
+)	O
+-	O
+receptors	O
+.	O
+
+Findings	O
+suggest	O
+a	O
+potential	O
+for	O
+H	O
+(	O
+3	O
+)	O
+-	O
+receptor	O
+antagonists	O
+in	O
+improving	O
+the	O
+refractory	O
+cases	O
+of	O
+schizophrenia	B
+.	O
+
+Cauda	B
+equina	I
+syndrome	I
+after	O
+epidural	O
+steroid	O
+injection	O
+:	O
+a	O
+case	O
+report	O
+.	O
+
+OBJECTIVE	O
+:	O
+Conventional	O
+treatment	O
+methods	O
+of	O
+lumbusacral	O
+radiculopathy	B
+are	O
+physical	O
+therapy	O
+,	O
+epidural	O
+steroid	O
+injections	O
+,	O
+oral	O
+medications	O
+,	O
+and	O
+spinal	O
+manipulative	O
+therapy	O
+.	O
+
+Cauda	B
+equina	I
+syndrome	I
+is	O
+a	O
+rare	O
+complication	O
+of	O
+epidural	O
+anesthesia	O
+.	O
+
+The	O
+following	O
+case	O
+is	O
+a	O
+report	O
+of	O
+cauda	B
+equina	I
+syndrome	I
+possibly	O
+caused	O
+by	O
+epidural	O
+injection	O
+of	O
+triamcinolone	O
+and	O
+bupivacaine	O
+.	O
+
+CLINICAL	O
+FEATURES	O
+:	O
+A	O
+50	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+low	B
+back	I
+and	I
+right	I
+leg	I
+pain	I
+was	O
+scheduled	O
+for	O
+epidural	O
+steroid	O
+injection	O
+.	O
+
+INTERVENTION	O
+AND	O
+OUTCOME	O
+:	O
+An	O
+18	O
+-	O
+gauge	O
+Touhy	O
+needle	O
+was	O
+inserted	O
+until	O
+loss	O
+of	O
+resistance	O
+occurred	O
+at	O
+the	O
+L4	O
+-	O
+5	O
+level	O
+.	O
+
+Spread	O
+of	O
+the	O
+contrast	O
+medium	O
+within	O
+the	O
+epidural	O
+space	O
+was	O
+determined	O
+by	O
+radiographic	O
+imaging	O
+.	O
+
+After	O
+verifying	O
+the	O
+epidural	O
+space	O
+,	O
+bupivacaine	O
+and	O
+triamcinolone	O
+diacetate	O
+were	O
+injected	O
+.	O
+
+After	O
+the	O
+injection	O
+,	O
+there	O
+was	O
+a	O
+reduction	O
+in	O
+radicular	O
+symptoms	O
+.	O
+
+Three	O
+hours	O
+later	O
+,	O
+she	O
+complained	O
+of	O
+perineal	O
+numbness	B
+and	O
+lower	B
+extremity	I
+weakness	I
+.	O
+
+The	O
+neurologic	O
+evaluation	O
+revealed	O
+loss	B
+of	I
+sensation	I
+in	O
+the	O
+saddle	O
+area	O
+and	O
+medial	O
+aspect	O
+of	O
+her	O
+right	O
+leg	O
+.	O
+
+There	O
+was	O
+a	O
+decrease	O
+in	O
+the	O
+perception	O
+of	O
+pinprick	O
+test	O
+.	O
+
+Deep	O
+-	O
+tendon	O
+reflexes	O
+were	O
+decreased	O
+especially	O
+in	O
+the	O
+right	O
+leg	O
+.	O
+
+She	O
+was	O
+unable	O
+to	O
+urinate	O
+.	O
+
+The	O
+patient	O
+'	O
+s	O
+symptoms	O
+improved	O
+slightly	O
+over	O
+the	O
+next	O
+few	O
+hours	O
+.	O
+
+She	O
+had	O
+a	O
+gradual	O
+return	O
+of	O
+motor	O
+function	O
+and	O
+ability	O
+of	O
+feeling	O
+Foley	O
+catheter	O
+.	O
+
+All	O
+of	O
+the	O
+symptoms	O
+were	O
+completely	O
+resolved	O
+over	O
+the	O
+next	O
+8	O
+hours	O
+.	O
+
+CONCLUSION	O
+:	O
+Complications	O
+associated	O
+with	O
+epidural	O
+steroid	O
+injections	O
+are	O
+rare	O
+.	O
+
+Clinical	O
+examination	O
+and	O
+continued	O
+vigilance	O
+for	O
+neurologic	B
+deterioration	I
+after	O
+epidural	O
+steroid	O
+injections	O
+is	O
+important	O
+.	O
+
+High	O
+-	O
+dose	O
+testosterone	O
+is	O
+associated	O
+with	O
+atherosclerosis	B
+in	O
+postmenopausal	O
+women	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+study	O
+the	O
+long	O
+-	O
+term	O
+effects	O
+of	O
+androgen	O
+treatment	O
+on	O
+atherosclerosis	B
+in	O
+postmenopausal	O
+women	O
+.	O
+
+METHODS	O
+:	O
+In	O
+a	O
+population	O
+-	O
+based	O
+study	O
+in	O
+513	O
+naturally	O
+postmenopausal	O
+women	O
+aged	O
+54	O
+-	O
+67	O
+years	O
+,	O
+we	O
+studied	O
+the	O
+association	O
+between	O
+self	O
+-	O
+reported	O
+intramuscularly	O
+administered	O
+high	O
+-	O
+dose	O
+estrogen	O
+-	O
+testosterone	O
+therapy	O
+(	O
+estradiol	O
+-	O
+and	O
+testosterone	O
+esters	O
+)	O
+and	O
+aortic	O
+atherosclerosis	B
+.	O
+
+Aortic	O
+atherosclerosis	B
+was	O
+diagnosed	O
+by	O
+radiographic	O
+detection	O
+of	O
+calcified	O
+deposits	O
+in	O
+the	O
+abdominal	O
+aorta	O
+,	O
+which	O
+have	O
+been	O
+shown	O
+to	O
+reflect	O
+intima	O
+atherosclerosis	B
+.	O
+
+Hormone	O
+therapy	O
+users	O
+were	O
+compared	O
+with	O
+never	O
+users	O
+.	O
+
+RESULTS	O
+:	O
+Intramuscular	O
+hormone	O
+therapy	O
+use	O
+for	O
+1	O
+year	O
+or	O
+longer	O
+was	O
+reported	O
+by	O
+25	O
+women	O
+.	O
+
+In	O
+almost	O
+half	O
+of	O
+these	O
+women	O
+severe	O
+atherosclerosis	B
+of	O
+the	O
+aorta	O
+was	O
+present	O
+(	O
+n	O
+=	O
+11	O
+)	O
+,	O
+while	O
+in	O
+women	O
+without	O
+hormone	O
+use	O
+severe	O
+atherosclerosis	B
+of	O
+the	O
+aorta	O
+was	O
+present	O
+in	O
+less	O
+than	O
+20	O
+%	O
+(	O
+OR	O
+3	O
+.	O
+1	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+1	O
+-	O
+8	O
+.	O
+5	O
+,	O
+adjusted	O
+for	O
+age	O
+,	O
+years	O
+since	O
+menopause	O
+,	O
+smoking	O
+,	O
+and	O
+body	O
+mass	O
+index	O
+)	O
+.	O
+
+The	O
+association	O
+remained	O
+after	O
+additional	O
+adjustment	O
+for	O
+diabetes	B
+,	O
+cholesterol	O
+level	O
+,	O
+systolic	O
+blood	O
+pressure	O
+,	O
+or	O
+alcohol	O
+use	O
+.	O
+
+No	O
+association	O
+was	O
+found	O
+for	O
+hormone	O
+use	O
+less	O
+than	O
+1	O
+year	O
+.	O
+
+CONCLUSION	O
+:	O
+Our	O
+results	O
+suggest	O
+that	O
+high	O
+-	O
+dose	O
+testosterone	O
+therapy	O
+may	O
+adversely	O
+affect	O
+atherosclerosis	B
+in	O
+postmenopausal	O
+women	O
+and	O
+indicate	O
+that	O
+androgen	O
+replacement	O
+in	O
+these	O
+women	O
+may	O
+not	O
+be	O
+harmless	O
+.	O
+
+Optimising	O
+stroke	B
+prevention	O
+in	O
+non	O
+-	O
+valvular	O
+atrial	B
+fibrillation	I
+.	O
+
+Atrial	B
+fibrillation	I
+is	O
+associated	O
+with	O
+substantial	O
+morbidity	O
+and	O
+mortality	O
+.	O
+
+Pooled	O
+data	O
+from	O
+trials	O
+comparing	O
+antithrombotic	O
+treatment	O
+with	O
+placebo	O
+have	O
+shown	O
+that	O
+warfarin	O
+reduces	O
+the	O
+risk	O
+of	O
+stroke	B
+by	O
+62	O
+%	O
+,	O
+and	O
+that	O
+aspirin	O
+alone	O
+reduces	O
+the	O
+risk	O
+by	O
+22	O
+%	O
+.	O
+
+Overall	O
+,	O
+in	O
+high	O
+-	O
+risk	O
+patients	O
+,	O
+warfarin	O
+is	O
+superior	O
+to	O
+aspirin	O
+in	O
+preventing	O
+strokes	B
+,	O
+with	O
+a	O
+relative	O
+risk	O
+reduction	O
+of	O
+36	O
+%	O
+.	O
+
+Ximelagatran	O
+,	O
+an	O
+oral	O
+direct	O
+thrombin	O
+inhibitor	O
+,	O
+was	O
+found	O
+to	O
+be	O
+as	O
+efficient	O
+as	O
+vitamin	O
+K	O
+antagonist	O
+drugs	O
+in	O
+the	O
+prevention	O
+of	O
+embolic	B
+events	I
+,	O
+but	O
+has	O
+been	O
+recently	O
+withdrawn	O
+because	O
+of	O
+abnormal	B
+liver	I
+function	I
+tests	O
+.	O
+
+The	O
+ACTIVE	O
+-	O
+W	O
+(	O
+Atrial	B
+Fibrillation	I
+Clopidogrel	O
+Trial	O
+with	O
+Irbesartan	O
+for	O
+Prevention	O
+of	O
+Vascular	O
+Events	O
+)	O
+study	O
+has	O
+demonstrated	O
+that	O
+warfarin	O
+is	O
+superior	O
+to	O
+platelet	O
+therapy	O
+(	O
+clopidogrel	O
+plus	O
+aspirin	O
+)	O
+in	O
+the	O
+prevention	O
+af	O
+embolic	B
+events	I
+.	O
+
+Idraparinux	O
+,	O
+a	O
+Factor	O
+Xa	O
+inhibitor	O
+,	O
+is	O
+being	O
+evaluated	O
+in	O
+patients	O
+with	O
+atrial	B
+fibrillation	I
+.	O
+
+Angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitors	O
+and	O
+angiotensin	O
+II	O
+receptor	O
+-	O
+blocking	O
+drugs	O
+hold	O
+promise	O
+in	O
+atrial	B
+fibrillation	I
+through	O
+cardiac	B
+remodelling	I
+.	O
+
+Preliminary	O
+studies	O
+suggest	O
+that	O
+statins	O
+could	O
+interfere	O
+with	O
+the	O
+risk	O
+of	O
+recurrence	O
+after	O
+electrical	O
+cardioversion	O
+.	O
+
+Finally	O
+,	O
+percutaneous	O
+methods	O
+for	O
+the	O
+exclusion	O
+of	O
+left	O
+atrial	O
+appendage	O
+are	O
+under	O
+investigation	O
+in	O
+high	O
+-	O
+risk	O
+patients	O
+.	O
+
+Anti	O
+-	O
+oxidant	O
+effects	O
+of	O
+atorvastatin	O
+in	O
+dexamethasone	O
+-	O
+induced	O
+hypertension	B
+in	O
+the	O
+rat	O
+.	O
+
+1	O
+.	O
+
+Dexamethasone	O
+(	O
+Dex	O
+)	O
+-	O
+induced	O
+hypertension	B
+is	O
+characterized	O
+by	O
+endothelial	O
+dysfunction	O
+associated	O
+with	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+deficiency	O
+and	O
+increased	O
+superoxide	O
+(	O
+O2	O
+-	O
+)	O
+production	O
+.	O
+
+Atorvastatin	O
+(	O
+Ato	O
+)	O
+possesses	O
+pleiotropic	O
+properties	O
+that	O
+have	O
+been	O
+reported	O
+to	O
+improve	O
+endothelial	O
+function	O
+through	O
+increased	O
+availability	O
+of	O
+NO	O
+and	O
+reduced	O
+O2	O
+-	O
+production	O
+in	O
+various	O
+forms	O
+of	O
+hypertension	B
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+we	O
+investigated	O
+whether	O
+50	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+,	O
+p	O
+.	O
+o	O
+.	O
+,	O
+Ato	O
+could	O
+prevent	O
+endothelial	O
+NO	O
+synthase	O
+(	O
+eNOS	O
+)	O
+downregulation	O
+and	O
+the	O
+increase	O
+in	O
+O2	O
+-	O
+in	O
+Sprague	O
+-	O
+Dawley	O
+(	O
+SD	O
+)	O
+rats	O
+,	O
+thereby	O
+reducing	O
+blood	O
+pressure	O
+.	O
+
+2	O
+.	O
+
+Male	O
+SD	O
+rats	O
+(	O
+n	O
+=	O
+30	O
+)	O
+were	O
+treated	O
+with	O
+Ato	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+in	O
+drinking	O
+water	O
+)	O
+or	O
+tap	O
+water	O
+for	O
+15	O
+days	O
+.	O
+
+Dexamethasone	O
+(	O
+10	O
+microg	O
+/	O
+kg	O
+per	O
+day	O
+,	O
+s	O
+.	O
+c	O
+.	O
+)	O
+or	O
+saline	O
+was	O
+started	O
+after	O
+4	O
+days	O
+in	O
+Ato	O
+-	O
+treated	O
+and	O
+non	O
+-	O
+treated	O
+rats	O
+and	O
+continued	O
+for	O
+11	O
+-	O
+13	O
+days	O
+.	O
+
+Systolic	O
+blood	O
+pressure	O
+(	O
+SBP	O
+)	O
+was	O
+measured	O
+on	O
+alternate	O
+days	O
+using	O
+the	O
+tail	O
+-	O
+cuff	O
+method	O
+.	O
+
+Endothelial	O
+function	O
+was	O
+assessed	O
+by	O
+acetylcholine	O
+-	O
+induced	O
+vasorelaxation	O
+and	O
+phenylephrine	O
+-	O
+induced	O
+vasoconstriction	O
+in	O
+aortic	O
+segments	O
+.	O
+
+Vascular	O
+eNOS	O
+mRNA	O
+was	O
+assessed	O
+by	O
+semi	O
+-	O
+quantitative	O
+reverse	O
+transcription	O
+-	O
+polymerase	O
+chain	O
+reaction	O
+.	O
+
+3	O
+.	O
+
+In	O
+rats	O
+treated	O
+with	O
+Dex	O
+alone	O
+,	O
+SBP	O
+was	O
+increased	O
+from	O
+109	O
++	O
+/	O
+-	O
+2	O
+to	O
+133	O
++	O
+/	O
+-	O
+2	O
+mmHg	O
+on	O
+Days	O
+4	O
+and	O
+Day	O
+14	O
+,	O
+respectively	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+In	O
+the	O
+Ato	O
++	O
+Dex	O
+group	O
+,	O
+SBP	O
+was	O
+increased	O
+from	O
+113	O
++	O
+/	O
+-	O
+2	O
+to	O
+119	O
++	O
+/	O
+-	O
+2	O
+mmHg	O
+on	O
+Days	O
+4	O
+to	O
+14	O
+,	O
+respectively	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+,	O
+but	O
+was	O
+significantly	O
+lower	O
+than	O
+SBP	O
+in	O
+the	O
+group	O
+treated	O
+with	O
+Dex	O
+alone	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Endothelial	O
+-	O
+dependent	O
+relaxation	O
+and	O
+eNOS	O
+mRNA	O
+expression	O
+were	O
+greater	O
+in	O
+the	O
+Dex	O
++	O
+Ato	O
+group	O
+than	O
+in	O
+the	O
+Dex	O
+only	O
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+and	O
+P	O
+<	O
+0	O
+.	O
+0001	O
+,	O
+respectively	O
+)	O
+.	O
+
+Aortic	O
+superoxide	O
+production	O
+was	O
+lower	O
+in	O
+the	O
+Dex	O
++	O
+Ato	O
+group	O
+compared	O
+with	O
+the	O
+group	O
+treated	O
+with	O
+Dex	O
+alone	O
+(	O
+P	O
+<	O
+0	O
+.	O
+0001	O
+)	O
+.	O
+
+4	O
+.	O
+
+Treatment	O
+with	O
+Ato	O
+improved	O
+endothelial	O
+function	O
+,	O
+reduced	O
+superoxide	O
+production	O
+and	O
+reduced	O
+SBP	O
+in	O
+Dex	O
+-	O
+treated	O
+SD	O
+rats	O
+.	O
+
+Severe	O
+citrate	O
+toxicity	B
+complicating	O
+volunteer	O
+apheresis	O
+platelet	O
+donation	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+severe	O
+citrate	O
+toxicity	B
+during	O
+volunteer	O
+donor	O
+apheresis	O
+platelet	O
+collection	O
+.	O
+
+The	O
+donor	O
+was	O
+a	O
+40	O
+-	O
+year	O
+-	O
+old	O
+female	O
+,	O
+first	O
+-	O
+time	O
+apheresis	O
+platelet	O
+donor	O
+.	O
+
+Past	O
+medical	O
+history	O
+was	O
+remarkable	O
+for	O
+hypertension	B
+,	O
+hyperlipidemia	B
+,	O
+and	O
+depression	B
+.	O
+
+Reported	O
+medications	O
+included	O
+bumetanide	O
+,	O
+pravastatin	O
+,	O
+and	O
+paroxetine	O
+.	O
+
+Thirty	O
+minutes	O
+from	O
+the	O
+start	O
+of	O
+the	O
+procedure	O
+,	O
+the	O
+donor	O
+noted	O
+tingling	O
+around	O
+the	O
+mouth	O
+,	O
+hands	O
+,	O
+and	O
+feet	O
+.	O
+
+She	O
+then	O
+very	O
+rapidly	O
+developed	O
+acute	O
+onset	O
+of	O
+severe	O
+facial	O
+and	O
+extremity	O
+tetany	B
+.	O
+
+Empirical	O
+treatment	O
+with	O
+intravenous	O
+calcium	O
+gluconate	O
+was	O
+initiated	O
+,	O
+and	O
+muscle	B
+contractions	I
+slowly	O
+subsided	O
+over	O
+approximately	O
+10	O
+to	O
+15	O
+minutes	O
+.	O
+
+The	O
+events	O
+are	O
+consistent	O
+with	O
+a	O
+severe	O
+reaction	O
+to	O
+calcium	O
+chelation	O
+by	O
+sodium	O
+citrate	O
+anticoagulant	O
+resulting	O
+in	O
+symptomatic	O
+systemic	O
+hypocalcemia	B
+.	O
+
+Upon	O
+additional	O
+retrospective	O
+analysis	O
+,	O
+it	O
+was	O
+noted	O
+that	O
+bumetanide	O
+is	O
+a	O
+loop	O
+diuretic	O
+that	O
+may	O
+cause	O
+significant	O
+hypocalcemia	B
+.	O
+
+We	O
+conclude	O
+that	O
+careful	O
+screening	O
+for	O
+medications	O
+and	O
+underlying	O
+conditions	O
+predisposing	O
+to	O
+hypocalcemia	B
+is	O
+recommended	O
+to	O
+help	O
+prevent	O
+severe	O
+reactions	O
+due	O
+to	O
+citrate	O
+toxicity	B
+.	O
+
+Laboratory	O
+measurement	O
+of	O
+pre	O
+-	O
+procedure	O
+serum	O
+calcium	O
+levels	O
+in	O
+selected	O
+donors	O
+may	O
+identify	O
+cases	O
+requiring	O
+heightened	O
+vigilance	O
+.	O
+
+The	O
+case	O
+also	O
+illustrates	O
+the	O
+importance	O
+of	O
+maintaining	O
+preparedness	O
+for	O
+managing	O
+rare	O
+but	O
+serious	O
+reactions	O
+in	O
+volunteer	O
+apheresis	O
+blood	O
+donors	O
+.	O
+
+Sirolimus	O
+-	O
+associated	O
+proteinuria	B
+and	O
+renal	B
+dysfunction	I
+.	O
+
+Sirolimus	O
+is	O
+a	O
+novel	O
+immunosuppressant	O
+with	O
+potent	O
+antiproliferative	O
+actions	O
+through	O
+its	O
+ability	O
+to	O
+inhibit	O
+the	O
+raptor	O
+-	O
+containing	O
+mammalian	O
+target	O
+of	O
+rapamycin	O
+protein	O
+kinase	O
+.	O
+
+Sirolimus	O
+represents	O
+a	O
+major	O
+therapeutic	O
+advance	O
+in	O
+the	O
+prevention	O
+of	O
+acute	O
+renal	O
+allograft	O
+rejection	O
+and	O
+chronic	O
+allograft	O
+nephropathy	B
+.	O
+
+Its	O
+role	O
+in	O
+the	O
+therapy	O
+of	O
+glomerulonephritis	B
+,	O
+autoimmunity	B
+,	O
+cystic	B
+renal	I
+diseases	I
+and	O
+renal	B
+cancer	I
+is	O
+under	O
+investigation	O
+.	O
+
+Because	O
+sirolimus	O
+does	O
+not	O
+share	O
+the	O
+vasomotor	O
+renal	O
+adverse	O
+effects	O
+exhibited	O
+by	O
+calcineurin	O
+inhibitors	O
+,	O
+it	O
+has	O
+been	O
+designated	O
+a	O
+'	O
+non	O
+-	O
+nephrotoxic	B
+drug	O
+'	O
+.	O
+
+However	O
+,	O
+clinical	O
+reports	O
+suggest	O
+that	O
+,	O
+under	O
+some	O
+circumstances	O
+,	O
+sirolimus	O
+is	O
+associated	O
+with	O
+proteinuria	B
+and	O
+acute	B
+renal	I
+dysfunction	I
+.	O
+
+A	O
+common	O
+risk	O
+factor	O
+appears	O
+to	O
+be	O
+presence	O
+of	O
+pre	O
+-	O
+existing	O
+chronic	B
+renal	I
+damage	I
+.	O
+
+The	O
+mechanisms	O
+of	O
+sirolimus	O
+-	O
+associated	O
+proteinuria	B
+are	O
+multifactorial	O
+and	O
+may	O
+be	O
+due	O
+to	O
+an	O
+increase	O
+in	O
+glomerular	O
+capillary	O
+pressure	O
+following	O
+calcineurin	O
+inhibitor	O
+withdrawal	O
+.	O
+
+It	O
+has	O
+also	O
+been	O
+suggested	O
+that	O
+sirolimus	O
+directly	O
+causes	O
+increased	O
+glomerular	O
+permeability	O
+/	O
+injury	O
+,	O
+but	O
+evidence	O
+for	O
+this	O
+mechanism	O
+is	O
+currently	O
+inconclusive	O
+.	O
+
+The	O
+acute	B
+renal	I
+dysfunction	I
+associated	O
+with	O
+sirolimus	O
+(	O
+such	O
+as	O
+in	O
+delayed	O
+graft	O
+function	O
+)	O
+may	O
+be	O
+due	O
+to	O
+suppression	O
+of	O
+compensatory	O
+renal	O
+cell	O
+proliferation	O
+and	O
+survival	O
+/	O
+repair	O
+processes	O
+.	O
+
+Although	O
+these	O
+adverse	O
+effects	O
+occur	O
+in	O
+some	O
+patients	O
+,	O
+their	O
+occurrence	O
+could	O
+be	O
+minimised	O
+by	O
+knowledge	O
+of	O
+the	O
+molecular	O
+effects	O
+of	O
+sirolimus	O
+on	O
+the	O
+kidney	O
+,	O
+the	O
+use	O
+of	O
+sirolimus	O
+in	O
+appropriate	O
+patient	O
+populations	O
+,	O
+close	O
+monitoring	O
+of	O
+proteinuria	B
+and	O
+renal	O
+function	O
+,	O
+use	O
+of	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitors	O
+or	O
+angiotensin	O
+II	O
+receptor	O
+blockers	O
+if	O
+proteinuria	B
+occurs	O
+and	O
+withdrawal	O
+if	O
+needed	O
+.	O
+
+Further	O
+long	O
+-	O
+term	O
+analysis	O
+of	O
+renal	O
+allograft	O
+studies	O
+using	O
+sirolimus	O
+as	O
+de	O
+novo	O
+immunosuppression	O
+along	O
+with	O
+clinical	O
+and	O
+laboratory	O
+studies	O
+will	O
+refine	O
+these	O
+issues	O
+in	O
+the	O
+future	O
+.	O
+
+Proteinuria	B
+after	O
+conversion	O
+to	O
+sirolimus	O
+in	O
+renal	O
+transplant	O
+recipients	O
+.	O
+
+Sirolimus	O
+(	O
+SRL	O
+)	O
+is	O
+a	O
+new	O
+,	O
+potent	O
+immunosuppressive	O
+agent	O
+.	O
+
+More	O
+recently	O
+,	O
+proteinuria	B
+has	O
+been	O
+reported	O
+as	O
+a	O
+consequence	O
+of	O
+sirolimus	O
+therapy	O
+,	O
+although	O
+the	O
+mechanism	O
+has	O
+remained	O
+unclear	O
+.	O
+
+We	O
+retrospectively	O
+examined	O
+the	O
+records	O
+of	O
+25	O
+renal	O
+transplant	O
+patients	O
+,	O
+who	O
+developed	O
+or	O
+displayed	O
+increased	O
+proteinuria	B
+after	O
+SRL	O
+conversion	O
+.	O
+
+The	O
+patient	O
+cohort	O
+(	O
+14	O
+men	O
+,	O
+11	O
+women	O
+)	O
+was	O
+treated	O
+with	O
+SRL	O
+as	O
+conversion	O
+therapy	O
+,	O
+due	O
+to	O
+chronic	B
+allograft	I
+nephropathy	I
+(	O
+CAN	B
+)	O
+(	O
+n	O
+=	O
+15	O
+)	O
+neoplasia	B
+(	O
+n	O
+=	O
+8	O
+)	O
+;	O
+Kaposi	B
+'	I
+s	I
+sarcoma	I
+,	O
+Four	O
+skin	B
+cancers	I
+,	O
+One	O
+intestinal	B
+tumors	I
+,	O
+One	O
+renal	B
+cell	I
+carsinom	I
+)	O
+or	O
+BK	O
+virus	O
+nephropathy	B
+(	O
+n	O
+=	O
+2	O
+)	O
+.	O
+
+SRL	O
+was	O
+started	O
+at	O
+a	O
+mean	O
+of	O
+78	O
++	O
+/	O
+-	O
+42	O
+(	O
+15	O
+to	O
+163	O
+)	O
+months	O
+after	O
+transplantation	O
+.	O
+
+Mean	O
+follow	O
+-	O
+up	O
+on	O
+SRL	O
+therapy	O
+was	O
+20	O
++	O
+/	O
+-	O
+12	O
+(	O
+6	O
+to	O
+43	O
+)	O
+months	O
+.	O
+
+Proteinuria	B
+increased	O
+from	O
+0	O
+.	O
+445	O
+(	O
+0	O
+to	O
+1	O
+.	O
+5	O
+)	O
+g	O
+/	O
+d	O
+before	O
+conversion	O
+to	O
+3	O
+.	O
+2	O
+g	O
+/	O
+dL	O
+(	O
+0	O
+.	O
+2	O
+to	O
+12	O
+)	O
+after	O
+conversion	O
+(	O
+P	O
+=	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Before	O
+conversion	O
+8	O
+(	O
+32	O
+%	O
+)	O
+patients	O
+had	O
+no	O
+proteinuria	B
+,	O
+whereas	O
+afterwards	O
+all	O
+patients	O
+had	O
+proteinuria	B
+.	O
+
+In	O
+28	O
+%	O
+of	O
+patients	O
+proteinuria	B
+remained	O
+unchanged	O
+,	O
+whereas	O
+it	O
+increased	O
+in	O
+68	O
+%	O
+of	O
+patients	O
+.	O
+
+In	O
+40	O
+%	O
+it	O
+increased	O
+by	O
+more	O
+than	O
+100	O
+%	O
+.	O
+
+Twenty	O
+-	O
+eight	O
+percent	O
+of	O
+patients	O
+showed	O
+increased	O
+proteinuria	B
+to	O
+the	O
+nephrotic	B
+range	O
+.	O
+
+Biopsies	O
+performed	O
+in	O
+five	O
+patients	O
+revealed	O
+new	O
+pathological	O
+changes	O
+:	O
+One	O
+membranoproliferative	B
+glomerulopathy	I
+and	O
+interstitial	B
+nephritis	I
+.	O
+
+These	O
+patients	O
+showed	O
+persistently	O
+good	O
+graft	O
+function	O
+.	O
+
+Serum	O
+creatinine	O
+values	O
+did	O
+not	O
+change	O
+significantly	O
+:	O
+1	O
+.	O
+98	O
++	O
+/	O
+-	O
+0	O
+.	O
+8	O
+mg	O
+/	O
+dL	O
+before	O
+SRL	O
+therapy	O
+and	O
+2	O
+.	O
+53	O
++	O
+/	O
+-	O
+1	O
+.	O
+9	O
+mg	O
+/	O
+dL	O
+at	O
+last	O
+follow	O
+-	O
+up	O
+(	O
+P	O
+=	O
+.	O
+14	O
+)	O
+.	O
+
+Five	O
+grafts	O
+were	O
+lost	O
+and	O
+the	O
+patients	O
+returned	O
+to	O
+dialysis	O
+.	O
+
+Five	O
+patients	O
+displayed	O
+CAN	B
+and	O
+Kaposi	B
+'	I
+s	I
+sarcoma	I
+.	O
+
+Mean	O
+urinary	O
+protein	O
+of	O
+patients	O
+who	O
+returned	O
+to	O
+dialysis	O
+was	O
+1	O
+.	O
+26	O
+(	O
+0	O
+.	O
+5	O
+to	O
+3	O
+.	O
+5	O
+)	O
+g	O
+/	O
+d	O
+before	O
+and	O
+4	O
+.	O
+7	O
+(	O
+3	O
+to	O
+12	O
+)	O
+g	O
+/	O
+d	O
+after	O
+conversion	O
+(	O
+P	O
+=	O
+.	O
+01	O
+)	O
+.	O
+
+Mean	O
+serum	O
+creatinine	O
+level	O
+before	O
+conversion	O
+was	O
+2	O
+.	O
+21	O
+mg	O
+/	O
+dL	O
+and	O
+thereafter	O
+,	O
+4	O
+.	O
+93	O
+mg	O
+/	O
+dL	O
+(	O
+P	O
+=	O
+.	O
+02	O
+)	O
+.	O
+
+Heavy	O
+proteinuria	B
+was	O
+common	O
+after	O
+the	O
+use	O
+of	O
+SRL	O
+as	O
+rescue	O
+therapy	O
+for	O
+renal	O
+transplantation	O
+.	O
+
+Therefore	O
+,	O
+conversion	O
+should	O
+be	O
+considered	O
+for	O
+patients	O
+who	O
+have	O
+not	O
+developed	O
+advanced	O
+CAN	B
+and	O
+proteinuria	B
+.	O
+
+The	O
+possibility	O
+of	O
+de	O
+novo	O
+glomerular	O
+pathology	O
+under	O
+SRL	O
+treatment	O
+requires	O
+further	O
+investigation	O
+by	O
+renal	O
+biopsy	O
+.	O
+
+Long	O
+-	O
+term	O
+follow	O
+-	O
+up	O
+of	O
+ifosfamide	O
+renal	B
+toxicity	I
+in	O
+children	O
+treated	O
+for	O
+malignant	B
+mesenchymal	I
+tumors	I
+:	O
+an	O
+International	O
+Society	O
+of	O
+Pediatric	O
+Oncology	O
+report	O
+.	O
+
+The	O
+renal	O
+function	O
+of	O
+74	O
+children	O
+with	O
+malignant	B
+mesenchymal	I
+tumors	I
+in	O
+complete	O
+remission	O
+and	O
+who	O
+have	O
+received	O
+the	O
+same	O
+ifosfamide	O
+chemotherapy	O
+protocol	O
+(	O
+International	O
+Society	O
+of	O
+Pediatric	O
+Oncology	O
+Malignant	B
+Mesenchymal	I
+Tumor	I
+Study	O
+84	O
+[	O
+SIOP	O
+MMT	O
+84	O
+]	O
+)	O
+were	O
+studied	O
+1	O
+year	O
+after	O
+the	O
+completion	O
+of	O
+treatment	O
+.	O
+
+Total	O
+cumulative	O
+doses	O
+were	O
+36	O
+or	O
+60	O
+g	O
+/	O
+m2	O
+of	O
+ifosfamide	O
+(	O
+six	O
+or	O
+10	O
+cycles	O
+of	O
+ifosfamide	O
+,	O
+vincristine	O
+,	O
+and	O
+dactinomycin	O
+[	O
+IVA	O
+]	O
+)	O
+.	O
+
+None	O
+of	O
+them	O
+had	O
+received	O
+cisplatin	O
+chemotherapy	O
+.	O
+
+Ages	O
+ranged	O
+from	O
+4	O
+months	O
+to	O
+17	O
+years	O
+;	O
+58	O
+patients	O
+were	O
+males	O
+and	O
+42	O
+females	O
+.	O
+
+The	O
+most	O
+common	O
+primary	O
+tumor	B
+site	O
+was	O
+the	O
+head	O
+and	O
+neck	O
+.	O
+
+Renal	O
+function	O
+was	O
+investigated	O
+by	O
+measuring	O
+plasma	O
+and	O
+urinary	O
+electrolytes	O
+,	O
+glucosuria	B
+,	O
+proteinuria	B
+,	O
+aminoaciduria	B
+,	O
+urinary	O
+pH	O
+,	O
+osmolarity	O
+,	O
+creatinine	O
+clearance	O
+,	O
+phosphate	O
+tubular	O
+reabsorption	O
+,	O
+beta	O
+2	O
+microglobulinuria	O
+,	O
+and	O
+lysozymuria	O
+.	O
+
+Fifty	O
+-	O
+eight	O
+patients	O
+(	O
+78	O
+%	O
+)	O
+had	O
+normal	O
+renal	O
+tests	O
+,	O
+whereas	O
+16	O
+patients	O
+(	O
+22	O
+%	O
+)	O
+had	O
+renal	B
+abnormalities	I
+.	O
+
+Two	O
+subsets	O
+of	O
+patients	O
+were	O
+identified	O
+from	O
+this	O
+latter	O
+group	O
+:	O
+the	O
+first	O
+included	O
+four	O
+patients	O
+(	O
+5	O
+%	O
+of	O
+the	O
+total	O
+population	O
+)	O
+who	O
+developed	O
+major	O
+toxicity	B
+resulting	O
+in	O
+Fanconi	B
+'	I
+s	I
+syndrome	I
+(	O
+TDFS	B
+)	O
+;	O
+and	O
+the	O
+second	O
+group	O
+included	O
+five	O
+patients	O
+with	O
+elevated	O
+beta	O
+2	O
+microglobulinuria	O
+and	O
+low	O
+phosphate	O
+reabsorption	O
+.	O
+
+The	O
+remaining	O
+seven	O
+patients	O
+had	O
+isolated	O
+beta	O
+2	O
+microglobulinuria	O
+.	O
+
+Severe	O
+toxicity	B
+was	O
+correlated	O
+with	O
+the	O
+higher	O
+cumulative	O
+dose	O
+of	O
+60	O
+g	O
+/	O
+m2	O
+of	O
+ifosfamide	O
+,	O
+a	O
+younger	O
+age	O
+(	O
+less	O
+than	O
+2	O
+1	O
+/	O
+2	O
+years	O
+old	O
+)	O
+,	O
+and	O
+a	O
+predominance	O
+of	O
+vesicoprostatic	O
+tumor	B
+involvement	O
+.	O
+
+This	O
+low	O
+percentage	O
+(	O
+5	O
+%	O
+)	O
+of	O
+TDFS	O
+must	O
+be	O
+evaluated	O
+with	O
+respect	O
+to	O
+the	O
+efficacy	O
+of	O
+ifosfamide	O
+in	O
+the	O
+treatment	O
+of	O
+mesenchymal	B
+tumors	I
+in	O
+children	O
+.	O
+
+Progressive	O
+myopathy	B
+with	O
+up	O
+-	O
+regulation	O
+of	O
+MHC	O
+-	O
+I	O
+associated	O
+with	O
+statin	O
+therapy	O
+.	O
+
+Statins	O
+can	O
+cause	O
+a	O
+necrotizing	O
+myopathy	B
+and	O
+hyperCKaemia	B
+which	O
+is	O
+reversible	O
+on	O
+cessation	O
+of	O
+the	O
+drug	O
+.	O
+
+What	O
+is	O
+less	O
+well	O
+known	O
+is	O
+a	O
+phenomenon	O
+whereby	O
+statins	O
+may	O
+induce	O
+a	O
+myopathy	B
+,	O
+which	O
+persists	O
+or	O
+may	O
+progress	O
+after	O
+stopping	O
+the	O
+drug	O
+.	O
+
+We	O
+investigated	O
+the	O
+muscle	O
+pathology	O
+in	O
+8	O
+such	O
+cases	O
+.	O
+
+All	O
+had	O
+myofibre	O
+necrosis	B
+but	O
+only	O
+3	O
+had	O
+an	O
+inflammatory	O
+infiltrate	O
+.	O
+
+In	O
+all	O
+cases	O
+there	O
+was	O
+diffuse	O
+or	O
+multifocal	O
+up	O
+-	O
+regulation	O
+of	O
+MHC	O
+-	O
+I	O
+expression	O
+even	O
+in	O
+non	O
+-	O
+necrotic	B
+fibres	O
+.	O
+
+Progressive	O
+improvement	O
+occurred	O
+in	O
+7	O
+cases	O
+after	O
+commencement	O
+of	O
+prednisolone	O
+and	O
+methotrexate	O
+,	O
+and	O
+in	O
+one	O
+case	O
+spontaneously	O
+.	O
+
+These	O
+observations	O
+suggest	O
+that	O
+statins	O
+may	O
+initiate	O
+an	O
+immune	O
+-	O
+mediated	O
+myopathy	B
+that	O
+persists	O
+after	O
+withdrawal	O
+of	O
+the	O
+drug	O
+and	O
+responds	O
+to	O
+immunosuppressive	O
+therapy	O
+.	O
+
+The	O
+mechanism	O
+of	O
+this	O
+myopathy	B
+is	O
+uncertain	O
+but	O
+may	O
+involve	O
+the	O
+induction	O
+by	O
+statins	O
+of	O
+an	O
+endoplasmic	O
+reticulum	O
+stress	O
+response	O
+with	O
+associated	O
+up	O
+-	O
+regulation	O
+of	O
+MHC	O
+-	O
+I	O
+expression	O
+and	O
+antigen	O
+presentation	O
+by	O
+muscle	O
+fibres	O
+.	O
+
+Use	O
+of	O
+chromosome	O
+substitution	O
+strains	O
+to	O
+identify	O
+seizure	B
+susceptibility	O
+loci	O
+in	O
+mice	O
+.	O
+
+Seizure	B
+susceptibility	O
+varies	O
+among	O
+inbred	O
+mouse	O
+strains	O
+.	O
+
+Chromosome	O
+substitution	O
+strains	O
+(	O
+CSS	O
+)	O
+,	O
+in	O
+which	O
+a	O
+single	O
+chromosome	O
+from	O
+one	O
+inbred	O
+strain	O
+(	O
+donor	O
+)	O
+has	O
+been	O
+transferred	O
+onto	O
+a	O
+second	O
+strain	O
+(	O
+host	O
+)	O
+by	O
+repeated	O
+backcrossing	O
+,	O
+may	O
+be	O
+used	O
+to	O
+identify	O
+quantitative	O
+trait	O
+loci	O
+(	O
+QTLs	O
+)	O
+that	O
+contribute	O
+to	O
+seizure	B
+susceptibility	O
+.	O
+
+QTLs	O
+for	O
+susceptibility	O
+to	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+,	O
+a	O
+model	O
+of	O
+temporal	B
+lobe	I
+epilepsy	I
+,	O
+have	O
+not	O
+been	O
+reported	O
+,	O
+and	O
+CSS	O
+have	O
+not	O
+previously	O
+been	O
+used	O
+to	O
+localize	O
+seizure	B
+susceptibility	O
+genes	O
+.	O
+
+We	O
+report	O
+QTLs	O
+identified	O
+using	O
+a	O
+B6	O
+(	O
+host	O
+)	O
+x	O
+A	O
+/	O
+J	O
+(	O
+donor	O
+)	O
+CSS	O
+panel	O
+to	O
+localize	O
+genes	O
+involved	O
+in	O
+susceptibility	O
+to	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+.	O
+
+Three	O
+hundred	O
+fifty	O
+-	O
+five	O
+adult	O
+male	O
+CSS	O
+mice	O
+,	O
+58	O
+B6	O
+,	O
+and	O
+39	O
+A	O
+/	O
+J	O
+were	O
+tested	O
+for	O
+susceptibility	O
+to	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+.	O
+
+Highest	O
+stage	O
+reached	O
+and	O
+latency	O
+to	O
+each	O
+stage	O
+were	O
+recorded	O
+for	O
+all	O
+mice	O
+.	O
+
+B6	O
+mice	O
+were	O
+resistant	O
+to	O
+seizures	B
+and	O
+slower	O
+to	O
+reach	O
+stages	O
+compared	O
+to	O
+A	O
+/	O
+J	O
+mice	O
+.	O
+
+The	O
+CSS	O
+for	O
+Chromosomes	O
+10	O
+and	O
+18	O
+progressed	O
+to	O
+the	O
+most	O
+severe	O
+stages	O
+,	O
+diverging	O
+dramatically	O
+from	O
+the	O
+B6	O
+phenotype	O
+.	O
+
+Latencies	O
+to	O
+stages	O
+were	O
+also	O
+significantly	O
+shorter	O
+for	O
+CSS10	O
+and	O
+CSS18	O
+mice	O
+.	O
+
+CSS	O
+mapping	O
+suggests	O
+seizure	B
+susceptibility	O
+loci	O
+on	O
+mouse	O
+Chromosomes	O
+10	O
+and	O
+18	O
+.	O
+
+This	O
+approach	O
+provides	O
+a	O
+framework	O
+for	O
+identifying	O
+potentially	O
+novel	O
+homologous	O
+candidate	O
+genes	O
+for	O
+human	O
+temporal	B
+lobe	I
+epilepsy	I
+.	O
+
+In	O
+vitro	O
+characterization	O
+of	O
+parasympathetic	O
+and	O
+sympathetic	O
+responses	O
+in	O
+cyclophosphamide	O
+-	O
+induced	O
+cystitis	B
+in	O
+the	O
+rat	O
+.	O
+
+In	O
+cyclophosphamide	O
+-	O
+induced	O
+cystitis	B
+in	O
+the	O
+rat	O
+,	O
+detrusor	O
+function	O
+is	O
+impaired	O
+and	O
+the	O
+expression	O
+and	O
+effects	O
+of	O
+muscarinic	O
+receptors	O
+altered	O
+.	O
+
+Whether	O
+or	O
+not	O
+the	O
+neuronal	O
+transmission	O
+may	O
+be	O
+affected	O
+by	O
+cystitis	B
+was	O
+presently	O
+investigated	O
+.	O
+
+Responses	O
+of	O
+urinary	O
+strip	O
+preparations	O
+from	O
+control	O
+and	O
+cyclophosphamide	O
+-	O
+pretreated	O
+rats	O
+to	O
+electrical	O
+field	O
+stimulation	O
+and	O
+to	O
+agonists	O
+were	O
+assessed	O
+in	O
+the	O
+absence	O
+and	O
+presence	O
+of	O
+muscarinic	O
+,	O
+adrenergic	O
+and	O
+purinergic	O
+receptor	O
+antagonists	O
+.	O
+
+Generally	O
+,	O
+atropine	O
+reduced	O
+contractions	O
+,	O
+but	O
+in	O
+contrast	O
+to	O
+controls	O
+,	O
+it	O
+also	O
+reduced	O
+responses	O
+to	O
+low	O
+electrical	O
+field	O
+stimulation	O
+intensity	O
+(	O
+1	O
+-	O
+5	O
+Hz	O
+)	O
+in	O
+inflamed	O
+preparations	O
+.	O
+
+In	O
+both	O
+types	O
+,	O
+purinoceptor	O
+desensitization	O
+with	O
+alpha	O
+,	O
+beta	O
+-	O
+methylene	O
+adenosine	O
+-	O
+5	O
+'	O
+-	O
+triphosphate	O
+(	O
+alpha	O
+,	O
+beta	O
+-	O
+meATP	O
+)	O
+caused	O
+further	O
+reductions	O
+at	O
+low	O
+frequencies	O
+(	O
+<	O
+10	O
+Hz	O
+)	O
+.	O
+
+The	O
+muscarinic	O
+receptor	O
+antagonists	O
+atropine	O
+,	O
+4	O
+-	O
+diphenylacetoxy	O
+-	O
+N	O
+-	O
+methylpiperidine	O
+(	O
+4	O
+-	O
+DAMP	O
+)	O
+(	O
+'	O
+M	O
+(	O
+1	O
+)	O
+/	O
+M	O
+(	O
+3	O
+)	O
+/	O
+M	O
+(	O
+5	O
+)	O
+-	O
+selective	O
+'	O
+)	O
+,	O
+methoctramine	O
+(	O
+'	O
+M	O
+(	O
+2	O
+)	O
+-	O
+selective	O
+'	O
+)	O
+and	O
+pirenzepine	O
+(	O
+'	O
+M	O
+(	O
+1	O
+)	O
+-	O
+selective	O
+'	O
+)	O
+antagonized	O
+the	O
+tonic	O
+component	O
+of	O
+the	O
+electrical	O
+field	O
+stimulation	O
+-	O
+evoked	O
+contractile	O
+response	O
+more	O
+potently	O
+than	O
+the	O
+phasic	O
+component	O
+.	O
+
+4	O
+-	O
+DAMP	O
+inhibited	O
+the	O
+tonic	O
+contractions	O
+in	O
+controls	O
+more	O
+potently	O
+than	O
+methoctramine	O
+and	O
+pirenzepine	O
+.	O
+
+In	O
+inflamed	O
+preparations	O
+,	O
+the	O
+muscarinic	O
+receptor	O
+antagonism	O
+on	O
+the	O
+phasic	O
+component	O
+of	O
+the	O
+electrical	O
+field	O
+stimulation	O
+-	O
+evoked	O
+contraction	O
+was	O
+decreased	O
+and	O
+the	O
+pirenzepine	O
+and	O
+4	O
+-	O
+DAMP	O
+antagonism	O
+on	O
+the	O
+tonic	O
+component	O
+was	O
+much	O
+less	O
+efficient	O
+than	O
+in	O
+controls	O
+.	O
+
+In	O
+contrast	O
+to	O
+controls	O
+,	O
+methoctramine	O
+increased	O
+-	O
+-	O
+instead	O
+of	O
+decreased	O
+-	O
+-	O
+the	O
+tonic	O
+responses	O
+at	O
+high	O
+frequencies	O
+.	O
+
+While	O
+contractions	O
+to	O
+carbachol	O
+and	O
+ATP	O
+were	O
+the	O
+same	O
+in	O
+inflamed	O
+and	O
+in	O
+control	O
+strips	O
+when	O
+related	O
+to	O
+a	O
+reference	O
+potassium	O
+response	O
+,	O
+isoprenaline	O
+-	O
+induced	O
+relaxations	O
+were	O
+smaller	O
+in	O
+inflamed	O
+strips	O
+.	O
+
+Thus	O
+,	O
+in	O
+cystitis	B
+substantial	O
+changes	O
+of	O
+the	O
+efferent	O
+functional	O
+responses	O
+occur	O
+.	O
+
+While	O
+postjunctional	O
+beta	O
+-	O
+adrenoceptor	O
+-	O
+mediated	O
+relaxations	O
+are	O
+reduced	O
+,	O
+effects	O
+by	O
+prejunctional	O
+inhibitory	O
+muscarinic	O
+receptors	O
+may	O
+be	O
+increased	O
+.	O
+
+Direct	O
+inhibition	O
+of	O
+cardiac	O
+hyperpolarization	O
+-	O
+activated	O
+cyclic	O
+nucleotide	O
+-	O
+gated	O
+pacemaker	O
+channels	O
+by	O
+clonidine	O
+.	O
+
+BACKGROUND	O
+:	O
+Inhibition	O
+of	O
+cardiac	O
+sympathetic	O
+tone	O
+represents	O
+an	O
+important	O
+strategy	O
+for	O
+treatment	O
+of	O
+cardiovascular	B
+disease	I
+,	O
+including	O
+arrhythmia	B
+,	O
+coronary	B
+heart	I
+disease	I
+,	O
+and	O
+chronic	O
+heart	B
+failure	I
+.	O
+
+Activation	O
+of	O
+presynaptic	O
+alpha2	O
+-	O
+adrenoceptors	O
+is	O
+the	O
+most	O
+widely	O
+accepted	O
+mechanism	O
+of	O
+action	O
+of	O
+the	O
+antisympathetic	O
+drug	O
+clonidine	O
+;	O
+however	O
+,	O
+other	O
+target	O
+proteins	O
+have	O
+been	O
+postulated	O
+to	O
+contribute	O
+to	O
+the	O
+in	O
+vivo	O
+actions	O
+of	O
+clonidine	O
+.	O
+
+METHODS	O
+AND	O
+RESULTS	O
+:	O
+To	O
+test	O
+whether	O
+clonidine	O
+elicits	O
+pharmacological	O
+effects	O
+independent	O
+of	O
+alpha2	O
+-	O
+adrenoceptors	O
+,	O
+we	O
+have	O
+generated	O
+mice	O
+with	O
+a	O
+targeted	O
+deletion	O
+of	O
+all	O
+3	O
+alpha2	O
+-	O
+adrenoceptor	O
+subtypes	O
+(	O
+alpha2ABC	O
+-	O
+/	O
+-	O
+)	O
+.	O
+
+Alpha2ABC	O
+-	O
+/	O
+-	O
+mice	O
+were	O
+completely	O
+unresponsive	O
+to	O
+the	O
+analgesic	O
+and	O
+hypnotic	O
+effects	O
+of	O
+clonidine	O
+;	O
+however	O
+,	O
+clonidine	O
+significantly	O
+lowered	O
+heart	O
+rate	O
+in	O
+alpha2ABC	O
+-	O
+/	O
+-	O
+mice	O
+by	O
+up	O
+to	O
+150	O
+bpm	O
+.	O
+
+Clonidine	O
+-	O
+induced	O
+bradycardia	B
+in	O
+conscious	O
+alpha2ABC	O
+-	O
+/	O
+-	O
+mice	O
+was	O
+32	O
+.	O
+3	O
+%	O
+(	O
+10	O
+microg	O
+/	O
+kg	O
+)	O
+and	O
+26	O
+.	O
+6	O
+%	O
+(	O
+100	O
+microg	O
+/	O
+kg	O
+)	O
+of	O
+the	O
+effect	O
+in	O
+wild	O
+-	O
+type	O
+mice	O
+.	O
+
+A	O
+similar	O
+bradycardic	O
+effect	O
+of	O
+clonidine	O
+was	O
+observed	O
+in	O
+isolated	O
+spontaneously	O
+beating	O
+right	O
+atria	O
+from	O
+alpha2ABC	O
+-	O
+knockout	O
+and	O
+wild	O
+-	O
+type	O
+mice	O
+.	O
+
+Clonidine	O
+inhibited	O
+the	O
+native	O
+pacemaker	O
+current	O
+(	O
+I	O
+(	O
+f	O
+)	O
+)	O
+in	O
+isolated	O
+sinoatrial	O
+node	O
+pacemaker	O
+cells	O
+and	O
+the	O
+I	O
+(	O
+f	O
+)	O
+-	O
+generating	O
+hyperpolarization	O
+-	O
+activated	O
+cyclic	O
+nucleotide	O
+-	O
+gated	O
+(	O
+HCN	O
+)	O
+2	O
+and	O
+HCN4	O
+channels	O
+in	O
+transfected	O
+HEK293	O
+cells	O
+.	O
+
+As	O
+a	O
+consequence	O
+of	O
+blocking	O
+I	O
+(	O
+f	O
+)	O
+,	O
+clonidine	O
+reduced	O
+the	O
+slope	O
+of	O
+the	O
+diastolic	O
+depolarization	O
+and	O
+the	O
+frequency	O
+of	O
+pacemaker	O
+potentials	O
+in	O
+sinoatrial	O
+node	O
+cells	O
+from	O
+wild	O
+-	O
+type	O
+and	O
+alpha2ABC	O
+-	O
+knockout	O
+mice	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Direct	O
+inhibition	O
+of	O
+cardiac	O
+HCN	O
+pacemaker	O
+channels	O
+contributes	O
+to	O
+the	O
+bradycardic	O
+effects	O
+of	O
+clonidine	O
+gene	O
+-	O
+targeted	O
+mice	O
+in	O
+vivo	O
+,	O
+and	O
+thus	O
+,	O
+clonidine	O
+-	O
+like	O
+drugs	O
+represent	O
+novel	O
+structures	O
+for	O
+future	O
+HCN	O
+channel	O
+inhibitors	O
+.	O
+
+Granulomatous	B
+hepatitis	I
+due	O
+to	O
+combination	O
+of	O
+amoxicillin	O
+and	O
+clavulanic	O
+acid	O
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+patient	O
+with	O
+amoxicillin	O
+-	O
+clavulanic	O
+acid	O
+-	O
+induced	O
+hepatitis	B
+with	O
+histologic	O
+multiple	O
+granulomas	B
+.	O
+
+This	O
+type	O
+of	O
+lesion	O
+broadens	O
+the	O
+spectrum	O
+of	O
+liver	B
+injury	I
+due	O
+to	O
+this	O
+drug	O
+combination	O
+,	O
+mainly	O
+represented	O
+by	O
+a	O
+benign	O
+cholestatic	B
+syndrome	I
+.	O
+
+The	O
+association	O
+of	O
+granulomas	B
+and	O
+eosinophilia	B
+favor	O
+an	O
+immunoallergic	O
+mechanism	O
+.	O
+
+As	O
+penicillin	O
+derivatives	O
+and	O
+amoxicillin	O
+alone	O
+are	O
+known	O
+to	O
+induce	O
+such	O
+types	O
+of	O
+lesions	O
+,	O
+the	O
+amoxicillin	O
+component	O
+,	O
+with	O
+or	O
+without	O
+a	O
+potentiating	O
+effect	O
+of	O
+clavulanic	O
+acid	O
+,	O
+might	O
+have	O
+a	O
+major	O
+role	O
+.	O
+
+Dobutamine	O
+stress	O
+echocardiography	O
+:	O
+a	O
+sensitive	O
+indicator	O
+of	O
+diminished	O
+myocardial	O
+function	O
+in	O
+asymptomatic	O
+doxorubicin	O
+-	O
+treated	O
+long	O
+-	O
+term	O
+survivors	O
+of	O
+childhood	O
+cancer	B
+.	O
+
+Doxorubicin	O
+is	O
+an	O
+effective	O
+anticancer	O
+chemotherapeutic	O
+agent	O
+known	O
+to	O
+cause	O
+acute	O
+and	O
+chronic	O
+cardiomyopathy	B
+.	O
+
+To	O
+develop	O
+a	O
+more	O
+sensitive	O
+echocardiographic	O
+screening	O
+test	O
+for	O
+cardiac	B
+damage	I
+due	O
+to	O
+doxorubicin	O
+,	O
+a	O
+cohort	O
+study	O
+was	O
+performed	O
+using	O
+dobutamine	O
+infusion	O
+to	O
+differentiate	O
+asymptomatic	O
+long	O
+-	O
+term	O
+survivors	O
+of	O
+childhood	O
+cancer	B
+treated	O
+with	O
+doxorubicin	O
+from	O
+healthy	O
+control	O
+subjects	O
+.	O
+
+Echocardiographic	O
+data	O
+from	O
+the	O
+experimental	O
+group	O
+of	O
+21	O
+patients	O
+(	O
+mean	O
+age	O
+16	O
++	O
+/	O
+-	O
+5	O
+years	O
+)	O
+treated	O
+from	O
+1	O
+.	O
+6	O
+to	O
+14	O
+.	O
+3	O
+years	O
+(	O
+median	O
+5	O
+.	O
+3	O
+)	O
+before	O
+this	O
+study	O
+with	O
+27	O
+to	O
+532	O
+mg	O
+/	O
+m2	O
+of	O
+doxorubicin	O
+(	O
+mean	O
+196	O
+)	O
+were	O
+compared	O
+with	O
+echocardiographic	O
+data	O
+from	O
+12	O
+normal	O
+age	O
+-	O
+matched	O
+control	O
+subjects	O
+.	O
+
+Graded	O
+dobutamine	O
+infusions	O
+of	O
+0	O
+.	O
+5	O
+,	O
+2	O
+.	O
+5	O
+,	O
+5	O
+and	O
+10	O
+micrograms	O
+/	O
+kg	O
+per	O
+min	O
+were	O
+administered	O
+.	O
+
+Echocardiographic	O
+Doppler	O
+studies	O
+were	O
+performed	O
+before	O
+infusion	O
+and	O
+after	O
+15	O
+min	O
+of	O
+infusion	O
+at	O
+each	O
+rate	O
+.	O
+
+Dobutamine	O
+infusion	O
+at	O
+10	O
+micrograms	O
+/	O
+kg	O
+per	O
+min	O
+was	O
+discontinued	O
+after	O
+six	O
+studies	O
+secondary	O
+to	O
+a	O
+50	O
+%	O
+incidence	O
+rate	O
+of	O
+adverse	O
+symptoms	O
+.	O
+
+The	O
+most	O
+important	O
+findings	O
+were	O
+that	O
+compared	O
+with	O
+values	O
+in	O
+control	O
+subjects	O
+,	O
+end	O
+-	O
+systolic	O
+left	O
+ventricular	O
+posterior	O
+wall	O
+dimension	O
+and	O
+percent	O
+of	O
+left	O
+ventricular	O
+posterior	O
+wall	O
+thickening	O
+in	O
+doxorubicin	O
+-	O
+treated	O
+patients	O
+were	O
+decreased	O
+at	O
+baseline	O
+study	O
+and	O
+these	O
+findings	O
+were	O
+more	O
+clearly	O
+delineated	O
+with	O
+dobutamine	O
+stimulation	O
+.	O
+
+End	O
+-	O
+systolic	O
+left	O
+ventricular	O
+posterior	O
+wall	O
+dimension	O
+at	O
+baseline	O
+for	O
+the	O
+doxorubicin	O
+-	O
+treated	O
+group	O
+was	O
+11	O
++	O
+/	O
+-	O
+1	O
+.	O
+9	O
+mm	O
+versus	O
+13	O
+.	O
+1	O
++	O
+/	O
+-	O
+1	O
+.	O
+5	O
+mm	O
+for	O
+control	O
+subjects	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+End	O
+-	O
+systolic	O
+left	O
+ventricular	O
+posterior	O
+wall	O
+dimension	O
+at	O
+the	O
+5	O
+-	O
+micrograms	O
+/	O
+kg	O
+per	O
+min	O
+dobutamine	O
+infusion	O
+for	O
+the	O
+doxorubicin	O
+-	O
+treated	O
+group	O
+was	O
+14	O
+.	O
+1	O
++	O
+/	O
+-	O
+2	O
+.	O
+4	O
+mm	O
+versus	O
+19	O
+.	O
+3	O
++	O
+/	O
+-	O
+2	O
+.	O
+6	O
+mm	O
+for	O
+control	O
+subjects	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Influence	O
+of	O
+smoking	O
+on	O
+developing	O
+cochlea	O
+.	O
+
+Does	O
+smoking	O
+during	O
+pregnancy	O
+affect	O
+the	O
+amplitudes	O
+of	O
+transient	O
+evoked	O
+otoacoustic	O
+emissions	O
+in	O
+newborns	O
+?	O
+
+OBJECTIVE	O
+:	O
+Maternal	O
+tobacco	O
+smoking	O
+has	O
+negative	O
+effects	O
+on	O
+fetal	O
+growth	O
+.	O
+
+The	O
+influence	O
+of	O
+smoking	O
+during	O
+pregnancy	O
+on	O
+the	O
+developing	O
+cochlea	O
+has	O
+not	O
+been	O
+estimated	O
+,	O
+although	O
+smoking	O
+has	O
+been	O
+positively	O
+associated	O
+with	O
+hearing	B
+loss	I
+in	O
+adults	O
+.	O
+
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+effects	O
+of	O
+maternal	O
+smoking	O
+on	O
+transient	O
+evoked	O
+otoacoustic	O
+emissions	O
+(	O
+TEOAEs	O
+)	O
+of	O
+healthy	O
+neonates	O
+.	O
+
+METHODS	O
+:	O
+This	O
+study	O
+was	O
+undertaken	O
+as	O
+part	O
+of	O
+neonatal	O
+screening	O
+for	O
+hearing	B
+impairment	I
+and	O
+involved	O
+both	O
+ears	O
+of	O
+200	O
+newborns	O
+.	O
+
+Newborns	O
+whose	O
+mothers	O
+reported	O
+smoking	O
+during	O
+pregnancy	O
+(	O
+n	O
+=	O
+200	O
+ears	O
+)	O
+were	O
+compared	O
+to	O
+a	O
+control	O
+group	O
+of	O
+newborns	O
+(	O
+n	O
+=	O
+200	O
+ears	O
+)	O
+,	O
+whose	O
+mothers	O
+were	O
+non	O
+-	O
+smokers	O
+.	O
+
+Exposure	O
+to	O
+tobacco	O
+was	O
+characterized	O
+as	O
+low	O
+(	O
+<	O
+5	O
+cigarettes	O
+per	O
+day	O
+,	O
+n	O
+=	O
+88	O
+ears	O
+)	O
+,	O
+moderate	O
+(	O
+5	O
+<	O
+or	O
+=	O
+cigarettes	O
+per	O
+day	O
+<	O
+10	O
+,	O
+n	O
+=	O
+76	O
+)	O
+or	O
+high	O
+(	O
+>	O
+or	O
+=	O
+10	O
+cigarettes	O
+per	O
+day	O
+,	O
+n	O
+=	O
+36	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+In	O
+exposed	O
+neonates	O
+,	O
+TEOAEs	O
+mean	O
+response	O
+(	O
+across	O
+frequency	O
+)	O
+and	O
+mean	O
+amplitude	O
+at	O
+4000Hz	O
+was	O
+significantly	O
+lower	O
+than	O
+in	O
+non	O
+-	O
+exposed	O
+neonates	O
+.	O
+
+Comparisons	O
+between	O
+exposed	O
+newborns	O
+'	O
+subgroups	O
+revealed	O
+no	O
+significant	O
+differences	O
+.	O
+
+However	O
+,	O
+by	O
+comparing	O
+each	O
+subgroup	O
+to	O
+control	O
+group	O
+,	O
+we	O
+found	O
+statistically	O
+significant	O
+decreases	B
+of	I
+TEOAEs	I
+amplitudes	I
+at	O
+4000Hz	O
+for	O
+all	O
+three	O
+groups	O
+.	O
+
+Mean	O
+TEOAEs	O
+responses	O
+of	O
+highly	O
+exposed	O
+newborns	O
+were	O
+also	O
+significantly	O
+lower	O
+in	O
+comparison	O
+to	O
+our	O
+control	O
+group	O
+.	O
+
+CONCLUSION	O
+:	O
+In	O
+utero	O
+,	O
+exposure	O
+to	O
+tobacco	O
+smoking	O
+seems	O
+to	O
+have	O
+a	O
+small	O
+impact	O
+on	O
+outer	O
+hair	O
+cells	O
+.	O
+
+These	O
+effects	O
+seem	O
+to	O
+be	O
+equally	O
+true	O
+for	O
+all	O
+exposed	O
+newborns	O
+,	O
+regardless	O
+of	O
+the	O
+degree	O
+of	O
+exposure	O
+.	O
+
+Further	O
+studies	O
+are	O
+needed	O
+in	O
+order	O
+to	O
+establish	O
+a	O
+potential	O
+negative	O
+effect	O
+of	O
+maternal	O
+smoking	O
+on	O
+the	O
+neonate	O
+'	O
+s	O
+hearing	O
+acuity	O
+.	O
+
+Simvastatin	O
+-	O
+induced	O
+bilateral	O
+leg	O
+compartment	B
+syndrome	I
+and	O
+myonecrosis	B
+associated	O
+with	O
+hypothyroidism	B
+.	O
+
+A	O
+54	O
+-	O
+year	O
+-	O
+old	O
+hypothyroid	B
+male	O
+taking	O
+thyroxine	O
+and	O
+simvastatin	O
+presented	O
+with	O
+bilateral	O
+leg	O
+compartment	B
+syndrome	I
+and	O
+myonecrosis	B
+.	O
+
+Urgent	O
+fasciotomies	O
+were	O
+performed	O
+and	O
+the	O
+patient	O
+made	O
+an	O
+uneventful	O
+recovery	O
+with	O
+the	O
+withdrawal	O
+of	O
+simvastatin	O
+.	O
+
+It	O
+is	O
+likely	O
+that	O
+this	O
+complication	O
+will	O
+be	O
+seen	O
+more	O
+often	O
+with	O
+the	O
+increased	O
+worldwide	O
+use	O
+of	O
+this	O
+drug	O
+and	O
+its	O
+approval	O
+for	O
+all	O
+arteriopathic	B
+patients	O
+.	O
+
+Neuroinflammation	B
+and	O
+behavioral	B
+abnormalities	I
+after	O
+neonatal	O
+terbutaline	O
+treatment	O
+in	O
+rats	O
+:	O
+implications	O
+for	O
+autism	B
+.	O
+
+Autism	B
+is	O
+a	O
+neurodevelopmental	B
+disorder	I
+presenting	O
+before	O
+3	O
+years	O
+of	O
+age	O
+with	O
+deficits	B
+in	I
+communication	I
+and	I
+social	I
+skills	I
+and	O
+repetitive	B
+behaviors	I
+.	O
+
+In	O
+addition	O
+to	O
+genetic	O
+influences	O
+,	O
+recent	O
+studies	O
+suggest	O
+that	O
+prenatal	O
+drug	O
+or	O
+chemical	O
+exposures	O
+are	O
+risk	O
+factors	O
+for	O
+autism	B
+.	O
+
+Terbutaline	O
+,	O
+a	O
+beta2	O
+-	O
+adrenoceptor	O
+agonist	O
+used	O
+to	O
+arrest	O
+preterm	B
+labor	I
+,	O
+has	O
+been	O
+associated	O
+with	O
+increased	O
+concordance	O
+for	O
+autism	B
+in	O
+dizygotic	O
+twins	O
+.	O
+
+We	O
+studied	O
+the	O
+effects	O
+of	O
+terbutaline	O
+on	O
+microglial	O
+activation	O
+in	O
+different	O
+brain	O
+regions	O
+and	O
+behavioral	O
+outcomes	O
+in	O
+developing	O
+rats	O
+.	O
+
+Newborn	O
+rats	O
+were	O
+given	O
+terbutaline	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+daily	O
+on	O
+postnatal	O
+days	O
+(	O
+PN	O
+)	O
+2	O
+to	O
+5	O
+or	O
+PN	O
+11	O
+to	O
+14	O
+and	O
+examined	O
+24	O
+h	O
+after	O
+the	O
+last	O
+dose	O
+and	O
+at	O
+PN	O
+30	O
+.	O
+
+Immunohistochemical	O
+studies	O
+showed	O
+that	O
+administration	O
+of	O
+terbutaline	O
+on	O
+PN	O
+2	O
+to	O
+5	O
+produced	O
+a	O
+robust	O
+increase	O
+in	O
+microglial	O
+activation	O
+on	O
+PN	O
+30	O
+in	O
+the	O
+cerebral	O
+cortex	O
+,	O
+as	O
+well	O
+as	O
+in	O
+cerebellar	O
+and	O
+cerebrocortical	O
+white	O
+matter	O
+.	O
+
+None	O
+of	O
+these	O
+effects	O
+occurred	O
+in	O
+animals	O
+given	O
+terbutaline	O
+on	O
+PN	O
+11	O
+to	O
+14	O
+.	O
+
+In	O
+behavioral	O
+tests	O
+,	O
+animals	O
+treated	O
+with	O
+terbutaline	O
+on	O
+PN	O
+2	O
+to	O
+5	O
+showed	O
+consistent	O
+patterns	O
+of	O
+hyper	O
+-	O
+reactivity	O
+to	O
+novelty	O
+and	O
+aversive	O
+stimuli	O
+when	O
+assessed	O
+in	O
+a	O
+novel	O
+open	O
+field	O
+,	O
+as	O
+well	O
+as	O
+in	O
+the	O
+acoustic	O
+startle	O
+response	O
+test	O
+.	O
+
+Our	O
+findings	O
+indicate	O
+that	O
+beta2	O
+-	O
+adrenoceptor	O
+overstimulation	O
+during	O
+an	O
+early	O
+critical	O
+period	O
+results	O
+in	O
+microglial	O
+activation	O
+associated	O
+with	O
+innate	O
+neuroinflammatory	O
+pathways	O
+and	O
+behavioral	B
+abnormalities	I
+,	O
+similar	O
+to	O
+those	O
+described	O
+in	O
+autism	B
+.	O
+
+This	O
+study	O
+provides	O
+a	O
+useful	O
+animal	O
+model	O
+for	O
+understanding	O
+the	O
+neuropathological	O
+processes	O
+underlying	O
+autism	B
+spectrum	I
+disorders	I
+.	O
+
+Upregulation	O
+of	O
+brain	O
+expression	O
+of	O
+P	O
+-	O
+glycoprotein	O
+in	O
+MRP2	O
+-	O
+deficient	O
+TR	O
+(	O
+-	O
+)	O
+rats	O
+resembles	O
+seizure	B
+-	O
+induced	O
+up	O
+-	O
+regulation	O
+of	O
+this	O
+drug	O
+efflux	O
+transporter	O
+in	O
+normal	O
+rats	O
+.	O
+
+PURPOSE	O
+:	O
+The	O
+multidrug	O
+resistance	O
+protein	O
+2	O
+(	O
+MRP2	O
+)	O
+is	O
+a	O
+drug	O
+efflux	O
+transporter	O
+that	O
+is	O
+expressed	O
+predominantly	O
+at	O
+the	O
+apical	O
+domain	O
+of	O
+hepatocytes	O
+but	O
+seems	O
+also	O
+to	O
+be	O
+expressed	O
+at	O
+the	O
+apical	O
+membrane	O
+of	O
+brain	O
+capillary	O
+endothelial	O
+cells	O
+that	O
+form	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+(	O
+BBB	O
+)	O
+.	O
+
+MRP2	O
+is	O
+absent	O
+in	O
+the	O
+transport	O
+-	O
+deficient	O
+(	O
+TR	O
+(	O
+-	O
+)	O
+)	O
+Wistar	O
+rat	O
+mutant	O
+,	O
+so	O
+that	O
+this	O
+rat	O
+strain	O
+was	O
+very	O
+helpful	O
+in	O
+defining	O
+substrates	O
+of	O
+MRP2	O
+by	O
+comparing	O
+tissue	O
+concentrations	O
+or	O
+functional	O
+activities	O
+of	O
+compounds	O
+in	O
+MRP2	O
+-	O
+deficient	O
+rats	O
+with	O
+those	O
+in	O
+transport	O
+-	O
+competent	O
+Wistar	O
+rats	O
+.	O
+
+By	O
+using	O
+this	O
+strategy	O
+to	O
+study	O
+the	O
+involvement	O
+of	O
+MRP2	O
+in	O
+brain	O
+access	O
+of	O
+antiepileptic	O
+drugs	O
+(	O
+AEDs	O
+)	O
+,	O
+we	O
+recently	O
+reported	O
+that	O
+phenytoin	O
+is	O
+a	O
+substrate	O
+for	O
+MRP2	O
+in	O
+the	O
+BBB	O
+.	O
+
+However	O
+,	O
+one	O
+drawback	O
+of	O
+such	O
+studies	O
+in	O
+genetically	O
+deficient	O
+rats	O
+is	O
+the	O
+fact	O
+that	O
+compensatory	O
+changes	O
+with	O
+upregulation	O
+of	O
+other	O
+transporters	O
+can	O
+occur	O
+.	O
+
+This	O
+prompted	O
+us	O
+to	O
+study	O
+the	O
+brain	O
+expression	O
+of	O
+P	O
+-	O
+glycoprotein	O
+(	O
+Pgp	O
+)	O
+,	O
+a	O
+major	O
+drug	O
+efflux	O
+transporter	O
+in	O
+many	O
+tissues	O
+,	O
+including	O
+the	O
+BBB	O
+,	O
+in	O
+TR	O
+(	O
+-	O
+)	O
+rats	O
+compared	O
+with	O
+nonmutant	O
+(	O
+wild	O
+-	O
+type	O
+)	O
+Wistar	O
+rats	O
+.	O
+
+METHODS	O
+:	O
+The	O
+expression	O
+of	O
+MRP2	O
+and	O
+Pgp	O
+in	O
+brain	O
+and	O
+liver	O
+sections	O
+of	O
+TR	O
+(	O
+-	O
+)	O
+rats	O
+and	O
+normal	O
+Wistar	O
+rats	O
+was	O
+determined	O
+with	O
+immunohistochemistry	O
+,	O
+by	O
+using	O
+a	O
+novel	O
+,	O
+highly	O
+selective	O
+monoclonal	O
+MRP2	O
+antibody	O
+and	O
+the	O
+monoclonal	O
+Pgp	O
+antibody	O
+C219	O
+,	O
+respectively	O
+.	O
+
+RESULTS	O
+:	O
+Immunofluorescence	O
+staining	O
+with	O
+the	O
+MRP2	O
+antibody	O
+was	O
+found	O
+to	O
+label	O
+a	O
+high	O
+number	O
+of	O
+microvessels	O
+throughout	O
+the	O
+brain	O
+in	O
+normal	O
+Wistar	O
+rats	O
+,	O
+whereas	O
+such	O
+labeling	O
+was	O
+absent	O
+in	O
+TR	O
+(	O
+-	O
+)	O
+rats	O
+.	O
+
+TR	O
+(	O
+-	O
+)	O
+rats	O
+exhibited	O
+a	O
+significant	O
+up	O
+-	O
+regulation	O
+of	O
+Pgp	O
+in	O
+brain	O
+capillary	O
+endothelial	O
+cells	O
+compared	O
+with	O
+wild	O
+-	O
+type	O
+controls	O
+.	O
+
+No	O
+such	O
+obvious	O
+upregulation	O
+of	O
+Pgp	O
+was	O
+observed	O
+in	O
+liver	O
+sections	O
+.	O
+
+A	O
+comparable	O
+overexpression	O
+of	O
+Pgp	O
+in	O
+the	O
+BBB	O
+was	O
+obtained	O
+after	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+in	O
+wild	O
+-	O
+type	O
+Wistar	O
+rats	O
+.	O
+
+Experiments	O
+with	O
+systemic	O
+administration	O
+of	O
+the	O
+Pgp	O
+substrate	O
+phenobarbital	O
+and	O
+the	O
+selective	O
+Pgp	O
+inhibitor	O
+tariquidar	O
+in	O
+TR	O
+(	O
+-	O
+)	O
+rats	O
+substantiated	O
+that	O
+Pgp	O
+is	O
+functional	O
+and	O
+compensates	O
+for	O
+the	O
+lack	O
+of	O
+MRP2	O
+in	O
+the	O
+BBB	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+data	O
+on	O
+TR	O
+(	O
+-	O
+)	O
+rats	O
+indicate	O
+that	O
+Pgp	O
+plays	O
+an	O
+important	O
+role	O
+in	O
+the	O
+compensation	O
+of	O
+MRP2	O
+deficiency	O
+in	O
+the	O
+BBB	O
+.	O
+
+Because	O
+such	O
+a	O
+compensatory	O
+mechanism	O
+most	O
+likely	O
+occurs	O
+to	O
+reduce	O
+injury	B
+to	I
+the	I
+brain	I
+from	O
+cytotoxic	O
+compounds	O
+,	O
+the	O
+present	O
+data	O
+substantiate	O
+the	O
+concept	O
+that	O
+MRP2	O
+performs	O
+a	O
+protective	O
+role	O
+in	O
+the	O
+BBB	O
+.	O
+
+Furthermore	O
+,	O
+our	O
+data	O
+suggest	O
+that	O
+TR	O
+(	O
+-	O
+)	O
+rats	O
+are	O
+an	O
+interesting	O
+tool	O
+to	O
+study	O
+consequences	O
+of	O
+overexpression	O
+of	O
+Pgp	O
+in	O
+the	O
+BBB	O
+on	O
+access	O
+of	O
+drugs	O
+in	O
+the	O
+brain	O
+,	O
+without	O
+the	O
+need	O
+of	O
+inducing	O
+seizures	B
+or	O
+other	O
+Pgp	O
+-	O
+enhancing	O
+events	O
+for	O
+this	O
+purpose	O
+.	O
+
+Role	O
+of	O
+xanthine	O
+oxidase	O
+in	O
+dexamethasone	O
+-	O
+induced	O
+hypertension	B
+in	O
+rats	O
+.	O
+
+1	O
+.	O
+
+Glucocorticoid	O
+-	O
+induced	O
+hypertension	B
+(	O
+GC	O
+-	O
+HT	B
+)	O
+in	O
+the	O
+rat	O
+is	O
+associated	O
+with	O
+nitric	O
+oxide	O
+-	O
+redox	O
+imbalance	O
+.	O
+
+2	O
+.	O
+
+We	O
+studied	O
+the	O
+role	O
+of	O
+xanthine	O
+oxidase	O
+(	O
+XO	O
+)	O
+,	O
+which	O
+is	O
+implicated	O
+in	O
+the	O
+production	O
+of	O
+reactive	O
+oxygen	O
+species	O
+,	O
+in	O
+dexamethasone	O
+-	O
+induced	O
+hypertension	B
+(	O
+dex	O
+-	O
+HT	B
+)	O
+.	O
+
+3	O
+.	O
+
+Thirty	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+were	O
+divided	O
+randomly	O
+into	O
+four	O
+treatment	O
+groups	O
+:	O
+saline	O
+,	O
+dexamethasone	O
+(	O
+dex	O
+)	O
+,	O
+allopurinol	O
+plus	O
+saline	O
+,	O
+and	O
+allopurinol	O
+plus	O
+dex	O
+.	O
+
+4	O
+.	O
+
+Systolic	O
+blood	O
+pressures	O
+(	O
+SBP	O
+)	O
+and	O
+bodyweights	O
+were	O
+recorded	O
+each	O
+alternate	O
+day	O
+.	O
+
+Thymus	O
+weight	O
+was	O
+used	O
+as	O
+a	O
+marker	O
+of	O
+glucocorticoid	O
+activity	O
+,	O
+and	O
+serum	O
+urate	O
+to	O
+assess	O
+XO	O
+inhibition	O
+.	O
+
+5	O
+.	O
+
+Dex	O
+increased	B
+SBP	I
+(	O
+110	O
++	O
+/	O
+-	O
+2	O
+-	O
+126	O
++	O
+/	O
+-	O
+3	O
+mmHg	O
+;	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+and	O
+decreased	B
+thymus	I
+(	I
+P	I
+<	I
+0	I
+.	I
+001	I
+)	I
+and	I
+bodyweights	I
+(	O
+P	O
+"	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+Allopurinol	O
+decreased	O
+serum	O
+urate	O
+from	O
+76	O
++	O
+/	O
+-	O
+5	O
+to	O
+30	O
++	O
+/	O
+-	O
+3	O
+micromol	O
+/	O
+L	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+in	O
+saline	O
+and	O
+from	O
+84	O
++	O
+/	O
+-	O
+13	O
+to	O
+28	O
++	O
+/	O
+-	O
+2	O
+micromol	O
+/	O
+L	O
+in	O
+dex	O
+-	O
+treated	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+groups	O
+.	O
+
+6	O
+.	O
+
+Allopurinol	O
+did	O
+not	O
+prevent	O
+dex	O
+-	O
+HT	B
+.	O
+
+This	O
+,	O
+together	O
+with	O
+our	O
+previous	O
+findings	O
+that	O
+allopurinol	O
+failed	O
+to	O
+prevent	O
+adrenocorticotrophic	O
+hormone	O
+induced	O
+hypertension	B
+,	O
+suggests	O
+that	O
+XO	O
+activity	O
+is	O
+not	O
+a	O
+major	O
+determinant	O
+of	O
+GC	O
+-	O
+HT	B
+in	O
+the	O
+rat	O
+.	O
+
+Side	O
+effects	O
+of	O
+postoperative	O
+administration	O
+of	O
+methylprednisolone	O
+and	O
+gentamicin	O
+into	O
+the	O
+posterior	O
+sub	O
+-	O
+Tenon	O
+'	O
+s	O
+space	O
+.	O
+
+PURPOSE	O
+:	O
+To	O
+assess	O
+the	O
+incidence	O
+of	O
+postoperative	O
+emetic	O
+side	O
+effects	O
+after	O
+the	O
+administration	O
+of	O
+methylprednisolone	O
+and	O
+gentamicin	O
+into	O
+the	O
+posterior	O
+sub	O
+-	O
+Tenon	O
+'	O
+s	O
+space	O
+at	O
+the	O
+end	O
+of	O
+routine	O
+cataract	B
+surgery	O
+.	O
+
+SETTING	O
+:	O
+St	O
+.	O
+
+Luke	O
+'	O
+s	O
+Hospital	O
+,	O
+Gwardamangia	O
+,	O
+Malta	O
+.	O
+
+METHODS	O
+:	O
+A	O
+double	O
+-	O
+blind	O
+double	O
+-	O
+armed	O
+prospective	O
+study	O
+comprised	O
+40	O
+patients	O
+who	O
+had	O
+uneventful	O
+sutureless	O
+phacoemulsification	O
+under	O
+sub	O
+-	O
+Tenon	O
+'	O
+s	O
+local	O
+infiltration	O
+of	O
+3	O
+mL	O
+of	O
+plain	O
+lignocaine	O
+.	O
+
+At	O
+the	O
+end	O
+of	O
+the	O
+procedure	O
+,	O
+Group	O
+A	O
+(	O
+n	O
+=	O
+20	O
+)	O
+had	O
+20	O
+mg	O
+/	O
+0	O
+.	O
+5	O
+mL	O
+of	O
+methylprednisolone	O
+and	O
+10	O
+mg	O
+/	O
+0	O
+.	O
+5	O
+mL	O
+of	O
+gentamicin	O
+injected	O
+into	O
+the	O
+posterior	O
+sub	O
+-	O
+Tenon	O
+'	O
+s	O
+space	O
+and	O
+Group	O
+B	O
+(	O
+n	O
+=	O
+20	O
+)	O
+had	O
+the	O
+same	O
+combination	O
+injected	O
+into	O
+the	O
+anterior	O
+sub	O
+-	O
+Tenon	O
+'	O
+s	O
+space	O
+.	O
+
+Postoperatively	O
+,	O
+all	O
+patients	O
+were	O
+assessed	O
+for	O
+symptoms	O
+of	O
+nausea	B
+,	I
+vomiting	I
+,	O
+and	O
+headache	B
+.	O
+
+A	O
+chi	O
+-	O
+square	O
+test	O
+was	O
+used	O
+to	O
+assess	O
+the	O
+statistical	O
+significance	O
+of	O
+results	O
+.	O
+
+RESULTS	O
+:	O
+Sixty	O
+percent	O
+in	O
+Group	O
+A	O
+developed	O
+postoperative	B
+emetic	I
+symptoms	I
+,	O
+headache	B
+,	O
+or	O
+both	O
+;	O
+1	O
+patient	O
+in	O
+Group	O
+B	O
+developed	O
+symptoms	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+administration	O
+of	O
+methylprednisolone	O
+and	O
+gentamicin	O
+in	O
+the	O
+posterior	O
+sub	O
+-	O
+Tenon	O
+'	O
+s	O
+space	O
+was	O
+related	O
+to	O
+a	O
+high	O
+incidence	O
+of	O
+side	O
+effects	O
+including	O
+nausea	B
+,	I
+vomiting	I
+,	O
+and	O
+headache	B
+.	O
+
+All	O
+adverse	O
+effects	O
+were	O
+self	O
+-	O
+limiting	O
+.	O
+
+Assessment	O
+of	O
+a	O
+new	O
+non	O
+-	O
+invasive	O
+index	O
+of	O
+cardiac	O
+performance	O
+for	O
+detection	O
+of	O
+dobutamine	O
+-	O
+induced	O
+myocardial	B
+ischemia	I
+.	O
+
+BACKGROUND	O
+:	O
+Electrocardiography	O
+has	O
+a	O
+very	O
+low	O
+sensitivity	O
+in	O
+detecting	O
+dobutamine	O
+-	O
+induced	O
+myocardial	B
+ischemia	I
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+assess	O
+the	O
+added	O
+diagnostic	O
+value	O
+of	O
+a	O
+new	O
+cardiac	O
+performance	O
+index	O
+(	O
+dP	O
+/	O
+dtejc	O
+)	O
+measurement	O
+,	O
+based	O
+on	O
+brachial	O
+artery	O
+flow	O
+changes	O
+,	O
+as	O
+compared	O
+to	O
+standard	O
+12	O
+-	O
+lead	O
+ECG	O
+,	O
+for	O
+detecting	O
+dobutamine	O
+-	O
+induced	O
+myocardial	B
+ischemia	I
+,	O
+using	O
+Tc99m	O
+-	O
+Sestamibi	O
+single	O
+-	O
+photon	O
+emission	O
+computed	O
+tomography	O
+as	O
+the	O
+gold	O
+standard	O
+of	O
+comparison	O
+to	O
+assess	O
+the	O
+presence	O
+or	O
+absence	O
+of	O
+ischemia	B
+.	O
+
+METHODS	O
+:	O
+The	O
+study	O
+group	O
+comprised	O
+40	O
+patients	O
+undergoing	O
+Sestamibi	O
+-	O
+SPECT	O
+/	O
+dobutamine	O
+stress	O
+test	O
+.	O
+
+Simultaneous	O
+measurements	O
+of	O
+ECG	O
+and	O
+brachial	O
+artery	O
+dP	O
+/	O
+dtejc	O
+were	O
+performed	O
+at	O
+each	O
+dobutamine	O
+level	O
+.	O
+
+In	O
+19	O
+of	O
+the	O
+40	O
+patients	O
+perfusion	O
+defects	O
+compatible	O
+with	O
+ischemia	B
+were	O
+detected	O
+on	O
+SPECT	O
+.	O
+
+The	O
+increase	O
+in	O
+dP	O
+/	O
+dtejc	O
+during	O
+infusion	O
+of	O
+dobutamine	O
+in	O
+this	O
+group	O
+was	O
+severely	O
+impaired	O
+as	O
+compared	O
+to	O
+the	O
+non	O
+-	O
+ischemic	O
+group	O
+.	O
+
+dP	O
+/	O
+dtejc	O
+outcome	O
+was	O
+combined	O
+with	O
+the	O
+ECG	O
+results	O
+,	O
+giving	O
+an	O
+ECG	O
+-	O
+enhanced	O
+value	O
+,	O
+and	O
+compared	O
+to	O
+ECG	O
+alone	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+sensitivity	O
+improved	O
+dramatically	O
+from	O
+16	O
+%	O
+to	O
+79	O
+%	O
+,	O
+positive	O
+predictive	O
+value	O
+increased	O
+from	O
+60	O
+%	O
+to	O
+68	O
+%	O
+and	O
+negative	O
+predictive	O
+value	O
+from	O
+54	O
+%	O
+to	O
+78	O
+%	O
+,	O
+and	O
+specificity	O
+decreased	O
+from	O
+90	O
+%	O
+to	O
+67	O
+%	O
+.	O
+
+CONCLUSIONS	O
+:	O
+If	O
+ECG	O
+alone	O
+is	O
+used	O
+for	O
+specificity	O
+,	O
+the	O
+combination	O
+with	O
+dP	O
+/	O
+dtejc	O
+improved	O
+the	O
+sensitivity	O
+of	O
+the	O
+test	O
+and	O
+could	O
+be	O
+a	O
+cost	O
+-	O
+savings	O
+alternative	O
+to	O
+cardiac	O
+imaging	O
+or	O
+perfusion	O
+studies	O
+to	O
+detect	O
+myocardial	B
+ischemia	I
+,	O
+especially	O
+in	O
+patients	O
+unable	O
+to	O
+exercise	O
+.	O
+
+Cocaine	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+:	O
+clinical	O
+observations	O
+and	O
+pathogenetic	O
+considerations	O
+.	O
+
+Clinical	O
+and	O
+experimental	O
+data	O
+published	O
+to	O
+date	O
+suggest	O
+several	O
+possible	O
+mechanisms	O
+by	O
+which	O
+cocaine	O
+may	O
+result	O
+in	O
+acute	B
+myocardial	I
+infarction	I
+.	O
+
+In	O
+individuals	O
+with	O
+preexisting	O
+,	O
+high	O
+-	O
+grade	O
+coronary	O
+arterial	O
+narrowing	O
+,	O
+acute	B
+myocardial	I
+infarction	I
+may	O
+result	O
+from	O
+an	O
+increase	O
+in	O
+myocardial	O
+oxygen	O
+demand	O
+associated	O
+with	O
+cocaine	O
+-	O
+induced	O
+increase	O
+in	O
+rate	O
+-	O
+pressure	O
+product	O
+.	O
+
+In	O
+other	O
+individuals	O
+with	O
+no	O
+underlying	O
+atherosclerotic	B
+obstruction	I
+,	O
+coronary	B
+occlusion	I
+may	O
+be	O
+due	O
+to	O
+spasm	B
+,	O
+thrombus	B
+,	O
+or	O
+both	O
+.	O
+
+With	O
+regard	O
+to	O
+spasm	B
+,	O
+the	O
+clinical	O
+findings	O
+are	O
+largely	O
+circumstantial	O
+,	O
+and	O
+the	O
+locus	O
+of	O
+cocaine	O
+-	O
+induced	O
+vasoconstriction	O
+remains	O
+speculative	O
+.	O
+
+Although	O
+certain	O
+clinical	O
+and	O
+experimental	O
+findings	O
+support	O
+the	O
+hypothesis	O
+that	O
+spasm	B
+involves	O
+the	O
+epicardial	O
+,	O
+medium	O
+-	O
+size	O
+vessels	O
+,	O
+other	O
+data	O
+suggest	O
+intramural	O
+vasoconstriction	O
+.	O
+
+Diffuse	O
+intramural	O
+vasoconstriction	O
+is	O
+not	O
+consistent	O
+with	O
+reports	O
+of	O
+segmental	O
+,	O
+discrete	O
+infarction	B
+.	O
+
+Whereas	O
+certain	O
+in	O
+vivo	O
+data	O
+suggest	O
+that	O
+these	O
+effects	O
+are	O
+alpha	O
+-	O
+mediated	O
+,	O
+other	O
+in	O
+vitro	O
+data	O
+suggest	O
+the	O
+opposite	O
+.	O
+
+The	O
+finding	O
+of	O
+cocaine	O
+-	O
+induced	O
+vasoconstriction	O
+in	O
+segments	O
+of	O
+(	O
+noninnervated	O
+)	O
+human	O
+umbilical	O
+artery	O
+suggests	O
+that	O
+the	O
+presence	O
+or	O
+absence	O
+of	O
+intact	O
+innervation	O
+is	O
+not	O
+sufficient	O
+to	O
+explain	O
+the	O
+discrepant	O
+data	O
+involving	O
+the	O
+possibility	O
+of	O
+alpha	O
+-	O
+mediated	O
+effects	O
+.	O
+
+Finally	O
+,	O
+the	O
+contribution	O
+of	O
+a	O
+primary	O
+,	O
+thrombotic	B
+effect	O
+of	O
+cocaine	O
+has	O
+not	O
+been	O
+excluded	O
+.	O
+
+Proteomic	O
+analysis	O
+of	O
+striatal	O
+proteins	O
+in	O
+the	O
+rat	O
+model	O
+of	O
+L	O
+-	O
+DOPA	O
+-	O
+induced	O
+dyskinesia	B
+.	O
+
+L	O
+-	O
+DOPA	O
+-	O
+induced	O
+dyskinesia	B
+(	O
+LID	B
+)	O
+is	O
+among	O
+the	O
+motor	O
+complications	O
+that	O
+arise	O
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+patients	O
+after	O
+a	O
+prolonged	O
+treatment	O
+with	O
+L	O
+-	O
+DOPA	O
+.	O
+
+To	O
+this	O
+day	O
+,	O
+transcriptome	O
+analysis	O
+has	O
+been	O
+performed	O
+in	O
+a	O
+rat	O
+model	O
+of	O
+LID	B
+[	O
+Neurobiol	O
+.	O
+Dis	O
+.	O
+,	O
+17	O
+(	O
+2004	O
+)	O
+,	O
+219	O
+]	O
+but	O
+information	O
+regarding	O
+the	O
+proteome	O
+is	O
+still	O
+lacking	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+we	O
+investigated	O
+the	O
+changes	O
+occurring	O
+at	O
+the	O
+protein	O
+level	O
+in	O
+striatal	O
+samples	O
+obtained	O
+from	O
+the	O
+unilaterally	O
+6	O
+-	O
+hydroxydopamine	O
+-	O
+lesion	O
+rat	O
+model	O
+of	O
+PD	B
+treated	O
+with	O
+saline	O
+,	O
+L	O
+-	O
+DOPA	O
+or	O
+bromocriptine	O
+using	O
+two	O
+-	O
+dimensional	O
+difference	O
+gel	O
+electrophoresis	O
+and	O
+mass	O
+spectrometry	O
+(	O
+MS	O
+)	O
+.	O
+
+Rats	O
+treated	O
+with	O
+L	O
+-	O
+DOPA	O
+were	O
+allocated	O
+to	O
+two	O
+groups	O
+based	O
+on	O
+the	O
+presence	O
+or	O
+absence	O
+of	O
+LID	B
+.	O
+
+Among	O
+the	O
+2000	O
+spots	O
+compared	O
+for	O
+statistical	O
+difference	O
+,	O
+67	O
+spots	O
+were	O
+significantly	O
+changed	O
+in	O
+abundance	O
+and	O
+identified	O
+using	O
+matrix	O
+-	O
+assisted	O
+laser	O
+desorption	O
+/	O
+ionization	O
+time	O
+-	O
+of	O
+-	O
+flight	O
+MS	O
+,	O
+atmospheric	O
+pressure	O
+matrix	O
+-	O
+assisted	O
+laser	O
+desorption	O
+/	O
+ionization	O
+and	O
+HPLC	O
+coupled	O
+tandem	O
+MS	O
+(	O
+LC	O
+/	O
+MS	O
+/	O
+MS	O
+)	O
+.	O
+
+Out	O
+of	O
+these	O
+67	O
+proteins	O
+,	O
+LID	B
+significantly	O
+changed	O
+the	O
+expression	O
+level	O
+of	O
+five	O
+proteins	O
+:	O
+alphabeta	O
+-	O
+crystalin	O
+,	O
+gamma	O
+-	O
+enolase	O
+,	O
+guanidoacetate	O
+methyltransferase	O
+,	O
+vinculin	O
+,	O
+and	O
+proteasome	O
+alpha	O
+-	O
+2	O
+subunit	O
+.	O
+
+Complementary	O
+techniques	O
+such	O
+as	O
+western	O
+immunoblotting	O
+and	O
+immunohistochemistry	O
+were	O
+performed	O
+to	O
+investigate	O
+the	O
+validity	O
+of	O
+the	O
+data	O
+obtained	O
+using	O
+the	O
+proteomic	O
+approach	O
+.	O
+
+In	O
+conclusion	O
+,	O
+this	O
+study	O
+provides	O
+new	O
+insights	O
+into	O
+the	O
+protein	O
+changes	O
+occurring	O
+in	O
+LID	B
+.	O
+
+Cardiac	O
+Angiography	O
+in	O
+Renally	O
+Impaired	O
+Patients	O
+(	O
+CARE	O
+)	O
+study	O
+:	O
+a	O
+randomized	O
+double	O
+-	O
+blind	O
+trial	O
+of	O
+contrast	O
+-	O
+induced	O
+nephropathy	B
+in	O
+patients	O
+with	O
+chronic	B
+kidney	I
+disease	I
+.	O
+
+BACKGROUND	O
+:	O
+No	O
+direct	O
+comparisons	O
+exist	O
+of	O
+the	O
+renal	O
+tolerability	O
+of	O
+the	O
+low	O
+-	O
+osmolality	O
+contrast	O
+medium	O
+iopamidol	O
+with	O
+that	O
+of	O
+the	O
+iso	O
+-	O
+osmolality	O
+contrast	O
+medium	O
+iodixanol	O
+in	O
+high	O
+-	O
+risk	O
+patients	O
+.	O
+
+METHODS	O
+AND	O
+RESULTS	O
+:	O
+The	O
+present	O
+study	O
+is	O
+a	O
+multicenter	O
+,	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+comparison	O
+of	O
+iopamidol	O
+and	O
+iodixanol	O
+in	O
+patients	O
+with	O
+chronic	B
+kidney	I
+disease	I
+(	O
+estimated	O
+glomerular	O
+filtration	O
+rate	O
+,	O
+20	O
+to	O
+59	O
+mL	O
+/	O
+min	O
+)	O
+who	O
+underwent	O
+cardiac	O
+angiography	O
+or	O
+percutaneous	O
+coronary	O
+interventions	O
+.	O
+
+Serum	O
+creatinine	O
+(	O
+SCr	O
+)	O
+levels	O
+and	O
+estimated	O
+glomerular	O
+filtration	O
+rate	O
+were	O
+assessed	O
+at	O
+baseline	O
+and	O
+2	O
+to	O
+5	O
+days	O
+after	O
+receiving	O
+medications	O
+.	O
+
+The	O
+primary	O
+outcome	O
+was	O
+a	O
+postdose	O
+SCr	O
+increase	O
+>	O
+or	O
+=	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+dL	O
+(	O
+44	O
+.	O
+2	O
+micromol	O
+/	O
+L	O
+)	O
+over	O
+baseline	O
+.	O
+
+Secondary	O
+outcomes	O
+were	O
+a	O
+postdose	O
+SCr	O
+increase	O
+>	O
+or	O
+=	O
+25	O
+%	O
+,	O
+a	O
+postdose	O
+estimated	O
+glomerular	O
+filtration	O
+rate	O
+decrease	O
+of	O
+>	O
+or	O
+=	O
+25	O
+%	O
+,	O
+and	O
+the	O
+mean	O
+peak	O
+change	O
+in	O
+SCr	O
+.	O
+
+In	O
+414	O
+patients	O
+,	O
+contrast	O
+volume	O
+,	O
+presence	O
+of	O
+diabetes	B
+mellitus	I
+,	O
+use	O
+of	O
+N	O
+-	O
+acetylcysteine	O
+,	O
+mean	O
+baseline	O
+SCr	O
+,	O
+and	O
+estimated	O
+glomerular	O
+filtration	O
+rate	O
+were	O
+comparable	O
+in	O
+the	O
+2	O
+groups	O
+.	O
+
+SCr	O
+increases	O
+>	O
+or	O
+=	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+dL	O
+occurred	O
+in	O
+4	O
+.	O
+4	O
+%	O
+(	O
+9	O
+of	O
+204	O
+patients	O
+)	O
+after	O
+iopamidol	O
+and	O
+6	O
+.	O
+7	O
+%	O
+(	O
+14	O
+of	O
+210	O
+patients	O
+)	O
+after	O
+iodixanol	O
+(	O
+P	O
+=	O
+0	O
+.	O
+39	O
+)	O
+,	O
+whereas	O
+rates	O
+of	O
+SCr	O
+increases	O
+>	O
+or	O
+=	O
+25	O
+%	O
+were	O
+9	O
+.	O
+8	O
+%	O
+and	O
+12	O
+.	O
+4	O
+%	O
+,	O
+respectively	O
+(	O
+P	O
+=	O
+0	O
+.	O
+44	O
+)	O
+.	O
+
+In	O
+patients	O
+with	O
+diabetes	B
+,	O
+SCr	O
+increases	O
+>	O
+or	O
+=	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+dL	O
+were	O
+5	O
+.	O
+1	O
+%	O
+(	O
+4	O
+of	O
+78	O
+patients	O
+)	O
+with	O
+iopamidol	O
+and	O
+13	O
+.	O
+0	O
+%	O
+(	O
+12	O
+of	O
+92	O
+patients	O
+)	O
+with	O
+iodixanol	O
+(	O
+P	O
+=	O
+0	O
+.	O
+11	O
+)	O
+,	O
+whereas	O
+SCr	O
+increases	O
+>	O
+or	O
+=	O
+25	O
+%	O
+were	O
+10	O
+.	O
+3	O
+%	O
+and	O
+15	O
+.	O
+2	O
+%	O
+,	O
+respectively	O
+(	O
+P	O
+=	O
+0	O
+.	O
+37	O
+)	O
+.	O
+
+Mean	O
+post	O
+-	O
+SCr	O
+increases	O
+were	O
+significantly	O
+less	O
+with	O
+iopamidol	O
+(	O
+all	O
+patients	O
+:	O
+0	O
+.	O
+07	O
+versus	O
+0	O
+.	O
+12	O
+mg	O
+/	O
+dL	O
+,	O
+6	O
+.	O
+2	O
+versus	O
+10	O
+.	O
+6	O
+micromol	O
+/	O
+L	O
+,	O
+P	O
+=	O
+0	O
+.	O
+03	O
+;	O
+patients	O
+with	O
+diabetes	B
+:	O
+0	O
+.	O
+07	O
+versus	O
+0	O
+.	O
+16	O
+mg	O
+/	O
+dL	O
+,	O
+6	O
+.	O
+2	O
+versus	O
+14	O
+.	O
+1	O
+micromol	O
+/	O
+L	O
+,	O
+P	O
+=	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+rate	O
+of	O
+contrast	O
+-	O
+induced	O
+nephropathy	B
+,	O
+defined	O
+by	O
+multiple	O
+end	O
+points	O
+,	O
+is	O
+not	O
+statistically	O
+different	O
+after	O
+the	O
+intraarterial	O
+administration	O
+of	O
+iopamidol	O
+or	O
+iodixanol	O
+to	O
+high	O
+-	O
+risk	O
+patients	O
+,	O
+with	O
+or	O
+without	O
+diabetes	B
+mellitus	I
+.	O
+
+Any	O
+true	O
+difference	O
+between	O
+the	O
+agents	O
+is	O
+small	O
+and	O
+not	O
+likely	O
+to	O
+be	O
+clinically	O
+significant	O
+.	O
+
+A	O
+novel	O
+compound	O
+,	O
+maltolyl	O
+p	O
+-	O
+coumarate	O
+,	O
+attenuates	O
+cognitive	B
+deficits	I
+and	O
+shows	O
+neuroprotective	O
+effects	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+dementia	B
+models	O
+.	O
+
+To	O
+develop	O
+a	O
+novel	O
+and	O
+effective	O
+drug	O
+that	O
+could	O
+enhance	O
+cognitive	O
+function	O
+and	O
+neuroprotection	O
+,	O
+we	O
+newly	O
+synthesized	O
+maltolyl	O
+p	O
+-	O
+coumarate	O
+by	O
+the	O
+esterification	O
+of	O
+maltol	O
+and	O
+p	O
+-	O
+coumaric	O
+acid	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+we	O
+investigated	O
+whether	O
+maltolyl	O
+p	O
+-	O
+coumarate	O
+could	O
+improve	O
+cognitive	B
+decline	I
+in	O
+scopolamine	O
+-	O
+injected	O
+rats	O
+and	O
+in	O
+amyloid	O
+beta	O
+peptide	O
+(	O
+1	O
+-	O
+42	O
+)	O
+-	O
+infused	O
+rats	O
+.	O
+
+Maltolyl	O
+p	O
+-	O
+coumarate	O
+was	O
+found	O
+to	O
+attenuate	O
+cognitive	B
+deficits	I
+in	O
+both	O
+rat	O
+models	O
+using	O
+passive	O
+avoidance	O
+test	O
+and	O
+to	O
+reduce	O
+apoptotic	O
+cell	O
+death	O
+observed	O
+in	O
+the	O
+hippocampus	O
+of	O
+the	O
+amyloid	O
+beta	O
+peptide	O
+(	O
+1	O
+-	O
+42	O
+)	O
+-	O
+infused	O
+rats	O
+.	O
+
+We	O
+also	O
+examined	O
+the	O
+neuroprotective	O
+effects	O
+of	O
+maltolyl	O
+p	O
+-	O
+coumarate	O
+in	O
+vitro	O
+using	O
+SH	O
+-	O
+SY5Y	O
+cells	O
+.	O
+
+Cells	O
+were	O
+pretreated	O
+with	O
+maltolyl	O
+p	O
+-	O
+coumarate	O
+,	O
+before	O
+exposed	O
+to	O
+amyloid	O
+beta	O
+peptide	O
+(	O
+1	O
+-	O
+42	O
+)	O
+,	O
+glutamate	O
+or	O
+H2O2	O
+.	O
+
+We	O
+found	O
+that	O
+maltolyl	O
+p	O
+-	O
+coumarate	O
+significantly	O
+decreased	O
+apoptotic	O
+cell	O
+death	O
+and	O
+reduced	O
+reactive	O
+oxygen	O
+species	O
+,	O
+cytochrome	O
+c	O
+release	O
+,	O
+and	O
+caspase	O
+3	O
+activation	O
+.	O
+
+Taking	O
+these	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+results	O
+together	O
+,	O
+our	O
+study	O
+suggests	O
+that	O
+maltolyl	O
+p	O
+-	O
+coumarate	O
+is	O
+a	O
+potentially	O
+effective	O
+candidate	O
+against	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+that	O
+is	O
+characterized	O
+by	O
+wide	O
+spread	O
+neuronal	B
+death	I
+and	O
+progressive	O
+decline	B
+of	I
+cognitive	I
+function	I
+.	O
+
+Attenuation	O
+of	O
+methamphetamine	O
+-	O
+induced	O
+nigrostriatal	O
+dopaminergic	O
+neurotoxicity	B
+in	O
+mice	O
+by	O
+lipopolysaccharide	O
+pretreatment	O
+.	O
+
+Immunological	O
+activation	O
+has	O
+been	O
+proposed	O
+to	O
+play	O
+a	O
+role	O
+in	O
+methamphetamine	O
+-	O
+induced	O
+dopaminergic	B
+terminal	I
+damage	I
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+examined	O
+the	O
+roles	O
+of	O
+lipopolysaccharide	O
+,	O
+a	O
+pro	O
+-	O
+inflammatory	O
+and	O
+inflammatory	O
+factor	O
+,	O
+treatment	O
+in	O
+modulating	O
+the	O
+methamphetamine	O
+-	O
+induced	O
+nigrostriatal	O
+dopamine	O
+neurotoxicity	B
+.	O
+
+Lipopolysaccharide	O
+pretreatment	O
+did	O
+not	O
+affect	O
+the	O
+basal	O
+body	O
+temperature	O
+or	O
+methamphetamine	O
+-	O
+elicited	O
+hyperthermia	B
+three	O
+days	O
+later	O
+.	O
+
+Such	O
+systemic	O
+lipopolysaccharide	O
+treatment	O
+mitigated	O
+methamphetamine	O
+-	O
+induced	O
+striatal	O
+dopamine	O
+and	O
+3	O
+,	O
+4	O
+-	O
+dihydroxyphenylacetic	O
+acid	O
+depletions	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+.	O
+
+As	O
+the	O
+most	O
+potent	O
+dose	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+of	O
+lipopolysaccharide	O
+was	O
+administered	O
+two	O
+weeks	O
+,	O
+one	O
+day	O
+before	O
+or	O
+after	O
+the	O
+methamphetamine	O
+dosing	O
+regimen	O
+,	O
+methamphetamine	O
+-	O
+induced	O
+striatal	O
+dopamine	O
+and	O
+3	O
+,	O
+4	O
+-	O
+dihydroxyphenylacetic	O
+acid	O
+depletions	O
+remained	O
+unaltered	O
+.	O
+
+Moreover	O
+,	O
+systemic	O
+lipopolysaccharide	O
+pretreatment	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+attenuated	O
+local	O
+methamphetamine	O
+infusion	O
+-	O
+produced	O
+dopamine	O
+and	O
+3	O
+,	O
+4	O
+-	O
+dihydroxyphenylacetic	O
+acid	O
+depletions	O
+in	O
+the	O
+striatum	O
+,	O
+indicating	O
+that	O
+the	O
+protective	O
+effect	O
+of	O
+lipopolysaccharide	O
+is	O
+less	O
+likely	O
+due	O
+to	O
+interrupted	O
+peripheral	O
+distribution	O
+or	O
+metabolism	O
+of	O
+methamphetamine	O
+.	O
+
+We	O
+concluded	O
+a	O
+critical	O
+time	O
+window	O
+for	O
+systemic	O
+lipopolysaccharide	O
+pretreatment	O
+in	O
+exerting	O
+effective	O
+protection	O
+against	O
+methamphetamine	O
+-	O
+induced	O
+nigrostriatal	O
+dopamine	O
+neurotoxicity	B
+.	O
+
+Acute	O
+myocarditis	B
+associated	O
+with	O
+clozapine	O
+.	O
+
+OBJECTIVE	O
+:	O
+A	O
+case	O
+of	O
+acute	O
+myocarditis	B
+associated	O
+with	O
+the	O
+commencement	O
+of	O
+clozapine	O
+is	O
+described	O
+,	O
+highlighting	O
+the	O
+onset	O
+,	O
+course	O
+and	O
+possible	O
+contributing	O
+factors	O
+.	O
+
+There	O
+is	O
+an	O
+urgent	O
+need	O
+to	O
+raise	O
+awareness	O
+about	O
+this	O
+potentially	O
+fatal	O
+complication	O
+of	O
+clozapine	O
+use	O
+.	O
+
+RESULTS	O
+:	O
+A	O
+20	O
+-	O
+year	O
+-	O
+old	O
+male	O
+with	O
+schizophrenia	B
+developed	O
+a	O
+sudden	O
+onset	O
+of	O
+myocarditis	B
+after	O
+commencement	O
+of	O
+clozapine	O
+.	O
+
+The	O
+patient	O
+recovered	O
+with	O
+intensive	O
+medical	O
+support	O
+.	O
+
+The	O
+symptoms	O
+occurred	O
+around	O
+2	O
+weeks	O
+after	O
+starting	O
+clozapine	O
+in	O
+an	O
+inpatient	O
+setting	O
+.	O
+
+Possible	O
+contributing	O
+factors	O
+may	O
+have	O
+been	O
+concomitant	O
+antidepressant	O
+use	O
+and	O
+unaccustomed	O
+physical	O
+activity	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Myocarditis	B
+is	O
+an	O
+increasingly	O
+recognized	O
+complication	O
+associated	O
+with	O
+the	O
+use	O
+of	O
+clozapine	O
+.	O
+
+It	O
+can	O
+be	O
+fatal	O
+if	O
+not	O
+recognized	O
+and	O
+treated	O
+early	O
+.	O
+
+Considering	O
+that	O
+clozapine	O
+remains	O
+the	O
+gold	O
+standard	O
+in	O
+treatment	O
+of	O
+resistant	O
+psychosis	B
+,	O
+there	O
+is	O
+an	O
+urgent	O
+need	O
+to	O
+raise	O
+awareness	O
+among	O
+medical	O
+and	O
+paramedical	O
+staff	O
+involved	O
+in	O
+the	O
+care	O
+of	O
+these	O
+patients	O
+.	O
+
+There	O
+are	O
+also	O
+implications	O
+for	O
+recommendations	O
+and	O
+regulations	O
+regarding	O
+the	O
+use	O
+of	O
+clozapine	O
+.	O
+
+Severe	O
+rhabdomyolysis	B
+and	O
+acute	B
+renal	I
+failure	I
+secondary	O
+to	O
+concomitant	O
+use	O
+of	O
+simvastatin	O
+,	O
+amiodarone	O
+,	O
+and	O
+atazanavir	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+a	O
+severe	O
+interaction	O
+between	O
+simvastatin	O
+,	O
+amiodarone	O
+,	O
+and	O
+atazanavir	O
+resulting	O
+in	O
+rhabdomyolysis	B
+and	O
+acute	B
+renal	I
+failure	I
+.	O
+
+BACKGROUND	O
+:	O
+A	O
+72	O
+-	O
+year	O
+-	O
+old	O
+white	O
+man	O
+with	O
+underlying	O
+human	B
+immunodeficiency	I
+virus	I
+,	O
+atrial	B
+fibrillation	I
+,	O
+coronary	B
+artery	I
+disease	I
+,	O
+and	O
+hyperlipidemia	B
+presented	O
+with	O
+generalized	O
+pain	B
+,	O
+fatigue	B
+,	O
+and	O
+dark	O
+orange	O
+urine	O
+for	O
+3	O
+days	O
+.	O
+
+The	O
+patient	O
+was	O
+taking	O
+80	O
+mg	O
+simvastatin	O
+at	O
+bedtime	O
+(	O
+initiated	O
+27	O
+days	O
+earlier	O
+)	O
+;	O
+amiodarone	O
+at	O
+a	O
+dose	O
+of	O
+400	O
+mg	O
+daily	O
+for	O
+7	O
+days	O
+,	O
+then	O
+200	O
+mg	O
+daily	O
+(	O
+initiated	O
+19	O
+days	O
+earlier	O
+)	O
+;	O
+and	O
+400	O
+mg	O
+atazanavir	O
+daily	O
+(	O
+initiated	O
+at	O
+least	O
+2	O
+years	O
+previously	O
+)	O
+.	O
+
+Laboratory	O
+evaluation	O
+revealed	O
+66	O
+,	O
+680	O
+U	O
+/	O
+L	O
+creatine	O
+kinase	O
+,	O
+93	O
+mg	O
+/	O
+dL	O
+blood	O
+urea	O
+nitrogen	O
+,	O
+4	O
+.	O
+6	O
+mg	O
+/	O
+dL	O
+creatinine	O
+,	O
+1579	O
+U	O
+/	O
+L	O
+aspartate	O
+aminotransferase	O
+,	O
+and	O
+738	O
+U	O
+/	O
+L	O
+alanine	O
+aminotransferase	O
+.	O
+
+Simvastatin	O
+,	O
+amiodarone	O
+,	O
+and	O
+the	O
+patient	O
+'	O
+s	O
+human	B
+immunodeficiency	I
+virus	I
+medications	O
+were	O
+all	O
+temporarily	O
+discontinued	O
+and	O
+the	O
+patient	O
+was	O
+given	O
+forced	O
+alkaline	O
+diuresis	O
+and	O
+started	O
+on	O
+dialysis	O
+.	O
+
+Nine	O
+days	O
+later	O
+the	O
+patient	O
+'	O
+s	O
+creatine	O
+kinase	O
+had	O
+dropped	O
+to	O
+1695	O
+U	O
+/	O
+L	O
+and	O
+creatinine	O
+was	O
+3	O
+.	O
+3	O
+mg	O
+/	O
+dL	O
+.	O
+
+The	O
+patient	O
+was	O
+discharged	O
+and	O
+continued	O
+outpatient	O
+dialysis	O
+for	O
+1	O
+month	O
+until	O
+his	O
+renal	O
+function	O
+recovered	O
+.	O
+
+DISCUSSION	O
+:	O
+The	O
+risk	O
+of	O
+rhabdomyolysis	B
+is	O
+increased	O
+in	O
+the	O
+presence	O
+of	O
+concomitant	O
+drugs	O
+that	O
+inhibit	O
+simvastatin	O
+metabolism	O
+.	O
+
+Simvastatin	O
+is	O
+metabolized	O
+by	O
+CYP3A4	O
+.	O
+
+Amiodarone	O
+and	O
+atazanavir	O
+are	O
+recognized	O
+CYP3A4	O
+inhibitors	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Pharmacokinetic	O
+differences	O
+in	O
+statins	O
+are	O
+an	O
+important	O
+consideration	O
+for	O
+assessing	O
+the	O
+risk	O
+of	O
+potential	O
+drug	O
+interactions	O
+.	O
+
+In	O
+patients	O
+requiring	O
+the	O
+concurrent	O
+use	O
+of	O
+statins	O
+and	O
+CYP3A4	O
+inhibitors	O
+,	O
+pravastatin	O
+,	O
+fluvastatin	O
+,	O
+and	O
+rosuvastatin	O
+carry	O
+the	O
+lowest	O
+risk	O
+of	O
+drug	O
+interactions	O
+;	O
+atorvastatin	O
+carries	O
+moderate	O
+risk	O
+,	O
+whereas	O
+simvastatin	O
+and	O
+lovastatin	O
+have	O
+the	O
+highest	O
+risk	O
+and	O
+should	O
+be	O
+avoided	O
+in	O
+patients	O
+taking	O
+concomitant	O
+CYP3A4	O
+inhibitors	O
+.	O
+
+Interaction	O
+between	O
+warfarin	O
+and	O
+levofloxacin	O
+:	O
+case	O
+series	O
+.	O
+
+Warfarin	O
+is	O
+the	O
+most	O
+widely	O
+used	O
+oral	O
+anticoagulant	O
+and	O
+is	O
+indicated	O
+for	O
+many	O
+clinical	O
+conditions	O
+.	O
+
+Levofloxacin	O
+,	O
+a	O
+fluoroquinolone	O
+,	O
+is	O
+one	O
+of	O
+the	O
+most	O
+commonly	O
+prescribed	O
+antibiotics	O
+in	O
+clinical	O
+practice	O
+and	O
+is	O
+effective	O
+against	O
+Gram	O
+-	O
+positive	O
+,	O
+Gram	O
+-	O
+negative	O
+,	O
+and	O
+atypical	O
+bacteria	O
+.	O
+
+While	O
+small	O
+prospective	O
+studies	O
+have	O
+not	O
+revealed	O
+any	O
+significant	O
+drug	O
+-	O
+drug	O
+interaction	O
+between	O
+warfarin	O
+and	O
+levofloxacin	O
+,	O
+several	O
+case	O
+reports	O
+have	O
+indicated	O
+that	O
+levofloxacin	O
+may	O
+significantly	O
+potentiate	O
+the	O
+anticoagulation	O
+effect	O
+of	O
+warfarin	O
+.	O
+
+We	O
+report	O
+3	O
+cases	O
+of	O
+serious	O
+bleeding	B
+complications	O
+that	O
+appear	O
+to	O
+be	O
+the	O
+result	O
+of	O
+the	O
+interaction	O
+between	O
+warfarin	O
+and	O
+levofloxacin	O
+.	O
+
+Physicians	O
+should	O
+be	O
+aware	O
+of	O
+this	O
+potential	O
+interaction	O
+and	O
+use	O
+caution	O
+when	O
+prescribing	O
+levofloxacin	O
+to	O
+patients	O
+taking	O
+warfarin	O
+.	O
+
+Mutations	O
+associated	O
+with	O
+lamivudine	O
+-	O
+resistance	O
+in	O
+therapy	O
+-	O
+na	O
+ve	O
+hepatitis	B
+B	I
+virus	I
+(	I
+HBV	I
+)	I
+infected	I
+patients	O
+with	O
+and	O
+without	O
+HIV	B
+co	I
+-	I
+infection	I
+:	O
+implications	O
+for	O
+antiretroviral	O
+therapy	O
+in	O
+HBV	B
+and	I
+HIV	I
+co	I
+-	I
+infected	I
+South	O
+African	O
+patients	O
+.	O
+
+This	O
+was	O
+an	O
+exploratory	O
+study	O
+to	O
+investigate	O
+lamivudine	O
+-	O
+resistant	O
+hepatitis	B
+B	I
+virus	O
+(	O
+HBV	O
+)	O
+strains	O
+in	O
+selected	O
+lamivudine	O
+-	O
+na	O
+ve	O
+HBV	O
+carriers	O
+with	O
+and	O
+without	O
+human	B
+immunodeficiency	I
+virus	I
+(	I
+HIV	I
+)	I
+co	I
+-	I
+infection	I
+in	O
+South	O
+African	O
+patients	O
+.	O
+
+Thirty	O
+-	O
+five	O
+lamivudine	O
+-	O
+na	O
+ve	O
+HBV	B
+infected	I
+patients	O
+with	O
+or	O
+without	O
+HIV	B
+co	I
+-	I
+infection	I
+were	O
+studied	O
+:	O
+15	O
+chronic	O
+HBV	B
+mono	I
+-	I
+infected	I
+patients	O
+and	O
+20	O
+HBV	B
+-	I
+HIV	I
+co	I
+-	I
+infected	I
+patients	O
+.	O
+
+The	O
+latter	O
+group	O
+was	O
+further	O
+sub	O
+-	O
+divided	O
+into	O
+13	O
+occult	O
+HBV	O
+(	O
+HBsAg	O
+-	O
+negative	O
+)	O
+and	O
+7	O
+overt	O
+HBV	O
+(	O
+HBsAg	O
+-	O
+positive	O
+)	O
+patients	O
+.	O
+
+HBsAg	O
+,	O
+anti	O
+-	O
+HBs	O
+,	O
+anti	O
+-	O
+HBc	O
+,	O
+and	O
+anti	O
+-	O
+HIV	O
+1	O
+/	O
+2	O
+were	O
+determined	O
+as	O
+part	O
+of	O
+routine	O
+diagnosis	O
+using	O
+Axsym	O
+assays	O
+(	O
+Abbott	O
+Laboratories	O
+,	O
+North	O
+Chicago	O
+,	O
+IL	O
+)	O
+.	O
+
+Serum	O
+samples	O
+were	O
+PCR	O
+amplified	O
+with	O
+HBV	O
+reverse	O
+transcriptase	O
+(	O
+RT	O
+)	O
+primers	O
+,	O
+followed	O
+by	O
+direct	O
+sequencing	O
+across	O
+the	O
+tyrosine	O
+-	O
+methionine	O
+-	O
+aspartate	O
+-	O
+aspartate	O
+(	O
+YMDD	O
+)	O
+motif	O
+of	O
+the	O
+major	O
+catalytic	O
+region	O
+in	O
+the	O
+C	O
+domain	O
+of	O
+the	O
+HBV	O
+RT	O
+enzyme	O
+.	O
+
+HBV	O
+viral	O
+load	O
+was	O
+performed	O
+with	O
+Amplicor	O
+HBV	O
+Monitor	O
+test	O
+v2	O
+.	O
+0	O
+(	O
+Roche	O
+Diagnostics	O
+,	O
+Penzberg	O
+,	O
+Germany	O
+)	O
+.	O
+
+HBV	O
+lamivudine	O
+-	O
+resistant	O
+strains	O
+were	O
+detected	O
+in	O
+3	O
+of	O
+15	O
+mono	O
+-	O
+infected	O
+chronic	O
+hepatitis	B
+B	I
+patients	O
+and	O
+10	O
+of	O
+20	O
+HBV	B
+-	I
+HIV	I
+co	I
+-	I
+infected	I
+patients	O
+.	O
+
+To	O
+the	O
+best	O
+of	O
+our	O
+knowledge	O
+,	O
+this	O
+constitutes	O
+the	O
+first	O
+report	O
+of	O
+HBV	O
+lamivudine	O
+-	O
+resistant	O
+strains	O
+in	O
+therapy	O
+-	O
+na	O
+ve	O
+HBV	B
+-	I
+HIV	I
+co	I
+-	I
+infected	I
+patients	O
+.	O
+
+The	O
+HBV	O
+viral	O
+loads	O
+for	O
+mono	O
+-	O
+infected	O
+and	O
+co	O
+-	O
+infected	O
+patients	O
+ranged	O
+from	O
+3	O
+.	O
+32	O
+x	O
+10	O
+(	O
+2	O
+)	O
+to	O
+3	O
+.	O
+82	O
+x	O
+10	O
+(	O
+7	O
+)	O
+and	O
+<	O
+200	O
+to	O
+4	O
+.	O
+40	O
+x	O
+10	O
+(	O
+3	O
+)	O
+copies	O
+/	O
+ml	O
+,	O
+respectively	O
+.	O
+
+It	O
+remains	O
+to	O
+be	O
+seen	O
+whether	O
+such	O
+pre	O
+-	O
+existing	O
+antiviral	O
+mutations	O
+could	O
+result	O
+in	O
+widespread	O
+emergence	O
+of	O
+HBV	O
+resistant	O
+strains	O
+when	O
+lamivudine	O
+-	O
+containing	O
+highly	O
+active	O
+antiretroviral	O
+(	O
+ARV	O
+)	O
+treatment	O
+(	O
+HAART	O
+)	O
+regimens	O
+become	O
+widely	O
+applied	O
+in	O
+South	O
+Africa	O
+,	O
+as	O
+this	O
+is	O
+likely	O
+to	O
+have	O
+potential	O
+implications	O
+in	O
+the	O
+management	O
+of	O
+HBV	B
+-	I
+HIV	I
+co	I
+-	I
+infected	I
+patients	O
+.	O
+
+Rabbit	B
+syndrome	I
+,	O
+antidepressant	O
+use	O
+,	O
+and	O
+cerebral	O
+perfusion	O
+SPECT	O
+scan	O
+findings	O
+.	O
+
+The	O
+rabbit	B
+syndrome	I
+is	O
+an	O
+extrapyramidal	O
+side	O
+effect	O
+associated	O
+with	O
+chronic	O
+neuroleptic	O
+therapy	O
+.	O
+
+Its	O
+occurrence	O
+in	O
+a	O
+patient	O
+being	O
+treated	O
+with	O
+imipramine	O
+is	O
+described	O
+,	O
+representing	O
+the	O
+first	O
+reported	O
+case	O
+of	O
+this	O
+syndrome	O
+in	O
+conjunction	O
+with	O
+antidepressants	O
+.	O
+
+Repeated	O
+cerebral	O
+perfusion	O
+SPECT	O
+scans	O
+revealed	O
+decreased	B
+basal	I
+ganglia	I
+perfusion	I
+while	O
+the	O
+movement	B
+disorder	I
+was	O
+present	O
+,	O
+and	O
+a	O
+return	O
+to	O
+normal	O
+perfusion	O
+when	O
+the	O
+rabbit	B
+syndrome	I
+resolved	O
+.	O
+
+Estrogen	O
+prevents	O
+cholesteryl	O
+ester	O
+accumulation	O
+in	O
+macrophages	O
+induced	O
+by	O
+the	O
+HIV	O
+protease	O
+inhibitor	O
+ritonavir	O
+.	O
+
+Individuals	O
+with	O
+HIV	O
+can	O
+now	O
+live	O
+long	O
+lives	O
+with	O
+drug	O
+therapy	O
+that	O
+often	O
+includes	O
+protease	O
+inhibitors	O
+such	O
+as	O
+ritonavir	O
+.	O
+
+Many	O
+patients	O
+,	O
+however	O
+,	O
+develop	O
+negative	O
+long	O
+-	O
+term	O
+side	O
+effects	O
+such	O
+as	O
+premature	B
+atherosclerosis	I
+.	O
+
+We	O
+have	O
+previously	O
+demonstrated	O
+that	O
+ritonavir	O
+treatment	O
+increases	O
+atherosclerotic	B
+lesion	I
+formation	O
+in	O
+male	O
+mice	O
+to	O
+a	O
+greater	O
+extent	O
+than	O
+in	O
+female	O
+mice	O
+.	O
+
+Furthermore	O
+,	O
+peripheral	O
+blood	O
+monocytes	O
+isolated	O
+from	O
+ritonavir	O
+-	O
+treated	O
+females	O
+had	O
+less	O
+cholesteryl	O
+ester	O
+accumulation	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+we	O
+have	O
+investigated	O
+the	O
+molecular	O
+mechanisms	O
+by	O
+which	O
+female	O
+hormones	O
+influence	O
+cholesterol	O
+metabolism	O
+in	O
+macrophages	O
+in	O
+response	O
+to	O
+the	O
+HIV	O
+protease	O
+inhibitor	O
+ritonavir	O
+.	O
+
+We	O
+have	O
+utilized	O
+the	O
+human	O
+monocyte	O
+cell	O
+line	O
+,	O
+THP	O
+-	O
+1	O
+as	O
+a	O
+model	O
+to	O
+address	O
+this	O
+question	O
+.	O
+
+Briefly	O
+,	O
+cells	O
+were	O
+differentiated	O
+for	O
+72	O
+h	O
+with	O
+100	O
+nM	O
+PMA	O
+to	O
+obtain	O
+a	O
+macrophage	O
+-	O
+like	O
+phenotype	O
+in	O
+the	O
+presence	O
+or	O
+absence	O
+of	O
+1	O
+nM	O
+17beta	O
+-	O
+estradiol	O
+(	O
+E2	O
+)	O
+,	O
+100	O
+nM	O
+progesterone	O
+or	O
+vehicle	O
+(	O
+0	O
+.	O
+01	O
+%	O
+ethanol	O
+)	O
+.	O
+
+Cells	O
+were	O
+then	O
+treated	O
+with	O
+30	O
+ng	O
+/	O
+ml	O
+ritonavir	O
+or	O
+vehicle	O
+in	O
+the	O
+presence	O
+of	O
+aggregated	O
+LDL	O
+for	O
+24	O
+h	O
+.	O
+
+Cell	O
+extracts	O
+were	O
+harvested	O
+,	O
+and	O
+lipid	O
+or	O
+total	O
+RNA	O
+was	O
+isolated	O
+.	O
+
+E2	O
+decreased	O
+the	O
+accumulation	O
+of	O
+cholesteryl	O
+esters	O
+in	O
+macrophages	O
+following	O
+ritonavir	O
+treatment	O
+.	O
+
+Ritonavir	O
+increased	O
+the	O
+expression	O
+of	O
+the	O
+scavenger	O
+receptor	O
+,	O
+CD36	O
+mRNA	O
+,	O
+responsible	O
+for	O
+the	O
+uptake	O
+of	O
+LDL	O
+.	O
+
+Additionally	O
+,	O
+ritonavir	O
+treatment	O
+selectively	O
+increased	O
+the	O
+relative	O
+levels	O
+of	O
+PPARgamma	O
+mRNA	O
+,	O
+a	O
+transcription	O
+factor	O
+responsible	O
+for	O
+the	O
+regulation	O
+of	O
+CD36	O
+mRNA	O
+expression	O
+.	O
+
+Treatment	O
+with	O
+E2	O
+,	O
+however	O
+,	O
+failed	O
+to	O
+prevent	O
+these	O
+increases	O
+at	O
+the	O
+mRNA	O
+level	O
+.	O
+
+E2	O
+did	O
+,	O
+however	O
+,	O
+significantly	O
+suppress	O
+CD36	O
+protein	O
+levels	O
+as	O
+measured	O
+by	O
+fluorescent	O
+immunocytochemistry	O
+.	O
+
+This	O
+data	O
+suggests	O
+that	O
+E2	O
+modifies	O
+the	O
+expression	O
+of	O
+CD36	O
+at	O
+the	O
+level	O
+of	O
+protein	O
+expression	O
+in	O
+monocyte	O
+-	O
+derived	O
+macrophages	O
+resulting	O
+in	O
+reduced	O
+cholesteryl	O
+ester	O
+accumulation	O
+following	O
+ritonavir	O
+treatment	O
+.	O
+
+Acute	O
+hepatitis	B
+attack	O
+after	O
+exposure	O
+to	O
+telithromycin	O
+.	O
+
+INTRODUCTION	O
+:	O
+Antibiotic	O
+-	O
+associated	O
+hepatotoxicity	B
+is	O
+rare	O
+.	O
+
+With	O
+widespread	O
+use	O
+of	O
+antimicrobial	O
+agents	O
+,	O
+however	O
+,	O
+hepatic	B
+injury	I
+occurs	O
+frequently	O
+,	O
+and	O
+among	O
+adverse	B
+drug	I
+reactions	I
+,	O
+idiosyncratic	O
+reactions	O
+are	O
+the	O
+most	O
+serious	O
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+25	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+,	O
+with	O
+a	O
+height	O
+of	O
+175	O
+cm	O
+and	O
+weight	O
+of	O
+72	O
+kg	O
+presented	O
+to	O
+Marmara	O
+University	O
+Hospital	O
+Emergency	O
+Department	O
+,	O
+Istanbul	O
+,	O
+Turkey	O
+,	O
+with	O
+5	O
+days	O
+'	O
+history	O
+of	O
+jaundice	B
+,	O
+malaise	O
+,	O
+nausea	B
+,	O
+and	O
+vomiting	B
+.	O
+
+He	O
+had	O
+been	O
+prescribed	O
+telithromycin	O
+400	O
+mg	O
+/	O
+d	O
+PO	O
+to	O
+treat	O
+an	O
+upper	B
+respiratory	I
+tract	I
+infection	I
+7	O
+days	O
+prior	O
+.	O
+
+Admission	O
+laboratory	O
+tests	O
+were	O
+as	O
+follows	O
+:	O
+alanine	O
+aminotransferase	O
+,	O
+67	O
+U	O
+/	O
+L	O
+(	O
+reference	O
+range	O
+,	O
+10	O
+-	O
+37	O
+U	O
+/	O
+L	O
+)	O
+;	O
+aspartate	O
+aminotransferase	O
+,	O
+98	O
+U	O
+/	O
+L	O
+(	O
+10	O
+-	O
+40	O
+U	O
+/	O
+L	O
+)	O
+;	O
+alkaline	O
+phosphatase	O
+,	O
+513	O
+U	O
+/	O
+L	O
+(	O
+0	O
+-	O
+270	O
+U	O
+/	O
+L	O
+)	O
+;	O
+gamma	O
+-	O
+glutamyltransferase	O
+,	O
+32	O
+U	O
+/	O
+L	O
+(	O
+7	O
+-	O
+49	O
+U	O
+/	O
+L	O
+)	O
+;	O
+amylase	O
+,	O
+46	O
+U	O
+/	O
+L	O
+(	O
+0	O
+-	O
+220	O
+U	O
+/	O
+L	O
+)	O
+;	O
+total	O
+bilirubin	O
+,	O
+20	O
+.	O
+1	O
+mg	O
+/	O
+dL	O
+(	O
+0	O
+.	O
+2	O
+-	O
+1	O
+.	O
+0	O
+mg	O
+/	O
+dL	O
+)	O
+;	O
+direct	O
+bilirubin	O
+,	O
+14	O
+.	O
+8	O
+mg	O
+/	O
+dL	O
+(	O
+0	O
+-	O
+0	O
+.	O
+3	O
+mg	O
+/	O
+dL	O
+)	O
+;	O
+and	O
+albumin	O
+,	O
+4	O
+.	O
+7	O
+mg	O
+/	O
+dL	O
+(	O
+3	O
+.	O
+5	O
+-	O
+5	O
+.	O
+4	O
+mg	O
+/	O
+dL	O
+)	O
+.	O
+
+No	O
+toxin	O
+,	O
+alcohol	O
+,	O
+or	O
+other	O
+drugs	O
+were	O
+reported	O
+.	O
+
+The	O
+patient	O
+had	O
+suffered	O
+a	O
+previous	O
+episode	O
+of	O
+"	O
+acute	O
+hepatitis	B
+of	O
+unknown	O
+origin	O
+,	O
+"	O
+that	O
+occurred	O
+after	O
+telithromycin	O
+usage	O
+.	O
+
+Both	O
+incidents	O
+occurred	O
+within	O
+a	O
+year	O
+.	O
+
+DISCUSSION	O
+:	O
+Telithromycin	O
+is	O
+the	O
+first	O
+of	O
+the	O
+ketolide	O
+antibacterials	O
+to	O
+receive	O
+US	O
+Food	O
+and	O
+Drug	O
+Administration	O
+approval	O
+for	O
+clinical	O
+use	O
+.	O
+
+It	O
+has	O
+been	O
+associated	O
+with	O
+infrequent	O
+and	O
+usually	O
+reversible	O
+severe	O
+hepatic	B
+dysfunction	I
+.	O
+
+Based	O
+on	O
+a	O
+score	O
+of	O
+8	O
+on	O
+the	O
+Naranjo	O
+adverse	B
+drug	I
+reaction	I
+probability	O
+scale	O
+,	O
+telithromycin	O
+was	O
+the	O
+probable	O
+cause	O
+of	O
+acute	O
+hepatitis	B
+in	O
+this	O
+patient	O
+,	O
+and	O
+pathological	O
+findings	O
+suggested	O
+drug	O
+-	O
+induced	O
+toxic	B
+hepatitis	I
+.	O
+
+Recurrence	O
+of	O
+hepatitis	B
+attack	O
+might	O
+have	O
+been	O
+avoided	O
+if	O
+the	O
+initial	O
+incident	O
+had	O
+been	O
+communicated	O
+to	O
+the	O
+attending	O
+physician	O
+who	O
+prescribed	O
+telithromycin	O
+the	O
+second	O
+time	O
+.	O
+
+CONCLUSION	O
+:	O
+Here	O
+we	O
+report	O
+a	O
+case	O
+of	O
+acute	O
+hepatitis	B
+probably	O
+associated	O
+with	O
+the	O
+administration	O
+of	O
+telithromycin	O
+.	O
+
+A	O
+study	O
+on	O
+the	O
+effect	O
+of	O
+the	O
+duration	O
+of	O
+subcutaneous	O
+heparin	O
+injection	O
+on	O
+bruising	B
+and	O
+pain	B
+.	O
+
+AIM	O
+:	O
+This	O
+study	O
+was	O
+carried	O
+out	O
+to	O
+determine	O
+the	O
+effect	O
+of	O
+injection	O
+duration	O
+on	O
+bruising	B
+and	O
+pain	B
+following	O
+the	O
+administration	O
+of	O
+the	O
+subcutaneous	O
+injection	O
+of	O
+heparin	O
+.	O
+
+BACKGROUND	O
+:	O
+Although	O
+different	O
+methods	O
+to	O
+prevent	O
+bruising	B
+and	O
+pain	B
+following	O
+the	O
+subcutaneous	O
+injection	O
+of	O
+heparin	O
+have	O
+been	O
+widely	O
+studied	O
+and	O
+described	O
+,	O
+the	O
+effect	O
+of	O
+injection	O
+duration	O
+on	O
+the	O
+occurrence	O
+of	O
+bruising	B
+and	O
+pain	B
+is	O
+little	O
+documented	O
+.	O
+
+DESIGN	O
+:	O
+This	O
+study	O
+was	O
+designed	O
+as	O
+within	O
+-	O
+subject	O
+,	O
+quasi	O
+-	O
+experimental	O
+research	O
+.	O
+
+METHOD	O
+:	O
+The	O
+sample	O
+for	O
+the	O
+study	O
+consisted	O
+of	O
+50	O
+patients	O
+to	O
+whom	O
+subcutaneous	O
+heparin	O
+was	O
+administered	O
+.	O
+
+Heparin	O
+was	O
+injected	O
+over	O
+10	O
+seconds	O
+on	O
+the	O
+right	O
+abdominal	O
+site	O
+and	O
+30	O
+seconds	O
+on	O
+the	O
+left	O
+abdominal	O
+site	O
+.	O
+
+Injections	O
+areas	O
+were	O
+assessed	O
+for	O
+the	O
+presence	O
+of	O
+bruising	B
+at	O
+48	O
+and	O
+72	O
+hours	O
+after	O
+each	O
+injection	O
+.	O
+
+Dimensions	O
+of	O
+the	O
+bruising	B
+on	O
+the	O
+heparin	O
+applied	O
+areas	O
+were	O
+measured	O
+using	O
+transparent	O
+millimetric	O
+measuring	O
+paper	O
+.	O
+
+The	O
+visual	O
+analog	O
+scale	O
+(	O
+VAS	O
+)	O
+was	O
+used	O
+to	O
+measure	O
+pain	B
+intensity	O
+and	O
+a	O
+stop	O
+-	O
+watch	O
+was	O
+used	O
+to	O
+time	O
+the	O
+pain	B
+period	O
+.	O
+
+Data	O
+were	O
+analysed	O
+using	O
+chi	O
+-	O
+square	O
+test	O
+,	O
+Mann	O
+-	O
+Whitney	O
+U	O
+,	O
+Wilcoxon	O
+signed	O
+ranks	O
+tests	O
+and	O
+correlation	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+percentage	O
+of	O
+bruising	B
+occurrence	O
+was	O
+64	O
+%	O
+with	O
+the	O
+injection	O
+of	O
+10	O
+seconds	O
+duration	O
+and	O
+42	O
+%	O
+in	O
+the	O
+30	O
+-	O
+second	O
+injection	O
+.	O
+
+It	O
+was	O
+determined	O
+that	O
+the	O
+size	O
+of	O
+the	O
+bruising	B
+was	O
+smaller	O
+in	O
+the	O
+30	O
+-	O
+second	O
+injection	O
+.	O
+
+Pain	B
+intensity	O
+and	O
+pain	B
+period	O
+were	O
+statistically	O
+significantly	O
+lower	O
+for	O
+the	O
+30	O
+-	O
+second	O
+injection	O
+than	O
+for	O
+the	O
+10	O
+-	O
+second	O
+injection	O
+.	O
+
+CONCLUSIONS	O
+:	O
+It	O
+was	O
+determined	O
+that	O
+injection	O
+duration	O
+had	O
+an	O
+effect	O
+on	O
+bruising	B
+and	O
+pain	B
+following	O
+the	O
+subcutaneous	O
+administration	O
+of	O
+heparin	O
+.	O
+
+This	O
+study	O
+should	O
+be	O
+repeated	O
+on	O
+a	O
+larger	O
+sample	O
+.	O
+
+RELEVANCE	O
+TO	O
+CLINICAL	O
+PRACTICE	O
+:	O
+When	O
+administering	O
+subcutaneous	O
+heparin	O
+injections	O
+,	O
+it	O
+is	O
+important	O
+to	O
+extend	O
+the	O
+duration	O
+of	O
+the	O
+injection	O
+.	O
+
+Acute	B
+liver	I
+failure	I
+in	O
+two	O
+patients	O
+with	O
+regular	O
+alcohol	O
+consumption	O
+ingesting	O
+paracetamol	O
+at	O
+therapeutic	O
+dosage	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+possible	O
+role	O
+of	O
+alcohol	O
+in	O
+the	O
+development	O
+of	O
+hepatotoxicity	B
+associated	O
+with	O
+therapeutic	O
+doses	O
+of	O
+paracetamol	O
+(	O
+acetaminophen	O
+)	O
+is	O
+currently	O
+debated	O
+.	O
+
+CASE	O
+REPORT	O
+:	O
+We	O
+describe	O
+2	O
+patients	O
+who	O
+were	O
+regular	O
+consumers	O
+of	O
+alcohol	O
+and	O
+who	O
+developed	O
+liver	B
+failure	I
+within	O
+3	O
+-	O
+5	O
+days	O
+after	O
+hospitalization	O
+and	O
+stopping	O
+alcohol	O
+consumption	O
+while	O
+being	O
+treated	O
+with	O
+4	O
+g	O
+paracetamol	O
+/	O
+day	O
+.	O
+
+A	O
+paracetamol	O
+serum	O
+level	O
+obtained	O
+in	O
+one	O
+of	O
+these	O
+patients	O
+was	O
+not	O
+in	O
+the	O
+toxic	O
+range	O
+.	O
+
+Possible	O
+risk	O
+factors	O
+for	O
+the	O
+development	O
+of	O
+hepatotoxicity	B
+in	O
+patients	O
+treated	O
+with	O
+therapeutic	O
+doses	O
+of	O
+paracetamol	O
+are	O
+discussed	O
+.	O
+
+CONCLUSION	O
+:	O
+In	O
+patients	O
+with	O
+risk	O
+factors	O
+,	O
+e	O
+.	O
+g	O
+.	O
+regular	O
+consumption	O
+of	O
+alcohol	O
+,	O
+liver	B
+failure	I
+is	O
+possible	O
+when	O
+therapeutic	O
+doses	O
+are	O
+ingested	O
+.	O
+
+We	O
+propose	O
+that	O
+the	O
+paracetamol	O
+dose	O
+should	O
+not	O
+exceed	O
+2	O
+g	O
+/	O
+day	O
+in	O
+such	O
+patients	O
+and	O
+that	O
+their	O
+liver	O
+function	O
+should	O
+be	O
+monitored	O
+closely	O
+while	O
+being	O
+treated	O
+with	O
+paracetamol	O
+.	O
+
+Associations	O
+between	O
+use	O
+of	O
+benzodiazepines	O
+or	O
+related	O
+drugs	O
+and	O
+health	O
+,	O
+physical	O
+abilities	O
+and	O
+cognitive	O
+function	O
+:	O
+a	O
+non	O
+-	O
+randomised	O
+clinical	O
+study	O
+in	O
+the	O
+elderly	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+describe	O
+associations	O
+between	O
+the	O
+use	O
+of	O
+benzodiazepines	O
+or	O
+related	O
+drugs	O
+(	O
+BZDs	O
+/	O
+RDs	O
+)	O
+and	O
+health	O
+,	O
+functional	O
+abilities	O
+and	O
+cognitive	O
+function	O
+in	O
+the	O
+elderly	O
+.	O
+
+METHODS	O
+:	O
+A	O
+non	O
+-	O
+randomised	O
+clinical	O
+study	O
+of	O
+patients	O
+aged	O
+>	O
+or	O
+=	O
+65	O
+years	O
+admitted	O
+to	O
+acute	O
+hospital	O
+wards	O
+during	O
+1	O
+month	O
+.	O
+
+164	O
+patients	O
+(	O
+mean	O
+age	O
++	O
+/	O
+-	O
+standard	O
+deviation	O
+[	O
+SD	O
+]	O
+81	O
+.	O
+6	O
++	O
+/	O
+-	O
+6	O
+.	O
+8	O
+years	O
+)	O
+were	O
+admitted	O
+.	O
+
+Of	O
+these	O
+,	O
+nearly	O
+half	O
+(	O
+n	O
+=	O
+78	O
+)	O
+had	O
+used	O
+BZDs	O
+/	O
+RDs	O
+before	O
+admission	O
+,	O
+and	O
+the	O
+remainder	O
+(	O
+n	O
+=	O
+86	O
+)	O
+were	O
+non	O
+-	O
+users	O
+.	O
+
+Cognitive	O
+ability	O
+was	O
+assessed	O
+by	O
+the	O
+Mini	O
+-	O
+Mental	O
+State	O
+Examination	O
+(	O
+MMSE	O
+)	O
+.	O
+
+Patients	O
+scoring	O
+>	O
+or	O
+=	O
+20	O
+MMSE	O
+sum	O
+points	O
+were	O
+interviewed	O
+(	O
+n	O
+=	O
+79	O
+)	O
+and	O
+questioned	O
+regarding	O
+symptoms	O
+and	O
+functional	O
+abilities	O
+during	O
+the	O
+week	O
+prior	O
+to	O
+admission	O
+.	O
+
+Data	O
+on	O
+use	O
+of	O
+BZDs	O
+/	O
+RDs	O
+before	O
+admission	O
+,	O
+current	O
+medications	O
+and	O
+discharge	O
+diagnoses	O
+were	O
+collected	O
+from	O
+medical	O
+records	O
+.	O
+
+Health	O
+,	O
+physical	O
+abilities	O
+and	O
+cognitive	O
+function	O
+were	O
+compared	O
+between	O
+BZD	O
+/	O
+RD	O
+users	O
+and	O
+non	O
+-	O
+users	O
+,	O
+and	O
+adjustments	O
+were	O
+made	O
+for	O
+confounding	O
+variables	O
+.	O
+
+The	O
+residual	O
+serum	O
+concentrations	O
+of	O
+oxazepam	O
+,	O
+temazepam	O
+and	O
+zopiclone	O
+were	O
+analysed	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+duration	O
+of	O
+BZD	O
+/	O
+RD	O
+use	O
+was	O
+7	O
++	O
+/	O
+-	O
+7	O
+years	O
+(	O
+range	O
+1	O
+-	O
+31	O
+)	O
+.	O
+
+Two	O
+or	O
+three	O
+BZDs	O
+/	O
+RDs	O
+were	O
+concomitantly	O
+taken	O
+by	O
+26	O
+%	O
+of	O
+users	O
+(	O
+n	O
+=	O
+20	O
+)	O
+.	O
+
+Long	O
+-	O
+term	O
+use	O
+of	O
+these	O
+drugs	O
+was	O
+associated	O
+with	O
+female	O
+sex	O
+and	O
+use	O
+of	O
+a	O
+higher	O
+number	O
+of	O
+drugs	O
+with	O
+effects	O
+on	O
+the	O
+CNS	O
+,	O
+which	O
+tended	O
+to	O
+be	O
+related	O
+to	O
+diagnosed	O
+dementia	B
+.	O
+
+After	O
+adjustment	O
+for	O
+these	O
+variables	O
+as	O
+confounders	O
+,	O
+use	O
+of	O
+BZDs	O
+/	O
+RDs	O
+was	O
+not	O
+associated	O
+with	O
+cognitive	O
+function	O
+as	O
+measured	O
+by	O
+the	O
+MMSE	O
+.	O
+
+However	O
+,	O
+use	O
+of	O
+BZDs	O
+/	O
+RDs	O
+was	O
+associated	O
+with	O
+dizziness	B
+,	O
+inability	B
+to	I
+sleep	I
+after	O
+awaking	O
+at	O
+night	O
+and	O
+tiredness	B
+in	O
+the	O
+mornings	O
+during	O
+the	O
+week	O
+prior	O
+to	O
+admission	O
+and	O
+with	O
+stronger	O
+depressive	B
+symptoms	I
+measured	O
+at	O
+the	O
+beginning	O
+of	O
+the	O
+hospital	O
+stay	O
+.	O
+
+Use	O
+of	O
+BZDs	O
+/	O
+RDs	O
+tended	O
+to	O
+be	O
+associated	O
+with	O
+a	O
+reduced	O
+ability	O
+to	O
+walk	O
+and	O
+shorter	O
+night	O
+-	O
+time	O
+sleep	O
+during	O
+the	O
+week	O
+prior	O
+to	O
+admission	O
+.	O
+
+A	O
+higher	O
+residual	O
+serum	O
+concentration	O
+of	O
+temazepam	O
+correlated	O
+with	O
+a	O
+lower	O
+MMSE	O
+sum	O
+score	O
+after	O
+adjustment	O
+for	O
+confounding	O
+variables	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Long	O
+-	O
+term	O
+use	O
+and	O
+concomitant	O
+use	O
+of	O
+more	O
+than	O
+one	O
+BZD	O
+/	O
+RD	O
+were	O
+common	O
+in	O
+elderly	O
+patients	O
+hospitalised	O
+because	O
+of	O
+acute	O
+illnesses	O
+.	O
+
+Long	O
+-	O
+term	O
+use	O
+was	O
+associated	O
+with	O
+daytime	O
+and	O
+night	O
+-	O
+time	O
+symptoms	O
+indicative	O
+of	O
+poorer	O
+health	O
+and	O
+potentially	O
+caused	O
+by	O
+the	O
+adverse	O
+effects	O
+of	O
+these	O
+drugs	O
+.	O
+
+Acute	O
+vocal	B
+fold	I
+palsy	I
+after	O
+acute	O
+disulfiram	O
+intoxication	O
+.	O
+
+Acute	O
+peripheral	B
+neuropathy	I
+caused	O
+by	O
+a	O
+disulfiram	O
+overdose	B
+is	O
+very	O
+rare	O
+and	O
+there	O
+is	O
+no	O
+report	O
+of	O
+it	O
+leading	O
+to	O
+vocal	B
+fold	I
+palsy	I
+.	O
+
+A	O
+49	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+was	O
+transferred	O
+to	O
+our	O
+department	O
+because	O
+of	O
+quadriparesis	B
+,	O
+lancinating	O
+pain	B
+,	O
+sensory	B
+loss	I
+,	O
+and	O
+paresthesia	B
+of	O
+the	O
+distal	O
+limbs	O
+.	O
+
+One	O
+month	O
+previously	O
+,	O
+she	O
+had	O
+taken	O
+a	O
+single	O
+high	O
+dose	O
+of	O
+disulfiram	O
+(	O
+130	O
+tablets	O
+of	O
+ALCOHOL	O
+STOP	O
+TAB	O
+,	O
+Shin	O
+-	O
+Poong	O
+Pharm	O
+.	O
+Co	O
+.	O
+,	O
+Ansan	O
+,	O
+Korea	O
+)	O
+in	O
+a	O
+suicide	O
+attempt	O
+.	O
+
+She	O
+was	O
+not	O
+an	O
+alcoholic	O
+.	O
+
+For	O
+the	O
+first	O
+few	O
+days	O
+after	O
+ingestion	O
+,	O
+she	O
+was	O
+in	O
+a	O
+confused	O
+state	O
+and	O
+had	O
+mild	O
+to	O
+moderate	O
+ataxia	B
+and	O
+giddiness	B
+.	O
+
+She	O
+noticed	O
+hoarseness	B
+and	O
+distally	O
+accentuated	O
+motor	O
+and	O
+sensory	O
+dysfunction	O
+after	O
+she	O
+had	O
+recovered	O
+from	O
+this	O
+state	O
+.	O
+
+A	O
+nerve	O
+conduction	O
+study	O
+was	O
+consistent	O
+with	O
+severe	O
+sensorimotor	O
+axonal	O
+polyneuropathy	B
+.	O
+
+Laryngeal	O
+electromyography	O
+(	O
+thyroarytenoid	O
+muscle	O
+)	O
+showed	O
+ample	O
+denervation	O
+potentials	O
+.	O
+
+Laryngoscopy	O
+revealed	O
+asymmetric	O
+vocal	O
+fold	O
+movements	O
+during	O
+phonation	O
+.	O
+
+Her	O
+vocal	O
+change	O
+and	O
+weakness	O
+began	O
+to	O
+improve	O
+spontaneously	O
+about	O
+3	O
+weeks	O
+after	O
+transfer	O
+.	O
+
+This	O
+was	O
+a	O
+case	O
+of	O
+acute	O
+palsy	B
+of	O
+the	O
+recurrent	O
+laryngeal	O
+nerve	O
+and	O
+superimposed	O
+severe	O
+acute	O
+sensorimotor	O
+axonal	O
+polyneuropathy	B
+caused	O
+by	O
+high	O
+-	O
+dose	O
+disulfiram	O
+intoxication	O
+.	O
+
+Encephalopathy	B
+induced	O
+by	O
+levetiracetam	O
+added	O
+to	O
+valproate	O
+.	O
+
+BACKGROUND	O
+:	O
+We	O
+report	O
+on	O
+the	O
+manifestation	O
+of	O
+a	O
+levetiracetam	O
+(	O
+LEV	O
+)	O
+-	O
+induced	O
+encephalopathy	B
+.	O
+
+FINDINGS	O
+:	O
+A	O
+28	O
+-	O
+year	O
+-	O
+old	O
+man	O
+suffering	O
+from	O
+idiopathic	B
+epilepsy	I
+with	O
+generalized	O
+seizures	B
+was	O
+treated	O
+with	O
+LEV	O
+(	O
+3000	O
+mg	O
+)	O
+added	O
+to	O
+valproate	O
+(	O
+VPA	O
+)	O
+(	O
+2000	O
+mg	O
+)	O
+.	O
+
+Frequency	O
+of	O
+generalized	O
+tonic	B
+-	I
+clonic	I
+seizures	I
+increased	O
+from	O
+one	O
+per	O
+6	O
+months	O
+to	O
+two	O
+per	O
+month	O
+.	O
+
+Neuropsychological	O
+testing	O
+showed	O
+impaired	B
+word	I
+fluency	I
+,	I
+psychomotor	I
+speed	I
+and	I
+working	I
+memory	I
+.	O
+
+The	O
+interictal	O
+electroencephalogram	O
+(	O
+EEG	O
+)	O
+showed	O
+a	O
+generalized	O
+slowing	O
+to	O
+5	O
+per	O
+second	O
+theta	O
+rhythms	O
+with	O
+bilateral	O
+generalized	O
+high	O
+-	O
+amplitude	O
+discharges	O
+.	O
+
+OUTCOME	O
+:	O
+Following	O
+discontinuation	O
+of	O
+LEV	O
+,	O
+EEG	O
+and	O
+neuropsychological	O
+findings	O
+improved	O
+and	O
+seizure	B
+frequency	O
+decreased	O
+.	O
+
+Norepinephrine	O
+signaling	O
+through	O
+beta	O
+-	O
+adrenergic	O
+receptors	O
+is	O
+critical	O
+for	O
+expression	O
+of	O
+cocaine	O
+-	O
+induced	O
+anxiety	B
+.	O
+
+BACKGROUND	O
+:	O
+Cocaine	O
+is	O
+a	O
+widely	O
+abused	O
+psychostimulant	O
+that	O
+has	O
+both	O
+rewarding	O
+and	O
+aversive	O
+properties	O
+.	O
+
+While	O
+the	O
+mechanisms	O
+underlying	O
+cocaine	O
+'	O
+s	O
+rewarding	O
+effects	O
+have	O
+been	O
+studied	O
+extensively	O
+,	O
+less	O
+attention	O
+has	O
+been	O
+paid	O
+to	O
+the	O
+unpleasant	O
+behavioral	O
+states	O
+induced	O
+by	O
+cocaine	O
+,	O
+such	O
+as	O
+anxiety	B
+.	O
+
+METHODS	O
+:	O
+In	O
+this	O
+study	O
+,	O
+we	O
+evaluated	O
+the	O
+performance	O
+of	O
+dopamine	O
+beta	O
+-	O
+hydroxylase	O
+knockout	O
+(	O
+Dbh	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+,	O
+which	O
+lack	O
+norepinephrine	O
+(	O
+NE	O
+)	O
+,	O
+in	O
+the	O
+elevated	O
+plus	O
+maze	O
+(	O
+EPM	O
+)	O
+to	O
+examine	O
+the	O
+contribution	O
+of	O
+noradrenergic	O
+signaling	O
+to	O
+cocaine	O
+-	O
+induced	O
+anxiety	B
+.	O
+
+RESULTS	O
+:	O
+We	O
+found	O
+that	O
+cocaine	O
+dose	O
+-	O
+dependently	O
+increased	O
+anxiety	B
+-	O
+like	O
+behavior	O
+in	O
+control	O
+(	O
+Dbh	O
++	O
+/	O
+-	O
+)	O
+mice	O
+,	O
+as	O
+measured	O
+by	O
+a	O
+decrease	O
+in	O
+open	O
+arm	O
+exploration	O
+.	O
+
+The	O
+Dbh	O
+-	O
+/	O
+-	O
+mice	O
+had	O
+normal	O
+baseline	O
+performance	O
+in	O
+the	O
+EPM	O
+but	O
+were	O
+completely	O
+resistant	O
+to	O
+the	O
+anxiogenic	O
+effects	O
+of	O
+cocaine	O
+.	O
+
+Cocaine	O
+-	O
+induced	O
+anxiety	B
+was	O
+also	O
+attenuated	O
+in	O
+Dbh	O
++	O
+/	O
+-	O
+mice	O
+following	O
+administration	O
+of	O
+disulfiram	O
+,	O
+a	O
+dopamine	O
+beta	O
+-	O
+hydroxylase	O
+(	O
+DBH	O
+)	O
+inhibitor	O
+.	O
+
+In	O
+experiments	O
+using	O
+specific	O
+adrenergic	O
+antagonists	O
+,	O
+we	O
+found	O
+that	O
+pretreatment	O
+with	O
+the	O
+beta	O
+-	O
+adrenergic	O
+receptor	O
+antagonist	O
+propranolol	O
+blocked	O
+cocaine	O
+-	O
+induced	O
+anxiety	B
+-	O
+like	O
+behavior	O
+in	O
+Dbh	O
++	O
+/	O
+-	O
+and	O
+wild	O
+-	O
+type	O
+C57BL6	O
+/	O
+J	O
+mice	O
+,	O
+while	O
+the	O
+alpha	O
+(	O
+1	O
+)	O
+antagonist	O
+prazosin	O
+and	O
+the	O
+alpha	O
+(	O
+2	O
+)	O
+antagonist	O
+yohimbine	O
+had	O
+no	O
+effect	O
+.	O
+
+CONCLUSIONS	O
+:	O
+These	O
+results	O
+indicate	O
+that	O
+noradrenergic	O
+signaling	O
+via	O
+beta	O
+-	O
+adrenergic	O
+receptors	O
+is	O
+required	O
+for	O
+cocaine	O
+-	O
+induced	O
+anxiety	B
+in	O
+mice	O
+.	O
+
+Hypothalamic	O
+prolactin	O
+receptor	O
+messenger	O
+ribonucleic	O
+acid	O
+levels	O
+,	O
+prolactin	O
+signaling	O
+,	O
+and	O
+hyperprolactinemic	B
+inhibition	O
+of	O
+pulsatile	O
+luteinizing	O
+hormone	O
+secretion	O
+are	O
+dependent	O
+on	O
+estradiol	O
+.	O
+
+Hyperprolactinemia	B
+can	O
+reduce	O
+fertility	O
+and	O
+libido	O
+.	O
+
+Although	O
+central	O
+prolactin	O
+actions	O
+are	O
+thought	O
+to	O
+contribute	O
+to	O
+this	O
+,	O
+the	O
+mechanisms	O
+are	O
+poorly	O
+understood	O
+.	O
+
+We	O
+first	O
+tested	O
+whether	O
+chronic	O
+hyperprolactinemia	B
+inhibited	O
+two	O
+neuroendocrine	O
+parameters	O
+necessary	O
+for	O
+female	O
+fertility	O
+:	O
+pulsatile	O
+LH	O
+secretion	O
+and	O
+the	O
+estrogen	O
+-	O
+induced	O
+LH	O
+surge	O
+.	O
+
+Chronic	O
+hyperprolactinemia	B
+induced	O
+by	O
+the	O
+dopamine	O
+antagonist	O
+sulpiride	O
+caused	O
+a	O
+40	O
+%	O
+reduction	O
+LH	O
+pulse	O
+frequency	O
+in	O
+ovariectomized	O
+rats	O
+,	O
+but	O
+only	O
+in	O
+the	O
+presence	O
+of	O
+chronic	O
+low	O
+levels	O
+of	O
+estradiol	O
+.	O
+
+Sulpiride	O
+did	O
+not	O
+affect	O
+the	O
+magnitude	O
+of	O
+a	O
+steroid	O
+-	O
+induced	O
+LH	O
+surge	O
+or	O
+the	O
+percentage	O
+of	O
+GnRH	O
+neurons	O
+activated	O
+during	O
+the	O
+surge	O
+.	O
+
+Estradiol	O
+is	O
+known	O
+to	O
+influence	O
+expression	O
+of	O
+the	O
+long	O
+form	O
+of	O
+prolactin	O
+receptors	O
+(	O
+PRL	O
+-	O
+R	O
+)	O
+and	O
+components	O
+of	O
+prolactin	O
+'	O
+s	O
+signaling	O
+pathway	O
+.	O
+
+To	O
+test	O
+the	O
+hypothesis	O
+that	O
+estrogen	O
+increases	O
+PRL	O
+-	O
+R	O
+expression	O
+and	O
+sensitivity	O
+to	O
+prolactin	O
+,	O
+we	O
+next	O
+demonstrated	O
+that	O
+estradiol	O
+greatly	O
+augments	O
+prolactin	O
+-	O
+induced	O
+STAT5	O
+activation	O
+.	O
+
+Lastly	O
+,	O
+we	O
+measured	O
+PRL	O
+-	O
+R	O
+and	O
+suppressor	O
+of	O
+cytokine	O
+signaling	O
+(	O
+SOCS	O
+-	O
+1	O
+and	O
+-	O
+3	O
+and	O
+CIS	O
+,	O
+which	O
+reflect	O
+the	O
+level	O
+of	O
+prolactin	O
+signaling	O
+)	O
+mRNAs	O
+in	O
+response	O
+to	O
+sulpiride	O
+and	O
+estradiol	O
+.	O
+
+Sulpiride	O
+induced	O
+only	O
+SOCS	O
+-	O
+1	O
+in	O
+the	O
+medial	O
+preoptic	O
+area	O
+,	O
+where	O
+GnRH	O
+neurons	O
+are	O
+regulated	O
+,	O
+but	O
+in	O
+the	O
+arcuate	O
+nucleus	O
+and	O
+choroid	O
+plexus	O
+,	O
+PRL	O
+-	O
+R	O
+,	O
+SOCS	O
+-	O
+3	O
+,	O
+and	O
+CIS	O
+mRNA	O
+levels	O
+were	O
+also	O
+induced	O
+.	O
+
+Estradiol	O
+enhanced	O
+these	O
+effects	O
+on	O
+SOCS	O
+-	O
+3	O
+and	O
+CIS	O
+.	O
+
+Interestingly	O
+,	O
+estradiol	O
+also	O
+induced	O
+PRL	O
+-	O
+R	O
+,	O
+SOCS	O
+-	O
+3	O
+,	O
+and	O
+CIS	O
+mRNA	O
+levels	O
+independently	O
+.	O
+
+These	O
+data	O
+show	O
+that	O
+GnRH	O
+pulse	O
+frequency	O
+is	O
+inhibited	O
+by	O
+chronic	O
+hyperprolactinemia	B
+in	O
+a	O
+steroid	O
+-	O
+dependent	O
+manner	O
+.	O
+
+They	O
+also	O
+provide	O
+evidence	O
+for	O
+estradiol	O
+-	O
+dependent	O
+and	O
+brain	O
+region	O
+-	O
+specific	O
+regulation	O
+of	O
+PRL	O
+-	O
+R	O
+expression	O
+and	O
+signaling	O
+responses	O
+by	O
+prolactin	O
+.	O
+
+Clonidine	O
+for	O
+attention	B
+-	I
+deficit	I
+/	I
+hyperactivity	I
+disorder	I
+:	O
+II	O
+.	O
+
+ECG	O
+changes	O
+and	O
+adverse	O
+events	O
+analysis	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+examine	O
+the	O
+safety	O
+and	O
+tolerability	O
+of	O
+clonidine	O
+used	O
+alone	O
+or	O
+with	O
+methylphenidate	O
+in	O
+children	O
+with	O
+attention	B
+-	I
+deficit	I
+/	I
+hyperactivity	I
+disorder	I
+(	O
+ADHD	B
+)	O
+.	O
+
+METHOD	O
+:	O
+In	O
+a	O
+16	O
+-	O
+week	O
+multicenter	O
+,	O
+double	O
+-	O
+blind	O
+trial	O
+,	O
+122	O
+children	O
+with	O
+ADHD	B
+were	O
+randomly	O
+assigned	O
+to	O
+clonidine	O
+(	O
+n	O
+=	O
+31	O
+)	O
+,	O
+methylphenidate	O
+(	O
+n	O
+=	O
+29	O
+)	O
+,	O
+clonidine	O
+and	O
+methylphenidate	O
+(	O
+n	O
+=	O
+32	O
+)	O
+,	O
+or	O
+placebo	O
+(	O
+n	O
+=	O
+30	O
+)	O
+.	O
+
+Doses	O
+were	O
+flexibly	O
+titrated	O
+up	O
+to	O
+0	O
+.	O
+6	O
+mg	O
+/	O
+day	O
+for	O
+clonidine	O
+and	O
+60	O
+mg	O
+/	O
+day	O
+for	O
+methylphenidate	O
+(	O
+both	O
+with	O
+divided	O
+dosing	O
+)	O
+.	O
+
+Groups	O
+were	O
+compared	O
+regarding	O
+adverse	O
+events	O
+and	O
+changes	O
+from	O
+baseline	O
+to	O
+week	O
+16	O
+in	O
+electrocardiograms	O
+and	O
+vital	O
+signs	O
+.	O
+
+RESULTS	O
+:	O
+There	O
+were	O
+more	O
+incidents	O
+of	O
+bradycardia	B
+in	O
+subjects	O
+treated	O
+with	O
+clonidine	O
+compared	O
+with	O
+those	O
+not	O
+treated	O
+with	O
+clonidine	O
+(	O
+17	O
+.	O
+5	O
+%	O
+versus	O
+3	O
+.	O
+4	O
+%	O
+;	O
+p	O
+=	O
+.	O
+02	O
+)	O
+,	O
+but	O
+no	O
+other	O
+significant	O
+group	O
+differences	O
+regarding	O
+electrocardiogram	O
+and	O
+other	O
+cardiovascular	O
+outcomes	O
+.	O
+
+There	O
+were	O
+no	O
+suggestions	O
+of	O
+interactions	O
+between	O
+clonidine	O
+and	O
+methylphenidate	O
+regarding	O
+cardiovascular	O
+outcomes	O
+.	O
+
+Moderate	O
+or	O
+severe	O
+adverse	O
+events	O
+were	O
+more	O
+common	O
+in	O
+subjects	O
+on	O
+clonidine	O
+(	O
+79	O
+.	O
+4	O
+%	O
+versus	O
+49	O
+.	O
+2	O
+%	O
+;	O
+p	O
+=	O
+.	O
+0006	O
+)	O
+but	O
+not	O
+associated	O
+with	O
+higher	O
+rates	O
+of	O
+early	O
+study	O
+withdrawal	O
+.	O
+
+Drowsiness	B
+was	O
+common	O
+on	O
+clonidine	O
+,	O
+but	O
+generally	O
+resolved	O
+by	O
+6	O
+to	O
+8	O
+weeks	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Clonidine	O
+,	O
+used	O
+alone	O
+or	O
+with	O
+methylphenidate	O
+,	O
+appears	O
+safe	O
+and	O
+well	O
+tolerated	O
+in	O
+childhood	O
+ADHD	B
+.	O
+
+Physicians	O
+prescribing	O
+clonidine	O
+should	O
+monitor	O
+for	O
+bradycardia	B
+and	O
+advise	O
+patients	O
+about	O
+the	O
+high	O
+likelihood	O
+of	O
+initial	O
+drowsiness	B
+.	O
+
+Renal	B
+Fanconi	I
+syndrome	I
+and	O
+myopathy	B
+after	O
+liver	O
+transplantation	O
+:	O
+drug	O
+-	O
+related	O
+mitochondrial	B
+cytopathy	I
+?	O
+
+Advances	O
+in	O
+the	O
+field	O
+of	O
+transplantation	O
+provide	O
+a	O
+better	O
+quality	O
+of	O
+life	O
+and	O
+allow	O
+more	O
+favorable	O
+conditions	O
+for	O
+growth	O
+and	O
+development	O
+in	O
+children	O
+.	O
+
+However	O
+,	O
+combinations	O
+of	O
+different	O
+therapeutic	O
+regimens	O
+require	O
+consideration	O
+of	O
+potential	O
+adverse	O
+reactions	O
+.	O
+
+We	O
+describe	O
+a	O
+15	O
+-	O
+yr	O
+-	O
+old	O
+girl	O
+who	O
+had	O
+orthotopic	O
+liver	O
+transplantation	O
+because	O
+of	O
+Wilson	B
+'	I
+s	I
+disease	I
+.	O
+
+Tacrolimus	O
+,	O
+MMF	O
+,	O
+and	O
+steroids	O
+were	O
+given	O
+as	O
+immunosuppressant	O
+.	O
+
+Lamivudine	O
+was	O
+added	O
+because	O
+of	O
+de	O
+nova	O
+hepatitis	B
+B	I
+infection	I
+during	O
+her	O
+follow	O
+-	O
+up	O
+.	O
+
+Three	O
+yr	O
+after	O
+transplantation	O
+she	O
+developed	O
+renal	B
+Fanconi	I
+syndrome	I
+with	O
+severe	O
+metabolic	B
+acidosis	I
+,	O
+hypophosphatemia	B
+,	O
+glycosuria	B
+,	O
+and	O
+aminoaciduria	B
+.	O
+
+Although	O
+tacrolimus	O
+was	O
+suspected	O
+to	O
+be	O
+the	O
+cause	O
+of	O
+late	O
+post	O
+-	O
+transplant	O
+renal	O
+acidosis	B
+and	O
+was	O
+replaced	O
+by	O
+sirolimus	O
+,	O
+acidosis	B
+,	O
+and	O
+electrolyte	O
+imbalance	O
+got	O
+worse	O
+.	O
+
+Proximal	O
+muscle	B
+weakness	I
+has	O
+developed	O
+during	O
+her	O
+follow	O
+-	O
+up	O
+.	O
+
+Fanconi	B
+syndrome	I
+,	O
+as	O
+well	O
+as	O
+myopathy	B
+,	O
+is	O
+well	O
+recognized	O
+in	O
+patients	O
+with	O
+mitochondrial	B
+disorders	I
+and	O
+caused	O
+by	O
+depletion	O
+of	O
+mtDNA	O
+.	O
+
+We	O
+suggest	O
+that	O
+our	O
+patient	O
+'	O
+s	O
+tubular	B
+dysfunction	I
+and	O
+myopathy	B
+may	O
+have	O
+resulted	O
+from	O
+mitochondrial	B
+dysfunction	I
+which	O
+is	O
+triggered	O
+by	O
+tacrolimus	O
+and	O
+augmented	O
+by	O
+lamivudine	O
+.	O
+
+Higher	O
+optical	O
+density	O
+of	O
+an	O
+antigen	O
+assay	O
+predicts	O
+thrombosis	B
+in	O
+patients	O
+with	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+correlate	O
+optical	O
+density	O
+and	O
+percent	O
+inhibition	O
+of	O
+a	O
+two	O
+-	O
+step	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+(	O
+HIT	B
+)	O
+antigen	O
+assay	O
+with	O
+thrombosis	B
+;	O
+the	O
+assay	O
+utilizes	O
+reaction	O
+inhibition	O
+characteristics	O
+of	O
+a	O
+high	O
+heparin	O
+concentration	O
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+Patients	O
+with	O
+more	O
+than	O
+50	O
+%	O
+decrease	O
+in	O
+platelet	O
+count	O
+or	O
+thrombocytopenia	B
+(	O
+<	O
+150	O
+x	O
+10	O
+(	O
+9	O
+)	O
+/	O
+L	O
+)	O
+after	O
+exposure	O
+to	O
+heparin	O
+,	O
+who	O
+had	O
+a	O
+positive	O
+two	O
+-	O
+step	O
+antigen	O
+assay	O
+[	O
+optical	O
+density	O
+(	O
+OD	O
+)	O
+>	O
+0	O
+.	O
+4	O
+and	O
+>	O
+50	O
+inhibition	O
+with	O
+high	O
+concentration	O
+of	O
+heparin	O
+]	O
+were	O
+included	O
+in	O
+the	O
+study	O
+.	O
+
+RESULTS	O
+:	O
+Forty	O
+of	O
+94	O
+HIT	B
+patients	O
+had	O
+thrombosis	B
+at	O
+diagnosis	O
+;	O
+54	O
+/	O
+94	O
+had	O
+isolated	O
+-	O
+HIT	B
+without	O
+thrombosis	B
+.	O
+
+Eight	O
+of	O
+the	O
+isolated	O
+-	O
+HIT	B
+patients	O
+developed	O
+thrombosis	B
+within	O
+the	O
+next	O
+30	O
+d	O
+;	O
+thus	O
+,	O
+a	O
+total	O
+of	O
+48	O
+patients	O
+had	O
+thrombosis	B
+at	O
+day	O
+30	O
+.	O
+
+At	O
+diagnosis	O
+there	O
+was	O
+no	O
+significant	O
+difference	O
+in	O
+OD	O
+between	O
+HIT	B
+patients	O
+with	O
+thrombosis	B
+and	O
+those	O
+with	O
+isolated	O
+-	O
+HIT	B
+.	O
+
+However	O
+,	O
+OD	O
+was	O
+significantly	O
+higher	O
+in	O
+all	O
+patients	O
+with	O
+thrombosis	B
+(	O
+n	O
+=	O
+48	O
+,	O
+1	O
+.	O
+34	O
++	O
+/	O
+-	O
+0	O
+.	O
+89	O
+)	O
+,	O
+including	O
+isolated	O
+-	O
+HIT	B
+patients	O
+who	O
+later	O
+developed	O
+thrombosis	B
+within	O
+30	O
+d	O
+(	O
+n	O
+=	O
+8	O
+,	O
+1	O
+.	O
+84	O
++	O
+/	O
+-	O
+0	O
+.	O
+64	O
+)	O
+as	O
+compared	O
+to	O
+isolated	O
+-	O
+HIT	B
+patients	O
+who	O
+did	O
+not	O
+develop	O
+thrombosis	B
+(	O
+0	O
+.	O
+96	O
++	O
+/	O
+-	O
+0	O
+.	O
+75	O
+;	O
+P	O
+=	O
+0	O
+.	O
+011	O
+and	O
+P	O
+=	O
+0	O
+.	O
+008	O
+)	O
+.	O
+
+The	O
+Receiver	O
+Operative	O
+Characteristic	O
+Curve	O
+showed	O
+that	O
+OD	O
+>	O
+1	O
+.	O
+27	O
+in	O
+the	O
+isolated	O
+-	O
+HIT	B
+group	O
+had	O
+a	O
+significantly	O
+higher	O
+chance	O
+of	O
+developing	O
+thrombosis	B
+by	O
+day	O
+30	O
+.	O
+
+None	O
+of	O
+these	O
+groups	O
+showed	O
+significant	O
+difference	O
+in	O
+percent	O
+inhibition	O
+.	O
+
+Multivariate	O
+analysis	O
+showed	O
+a	O
+2	O
+.	O
+8	O
+-	O
+fold	O
+increased	O
+risk	O
+of	O
+thrombosis	B
+in	O
+females	O
+.	O
+
+Similarly	O
+,	O
+thrombotic	B
+risk	O
+increased	O
+with	O
+age	O
+and	O
+OD	O
+values	O
+.	O
+
+CONCLUSION	O
+:	O
+Higher	O
+OD	O
+is	O
+associated	O
+with	O
+significant	O
+risk	O
+of	O
+subsequent	O
+thrombosis	B
+in	O
+patients	O
+with	O
+isolated	O
+-	O
+HIT	B
+;	O
+percent	O
+inhibition	O
+,	O
+however	O
+,	O
+was	O
+not	O
+predictive	O
+.	O
+
+Thalidomide	O
+has	O
+limited	O
+single	O
+-	O
+agent	O
+activity	O
+in	O
+relapsed	O
+or	O
+refractory	O
+indolent	O
+non	B
+-	I
+Hodgkin	I
+lymphomas	I
+:	O
+a	O
+phase	O
+II	O
+trial	O
+of	O
+the	O
+Cancer	B
+and	O
+Leukemia	B
+Group	O
+B	O
+.	O
+
+Thalidomide	O
+is	O
+an	O
+immunomodulatory	O
+agent	O
+with	O
+demonstrated	O
+activity	O
+in	O
+multiple	B
+myeloma	I
+,	O
+mantle	B
+cell	I
+lymphoma	I
+and	O
+lymphoplasmacytic	B
+lymphoma	I
+.	O
+
+Its	O
+activity	O
+is	O
+believed	O
+to	O
+be	O
+due	O
+modulation	O
+of	O
+the	O
+tumour	B
+milieu	O
+,	O
+including	O
+downregulation	O
+of	O
+angiogenesis	O
+and	O
+inflammatory	O
+cytokines	O
+.	O
+
+Between	O
+July	O
+2001	O
+and	O
+April	O
+2004	O
+,	O
+24	O
+patients	O
+with	O
+relapsed	O
+/	O
+refractory	O
+indolent	O
+lymphomas	B
+received	O
+thalidomide	O
+200	O
+mg	O
+daily	O
+with	O
+escalation	O
+by	O
+100	O
+mg	O
+daily	O
+every	O
+1	O
+-	O
+2	O
+weeks	O
+as	O
+tolerated	O
+,	O
+up	O
+to	O
+a	O
+maximum	O
+of	O
+800	O
+mg	O
+daily	O
+.	O
+
+Patients	O
+had	O
+received	O
+a	O
+median	O
+of	O
+2	O
+(	O
+range	O
+,	O
+1	O
+-	O
+4	O
+)	O
+prior	O
+regimens	O
+.	O
+
+Of	O
+24	O
+evaluable	O
+patients	O
+,	O
+two	O
+achieved	O
+a	O
+complete	O
+remission	O
+and	O
+one	O
+achieved	O
+a	O
+partial	O
+remission	O
+for	O
+an	O
+overall	O
+response	O
+rate	O
+of	O
+12	O
+.	O
+5	O
+%	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+:	O
+2	O
+.	O
+6	O
+-	O
+32	O
+.	O
+4	O
+%	O
+)	O
+.	O
+
+Eleven	O
+patients	O
+progressed	O
+during	O
+therapy	O
+.	O
+
+Grade	O
+3	O
+-	O
+4	O
+adverse	O
+effects	O
+included	O
+myelosuppression	B
+,	O
+fatigue	B
+,	O
+somnolence	B
+/	O
+depressed	B
+mood	I
+,	O
+neuropathy	B
+and	O
+dyspnea	B
+.	O
+
+Of	O
+concern	O
+was	O
+the	O
+occurrence	O
+of	O
+four	O
+thromboembolic	B
+events	O
+.	O
+
+Our	O
+results	O
+failed	O
+to	O
+demonstrate	O
+an	O
+important	O
+response	O
+rate	O
+to	O
+single	O
+agent	O
+thalidomide	O
+in	O
+indolent	O
+lymphomas	B
+and	O
+contrast	O
+with	O
+the	O
+higher	O
+activity	O
+level	O
+reported	O
+with	O
+the	O
+second	O
+generation	O
+immunomodulatory	O
+agent	O
+,	O
+lenalidomide	O
+.	O
+
+Sex	O
+differences	O
+in	O
+NMDA	O
+antagonist	O
+enhancement	O
+of	O
+morphine	O
+antihyperalgesia	O
+in	O
+a	O
+capsaicin	O
+model	O
+of	O
+persistent	O
+pain	B
+:	O
+comparisons	O
+to	O
+two	O
+models	O
+of	O
+acute	B
+pain	I
+.	O
+
+In	O
+acute	B
+pain	I
+models	O
+,	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+antagonists	O
+enhance	O
+the	O
+antinociceptive	O
+effects	O
+of	O
+morphine	O
+to	O
+a	O
+greater	O
+extent	O
+in	O
+males	O
+than	O
+females	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+investigation	O
+was	O
+to	O
+extend	O
+these	O
+findings	O
+to	O
+a	O
+persistent	O
+pain	B
+model	O
+which	O
+could	O
+be	O
+distinguished	O
+from	O
+acute	B
+pain	I
+models	O
+on	O
+the	O
+basis	O
+of	O
+the	O
+nociceptive	O
+fibers	O
+activated	O
+,	O
+neurochemical	O
+substrates	O
+,	O
+and	O
+duration	O
+of	O
+the	O
+nociceptive	O
+stimulus	O
+.	O
+
+To	O
+this	O
+end	O
+,	O
+persistent	O
+hyperalgesia	B
+was	O
+induced	O
+by	O
+administration	O
+of	O
+capsaicin	O
+in	O
+the	O
+tail	O
+of	O
+gonadally	O
+intact	O
+F344	O
+rats	O
+,	O
+following	O
+which	O
+the	O
+tail	O
+was	O
+immersed	O
+in	O
+a	O
+mildly	O
+noxious	O
+thermal	O
+stimulus	O
+,	O
+and	O
+tail	O
+-	O
+withdrawal	O
+latencies	O
+measured	O
+.	O
+
+For	O
+comparison	O
+,	O
+tests	O
+were	O
+conducted	O
+in	O
+two	O
+acute	B
+pain	I
+models	O
+,	O
+the	O
+hotplate	O
+and	O
+warm	O
+water	O
+tail	O
+-	O
+withdrawal	O
+procedures	O
+.	O
+
+In	O
+males	O
+,	O
+the	O
+non	O
+-	O
+competitive	O
+NMDA	O
+antagonist	O
+dextromethorphan	O
+enhanced	O
+the	O
+antihyperalgesic	O
+effect	O
+of	O
+low	O
+to	O
+moderate	O
+doses	O
+of	O
+morphine	O
+in	O
+a	O
+dose	O
+-	O
+and	O
+time	O
+-	O
+dependent	O
+manner	O
+.	O
+
+Across	O
+the	O
+doses	O
+and	O
+pretreatment	O
+times	O
+examined	O
+,	O
+enhancement	O
+was	O
+not	O
+observed	O
+in	O
+females	O
+.	O
+
+Enhancement	O
+of	O
+morphine	O
+antinociception	O
+by	O
+dextromethorphan	O
+was	O
+seen	O
+in	O
+both	O
+males	O
+and	O
+females	O
+in	O
+the	O
+acute	B
+pain	I
+models	O
+,	O
+with	O
+the	O
+magnitude	O
+of	O
+this	O
+effect	O
+being	O
+greater	O
+in	O
+males	O
+.	O
+
+These	O
+findings	O
+demonstrate	O
+a	O
+sexually	O
+-	O
+dimorphic	O
+interaction	O
+between	O
+NMDA	O
+antagonists	O
+and	O
+morphine	O
+in	O
+a	O
+persistent	O
+pain	B
+model	O
+that	O
+can	O
+be	O
+distinguished	O
+from	O
+those	O
+observed	O
+in	O
+acute	B
+pain	I
+models	O
+.	O
+
+Development	O
+of	O
+proteinuria	B
+after	O
+switch	O
+to	O
+sirolimus	O
+-	O
+based	O
+immunosuppression	O
+in	O
+long	O
+-	O
+term	O
+cardiac	O
+transplant	O
+patients	O
+.	O
+
+Calcineurin	O
+-	O
+inhibitor	O
+therapy	O
+can	O
+lead	O
+to	O
+renal	B
+dysfunction	I
+in	O
+heart	O
+transplantation	O
+patients	O
+.	O
+
+The	O
+novel	O
+immunosuppressive	O
+(	O
+IS	O
+)	O
+drug	O
+sirolmus	O
+(	O
+Srl	O
+)	O
+lacks	O
+nephrotoxic	B
+effects	O
+;	O
+however	O
+,	O
+proteinuria	B
+associated	O
+with	O
+Srl	O
+has	O
+been	O
+reported	O
+following	O
+renal	O
+transplantation	O
+.	O
+
+In	O
+cardiac	O
+transplantation	O
+,	O
+the	O
+incidence	O
+of	O
+proteinuria	B
+associated	O
+with	O
+Srl	O
+is	O
+unknown	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+long	O
+-	O
+term	O
+cardiac	O
+transplant	O
+patients	O
+were	O
+switched	O
+from	O
+cyclosporine	O
+to	O
+Srl	O
+-	O
+based	O
+IS	O
+.	O
+
+Concomitant	O
+IS	O
+consisted	O
+of	O
+mycophenolate	O
+mofetil	O
++	O
+/	O
+-	O
+steroids	O
+.	O
+
+Proteinuria	O
+increased	O
+significantly	O
+from	O
+a	O
+median	O
+of	O
+0	O
+.	O
+13	O
+g	O
+/	O
+day	O
+(	O
+range	O
+0	O
+-	O
+5	O
+.	O
+7	O
+)	O
+preswitch	O
+to	O
+0	O
+.	O
+23	O
+g	O
+/	O
+day	O
+(	O
+0	O
+-	O
+9	O
+.	O
+88	O
+)	O
+at	O
+24	O
+months	O
+postswitch	O
+(	O
+p	O
+=	O
+0	O
+.	O
+0024	O
+)	O
+.	O
+
+Before	O
+the	O
+switch	O
+,	O
+11	O
+.	O
+5	O
+%	O
+of	O
+patients	O
+had	O
+high	O
+-	O
+grade	O
+proteinuria	B
+(	O
+>	O
+1	O
+.	O
+0	O
+g	O
+/	O
+day	O
+)	O
+;	O
+this	O
+increased	O
+to	O
+22	O
+.	O
+9	O
+%	O
+postswitch	O
+(	O
+p	O
+=	O
+0	O
+.	O
+006	O
+)	O
+.	O
+
+ACE	O
+inhibitor	O
+and	O
+angiotensin	O
+-	O
+releasing	O
+blocker	O
+(	O
+ARB	O
+)	O
+therapy	O
+reduced	O
+proteinuria	B
+development	O
+.	O
+
+Patients	O
+without	O
+proteinuria	B
+had	O
+increased	O
+renal	O
+function	O
+(	O
+median	O
+42	O
+.	O
+5	O
+vs	O
+.	O
+64	O
+.	O
+1	O
+,	O
+p	O
+=	O
+0	O
+.	O
+25	O
+)	O
+,	O
+whereas	O
+patients	O
+who	O
+developed	O
+high	O
+-	O
+grade	O
+proteinuria	B
+showed	O
+decreased	O
+renal	O
+function	O
+at	O
+the	O
+end	O
+of	O
+follow	O
+-	O
+up	O
+(	O
+median	O
+39	O
+.	O
+6	O
+vs	O
+.	O
+29	O
+.	O
+2	O
+,	O
+p	O
+=	O
+0	O
+.	O
+125	O
+)	O
+.	O
+
+Thus	O
+,	O
+proteinuria	B
+may	O
+develop	O
+in	O
+cardiac	O
+transplant	O
+patients	O
+after	O
+switch	O
+to	O
+Srl	O
+,	O
+which	O
+may	O
+have	O
+an	O
+adverse	O
+effect	O
+on	O
+renal	O
+function	O
+in	O
+these	O
+patients	O
+.	O
+
+Srl	O
+should	O
+be	O
+used	O
+with	O
+ACEi	O
+/	O
+ARB	O
+therapy	O
+and	O
+patients	O
+monitored	O
+for	O
+proteinuria	B
+and	O
+increased	O
+renal	B
+dysfunction	I
+.	O
+
+Ginsenoside	O
+Rg1	O
+restores	O
+the	O
+impairment	B
+of	I
+learning	I
+induced	O
+by	O
+chronic	O
+morphine	O
+administration	O
+in	O
+rats	O
+.	O
+
+Rg1	O
+,	O
+as	O
+a	O
+ginsenoside	O
+extracted	O
+from	O
+Panax	O
+ginseng	O
+,	O
+could	O
+ameliorate	O
+spatial	O
+learning	B
+impairment	I
+.	O
+
+Previous	O
+studies	O
+have	O
+demonstrated	O
+that	O
+Rg1	O
+might	O
+be	O
+a	O
+useful	O
+agent	O
+for	O
+the	O
+prevention	O
+and	O
+treatment	O
+of	O
+the	O
+adverse	O
+effects	O
+of	O
+morphine	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+effect	O
+of	O
+Rg1	O
+on	O
+learning	B
+impairment	I
+by	O
+chronic	O
+morphine	O
+administration	O
+and	O
+the	O
+mechanism	O
+responsible	O
+for	O
+this	O
+effect	O
+.	O
+
+Male	O
+rats	O
+were	O
+subcutaneously	O
+injected	O
+with	O
+morphine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+twice	O
+a	O
+day	O
+at	O
+12	O
+hour	O
+intervals	O
+for	O
+10	O
+days	O
+,	O
+and	O
+Rg1	O
+(	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+intraperitoneally	O
+injected	O
+2	O
+hours	O
+after	O
+the	O
+second	O
+injection	O
+of	O
+morphine	O
+once	O
+a	O
+day	O
+for	O
+10	O
+days	O
+.	O
+
+Spatial	O
+learning	O
+capacity	O
+was	O
+assessed	O
+in	O
+the	O
+Morris	O
+water	O
+maze	O
+.	O
+
+The	O
+results	O
+showed	O
+that	O
+rats	O
+treated	O
+with	O
+Morphine	O
+/	O
+Rg1	O
+decreased	O
+escape	O
+latency	O
+and	O
+increased	O
+the	O
+time	O
+spent	O
+in	O
+platform	O
+quadrant	O
+and	O
+entering	O
+frequency	O
+.	O
+
+By	O
+implantation	O
+of	O
+electrodes	O
+and	O
+electrophysiological	O
+recording	O
+in	O
+vivo	O
+,	O
+the	O
+results	O
+showed	O
+that	O
+Rg1	O
+restored	O
+the	O
+long	O
+-	O
+term	O
+potentiation	O
+(	O
+LTP	O
+)	O
+impaired	O
+by	O
+morphine	O
+in	O
+both	O
+freely	O
+moving	O
+and	O
+anaesthetised	O
+rats	O
+.	O
+
+The	O
+electrophysiological	O
+recording	O
+in	O
+vitro	O
+showed	O
+that	O
+Rg1	O
+restored	O
+the	O
+LTP	O
+in	O
+slices	O
+from	O
+the	O
+rats	O
+treated	O
+with	O
+morphine	O
+,	O
+but	O
+not	O
+changed	O
+LTP	O
+in	O
+the	O
+slices	O
+from	O
+normal	O
+saline	O
+-	O
+or	O
+morphine	O
+/	O
+Rg1	O
+-	O
+treated	O
+rats	O
+;	O
+this	O
+restoration	O
+could	O
+be	O
+inhibited	O
+by	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+receptor	O
+antagonist	O
+MK801	O
+.	O
+
+We	O
+conclude	O
+that	O
+Rg1	O
+may	O
+significantly	O
+improve	O
+the	O
+spatial	O
+learning	O
+capacity	O
+impaired	O
+by	O
+chonic	O
+morphine	O
+administration	O
+and	O
+restore	O
+the	O
+morphine	O
+-	O
+inhibited	O
+LTP	O
+.	O
+
+This	O
+effect	O
+is	O
+NMDA	O
+receptor	O
+dependent	O
+.	O
+
+Synthesis	O
+of	O
+N	O
+-	O
+pyrimidinyl	O
+-	O
+2	O
+-	O
+phenoxyacetamides	O
+as	O
+adenosine	O
+A2A	O
+receptor	O
+antagonists	O
+.	O
+
+A	O
+series	O
+of	O
+N	O
+-	O
+pyrimidinyl	O
+-	O
+2	O
+-	O
+phenoxyacetamide	O
+adenosine	O
+A	O
+(	O
+2A	O
+)	O
+antagonists	O
+is	O
+described	O
+.	O
+
+SAR	O
+studies	O
+led	O
+to	O
+compound	O
+14	O
+with	O
+excellent	O
+potency	O
+(	O
+K	O
+(	O
+i	O
+)	O
+=	O
+0	O
+.	O
+4	O
+nM	O
+)	O
+,	O
+selectivity	O
+(	O
+A	O
+(	O
+1	O
+)	O
+/	O
+A	O
+(	O
+2A	O
+)	O
+>	O
+100	O
+)	O
+,	O
+and	O
+efficacy	O
+(	O
+MED	O
+10	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+)	O
+in	O
+the	O
+rat	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+model	O
+for	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+Evidence	O
+for	O
+an	O
+involvement	O
+of	O
+D1	O
+and	O
+D2	O
+dopamine	O
+receptors	O
+in	O
+mediating	O
+nicotine	O
+-	O
+induced	O
+hyperactivity	B
+in	O
+rats	O
+.	O
+
+Previous	O
+studies	O
+have	O
+suggested	O
+that	O
+repeated	O
+exposure	O
+of	O
+rats	O
+to	O
+the	O
+drug	O
+or	O
+to	O
+the	O
+experimental	O
+environment	O
+is	O
+necessary	O
+to	O
+observe	O
+nicotine	O
+-	O
+induced	O
+locomotor	O
+stimulation	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+the	O
+role	O
+of	O
+habituation	O
+to	O
+the	O
+experimental	O
+environment	O
+on	O
+the	O
+stimulant	O
+effect	O
+of	O
+nicotine	O
+in	O
+rats	O
+was	O
+examined	O
+.	O
+
+In	O
+addition	O
+,	O
+the	O
+role	O
+of	O
+dopamine	O
+receptors	O
+in	O
+mediating	O
+nicotine	O
+-	O
+induced	O
+locomotor	O
+stimulation	O
+was	O
+investigated	O
+by	O
+examining	O
+the	O
+effects	O
+of	O
+selective	O
+D1	O
+and	O
+D2	O
+dopamine	O
+receptor	O
+antagonists	O
+on	O
+activity	O
+induced	O
+by	O
+nicotine	O
+.	O
+
+Locomotor	O
+activity	O
+was	O
+assessed	O
+in	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+tested	O
+in	O
+photocell	O
+cages	O
+.	O
+
+Nicotine	O
+(	O
+1	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+)	O
+caused	O
+a	O
+significant	O
+increase	B
+in	I
+locomotor	I
+activity	I
+in	O
+rats	O
+that	O
+were	O
+habituated	O
+to	O
+the	O
+test	O
+environment	O
+,	O
+but	O
+had	O
+only	O
+a	O
+weak	O
+and	O
+delayed	O
+stimulant	O
+action	O
+in	O
+rats	O
+that	O
+were	O
+unfamiliar	O
+with	O
+the	O
+test	O
+environment	O
+.	O
+
+The	O
+stimulant	O
+action	O
+of	O
+nicotine	O
+was	O
+blocked	O
+by	O
+the	O
+central	O
+nicotinic	O
+antagonist	O
+mecamylamine	O
+but	O
+not	O
+by	O
+the	O
+peripheral	O
+nicotinic	O
+blocker	O
+hexamethonium	O
+,	O
+indicating	O
+that	O
+the	O
+response	O
+is	O
+probably	O
+mediated	O
+by	O
+central	O
+nicotinic	O
+receptors	O
+.	O
+
+Nicotine	O
+-	O
+induced	O
+hyperactivity	B
+was	O
+blocked	O
+by	O
+the	O
+selective	O
+D1	O
+antagonist	O
+SCH	O
+23390	O
+,	O
+the	O
+selective	O
+D2	O
+antagonist	O
+raclopride	O
+and	O
+the	O
+D1	O
+/	O
+D2	O
+antagonist	O
+fluphenazine	O
+.	O
+
+Pretreatment	O
+with	O
+the	O
+D2	O
+agonist	O
+PHNO	O
+enhanced	O
+nicotine	O
+-	O
+induced	O
+hyperactivity	B
+,	O
+whereas	O
+the	O
+D1	O
+agonist	O
+SKF	O
+38393	O
+had	O
+no	O
+effect	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+acute	O
+nicotine	O
+injection	O
+induces	O
+a	O
+pronounced	O
+hyperactivity	B
+in	O
+rats	O
+habituated	O
+to	O
+the	O
+test	O
+environment	O
+.	O
+
+The	O
+effect	O
+appears	O
+to	O
+be	O
+mediated	O
+by	O
+central	O
+nicotine	O
+receptors	O
+,	O
+possibly	O
+located	O
+on	O
+dopaminergic	O
+neurons	O
+,	O
+and	O
+also	O
+requires	O
+the	O
+activation	O
+of	O
+both	O
+D1	O
+and	O
+D2	O
+dopamine	O
+receptors	O
+.	O
+
+Central	O
+retinal	B
+vein	I
+occlusion	I
+associated	O
+with	O
+clomiphene	O
+-	O
+induced	O
+ovulation	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+central	O
+retinal	B
+vein	I
+occlusion	I
+associated	O
+with	O
+clomiphene	O
+citrate	O
+(	O
+CC	O
+)	O
+.	O
+
+DESIGN	O
+:	O
+Case	O
+study	O
+.	O
+
+SETTING	O
+:	O
+Ophthalmology	O
+clinic	O
+of	O
+an	O
+academic	O
+hospital	O
+.	O
+
+PATIENT	O
+(	O
+S	O
+)	O
+:	O
+A	O
+36	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+referred	O
+from	O
+the	O
+infertility	B
+clinic	O
+for	O
+blurred	B
+vision	I
+.	O
+
+INTERVENTION	O
+(	O
+S	O
+)	O
+:	O
+Ophthalmic	O
+examination	O
+after	O
+CC	O
+therapy	O
+.	O
+
+MAIN	O
+OUTCOME	O
+MEASURE	O
+(	O
+S	O
+)	O
+:	O
+Central	O
+retinal	B
+vein	I
+occlusion	I
+after	O
+ovulation	O
+induction	O
+with	O
+CC	O
+.	O
+
+RESULT	O
+(	O
+S	O
+)	O
+:	O
+A	O
+36	O
+-	O
+year	O
+-	O
+old	O
+Chinese	O
+woman	O
+developed	O
+central	O
+retinal	B
+vein	I
+occlusion	I
+after	O
+eight	O
+courses	O
+of	O
+CC	O
+.	O
+
+A	O
+search	O
+of	O
+the	O
+literature	O
+on	O
+the	O
+thromboembolic	B
+complications	O
+of	O
+CC	O
+does	O
+not	O
+include	O
+this	O
+severe	O
+ophthalmic	O
+complication	O
+,	O
+although	O
+mild	O
+visual	B
+disturbance	I
+after	O
+CC	O
+intake	O
+is	O
+not	O
+uncommon	O
+.	O
+
+CONCLUSION	O
+(	O
+S	O
+)	O
+:	O
+This	O
+is	O
+the	O
+first	O
+reported	O
+case	O
+of	O
+central	O
+retinal	B
+vein	I
+occlusion	I
+after	O
+treatment	O
+with	O
+CC	O
+.	O
+
+Extra	O
+caution	O
+is	O
+warranted	O
+in	O
+treating	O
+infertility	B
+patients	O
+with	O
+CC	O
+,	O
+and	O
+patients	O
+should	O
+be	O
+well	O
+informed	O
+of	O
+this	O
+side	O
+effect	O
+before	O
+commencement	O
+of	O
+therapy	O
+.	O
+
+Acute	O
+bronchodilating	O
+effects	O
+of	O
+ipratropium	O
+bromide	O
+and	O
+theophylline	O
+in	O
+chronic	B
+obstructive	I
+pulmonary	I
+disease	I
+.	O
+
+The	O
+bronchodilator	O
+effects	O
+of	O
+a	O
+single	O
+dose	O
+of	O
+ipratropium	O
+bromide	O
+aerosol	O
+(	O
+36	O
+micrograms	O
+)	O
+and	O
+short	O
+-	O
+acting	O
+theophylline	O
+tablets	O
+(	O
+dose	O
+titrated	O
+to	O
+produce	O
+serum	O
+levels	O
+of	O
+10	O
+-	O
+20	O
+micrograms	O
+/	O
+mL	O
+)	O
+were	O
+compared	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+crossover	O
+study	O
+in	O
+21	O
+patients	O
+with	O
+stable	O
+,	O
+chronic	B
+obstructive	I
+pulmonary	I
+disease	I
+.	O
+
+Mean	O
+peak	O
+forced	O
+expiratory	O
+volume	O
+in	O
+1	O
+second	O
+(	O
+FEV1	O
+)	O
+increases	O
+over	O
+baseline	O
+and	O
+the	O
+proportion	O
+of	O
+patients	O
+attaining	O
+at	O
+least	O
+a	O
+15	O
+%	O
+increase	O
+in	O
+the	O
+FEV1	O
+(	O
+responders	O
+)	O
+were	O
+31	O
+%	O
+and	O
+90	O
+%	O
+,	O
+respectively	O
+,	O
+for	O
+ipratropium	O
+and	O
+17	O
+%	O
+and	O
+50	O
+%	O
+,	O
+respectively	O
+,	O
+for	O
+theophylline	O
+.	O
+
+The	O
+average	O
+FEV1	O
+increases	O
+during	O
+the	O
+6	O
+-	O
+hour	O
+observation	O
+period	O
+were	O
+18	O
+%	O
+for	O
+ipratropium	O
+and	O
+8	O
+%	O
+for	O
+theophylline	O
+.	O
+
+The	O
+mean	O
+duration	O
+of	O
+action	O
+was	O
+3	O
+.	O
+8	O
+hours	O
+with	O
+ipratropium	O
+and	O
+2	O
+.	O
+4	O
+hours	O
+with	O
+theophylline	O
+.	O
+
+While	O
+side	O
+effects	O
+were	O
+rare	O
+,	O
+those	O
+experienced	O
+after	O
+theophylline	O
+use	O
+did	O
+involve	O
+the	O
+cardiovascular	B
+and	I
+gastrointestinal	I
+systems	I
+.	O
+
+These	O
+results	O
+show	O
+that	O
+ipratropium	O
+is	O
+a	O
+more	O
+potent	O
+bronchodilator	O
+than	O
+oral	O
+theophylline	O
+in	O
+patients	O
+with	O
+chronic	B
+airflow	I
+obstruction	I
+.	O
+
+Methamphetamine	O
+-	O
+induced	O
+neurotoxicity	B
+and	O
+microglial	O
+activation	O
+are	O
+not	O
+mediated	O
+by	O
+fractalkine	O
+receptor	O
+signaling	O
+.	O
+
+Methamphetamine	O
+(	O
+METH	O
+)	O
+damages	O
+dopamine	O
+(	O
+DA	O
+)	O
+nerve	O
+endings	O
+by	O
+a	O
+process	O
+that	O
+has	O
+been	O
+linked	O
+to	O
+microglial	O
+activation	O
+but	O
+the	O
+signaling	O
+pathways	O
+that	O
+mediate	O
+this	O
+response	O
+have	O
+not	O
+yet	O
+been	O
+delineated	O
+.	O
+
+Cardona	O
+et	O
+al	O
+.	O
+
+[	O
+Nat	O
+.	O
+Neurosci	O
+.	O
+9	O
+(	O
+2006	O
+)	O
+,	O
+917	O
+]	O
+recently	O
+identified	O
+the	O
+microglial	O
+-	O
+specific	O
+fractalkine	O
+receptor	O
+(	O
+CX3CR1	O
+)	O
+as	O
+an	O
+important	O
+mediator	O
+of	O
+MPTP	O
+-	O
+induced	O
+neurodegeneration	B
+of	O
+DA	O
+neurons	O
+.	O
+
+Because	O
+the	O
+CNS	B
+damage	I
+caused	O
+by	O
+METH	O
+and	O
+MPTP	O
+is	O
+highly	O
+selective	O
+for	O
+the	O
+DA	O
+neuronal	O
+system	O
+in	O
+mouse	O
+models	O
+of	O
+neurotoxicity	B
+,	O
+we	O
+hypothesized	O
+that	O
+the	O
+CX3CR1	O
+plays	O
+a	O
+role	O
+in	O
+METH	O
+-	O
+induced	O
+neurotoxicity	B
+and	O
+microglial	O
+activation	O
+.	O
+
+Mice	O
+in	O
+which	O
+the	O
+CX3CR1	O
+gene	O
+has	O
+been	O
+deleted	O
+and	O
+replaced	O
+with	O
+a	O
+cDNA	O
+encoding	O
+enhanced	O
+green	O
+fluorescent	O
+protein	O
+(	O
+eGFP	O
+)	O
+were	O
+treated	O
+with	O
+METH	O
+and	O
+examined	O
+for	O
+striatal	O
+neurotoxicity	B
+.	O
+
+METH	O
+depleted	O
+DA	O
+,	O
+caused	O
+microglial	O
+activation	O
+,	O
+and	O
+increased	O
+body	O
+temperature	O
+in	O
+CX3CR1	O
+knockout	O
+mice	O
+to	O
+the	O
+same	O
+extent	O
+and	O
+over	O
+the	O
+same	O
+time	O
+course	O
+seen	O
+in	O
+wild	O
+-	O
+type	O
+controls	O
+.	O
+
+The	O
+effects	O
+of	O
+METH	O
+in	O
+CX3CR1	O
+knockout	O
+mice	O
+were	O
+not	O
+gender	O
+-	O
+dependent	O
+and	O
+did	O
+not	O
+extend	O
+beyond	O
+the	O
+striatum	O
+.	O
+
+Striatal	O
+microglia	O
+expressing	O
+eGFP	O
+constitutively	O
+show	O
+morphological	O
+changes	O
+after	O
+METH	O
+that	O
+are	O
+characteristic	O
+of	O
+activation	O
+.	O
+
+This	O
+response	O
+was	O
+restricted	O
+to	O
+the	O
+striatum	O
+and	O
+contrasted	O
+sharply	O
+with	O
+unresponsive	O
+eGFP	O
+-	O
+microglia	O
+in	O
+surrounding	O
+brain	O
+areas	O
+that	O
+are	O
+not	O
+damaged	O
+by	O
+METH	O
+.	O
+
+We	O
+conclude	O
+from	O
+these	O
+studies	O
+that	O
+CX3CR1	O
+signaling	O
+does	O
+not	O
+modulate	O
+METH	O
+neurotoxicity	B
+or	O
+microglial	O
+activation	O
+.	O
+
+Furthermore	O
+,	O
+it	O
+appears	O
+that	O
+striatal	O
+-	O
+resident	O
+microglia	O
+respond	O
+to	O
+METH	O
+with	O
+an	O
+activation	O
+cascade	O
+and	O
+then	O
+return	O
+to	O
+a	O
+surveying	O
+state	O
+without	O
+undergoing	O
+apoptosis	O
+or	O
+migration	O
+.	O
+
+Nicotine	O
+-	O
+induced	O
+nystagmus	B
+correlates	O
+with	O
+midpontine	O
+activation	O
+.	O
+
+The	O
+pathomechanism	O
+of	O
+nicotine	O
+-	O
+induced	O
+nystagmus	B
+(	O
+NIN	B
+)	O
+is	O
+unknown	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+delineate	O
+brain	O
+structures	O
+that	O
+are	O
+involved	O
+in	O
+NIN	B
+generation	O
+.	O
+
+Eight	O
+healthy	O
+volunteers	O
+inhaled	O
+nicotine	O
+in	O
+darkness	O
+during	O
+a	O
+functional	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+fMRI	O
+)	O
+experiment	O
+;	O
+eye	O
+movements	O
+were	O
+registered	O
+using	O
+video	O
+-	O
+oculography	O
+.	O
+
+NIN	B
+correlated	O
+with	O
+blood	O
+oxygen	O
+level	O
+-	O
+dependent	O
+(	O
+BOLD	O
+)	O
+activity	O
+levels	O
+in	O
+a	O
+midpontine	O
+site	O
+in	O
+the	O
+posterior	O
+basis	O
+pontis	O
+.	O
+
+NIN	B
+-	O
+induced	O
+midpontine	O
+activation	O
+may	O
+correspond	O
+to	O
+activation	O
+of	O
+the	O
+dorsomedial	O
+pontine	O
+nuclei	O
+and	O
+the	O
+nucleus	O
+reticularis	O
+tegmenti	O
+pontis	O
+,	O
+structures	O
+known	O
+to	O
+participate	O
+in	O
+the	O
+generation	O
+of	O
+multidirectional	O
+saccades	O
+and	O
+smooth	O
+pursuit	O
+eye	O
+movements	O
+.	O
+
+Acute	O
+effects	O
+of	O
+N	O
+-	O
+(	O
+2	O
+-	O
+propylpentanoyl	O
+)	O
+urea	O
+on	O
+hippocampal	O
+amino	O
+acid	O
+neurotransmitters	O
+in	O
+pilocarpine	O
+-	O
+induced	O
+seizure	B
+in	O
+rats	O
+.	O
+
+The	O
+present	O
+study	O
+aimed	O
+to	O
+investigate	O
+the	O
+anticonvulsant	O
+activity	O
+as	O
+well	O
+as	O
+the	O
+effects	O
+on	O
+the	O
+level	O
+of	O
+hippocampal	O
+amino	O
+acid	O
+neurotransmitters	O
+(	O
+glutamate	O
+,	O
+aspartate	O
+,	O
+glycine	O
+and	O
+GABA	O
+)	O
+of	O
+N	O
+-	O
+(	O
+2	O
+-	O
+propylpentanoyl	O
+)	O
+urea	O
+(	O
+VPU	O
+)	O
+in	O
+comparison	O
+to	O
+its	O
+parent	O
+compound	O
+,	O
+valproic	O
+acid	O
+(	O
+VPA	O
+)	O
+.	O
+
+VPU	O
+was	O
+more	O
+potent	O
+than	O
+VPA	O
+,	O
+exhibiting	O
+the	O
+median	O
+effective	O
+dose	O
+(	O
+ED	O
+(	O
+50	O
+)	O
+)	O
+of	O
+49	O
+mg	O
+/	O
+kg	O
+in	O
+protecting	O
+rats	O
+against	O
+pilocarpine	O
+-	O
+induced	O
+seizure	B
+whereas	O
+the	O
+corresponding	O
+value	O
+for	O
+VPA	O
+was	O
+322	O
+mg	O
+/	O
+kg	O
+.	O
+
+In	O
+vivo	O
+microdialysis	O
+demonstrated	O
+that	O
+an	O
+intraperitoneal	O
+administration	O
+of	O
+pilocarpine	O
+induced	O
+a	O
+pronounced	O
+increment	O
+of	O
+hippocampal	O
+glutamate	O
+and	O
+aspartate	O
+whereas	O
+no	O
+significant	O
+change	O
+was	O
+observed	O
+on	O
+the	O
+level	O
+of	O
+glycine	O
+and	O
+GABA	O
+.	O
+
+Pretreatment	O
+with	O
+either	O
+VPU	O
+(	O
+50	O
+and	O
+100	O
+mg	O
+/	O
+kg	O
+)	O
+or	O
+VPA	O
+(	O
+300	O
+and	O
+600	O
+mg	O
+/	O
+kg	O
+)	O
+completely	O
+abolished	O
+pilocarpine	O
+-	O
+evoked	O
+increases	O
+in	O
+extracellular	O
+glutamate	O
+and	O
+aspartate	O
+.	O
+
+In	O
+addition	O
+,	O
+a	O
+statistically	O
+significant	O
+reduction	O
+was	O
+also	O
+observed	O
+on	O
+the	O
+level	O
+of	O
+GABA	O
+and	O
+glycine	O
+but	O
+less	O
+than	O
+a	O
+drastic	O
+reduction	O
+of	O
+glutamate	O
+and	O
+aspartate	O
+level	O
+.	O
+
+Based	O
+on	O
+the	O
+finding	O
+that	O
+VPU	O
+and	O
+VPA	O
+could	O
+protect	O
+the	O
+animals	O
+against	O
+pilocarpine	O
+-	O
+induced	O
+seizure	B
+it	O
+is	O
+suggested	O
+that	O
+the	O
+reduction	O
+of	O
+inhibitory	O
+amino	O
+acid	O
+neurotransmitters	O
+was	O
+comparatively	O
+minor	O
+and	O
+offset	O
+by	O
+a	O
+pronounced	O
+reduction	O
+of	O
+glutamate	O
+and	O
+aspartate	O
+.	O
+
+Therefore	O
+,	O
+like	O
+VPA	O
+,	O
+the	O
+finding	O
+that	O
+VPU	O
+could	O
+drastically	O
+reduce	O
+pilocarpine	O
+-	O
+induced	O
+increases	O
+in	O
+glutamate	O
+and	O
+aspartate	O
+should	O
+account	O
+,	O
+at	O
+least	O
+partly	O
+,	O
+for	O
+its	O
+anticonvulsant	O
+activity	O
+observed	O
+in	O
+pilocarpine	O
+-	O
+induced	O
+seizure	B
+in	O
+experimental	O
+animals	O
+.	O
+
+Some	O
+other	O
+mechanism	O
+than	O
+those	O
+being	O
+reported	O
+herein	O
+should	O
+be	O
+further	O
+investigated	O
+.	O
+
+Protective	O
+effect	O
+of	O
+verapamil	O
+on	O
+gastric	B
+hemorrhagic	I
+ulcers	B
+in	O
+severe	O
+atherosclerotic	B
+rats	O
+.	O
+
+Studies	O
+concerning	O
+with	O
+pathogenesis	O
+of	O
+gastric	B
+hemorrhage	I
+and	O
+mucosal	O
+ulceration	O
+produced	O
+in	O
+atherosclerotic	B
+rats	O
+are	O
+lacking	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+is	O
+to	O
+examine	O
+the	O
+role	O
+of	O
+gastric	O
+acid	O
+back	O
+-	O
+diffusion	O
+,	O
+mast	O
+cell	O
+histamine	O
+release	O
+,	O
+lipid	O
+peroxide	O
+(	O
+LPO	O
+)	O
+generation	O
+and	O
+mucosal	O
+microvascular	O
+permeability	O
+in	O
+modulating	O
+gastric	B
+hemorrhage	I
+and	O
+ulcer	B
+in	O
+rats	O
+with	O
+atherosclerosis	B
+induced	O
+by	O
+coadministration	O
+of	O
+vitamin	O
+D2	O
+and	O
+cholesterol	O
+.	O
+
+Additionally	O
+,	O
+the	O
+protective	O
+effect	O
+of	O
+verapamil	O
+on	O
+this	O
+ulcer	B
+model	O
+was	O
+evaluated	O
+.	O
+
+Male	O
+Wistar	O
+rats	O
+were	O
+challenged	O
+intragastrically	O
+once	O
+daily	O
+for	O
+9	O
+days	O
+with	O
+1	O
+.	O
+0	O
+ml	O
+/	O
+kg	O
+of	O
+corn	O
+oil	O
+containing	O
+vitamin	O
+D2	O
+and	O
+cholesterol	O
+to	O
+induce	O
+atherosclerosis	B
+.	O
+
+Control	O
+rats	O
+received	O
+corn	O
+oil	O
+only	O
+.	O
+
+After	O
+gastric	O
+surgery	O
+,	O
+rat	O
+stomachs	O
+were	O
+irrigated	O
+for	O
+3	O
+h	O
+with	O
+either	O
+simulated	O
+gastric	O
+juice	O
+or	O
+normal	O
+saline	O
+.	O
+
+Gastric	O
+acid	O
+back	O
+-	O
+diffusion	O
+,	O
+mucosal	O
+LPO	O
+generation	O
+,	O
+histamine	O
+concentration	O
+,	O
+microvascular	O
+permeability	O
+,	O
+luminal	O
+hemoglobin	O
+content	O
+and	O
+ulcer	B
+areas	O
+were	O
+determined	O
+.	O
+
+Elevated	O
+atherosclerotic	B
+parameters	O
+,	O
+such	O
+as	O
+serum	O
+calcium	O
+,	O
+total	O
+cholesterol	O
+and	O
+low	O
+-	O
+density	O
+lipoprotein	O
+concentration	O
+were	O
+obtained	O
+in	O
+atherosclerotic	B
+rats	O
+.	O
+
+Severe	O
+gastric	O
+ulcers	B
+accompanied	O
+with	O
+increased	O
+ulcerogenic	O
+factors	O
+,	O
+including	O
+gastric	O
+acid	O
+back	O
+-	O
+diffusion	O
+,	O
+histamine	O
+release	O
+,	O
+LPO	O
+generation	O
+and	O
+luminal	O
+hemoglobin	O
+content	O
+were	O
+also	O
+observed	O
+in	O
+these	O
+rats	O
+.	O
+
+Moreover	O
+,	O
+a	O
+positive	O
+correlation	O
+of	O
+histamine	O
+to	O
+gastric	B
+hemorrhage	I
+and	O
+to	O
+ulcer	B
+was	O
+found	O
+in	O
+those	O
+atherosclerotic	B
+rats	O
+.	O
+
+This	O
+hemorrhagic	B
+ulcer	B
+and	O
+various	O
+ulcerogenic	O
+parameters	O
+were	O
+dose	O
+-	O
+dependently	O
+ameliorated	O
+by	O
+daily	O
+intragastric	O
+verapamil	O
+.	O
+
+Atherosclerosis	B
+could	O
+produce	O
+gastric	B
+hemorrhagic	I
+ulcer	B
+via	O
+aggravation	O
+of	O
+gastric	O
+acid	O
+back	O
+-	O
+diffusion	O
+,	O
+LPO	O
+generation	O
+,	O
+histamine	O
+release	O
+and	O
+microvascular	O
+permeability	O
+that	O
+could	O
+be	O
+ameliorated	O
+by	O
+verapamil	O
+in	O
+rats	O
+.	O
+
+Lamivudine	O
+for	O
+the	O
+prevention	O
+of	O
+hepatitis	B
+B	I
+virus	O
+reactivation	O
+in	O
+hepatitis	O
+-	O
+B	O
+surface	O
+antigen	O
+(	O
+HBSAG	O
+)	O
+seropositive	O
+cancer	B
+patients	O
+undergoing	O
+cytotoxic	O
+chemotherapy	O
+.	O
+
+Hepatitis	B
+B	I
+virus	O
+(	O
+HBV	O
+)	O
+is	O
+one	O
+of	O
+the	O
+major	O
+causes	O
+of	O
+chronic	O
+liver	B
+disease	I
+worldwide	O
+.	O
+
+Cancer	B
+patients	O
+who	O
+are	O
+chronic	O
+carriers	O
+of	O
+HBV	O
+have	O
+a	O
+higher	O
+hepatic	B
+complication	I
+rate	O
+while	O
+receiving	O
+cytotoxic	O
+chemotherapy	O
+(	O
+CT	O
+)	O
+and	O
+this	O
+has	O
+mainly	O
+been	O
+attributed	O
+to	O
+HBV	O
+reactivation	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+cancer	B
+patients	O
+who	O
+have	O
+solid	O
+and	O
+hematological	B
+malignancies	I
+with	O
+chronic	O
+HBV	B
+infection	I
+received	O
+the	O
+antiviral	O
+agent	O
+lamivudine	O
+prior	O
+and	O
+during	O
+CT	O
+compared	O
+with	O
+historical	O
+control	O
+group	O
+who	O
+did	O
+not	O
+receive	O
+lamivudine	O
+.	O
+
+The	O
+objectives	O
+were	O
+to	O
+assess	O
+the	O
+efficacy	O
+of	O
+lamivudine	O
+in	O
+reducing	O
+the	O
+incidence	O
+of	O
+HBV	O
+reactivation	O
+,	O
+and	O
+diminishing	O
+morbidity	O
+and	O
+mortality	O
+during	O
+CT	O
+.	O
+
+Two	O
+groups	O
+were	O
+compared	O
+in	O
+this	O
+study	O
+.	O
+
+The	O
+prophylactic	O
+lamivudin	O
+group	O
+consisted	O
+of	O
+37	O
+patients	O
+who	O
+received	O
+prophylactic	O
+lamivudine	O
+treatment	O
+.	O
+
+The	O
+historical	O
+controls	O
+consisted	O
+of	O
+50	O
+consecutive	O
+patients	O
+who	O
+underwent	O
+CT	O
+without	O
+prophylactic	O
+lamivudine	O
+.	O
+
+They	O
+were	O
+followed	O
+up	O
+during	O
+and	O
+for	O
+8	O
+weeks	O
+after	O
+CT	O
+.	O
+
+The	O
+outcomes	O
+were	O
+compared	O
+for	O
+both	O
+groups	O
+.	O
+
+Of	O
+our	O
+control	O
+group	O
+(	O
+n	O
+=	O
+50	O
+)	O
+,	O
+21	O
+patients	O
+(	O
+42	O
+%	O
+)	O
+were	O
+established	O
+hepatitis	B
+.	O
+
+Twelve	O
+(	O
+24	O
+%	O
+)	O
+of	O
+them	O
+were	O
+evaluated	O
+as	O
+severe	O
+hepatitis	B
+.	O
+
+In	O
+the	O
+prophylactic	O
+lamivudine	O
+group	O
+severe	O
+hepatitis	B
+were	O
+observed	O
+only	O
+in	O
+1	O
+patient	O
+(	O
+2	O
+.	O
+7	O
+%	O
+)	O
+of	O
+37	O
+patients	O
+(	O
+p	O
+<	O
+0	O
+.	O
+006	O
+)	O
+.	O
+
+Comparison	O
+of	O
+the	O
+mean	O
+ALT	O
+values	O
+revealed	O
+significantly	O
+higher	O
+mean	O
+alanine	O
+aminotransferase	O
+(	O
+ALT	O
+)	O
+values	O
+in	O
+the	O
+control	O
+group	O
+than	O
+the	O
+prophylactic	O
+lamivudine	O
+group	O
+;	O
+154	O
+:	O
+64	O
+(	O
+p	O
+<	O
+0	O
+.	O
+32	O
+)	O
+.	O
+
+Our	O
+study	O
+suggests	O
+that	O
+prophylactic	O
+lamivudine	O
+significantly	O
+decreases	O
+the	O
+incidence	O
+of	O
+HBV	O
+reactivation	O
+and	O
+overall	O
+morbidity	O
+in	O
+cancer	B
+patients	O
+during	O
+and	O
+after	O
+immunosuppressive	O
+therapy	O
+.	O
+
+Further	O
+studies	O
+are	O
+needed	O
+to	O
+determine	O
+the	O
+most	O
+appropriate	O
+nucleoside	O
+or	O
+nucleotide	O
+analogue	O
+for	O
+antiviral	O
+prophylaxis	O
+during	O
+CT	O
+and	O
+the	O
+optimal	O
+duration	O
+of	O
+administration	O
+after	O
+completion	O
+of	O
+CT	O
+.	O
+
+Recovery	O
+of	O
+tacrolimus	O
+-	O
+associated	O
+brachial	B
+neuritis	I
+after	O
+conversion	O
+to	O
+everolimus	O
+in	O
+a	O
+pediatric	O
+renal	O
+transplant	O
+recipient	O
+-	O
+-	O
+case	O
+report	O
+and	O
+review	O
+of	O
+the	O
+literature	O
+.	O
+
+TAC	O
+has	O
+been	O
+shown	O
+to	O
+be	O
+a	O
+potent	O
+immunosuppressive	O
+agent	O
+for	O
+solid	O
+organ	O
+transplantation	O
+in	O
+pediatrics	O
+.	O
+
+Neurotoxicity	B
+is	O
+a	O
+potentially	O
+serious	O
+toxic	O
+effect	O
+.	O
+
+It	O
+is	O
+characterized	O
+by	O
+encephalopathy	B
+,	O
+headaches	B
+,	O
+seizures	B
+,	O
+or	O
+neurological	B
+deficits	I
+.	O
+
+Here	O
+,	O
+we	O
+describe	O
+an	O
+eight	O
+-	O
+and	O
+-	O
+a	O
+-	O
+half	O
+-	O
+yr	O
+-	O
+old	O
+male	O
+renal	O
+transplant	O
+recipient	O
+with	O
+right	O
+BN	O
+.	O
+
+MRI	O
+demonstrated	O
+hyperintense	O
+T2	O
+signals	O
+in	O
+the	O
+cervical	O
+cord	O
+and	O
+right	O
+brachial	O
+plexus	O
+roots	O
+indicative	O
+of	O
+both	O
+myelitis	B
+and	O
+right	O
+brachial	B
+plexitis	I
+.	O
+
+Symptoms	O
+persisted	O
+for	O
+three	O
+months	O
+despite	O
+TAC	O
+dose	O
+reduction	O
+,	O
+administration	O
+of	O
+IVIG	O
+and	O
+four	O
+doses	O
+of	O
+methylprednisolone	O
+pulse	O
+therapy	O
+.	O
+
+Improvement	O
+and	O
+eventually	O
+full	O
+recovery	O
+only	O
+occurred	O
+after	O
+TAC	O
+was	O
+completely	O
+discontinued	O
+and	O
+successfully	O
+replaced	O
+by	O
+everolimus	O
+.	O
+
+Omitting	O
+fentanyl	O
+reduces	O
+nausea	B
+and	O
+vomiting	B
+,	O
+without	O
+increasing	O
+pain	B
+,	O
+after	O
+sevoflurane	O
+for	O
+day	O
+surgery	O
+.	O
+
+BACKGROUND	O
+AND	O
+OBJECTIVE	O
+:	O
+Despite	O
+advantages	O
+of	O
+induction	O
+and	O
+maintenance	O
+of	O
+anaesthesia	O
+with	O
+sevoflurane	O
+,	O
+postoperative	B
+nausea	I
+and	I
+vomiting	I
+occurs	O
+frequently	O
+.	O
+
+Fentanyl	O
+is	O
+a	O
+commonly	O
+used	O
+supplement	O
+that	O
+may	O
+contribute	O
+to	O
+this	O
+,	O
+although	O
+it	O
+may	O
+also	O
+improve	O
+analgesia	O
+.	O
+
+METHODS	O
+:	O
+This	O
+double	O
+-	O
+blind	O
+study	O
+examined	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+postoperative	B
+nausea	I
+and	I
+vomiting	I
+and	O
+pain	B
+in	O
+the	O
+first	O
+24	O
+h	O
+after	O
+sevoflurane	O
+anaesthesia	O
+in	O
+216	O
+adult	O
+day	O
+surgery	O
+patients	O
+.	O
+
+Patients	O
+were	O
+randomly	O
+allocated	O
+to	O
+either	O
+receive	O
+or	O
+not	O
+receive	O
+1	O
+1	O
+fentanyl	O
+,	O
+while	O
+a	O
+third	O
+group	O
+received	O
+dexamethasone	O
+in	O
+addition	O
+to	O
+fentanyl	O
+.	O
+
+RESULTS	O
+:	O
+Omission	O
+of	O
+fentanyl	O
+did	O
+not	O
+reduce	O
+the	O
+overall	O
+incidence	O
+of	O
+postoperative	B
+nausea	I
+and	I
+vomiting	I
+,	O
+but	O
+did	O
+reduce	O
+the	O
+incidence	O
+of	O
+vomiting	B
+and	O
+/	O
+or	O
+moderate	O
+to	O
+severe	O
+nausea	B
+prior	O
+to	O
+discharge	O
+from	O
+20	O
+%	O
+and	O
+17	O
+%	O
+with	O
+fentanyl	O
+and	O
+fentanyl	O
+-	O
+dexamethasone	O
+,	O
+respectively	O
+,	O
+to	O
+5	O
+%	O
+(	O
+P	O
+=	O
+0	O
+.	O
+013	O
+)	O
+.	O
+
+Antiemetic	O
+requirements	O
+were	O
+reduced	O
+from	O
+24	O
+%	O
+and	O
+31	O
+%	O
+to	O
+7	O
+%	O
+(	O
+P	O
+=	O
+0	O
+.	O
+0012	O
+)	O
+.	O
+
+Dexamethasone	O
+had	O
+no	O
+significant	O
+effect	O
+on	O
+the	O
+incidence	O
+or	O
+severity	O
+of	O
+postoperative	B
+nausea	I
+and	I
+vomiting	I
+.	O
+
+Combining	O
+the	O
+two	O
+fentanyl	O
+groups	O
+revealed	O
+further	O
+significant	O
+benefits	O
+from	O
+the	O
+avoidance	O
+of	O
+opioids	O
+,	O
+reducing	O
+postoperative	B
+nausea	I
+and	I
+vomiting	I
+and	O
+nausea	B
+prior	O
+to	O
+discharge	O
+from	O
+35	O
+%	O
+and	O
+33	O
+%	O
+to	O
+22	O
+%	O
+and	O
+19	O
+%	O
+(	O
+P	O
+=	O
+0	O
+.	O
+049	O
+and	O
+P	O
+=	O
+0	O
+.	O
+035	O
+)	O
+,	O
+respectively	O
+,	O
+while	O
+nausea	B
+in	O
+the	O
+first	O
+24	O
+h	O
+was	O
+decreased	O
+from	O
+42	O
+%	O
+to	O
+27	O
+%	O
+(	O
+P	O
+=	O
+0	O
+.	O
+034	O
+)	O
+.	O
+
+Pain	B
+severity	O
+and	O
+analgesic	O
+requirements	O
+were	O
+unaffected	O
+by	O
+the	O
+omission	O
+of	O
+fentanyl	O
+.	O
+
+Fentanyl	O
+did	O
+reduce	O
+minor	O
+intraoperative	O
+movement	O
+but	O
+had	O
+no	O
+sevoflurane	O
+-	O
+sparing	O
+effect	O
+and	O
+increased	O
+respiratory	B
+depression	I
+,	O
+hypotension	B
+and	O
+bradycardia	B
+.	O
+
+CONCLUSION	O
+:	O
+As	O
+fentanyl	O
+exacerbated	O
+postoperative	B
+nausea	I
+and	I
+vomiting	I
+without	O
+an	O
+improvement	O
+in	O
+postoperative	B
+pain	I
+and	O
+also	O
+had	O
+adverse	O
+cardiorespiratory	O
+effects	O
+,	O
+it	O
+appears	O
+to	O
+be	O
+an	O
+unnecessary	O
+and	O
+possibly	O
+detrimental	O
+supplement	O
+to	O
+sevoflurane	O
+in	O
+day	O
+surgery	O
+.	O
+
+Valvular	B
+heart	I
+disease	I
+in	O
+patients	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+treated	O
+with	O
+pergolide	O
+.	O
+
+Course	O
+following	O
+treatment	O
+modifications	O
+.	O
+
+Valvular	B
+heart	I
+abnormalities	I
+have	O
+been	O
+reported	O
+in	O
+patients	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+treated	O
+with	O
+pergolide	O
+.	O
+
+However	O
+,	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+these	O
+abnormalities	O
+vary	O
+from	O
+study	O
+to	O
+study	O
+and	O
+their	O
+course	O
+after	O
+drug	O
+withdrawal	O
+has	O
+not	O
+been	O
+systematically	O
+assessed	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+estimate	O
+the	O
+frequency	O
+and	O
+severity	O
+of	O
+valvular	B
+heart	I
+abnormality	I
+and	O
+its	O
+possible	O
+reversibility	O
+after	O
+drug	O
+withdrawal	O
+in	O
+a	O
+case	O
+-	O
+control	O
+study	O
+.	O
+
+METHODS	O
+:	O
+All	O
+PD	B
+patients	O
+in	O
+the	O
+Amiens	O
+area	O
+treated	O
+with	O
+pergolide	O
+were	O
+invited	O
+to	O
+attend	O
+a	O
+cardiologic	O
+assessment	O
+including	O
+transthoracic	O
+echocardiography	O
+.	O
+
+Thirty	O
+PD	B
+patients	O
+participated	O
+in	O
+the	O
+study	O
+.	O
+
+A	O
+second	O
+echocardiography	O
+was	O
+performed	O
+(	O
+median	O
+interval	O
+:	O
+13	O
+months	O
+)	O
+after	O
+pergolide	O
+withdrawal	O
+(	O
+n	O
+=	O
+10	O
+patients	O
+)	O
+.	O
+
+Controls	O
+were	O
+age	O
+-	O
+and	O
+sex	O
+-	O
+matched	O
+non	O
+-	O
+PD	B
+patients	O
+referred	O
+to	O
+the	O
+cardiology	O
+department	O
+.	O
+
+RESULTS	O
+:	O
+Compared	O
+to	O
+controls	O
+,	O
+aortic	B
+regurgitation	I
+(	O
+OR	O
+:	O
+3	O
+.	O
+1	O
+;	O
+95	O
+%	O
+IC	O
+:	O
+1	O
+.	O
+1	O
+-	O
+8	O
+.	O
+8	O
+)	O
+and	O
+mitral	B
+regurgitation	I
+(	O
+OR	O
+:	O
+10	O
+.	O
+7	O
+;	O
+95	O
+%	O
+IC	O
+:	O
+2	O
+.	O
+1	O
+-	O
+53	O
+)	O
+were	O
+more	O
+frequent	O
+in	O
+PD	B
+patients	O
+(	O
+tricuspid	O
+:	O
+NS	O
+)	O
+.	O
+
+The	O
+number	O
+of	O
+affected	O
+valves	O
+(	O
+n	O
+=	O
+2	O
+.	O
+4	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+)	O
+and	O
+the	O
+sum	O
+of	O
+regurgitation	O
+grades	O
+(	O
+n	O
+=	O
+2	O
+.	O
+8	O
++	O
+/	O
+-	O
+1	O
+.	O
+09	O
+)	O
+were	O
+higher	O
+(	O
+p	O
+=	O
+0	O
+.	O
+008	O
+and	O
+p	O
+=	O
+0	O
+.	O
+006	O
+,	O
+respectively	O
+)	O
+in	O
+the	O
+pergolide	O
+group	O
+.	O
+
+Severity	O
+of	O
+regurgitation	O
+was	O
+not	O
+correlated	O
+with	O
+pergolide	O
+cumulative	O
+dose	O
+.	O
+
+A	O
+restrictive	O
+pattern	O
+of	O
+valvular	B
+regurgitation	I
+,	O
+suggestive	O
+of	O
+the	O
+role	O
+of	O
+pergolide	O
+,	O
+was	O
+observed	O
+in	O
+12	O
+/	O
+30	O
+(	O
+40	O
+%	O
+)	O
+patients	O
+including	O
+two	O
+with	O
+heart	B
+failure	I
+.	O
+
+Pergolide	O
+was	O
+discontinued	O
+in	O
+10	O
+patients	O
+with	O
+valvular	B
+heart	I
+disease	I
+,	O
+resulting	O
+in	O
+a	O
+lower	O
+regurgitation	O
+grade	O
+(	O
+p	O
+=	O
+0	O
+.	O
+01	O
+)	O
+at	O
+the	O
+second	O
+transthoracic	O
+echocardiography	O
+and	O
+the	O
+two	O
+patients	O
+with	O
+heart	B
+failure	I
+returned	O
+to	O
+nearly	O
+normal	O
+clinical	O
+examination	O
+.	O
+
+This	O
+study	O
+supports	O
+the	O
+high	O
+frequency	O
+of	O
+restrictive	O
+valve	B
+regurgitation	I
+in	O
+PD	B
+patients	O
+treated	O
+with	O
+pergolide	O
+and	O
+reveals	O
+that	O
+a	O
+significant	O
+improvement	O
+is	O
+usual	O
+when	O
+the	O
+treatment	O
+is	O
+converted	O
+to	O
+non	O
+-	O
+ergot	O
+dopamine	O
+agonists	O
+.	O
+
+Adriamycin	O
+-	O
+induced	O
+autophagic	O
+cardiomyocyte	O
+death	B
+plays	O
+a	O
+pathogenic	O
+role	O
+in	O
+a	O
+rat	O
+model	O
+of	O
+heart	B
+failure	I
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+mechanisms	O
+underlying	O
+heart	B
+failure	I
+induced	O
+by	O
+adriamycin	O
+are	O
+very	O
+complicated	O
+and	O
+still	O
+unclear	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+investigate	O
+whether	O
+autophagy	O
+was	O
+involved	O
+in	O
+the	O
+progression	O
+of	O
+heart	B
+failure	I
+induced	O
+by	O
+adriamycin	O
+,	O
+so	O
+that	O
+we	O
+can	O
+develop	O
+a	O
+novel	O
+treatment	O
+strategy	O
+for	O
+heart	B
+failure	I
+.	O
+
+METHODS	O
+:	O
+3	O
+-	O
+methyladenine	O
+(	O
+3MA	O
+)	O
+,	O
+a	O
+specific	O
+inhibitor	O
+on	O
+autophagy	O
+was	O
+used	O
+in	O
+a	O
+heart	B
+failure	I
+model	O
+of	O
+rats	O
+induced	O
+by	O
+adriamycin	O
+.	O
+
+Neonatal	O
+cardiomyocytes	O
+were	O
+isolated	O
+from	O
+Sprague	O
+-	O
+Dawley	O
+rat	O
+hearts	O
+and	O
+randomly	O
+divided	O
+into	O
+controls	O
+,	O
+an	O
+adriamycin	O
+-	O
+treated	O
+group	O
+,	O
+and	O
+a	O
+3MA	O
+plus	O
+adriamycin	O
+-	O
+treated	O
+group	O
+.	O
+
+We	O
+then	O
+examined	O
+the	O
+morphology	O
+,	O
+expression	O
+of	O
+beclin	O
+1	O
+gene	O
+,	O
+mitochondrial	O
+permeability	O
+transition	O
+(	O
+MPT	O
+)	O
+,	O
+and	O
+Na	O
++	O
+-	O
+K	O
++	O
+ATPase	O
+activity	O
+in	O
+vivo	O
+.	O
+
+We	O
+also	O
+assessed	O
+cell	O
+viability	O
+,	O
+mitochondrial	O
+membrane	O
+potential	O
+changes	O
+and	O
+counted	O
+autophagic	O
+vacuoles	O
+in	O
+cultured	O
+cardiomyocytes	O
+.	O
+
+In	O
+addition	O
+,	O
+we	O
+analyzed	O
+the	O
+expression	O
+of	O
+autophagy	O
+associated	O
+gene	O
+,	O
+beclin	O
+1	O
+using	O
+RT	O
+-	O
+PCR	O
+and	O
+Western	O
+blotting	O
+in	O
+an	O
+animal	O
+model	O
+.	O
+
+RESULTS	O
+:	O
+3MA	O
+significantly	O
+improved	O
+cardiac	O
+function	O
+and	O
+reduced	O
+mitochondrial	O
+injury	O
+.	O
+
+Furthermore	O
+,	O
+adriamycin	O
+induced	O
+the	O
+formation	O
+of	O
+autophagic	O
+vacuoles	O
+,	O
+and	O
+3MA	O
+strongly	O
+downregulated	O
+the	O
+expression	O
+of	O
+beclin	O
+1	O
+in	O
+adriamycin	O
+-	O
+induced	O
+failing	O
+heart	O
+and	O
+inhibited	O
+the	O
+formation	O
+of	O
+autophagic	O
+vacuoles	O
+.	O
+
+CONCLUSION	O
+:	O
+Autophagic	O
+cardiomyocyte	O
+death	B
+plays	O
+an	O
+important	O
+role	O
+in	O
+the	O
+pathogenesis	O
+of	O
+heart	B
+failure	I
+in	O
+rats	O
+induced	O
+by	O
+adriamycin	O
+.	O
+
+Mitochondrial	O
+injury	O
+may	O
+be	O
+involved	O
+in	O
+the	O
+progression	O
+of	O
+heart	B
+failure	I
+caused	O
+by	O
+adriamycin	O
+via	O
+the	O
+autophagy	O
+pathway	O
+.	O
+
+mToR	O
+inhibitors	O
+-	O
+induced	O
+proteinuria	B
+:	O
+mechanisms	O
+,	O
+significance	O
+,	O
+and	O
+management	O
+.	O
+
+Massive	O
+urinary	O
+protein	O
+excretion	O
+has	O
+been	O
+observed	O
+after	O
+conversion	O
+from	O
+calcineurin	O
+inhibitors	O
+to	O
+mammalian	O
+target	O
+of	O
+rapamycin	O
+(	O
+mToR	O
+)	O
+inhibitors	O
+,	O
+especially	O
+sirolimus	O
+,	O
+in	O
+renal	O
+transplant	O
+recipients	O
+with	O
+chronic	B
+allograft	I
+nephropathy	I
+.	O
+
+Because	O
+proteinuria	B
+is	O
+a	O
+major	O
+predictive	O
+factor	O
+of	O
+poor	O
+transplantation	O
+outcome	O
+,	O
+many	O
+studies	O
+focused	O
+on	O
+this	O
+adverse	O
+event	O
+during	O
+the	O
+past	O
+years	O
+.	O
+
+Whether	O
+proteinuria	B
+was	O
+due	O
+to	O
+sirolimus	O
+or	O
+only	O
+a	O
+consequence	O
+of	O
+calcineurin	O
+inhibitors	O
+withdrawal	O
+remained	O
+unsolved	O
+until	O
+high	O
+range	O
+proteinuria	B
+has	O
+been	O
+observed	O
+during	O
+sirolimus	O
+therapy	O
+in	O
+islet	O
+transplantation	O
+and	O
+in	O
+patients	O
+who	O
+received	O
+sirolimus	O
+de	O
+novo	O
+.	O
+
+Podocyte	O
+injury	O
+and	O
+focal	O
+segmental	O
+glomerulosclerosis	B
+have	O
+been	O
+related	O
+to	O
+mToR	O
+inhibition	O
+in	O
+some	O
+patients	O
+,	O
+but	O
+the	O
+pathways	O
+underlying	O
+these	O
+lesions	O
+remain	O
+hypothetic	O
+.	O
+
+We	O
+discuss	O
+herein	O
+the	O
+possible	O
+mechanisms	O
+and	O
+the	O
+significance	O
+of	O
+mToR	O
+blockade	O
+-	O
+induced	O
+proteinuria	B
+.	O
+
+Neuropsychiatric	O
+side	O
+effects	O
+after	O
+the	O
+use	O
+of	O
+mefloquine	O
+.	O
+
+This	O
+study	O
+describes	O
+neuropsychiatric	O
+side	O
+effects	O
+in	O
+patients	O
+after	O
+treatment	O
+with	O
+mefloquine	O
+.	O
+
+Reactions	O
+consisted	O
+mainly	O
+of	O
+seizures	B
+,	O
+acute	O
+psychoses	B
+,	O
+anxiety	B
+neurosis	I
+,	O
+and	O
+major	O
+disturbances	B
+of	I
+sleep	I
+-	I
+wake	I
+rhythm	I
+.	O
+
+Side	O
+effects	O
+occurred	O
+after	O
+both	O
+therapeutic	O
+and	O
+prophylactic	O
+intake	O
+and	O
+were	O
+graded	O
+from	O
+moderate	O
+to	O
+severe	O
+.	O
+
+In	O
+a	O
+risk	O
+analysis	O
+of	O
+neuropsychiatric	O
+side	O
+effects	O
+in	O
+Germany	O
+,	O
+it	O
+is	O
+estimated	O
+that	O
+one	O
+of	O
+8	O
+,	O
+000	O
+mefloquine	O
+users	O
+suffers	O
+from	O
+such	O
+reactions	O
+.	O
+
+The	O
+incidence	O
+calculation	O
+revealed	O
+that	O
+one	O
+of	O
+215	O
+therapeutic	O
+users	O
+had	O
+reactions	O
+,	O
+compared	O
+with	O
+one	O
+of	O
+13	O
+,	O
+000	O
+in	O
+the	O
+prophylaxis	O
+group	O
+,	O
+making	O
+the	O
+risk	O
+of	O
+neuropsychiatric	O
+reactions	O
+after	O
+mefloquine	O
+treatment	O
+60	O
+times	O
+higher	O
+than	O
+after	O
+prophylaxis	O
+.	O
+
+Therefore	O
+,	O
+certain	O
+limitations	O
+for	O
+malaria	B
+prophylaxis	O
+and	O
+treatment	O
+with	O
+mefloquine	O
+are	O
+recommended	O
+.	O
+
+Prenatal	O
+protein	O
+deprivation	O
+alters	O
+dopamine	O
+-	O
+mediated	O
+behaviors	O
+and	O
+dopaminergic	O
+and	O
+glutamatergic	O
+receptor	O
+binding	O
+.	O
+
+Epidemiological	O
+evidence	O
+indicates	O
+that	O
+prenatal	O
+nutritional	O
+deprivation	O
+may	O
+increase	O
+the	O
+risk	O
+of	O
+schizophrenia	B
+.	O
+
+The	O
+goal	O
+of	O
+these	O
+studies	O
+was	O
+to	O
+use	O
+an	O
+animal	O
+model	O
+to	O
+examine	O
+the	O
+effects	O
+of	O
+prenatal	O
+protein	O
+deprivation	O
+on	O
+behaviors	O
+and	O
+receptor	O
+binding	O
+with	O
+relevance	O
+to	O
+schizophrenia	B
+.	O
+
+We	O
+report	O
+that	O
+prenatally	O
+protein	O
+deprived	O
+(	O
+PD	O
+)	O
+female	O
+rats	O
+showed	O
+an	O
+increased	O
+stereotypic	O
+response	O
+to	O
+apomorphine	O
+and	O
+an	O
+increased	O
+locomotor	O
+response	O
+to	O
+amphetamine	O
+in	O
+adulthood	O
+.	O
+
+These	O
+differences	O
+were	O
+not	O
+observed	O
+during	O
+puberty	O
+.	O
+
+No	O
+changes	O
+in	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+or	O
+MK	O
+-	O
+801	O
+-	O
+induced	O
+locomotion	O
+were	O
+seen	O
+following	O
+PD	O
+.	O
+
+In	O
+addition	O
+,	O
+PD	O
+female	O
+rats	O
+showed	O
+increased	O
+(	O
+3	O
+)	O
+H	O
+-	O
+MK	O
+-	O
+801	O
+binding	O
+in	O
+the	O
+striatum	O
+and	O
+hippocampus	O
+,	O
+but	O
+not	O
+in	O
+the	O
+cortex	O
+.	O
+
+PD	O
+female	O
+rats	O
+also	O
+showed	O
+increased	O
+(	O
+3	O
+)	O
+H	O
+-	O
+haloperidol	O
+binding	O
+and	O
+decreased	O
+dopamine	O
+transporter	O
+binding	O
+in	O
+striatum	O
+.	O
+
+No	O
+statistically	O
+significant	O
+changes	O
+in	O
+behavior	O
+or	O
+receptor	O
+binding	O
+were	O
+found	O
+in	O
+PD	O
+males	O
+with	O
+the	O
+exception	O
+of	O
+increased	O
+(	O
+3	O
+)	O
+H	O
+-	O
+MK	O
+-	O
+801	O
+binding	O
+in	O
+cortex	O
+.	O
+
+This	O
+animal	O
+model	O
+may	O
+be	O
+useful	O
+to	O
+explore	O
+the	O
+mechanisms	O
+by	O
+which	O
+prenatal	O
+nutritional	B
+deficiency	I
+enhances	O
+risk	O
+for	O
+schizophrenia	B
+in	O
+humans	O
+and	O
+may	O
+also	O
+have	O
+implications	O
+for	O
+developmental	O
+processes	O
+leading	O
+to	O
+differential	O
+sensitivity	O
+to	O
+drugs	O
+of	O
+abuse	O
+.	O
+
+Adverse	O
+effects	O
+of	O
+topical	O
+papaverine	O
+on	O
+auditory	O
+nerve	O
+function	O
+.	O
+
+BACKGROUND	O
+:	O
+Papaverine	O
+hydrochloride	O
+is	O
+a	O
+direct	O
+-	O
+acting	O
+vasodilator	O
+used	O
+to	O
+manage	O
+vasospasm	B
+during	O
+various	O
+neurosurgical	O
+operations	O
+.	O
+
+Transient	O
+cranial	B
+nerve	I
+dysfunction	I
+has	O
+been	O
+described	O
+in	O
+a	O
+few	O
+cases	O
+with	O
+topical	O
+papaverine	O
+.	O
+
+This	O
+study	O
+supports	O
+previous	O
+reports	O
+and	O
+provides	O
+neurophysiological	O
+evidence	O
+of	O
+an	O
+adverse	O
+effect	O
+on	O
+the	O
+auditory	O
+nerve	O
+.	O
+
+METHODS	O
+:	O
+We	O
+conducted	O
+a	O
+retrospective	O
+review	O
+of	O
+70	O
+consecutive	O
+microvascular	O
+decompression	O
+operations	O
+and	O
+studied	O
+those	O
+patients	O
+who	O
+received	O
+topical	O
+papaverine	O
+for	O
+vasospasm	B
+.	O
+
+Topical	O
+papaverine	O
+was	O
+used	O
+as	O
+a	O
+direct	O
+therapeutic	O
+action	O
+to	O
+manage	O
+vasospasm	B
+in	O
+a	O
+total	O
+of	O
+11	O
+patients	O
+.	O
+
+The	O
+timing	O
+of	O
+papaverine	O
+application	O
+and	O
+ongoing	O
+operative	O
+events	O
+was	O
+reviewed	O
+relative	O
+to	O
+changes	O
+in	O
+neurophysiological	O
+recordings	O
+.	O
+
+Brainstem	O
+auditory	O
+evoked	O
+potentials	O
+(	O
+BAEPs	O
+)	O
+were	O
+routinely	O
+used	O
+to	O
+monitor	O
+cochlear	O
+nerve	O
+function	O
+during	O
+these	O
+operations	O
+.	O
+
+FINDINGS	O
+:	O
+A	O
+temporal	O
+relationship	O
+was	O
+found	O
+between	O
+topical	O
+papaverine	O
+and	O
+BAEP	O
+changes	O
+leading	O
+to	O
+complete	O
+waveform	O
+loss	O
+.	O
+
+The	O
+average	O
+temporal	O
+delay	O
+between	O
+papaverine	O
+and	O
+the	O
+onset	O
+of	O
+an	O
+adverse	O
+BAEP	O
+change	O
+was	O
+5	O
+min	O
+.	O
+
+In	O
+10	O
+of	O
+11	O
+patients	O
+,	O
+BAEP	O
+waves	O
+II	O
+/	O
+III	O
+-	O
+V	O
+completely	O
+disappeared	O
+within	O
+2	O
+to	O
+25	O
+min	O
+after	O
+papaverine	O
+.	O
+
+Eight	O
+of	O
+these	O
+10	O
+patients	O
+had	O
+complete	O
+loss	O
+of	O
+BAEP	O
+waveforms	O
+within	O
+10	O
+min	O
+.	O
+
+One	O
+patient	O
+showed	O
+no	O
+recovery	O
+of	O
+later	O
+waves	O
+and	O
+a	O
+delayed	O
+profound	O
+sensorineural	B
+hearing	I
+loss	I
+.	O
+
+The	O
+average	O
+recovery	O
+time	O
+of	O
+BAEP	O
+waveforms	O
+to	O
+pre	O
+-	O
+papaverine	O
+baseline	O
+values	O
+was	O
+39	O
+min	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Topical	O
+papaverine	O
+for	O
+the	O
+treatment	O
+of	O
+vasospasm	B
+was	O
+associated	O
+with	O
+the	O
+onset	O
+of	O
+a	O
+transient	O
+disturbance	O
+in	O
+neurophysiological	O
+function	O
+of	O
+the	O
+ascending	O
+auditory	O
+brainstem	O
+pathway	O
+.	O
+
+The	O
+complete	O
+disappearance	O
+of	O
+BAEP	O
+waveforms	O
+with	O
+a	O
+consistent	O
+temporal	O
+delay	O
+suggests	O
+a	O
+possible	O
+adverse	B
+effect	I
+on	I
+the	I
+proximal	I
+eighth	I
+nerve	I
+.	O
+
+Recommendations	O
+to	O
+avoid	O
+potential	O
+cranial	B
+nerve	I
+deficits	I
+from	O
+papaverine	O
+are	O
+provided	O
+.	O
+
+Simvastatin	O
+-	O
+ezetimibe	O
+-	O
+induced	O
+hepatic	B
+failure	I
+necessitating	O
+liver	O
+transplantation	O
+.	O
+
+Abstract	O
+Serum	O
+aminotransferase	O
+elevations	O
+are	O
+a	O
+commonly	O
+known	O
+adverse	O
+effect	O
+of	O
+3	O
+-	O
+hydroxy	O
+-	O
+3	O
+-	O
+methylglutaryl	O
+coenzyme	O
+A	O
+reductase	O
+inhibitor	O
+(	O
+statin	O
+)	O
+therapy	O
+.	O
+
+However	O
+,	O
+hepatotoxic	B
+events	O
+have	O
+not	O
+been	O
+widely	O
+published	O
+with	O
+ezetimibe	O
+or	O
+the	O
+combination	O
+agent	O
+simvastatin	O
+-	O
+ezetimibe	O
+.	O
+
+We	O
+describe	O
+a	O
+70	O
+-	O
+year	O
+-	O
+old	O
+Hispanic	O
+woman	O
+who	O
+developed	O
+fulminant	B
+hepatic	I
+failure	I
+necessitating	O
+liver	O
+transplantation	O
+10	O
+weeks	O
+after	O
+conversion	O
+from	O
+simvastatin	O
+40	O
+mg	O
+/	O
+day	O
+to	O
+simvastatin	O
+10	O
+mg	O
+-	O
+ezetimibe	O
+40	O
+mg	O
+/	O
+day	O
+.	O
+
+The	O
+patient	O
+'	O
+s	O
+lipid	O
+panel	O
+had	O
+been	O
+maintained	O
+with	O
+simvastatin	O
+for	O
+18	O
+months	O
+before	O
+the	O
+conversion	O
+without	O
+evidence	O
+of	O
+hepatotoxicity	B
+.	O
+
+A	O
+routine	O
+laboratory	O
+work	O
+-	O
+up	O
+10	O
+weeks	O
+after	O
+conversion	O
+revealed	O
+elevated	O
+serum	O
+aminotransferase	O
+levels	O
+.	O
+
+Simvastatinezetimibe	O
+and	O
+escitalopram	O
+(	O
+which	O
+she	O
+was	O
+taking	O
+for	O
+depression	B
+)	O
+were	O
+discontinued	O
+,	O
+and	O
+other	O
+potential	O
+causes	O
+of	O
+hepatotoxicity	B
+were	O
+excluded	O
+.	O
+
+A	O
+repeat	O
+work	O
+-	O
+up	O
+revealed	O
+further	O
+elevations	O
+in	O
+aminotransferase	O
+levels	O
+,	O
+and	O
+liver	O
+biopsy	O
+revealed	O
+evidence	O
+of	O
+moderate	O
+-	O
+to	O
+-	O
+severe	O
+drug	B
+toxicity	I
+.	O
+
+She	O
+underwent	O
+liver	O
+transplantation	O
+with	O
+an	O
+uneventful	O
+postoperative	O
+course	O
+.	O
+
+Her	O
+aminotransferase	O
+levels	O
+returned	O
+to	O
+normal	O
+by	O
+postoperative	O
+day	O
+23	O
+,	O
+and	O
+her	O
+2	O
+-	O
+year	O
+follow	O
+-	O
+up	O
+showed	O
+no	O
+adverse	O
+events	O
+.	O
+
+Ezetimibe	O
+undergoes	O
+extensive	O
+glucuronidation	O
+by	O
+uridine	O
+diphosphate	O
+glucoronosyltransferases	O
+(	O
+UGT	O
+)	O
+in	O
+the	O
+intestine	O
+and	O
+liver	O
+and	O
+may	O
+have	O
+inhibited	O
+the	O
+glucuronidation	O
+of	O
+simvastatin	O
+hydroxy	O
+acid	O
+,	O
+resulting	O
+in	O
+increased	O
+simvastatin	O
+exposure	O
+and	O
+subsequent	O
+hepatotoxicity	B
+.	O
+
+To	O
+our	O
+knowledge	O
+,	O
+this	O
+is	O
+the	O
+first	O
+case	O
+report	O
+of	O
+simvastatin	O
+-	O
+ezetimibe	O
+-	O
+induced	O
+liver	B
+failure	I
+that	O
+resulted	O
+in	O
+liver	O
+transplantation	O
+.	O
+
+We	O
+postulate	O
+that	O
+the	O
+mechanism	O
+of	O
+the	O
+simvastatinezetimibe	O
+-	O
+induced	O
+hepatotoxicity	B
+is	O
+the	O
+increased	O
+simvastatin	O
+exposure	O
+by	O
+ezetimibe	O
+inhibition	O
+of	O
+UGT	O
+enzymes	O
+.	O
+
+Clinicians	O
+should	O
+be	O
+aware	O
+of	O
+potential	O
+hepatotoxicity	B
+with	O
+simvastatin	O
+-	O
+ezetimibe	O
+especially	O
+in	O
+elderly	O
+patients	O
+and	O
+should	O
+carefully	O
+monitor	O
+serum	O
+aminotransferase	O
+levels	O
+when	O
+starting	O
+therapy	O
+and	O
+titrating	O
+the	O
+dosage	O
+.	O
+
+Massive	O
+proteinuria	B
+and	O
+acute	B
+renal	I
+failure	I
+after	O
+oral	O
+bisphosphonate	O
+(	O
+alendronate	O
+)	O
+administration	O
+in	O
+a	O
+patient	O
+with	O
+focal	B
+segmental	I
+glomerulosclerosis	I
+.	O
+
+A	O
+61	O
+-	O
+year	O
+-	O
+old	O
+Japanese	O
+man	O
+with	O
+nephrotic	B
+syndrome	I
+due	O
+to	O
+focal	B
+segmental	I
+glomerulosclerosis	I
+was	O
+initially	O
+responding	O
+well	O
+to	O
+steroid	O
+therapy	O
+.	O
+
+The	O
+amount	O
+of	O
+daily	O
+urinary	O
+protein	O
+decreased	O
+from	O
+15	O
+.	O
+6	O
+to	O
+2	O
+.	O
+8	O
+g	O
+.	O
+
+Within	O
+14	O
+days	O
+of	O
+the	O
+oral	O
+bisphosphonate	O
+(	O
+alendronate	O
+sodium	O
+)	O
+administration	O
+,	O
+the	O
+amount	O
+of	O
+daily	O
+urinary	O
+protein	O
+increased	O
+rapidly	O
+up	O
+to	O
+12	O
+.	O
+8	O
+g	O
+with	O
+acute	B
+renal	I
+failure	I
+.	O
+
+After	O
+discontinuing	O
+the	O
+oral	O
+alendronate	O
+,	O
+the	O
+patient	O
+underwent	O
+six	O
+cycles	O
+of	O
+hemodialysis	O
+and	O
+four	O
+cycles	O
+of	O
+LDL	O
+apheresis	O
+.	O
+
+Urinary	O
+volume	O
+and	O
+serum	O
+creatinine	O
+levels	O
+recovered	O
+to	O
+the	O
+normal	O
+range	O
+,	O
+with	O
+urinary	O
+protein	O
+disappearing	O
+completely	O
+within	O
+40	O
+days	O
+.	O
+
+This	O
+report	O
+demonstrates	O
+that	O
+not	O
+only	O
+intravenous	O
+,	O
+but	O
+also	O
+oral	O
+bisphosphonates	O
+can	O
+aggravate	O
+proteinuria	B
+and	O
+acute	B
+renal	I
+failure	I
+.	O
+
+Serum	O
+-	O
+and	O
+glucocorticoid	O
+-	O
+inducible	O
+kinase	O
+1	O
+in	O
+doxorubicin	O
+-	O
+induced	O
+nephrotic	B
+syndrome	I
+.	O
+
+Doxorubicin	O
+-	O
+induced	O
+nephropathy	B
+leads	O
+to	O
+epithelial	O
+sodium	O
+channel	O
+(	O
+ENaC	O
+)	O
+-	O
+dependent	O
+volume	B
+retention	I
+and	O
+renal	O
+fibrosis	B
+.	O
+
+The	O
+aldosterone	O
+-	O
+sensitive	O
+serum	O
+-	O
+and	O
+glucocorticoid	O
+-	O
+inducible	O
+kinase	O
+SGK1	O
+has	O
+been	O
+shown	O
+to	O
+participate	O
+in	O
+the	O
+stimulation	O
+of	O
+ENaC	O
+and	O
+to	O
+mediate	O
+renal	O
+fibrosis	B
+following	O
+mineralocorticoid	O
+and	O
+salt	O
+excess	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+performed	O
+to	O
+elucidate	O
+the	O
+role	O
+of	O
+SGK1	O
+in	O
+the	O
+volume	B
+retention	I
+and	O
+fibrosis	B
+during	O
+nephrotic	B
+syndrome	I
+.	O
+
+To	O
+this	O
+end	O
+,	O
+doxorubicin	O
+(	O
+15	O
+mug	O
+/	O
+g	O
+body	O
+wt	O
+)	O
+was	O
+injected	O
+intravenously	O
+into	O
+gene	O
+-	O
+targeted	O
+mice	O
+lacking	O
+SGK1	O
+(	O
+sgk1	O
+(	O
+-	O
+/	O
+-	O
+)	O
+)	O
+and	O
+their	O
+wild	O
+-	O
+type	O
+littermates	O
+(	O
+sgk1	O
+(	O
++	O
+/	O
++	O
+)	O
+)	O
+.	O
+
+Doxorubicin	O
+treatment	O
+resulted	O
+in	O
+heavy	O
+proteinuria	B
+(	O
+>	O
+100	O
+mg	O
+protein	O
+/	O
+mg	O
+crea	O
+)	O
+in	O
+15	O
+/	O
+44	O
+of	O
+sgk1	O
+(	O
++	O
+/	O
++	O
+)	O
+and	O
+15	O
+/	O
+44	O
+of	O
+sgk1	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+leading	O
+to	O
+severe	O
+nephrotic	B
+syndrome	I
+with	O
+ascites	B
+,	O
+lipidemia	B
+,	O
+and	O
+hypoalbuminemia	B
+in	O
+both	O
+genotypes	O
+.	O
+
+Plasma	O
+aldosterone	O
+levels	O
+increased	O
+in	O
+nephrotic	B
+mice	O
+of	O
+both	O
+genotypes	O
+and	O
+was	O
+followed	O
+by	O
+increased	O
+SGK1	O
+protein	O
+expression	O
+in	O
+sgk1	O
+(	O
++	O
+/	O
++	O
+)	O
+mice	O
+.	O
+
+Urinary	O
+sodium	O
+excretion	O
+reached	O
+signficantly	O
+lower	O
+values	O
+in	O
+sgk1	O
+(	O
++	O
+/	O
++	O
+)	O
+mice	O
+(	O
+15	O
++	O
+/	O
+-	O
+5	O
+mumol	O
+/	O
+mg	O
+crea	O
+)	O
+than	O
+in	O
+sgk1	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+(	O
+35	O
++	O
+/	O
+-	O
+5	O
+mumol	O
+/	O
+mg	O
+crea	O
+)	O
+and	O
+was	O
+associated	O
+with	O
+a	O
+significantly	O
+higher	O
+body	O
+weight	B
+gain	I
+in	O
+sgk1	O
+(	O
++	O
+/	O
++	O
+)	O
+compared	O
+with	O
+sgk1	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+(	O
++	O
+6	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+vs	O
+.	O
++	O
+4	O
+.	O
+1	O
++	O
+/	O
+-	O
+0	O
+.	O
+8	O
+g	O
+)	O
+.	O
+
+During	O
+the	O
+course	O
+of	O
+nephrotic	B
+syndrome	I
+,	O
+serum	O
+urea	O
+concentrations	O
+increased	O
+significantly	O
+faster	O
+in	O
+sgk1	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+than	O
+in	O
+sgk1	O
+(	O
++	O
+/	O
++	O
+)	O
+mice	O
+leading	O
+to	O
+uremia	B
+and	O
+a	O
+reduced	O
+median	O
+survival	O
+in	O
+sgk1	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+(	O
+29	O
+vs	O
+.	O
+40	O
+days	O
+in	O
+sgk1	O
+(	O
++	O
+/	O
++	O
+)	O
+mice	O
+)	O
+.	O
+
+In	O
+conclusion	O
+,	O
+gene	O
+-	O
+targeted	O
+mice	O
+lacking	O
+SGK1	O
+showed	O
+blunted	O
+volume	B
+retention	I
+,	O
+yet	O
+were	O
+not	O
+protected	O
+against	O
+renal	O
+fibrosis	B
+during	O
+experimental	O
+nephrotic	B
+syndrome	I
+.	O
+
+Severe	O
+thrombocytopenia	B
+and	O
+haemolytic	B
+anaemia	I
+associated	O
+with	O
+ciprofloxacin	O
+:	O
+a	O
+case	O
+report	O
+with	O
+fatal	O
+outcome	O
+.	O
+
+Haematological	O
+adverse	O
+reactions	O
+associated	O
+with	O
+fatal	O
+outcome	O
+are	O
+rare	O
+during	O
+treatment	O
+with	O
+ciprofloxacin	O
+.	O
+
+A	O
+30	O
+-	O
+year	O
+old	O
+Caucasian	O
+man	O
+reported	O
+with	O
+abdominal	B
+pain	I
+and	O
+jaundice	B
+after	O
+3	O
+-	O
+day	O
+administration	O
+of	O
+oral	O
+ciprofloxacin	O
+for	O
+a	O
+suspect	O
+of	O
+urinary	B
+tract	I
+infection	I
+.	O
+
+Clinical	O
+evaluations	O
+suggested	O
+an	O
+initial	O
+diagnosis	O
+of	O
+severe	O
+thrombocytopenia	B
+and	O
+haemolysis	B
+.	O
+
+The	O
+patient	O
+progressively	O
+developed	O
+petechiae	B
+and	O
+purpura	B
+on	O
+thorax	O
+and	O
+lower	O
+limbs	O
+.	O
+
+Despite	O
+pharmacological	O
+and	O
+supportive	O
+interventions	O
+,	O
+laboratory	O
+parameters	O
+worsened	O
+and	O
+the	O
+patient	O
+died	O
+17	O
+hours	O
+after	O
+admission	O
+.	O
+
+An	O
+accurate	O
+autopsy	O
+revealed	O
+most	O
+organs	O
+with	O
+diffuse	O
+petechial	O
+haemorrhages	B
+.	O
+
+No	O
+signs	O
+of	O
+bone	B
+marrow	I
+depression	I
+were	O
+found	O
+.	O
+
+No	O
+thrombi	B
+or	O
+signs	O
+of	O
+microangiopathies	B
+were	O
+observed	O
+in	O
+arterial	O
+vessels	O
+.	O
+
+Blood	O
+and	O
+urine	O
+cultures	O
+did	O
+not	O
+show	O
+any	O
+bacterial	O
+growth	O
+.	O
+
+This	O
+case	O
+report	O
+shows	O
+that	O
+ciprofloxacin	O
+may	O
+precipitate	O
+life	O
+-	O
+threatening	O
+thrombocytopenia	B
+and	O
+haemolytic	B
+anaemia	I
+,	O
+even	O
+in	O
+the	O
+early	O
+phases	O
+of	O
+treatment	O
+and	O
+without	O
+apparent	O
+previous	O
+exposures	O
+.	O
+
+Alpha	O
+-	O
+lipoic	O
+acid	O
+prevents	O
+mitochondrial	B
+damage	I
+and	O
+neurotoxicity	B
+in	O
+experimental	O
+chemotherapy	O
+neuropathy	B
+.	O
+
+The	O
+study	O
+investigates	O
+if	O
+alpha	O
+-	O
+lipoic	O
+acid	O
+is	O
+neuroprotective	O
+against	O
+chemotherapy	O
+induced	O
+neurotoxicity	B
+,	O
+if	O
+mitochondrial	B
+damage	I
+plays	O
+a	O
+critical	O
+role	O
+in	O
+toxic	B
+neurodegenerative	I
+cascade	I
+,	O
+and	O
+if	O
+neuroprotective	O
+effects	O
+of	O
+alpha	O
+-	O
+lipoic	O
+acid	O
+depend	O
+on	O
+mitochondria	O
+protection	O
+.	O
+
+We	O
+used	O
+an	O
+in	O
+vitro	O
+model	O
+of	O
+chemotherapy	O
+induced	O
+peripheral	B
+neuropathy	I
+that	O
+closely	O
+mimic	O
+the	O
+in	O
+vivo	O
+condition	O
+by	O
+exposing	O
+primary	O
+cultures	O
+of	O
+dorsal	O
+root	O
+ganglion	O
+(	O
+DRG	O
+)	O
+sensory	O
+neurons	O
+to	O
+paclitaxel	O
+and	O
+cisplatin	O
+,	O
+two	O
+widely	O
+used	O
+and	O
+highly	O
+effective	O
+chemotherapeutic	O
+drugs	O
+.	O
+
+This	O
+approach	O
+allowed	O
+investigating	O
+the	O
+efficacy	O
+of	O
+alpha	O
+-	O
+lipoic	O
+acid	O
+in	O
+preventing	O
+axonal	B
+damage	I
+and	O
+apoptosis	O
+and	O
+the	O
+function	O
+and	O
+ultrastructural	O
+morphology	O
+of	O
+mitochondria	O
+after	O
+exposure	O
+to	O
+toxic	O
+agents	O
+and	O
+alpha	O
+-	O
+lipoic	O
+acid	O
+.	O
+
+Our	O
+results	O
+demonstrate	O
+that	O
+both	O
+cisplatin	O
+and	O
+paclitaxel	O
+cause	O
+early	O
+mitochondrial	B
+impairment	I
+with	O
+loss	O
+of	O
+membrane	O
+potential	O
+and	O
+induction	O
+of	O
+autophagic	O
+vacuoles	O
+in	O
+neurons	O
+.	O
+
+Alpha	O
+-	O
+lipoic	O
+acid	O
+exerts	O
+neuroprotective	O
+effects	O
+against	O
+chemotherapy	O
+induced	O
+neurotoxicity	B
+in	O
+sensory	O
+neurons	O
+:	O
+it	O
+rescues	O
+the	O
+mitochondrial	B
+toxicity	I
+and	O
+induces	O
+the	O
+expression	O
+of	O
+frataxin	O
+,	O
+an	O
+essential	O
+mitochondrial	O
+protein	O
+with	O
+anti	O
+-	O
+oxidant	O
+and	O
+chaperone	O
+properties	O
+.	O
+
+In	O
+conclusion	O
+mitochondrial	B
+toxicity	I
+is	O
+an	O
+early	O
+common	O
+event	O
+both	O
+in	O
+paclitaxel	O
+and	O
+cisplatin	O
+induced	O
+neurotoxicity	B
+.	O
+
+Alpha	O
+-	O
+lipoic	O
+acid	O
+protects	O
+sensory	O
+neurons	O
+through	O
+its	O
+anti	O
+-	O
+oxidant	O
+and	O
+mitochondrial	O
+regulatory	O
+functions	O
+,	O
+possibly	O
+inducing	O
+the	O
+expression	O
+of	O
+frataxin	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+alpha	O
+-	O
+lipoic	O
+acid	O
+might	O
+reduce	O
+the	O
+risk	O
+of	O
+developing	O
+peripheral	B
+nerve	I
+toxicity	I
+in	O
+patients	O
+undergoing	O
+chemotherapy	O
+and	O
+encourage	O
+further	O
+confirmatory	O
+clinical	O
+trials	O
+.	O
+
+Toxicity	B
+in	O
+rhesus	O
+monkeys	O
+following	O
+administration	O
+of	O
+the	O
+8	O
+-	O
+aminoquinoline	O
+8	O
+-	O
+[	O
+(	O
+4	O
+-	O
+amino	O
+-	O
+l	O
+-	O
+methylbutyl	O
+)	O
+amino	O
+]	O
+-	O
+5	O
+-	O
+(	O
+l	O
+-	O
+hexyloxy	O
+)	O
+-	O
+6	O
+-	O
+methoxy	O
+-	O
+4	O
+-	O
+methylquinoline	O
+(	O
+WR242511	O
+)	O
+.	O
+
+INTRODUCTION	O
+:	O
+Many	O
+substances	O
+that	O
+form	O
+methemoglobin	O
+(	O
+MHb	O
+)	O
+effectively	O
+counter	O
+cyanide	O
+(	O
+CN	O
+)	O
+toxicity	B
+.	O
+
+Although	O
+MHb	O
+formers	O
+are	O
+generally	O
+applied	O
+as	O
+treatments	O
+for	O
+CN	O
+poisoning	B
+,	O
+it	O
+has	O
+been	O
+proposed	O
+that	O
+a	O
+stable	O
+,	O
+long	O
+-	O
+acting	O
+MHb	O
+former	O
+could	O
+serve	O
+as	O
+a	O
+CN	O
+pretreatment	O
+.	O
+
+Using	O
+this	O
+rationale	O
+,	O
+the	O
+8	O
+-	O
+aminoquinoline	O
+WR242511	O
+,	O
+a	O
+potent	O
+long	O
+-	O
+lasting	O
+MHb	O
+former	O
+in	O
+rodents	O
+and	O
+beagle	O
+dogs	O
+,	O
+was	O
+studied	O
+in	O
+the	O
+rhesus	O
+monkey	O
+for	O
+advanced	O
+development	O
+as	O
+a	O
+potential	O
+CN	O
+pretreatment	O
+.	O
+
+METHODS	O
+:	O
+In	O
+this	O
+study	O
+,	O
+WR242511	O
+was	O
+administered	O
+intravenously	O
+(	O
+IV	O
+)	O
+in	O
+2	O
+female	O
+and	O
+4	O
+male	O
+rhesus	O
+monkeys	O
+in	O
+doses	O
+of	O
+3	O
+.	O
+5	O
+and	O
+/	O
+or	O
+7	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+;	O
+a	O
+single	O
+male	O
+also	O
+received	O
+WR242511	O
+orally	O
+(	O
+PO	O
+)	O
+at	O
+7	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+.	O
+
+Health	O
+status	O
+and	O
+MHb	O
+levels	O
+were	O
+monitored	O
+following	O
+exposure	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+selected	O
+doses	O
+of	O
+WR242511	O
+,	O
+which	O
+produced	O
+significant	O
+methemoglobinemia	B
+in	O
+beagle	O
+dogs	O
+in	O
+earlier	O
+studies	O
+conducted	O
+elsewhere	O
+,	O
+produced	O
+very	O
+little	O
+MHb	O
+(	O
+mean	O
+<	O
+2	O
+.	O
+0	O
+%	O
+)	O
+in	O
+the	O
+rhesus	O
+monkey	O
+.	O
+
+Furthermore	O
+,	O
+transient	O
+hemoglobinuria	B
+was	O
+noted	O
+approximately	O
+60	O
+minutes	O
+postinjection	O
+of	O
+WR242511	O
+(	O
+3	O
+.	O
+5	O
+or	O
+7	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+and	O
+2	O
+lethalities	O
+occurred	O
+(	O
+one	O
+IV	O
+and	O
+one	O
+PO	O
+)	O
+following	O
+the	O
+7	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+dose	O
+.	O
+
+Myoglobinuria	B
+was	O
+also	O
+observed	O
+following	O
+the	O
+7	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+dose	O
+.	O
+
+Histopathology	O
+analyses	O
+in	O
+the	O
+2	O
+animals	O
+that	O
+died	O
+revealed	O
+liver	B
+and	I
+kidney	I
+toxicity	I
+,	O
+with	O
+greater	O
+severity	O
+in	O
+the	O
+orally	O
+-	O
+treated	O
+animal	O
+.	O
+
+CONCLUSIONS	O
+:	O
+These	O
+data	O
+demonstrate	O
+direct	O
+and	O
+/	O
+or	O
+indirect	O
+drug	O
+-	O
+induced	O
+toxicity	B
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+WR242511	O
+should	O
+not	O
+be	O
+pursued	O
+as	O
+a	O
+pretreatment	O
+for	O
+CN	O
+poisoning	B
+unless	O
+the	O
+anti	O
+-	O
+CN	O
+characteristics	O
+of	O
+this	O
+compound	O
+can	O
+be	O
+successfully	O
+dissociated	O
+from	O
+those	O
+producing	O
+undesirable	O
+toxicity	B
+.	O
+
+Repetitive	O
+transcranial	O
+magnetic	O
+stimulation	O
+for	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+In	O
+a	O
+placebo	O
+-	O
+controlled	O
+,	O
+single	O
+-	O
+blinded	O
+,	O
+crossover	O
+study	O
+,	O
+we	O
+assessed	O
+the	O
+effect	O
+of	O
+"	O
+real	O
+"	O
+repetitive	O
+transcranial	O
+magnetic	O
+stimulation	O
+(	O
+rTMS	O
+)	O
+versus	O
+"	O
+sham	O
+"	O
+rTMS	O
+(	O
+placebo	O
+)	O
+on	O
+peak	O
+dose	O
+dyskinesias	B
+in	O
+patients	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+.	O
+
+Ten	O
+patients	O
+with	O
+PD	B
+and	O
+prominent	O
+dyskinesias	B
+had	O
+rTMS	O
+(	O
+1	O
+,	O
+800	O
+pulses	O
+;	O
+1	O
+Hz	O
+rate	O
+)	O
+delivered	O
+over	O
+the	O
+motor	O
+cortex	O
+for	O
+4	O
+consecutive	O
+days	O
+twice	O
+,	O
+once	O
+real	O
+stimuli	O
+and	O
+once	O
+sham	O
+stimulation	O
+were	O
+used	O
+;	O
+evaluations	O
+were	O
+done	O
+at	O
+the	O
+baseline	O
+and	O
+1	O
+day	O
+after	O
+the	O
+end	O
+of	O
+each	O
+of	O
+the	O
+treatment	O
+series	O
+.	O
+
+Direct	O
+comparison	O
+between	O
+sham	O
+and	O
+real	O
+rTMS	O
+effects	O
+showed	O
+no	O
+significant	O
+difference	O
+in	O
+clinician	O
+-	O
+assessed	O
+dyskinesia	B
+severity	O
+.	O
+
+However	O
+,	O
+comparison	O
+with	O
+the	O
+baseline	O
+showed	O
+small	O
+but	O
+significant	O
+reduction	O
+in	O
+dyskinesia	B
+severity	O
+following	O
+real	O
+rTMS	O
+but	O
+not	O
+placebo	O
+.	O
+
+The	O
+major	O
+effect	O
+was	O
+on	O
+dystonia	B
+subscore	O
+.	O
+
+Similarly	O
+,	O
+in	O
+patient	O
+diaries	O
+,	O
+although	O
+both	O
+treatments	O
+caused	O
+reduction	O
+in	O
+subjective	O
+dyskinesia	B
+scores	O
+during	O
+the	O
+days	O
+of	O
+intervention	O
+,	O
+the	O
+effect	O
+was	O
+sustained	O
+for	O
+3	O
+days	O
+after	O
+the	O
+intervention	O
+for	O
+the	O
+real	O
+rTMS	O
+only	O
+.	O
+
+Following	O
+rTMS	O
+,	O
+no	O
+side	O
+effects	O
+and	O
+no	O
+adverse	O
+effects	O
+on	O
+motor	O
+function	O
+and	O
+PD	B
+symptoms	O
+were	O
+noted	O
+.	O
+
+The	O
+results	O
+suggest	O
+the	O
+existence	O
+of	O
+residual	O
+beneficial	O
+clinical	O
+aftereffects	O
+of	O
+consecutive	O
+daily	O
+applications	O
+of	O
+low	O
+-	O
+frequency	O
+rTMS	O
+on	O
+dyskinesias	B
+in	O
+PD	B
+.	O
+
+The	O
+effects	O
+may	O
+be	O
+further	O
+exploited	O
+for	O
+potential	O
+therapeutic	O
+uses	O
+.	O
+
+Intracavernous	O
+epinephrine	O
+:	O
+a	O
+minimally	O
+invasive	O
+treatment	O
+for	O
+priapism	B
+in	O
+the	O
+emergency	O
+department	O
+.	O
+
+Priapism	B
+is	O
+the	O
+prolonged	O
+erection	O
+of	O
+the	O
+penis	O
+in	O
+the	O
+absence	O
+of	O
+sexual	O
+arousal	O
+.	O
+
+A	O
+45	O
+-	O
+year	O
+-	O
+old	O
+man	O
+,	O
+an	O
+admitted	O
+frequent	O
+cocaine	O
+user	O
+,	O
+presented	O
+to	O
+the	O
+Emergency	O
+Department	O
+(	O
+ED	O
+)	O
+on	O
+two	O
+separate	O
+occasions	O
+with	O
+a	O
+history	O
+of	O
+priapism	B
+after	O
+cocaine	O
+use	O
+.	O
+
+The	O
+management	O
+options	O
+in	O
+the	O
+ED	O
+,	O
+as	O
+exemplified	O
+by	O
+four	O
+individual	O
+case	O
+reports	O
+,	O
+in	O
+particular	O
+the	O
+use	O
+of	O
+a	O
+minimally	O
+invasive	O
+method	O
+of	O
+intracorporal	O
+epinephrine	O
+instillation	O
+,	O
+are	O
+discussed	O
+.	O
+
+Prophylactic	O
+use	O
+of	O
+lamivudine	O
+with	O
+chronic	O
+immunosuppressive	O
+therapy	O
+for	O
+rheumatologic	B
+disorders	I
+.	O
+
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+report	O
+our	O
+experience	O
+concerning	O
+the	O
+effectiveness	O
+of	O
+the	O
+prophylactic	O
+administration	O
+of	O
+lamivudine	O
+in	O
+hepatitis	O
+B	O
+virus	O
+surface	O
+antigen	O
+(	O
+HBs	O
+Ag	O
+)	O
+positive	O
+patients	O
+with	O
+rheumatologic	B
+disease	I
+.	O
+
+From	O
+June	O
+2004	O
+to	O
+October	O
+2006	O
+,	O
+11	O
+HBs	O
+Ag	O
+positive	O
+patients	O
+with	O
+rheumatologic	B
+diseases	I
+,	O
+who	O
+were	O
+on	O
+both	O
+immunosuppressive	O
+and	O
+prophylactic	O
+lamivudine	O
+therapies	O
+,	O
+were	O
+retrospectively	O
+assessed	O
+.	O
+
+Liver	O
+function	O
+tests	O
+,	O
+hepatitis	B
+B	I
+virus	O
+(	O
+HBV	O
+)	O
+serologic	O
+markers	O
+,	O
+and	O
+HBV	O
+DNA	O
+levels	O
+of	O
+the	O
+patients	O
+during	O
+follow	O
+-	O
+up	O
+were	O
+obtained	O
+from	O
+hospital	O
+file	O
+records	O
+.	O
+
+Eleven	O
+patients	O
+(	O
+six	O
+male	O
+)	O
+with	O
+median	O
+age	O
+47	O
+years	O
+(	O
+range	O
+27	O
+-	O
+73	O
+)	O
+,	O
+median	O
+disease	O
+duration	O
+50	O
+months	O
+(	O
+range	O
+9	O
+-	O
+178	O
+)	O
+and	O
+median	O
+follow	O
+-	O
+up	O
+period	O
+of	O
+patients	O
+13	O
+.	O
+8	O
+months	O
+(	O
+range	O
+5	O
+-	O
+27	O
+)	O
+were	O
+enrolled	O
+in	O
+this	O
+study	O
+.	O
+
+Lamivudine	O
+therapy	O
+was	O
+started	O
+3	O
+-	O
+7	O
+days	O
+prior	O
+to	O
+immunosuppressive	O
+therapy	O
+in	O
+all	O
+patients	O
+.	O
+
+Baseline	O
+,	O
+liver	O
+function	O
+tests	O
+were	O
+elevated	O
+in	O
+two	O
+patients	O
+(	O
+fourth	O
+patient	O
+:	O
+ALT	O
+:	O
+122	O
+IU	O
+/	O
+l	O
+,	O
+AST	O
+:	O
+111	O
+IU	O
+/	O
+l	O
+,	O
+tenth	O
+patient	O
+:	O
+ALT	O
+:	O
+294	O
+IU	O
+/	O
+l	O
+,	O
+AST	O
+:	O
+274	O
+IU	O
+/	O
+l	O
+,	O
+with	O
+minimal	O
+changes	O
+in	O
+the	O
+liver	O
+biopsy	O
+in	O
+both	O
+)	O
+.	O
+
+Shortly	O
+after	O
+treatment	O
+their	O
+tests	O
+normalized	O
+and	O
+during	O
+follow	O
+-	O
+up	O
+period	O
+none	O
+of	O
+the	O
+patients	O
+had	O
+abnormal	B
+liver	I
+function	I
+tests	O
+.	O
+
+In	O
+four	O
+patients	O
+HBV	O
+DNA	O
+levels	O
+were	O
+higher	O
+than	O
+normal	O
+at	O
+baseline	O
+.	O
+
+Two	O
+of	O
+these	O
+normalized	O
+and	O
+the	O
+others	O
+increased	O
+later	O
+.	O
+
+In	O
+three	O
+additional	O
+patients	O
+,	O
+HBV	O
+DNA	O
+levels	O
+were	O
+increased	O
+during	O
+follow	O
+-	O
+up	O
+.	O
+
+None	O
+of	O
+the	O
+patients	O
+had	O
+significant	O
+clinical	O
+sings	O
+of	O
+HBV	O
+activation	O
+.	O
+
+Lamivudine	O
+was	O
+well	O
+tolerated	O
+and	O
+was	O
+continued	O
+in	O
+all	O
+patients	O
+.	O
+
+Prophylactic	O
+administration	O
+of	O
+lamivudine	O
+in	O
+patients	O
+who	O
+required	O
+immunosuppressive	O
+therapy	O
+seems	O
+to	O
+be	O
+safe	O
+,	O
+well	O
+tolerated	O
+and	O
+effective	O
+in	O
+preventing	O
+HBV	O
+reactivation	O
+.	O
+
+Effect	O
+of	O
+green	O
+tea	O
+and	O
+vitamin	O
+E	O
+combination	O
+in	O
+isoproterenol	O
+induced	O
+myocardial	B
+infarction	I
+in	O
+rats	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+aimed	O
+to	O
+investigate	O
+the	O
+combined	O
+effects	O
+of	O
+green	O
+tea	O
+and	O
+vitamin	O
+E	O
+on	O
+heart	O
+weight	O
+,	O
+body	O
+weight	O
+,	O
+serum	O
+marker	O
+enzymes	O
+,	O
+lipid	O
+peroxidation	O
+,	O
+endogenous	O
+antioxidants	O
+and	O
+membrane	O
+bound	O
+ATPases	O
+in	O
+isoproterenol	O
+(	O
+ISO	O
+)	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+in	O
+rats	O
+.	O
+
+Adult	O
+male	O
+albino	O
+rats	O
+,	O
+treated	O
+with	O
+ISO	O
+(	O
+200	O
+mg	O
+/	O
+kg	O
+,	O
+s	O
+.	O
+c	O
+.	O
+)	O
+for	O
+2	O
+days	O
+at	O
+an	O
+interval	O
+of	O
+24	O
+h	O
+caused	O
+a	O
+significant	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+elevation	O
+of	O
+heart	O
+weight	O
+,	O
+serum	O
+marker	O
+enzymes	O
+,	O
+lipid	O
+peroxidation	O
+and	O
+Ca	O
++	O
+2	O
+ATPase	O
+level	O
+whereas	O
+there	O
+was	O
+a	O
+significant	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+decrease	O
+in	O
+body	O
+weight	O
+,	O
+endogenous	O
+antioxidants	O
+,	O
+Na	O
++	O
+/	O
+K	O
++	O
+ATPase	O
+and	O
+Mg	O
++	O
+2	O
+ATPase	O
+levels	O
+.	O
+
+Administration	O
+of	O
+green	O
+tea	O
+(	O
+100	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+,	O
+p	O
+.	O
+o	O
+.	O
+)	O
+and	O
+vitamin	O
+E	O
+(	O
+100	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+,	O
+p	O
+.	O
+o	O
+.	O
+)	O
+together	O
+for	O
+30	O
+consecutive	O
+days	O
+and	O
+challenged	O
+with	O
+ISO	O
+on	O
+the	O
+day	O
+29th	O
+and	O
+30th	O
+,	O
+showed	O
+a	O
+significant	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+decrease	O
+in	O
+heart	O
+weight	O
+,	O
+serum	O
+marker	O
+enzymes	O
+,	O
+lipid	O
+peroxidation	O
+,	O
+Ca	O
++	O
+2	O
+ATPase	O
+and	O
+a	O
+significant	O
+increase	O
+in	O
+the	O
+body	O
+weight	O
+,	O
+endogenous	O
+antioxidants	O
+,	O
+Na	O
++	O
+/	O
+K	O
++	O
+ATPase	O
+and	O
+Mg	O
++	O
+2	O
+ATPase	O
+when	O
+compared	O
+with	O
+ISO	O
+treated	O
+group	O
+and	O
+green	O
+tea	O
+or	O
+vitamin	O
+E	O
+alone	O
+treated	O
+groups	O
+.	O
+
+These	O
+findings	O
+indicate	O
+the	O
+synergistic	O
+protective	O
+effect	O
+of	O
+green	O
+tea	O
+and	O
+vitamin	O
+E	O
+during	O
+ISO	O
+induced	O
+myocardial	B
+infarction	I
+in	O
+rats	O
+.	O
+
+Irreversible	O
+damage	O
+to	O
+the	O
+medullary	O
+interstitium	O
+in	O
+experimental	O
+analgesic	O
+nephropathy	B
+in	O
+F344	O
+rats	O
+.	O
+
+Renal	B
+papillary	I
+necrosis	I
+(	O
+RPN	B
+)	O
+and	O
+a	O
+decreased	O
+urinary	O
+concentrating	O
+ability	O
+developed	O
+during	O
+continuous	O
+long	O
+-	O
+term	O
+treatment	O
+with	O
+aspirin	O
+and	O
+paracetamol	O
+in	O
+female	O
+Fischer	O
+344	O
+rats	O
+.	O
+
+Renal	O
+structure	O
+and	O
+concentrating	O
+ability	O
+were	O
+examined	O
+after	O
+a	O
+recovery	O
+period	O
+of	O
+up	O
+to	O
+18	O
+weeks	O
+,	O
+when	O
+no	O
+analgesics	O
+were	O
+given	O
+,	O
+to	O
+investigate	O
+whether	O
+the	O
+analgesic	O
+-	O
+induced	O
+changes	O
+were	O
+reversible	O
+.	O
+
+There	O
+was	O
+no	O
+evidence	O
+of	O
+repair	O
+to	O
+the	O
+damaged	O
+medullary	O
+interstitial	O
+matrix	O
+,	O
+or	O
+proliferation	O
+of	O
+remaining	O
+undamaged	O
+type	O
+1	O
+medullary	O
+interstitial	O
+cells	O
+after	O
+the	O
+recovery	O
+period	O
+following	O
+analgesic	O
+treatment	O
+.	O
+
+The	O
+recovery	O
+of	O
+urinary	O
+concentrating	O
+ability	O
+was	O
+related	O
+to	O
+the	O
+length	O
+of	O
+analgesic	O
+treatment	O
+and	O
+the	O
+extent	O
+of	O
+the	O
+resulting	O
+inner	O
+medullary	O
+structural	O
+damage	O
+.	O
+
+During	O
+the	O
+early	O
+stages	O
+of	O
+analgesic	O
+treatment	O
+,	O
+the	O
+changes	O
+in	O
+urinary	O
+concentrating	O
+ability	O
+were	O
+reversible	O
+,	O
+but	O
+after	O
+prolonged	O
+analgesic	O
+treatment	O
+,	O
+maximum	O
+urinary	O
+concentrating	O
+ability	O
+failed	O
+to	O
+recover	O
+.	O
+
+This	O
+study	O
+shows	O
+that	O
+prolonged	O
+analgesic	O
+treatment	O
+in	O
+Fischer	O
+344	O
+rats	O
+causes	O
+progressive	O
+and	O
+irreversible	O
+damage	O
+to	O
+the	O
+interstitial	O
+matrix	O
+and	O
+type	O
+1	O
+interstitial	O
+cells	O
+leading	O
+to	O
+RPN	B
+.	O
+
+The	O
+associated	O
+urinary	O
+concentrating	O
+defect	O
+is	O
+reversible	O
+only	O
+during	O
+the	O
+early	O
+stages	O
+of	O
+structural	O
+damage	O
+to	O
+the	O
+inner	O
+medulla	O
+.	O
+
+Testosterone	O
+-	O
+dependent	O
+hypertension	B
+and	O
+upregulation	O
+of	O
+intrarenal	O
+angiotensinogen	O
+in	O
+Dahl	O
+salt	O
+-	O
+sensitive	O
+rats	O
+.	O
+
+Blood	O
+pressure	O
+(	O
+BP	O
+)	O
+is	O
+more	O
+salt	O
+sensitive	O
+in	O
+men	O
+than	O
+in	O
+premenopausal	O
+women	O
+.	O
+
+In	O
+Dahl	O
+salt	O
+-	O
+sensitive	O
+rats	O
+(	O
+DS	O
+)	O
+,	O
+high	O
+-	O
+salt	O
+(	O
+HS	O
+)	O
+diet	O
+increases	O
+BP	O
+more	O
+in	O
+males	O
+than	O
+females	O
+.	O
+
+In	O
+contrast	O
+to	O
+the	O
+systemic	O
+renin	O
+-	O
+angiotensin	O
+system	O
+,	O
+which	O
+is	O
+suppressed	O
+in	O
+response	O
+to	O
+HS	O
+in	O
+male	O
+DS	O
+,	O
+intrarenal	O
+angiotensinogen	O
+expression	O
+is	O
+increased	O
+,	O
+and	O
+intrarenal	O
+levels	O
+of	O
+ANG	O
+II	O
+are	O
+not	O
+suppressed	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+the	O
+hypothesis	O
+was	O
+tested	O
+that	O
+there	O
+is	O
+a	O
+sexual	O
+dimorphism	O
+in	O
+HS	O
+-	O
+induced	O
+upregulation	O
+of	O
+intrarenal	O
+angiotensinogen	O
+mediated	O
+by	O
+testosterone	O
+that	O
+also	O
+causes	O
+increases	O
+in	O
+BP	O
+and	O
+renal	B
+injury	I
+.	O
+
+On	O
+a	O
+low	O
+-	O
+salt	O
+(	O
+LS	O
+)	O
+diet	O
+,	O
+male	O
+DS	O
+had	O
+higher	O
+levels	O
+of	O
+intrarenal	O
+angiotensinogen	O
+mRNA	O
+than	O
+females	O
+.	O
+
+HS	O
+diet	O
+for	O
+4	O
+wk	O
+increased	O
+renal	O
+cortical	O
+angiotensinogen	O
+mRNA	O
+and	O
+protein	O
+only	O
+in	O
+male	O
+DS	O
+,	O
+which	O
+was	O
+prevented	O
+by	O
+castration	O
+.	O
+
+Ovariectomy	O
+of	O
+female	O
+DS	O
+had	O
+no	O
+effect	O
+on	O
+intrarenal	O
+angiotensinogen	O
+expression	O
+on	O
+either	O
+diet	O
+.	O
+
+Radiotelemetric	O
+BP	O
+was	O
+similar	O
+between	O
+males	O
+and	O
+castrated	O
+rats	O
+on	O
+LS	O
+diet	O
+.	O
+
+HS	O
+diet	O
+for	O
+4	O
+wk	O
+caused	O
+a	O
+progressive	O
+increase	O
+in	O
+BP	O
+,	O
+protein	O
+and	O
+albumin	O
+excretion	O
+,	O
+and	O
+glomerular	B
+sclerosis	I
+in	O
+male	O
+DS	O
+rats	O
+,	O
+which	O
+were	O
+attenuated	O
+by	O
+castration	O
+.	O
+
+Testosterone	O
+replacement	O
+in	O
+castrated	O
+DS	O
+rats	O
+increased	O
+BP	O
+,	O
+renal	B
+injury	I
+,	O
+and	O
+upregulation	O
+of	O
+renal	O
+angiotensinogen	O
+associated	O
+with	O
+HS	O
+diet	O
+.	O
+
+Testosterone	O
+contributes	O
+to	O
+the	O
+development	O
+of	O
+hypertension	B
+and	O
+renal	B
+injury	I
+in	O
+male	O
+DS	O
+rats	O
+on	O
+HS	O
+diet	O
+possibly	O
+through	O
+upregulation	O
+of	O
+the	O
+intrarenal	O
+renin	O
+-	O
+angiotensin	O
+system	O
+.	O
+
+Explicit	O
+episodic	O
+memory	O
+for	O
+sensory	O
+-	O
+discriminative	O
+components	O
+of	O
+capsaicin	O
+-	O
+induced	O
+pain	B
+:	O
+immediate	O
+and	O
+delayed	O
+ratings	O
+.	O
+
+Pain	B
+memory	O
+is	O
+thought	O
+to	O
+affect	O
+future	O
+pain	B
+sensitivity	O
+and	O
+thus	O
+contribute	O
+to	O
+clinical	O
+pain	B
+conditions	O
+.	O
+
+Systematic	O
+investigations	O
+of	O
+the	O
+human	O
+capacity	O
+to	O
+remember	O
+sensory	O
+features	O
+of	O
+experimental	O
+pain	B
+are	O
+sparse	O
+.	O
+
+In	O
+order	O
+to	O
+address	O
+long	O
+-	O
+term	O
+pain	B
+memory	O
+,	O
+nine	O
+healthy	O
+male	O
+volunteers	O
+received	O
+intradermal	O
+injections	O
+of	O
+three	O
+doses	O
+of	O
+capsaicin	O
+(	O
+0	O
+.	O
+05	O
+,	O
+1	O
+and	O
+20	O
+microg	O
+,	O
+separated	O
+by	O
+15	O
+min	O
+breaks	O
+)	O
+,	O
+each	O
+given	O
+three	O
+times	O
+in	O
+a	O
+balanced	O
+design	O
+across	O
+three	O
+sessions	O
+at	O
+one	O
+week	O
+intervals	O
+.	O
+
+Pain	B
+rating	O
+was	O
+performed	O
+using	O
+a	O
+computerized	O
+visual	O
+analogue	O
+scale	O
+(	O
+0	O
+-	O
+100	O
+)	O
+digitized	O
+at	O
+1	O
+/	O
+s	O
+,	O
+either	O
+immediately	O
+online	O
+or	O
+one	O
+hour	O
+or	O
+one	O
+day	O
+after	O
+injection	O
+.	O
+
+Subjects	O
+also	O
+recalled	O
+their	O
+pains	B
+one	O
+week	O
+later	O
+.	O
+
+Capsaicin	O
+injection	O
+reliably	O
+induced	O
+a	O
+dose	O
+-	O
+dependent	O
+flare	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+without	O
+any	O
+difference	O
+within	O
+or	O
+across	O
+sessions	O
+.	O
+
+The	O
+strong	O
+burning	O
+pain	B
+decayed	O
+exponentially	O
+within	O
+a	O
+few	O
+minutes	O
+.	O
+
+Subjects	O
+were	O
+able	O
+to	O
+reliably	O
+discriminate	O
+pain	B
+magnitude	O
+and	O
+duration	O
+across	O
+capsaicin	O
+doses	O
+(	O
+both	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+,	O
+regardless	O
+of	O
+whether	O
+first	O
+-	O
+time	O
+ratings	O
+were	O
+requested	O
+immediately	O
+,	O
+after	O
+one	O
+hour	O
+or	O
+after	O
+one	O
+day	O
+.	O
+
+Pain	B
+recall	O
+after	O
+one	O
+week	O
+was	O
+similarly	O
+precise	O
+(	O
+magnitude	O
+:	O
+p	O
+<	O
+0	O
+.	O
+01	O
+,	O
+duration	O
+:	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Correlation	O
+with	O
+rating	O
+recall	O
+after	O
+one	O
+week	O
+was	O
+best	O
+when	O
+first	O
+-	O
+time	O
+ratings	O
+were	O
+requested	O
+as	O
+late	O
+as	O
+one	O
+day	O
+after	O
+injection	O
+(	O
+R	O
+(	O
+2	O
+)	O
+=	O
+0	O
+.	O
+79	O
+)	O
+indicating	O
+that	O
+both	O
+rating	O
+retrievals	O
+utilized	O
+similar	O
+memory	O
+traces	O
+.	O
+
+These	O
+results	O
+indicate	O
+a	O
+reliable	O
+memory	O
+for	O
+magnitude	O
+and	O
+duration	O
+of	O
+experimentally	O
+induced	O
+pain	B
+.	O
+
+The	O
+data	O
+further	O
+suggest	O
+that	O
+the	O
+consolidation	O
+of	O
+this	O
+memory	O
+is	O
+an	O
+important	O
+interim	O
+stage	O
+,	O
+and	O
+may	O
+take	O
+up	O
+to	O
+one	O
+day	O
+.	O
+
+Severe	O
+and	O
+long	O
+lasting	O
+cholestasis	B
+after	O
+high	O
+-	O
+dose	O
+co	O
+-	O
+trimoxazole	O
+treatment	O
+for	O
+Pneumocystis	B
+pneumonia	I
+in	O
+HIV	B
+-	I
+infected	I
+patients	O
+-	O
+-	O
+a	O
+report	O
+of	O
+two	O
+cases	O
+.	O
+
+Pneumocystis	B
+pneumonia	I
+(	O
+PCP	B
+)	O
+,	O
+a	O
+common	O
+opportunistic	B
+infection	I
+in	O
+HIV	B
+-	I
+infected	I
+individuals	O
+,	O
+is	O
+generally	O
+treated	O
+with	O
+high	O
+doses	O
+of	O
+co	O
+-	O
+trimoxazole	O
+.	O
+
+However	O
+,	O
+treatment	O
+is	O
+often	O
+limited	O
+by	O
+adverse	O
+effects	O
+.	O
+
+Here	O
+,	O
+we	O
+report	O
+two	O
+cases	O
+of	O
+severely	O
+immunocompromised	O
+HIV	B
+-	I
+infected	I
+patients	O
+who	O
+developed	O
+severe	O
+intrahepatic	B
+cholestasis	I
+,	O
+and	O
+in	O
+one	O
+patient	O
+lesions	O
+mimicking	O
+liver	B
+abscess	I
+formation	O
+on	O
+radiologic	O
+exams	O
+,	O
+during	O
+co	O
+-	O
+trimoxazole	O
+treatment	O
+for	O
+PCP	B
+.	O
+
+Whereas	O
+patient	O
+1	O
+showed	O
+lesions	O
+of	O
+up	O
+to	O
+1	O
+cm	O
+readily	O
+detectable	O
+on	O
+magnetic	O
+resonance	O
+imaging	O
+under	O
+prolonged	O
+co	O
+-	O
+trimoxazole	O
+treatment	O
+,	O
+therapy	O
+of	O
+patient	O
+2	O
+was	O
+switched	O
+early	O
+.	O
+
+Bradykinin	O
+receptors	O
+antagonists	O
+and	O
+nitric	O
+oxide	O
+synthase	O
+inhibitors	O
+in	O
+vincristine	O
+and	O
+streptozotocin	O
+induced	O
+hyperalgesia	B
+in	O
+chemotherapy	O
+and	O
+diabetic	B
+neuropathy	I
+rat	O
+model	O
+.	O
+
+PURPOSE	O
+:	O
+The	O
+influence	O
+of	O
+an	O
+irreversible	O
+inhibitor	O
+of	O
+constitutive	O
+NO	O
+synthase	O
+(	O
+L	O
+-	O
+NOArg	O
+;	O
+1	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+ip	O
+)	O
+,	O
+a	O
+relatively	O
+selective	O
+inhibitor	O
+of	O
+inducible	O
+NO	O
+synthase	O
+(	O
+L	O
+-	O
+NIL	O
+;	O
+1	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+ip	O
+)	O
+and	O
+a	O
+relatively	O
+specific	O
+inhibitor	O
+of	O
+neuronal	O
+NO	O
+synthase	O
+(	O
+7	O
+-	O
+NI	O
+;	O
+0	O
+.	O
+1	O
+mg	O
+/	O
+kg	O
+ip	O
+)	O
+,	O
+on	O
+antihyperalgesic	O
+action	O
+of	O
+selective	O
+antagonists	O
+of	O
+B2	O
+and	O
+B1	O
+receptors	O
+:	O
+D	O
+-	O
+Arg	O
+-	O
+[	O
+Hyp3	O
+,	O
+Thi5	O
+,	O
+D	O
+-	O
+Tic7	O
+,	O
+Oic8	O
+]	O
+bradykinin	O
+(	O
+HOE	O
+140	O
+;	O
+70	O
+nmol	O
+/	O
+kg	O
+ip	O
+)	O
+or	O
+des	O
+Arg10	O
+HOE	O
+140	O
+(	O
+70	O
+nmol	O
+/	O
+kg	O
+ip	O
+)	O
+respectively	O
+,	O
+in	O
+model	O
+of	O
+diabetic	B
+(	I
+streptozotocin	I
+-	I
+induced	I
+)	I
+and	I
+toxic	I
+(	I
+vincristine	I
+-	I
+induced	I
+)	I
+neuropathy	I
+was	O
+investigated	O
+.	O
+
+METHODS	O
+:	O
+The	O
+changes	O
+in	O
+pain	B
+thresholds	O
+were	O
+determined	O
+using	O
+mechanical	O
+stimuli	O
+-	O
+-	O
+the	O
+modification	O
+of	O
+the	O
+classic	O
+paw	O
+withdrawal	O
+test	O
+described	O
+by	O
+Randall	O
+-	O
+Selitto	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+results	O
+of	O
+this	O
+paper	O
+confirm	O
+that	O
+inhibition	O
+of	O
+bradykinin	O
+receptors	O
+and	O
+inducible	O
+NO	O
+synthase	O
+but	O
+not	O
+neuronal	O
+NO	O
+synthase	O
+activity	O
+reduces	O
+diabetic	B
+hyperalgesia	I
+.	O
+
+Pretreatment	O
+with	O
+L	O
+-	O
+NOArg	O
+and	O
+L	O
+-	O
+NIL	O
+but	O
+not	O
+7	O
+-	O
+NI	O
+,	O
+significantly	O
+increases	O
+antihyperalgesic	O
+activity	O
+both	O
+HOE	O
+140	O
+and	O
+des	O
+Arg10	O
+HOE	O
+140	O
+.	O
+
+It	O
+was	O
+also	O
+shown	O
+that	O
+both	O
+products	O
+of	O
+inducible	O
+NO	O
+synthase	O
+and	O
+neuronal	O
+NO	O
+synthase	O
+activation	O
+as	O
+well	O
+as	O
+bradykinin	O
+are	O
+involved	O
+in	O
+hyperalgesia	B
+produced	O
+by	O
+vincristine	O
+.	O
+
+Moreover	O
+,	O
+L	O
+-	O
+NOArg	O
+and	O
+7	O
+-	O
+NI	O
+but	O
+not	O
+L	O
+-	O
+NIL	O
+intensify	O
+antihyperalgesic	O
+activity	O
+of	O
+HOE	O
+140	O
+or	O
+des	O
+-	O
+Arg10HOE	O
+140	O
+in	O
+toxic	B
+neuropathy	I
+.	O
+
+CONCLUSIONS	O
+:	O
+Results	O
+of	O
+these	O
+studies	O
+suggest	O
+that	O
+B1	O
+and	O
+B2	O
+receptors	O
+are	O
+engaged	O
+in	O
+transmission	O
+of	O
+nociceptive	O
+stimuli	O
+in	O
+both	O
+diabetic	B
+and	I
+toxic	I
+neuropathy	I
+.	O
+
+In	O
+streptozotocin	O
+-	O
+induced	O
+hyperalgesia	B
+,	O
+inducible	O
+NO	O
+synthase	O
+participates	O
+in	O
+pronociceptive	O
+activity	O
+of	O
+bradykinin	O
+,	O
+whereas	O
+in	O
+vincristine	O
+-	O
+induced	O
+hyperalgesia	B
+bradykinin	O
+seemed	O
+to	O
+activate	O
+neuronal	O
+NO	O
+synthase	O
+pathway	O
+.	O
+
+Therefore	O
+,	O
+concomitant	O
+administration	O
+of	O
+small	O
+doses	O
+of	O
+bradykinin	O
+receptor	O
+antagonists	O
+and	O
+NO	O
+synthase	O
+inhibitors	O
+can	O
+be	O
+effective	O
+in	O
+alleviation	O
+of	O
+neuropathic	B
+pain	I
+,	O
+even	O
+in	O
+hospital	O
+care	O
+.	O
+
+Confusion	B
+,	O
+a	O
+rather	O
+serious	O
+adverse	O
+drug	O
+reaction	O
+with	O
+valproic	O
+acid	O
+:	O
+a	O
+review	O
+of	O
+the	O
+French	O
+Pharmacovigilance	O
+database	O
+.	O
+
+INTRODUCTION	O
+:	O
+Confusion	B
+is	O
+an	O
+adverse	O
+drug	O
+reaction	O
+frequently	O
+observed	O
+with	O
+valproic	O
+acid	O
+.	O
+
+Some	O
+case	O
+reports	O
+are	O
+published	O
+in	O
+the	O
+literature	O
+but	O
+no	O
+systematic	O
+study	O
+from	O
+a	O
+sample	O
+of	O
+patients	O
+has	O
+been	O
+published	O
+.	O
+
+We	O
+performed	O
+this	O
+study	O
+in	O
+order	O
+to	O
+describe	O
+the	O
+main	O
+characteristics	O
+of	O
+this	O
+adverse	O
+drug	O
+reaction	O
+.	O
+
+METHODS	O
+:	O
+Using	O
+the	O
+French	O
+Pharmacovigilance	O
+database	O
+,	O
+we	O
+selected	O
+the	O
+cases	O
+of	O
+confusion	B
+reported	O
+since	O
+1985	O
+with	O
+valproic	O
+acid	O
+.	O
+
+RESULTS	O
+:	O
+272	O
+cases	O
+of	O
+confusion	B
+were	O
+reported	O
+with	O
+valproic	O
+acid	O
+:	O
+153	O
+women	O
+and	O
+119	O
+men	O
+.	O
+
+Confusion	B
+mostly	O
+occurred	O
+during	O
+the	O
+two	O
+first	O
+weeks	O
+following	O
+valproic	O
+acid	O
+exposure	O
+(	O
+39	O
+.	O
+7	O
+%	O
+)	O
+.	O
+
+It	O
+was	O
+"	O
+serious	O
+"	O
+for	O
+almost	O
+2	O
+/	O
+3	O
+of	O
+the	O
+patients	O
+(	O
+62	O
+.	O
+5	O
+%	O
+)	O
+and	O
+its	O
+outcome	O
+favourable	O
+in	O
+most	O
+of	O
+the	O
+cases	O
+(	O
+82	O
+%	O
+)	O
+.	O
+
+The	O
+occurrence	O
+of	O
+this	O
+ADR	O
+was	O
+more	O
+frequent	O
+in	O
+patients	O
+aged	O
+between	O
+61	O
+and	O
+80	O
+years	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+work	O
+shows	O
+that	O
+confusion	B
+with	O
+valproic	O
+acid	O
+is	O
+a	O
+serious	O
+,	O
+rather	O
+frequent	O
+but	O
+reversible	O
+adverse	O
+drug	O
+reaction	O
+.	O
+
+It	O
+occurs	O
+especially	O
+in	O
+older	O
+patients	O
+and	O
+during	O
+the	O
+first	O
+two	O
+weeks	O
+of	O
+treatment	O
+.	O
+
+Reversible	O
+inferior	B
+colliculus	I
+lesion	I
+in	O
+metronidazole	O
+-	O
+induced	O
+encephalopathy	B
+:	O
+magnetic	O
+resonance	O
+findings	O
+on	O
+diffusion	O
+-	O
+weighted	O
+and	O
+fluid	O
+attenuated	O
+inversion	O
+recovery	O
+imaging	O
+.	O
+
+OBJECTIVE	O
+:	O
+This	O
+is	O
+to	O
+present	O
+reversible	O
+inferior	B
+colliculus	I
+lesions	I
+in	O
+metronidazole	O
+-	O
+induced	O
+encephalopathy	B
+,	O
+to	O
+focus	O
+on	O
+the	O
+diffusion	O
+-	O
+weighted	O
+imaging	O
+(	O
+DWI	O
+)	O
+and	O
+fluid	O
+attenuated	O
+inversion	O
+recovery	O
+(	O
+FLAIR	O
+)	O
+imaging	O
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+From	O
+November	O
+2005	O
+to	O
+September	O
+2007	O
+,	O
+8	O
+patients	O
+(	O
+5	O
+men	O
+and	O
+3	O
+women	O
+)	O
+were	O
+diagnosed	O
+as	O
+having	O
+metronidazole	O
+-	O
+induced	O
+encephalopathy	B
+(	O
+age	O
+range	O
+;	O
+43	O
+-	O
+78	O
+years	O
+)	O
+.	O
+
+They	O
+had	O
+been	O
+taking	O
+metronidazole	O
+(	O
+total	O
+dosage	O
+,	O
+45	O
+-	O
+120	O
+g	O
+;	O
+duration	O
+,	O
+30	O
+days	O
+to	O
+2	O
+months	O
+)	O
+to	O
+treat	O
+the	O
+infection	B
+in	O
+various	O
+organs	O
+.	O
+
+Initial	O
+brain	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+were	O
+obtained	O
+after	O
+the	O
+hospitalization	O
+,	O
+including	O
+DWI	O
+(	O
+8	O
+/	O
+8	O
+)	O
+,	O
+apparent	O
+diffusion	O
+coefficient	O
+(	O
+ADC	O
+)	O
+map	O
+(	O
+4	O
+/	O
+8	O
+)	O
+,	O
+FLAIR	O
+(	O
+7	O
+/	O
+8	O
+)	O
+,	O
+and	O
+T2	O
+-	O
+weighted	O
+image	O
+(	O
+8	O
+/	O
+8	O
+)	O
+.	O
+
+Follow	O
+-	O
+up	O
+MRIs	O
+were	O
+performed	O
+on	O
+5	O
+patients	O
+from	O
+third	O
+to	O
+14th	O
+days	O
+after	O
+discontinuation	O
+of	O
+metronidazole	O
+administration	O
+.	O
+
+Findings	O
+of	O
+initial	O
+and	O
+follow	O
+-	O
+up	O
+MRIs	O
+were	O
+retrospectively	O
+evaluated	O
+by	O
+2	O
+neuroradiologists	O
+by	O
+consensus	O
+,	O
+to	O
+analyze	O
+the	O
+presence	O
+of	O
+abnormal	O
+signal	O
+intensities	O
+,	O
+their	O
+locations	O
+,	O
+and	O
+signal	O
+changes	O
+on	O
+follow	O
+-	O
+up	O
+images	O
+.	O
+
+RESULTS	O
+:	O
+Initial	O
+MRIs	O
+showed	O
+abnormal	O
+high	O
+signal	O
+intensities	O
+on	O
+DWI	O
+and	O
+FLAIR	O
+(	O
+or	O
+T2	O
+-	O
+weighted	O
+image	O
+)	O
+at	O
+the	O
+dentate	O
+nucleus	O
+(	O
+8	O
+/	O
+8	O
+)	O
+,	O
+inferior	O
+colliculus	O
+(	O
+6	O
+/	O
+8	O
+)	O
+,	O
+corpus	O
+callosum	O
+(	O
+2	O
+/	O
+8	O
+)	O
+,	O
+pons	O
+(	O
+2	O
+/	O
+8	O
+)	O
+,	O
+medulla	O
+(	O
+1	O
+/	O
+8	O
+)	O
+,	O
+and	O
+bilateral	O
+cerebral	O
+white	O
+matter	O
+(	O
+1	O
+/	O
+8	O
+)	O
+.	O
+
+High	O
+-	O
+signal	O
+intensity	O
+lesions	O
+on	O
+DWI	O
+tended	O
+to	O
+show	O
+low	O
+signal	O
+intensity	O
+on	O
+ADC	O
+map	O
+(	O
+3	O
+/	O
+4	O
+)	O
+,	O
+but	O
+in	O
+one	O
+patient	O
+,	O
+high	O
+signal	O
+intensity	O
+was	O
+shown	O
+at	O
+bilateral	O
+dentate	O
+nuclei	O
+on	O
+not	O
+only	O
+DWI	O
+but	O
+also	O
+ADC	O
+map	O
+.	O
+
+All	O
+the	O
+lesions	O
+in	O
+dentate	O
+,	O
+inferior	O
+colliculus	O
+,	O
+pons	O
+,	O
+and	O
+medullas	O
+had	O
+been	O
+resolved	O
+completely	O
+on	O
+follow	O
+-	O
+up	O
+MRIs	O
+in	O
+5	O
+patients	O
+,	O
+but	O
+in	O
+1	O
+patient	O
+of	O
+them	O
+,	O
+corpus	O
+callosal	B
+lesion	I
+persisted	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Reversible	O
+inferior	B
+colliculus	I
+lesions	I
+could	O
+be	O
+considered	O
+as	O
+the	O
+characteristic	O
+for	O
+metronidazole	O
+-	O
+induced	O
+encephalopathy	B
+,	O
+next	O
+to	O
+the	O
+dentate	O
+nucleus	O
+involvement	O
+.	O
+
+Clinically	O
+significant	O
+proteinuria	B
+following	O
+the	O
+administration	O
+of	O
+sirolimus	O
+to	O
+renal	O
+transplant	O
+recipients	O
+.	O
+
+BACKGROUND	O
+:	O
+Sirolimus	O
+is	O
+the	O
+latest	O
+immunosuppressive	O
+agent	O
+used	O
+to	O
+prevent	O
+rejection	O
+,	O
+and	O
+may	O
+have	O
+less	O
+nephrotoxicity	B
+than	O
+calcineurin	O
+inhibitor	O
+(	O
+CNI	O
+)	O
+-	O
+based	O
+regimens	O
+.	O
+
+To	O
+date	O
+there	O
+has	O
+been	O
+little	O
+documentation	O
+of	O
+clinically	O
+significant	O
+proteinuria	B
+linked	O
+with	O
+the	O
+use	O
+of	O
+sirolimus	O
+.	O
+
+We	O
+have	O
+encountered	O
+several	O
+patients	O
+who	O
+developed	O
+substantial	O
+proteinuria	B
+associated	O
+with	O
+sirolimus	O
+use	O
+.	O
+
+In	O
+each	O
+patient	O
+,	O
+the	O
+close	O
+temporal	O
+association	O
+between	O
+the	O
+commencement	O
+of	O
+sirolimus	O
+therapy	O
+and	O
+proteinuria	B
+implicated	O
+sirolimus	O
+as	O
+the	O
+most	O
+likely	O
+etiology	O
+of	O
+the	O
+proteinuria	B
+.	O
+
+METHODS	O
+:	O
+We	O
+analyzed	O
+the	O
+clinical	O
+and	O
+laboratory	O
+information	O
+available	O
+for	O
+all	O
+119	O
+patients	O
+transplanted	O
+at	O
+the	O
+Washington	O
+Hospital	O
+Center	O
+between	O
+1999	O
+-	O
+2003	O
+for	O
+whom	O
+sirolimus	O
+was	O
+a	O
+component	O
+of	O
+their	O
+immunosuppressant	O
+regimen	O
+.	O
+
+In	O
+these	O
+patients	O
+,	O
+the	O
+magnitude	O
+of	O
+proteinuria	B
+was	O
+assessed	O
+on	O
+morning	O
+urine	O
+samples	O
+by	O
+turbidometric	O
+measurement	O
+or	O
+random	O
+urine	O
+protein	O
+:	O
+creatinine	O
+ratios	O
+,	O
+an	O
+estimate	O
+of	O
+grams	O
+of	O
+proteinuria	B
+/	O
+day	O
+.	O
+
+Laboratory	O
+results	O
+were	O
+compared	O
+between	O
+prior	O
+,	O
+during	O
+and	O
+following	O
+sirolimus	O
+use	O
+.	O
+
+RESULTS	O
+:	O
+Twenty	O
+-	O
+eight	O
+patients	O
+(	O
+24	O
+%	O
+)	O
+developed	O
+increased	O
+proteinuria	B
+from	O
+baseline	O
+during	O
+their	O
+post	O
+-	O
+transplantation	O
+course	O
+.	O
+
+In	O
+21	O
+patients	O
+an	O
+alternative	O
+cause	O
+of	O
+proteinuria	B
+was	O
+either	O
+obvious	O
+or	O
+insufficient	O
+data	O
+was	O
+available	O
+to	O
+be	O
+conclusive	O
+.	O
+
+In	O
+7	O
+of	O
+the	O
+28	O
+patients	O
+there	O
+was	O
+a	O
+striking	O
+temporal	O
+association	O
+between	O
+the	O
+initiation	O
+of	O
+sirolimus	O
+and	O
+the	O
+development	O
+of	O
+nephrotic	B
+-	O
+range	O
+proteinuria	B
+.	O
+
+Proteinuria	B
+correlated	O
+most	O
+strongly	O
+with	O
+sirolimus	O
+therapy	O
+when	O
+compared	O
+to	O
+other	O
+demographic	O
+and	O
+clinical	O
+variables	O
+.	O
+
+In	O
+most	O
+patients	O
+,	O
+discontinuation	O
+of	O
+sirolimus	O
+resulted	O
+in	O
+a	O
+decrease	O
+,	O
+but	O
+not	O
+resolution	O
+,	O
+of	O
+proteinuria	B
+.	O
+
+CONCLUSIONS	O
+:	O
+Sirolimus	O
+induces	O
+or	O
+aggravates	O
+pre	O
+-	O
+existing	O
+proteinuria	B
+in	O
+an	O
+unpredictable	O
+subset	O
+of	O
+renal	O
+allograft	O
+recipients	O
+.	O
+
+Proteinuria	B
+may	O
+improve	O
+,	O
+but	O
+does	O
+not	O
+resolve	O
+,	O
+when	O
+sirolimus	O
+is	O
+withdrawn	O
+.	O
+
+Components	O
+of	O
+lemon	O
+essential	O
+oil	O
+attenuate	O
+dementia	B
+induced	O
+by	O
+scopolamine	O
+.	O
+
+The	O
+anti	O
+-	O
+dementia	B
+effects	O
+of	O
+s	O
+-	O
+limonene	O
+and	O
+s	O
+-	O
+perillyl	O
+alcohol	O
+were	O
+observed	O
+using	O
+the	O
+passive	O
+avoidance	O
+test	O
+(	O
+PA	O
+)	O
+and	O
+the	O
+open	O
+field	O
+habituation	O
+test	O
+(	O
+OFH	O
+)	O
+.	O
+
+These	O
+lemon	O
+essential	O
+oils	O
+showed	O
+strong	O
+ability	O
+to	O
+improve	O
+memory	B
+impaired	I
+by	O
+scopolamine	O
+;	O
+however	O
+,	O
+s	O
+-	O
+perillyl	O
+alcohol	O
+relieved	O
+the	O
+deficit	B
+of	I
+associative	I
+memory	I
+in	O
+PA	O
+only	O
+,	O
+and	O
+did	O
+not	O
+improve	O
+non	O
+-	O
+associative	O
+memory	O
+significantly	O
+in	O
+OFH	O
+.	O
+
+Analysis	O
+of	O
+neurotransmitter	O
+concentration	O
+in	O
+some	O
+brain	O
+regions	O
+on	O
+the	O
+test	O
+day	O
+showed	O
+that	O
+dopamine	O
+concentration	O
+of	O
+the	O
+vehicle	O
+/	O
+scopolamine	O
+group	O
+was	O
+significantly	O
+lower	O
+than	O
+that	O
+of	O
+the	O
+vehicle	O
+/	O
+vehicle	O
+group	O
+,	O
+but	O
+this	O
+phenomenon	O
+was	O
+reversed	O
+when	O
+s	O
+-	O
+limonene	O
+or	O
+s	O
+-	O
+perillyl	O
+alcohol	O
+were	O
+administered	O
+before	O
+the	O
+injection	O
+of	O
+scopolamine	O
+.	O
+
+Simultaneously	O
+,	O
+we	O
+found	O
+that	O
+these	O
+two	O
+lemon	O
+essential	O
+oil	O
+components	O
+could	O
+inhibit	O
+acetylcholinesterase	O
+activity	O
+in	O
+vitro	O
+using	O
+the	O
+Ellman	O
+method	O
+.	O
+
+Attentional	O
+modulation	O
+of	O
+perceived	O
+pain	B
+intensity	O
+in	O
+capsaicin	O
+-	O
+induced	O
+secondary	O
+hyperalgesia	B
+.	O
+
+Perceived	O
+pain	B
+intensity	O
+is	O
+modulated	O
+by	O
+attention	O
+.	O
+
+However	O
+,	O
+it	O
+is	O
+not	O
+known	O
+that	O
+how	O
+pain	B
+intensity	O
+ratings	O
+are	O
+affected	O
+by	O
+attention	O
+in	O
+capsaicin	O
+-	O
+induced	O
+secondary	O
+hyperalgesia	B
+.	O
+
+Here	O
+we	O
+show	O
+that	O
+perceived	O
+pain	B
+intensity	O
+in	O
+secondary	O
+hyperalgesia	B
+is	O
+decreased	O
+when	O
+attention	O
+is	O
+distracted	O
+away	O
+from	O
+the	O
+painful	O
+pinprick	O
+stimulus	O
+with	O
+a	O
+visual	O
+task	O
+.	O
+
+Furthermore	O
+,	O
+it	O
+was	O
+found	O
+that	O
+the	O
+magnitude	O
+of	O
+attentional	O
+modulation	O
+in	O
+secondary	O
+hyperalgesia	B
+is	O
+very	O
+similar	O
+to	O
+that	O
+of	O
+capsaicin	O
+-	O
+untreated	O
+,	O
+control	O
+condition	O
+.	O
+
+Our	O
+findings	O
+,	O
+showing	O
+no	O
+interaction	O
+between	O
+capsaicin	O
+treatment	O
+and	O
+attentional	O
+modulation	O
+suggest	O
+that	O
+capsaicin	O
+-	O
+induced	O
+secondary	O
+hyperalgesia	B
+and	O
+attention	O
+might	O
+affect	O
+mechanical	O
+pain	B
+through	O
+independent	O
+mechanisms	O
+.	O
+
+Cardioprotective	O
+effect	O
+of	O
+salvianolic	O
+acid	O
+A	O
+on	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+in	O
+rats	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+evaluate	O
+the	O
+cardioprotective	O
+potential	O
+of	O
+salvianolic	O
+acid	O
+A	O
+on	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+in	O
+rats	O
+.	O
+
+Hemodynamic	O
+parameters	O
+and	O
+lead	O
+II	O
+electrocardiograph	O
+were	O
+monitored	O
+and	O
+recorded	O
+continuously	O
+.	O
+
+Cardiac	O
+marker	O
+enzymes	O
+and	O
+antioxidative	O
+parameters	O
+in	O
+serum	O
+and	O
+heart	O
+tissues	O
+were	O
+measured	O
+.	O
+
+Assay	O
+for	O
+mitochondrial	O
+respiratory	O
+function	O
+and	O
+histopathological	O
+examination	O
+of	O
+heart	O
+tissues	O
+were	O
+performed	O
+.	O
+
+Isoproterenol	O
+-	O
+treated	O
+rats	O
+showed	O
+significant	O
+increases	O
+in	O
+the	O
+levels	O
+of	O
+lactate	O
+dehydrogenase	O
+,	O
+aspartate	O
+transaminase	O
+,	O
+creatine	O
+kinase	O
+and	O
+malondialdehyde	O
+and	O
+significant	O
+decreases	O
+in	O
+the	O
+activities	O
+of	O
+superoxide	O
+dismutase	O
+,	O
+catalase	O
+and	O
+glutathione	O
+peroxidase	O
+in	O
+serum	O
+and	O
+heart	O
+.	O
+
+These	O
+rats	O
+also	O
+showed	O
+declines	O
+in	O
+left	O
+ventricular	O
+systolic	O
+pressure	O
+,	O
+maximum	O
+and	O
+minimum	O
+rate	O
+of	O
+developed	O
+left	O
+ventricular	O
+pressure	O
+,	O
+and	O
+elevation	O
+of	O
+left	O
+ventricular	O
+end	O
+-	O
+diastolic	O
+pressure	O
+and	O
+ST	O
+-	O
+segment	O
+.	O
+
+In	O
+addition	O
+,	O
+mitochondrial	O
+respiratory	B
+dysfunction	I
+characterized	O
+by	O
+decreased	O
+respiratory	O
+control	O
+ratio	O
+and	O
+ADP	O
+/	O
+O	O
+was	O
+observed	O
+in	O
+isoproterenol	O
+-	O
+treated	O
+rats	O
+.	O
+
+Administration	O
+of	O
+salvianolic	O
+acid	O
+A	O
+for	O
+a	O
+period	O
+of	O
+8	O
+days	O
+significantly	O
+attenuated	O
+isoproterenol	O
+-	O
+induced	O
+cardiac	B
+dysfunction	I
+and	O
+myocardial	B
+injury	I
+and	O
+improved	O
+mitochondrial	O
+respiratory	O
+function	O
+.	O
+
+The	O
+protective	O
+role	O
+of	O
+salvianolic	O
+acid	O
+A	O
+against	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+damage	I
+was	O
+further	O
+confirmed	O
+by	O
+histopathological	O
+examination	O
+.	O
+
+The	O
+results	O
+of	O
+our	O
+study	O
+suggest	O
+that	O
+salvianolic	O
+acid	O
+A	O
+possessing	O
+antioxidant	O
+activity	O
+has	O
+a	O
+significant	O
+protective	O
+effect	O
+against	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+.	O
+
+Long	O
+-	O
+term	O
+glutamate	O
+supplementation	O
+failed	O
+to	O
+protect	O
+against	O
+peripheral	B
+neurotoxicity	I
+of	O
+paclitaxel	O
+.	O
+
+Toxic	O
+peripheral	B
+neuropathy	I
+is	O
+still	O
+a	O
+significant	O
+limiting	O
+factor	O
+for	O
+chemotherapy	O
+with	O
+paclitaxel	O
+(	O
+PAC	O
+)	O
+,	O
+although	O
+glutamate	O
+and	O
+its	O
+closely	O
+related	O
+amino	O
+acid	O
+glutamine	O
+were	O
+claimed	O
+to	O
+ameliorate	O
+PAC	O
+neurotoxicity	B
+.	O
+
+This	O
+pilot	O
+trial	O
+aimed	O
+to	O
+evaluate	O
+the	O
+role	O
+of	O
+glutamate	O
+supplementation	O
+for	O
+preventing	O
+PAC	O
+-	O
+induced	O
+peripheral	B
+neuropathy	I
+in	O
+a	O
+randomized	O
+,	O
+placebo	O
+-	O
+controlled	O
+,	O
+double	O
+-	O
+blinded	O
+clinical	O
+and	O
+electro	O
+-	O
+diagnostic	O
+study	O
+.	O
+
+Forty	O
+-	O
+three	O
+ovarian	B
+cancer	I
+patients	O
+were	O
+available	O
+for	O
+analysis	O
+following	O
+six	O
+cycles	O
+of	O
+the	O
+same	O
+PAC	O
+-	O
+containing	O
+regimen	O
+:	O
+23	O
+had	O
+been	O
+supplemented	O
+by	O
+glutamate	O
+all	O
+along	O
+the	O
+treatment	O
+period	O
+,	O
+at	O
+a	O
+daily	O
+dose	O
+of	O
+three	O
+times	O
+500	O
+mg	O
+(	O
+group	O
+G	O
+)	O
+,	O
+and	O
+20	O
+had	O
+received	O
+a	O
+placebo	O
+(	O
+group	O
+P	O
+)	O
+.	O
+
+Patients	O
+were	O
+evaluated	O
+by	O
+neurological	O
+examinations	O
+,	O
+questionnaires	O
+and	O
+sensory	O
+-	O
+motor	O
+nerve	O
+conduction	O
+studies	O
+.	O
+
+There	O
+was	O
+no	O
+significant	O
+difference	O
+in	O
+the	O
+frequency	O
+of	O
+signs	O
+or	O
+symptoms	O
+between	O
+the	O
+two	O
+groups	O
+although	O
+neurotoxicity	B
+symptoms	O
+presented	O
+mostly	O
+with	O
+lower	O
+scores	O
+of	O
+severity	O
+in	O
+group	O
+G	O
+.	O
+
+However	O
+,	O
+this	O
+difference	O
+reached	O
+statistical	O
+significance	O
+only	O
+with	O
+regard	O
+to	O
+reported	O
+pain	B
+sensation	O
+(	O
+P	O
+=	O
+0	O
+.	O
+011	O
+)	O
+.	O
+
+Also	O
+the	O
+frequency	O
+of	O
+abnormal	O
+electro	O
+-	O
+diagnostic	O
+findings	O
+showed	O
+similarity	O
+between	O
+the	O
+two	O
+groups	O
+(	O
+G	O
+:	O
+7	O
+/	O
+23	O
+=	O
+30	O
+.	O
+4	O
+%	O
+;	O
+P	O
+:	O
+6	O
+/	O
+20	O
+=	O
+30	O
+%	O
+)	O
+.	O
+
+This	O
+pilot	O
+study	O
+leads	O
+to	O
+the	O
+conclusion	O
+that	O
+glutamate	O
+supplementation	O
+at	O
+the	O
+chosen	O
+regimen	O
+fails	O
+to	O
+protect	O
+against	O
+peripheral	B
+neurotoxicity	I
+of	O
+PAC	O
+.	O
+
+Development	O
+of	O
+ocular	B
+myasthenia	I
+during	O
+pegylated	O
+interferon	O
+and	O
+ribavirin	O
+treatment	O
+for	O
+chronic	B
+hepatitis	I
+C	I
+.	O
+
+A	O
+63	O
+-	O
+year	O
+-	O
+old	O
+male	O
+experienced	O
+sudden	O
+diplopia	B
+after	O
+9	O
+weeks	O
+of	O
+administration	O
+of	O
+pegylated	O
+interferon	O
+(	O
+IFN	O
+)	O
+alpha	O
+-	O
+2b	O
+and	O
+ribavirin	O
+for	O
+chronic	B
+hepatitis	I
+C	I
+(	O
+CHC	B
+)	O
+.	O
+
+Ophthalmologic	O
+examinations	O
+showed	O
+ptosis	B
+on	I
+the	I
+right	I
+upper	I
+lid	I
+and	O
+restricted	B
+right	I
+eye	I
+movement	I
+without	O
+any	O
+other	O
+neurological	O
+signs	O
+.	O
+
+A	O
+brain	O
+imaging	O
+study	O
+and	O
+repetitive	O
+nerve	O
+stimulation	O
+test	O
+indicated	O
+no	O
+abnormality	O
+.	O
+
+The	O
+acetylcholine	O
+receptor	O
+antibody	O
+titer	O
+and	O
+response	O
+to	O
+acetylcholinesterase	O
+inhibitors	O
+were	O
+negative	O
+,	O
+and	O
+the	O
+results	O
+of	O
+thyroid	O
+function	O
+tests	O
+were	O
+normal	O
+.	O
+
+The	O
+patient	O
+'	O
+s	O
+ophthalmological	O
+symptoms	O
+improved	O
+rapidly	O
+3	O
+weeks	O
+after	O
+discontinuation	O
+of	O
+pegylated	O
+IFN	O
+alpha	O
+-	O
+2b	O
+and	O
+ribavirin	O
+.	O
+
+The	O
+ocular	B
+myasthenia	I
+associated	O
+with	O
+combination	O
+therapy	O
+of	O
+pegylated	O
+IFN	O
+alpha	O
+-	O
+2b	O
+and	O
+ribavirin	O
+for	O
+CHC	B
+is	O
+very	O
+rarely	O
+reported	O
+;	O
+therefore	O
+,	O
+we	O
+present	O
+this	O
+case	O
+with	O
+a	O
+review	O
+of	O
+the	O
+various	O
+eye	O
+complications	O
+of	O
+IFN	O
+therapy	O
+.	O
+
+Learning	B
+and	I
+memory	I
+deficits	I
+in	O
+ecstasy	O
+users	O
+and	O
+their	O
+neural	O
+correlates	O
+during	O
+a	O
+face	O
+-	O
+learning	O
+task	O
+.	O
+
+It	O
+has	O
+been	O
+consistently	O
+shown	O
+that	O
+ecstasy	O
+users	O
+display	O
+impairments	B
+in	I
+learning	I
+and	I
+memory	I
+performance	O
+.	O
+
+In	O
+addition	O
+,	O
+working	O
+memory	O
+processing	O
+in	O
+ecstasy	O
+users	O
+has	O
+been	O
+shown	O
+to	O
+be	O
+associated	O
+with	O
+neural	O
+alterations	O
+in	O
+hippocampal	O
+and	O
+/	O
+or	O
+cortical	O
+regions	O
+as	O
+measured	O
+by	O
+functional	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+fMRI	O
+)	O
+.	O
+
+Using	O
+functional	O
+imaging	O
+and	O
+a	O
+face	O
+-	O
+learning	O
+task	O
+,	O
+we	O
+investigated	O
+neural	O
+correlates	O
+of	O
+encoding	O
+and	O
+recalling	O
+face	O
+-	O
+name	O
+associations	O
+in	O
+20	O
+recreational	O
+drug	O
+users	O
+whose	O
+predominant	O
+drug	O
+use	O
+was	O
+ecstasy	O
+and	O
+20	O
+controls	O
+.	O
+
+To	O
+address	O
+the	O
+potential	O
+confounding	O
+effects	O
+of	O
+the	O
+cannabis	O
+use	O
+of	O
+the	O
+ecstasy	O
+using	O
+group	O
+,	O
+a	O
+second	O
+analysis	O
+included	O
+14	O
+previously	O
+tested	O
+cannabis	O
+users	O
+(	O
+Nestor	O
+,	O
+L	O
+.	O
+,	O
+Roberts	O
+,	O
+G	O
+.	O
+,	O
+Garavan	O
+,	O
+H	O
+.	O
+,	O
+Hester	O
+,	O
+R	O
+.	O
+,	O
+2008	O
+.	O
+Deficits	B
+in	I
+learning	I
+and	I
+memory	I
+:	O
+parahippocampal	O
+hyperactivity	B
+and	O
+frontocortical	O
+hypoactivity	O
+in	O
+cannabis	O
+users	O
+.	O
+Neuroimage	O
+40	O
+,	O
+1328	O
+-	O
+1339	O
+)	O
+.	O
+
+Ecstasy	O
+users	O
+performed	O
+significantly	O
+worse	O
+in	O
+learning	O
+and	O
+memory	O
+compared	O
+to	O
+controls	O
+and	O
+cannabis	O
+users	O
+.	O
+
+A	O
+conjunction	O
+analysis	O
+of	O
+the	O
+encode	O
+and	O
+recall	O
+phases	O
+of	O
+the	O
+task	O
+revealed	O
+ecstasy	O
+-	O
+specific	O
+hyperactivity	B
+in	O
+bilateral	O
+frontal	O
+regions	O
+,	O
+left	O
+temporal	O
+,	O
+right	O
+parietal	O
+,	O
+bilateral	O
+temporal	O
+,	O
+and	O
+bilateral	O
+occipital	O
+brain	O
+regions	O
+.	O
+
+Ecstasy	O
+-	O
+specific	O
+hypoactivity	O
+was	O
+evident	O
+in	O
+the	O
+right	O
+dorsal	O
+anterior	O
+cingulated	O
+cortex	O
+(	O
+ACC	O
+)	O
+and	O
+left	O
+posterior	O
+cingulated	O
+cortex	O
+.	O
+
+In	O
+both	O
+ecstasy	O
+and	O
+cannabis	O
+groups	O
+brain	O
+activation	O
+was	O
+decreased	O
+in	O
+the	O
+right	O
+medial	O
+frontal	O
+gyrus	O
+,	O
+left	O
+parahippocampal	O
+gyrus	O
+,	O
+left	O
+dorsal	O
+cingulate	O
+gyrus	O
+,	O
+and	O
+left	O
+caudate	O
+.	O
+
+These	O
+results	O
+elucidated	O
+ecstasy	O
+-	O
+related	O
+deficits	O
+,	O
+only	O
+some	O
+of	O
+which	O
+might	O
+be	O
+attributed	O
+to	O
+cannabis	O
+use	O
+.	O
+
+These	O
+ecstasy	O
+-	O
+specific	O
+effects	O
+may	O
+be	O
+related	O
+to	O
+the	O
+vulnerability	O
+of	O
+isocortical	O
+and	O
+allocortical	O
+regions	O
+to	O
+the	O
+neurotoxic	B
+effects	O
+of	O
+ecstasy	O
+.	O
+
+Disulfiram	O
+-	O
+like	O
+syndrome	O
+after	O
+hydrogen	O
+cyanamide	O
+professional	O
+skin	O
+exposure	O
+:	O
+two	O
+case	O
+reports	O
+in	O
+France	O
+.	O
+
+Hydrogen	O
+cyanamide	O
+is	O
+a	O
+plant	O
+growth	O
+regulator	O
+used	O
+in	O
+agriculture	O
+to	O
+induce	O
+bud	O
+break	O
+in	O
+fruit	O
+trees	O
+.	O
+
+Contact	O
+with	O
+the	O
+skin	O
+can	O
+result	O
+in	O
+percutaneous	O
+absorption	O
+of	O
+the	O
+substance	O
+that	O
+inhibits	O
+aldehyde	O
+dehydrogenase	O
+and	O
+can	O
+induce	O
+acetaldehyde	O
+syndrome	O
+in	O
+case	O
+of	O
+alcohol	O
+use	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+report	O
+is	O
+to	O
+describe	O
+two	O
+cases	O
+of	O
+a	O
+disulfiram	O
+-	O
+like	O
+syndrome	O
+following	O
+occupational	O
+exposure	O
+to	O
+hydrogen	O
+cyanamide	O
+.	O
+
+The	O
+first	O
+case	O
+involved	O
+a	O
+59	O
+-	O
+year	O
+-	O
+old	O
+man	O
+who	O
+used	O
+Dormex	O
+,	O
+which	O
+contains	O
+hydrogen	O
+cyanamide	O
+,	O
+without	O
+protection	O
+after	O
+consuming	O
+a	O
+large	O
+amount	O
+of	O
+alcohol	O
+during	O
+a	O
+meal	O
+.	O
+
+In	O
+less	O
+than	O
+1	O
+hour	O
+after	O
+the	O
+ingestion	O
+of	O
+alcohol	O
+,	O
+he	O
+developed	O
+malaise	O
+with	O
+flushing	B
+of	I
+the	I
+face	I
+,	O
+tachycardia	B
+,	O
+and	O
+dyspnea	B
+.	O
+
+Manifestations	O
+regressed	O
+spontaneously	O
+under	O
+surveillance	O
+in	O
+the	O
+hospital	O
+.	O
+
+The	O
+second	O
+case	O
+occurred	O
+in	O
+a	O
+55	O
+-	O
+year	O
+-	O
+old	O
+farmer	O
+following	O
+cutaneous	O
+contact	O
+with	O
+Dormex	O
+.	O
+
+Five	O
+hours	O
+after	O
+exposure	O
+,	O
+he	O
+developed	O
+disulfiram	O
+-	O
+like	O
+syndrome	O
+with	O
+flushing	B
+,	O
+tachycardia	B
+,	O
+and	O
+arterial	B
+hypotension	I
+after	O
+consuming	O
+three	O
+glasses	O
+of	O
+wine	O
+.	O
+
+The	O
+patient	O
+recovered	O
+spontaneously	O
+in	O
+3	O
+hours	O
+under	O
+surveillance	O
+in	O
+the	O
+hospital	O
+.	O
+
+These	O
+cases	O
+confirm	O
+the	O
+necessity	O
+of	O
+avoiding	O
+alcohol	O
+consumption	O
+as	O
+recommended	O
+in	O
+the	O
+instructions	O
+for	O
+use	O
+of	O
+Dormex	O
+and	O
+of	O
+preventing	O
+cutaneous	O
+contact	O
+during	O
+use	O
+.	O
+
+Sulpiride	O
+-	O
+induced	O
+tardive	B
+dystonia	I
+.	O
+
+Sulpiride	O
+is	O
+a	O
+selective	O
+D2	O
+-	O
+receptor	O
+antagonist	O
+with	O
+antipsychotic	O
+and	O
+antidepressant	O
+properties	O
+.	O
+
+Although	O
+initially	O
+thought	O
+to	O
+be	O
+free	O
+of	O
+extrapyramidal	O
+side	O
+effects	O
+,	O
+sulpiride	O
+-	O
+induced	O
+tardive	B
+dyskinesia	I
+and	O
+parkinsonism	B
+have	O
+been	O
+reported	O
+occasionally	O
+.	O
+
+We	O
+studied	O
+a	O
+37	O
+-	O
+year	O
+-	O
+old	O
+man	O
+who	O
+developed	O
+persistent	O
+segmental	O
+dystonia	B
+within	O
+2	O
+months	O
+after	O
+starting	O
+sulpiride	O
+therapy	O
+.	O
+
+We	O
+could	O
+not	O
+find	O
+any	O
+previous	O
+reports	O
+of	O
+sulpiride	O
+-	O
+induced	O
+tardive	B
+dystonia	I
+.	O
+
+Comparative	O
+cognitive	O
+and	O
+subjective	O
+side	O
+effects	O
+of	O
+immediate	O
+-	O
+release	O
+oxycodone	O
+in	O
+healthy	O
+middle	O
+-	O
+aged	O
+and	O
+older	O
+adults	O
+.	O
+
+This	O
+study	O
+measured	O
+the	O
+objective	O
+and	O
+subjective	O
+neurocognitive	O
+effects	O
+of	O
+a	O
+single	O
+10	O
+-	O
+mg	O
+dose	O
+of	O
+immediate	O
+-	O
+release	O
+oxycodone	O
+in	O
+healthy	O
+,	O
+older	O
+(	O
+>	O
+65	O
+years	O
+)	O
+,	O
+and	O
+middle	O
+-	O
+aged	O
+(	O
+35	O
+to	O
+55	O
+years	O
+)	O
+adults	O
+who	O
+were	O
+not	O
+suffering	O
+from	O
+chronic	O
+or	O
+significant	O
+daily	O
+pain	B
+.	O
+
+Seventy	O
+-	O
+one	O
+participants	O
+completed	O
+2	O
+separate	O
+study	O
+days	O
+and	O
+were	O
+blind	O
+to	O
+medication	O
+condition	O
+(	O
+placebo	O
+,	O
+10	O
+-	O
+mg	O
+oxycodone	O
+)	O
+.	O
+
+Plasma	O
+oxycodone	O
+concentration	O
+peaked	O
+between	O
+60	O
+and	O
+90	O
+minutes	O
+postdose	O
+(	O
+P	O
+<	O
+.	O
+01	O
+)	O
+and	O
+pupil	O
+size	O
+,	O
+an	O
+indication	O
+of	O
+physiological	O
+effects	O
+of	O
+the	O
+medication	O
+,	O
+peaked	O
+at	O
+approximately	O
+90	O
+to	O
+120	O
+minutes	O
+postdose	O
+(	O
+P	O
+<	O
+.	O
+01	O
+)	O
+.	O
+
+Significant	O
+declines	B
+in	I
+simple	I
+and	I
+sustained	I
+attention	I
+,	I
+working	I
+memory	I
+,	I
+and	I
+verbal	I
+memory	I
+were	O
+observed	O
+at	O
+1	O
+hour	O
+postdose	O
+compared	O
+to	O
+baseline	O
+for	O
+both	O
+age	O
+groups	O
+with	O
+a	O
+trend	O
+toward	O
+return	O
+to	O
+baseline	O
+by	O
+5	O
+hours	O
+postdose	O
+.	O
+
+For	O
+almost	O
+all	O
+cognitive	O
+measures	O
+,	O
+there	O
+were	O
+no	O
+medication	O
+by	O
+age	O
+-	O
+interaction	O
+effects	O
+,	O
+which	O
+indicates	O
+that	O
+the	O
+2	O
+age	O
+groups	O
+exhibited	O
+similar	O
+responses	O
+to	O
+the	O
+medication	O
+challenge	O
+.	O
+
+This	O
+study	O
+suggests	O
+that	O
+for	O
+healthy	O
+older	O
+adults	O
+who	O
+are	O
+not	O
+suffering	O
+from	O
+chronic	B
+pain	I
+,	O
+neurocognitive	O
+and	O
+pharmacodynamic	O
+changes	O
+in	O
+response	O
+to	O
+a	O
+10	O
+-	O
+mg	O
+dose	O
+of	O
+immediate	O
+-	O
+release	O
+oxycodone	O
+are	O
+similar	O
+to	O
+those	O
+observed	O
+for	O
+middle	O
+-	O
+aged	O
+adults	O
+.	O
+
+PERSPECTIVE	O
+:	O
+Study	O
+findings	O
+indicate	O
+that	O
+the	O
+metabolism	O
+,	O
+neurocognitive	O
+effects	O
+,	O
+and	O
+physical	O
+side	O
+effects	O
+of	O
+oral	O
+oxycodone	O
+are	O
+similar	O
+for	O
+healthy	O
+middle	O
+-	O
+aged	O
+and	O
+older	O
+adults	O
+.	O
+
+Therefore	O
+,	O
+clinicians	O
+should	O
+not	O
+avoid	O
+prescribing	O
+oral	O
+opioids	O
+to	O
+older	O
+adults	O
+based	O
+on	O
+the	O
+belief	O
+that	O
+older	O
+adults	O
+are	O
+at	O
+higher	O
+risk	O
+for	O
+side	O
+effects	O
+than	O
+younger	O
+adults	O
+.	O
+
+The	O
+glycine	O
+transporter	O
+-	O
+1	O
+inhibitor	O
+SSR103800	O
+displays	O
+a	O
+selective	O
+and	O
+specific	O
+antipsychotic	O
+-	O
+like	O
+profile	O
+in	O
+normal	O
+and	O
+transgenic	O
+mice	O
+.	O
+
+Schizophrenia	B
+has	O
+been	O
+initially	O
+associated	O
+with	O
+dysfunction	O
+in	O
+dopamine	O
+neurotransmission	O
+.	O
+
+However	O
+,	O
+the	O
+observation	O
+that	O
+antagonists	O
+of	O
+the	O
+glutamate	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+receptor	O
+produce	O
+schizophrenic	B
+-	O
+like	O
+symptoms	O
+in	O
+humans	O
+has	O
+led	O
+to	O
+the	O
+idea	O
+of	O
+a	O
+dysfunctioning	O
+of	O
+the	O
+glutamatergic	O
+system	O
+via	O
+its	O
+NMDA	O
+receptor	O
+.	O
+
+As	O
+a	O
+result	O
+,	O
+there	O
+is	O
+a	O
+growing	O
+interest	O
+in	O
+the	O
+development	O
+of	O
+pharmacological	O
+agents	O
+with	O
+potential	O
+antipsychotic	O
+properties	O
+that	O
+enhance	O
+the	O
+activity	O
+of	O
+the	O
+glutamatergic	O
+system	O
+via	O
+a	O
+modulation	O
+of	O
+the	O
+NMDA	O
+receptor	O
+.	O
+
+Among	O
+them	O
+are	O
+glycine	O
+transporter	O
+-	O
+1	O
+(	O
+GlyT1	O
+)	O
+inhibitors	O
+such	O
+as	O
+SSR103800	O
+,	O
+which	O
+indirectly	O
+enhance	O
+NMDA	O
+receptor	O
+function	O
+by	O
+increasing	O
+the	O
+glycine	O
+(	O
+a	O
+co	O
+-	O
+agonist	O
+for	O
+the	O
+NMDA	O
+receptor	O
+)	O
+levels	O
+in	O
+the	O
+synapse	O
+.	O
+
+This	O
+study	O
+aimed	O
+at	O
+investigating	O
+the	O
+potential	O
+antipsychotic	O
+-	O
+like	O
+properties	O
+of	O
+SSR103800	O
+,	O
+with	O
+a	O
+particular	O
+focus	O
+on	O
+models	O
+of	O
+hyperactivity	B
+,	O
+involving	O
+either	O
+drug	O
+challenge	O
+(	O
+ie	O
+,	O
+amphetamine	O
+and	O
+MK	O
+-	O
+801	O
+)	O
+or	O
+transgenic	O
+mice	O
+(	O
+ie	O
+,	O
+NMDA	O
+Nr1	O
+(	O
+neo	O
+-	O
+/	O
+-	O
+)	O
+and	O
+DAT	O
+(	O
+-	O
+/	O
+-	O
+)	O
+)	O
+.	O
+
+Results	O
+showed	O
+that	O
+SSR103800	O
+(	O
+10	O
+-	O
+30	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+)	O
+blocked	O
+hyperactivity	B
+induced	O
+by	O
+the	O
+non	O
+-	O
+competitive	O
+NMDA	O
+receptor	O
+antagonist	O
+,	O
+MK	O
+-	O
+801	O
+and	O
+partially	O
+reversed	O
+spontaneous	O
+hyperactivity	B
+of	O
+NMDA	O
+Nr1	O
+(	O
+neo	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+.	O
+
+In	O
+contrast	O
+,	O
+SSR103800	O
+failed	O
+to	O
+affect	O
+hyperactivity	B
+induced	O
+by	O
+amphetamine	O
+or	O
+naturally	O
+observed	O
+in	O
+dopamine	O
+transporter	O
+(	O
+DAT	O
+(	O
+-	O
+/	O
+-	O
+)	O
+)	O
+knockout	O
+mice	O
+(	O
+10	O
+-	O
+30	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+)	O
+.	O
+
+Importantly	O
+,	O
+both	O
+classical	O
+(	O
+haloperidol	O
+)	O
+and	O
+atypical	O
+(	O
+olanzapine	O
+,	O
+clozapine	O
+and	O
+aripiprazole	O
+)	O
+antipsychotics	O
+were	O
+effective	O
+in	O
+all	O
+these	O
+models	O
+of	O
+hyperactivity	B
+.	O
+
+However	O
+,	O
+unlike	O
+these	O
+latter	O
+,	O
+SSR103800	O
+did	O
+not	O
+produce	O
+catalepsy	B
+(	O
+retention	O
+on	O
+the	O
+bar	O
+test	O
+)	O
+up	O
+to	O
+30	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+
+Together	O
+these	O
+findings	O
+show	O
+that	O
+the	O
+GlyT1	O
+inhibitor	O
+,	O
+SSR103800	O
+,	O
+produces	O
+antipsychotic	O
+-	O
+like	O
+effects	O
+,	O
+which	O
+differ	O
+from	O
+those	O
+observed	O
+with	O
+compounds	O
+primarily	O
+targeting	O
+the	O
+dopaminergic	O
+system	O
+,	O
+and	O
+has	O
+a	O
+reduced	O
+side	O
+-	O
+effect	O
+potential	O
+as	O
+compared	O
+with	O
+these	O
+latter	O
+drugs	O
+.	O
+
+Pyrrolidine	O
+dithiocarbamate	O
+protects	O
+the	O
+piriform	O
+cortex	O
+in	O
+the	O
+pilocarpine	O
+status	B
+epilepticus	I
+model	O
+.	O
+
+Pyrrolidine	O
+dithiocarbamate	O
+(	O
+PDTC	O
+)	O
+has	O
+a	O
+dual	O
+mechanism	O
+of	O
+action	O
+as	O
+an	O
+antioxidant	O
+and	O
+an	O
+inhibitor	O
+of	O
+the	O
+transcription	O
+factor	O
+kappa	O
+-	O
+beta	O
+.	O
+
+Both	O
+,	O
+production	O
+of	O
+reactive	O
+oxygen	O
+species	O
+as	O
+well	O
+as	O
+activation	O
+of	O
+NF	O
+-	O
+kappaB	O
+have	O
+been	O
+implicated	O
+in	O
+severe	O
+neuronal	B
+damage	I
+in	O
+different	O
+sub	O
+-	O
+regions	O
+of	O
+the	O
+hippocampus	O
+as	O
+well	O
+as	O
+in	O
+the	O
+surrounding	O
+cortices	O
+.	O
+
+The	O
+effect	O
+of	O
+PDTC	O
+on	O
+status	B
+epilepticus	I
+-	O
+associated	O
+cell	O
+loss	O
+in	O
+the	O
+hippocampus	O
+and	O
+piriform	O
+cortex	O
+was	O
+evaluated	O
+in	O
+the	O
+rat	O
+fractionated	O
+pilocarpine	O
+model	O
+.	O
+
+Treatment	O
+with	O
+150	O
+mg	O
+/	O
+kg	O
+PDTC	O
+before	O
+and	O
+following	O
+status	B
+epilepticus	I
+significantly	O
+increased	O
+the	O
+mortality	O
+rate	O
+to	O
+100	O
+%	O
+.	O
+
+Administration	O
+of	O
+50	O
+mg	O
+/	O
+kg	O
+PDTC	O
+(	O
+low	O
+-	O
+dose	O
+)	O
+did	O
+not	O
+exert	O
+major	O
+effects	O
+on	O
+the	O
+development	O
+of	O
+a	O
+status	B
+epilepticus	I
+or	O
+the	O
+mortality	O
+rate	O
+.	O
+
+In	O
+vehicle	O
+-	O
+treated	O
+rats	O
+,	O
+status	B
+epilepticus	I
+caused	O
+pronounced	O
+neuronal	B
+damage	I
+in	O
+the	O
+piriform	O
+cortex	O
+comprising	O
+both	O
+pyramidal	O
+cells	O
+and	O
+interneurons	O
+.	O
+
+Low	O
+-	O
+dose	O
+PDTC	O
+treatment	O
+almost	O
+completely	O
+protected	O
+from	O
+lesions	O
+in	O
+the	O
+piriform	O
+cortex	O
+.	O
+
+A	O
+significant	O
+decrease	O
+in	O
+neuronal	O
+density	O
+of	O
+the	O
+hippocampal	O
+hilar	O
+formation	O
+was	O
+identified	O
+in	O
+vehicle	O
+-	O
+and	O
+PDTC	O
+-	O
+treated	O
+rats	O
+following	O
+status	B
+epilepticus	I
+.	O
+
+In	O
+conclusion	O
+,	O
+the	O
+NF	O
+-	O
+kappaB	O
+inhibitor	O
+and	O
+antioxidant	O
+PDTC	O
+protected	O
+the	O
+piriform	O
+cortex	O
+,	O
+whereas	O
+it	O
+did	O
+not	O
+affect	O
+hilar	O
+neuronal	B
+loss	I
+.	O
+
+These	O
+data	O
+might	O
+indicate	O
+that	O
+the	O
+generation	O
+of	O
+reactive	O
+oxygen	O
+species	O
+and	O
+activation	O
+of	O
+NF	O
+-	O
+kappaB	O
+plays	O
+a	O
+more	O
+central	O
+role	O
+in	O
+seizure	B
+-	O
+associated	O
+neuronal	B
+damage	I
+in	O
+the	O
+temporal	O
+cortex	O
+as	O
+compared	O
+to	O
+the	O
+hippocampal	O
+hilus	O
+.	O
+
+However	O
+,	O
+future	O
+investigations	O
+are	O
+necessary	O
+to	O
+exactly	O
+analyze	O
+the	O
+biochemical	O
+mechanisms	O
+by	O
+which	O
+PDTC	O
+exerted	O
+its	O
+beneficial	O
+effects	O
+in	O
+the	O
+piriform	O
+cortex	O
+.	O
+
+Anaesthetists	O
+'	O
+nightmare	O
+:	O
+masseter	B
+spasm	I
+after	O
+induction	O
+in	O
+an	O
+undiagnosed	O
+case	O
+of	O
+myotonia	B
+congenita	I
+.	O
+
+We	O
+report	O
+an	O
+undiagnosed	O
+case	O
+of	O
+myotonia	B
+congenita	I
+in	O
+a	O
+24	O
+-	O
+year	O
+-	O
+old	O
+previously	O
+healthy	O
+primigravida	O
+,	O
+who	O
+developed	O
+life	O
+threatening	O
+masseter	B
+spasm	I
+following	O
+a	O
+standard	O
+dose	O
+of	O
+intravenous	O
+suxamethonium	O
+for	O
+induction	O
+of	O
+anaesthesia	O
+.	O
+
+Neither	O
+the	O
+patient	O
+nor	O
+the	O
+anaesthetist	O
+was	O
+aware	O
+of	O
+the	O
+diagnosis	O
+before	O
+this	O
+potentially	O
+lethal	O
+complication	O
+occurred	O
+.	O
+
+Twin	O
+preterm	O
+neonates	O
+with	O
+cardiac	B
+toxicity	I
+related	O
+to	O
+lopinavir	O
+/	O
+ritonavir	O
+therapy	O
+.	O
+
+We	O
+report	O
+twin	O
+neonates	O
+who	O
+were	O
+born	O
+prematurely	O
+at	O
+32	O
+weeks	O
+of	O
+gestation	O
+to	O
+a	O
+mother	O
+with	O
+human	B
+immunodeficiency	I
+virus	I
+infection	I
+.	O
+
+One	O
+of	O
+the	O
+twins	O
+developed	O
+complete	O
+heart	B
+block	I
+and	O
+dilated	B
+cardiomyopathy	I
+related	O
+to	O
+lopinavir	O
+/	O
+ritonavir	O
+therapy	O
+,	O
+a	O
+boosted	O
+protease	O
+-	O
+inhibitor	O
+agent	O
+,	O
+while	O
+the	O
+other	O
+twin	O
+developed	O
+mild	O
+bradycardia	B
+.	O
+
+We	O
+recommend	O
+caution	O
+in	O
+the	O
+use	O
+of	O
+lopinavir	O
+/	O
+ritonavir	O
+in	O
+the	O
+immediate	O
+neonatal	O
+period	O
+.	O
+
+When	O
+drugs	O
+disappear	O
+from	O
+the	O
+patient	O
+:	O
+elimination	O
+of	O
+intravenous	O
+medication	O
+by	O
+hemodiafiltration	O
+.	O
+
+Twenty	O
+-	O
+three	O
+hours	O
+after	O
+heart	O
+transplantation	O
+,	O
+life	O
+-	O
+threatening	O
+acute	O
+right	B
+heart	I
+failure	I
+was	O
+diagnosed	O
+in	O
+a	O
+patient	O
+requiring	O
+continuous	O
+venovenous	O
+hemodiafiltration	O
+(	O
+CVVHDF	O
+)	O
+.	O
+
+Increasing	O
+doses	O
+of	O
+catecholamines	O
+,	O
+sedatives	O
+,	O
+and	O
+muscle	O
+relaxants	O
+administered	O
+through	O
+a	O
+central	O
+venous	O
+catheter	O
+were	O
+ineffective	O
+.	O
+
+However	O
+,	O
+a	O
+bolus	O
+of	O
+epinephrine	O
+injected	O
+through	O
+an	O
+alternative	O
+catheter	O
+provoked	O
+a	O
+hypertensive	B
+crisis	O
+.	O
+
+Thus	O
+,	O
+interference	O
+with	O
+the	O
+central	O
+venous	O
+infusion	O
+by	O
+the	O
+dialysis	O
+catheter	O
+was	O
+suspected	O
+.	O
+
+The	O
+catheters	O
+were	O
+changed	O
+,	O
+and	O
+hemodynamics	O
+stabilized	O
+at	O
+lower	O
+catecholamine	O
+doses	O
+.	O
+
+When	O
+the	O
+effects	O
+of	O
+IV	O
+drugs	O
+are	O
+inadequate	O
+in	O
+patients	O
+receiving	O
+CVVHDF	O
+,	O
+interference	O
+with	O
+adjacent	O
+catheters	O
+resulting	O
+in	O
+elimination	O
+of	O
+the	O
+drug	O
+by	O
+CVVHDF	O
+should	O
+be	O
+suspected	O
+.	O
+
+Less	O
+frequent	O
+lithium	O
+administration	O
+and	O
+lower	O
+urine	O
+volume	O
+.	O
+
+OBJECTIVE	O
+:	O
+This	O
+study	O
+was	O
+designed	O
+to	O
+determine	O
+whether	O
+patients	O
+maintained	O
+on	O
+a	O
+regimen	O
+of	O
+lithium	O
+on	O
+a	O
+once	O
+-	O
+per	O
+-	O
+day	O
+schedule	O
+have	O
+lower	O
+urine	O
+volumes	O
+than	O
+do	O
+patients	O
+receiving	O
+multiple	O
+doses	O
+per	O
+day	O
+.	O
+
+METHOD	O
+:	O
+This	O
+was	O
+a	O
+cross	O
+-	O
+sectional	O
+study	O
+of	O
+85	O
+patients	O
+from	O
+a	O
+lithium	O
+clinic	O
+who	O
+received	O
+different	O
+dose	O
+schedules	O
+.	O
+
+Patients	O
+were	O
+admitted	O
+to	O
+the	O
+hospital	O
+for	O
+measurement	O
+of	O
+lithium	O
+level	O
+,	O
+creatinine	O
+clearance	O
+,	O
+urine	O
+volume	O
+,	O
+and	O
+maximum	O
+osmolality	O
+.	O
+
+RESULTS	O
+:	O
+Multiple	O
+daily	O
+doses	O
+of	O
+lithium	O
+were	O
+associated	O
+with	O
+higher	O
+urine	O
+volumes	O
+.	O
+
+The	O
+dosing	O
+schedule	O
+,	O
+duration	O
+of	O
+lithium	O
+treatment	O
+,	O
+and	O
+daily	O
+dose	O
+of	O
+lithium	O
+did	O
+not	O
+affect	O
+maximum	O
+osmolality	O
+or	O
+creatinine	O
+clearance	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Urine	O
+volume	O
+can	O
+be	O
+reduced	O
+by	O
+giving	O
+lithium	O
+once	O
+daily	O
+and	O
+/	O
+or	O
+by	O
+lowering	O
+the	O
+total	O
+daily	O
+dose	O
+.	O
+
+Lithium	O
+-	O
+induced	O
+polyuria	B
+seems	O
+to	O
+be	O
+related	O
+to	O
+extrarenal	O
+as	O
+well	O
+as	O
+to	O
+renal	O
+effects	O
+.	O
+
+Antibacterial	O
+medication	O
+use	O
+during	O
+pregnancy	O
+and	O
+risk	O
+of	O
+birth	B
+defects	I
+:	O
+National	O
+Birth	B
+Defects	I
+Prevention	O
+Study	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+estimate	O
+the	O
+association	O
+between	O
+antibacterial	O
+medications	O
+and	O
+selected	O
+birth	B
+defects	I
+.	O
+
+DESIGN	O
+,	O
+SETTING	O
+,	O
+AND	O
+PARTICIPANTS	O
+:	O
+Population	O
+-	O
+based	O
+,	O
+multisite	O
+,	O
+case	O
+-	O
+control	O
+study	O
+of	O
+women	O
+who	O
+had	O
+pregnancies	O
+affected	O
+by	O
+1	O
+of	O
+more	O
+than	O
+30	O
+eligible	O
+major	O
+birth	B
+defects	I
+identified	O
+via	O
+birth	B
+defect	I
+surveillance	O
+programs	O
+in	O
+10	O
+states	O
+(	O
+n	O
+=	O
+13	O
+155	O
+)	O
+and	O
+control	O
+women	O
+randomly	O
+selected	O
+from	O
+the	O
+same	O
+geographical	O
+regions	O
+(	O
+n	O
+=	O
+4941	O
+)	O
+.	O
+
+MAIN	O
+EXPOSURE	O
+:	O
+Reported	O
+maternal	O
+use	O
+of	O
+antibacterials	O
+(	O
+1	O
+month	O
+before	O
+pregnancy	O
+through	O
+the	O
+end	O
+of	O
+the	O
+first	O
+trimester	O
+)	O
+.	O
+
+MAIN	O
+OUTCOME	O
+MEASURE	O
+:	O
+Odds	O
+ratios	O
+(	O
+ORs	O
+)	O
+measuring	O
+the	O
+association	O
+between	O
+antibacterial	O
+use	O
+and	O
+selected	O
+birth	B
+defects	I
+adjusted	O
+for	O
+potential	O
+confounders	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+reported	O
+use	O
+of	O
+antibacterials	O
+increased	O
+during	O
+pregnancy	O
+,	O
+peaking	O
+during	O
+the	O
+third	O
+month	O
+.	O
+
+Sulfonamides	O
+were	O
+associated	O
+with	O
+anencephaly	B
+(	O
+adjusted	O
+OR	O
+[	O
+AOR	O
+]	O
+=	O
+3	O
+.	O
+4	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+,	O
+1	O
+.	O
+3	O
+-	O
+8	O
+.	O
+8	O
+)	O
+,	O
+hypoplastic	B
+left	I
+heart	I
+syndrome	I
+(	O
+AOR	O
+=	O
+3	O
+.	O
+2	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+3	O
+-	O
+7	O
+.	O
+6	O
+)	O
+,	O
+coarctation	B
+of	I
+the	I
+aorta	I
+(	O
+AOR	O
+=	O
+2	O
+.	O
+7	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+3	O
+-	O
+5	O
+.	O
+6	O
+)	O
+,	O
+choanal	B
+atresia	I
+(	O
+AOR	O
+=	O
+8	O
+.	O
+0	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+2	O
+.	O
+7	O
+-	O
+23	O
+.	O
+5	O
+)	O
+,	O
+transverse	B
+limb	I
+deficiency	I
+(	O
+AOR	O
+=	O
+2	O
+.	O
+5	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+0	O
+-	O
+5	O
+.	O
+9	O
+)	O
+,	O
+and	O
+diaphragmatic	B
+hernia	I
+(	O
+AOR	O
+=	O
+2	O
+.	O
+4	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+1	O
+-	O
+5	O
+.	O
+4	O
+)	O
+.	O
+
+Nitrofurantoins	O
+were	O
+associated	O
+with	O
+anophthalmia	B
+or	O
+microphthalmos	B
+(	O
+AOR	O
+=	O
+3	O
+.	O
+7	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+1	O
+-	O
+12	O
+.	O
+2	O
+)	O
+,	O
+hypoplastic	B
+left	I
+heart	I
+syndrome	I
+(	O
+AOR	O
+=	O
+4	O
+.	O
+2	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+9	O
+-	O
+9	O
+.	O
+1	O
+)	O
+,	O
+atrial	B
+septal	I
+defects	I
+(	O
+AOR	O
+=	O
+1	O
+.	O
+9	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+1	O
+-	O
+3	O
+.	O
+4	O
+)	O
+,	O
+and	O
+cleft	B
+lip	I
+with	O
+cleft	B
+palate	I
+(	O
+AOR	O
+=	O
+2	O
+.	O
+1	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+2	O
+-	O
+3	O
+.	O
+9	O
+)	O
+.	O
+
+Other	O
+antibacterial	O
+agents	O
+that	O
+showed	O
+associations	O
+included	O
+erythromycins	O
+(	O
+2	O
+defects	O
+)	O
+,	O
+penicillins	O
+(	O
+1	O
+defect	O
+)	O
+,	O
+cephalosporins	O
+(	O
+1	O
+defect	O
+)	O
+,	O
+and	O
+quinolones	O
+(	O
+1	O
+defect	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Reassuringly	O
+,	O
+penicillins	O
+,	O
+erythromycins	O
+,	O
+and	O
+cephalosporins	O
+,	O
+although	O
+used	O
+commonly	O
+by	O
+pregnant	O
+women	O
+,	O
+were	O
+not	O
+associated	O
+with	O
+many	O
+birth	B
+defects	I
+.	O
+
+Sulfonamides	O
+and	O
+nitrofurantoins	O
+were	O
+associated	O
+with	O
+several	O
+birth	B
+defects	I
+,	O
+indicating	O
+a	O
+need	O
+for	O
+additional	O
+scrutiny	O
+.	O
+
+Differential	O
+impact	O
+of	O
+immune	O
+escape	O
+mutations	O
+G145R	O
+and	O
+P120T	O
+on	O
+the	O
+replication	O
+of	O
+lamivudine	O
+-	O
+resistant	O
+hepatitis	O
+B	O
+virus	O
+e	O
+antigen	O
+-	O
+positive	O
+and	O
+-	O
+negative	O
+strains	O
+.	O
+
+Immune	O
+escape	O
+variants	O
+of	O
+the	O
+hepatitis	B
+B	I
+virus	O
+(	O
+HBV	O
+)	O
+represent	O
+an	O
+emerging	O
+clinical	O
+challenge	O
+,	O
+because	O
+they	O
+can	O
+be	O
+associated	O
+with	O
+vaccine	O
+escape	O
+,	O
+HBV	O
+reactivation	O
+,	O
+and	O
+failure	O
+of	O
+diagnostic	O
+tests	O
+.	O
+
+Recent	O
+data	O
+suggest	O
+a	O
+preferential	O
+selection	O
+of	O
+immune	O
+escape	O
+mutants	O
+in	O
+distinct	O
+peripheral	O
+blood	O
+leukocyte	O
+compartments	O
+of	O
+infected	O
+individuals	O
+.	O
+
+We	O
+therefore	O
+systematically	O
+analyzed	O
+the	O
+functional	O
+impact	O
+of	O
+the	O
+most	O
+prevalent	O
+immune	O
+escape	O
+variants	O
+,	O
+the	O
+sG145R	O
+and	O
+sP120T	O
+mutants	O
+,	O
+on	O
+the	O
+viral	O
+replication	O
+efficacy	O
+and	O
+antiviral	O
+drug	O
+susceptibility	O
+of	O
+common	O
+treatment	O
+-	O
+associated	O
+mutants	O
+with	O
+resistance	O
+to	O
+lamivudine	O
+(	O
+LAM	O
+)	O
+and	O
+/	O
+or	O
+HBeAg	O
+negativity	O
+.	O
+
+Replication	O
+-	O
+competent	O
+HBV	O
+strains	O
+with	O
+sG145R	O
+or	O
+sP120T	O
+and	O
+LAM	O
+resistance	O
+(	O
+rtM204I	O
+or	O
+rtL180M	O
+/	O
+rtM204V	O
+)	O
+were	O
+generated	O
+on	O
+an	O
+HBeAg	O
+-	O
+positive	O
+and	O
+an	O
+HBeAg	O
+-	O
+negative	O
+background	O
+with	O
+precore	O
+(	O
+PC	O
+)	O
+and	O
+basal	O
+core	O
+promoter	O
+(	O
+BCP	O
+)	O
+mutants	O
+.	O
+
+The	O
+sG145R	O
+mutation	O
+strongly	O
+reduced	O
+HBsAg	O
+levels	O
+and	O
+was	O
+able	O
+to	O
+fully	O
+restore	O
+the	O
+impaired	O
+replication	O
+of	O
+LAM	O
+-	O
+resistant	O
+HBV	O
+mutants	O
+to	O
+the	O
+levels	O
+of	O
+wild	O
+-	O
+type	O
+HBV	O
+,	O
+and	O
+PC	O
+or	O
+BCP	O
+mutations	O
+further	O
+enhanced	O
+viral	O
+replication	O
+.	O
+
+Although	O
+the	O
+sP120T	O
+substitution	O
+also	O
+impaired	O
+HBsAg	O
+secretion	O
+,	O
+it	O
+did	O
+not	O
+enhance	O
+the	O
+replication	O
+of	O
+LAM	O
+-	O
+resistant	O
+clones	O
+.	O
+
+However	O
+,	O
+the	O
+concomitant	O
+occurrence	O
+of	O
+HBeAg	O
+negativity	O
+(	O
+PC	O
+/	O
+BCP	O
+)	O
+,	O
+sP120T	O
+,	O
+and	O
+LAM	O
+resistance	O
+resulted	O
+in	O
+the	O
+restoration	O
+of	O
+replication	O
+to	O
+levels	O
+of	O
+wild	O
+-	O
+type	O
+HBV	O
+.	O
+
+In	O
+all	O
+clones	O
+with	O
+combined	O
+immune	O
+escape	O
+and	O
+LAM	O
+resistance	O
+mutations	O
+,	O
+the	O
+nucleotide	O
+analogues	O
+adefovir	O
+and	O
+tenofovir	O
+remained	O
+effective	O
+in	O
+suppressing	O
+viral	O
+replication	O
+in	O
+vitro	O
+.	O
+
+These	O
+findings	O
+reveal	O
+the	O
+differential	O
+impact	O
+of	O
+immune	O
+escape	O
+variants	O
+on	O
+the	O
+replication	O
+and	O
+drug	O
+susceptibility	O
+of	O
+complex	O
+HBV	O
+mutants	O
+,	O
+supporting	O
+the	O
+need	O
+of	O
+close	O
+surveillance	O
+and	O
+treatment	O
+adjustment	O
+in	O
+response	O
+to	O
+the	O
+selection	O
+of	O
+distinct	O
+mutational	O
+patterns	O
+.	O
+
+Hemolytic	B
+anemia	I
+associated	O
+with	O
+the	O
+use	O
+of	O
+omeprazole	O
+.	O
+
+Omeprazole	O
+is	O
+the	O
+first	O
+drug	O
+designed	O
+to	O
+block	O
+the	O
+final	O
+step	O
+in	O
+the	O
+acid	O
+secretory	O
+process	O
+within	O
+the	O
+parietal	O
+cell	O
+.	O
+
+It	O
+has	O
+been	O
+shown	O
+to	O
+be	O
+extremely	O
+effective	O
+in	O
+the	O
+treatment	O
+of	O
+peptic	B
+ulcer	I
+disease	I
+,	O
+reflux	B
+esophagitis	I
+,	O
+and	O
+the	O
+Zollinger	B
+-	I
+Ellison	I
+syndrome	I
+.	O
+
+Although	O
+clinical	O
+experience	O
+with	O
+omeprazole	O
+is	O
+still	O
+limited	O
+,	O
+many	O
+controlled	O
+studies	O
+have	O
+established	O
+the	O
+short	O
+-	O
+term	O
+safety	O
+of	O
+this	O
+drug	O
+.	O
+
+We	O
+report	O
+the	O
+first	O
+case	O
+of	O
+a	O
+serious	O
+short	O
+-	O
+term	O
+adverse	O
+reaction	O
+with	O
+the	O
+use	O
+of	O
+omeprazole	O
+:	O
+hemolytic	B
+anemia	I
+.	O
+
+The	O
+patient	O
+developed	O
+weakness	O
+,	O
+lethargy	B
+,	O
+and	O
+shortness	B
+of	I
+breath	I
+2	O
+days	O
+after	O
+starting	O
+therapy	O
+with	O
+omeprazole	O
+.	O
+
+Two	O
+weeks	O
+after	O
+the	O
+initiation	O
+of	O
+therapy	O
+,	O
+her	O
+hematocrit	O
+had	O
+decreased	O
+from	O
+44	O
+.	O
+1	O
+%	O
+to	O
+20	O
+.	O
+4	O
+%	O
+,	O
+and	O
+she	O
+had	O
+a	O
+positive	O
+direct	O
+Coombs	O
+antiglobulin	O
+test	O
+and	O
+an	O
+elevated	O
+indirect	O
+bilirubin	O
+.	O
+
+After	O
+she	O
+discontinued	O
+the	O
+omeprazole	O
+,	O
+her	O
+hemoglobin	O
+and	O
+hematocrit	O
+gradually	O
+returned	O
+to	O
+normal	O
+.	O
+
+The	O
+mechanism	O
+by	O
+which	O
+omeprazole	O
+caused	O
+the	O
+patient	O
+'	O
+s	O
+hemolytic	B
+anemia	I
+is	O
+uncertain	O
+,	O
+but	O
+physicians	O
+should	O
+be	O
+alerted	O
+to	O
+this	O
+possible	O
+adverse	O
+effect	O
+.	O
+
+Phenylephrine	O
+but	O
+not	O
+ephedrine	O
+reduces	B
+frontal	I
+lobe	I
+oxygenation	I
+following	O
+anesthesia	O
+-	O
+induced	O
+hypotension	B
+.	O
+
+BACKGROUND	O
+:	O
+Vasopressor	O
+agents	O
+are	O
+used	O
+to	O
+correct	O
+anesthesia	O
+-	O
+induced	O
+hypotension	B
+.	O
+
+We	O
+describe	O
+the	O
+effect	O
+of	O
+phenylephrine	O
+and	O
+ephedrine	O
+on	O
+frontal	O
+lobe	O
+oxygenation	O
+(	O
+S	O
+(	O
+c	O
+)	O
+O	O
+(	O
+2	O
+)	O
+)	O
+following	O
+anesthesia	O
+-	O
+induced	O
+hypotension	B
+.	O
+
+METHODS	O
+:	O
+Following	O
+induction	O
+of	O
+anesthesia	O
+by	O
+fentanyl	O
+(	O
+0	O
+.	O
+15	O
+mg	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+)	O
+and	O
+propofol	O
+(	O
+2	O
+.	O
+0	O
+mg	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+)	O
+,	O
+13	O
+patients	O
+received	O
+phenylephrine	O
+(	O
+0	O
+.	O
+1	O
+mg	O
+iv	O
+)	O
+and	O
+12	O
+patients	O
+received	O
+ephedrine	O
+(	O
+10	O
+mg	O
+iv	O
+)	O
+to	O
+restore	O
+mean	O
+arterial	O
+pressure	O
+(	O
+MAP	O
+)	O
+.	O
+
+Heart	O
+rate	O
+(	O
+HR	O
+)	O
+,	O
+MAP	O
+,	O
+stroke	B
+volume	O
+(	O
+SV	O
+)	O
+,	O
+cardiac	O
+output	O
+(	O
+CO	O
+)	O
+,	O
+and	O
+frontal	O
+lobe	O
+oxygenation	O
+(	O
+S	O
+(	O
+c	O
+)	O
+O	O
+(	O
+2	O
+)	O
+)	O
+were	O
+registered	O
+.	O
+
+RESULTS	O
+:	O
+Induction	O
+of	O
+anesthesia	O
+was	O
+followed	O
+by	O
+a	B
+decrease	I
+in	I
+MAP	I
+,	I
+HR	I
+,	I
+SV	I
+,	I
+and	I
+CO	I
+concomitant	O
+with	O
+an	O
+elevation	O
+in	O
+S	O
+(	O
+c	O
+)	O
+O	O
+(	O
+2	O
+)	O
+.	O
+
+After	O
+administration	O
+of	O
+phenylephrine	O
+,	O
+MAP	O
+increased	O
+(	O
+51	O
++	O
+/	O
+-	O
+12	O
+to	O
+81	O
++	O
+/	O
+-	O
+13	O
+mmHg	O
+;	O
+P	O
+<	O
+0	O
+.	O
+001	O
+;	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+)	O
+.	O
+
+However	O
+,	O
+a	O
+14	O
+%	O
+(	O
+from	O
+70	O
++	O
+/	O
+-	O
+8	O
+%	O
+to	O
+60	O
++	O
+/	O
+-	O
+7	O
+%	O
+)	O
+reduction	O
+in	O
+S	O
+(	O
+c	O
+)	O
+O	O
+(	O
+2	O
+)	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+followed	O
+with	O
+no	O
+change	O
+in	O
+CO	O
+(	O
+3	O
+.	O
+7	O
++	O
+/	O
+-	O
+1	O
+.	O
+1	O
+to	O
+3	O
+.	O
+4	O
++	O
+/	O
+-	O
+0	O
+.	O
+9	O
+l	O
+min	O
+(	O
+-	O
+1	O
+)	O
+)	O
+.	O
+
+The	O
+administration	O
+of	O
+ephedrine	O
+led	O
+to	O
+a	O
+similar	O
+increase	O
+in	O
+MAP	O
+(	O
+53	O
++	O
+/	O
+-	O
+9	O
+to	O
+79	O
++	O
+/	O
+-	O
+8	O
+mmHg	O
+;	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+,	O
+restored	O
+CO	O
+(	O
+3	O
+.	O
+2	O
++	O
+/	O
+-	O
+1	O
+.	O
+2	O
+to	O
+5	O
+.	O
+0	O
++	O
+/	O
+-	O
+1	O
+.	O
+3	O
+l	O
+min	O
+(	O
+-	O
+1	O
+)	O
+)	O
+,	O
+and	O
+preserved	O
+S	O
+(	O
+c	O
+)	O
+O	O
+(	O
+2	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+utilization	O
+of	O
+phenylephrine	O
+to	O
+correct	O
+hypotension	B
+induced	O
+by	O
+anesthesia	O
+has	O
+a	O
+negative	O
+impact	O
+on	O
+S	O
+(	O
+c	O
+)	O
+O	O
+(	O
+2	O
+)	O
+while	O
+ephedrine	O
+maintains	O
+frontal	O
+lobe	O
+oxygenation	O
+potentially	O
+related	O
+to	O
+an	O
+increase	O
+in	O
+CO	O
+.	O
+
+Prolonged	O
+elevation	O
+of	O
+plasma	O
+argatroban	O
+in	O
+a	O
+cardiac	O
+transplant	O
+patient	O
+with	O
+a	O
+suspected	O
+history	O
+of	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+with	O
+thrombosis	B
+.	O
+
+BACKGROUND	O
+:	O
+Direct	O
+thrombin	O
+inhibitors	O
+(	O
+DTIs	O
+)	O
+provide	O
+an	O
+alternative	O
+method	O
+of	O
+anticoagulation	O
+for	O
+patients	O
+with	O
+a	O
+history	O
+of	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+(	O
+HIT	B
+)	O
+or	O
+HIT	B
+with	O
+thrombosis	B
+(	O
+HITT	B
+)	O
+undergoing	O
+cardiopulmonary	O
+bypass	O
+(	O
+CPB	O
+)	O
+.	O
+
+In	O
+the	O
+following	O
+report	O
+,	O
+a	O
+65	O
+-	O
+year	O
+-	O
+old	O
+critically	B
+ill	I
+patient	O
+with	O
+a	O
+suspected	O
+history	O
+of	O
+HITT	B
+was	O
+administered	O
+argatroban	O
+for	O
+anticoagulation	O
+on	O
+bypass	O
+during	O
+heart	O
+transplantation	O
+.	O
+
+The	O
+patient	O
+required	O
+massive	O
+transfusion	O
+support	O
+(	O
+55	O
+units	O
+of	O
+red	O
+blood	O
+cells	O
+,	O
+42	O
+units	O
+of	O
+fresh	O
+-	O
+frozen	O
+plasma	O
+,	O
+40	O
+units	O
+of	O
+cryoprecipitate	O
+,	O
+40	O
+units	O
+of	O
+platelets	O
+,	O
+and	O
+three	O
+doses	O
+of	O
+recombinant	O
+Factor	O
+VIIa	O
+)	O
+for	O
+severe	O
+intraoperative	B
+and	I
+postoperative	I
+bleeding	I
+.	O
+
+STUDY	O
+DESIGN	O
+AND	O
+METHODS	O
+:	O
+Plasma	O
+samples	O
+from	O
+before	O
+and	O
+after	O
+CPB	O
+were	O
+analyzed	O
+postoperatively	O
+for	O
+argatroban	O
+concentration	O
+using	O
+a	O
+modified	O
+ecarin	O
+clotting	O
+time	O
+(	O
+ECT	O
+)	O
+assay	O
+.	O
+
+RESULTS	O
+:	O
+Unexpectedly	O
+high	O
+concentrations	O
+of	O
+argatroban	O
+were	O
+measured	O
+in	O
+these	O
+samples	O
+(	O
+range	O
+,	O
+0	O
+-	O
+32	O
+microg	O
+/	O
+mL	O
+)	O
+,	O
+and	O
+a	O
+prolonged	O
+plasma	O
+argatroban	O
+half	O
+life	O
+(	O
+t	O
+(	O
+1	O
+/	O
+2	O
+)	O
+)	O
+of	O
+514	O
+minutes	O
+was	O
+observed	O
+(	O
+published	O
+elimination	O
+t	O
+(	O
+1	O
+/	O
+2	O
+)	O
+is	O
+39	O
+-	O
+51	O
+minutes	O
+[	O
+<	O
+or	O
+=	O
+181	O
+minutes	O
+with	O
+hepatic	B
+impairment	I
+]	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Correlation	O
+of	O
+plasma	O
+argatroban	O
+concentration	O
+versus	O
+the	O
+patient	O
+'	O
+s	O
+coagulation	O
+variables	O
+and	O
+clinical	O
+course	O
+suggest	O
+that	O
+prolonged	O
+elevated	O
+levels	O
+of	O
+plasma	O
+argatroban	O
+may	O
+have	O
+contributed	O
+to	O
+the	O
+patient	O
+'	O
+s	O
+extended	O
+coagulopathy	B
+.	O
+
+Because	O
+DTIs	O
+do	O
+not	O
+have	O
+reversal	O
+agents	O
+,	O
+surgical	O
+teams	O
+and	O
+transfusion	O
+services	O
+should	O
+remain	O
+aware	O
+of	O
+the	O
+possibility	O
+of	O
+massive	O
+transfusion	O
+events	O
+during	O
+anticoagulation	O
+with	O
+these	O
+agents	O
+.	O
+
+This	O
+is	O
+the	O
+first	O
+report	O
+to	O
+measure	O
+plasma	O
+argatroban	O
+concentration	O
+in	O
+the	O
+context	O
+of	O
+CPB	O
+and	O
+extended	O
+coagulopathy	B
+.	O
+
+The	O
+effects	O
+of	O
+the	O
+adjunctive	O
+bupropion	O
+on	O
+male	O
+sexual	B
+dysfunction	I
+induced	O
+by	O
+a	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitor	O
+:	O
+a	O
+double	O
+-	O
+blind	O
+placebo	O
+-	O
+controlled	O
+and	O
+randomized	O
+study	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+determine	O
+the	O
+safety	O
+and	O
+efficacy	O
+of	O
+adjunctive	O
+bupropion	O
+sustained	O
+-	O
+release	O
+(	O
+SR	O
+)	O
+on	O
+male	O
+sexual	B
+dysfunction	I
+(	O
+SD	B
+)	O
+induced	O
+by	O
+a	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitor	O
+(	O
+SSRI	O
+)	O
+,	O
+as	O
+SD	B
+is	O
+a	O
+common	O
+side	O
+-	O
+effect	O
+of	O
+SSRIs	O
+and	O
+the	O
+most	O
+effective	O
+treatments	O
+have	O
+yet	O
+to	O
+be	O
+determined	O
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+The	O
+randomized	O
+sample	O
+consisted	O
+of	O
+234	O
+euthymic	O
+men	O
+who	O
+were	O
+receiving	O
+some	O
+type	O
+of	O
+SSRI	O
+.	O
+
+The	O
+men	O
+were	O
+randomly	O
+assigned	O
+to	O
+bupropion	O
+SR	O
+(	O
+150	O
+mg	O
+twice	O
+daily	O
+,	O
+117	O
+)	O
+or	O
+placebo	O
+(	O
+twice	O
+daily	O
+,	O
+117	O
+)	O
+for	O
+12	O
+weeks	O
+.	O
+
+Efficacy	O
+was	O
+evaluated	O
+using	O
+the	O
+Clinical	O
+Global	O
+Impression	O
+-	O
+Sexual	O
+Function	O
+(	O
+CGI	O
+-	O
+SF	O
+;	O
+the	O
+primary	O
+outcome	O
+measure	O
+)	O
+,	O
+the	O
+International	O
+Index	O
+of	O
+Erectile	O
+Function	O
+(	O
+IIEF	O
+)	O
+,	O
+Arizona	O
+Sexual	O
+Experience	O
+Scale	O
+(	O
+ASEX	O
+)	O
+,	O
+and	O
+Erectile	B
+Dysfunction	I
+Inventory	O
+of	O
+Treatment	O
+Satisfaction	O
+(	O
+EDITS	O
+)	O
+(	O
+secondary	O
+outcome	O
+measures	O
+)	O
+.	O
+
+Participants	O
+were	O
+followed	O
+biweekly	O
+during	O
+study	O
+period	O
+.	O
+
+RESULTS	O
+:	O
+After	O
+12	O
+weeks	O
+of	O
+treatment	O
+,	O
+the	O
+mean	O
+(	O
+sd	O
+)	O
+scores	O
+for	O
+CGI	O
+-	O
+SF	O
+were	O
+significantly	O
+lower	O
+,	O
+i	O
+.	O
+e	O
+.	O
+better	O
+,	O
+in	O
+patients	O
+on	O
+bupropion	O
+SR	O
+,	O
+at	O
+2	O
+.	O
+4	O
+(	O
+1	O
+.	O
+2	O
+)	O
+,	O
+than	O
+in	O
+the	O
+placebo	O
+group	O
+,	O
+at	O
+3	O
+.	O
+9	O
+(	O
+1	O
+.	O
+1	O
+)	O
+(	O
+P	O
+=	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+Men	O
+who	O
+received	O
+bupropion	O
+had	O
+a	O
+significant	O
+increase	O
+in	O
+the	O
+total	O
+IIEF	O
+score	O
+(	O
+54	O
+.	O
+4	O
+%	O
+vs	O
+1	O
+.	O
+2	O
+%	O
+;	O
+P	O
+=	O
+0	O
+.	O
+003	O
+)	O
+,	O
+and	O
+in	O
+the	O
+five	O
+different	O
+domains	O
+of	O
+the	O
+IIEF	O
+.	O
+
+Total	O
+ASEX	O
+scores	O
+were	O
+significantly	O
+lower	O
+,	O
+i	O
+.	O
+e	O
+.	O
+better	O
+,	O
+among	O
+men	O
+who	O
+received	O
+bupropion	O
+than	O
+placebo	O
+,	O
+at	O
+15	O
+.	O
+5	O
+(	O
+4	O
+.	O
+3	O
+)	O
+vs	O
+21	O
+.	O
+5	O
+(	O
+4	O
+.	O
+7	O
+)	O
+(	O
+P	O
+=	O
+0	O
+.	O
+002	O
+)	O
+.	O
+
+The	O
+EDITS	O
+scores	O
+were	O
+67	O
+.	O
+4	O
+(	O
+10	O
+.	O
+2	O
+)	O
+for	O
+the	O
+bupropion	O
+and	O
+36	O
+.	O
+3	O
+(	O
+11	O
+.	O
+7	O
+)	O
+for	O
+the	O
+placebo	O
+group	O
+(	O
+P	O
+=	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+The	O
+ASEX	O
+score	O
+and	O
+CGI	O
+-	O
+SF	O
+score	O
+were	O
+correlated	O
+(	O
+P	O
+=	O
+0	O
+.	O
+003	O
+)	O
+.	O
+
+In	O
+linear	O
+regression	O
+analyses	O
+the	O
+CGI	O
+-	O
+SF	O
+score	O
+was	O
+not	O
+affected	O
+significantly	O
+by	O
+the	O
+duration	O
+of	O
+SD	B
+,	O
+type	O
+of	O
+SSRI	O
+used	O
+and	O
+age	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Bupropion	O
+is	O
+an	O
+effective	O
+treatment	O
+for	O
+male	O
+SD	B
+induced	O
+by	O
+SSRIs	O
+.	O
+
+These	O
+results	O
+provide	O
+empirical	O
+support	O
+for	O
+conducting	O
+a	O
+further	O
+study	O
+of	O
+bupropion	O
+.	O
+
+Prevention	O
+of	O
+seizures	B
+and	O
+reorganization	O
+of	O
+hippocampal	O
+functions	O
+by	O
+transplantation	O
+of	O
+bone	O
+marrow	O
+cells	O
+in	O
+the	O
+acute	O
+phase	O
+of	O
+experimental	O
+epilepsy	B
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+investigated	O
+the	O
+therapeutic	O
+potential	O
+of	O
+bone	O
+marrow	O
+mononuclear	O
+cells	O
+(	O
+BMCs	O
+)	O
+in	O
+a	O
+model	O
+of	O
+epilepsy	B
+induced	O
+by	O
+pilocarpine	O
+in	O
+rats	O
+.	O
+
+BMCs	O
+obtained	O
+from	O
+green	O
+fluorescent	O
+protein	O
+(	O
+GFP	O
+)	O
+transgenic	O
+mice	O
+or	O
+rats	O
+were	O
+transplanted	O
+intravenously	O
+after	O
+induction	O
+of	O
+status	B
+epilepticus	I
+(	O
+SE	B
+)	O
+.	O
+
+Spontaneous	B
+recurrent	I
+seizures	I
+(	O
+SRS	B
+)	O
+were	O
+monitored	O
+using	O
+Racine	O
+'	O
+s	O
+seizure	B
+severity	O
+scale	O
+.	O
+
+All	O
+of	O
+the	O
+rats	O
+in	O
+the	O
+saline	O
+-	O
+treated	O
+epileptic	B
+control	O
+group	O
+developed	O
+SRS	B
+,	O
+whereas	O
+none	O
+of	O
+the	O
+BMC	O
+-	O
+treated	O
+epileptic	B
+animals	O
+had	O
+seizures	B
+in	O
+the	O
+short	O
+term	O
+(	O
+15	O
+days	O
+after	O
+transplantation	O
+)	O
+,	O
+regardless	O
+of	O
+the	O
+BMC	O
+source	O
+.	O
+
+Over	O
+the	O
+long	O
+-	O
+term	O
+chronic	O
+phase	O
+(	O
+120	O
+days	O
+after	O
+transplantation	O
+)	O
+,	O
+only	O
+25	O
+%	O
+of	O
+BMC	O
+-	O
+treated	O
+epileptic	B
+animals	O
+had	O
+seizures	B
+,	O
+but	O
+with	O
+a	O
+lower	O
+frequency	O
+and	O
+duration	O
+compared	O
+to	O
+the	O
+epileptic	B
+control	O
+group	O
+.	O
+
+The	O
+density	O
+of	O
+hippocampal	O
+neurons	O
+in	O
+the	O
+brains	O
+of	O
+animals	O
+treated	O
+with	O
+BMCs	O
+was	O
+markedly	O
+preserved	O
+.	O
+
+At	O
+hippocampal	O
+Schaeffer	O
+collateral	O
+-	O
+CA1	O
+synapses	O
+,	O
+long	O
+-	O
+term	O
+potentiation	O
+was	O
+preserved	O
+in	O
+BMC	O
+-	O
+transplanted	O
+rats	O
+compared	O
+to	O
+epileptic	B
+controls	O
+.	O
+
+The	O
+donor	O
+-	O
+derived	O
+GFP	O
+(	O
++	O
+)	O
+cells	O
+were	O
+rarely	O
+found	O
+in	O
+the	O
+brains	O
+of	O
+transplanted	O
+epileptic	B
+rats	O
+.	O
+
+In	O
+conclusion	O
+,	O
+treatment	O
+with	O
+BMCs	O
+can	O
+prevent	O
+the	O
+development	O
+of	O
+chronic	O
+seizures	B
+,	O
+reduce	O
+neuronal	B
+loss	I
+,	O
+and	O
+influence	O
+the	O
+reorganization	O
+of	O
+the	O
+hippocampal	O
+neuronal	O
+network	O
+.	O
+
+Normalizing	O
+effects	O
+of	O
+modafinil	O
+on	O
+sleep	O
+in	O
+chronic	O
+cocaine	O
+users	O
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+purpose	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+effect	O
+of	O
+morning	O
+-	O
+dosed	O
+modafinil	O
+on	O
+sleep	O
+and	O
+daytime	B
+sleepiness	I
+in	O
+chronic	O
+cocaine	O
+users	O
+.	O
+
+METHOD	O
+:	O
+Twenty	O
+cocaine	O
+-	O
+dependent	O
+participants	O
+were	O
+randomly	O
+assigned	O
+to	O
+receive	O
+modafinil	O
+,	O
+400	O
+mg	O
+(	O
+N	O
+=	O
+10	O
+)	O
+,	O
+or	O
+placebo	O
+(	O
+N	O
+=	O
+10	O
+)	O
+every	O
+morning	O
+at	O
+7	O
+:	O
+30	O
+a	O
+.	O
+m	O
+.	O
+for	O
+16	O
+days	O
+in	O
+an	O
+inpatient	O
+,	O
+double	O
+-	O
+blind	O
+randomized	O
+trial	O
+.	O
+
+Participants	O
+underwent	O
+polysomnographic	O
+sleep	O
+recordings	O
+on	O
+days	O
+1	O
+to	O
+3	O
+,	O
+7	O
+to	O
+9	O
+,	O
+and	O
+14	O
+to	O
+16	O
+(	O
+first	O
+,	O
+second	O
+,	O
+and	O
+third	O
+weeks	O
+of	O
+abstinence	O
+)	O
+.	O
+
+The	O
+Multiple	O
+Sleep	O
+Latency	O
+Test	O
+was	O
+performed	O
+at	O
+11	O
+:	O
+30	O
+a	O
+.	O
+m	O
+.	O
+,	O
+2	O
+:	O
+00	O
+p	O
+.	O
+m	O
+.	O
+,	O
+and	O
+4	O
+:	O
+30	O
+p	O
+.	O
+m	O
+.	O
+on	O
+days	O
+2	O
+,	O
+8	O
+,	O
+and	O
+15	O
+.	O
+
+For	O
+comparison	O
+of	O
+sleep	O
+architecture	O
+variables	O
+,	O
+12	O
+healthy	O
+comparison	O
+participants	O
+underwent	O
+a	O
+single	O
+night	O
+of	O
+experimental	O
+polysomnography	O
+that	O
+followed	O
+1	O
+night	O
+of	O
+accommodation	O
+polysomnography	O
+.	O
+
+RESULTS	O
+:	O
+Progressive	O
+abstinence	O
+from	O
+cocaine	O
+was	O
+associated	O
+with	O
+worsening	O
+of	O
+all	O
+measured	O
+polysomnographic	O
+sleep	O
+outcomes	O
+.	O
+
+Compared	O
+with	O
+placebo	O
+,	O
+modafinil	O
+decreased	O
+nighttime	O
+sleep	O
+latency	O
+and	O
+increased	O
+slow	O
+-	O
+wave	O
+sleep	O
+time	O
+in	O
+cocaine	O
+-	O
+dependent	O
+participants	O
+.	O
+
+The	O
+effect	O
+of	O
+modafinil	O
+interacted	O
+with	O
+the	O
+abstinence	O
+week	O
+and	O
+was	O
+associated	O
+with	O
+longer	O
+total	O
+sleep	O
+time	O
+and	O
+shorter	O
+REM	O
+sleep	O
+latency	O
+in	O
+the	O
+third	O
+week	O
+of	O
+abstinence	O
+.	O
+
+Comparison	O
+of	O
+slow	O
+-	O
+wave	O
+sleep	O
+time	O
+,	O
+total	O
+sleep	O
+time	O
+,	O
+and	O
+sleep	O
+latency	O
+in	O
+cocaine	O
+-	O
+dependent	O
+and	O
+healthy	O
+participants	O
+revealed	O
+a	O
+normalizing	O
+effect	O
+of	O
+modafinil	O
+in	O
+cocaine	O
+-	O
+dependent	O
+participants	O
+.	O
+
+Modafinil	O
+was	O
+associated	O
+with	O
+increased	O
+daytime	O
+sleep	O
+latency	O
+,	O
+as	O
+measured	O
+by	O
+the	O
+Multiple	O
+Sleep	O
+Latency	O
+Test	O
+,	O
+and	O
+a	O
+nearly	O
+significant	O
+decrease	O
+in	O
+subjective	O
+daytime	B
+sleepiness	I
+.	O
+
+CONCLUSIONS	O
+:	O
+Morning	O
+-	O
+dosed	O
+modafinil	O
+promotes	O
+nocturnal	O
+sleep	O
+,	O
+normalizes	O
+sleep	O
+architecture	O
+,	O
+and	O
+decreases	O
+daytime	B
+sleepiness	I
+in	O
+abstinent	O
+cocaine	O
+users	O
+.	O
+
+These	O
+effects	O
+may	O
+be	O
+relevant	O
+in	O
+the	O
+treatment	O
+of	O
+cocaine	O
+dependence	O
+.	O
+
+Safety	O
+of	O
+transesophageal	O
+echocardiography	O
+in	O
+adults	O
+:	O
+study	O
+in	O
+a	O
+multidisciplinary	O
+hospital	O
+.	O
+
+BACKGROUND	O
+:	O
+TEE	O
+is	O
+a	O
+semi	O
+-	O
+invasive	O
+tool	O
+broadly	O
+used	O
+and	O
+its	O
+utilization	O
+associated	O
+to	O
+sedatives	O
+drugs	O
+might	O
+to	O
+affect	O
+the	O
+procedure	O
+safety	O
+.	O
+
+OBJECTIVE	O
+:	O
+to	O
+analyze	O
+aspects	O
+of	O
+TEE	O
+safety	O
+associated	O
+to	O
+the	O
+use	O
+of	O
+Midazolan	O
+(	O
+MZ	O
+)	O
+and	O
+Flumazenil	O
+(	O
+FL	O
+)	O
+and	O
+the	O
+influence	O
+of	O
+the	O
+clinical	O
+variables	O
+on	O
+the	O
+event	O
+rate	O
+.	O
+
+METHOD	O
+:	O
+prospective	O
+study	O
+with	O
+137	O
+patients	O
+that	O
+underwent	O
+TEE	O
+with	O
+MZ	O
+associated	O
+to	O
+moderate	O
+sedation	O
+.	O
+
+We	O
+analyzed	O
+the	O
+following	O
+events	O
+:	O
+complications	O
+related	O
+with	O
+the	O
+topical	O
+anesthesia	O
+,	O
+with	O
+MZ	O
+use	O
+and	O
+with	O
+the	O
+procedure	O
+.	O
+
+Uni	O
+-	O
+and	O
+multivariate	O
+analyses	O
+were	O
+used	O
+to	O
+test	O
+the	O
+influence	O
+of	O
+the	O
+clinical	O
+variables	O
+:	O
+age	O
+,	O
+sex	O
+,	O
+stroke	B
+,	O
+myocardiopathy	B
+(	O
+MP	B
+)	O
+,	O
+duration	O
+of	O
+the	O
+test	O
+,	O
+mitral	B
+regurgitation	I
+(	O
+MR	B
+)	O
+and	O
+the	O
+MZ	O
+dose	O
+.	O
+
+RESULTS	O
+:	O
+All	O
+patients	O
+(	O
+65	O
++	O
+/	O
+-	O
+16	O
+yrs	O
+;	O
+58	O
+%	O
+males	O
+)	O
+finished	O
+the	O
+examination	O
+.	O
+
+The	O
+mean	O
+doses	O
+of	O
+MZ	O
+and	O
+FL	O
+were	O
+4	O
+.	O
+3	O
++	O
+/	O
+-	O
+1	O
+.	O
+9	O
+mg	O
+and	O
+0	O
+.	O
+28	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+mg	O
+,	O
+respectively	O
+.	O
+
+The	O
+duration	O
+of	O
+the	O
+examination	O
+and	O
+the	O
+mean	O
+ejection	O
+fraction	O
+(	O
+EF	O
+)	O
+were	O
+16	O
+.	O
+4	O
++	O
+/	O
+-	O
+6	O
+.	O
+1	O
+minutes	O
+and	O
+60	O
++	O
+/	O
+-	O
+9	O
+%	O
+,	O
+respectively	O
+.	O
+
+Mild	O
+hypoxia	B
+(	O
+SO2	O
+<	O
+90	O
+%	O
+)	O
+was	O
+the	O
+most	O
+common	O
+event	O
+(	O
+11	O
+patients	O
+)	O
+;	O
+3	O
+patients	O
+(	O
+2	O
+%	O
+)	O
+presented	O
+transient	O
+hypoxia	B
+due	O
+to	O
+upper	O
+airway	B
+obstruction	I
+by	O
+probe	O
+introduction	O
+and	O
+8	O
+(	O
+5	O
+.	O
+8	O
+%	O
+)	O
+due	O
+to	O
+hypoxia	B
+caused	O
+by	O
+MZ	O
+use	O
+.	O
+
+Transient	O
+hypotension	B
+(	O
+SAP	O
+<	O
+90mmHg	O
+)	O
+occurred	O
+in	O
+1	O
+patient	O
+(	O
+0	O
+.	O
+7	O
+%	O
+)	O
+.	O
+
+The	O
+multivariate	O
+analysis	O
+showed	O
+that	O
+severe	O
+MR	B
+,	O
+MP	B
+(	O
+EF	O
+<	O
+45	O
+%	O
+)	O
+and	O
+high	O
+doses	O
+of	O
+MZ	O
+(	O
+>	O
+5mg	O
+)	O
+were	O
+associated	O
+with	O
+events	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+The	O
+EF	O
+was	O
+40	O
+%	O
+,	O
+in	O
+the	O
+group	O
+with	O
+MP	B
+and	O
+44	O
+%	O
+in	O
+the	O
+group	O
+with	O
+severe	O
+MR	B
+and	O
+it	O
+can	O
+be	O
+a	O
+factor	O
+associated	O
+with	O
+clinical	O
+events	O
+in	O
+the	O
+last	O
+group	O
+.	O
+
+CONCLUSION	O
+:	O
+TEE	O
+with	O
+sedation	O
+presents	O
+a	O
+low	O
+rate	O
+of	O
+events	O
+.	O
+
+There	O
+were	O
+no	O
+severe	O
+events	O
+and	O
+there	O
+was	O
+no	O
+need	O
+to	O
+interrupt	O
+the	O
+examinations	O
+.	O
+
+Effect	O
+of	O
+direct	O
+intracoronary	O
+administration	O
+of	O
+methylergonovine	O
+in	O
+patients	O
+with	O
+and	O
+without	O
+variant	B
+angina	I
+.	O
+
+The	O
+effects	O
+of	O
+intracoronary	O
+administration	O
+of	O
+methylergonovine	O
+were	O
+studied	O
+in	O
+21	O
+patients	O
+with	O
+variant	B
+angina	I
+and	O
+22	O
+patients	O
+with	O
+atypical	O
+chest	B
+pain	I
+and	O
+in	O
+others	O
+without	O
+angina	B
+pectoris	I
+(	O
+control	O
+group	O
+)	O
+.	O
+
+Methylergonovine	O
+was	O
+administered	O
+continuously	O
+at	O
+a	O
+rate	O
+of	O
+10	O
+micrograms	O
+/	O
+min	O
+up	O
+to	O
+50	O
+micrograms	O
+.	O
+
+In	O
+all	O
+patients	O
+with	O
+variant	B
+angina	I
+,	O
+coronary	B
+spasm	I
+was	O
+provoked	O
+at	O
+a	O
+mean	O
+dose	O
+of	O
+28	O
++	O
+/	O
+-	O
+13	O
+micrograms	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+)	O
+.	O
+
+In	O
+the	O
+control	O
+group	O
+neither	O
+ischemic	O
+ST	O
+change	O
+nor	O
+localized	O
+spasm	B
+occurred	O
+.	O
+
+The	O
+basal	O
+tone	O
+of	O
+the	O
+right	O
+coronary	O
+artery	O
+was	O
+significantly	O
+lower	O
+than	O
+that	O
+of	O
+the	O
+left	O
+coronary	O
+artery	O
+.	O
+
+The	O
+percentage	O
+of	O
+vasoconstriction	O
+of	O
+the	O
+right	O
+coronary	O
+artery	O
+was	O
+significantly	O
+higher	O
+than	O
+that	O
+of	O
+the	O
+left	O
+coronary	O
+artery	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+spasm	B
+provocation	O
+tests	O
+,	O
+which	O
+use	O
+an	O
+intracoronary	O
+injection	O
+of	O
+a	O
+relatively	O
+low	O
+dose	O
+of	O
+methylergonovine	O
+,	O
+have	O
+a	O
+high	O
+sensitivity	O
+in	O
+variant	B
+angina	I
+and	O
+the	O
+vasoreactivity	O
+of	O
+the	O
+right	O
+coronary	O
+artery	O
+may	O
+be	O
+greater	O
+than	O
+that	O
+of	O
+the	O
+other	O
+coronary	O
+arteries	O
+.	O
+
+Oral	O
+manifestations	O
+of	O
+"	O
+meth	B
+mouth	I
+"	O
+:	O
+a	O
+case	O
+report	O
+.	O
+
+AIM	O
+:	O
+The	O
+aim	O
+of	O
+the	O
+documentation	O
+of	O
+this	O
+clinical	O
+case	O
+is	O
+to	O
+make	O
+clinicians	O
+aware	O
+of	O
+"	O
+meth	B
+mouth	I
+"	O
+and	O
+the	O
+medical	O
+risks	O
+associated	O
+with	O
+this	O
+serious	O
+condition	O
+.	O
+
+BACKGROUND	O
+:	O
+Methamphetamine	O
+is	O
+a	O
+very	O
+addictive	O
+,	O
+powerful	O
+stimulant	O
+that	O
+increases	O
+wakefulness	O
+and	O
+physical	O
+activity	O
+and	O
+can	O
+produce	O
+other	O
+effects	O
+such	O
+as	O
+cardiac	B
+dysrhythmias	I
+,	O
+hypertension	B
+,	O
+hallucinations	B
+,	O
+and	O
+violent	B
+behavior	I
+.	O
+
+Dental	O
+patients	O
+abusing	O
+methamphetamine	O
+can	O
+present	O
+with	O
+poor	O
+oral	O
+hygiene	O
+,	O
+xerostomia	B
+,	O
+rampant	O
+caries	B
+(	O
+"	O
+meth	B
+mouth	I
+"	O
+)	O
+,	O
+and	O
+excessive	O
+tooth	B
+wear	I
+.	O
+
+Oral	O
+rehabilitation	O
+of	O
+patients	O
+using	O
+methamphetamine	O
+can	O
+be	O
+challenging	O
+.	O
+
+CASE	O
+DESCRIPTION	O
+:	O
+A	O
+30	O
+-	O
+year	O
+-	O
+old	O
+Caucasian	O
+woman	O
+presented	O
+with	O
+dental	O
+pain	B
+,	O
+bad	B
+breath	I
+,	O
+and	O
+self	O
+-	O
+reported	O
+poor	O
+esthetics	O
+.	O
+
+A	O
+comprehensive	O
+examination	O
+including	O
+her	O
+medical	O
+history	O
+,	O
+panoramic	O
+radiograph	O
+,	O
+and	O
+intraoral	O
+examination	O
+revealed	O
+19	O
+carious	B
+lesions	I
+,	O
+which	O
+is	O
+not	O
+very	O
+common	O
+for	O
+a	O
+healthy	O
+adult	O
+.	O
+
+She	O
+reported	O
+her	O
+use	O
+of	O
+methamphetamine	O
+for	O
+five	O
+years	O
+and	O
+had	O
+not	O
+experienced	O
+any	O
+major	O
+carious	B
+episodes	I
+before	O
+she	O
+started	O
+using	O
+the	O
+drug	O
+.	O
+
+SUMMARY	O
+:	O
+The	O
+patient	O
+'	O
+s	O
+medical	O
+and	O
+dental	O
+histories	O
+along	O
+with	O
+radiographic	O
+and	O
+clinical	O
+findings	O
+lead	O
+to	O
+a	O
+diagnosis	O
+of	O
+"	O
+meth	B
+mouth	I
+.	O
+"	O
+Although	O
+three	O
+different	O
+dental	O
+treatment	O
+modalities	O
+(	O
+either	O
+conventional	O
+or	O
+implant	O
+-	O
+supported	O
+)	O
+have	O
+been	O
+offered	O
+to	O
+the	O
+patient	O
+since	O
+August	O
+2007	O
+,	O
+the	O
+patient	O
+has	O
+yet	O
+to	O
+initiate	O
+any	O
+treatment	O
+.	O
+
+CLINICAL	O
+SIGNIFICANCE	O
+:	O
+This	O
+clinical	O
+case	O
+showing	O
+oral	O
+manifestations	O
+of	O
+meth	B
+mouth	I
+was	O
+presented	O
+to	O
+help	O
+dental	O
+practitioners	O
+recognize	O
+and	O
+manage	O
+patients	O
+who	O
+may	O
+be	O
+abusing	O
+methamphetamines	O
+.	O
+
+Dental	O
+practitioners	O
+also	O
+may	O
+be	O
+skeptical	O
+about	O
+the	O
+reliability	O
+of	O
+appointment	O
+keeping	O
+by	O
+these	O
+patients	O
+,	O
+as	O
+they	O
+frequently	O
+miss	O
+their	O
+appointments	O
+without	O
+reasonable	O
+justification	O
+.	O
+
+Antituberculosis	O
+therapy	O
+-	O
+induced	O
+acute	B
+liver	I
+failure	I
+:	O
+magnitude	O
+,	O
+profile	O
+,	O
+prognosis	O
+,	O
+and	O
+predictors	O
+of	O
+outcome	O
+.	O
+
+Antituberculosis	O
+therapy	O
+(	O
+ATT	O
+)	O
+-	O
+associated	O
+acute	B
+liver	I
+failure	I
+(	O
+ATT	O
+-	O
+ALF	B
+)	O
+is	O
+the	O
+commonest	O
+drug	O
+-	O
+induced	O
+ALF	B
+in	O
+South	O
+Asia	O
+.	O
+
+Prospective	O
+studies	O
+on	O
+ATT	O
+-	O
+ALF	B
+are	O
+lacking	O
+.	O
+
+The	O
+current	O
+study	O
+prospectively	O
+evaluated	O
+the	O
+magnitude	O
+,	O
+clinical	O
+course	O
+,	O
+outcome	O
+,	O
+and	O
+prognostic	O
+factors	O
+in	O
+ATT	O
+-	O
+ALF	B
+.	O
+
+From	O
+January	O
+1986	O
+to	O
+January	O
+2009	O
+,	O
+1223	O
+consecutive	O
+ALF	B
+patients	O
+were	O
+evaluated	O
+:	O
+ATT	O
+alone	O
+was	O
+the	O
+cause	O
+in	O
+70	O
+(	O
+5	O
+.	O
+7	O
+%	O
+)	O
+patients	O
+.	O
+
+Another	O
+15	O
+(	O
+1	O
+.	O
+2	O
+%	O
+)	O
+had	O
+ATT	O
+and	O
+simultaneous	O
+hepatitis	B
+virus	I
+infection	I
+.	O
+
+In	O
+44	O
+(	O
+62	O
+.	O
+8	O
+%	O
+)	O
+patients	O
+,	O
+ATT	O
+was	O
+prescribed	O
+empirically	O
+without	O
+definitive	O
+evidence	O
+of	O
+tuberculosis	B
+.	O
+
+ATT	O
+-	O
+ALF	B
+patients	O
+were	O
+younger	O
+(	O
+32	O
+.	O
+87	O
+[	O
++	O
+/	O
+-	O
+15	O
+.	O
+8	O
+]	O
+years	O
+)	O
+,	O
+and	O
+49	O
+(	O
+70	O
+%	O
+)	O
+of	O
+them	O
+were	O
+women	O
+.	O
+
+Most	O
+had	O
+hyperacute	O
+presentation	O
+;	O
+the	O
+median	O
+icterus	B
+encephalopathy	B
+interval	O
+was	O
+4	O
+.	O
+5	O
+(	O
+0	O
+-	O
+30	O
+)	O
+days	O
+.	O
+
+The	O
+median	O
+duration	O
+of	O
+ATT	O
+before	O
+ALF	B
+was	O
+30	O
+(	O
+7	O
+-	O
+350	O
+)	O
+days	O
+.	O
+
+At	O
+presentation	O
+,	O
+advanced	O
+encephalopathy	B
+and	O
+cerebral	B
+edema	I
+were	O
+present	O
+in	O
+51	O
+(	O
+76	O
+%	O
+)	O
+and	O
+29	O
+(	O
+41	O
+.	O
+4	O
+%	O
+)	O
+patients	O
+,	O
+respectively	O
+.	O
+
+Gastrointestinal	B
+bleed	I
+,	O
+seizures	B
+,	O
+infection	B
+,	O
+and	O
+acute	B
+renal	I
+failure	I
+were	O
+documented	O
+in	O
+seven	O
+(	O
+10	O
+%	O
+)	O
+,	O
+five	O
+(	O
+7	O
+.	O
+1	O
+%	O
+)	O
+,	O
+26	O
+(	O
+37	O
+.	O
+1	O
+%	O
+)	O
+,	O
+and	O
+seven	O
+(	O
+10	O
+%	O
+)	O
+patients	O
+,	O
+respectively	O
+.	O
+
+Compared	O
+with	O
+hepatitis	B
+E	I
+virus	O
+(	O
+HEV	O
+)	O
+and	O
+non	O
+-	O
+A	O
+non	O
+-	O
+E	O
+-	O
+induced	O
+ALF	B
+,	O
+ATT	O
+-	O
+ALF	B
+patients	O
+had	O
+nearly	O
+similar	O
+presentations	O
+except	O
+for	O
+older	O
+age	O
+and	O
+less	O
+elevation	O
+of	O
+liver	O
+enzymes	O
+.	O
+
+The	O
+mortality	O
+rate	O
+among	O
+patients	O
+with	O
+ATT	O
+-	O
+ALF	B
+was	O
+high	O
+(	O
+67	O
+.	O
+1	O
+%	O
+,	O
+n	O
+=	O
+47	O
+)	O
+,	O
+and	O
+only	O
+23	O
+(	O
+32	O
+.	O
+9	O
+%	O
+)	O
+patients	O
+recovered	O
+with	O
+medical	O
+treatment	O
+.	O
+
+In	O
+multivariate	O
+analysis	O
+,	O
+three	O
+factors	O
+independently	O
+predicted	O
+mortality	O
+:	O
+serum	O
+bilirubin	O
+(	O
+>	O
+or	O
+=	O
+10	O
+.	O
+8	O
+mg	O
+/	O
+dL	O
+)	O
+,	O
+prothrombin	O
+time	O
+(	O
+PT	O
+)	O
+prolongation	O
+(	O
+>	O
+or	O
+=	O
+26	O
+seconds	O
+)	O
+,	O
+and	O
+grade	O
+III	O
+/	O
+IV	O
+encephalopathy	B
+at	O
+presentation	O
+.	O
+
+CONCLUSION	O
+:	O
+ATT	O
+-	O
+ALF	B
+constituted	O
+5	O
+.	O
+7	O
+%	O
+of	O
+ALF	B
+at	O
+our	O
+center	O
+and	O
+had	O
+a	O
+high	O
+mortality	O
+rate	O
+.	O
+
+Because	O
+the	O
+mortality	O
+rate	O
+is	O
+so	O
+high	O
+,	O
+determining	O
+which	O
+factors	O
+are	O
+predictors	O
+is	O
+less	O
+important	O
+.	O
+
+A	O
+high	O
+proportion	O
+of	O
+patients	O
+had	O
+consumed	O
+ATT	O
+empirically	O
+,	O
+which	O
+could	O
+have	O
+been	O
+prevented	O
+.	O
+
+Design	O
+and	O
+analysis	O
+of	O
+the	O
+HYPREN	O
+-	O
+trial	O
+:	O
+safety	O
+of	O
+enalapril	O
+and	O
+prazosin	O
+in	O
+the	O
+initial	O
+treatment	O
+phase	O
+of	O
+patients	O
+with	O
+congestive	B
+heart	I
+failure	I
+.	O
+
+Since	O
+the	O
+introduction	O
+of	O
+angiotensin	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+inhibitors	O
+into	O
+the	O
+adjunctive	O
+treatment	O
+of	O
+patients	O
+with	O
+congestive	B
+heart	I
+failure	I
+,	O
+cases	O
+of	O
+severe	O
+hypotension	B
+,	O
+especially	O
+on	O
+the	O
+first	O
+day	O
+of	O
+treatment	O
+,	O
+have	O
+occasionally	O
+been	O
+reported	O
+.	O
+
+To	O
+assess	O
+the	O
+safety	O
+of	O
+the	O
+ACE	O
+inhibitor	O
+enalapril	O
+a	O
+multicenter	O
+,	O
+randomized	O
+,	O
+prazosin	O
+-	O
+controlled	O
+trial	O
+was	O
+designed	O
+that	O
+compared	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+symptomatic	O
+hypotension	B
+on	O
+the	O
+first	O
+day	O
+of	O
+treatment	O
+.	O
+
+Trial	O
+medication	O
+was	O
+2	O
+.	O
+5	O
+mg	O
+enalapril	O
+or	O
+0	O
+.	O
+5	O
+prazosin	O
+.	O
+
+Subjects	O
+were	O
+1210	O
+inpatients	O
+with	O
+New	O
+York	O
+Heart	O
+Association	O
+(	O
+NYHA	O
+)	O
+functional	O
+class	O
+II	O
+and	O
+III	O
+.	O
+
+Patients	O
+who	O
+received	O
+enalapril	O
+experienced	O
+clinically	O
+and	O
+statistically	O
+significantly	O
+less	O
+symptomatic	O
+hypotension	B
+(	O
+5	O
+.	O
+2	O
+%	O
+)	O
+than	O
+the	O
+patients	O
+who	O
+received	O
+prazosin	O
+(	O
+12	O
+.	O
+9	O
+%	O
+)	O
+.	O
+
+All	O
+patients	O
+recovered	O
+.	O
+
+It	O
+was	O
+concluded	O
+that	O
+treatment	O
+with	O
+enalapril	O
+was	O
+well	O
+tolerated	O
+and	O
+it	O
+is	O
+,	O
+therefore	O
+,	O
+unreasonable	O
+to	O
+restrict	O
+the	O
+initiation	O
+of	O
+treatment	O
+with	O
+enalapril	O
+to	O
+inpatients	O
+.	O
+
+Central	B
+nervous	I
+system	I
+complications	I
+during	O
+treatment	O
+of	O
+acute	B
+lymphoblastic	I
+leukemia	I
+in	O
+a	O
+single	O
+pediatric	O
+institution	O
+.	O
+
+Central	B
+nervous	I
+system	I
+(	I
+CNS	I
+)	I
+complications	I
+during	O
+treatment	O
+of	O
+childhood	O
+acute	B
+lymphoblastic	I
+leukemia	I
+(	O
+ALL	B
+)	O
+remain	O
+a	O
+challenging	O
+clinical	O
+problem	O
+.	O
+
+Outcome	O
+improvement	O
+with	O
+more	O
+intensive	O
+chemotherapy	O
+has	O
+significantly	O
+increased	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+adverse	O
+events	O
+.	O
+
+This	O
+study	O
+analyzed	O
+the	O
+incidence	O
+of	O
+neurological	B
+complications	I
+during	O
+ALL	B
+treatment	O
+in	O
+a	O
+single	O
+pediatric	O
+institution	O
+,	O
+focusing	O
+on	O
+clinical	O
+,	O
+radiological	O
+,	O
+and	O
+electrophysiological	O
+findings	O
+.	O
+
+Exclusion	O
+criteria	O
+included	O
+CNS	O
+leukemic	B
+infiltration	I
+at	O
+diagnosis	O
+,	O
+therapy	O
+-	O
+related	O
+peripheral	B
+neuropathy	I
+,	O
+late	O
+-	O
+onset	O
+encephalopathy	B
+,	O
+or	O
+long	O
+-	O
+term	O
+neurocognitive	B
+defects	I
+.	O
+
+During	O
+a	O
+9	O
+-	O
+year	O
+period	O
+,	O
+we	O
+retrospectively	O
+collected	O
+27	O
+neurological	O
+events	O
+(	O
+11	O
+%	O
+)	O
+in	O
+as	O
+many	O
+patients	O
+,	O
+from	O
+253	O
+children	O
+enrolled	O
+in	O
+the	O
+ALL	B
+front	O
+-	O
+line	O
+protocol	O
+.	O
+
+CNS	O
+complications	O
+included	O
+posterior	O
+reversible	O
+leukoencephalopathy	B
+syndrome	O
+(	O
+n	O
+=	O
+10	O
+)	O
+,	O
+stroke	B
+(	O
+n	O
+=	O
+5	O
+)	O
+,	O
+temporal	B
+lobe	I
+epilepsy	I
+(	O
+n	O
+=	O
+2	O
+)	O
+,	O
+high	O
+-	O
+dose	O
+methotrexate	O
+toxicity	B
+(	O
+n	O
+=	O
+2	O
+)	O
+,	O
+syndrome	O
+of	O
+inappropriate	B
+antidiuretic	I
+hormone	I
+secretion	I
+(	O
+n	O
+=	O
+1	O
+)	O
+,	O
+and	O
+other	O
+unclassified	O
+events	O
+(	O
+n	O
+=	O
+7	O
+)	O
+.	O
+
+In	O
+conclusion	O
+,	O
+CNS	O
+complications	O
+are	O
+frequent	O
+events	O
+during	O
+ALL	B
+therapy	O
+,	O
+and	O
+require	O
+rapid	O
+detection	O
+and	O
+prompt	O
+treatment	O
+to	O
+limit	O
+permanent	O
+damage	O
+.	O
+
+Cocaine	O
+causes	O
+memory	B
+and	I
+learning	I
+impairments	I
+in	O
+rats	O
+:	O
+involvement	O
+of	O
+nuclear	O
+factor	O
+kappa	O
+B	O
+and	O
+oxidative	O
+stress	O
+,	O
+and	O
+prevention	O
+by	O
+topiramate	O
+.	O
+
+Different	O
+mechanisms	O
+have	O
+been	O
+suggested	O
+for	O
+cocaine	O
+toxicity	B
+including	O
+an	O
+increase	O
+in	O
+oxidative	O
+stress	O
+but	O
+the	O
+association	O
+between	O
+oxidative	O
+status	O
+in	O
+the	O
+brain	O
+and	O
+cocaine	O
+induced	O
+-	O
+behaviour	O
+is	O
+poorly	O
+understood	O
+.	O
+
+Nuclear	O
+factor	O
+kappa	O
+B	O
+(	O
+NFkappaB	O
+)	O
+is	O
+a	O
+sensor	O
+of	O
+oxidative	O
+stress	O
+and	O
+participates	O
+in	O
+memory	O
+formation	O
+that	O
+could	O
+be	O
+involved	O
+in	O
+drug	O
+toxicity	B
+and	O
+addiction	O
+mechanisms	O
+.	O
+
+Therefore	O
+NFkappaB	O
+activity	O
+,	O
+oxidative	O
+stress	O
+,	O
+neuronal	O
+nitric	O
+oxide	O
+synthase	O
+(	O
+nNOS	O
+)	O
+activity	O
+,	O
+spatial	O
+learning	O
+and	O
+memory	O
+as	O
+well	O
+as	O
+the	O
+effect	O
+of	O
+topiramate	O
+,	O
+a	O
+previously	O
+proposed	O
+therapy	O
+for	O
+cocaine	B
+addiction	I
+,	O
+were	O
+evaluated	O
+in	O
+an	O
+experimental	O
+model	O
+of	O
+cocaine	O
+administration	O
+in	O
+rats	O
+.	O
+
+NFkappaB	O
+activity	O
+was	O
+decreased	O
+in	O
+the	O
+frontal	O
+cortex	O
+of	O
+cocaine	O
+treated	O
+rats	O
+,	O
+as	O
+well	O
+as	O
+GSH	O
+concentration	O
+and	O
+glutathione	O
+peroxidase	O
+activity	O
+in	O
+the	O
+hippocampus	O
+,	O
+whereas	O
+nNOS	O
+activity	O
+in	O
+the	O
+hippocampus	O
+was	O
+increased	O
+.	O
+
+Memory	O
+retrieval	O
+of	O
+experiences	O
+acquired	O
+prior	O
+to	O
+cocaine	O
+administration	O
+was	O
+impaired	O
+and	O
+negatively	O
+correlated	O
+with	O
+NFkappaB	O
+activity	O
+in	O
+the	O
+frontal	O
+cortex	O
+.	O
+
+In	O
+contrast	O
+,	O
+learning	O
+of	O
+new	O
+tasks	O
+was	O
+enhanced	O
+and	O
+correlated	O
+with	O
+the	O
+increase	O
+of	O
+nNOS	O
+activity	O
+and	O
+the	O
+decrease	O
+of	O
+glutathione	O
+peroxidase	O
+.	O
+
+These	O
+results	O
+provide	O
+evidence	O
+for	O
+a	O
+possible	O
+mechanistic	O
+role	O
+of	O
+oxidative	O
+and	O
+nitrosative	O
+stress	O
+and	O
+NFkappaB	O
+in	O
+the	O
+alterations	O
+induced	O
+by	O
+cocaine	O
+.	O
+
+Topiramate	O
+prevented	O
+all	O
+the	O
+alterations	O
+observed	O
+,	O
+showing	O
+novel	O
+neuroprotective	O
+properties	O
+.	O
+
+Efficacy	O
+and	O
+safety	O
+of	O
+asenapine	O
+in	O
+a	O
+placebo	O
+-	O
+and	O
+haloperidol	O
+-	O
+controlled	O
+trial	O
+in	O
+patients	O
+with	O
+acute	O
+exacerbation	O
+of	O
+schizophrenia	B
+.	O
+
+Asenapine	O
+is	O
+approved	O
+by	O
+the	O
+Food	O
+and	O
+Drugs	O
+Administration	O
+in	O
+adults	O
+for	O
+acute	O
+treatment	O
+of	O
+schizophrenia	B
+or	O
+of	O
+manic	B
+or	O
+mixed	O
+episodes	O
+associated	O
+with	O
+bipolar	B
+I	I
+disorder	I
+with	O
+or	O
+without	O
+psychotic	B
+features	O
+.	O
+
+In	O
+a	O
+double	O
+-	O
+blind	O
+6	O
+-	O
+week	O
+trial	O
+,	O
+458	O
+patients	O
+with	O
+acute	O
+schizophrenia	B
+were	O
+randomly	O
+assigned	O
+to	O
+fixed	O
+-	O
+dose	O
+treatment	O
+with	O
+asenapine	O
+at	O
+5	O
+mg	O
+twice	O
+daily	O
+(	O
+BID	O
+)	O
+,	O
+asenapine	O
+at	O
+10	O
+mg	O
+BID	O
+,	O
+placebo	O
+,	O
+or	O
+haloperidol	O
+at	O
+4	O
+mg	O
+BID	O
+(	O
+to	O
+verify	O
+assay	O
+sensitivity	O
+)	O
+.	O
+
+With	O
+last	O
+observations	O
+carried	O
+forward	O
+(	O
+LOCF	O
+)	O
+,	O
+mean	O
+Positive	O
+and	O
+Negative	O
+Syndrome	O
+Scale	O
+total	O
+score	O
+reductions	O
+from	O
+baseline	O
+to	O
+endpoint	O
+were	O
+significantly	O
+greater	O
+with	O
+asenapine	O
+at	O
+5	O
+mg	O
+BID	O
+(	O
+-	O
+16	O
+.	O
+2	O
+)	O
+and	O
+haloperidol	O
+(	O
+-	O
+15	O
+.	O
+4	O
+)	O
+than	O
+placebo	O
+(	O
+-	O
+10	O
+.	O
+7	O
+;	O
+both	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+;	O
+using	O
+mixed	O
+model	O
+for	O
+repeated	O
+measures	O
+(	O
+MMRM	O
+)	O
+,	O
+changes	O
+at	O
+day	O
+42	O
+were	O
+significantly	O
+greater	O
+with	O
+asenapine	O
+at	O
+5	O
+and	O
+10	O
+mg	O
+BID	O
+(	O
+-	O
+21	O
+.	O
+3	O
+and	O
+-	O
+19	O
+.	O
+4	O
+,	O
+respectively	O
+)	O
+and	O
+haloperidol	O
+(	O
+-	O
+20	O
+.	O
+0	O
+)	O
+than	O
+placebo	O
+(	O
+-	O
+14	O
+.	O
+6	O
+;	O
+all	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+On	O
+the	O
+Positive	O
+and	O
+Negative	O
+Syndrome	O
+Scale	O
+positive	O
+subscale	O
+,	O
+all	O
+treatments	O
+were	O
+superior	O
+to	O
+placebo	O
+with	O
+LOCF	O
+and	O
+MMRM	O
+;	O
+asenapine	O
+at	O
+5	O
+mg	O
+BID	O
+was	O
+superior	O
+to	O
+placebo	O
+on	O
+the	O
+negative	O
+subscale	O
+with	O
+MMRM	O
+and	O
+on	O
+the	O
+general	O
+psychopathology	O
+subscale	O
+with	O
+LOCF	O
+and	O
+MMRM	O
+.	O
+
+Treatment	O
+-	O
+related	O
+adverse	O
+events	O
+(	O
+AEs	O
+)	O
+occurred	O
+in	O
+44	O
+%	O
+and	O
+52	O
+%	O
+,	O
+57	O
+%	O
+,	O
+and	O
+41	O
+%	O
+of	O
+the	O
+asenapine	O
+at	O
+5	O
+and	O
+10	O
+mg	O
+BID	O
+,	O
+haloperidol	O
+,	O
+and	O
+placebo	O
+groups	O
+,	O
+respectively	O
+.	O
+
+Extrapyramidal	B
+symptoms	I
+reported	O
+as	O
+AEs	O
+occurred	O
+in	O
+15	O
+%	O
+and	O
+18	O
+%	O
+,	O
+34	O
+%	O
+,	O
+and	O
+10	O
+%	O
+of	O
+the	O
+asenapine	O
+at	O
+5	O
+and	O
+10	O
+mg	O
+BID	O
+,	O
+haloperidol	O
+,	O
+and	O
+placebo	O
+groups	O
+,	O
+respectively	O
+.	O
+
+Across	O
+all	O
+groups	O
+,	O
+no	O
+more	O
+than	O
+5	O
+%	O
+of	O
+patients	O
+had	O
+clinically	O
+significant	O
+weight	O
+change	O
+.	O
+
+Post	O
+hoc	O
+analyses	O
+indicated	O
+that	O
+efficacy	O
+was	O
+similar	O
+with	O
+asenapine	O
+and	O
+haloperidol	O
+;	O
+greater	O
+contrasts	O
+were	O
+seen	O
+in	O
+AEs	O
+,	O
+especially	O
+extrapyramidal	B
+symptoms	I
+.	O
+
+Salvage	O
+therapy	O
+with	O
+nelarabine	O
+,	O
+etoposide	O
+,	O
+and	O
+cyclophosphamide	O
+in	O
+relapsed	O
+/	O
+refractory	O
+paediatric	O
+T	B
+-	I
+cell	I
+lymphoblastic	I
+leukaemia	I
+and	I
+lymphoma	I
+.	O
+
+A	O
+combination	O
+of	O
+5	O
+d	O
+of	O
+nelarabine	O
+(	O
+AraG	O
+)	O
+with	O
+5	O
+d	O
+of	O
+etoposide	O
+(	O
+VP	O
+)	O
+and	O
+cyclophosphamide	O
+(	O
+CPM	O
+)	O
+and	O
+prophylactic	O
+intrathecal	O
+chemotherapy	O
+was	O
+used	O
+as	O
+salvage	O
+therapy	O
+in	O
+seven	O
+children	O
+with	O
+refractory	O
+or	O
+relapsed	O
+T	B
+-	I
+cell	I
+leukaemia	I
+or	I
+lymphoma	I
+.	O
+
+The	O
+most	O
+common	O
+side	O
+effects	O
+attributable	O
+to	O
+the	O
+AraG	O
+included	O
+Grade	O
+2	O
+and	O
+3	O
+sensory	O
+and	O
+motor	O
+neuropathy	B
+and	O
+musculoskeletal	B
+pain	I
+.	O
+
+Haematological	B
+toxicity	I
+was	O
+greater	O
+for	O
+the	O
+combination	O
+than	O
+AraG	O
+alone	O
+,	O
+although	O
+median	O
+time	O
+to	O
+neutrophil	O
+and	O
+platelet	O
+recovery	O
+was	O
+consistent	O
+with	O
+other	O
+salvage	O
+therapies	O
+.	O
+
+All	O
+patients	O
+had	O
+some	O
+response	O
+to	O
+the	O
+combined	O
+therapy	O
+and	O
+five	O
+of	O
+the	O
+seven	O
+went	O
+into	O
+complete	O
+remission	O
+after	O
+one	O
+or	O
+two	O
+courses	O
+of	O
+AraG	O
+/	O
+VP	O
+/	O
+CPM	O
+.	O
+
+Our	O
+experience	O
+supports	O
+the	O
+safety	O
+of	O
+giving	O
+AraG	O
+as	O
+salvage	O
+therapy	O
+in	O
+synchrony	O
+with	O
+etoposide	O
+and	O
+cyclophosphamide	O
+,	O
+although	O
+neurological	B
+toxicity	I
+must	O
+be	O
+closely	O
+monitored	O
+.	O
+
+Effect	O
+of	O
+adriamycin	O
+combined	O
+with	O
+whole	O
+body	O
+hyperthermia	B
+on	O
+tumor	B
+and	O
+normal	O
+tissues	O
+.	O
+
+Thermal	O
+enhancement	O
+of	O
+Adriamycin	O
+-	O
+mediated	O
+antitumor	O
+activity	O
+and	O
+normal	O
+tissue	O
+toxicities	B
+by	O
+whole	O
+body	O
+hyperthermia	B
+were	O
+compared	O
+using	O
+a	O
+F344	O
+rat	O
+model	O
+.	O
+
+Antitumor	O
+activity	O
+was	O
+studied	O
+using	O
+a	O
+tumor	B
+growth	O
+delay	O
+assay	O
+.	O
+
+Acute	O
+normal	O
+tissue	O
+toxicities	B
+(	O
+i	O
+.	O
+e	O
+.	O
+,	O
+leukopenia	B
+and	O
+thrombocytopenia	B
+)	O
+and	O
+late	O
+normal	O
+tissue	O
+toxicities	B
+(	O
+i	O
+.	O
+e	O
+.	O
+,	O
+myocardial	B
+and	I
+kidney	I
+injury	I
+)	O
+were	O
+evaluated	O
+by	O
+functional	O
+/	O
+physiological	O
+assays	O
+and	O
+by	O
+morphological	O
+techniques	O
+.	O
+
+Whole	O
+body	O
+hyperthermia	B
+(	O
+120	O
+min	O
+at	O
+41	O
+.	O
+5	O
+degrees	O
+C	O
+)	O
+enhanced	O
+both	O
+Adriamycin	O
+-	O
+mediated	O
+antitumor	O
+activity	O
+and	O
+toxic	O
+side	O
+effects	O
+.	O
+
+The	O
+thermal	O
+enhancement	O
+ratio	O
+calculated	O
+for	O
+antitumor	O
+activity	O
+was	O
+1	O
+.	O
+6	O
+.	O
+
+Thermal	O
+enhancement	O
+ratios	O
+estimated	O
+for	O
+"	O
+acute	O
+"	O
+hematological	O
+changes	O
+were	O
+1	O
+.	O
+3	O
+,	O
+whereas	O
+those	O
+estimated	O
+for	O
+"	O
+late	O
+"	O
+damage	O
+(	O
+based	O
+on	O
+morphological	O
+cardiac	B
+and	I
+renal	I
+lesions	I
+)	O
+varied	O
+between	O
+2	O
+.	O
+4	O
+and	O
+4	O
+.	O
+3	O
+.	O
+
+Thus	O
+,	O
+while	O
+whole	O
+body	O
+hyperthermia	B
+enhances	O
+Adriamycin	O
+-	O
+mediated	O
+antitumor	O
+effect	O
+,	O
+normal	O
+tissue	O
+toxicity	B
+is	O
+also	O
+increased	O
+,	O
+and	O
+the	O
+potential	O
+therapeutic	O
+gain	O
+of	O
+the	O
+combined	O
+modality	O
+treatment	O
+is	O
+eroded	O
+.	O
+
+Permeability	O
+,	O
+ultrastructural	O
+changes	O
+,	O
+and	O
+distribution	O
+of	O
+novel	O
+proteins	O
+in	O
+the	O
+glomerular	O
+barrier	O
+in	O
+early	O
+puromycin	O
+aminonucleoside	O
+nephrosis	B
+.	O
+
+BACKGROUND	O
+/	O
+AIMS	O
+:	O
+It	O
+is	O
+still	O
+unclear	O
+what	O
+happens	O
+in	O
+the	O
+glomerulus	O
+when	O
+proteinuria	B
+starts	O
+.	O
+
+Using	O
+puromycin	O
+aminonucleoside	O
+nephrosis	B
+(	O
+PAN	O
+)	O
+rats	O
+,	O
+we	O
+studied	O
+early	O
+ultrastructural	O
+and	O
+permeability	O
+changes	O
+in	O
+relation	O
+to	O
+the	O
+expression	O
+of	O
+the	O
+podocyte	O
+-	O
+associated	O
+molecules	O
+nephrin	O
+,	O
+a	O
+-	O
+actinin	O
+,	O
+dendrin	O
+,	O
+and	O
+plekhh2	O
+,	O
+the	O
+last	O
+two	O
+of	O
+which	O
+were	O
+only	O
+recently	O
+discovered	O
+in	O
+podocytes	O
+.	O
+
+METHODS	O
+:	O
+Using	O
+immune	O
+stainings	O
+,	O
+semiquantitative	O
+measurement	O
+was	O
+performed	O
+under	O
+the	O
+electron	O
+microscope	O
+.	O
+
+Permeability	O
+was	O
+assessed	O
+using	O
+isolated	O
+kidney	O
+perfusion	O
+with	O
+tracers	O
+.	O
+
+Possible	O
+effects	O
+of	O
+ACE	O
+inhibition	O
+were	O
+tested	O
+.	O
+
+RESULTS	O
+:	O
+By	O
+day	O
+2	O
+,	O
+some	O
+patchy	O
+foot	O
+process	O
+effacement	O
+,	O
+but	O
+no	O
+proteinuria	B
+,	O
+appeared	O
+.	O
+
+The	O
+amount	O
+of	O
+nephrin	O
+was	O
+reduced	O
+in	O
+both	O
+diseased	O
+and	O
+normal	O
+areas	O
+.	O
+
+The	O
+other	O
+proteins	O
+showed	O
+few	O
+changes	O
+,	O
+which	O
+were	O
+limited	O
+to	O
+diseased	O
+areas	O
+.	O
+
+By	O
+day	O
+4	O
+,	O
+foot	O
+process	O
+effacement	O
+was	O
+complete	O
+and	O
+proteinuria	B
+appeared	O
+in	O
+parallel	O
+with	O
+signs	O
+of	O
+size	O
+barrier	O
+damage	O
+.	O
+
+Nephrin	O
+decreased	O
+further	O
+,	O
+while	O
+dendrin	O
+and	O
+plekhh2	O
+also	O
+decreased	O
+but	O
+a	O
+-	O
+actinin	O
+remained	O
+unchanged	O
+.	O
+
+ACE	O
+inhibition	O
+had	O
+no	O
+significant	O
+protective	O
+effect	O
+.	O
+
+CONCLUSIONS	O
+:	O
+PAN	O
+glomeruli	O
+already	O
+showed	O
+significant	O
+pathology	O
+by	O
+day	O
+4	O
+,	O
+despite	O
+relatively	O
+mild	O
+proteinuria	B
+.	O
+
+This	O
+was	O
+preceded	O
+by	O
+altered	O
+nephrin	O
+expression	O
+,	O
+supporting	O
+its	O
+pivotal	O
+role	O
+in	O
+podocyte	O
+morphology	O
+.	O
+
+The	O
+novel	O
+proteins	O
+dendrin	O
+and	O
+plekhh2	O
+were	O
+both	O
+reduced	O
+,	O
+suggesting	O
+roles	O
+in	O
+PAN	O
+,	O
+whereas	O
+a	O
+-	O
+actinin	O
+was	O
+unchanged	O
+.	O
+
+A	O
+novel	O
+,	O
+multiple	O
+symptom	O
+model	O
+of	O
+obsessive	B
+-	I
+compulsive	I
+-	I
+like	I
+behaviors	I
+in	O
+animals	O
+.	O
+
+BACKGROUND	O
+:	O
+Current	O
+animal	O
+models	O
+of	O
+obsessive	B
+-	I
+compulsive	I
+disorder	I
+(	O
+OCD	B
+)	O
+typically	O
+involve	O
+acute	O
+,	O
+drug	O
+-	O
+induced	O
+symptom	O
+provocation	O
+or	O
+a	O
+genetic	O
+association	O
+with	O
+stereotypies	O
+or	O
+anxiety	B
+.	O
+
+None	O
+of	O
+these	O
+current	O
+models	O
+demonstrate	O
+multiple	O
+OCD	B
+-	O
+like	O
+behaviors	O
+.	O
+
+METHODS	O
+:	O
+Neonatal	O
+rats	O
+were	O
+treated	O
+with	O
+the	O
+tricyclic	O
+antidepressant	O
+clomipramine	O
+or	O
+vehicle	O
+between	O
+days	O
+9	O
+and	O
+16	O
+twice	O
+daily	O
+and	O
+behaviorally	O
+tested	O
+in	O
+adulthood	O
+.	O
+
+RESULTS	O
+:	O
+Clomipramine	O
+exposure	O
+in	O
+immature	O
+rats	O
+produced	O
+significant	O
+behavioral	O
+and	O
+biochemical	O
+changes	O
+that	O
+include	O
+enhanced	O
+anxiety	B
+(	O
+elevated	O
+plus	O
+maze	O
+and	O
+marble	O
+burying	O
+)	O
+,	O
+behavioral	B
+inflexibility	I
+(	O
+perseveration	O
+in	O
+the	O
+spontaneous	O
+alternation	O
+task	O
+and	O
+impaired	O
+reversal	O
+learning	O
+)	O
+,	O
+working	O
+memory	B
+impairment	I
+(	O
+e	O
+.	O
+g	O
+.	O
+,	O
+win	O
+-	O
+shift	O
+paradigm	O
+)	O
+,	O
+hoarding	B
+,	O
+and	O
+corticostriatal	B
+dysfunction	I
+.	O
+
+Dopamine	O
+D2	O
+receptors	O
+were	O
+elevated	O
+in	O
+the	O
+striatum	O
+,	O
+whereas	O
+serotonin	O
+2C	O
+,	O
+but	O
+not	O
+serotonin	O
+1A	O
+,	O
+receptors	O
+were	O
+elevated	O
+in	O
+the	O
+orbital	O
+frontal	O
+cortex	O
+.	O
+
+CONCLUSIONS	O
+:	O
+This	O
+is	O
+the	O
+first	O
+demonstration	O
+of	O
+multiple	O
+symptoms	O
+consistent	O
+with	O
+an	O
+OCD	B
+-	O
+like	O
+profile	O
+in	O
+animals	O
+.	O
+
+Moreover	O
+,	O
+these	O
+behaviors	O
+are	O
+accompanied	O
+by	O
+biochemical	O
+changes	O
+in	O
+brain	O
+regions	O
+previously	O
+identified	O
+as	O
+relevant	O
+to	O
+OCD	B
+.	O
+
+This	O
+novel	O
+model	O
+of	O
+OCD	B
+demonstrates	O
+that	O
+drug	O
+exposure	O
+during	O
+a	O
+sensitive	O
+period	O
+can	O
+program	O
+disease	O
+-	O
+like	O
+systems	O
+permanently	O
+,	O
+which	O
+could	O
+have	O
+implications	O
+for	O
+current	O
+and	O
+future	O
+therapeutic	O
+strategies	O
+for	O
+this	O
+and	O
+other	O
+psychiatric	B
+disorders	I
+.	O
+
+Elevation	O
+of	O
+ADAM10	O
+,	O
+ADAM17	O
+,	O
+MMP	O
+-	O
+2	O
+and	O
+MMP	O
+-	O
+9	O
+expression	O
+with	O
+media	O
+degeneration	O
+features	O
+CaCl2	O
+-	O
+induced	O
+thoracic	B
+aortic	I
+aneurysm	I
+in	O
+a	O
+rat	O
+model	O
+.	O
+
+PURPOSE	O
+:	O
+This	O
+study	O
+was	O
+designed	O
+to	O
+establish	O
+a	O
+rat	O
+model	O
+of	O
+thoracic	B
+aortic	I
+aneurysm	I
+(	O
+TAA	B
+)	O
+by	O
+calcium	O
+chloride	O
+(	O
+CaCl	O
+(	O
+2	O
+)	O
+)	O
+-	O
+induced	O
+arterial	B
+injury	I
+and	O
+to	O
+explore	O
+the	O
+potential	O
+role	O
+of	O
+a	O
+disintegrin	O
+and	O
+metalloproteinase	O
+(	O
+ADAM	O
+)	O
+,	O
+matrix	O
+metalloproteinases	O
+(	O
+MMPs	O
+)	O
+and	O
+their	O
+endogenous	O
+inhibitors	O
+(	O
+TIMPs	O
+)	O
+in	O
+TAA	B
+formation	O
+.	O
+
+METHODS	O
+:	O
+Thoracic	O
+aorta	O
+of	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+was	O
+exposed	O
+to	O
+0	O
+.	O
+5M	O
+CaCl	O
+(	O
+2	O
+)	O
+or	O
+normal	O
+saline	O
+(	O
+NaCl	O
+)	O
+.	O
+
+After	O
+12weeks	O
+,	O
+animals	O
+were	O
+euthanized	O
+,	O
+and	O
+CaCl	O
+(	O
+2	O
+)	O
+-	O
+treated	O
+,	O
+CaCl	O
+(	O
+2	O
+)	O
+-	O
+untreated	O
+(	O
+n	O
+=	O
+12	O
+)	O
+and	O
+NaCl	O
+-	O
+treated	O
+aortic	O
+segments	O
+(	O
+n	O
+=	O
+12	O
+)	O
+were	O
+collected	O
+for	O
+histological	O
+and	O
+molecular	O
+assessments	O
+.	O
+
+MMP	O
+-	O
+TIMP	O
+and	O
+ADAM	O
+mRNAs	O
+were	O
+semi	O
+-	O
+quantitatively	O
+analyzed	O
+and	O
+protein	O
+expressions	O
+were	O
+determined	O
+by	O
+immunohistochemistry	O
+.	O
+
+RESULTS	O
+:	O
+Despite	O
+similar	O
+external	O
+diameters	O
+among	O
+CaCl	O
+(	O
+2	O
+)	O
+-	O
+treated	O
+,	O
+non	O
+-	O
+CaCl	O
+(	O
+2	O
+)	O
+-	O
+treated	O
+and	O
+NaCl	O
+-	O
+treated	O
+segments	O
+,	O
+aneurymal	O
+alteration	O
+(	O
+n	O
+=	O
+6	O
+,	O
+50	O
+%	O
+)	O
+,	O
+media	O
+degeneration	O
+with	O
+regional	O
+disruption	O
+,	O
+fragmentation	O
+of	O
+elastic	O
+fiber	O
+,	O
+and	O
+increased	O
+collagen	O
+deposition	O
+(	O
+n	O
+=	O
+12	O
+,	O
+100	O
+%	O
+)	O
+were	O
+demonstrated	O
+in	O
+CaCl	O
+(	O
+2	O
+)	O
+-	O
+treated	O
+segments	O
+.	O
+
+MMP	O
+-	O
+2	O
+,	O
+MMP	O
+-	O
+9	O
+,	O
+ADAM	O
+-	O
+10	O
+and	O
+ADAM	O
+-	O
+17	O
+mRNA	O
+levels	O
+were	O
+increased	O
+in	O
+CaCl	O
+(	O
+2	O
+)	O
+-	O
+treated	O
+segments	O
+(	O
+all	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+,	O
+with	O
+trends	O
+of	O
+elevation	O
+in	O
+CaCl	O
+(	O
+2	O
+)	O
+-	O
+untreated	O
+segments	O
+,	O
+as	O
+compared	O
+with	O
+NaCl	O
+-	O
+treated	O
+segments	O
+.	O
+
+Immunohistochemistry	O
+displayed	O
+significantly	O
+increased	O
+expressions	O
+of	O
+MMP	O
+-	O
+2	O
+,	O
+MMP	O
+-	O
+9	O
+,	O
+ADAM	O
+-	O
+10	O
+and	O
+ADAM	O
+-	O
+17	O
+(	O
+all	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+in	O
+intima	O
+and	O
+media	O
+for	O
+CaCl	O
+(	O
+2	O
+)	O
+-	O
+treated	O
+segments	O
+.	O
+
+TIMP	O
+mRNA	O
+and	O
+tissue	O
+levels	O
+did	O
+not	O
+differ	O
+obviously	O
+among	O
+the	O
+three	O
+aortic	O
+segments	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+study	O
+establishes	O
+a	O
+TAA	B
+model	O
+by	O
+periarterial	O
+CaCl	O
+(	O
+2	O
+)	O
+exposure	O
+in	O
+rats	O
+,	O
+and	O
+demonstrates	O
+a	O
+significant	O
+elevation	O
+of	O
+expression	O
+of	O
+MMP	O
+-	O
+2	O
+,	O
+MMP	O
+-	O
+9	O
+,	O
+ADAM10	O
+and	O
+ADAM17	O
+in	O
+the	O
+pathogenesis	O
+of	O
+vascular	O
+remodeling	O
+.	O
+
+Suxamethonium	O
+induced	O
+prolonged	O
+apnea	B
+in	O
+a	O
+patient	O
+receiving	O
+electroconvulsive	O
+therapy	O
+.	O
+
+Suxamethonium	O
+causes	O
+prolonged	O
+apnea	B
+in	O
+patients	O
+in	O
+whom	O
+pseudocholinesterase	O
+enzyme	O
+gets	O
+deactivated	O
+by	O
+organophosphorus	O
+(	O
+OP	O
+)	O
+poisons	O
+.	O
+
+Here	O
+,	O
+we	O
+present	O
+a	O
+similar	O
+incident	O
+in	O
+a	O
+severely	O
+depressed	B
+patient	O
+who	O
+received	O
+electroconvulsive	O
+therapy	O
+(	O
+ECT	O
+)	O
+.	O
+
+Prolonged	O
+apnea	B
+in	O
+our	O
+case	O
+ensued	O
+because	O
+the	O
+information	O
+about	O
+suicidal	O
+attempt	O
+by	O
+OP	O
+compound	O
+was	O
+concealed	O
+from	O
+the	O
+treating	O
+team	O
+.	O
+
+Curcumin	O
+ameliorates	O
+cognitive	B
+dysfunction	I
+and	O
+oxidative	O
+damage	O
+in	O
+phenobarbitone	O
+and	O
+carbamazepine	O
+administered	O
+rats	O
+.	O
+
+The	O
+antiepileptic	O
+drugs	O
+,	O
+phenobarbitone	O
+and	O
+carbamazepine	O
+are	O
+well	O
+known	O
+to	O
+cause	O
+cognitive	B
+impairment	I
+on	O
+chronic	O
+use	O
+.	O
+
+The	O
+increase	O
+in	O
+free	O
+radical	O
+generation	O
+has	O
+been	O
+implicated	O
+as	O
+one	O
+of	O
+the	O
+important	O
+mechanisms	O
+of	O
+cognitive	B
+impairment	I
+by	O
+antiepileptic	O
+drugs	O
+.	O
+
+Curcumin	O
+has	O
+shown	O
+antioxidant	O
+,	O
+anti	O
+-	O
+inflammatory	O
+and	O
+neuro	O
+-	O
+protective	O
+properties	O
+.	O
+
+Therefore	O
+,	O
+the	O
+present	O
+study	O
+was	O
+carried	O
+out	O
+to	O
+investigate	O
+the	O
+effect	O
+of	O
+chronic	O
+curcumin	O
+administration	O
+on	O
+phenobarbitone	O
+-	O
+and	O
+carbamazepine	O
+-	O
+induced	O
+cognitive	B
+impairment	I
+and	O
+oxidative	O
+stress	O
+in	O
+rats	O
+.	O
+
+Pharmacokinetic	O
+interactions	O
+of	O
+curcumin	O
+with	O
+phenobarbitone	O
+and	O
+carbamazepine	O
+were	O
+also	O
+studied	O
+.	O
+
+Vehicle	O
+/	O
+drugs	O
+were	O
+administered	O
+daily	O
+for	O
+21days	O
+to	O
+male	O
+Wistar	O
+rats	O
+.	O
+
+Passive	O
+avoidance	O
+paradigm	O
+and	O
+elevated	O
+plus	O
+maze	O
+test	O
+were	O
+used	O
+to	O
+assess	O
+cognitive	O
+function	O
+.	O
+
+At	O
+the	O
+end	O
+of	O
+study	O
+period	O
+,	O
+serum	O
+phenobarbitone	O
+and	O
+carbamazepine	O
+,	O
+whole	O
+brain	O
+malondialdehyde	O
+and	O
+reduced	O
+glutathione	O
+levels	O
+were	O
+estimated	O
+.	O
+
+The	O
+administration	O
+of	O
+phenobarbitone	O
+and	O
+carbamazepine	O
+for	O
+21days	O
+caused	O
+a	O
+significant	O
+impairment	B
+of	I
+learning	I
+and	I
+memory	I
+as	O
+well	O
+as	O
+an	O
+increased	O
+oxidative	O
+stress	O
+.	O
+
+Concomitant	O
+curcumin	O
+administration	O
+prevented	O
+the	O
+cognitive	B
+impairment	I
+and	O
+decreased	O
+the	O
+increased	O
+oxidative	O
+stress	O
+induced	O
+by	O
+these	O
+antiepileptic	O
+drugs	O
+.	O
+
+Curcumin	O
+co	O
+-	O
+administration	O
+did	O
+not	O
+cause	O
+any	O
+significant	O
+alteration	O
+in	O
+the	O
+serum	O
+concentrations	O
+of	O
+both	O
+phenobarbitone	O
+as	O
+well	O
+as	O
+carbamazepine	O
+.	O
+
+These	O
+results	O
+show	O
+that	O
+curcumin	O
+has	O
+beneficial	O
+effect	O
+in	O
+mitigating	O
+the	O
+deterioration	B
+of	I
+cognitive	I
+functions	I
+and	O
+oxidative	O
+damage	O
+in	O
+rats	O
+treated	O
+with	O
+phenobarbitone	O
+and	O
+carbamazepine	O
+without	O
+significantly	O
+altering	O
+their	O
+serum	O
+concentrations	O
+.	O
+
+The	O
+findings	O
+suggest	O
+that	O
+curcumin	O
+can	O
+be	O
+considered	O
+as	O
+a	O
+potential	O
+safe	O
+and	O
+effective	O
+adjuvant	O
+to	O
+phenobarbitone	O
+and	O
+carbamazepine	O
+therapy	O
+in	O
+preventing	O
+cognitive	B
+impairment	I
+associated	O
+with	O
+these	O
+drugs	O
+.	O
+
+Can	O
+angiogenesis	O
+be	O
+a	O
+target	O
+of	O
+treatment	O
+for	O
+ribavirin	O
+associated	O
+hemolytic	B
+anemia	I
+?	O
+
+BACKGROUND	O
+/	O
+AIMS	O
+:	O
+Recently	O
+ribavirin	O
+has	O
+been	O
+found	O
+to	O
+inhibit	O
+angiogenesis	O
+and	O
+a	O
+number	O
+of	O
+angiogenesis	O
+inhibitors	O
+such	O
+as	O
+sunitinib	O
+and	O
+sorafenib	O
+have	O
+been	O
+found	O
+to	O
+cause	O
+acute	O
+hemolysis	B
+.	O
+
+We	O
+aimed	O
+to	O
+investigate	O
+whether	O
+there	O
+is	O
+a	O
+relation	O
+between	O
+hemoglobin	O
+,	O
+haptoglobin	O
+and	O
+angiogenesis	O
+soluble	O
+markers	O
+which	O
+are	O
+modifiable	O
+and	O
+can	O
+help	O
+in	O
+developing	O
+strategies	O
+against	O
+anemia	B
+.	O
+
+METHODS	O
+:	O
+Fourteen	O
+patients	O
+chronically	B
+infected	I
+with	I
+hepatitis	I
+C	I
+virus	I
+were	O
+treated	O
+by	O
+pegylated	O
+interferon	O
+alpha	O
+2a	O
+and	O
+ribavirin	O
+.	O
+
+Serum	O
+hemoglobin	O
+,	O
+haptoglobin	O
+and	O
+angiogenesis	O
+markers	O
+of	O
+vascular	O
+endothelial	O
+growth	O
+factor	O
+and	O
+angiopoetin	O
+-	O
+2	O
+were	O
+investigated	O
+before	O
+and	O
+after	O
+therapy	O
+.	O
+
+RESULTS	O
+:	O
+We	O
+observed	O
+a	O
+significant	O
+decrease	O
+in	O
+haptoglobin	O
+levels	O
+at	O
+the	O
+end	O
+of	O
+the	O
+treatment	O
+period	O
+.	O
+
+Hemoglobin	O
+levels	O
+also	O
+decreased	O
+but	O
+insignificantly	O
+by	O
+treatment	O
+.	O
+
+In	O
+contrast	O
+with	O
+the	O
+literature	O
+,	O
+serum	O
+levels	O
+of	O
+angiogenesis	O
+factors	O
+did	O
+not	O
+change	O
+significantly	O
+by	O
+pegylated	O
+interferon	O
+and	O
+ribavirin	O
+therapy	O
+.	O
+
+We	O
+found	O
+no	O
+correlation	O
+of	O
+angiogenesis	O
+soluble	O
+markers	O
+with	O
+either	O
+hemoglobin	O
+or	O
+haptoglobin	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+is	O
+the	O
+first	O
+study	O
+in	O
+the	O
+literature	O
+investigating	O
+a	O
+link	O
+between	O
+angiogenesis	O
+soluble	O
+markers	O
+and	O
+ribavirin	O
+induced	O
+anemia	B
+in	O
+patients	O
+with	O
+hepatitis	B
+C	I
+and	O
+we	O
+could	O
+not	O
+find	O
+any	O
+relation	O
+.	O
+
+Future	O
+research	O
+with	O
+larger	O
+number	O
+of	O
+patients	O
+is	O
+needed	O
+to	O
+find	O
+out	O
+modifiable	O
+factors	O
+that	O
+will	O
+improve	O
+the	O
+safety	O
+of	O
+ribavirin	O
+therapy	O
+.	O
+
+Reduction	O
+in	O
+injection	O
+pain	B
+using	O
+buffered	O
+lidocaine	O
+as	O
+a	O
+local	O
+anesthetic	O
+before	O
+cardiac	O
+catheterization	O
+.	O
+
+Previous	O
+reports	O
+have	O
+suggested	O
+that	O
+pain	B
+associated	O
+with	O
+the	O
+injection	O
+of	O
+lidocaine	O
+is	O
+related	O
+to	O
+the	O
+acidic	O
+pH	O
+of	O
+the	O
+solution	O
+.	O
+
+To	O
+determine	O
+if	O
+the	O
+addition	O
+of	O
+a	O
+buffering	O
+solution	O
+to	O
+adjust	O
+the	O
+pH	O
+of	O
+lidocaine	O
+into	O
+the	O
+physiologic	O
+range	O
+would	O
+reduce	O
+pain	B
+during	O
+injection	O
+,	O
+we	O
+performed	O
+a	O
+blinded	O
+randomized	O
+study	O
+in	O
+patients	O
+undergoing	O
+cardiac	O
+catheterization	O
+.	O
+
+Twenty	O
+patients	O
+were	O
+asked	O
+to	O
+quantify	O
+the	O
+severity	O
+of	O
+pain	B
+after	O
+receiving	O
+standard	O
+lidocaine	O
+in	O
+one	O
+femoral	O
+area	O
+and	O
+buffered	O
+lidocaine	O
+in	O
+the	O
+opposite	O
+femoral	O
+area	O
+.	O
+
+The	O
+mean	O
+pain	B
+score	O
+for	O
+buffered	O
+lidocaine	O
+was	O
+significantly	O
+lower	O
+than	O
+the	O
+mean	O
+score	O
+for	O
+standard	O
+lidocaine	O
+(	O
+2	O
+.	O
+7	O
++	O
+/	O
+-	O
+1	O
+.	O
+9	O
+vs	O
+.	O
+3	O
+.	O
+8	O
++	O
+/	O
+-	O
+2	O
+.	O
+2	O
+,	O
+P	O
+=	O
+0	O
+.	O
+03	O
+)	O
+.	O
+
+The	O
+pH	O
+adjustment	O
+of	O
+standard	O
+lidocaine	O
+can	O
+be	O
+accomplished	O
+easily	O
+in	O
+the	O
+catheterization	O
+laboratory	O
+before	O
+injection	O
+and	O
+results	O
+in	O
+a	O
+reduction	O
+of	O
+the	O
+pain	B
+occurring	O
+during	O
+the	O
+infiltration	O
+of	O
+tissues	O
+.	O
+
+Effect	O
+of	O
+L	O
+-	O
+alpha	O
+-	O
+glyceryl	O
+-	O
+phosphorylcholine	O
+on	O
+amnesia	B
+caused	O
+by	O
+scopolamine	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+carried	O
+out	O
+to	O
+test	O
+the	O
+effects	O
+of	O
+L	O
+-	O
+alpha	O
+-	O
+glycerylphosphorylcholine	O
+(	O
+L	O
+-	O
+alpha	O
+-	O
+GFC	O
+)	O
+on	O
+memory	B
+impairment	I
+induced	O
+by	O
+scopolamine	O
+in	O
+man	O
+.	O
+
+Thirty	O
+-	O
+two	O
+healthy	O
+young	O
+volunteers	O
+were	O
+randomly	O
+allocated	O
+to	O
+four	O
+different	O
+groups	O
+.	O
+
+They	O
+were	O
+given	O
+a	O
+ten	O
+day	O
+pretreatment	O
+with	O
+either	O
+L	O
+-	O
+alpha	O
+-	O
+GFC	O
+or	O
+placebo	O
+,	O
+p	O
+.	O
+o	O
+.	O
+,	O
+and	O
+on	O
+the	O
+eleventh	O
+day	O
+either	O
+scopolamine	O
+or	O
+placebo	O
+,	O
+i	O
+.	O
+m	O
+.	O
+
+Before	O
+and	O
+0	O
+.	O
+5	O
+,	O
+1	O
+,	O
+2	O
+,	O
+3	O
+,	O
+and	O
+6	O
+h	O
+after	O
+injection	O
+the	O
+subjects	O
+were	O
+given	O
+attention	O
+and	O
+mnemonic	O
+tests	O
+.	O
+
+The	O
+findings	O
+of	O
+this	O
+study	O
+indicate	O
+that	O
+the	O
+drug	O
+is	O
+able	O
+to	O
+antagonize	O
+impairment	B
+of	I
+attention	I
+and	I
+memory	I
+induced	O
+by	O
+scopolamine	O
+.	O
+
+Safety	O
+of	O
+capecitabine	O
+:	O
+a	O
+review	O
+.	O
+
+IMPORTANCE	O
+OF	O
+THE	O
+FIELD	O
+:	O
+Fluoropyrimidines	O
+,	O
+in	O
+particular	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+,	O
+have	O
+been	O
+the	O
+mainstay	O
+of	O
+treatment	O
+for	O
+several	O
+solid	O
+tumors	B
+,	O
+including	O
+colorectal	B
+,	I
+breast	I
+and	I
+head	I
+and	I
+neck	I
+cancers	I
+,	O
+for	O
+>	O
+40	O
+years	O
+.	O
+
+AREAS	O
+COVERED	O
+IN	O
+THIS	O
+REVIEW	O
+:	O
+This	O
+article	O
+reviews	O
+the	O
+pharmacology	O
+and	O
+efficacy	O
+of	O
+capecitabine	O
+with	O
+a	O
+special	O
+emphasis	O
+on	O
+its	O
+safety	O
+.	O
+
+WHAT	O
+THE	O
+READER	O
+WILL	O
+GAIN	O
+:	O
+The	O
+reader	O
+will	O
+gain	O
+better	O
+insight	O
+into	O
+the	O
+safety	O
+of	O
+capecitabine	O
+in	O
+special	O
+populations	O
+such	O
+as	O
+patients	O
+with	O
+advanced	O
+age	O
+,	O
+renal	B
+and	I
+kidney	I
+disease	I
+.	O
+
+We	O
+also	O
+explore	O
+different	O
+dosing	O
+and	O
+schedules	O
+of	O
+capecitabine	O
+administration	O
+.	O
+
+TAKE	O
+HOME	O
+MESSAGE	O
+:	O
+Capecitabine	O
+is	O
+an	O
+oral	O
+prodrug	O
+of	O
+5	O
+-	O
+FU	O
+and	O
+was	O
+developed	O
+to	O
+fulfill	O
+the	O
+need	O
+for	O
+a	O
+more	O
+convenient	O
+therapy	O
+and	O
+provide	O
+an	O
+improved	O
+safety	O
+/	O
+efficacy	O
+profile	O
+.	O
+
+It	O
+has	O
+shown	O
+promising	O
+results	O
+alone	O
+or	O
+in	O
+combination	O
+with	O
+other	O
+chemotherapeutic	O
+agents	O
+in	O
+colorectal	B
+,	I
+breast	I
+,	I
+pancreaticobiliary	I
+,	I
+gastric	I
+,	I
+renal	I
+cell	I
+and	I
+head	I
+and	I
+neck	I
+cancers	I
+.	O
+
+The	O
+most	O
+commonly	O
+reported	O
+toxic	O
+effects	O
+of	O
+capecitabine	O
+are	O
+diarrhea	B
+,	O
+nausea	B
+,	O
+vomiting	B
+,	O
+stomatitis	B
+and	O
+hand	B
+-	I
+foot	I
+syndrome	I
+.	O
+
+Capecitabine	O
+has	O
+a	O
+well	O
+-	O
+established	O
+safety	O
+profile	O
+and	O
+can	O
+be	O
+given	O
+safely	O
+to	O
+patients	O
+with	O
+advanced	O
+age	O
+,	O
+hepatic	B
+and	I
+renal	I
+dysfunctions	I
+.	O
+
+Levodopa	O
+-	O
+induced	O
+dyskinesias	B
+in	O
+patients	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+:	O
+filling	O
+the	O
+bench	O
+-	O
+to	O
+-	O
+bedside	O
+gap	O
+.	O
+
+Levodopa	O
+is	O
+the	O
+most	O
+effective	O
+drug	O
+for	O
+the	O
+treatment	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+However	O
+,	O
+the	O
+long	O
+-	O
+term	O
+use	O
+of	O
+this	O
+dopamine	O
+precursor	O
+is	O
+complicated	O
+by	O
+highly	O
+disabling	O
+fluctuations	O
+and	O
+dyskinesias	B
+.	O
+
+Although	O
+preclinical	O
+and	O
+clinical	O
+findings	O
+suggest	O
+pulsatile	O
+stimulation	O
+of	O
+striatal	O
+postsynaptic	O
+receptors	O
+as	O
+a	O
+key	O
+mechanism	O
+underlying	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+,	O
+their	O
+pathogenesis	O
+is	O
+still	O
+unclear	O
+.	O
+
+In	O
+recent	O
+years	O
+,	O
+evidence	O
+from	O
+animal	O
+models	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+has	O
+provided	O
+important	O
+information	O
+to	O
+understand	O
+the	O
+effect	O
+of	O
+specific	O
+receptor	O
+and	O
+post	O
+-	O
+receptor	O
+molecular	O
+mechanisms	O
+underlying	O
+the	O
+development	O
+of	O
+dyskinetic	B
+movements	I
+.	O
+
+Recent	O
+preclinical	O
+and	O
+clinical	O
+data	O
+from	O
+promising	O
+lines	O
+of	O
+research	O
+focus	O
+on	O
+the	O
+differential	O
+role	O
+of	O
+presynaptic	O
+versus	O
+postsynaptic	O
+mechanisms	O
+,	O
+dopamine	O
+receptor	O
+subtypes	O
+,	O
+ionotropic	O
+and	O
+metabotropic	O
+glutamate	O
+receptors	O
+,	O
+and	O
+non	O
+-	O
+dopaminergic	O
+neurotransmitter	O
+systems	O
+in	O
+the	O
+pathophysiology	O
+of	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+.	O
+
+Effects	O
+of	O
+pallidal	O
+neurotensin	O
+on	O
+haloperidol	O
+-	O
+induced	O
+parkinsonian	B
+catalepsy	I
+:	O
+behavioral	O
+and	O
+electrophysiological	O
+studies	O
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+globus	O
+pallidus	O
+plays	O
+a	O
+critical	O
+role	O
+in	O
+movement	O
+regulation	O
+.	O
+
+Previous	O
+studies	O
+have	O
+indicated	O
+that	O
+the	O
+globus	O
+pallidus	O
+receives	O
+neurotensinergic	O
+innervation	O
+from	O
+the	O
+striatum	O
+,	O
+and	O
+systemic	O
+administration	O
+of	O
+a	O
+neurotensin	O
+analog	O
+could	O
+produce	O
+antiparkinsonian	O
+effects	O
+.	O
+
+The	O
+present	O
+study	O
+aimed	O
+to	O
+investigate	O
+the	O
+effects	O
+of	O
+pallidal	O
+neurotensin	O
+on	O
+haloperidol	O
+-	O
+induced	O
+parkinsonian	B
+symptoms	I
+.	O
+
+METHODS	O
+:	O
+Behavioral	O
+experiments	O
+and	O
+electrophysiological	O
+recordings	O
+were	O
+performed	O
+in	O
+the	O
+present	O
+study	O
+.	O
+
+RESULTS	O
+:	O
+Bilateral	O
+infusions	O
+of	O
+neurotensin	O
+into	O
+the	O
+globus	O
+pallidus	O
+reversed	O
+haloperidol	O
+-	O
+induced	O
+parkinsonian	B
+catalepsy	I
+in	O
+rats	O
+.	O
+
+Electrophysiological	O
+recordings	O
+showed	O
+that	O
+microinjection	O
+of	O
+neurotensin	O
+induced	O
+excitation	O
+of	O
+pallidal	O
+neurons	O
+in	O
+the	O
+presence	O
+of	O
+systemic	O
+haloperidol	O
+administration	O
+.	O
+
+The	O
+neurotensin	O
+type	O
+-	O
+1	O
+receptor	O
+antagonist	O
+SR48692	O
+blocked	O
+both	O
+the	O
+behavioral	O
+and	O
+the	O
+electrophysiological	O
+effects	O
+induced	O
+by	O
+neurotensin	O
+.	O
+
+CONCLUSION	O
+:	O
+Activation	O
+of	O
+pallidal	O
+neurotensin	O
+receptors	O
+may	O
+be	O
+involved	O
+in	O
+neurotensin	O
+-	O
+induced	O
+antiparkinsonian	O
+effects	O
+.	O
+
+Carmofur	O
+-	O
+induced	O
+organic	B
+mental	I
+disorders	I
+.	O
+
+Organic	B
+mental	I
+disorder	I
+was	O
+observed	O
+in	O
+a	O
+29	O
+-	O
+year	O
+-	O
+old	O
+female	O
+in	O
+the	O
+prognostic	O
+period	O
+after	O
+the	O
+onset	O
+of	O
+carmofur	O
+-	O
+induced	O
+leukoencephalopathy	B
+.	O
+
+Symptoms	O
+such	O
+as	O
+euphoria	O
+,	O
+emotional	O
+lability	O
+and	O
+puerile	O
+attitude	O
+noted	O
+in	O
+the	O
+patient	O
+were	O
+diagnosed	O
+as	O
+organic	B
+personality	I
+syndrome	I
+according	O
+to	O
+the	O
+criteria	O
+defined	O
+in	O
+the	O
+DSM	O
+-	O
+III	O
+-	O
+R	O
+.	O
+
+It	O
+is	O
+referred	O
+to	O
+as	O
+a	O
+frontal	B
+lobe	I
+syndrome	I
+.	O
+
+Brain	O
+CT	O
+revealed	O
+a	O
+periventricular	O
+low	O
+density	O
+area	O
+in	O
+the	O
+frontal	O
+white	O
+matter	O
+and	O
+moderate	O
+dilatation	O
+of	O
+the	O
+lateral	O
+ventricles	O
+especially	O
+at	O
+the	O
+bilateral	O
+anterior	O
+horns	O
+.	O
+
+Consequently	O
+,	O
+carmofur	O
+-	O
+induced	O
+leukoencephalopathy	B
+may	O
+uncommonly	O
+result	O
+in	O
+organic	B
+personality	I
+syndrome	I
+in	O
+the	O
+residual	O
+state	O
+.	O
+
+It	O
+may	O
+be	O
+attributed	O
+to	O
+the	O
+structural	B
+damage	I
+to	I
+the	I
+frontal	I
+lobe	I
+.	O
+
+Butyrylcholinesterase	O
+gene	O
+mutations	O
+in	O
+patients	O
+with	O
+prolonged	O
+apnea	B
+after	O
+succinylcholine	O
+for	O
+electroconvulsive	O
+therapy	O
+.	O
+
+BACKGROUND	O
+:	O
+patients	O
+undergoing	O
+electroconvulsive	O
+therapy	O
+(	O
+ECT	O
+)	O
+often	O
+receive	O
+succinylcholine	O
+as	O
+part	O
+of	O
+the	O
+anesthetic	O
+procedure	O
+.	O
+
+The	O
+duration	O
+of	O
+action	O
+may	O
+be	O
+prolonged	O
+in	O
+patients	O
+with	O
+genetic	O
+variants	O
+of	O
+the	O
+butyrylcholinesterase	O
+enzyme	O
+(	O
+BChE	O
+)	O
+,	O
+the	O
+most	O
+common	O
+being	O
+the	O
+K	O
+-	O
+and	O
+the	O
+A	O
+-	O
+variants	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+assess	O
+the	O
+clinical	O
+significance	O
+of	O
+genetic	O
+variants	O
+in	O
+butyrylcholinesterase	O
+gene	O
+(	O
+BCHE	O
+)	O
+in	O
+patients	O
+with	O
+a	O
+suspected	O
+prolonged	O
+duration	O
+of	O
+action	O
+of	O
+succinylcholine	O
+after	O
+ECT	O
+.	O
+
+METHODS	O
+:	O
+a	O
+total	O
+of	O
+13	O
+patients	O
+were	O
+referred	O
+to	O
+the	O
+Danish	O
+Cholinesterase	O
+Research	O
+Unit	O
+after	O
+ECT	O
+during	O
+38	O
+months	O
+.	O
+
+We	O
+determined	O
+the	O
+BChE	O
+activity	O
+and	O
+the	O
+BCHE	O
+genotype	O
+using	O
+molecular	O
+genetic	O
+methods	O
+,	O
+the	O
+duration	O
+of	O
+apnea	B
+,	O
+time	O
+to	O
+sufficient	O
+spontaneous	O
+ventilation	O
+and	O
+whether	O
+neuromuscular	O
+monitoring	O
+was	O
+used	O
+.	O
+
+The	O
+duration	O
+of	O
+apnea	B
+was	O
+compared	O
+with	O
+published	O
+data	O
+on	O
+normal	O
+subjects	O
+.	O
+
+RESULTS	O
+:	O
+in	O
+11	O
+patients	O
+,	O
+mutations	O
+were	O
+found	O
+in	O
+the	O
+BCHE	O
+gene	O
+,	O
+the	O
+K	O
+-	O
+variant	O
+being	O
+the	O
+most	O
+frequent	O
+.	O
+
+The	O
+duration	O
+of	O
+apnea	B
+was	O
+5	O
+-	O
+15	O
+min	O
+compared	O
+with	O
+3	O
+-	O
+5	O
+.	O
+3	O
+min	O
+from	O
+the	O
+literature	O
+.	O
+
+Severe	O
+distress	O
+was	O
+noted	O
+in	O
+the	O
+recovery	O
+phase	O
+in	O
+two	O
+patients	O
+.	O
+
+Neuromuscular	O
+monitoring	O
+was	O
+used	O
+in	O
+two	O
+patients	O
+.	O
+
+CONCLUSION	O
+:	O
+eleven	O
+of	O
+13	O
+patients	O
+with	O
+a	O
+prolonged	O
+duration	O
+of	O
+action	O
+of	O
+succinylcholine	O
+had	O
+mutations	O
+in	O
+BCHE	O
+,	O
+indicating	O
+that	O
+this	O
+is	O
+the	O
+possible	O
+reason	O
+for	O
+a	O
+prolonged	O
+period	O
+of	O
+apnea	B
+.	O
+
+We	O
+recommend	O
+objective	O
+neuromuscular	O
+monitoring	O
+during	O
+the	O
+first	O
+ECT	O
+.	O
+
+Perhexiline	O
+maleate	O
+and	O
+peripheral	B
+neuropathy	I
+.	O
+
+Peripheral	B
+neuropathy	I
+has	O
+been	O
+noted	O
+as	O
+a	O
+complication	O
+of	O
+therapy	O
+with	O
+perhexiline	O
+maleate	O
+,	O
+a	O
+drug	O
+widely	O
+used	O
+in	O
+France	O
+(	O
+and	O
+in	O
+clinical	O
+trials	O
+in	O
+the	O
+United	O
+States	O
+)	O
+for	O
+the	O
+prophylactic	O
+treatment	O
+of	O
+angina	B
+pectoris	I
+.	O
+
+In	O
+24	O
+patients	O
+with	O
+this	O
+complication	O
+,	O
+the	O
+marked	O
+slowing	O
+of	O
+motor	O
+nerve	O
+conduction	O
+velocity	O
+and	O
+the	O
+electromyographic	O
+changes	O
+imply	O
+mainly	O
+a	O
+demyelinating	B
+disorder	I
+.	O
+
+Improvement	O
+was	O
+noted	O
+with	O
+cessation	O
+of	O
+therapy	O
+.	O
+
+In	O
+a	O
+few	O
+cases	O
+the	O
+presence	O
+of	O
+active	O
+denervation	O
+signified	O
+a	O
+poor	O
+prognosis	O
+,	O
+with	O
+only	O
+slight	O
+improvement	O
+.	O
+
+The	O
+underlying	O
+mechanism	O
+causing	O
+the	O
+neuropathy	B
+is	O
+not	O
+yet	O
+fully	O
+known	O
+,	O
+although	O
+some	O
+evidence	O
+indicates	O
+that	O
+it	O
+may	O
+be	O
+a	O
+lipid	O
+storage	O
+process	O
+.	O
+
+A	O
+phase	O
+I	O
+study	O
+of	O
+4	O
+'	O
+-	O
+0	O
+-	O
+tetrahydropyranyladriamycin	O
+.	O
+
+Clinical	O
+pharmacology	O
+and	O
+pharmacokinetics	O
+.	O
+
+A	O
+Phase	O
+I	O
+study	O
+of	O
+intravenous	O
+(	O
+IV	O
+)	O
+bolus	O
+4	O
+'	O
+-	O
+0	O
+-	O
+tetrahydropyranyladriamycin	O
+(	O
+Pirarubicin	O
+)	O
+was	O
+done	O
+in	O
+55	O
+patients	O
+in	O
+good	O
+performance	O
+status	O
+with	O
+refractory	O
+tumors	B
+.	O
+
+Twenty	O
+-	O
+six	O
+had	O
+minimal	O
+prior	O
+therapy	O
+(	O
+good	O
+risk	O
+)	O
+,	O
+23	O
+had	O
+extensive	O
+prior	O
+therapy	O
+(	O
+poor	O
+risk	O
+)	O
+,	O
+and	O
+six	O
+had	O
+renal	B
+and	I
+/	I
+or	I
+hepatic	I
+dysfunction	I
+.	O
+
+A	O
+total	O
+of	O
+167	O
+courses	O
+at	O
+doses	O
+of	O
+15	O
+to	O
+70	O
+mg	O
+/	O
+m2	O
+were	O
+evaluable	O
+.	O
+
+Maximum	O
+tolerated	O
+dose	O
+in	O
+good	O
+-	O
+risk	O
+patients	O
+was	O
+70	O
+mg	O
+/	O
+m2	O
+,	O
+and	O
+in	O
+poor	O
+-	O
+risk	O
+patients	O
+,	O
+60	O
+mg	O
+/	O
+m2	O
+.	O
+
+The	O
+dose	O
+-	O
+limiting	O
+toxic	O
+effect	O
+was	O
+transient	O
+noncumulative	O
+granulocytopenia	B
+.	O
+
+Granulocyte	O
+nadir	O
+was	O
+on	O
+day	O
+14	O
+(	O
+range	O
+,	O
+4	O
+-	O
+22	O
+)	O
+.	O
+
+Less	O
+frequent	O
+toxic	O
+effects	O
+included	O
+thrombocytopenia	B
+,	O
+anemia	B
+,	O
+nausea	B
+,	O
+mild	O
+alopecia	B
+,	O
+phlebitis	B
+,	O
+and	O
+mucositis	B
+.	O
+
+Myelosuppression	B
+was	O
+more	O
+in	O
+patients	O
+with	O
+hepatic	B
+dysfunction	I
+.	O
+
+Pharmacokinetic	O
+analyses	O
+in	O
+21	O
+patients	O
+revealed	O
+Pirarubicin	O
+plasma	O
+T	O
+1	O
+/	O
+2	O
+alpha	O
+(	O
++	O
+/	O
+-	O
+SE	O
+)	O
+of	O
+2	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+85	O
+minutes	O
+,	O
+T	O
+beta	O
+1	O
+/	O
+2	O
+of	O
+25	O
+.	O
+6	O
++	O
+/	O
+-	O
+6	O
+.	O
+5	O
+minutes	O
+,	O
+and	O
+T	O
+1	O
+/	O
+2	O
+gamma	O
+of	O
+23	O
+.	O
+6	O
++	O
+/	O
+-	O
+7	O
+.	O
+6	O
+hours	O
+.	O
+
+The	O
+area	O
+under	O
+the	O
+curve	O
+was	O
+537	O
++	O
+/	O
+-	O
+149	O
+ng	O
+/	O
+ml	O
+x	O
+hours	O
+,	O
+volume	O
+of	O
+distribution	O
+(	O
+Vd	O
+)	O
+3504	O
++	O
+/	O
+-	O
+644	O
+l	O
+/	O
+m2	O
+,	O
+and	O
+total	O
+clearance	O
+(	O
+ClT	O
+)	O
+was	O
+204	O
++	O
+39	O
+.	O
+3	O
+l	O
+/	O
+hour	O
+/	O
+m2	O
+.	O
+
+Adriamycinol	O
+,	O
+doxorubicin	O
+,	O
+adriamycinone	O
+,	O
+and	O
+tetrahydropyranyladriamycinol	O
+were	O
+the	O
+metabolites	O
+detected	O
+in	O
+plasma	O
+and	O
+the	O
+amount	O
+of	O
+doxorubicin	O
+was	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+10	O
+%	O
+of	O
+the	O
+total	O
+metabolites	O
+.	O
+
+Urinary	O
+excretion	O
+of	O
+Pirarubicin	O
+in	O
+the	O
+first	O
+24	O
+hours	O
+was	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+10	O
+%	O
+.	O
+
+Activity	O
+was	O
+noted	O
+in	O
+mesothelioma	B
+,	O
+leiomyosarcoma	B
+,	O
+and	O
+basal	B
+cell	I
+carcinoma	I
+.	O
+
+The	O
+recommended	O
+starting	O
+dose	O
+for	O
+Phase	O
+II	O
+trials	O
+is	O
+60	O
+mg	O
+/	O
+m2	O
+IV	O
+bolus	O
+every	O
+3	O
+weeks	O
+.	O
+
+Ocular	B
+and	I
+auditory	I
+toxicity	I
+in	O
+hemodialyzed	O
+patients	O
+receiving	O
+desferrioxamine	O
+.	O
+
+During	O
+an	O
+18	O
+-	O
+month	O
+period	O
+of	O
+study	O
+41	O
+hemodialyzed	O
+patients	O
+receiving	O
+desferrioxamine	O
+(	O
+10	O
+-	O
+40	O
+mg	O
+/	O
+kg	O
+BW	O
+/	O
+3	O
+times	O
+weekly	O
+)	O
+for	O
+the	O
+first	O
+time	O
+were	O
+monitored	O
+for	O
+detection	O
+of	O
+audiovisual	B
+toxicity	I
+.	O
+
+6	O
+patients	O
+presented	O
+clinical	O
+symptoms	O
+of	O
+visual	B
+or	I
+auditory	I
+toxicity	I
+.	O
+
+Moreover	O
+,	O
+detailed	O
+ophthalmologic	O
+and	O
+audiologic	O
+studies	O
+disclosed	O
+abnormalities	O
+in	O
+7	O
+more	O
+asymptomatic	O
+patients	O
+.	O
+
+Visual	B
+toxicity	I
+was	O
+of	O
+retinal	O
+origin	O
+and	O
+was	O
+characterized	O
+by	O
+a	O
+tritan	O
+-	O
+type	O
+dyschromatopsy	B
+,	O
+sometimes	O
+associated	O
+with	O
+a	B
+loss	I
+of	I
+visual	I
+acuity	I
+and	O
+pigmentary	B
+retinal	I
+deposits	I
+.	O
+
+Auditory	B
+toxicity	I
+was	O
+characterized	O
+by	O
+a	O
+mid	O
+-	O
+to	O
+high	O
+-	O
+frequency	O
+neurosensorial	B
+hearing	I
+loss	I
+and	O
+the	O
+lesion	O
+was	O
+of	O
+the	O
+cochlear	O
+type	O
+.	O
+
+Desferrioxamine	O
+withdrawal	O
+resulted	O
+in	O
+a	O
+complete	O
+recovery	O
+of	O
+visual	O
+function	O
+in	O
+1	O
+patient	O
+and	O
+partial	O
+recovery	O
+in	O
+3	O
+,	O
+and	O
+a	O
+complete	O
+reversal	O
+of	O
+hearing	B
+loss	I
+in	O
+3	O
+patients	O
+and	O
+partial	O
+recovery	O
+in	O
+3	O
+.	O
+
+This	O
+toxicity	B
+appeared	O
+in	O
+patients	O
+receiving	O
+the	O
+higher	O
+doses	O
+of	O
+desferrioxamine	O
+or	O
+coincided	O
+with	O
+the	O
+normalization	O
+of	O
+ferritin	O
+or	O
+aluminium	O
+serum	O
+levels	O
+.	O
+
+The	O
+data	O
+indicate	O
+that	O
+audiovisual	B
+toxicity	I
+is	O
+not	O
+an	O
+infrequent	O
+complication	O
+in	O
+hemodialyzed	O
+patients	O
+receiving	O
+desferrioxamine	O
+.	O
+
+Periodical	O
+audiovisual	O
+monitoring	O
+should	O
+be	O
+performed	O
+on	O
+hemodialyzed	O
+patients	O
+receiving	O
+the	O
+drug	O
+in	O
+order	O
+to	O
+detect	O
+adverse	O
+effects	O
+as	O
+early	O
+as	O
+possible	O
+.	O
+
+Serial	O
+epilepsy	B
+caused	O
+by	O
+levodopa	O
+/	O
+carbidopa	O
+administration	O
+in	O
+two	O
+patients	O
+on	O
+hemodialysis	O
+.	O
+
+Two	O
+patients	O
+with	O
+similar	O
+clinical	O
+features	O
+are	O
+presented	O
+:	O
+both	O
+patients	O
+had	O
+chronic	B
+renal	I
+failure	I
+,	O
+on	O
+hemodialysis	O
+for	O
+many	O
+years	O
+but	O
+recently	O
+begun	O
+on	O
+a	O
+high	O
+-	O
+flux	O
+dialyzer	O
+;	O
+both	O
+had	O
+been	O
+receiving	O
+a	O
+carbidopa	O
+/	O
+levodopa	O
+preparation	O
+;	O
+and	O
+both	O
+had	O
+the	O
+onset	O
+of	O
+hallucinosis	B
+and	O
+recurrent	O
+seizures	B
+,	O
+which	O
+were	O
+refractory	O
+to	O
+anticonvulsants	O
+.	O
+
+The	O
+first	O
+patient	O
+died	O
+without	O
+a	O
+diagnosis	O
+;	O
+the	O
+second	O
+patient	O
+had	O
+a	O
+dramatic	O
+recovery	O
+following	O
+the	O
+administration	O
+of	O
+vitamin	O
+B6	O
+.	O
+
+Neither	O
+patient	O
+was	O
+considered	O
+to	O
+have	O
+a	O
+renal	O
+state	O
+sufficiently	O
+severe	O
+enough	O
+to	O
+explain	O
+their	O
+presentation	O
+.	O
+
+Randomized	O
+,	O
+double	O
+-	O
+blind	O
+trial	O
+of	O
+mazindol	O
+in	O
+Duchenne	B
+dystrophy	I
+.	O
+
+There	O
+is	O
+evidence	O
+that	O
+growth	O
+hormone	O
+may	O
+be	O
+related	O
+to	O
+the	O
+progression	O
+of	O
+weakness	B
+in	O
+Duchenne	B
+dystrophy	I
+.	O
+
+We	O
+conducted	O
+a	O
+12	O
+-	O
+month	O
+controlled	O
+trial	O
+of	O
+mazindol	O
+,	O
+a	O
+putative	O
+growth	O
+hormone	O
+secretion	O
+inhibitor	O
+,	O
+in	O
+83	O
+boys	O
+with	O
+Duchenne	B
+dystrophy	I
+.	O
+
+Muscle	O
+strength	O
+,	O
+contractures	O
+,	O
+functional	O
+ability	O
+and	O
+pulmonary	O
+function	O
+were	O
+tested	O
+at	O
+baseline	O
+,	O
+and	O
+6	O
+and	O
+12	O
+months	O
+after	O
+treatment	O
+with	O
+mazindol	O
+(	O
+3	O
+mg	O
+/	O
+d	O
+)	O
+or	O
+placebo	O
+.	O
+
+The	O
+study	O
+was	O
+designed	O
+to	O
+have	O
+a	O
+power	O
+of	O
+greater	O
+than	O
+0	O
+.	O
+90	O
+to	O
+detect	O
+a	O
+slowing	O
+to	O
+25	O
+%	O
+of	O
+the	O
+expected	O
+rate	O
+of	O
+progression	O
+of	O
+weakness	B
+at	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+.	O
+
+Mazindol	O
+did	O
+not	O
+benefit	O
+strength	O
+at	O
+any	O
+point	O
+in	O
+the	O
+study	O
+.	O
+
+Side	O
+effects	O
+attributable	O
+to	O
+mazindol	O
+included	O
+decreased	B
+appetite	I
+(	O
+36	O
+%	O
+)	O
+,	O
+dry	B
+mouth	I
+(	O
+10	O
+%	O
+)	O
+,	O
+behavioral	O
+change	O
+(	O
+22	O
+%	O
+)	O
+,	O
+and	O
+gastrointestinal	B
+symptoms	I
+(	O
+18	O
+%	O
+)	O
+;	O
+mazindol	O
+dosage	O
+was	O
+reduced	O
+in	O
+43	O
+%	O
+of	O
+patients	O
+.	O
+
+The	O
+effect	O
+of	O
+mazindol	O
+on	O
+GH	O
+secretion	O
+was	O
+estimated	O
+indirectly	O
+by	O
+comparing	O
+the	O
+postabsorptive	O
+IGF	O
+-	O
+I	O
+levels	O
+obtained	O
+following	O
+3	O
+,	O
+6	O
+,	O
+9	O
+,	O
+and	O
+12	O
+months	O
+in	O
+the	O
+mazindol	O
+treated	O
+to	O
+those	O
+in	O
+the	O
+placebo	O
+groups	O
+.	O
+
+Although	O
+mazindol	O
+-	O
+treated	O
+patients	O
+gained	O
+less	O
+weight	O
+and	O
+height	O
+than	O
+placebo	O
+-	O
+treated	O
+patients	O
+,	O
+no	O
+significant	O
+effect	O
+on	O
+IGF	O
+-	O
+I	O
+levels	O
+was	O
+observed	O
+.	O
+
+Mazindol	O
+doses	O
+not	O
+slow	O
+the	O
+progression	O
+of	O
+weakness	B
+in	O
+Duchenne	B
+dystrophy	I
+.	O
+
+Facilitation	O
+of	O
+memory	O
+retrieval	O
+by	O
+pre	O
+-	O
+test	O
+morphine	O
+and	O
+its	O
+state	O
+dependency	O
+in	O
+the	O
+step	O
+-	O
+through	O
+type	O
+passive	O
+avoidance	O
+learning	O
+test	O
+in	O
+mice	O
+.	O
+
+Amnesia	B
+produced	O
+by	O
+scopolamine	O
+and	O
+cycloheximide	O
+were	O
+reversed	O
+by	O
+morphine	O
+given	O
+30	O
+min	O
+before	O
+the	O
+test	O
+trial	O
+(	O
+pre	O
+-	O
+test	O
+)	O
+,	O
+and	O
+pre	O
+-	O
+test	O
+morphine	O
+also	O
+facilitated	O
+the	O
+memory	O
+retrieval	O
+in	O
+the	O
+animals	O
+administered	O
+naloxone	O
+during	O
+the	O
+training	O
+trial	O
+.	O
+
+Similarly	O
+,	O
+pre	O
+-	O
+test	O
+scopolamine	O
+partially	O
+reversed	O
+the	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+,	O
+but	O
+not	O
+significantly	O
+;	O
+and	O
+pre	O
+-	O
+test	O
+cycloheximide	O
+failed	O
+to	O
+reverse	O
+the	O
+cycloheximide	O
+-	O
+induced	O
+amnesia	B
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+the	O
+facilitation	O
+of	O
+memory	O
+retrieval	O
+by	O
+pre	O
+-	O
+test	O
+morphine	O
+might	O
+be	O
+the	O
+direct	O
+action	O
+of	O
+morphine	O
+rather	O
+than	O
+a	O
+state	O
+dependent	O
+effect	O
+.	O
+
+Naloxone	O
+reverses	O
+the	O
+antihypertensive	O
+effect	O
+of	O
+clonidine	O
+.	O
+
+In	O
+unanesthetized	O
+,	O
+spontaneously	O
+hypertensive	B
+rats	O
+the	O
+decrease	O
+in	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+produced	O
+by	O
+intravenous	O
+clonidine	O
+,	O
+5	O
+to	O
+20	O
+micrograms	O
+/	O
+kg	O
+,	O
+was	O
+inhibited	O
+or	O
+reversed	O
+by	O
+nalozone	O
+,	O
+0	O
+.	O
+2	O
+to	O
+2	O
+mg	O
+/	O
+kg	O
+.	O
+
+The	O
+hypotensive	B
+effect	O
+of	O
+100	O
+mg	O
+/	O
+kg	O
+alpha	O
+-	O
+methyldopa	O
+was	O
+also	O
+partially	O
+reversed	O
+by	O
+naloxone	O
+.	O
+
+Naloxone	O
+alone	O
+did	O
+not	O
+affect	O
+either	O
+blood	O
+pressure	O
+or	O
+heart	O
+rate	O
+.	O
+
+In	O
+brain	O
+membranes	O
+from	O
+spontaneously	O
+hypertensive	B
+rats	O
+clonidine	O
+,	O
+10	O
+(	O
+-	O
+8	O
+)	O
+to	O
+10	O
+(	O
+-	O
+5	O
+)	O
+M	O
+,	O
+did	O
+not	O
+influence	O
+stereoselective	O
+binding	O
+of	O
+[	O
+3H	O
+]	O
+-	O
+naloxone	O
+(	O
+8	O
+nM	O
+)	O
+,	O
+and	O
+naloxone	O
+,	O
+10	O
+(	O
+-	O
+8	O
+)	O
+to	O
+10	O
+(	O
+-	O
+4	O
+)	O
+M	O
+,	O
+did	O
+not	O
+influence	O
+clonidine	O
+-	O
+suppressible	O
+binding	O
+of	O
+[	O
+3H	O
+]	O
+-	O
+dihydroergocryptine	O
+(	O
+1	O
+nM	O
+)	O
+.	O
+
+These	O
+findings	O
+indicate	O
+that	O
+in	O
+spontaneously	O
+hypertensive	B
+rats	O
+the	O
+effects	O
+of	O
+central	O
+alpha	O
+-	O
+adrenoceptor	O
+stimulation	O
+involve	O
+activation	O
+of	O
+opiate	O
+receptors	O
+.	O
+
+As	O
+naloxone	O
+and	O
+clonidine	O
+do	O
+not	O
+appear	O
+to	O
+interact	O
+with	O
+the	O
+same	O
+receptor	O
+site	O
+,	O
+the	O
+observed	O
+functional	O
+antagonism	O
+suggests	O
+the	O
+release	O
+of	O
+an	O
+endogenous	O
+opiate	O
+by	O
+clonidine	O
+or	O
+alpha	O
+-	O
+methyldopa	O
+and	O
+the	O
+possible	O
+role	O
+of	O
+the	O
+opiate	O
+in	O
+the	O
+central	O
+control	O
+of	O
+sympathetic	O
+tone	O
+.	O
+
+Neurotoxicity	B
+of	O
+halogenated	O
+hydroxyquinolines	O
+:	O
+clinical	O
+analysis	O
+of	O
+cases	O
+reported	O
+outside	O
+Japan	O
+.	O
+
+An	O
+analysis	O
+is	O
+presented	O
+of	O
+220	O
+cases	O
+of	O
+possible	O
+neurotoxic	B
+reactions	O
+to	O
+halogenated	O
+hydroxyquinolines	O
+reported	O
+from	O
+outside	O
+Japan	O
+.	O
+
+In	O
+80	O
+cases	O
+insufficient	O
+information	O
+was	O
+available	O
+for	O
+adequate	O
+comment	O
+and	O
+in	O
+29	O
+a	O
+relationship	O
+to	O
+the	O
+administration	O
+of	O
+clioquinol	O
+could	O
+be	O
+excluded	O
+.	O
+
+Of	O
+the	O
+remainder	O
+,	O
+a	O
+relationship	O
+to	O
+clioquinol	O
+was	O
+considered	O
+probable	O
+in	O
+42	O
+and	O
+possible	O
+in	O
+69	O
+cases	O
+.	O
+
+In	O
+six	O
+of	O
+the	O
+probable	O
+cases	O
+the	O
+neurological	B
+disturbance	I
+consisted	O
+of	O
+an	O
+acute	O
+reversible	O
+encephalopathy	B
+usually	O
+related	O
+to	O
+the	O
+ingestion	O
+of	O
+a	O
+high	O
+dose	O
+of	O
+clioquinol	O
+over	O
+a	O
+short	O
+period	O
+.	O
+
+The	O
+most	O
+common	O
+manifestation	O
+,	O
+observed	O
+in	O
+15	O
+further	O
+cases	O
+,	O
+was	O
+isolated	O
+optic	B
+atrophy	I
+.	O
+
+This	O
+was	O
+most	O
+frequently	O
+found	O
+in	O
+children	O
+,	O
+many	O
+of	O
+whom	O
+had	O
+received	O
+clioquinol	O
+as	O
+treatment	O
+for	O
+acrodermatitis	B
+enteropathica	I
+.	O
+
+In	O
+the	O
+remaining	O
+cases	O
+,	O
+a	O
+combination	O
+of	O
+myelopathy	B
+,	O
+visual	B
+disturbance	I
+,	O
+and	O
+peripheral	B
+neuropathy	I
+was	O
+the	O
+most	O
+common	O
+manifestation	O
+.	O
+
+Isolated	O
+myelopathy	B
+or	O
+peripheral	B
+neuropathy	I
+,	O
+or	O
+these	O
+manifestations	O
+occurring	O
+together	O
+,	O
+were	O
+infrequent	O
+.	O
+
+The	O
+onset	O
+of	O
+all	O
+manifestations	O
+(	O
+except	O
+toxic	O
+encephalopathy	B
+)	O
+was	O
+usually	O
+subacute	O
+,	O
+with	O
+subsequent	O
+partial	O
+recovery	O
+.	O
+
+Older	O
+subjects	O
+tended	O
+to	O
+display	O
+more	O
+side	O
+effects	O
+.	O
+
+The	O
+full	O
+syndrome	O
+of	O
+subacute	O
+myelo	B
+-	I
+optic	I
+neuropathy	I
+was	O
+more	O
+frequent	O
+in	O
+women	O
+,	O
+but	O
+they	O
+tended	O
+to	O
+have	O
+taken	O
+greater	O
+quantities	O
+of	O
+the	O
+drug	O
+.	O
+
+Prazosin	O
+-	O
+induced	O
+stress	B
+incontinence	I
+.	O
+
+A	O
+case	O
+of	O
+genuine	O
+stress	B
+incontinence	I
+due	O
+to	O
+prazosin	O
+,	O
+a	O
+common	O
+antihypertensive	O
+drug	O
+,	O
+is	O
+presented	O
+.	O
+
+Prazosin	O
+exerts	O
+its	O
+antihypertensive	O
+effects	O
+through	O
+vasodilatation	O
+caused	O
+by	O
+selective	O
+blockade	O
+of	O
+postsynaptic	O
+alpha	O
+-	O
+1	O
+adrenergic	O
+receptors	O
+.	O
+
+As	O
+an	O
+alpha	O
+-	O
+blocker	O
+,	O
+it	O
+also	O
+exerts	O
+a	O
+significant	O
+relaxant	O
+effect	O
+on	O
+the	O
+bladder	O
+neck	O
+and	O
+urethra	O
+.	O
+
+The	O
+patient	O
+'	O
+s	O
+clinical	O
+course	O
+is	O
+described	O
+and	O
+correlated	O
+with	O
+initial	O
+urodynamic	O
+studies	O
+while	O
+on	O
+prazosin	O
+and	O
+subsequent	O
+studies	O
+while	O
+taking	O
+verapamil	O
+.	O
+
+Her	O
+incontinence	B
+resolved	O
+with	O
+the	O
+change	O
+of	O
+medication	O
+.	O
+
+The	O
+restoration	O
+of	O
+continence	O
+was	O
+accompanied	O
+by	O
+a	O
+substantial	O
+rise	O
+in	O
+maximum	O
+urethral	O
+pressure	O
+,	O
+maximum	O
+urethral	O
+closure	O
+pressure	O
+,	O
+and	O
+functional	O
+urethral	O
+length	O
+.	O
+
+Patients	O
+who	O
+present	O
+with	O
+stress	B
+incontinence	I
+while	O
+taking	O
+prazosin	O
+should	O
+change	O
+their	O
+antihypertensive	O
+medication	O
+before	O
+considering	O
+surgery	O
+,	O
+because	O
+their	O
+incontinence	B
+may	O
+resolve	O
+spontaneously	O
+with	O
+a	O
+change	O
+in	O
+drug	O
+therapy	O
+.	O
+
+Myocardial	B
+infarction	I
+following	O
+sublingual	O
+administration	O
+of	O
+isosorbide	O
+dinitrate	O
+.	O
+
+A	O
+78	O
+-	O
+year	O
+-	O
+old	O
+with	O
+healed	O
+septal	O
+necrosis	B
+suffered	O
+a	O
+recurrent	O
+myocardial	B
+infarction	I
+of	O
+the	O
+anterior	O
+wall	O
+following	O
+the	O
+administration	O
+of	O
+isosorbide	O
+dinitrate	O
+5	O
+mg	O
+sublingually	O
+.	O
+
+After	O
+detailing	O
+the	O
+course	O
+of	O
+events	O
+,	O
+we	O
+discuss	O
+the	O
+role	O
+of	O
+paradoxical	O
+coronary	O
+spasm	B
+and	O
+hypotension	B
+-	O
+mediated	O
+myocardial	B
+ischemia	I
+occurring	O
+downstream	O
+to	O
+significant	O
+coronary	B
+arterial	I
+stenosis	I
+in	O
+the	O
+pathophysiology	O
+of	O
+acute	B
+coronary	I
+insufficiency	I
+.	O
+
+Comparison	O
+of	O
+the	O
+respiratory	O
+effects	O
+of	O
+i	O
+.	O
+v	O
+.	O
+infusions	O
+of	O
+morphine	O
+and	O
+regional	O
+analgesia	O
+by	O
+extradural	O
+block	O
+.	O
+
+The	O
+incidence	O
+of	O
+postoperative	O
+respiratory	O
+apnoea	B
+was	O
+compared	O
+between	O
+five	O
+patients	O
+receiving	O
+a	O
+continuous	O
+i	O
+.	O
+v	O
+.	O
+infusion	O
+of	O
+morphine	O
+(	O
+mean	O
+73	O
+.	O
+6	O
+mg	O
+)	O
+and	O
+five	O
+patients	O
+receiving	O
+a	O
+continuous	O
+extradural	O
+infusion	O
+of	O
+0	O
+.	O
+25	O
+%	O
+bupivacaine	O
+(	O
+mean	O
+192	O
+mg	O
+)	O
+in	O
+the	O
+24	O
+-	O
+h	O
+period	O
+following	O
+upper	O
+abdominal	O
+surgery	O
+.	O
+
+Monitoring	O
+consisted	O
+of	O
+airflow	O
+detection	O
+by	O
+a	O
+carbon	O
+dioxide	O
+analyser	O
+,	O
+chest	O
+wall	O
+movement	O
+detected	O
+by	O
+pneumatic	O
+capsules	O
+,	O
+and	O
+continuous	O
+electrocardiograph	O
+recorded	O
+with	O
+a	O
+Holter	O
+ambulatory	O
+monitor	O
+.	O
+
+Both	O
+obstructive	B
+(	I
+P	I
+less	I
+than	I
+0	I
+.	I
+05	I
+)	I
+and	I
+central	I
+apnoea	I
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+occurred	O
+more	O
+frequently	O
+in	O
+patients	O
+who	O
+had	O
+a	O
+morphine	O
+infusion	O
+.	O
+
+There	O
+was	O
+also	O
+a	O
+higher	O
+incidence	O
+of	O
+tachyarrhythmias	B
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+and	O
+ventricular	B
+ectopic	I
+beats	I
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+in	O
+the	O
+morphine	O
+infusion	O
+group	O
+.	O
+
+Effects	O
+of	O
+aminophylline	O
+on	O
+the	O
+threshold	O
+for	O
+initiating	O
+ventricular	B
+fibrillation	I
+during	O
+respiratory	B
+failure	I
+.	O
+
+Cardiac	B
+arrhythmias	I
+have	O
+frequently	O
+been	O
+reported	O
+in	O
+association	O
+with	O
+respiratory	B
+failure	I
+.	O
+
+The	O
+possible	O
+additive	O
+role	O
+of	O
+pharmacologic	O
+agents	O
+in	O
+precipitating	O
+cardiac	B
+disturbances	I
+in	O
+patients	O
+with	O
+respiratory	B
+failure	I
+has	O
+only	O
+recently	O
+been	O
+emphasized	O
+.	O
+
+The	O
+effects	O
+of	O
+aminophylline	O
+on	O
+the	O
+ventricular	B
+fibrillation	I
+threshold	O
+during	O
+normal	O
+acid	O
+-	O
+base	O
+conditions	O
+and	O
+during	O
+respiratory	B
+failure	I
+were	O
+studied	O
+in	O
+anesthetized	O
+open	O
+chest	O
+dogs	O
+.	O
+
+The	O
+ventricular	B
+fibrillation	I
+threshold	O
+was	O
+measured	O
+by	O
+passing	O
+a	O
+gated	O
+train	O
+of	O
+12	O
+constant	O
+current	O
+pulses	O
+through	O
+the	O
+ventricular	O
+myocardium	O
+during	O
+the	O
+vulnerable	O
+period	O
+of	O
+the	O
+cardiac	O
+cycle	O
+.	O
+
+During	O
+the	O
+infusion	O
+of	O
+aminophylline	O
+,	O
+the	O
+ventricular	B
+fibrillation	I
+threshold	O
+was	O
+reduced	O
+by	O
+30	O
+to	O
+40	O
+percent	O
+of	O
+the	O
+control	O
+when	O
+pH	O
+and	O
+partial	O
+pressures	O
+of	O
+oxygen	O
+(	O
+PO2	O
+)	O
+and	O
+carbon	O
+dioxide	O
+(	O
+CO2	O
+)	O
+were	O
+kept	O
+within	O
+normal	O
+limits	O
+.	O
+
+When	O
+respiratory	B
+failure	I
+was	O
+produced	O
+by	O
+hypoventilation	B
+(	O
+pH	O
+7	O
+.	O
+05	O
+to	O
+7	O
+.	O
+25	O
+;	O
+PC02	O
+70	O
+to	O
+100	O
+mm	O
+Hg	O
+:	O
+P02	O
+20	O
+to	O
+40	O
+mm	O
+Hg	O
+)	O
+,	O
+infusion	O
+of	O
+aminophylline	O
+resulted	O
+in	O
+an	O
+even	O
+greater	O
+decrease	O
+in	O
+ventricular	B
+fibrillation	I
+threshold	O
+to	O
+60	O
+percent	O
+of	O
+the	O
+control	O
+level	O
+.	O
+
+These	O
+experiments	O
+suggest	O
+that	O
+although	O
+many	O
+factors	O
+may	O
+contribute	O
+to	O
+the	O
+increased	O
+incidence	O
+of	O
+ventricular	B
+arrhythmias	I
+in	O
+respiratory	B
+failure	I
+,	O
+pharmacologic	O
+agents	O
+,	O
+particularly	O
+aminophylline	O
+,	O
+may	O
+play	O
+a	O
+significant	O
+role	O
+.	O
+
+Pentoxifylline	O
+(	O
+Trental	O
+)	O
+does	O
+not	O
+inhibit	O
+dipyridamole	O
+-	O
+induced	O
+coronary	O
+hyperemia	B
+:	O
+implications	O
+for	O
+dipyridamole	O
+-	O
+thallium	O
+-	O
+201	O
+myocardial	O
+imaging	O
+.	O
+
+Dipyridamole	O
+-	O
+thallium	O
+-	O
+201	O
+imaging	O
+is	O
+often	O
+performed	O
+in	O
+patients	O
+unable	O
+to	O
+exercise	O
+because	O
+of	O
+peripheral	B
+vascular	I
+disease	I
+.	O
+
+Many	O
+of	O
+these	O
+patients	O
+are	O
+taking	O
+pentoxifylline	O
+(	O
+Trental	O
+)	O
+,	O
+a	O
+methylxanthine	O
+derivative	O
+which	O
+may	O
+improve	O
+intermittent	B
+claudication	I
+.	O
+
+Whether	O
+pentoxifylline	O
+inhibits	O
+dipyridamole	O
+-	O
+induced	O
+coronary	O
+hyperemia	B
+like	O
+other	O
+methylxanthines	O
+such	O
+as	O
+theophylline	O
+and	O
+should	O
+be	O
+stopped	O
+prior	O
+to	O
+dipyridamole	O
+-	O
+thallium	O
+-	O
+201	O
+imaging	O
+is	O
+unknown	O
+.	O
+
+Therefore	O
+,	O
+we	O
+studied	O
+the	O
+hyperemic	O
+response	O
+to	O
+dipyridamole	O
+in	O
+seven	O
+open	O
+-	O
+chest	O
+anesthetized	O
+dogs	O
+after	O
+pretreatment	O
+with	O
+either	O
+pentoxifylline	O
+(	O
+0	O
+,	O
+7	O
+.	O
+5	O
+,	O
+or	O
+15	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+or	O
+theophylline	O
+(	O
+3	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+.	O
+
+Baseline	O
+circumflex	O
+coronary	O
+blood	O
+flows	O
+did	O
+not	O
+differ	O
+significantly	O
+among	O
+treatment	O
+groups	O
+.	O
+
+Dipyridamole	O
+significantly	O
+increased	O
+coronary	O
+blood	O
+flow	O
+before	O
+and	O
+after	O
+7	O
+.	O
+5	O
+or	O
+15	O
+mm	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+pentoxifylline	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+002	O
+)	O
+.	O
+
+Neither	O
+dose	O
+of	O
+pentoxifylline	O
+significantly	O
+decreased	O
+the	O
+dipyridamole	O
+-	O
+induced	O
+hyperemia	B
+,	O
+while	O
+peak	O
+coronary	O
+blood	O
+flow	O
+was	O
+significantly	O
+lower	O
+after	O
+theophylline	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+We	O
+conclude	O
+that	O
+pentoxyifylline	O
+does	O
+not	O
+inhibit	O
+dipyridamole	O
+-	O
+induced	O
+coronary	O
+hyperemia	B
+even	O
+at	O
+high	O
+doses	O
+.	O
+
+Cause	O
+of	O
+death	B
+among	O
+patients	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+:	O
+a	O
+rare	O
+mortality	O
+due	O
+to	O
+cerebral	B
+haemorrhage	I
+.	O
+
+Causes	O
+of	O
+death	B
+,	O
+with	O
+special	O
+reference	O
+to	O
+cerebral	B
+haemorrhage	I
+,	O
+among	O
+240	O
+patients	O
+with	O
+pathologically	O
+verified	O
+Parkinson	B
+'	I
+s	I
+disease	I
+were	O
+investigated	O
+using	O
+the	O
+Annuals	O
+of	O
+the	O
+Pathological	O
+Autopsy	O
+Cases	O
+in	O
+Japan	O
+from	O
+1981	O
+to	O
+1985	O
+.	O
+
+The	O
+leading	O
+causes	O
+of	O
+death	B
+were	O
+pneumonia	B
+and	O
+bronchitis	B
+(	O
+44	O
+.	O
+1	O
+%	O
+)	O
+,	O
+malignant	O
+neoplasms	B
+(	O
+11	O
+.	O
+6	O
+%	O
+)	O
+,	O
+heart	B
+diseases	I
+(	O
+4	O
+.	O
+1	O
+%	O
+)	O
+,	O
+cerebral	B
+infarction	I
+(	O
+3	O
+.	O
+7	O
+%	O
+)	O
+and	O
+septicaemia	B
+(	O
+3	O
+.	O
+3	O
+%	O
+)	O
+.	O
+
+Cerebral	B
+haemorrhage	I
+was	O
+the	O
+11th	O
+most	O
+frequent	O
+cause	O
+of	O
+death	B
+,	O
+accounting	O
+for	O
+only	O
+0	O
+.	O
+8	O
+%	O
+of	O
+deaths	B
+among	O
+the	O
+patients	O
+,	O
+whereas	O
+it	O
+was	O
+the	O
+5th	O
+most	O
+common	O
+cause	O
+of	O
+death	B
+among	O
+the	O
+Japanese	O
+general	O
+population	O
+in	O
+1985	O
+.	O
+
+The	O
+low	O
+incidence	O
+of	O
+cerebral	B
+haemorrhage	I
+as	O
+a	O
+cause	O
+of	O
+death	B
+in	O
+patients	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+may	O
+reflect	O
+the	O
+hypotensive	B
+effect	O
+of	O
+levodopa	O
+and	O
+a	O
+hypotensive	B
+mechanism	O
+due	O
+to	O
+reduced	O
+noradrenaline	O
+levels	O
+in	O
+the	O
+parkinsonian	B
+brain	O
+.	O
+
+Possible	O
+intramuscular	O
+midazolam	O
+-	O
+associated	O
+cardiorespiratory	B
+arrest	I
+and	O
+death	B
+.	O
+
+Midazolam	O
+hydrochloride	O
+is	O
+commonly	O
+used	O
+for	O
+dental	O
+or	O
+endoscopic	O
+procedures	O
+.	O
+
+Although	O
+generally	O
+consisted	O
+safe	O
+when	O
+given	O
+intramuscularly	O
+,	O
+intravenous	O
+administration	O
+is	O
+known	O
+to	O
+cause	O
+respiratory	B
+and	I
+cardiovascular	I
+depression	I
+.	O
+
+This	O
+report	O
+describes	O
+the	O
+first	O
+published	O
+case	O
+of	O
+cardiorespiratory	B
+arrest	I
+and	O
+death	B
+associated	O
+with	O
+intramuscular	O
+administration	O
+of	O
+midazolam	O
+.	O
+
+Information	O
+regarding	O
+midazolam	O
+use	O
+is	O
+reviewed	O
+to	O
+provide	O
+recommendation	O
+for	O
+safe	O
+administration	O
+.	O
+
+Myasthenia	B
+gravis	I
+presenting	O
+as	O
+weakness	O
+after	O
+magnesium	O
+administration	O
+.	O
+
+We	O
+studied	O
+a	O
+patient	O
+with	O
+no	O
+prior	O
+history	O
+of	O
+neuromuscular	B
+disease	I
+who	O
+became	O
+virtually	O
+quadriplegic	B
+after	O
+parenteral	O
+magnesium	O
+administration	O
+for	O
+preeclampsia	B
+.	O
+
+The	O
+serum	O
+magnesium	O
+concentration	O
+was	O
+3	O
+.	O
+0	O
+mEq	O
+/	O
+L	O
+,	O
+which	O
+is	O
+usually	O
+well	O
+tolerated	O
+.	O
+
+The	O
+magnesium	O
+was	O
+stopped	O
+and	O
+she	O
+recovered	O
+over	O
+a	O
+few	O
+days	O
+.	O
+
+While	O
+she	O
+was	O
+weak	O
+,	O
+2	O
+-	O
+Hz	O
+repetitive	O
+stimulation	O
+revealed	O
+a	O
+decrement	O
+without	O
+significant	O
+facilitation	O
+at	O
+rapid	O
+rates	O
+or	O
+after	O
+exercise	O
+,	O
+suggesting	O
+postsynaptic	B
+neuromuscular	I
+blockade	I
+.	O
+
+After	O
+her	O
+strength	O
+returned	O
+,	O
+repetitive	O
+stimulation	O
+was	O
+normal	O
+,	O
+but	O
+single	O
+fiber	O
+EMG	O
+revealed	O
+increased	O
+jitter	O
+and	O
+blocking	O
+.	O
+
+Her	O
+acetylcholine	O
+receptor	O
+antibody	O
+level	O
+was	O
+markedly	O
+elevated	O
+.	O
+
+Although	O
+paralysis	B
+after	O
+magnesium	O
+administration	O
+has	O
+been	O
+described	O
+in	O
+patients	O
+with	O
+known	O
+myasthenia	B
+gravis	I
+,	O
+it	O
+has	O
+not	O
+previously	O
+been	O
+reported	O
+to	O
+be	O
+the	O
+initial	O
+or	O
+only	O
+manifestation	O
+of	O
+the	O
+disease	O
+.	O
+
+Patients	O
+who	O
+are	O
+unusually	O
+sensitive	O
+to	O
+the	O
+neuromuscular	O
+effects	O
+of	O
+magnesium	O
+should	O
+be	O
+suspected	O
+of	O
+having	O
+an	O
+underlying	O
+disorder	B
+of	I
+neuromuscular	I
+transmission	I
+.	O
+
+No	O
+enhancement	O
+by	O
+phenobarbital	O
+of	O
+the	O
+hepatocarcinogenicity	O
+of	O
+a	O
+choline	O
+-	O
+devoid	O
+diet	O
+in	O
+the	O
+rat	O
+.	O
+
+An	O
+experiment	O
+was	O
+performed	O
+to	O
+test	O
+whether	O
+inclusion	O
+of	O
+phenobarbital	O
+in	O
+a	O
+choline	O
+-	O
+devoid	O
+diet	O
+would	O
+increase	O
+the	O
+hepatocarcinogenicity	O
+of	O
+the	O
+diet	O
+.	O
+
+Groups	O
+of	O
+5	O
+-	O
+week	O
+old	O
+male	O
+Fischer	O
+-	O
+344	O
+rats	O
+were	O
+fed	O
+for	O
+7	O
+-	O
+25	O
+months	O
+semipurified	O
+choline	O
+-	O
+devoid	O
+or	O
+choline	O
+-	O
+supplemented	O
+diets	O
+,	O
+containing	O
+or	O
+not	O
+0	O
+.	O
+06	O
+%	O
+phenobarbital	O
+.	O
+
+No	O
+hepatic	O
+preneoplastic	O
+nodules	O
+or	O
+hepatocellular	B
+carcinomas	I
+developed	O
+in	O
+rats	O
+fed	O
+the	O
+plain	O
+choline	O
+-	O
+supplemented	O
+diet	O
+,	O
+while	O
+one	O
+preneoplastic	O
+nodule	O
+and	O
+one	O
+hepatocellular	B
+carcinoma	I
+developed	O
+in	O
+two	O
+rats	O
+fed	O
+the	O
+same	O
+diet	O
+containing	O
+phenobarbital	O
+.	O
+
+The	O
+incidence	O
+of	O
+preneoplastic	O
+nodules	O
+and	O
+of	O
+hepatocellular	B
+carcinomas	I
+was	O
+10	O
+%	O
+and	O
+37	O
+%	O
+,	O
+respectively	O
+,	O
+in	O
+rats	O
+fed	O
+the	O
+plain	O
+choline	O
+-	O
+devoid	O
+diet	O
+,	O
+and	O
+17	O
+%	O
+and	O
+30	O
+%	O
+,	O
+in	O
+rats	O
+fed	O
+the	O
+phenobarbital	O
+-	O
+containing	O
+choline	O
+-	O
+devoid	O
+diet	O
+.	O
+
+The	O
+results	O
+evinced	O
+no	O
+enhancement	O
+of	O
+the	O
+hepatocarcinogenicity	O
+of	O
+the	O
+choline	O
+-	O
+devoid	O
+diet	O
+by	O
+phenobarbital	O
+.	O
+
+Sporadic	O
+neoplastic	O
+lesions	O
+were	O
+observed	O
+in	O
+organs	O
+other	O
+than	O
+the	O
+liver	O
+of	O
+some	O
+of	O
+the	O
+animals	O
+,	O
+irrespective	O
+of	O
+the	O
+diet	O
+fed	O
+.	O
+
+On	O
+two	O
+paradoxical	O
+side	O
+-	O
+effects	O
+of	O
+prednisolone	O
+in	O
+rats	O
+,	O
+ribosomal	O
+RNA	O
+biosyntheses	O
+,	O
+and	O
+a	O
+mechanism	O
+of	O
+action	O
+.	O
+
+Liver	B
+enlargement	I
+and	O
+muscle	B
+wastage	I
+occurred	O
+in	O
+Wistar	O
+rats	O
+following	O
+the	O
+subcutaneous	O
+administration	O
+of	O
+prednisolone	O
+.	O
+
+In	O
+the	O
+liver	O
+both	O
+the	O
+content	O
+of	O
+RNA	O
+and	O
+the	O
+biosynthesis	O
+of	O
+ribosomal	O
+RNA	O
+increased	O
+while	O
+both	O
+the	O
+RNA	O
+content	O
+and	O
+ribosomal	O
+RNA	O
+biosynthesis	O
+were	O
+reduced	O
+in	O
+the	O
+gastrocnemius	O
+muscle	O
+.	O
+
+It	O
+is	O
+suggested	O
+that	O
+the	O
+drug	O
+acted	O
+in	O
+a	O
+selective	O
+and	O
+tissue	O
+-	O
+specific	O
+manner	O
+to	O
+enhance	O
+ribosomal	O
+RNA	O
+synthesis	O
+in	O
+the	O
+liver	O
+and	O
+depress	O
+such	O
+synthesis	O
+in	O
+the	O
+muscle	O
+.	O
+
+This	O
+view	O
+supports	O
+the	O
+contention	O
+that	O
+the	O
+liver	O
+and	O
+muscle	O
+are	O
+independent	O
+sites	O
+of	O
+prednisolone	O
+action	O
+.	O
+
+Differential	O
+effects	O
+of	O
+gamma	O
+-	O
+hexachlorocyclohexane	O
+(	O
+lindane	O
+)	O
+on	O
+pharmacologically	O
+-	O
+induced	O
+seizures	B
+.	O
+
+Gamma	O
+-	O
+hexachlorocyclohexane	O
+(	O
+gamma	O
+-	O
+HCH	O
+)	O
+,	O
+the	O
+active	O
+ingredient	O
+of	O
+the	O
+insecticide	O
+lindane	O
+,	O
+has	O
+been	O
+shown	O
+to	O
+decrease	O
+seizure	B
+threshold	O
+to	O
+pentylenetrazol	O
+(	O
+PTZ	O
+)	O
+3	O
+h	O
+after	O
+exposure	O
+to	O
+gamma	O
+-	O
+HCH	O
+and	O
+conversely	O
+increase	O
+threshold	O
+to	O
+PTZ	O
+-	O
+induced	O
+seizures	B
+24	O
+h	O
+after	O
+exposure	O
+to	O
+gamma	O
+-	O
+HCH	O
+(	O
+Vohland	O
+et	O
+al	O
+.	O
+1981	O
+)	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+the	O
+severity	O
+of	O
+response	O
+to	O
+other	O
+seizure	B
+-	O
+inducing	O
+agents	O
+was	O
+tested	O
+in	O
+mice	O
+1	O
+and	O
+24	O
+h	O
+after	O
+intraperitoneal	O
+administration	O
+of	O
+80	O
+mg	O
+/	O
+kg	O
+gamma	O
+-	O
+HCH	O
+.	O
+
+One	O
+hour	O
+after	O
+the	O
+administration	O
+of	O
+gamma	O
+-	O
+HCH	O
+,	O
+the	O
+activity	O
+of	O
+seizure	B
+-	O
+inducing	O
+agents	O
+was	O
+increased	O
+,	O
+regardless	O
+of	O
+their	O
+mechanism	O
+,	O
+while	O
+24	O
+h	O
+after	O
+gamma	O
+-	O
+HCH	O
+a	O
+differential	O
+response	O
+was	O
+observed	O
+.	O
+
+Seizure	B
+activity	O
+due	O
+to	O
+PTZ	O
+and	O
+picrotoxin	O
+(	O
+PTX	O
+)	O
+was	O
+significantly	O
+decreased	O
+;	O
+however	O
+,	O
+seizure	B
+activity	O
+due	O
+to	O
+3	O
+-	O
+mercaptopropionic	O
+acid	O
+(	O
+MPA	O
+)	O
+,	O
+bicuculline	O
+(	O
+BCC	O
+)	O
+,	O
+methyl	O
+6	O
+,	O
+7	O
+-	O
+dimethoxy	O
+-	O
+4	O
+-	O
+ethyl	O
+-	O
+B	O
+-	O
+carboline	O
+-	O
+3	O
+-	O
+carboxylate	O
+(	O
+DMCM	O
+)	O
+,	O
+or	O
+strychnine	O
+(	O
+STR	O
+)	O
+was	O
+not	O
+different	O
+from	O
+control	O
+.	O
+
+In	O
+vitro	O
+,	O
+gamma	O
+-	O
+HCH	O
+,	O
+pentylenetetrazol	O
+and	O
+picrotoxin	O
+were	O
+shown	O
+to	O
+inhibit	O
+3H	O
+-	O
+TBOB	O
+binding	O
+in	O
+mouse	O
+whole	O
+brain	O
+,	O
+with	O
+IC50	O
+values	O
+of	O
+4	O
+.	O
+6	O
+,	O
+404	O
+and	O
+9	O
+.	O
+4	O
+microM	O
+,	O
+respectively	O
+.	O
+
+MPA	O
+,	O
+BCC	O
+,	O
+DMCM	O
+,	O
+and	O
+STR	O
+showed	O
+no	O
+inhibition	O
+of	O
+3H	O
+-	O
+TBOB	O
+(	O
+t	O
+-	O
+butyl	O
+bicyclo	O
+-	O
+orthobenzoate	O
+)	O
+binding	O
+at	O
+concentrations	O
+of	O
+100	O
+micron	O
+.	O
+
+The	O
+pharmacological	O
+challenge	O
+data	O
+suggest	O
+that	O
+tolerance	O
+may	O
+occur	O
+to	O
+seizure	B
+activity	O
+induced	O
+by	O
+PTZ	O
+and	O
+PTX	O
+24	O
+h	O
+after	O
+gamma	O
+-	O
+HCH	O
+,	O
+since	O
+the	O
+response	O
+to	O
+only	O
+these	O
+two	O
+seizure	B
+-	O
+inducing	O
+agents	O
+is	O
+decreased	O
+.	O
+
+The	O
+in	O
+vitro	O
+data	O
+suggest	O
+that	O
+the	O
+site	O
+responsible	O
+for	O
+the	O
+decrease	O
+in	O
+seizure	B
+activity	O
+24	O
+h	O
+after	O
+gamma	O
+-	O
+HCH	O
+may	O
+be	O
+the	O
+GABA	O
+-	O
+A	O
+receptor	O
+-	O
+linked	O
+chloride	O
+channel	O
+.	O
+
+Tolerance	O
+and	O
+antiviral	O
+effect	O
+of	O
+ribavirin	O
+in	O
+patients	O
+with	O
+Argentine	B
+hemorrhagic	I
+fever	I
+.	O
+
+Tolerance	O
+and	O
+antiviral	O
+effect	O
+of	O
+ribavirin	O
+was	O
+studied	O
+in	O
+6	O
+patients	O
+with	O
+Argentine	B
+hemorrhagic	I
+fever	I
+(	O
+AHF	B
+)	O
+of	O
+more	O
+than	O
+8	O
+days	O
+of	O
+evolution	O
+.	O
+
+Administration	O
+of	O
+ribavirin	O
+resulted	O
+in	O
+a	O
+neutralization	O
+of	O
+viremia	B
+and	O
+a	O
+drop	O
+of	O
+endogenous	O
+interferon	O
+titers	O
+.	O
+
+The	O
+average	O
+time	O
+of	O
+death	B
+was	O
+delayed	O
+.	O
+
+A	O
+reversible	O
+anemia	B
+was	O
+the	O
+only	O
+adverse	O
+effect	O
+observed	O
+.	O
+
+From	O
+these	O
+results	O
+,	O
+we	O
+conclude	O
+that	O
+ribavirin	O
+has	O
+an	O
+antiviral	O
+effect	O
+in	O
+advanced	O
+cases	O
+of	O
+AHF	B
+,	O
+and	O
+that	O
+anemia	B
+,	O
+the	O
+only	O
+secondary	O
+reaction	O
+observed	O
+,	O
+can	O
+be	O
+easily	O
+managed	O
+.	O
+
+The	O
+possible	O
+beneficial	O
+effect	O
+of	O
+ribavirin	O
+during	O
+the	O
+initial	O
+days	O
+of	O
+AHF	B
+is	O
+discussed	O
+.	O
+
+Is	O
+the	O
+treatment	O
+of	O
+scabies	B
+hazardous	O
+?	O
+
+Treatment	O
+for	O
+scabies	B
+is	O
+usually	O
+initiated	O
+by	O
+general	O
+practitioners	O
+;	O
+most	O
+consider	O
+lindane	O
+(	O
+gamma	O
+benzene	O
+hexachloride	O
+)	O
+the	O
+treatment	O
+of	O
+choice	O
+.	O
+
+Lindane	O
+is	O
+also	O
+widely	O
+used	O
+as	O
+an	O
+agricultural	O
+and	O
+industrial	O
+pesticide	O
+,	O
+and	O
+as	O
+a	O
+result	O
+the	O
+toxic	O
+profile	O
+of	O
+this	O
+insecticide	O
+is	O
+well	O
+understood	O
+.	O
+
+Evidence	O
+is	O
+accumulating	O
+that	O
+lindane	O
+can	O
+be	O
+toxic	B
+to	I
+the	I
+central	I
+nervous	I
+system	I
+and	O
+may	O
+be	O
+associated	O
+with	O
+aplastic	B
+anaemia	I
+.	O
+
+Preparations	O
+containing	O
+lindane	O
+continue	O
+to	O
+be	O
+sold	O
+over	O
+the	O
+counter	O
+and	O
+may	O
+represent	O
+a	O
+hazard	O
+to	O
+poorly	O
+informed	O
+patients	O
+.	O
+
+This	O
+literature	O
+review	O
+suggests	O
+that	O
+general	O
+practitioners	O
+should	O
+prescribe	O
+scabicides	O
+with	O
+increased	O
+caution	O
+for	O
+certain	O
+at	O
+-	O
+risk	O
+groups	O
+,	O
+and	O
+give	O
+adequate	O
+warnings	O
+regarding	O
+potential	O
+toxicity	B
+.	O
+
+Mouse	O
+strain	O
+-	O
+dependent	O
+effect	O
+of	O
+amantadine	O
+on	O
+motility	O
+and	O
+brain	O
+biogenic	O
+amines	O
+.	O
+
+The	O
+effect	O
+of	O
+amantadine	O
+hydrochloride	O
+,	O
+injected	O
+i	O
+.	O
+p	O
+.	O
+in	O
+6	O
+increments	O
+of	O
+100	O
+mg	O
+/	O
+kg	O
+each	O
+over	O
+30	O
+hr	O
+,	O
+on	O
+mouse	O
+motility	O
+and	O
+whole	O
+brain	O
+content	O
+of	O
+selected	O
+biogenic	O
+amines	O
+and	O
+major	O
+metabolites	O
+was	O
+studied	O
+in	O
+4	O
+strains	O
+of	O
+mice	O
+.	O
+
+These	O
+were	O
+the	O
+albino	O
+Sprague	O
+-	O
+Dawley	O
+ICR	O
+and	O
+BALB	O
+/	O
+C	O
+,	O
+the	O
+black	O
+C57BL	O
+/	O
+6	O
+and	O
+the	O
+brown	O
+CDF	O
+-	O
+I	O
+mouse	O
+strains	O
+.	O
+
+Amantadine	O
+treatment	O
+produced	O
+a	O
+biphasic	O
+effect	O
+on	O
+mouse	O
+motility	O
+.	O
+
+The	O
+initial	O
+dose	O
+of	O
+amantadine	O
+depressed	B
+locomotor	O
+activity	O
+in	O
+all	O
+mouse	O
+strains	O
+studied	O
+with	O
+the	O
+BALB	O
+/	O
+C	O
+mice	O
+being	O
+the	O
+most	O
+sensitive	O
+.	O
+
+Subsequent	O
+amantadine	O
+treatments	O
+produced	O
+enhancement	O
+of	O
+motility	O
+from	O
+corresponding	O
+control	O
+in	O
+all	O
+mouse	O
+strains	O
+with	O
+the	O
+BALB	O
+/	O
+C	O
+mice	O
+being	O
+the	O
+least	O
+sensitive	O
+.	O
+
+The	O
+locomotor	O
+activity	O
+was	O
+decreased	O
+from	O
+corresponding	O
+controls	O
+in	O
+all	O
+strains	O
+studied	O
+,	O
+except	O
+for	O
+the	O
+ICR	O
+mice	O
+,	O
+during	O
+an	O
+overnight	O
+drug	O
+-	O
+free	O
+period	O
+following	O
+the	O
+fourth	O
+amantadine	O
+treatment	O
+.	O
+
+Readministration	O
+of	O
+amantadine	O
+,	O
+after	O
+a	O
+drug	O
+-	O
+free	O
+overnight	O
+period	O
+,	O
+increased	O
+motility	O
+from	O
+respective	O
+saline	O
+control	O
+in	O
+all	O
+strains	O
+with	O
+exception	O
+of	O
+the	O
+BALB	O
+/	O
+C	O
+mice	O
+where	O
+suppression	B
+of	I
+motility	I
+occurred	O
+.	O
+
+Treatment	O
+with	O
+amantadine	O
+did	O
+not	O
+alter	O
+whole	O
+brain	O
+dopamine	O
+levels	O
+but	O
+decreased	O
+the	O
+amounts	O
+of	O
+3	O
+,	O
+4	O
+-	O
+dihydroxyphenylacetic	O
+acid	O
+in	O
+the	O
+BALB	O
+/	O
+C	O
+mice	O
+compared	O
+to	O
+saline	O
+control	O
+.	O
+
+Conversely	O
+,	O
+brain	O
+normetanephrine	O
+concentration	O
+was	O
+increased	O
+from	O
+saline	O
+control	O
+by	O
+amantadine	O
+in	O
+the	O
+BALB	O
+/	O
+C	O
+mice	O
+.	O
+
+The	O
+results	O
+suggest	O
+a	O
+strain	O
+-	O
+dependent	O
+effect	O
+of	O
+amantadine	O
+on	O
+motility	O
+and	O
+indicate	O
+a	O
+differential	O
+response	O
+to	O
+the	O
+acute	O
+and	O
+multiple	O
+dose	O
+regimens	O
+used	O
+.	O
+
+The	O
+BALB	O
+/	O
+C	O
+mouse	O
+was	O
+the	O
+most	O
+sensitive	O
+strain	O
+and	O
+could	O
+serve	O
+as	O
+the	O
+strain	O
+of	O
+choice	O
+for	O
+evaluating	O
+the	O
+side	O
+effects	O
+of	O
+amantadine	O
+.	O
+
+The	O
+biochemical	O
+results	O
+of	O
+brain	O
+biogenic	O
+amines	O
+of	O
+BALB	O
+/	O
+C	O
+mouse	O
+strain	O
+suggest	O
+a	O
+probable	O
+decrease	O
+of	O
+catecholamine	O
+turnover	O
+rate	O
+and	O
+/	O
+or	O
+metabolism	O
+by	O
+monoamine	O
+oxidase	O
+and	O
+a	O
+resulting	O
+increase	O
+in	O
+O	O
+-	O
+methylation	O
+of	O
+norepinephrine	O
+which	O
+may	O
+account	O
+for	O
+a	O
+behavioral	B
+depression	I
+caused	O
+by	O
+amantadine	O
+in	O
+the	O
+BALB	O
+/	O
+C	O
+mice	O
+.	O
+
+Chloroacetaldehyde	O
+and	O
+its	O
+contribution	O
+to	O
+urotoxicity	O
+during	O
+treatment	O
+with	O
+cyclophosphamide	O
+or	O
+ifosfamide	O
+.	O
+
+An	O
+experimental	O
+study	O
+/	O
+short	O
+communication	O
+.	O
+
+Based	O
+on	O
+clinical	O
+data	O
+,	O
+indicating	O
+that	O
+chloroacetaldehyde	O
+(	O
+CAA	O
+)	O
+is	O
+an	O
+important	O
+metabolite	O
+of	O
+oxazaphosphorine	O
+cytostatics	O
+,	O
+an	O
+experimental	O
+study	O
+was	O
+carried	O
+out	O
+in	O
+order	O
+to	O
+elucidate	O
+the	O
+role	O
+of	O
+CAA	O
+in	O
+the	O
+development	O
+of	O
+hemorrhagic	B
+cystitis	I
+.	O
+
+The	O
+data	O
+demonstrate	O
+that	O
+CAA	O
+after	O
+i	O
+.	O
+v	O
+.	O
+administration	O
+does	O
+not	O
+contribute	O
+to	O
+bladder	B
+damage	I
+.	O
+
+When	O
+instilled	O
+directly	O
+into	O
+the	O
+bladder	O
+,	O
+CAA	O
+exerts	O
+urotoxic	O
+effects	O
+,	O
+it	O
+is	O
+,	O
+however	O
+,	O
+susceptible	O
+to	O
+detoxification	O
+with	O
+mesna	O
+.	O
+
+Source	O
+of	O
+pain	B
+and	O
+primitive	O
+dysfunction	O
+in	O
+migraine	B
+:	O
+an	O
+identical	O
+site	O
+?	O
+
+Twenty	O
+common	O
+migraine	B
+patients	O
+received	O
+a	O
+one	O
+sided	O
+frontotemporal	O
+application	O
+of	O
+nitroglycerin	O
+(	O
+10	O
+patients	O
+)	O
+or	O
+placebo	O
+ointment	O
+(	O
+10	O
+patients	O
+)	O
+in	O
+a	O
+double	O
+blind	O
+study	O
+.	O
+
+Early	O
+onset	O
+migraine	B
+attacks	O
+were	O
+induced	O
+by	O
+nitroglycerin	O
+in	O
+seven	O
+out	O
+of	O
+10	O
+patients	O
+versus	O
+no	O
+patient	O
+in	O
+the	O
+placebo	O
+group	O
+.	O
+
+Subsequently	O
+20	O
+migraine	B
+patients	O
+,	O
+who	O
+developed	O
+an	O
+early	O
+onset	O
+attack	O
+with	O
+frontotemporal	O
+nitroglycerin	O
+,	O
+received	O
+the	O
+drug	O
+in	O
+a	O
+second	O
+induction	O
+test	O
+at	O
+other	O
+body	O
+areas	O
+.	O
+
+No	O
+early	O
+onset	O
+migraine	B
+was	O
+observed	O
+.	O
+
+Thus	O
+the	O
+migraine	B
+-	O
+inducing	O
+effect	O
+of	O
+nitroglycerin	O
+seems	O
+to	O
+depend	O
+on	O
+direct	O
+stimulation	O
+of	O
+the	O
+habitual	O
+site	O
+of	O
+pain	B
+,	O
+suggesting	O
+that	O
+the	O
+frontotemporal	O
+region	O
+is	O
+of	O
+crucial	O
+importance	O
+in	O
+the	O
+development	O
+of	O
+a	O
+migraine	B
+crisis	O
+.	O
+
+This	O
+is	O
+not	O
+consistent	O
+with	O
+a	O
+CNS	O
+origin	O
+of	O
+migraine	B
+attack	O
+.	O
+
+Hypersensitivity	B
+to	O
+carbamazepine	O
+presenting	O
+with	O
+a	O
+leukemoid	B
+reaction	I
+,	O
+eosinophilia	B
+,	O
+erythroderma	B
+,	O
+and	O
+renal	B
+failure	I
+.	O
+
+We	O
+report	O
+a	O
+patient	O
+in	O
+whom	O
+hypersensitivity	B
+to	O
+carbamazepine	O
+presented	O
+with	O
+generalized	O
+erythroderma	B
+,	O
+a	O
+severe	O
+leukemoid	B
+reaction	I
+,	O
+eosinophilia	B
+,	O
+hyponatremia	B
+,	O
+and	O
+renal	B
+failure	I
+.	O
+
+This	O
+is	O
+the	O
+first	O
+report	O
+of	O
+such	O
+an	O
+unusual	O
+reaction	O
+to	O
+carbamazepine	O
+.	O
+
+Fluoxetine	O
+-	O
+induced	O
+akathisia	B
+:	O
+clinical	O
+and	O
+theoretical	O
+implications	O
+.	O
+
+Five	O
+patients	O
+receiving	O
+fluoxetine	O
+for	O
+the	O
+treatment	O
+of	O
+obsessive	B
+compulsive	I
+disorder	I
+or	O
+major	B
+depression	I
+developed	O
+akathisia	B
+.	O
+
+The	O
+typical	O
+fluoxetine	O
+-	O
+induced	O
+symptoms	O
+of	O
+restlessness	O
+,	O
+constant	O
+pacing	O
+,	O
+purposeless	O
+movements	O
+of	O
+the	O
+feet	O
+and	O
+legs	O
+,	O
+and	O
+marked	O
+anxiety	B
+were	O
+indistinguishable	O
+from	O
+those	O
+of	O
+neuroleptic	O
+-	O
+induced	O
+akathisia	B
+.	O
+
+Three	O
+patients	O
+who	O
+had	O
+experienced	O
+neuroleptic	O
+-	O
+induced	O
+akathisia	B
+in	O
+the	O
+past	O
+reported	O
+that	O
+the	O
+symptoms	O
+of	O
+fluoxetine	O
+-	O
+induced	O
+akathisia	B
+were	O
+identical	O
+,	O
+although	O
+somewhat	O
+milder	O
+.	O
+
+Akathisia	B
+appeared	O
+to	O
+be	O
+a	O
+common	O
+side	O
+effect	O
+of	O
+fluoxetine	O
+and	O
+generally	O
+responded	O
+well	O
+to	O
+treatment	O
+with	O
+the	O
+beta	O
+-	O
+adrenergic	O
+antagonist	O
+propranolol	O
+,	O
+dose	O
+reduction	O
+,	O
+or	O
+both	O
+.	O
+
+The	O
+authors	O
+suggest	O
+that	O
+fluoxetine	O
+-	O
+induced	O
+akathisia	B
+may	O
+be	O
+caused	O
+by	O
+serotonergically	O
+mediated	O
+inhibition	O
+of	O
+dopaminergic	O
+neurotransmission	O
+and	O
+that	O
+the	O
+pathophysiology	O
+of	O
+fluoxetine	O
+-	O
+induced	O
+akathisia	B
+and	O
+tricyclic	O
+antidepressant	O
+-	O
+induced	O
+"	O
+jitteriness	O
+"	O
+may	O
+be	O
+identical	O
+.	O
+
+Effect	O
+of	O
+converting	O
+enzyme	O
+inhibition	O
+on	O
+the	O
+course	O
+of	O
+adriamycin	O
+-	O
+induced	O
+nephropathy	B
+.	O
+
+The	O
+effect	O
+of	O
+the	O
+converting	O
+enzyme	O
+inhibitor	O
+(	O
+CEI	O
+)	O
+enalapril	O
+was	O
+assessed	O
+in	O
+Munich	O
+-	O
+Wistar	O
+rats	O
+with	O
+established	O
+adriamycin	O
+nephrosis	B
+.	O
+
+Rats	O
+were	O
+given	O
+a	O
+single	O
+dose	O
+of	O
+adriamycin	O
+and	O
+one	O
+month	O
+later	O
+divided	O
+into	O
+four	O
+groups	O
+matched	O
+for	O
+albuminuria	B
+,	O
+blood	O
+pressure	O
+,	O
+and	O
+plasma	O
+albumin	O
+concentration	O
+.	O
+
+Groups	O
+1	O
+and	O
+3	O
+remained	O
+untreated	O
+while	O
+groups	O
+2	O
+and	O
+4	O
+received	O
+enalapril	O
+.	O
+
+Groups	O
+1	O
+and	O
+2	O
+underwent	O
+micropuncture	O
+studies	O
+after	O
+10	O
+days	O
+.	O
+
+These	O
+short	O
+-	O
+term	O
+studies	O
+showed	O
+that	O
+enalapril	O
+reduced	O
+arterial	O
+blood	O
+pressure	O
+(	O
+101	O
++	O
+/	O
+-	O
+2	O
+vs	O
+.	O
+124	O
++	O
+/	O
+-	O
+3	O
+mm	O
+Hg	O
+,	O
+group	O
+2	O
+vs	O
+.	O
+1	O
+,	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+and	O
+glomerular	O
+capillary	O
+pressure	O
+(	O
+54	O
++	O
+/	O
+-	O
+1	O
+vs	O
+.	O
+61	O
++	O
+/	O
+-	O
+2	O
+mm	O
+Hg	O
+,	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+without	O
+reducing	O
+albuminuria	B
+(	O
+617	O
++	O
+/	O
+-	O
+50	O
+vs	O
+.	O
+570	O
++	O
+/	O
+-	O
+47	O
+mg	O
+/	O
+day	O
+)	O
+or	O
+GFR	O
+(	O
+1	O
+.	O
+03	O
++	O
+/	O
+-	O
+0	O
+.	O
+04	O
+vs	O
+.	O
+1	O
+.	O
+04	O
++	O
+/	O
+-	O
+0	O
+.	O
+11	O
+ml	O
+/	O
+min	O
+)	O
+.	O
+
+Groups	O
+3	O
+and	O
+4	O
+were	O
+studied	O
+at	O
+four	O
+and	O
+at	O
+six	O
+months	O
+to	O
+assess	O
+the	O
+effect	O
+of	O
+enalapril	O
+on	O
+progression	O
+of	O
+renal	B
+injury	I
+in	O
+adriamycin	O
+nephrosis	B
+.	O
+
+Chronic	O
+enalapril	O
+treatment	O
+reduced	O
+blood	O
+pressure	O
+without	O
+reducing	O
+albuminuria	B
+in	O
+group	O
+4	O
+.	O
+
+Untreated	O
+group	O
+3	O
+rats	O
+exhibited	O
+a	O
+progressive	O
+reduction	O
+in	O
+GFR	O
+(	O
+0	O
+.	O
+35	O
++	O
+/	O
+-	O
+0	O
+.	O
+08	O
+ml	O
+/	O
+min	O
+at	O
+4	O
+months	O
+,	O
+0	O
+.	O
+27	O
++	O
+/	O
+-	O
+0	O
+.	O
+07	O
+ml	O
+/	O
+min	O
+at	O
+6	O
+months	O
+)	O
+.	O
+
+Enalapril	O
+treatment	O
+blunted	O
+but	O
+did	O
+not	O
+prevent	O
+reduction	O
+in	O
+GFR	O
+in	O
+group	O
+4	O
+(	O
+0	O
+.	O
+86	O
++	O
+/	O
+-	O
+0	O
+.	O
+15	O
+ml	O
+/	O
+min	O
+at	O
+4	O
+months	O
+,	O
+0	O
+.	O
+69	O
++	O
+/	O
+-	O
+0	O
+.	O
+13	O
+ml	O
+/	O
+min	O
+at	O
+6	O
+months	O
+,	O
+both	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+vs	O
+.	O
+group	O
+3	O
+)	O
+.	O
+
+Reduction	O
+in	O
+GFR	O
+was	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+glomerular	B
+sclerosis	I
+in	O
+both	O
+treated	O
+and	O
+untreated	O
+rats	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Clotiazepam	O
+-	O
+induced	O
+acute	O
+hepatitis	B
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+patient	O
+who	O
+developed	O
+acute	O
+hepatitis	B
+with	O
+extensive	B
+hepatocellular	I
+necrosis	I
+,	O
+7	O
+months	O
+after	O
+the	O
+onset	O
+of	O
+administration	O
+of	O
+clotiazepam	O
+,	O
+a	O
+thienodiazepine	O
+derivative	O
+.	O
+
+Clotiazepam	O
+withdrawal	O
+was	O
+followed	O
+by	O
+prompt	O
+recovery	O
+.	O
+
+The	O
+administration	O
+of	O
+several	O
+benzodiazepines	O
+,	O
+chemically	O
+related	O
+to	O
+clotiazepam	O
+,	O
+did	O
+not	O
+interfere	O
+with	O
+recovery	O
+and	O
+did	O
+not	O
+induce	O
+any	O
+relapse	O
+of	O
+hepatitis	B
+.	O
+
+This	O
+observation	O
+shows	O
+that	O
+clotiazepam	O
+can	O
+induce	O
+acute	O
+hepatitis	B
+and	O
+suggests	O
+that	O
+there	O
+is	O
+no	O
+cross	O
+hepatotoxicity	B
+between	O
+clotiazepam	O
+and	O
+several	O
+benzodiazepines	O
+.	O
+
+5	O
+-	O
+azacytidine	O
+potentiates	O
+initiation	B
+induced	I
+by	I
+carcinogens	I
+in	O
+rat	O
+liver	O
+.	O
+
+To	O
+test	O
+the	O
+validity	O
+of	O
+the	O
+hypothesis	O
+that	O
+hypomethylation	O
+of	O
+DNA	O
+plays	O
+an	O
+important	O
+role	O
+in	O
+the	O
+initiation	B
+of	I
+carcinogenic	I
+process	I
+,	O
+5	O
+-	O
+azacytidine	O
+(	O
+5	O
+-	O
+AzC	O
+)	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+an	O
+inhibitor	O
+of	O
+DNA	O
+methylation	O
+,	O
+was	O
+given	O
+to	O
+rats	O
+during	O
+the	O
+phase	O
+of	O
+repair	O
+synthesis	O
+induced	O
+by	O
+the	O
+three	O
+carcinogens	O
+,	O
+benzo	O
+[	O
+a	O
+]	O
+-	O
+pyrene	O
+(	O
+200	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+N	O
+-	O
+methyl	O
+-	O
+N	O
+-	O
+nitrosourea	O
+(	O
+60	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+1	O
+,	O
+2	O
+-	O
+dimethylhydrazine	O
+(	O
+1	O
+,	O
+2	O
+-	O
+DMH	O
+)	O
+(	O
+100	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+The	O
+initiated	O
+hepatocytes	O
+in	O
+the	O
+liver	O
+were	O
+assayed	O
+as	O
+the	O
+gamma	O
+-	O
+glutamyltransferase	O
+(	O
+gamma	O
+-	O
+GT	O
+)	O
+positive	O
+foci	O
+formed	O
+following	O
+a	O
+2	O
+-	O
+week	O
+selection	O
+regimen	O
+consisting	O
+of	O
+dietary	O
+0	O
+.	O
+02	O
+%	O
+2	O
+-	O
+acetylaminofluorene	O
+coupled	O
+with	O
+a	O
+necrogenic	O
+dose	O
+of	O
+CCl4	O
+.	O
+
+The	O
+results	O
+obtained	O
+indicate	O
+that	O
+with	O
+all	O
+three	O
+carcinogens	O
+,	O
+administration	O
+of	O
+5	O
+-	O
+AzC	O
+during	O
+repair	O
+synthesis	O
+increased	O
+the	O
+incidence	O
+of	O
+initiated	O
+hepatocytes	O
+,	O
+for	O
+example	O
+10	O
+-	O
+20	O
+foci	O
+/	O
+cm2	O
+in	O
+5	O
+-	O
+AzC	O
+and	O
+carcinogen	O
+-	O
+treated	O
+rats	O
+compared	O
+with	O
+3	O
+-	O
+5	O
+foci	O
+/	O
+cm2	O
+in	O
+rats	O
+treated	O
+with	O
+carcinogen	O
+only	O
+.	O
+
+Administration	O
+of	O
+[	O
+3H	O
+]	O
+-	O
+5	O
+-	O
+azadeoxycytidine	O
+during	O
+the	O
+repair	O
+synthesis	O
+induced	O
+by	O
+1	O
+,	O
+2	O
+-	O
+DMH	O
+further	O
+showed	O
+that	O
+0	O
+.	O
+019	O
+mol	O
+%	O
+of	O
+cytosine	O
+residues	O
+in	O
+DNA	O
+were	O
+substituted	O
+by	O
+the	O
+analogue	O
+,	O
+indicating	O
+that	O
+incorporation	O
+of	O
+5	O
+-	O
+AzC	O
+occurs	O
+during	O
+repair	O
+synthesis	O
+.	O
+
+In	O
+the	O
+absence	O
+of	O
+the	O
+carcinogen	O
+,	O
+5	O
+-	O
+AzC	O
+given	O
+after	O
+a	O
+two	O
+thirds	O
+partial	O
+hepatectomy	O
+,	O
+when	O
+its	O
+incorporation	O
+should	O
+be	O
+maximum	O
+,	O
+failed	O
+to	O
+induce	O
+any	O
+gamma	O
+-	O
+GT	O
+positive	O
+foci	O
+.	O
+
+The	O
+results	O
+suggest	O
+that	O
+hypomethylation	O
+of	O
+DNA	O
+per	O
+se	O
+may	O
+not	O
+be	O
+sufficient	O
+for	O
+initiation	O
+.	O
+
+Perhaps	O
+two	O
+events	O
+might	O
+be	O
+necessary	O
+for	O
+initiation	O
+,	O
+the	O
+first	O
+caused	O
+by	O
+the	O
+carcinogen	O
+and	O
+a	O
+second	O
+involving	O
+hypomethylation	O
+of	O
+DNA	O
+.	O
+
+Antihypertensive	O
+drugs	O
+and	O
+depression	B
+:	O
+a	O
+reappraisal	O
+.	O
+
+Eighty	O
+-	O
+nine	O
+new	O
+referral	O
+hypertensive	B
+out	O
+-	O
+patients	O
+and	O
+46	O
+new	O
+referral	O
+non	O
+-	O
+hypertensive	B
+chronically	O
+physically	O
+ill	O
+out	O
+-	O
+patients	O
+completed	O
+a	O
+mood	O
+rating	O
+scale	O
+at	O
+regular	O
+intervals	O
+for	O
+one	O
+year	O
+.	O
+
+The	O
+results	O
+showed	O
+a	O
+high	O
+prevalence	O
+of	O
+depression	B
+in	O
+both	O
+groups	O
+of	O
+patients	O
+,	O
+with	O
+no	O
+preponderance	O
+in	O
+the	O
+hypertensive	B
+group	O
+.	O
+
+Hypertensive	B
+patients	O
+with	O
+psychiatric	B
+histories	O
+had	O
+a	O
+higher	O
+prevalence	O
+of	O
+depression	B
+than	O
+the	O
+comparison	O
+patients	O
+.	O
+
+This	O
+was	O
+accounted	O
+for	O
+by	O
+a	O
+significant	O
+number	O
+of	O
+depressions	B
+occurring	O
+in	O
+methyl	O
+dopa	O
+treated	O
+patients	O
+with	O
+psychiatric	B
+histories	O
+.	O
+
+Chronic	B
+active	I
+hepatitis	I
+associated	O
+with	O
+diclofenac	O
+sodium	O
+therapy	O
+.	O
+
+Diclofenac	O
+sodium	O
+(	O
+Voltarol	O
+,	O
+Geigy	O
+Pharmaceuticals	O
+)	O
+is	O
+a	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+derivative	O
+of	O
+phenylacetic	O
+acid	O
+.	O
+
+Although	O
+generally	O
+well	O
+-	O
+tolerated	O
+,	O
+asymptomatic	O
+abnormalities	B
+of	I
+liver	I
+function	I
+have	O
+been	O
+recorded	O
+and	O
+,	O
+less	O
+commonly	O
+,	O
+severe	O
+hepatitis	B
+induced	O
+by	O
+diclofenac	O
+.	O
+
+The	O
+patient	O
+described	O
+developed	O
+chronic	B
+active	I
+hepatitis	I
+after	O
+six	O
+months	O
+therapy	O
+with	O
+diclofenac	O
+sodium	O
+which	O
+progressed	O
+despite	O
+the	O
+withdrawal	O
+of	O
+the	O
+drug	O
+,	O
+a	O
+finding	O
+not	O
+previously	O
+reported	O
+.	O
+
+Arterial	O
+hypertension	B
+as	O
+a	O
+complication	O
+of	O
+prolonged	O
+ketoconazole	O
+treatment	O
+.	O
+
+Two	O
+of	O
+14	O
+patients	O
+with	O
+Cushing	B
+'	I
+s	I
+syndrome	I
+treated	O
+on	O
+a	O
+long	O
+-	O
+term	O
+basis	O
+with	O
+ketoconazole	O
+developed	O
+sustained	O
+hypertension	B
+.	O
+
+In	O
+both	O
+cases	O
+normal	O
+plasma	O
+and	O
+urinary	O
+free	O
+cortisol	O
+levels	O
+had	O
+been	O
+achieved	O
+following	O
+ketoconazole	O
+therapy	O
+,	O
+yet	O
+continuous	O
+blood	O
+pressure	O
+monitoring	O
+demonstrated	O
+hypertension	B
+31	O
+(	O
+patient	O
+1	O
+)	O
+and	O
+52	O
+weeks	O
+(	O
+patient	O
+2	O
+)	O
+after	O
+treatment	O
+.	O
+
+In	O
+patient	O
+1	O
+,	O
+plasma	O
+levels	O
+of	O
+deoxycorticosterone	O
+and	O
+11	O
+-	O
+deoxycortisol	O
+were	O
+elevated	O
+.	O
+
+In	O
+patient	O
+2	O
+,	O
+in	O
+addition	O
+to	O
+an	O
+increase	O
+in	O
+both	O
+deoxycorticosterone	O
+and	O
+11	O
+-	O
+deoxycortisol	O
+levels	O
+,	O
+plasma	O
+aldosterone	O
+values	O
+were	O
+raised	O
+,	O
+with	O
+a	O
+concomitant	O
+suppression	O
+of	O
+renin	O
+levels	O
+.	O
+
+Our	O
+findings	O
+show	O
+that	O
+long	O
+-	O
+term	O
+treatment	O
+with	O
+high	O
+doses	O
+of	O
+ketoconazole	O
+may	O
+induce	O
+enzyme	O
+blockade	O
+leading	O
+to	O
+mineralocorticoid	O
+-	O
+related	O
+hypertension	B
+.	O
+
+Effects	O
+of	O
+an	O
+inhibitor	O
+of	O
+angiotensin	O
+converting	O
+enzyme	O
+(	O
+Captopril	O
+)	O
+on	O
+pulmonary	B
+and	I
+renal	I
+insufficiency	I
+due	O
+to	O
+intravascular	B
+coagulation	I
+in	O
+the	O
+rat	O
+.	O
+
+Induction	O
+of	O
+intravascular	B
+coagulation	I
+and	O
+inhibition	O
+of	O
+fibrinolysis	O
+by	O
+injection	O
+of	O
+thrombin	O
+and	O
+tranexamic	O
+acid	O
+(	O
+AMCA	O
+)	O
+in	O
+the	O
+rat	O
+gives	O
+rise	O
+to	O
+pulmonary	B
+and	I
+renal	I
+insufficiency	I
+resembling	O
+that	O
+occurring	O
+after	O
+trauma	B
+or	O
+sepsis	B
+in	O
+man	O
+.	O
+
+Injection	O
+of	O
+Captopril	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+an	O
+inhibitor	O
+of	O
+angiotensin	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+,	O
+reduced	O
+both	O
+pulmonary	B
+and	I
+renal	I
+insufficiency	I
+in	O
+this	O
+rat	O
+model	O
+.	O
+
+The	O
+lung	O
+weights	O
+were	O
+lower	O
+and	O
+PaO2	O
+was	O
+improved	O
+in	O
+rats	O
+given	O
+this	O
+enzyme	O
+-	O
+blocking	O
+agent	O
+.	O
+
+The	O
+contents	O
+of	O
+albumin	O
+in	O
+the	O
+lungs	O
+were	O
+not	O
+changed	O
+,	O
+indicating	O
+that	O
+Captopril	O
+did	O
+not	O
+influence	O
+the	O
+extravasation	O
+of	O
+protein	O
+.	O
+
+Renal	B
+damage	I
+as	O
+reflected	O
+by	O
+an	O
+increase	O
+in	O
+serum	O
+urea	O
+and	O
+in	O
+kidney	O
+weight	O
+was	O
+prevented	O
+by	O
+Captopril	O
+.	O
+
+The	O
+amount	O
+of	O
+fibrin	O
+in	O
+the	O
+kidneys	O
+was	O
+also	O
+considerably	O
+lower	O
+than	O
+in	O
+animals	O
+which	O
+received	O
+thrombin	O
+and	O
+AMCA	O
+alone	O
+.	O
+
+It	O
+is	O
+suggested	O
+that	O
+the	O
+effects	O
+of	O
+Captopril	O
+on	O
+the	O
+lungs	O
+may	O
+be	O
+attributable	O
+to	O
+a	O
+vasodilatory	O
+effect	O
+due	O
+to	O
+a	O
+reduction	O
+in	O
+the	O
+circulating	O
+level	O
+of	O
+Angiotension	O
+II	O
+and	O
+an	O
+increase	O
+in	O
+prostacyclin	O
+(	O
+secondary	O
+to	O
+an	O
+increase	O
+in	O
+bradykinin	O
+)	O
+.	O
+
+Captopril	O
+may	O
+,	O
+by	O
+the	O
+same	O
+mechanism	O
+,	O
+reduce	O
+the	O
+increase	O
+in	O
+glomerular	O
+filtration	O
+that	O
+is	O
+known	O
+to	O
+occur	O
+after	O
+an	O
+injection	O
+of	O
+thrombin	O
+,	O
+thereby	O
+diminishing	O
+the	O
+aggregation	O
+of	O
+fibrin	O
+monomers	O
+in	O
+the	O
+glomeruli	O
+,	O
+with	O
+the	O
+result	O
+that	O
+less	O
+fibrin	O
+will	O
+be	O
+deposited	O
+and	O
+thus	O
+less	O
+kidney	B
+damage	I
+will	O
+be	O
+produced	O
+.	O
+
+Stroke	B
+associated	O
+with	O
+cocaine	O
+use	O
+.	O
+
+We	O
+describe	O
+eight	O
+patients	O
+in	O
+whom	O
+cocaine	O
+use	O
+was	O
+related	O
+to	O
+stroke	B
+and	O
+review	O
+39	O
+cases	O
+from	O
+the	O
+literature	O
+.	O
+
+Among	O
+these	O
+47	O
+patients	O
+the	O
+mean	O
+(	O
++	O
+/	O
+-	O
+SD	O
+)	O
+age	O
+was	O
+32	O
+.	O
+5	O
++	O
+/	O
+-	O
+12	O
+.	O
+1	O
+years	O
+;	O
+76	O
+%	O
+(	O
+34	O
+/	O
+45	O
+)	O
+were	O
+men	O
+.	O
+
+Stroke	B
+followed	O
+cocaine	O
+use	O
+by	O
+inhalation	O
+,	O
+intranasal	O
+,	O
+intravenous	O
+,	O
+and	O
+intramuscular	O
+routes	O
+.	O
+
+Intracranial	B
+aneurysms	I
+or	O
+arteriovenous	B
+malformations	I
+were	O
+present	O
+in	O
+17	O
+of	O
+32	O
+patients	O
+studied	O
+angiographically	O
+or	O
+at	O
+autopsy	O
+;	O
+cerebral	B
+vasculitis	I
+was	O
+present	O
+in	O
+two	O
+patients	O
+.	O
+
+Cerebral	B
+infarction	I
+occurred	O
+in	O
+10	O
+patients	O
+(	O
+22	O
+%	O
+)	O
+,	O
+intracerebral	B
+hemorrhage	I
+in	O
+22	O
+(	O
+49	O
+%	O
+)	O
+,	O
+and	O
+subarachnoid	B
+hemorrhage	I
+in	O
+13	O
+(	O
+29	O
+%	O
+)	O
+.	O
+
+These	O
+data	O
+indicate	O
+that	O
+(	O
+1	O
+)	O
+the	O
+apparent	O
+incidence	O
+of	O
+stroke	B
+related	O
+to	O
+cocaine	O
+use	O
+is	O
+increasing	O
+;	O
+(	O
+2	O
+)	O
+cocaine	O
+-	O
+associated	O
+stroke	B
+occurs	O
+primarily	O
+in	O
+young	O
+adults	O
+;	O
+(	O
+3	O
+)	O
+stroke	B
+may	O
+follow	O
+any	O
+route	O
+of	O
+cocaine	O
+administration	O
+;	O
+(	O
+4	O
+)	O
+stroke	B
+after	O
+cocaine	O
+use	O
+is	O
+frequently	O
+associated	O
+with	O
+intracranial	B
+aneurysms	I
+and	O
+arteriovenous	B
+malformations	I
+;	O
+and	O
+(	O
+5	O
+)	O
+in	O
+cocaine	O
+-	O
+associated	O
+stroke	B
+,	O
+the	O
+frequency	O
+of	O
+intracranial	B
+hemorrhage	I
+exceeds	O
+that	O
+of	O
+cerebral	B
+infarction	I
+.	O
+
+A	O
+randomized	O
+comparison	O
+of	O
+labetalol	O
+and	O
+nitroprusside	O
+for	O
+induced	O
+hypotension	B
+.	O
+
+In	O
+a	O
+randomized	O
+study	O
+,	O
+labetalol	O
+-	O
+induced	O
+hypotension	B
+and	O
+nitroprusside	O
+-	O
+induced	O
+hypotension	B
+were	O
+compared	O
+in	O
+20	O
+patients	O
+(	O
+10	O
+in	O
+each	O
+group	O
+)	O
+scheduled	O
+for	O
+major	O
+orthopedic	O
+procedures	O
+.	O
+
+Each	O
+patient	O
+was	O
+subjected	O
+to	O
+an	O
+identical	O
+anesthetic	O
+protocol	O
+and	O
+similar	O
+drug	O
+-	O
+induced	O
+reductions	B
+in	I
+mean	I
+arterial	I
+blood	I
+pressure	I
+(	O
+BP	O
+)	O
+(	O
+50	O
+to	O
+55	O
+mmHg	O
+)	O
+.	O
+
+Nitroprusside	O
+infusion	O
+was	O
+associated	O
+with	O
+a	O
+significant	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+increase	B
+in	I
+heart	I
+rate	I
+and	I
+cardiac	I
+output	I
+;	O
+rebound	O
+hypertension	B
+was	O
+observed	O
+in	O
+three	O
+patients	O
+after	O
+discontinuation	O
+of	O
+nitroprusside	O
+.	O
+
+Labetalol	O
+administration	O
+was	O
+not	O
+associated	O
+with	O
+any	O
+of	O
+these	O
+findings	O
+.	O
+
+Arterial	O
+PO2	O
+decreased	O
+in	O
+both	O
+groups	O
+.	O
+
+It	O
+was	O
+concluded	O
+that	O
+labetalol	O
+offers	O
+advantages	O
+over	O
+nitroprusside	O
+.	O
+
+Sodium	O
+status	O
+influences	O
+chronic	O
+amphotericin	O
+B	O
+nephrotoxicity	B
+in	O
+rats	O
+.	O
+
+The	O
+nephrotoxic	B
+potential	O
+of	O
+amphotericin	O
+B	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+intraperitoneally	O
+for	O
+3	O
+weeks	O
+)	O
+has	O
+been	O
+investigated	O
+in	O
+salt	O
+-	O
+depleted	O
+,	O
+normal	O
+-	O
+salt	O
+,	O
+and	O
+salt	O
+-	O
+loaded	O
+rats	O
+.	O
+
+In	O
+salt	O
+-	O
+depleted	O
+rats	O
+,	O
+amphotericin	O
+B	O
+decreased	O
+creatinine	O
+clearance	O
+linearly	O
+with	O
+time	O
+,	O
+with	O
+an	O
+85	O
+%	O
+reduction	O
+by	O
+week	O
+3	O
+.	O
+
+In	O
+contrast	O
+,	O
+in	O
+normal	O
+-	O
+salt	O
+rats	O
+creatinine	O
+clearance	O
+was	O
+decreased	O
+but	O
+to	O
+a	O
+lesser	O
+extent	O
+at	O
+week	O
+2	O
+and	O
+3	O
+,	O
+and	O
+in	O
+salt	O
+-	O
+loaded	O
+rats	O
+creatinine	O
+clearance	O
+did	O
+not	O
+change	O
+for	O
+2	O
+weeks	O
+and	O
+was	O
+decreased	O
+by	O
+43	O
+%	O
+at	O
+week	O
+3	O
+.	O
+
+All	O
+rats	O
+in	O
+the	O
+sodium	O
+-	O
+depleted	O
+group	O
+had	O
+histopathological	O
+evidence	O
+of	O
+patchy	O
+tubular	O
+cytoplasmic	O
+degeneration	O
+in	O
+tubules	O
+that	O
+was	O
+not	O
+observed	O
+in	O
+any	O
+normal	O
+-	O
+salt	O
+or	O
+salt	O
+-	O
+loaded	O
+rat	O
+.	O
+
+Concentrations	O
+of	O
+amphotericin	O
+B	O
+in	O
+plasma	O
+were	O
+not	O
+significantly	O
+different	O
+among	O
+the	O
+three	O
+groups	O
+at	O
+any	O
+time	O
+during	O
+the	O
+study	O
+.	O
+
+However	O
+,	O
+at	O
+the	O
+end	O
+of	O
+3	O
+weeks	O
+,	O
+amphotericin	O
+B	O
+levels	O
+in	O
+the	O
+kidneys	O
+and	O
+liver	O
+were	O
+significantly	O
+higher	O
+in	O
+salt	O
+-	O
+depleted	O
+and	O
+normal	O
+-	O
+salt	O
+rats	O
+than	O
+those	O
+in	O
+salt	O
+-	O
+loaded	O
+rats	O
+,	O
+with	O
+plasma	O
+/	O
+kidney	O
+ratios	O
+of	O
+21	O
+,	O
+14	O
+,	O
+and	O
+8	O
+in	O
+salt	O
+-	O
+depleted	O
+,	O
+normal	O
+-	O
+salt	O
+,	O
+and	O
+salt	O
+-	O
+loaded	O
+rats	O
+,	O
+respectively	O
+.	O
+
+In	O
+conclusion	O
+,	O
+reductions	O
+in	O
+creatinine	O
+clearance	O
+and	O
+renal	O
+amphotericin	O
+B	O
+accumulation	O
+after	O
+chronic	O
+amphotericin	O
+B	O
+administration	O
+were	O
+enhanced	O
+by	O
+salt	O
+depletion	O
+and	O
+attenuated	O
+by	O
+sodium	O
+loading	O
+in	O
+rats	O
+.	O
+
+Flestolol	O
+:	O
+an	O
+ultra	O
+-	O
+short	O
+-	O
+acting	O
+beta	O
+-	O
+adrenergic	O
+blocking	O
+agent	O
+.	O
+
+Flestolol	O
+(	O
+ACC	O
+-	O
+9089	O
+)	O
+is	O
+a	O
+nonselective	O
+,	O
+competitive	O
+,	O
+ultra	O
+-	O
+short	O
+-	O
+acting	O
+beta	O
+-	O
+adrenergic	O
+blocking	O
+agent	O
+,	O
+without	O
+any	O
+intrinsic	O
+sympathomimetic	O
+activity	O
+.	O
+
+Flestolol	O
+is	O
+metabolized	O
+by	O
+plasma	O
+esterases	O
+and	O
+has	O
+an	O
+elimination	O
+half	O
+-	O
+life	O
+of	O
+approximately	O
+6	O
+.	O
+5	O
+minutes	O
+.	O
+
+This	O
+agent	O
+was	O
+well	O
+tolerated	O
+in	O
+healthy	O
+volunteers	O
+at	O
+doses	O
+up	O
+to	O
+100	O
+micrograms	O
+/	O
+kg	O
+/	O
+min	O
+.	O
+
+In	O
+long	O
+-	O
+term	O
+infusion	O
+studies	O
+,	O
+flestolol	O
+was	O
+well	O
+tolerated	O
+at	O
+the	O
+effective	O
+beta	O
+-	O
+blocking	O
+dose	O
+(	O
+5	O
+micrograms	O
+/	O
+kg	O
+/	O
+min	O
+)	O
+for	O
+up	O
+to	O
+seven	O
+days	O
+.	O
+
+Flestolol	O
+blood	O
+concentrations	O
+increased	O
+linearly	O
+with	O
+increasing	O
+dose	O
+and	O
+good	O
+correlation	O
+exists	O
+between	O
+blood	O
+concentrations	O
+of	O
+flestolol	O
+and	O
+beta	O
+-	O
+adrenergic	O
+blockade	O
+.	O
+
+Flestolol	O
+produced	O
+a	O
+dose	O
+-	O
+dependent	O
+attenuation	O
+of	O
+isoproterenol	O
+-	O
+induced	O
+tachycardia	B
+.	O
+
+Electrophysiologic	O
+and	O
+hemodynamic	O
+effects	O
+of	O
+flestolol	O
+are	O
+similar	O
+to	O
+those	O
+of	O
+other	O
+beta	O
+blockers	O
+.	O
+
+In	O
+contrast	O
+with	O
+other	O
+beta	O
+blockers	O
+,	O
+flestolol	O
+-	O
+induced	O
+effects	O
+reverse	O
+rapidly	O
+(	O
+within	O
+30	O
+minutes	O
+)	O
+following	O
+discontinuation	O
+because	O
+of	O
+its	O
+short	O
+half	O
+-	O
+life	O
+.	O
+
+Flestolol	O
+effectively	O
+reduced	O
+heart	O
+rate	O
+in	O
+patients	O
+with	O
+supraventricular	B
+tachyarrhythmia	I
+.	O
+
+In	O
+patients	O
+with	O
+unstable	B
+angina	I
+,	O
+flestolol	O
+infusion	O
+was	O
+found	O
+to	O
+be	O
+safe	O
+and	O
+effective	O
+in	O
+controlling	O
+chest	B
+pain	I
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+flestolol	O
+is	O
+a	O
+potent	O
+,	O
+well	O
+-	O
+tolerated	O
+,	O
+ultra	O
+-	O
+short	O
+-	O
+acting	O
+beta	O
+-	O
+adrenergic	O
+blocking	O
+agent	O
+.	O
+
+Use	O
+of	O
+flestolol	O
+in	O
+the	O
+critical	O
+care	O
+setting	O
+is	O
+currently	O
+undergoing	O
+investigation	O
+.	O
+
+Immunohistochemical	O
+,	O
+electron	O
+microscopic	O
+and	O
+morphometric	O
+studies	O
+of	O
+estrogen	O
+-	O
+induced	O
+rat	O
+prolactinomas	B
+after	O
+bromocriptine	O
+treatment	O
+.	O
+
+To	O
+clarify	O
+the	O
+effects	O
+of	O
+bromocriptine	O
+on	O
+prolactinoma	B
+cells	O
+in	O
+vivo	O
+,	O
+immunohistochemical	O
+,	O
+ultrastructural	O
+and	O
+morphometrical	O
+analyses	O
+were	O
+applied	O
+to	O
+estrogen	O
+-	O
+induced	O
+rat	O
+prolactinoma	B
+cells	O
+1	O
+h	O
+and	O
+6	O
+h	O
+after	O
+injection	O
+of	O
+bromocriptine	O
+(	O
+3	O
+mg	O
+/	O
+kg	O
+of	O
+body	O
+weight	O
+)	O
+.	O
+
+One	O
+h	O
+after	O
+treatment	O
+,	O
+serum	O
+prolactin	O
+levels	O
+decreased	O
+markedly	O
+.	O
+
+Electron	O
+microscopy	O
+disclosed	O
+many	O
+secretory	O
+granules	O
+,	O
+slightly	O
+distorted	O
+rough	O
+endoplasmic	O
+reticulum	O
+,	O
+and	O
+partially	O
+dilated	O
+Golgi	O
+cisternae	O
+in	O
+the	O
+prolactinoma	B
+cells	O
+.	O
+
+Morphometric	O
+analysis	O
+revealed	O
+that	O
+the	O
+volume	O
+density	O
+of	O
+secretory	O
+granules	O
+increased	O
+,	O
+while	O
+the	O
+volume	O
+density	O
+of	O
+cytoplasmic	O
+microtubules	O
+decreased	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+lowered	O
+serum	O
+prolactin	O
+levels	O
+in	O
+the	O
+early	O
+phase	O
+of	O
+bromocriptine	O
+treatment	O
+may	O
+result	O
+from	O
+an	O
+impaired	O
+secretion	O
+of	O
+prolactin	O
+due	O
+to	O
+decreasing	O
+numbers	O
+of	O
+cytoplasmic	O
+microtubules	O
+.	O
+
+At	O
+6	O
+h	O
+after	O
+injection	O
+,	O
+serum	O
+prolactin	O
+levels	O
+were	O
+still	O
+considerably	O
+lower	O
+than	O
+in	O
+controls	O
+.	O
+
+The	O
+prolactinoma	B
+cells	O
+at	O
+this	O
+time	O
+were	O
+well	O
+granulated	O
+,	O
+with	O
+vesiculated	O
+rough	O
+endoplasmic	O
+reticulum	O
+and	O
+markedly	O
+dilated	O
+Golgi	O
+cisternae	O
+.	O
+
+Electron	O
+microscopical	O
+immunohistochemistry	O
+revealed	O
+positive	O
+reaction	O
+products	O
+noted	O
+on	O
+the	O
+secretory	O
+granules	O
+,	O
+Golgi	O
+cisternae	O
+,	O
+and	O
+endoplasmic	O
+reticulum	O
+of	O
+the	O
+untreated	O
+rat	O
+prolactinoma	B
+cells	O
+.	O
+
+However	O
+,	O
+only	O
+secretory	O
+granules	O
+showed	O
+the	O
+positive	O
+reaction	O
+products	O
+for	O
+prolactin	O
+6	O
+h	O
+after	O
+bromocriptine	O
+treatment	O
+of	O
+the	O
+adenoma	B
+cells	O
+.	O
+
+An	O
+increase	O
+in	O
+the	O
+volume	O
+density	O
+of	O
+secretory	O
+granules	O
+and	O
+a	O
+decrease	O
+in	O
+the	O
+volume	O
+densities	O
+of	O
+rough	O
+endoplasmic	O
+reticulum	O
+and	O
+microtubules	O
+was	O
+determined	O
+by	O
+morphometric	O
+analysis	O
+,	O
+suggesting	O
+that	O
+bromocriptine	O
+inhibits	O
+protein	O
+synthesis	O
+as	O
+well	O
+as	O
+bringing	O
+about	O
+a	O
+disturbance	O
+of	O
+the	O
+prolactin	O
+secretion	O
+.	O
+
+Sulfasalazine	O
+-	O
+induced	O
+lupus	B
+erythematosus	I
+.	O
+
+Pneumonitis	B
+,	O
+bilateral	O
+pleural	B
+effusions	I
+,	O
+echocardiographic	O
+evidence	O
+of	O
+cardiac	B
+tamponade	I
+,	O
+and	O
+positive	O
+autoantibodies	O
+developed	O
+in	O
+a	O
+43	O
+-	O
+year	O
+-	O
+old	O
+man	O
+,	O
+who	O
+was	O
+receiving	O
+long	O
+-	O
+term	O
+sulfasalazine	O
+therapy	O
+for	O
+chronic	O
+ulcerative	B
+colitis	I
+.	O
+
+After	O
+cessation	O
+of	O
+the	O
+sulfasalazine	O
+and	O
+completion	O
+of	O
+a	O
+six	O
+-	O
+week	O
+course	O
+of	O
+corticosteroids	O
+,	O
+these	O
+problems	O
+resolved	O
+over	O
+a	O
+period	O
+of	O
+four	O
+to	O
+six	O
+months	O
+.	O
+
+It	O
+is	O
+suggested	O
+that	O
+the	O
+patient	O
+had	O
+sulfasalazine	O
+-	O
+induced	O
+lupus	B
+,	O
+which	O
+manifested	O
+with	O
+serositis	B
+and	O
+pulmonary	O
+parenchymal	O
+involvement	O
+in	O
+the	O
+absence	O
+of	O
+joint	O
+symptoms	O
+.	O
+
+Physicians	O
+who	O
+use	O
+sulfasalazine	O
+to	O
+treat	O
+patients	O
+with	O
+inflammatory	B
+bowel	I
+disease	I
+should	O
+be	O
+aware	O
+of	O
+the	O
+signs	O
+of	O
+sulfasalazine	O
+-	O
+induced	O
+lupus	B
+syndrome	I
+.	O
+
+Chronic	O
+carbamazepine	O
+treatment	O
+in	O
+the	O
+rat	O
+:	O
+efficacy	O
+,	O
+toxicity	B
+,	O
+and	O
+effect	O
+on	O
+plasma	O
+and	O
+tissue	O
+folate	O
+concentrations	O
+.	O
+
+Folate	O
+depletion	O
+has	O
+often	O
+been	O
+a	O
+problem	O
+in	O
+chronic	O
+antiepileptic	O
+drug	O
+(	O
+AED	O
+)	O
+therapy	O
+.	O
+
+Carbamazepine	O
+(	O
+CBZ	O
+)	O
+,	O
+a	O
+commonly	O
+used	O
+AED	O
+,	O
+has	O
+been	O
+implicated	O
+in	O
+some	O
+clinical	O
+studies	O
+.	O
+
+A	O
+rat	O
+model	O
+was	O
+developed	O
+to	O
+examine	O
+the	O
+effects	O
+of	O
+chronic	O
+CBZ	O
+treatment	O
+on	O
+folate	O
+concentrations	O
+in	O
+the	O
+rat	O
+.	O
+
+In	O
+the	O
+course	O
+of	O
+developing	O
+this	O
+model	O
+,	O
+a	O
+common	O
+vehicle	O
+,	O
+propylene	O
+glycol	O
+,	O
+by	O
+itself	O
+in	O
+high	O
+doses	O
+,	O
+was	O
+found	O
+to	O
+exhibit	O
+protective	O
+properties	O
+against	O
+induced	O
+seizures	B
+and	O
+inhibited	O
+weight	B
+gain	I
+.	O
+
+Seizures	B
+induced	O
+by	O
+hexafluorodiethyl	O
+ether	O
+(	O
+HFDE	O
+)	O
+were	O
+also	O
+found	O
+to	O
+be	O
+a	O
+more	O
+sensitive	O
+measure	O
+of	O
+protection	O
+by	O
+CBZ	O
+than	O
+seizures	B
+induced	O
+by	O
+maximal	O
+electroshock	O
+(	O
+MES	O
+)	O
+.	O
+
+Oral	O
+administration	O
+of	O
+CBZ	O
+as	O
+an	O
+aqueous	O
+suspension	O
+every	O
+8	O
+h	O
+at	O
+a	O
+dose	O
+of	O
+250	O
+mg	O
+/	O
+kg	O
+was	O
+continuously	O
+protective	O
+against	O
+HFDE	O
+-	O
+induced	O
+seizures	B
+and	O
+was	O
+minimally	O
+toxic	O
+as	O
+measured	O
+by	O
+weight	B
+gain	I
+over	O
+8	O
+weeks	O
+of	O
+treatment	O
+.	O
+
+The	O
+CBZ	O
+levels	O
+measured	O
+in	O
+plasma	O
+and	O
+brain	O
+of	O
+these	O
+animals	O
+,	O
+however	O
+,	O
+were	O
+below	O
+those	O
+normally	O
+considered	O
+protective	O
+.	O
+
+This	O
+treatment	O
+with	O
+CBZ	O
+had	O
+no	O
+apparent	O
+adverse	O
+effect	O
+on	O
+folate	O
+concentrations	O
+in	O
+the	O
+rat	O
+,	O
+and	O
+,	O
+indeed	O
+,	O
+the	O
+folate	O
+concentration	O
+increased	O
+in	O
+liver	O
+after	O
+6	O
+weeks	O
+of	O
+treatment	O
+and	O
+in	O
+plasma	O
+at	O
+8	O
+weeks	O
+of	O
+treatment	O
+.	O
+
+Dipyridamole	O
+-	O
+induced	O
+myocardial	B
+ischemia	I
+.	O
+
+Angina	B
+and	O
+ischemic	O
+electrocardiographic	O
+changes	O
+occurred	O
+after	O
+administration	O
+of	O
+oral	O
+dipyridamole	O
+in	O
+four	O
+patients	O
+awaiting	O
+urgent	O
+myocardial	O
+revascularization	O
+procedures	O
+.	O
+
+To	O
+our	O
+knowledge	O
+,	O
+this	O
+has	O
+not	O
+previously	O
+been	O
+reported	O
+as	O
+a	O
+side	O
+effect	O
+of	O
+preoperative	O
+dipyridamole	O
+therapy	O
+,	O
+although	O
+dipyridamole	O
+-	O
+induced	O
+myocardial	B
+ischemia	I
+has	O
+been	O
+demonstrated	O
+to	O
+occur	O
+in	O
+animals	O
+and	O
+humans	O
+with	O
+coronary	B
+artery	I
+disease	I
+.	O
+
+Epicardial	O
+coronary	O
+collateral	O
+vessels	O
+were	O
+demonstrated	O
+in	O
+all	O
+four	O
+patients	O
+;	O
+a	O
+coronary	O
+"	O
+steal	O
+"	O
+phenomenon	O
+may	O
+be	O
+the	O
+mechanism	O
+of	O
+the	O
+dipyridamole	O
+-	O
+induced	O
+ischemia	B
+observed	O
+.	O
+
+Inhibition	O
+of	O
+sympathoadrenal	O
+activity	O
+by	O
+atrial	O
+natriuretic	O
+factor	O
+in	O
+dogs	O
+.	O
+
+In	O
+six	O
+conscious	O
+,	O
+trained	O
+dogs	O
+,	O
+maintained	O
+on	O
+a	O
+normal	O
+sodium	O
+intake	O
+of	O
+2	O
+to	O
+4	O
+mEq	O
+/	O
+kg	O
+/	O
+day	O
+,	O
+sympathetic	O
+activity	O
+was	O
+assessed	O
+as	O
+the	O
+release	O
+rate	O
+of	O
+norepinephrine	O
+and	O
+epinephrine	O
+during	O
+15	O
+-	O
+minute	O
+i	O
+.	O
+v	O
+.	O
+infusions	O
+of	O
+human	O
+alpha	O
+-	O
+atrial	O
+natriuretic	O
+factor	O
+.	O
+
+Mean	O
+arterial	O
+pressure	O
+(	O
+as	O
+a	O
+percentage	O
+of	O
+control	O
++	O
+/	O
+-	O
+SEM	O
+)	O
+during	O
+randomized	O
+infusions	O
+of	O
+0	O
+.	O
+03	O
+,	O
+0	O
+.	O
+1	O
+,	O
+0	O
+.	O
+3	O
+,	O
+or	O
+1	O
+.	O
+0	O
+microgram	O
+/	O
+kg	O
+/	O
+min	O
+was	O
+99	O
++	O
+/	O
+-	O
+1	O
+,	O
+95	O
++	O
+/	O
+-	O
+1	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+,	O
+93	O
++	O
+/	O
+-	O
+1	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+,	O
+or	O
+79	O
++	O
+/	O
+-	O
+6	O
+%	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+,	O
+respectively	O
+,	O
+but	O
+no	O
+tachycardia	B
+and	O
+no	O
+augmentation	O
+of	O
+the	O
+norepinephrine	O
+release	O
+rate	O
+(	O
+up	O
+to	O
+0	O
+.	O
+3	O
+microgram	O
+/	O
+kg	O
+/	O
+min	O
+)	O
+were	O
+observed	O
+,	O
+which	O
+is	O
+in	O
+contrast	O
+to	O
+comparable	O
+hypotension	B
+induced	O
+by	O
+hydralazine	O
+or	O
+nitroglycerin	O
+.	O
+
+The	O
+release	O
+rate	O
+of	O
+epinephrine	O
+(	O
+control	O
+,	O
+6	O
+.	O
+7	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+ng	O
+/	O
+kg	O
+/	O
+min	O
+)	O
+declined	O
+immediately	O
+during	O
+infusions	O
+of	O
+atrial	O
+natriuretic	O
+factor	O
+to	O
+a	O
+minimum	O
+of	O
+49	O
++	O
+/	O
+-	O
+5	O
+%	O
+of	O
+control	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+during	O
+0	O
+.	O
+1	O
+microgram	O
+/	O
+kg	O
+/	O
+min	O
+and	O
+to	O
+63	O
++	O
+/	O
+-	O
+5	O
+%	O
+(	O
+0	O
+.	O
+1	O
+greater	O
+than	O
+p	O
+greater	O
+than	O
+0	O
+.	O
+05	O
+)	O
+or	O
+95	O
++	O
+/	O
+-	O
+13	O
+%	O
+(	O
+not	O
+significant	O
+)	O
+during	O
+0	O
+.	O
+3	O
+or	O
+1	O
+.	O
+0	O
+microgram	O
+/	O
+kg	O
+/	O
+min	O
+.	O
+
+Steady	O
+state	O
+arterial	O
+plasma	O
+concentrations	O
+of	O
+atrial	O
+natriuretic	O
+factor	O
+were	O
+39	O
++	O
+/	O
+-	O
+10	O
+pg	O
+/	O
+ml	O
+(	O
+n	O
+=	O
+6	O
+)	O
+during	O
+infusions	O
+of	O
+saline	O
+and	O
+284	O
++	O
+/	O
+-	O
+24	O
+pg	O
+/	O
+ml	O
+(	O
+n	O
+=	O
+6	O
+)	O
+and	O
+1520	O
++	O
+/	O
+-	O
+300	O
+pg	O
+/	O
+ml	O
+(	O
+n	O
+=	O
+9	O
+)	O
+during	O
+0	O
+.	O
+03	O
+and	O
+0	O
+.	O
+1	O
+microgram	O
+/	O
+kg	O
+/	O
+min	O
+infusions	O
+of	O
+the	O
+factor	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Inhibition	O
+of	O
+immunoreactive	O
+corticotropin	O
+-	O
+releasing	O
+factor	O
+secretion	O
+into	O
+the	O
+hypophysial	O
+-	O
+portal	O
+circulation	O
+by	O
+delayed	O
+glucocorticoid	O
+feedback	O
+.	O
+
+Nitroprusside	O
+-	O
+induced	O
+hypotension	B
+evokes	O
+ACTH	O
+secretion	O
+which	O
+is	O
+primarily	O
+mediated	O
+by	O
+enhanced	O
+secretion	O
+of	O
+immunoreactive	O
+corticotropin	O
+-	O
+releasing	O
+factor	O
+(	O
+irCRF	O
+)	O
+into	O
+the	O
+hypophysial	O
+-	O
+portal	O
+circulation	O
+.	O
+
+Portal	O
+plasma	O
+concentrations	O
+of	O
+neither	O
+arginine	O
+vasopressin	O
+nor	O
+oxytocin	O
+are	O
+significantly	O
+altered	O
+in	O
+this	O
+paradigm	O
+.	O
+
+Application	O
+of	O
+a	O
+delayed	O
+feedback	O
+signal	O
+,	O
+in	O
+the	O
+form	O
+of	O
+a	O
+2	O
+-	O
+h	O
+systemic	O
+corticosterone	O
+infusion	O
+in	O
+urethane	O
+-	O
+anesthetized	O
+rats	O
+with	O
+pharmacological	O
+blockade	O
+of	O
+glucocorticoid	O
+synthesis	O
+,	O
+is	O
+without	O
+effect	O
+on	O
+the	O
+resting	O
+secretion	O
+of	O
+arginine	O
+vasopressin	O
+and	O
+oxytocin	O
+at	O
+any	O
+corticosterone	O
+feedback	O
+dose	O
+tested	O
+.	O
+
+Resting	O
+irCRF	O
+levels	O
+are	O
+suppressed	O
+only	O
+at	O
+the	O
+highest	O
+corticosterone	O
+infusion	O
+rate	O
+,	O
+which	O
+resulted	O
+in	O
+systemic	O
+corticosterone	O
+levels	O
+of	O
+40	O
+micrograms	O
+/	O
+dl	O
+.	O
+
+Suppression	O
+of	O
+irCRF	O
+secretion	O
+in	O
+response	O
+to	O
+nitroprusside	O
+-	O
+induced	O
+hypotension	B
+is	O
+observed	O
+and	O
+occurs	O
+at	O
+a	O
+plasma	O
+corticosterone	O
+level	O
+between	O
+8	O
+-	O
+12	O
+micrograms	O
+/	O
+dl	O
+.	O
+
+These	O
+studies	O
+provide	O
+further	O
+evidence	O
+for	O
+a	O
+strong	O
+central	O
+component	O
+of	O
+the	O
+delayed	O
+feedback	O
+process	O
+which	O
+is	O
+mediated	O
+by	O
+modulation	O
+of	O
+irCRF	O
+release	O
+.	O
+
+Noradrenergic	O
+involvement	O
+in	O
+catalepsy	B
+induced	O
+by	O
+delta	O
+9	O
+-	O
+tetrahydrocannabinol	O
+.	O
+
+In	O
+order	O
+to	O
+elucidate	O
+the	O
+role	O
+of	O
+the	O
+catecholaminergic	O
+system	O
+in	O
+the	O
+cataleptogenic	O
+effect	O
+of	O
+delta	O
+9	O
+-	O
+tetrahydrocannabinol	O
+(	O
+THC	O
+)	O
+,	O
+the	O
+effect	O
+of	O
+pretreatment	O
+with	O
+6	O
+-	O
+hydroxydopamine	O
+(	O
+6	O
+-	O
+OHDA	O
+)	O
+or	O
+with	O
+desipramine	O
+and	O
+6	O
+-	O
+OHDA	O
+and	O
+lesions	O
+of	O
+the	O
+locus	O
+coeruleus	O
+were	O
+investigated	O
+in	O
+rats	O
+.	O
+
+The	O
+cataleptogenic	O
+effect	O
+of	O
+THC	O
+was	O
+significantly	O
+reduced	O
+in	O
+rats	O
+treated	O
+with	O
+6	O
+-	O
+OHDA	O
+and	O
+in	O
+rats	O
+with	O
+lesions	O
+of	O
+the	O
+locus	O
+coeruleus	O
+but	O
+not	O
+in	O
+rats	O
+treated	O
+with	O
+desipramine	O
+and	O
+6	O
+-	O
+OHDA	O
+,	O
+as	O
+compared	O
+with	O
+control	O
+rats	O
+.	O
+
+On	O
+the	O
+contrary	O
+,	O
+the	O
+cataleptogenic	O
+effect	O
+of	O
+haloperidol	O
+was	O
+significantly	O
+reduced	O
+in	O
+rats	O
+treated	O
+with	O
+desipramine	O
+and	O
+6	O
+-	O
+OHDA	O
+but	O
+not	O
+in	O
+rats	O
+treated	O
+with	O
+6	O
+-	O
+OHDA	O
+or	O
+in	O
+rats	O
+with	O
+lesions	O
+of	O
+the	O
+locus	O
+coeruleus	O
+.	O
+
+These	O
+results	O
+indicate	O
+that	O
+noradrenergic	O
+neurons	O
+have	O
+an	O
+important	O
+role	O
+in	O
+the	O
+manifestation	O
+of	O
+catalepsy	B
+induced	O
+by	O
+THC	O
+,	O
+whereas	O
+dopaminergic	O
+neurons	O
+are	O
+important	O
+in	O
+catalepsy	B
+induced	O
+by	O
+haloperidol	O
+.	O
+
+Reversibility	O
+of	O
+captopril	O
+-	O
+induced	O
+renal	B
+insufficiency	I
+after	O
+prolonged	O
+use	O
+in	O
+an	O
+unusual	O
+case	O
+of	O
+renovascular	B
+hypertension	I
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+severe	O
+hypertension	B
+with	O
+an	O
+occluded	O
+renal	O
+artery	O
+to	O
+a	O
+solitary	O
+kidney	O
+,	O
+who	O
+developed	O
+sudden	B
+deterioration	I
+of	I
+renal	I
+function	I
+following	O
+treatment	O
+with	O
+captopril	O
+.	O
+
+His	O
+renal	O
+function	O
+remained	O
+impaired	O
+but	O
+stable	O
+during	O
+2	O
+years	O
+'	O
+treatment	O
+with	O
+captopril	O
+but	O
+returned	O
+to	O
+pre	O
+-	O
+treatment	O
+levels	O
+soon	O
+after	O
+cessation	O
+of	O
+the	O
+drug	O
+.	O
+
+This	O
+indicates	O
+reversibility	O
+in	O
+captopril	O
+-	O
+induced	O
+renal	B
+failure	I
+even	O
+after	O
+its	O
+prolonged	O
+use	O
+and	O
+suggests	O
+that	O
+no	O
+organic	O
+damage	O
+occurs	O
+to	O
+glomerular	O
+arterioles	O
+following	O
+chronic	O
+ACE	O
+inhibition	O
+.	O
+
+HMG	O
+CoA	O
+reductase	O
+inhibitors	O
+.	O
+
+Current	O
+clinical	O
+experience	O
+.	O
+
+Lovastatin	O
+and	O
+simvastatin	O
+are	O
+the	O
+2	O
+best	O
+-	O
+known	O
+members	O
+of	O
+the	O
+class	O
+of	O
+hypolipidaemic	O
+agents	O
+known	O
+as	O
+HMG	O
+CoA	O
+reductase	O
+inhibitors	O
+.	O
+
+Clinical	O
+experience	O
+with	O
+lovastatin	O
+includes	O
+over	O
+5000	O
+patients	O
+,	O
+700	O
+of	O
+whom	O
+have	O
+been	O
+treated	O
+for	O
+2	O
+years	O
+or	O
+more	O
+,	O
+and	O
+experience	O
+with	O
+simvastatin	O
+includes	O
+over	O
+3500	O
+patients	O
+,	O
+of	O
+whom	O
+350	O
+have	O
+been	O
+treated	O
+for	O
+18	O
+months	O
+or	O
+more	O
+.	O
+
+Lovastatin	O
+has	O
+been	O
+marketed	O
+in	O
+the	O
+United	O
+States	O
+for	O
+over	O
+6	O
+months	O
+.	O
+
+Both	O
+agents	O
+show	O
+substantial	O
+clinical	O
+efficacy	O
+,	O
+with	O
+reductions	O
+in	O
+total	O
+cholesterol	O
+of	O
+over	O
+30	O
+%	O
+and	O
+in	O
+LDL	O
+-	O
+cholesterol	O
+of	O
+40	O
+%	O
+in	O
+clinical	O
+studies	O
+.	O
+
+Modest	O
+increases	O
+in	O
+HDL	O
+-	O
+cholesterol	O
+levels	O
+of	O
+about	O
+10	O
+%	O
+are	O
+also	O
+reported	O
+.	O
+
+Clinical	O
+tolerability	O
+of	O
+both	O
+agents	O
+has	O
+been	O
+good	O
+,	O
+with	O
+fewer	O
+than	O
+3	O
+%	O
+of	O
+patients	O
+withdrawn	O
+from	O
+treatment	O
+because	O
+of	O
+clinical	O
+adverse	O
+experiences	O
+.	O
+
+Ophthalmological	O
+examinations	O
+in	O
+over	O
+1100	O
+patients	O
+treated	O
+with	O
+one	O
+or	O
+the	O
+other	O
+agent	O
+have	O
+revealed	O
+no	O
+evidence	O
+of	O
+significant	O
+short	O
+term	O
+(	O
+up	O
+to	O
+2	O
+years	O
+)	O
+cataractogenic	O
+potential	O
+.	O
+
+One	O
+to	O
+2	O
+%	O
+of	O
+patients	O
+have	O
+elevations	O
+of	O
+serum	O
+transaminases	O
+to	O
+greater	O
+than	O
+3	O
+times	O
+the	O
+upper	O
+limit	O
+of	O
+normal	O
+.	O
+
+These	O
+episodes	O
+are	O
+asymptomatic	O
+and	O
+reversible	O
+when	O
+therapy	O
+is	O
+discontinued	O
+.	O
+
+Minor	O
+elevations	O
+of	O
+creatine	O
+kinase	O
+levels	O
+are	O
+reported	O
+in	O
+about	O
+5	O
+%	O
+of	O
+patients	O
+.	O
+
+Myopathy	B
+,	O
+associated	O
+in	O
+some	O
+cases	O
+with	O
+myoglobinuria	B
+,	O
+and	O
+in	O
+2	O
+cases	O
+with	O
+transient	O
+renal	B
+failure	I
+,	O
+has	O
+been	O
+rarely	O
+reported	O
+with	O
+lovastatin	O
+,	O
+especially	O
+in	O
+patients	O
+concomitantly	O
+treated	O
+with	O
+cyclosporin	O
+,	O
+gemfibrozil	O
+or	O
+niacin	O
+.	O
+
+Lovastatin	O
+and	O
+simvastatin	O
+are	O
+both	O
+effective	O
+and	O
+well	O
+-	O
+tolerated	O
+agents	O
+for	O
+lowering	O
+elevated	O
+levels	O
+of	O
+serum	O
+cholesterol	O
+.	O
+
+As	O
+wider	O
+use	O
+confirms	O
+their	O
+safety	O
+profile	O
+,	O
+they	O
+will	O
+gain	O
+increasing	O
+importance	O
+in	O
+the	O
+therapeutic	O
+approach	O
+to	O
+hypercholesterolaemia	B
+and	O
+its	O
+consequences	O
+.	O
+
+Hepatic	O
+reactions	O
+associated	O
+with	O
+ketoconazole	O
+in	O
+the	O
+United	O
+Kingdom	O
+.	O
+
+Ketoconazole	O
+was	O
+introduced	O
+in	O
+the	O
+United	O
+Kingdom	O
+in	O
+1981	O
+.	O
+
+By	O
+November	O
+1984	O
+the	O
+Committee	O
+on	O
+Safety	O
+of	O
+Medicines	O
+had	O
+received	O
+82	O
+reports	O
+of	O
+possible	O
+hepatotoxicity	B
+associated	O
+with	O
+the	O
+drug	O
+,	O
+including	O
+five	O
+deaths	B
+.	O
+
+An	O
+analysis	O
+of	O
+the	O
+75	O
+cases	O
+that	O
+had	O
+been	O
+adequately	O
+followed	O
+up	O
+suggested	O
+that	O
+16	O
+,	O
+including	O
+three	O
+deaths	B
+,	O
+were	O
+probably	O
+related	O
+to	O
+treatment	O
+with	O
+the	O
+drug	O
+.	O
+
+Of	O
+the	O
+remainder	O
+,	O
+48	O
+were	O
+possibly	O
+related	O
+to	O
+treatment	O
+,	O
+five	O
+were	O
+unlikely	O
+to	O
+be	O
+so	O
+,	O
+and	O
+six	O
+were	O
+unclassifiable	O
+.	O
+
+The	O
+mean	O
+age	O
+of	O
+patients	O
+in	O
+the	O
+16	O
+probable	O
+cases	O
+was	O
+57	O
+.	O
+9	O
+,	O
+with	O
+hepatotoxicity	B
+being	O
+more	O
+common	O
+in	O
+women	O
+.	O
+
+The	O
+average	O
+duration	O
+of	O
+treatment	O
+before	O
+the	O
+onset	O
+of	O
+jaundice	B
+was	O
+61	O
+days	O
+.	O
+
+None	O
+of	O
+these	O
+well	O
+validated	O
+cases	O
+occurred	O
+within	O
+the	O
+first	O
+10	O
+days	O
+after	O
+treatment	O
+.	O
+
+The	O
+results	O
+of	O
+serum	O
+liver	O
+function	O
+tests	O
+suggested	O
+hepatocellular	B
+injury	I
+in	O
+10	O
+(	O
+63	O
+%	O
+)	O
+;	O
+the	O
+rest	O
+showed	O
+a	O
+mixed	O
+pattern	O
+.	O
+
+In	O
+contrast	O
+,	O
+the	O
+results	O
+of	O
+histological	O
+examination	O
+of	O
+the	O
+liver	O
+often	O
+showed	O
+evidence	O
+of	O
+cholestasis	B
+.	O
+
+The	O
+characteristics	O
+of	O
+the	O
+48	O
+patients	O
+in	O
+the	O
+possible	O
+cases	O
+were	O
+similar	O
+.	O
+
+Allergic	O
+manifestations	O
+such	O
+as	O
+rash	B
+and	O
+eosinophilia	B
+were	O
+rare	O
+.	O
+
+Hepatitis	B
+was	O
+usually	O
+reversible	O
+when	O
+treatment	O
+was	O
+stopped	O
+,	O
+with	O
+the	O
+results	O
+of	O
+liver	O
+function	O
+tests	O
+returning	O
+to	O
+normal	O
+after	O
+an	O
+average	O
+of	O
+3	O
+.	O
+1	O
+months	O
+.	O
+
+In	O
+two	O
+of	O
+the	O
+three	O
+deaths	B
+probably	O
+associated	O
+with	O
+ketoconazole	O
+treatment	O
+the	O
+drug	O
+had	O
+been	O
+continued	O
+after	O
+the	O
+onset	O
+of	O
+jaundice	B
+and	O
+other	O
+symptoms	O
+of	O
+hepatitis	B
+.	O
+
+Clinical	O
+and	O
+biochemical	O
+monitoring	O
+at	O
+regular	O
+intervals	O
+for	O
+evidence	O
+of	O
+hepatitis	B
+is	O
+advised	O
+during	O
+long	O
+term	O
+treatment	O
+with	O
+ketoconazole	O
+to	O
+prevent	O
+possible	O
+serious	O
+hepatic	B
+injury	I
+.	O
+
+Glyburide	O
+-	O
+induced	O
+hepatitis	B
+.	O
+
+Drug	O
+-	O
+induced	O
+hepatotoxicity	B
+,	O
+although	O
+common	O
+,	O
+has	O
+been	O
+reported	O
+only	O
+infrequently	O
+with	O
+sulfonylureas	O
+.	O
+
+For	O
+glyburide	O
+,	O
+a	O
+second	O
+-	O
+generation	O
+sulfonylurea	O
+,	O
+only	O
+two	O
+brief	O
+reports	O
+of	O
+hepatotoxicity	B
+exist	O
+.	O
+
+Two	O
+patients	O
+with	O
+type	B
+II	I
+diabetes	I
+mellitus	I
+developed	O
+an	O
+acute	B
+hepatitis	I
+-	I
+like	I
+syndrome	I
+soon	O
+after	O
+initiation	O
+of	O
+glyburide	O
+therapy	O
+.	O
+
+There	O
+was	O
+no	O
+serologic	O
+evidence	O
+of	O
+viral	B
+infection	I
+,	O
+and	O
+a	O
+liver	O
+biopsy	O
+sample	O
+showed	O
+a	O
+histologic	O
+pattern	O
+consistent	O
+with	O
+drug	B
+-	I
+induced	I
+hepatitis	I
+.	O
+
+Both	O
+patients	O
+recovered	O
+quickly	O
+after	O
+stopping	O
+glyburide	O
+therapy	O
+and	O
+have	O
+remained	O
+well	O
+for	O
+a	O
+follow	O
+-	O
+up	O
+period	O
+of	O
+1	O
+year	O
+.	O
+
+Glyburide	O
+can	O
+produce	O
+an	O
+acute	B
+hepatitis	I
+-	I
+like	I
+illness	I
+in	O
+some	O
+persons	O
+.	O
+
+Intracranial	O
+pressure	O
+increases	O
+during	O
+alfentanil	O
+-	O
+induced	O
+rigidity	B
+.	O
+
+Intracranial	O
+pressure	O
+(	O
+ICP	O
+)	O
+was	O
+measured	O
+during	O
+alfentanil	O
+-	O
+induced	O
+rigidity	B
+in	O
+rats	O
+.	O
+
+Ten	O
+rats	O
+had	O
+arterial	O
+,	O
+central	O
+venous	O
+(	O
+CVP	O
+)	O
+,	O
+and	O
+subdural	O
+cannulae	O
+inserted	O
+under	O
+halothane	O
+anesthesia	O
+.	O
+
+The	O
+animals	O
+were	O
+mechanically	O
+ventilated	O
+to	O
+achieve	O
+normocarbia	O
+(	O
+PCO2	O
+=	O
+42	O
++	O
+/	O
+-	O
+1	O
+mmHg	O
+,	O
+mean	O
++	O
+/	O
+-	O
+SE	O
+)	O
+.	O
+
+Following	O
+instrumentation	O
+,	O
+halothane	O
+was	O
+discontinued	O
+and	O
+alfentanil	O
+(	O
+125	O
+mu	O
+/	O
+kg	O
+)	O
+administered	O
+iv	O
+during	O
+emergence	O
+from	O
+halothane	O
+anesthesia	O
+.	O
+
+In	O
+the	O
+five	O
+rats	O
+that	O
+developed	O
+somatic	B
+rigidity	I
+,	O
+ICP	O
+and	O
+CVP	O
+increased	O
+significantly	O
+above	O
+baseline	O
+(	O
+delta	O
+ICP	O
+7	O
+.	O
+5	O
++	O
+/	O
+-	O
+1	O
+.	O
+0	O
+mmHg	O
+,	O
+delta	O
+CVP	O
+5	O
+.	O
+9	O
++	O
+/	O
+-	O
+1	O
+.	O
+3	O
+mmHg	O
+)	O
+.	O
+
+These	O
+variables	O
+returned	O
+to	O
+baseline	O
+when	O
+rigidity	B
+was	O
+abolished	O
+with	O
+metocurine	O
+.	O
+
+In	O
+five	O
+rats	O
+that	O
+did	O
+not	O
+become	O
+rigid	O
+,	O
+ICP	O
+and	O
+CVP	O
+did	O
+not	O
+change	O
+following	O
+alfentanil	O
+.	O
+
+These	O
+observations	O
+suggest	O
+that	O
+rigidity	B
+should	O
+be	O
+prevented	O
+when	O
+alfentanil	O
+,	O
+and	O
+,	O
+presumably	O
+,	O
+other	O
+opiates	O
+,	O
+are	O
+used	O
+in	O
+the	O
+anesthetic	O
+management	O
+of	O
+patients	O
+with	O
+ICP	O
+problems	O
+.	O
+
+Verapamil	O
+withdrawal	O
+as	O
+a	O
+possible	O
+cause	O
+of	O
+myocardial	B
+infarction	I
+in	O
+a	O
+hypertensive	B
+woman	O
+with	O
+a	O
+normal	O
+coronary	O
+angiogram	O
+.	O
+
+Verapamil	O
+is	O
+an	O
+effective	O
+and	O
+relatively	O
+-	O
+safe	O
+antihypertensive	O
+drug	O
+.	O
+
+Serious	O
+adverse	O
+effects	O
+are	O
+uncommon	O
+and	O
+mainly	O
+have	O
+been	O
+related	O
+to	O
+the	O
+depression	B
+of	O
+cardiac	O
+contractility	O
+and	O
+conduction	O
+,	O
+especially	O
+when	O
+the	O
+drug	O
+is	O
+combined	O
+with	O
+beta	O
+-	O
+blocking	O
+agents	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+in	O
+which	O
+myocardial	B
+infarction	I
+coincided	O
+with	O
+the	O
+introduction	O
+of	O
+captopril	O
+and	O
+the	O
+withdrawal	O
+of	O
+verapamil	O
+in	O
+a	O
+previously	O
+asymptomatic	O
+woman	O
+with	O
+severe	O
+hypertension	B
+.	O
+
+Possible	O
+mechanisms	O
+that	O
+involve	O
+a	O
+verapamil	O
+-	O
+related	O
+increase	O
+in	O
+platelet	O
+and	O
+/	O
+or	O
+vascular	O
+alpha	O
+2	O
+-	O
+adrenoreceptor	O
+affinity	O
+for	O
+catecholamines	O
+are	O
+discussed	O
+.	O
+
+Haemolytic	B
+-	I
+uraemic	I
+syndrome	I
+after	O
+treatment	O
+with	O
+metronidazole	O
+.	O
+
+This	O
+paper	O
+describes	O
+the	O
+clinical	O
+features	O
+of	O
+six	O
+children	O
+who	O
+developed	O
+the	O
+haemolytic	B
+-	I
+uraemic	I
+syndrome	I
+after	O
+treatment	O
+with	O
+metronidazole	O
+.	O
+
+These	O
+children	O
+were	O
+older	O
+and	O
+were	O
+more	O
+likely	O
+to	O
+have	O
+undergone	O
+recent	O
+bowel	O
+surgery	O
+than	O
+are	O
+other	O
+children	O
+with	O
+this	O
+condition	O
+.	O
+
+While	O
+the	O
+involvement	O
+of	O
+metronidazole	O
+in	O
+the	O
+aetiology	O
+of	O
+the	O
+haemolytic	B
+-	I
+uraemic	I
+syndrome	I
+is	O
+not	O
+established	O
+firmly	O
+,	O
+the	O
+action	O
+of	O
+this	O
+drug	O
+in	O
+sensitizing	O
+tissues	O
+to	O
+oxidation	O
+injury	O
+and	O
+the	O
+reported	O
+evidence	O
+of	O
+oxidation	O
+changes	O
+in	O
+the	O
+haemolytic	B
+-	I
+uraemic	I
+syndrome	I
+suggest	O
+a	O
+possible	O
+link	O
+between	O
+metronidazole	O
+treatment	O
+and	O
+some	O
+cases	O
+of	O
+the	O
+haemolytic	B
+-	I
+uraemic	I
+syndrome	I
+.	O
+
+Adverse	O
+cardiac	O
+effects	O
+during	O
+induction	O
+chemotherapy	O
+treatment	O
+with	O
+cis	O
+-	O
+platin	O
+and	O
+5	O
+-	O
+fluorouracil	O
+.	O
+
+Survival	O
+for	O
+patients	O
+with	O
+advanced	O
+head	B
+and	I
+neck	I
+carcinoma	I
+and	O
+esophageal	B
+carcinoma	I
+is	O
+poor	O
+with	O
+radiotherapy	O
+and	O
+/	O
+or	O
+surgery	O
+.	O
+
+Obviously	O
+,	O
+there	O
+is	O
+a	O
+need	O
+for	O
+effective	O
+chemotherapy	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+cis	O
+-	O
+platin	O
+(	O
+80	O
+-	O
+120	O
+mg	O
+/	O
+m2BSA	O
+)	O
+and	O
+5	O
+-	O
+FU	O
+(	O
+1000	O
+mg	O
+/	O
+m2BSA	O
+daily	O
+as	O
+a	O
+continuous	O
+infusion	O
+during	O
+5	O
+days	O
+)	O
+were	O
+given	O
+to	O
+76	O
+patients	O
+before	O
+radiotherapy	O
+and	O
+surgery	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+clarify	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+adverse	O
+cardiac	O
+effects	O
+to	O
+this	O
+treatment	O
+.	O
+
+Before	O
+treatment	O
+all	O
+patients	O
+had	O
+a	O
+cardiac	O
+evaluation	O
+and	O
+during	O
+treatment	O
+serial	O
+ECG	O
+recordings	O
+were	O
+performed	O
+.	O
+
+In	O
+the	O
+pre	O
+-	O
+treatment	O
+evaluation	O
+,	O
+signs	O
+of	O
+cardiovascular	B
+disease	I
+were	O
+found	O
+in	O
+33	O
+patients	O
+(	O
+43	O
+%	O
+)	O
+.	O
+
+During	O
+treatment	O
+,	O
+adverse	O
+cardiac	O
+effects	O
+were	O
+observed	O
+in	O
+14	O
+patients	O
+(	O
+18	O
+%	O
+)	O
+.	O
+
+The	O
+mean	O
+age	O
+of	O
+these	O
+patients	O
+was	O
+the	O
+same	O
+as	O
+for	O
+the	O
+entire	O
+group	O
+,	O
+64	O
+years	O
+.	O
+
+The	O
+incidence	O
+of	O
+cardiotoxicity	B
+was	O
+not	O
+higher	O
+in	O
+patients	O
+with	O
+signs	O
+of	O
+cardiovascular	B
+disease	I
+than	O
+in	O
+those	O
+without	O
+in	O
+the	O
+pre	O
+-	O
+treatment	O
+evaluation	O
+.	O
+
+The	O
+most	O
+common	O
+signs	O
+of	O
+cardiotoxicity	B
+were	O
+chest	B
+pain	I
+,	O
+ST	O
+-	O
+T	O
+wave	O
+changes	O
+and	O
+atrial	B
+fibrillation	I
+.	O
+
+This	O
+was	O
+followed	O
+by	O
+ventricular	B
+fibrillation	I
+in	O
+one	O
+patient	O
+and	O
+sudden	B
+death	I
+in	O
+another	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+patients	O
+on	O
+5	O
+-	O
+FU	O
+treatment	O
+should	O
+be	O
+under	O
+close	O
+supervision	O
+and	O
+that	O
+the	O
+treatment	O
+should	O
+be	O
+discontinued	O
+if	O
+chest	B
+pain	I
+or	O
+tachyarrhythmia	B
+is	O
+observed	O
+.	O
+
+Death	B
+from	O
+chemotherapy	O
+in	O
+gestational	B
+trophoblastic	I
+disease	I
+.	O
+
+Multiple	O
+cytotoxic	O
+drug	O
+administration	O
+is	O
+the	O
+generally	O
+accepted	O
+treatment	O
+of	O
+patients	O
+with	O
+a	O
+high	O
+-	O
+risk	O
+stage	O
+of	O
+choriocarcinoma	B
+.	O
+
+Based	O
+on	O
+this	O
+principle	O
+a	O
+27	O
+-	O
+year	O
+old	O
+woman	O
+,	O
+classified	O
+as	O
+being	O
+in	O
+the	O
+high	O
+-	O
+risk	O
+group	O
+(	O
+Goldstein	O
+and	O
+Berkowitz	O
+score	O
+:	O
+11	O
+)	O
+,	O
+was	O
+treated	O
+with	O
+multiple	O
+cytotoxic	O
+drugs	O
+.	O
+
+The	O
+multiple	O
+drug	O
+schema	O
+consisted	O
+of	O
+:	O
+Etoposide	O
+16	O
+.	O
+213	O
+,	O
+Methotrexate	O
+,	O
+Cyclophosphamide	O
+,	O
+Actomycin	O
+-	O
+D	O
+,	O
+and	O
+Cisplatin	O
+.	O
+
+On	O
+the	O
+first	O
+day	O
+of	O
+the	O
+schedule	O
+,	O
+moderate	O
+high	O
+doses	O
+of	O
+Methotrexate	O
+,	O
+Etoposide	O
+and	O
+Cyclophosphamide	O
+were	O
+administered	O
+.	O
+
+Within	O
+8	O
+hours	O
+after	O
+initiation	O
+of	O
+therapy	O
+the	O
+patient	O
+died	O
+with	O
+a	O
+clinical	O
+picture	O
+resembling	O
+massive	O
+pulmonary	B
+obstruction	I
+due	O
+to	O
+choriocarcinomic	O
+tissue	O
+plugs	O
+,	O
+probably	O
+originating	O
+from	O
+the	O
+uterus	O
+.	O
+
+Formation	O
+of	O
+these	O
+plugs	O
+was	O
+probably	O
+due	O
+to	O
+extensive	O
+tumor	B
+necrosis	B
+at	O
+the	O
+level	O
+of	O
+the	O
+walls	O
+of	O
+the	O
+major	O
+uterine	O
+veins	O
+,	O
+which	O
+resulted	O
+in	O
+an	O
+open	O
+exchange	O
+of	O
+tumor	B
+plugs	O
+to	O
+the	O
+vascular	O
+spaces	O
+;	O
+decrease	O
+in	O
+tumor	B
+tissue	O
+coherence	O
+secondary	O
+to	O
+chemotherapy	O
+may	O
+have	O
+further	O
+contributed	O
+to	O
+the	O
+formation	O
+of	O
+tumor	B
+emboli	O
+.	O
+
+In	O
+view	O
+of	O
+the	O
+close	O
+time	O
+association	O
+between	O
+the	O
+start	O
+of	O
+chemotherapy	O
+and	O
+the	O
+acute	O
+onset	O
+of	O
+massive	O
+embolism	B
+other	O
+explanations	O
+,	O
+such	O
+as	O
+spontaneous	O
+necrosis	B
+,	O
+must	O
+be	O
+considered	O
+less	O
+likely	O
+.	O
+
+Patients	O
+with	O
+large	O
+pelvic	B
+tumor	I
+loads	O
+are	O
+,	O
+according	O
+to	O
+existing	O
+classifications	O
+,	O
+at	O
+high	O
+risk	O
+to	O
+die	O
+and	O
+to	O
+develop	O
+drug	O
+resistance	O
+.	O
+
+Notwithstanding	O
+these	O
+facts	O
+our	O
+findings	O
+suggest	O
+that	O
+these	O
+patients	O
+might	O
+benefit	O
+from	O
+relatively	O
+mild	O
+initial	O
+treatment	O
+,	O
+especially	O
+true	O
+for	O
+patients	O
+not	O
+previously	O
+exposed	O
+to	O
+this	O
+drug	O
+.	O
+
+Close	O
+observation	O
+of	O
+the	O
+response	O
+status	O
+both	O
+clinically	O
+and	O
+with	O
+beta	O
+-	O
+hCG	O
+values	O
+may	O
+indicate	O
+whether	O
+and	O
+when	O
+more	O
+agressive	O
+combination	O
+chemotherapy	O
+should	O
+be	O
+started	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Pulmonary	O
+shunt	O
+and	O
+cardiovascular	O
+responses	O
+to	O
+CPAP	O
+during	O
+nitroprusside	O
+-	O
+induced	O
+hypotension	B
+.	O
+
+The	O
+effects	O
+of	O
+continuous	O
+positive	O
+airway	O
+pressure	O
+(	O
+CPAP	O
+)	O
+on	O
+cardiovascular	O
+dynamics	O
+and	O
+pulmonary	O
+shunt	O
+(	O
+QS	O
+/	O
+QT	O
+)	O
+were	O
+investigated	O
+in	O
+12	O
+dogs	O
+before	O
+and	O
+during	O
+sodium	O
+nitroprusside	O
+infusion	O
+that	O
+decreased	O
+mean	O
+arterial	O
+blood	O
+pressure	O
+40	O
+-	O
+50	O
+per	O
+cent	O
+.	O
+
+Before	O
+nitroprusside	O
+infusion	O
+,	O
+5	O
+cm	O
+H2O	O
+CPAP	O
+significantly	O
+,	O
+P	O
+less	O
+than	O
+.	O
+05	O
+,	O
+decreased	O
+arterial	O
+blood	O
+pressure	O
+,	O
+but	O
+did	O
+not	O
+significantly	O
+alter	O
+heart	O
+rate	O
+,	O
+cardiac	O
+output	O
+,	O
+systemic	O
+vascular	O
+resistance	O
+,	O
+or	O
+QS	O
+/	O
+QT	O
+.	O
+
+Ten	O
+cm	O
+H2O	O
+CPAP	O
+before	O
+nitroprusside	O
+infusion	O
+produced	O
+a	O
+further	O
+decrease	B
+in	I
+arterial	I
+blood	I
+pressure	I
+and	O
+significantly	O
+increased	O
+heart	O
+rate	O
+and	O
+decreased	B
+cardiac	I
+output	I
+and	O
+QS	O
+/	O
+QT	O
+.	O
+
+Nitroprusside	O
+caused	O
+significant	O
+decreases	B
+in	I
+arterial	I
+blood	I
+pressure	I
+and	O
+systemic	O
+vascular	O
+resistance	O
+and	O
+increases	O
+in	O
+heart	O
+rate	O
+,	O
+but	O
+did	O
+not	O
+change	O
+cardiac	O
+output	O
+or	O
+QS	O
+/	O
+QT	O
+.	O
+
+Five	O
+cm	O
+H2O	O
+CPAP	O
+during	O
+nitroprusside	O
+did	O
+not	O
+further	O
+alter	O
+any	O
+of	O
+the	O
+above	O
+-	O
+mentioned	O
+variables	O
+.	O
+
+However	O
+,	O
+10	O
+cm	O
+H2O	O
+CPAP	O
+decreased	O
+arterial	O
+blood	O
+pressure	O
+,	O
+cardiac	O
+output	O
+,	O
+and	O
+QS	O
+/	O
+QT	O
+.	O
+
+These	O
+data	O
+indicate	O
+that	O
+nitroprusside	O
+infusion	O
+rates	O
+that	O
+decrease	O
+mean	O
+arterial	O
+blood	O
+pressure	O
+by	O
+40	O
+-	O
+50	O
+per	O
+cent	O
+do	O
+not	O
+change	O
+cardiac	O
+output	O
+or	O
+QS	O
+/	O
+QT	O
+.	O
+
+During	O
+nitroprusside	O
+infusion	O
+low	O
+levels	O
+of	O
+CPAP	O
+do	O
+not	O
+markedly	O
+alter	O
+cardiovascular	O
+dynamics	O
+,	O
+but	O
+high	O
+levels	O
+of	O
+CPAP	O
+(	O
+10	O
+cm	O
+H2O	O
+)	O
+,	O
+while	O
+decreasing	O
+QS	O
+/	O
+QT	O
+,	O
+produce	O
+marked	O
+decreases	B
+in	I
+arterial	I
+blood	I
+pressure	I
+and	I
+cardiac	I
+output	I
+.	O
+
+Systolic	O
+pressure	O
+variation	O
+is	O
+greater	O
+during	O
+hemorrhage	B
+than	O
+during	O
+sodium	O
+nitroprusside	O
+-	O
+induced	O
+hypotension	B
+in	O
+ventilated	O
+dogs	O
+.	O
+
+The	O
+systolic	O
+pressure	O
+variation	O
+(	O
+SPV	O
+)	O
+,	O
+which	O
+is	O
+the	O
+difference	O
+between	O
+the	O
+maximal	O
+and	O
+minimal	O
+values	O
+of	O
+the	O
+systolic	O
+blood	O
+pressure	O
+(	O
+SBP	O
+)	O
+after	O
+one	O
+positive	O
+-	O
+pressure	O
+breath	O
+,	O
+was	O
+studied	O
+in	O
+ventilated	O
+dogs	O
+subjected	O
+to	O
+hypotension	B
+.	O
+
+Mean	O
+arterial	O
+pressure	O
+was	O
+decreased	O
+to	O
+50	O
+mm	O
+Hg	O
+for	O
+30	O
+minutes	O
+either	O
+by	O
+hemorrhage	B
+(	O
+HEM	B
+,	O
+n	O
+=	O
+7	O
+)	O
+or	O
+by	O
+continuous	O
+infusion	O
+of	O
+sodium	O
+nitroprusside	O
+(	O
+SNP	O
+,	O
+n	O
+=	O
+7	O
+)	O
+.	O
+
+During	O
+HEM	B
+-	O
+induced	O
+hypotension	B
+the	O
+cardiac	O
+output	O
+was	O
+significantly	O
+lower	O
+and	O
+systemic	O
+vascular	O
+resistance	O
+higher	O
+compared	O
+with	O
+that	O
+in	O
+the	O
+SNP	O
+group	O
+.	O
+
+The	O
+systemic	O
+,	O
+central	O
+venous	O
+,	O
+pulmonary	O
+capillary	O
+wedge	O
+pressures	O
+,	O
+and	O
+heart	O
+rates	O
+,	O
+were	O
+similar	O
+in	O
+the	O
+two	O
+groups	O
+.	O
+
+Analysis	O
+of	O
+the	O
+respiratory	O
+changes	O
+in	O
+the	O
+arterial	O
+pressure	O
+waveform	O
+enabled	O
+differentiation	O
+between	O
+the	O
+two	O
+groups	O
+.	O
+
+The	O
+SPV	O
+during	O
+hypotension	B
+was	O
+15	O
+.	O
+7	O
++	O
+/	O
+-	O
+6	O
+.	O
+7	O
+mm	O
+Hg	O
+in	O
+the	O
+HEM	B
+group	O
+,	O
+compared	O
+with	O
+9	O
+.	O
+1	O
++	O
+/	O
+-	O
+2	O
+.	O
+0	O
+mm	O
+Hg	O
+in	O
+the	O
+SNP	O
+group	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+02	O
+)	O
+.	O
+
+The	O
+delta	O
+down	O
+,	O
+which	O
+is	O
+the	O
+measure	O
+of	O
+decrease	O
+of	O
+SBP	O
+after	O
+a	O
+mechanical	O
+breath	O
+,	O
+was	O
+20	O
+.	O
+3	O
++	O
+/	O
+-	O
+8	O
+.	O
+4	O
+and	O
+10	O
+.	O
+1	O
++	O
+/	O
+-	O
+3	O
+.	O
+8	O
+mm	O
+Hg	O
+in	O
+the	O
+HEM	B
+and	O
+SNP	O
+groups	O
+,	O
+respectively	O
+,	O
+during	O
+hypotension	B
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+02	O
+)	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+increases	O
+in	O
+the	O
+SPV	O
+and	O
+the	O
+delta	O
+down	O
+are	O
+characteristic	O
+of	O
+a	O
+hypotensive	B
+state	O
+due	O
+to	O
+a	O
+predominant	O
+decrease	O
+in	O
+preload	O
+.	O
+
+They	O
+are	O
+thus	O
+more	O
+important	O
+during	O
+absolute	O
+hypovolemia	B
+than	O
+during	O
+deliberate	O
+hypotension	B
+.	O
+
+Ventricular	B
+tachyarrhythmias	I
+during	O
+cesarean	O
+section	O
+after	O
+ritodrine	O
+therapy	O
+:	O
+interaction	O
+with	O
+anesthetics	O
+.	O
+
+This	O
+case	O
+illustrates	O
+that	O
+patients	O
+receiving	O
+ritodrine	O
+for	O
+preterm	B
+labor	I
+may	O
+risk	O
+interactions	O
+between	O
+the	O
+residual	O
+betamimetic	O
+effects	O
+of	O
+ritodrine	O
+and	O
+the	O
+effects	O
+of	O
+anesthetics	O
+during	O
+cesarean	O
+section	O
+.	O
+
+Such	O
+interactions	O
+may	O
+result	O
+in	O
+serious	O
+cardiovascular	B
+complications	I
+even	O
+after	O
+cessation	O
+of	O
+an	O
+infusion	O
+of	O
+ritodrine	O
+.	O
+
+Preoperative	O
+assessment	O
+should	O
+focus	O
+on	O
+cardiovascular	O
+status	O
+and	O
+serum	O
+potassium	O
+level	O
+.	O
+
+Delaying	O
+induction	O
+of	O
+anesthesia	O
+should	O
+be	O
+considered	O
+whenever	O
+possible	O
+.	O
+
+Careful	O
+fluid	O
+administration	O
+and	O
+cautious	O
+use	O
+of	O
+titrated	O
+doses	O
+of	O
+ephedrine	O
+are	O
+advised	O
+.	O
+
+After	O
+delivery	O
+of	O
+the	O
+infant	O
+,	O
+there	O
+should	O
+be	O
+no	O
+contraindication	O
+to	O
+the	O
+use	O
+of	O
+an	O
+alpha	O
+-	O
+adrenergic	O
+vasopressor	O
+such	O
+as	O
+phenylephrine	O
+to	O
+treat	O
+hypotensive	B
+patients	O
+with	O
+tachycardia	B
+.	O
+
+Verapamil	O
+-	O
+induced	O
+carbamazepine	O
+neurotoxicity	B
+.	O
+
+A	O
+report	O
+of	O
+two	O
+cases	O
+.	O
+
+Two	O
+patients	O
+with	O
+signs	O
+of	O
+carbamazepine	O
+neurotoxicity	B
+after	O
+combined	O
+treatment	O
+with	O
+verapamil	O
+showed	O
+complete	O
+recovery	O
+after	O
+discontinuation	O
+of	O
+the	O
+calcium	O
+entry	O
+blocker	O
+.	O
+
+Use	O
+of	O
+verapamil	O
+in	O
+combination	O
+with	O
+carbamazepine	O
+should	O
+either	O
+be	O
+avoided	O
+or	O
+prescribed	O
+only	O
+with	O
+appropriate	O
+adjustment	O
+of	O
+the	O
+carbamazepine	O
+dose	O
+(	O
+usually	O
+reduction	O
+of	O
+the	O
+carbamazepine	O
+dose	O
+by	O
+one	O
+half	O
+)	O
+.	O
+
+Paracetamol	O
+-	O
+associated	O
+coma	B
+,	O
+metabolic	B
+acidosis	I
+,	O
+renal	B
+and	I
+hepatic	I
+failure	I
+.	O
+
+A	O
+case	O
+of	O
+metabolic	B
+acidosis	I
+,	O
+acute	B
+renal	I
+failure	I
+and	I
+hepatic	I
+failure	I
+following	O
+paracetamol	O
+ingestion	O
+is	O
+presented	O
+.	O
+
+The	O
+diagnostic	O
+difficulty	O
+at	O
+presentation	O
+is	O
+highlighted	O
+.	O
+
+Continuous	O
+arteriovenous	O
+haemofiltration	O
+proved	O
+a	O
+valuable	O
+means	O
+of	O
+maintaining	O
+fluid	O
+and	O
+electrolyte	O
+balance	O
+.	O
+
+The	O
+patient	O
+recovered	O
+.	O
+
+Sexual	B
+dysfunction	I
+among	O
+patients	O
+with	O
+arthritis	B
+.	O
+
+The	O
+relationship	O
+of	O
+arthritis	B
+and	O
+sexual	B
+dysfunction	I
+was	O
+investigated	O
+among	O
+169	O
+patients	O
+with	O
+rheumatoid	B
+arthritis	I
+,	O
+osteoarthritis	B
+and	O
+spondyloarthropathy	B
+,	O
+130	O
+of	O
+whom	O
+were	O
+pair	O
+-	O
+matched	O
+to	O
+controls	O
+.	O
+
+Assessments	O
+of	O
+marital	O
+happiness	O
+and	O
+depressed	B
+mood	I
+were	O
+also	O
+made	O
+using	O
+the	O
+CES	O
+-	O
+D	O
+and	O
+the	O
+Azrin	O
+Marital	O
+Happiness	O
+Scale	O
+(	O
+AMHS	O
+)	O
+.	O
+
+Sexual	B
+dysfunctions	I
+were	O
+found	O
+to	O
+be	O
+common	O
+among	O
+patients	O
+and	O
+controls	O
+,	O
+the	O
+majority	O
+in	O
+both	O
+groups	O
+reporting	O
+one	O
+or	O
+more	O
+dysfunctions	O
+.	O
+
+Impotence	B
+was	O
+more	O
+common	O
+among	O
+male	O
+patients	O
+than	O
+controls	O
+and	O
+was	O
+found	O
+to	O
+be	O
+associated	O
+with	O
+co	O
+-	O
+morbidity	O
+and	O
+the	O
+taking	O
+of	O
+methotrexate	O
+.	O
+
+Depressed	B
+mood	I
+was	O
+more	O
+common	O
+among	O
+patients	O
+and	O
+was	O
+associated	O
+with	O
+certain	O
+sexual	O
+difficulties	O
+,	O
+but	O
+not	O
+with	O
+impotence	B
+.	O
+
+Marital	O
+unhappiness	O
+,	O
+as	O
+indicated	O
+by	O
+AMHS	O
+scores	O
+,	O
+was	O
+not	O
+associated	O
+with	O
+arthritis	B
+but	O
+was	O
+associated	O
+with	O
+sexual	B
+dysfunction	I
+,	O
+sexual	O
+dissatisfaction	O
+and	O
+being	O
+female	O
+.	O
+
+Does	O
+paracetamol	O
+cause	O
+urothelial	B
+cancer	I
+or	O
+renal	B
+papillary	I
+necrosis	I
+?	O
+
+The	O
+risk	O
+of	O
+developing	O
+renal	B
+papillary	I
+necrosis	I
+or	O
+cancer	B
+of	I
+the	I
+renal	I
+pelvis	I
+,	I
+ureter	I
+or	I
+bladder	I
+associated	O
+with	O
+consumption	O
+of	O
+either	O
+phenacetin	O
+or	O
+paracetamol	O
+was	O
+calculated	O
+from	O
+data	O
+acquired	O
+by	O
+questionnaire	O
+from	O
+381	O
+cases	O
+and	O
+808	O
+controls	O
+.	O
+
+The	O
+risk	O
+of	O
+renal	B
+papillary	I
+necrosis	I
+was	O
+increased	O
+nearly	O
+20	O
+-	O
+fold	O
+by	O
+consumption	O
+of	O
+phenacetin	O
+,	O
+which	O
+also	O
+increased	O
+the	O
+risk	O
+for	O
+cancer	B
+of	I
+the	I
+renal	I
+pelvis	I
+and	I
+bladder	I
+but	O
+not	O
+for	O
+ureteric	B
+cancer	I
+.	O
+
+By	O
+contrast	O
+,	O
+we	O
+were	O
+unable	O
+to	O
+substantiate	O
+an	O
+increased	O
+risk	O
+from	O
+paracetamol	O
+consumption	O
+for	O
+renal	B
+papillary	I
+necrosis	I
+or	O
+any	O
+of	O
+these	O
+cancers	B
+although	O
+there	O
+was	O
+a	O
+suggestion	O
+of	O
+an	O
+association	O
+with	O
+cancer	B
+of	I
+the	I
+ureter	I
+.	O
+
+Dapsone	O
+-	O
+associated	O
+Heinz	O
+body	O
+hemolytic	B
+anemia	I
+in	O
+a	O
+Cambodian	O
+woman	O
+with	O
+hemoglobin	O
+E	O
+trait	O
+.	O
+
+A	O
+Cambodian	O
+woman	O
+with	O
+hemoglobin	O
+E	O
+trait	O
+(	O
+AE	O
+)	O
+and	O
+leprosy	B
+developed	O
+a	O
+Heinz	O
+body	O
+hemolytic	B
+anemia	I
+while	O
+taking	O
+a	O
+dose	O
+of	O
+dapsone	O
+(	O
+50	O
+mg	O
+/	O
+day	O
+)	O
+not	O
+usually	O
+associated	O
+with	O
+clinical	O
+hemolysis	B
+.	O
+
+Her	O
+red	O
+blood	O
+cells	O
+(	O
+RBCs	O
+)	O
+had	O
+increased	O
+incubated	O
+Heinz	O
+body	O
+formation	O
+,	O
+decreased	O
+reduced	O
+glutathione	O
+(	O
+GSH	O
+)	O
+,	O
+and	O
+decreased	O
+GSH	O
+stability	O
+.	O
+
+The	O
+pentose	O
+phosphate	O
+shunt	O
+activity	O
+of	O
+the	O
+dapsone	O
+-	O
+exposed	O
+AE	O
+RBCs	O
+was	O
+increased	O
+compared	O
+to	O
+normal	O
+RBCs	O
+.	O
+
+Although	O
+the	O
+AE	O
+RBCs	O
+from	O
+an	O
+individual	O
+not	O
+taking	O
+dapsone	O
+had	O
+increased	O
+incubated	O
+Heinz	O
+body	O
+formation	O
+,	O
+the	O
+GSH	O
+content	O
+and	O
+GSH	O
+stability	O
+were	O
+normal	O
+.	O
+
+The	O
+pentose	O
+phosphate	O
+shunt	O
+activity	O
+of	O
+the	O
+non	O
+-	O
+dapsone	O
+-	O
+exposed	O
+AE	O
+RBCs	O
+was	O
+decreased	O
+compared	O
+to	O
+normal	O
+RBCs	O
+.	O
+
+Thus	O
+,	O
+AE	O
+RBCs	O
+appear	O
+to	O
+have	O
+an	O
+increased	O
+sensitivity	O
+to	O
+oxidant	O
+stress	O
+both	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+,	O
+since	O
+dapsone	O
+does	O
+not	O
+cause	O
+hemolytic	B
+anemia	I
+at	O
+this	O
+dose	O
+in	O
+hematologically	O
+normal	O
+individuals	O
+.	O
+
+Given	O
+the	O
+influx	O
+of	O
+Southeast	O
+Asians	O
+into	O
+the	O
+United	O
+States	O
+,	O
+oxidant	O
+medications	O
+should	O
+be	O
+used	O
+with	O
+caution	O
+,	O
+especially	O
+if	O
+an	O
+infection	B
+is	O
+present	O
+,	O
+in	O
+individuals	O
+of	O
+ethnic	O
+backgrounds	O
+that	O
+have	O
+an	O
+increased	O
+prevalence	O
+of	O
+hemoglobin	O
+E	O
+.	O
+
+Severe	O
+complications	O
+of	O
+antianginal	O
+drug	O
+therapy	O
+in	O
+a	O
+patient	O
+identified	O
+as	O
+a	O
+poor	O
+metabolizer	O
+of	O
+metoprolol	O
+,	O
+propafenone	O
+,	O
+diltiazem	O
+,	O
+and	O
+sparteine	O
+.	O
+
+A	O
+47	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+suffering	O
+from	O
+coronary	B
+artery	I
+disease	I
+was	O
+admitted	O
+to	O
+the	O
+CCU	O
+in	O
+shock	B
+with	O
+III	O
+.	O
+
+AV	B
+block	I
+,	O
+severe	O
+hypotension	B
+,	O
+and	O
+impairment	B
+of	I
+ventricular	I
+function	I
+.	O
+
+One	O
+week	O
+prior	O
+to	O
+admission	O
+a	O
+therapy	O
+with	O
+standard	O
+doses	O
+of	O
+metoprolol	O
+(	O
+100	O
+mg	O
+t	O
+.	O
+i	O
+.	O
+d	O
+.	O
+and	O
+then	O
+100	O
+mg	O
+b	O
+.	O
+i	O
+.	O
+d	O
+.	O
+)	O
+had	O
+been	O
+initiated	O
+.	O
+
+Two	O
+days	O
+before	O
+admission	O
+diltiazem	O
+(	O
+60	O
+mg	O
+b	O
+.	O
+i	O
+.	O
+d	O
+.	O
+)	O
+was	O
+prescribed	O
+in	O
+addition	O
+.	O
+
+Analyses	O
+of	O
+a	O
+blood	O
+sample	O
+revealed	O
+unusually	O
+high	O
+plasma	O
+concentrations	O
+of	O
+metoprolol	O
+(	O
+greater	O
+than	O
+3000	O
+ng	O
+/	O
+ml	O
+)	O
+and	O
+diltiazem	O
+(	O
+526	O
+ng	O
+/	O
+ml	O
+)	O
+.	O
+
+The	O
+patient	O
+recovered	O
+within	O
+1	O
+week	O
+following	O
+discontinuation	O
+of	O
+antianginal	O
+therapy	O
+.	O
+
+Three	O
+months	O
+later	O
+the	O
+patient	O
+was	O
+exposed	O
+to	O
+a	O
+single	O
+dose	O
+of	O
+metoprolol	O
+,	O
+diltiazem	O
+,	O
+propafenone	O
+(	O
+since	O
+he	O
+had	O
+received	O
+this	O
+drug	O
+in	O
+the	O
+past	O
+)	O
+,	O
+and	O
+sparteine	O
+(	O
+as	O
+a	O
+probe	O
+for	O
+the	O
+debrisoquine	O
+/	O
+sparteine	O
+type	O
+polymorphism	O
+of	O
+oxidative	O
+drug	O
+metabolism	O
+)	O
+.	O
+
+It	O
+was	O
+found	O
+that	O
+he	O
+was	O
+a	O
+poor	O
+metabolizer	O
+of	O
+all	O
+four	O
+drugs	O
+,	O
+indicating	O
+that	O
+their	O
+metabolism	O
+is	O
+under	O
+the	O
+same	O
+genetic	O
+control	O
+.	O
+
+Therefore	O
+,	O
+patients	O
+belonging	O
+to	O
+the	O
+poor	O
+-	O
+metabolizer	O
+phenotype	O
+of	O
+sparteine	O
+/	O
+debrisoquine	O
+polymorphism	O
+in	O
+drug	O
+metabolism	O
+,	O
+which	O
+constitutes	O
+6	O
+.	O
+4	O
+%	O
+of	O
+the	O
+German	O
+population	O
+,	O
+may	O
+experience	O
+adverse	B
+drug	I
+reactions	I
+when	O
+treated	O
+with	O
+standard	O
+doses	O
+of	O
+one	O
+of	O
+these	O
+drugs	O
+alone	O
+.	O
+
+Moreover	O
+,	O
+the	O
+coadministration	O
+of	O
+these	O
+frequently	O
+used	O
+drugs	O
+is	O
+expected	O
+to	O
+be	O
+especially	O
+harmful	O
+in	O
+this	O
+subgroup	O
+of	O
+patients	O
+.	O
+
+Clinical	O
+experiences	O
+in	O
+an	O
+open	O
+and	O
+a	O
+double	O
+-	O
+blind	O
+trial	O
+.	O
+
+A	O
+total	O
+of	O
+sixty	O
+patients	O
+were	O
+trated	O
+with	O
+bromperidol	O
+first	O
+in	O
+open	O
+conditions	O
+(	O
+20	O
+patients	O
+)	O
+,	O
+then	O
+on	O
+a	O
+double	O
+blind	O
+basis	O
+(	O
+40	O
+patients	O
+)	O
+with	O
+haloperidol	O
+as	O
+the	O
+reference	O
+substance	O
+.	O
+
+The	O
+open	O
+study	O
+lasted	O
+for	O
+four	O
+weeks	O
+;	O
+the	O
+drug	O
+was	O
+administrated	O
+in	O
+the	O
+form	O
+of	O
+1	O
+mg	O
+tablets	O
+.	O
+
+The	O
+daily	O
+dose	O
+(	O
+initial	O
+dose	O
+:	O
+1	O
+mg	O
+;	O
+mean	O
+dose	O
+at	O
+the	O
+end	O
+of	O
+the	O
+trial	O
+:	O
+4	O
+.	O
+47	O
+mg	O
+)	O
+was	O
+always	O
+administered	O
+in	O
+one	O
+single	O
+dose	O
+.	O
+
+Nineteen	O
+patients	O
+finished	O
+the	O
+trial	O
+,	O
+and	O
+in	O
+18	O
+cases	O
+the	O
+therapeutic	O
+result	O
+was	O
+considered	O
+very	O
+good	O
+to	O
+good	O
+.	O
+
+These	O
+results	O
+were	O
+confirmed	O
+by	O
+statistical	O
+analysis	O
+.	O
+
+Nine	O
+patients	O
+exhibited	O
+mild	O
+to	O
+moderate	O
+extrapyramidal	B
+concomitant	I
+symptoms	I
+;	O
+no	O
+other	O
+side	O
+effects	O
+were	O
+observed	O
+.	O
+
+The	O
+results	O
+of	O
+detailed	O
+laboratory	O
+tests	O
+and	O
+evaluations	O
+of	O
+various	O
+quantitative	O
+and	O
+qualitative	O
+tolerability	O
+parameters	O
+were	O
+not	O
+indicative	O
+of	O
+toxic	O
+effects	O
+.	O
+
+In	O
+the	O
+double	O
+blind	O
+study	O
+with	O
+haloperidol	O
+,	O
+both	O
+substances	O
+were	O
+found	O
+to	O
+be	O
+highly	O
+effective	O
+in	O
+the	O
+treatment	O
+of	O
+psychotic	B
+syndromes	I
+belonging	I
+predominantly	I
+to	I
+the	I
+schizophrenia	I
+group	I
+.	O
+
+Certain	O
+clues	O
+,	O
+including	O
+the	O
+onset	O
+of	O
+action	O
+,	O
+seem	O
+to	O
+be	O
+indicative	O
+of	O
+the	O
+superiority	O
+of	O
+bromperidol	O
+.	O
+
+No	O
+differences	O
+were	O
+observed	O
+with	O
+respect	O
+to	O
+side	O
+effects	O
+and	O
+general	O
+tolerability	O
+.	O
+
+Prolonged	O
+cholestasis	B
+after	O
+troleandomycin	O
+-	O
+induced	O
+acute	O
+hepatitis	B
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+patient	O
+in	O
+whom	O
+troleandomycin	O
+-	O
+induced	O
+hepatitis	B
+was	O
+followed	O
+by	O
+prolonged	O
+anicteric	O
+cholestasis	B
+.	O
+
+Jaundice	B
+occurred	O
+after	O
+administration	O
+of	O
+troleandomycin	O
+for	O
+7	O
+days	O
+and	O
+was	O
+associated	O
+with	O
+hypereosinophilia	B
+.	O
+
+Jaundice	B
+disappeared	O
+within	O
+3	O
+months	O
+but	O
+was	O
+followed	O
+by	O
+prolonged	O
+anicteric	O
+cholestasis	B
+marked	O
+by	O
+pruritus	B
+and	O
+high	O
+levels	O
+of	O
+alkaline	O
+phosphatase	O
+and	O
+gammaglutamyltransferase	O
+activities	O
+.	O
+
+Finally	O
+,	O
+pruritus	B
+disappeared	O
+within	O
+19	O
+months	O
+,	O
+and	O
+liver	O
+tests	O
+returned	O
+to	O
+normal	O
+27	O
+months	O
+after	O
+the	O
+onset	O
+of	O
+hepatitis	B
+.	O
+
+This	O
+observation	O
+demonstrates	O
+that	O
+prolonged	O
+cholestasis	B
+can	O
+follow	O
+troleandomycin	O
+-	O
+induced	O
+acute	O
+hepatitis	B
+.	O
+
+Serial	O
+studies	O
+of	O
+auditory	B
+neurotoxicity	I
+in	O
+patients	O
+receiving	O
+deferoxamine	O
+therapy	O
+.	O
+
+Visual	B
+and	I
+auditory	I
+neurotoxicity	I
+was	O
+previously	O
+documented	O
+in	O
+42	O
+of	O
+89	O
+patients	O
+with	O
+transfusion	O
+-	O
+dependent	O
+anemia	B
+who	O
+were	O
+receiving	O
+iron	O
+chelation	O
+therapy	O
+with	O
+daily	O
+subcutaneous	O
+deferoxamine	O
+.	O
+
+Twenty	O
+-	O
+two	O
+patients	O
+in	O
+the	O
+affected	O
+group	O
+had	O
+abnormal	B
+audiograms	I
+with	I
+deficits	I
+mostly	I
+in	I
+the	I
+high	I
+frequency	I
+range	I
+of	I
+4	I
+,	I
+000	I
+to	I
+8	I
+,	I
+000	I
+Hz	I
+and	O
+in	O
+the	O
+hearing	O
+threshold	O
+levels	O
+of	O
+30	O
+to	O
+100	O
+decibels	O
+.	O
+
+When	O
+deferoxamine	O
+therapy	O
+was	O
+discontinued	O
+and	O
+serial	O
+studies	O
+were	O
+performed	O
+,	O
+audiograms	O
+in	O
+seven	O
+cases	O
+reverted	O
+to	O
+normal	O
+or	O
+near	O
+normal	O
+within	O
+two	O
+to	O
+three	O
+weeks	O
+,	O
+and	O
+nine	O
+of	O
+13	O
+patients	O
+with	O
+symptoms	O
+became	O
+asymptomatic	O
+.	O
+
+Audiograms	O
+from	O
+15	O
+patients	O
+remained	O
+abnormal	O
+and	O
+four	O
+patients	O
+required	O
+hearing	O
+aids	O
+because	O
+of	O
+permanent	B
+disability	I
+.	O
+
+Since	O
+18	O
+of	O
+the	O
+22	O
+patients	O
+were	O
+initially	O
+receiving	O
+deferoxamine	O
+doses	O
+in	O
+excess	O
+of	O
+the	O
+commonly	O
+recommended	O
+50	O
+mg	O
+/	O
+kg	O
+per	O
+dose	O
+,	O
+therapy	O
+was	O
+restarted	O
+with	O
+lower	O
+doses	O
+,	O
+usually	O
+50	O
+mg	O
+/	O
+kg	O
+per	O
+dose	O
+or	O
+less	O
+depending	O
+on	O
+the	O
+degree	O
+of	O
+auditory	B
+abnormality	I
+,	O
+and	O
+with	O
+the	O
+exception	O
+of	O
+two	O
+cases	O
+no	O
+further	O
+toxicity	B
+was	O
+demonstrated	O
+.	O
+
+Auditory	O
+deterioration	O
+and	O
+improvement	O
+,	O
+demonstrated	O
+serially	O
+in	O
+individual	O
+patients	O
+receiving	O
+and	O
+not	O
+receiving	O
+deferoxamine	O
+,	O
+respectively	O
+,	O
+provided	O
+convincing	O
+evidence	O
+for	O
+a	O
+cause	O
+-	O
+and	O
+-	O
+effect	O
+relation	O
+between	O
+deferoxamine	O
+administration	O
+and	O
+ototoxicity	B
+.	O
+
+Based	O
+on	O
+these	O
+data	O
+,	O
+a	O
+plan	O
+of	O
+management	O
+was	O
+developed	O
+that	O
+allows	O
+effective	O
+yet	O
+safe	O
+administration	O
+of	O
+deferoxamine	O
+.	O
+
+A	O
+dose	O
+of	O
+50	O
+mg	O
+/	O
+kg	O
+is	O
+recommended	O
+in	O
+those	O
+without	O
+audiogram	O
+abnormalities	O
+.	O
+
+With	O
+mild	O
+toxicity	B
+,	O
+a	O
+reduction	O
+to	O
+30	O
+or	O
+40	O
+mg	O
+/	O
+kg	O
+per	O
+dose	O
+should	O
+result	O
+in	O
+a	O
+reversal	O
+of	O
+the	O
+abnormal	O
+results	O
+to	O
+normal	O
+within	O
+four	O
+weeks	O
+.	O
+
+Moderate	O
+abnormalities	O
+require	O
+a	O
+reduction	O
+of	O
+deferoxamine	O
+to	O
+25	O
+mg	O
+/	O
+kg	O
+per	O
+dose	O
+with	O
+careful	O
+monitoring	O
+.	O
+
+In	O
+those	O
+with	O
+symptoms	O
+of	O
+hearing	B
+loss	I
+,	O
+the	O
+drug	O
+should	O
+be	O
+stopped	O
+for	O
+four	O
+weeks	O
+,	O
+and	O
+when	O
+the	O
+audiogram	O
+is	O
+stable	O
+or	O
+improved	O
+,	O
+therapy	O
+should	O
+be	O
+restarted	O
+at	O
+10	O
+to	O
+25	O
+mg	O
+/	O
+kg	O
+per	O
+dose	O
+.	O
+
+Serial	O
+audiograms	O
+should	O
+be	O
+performed	O
+every	O
+six	O
+months	O
+in	O
+those	O
+without	O
+problems	O
+and	O
+more	O
+frequently	O
+in	O
+young	O
+patients	O
+with	O
+normal	O
+serum	O
+ferritin	O
+values	O
+and	O
+in	O
+those	O
+with	O
+auditory	B
+dysfunction	I
+.	O
+
+Lidocaine	O
+-	O
+induced	O
+cardiac	B
+asystole	I
+.	O
+
+Intravenous	O
+administration	O
+of	O
+a	O
+single	O
+50	O
+-	O
+mg	O
+bolus	O
+of	O
+lidocaine	O
+in	O
+a	O
+67	O
+-	O
+year	O
+-	O
+old	O
+man	O
+resulted	O
+in	O
+profound	O
+depression	B
+of	O
+the	O
+activity	O
+of	O
+the	O
+sinoatrial	O
+and	O
+atrioventricular	O
+nodal	O
+pacemakers	O
+.	O
+
+The	O
+patient	O
+had	O
+no	O
+apparent	O
+associated	O
+conditions	O
+which	O
+might	O
+have	O
+predisposed	O
+him	O
+to	O
+the	O
+development	O
+of	O
+bradyarrhythmias	B
+;	O
+and	O
+,	O
+thus	O
+,	O
+this	O
+probably	O
+represented	O
+a	O
+true	O
+idiosyncrasy	O
+to	O
+lidocaine	O
+.	O
+
+Flurbiprofen	O
+in	O
+the	O
+treatment	O
+of	O
+juvenile	B
+rheumatoid	I
+arthritis	I
+.	O
+
+Thirty	O
+-	O
+four	O
+patients	O
+with	O
+juvenile	B
+rheumatoid	I
+arthritis	I
+,	O
+who	O
+were	O
+treated	O
+with	O
+flurbiprofen	O
+at	O
+a	O
+maximum	O
+dose	O
+of	O
+4	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+,	O
+had	O
+statistically	O
+significant	O
+decreases	O
+from	O
+baseline	O
+in	O
+6	O
+arthritis	B
+indices	O
+after	O
+12	O
+weeks	O
+of	O
+treatment	O
+.	O
+
+Improvements	O
+were	O
+seen	O
+in	O
+the	O
+number	O
+of	O
+tender	B
+joints	I
+,	O
+the	O
+severity	O
+of	O
+swelling	B
+and	O
+tenderness	B
+,	O
+the	O
+time	O
+of	O
+walk	O
+50	O
+feet	O
+,	O
+the	O
+duration	O
+of	O
+morning	B
+stiffness	I
+and	O
+the	O
+circumference	O
+of	O
+the	O
+left	O
+knee	O
+.	O
+
+The	O
+most	O
+frequently	O
+observed	O
+side	O
+effect	O
+was	O
+fecal	B
+occult	I
+blood	I
+(	O
+25	O
+%	O
+of	O
+patients	O
+)	O
+;	O
+however	O
+,	O
+there	O
+was	O
+no	O
+other	O
+evidence	O
+of	O
+gastrointestinal	B
+(	I
+GI	I
+)	I
+bleeding	I
+in	O
+these	O
+patients	O
+.	O
+
+One	O
+patient	O
+was	O
+prematurely	O
+discontinued	O
+from	O
+the	O
+study	O
+for	O
+severe	O
+headache	B
+and	O
+abdominal	B
+pain	I
+.	O
+
+Most	O
+side	O
+effects	O
+were	O
+mild	O
+and	O
+related	O
+to	O
+the	O
+GI	O
+tract	O
+.	O
+
+Hyperkalemia	B
+associated	O
+with	O
+sulindac	O
+therapy	O
+.	O
+
+Hyperkalemia	B
+has	O
+recently	O
+been	O
+recognized	O
+as	O
+a	O
+complication	O
+of	O
+nonsteroidal	O
+antiinflammatory	O
+agents	O
+(	O
+NSAID	O
+)	O
+such	O
+as	O
+indomethacin	O
+.	O
+
+Several	O
+recent	O
+studies	O
+have	O
+stressed	O
+the	O
+renal	O
+sparing	O
+features	O
+of	O
+sulindac	O
+,	O
+owing	O
+to	O
+its	O
+lack	O
+of	O
+interference	O
+with	O
+renal	O
+prostacyclin	O
+synthesis	O
+.	O
+
+We	O
+describe	O
+4	O
+patients	O
+in	O
+whom	O
+hyperkalemia	B
+ranging	O
+from	O
+6	O
+.	O
+1	O
+to	O
+6	O
+.	O
+9	O
+mEq	O
+/	O
+l	O
+developed	O
+within	O
+3	O
+to	O
+8	O
+days	O
+of	O
+sulindac	O
+administration	O
+.	O
+
+In	O
+all	O
+of	O
+them	O
+normal	O
+serum	O
+potassium	O
+levels	O
+reached	O
+within	O
+2	O
+to	O
+4	O
+days	O
+of	O
+stopping	O
+sulindac	O
+.	O
+
+As	O
+no	O
+other	O
+medications	O
+known	O
+to	O
+effect	O
+serum	O
+potassium	O
+had	O
+been	O
+given	O
+concomitantly	O
+,	O
+this	O
+course	O
+of	O
+events	O
+is	O
+suggestive	O
+of	O
+a	O
+cause	O
+-	O
+and	O
+-	O
+effect	O
+relationship	O
+between	O
+sulindac	O
+and	O
+hyperkalemia	B
+.	O
+
+These	O
+observations	O
+indicate	O
+that	O
+initial	O
+hopes	O
+that	O
+sulindac	O
+may	O
+not	O
+be	O
+associated	O
+with	O
+the	O
+adverse	O
+renal	O
+effects	O
+of	O
+other	O
+NSAID	O
+are	O
+probably	O
+not	O
+justified	O
+.	O
+
+Drug	O
+-	O
+induced	O
+arterial	O
+spasm	B
+relieved	O
+by	O
+lidocaine	O
+.	O
+
+Case	O
+report	O
+.	O
+
+Following	O
+major	O
+intracranial	O
+surgery	O
+in	O
+a	O
+35	O
+-	O
+year	O
+-	O
+old	O
+man	O
+,	O
+sodium	O
+pentothal	O
+was	O
+intravenously	O
+infused	O
+to	O
+minimize	O
+cerebral	B
+ischaemia	I
+.	O
+
+Intense	O
+vasospasm	B
+with	O
+threatened	O
+gangrene	B
+arose	O
+in	O
+the	O
+arm	O
+used	O
+for	O
+the	O
+infusion	O
+.	O
+
+Since	O
+the	O
+cranial	O
+condition	O
+precluded	O
+use	O
+of	O
+more	O
+usual	O
+methods	O
+,	O
+lidocaine	O
+was	O
+given	O
+intra	O
+-	O
+arterially	O
+,	O
+with	O
+careful	O
+cardiovascular	O
+monitoring	O
+,	O
+to	O
+counteract	O
+the	O
+vasospasm	B
+.	O
+
+The	O
+treatment	O
+was	O
+rapidly	O
+successful	O
+.	O
+
+Regional	O
+localization	O
+of	O
+the	O
+antagonism	O
+of	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B
+by	O
+intracerebral	O
+calcitonin	O
+injections	O
+.	O
+
+Calcitonin	O
+receptors	O
+are	O
+found	O
+in	O
+the	O
+brain	O
+,	O
+and	O
+intracerebral	O
+infusions	O
+of	O
+calcitonin	O
+can	O
+produce	O
+behavioral	O
+effects	O
+.	O
+
+Among	O
+these	O
+behavioral	O
+effects	O
+are	O
+decreases	O
+in	O
+food	O
+intake	O
+and	O
+decreases	O
+in	O
+amphetamine	O
+-	O
+induced	O
+locomotor	O
+activity	O
+.	O
+
+In	O
+previous	O
+experiments	O
+we	O
+found	O
+that	O
+decreases	O
+in	O
+food	O
+intake	O
+were	O
+induced	O
+by	O
+local	O
+administration	O
+of	O
+calcitonin	O
+into	O
+several	O
+hypothalamic	O
+sites	O
+and	O
+into	O
+the	O
+nucleus	O
+accumbens	O
+.	O
+
+In	O
+the	O
+present	O
+experiment	O
+calcitonin	O
+decreased	O
+locomotor	O
+activity	O
+when	O
+locally	O
+injected	O
+into	O
+the	O
+same	O
+sites	O
+where	O
+it	O
+decreases	O
+food	O
+intake	O
+.	O
+
+The	O
+areas	O
+where	O
+calcitonin	O
+is	O
+most	O
+effective	O
+in	O
+decreasing	O
+locomotor	O
+activity	O
+are	O
+located	O
+in	O
+the	O
+hypothalamus	O
+and	O
+nucleus	O
+accumbens	O
+,	O
+suggesting	O
+that	O
+these	O
+areas	O
+are	O
+the	O
+major	O
+sites	O
+of	O
+action	O
+of	O
+calcitonin	O
+in	O
+inhibiting	O
+amphetamine	O
+-	O
+induced	O
+locomotor	O
+activity	O
+.	O
+
+The	O
+hematologic	O
+effects	O
+of	O
+cefonicid	O
+and	O
+cefazedone	O
+in	O
+the	O
+dog	O
+:	O
+a	O
+potential	O
+model	O
+of	O
+cephalosporin	O
+hematotoxicity	B
+in	O
+man	O
+.	O
+
+Cephalosporin	O
+antibiotics	O
+cause	O
+a	O
+variety	O
+of	O
+hematologic	B
+disturbances	I
+in	O
+man	O
+,	O
+the	O
+pathogeneses	O
+and	O
+hematopathology	O
+of	O
+which	O
+remain	O
+poorly	O
+characterized	O
+.	O
+
+There	O
+is	O
+a	O
+need	O
+for	O
+a	O
+well	O
+-	O
+defined	O
+animal	O
+model	O
+in	O
+which	O
+these	O
+blood	B
+dyscrasias	I
+can	O
+be	O
+studied	O
+.	O
+
+In	O
+four	O
+subacute	O
+toxicity	B
+studies	O
+,	O
+the	O
+intravenous	O
+administration	O
+of	O
+cefonicid	O
+or	O
+cefazedone	O
+to	O
+beagle	O
+dogs	O
+caused	O
+a	O
+dose	O
+-	O
+dependent	O
+incidence	O
+of	O
+anemia	B
+,	O
+neutropenia	B
+,	O
+and	O
+thrombocytopenia	B
+after	O
+1	O
+-	O
+3	O
+months	O
+of	O
+treatment	O
+.	O
+
+A	O
+nonregenerative	O
+anemia	B
+was	O
+the	O
+most	O
+compromising	O
+of	O
+the	O
+cytopenias	B
+and	O
+occurred	O
+in	O
+approximately	O
+50	O
+%	O
+of	O
+dogs	O
+receiving	O
+400	O
+-	O
+500	O
+mg	O
+/	O
+kg	O
+cefonicid	O
+or	O
+540	O
+-	O
+840	O
+mg	O
+/	O
+kg	O
+cefazedone	O
+.	O
+
+All	O
+three	O
+cytopenias	B
+were	O
+completely	O
+reversible	O
+following	O
+cessation	O
+of	O
+treatment	O
+;	O
+the	O
+time	O
+required	O
+for	O
+recovery	O
+of	O
+the	O
+erythron	O
+(	O
+approximately	O
+1	O
+month	O
+)	O
+was	O
+considerably	O
+longer	O
+than	O
+that	O
+of	O
+the	O
+granulocytes	O
+and	O
+platelets	O
+(	O
+hours	O
+to	O
+a	O
+few	O
+days	O
+)	O
+.	O
+
+Upon	O
+rechallenge	O
+with	O
+either	O
+cephalosporin	O
+,	O
+the	O
+hematologic	B
+syndrome	I
+was	O
+reproduced	O
+in	O
+most	O
+dogs	O
+tested	O
+;	O
+cefonicid	O
+(	O
+but	O
+not	O
+cefazedone	O
+)	O
+-	O
+treated	O
+dogs	O
+showed	O
+a	O
+substantially	O
+reduced	O
+induction	O
+period	O
+(	O
+15	O
++	O
+/	O
+-	O
+5	O
+days	O
+)	O
+compared	O
+to	O
+that	O
+of	O
+the	O
+first	O
+exposure	O
+to	O
+the	O
+drug	O
+(	O
+61	O
++	O
+/	O
+-	O
+24	O
+days	O
+)	O
+.	O
+
+This	O
+observation	O
+,	O
+along	O
+with	O
+the	O
+rapid	O
+rate	O
+of	O
+decline	O
+in	O
+red	O
+cell	O
+mass	O
+parameters	O
+of	O
+affected	O
+dogs	O
+,	O
+suggests	O
+that	O
+a	O
+hemolytic	B
+component	O
+complicated	O
+the	O
+red	O
+cell	O
+production	O
+problem	O
+and	O
+that	O
+multiple	O
+toxicologic	O
+mechanisms	O
+contributed	O
+to	O
+the	O
+cytopenia	B
+.	O
+
+We	O
+conclude	O
+that	O
+the	O
+administration	O
+of	O
+high	O
+doses	O
+of	O
+cefonicid	O
+or	O
+cefazedone	O
+to	O
+dogs	O
+can	O
+induce	O
+hematotoxicity	B
+similar	O
+to	O
+the	O
+cephalosporin	O
+-	O
+induced	O
+blood	B
+dyscrasias	I
+described	O
+in	O
+man	O
+and	O
+thus	O
+provides	O
+a	O
+useful	O
+model	O
+for	O
+studying	O
+the	O
+mechanisms	O
+of	O
+these	O
+disorders	O
+.	O
+
+Cerebral	O
+blood	O
+flow	O
+and	O
+metabolism	O
+during	O
+isoflurane	O
+-	O
+induced	O
+hypotension	B
+in	O
+patients	O
+subjected	O
+to	O
+surgery	O
+for	O
+cerebral	B
+aneurysms	I
+.	O
+
+Cerebral	O
+blood	O
+flow	O
+and	O
+cerebral	O
+metabolic	O
+rate	O
+for	O
+oxygen	O
+were	O
+measured	O
+during	O
+isoflurane	O
+-	O
+induced	O
+hypotension	B
+in	O
+10	O
+patients	O
+subjected	O
+to	O
+craniotomy	O
+for	O
+clipping	O
+of	O
+a	O
+cerebral	B
+aneurysm	I
+.	O
+
+Flow	O
+and	O
+metabolism	O
+were	O
+measured	O
+5	O
+-	O
+13	O
+days	O
+after	O
+the	O
+subarachnoid	B
+haemorrhage	I
+by	O
+a	O
+modification	O
+of	O
+the	O
+classical	O
+Kety	O
+-	O
+Schmidt	O
+technique	O
+using	O
+xenon	O
+-	O
+133	O
+i	O
+.	O
+v	O
+.	O
+Anaesthesia	O
+was	O
+maintained	O
+with	O
+an	O
+inspired	O
+isoflurane	O
+concentration	O
+of	O
+0	O
+.	O
+75	O
+%	O
+(	O
+plus	O
+67	O
+%	O
+nitrous	O
+oxide	O
+in	O
+oxygen	O
+)	O
+,	O
+during	O
+which	O
+CBF	O
+and	O
+CMRO2	O
+were	O
+34	O
+.	O
+3	O
++	O
+/	O
+-	O
+2	O
+.	O
+1	O
+ml	O
+/	O
+100	O
+g	O
+min	O
+-	O
+1	O
+and	O
+2	O
+.	O
+32	O
++	O
+/	O
+-	O
+0	O
+.	O
+16	O
+ml	O
+/	O
+100	O
+g	O
+min	O
+-	O
+1	O
+at	O
+PaCO2	O
+4	O
+.	O
+1	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+kPa	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SEM	O
+)	O
+.	O
+
+Controlled	O
+hypotension	B
+to	O
+an	O
+average	O
+MAP	O
+of	O
+50	O
+-	O
+55	O
+mm	O
+Hg	O
+was	O
+induced	O
+by	O
+increasing	O
+the	O
+dose	O
+of	O
+isoflurane	O
+,	O
+and	O
+maintained	O
+at	O
+an	O
+inspired	O
+concentration	O
+of	O
+2	O
+.	O
+2	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+%	O
+.	O
+
+This	O
+resulted	O
+in	O
+a	O
+significant	O
+decrease	O
+in	O
+CMRO2	O
+(	O
+to	O
+1	O
+.	O
+73	O
++	O
+/	O
+-	O
+0	O
+.	O
+16	O
+ml	O
+/	O
+100	O
+g	O
+min	O
+-	O
+1	O
+)	O
+,	O
+while	O
+CBF	O
+was	O
+unchanged	O
+.	O
+
+After	O
+the	O
+clipping	O
+of	O
+the	O
+aneurysm	B
+the	O
+isoflurane	O
+concentration	O
+was	O
+reduced	O
+to	O
+0	O
+.	O
+75	O
+%	O
+.	O
+
+There	O
+was	O
+a	O
+significant	O
+increase	O
+in	O
+CBF	O
+,	O
+although	O
+CMRO2	O
+was	O
+unchanged	O
+,	O
+compared	O
+with	O
+pre	O
+-	O
+hypotensive	B
+values	O
+.	O
+
+These	O
+changes	O
+might	O
+offer	O
+protection	O
+to	O
+brain	O
+tissue	O
+during	O
+periods	O
+of	O
+induced	O
+hypotension	B
+.	O
+
+Triazolam	O
+-	O
+induced	O
+brief	O
+episodes	O
+of	O
+secondary	O
+mania	B
+in	O
+a	O
+depressed	B
+patient	O
+.	O
+
+Large	O
+doses	O
+of	O
+triazolam	O
+repeatedly	O
+induced	O
+brief	O
+episodes	O
+of	O
+mania	B
+in	O
+a	O
+depressed	B
+elderly	O
+woman	O
+.	O
+
+Features	O
+of	O
+organic	B
+mental	I
+disorder	I
+(	O
+delirium	B
+)	O
+were	O
+not	O
+present	O
+.	O
+
+Manic	B
+excitement	O
+was	O
+coincident	O
+with	O
+the	O
+duration	O
+of	O
+action	O
+of	O
+triazolam	O
+.	O
+
+The	O
+possible	O
+contribution	O
+of	O
+the	O
+triazolo	O
+group	O
+to	O
+changes	O
+in	O
+affective	O
+status	O
+is	O
+discussed	O
+.	O
+
+The	O
+correlation	O
+between	O
+neurotoxic	B
+esterase	O
+inhibition	O
+and	O
+mipafox	O
+-	O
+induced	O
+neuropathic	B
+damage	I
+in	O
+rats	O
+.	O
+
+The	O
+correlation	O
+between	O
+neuropathic	B
+damage	I
+and	O
+inhibition	O
+of	O
+neurotoxic	B
+esterase	O
+or	O
+neuropathy	B
+target	O
+enzyme	O
+(	O
+NTE	O
+)	O
+was	O
+examined	O
+in	O
+rats	O
+acutely	O
+exposed	O
+to	O
+Mipafox	O
+(	O
+N	O
+,	O
+N	O
+'	O
+-	O
+diisopropylphosphorodiamidofluoridate	O
+)	O
+,	O
+a	O
+neurotoxic	B
+organophosphate	O
+.	O
+
+Brain	O
+and	O
+spinal	O
+cord	O
+NTE	O
+activities	O
+were	O
+measured	O
+in	O
+Long	O
+-	O
+Evans	O
+male	O
+rats	O
+1	O
+hr	O
+post	O
+-	O
+exposure	O
+to	O
+various	O
+dosages	O
+of	O
+Mipafox	O
+(	O
+ip	O
+,	O
+1	O
+-	O
+15	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+These	O
+data	O
+were	O
+correlated	O
+with	O
+histologically	O
+scored	O
+cervical	O
+cord	B
+damage	I
+in	O
+a	O
+separate	O
+group	O
+of	O
+similarly	O
+dosed	O
+rats	O
+sampled	O
+14	O
+-	O
+21	O
+days	O
+post	O
+-	O
+exposure	O
+.	O
+
+Those	O
+dosages	O
+(	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+that	O
+inhibited	O
+mean	O
+NTE	O
+activity	O
+in	O
+the	O
+spinal	O
+cord	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+73	O
+%	O
+and	O
+brain	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+67	O
+%	O
+of	O
+control	O
+values	O
+produced	O
+severe	O
+(	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+3	O
+)	O
+cervical	O
+cord	O
+pathology	O
+in	O
+85	O
+%	O
+of	O
+the	O
+rats	O
+.	O
+
+In	O
+contrast	O
+,	O
+dosages	O
+of	O
+Mipafox	O
+(	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+which	O
+inhibited	O
+mean	O
+NTE	O
+activity	O
+in	O
+spinal	O
+cord	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+61	O
+%	O
+and	O
+brain	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+60	O
+%	O
+produced	O
+this	O
+degree	O
+of	O
+cord	B
+damage	I
+in	O
+only	O
+9	O
+%	O
+of	O
+the	O
+animals	O
+.	O
+
+These	O
+data	O
+indicate	O
+that	O
+a	O
+critical	O
+percentage	O
+of	O
+NTE	O
+inhibition	O
+in	O
+brain	O
+and	O
+spinal	O
+cord	O
+sampled	O
+shortly	O
+after	O
+Mipafox	O
+exposure	O
+can	O
+predict	O
+neuropathic	B
+damage	I
+in	O
+rats	O
+several	O
+weeks	O
+later	O
+.	O
+
+Allergic	B
+reaction	I
+to	O
+5	O
+-	O
+fluorouracil	O
+infusion	O
+.	O
+
+An	O
+allergic	B
+reaction	I
+consisting	O
+of	O
+angioneurotic	B
+edema	I
+secondary	O
+to	O
+continuous	O
+infusion	O
+5	O
+-	O
+fluorouracil	O
+occurred	O
+in	O
+a	O
+patient	O
+with	O
+recurrent	O
+carcinoma	B
+of	I
+the	I
+oral	I
+cavity	I
+,	O
+cirrhosis	B
+,	O
+and	O
+cisplatin	O
+-	O
+induced	O
+impaired	B
+renal	I
+function	I
+.	O
+
+This	O
+reaction	O
+occurred	O
+during	O
+the	O
+sixth	O
+and	O
+seventh	O
+courses	O
+of	O
+infusional	O
+chemotherapy	O
+.	O
+
+Oral	O
+diphenhydramine	O
+and	O
+prednisone	O
+were	O
+ineffective	O
+in	O
+preventing	O
+the	O
+recurrence	O
+of	O
+the	O
+allergic	B
+reaction	I
+.	O
+
+Discontinuance	O
+of	O
+effective	O
+chemotherapy	O
+in	O
+this	O
+patient	O
+during	O
+partial	O
+remission	O
+resulted	O
+in	O
+fatal	O
+disease	O
+progression	O
+.	O
+
+Myasthenia	B
+gravis	I
+caused	O
+by	O
+penicillamine	O
+and	O
+chloroquine	O
+therapy	O
+for	O
+rheumatoid	B
+arthritis	I
+.	O
+
+We	O
+have	O
+described	O
+a	O
+unique	O
+patient	O
+who	O
+had	O
+reversible	O
+and	O
+dose	O
+-	O
+related	O
+myasthenia	B
+gravis	I
+after	O
+penicillamine	O
+and	O
+chloroquine	O
+therapy	O
+for	O
+rheumatoid	B
+arthritis	I
+.	O
+
+Although	O
+acetylcholine	O
+receptor	O
+antibodies	O
+were	O
+not	O
+detectable	O
+,	O
+the	O
+time	O
+course	O
+was	O
+consistent	O
+with	O
+an	O
+autoimmune	O
+process	O
+.	O
+
+On	O
+the	O
+mechanisms	O
+of	O
+the	O
+development	O
+of	O
+tolerance	O
+to	O
+the	O
+muscular	B
+rigidity	I
+produced	O
+by	O
+morphine	O
+in	O
+rats	O
+.	O
+
+The	O
+development	O
+of	O
+tolerance	O
+to	O
+the	O
+muscular	B
+rigidity	I
+produced	O
+by	O
+morphine	O
+was	O
+studied	O
+in	O
+rats	O
+.	O
+
+Saline	O
+-	O
+pretreated	O
+controls	O
+given	O
+a	O
+test	O
+dose	O
+of	O
+morphine	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+showed	O
+a	O
+pronounced	O
+rigidity	B
+recorded	O
+as	O
+tonic	O
+activity	O
+in	O
+the	O
+electromyogram	O
+.	O
+
+Rats	O
+treated	O
+for	O
+11	O
+days	O
+with	O
+morphine	O
+and	O
+withdrawn	O
+for	O
+36	O
+-	O
+40	O
+h	O
+showed	O
+differences	O
+in	O
+the	O
+development	O
+of	O
+tolerance	O
+:	O
+about	O
+half	O
+of	O
+the	O
+animals	O
+showed	O
+a	O
+rigidity	B
+after	O
+the	O
+test	O
+dose	O
+of	O
+morphine	O
+that	O
+was	O
+not	O
+significantly	O
+less	O
+than	O
+in	O
+the	O
+controls	O
+and	O
+were	O
+akinetic	B
+(	O
+A	O
+group	O
+)	O
+.	O
+
+The	O
+other	O
+rats	O
+showed	O
+a	O
+strong	O
+decrease	O
+in	O
+the	O
+rigidity	B
+and	O
+the	O
+occurrence	O
+of	O
+stereotyped	O
+(	O
+S	O
+)	O
+licking	O
+and	O
+/	O
+or	O
+gnawing	O
+in	O
+presence	O
+of	O
+akinetic	B
+or	O
+hyperkinetic	B
+(	O
+K	O
+)	O
+behaviour	O
+(	O
+AS	O
+/	O
+KS	O
+group	O
+)	O
+,	O
+suggesting	O
+signs	O
+of	O
+dopaminergic	O
+activation	O
+.	O
+
+The	O
+rigidity	B
+was	O
+considerably	O
+decreased	O
+in	O
+both	O
+groups	O
+after	O
+20	O
+days	O
+'	O
+treatment	O
+.	O
+
+In	O
+a	O
+further	O
+series	O
+of	O
+experiments	O
+,	O
+haloperidol	O
+(	O
+0	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+was	O
+used	O
+in	O
+order	O
+to	O
+block	O
+the	O
+dopaminergic	O
+activation	O
+and	O
+to	O
+estimate	O
+the	O
+real	O
+degree	O
+of	O
+the	O
+tolerance	O
+to	O
+the	O
+rigidity	B
+without	O
+any	O
+dopaminergic	O
+interference	O
+.	O
+
+Haloperidol	O
+enhanced	O
+the	O
+rigidity	B
+in	O
+the	O
+A	O
+group	O
+.	O
+
+However	O
+,	O
+the	O
+level	O
+in	O
+the	O
+AS	O
+/	O
+KS	O
+group	O
+remained	O
+considerably	O
+lower	O
+than	O
+in	O
+the	O
+A	O
+group	O
+.	O
+
+The	O
+results	O
+suggest	O
+that	O
+rigidity	B
+,	O
+which	O
+is	O
+assumed	O
+to	O
+be	O
+due	O
+to	O
+an	O
+action	O
+of	O
+morphine	O
+in	O
+the	O
+striatum	O
+,	O
+can	O
+be	O
+antagonized	O
+by	O
+another	O
+process	O
+leading	O
+to	O
+dopaminergic	O
+activation	O
+in	O
+the	O
+striatum	O
+.	O
+
+Nevertheless	O
+,	O
+there	O
+occurs	O
+some	O
+real	O
+tolerance	O
+to	O
+this	O
+effect	O
+.	O
+
+The	O
+rapid	O
+alternations	O
+of	O
+rigidity	B
+and	O
+the	O
+signs	O
+of	O
+dopaminergic	O
+activation	O
+observed	O
+in	O
+the	O
+animals	O
+of	O
+the	O
+AS	O
+/	O
+KS	O
+group	O
+might	O
+be	O
+due	O
+to	O
+rapid	O
+shifts	O
+in	O
+the	O
+predominance	O
+of	O
+various	O
+DA	O
+-	O
+innervated	O
+structures	O
+.	O
+
+A	O
+case	O
+of	O
+massive	O
+rhabdomyolysis	B
+following	O
+molindone	O
+administration	O
+.	O
+
+Rhabdomyolysis	B
+is	O
+a	O
+potentially	O
+lethal	O
+syndrome	O
+that	O
+psychiatric	B
+patients	O
+seem	O
+predisposed	O
+to	O
+develop	O
+.	O
+
+The	O
+clinical	O
+signs	O
+and	O
+symptoms	O
+,	O
+typical	O
+laboratory	O
+features	O
+,	O
+and	O
+complications	O
+of	O
+rhabdomyolysis	B
+are	O
+presented	O
+.	O
+
+The	O
+case	O
+of	O
+a	O
+schizophrenic	B
+patient	O
+is	O
+reported	O
+to	O
+illustrate	O
+massive	O
+rhabdomyolysis	B
+and	O
+subsequent	O
+acute	B
+renal	I
+failure	I
+following	O
+molindone	O
+administration	O
+.	O
+
+Physicians	O
+who	O
+prescribe	O
+molindone	O
+should	O
+be	O
+aware	O
+of	O
+this	O
+reaction	O
+.	O
+
+Compression	B
+neuropathy	I
+of	I
+the	I
+radial	I
+nerve	I
+due	O
+to	O
+pentazocine	O
+-	O
+induced	O
+fibrous	B
+myopathy	I
+.	O
+
+Fibrous	B
+myopathy	I
+is	O
+a	O
+common	O
+,	O
+well	O
+-	O
+known	O
+side	O
+effect	O
+of	O
+repeated	O
+pentazocine	O
+injection	O
+.	O
+
+However	O
+,	O
+compression	B
+neuropathy	I
+due	O
+to	O
+fibrotic	O
+muscle	O
+affected	O
+by	O
+pentazocine	O
+-	O
+induced	O
+myopathy	B
+has	O
+not	O
+previously	O
+been	O
+reported	O
+.	O
+
+In	O
+a	O
+37	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+documented	O
+pentazocine	O
+-	O
+induced	O
+fibrous	B
+myopathy	I
+of	O
+triceps	O
+and	O
+deltoid	O
+muscles	O
+bilaterally	O
+and	O
+a	O
+three	O
+-	O
+week	O
+history	O
+of	O
+right	O
+wrist	O
+drop	O
+,	O
+electrodiagnostic	O
+examination	O
+showed	O
+a	O
+severe	O
+but	O
+partial	O
+lesion	O
+of	O
+the	O
+right	O
+radial	O
+nerve	O
+distal	O
+to	O
+the	O
+branches	O
+to	O
+the	O
+triceps	O
+,	O
+in	O
+addition	O
+to	O
+the	O
+fibrous	B
+myopathy	I
+.	O
+
+Surgery	O
+revealed	O
+the	O
+right	O
+radial	O
+nerve	O
+to	O
+be	O
+severely	O
+compressed	O
+by	O
+the	O
+densely	O
+fibrotic	O
+lateral	O
+head	O
+of	O
+the	O
+triceps	O
+.	O
+
+Decompression	O
+and	O
+neurolysis	O
+were	O
+performed	O
+with	O
+good	O
+subsequent	O
+recovery	O
+of	O
+function	O
+.	O
+
+Recurrent	O
+reversible	O
+acute	B
+renal	I
+failure	I
+from	O
+amphotericin	O
+.	O
+
+A	O
+patient	O
+with	O
+cryptogenic	O
+cirrhosis	B
+and	O
+disseminated	O
+sporotrichosis	B
+developed	O
+acute	B
+renal	I
+failure	I
+immediately	O
+following	O
+the	O
+administration	O
+of	O
+amphotericin	O
+B	O
+on	O
+four	O
+separate	O
+occasions	O
+.	O
+
+The	O
+abruptness	O
+of	O
+the	O
+renal	B
+failure	I
+and	O
+its	O
+reversibility	O
+within	O
+days	O
+suggests	O
+that	O
+there	O
+was	O
+a	O
+functional	O
+component	O
+to	O
+the	O
+renal	B
+dysfunction	I
+.	O
+
+We	O
+propose	O
+that	O
+amphotericin	O
+,	O
+in	O
+the	O
+setting	O
+of	O
+reduced	O
+effective	O
+arterial	O
+volume	O
+,	O
+may	O
+activate	O
+tubuloglomerular	O
+feedback	O
+,	O
+thereby	O
+contributing	O
+to	O
+acute	B
+renal	I
+failure	I
+.	O
+
+Cerebral	B
+infarction	I
+with	O
+a	O
+single	O
+oral	O
+dose	O
+of	O
+phenylpropanolamine	O
+.	O
+
+Phenylpropanolamine	O
+(	O
+PPA	O
+)	O
+,	O
+a	O
+synthetic	O
+sympathomimetic	O
+that	O
+is	O
+structurally	O
+similar	O
+to	O
+amphetamine	O
+,	O
+is	O
+available	O
+over	O
+the	O
+counter	O
+in	O
+anorectics	O
+,	O
+nasal	O
+congestants	O
+,	O
+and	O
+cold	O
+preparations	O
+.	O
+
+Its	O
+prolonged	O
+use	O
+or	O
+overuse	O
+has	O
+been	O
+associated	O
+with	O
+seizures	B
+,	O
+intracerebral	B
+hemorrhage	I
+,	O
+neuropsychiatric	B
+symptoms	I
+,	O
+and	O
+nonhemorrhagic	O
+cerebral	B
+infarction	I
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+young	O
+woman	O
+who	O
+suffered	O
+a	O
+cerebral	B
+infarction	I
+after	O
+taking	O
+a	O
+single	O
+oral	O
+dose	O
+of	O
+PPA	O
+.	O
+
+Remission	O
+induction	O
+of	O
+meningeal	B
+leukemia	I
+with	O
+high	O
+-	O
+dose	O
+intravenous	O
+methotrexate	O
+.	O
+
+Twenty	O
+children	O
+with	O
+acute	B
+lymphoblastic	I
+leukemia	I
+who	O
+developed	O
+meningeal	B
+disease	I
+were	O
+treated	O
+with	O
+a	O
+high	O
+-	O
+dose	O
+intravenous	O
+methotrexate	O
+regimen	O
+that	O
+was	O
+designed	O
+to	O
+achieve	O
+and	O
+maintain	O
+CSF	O
+methotrexate	O
+concentrations	O
+of	O
+10	O
+(	O
+-	O
+5	O
+)	O
+mol	O
+/	O
+L	O
+without	O
+the	O
+need	O
+for	O
+concomitant	O
+intrathecal	O
+dosing	O
+.	O
+
+The	O
+methotrexate	O
+was	O
+administered	O
+as	O
+a	O
+loading	O
+dose	O
+of	O
+6	O
+,	O
+000	O
+mg	O
+/	O
+m2	O
+for	O
+a	O
+period	O
+of	O
+one	O
+hour	O
+followed	O
+by	O
+an	O
+infusion	O
+of	O
+1	O
+,	O
+200	O
+mg	O
+/	O
+m2	O
+/	O
+h	O
+for	O
+23	O
+hours	O
+.	O
+
+Leucovorin	O
+rescue	O
+was	O
+initiated	O
+12	O
+hours	O
+after	O
+the	O
+end	O
+of	O
+the	O
+infusion	O
+with	O
+a	O
+loading	O
+dose	O
+of	O
+200	O
+mg	O
+/	O
+m2	O
+followed	O
+by	O
+12	O
+mg	O
+/	O
+m2	O
+every	O
+three	O
+hours	O
+for	O
+six	O
+doses	O
+and	O
+then	O
+every	O
+six	O
+hours	O
+until	O
+the	O
+plasma	O
+methotrexate	O
+level	O
+decreased	O
+to	O
+less	O
+than	O
+1	O
+X	O
+10	O
+(	O
+-	O
+7	O
+)	O
+mol	O
+/	O
+L	O
+.	O
+
+The	O
+mean	O
+steady	O
+-	O
+state	O
+plasma	O
+and	O
+CSF	O
+methotrexate	O
+concentrations	O
+achieved	O
+were	O
+1	O
+.	O
+1	O
+X	O
+10	O
+(	O
+-	O
+3	O
+)	O
+mol	O
+/	O
+L	O
+and	O
+3	O
+.	O
+6	O
+X	O
+10	O
+(	O
+-	O
+5	O
+)	O
+mol	O
+/	O
+L	O
+,	O
+respectively	O
+.	O
+
+All	O
+20	O
+patients	O
+responded	O
+to	O
+this	O
+regimen	O
+,	O
+16	O
+/	O
+20	O
+(	O
+80	O
+%	O
+)	O
+achieved	O
+a	O
+complete	O
+remission	O
+,	O
+and	O
+20	O
+%	O
+obtained	O
+a	O
+partial	O
+remission	O
+.	O
+
+The	O
+most	O
+common	O
+toxicities	B
+encountered	O
+were	O
+transient	O
+serum	O
+transaminase	O
+and	O
+bilirubin	O
+elevations	O
+,	O
+neutropenia	B
+,	O
+and	O
+mucositis	B
+.	O
+
+One	O
+patient	O
+had	O
+focal	O
+seizures	B
+and	O
+transient	B
+hemiparesis	I
+but	O
+recovered	O
+completely	O
+.	O
+
+High	O
+-	O
+dose	O
+intravenous	O
+methotrexate	O
+is	O
+an	O
+effective	O
+treatment	O
+for	O
+the	O
+induction	O
+of	O
+remission	O
+after	O
+meningeal	O
+relapse	O
+in	O
+acute	B
+lymphoblastic	I
+leukemia	I
+.	O
+
+Interaction	O
+of	O
+cyclosporin	O
+A	O
+with	O
+antineoplastic	O
+agents	O
+.	O
+
+A	O
+synergistic	O
+effect	O
+of	O
+etoposide	O
+and	O
+cyclosporin	O
+A	O
+was	O
+observed	O
+in	O
+a	O
+patient	O
+with	O
+acute	B
+T	I
+-	I
+lymphocytic	I
+leukemia	I
+in	O
+relapse	O
+.	O
+
+The	O
+concomitant	O
+administration	O
+of	O
+etoposide	O
+and	O
+cyclosporin	O
+A	O
+resulted	O
+in	O
+eradication	O
+of	O
+hitherto	O
+refractory	O
+leukemic	B
+infiltration	I
+of	O
+bone	O
+marrow	O
+.	O
+
+Severe	O
+side	O
+effects	O
+in	O
+terms	O
+of	O
+mental	O
+confusion	B
+and	O
+progressive	O
+hyperbilirubinemia	B
+,	O
+however	O
+,	O
+point	O
+to	O
+an	O
+enhancement	O
+not	O
+only	O
+of	O
+antineoplastic	O
+effects	O
+but	O
+also	O
+of	O
+toxicity	B
+in	O
+normal	O
+tissues	O
+.	O
+
+This	O
+report	O
+demonstrates	O
+for	O
+the	O
+first	O
+time	O
+that	O
+the	O
+pharmacodynamic	O
+properties	O
+of	O
+cyclosporin	O
+A	O
+may	O
+not	O
+be	O
+confined	O
+strictly	O
+to	O
+suppression	O
+of	O
+normal	O
+T	O
+-	O
+cell	O
+functions	O
+.	O
+
+Incidence	O
+of	O
+neoplasms	B
+in	O
+patients	O
+with	O
+rheumatoid	B
+arthritis	I
+exposed	O
+to	O
+different	O
+treatment	O
+regimens	O
+.	O
+
+Immunosuppressive	O
+drugs	O
+have	O
+been	O
+used	O
+during	O
+the	O
+last	O
+30	O
+years	O
+in	O
+treatment	O
+of	O
+patients	O
+with	O
+severe	O
+rheumatoid	B
+arthritis	I
+.	O
+
+The	O
+drugs	O
+commonly	O
+used	O
+are	O
+cyclophosphamide	O
+and	O
+chlorambucil	O
+(	O
+alkylating	O
+agents	O
+)	O
+,	O
+azathioprine	O
+(	O
+purine	O
+analogue	O
+)	O
+,	O
+and	O
+methotrexate	O
+(	O
+folic	O
+acid	O
+analogue	O
+)	O
+.	O
+
+There	O
+is	O
+evidence	O
+that	O
+all	O
+four	O
+immunosuppressive	O
+drugs	O
+can	O
+reduce	O
+synovitis	B
+,	O
+but	O
+disease	O
+activity	O
+almost	O
+always	O
+recurs	O
+after	O
+therapy	O
+is	O
+stopped	O
+.	O
+
+Since	O
+adverse	O
+reactions	O
+are	O
+frequent	O
+,	O
+less	O
+than	O
+50	O
+percent	O
+of	O
+patients	O
+are	O
+able	O
+to	O
+continue	O
+a	O
+particular	O
+drug	O
+for	O
+more	O
+than	O
+one	O
+year	O
+.	O
+
+Since	O
+it	O
+takes	O
+three	O
+to	O
+12	O
+months	O
+to	O
+achieve	O
+maximal	O
+effects	O
+,	O
+those	O
+patients	O
+who	O
+are	O
+unable	O
+to	O
+continue	O
+the	O
+drug	O
+receive	O
+little	O
+benefit	O
+from	O
+it	O
+.	O
+
+Patients	O
+treated	O
+with	O
+alkylating	O
+agents	O
+have	O
+an	O
+increased	O
+risk	O
+of	O
+development	O
+of	O
+acute	B
+nonlymphocytic	I
+leukemia	I
+,	O
+and	O
+both	O
+alkylating	O
+agents	O
+and	O
+azathioprine	O
+are	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+non	B
+-	I
+Hodgkin	I
+'	I
+s	I
+lymphoma	I
+.	O
+
+Cyclophosphamide	O
+therapy	O
+increases	O
+the	O
+risk	O
+of	O
+carcinoma	B
+of	I
+the	I
+bladder	I
+.	O
+
+There	O
+have	O
+been	O
+several	O
+long	O
+-	O
+term	O
+studies	O
+of	O
+patients	O
+with	O
+rheumatoid	B
+arthritis	I
+treated	O
+with	O
+azathioprine	O
+and	O
+cyclophosphamide	O
+and	O
+the	O
+incidence	O
+of	O
+most	O
+of	O
+the	O
+common	O
+cancers	B
+is	O
+not	O
+increased	O
+.	O
+
+Data	O
+on	O
+the	O
+possible	O
+increased	O
+risk	O
+of	O
+malignancy	B
+in	O
+rheumatoid	B
+arthritis	I
+are	O
+still	O
+being	O
+collected	O
+,	O
+and	O
+until	O
+further	O
+information	O
+is	O
+available	O
+,	O
+the	O
+use	O
+of	O
+immunosuppressive	O
+drugs	O
+,	O
+particularly	O
+alkylating	O
+agents	O
+,	O
+in	O
+the	O
+treatment	O
+of	O
+rheumatoid	B
+arthritis	I
+should	O
+be	O
+reserved	O
+for	O
+patients	O
+with	O
+severe	O
+progressive	O
+disease	O
+or	O
+life	O
+-	O
+threatening	O
+complications	O
+.	O
+
+Warfarin	O
+-	O
+induced	O
+iliopsoas	O
+hemorrhage	B
+with	O
+subsequent	O
+femoral	B
+nerve	I
+palsy	I
+.	O
+
+We	O
+present	O
+the	O
+case	O
+of	O
+a	O
+28	O
+-	O
+year	O
+-	O
+old	O
+man	O
+on	O
+chronic	O
+warfarin	O
+therapy	O
+who	O
+sustained	O
+a	O
+minor	O
+muscle	B
+tear	I
+and	O
+developed	O
+increasing	O
+pain	B
+and	O
+a	O
+flexure	O
+contracture	B
+of	O
+the	O
+right	O
+hip	O
+.	O
+
+Surgical	O
+exploration	O
+revealed	O
+an	O
+iliopsoas	O
+hematoma	B
+and	O
+femoral	O
+nerve	B
+entrapment	I
+,	O
+resulting	O
+in	O
+a	O
+femoral	B
+nerve	I
+palsy	I
+and	O
+partial	B
+loss	I
+of	I
+quadriceps	I
+functions	I
+.	O
+
+Anticoagulant	O
+-	O
+induced	O
+femoral	B
+nerve	I
+palsy	I
+represents	O
+the	O
+most	O
+common	O
+form	O
+of	O
+warfarin	O
+-	O
+induced	O
+peripheral	B
+neuropathy	I
+;	O
+it	O
+is	O
+characterized	O
+by	O
+severe	O
+pain	B
+in	O
+the	O
+inguinal	O
+region	O
+,	O
+varying	O
+degrees	O
+of	O
+motor	B
+and	I
+sensory	I
+impairment	I
+,	O
+and	O
+flexure	O
+contracture	B
+of	O
+the	O
+involved	O
+extremity	O
+.	O
+
+Pneumonitis	O
+with	O
+pleural	B
+and	I
+pericardial	I
+effusion	I
+and	O
+neuropathy	B
+during	O
+amiodarone	O
+therapy	O
+.	O
+
+A	O
+patient	O
+with	O
+sinuatrial	B
+disease	I
+and	O
+implanted	O
+pacemaker	O
+was	O
+treated	O
+with	O
+amiodarone	O
+(	O
+maximum	O
+dose	O
+1000	O
+mg	O
+,	O
+maintenance	O
+dose	O
+800	O
+mg	O
+daily	O
+)	O
+for	O
+10	O
+months	O
+,	O
+for	O
+control	O
+of	O
+supraventricular	B
+tachyarrhythmias	I
+.	O
+
+He	O
+developed	O
+pneumonitis	B
+,	O
+pleural	B
+and	I
+pericardial	I
+effusions	I
+,	O
+and	O
+a	O
+predominantly	O
+proximal	B
+motor	I
+neuropathy	I
+.	O
+
+Immediate	O
+but	O
+gradual	O
+improvement	O
+followed	O
+withdrawal	O
+of	O
+amiodarone	O
+and	O
+treatment	O
+with	O
+prednisolone	O
+.	O
+
+Review	O
+of	O
+this	O
+and	O
+previously	O
+reported	O
+cases	O
+indicates	O
+the	O
+need	O
+for	O
+early	O
+diagnosis	O
+of	O
+amiodarone	O
+pneumonitis	B
+,	O
+immediate	O
+withdrawal	O
+of	O
+amiodarone	O
+,	O
+and	O
+prompt	O
+but	O
+continued	O
+steroid	O
+therapy	O
+to	O
+ensure	O
+full	O
+recovery	O
+.	O
+
+Amiodarone	O
+-	O
+induced	O
+sinoatrial	B
+block	I
+.	O
+
+We	O
+observed	O
+sinoatrial	B
+block	I
+due	O
+to	O
+chronic	O
+amiodarone	O
+administration	O
+in	O
+a	O
+5	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+with	O
+primary	B
+cardiomyopathy	I
+,	O
+Wolff	B
+-	I
+Parkinson	I
+-	I
+White	I
+syndrome	I
+and	O
+supraventricular	B
+tachycardia	I
+.	O
+
+Reduction	O
+in	O
+the	O
+dosage	O
+of	O
+amiodarone	O
+resulted	O
+in	O
+the	O
+disappearance	O
+of	O
+the	O
+sinoatrial	B
+block	I
+and	O
+the	O
+persistence	O
+of	O
+asymptomatic	O
+sinus	B
+bradycardia	I
+.	O
+
+Desipramine	O
+-	O
+induced	O
+delirium	B
+at	O
+"	O
+subtherapeutic	O
+"	O
+concentrations	O
+:	O
+a	O
+case	O
+report	O
+.	O
+
+An	O
+elderly	O
+patient	O
+treated	O
+with	O
+low	O
+dose	O
+Desipramine	O
+developed	O
+a	O
+delirium	B
+while	O
+her	O
+plasma	O
+level	O
+was	O
+in	O
+the	O
+"	O
+subtherapeutic	O
+"	O
+range	O
+.	O
+
+Delirium	B
+,	O
+which	O
+may	O
+be	O
+induced	O
+by	O
+tricyclic	O
+drug	O
+therapy	O
+in	O
+the	O
+elderly	O
+,	O
+can	O
+be	O
+caused	O
+by	O
+tricyclics	O
+with	O
+low	O
+anticholinergic	O
+potency	O
+.	O
+
+Therapeutic	O
+ranges	O
+for	O
+antidepressants	O
+that	O
+have	O
+been	O
+derived	O
+from	O
+general	O
+adult	O
+population	O
+studies	O
+may	O
+not	O
+be	O
+appropriate	O
+for	O
+the	O
+elderly	O
+.	O
+
+Further	O
+studies	O
+of	O
+specifically	O
+elderly	O
+patients	O
+are	O
+now	O
+required	O
+to	O
+establish	O
+safer	O
+and	O
+more	O
+appropriate	O
+guidelines	O
+for	O
+drug	O
+therapy	O
+.	O
+
+Indomethacin	O
+-	O
+induced	O
+renal	B
+insufficiency	I
+:	O
+recurrence	O
+on	O
+rechallenge	O
+.	O
+
+We	O
+have	O
+reported	O
+a	O
+case	O
+of	O
+acute	O
+oliguric	O
+renal	B
+failure	I
+with	O
+hyperkalemia	B
+in	O
+a	O
+patient	O
+with	O
+cirrhosis	B
+,	O
+ascites	B
+,	O
+and	O
+cor	B
+pulmonale	I
+after	O
+indomethacin	O
+therapy	O
+.	O
+
+Prompt	O
+restoration	O
+of	O
+renal	O
+function	O
+followed	O
+drug	O
+withdrawal	O
+,	O
+while	O
+re	O
+-	O
+exposure	O
+to	O
+a	O
+single	O
+dose	O
+of	O
+indomethacin	O
+caused	O
+recurrence	O
+of	O
+acute	O
+reversible	O
+oliguria	B
+.	O
+
+Our	O
+case	O
+supports	O
+the	O
+hypothesis	O
+that	O
+endogenous	O
+renal	O
+prostaglandins	O
+play	O
+a	O
+role	O
+in	O
+the	O
+maintenance	O
+of	O
+renal	O
+blood	O
+flow	O
+when	O
+circulating	O
+plasma	O
+volume	O
+is	O
+diminished	O
+.	O
+
+Since	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+agents	O
+interfere	O
+with	O
+this	O
+compensatory	O
+mechanism	O
+and	O
+may	O
+cause	O
+acute	B
+renal	I
+failure	I
+,	O
+they	O
+should	O
+be	O
+used	O
+with	O
+caution	O
+in	O
+such	O
+patients	O
+.	O
+
+Patterns	O
+of	O
+hepatic	B
+injury	I
+induced	O
+by	O
+methyldopa	O
+.	O
+
+Twelve	O
+patients	O
+with	O
+liver	B
+disease	I
+related	O
+to	O
+methyldopa	O
+were	O
+seen	O
+between	O
+1967	O
+and	O
+1977	O
+.	O
+
+Illness	O
+occurred	O
+within	O
+1	O
+-	O
+-	O
+9	O
+weeks	O
+of	O
+commencement	O
+of	O
+therapy	O
+in	O
+9	O
+patients	O
+,	O
+the	O
+remaining	O
+3	O
+patients	O
+having	O
+received	O
+the	O
+drug	O
+for	O
+13	O
+months	O
+,	O
+15	O
+months	O
+and	O
+7	O
+years	O
+before	O
+experiencing	O
+symptoms	O
+.	O
+
+Jaundice	B
+with	O
+tender	O
+hepatomegaly	B
+,	O
+usually	O
+preceded	O
+by	O
+symptoms	O
+of	O
+malaise	O
+,	O
+anorexia	B
+,	O
+nausea	B
+and	O
+vomiting	B
+,	O
+and	O
+associated	O
+with	O
+upper	O
+abdominal	B
+pain	I
+,	O
+was	O
+an	O
+invariable	O
+finding	O
+in	O
+all	O
+patients	O
+.	O
+
+Biochemical	O
+liver	O
+function	O
+tests	O
+indicated	O
+hepatocellular	O
+necrosis	B
+and	O
+correlated	O
+with	O
+histopathological	O
+evidence	O
+of	O
+hepatic	B
+injury	I
+,	O
+the	O
+spectrum	O
+of	O
+which	O
+ranged	O
+from	O
+fatty	B
+change	I
+and	O
+focal	O
+hepatocellular	O
+necrosis	B
+to	O
+massive	B
+hepatic	I
+necrosis	I
+.	O
+
+Most	O
+patients	O
+showed	O
+moderate	O
+to	O
+severe	O
+acute	B
+hepatitis	I
+or	O
+chronic	B
+active	I
+hepatitis	I
+with	O
+associated	O
+cholestasis	B
+.	O
+
+The	O
+drug	O
+was	O
+withdrawn	O
+on	O
+presentation	O
+to	O
+hospital	O
+in	O
+11	O
+patients	O
+,	O
+with	O
+rapid	O
+clinical	O
+improvement	O
+in	O
+9	O
+.	O
+
+One	O
+patient	O
+died	O
+,	O
+having	O
+presented	O
+in	O
+hepatic	B
+failure	I
+,	O
+and	O
+another	O
+,	O
+who	O
+had	O
+been	O
+taking	O
+methyldopa	O
+for	O
+7	O
+years	O
+,	O
+showed	O
+slower	O
+clinical	O
+and	O
+biochemical	O
+resolution	O
+over	O
+a	O
+period	O
+of	O
+several	O
+months	O
+.	O
+
+The	O
+remaining	O
+patient	O
+in	O
+the	O
+series	O
+developed	O
+fulminant	B
+hepatitis	I
+when	O
+the	O
+drug	O
+was	O
+accidentally	O
+recommenced	O
+1	O
+year	O
+after	O
+a	O
+prior	O
+episode	O
+of	O
+methyldopa	O
+-	O
+induced	O
+hepatitis	B
+.	O
+
+In	O
+this	O
+latter	O
+patient	O
+,	O
+and	O
+in	O
+2	O
+others	O
+,	O
+the	O
+causal	O
+relationship	O
+between	O
+methyldopa	O
+and	O
+hepatic	B
+dysfunction	I
+was	O
+proved	O
+with	O
+the	O
+recurrence	O
+of	O
+hepatitis	B
+within	O
+2	O
+weeks	O
+of	O
+re	O
+-	O
+exposure	O
+to	O
+the	O
+drug	O
+.	O
+
+Suxamethonium	O
+infusion	O
+rate	O
+and	O
+observed	O
+fasciculations	B
+.	O
+
+A	O
+dose	O
+-	O
+response	O
+study	O
+.	O
+
+Suxamethonium	O
+chloride	O
+(	O
+Sch	O
+)	O
+was	O
+administered	O
+i	O
+.	O
+v	O
+.	O
+to	O
+36	O
+adult	O
+males	O
+at	O
+six	O
+rates	O
+:	O
+0	O
+.	O
+25	O
+mg	O
+s	O
+-	O
+1	O
+to	O
+20	O
+mg	O
+s	O
+-	O
+1	O
+.	O
+
+The	O
+infusion	O
+was	O
+discontinued	O
+either	O
+when	O
+there	O
+was	O
+no	O
+muscular	O
+response	O
+to	O
+tetanic	B
+stimulation	O
+of	O
+the	O
+ulnar	O
+nerve	O
+or	O
+when	O
+Sch	O
+120	O
+mg	O
+was	O
+exceeded	O
+.	O
+
+Six	O
+additional	O
+patients	O
+received	O
+a	O
+30	O
+-	O
+mg	O
+i	O
+.	O
+v	O
+.	O
+bolus	O
+dose	O
+.	O
+
+Fasciculations	B
+in	O
+six	O
+areas	O
+of	O
+the	O
+body	O
+were	O
+scored	O
+from	O
+0	O
+to	O
+3	O
+and	O
+summated	O
+as	O
+a	O
+total	O
+fasciculation	B
+score	O
+.	O
+
+The	O
+times	O
+to	O
+first	O
+fasciculation	B
+,	O
+twitch	B
+suppression	O
+and	O
+tetanus	B
+suppression	O
+were	O
+inversely	O
+related	O
+to	O
+the	O
+infusion	O
+rates	O
+.	O
+
+Fasciculations	B
+in	O
+the	O
+six	O
+areas	O
+and	O
+the	O
+total	O
+fasciculation	B
+score	O
+were	O
+related	O
+directly	O
+to	O
+the	O
+rate	O
+of	O
+infusion	O
+.	O
+
+Total	O
+fasciculation	B
+scores	O
+in	O
+the	O
+30	O
+-	O
+mg	O
+bolus	O
+group	O
+and	O
+the	O
+5	O
+-	O
+mg	O
+s	O
+-	O
+1	O
+and	O
+20	O
+-	O
+mg	O
+s	O
+-	O
+1	O
+infusion	O
+groups	O
+were	O
+not	O
+significantly	O
+different	O
+.	O
+
+Treatment	O
+of	O
+psoriasis	B
+with	O
+azathioprine	O
+.	O
+
+Azathioprine	O
+treatment	O
+benefited	O
+19	O
+(	O
+66	O
+%	O
+)	O
+out	O
+of	O
+29	O
+patients	O
+suffering	O
+from	O
+severe	O
+psoriasis	B
+.	O
+
+Haematological	O
+complications	O
+were	O
+not	O
+troublesome	O
+and	O
+results	O
+of	O
+biochemical	O
+liver	O
+function	O
+tests	O
+remained	O
+normal	O
+.	O
+
+Minimal	O
+cholestasis	B
+was	O
+seen	O
+in	O
+two	O
+cases	O
+and	O
+portal	O
+fibrosis	B
+of	O
+a	O
+reversible	O
+degree	O
+in	O
+eight	O
+.	O
+
+Liver	O
+biopsies	O
+should	O
+be	O
+undertaken	O
+at	O
+regular	O
+intervals	O
+if	O
+azathioprine	O
+therapy	O
+is	O
+continued	O
+so	O
+that	O
+structural	O
+liver	B
+damage	I
+may	O
+be	O
+detected	O
+at	O
+an	O
+early	O
+and	O
+reversible	O
+stage	O
+.	O
+
+Angiosarcoma	B
+of	I
+the	I
+liver	I
+associated	O
+with	O
+diethylstilbestrol	O
+.	O
+
+Angiosarcoma	B
+of	I
+the	I
+liver	I
+occurred	O
+in	O
+a	O
+76	O
+-	O
+year	O
+-	O
+old	O
+man	O
+who	O
+had	O
+been	O
+treated	O
+for	O
+a	O
+well	O
+-	O
+differentiated	O
+adenocarcinoma	B
+of	I
+the	I
+liver	I
+with	O
+diethylstilbestrol	O
+for	O
+13	O
+years	O
+.	O
+
+Angiosarcoma	B
+was	O
+also	O
+present	O
+within	O
+pulmonary	O
+and	O
+renal	O
+arteries	O
+.	O
+
+The	O
+possibility	O
+that	O
+the	O
+intraarterial	B
+lesions	I
+might	O
+represent	O
+independent	O
+primary	O
+tumors	B
+is	O
+considered	O
+.	O
+
+Galanthamine	O
+hydrobromide	O
+,	O
+a	O
+longer	O
+acting	O
+anticholinesterase	O
+drug	O
+,	O
+in	O
+the	O
+treatment	O
+of	O
+the	O
+central	O
+effects	O
+of	O
+scopolamine	O
+(	O
+Hyoscine	O
+)	O
+.	O
+
+Galanthamine	O
+hydrobromide	O
+,	O
+an	O
+anticholinesterase	O
+drug	O
+capable	O
+of	O
+penetrating	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+,	O
+was	O
+used	O
+in	O
+a	O
+patient	O
+demonstrating	O
+central	O
+effects	O
+of	O
+scopolamine	O
+(	O
+hyoscine	O
+)	O
+overdosage	B
+.	O
+
+It	O
+is	O
+longer	O
+acting	O
+than	O
+physostigmine	O
+and	O
+is	O
+used	O
+in	O
+anaesthesia	O
+to	O
+reverse	O
+the	O
+non	O
+-	O
+depolarizing	O
+neuromuscular	O
+block	O
+.	O
+
+However	O
+,	O
+studies	O
+into	O
+the	O
+dose	O
+necessary	O
+to	O
+combating	O
+scopolamine	O
+intoxication	O
+are	O
+indicated	O
+.	O
+
+Comparison	O
+of	O
+the	O
+subjective	O
+effects	O
+and	O
+plasma	O
+concentrations	O
+following	O
+oral	O
+and	O
+i	O
+.	O
+m	O
+.	O
+administration	O
+of	O
+flunitrazepam	O
+in	O
+volunteers	O
+.	O
+
+Flunitrazepam	O
+0	O
+.	O
+5	O
+,	O
+1	O
+.	O
+0	O
+or	O
+2	O
+.	O
+0	O
+mg	O
+was	O
+given	O
+by	O
+the	O
+oral	O
+or	O
+i	O
+.	O
+m	O
+.	O
+routes	O
+to	O
+groups	O
+of	O
+volunteers	O
+and	O
+its	O
+effects	O
+compared	O
+.	O
+
+Plasma	O
+concentrations	O
+of	O
+the	O
+drug	O
+were	O
+estimated	O
+by	O
+gas	O
+-	O
+liquid	O
+chromatography	O
+,	O
+in	O
+a	O
+smaller	O
+number	O
+of	O
+the	O
+subjects	O
+.	O
+
+The	O
+most	O
+striking	O
+effect	O
+was	O
+sedation	O
+which	O
+increased	O
+with	O
+the	O
+dose	O
+,	O
+2	O
+mg	O
+producing	O
+deep	O
+sleep	O
+although	O
+the	O
+subjects	O
+could	O
+still	O
+be	O
+aroused	O
+.	O
+
+The	O
+effects	O
+of	O
+i	O
+.	O
+m	O
+.	O
+administration	O
+were	O
+apparent	O
+earlier	O
+and	O
+sometimes	O
+lasted	O
+longer	O
+than	O
+those	O
+following	O
+oral	O
+administration	O
+.	O
+
+Dizziness	B
+was	O
+less	O
+marked	O
+than	O
+sedation	O
+,	O
+but	O
+increased	O
+with	O
+the	O
+dose	O
+.	O
+
+There	O
+was	O
+pain	B
+on	O
+i	O
+.	O
+m	O
+.	O
+injection	O
+of	O
+flunitrazepam	O
+significantly	O
+more	O
+often	O
+than	O
+with	O
+isotonic	O
+saline	O
+.	O
+
+Plasma	O
+concentrations	O
+varied	O
+with	O
+dose	O
+and	O
+route	O
+and	O
+corresponded	O
+qualitatively	O
+with	O
+the	O
+subjective	O
+effects	O
+.	O
+
+The	O
+drug	O
+was	O
+still	O
+present	O
+in	O
+measurable	O
+quantities	O
+after	O
+24	O
+h	O
+even	O
+with	O
+the	O
+smallest	O
+dose	O
+.	O
+
+Possible	O
+teratogenicity	O
+of	O
+sulphasalazine	O
+.	O
+
+Three	O
+infants	O
+,	O
+born	O
+of	O
+two	O
+mothers	O
+with	O
+inflammatory	B
+bowel	I
+disease	I
+who	O
+received	O
+treatment	O
+with	O
+sulphasalazine	O
+throughout	O
+pregnancy	O
+,	O
+were	O
+found	O
+to	O
+have	O
+major	O
+congenital	B
+anomalies	I
+.	O
+
+In	O
+the	O
+singleton	O
+pregnancy	O
+,	O
+the	O
+mother	O
+had	O
+ulcerative	B
+colitis	I
+,	O
+and	O
+the	O
+infant	O
+,	O
+a	O
+male	O
+,	O
+had	O
+coarctation	B
+of	I
+the	I
+aorta	I
+and	O
+a	O
+ventricular	B
+septal	I
+defect	I
+.	O
+
+In	O
+the	O
+twin	O
+pregnancy	O
+,	O
+the	O
+mother	O
+had	O
+Crohn	B
+'	I
+s	I
+disease	I
+.	O
+
+The	O
+first	O
+twin	O
+,	O
+a	O
+female	O
+,	O
+had	O
+a	O
+left	O
+Potter	B
+-	I
+type	I
+IIa	I
+polycystic	I
+kidney	I
+and	O
+a	O
+rudimentary	B
+left	I
+uterine	I
+cornu	I
+.	O
+
+The	O
+second	O
+twin	O
+,	O
+a	O
+male	O
+,	O
+had	O
+some	O
+features	O
+of	O
+Potter	B
+'	I
+s	I
+facies	I
+,	O
+hypoplastic	B
+lungs	I
+,	O
+absent	B
+kidneys	I
+and	I
+ureters	I
+,	O
+and	O
+talipes	B
+equinovarus	I
+.	O
+
+Despite	O
+reports	O
+to	O
+the	O
+contrary	O
+,	O
+it	O
+is	O
+suggested	O
+that	O
+sulphasalazine	O
+may	O
+be	O
+teratogenic	O
+.	O
+
+Thrombotic	B
+microangiopathy	I
+and	O
+renal	B
+failure	I
+associated	O
+with	O
+antineoplastic	O
+chemotherapy	O
+.	O
+
+Five	O
+patients	O
+with	O
+carcinoma	B
+developed	O
+thrombotic	B
+microangiopathy	I
+(	O
+characterized	O
+by	O
+renal	B
+insufficiency	I
+,	O
+microangiopathic	B
+hemolytic	I
+anemia	I
+,	O
+and	O
+usually	O
+thrombocytopenia	B
+)	O
+after	O
+treatment	O
+with	O
+cisplatin	O
+,	O
+bleomycin	O
+,	O
+and	O
+a	O
+vinca	O
+alkaloid	O
+.	O
+
+One	O
+patient	O
+had	O
+thrombotic	B
+thrombocytopenic	I
+purpura	I
+,	O
+three	O
+the	O
+hemolytic	B
+-	I
+uremic	I
+syndrome	I
+,	O
+and	O
+one	O
+an	O
+apparent	O
+forme	O
+fruste	O
+of	O
+one	O
+of	O
+these	O
+disorders	O
+.	O
+
+Histologic	O
+examination	O
+of	O
+the	O
+renal	O
+tissue	O
+showed	O
+evidence	O
+of	O
+intravascular	B
+coagulation	I
+,	O
+primarily	O
+affecting	O
+the	O
+small	O
+arteries	O
+,	O
+arterioles	O
+,	O
+and	O
+glomeruli	O
+.	O
+
+Because	O
+each	O
+patient	O
+was	O
+tumor	B
+-	O
+free	O
+or	O
+had	O
+only	O
+a	O
+small	O
+tumor	B
+at	O
+the	O
+onset	O
+of	O
+this	O
+syndrome	O
+,	O
+the	O
+thrombotic	B
+microangiopathy	I
+may	O
+have	O
+been	O
+induced	O
+by	O
+chemotherapy	O
+.	O
+
+Diagnosis	O
+of	O
+this	O
+potentially	O
+fatal	O
+complication	O
+may	O
+be	O
+delayed	O
+or	O
+missed	O
+if	O
+renal	O
+tissue	O
+or	O
+the	O
+peripheral	O
+blood	O
+smear	O
+is	O
+not	O
+examined	O
+,	O
+because	O
+renal	B
+failure	I
+may	O
+be	O
+ascribed	O
+to	O
+cisplatin	O
+nephrotoxicity	B
+and	O
+the	O
+anemia	B
+and	O
+thrombocytopenia	B
+to	O
+drug	O
+-	O
+induced	O
+bone	B
+marrow	I
+suppression	I
+.	O
+
+International	O
+mexiletine	O
+and	O
+placebo	O
+antiarrhythmic	O
+coronary	O
+trial	O
+:	O
+I	O
+.	O
+
+Report	O
+on	O
+arrhythmia	B
+and	O
+other	O
+findings	O
+.	O
+
+Impact	O
+Research	O
+Group	O
+.	O
+
+The	O
+antiarrhythmic	O
+effects	O
+of	O
+the	O
+sustained	O
+release	O
+form	O
+of	O
+mexiletine	O
+(	O
+Mexitil	O
+-	O
+Perlongets	O
+)	O
+were	O
+evaluated	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+placebo	O
+trial	O
+in	O
+630	O
+patients	O
+with	O
+recent	O
+documented	O
+myocardial	B
+infarction	I
+.	O
+
+The	O
+primary	O
+response	O
+variable	O
+was	O
+based	O
+on	O
+central	O
+reading	O
+of	O
+24	O
+hour	O
+ambulatory	O
+electrocardiographic	O
+recordings	O
+and	O
+was	O
+defined	O
+as	O
+the	O
+occurrence	O
+of	O
+30	O
+or	O
+more	O
+single	O
+premature	O
+ventricular	O
+complexes	O
+in	O
+any	O
+two	O
+consecutive	O
+30	O
+minute	O
+blocks	O
+or	O
+one	O
+or	O
+more	O
+runs	O
+of	O
+two	O
+or	O
+more	O
+premature	O
+ventricular	O
+complexes	O
+in	O
+the	O
+entire	O
+24	O
+hour	O
+electrocardiographic	O
+recording	O
+.	O
+
+Large	O
+differences	O
+,	O
+regarded	O
+as	O
+statistically	O
+significant	O
+,	O
+between	O
+the	O
+mexiletine	O
+and	O
+placebo	O
+groups	O
+were	O
+noted	O
+in	O
+that	O
+end	O
+point	O
+at	O
+months	O
+1	O
+and	O
+4	O
+,	O
+but	O
+only	O
+trends	O
+were	O
+observed	O
+at	O
+month	O
+12	O
+.	O
+
+These	O
+differences	O
+were	O
+observed	O
+even	O
+though	O
+the	O
+serum	O
+mexiletine	O
+levels	O
+obtained	O
+in	O
+this	O
+study	O
+were	O
+generally	O
+lower	O
+than	O
+those	O
+observed	O
+in	O
+studies	O
+that	O
+have	O
+used	O
+the	O
+regular	O
+form	O
+of	O
+the	O
+drug	O
+.	O
+
+There	O
+were	O
+more	O
+deaths	B
+in	O
+the	O
+mexiletine	O
+group	O
+(	O
+7	O
+.	O
+6	O
+%	O
+)	O
+than	O
+in	O
+the	O
+placebo	O
+group	O
+(	O
+4	O
+.	O
+8	O
+%	O
+)	O
+;	O
+the	O
+difference	O
+was	O
+not	O
+statistically	O
+significant	O
+.	O
+
+The	O
+incidence	O
+of	O
+coronary	O
+events	O
+was	O
+similar	O
+in	O
+both	O
+groups	O
+.	O
+
+Previously	O
+recognized	O
+side	O
+effects	O
+,	O
+particularly	O
+tremor	B
+and	O
+gastrointestinal	B
+problems	I
+,	O
+were	O
+more	O
+frequent	O
+in	O
+the	O
+mexiletine	O
+group	O
+than	O
+in	O
+the	O
+placebo	O
+group	O
+.	O
+
+Changes	O
+in	O
+heart	O
+size	O
+during	O
+long	O
+-	O
+term	O
+timolol	O
+treatment	O
+after	O
+myocardial	B
+infarction	I
+.	O
+
+The	O
+effect	O
+of	O
+long	O
+-	O
+term	O
+timolol	O
+treatment	O
+on	O
+heart	O
+size	O
+after	O
+myocardial	B
+infarction	I
+was	O
+evaluated	O
+by	O
+X	O
+-	O
+ray	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+study	O
+including	O
+241	O
+patients	O
+(	O
+placebo	O
+126	O
+,	O
+timolol	O
+115	O
+)	O
+.	O
+
+The	O
+follow	O
+-	O
+up	O
+period	O
+was	O
+12	O
+months	O
+.	O
+
+The	O
+timolol	O
+-	O
+treated	O
+patients	O
+showed	O
+a	O
+small	O
+but	O
+significant	O
+increase	O
+in	O
+heart	O
+size	O
+from	O
+baseline	O
+in	O
+contrast	O
+to	O
+a	O
+decrease	O
+in	O
+the	O
+placebo	O
+group	O
+.	O
+
+These	O
+differences	O
+may	O
+be	O
+caused	O
+by	O
+timolol	O
+-	O
+induced	O
+bradycardia	B
+and	O
+a	O
+compensatory	O
+increase	O
+in	O
+end	O
+-	O
+diastolic	O
+volume	O
+.	O
+
+The	O
+timolol	O
+-	O
+related	O
+increase	O
+in	O
+heart	O
+size	O
+was	O
+observed	O
+only	O
+in	O
+patients	O
+with	O
+normal	O
+and	O
+borderline	O
+heart	O
+size	O
+.	O
+
+In	O
+patients	O
+with	O
+cardiomegaly	B
+,	O
+the	O
+increase	O
+in	O
+heart	O
+size	O
+was	O
+similar	O
+in	O
+both	O
+groups	O
+.	O
+
+After	O
+re	O
+-	O
+infarction	B
+,	O
+heart	O
+size	O
+increased	O
+in	O
+the	O
+placebo	O
+group	O
+and	O
+remained	O
+unchanged	O
+in	O
+the	O
+timolol	O
+group	O
+.	O
+
+Vitamin	O
+D3	O
+toxicity	B
+in	O
+dairy	O
+cows	O
+.	O
+
+Large	O
+parenteral	O
+doses	O
+of	O
+vitamin	O
+D3	O
+(	O
+15	O
+to	O
+17	O
+.	O
+5	O
+x	O
+10	O
+(	O
+6	O
+)	O
+IU	O
+vitamin	O
+D3	O
+)	O
+were	O
+associated	O
+with	O
+prolonged	O
+hypercalcemia	B
+,	O
+hyperphosphatemia	B
+,	O
+and	O
+large	O
+increases	O
+of	O
+vitamin	O
+D3	O
+and	O
+its	O
+metabolites	O
+in	O
+the	O
+blood	O
+plasma	O
+of	O
+nonlactating	O
+nonpregnant	O
+and	O
+pregnant	O
+Jersey	O
+cows	O
+.	O
+
+Calcium	O
+concentrations	O
+1	O
+day	O
+postpartum	O
+were	O
+higher	O
+in	O
+cows	O
+treated	O
+with	O
+vitamin	O
+D3	O
+about	O
+32	O
+days	O
+prepartum	O
+(	O
+8	O
+.	O
+8	O
+mg	O
+/	O
+100	O
+ml	O
+)	O
+than	O
+in	O
+control	O
+cows	O
+(	O
+5	O
+.	O
+5	O
+mg	O
+/	O
+100	O
+ml	O
+)	O
+.	O
+
+None	O
+of	O
+the	O
+cows	O
+treated	O
+with	O
+vitamin	O
+D3	O
+showed	O
+signs	O
+of	O
+milk	B
+fever	I
+during	O
+the	O
+peripartal	O
+period	O
+;	O
+however	O
+,	O
+22	O
+%	O
+of	O
+the	O
+control	O
+cows	O
+developed	O
+clinical	O
+signs	O
+of	O
+milk	B
+fever	I
+during	O
+this	O
+period	O
+.	O
+
+Signs	O
+of	O
+vitamin	O
+D3	O
+toxicity	B
+were	O
+not	O
+observed	O
+in	O
+nonlactating	O
+nonpregnant	O
+cows	O
+;	O
+however	O
+,	O
+pregnant	O
+cows	O
+commonly	O
+developed	O
+severe	O
+signs	O
+of	O
+vitamin	O
+D3	O
+toxicity	B
+and	O
+10	O
+of	O
+17	O
+cows	O
+died	O
+.	O
+
+There	O
+was	O
+widespread	O
+metastatic	O
+calcification	O
+in	O
+the	O
+cows	O
+that	O
+died	O
+.	O
+
+Because	O
+of	O
+the	O
+extreme	O
+toxicity	B
+of	O
+vitamin	O
+D3	O
+in	O
+pregnant	O
+Jersey	O
+cows	O
+and	O
+the	O
+low	O
+margin	O
+of	O
+safety	O
+between	O
+doses	O
+of	O
+vitamin	O
+D3	O
+that	O
+prevent	O
+milk	B
+fever	I
+and	O
+doses	O
+that	O
+induce	O
+milk	B
+fever	I
+,	O
+we	O
+concluded	O
+that	O
+vitamin	O
+D3	O
+cannot	O
+be	O
+used	O
+practically	O
+to	O
+prevent	O
+milk	B
+fever	I
+when	O
+injected	O
+several	O
+weeks	O
+prepartum	O
+.	O
+
+Diseases	B
+of	I
+peripheral	I
+nerves	I
+as	O
+seen	O
+in	O
+the	O
+Nigerian	O
+African	O
+.	O
+
+The	O
+anatomical	O
+and	O
+aetiological	O
+diagnoses	O
+of	O
+peripheral	B
+nerve	I
+disease	I
+excluding	O
+its	O
+primary	O
+benign	O
+and	O
+malignant	O
+disorders	O
+,	O
+as	O
+seen	O
+in	O
+358	O
+Nigerians	O
+are	O
+presented	O
+.	O
+
+There	O
+is	O
+a	O
+male	O
+preponderance	O
+and	O
+the	O
+peak	O
+incidence	O
+is	O
+in	O
+the	O
+fourth	O
+decade	O
+.	O
+
+Sensori	B
+-	I
+motor	I
+neuropathy	I
+was	O
+the	O
+commonest	O
+presentation	O
+(	O
+50	O
+%	O
+)	O
+.	O
+
+Guillain	B
+-	I
+Barr	I
+syndrome	I
+was	O
+the	O
+commonest	O
+identifiable	O
+cause	O
+(	O
+15	O
+.	O
+6	O
+%	O
+)	O
+,	O
+accounting	O
+for	O
+half	O
+of	O
+the	O
+cases	O
+with	O
+motor	B
+neuropathy	I
+.	O
+
+Peripheral	B
+neuropathy	I
+due	O
+to	O
+nutritional	B
+deficiency	I
+of	O
+thiamine	O
+and	O
+riboflavin	O
+was	O
+common	O
+(	O
+10	O
+.	O
+1	O
+%	O
+)	O
+and	O
+presented	O
+mainly	O
+as	O
+sensory	O
+and	O
+sensori	B
+-	I
+motor	I
+neuropathy	I
+.	O
+
+Diabetes	B
+mellitus	I
+was	O
+the	O
+major	O
+cause	O
+of	O
+autonomic	B
+neuropathy	I
+.	O
+
+Isoniazid	O
+was	O
+the	O
+most	O
+frequent	O
+agent	O
+in	O
+drug	O
+-	O
+induced	O
+neuropathy	B
+.	O
+
+Migraine	B
+(	O
+20	O
+%	O
+)	O
+was	O
+not	O
+an	O
+uncommon	O
+cause	O
+of	O
+cranial	B
+neuropathy	I
+although	O
+malignancies	B
+arising	O
+from	O
+the	O
+reticuloendothelial	O
+system	O
+or	O
+related	O
+structures	O
+of	O
+the	O
+head	O
+and	O
+neck	O
+were	O
+more	O
+frequent	O
+(	O
+26	O
+%	O
+)	O
+.	O
+
+In	O
+26	O
+.	O
+5	O
+%	O
+of	O
+all	O
+the	O
+cases	O
+,	O
+the	O
+aetiology	O
+of	O
+the	O
+neuropathy	B
+was	O
+undetermined	O
+.	O
+
+Heredofamilial	O
+and	O
+connective	B
+tissue	I
+disorders	I
+were	O
+rare	O
+.	O
+
+Some	O
+of	O
+the	O
+factors	O
+related	O
+to	O
+the	O
+clinical	O
+presentation	O
+and	O
+pathogenesis	O
+of	O
+the	O
+neuropathies	B
+are	O
+briefly	O
+discussed	O
+.	O
+
+Reduction	O
+in	O
+caffeine	O
+toxicity	B
+by	O
+acetaminophen	O
+.	O
+
+A	O
+patient	O
+who	O
+allegedly	O
+consumed	O
+100	O
+tablets	O
+of	O
+an	O
+over	O
+-	O
+the	O
+-	O
+counter	O
+analgesic	O
+containing	O
+sodium	O
+acetylsalicylate	O
+,	O
+caffeine	O
+,	O
+and	O
+acetaminophen	O
+displayed	O
+no	O
+significant	O
+CNS	O
+stimulation	O
+despite	O
+the	O
+presence	O
+of	O
+175	O
+micrograms	O
+of	O
+caffeine	O
+per	O
+mL	O
+of	O
+serum	O
+.	O
+
+Because	O
+salicylates	O
+have	O
+been	O
+reported	O
+to	O
+augment	O
+the	O
+stimulatory	O
+effects	O
+of	O
+caffeine	O
+on	O
+the	O
+CNS	O
+,	O
+attention	O
+was	O
+focused	O
+on	O
+the	O
+possibility	O
+that	O
+the	O
+presence	O
+of	O
+acetaminophen	O
+(	O
+52	O
+micrograms	O
+/	O
+mL	O
+)	O
+reduced	O
+the	O
+CNS	O
+toxicity	B
+of	O
+caffeine	O
+.	O
+
+Studies	O
+in	O
+DBA	O
+/	O
+2J	O
+mice	O
+showed	O
+that	O
+:	O
+1	O
+)	O
+pretreatment	O
+with	O
+acetaminophen	O
+(	O
+100	O
+mg	O
+/	O
+kg	O
+)	O
+increased	O
+the	O
+interval	O
+between	O
+the	O
+administration	O
+of	O
+caffeine	O
+(	O
+300	O
+to	O
+450	O
+mg	O
+/	O
+kg	O
+IP	O
+)	O
+and	O
+the	O
+onset	O
+of	O
+fatal	O
+convulsions	B
+by	O
+a	O
+factor	O
+of	O
+about	O
+two	O
+;	O
+and	O
+2	O
+)	O
+pretreatment	O
+with	O
+acetaminophen	O
+(	O
+75	O
+mg	O
+/	O
+kg	O
+)	O
+reduced	O
+the	O
+incidence	O
+of	O
+audiogenic	O
+seizures	B
+produced	O
+in	O
+the	O
+presence	O
+of	O
+caffeine	O
+(	O
+12	O
+.	O
+5	O
+to	O
+75	O
+mg	O
+/	O
+kg	O
+IP	O
+)	O
+.	O
+
+The	O
+frequency	O
+of	O
+sound	O
+-	O
+induced	O
+seizures	B
+after	O
+12	O
+.	O
+5	O
+or	O
+25	O
+mg	O
+/	O
+kg	O
+caffeine	O
+was	O
+reduced	O
+from	O
+50	O
+to	O
+5	O
+%	O
+by	O
+acetaminophen	O
+.	O
+
+In	O
+the	O
+absence	O
+of	O
+caffeine	O
+,	O
+acetaminophen	O
+(	O
+up	O
+to	O
+300	O
+mg	O
+/	O
+kg	O
+)	O
+did	O
+not	O
+modify	O
+the	O
+seizures	B
+induced	O
+by	O
+maximal	O
+electroshock	O
+and	O
+did	O
+not	O
+alter	O
+the	O
+convulsant	O
+dose	O
+of	O
+pentylenetetrezol	O
+in	O
+mice	O
+(	O
+tests	O
+performed	O
+by	O
+the	O
+Anticonvulsant	O
+Screening	O
+Project	O
+of	O
+NINCDS	O
+)	O
+.	O
+
+Acetaminophen	O
+(	O
+up	O
+to	O
+150	O
+micrograms	O
+/	O
+mL	O
+)	O
+did	O
+not	O
+retard	O
+the	O
+incorporation	O
+of	O
+radioactive	O
+adenosine	O
+into	O
+ATP	O
+in	O
+slices	O
+of	O
+rat	O
+cerebral	O
+cortex	O
+.	O
+
+Thus	O
+the	O
+mechanism	O
+by	O
+which	O
+acetaminophen	O
+antagonizes	O
+the	O
+actions	O
+of	O
+caffeine	O
+in	O
+the	O
+CNS	O
+remains	O
+unknown	O
+.	O
+
+A	O
+double	O
+-	O
+blind	O
+study	O
+of	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+dothiepin	O
+hydrochloride	O
+in	O
+the	O
+treatment	O
+of	O
+major	O
+depressive	B
+disorder	I
+.	O
+
+In	O
+a	O
+6	O
+-	O
+week	O
+double	O
+-	O
+blind	O
+parallel	O
+treatment	O
+study	O
+,	O
+dothiepin	O
+and	O
+amitriptyline	O
+were	O
+compared	O
+to	O
+placebo	O
+in	O
+the	O
+treatment	O
+of	O
+33	O
+depressed	B
+outpatients	O
+.	O
+
+Dothiepin	O
+and	O
+amitriptyline	O
+were	O
+equally	O
+effective	O
+in	O
+alleviating	O
+the	O
+symptoms	O
+of	O
+depressive	B
+illness	I
+,	O
+and	O
+both	O
+were	O
+significantly	O
+superior	O
+to	O
+placebo	O
+.	O
+
+The	O
+overall	O
+incidence	O
+of	O
+side	O
+effects	O
+and	O
+the	O
+frequency	O
+and	O
+severity	O
+of	O
+blurred	B
+vision	I
+,	O
+dry	B
+mouth	I
+,	O
+and	O
+drowsiness	O
+were	O
+significantly	O
+less	O
+with	O
+dothiepin	O
+than	O
+with	O
+amitriptyline	O
+.	O
+
+Dothiepin	O
+also	O
+produced	O
+fewer	O
+CNS	O
+and	O
+cardiovascular	O
+effects	O
+.	O
+
+There	O
+were	O
+no	O
+clinically	O
+important	O
+changes	O
+in	O
+laboratory	O
+parameters	O
+.	O
+
+Dothiepin	O
+thus	O
+was	O
+found	O
+to	O
+be	O
+an	O
+effective	O
+antidepressant	O
+drug	O
+associated	O
+with	O
+fewer	O
+side	O
+effects	O
+than	O
+amitriptyline	O
+in	O
+the	O
+treatment	O
+of	O
+depressed	B
+outpatients	O
+.	O
+
+Behavioral	O
+effects	O
+of	O
+diazepam	O
+and	O
+propranolol	O
+in	O
+patients	O
+with	O
+panic	B
+disorder	I
+and	O
+agoraphobia	B
+.	O
+
+The	O
+effects	O
+of	O
+oral	O
+doses	O
+of	O
+diazepam	O
+(	O
+single	O
+dose	O
+of	O
+10	O
+mg	O
+and	O
+a	O
+median	O
+dose	O
+of	O
+30	O
+mg	O
+/	O
+day	O
+for	O
+2	O
+weeks	O
+)	O
+and	O
+propranolol	O
+(	O
+single	O
+dose	O
+of	O
+80	O
+mg	O
+and	O
+a	O
+median	O
+dose	O
+of	O
+240	O
+mg	O
+/	O
+day	O
+for	O
+2	O
+weeks	O
+)	O
+on	O
+psychological	O
+performance	O
+of	O
+patients	O
+with	O
+panic	B
+disorders	I
+and	O
+agoraphobia	B
+were	O
+investigated	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+,	O
+randomized	O
+and	O
+crossover	O
+design	O
+.	O
+
+Both	O
+drugs	O
+impaired	B
+immediate	I
+free	I
+recall	I
+but	O
+the	O
+decrease	O
+was	O
+greater	O
+for	O
+diazepam	O
+than	O
+propranolol	O
+.	O
+
+Delayed	B
+free	I
+recall	I
+was	I
+also	I
+impaired	I
+but	O
+the	O
+two	O
+drugs	O
+did	O
+not	O
+differ	O
+.	O
+
+Patients	O
+tapped	O
+faster	O
+after	O
+propranolol	O
+than	O
+diazepam	O
+and	O
+they	O
+were	O
+more	O
+sedated	O
+after	O
+diazepam	O
+than	O
+propranolol	O
+.	O
+
+After	O
+2	O
+weeks	O
+of	O
+treatment	O
+,	O
+patients	O
+tested	O
+5	O
+-	O
+8	O
+h	O
+after	O
+the	O
+last	O
+dose	O
+of	O
+medication	O
+did	O
+not	O
+show	O
+any	O
+decrement	O
+of	O
+performance	O
+.	O
+
+These	O
+results	O
+are	O
+similar	O
+to	O
+those	O
+previously	O
+found	O
+in	O
+healthy	O
+subjects	O
+.	O
+
+Accumulation	O
+of	O
+drugs	O
+was	O
+not	O
+reflected	O
+in	O
+prolonged	O
+behavioral	B
+impairment	I
+.	O
+
+Comparison	O
+of	O
+i	O
+.	O
+v	O
+.	O
+glycopyrrolate	O
+and	O
+atropine	O
+in	O
+the	O
+prevention	O
+of	O
+bradycardia	B
+and	O
+arrhythmias	B
+following	O
+repeated	O
+doses	O
+of	O
+suxamethonium	O
+in	O
+children	O
+.	O
+
+The	O
+effectiveness	O
+of	O
+administration	O
+of	O
+glycopyrrolate	O
+5	O
+and	O
+10	O
+micrograms	O
+kg	O
+-	O
+1	O
+and	O
+atropine	O
+10	O
+and	O
+20	O
+micrograms	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+v	O
+.	O
+immediately	O
+before	O
+the	O
+induction	O
+of	O
+anaesthesia	O
+,	O
+to	O
+prevent	O
+arrhythmia	B
+and	O
+bradycardia	B
+following	O
+repeated	O
+doses	O
+of	O
+suxamethonium	O
+in	O
+children	O
+,	O
+was	O
+studied	O
+.	O
+
+A	O
+control	O
+group	O
+was	O
+included	O
+for	O
+comparison	O
+with	O
+the	O
+lower	O
+dose	O
+range	O
+of	O
+glycopyrrolate	O
+and	O
+atropine	O
+.	O
+
+A	O
+frequency	O
+of	O
+bradycardia	B
+of	O
+50	O
+%	O
+was	O
+noted	O
+in	O
+the	O
+control	O
+group	O
+,	O
+but	O
+this	O
+was	O
+not	O
+significantly	O
+different	O
+from	O
+the	O
+frequency	O
+with	O
+the	O
+active	O
+drugs	O
+.	O
+
+Bradycardia	B
+(	O
+defined	O
+as	O
+a	O
+decrease	O
+in	O
+heart	O
+rate	O
+to	O
+less	O
+than	O
+50	O
+beat	O
+min	O
+-	O
+1	O
+)	O
+was	O
+prevented	O
+when	O
+the	O
+larger	O
+dose	O
+of	O
+either	O
+active	O
+drug	O
+was	O
+used	O
+.	O
+
+It	O
+is	O
+recommended	O
+that	O
+either	O
+glycopyrrolate	O
+10	O
+micrograms	O
+kg	O
+-	O
+1	O
+or	O
+atropine	O
+20	O
+micrograms	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+v	O
+.	O
+should	O
+immediately	O
+precede	O
+induction	O
+of	O
+anaesthesia	O
+,	O
+in	O
+children	O
+,	O
+if	O
+the	O
+repeated	O
+administration	O
+of	O
+suxamethonium	O
+is	O
+anticipated	O
+.	O
+
+Veno	B
+-	I
+occlusive	I
+liver	I
+disease	I
+after	O
+dacarbazine	O
+therapy	O
+(	O
+DTIC	O
+)	O
+for	O
+melanoma	B
+.	O
+
+A	O
+case	O
+of	O
+veno	B
+-	I
+occlusive	I
+disease	I
+of	I
+the	I
+liver	I
+with	O
+fatal	O
+outcome	O
+after	O
+dacarbazine	O
+(	O
+DTIC	O
+)	O
+therapy	O
+for	O
+melanoma	B
+is	O
+reported	O
+.	O
+
+There	O
+was	O
+a	O
+fulminant	O
+clinical	O
+course	O
+from	O
+start	O
+of	O
+symptoms	O
+until	O
+death	B
+.	O
+
+At	O
+autopsy	O
+the	O
+liver	O
+was	O
+enlarged	O
+and	O
+firm	O
+with	O
+signs	O
+of	O
+venous	B
+congestion	I
+.	O
+
+Small	O
+-	O
+and	O
+medium	O
+-	O
+sized	O
+hepatic	O
+veins	O
+were	O
+blocked	O
+by	O
+thrombosis	B
+.	O
+
+Eosinophilic	O
+infiltrations	O
+were	O
+found	O
+around	O
+the	O
+vessels	O
+.	O
+
+Published	O
+cases	O
+from	O
+the	O
+literature	O
+are	O
+reviewed	O
+and	O
+pertinent	O
+features	O
+discussed	O
+.	O
+
+Maternal	O
+lithium	O
+and	O
+neonatal	O
+Ebstein	B
+'	I
+s	I
+anomaly	I
+:	O
+evaluation	O
+with	O
+cross	O
+-	O
+sectional	O
+echocardiography	O
+.	O
+
+Cross	O
+-	O
+sectional	O
+echocardiography	O
+was	O
+used	O
+to	O
+evaluate	O
+two	O
+neonates	O
+whose	O
+mothers	O
+ingested	O
+lithium	O
+during	O
+pregnancy	O
+.	O
+
+In	O
+one	O
+infant	O
+,	O
+Ebstein	B
+'	I
+s	I
+anomaly	I
+of	O
+the	O
+tricuspid	O
+valve	O
+was	O
+identified	O
+.	O
+
+In	O
+the	O
+other	O
+infant	O
+cross	O
+-	O
+sectional	O
+echocardiography	O
+provided	O
+reassurance	O
+that	O
+the	O
+infant	O
+did	O
+not	O
+have	O
+Ebstein	B
+'	I
+s	I
+anomaly	I
+.	O
+
+Cross	O
+-	O
+sectional	O
+echocardiographic	O
+screening	O
+of	O
+newborns	O
+exposed	O
+to	O
+lithium	O
+during	O
+gestation	O
+can	O
+provide	O
+highly	O
+accurate	O
+,	O
+noninvasive	O
+assessment	O
+of	O
+the	O
+presence	O
+or	O
+absence	O
+of	O
+lithium	O
+-	O
+induced	O
+cardiac	B
+malformations	I
+.	O
+
+Effects	O
+of	O
+training	O
+on	O
+the	O
+extent	O
+of	O
+experimental	O
+myocardial	B
+infarction	I
+in	O
+aging	O
+rats	O
+.	O
+
+The	O
+effects	O
+of	O
+exercise	O
+on	O
+the	O
+severity	O
+of	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+were	O
+studied	O
+in	O
+female	O
+albino	O
+rats	O
+of	O
+20	O
+,	O
+40	O
+,	O
+60	O
+and	O
+80	O
+weeks	O
+of	O
+age	O
+.	O
+
+The	O
+rats	O
+were	O
+trained	O
+to	O
+swim	O
+for	O
+a	O
+specific	O
+duration	O
+and	O
+for	O
+a	O
+particular	O
+period	O
+.	O
+
+The	O
+occurrence	O
+of	O
+infarcts	B
+were	O
+confirmed	O
+by	O
+histological	O
+methods	O
+.	O
+
+Elevations	O
+in	O
+the	O
+serum	O
+GOT	O
+and	O
+GPT	O
+were	O
+maximum	O
+in	O
+the	O
+sedentary	O
+-	O
+isoproterenols	O
+and	O
+minimum	O
+in	O
+the	O
+exercise	O
+-	O
+controls	O
+.	O
+
+These	O
+changes	O
+in	O
+the	O
+serum	O
+transaminases	O
+were	O
+associated	O
+with	O
+corresponding	O
+depletions	O
+in	O
+the	O
+cardiac	O
+GOT	O
+and	O
+GPT	O
+.	O
+
+However	O
+,	O
+age	O
+was	O
+seen	O
+to	O
+interfere	O
+with	O
+the	O
+responses	O
+exhibited	O
+by	O
+the	O
+young	O
+and	O
+old	O
+rats	O
+.	O
+
+Studies	O
+dealing	O
+with	O
+myocardial	B
+infarction	I
+are	O
+more	O
+informative	O
+when	O
+dealt	O
+with	O
+age	O
+.	O
+
+Effect	O
+of	O
+polyethylene	O
+glycol	O
+400	O
+on	O
+adriamycin	O
+toxicity	B
+in	O
+mice	O
+.	O
+
+The	O
+effect	O
+of	O
+a	O
+widely	O
+used	O
+organic	O
+solvent	O
+,	O
+polyethylene	O
+glycol	O
+400	O
+(	O
+PEG	O
+400	O
+)	O
+,	O
+on	O
+the	O
+toxic	O
+action	O
+of	O
+an	O
+acute	O
+or	O
+chronic	O
+treatment	O
+with	O
+adriamycin	O
+(	O
+ADR	O
+)	O
+was	O
+evaluated	O
+in	O
+mice	O
+.	O
+
+PEG	O
+400	O
+impressively	O
+decreased	O
+both	O
+acute	O
+high	O
+-	O
+dose	O
+and	O
+chronic	O
+low	O
+-	O
+dose	O
+-	O
+ADR	O
+-	O
+associated	O
+lethality	O
+.	O
+
+Light	O
+microscopic	O
+analysis	O
+showed	O
+a	O
+significant	O
+protection	O
+against	O
+ADR	O
+-	O
+induced	O
+cardiac	B
+morphological	I
+alterations	I
+.	O
+
+Such	O
+treatment	O
+did	O
+not	O
+diminish	O
+the	O
+ADR	O
+antitumor	O
+activity	O
+in	O
+L1210	B
+leukemia	I
+and	O
+in	O
+Ehrlich	B
+ascites	I
+tumor	I
+.	O
+
+Sublingual	O
+absorption	O
+of	O
+the	O
+quaternary	O
+ammonium	O
+antiarrhythmic	O
+agent	O
+,	O
+UM	O
+-	O
+272	O
+.	O
+
+UM	O
+-	O
+272	O
+(	O
+N	O
+,	O
+N	O
+-	O
+dimethylpropranolol	O
+)	O
+,	O
+a	O
+quaternary	O
+antiarrhythmic	O
+agent	O
+,	O
+was	O
+administered	O
+sublingually	O
+to	O
+dogs	O
+with	O
+ouabain	O
+-	O
+induced	O
+ventricular	B
+tachycardias	I
+.	O
+
+Both	O
+anti	O
+-	O
+arrhythmic	O
+efficacy	O
+and	O
+bioavailability	O
+were	O
+compared	O
+to	O
+oral	O
+drug	O
+.	O
+
+Sublingual	O
+UM	O
+-	O
+272	O
+converted	O
+ventricular	B
+tachycardia	I
+to	O
+sinus	O
+rhythm	O
+in	O
+all	O
+5	O
+dogs	O
+.	O
+
+The	O
+area	O
+under	O
+the	O
+plasma	O
+concentration	O
+time	O
+curve	O
+at	O
+90	O
+min	O
+was	O
+4	O
+-	O
+12	O
+times	O
+greater	O
+than	O
+for	O
+oral	O
+drug	O
+,	O
+suggesting	O
+the	O
+existence	O
+of	O
+an	O
+absorption	O
+-	O
+limiting	O
+process	O
+in	O
+the	O
+intestine	O
+,	O
+and	O
+providing	O
+an	O
+alternate	O
+form	O
+of	O
+administration	O
+for	O
+quaternary	O
+drugs	O
+.	O
+
+Early	O
+adjuvant	O
+adriamycin	O
+in	O
+superficial	O
+bladder	B
+carcinoma	I
+.	O
+
+A	O
+multicenter	O
+study	O
+was	O
+performed	O
+in	O
+110	O
+patients	O
+with	O
+superficial	O
+transitional	O
+cell	O
+carcinoma	B
+of	I
+the	I
+bladder	I
+.	O
+
+Adriamycin	O
+(	O
+50	O
+mg	O
+/	O
+50	O
+ml	O
+)	O
+was	O
+administered	O
+intravesically	O
+within	O
+24	O
+h	O
+after	O
+transurethral	O
+resection	O
+of	O
+TA	O
+-	O
+T1	O
+(	O
+O	O
+-	O
+A	O
+)	O
+bladder	B
+tumors	I
+.	O
+
+Instillation	O
+was	O
+repeated	O
+twice	O
+during	O
+the	O
+first	O
+week	O
+,	O
+then	O
+weekly	O
+during	O
+the	O
+first	O
+month	O
+and	O
+afterwards	O
+monthly	O
+for	O
+1	O
+year	O
+.	O
+
+The	O
+tolerance	O
+was	O
+evaluated	O
+in	O
+these	O
+110	O
+patients	O
+,	O
+and	O
+29	O
+patients	O
+presented	O
+with	O
+local	O
+side	O
+-	O
+effects	O
+.	O
+
+In	O
+24	O
+of	O
+these	O
+patients	O
+chemical	O
+cystitis	B
+was	O
+severe	O
+enough	O
+for	O
+them	O
+to	O
+drop	O
+out	O
+of	O
+the	O
+study	O
+.	O
+
+No	O
+systemic	O
+side	O
+-	O
+effects	O
+were	O
+observed	O
+.	O
+
+Recurrence	O
+was	O
+studied	O
+in	O
+82	O
+evaluable	O
+patients	O
+after	O
+1	O
+year	O
+of	O
+follow	O
+-	O
+up	O
+and	O
+in	O
+72	O
+patients	O
+followed	O
+for	O
+2	O
+-	O
+3	O
+years	O
+(	O
+mean	O
+32	O
+months	O
+)	O
+.	O
+
+Of	O
+the	O
+82	O
+patients	O
+studied	O
+after	O
+1	O
+year	O
+,	O
+23	O
+had	O
+primary	O
+and	O
+59	O
+recurrent	O
+disease	O
+.	O
+
+Of	O
+the	O
+82	O
+evaluable	O
+patients	O
+,	O
+50	O
+did	O
+not	O
+show	O
+any	O
+recurrence	O
+after	O
+1	O
+year	O
+(	O
+61	O
+%	O
+)	O
+,	O
+while	O
+32	O
+presented	O
+with	O
+one	O
+or	O
+more	O
+recurrences	O
+(	O
+39	O
+%	O
+)	O
+.	O
+
+Of	O
+these	O
+recurrences	O
+,	O
+27	O
+were	O
+T1	O
+tumors	B
+while	O
+five	O
+progressed	O
+to	O
+more	O
+highly	O
+invasive	O
+lesions	O
+.	O
+
+In	O
+patients	O
+that	O
+were	O
+free	O
+of	O
+recurrence	O
+during	O
+the	O
+first	O
+year	O
+,	O
+80	O
+%	O
+remained	O
+tumor	B
+-	O
+free	O
+during	O
+the	O
+2	O
+-	O
+to	O
+3	O
+-	O
+year	O
+follow	O
+-	O
+up	O
+period	O
+.	O
+
+Of	O
+the	O
+patients	O
+developing	O
+one	O
+or	O
+more	O
+recurrences	O
+during	O
+the	O
+first	O
+year	O
+,	O
+only	O
+50	O
+%	O
+presented	O
+with	O
+further	O
+recurrence	O
+once	O
+the	O
+instillations	O
+were	O
+stopped	O
+.	O
+
+The	O
+beneficial	O
+effect	O
+of	O
+Adriamycin	O
+appears	O
+obvious	O
+and	O
+might	O
+be	O
+related	O
+to	O
+the	O
+drug	O
+itself	O
+,	O
+the	O
+early	O
+and	O
+repeated	O
+instillations	O
+after	O
+TUR	O
+,	O
+or	O
+both	O
+.	O
+
+D	O
+-	O
+penicillamine	O
+-	O
+induced	O
+angiopathy	B
+in	O
+rats	O
+.	O
+
+The	O
+effect	O
+of	O
+high	O
+dose	O
+D	O
+-	O
+penicillamine	O
+treatment	O
+on	O
+aortic	O
+permeability	O
+to	O
+albumin	O
+and	O
+on	O
+the	O
+ultrastructure	O
+of	O
+the	O
+vessel	O
+.	O
+
+Male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+were	O
+treated	O
+with	O
+D	O
+-	O
+penicillamine	O
+(	O
+D	O
+-	O
+pen	O
+)	O
+500	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+for	O
+10	O
+or	O
+42	O
+days	O
+.	O
+
+Pair	O
+fed	O
+rats	O
+served	O
+as	O
+controls	O
+.	O
+
+Changes	O
+in	O
+aortic	O
+morphology	O
+were	O
+examined	O
+by	O
+light	O
+-	O
+and	O
+transmission	O
+-	O
+electron	O
+microscopy	O
+(	O
+TEM	O
+)	O
+.	O
+
+In	O
+addition	O
+,	O
+the	O
+endothelial	O
+permeability	O
+and	O
+the	O
+penetration	O
+through	O
+the	O
+aortic	O
+wall	O
+of	O
+albumin	O
+were	O
+studied	O
+10	O
+minutes	O
+,	O
+24	O
+and	O
+48	O
+hours	O
+after	O
+i	O
+.	O
+v	O
+.	O
+injection	O
+of	O
+human	O
+serum	O
+131I	O
+-	O
+albumin	O
+(	O
+131I	O
+-	O
+HSA	O
+)	O
+.	O
+
+TEM	O
+revealed	O
+extensive	O
+elastolysis	O
+in	O
+the	O
+arterial	O
+wall	O
+of	O
+D	O
+-	O
+pen	O
+-	O
+treated	O
+rats	O
+,	O
+consistent	O
+with	O
+an	O
+inhibitory	O
+effect	O
+on	O
+crosslink	O
+formation	O
+.	O
+
+In	O
+experimental	O
+animals	O
+excess	O
+deposition	O
+of	O
+collagen	O
+and	O
+glycoaminoglycans	O
+was	O
+observed	O
+in	O
+the	O
+subendothelial	O
+and	O
+medial	O
+layer	O
+of	O
+the	O
+aortic	O
+wall	O
+,	O
+together	O
+with	O
+prominent	O
+basal	O
+membrane	O
+substance	O
+around	O
+aortic	O
+smooth	O
+muscle	O
+cells	O
+.	O
+
+The	O
+aorta	O
+/	O
+serum	O
+-	O
+ratio	O
+and	O
+the	O
+radioactive	O
+build	O
+-	O
+up	O
+24	O
+and	O
+48	O
+hours	O
+after	O
+injection	O
+of	O
+131I	O
+-	O
+HSA	O
+was	O
+reduced	O
+in	O
+animals	O
+treated	O
+with	O
+D	O
+-	O
+pen	O
+for	O
+42	O
+days	O
+,	O
+indicating	O
+an	O
+impeded	O
+transmural	O
+transport	O
+of	O
+tracer	O
+which	O
+may	O
+be	O
+caused	O
+by	O
+a	O
+steric	O
+exclusion	O
+effect	O
+of	O
+abundant	O
+hyaluronate	O
+.	O
+
+The	O
+endothelial	O
+ultrastructure	O
+was	O
+unaffected	O
+by	O
+D	O
+-	O
+pen	O
+,	O
+and	O
+no	O
+differences	O
+in	O
+aortic	O
+131I	O
+-	O
+HSA	O
+radioactivity	O
+or	O
+aorta	O
+/	O
+serum	O
+-	O
+ratio	O
+were	O
+recorded	O
+between	O
+experimental	O
+and	O
+control	O
+groups	O
+10	O
+minutes	O
+after	O
+tracer	O
+injection	O
+,	O
+indicating	O
+that	O
+the	O
+permeability	O
+of	O
+the	O
+endothelial	O
+barrier	O
+to	O
+albumin	O
+remained	O
+unaffected	O
+by	O
+D	O
+-	O
+pen	O
+treatment	O
+.	O
+
+These	O
+observations	O
+support	O
+the	O
+hypothesis	O
+that	O
+treatment	O
+with	O
+high	O
+doses	O
+of	O
+D	O
+-	O
+pen	O
+may	O
+induce	O
+a	O
+fibroproliferative	O
+response	O
+in	O
+rat	O
+aorta	O
+,	O
+possibly	O
+by	O
+an	O
+inhibitory	O
+effect	O
+on	O
+the	O
+cross	O
+-	O
+linking	O
+of	O
+collagen	O
+and	O
+elastin	O
+.	O
+
+Effect	O
+of	O
+aspirin	O
+on	O
+N	O
+-	O
+[	O
+4	O
+-	O
+(	O
+5	O
+-	O
+nitro	O
+-	O
+2	O
+-	O
+furyl	O
+)	O
+-	O
+2	O
+-	O
+thiazolyl	O
+]	O
+-	O
+formamide	O
+-	O
+induced	O
+epithelial	O
+proliferation	O
+in	O
+the	O
+urinary	O
+bladder	O
+and	O
+forestomach	O
+of	O
+the	O
+rat	O
+.	O
+
+The	O
+co	O
+-	O
+administration	O
+of	O
+aspirin	O
+with	O
+N	O
+-	O
+[	O
+4	O
+-	O
+(	O
+5	O
+-	O
+nitro	O
+-	O
+2	O
+-	O
+furyl	O
+)	O
+-	O
+2	O
+-	O
+thiazolyl	O
+]	O
+-	O
+formamide	O
+(	O
+FANFT	O
+)	O
+to	O
+rats	O
+resulted	O
+in	O
+a	O
+reduced	O
+incidence	O
+of	O
+FANFT	O
+-	O
+induced	O
+bladder	B
+carcinomas	I
+but	O
+a	O
+concomitant	O
+induction	O
+of	O
+forestomach	B
+tumors	I
+.	O
+
+An	O
+autoradiographic	O
+study	O
+was	O
+performed	O
+on	O
+male	O
+F	O
+-	O
+344	O
+rats	O
+fed	O
+diet	O
+containing	O
+FANFT	O
+at	O
+a	O
+level	O
+of	O
+0	O
+.	O
+2	O
+%	O
+and	O
+/	O
+or	O
+aspirin	O
+at	O
+a	O
+level	O
+of	O
+0	O
+.	O
+5	O
+%	O
+to	O
+evaluate	O
+the	O
+effect	O
+of	O
+aspirin	O
+on	O
+the	O
+increased	O
+cell	O
+proliferation	O
+induced	O
+by	O
+FANFT	O
+in	O
+the	O
+forestomach	O
+and	O
+bladder	O
+.	O
+
+FANFT	O
+-	O
+induced	O
+cell	O
+proliferation	O
+in	O
+the	O
+bladder	O
+was	O
+significantly	O
+suppressed	O
+by	O
+aspirin	O
+co	O
+-	O
+administration	O
+after	O
+4	O
+weeks	O
+but	O
+not	O
+after	O
+12	O
+weeks	O
+.	O
+
+In	O
+the	O
+forestomach	O
+,	O
+and	O
+also	O
+in	O
+the	O
+liver	O
+,	O
+aspirin	O
+did	O
+not	O
+affect	O
+the	O
+FANFT	O
+-	O
+induced	O
+increase	O
+in	O
+labeling	O
+index	O
+.	O
+
+The	O
+present	O
+results	O
+are	O
+consistent	O
+with	O
+the	O
+carcinogenicity	O
+experiment	O
+suggesting	O
+that	O
+different	O
+mechanisms	O
+are	O
+involved	O
+in	O
+FANFT	O
+carcinogenesis	B
+in	O
+the	O
+bladder	O
+and	O
+forestomach	O
+,	O
+and	O
+that	O
+aspirin	O
+'	O
+s	O
+effect	O
+on	O
+FANFT	O
+in	O
+the	O
+forestomach	O
+is	O
+not	O
+due	O
+to	O
+an	O
+irritant	O
+effect	O
+associated	O
+with	O
+increased	O
+cell	O
+proliferation	O
+.	O
+
+Also	O
+,	O
+there	O
+appears	O
+to	O
+be	O
+an	O
+adaptation	O
+by	O
+the	O
+rats	O
+to	O
+the	O
+chronic	O
+ingestion	O
+of	O
+aspirin	O
+.	O
+
+A	O
+case	O
+of	O
+tardive	B
+dyskinesia	I
+caused	O
+by	O
+metoclopramide	O
+.	O
+
+Abnormal	B
+involuntary	I
+movements	I
+appeared	O
+in	O
+the	O
+mouth	O
+,	O
+tongue	O
+,	O
+neck	O
+and	O
+abdomen	O
+of	O
+a	O
+64	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+after	O
+he	O
+took	O
+metoclopramide	O
+for	O
+gastrointestinal	B
+disorder	I
+in	O
+a	O
+regimen	O
+of	O
+30	O
+mg	O
+per	O
+day	O
+for	O
+a	O
+total	O
+of	O
+about	O
+260	O
+days	O
+.	O
+
+The	O
+symptoms	O
+exacerbated	O
+to	O
+a	O
+maximum	O
+in	O
+a	O
+month	O
+.	O
+
+When	O
+the	O
+metoclopramide	O
+administration	O
+was	O
+discontinued	O
+,	O
+the	O
+abnormal	B
+movements	I
+gradually	O
+improved	O
+to	O
+a	O
+considerable	O
+extent	O
+.	O
+
+Attention	O
+to	O
+the	O
+possible	O
+induction	O
+of	O
+specific	O
+tardive	B
+dyskinesia	I
+is	O
+called	O
+for	O
+in	O
+the	O
+use	O
+of	O
+this	O
+drug	O
+.	O
+
+Intra	O
+-	O
+arterial	O
+BCNU	O
+chemotherapy	O
+for	O
+treatment	O
+of	O
+malignant	B
+gliomas	I
+of	O
+the	O
+central	O
+nervous	O
+system	O
+.	O
+
+Because	O
+of	O
+the	O
+rapid	O
+systemic	O
+clearance	O
+of	O
+BCNU	O
+(	O
+1	O
+,	O
+3	O
+-	O
+bis	O
+-	O
+(	O
+2	O
+-	O
+chloroethyl	O
+)	O
+-	O
+1	O
+-	O
+nitrosourea	O
+)	O
+,	O
+intra	O
+-	O
+arterial	O
+administration	O
+should	O
+provide	O
+a	O
+substantial	O
+advantage	O
+over	O
+intravenous	O
+administration	O
+for	O
+the	O
+treatment	O
+of	O
+malignant	B
+gliomas	I
+.	O
+
+Thirty	O
+-	O
+six	O
+patients	O
+were	O
+treated	O
+with	O
+BCNU	O
+every	O
+6	O
+to	O
+8	O
+weeks	O
+,	O
+either	O
+by	O
+transfemoral	O
+catheterization	O
+of	O
+the	O
+internal	O
+carotid	O
+or	O
+vertebral	O
+artery	O
+or	O
+through	O
+a	O
+fully	O
+implantable	O
+intracarotid	O
+drug	O
+delivery	O
+system	O
+,	O
+beginning	O
+with	O
+a	O
+dose	O
+of	O
+200	O
+mg	O
+/	O
+sq	O
+m	O
+body	O
+surface	O
+area	O
+.	O
+
+Twelve	O
+patients	O
+with	O
+Grade	O
+III	O
+or	O
+IV	O
+astrocytomas	B
+were	O
+treated	O
+after	O
+partial	O
+resection	O
+of	O
+the	O
+tumor	B
+without	O
+prior	O
+radiation	O
+therapy	O
+.	O
+
+After	O
+two	O
+to	O
+seven	O
+cycles	O
+of	O
+chemotherapy	O
+,	O
+nine	O
+patients	O
+showed	O
+a	O
+decrease	O
+in	O
+tumor	B
+size	O
+and	O
+surrounding	O
+edema	B
+on	O
+contrast	O
+-	O
+enhanced	O
+computerized	O
+tomography	O
+scans	O
+.	O
+
+In	O
+the	O
+nine	O
+responders	O
+,	O
+median	O
+duration	O
+of	O
+chemotherapy	O
+response	O
+from	O
+the	O
+time	O
+of	O
+operation	O
+was	O
+25	O
+weeks	O
+(	O
+range	O
+12	O
+to	O
+more	O
+than	O
+91	O
+weeks	O
+)	O
+.	O
+
+The	O
+median	O
+duration	O
+of	O
+survival	O
+in	O
+the	O
+12	O
+patients	O
+was	O
+54	O
+weeks	O
+(	O
+range	O
+21	O
+to	O
+more	O
+than	O
+156	O
+weeks	O
+)	O
+,	O
+with	O
+an	O
+18	O
+-	O
+month	O
+survival	O
+rate	O
+of	O
+42	O
+%	O
+.	O
+
+Twenty	O
+-	O
+four	O
+patients	O
+with	O
+recurrent	O
+Grade	O
+I	O
+to	O
+IV	O
+astrocytomas	B
+,	O
+whose	O
+resection	O
+and	O
+irradiation	O
+therapy	O
+had	O
+failed	O
+,	O
+received	O
+two	O
+to	O
+eight	O
+courses	O
+of	O
+intra	O
+-	O
+arterial	O
+BCNU	O
+therapy	O
+.	O
+
+Seventeen	O
+of	O
+these	O
+had	O
+a	O
+response	O
+or	O
+were	O
+stable	O
+for	O
+a	O
+median	O
+of	O
+20	O
+weeks	O
+(	O
+range	O
+6	O
+to	O
+more	O
+than	O
+66	O
+weeks	O
+)	O
+.	O
+
+The	O
+catheterization	O
+procedure	O
+is	O
+safe	O
+,	O
+with	O
+no	O
+immediate	O
+complication	O
+in	O
+111	O
+infusions	O
+of	O
+BCNU	O
+.	O
+
+A	O
+delayed	O
+complication	O
+in	O
+nine	O
+patients	O
+has	O
+been	O
+unilateral	O
+loss	B
+of	I
+vision	I
+secondary	O
+to	O
+a	O
+retinal	B
+vasculitis	I
+.	O
+
+The	O
+frequency	O
+of	O
+visual	B
+loss	I
+decreased	O
+after	O
+the	O
+concentration	O
+of	O
+the	O
+ethanol	O
+diluent	O
+was	O
+lowered	O
+.	O
+
+Provocation	O
+of	O
+postural	O
+hypotension	B
+by	O
+nitroglycerin	O
+in	O
+diabetic	B
+autonomic	I
+neuropathy	I
+?	O
+
+The	O
+effect	O
+of	O
+nitroglycerin	O
+on	O
+heart	O
+rate	O
+and	O
+systolic	O
+blood	O
+pressure	O
+was	O
+compared	O
+in	O
+5	O
+normal	O
+subjects	O
+,	O
+12	O
+diabetic	B
+subjects	O
+without	O
+autonomic	B
+neuropathy	I
+,	O
+and	O
+5	O
+diabetic	B
+subjects	O
+with	O
+autonomic	B
+neuropathy	I
+.	O
+
+The	O
+magnitude	O
+and	O
+time	O
+course	O
+of	O
+the	O
+increase	O
+in	O
+heart	O
+rate	O
+and	O
+the	O
+decrease	O
+in	O
+systolic	O
+blood	O
+pressure	O
+after	O
+nitroglycerin	O
+were	O
+similar	O
+in	O
+the	O
+normal	O
+and	O
+diabetic	B
+subjects	O
+without	O
+autonomic	B
+neuropathy	I
+,	O
+whereas	O
+a	O
+lesser	O
+increase	O
+in	O
+heart	O
+rate	O
+and	O
+a	O
+greater	O
+decrease	O
+in	O
+systolic	O
+blood	O
+pressure	O
+occurred	O
+in	O
+the	O
+diabetic	B
+subjects	O
+with	O
+autonomic	B
+neuropathy	I
+.	O
+
+It	O
+is	O
+therefore	O
+suggested	O
+that	O
+caution	O
+should	O
+be	O
+exercised	O
+when	O
+prescribing	O
+vasodilator	O
+drugs	O
+in	O
+diabetic	B
+patients	O
+,	O
+particularly	O
+those	O
+with	O
+autonomic	B
+neuropathy	I
+.	O
+
+Blood	O
+pressure	O
+response	O
+to	O
+chronic	O
+low	O
+-	O
+dose	O
+intrarenal	O
+noradrenaline	O
+infusion	O
+in	O
+conscious	O
+rats	O
+.	O
+
+Sodium	O
+chloride	O
+solution	O
+(	O
+0	O
+.	O
+9	O
+%	O
+)	O
+or	O
+noradrenaline	O
+in	O
+doses	O
+of	O
+4	O
+,	O
+12	O
+and	O
+36	O
+micrograms	O
+h	O
+-	O
+1	O
+kg	O
+-	O
+1	O
+was	O
+infused	O
+for	O
+five	O
+consecutive	O
+days	O
+,	O
+either	O
+intrarenally	O
+(	O
+by	O
+a	O
+new	O
+technique	O
+)	O
+or	O
+intravenously	O
+into	O
+rats	O
+with	O
+one	O
+kidney	O
+removed	O
+.	O
+
+Intrarenal	O
+infusion	O
+of	O
+noradrenaline	O
+caused	O
+hypertension	B
+at	O
+doses	O
+which	O
+did	O
+not	O
+do	O
+so	O
+when	O
+infused	O
+intravenously	O
+.	O
+
+Intrarenal	O
+compared	O
+with	O
+intravenous	O
+infusion	O
+of	O
+noradrenaline	O
+caused	O
+higher	O
+plasma	O
+noradrenaline	O
+concentrations	O
+and	O
+a	O
+shift	O
+of	O
+the	O
+plasma	O
+noradrenaline	O
+concentration	O
+-	O
+blood	O
+pressure	O
+effect	O
+curve	O
+towards	O
+lower	O
+plasma	O
+noradrenaline	O
+levels	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+hypertension	B
+after	O
+chronic	O
+intrarenal	O
+noradrenaline	O
+infusion	O
+is	O
+produced	O
+by	O
+relatively	O
+higher	O
+levels	O
+of	O
+circulating	O
+noradrenaline	O
+and	O
+by	O
+triggering	O
+of	O
+an	O
+additional	O
+intrarenal	O
+pressor	O
+mechanism	O
+.	O
+
+Characterization	O
+of	O
+estrogen	O
+-	O
+induced	O
+adenohypophyseal	B
+tumors	I
+in	O
+the	O
+Fischer	O
+344	O
+rat	O
+.	O
+
+Pituitary	B
+tumors	I
+were	O
+induced	O
+in	O
+F344	O
+female	O
+rats	O
+by	O
+chronic	O
+treatment	O
+with	O
+diethylstilbestrol	O
+(	O
+DES	O
+,	O
+8	O
+-	O
+10	O
+mg	O
+)	O
+implanted	O
+subcutaneously	O
+in	O
+silastic	O
+capsules	O
+.	O
+
+Over	O
+a	O
+range	O
+of	O
+1	O
+-	O
+150	O
+days	O
+of	O
+DES	O
+treatment	O
+,	O
+pairs	O
+of	O
+control	O
+and	O
+DES	O
+-	O
+treated	O
+rats	O
+were	O
+sacrificed	O
+,	O
+and	O
+their	O
+pituitaries	O
+dissociated	O
+enzymatically	O
+into	O
+single	O
+-	O
+cell	O
+preparations	O
+.	O
+
+The	O
+cell	O
+populations	O
+were	O
+examined	O
+regarding	O
+total	O
+cell	O
+recovery	O
+correlated	O
+with	O
+gland	O
+weight	O
+,	O
+intracellular	O
+prolactin	O
+(	O
+PRL	O
+)	O
+content	O
+and	O
+subsequent	O
+release	O
+in	O
+primary	O
+culture	O
+,	O
+immunocytochemical	O
+PRL	O
+staining	O
+,	O
+density	O
+and	O
+/	O
+or	O
+size	O
+alterations	O
+via	O
+separation	O
+on	O
+Ficoll	O
+-	O
+Hypaque	O
+and	O
+by	O
+unit	O
+gravity	O
+sedimentation	O
+,	O
+and	O
+cell	O
+cycle	O
+analysis	O
+,	O
+after	O
+acriflavine	O
+DNA	O
+staining	O
+,	O
+by	O
+laser	O
+flow	O
+cytometry	O
+.	O
+
+Total	O
+cell	O
+yields	O
+from	O
+DES	O
+-	O
+treated	O
+pituitaries	O
+increased	O
+from	O
+1	O
+.	O
+3	O
+times	O
+control	O
+yields	O
+at	O
+8	O
+days	O
+of	O
+treatment	O
+to	O
+58	O
+.	O
+9	O
+times	O
+control	O
+values	O
+by	O
+day	O
+150	O
+.	O
+
+Intracellular	O
+PRL	O
+content	O
+ranged	O
+from	O
+1	O
+.	O
+9	O
+to	O
+9	O
+.	O
+4	O
+times	O
+control	O
+levels	O
+,	O
+and	O
+PRL	O
+release	O
+in	O
+vitro	O
+was	O
+significantly	O
+and	O
+consistently	O
+higher	O
+than	O
+controls	O
+,	O
+after	O
+at	O
+least	O
+8	O
+days	O
+of	O
+DES	O
+exposure	O
+.	O
+
+Beyond	O
+8	O
+days	O
+of	O
+DES	O
+exposure	O
+,	O
+the	O
+immunochemically	O
+PRL	O
+-	O
+positive	O
+proportion	O
+of	O
+cells	O
+increased	O
+to	O
+over	O
+50	O
+%	O
+of	O
+the	O
+total	O
+population	O
+.	O
+
+Increased	O
+density	O
+and	O
+/	O
+or	O
+size	O
+and	O
+PRL	O
+content	O
+were	O
+indicated	O
+for	O
+the	O
+majority	O
+of	O
+the	O
+PRL	O
+cell	O
+population	O
+in	O
+both	O
+types	O
+of	O
+separation	O
+protocols	O
+.	O
+
+All	O
+these	O
+effects	O
+of	O
+DES	O
+were	O
+more	O
+pronounced	O
+among	O
+previously	O
+ovariectomized	O
+animals	O
+.	O
+
+The	O
+data	O
+extend	O
+the	O
+findings	O
+of	O
+other	O
+investigators	O
+,	O
+further	O
+establishing	O
+the	O
+DES	O
+-	O
+induced	O
+tumor	B
+as	O
+a	O
+model	O
+for	O
+study	O
+of	O
+PRL	O
+cellular	O
+control	O
+mechanisms	O
+.	O
+
+Age	O
+and	O
+renal	O
+clearance	O
+of	O
+cimetidine	O
+.	O
+
+In	O
+35	O
+patients	O
+(	O
+ages	O
+20	O
+to	O
+86	O
+yr	O
+)	O
+receiving	O
+cimetidine	O
+therapeutically	O
+two	O
+serum	O
+samples	O
+and	O
+all	O
+urine	O
+formed	O
+in	O
+the	O
+interim	O
+were	O
+collected	O
+for	O
+analysis	O
+of	O
+cimetidine	O
+by	O
+high	O
+-	O
+pressure	O
+liquid	O
+chromatography	O
+and	O
+for	O
+creatinine	O
+.	O
+
+Cimetidine	O
+clearance	O
+decreased	O
+with	O
+age	O
+.	O
+
+The	O
+extrapolated	O
+6	O
+-	O
+hr	O
+serum	O
+concentration	O
+of	O
+cimetidine	O
+per	O
+unit	O
+dose	O
+,	O
+after	O
+intravenous	O
+cimetidine	O
+,	O
+increased	O
+with	O
+age	O
+of	O
+the	O
+patients	O
+.	O
+
+The	O
+ratio	O
+of	O
+cimetidine	O
+clearance	O
+to	O
+creatinine	O
+clearance	O
+(	O
+Rc	O
+)	O
+averaged	O
+4	O
+.	O
+8	O
++	O
+/	O
+-	O
+2	O
+.	O
+0	O
+,	O
+indicating	O
+net	O
+tubular	O
+secretion	O
+for	O
+cimetidine	O
+.	O
+
+Rc	O
+seemed	O
+to	O
+be	O
+independent	O
+of	O
+age	O
+and	O
+decreased	O
+with	O
+increasing	O
+serum	O
+concentration	O
+of	O
+cimetidine	O
+,	O
+suggesting	O
+that	O
+secretion	O
+of	O
+cimetidine	O
+is	O
+a	O
+saturable	O
+process	O
+.	O
+
+There	O
+was	O
+only	O
+one	O
+case	O
+of	O
+dementia	B
+possibly	O
+due	O
+to	O
+cimetidine	O
+(	O
+with	O
+a	O
+drug	O
+level	O
+of	O
+1	O
+.	O
+9	O
+microgram	O
+/	O
+ml	O
+6	O
+hr	O
+after	O
+a	O
+dose	O
+)	O
+in	O
+a	O
+group	O
+of	O
+13	O
+patients	O
+without	O
+liver	B
+or	I
+kidney	I
+disease	I
+who	O
+had	O
+cimetidine	O
+levels	O
+above	O
+1	O
+.	O
+25	O
+microgram	O
+/	O
+ml	O
+.	O
+
+Thus	O
+,	O
+high	O
+cimetidine	O
+levels	O
+alone	O
+do	O
+not	O
+always	O
+induce	O
+dementia	B
+.	O
+
+Further	O
+observations	O
+on	O
+the	O
+electrophysiologic	O
+effects	O
+of	O
+oral	O
+amiodarone	O
+therapy	O
+.	O
+
+A	O
+case	O
+is	O
+presented	O
+of	O
+a	O
+reversible	O
+intra	B
+-	I
+Hisian	I
+block	I
+occurring	O
+under	O
+amiodarone	O
+treatment	O
+for	O
+atrial	B
+tachycardia	I
+in	O
+a	O
+patient	O
+without	O
+clear	O
+intraventricular	B
+conduction	I
+abnormalities	I
+.	O
+
+His	O
+bundle	O
+recordings	O
+showed	O
+an	O
+atrial	B
+tachycardia	I
+with	O
+intermittent	O
+exit	O
+block	O
+and	O
+greatly	O
+prolonged	O
+BH	O
+and	O
+HV	O
+intervals	O
+(	O
+40	O
+and	O
+100	O
+msec	O
+,	O
+respectively	O
+)	O
+.	O
+
+Thirty	O
+days	O
+after	O
+amiodarone	O
+discontinuation	O
+,	O
+His	O
+bundle	O
+electrograms	O
+showed	O
+atrial	B
+flutter	I
+without	O
+intra	O
+-	O
+Hisian	O
+or	O
+infra	O
+-	O
+Hisian	O
+delay	O
+.	O
+
+Amiodarone	O
+should	O
+be	O
+used	O
+with	O
+caution	O
+during	O
+long	O
+-	O
+term	O
+oral	O
+therapy	O
+in	O
+patients	O
+with	O
+or	O
+without	O
+clear	O
+intraventricular	O
+conduction	O
+defects	O
+.	O
+
+Development	O
+of	O
+clear	B
+cell	I
+adenocarcinoma	I
+in	O
+DES	O
+-	O
+exposed	O
+offspring	O
+under	O
+observation	O
+.	O
+
+Two	O
+cases	O
+of	O
+clear	B
+cell	I
+adenocarcinoma	I
+of	I
+the	I
+vagina	I
+detected	O
+at	O
+follow	O
+-	O
+up	O
+in	O
+young	O
+women	O
+exposed	O
+in	O
+utero	O
+to	O
+diethylstilbestrol	O
+are	O
+reported	O
+.	O
+
+One	O
+patient	O
+,	O
+aged	O
+23	O
+,	O
+had	O
+been	O
+followed	O
+for	O
+2	O
+years	O
+before	O
+carcinoma	B
+was	O
+diagnosed	O
+;	O
+the	O
+second	O
+patient	O
+,	O
+aged	O
+22	O
+,	O
+had	O
+been	O
+seen	O
+on	O
+a	O
+regular	O
+basis	O
+for	O
+5	O
+years	O
+,	O
+8	O
+months	O
+.	O
+
+In	O
+both	O
+instances	O
+,	O
+suspicion	O
+of	O
+the	O
+presence	O
+of	O
+carcinoma	B
+was	O
+aroused	O
+by	O
+the	O
+palpation	O
+of	O
+a	O
+small	O
+nodule	O
+in	O
+the	O
+vaginal	O
+fornix	O
+.	O
+
+Hysterosalpingography	O
+was	O
+performed	O
+on	O
+both	O
+patients	O
+and	O
+,	O
+in	O
+1	O
+instance	O
+,	O
+an	O
+abnormal	O
+x	O
+-	O
+ray	O
+film	O
+was	O
+reflected	O
+by	O
+the	O
+gross	O
+appearance	O
+of	O
+the	O
+uterine	O
+cavity	O
+found	O
+in	O
+the	O
+surgical	O
+specimen	O
+.	O
+
+Neurologic	O
+effects	O
+of	O
+subarachnoid	O
+administration	O
+of	O
+2	O
+-	O
+chloroprocaine	O
+-	O
+CE	O
+,	O
+bupivacaine	O
+,	O
+and	O
+low	O
+pH	O
+normal	O
+saline	O
+in	O
+dogs	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+evaluate	O
+the	O
+neurologic	O
+consequences	O
+of	O
+deliberate	O
+subarachnoid	O
+injection	O
+of	O
+large	O
+volumes	O
+of	O
+2	O
+-	O
+chloroprocaine	O
+-	O
+CE	O
+in	O
+experimental	O
+animals	O
+.	O
+
+The	O
+possible	O
+role	O
+of	O
+low	O
+pH	O
+as	O
+well	O
+as	O
+total	O
+volume	O
+as	O
+potential	O
+factors	O
+in	O
+causing	O
+neurotoxicity	B
+was	O
+evaluated	O
+.	O
+
+The	O
+65	O
+dogs	O
+in	O
+the	O
+study	O
+received	O
+injections	O
+in	O
+the	O
+subarachnoid	O
+space	O
+as	O
+follows	O
+:	O
+6	O
+to	O
+8	O
+ml	O
+of	O
+bupivacaine	O
+(	O
+N	O
+=	O
+15	O
+)	O
+,	O
+2	O
+-	O
+chloroprocaine	O
+-	O
+CE	O
+(	O
+N	O
+=	O
+20	O
+)	O
+,	O
+low	O
+pH	O
+normal	O
+saline	O
+(	O
+pH	O
+3	O
+.	O
+0	O
+)	O
+(	O
+N	O
+=	O
+20	O
+)	O
+,	O
+or	O
+normal	O
+saline	O
+(	O
+N	O
+=	O
+10	O
+)	O
+.	O
+
+Of	O
+the	O
+20	O
+animals	O
+that	O
+received	O
+subarachnoid	O
+injection	O
+of	O
+2	O
+-	O
+chloroprocaine	O
+-	O
+CE	O
+seven	O
+(	O
+35	O
+%	O
+)	O
+developed	O
+hind	O
+-	O
+limb	O
+paralysis	B
+.	O
+
+None	O
+of	O
+the	O
+animals	O
+that	O
+received	O
+bupivacaine	O
+,	O
+normal	O
+saline	O
+,	O
+or	O
+normal	O
+saline	O
+titrated	O
+to	O
+a	O
+pH	O
+3	O
+.	O
+0	O
+developed	O
+hind	O
+-	O
+limb	O
+paralysis	B
+.	O
+
+Of	O
+the	O
+15	O
+spinal	O
+cords	O
+of	O
+the	O
+animals	O
+that	O
+received	O
+2	O
+-	O
+chloroprocaine	O
+-	O
+CE	O
+,	O
+13	O
+showed	O
+subpial	B
+necrosis	I
+;	O
+the	O
+nerve	O
+roots	O
+and	O
+subarachnoid	O
+vessels	O
+were	O
+normal	O
+.	O
+
+The	O
+spinal	O
+cords	O
+of	O
+the	O
+animals	O
+that	O
+received	O
+bupivacaine	O
+,	O
+low	O
+pH	O
+normal	O
+saline	O
+(	O
+pH	O
+3	O
+.	O
+0	O
+)	O
+,	O
+or	O
+normal	O
+saline	O
+did	O
+not	O
+show	O
+abnormal	O
+findings	O
+.	O
+
+Procainamide	O
+-	O
+induced	O
+polymorphous	O
+ventricular	B
+tachycardia	I
+.	O
+
+Seven	O
+cases	O
+of	O
+procainamide	O
+-	O
+induced	O
+polymorphous	O
+ventricular	B
+tachycardia	I
+are	O
+presented	O
+.	O
+
+In	O
+four	O
+patients	O
+,	O
+polymorphous	O
+ventricular	B
+tachycardia	I
+appeared	O
+after	O
+intravenous	O
+administration	O
+of	O
+200	O
+to	O
+400	O
+mg	O
+of	O
+procainamide	O
+for	O
+the	O
+treatment	O
+of	O
+sustained	O
+ventricular	B
+tachycardia	I
+.	O
+
+In	O
+the	O
+remaining	O
+three	O
+patients	O
+,	O
+procainamide	O
+was	O
+administered	O
+orally	O
+for	O
+treatment	O
+of	O
+chronic	O
+premature	B
+ventricular	I
+contractions	I
+or	O
+atrial	B
+flutter	I
+.	O
+
+These	O
+patients	O
+had	O
+Q	B
+-	I
+T	I
+prolongation	I
+and	O
+recurrent	O
+syncope	B
+due	O
+to	O
+polymorphous	O
+ventricular	B
+tachycardia	I
+.	O
+
+In	O
+four	O
+patients	O
+,	O
+the	O
+arrhythmia	B
+was	O
+rapidly	O
+diagnosed	O
+and	O
+treated	O
+with	O
+disappearance	O
+of	O
+further	O
+episodes	O
+of	O
+the	O
+arrhythmia	B
+.	O
+
+In	O
+two	O
+patients	O
+,	O
+the	O
+arrhythmia	B
+degenerated	O
+into	O
+irreversible	O
+ventricular	B
+fibrillation	I
+and	O
+both	O
+patients	O
+died	O
+.	O
+
+In	O
+the	O
+seventh	O
+patient	O
+,	O
+a	O
+permanent	O
+ventricular	O
+pacemaker	O
+was	O
+inserted	O
+and	O
+,	O
+despite	O
+continuation	O
+of	O
+procainamide	O
+therapy	O
+,	O
+polymorphous	O
+ventricular	B
+tachycardia	I
+did	O
+not	O
+reoccur	O
+.	O
+
+These	O
+seven	O
+cases	O
+demonstrate	O
+that	O
+procainamide	O
+can	O
+produce	O
+an	O
+acquired	O
+prolonged	B
+Q	I
+-	I
+T	I
+syndrome	I
+with	O
+polymorphous	O
+ventricular	B
+tachycardia	I
+.	O
+
+Phenobarbitone	O
+-	O
+induced	O
+enlargement	B
+of	I
+the	I
+liver	I
+in	O
+the	O
+rat	O
+:	O
+its	O
+relationship	O
+to	O
+carbon	O
+tetrachloride	O
+-	O
+induced	O
+cirrhosis	B
+.	O
+
+The	O
+yield	O
+of	O
+severe	O
+cirrhosis	B
+of	I
+the	I
+liver	I
+(	O
+defined	O
+as	O
+a	O
+shrunken	O
+finely	O
+nodular	O
+liver	O
+with	O
+micronodular	O
+histology	O
+,	O
+ascites	B
+greater	O
+than	O
+30	O
+ml	O
+,	O
+plasma	O
+albumin	O
+less	O
+than	O
+2	O
+.	O
+2	O
+g	O
+/	O
+dl	O
+,	O
+splenomegaly	B
+2	O
+-	O
+3	O
+times	O
+normal	O
+,	O
+and	O
+testicular	O
+atrophy	B
+approximately	O
+half	O
+normal	O
+weight	O
+)	O
+after	O
+12	O
+doses	O
+of	O
+carbon	O
+tetrachloride	O
+given	O
+intragastrically	O
+in	O
+the	O
+phenobarbitone	O
+-	O
+primed	O
+rat	O
+was	O
+increased	O
+from	O
+25	O
+%	O
+to	O
+56	O
+%	O
+by	O
+giving	O
+the	O
+initial	O
+"	O
+calibrating	O
+"	O
+dose	O
+of	O
+carbon	O
+tetrachloride	O
+at	O
+the	O
+peak	O
+of	O
+the	O
+phenobarbitone	O
+-	O
+induced	O
+enlargement	B
+of	I
+the	I
+liver	I
+.	O
+
+At	O
+this	O
+point	O
+it	O
+was	O
+assumed	O
+that	O
+the	O
+cytochrome	O
+P450	O
+/	O
+CCl4	O
+toxic	O
+state	O
+was	O
+both	O
+maximal	O
+and	O
+stable	O
+.	O
+
+The	O
+optimal	O
+rat	O
+size	O
+to	O
+begin	O
+phenobarbitone	O
+was	O
+determined	O
+as	O
+100	O
+g	O
+,	O
+and	O
+this	O
+size	O
+as	O
+a	O
+group	O
+had	O
+a	O
+mean	O
+maximum	O
+relative	O
+liver	O
+weight	O
+increase	O
+47	O
+%	O
+greater	O
+than	O
+normal	O
+rats	O
+of	O
+the	O
+same	O
+body	O
+weight	O
+.	O
+
+The	O
+optimal	O
+time	O
+for	O
+the	O
+initial	O
+dose	O
+of	O
+carbon	O
+tetrachloride	O
+was	O
+after	O
+14	O
+days	O
+on	O
+phenobarbitone	O
+.	O
+
+Triamterene	O
+nephrolithiasis	B
+complicating	O
+dyazide	O
+therapy	O
+.	O
+
+A	O
+case	O
+of	O
+triamterene	O
+nephrolithiasis	B
+is	O
+reported	O
+in	O
+a	O
+man	O
+after	O
+4	O
+years	O
+of	O
+hydrochlorothiazide	O
+-	O
+triamterene	O
+therapy	O
+for	O
+hypertension	B
+.	O
+
+The	O
+stone	O
+passed	O
+spontaneously	O
+and	O
+was	O
+found	O
+to	O
+contain	O
+a	O
+triamterene	O
+metabolite	O
+admixed	O
+with	O
+uric	O
+acid	O
+salts	O
+.	O
+
+Factors	O
+affecting	O
+triamterene	O
+nephrolithiasis	B
+are	O
+discussed	O
+and	O
+2	O
+previously	O
+reported	O
+cases	O
+are	O
+reviewed	O
+.	O
+
+Busulfan	O
+-	O
+induced	O
+hemorrhagic	B
+cystitis	I
+.	O
+
+A	O
+case	O
+of	O
+a	O
+busulfan	O
+-	O
+induced	O
+hemorrhage	B
+cystitis	I
+is	O
+reported	O
+.	O
+
+Spontaneous	O
+resolution	O
+occurred	O
+following	O
+cessation	O
+of	O
+the	O
+drug	O
+.	O
+
+The	O
+similarity	O
+between	O
+the	O
+histologic	O
+appearances	O
+of	O
+busulfan	O
+cystitis	B
+and	O
+both	O
+radiation	O
+and	O
+cyclophosphamide	O
+-	O
+induced	O
+cystitis	B
+is	O
+discussed	O
+and	O
+the	O
+world	O
+literature	O
+reviewed	O
+.	O
+
+In	O
+view	O
+of	O
+the	O
+known	O
+tendency	O
+of	O
+busulfan	O
+to	O
+induce	O
+cellular	O
+atypia	O
+and	O
+carcinoma	B
+in	O
+other	O
+sites	O
+,	O
+periodic	O
+urinary	O
+cytology	O
+is	O
+suggested	O
+in	O
+patients	O
+on	O
+long	O
+-	O
+term	O
+therapy	O
+.	O
+
+Variant	O
+ventricular	B
+tachycardia	I
+in	O
+desipramine	O
+toxicity	B
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+variant	O
+ventricular	B
+tachycardia	I
+induced	O
+by	O
+desipramine	O
+toxicity	B
+.	O
+
+Unusual	O
+features	O
+of	O
+the	O
+arrhythmia	B
+are	O
+repetitive	O
+group	O
+beating	O
+,	O
+progressive	O
+shortening	O
+of	O
+the	O
+R	O
+-	O
+R	O
+interval	O
+,	O
+progressive	O
+widening	O
+of	O
+the	O
+QRS	O
+complex	O
+with	O
+eventual	O
+failure	O
+of	O
+intraventricular	O
+conduction	O
+,	O
+and	O
+changes	O
+in	O
+direction	O
+of	O
+the	O
+QRS	O
+axis	O
+.	O
+
+Recognition	O
+of	O
+variant	O
+ventricular	B
+tachycardia	I
+is	O
+important	O
+because	O
+therapy	O
+differs	O
+from	O
+that	O
+of	O
+classic	O
+ventricular	B
+tachycardia	I
+.	O
+
+Rebound	O
+hypertensive	B
+after	O
+sodium	O
+nitroprusside	O
+prevented	O
+by	O
+saralasin	O
+in	O
+rats	O
+.	O
+
+The	O
+role	O
+of	O
+the	O
+renin	O
+-	O
+-	O
+angiotensin	O
+system	O
+in	O
+the	O
+maintenance	O
+of	O
+blood	O
+pressure	O
+during	O
+halothane	O
+anesthesia	O
+and	O
+sodium	O
+nitroprusside	O
+(	O
+SNP	O
+)	O
+-	O
+induced	O
+hypotension	B
+was	O
+evaluated	O
+.	O
+
+Control	O
+rats	O
+received	O
+halothane	O
+anesthesia	O
+(	O
+1	O
+MAC	O
+)	O
+for	O
+one	O
+hour	O
+,	O
+followed	O
+by	O
+SNP	O
+infusion	O
+,	O
+40	O
+microgram	O
+/	O
+kg	O
+/	O
+min	O
+,	O
+for	O
+30	O
+min	O
+,	O
+followed	O
+by	O
+a	O
+30	O
+-	O
+min	O
+recovery	O
+period	O
+.	O
+
+A	O
+second	O
+group	O
+of	O
+rats	O
+was	O
+treated	O
+identically	O
+and	O
+,	O
+in	O
+addition	O
+,	O
+received	O
+an	O
+infusion	O
+of	O
+saralasin	O
+(	O
+a	O
+competitive	O
+inhibitor	O
+of	O
+angiotensin	O
+II	O
+)	O
+throughout	O
+the	O
+experimental	O
+period	O
+.	O
+
+In	O
+each	O
+group	O
+,	O
+SNP	O
+infusion	O
+resulted	O
+in	O
+an	O
+initial	O
+decrease	O
+in	O
+blood	O
+pressure	O
+from	O
+86	O
+torr	O
+and	O
+83	O
+torr	O
+,	O
+respectively	O
+,	O
+to	O
+48	O
+torr	O
+.	O
+
+During	O
+the	O
+SNP	O
+infusion	O
+the	O
+control	O
+animals	O
+demonstrated	O
+a	O
+progressive	O
+increase	B
+in	I
+blood	I
+pressure	I
+to	O
+61	O
+torr	O
+,	O
+whereas	O
+the	O
+saralasin	O
+-	O
+treated	O
+animals	O
+showed	O
+no	O
+change	O
+.	O
+
+Following	O
+discontinuation	O
+of	O
+SNP	O
+,	O
+blood	O
+pressure	O
+in	O
+the	O
+control	O
+animals	O
+rebounded	O
+to	O
+94	O
+torr	O
+,	O
+as	O
+compared	O
+with	O
+78	O
+torr	O
+in	O
+the	O
+saralasin	O
+-	O
+treated	O
+rats	O
+.	O
+
+This	O
+study	O
+indicates	O
+that	O
+with	O
+stable	O
+halothane	O
+anesthesia	O
+,	O
+the	O
+partial	O
+recovery	O
+of	O
+blood	O
+pressure	O
+during	O
+SNP	O
+infusion	O
+and	O
+the	O
+post	O
+-	O
+SNP	O
+rebound	O
+of	O
+blood	O
+pressure	O
+can	O
+be	O
+completely	O
+blocked	O
+by	O
+saralasin	O
+.	O
+
+This	O
+demonstrates	O
+the	O
+participation	O
+of	O
+the	O
+renin	O
+-	O
+-	O
+angiotensin	O
+system	O
+in	O
+antagonizing	O
+the	O
+combined	O
+hypotensive	B
+effects	O
+of	O
+halothane	O
+and	O
+SNP	O
+.	O
+
+Clinical	O
+nephrotoxicity	B
+of	O
+tobramycin	O
+and	O
+gentamicin	O
+.	O
+
+A	O
+prospective	O
+study	O
+.	O
+
+Nearly	O
+3	O
+.	O
+2	O
+million	O
+people	O
+in	O
+this	O
+country	O
+receive	O
+aminoglycoside	O
+antibiotics	O
+annually	O
+.	O
+
+Gentamicin	O
+sulfate	O
+and	O
+tobramycin	O
+sulfate	O
+continue	O
+to	O
+demonstrate	O
+ototoxicity	B
+and	O
+nephrotoxicity	B
+in	O
+both	O
+animal	O
+and	O
+clinical	O
+studies	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+62	O
+patients	O
+with	O
+confirmed	O
+initial	O
+normal	O
+renal	O
+function	O
+and	O
+treated	O
+with	O
+2	O
+to	O
+5	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+of	O
+gentamicin	O
+sulfate	O
+or	O
+tobramycin	O
+sulfate	O
+for	O
+a	O
+minimum	O
+of	O
+seven	O
+days	O
+were	O
+followed	O
+up	O
+prospectively	O
+for	O
+the	O
+development	O
+of	O
+aminoglycoside	O
+-	O
+related	O
+renal	B
+failure	I
+,	O
+defined	O
+as	O
+at	O
+least	O
+a	O
+one	O
+-	O
+third	O
+reduction	O
+in	O
+renal	O
+function	O
+.	O
+
+In	O
+these	O
+62	O
+patients	O
+,	O
+no	O
+other	O
+causes	O
+for	O
+renal	B
+failure	I
+could	O
+be	O
+identified	O
+.	O
+
+Five	O
+of	O
+33	O
+(	O
+15	O
+%	O
+)	O
+of	O
+the	O
+tobramycin	O
+-	O
+treated	O
+patients	O
+and	O
+16	O
+of	O
+29	O
+(	O
+55	O
+.	O
+2	O
+%	O
+)	O
+of	O
+the	O
+gentamicin	O
+-	O
+treated	O
+patients	O
+had	O
+renal	B
+failure	I
+.	O
+
+Thus	O
+,	O
+gentamicin	O
+was	O
+associated	O
+with	O
+renal	B
+failure	I
+more	O
+than	O
+three	O
+times	O
+as	O
+often	O
+as	O
+was	O
+tobramycin	O
+.	O
+
+Metabolic	O
+involvement	O
+in	O
+adriamycin	O
+cardiotoxicity	B
+.	O
+
+The	O
+cardiotoxic	B
+effects	O
+of	O
+adriamycin	O
+were	O
+studied	O
+in	O
+mammalian	O
+myocardial	O
+cells	O
+in	O
+culture	O
+as	O
+a	O
+model	O
+system	O
+.	O
+
+Adriamycin	O
+inhibited	O
+cell	O
+growth	O
+and	O
+the	O
+rhythmic	O
+contractions	O
+characteristic	O
+of	O
+myocardial	O
+cells	O
+in	O
+culture	O
+.	O
+
+A	O
+possible	O
+involvement	O
+of	O
+energy	O
+metabolism	O
+was	O
+suggested	O
+previously	O
+,	O
+and	O
+in	O
+this	O
+study	O
+the	O
+adenylate	O
+energy	O
+charge	O
+and	O
+phosphorylcreatine	O
+mole	O
+fraction	O
+were	O
+determined	O
+in	O
+the	O
+adriamycin	O
+-	O
+treated	O
+cells	O
+.	O
+
+The	O
+adenylate	O
+energy	O
+charge	O
+was	O
+found	O
+to	O
+be	O
+significantly	O
+decreased	O
+,	O
+while	O
+the	O
+phophorylcreatine	O
+mole	O
+fraction	O
+was	O
+unchanged	O
+.	O
+
+Such	O
+disparity	O
+suggests	O
+an	O
+inhibition	O
+of	O
+creatine	O
+phosphokinase	O
+.	O
+
+The	O
+addition	O
+of	O
+1	O
+mM	O
+adenosine	O
+to	O
+the	O
+myocardial	O
+cell	O
+cultures	O
+markedly	O
+increases	O
+the	O
+ATP	O
+concentration	O
+through	O
+a	O
+pathway	O
+reportedly	O
+leading	O
+to	O
+a	O
+compartmentalized	O
+ATP	O
+pool	O
+.	O
+
+In	O
+the	O
+adriamycin	O
+-	O
+treated	O
+cells	O
+,	O
+the	O
+addition	O
+of	O
+adenosine	O
+increased	O
+the	O
+adenylate	O
+charge	O
+and	O
+,	O
+concomitant	O
+with	O
+this	O
+inrcease	O
+,	O
+the	O
+cells	O
+'	O
+functional	O
+integrity	O
+,	O
+in	O
+terms	O
+of	O
+percentage	O
+of	O
+beating	O
+cells	O
+and	O
+rate	O
+of	O
+contractions	O
+,	O
+was	O
+maintained	O
+.	O
+
+Age	O
+-	O
+dependent	O
+sensitivity	O
+of	O
+the	O
+rat	O
+to	O
+neurotoxic	B
+effects	O
+of	O
+streptomycin	O
+.	O
+
+Streptomycin	O
+sulfate	O
+(	O
+300	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+was	O
+injected	O
+for	O
+various	O
+periods	O
+into	O
+preweanling	O
+rats	O
+and	O
+for	O
+3	O
+weeks	O
+into	O
+weanling	O
+rats	O
+.	O
+
+Beginning	O
+at	O
+8	O
+days	O
+of	O
+age	O
+,	O
+body	O
+movement	O
+and	O
+hearing	O
+were	O
+examined	O
+for	O
+6	O
+and	O
+up	O
+to	O
+17	O
+weeks	O
+,	O
+respectively	O
+.	O
+
+Abnormal	B
+movements	I
+and	O
+deafness	B
+occurred	O
+only	O
+in	O
+rats	O
+treated	O
+during	O
+the	O
+preweaning	O
+period	O
+;	O
+within	O
+this	O
+period	O
+the	O
+greatest	O
+sensitivities	O
+for	O
+these	O
+abnormalities	O
+occurred	O
+from	O
+2	O
+to	O
+11	O
+-	O
+17	O
+and	O
+5	O
+to	O
+11	O
+days	O
+of	O
+age	O
+,	O
+respectively	O
+,	O
+indicating	O
+that	O
+the	O
+cochlea	O
+is	O
+more	O
+sensitive	O
+to	O
+streptomycin	O
+than	O
+the	O
+site	O
+(	O
+vestibular	O
+or	O
+central	O
+)	O
+responsible	O
+for	O
+the	O
+dyskinesias	B
+.	O
+
+Late	O
+,	O
+late	O
+doxorubicin	O
+cardiotoxicity	B
+.	O
+
+Cardiac	B
+toxicity	I
+is	O
+a	O
+major	O
+complication	O
+which	O
+limits	O
+the	O
+use	O
+of	O
+adriamycin	O
+as	O
+a	O
+chemotherapeutic	O
+agent	O
+.	O
+
+Cardiomyopathy	B
+is	O
+frequent	O
+when	O
+the	O
+total	O
+dose	O
+exceeds	O
+600	O
+mg	O
+/	O
+m2	O
+and	O
+occurs	O
+within	O
+one	O
+to	O
+six	O
+months	O
+after	O
+cessation	O
+of	O
+therapy	O
+.	O
+
+A	O
+patient	O
+is	O
+reported	O
+who	O
+developed	O
+progressive	O
+cardiomyopathy	B
+two	O
+and	O
+one	O
+-	O
+half	O
+years	O
+after	O
+receiving	O
+580	O
+mg	O
+/	O
+m2	O
+which	O
+apparently	O
+represents	O
+late	O
+,	O
+late	O
+cardiotoxicity	B
+.	O
+
+Attenuation	O
+of	O
+the	O
+lithium	O
+-	O
+induced	O
+diabetes	B
+-	I
+insipidus	I
+-	I
+like	I
+syndrome	I
+by	O
+amiloride	O
+in	O
+rats	O
+.	O
+
+The	O
+effect	O
+of	O
+amiloride	O
+on	O
+lithium	O
+-	O
+induced	O
+polydipsia	B
+and	O
+polyuria	B
+and	O
+on	O
+the	O
+lithium	O
+concentration	O
+in	O
+the	O
+plasma	O
+,	O
+brain	O
+,	O
+kidney	O
+,	O
+thyroid	O
+and	O
+red	O
+blood	O
+cells	O
+was	O
+investigated	O
+in	O
+rats	O
+,	O
+chronically	O
+treated	O
+with	O
+LiCl	O
+.	O
+
+Amiloride	O
+reduced	O
+the	O
+drinking	O
+and	O
+urine	O
+volume	O
+of	O
+rats	O
+in	O
+an	O
+acute	O
+(	O
+6	O
+or	O
+12	O
+h	O
+)	O
+and	O
+a	O
+subacute	O
+(	O
+3	O
+days	O
+)	O
+experiment	O
+.	O
+
+6	O
+h	O
+after	O
+the	O
+administration	O
+of	O
+amiloride	O
+,	O
+a	O
+reduction	O
+was	O
+observed	O
+in	O
+the	O
+lithium	O
+content	O
+of	O
+the	O
+renal	O
+medulla	O
+but	O
+not	O
+in	O
+the	O
+other	O
+organs	O
+studied	O
+.	O
+
+At	O
+12	O
+h	O
+,	O
+all	O
+the	O
+tissues	O
+showed	O
+a	O
+slight	O
+increase	O
+in	O
+lithium	O
+levels	O
+.	O
+
+After	O
+3	O
+days	O
+of	O
+combined	O
+treatment	O
+,	O
+a	O
+marked	O
+elevation	O
+in	O
+plasma	O
+and	O
+tissue	O
+lithium	O
+levels	O
+accompanied	O
+a	O
+reduction	O
+in	O
+water	O
+intake	O
+.	O
+
+In	O
+all	O
+the	O
+experiments	O
+,	O
+the	O
+attenuation	O
+of	O
+the	O
+lithium	O
+-	O
+induced	O
+diabetes	B
+-	I
+insipidus	I
+-	I
+like	I
+syndrome	I
+by	O
+amiloride	O
+was	O
+accompanied	O
+by	O
+a	O
+reduction	O
+of	O
+the	O
+ratio	O
+between	O
+the	O
+lithium	O
+concentration	O
+in	O
+the	O
+renal	O
+medulla	O
+and	O
+its	O
+levels	O
+in	O
+the	O
+blood	O
+and	O
+an	O
+elevation	O
+in	O
+the	O
+plasma	O
+potassium	O
+level	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+acute	O
+amiloride	O
+administration	O
+to	O
+lithium	O
+-	O
+treated	O
+patients	O
+suffering	O
+from	O
+polydipsia	B
+and	O
+polyuria	B
+might	O
+relieve	O
+these	O
+patients	O
+but	O
+prolonged	O
+amiloride	O
+supplementation	O
+would	O
+result	O
+in	O
+elevated	O
+lithium	O
+levels	O
+and	O
+might	O
+be	O
+hazardous	O
+.	O
+
+Cardiovascular	B
+complications	I
+associated	O
+with	O
+terbutaline	O
+treatment	O
+for	O
+preterm	B
+labor	I
+.	O
+
+Severe	O
+cardiovascular	B
+complications	I
+occurred	O
+in	O
+eight	O
+of	O
+160	O
+patients	O
+treated	O
+with	O
+terbutaline	O
+for	O
+preterm	B
+labor	I
+.	O
+
+Associated	O
+corticosteroid	O
+therapy	O
+and	O
+twin	O
+gestations	O
+appear	O
+to	O
+be	O
+predisposing	O
+factors	O
+.	O
+
+Potential	O
+mechanisms	O
+of	O
+the	O
+pathophysiology	O
+are	O
+briefly	O
+discussed	O
+.	O
+
+Toxic	B
+hepatitis	I
+induced	O
+by	O
+antithyroid	O
+drugs	O
+:	O
+four	O
+cases	O
+including	O
+one	O
+with	O
+cross	O
+-	O
+reactivity	O
+between	O
+carbimazole	O
+and	O
+benzylthiouracil	O
+.	O
+
+OBJECTIVE	O
+:	O
+This	O
+study	O
+was	O
+conducted	O
+to	O
+assess	O
+the	O
+occurrence	O
+of	O
+hepatic	B
+adverse	I
+effects	I
+encountered	O
+with	O
+antithyroid	O
+drugs	O
+.	O
+
+METHODS	O
+:	O
+Retrospective	O
+review	O
+of	O
+medical	O
+records	O
+of	O
+236	O
+patients	O
+with	O
+hyperthyroidism	B
+admitted	O
+in	O
+our	O
+department	O
+(	O
+in	O
+-	O
+or	O
+out	O
+-	O
+patients	O
+)	O
+from	O
+1986	O
+to	O
+1992	O
+.	O
+
+RESULTS	O
+:	O
+Four	O
+patients	O
+(	O
+1	O
+.	O
+7	O
+%	O
+)	O
+were	O
+identified	O
+with	O
+toxic	B
+hepatitis	I
+which	O
+could	O
+reasonably	O
+be	O
+attributed	O
+to	O
+the	O
+use	O
+of	O
+antithyroid	O
+agent	O
+.	O
+
+Two	O
+patients	O
+had	O
+a	O
+cholestatic	B
+hepatitis	I
+induced	O
+by	O
+carbimazole	O
+(	O
+N	O
+omercazole	O
+)	O
+.	O
+
+Two	O
+others	O
+had	O
+a	O
+mixed	O
+(	O
+cholestatic	B
+and	O
+cytolytic	O
+)	O
+hepatitis	B
+following	O
+carbimazole	O
+.	O
+
+One	O
+of	O
+the	O
+latter	O
+two	O
+patients	O
+further	O
+experienced	O
+a	O
+cytolytic	O
+hepatitis	B
+which	O
+appeared	O
+after	O
+Benzylthiouracil	O
+(	O
+Basd	O
+ne	O
+)	O
+had	O
+replaced	O
+carbimazole	O
+.	O
+
+Biological	O
+features	O
+of	O
+hepatitis	B
+disappeared	O
+in	O
+all	O
+cases	O
+after	O
+cessation	O
+of	O
+the	O
+incriminated	O
+drug	O
+,	O
+while	O
+biliary	O
+,	O
+viral	O
+and	O
+immunological	O
+searches	O
+were	O
+negative	O
+.	O
+
+Only	O
+2	O
+patients	O
+of	O
+our	O
+retrospective	O
+study	O
+experienced	O
+a	O
+mild	O
+or	O
+severe	O
+neutropenia	B
+.	O
+
+CONCLUSION	O
+:	O
+Toxic	B
+hepatitis	I
+is	O
+a	O
+potential	O
+adverse	O
+effect	O
+of	O
+antithyroid	O
+drugs	O
+which	O
+warrants	O
+,	O
+as	O
+for	O
+haematological	O
+disturbances	O
+,	O
+a	O
+pre	O
+-	O
+therapeutic	O
+determination	O
+and	O
+a	O
+careful	O
+follow	O
+-	O
+up	O
+of	O
+relevant	O
+biological	O
+markers	O
+.	O
+
+Moreover	O
+,	O
+hepatotoxicity	B
+may	O
+not	O
+be	O
+restricted	O
+to	O
+one	O
+class	O
+of	O
+antithyroid	O
+agents	O
+.	O
+
+Interactive	O
+effects	O
+of	O
+variations	O
+in	O
+[	O
+Na	O
+]	O
+o	O
+and	O
+[	O
+Ca	O
+]	O
+o	O
+on	O
+rat	O
+atrial	O
+spontaneous	O
+frequency	O
+.	O
+
+The	O
+effects	O
+of	O
+varying	O
+the	O
+extracellular	O
+concentrations	O
+of	O
+Na	O
+and	O
+Ca	O
+(	O
+[	O
+Na	O
+]	O
+o	O
+and	O
+[	O
+Ca	O
+]	O
+o	O
+)	O
+on	O
+both	O
+,	O
+the	O
+spontaneous	O
+beating	O
+and	O
+the	O
+negative	O
+chronotropic	O
+action	O
+of	O
+verapamil	O
+,	O
+were	O
+studied	O
+in	O
+the	O
+isolated	O
+rat	O
+atria	O
+.	O
+
+Basal	O
+frequency	O
+(	O
+BF	O
+)	O
+evaluated	O
+by	O
+surface	O
+electrogram	O
+was	O
+223	O
++	O
+/	O
+-	O
+4	O
+beats	O
+/	O
+min	O
+.	O
+in	O
+control	O
+Krebs	O
+-	O
+Ringer	O
+containing	O
+137	O
+mM	O
+Na	O
+and	O
+1	O
+.	O
+35	O
+mM	O
+Ca	O
+(	O
+N	O
+)	O
+.	O
+
+It	O
+decreased	O
+by	O
+16	O
++	O
+/	O
+-	O
+3	O
+%	O
+by	O
+lowering	O
+[	O
+Na	O
+]	O
+o	O
+to	O
+78	O
+mM	O
+(	O
+LNa	O
+)	O
+,	O
+23	O
++	O
+/	O
+-	O
+2	O
+%	O
+by	O
+lowering	O
+simultaneously	O
+[	O
+Na	O
+]	O
+o	O
+to	O
+78	O
+mM	O
+and	O
+[	O
+Ca	O
+]	O
+o	O
+to	O
+0	O
+.	O
+675	O
+mM	O
+(	O
+LNa	O
++	O
+LCa	O
+)	O
+and	O
+31	O
++	O
+/	O
+-	O
+5	O
+%	O
+by	O
+lowering	O
+[	O
+Na	O
+]	O
+o	O
+to	O
+78	O
+mM	O
+plus	O
+increasing	O
+[	O
+Ca	O
+]	O
+o	O
+to	O
+3	O
+.	O
+6	O
+mM	O
+(	O
+LNa	O
++	O
+HCa	O
+)	O
+.	O
+
+At	O
+normal	O
+[	O
+Na	O
+]	O
+o	O
+,	O
+decrease	O
+(	O
+0	O
+.	O
+675	O
+mM	O
+)	O
+or	O
+increase	O
+(	O
+3	O
+.	O
+6	O
+mM	O
+)	O
+of	O
+[	O
+Ca	O
+]	O
+o	O
+did	O
+not	O
+modify	O
+BF	O
+;	O
+a	O
+reduction	O
+of	O
+ten	O
+times	O
+(	O
+0	O
+.	O
+135	O
+mM	O
+of	O
+normal	O
+[	O
+Ca	O
+]	O
+o	O
+was	O
+effective	O
+to	O
+reduce	O
+BF	O
+by	O
+40	O
++	O
+/	O
+-	O
+13	O
+%	O
+.	O
+
+All	O
+negative	O
+chronotropic	O
+effects	O
+were	O
+BF	O
+-	O
+dependent	O
+.	O
+
+Dose	O
+-	O
+dependent	O
+bradycardia	B
+induced	O
+by	O
+verapamil	O
+was	O
+potentiated	O
+by	O
+LNa	O
+,	O
+LCa	O
+,	O
+and	O
+HCa	O
+.	O
+
+Independent	O
+but	O
+not	O
+additive	O
+effects	O
+of	O
+Na	O
+and	O
+Ca	O
+are	O
+shown	O
+by	O
+decreases	O
+in	O
+the	O
+values	O
+of	O
+[	O
+verapamil	O
+]	O
+o	O
+needed	O
+to	O
+reduce	O
+BF	O
+by	O
+30	O
+%	O
+(	O
+IC30	O
+)	O
+with	O
+the	O
+following	O
+order	O
+of	O
+inhibitory	O
+potency	O
+:	O
+LNa	O
+>	O
+LCa	O
+>	O
+HCa	O
+>	O
+N	O
+,	O
+resulting	O
+LNa	O
++	O
+HCa	O
+similar	O
+to	O
+LNa	O
+.	O
+
+The	O
+[	O
+verapamil	O
+]	O
+o	O
+that	O
+arrested	O
+atrial	O
+beating	O
+(	O
+AC	O
+)	O
+was	O
+also	O
+potentiated	O
+with	O
+the	O
+order	O
+LNa	O
+=	O
+LNa	O
++	O
+LCa	O
+=	O
+LNa	O
++	O
+HCa	O
+=	O
+LCa	O
+>	O
+HCa	O
+=	O
+N	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+rat	O
+atrial	O
+spontaneous	O
+beating	O
+is	O
+more	O
+dependent	O
+on	O
+[	O
+Na	O
+]	O
+o	O
+than	O
+on	O
+[	O
+Ca	O
+]	O
+o	O
+in	O
+a	O
+range	O
+of	O
++	O
+/	O
+-	O
+50	O
+%	O
+of	O
+their	O
+normal	O
+concentration	O
+.	O
+
+Also	O
+the	O
+enhancement	O
+of	O
+verapamil	O
+effects	O
+on	O
+atrial	O
+beating	O
+was	O
+more	O
+pronounced	O
+at	O
+LNa	O
+than	O
+at	O
+LCa	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Pseudo	O
+-	O
+allergic	B
+reactions	I
+to	O
+corticosteroids	O
+:	O
+diagnosis	O
+and	O
+alternatives	O
+.	O
+
+Two	O
+patients	O
+treated	O
+with	O
+parenteral	O
+paramethasone	O
+(	O
+Triniol	O
+)	O
+and	O
+dexamethasone	O
+(	O
+Sedionbel	O
+)	O
+are	O
+described	O
+.	O
+
+A	O
+few	O
+minutes	O
+after	O
+administration	O
+of	O
+the	O
+drugs	O
+,	O
+they	O
+presented	O
+urticaria	B
+(	O
+patients	O
+1	O
+and	O
+2	O
+)	O
+and	O
+conjunctivitis	B
+(	O
+patient	O
+1	O
+)	O
+.	O
+
+The	O
+purpose	O
+of	O
+our	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+cause	O
+of	O
+the	O
+patients	O
+'	O
+reactions	O
+,	O
+the	O
+immunological	O
+mechanisms	O
+involved	O
+and	O
+whether	O
+these	O
+patients	O
+would	O
+be	O
+able	O
+to	O
+tolerate	O
+any	O
+kind	O
+of	O
+corticoid	O
+.	O
+
+Clinical	O
+examinations	O
+and	O
+skin	O
+,	O
+oral	O
+and	O
+parenteral	O
+challenges	O
+with	O
+different	O
+corticosteroids	O
+and	O
+ELISA	O
+tests	O
+were	O
+performed	O
+.	O
+
+In	O
+the	O
+two	O
+patients	O
+,	O
+skin	O
+and	O
+ELISA	O
+tests	O
+with	O
+paramethasone	O
+were	O
+negative	O
+,	O
+as	O
+was	O
+the	O
+prick	O
+test	O
+with	O
+each	O
+of	O
+its	O
+excipients	O
+.	O
+
+A	O
+single	O
+-	O
+blind	O
+parenteral	O
+challenge	O
+with	O
+Triniol	O
+was	O
+positive	O
+in	O
+both	O
+patients	O
+after	O
+the	O
+administration	O
+of	O
+1	O
+ml	O
+of	O
+the	O
+drug	O
+,	O
+and	O
+negative	O
+with	O
+its	O
+excipients	O
+.	O
+
+We	O
+also	O
+carried	O
+out	O
+oral	O
+and	O
+parenteral	O
+challenges	O
+with	O
+other	O
+corticosteroids	O
+and	O
+found	O
+intolerance	O
+to	O
+some	O
+of	O
+them	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+paramethasone	O
+caused	O
+pseudoallergic	O
+reactions	O
+in	O
+our	O
+patients	O
+.	O
+
+Corticosteroids	O
+different	O
+from	O
+paramethasone	O
+also	O
+produced	O
+hypersensitivity	B
+reactions	O
+in	O
+these	O
+patients	O
+;	O
+however	O
+,	O
+a	O
+few	O
+of	O
+them	O
+were	O
+tolerated	O
+.	O
+
+The	O
+basic	O
+mechanisms	O
+of	O
+those	O
+reactions	O
+are	O
+not	O
+yet	O
+fully	O
+understood	O
+.	O
+
+To	O
+our	O
+knowledge	O
+,	O
+this	O
+is	O
+the	O
+first	O
+report	O
+of	O
+a	O
+pseudo	O
+-	O
+allergy	B
+caused	O
+by	O
+paramethasone	O
+.	O
+
+Study	O
+of	O
+the	O
+role	O
+of	O
+vitamin	O
+B12	O
+and	O
+folinic	O
+acid	O
+supplementation	O
+in	O
+preventing	O
+hematologic	O
+toxicity	B
+of	O
+zidovudine	O
+.	O
+
+A	O
+prospective	O
+,	O
+randomized	O
+study	O
+was	O
+conducted	O
+to	O
+evaluate	O
+the	O
+role	O
+of	O
+vitamin	O
+B12	O
+and	O
+folinic	O
+acid	O
+supplementation	O
+in	O
+preventing	O
+zidovudine	O
+(	O
+ZDV	O
+)	O
+-	O
+induced	O
+bone	B
+marrow	I
+suppression	I
+.	O
+
+Seventy	O
+-	O
+five	O
+human	B
+immunodeficiency	I
+virus	I
+(	I
+HIV	I
+)	I
+-	I
+infected	I
+patients	O
+with	O
+CD4	O
++	O
+cell	O
+counts	O
+<	O
+500	O
+/	O
+mm3	O
+were	O
+randomized	O
+to	O
+receive	O
+either	O
+ZDV	O
+(	O
+500	O
+mg	O
+daily	O
+)	O
+alone	O
+(	O
+group	O
+I	O
+,	O
+n	O
+=	O
+38	O
+)	O
+or	O
+in	O
+combination	O
+with	O
+folinic	O
+acid	O
+(	O
+15	O
+mg	O
+daily	O
+)	O
+and	O
+intramascular	O
+vitamin	O
+B12	O
+(	O
+1000	O
+micrograms	O
+monthly	O
+)	O
+(	O
+group	O
+II	O
+,	O
+n	O
+=	O
+37	O
+)	O
+.	O
+
+Finally	O
+,	O
+15	O
+patients	O
+were	O
+excluded	O
+from	O
+the	O
+study	O
+(	O
+noncompliance	O
+14	O
+,	O
+death	B
+1	O
+)	O
+;	O
+thus	O
+,	O
+60	O
+patients	O
+(	O
+31	O
+in	O
+group	O
+I	O
+and	O
+29	O
+in	O
+group	O
+II	O
+)	O
+were	O
+eligible	O
+for	O
+analysis	O
+.	O
+
+No	O
+significant	O
+differences	O
+between	O
+groups	O
+were	O
+found	O
+at	O
+enrollment	O
+.	O
+
+During	O
+the	O
+study	O
+,	O
+vitamin	O
+B12	O
+and	O
+folate	O
+levels	O
+were	O
+significantly	O
+higher	O
+in	O
+group	O
+II	O
+patients	O
+;	O
+however	O
+,	O
+no	O
+differences	O
+in	O
+hemoglobin	O
+,	O
+hematocrit	O
+,	O
+mean	O
+corpuscular	O
+volume	O
+,	O
+and	O
+white	O
+-	O
+cell	O
+,	O
+neutrophil	O
+and	O
+platelet	O
+counts	O
+were	O
+observed	O
+between	O
+groups	O
+at	O
+3	O
+,	O
+6	O
+,	O
+9	O
+and	O
+12	O
+months	O
+.	O
+
+Severe	O
+hematologic	O
+toxicity	B
+(	O
+neutrophil	O
+count	O
+<	O
+1000	O
+/	O
+mm3	O
+and	O
+/	O
+or	O
+hemoglobin	O
+<	O
+8	O
+g	O
+/	O
+dl	O
+)	O
+occurred	O
+in	O
+4	O
+patients	O
+assigned	O
+to	O
+group	O
+I	O
+and	O
+7	O
+assigned	O
+to	O
+group	O
+II	O
+.	O
+
+There	O
+was	O
+no	O
+correlation	O
+between	O
+vitamin	O
+B12	O
+or	O
+folate	O
+levels	O
+and	O
+development	O
+of	O
+myelosuppression	B
+.	O
+
+Vitamin	O
+B12	O
+and	O
+folinic	O
+acid	O
+supplementation	O
+of	O
+ZDV	O
+therapy	O
+does	O
+not	O
+seem	O
+useful	O
+in	O
+preventing	O
+or	O
+reducing	O
+ZDV	O
+-	O
+induced	O
+myelotoxicity	B
+in	O
+the	O
+overall	O
+treated	O
+population	O
+,	O
+although	O
+a	O
+beneficial	O
+effect	O
+in	O
+certain	O
+subgroups	O
+of	O
+patients	O
+cannot	O
+be	O
+excluded	O
+.	O
+
+Safety	O
+and	O
+side	O
+-	O
+effects	O
+of	O
+alprazolam	O
+.	O
+
+Controlled	O
+study	O
+in	O
+agoraphobia	B
+with	O
+panic	B
+disorder	I
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+widespread	O
+use	O
+of	O
+benzodiazepines	O
+has	O
+led	O
+to	O
+increasing	O
+recognition	O
+of	O
+their	O
+unwanted	O
+effects	O
+.	O
+
+The	O
+efficacy	O
+of	O
+alprazolam	O
+and	O
+placebo	O
+in	O
+panic	B
+disorder	I
+with	O
+agoraphobia	B
+,	O
+and	O
+the	O
+side	O
+-	O
+effect	O
+and	O
+adverse	O
+effect	O
+profiles	O
+of	O
+both	O
+drug	O
+groups	O
+were	O
+measured	O
+.	O
+
+METHOD	O
+:	O
+In	O
+London	O
+and	O
+Toronto	O
+154	O
+patients	O
+who	O
+met	O
+DSM	O
+-	O
+III	O
+criteria	O
+for	O
+panic	B
+disorder	I
+with	O
+agoraphobia	B
+were	O
+randomised	O
+to	O
+alprazolam	O
+or	O
+placebo	O
+.	O
+
+Subjects	O
+in	O
+each	O
+drug	O
+group	O
+also	O
+received	O
+either	O
+exposure	O
+or	O
+relaxation	O
+.	O
+
+Treatment	O
+was	O
+from	O
+weeks	O
+0	O
+to	O
+8	O
+and	O
+was	O
+then	O
+tapered	O
+from	O
+weeks	O
+8	O
+to	O
+16	O
+.	O
+
+RESULTS	O
+:	O
+Mean	O
+alprazolam	O
+dose	O
+was	O
+5	O
+mg	O
+daily	O
+.	O
+
+Compared	O
+with	O
+placebo	O
+subjects	O
+,	O
+alprazolam	O
+patients	O
+developed	O
+more	O
+adverse	O
+reactions	O
+(	O
+21	O
+%	O
+v	O
+.	O
+0	O
+%	O
+)	O
+of	O
+depression	B
+,	O
+enuresis	B
+,	O
+disinhibition	O
+and	O
+aggression	B
+;	O
+and	O
+more	O
+side	O
+-	O
+effects	O
+,	O
+particularly	O
+sedation	O
+,	O
+irritability	B
+,	O
+impaired	B
+memory	I
+,	O
+weight	B
+loss	I
+and	O
+ataxia	B
+.	O
+
+Side	O
+-	O
+effects	O
+tended	O
+to	O
+diminish	O
+during	O
+treatment	O
+but	O
+remained	O
+significant	O
+at	O
+week	O
+8	O
+.	O
+
+Despite	O
+this	O
+,	O
+the	O
+drop	O
+-	O
+out	O
+rate	O
+was	O
+low	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Alprazolam	O
+caused	O
+side	O
+-	O
+effects	O
+and	O
+adverse	O
+effects	O
+during	O
+treatment	O
+but	O
+many	O
+patients	O
+were	O
+willing	O
+to	O
+accept	O
+these	O
+.	O
+
+Crescentic	O
+fibrillary	O
+glomerulonephritis	B
+associated	O
+with	O
+intermittent	O
+rifampin	O
+therapy	O
+for	O
+pulmonary	B
+tuberculosis	I
+.	O
+
+This	O
+case	O
+study	O
+reveals	O
+an	O
+unusual	O
+finding	O
+of	O
+rapidly	O
+proliferative	O
+crescentic	O
+glomerulonephritis	B
+in	O
+a	O
+patient	O
+treated	O
+with	O
+rifampin	O
+who	O
+had	O
+no	O
+other	O
+identifiable	O
+causes	O
+for	O
+developing	O
+this	O
+disease	O
+.	O
+
+This	O
+patient	O
+underwent	O
+a	O
+10	O
+-	O
+month	O
+regimen	O
+of	O
+rifampin	O
+and	O
+isoniazid	O
+for	O
+pulmonary	B
+tuberculosis	I
+and	O
+was	O
+discovered	O
+to	O
+have	O
+developed	O
+signs	O
+of	O
+severe	O
+renal	B
+failure	I
+five	O
+weeks	O
+after	O
+completion	O
+of	O
+therapy	O
+.	O
+
+Renal	O
+biopsy	O
+revealed	O
+severe	O
+glomerulonephritis	B
+with	O
+crescents	O
+,	O
+electron	O
+dense	O
+fibrillar	O
+deposits	O
+and	O
+moderate	O
+lymphocytic	O
+interstitial	O
+infiltrate	O
+.	O
+
+Other	O
+possible	O
+causes	O
+of	O
+rapidly	O
+progressive	O
+glomerulonephritis	B
+were	O
+investigated	O
+and	O
+ruled	O
+out	O
+.	O
+
+This	O
+report	O
+documents	O
+the	O
+unusual	O
+occurrence	O
+of	O
+rapidly	O
+progressive	O
+glomerulonephritis	B
+with	O
+crescents	O
+and	O
+fibrillar	O
+glomerulonephritis	B
+in	O
+a	O
+patient	O
+treated	O
+with	O
+rifampin	O
+.	O
+
+Acute	O
+confusion	B
+induced	O
+by	O
+a	O
+high	O
+-	O
+dose	O
+infusion	O
+of	O
+5	O
+-	O
+fluorouracil	O
+and	O
+folinic	O
+acid	O
+.	O
+
+A	O
+61	O
+-	O
+year	O
+-	O
+old	O
+man	O
+was	O
+treated	O
+with	O
+combination	O
+chemotherapy	O
+incorporating	O
+cisplatinum	O
+,	O
+etoposide	O
+,	O
+high	O
+-	O
+dose	O
+5	O
+-	O
+fluorouracil	O
+(	O
+2	O
+,	O
+250	O
+mg	O
+/	O
+m2	O
+/	O
+24	O
+hours	O
+)	O
+and	O
+folinic	O
+acid	O
+for	O
+an	O
+inoperable	O
+gastric	B
+adenocarcinoma	I
+.	O
+
+He	O
+developed	O
+acute	O
+neurologic	O
+symptoms	O
+of	O
+mental	O
+confusion	B
+,	O
+disorientation	B
+and	O
+irritability	B
+,	O
+and	O
+then	O
+lapsed	O
+into	O
+a	O
+deep	O
+coma	B
+,	O
+lasting	O
+for	O
+approximately	O
+40	O
+hours	O
+during	O
+the	O
+first	O
+dose	O
+(	O
+day	O
+2	O
+)	O
+of	O
+5	O
+-	O
+fluorouracil	O
+and	O
+folinic	O
+acid	O
+infusion	O
+.	O
+
+This	O
+complication	O
+reappeared	O
+on	O
+day	O
+25	O
+during	O
+the	O
+second	O
+dose	O
+of	O
+5	O
+-	O
+fluorouracil	O
+and	O
+folinic	O
+acid	O
+,	O
+which	O
+were	O
+then	O
+the	O
+only	O
+drugs	O
+given	O
+.	O
+
+Because	O
+folinic	O
+acid	O
+was	O
+unlikely	O
+to	O
+be	O
+associated	O
+with	O
+this	O
+condition	O
+,	O
+neurotoxicity	B
+due	O
+to	O
+high	O
+-	O
+dose	O
+5	O
+-	O
+fluorouracil	O
+was	O
+highly	O
+suspected	O
+.	O
+
+The	O
+pathogenesis	O
+of	O
+5	O
+-	O
+fluorouracil	O
+neurotoxicity	B
+may	O
+be	O
+due	O
+to	O
+a	O
+Krebs	O
+cycle	O
+blockade	O
+by	O
+fluoroacetate	O
+and	O
+fluorocitrate	O
+,	O
+thiamine	O
+deficiency	O
+,	O
+or	O
+dihydrouracil	O
+dehydrogenase	O
+deficiency	O
+.	O
+
+High	O
+-	O
+dose	O
+5	O
+-	O
+fluorouracil	O
+/	O
+folinic	O
+acid	O
+infusion	O
+therapy	O
+has	O
+recently	O
+become	O
+a	O
+popular	O
+regimen	O
+for	O
+various	O
+cancers	B
+.	O
+
+It	O
+is	O
+necessary	O
+that	O
+both	O
+oncologists	O
+and	O
+neurologists	O
+be	O
+fully	O
+aware	O
+of	O
+this	O
+unusual	O
+complication	O
+.	O
+
+Effect	O
+of	O
+switching	O
+carbamazepine	O
+to	O
+oxcarbazepine	O
+on	O
+the	O
+plasma	O
+levels	O
+of	O
+neuroleptics	O
+.	O
+
+A	O
+case	O
+report	O
+.	O
+
+Carbamazepine	O
+was	O
+switched	O
+to	O
+its	O
+10	O
+-	O
+keto	O
+analogue	O
+oxcarbazepine	O
+among	O
+six	O
+difficult	O
+-	O
+to	O
+-	O
+treat	O
+schizophrenic	B
+or	O
+organic	B
+psychotic	I
+patients	O
+using	O
+concomitantly	O
+haloperidol	O
+,	O
+chlorpromazine	O
+or	O
+clozapine	O
+.	O
+
+This	O
+change	O
+resulted	O
+within	O
+2	O
+-	O
+4	O
+weeks	O
+in	O
+the	O
+50	O
+-	O
+200	O
+%	O
+increase	O
+in	O
+the	O
+plasma	O
+levels	O
+of	O
+these	O
+neuroleptics	O
+and	O
+the	O
+appearance	O
+of	O
+extrapyramidal	B
+symptoms	I
+.	O
+
+None	O
+of	O
+the	O
+patients	O
+showed	O
+any	O
+clinical	O
+deteriotation	O
+during	O
+the	O
+following	O
+3	O
+-	O
+6	O
+months	O
+.	O
+
+The	O
+results	O
+of	O
+this	O
+case	O
+report	O
+support	O
+the	O
+idea	O
+that	O
+in	O
+contrast	O
+with	O
+carbamazepine	O
+oxcarbazepine	O
+does	O
+not	O
+induce	O
+the	O
+hepatic	O
+microsomal	O
+enzyme	O
+systems	O
+regulating	O
+the	O
+inactivation	O
+of	O
+antipsychotic	O
+drugs	O
+.	O
+
+Time	O
+course	O
+of	O
+lipid	O
+peroxidation	O
+in	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+nephropathy	B
+.	O
+
+Reactive	O
+oxygen	O
+species	O
+have	O
+been	O
+implicated	O
+in	O
+the	O
+pathogenesis	O
+of	O
+acute	O
+puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+)	O
+-	O
+induced	O
+nephropathy	B
+,	O
+with	O
+antioxidants	O
+significantly	O
+reducing	O
+the	O
+proteinuria	B
+.	O
+
+The	O
+temporal	O
+relationship	O
+between	O
+lipid	O
+peroxidation	O
+in	O
+the	O
+kidney	O
+and	O
+proteinuria	B
+was	O
+examined	O
+in	O
+this	O
+study	O
+.	O
+
+Rats	O
+were	O
+treated	O
+with	O
+a	O
+single	O
+IV	O
+injection	O
+of	O
+puromycin	O
+aminonucleoside	O
+,	O
+(	O
+PAN	O
+,	O
+7	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+24	O
+hour	O
+urine	O
+samples	O
+were	O
+obtained	O
+prior	O
+to	O
+sacrifice	O
+on	O
+days	O
+3	O
+,	O
+5	O
+,	O
+7	O
+,	O
+10	O
+,	O
+17	O
+,	O
+27	O
+,	O
+41	O
+(	O
+N	O
+=	O
+5	O
+-	O
+10	O
+per	O
+group	O
+)	O
+.	O
+
+The	O
+kidneys	O
+were	O
+removed	O
+,	O
+flushed	O
+with	O
+ice	O
+cold	O
+TRIS	O
+buffer	O
+.	O
+
+Kidney	O
+cortices	O
+from	O
+each	O
+animal	O
+were	O
+used	O
+to	O
+prepare	O
+homogenates	O
+.	O
+
+Tissue	O
+lipid	O
+peroxidation	O
+was	O
+measured	O
+in	O
+whole	O
+homogenates	O
+as	O
+well	O
+as	O
+in	O
+lipid	O
+extracts	O
+from	O
+homogenates	O
+as	O
+thiobarbituric	O
+acid	O
+reactive	O
+substances	O
+.	O
+
+Proteinuria	B
+was	O
+evident	O
+at	O
+day	O
+5	O
+,	O
+peaked	O
+at	O
+day	O
+7	O
+and	O
+persisted	O
+to	O
+day	O
+27	O
+.	O
+
+Lipid	O
+peroxidation	O
+in	O
+homogenates	O
+was	O
+maximal	O
+at	O
+day	O
+3	O
+and	O
+declined	O
+rapidly	O
+to	O
+control	O
+levels	O
+by	O
+day	O
+17	O
+.	O
+
+This	O
+study	O
+supports	O
+the	O
+role	O
+of	O
+lipid	O
+peroxidation	O
+in	O
+mediating	O
+the	O
+proteinuric	B
+injury	I
+in	O
+PAN	O
+nephropathy	B
+.	O
+
+Composition	O
+of	O
+gall	B
+bladder	I
+stones	I
+associated	O
+with	O
+octreotide	O
+:	O
+response	O
+to	O
+oral	O
+ursodeoxycholic	O
+acid	O
+.	O
+
+Octreotide	O
+,	O
+an	O
+effective	O
+treatment	O
+for	O
+acromegaly	B
+,	O
+induces	O
+gall	B
+bladder	I
+stones	I
+in	O
+13	O
+-	O
+60	O
+%	O
+of	O
+patients	O
+.	O
+
+Because	O
+knowledge	O
+of	O
+stone	O
+composition	O
+is	O
+essential	O
+for	O
+studies	O
+of	O
+their	O
+pathogenesis	O
+,	O
+treatment	O
+,	O
+and	O
+prevention	O
+,	O
+this	O
+was	O
+investigated	O
+by	O
+direct	O
+and	O
+indirect	O
+methods	O
+in	O
+14	O
+octreotide	O
+treated	O
+acromegalic	B
+patients	O
+with	O
+gall	B
+stones	I
+.	O
+
+Chemical	O
+analysis	O
+of	O
+gall	B
+stones	I
+retrieved	O
+at	O
+cholecystectomy	O
+from	O
+two	O
+patients	O
+,	O
+showed	O
+that	O
+they	O
+contained	O
+71	O
+%	O
+and	O
+87	O
+%	O
+cholesterol	O
+by	O
+weight	O
+.	O
+
+In	O
+the	O
+remaining	O
+12	O
+patients	O
+,	O
+localised	O
+computed	O
+tomography	O
+of	O
+the	O
+gall	O
+bladder	O
+showed	O
+that	O
+eight	O
+had	O
+stones	O
+with	O
+maximum	O
+attenuation	O
+scores	O
+of	O
+<	O
+100	O
+Hounsfield	O
+units	O
+(	O
+values	O
+of	O
+<	O
+100	O
+HU	O
+predict	O
+cholesterol	O
+rich	O
+,	O
+dissolvable	O
+stones	O
+)	O
+.	O
+
+Gall	O
+bladder	O
+bile	O
+was	O
+obtained	O
+by	O
+ultrasound	O
+guided	O
+,	O
+fine	O
+needle	O
+puncture	O
+from	O
+six	O
+patients	O
+.	O
+
+All	O
+six	O
+patients	O
+had	O
+supersaturated	O
+bile	O
+(	O
+mean	O
+(	O
+SEM	O
+)	O
+cholesterol	O
+saturation	O
+index	O
+of	O
+1	O
+.	O
+19	O
+(	O
+0	O
+.	O
+08	O
+)	O
+(	O
+range	O
+1	O
+.	O
+01	O
+-	O
+1	O
+.	O
+53	O
+)	O
+)	O
+and	O
+all	O
+had	O
+abnormally	O
+rapid	O
+cholesterol	O
+microcrystal	O
+nucleation	O
+times	O
+(	O
+<	O
+4	O
+days	O
+(	O
+range	O
+1	O
+-	O
+4	O
+)	O
+)	O
+,	O
+whilst	O
+in	O
+four	O
+,	O
+the	O
+bile	O
+contained	O
+cholesterol	O
+microcrystals	O
+immediately	O
+after	O
+sampling	O
+.	O
+
+Of	O
+the	O
+12	O
+patients	O
+considered	O
+for	O
+oral	O
+ursodeoxycholic	O
+acid	O
+(	O
+UDCA	O
+)	O
+treatment	O
+,	O
+two	O
+had	O
+a	O
+blocked	O
+cystic	O
+duct	O
+and	O
+were	O
+not	O
+started	O
+on	O
+UDCA	O
+while	O
+one	O
+was	O
+lost	O
+to	O
+follow	O
+up	O
+.	O
+
+After	O
+one	O
+year	O
+of	O
+treatment	O
+,	O
+five	O
+of	O
+the	O
+remaining	O
+nine	O
+patients	O
+showed	O
+either	O
+partial	O
+(	O
+n	O
+=	O
+3	O
+)	O
+or	O
+complete	O
+(	O
+n	O
+=	O
+2	O
+)	O
+gall	B
+stone	I
+dissolution	O
+,	O
+suggesting	O
+that	O
+their	O
+stones	O
+were	O
+cholesterol	O
+rich	O
+.	O
+
+This	O
+corresponds	O
+,	O
+by	O
+actuarial	O
+(	O
+life	O
+table	O
+)	O
+analysis	O
+,	O
+to	O
+a	O
+combined	O
+gall	B
+stone	I
+dissolution	O
+rate	O
+of	O
+58	O
+.	O
+3	O
+(	O
+15	O
+.	O
+9	O
+%	O
+)	O
+.	O
+
+In	O
+conclusion	O
+,	O
+octreotide	O
+induced	O
+gall	B
+stones	I
+are	O
+generally	O
+small	O
+,	O
+multiple	O
+,	O
+and	O
+cholesterol	O
+rich	O
+although	O
+,	O
+in	O
+common	O
+with	O
+spontaneous	O
+gall	B
+stone	I
+disease	I
+,	O
+at	O
+presentation	O
+some	O
+patients	O
+will	O
+have	O
+a	O
+blocked	O
+cystic	O
+duct	O
+and	O
+some	O
+gall	B
+stones	I
+containing	O
+calcium	O
+.	O
+
+Erythema	B
+multiforme	I
+and	O
+hypersensitivity	B
+myocarditis	I
+caused	O
+by	O
+ampicillin	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+erythema	B
+multiforme	I
+and	O
+hypersensitivity	B
+myocarditis	I
+caused	O
+by	O
+ampicillin	O
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+13	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+was	O
+treated	O
+with	O
+ampicillin	O
+and	O
+gentamicin	O
+because	O
+of	O
+suspected	O
+septicemia	B
+.	O
+
+Medications	O
+were	O
+discontinued	O
+when	O
+erythema	B
+multiforme	I
+and	O
+congestive	B
+heart	I
+failure	I
+caused	O
+by	O
+myocarditis	B
+occurred	O
+.	O
+
+The	O
+patient	O
+was	O
+treated	O
+with	O
+methylprednisolone	O
+and	O
+gradually	O
+improved	O
+.	O
+
+Macrophage	O
+-	O
+migration	O
+inhibition	O
+(	O
+MIF	O
+)	O
+test	O
+with	O
+ampicillin	O
+was	O
+positive	O
+.	O
+
+DISCUSSION	O
+:	O
+After	O
+most	O
+infections	B
+causing	O
+erythema	B
+multiforme	I
+and	O
+myocarditis	B
+were	O
+ruled	O
+out	O
+,	O
+a	O
+drug	B
+-	I
+induced	I
+allergic	I
+reaction	I
+was	O
+suspected	O
+.	O
+
+Positive	O
+MIF	O
+test	O
+for	O
+ampicillin	O
+showed	O
+sensitization	O
+of	O
+the	O
+patient	O
+'	O
+s	O
+lymphocytes	O
+to	O
+ampicillin	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Hypersensitivity	B
+myocarditis	I
+is	O
+a	O
+rare	O
+and	O
+dangerous	O
+manifestation	O
+of	O
+allergy	B
+to	O
+penicillins	O
+.	O
+
+Clomipramine	O
+-	O
+induced	O
+sleep	B
+disturbance	I
+does	O
+not	O
+impair	O
+its	O
+prolactin	O
+-	O
+releasing	O
+action	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+undertaken	O
+to	O
+examine	O
+the	O
+role	O
+of	O
+sleep	B
+disturbance	I
+,	O
+induced	O
+by	O
+clomipramine	O
+administration	O
+,	O
+on	O
+the	O
+secretory	O
+rate	O
+of	O
+prolactin	O
+(	O
+PRL	O
+)	O
+in	O
+addition	O
+to	O
+the	O
+direct	O
+drug	O
+effect	O
+.	O
+
+Two	O
+groups	O
+of	O
+supine	O
+subjects	O
+were	O
+studied	O
+under	O
+placebo	O
+-	O
+controlled	O
+conditions	O
+,	O
+one	O
+during	O
+the	O
+night	O
+,	O
+when	O
+sleeping	O
+(	O
+n	O
+=	O
+7	O
+)	O
+and	O
+the	O
+other	O
+at	O
+daytime	O
+,	O
+when	O
+awake	O
+(	O
+n	O
+=	O
+6	O
+)	O
+.	O
+
+Each	O
+subject	O
+received	O
+a	O
+single	O
+50	O
+mg	O
+dose	O
+of	O
+clomipramine	O
+given	O
+orally	O
+2	O
+hours	O
+before	O
+blood	O
+collection	O
+.	O
+
+Plasma	O
+PRL	O
+concentrations	O
+were	O
+analysed	O
+at	O
+10	O
+min	O
+intervals	O
+and	O
+underlying	O
+secretory	O
+rates	O
+calculated	O
+by	O
+a	O
+deconvolution	O
+procedure	O
+.	O
+
+For	O
+both	O
+experiments	O
+the	O
+drug	O
+intake	O
+led	O
+to	O
+significant	O
+increases	O
+in	O
+PRL	O
+secretion	O
+,	O
+acting	O
+preferentially	O
+on	O
+tonic	O
+secretion	O
+as	O
+pulse	O
+amplitude	O
+and	O
+frequency	O
+did	O
+not	O
+differ	O
+significantly	O
+from	O
+corresponding	O
+control	O
+values	O
+.	O
+
+During	O
+the	O
+night	O
+clomipramine	O
+ingestion	O
+altered	O
+the	O
+complete	O
+sleep	O
+architecture	O
+in	O
+that	O
+it	O
+suppressed	O
+REM	O
+sleep	O
+and	O
+the	O
+sleep	O
+cycles	O
+and	O
+induced	O
+increased	O
+wakefulness	O
+.	O
+
+As	O
+the	O
+relative	O
+increase	O
+in	O
+PRL	O
+secretion	O
+expressed	O
+as	O
+a	O
+percentage	O
+of	O
+the	O
+mean	O
+did	O
+not	O
+significantly	O
+differ	O
+between	O
+the	O
+night	O
+and	O
+day	O
+time	O
+studies	O
+(	O
+46	O
++	O
+/	O
+-	O
+19	O
+%	O
+vs	O
+34	O
++	O
+/	O
+-	O
+10	O
+%	O
+)	O
+,	O
+it	O
+can	O
+be	O
+concluded	O
+that	O
+the	O
+observed	O
+sleep	B
+disturbance	I
+did	O
+not	O
+interfere	O
+with	O
+the	O
+drug	O
+action	O
+per	O
+se	O
+.	O
+
+The	O
+presence	O
+of	O
+REM	O
+sleep	O
+was	O
+shown	O
+not	O
+to	O
+be	O
+a	O
+determining	O
+factor	O
+either	O
+for	O
+secretory	O
+pulse	O
+amplitude	O
+and	O
+frequency	O
+,	O
+as	O
+,	O
+for	O
+both	O
+,	O
+mean	O
+nocturnal	O
+values	O
+were	O
+similar	O
+with	O
+and	O
+without	O
+prior	O
+clomipramine	O
+ingestion	O
+.	O
+
+Survey	O
+of	O
+complications	O
+of	O
+indocyanine	O
+green	O
+angiography	O
+in	O
+Japan	O
+.	O
+
+PURPOSE	O
+:	O
+We	O
+evaluated	O
+the	O
+safety	O
+of	O
+indocyanine	O
+green	O
+for	O
+use	O
+in	O
+fundus	O
+angiography	O
+.	O
+
+METHODS	O
+:	O
+We	O
+sent	O
+a	O
+questionnaire	O
+concerning	O
+complications	O
+of	O
+indocyanine	O
+green	O
+to	O
+32	O
+institutions	O
+in	O
+Japan	O
+,	O
+which	O
+were	O
+selected	O
+on	O
+the	O
+basis	O
+of	O
+the	O
+client	O
+list	O
+from	O
+the	O
+Topcon	O
+Company	O
+,	O
+which	O
+manufactures	O
+the	O
+indocyanine	O
+green	O
+fundus	O
+camera	O
+.	O
+
+RESULTS	O
+:	O
+Ophthalmologists	O
+at	O
+15	O
+institutions	O
+responded	O
+,	O
+reporting	O
+a	O
+total	O
+of	O
+3	O
+,	O
+774	O
+indocyanine	O
+green	O
+angiograms	O
+performed	O
+on	O
+2	O
+,	O
+820	O
+patients	O
+between	O
+June	O
+1984	O
+and	O
+September	O
+1992	O
+.	O
+
+Before	O
+angiography	O
+,	O
+intradermal	O
+or	O
+intravenous	O
+indocyanine	O
+green	O
+testing	O
+,	O
+or	O
+both	O
+was	O
+performed	O
+at	O
+13	O
+of	O
+15	O
+institutions	O
+.	O
+
+For	O
+three	O
+patients	O
+,	O
+the	O
+decision	O
+was	O
+made	O
+not	O
+to	O
+proceed	O
+with	O
+angiography	O
+after	O
+positive	O
+preangiographic	O
+testing	O
+.	O
+
+The	O
+dosage	O
+of	O
+indocyanine	O
+green	O
+used	O
+for	O
+angiography	O
+varied	O
+from	O
+25	O
+to	O
+75	O
+mg	O
+,	O
+depending	O
+upon	O
+the	O
+institution	O
+.	O
+
+There	O
+were	O
+13	O
+cases	O
+of	O
+adverse	O
+reactions	O
+(	O
+0	O
+.	O
+34	O
+%	O
+)	O
+,	O
+ten	O
+of	O
+which	O
+were	O
+mild	O
+reactions	O
+such	O
+as	O
+nausea	B
+,	O
+exanthema	B
+,	O
+urtication	B
+,	O
+itchiness	B
+,	O
+and	O
+urgency	O
+to	O
+defecate	O
+,	O
+and	O
+did	O
+not	O
+require	O
+treatment	O
+.	O
+
+Also	O
+recorded	O
+were	O
+one	O
+case	O
+of	O
+pain	B
+of	O
+the	O
+vein	O
+,	O
+which	O
+required	O
+treatment	O
+,	O
+and	O
+two	O
+cases	O
+of	O
+hypotension	B
+.	O
+
+The	O
+two	O
+hypotensive	B
+patients	O
+required	O
+treatment	O
+for	O
+shock	B
+.	O
+
+CONCLUSIONS	O
+:	O
+A	O
+comparison	O
+of	O
+frequency	O
+of	O
+adverse	O
+reactions	O
+to	O
+indocyanine	O
+green	O
+with	O
+the	O
+previously	O
+reported	O
+frequency	O
+of	O
+such	O
+reactions	O
+to	O
+fluorescein	O
+sodium	O
+indicated	O
+that	O
+indocyanine	O
+green	O
+is	O
+a	O
+safe	O
+as	O
+fluorescein	O
+for	O
+use	O
+in	O
+angiography	O
+.	O
+
+Angioedema	B
+following	O
+the	O
+intravenous	O
+administration	O
+of	O
+metoprolol	O
+.	O
+
+A	O
+72	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+was	O
+admitted	O
+to	O
+the	O
+hospital	O
+with	O
+"	O
+flash	O
+"	O
+pulmonary	B
+edema	I
+,	O
+preceded	O
+by	O
+chest	B
+pain	I
+,	O
+requiring	O
+intubation	O
+.	O
+
+Her	O
+medical	O
+history	O
+included	O
+coronary	B
+artery	I
+disease	I
+with	O
+previous	O
+myocardial	B
+infarctions	I
+,	O
+hypertension	B
+,	O
+and	O
+diabetes	B
+mellitus	I
+.	O
+
+A	O
+history	O
+of	O
+angioedema	B
+secondary	O
+to	O
+lisinopril	O
+therapy	O
+was	O
+elicited	O
+.	O
+
+Current	O
+medications	O
+did	O
+not	O
+include	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitors	O
+or	O
+beta	O
+-	O
+blockers	O
+.	O
+
+She	O
+had	O
+no	O
+previous	O
+beta	O
+-	O
+blocking	O
+drug	O
+exposure	O
+.	O
+
+During	O
+the	O
+first	O
+day	O
+of	O
+hospitalization	O
+(	O
+while	O
+intubated	O
+)	O
+,	O
+intravenous	O
+metoprolol	O
+was	O
+given	O
+,	O
+resulting	O
+in	O
+severe	O
+angioedema	B
+.	O
+
+The	O
+angioedema	B
+resolved	O
+after	O
+therapy	O
+with	O
+intravenous	O
+steroids	O
+and	O
+diphenhydramine	O
+hydrochloride	O
+.	O
+
+Effect	O
+of	O
+coniine	O
+on	O
+the	O
+developing	O
+chick	O
+embryo	O
+.	O
+
+Coniine	O
+,	O
+an	O
+alkaloid	O
+from	O
+Conium	O
+maculatum	O
+(	O
+poison	O
+hemlock	O
+)	O
+,	O
+has	O
+been	O
+shown	O
+to	O
+be	O
+teratogenic	O
+in	O
+livestock	O
+.	O
+
+The	O
+major	O
+teratogenic	O
+outcome	O
+is	O
+arthrogryposis	B
+,	O
+presumably	O
+due	O
+to	O
+nicotinic	O
+receptor	O
+blockade	O
+.	O
+
+However	O
+,	O
+coniine	O
+has	O
+failed	O
+to	O
+produce	O
+arthrogryposis	B
+in	O
+rats	O
+or	O
+mice	O
+and	O
+is	O
+only	O
+weakly	O
+teratogenic	O
+in	O
+rabbits	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+evaluate	O
+and	O
+compare	O
+the	O
+effects	O
+of	O
+coniine	O
+and	O
+nicotine	O
+in	O
+the	O
+developing	O
+chick	O
+.	O
+
+Concentrations	O
+of	O
+coniine	O
+and	O
+nicotine	O
+sulfate	O
+were	O
+0	O
+.	O
+015	O
+%	O
+,	O
+0	O
+.	O
+03	O
+%	O
+,	O
+0	O
+.	O
+075	O
+%	O
+,	O
+0	O
+.	O
+15	O
+%	O
+,	O
+0	O
+.	O
+75	O
+%	O
+,	O
+1	O
+.	O
+5	O
+%	O
+,	O
+3	O
+%	O
+,	O
+and	O
+6	O
+%	O
+and	O
+1	O
+%	O
+,	O
+5	O
+%	O
+,	O
+and	O
+10	O
+%	O
+,	O
+respectively	O
+.	O
+
+Both	O
+compounds	O
+caused	O
+deformations	B
+and	O
+lethality	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+.	O
+
+All	O
+concentrations	O
+of	O
+nicotine	O
+sulfate	O
+caused	O
+some	O
+lethality	O
+but	O
+a	O
+no	O
+effect	O
+level	O
+for	O
+coniine	O
+lethality	O
+was	O
+0	O
+.	O
+75	O
+%	O
+.	O
+
+The	O
+deformations	B
+caused	O
+by	O
+both	O
+coniine	O
+and	O
+nicotine	O
+sulfate	O
+were	O
+excessive	B
+flexion	I
+or	I
+extension	I
+of	I
+one	I
+or	I
+more	I
+toes	I
+.	O
+
+No	O
+histopathological	O
+alterations	O
+or	O
+differences	O
+in	O
+bone	O
+formation	O
+were	O
+seen	O
+in	O
+the	O
+limbs	O
+or	O
+toes	O
+of	O
+any	O
+chicks	O
+from	O
+any	O
+group	O
+;	O
+however	O
+,	O
+extensive	O
+cranial	B
+hemorrhage	I
+occurred	O
+in	O
+all	O
+nicotine	O
+sulfate	O
+-	O
+treated	O
+chicks	O
+.	O
+
+There	O
+was	O
+a	O
+statistically	O
+significant	O
+(	O
+P	O
+<	O
+or	O
+=	O
+0	O
+.	O
+01	O
+)	O
+decrease	O
+in	O
+movement	O
+in	O
+coniine	O
+and	O
+nicotine	O
+sulfate	O
+treated	O
+chicks	O
+as	O
+determined	O
+by	O
+ultrasound	O
+.	O
+
+Control	O
+chicks	O
+were	O
+in	O
+motion	O
+an	O
+average	O
+of	O
+33	O
+.	O
+67	O
+%	O
+of	O
+the	O
+time	O
+,	O
+while	O
+coniine	O
+-	O
+treated	O
+chicks	O
+were	O
+only	O
+moving	O
+8	O
+.	O
+95	O
+%	O
+of	O
+a	O
+5	O
+-	O
+min	O
+interval	O
+,	O
+and	O
+no	O
+movement	O
+was	O
+observed	O
+for	O
+nicotine	O
+sulfate	O
+treated	O
+chicks	O
+.	O
+
+In	O
+summary	O
+,	O
+the	O
+chick	O
+embryo	O
+provides	O
+a	O
+reliable	O
+and	O
+simple	O
+experimental	O
+animal	O
+model	O
+of	O
+coniine	O
+-	O
+induced	O
+arthrogryposis	B
+.	O
+
+Data	O
+from	O
+this	O
+model	O
+support	O
+a	O
+mechanism	O
+involving	O
+nicotinic	O
+receptor	O
+blockade	O
+with	O
+subsequent	O
+decreased	O
+fetal	O
+movement	O
+.	O
+
+Immediate	O
+allergic	B
+reactions	I
+to	O
+amoxicillin	O
+.	O
+
+A	O
+large	O
+group	O
+of	O
+patients	O
+with	O
+suspected	O
+allergic	B
+reactions	I
+to	O
+beta	O
+-	O
+lactam	O
+antibiotics	O
+was	O
+evaluated	O
+.	O
+
+A	O
+detailed	O
+clinical	O
+history	O
+,	O
+together	O
+with	O
+skin	O
+tests	O
+,	O
+RAST	O
+(	O
+radioallergosorbent	O
+test	O
+)	O
+,	O
+and	O
+controlled	O
+challenge	O
+tests	O
+,	O
+was	O
+used	O
+to	O
+establish	O
+whether	O
+patients	O
+allergic	B
+to	O
+beta	O
+-	O
+lactam	O
+antibiotics	O
+had	O
+selective	O
+immediate	O
+allergic	B
+responses	O
+to	O
+amoxicillin	O
+(	O
+AX	O
+)	O
+or	O
+were	O
+cross	O
+-	O
+reacting	O
+with	O
+other	O
+penicillin	O
+derivatives	O
+.	O
+
+Skin	O
+tests	O
+were	O
+performed	O
+with	O
+benzylpenicilloyl	O
+-	O
+poly	O
+-	O
+L	O
+-	O
+lysine	O
+(	O
+BPO	O
+-	O
+PLL	O
+)	O
+,	O
+benzylpenicilloate	O
+,	O
+benzylpenicillin	O
+(	O
+PG	O
+)	O
+,	O
+ampicillin	O
+(	O
+AMP	O
+)	O
+,	O
+and	O
+AX	O
+.	O
+
+RAST	O
+for	O
+BPO	O
+-	O
+PLL	O
+and	O
+AX	O
+-	O
+PLL	O
+was	O
+done	O
+.	O
+
+When	O
+both	O
+skin	O
+test	O
+and	O
+RAST	O
+for	O
+BPO	O
+were	O
+negative	O
+,	O
+single	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+challenge	O
+tests	O
+were	O
+done	O
+to	O
+ensure	O
+tolerance	O
+of	O
+PG	O
+or	O
+sensitivity	O
+to	O
+AX	O
+.	O
+
+A	O
+total	O
+of	O
+177	O
+patients	O
+were	O
+diagnosed	O
+as	O
+allergic	B
+to	O
+beta	O
+-	O
+lactam	O
+antibiotics	O
+.	O
+
+We	O
+selected	O
+the	O
+54	O
+(	O
+30	O
+.	O
+5	O
+%	O
+)	O
+cases	O
+of	O
+immediate	O
+AX	O
+allergy	B
+with	O
+good	O
+tolerance	O
+of	O
+PG	O
+.	O
+
+Anaphylaxis	B
+was	O
+seen	O
+in	O
+37	O
+patients	O
+(	O
+69	O
+%	O
+)	O
+,	O
+the	O
+other	O
+17	O
+(	O
+31	O
+%	O
+)	O
+having	O
+urticaria	B
+and	O
+/	O
+or	O
+angioedema	B
+.	O
+
+All	O
+the	O
+patients	O
+were	O
+skin	O
+test	O
+negative	O
+to	O
+BPO	O
+;	O
+49	O
+of	O
+51	O
+(	O
+96	O
+%	O
+)	O
+were	O
+also	O
+negative	O
+to	O
+MDM	B
+,	O
+and	O
+44	O
+of	O
+46	O
+(	O
+96	O
+%	O
+)	O
+to	O
+PG	O
+.	O
+
+Skin	O
+tests	O
+with	O
+AX	O
+were	O
+positive	O
+in	O
+34	O
+(	O
+63	O
+%	O
+)	O
+patients	O
+.	O
+
+RAST	O
+was	O
+positive	O
+for	O
+AX	O
+in	O
+22	O
+patients	O
+(	O
+41	O
+%	O
+)	O
+and	O
+to	O
+BPO	O
+in	O
+just	O
+5	O
+(	O
+9	O
+%	O
+)	O
+.	O
+
+None	O
+of	O
+the	O
+sera	O
+with	O
+negative	O
+RAST	O
+for	O
+AX	O
+were	O
+positive	O
+to	O
+BPO	O
+.	O
+
+Challenge	O
+tests	O
+with	O
+AX	O
+were	O
+performed	O
+in	O
+23	O
+subjects	O
+(	O
+43	O
+%	O
+)	O
+to	O
+establish	O
+the	O
+diagnosis	O
+of	O
+immediate	O
+allergic	B
+reaction	I
+to	O
+AX	O
+,	O
+and	O
+in	O
+15	O
+cases	O
+(	O
+28	O
+%	O
+)	O
+both	O
+skin	O
+test	O
+and	O
+RAST	O
+for	O
+AX	O
+were	O
+negative	O
+.	O
+
+PG	O
+was	O
+well	O
+tolerated	O
+by	O
+all	O
+54	O
+patients	O
+.	O
+
+We	O
+describe	O
+the	O
+largest	O
+group	O
+of	O
+AX	O
+-	O
+allergic	B
+patients	O
+who	O
+have	O
+tolerated	O
+PG	O
+reported	O
+so	O
+far	O
+.	O
+
+Diagnosis	O
+of	O
+these	O
+patients	O
+can	O
+be	O
+achieved	O
+only	O
+if	O
+specific	O
+AX	O
+-	O
+related	O
+reagents	O
+are	O
+employed	O
+.	O
+
+Further	O
+studies	O
+are	O
+necessary	O
+to	O
+determine	O
+the	O
+exact	O
+extent	O
+of	O
+this	O
+problem	O
+and	O
+to	O
+improve	O
+the	O
+efficacy	O
+of	O
+diagnostic	O
+methods	O
+.	O
+
+Reversal	O
+by	O
+phenylephrine	O
+of	O
+the	O
+beneficial	O
+effects	O
+of	O
+intravenous	O
+nitroglycerin	O
+in	O
+patients	O
+with	O
+acute	B
+myocardial	I
+infarction	I
+.	O
+
+Nitroglycerin	O
+has	O
+been	O
+shown	O
+to	O
+reduce	O
+ST	O
+-	O
+segment	O
+elevation	O
+during	O
+acute	B
+myocardial	I
+infarction	I
+,	O
+an	O
+effect	O
+potentiated	O
+in	O
+the	O
+dog	O
+by	O
+agents	O
+that	O
+reverse	O
+nitroglycerin	O
+-	O
+induced	O
+hypotension	B
+.	O
+
+Our	O
+study	O
+was	O
+designed	O
+to	O
+determine	O
+the	O
+effects	O
+of	O
+combined	O
+nitroglycerin	O
+and	O
+phenylephrine	O
+therapy	O
+.	O
+
+Ten	O
+patients	O
+with	O
+acute	O
+transmural	O
+myocardial	B
+infarctions	I
+received	O
+intravenous	O
+nitroglycerin	O
+,	O
+sufficient	O
+to	O
+reduce	O
+mean	O
+arterial	O
+pressure	O
+from	O
+107	O
++	O
+/	O
+-	O
+6	O
+to	O
+85	O
++	O
+/	O
+-	O
+6	O
+mm	O
+Hg	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+,	O
+for	O
+60	O
+minutes	O
+.	O
+
+Left	O
+ventricular	O
+filling	O
+pressure	O
+decreased	O
+from	O
+19	O
++	O
+/	O
+-	O
+2	O
+to	O
+11	O
++	O
+/	O
+-	O
+2	O
+mm	O
+Hg	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+SigmaST	O
+,	O
+the	O
+sum	O
+of	O
+ST	O
+-	O
+segment	O
+elevations	O
+in	O
+16	O
+precordial	O
+leads	O
+,	O
+decreased	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+02	O
+)	O
+with	O
+intravenous	O
+nitroglycerin	O
+.	O
+
+Subsequent	O
+addition	O
+of	O
+phenylephrine	O
+infusion	O
+,	O
+sufficient	O
+to	O
+re	O
+-	O
+elevate	O
+mean	O
+arterial	O
+pressure	O
+to	O
+106	O
++	O
+/	O
+-	O
+4	O
+mm	O
+Hg	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+for	O
+30	O
+minutes	O
+,	O
+increased	O
+left	O
+ventricular	O
+filling	O
+pressure	O
+to	O
+17	O
++	O
+/	O
+-	O
+2	O
+mm	O
+Hg	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+and	O
+also	O
+significantly	O
+increased	O
+sigmaST	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Our	O
+results	O
+suggest	O
+that	O
+addition	O
+of	O
+phenylephrine	O
+to	O
+nitroglycerin	O
+is	O
+not	O
+beneficial	O
+in	O
+the	O
+treatment	O
+of	O
+patients	O
+with	O
+acute	B
+myocardial	I
+infarction	I
+.	O
+
+Acetazolamide	O
+-	O
+induced	O
+nephrolithiasis	B
+:	O
+implications	O
+for	O
+treatment	O
+of	O
+neuromuscular	B
+disorders	I
+.	O
+
+Carbonic	O
+anhydrase	O
+inhibitors	O
+can	O
+cause	O
+nephrolithiasis	B
+.	O
+
+We	O
+studied	O
+20	O
+patients	O
+receiving	O
+long	O
+-	O
+term	O
+carbonic	O
+anhydrase	O
+inhibitor	O
+treatment	O
+for	O
+periodic	O
+paralysis	B
+and	O
+myotonia	B
+.	O
+
+Three	O
+patients	O
+on	O
+acetazolamide	O
+(	O
+15	O
+%	O
+)	O
+developed	O
+renal	B
+calculi	I
+.	O
+
+Extracorporeal	O
+lithotripsy	O
+successfully	O
+removed	O
+a	O
+renal	B
+calculus	I
+in	O
+one	O
+patient	O
+and	O
+surgery	O
+removed	O
+a	O
+staghorn	O
+calculus	B
+in	O
+another	O
+,	O
+permitting	O
+continued	O
+treatment	O
+.	O
+
+Renal	O
+function	O
+remained	O
+normal	O
+in	O
+all	O
+patients	O
+.	O
+
+Nephrolithiasis	B
+is	O
+a	O
+complication	O
+of	O
+acetazolamide	O
+but	O
+does	O
+not	O
+preclude	O
+its	O
+use	O
+.	O
+
+Effects	O
+of	O
+calcium	O
+channel	O
+blockers	O
+on	O
+bupivacaine	O
+-	O
+induced	O
+toxicity	B
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+influence	O
+of	O
+calcium	O
+channel	O
+blockers	O
+on	O
+bupivacaine	O
+-	O
+induced	O
+acute	O
+toxicity	B
+.	O
+
+For	O
+each	O
+of	O
+the	O
+three	O
+tested	O
+calcium	O
+channel	O
+blockers	O
+(	O
+diltiazem	O
+,	O
+verapamil	O
+and	O
+bepridil	O
+)	O
+6	O
+groups	O
+of	O
+mice	O
+were	O
+treated	O
+by	O
+two	O
+different	O
+doses	O
+,	O
+i	O
+.	O
+e	O
+.	O
+2	O
+and	O
+10	O
+mg	O
+/	O
+kg	O
+/	O
+i	O
+.	O
+p	O
+.	O
+,	O
+or	O
+an	O
+equal	O
+volume	O
+of	O
+saline	O
+for	O
+the	O
+control	O
+group	O
+(	O
+n	O
+=	O
+20	O
+)	O
+;	O
+15	O
+minutes	O
+later	O
+,	O
+all	O
+the	O
+animals	O
+were	O
+injected	O
+with	O
+a	O
+single	O
+50	O
+mg	O
+/	O
+kg	O
+/	O
+i	O
+.	O
+p	O
+.	O
+dose	O
+of	O
+bupivacaine	O
+.	O
+
+The	O
+convulsant	O
+activity	O
+,	O
+the	O
+time	O
+of	O
+latency	O
+to	O
+convulse	O
+and	O
+the	O
+mortality	O
+rate	O
+were	O
+assessed	O
+in	O
+each	O
+group	O
+.	O
+
+The	O
+local	O
+anesthetic	O
+-	O
+induced	O
+mortality	O
+was	O
+significantly	O
+increased	O
+by	O
+the	O
+three	O
+different	O
+calcium	O
+channel	O
+blockers	O
+.	O
+
+The	O
+convulsant	O
+activity	O
+of	O
+bupivacaine	O
+was	O
+not	O
+significantly	O
+modified	O
+but	O
+calcium	O
+channel	O
+blockers	O
+decreased	O
+the	O
+time	O
+of	O
+latency	O
+to	O
+obtain	O
+bupivacaine	O
+-	O
+induced	O
+convulsions	B
+;	O
+this	O
+effect	O
+was	O
+less	O
+pronounced	O
+with	O
+bepridil	O
+.	O
+
+Epidural	O
+blood	O
+flow	O
+during	O
+prostaglandin	O
+E1	O
+or	O
+trimethaphan	O
+induced	O
+hypotension	B
+.	O
+
+To	O
+evaluate	O
+the	O
+effect	O
+of	O
+prostaglandin	O
+E1	O
+(	O
+PGE1	O
+)	O
+or	O
+trimethaphan	O
+(	O
+TMP	O
+)	O
+induced	O
+hypotension	B
+on	O
+epidural	O
+blood	O
+flow	O
+(	O
+EBF	O
+)	O
+during	O
+spinal	O
+surgery	O
+,	O
+EBF	O
+was	O
+measured	O
+using	O
+the	O
+heat	O
+clearance	O
+method	O
+in	O
+30	O
+patients	O
+who	O
+underwent	O
+postero	O
+-	O
+lateral	O
+interbody	O
+fusion	O
+under	O
+isoflurane	O
+anaesthesia	O
+.	O
+
+An	O
+initial	O
+dose	O
+of	O
+0	O
+.	O
+1	O
+microgram	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+of	O
+PGE1	O
+(	O
+15	O
+patients	O
+)	O
+,	O
+or	O
+10	O
+micrograms	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+of	O
+TMP	O
+(	O
+15	O
+patients	O
+)	O
+was	O
+administered	O
+intravenously	O
+after	O
+the	O
+dural	O
+opening	O
+and	O
+the	O
+dose	O
+was	O
+adjusted	O
+to	O
+maintain	O
+the	O
+mean	O
+arterial	O
+blood	O
+pressure	O
+(	O
+MAP	O
+)	O
+at	O
+about	O
+60	O
+mmHg	O
+.	O
+
+The	O
+hypotensive	B
+drug	O
+was	O
+discontinued	O
+at	O
+the	O
+completion	O
+of	O
+the	O
+operative	O
+procedure	O
+.	O
+
+After	O
+starting	O
+PGE1	O
+or	O
+TMP	O
+,	O
+MAP	O
+and	O
+rate	O
+pressure	O
+product	O
+(	O
+RPP	O
+)	O
+decreased	O
+significantly	O
+compared	O
+with	O
+preinfusion	O
+values	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+,	O
+and	O
+the	O
+degree	O
+of	O
+hypotension	B
+due	O
+to	O
+PGE1	O
+remained	O
+constant	O
+until	O
+60	O
+min	O
+after	O
+its	O
+discontinuation	O
+.	O
+
+Heart	O
+rate	O
+(	O
+HR	O
+)	O
+did	O
+not	O
+change	O
+in	O
+either	O
+group	O
+.	O
+
+EBFF	O
+did	O
+not	O
+change	O
+during	O
+PGE1	O
+infusion	O
+whereas	O
+in	O
+the	O
+TMP	O
+group	O
+,	O
+EBF	O
+decreased	O
+significantly	O
+at	O
+30	O
+and	O
+60	O
+min	O
+after	O
+the	O
+start	O
+of	O
+TMP	O
+(	O
+preinfusion	O
+:	O
+45	O
+.	O
+9	O
++	O
+/	O
+-	O
+13	O
+.	O
+9	O
+ml	O
+/	O
+100g	O
+/	O
+min	O
+.	O
+30	O
+min	O
+:	O
+32	O
+.	O
+3	O
++	O
+/	O
+-	O
+9	O
+.	O
+9	O
+ml	O
+/	O
+100	O
+g	O
+/	O
+min	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+60	O
+min	O
+:	O
+30	O
++	O
+/	O
+-	O
+7	O
+.	O
+5	O
+ml	O
+/	O
+100	O
+g	O
+/	O
+min	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+)	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+PGE1	O
+may	O
+be	O
+preferable	O
+to	O
+TMP	O
+for	O
+hypotensive	B
+anaesthesia	O
+in	O
+spinal	O
+surgery	O
+because	O
+TMP	O
+decreased	O
+EBF	O
+.	O
+
+Dup	O
+753	O
+prevents	O
+the	O
+development	O
+of	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+nephrosis	B
+.	O
+
+The	O
+appearance	O
+of	O
+nephrotic	B
+syndromes	I
+such	O
+as	O
+proteinuria	B
+,	O
+hypoalbuminemia	B
+,	O
+hypercholesterolemia	B
+and	O
+increase	O
+in	O
+blood	O
+nitrogen	O
+urea	O
+,	O
+induced	O
+in	O
+rats	O
+by	O
+injection	O
+of	O
+puromycin	O
+aminonucleoside	O
+was	O
+markedly	O
+inhibited	O
+by	O
+oral	O
+administration	O
+of	O
+Dup	O
+753	O
+(	O
+losartan	O
+)	O
+,	O
+a	O
+novel	O
+angiotensin	O
+II	O
+receptor	O
+antagonist	O
+,	O
+at	O
+a	O
+dose	O
+of	O
+1	O
+or	O
+2	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+.	O
+
+The	O
+results	O
+suggest	O
+a	O
+possible	O
+involvement	O
+of	O
+the	O
+renin	O
+-	O
+angiotensin	O
+system	O
+in	O
+the	O
+development	O
+of	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+nephrosis	B
+.	O
+
+Neuroplasticity	O
+of	O
+the	O
+adult	O
+primate	O
+auditory	O
+cortex	O
+following	O
+cochlear	O
+hearing	B
+loss	I
+.	O
+
+Tonotopic	O
+organization	O
+is	O
+an	O
+essential	O
+feature	O
+of	O
+the	O
+primary	O
+auditory	O
+area	O
+(	O
+A1	O
+)	O
+of	O
+primate	O
+cortex	O
+.	O
+
+In	O
+A1	O
+of	O
+macaque	O
+monkeys	O
+,	O
+low	O
+frequencies	O
+are	O
+represented	O
+rostrolaterally	O
+and	O
+high	O
+frequencies	O
+are	O
+represented	O
+caudomedially	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+if	O
+changes	O
+occur	O
+in	O
+this	O
+tonotopic	O
+organization	O
+following	O
+cochlear	O
+hearing	B
+loss	I
+.	O
+
+Under	O
+anesthesia	O
+,	O
+the	O
+superior	O
+temporal	O
+gyrus	O
+of	O
+adult	O
+macaque	O
+monkeys	O
+was	O
+exposed	O
+,	O
+and	O
+the	O
+tonotopic	O
+organization	O
+of	O
+A1	O
+was	O
+mapped	O
+using	O
+conventional	O
+microelectrode	O
+recording	O
+techniques	O
+.	O
+
+Following	O
+recovery	O
+,	O
+the	O
+monkeys	O
+were	O
+selectively	O
+deafened	O
+for	O
+high	O
+frequencies	O
+using	O
+kanamycin	O
+and	O
+furosemide	O
+.	O
+
+The	O
+actual	O
+frequencies	O
+deafened	O
+were	O
+determined	O
+by	O
+the	O
+loss	O
+of	O
+tone	O
+-	O
+burst	O
+elicited	O
+auditory	O
+brainstem	O
+responses	O
+.	O
+
+Three	O
+months	O
+after	O
+deafening	O
+,	O
+A1	O
+was	O
+remapped	O
+.	O
+
+Postmortem	O
+cytoarchitectural	O
+features	O
+identifying	O
+A1	O
+were	O
+correlated	O
+with	O
+the	O
+electrophysiologic	O
+data	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+the	O
+deprived	O
+area	O
+of	O
+A1	O
+undergoes	O
+extensive	O
+reorganization	O
+and	O
+becomes	O
+responsive	O
+to	O
+intact	O
+cochlear	O
+frequencies	O
+.	O
+
+The	O
+region	O
+of	O
+cortex	O
+that	O
+represents	O
+the	O
+low	O
+frequencies	O
+was	O
+not	O
+obviously	O
+affected	O
+by	O
+the	O
+cochlear	O
+hearing	B
+loss	I
+.	O
+
+Sodium	O
+bicarbonate	O
+alleviates	O
+penile	B
+pain	I
+induced	O
+by	O
+intracavernous	O
+injections	O
+for	O
+erectile	B
+dysfunction	I
+.	O
+
+In	O
+an	O
+attempt	O
+to	O
+determine	O
+whether	O
+penile	B
+pain	I
+associated	O
+with	O
+intracorporeal	O
+injections	O
+could	O
+be	O
+due	O
+to	O
+the	O
+acidity	O
+of	O
+the	O
+medication	O
+,	O
+we	O
+performed	O
+a	O
+randomized	O
+study	O
+comparing	O
+the	O
+incidence	O
+of	O
+penile	B
+pain	I
+following	O
+intracorporeal	O
+injections	O
+with	O
+or	O
+without	O
+the	O
+addition	O
+of	O
+sodium	O
+bicarbonate	O
+to	O
+the	O
+intracorporeal	O
+medications	O
+.	O
+
+A	O
+total	O
+of	O
+38	O
+consecutive	O
+patients	O
+who	O
+presented	O
+to	O
+our	O
+clinic	O
+with	O
+impotence	B
+received	O
+0	O
+.	O
+2	O
+ml	O
+.	O
+of	O
+a	O
+combination	O
+of	O
+3	O
+drugs	O
+:	O
+6	O
+mg	O
+.	O
+papaverine	O
+,	O
+100	O
+micrograms	O
+.	O
+phentolamine	O
+and	O
+10	O
+micrograms	O
+.	O
+prostaglandin	O
+E1	O
+with	O
+(	O
+pH	O
+7	O
+.	O
+05	O
+)	O
+or	O
+without	O
+(	O
+pH	O
+4	O
+.	O
+17	O
+)	O
+the	O
+addition	O
+of	O
+sodium	O
+bicarbonate	O
+(	O
+0	O
+.	O
+03	O
+mEq	O
+.	O
+)	O
+.	O
+
+Of	O
+the	O
+19	O
+patients	O
+without	O
+sodium	O
+bicarbonate	O
+added	O
+to	O
+the	O
+medication	O
+11	O
+(	O
+58	O
+%	O
+)	O
+complained	O
+of	O
+penile	B
+pain	I
+due	O
+to	O
+the	O
+medication	O
+,	O
+while	O
+only	O
+1	O
+of	O
+the	O
+19	O
+men	O
+(	O
+5	O
+%	O
+)	O
+who	O
+received	O
+sodium	O
+bicarbonate	O
+complained	O
+of	O
+penile	B
+pain	I
+.	O
+
+From	O
+these	O
+data	O
+we	O
+conclude	O
+that	O
+the	O
+penile	B
+pain	I
+following	O
+intracorporeal	O
+injections	O
+is	O
+most	O
+likely	O
+due	O
+to	O
+the	O
+acidity	O
+of	O
+the	O
+medication	O
+,	O
+which	O
+can	O
+be	O
+overcome	O
+by	O
+elevating	O
+the	O
+pH	O
+to	O
+a	O
+neutral	O
+level	O
+.	O
+
+The	O
+use	O
+and	O
+toxicity	B
+of	O
+didanosine	O
+(	O
+ddI	O
+)	O
+in	O
+HIV	B
+antibody	I
+-	I
+positive	I
+individuals	O
+intolerant	O
+to	O
+zidovudine	O
+(	O
+AZT	O
+)	O
+
+One	O
+hundred	O
+and	O
+fifty	O
+-	O
+one	O
+patients	O
+intolerant	O
+to	O
+zidovudine	O
+(	O
+AZT	O
+)	O
+received	O
+didanosine	O
+(	O
+ddI	O
+)	O
+to	O
+a	O
+maximum	O
+dose	O
+of	O
+12	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+.	O
+
+Patient	O
+response	O
+was	O
+assessed	O
+using	O
+changes	O
+in	O
+CD4	O
++	O
+lymphocyte	O
+subset	O
+count	O
+,	O
+HIV	O
+p24	O
+antigen	O
+,	O
+weight	O
+,	O
+and	O
+quality	O
+of	O
+life	O
+.	O
+
+Seventy	O
+patients	O
+developed	O
+major	O
+opportunistic	B
+infections	I
+whilst	O
+on	O
+therapy	O
+;	O
+this	O
+was	O
+the	O
+first	O
+AIDS	B
+diagnosis	O
+in	O
+17	O
+.	O
+
+Only	O
+minor	O
+changes	O
+in	O
+CD4	O
++	O
+lymphocyte	O
+subset	O
+count	O
+were	O
+observed	O
+in	O
+AIDS	B
+patients	O
+,	O
+although	O
+a	O
+more	O
+significant	O
+rise	O
+occurred	O
+in	O
+those	O
+with	O
+earlier	O
+stages	O
+of	O
+disease	O
+.	O
+
+Of	O
+those	O
+positive	O
+for	O
+p24	O
+antigen	O
+at	O
+the	O
+commencement	O
+of	O
+the	O
+study	O
+67	O
+%	O
+showed	O
+a	O
+positive	O
+response	O
+,	O
+and	O
+this	O
+was	O
+most	O
+likely	O
+in	O
+those	O
+with	O
+CD4	O
++	O
+lymphocyte	O
+subset	O
+counts	O
+above	O
+100	O
+mm3	O
+.	O
+
+A	O
+positive	O
+weight	O
+response	O
+was	O
+seen	O
+in	O
+16	O
+%	O
+of	O
+patients	O
+.	O
+
+Most	O
+patients	O
+showed	O
+improvement	O
+in	O
+individual	O
+parameters	O
+and	O
+global	O
+score	O
+of	O
+quality	O
+of	O
+life	O
+.	O
+
+Adverse	O
+reactions	O
+possibly	O
+attributable	O
+to	O
+didanosine	O
+were	O
+common	O
+.	O
+
+The	O
+most	O
+common	O
+side	O
+-	O
+effect	O
+was	O
+diarrhoea	B
+,	O
+which	O
+resulted	O
+in	O
+cessation	O
+of	O
+therapy	O
+in	O
+19	O
+individuals	O
+.	O
+
+Peripheral	B
+neuropathy	I
+occurred	O
+in	O
+12	O
+patients	O
+and	O
+pancreatitis	B
+in	O
+six	O
+.	O
+
+Thirteen	O
+patients	O
+developed	O
+a	O
+raised	O
+serum	O
+amylase	O
+without	O
+abdominal	B
+pain	I
+.	O
+
+Seven	O
+patients	O
+developed	O
+glucose	B
+tolerance	I
+curves	I
+characteristic	O
+of	O
+diabetes	B
+but	O
+these	O
+were	O
+mild	O
+,	O
+did	O
+not	O
+require	O
+treatment	O
+and	O
+returned	O
+to	O
+normal	O
+on	O
+ceasing	O
+didanosine	O
+.	O
+
+Immunohistochemical	O
+studies	O
+with	O
+antibodies	O
+to	O
+neurofilament	O
+proteins	O
+on	O
+axonal	B
+damage	I
+in	O
+experimental	O
+focal	O
+lesions	O
+in	O
+rat	O
+.	O
+
+Immunohistochemistry	O
+with	O
+monoclonal	O
+antibodies	O
+against	O
+neurofilament	O
+(	O
+NF	O
+)	O
+proteins	O
+of	O
+middle	O
+and	O
+high	O
+molecular	O
+weight	O
+class	O
+,	O
+NF	O
+-	O
+M	O
+and	O
+NF	O
+-	O
+H	O
+,	O
+was	O
+used	O
+to	O
+study	O
+axonal	B
+injury	I
+in	O
+the	O
+borderzone	O
+of	O
+focal	O
+lesions	O
+in	O
+rats	O
+.	O
+
+Focal	O
+injury	B
+in	I
+the	I
+cortex	I
+was	O
+produced	O
+by	O
+infusion	O
+of	O
+lactate	O
+at	O
+acid	O
+pH	O
+or	O
+by	O
+stab	O
+caused	O
+by	O
+needle	O
+insertion	O
+.	O
+
+Infarcts	B
+in	I
+substantia	I
+nigra	I
+pars	I
+reticulata	I
+were	O
+evoked	O
+by	O
+prolonged	O
+pilocarpine	O
+-	O
+induced	O
+status	B
+epilepticus	I
+.	O
+
+Immunohistochemical	O
+staining	O
+for	O
+NFs	O
+showed	O
+characteristic	O
+terminal	O
+clubs	O
+of	O
+axons	O
+in	O
+the	O
+borderzone	O
+of	O
+lesions	O
+.	O
+
+Differences	O
+in	O
+the	O
+labelling	O
+pattern	O
+occurred	O
+with	O
+different	O
+antibodies	O
+which	O
+apparently	O
+depended	O
+on	O
+molecular	O
+weight	O
+class	O
+of	O
+NFs	O
+and	O
+phosphorylation	O
+state	O
+.	O
+
+These	O
+immunohistochemical	O
+changes	O
+of	O
+NFs	O
+can	O
+serve	O
+as	O
+a	O
+marker	O
+for	O
+axonal	B
+damage	I
+in	O
+various	O
+experimental	O
+traumatic	B
+or	O
+ischemic	O
+lesions	O
+.	O
+
+Pharmacokinetic	O
+and	O
+clinical	O
+studies	O
+in	O
+patients	O
+with	O
+cimetidine	O
+-	O
+associated	O
+mental	O
+confusion	B
+.	O
+
+15	O
+cases	O
+of	O
+cimetidine	O
+-	O
+associated	O
+mental	O
+confusion	B
+have	O
+been	O
+reported	O
+.	O
+
+In	O
+order	O
+that	O
+this	O
+syndrome	O
+might	O
+be	O
+investigated	O
+changes	O
+in	O
+mental	O
+status	O
+(	O
+M	O
+.	O
+S	O
+.	O
+)	O
+were	O
+correlated	O
+with	O
+serum	O
+concentrations	O
+and	O
+renal	O
+and	O
+hepatic	O
+function	O
+in	O
+36	O
+patients	O
+,	O
+30	O
+patients	O
+had	O
+no	O
+M	O
+.	O
+S	O
+.	O
+change	O
+on	O
+cimetidine	O
+and	O
+6	O
+had	O
+moderate	O
+to	O
+severe	O
+changes	O
+.	O
+
+These	O
+6	O
+patients	O
+had	O
+both	O
+renal	B
+and	I
+liver	I
+dysfunction	I
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+,	O
+as	O
+well	O
+as	O
+cimetidine	O
+trough	O
+-	O
+concentrations	O
+of	O
+more	O
+than	O
+1	O
+.	O
+25	O
+microgram	O
+/	O
+ml	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+severity	O
+of	O
+M	O
+.	O
+S	O
+.	O
+changes	O
+increased	O
+as	O
+trough	O
+-	O
+concentrations	O
+rose	O
+,	O
+5	O
+patients	O
+had	O
+lumbar	O
+puncture	O
+.	O
+
+The	O
+cerebrospinal	O
+fluid	O
+:	O
+serum	O
+ratio	O
+of	O
+cimetidine	O
+concentrations	O
+was	O
+0	O
+.	O
+24	O
+:	O
+1	O
+and	O
+indicates	O
+that	O
+cimetidine	O
+passes	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+;	O
+it	O
+also	O
+raises	O
+the	O
+possibility	O
+that	O
+M	O
+.	O
+S	O
+.	O
+changes	O
+are	O
+due	O
+to	O
+blockade	O
+of	O
+histamine	O
+H2	O
+-	O
+receptors	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+.	O
+
+Patients	O
+likely	O
+to	O
+have	O
+both	O
+raised	O
+trough	O
+-	O
+concentrations	O
+and	O
+mental	O
+confusion	B
+are	O
+those	O
+with	O
+both	O
+severe	O
+renal	B
+and	I
+hepatic	I
+dysfunction	I
+.	O
+
+They	O
+should	O
+be	O
+closely	O
+observed	O
+and	O
+should	O
+be	O
+given	O
+reduced	O
+doses	O
+of	O
+cimetidine	O
+.	O
+
+Prospective	O
+study	O
+of	O
+the	O
+long	O
+-	O
+term	O
+effects	O
+of	O
+somatostatin	O
+analog	O
+(	O
+octreotide	O
+)	O
+on	O
+gallbladder	O
+function	O
+and	O
+gallstone	B
+formation	O
+in	O
+Chinese	O
+acromegalic	B
+patients	O
+.	O
+
+This	O
+article	O
+reports	O
+the	O
+changes	O
+in	O
+gallbladder	O
+function	O
+examined	O
+by	O
+ultrasonography	O
+in	O
+20	O
+Chinese	O
+patients	O
+with	O
+active	O
+acromegaly	B
+treated	O
+with	O
+sc	O
+injection	O
+of	O
+the	O
+somatostatin	O
+analog	O
+octreotide	O
+in	O
+dosages	O
+of	O
+300	O
+-	O
+1500	O
+micrograms	O
+/	O
+day	O
+for	O
+a	O
+mean	O
+of	O
+24	O
+.	O
+2	O
++	O
+/	O
+-	O
+13	O
+.	O
+9	O
+months	O
+.	O
+
+During	O
+treatment	O
+with	O
+octreotide	O
+,	O
+17	O
+patients	O
+developed	O
+sludge	O
+,	O
+10	O
+had	O
+gallstones	B
+,	O
+and	O
+1	O
+developed	O
+acute	B
+cholecystitis	I
+requiring	O
+surgery	O
+.	O
+
+In	O
+all	O
+of	O
+7	O
+patients	O
+examined	O
+acutely	O
+,	O
+gallbladder	O
+contractility	O
+was	O
+inhibited	O
+after	O
+a	O
+single	O
+100	O
+-	O
+micrograms	O
+injection	O
+.	O
+
+In	O
+8	O
+patients	O
+followed	O
+for	O
+24	O
+weeks	O
+,	O
+gallbladder	O
+contractility	O
+remained	O
+depressed	B
+throughout	O
+therapy	O
+.	O
+
+After	O
+withdrawal	O
+of	O
+octreotide	O
+in	O
+10	O
+patients	O
+without	O
+gallstones	B
+,	O
+8	O
+patients	O
+assessed	O
+had	O
+return	O
+of	O
+normal	O
+gallbladder	O
+contractility	O
+within	O
+1	O
+month	O
+.	O
+
+In	O
+8	O
+of	O
+the	O
+remaining	O
+10	O
+patients	O
+who	O
+developed	O
+gallstones	B
+during	O
+treatment	O
+,	O
+gallbladder	O
+contractility	O
+normalized	O
+in	O
+5	O
+patients	O
+(	O
+3	O
+of	O
+whom	O
+has	O
+disappearance	O
+of	O
+their	O
+stones	O
+within	O
+3	O
+weeks	O
+)	O
+,	O
+and	O
+remained	O
+depressed	B
+in	O
+3	O
+(	O
+2	O
+of	O
+whom	O
+had	O
+stones	O
+present	O
+at	O
+6	O
+months	O
+)	O
+.	O
+
+Our	O
+results	O
+suggest	O
+that	O
+the	O
+suppression	O
+of	O
+gallbladder	O
+contractility	O
+is	O
+the	O
+cause	O
+of	O
+the	O
+successive	O
+formation	O
+of	O
+bile	O
+sludge	O
+,	O
+gallstones	B
+,	O
+and	O
+cholecystitis	B
+during	O
+octreotide	O
+therapy	O
+in	O
+Chinese	O
+acromegalic	B
+patients	O
+.	O
+
+It	O
+is	O
+therefore	O
+very	O
+important	O
+to	O
+follow	O
+the	O
+changes	O
+of	O
+gallbladder	O
+function	O
+during	O
+long	O
+-	O
+term	O
+octreotide	O
+therapy	O
+of	O
+acromegalic	B
+patients	O
+.	O
+
+Increase	O
+of	O
+Parkinson	B
+disability	I
+after	O
+fluoxetine	O
+medication	O
+.	O
+
+Depression	B
+is	O
+a	O
+major	O
+clinical	O
+feature	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+We	O
+report	O
+the	O
+increased	O
+amount	O
+of	O
+motor	B
+disability	I
+in	O
+four	O
+patients	O
+with	O
+idiopathic	B
+Parkinson	I
+'	I
+s	I
+disease	I
+after	O
+exposure	O
+to	O
+the	O
+antidepressant	O
+fluoxetine	O
+.	O
+
+The	O
+possibility	O
+of	O
+a	O
+clinically	O
+relevant	O
+dopamine	O
+-	O
+antagonistic	O
+capacity	O
+of	O
+fluoxetine	O
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+patients	O
+must	O
+be	O
+considered	O
+.	O
+
+Sinus	B
+arrest	I
+associated	O
+with	O
+continuous	O
+-	O
+infusion	O
+cimetidine	O
+.	O
+
+The	O
+administration	O
+of	O
+intermittent	O
+intravenous	O
+infusions	O
+of	O
+cimetidine	O
+is	O
+infrequently	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+bradyarrhythmias	B
+.	O
+
+A	O
+40	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+leukemia	B
+and	O
+no	O
+history	O
+of	O
+cardiac	B
+disease	I
+developed	O
+recurrent	O
+,	O
+brief	O
+episodes	O
+of	O
+apparent	O
+sinus	B
+arrest	I
+while	O
+receiving	O
+continuous	O
+-	O
+infusion	O
+cimetidine	O
+50	O
+mg	O
+/	O
+hour	O
+.	O
+
+The	O
+arrhythmias	B
+were	O
+temporally	O
+related	O
+to	O
+cimetidine	O
+administration	O
+,	O
+disappeared	O
+after	O
+dechallenge	O
+,	O
+and	O
+did	O
+not	O
+recur	O
+during	O
+ranitidine	O
+treatment	O
+.	O
+
+This	O
+is	O
+the	O
+first	O
+reported	O
+case	O
+of	O
+sinus	B
+arrest	I
+associated	O
+with	O
+continuous	O
+-	O
+infusion	O
+cimetidine	O
+.	O
+
+Phase	O
+II	O
+trial	O
+of	O
+vinorelbine	O
+in	O
+metastatic	O
+squamous	B
+cell	I
+esophageal	I
+carcinoma	I
+.	O
+
+European	O
+Organization	O
+for	O
+Research	O
+and	O
+Treatment	O
+of	O
+Cancer	B
+Gastrointestinal	O
+Treat	O
+Cancer	B
+Cooperative	O
+Group	O
+.	O
+
+PURPOSE	O
+:	O
+To	O
+evaluate	O
+the	O
+response	O
+rate	O
+and	O
+toxic	O
+effects	O
+of	O
+vinorelbine	O
+(	O
+VNB	O
+)	O
+administered	O
+as	O
+a	O
+single	O
+agent	O
+in	O
+metastatic	O
+squamous	B
+cell	I
+esophageal	I
+carcinoma	I
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+Forty	O
+-	O
+six	O
+eligible	O
+patients	O
+with	O
+measurable	O
+lesions	O
+were	O
+included	O
+and	O
+were	O
+stratified	O
+according	O
+to	O
+previous	O
+chemotherapy	O
+.	O
+
+Thirty	O
+patients	O
+without	O
+prior	O
+chemotherapy	O
+and	O
+16	O
+pretreated	O
+with	O
+cisplatin	O
+-	O
+based	O
+chemotherapy	O
+were	O
+assessable	O
+for	O
+toxicity	B
+and	O
+response	O
+.	O
+
+VNB	O
+was	O
+administered	O
+weekly	O
+as	O
+a	O
+25	O
+-	O
+mg	O
+/	O
+m2	O
+short	O
+intravenous	O
+(	O
+i	O
+.	O
+v	O
+.	O
+)	O
+infusion	O
+.	O
+
+RESULTS	O
+:	O
+Six	O
+of	O
+30	O
+patients	O
+(	O
+20	O
+%	O
+)	O
+without	O
+prior	O
+chemotherapy	O
+achieved	O
+a	O
+partial	O
+response	O
+(	O
+PR	O
+)	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+,	O
+8	O
+%	O
+to	O
+39	O
+%	O
+)	O
+.	O
+
+The	O
+median	O
+duration	O
+of	O
+response	O
+was	O
+21	O
+weeks	O
+(	O
+range	O
+,	O
+17	O
+to	O
+28	O
+)	O
+.	O
+
+One	O
+of	O
+16	O
+patients	O
+(	O
+6	O
+%	O
+)	O
+with	O
+prior	O
+chemotherapy	O
+had	O
+a	O
+complete	O
+response	O
+(	O
+CR	O
+)	O
+of	O
+31	O
+weeks	O
+'	O
+duration	O
+(	O
+95	O
+%	O
+CI	O
+,	O
+0	O
+%	O
+to	O
+30	O
+%	O
+)	O
+.	O
+
+The	O
+overall	O
+response	O
+rate	O
+(	O
+World	O
+Health	O
+Organization	O
+[	O
+WHO	O
+]	O
+criteria	O
+)	O
+was	O
+15	O
+%	O
+(	O
+CR	O
+,	O
+2	O
+%	O
+;	O
+PR	O
+13	O
+%	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+6	O
+%	O
+to	O
+29	O
+%	O
+)	O
+.	O
+
+The	O
+median	O
+dose	O
+-	O
+intensity	O
+(	O
+DI	O
+)	O
+was	O
+20	O
+mg	O
+/	O
+m2	O
+/	O
+wk	O
+.	O
+
+VNB	O
+was	O
+well	O
+tolerated	O
+and	O
+zero	O
+instances	O
+of	O
+WHO	O
+grade	O
+4	O
+nonhematologic	O
+toxicity	B
+occurred	O
+.	O
+
+At	O
+least	O
+one	O
+episode	O
+of	O
+grade	O
+3	O
+or	O
+4	O
+granulocytopenia	B
+was	O
+seen	O
+in	O
+59	O
+%	O
+of	O
+patients	O
+.	O
+
+A	O
+grade	O
+2	O
+or	O
+3	O
+infection	B
+occurred	O
+in	O
+16	O
+%	O
+of	O
+patients	O
+,	O
+but	O
+no	O
+toxic	O
+deaths	B
+occurred	O
+.	O
+
+Other	O
+side	O
+effects	O
+were	O
+rare	O
+,	O
+and	O
+peripheral	B
+neurotoxicity	I
+has	O
+been	O
+minor	O
+(	O
+26	O
+%	O
+grade	O
+1	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+These	O
+data	O
+indicate	O
+that	O
+VNB	O
+is	O
+an	O
+active	O
+agent	O
+in	O
+metastatic	O
+esophageal	B
+squamous	I
+cell	I
+carcinoma	I
+.	O
+
+Given	O
+its	O
+excellent	O
+tolerance	O
+profile	O
+and	O
+low	O
+toxicity	B
+,	O
+further	O
+evaluation	O
+of	O
+VNB	O
+in	O
+combination	O
+therapy	O
+is	O
+warranted	O
+.	O
+
+Evaluation	O
+of	O
+adverse	O
+reactions	O
+of	O
+aponidine	O
+hydrochloride	O
+ophthalmic	O
+solution	O
+.	O
+
+We	O
+prospectively	O
+evaluated	O
+the	O
+adverse	O
+reactions	O
+of	O
+apraclonidine	O
+in	O
+20	O
+normal	O
+volunteers	O
+by	O
+instilling	O
+a	O
+single	O
+drop	O
+of	O
+1	O
+%	O
+apraclonidine	O
+in	O
+their	O
+right	O
+eyes	O
+.	O
+
+Examinations	O
+,	O
+including	O
+blood	O
+pressure	O
+,	O
+pulse	O
+rate	O
+,	O
+conjunctiva	O
+and	O
+cornea	O
+,	O
+intraocular	O
+pressure	O
+(	O
+IOP	O
+)	O
+,	O
+pupil	O
+diameter	O
+,	O
+basal	O
+tear	O
+secretion	O
+and	O
+margin	O
+reflex	O
+distance	O
+of	O
+both	O
+upper	O
+and	O
+lower	O
+eyelids	O
+,	O
+were	O
+performed	O
+prior	O
+to	O
+entry	O
+and	O
+at	O
+1	O
+,	O
+3	O
+,	O
+5	O
+and	O
+7	O
+hours	O
+after	O
+instillation	O
+.	O
+
+The	O
+ocular	B
+hypotensive	I
+effects	O
+were	O
+statistically	O
+significant	O
+for	O
+apraclonidine	O
+-	O
+treated	O
+eyes	O
+throughout	O
+the	O
+study	O
+and	O
+also	O
+statistically	O
+significant	O
+for	O
+contralateral	O
+eyes	O
+from	O
+three	O
+hours	O
+after	O
+topical	O
+administration	O
+of	O
+1	O
+%	O
+apraclonidine	O
+.	O
+
+Decreases	B
+in	I
+systolic	I
+blood	I
+pressure	I
+were	O
+statistically	O
+,	O
+but	O
+not	O
+clinically	O
+,	O
+significant	O
+.	O
+
+No	O
+significant	O
+changes	O
+in	O
+diastolic	O
+blood	O
+pressure	O
+,	O
+pulse	O
+rate	O
+and	O
+basal	O
+tear	O
+secretion	O
+were	O
+noted	O
+.	O
+
+Conjunctival	B
+blanching	I
+and	O
+mydriasis	B
+were	O
+commonly	O
+found	O
+.	O
+
+Upper	O
+lid	O
+retraction	O
+was	O
+frequently	O
+noted	O
+.	O
+
+While	O
+the	O
+elevations	O
+of	O
+the	O
+upper	O
+lid	O
+margin	O
+in	O
+most	O
+subjects	O
+were	O
+not	O
+more	O
+than	O
+2	O
+mm	O
+and	O
+did	O
+not	O
+cause	O
+noticeable	O
+change	O
+in	O
+appearance	O
+,	O
+one	O
+subject	O
+suffered	O
+from	O
+mechanical	O
+entropion	B
+and	O
+marked	O
+corneal	B
+abrasion	I
+3	O
+hours	O
+after	O
+instillation	O
+of	O
+the	O
+medication	O
+.	O
+
+This	O
+may	O
+well	O
+be	O
+a	O
+particularly	O
+notable	O
+finding	O
+in	O
+Asian	O
+people	O
+.	O
+
+Thiopentone	O
+pretreatment	O
+for	O
+propofol	O
+injection	O
+pain	B
+in	O
+ambulatory	O
+patients	O
+.	O
+
+This	O
+study	O
+investigated	O
+propofol	O
+injection	O
+pain	B
+in	O
+patients	O
+undergoing	O
+ambulatory	O
+anaesthesia	O
+.	O
+
+In	O
+a	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+trial	O
+,	O
+90	O
+women	O
+were	O
+allocated	O
+to	O
+receive	O
+one	O
+of	O
+three	O
+treatments	O
+prior	O
+to	O
+induction	O
+of	O
+anaesthesia	O
+with	O
+propofol	O
+.	O
+
+Patients	O
+in	O
+Group	O
+C	O
+received	O
+2	O
+ml	O
+normal	O
+saline	O
+,	O
+Group	O
+L	O
+,	O
+2	O
+ml	O
+,	O
+lidocaine	O
+2	O
+%	O
+(	O
+40	O
+mg	O
+)	O
+and	O
+Group	O
+T	O
+,	O
+2	O
+ml	O
+thiopentone	O
+2	O
+.	O
+5	O
+%	O
+(	O
+50	O
+mg	O
+)	O
+.	O
+
+Venous	O
+discomfort	O
+was	O
+assessed	O
+with	O
+a	O
+visual	O
+analogue	O
+scale	O
+(	O
+VAS	O
+)	O
+5	O
+-	O
+15	O
+sec	O
+after	O
+commencing	O
+propofol	O
+administration	O
+using	O
+an	O
+infusion	O
+pump	O
+(	O
+rate	O
+1000	O
+micrograms	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+)	O
+.	O
+
+Loss	B
+of	I
+consciousness	I
+occurred	O
+in	O
+60	O
+-	O
+90	O
+sec	O
+.	O
+
+Visual	O
+analogue	O
+scores	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+)	O
+during	O
+induction	O
+were	O
+lower	O
+in	O
+Groups	O
+L	O
+(	O
+3	O
+.	O
+3	O
++	O
+/	O
+-	O
+2	O
+.	O
+5	O
+)	O
+and	O
+T	O
+(	O
+4	O
+.	O
+1	O
++	O
+/	O
+-	O
+2	O
+.	O
+7	O
+)	O
+than	O
+in	O
+Group	O
+C	O
+(	O
+5	O
+.	O
+6	O
++	O
+/	O
+-	O
+2	O
+.	O
+3	O
+)	O
+;	O
+P	O
+=	O
+0	O
+.	O
+0031	O
+.	O
+
+The	O
+incidence	O
+of	O
+venous	O
+discomfort	O
+was	O
+lower	O
+in	O
+Group	O
+L	O
+(	O
+76	O
+.	O
+6	O
+%	O
+;	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+than	O
+in	O
+Group	O
+C	O
+(	O
+100	O
+%	O
+)	O
+but	O
+not	O
+different	O
+from	O
+Group	O
+T	O
+(	O
+90	O
+%	O
+)	O
+.	O
+
+The	O
+VAS	O
+scores	O
+for	O
+recall	O
+of	O
+pain	B
+in	O
+the	O
+recovery	O
+room	O
+were	O
+correlated	O
+with	O
+the	O
+VAS	O
+scores	O
+during	O
+induction	O
+(	O
+r	O
+=	O
+0	O
+.	O
+7045	O
+;	O
+P	O
+<	O
+0	O
+.	O
+0001	O
+)	O
+.	O
+
+Recovery	O
+room	O
+discharge	O
+times	O
+were	O
+similar	O
+:	O
+C	O
+(	O
+75	O
+.	O
+9	O
++	O
+/	O
+-	O
+19	O
+.	O
+4	O
+min	O
+)	O
+;	O
+L	O
+73	O
+.	O
+6	O
++	O
+/	O
+-	O
+21	O
+.	O
+6	O
+min	O
+)	O
+;	O
+T	O
+(	O
+77	O
+.	O
+1	O
++	O
+/	O
+-	O
+18	O
+.	O
+9	O
+min	O
+)	O
+.	O
+
+Assessing	O
+their	O
+overall	O
+satisfaction	O
+,	O
+89	O
+.	O
+7	O
+%	O
+would	O
+choose	O
+propofol	O
+anaesthesia	O
+again	O
+.	O
+
+We	O
+conclude	O
+that	O
+lidocaine	O
+reduces	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+propofol	O
+injection	O
+pain	B
+in	O
+ambulatory	O
+patients	O
+whereas	O
+thiopentone	O
+only	O
+reduces	O
+its	O
+severity	O
+.	O
+
+Persistent	O
+paralysis	B
+after	O
+prolonged	O
+use	O
+of	O
+atracurium	O
+in	O
+the	O
+absence	O
+of	O
+corticosteroids	O
+.	O
+
+Neuromuscular	O
+blocking	O
+agents	O
+(	O
+NMBAs	O
+)	O
+are	O
+often	O
+used	O
+for	O
+patients	O
+requiring	O
+prolonged	O
+mechanical	O
+ventilation	O
+.	O
+
+Reports	O
+of	O
+persistent	O
+paralysis	B
+after	O
+the	O
+discontinuance	O
+of	O
+these	O
+drugs	O
+have	O
+most	O
+often	O
+involved	O
+aminosteroid	O
+-	O
+based	O
+NMBAs	O
+such	O
+as	O
+vecuronium	O
+bromide	O
+,	O
+especially	O
+when	O
+used	O
+in	O
+conjunction	O
+with	O
+corticosteroids	O
+.	O
+
+Atracurium	O
+besylate	O
+,	O
+a	O
+short	O
+-	O
+acting	O
+benzylisoquinolinium	O
+NMBA	O
+that	O
+is	O
+eliminated	O
+independently	O
+of	O
+renal	O
+or	O
+hepatic	O
+function	O
+,	O
+has	O
+also	O
+been	O
+associated	O
+with	O
+persistent	O
+paralysis	B
+,	O
+but	O
+only	O
+when	O
+used	O
+with	O
+corticosteroids	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+atracurium	O
+-	O
+related	O
+paralysis	B
+persisting	O
+for	O
+approximately	O
+50	O
+hours	O
+in	O
+a	O
+patient	O
+who	O
+was	O
+not	O
+treated	O
+with	O
+corticosteroids	O
+.	O
+
+A	O
+phase	O
+I	O
+/	O
+II	O
+study	O
+of	O
+paclitaxel	O
+plus	O
+cisplatin	O
+as	O
+first	O
+-	O
+line	O
+therapy	O
+for	O
+head	B
+and	I
+neck	I
+cancers	I
+:	O
+preliminary	O
+results	O
+.	O
+
+Improved	O
+outcomes	O
+among	O
+patients	O
+with	O
+head	B
+and	I
+neck	I
+carcinomas	I
+require	O
+investigations	O
+of	O
+new	O
+drugs	O
+for	O
+induction	O
+therapy	O
+.	O
+
+Preliminary	O
+results	O
+of	O
+an	O
+Eastern	O
+Cooperative	O
+Oncology	O
+Group	O
+study	O
+of	O
+single	O
+-	O
+agent	O
+paclitaxel	O
+(	O
+Taxol	O
+;	O
+Bristol	O
+-	O
+Myers	O
+Squibb	O
+Company	O
+,	O
+Princeton	O
+,	O
+NJ	O
+)	O
+reported	O
+a	O
+37	O
+%	O
+response	O
+rate	O
+in	O
+patients	O
+with	O
+head	B
+and	I
+neck	I
+cancer	I
+,	O
+and	O
+the	O
+paclitaxel	O
+/	O
+cisplatin	O
+combination	O
+has	O
+been	O
+used	O
+successfully	O
+and	O
+has	O
+significantly	O
+improved	O
+median	O
+response	O
+duration	O
+in	O
+ovarian	B
+cancer	I
+patients	O
+.	O
+
+We	O
+initiated	O
+a	O
+phase	O
+I	O
+/	O
+II	O
+trial	O
+to	O
+determine	O
+the	O
+response	O
+and	O
+toxicity	B
+of	O
+escalating	O
+paclitaxel	O
+doses	O
+combined	O
+with	O
+fixed	O
+-	O
+dose	O
+cisplatin	O
+with	O
+granulocyte	O
+colony	O
+-	O
+stimulating	O
+factor	O
+support	O
+in	O
+patients	O
+with	O
+untreated	O
+locally	O
+advanced	O
+inoperable	O
+head	B
+and	I
+neck	I
+carcinoma	I
+.	O
+
+To	O
+date	O
+,	O
+23	O
+men	O
+with	O
+a	O
+median	O
+age	O
+of	O
+50	O
+years	O
+and	O
+good	O
+performance	O
+status	O
+have	O
+entered	O
+the	O
+trial	O
+.	O
+
+Primary	O
+tumor	B
+sites	O
+were	O
+oropharynx	O
+,	O
+10	O
+patients	O
+;	O
+hypopharynx	O
+,	O
+four	O
+;	O
+larynx	O
+,	O
+two	O
+;	O
+oral	O
+cavity	O
+,	O
+three	O
+;	O
+unknown	O
+primary	O
+,	O
+two	O
+;	O
+and	O
+nasal	O
+cavity	O
+and	O
+parotid	O
+gland	O
+,	O
+one	O
+each	O
+.	O
+
+Of	O
+20	O
+patients	O
+evaluable	O
+for	O
+toxicity	B
+,	O
+four	O
+had	O
+stage	O
+III	O
+and	O
+16	O
+had	O
+stage	O
+IV	O
+disease	O
+.	O
+
+Treatment	O
+,	O
+given	O
+every	O
+21	O
+days	O
+for	O
+a	O
+maximum	O
+of	O
+three	O
+cycles	O
+,	O
+consisted	O
+of	O
+paclitaxel	O
+by	O
+3	O
+-	O
+hour	O
+infusion	O
+followed	O
+the	O
+next	O
+day	O
+by	O
+a	O
+fixed	O
+dose	O
+of	O
+cisplatin	O
+(	O
+75	O
+mg	O
+/	O
+m2	O
+)	O
+.	O
+
+The	O
+dose	O
+levels	O
+incorporate	O
+escalating	O
+paclitaxel	O
+doses	O
+,	O
+and	O
+intrapatient	O
+escalations	O
+within	O
+a	O
+given	O
+dose	O
+level	O
+are	O
+permitted	O
+if	O
+toxicity	B
+permits	O
+.	O
+
+At	O
+the	O
+time	O
+of	O
+this	O
+writing	O
+,	O
+dose	O
+level	O
+4	O
+(	O
+260	O
+,	O
+270	O
+,	O
+and	O
+280	O
+mg	O
+/	O
+m2	O
+)	O
+is	O
+being	O
+evaluated	O
+;	O
+three	O
+patients	O
+from	O
+this	O
+level	O
+are	O
+evaluable	O
+.	O
+
+With	O
+paclitaxel	O
+doses	O
+of	O
+200	O
+mg	O
+/	O
+m2	O
+and	O
+higher	O
+,	O
+granulocyte	O
+colony	O
+-	O
+stimulating	O
+factor	O
+5	O
+micrograms	O
+/	O
+kg	O
+/	O
+d	O
+is	O
+given	O
+(	O
+days	O
+4	O
+through	O
+12	O
+)	O
+.	O
+
+Of	O
+18	O
+patients	O
+evaluable	O
+for	O
+response	O
+,	O
+seven	O
+(	O
+39	O
+%	O
+)	O
+achieved	O
+a	O
+complete	O
+response	O
+and	O
+six	O
+(	O
+33	O
+%	O
+)	O
+achieved	O
+a	O
+partial	O
+response	O
+.	O
+
+Three	O
+patients	O
+had	O
+no	O
+change	O
+and	O
+disease	O
+progressed	O
+in	O
+two	O
+.	O
+
+The	O
+overall	O
+response	O
+rate	O
+is	O
+72	O
+%	O
+.	O
+
+Eleven	O
+responding	O
+patients	O
+had	O
+subsequent	O
+surgery	O
+/	O
+radiotherapy	O
+or	O
+radical	O
+radiotherapy	O
+.	O
+
+Two	O
+pathologic	O
+complete	O
+responses	O
+were	O
+observed	O
+in	O
+patients	O
+who	O
+had	O
+achieved	O
+clinical	O
+complete	O
+responses	O
+.	O
+
+Alopecia	B
+,	O
+paresthesias	B
+,	O
+and	O
+arthralgias	B
+/	O
+myalgias	B
+have	O
+occurred	O
+frequently	O
+,	O
+but	O
+with	O
+one	O
+exception	O
+(	O
+a	O
+grade	O
+3	O
+myalgia	B
+)	O
+they	O
+have	O
+been	O
+grade	O
+1	O
+or	O
+2	O
+.	O
+
+No	O
+dose	O
+-	O
+limiting	O
+hematologic	O
+toxicity	B
+has	O
+been	O
+seen	O
+.	O
+
+Paclitaxel	O
+/	O
+cisplatin	O
+is	O
+an	O
+effective	O
+first	O
+-	O
+line	O
+regimen	O
+for	O
+locoregionally	O
+advanced	O
+head	B
+and	I
+neck	I
+cancer	I
+and	O
+continued	O
+study	O
+is	O
+warranted	O
+.	O
+
+Results	O
+thus	O
+far	O
+suggest	O
+no	O
+dose	O
+-	O
+response	O
+effect	O
+for	O
+paclitaxel	O
+doses	O
+above	O
+200	O
+mg	O
+/	O
+m2	O
+.	O
+
+Improvement	O
+of	O
+levodopa	O
+-	O
+induced	O
+dyskinesia	B
+by	O
+propranolol	O
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+Seven	O
+patients	O
+suffering	O
+from	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+with	O
+severely	O
+disabling	O
+dyskinesia	B
+received	O
+low	O
+-	O
+dose	O
+propranolol	O
+as	O
+an	O
+adjunct	O
+to	O
+the	O
+currently	O
+used	O
+medical	O
+treatment	O
+.	O
+
+There	O
+was	O
+a	O
+significant	O
+40	O
+%	O
+improvement	O
+in	O
+the	O
+dyskinesia	B
+score	O
+without	O
+increase	O
+of	O
+parkinsonian	B
+motor	B
+disability	I
+.	O
+
+Ballistic	O
+and	O
+choreic	O
+dyskinesia	B
+were	O
+markedly	O
+ameliorated	O
+,	O
+whereas	O
+dystonia	B
+was	O
+not	O
+.	O
+
+This	O
+study	O
+suggests	O
+that	O
+administration	O
+of	O
+low	O
+doses	O
+of	O
+beta	O
+-	O
+blockers	O
+may	O
+improve	O
+levodopa	O
+-	O
+induced	O
+ballistic	O
+and	O
+choreic	O
+dyskinesia	B
+in	O
+PD	B
+.	O
+
+Habitual	O
+use	O
+of	O
+acetaminophen	O
+as	O
+a	O
+risk	O
+factor	O
+for	O
+chronic	B
+renal	I
+failure	I
+:	O
+a	O
+comparison	O
+with	O
+phenacetin	O
+.	O
+
+Six	O
+epidemiologic	O
+studies	O
+in	O
+the	O
+United	O
+States	O
+and	O
+Europe	O
+indicate	O
+that	O
+habitual	O
+use	O
+of	O
+phenacetin	O
+is	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+chronic	B
+renal	I
+failure	I
+and	O
+end	B
+-	I
+stage	I
+renal	I
+disease	I
+(	O
+ESRD	B
+)	O
+,	O
+with	O
+a	O
+relative	O
+risk	O
+in	O
+the	O
+range	O
+of	O
+4	O
+to	O
+19	O
+.	O
+
+As	O
+a	O
+result	O
+of	O
+these	O
+and	O
+other	O
+studies	O
+,	O
+phenacetin	O
+has	O
+now	O
+been	O
+withdrawn	O
+from	O
+the	O
+market	O
+in	O
+most	O
+countries	O
+.	O
+
+However	O
+,	O
+three	O
+case	O
+control	O
+studies	O
+,	O
+one	O
+each	O
+in	O
+North	O
+Carolina	O
+,	O
+northern	O
+Maryland	O
+,	O
+and	O
+West	O
+Berlin	O
+,	O
+Germany	O
+,	O
+showed	O
+that	O
+habitual	O
+use	O
+of	O
+acetaminophen	O
+is	O
+also	O
+associated	O
+with	O
+chronic	B
+renal	I
+failure	I
+and	O
+ESRD	B
+,	O
+with	O
+a	O
+relative	O
+risk	O
+in	O
+the	O
+range	O
+of	O
+2	O
+to	O
+4	O
+.	O
+
+These	O
+studies	O
+suggest	O
+that	O
+both	O
+phenacetin	O
+and	O
+acetaminophen	O
+may	O
+contribute	O
+to	O
+the	O
+burden	O
+of	O
+ESRD	B
+,	O
+with	O
+the	O
+risk	O
+of	O
+the	O
+latter	O
+being	O
+somewhat	O
+less	O
+than	O
+that	O
+of	O
+the	O
+former	O
+.	O
+
+This	O
+apparent	O
+difference	O
+in	O
+risk	O
+may	O
+not	O
+be	O
+due	O
+to	O
+differences	O
+in	O
+nephrotoxic	B
+potential	O
+of	O
+the	O
+drugs	O
+themselves	O
+.	O
+
+A	O
+lower	O
+relative	O
+risk	O
+would	O
+be	O
+expected	O
+for	O
+acetaminophen	O
+if	O
+the	O
+risk	O
+of	O
+both	O
+drugs	O
+in	O
+combination	O
+with	O
+other	O
+analgesics	O
+was	O
+higher	O
+than	O
+the	O
+risk	O
+of	O
+either	O
+agent	O
+alone	O
+.	O
+
+Thus	O
+,	O
+acetaminophen	O
+has	O
+been	O
+used	O
+both	O
+as	O
+a	O
+single	O
+agent	O
+and	O
+in	O
+combination	O
+with	O
+other	O
+analgesics	O
+,	O
+whereas	O
+phenacetin	O
+was	O
+available	O
+only	O
+in	O
+combinations	O
+.	O
+
+The	O
+possibility	O
+that	O
+habitual	O
+use	O
+of	O
+acetaminophen	O
+alone	O
+increases	O
+the	O
+risk	O
+of	O
+ESRD	B
+has	O
+not	O
+been	O
+clearly	O
+demonstrated	O
+,	O
+but	O
+cannot	O
+be	O
+dismissed	O
+.	O
+
+Acetaminophen	O
+-	O
+induced	O
+hypotension	B
+.	O
+
+Through	O
+30	O
+years	O
+of	O
+widespread	O
+use	O
+,	O
+acetaminophen	O
+has	O
+been	O
+shown	O
+to	O
+be	O
+a	O
+remarkably	O
+safe	O
+medication	O
+in	O
+therapeutic	O
+dosages	O
+.	O
+
+The	O
+potential	O
+for	O
+acetaminophen	O
+to	O
+produce	O
+cardiovascular	B
+toxicities	I
+is	O
+very	O
+low	O
+.	O
+
+However	O
+,	O
+acetaminophen	O
+has	O
+been	O
+demonstrated	O
+to	O
+produce	O
+symptoms	O
+of	O
+anaphylaxis	B
+,	O
+including	O
+hypotension	B
+,	O
+in	O
+sensitive	O
+individuals	O
+.	O
+
+This	O
+article	O
+describes	O
+two	O
+critically	B
+ill	I
+patients	O
+in	O
+whom	O
+transient	O
+episodes	O
+of	O
+hypotension	B
+reproducibly	O
+developed	O
+after	O
+administration	O
+of	O
+acetaminophen	O
+.	O
+
+Other	O
+symptoms	O
+of	O
+allergic	B
+reactions	I
+were	O
+not	O
+clinically	O
+detectable	O
+.	O
+
+The	O
+hypotensive	B
+episodes	O
+were	O
+severe	O
+enough	O
+to	O
+require	O
+vasopressor	O
+administration	O
+.	O
+
+The	O
+reports	O
+illustrate	O
+the	O
+need	O
+for	O
+clinicians	O
+to	O
+consider	O
+acetaminophen	O
+in	O
+patients	O
+with	O
+hypotension	B
+of	O
+unknown	O
+origin	O
+.	O
+
+Reduction	O
+of	O
+heparan	O
+sulphate	O
+-	O
+associated	O
+anionic	O
+sites	O
+in	O
+the	O
+glomerular	O
+basement	O
+membrane	O
+of	O
+rats	O
+with	O
+streptozotocin	O
+-	O
+induced	O
+diabetic	B
+nephropathy	I
+.	O
+
+Heparan	O
+sulphate	O
+-	O
+associated	O
+anionic	O
+sites	O
+in	O
+the	O
+glomerular	O
+basement	O
+membrane	O
+were	O
+studied	O
+in	O
+rats	O
+8	O
+months	O
+after	O
+induction	O
+of	O
+diabetes	B
+by	O
+streptozotocin	O
+and	O
+in	O
+age	O
+-	O
+adn	O
+sex	O
+-	O
+matched	O
+control	O
+rats	O
+,	O
+employing	O
+the	O
+cationic	O
+dye	O
+cuprolinic	O
+blue	O
+.	O
+
+Morphometric	O
+analysis	O
+at	O
+the	O
+ultrastructural	O
+level	O
+was	O
+performed	O
+using	O
+a	O
+computerized	O
+image	O
+processor	O
+.	O
+
+The	O
+heparan	O
+sulphate	O
+specificity	O
+of	O
+the	O
+cuprolinic	O
+blue	O
+staining	O
+was	O
+demonstrated	O
+by	O
+glycosaminoglycan	O
+-	O
+degrading	O
+enzymes	O
+,	O
+showing	O
+that	O
+pretreatment	O
+of	O
+the	O
+sections	O
+with	O
+heparitinase	O
+abolished	O
+all	O
+staining	O
+,	O
+whereas	O
+chondroitinase	O
+ABC	O
+had	O
+no	O
+effect	O
+.	O
+
+The	O
+majority	O
+of	O
+anionic	O
+sites	O
+(	O
+74	O
+%	O
+in	O
+diabetic	B
+and	O
+81	O
+%	O
+in	O
+control	O
+rats	O
+)	O
+were	O
+found	O
+within	O
+the	O
+lamina	O
+rara	O
+externa	O
+of	O
+the	O
+glomerular	O
+basement	O
+membrane	O
+.	O
+
+A	O
+minority	O
+of	O
+anionic	O
+sites	O
+were	O
+scattered	O
+throughout	O
+the	O
+lamina	O
+densa	O
+and	O
+lamina	O
+rara	O
+interna	O
+,	O
+and	O
+were	O
+significantly	O
+smaller	O
+than	O
+those	O
+in	O
+the	O
+lamina	O
+rara	O
+externa	O
+of	O
+the	O
+glomerular	O
+basement	O
+membrane	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+and	O
+p	O
+<	O
+0	O
+.	O
+01	O
+for	O
+diabetic	B
+and	O
+control	O
+rats	O
+,	O
+respectively	O
+)	O
+.	O
+
+Diabetic	B
+rats	O
+progressively	O
+developed	O
+albuminuria	B
+reaching	O
+40	O
+.	O
+3	O
+(	O
+32	O
+.	O
+2	O
+-	O
+62	O
+.	O
+0	O
+)	O
+mg	O
+/	O
+24	O
+h	O
+after	O
+8	O
+months	O
+in	O
+contrast	O
+to	O
+the	O
+control	O
+animals	O
+(	O
+0	O
+.	O
+8	O
+(	O
+0	O
+.	O
+2	O
+-	O
+0	O
+.	O
+9	O
+)	O
+mg	O
+/	O
+24	O
+h	O
+,	O
+p	O
+<	O
+0	O
+.	O
+002	O
+)	O
+.	O
+
+At	O
+the	O
+same	O
+time	O
+,	O
+the	O
+number	O
+of	O
+heparan	O
+sulphate	O
+anionic	O
+sites	O
+and	O
+the	O
+total	O
+anionic	O
+site	O
+surface	O
+(	O
+number	O
+of	O
+anionic	O
+sites	O
+x	O
+mean	O
+anionic	O
+site	O
+surface	O
+)	O
+in	O
+the	O
+lamina	O
+rara	O
+externa	O
+of	O
+the	O
+glomerular	O
+basement	O
+membrane	O
+was	O
+reduced	O
+by	O
+19	O
+%	O
+(	O
+p	O
+<	O
+0	O
+.	O
+021	O
+)	O
+and	O
+by	O
+26	O
+%	O
+(	O
+p	O
+<	O
+0	O
+.	O
+02	O
+)	O
+,	O
+respectively	O
+.	O
+
+Number	O
+and	O
+total	O
+anionic	O
+site	O
+surface	O
+in	O
+the	O
+remaining	O
+part	O
+of	O
+the	O
+glomerular	O
+basement	O
+membrane	O
+(	O
+lamina	O
+densa	O
+and	O
+lamina	O
+rara	O
+interna	O
+)	O
+were	O
+not	O
+significantly	O
+changed	O
+.	O
+
+We	O
+conclude	O
+that	O
+in	O
+streptozotocin	O
+-	O
+diabetic	B
+rats	O
+with	O
+an	O
+increased	O
+urinary	O
+albumin	O
+excretion	O
+,	O
+a	O
+reduced	O
+heparan	O
+sulphate	O
+charge	O
+barrier	O
+/	O
+density	O
+is	O
+found	O
+at	O
+the	O
+lamina	O
+rara	O
+externa	O
+of	O
+the	O
+glomerular	O
+basement	O
+membrane	O
+.	O
+
+Mediation	O
+of	O
+enhanced	O
+reflex	O
+vagal	O
+bradycardia	B
+by	O
+L	O
+-	O
+dopa	O
+via	O
+central	O
+dopamine	O
+formation	O
+in	O
+dogs	O
+.	O
+
+L	O
+-	O
+Dopa	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+decreased	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+after	O
+extracerebral	O
+decarboxylase	O
+inhibition	O
+with	O
+MK	O
+-	O
+486	O
+(	O
+25	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+in	O
+anesthetize	O
+MAO	O
+-	O
+inhibited	O
+dogs	O
+.	O
+
+In	O
+addition	O
+,	O
+reflex	O
+bradycardia	B
+caused	O
+by	O
+injected	O
+norepinephrine	O
+was	O
+significantly	O
+enhanced	O
+by	O
+L	O
+-	O
+dopa	O
+,	O
+DL	O
+-	O
+Threo	O
+-	O
+dihydroxyphenylserine	O
+had	O
+no	O
+effect	O
+on	O
+blood	O
+pressure	O
+,	O
+heart	O
+rate	O
+or	O
+reflex	O
+responses	O
+to	O
+norepinephrine	O
+.	O
+
+FLA	O
+-	O
+63	O
+,	O
+a	O
+dopamine	O
+-	O
+beta	O
+-	O
+oxidase	O
+inhibitor	O
+,	O
+did	O
+not	O
+have	O
+any	O
+effect	O
+on	O
+the	O
+hypotension	B
+,	O
+bradycardia	B
+or	O
+reflex	O
+-	O
+enhancing	O
+effect	O
+of	O
+L	O
+-	O
+dopa	O
+.	O
+
+Pimozide	O
+did	O
+not	O
+affect	O
+the	O
+actions	O
+of	O
+L	O
+-	O
+dopa	O
+on	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+but	O
+completely	O
+blocked	O
+the	O
+enhancement	O
+of	O
+reflexes	O
+.	O
+
+Removal	O
+of	O
+the	O
+carotid	O
+sinuses	O
+caused	O
+an	O
+elevation	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+and	O
+abolished	O
+the	O
+negative	O
+chronotropic	O
+effect	O
+of	O
+norepinephrine	O
+.	O
+
+However	O
+,	O
+L	O
+-	O
+dopa	O
+restored	O
+the	O
+bradycardia	B
+caused	O
+by	O
+norepinephrine	O
+in	O
+addition	O
+to	O
+decreasing	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+.	O
+
+5	O
+-	O
+HTP	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+decreased	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+and	O
+decreased	O
+the	O
+reflex	O
+bradycardia	B
+to	O
+norepinephrine	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+L	O
+-	O
+dopa	O
+enhances	O
+reflex	O
+bradycardia	B
+through	O
+central	O
+alpha	O
+-	O
+receptor	O
+stimulation	O
+.	O
+
+Furthermore	O
+,	O
+the	O
+effects	O
+are	O
+mediated	O
+through	O
+dopamine	O
+rather	O
+than	O
+norepinephrine	O
+and	O
+do	O
+not	O
+require	O
+the	O
+carotid	O
+sinus	O
+baroreceptors	O
+.	O
+
+Microangiopathic	B
+hemolytic	I
+anemia	I
+complicating	O
+FK506	O
+(	O
+tacrolimus	O
+)	O
+therapy	O
+.	O
+
+We	O
+describe	O
+3	O
+episodes	O
+of	O
+microangiopathic	B
+hemolytic	I
+anemia	I
+(	O
+MAHA	B
+)	O
+in	O
+2	O
+solid	O
+organ	O
+recipients	O
+under	O
+FK506	O
+(	O
+tacrolimus	O
+)	O
+therapy	O
+.	O
+
+In	O
+both	O
+cases	O
+,	O
+discontinuation	O
+of	O
+FK506	O
+and	O
+treatment	O
+with	O
+plasma	O
+exchange	O
+,	O
+fresh	O
+frozen	O
+plasma	O
+replacement	O
+,	O
+corticosteroids	O
+,	O
+aspirin	O
+,	O
+and	O
+dipyridamole	O
+led	O
+to	O
+resolution	O
+of	O
+MAHA	B
+.	O
+
+In	O
+one	O
+patient	O
+,	O
+reintroduction	O
+of	O
+FK506	O
+led	O
+to	O
+rapid	O
+recurrence	O
+of	O
+MAHA	B
+.	O
+
+FK506	O
+-	O
+associated	O
+MAHA	B
+is	O
+probably	O
+rare	O
+but	O
+physicians	O
+must	O
+be	O
+aware	O
+of	O
+this	O
+severe	O
+complication	O
+.	O
+
+In	O
+our	O
+experience	O
+and	O
+according	O
+to	O
+the	O
+literature	O
+,	O
+FK506	O
+does	O
+not	O
+seem	O
+to	O
+cross	O
+-	O
+react	O
+with	O
+cyclosporin	O
+A	O
+(	O
+CyA	O
+)	O
+,	O
+an	O
+immuno	O
+-	O
+suppressive	O
+drug	O
+already	O
+known	O
+to	O
+induce	O
+MAHA	B
+.	O
+
+Effect	O
+of	O
+some	O
+anticancer	O
+drugs	O
+and	O
+combined	O
+chemotherapy	O
+on	O
+renal	B
+toxicity	I
+.	O
+
+The	O
+nephrotoxic	B
+action	O
+of	O
+anticancer	O
+drugs	O
+such	O
+as	O
+nitrogranulogen	O
+(	O
+NG	O
+)	O
+,	O
+methotrexate	O
+(	O
+MTX	O
+)	O
+,	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+and	O
+cyclophosphamide	O
+(	O
+CY	O
+)	O
+administered	O
+alone	O
+or	O
+in	O
+combination	O
+[	O
+MTX	O
++	O
+5	O
+-	O
+FU	O
++	O
+CY	O
+(	O
+CMF	O
+)	O
+]	O
+was	O
+evaluated	O
+in	O
+experiments	O
+on	O
+Wistar	O
+rats	O
+.	O
+
+After	O
+drug	O
+administration	O
+,	O
+creatinine	O
+concentrations	O
+in	O
+the	O
+plasma	O
+and	O
+in	O
+the	O
+urine	O
+of	O
+the	O
+rats	O
+were	O
+determined	O
+,	O
+as	O
+well	O
+as	O
+creatinine	O
+clearance	O
+.	O
+
+Histopathologic	O
+evaluation	O
+of	O
+the	O
+kidneys	O
+was	O
+also	O
+performed	O
+.	O
+
+After	O
+MTX	O
+administration	O
+a	O
+significant	O
+increase	O
+(	O
+p	O
+=	O
+0	O
+.	O
+0228	O
+)	O
+in	O
+the	O
+plasma	O
+creatinine	O
+concentration	O
+and	O
+a	O
+significant	O
+(	O
+p	O
+=	O
+0	O
+.	O
+0001	O
+)	O
+decrease	O
+in	O
+creatinine	O
+clearance	O
+was	O
+noted	O
+compared	O
+to	O
+controls	O
+.	O
+
+After	O
+the	O
+administration	O
+of	O
+NG	O
+,	O
+5	O
+-	O
+FU	O
+and	O
+CY	O
+neither	O
+a	O
+statistically	O
+significant	O
+increase	O
+in	O
+creatinine	O
+concentration	O
+nor	O
+an	O
+increase	O
+in	O
+creatinine	O
+clearance	O
+was	O
+observed	O
+compared	O
+to	O
+the	O
+group	O
+receiving	O
+no	O
+cytostatics	O
+.	O
+
+Following	O
+polytherapy	O
+according	O
+to	O
+the	O
+CMF	O
+regimen	O
+,	O
+a	O
+statistically	O
+significant	O
+decrease	O
+(	O
+p	O
+=	O
+0	O
+.	O
+0343	O
+)	O
+in	O
+creatinine	O
+clearance	O
+was	O
+found	O
+,	O
+but	O
+creatinine	O
+concentration	O
+did	O
+not	O
+increase	O
+significantly	O
+compared	O
+to	O
+controls	O
+.	O
+
+CY	O
+caused	O
+hemorrhagic	B
+cystitis	I
+in	O
+40	O
+%	O
+of	O
+rats	O
+,	O
+but	O
+it	O
+did	O
+not	O
+cause	O
+this	O
+complication	O
+when	O
+combined	O
+with	O
+5	O
+-	O
+FU	O
+and	O
+MTX	O
+.	O
+
+Histologic	O
+changes	O
+were	O
+found	O
+in	O
+rat	O
+kidneys	O
+after	O
+administration	O
+of	O
+MTX	O
+,	O
+CY	O
+and	O
+NG	O
+,	O
+while	O
+no	O
+such	O
+change	O
+was	O
+observed	O
+after	O
+5	O
+-	O
+FU	O
+and	O
+joint	O
+administration	O
+of	O
+MTX	O
++	O
+5	O
+-	O
+FU	O
++	O
+CY	O
+compared	O
+to	O
+controls	O
+.	O
+
+Our	O
+studies	O
+indicate	O
+that	O
+nephrotoxicity	B
+of	O
+MTX	O
++	O
+5	O
+-	O
+FU	O
++	O
+CY	O
+administered	O
+jointly	O
+is	O
+lower	O
+than	O
+in	O
+monotherapy	O
+.	O
+
+The	O
+interpeduncular	O
+nucleus	O
+regulates	O
+nicotine	O
+'	O
+s	O
+effects	O
+on	O
+free	O
+-	O
+field	O
+activity	O
+.	O
+
+Partial	O
+lesions	O
+were	O
+made	O
+with	O
+kainic	O
+acid	O
+in	O
+the	O
+interpeduncular	O
+nucleus	O
+of	O
+the	O
+ventral	O
+midbrain	O
+of	O
+the	O
+rat	O
+.	O
+
+Compared	O
+with	O
+sham	O
+-	O
+operated	O
+controls	O
+,	O
+lesions	O
+significantly	O
+(	O
+p	O
+<	O
+0	O
+.	O
+25	O
+)	O
+blunted	O
+the	O
+early	O
+(	O
+<	O
+60	O
+min	O
+)	O
+free	O
+-	O
+field	O
+locomotor	B
+hypoactivity	I
+caused	O
+by	O
+nicotine	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+,	O
+i	O
+.	O
+m	O
+.	O
+)	O
+,	O
+enhanced	O
+the	O
+later	O
+(	O
+60	O
+-	O
+120	O
+min	O
+)	O
+nicotine	O
+-	O
+induced	O
+hyperactivity	B
+,	O
+and	O
+raised	O
+spontaneous	O
+nocturnal	O
+activity	O
+.	O
+
+Lesions	O
+reduced	O
+the	O
+extent	O
+of	O
+immunohistological	O
+staining	O
+for	O
+choline	O
+acetyltransferase	O
+in	O
+the	O
+interpeduncular	O
+nucleus	O
+(	O
+p	O
+<	O
+0	O
+.	O
+025	O
+)	O
+,	O
+but	O
+not	O
+for	O
+tyrosine	O
+hydroxylase	O
+in	O
+the	O
+surrounding	O
+catecholaminergic	O
+A10	O
+region	O
+.	O
+
+We	O
+conclude	O
+that	O
+the	O
+interpeduncular	O
+nucleus	O
+mediates	O
+nicotinic	O
+depression	B
+of	O
+locomotor	O
+activity	O
+and	O
+dampens	O
+nicotinic	O
+arousal	O
+mechanisms	O
+located	O
+elsewhere	O
+in	O
+the	O
+brain	O
+.	O
+
+Lithium	O
+-	O
+associated	O
+cognitive	B
+and	I
+functional	I
+deficits	I
+reduced	O
+by	O
+a	O
+switch	O
+to	O
+divalproex	O
+sodium	O
+:	O
+a	O
+case	O
+series	O
+.	O
+
+BACKGROUND	O
+:	O
+Lithium	O
+remains	O
+a	O
+first	O
+-	O
+line	O
+treatment	O
+for	O
+the	O
+acute	O
+and	O
+maintenance	O
+treatment	O
+of	O
+bipolar	B
+disorder	I
+.	O
+
+Although	O
+much	O
+has	O
+been	O
+written	O
+about	O
+the	O
+management	O
+of	O
+the	O
+more	O
+common	O
+adverse	O
+effects	O
+of	O
+lithium	O
+,	O
+such	O
+as	O
+polyuria	B
+and	O
+tremor	B
+,	O
+more	O
+subtle	O
+lithium	O
+side	O
+effects	O
+such	O
+as	O
+cognitive	B
+deficits	I
+,	O
+loss	B
+of	I
+creativity	I
+,	O
+and	O
+functional	B
+impairments	I
+remain	O
+understudied	O
+.	O
+
+This	O
+report	O
+summarizes	O
+our	O
+experience	O
+in	O
+switching	O
+bipolar	B
+patients	O
+from	O
+lithium	O
+to	O
+divalproex	O
+sodium	O
+to	O
+alleviate	O
+such	O
+cognitive	B
+and	I
+functional	I
+impairments	I
+.	O
+
+METHOD	O
+:	O
+Open	O
+,	O
+case	O
+series	O
+design	O
+.	O
+
+RESULTS	O
+:	O
+We	O
+report	O
+seven	O
+cases	O
+where	O
+substitution	O
+of	O
+lithium	O
+,	O
+either	O
+fully	O
+or	O
+partially	O
+,	O
+with	O
+divalproex	O
+sodium	O
+was	O
+extremely	O
+helpful	O
+in	O
+reducing	O
+the	O
+cognitive	B
+,	I
+motivational	I
+,	I
+or	I
+creative	I
+deficits	I
+attributed	O
+to	O
+lithium	O
+in	O
+our	O
+bipolar	B
+patients	O
+.	O
+
+CONCLUSION	O
+:	O
+In	O
+this	O
+preliminary	O
+report	O
+,	O
+divalproex	O
+sodium	O
+was	O
+a	O
+superior	O
+alternative	O
+to	O
+lithium	O
+in	O
+bipolar	B
+patients	O
+experiencing	O
+cognitive	B
+deficits	I
+,	O
+loss	B
+of	I
+creativity	I
+,	O
+and	O
+functional	B
+impairments	I
+.	O
+
+Effect	O
+of	O
+nifedipine	O
+on	O
+renal	O
+function	O
+in	O
+liver	O
+transplant	O
+recipients	O
+receiving	O
+tacrolimus	O
+.	O
+
+The	O
+effect	O
+of	O
+nifedipine	O
+on	O
+renal	O
+function	O
+in	O
+liver	O
+transplant	O
+recipients	O
+who	O
+were	O
+receiving	O
+tacrolimus	O
+was	O
+evaluated	O
+between	O
+January	O
+1992	O
+and	O
+January	O
+1996	O
+.	O
+
+Two	O
+groups	O
+of	O
+patients	O
+receiving	O
+tacrolimus	O
+were	O
+compared	O
+over	O
+a	O
+period	O
+of	O
+1	O
+year	O
+,	O
+one	O
+group	O
+comprising	O
+hypertensive	B
+patients	O
+who	O
+were	O
+receiving	O
+nifedipine	O
+,	O
+and	O
+the	O
+other	O
+comprising	O
+nonhypertensive	O
+patients	O
+not	O
+receiving	O
+nifedipine	O
+.	O
+
+The	O
+time	O
+from	O
+transplant	O
+to	O
+baseline	O
+was	O
+similar	O
+in	O
+all	O
+patients	O
+.	O
+
+Nifedipine	O
+significantly	O
+improved	O
+kidney	O
+function	O
+as	O
+indicated	O
+by	O
+a	O
+significant	O
+lowering	O
+of	O
+serum	O
+creatinine	O
+levels	O
+at	O
+6	O
+and	O
+12	O
+months	O
+.	O
+
+The	O
+observed	O
+positive	O
+impact	O
+of	O
+nifedipine	O
+on	O
+reducing	O
+the	O
+nephrotoxicity	B
+associated	O
+with	O
+tacrolimus	O
+in	O
+liver	O
+transplant	O
+recipients	O
+should	O
+be	O
+an	O
+important	O
+factor	O
+in	O
+selecting	O
+an	O
+agent	O
+to	O
+treat	O
+hypertension	B
+in	O
+this	O
+population	O
+.	O
+
+Alpha	O
+and	O
+beta	O
+coma	B
+in	O
+drug	O
+intoxication	O
+uncomplicated	O
+by	O
+cerebral	B
+hypoxia	I
+.	O
+
+Four	O
+patients	O
+who	O
+were	O
+rendered	O
+comatose	B
+or	O
+stuporous	B
+by	O
+drug	O
+intoxication	O
+,	O
+but	O
+who	O
+were	O
+not	O
+hypoxic	O
+,	O
+are	O
+described	O
+.	O
+
+Three	O
+patients	O
+received	O
+high	O
+doses	O
+of	O
+chlormethiazole	O
+for	O
+alcohol	O
+withdrawal	B
+symptoms	I
+,	O
+and	O
+one	O
+took	O
+a	O
+suicidal	O
+overdose	B
+of	O
+nitrazepam	O
+.	O
+
+The	O
+patient	O
+with	O
+nitrazepam	O
+overdose	B
+and	O
+two	O
+of	O
+those	O
+with	O
+chlormethiazole	O
+intoxication	O
+conformed	O
+to	O
+the	O
+criteria	O
+of	O
+'	O
+alpha	O
+coma	B
+'	O
+,	O
+showing	O
+non	O
+-	O
+reactive	O
+generalized	O
+or	O
+frontally	O
+predominant	O
+alpha	O
+activity	O
+in	O
+the	O
+EEG	O
+.	O
+
+The	O
+fourth	O
+patient	O
+who	O
+was	O
+unconscious	O
+after	O
+chlormethiazole	O
+administration	O
+exhibite	O
+generalized	O
+non	O
+-	O
+reactive	O
+activity	O
+in	O
+the	O
+slow	O
+beta	O
+range	O
+.	O
+
+All	O
+four	O
+recovered	O
+completely	O
+without	O
+neurological	B
+sequelae	I
+following	O
+the	O
+withdrawal	O
+of	O
+the	O
+offending	O
+agents	O
+.	O
+
+The	O
+similarities	O
+between	O
+the	O
+effects	O
+of	O
+structural	O
+lesions	O
+and	O
+pharmacological	O
+depression	B
+of	O
+the	O
+brain	O
+stem	O
+reticular	O
+formation	O
+are	O
+discussed	O
+.	O
+
+It	O
+is	O
+suggested	O
+that	O
+in	O
+both	O
+situations	O
+disturbed	O
+reticulo	O
+-	O
+thalamic	O
+interactions	O
+are	O
+important	O
+in	O
+the	O
+pathogenesis	O
+of	O
+alpha	O
+coma	B
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+when	O
+this	O
+electroencephalographic	O
+and	O
+behavioural	O
+picture	O
+is	O
+seen	O
+in	O
+drug	O
+intoxication	O
+,	O
+in	O
+the	O
+absence	O
+of	O
+significant	O
+hypoxaemia	B
+,	O
+a	O
+favourable	O
+outcome	O
+may	O
+be	O
+anticipated	O
+.	O
+
+Magnetic	O
+resonance	O
+volumetry	O
+of	O
+the	O
+cerebellum	O
+in	O
+epileptic	B
+patients	O
+after	O
+phenytoin	O
+overdosages	B
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+evaluate	O
+the	O
+relationship	O
+between	O
+phenytoin	O
+medication	O
+and	O
+cerebellar	B
+atrophy	I
+in	O
+patients	O
+who	O
+had	O
+experienced	O
+clinical	O
+intoxication	O
+.	O
+
+Five	O
+females	O
+and	O
+6	O
+males	O
+,	O
+21	O
+-	O
+59	O
+years	O
+of	O
+age	O
+,	O
+were	O
+examined	O
+with	O
+a	O
+1	O
+.	O
+5	O
+-	O
+T	O
+whole	O
+-	O
+body	O
+system	O
+using	O
+a	O
+circular	O
+polarized	O
+head	O
+coil	O
+.	O
+
+Conventional	O
+spin	O
+echo	O
+images	O
+were	O
+acquired	O
+in	O
+the	O
+sagittal	O
+and	O
+transverse	O
+orientation	O
+.	O
+
+In	O
+addition	O
+,	O
+we	O
+performed	O
+a	O
+high	O
+-	O
+resolution	O
+3D	O
+gradient	O
+echo	O
+,	O
+T1	O
+-	O
+weighted	O
+sequences	O
+at	O
+a	O
+1	O
+-	O
+mm	O
+slice	O
+thickness	O
+.	O
+
+The	O
+images	O
+were	O
+subsequently	O
+processed	O
+to	O
+obtain	O
+volumetric	O
+data	O
+for	O
+the	O
+cerebellum	O
+.	O
+
+Cerebellar	O
+volume	O
+for	O
+the	O
+patient	O
+group	O
+ranged	O
+between	O
+67	O
+.	O
+66	O
+and	O
+131	O
+.	O
+08	O
+ml	O
+(	O
+mean	O
+108	O
+.	O
+9	O
+ml	O
+)	O
+.	O
+
+In	O
+addition	O
+3D	O
+gradient	O
+echo	O
+data	O
+sets	O
+from	O
+10	O
+healthy	O
+male	O
+and	O
+10	O
+healthy	O
+female	O
+age	O
+-	O
+matched	O
+volunteers	O
+were	O
+used	O
+to	O
+compare	O
+cerebellar	O
+volumes	O
+.	O
+
+Using	O
+linear	O
+regression	O
+we	O
+found	O
+that	O
+no	O
+correlation	O
+exists	O
+between	O
+seizure	B
+duration	O
+,	O
+elevation	O
+of	O
+phenytoin	O
+serum	O
+levels	O
+and	O
+cerebellar	O
+volume	O
+.	O
+
+However	O
+,	O
+multiple	O
+regression	O
+for	O
+the	O
+daily	O
+dosage	O
+,	O
+duration	O
+of	O
+phenytoin	O
+treatment	O
+and	O
+cerebellar	O
+volume	O
+revealed	O
+a	O
+correlation	O
+of	O
+these	O
+parameters	O
+.	O
+
+We	O
+conclude	O
+that	O
+phenytoin	O
+overdosage	B
+does	O
+not	O
+necessarily	O
+result	O
+in	O
+cerebellar	B
+atrophy	I
+and	O
+it	O
+is	O
+unlikely	O
+that	O
+phenytoin	O
+medication	O
+was	O
+the	O
+only	O
+cause	O
+of	O
+cerebellar	B
+atrophy	I
+in	O
+the	O
+remaining	O
+patients	O
+.	O
+
+Quantitative	O
+morphometric	O
+studies	O
+of	O
+the	O
+cerebellum	O
+provide	O
+valuable	O
+insights	O
+into	O
+the	O
+pathogenesis	O
+of	O
+cerebellar	B
+disorders	I
+.	O
+
+Late	O
+recovery	O
+of	O
+renal	O
+function	O
+in	O
+a	O
+woman	O
+with	O
+the	O
+hemolytic	B
+uremic	I
+syndrome	I
+.	O
+
+A	O
+case	O
+is	O
+reported	O
+of	O
+the	O
+hemolytic	B
+uremic	I
+syndrome	I
+(	O
+HUS	B
+)	O
+in	O
+a	O
+woman	O
+taking	O
+oral	O
+contraceptives	O
+.	O
+
+She	O
+was	O
+treated	O
+with	O
+heparin	O
+,	O
+dipyridamole	O
+and	O
+hemodialysis	O
+;	O
+and	O
+after	O
+more	O
+than	O
+three	O
+months	O
+,	O
+her	O
+urinary	O
+output	O
+rose	O
+above	O
+500	O
+ml	O
+;	O
+and	O
+six	O
+months	O
+after	O
+the	O
+onset	O
+of	O
+anuria	B
+,	O
+dialysis	O
+treatment	O
+was	O
+stopped	O
+.	O
+
+This	O
+case	O
+emphasizes	O
+the	O
+possibility	O
+that	O
+HUS	B
+in	O
+adults	O
+is	O
+not	O
+invariably	O
+irreversible	O
+and	O
+that	O
+,	O
+despite	O
+prolonged	O
+oliguria	B
+,	O
+recovery	O
+of	O
+renal	O
+function	O
+can	O
+be	O
+obtained	O
+.	O
+
+Therefore	O
+,	O
+in	O
+adult	O
+patients	O
+affected	O
+by	O
+HUS	B
+,	O
+dialysis	O
+should	O
+not	O
+be	O
+discontinued	O
+prematurely	O
+;	O
+moreover	O
+,	O
+bilateral	O
+nephrectomy	O
+,	O
+for	O
+treatment	O
+of	O
+severe	O
+hypertension	B
+and	O
+microangiopathic	B
+hemolytic	I
+anemia	I
+,	O
+should	O
+be	O
+performed	O
+with	O
+caution	O
+.	O
+
+Morphological	O
+features	O
+of	O
+encephalopathy	B
+after	O
+chronic	O
+administration	O
+of	O
+the	O
+antiepileptic	O
+drug	O
+valproate	O
+to	O
+rats	O
+.	O
+
+A	O
+transmission	O
+electron	O
+microscopic	O
+study	O
+of	O
+capillaries	O
+in	O
+the	O
+cerebellar	O
+cortex	O
+.	O
+
+Long	O
+-	O
+term	O
+intragastric	O
+application	O
+of	O
+the	O
+antiepileptic	O
+drug	O
+sodium	O
+valproate	O
+(	O
+Vupral	O
+"	O
+Polfa	O
+"	O
+)	O
+at	O
+the	O
+effective	O
+dose	O
+of	O
+200	O
+mg	O
+/	O
+kg	O
+b	O
+.	O
+
+w	O
+.	O
+once	O
+daily	O
+to	O
+rats	O
+for	O
+1	O
+,	O
+3	O
+,	O
+6	O
+,	O
+9	O
+and	O
+12	O
+months	O
+revealed	O
+neurological	B
+disorders	I
+indicating	O
+cerebellum	B
+damage	I
+(	O
+"	O
+valproate	O
+encephalopathy	B
+"	O
+)	O
+.	O
+
+The	O
+first	O
+ultrastructural	O
+changes	O
+in	O
+structural	O
+elements	O
+of	O
+the	O
+blood	O
+-	O
+brain	O
+-	O
+barrier	O
+(	O
+BBB	O
+)	O
+in	O
+the	O
+cerebellar	O
+cortex	O
+were	O
+detectable	O
+after	O
+3	O
+months	O
+of	O
+the	O
+experiment	O
+.	O
+
+They	O
+became	O
+more	O
+severe	O
+in	O
+the	O
+later	O
+months	O
+of	O
+the	O
+experiment	O
+,	O
+and	O
+were	O
+most	O
+severe	O
+after	O
+12	O
+months	O
+,	O
+located	O
+mainly	O
+in	O
+the	O
+molecular	O
+layer	O
+of	O
+the	O
+cerebellar	O
+cortex	O
+.	O
+
+Lesions	O
+of	O
+the	O
+capillary	O
+included	O
+necrosis	B
+of	O
+endothelial	O
+cells	O
+.	O
+
+Organelles	O
+of	O
+these	O
+cells	O
+,	O
+in	O
+particular	O
+the	O
+mitochondria	O
+(	O
+increased	O
+number	O
+and	O
+size	O
+,	O
+distinct	O
+degeneration	O
+of	O
+their	O
+matrix	O
+and	O
+cristae	O
+)	O
+and	O
+Golgi	O
+apparatus	O
+were	O
+altered	O
+.	O
+
+Reduced	O
+size	O
+of	O
+capillary	O
+lumen	O
+and	O
+occlusion	O
+were	O
+caused	O
+by	O
+swollen	O
+endothelial	O
+cells	O
+which	O
+had	O
+luminal	O
+protrusions	O
+and	O
+swollen	O
+microvilli	O
+.	O
+
+Pressure	O
+on	O
+the	O
+vessel	O
+wall	O
+was	O
+produced	O
+by	O
+enlarged	O
+perivascular	O
+astrocytic	O
+processes	O
+.	O
+
+Fragments	O
+of	O
+necrotic	B
+endothelial	O
+cells	O
+were	O
+in	O
+the	O
+vascular	O
+lumens	O
+and	O
+in	O
+these	O
+there	O
+was	O
+loosening	O
+and	O
+breaking	O
+of	O
+tight	O
+cellular	O
+junctions	O
+.	O
+
+Damage	O
+to	O
+the	O
+vascular	O
+basement	O
+lamina	O
+was	O
+also	O
+observed	O
+.	O
+
+Damage	O
+to	O
+the	O
+capillary	O
+was	O
+accompanied	O
+by	O
+marked	O
+damage	O
+to	O
+neuroglial	O
+cells	O
+,	O
+mainly	O
+to	O
+perivascular	O
+processes	O
+of	O
+astrocytes	O
+.	O
+
+The	O
+proliferation	O
+of	O
+astrocytes	O
+(	O
+Bergmann	O
+'	O
+s	O
+in	O
+particular	O
+)	O
+and	O
+occasionally	O
+of	O
+oligodendrocytes	O
+was	O
+found	O
+.	O
+
+Alterations	O
+in	O
+the	O
+structural	O
+elements	O
+of	O
+the	O
+BBB	O
+coexisted	O
+with	O
+marked	O
+lesions	O
+of	O
+neurons	O
+of	O
+the	O
+cerebellum	O
+(	O
+Purkinje	O
+cells	O
+are	O
+earliest	O
+)	O
+.	O
+
+In	O
+electron	O
+micrographs	O
+both	O
+luminal	O
+and	O
+antiluminal	O
+sides	O
+of	O
+the	O
+BBB	O
+of	O
+the	O
+cerebellar	O
+cortex	O
+had	O
+similar	O
+lesions	O
+.	O
+
+The	O
+possible	O
+influence	O
+of	O
+the	O
+hepatic	B
+damage	I
+,	O
+mainly	O
+hyperammonemia	B
+,	O
+upon	O
+the	O
+development	O
+of	O
+valproate	O
+encephalopathy	B
+is	O
+discussed	O
+.	O
+
+Fatal	O
+intracranial	B
+bleeding	I
+associated	O
+with	O
+prehospital	O
+use	O
+of	O
+epinephrine	O
+.	O
+
+We	O
+present	O
+a	O
+case	O
+of	O
+paramedic	O
+misjudgment	O
+in	O
+the	O
+execution	O
+of	O
+a	O
+protocol	O
+for	O
+the	O
+treatment	O
+of	O
+allergic	B
+reaction	I
+in	O
+a	O
+case	O
+of	O
+pulmonary	B
+edema	I
+with	O
+wheezing	B
+.	O
+
+The	O
+sudden	O
+onset	O
+of	O
+respiratory	B
+distress	I
+,	O
+rash	B
+,	O
+and	O
+a	O
+history	O
+of	O
+a	O
+new	O
+medicine	O
+led	O
+the	O
+two	O
+paramedics	O
+on	O
+the	O
+scene	O
+to	O
+administer	O
+subcutaneous	O
+epinephrine	O
+.	O
+
+Subsequently	O
+,	O
+acute	O
+cardiac	B
+arrest	I
+and	O
+fatal	O
+subarachnoid	B
+hemorrhage	I
+occurred	O
+.	O
+
+Epinephrine	O
+has	O
+a	O
+proven	O
+role	O
+in	O
+cardiac	B
+arrest	I
+in	O
+prehospital	O
+care	O
+;	O
+however	O
+,	O
+use	O
+by	O
+paramedics	O
+in	O
+patients	O
+with	O
+suspected	O
+allergic	B
+reaction	I
+and	O
+severe	O
+hypertension	B
+should	O
+be	O
+viewed	O
+with	O
+caution	O
+.	O
+
+Role	O
+of	O
+activation	O
+of	O
+bradykinin	O
+B2	O
+receptors	O
+in	O
+disruption	O
+of	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+during	O
+acute	O
+hypertension	B
+.	O
+
+Cellular	O
+mechanisms	O
+which	O
+account	O
+for	O
+disruption	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+during	O
+acute	O
+hypertension	B
+are	O
+not	O
+clear	O
+.	O
+
+The	O
+goal	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+role	O
+of	O
+synthesis	O
+/	O
+release	O
+of	O
+bradykinin	O
+to	O
+activate	O
+B2	O
+receptors	O
+in	O
+disruption	O
+of	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+during	O
+acute	O
+hypertension	B
+.	O
+
+Permeability	O
+of	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+was	O
+quantitated	O
+by	O
+clearance	O
+of	O
+fluorescent	O
+-	O
+labeled	O
+dextran	O
+before	O
+and	O
+during	O
+phenylephrine	O
+-	O
+induced	O
+acute	O
+hypertension	B
+in	O
+rats	O
+treated	O
+with	O
+vehicle	O
+and	O
+Hoe	O
+-	O
+140	O
+(	O
+0	O
+.	O
+1	O
+microM	O
+)	O
+.	O
+
+Phenylephrine	O
+infusion	O
+increased	O
+arterial	O
+pressure	O
+,	O
+arteriolar	O
+diameter	O
+and	O
+clearance	O
+of	O
+fluorescent	O
+dextran	O
+by	O
+a	O
+similar	O
+magnitude	O
+in	O
+both	O
+groups	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+disruption	O
+of	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+during	O
+acute	O
+hypertension	B
+is	O
+not	O
+related	O
+to	O
+the	O
+synthesis	O
+/	O
+release	O
+of	O
+bradykinin	O
+to	O
+activate	O
+B2	O
+receptors	O
+.	O
+
+Risk	O
+factors	O
+of	O
+sensorineural	B
+hearing	I
+loss	I
+in	O
+preterm	O
+infants	O
+.	O
+
+Among	O
+547	O
+preterm	O
+infants	O
+of	O
+<	O
+or	O
+=	O
+34	O
+weeks	O
+gestation	O
+born	O
+between	O
+1987	O
+and	O
+1991	O
+,	O
+8	O
+children	O
+(	O
+1	O
+.	O
+46	O
+%	O
+)	O
+developed	O
+severe	O
+progressive	O
+and	O
+bilateral	O
+sensorineural	B
+hearing	I
+loss	I
+.	O
+
+Perinatal	O
+risk	O
+factors	O
+of	O
+infants	O
+with	O
+hearing	B
+loss	I
+were	O
+compared	O
+with	O
+those	O
+of	O
+two	O
+control	O
+groups	O
+matched	O
+for	O
+gestation	O
+and	O
+birth	O
+weight	O
+and	O
+for	O
+perinatal	O
+complications	O
+.	O
+
+Our	O
+observations	O
+demonstrated	O
+an	O
+association	O
+of	O
+hearing	B
+loss	I
+with	O
+a	O
+higher	O
+incidence	O
+of	O
+perinatal	O
+complications	O
+.	O
+
+Ototoxicity	B
+appeared	O
+closely	O
+related	O
+to	O
+a	O
+prolonged	O
+administration	O
+and	O
+higher	O
+total	O
+dose	O
+of	O
+ototoxic	B
+drugs	O
+,	O
+particularly	O
+aminoglycosides	O
+and	O
+furosemide	O
+.	O
+
+Finally	O
+,	O
+we	O
+strongly	O
+recommend	O
+to	O
+prospectively	O
+and	O
+regularly	O
+perform	O
+audiologic	O
+assessment	O
+in	O
+sick	O
+preterm	O
+children	O
+as	O
+hearing	B
+loss	I
+is	O
+of	O
+delayed	O
+onset	O
+and	O
+in	O
+most	O
+cases	O
+bilateral	O
+and	O
+severe	O
+.	O
+
+Seizure	B
+resulting	O
+from	O
+a	O
+venlafaxine	O
+overdose	B
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+venlafaxine	O
+overdose	B
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+40	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+major	B
+depression	I
+took	O
+an	O
+overdose	B
+of	O
+venlafaxine	O
+in	O
+an	O
+apparent	O
+suicide	O
+attempt	O
+.	O
+
+After	O
+the	O
+ingestion	O
+of	O
+26	O
+venlafaxine	O
+50	O
+-	O
+mg	O
+tablets	O
+,	O
+the	O
+patient	O
+experienced	O
+a	O
+witnessed	O
+generalized	O
+seizure	B
+.	O
+
+She	O
+was	O
+admitted	O
+to	O
+the	O
+medical	O
+intensive	O
+care	O
+unit	O
+,	O
+venlafaxine	O
+was	O
+discontinued	O
+,	O
+and	O
+no	O
+further	O
+sequelae	O
+were	O
+seen	O
+.	O
+
+DISCUSSION	O
+:	O
+To	O
+our	O
+knowledge	O
+,	O
+this	O
+is	O
+the	O
+first	O
+reported	O
+case	O
+of	O
+venlafaxine	O
+overdose	B
+that	O
+resulted	O
+in	O
+a	O
+generalized	O
+seizure	B
+.	O
+
+Based	O
+on	O
+nonoverdose	O
+pharmacokinetics	O
+and	O
+pharmacodynamics	O
+of	O
+venlafaxine	O
+and	O
+the	O
+potential	O
+risks	O
+of	O
+available	O
+interventions	O
+,	O
+no	O
+emergent	O
+therapy	O
+was	O
+instituted	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+venlafaxine	O
+overdose	B
+in	O
+our	O
+patient	O
+resulted	O
+in	O
+a	O
+single	O
+episode	O
+of	O
+generalized	O
+seizure	B
+but	O
+elicited	O
+no	O
+further	O
+sequelae	O
+.	O
+
+Combined	O
+effects	O
+of	O
+prolonged	O
+prostaglandin	O
+E1	O
+-	O
+induced	O
+hypotension	B
+and	O
+haemodilution	B
+on	O
+human	O
+hepatic	O
+function	O
+.	O
+
+Combined	O
+effects	O
+of	O
+prolonged	O
+prostaglandin	O
+E1	O
+(	O
+PGE1	O
+)	O
+-	O
+induced	O
+hypotension	B
+and	O
+haemodilution	B
+on	O
+hepatic	O
+function	O
+were	O
+studied	O
+in	O
+30	O
+patients	O
+undergoing	O
+hip	O
+surgery	O
+.	O
+
+The	O
+patients	O
+were	O
+randomly	O
+allocated	O
+to	O
+one	O
+of	O
+three	O
+groups	O
+;	O
+those	O
+in	O
+group	O
+A	O
+(	O
+n	O
+=	O
+10	O
+)	O
+were	O
+subjected	O
+to	O
+controlled	O
+hypotension	B
+alone	O
+,	O
+those	O
+in	O
+group	O
+B	O
+(	O
+n	O
+=	O
+10	O
+)	O
+to	O
+haemodilution	B
+alone	O
+and	O
+those	O
+in	O
+group	O
+C	O
+(	O
+n	O
+=	O
+10	O
+)	O
+to	O
+both	O
+controlled	O
+hypotension	B
+and	O
+haemodilution	B
+.	O
+
+Haemodilution	B
+in	O
+groups	O
+B	O
+and	O
+C	O
+was	O
+produced	O
+by	O
+withdrawing	O
+approximately	O
+1000	O
+mL	O
+of	O
+blood	O
+and	O
+replacing	O
+it	O
+with	O
+the	O
+same	O
+amount	O
+of	O
+dextran	O
+solution	O
+,	O
+and	O
+final	O
+haematocrit	O
+values	O
+were	O
+21	O
+or	O
+22	O
+%	O
+.	O
+
+Controlled	O
+hypotension	B
+in	O
+groups	O
+A	O
+and	O
+C	O
+was	O
+induced	O
+with	O
+PGE1	O
+to	O
+maintain	O
+mean	O
+arterial	O
+blood	O
+pressure	O
+at	O
+55	O
+mmHg	O
+for	O
+180	O
+min	O
+.	O
+
+Measurements	O
+included	O
+arterial	O
+ketone	O
+body	O
+ratio	O
+(	O
+AKBR	O
+,	O
+aceto	O
+-	O
+acetate	O
+/	O
+3	O
+-	O
+hydroxybutyrate	O
+)	O
+and	O
+clinical	O
+hepatic	O
+function	O
+parameters	O
+.	O
+
+AKBR	O
+and	O
+biological	O
+hepatic	O
+function	O
+tests	O
+showed	O
+no	O
+change	O
+throughout	O
+the	O
+time	O
+course	O
+in	O
+groups	O
+A	O
+and	O
+B	O
+.	O
+
+In	O
+group	O
+C	O
+,	O
+AKBR	O
+showed	O
+a	O
+significant	O
+decrease	O
+at	O
+120	O
+min	O
+(	O
+-	O
+40	O
+%	O
+)	O
+and	O
+at	O
+180	O
+min	O
+(	O
+-	O
+49	O
+%	O
+)	O
+after	O
+the	O
+start	O
+of	O
+hypotension	B
+and	O
+at	O
+60	O
+min	O
+(	O
+-	O
+32	O
+%	O
+)	O
+after	O
+recovery	O
+of	O
+normotension	O
+,	O
+and	O
+SGOT	O
+,	O
+SGPT	O
+,	O
+LDH	O
+and	O
+total	O
+bilirubin	O
+showed	O
+significant	O
+increases	O
+after	O
+operation	O
+.	O
+
+The	O
+results	O
+suggest	O
+that	O
+a	O
+prolonged	O
+combination	O
+of	O
+more	O
+than	O
+120	O
+min	O
+of	O
+PGE1	O
+-	O
+induced	O
+hypotension	B
+and	O
+moderate	O
+haemodilution	B
+would	O
+cause	O
+impairment	B
+of	I
+hepatic	I
+function	I
+.	O
+
+Cardiovascular	B
+alterations	I
+in	O
+rat	O
+fetuses	O
+exposed	O
+to	O
+calcium	O
+channel	O
+blockers	O
+.	O
+
+Preclinical	O
+toxicologic	O
+investigation	O
+suggested	O
+that	O
+a	O
+new	O
+calcium	O
+channel	O
+blocker	O
+,	O
+Ro	O
+40	O
+-	O
+5967	O
+,	O
+induced	O
+cardiovascular	B
+alterations	I
+in	O
+rat	O
+fetuses	O
+exposed	O
+to	O
+this	O
+agent	O
+during	O
+organogenesis	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+investigate	O
+the	O
+hypothesis	O
+that	O
+calcium	O
+channel	O
+blockers	O
+in	O
+general	O
+induce	O
+cardiovascular	B
+malformations	I
+indicating	O
+a	O
+pharmacologic	O
+class	O
+effect	O
+.	O
+
+We	O
+studied	O
+three	O
+calcium	O
+channel	O
+blockers	O
+of	O
+different	O
+structure	O
+,	O
+nifedipine	O
+,	O
+diltiazem	O
+,	O
+and	O
+verapamil	O
+,	O
+along	O
+with	O
+the	O
+new	O
+agent	O
+.	O
+
+Pregnant	O
+rats	O
+were	O
+administered	O
+one	O
+of	O
+these	O
+calcium	O
+channel	O
+blockers	O
+during	O
+the	O
+period	O
+of	O
+cardiac	O
+morphogenesis	O
+and	O
+the	O
+offspring	O
+examined	O
+on	O
+day	O
+20	O
+of	O
+gestation	O
+for	O
+cardiovascular	B
+malformations	I
+.	O
+
+A	O
+low	O
+incidence	O
+of	O
+cardiovascular	B
+malformations	I
+was	O
+observed	O
+after	O
+exposure	O
+to	O
+each	O
+of	O
+the	O
+four	O
+calcium	O
+channel	O
+blockers	O
+,	O
+but	O
+this	O
+incidence	O
+was	O
+statistically	O
+significant	O
+only	O
+for	O
+verapamil	O
+and	O
+nifedipine	O
+.	O
+
+All	O
+four	O
+agents	O
+were	O
+associated	O
+with	O
+aortic	O
+arch	O
+branching	O
+variants	O
+,	O
+although	O
+significantly	O
+increased	O
+only	O
+for	O
+Ro	O
+40	O
+-	O
+5967	O
+and	O
+verapamil	O
+.	O
+
+The	O
+site	O
+of	O
+common	O
+side	O
+effects	O
+of	O
+sumatriptan	O
+.	O
+
+Atypical	B
+sensations	I
+following	O
+the	O
+use	O
+of	O
+subcutaneous	O
+sumatriptan	O
+are	O
+common	O
+,	O
+but	O
+of	O
+uncertain	O
+origin	O
+.	O
+
+They	O
+are	O
+almost	O
+always	O
+benign	O
+,	O
+but	O
+can	O
+be	O
+mistaken	O
+for	O
+a	O
+serious	O
+adverse	O
+event	O
+by	O
+the	O
+patient	O
+.	O
+
+Two	O
+patients	O
+are	O
+presented	O
+with	O
+tingling	B
+or	I
+burning	I
+sensations	I
+limited	O
+to	O
+areas	O
+of	O
+heat	O
+exposure	O
+or	O
+sunburn	B
+.	O
+
+In	O
+these	O
+individuals	O
+,	O
+side	O
+effects	O
+are	O
+most	O
+likely	O
+generated	O
+superficially	O
+in	O
+the	O
+skin	O
+.	O
+
+Macula	O
+toxicity	B
+after	O
+intravitreal	O
+amikacin	O
+.	O
+
+BACKGROUND	O
+:	O
+Although	O
+intravitreal	O
+aminoglycosides	O
+have	O
+substantially	O
+improved	O
+visual	O
+prognosis	O
+in	O
+endophthalmitis	B
+,	O
+macular	O
+infarction	B
+may	O
+impair	O
+full	O
+visual	O
+recovery	O
+.	O
+
+METHODS	O
+:	O
+We	O
+present	O
+a	O
+case	O
+of	O
+presumed	O
+amikacin	O
+retinal	B
+toxicity	I
+following	O
+treatment	O
+with	O
+amikacin	O
+and	O
+vancomycin	O
+for	O
+alpha	O
+-	O
+haemolytic	O
+streptococcal	B
+endophthalmitis	I
+.	O
+
+RESULTS	O
+:	O
+Endophthalmitis	B
+resolved	O
+with	O
+improvement	O
+in	O
+visual	O
+acuity	O
+to	O
+6	O
+/	O
+24	O
+at	O
+three	O
+months	O
+.	O
+
+Fundus	O
+fluorescein	O
+angiography	O
+confirmed	O
+macular	O
+capillary	O
+closure	O
+and	O
+telangiectasis	B
+.	O
+
+CONCLUSIONS	O
+:	O
+Currently	O
+accepted	O
+intravitreal	O
+antibiotic	O
+regimens	O
+may	O
+cause	O
+retinal	B
+toxicity	I
+and	O
+macular	O
+ischaemia	B
+.	O
+
+Treatment	O
+strategies	O
+aimed	O
+at	O
+avoiding	O
+retinal	B
+toxicity	I
+are	O
+discussed	O
+.	O
+
+The	O
+role	O
+of	O
+nicotine	O
+in	O
+smoking	O
+-	O
+related	O
+cardiovascular	B
+disease	I
+.	O
+
+Nicotine	O
+activates	O
+the	O
+sympathetic	O
+nervous	O
+system	O
+and	O
+in	O
+this	O
+way	O
+could	O
+contribute	O
+to	O
+cardiovascular	B
+disease	I
+.	O
+
+Animal	O
+studies	O
+and	O
+mechanistic	O
+studies	O
+indicate	O
+that	O
+nicotine	O
+could	O
+play	O
+a	O
+role	O
+in	O
+accelerating	O
+atherosclerosis	B
+,	O
+but	O
+evidence	O
+among	O
+humans	O
+is	O
+too	O
+inadequate	O
+to	O
+be	O
+definitive	O
+about	O
+such	O
+an	O
+effect	O
+.	O
+
+Almost	O
+certainly	O
+,	O
+nicotine	O
+via	O
+its	O
+hemodynamic	O
+effects	O
+contributes	O
+to	O
+acute	O
+cardiovascular	O
+events	O
+,	O
+although	O
+current	O
+evidence	O
+suggests	O
+that	O
+the	O
+effects	O
+of	O
+nicotine	O
+are	O
+much	O
+less	O
+important	O
+than	O
+are	O
+the	O
+prothrombotic	O
+effects	O
+of	O
+cigarette	O
+smoking	O
+or	O
+the	O
+effects	O
+of	O
+carbon	O
+monoxide	O
+.	O
+
+Nicotine	O
+does	O
+not	O
+appear	O
+to	O
+enhance	O
+thrombosis	B
+among	O
+humans	O
+.	O
+
+Clinical	O
+studies	O
+of	O
+pipe	O
+smokers	O
+and	O
+people	O
+using	O
+transdermal	O
+nicotine	O
+support	O
+the	O
+idea	O
+that	O
+toxins	O
+other	O
+than	O
+nicotine	O
+are	O
+the	O
+most	O
+important	O
+causes	O
+of	O
+acute	O
+cardiovascular	O
+events	O
+.	O
+
+Finally	O
+,	O
+the	O
+dose	O
+response	O
+for	O
+cardiovascular	O
+events	O
+of	O
+nicotine	O
+appears	O
+to	O
+be	O
+flat	O
+,	O
+suggesting	O
+that	O
+if	O
+nicotine	O
+is	O
+involved	O
+,	O
+adverse	O
+effects	O
+might	O
+be	O
+seen	O
+with	O
+relatively	O
+low	O
+-	O
+level	O
+cigarette	O
+exposures	O
+.	O
+
+Iatrogenically	O
+induced	O
+intractable	O
+atrioventricular	B
+reentrant	I
+tachycardia	I
+after	O
+verapamil	O
+and	O
+catheter	O
+ablation	O
+in	O
+a	O
+patient	O
+with	O
+Wolff	B
+-	I
+Parkinson	I
+-	I
+White	I
+syndrome	I
+and	O
+idiopathic	B
+dilated	I
+cardiomyopathy	I
+.	O
+
+In	O
+a	O
+patient	O
+with	O
+WPW	B
+syndrome	I
+and	O
+idiopathic	B
+dilated	I
+cardiomyopathy	I
+,	O
+intractable	O
+atrioventricular	B
+reentrant	I
+tachycardia	I
+(	O
+AVRT	B
+)	O
+was	O
+iatrogenically	O
+induced	O
+.	O
+
+QRS	O
+without	O
+preexcitation	O
+,	O
+caused	O
+by	O
+junctional	O
+escape	O
+beats	O
+after	O
+verapamil	O
+or	O
+unidirectional	O
+antegrade	O
+block	O
+of	O
+accessory	O
+pathway	O
+after	O
+catheter	O
+ablation	O
+,	O
+established	O
+frequent	O
+AVRT	B
+attack	O
+.	O
+
+Epidemic	O
+of	O
+liver	B
+disease	I
+caused	O
+by	O
+hydrochlorofluorocarbons	O
+used	O
+as	O
+ozone	O
+-	O
+sparing	O
+substitutes	O
+of	O
+chlorofluorocarbons	O
+.	O
+
+BACKGROUND	O
+:	O
+Hydrochlorofluorocarbons	O
+(	O
+HCFCs	O
+)	O
+are	O
+used	O
+increasingly	O
+in	O
+industry	O
+as	O
+substitutes	O
+for	O
+ozone	O
+-	O
+depleting	O
+chlorofluorocarbons	O
+(	O
+CFCs	O
+)	O
+.	O
+
+Limited	O
+studies	O
+in	O
+animals	O
+indicate	O
+potential	O
+hepatotoxicity	B
+of	O
+some	O
+of	O
+these	O
+compounds	O
+.	O
+
+We	O
+investigated	O
+an	O
+epidemic	O
+of	O
+liver	B
+disease	I
+in	O
+nine	O
+industrial	O
+workers	O
+who	O
+had	O
+had	O
+repeated	O
+accidental	O
+exposure	O
+to	O
+a	O
+mixture	O
+of	O
+1	O
+,	O
+1	O
+-	O
+dichloro	O
+-	O
+2	O
+,	O
+2	O
+,	O
+2	O
+-	O
+trifluoroethane	O
+(	O
+HCFC	O
+123	O
+)	O
+and	O
+1	O
+-	O
+chloro	O
+-	O
+1	O
+,	O
+2	O
+,	O
+2	O
+,	O
+2	O
+-	O
+tetrafluoroethane	O
+(	O
+HCFC	O
+124	O
+)	O
+.	O
+
+All	O
+nine	O
+exposed	O
+workers	O
+were	O
+affected	O
+to	O
+various	O
+degrees	O
+.	O
+
+Both	O
+compounds	O
+are	O
+metabolised	O
+in	O
+the	O
+same	O
+way	O
+as	O
+1	O
+-	O
+bromo	O
+-	O
+1	O
+-	O
+chloro	O
+-	O
+2	O
+,	O
+2	O
+,	O
+2	O
+-	O
+trifluoroethane	O
+(	O
+halothane	O
+)	O
+to	O
+form	O
+reactive	O
+trifluoroacetyl	O
+halide	O
+intermediates	O
+,	O
+which	O
+have	O
+been	O
+implicated	O
+in	O
+the	O
+hepatotoxicity	B
+of	O
+halothane	O
+.	O
+
+We	O
+aimed	O
+to	O
+test	O
+whether	O
+HCFCs	O
+123	O
+and	O
+124	O
+can	O
+result	O
+in	O
+serious	O
+liver	B
+disease	I
+.	O
+
+METHODS	O
+:	O
+For	O
+one	O
+severely	O
+affected	O
+worker	O
+liver	O
+biopsy	O
+and	O
+immunohistochemical	O
+stainings	O
+for	O
+the	O
+presence	O
+of	O
+trifluoroacetyl	O
+protein	O
+adducts	O
+were	O
+done	O
+.	O
+
+The	O
+serum	O
+of	O
+six	O
+affected	O
+workers	O
+and	O
+five	O
+controls	O
+was	O
+tested	O
+for	O
+autoantibodies	O
+that	O
+react	O
+with	O
+human	O
+liver	O
+cytochrome	O
+-	O
+P450	O
+2E1	O
+(	O
+P450	O
+2E1	O
+)	O
+and	O
+P58	O
+protein	O
+disulphide	O
+isomerase	O
+isoform	O
+(	O
+P58	O
+)	O
+.	O
+
+FINDINGS	O
+:	O
+The	O
+liver	O
+biopsy	O
+sample	O
+showed	O
+hepatocellular	O
+necrosis	B
+which	O
+was	O
+prominent	O
+in	O
+perivenular	O
+zone	O
+three	O
+and	O
+extended	O
+focally	O
+from	O
+portal	O
+tracts	O
+to	O
+portal	O
+tracts	O
+and	O
+centrilobular	O
+areas	O
+(	O
+bridging	O
+necrosis	B
+)	O
+.	O
+
+Trifluoroacetyl	O
+-	O
+adducted	O
+proteins	O
+were	O
+detected	O
+in	O
+surviving	O
+hepatocytes	O
+.	O
+
+Autoantibodies	O
+against	O
+P450	O
+2E1	O
+or	O
+P58	O
+,	O
+previously	O
+associated	O
+with	O
+halothane	B
+hepatitis	I
+,	O
+were	O
+detected	O
+in	O
+the	O
+serum	O
+of	O
+five	O
+affected	O
+workers	O
+.	O
+
+INTERPRETATION	O
+:	O
+Repeated	O
+exposure	O
+of	O
+human	O
+beings	O
+to	O
+HCFCs	O
+123	O
+and	O
+124	O
+can	O
+result	O
+in	O
+serious	O
+liver	B
+injury	I
+in	O
+a	O
+large	O
+proportion	O
+of	O
+the	O
+exposed	O
+population	O
+.	O
+
+Although	O
+the	O
+exact	O
+mechanism	O
+of	O
+hepatotoxicity	B
+of	O
+these	O
+agents	O
+is	O
+not	O
+known	O
+,	O
+the	O
+results	O
+suggest	O
+that	O
+trifluoroacetyl	O
+-	O
+altered	O
+liver	O
+proteins	O
+are	O
+involved	O
+.	O
+
+In	O
+view	O
+of	O
+the	O
+potentially	O
+widespread	O
+use	O
+of	O
+these	O
+compounds	O
+,	O
+there	O
+is	O
+an	O
+urgent	O
+need	O
+to	O
+develop	O
+safer	O
+alternatives	O
+.	O
+
+Bile	B
+duct	I
+hamartoma	I
+occurring	O
+in	O
+association	O
+with	O
+long	O
+-	O
+term	O
+treatment	O
+with	O
+danazol	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+bile	B
+duct	I
+hamartoma	I
+which	O
+developed	O
+in	O
+a	O
+patient	O
+who	O
+had	O
+been	O
+on	O
+long	O
+-	O
+term	O
+danazol	O
+treatment	O
+.	O
+
+Such	O
+patients	O
+should	O
+be	O
+under	O
+close	O
+follow	O
+-	O
+up	O
+,	O
+preferably	O
+with	O
+periodic	O
+ultrasound	O
+examination	O
+of	O
+the	O
+liver	O
+.	O
+
+If	O
+the	O
+patient	O
+develops	O
+a	O
+liver	B
+mass	I
+,	O
+because	O
+of	O
+non	O
+-	O
+specific	O
+clinical	O
+features	O
+and	O
+imaging	O
+appearances	O
+,	O
+biopsy	O
+may	O
+be	O
+the	O
+only	O
+way	O
+to	O
+achieve	O
+a	O
+definitive	O
+diagnosis	O
+.	O
+
+Endocrine	O
+screening	O
+in	O
+1	O
+,	O
+022	O
+men	O
+with	O
+erectile	B
+dysfunction	I
+:	O
+clinical	O
+significance	O
+and	O
+cost	O
+-	O
+effective	O
+strategy	O
+.	O
+
+PURPOSE	O
+:	O
+We	O
+reviewed	O
+the	O
+results	O
+of	O
+serum	O
+testosterone	O
+and	O
+prolactin	O
+determination	O
+in	O
+1	O
+,	O
+022	O
+patients	O
+referred	O
+because	O
+of	O
+erectile	B
+dysfunction	I
+and	O
+compared	O
+the	O
+data	O
+with	O
+history	O
+,	O
+results	O
+of	O
+physical	O
+examination	O
+,	O
+other	O
+etiological	O
+investigations	O
+and	O
+effects	O
+of	O
+endocrine	O
+therapy	O
+to	O
+refine	O
+the	O
+rules	O
+of	O
+cost	O
+-	O
+effective	O
+endocrine	O
+screening	O
+and	O
+to	O
+pinpoint	O
+actual	O
+responsibility	O
+for	O
+hormonal	O
+abnormalities	O
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+Testosterone	O
+and	O
+prolactin	O
+were	O
+determined	O
+by	O
+radioimmunoassay	O
+.	O
+
+Every	O
+patient	O
+was	O
+screened	O
+for	O
+testosterone	O
+and	O
+451	O
+were	O
+screened	O
+for	O
+prolactin	O
+on	O
+the	O
+basis	O
+of	O
+low	B
+sexual	I
+desire	I
+,	O
+gynecomastia	B
+or	O
+testosterone	O
+less	O
+than	O
+4	O
+ng	O
+.	O
+/	O
+ml	O
+.	O
+
+Determination	O
+was	O
+repeated	O
+in	O
+case	O
+of	O
+abnormal	O
+first	O
+results	O
+.	O
+
+Prolactin	O
+results	O
+were	O
+compared	O
+with	O
+those	O
+of	O
+a	O
+previous	O
+personal	O
+cohort	O
+of	O
+1	O
+,	O
+340	O
+patients	O
+with	O
+erectile	B
+dysfunction	I
+and	O
+systematic	O
+prolactin	O
+determination	O
+.	O
+
+Main	O
+clinical	O
+criteria	O
+tested	O
+regarding	O
+efficiency	O
+in	O
+hormone	O
+determination	O
+were	O
+low	B
+sexual	I
+desire	I
+,	O
+small	O
+testes	O
+and	O
+gynecomastia	B
+.	O
+
+Endocrine	O
+therapy	O
+consisted	O
+of	O
+testosterone	O
+heptylate	O
+or	O
+human	O
+chorionic	O
+gonadotropin	O
+for	O
+hypogonadism	B
+and	O
+bromocriptine	O
+for	O
+hyperprolactinemia	B
+.	O
+
+RESULTS	O
+:	O
+Testosterone	O
+was	O
+less	O
+than	O
+3	O
+ng	O
+.	O
+/	O
+ml	O
+.	O
+in	O
+107	O
+patients	O
+but	O
+normal	O
+in	O
+40	O
+%	O
+at	O
+repeat	O
+determination	O
+.	O
+
+The	O
+prevalence	O
+of	O
+repeatedly	O
+low	O
+testosterone	O
+increased	O
+with	O
+age	O
+(	O
+4	O
+%	O
+before	O
+age	O
+50	O
+years	O
+and	O
+9	O
+%	O
+50	O
+years	O
+or	O
+older	O
+)	O
+.	O
+
+Two	O
+pituitary	B
+tumors	I
+were	O
+discovered	O
+after	O
+testosterone	O
+determination	O
+.	O
+
+Most	O
+of	O
+the	O
+other	O
+low	O
+testosterone	O
+levels	O
+seemed	O
+to	O
+result	O
+from	O
+nonorganic	O
+hypothalamic	B
+dysfunction	I
+because	O
+of	O
+normal	O
+serum	O
+luteinizing	O
+hormone	O
+and	O
+prolactin	O
+and	O
+to	O
+have	O
+only	O
+a	O
+small	O
+role	O
+in	O
+erectile	B
+dysfunction	I
+(	O
+definite	O
+improvement	O
+in	O
+only	O
+16	O
+of	O
+44	O
+[	O
+36	O
+%	O
+]	O
+after	O
+androgen	O
+therapy	O
+,	O
+normal	O
+morning	O
+or	O
+nocturnal	O
+erections	O
+in	O
+30	O
+%	O
+and	O
+definite	O
+vasculogenic	O
+contributions	O
+in	O
+42	O
+%	O
+)	O
+.	O
+
+Determining	O
+testosterone	O
+only	O
+in	O
+cases	O
+of	O
+low	B
+sexual	I
+desire	I
+or	O
+abnormal	O
+physical	O
+examination	O
+would	O
+have	O
+missed	O
+40	O
+%	O
+of	O
+the	O
+cases	O
+with	O
+low	O
+testosterone	O
+,	O
+including	O
+37	O
+%	O
+of	O
+those	O
+subsequently	O
+improved	O
+by	O
+androgen	O
+therapy	O
+.	O
+
+Prolactin	O
+exceeded	O
+20	O
+ng	O
+.	O
+/	O
+ml	O
+.	O
+in	O
+5	O
+men	O
+and	O
+was	O
+normal	O
+in	O
+2	O
+at	O
+repeat	O
+determination	O
+.	O
+
+Only	O
+1	O
+prolactinoma	B
+was	O
+discovered	O
+.	O
+
+These	O
+data	O
+are	O
+lower	O
+than	O
+those	O
+we	O
+found	O
+during	O
+the	O
+last	O
+2	O
+decades	O
+(	O
+overall	O
+prolactin	O
+greater	O
+than	O
+20	O
+ng	O
+.	O
+/	O
+ml	O
+.	O
+in	O
+1	O
+.	O
+86	O
+%	O
+of	O
+1	O
+,	O
+821	O
+patients	O
+,	O
+prolactinomas	B
+in	O
+7	O
+,	O
+0	O
+.	O
+38	O
+%	O
+)	O
+.	O
+
+Bromocriptine	O
+was	O
+definitely	O
+effective	O
+in	O
+cases	O
+with	O
+prolactin	O
+greater	O
+than	O
+35	O
+ng	O
+.	O
+/	O
+ml	O
+.	O
+
+(	O
+8	O
+of	O
+12	O
+compared	O
+to	O
+only	O
+9	O
+of	O
+22	O
+cases	O
+with	O
+prolactin	O
+between	O
+20	O
+and	O
+35	O
+ng	O
+.	O
+/	O
+ml	O
+.	O
+)	O
+.	O
+
+Testosterone	O
+was	O
+low	O
+in	O
+less	O
+than	O
+50	O
+%	O
+of	O
+cases	O
+with	O
+prolactin	O
+greater	O
+than	O
+35	O
+ng	O
+.	O
+/	O
+ml	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Low	O
+prevalences	O
+and	O
+effects	O
+of	O
+low	O
+testosterone	O
+and	O
+high	O
+prolactin	O
+in	O
+erectile	B
+dysfunction	I
+cannot	O
+justify	O
+their	O
+routine	O
+determination	O
+.	O
+
+However	O
+,	O
+cost	O
+-	O
+effective	O
+screening	O
+strategies	O
+recommended	O
+so	O
+far	O
+missed	O
+40	O
+to	O
+50	O
+%	O
+of	O
+cases	O
+improved	O
+with	O
+endocrine	O
+therapy	O
+and	O
+the	O
+pituitary	B
+tumors	I
+.	O
+
+We	O
+now	O
+advocate	O
+that	O
+before	O
+age	O
+50	O
+years	O
+testosterone	O
+be	O
+determined	O
+only	O
+in	O
+cases	O
+of	O
+low	B
+sexual	I
+desire	I
+and	O
+abnormal	O
+physical	O
+examination	O
+but	O
+that	O
+it	O
+be	O
+measured	O
+in	O
+all	O
+men	O
+older	O
+than	O
+50	O
+years	O
+.	O
+
+Prolactin	O
+should	O
+be	O
+determined	O
+only	O
+in	O
+cases	O
+of	O
+low	B
+sexual	I
+desire	I
+,	O
+gynecomastia	B
+and	O
+/	O
+or	O
+testosterone	O
+less	O
+than	O
+4	O
+ng	O
+.	O
+/	O
+ml	O
+.	O
+
+Extrapyramidal	O
+side	O
+effects	O
+with	O
+risperidone	O
+and	O
+haloperidol	O
+at	O
+comparable	O
+D2	O
+receptor	O
+occupancy	O
+levels	O
+.	O
+
+Risperidone	O
+is	O
+an	O
+antipsychotic	O
+drug	O
+with	O
+high	O
+affinity	O
+at	O
+dopamine	O
+D2	O
+and	O
+serotonin	O
+5	O
+-	O
+HT2	O
+receptors	O
+.	O
+
+Previous	O
+clinical	O
+studies	O
+have	O
+proposed	O
+that	O
+risperidone	O
+'	O
+s	O
+pharmacologic	O
+profile	O
+may	O
+produce	O
+improved	O
+efficacy	O
+for	O
+negative	O
+psychotic	B
+symptoms	I
+and	O
+decreased	O
+propensity	O
+for	O
+extrapyramidal	O
+side	O
+effects	O
+;	O
+features	O
+shared	O
+by	O
+so	O
+-	O
+called	O
+'	O
+atypical	O
+'	O
+neuroleptics	O
+.	O
+
+To	O
+determine	O
+if	O
+routine	O
+risperidone	O
+treatment	O
+is	O
+associated	O
+with	O
+a	O
+unique	O
+degree	O
+of	O
+D2	O
+receptor	O
+occupancy	O
+and	O
+pattern	O
+of	O
+clinical	O
+effects	O
+,	O
+we	O
+used	O
+[	O
+123I	O
+]	O
+IBZM	O
+SPECT	O
+to	O
+determine	O
+D2	O
+occupancy	O
+in	O
+subjects	O
+treated	O
+with	O
+routine	O
+clinical	O
+doses	O
+of	O
+risperidone	O
+(	O
+n	O
+=	O
+12	O
+)	O
+or	O
+haloperidol	O
+(	O
+n	O
+=	O
+7	O
+)	O
+.	O
+
+Both	O
+risperidone	O
+and	O
+haloperidol	O
+produced	O
+D2	O
+occupancy	O
+levels	O
+between	O
+approximately	O
+60	O
+and	O
+90	O
+%	O
+at	O
+standard	O
+clinical	O
+doses	O
+.	O
+
+There	O
+was	O
+no	O
+significant	O
+difference	O
+between	O
+occupancy	O
+levels	O
+obtained	O
+with	O
+haloperidol	O
+or	O
+risperidone	O
+.	O
+
+Drug	B
+-	I
+induced	I
+parkinsonism	I
+was	O
+observed	O
+in	O
+subjects	O
+treated	O
+with	O
+risperidone	O
+(	O
+42	O
+%	O
+)	O
+and	O
+haloperidol	O
+(	O
+29	O
+%	O
+)	O
+and	O
+was	O
+observed	O
+at	O
+occupancy	O
+levels	O
+above	O
+60	O
+%	O
+.	O
+
+Based	O
+on	O
+these	O
+observations	O
+,	O
+it	O
+is	O
+concluded	O
+that	O
+5	O
+-	O
+HT2	O
+blockade	O
+obtained	O
+with	O
+risperidone	O
+at	O
+D2	O
+occupancy	O
+rates	O
+of	O
+60	O
+%	O
+and	O
+above	O
+does	O
+not	O
+appear	O
+to	O
+protect	O
+against	O
+the	O
+risk	O
+for	O
+extrapyramidal	O
+side	O
+effects	O
+.	O
+
+Treatment	O
+of	O
+previously	O
+treated	O
+metastatic	O
+breast	B
+cancer	I
+by	O
+mitoxantrone	O
+and	O
+48	O
+-	O
+hour	O
+continuous	O
+infusion	O
+of	O
+high	O
+-	O
+dose	O
+5	O
+-	O
+FU	O
+and	O
+leucovorin	O
+(	O
+MFL	O
+)	O
+:	O
+low	O
+palliative	O
+benefit	O
+and	O
+high	O
+treatment	O
+-	O
+related	O
+toxicity	B
+.	O
+
+For	O
+previously	O
+treated	O
+advanced	O
+breast	B
+cancer	I
+,	O
+there	O
+is	O
+no	O
+standard	O
+second	O
+-	O
+line	O
+therapy	O
+.	O
+
+Combination	O
+chemotherapy	O
+with	O
+mitoxantrone	O
+,	O
+high	O
+-	O
+dose	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+and	O
+leucovorin	O
+(	O
+MFL	O
+regimen	O
+)	O
+had	O
+been	O
+reported	O
+as	O
+an	O
+effective	O
+and	O
+well	O
+tolerated	O
+regimen	O
+.	O
+
+From	O
+October	O
+1993	O
+to	O
+November	O
+1995	O
+,	O
+we	O
+treated	O
+13	O
+patients	O
+with	O
+previously	O
+chemotherapy	O
+-	O
+treated	O
+metastatic	O
+breast	B
+cancer	I
+by	O
+mitoxantrone	O
+,	O
+12	O
+mg	O
+/	O
+m2	O
+,	O
+on	O
+day	O
+1	O
+and	O
+continuous	O
+infusion	O
+of	O
+5	O
+-	O
+FU	O
+,	O
+3000	O
+mg	O
+/	O
+m2	O
+,	O
+together	O
+with	O
+leucovorin	O
+,	O
+300	O
+mg	O
+/	O
+m2	O
+,	O
+for	O
+48	O
+h	O
+from	O
+day	O
+1	O
+to	O
+2	O
+.	O
+
+Each	O
+course	O
+of	O
+chemotherapy	O
+was	O
+given	O
+every	O
+4	O
+weeks	O
+.	O
+
+Most	O
+of	O
+these	O
+patients	O
+had	O
+more	O
+than	O
+two	O
+metastatic	O
+sites	O
+,	O
+with	O
+lung	O
+metastasis	O
+predominant	O
+.	O
+
+Seven	O
+patients	O
+had	O
+been	O
+treated	O
+with	O
+anthracycline	O
+.	O
+
+Seven	O
+patients	O
+had	O
+previously	O
+received	O
+radiotherapy	O
+and	O
+seven	O
+had	O
+received	O
+hormone	O
+therapy	O
+.	O
+
+Median	O
+number	O
+of	O
+courses	O
+of	O
+MFL	O
+regimen	O
+given	O
+was	O
+six	O
+and	O
+the	O
+median	O
+cumulative	O
+dose	O
+of	O
+mitoxantrone	O
+was	O
+68	O
+.	O
+35	O
+mg	O
+/	O
+m2	O
+.	O
+
+One	O
+patient	O
+had	O
+complete	O
+response	O
+,	O
+seven	O
+had	O
+stable	O
+disease	O
+,	O
+none	O
+had	O
+partial	O
+response	O
+and	O
+five	O
+had	O
+progressive	O
+disease	O
+.	O
+
+The	O
+overall	O
+objective	O
+response	O
+rate	O
+was	O
+7	O
+.	O
+6	O
+%	O
+.	O
+
+The	O
+median	O
+follow	O
+-	O
+up	O
+period	O
+was	O
+14	O
+months	O
+.	O
+
+Median	O
+survival	O
+was	O
+16	O
+months	O
+.	O
+
+Median	O
+progression	O
+-	O
+free	O
+survival	O
+was	O
+5	O
+months	O
+.	O
+
+A	O
+complete	O
+responder	O
+had	O
+relapse	O
+-	O
+free	O
+survival	O
+up	O
+to	O
+17	O
+months	O
+.	O
+
+Major	O
+toxicities	B
+were	O
+cardiotoxicity	B
+and	O
+leukopenia	B
+.	O
+
+Eight	O
+patients	O
+were	O
+dead	O
+in	O
+the	O
+last	O
+follow	O
+-	O
+up	O
+;	O
+two	O
+of	O
+them	O
+died	O
+of	O
+treatment	O
+-	O
+related	O
+toxicity	B
+.	O
+
+The	O
+MFL	O
+regimen	O
+achieves	O
+little	O
+palliative	O
+benefit	O
+and	O
+induces	O
+severe	O
+toxicity	B
+at	O
+a	O
+fairly	O
+high	O
+rate	O
+.	O
+
+Administration	O
+of	O
+this	O
+regimen	O
+to	O
+breast	B
+cancer	I
+patients	O
+who	O
+have	O
+been	O
+treated	O
+by	O
+chemotherapy	O
+and	O
+those	O
+with	O
+impaired	B
+heart	I
+function	I
+requires	O
+careful	O
+attention	O
+.	O
+
+Ticlopidine	O
+-	O
+induced	O
+aplastic	B
+anemia	I
+:	O
+report	O
+of	O
+three	O
+Chinese	O
+patients	O
+and	O
+review	O
+of	O
+the	O
+literature	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+three	O
+Chinese	O
+patients	O
+with	O
+ticlopidine	O
+-	O
+induced	O
+aplastic	B
+anemia	I
+were	O
+reported	O
+and	O
+another	O
+13	O
+patients	O
+in	O
+the	O
+English	O
+literature	O
+were	O
+reviewed	O
+.	O
+
+We	O
+attempted	O
+to	O
+find	O
+underlying	O
+similarities	O
+,	O
+evaluate	O
+the	O
+risk	O
+factors	O
+,	O
+and	O
+identify	O
+appropriate	O
+treatment	O
+for	O
+this	O
+complication	O
+.	O
+
+All	O
+but	O
+one	O
+of	O
+the	O
+patients	O
+were	O
+over	O
+60	O
+years	O
+old	O
+,	O
+and	O
+the	O
+6	O
+who	O
+died	O
+were	O
+all	O
+older	O
+than	O
+65	O
+.	O
+
+Therefore	O
+,	O
+old	O
+age	O
+may	O
+be	O
+a	O
+risk	O
+factor	O
+for	O
+developing	O
+this	O
+complication	O
+.	O
+
+Agranulocytosis	B
+occurred	O
+3	O
+-	O
+20	O
+weeks	O
+after	O
+initiation	O
+of	O
+ticlopidine	O
+,	O
+so	O
+frequent	O
+examination	O
+of	O
+white	O
+cell	O
+count	O
+during	O
+treatment	O
+is	O
+recommended	O
+.	O
+
+There	O
+seemed	O
+to	O
+be	O
+no	O
+direct	O
+correlation	O
+between	O
+the	O
+dose	O
+or	O
+duration	O
+used	O
+and	O
+the	O
+severity	O
+of	O
+bone	B
+marrow	I
+suppression	I
+.	O
+
+Treatment	O
+for	O
+ticlopidine	O
+-	O
+induced	O
+aplastic	B
+anemia	I
+with	O
+colony	O
+-	O
+stimulating	O
+factors	O
+seemed	O
+to	O
+have	O
+little	O
+effect	O
+.	O
+
+The	O
+fact	O
+that	O
+5	O
+of	O
+the	O
+6	O
+patients	O
+who	O
+received	O
+concurrent	O
+calcium	O
+channel	O
+blockers	O
+died	O
+,	O
+should	O
+alert	O
+clinicians	O
+to	O
+be	O
+more	O
+cautious	O
+when	O
+using	O
+these	O
+two	O
+drugs	O
+simultaneously	O
+.	O
+
+Upregulation	O
+of	O
+the	O
+expression	O
+of	O
+vasopressin	O
+gene	O
+in	O
+the	O
+paraventricular	O
+and	O
+supraoptic	O
+nuclei	O
+of	O
+the	O
+lithium	O
+-	O
+induced	O
+diabetes	B
+insipidus	I
+rat	O
+.	O
+
+The	O
+expression	O
+of	O
+arginine	O
+vasopressin	O
+(	O
+AVP	O
+)	O
+gene	O
+in	O
+the	O
+paraventricular	O
+(	O
+PVN	O
+)	O
+and	O
+supraoptic	O
+nuclei	O
+(	O
+SON	O
+)	O
+was	O
+investigated	O
+in	O
+rats	O
+with	O
+lithium	O
+(	O
+Li	O
+)	O
+-	O
+induced	O
+polyuria	B
+,	O
+using	O
+in	O
+situ	O
+hybridization	O
+histochemistry	O
+and	O
+radioimmunoassay	O
+.	O
+
+The	O
+male	O
+Wistar	O
+rats	O
+consuming	O
+a	O
+diet	O
+that	O
+contained	O
+LiCl	O
+(	O
+60	O
+mmol	O
+/	O
+kg	O
+)	O
+for	O
+4	O
+weeks	O
+developed	O
+marked	O
+polyuria	B
+.	O
+
+The	O
+Li	O
+-	O
+treated	O
+rats	O
+produced	O
+a	O
+large	O
+volume	O
+of	O
+hypotonic	O
+urine	O
+with	O
+low	O
+ionic	O
+concentrations	O
+.	O
+
+Plasma	O
+sodium	O
+concentrations	O
+were	O
+found	O
+to	O
+be	O
+slightly	O
+increased	O
+in	O
+the	O
+Li	O
+-	O
+treated	O
+rats	O
+compared	O
+with	O
+those	O
+in	O
+controls	O
+.	O
+
+Plasma	O
+concentration	O
+of	O
+AVP	O
+and	O
+transcripts	O
+of	O
+AVP	O
+gene	O
+in	O
+the	O
+PVN	O
+and	O
+SON	O
+were	O
+significantly	O
+increased	O
+in	O
+the	O
+Li	O
+-	O
+treated	O
+rats	O
+compared	O
+with	O
+controls	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+dehydration	B
+and	O
+/	O
+or	O
+the	O
+activation	O
+of	O
+visceral	O
+afferent	O
+inputs	O
+may	O
+contribute	O
+to	O
+the	O
+elevation	O
+of	O
+plasma	O
+AVP	O
+and	O
+the	O
+upregulation	O
+of	O
+AVP	O
+gene	O
+expression	O
+in	O
+the	O
+PVN	O
+and	O
+the	O
+SON	O
+of	O
+the	O
+Li	O
+-	O
+induced	O
+diabetes	B
+insipidus	I
+rat	O
+.	O
+
+Antinociceptive	O
+and	O
+antiamnesic	O
+properties	O
+of	O
+the	O
+presynaptic	O
+cholinergic	O
+amplifier	O
+PG	O
+-	O
+9	O
+.	O
+
+The	O
+antinociceptive	O
+effect	O
+of	O
+3	O
+alpha	O
+-	O
+tropyl	O
+2	O
+-	O
+(	O
+p	O
+-	O
+bromophenyl	O
+)	O
+propionate	O
+[	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+PG	O
+-	O
+9	O
+]	O
+(	O
+10	O
+-	O
+40	O
+mg	O
+kg	O
+-	O
+1	O
+s	O
+.	O
+c	O
+.	O
+;	O
+30	O
+-	O
+60	O
+mg	O
+kg	O
+-	O
+1	O
+p	O
+.	O
+o	O
+.	O
+;	O
+10	O
+-	O
+30	O
+mg	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+v	O
+.	O
+;	O
+10	O
+-	O
+30	O
+micrograms	O
+/	O
+mouse	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+was	O
+examined	O
+in	O
+mice	O
+,	O
+rats	O
+and	O
+guinea	O
+pigs	O
+by	O
+use	O
+of	O
+the	O
+hot	O
+-	O
+plate	O
+,	O
+abdominal	O
+-	O
+constriction	O
+,	O
+tail	O
+-	O
+flick	O
+and	O
+paw	O
+-	O
+pressure	O
+tests	O
+.	O
+
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+PG	O
+-	O
+9	O
+antinociception	O
+peaked	O
+15	O
+min	O
+after	O
+injection	O
+and	O
+then	O
+slowly	O
+diminished	O
+.	O
+
+The	O
+antinociception	O
+produced	O
+by	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+PG	O
+-	O
+9	O
+was	O
+prevented	O
+by	O
+the	O
+unselective	O
+muscarinic	O
+antagonist	O
+atropine	O
+,	O
+the	O
+M1	O
+-	O
+selective	O
+antagonists	O
+pirenzepine	O
+and	O
+dicyclomine	O
+and	O
+the	O
+acetylcholine	O
+depletor	O
+hemicholinium	O
+-	O
+3	O
+,	O
+but	O
+not	O
+by	O
+the	O
+opioid	O
+antagonist	O
+naloxone	O
+,	O
+the	O
+gamma	O
+-	O
+aminobutyric	O
+acidB	O
+antagonist	O
+3	O
+-	O
+aminopropyl	O
+-	O
+diethoxy	O
+-	O
+methyl	O
+-	O
+phosphinic	O
+acid	O
+,	O
+the	O
+H3	O
+agonist	O
+R	O
+-	O
+(	O
+alpha	O
+)	O
+-	O
+methylhistamine	O
+,	O
+the	O
+D2	O
+antagonist	O
+quinpirole	O
+,	O
+the	O
+5	O
+-	O
+hydroxytryptamine4	O
+antagonist	O
+2	O
+-	O
+methoxy	O
+-	O
+4	O
+-	O
+amino	O
+-	O
+5	O
+-	O
+chlorobenzoic	O
+acid	O
+2	O
+-	O
+(	O
+diethylamino	O
+)	O
+ethyl	O
+ester	O
+hydrochloride	O
+,	O
+the	O
+5	O
+-	O
+hydroxytryptamin1A	O
+antagonist	O
+1	O
+-	O
+(	O
+2	O
+-	O
+methoxyphenyl	O
+)	O
+-	O
+4	O
+-	O
+[	O
+4	O
+-	O
+(	O
+2	O
+-	O
+phthalimido	O
+)	O
+butyl	O
+]	O
+piperazine	O
+hydrobromide	O
+and	O
+the	O
+polyamines	O
+depletor	O
+reserpine	O
+.	O
+
+Based	O
+on	O
+these	O
+data	O
+,	O
+it	O
+can	O
+be	O
+postulated	O
+that	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+PG	O
+-	O
+9	O
+exerted	O
+an	O
+antinociceptive	O
+effect	O
+mediated	O
+by	O
+a	O
+central	O
+potentiation	O
+of	O
+cholinergic	O
+transmission	O
+.	O
+
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+PG	O
+-	O
+9	O
+(	O
+10	O
+-	O
+40	O
+mg	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+p	O
+.	O
+)	O
+was	O
+able	O
+to	O
+prevent	O
+amnesia	B
+induced	O
+by	O
+scopolamine	O
+(	O
+1	O
+mg	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+p	O
+.	O
+)	O
+and	O
+dicyclomine	O
+(	O
+2	O
+mg	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+p	O
+.	O
+)	O
+in	O
+the	O
+mouse	O
+passive	O
+-	O
+avoidance	O
+test	O
+.	O
+
+Affinity	O
+profiles	O
+of	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+PG	O
+-	O
+9	O
+for	O
+muscarinic	O
+receptor	O
+subtypes	O
+,	O
+determined	O
+by	O
+functional	O
+studies	O
+(	O
+rabbit	O
+vas	O
+deferens	O
+for	O
+M1	O
+,	O
+guinea	O
+pig	O
+atrium	O
+for	O
+M2	O
+,	O
+guinea	O
+pig	O
+ileum	O
+for	O
+M3	O
+and	O
+immature	O
+guinea	O
+pig	O
+uterus	O
+for	O
+putative	O
+M4	O
+)	O
+,	O
+have	O
+shown	O
+an	O
+M4	O
+/	O
+M1	O
+selectivity	O
+ratio	O
+of	O
+10	O
+.	O
+2	O
+that	O
+might	O
+be	O
+responsible	O
+for	O
+the	O
+antinociception	O
+and	O
+the	O
+anti	O
+-	O
+amnesic	B
+effect	O
+induced	O
+by	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+PG	O
+-	O
+9	O
+through	O
+an	O
+increase	O
+in	O
+acetylcholine	O
+extracellular	O
+levels	O
+.	O
+
+In	O
+the	O
+antinociceptive	O
+and	O
+antiamnesic	O
+dose	O
+range	O
+,	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+PG	O
+-	O
+9	O
+did	O
+not	O
+impair	O
+mouse	O
+performance	O
+evaluated	O
+by	O
+the	O
+rota	O
+-	O
+rod	O
+test	O
+and	O
+Animex	O
+apparatus	O
+.	O
+
+The	O
+effect	O
+of	O
+different	O
+anaesthetic	O
+agents	O
+in	O
+hearing	B
+loss	I
+following	O
+spinal	O
+anaesthesia	O
+.	O
+
+The	O
+cause	O
+of	O
+hearing	B
+loss	I
+after	O
+spinal	O
+anaesthesia	O
+is	O
+unknown	O
+.	O
+
+Up	O
+until	O
+now	O
+,	O
+the	O
+only	O
+factor	O
+studied	O
+has	O
+been	O
+the	O
+effect	O
+of	O
+the	O
+diameter	O
+of	O
+the	O
+spinal	O
+needle	O
+on	O
+post	O
+-	O
+operative	O
+sensorineural	B
+hearing	I
+loss	I
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+describe	O
+this	O
+hearing	B
+loss	I
+and	O
+to	O
+investigate	O
+other	O
+factors	O
+influencing	O
+the	O
+degree	O
+of	O
+hearing	B
+loss	I
+.	O
+
+Two	O
+groups	O
+of	O
+22	O
+similar	O
+patients	O
+were	O
+studied	O
+:	O
+one	O
+group	O
+received	O
+6	O
+mL	O
+prilocaine	O
+2	O
+%	O
+;	O
+and	O
+the	O
+other	O
+received	O
+3	O
+mL	O
+bupivacaine	O
+0	O
+.	O
+5	O
+%	O
+.	O
+
+Patients	O
+given	O
+prilocaine	O
+were	O
+more	O
+likely	O
+to	O
+develop	O
+hearing	B
+loss	I
+(	O
+10	O
+out	O
+of	O
+22	O
+)	O
+than	O
+those	O
+given	O
+bupivacaine	O
+(	O
+4	O
+out	O
+of	O
+22	O
+)	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+average	O
+hearing	B
+loss	I
+for	O
+speech	O
+frequencies	O
+was	O
+about	O
+10	O
+dB	O
+after	O
+prilocaine	O
+and	O
+15	O
+dB	O
+after	O
+bupivacaine	O
+.	O
+
+None	O
+of	O
+the	O
+patients	O
+complained	O
+of	O
+subjective	O
+hearing	B
+loss	I
+.	O
+
+Long	O
+-	O
+term	O
+follow	O
+-	O
+up	O
+of	O
+the	O
+patients	O
+was	O
+not	O
+possible	O
+.	O
+
+A	O
+transient	O
+neurological	B
+deficit	I
+following	O
+intrathecal	O
+injection	O
+of	O
+1	O
+%	O
+hyperbaric	O
+bupivacaine	O
+for	O
+unilateral	O
+spinal	O
+anaesthesia	O
+.	O
+
+We	O
+describe	O
+a	O
+case	O
+of	O
+transient	O
+neurological	B
+deficit	I
+that	O
+occurred	O
+after	O
+unilateral	O
+spinal	O
+anaesthesia	O
+with	O
+8	O
+mg	O
+of	O
+1	O
+%	O
+hyperbaric	O
+bupivacaine	O
+slowly	O
+injected	O
+through	O
+a	O
+25	O
+-	O
+gauge	O
+pencil	O
+-	O
+point	O
+spinal	O
+needle	O
+.	O
+
+The	O
+surgery	O
+and	O
+anaesthesia	O
+were	O
+uneventful	O
+,	O
+but	O
+3	O
+days	O
+after	O
+surgery	O
+,	O
+the	O
+patient	O
+reported	O
+an	O
+area	O
+of	O
+hypoaesthesia	O
+over	O
+L3	O
+-	O
+L4	O
+dermatomes	O
+of	O
+the	O
+leg	O
+which	O
+had	O
+been	O
+operated	O
+on	O
+(	O
+loss	B
+of	I
+pinprick	I
+sensation	I
+)	O
+without	O
+reduction	O
+in	O
+muscular	O
+strength	O
+.	O
+
+Sensation	O
+in	O
+this	O
+area	O
+returned	O
+to	O
+normal	O
+over	O
+the	O
+following	O
+2	O
+weeks	O
+.	O
+
+Prospective	O
+multicentre	O
+studies	O
+with	O
+a	O
+large	O
+population	O
+and	O
+a	O
+long	O
+follow	O
+-	O
+up	O
+should	O
+be	O
+performed	O
+in	O
+order	O
+to	O
+evaluate	O
+the	O
+incidence	O
+of	O
+this	O
+unusual	O
+side	O
+effect	O
+.	O
+
+However	O
+,	O
+we	O
+suggest	O
+that	O
+a	O
+low	O
+solution	O
+concentration	O
+should	O
+be	O
+preferred	O
+for	O
+unilateral	O
+spinal	O
+anaesthesia	O
+with	O
+a	O
+hyperbaric	O
+anaesthetic	O
+solution	O
+(	O
+if	O
+pencil	O
+-	O
+point	O
+needle	O
+and	O
+slow	O
+injection	O
+rate	O
+are	O
+employed	O
+)	O
+,	O
+in	O
+order	O
+to	O
+minimize	O
+the	O
+risk	O
+of	O
+a	O
+localized	O
+high	O
+peak	O
+anaesthetic	O
+concentration	O
+,	O
+which	O
+might	O
+lead	O
+to	O
+a	O
+transient	O
+neurological	B
+deficit	I
+.	O
+
+Transient	B
+neurologic	I
+symptoms	I
+after	O
+spinal	O
+anesthesia	O
+:	O
+a	O
+lower	O
+incidence	O
+with	O
+prilocaine	O
+and	O
+bupivacaine	O
+than	O
+with	O
+lidocaine	O
+.	O
+
+BACKGROUND	O
+:	O
+Recent	O
+evidence	O
+suggests	O
+that	O
+transient	B
+neurologic	I
+symptoms	I
+(	O
+TNSs	B
+)	O
+frequently	O
+follow	O
+lidocaine	O
+spinal	O
+anesthesia	O
+but	O
+are	O
+infrequent	O
+with	O
+bupivacaine	O
+.	O
+
+However	O
+,	O
+identification	O
+of	O
+a	O
+short	O
+-	O
+acting	O
+local	O
+anesthetic	O
+to	O
+substitute	O
+for	O
+lidocaine	O
+for	O
+brief	O
+surgical	O
+procedures	O
+remains	O
+an	O
+important	O
+goal	O
+.	O
+
+Prilocaine	O
+is	O
+an	O
+amide	O
+local	O
+anesthetic	O
+with	O
+a	O
+duration	O
+of	O
+action	O
+similar	O
+to	O
+that	O
+of	O
+lidocaine	O
+.	O
+
+Accordingly	O
+,	O
+the	O
+present	O
+,	O
+prospective	O
+double	O
+-	O
+blind	O
+study	O
+compares	O
+prilocaine	O
+with	O
+lidocaine	O
+and	O
+bupivacaine	O
+with	O
+respect	O
+to	O
+duration	O
+of	O
+action	O
+and	O
+relative	O
+risk	O
+of	O
+TNSs	B
+.	O
+
+METHODS	O
+:	O
+Ninety	O
+patients	O
+classified	O
+as	O
+American	O
+Society	O
+of	O
+Anesthesiologists	O
+physical	O
+status	O
+I	O
+or	O
+II	O
+who	O
+were	O
+scheduled	O
+for	O
+short	O
+gynecologic	O
+procedures	O
+under	O
+spinal	O
+anesthesia	O
+were	O
+randomly	O
+allocated	O
+to	O
+receive	O
+2	O
+.	O
+5	O
+ml	O
+2	O
+%	O
+lidocaine	O
+in	O
+7	O
+.	O
+5	O
+%	O
+glucose	O
+,	O
+2	O
+%	O
+prilocaine	O
+in	O
+7	O
+.	O
+5	O
+%	O
+glucose	O
+,	O
+or	O
+0	O
+.	O
+5	O
+%	O
+bupivacaine	O
+in	O
+7	O
+.	O
+5	O
+%	O
+glucose	O
+.	O
+
+All	O
+solutions	O
+were	O
+provided	O
+in	O
+blinded	O
+vials	O
+by	O
+the	O
+hospital	O
+pharmacy	O
+.	O
+
+Details	O
+of	O
+spinal	O
+puncture	O
+,	O
+extension	O
+and	O
+regression	O
+of	O
+spinal	O
+block	O
+,	O
+and	O
+the	O
+times	O
+to	O
+reach	O
+discharge	O
+criteria	O
+were	O
+noted	O
+.	O
+
+In	O
+the	O
+evening	O
+of	O
+postoperative	O
+day	O
+1	O
+,	O
+patients	O
+were	O
+evaluated	O
+for	O
+TNSs	B
+by	O
+a	O
+physician	O
+unaware	O
+of	O
+the	O
+drug	O
+administered	O
+and	O
+the	O
+details	O
+of	O
+the	O
+anesthetic	O
+procedure	O
+.	O
+
+RESULTS	O
+:	O
+Nine	O
+of	O
+30	O
+patients	O
+receiving	O
+lidocaine	O
+experienced	O
+TNSs	B
+,	O
+1	O
+of	O
+30	O
+patients	O
+receiving	O
+prilocaine	O
+(	O
+P	O
+=	O
+0	O
+.	O
+03	O
+)	O
+had	O
+them	O
+,	O
+and	O
+none	O
+of	O
+30	O
+patients	O
+receiving	O
+bupivacaine	O
+had	O
+TNSs	B
+.	O
+
+Times	O
+to	O
+ambulate	O
+and	O
+to	O
+void	O
+were	O
+similar	O
+after	O
+lidocaine	O
+and	O
+prilocaine	O
+(	O
+150	O
+vs	O
+.	O
+165	O
+min	O
+and	O
+238	O
+vs	O
+.	O
+253	O
+min	O
+,	O
+respectively	O
+)	O
+but	O
+prolonged	O
+after	O
+bupivacaine	O
+(	O
+200	O
+and	O
+299	O
+min	O
+,	O
+respectively	O
+;	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Prilocaine	O
+may	O
+be	O
+preferable	O
+to	O
+lidocaine	O
+for	O
+short	O
+surgical	O
+procedures	O
+because	O
+it	O
+has	O
+a	O
+similar	O
+duration	O
+of	O
+action	O
+but	O
+a	O
+lower	O
+incidence	O
+of	O
+TNSs	B
+.	O
+
+Suxamethonium	O
+-	O
+induced	O
+cardiac	B
+arrest	I
+and	O
+death	B
+following	O
+5	O
+days	O
+of	O
+immobilization	O
+.	O
+
+The	O
+present	O
+report	O
+describes	O
+a	O
+case	O
+of	O
+cardiac	B
+arrest	I
+and	O
+subsequent	O
+death	B
+as	O
+a	O
+result	O
+of	O
+hyperkalaemia	B
+following	O
+the	O
+use	O
+of	O
+suxamethonium	O
+in	O
+a	O
+23	O
+-	O
+year	O
+-	O
+old	O
+Malawian	O
+woman	O
+.	O
+
+Five	O
+days	O
+after	O
+the	O
+onset	O
+of	O
+the	O
+symptoms	O
+of	O
+meningitis	B
+,	O
+the	O
+patient	O
+aspirated	O
+stomach	O
+contents	O
+and	O
+needed	O
+endotracheal	O
+intubation	O
+.	O
+
+Forty	O
+seconds	O
+after	O
+injection	O
+of	O
+suxamethonium	O
+,	O
+bradycardia	B
+and	O
+cardiac	B
+arrest	I
+occurred	O
+.	O
+
+Attempts	O
+to	O
+resuscitate	O
+the	O
+patient	O
+were	O
+not	O
+successful	O
+.	O
+
+The	O
+serum	O
+level	O
+of	O
+potassium	O
+was	O
+observed	O
+to	O
+be	O
+8	O
+.	O
+4	O
+mequiv	O
+L	O
+-	O
+1	O
+.	O
+
+Apart	O
+from	O
+the	O
+reduction	O
+in	O
+the	O
+patient	O
+'	O
+s	O
+level	O
+of	O
+consciousness	O
+,	O
+there	O
+were	O
+no	O
+signs	O
+of	O
+motor	O
+neurone	O
+damage	O
+or	O
+of	O
+any	O
+of	O
+the	O
+other	O
+known	O
+predisposing	O
+conditions	O
+for	O
+hyperkalaemia	B
+following	O
+the	O
+administration	O
+of	O
+suxamethonium	O
+.	O
+
+It	O
+is	O
+postulated	O
+that	O
+her	O
+death	B
+was	O
+caused	O
+by	O
+hypersensitivity	B
+to	O
+suxamethonium	O
+,	O
+associated	O
+with	O
+her	O
+5	O
+-	O
+day	O
+immobilization	O
+.	O
+
+Acute	O
+hepatitis	B
+,	O
+autoimmune	B
+hemolytic	I
+anemia	I
+,	O
+and	O
+erythroblastocytopenia	B
+induced	O
+by	O
+ceftriaxone	O
+.	O
+
+An	O
+80	O
+-	O
+yr	O
+-	O
+old	O
+man	O
+developed	O
+acute	O
+hepatitis	B
+shortly	O
+after	O
+ingesting	O
+oral	O
+ceftriaxone	O
+.	O
+
+Although	O
+the	O
+transaminases	O
+gradually	O
+returned	O
+to	O
+baseline	O
+after	O
+withholding	O
+the	O
+beta	O
+lactam	O
+antibiotic	O
+,	O
+there	O
+was	O
+a	O
+gradual	O
+increase	O
+in	O
+serum	O
+bilirubin	O
+and	O
+a	O
+decrease	O
+in	O
+hemoglobin	O
+concentration	O
+caused	O
+by	O
+an	O
+autoimmune	B
+hemolytic	I
+anemia	I
+and	O
+erythroblastocytopenia	B
+.	O
+
+These	O
+responded	O
+to	O
+systemic	O
+steroids	O
+and	O
+immunoglobulins	O
+.	O
+
+Despite	O
+the	O
+widespread	O
+use	O
+of	O
+these	O
+agents	O
+this	O
+triad	O
+of	O
+side	O
+effects	O
+has	O
+not	O
+previously	O
+been	O
+reported	O
+in	O
+connection	O
+with	O
+beta	O
+lactam	O
+antibiotics	O
+.	O
+
+Thyroxine	O
+abuse	O
+:	O
+an	O
+unusual	O
+case	O
+of	O
+thyrotoxicosis	B
+in	O
+pregnancy	O
+.	O
+
+Eating	B
+disorders	I
+and	O
+the	O
+associated	O
+behavioural	O
+problems	O
+and	O
+drug	B
+abuse	I
+are	O
+uncommon	O
+in	O
+pregnancy	O
+.	O
+
+When	O
+they	O
+do	O
+occur	O
+they	O
+are	O
+often	O
+unrecognized	O
+because	O
+of	O
+denial	O
+but	O
+when	O
+significant	O
+may	O
+pose	O
+a	O
+risk	O
+to	O
+both	O
+the	O
+mother	O
+and	O
+her	O
+fetus	O
+.	O
+
+This	O
+case	O
+illustrates	O
+a	O
+number	O
+of	O
+problems	O
+that	O
+may	O
+be	O
+encountered	O
+in	O
+women	O
+with	O
+eating	B
+disorders	I
+in	O
+pregnancy	O
+,	O
+including	O
+prolonged	O
+and	O
+recurrent	O
+metabolic	O
+disturbances	O
+and	O
+diuretic	O
+abuse	O
+.	O
+
+In	O
+particular	O
+it	O
+illustrates	O
+the	O
+derangements	O
+of	O
+thyroid	O
+function	O
+seen	O
+in	O
+pregnant	O
+women	O
+with	O
+eating	B
+disorders	I
+and	O
+reminds	O
+us	O
+that	O
+when	O
+a	O
+cause	O
+for	O
+thyrotoxicosis	B
+remains	O
+obscure	O
+,	O
+thyroxine	O
+abuse	O
+should	O
+be	O
+considered	O
+and	O
+explored	O
+.	O
+
+Repeated	O
+trimipramine	O
+induces	O
+dopamine	O
+D2	O
+/	O
+D3	O
+and	O
+alpha1	O
+-	O
+adrenergic	O
+up	O
+-	O
+regulation	O
+.	O
+
+Trimipramine	O
+(	O
+TRI	O
+)	O
+,	O
+which	O
+shows	O
+a	O
+clinical	O
+antidepressant	O
+activity	O
+,	O
+is	O
+chemically	O
+related	O
+to	O
+imipramine	O
+but	O
+does	O
+not	O
+inhibit	O
+the	O
+reuptake	O
+of	O
+noradrenaline	O
+and	O
+5	O
+-	O
+hydroxytryptamine	O
+,	O
+nor	O
+does	O
+it	O
+induce	O
+beta	O
+-	O
+adrenergic	O
+down	O
+-	O
+regulation	O
+.	O
+
+The	O
+mechanism	O
+of	O
+its	O
+antidepressant	O
+activity	O
+is	O
+still	O
+unknown	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+find	O
+out	O
+whether	O
+TRI	O
+given	O
+repeatedly	O
+was	O
+able	O
+to	O
+induce	O
+adaptive	O
+changes	O
+in	O
+the	O
+dopaminergic	O
+and	O
+alpha1	O
+-	O
+adrenergic	O
+systems	O
+,	O
+demonstrated	O
+by	O
+us	O
+previously	O
+for	O
+various	O
+antidepressants	O
+.	O
+
+TRI	O
+was	O
+given	O
+to	O
+male	O
+Wistar	O
+rats	O
+and	O
+male	O
+Albino	O
+Swiss	O
+mice	O
+perorally	O
+twice	O
+daily	O
+for	O
+14	O
+days	O
+.	O
+
+In	O
+the	O
+acute	O
+experiment	O
+TRI	O
+(	O
+given	O
+i	O
+.	O
+p	O
+.	O
+)	O
+does	O
+not	O
+antagonize	O
+the	O
+reserpine	O
+hypothermia	B
+in	O
+mice	O
+and	O
+does	O
+not	O
+potentiate	O
+the	O
+5	O
+-	O
+hydroxytryptophan	O
+head	O
+twitches	O
+in	O
+rats	O
+.	O
+
+TRI	O
+given	O
+repeatedly	O
+to	O
+rats	O
+increases	O
+the	O
+locomotor	O
+hyperactivity	B
+induced	O
+by	O
+d	O
+-	O
+amphetamine	O
+,	O
+quinpirole	O
+and	O
+(	O
++	O
+)	O
+-	O
+7	O
+-	O
+hydroxy	O
+-	O
+dipropyloaminotetralin	O
+(	O
+dopamine	O
+D2	O
+and	O
+D3	O
+effects	O
+)	O
+.	O
+
+The	O
+stereotypies	O
+induced	O
+by	O
+d	O
+-	O
+amphetamine	O
+or	O
+apomorphine	O
+are	O
+not	O
+potentiated	O
+by	O
+TRI	O
+.	O
+
+It	O
+increases	O
+the	O
+behaviour	O
+stimulation	O
+evoked	O
+by	O
+phenylephrine	O
+(	O
+given	O
+intraventricularly	O
+)	O
+in	O
+rats	O
+,	O
+evaluated	O
+in	O
+the	O
+open	O
+field	O
+test	O
+as	O
+well	O
+as	O
+the	O
+aggressiveness	B
+evoked	O
+by	O
+clonidine	O
+in	O
+mice	O
+,	O
+both	O
+these	O
+effects	O
+being	O
+mediated	O
+by	O
+an	O
+alpha1	O
+-	O
+adrenergic	O
+receptor	O
+.	O
+
+It	O
+may	O
+be	O
+concluded	O
+that	O
+,	O
+like	O
+other	O
+tricyclic	O
+antidepressants	O
+studied	O
+previously	O
+,	O
+TRI	O
+given	O
+repeatedly	O
+increases	O
+the	O
+responsiveness	O
+of	O
+brain	O
+dopamine	O
+D2	O
+and	O
+D3	O
+(	O
+locomotor	O
+activity	O
+but	O
+not	O
+stereotypy	O
+)	O
+as	O
+well	O
+as	O
+alpha1	O
+-	O
+adrenergic	O
+receptors	O
+to	O
+their	O
+agonists	O
+.	O
+
+A	O
+question	O
+arises	O
+whether	O
+the	O
+reuptake	O
+inhibition	O
+is	O
+of	O
+any	O
+importance	O
+to	O
+the	O
+adaptive	O
+changes	O
+induced	O
+by	O
+repeated	O
+antidepressants	O
+,	O
+suggested	O
+to	O
+be	O
+responsible	O
+for	O
+the	O
+antidepressant	O
+activity	O
+.	O
+
+Pethidine	O
+-	O
+associated	O
+seizure	B
+in	O
+a	O
+healthy	O
+adolescent	O
+receiving	O
+pethidine	O
+for	O
+postoperative	B
+pain	I
+control	O
+.	O
+
+A	O
+healthy	O
+17	O
+-	O
+year	O
+-	O
+old	O
+male	O
+received	O
+standard	O
+intermittent	O
+doses	O
+of	O
+pethidine	O
+via	O
+a	O
+patient	O
+-	O
+controlled	O
+analgesia	O
+(	O
+PCA	O
+)	O
+pump	O
+for	O
+management	O
+of	O
+postoperative	B
+pain	I
+control	O
+.	O
+
+Twenty	O
+-	O
+three	O
+h	O
+postoperatively	O
+he	O
+developed	O
+a	O
+brief	O
+self	O
+-	O
+limited	O
+seizure	B
+.	O
+
+Both	O
+plasma	O
+pethidine	O
+and	O
+norpethidine	O
+were	O
+elevated	O
+in	O
+the	O
+range	O
+associated	O
+with	O
+clinical	O
+manifestations	O
+of	O
+central	O
+nervous	O
+system	O
+excitation	O
+.	O
+
+No	O
+other	O
+risk	O
+factors	O
+for	O
+CNS	O
+toxicity	B
+were	O
+identified	O
+.	O
+
+This	O
+method	O
+allowed	O
+frequent	O
+self	O
+-	O
+dosing	O
+of	O
+pethidine	O
+at	O
+short	O
+time	O
+intervals	O
+and	O
+rapid	O
+accumulation	O
+of	O
+pethidine	O
+and	O
+norpethidine	O
+.	O
+
+The	O
+routine	O
+use	O
+of	O
+pethidine	O
+via	O
+PCA	O
+even	O
+for	O
+a	O
+brief	O
+postoperative	O
+analgesia	O
+should	O
+be	O
+reconsidered	O
+.	O
+
+An	O
+unusual	O
+toxic	O
+reaction	O
+to	O
+axillary	O
+block	O
+by	O
+mepivacaine	O
+with	O
+adrenaline	O
+.	O
+
+An	O
+increase	B
+in	I
+blood	I
+pressure	I
+,	O
+accompanied	O
+by	O
+atrial	B
+fibrillation	I
+,	O
+agitation	B
+,	O
+incomprehensible	B
+shouts	I
+and	O
+loss	B
+of	I
+consciousness	I
+,	O
+was	O
+observed	O
+in	O
+an	O
+elderly	O
+,	O
+ASA	O
+classification	O
+group	O
+II	O
+,	O
+cardiovascularly	O
+medicated	O
+male	O
+,	O
+12	O
+min	O
+after	O
+performance	O
+of	O
+axillary	O
+block	O
+with	O
+mepivacaine	O
+850	O
+mg	O
+containing	O
+adrenaline	O
+0	O
+.	O
+225	O
+mg	O
+,	O
+for	O
+correction	O
+of	O
+Dupuytren	B
+'	I
+s	I
+contracture	I
+.	O
+
+After	O
+intravenous	O
+administration	O
+of	O
+labetalol	O
+,	O
+metoprolol	O
+and	O
+midazolam	O
+the	O
+patient	O
+'	O
+s	O
+condition	O
+improved	O
+,	O
+and	O
+15	O
+min	O
+later	O
+he	O
+woke	O
+up	O
+.	O
+
+The	O
+block	O
+was	O
+successful	O
+and	O
+surgery	O
+was	O
+conducted	O
+as	O
+scheduled	O
+despite	O
+persisting	O
+atrial	B
+fibrillation	I
+.	O
+
+Postoperatively	O
+,	O
+the	O
+patient	O
+refused	O
+DC	O
+cardioversion	O
+and	O
+was	O
+treated	O
+medically	O
+.	O
+
+Both	O
+the	O
+temporal	O
+relationship	O
+of	O
+events	O
+and	O
+the	O
+response	O
+to	O
+treatment	O
+suggest	O
+that	O
+a	O
+rapid	O
+systemic	O
+absorption	O
+of	O
+mepivacaine	O
+with	O
+adrenaline	O
+and	O
+/	O
+or	O
+interaction	O
+of	O
+these	O
+drugs	O
+with	O
+the	O
+patient	O
+'	O
+s	O
+cardiovascular	O
+medications	O
+were	O
+responsible	O
+for	O
+the	O
+perioperative	O
+complications	O
+.	O
+
+Drug	O
+-	O
+associated	O
+acute	O
+-	O
+onset	O
+vanishing	B
+bile	I
+duct	I
+and	O
+Stevens	B
+-	I
+Johnson	I
+syndromes	I
+in	O
+a	O
+child	O
+.	O
+
+Acute	O
+vanishing	B
+bile	I
+duct	I
+syndrome	O
+is	O
+a	O
+rare	O
+but	O
+established	O
+cause	O
+of	O
+progressive	O
+cholestasis	B
+in	O
+adults	O
+,	O
+is	O
+most	O
+often	O
+drug	O
+or	O
+toxin	O
+related	O
+,	O
+and	O
+is	O
+of	O
+unknown	O
+pathogenesis	O
+.	O
+
+It	O
+has	O
+not	O
+been	O
+reported	O
+previously	O
+in	O
+children	O
+.	O
+
+Stevens	B
+-	I
+Johnson	I
+syndrome	I
+is	O
+a	O
+well	O
+-	O
+recognized	O
+immune	O
+complex	O
+-	O
+mediated	O
+hypersensitivity	B
+reaction	O
+that	O
+affects	O
+all	O
+age	O
+groups	O
+,	O
+is	O
+drug	O
+or	O
+infection	B
+induced	O
+,	O
+and	O
+has	O
+classic	O
+systemic	O
+,	O
+mucosal	O
+,	O
+and	O
+dermatologic	O
+manifestations	O
+.	O
+
+A	O
+previously	O
+healthy	O
+child	O
+who	O
+developed	O
+acute	O
+,	O
+severe	O
+,	O
+rapidly	O
+progressive	O
+vanishing	B
+bile	I
+duct	I
+syndrome	I
+shortly	O
+after	O
+Stevens	B
+-	I
+Johnson	I
+syndrome	I
+is	O
+described	O
+;	O
+this	O
+was	O
+temporally	O
+associated	O
+with	O
+ibuprofen	O
+use	O
+.	O
+
+Despite	O
+therapy	O
+with	O
+ursodeoxycholic	O
+acid	O
+,	O
+prednisone	O
+,	O
+and	O
+then	O
+tacrolimus	O
+,	O
+her	O
+cholestatic	B
+disease	I
+was	O
+unrelenting	O
+,	O
+with	O
+cirrhosis	B
+shown	O
+by	O
+biopsy	O
+6	O
+months	O
+after	O
+presentation	O
+.	O
+
+This	O
+case	O
+documents	O
+acute	O
+drug	O
+-	O
+related	O
+vanishing	B
+bile	I
+duct	I
+syndrome	I
+in	O
+the	O
+pediatric	O
+age	O
+group	O
+and	O
+suggests	O
+shared	O
+immune	O
+mechanisms	O
+in	O
+the	O
+pathogenesis	O
+of	O
+both	O
+Stevens	B
+-	I
+Johnson	I
+syndrome	I
+and	O
+vanishing	B
+bile	I
+duct	I
+syndrome	I
+.	O
+
+High	O
+incidence	O
+of	O
+primary	B
+pulmonary	I
+hypertension	I
+associated	O
+with	O
+appetite	O
+suppressants	O
+in	O
+Belgium	O
+.	O
+
+Primary	B
+pulmonary	I
+hypertension	I
+is	O
+a	O
+rare	O
+,	O
+progressive	O
+and	O
+incurable	O
+disease	O
+,	O
+which	O
+has	O
+been	O
+associated	O
+with	O
+the	O
+intake	O
+of	O
+appetite	O
+suppressant	O
+drugs	O
+.	O
+
+The	O
+importance	O
+of	O
+this	O
+association	O
+was	O
+evaluated	O
+in	O
+Belgium	O
+while	O
+this	O
+country	O
+still	O
+had	O
+no	O
+restriction	O
+on	O
+the	O
+prescription	O
+of	O
+appetite	O
+suppressants	O
+.	O
+
+Thirty	O
+-	O
+five	O
+patients	O
+with	O
+primary	B
+pulmonary	I
+hypertension	I
+and	O
+85	O
+matched	O
+controls	O
+were	O
+recruited	O
+over	O
+32	O
+months	O
+(	O
+1992	O
+-	O
+1994	O
+)	O
+in	O
+Belgium	O
+.	O
+
+Exposure	O
+to	O
+appetite	O
+-	O
+suppressants	O
+was	O
+assessed	O
+on	O
+the	O
+basis	O
+of	O
+hospital	O
+records	O
+and	O
+standardized	O
+interview	O
+.	O
+
+Twenty	O
+-	O
+three	O
+of	O
+the	O
+patients	O
+had	O
+previously	O
+taken	O
+appetite	O
+suppressants	O
+,	O
+mainly	O
+fenfluramines	O
+,	O
+as	O
+compared	O
+with	O
+only	O
+5	O
+of	O
+the	O
+controls	O
+(	O
+66	O
+versus	O
+6	O
+%	O
+,	O
+p	O
+<	O
+0	O
+.	O
+0001	O
+)	O
+.	O
+
+Five	O
+patients	O
+died	O
+before	O
+the	O
+interview	O
+,	O
+all	O
+of	O
+them	O
+had	O
+taken	O
+appetite	O
+suppressants	O
+.	O
+
+In	O
+8	O
+patients	O
+the	O
+diagnosis	O
+of	O
+primary	B
+pulmonary	I
+hypertension	I
+was	O
+uncertain	O
+,	O
+5	O
+of	O
+them	O
+had	O
+taken	O
+appetite	O
+suppressants	O
+.	O
+
+The	O
+patients	O
+who	O
+had	O
+been	O
+exposed	O
+to	O
+appetite	O
+suppressants	O
+tended	O
+to	O
+be	O
+on	O
+average	O
+more	O
+severely	O
+ill	O
+,	O
+and	O
+to	O
+have	O
+a	O
+shorter	O
+median	O
+delay	O
+between	O
+onset	O
+of	O
+symptoms	O
+and	O
+diagnosis	O
+.	O
+
+A	O
+policy	O
+of	O
+unrestricted	O
+prescription	O
+of	O
+appetite	O
+suppressants	O
+may	O
+lead	O
+to	O
+a	O
+high	O
+incidence	O
+of	O
+associated	O
+primary	B
+pulmonary	I
+hypertension	I
+.	O
+
+Intake	O
+of	O
+appetite	O
+suppressants	O
+may	O
+accelerate	O
+the	O
+progression	O
+of	O
+the	O
+disease	O
+.	O
+
+Inappropriate	O
+use	O
+of	O
+carbamazepine	O
+and	O
+vigabatrin	O
+in	O
+typical	O
+absence	B
+seizures	I
+.	O
+
+Carbamazepine	O
+and	O
+vigabatrin	O
+are	O
+contraindicated	O
+in	O
+typical	O
+absence	B
+seizures	I
+.	O
+
+Of	O
+18	O
+consecutive	O
+referrals	O
+of	O
+children	O
+with	O
+resistant	O
+typical	O
+absences	O
+only	O
+,	O
+eight	O
+were	O
+erroneously	O
+treated	O
+with	O
+carbamazepine	O
+either	O
+as	O
+monotherapy	O
+or	O
+as	O
+an	O
+add	O
+-	O
+on	O
+.	O
+
+Vigabatrin	O
+was	O
+also	O
+used	O
+in	O
+the	O
+treatment	O
+of	O
+two	O
+children	O
+.	O
+
+Frequency	O
+of	O
+absences	O
+increased	O
+in	O
+four	O
+children	O
+treated	O
+with	O
+carbamazepine	O
+and	O
+two	O
+of	O
+these	O
+developed	O
+myoclonic	B
+jerks	I
+,	O
+which	O
+resolved	O
+on	O
+withdrawal	O
+of	O
+carbamazepine	O
+.	O
+
+Absences	O
+were	O
+aggravated	O
+in	O
+both	O
+cases	O
+where	O
+vigabatrin	O
+was	O
+added	O
+on	O
+to	O
+concurrent	O
+treatment	O
+.	O
+
+Optimal	O
+control	O
+of	O
+the	O
+absences	O
+was	O
+achieved	O
+with	O
+sodium	O
+valproate	O
+,	O
+lamotrigine	O
+,	O
+or	O
+ethosuximide	O
+alone	O
+or	O
+in	O
+combination	O
+.	O
+
+Choreoathetoid	B
+movements	I
+associated	O
+with	O
+rapid	O
+adjustment	O
+to	O
+methadone	O
+.	O
+
+Choreatiform	B
+hyperkinesias	I
+are	O
+known	O
+to	O
+be	O
+occasional	O
+movement	B
+abnormalities	I
+during	O
+intoxications	O
+with	O
+cocaine	O
+but	O
+not	O
+opiates	O
+.	O
+
+This	O
+is	O
+a	O
+case	O
+report	O
+of	O
+euphoria	O
+and	O
+choreoathetoid	B
+movements	I
+both	O
+transiently	O
+induced	O
+by	O
+rapid	O
+adjustment	O
+to	O
+the	O
+selective	O
+mu	O
+-	O
+opioid	O
+receptor	O
+agonist	O
+methadone	O
+in	O
+an	O
+inpatient	O
+previously	O
+abusing	O
+heroine	O
+and	O
+cocaine	O
+.	O
+
+In	O
+addition	O
+,	O
+minor	O
+EEG	O
+abnormalities	O
+occurred	O
+.	O
+
+Possible	O
+underlying	O
+neurobiological	O
+phenomena	O
+are	O
+discussed	O
+.	O
+
+Adverse	O
+effects	O
+of	O
+the	O
+atypical	O
+antipsychotics	O
+.	O
+
+Collaborative	O
+Working	O
+Group	O
+on	O
+Clinical	O
+Trial	O
+Evaluations	O
+.	O
+
+Adverse	O
+effects	O
+of	O
+antipsychotics	O
+often	O
+lead	O
+to	O
+noncompliance	O
+.	O
+
+Thus	O
+,	O
+clinicians	O
+should	O
+address	O
+patients	O
+'	O
+concerns	O
+about	O
+adverse	O
+effects	O
+and	O
+attempt	O
+to	O
+choose	O
+medications	O
+that	O
+will	O
+improve	O
+their	O
+patients	O
+'	O
+quality	O
+of	O
+life	O
+as	O
+well	O
+as	O
+overall	O
+health	O
+.	O
+
+The	O
+side	O
+effect	O
+profiles	O
+of	O
+the	O
+atypical	O
+antipsychotics	O
+are	O
+more	O
+advantageous	O
+than	O
+those	O
+of	O
+the	O
+conventional	O
+neuroleptics	O
+.	O
+
+Conventional	O
+agents	O
+are	O
+associated	O
+with	O
+unwanted	O
+central	O
+nervous	O
+system	O
+effects	O
+,	O
+including	O
+extrapyramidal	B
+symptoms	I
+(	O
+EPS	B
+)	O
+,	O
+tardive	B
+dyskinesia	I
+,	O
+sedation	O
+,	O
+and	O
+possible	O
+impairment	O
+of	O
+some	O
+cognitive	O
+measures	O
+,	O
+as	O
+well	O
+as	O
+cardiac	O
+effects	O
+,	O
+orthostatic	B
+hypotension	I
+,	O
+hepatic	O
+changes	O
+,	O
+anticholinergic	O
+side	O
+effects	O
+,	O
+sexual	B
+dysfunction	I
+,	O
+and	O
+weight	B
+gain	I
+.	O
+
+The	O
+newer	O
+atypical	O
+agents	O
+have	O
+a	O
+lower	O
+risk	O
+of	O
+EPS	B
+,	O
+but	O
+are	O
+associated	O
+in	O
+varying	O
+degrees	O
+with	O
+sedation	O
+,	O
+cardiovascular	O
+effects	O
+,	O
+anticholinergic	O
+effects	O
+,	O
+weight	B
+gain	I
+,	O
+sexual	B
+dysfunction	I
+,	O
+hepatic	O
+effects	O
+,	O
+lowered	O
+seizure	B
+threshold	O
+(	O
+primarily	O
+clozapine	O
+)	O
+,	O
+and	O
+agranulocytosis	B
+(	O
+clozapine	O
+only	O
+)	O
+.	O
+
+Since	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+specific	O
+adverse	O
+effects	O
+differ	O
+among	O
+the	O
+various	O
+atypicals	O
+,	O
+the	O
+clinician	O
+should	O
+carefully	O
+consider	O
+which	O
+side	O
+effects	O
+are	O
+most	O
+likely	O
+to	O
+lead	O
+to	O
+the	O
+individual	O
+'	O
+s	O
+dissatisfaction	O
+and	O
+noncompliance	O
+before	O
+choosing	O
+an	O
+antipsychotic	O
+for	O
+a	O
+particular	O
+patient	O
+.	O
+
+A	O
+randomized	O
+,	O
+placebo	O
+-	O
+controlled	O
+dose	O
+-	O
+comparison	O
+trial	O
+of	O
+haloperidol	O
+for	O
+psychosis	B
+and	O
+disruptive	B
+behaviors	I
+in	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+goal	O
+of	O
+this	O
+study	O
+was	O
+to	O
+compare	O
+the	O
+efficacy	O
+and	O
+side	O
+effects	O
+of	O
+two	O
+doses	O
+of	O
+haloperidol	O
+and	O
+placebo	O
+in	O
+the	O
+treatment	O
+of	O
+psychosis	B
+and	O
+disruptive	B
+behaviors	I
+in	O
+patients	O
+with	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+.	O
+
+METHOD	O
+:	O
+In	O
+a	O
+6	O
+-	O
+week	O
+random	O
+-	O
+assignment	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+trial	O
+(	O
+phase	O
+A	O
+)	O
+,	O
+haloperidol	O
+,	O
+2	O
+-	O
+3	O
+mg	O
+/	O
+day	O
+(	O
+standard	O
+dose	O
+)	O
+,	O
+and	O
+haloperidol	O
+,	O
+0	O
+.	O
+50	O
+-	O
+0	O
+.	O
+75	O
+mg	O
+/	O
+day	O
+(	O
+low	O
+dose	O
+)	O
+,	O
+were	O
+compared	O
+in	O
+71	O
+outpatients	O
+with	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+.	O
+
+For	O
+the	O
+subsequent	O
+6	O
+-	O
+week	O
+double	O
+-	O
+blind	O
+crossover	O
+phase	O
+(	O
+phase	O
+B	O
+)	O
+,	O
+patients	O
+taking	O
+standard	O
+-	O
+or	O
+low	O
+-	O
+dose	O
+haloperidol	O
+were	O
+switched	O
+to	O
+placebo	O
+,	O
+and	O
+patients	O
+taking	O
+placebo	O
+were	O
+randomly	O
+assigned	O
+to	O
+standard	O
+-	O
+or	O
+low	O
+-	O
+dose	O
+haloperidol	O
+.	O
+
+RESULTS	O
+:	O
+For	O
+the	O
+60	O
+patients	O
+who	O
+completed	O
+phase	O
+A	O
+,	O
+standard	O
+-	O
+dose	O
+haloperidol	O
+was	O
+efficacious	O
+and	O
+superior	O
+to	O
+both	O
+low	O
+-	O
+dose	O
+haloperidol	O
+and	O
+placebo	O
+for	O
+scores	O
+on	O
+the	O
+Brief	O
+Psychiatric	O
+Rating	O
+Scale	O
+psychosis	B
+factor	O
+and	O
+on	O
+psychomotor	B
+agitation	I
+.	O
+
+Response	O
+rates	O
+according	O
+to	O
+three	O
+sets	O
+of	O
+criteria	O
+were	O
+greater	O
+with	O
+the	O
+standard	O
+dose	O
+(	O
+55	O
+%	O
+-	O
+60	O
+%	O
+)	O
+than	O
+the	O
+low	O
+dose	O
+(	O
+25	O
+%	O
+-	O
+35	O
+%	O
+)	O
+and	O
+placebo	O
+(	O
+25	O
+%	O
+-	O
+30	O
+%	O
+)	O
+.	O
+
+The	O
+advantage	O
+of	O
+standard	O
+dose	O
+over	O
+low	O
+dose	O
+was	O
+replicated	O
+in	O
+phase	O
+B	O
+.	O
+
+In	O
+phase	O
+A	O
+,	O
+extrapyramidal	B
+signs	I
+tended	O
+to	O
+be	O
+greater	O
+with	O
+the	O
+standard	O
+dose	O
+than	O
+in	O
+the	O
+other	O
+two	O
+conditions	O
+,	O
+primarily	O
+because	O
+of	O
+a	O
+subgroup	O
+(	O
+20	O
+%	O
+)	O
+who	O
+developed	O
+moderate	O
+to	O
+severe	O
+signs	O
+.	O
+
+Low	O
+-	O
+dose	O
+haloperidol	O
+did	O
+not	O
+differ	O
+from	O
+placebo	O
+on	O
+any	O
+measure	O
+of	O
+efficacy	O
+or	O
+side	O
+effects	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+results	O
+indicated	O
+a	O
+favorable	O
+therapeutic	O
+profile	O
+for	O
+haloperidol	O
+in	O
+doses	O
+of	O
+2	O
+-	O
+3	O
+mg	O
+/	O
+day	O
+,	O
+although	O
+a	O
+subgroup	O
+developed	O
+moderate	O
+to	O
+severe	O
+extrapyramidal	B
+signs	I
+.	O
+
+A	O
+starting	O
+dose	O
+of	O
+1	O
+mg	O
+/	O
+day	O
+with	O
+gradual	O
+,	O
+upward	O
+dose	O
+titration	O
+is	O
+recommended	O
+.	O
+
+The	O
+narrow	O
+therapeutic	O
+window	O
+observed	O
+with	O
+haloperidol	O
+may	O
+also	O
+apply	O
+to	O
+other	O
+neuroleptics	O
+used	O
+in	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+patients	O
+with	O
+psychosis	B
+and	O
+disruptive	B
+behaviors	I
+.	O
+
+Effects	O
+of	O
+acetylsalicylic	O
+acid	O
+,	O
+dipyridamole	O
+,	O
+and	O
+hydrocortisone	O
+on	O
+epinephrine	O
+-	O
+induced	O
+myocardial	B
+injury	I
+in	O
+dogs	O
+.	O
+
+A	O
+reproducible	O
+model	O
+for	O
+producing	O
+diffuse	O
+myocardial	B
+injury	I
+(	O
+epinephrine	O
+infusion	O
+)	O
+has	O
+been	O
+developed	O
+to	O
+study	O
+the	O
+cardioprotective	O
+effects	O
+of	O
+agents	O
+or	O
+maneuvers	O
+which	O
+might	O
+alter	O
+the	O
+evolution	O
+of	O
+acute	O
+myocardial	B
+infarction	I
+.	O
+
+Infusions	O
+of	O
+epinephrine	O
+(	O
+4	O
+mug	O
+per	O
+kilogram	O
+per	O
+minute	O
+for	O
+6	O
+hours	O
+)	O
+increased	O
+radiocalcium	O
+uptakes	O
+into	O
+intact	O
+myocardium	O
+and	O
+each	O
+of	O
+its	O
+subcellular	O
+components	O
+with	O
+the	O
+mitochondrial	O
+fraction	O
+showing	O
+the	O
+most	O
+consistent	O
+changes	O
+when	O
+compared	O
+to	O
+saline	O
+-	O
+infused	O
+control	O
+animals	O
+(	O
+4	O
+,	O
+957	O
+vs	O
+.	O
+827	O
+counts	O
+per	O
+minute	O
+per	O
+gram	O
+of	O
+dried	O
+tissue	O
+or	O
+fraction	O
+)	O
+.	O
+
+Myocardial	O
+concentrations	O
+of	O
+calcium	O
+also	O
+increased	O
+significantly	O
+(	O
+12	O
+.	O
+0	O
+vs	O
+.	O
+5	O
+.	O
+0	O
+mg	O
+.	O
+per	O
+100	O
+Gm	O
+.	O
+of	O
+fat	O
+-	O
+free	O
+dry	O
+weight	O
+)	O
+.	O
+
+Infusions	O
+of	O
+calcium	O
+chloride	O
+sufficient	O
+to	O
+raise	O
+serum	O
+calcium	O
+concentrations	O
+2	O
+mEq	O
+.	O
+per	O
+liter	O
+failed	O
+to	O
+increase	O
+calcium	O
+influx	O
+into	O
+the	O
+myocardial	O
+cell	O
+.	O
+
+Mitochondrial	O
+radiocalcium	O
+uptakes	O
+were	O
+significantly	O
+decreased	O
+in	O
+animals	O
+pretreated	O
+with	O
+acetylsalicylic	O
+acid	O
+or	O
+dipyridamole	O
+or	O
+when	O
+hydrocortisone	O
+was	O
+added	O
+to	O
+the	O
+epinephrine	O
+infusion	O
+(	O
+2	O
+,	O
+682	O
+,	O
+2	O
+,	O
+803	O
+,	O
+and	O
+3	O
+,	O
+424	O
+counts	O
+per	O
+minute	O
+per	O
+gram	O
+of	O
+dried	O
+fraction	O
+,	O
+respectively	O
+)	O
+.	O
+
+Myocardial	O
+calcium	O
+concentrations	O
+also	O
+were	O
+decreased	O
+(	O
+11	O
+.	O
+2	O
+,	O
+8	O
+.	O
+3	O
+,	O
+and	O
+8	O
+.	O
+9	O
+mg	O
+.	O
+per	O
+100	O
+Gm	O
+.	O
+of	O
+fat	O
+-	O
+free	O
+dry	O
+weight	O
+,	O
+respectively	O
+)	O
+in	O
+the	O
+three	O
+treatment	O
+groups	O
+,	O
+being	O
+significantly	O
+decreased	O
+only	O
+in	O
+the	O
+last	O
+two	O
+.	O
+
+Evidence	O
+of	O
+microscopic	O
+damage	O
+was	O
+graded	O
+as	O
+less	O
+severe	O
+in	O
+the	O
+three	O
+treatment	O
+groups	O
+.	O
+
+Acetylsalicylic	O
+acid	O
+,	O
+dipyridamole	O
+,	O
+and	O
+hydrocortisone	O
+all	O
+appear	O
+to	O
+have	O
+cardioprotective	O
+effects	O
+when	O
+tested	O
+in	O
+this	O
+model	O
+.	O
+
+Clinical	O
+and	O
+histopathologic	O
+examination	O
+of	O
+renal	O
+allografts	O
+treated	O
+with	O
+tacrolimus	O
+(	O
+FK506	O
+)	O
+for	O
+at	O
+least	O
+one	O
+year	O
+.	O
+
+BACKGROUND	O
+:	O
+We	O
+clinically	O
+and	O
+pathologically	O
+analyzed	O
+renal	O
+allografts	O
+from	O
+1	O
+9	O
+renal	O
+transplant	O
+patients	O
+treated	O
+with	O
+tacrolimus	O
+(	O
+FK506	O
+)	O
+for	O
+more	O
+than	O
+1	O
+year	O
+.	O
+
+METHODS	O
+:	O
+Twenty	O
+-	O
+six	O
+renal	O
+allograft	O
+biopsy	O
+specimens	O
+from	O
+1	O
+9	O
+renal	O
+transplant	O
+patients	O
+who	O
+underwent	O
+transplantations	O
+between	O
+1991	O
+and	O
+1993	O
+were	O
+evaluated	O
+.	O
+
+Thirteen	O
+biopsies	O
+were	O
+performed	O
+from	O
+stable	O
+functioning	O
+renal	O
+allografts	O
+with	O
+informed	O
+consent	O
+(	O
+nonepisode	O
+biopsy	O
+)	O
+and	O
+the	O
+other	O
+13	O
+were	O
+from	O
+dysfunctional	O
+renal	O
+allografts	O
+with	O
+a	O
+clinical	O
+indication	O
+for	O
+biopsy	O
+(	O
+episode	O
+biopsy	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+main	O
+pathologic	O
+diagnoses	O
+(	O
+some	O
+overlap	O
+)	O
+were	O
+acute	O
+rejection	O
+(	O
+AR	O
+;	O
+n	O
+=	O
+4	O
+)	O
+,	O
+chronic	O
+rejection	O
+(	O
+CR	O
+;	O
+n	O
+=	O
+5	O
+)	O
+,	O
+AR	O
++	O
+CR	O
+(	O
+n	O
+=	O
+4	O
+)	O
+,	O
+recurrent	O
+IgA	B
+nephropathy	I
+(	O
+n	O
+=	O
+5	O
+)	O
+,	O
+normal	O
+findings	O
+(	O
+n	O
+=	O
+2	O
+)	O
+,	O
+minimal	O
+-	O
+type	O
+chronic	O
+FK506	O
+nephropathy	B
+(	O
+n	O
+=	O
+9	O
+)	O
+,	O
+and	O
+mild	O
+-	O
+type	O
+FK506	O
+nephropathy	B
+(	O
+n	O
+=	O
+11	O
+)	O
+.	O
+
+Of	O
+the	O
+nonepisode	O
+biopsies	O
+,	O
+7	O
+and	O
+4	O
+biopsies	O
+showed	O
+minimal	O
+-	O
+type	O
+and	O
+mild	O
+-	O
+type	O
+chronic	O
+FK506	O
+nephropathy	B
+,	O
+respectively	O
+.	O
+
+Chronic	O
+FK506	O
+nephropathy	B
+consisted	O
+of	O
+rough	O
+and	O
+foamy	O
+tubular	O
+vacuolization	O
+(	O
+5	O
+biopsies	O
+)	O
+,	O
+arteriolopathy	O
+(	O
+angiodegeneration	O
+of	O
+the	O
+arteriolar	O
+wall	O
+;	O
+20	O
+biopsies	O
+)	O
+,	O
+focal	B
+segmental	I
+glomerulosclerosis	I
+(	O
+4	O
+biopsies	O
+)	O
+and	O
+the	O
+striped	O
+form	O
+of	O
+interstitial	B
+fibrosis	I
+(	O
+11	O
+biopsies	O
+)	O
+.	O
+
+The	O
+serum	O
+creatinine	O
+levels	O
+of	O
+patients	O
+in	O
+the	O
+mild	O
+-	O
+type	O
+chronic	O
+FK506	O
+nephropathy	B
+group	O
+,	O
+which	O
+included	O
+7	O
+episode	O
+biopsies	O
+,	O
+were	O
+statistically	O
+higher	O
+than	O
+those	O
+in	O
+the	O
+minimum	O
+-	O
+type	O
+chronic	O
+FK506	O
+-	O
+nephropathy	B
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+This	O
+study	O
+demonstrates	O
+that	O
+chronic	O
+FK506	O
+nephropathy	B
+consists	O
+primarily	O
+of	O
+arteriolopathy	O
+manifesting	O
+as	O
+insudative	O
+hyalinosis	O
+of	O
+the	O
+arteriolar	O
+wall	O
+,	O
+and	O
+suggests	O
+that	O
+mild	O
+-	O
+type	O
+chronic	O
+FK506	O
+nephropathy	B
+is	O
+a	O
+condition	O
+which	O
+may	O
+lead	O
+to	O
+deterioration	O
+of	O
+renal	O
+allograft	O
+function	O
+.	O
+
+Different	O
+lobular	O
+distributions	O
+of	O
+altered	O
+hepatocyte	O
+tight	O
+junctions	O
+in	O
+rat	O
+models	O
+of	O
+intrahepatic	B
+and	I
+extrahepatic	I
+cholestasis	I
+.	O
+
+Hepatocyte	O
+tight	O
+junctions	O
+(	O
+TJs	O
+)	O
+,	O
+the	O
+only	O
+intercellular	O
+barrier	O
+between	O
+the	O
+sinusoidal	O
+and	O
+the	O
+canalicular	O
+spaces	O
+,	O
+play	O
+a	O
+key	O
+role	O
+in	O
+bile	O
+formation	O
+.	O
+
+Although	O
+hepatocyte	O
+TJs	O
+are	O
+impaired	O
+in	O
+cholestasis	B
+,	O
+attempts	O
+to	O
+localize	O
+the	O
+precise	O
+site	O
+of	O
+hepatocyte	O
+TJ	O
+damage	O
+by	O
+freeze	O
+-	O
+fracture	O
+electron	O
+microscopy	O
+have	O
+produced	O
+limited	O
+information	O
+.	O
+
+Recently	O
+,	O
+several	O
+TJ	O
+-	O
+associated	O
+proteins	O
+like	O
+ZO	O
+-	O
+1	O
+and	O
+7H6	O
+have	O
+been	O
+identified	O
+and	O
+characterized	O
+.	O
+
+Immunolocalization	O
+of	O
+7H6	O
+appears	O
+to	O
+closely	O
+correlate	O
+with	O
+paracellular	O
+permeability	O
+.	O
+
+We	O
+used	O
+rat	O
+models	O
+of	O
+intrahepatic	B
+cholestasis	I
+by	O
+ethinyl	O
+estradiol	O
+(	O
+EE	O
+)	O
+treatment	O
+and	O
+extrahepatic	B
+cholestasis	I
+by	O
+bile	O
+duct	O
+ligation	O
+(	O
+BDL	O
+)	O
+to	O
+precisely	O
+determine	O
+the	O
+site	O
+of	O
+TJ	O
+damage	O
+.	O
+
+Alterations	O
+in	O
+hepatocyte	O
+TJs	O
+were	O
+assessed	O
+by	O
+double	O
+-	O
+immunolabeling	O
+for	O
+7H6	O
+and	O
+ZO	O
+-	O
+1	O
+using	O
+a	O
+confocal	O
+laser	O
+scanning	O
+microscope	O
+.	O
+
+In	O
+control	O
+rats	O
+,	O
+immunostaining	O
+for	O
+7H6	O
+and	O
+ZO	O
+-	O
+1	O
+colocalized	O
+to	O
+outline	O
+bile	O
+canaliculi	O
+in	O
+a	O
+continuous	O
+fashion	O
+.	O
+
+In	O
+contrast	O
+,	O
+7H6	O
+and	O
+ZO	O
+-	O
+1	O
+immunostaining	O
+was	O
+more	O
+discontinuous	O
+,	O
+outlining	O
+the	O
+bile	O
+canaliculi	O
+after	O
+BDL	O
+.	O
+
+Immunostaining	O
+for	O
+7H6	O
+,	O
+not	O
+ZO	O
+-	O
+1	O
+,	O
+decreased	O
+and	O
+predominantly	O
+appeared	O
+as	O
+discrete	O
+signals	O
+in	O
+the	O
+submembranous	O
+cytoplasm	O
+of	O
+periportal	O
+hepatocytes	O
+after	O
+BDL	O
+.	O
+
+After	O
+EE	O
+treatment	O
+,	O
+changes	O
+in	O
+immunostaining	O
+for	O
+7H6	O
+and	O
+ZO	O
+-	O
+1	O
+were	O
+similar	O
+to	O
+those	O
+seen	O
+in	O
+periportal	O
+hepatocytes	O
+after	O
+BDL	O
+,	O
+but	O
+distributed	O
+more	O
+diffusely	O
+throughout	O
+the	O
+lobule	O
+.	O
+
+This	O
+study	O
+is	O
+the	O
+first	O
+to	O
+demonstrate	O
+that	O
+impairment	O
+of	O
+hepatocyte	O
+TJs	O
+occurs	O
+heterogenously	O
+in	O
+the	O
+liver	O
+lobule	O
+after	O
+BDL	O
+and	O
+suggests	O
+that	O
+BDL	O
+and	O
+EE	O
+treatments	O
+produce	O
+different	O
+lobular	O
+distributions	O
+of	O
+increased	O
+paracellular	O
+permeability	O
+.	O
+
+Memory	O
+facilitation	O
+and	O
+stimulation	O
+of	O
+endogenous	O
+nerve	O
+growth	O
+factor	O
+synthesis	O
+by	O
+the	O
+acetylcholine	O
+releaser	O
+PG	O
+-	O
+9	O
+.	O
+
+The	O
+effects	O
+of	O
+PG	O
+-	O
+9	O
+(	O
+3alpha	O
+-	O
+tropyl	O
+2	O
+-	O
+(	O
+p	O
+-	O
+bromophenyl	O
+)	O
+propionate	O
+)	O
+,	O
+the	O
+acetylcholine	O
+releaser	O
+,	O
+on	O
+memory	O
+processes	O
+and	O
+nerve	O
+growth	O
+factor	O
+(	O
+NGF	O
+)	O
+synthesis	O
+were	O
+evaluated	O
+.	O
+
+In	O
+the	O
+mouse	O
+passive	O
+-	O
+avoidance	O
+test	O
+,	O
+PG	O
+-	O
+9	O
+(	O
+10	O
+-	O
+30	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+,	O
+administered	O
+20	O
+min	O
+before	O
+the	O
+training	O
+session	O
+,	O
+prevented	O
+amnesia	B
+induced	O
+by	O
+both	O
+the	O
+non	O
+selective	O
+antimuscarinic	O
+drug	O
+scopolamine	O
+and	O
+the	O
+M1	O
+-	O
+selective	O
+antagonist	O
+S	O
+-	O
+(	O
+-	O
+)	O
+-	O
+ET	O
+-	O
+126	O
+.	O
+
+In	O
+the	O
+same	O
+experimental	O
+conditions	O
+,	O
+PG	O
+-	O
+9	O
+(	O
+5	O
+-	O
+20	O
+microg	O
+per	O
+mouse	O
+,	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+was	O
+also	O
+able	O
+to	O
+prevent	O
+antimuscarine	O
+-	O
+induced	O
+amnesia	B
+,	O
+demonstrating	O
+a	O
+central	O
+localization	O
+of	O
+the	O
+activity	O
+.	O
+
+At	O
+the	O
+highest	O
+effective	O
+doses	O
+,	O
+PG	O
+-	O
+9	O
+did	O
+not	O
+produce	O
+any	O
+collateral	O
+symptoms	O
+as	O
+revealed	O
+by	O
+the	O
+Irwin	O
+test	O
+,	O
+and	O
+it	O
+did	O
+not	O
+modify	O
+spontaneous	O
+motility	O
+and	O
+inspection	O
+activity	O
+,	O
+as	O
+revealed	O
+by	O
+the	O
+hole	O
+-	O
+board	O
+test	O
+.	O
+
+PG	O
+-	O
+9	O
+was	O
+also	O
+able	O
+to	O
+increase	O
+the	O
+amount	O
+of	O
+NGF	O
+secreted	O
+in	O
+vitro	O
+by	O
+astrocytes	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+.	O
+
+The	O
+maximal	O
+NGF	O
+contents	O
+obtained	O
+by	O
+PG	O
+-	O
+9	O
+were	O
+17	O
+.	O
+6	O
+-	O
+fold	O
+of	O
+the	O
+control	O
+value	O
+.	O
+
+During	O
+culture	O
+,	O
+no	O
+morphological	O
+changes	O
+were	O
+found	O
+at	O
+effective	O
+concentrations	O
+of	O
+PG	O
+-	O
+9	O
+.	O
+
+The	O
+current	O
+work	O
+indicates	O
+the	O
+ability	O
+of	O
+PG	O
+-	O
+9	O
+to	O
+induce	O
+beneficial	O
+effects	O
+on	O
+cognitive	O
+processes	O
+and	O
+stimulate	O
+activity	O
+of	O
+NGF	O
+synthesis	O
+in	O
+astroglial	O
+cells	O
+.	O
+
+Therefore	O
+,	O
+PG	O
+-	O
+9	O
+could	O
+represent	O
+a	O
+potential	O
+useful	O
+drug	O
+able	O
+to	O
+improve	O
+the	O
+function	O
+of	O
+impaired	O
+cognitive	O
+processes	O
+.	O
+
+Mechanisms	O
+of	O
+FK	O
+506	O
+-	O
+induced	O
+hypertension	B
+in	O
+the	O
+rat	O
+.	O
+
+-	O
+Tacrolimus	O
+(	O
+FK	O
+506	O
+)	O
+is	O
+a	O
+powerful	O
+,	O
+widely	O
+used	O
+immunosuppressant	O
+.	O
+
+The	O
+clinical	O
+utility	O
+of	O
+FK	O
+506	O
+is	O
+complicated	O
+by	O
+substantial	O
+hypertension	B
+and	O
+nephrotoxicity	B
+.	O
+
+To	O
+clarify	O
+the	O
+mechanisms	O
+of	O
+FK	O
+506	O
+-	O
+induced	O
+hypertension	B
+,	O
+we	O
+studied	O
+the	O
+chronic	O
+effects	O
+of	O
+FK	O
+506	O
+on	O
+the	O
+synthesis	O
+of	O
+endothelin	O
+-	O
+1	O
+(	O
+ET	O
+-	O
+1	O
+)	O
+,	O
+the	O
+expression	O
+of	O
+mRNA	O
+of	O
+ET	O
+-	O
+1	O
+and	O
+endothelin	O
+-	O
+converting	O
+enzyme	O
+-	O
+1	O
+(	O
+ECE	O
+-	O
+1	O
+)	O
+,	O
+the	O
+endothelial	O
+nitric	O
+oxide	O
+synthase	O
+(	O
+eNOS	O
+)	O
+activity	O
+,	O
+and	O
+the	O
+expression	O
+of	O
+mRNA	O
+of	O
+eNOS	O
+and	O
+C	O
+-	O
+type	O
+natriuretic	O
+peptide	O
+(	O
+CNP	O
+)	O
+in	O
+rat	O
+blood	O
+vessels	O
+.	O
+
+In	O
+addition	O
+,	O
+the	O
+effect	O
+of	O
+the	O
+specific	O
+endothelin	O
+type	O
+A	O
+receptor	O
+antagonist	O
+FR	O
+139317	O
+on	O
+FK	O
+506	O
+-	O
+induced	O
+hypertension	B
+in	O
+rats	O
+was	O
+studied	O
+.	O
+
+FK	O
+506	O
+,	O
+5	O
+mg	O
+.	O
+
+kg	O
+-	O
+1	O
+.	O
+
+d	O
+-	O
+1	O
+given	O
+for	O
+4	O
+weeks	O
+,	O
+elevated	O
+blood	O
+pressure	O
+from	O
+102	O
++	O
+/	O
+-	O
+13	O
+to	O
+152	O
++	O
+/	O
+-	O
+15	O
+mm	O
+Hg	O
+and	O
+increased	O
+the	O
+synthesis	O
+of	O
+ET	O
+-	O
+1	O
+and	O
+the	O
+levels	O
+of	O
+ET	O
+-	O
+1	O
+mRNA	O
+in	O
+the	O
+mesenteric	O
+artery	O
+(	O
+240	O
+%	O
+and	O
+230	O
+%	O
+,	O
+respectively	O
+)	O
+.	O
+
+Little	O
+change	O
+was	O
+observed	O
+in	O
+the	O
+expression	O
+of	O
+ECE	O
+-	O
+1	O
+mRNA	O
+and	O
+CNP	O
+mRNA	O
+.	O
+
+FK	O
+506	O
+decreased	O
+eNOS	O
+activity	O
+and	O
+the	O
+levels	O
+of	O
+eNOS	O
+mRNA	O
+in	O
+the	O
+aorta	O
+(	O
+48	O
+%	O
+and	O
+55	O
+%	O
+,	O
+respectively	O
+)	O
+.	O
+
+The	O
+administration	O
+of	O
+FR	O
+139317	O
+(	O
+10	O
+mg	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+d	O
+-	O
+1	O
+)	O
+prevented	O
+FK	O
+506	O
+-	O
+induced	O
+hypertension	B
+in	O
+rats	O
+.	O
+
+These	O
+results	O
+indicate	O
+that	O
+FK	O
+506	O
+may	O
+increase	O
+blood	O
+pressure	O
+not	O
+only	O
+by	O
+increasing	O
+ET	O
+-	O
+1	O
+production	O
+but	O
+also	O
+by	O
+decreasing	O
+NO	O
+synthesis	O
+in	O
+the	O
+vasculature	O
+.	O
+
diff --git a/data/BC5CDR-disease/train_dev.tsv b/data/BC5CDR-disease/train_dev.tsv
new file mode 100644
index 0000000..04ad89e
--- /dev/null
+++ b/data/BC5CDR-disease/train_dev.tsv
@@ -0,0 +1,244764 @@
+Selegiline	O
+-	O
+induced	O
+postural	B
+hypotension	I
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+:	O
+a	O
+longitudinal	O
+study	O
+on	O
+the	O
+effects	O
+of	O
+drug	O
+withdrawal	O
+.	O
+
+OBJECTIVES	O
+:	O
+The	O
+United	O
+Kingdom	O
+Parkinson	B
+'	I
+s	I
+Disease	I
+Research	O
+Group	O
+(	O
+UKPDRG	O
+)	O
+trial	O
+found	O
+an	O
+increased	O
+mortality	O
+in	O
+patients	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+randomized	O
+to	O
+receive	O
+10	O
+mg	O
+selegiline	O
+per	O
+day	O
+and	O
+L	O
+-	O
+dopa	O
+compared	O
+with	O
+those	O
+taking	O
+L	O
+-	O
+dopa	O
+alone	O
+.	O
+
+Recently	O
+,	O
+we	O
+found	O
+that	O
+therapy	O
+with	O
+selegiline	O
+and	O
+L	O
+-	O
+dopa	O
+was	O
+associated	O
+with	O
+selective	O
+systolic	B
+orthostatic	I
+hypotension	I
+which	O
+was	O
+abolished	O
+by	O
+withdrawal	O
+of	O
+selegiline	O
+.	O
+
+This	O
+unwanted	O
+effect	O
+on	O
+postural	O
+blood	O
+pressure	O
+was	O
+not	O
+the	O
+result	O
+of	O
+underlying	O
+autonomic	O
+failure	O
+.	O
+
+The	O
+aims	O
+of	O
+this	O
+study	O
+were	O
+to	O
+confirm	O
+our	O
+previous	O
+findings	O
+in	O
+a	O
+separate	O
+cohort	O
+of	O
+patients	O
+and	O
+to	O
+determine	O
+the	O
+time	O
+course	O
+of	O
+the	O
+cardiovascular	O
+consequences	O
+of	O
+stopping	O
+selegiline	O
+in	O
+the	O
+expectation	O
+that	O
+this	O
+might	O
+shed	O
+light	O
+on	O
+the	O
+mechanisms	O
+by	O
+which	O
+the	O
+drug	O
+causes	O
+orthostatic	B
+hypotension	I
+.	O
+
+METHODS	O
+:	O
+The	O
+cardiovascular	O
+responses	O
+to	O
+standing	O
+and	O
+head	O
+-	O
+up	O
+tilt	O
+were	O
+studied	O
+repeatedly	O
+in	O
+PD	B
+patients	O
+receiving	O
+selegiline	O
+and	O
+as	O
+the	O
+drug	O
+was	O
+withdrawn	O
+.	O
+
+RESULTS	O
+:	O
+Head	O
+-	O
+up	O
+tilt	O
+caused	O
+systolic	B
+orthostatic	I
+hypotension	I
+which	O
+was	O
+marked	O
+in	O
+six	O
+of	O
+20	O
+PD	B
+patients	O
+on	O
+selegiline	O
+,	O
+one	O
+of	O
+whom	O
+lost	O
+consciousness	O
+with	O
+unrecordable	O
+blood	O
+pressures	O
+.	O
+
+A	O
+lesser	O
+degree	O
+of	O
+orthostatic	B
+hypotension	I
+occurred	O
+with	O
+standing	O
+.	O
+
+Orthostatic	B
+hypotension	I
+was	O
+ameliorated	O
+4	O
+days	O
+after	O
+withdrawal	O
+of	O
+selegiline	O
+and	O
+totally	O
+abolished	O
+7	O
+days	O
+after	O
+discontinuation	O
+of	O
+the	O
+drug	O
+.	O
+
+Stopping	O
+selegiline	O
+also	O
+significantly	O
+reduced	B
+the	I
+supine	I
+systolic	I
+and	I
+diastolic	I
+blood	I
+pressures	I
+consistent	O
+with	O
+a	O
+previously	O
+undescribed	O
+supine	O
+pressor	O
+action	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+study	O
+confirms	O
+our	O
+previous	O
+finding	O
+that	O
+selegiline	O
+in	O
+combination	O
+with	O
+L	O
+-	O
+dopa	O
+is	O
+associated	O
+with	O
+selective	O
+orthostatic	B
+hypotension	I
+.	O
+
+The	O
+possibilities	O
+that	O
+these	O
+cardiovascular	O
+findings	O
+might	O
+be	O
+the	O
+result	O
+of	O
+non	O
+-	O
+selective	O
+inhibition	O
+of	O
+monoamine	O
+oxidase	O
+or	O
+of	O
+amphetamine	O
+and	O
+metamphetamine	O
+are	O
+discussed	O
+.	O
+
+Further	O
+studies	O
+on	O
+effects	O
+of	O
+irrigation	O
+solutions	O
+on	O
+rat	O
+bladders	O
+.	O
+
+Further	O
+studies	O
+on	O
+the	O
+effects	O
+of	O
+certain	O
+irrigating	O
+fluids	O
+on	O
+the	O
+rat	O
+bladder	O
+for	O
+18	O
+hours	O
+are	O
+reported	O
+.	O
+
+The	O
+results	O
+have	O
+shown	O
+that	O
+the	O
+degradation	O
+product	O
+p	O
+-	O
+choloroaniline	O
+is	O
+not	O
+a	O
+significant	O
+factor	O
+in	O
+chlorhexidine	O
+-	O
+digluconate	O
+associated	O
+erosive	O
+cystitis	B
+.	O
+
+A	O
+high	O
+percentage	O
+of	O
+kanamycin	O
+-	O
+colistin	O
+and	O
+povidone	O
+-	O
+iodine	O
+irrigations	O
+were	O
+associated	O
+with	O
+erosive	O
+cystitis	B
+and	O
+suggested	O
+a	O
+possible	O
+complication	O
+with	O
+human	O
+usage	O
+.	O
+
+Picloxydine	O
+irrigations	O
+appeared	O
+to	O
+have	O
+a	O
+lower	O
+incidence	O
+of	O
+erosive	O
+cystitis	B
+but	O
+further	O
+studies	O
+would	O
+have	O
+to	O
+be	O
+performed	O
+before	O
+it	O
+could	O
+be	O
+recommended	O
+for	O
+use	O
+in	O
+urological	O
+procedures	O
+.	O
+
+Effects	O
+of	O
+tetrandrine	O
+and	O
+fangchinoline	O
+on	O
+experimental	O
+thrombosis	B
+in	O
+mice	O
+and	O
+human	O
+platelet	B
+aggregation	I
+.	O
+
+Tetrandrine	O
+(	O
+TET	O
+)	O
+and	O
+fangchinoline	O
+(	O
+FAN	O
+)	O
+are	O
+two	O
+naturally	O
+occurring	O
+analogues	O
+with	O
+a	O
+bisbenzylisoquinoline	O
+structure	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+undertaken	O
+to	O
+investigate	O
+the	O
+effects	O
+of	O
+TET	O
+and	O
+FAN	O
+on	O
+the	O
+experimental	O
+thrombosis	B
+induced	O
+by	O
+collagen	O
+plus	O
+epinephrine	O
+(	O
+EP	O
+)	O
+in	O
+mice	O
+,	O
+and	O
+platelet	B
+aggregation	I
+and	O
+blood	B
+coagulation	I
+in	O
+vitro	O
+.	O
+
+In	O
+the	O
+in	O
+vivo	O
+study	O
+,	O
+the	O
+administration	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+of	O
+TET	O
+and	O
+FAN	O
+in	O
+mice	O
+showed	O
+the	O
+inhibition	O
+of	O
+thrombosis	B
+by	O
+55	O
+%	O
+and	O
+35	O
+%	O
+,	O
+respectively	O
+,	O
+while	O
+acetylsalicylic	O
+acid	O
+(	O
+ASA	O
+,	O
+50	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+,	O
+a	O
+positive	O
+control	O
+,	O
+showed	O
+only	O
+30	O
+%	O
+inhibition	O
+.	O
+
+In	O
+the	O
+vitro	O
+human	O
+platelet	B
+aggregations	I
+induced	O
+by	O
+the	O
+agonists	O
+used	O
+in	O
+tests	O
+,	O
+TET	O
+and	O
+FAN	O
+showed	O
+the	O
+inhibitions	O
+dose	O
+dependently	O
+.	O
+
+In	O
+addition	O
+,	O
+neither	O
+TET	O
+nor	O
+FAN	O
+showed	O
+any	O
+anticoagulation	O
+activities	O
+in	O
+the	O
+measurement	O
+of	O
+the	O
+activated	O
+partial	O
+thromboplastin	O
+time	O
+(	O
+APTT	O
+)	O
+,	O
+prothrombin	O
+time	O
+(	O
+PT	O
+)	O
+and	O
+thrombin	O
+time	O
+(	O
+TT	O
+)	O
+using	O
+human	O
+-	O
+citrated	O
+plasma	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+antithrombosis	O
+of	O
+TET	O
+and	O
+FAN	O
+in	O
+mice	O
+may	O
+be	O
+mainly	O
+related	O
+to	O
+the	O
+antiplatelet	O
+aggregation	O
+activities	O
+.	O
+
+Angioedema	B
+due	O
+to	O
+ACE	O
+inhibitors	O
+:	O
+common	O
+and	O
+inadequately	O
+diagnosed	O
+.	O
+
+The	O
+estimated	O
+incidence	O
+of	O
+angioedema	B
+during	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+inhibitor	O
+treatment	O
+is	O
+between	O
+1	O
+and	O
+7	O
+per	O
+thousand	O
+patients	O
+.	O
+
+This	O
+potentially	O
+serious	O
+adverse	O
+effect	O
+is	O
+often	O
+preceded	O
+by	O
+minor	O
+manifestations	O
+that	O
+may	O
+serve	O
+as	O
+a	O
+warning	O
+.	O
+
+Cocaine	O
+-	O
+induced	O
+mood	B
+disorder	I
+:	O
+prevalence	O
+rates	O
+and	O
+psychiatric	B
+symptoms	O
+in	O
+an	O
+outpatient	O
+cocaine	O
+-	O
+dependent	O
+sample	O
+.	O
+
+This	O
+paper	O
+attempts	O
+to	O
+examine	O
+and	O
+compare	O
+prevalence	O
+rates	O
+and	O
+symptom	O
+patterns	O
+of	O
+DSM	O
+substance	O
+-	O
+induced	O
+and	O
+other	O
+mood	B
+disorders	I
+.	O
+
+243	O
+cocaine	O
+-	O
+dependent	O
+outpatients	O
+with	O
+cocaine	O
+-	O
+induced	O
+mood	B
+disorder	I
+(	O
+CIMD	B
+)	O
+,	O
+other	O
+mood	B
+disorders	I
+,	O
+or	O
+no	O
+mood	B
+disorder	I
+were	O
+compared	O
+on	O
+measures	O
+of	O
+psychiatric	B
+symptoms	O
+.	O
+
+The	O
+prevalence	O
+rate	O
+for	O
+CIMD	B
+was	O
+12	O
+%	O
+at	O
+baseline	O
+.	O
+
+Introduction	O
+of	O
+the	O
+DSM	O
+-	O
+IV	O
+diagnosis	O
+of	O
+CIMD	B
+did	O
+not	O
+substantially	O
+affect	O
+rates	O
+of	O
+the	O
+other	O
+depressive	B
+disorders	I
+.	O
+
+Patients	O
+with	O
+CIMD	B
+had	O
+symptom	O
+severity	O
+levels	O
+between	O
+those	O
+of	O
+patients	O
+with	O
+and	O
+without	O
+a	O
+mood	B
+disorder	I
+.	O
+
+These	O
+findings	O
+suggest	O
+some	O
+validity	O
+for	O
+the	O
+new	O
+DSM	O
+-	O
+IV	O
+diagnosis	O
+of	O
+CIMD	B
+,	O
+but	O
+also	O
+suggest	O
+that	O
+it	O
+requires	O
+further	O
+specification	O
+and	O
+replication	O
+.	O
+
+Effect	O
+of	O
+fucoidan	O
+treatment	O
+on	O
+collagenase	O
+-	O
+induced	O
+intracerebral	B
+hemorrhage	I
+in	O
+rats	O
+.	O
+
+Inflammatory	O
+cells	O
+are	O
+postulated	O
+to	O
+mediate	O
+some	O
+of	O
+the	O
+brain	B
+damage	I
+following	O
+ischemic	B
+stroke	I
+.	O
+
+Intracerebral	B
+hemorrhage	I
+is	O
+associated	O
+with	O
+more	O
+inflammation	B
+than	O
+ischemic	B
+stroke	I
+.	O
+
+We	O
+tested	O
+the	O
+sulfated	O
+polysaccharide	O
+fucoidan	O
+,	O
+which	O
+has	O
+been	O
+reported	O
+to	O
+reduce	O
+inflammatory	O
+brain	B
+damage	I
+,	O
+in	O
+a	O
+rat	O
+model	O
+of	O
+intracerebral	B
+hemorrhage	I
+induced	O
+by	O
+injection	O
+of	O
+bacterial	O
+collagenase	O
+into	O
+the	O
+caudate	O
+nucleus	O
+.	O
+
+Rats	O
+were	O
+treated	O
+with	O
+seven	O
+day	O
+intravenous	O
+infusion	O
+of	O
+fucoidan	O
+(	O
+30	O
+micrograms	O
+h	O
+-	O
+1	O
+)	O
+or	O
+vehicle	O
+.	O
+
+The	O
+hematoma	B
+was	O
+assessed	O
+in	O
+vivo	O
+by	O
+magnetic	O
+resonance	O
+imaging	O
+.	O
+
+Motor	O
+behavior	O
+,	O
+passive	O
+avoidance	O
+,	O
+and	O
+skilled	O
+forelimb	O
+function	O
+were	O
+tested	O
+repeatedly	O
+for	O
+six	O
+weeks	O
+.	O
+
+Fucoidan	O
+-	O
+treated	O
+rats	O
+exhibited	O
+evidence	O
+of	O
+impaired	B
+blood	I
+clotting	I
+and	O
+hemodilution	B
+,	O
+had	O
+larger	O
+hematomas	B
+,	O
+and	O
+tended	O
+to	O
+have	O
+less	O
+inflammation	B
+in	O
+the	O
+vicinity	O
+of	O
+the	O
+hematoma	B
+after	O
+three	O
+days	O
+.	O
+
+They	O
+showed	O
+significantly	O
+more	O
+rapid	O
+improvement	O
+of	O
+motor	O
+function	O
+in	O
+the	O
+first	O
+week	O
+following	O
+hemorrhage	B
+and	O
+better	O
+memory	O
+retention	O
+in	O
+the	O
+passive	O
+avoidance	O
+test	O
+.	O
+
+Acute	O
+white	B
+matter	I
+edema	I
+and	O
+eventual	O
+neuronal	B
+loss	I
+in	O
+the	O
+striatum	O
+adjacent	O
+to	O
+the	O
+hematoma	B
+did	O
+not	O
+differ	O
+between	O
+the	O
+two	O
+groups	O
+.	O
+
+Investigation	O
+of	O
+more	O
+specific	O
+anti	O
+-	O
+inflammatory	O
+agents	O
+and	O
+hemodiluting	O
+agents	O
+are	O
+warranted	O
+in	O
+intracerebral	B
+hemorrhage	I
+.	O
+
+Recurarization	O
+in	O
+the	O
+recovery	O
+room	O
+.	O
+
+A	O
+case	O
+of	O
+recurarization	O
+in	O
+the	O
+recovery	O
+room	O
+is	O
+reported	O
+.	O
+
+Accumulation	O
+of	O
+atracurium	O
+in	O
+the	O
+intravenous	O
+line	O
+led	O
+to	O
+recurarization	O
+after	O
+flushing	O
+the	O
+line	O
+in	O
+the	O
+recovery	O
+room	O
+.	O
+
+A	O
+respiratory	B
+arrest	I
+with	O
+severe	O
+desaturation	B
+and	O
+bradycardia	B
+occurred	O
+.	O
+
+Circumstances	O
+leading	O
+to	O
+this	O
+event	O
+and	O
+the	O
+mechanisms	O
+enabling	O
+a	O
+neuromuscular	B
+blockade	I
+to	O
+occur	O
+,	O
+following	O
+the	O
+administration	O
+of	O
+a	O
+small	O
+dose	O
+of	O
+relaxant	O
+,	O
+are	O
+discussed	O
+.	O
+
+The	O
+haemodynamic	O
+effects	O
+of	O
+propofol	O
+in	O
+combination	O
+with	O
+ephedrine	O
+in	O
+elderly	O
+patients	O
+(	O
+ASA	O
+groups	O
+3	O
+and	O
+4	O
+)	O
+.	O
+
+The	O
+marked	O
+vasodilator	O
+and	O
+negative	O
+inotropic	O
+effects	O
+of	O
+propofol	O
+are	O
+disadvantages	O
+in	O
+frail	O
+elderly	O
+patients	O
+.	O
+
+We	O
+investigated	O
+the	O
+safety	O
+and	O
+efficacy	O
+of	O
+adding	O
+different	O
+doses	O
+of	O
+ephedrine	O
+to	O
+propofol	O
+in	O
+order	O
+to	O
+obtund	O
+the	O
+hypotensive	B
+response	O
+.	O
+
+The	O
+haemodynamic	O
+effects	O
+of	O
+adding	O
+15	O
+,	O
+20	O
+or	O
+25	O
+mg	O
+of	O
+ephedrine	O
+to	O
+200	O
+mg	O
+of	O
+propofol	O
+were	O
+compared	O
+to	O
+control	O
+in	O
+40	O
+ASA	O
+3	O
+/	O
+4	O
+patients	O
+over	O
+60	O
+years	O
+presenting	O
+for	O
+genito	O
+-	O
+urinary	O
+surgery	O
+.	O
+
+The	O
+addition	O
+of	O
+ephedrine	O
+to	O
+propofol	O
+appears	O
+to	O
+be	O
+an	O
+effective	O
+method	O
+of	O
+obtunding	O
+the	O
+hypotensive	B
+response	O
+to	O
+propofol	O
+at	O
+all	O
+doses	O
+used	O
+in	O
+this	O
+study	O
+.	O
+
+However	O
+,	O
+marked	O
+tachycardia	B
+associated	O
+with	O
+the	O
+use	O
+of	O
+ephedrine	O
+in	O
+combination	O
+with	O
+propofol	O
+occurred	O
+in	O
+the	O
+majority	O
+of	O
+patients	O
+,	O
+occasionally	O
+reaching	O
+high	O
+levels	O
+in	O
+individual	O
+patients	O
+.	O
+
+Due	O
+to	O
+the	O
+risk	O
+of	O
+this	O
+tachycardia	B
+inducing	O
+myocardial	B
+ischemia	I
+,	O
+we	O
+would	O
+not	O
+recommend	O
+the	O
+use	O
+in	O
+elderly	O
+patients	O
+of	O
+any	O
+of	O
+the	O
+ephedrine	O
+/	O
+propofol	O
+/	O
+mixtures	O
+studied	O
+.	O
+
+Gemcitabine	O
+plus	O
+vinorelbine	O
+in	O
+nonsmall	B
+cell	I
+lung	I
+carcinoma	I
+patients	O
+age	O
+70	O
+years	O
+or	O
+older	O
+or	O
+patients	O
+who	O
+cannot	O
+receive	O
+cisplatin	O
+.	O
+
+Oncopaz	O
+Cooperative	O
+Group	O
+.	O
+
+BACKGROUND	O
+:	O
+Although	O
+the	O
+prevalence	O
+of	O
+nonsmall	B
+cell	I
+lung	I
+carcinoma	I
+(	O
+NSCLC	B
+)	O
+is	O
+high	O
+among	O
+elderly	O
+patients	O
+,	O
+few	O
+data	O
+are	O
+available	O
+regarding	O
+the	O
+efficacy	O
+and	O
+toxicity	B
+of	O
+chemotherapy	O
+in	O
+this	O
+group	O
+of	O
+patients	O
+.	O
+
+Recent	O
+reports	O
+indicate	O
+that	O
+single	O
+agent	O
+therapy	O
+with	O
+vinorelbine	O
+(	O
+VNB	O
+)	O
+or	O
+gemcitabine	O
+(	O
+GEM	O
+)	O
+may	O
+obtain	O
+a	O
+response	O
+rate	O
+of	O
+20	O
+-	O
+30	O
+%	O
+in	O
+elderly	O
+patients	O
+,	O
+with	O
+acceptable	O
+toxicity	B
+and	O
+improvement	O
+in	O
+symptoms	O
+and	O
+quality	O
+of	O
+life	O
+.	O
+
+In	O
+the	O
+current	O
+study	O
+the	O
+efficacy	O
+and	O
+toxicity	B
+of	O
+the	O
+combination	O
+of	O
+GEM	O
+and	O
+VNB	O
+in	O
+elderly	O
+patients	O
+with	O
+advanced	O
+NSCLC	B
+or	O
+those	O
+with	O
+some	O
+contraindication	O
+to	O
+receiving	O
+cisplatin	O
+were	O
+assessed	O
+.	O
+
+METHODS	O
+:	O
+Forty	O
+-	O
+nine	O
+patients	O
+with	O
+advanced	O
+NSCLC	B
+were	O
+included	O
+,	O
+38	O
+of	O
+whom	O
+were	O
+age	O
+>	O
+/	O
+=	O
+70	O
+years	O
+and	O
+11	O
+were	O
+age	O
+<	O
+70	O
+years	O
+but	O
+who	O
+had	O
+some	O
+contraindication	O
+to	O
+receiving	O
+cisplatin	O
+.	O
+
+All	O
+patients	O
+were	O
+evaluable	O
+for	O
+response	O
+and	O
+toxicity	B
+.	O
+
+Treatment	O
+was	O
+comprised	O
+of	O
+VNB	O
+,	O
+25	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+,	O
+plus	O
+GEM	O
+,	O
+1000	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+,	O
+both	O
+on	O
+Days	O
+1	O
+,	O
+8	O
+,	O
+and	O
+15	O
+every	O
+28	O
+days	O
+.	O
+
+Patients	O
+received	O
+a	O
+minimum	O
+of	O
+three	O
+courses	O
+unless	O
+progressive	O
+disease	O
+was	O
+detected	O
+.	O
+
+RESULTS	O
+:	O
+One	O
+hundred	O
+sixty	O
+-	O
+five	O
+courses	O
+were	O
+administered	O
+,	O
+with	O
+a	O
+median	O
+of	O
+3	O
+.	O
+
+6	O
+courses	O
+per	O
+patient	O
+.	O
+
+The	O
+overall	O
+response	O
+rate	O
+was	O
+26	O
+%	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+15	O
+-	O
+41	O
+%	O
+)	O
+.	O
+
+Two	O
+patients	O
+attained	O
+a	O
+complete	O
+response	O
+(	O
+4	O
+%	O
+)	O
+and	O
+11	O
+patients	O
+(	O
+22	O
+%	O
+)	O
+achieved	O
+a	O
+partial	O
+response	O
+.	O
+
+Eastern	O
+Cooperative	O
+Oncology	O
+Group	O
+performance	O
+status	O
+improved	O
+in	O
+35	O
+%	O
+of	O
+those	O
+patients	O
+with	O
+an	O
+initial	O
+value	O
+>	O
+0	O
+,	O
+whereas	O
+relief	O
+of	O
+at	O
+least	O
+1	O
+symptom	O
+without	O
+worsening	O
+of	O
+other	O
+symptoms	O
+was	O
+noted	O
+in	O
+27	O
+patients	O
+(	O
+55	O
+%	O
+)	O
+.	O
+
+The	O
+median	O
+time	O
+to	O
+progression	O
+was	O
+16	O
+weeks	O
+and	O
+the	O
+1	O
+-	O
+year	O
+survival	O
+rate	O
+was	O
+33	O
+%	O
+.	O
+
+Toxicity	B
+was	O
+mild	O
+.	O
+
+Six	O
+patients	O
+(	O
+12	O
+%	O
+)	O
+had	O
+World	O
+Health	O
+Organization	O
+Grade	O
+3	O
+-	O
+4	O
+neutropenia	B
+,	O
+2	O
+patients	O
+(	O
+4	O
+%	O
+)	O
+had	O
+Grade	O
+3	O
+-	O
+4	O
+thrombocytopenia	B
+,	O
+and	O
+2	O
+patients	O
+(	O
+4	O
+%	O
+)	O
+had	O
+Grade	O
+3	O
+neurotoxicity	B
+.	O
+
+Three	O
+patients	O
+with	O
+severe	O
+neutropenia	B
+(	O
+6	O
+%	O
+)	O
+died	O
+of	O
+sepsis	B
+.	O
+
+The	O
+median	O
+age	O
+of	O
+those	O
+patients	O
+developing	O
+Grade	O
+3	O
+-	O
+4	O
+neutropenia	B
+was	O
+significantly	O
+higher	O
+than	O
+that	O
+of	O
+the	O
+remaining	O
+patients	O
+(	O
+75	O
+years	O
+vs	O
+.	O
+72	O
+years	O
+;	O
+P	O
+=	O
+0	O
+.	O
+047	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+combination	O
+of	O
+GEM	O
+and	O
+VNB	O
+is	O
+moderately	O
+active	O
+and	O
+well	O
+tolerated	O
+except	O
+in	O
+patients	O
+age	O
+>	O
+/	O
+=	O
+75	O
+years	O
+.	O
+
+This	O
+age	O
+group	O
+had	O
+an	O
+increased	O
+risk	O
+of	O
+myelosuppression	B
+.	O
+
+Therefore	O
+the	O
+prophylactic	O
+use	O
+of	O
+granulocyte	O
+-	O
+colony	O
+stimulating	O
+factor	O
+should	O
+be	O
+considered	O
+with	O
+this	O
+treatment	O
+.	O
+
+New	O
+chemotherapy	O
+combinations	O
+with	O
+higher	O
+activity	O
+and	O
+lower	O
+toxicity	B
+are	O
+needed	O
+for	O
+elderly	O
+patients	O
+with	O
+advanced	O
+NSCLC	B
+.	O
+
+A	O
+selective	O
+dopamine	O
+D4	O
+receptor	O
+antagonist	O
+,	O
+NRA0160	O
+:	O
+a	O
+preclinical	O
+neuropharmacological	O
+profile	O
+.	O
+
+NRA0160	O
+,	O
+5	O
+-	O
+[	O
+2	O
+-	O
+(	O
+4	O
+-	O
+(	O
+3	O
+-	O
+fluorobenzylidene	O
+)	O
+piperidin	O
+-	O
+1	O
+-	O
+yl	O
+)	O
+ethyl	O
+]	O
+-	O
+4	O
+-	O
+(	O
+4	O
+-	O
+fluorophenyl	O
+)	O
+thiazole	O
+-	O
+2	O
+-	O
+carboxamide	O
+,	O
+has	O
+a	O
+high	O
+affinity	O
+for	O
+human	O
+cloned	O
+dopamine	O
+D4	O
+.	O
+2	O
+,	O
+D4	O
+.	O
+4	O
+and	O
+D4	O
+.	O
+7	O
+receptors	O
+,	O
+with	O
+Ki	O
+values	O
+of	O
+0	O
+.	O
+5	O
+,	O
+0	O
+.	O
+9	O
+and	O
+2	O
+.	O
+7	O
+nM	O
+,	O
+respectively	O
+.	O
+
+NRA0160	O
+is	O
+over	O
+20	O
+,	O
+000fold	O
+more	O
+potent	O
+at	O
+the	O
+dopamine	O
+D4	O
+.	O
+2	O
+receptor	O
+compared	O
+with	O
+the	O
+human	O
+cloned	O
+dopamine	O
+D2L	O
+receptor	O
+.	O
+
+NRA0160	O
+has	O
+negligible	O
+affinity	O
+for	O
+the	O
+human	O
+cloned	O
+dopamine	O
+D3	O
+receptor	O
+(	O
+Ki	O
+=	O
+39	O
+nM	O
+)	O
+,	O
+rat	O
+serotonin	O
+(	O
+5	O
+-	O
+HT	O
+)	O
+2A	O
+receptors	O
+(	O
+Ki	O
+=	O
+180	O
+nM	O
+)	O
+and	O
+rat	O
+alpha1	O
+adrenoceptor	O
+(	O
+Ki	O
+=	O
+237	O
+nM	O
+)	O
+.	O
+
+NRA0160	O
+and	O
+clozapine	O
+antagonized	O
+locomotor	O
+hyperactivity	B
+induced	O
+by	O
+methamphetamine	O
+(	O
+MAP	O
+)	O
+in	O
+mice	O
+.	O
+
+NRA0160	O
+and	O
+clozapine	O
+antagonized	O
+MAP	O
+-	O
+induced	O
+stereotyped	O
+behavior	O
+in	O
+mice	O
+,	O
+although	O
+their	O
+effects	O
+did	O
+not	O
+exceed	O
+50	O
+%	O
+inhibition	O
+,	O
+even	O
+at	O
+the	O
+highest	O
+dose	O
+given	O
+.	O
+
+NRA0160	O
+and	O
+clozapine	O
+significantly	O
+induced	O
+catalepsy	B
+in	O
+rats	O
+,	O
+although	O
+their	O
+effects	O
+did	O
+not	O
+exceed	O
+50	O
+%	O
+induction	O
+even	O
+at	O
+the	O
+highest	O
+dose	O
+given	O
+.	O
+
+NRA0160	O
+and	O
+clozapine	O
+significantly	O
+reversed	O
+the	O
+disruption	O
+of	O
+prepulse	O
+inhibition	O
+(	O
+PPI	O
+)	O
+in	O
+rats	O
+produced	O
+by	O
+apomorphine	O
+.	O
+
+NRA0160	O
+and	O
+clozapine	O
+significantly	O
+shortened	O
+the	O
+phencyclidine	O
+(	O
+PCP	O
+)	O
+-	O
+induced	O
+prolonged	O
+swimming	O
+latency	O
+in	O
+rats	O
+in	O
+a	O
+water	O
+maze	O
+task	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+NRA0160	O
+may	O
+have	O
+unique	O
+antipsychotic	O
+activities	O
+without	O
+the	O
+liability	O
+of	O
+motor	O
+side	O
+effects	O
+typical	O
+of	O
+classical	O
+antipsychotics	O
+.	O
+
+Warfarin	O
+-	O
+induced	O
+artery	B
+calcification	I
+is	O
+accelerated	O
+by	O
+growth	O
+and	O
+vitamin	O
+D	O
+.	O
+
+The	O
+present	O
+studies	O
+demonstrate	O
+that	O
+growth	O
+and	O
+vitamin	O
+D	O
+treatment	O
+enhance	O
+the	O
+extent	O
+of	O
+artery	B
+calcification	I
+in	O
+rats	O
+given	O
+sufficient	O
+doses	O
+of	O
+Warfarin	O
+to	O
+inhibit	O
+gamma	O
+-	O
+carboxylation	O
+of	O
+matrix	O
+Gla	O
+protein	O
+,	O
+a	O
+calcification	B
+inhibitor	O
+known	O
+to	O
+be	O
+expressed	O
+by	O
+smooth	O
+muscle	O
+cells	O
+and	O
+macrophages	O
+in	O
+the	O
+artery	O
+wall	O
+.	O
+
+The	O
+first	O
+series	O
+of	O
+experiments	O
+examined	O
+the	O
+influence	O
+of	O
+age	O
+and	O
+growth	O
+status	O
+on	O
+artery	B
+calcification	I
+in	O
+Warfarin	O
+-	O
+treated	O
+rats	O
+.	O
+
+Treatment	O
+for	O
+2	O
+weeks	O
+with	O
+Warfarin	O
+caused	O
+massive	O
+focal	O
+calcification	B
+of	I
+the	I
+artery	I
+media	O
+in	O
+20	O
+-	O
+day	O
+-	O
+old	O
+rats	O
+and	O
+less	O
+extensive	O
+focal	O
+calcification	B
+in	O
+42	O
+-	O
+day	O
+-	O
+old	O
+rats	O
+.	O
+
+In	O
+contrast	O
+,	O
+no	O
+artery	B
+calcification	I
+could	O
+be	O
+detected	O
+in	O
+10	O
+-	O
+month	O
+-	O
+old	O
+adult	O
+rats	O
+even	O
+after	O
+4	O
+weeks	O
+of	O
+Warfarin	O
+treatment	O
+.	O
+
+To	O
+directly	O
+examine	O
+the	O
+importance	O
+of	O
+growth	O
+to	O
+Warfarin	O
+-	O
+induced	O
+artery	B
+calcification	I
+in	O
+animals	O
+of	O
+the	O
+same	O
+age	O
+,	O
+20	O
+-	O
+day	O
+-	O
+old	O
+rats	O
+were	O
+fed	O
+for	O
+2	O
+weeks	O
+either	O
+an	O
+ad	O
+libitum	O
+diet	O
+or	O
+a	O
+6	O
+-	O
+g	O
+/	O
+d	O
+restricted	O
+diet	O
+that	O
+maintains	O
+weight	O
+but	O
+prevents	O
+growth	O
+.	O
+
+Concurrent	O
+treatment	O
+of	O
+both	O
+dietary	O
+groups	O
+with	O
+Warfarin	O
+produced	O
+massive	O
+focal	O
+calcification	B
+of	I
+the	I
+artery	I
+media	O
+in	O
+the	O
+ad	O
+libitum	O
+-	O
+fed	O
+rats	O
+but	O
+no	O
+detectable	O
+artery	B
+calcification	I
+in	O
+the	O
+restricted	O
+-	O
+diet	O
+,	O
+growth	O
+-	O
+inhibited	O
+group	O
+.	O
+
+Although	O
+the	O
+explanation	O
+for	O
+the	O
+association	O
+between	O
+artery	B
+calcification	I
+and	O
+growth	O
+status	O
+cannot	O
+be	O
+determined	O
+from	O
+the	O
+present	O
+study	O
+,	O
+there	O
+was	O
+a	O
+relationship	O
+between	O
+higher	O
+serum	O
+phosphate	O
+and	O
+susceptibility	O
+to	O
+artery	B
+calcification	I
+,	O
+with	O
+30	O
+%	O
+higher	O
+levels	O
+of	O
+serum	O
+phosphate	O
+in	O
+young	O
+,	O
+ad	O
+libitum	O
+-	O
+fed	O
+rats	O
+compared	O
+with	O
+either	O
+of	O
+the	O
+groups	O
+that	O
+was	O
+resistant	O
+to	O
+Warfarin	O
+-	O
+induced	O
+artery	B
+calcification	I
+,	O
+ie	O
+,	O
+the	O
+10	O
+-	O
+month	O
+-	O
+old	O
+rats	O
+and	O
+the	O
+restricted	O
+-	O
+diet	O
+,	O
+growth	O
+-	O
+inhibited	O
+young	O
+rats	O
+.	O
+
+This	O
+observation	O
+suggests	O
+that	O
+increased	O
+susceptibility	O
+to	O
+Warfarin	O
+-	O
+induced	O
+artery	B
+calcification	I
+could	O
+be	O
+related	O
+to	O
+higher	O
+serum	O
+phosphate	O
+levels	O
+.	O
+
+The	O
+second	O
+set	O
+of	O
+experiments	O
+examined	O
+the	O
+possible	O
+synergy	O
+between	O
+vitamin	O
+D	O
+and	O
+Warfarin	O
+in	O
+artery	B
+calcification	I
+.	O
+
+High	O
+doses	O
+of	O
+vitamin	O
+D	O
+are	O
+known	O
+to	O
+cause	O
+calcification	B
+of	I
+the	I
+artery	I
+media	O
+in	O
+as	O
+little	O
+as	O
+3	O
+to	O
+4	O
+days	O
+.	O
+
+High	O
+doses	O
+of	O
+the	O
+vitamin	O
+K	O
+antagonist	O
+Warfarin	O
+are	O
+also	O
+known	O
+to	O
+cause	O
+calcification	B
+of	I
+the	I
+artery	I
+media	O
+,	O
+but	O
+at	O
+treatment	O
+times	O
+of	O
+2	O
+weeks	O
+or	O
+longer	O
+yet	O
+not	O
+at	O
+1	O
+week	O
+.	O
+
+In	O
+the	O
+current	O
+study	O
+,	O
+we	O
+investigated	O
+the	O
+synergy	O
+between	O
+these	O
+2	O
+treatments	O
+and	O
+found	O
+that	O
+concurrent	O
+Warfarin	O
+administration	O
+dramatically	O
+increased	O
+the	O
+extent	O
+of	O
+calcification	B
+in	O
+the	O
+media	O
+of	O
+vitamin	O
+D	O
+-	O
+treated	O
+rats	O
+at	O
+3	O
+and	O
+4	O
+days	O
+.	O
+
+There	O
+was	O
+a	O
+close	O
+parallel	O
+between	O
+the	O
+effect	O
+of	O
+vitamin	O
+D	O
+dose	O
+on	O
+artery	B
+calcification	I
+and	O
+the	O
+effect	O
+of	O
+vitamin	O
+D	O
+dose	O
+on	O
+the	O
+elevation	O
+of	O
+serum	O
+calcium	O
+,	O
+which	O
+suggests	O
+that	O
+vitamin	O
+D	O
+may	O
+induce	O
+artery	B
+calcification	I
+through	O
+its	O
+effect	O
+on	O
+serum	O
+calcium	O
+.	O
+
+Because	O
+Warfarin	O
+treatment	O
+had	O
+no	O
+effect	O
+on	O
+the	O
+elevation	O
+in	O
+serum	O
+calcium	O
+produced	O
+by	O
+vitamin	O
+D	O
+,	O
+the	O
+synergy	O
+between	O
+Warfarin	O
+and	O
+vitamin	O
+D	O
+is	O
+probably	O
+best	O
+explained	O
+by	O
+the	O
+hypothesis	O
+that	O
+Warfarin	O
+inhibits	O
+the	O
+activity	O
+of	O
+matrix	O
+Gla	O
+protein	O
+as	O
+a	O
+calcification	B
+inhibitor	O
+.	O
+
+High	O
+levels	O
+of	O
+matrix	O
+Gla	O
+protein	O
+are	O
+found	O
+at	O
+sites	O
+of	O
+artery	B
+calcification	I
+in	O
+rats	O
+treated	O
+with	O
+vitamin	O
+D	O
+plus	O
+Warfarin	O
+,	O
+and	O
+chemical	O
+analysis	O
+showed	O
+that	O
+the	O
+protein	O
+that	O
+accumulated	O
+was	O
+indeed	O
+not	O
+gamma	O
+-	O
+carboxylated	O
+.	O
+
+These	O
+observations	O
+indicate	O
+that	O
+although	O
+the	O
+gamma	O
+-	O
+carboxyglutamate	O
+residues	O
+of	O
+matrix	O
+Gla	O
+protein	O
+are	O
+apparently	O
+required	O
+for	O
+its	O
+function	O
+as	O
+a	O
+calcification	B
+inhibitor	O
+,	O
+they	O
+are	O
+not	O
+required	O
+for	O
+its	O
+accumulation	O
+at	O
+calcification	B
+sites	O
+.	O
+
+Test	O
+conditions	O
+influence	O
+the	O
+response	O
+to	O
+a	O
+drug	O
+challenge	O
+in	O
+rodents	O
+.	O
+
+These	O
+studies	O
+were	O
+conducted	O
+to	O
+examine	O
+the	O
+differential	O
+response	O
+to	O
+a	O
+drug	O
+challenge	O
+under	O
+varied	O
+experimental	O
+test	O
+conditions	O
+routinely	O
+employed	O
+to	O
+study	O
+drug	O
+-	O
+induced	O
+behavioral	O
+and	O
+neurophysiological	O
+responses	O
+in	O
+rodents	O
+.	O
+
+Apomorphine	O
+,	O
+a	O
+nonselective	O
+dopamine	O
+agonist	O
+,	O
+was	O
+selected	O
+due	O
+to	O
+its	O
+biphasic	O
+behavioral	O
+effects	O
+,	O
+its	O
+ability	O
+to	O
+induce	O
+hypothermia	B
+,	O
+and	O
+to	O
+produce	O
+distinct	O
+changes	O
+to	O
+dopamine	O
+turnover	O
+in	O
+the	O
+rodent	O
+brain	O
+.	O
+
+From	O
+such	O
+experiments	O
+there	O
+is	O
+evidence	O
+that	O
+characterization	O
+and	O
+detection	O
+of	O
+apomorphine	O
+-	O
+induced	O
+activity	O
+in	O
+rodents	O
+critically	O
+depends	O
+upon	O
+the	O
+test	O
+conditions	O
+employed	O
+.	O
+
+In	O
+rats	O
+,	O
+detection	O
+of	O
+apomorphine	O
+-	O
+induced	O
+hyperactivity	B
+was	O
+facilitated	O
+by	O
+a	O
+period	O
+of	O
+acclimatization	O
+to	O
+the	O
+test	O
+conditions	O
+.	O
+
+Moreover	O
+,	O
+test	O
+conditions	O
+can	O
+impact	O
+upon	O
+other	O
+physiological	O
+responses	O
+to	O
+apomorphine	O
+such	O
+as	O
+drug	O
+-	O
+induced	O
+hypothermia	B
+.	O
+
+In	O
+mice	O
+,	O
+apomorphine	O
+produced	O
+qualitatively	O
+different	O
+responses	O
+under	O
+novel	O
+conditions	O
+when	O
+compared	O
+to	O
+those	O
+behaviors	O
+elicited	O
+in	O
+the	O
+home	O
+test	O
+cage	O
+.	O
+
+Drug	O
+-	O
+induced	O
+gross	O
+activity	O
+counts	O
+were	O
+increased	O
+in	O
+the	O
+novel	O
+exploratory	O
+box	O
+only	O
+,	O
+while	O
+measures	O
+of	O
+stereotypic	O
+behavior	O
+were	O
+similar	O
+in	O
+both	O
+.	O
+
+By	O
+contrast	O
+,	O
+apomorphine	O
+-	O
+induced	O
+locomotion	O
+was	O
+more	O
+prominent	O
+in	O
+the	O
+novel	O
+exploratory	O
+box	O
+.	O
+
+Dopamine	O
+turnover	O
+ratios	O
+(	O
+DOPAC	O
+:	O
+DA	O
+and	O
+HVA	O
+:	O
+DA	O
+)	O
+were	O
+found	O
+to	O
+be	O
+lower	O
+in	O
+those	O
+animals	O
+exposed	O
+to	O
+the	O
+exploratory	O
+box	O
+when	O
+compared	O
+to	O
+their	O
+home	O
+cage	O
+counterparts	O
+.	O
+
+However	O
+,	O
+apomorphine	O
+-	O
+induced	O
+reductions	O
+in	O
+striatal	O
+dopamine	O
+turnover	O
+were	O
+detected	O
+in	O
+both	O
+novel	O
+and	O
+home	O
+cage	O
+environments	O
+.	O
+
+The	O
+implications	O
+of	O
+these	O
+findings	O
+are	O
+discussed	O
+with	O
+particular	O
+emphasis	O
+upon	O
+conducting	O
+psychopharmacological	O
+challenge	O
+tests	O
+in	O
+rodents	O
+.	O
+
+Hemolysis	B
+of	O
+human	O
+erythrocytes	O
+induced	O
+by	O
+tamoxifen	O
+is	O
+related	O
+to	O
+disruption	O
+of	O
+membrane	O
+structure	O
+.	O
+
+Tamoxifen	O
+(	O
+TAM	O
+)	O
+,	O
+the	O
+antiestrogenic	O
+drug	O
+most	O
+widely	O
+prescribed	O
+in	O
+the	O
+chemotherapy	O
+of	O
+breast	B
+cancer	I
+,	O
+induces	O
+changes	O
+in	O
+normal	O
+discoid	O
+shape	O
+of	O
+erythrocytes	O
+and	O
+hemolytic	B
+anemia	I
+.	O
+
+This	O
+work	O
+evaluates	O
+the	O
+effects	O
+of	O
+TAM	O
+on	O
+isolated	O
+human	O
+erythrocytes	O
+,	O
+attempting	O
+to	O
+identify	O
+the	O
+underlying	O
+mechanisms	O
+on	O
+TAM	O
+-	O
+induced	O
+hemolytic	B
+anemia	I
+and	O
+the	O
+involvement	O
+of	O
+biomembranes	O
+in	O
+its	O
+cytostatic	O
+action	O
+mechanisms	O
+.	O
+
+TAM	O
+induces	O
+hemolysis	B
+of	O
+erythrocytes	O
+as	O
+a	O
+function	O
+of	O
+concentration	O
+.	O
+
+The	O
+extension	O
+of	O
+hemolysis	B
+is	O
+variable	O
+with	O
+erythrocyte	O
+samples	O
+,	O
+but	O
+12	O
+.	O
+5	O
+microM	O
+TAM	O
+induces	O
+total	O
+hemolysis	B
+of	O
+all	O
+tested	O
+suspensions	O
+.	O
+
+Despite	O
+inducing	O
+extensive	O
+erythrocyte	O
+lysis	O
+,	O
+TAM	O
+does	O
+not	O
+shift	O
+the	O
+osmotic	O
+fragility	O
+curves	O
+of	O
+erythrocytes	O
+.	O
+
+The	O
+hemolytic	B
+effect	O
+of	O
+TAM	O
+is	O
+prevented	O
+by	O
+low	O
+concentrations	O
+of	O
+alpha	O
+-	O
+tocopherol	O
+(	O
+alpha	O
+-	O
+T	O
+)	O
+and	O
+alpha	O
+-	O
+tocopherol	O
+acetate	O
+(	O
+alpha	O
+-	O
+TAc	O
+)	O
+(	O
+inactivated	O
+functional	O
+hydroxyl	O
+)	O
+indicating	O
+that	O
+TAM	O
+-	O
+induced	O
+hemolysis	B
+is	O
+not	O
+related	O
+to	O
+oxidative	O
+membrane	O
+damage	O
+.	O
+
+This	O
+was	O
+further	O
+evidenced	O
+by	O
+absence	O
+of	O
+oxygen	O
+consumption	O
+and	O
+hemoglobin	O
+oxidation	O
+both	O
+determined	O
+in	O
+parallel	O
+with	O
+TAM	O
+-	O
+induced	O
+hemolysis	B
+.	O
+
+Furthermore	O
+,	O
+it	O
+was	O
+observed	O
+that	O
+TAM	O
+inhibits	O
+the	O
+peroxidation	O
+of	O
+human	O
+erythrocytes	O
+induced	O
+by	O
+AAPH	O
+,	O
+thus	O
+ruling	O
+out	O
+TAM	O
+-	O
+induced	O
+cell	O
+oxidative	O
+stress	O
+.	O
+
+Hemolysis	B
+caused	O
+by	O
+TAM	O
+was	O
+not	O
+preceded	O
+by	O
+the	O
+leakage	O
+of	O
+K	O
+(	O
++	O
+)	O
+from	O
+the	O
+cells	O
+,	O
+also	O
+excluding	O
+a	O
+colloid	O
+-	O
+osmotic	O
+type	O
+mechanism	O
+of	O
+hemolysis	B
+,	O
+according	O
+to	O
+the	O
+effects	O
+on	O
+osmotic	O
+fragility	O
+curves	O
+.	O
+
+However	O
+,	O
+TAM	O
+induces	O
+release	O
+of	O
+peripheral	O
+proteins	O
+of	O
+membrane	O
+-	O
+cytoskeleton	O
+and	O
+cytosol	O
+proteins	O
+essentially	O
+bound	O
+to	O
+band	O
+3	O
+.	O
+
+Either	O
+alpha	O
+-	O
+T	O
+or	O
+alpha	O
+-	O
+TAc	O
+increases	O
+membrane	O
+packing	O
+and	O
+prevents	O
+TAM	O
+partition	O
+into	O
+model	O
+membranes	O
+.	O
+
+These	O
+effects	O
+suggest	O
+that	O
+the	O
+protection	O
+from	O
+hemolysis	B
+by	O
+tocopherols	O
+is	O
+related	O
+to	O
+a	O
+decreased	O
+TAM	O
+incorporation	O
+in	O
+condensed	O
+membranes	O
+and	O
+the	O
+structural	O
+damage	O
+of	O
+the	O
+erythrocyte	O
+membrane	O
+is	O
+consequently	O
+avoided	O
+.	O
+
+Therefore	O
+,	O
+TAM	O
+-	O
+induced	O
+hemolysis	B
+results	O
+from	O
+a	O
+structural	O
+perturbation	O
+of	O
+red	O
+cell	O
+membrane	O
+,	O
+leading	O
+to	O
+changes	O
+in	O
+the	O
+framework	O
+of	O
+the	O
+erythrocyte	O
+membrane	O
+and	O
+its	O
+cytoskeleton	O
+caused	O
+by	O
+its	O
+high	O
+partition	O
+in	O
+the	O
+membrane	O
+.	O
+
+These	O
+defects	O
+explain	O
+the	O
+abnormal	O
+erythrocyte	O
+shape	O
+and	O
+decreased	O
+mechanical	O
+stability	O
+promoted	O
+by	O
+TAM	O
+,	O
+resulting	O
+in	O
+hemolytic	B
+anemia	I
+.	O
+
+Additionally	O
+,	O
+since	O
+membrane	O
+leakage	O
+is	O
+a	O
+final	O
+stage	O
+of	O
+cytotoxicity	O
+,	O
+the	O
+disruption	O
+of	O
+the	O
+structural	O
+characteristics	O
+of	O
+biomembranes	O
+by	O
+TAM	O
+may	O
+contribute	O
+to	O
+the	O
+multiple	O
+mechanisms	O
+of	O
+its	O
+anticancer	O
+action	O
+.	O
+
+Changes	O
+of	O
+sodium	O
+and	O
+ATP	O
+affinities	O
+of	O
+the	O
+cardiac	O
+(	O
+Na	O
+,	O
+K	O
+)	O
+-	O
+ATPase	O
+during	O
+and	O
+after	O
+nitric	O
+oxide	O
+deficient	O
+hypertension	B
+.	O
+
+In	O
+the	O
+cardiovascular	O
+system	O
+,	O
+NO	O
+is	O
+involved	O
+in	O
+the	O
+regulation	O
+of	O
+a	O
+variety	O
+of	O
+functions	O
+.	O
+
+Inhibition	O
+of	O
+NO	O
+synthesis	O
+induces	O
+sustained	O
+hypertension	B
+.	O
+
+In	O
+several	O
+models	O
+of	O
+hypertension	B
+,	O
+elevation	O
+of	O
+intracellular	O
+sodium	O
+level	O
+was	O
+documented	O
+in	O
+cardiac	O
+tissue	O
+.	O
+
+To	O
+assess	O
+the	O
+molecular	O
+basis	O
+of	O
+disturbances	O
+in	O
+transmembraneous	O
+transport	O
+of	O
+Na	O
++	O
+,	O
+we	O
+studied	O
+the	O
+response	O
+of	O
+cardiac	O
+(	O
+Na	O
+,	O
+K	O
+)	O
+-	O
+ATPase	O
+to	O
+NO	O
+-	O
+deficient	O
+hypertension	B
+induced	O
+in	O
+rats	O
+by	O
+NO	O
+-	O
+synthase	O
+inhibition	O
+with	O
+40	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+N	O
+(	O
+G	O
+)	O
+-	O
+nitro	O
+-	O
+L	O
+-	O
+arginine	O
+methyl	O
+ester	O
+(	O
+L	O
+-	O
+NAME	O
+)	O
+for	O
+4	O
+four	O
+weeks	O
+.	O
+
+After	O
+4	O
+-	O
+week	O
+administration	O
+of	O
+L	O
+-	O
+NAME	O
+,	O
+the	O
+systolic	O
+blood	O
+pressure	O
+(	O
+SBP	O
+)	O
+increased	O
+by	O
+36	O
+%	O
+.	O
+
+Two	O
+weeks	O
+after	O
+terminating	O
+the	O
+treatment	O
+,	O
+the	O
+SBP	O
+recovered	O
+to	O
+control	O
+value	O
+.	O
+
+When	O
+activating	O
+the	O
+(	O
+Na	O
+,	O
+K	O
+)	O
+-	O
+ATPase	O
+with	O
+its	O
+substrate	O
+ATP	O
+,	O
+no	O
+changes	O
+in	O
+Km	O
+and	O
+Vmax	O
+values	O
+were	O
+observed	O
+in	O
+NO	O
+-	O
+deficient	O
+rats	O
+.	O
+
+During	O
+activation	O
+with	O
+Na	O
++	O
+,	O
+the	O
+Vmax	O
+remained	O
+unchanged	O
+,	O
+however	O
+the	O
+K	O
+(	O
+Na	O
+)	O
+increased	O
+by	O
+50	O
+%	O
+,	O
+indicating	O
+a	O
+profound	O
+decrease	O
+in	O
+the	O
+affinity	O
+of	O
+the	O
+Na	O
++	O
+-	O
+binding	O
+site	O
+in	O
+NO	O
+-	O
+deficient	O
+rats	O
+.	O
+
+After	O
+recovery	O
+from	O
+hypertension	B
+,	O
+the	O
+activity	O
+of	O
+(	O
+Na	O
+,	O
+K	O
+)	O
+-	O
+ATPase	O
+increased	O
+,	O
+due	O
+to	O
+higher	O
+affinity	O
+of	O
+the	O
+ATP	O
+-	O
+binding	O
+site	O
+,	O
+as	O
+revealed	O
+from	O
+the	O
+lowered	O
+Km	O
+value	O
+for	O
+ATP	O
+.	O
+
+The	O
+K	O
+(	O
+Na	O
+)	O
+value	O
+for	O
+Na	O
++	O
+returned	O
+to	O
+control	O
+value	O
+.	O
+
+Inhibition	O
+of	O
+NO	O
+-	O
+synthase	O
+induced	O
+a	O
+reversible	O
+hypertension	B
+accompanied	O
+by	O
+depressed	B
+Na	O
++	O
+-	O
+extrusion	O
+from	O
+cardiac	O
+cells	O
+as	O
+a	O
+consequence	O
+of	O
+deteriorated	O
+Na	O
++	O
+-	O
+binding	O
+properties	O
+of	O
+the	O
+(	O
+Na	O
+,	O
+K	O
+)	O
+-	O
+ATPase	O
+.	O
+
+After	O
+recovery	O
+of	O
+blood	O
+pressure	O
+to	O
+control	O
+values	O
+,	O
+the	O
+extrusion	O
+of	O
+Na	O
++	O
+from	O
+cardiac	O
+cells	O
+was	O
+normalized	O
+,	O
+as	O
+revealed	O
+by	O
+restoration	O
+of	O
+the	O
+(	O
+Na	O
+,	O
+K	O
+)	O
+-	O
+ATPase	O
+activity	O
+.	O
+
+Effects	O
+of	O
+long	O
+-	O
+term	O
+pretreatment	O
+with	O
+isoproterenol	O
+on	O
+bromocriptine	O
+-	O
+induced	O
+tachycardia	B
+in	O
+conscious	O
+rats	O
+.	O
+
+It	O
+has	O
+been	O
+shown	O
+that	O
+bromocriptine	O
+-	O
+induced	O
+tachycardia	B
+,	O
+which	O
+persisted	O
+after	O
+adrenalectomy	O
+,	O
+is	O
+(	O
+i	O
+)	O
+mediated	O
+by	O
+central	O
+dopamine	O
+D2	O
+receptor	O
+activation	O
+and	O
+(	O
+ii	O
+)	O
+reduced	O
+by	O
+5	O
+-	O
+day	O
+isoproterenol	O
+pretreatment	O
+,	O
+supporting	O
+therefore	O
+the	O
+hypothesis	O
+that	O
+this	O
+effect	O
+is	O
+dependent	O
+on	O
+sympathetic	O
+outflow	O
+to	O
+the	O
+heart	O
+.	O
+
+This	O
+study	O
+was	O
+conducted	O
+to	O
+examine	O
+whether	O
+prolonged	O
+pretreatment	O
+with	O
+isoproterenol	O
+could	O
+abolish	O
+bromocriptine	O
+-	O
+induced	O
+tachycardia	B
+in	O
+conscious	O
+rats	O
+.	O
+
+Isoproterenol	O
+pretreatment	O
+for	O
+15	O
+days	O
+caused	O
+cardiac	B
+hypertrophy	I
+without	O
+affecting	O
+baseline	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+.	O
+
+In	O
+control	O
+rats	O
+,	O
+intravenous	O
+bromocriptine	O
+(	O
+150	O
+microg	O
+/	O
+kg	O
+)	O
+induced	O
+significant	O
+hypotension	B
+and	O
+tachycardia	B
+.	O
+
+Bromocriptine	O
+-	O
+induced	O
+hypotension	B
+was	O
+unaffected	O
+by	O
+isoproterenol	O
+pretreatment	O
+,	O
+while	O
+tachycardia	B
+was	O
+reversed	O
+to	O
+significant	O
+bradycardia	B
+,	O
+an	O
+effect	O
+that	O
+was	O
+partly	O
+reduced	O
+by	O
+i	O
+.	O
+v	O
+.	O
+domperidone	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+Neither	O
+cardiac	O
+vagal	O
+nor	O
+sympathetic	O
+tone	O
+was	O
+altered	O
+by	O
+isoproterenol	O
+pretreatment	O
+.	O
+
+In	O
+isolated	O
+perfused	O
+heart	O
+preparations	O
+from	O
+isoproterenol	O
+-	O
+pretreated	O
+rats	O
+,	O
+the	O
+isoproterenol	O
+-	O
+induced	O
+maximal	O
+increase	O
+in	O
+left	O
+ventricular	O
+systolic	O
+pressure	O
+was	O
+significantly	O
+reduced	O
+,	O
+compared	O
+with	O
+saline	O
+-	O
+pretreated	O
+rats	O
+(	O
+the	O
+EC50	O
+of	O
+the	O
+isoproterenol	O
+-	O
+induced	O
+increase	O
+in	O
+left	O
+ventricular	O
+systolic	O
+pressure	O
+was	O
+enhanced	O
+approximately	O
+22	O
+-	O
+fold	O
+)	O
+.	O
+
+These	O
+results	O
+show	O
+that	O
+15	O
+-	O
+day	O
+isoproterenol	O
+pretreatment	O
+not	O
+only	O
+abolished	O
+but	O
+reversed	O
+bromocriptine	O
+-	O
+induced	O
+tachycardia	B
+to	O
+bradycardia	B
+,	O
+an	O
+effect	O
+that	O
+is	O
+mainly	O
+related	O
+to	O
+further	O
+cardiac	O
+beta	O
+-	O
+adrenoceptor	O
+desensitization	O
+rather	O
+than	O
+to	O
+impairment	O
+of	O
+autonomic	O
+regulation	O
+of	O
+the	O
+heart	O
+.	O
+
+They	O
+suggest	O
+that	O
+,	O
+in	O
+normal	O
+conscious	O
+rats	O
+,	O
+the	O
+central	O
+tachycardia	B
+of	O
+bromocriptine	O
+appears	O
+to	O
+predominate	O
+and	O
+to	O
+mask	O
+the	O
+bradycardia	B
+of	O
+this	O
+agonist	O
+at	O
+peripheral	O
+dopamine	O
+D2	O
+receptors	O
+.	O
+
+A	O
+developmental	O
+analysis	O
+of	O
+clonidine	O
+'	O
+s	O
+effects	O
+on	O
+cardiac	O
+rate	O
+and	O
+ultrasound	O
+production	O
+in	O
+infant	O
+rats	O
+.	O
+
+Under	O
+controlled	O
+conditions	O
+,	O
+infant	O
+rats	O
+emit	O
+ultrasonic	O
+vocalizations	O
+during	O
+extreme	O
+cold	O
+exposure	O
+and	O
+after	O
+administration	O
+of	O
+the	O
+alpha	O
+(	O
+2	O
+)	O
+adrenoceptor	O
+agonist	O
+,	O
+clonidine	O
+.	O
+
+Previous	O
+investigations	O
+have	O
+determined	O
+that	O
+,	O
+in	O
+response	O
+to	O
+clonidine	O
+,	O
+ultrasound	O
+production	O
+increases	O
+through	O
+the	O
+2nd	O
+-	O
+week	O
+postpartum	O
+and	O
+decreases	O
+thereafter	O
+.	O
+
+Given	O
+that	O
+sympathetic	O
+neural	O
+dominance	O
+exhibits	O
+a	O
+similar	O
+developmental	O
+pattern	O
+,	O
+and	O
+given	O
+that	O
+clonidine	O
+induces	O
+sympathetic	O
+withdrawal	O
+and	O
+bradycardia	B
+,	O
+we	O
+hypothesized	O
+that	O
+clonidine	O
+'	O
+s	O
+developmental	O
+effects	O
+on	O
+cardiac	O
+rate	O
+and	O
+ultrasound	O
+production	O
+would	O
+mirror	O
+each	O
+other	O
+.	O
+
+Therefore	O
+,	O
+in	O
+the	O
+present	O
+experiment	O
+,	O
+the	O
+effects	O
+of	O
+clonidine	O
+administration	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+on	O
+cardiac	O
+rate	O
+and	O
+ultrasound	O
+production	O
+were	O
+examined	O
+in	O
+2	O
+-	O
+,	O
+8	O
+-	O
+,	O
+15	O
+-	O
+,	O
+and	O
+20	O
+-	O
+day	O
+-	O
+old	O
+rats	O
+.	O
+
+Age	O
+-	O
+related	O
+changes	O
+in	O
+ultrasound	O
+production	O
+corresponded	O
+with	O
+changes	O
+in	O
+cardiovascular	O
+variables	O
+,	O
+including	O
+baseline	O
+cardiac	O
+rate	O
+and	O
+clonidine	O
+-	O
+induced	O
+bradycardia	B
+.	O
+
+This	O
+experiment	O
+is	O
+discussed	O
+with	O
+regard	O
+to	O
+the	O
+hypothesis	O
+that	O
+ultrasound	O
+production	O
+is	O
+the	O
+acoustic	O
+by	O
+-	O
+product	O
+of	O
+a	O
+physiological	O
+maneuver	O
+that	O
+compensates	O
+for	O
+clonidine	O
+'	O
+s	O
+detrimental	O
+effects	O
+on	O
+cardiovascular	O
+function	O
+.	O
+
+Recurrent	O
+use	O
+of	O
+newer	O
+oral	O
+contraceptives	O
+and	O
+the	O
+risk	O
+of	O
+venous	B
+thromboembolism	I
+.	O
+
+The	O
+epidemiological	O
+studies	O
+that	O
+assessed	O
+the	O
+risk	O
+of	O
+venous	B
+thromboembolism	I
+(	O
+VTE	B
+)	O
+associated	O
+with	O
+newer	O
+oral	O
+contraceptives	O
+(	O
+OC	O
+)	O
+did	O
+not	O
+distinguish	O
+between	O
+patterns	O
+of	O
+OC	O
+use	O
+,	O
+namely	O
+first	O
+-	O
+time	O
+users	O
+,	O
+repeaters	O
+and	O
+switchers	O
+.	O
+
+Data	O
+from	O
+a	O
+Transnational	O
+case	O
+-	O
+control	O
+study	O
+were	O
+used	O
+to	O
+assess	O
+the	O
+risk	O
+of	O
+VTE	B
+for	O
+the	O
+latter	O
+patterns	O
+of	O
+use	O
+,	O
+while	O
+accounting	O
+for	O
+duration	O
+of	O
+use	O
+.	O
+
+Over	O
+the	O
+period	O
+1993	O
+-	O
+1996	O
+,	O
+551	O
+cases	O
+of	O
+VTE	B
+were	O
+identified	O
+in	O
+Germany	O
+and	O
+the	O
+UK	O
+along	O
+with	O
+2066	O
+controls	O
+.	O
+
+Totals	O
+of	O
+128	O
+cases	O
+and	O
+650	O
+controls	O
+were	O
+analysed	O
+for	O
+repeat	O
+use	O
+and	O
+135	O
+cases	O
+and	O
+622	O
+controls	O
+for	O
+switching	O
+patterns	O
+.	O
+
+The	O
+adjusted	O
+rate	O
+ratio	O
+of	O
+VTE	B
+for	O
+repeat	O
+users	O
+of	O
+third	O
+generation	O
+OC	O
+was	O
+0	O
+.	O
+6	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+0	O
+.	O
+3	O
+-	O
+1	O
+.	O
+2	O
+)	O
+relative	O
+to	O
+repeat	O
+users	O
+of	O
+second	O
+generation	O
+pills	O
+,	O
+whereas	O
+it	O
+was	O
+1	O
+.	O
+3	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+0	O
+.	O
+7	O
+-	O
+2	O
+.	O
+4	O
+)	O
+for	O
+switchers	O
+from	O
+second	O
+to	O
+third	O
+generation	O
+pills	O
+relative	O
+to	O
+switchers	O
+from	O
+third	O
+to	O
+second	O
+generation	O
+pills	O
+.	O
+
+We	O
+conclude	O
+that	O
+second	O
+and	O
+third	O
+generation	O
+agents	O
+are	O
+associated	O
+with	O
+equivalent	O
+risks	O
+of	O
+VTE	B
+when	O
+the	O
+same	O
+agent	O
+is	O
+used	O
+repeatedly	O
+after	O
+interruption	O
+periods	O
+or	O
+when	O
+users	O
+are	O
+switched	O
+between	O
+the	O
+two	O
+generations	O
+of	O
+pills	O
+.	O
+
+These	O
+analyses	O
+suggest	O
+that	O
+the	O
+higher	O
+risk	O
+observed	O
+for	O
+the	O
+newer	O
+OC	O
+in	O
+other	O
+studies	O
+may	O
+be	O
+the	O
+result	O
+of	O
+inadequate	O
+comparisons	O
+of	O
+pill	O
+users	O
+with	O
+different	O
+patterns	O
+of	O
+pill	O
+use	O
+.	O
+
+Differential	O
+effects	O
+of	O
+systemically	O
+administered	O
+ketamine	O
+and	O
+lidocaine	O
+on	O
+dynamic	O
+and	O
+static	O
+hyperalgesia	B
+induced	O
+by	O
+intradermal	O
+capsaicin	O
+in	O
+humans	O
+.	O
+
+We	O
+have	O
+examined	O
+the	O
+effect	O
+of	O
+systemic	O
+administration	O
+of	O
+ketamine	O
+and	O
+lidocaine	O
+on	O
+brush	O
+-	O
+evoked	O
+(	O
+dynamic	O
+)	O
+pain	B
+and	O
+punctate	O
+-	O
+evoked	O
+(	O
+static	O
+)	O
+hyperalgesia	B
+induced	O
+by	O
+capsaicin	O
+.	O
+
+In	O
+a	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+,	O
+crossover	O
+study	O
+,	O
+we	O
+studied	O
+12	O
+volunteers	O
+in	O
+three	O
+experiments	O
+.	O
+
+Capsaicin	O
+100	O
+micrograms	O
+was	O
+injected	O
+intradermally	O
+on	O
+the	O
+volar	O
+forearm	O
+followed	O
+by	O
+an	O
+i	O
+.	O
+v	O
+.	O
+infusion	O
+of	O
+ketamine	O
+(	O
+bolus	O
+0	O
+.	O
+1	O
+mg	O
+kg	O
+-	O
+1	O
+over	O
+10	O
+min	O
+followed	O
+by	O
+infusion	O
+of	O
+7	O
+micrograms	O
+kg	O
+-	O
+1	O
+min	O
+-	O
+1	O
+)	O
+,	O
+lidocaine	O
+5	O
+mg	O
+kg	O
+-	O
+1	O
+or	O
+saline	O
+for	O
+50	O
+min	O
+.	O
+
+Infusion	O
+started	O
+15	O
+min	O
+after	O
+injection	O
+of	O
+capsaicin	O
+.	O
+
+The	O
+following	O
+were	O
+measured	O
+:	O
+spontaneous	O
+pain	B
+,	O
+pain	B
+evoked	O
+by	O
+punctate	O
+and	O
+brush	O
+stimuli	O
+(	O
+VAS	O
+)	O
+,	O
+and	O
+areas	O
+of	O
+brush	O
+-	O
+evoked	O
+and	O
+punctate	O
+-	O
+evoked	O
+hyperalgesia	B
+.	O
+
+Ketamine	O
+reduced	O
+both	O
+the	O
+area	O
+of	O
+brush	O
+-	O
+evoked	O
+and	O
+punctate	O
+-	O
+evoked	O
+hyperalgesia	B
+significantly	O
+and	O
+it	O
+tended	O
+to	O
+reduce	O
+brush	O
+-	O
+evoked	O
+pain	B
+.	O
+
+Lidocaine	O
+reduced	O
+the	O
+area	O
+of	O
+punctate	O
+-	O
+evoked	O
+hyperalgesia	B
+significantly	O
+.	O
+
+It	O
+tended	O
+to	O
+reduce	O
+VAS	O
+scores	O
+of	O
+spontaneous	O
+pain	B
+but	O
+had	O
+no	O
+effect	O
+on	O
+evoked	O
+pain	B
+.	O
+
+The	O
+differential	O
+effects	O
+of	O
+ketamine	O
+and	O
+lidocaine	O
+on	O
+static	O
+and	O
+dynamic	O
+hyperalgesia	B
+suggest	O
+that	O
+the	O
+two	O
+types	O
+of	O
+hyperalgesia	B
+are	O
+mediated	O
+by	O
+separate	O
+mechanisms	O
+and	O
+have	O
+a	O
+distinct	O
+pharmacology	O
+.	O
+
+Development	O
+of	O
+apomorphine	O
+-	O
+induced	O
+aggressive	B
+behavior	I
+:	O
+comparison	O
+of	O
+adult	O
+male	O
+and	O
+female	O
+Wistar	O
+rats	O
+.	O
+
+The	O
+development	O
+of	O
+apomorphine	O
+-	O
+induced	O
+(	O
+1	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+once	O
+daily	O
+)	O
+aggressive	B
+behavior	I
+of	O
+adult	O
+male	O
+and	O
+female	O
+Wistar	O
+rats	O
+obtained	O
+from	O
+the	O
+same	O
+breeder	O
+was	O
+studied	O
+in	O
+two	O
+consecutive	O
+sets	O
+.	O
+
+In	O
+male	O
+animals	O
+,	O
+repeated	O
+apomorphine	O
+treatment	O
+induced	O
+a	O
+gradual	O
+development	O
+of	O
+aggressive	B
+behavior	I
+as	O
+evidenced	O
+by	O
+the	O
+increased	O
+intensity	O
+of	O
+aggressiveness	B
+and	O
+shortened	O
+latency	O
+before	O
+the	O
+first	O
+attack	O
+toward	O
+the	O
+opponent	O
+.	O
+
+In	O
+female	O
+rats	O
+,	O
+only	O
+a	O
+weak	O
+tendency	O
+toward	O
+aggressiveness	B
+was	O
+found	O
+.	O
+
+In	O
+conclusion	O
+,	O
+the	O
+present	O
+study	O
+demonstrates	O
+gender	O
+differences	O
+in	O
+the	O
+development	O
+of	O
+the	O
+apomorphine	O
+-	O
+induced	O
+aggressive	B
+behavior	I
+and	O
+indicates	O
+that	O
+the	O
+female	O
+rats	O
+do	O
+not	O
+fill	O
+the	O
+validation	O
+criteria	O
+for	O
+use	O
+in	O
+this	O
+method	O
+.	O
+
+Intracranial	B
+aneurysms	I
+and	O
+cocaine	B
+abuse	I
+:	O
+analysis	O
+of	O
+prognostic	O
+indicators	O
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+outcome	O
+of	O
+subarachnoid	B
+hemorrhage	I
+associated	O
+with	O
+cocaine	B
+abuse	I
+is	O
+reportedly	O
+poor	O
+.	O
+
+However	O
+,	O
+no	O
+study	O
+in	O
+the	O
+literature	O
+has	O
+reported	O
+the	O
+use	O
+of	O
+a	O
+statistical	O
+model	O
+to	O
+analyze	O
+the	O
+variables	O
+that	O
+influence	O
+outcome	O
+.	O
+
+METHODS	O
+:	O
+A	O
+review	O
+of	O
+admissions	O
+during	O
+a	O
+6	O
+-	O
+year	O
+period	O
+revealed	O
+14	O
+patients	O
+with	O
+cocaine	O
+-	O
+related	O
+aneurysms	B
+.	O
+
+This	O
+group	O
+was	O
+compared	O
+with	O
+a	O
+control	O
+group	O
+of	O
+135	O
+patients	O
+with	O
+ruptured	B
+aneurysms	I
+and	O
+no	O
+history	O
+of	O
+cocaine	B
+abuse	I
+.	O
+
+Age	O
+at	O
+presentation	O
+,	O
+time	O
+of	O
+ictus	O
+after	O
+intoxication	O
+,	O
+Hunt	O
+and	O
+Hess	O
+grade	O
+of	O
+subarachnoid	B
+hemorrhage	I
+,	O
+size	O
+of	O
+the	O
+aneurysm	B
+,	O
+location	O
+of	O
+the	O
+aneurysm	B
+,	O
+and	O
+the	O
+Glasgow	O
+Outcome	O
+Scale	O
+score	O
+were	O
+assessed	O
+and	O
+compared	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+patients	O
+in	O
+the	O
+study	O
+group	O
+were	O
+significantly	O
+younger	O
+than	O
+the	O
+patients	O
+in	O
+the	O
+control	O
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+002	O
+)	O
+.	O
+
+In	O
+patients	O
+in	O
+the	O
+study	O
+group	O
+,	O
+all	O
+aneurysms	B
+were	O
+located	O
+in	O
+the	O
+anterior	O
+circulation	O
+.	O
+
+The	O
+majority	O
+of	O
+these	O
+aneurysms	B
+were	O
+smaller	O
+than	O
+those	O
+of	O
+the	O
+control	O
+group	O
+(	O
+8	O
++	O
+/	O
+-	O
+6	O
+.	O
+08	O
+mm	O
+versus	O
+11	O
++	O
+/	O
+-	O
+5	O
+.	O
+4	O
+mm	O
+;	O
+P	O
+=	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+differences	O
+in	O
+mortality	O
+and	O
+morbidity	O
+between	O
+the	O
+two	O
+groups	O
+were	O
+not	O
+significant	O
+.	O
+
+Hunt	O
+and	O
+Hess	O
+grade	O
+(	O
+P	O
+<	O
+0	O
+.	O
+005	O
+)	O
+and	O
+age	O
+(	O
+P	O
+<	O
+0	O
+.	O
+007	O
+)	O
+were	O
+significant	O
+predictors	O
+of	O
+outcome	O
+for	O
+the	O
+patients	O
+with	O
+cocaine	O
+-	O
+related	O
+aneurysms	B
+.	O
+
+CONCLUSION	O
+:	O
+Cocaine	O
+use	O
+predisposed	O
+aneurysmal	B
+rupture	I
+at	O
+a	O
+significantly	O
+earlier	O
+age	O
+and	O
+in	O
+much	O
+smaller	O
+aneurysms	B
+.	O
+
+Contrary	O
+to	O
+the	O
+published	O
+literature	O
+,	O
+this	O
+group	O
+did	O
+reasonably	O
+well	O
+with	O
+aggressive	O
+management	O
+.	O
+
+Effect	O
+of	O
+intravenous	O
+nimodipine	O
+on	O
+blood	O
+pressure	O
+and	O
+outcome	O
+after	O
+acute	B
+stroke	I
+.	O
+
+BACKGROUND	O
+AND	O
+PURPOSE	O
+:	O
+The	O
+Intravenous	O
+Nimodipine	O
+West	O
+European	O
+Stroke	B
+Trial	O
+(	O
+INWEST	O
+)	O
+found	O
+a	O
+correlation	O
+between	O
+nimodipine	O
+-	O
+induced	O
+reduction	B
+in	I
+blood	I
+pressure	I
+(	O
+BP	O
+)	O
+and	O
+an	O
+unfavorable	O
+outcome	O
+in	O
+acute	B
+stroke	I
+.	O
+
+We	O
+sought	O
+to	O
+confirm	O
+this	O
+correlation	O
+with	O
+and	O
+without	O
+adjustment	O
+for	O
+prognostic	O
+variables	O
+and	O
+to	O
+investigate	O
+outcome	O
+in	O
+subgroups	O
+with	O
+increasing	O
+levels	O
+of	O
+BP	B
+reduction	I
+.	O
+
+METHODS	O
+:	O
+Patients	O
+with	O
+a	O
+clinical	O
+diagnosis	O
+of	O
+ischemic	B
+stroke	I
+(	O
+within	O
+24	O
+hours	O
+)	O
+were	O
+consecutively	O
+allocated	O
+to	O
+receive	O
+placebo	O
+(	O
+n	O
+=	O
+100	O
+)	O
+,	O
+1	O
+mg	O
+/	O
+h	O
+(	O
+low	O
+-	O
+dose	O
+)	O
+nimodipine	O
+(	O
+n	O
+=	O
+101	O
+)	O
+,	O
+or	O
+2	O
+mg	O
+/	O
+h	O
+(	O
+high	O
+-	O
+dose	O
+)	O
+nimodipine	O
+(	O
+n	O
+=	O
+94	O
+)	O
+.	O
+
+The	O
+correlation	O
+between	O
+average	O
+BP	O
+change	O
+during	O
+the	O
+first	O
+2	O
+days	O
+and	O
+the	O
+outcome	O
+at	O
+day	O
+21	O
+was	O
+analyzed	O
+.	O
+
+RESULTS	O
+:	O
+Two	O
+hundred	O
+sixty	O
+-	O
+five	O
+patients	O
+were	O
+included	O
+in	O
+this	O
+analysis	O
+(	O
+n	O
+=	O
+92	O
+,	O
+93	O
+,	O
+and	O
+80	O
+for	O
+placebo	O
+,	O
+low	O
+dose	O
+,	O
+and	O
+high	O
+dose	O
+,	O
+respectively	O
+)	O
+.	O
+
+Nimodipine	O
+treatment	O
+resulted	O
+in	O
+a	O
+statistically	O
+significant	O
+reduction	B
+in	I
+systolic	I
+BP	I
+(	O
+SBP	O
+)	O
+and	O
+diastolic	O
+BP	O
+(	O
+DBP	O
+)	O
+from	O
+baseline	O
+compared	O
+with	O
+placebo	O
+during	O
+the	O
+first	O
+few	O
+days	O
+.	O
+
+In	O
+multivariate	O
+analysis	O
+,	O
+a	O
+significant	O
+correlation	O
+between	O
+DBP	B
+reduction	I
+and	O
+worsening	O
+of	O
+the	O
+neurological	O
+score	O
+was	O
+found	O
+for	O
+the	O
+high	O
+-	O
+dose	O
+group	O
+(	O
+beta	O
+=	O
+0	O
+.	O
+49	O
+,	O
+P	O
+=	O
+0	O
+.	O
+048	O
+)	O
+.	O
+
+Patients	O
+with	O
+a	O
+DBP	B
+reduction	I
+of	O
+>	O
+or	O
+=	O
+20	O
+%	O
+in	O
+the	O
+high	O
+-	O
+dose	O
+group	O
+had	O
+a	O
+significantly	O
+increased	O
+adjusted	O
+OR	O
+for	O
+the	O
+compound	O
+outcome	O
+variable	O
+death	B
+or	O
+dependency	O
+(	O
+Barthel	O
+Index	O
+<	O
+60	O
+)	O
+(	O
+n	O
+/	O
+N	O
+=	O
+25	O
+/	O
+26	O
+,	O
+OR	O
+10	O
+.	O
+16	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+02	O
+to	O
+101	O
+.	O
+74	O
+)	O
+and	O
+death	B
+alone	O
+(	O
+n	O
+/	O
+N	O
+=	O
+9	O
+/	O
+26	O
+,	O
+OR	O
+4	O
+.	O
+336	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+131	O
+16	O
+.	O
+619	O
+)	O
+compared	O
+with	O
+all	O
+placebo	O
+patients	O
+(	O
+n	O
+/	O
+N	O
+=	O
+62	O
+/	O
+92	O
+and	O
+14	O
+/	O
+92	O
+,	O
+respectively	O
+)	O
+.	O
+
+There	O
+was	O
+no	O
+correlation	O
+between	O
+SBP	O
+change	O
+and	O
+outcome	O
+.	O
+
+CONCLUSIONS	O
+:	O
+DBP	O
+,	O
+but	O
+not	O
+SBP	O
+,	O
+reduction	O
+was	O
+associated	O
+with	O
+neurological	O
+worsening	O
+after	O
+the	O
+intravenous	O
+administration	O
+of	O
+high	O
+-	O
+dose	O
+nimodipine	O
+after	O
+acute	B
+stroke	I
+.	O
+
+For	O
+low	O
+-	O
+dose	O
+nimodipine	O
+,	O
+the	O
+results	O
+were	O
+not	O
+conclusive	O
+.	O
+
+These	O
+results	O
+do	O
+not	O
+confirm	O
+or	O
+exclude	O
+a	O
+neuroprotective	O
+property	O
+of	O
+nimodipine	O
+.	O
+
+Neonatal	O
+pyridoxine	O
+responsive	O
+convulsions	B
+due	O
+to	O
+isoniazid	O
+therapy	O
+.	O
+
+A	O
+17	O
+-	O
+day	O
+-	O
+old	O
+infant	O
+on	O
+isoniazid	O
+therapy	O
+13	O
+mg	O
+/	O
+kg	O
+daily	O
+from	O
+birth	O
+because	O
+of	O
+maternal	O
+tuberculosis	B
+was	O
+admitted	O
+after	O
+4	O
+days	O
+of	O
+clonic	B
+fits	I
+.	O
+
+No	O
+underlying	O
+infective	O
+or	O
+biochemical	O
+cause	O
+could	O
+be	O
+found	O
+.	O
+
+The	O
+fits	B
+ceased	O
+within	O
+4	O
+hours	O
+of	O
+administering	O
+intramuscular	O
+pyridoxine	O
+,	O
+suggesting	O
+an	O
+aetiology	O
+of	O
+pyridoxine	O
+deficiency	O
+secondary	O
+to	O
+isoniazid	O
+medication	O
+.	O
+
+Ketamine	O
+sedation	O
+for	O
+the	O
+reduction	O
+of	O
+children	O
+'	O
+s	O
+fractures	B
+in	O
+the	O
+emergency	O
+department	O
+.	O
+
+BACKGROUND	O
+:	O
+There	O
+recently	O
+has	O
+been	O
+a	O
+resurgence	O
+in	O
+the	O
+utilization	O
+of	O
+ketamine	O
+,	O
+a	O
+unique	O
+anesthetic	O
+,	O
+for	O
+emergency	O
+-	O
+department	O
+procedures	O
+requiring	O
+sedation	O
+.	O
+
+The	O
+purpose	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+examine	O
+the	O
+safety	O
+and	O
+efficacy	O
+of	O
+ketamine	O
+for	O
+sedation	O
+in	O
+the	O
+treatment	O
+of	O
+children	O
+'	O
+s	O
+fractures	B
+in	O
+the	O
+emergency	O
+department	O
+.	O
+
+METHODS	O
+:	O
+One	O
+hundred	O
+and	O
+fourteen	O
+children	O
+(	O
+average	O
+age	O
+,	O
+5	O
+.	O
+3	O
+years	O
+;	O
+range	O
+,	O
+twelve	O
+months	O
+to	O
+ten	O
+years	O
+and	O
+ten	O
+months	O
+)	O
+who	O
+underwent	O
+closed	O
+reduction	O
+of	O
+an	O
+isolated	O
+fracture	B
+or	O
+dislocation	B
+in	O
+the	O
+emergency	O
+department	O
+at	O
+a	O
+level	O
+-	O
+I	O
+trauma	B
+center	O
+were	O
+prospectively	O
+evaluated	O
+.	O
+
+Ketamine	O
+hydrochloride	O
+was	O
+administered	O
+intravenously	O
+(	O
+at	O
+a	O
+dose	O
+of	O
+two	O
+milligrams	O
+per	O
+kilogram	O
+of	O
+body	O
+weight	O
+)	O
+in	O
+ninety	O
+-	O
+nine	O
+of	O
+the	O
+patients	O
+and	O
+intramuscularly	O
+(	O
+at	O
+a	O
+dose	O
+of	O
+four	O
+milligrams	O
+per	O
+kilogram	O
+of	O
+body	O
+weight	O
+)	O
+in	O
+the	O
+other	O
+fifteen	O
+.	O
+
+A	O
+board	O
+-	O
+certified	O
+emergency	O
+physician	O
+skilled	O
+in	O
+airway	O
+management	O
+supervised	O
+administration	O
+of	O
+the	O
+anesthetic	O
+,	O
+and	O
+the	O
+patients	O
+were	O
+monitored	O
+by	O
+a	O
+registered	O
+nurse	O
+.	O
+
+Any	O
+pain	B
+during	O
+the	O
+reduction	O
+was	O
+rated	O
+by	O
+the	O
+orthopaedic	O
+surgeon	O
+treating	O
+the	O
+patient	O
+according	O
+to	O
+the	O
+Children	O
+'	O
+s	O
+Hospital	O
+of	O
+Eastern	O
+Ontario	O
+Pain	B
+Scale	O
+(	O
+CHEOPS	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+average	O
+time	O
+from	O
+intravenous	O
+administration	O
+of	O
+ketamine	O
+to	O
+manipulation	O
+of	O
+the	O
+fracture	B
+or	O
+dislocation	B
+was	O
+one	O
+minute	O
+and	O
+thirty	O
+-	O
+six	O
+seconds	O
+(	O
+range	O
+,	O
+twenty	O
+seconds	O
+to	O
+five	O
+minutes	O
+)	O
+,	O
+and	O
+the	O
+average	O
+time	O
+from	O
+intramuscular	O
+administration	O
+to	O
+manipulation	O
+was	O
+four	O
+minutes	O
+and	O
+forty	O
+-	O
+two	O
+seconds	O
+(	O
+range	O
+,	O
+sixty	O
+seconds	O
+to	O
+fifteen	O
+minutes	O
+)	O
+.	O
+
+The	O
+average	O
+score	O
+according	O
+to	O
+the	O
+Children	O
+'	O
+s	O
+Hospital	O
+of	O
+Eastern	O
+Ontario	O
+Pain	B
+Scale	O
+was	O
+6	O
+.	O
+4	O
+points	O
+(	O
+range	O
+,	O
+5	O
+to	O
+10	O
+points	O
+)	O
+,	O
+reflecting	O
+minimal	O
+or	O
+no	O
+pain	B
+during	O
+fracture	B
+reduction	O
+.	O
+
+Adequate	O
+fracture	B
+reduction	O
+was	O
+obtained	O
+in	O
+111	O
+of	O
+the	O
+children	O
+.	O
+
+Ninety	O
+-	O
+nine	O
+percent	O
+(	O
+sixty	O
+-	O
+eight	O
+)	O
+of	O
+the	O
+sixty	O
+-	O
+nine	O
+parents	O
+present	O
+during	O
+the	O
+reduction	O
+were	O
+pleased	O
+with	O
+the	O
+sedation	O
+and	O
+would	O
+allow	O
+it	O
+to	O
+be	O
+used	O
+again	O
+in	O
+a	O
+similar	O
+situation	O
+.	O
+
+Patency	O
+of	O
+the	O
+airway	O
+and	O
+independent	O
+respiration	O
+were	O
+maintained	O
+in	O
+all	O
+of	O
+the	O
+patients	O
+.	O
+
+Blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+remained	O
+stable	O
+.	O
+
+Minor	O
+side	O
+effects	O
+included	O
+nausea	B
+(	O
+thirteen	O
+patients	O
+)	O
+,	O
+emesis	B
+(	O
+eight	O
+of	O
+the	O
+thirteen	O
+patients	O
+with	O
+nausea	B
+)	O
+,	O
+clumsiness	B
+(	O
+evident	O
+as	O
+ataxic	B
+movements	I
+in	O
+ten	O
+patients	O
+)	O
+,	O
+and	O
+dysphoric	B
+reaction	I
+(	O
+one	O
+patient	O
+)	O
+.	O
+
+No	O
+long	O
+-	O
+term	O
+sequelae	O
+were	O
+noted	O
+,	O
+and	O
+no	O
+patients	O
+had	O
+hallucinations	B
+or	O
+nightmares	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Ketamine	O
+reliably	O
+,	O
+safely	O
+,	O
+and	O
+quickly	O
+provided	O
+adequate	O
+sedation	O
+to	O
+effectively	O
+facilitate	O
+the	O
+reduction	O
+of	O
+children	O
+'	O
+s	O
+fractures	B
+in	O
+the	O
+emergency	O
+department	O
+at	O
+our	O
+institution	O
+.	O
+
+Ketamine	O
+should	O
+only	O
+be	O
+used	O
+in	O
+an	O
+environment	O
+such	O
+as	O
+the	O
+emergency	O
+department	O
+,	O
+where	O
+proper	O
+one	O
+-	O
+on	O
+-	O
+one	O
+monitoring	O
+is	O
+used	O
+and	O
+board	O
+-	O
+certified	O
+physicians	O
+skilled	O
+in	O
+airway	O
+management	O
+are	O
+directly	O
+involved	O
+in	O
+the	O
+care	O
+of	O
+the	O
+patient	O
+.	O
+
+Cyclosporine	O
+and	O
+tacrolimus	O
+-	O
+associated	O
+thrombotic	B
+microangiopathy	I
+.	O
+
+The	O
+development	O
+of	O
+thrombotic	B
+microangiopathy	I
+(	O
+TMA	B
+)	O
+associated	O
+with	O
+the	O
+use	O
+of	O
+cyclosporine	O
+has	O
+been	O
+well	O
+documented	O
+.	O
+
+Treatments	O
+have	O
+included	O
+discontinuation	O
+or	O
+reduction	O
+of	O
+cyclosporine	O
+dose	O
+with	O
+or	O
+without	O
+concurrent	O
+plasma	O
+exchange	O
+,	O
+plasma	O
+infusion	O
+,	O
+anticoagulation	O
+,	O
+and	O
+intravenous	O
+immunoglobulin	O
+G	O
+infusion	O
+.	O
+
+However	O
+,	O
+for	O
+recipients	O
+of	O
+organ	O
+transplantation	O
+,	O
+removing	O
+the	O
+inciting	O
+agent	O
+is	O
+not	O
+without	O
+the	O
+attendant	O
+risk	O
+of	O
+precipitating	O
+acute	O
+rejection	O
+and	O
+graft	O
+loss	O
+.	O
+
+The	O
+last	O
+decade	O
+has	O
+seen	O
+the	O
+emergence	O
+of	O
+tacrolimus	O
+as	O
+a	O
+potent	O
+immunosuppressive	O
+agent	O
+with	O
+mechanisms	O
+of	O
+action	O
+virtually	O
+identical	O
+to	O
+those	O
+of	O
+cyclosporine	O
+.	O
+
+As	O
+a	O
+result	O
+,	O
+switching	O
+to	O
+tacrolimus	O
+has	O
+been	O
+reported	O
+to	O
+be	O
+a	O
+viable	O
+therapeutic	O
+option	O
+in	O
+the	O
+setting	O
+of	O
+cyclosporine	O
+-	O
+induced	O
+TMA	B
+.	O
+
+With	O
+the	O
+more	O
+widespread	O
+application	O
+of	O
+tacrolimus	O
+in	O
+organ	O
+transplantation	O
+,	O
+tacrolimus	O
+-	O
+associated	O
+TMA	B
+has	O
+also	O
+been	O
+recognized	O
+.	O
+
+However	O
+,	O
+literature	O
+regarding	O
+the	O
+incidence	O
+of	O
+the	O
+recurrence	O
+of	O
+TMA	B
+in	O
+patients	O
+exposed	O
+sequentially	O
+to	O
+cyclosporine	O
+and	O
+tacrolimus	O
+is	O
+limited	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+a	O
+living	O
+donor	O
+renal	O
+transplant	O
+recipient	O
+who	O
+developed	O
+cyclosporine	O
+-	O
+induced	O
+TMA	B
+that	O
+responded	O
+to	O
+the	O
+withdrawal	O
+of	O
+cyclosporine	O
+in	O
+conjunction	O
+with	O
+plasmapheresis	O
+and	O
+fresh	O
+frozen	O
+plasma	O
+replacement	O
+therapy	O
+.	O
+
+Introduction	O
+of	O
+tacrolimus	O
+as	O
+an	O
+alternative	O
+immunosuppressive	O
+agent	O
+resulted	O
+in	O
+the	O
+recurrence	O
+of	O
+TMA	B
+and	O
+the	O
+subsequent	O
+loss	O
+of	O
+the	O
+renal	O
+allograft	O
+.	O
+
+Patients	O
+who	O
+are	O
+switched	O
+from	O
+cyclosporine	O
+to	O
+tacrolimus	O
+or	O
+vice	O
+versa	O
+should	O
+be	O
+closely	O
+monitored	O
+for	O
+the	O
+signs	O
+and	O
+symptoms	O
+of	O
+recurrent	O
+TMA	B
+.	O
+
+Analgesic	O
+effect	O
+of	O
+intravenous	O
+ketamine	O
+in	O
+cancer	B
+patients	O
+on	O
+morphine	O
+therapy	O
+:	O
+a	O
+randomized	O
+,	O
+controlled	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+crossover	O
+,	O
+double	O
+-	O
+dose	O
+study	O
+.	O
+
+Pain	B
+not	O
+responsive	O
+to	O
+morphine	O
+is	O
+often	O
+problematic	O
+.	O
+
+Animal	O
+and	O
+clinical	O
+studies	O
+have	O
+suggested	O
+that	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+antagonists	O
+,	O
+such	O
+as	O
+ketamine	O
+,	O
+may	O
+be	O
+effective	O
+in	O
+improving	O
+opioid	O
+analgesia	O
+in	O
+difficult	O
+pain	B
+syndromes	O
+,	O
+such	O
+as	O
+neuropathic	B
+pain	I
+.	O
+
+A	O
+slow	O
+bolus	O
+of	O
+subhypnotic	O
+doses	O
+of	O
+ketamine	O
+(	O
+0	O
+.	O
+25	O
+mg	O
+/	O
+kg	O
+or	O
+0	O
+.	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+given	O
+to	O
+10	O
+cancer	B
+patients	O
+whose	O
+pain	B
+was	O
+unrelieved	O
+by	O
+morphine	O
+in	O
+a	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+crossover	O
+,	O
+double	O
+-	O
+dose	O
+study	O
+.	O
+
+Pain	B
+intensity	O
+on	O
+a	O
+0	O
+to	O
+10	O
+numerical	O
+scale	O
+;	O
+nausea	B
+and	O
+vomiting	B
+,	O
+drowsiness	O
+,	O
+confusion	B
+,	O
+and	O
+dry	B
+mouth	I
+,	O
+using	O
+a	O
+scale	O
+from	O
+0	O
+to	O
+3	O
+(	O
+not	O
+at	O
+all	O
+,	O
+slight	O
+,	O
+a	O
+lot	O
+,	O
+awful	O
+)	O
+;	O
+Mini	O
+-	O
+Mental	O
+State	O
+Examination	O
+(	O
+MMSE	O
+)	O
+(	O
+0	O
+-	O
+30	O
+)	O
+;	O
+and	O
+arterial	O
+pressure	O
+were	O
+recorded	O
+before	O
+administration	O
+of	O
+drugs	O
+(	O
+T0	O
+)	O
+and	O
+after	O
+30	O
+minutes	O
+(	O
+T30	O
+)	O
+,	O
+60	O
+minutes	O
+(	O
+T60	O
+)	O
+,	O
+120	O
+minutes	O
+(	O
+T120	O
+)	O
+,	O
+and	O
+180	O
+minutes	O
+(	O
+T180	O
+)	O
+.	O
+
+Ketamine	O
+,	O
+but	O
+not	O
+saline	O
+solution	O
+,	O
+significantly	O
+reduced	O
+the	O
+pain	B
+intensity	O
+in	O
+almost	O
+all	O
+the	O
+patients	O
+at	O
+both	O
+doses	O
+.	O
+
+This	O
+effect	O
+was	O
+more	O
+relevant	O
+in	O
+patients	O
+treated	O
+with	O
+higher	O
+doses	O
+.	O
+
+Hallucinations	B
+occurred	O
+in	O
+4	O
+patients	O
+,	O
+and	O
+an	O
+unpleasant	O
+sensation	O
+(	O
+"	O
+empty	O
+head	O
+"	O
+)	O
+was	O
+also	O
+reported	O
+by	O
+2	O
+patients	O
+.	O
+
+These	O
+episodes	O
+reversed	O
+after	O
+the	O
+administration	O
+of	O
+diazepam	O
+1	O
+mg	O
+intravenously	O
+.	O
+
+Significant	O
+increases	O
+in	O
+drowsiness	O
+were	O
+reported	O
+in	O
+patients	O
+treated	O
+with	O
+ketamine	O
+in	O
+both	O
+groups	O
+and	O
+were	O
+more	O
+marked	O
+with	O
+ketamine	O
+0	O
+.	O
+50	O
+mg	O
+/	O
+kg	O
+.	O
+
+A	O
+significant	O
+difference	O
+in	O
+MMSE	O
+was	O
+observed	O
+at	O
+T30	O
+in	O
+patients	O
+who	O
+received	O
+0	O
+.	O
+50	O
+mg	O
+/	O
+kg	O
+of	O
+ketamine	O
+.	O
+
+Ketamine	O
+can	O
+improve	O
+morphine	O
+analgesia	O
+in	O
+difficult	O
+pain	B
+syndromes	O
+,	O
+such	O
+as	O
+neuropathic	B
+pain	I
+.	O
+
+However	O
+,	O
+the	O
+occurrence	O
+of	O
+central	O
+adverse	O
+effects	O
+should	O
+be	O
+taken	O
+into	O
+account	O
+,	O
+especially	O
+when	O
+using	O
+higher	O
+doses	O
+.	O
+
+This	O
+observation	O
+should	O
+be	O
+tested	O
+in	O
+studies	O
+of	O
+prolonged	O
+ketamine	O
+administration	O
+.	O
+
+Paclitaxel	O
+,	O
+cisplatin	O
+,	O
+and	O
+gemcitabine	O
+combination	O
+chemotherapy	O
+within	O
+a	O
+multidisciplinary	O
+therapeutic	O
+approach	O
+in	O
+metastatic	O
+nonsmall	B
+cell	I
+lung	I
+carcinoma	I
+.	O
+
+BACKGROUND	O
+:	O
+Cisplatin	O
+-	O
+based	O
+chemotherapy	O
+combinations	O
+improve	O
+quality	O
+of	O
+life	O
+and	O
+survival	O
+in	O
+advanced	O
+nonsmall	B
+cell	I
+lung	I
+carcinoma	I
+(	O
+NSCLC	B
+)	O
+.	O
+
+The	O
+emergence	O
+of	O
+new	O
+active	O
+drugs	O
+might	O
+translate	O
+into	O
+more	O
+effective	O
+regimens	O
+for	O
+the	O
+treatment	O
+of	O
+this	O
+disease	O
+.	O
+
+METHODS	O
+:	O
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+feasibility	O
+,	O
+response	O
+rate	O
+,	O
+and	O
+toxicity	B
+of	O
+a	O
+paclitaxel	O
+,	O
+cisplatin	O
+,	O
+and	O
+gemcitabine	O
+combination	O
+to	O
+treat	O
+metastatic	O
+NSCLC	B
+.	O
+
+Thirty	O
+-	O
+five	O
+consecutive	O
+chemotherapy	O
+-	O
+naive	O
+patients	O
+with	O
+Stage	O
+IV	O
+NSCLC	B
+and	O
+an	O
+Eastern	O
+Cooperative	O
+Oncology	O
+Group	O
+performance	O
+status	O
+of	O
+0	O
+-	O
+2	O
+were	O
+treated	O
+with	O
+a	O
+combination	O
+of	O
+paclitaxel	O
+(	O
+135	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+given	O
+intravenously	O
+in	O
+3	O
+hours	O
+)	O
+on	O
+Day	O
+1	O
+,	O
+cisplatin	O
+(	O
+120	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+given	O
+intravenously	O
+in	O
+6	O
+hours	O
+)	O
+on	O
+Day	O
+1	O
+,	O
+and	O
+gemcitabine	O
+(	O
+800	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+given	O
+intravenously	O
+in	O
+30	O
+minutes	O
+)	O
+on	O
+Days	O
+1	O
+and	O
+8	O
+,	O
+every	O
+4	O
+weeks	O
+.	O
+
+Although	O
+responding	O
+patients	O
+were	O
+scheduled	O
+to	O
+receive	O
+consolidation	O
+radiotherapy	O
+and	O
+24	O
+patients	O
+received	O
+preplanned	O
+second	O
+-	O
+line	O
+chemotherapy	O
+after	O
+disease	O
+progression	O
+,	O
+the	O
+response	O
+and	O
+toxicity	B
+rates	O
+reported	O
+refer	O
+only	O
+to	O
+the	O
+chemotherapy	O
+regimen	O
+given	O
+.	O
+
+RESULTS	O
+:	O
+All	O
+the	O
+patients	O
+were	O
+examined	O
+for	O
+toxicity	B
+;	O
+34	O
+were	O
+examinable	O
+for	O
+response	O
+.	O
+
+An	O
+objective	O
+response	O
+was	O
+observed	O
+in	O
+73	O
+.	O
+5	O
+%	O
+of	O
+the	O
+patients	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+,	O
+55	O
+.	O
+6	O
+-	O
+87	O
+.	O
+1	O
+%	O
+)	O
+,	O
+including	O
+4	O
+complete	O
+responses	O
+(	O
+11	O
+.	O
+7	O
+%	O
+)	O
+.	O
+
+According	O
+to	O
+intention	O
+-	O
+to	O
+-	O
+treat	O
+,	O
+the	O
+overall	O
+response	O
+rate	O
+was	O
+71	O
+.	O
+4	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+,	O
+53	O
+.	O
+7	O
+-	O
+85	O
+.	O
+4	O
+%	O
+)	O
+.	O
+
+After	O
+154	O
+courses	O
+of	O
+therapy	O
+,	O
+the	O
+median	O
+dose	O
+intensity	O
+was	O
+131	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+for	O
+paclitaxel	O
+(	O
+97	O
+.	O
+3	O
+%	O
+)	O
+,	O
+117	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+for	O
+cisplatin	O
+(	O
+97	O
+.	O
+3	O
+%	O
+)	O
+,	O
+and	O
+1378	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+for	O
+gemcitabine	O
+(	O
+86	O
+.	O
+2	O
+%	O
+)	O
+.	O
+
+World	O
+Health	O
+Organization	O
+Grade	O
+3	O
+-	O
+4	O
+neutropenia	B
+and	O
+thrombocytopenia	B
+occurred	O
+in	O
+39	O
+.	O
+9	O
+%	O
+and	O
+11	O
+.	O
+4	O
+%	O
+of	O
+patients	O
+,	O
+respectively	O
+.	O
+
+There	O
+was	O
+one	O
+treatment	O
+-	O
+related	O
+death	B
+.	O
+
+Nonhematologic	O
+toxicities	B
+were	O
+mild	O
+.	O
+
+After	O
+a	O
+median	O
+follow	O
+-	O
+up	O
+of	O
+22	O
+months	O
+,	O
+the	O
+median	O
+progression	O
+free	O
+survival	O
+rate	O
+was	O
+7	O
+months	O
+,	O
+and	O
+the	O
+median	O
+survival	O
+time	O
+was	O
+16	O
+months	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+combination	O
+of	O
+paclitaxel	O
+,	O
+cisplatin	O
+,	O
+and	O
+gemcitabine	O
+is	O
+well	O
+tolerated	O
+and	O
+shows	O
+high	O
+activity	O
+in	O
+metastatic	O
+NSCLC	B
+.	O
+
+This	O
+treatment	O
+merits	O
+further	O
+comparison	O
+with	O
+other	O
+cisplatin	O
+-	O
+based	O
+regimens	O
+.	O
+
+Serotonergic	O
+antidepressants	O
+and	O
+urinary	B
+incontinence	I
+.	O
+
+Many	O
+new	O
+serotonergic	O
+antidepressants	O
+have	O
+been	O
+introduced	O
+over	O
+the	O
+past	O
+decade	O
+.	O
+
+Although	O
+urinary	B
+incontinence	I
+is	O
+listed	O
+as	O
+one	O
+side	O
+effect	O
+of	O
+these	O
+drugs	O
+in	O
+their	O
+package	O
+inserts	O
+there	O
+is	O
+only	O
+one	O
+report	O
+in	O
+the	O
+literature	O
+.	O
+
+This	O
+concerns	O
+2	O
+male	O
+patients	O
+who	O
+experienced	O
+incontinence	B
+while	O
+taking	O
+venlafaxine	O
+.	O
+
+In	O
+the	O
+present	O
+paper	O
+the	O
+authors	O
+describe	O
+2	O
+female	O
+patients	O
+who	O
+developed	O
+incontinence	B
+secondary	O
+to	O
+the	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitors	O
+paroxetine	O
+and	O
+sertraline	O
+,	O
+as	O
+well	O
+as	O
+a	O
+third	O
+who	O
+developed	O
+this	O
+side	O
+effect	O
+on	O
+venlafaxine	O
+.	O
+
+In	O
+2	O
+of	O
+the	O
+3	O
+cases	O
+the	O
+patients	O
+were	O
+also	O
+taking	O
+lithium	O
+carbonate	O
+and	O
+beta	O
+-	O
+blockers	O
+,	O
+both	O
+of	O
+which	O
+could	O
+have	O
+contributed	O
+to	O
+the	O
+incontinence	B
+.	O
+
+Animal	O
+studies	O
+suggest	O
+that	O
+incontinence	B
+secondary	O
+to	O
+serotonergic	O
+antidepressants	O
+could	O
+be	O
+mediated	O
+by	O
+the	O
+5HT4	O
+receptors	O
+found	O
+on	O
+the	O
+bladder	O
+.	O
+
+Further	O
+research	O
+is	O
+needed	O
+to	O
+delineate	O
+the	O
+frequency	O
+of	O
+this	O
+troubling	O
+side	O
+effect	O
+and	O
+how	O
+best	O
+to	O
+treat	O
+it	O
+.	O
+
+Acute	O
+cocaine	O
+-	O
+induced	O
+seizures	B
+:	O
+differential	O
+sensitivity	O
+of	O
+six	O
+inbred	O
+mouse	O
+strains	O
+.	O
+
+Mature	O
+male	O
+and	O
+female	O
+mice	O
+from	O
+six	O
+inbred	O
+stains	O
+were	O
+tested	O
+for	O
+susceptibility	O
+to	O
+behavioral	O
+seizures	B
+induced	O
+by	O
+a	O
+single	O
+injection	O
+of	O
+cocaine	O
+.	O
+
+Cocaine	O
+was	O
+injected	O
+ip	O
+over	O
+a	O
+range	O
+of	O
+doses	O
+(	O
+50	O
+-	O
+100	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+behavior	O
+was	O
+monitored	O
+for	O
+20	O
+minutes	O
+.	O
+
+Seizure	B
+end	O
+points	O
+included	O
+latency	O
+to	O
+forelimb	O
+or	O
+hindlimb	O
+clonus	O
+,	O
+latency	O
+to	O
+clonic	O
+running	O
+seizure	B
+and	O
+latency	O
+to	O
+jumping	O
+bouncing	O
+seizure	B
+.	O
+
+A	O
+range	O
+of	O
+strain	O
+specific	O
+sensitivities	O
+was	O
+documented	O
+with	O
+A	O
+/	O
+J	O
+and	O
+SJL	O
+mice	O
+being	O
+most	O
+sensitive	O
+and	O
+C57BL	O
+/	O
+6J	O
+most	O
+resistant	O
+.	O
+
+DBA	O
+/	O
+2J	O
+,	O
+BALB	O
+/	O
+cByJ	O
+and	O
+NZW	O
+/	O
+LacJ	O
+strains	O
+exhibited	O
+intermediate	O
+sensitivity	O
+.	O
+
+EEG	O
+recordings	O
+were	O
+made	O
+in	O
+SJL	O
+,	O
+A	O
+/	O
+J	O
+and	O
+C57BL	O
+/	O
+6J	O
+mice	O
+revealing	O
+a	O
+close	O
+correspondence	O
+between	O
+electrical	O
+activity	O
+and	O
+behavior	O
+.	O
+
+Additionally	O
+,	O
+levels	O
+of	O
+cocaine	O
+determined	O
+in	O
+hippocampus	O
+and	O
+cortex	O
+were	O
+not	O
+different	O
+between	O
+sensitive	O
+and	O
+resistant	O
+strains	O
+.	O
+
+Additional	O
+studies	O
+of	O
+these	O
+murine	O
+strains	O
+may	O
+be	O
+useful	O
+for	O
+investigating	O
+genetic	O
+influences	O
+on	O
+cocaine	O
+-	O
+induced	O
+seizures	B
+.	O
+
+Hypotension	B
+following	O
+the	O
+initiation	O
+of	O
+tizanidine	O
+in	O
+a	O
+patient	O
+treated	O
+with	O
+an	O
+angiotensin	O
+converting	O
+enzyme	O
+inhibitor	O
+for	O
+chronic	O
+hypertension	B
+.	O
+
+Centrally	O
+acting	O
+alpha	O
+-	O
+2	O
+adrenergic	O
+agonists	O
+are	O
+one	O
+of	O
+several	O
+pharmacologic	O
+agents	O
+used	O
+in	O
+the	O
+treatment	O
+of	O
+spasticity	B
+related	O
+to	O
+disorders	B
+of	I
+the	I
+central	I
+nervous	I
+system	I
+.	O
+
+In	O
+addition	O
+to	O
+their	O
+effects	O
+on	O
+spasticity	B
+,	O
+certain	O
+adverse	O
+cardiorespiratory	O
+effects	O
+have	O
+been	O
+reported	O
+.	O
+
+Adults	O
+chronically	O
+treated	O
+with	O
+angiotensin	O
+converting	O
+enzyme	O
+inhibitors	O
+may	O
+have	O
+a	O
+limited	O
+ability	O
+to	O
+respond	O
+to	O
+hypotension	B
+when	O
+the	O
+sympathetic	O
+response	O
+is	O
+simultaneously	O
+blocked	O
+.	O
+
+The	O
+authors	O
+present	O
+a	O
+10	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+chronically	O
+treated	O
+with	O
+lisinopril	O
+,	O
+an	O
+angiotensin	O
+converting	O
+enzyme	O
+inhibitor	O
+,	O
+to	O
+control	O
+hypertension	B
+who	O
+developed	O
+hypotension	B
+following	O
+the	O
+addition	O
+of	O
+tizanidine	O
+,	O
+an	O
+alpha	O
+-	O
+2	O
+agonist	O
+,	O
+for	O
+the	O
+treatment	O
+of	O
+spasticity	B
+.	O
+
+The	O
+possible	O
+interaction	O
+of	O
+tizanidine	O
+and	O
+other	O
+antihypertensive	O
+agents	O
+should	O
+be	O
+kept	O
+in	O
+mind	O
+when	O
+prescribing	O
+therapy	O
+to	O
+treat	O
+either	O
+hypertension	B
+or	O
+spasticity	B
+in	O
+such	O
+patients	O
+.	O
+
+Two	O
+mouse	O
+lines	O
+selected	O
+for	O
+differential	O
+sensitivities	O
+to	O
+beta	O
+-	O
+carboline	O
+-	O
+induced	O
+seizures	B
+are	O
+also	O
+differentially	O
+sensitive	O
+to	O
+various	O
+pharmacological	O
+effects	O
+of	O
+other	O
+GABA	O
+(	O
+A	O
+)	O
+receptor	O
+ligands	O
+.	O
+
+Two	O
+mouse	O
+lines	O
+were	O
+selectively	O
+bred	O
+according	O
+to	O
+their	O
+sensitivity	O
+(	O
+BS	O
+line	O
+)	O
+or	O
+resistance	O
+(	O
+BR	O
+line	O
+)	O
+to	O
+seizures	B
+induced	O
+by	O
+a	O
+single	O
+i	O
+.	O
+p	O
+.	O
+injection	O
+of	O
+methyl	O
+beta	O
+-	O
+carboline	O
+-	O
+3	O
+-	O
+carboxylate	O
+(	O
+beta	O
+-	O
+CCM	O
+)	O
+,	O
+an	O
+inverse	O
+agonist	O
+of	O
+the	O
+GABA	O
+(	O
+A	O
+)	O
+receptor	O
+benzodiazepine	O
+site	O
+.	O
+
+Our	O
+aim	O
+was	O
+to	O
+characterize	O
+both	O
+lines	O
+'	O
+sensitivities	O
+to	O
+various	O
+physiological	O
+effects	O
+of	O
+other	O
+ligands	O
+of	O
+the	O
+GABA	O
+(	O
+A	O
+)	O
+receptor	O
+.	O
+
+We	O
+measured	O
+diazepam	O
+-	O
+induced	O
+anxiolysis	O
+with	O
+the	O
+elevated	O
+plus	O
+-	O
+maze	O
+test	O
+,	O
+diazepam	O
+-	O
+induced	O
+sedation	O
+by	O
+recording	O
+the	O
+vigilance	O
+states	O
+,	O
+and	O
+picrotoxin	O
+-	O
+and	O
+pentylenetetrazol	O
+-	O
+induced	O
+seizures	B
+after	O
+i	O
+.	O
+p	O
+.	O
+injections	O
+.	O
+
+Results	O
+presented	O
+here	O
+show	O
+that	O
+the	O
+differential	O
+sensitivities	O
+of	O
+BS	O
+and	O
+BR	O
+lines	O
+to	O
+beta	O
+-	O
+CCM	O
+can	O
+be	O
+extended	O
+to	O
+diazepam	O
+,	O
+picrotoxin	O
+,	O
+and	O
+pentylenetetrazol	O
+,	O
+suggesting	O
+a	O
+genetic	O
+selection	O
+of	O
+a	O
+general	O
+sensitivity	O
+and	O
+resistance	O
+to	O
+several	O
+ligands	O
+of	O
+the	O
+GABA	O
+(	O
+A	O
+)	O
+receptor	O
+.	O
+
+Propylthiouracil	O
+-	O
+induced	O
+perinuclear	O
+-	O
+staining	O
+antineutrophil	O
+cytoplasmic	O
+autoantibody	O
+-	O
+positive	O
+vasculitis	B
+in	O
+conjunction	O
+with	O
+pericarditis	B
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+describe	O
+a	O
+case	O
+of	O
+propylthiouracil	O
+-	O
+induced	O
+vasculitis	B
+manifesting	O
+with	O
+pericarditis	B
+.	O
+
+METHODS	O
+:	O
+We	O
+present	O
+the	O
+first	O
+case	O
+report	O
+of	O
+a	O
+woman	O
+with	O
+hyperthyroidism	B
+treated	O
+with	O
+propylthiouracil	O
+in	O
+whom	O
+a	O
+syndrome	O
+of	O
+pericarditis	B
+,	O
+fever	B
+,	O
+and	O
+glomerulonephritis	B
+developed	O
+.	O
+
+Serologic	O
+testing	O
+and	O
+immunologic	O
+studies	O
+were	O
+done	O
+,	O
+and	O
+a	O
+pericardial	O
+biopsy	O
+was	O
+performed	O
+.	O
+
+RESULTS	O
+:	O
+A	O
+25	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+Graves	B
+'	I
+disease	I
+had	O
+a	O
+febrile	B
+illness	I
+and	O
+evidence	O
+of	O
+pericarditis	B
+,	O
+which	O
+was	O
+confirmed	O
+by	O
+biopsy	O
+.	O
+
+Serologic	O
+evaluation	O
+revealed	O
+the	O
+presence	O
+of	O
+perinuclear	O
+-	O
+staining	O
+antineutrophil	O
+cytoplasmic	O
+autoantibodies	O
+(	O
+pANCA	O
+)	O
+against	O
+myeloperoxidase	O
+(	O
+MPO	O
+)	O
+.	O
+
+Propylthiouracil	O
+therapy	O
+was	O
+withdrawn	O
+,	O
+and	O
+she	O
+was	O
+treated	O
+with	O
+a	O
+1	O
+-	O
+month	O
+course	O
+of	O
+prednisone	O
+,	O
+which	O
+alleviated	O
+her	O
+symptoms	O
+.	O
+
+A	O
+literature	O
+review	O
+revealed	O
+no	O
+prior	O
+reports	O
+of	O
+pericarditis	B
+in	O
+anti	O
+-	O
+MPO	O
+pANCA	O
+-	O
+positive	O
+vasculitis	B
+associated	O
+with	O
+propylthio	O
+-	O
+uracil	O
+therapy	O
+.	O
+
+CONCLUSION	O
+:	O
+Pericarditis	B
+may	O
+be	O
+the	O
+initial	O
+manifestation	O
+of	O
+drug	O
+-	O
+induced	O
+vasculitis	B
+attributable	O
+to	O
+propylthio	O
+-	O
+uracil	O
+therapy	O
+.	O
+
+Repeated	O
+transient	O
+anuria	B
+following	O
+losartan	O
+administration	O
+in	O
+a	O
+patient	O
+with	O
+a	O
+solitary	O
+kidney	O
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+70	O
+-	O
+year	O
+-	O
+old	O
+hypertensive	B
+man	O
+with	O
+a	O
+solitary	O
+kidney	O
+and	O
+chronic	B
+renal	I
+insufficiency	I
+who	O
+developed	O
+two	O
+episodes	O
+of	O
+transient	O
+anuria	B
+after	O
+losartan	O
+administration	O
+.	O
+
+He	O
+was	O
+hospitalized	O
+for	O
+a	O
+myocardial	B
+infarction	I
+with	O
+pulmonary	B
+edema	I
+,	O
+treated	O
+with	O
+high	O
+-	O
+dose	O
+diuretics	O
+.	O
+
+Due	O
+to	O
+severe	O
+systolic	B
+dysfunction	I
+losartan	O
+was	O
+prescribed	O
+.	O
+
+Surprisingly	O
+,	O
+the	O
+first	O
+dose	O
+of	O
+50	O
+mg	O
+of	O
+losartan	O
+resulted	O
+in	O
+a	O
+sudden	O
+anuria	B
+,	O
+which	O
+lasted	O
+eight	O
+hours	O
+despite	O
+high	O
+-	O
+dose	O
+furosemide	O
+and	O
+amine	O
+infusion	O
+.	O
+
+One	O
+week	O
+later	O
+,	O
+by	O
+mistake	O
+,	O
+losartan	O
+was	O
+prescribed	O
+again	O
+and	O
+after	O
+the	O
+second	O
+dose	O
+of	O
+50	O
+mg	O
+,	O
+the	O
+patient	O
+developed	O
+a	O
+second	O
+episode	O
+of	O
+transient	O
+anuria	B
+lasting	O
+10	O
+hours	O
+.	O
+
+During	O
+these	O
+two	O
+episodes	O
+,	O
+his	O
+blood	O
+pressure	O
+diminished	O
+but	O
+no	O
+severe	O
+hypotension	B
+was	O
+noted	O
+.	O
+
+Ultimately	O
+,	O
+an	O
+arteriography	O
+showed	O
+a	O
+70	O
+-	O
+80	O
+%	O
+renal	B
+artery	I
+stenosis	I
+.	O
+
+In	O
+this	O
+patient	O
+,	O
+renal	B
+artery	I
+stenosis	I
+combined	O
+with	O
+heart	B
+failure	I
+and	O
+diuretic	O
+therapy	O
+certainly	O
+resulted	O
+in	O
+a	O
+strong	O
+activation	O
+of	O
+the	O
+renin	O
+-	O
+angiotensin	O
+system	O
+(	O
+RAS	O
+)	O
+.	O
+
+Under	O
+such	O
+conditions	O
+,	O
+angiotensin	O
+II	O
+receptor	O
+blockade	O
+by	O
+losartan	O
+probably	O
+induced	O
+a	O
+critical	O
+fall	O
+in	O
+glomerular	O
+filtration	O
+pressure	O
+.	O
+
+This	O
+case	O
+report	O
+highlights	O
+the	O
+fact	O
+that	O
+the	O
+angiotensin	O
+II	O
+receptor	O
+antagonist	O
+losartan	O
+can	O
+cause	O
+serious	O
+unexpected	O
+complications	O
+in	O
+patients	O
+with	O
+renovascular	B
+disease	I
+and	O
+should	O
+be	O
+used	O
+with	O
+extreme	O
+caution	O
+in	O
+this	O
+setting	O
+.	O
+
+Calcineurin	O
+-	O
+inhibitor	O
+induced	O
+pain	B
+syndrome	O
+(	O
+CIPS	B
+)	O
+:	O
+a	O
+severe	O
+disabling	O
+complication	O
+after	O
+organ	O
+transplantation	O
+.	O
+
+Bone	O
+pain	B
+after	O
+transplantation	O
+is	O
+a	O
+frequent	O
+complication	O
+that	O
+can	O
+be	O
+caused	O
+by	O
+several	O
+diseases	O
+.	O
+
+Treatment	O
+strategies	O
+depend	O
+on	O
+the	O
+correct	O
+diagnosis	O
+of	O
+the	O
+pain	B
+.	O
+
+Nine	O
+patients	O
+with	O
+severe	O
+pain	B
+in	O
+their	O
+feet	O
+,	O
+which	O
+was	O
+registered	O
+after	O
+transplantation	O
+,	O
+were	O
+investigated	O
+.	O
+
+Bone	O
+scans	O
+showed	O
+an	O
+increased	O
+tracer	O
+uptake	O
+of	O
+the	O
+foot	O
+bones	O
+.	O
+
+Magnetic	O
+resonance	O
+imaging	O
+demonstrated	O
+bone	B
+marrow	I
+oedema	I
+in	O
+the	O
+painful	O
+bones	O
+.	O
+
+Pain	B
+was	O
+not	O
+explained	O
+by	O
+other	O
+diseases	O
+causing	O
+foot	O
+pain	B
+,	O
+like	O
+reflex	B
+sympathetic	I
+dystrophy	I
+,	O
+polyneuropathy	B
+,	O
+Morton	B
+'	I
+s	I
+neuralgia	I
+,	O
+gout	B
+,	O
+osteoporosis	B
+,	O
+avascular	B
+necrosis	I
+,	O
+intermittent	B
+claudication	I
+,	O
+orthopaedic	O
+foot	B
+deformities	I
+,	O
+stress	B
+fractures	I
+,	O
+and	O
+hyperparathyroidism	B
+.	O
+
+The	O
+reduction	O
+of	O
+cyclosporine	O
+-	O
+or	O
+tacrolimus	O
+trough	O
+levels	O
+and	O
+the	O
+administration	O
+of	O
+calcium	O
+channel	O
+blockers	O
+led	O
+to	O
+relief	O
+of	O
+pain	B
+.	O
+
+The	O
+Calcineurin	O
+-	O
+inhibitor	O
+Induced	O
+Pain	B
+Syndrome	O
+(	O
+CIPS	B
+)	O
+is	O
+a	O
+rare	O
+but	O
+severe	O
+side	O
+effect	O
+of	O
+cyclosporine	O
+or	O
+tacrolimus	O
+and	O
+is	O
+accurately	O
+diagnosed	O
+by	O
+its	O
+typical	O
+presentation	O
+,	O
+magnetic	O
+resonance	O
+imaging	O
+and	O
+bone	O
+scans	O
+.	O
+
+Incorrect	O
+diagnosis	O
+of	O
+the	O
+syndrome	O
+will	O
+lead	O
+to	O
+a	O
+significant	O
+reduction	O
+of	O
+life	O
+quality	O
+in	O
+patients	O
+suffering	O
+from	O
+CIPS	B
+.	O
+
+Brain	O
+natriuretic	O
+peptide	O
+is	O
+a	O
+predictor	O
+of	O
+anthracycline	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+Anthracyclines	O
+are	O
+effective	O
+antineoplastic	O
+drugs	O
+,	O
+but	O
+they	O
+frequently	O
+cause	O
+dose	O
+-	O
+related	O
+cardiotoxicity	B
+.	O
+
+The	O
+cardiotoxicity	B
+of	O
+conventional	O
+anthracycline	O
+therapy	O
+highlights	O
+a	O
+need	O
+to	O
+search	O
+for	O
+methods	O
+that	O
+are	O
+highly	O
+sensitive	O
+and	O
+capable	O
+of	O
+predicting	O
+cardiac	B
+dysfunction	I
+.	O
+
+We	O
+measured	O
+the	O
+plasma	O
+level	O
+of	O
+brain	O
+natriuretic	O
+peptide	O
+(	O
+BNP	O
+)	O
+to	O
+determine	O
+whether	O
+BNP	O
+might	O
+serve	O
+as	O
+a	O
+simple	O
+diagnostic	O
+indicator	O
+of	O
+anthracycline	O
+-	O
+induced	O
+cardiotoxicity	B
+in	O
+patients	O
+with	O
+acute	B
+leukemia	I
+treated	O
+with	O
+a	O
+daunorubicin	O
+(	O
+DNR	O
+)	O
+-	O
+containing	O
+regimen	O
+.	O
+
+Thirteen	O
+patients	O
+with	O
+acute	B
+leukemia	I
+were	O
+treated	O
+with	O
+a	O
+DNR	O
+-	O
+containing	O
+regimen	O
+.	O
+
+Cardiac	O
+functions	O
+were	O
+evaluated	O
+with	O
+radionuclide	O
+angiography	O
+before	O
+chemotherapies	O
+.	O
+
+The	O
+plasma	O
+levels	O
+of	O
+atrial	O
+natriuretic	O
+peptide	O
+(	O
+ANP	O
+)	O
+and	O
+BNP	O
+were	O
+measured	O
+at	O
+the	O
+time	O
+of	O
+radionuclide	O
+angiography	O
+.	O
+
+Three	O
+patients	O
+developed	O
+congestive	B
+heart	I
+failure	I
+after	O
+the	O
+completion	O
+of	O
+chemotherapy	O
+.	O
+
+Five	O
+patients	O
+were	O
+diagnosed	O
+as	O
+having	O
+subclinical	O
+heart	B
+failure	I
+after	O
+the	O
+completion	O
+of	O
+chemotherapy	O
+.	O
+
+The	O
+plasma	O
+levels	O
+of	O
+BNP	O
+in	O
+all	O
+the	O
+patients	O
+with	O
+clinical	O
+and	O
+subclinical	O
+heart	B
+failure	I
+increased	O
+above	O
+the	O
+normal	O
+limit	O
+(	O
+40	O
+pg	O
+/	O
+ml	O
+)	O
+before	O
+the	O
+detection	O
+of	O
+clinical	O
+or	O
+subclinical	O
+heart	B
+failure	I
+by	O
+radionuclide	O
+angiography	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+BNP	O
+did	O
+not	O
+increase	O
+in	O
+the	O
+patients	O
+without	O
+heart	B
+failure	I
+given	O
+DNR	O
+,	O
+even	O
+at	O
+more	O
+than	O
+700	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+.	O
+
+The	O
+plasma	O
+level	O
+of	O
+ANP	O
+did	O
+not	O
+always	O
+increase	O
+in	O
+all	O
+the	O
+patients	O
+with	O
+clinical	O
+and	O
+subclinical	O
+heart	B
+failure	I
+.	O
+
+These	O
+preliminary	O
+results	O
+suggest	O
+that	O
+BNP	O
+may	O
+be	O
+useful	O
+as	O
+an	O
+early	O
+and	O
+sensitive	O
+indicator	O
+of	O
+anthracycline	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+Nephrotoxicity	B
+of	O
+combined	O
+cephalothin	O
+-	O
+gentamicin	O
+regimen	O
+.	O
+
+Two	O
+patients	O
+developed	O
+acute	B
+tubular	I
+necrosis	I
+,	O
+characterized	O
+clinically	O
+by	O
+acute	O
+oliguric	B
+renal	I
+failure	I
+,	O
+while	O
+they	O
+were	O
+receiving	O
+a	O
+combination	O
+of	O
+cephalothin	O
+sodium	O
+and	O
+gentamicin	O
+sulfate	O
+therapy	O
+.	O
+
+Patients	O
+who	O
+are	O
+given	O
+this	O
+drug	O
+regimen	O
+should	O
+be	O
+observed	O
+very	O
+carefully	O
+for	O
+early	O
+signs	O
+of	O
+nephrotoxicity	B
+.	O
+
+High	O
+doses	O
+of	O
+this	O
+antibiotic	O
+combination	O
+should	O
+be	O
+avoided	O
+especially	O
+in	O
+elderly	O
+patients	O
+.	O
+
+Patients	O
+with	O
+renal	B
+insufficiency	I
+should	O
+not	O
+be	O
+given	O
+this	O
+regimen	O
+.	O
+
+In	O
+vivo	O
+protection	O
+of	O
+dna	O
+damage	O
+associated	O
+apoptotic	O
+and	O
+necrotic	B
+cell	O
+deaths	O
+during	O
+acetaminophen	O
+-	O
+induced	O
+nephrotoxicity	B
+,	O
+amiodarone	O
+-	O
+induced	O
+lung	B
+toxicity	I
+and	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B
+by	O
+a	O
+novel	O
+IH636	O
+grape	O
+seed	O
+proanthocyanidin	O
+extract	O
+.	O
+
+Grape	O
+seed	O
+extract	O
+,	O
+primarily	O
+a	O
+mixture	O
+of	O
+proanthocyanidins	O
+,	O
+has	O
+been	O
+shown	O
+to	O
+modulate	O
+a	O
+wide	O
+-	O
+range	O
+of	O
+biological	O
+,	O
+pharmacological	O
+and	O
+toxicological	O
+effects	O
+which	O
+are	O
+mainly	O
+cytoprotective	O
+.	O
+
+This	O
+study	O
+assessed	O
+the	O
+ability	O
+of	O
+IH636	O
+grape	O
+seed	O
+proanthocyanidin	O
+extract	O
+(	O
+GSPE	O
+)	O
+to	O
+prevent	O
+acetaminophen	O
+(	O
+AAP	O
+)	O
+-	O
+induced	O
+nephrotoxicity	B
+,	O
+amiodarone	O
+(	O
+AMI	O
+)	O
+-	O
+induced	O
+lung	B
+toxicity	I
+,	O
+and	O
+doxorubicin	O
+(	O
+DOX	O
+)	O
+-	O
+induced	O
+cardiotoxicity	B
+in	O
+mice	O
+.	O
+
+Experimental	O
+design	O
+consisted	O
+of	O
+four	O
+groups	O
+:	O
+control	O
+(	O
+vehicle	O
+alone	O
+)	O
+,	O
+GSPE	O
+alone	O
+,	O
+drug	O
+alone	O
+and	O
+GSPE	O
++	O
+drug	O
+.	O
+
+For	O
+the	O
+cytoprotection	O
+study	O
+,	O
+animals	O
+were	O
+orally	O
+gavaged	O
+100	O
+mg	O
+/	O
+Kg	O
+GSPE	O
+for	O
+7	O
+-	O
+10	O
+days	O
+followed	O
+by	O
+i	O
+.	O
+p	O
+.	O
+injections	O
+of	O
+organ	O
+specific	O
+three	O
+drugs	O
+(	O
+AAP	O
+:	O
+500	O
+mg	O
+/	O
+Kg	O
+for	O
+24	O
+h	O
+;	O
+AMI	O
+:	O
+50	O
+mg	O
+/	O
+Kg	O
+/	O
+day	O
+for	O
+four	O
+days	O
+;	O
+DOX	O
+:	O
+20	O
+mg	O
+/	O
+Kg	O
+for	O
+48	O
+h	O
+)	O
+.	O
+
+Parameters	O
+of	O
+study	O
+included	O
+analysis	O
+of	O
+serum	O
+chemistry	O
+(	O
+ALT	O
+,	O
+BUN	O
+and	O
+CPK	O
+)	O
+,	O
+and	O
+orderly	O
+fragmentation	O
+of	O
+genomic	O
+DNA	O
+(	O
+both	O
+endonuclease	O
+-	O
+dependent	O
+and	O
+independent	O
+)	O
+in	O
+addition	O
+to	O
+microscopic	O
+evaluation	O
+of	O
+damage	O
+and	O
+/	O
+or	O
+protection	O
+in	O
+corresponding	O
+PAS	O
+stained	O
+tissues	O
+.	O
+
+Results	O
+indicate	O
+that	O
+GSPE	O
+preexposure	O
+prior	O
+to	O
+AAP	O
+,	O
+AMI	O
+and	O
+DOX	O
+,	O
+provided	O
+near	O
+complete	O
+protection	O
+in	O
+terms	O
+of	O
+serum	O
+chemistry	O
+changes	O
+(	O
+ALT	O
+,	O
+BUN	O
+and	O
+CPK	O
+)	O
+,	O
+and	O
+significantly	O
+reduced	O
+DNA	O
+fragmentation	O
+.	O
+
+Histopathological	O
+examination	O
+of	O
+kidney	O
+,	O
+heart	O
+and	O
+lung	O
+sections	O
+revealed	O
+moderate	O
+to	O
+massive	O
+tissue	B
+damage	I
+with	O
+a	O
+variety	O
+of	O
+morphological	O
+aberrations	O
+by	O
+all	O
+the	O
+three	O
+drugs	O
+in	O
+the	O
+absence	O
+of	O
+GSPE	O
+preexposure	O
+than	O
+in	O
+its	O
+presence	O
+.	O
+
+GSPE	O
++	O
+drug	O
+exposed	O
+tissues	O
+exhibited	O
+minor	O
+residual	O
+damage	O
+or	O
+near	O
+total	O
+recovery	O
+.	O
+
+Additionally	O
+,	O
+histopathological	O
+alterations	O
+mirrored	O
+both	O
+serum	O
+chemistry	O
+changes	O
+and	O
+the	O
+pattern	O
+of	O
+DNA	O
+fragmentation	O
+.	O
+
+Interestingly	O
+,	O
+all	O
+the	O
+drugs	O
+,	O
+such	O
+as	O
+,	O
+AAP	O
+,	O
+AMI	O
+and	O
+DOX	O
+induced	O
+apoptotic	O
+death	O
+in	O
+addition	O
+to	O
+necrosis	B
+in	O
+the	O
+respective	O
+organs	O
+which	O
+was	O
+very	O
+effectively	O
+blocked	O
+by	O
+GSPE	O
+.	O
+
+Since	O
+AAP	O
+,	O
+AMI	O
+and	O
+DOX	O
+undergo	O
+biotransformation	O
+and	O
+are	O
+known	O
+to	O
+produce	O
+damaging	O
+radicals	O
+in	O
+vivo	O
+,	O
+the	O
+protection	O
+by	O
+GSPE	O
+may	O
+be	O
+linked	O
+to	O
+both	O
+inhibition	O
+of	O
+metabolism	O
+and	O
+/	O
+or	O
+detoxification	O
+of	O
+cytotoxic	O
+radicals	O
+.	O
+
+In	O
+addition	O
+,	O
+its	O
+'	O
+presumed	O
+contribution	O
+to	O
+DNA	O
+repair	O
+may	O
+be	O
+another	O
+important	O
+attribute	O
+,	O
+which	O
+played	O
+a	O
+role	O
+in	O
+the	O
+chemoprevention	O
+process	O
+.	O
+
+Additionally	O
+,	O
+this	O
+may	O
+have	O
+been	O
+the	O
+first	O
+report	O
+on	O
+AMI	O
+-	O
+induced	O
+apoptotic	O
+death	O
+in	O
+the	O
+lung	O
+tissue	O
+.	O
+
+Taken	O
+together	O
+,	O
+these	O
+events	O
+undoubtedly	O
+establish	O
+GSPE	O
+'	O
+s	O
+abundant	O
+bioavailability	O
+,	O
+and	O
+the	O
+power	O
+to	O
+defend	O
+multiple	O
+target	O
+organs	O
+from	O
+toxic	O
+assaults	O
+induced	O
+by	O
+structurally	O
+diverse	O
+and	O
+functionally	O
+different	O
+entities	O
+in	O
+vivo	O
+.	O
+
+Antidepressant	O
+-	O
+induced	O
+mania	B
+in	O
+bipolar	B
+patients	O
+:	O
+identification	O
+of	O
+risk	O
+factors	O
+.	O
+
+BACKGROUND	O
+:	O
+Concerns	O
+about	O
+possible	O
+risks	O
+of	O
+switching	O
+to	O
+mania	B
+associated	O
+with	O
+antidepressants	O
+continue	O
+to	O
+interfere	O
+with	O
+the	O
+establishment	O
+of	O
+an	O
+optimal	O
+treatment	O
+paradigm	O
+for	O
+bipolar	B
+depression	I
+.	O
+
+METHOD	O
+:	O
+The	O
+response	O
+of	O
+44	O
+patients	O
+meeting	O
+DSM	O
+-	O
+IV	O
+criteria	O
+for	O
+bipolar	B
+disorder	I
+to	O
+naturalistic	O
+treatment	O
+was	O
+assessed	O
+for	O
+at	O
+least	O
+6	O
+weeks	O
+using	O
+the	O
+Montgomery	O
+-	O
+Asberg	O
+Depression	O
+Rating	O
+Scale	O
+and	O
+the	O
+Bech	O
+-	O
+Rafaelson	O
+Mania	O
+Rating	O
+Scale	O
+.	O
+
+Patients	O
+who	O
+experienced	O
+a	O
+manic	B
+or	O
+hypomanic	B
+switch	O
+were	O
+compared	O
+with	O
+those	O
+who	O
+did	O
+not	O
+on	O
+several	O
+variables	O
+including	O
+age	O
+,	O
+sex	O
+,	O
+diagnosis	O
+(	O
+DSM	B
+-	I
+IV	I
+bipolar	I
+I	I
+vs	O
+.	O
+bipolar	B
+II	I
+)	O
+,	O
+number	O
+of	O
+previous	O
+manic	B
+episodes	O
+,	O
+type	O
+of	O
+antidepressant	O
+therapy	O
+used	O
+(	O
+electroconvulsive	O
+therapy	O
+vs	O
+.	O
+antidepressant	O
+drugs	O
+and	O
+,	O
+more	O
+particularly	O
+,	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitors	O
+[	O
+SSRIs	O
+]	O
+)	O
+,	O
+use	O
+and	O
+type	O
+of	O
+mood	O
+stabilizers	O
+(	O
+lithium	O
+vs	O
+.	O
+anticonvulsants	O
+)	O
+,	O
+and	O
+temperament	O
+of	O
+the	O
+patient	O
+,	O
+assessed	O
+during	O
+a	O
+normothymic	O
+period	O
+using	O
+the	O
+hyperthymia	O
+component	O
+of	O
+the	O
+Semi	O
+-	O
+structured	O
+Affective	O
+Temperament	O
+Interview	O
+.	O
+
+RESULTS	O
+:	O
+Switches	O
+to	O
+hypomania	B
+or	O
+mania	B
+occurred	O
+in	O
+27	O
+%	O
+of	O
+all	O
+patients	O
+(	O
+N	O
+=	O
+12	O
+)	O
+(	O
+and	O
+in	O
+24	O
+%	O
+of	O
+the	O
+subgroup	O
+of	O
+patients	O
+treated	O
+with	O
+SSRIs	O
+[	O
+8	O
+/	O
+33	O
+]	O
+)	O
+;	O
+16	O
+%	O
+(	O
+N	O
+=	O
+7	O
+)	O
+experienced	O
+manic	B
+episodes	O
+,	O
+and	O
+11	O
+%	O
+(	O
+N	O
+=	O
+5	O
+)	O
+experienced	O
+hypomanic	B
+episodes	O
+.	O
+
+Sex	O
+,	O
+age	O
+,	O
+diagnosis	O
+(	O
+bipolar	B
+I	I
+vs	O
+.	O
+bipolar	B
+II	I
+)	O
+,	O
+and	O
+additional	O
+treatment	O
+did	O
+not	O
+affect	O
+the	O
+risk	O
+of	O
+switching	O
+.	O
+
+The	O
+incidence	O
+of	O
+mood	O
+switches	O
+seemed	O
+not	O
+to	O
+differ	O
+between	O
+patients	O
+receiving	O
+an	O
+anticonvulsant	O
+and	O
+those	O
+receiving	O
+no	O
+mood	O
+stabilizer	O
+.	O
+
+In	O
+contrast	O
+,	O
+mood	O
+switches	O
+were	O
+less	O
+frequent	O
+in	O
+patients	O
+receiving	O
+lithium	O
+(	O
+15	O
+%	O
+,	O
+4	O
+/	O
+26	O
+)	O
+than	O
+in	O
+patients	O
+not	O
+treated	O
+with	O
+lithium	O
+(	O
+44	O
+%	O
+,	O
+8	O
+/	O
+18	O
+;	O
+p	O
+=	O
+.	O
+04	O
+)	O
+.	O
+
+The	O
+number	O
+of	O
+previous	O
+manic	B
+episodes	O
+did	O
+not	O
+affect	O
+the	O
+probability	O
+of	O
+switching	O
+,	O
+whereas	O
+a	O
+high	O
+score	O
+on	O
+the	O
+hyperthymia	O
+component	O
+of	O
+the	O
+Semistructured	O
+Affective	O
+Temperament	O
+Interview	O
+was	O
+associated	O
+with	O
+a	O
+greater	O
+risk	O
+of	O
+switching	O
+(	O
+p	O
+=	O
+.	O
+008	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+frequency	O
+of	O
+mood	O
+switching	O
+associated	O
+with	O
+acute	O
+antidepressant	O
+therapy	O
+may	O
+be	O
+reduced	O
+by	O
+lithium	O
+treatment	O
+.	O
+
+Particular	O
+attention	O
+should	O
+be	O
+paid	O
+to	O
+patients	O
+with	O
+a	O
+hyperthymic	O
+temperament	O
+,	O
+who	O
+have	O
+a	O
+greater	O
+risk	O
+of	O
+mood	O
+switches	O
+.	O
+
+Peritubular	O
+capillary	O
+basement	O
+membrane	O
+reduplication	O
+in	O
+allografts	O
+and	O
+native	O
+kidney	B
+disease	I
+:	O
+a	O
+clinicopathologic	O
+study	O
+of	O
+278	O
+consecutive	O
+renal	O
+specimens	O
+.	O
+
+BACKGROUND	O
+:	O
+An	O
+association	O
+has	O
+been	O
+found	O
+between	O
+transplant	B
+glomerulopathy	I
+(	O
+TG	B
+)	O
+and	O
+reduplication	O
+of	O
+peritubular	O
+capillary	O
+basement	O
+membranes	O
+(	O
+PTCR	O
+)	O
+.	O
+
+Although	O
+such	O
+an	O
+association	O
+is	O
+of	O
+practical	O
+and	O
+theoretical	O
+importance	O
+,	O
+only	O
+one	O
+prospective	O
+study	O
+has	O
+tried	O
+to	O
+confirm	O
+it	O
+.	O
+
+METHODS	O
+:	O
+We	O
+examined	O
+278	O
+consecutive	O
+renal	O
+specimens	O
+(	O
+from	O
+135	O
+transplants	O
+and	O
+143	O
+native	O
+kidneys	O
+)	O
+for	O
+ultrastructural	O
+evidence	O
+of	O
+PTCR	O
+.	O
+
+In	O
+addition	O
+to	O
+renal	O
+allografts	O
+with	O
+TG	B
+,	O
+we	O
+also	O
+examined	O
+grafts	O
+with	O
+acute	O
+rejection	O
+,	O
+recurrent	O
+glomerulonephritis	B
+,	O
+chronic	B
+allograft	I
+nephropathy	I
+and	O
+stable	O
+grafts	O
+(	O
+"	O
+protocol	O
+biopsies	O
+"	O
+)	O
+.	O
+
+Native	O
+kidney	O
+specimens	O
+included	O
+a	O
+wide	O
+range	O
+of	O
+glomerulopathies	B
+as	O
+well	O
+as	O
+cases	O
+of	O
+thrombotic	B
+microangiopathy	I
+,	O
+malignant	B
+hypertension	I
+,	O
+acute	O
+interstitial	B
+nephritis	I
+,	O
+and	O
+acute	B
+tubular	I
+necrosis	I
+.	O
+
+RESULTS	O
+:	O
+We	O
+found	O
+PTCR	O
+in	O
+14	O
+of	O
+15	O
+cases	O
+of	O
+TG	B
+,	O
+in	O
+7	O
+transplant	O
+biopsy	O
+specimens	O
+without	O
+TG	B
+,	O
+and	O
+in	O
+13	O
+of	O
+143	O
+native	O
+kidney	O
+biopsy	O
+specimens	O
+.	O
+
+These	O
+13	O
+included	O
+cases	O
+of	O
+malignant	B
+hypertension	I
+,	O
+thrombotic	B
+microangiopathy	I
+,	O
+lupus	B
+nephritis	I
+,	O
+Henoch	B
+-	I
+Schonlein	I
+nephritis	I
+,	O
+crescentic	O
+glomerulonephritis	B
+,	O
+and	O
+cocaine	O
+-	O
+related	O
+acute	B
+renal	I
+failure	I
+.	O
+
+Mild	O
+PTCR	O
+in	O
+allografts	O
+without	O
+TG	B
+did	O
+not	O
+predict	O
+renal	B
+failure	I
+or	O
+significant	O
+proteinuria	B
+after	O
+follow	O
+-	O
+up	O
+periods	O
+of	O
+between	O
+3	O
+months	O
+and	O
+1	O
+year	O
+.	O
+
+CONCLUSIONS	O
+:	O
+We	O
+conclude	O
+that	O
+in	O
+transplants	O
+,	O
+there	O
+is	O
+a	O
+strong	O
+association	O
+between	O
+well	O
+-	O
+developed	O
+PTCR	O
+and	O
+TG	B
+,	O
+while	O
+the	O
+significance	O
+of	O
+mild	O
+PTCR	O
+and	O
+its	O
+predictive	O
+value	O
+in	O
+the	O
+absence	O
+of	O
+TG	B
+is	O
+unclear	O
+.	O
+
+PTCR	O
+also	O
+occurs	O
+in	O
+certain	O
+native	O
+kidney	B
+diseases	I
+,	O
+though	O
+the	O
+association	O
+is	O
+not	O
+as	O
+strong	O
+as	O
+that	O
+for	O
+TG	B
+.	O
+
+We	O
+suggest	O
+that	O
+repeated	O
+endothelial	B
+injury	I
+,	O
+including	O
+immunologic	B
+injury	I
+,	O
+may	O
+be	O
+the	O
+cause	O
+of	O
+this	O
+lesion	O
+both	O
+in	O
+allografts	O
+and	O
+native	O
+kidneys	O
+.	O
+
+Caffeine	O
+-	O
+induced	O
+cardiac	B
+arrhythmia	I
+:	O
+an	O
+unrecognised	O
+danger	O
+of	O
+healthfood	O
+products	O
+.	O
+
+We	O
+describe	O
+a	O
+25	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+pre	O
+-	O
+existing	O
+mitral	B
+valve	I
+prolapse	I
+who	O
+developed	O
+intractable	O
+ventricular	B
+fibrillation	I
+after	O
+consuming	O
+a	O
+"	O
+natural	O
+energy	O
+"	O
+guarana	O
+health	O
+drink	O
+containing	O
+a	O
+high	O
+concentration	O
+of	O
+caffeine	O
+.	O
+
+This	O
+case	O
+highlights	O
+the	O
+need	O
+for	O
+adequate	O
+labelling	O
+and	O
+regulation	O
+of	O
+such	O
+products	O
+.	O
+
+Conformationally	O
+restricted	O
+analogs	O
+of	O
+BD1008	O
+and	O
+an	O
+antisense	O
+oligodeoxynucleotide	O
+targeting	O
+sigma1	O
+receptors	O
+produce	O
+anti	O
+-	O
+cocaine	O
+effects	O
+in	O
+mice	O
+.	O
+
+Cocaine	O
+'	O
+s	O
+ability	O
+to	O
+interact	O
+with	O
+sigma	O
+receptors	O
+suggests	O
+that	O
+these	O
+proteins	O
+mediate	O
+some	O
+of	O
+its	O
+behavioral	O
+effects	O
+.	O
+
+Therefore	O
+,	O
+three	O
+novel	O
+sigma	O
+receptor	O
+ligands	O
+with	O
+antagonist	O
+activity	O
+were	O
+evaluated	O
+in	O
+Swiss	O
+Webster	O
+mice	O
+:	O
+BD1018	O
+(	O
+3S	O
+-	O
+1	O
+-	O
+[	O
+2	O
+-	O
+(	O
+3	O
+,	O
+4	O
+-	O
+dichlorophenyl	O
+)	O
+ethyl	O
+]	O
+-	O
+1	O
+,	O
+4	O
+-	O
+diazabicyclo	O
+[	O
+4	O
+.	O
+3	O
+.	O
+0	O
+]	O
+nonane	O
+)	O
+,	O
+BD1063	O
+(	O
+1	O
+-	O
+[	O
+2	O
+-	O
+(	O
+3	O
+,	O
+4	O
+-	O
+dichlorophenyl	O
+)	O
+ethyl	O
+]	O
+-	O
+4	O
+-	O
+methylpiperazine	O
+)	O
+,	O
+and	O
+LR132	O
+(	O
+1R	O
+,	O
+2S	O
+-	O
+(	O
++	O
+)	O
+-	O
+cis	O
+-	O
+N	O
+-	O
+[	O
+2	O
+-	O
+(	O
+3	O
+,	O
+4	O
+-	O
+dichlorophenyl	O
+)	O
+ethyl	O
+]	O
+-	O
+2	O
+-	O
+(	O
+1	O
+-	O
+pyrrolidinyl	O
+)	O
+cyclohexylamine	O
+)	O
+.	O
+
+Competition	O
+binding	O
+assays	O
+demonstrated	O
+that	O
+all	O
+three	O
+compounds	O
+have	O
+high	O
+affinities	O
+for	O
+sigma1	O
+receptors	O
+.	O
+
+The	O
+three	O
+compounds	O
+vary	O
+in	O
+their	O
+affinities	O
+for	O
+sigma2	O
+receptors	O
+and	O
+exhibit	O
+negligible	O
+affinities	O
+for	O
+dopamine	O
+,	O
+opioid	O
+,	O
+GABA	O
+(	O
+A	O
+)	O
+and	O
+NMDA	O
+receptors	O
+.	O
+
+In	O
+behavioral	O
+studies	O
+,	O
+pre	O
+-	O
+treatment	O
+of	O
+mice	O
+with	O
+BD1018	O
+,	O
+BD1063	O
+,	O
+or	O
+LR132	O
+significantly	O
+attenuated	O
+cocaine	O
+-	O
+induced	O
+convulsions	B
+and	O
+lethality	O
+.	O
+
+Moreover	O
+,	O
+post	O
+-	O
+treatment	O
+with	O
+LR132	O
+prevented	O
+cocaine	O
+-	O
+induced	O
+lethality	O
+in	O
+a	O
+significant	O
+proportion	O
+of	O
+animals	O
+.	O
+
+In	O
+contrast	O
+to	O
+the	O
+protection	O
+provided	O
+by	O
+the	O
+putative	O
+antagonists	O
+,	O
+the	O
+well	O
+-	O
+characterized	O
+sigma	O
+receptor	O
+agonist	O
+di	O
+-	O
+o	O
+-	O
+tolylguanidine	O
+(	O
+DTG	O
+)	O
+and	O
+the	O
+novel	O
+sigma	O
+receptor	O
+agonist	O
+BD1031	O
+(	O
+3R	O
+-	O
+1	O
+-	O
+[	O
+2	O
+-	O
+(	O
+3	O
+,	O
+4	O
+-	O
+dichlorophenyl	O
+)	O
+ethyl	O
+]	O
+-	O
+1	O
+,	O
+4	O
+-	O
+diazabicyclo	O
+[	O
+4	O
+.	O
+3	O
+.	O
+0	O
+]	O
+nonane	O
+)	O
+each	O
+worsened	O
+the	O
+behavioral	O
+toxicity	B
+of	O
+cocaine	O
+.	O
+
+At	O
+doses	O
+where	O
+alone	O
+,	O
+they	O
+produced	O
+no	O
+significant	O
+effects	O
+on	O
+locomotion	O
+,	O
+BD1018	O
+,	O
+BD1063	O
+and	O
+LR132	O
+significantly	O
+attenuated	O
+the	O
+locomotor	O
+stimulatory	O
+effects	O
+of	O
+cocaine	O
+.	O
+
+To	O
+further	O
+validate	O
+the	O
+hypothesis	O
+that	O
+the	O
+anti	O
+-	O
+cocaine	O
+effects	O
+of	O
+the	O
+novel	O
+ligands	O
+involved	O
+antagonism	O
+of	O
+sigma	O
+receptors	O
+,	O
+an	O
+antisense	O
+oligodeoxynucleotide	O
+against	O
+sigma1	O
+receptors	O
+was	O
+also	O
+shown	O
+to	O
+significantly	O
+attenuate	O
+the	O
+convulsive	B
+and	O
+locomotor	O
+stimulatory	O
+effects	O
+of	O
+cocaine	O
+.	O
+
+Together	O
+,	O
+the	O
+data	O
+suggests	O
+that	O
+functional	O
+antagonism	O
+of	O
+sigma	O
+receptors	O
+is	O
+capable	O
+of	O
+attenuating	O
+a	O
+number	O
+of	O
+cocaine	O
+-	O
+induced	O
+behaviors	O
+.	O
+
+Ranitidine	O
+-	O
+induced	O
+acute	O
+interstitial	B
+nephritis	I
+in	O
+a	O
+cadaveric	O
+renal	O
+allograft	O
+.	O
+
+Ranitidine	O
+frequently	O
+is	O
+used	O
+for	O
+preventing	O
+peptic	O
+ulceration	O
+after	O
+renal	O
+transplantation	O
+.	O
+
+This	O
+drug	O
+occasionally	O
+has	O
+been	O
+associated	O
+with	O
+acute	O
+interstitial	B
+nephritis	I
+in	O
+native	O
+kidneys	O
+.	O
+
+There	O
+are	O
+no	O
+similar	O
+reports	O
+with	O
+renal	O
+transplantation	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+ranitidine	O
+-	O
+induced	O
+acute	O
+interstitial	B
+nephritis	I
+in	O
+a	O
+recipient	O
+of	O
+a	O
+cadaveric	O
+renal	O
+allograft	O
+presenting	O
+with	O
+acute	O
+allograft	O
+dysfunction	O
+within	O
+48	O
+hours	O
+of	O
+exposure	O
+to	O
+the	O
+drug	O
+.	O
+
+The	O
+biopsy	O
+specimen	O
+showed	O
+pathognomonic	O
+features	O
+,	O
+including	O
+eosinophilic	O
+infiltration	O
+of	O
+the	O
+interstitial	O
+compartment	O
+.	O
+
+Allograft	O
+function	O
+improved	O
+rapidly	O
+and	O
+returned	O
+to	O
+baseline	O
+after	O
+stopping	O
+the	O
+drug	O
+.	O
+
+Liver	B
+disease	I
+caused	O
+by	O
+propylthiouracil	O
+.	O
+
+This	O
+report	O
+presents	O
+the	O
+clinical	O
+,	O
+laboratory	O
+,	O
+and	O
+light	O
+and	O
+electron	O
+microscopic	O
+observations	O
+on	O
+a	O
+patient	O
+with	O
+chronic	B
+active	I
+(	I
+aggressive	I
+)	I
+hepatitis	I
+caused	O
+by	O
+the	O
+administration	O
+of	O
+propylthiouracil	O
+.	O
+
+This	O
+is	O
+an	O
+addition	O
+to	O
+the	O
+list	O
+of	O
+drugs	O
+that	O
+must	O
+be	O
+considered	O
+in	O
+the	O
+evaluation	O
+of	O
+chronic	O
+liver	B
+disease	I
+.	O
+
+Withdrawal	B
+-	I
+emergent	I
+rabbit	I
+syndrome	I
+during	O
+dose	O
+reduction	O
+of	O
+risperidone	O
+.	O
+
+Rabbit	B
+syndrome	I
+(	O
+RS	B
+)	O
+is	O
+a	O
+rare	O
+extrapyramidal	O
+side	O
+effect	O
+caused	O
+by	O
+prolonged	O
+neuroleptic	O
+medication	O
+.	O
+
+Here	O
+we	O
+present	O
+a	O
+case	O
+of	O
+withdrawal	B
+-	I
+emergent	I
+RS	I
+,	O
+which	O
+is	O
+the	O
+first	O
+of	O
+its	O
+kind	O
+to	O
+be	O
+reported	O
+.	O
+
+The	O
+patient	O
+developed	O
+RS	B
+during	O
+dose	O
+reduction	O
+of	O
+risperidone	O
+.	O
+
+The	O
+symptom	O
+was	O
+treated	O
+successfully	O
+with	O
+trihexyphenidyl	O
+anticholinergic	O
+therapy	O
+.	O
+
+The	O
+underlying	O
+mechanism	O
+of	O
+withdrawal	B
+-	I
+emergent	I
+RS	I
+in	O
+the	O
+present	O
+case	O
+may	O
+have	O
+been	O
+related	O
+to	O
+the	O
+pharmacological	O
+profile	O
+of	O
+risperidone	O
+,	O
+a	O
+serotonin	O
+-	O
+dopamine	O
+antagonist	O
+,	O
+suggesting	O
+the	O
+pathophysiologic	O
+influence	O
+of	O
+the	O
+serotonin	O
+system	O
+in	O
+the	O
+development	O
+of	O
+RS	B
+.	O
+
+Pharmacokinetic	O
+/	O
+pharmacodynamic	O
+assessment	O
+of	O
+the	O
+effects	O
+of	O
+E4031	O
+,	O
+cisapride	O
+,	O
+terfenadine	O
+and	O
+terodiline	O
+on	O
+monophasic	O
+action	O
+potential	O
+duration	O
+in	O
+dog	O
+.	O
+
+1	O
+.	O
+
+Torsades	B
+de	I
+pointes	I
+(	O
+TDP	B
+)	O
+is	O
+a	O
+potentially	O
+fatal	O
+ventricular	B
+tachycardia	I
+associated	O
+with	O
+increases	O
+in	O
+QT	O
+interval	O
+and	O
+monophasic	O
+action	O
+potential	O
+duration	O
+(	O
+MAPD	O
+)	O
+.	O
+
+TDP	B
+is	O
+a	O
+side	O
+-	O
+effect	O
+that	O
+has	O
+led	O
+to	O
+withdrawal	O
+of	O
+several	O
+drugs	O
+from	O
+the	O
+market	O
+(	O
+e	O
+.	O
+g	O
+.	O
+terfenadine	O
+and	O
+terodiline	O
+)	O
+.	O
+
+2	O
+.	O
+
+The	O
+potential	O
+of	O
+compounds	O
+to	O
+cause	O
+TDP	B
+was	O
+evaluated	O
+by	O
+monitoring	O
+their	O
+effects	O
+on	O
+MAPD	O
+in	O
+dog	O
+.	O
+
+Four	O
+compounds	O
+known	O
+to	O
+increase	O
+QT	O
+interval	O
+and	O
+cause	O
+TDP	B
+were	O
+investigated	O
+:	O
+terfenadine	O
+,	O
+terodiline	O
+,	O
+cisapride	O
+and	O
+E4031	O
+.	O
+
+On	O
+the	O
+basis	O
+that	O
+only	O
+free	O
+drug	O
+in	O
+the	O
+systemic	O
+circulation	O
+will	O
+elicit	O
+a	O
+pharmacological	O
+response	O
+target	O
+,	O
+free	O
+concentrations	O
+in	O
+plasma	O
+were	O
+selected	O
+to	O
+mimic	O
+the	O
+free	O
+drug	O
+exposures	O
+in	O
+man	O
+.	O
+
+Infusion	O
+regimens	O
+were	O
+designed	O
+that	O
+rapidly	O
+achieved	O
+and	O
+maintained	O
+target	O
+-	O
+free	O
+concentrations	O
+of	O
+these	O
+drugs	O
+in	O
+plasma	O
+and	O
+data	O
+on	O
+the	O
+relationship	O
+between	O
+free	O
+concentration	O
+and	O
+changes	O
+in	O
+MAPD	O
+were	O
+obtained	O
+for	O
+these	O
+compounds	O
+.	O
+
+3	O
+.	O
+
+These	O
+data	O
+indicate	O
+that	O
+the	O
+free	O
+ED50	O
+in	O
+plasma	O
+for	O
+terfenadine	O
+(	O
+1	O
+.	O
+9	O
+nM	O
+)	O
+,	O
+terodiline	O
+(	O
+76	O
+nM	O
+)	O
+,	O
+cisapride	O
+(	O
+11	O
+nM	O
+)	O
+and	O
+E4031	O
+(	O
+1	O
+.	O
+9	O
+nM	O
+)	O
+closely	O
+correlate	O
+with	O
+the	O
+free	O
+concentration	O
+in	O
+man	O
+causing	O
+QT	O
+effects	O
+.	O
+
+For	O
+compounds	O
+that	O
+have	O
+shown	O
+TDP	B
+in	O
+the	O
+clinic	O
+(	O
+terfenadine	O
+,	O
+terodiline	O
+,	O
+cisapride	O
+)	O
+there	O
+is	O
+little	O
+differentiation	O
+between	O
+the	O
+dog	O
+ED50	O
+and	O
+the	O
+efficacious	O
+free	O
+plasma	O
+concentrations	O
+in	O
+man	O
+(	O
+<	O
+10	O
+-	O
+fold	O
+)	O
+reflecting	O
+their	O
+limited	O
+safety	O
+margins	O
+.	O
+
+These	O
+data	O
+underline	O
+the	O
+need	O
+to	O
+maximize	O
+the	O
+therapeutic	O
+ratio	O
+with	O
+respect	O
+to	O
+TDP	B
+in	O
+potential	O
+development	O
+candidates	O
+and	O
+the	O
+importance	O
+of	O
+using	O
+free	O
+drug	O
+concentrations	O
+in	O
+pharmacokinetic	O
+/	O
+pharmacodynamic	O
+studies	O
+.	O
+
+Bladder	O
+retention	B
+of	I
+urine	I
+as	O
+a	O
+result	O
+of	O
+continuous	O
+intravenous	O
+infusion	O
+of	O
+fentanyl	O
+:	O
+2	O
+case	O
+reports	O
+.	O
+
+Sedation	O
+has	O
+been	O
+commonly	O
+used	O
+in	O
+the	O
+neonate	O
+to	O
+decrease	O
+the	O
+stress	O
+and	O
+pain	B
+from	O
+the	O
+noxious	O
+stimuli	O
+and	O
+invasive	O
+procedures	O
+in	O
+the	O
+neonatal	O
+intensive	O
+care	O
+unit	O
+,	O
+as	O
+well	O
+as	O
+to	O
+facilitate	O
+synchrony	O
+between	O
+ventilator	O
+and	O
+spontaneous	O
+breaths	O
+.	O
+
+Fentanyl	O
+,	O
+an	O
+opioid	O
+analgesic	O
+,	O
+is	O
+frequently	O
+used	O
+in	O
+the	O
+neonatal	O
+intensive	O
+care	O
+unit	O
+setting	O
+for	O
+these	O
+very	O
+purposes	O
+.	O
+
+Various	O
+reported	O
+side	O
+effects	O
+of	O
+fentanyl	O
+administration	O
+include	O
+chest	B
+wall	I
+rigidity	I
+,	O
+hypotension	B
+,	O
+respiratory	B
+depression	I
+,	O
+and	O
+bradycardia	B
+.	O
+
+Here	O
+,	O
+2	O
+cases	O
+of	O
+urinary	B
+bladder	I
+retention	I
+leading	O
+to	O
+renal	O
+pelvocalyceal	O
+dilatation	O
+mimicking	O
+hydronephrosis	B
+as	O
+a	O
+result	O
+of	O
+continuous	O
+infusion	O
+of	O
+fentanyl	O
+are	O
+reported	O
+.	O
+
+Fatal	O
+myeloencephalopathy	B
+due	O
+to	O
+accidental	O
+intrathecal	O
+vincristin	O
+administration	O
+:	O
+a	O
+report	O
+of	O
+two	O
+cases	O
+.	O
+
+We	O
+report	O
+on	O
+two	O
+fatal	O
+cases	O
+of	O
+accidental	O
+intrathecal	O
+vincristine	O
+instillation	O
+in	O
+a	O
+5	O
+-	O
+year	O
+old	O
+girl	O
+with	O
+recurrent	O
+acute	B
+lymphoblastic	I
+leucemia	I
+and	O
+a	O
+57	O
+-	O
+year	O
+old	O
+man	O
+with	O
+lymphoblastic	B
+lymphoma	I
+.	O
+
+The	O
+girl	O
+died	O
+seven	O
+days	O
+,	O
+the	O
+man	O
+four	O
+weeks	O
+after	O
+intrathecal	O
+injection	O
+of	O
+vincristine	O
+.	O
+
+Clinically	O
+,	O
+the	O
+onset	O
+was	O
+characterized	O
+by	O
+the	O
+signs	O
+of	O
+opistothonus	B
+,	I
+sensory	I
+and	I
+motor	I
+dysfunction	I
+and	O
+ascending	O
+paralysis	B
+.	O
+
+Histological	O
+and	O
+immunohistochemical	O
+investigations	O
+(	O
+HE	O
+-	O
+LFB	O
+,	O
+CD	O
+-	O
+68	O
+,	O
+Neurofilament	O
+)	O
+revealed	O
+degeneration	B
+of	I
+myelin	I
+and	I
+axons	I
+as	O
+well	O
+as	O
+pseudocystic	B
+transformation	I
+in	O
+areas	O
+exposed	O
+to	O
+vincristine	O
+,	O
+accompanied	O
+by	O
+secondary	O
+changes	O
+with	O
+numerous	O
+prominent	O
+macrophages	O
+.	O
+
+The	O
+clinical	O
+course	O
+and	O
+histopathological	O
+results	O
+of	O
+the	O
+two	O
+cases	O
+are	O
+presented	O
+.	O
+
+A	O
+review	O
+of	O
+all	O
+reported	O
+cases	O
+in	O
+the	O
+literature	O
+is	O
+given	O
+.	O
+
+A	O
+better	O
+controlled	O
+regimen	O
+for	O
+administering	O
+vincristine	O
+and	O
+intrathecal	O
+chemotherapy	O
+is	O
+recommended	O
+.	O
+
+Palpebral	B
+twitching	I
+in	O
+a	O
+depressed	B
+adolescent	O
+on	O
+citalopram	O
+.	O
+
+Current	O
+estimates	O
+suggest	O
+that	O
+between	O
+0	O
+.	O
+4	O
+%	O
+and	O
+8	O
+.	O
+3	O
+%	O
+of	O
+children	O
+and	O
+adolescents	O
+are	O
+affected	O
+by	O
+major	B
+depression	I
+.	O
+
+We	O
+report	O
+a	O
+favorable	O
+response	O
+to	O
+treatment	O
+with	O
+citalopram	O
+by	O
+a	O
+15	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+with	O
+major	B
+depression	I
+who	O
+exhibited	O
+palpebral	B
+twitching	I
+during	O
+his	O
+first	O
+2	O
+weeks	O
+of	O
+treatment	O
+.	O
+
+This	O
+may	O
+have	O
+been	O
+a	O
+side	O
+effect	O
+of	O
+citalopram	O
+as	O
+it	O
+remitted	O
+with	O
+redistribution	O
+of	O
+doses	O
+.	O
+
+The	O
+3	O
+-	O
+week	O
+sulphasalazine	O
+syndrome	O
+strikes	O
+again	O
+.	O
+
+A	O
+34	O
+-	O
+year	O
+-	O
+old	O
+lady	O
+developed	O
+a	O
+constellation	O
+of	O
+dermatitis	B
+,	O
+fever	B
+,	O
+lymphadenopathy	B
+and	O
+hepatitis	B
+,	O
+beginning	O
+on	O
+the	O
+17th	O
+day	O
+of	O
+a	O
+course	O
+of	O
+oral	O
+sulphasalazine	O
+for	O
+sero	O
+-	O
+negative	O
+rheumatoid	B
+arthritis	I
+.	O
+
+Cervical	O
+and	O
+inguinal	O
+lymph	O
+node	O
+biopsies	O
+showed	O
+the	O
+features	O
+of	O
+severe	O
+necrotising	O
+lymphadenitis	B
+,	O
+associated	O
+with	O
+erythrophagocytosis	O
+and	O
+prominent	O
+eosinophilic	O
+infiltrates	O
+,	O
+without	O
+viral	O
+inclusion	O
+bodies	O
+,	O
+suggestive	O
+of	O
+an	O
+adverse	B
+drug	I
+reaction	I
+.	O
+A	O
+week	O
+later	O
+,	O
+fulminant	O
+drug	B
+-	I
+induced	I
+hepatitis	I
+,	O
+associated	O
+with	O
+the	O
+presence	O
+of	O
+anti	O
+-	O
+nuclear	O
+autoantibodies	O
+(	O
+but	O
+not	O
+with	O
+other	O
+markers	O
+of	O
+autoimmunity	B
+)	O
+,	O
+and	O
+accompanied	O
+by	O
+multi	B
+-	I
+organ	I
+failure	I
+and	O
+sepsis	B
+,	O
+supervened	O
+.	O
+
+She	O
+subsequently	O
+died	O
+some	O
+5	O
+weeks	O
+after	O
+the	O
+commencement	O
+of	O
+her	O
+drug	O
+therapy	O
+.	O
+Post	O
+-	O
+mortem	O
+examination	O
+showed	O
+evidence	O
+of	O
+massive	B
+hepatocellular	I
+necrosis	I
+,	O
+acute	O
+hypersensitivity	O
+myocarditis	B
+,	O
+focal	O
+acute	O
+tubulo	O
+-	O
+interstitial	O
+nephritis	B
+and	O
+extensive	O
+bone	B
+marrow	I
+necrosis	I
+,	O
+with	O
+no	O
+evidence	O
+of	O
+malignancy	B
+.	O
+
+It	O
+is	O
+thought	O
+that	O
+the	O
+clinico	O
+-	O
+pathological	O
+features	O
+and	O
+chronology	O
+of	O
+this	O
+case	O
+bore	O
+the	O
+hallmarks	O
+of	O
+the	O
+so	O
+-	O
+called	O
+"	O
+3	O
+-	O
+week	O
+sulphasalazine	O
+syndrome	O
+"	O
+,	O
+a	O
+rare	O
+,	O
+but	O
+often	O
+fatal	O
+,	O
+immunoallergic	O
+reaction	O
+to	O
+sulphasalazine	O
+.	O
+
+Intravenous	O
+administration	O
+of	O
+prochlorperazine	O
+by	O
+15	O
+-	O
+minute	O
+infusion	O
+versus	O
+2	O
+-	O
+minute	O
+bolus	O
+does	O
+not	O
+affect	O
+the	O
+incidence	O
+of	O
+akathisia	B
+:	O
+a	O
+prospective	O
+,	O
+randomized	O
+,	O
+controlled	O
+trial	O
+.	O
+
+STUDY	O
+OBJECTIVE	O
+:	O
+We	O
+sought	O
+to	O
+compare	O
+the	O
+rate	O
+of	O
+akathisia	B
+after	O
+administration	O
+of	O
+intravenous	O
+prochlorperazine	O
+as	O
+a	O
+2	O
+-	O
+minute	O
+bolus	O
+or	O
+15	O
+-	O
+minute	O
+infusion	O
+.	O
+
+METHODS	O
+:	O
+We	O
+conducted	O
+a	O
+prospective	O
+,	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+study	O
+in	O
+the	O
+emergency	O
+department	O
+of	O
+a	O
+central	O
+-	O
+city	O
+teaching	O
+hospital	O
+.	O
+
+Patients	O
+aged	O
+18	O
+years	O
+or	O
+older	O
+treated	O
+with	O
+prochlorperazine	O
+for	O
+headache	B
+,	O
+nausea	B
+,	O
+or	O
+vomiting	B
+were	O
+eligible	O
+for	O
+inclusion	O
+.	O
+
+Study	O
+participants	O
+were	O
+randomized	O
+to	O
+receive	O
+10	O
+mg	O
+of	O
+prochlorperazine	O
+administered	O
+intravenously	O
+by	O
+means	O
+of	O
+2	O
+-	O
+minute	O
+push	O
+(	O
+bolus	O
+group	O
+)	O
+or	O
+10	O
+mg	O
+diluted	O
+in	O
+50	O
+mL	O
+of	O
+normal	O
+saline	O
+solution	O
+administered	O
+by	O
+means	O
+of	O
+intravenous	O
+infusion	O
+during	O
+a	O
+15	O
+-	O
+minute	O
+period	O
+(	O
+infusion	O
+group	O
+)	O
+.	O
+
+The	O
+main	O
+outcome	O
+was	O
+the	O
+number	O
+of	O
+study	O
+participants	O
+experiencing	O
+akathisia	B
+within	O
+60	O
+minutes	O
+of	O
+administration	O
+.	O
+
+Akathisia	O
+was	O
+defined	O
+as	O
+either	O
+a	O
+spontaneous	O
+report	O
+of	O
+restlessness	O
+or	O
+agitation	B
+or	O
+a	O
+change	O
+of	O
+2	O
+or	O
+more	O
+in	O
+the	O
+patient	O
+-	O
+reported	O
+akathisia	B
+rating	O
+scale	O
+and	O
+a	O
+change	O
+of	O
+at	O
+least	O
+1	O
+in	O
+the	O
+investigator	O
+-	O
+observed	O
+akathisia	B
+rating	O
+scale	O
+.	O
+
+The	O
+intensity	O
+of	O
+headache	B
+and	O
+nausea	B
+was	O
+measured	O
+with	O
+a	O
+100	O
+-	O
+mm	O
+visual	O
+analog	O
+scale	O
+.	O
+
+RESULTS	O
+:	O
+One	O
+hundred	O
+patients	O
+were	O
+enrolled	O
+.	O
+
+One	O
+study	O
+participant	O
+was	O
+excluded	O
+after	O
+protocol	O
+violation	O
+.	O
+
+Seventy	O
+-	O
+three	O
+percent	O
+(	O
+73	O
+/	O
+99	O
+)	O
+of	O
+the	O
+study	O
+participants	O
+were	O
+treated	O
+for	O
+headache	B
+and	O
+70	O
+%	O
+(	O
+70	O
+/	O
+99	O
+)	O
+for	O
+nausea	B
+.	O
+
+In	O
+the	O
+bolus	O
+group	O
+,	O
+26	O
+.	O
+0	O
+%	O
+(	O
+13	O
+/	O
+50	O
+)	O
+had	O
+akathisia	B
+compared	O
+with	O
+32	O
+.	O
+7	O
+%	O
+(	O
+16	O
+/	O
+49	O
+)	O
+in	O
+the	O
+infusion	O
+group	O
+(	O
+Delta	O
+=	O
+-	O
+6	O
+.	O
+7	O
+%	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+-	O
+24	O
+.	O
+6	O
+%	O
+to	O
+11	O
+.	O
+2	O
+%	O
+)	O
+.	O
+
+The	O
+difference	O
+between	O
+the	O
+bolus	O
+and	O
+infusion	O
+groups	O
+in	O
+the	O
+percentage	O
+of	O
+participants	O
+who	O
+saw	O
+a	O
+50	O
+%	O
+reduction	O
+in	O
+their	O
+headache	B
+intensity	O
+within	O
+30	O
+minutes	O
+was	O
+11	O
+.	O
+8	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+-	O
+9	O
+.	O
+6	O
+%	O
+to	O
+33	O
+.	O
+3	O
+%	O
+)	O
+.	O
+
+The	O
+difference	O
+in	O
+the	O
+percentage	O
+of	O
+patients	O
+with	O
+a	O
+50	O
+%	O
+reduction	O
+in	O
+their	O
+nausea	B
+was	O
+12	O
+.	O
+6	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+-	O
+4	O
+.	O
+6	O
+%	O
+to	O
+29	O
+.	O
+8	O
+%	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+A	O
+50	O
+%	O
+reduction	O
+in	O
+the	O
+incidence	O
+of	O
+akathisia	B
+when	O
+prochlorperazine	O
+was	O
+administered	O
+by	O
+means	O
+of	O
+15	O
+-	O
+minute	O
+intravenous	O
+infusion	O
+versus	O
+a	O
+2	O
+-	O
+minute	O
+intravenous	O
+push	O
+was	O
+not	O
+detected	O
+.	O
+
+The	O
+efficacy	O
+of	O
+prochlorperazine	O
+in	O
+the	O
+treatment	O
+of	O
+headache	B
+and	O
+nausea	B
+likewise	O
+did	O
+not	O
+appear	O
+to	O
+be	O
+affected	O
+by	O
+the	O
+rate	O
+of	O
+administration	O
+,	O
+although	O
+no	O
+formal	O
+statistical	O
+comparisons	O
+were	O
+made	O
+.	O
+
+Combined	O
+antiretroviral	O
+therapy	O
+causes	O
+cardiomyopathy	B
+and	O
+elevates	O
+plasma	O
+lactate	O
+in	O
+transgenic	O
+AIDS	B
+mice	O
+.	O
+
+Highly	O
+active	O
+antiretroviral	O
+therapy	O
+(	O
+HAART	O
+)	O
+is	O
+implicated	O
+in	O
+cardiomyopathy	B
+(	O
+CM	B
+)	O
+and	O
+in	O
+elevated	O
+plasma	O
+lactate	O
+(	O
+LA	O
+)	O
+in	O
+AIDS	B
+through	O
+mechanisms	O
+of	O
+mitochondrial	B
+dysfunction	I
+.	O
+
+To	O
+determine	O
+mitochondrial	O
+events	O
+from	O
+HAART	O
+in	O
+vivo	O
+,	O
+8	O
+-	O
+week	O
+-	O
+old	O
+hemizygous	O
+transgenic	O
+AIDS	B
+mice	O
+(	O
+NL4	O
+-	O
+3Delta	O
+gag	O
+/	O
+pol	O
+;	O
+TG	O
+)	O
+and	O
+wild	O
+-	O
+type	O
+FVB	O
+/	O
+n	O
+littermates	O
+were	O
+treated	O
+with	O
+the	O
+HAART	O
+combination	O
+of	O
+zidovudine	O
+,	O
+lamivudine	O
+,	O
+and	O
+indinavir	O
+or	O
+vehicle	O
+control	O
+for	O
+10	O
+days	O
+or	O
+35	O
+days	O
+.	O
+
+At	O
+termination	O
+of	O
+the	O
+experiments	O
+,	O
+mice	O
+underwent	O
+echocardiography	O
+,	O
+quantitation	O
+of	O
+abundance	O
+of	O
+molecular	O
+markers	O
+of	O
+CM	B
+(	O
+ventricular	O
+mRNA	O
+encoding	O
+atrial	O
+natriuretic	O
+factor	O
+[	O
+ANF	O
+]	O
+and	O
+sarcoplasmic	O
+calcium	O
+ATPase	O
+[	O
+SERCA2	O
+]	O
+)	O
+,	O
+and	O
+determination	O
+of	O
+plasma	O
+LA	O
+.	O
+
+Myocardial	O
+histologic	O
+features	O
+were	O
+analyzed	O
+semiquantitatively	O
+and	O
+results	O
+were	O
+confirmed	O
+by	O
+transmission	O
+electron	O
+microscopy	O
+.	O
+
+After	O
+35	O
+days	O
+in	O
+the	O
+TG	O
++	O
+HAART	O
+cohort	O
+,	O
+left	O
+ventricular	O
+mass	O
+increased	O
+160	O
+%	O
+by	O
+echocardiography	O
+.	O
+
+Molecularly	O
+,	O
+ANF	O
+mRNA	O
+increased	O
+250	O
+%	O
+and	O
+SERCA2	O
+mRNA	O
+decreased	O
+57	O
+%	O
+.	O
+
+Biochemically	O
+,	O
+LA	O
+was	O
+elevated	O
+(	O
+8	O
+.	O
+5	O
++	O
+/	O
+-	O
+2	O
+.	O
+0	O
+mM	O
+)	O
+.	O
+
+Pathologically	O
+,	O
+granular	O
+cytoplasmic	O
+changes	O
+were	O
+found	O
+in	O
+cardiac	O
+myocytes	O
+,	O
+indicating	O
+enlarged	O
+,	O
+damaged	O
+mitochondria	O
+.	O
+
+Findings	O
+were	O
+confirmed	O
+ultrastructurally	O
+.	O
+
+No	O
+changes	O
+were	O
+found	O
+in	O
+other	O
+cohorts	O
+.	O
+
+After	O
+10	O
+days	O
+,	O
+only	O
+ANF	O
+was	O
+elevated	O
+,	O
+and	O
+only	O
+in	O
+the	O
+TG	O
++	O
+HAART	O
+cohort	O
+.	O
+
+Results	O
+show	O
+that	O
+cumulative	O
+HAART	O
+caused	O
+mitochondrial	O
+CM	B
+with	O
+elevated	O
+LA	O
+in	O
+AIDS	B
+transgenic	O
+mice	O
+.	O
+
+A	O
+Phase	O
+II	O
+trial	O
+of	O
+cisplatin	O
+plus	O
+WR	O
+-	O
+2721	O
+(	O
+amifostine	O
+)	O
+for	O
+metastatic	O
+breast	B
+carcinoma	I
+:	O
+an	O
+Eastern	O
+Cooperative	O
+Oncology	O
+Group	O
+Study	O
+(	O
+E8188	O
+)	O
+.	O
+
+BACKGROUND	O
+:	O
+Cisplatin	O
+has	O
+minimal	O
+antitumor	O
+activity	O
+when	O
+used	O
+as	O
+second	O
+-	O
+or	O
+third	O
+-	O
+line	O
+treatment	O
+of	O
+metastatic	O
+breast	B
+carcinoma	I
+.	O
+
+Older	O
+reports	O
+suggest	O
+an	O
+objective	O
+response	O
+rate	O
+of	O
+8	O
+%	O
+when	O
+60	O
+-	O
+120	O
+mg	O
+/	O
+m2	O
+of	O
+cisplatin	O
+is	O
+administered	O
+every	O
+3	O
+-	O
+4	O
+weeks	O
+.	O
+
+Although	O
+a	O
+dose	O
+-	O
+response	O
+effect	O
+has	O
+been	O
+observed	O
+with	O
+cisplatin	O
+,	O
+the	O
+dose	O
+-	O
+limiting	O
+toxicities	B
+associated	O
+with	O
+cisplatin	O
+(	O
+e	O
+.	O
+g	O
+.	O
+,	O
+nephrotoxicity	B
+,	O
+ototoxicity	B
+,	O
+and	O
+neurotoxicity	B
+)	O
+have	O
+limited	O
+its	O
+use	O
+as	O
+a	O
+treatment	O
+for	O
+breast	B
+carcinoma	I
+.	O
+
+WR	O
+-	O
+2721	O
+or	O
+amifostine	O
+initially	O
+was	O
+developed	O
+to	O
+protect	O
+military	O
+personnel	O
+in	O
+the	O
+event	O
+of	O
+nuclear	O
+war	O
+.	O
+
+Amifostine	O
+subsequently	O
+was	O
+shown	O
+to	O
+protect	O
+normal	O
+tissues	O
+from	O
+the	O
+toxic	O
+effects	O
+of	O
+alkylating	O
+agents	O
+and	O
+cisplatin	O
+without	O
+decreasing	O
+the	O
+antitumor	O
+effect	O
+of	O
+the	O
+chemotherapy	O
+.	O
+
+Early	O
+trials	O
+of	O
+cisplatin	O
+and	O
+amifostine	O
+also	O
+suggested	O
+that	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+cisplatin	O
+-	O
+induced	O
+nephrotoxicity	B
+,	O
+ototoxicity	B
+,	O
+and	O
+neuropathy	B
+were	O
+reduced	O
+.	O
+
+METHODS	O
+:	O
+A	O
+Phase	O
+II	O
+study	O
+of	O
+the	O
+combination	O
+of	O
+cisplatin	O
+plus	O
+amifostine	O
+was	O
+conducted	O
+in	O
+patients	O
+with	O
+progressive	O
+metastatic	O
+breast	B
+carcinoma	I
+who	O
+had	O
+received	O
+one	O
+,	O
+but	O
+not	O
+more	O
+than	O
+one	O
+,	O
+chemotherapy	O
+regimen	O
+for	O
+metastatic	O
+disease	O
+.	O
+
+Patients	O
+received	O
+amifostine	O
+,	O
+910	O
+mg	O
+/	O
+m2	O
+intravenously	O
+over	O
+15	O
+minutes	O
+.	O
+
+After	O
+completion	O
+of	O
+the	O
+amifostine	O
+infusion	O
+,	O
+cisplatin	O
+120	O
+mg	O
+/	O
+m2	O
+was	O
+administered	O
+over	O
+30	O
+minutes	O
+.	O
+
+Intravenous	O
+hydration	O
+and	O
+mannitol	O
+was	O
+administered	O
+before	O
+and	O
+after	O
+cisplatin	O
+.	O
+
+Treatment	O
+was	O
+administered	O
+every	O
+3	O
+weeks	O
+until	O
+disease	O
+progression	O
+.	O
+
+RESULTS	O
+:	O
+Forty	O
+-	O
+four	O
+patients	O
+were	O
+enrolled	O
+in	O
+the	O
+study	O
+of	O
+which	O
+7	O
+(	O
+16	O
+%	O
+)	O
+were	O
+ineligible	O
+.	O
+
+A	O
+median	O
+of	O
+2	O
+cycles	O
+of	O
+therapy	O
+was	O
+administered	O
+to	O
+the	O
+37	O
+eligible	O
+patients	O
+.	O
+
+Six	O
+partial	O
+responses	O
+were	O
+observed	O
+for	O
+an	O
+overall	O
+response	O
+rate	O
+of	O
+16	O
+%	O
+.	O
+
+Most	O
+patients	O
+(	O
+57	O
+%	O
+)	O
+stopped	O
+treatment	O
+because	O
+of	O
+disease	O
+progression	O
+.	O
+
+Neurologic	B
+toxicity	I
+was	O
+reported	O
+in	O
+52	O
+%	O
+of	O
+patients	O
+.	O
+
+Seven	O
+different	O
+life	O
+-	O
+threatening	O
+toxicities	B
+were	O
+observed	O
+in	O
+patients	O
+while	O
+receiving	O
+treatment	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+combination	O
+of	O
+cisplatin	O
+and	O
+amifostine	O
+in	O
+this	O
+study	O
+resulted	O
+in	O
+an	O
+overall	O
+response	O
+rate	O
+of	O
+16	O
+%	O
+.	O
+
+Neither	O
+a	O
+tumor	B
+-	O
+protective	O
+effect	O
+nor	O
+reduced	O
+toxicity	B
+to	O
+normal	O
+tissues	O
+was	O
+observed	O
+with	O
+the	O
+addition	O
+of	O
+amifostine	O
+to	O
+cisplatin	O
+in	O
+this	O
+trial	O
+.	O
+
+Oral	O
+contraceptives	O
+and	O
+the	O
+risk	O
+of	O
+myocardial	B
+infarction	I
+.	O
+
+BACKGROUND	O
+:	O
+An	O
+association	O
+between	O
+the	O
+use	O
+of	O
+oral	O
+contraceptives	O
+and	O
+the	O
+risk	O
+of	O
+myocardial	B
+infarction	I
+has	O
+been	O
+found	O
+in	O
+some	O
+,	O
+but	O
+not	O
+all	O
+,	O
+studies	O
+.	O
+
+We	O
+investigated	O
+this	O
+association	O
+,	O
+according	O
+to	O
+the	O
+type	O
+of	O
+progestagen	O
+included	O
+in	O
+third	O
+-	O
+generation	O
+(	O
+i	O
+.	O
+e	O
+.	O
+,	O
+desogestrel	O
+or	O
+gestodene	O
+)	O
+and	O
+second	O
+-	O
+generation	O
+(	O
+i	O
+.	O
+e	O
+.	O
+,	O
+levonorgestrel	O
+)	O
+oral	O
+contraceptives	O
+,	O
+the	O
+dose	O
+of	O
+estrogen	O
+,	O
+and	O
+the	O
+presence	O
+or	O
+absence	O
+of	O
+prothrombotic	O
+mutations	O
+METHODS	O
+:	O
+In	O
+a	O
+nationwide	O
+,	O
+population	O
+-	O
+based	O
+,	O
+case	O
+-	O
+control	O
+study	O
+,	O
+we	O
+identified	O
+and	O
+enrolled	O
+248	O
+women	O
+18	O
+through	O
+49	O
+years	O
+of	O
+age	O
+who	O
+had	O
+had	O
+a	O
+first	O
+myocardial	B
+infarction	I
+between	O
+1990	O
+and	O
+1995	O
+and	O
+925	O
+control	O
+women	O
+who	O
+had	O
+not	O
+had	O
+a	O
+myocardial	B
+infarction	I
+and	O
+who	O
+were	O
+matched	O
+for	O
+age	O
+,	O
+calendar	O
+year	O
+of	O
+the	O
+index	O
+event	O
+,	O
+and	O
+area	O
+of	O
+residence	O
+.	O
+
+Subjects	O
+supplied	O
+information	O
+on	O
+oral	O
+-	O
+contraceptive	O
+use	O
+and	O
+major	O
+cardiovascular	O
+risk	O
+factors	O
+.	O
+
+An	O
+analysis	O
+for	O
+factor	O
+V	O
+Leiden	O
+and	O
+the	O
+G20210A	O
+mutation	O
+in	O
+the	O
+prothrombin	O
+gene	O
+was	O
+conducted	O
+in	O
+217	O
+patients	O
+and	O
+763	O
+controls	O
+RESULTS	O
+:	O
+The	O
+odds	O
+ratio	O
+for	O
+myocardial	B
+infarction	I
+among	O
+women	O
+who	O
+used	O
+any	O
+type	O
+of	O
+combined	O
+oral	O
+contraceptive	O
+,	O
+as	O
+compared	O
+with	O
+nonusers	O
+,	O
+was	O
+2	O
+.	O
+0	O
+(	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+1	O
+.	O
+5	O
+to	O
+2	O
+.	O
+8	O
+)	O
+.	O
+
+The	O
+adjusted	O
+odds	O
+ratio	O
+was	O
+2	O
+.	O
+5	O
+(	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+1	O
+.	O
+5	O
+to	O
+4	O
+.	O
+1	O
+)	O
+among	O
+women	O
+who	O
+used	O
+second	O
+-	O
+generation	O
+oral	O
+contraceptives	O
+and	O
+1	O
+.	O
+3	O
+(	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+0	O
+.	O
+7	O
+to	O
+2	O
+.	O
+5	O
+)	O
+among	O
+those	O
+who	O
+used	O
+third	O
+-	O
+generation	O
+oral	O
+contraceptives	O
+.	O
+
+Among	O
+women	O
+who	O
+used	O
+oral	O
+contraceptives	O
+,	O
+the	O
+odds	O
+ratio	O
+was	O
+2	O
+.	O
+1	O
+(	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+1	O
+.	O
+5	O
+to	O
+3	O
+.	O
+0	O
+)	O
+for	O
+those	O
+without	O
+a	O
+prothrombotic	O
+mutation	O
+and	O
+1	O
+.	O
+9	O
+(	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+0	O
+.	O
+6	O
+to	O
+5	O
+.	O
+5	O
+)	O
+for	O
+those	O
+with	O
+a	O
+mutation	O
+CONCLUSIONS	O
+:	O
+The	O
+risk	O
+of	O
+myocardial	B
+infarction	I
+was	O
+increased	O
+among	O
+women	O
+who	O
+used	O
+second	O
+-	O
+generation	O
+oral	O
+contraceptives	O
+.	O
+
+The	O
+results	O
+with	O
+respect	O
+to	O
+the	O
+use	O
+of	O
+third	O
+-	O
+generation	O
+oral	O
+contraceptives	O
+were	O
+inconclusive	O
+but	O
+suggested	O
+that	O
+the	O
+risk	O
+was	O
+lower	O
+than	O
+the	O
+risk	O
+associated	O
+with	O
+second	O
+-	O
+generation	O
+oral	O
+contraceptives	O
+.	O
+
+The	O
+risk	O
+of	O
+myocardial	B
+infarction	I
+was	O
+similar	O
+among	O
+women	O
+who	O
+used	O
+oral	O
+contraceptives	O
+whether	O
+or	O
+not	O
+they	O
+had	O
+a	O
+prothrombotic	O
+mutation	O
+.	O
+
+End	B
+-	I
+stage	I
+renal	I
+disease	I
+(	O
+ESRD	B
+)	O
+after	O
+orthotopic	O
+liver	O
+transplantation	O
+(	O
+OLTX	O
+)	O
+using	O
+calcineurin	O
+-	O
+based	O
+immunotherapy	O
+:	O
+risk	O
+of	O
+development	O
+and	O
+treatment	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+calcineurin	O
+inhibitors	O
+cyclosporine	O
+and	O
+tacrolimus	O
+are	O
+both	O
+known	O
+to	O
+be	O
+nephrotoxic	B
+.	O
+
+Their	O
+use	O
+in	O
+orthotopic	O
+liver	O
+transplantation	O
+(	O
+OLTX	O
+)	O
+has	O
+dramatically	O
+improved	O
+success	O
+rates	O
+.	O
+
+Recently	O
+,	O
+however	O
+,	O
+we	O
+have	O
+had	O
+an	O
+increase	O
+of	O
+patients	O
+who	O
+are	O
+presenting	O
+after	O
+OLTX	O
+with	O
+end	B
+-	I
+stage	I
+renal	I
+disease	I
+(	O
+ESRD	B
+)	O
+.	O
+
+This	O
+retrospective	O
+study	O
+examines	O
+the	O
+incidence	O
+and	O
+treatment	O
+of	O
+ESRD	B
+and	O
+chronic	B
+renal	I
+failure	I
+(	O
+CRF	B
+)	O
+in	O
+OLTX	O
+patients	O
+.	O
+
+METHODS	O
+:	O
+Patients	O
+receiving	O
+an	O
+OLTX	O
+only	O
+from	O
+June	O
+1985	O
+through	O
+December	O
+of	O
+1994	O
+who	O
+survived	O
+6	O
+months	O
+postoperatively	O
+were	O
+studied	O
+(	O
+n	O
+=	O
+834	O
+)	O
+.	O
+
+Our	O
+prospectively	O
+collected	O
+database	O
+was	O
+the	O
+source	O
+of	O
+information	O
+.	O
+
+Patients	O
+were	O
+divided	O
+into	O
+three	O
+groups	O
+:	O
+Controls	O
+,	O
+no	O
+CRF	B
+or	O
+ESRD	B
+,	O
+n	O
+=	O
+748	O
+;	O
+CRF	B
+,	O
+sustained	O
+serum	O
+creatinine	O
+>	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+dl	O
+,	O
+n	O
+=	O
+41	O
+;	O
+and	O
+ESRD	B
+,	O
+n	O
+=	O
+45	O
+.	O
+
+Groups	O
+were	O
+compared	O
+for	O
+preoperative	O
+laboratory	O
+variables	O
+,	O
+diagnosis	O
+,	O
+postoperative	O
+variables	O
+,	O
+survival	O
+,	O
+type	O
+of	O
+ESRD	B
+therapy	O
+,	O
+and	O
+survival	O
+from	O
+onset	O
+of	O
+ESRD	B
+.	O
+
+RESULTS	O
+:	O
+At	O
+13	O
+years	O
+after	O
+OLTX	O
+,	O
+the	O
+incidence	O
+of	O
+severe	O
+renal	B
+dysfunction	I
+was	O
+18	O
+.	O
+1	O
+%	O
+(	O
+CRF	B
+8	O
+.	O
+6	O
+%	O
+and	O
+ESRD	B
+9	O
+.	O
+5	O
+%	O
+)	O
+.	O
+
+Compared	O
+with	O
+control	O
+patients	O
+,	O
+CRF	B
+and	O
+ESRD	B
+patients	O
+had	O
+higher	O
+preoperative	O
+serum	O
+creatinine	O
+levels	O
+,	O
+a	O
+greater	O
+percentage	O
+of	O
+patients	O
+with	O
+hepatorenal	B
+syndrome	I
+,	O
+higher	O
+percentage	O
+requirement	O
+for	O
+dialysis	O
+in	O
+the	O
+first	O
+3	O
+months	O
+postoperatively	O
+,	O
+and	O
+a	O
+higher	O
+1	O
+-	O
+year	O
+serum	O
+creatinine	O
+.	O
+
+Multivariate	O
+stepwise	O
+logistic	O
+regression	O
+analysis	O
+using	O
+preoperative	O
+and	O
+postoperative	O
+variables	O
+identified	O
+that	O
+an	O
+increase	O
+of	O
+serum	O
+creatinine	O
+compared	O
+with	O
+average	O
+at	O
+1	O
+year	O
+,	O
+3	O
+months	O
+,	O
+and	O
+4	O
+weeks	O
+postoperatively	O
+were	O
+independent	O
+risk	O
+factors	O
+for	O
+the	O
+development	O
+of	O
+CRF	B
+or	O
+ESRD	B
+with	O
+odds	O
+ratios	O
+of	O
+2	O
+.	O
+6	O
+,	O
+2	O
+.	O
+2	O
+,	O
+and	O
+1	O
+.	O
+6	O
+,	O
+respectively	O
+.	O
+
+Overall	O
+survival	O
+from	O
+the	O
+time	O
+of	O
+OLTX	O
+was	O
+not	O
+significantly	O
+different	O
+among	O
+groups	O
+,	O
+but	O
+by	O
+year	O
+13	O
+,	O
+the	O
+survival	O
+of	O
+the	O
+patients	O
+who	O
+had	O
+ESRD	B
+was	O
+only	O
+28	O
+.	O
+2	O
+%	O
+compared	O
+with	O
+54	O
+.	O
+6	O
+%	O
+in	O
+the	O
+control	O
+group	O
+.	O
+
+Patients	O
+developing	O
+ESRD	B
+had	O
+a	O
+6	O
+-	O
+year	O
+survival	O
+after	O
+onset	O
+of	O
+ESRD	B
+of	O
+27	O
+%	O
+for	O
+the	O
+patients	O
+receiving	O
+hemodialysis	O
+versus	O
+71	O
+.	O
+4	O
+%	O
+for	O
+the	O
+patients	O
+developing	O
+ESRD	B
+who	O
+subsequently	O
+received	O
+kidney	O
+transplants	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Patients	O
+who	O
+are	O
+more	O
+than	O
+10	O
+years	O
+post	O
+-	O
+OLTX	O
+have	O
+CRF	B
+and	O
+ESRD	B
+at	O
+a	O
+high	O
+rate	O
+.	O
+
+The	O
+development	O
+of	O
+ESRD	B
+decreases	O
+survival	O
+,	O
+particularly	O
+in	O
+those	O
+patients	O
+treated	O
+with	O
+dialysis	O
+only	O
+.	O
+
+Patients	O
+who	O
+develop	O
+ESRD	B
+have	O
+a	O
+higher	O
+preoperative	O
+and	O
+1	O
+-	O
+year	O
+serum	O
+creatinine	O
+and	O
+are	O
+more	O
+likely	O
+to	O
+have	O
+hepatorenal	B
+syndrome	I
+.	O
+
+However	O
+,	O
+an	O
+increase	O
+of	O
+serum	O
+creatinine	O
+at	O
+various	O
+times	O
+postoperatively	O
+is	O
+more	O
+predictive	O
+of	O
+the	O
+development	O
+of	O
+CRF	B
+or	O
+ESRD	B
+.	O
+
+New	O
+strategies	O
+for	O
+long	O
+-	O
+term	O
+immunosuppression	O
+may	O
+be	O
+needed	O
+to	O
+decrease	O
+this	O
+complication	O
+.	O
+
+Epileptic	B
+seizures	I
+following	O
+cortical	O
+application	O
+of	O
+fibrin	O
+sealants	O
+containing	O
+tranexamic	O
+acid	O
+in	O
+rats	O
+.	O
+
+BACKGROUND	O
+:	O
+Fibrin	O
+sealants	O
+(	O
+FS	O
+)	O
+derived	O
+from	O
+human	O
+plasma	O
+are	O
+frequently	O
+used	O
+in	O
+neurosurgery	O
+.	O
+
+In	O
+order	O
+to	O
+increase	O
+clot	O
+stability	O
+,	O
+FS	O
+typically	O
+contain	O
+aprotinin	O
+,	O
+a	O
+natural	O
+fibrinolysis	O
+inhibitor	O
+.	O
+
+Recently	O
+,	O
+synthetic	O
+fibrinolysis	O
+inhibitors	O
+such	O
+as	O
+tranexamic	O
+acid	O
+(	O
+tAMCA	O
+)	O
+have	O
+been	O
+considered	O
+as	O
+substitutes	O
+for	O
+aprotinin	O
+.	O
+
+However	O
+,	O
+tAMCA	O
+has	O
+been	O
+shown	O
+to	O
+cause	O
+epileptic	B
+seizures	I
+.	O
+
+We	O
+wanted	O
+to	O
+study	O
+whether	O
+tAMCA	O
+retains	O
+its	O
+convulsive	B
+action	O
+if	O
+incorporated	O
+into	O
+a	O
+FS	O
+.	O
+
+METHOD	O
+:	O
+FS	O
+containing	O
+aprotinin	O
+or	O
+different	O
+concentrations	O
+of	O
+tAMCA	O
+(	O
+0	O
+.	O
+5	O
+-	O
+47	O
+.	O
+5	O
+mg	O
+/	O
+ml	O
+)	O
+were	O
+applied	O
+to	O
+the	O
+pial	O
+surface	O
+of	O
+the	O
+cortex	O
+of	O
+anaesthetized	O
+rats	O
+.	O
+
+The	O
+response	O
+of	O
+the	O
+animals	O
+was	O
+evaluated	O
+using	O
+electroencephalography	O
+and	O
+by	O
+monitoring	O
+the	O
+clinical	O
+behaviour	O
+during	O
+and	O
+after	O
+recovery	O
+from	O
+anaesthesia	O
+.	O
+
+FINDINGS	O
+:	O
+FS	O
+containing	O
+tAMCA	O
+caused	O
+paroxysmal	O
+brain	O
+activity	O
+which	O
+was	O
+associated	O
+with	O
+distinct	O
+convulsive	B
+behaviours	O
+.	O
+
+The	O
+degree	O
+of	O
+these	O
+seizures	B
+increased	O
+with	O
+increasing	O
+concentration	O
+of	O
+tAMCA	O
+.	O
+
+Thus	O
+,	O
+FS	O
+containing	O
+47	O
+.	O
+5	O
+mg	O
+/	O
+ml	O
+tAMCA	O
+evoked	O
+generalized	B
+seizures	I
+in	O
+all	O
+tested	O
+rats	O
+(	O
+n	O
+=	O
+6	O
+)	O
+while	O
+the	O
+lowest	O
+concentration	O
+of	O
+tAMCA	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+ml	O
+)	O
+only	O
+evoked	O
+brief	O
+episodes	O
+of	O
+jerk	O
+-	O
+correlated	O
+convulsive	B
+potentials	O
+in	O
+1	O
+of	O
+6	O
+rats	O
+.	O
+
+In	O
+contrast	O
+,	O
+FS	O
+containing	O
+aprotinin	O
+did	O
+not	O
+evoke	O
+any	O
+paroxysmal	O
+activity	O
+.	O
+
+INTERPRETATION	O
+:	O
+Tranexamic	O
+acid	O
+retains	O
+its	O
+convulsive	B
+action	O
+within	O
+FS	O
+.	O
+
+Thus	O
+,	O
+use	O
+of	O
+FS	O
+containing	O
+tAMCA	O
+for	O
+surgery	O
+within	O
+or	O
+close	O
+to	O
+the	O
+CNS	O
+may	O
+pose	O
+a	O
+substantial	O
+risk	O
+to	O
+the	O
+patient	O
+.	O
+
+Sequential	O
+observations	O
+of	O
+exencephaly	B
+and	O
+subsequent	O
+morphological	O
+changes	O
+by	O
+mouse	O
+exo	O
+utero	O
+development	O
+system	O
+:	O
+analysis	O
+of	O
+the	O
+mechanism	O
+of	O
+transformation	O
+from	O
+exencephaly	B
+to	O
+anencephaly	B
+.	O
+
+Anencephaly	B
+has	O
+been	O
+suggested	O
+to	O
+develop	O
+from	O
+exencephaly	B
+;	O
+however	O
+,	O
+there	O
+is	O
+little	O
+direct	O
+experimental	O
+evidence	O
+to	O
+support	O
+this	O
+,	O
+and	O
+the	O
+mechanism	O
+of	O
+transformation	O
+remains	O
+unclear	O
+.	O
+
+We	O
+examined	O
+this	O
+theory	O
+using	O
+the	O
+exo	O
+utero	O
+development	O
+system	O
+that	O
+allows	O
+direct	O
+and	O
+sequential	O
+observations	O
+of	O
+mid	O
+-	O
+to	O
+late	O
+-	O
+gestation	O
+mouse	O
+embryos	O
+.	O
+
+We	O
+observed	O
+the	O
+exencephaly	B
+induced	O
+by	O
+5	O
+-	O
+azacytidine	O
+at	O
+embryonic	O
+day	O
+13	O
+.	O
+5	O
+(	O
+E13	O
+.	O
+5	O
+)	O
+,	O
+let	O
+the	O
+embryos	O
+develop	O
+exo	O
+utero	O
+until	O
+E18	O
+.	O
+5	O
+,	O
+and	O
+re	O
+-	O
+observed	O
+the	O
+same	O
+embryos	O
+at	O
+E18	O
+.	O
+5	O
+.	O
+
+We	O
+confirmed	O
+several	O
+cases	O
+of	O
+transformation	O
+from	O
+exencephaly	B
+to	O
+anencephaly	B
+.	O
+
+However	O
+,	O
+in	O
+many	O
+cases	O
+,	O
+the	O
+exencephalic	B
+brain	O
+tissue	O
+was	O
+preserved	O
+with	O
+more	O
+or	O
+less	O
+reduction	O
+during	O
+this	O
+period	O
+.	O
+
+To	O
+analyze	O
+the	O
+transformation	O
+patterns	O
+,	O
+we	O
+classified	O
+the	O
+exencephaly	B
+by	O
+size	O
+and	O
+shape	O
+of	O
+the	O
+exencephalic	B
+tissue	O
+into	O
+several	O
+types	O
+at	O
+E13	O
+.	O
+5	O
+and	O
+E18	O
+.	O
+5	O
+.	O
+
+It	O
+was	O
+found	O
+that	O
+the	O
+transformation	O
+of	O
+exencephalic	B
+tissue	O
+was	O
+not	O
+simply	O
+size	O
+-	O
+dependent	O
+,	O
+and	O
+all	O
+cases	O
+of	O
+anencephaly	B
+at	O
+E18	O
+.	O
+5	O
+resulted	O
+from	O
+embryos	O
+with	O
+a	O
+large	O
+amount	O
+of	O
+exencephalic	B
+tissue	O
+at	O
+E13	O
+.	O
+5	O
+.	O
+
+Microscopic	O
+observation	O
+showed	O
+the	O
+configuration	O
+of	O
+exencephaly	B
+at	O
+E13	O
+.	O
+5	O
+,	O
+frequent	O
+hemorrhaging	B
+and	O
+detachment	O
+of	O
+the	O
+neural	O
+plate	O
+from	O
+surface	O
+ectoderm	O
+in	O
+the	O
+exencephalic	B
+head	O
+at	O
+E15	O
+.	O
+5	O
+,	O
+and	O
+multiple	O
+modes	O
+of	O
+reduction	O
+in	O
+the	O
+exencephalic	B
+tissue	O
+at	O
+E18	O
+.	O
+5	O
+.	O
+
+From	O
+observations	O
+of	O
+the	O
+vasculature	O
+,	O
+altered	O
+distribution	O
+patterns	O
+of	O
+vessels	O
+were	O
+identified	O
+in	O
+the	O
+exencephalic	B
+head	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+overgrowth	O
+of	O
+the	O
+exencephalic	B
+neural	O
+tissue	O
+causes	O
+the	O
+altered	O
+distribution	O
+patterns	O
+of	O
+vessels	O
+,	O
+subsequent	O
+peripheral	O
+circulatory	B
+failure	I
+and	O
+/	O
+or	O
+hemorrhaging	B
+in	O
+various	O
+parts	O
+of	O
+the	O
+exencephalic	B
+head	O
+,	O
+leading	O
+to	O
+the	O
+multiple	O
+modes	O
+of	O
+tissue	O
+reduction	O
+during	O
+transformation	O
+from	O
+exencephaly	B
+to	O
+anencephaly	B
+.	O
+
+99mTc	O
+-	O
+glucarate	O
+for	O
+detection	O
+of	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+in	O
+rats	O
+.	O
+
+Infarct	B
+-	O
+avid	O
+radiopharmaceuticals	O
+are	O
+necessary	O
+for	O
+rapid	O
+and	O
+timely	O
+diagnosis	O
+of	O
+acute	O
+myocardial	B
+infarction	I
+.	O
+
+The	O
+animal	O
+model	O
+used	O
+to	O
+produce	O
+infarction	B
+implies	O
+artery	O
+ligation	O
+but	O
+chemical	O
+induction	O
+can	O
+be	O
+easily	O
+obtained	O
+with	O
+isoproterenol	O
+.	O
+
+A	O
+new	O
+infarct	B
+-	O
+avid	O
+radiopharmaceutical	O
+based	O
+on	O
+glucaric	O
+acid	O
+was	O
+prepared	O
+in	O
+the	O
+hospital	O
+radiopharmacy	O
+of	O
+the	O
+INCMNSZ	O
+.	O
+
+99mTc	O
+-	O
+glucarate	O
+was	O
+easy	O
+to	O
+prepare	O
+,	O
+stable	O
+for	O
+96	O
+h	O
+and	O
+was	O
+used	O
+to	O
+study	O
+its	O
+biodistribution	O
+in	O
+rats	O
+with	O
+isoproterenol	O
+-	O
+induced	O
+acute	O
+myocardial	B
+infarction	I
+.	O
+
+Histological	O
+studies	O
+demonstrated	O
+that	O
+the	O
+rats	O
+developed	O
+an	O
+infarct	B
+18	O
+h	O
+after	O
+isoproterenol	O
+administration	O
+.	O
+
+The	O
+rat	O
+biodistribution	O
+studies	O
+showed	O
+a	O
+rapid	O
+blood	O
+clearance	O
+via	O
+the	O
+kidneys	O
+.	O
+
+Thirty	O
+minutes	O
+after	O
+99mTc	O
+-	O
+glucarate	O
+administration	O
+the	O
+standardised	O
+heart	O
+uptake	O
+value	O
+S	O
+(	O
+h	O
+)	O
+UV	O
+was	O
+4	O
+.	O
+7	O
+in	O
+infarcted	O
+rat	O
+heart	O
+which	O
+is	O
+six	O
+times	O
+more	O
+than	O
+in	O
+normal	O
+rats	O
+.	O
+
+ROIs	O
+drawn	O
+over	O
+the	O
+gamma	O
+camera	O
+images	O
+showed	O
+a	O
+ratio	O
+of	O
+4	O
+.	O
+4	O
+.	O
+
+The	O
+high	O
+image	O
+quality	O
+suggests	O
+that	O
+high	O
+contrast	O
+images	O
+can	O
+be	O
+obtained	O
+in	O
+humans	O
+and	O
+the	O
+96	O
+h	O
+stability	O
+makes	O
+it	O
+an	O
+ideal	O
+agent	O
+to	O
+detect	O
+,	O
+in	O
+patients	O
+,	O
+early	O
+cardiac	B
+infarction	I
+.	O
+
+Bupropion	O
+(	O
+Zyban	O
+)	O
+toxicity	B
+.	O
+
+Bupropion	O
+is	O
+a	O
+monocyclic	O
+antidepressant	O
+structurally	O
+related	O
+to	O
+amphetamine	O
+.	O
+
+Zyban	O
+,	O
+a	O
+sustained	O
+-	O
+release	O
+formulation	O
+of	O
+bupropion	O
+hydrochloride	O
+,	O
+was	O
+recently	O
+released	O
+in	O
+Ireland	O
+,	O
+as	O
+a	O
+smoking	O
+cessation	O
+aid	O
+.	O
+
+In	O
+the	O
+initial	O
+6	O
+months	O
+since	O
+it	O
+'	O
+s	O
+introduction	O
+,	O
+12	O
+overdose	B
+cases	O
+have	O
+been	O
+reported	O
+to	O
+The	O
+National	O
+Poisons	O
+Information	O
+Centre	O
+.	O
+
+8	O
+patients	O
+developed	O
+symptoms	O
+of	O
+toxicity	B
+.	O
+
+Common	O
+features	O
+included	O
+tachycardia	B
+,	O
+drowsiness	O
+,	O
+hallucinations	B
+and	O
+convulsions	B
+.	O
+
+Two	O
+patients	O
+developed	O
+severe	O
+cardiac	B
+arrhythmias	I
+,	O
+including	O
+one	O
+patient	O
+who	O
+was	O
+resuscitated	O
+following	O
+a	O
+cardiac	B
+arrest	I
+.	O
+
+All	O
+patients	O
+recovered	O
+without	O
+sequelae	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+a	O
+31	O
+year	O
+old	O
+female	O
+who	O
+required	O
+admission	O
+to	O
+the	O
+Intensive	O
+Care	O
+Unit	O
+for	O
+ventilation	O
+and	O
+full	O
+supportive	O
+therapy	O
+,	O
+following	O
+ingestion	O
+of	O
+13	O
+.	O
+5g	O
+bupropion	O
+.	O
+
+Recurrent	O
+seizures	B
+were	O
+treated	O
+with	O
+diazepam	O
+and	O
+broad	O
+complex	O
+tachycardia	B
+was	O
+successfully	O
+treated	O
+with	O
+adenosine	O
+.	O
+
+Zyban	O
+caused	O
+significant	O
+neurological	B
+and	I
+cardiovascular	I
+toxicity	I
+in	O
+overdose	B
+.	O
+
+The	O
+potential	O
+toxic	O
+effects	O
+should	O
+be	O
+considered	O
+when	O
+prescribing	O
+it	O
+as	O
+a	O
+smoking	O
+cessation	O
+aid	O
+.	O
+
+GLEPP1	O
+receptor	O
+tyrosine	O
+phosphatase	O
+(	O
+Ptpro	O
+)	O
+in	O
+rat	O
+PAN	O
+nephrosis	B
+.	O
+
+A	O
+marker	O
+of	O
+acute	O
+podocyte	O
+injury	O
+.	O
+
+Glomerular	O
+epithelial	O
+protein	O
+1	O
+(	O
+GLEPP1	O
+)	O
+is	O
+a	O
+podocyte	O
+receptor	O
+membrane	O
+protein	O
+tyrosine	O
+phosphatase	O
+located	O
+on	O
+the	O
+apical	O
+cell	O
+membrane	O
+of	O
+visceral	O
+glomerular	O
+epithelial	O
+cell	O
+and	O
+foot	O
+processes	O
+.	O
+
+This	O
+receptor	O
+plays	O
+a	O
+role	O
+in	O
+regulating	O
+the	O
+structure	O
+and	O
+function	O
+of	O
+podocyte	O
+foot	O
+process	O
+.	O
+
+To	O
+better	O
+understand	O
+the	O
+utility	O
+of	O
+GLEPP1	O
+as	O
+a	O
+marker	O
+of	O
+glomerular	B
+injury	I
+,	O
+the	O
+amount	O
+and	O
+distribution	O
+of	O
+GLEPP1	O
+protein	O
+and	O
+mRNA	O
+were	O
+examined	O
+by	O
+immunohistochemistry	O
+,	O
+Western	O
+blot	O
+and	O
+RNase	O
+protection	O
+assay	O
+in	O
+a	O
+model	O
+of	O
+podocyte	O
+injury	O
+in	O
+the	O
+rat	O
+.	O
+
+Puromycin	O
+aminonucleoside	O
+nephrosis	B
+was	O
+induced	O
+by	O
+single	O
+intraperitoneal	O
+injection	O
+of	O
+puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+,	O
+20	O
+mg	O
+/	O
+100g	O
+BW	O
+)	O
+.	O
+
+Tissues	O
+were	O
+analyzed	O
+at	O
+0	O
+,	O
+5	O
+,	O
+7	O
+,	O
+11	O
+,	O
+21	O
+,	O
+45	O
+,	O
+80	O
+and	O
+126	O
+days	O
+after	O
+PAN	O
+injection	O
+so	O
+as	O
+to	O
+include	O
+both	O
+the	O
+acute	O
+phase	O
+of	O
+proteinuria	B
+associated	O
+with	O
+foot	O
+process	O
+effacement	O
+(	O
+days	O
+5	O
+-	O
+11	O
+)	O
+and	O
+the	O
+chronic	O
+phase	O
+of	O
+proteinuria	B
+associated	O
+with	O
+glomerulosclerosis	B
+(	O
+days	O
+45	O
+-	O
+126	O
+)	O
+.	O
+
+At	O
+day	O
+5	O
+,	O
+GLEPP1	O
+protein	O
+and	O
+mRNA	O
+were	O
+reduced	O
+from	O
+the	O
+normal	O
+range	O
+(	O
+265	O
+.	O
+2	O
++	O
+/	O
+-	O
+79	O
+.	O
+6	O
+x	O
+10	O
+(	O
+6	O
+)	O
+moles	O
+/	O
+glomerulus	O
+and	O
+100	O
+%	O
+)	O
+to	O
+15	O
+%	O
+of	O
+normal	O
+(	O
+41	O
+.	O
+8	O
++	O
+/	O
+-	O
+4	O
+.	O
+8	O
+x	O
+10	O
+(	O
+6	O
+)	O
+moles	O
+/	O
+glomerulus	O
+,	O
+p	O
+<	O
+0	O
+.	O
+005	O
+)	O
+.	O
+
+This	O
+occurred	O
+in	O
+association	O
+with	O
+an	O
+increase	O
+in	O
+urinary	O
+protein	O
+content	O
+from	O
+1	O
+.	O
+8	O
++	O
+/	O
+-	O
+1	O
+to	O
+99	O
+.	O
+0	O
++	O
+/	O
+-	O
+61	O
+mg	O
+/	O
+day	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+In	O
+contrast	O
+,	O
+podocalyxin	O
+did	O
+not	O
+change	O
+significantly	O
+at	O
+this	O
+time	O
+.	O
+
+By	O
+day	O
+11	O
+,	O
+GLEPP1	O
+protein	O
+and	O
+mRNA	O
+had	O
+begun	O
+to	O
+return	O
+towards	O
+baseline	O
+.	O
+
+By	O
+day	O
+45	O
+-	O
+126	O
+,	O
+at	O
+a	O
+time	O
+when	O
+glomerular	O
+scarring	O
+was	O
+present	O
+,	O
+GLEPP1	O
+was	O
+absent	O
+from	O
+glomerulosclerotic	O
+areas	O
+although	O
+the	O
+total	O
+glomerular	O
+content	O
+of	O
+GLEPP1	O
+was	O
+not	O
+different	O
+from	O
+normal	O
+.	O
+
+We	O
+conclude	O
+that	O
+GLEPP1	O
+expression	O
+,	O
+unlike	O
+podocalyxin	O
+,	O
+reflects	O
+podocyte	O
+injury	O
+induced	O
+by	O
+PAN	O
+.	O
+
+GLEPP1	O
+expression	O
+may	O
+be	O
+a	O
+useful	O
+marker	O
+of	O
+podocyte	O
+injury	O
+.	O
+
+Antithymocyte	O
+globulin	O
+in	O
+the	O
+treatment	O
+of	O
+D	O
+-	O
+penicillamine	O
+-	O
+induced	O
+aplastic	B
+anemia	I
+.	O
+
+A	O
+patient	O
+who	O
+received	O
+antithymocyte	O
+globulin	O
+therapy	O
+for	O
+aplastic	B
+anemia	I
+due	O
+to	O
+D	O
+-	O
+penicillamine	O
+therapy	O
+is	O
+described	O
+.	O
+
+Bone	O
+marrow	O
+recovery	O
+and	O
+peripheral	O
+blood	O
+recovery	O
+were	O
+complete	O
+1	O
+month	O
+and	O
+3	O
+months	O
+,	O
+respectively	O
+,	O
+after	O
+treatment	O
+,	O
+and	O
+blood	O
+transfusion	O
+or	O
+other	O
+therapies	O
+were	O
+not	O
+necessary	O
+in	O
+a	O
+follow	O
+-	O
+up	O
+period	O
+of	O
+more	O
+than	O
+2	O
+years	O
+.	O
+
+Use	O
+of	O
+antithymocyte	O
+globulin	O
+may	O
+be	O
+the	O
+optimal	O
+treatment	O
+of	O
+D	O
+-	O
+penicillamine	O
+-	O
+induced	O
+aplastic	B
+anemia	I
+.	O
+
+Metamizol	O
+potentiates	O
+morphine	O
+antinociception	O
+but	O
+not	O
+constipation	B
+after	O
+chronic	O
+treatment	O
+.	O
+
+This	O
+work	O
+evaluates	O
+the	O
+antinociceptive	O
+and	O
+constipating	B
+effects	O
+of	O
+the	O
+combination	O
+of	O
+3	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+morphine	O
+with	O
+177	O
+.	O
+8	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+metamizol	O
+in	O
+acutely	O
+and	O
+chronically	O
+treated	O
+(	O
+once	O
+a	O
+day	O
+for	O
+12	O
+days	O
+)	O
+rats	O
+.	O
+
+On	O
+the	O
+13th	O
+day	O
+,	O
+antinociceptive	O
+effects	O
+were	O
+assessed	O
+using	O
+a	O
+model	O
+of	O
+inflammatory	O
+nociception	O
+,	O
+pain	B
+-	O
+induced	O
+functional	O
+impairment	O
+model	O
+,	O
+and	O
+the	O
+charcoal	O
+meal	O
+test	O
+was	O
+used	O
+to	O
+evaluate	O
+the	O
+intestinal	O
+transit	O
+.	O
+
+Simultaneous	O
+administration	O
+of	O
+morphine	O
+with	O
+metamizol	O
+resulted	O
+in	O
+a	O
+markedly	O
+antinociceptive	O
+potentiation	O
+and	O
+an	O
+increasing	O
+of	O
+the	O
+duration	O
+of	O
+action	O
+after	O
+a	O
+single	O
+(	O
+298	O
++	O
+/	O
+-	O
+7	O
+vs	O
+.	O
+139	O
++	O
+/	O
+-	O
+36	O
+units	O
+area	O
+(	O
+ua	O
+)	O
+;	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+and	O
+repeated	O
+administration	O
+(	O
+280	O
++	O
+/	O
+-	O
+17	O
+vs	O
+.	O
+131	O
++	O
+/	O
+-	O
+22	O
+ua	O
+;	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Antinociceptive	O
+effect	O
+of	O
+morphine	O
+was	O
+reduced	O
+in	O
+chronically	O
+treated	O
+rats	O
+(	O
+39	O
++	O
+/	O
+-	O
+10	O
+vs	O
+.	O
+18	O
++	O
+/	O
+-	O
+5	O
+au	O
+)	O
+while	O
+the	O
+combination	O
+-	O
+induced	O
+antinociception	O
+was	O
+remained	O
+similar	O
+as	O
+an	O
+acute	O
+treatment	O
+(	O
+298	O
++	O
+/	O
+-	O
+7	O
+vs	O
+.	O
+280	O
++	O
+/	O
+-	O
+17	O
+au	O
+)	O
+.	O
+
+Acute	O
+antinociceptive	O
+effects	O
+of	O
+the	O
+combination	O
+were	O
+partially	O
+prevented	O
+by	O
+3	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+naloxone	O
+s	O
+.	O
+c	O
+.	O
+
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+,	O
+suggesting	O
+the	O
+partial	O
+involvement	O
+of	O
+the	O
+opioidergic	O
+system	O
+in	O
+the	O
+synergism	O
+observed	O
+.	O
+
+In	O
+independent	O
+groups	O
+,	O
+morphine	O
+inhibited	O
+the	O
+intestinal	O
+transit	O
+in	O
+48	O
++	O
+/	O
+-	O
+4	O
+%	O
+and	O
+38	O
++	O
+/	O
+-	O
+4	O
+%	O
+after	O
+acute	O
+and	O
+chronic	O
+treatment	O
+,	O
+respectively	O
+,	O
+suggesting	O
+that	O
+tolerance	O
+did	O
+not	O
+develop	O
+to	O
+the	O
+constipating	B
+effects	O
+.	O
+
+The	O
+combination	O
+inhibited	O
+intestinal	O
+transit	O
+similar	O
+to	O
+that	O
+produced	O
+by	O
+morphine	O
+regardless	O
+of	O
+the	O
+time	O
+of	O
+treatment	O
+,	O
+suggesting	O
+that	O
+metamizol	O
+did	O
+not	O
+potentiate	O
+morphine	O
+-	O
+induced	O
+constipation	B
+.	O
+
+These	O
+findings	O
+show	O
+a	O
+significant	O
+interaction	O
+between	O
+morphine	O
+and	O
+metamizol	O
+in	O
+chronically	O
+treated	O
+rats	O
+,	O
+suggesting	O
+that	O
+this	O
+combination	O
+could	O
+be	O
+useful	O
+for	O
+the	O
+treatment	O
+of	O
+chronic	B
+pain	I
+.	O
+
+Ifosfamide	O
+encephalopathy	B
+presenting	O
+with	O
+asterixis	B
+.	O
+
+CNS	O
+toxic	O
+effects	O
+of	O
+the	O
+antineoplastic	O
+agent	O
+ifosfamide	O
+(	O
+IFX	O
+)	O
+are	O
+frequent	O
+and	O
+include	O
+a	O
+variety	O
+of	O
+neurological	O
+symptoms	O
+that	O
+can	O
+limit	O
+drug	O
+use	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+a	O
+51	O
+-	O
+year	O
+-	O
+old	O
+man	O
+who	O
+developed	O
+severe	O
+,	O
+disabling	O
+negative	O
+myoclonus	B
+of	O
+the	O
+upper	O
+and	O
+lower	O
+extremities	O
+after	O
+the	O
+infusion	O
+of	O
+ifosfamide	O
+for	O
+plasmacytoma	B
+.	O
+
+He	O
+was	O
+awake	O
+,	O
+revealed	O
+no	O
+changes	O
+of	O
+mental	O
+status	O
+and	O
+at	O
+rest	O
+there	O
+were	O
+no	O
+further	O
+motor	O
+symptoms	O
+.	O
+
+Cranial	O
+magnetic	O
+resonance	O
+imaging	O
+and	O
+extensive	O
+laboratory	O
+studies	O
+failed	O
+to	O
+reveal	O
+structural	B
+lesions	I
+of	I
+the	I
+brain	I
+and	O
+metabolic	B
+abnormalities	I
+.	O
+
+An	O
+electroencephalogram	O
+showed	O
+continuous	O
+,	O
+generalized	O
+irregular	O
+slowing	O
+with	O
+admixed	O
+periodic	O
+triphasic	O
+waves	O
+indicating	O
+symptomatic	O
+encephalopathy	B
+.	O
+
+The	O
+administration	O
+of	O
+ifosfamide	O
+was	O
+discontinued	O
+and	O
+within	O
+12	O
+h	O
+the	O
+asterixis	B
+resolved	O
+completely	O
+.	O
+
+In	O
+the	O
+patient	O
+described	O
+,	O
+the	O
+presence	O
+of	O
+asterixis	B
+during	O
+infusion	O
+of	O
+ifosfamide	O
+,	O
+normal	O
+laboratory	O
+findings	O
+and	O
+imaging	O
+studies	O
+and	O
+the	O
+resolution	O
+of	O
+symptoms	O
+following	O
+the	O
+discontinuation	O
+of	O
+the	O
+drug	O
+suggest	O
+that	O
+negative	O
+myoclonus	B
+is	O
+associated	O
+with	O
+the	O
+use	O
+of	O
+IFX	O
+.	O
+
+Antagonism	O
+between	O
+interleukin	O
+3	O
+and	O
+erythropoietin	O
+in	O
+mice	O
+with	O
+azidothymidine	O
+-	O
+induced	O
+anemia	B
+and	O
+in	O
+bone	O
+marrow	O
+endothelial	O
+cells	O
+.	O
+
+Azidothymidine	O
+(	O
+AZT	O
+)	O
+-	O
+induced	O
+anemia	B
+in	O
+mice	O
+can	O
+be	O
+reversed	O
+by	O
+the	O
+administration	O
+of	O
+IGF	O
+-	O
+IL	O
+-	O
+3	O
+(	O
+fusion	O
+protein	O
+of	O
+insulin	O
+-	O
+like	O
+growth	O
+factor	O
+II	O
+(	O
+IGF	O
+II	O
+)	O
+and	O
+interleukin	O
+3	O
+)	O
+.	O
+
+Although	O
+interleukin	O
+3	O
+(	O
+IL	O
+-	O
+3	O
+)	O
+and	O
+erythropoietin	O
+(	O
+EPO	O
+)	O
+are	O
+known	O
+to	O
+act	O
+synergistically	O
+on	O
+hematopoietic	O
+cell	O
+proliferation	O
+in	O
+vitro	O
+,	O
+injection	O
+of	O
+IGF	O
+-	O
+IL	O
+-	O
+3	O
+and	O
+EPO	O
+in	O
+AZT	O
+-	O
+treated	O
+mice	O
+resulted	O
+in	O
+a	O
+reduction	O
+of	O
+red	O
+cells	O
+and	O
+an	O
+increase	O
+of	O
+plasma	O
+EPO	O
+levels	O
+as	O
+compared	O
+to	O
+animals	O
+treated	O
+with	O
+IGF	O
+-	O
+IL	O
+-	O
+3	O
+or	O
+EPO	O
+alone	O
+.	O
+
+We	O
+tested	O
+the	O
+hypothesis	O
+that	O
+the	O
+antagonistic	O
+effect	O
+of	O
+IL	O
+-	O
+3	O
+and	O
+EPO	O
+on	O
+erythroid	O
+cells	O
+may	O
+be	O
+mediated	O
+by	O
+endothelial	O
+cells	O
+.	O
+
+Bovine	O
+liver	O
+erythroid	O
+cells	O
+were	O
+cultured	O
+on	O
+monolayers	O
+of	O
+human	O
+bone	O
+marrow	O
+endothelial	O
+cells	O
+previously	O
+treated	O
+with	O
+EPO	O
+and	O
+IGF	O
+-	O
+IL	O
+-	O
+3	O
+.	O
+
+There	O
+was	O
+a	O
+significant	O
+reduction	O
+of	O
+thymidine	O
+incorporation	O
+into	O
+both	O
+erythroid	O
+and	O
+endothelial	O
+cells	O
+in	O
+cultures	O
+pre	O
+-	O
+treated	O
+with	O
+IGF	O
+-	O
+IL	O
+-	O
+3	O
+and	O
+EPO	O
+.	O
+
+Endothelial	O
+cell	O
+culture	O
+supernatants	O
+separated	O
+by	O
+ultrafiltration	O
+and	O
+ultracentrifugation	O
+from	O
+cells	O
+treated	O
+with	O
+EPO	O
+and	O
+IL	O
+-	O
+3	O
+significantly	O
+reduced	O
+thymidine	O
+incorporation	O
+into	O
+erythroid	O
+cells	O
+as	O
+compared	O
+to	O
+identical	O
+fractions	O
+obtained	O
+from	O
+the	O
+media	O
+of	O
+cells	O
+cultured	O
+with	O
+EPO	O
+alone	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+endothelial	O
+cells	O
+treated	O
+simultaneously	O
+with	O
+EPO	O
+and	O
+IL	O
+-	O
+3	O
+have	O
+a	O
+negative	O
+effect	O
+on	O
+erythroid	O
+cell	O
+production	O
+.	O
+
+The	O
+relationship	O
+between	O
+hippocampal	O
+acetylcholine	O
+release	O
+and	O
+cholinergic	O
+convulsant	O
+sensitivity	O
+in	O
+withdrawal	O
+seizure	B
+-	O
+prone	O
+and	O
+withdrawal	O
+seizure	B
+-	O
+resistant	O
+selected	O
+mouse	O
+lines	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+septo	O
+-	O
+hippocampal	O
+cholinergic	O
+pathway	O
+has	O
+been	O
+implicated	O
+in	O
+epileptogenesis	O
+,	O
+and	O
+genetic	O
+factors	O
+influence	O
+the	O
+response	O
+to	O
+cholinergic	O
+agents	O
+,	O
+but	O
+limited	O
+data	O
+are	O
+available	O
+on	O
+cholinergic	O
+involvement	O
+in	O
+alcohol	O
+withdrawal	O
+severity	O
+.	O
+
+Thus	O
+,	O
+the	O
+relationship	O
+between	O
+cholinergic	O
+activity	O
+and	O
+responsiveness	O
+and	O
+alcohol	O
+withdrawal	O
+was	O
+investigated	O
+in	O
+a	O
+genetic	O
+animal	O
+model	O
+of	O
+ethanol	O
+withdrawal	O
+severity	O
+.	O
+
+METHODS	O
+:	O
+Cholinergic	O
+convulsant	O
+sensitivity	O
+was	O
+examined	O
+in	O
+alcohol	O
+-	O
+na	O
+ve	O
+Withdrawal	O
+Seizure	B
+-	O
+Prone	O
+(	O
+WSP	O
+)	O
+and	O
+-	O
+Resistant	O
+(	O
+WSR	O
+)	O
+mice	O
+.	O
+
+Animals	O
+were	O
+administered	O
+nicotine	O
+,	O
+carbachol	O
+,	O
+or	O
+neostigmine	O
+via	O
+timed	O
+tail	O
+vein	O
+infusion	O
+,	O
+and	O
+the	O
+latencies	O
+to	O
+onset	O
+of	O
+tremor	B
+and	O
+clonus	O
+were	O
+recorded	O
+and	O
+converted	O
+to	O
+threshold	O
+dose	O
+.	O
+
+We	O
+also	O
+used	O
+microdialysis	O
+to	O
+measure	O
+basal	O
+and	O
+potassium	O
+-	O
+stimulated	O
+acetylcholine	O
+(	O
+ACh	O
+)	O
+release	O
+in	O
+the	O
+CA1	O
+region	O
+of	O
+the	O
+hippocampus	O
+.	O
+
+Potassium	O
+was	O
+applied	O
+by	O
+reverse	O
+dialysis	O
+twice	O
+,	O
+separated	O
+by	O
+75	O
+min	O
+.	O
+
+Hippocampal	O
+ACh	O
+also	O
+was	O
+measured	O
+during	O
+testing	O
+for	O
+handling	O
+-	O
+induced	O
+convulsions	B
+.	O
+
+RESULTS	O
+:	O
+Sensitivity	O
+to	O
+several	O
+convulsion	B
+endpoints	O
+induced	O
+by	O
+nicotine	O
+,	O
+carbachol	O
+,	O
+and	O
+neostigmine	O
+were	O
+significantly	O
+greater	O
+in	O
+WSR	O
+versus	O
+WSP	O
+mice	O
+.	O
+
+In	O
+microdialysis	O
+experiments	O
+,	O
+the	O
+lines	O
+did	O
+not	O
+differ	O
+in	O
+basal	O
+release	O
+of	O
+ACh	O
+,	O
+and	O
+50	O
+mM	O
+KCl	O
+increased	O
+ACh	O
+output	O
+in	O
+both	O
+lines	O
+of	O
+mice	O
+.	O
+
+However	O
+,	O
+the	O
+increase	O
+in	O
+release	O
+of	O
+ACh	O
+produced	O
+by	O
+the	O
+first	O
+application	O
+of	O
+KCl	O
+was	O
+2	O
+-	O
+fold	O
+higher	O
+in	O
+WSP	O
+versus	O
+WSR	O
+mice	O
+.	O
+
+When	O
+hippocampal	O
+ACh	O
+was	O
+measured	O
+during	O
+testing	O
+for	O
+handling	O
+-	O
+induced	O
+convulsions	B
+,	O
+extracellular	O
+ACh	O
+was	O
+significantly	O
+elevated	O
+(	O
+192	O
+%	O
+)	O
+in	O
+WSP	O
+mice	O
+,	O
+but	O
+was	O
+nonsignificantly	O
+elevated	O
+(	O
+59	O
+%	O
+)	O
+in	O
+WSR	O
+mice	O
+.	O
+
+CONCLUSIONS	O
+:	O
+These	O
+results	O
+suggest	O
+that	O
+differences	O
+in	O
+cholinergic	O
+activity	O
+and	O
+postsynaptic	O
+sensitivity	O
+to	O
+cholinergic	O
+convulsants	B
+may	O
+be	O
+associated	O
+with	O
+ethanol	O
+withdrawal	O
+severity	O
+and	O
+implicate	O
+cholinergic	O
+mechanisms	O
+in	O
+alcohol	O
+withdrawal	O
+.	O
+
+Specifically	O
+,	O
+WSP	O
+mice	O
+may	O
+have	O
+lower	O
+sensitivity	O
+to	O
+cholinergic	O
+convulsants	B
+compared	O
+with	O
+WSR	O
+because	O
+of	O
+postsynaptic	O
+receptor	O
+desensitization	O
+brought	O
+on	O
+by	O
+higher	O
+activity	O
+of	O
+cholinergic	O
+neurons	O
+.	O
+
+Capsaicin	O
+-	O
+induced	O
+muscle	B
+pain	I
+alters	O
+the	O
+excitability	O
+of	O
+the	O
+human	O
+jaw	O
+-	O
+stretch	O
+reflex	O
+.	O
+
+The	O
+pathophysiology	O
+of	O
+painful	O
+temporomandibular	B
+disorders	I
+is	O
+not	O
+fully	O
+understood	O
+,	O
+but	O
+evidence	O
+suggests	O
+that	O
+muscle	B
+pain	I
+modulates	O
+motor	O
+function	O
+in	O
+characteristic	O
+ways	O
+.	O
+
+This	O
+study	O
+tested	O
+the	O
+hypothesis	O
+that	O
+activation	O
+of	O
+nociceptive	B
+muscle	I
+afferent	O
+fibers	O
+would	O
+be	O
+linked	O
+to	O
+an	O
+increased	O
+excitability	O
+of	O
+the	O
+human	O
+jaw	O
+-	O
+stretch	O
+reflex	O
+and	O
+whether	O
+this	O
+process	O
+would	O
+be	O
+sensitive	O
+to	O
+length	O
+and	O
+velocity	O
+of	O
+the	O
+stretch	O
+.	O
+
+Capsaicin	O
+(	O
+10	O
+micro	O
+g	O
+)	O
+was	O
+injected	O
+into	O
+the	O
+masseter	O
+muscle	O
+to	O
+induce	O
+pain	B
+in	O
+11	O
+healthy	O
+volunteers	O
+.	O
+
+Short	O
+-	O
+latency	O
+reflex	O
+responses	O
+were	O
+evoked	O
+in	O
+the	O
+masseter	O
+and	O
+temporalis	O
+muscles	O
+by	O
+a	O
+stretch	O
+device	O
+with	O
+different	O
+velocities	O
+and	O
+displacements	O
+before	O
+,	O
+during	O
+,	O
+and	O
+after	O
+the	O
+pain	B
+.	O
+
+The	O
+normalized	O
+reflex	O
+amplitude	O
+increased	O
+with	O
+an	O
+increase	O
+in	O
+velocity	O
+at	O
+a	O
+given	O
+displacement	O
+,	O
+but	O
+remained	O
+constant	O
+with	O
+different	O
+displacements	O
+at	O
+a	O
+given	O
+velocity	O
+.	O
+
+The	O
+normalized	O
+reflex	O
+amplitude	O
+was	O
+significantly	O
+higher	O
+during	O
+pain	B
+,	O
+but	O
+only	O
+at	O
+faster	O
+stretches	O
+in	O
+the	O
+painful	B
+muscle	I
+.	O
+
+Increased	O
+sensitivity	O
+of	O
+the	O
+fusimotor	O
+system	O
+during	O
+acute	O
+muscle	B
+pain	I
+could	O
+be	O
+one	O
+likely	O
+mechanism	O
+to	O
+explain	O
+the	O
+findings	O
+.	O
+
+Effects	O
+of	O
+5	O
+-	O
+HT1B	O
+receptor	O
+ligands	O
+microinjected	O
+into	O
+the	O
+accumbal	O
+shell	O
+or	O
+core	O
+on	O
+the	O
+cocaine	O
+-	O
+induced	O
+locomotor	B
+hyperactivity	I
+in	O
+rats	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+examine	O
+the	O
+effect	O
+of	O
+5	O
+-	O
+HT1B	O
+receptor	O
+ligands	O
+microinjected	O
+into	O
+the	O
+subregions	O
+of	O
+the	O
+nucleus	O
+accumbens	O
+(	O
+the	O
+shell	O
+and	O
+the	O
+core	O
+)	O
+on	O
+the	O
+locomotor	B
+hyperactivity	I
+induced	O
+by	O
+cocaine	O
+in	O
+rats	O
+.	O
+
+Male	O
+Wistar	O
+rats	O
+were	O
+implanted	O
+bilaterally	O
+with	O
+cannulae	O
+into	O
+the	O
+accumbens	O
+shell	O
+or	O
+core	O
+,	O
+and	O
+then	O
+were	O
+locally	O
+injected	O
+with	O
+GR	O
+55562	O
+(	O
+an	O
+antagonist	O
+of	O
+5	O
+-	O
+HT1B	O
+receptors	O
+)	O
+or	O
+CP	O
+93129	O
+(	O
+an	O
+agonist	O
+of	O
+5	O
+-	O
+HT1B	O
+receptors	O
+)	O
+.	O
+
+Given	O
+alone	O
+to	O
+any	O
+accumbal	O
+subregion	O
+,	O
+GR	O
+55562	O
+(	O
+0	O
+.	O
+1	O
+-	O
+10	O
+microg	O
+/	O
+side	O
+)	O
+or	O
+CP	O
+93129	O
+(	O
+0	O
+.	O
+1	O
+-	O
+10	O
+microg	O
+/	O
+side	O
+)	O
+did	O
+not	O
+change	O
+basal	O
+locomotor	O
+activity	O
+.	O
+
+Systemic	O
+cocaine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+significantly	O
+increased	O
+the	O
+locomotor	O
+activity	O
+of	O
+rats	O
+.	O
+
+GR	O
+55562	O
+(	O
+0	O
+.	O
+1	O
+-	O
+10	O
+microg	O
+/	O
+side	O
+)	O
+,	O
+administered	O
+intra	O
+-	O
+accumbens	O
+shell	O
+prior	O
+to	O
+cocaine	O
+,	O
+dose	O
+-	O
+dependently	O
+attenuated	O
+the	O
+psychostimulant	O
+-	O
+induced	O
+locomotor	B
+hyperactivity	I
+.	O
+
+Such	O
+attenuation	O
+was	O
+not	O
+found	O
+in	O
+animals	O
+which	O
+had	O
+been	O
+injected	O
+with	O
+GR	O
+55562	O
+into	O
+the	O
+accumbens	O
+core	O
+.	O
+
+When	O
+injected	O
+into	O
+the	O
+accumbens	O
+shell	O
+(	O
+but	O
+not	O
+the	O
+core	O
+)	O
+before	O
+cocaine	O
+,	O
+CP	O
+93129	O
+(	O
+0	O
+.	O
+1	O
+-	O
+10	O
+microg	O
+/	O
+side	O
+)	O
+enhanced	O
+the	O
+locomotor	O
+response	O
+to	O
+cocaine	O
+;	O
+the	O
+maximum	O
+effect	O
+being	O
+observed	O
+after	O
+10	O
+microg	O
+/	O
+side	O
+of	O
+the	O
+agonist	O
+.	O
+
+The	O
+later	O
+enhancement	O
+was	O
+attenuated	O
+after	O
+intra	O
+-	O
+accumbens	O
+shell	O
+treatment	O
+with	O
+GR	O
+55562	O
+(	O
+1	O
+microg	O
+/	O
+side	O
+)	O
+.	O
+
+Our	O
+findings	O
+indicate	O
+that	O
+cocaine	O
+induced	O
+hyperlocomotion	B
+is	O
+modified	O
+by	O
+5	O
+-	O
+HT1B	O
+receptor	O
+ligands	O
+microinjected	O
+into	O
+the	O
+accumbens	O
+shell	O
+,	O
+but	O
+not	O
+core	O
+,	O
+this	O
+modification	O
+consisting	O
+in	O
+inhibitory	O
+and	O
+facilitatory	O
+effects	O
+of	O
+the	O
+5	O
+-	O
+HT1B	O
+receptor	O
+antagonist	O
+(	O
+GR	O
+55562	O
+)	O
+and	O
+agonist	O
+(	O
+CP	O
+93129	O
+)	O
+,	O
+respectively	O
+.	O
+
+In	O
+other	O
+words	O
+,	O
+the	O
+present	O
+results	O
+suggest	O
+that	O
+the	O
+accumbal	O
+shell	O
+5	O
+-	O
+HT1B	O
+receptors	O
+play	O
+a	O
+permissive	O
+role	O
+in	O
+the	O
+behavioural	O
+response	O
+to	O
+the	O
+psychostimulant	O
+.	O
+
+Cocaine	O
+related	O
+chest	B
+pain	I
+:	O
+are	O
+we	O
+seeing	O
+the	O
+tip	O
+of	O
+an	O
+iceberg	O
+?	O
+
+The	O
+recreational	O
+use	O
+of	O
+cocaine	O
+is	O
+on	O
+the	O
+increase	O
+.	O
+
+The	O
+emergency	O
+nurse	O
+ought	O
+to	O
+be	O
+familiar	O
+with	O
+some	O
+of	O
+the	O
+cardiovascular	O
+consequences	O
+of	O
+cocaine	O
+use	O
+.	O
+
+In	O
+particular	O
+,	O
+the	O
+tendency	O
+of	O
+cocaine	O
+to	O
+produce	O
+chest	B
+pain	I
+ought	O
+to	O
+be	O
+in	O
+the	O
+mind	O
+of	O
+the	O
+emergency	O
+nurse	O
+when	O
+faced	O
+with	O
+a	O
+young	O
+victim	O
+of	O
+chest	B
+pain	I
+who	O
+is	O
+otherwise	O
+at	O
+low	O
+risk	O
+.	O
+
+The	O
+mechanism	O
+of	O
+chest	B
+pain	I
+related	O
+to	O
+cocaine	O
+use	O
+is	O
+discussed	O
+and	O
+treatment	O
+dilemmas	O
+are	O
+discussed	O
+.	O
+
+Finally	O
+,	O
+moral	O
+issues	O
+relating	O
+to	O
+the	O
+testing	O
+of	O
+potential	O
+cocaine	O
+users	O
+will	O
+be	O
+addressed	O
+.	O
+
+Crossover	O
+comparison	O
+of	O
+efficacy	O
+and	O
+preference	O
+for	O
+rizatriptan	O
+10	O
+mg	O
+versus	O
+ergotamine	O
+/	O
+caffeine	O
+in	O
+migraine	B
+.	O
+
+Rizatriptan	O
+is	O
+a	O
+selective	O
+5	O
+-	O
+HT	O
+(	O
+1B	O
+/	O
+1D	O
+)	O
+receptor	O
+agonist	O
+with	O
+rapid	O
+oral	O
+absorption	O
+and	O
+early	O
+onset	O
+of	O
+action	O
+in	O
+the	O
+acute	O
+treatment	O
+of	O
+migraine	B
+.	O
+
+This	O
+randomized	O
+double	O
+-	O
+blind	O
+crossover	O
+outpatient	O
+study	O
+assessed	O
+the	O
+preference	O
+for	O
+1	O
+rizatriptan	O
+10	O
+mg	O
+tablet	O
+to	O
+2	O
+ergotamine	O
+1	O
+mg	O
+/	O
+caffeine	O
+100	O
+mg	O
+tablets	O
+in	O
+439	O
+patients	O
+treating	O
+a	O
+single	O
+migraine	B
+attack	O
+with	O
+each	O
+therapy	O
+.	O
+
+Of	O
+patients	O
+expressing	O
+a	O
+preference	O
+(	O
+89	O
+.	O
+1	O
+%	O
+)	O
+,	O
+more	O
+than	O
+twice	O
+as	O
+many	O
+preferred	O
+rizatriptan	O
+to	O
+ergotamine	O
+/	O
+caffeine	O
+(	O
+69	O
+.	O
+9	O
+vs	O
+.	O
+30	O
+.	O
+1	O
+%	O
+,	O
+p	O
+<	O
+or	O
+=	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Faster	O
+relief	O
+of	O
+headache	B
+was	O
+the	O
+most	O
+important	O
+reason	O
+for	O
+preference	O
+,	O
+cited	O
+by	O
+67	O
+.	O
+3	O
+%	O
+of	O
+patients	O
+preferring	O
+rizatriptan	O
+and	O
+54	O
+.	O
+2	O
+%	O
+of	O
+patients	O
+who	O
+preferred	O
+ergotamine	O
+/	O
+caffeine	O
+.	O
+
+The	O
+co	O
+-	O
+primary	O
+endpoint	O
+of	O
+being	O
+pain	B
+free	O
+at	O
+2	O
+h	O
+was	O
+also	O
+in	O
+favor	O
+of	O
+rizatriptan	O
+.	O
+
+Forty	O
+-	O
+nine	O
+percent	O
+of	O
+patients	O
+were	O
+pain	B
+free	O
+2	O
+h	O
+after	O
+rizatriptan	O
+,	O
+compared	O
+with	O
+24	O
+.	O
+3	O
+%	O
+treated	O
+with	O
+ergotamine	O
+/	O
+caffeine	O
+(	O
+p	O
+<	O
+or	O
+=	O
+0	O
+.	O
+001	O
+)	O
+,	O
+rizatriptan	O
+being	O
+superior	O
+within	O
+1	O
+h	O
+of	O
+treatment	O
+.	O
+
+Headache	B
+relief	O
+at	O
+2	O
+h	O
+was	O
+75	O
+.	O
+9	O
+%	O
+for	O
+rizatriptan	O
+and	O
+47	O
+.	O
+3	O
+%	O
+for	O
+ergotamine	O
+/	O
+caffeine	O
+(	O
+p	O
+<	O
+or	O
+=	O
+0	O
+.	O
+001	O
+)	O
+,	O
+with	O
+rizatriptan	O
+being	O
+superior	O
+to	O
+ergotamine	O
+/	O
+caffeine	O
+within	O
+30	O
+min	O
+of	O
+dosing	O
+.	O
+
+Almost	O
+36	O
+%	O
+of	O
+patients	O
+taking	O
+rizatriptan	O
+were	O
+pain	B
+free	O
+at	O
+2	O
+h	O
+and	O
+had	O
+no	O
+recurrence	O
+or	O
+need	O
+for	O
+additional	O
+medication	O
+within	O
+24	O
+h	O
+,	O
+compared	O
+to	O
+20	O
+%	O
+of	O
+patients	O
+on	O
+ergotamine	O
+/	O
+caffeine	O
+(	O
+p	O
+<	O
+or	O
+=	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Rizatriptan	O
+was	O
+also	O
+superior	O
+to	O
+ergotamine	O
+/	O
+caffeine	O
+in	O
+the	O
+proportions	O
+of	O
+patients	O
+with	O
+no	O
+nausea	B
+,	O
+vomiting	B
+,	O
+phonophobia	B
+or	O
+photophobia	B
+and	O
+for	O
+patients	O
+with	O
+normal	O
+function	O
+2	O
+h	O
+after	O
+drug	O
+intake	O
+(	O
+p	O
+<	O
+or	O
+=	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+More	O
+patients	O
+were	O
+(	O
+completely	O
+,	O
+very	O
+or	O
+somewhat	O
+)	O
+satisfied	O
+2	O
+h	O
+after	O
+treatment	O
+with	O
+rizatriptan	O
+(	O
+69	O
+.	O
+8	O
+%	O
+)	O
+than	O
+at	O
+2	O
+h	O
+after	O
+treatment	O
+with	O
+ergotamine	O
+/	O
+caffeine	O
+(	O
+38	O
+.	O
+6	O
+%	O
+,	O
+p	O
+<	O
+or	O
+=	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Recurrence	O
+rates	O
+were	O
+31	O
+.	O
+4	O
+%	O
+with	O
+rizatriptan	O
+and	O
+15	O
+.	O
+3	O
+%	O
+with	O
+ergotamine	O
+/	O
+caffeine	O
+.	O
+
+Both	O
+active	O
+treatments	O
+were	O
+well	O
+tolerated	O
+.	O
+
+The	O
+most	O
+common	O
+adverse	O
+events	O
+(	O
+incidence	O
+>	O
+or	O
+=	O
+5	O
+%	O
+in	O
+one	O
+group	O
+)	O
+after	O
+rizatriptan	O
+and	O
+ergotamine	O
+/	O
+caffeine	O
+,	O
+respectively	O
+,	O
+were	O
+dizziness	B
+(	O
+6	O
+.	O
+7	O
+and	O
+5	O
+.	O
+3	O
+%	O
+)	O
+,	O
+nausea	B
+(	O
+4	O
+.	O
+2	O
+and	O
+8	O
+.	O
+5	O
+%	O
+)	O
+and	O
+somnolence	B
+(	O
+5	O
+.	O
+5	O
+and	O
+2	O
+.	O
+3	O
+%	O
+)	O
+.	O
+
+Severe	O
+ocular	B
+and	I
+orbital	I
+toxicity	I
+after	O
+intracarotid	O
+injection	O
+of	O
+carboplatin	O
+for	O
+recurrent	O
+glioblastomas	B
+.	O
+
+BACKGROUND	O
+:	O
+Glioblastoma	B
+is	O
+a	O
+malignant	B
+tumor	I
+that	O
+occurs	O
+in	O
+the	O
+cerebrum	O
+during	O
+adulthood	O
+.	O
+
+With	O
+current	O
+treatment	O
+regimens	O
+including	O
+combined	O
+surgery	O
+,	O
+radiation	O
+and	O
+chemotherapy	O
+,	O
+the	O
+average	O
+life	O
+expectancy	O
+of	O
+the	O
+patients	O
+is	O
+limited	O
+to	O
+approximately	O
+1	O
+year	O
+.	O
+
+Therefore	O
+,	O
+patients	O
+with	O
+glioblastoma	B
+sometimes	O
+have	O
+intracarotid	O
+injection	O
+of	O
+carcinostatics	O
+added	O
+to	O
+the	O
+treatment	O
+regimen	O
+.	O
+
+Generally	O
+,	O
+carboplatin	O
+is	O
+said	O
+to	O
+have	O
+milder	O
+side	O
+effects	O
+than	O
+cisplatin	O
+,	O
+whose	O
+ocular	B
+and	I
+orbital	I
+toxicity	I
+are	O
+well	O
+known	O
+.	O
+
+However	O
+,	O
+we	O
+experienced	O
+a	O
+case	O
+of	O
+severe	O
+ocular	B
+and	I
+orbital	I
+toxicity	I
+after	O
+intracarotid	O
+injection	O
+of	O
+carboplatin	O
+,	O
+which	O
+is	O
+infrequently	O
+reported	O
+.	O
+
+CASE	O
+:	O
+A	O
+58	O
+-	O
+year	O
+-	O
+old	O
+man	O
+received	O
+an	O
+intracarotid	O
+injection	O
+of	O
+carboplatin	O
+for	O
+recurrent	O
+glioblastomas	B
+in	O
+his	O
+left	O
+temporal	O
+lobe	O
+.	O
+
+He	O
+complained	O
+of	O
+pain	B
+and	I
+visual	I
+disturbance	I
+in	I
+the	I
+ipsilateral	I
+eye	I
+30	O
+h	O
+after	O
+the	O
+injection	O
+.	O
+
+Various	O
+ocular	O
+symptoms	O
+and	O
+findings	O
+caused	O
+by	O
+carboplatin	O
+toxicity	B
+were	O
+seen	O
+.	O
+
+RESULTS	O
+:	O
+He	O
+was	O
+treated	O
+with	O
+intravenous	O
+administration	O
+of	O
+corticosteroids	O
+and	O
+glycerin	O
+for	O
+6	O
+days	O
+after	O
+the	O
+injection	O
+.	O
+
+Although	O
+the	O
+intraocular	O
+pressure	O
+elevation	O
+caused	O
+by	O
+secondary	O
+acute	O
+angle	O
+-	O
+closure	O
+glaucoma	B
+decreased	O
+and	O
+ocular	B
+pain	I
+diminished	O
+,	O
+inexorable	O
+papilledema	B
+and	O
+exudative	O
+retinal	B
+detachment	I
+continued	O
+for	O
+3	O
+weeks	O
+.	O
+
+Finally	O
+,	O
+6	O
+weeks	O
+later	O
+,	O
+diffuse	O
+chorioretinal	B
+atrophy	I
+with	O
+optic	B
+atrophy	I
+occurred	O
+and	O
+the	O
+vision	O
+in	O
+his	O
+left	O
+eye	O
+was	O
+lost	O
+.	O
+
+CONCLUSION	O
+:	O
+When	O
+performing	O
+intracarotid	O
+injection	O
+of	O
+carboplatin	O
+,	O
+we	O
+must	O
+be	O
+aware	O
+of	O
+its	O
+potentially	O
+blinding	O
+ocular	B
+toxicity	I
+.	O
+
+It	O
+is	O
+recommended	O
+that	O
+further	O
+studies	O
+and	O
+investigations	O
+are	O
+undertaken	O
+in	O
+the	O
+effort	O
+to	O
+minimize	O
+such	O
+severe	O
+side	O
+effects	O
+.	O
+
+Visual	B
+hallucinations	I
+associated	O
+with	O
+zonisamide	O
+.	O
+
+Zonisamide	O
+is	O
+a	O
+broad	O
+-	O
+spectrum	O
+antiepileptic	O
+drug	O
+used	O
+to	O
+treat	O
+various	O
+types	O
+of	O
+seizures	B
+.	O
+
+Although	O
+visual	B
+hallucinations	I
+have	O
+not	O
+been	O
+reported	O
+as	O
+an	O
+adverse	O
+effect	O
+of	O
+this	O
+agent	O
+,	O
+we	O
+describe	O
+three	O
+patients	O
+who	O
+experienced	O
+complex	O
+visual	B
+hallucinations	I
+and	O
+altered	O
+mental	O
+status	O
+after	O
+zonisamide	O
+treatment	O
+was	O
+begun	O
+or	O
+its	O
+dosage	O
+increased	O
+.	O
+
+All	O
+three	O
+had	O
+been	O
+diagnosed	O
+earlier	O
+with	O
+epilepsy	B
+,	O
+and	O
+their	O
+electroencephalogram	O
+(	O
+EEG	O
+)	O
+findings	O
+were	O
+abnormal	O
+.	O
+
+During	O
+monitoring	O
+,	O
+visual	B
+hallucinations	I
+did	O
+not	O
+correlate	O
+with	O
+EEG	O
+readings	O
+,	O
+nor	O
+did	O
+video	O
+recording	O
+capture	O
+any	O
+of	O
+the	O
+described	O
+events	O
+.	O
+
+None	O
+of	O
+the	O
+patients	O
+had	O
+experienced	O
+visual	B
+hallucinations	I
+before	O
+this	O
+event	O
+.	O
+
+The	O
+only	O
+recent	O
+change	O
+in	O
+their	O
+treatment	O
+was	O
+the	O
+introduction	O
+or	O
+increased	O
+dosage	O
+of	O
+zonisamide	O
+.	O
+
+With	O
+either	O
+discontinuation	O
+or	O
+decreased	O
+dosage	O
+of	O
+the	O
+drug	O
+the	O
+symptoms	O
+disappeared	O
+and	O
+did	O
+not	O
+recur	O
+.	O
+
+Further	O
+observations	O
+and	O
+reports	O
+will	O
+help	O
+clarify	O
+this	O
+adverse	O
+effect	O
+.	O
+
+Until	O
+then	O
+,	O
+clinicians	O
+need	O
+to	O
+be	O
+aware	O
+of	O
+this	O
+possible	O
+complication	O
+associated	O
+with	O
+zonisamide	O
+.	O
+
+Anti	O
+-	O
+epileptic	B
+drugs	O
+-	O
+induced	O
+de	O
+novo	O
+absence	B
+seizures	I
+.	O
+
+The	O
+authors	O
+present	O
+three	O
+patients	O
+with	O
+de	O
+novo	O
+absence	B
+epilepsy	I
+after	O
+administration	O
+of	O
+carbamazepine	O
+and	O
+vigabatrin	O
+.	O
+
+Despite	O
+the	O
+underlying	O
+diseases	O
+,	O
+the	O
+prognosis	O
+for	O
+drug	O
+-	O
+induced	O
+de	O
+novo	O
+absence	B
+seizure	I
+is	O
+good	O
+because	O
+it	O
+subsides	O
+rapidly	O
+after	O
+discontinuing	O
+the	O
+use	O
+of	O
+the	O
+offending	O
+drugs	O
+.	O
+
+The	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+-	O
+transmitted	O
+thalamocortical	O
+circuitry	O
+accounts	O
+for	O
+a	O
+major	O
+part	O
+of	O
+the	O
+underlying	O
+neurophysiology	O
+of	O
+the	O
+absence	B
+epilepsy	I
+.	O
+
+Because	O
+drug	O
+-	O
+induced	O
+de	O
+novo	O
+absence	B
+seizure	I
+is	O
+rare	O
+,	O
+pro	O
+-	O
+absence	O
+drugs	O
+can	O
+only	O
+be	O
+considered	O
+a	O
+promoting	O
+factor	O
+.	O
+
+The	O
+underlying	O
+epileptogenecity	O
+of	O
+the	O
+patients	O
+or	O
+the	O
+synergistic	O
+effects	O
+of	O
+the	O
+accompanying	O
+drugs	O
+is	O
+required	O
+to	O
+trigger	O
+the	O
+de	O
+novo	O
+absence	B
+seizure	I
+.	O
+
+The	O
+possibility	O
+of	O
+drug	O
+-	O
+induced	O
+aggravation	O
+should	O
+be	O
+considered	O
+whenever	O
+an	O
+unexpected	O
+increase	O
+in	O
+seizure	B
+frequency	O
+and	O
+/	O
+or	O
+new	O
+seizure	B
+types	O
+appear	O
+following	O
+a	O
+change	O
+in	O
+drug	O
+treatment	O
+.	O
+
+By	O
+understanding	O
+the	O
+underlying	O
+mechanism	O
+of	O
+absence	B
+epilepsy	I
+,	O
+we	O
+can	O
+avoid	O
+the	O
+inappropriate	O
+use	O
+of	O
+anticonvulsants	O
+in	O
+children	O
+with	O
+epilepsy	B
+and	O
+prevent	O
+drug	O
+-	O
+induced	O
+absence	B
+seizures	I
+.	O
+
+Prenatal	O
+dexamethasone	O
+programs	O
+hypertension	B
+and	O
+renal	B
+injury	I
+in	O
+the	O
+rat	O
+.	O
+
+Dexamethasone	O
+is	O
+frequently	O
+administered	O
+to	O
+the	O
+developing	O
+fetus	O
+to	O
+accelerate	O
+pulmonary	O
+development	O
+.	O
+
+The	O
+purpose	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+determine	O
+if	O
+prenatal	O
+dexamethasone	O
+programmed	O
+a	O
+progressive	O
+increase	B
+in	I
+blood	I
+pressure	I
+and	O
+renal	B
+injury	I
+in	O
+rats	O
+.	O
+
+Pregnant	O
+rats	O
+were	O
+given	O
+either	O
+vehicle	O
+or	O
+2	O
+daily	O
+intraperitoneal	O
+injections	O
+of	O
+dexamethasone	O
+(	O
+0	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+)	O
+on	O
+gestational	O
+days	O
+11	O
+and	O
+12	O
+,	O
+13	O
+and	O
+14	O
+,	O
+15	O
+and	O
+16	O
+,	O
+17	O
+and	O
+18	O
+,	O
+or	O
+19	O
+and	O
+20	O
+.	O
+
+Offspring	O
+of	O
+rats	O
+administered	O
+dexamethasone	O
+on	O
+days	O
+15	O
+and	O
+16	O
+gestation	O
+had	O
+a	O
+20	O
+%	O
+reduction	B
+in	I
+glomerular	I
+number	I
+compared	O
+with	O
+control	O
+at	O
+6	O
+to	O
+9	O
+months	O
+of	O
+age	O
+(	O
+22	O
+527	O
++	O
+/	O
+-	O
+509	O
+versus	O
+28	O
+050	O
++	O
+/	O
+-	O
+561	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+,	O
+which	O
+was	O
+comparable	O
+to	O
+the	O
+percent	O
+reduction	O
+in	O
+glomeruli	O
+measured	O
+at	O
+3	O
+weeks	O
+of	O
+age	O
+.	O
+
+Six	O
+-	O
+to	O
+9	O
+-	O
+month	O
+old	O
+rats	O
+receiving	O
+prenatal	O
+dexamethasone	O
+on	O
+days	O
+17	O
+and	O
+18	O
+of	O
+gestation	O
+had	O
+a	O
+17	O
+%	O
+reduction	O
+in	O
+glomeruli	O
+(	O
+23	O
+380	O
++	O
+/	O
+-	O
+587	O
+)	O
+compared	O
+with	O
+control	O
+rats	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Male	O
+rats	O
+that	O
+received	O
+prenatal	O
+dexamethasone	O
+on	O
+days	O
+15	O
+and	O
+16	O
+,	O
+17	O
+and	O
+18	O
+,	O
+and	O
+13	O
+and	O
+14	O
+of	O
+gestation	O
+had	O
+elevated	B
+blood	I
+pressures	I
+at	O
+6	O
+months	O
+of	O
+age	O
+;	O
+the	O
+latter	O
+group	O
+did	O
+not	O
+have	O
+a	O
+reduction	B
+in	I
+glomerular	I
+number	I
+.	O
+
+Adult	O
+rats	O
+given	O
+dexamethasone	O
+on	O
+days	O
+15	O
+and	O
+16	O
+of	O
+gestation	O
+had	O
+more	O
+glomeruli	O
+with	O
+glomerulosclerosis	B
+than	O
+control	O
+rats	O
+.	O
+
+This	O
+study	O
+shows	O
+that	O
+prenatal	O
+dexamethasone	O
+in	O
+rats	O
+results	O
+in	O
+a	O
+reduction	B
+in	I
+glomerular	I
+number	I
+,	O
+glomerulosclerosis	B
+,	O
+and	O
+hypertension	B
+when	O
+administered	O
+at	O
+specific	O
+points	O
+during	O
+gestation	O
+.	O
+
+Hypertension	B
+was	O
+observed	O
+in	O
+animals	O
+that	O
+had	O
+a	O
+reduction	O
+in	O
+glomeruli	O
+as	O
+well	O
+as	O
+in	O
+a	O
+group	O
+that	O
+did	O
+not	O
+have	O
+a	O
+reduction	B
+in	I
+glomerular	I
+number	I
+,	O
+suggesting	O
+that	O
+a	O
+reduction	B
+in	I
+glomerular	I
+number	I
+is	O
+not	O
+the	O
+sole	O
+cause	O
+for	O
+the	O
+development	O
+of	O
+hypertension	B
+.	O
+
+Kidney	O
+function	O
+and	O
+morphology	O
+after	O
+short	O
+-	O
+term	O
+combination	O
+therapy	O
+with	O
+cyclosporine	O
+A	O
+,	O
+tacrolimus	O
+and	O
+sirolimus	O
+in	O
+the	O
+rat	O
+.	O
+
+BACKGROUND	O
+:	O
+Sirolimus	O
+(	O
+SRL	O
+)	O
+may	O
+supplement	O
+calcineurin	O
+inhibitors	O
+in	O
+clinical	O
+organ	O
+transplantation	O
+.	O
+
+These	O
+are	O
+nephrotoxic	B
+,	O
+but	O
+SRL	O
+seems	O
+to	O
+act	O
+differently	O
+displaying	O
+only	O
+minor	O
+nephrotoxic	B
+effects	O
+,	O
+although	O
+this	O
+question	O
+is	O
+still	O
+open	O
+.	O
+
+In	O
+a	O
+number	O
+of	O
+treatment	O
+protocols	O
+where	O
+SRL	O
+was	O
+combined	O
+with	O
+a	O
+calcineurin	O
+inhibitor	O
+indications	O
+of	O
+a	O
+synergistic	O
+nephrotoxic	B
+effect	O
+were	O
+described	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+examine	O
+further	O
+the	O
+renal	O
+function	O
+,	O
+including	O
+morphological	O
+analysis	O
+of	O
+the	O
+kidneys	O
+of	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+treated	O
+with	O
+either	O
+cyclosporine	O
+A	O
+(	O
+CsA	O
+)	O
+,	O
+tacrolimus	O
+(	O
+FK506	O
+)	O
+or	O
+SRL	O
+as	O
+monotherapies	O
+or	O
+in	O
+different	O
+combinations	O
+.	O
+
+METHODS	O
+:	O
+For	O
+a	O
+period	O
+of	O
+2	O
+weeks	O
+,	O
+CsA	O
+15	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+(	O
+given	O
+orally	O
+)	O
+,	O
+FK506	O
+3	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+(	O
+given	O
+orally	O
+)	O
+or	O
+SRL	O
+0	O
+.	O
+4	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+(	O
+given	O
+intraperitoneally	O
+)	O
+was	O
+administered	O
+once	O
+a	O
+day	O
+as	O
+these	O
+doses	O
+have	O
+earlier	O
+been	O
+found	O
+to	O
+achieve	O
+a	O
+significant	O
+immunosuppressive	O
+effect	O
+in	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+.	O
+
+In	O
+the	O
+'	O
+conscious	O
+catheterized	O
+rat	O
+'	O
+model	O
+,	O
+the	O
+glomerular	O
+filtration	O
+rate	O
+(	O
+GFR	O
+)	O
+was	O
+measured	O
+as	O
+the	O
+clearance	O
+of	O
+Cr	O
+(	O
+EDTA	O
+)	O
+.	O
+
+The	O
+morphological	O
+analysis	O
+of	O
+the	O
+kidneys	O
+included	O
+a	O
+semi	O
+-	O
+quantitative	O
+scoring	O
+system	O
+analysing	O
+the	O
+degree	O
+of	O
+striped	O
+fibrosis	B
+,	O
+subcapsular	O
+fibrosis	B
+and	O
+the	O
+number	O
+of	O
+basophilic	O
+tubules	O
+,	O
+plus	O
+an	O
+additional	O
+stereological	O
+analysis	O
+of	O
+the	O
+total	O
+grade	O
+of	O
+fibrosis	B
+in	O
+the	O
+cortex	O
+stained	O
+with	O
+Sirius	O
+Red	O
+.	O
+
+RESULTS	O
+:	O
+CsA	O
+,	O
+FK506	O
+and	O
+SRL	O
+all	O
+significantly	O
+decreased	O
+the	O
+GFR	O
+.	O
+
+A	O
+further	O
+deterioration	O
+was	O
+seen	O
+when	O
+CsA	O
+was	O
+combined	O
+with	O
+either	O
+FK506	O
+or	O
+SRL	O
+,	O
+whereas	O
+the	O
+GFR	O
+remained	O
+unchanged	O
+in	O
+the	O
+group	O
+treated	O
+with	O
+FK506	O
+plus	O
+SRL	O
+when	O
+compared	O
+with	O
+treatment	O
+with	O
+any	O
+of	O
+the	O
+single	O
+substances	O
+.	O
+
+The	O
+morphological	O
+changes	O
+presented	O
+a	O
+similar	O
+pattern	O
+.	O
+
+The	O
+semi	O
+-	O
+quantitative	O
+scoring	O
+was	O
+significantly	O
+worst	O
+in	O
+the	O
+group	O
+treated	O
+with	O
+CsA	O
+plus	O
+SRL	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+compared	O
+with	O
+controls	O
+)	O
+and	O
+the	O
+analysis	O
+of	O
+the	O
+total	O
+grade	O
+of	O
+fibrosis	B
+also	O
+showed	O
+the	O
+highest	O
+proportion	O
+in	O
+the	O
+same	O
+group	O
+and	O
+was	O
+significantly	O
+different	O
+from	O
+controls	O
+(	O
+P	O
+<	O
+0	O
+.	O
+02	O
+)	O
+.	O
+
+The	O
+FK506	O
+plus	O
+SRL	O
+combination	O
+showed	O
+only	O
+a	O
+marginally	O
+higher	O
+degree	O
+of	O
+fibrosis	B
+as	O
+compared	O
+with	O
+controls	O
+(	O
+P	O
+=	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+rat	O
+study	O
+demonstrated	O
+a	O
+synergistic	O
+nephrotoxic	B
+effect	O
+of	O
+CsA	O
+plus	O
+SRL	O
+,	O
+whereas	O
+FK506	O
+plus	O
+SRL	O
+was	O
+better	O
+tolerated	O
+.	O
+
+Evaluation	O
+of	O
+cardiac	O
+troponin	O
+I	O
+and	O
+T	O
+levels	O
+as	O
+markers	O
+of	O
+myocardial	B
+damage	I
+in	O
+doxorubicin	O
+-	O
+induced	O
+cardiomyopathy	B
+rats	O
+,	O
+and	O
+their	O
+relationship	O
+with	O
+echocardiographic	O
+and	O
+histological	O
+findings	O
+.	O
+
+BACKGROUND	O
+:	O
+Cardiac	O
+troponins	O
+I	O
+(	O
+cTnI	O
+)	O
+and	O
+T	O
+(	O
+cTnT	O
+)	O
+have	O
+been	O
+shown	O
+to	O
+be	O
+highly	O
+sensitive	O
+and	O
+specific	O
+markers	O
+of	O
+myocardial	B
+cell	I
+injury	I
+.	O
+
+We	O
+investigated	O
+the	O
+diagnostic	O
+value	O
+of	O
+cTnI	O
+and	O
+cTnT	O
+for	O
+the	O
+diagnosis	O
+of	O
+myocardial	B
+damage	I
+in	O
+a	O
+rat	O
+model	O
+of	O
+doxorubicin	O
+(	O
+DOX	O
+)	O
+-	O
+induced	O
+cardiomyopathy	B
+,	O
+and	O
+we	O
+examined	O
+the	O
+relationship	O
+between	O
+serial	O
+cTnI	O
+and	O
+cTnT	O
+with	O
+the	O
+development	O
+of	O
+cardiac	B
+disorders	I
+monitored	O
+by	O
+echocardiography	O
+and	O
+histological	O
+examinations	O
+in	O
+this	O
+model	O
+.	O
+
+METHODS	O
+:	O
+Thirty	O
+-	O
+five	O
+Wistar	O
+rats	O
+were	O
+given	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+DOX	O
+,	O
+i	O
+.	O
+v	O
+.	O
+,	O
+weekly	O
+for	O
+up	O
+to	O
+8	O
+weeks	O
+for	O
+a	O
+total	O
+cumulative	O
+dose	O
+of	O
+12	O
+mg	O
+/	O
+kg	O
+BW	O
+.	O
+
+Ten	O
+rats	O
+received	O
+saline	O
+as	O
+a	O
+control	O
+group	O
+.	O
+
+cTnI	O
+was	O
+measured	O
+with	O
+Access	O
+(	O
+R	O
+)	O
+(	O
+ng	O
+/	O
+ml	O
+)	O
+and	O
+a	O
+research	O
+immunoassay	O
+(	O
+pg	O
+/	O
+ml	O
+)	O
+,	O
+and	O
+compared	O
+with	O
+cTnT	O
+,	O
+CK	O
+-	O
+MB	O
+mass	O
+and	O
+CK	O
+.	O
+
+By	O
+using	O
+transthoracic	O
+echocardiography	O
+,	O
+anterior	O
+and	O
+posterior	O
+wall	O
+thickness	O
+,	O
+LV	O
+diameters	O
+and	O
+LV	O
+fractional	O
+shortening	O
+(	O
+FS	O
+)	O
+were	O
+measured	O
+in	O
+all	O
+rats	O
+before	O
+DOX	O
+or	O
+saline	O
+,	O
+and	O
+at	O
+weeks	O
+6	O
+and	O
+9	O
+after	O
+treatment	O
+in	O
+all	O
+surviving	O
+rats	O
+.	O
+
+Histology	O
+was	O
+performed	O
+in	O
+DOX	O
+-	O
+rats	O
+at	O
+6	O
+and	O
+9	O
+weeks	O
+after	O
+the	O
+last	O
+DOX	O
+dose	O
+and	O
+in	O
+all	O
+controls	O
+.	O
+
+RESULTS	O
+:	O
+Eighteen	O
+of	O
+the	O
+DOX	O
+rats	O
+died	O
+prematurely	O
+of	O
+general	O
+toxicity	B
+during	O
+the	O
+9	O
+-	O
+week	O
+period	O
+.	O
+
+End	O
+-	O
+diastolic	O
+(	O
+ED	O
+)	O
+and	O
+end	O
+-	O
+systolic	O
+(	O
+ES	O
+)	O
+LV	O
+diameters	O
+/	O
+BW	O
+significantly	O
+increased	O
+,	O
+whereas	O
+LV	O
+FS	O
+was	O
+decreased	O
+after	O
+9	O
+weeks	O
+in	O
+the	O
+DOX	O
+group	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+These	O
+parameters	O
+remained	O
+unchanged	O
+in	O
+controls	O
+.	O
+
+Histological	O
+evaluation	O
+of	O
+hearts	O
+from	O
+all	O
+rats	O
+given	O
+DOX	O
+revealed	O
+significant	O
+slight	O
+degrees	O
+of	O
+perivascular	O
+and	O
+interstitial	O
+fibrosis	B
+.	O
+
+In	O
+7	O
+of	O
+the	O
+18	O
+rats	O
+,	O
+degeneration	O
+and	O
+myocyte	O
+vacuolisation	O
+were	O
+found	O
+.	O
+
+Only	O
+five	O
+of	O
+the	O
+controls	O
+exhibited	O
+evidence	O
+of	O
+very	O
+slight	O
+perivascular	O
+fibrosis	B
+.	O
+
+A	O
+significant	O
+rise	O
+in	O
+cTnT	O
+was	O
+found	O
+in	O
+DOX	O
+rats	O
+after	O
+cumulative	O
+doses	O
+of	O
+7	O
+.	O
+5	O
+and	O
+12	O
+mg	O
+/	O
+kg	O
+in	O
+comparison	O
+with	O
+baseline	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+cTnT	O
+found	O
+in	O
+rats	O
+after	O
+12	O
+mg	O
+/	O
+kg	O
+were	O
+significantly	O
+greater	O
+than	O
+that	O
+found	O
+after	O
+7	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+DOX	O
+.	O
+
+Maximal	O
+cTnI	O
+(	O
+pg	O
+/	O
+ml	O
+)	O
+and	O
+cTnT	O
+levels	O
+were	O
+significantly	O
+increased	O
+in	O
+DOX	O
+rats	O
+compared	O
+with	O
+controls	O
+(	O
+p	O
+=	O
+0	O
+.	O
+006	O
+,	O
+0	O
+.	O
+007	O
+)	O
+.	O
+
+cTnI	O
+(	O
+ng	O
+/	O
+ml	O
+)	O
+,	O
+CK	O
+-	O
+MB	O
+mass	O
+and	O
+CK	O
+remained	O
+unchanged	O
+in	O
+DOX	O
+rats	O
+compared	O
+with	O
+controls	O
+.	O
+
+All	O
+markers	O
+remained	O
+stable	O
+in	O
+controls	O
+.	O
+
+Analysis	O
+of	O
+data	O
+revealed	O
+a	O
+significant	O
+correlation	O
+between	O
+maximal	O
+cTnT	O
+and	O
+ED	O
+and	O
+ES	O
+LV	O
+diameters	O
+/	O
+BW	O
+(	O
+r	O
+=	O
+0	O
+.	O
+81	O
+and	O
+0	O
+.	O
+65	O
+;	O
+p	O
+<	O
+0	O
+.	O
+0001	O
+)	O
+.	O
+
+A	O
+significant	O
+relationship	O
+was	O
+observed	O
+between	O
+maximal	O
+cTnT	O
+and	O
+the	O
+extent	O
+of	O
+myocardial	O
+morphological	O
+changes	O
+,	O
+and	O
+between	O
+LV	O
+diameters	O
+/	O
+BW	O
+and	O
+histological	O
+findings	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Among	O
+markers	O
+of	O
+ischemic	B
+injury	I
+after	O
+DOX	O
+in	O
+rats	O
+,	O
+cTnT	O
+showed	O
+the	O
+greatest	O
+ability	O
+to	O
+detect	O
+myocardial	B
+damage	I
+assessed	O
+by	O
+echocardiographic	O
+detection	O
+and	O
+histological	O
+changes	O
+.	O
+
+Although	O
+there	O
+was	O
+a	O
+discrepancy	O
+between	O
+the	O
+amount	O
+of	O
+cTnI	O
+and	O
+cTnT	O
+after	O
+DOX	O
+,	O
+probably	O
+due	O
+to	O
+heterogeneity	O
+in	O
+cross	O
+-	O
+reactivities	O
+of	O
+mAbs	O
+to	O
+various	O
+cTnI	O
+and	O
+cTnT	O
+forms	O
+,	O
+it	O
+is	O
+likely	O
+that	O
+cTnT	O
+in	O
+rats	O
+after	O
+DOX	O
+indicates	O
+cell	O
+damage	O
+determined	O
+by	O
+the	O
+magnitude	O
+of	O
+injury	O
+induced	O
+and	O
+that	O
+cTnT	O
+should	O
+be	O
+a	O
+useful	O
+marker	O
+for	O
+the	O
+prediction	O
+of	O
+experimentally	O
+induced	O
+cardiotoxicity	B
+and	O
+possibly	O
+for	O
+cardioprotective	O
+experiments	O
+.	O
+
+Octreotide	O
+-	O
+induced	O
+hypoxemia	B
+and	O
+pulmonary	B
+hypertension	I
+in	O
+premature	O
+neonates	O
+.	O
+
+The	O
+authors	O
+report	O
+2	O
+cases	O
+of	O
+premature	O
+neonates	O
+who	O
+had	O
+enterocutaneous	O
+fistula	B
+complicating	O
+necrotizing	B
+enterocolitis	I
+.	O
+
+Pulmonary	B
+hypertension	I
+developed	O
+after	O
+administration	O
+of	O
+a	O
+somatostatin	O
+analogue	O
+,	O
+octreotide	O
+,	O
+to	O
+enhance	O
+resolution	O
+of	O
+the	O
+fistula	B
+.	O
+
+The	O
+authors	O
+discuss	O
+the	O
+mechanism	O
+of	O
+the	O
+occurrence	O
+of	O
+this	O
+complication	O
+and	O
+recommend	O
+caution	O
+of	O
+its	O
+use	O
+in	O
+high	O
+-	O
+risk	O
+premature	O
+neonates	O
+.	O
+
+The	O
+risk	O
+of	O
+venous	B
+thromboembolism	I
+in	O
+women	O
+prescribed	O
+cyproterone	O
+acetate	O
+in	O
+combination	O
+with	O
+ethinyl	O
+estradiol	O
+:	O
+a	O
+nested	O
+cohort	O
+analysis	O
+and	O
+case	O
+-	O
+control	O
+study	O
+.	O
+
+BACKGROUND	O
+:	O
+Cyproterone	O
+acetate	O
+combined	O
+with	O
+ethinyl	O
+estradiol	O
+(	O
+CPA	O
+/	O
+EE	O
+)	O
+is	O
+licensed	O
+in	O
+the	O
+UK	O
+for	O
+the	O
+treatment	O
+of	O
+women	O
+with	O
+acne	B
+and	O
+hirsutism	B
+and	O
+is	O
+also	O
+a	O
+treatment	O
+option	O
+for	O
+polycystic	B
+ovary	I
+syndrome	I
+(	O
+PCOS	B
+)	O
+.	O
+
+Previous	O
+studies	O
+have	O
+demonstrated	O
+an	O
+increased	O
+risk	O
+of	O
+venous	B
+thromboembolism	I
+(	O
+VTE	B
+)	O
+associated	O
+with	O
+CPA	O
+/	O
+EE	O
+compared	O
+with	O
+conventional	O
+combined	O
+oral	O
+contraceptives	O
+(	O
+COCs	O
+)	O
+.	O
+
+We	O
+believe	O
+the	O
+results	O
+of	O
+those	O
+studies	O
+may	O
+have	O
+been	O
+affected	O
+by	O
+residual	O
+confounding	O
+.	O
+
+METHODS	O
+:	O
+Using	O
+the	O
+General	O
+Practice	O
+Research	O
+Database	O
+we	O
+conducted	O
+a	O
+cohort	O
+analysis	O
+and	O
+case	O
+-	O
+control	O
+study	O
+nested	O
+within	O
+a	O
+population	O
+of	O
+women	O
+aged	O
+between	O
+15	O
+and	O
+39	O
+years	O
+with	O
+acne	B
+,	O
+hirsutism	B
+or	O
+PCOS	B
+to	O
+estimate	O
+the	O
+risk	O
+of	O
+VTE	B
+associated	O
+with	O
+CPA	O
+/	O
+EE	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+age	O
+-	O
+adjusted	O
+incidence	O
+rate	O
+ratio	O
+for	O
+CPA	O
+/	O
+EE	O
+versus	O
+conventional	O
+COCs	O
+was	O
+2	O
+.	O
+20	O
+[	O
+95	O
+%	O
+confidence	O
+interval	O
+(	O
+CI	O
+)	O
+1	O
+.	O
+35	O
+-	O
+3	O
+.	O
+58	O
+]	O
+.	O
+
+Using	O
+as	O
+the	O
+reference	O
+group	O
+women	O
+who	O
+were	O
+not	O
+using	O
+oral	O
+contraception	O
+,	O
+had	O
+no	O
+recent	O
+pregnancy	O
+or	O
+menopausal	O
+symptoms	O
+,	O
+the	O
+case	O
+-	O
+control	O
+analysis	O
+gave	O
+an	O
+adjusted	O
+odds	O
+ratio	O
+(	O
+OR	O
+(	O
+adj	O
+)	O
+)	O
+of	O
+7	O
+.	O
+44	O
+(	O
+95	O
+%	O
+CI	O
+3	O
+.	O
+67	O
+-	O
+15	O
+.	O
+08	O
+)	O
+for	O
+CPA	O
+/	O
+EE	O
+use	O
+compared	O
+with	O
+an	O
+OR	O
+(	O
+adj	O
+)	O
+of	O
+2	O
+.	O
+58	O
+(	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+60	O
+-	O
+4	O
+.	O
+18	O
+)	O
+for	O
+use	O
+of	O
+conventional	O
+COCs	O
+.	O
+
+CONCLUSIONS	O
+:	O
+We	O
+have	O
+demonstrated	O
+an	O
+increased	O
+risk	O
+of	O
+VTE	B
+associated	O
+with	O
+the	O
+use	O
+of	O
+CPA	O
+/	O
+EE	O
+in	O
+women	O
+with	O
+acne	B
+,	O
+hirsutism	B
+or	O
+PCOS	B
+although	O
+residual	O
+confounding	O
+by	O
+indication	O
+cannot	O
+be	O
+excluded	O
+.	O
+
+The	O
+effect	O
+of	O
+treatment	O
+with	O
+gum	O
+Arabic	O
+on	O
+gentamicin	O
+nephrotoxicity	B
+in	O
+rats	O
+:	O
+a	O
+preliminary	O
+study	O
+.	O
+
+In	O
+the	O
+present	O
+work	O
+we	O
+assessed	O
+the	O
+effect	O
+of	O
+treatment	O
+of	O
+rats	O
+with	O
+gum	O
+Arabic	O
+on	O
+acute	B
+renal	I
+failure	I
+induced	O
+by	O
+gentamicin	O
+(	O
+GM	O
+)	O
+nephrotoxicity	B
+.	O
+
+Rats	O
+were	O
+treated	O
+with	O
+the	O
+vehicle	O
+(	O
+2	O
+mL	O
+/	O
+kg	O
+of	O
+distilled	O
+water	O
+and	O
+5	O
+%	O
+w	O
+/	O
+v	O
+cellulose	O
+,	O
+10	O
+days	O
+)	O
+,	O
+gum	O
+Arabic	O
+(	O
+2	O
+mL	O
+/	O
+kg	O
+of	O
+a	O
+10	O
+%	O
+w	O
+/	O
+v	O
+aqueous	O
+suspension	O
+of	O
+gum	O
+Arabic	O
+powder	O
+,	O
+orally	O
+for	O
+10	O
+days	O
+)	O
+,	O
+or	O
+gum	O
+Arabic	O
+concomitantly	O
+with	O
+GM	O
+(	O
+80mg	O
+/	O
+kg	O
+/	O
+day	O
+intramuscularly	O
+,	O
+during	O
+the	O
+last	O
+six	O
+days	O
+of	O
+the	O
+treatment	O
+period	O
+)	O
+.	O
+
+Nephrotoxicity	B
+was	O
+assessed	O
+by	O
+measuring	O
+the	O
+concentrations	O
+of	O
+creatinine	O
+and	O
+urea	O
+in	O
+the	O
+plasma	O
+and	O
+reduced	O
+glutathione	O
+(	O
+GSH	O
+)	O
+in	O
+the	O
+kidney	O
+cortex	O
+,	O
+and	O
+by	O
+light	O
+microscopic	O
+examination	O
+of	O
+kidney	O
+sections	O
+.	O
+
+The	O
+results	O
+indicated	O
+that	O
+concomitant	O
+treatment	O
+with	O
+gum	O
+Arabic	O
+and	O
+GM	O
+significantly	O
+increased	O
+creatinine	O
+and	O
+urea	O
+by	O
+about	O
+183	O
+and	O
+239	O
+%	O
+,	O
+respectively	O
+(	O
+compared	O
+to	O
+432	O
+and	O
+346	O
+%	O
+,	O
+respectively	O
+,	O
+in	O
+rats	O
+treated	O
+with	O
+cellulose	O
+and	O
+GM	O
+)	O
+,	O
+and	O
+decreased	O
+that	O
+of	O
+cortical	O
+GSH	O
+by	O
+21	O
+%	O
+(	O
+compared	O
+to	O
+27	O
+%	O
+in	O
+the	O
+cellulose	O
+plus	O
+GM	O
+group	O
+)	O
+The	O
+GM	O
+-	O
+induced	O
+proximal	O
+tubular	B
+necrosis	I
+appeared	O
+to	O
+be	O
+slightly	O
+less	O
+severe	O
+in	O
+rats	O
+given	O
+GM	O
+together	O
+with	O
+gum	O
+Arabic	O
+than	O
+in	O
+those	O
+given	O
+GM	O
+and	O
+cellulose	O
+.	O
+
+It	O
+could	O
+be	O
+inferred	O
+that	O
+gum	O
+Arabic	O
+treatment	O
+has	O
+induced	O
+a	O
+modest	O
+amelioration	O
+of	O
+some	O
+of	O
+the	O
+histological	O
+and	O
+biochemical	O
+indices	O
+of	O
+GM	O
+nephrotoxicity	B
+.	O
+
+Further	O
+work	O
+is	O
+warranted	O
+on	O
+the	O
+effect	O
+of	O
+the	O
+treatments	O
+on	O
+renal	O
+functional	O
+aspects	O
+in	O
+models	O
+of	O
+chronic	B
+renal	I
+failure	I
+,	O
+and	O
+on	O
+the	O
+mechanism	O
+(	O
+s	O
+)	O
+involved	O
+.	O
+
+Increased	O
+frequency	O
+of	O
+venous	B
+thromboembolism	I
+with	O
+the	O
+combination	O
+of	O
+docetaxel	O
+and	O
+thalidomide	O
+in	O
+patients	O
+with	O
+metastatic	O
+androgen	O
+-	O
+independent	O
+prostate	B
+cancer	I
+.	O
+
+STUDY	O
+OBJECTIVE	O
+:	O
+To	O
+evaluate	O
+the	O
+frequency	O
+of	O
+venous	B
+thromboembolism	I
+(	O
+VTE	B
+)	O
+in	O
+patients	O
+with	O
+advanced	O
+androgen	O
+-	O
+independent	O
+prostate	B
+cancer	I
+who	O
+were	O
+treated	O
+with	O
+docetaxel	O
+alone	O
+or	O
+in	O
+combination	O
+with	O
+thalidomide	O
+.	O
+
+DESIGN	O
+:	O
+Retrospective	O
+analysis	O
+of	O
+a	O
+randomized	O
+phase	O
+II	O
+trial	O
+.	O
+
+SETTING	O
+:	O
+National	O
+Institutes	O
+of	O
+Health	O
+clinical	O
+research	O
+center	O
+.	O
+
+PATIENTS	O
+:	O
+Seventy	O
+men	O
+,	O
+aged	O
+50	O
+-	O
+80	O
+years	O
+,	O
+with	O
+advanced	O
+androgen	O
+-	O
+independent	O
+prostate	B
+cancer	I
+.	O
+
+INTERVENTION	O
+:	O
+Each	O
+patient	O
+received	O
+either	O
+intravenous	O
+docetaxel	O
+30	O
+mg	O
+/	O
+m2	O
+/	O
+week	O
+for	O
+3	O
+consecutive	O
+weeks	O
+,	O
+followed	O
+by	O
+1	O
+week	O
+off	O
+,	O
+or	O
+the	O
+combination	O
+of	O
+continuous	O
+oral	O
+thalidomide	O
+200	O
+mg	O
+every	O
+evening	O
+plus	O
+the	O
+same	O
+docetaxel	O
+regimen	O
+.	O
+
+This	O
+4	O
+-	O
+week	O
+cycle	O
+was	O
+repeated	O
+until	O
+there	O
+was	O
+evidence	O
+of	O
+excessive	O
+toxicity	B
+or	O
+disease	O
+progression	O
+.	O
+
+MEASUREMENTS	O
+AND	O
+MAIN	O
+RESULTS	O
+:	O
+None	O
+of	O
+23	O
+patients	O
+who	O
+received	O
+docetaxel	O
+alone	O
+developed	O
+VTE	B
+,	O
+whereas	O
+9	O
+of	O
+47	O
+patients	O
+(	O
+19	O
+%	O
+)	O
+who	O
+received	O
+docetaxel	O
+plus	O
+thalidomide	O
+developed	O
+VTE	B
+(	O
+p	O
+=	O
+0	O
+.	O
+025	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+addition	O
+of	O
+thalidomide	O
+to	O
+docetaxel	O
+in	O
+the	O
+treatment	O
+of	O
+prostate	B
+cancer	I
+significantly	O
+increases	O
+the	O
+frequency	O
+of	O
+VTE	B
+.	O
+
+Clinicians	O
+should	O
+be	O
+aware	O
+of	O
+this	O
+potential	O
+complication	O
+when	O
+adding	O
+thalidomide	O
+to	O
+chemotherapeutic	O
+regimens	O
+.	O
+
+Ticlopidine	O
+-	O
+induced	O
+cholestatic	B
+hepatitis	I
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+2	O
+cases	O
+of	O
+ticlopidine	O
+-	O
+induced	O
+cholestatic	B
+hepatitis	I
+,	O
+investigate	O
+its	O
+mechanism	O
+,	O
+and	O
+compare	O
+the	O
+observed	O
+main	O
+characteristics	O
+with	O
+those	O
+of	O
+the	O
+published	O
+cases	O
+.	O
+
+CASE	O
+SUMMARIES	O
+:	O
+Two	O
+patients	O
+developed	O
+prolonged	O
+cholestatic	B
+hepatitis	I
+after	O
+receiving	O
+ticlopidine	O
+following	O
+percutaneous	O
+coronary	O
+angioplasty	O
+,	O
+with	O
+complete	O
+remission	O
+during	O
+the	O
+follow	O
+-	O
+up	O
+period	O
+.	O
+
+T	O
+-	O
+cell	O
+stimulation	O
+by	O
+therapeutic	O
+concentration	O
+of	O
+ticlopidine	O
+was	O
+demonstrated	O
+in	O
+vitro	O
+in	O
+the	O
+patients	O
+,	O
+but	O
+not	O
+in	O
+healthy	O
+controls	O
+.	O
+
+DISCUSSION	O
+:	O
+Cholestatic	B
+hepatitis	I
+is	O
+a	O
+rare	O
+complication	O
+of	O
+the	O
+antiplatelet	O
+agent	O
+ticlopidine	O
+;	O
+several	O
+cases	O
+have	O
+been	O
+reported	O
+but	O
+few	O
+in	O
+the	O
+English	O
+literature	O
+.	O
+
+Our	O
+patients	O
+developed	O
+jaundice	B
+following	O
+treatment	O
+with	O
+ticlopidine	O
+and	O
+showed	O
+the	O
+clinical	O
+and	O
+laboratory	O
+characteristics	O
+of	O
+cholestatic	B
+hepatitis	I
+,	O
+which	O
+resolved	O
+after	O
+discontinuation	O
+of	O
+the	O
+drug	O
+.	O
+
+Hepatitis	B
+may	O
+develop	O
+weeks	O
+after	O
+discontinuation	O
+of	O
+the	O
+drug	O
+and	O
+may	O
+run	O
+a	O
+prolonged	O
+course	O
+,	O
+but	O
+complete	O
+remission	O
+was	O
+observed	O
+in	O
+all	O
+reported	O
+cases	O
+.	O
+
+An	O
+objective	O
+causality	O
+assessment	O
+revealed	O
+that	O
+the	O
+adverse	O
+drug	O
+event	O
+was	O
+probably	O
+related	O
+to	O
+the	O
+use	O
+of	O
+ticlopidine	O
+.	O
+
+The	O
+mechanisms	O
+of	O
+this	O
+ticlopidine	O
+-	O
+induced	O
+cholestasis	B
+are	O
+unclear	O
+.	O
+
+Immune	O
+mechanisms	O
+may	O
+be	O
+involved	O
+in	O
+the	O
+drug	O
+'	O
+s	O
+hepatotoxicity	B
+,	O
+as	O
+suggested	O
+by	O
+the	O
+T	O
+-	O
+cell	O
+stimulation	O
+study	O
+reported	O
+here	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Cholestatic	B
+hepatitis	I
+is	O
+a	O
+rare	O
+adverse	O
+effect	O
+of	O
+ticlopidine	O
+that	O
+may	O
+be	O
+immune	O
+mediated	O
+.	O
+
+Patients	O
+receiving	O
+the	O
+drug	O
+should	O
+be	O
+monitored	O
+with	O
+liver	O
+function	O
+tests	O
+along	O
+with	O
+complete	O
+blood	O
+cell	O
+counts	O
+.	O
+
+This	O
+complication	O
+will	O
+be	O
+observed	O
+even	O
+less	O
+often	O
+in	O
+the	O
+future	O
+as	O
+ticlopidine	O
+is	O
+being	O
+replaced	O
+by	O
+the	O
+newer	O
+antiplatelet	O
+agent	O
+clopidogrel	O
+.	O
+
+Epithelial	O
+sodium	O
+channel	O
+(	O
+ENaC	O
+)	O
+subunit	O
+mRNA	O
+and	O
+protein	O
+expression	O
+in	O
+rats	O
+with	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+nephrotic	B
+syndrome	I
+.	O
+
+In	O
+experimental	O
+nephrotic	B
+syndrome	I
+,	O
+urinary	O
+sodium	O
+excretion	O
+is	O
+decreased	O
+during	O
+the	O
+early	O
+phase	O
+of	O
+the	O
+disease	O
+.	O
+
+The	O
+molecular	O
+mechanism	O
+(	O
+s	O
+)	O
+leading	O
+to	O
+salt	O
+retention	O
+has	O
+not	O
+been	O
+completely	O
+elucidated	O
+.	O
+
+The	O
+rate	O
+-	O
+limiting	O
+constituent	O
+of	O
+collecting	O
+duct	O
+sodium	O
+transport	O
+is	O
+the	O
+epithelial	O
+sodium	O
+channel	O
+(	O
+ENaC	O
+)	O
+.	O
+
+We	O
+examined	O
+the	O
+abundance	O
+of	O
+ENaC	O
+subunit	O
+mRNAs	O
+and	O
+proteins	O
+in	O
+puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+)	O
+-	O
+induced	O
+nephrotic	B
+syndrome	I
+.	O
+
+The	O
+time	O
+courses	O
+of	O
+urinary	O
+sodium	O
+excretion	O
+,	O
+plasma	O
+aldosterone	O
+concentration	O
+and	O
+proteinuria	B
+were	O
+studied	O
+in	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+treated	O
+with	O
+a	O
+single	O
+dose	O
+of	O
+either	O
+PAN	O
+or	O
+vehicle	O
+.	O
+
+The	O
+relative	O
+amounts	O
+of	O
+alphaENaC	O
+,	O
+betaENaC	O
+and	O
+gammaENaC	O
+mRNAs	O
+were	O
+determined	O
+in	O
+kidneys	O
+from	O
+these	O
+rats	O
+by	O
+real	O
+-	O
+time	O
+quantitative	O
+TaqMan	O
+PCR	O
+,	O
+and	O
+the	O
+amounts	O
+of	O
+proteins	O
+by	O
+Western	O
+blot	O
+.	O
+
+The	O
+kinetics	O
+of	O
+urinary	O
+sodium	O
+excretion	O
+and	O
+the	O
+appearance	O
+of	O
+proteinuria	B
+were	O
+comparable	O
+with	O
+those	O
+reported	O
+previously	O
+.	O
+
+Sodium	O
+retention	O
+occurred	O
+on	O
+days	O
+2	O
+,	O
+3	O
+and	O
+6	O
+after	O
+PAN	O
+injection	O
+.	O
+
+A	O
+significant	O
+up	O
+-	O
+regulation	O
+of	O
+alphaENaC	O
+and	O
+betaENaC	O
+mRNA	O
+abundance	O
+on	O
+days	O
+1	O
+and	O
+2	O
+preceded	O
+sodium	O
+retention	O
+on	O
+days	O
+2	O
+and	O
+3	O
+.	O
+
+Conversely	O
+,	O
+down	O
+-	O
+regulation	O
+of	O
+alphaENaC	O
+,	O
+betaENaC	O
+and	O
+gammaENaC	O
+mRNA	O
+expression	O
+on	O
+day	O
+3	O
+occurred	O
+in	O
+the	O
+presence	O
+of	O
+high	O
+aldosterone	O
+concentrations	O
+,	O
+and	O
+was	O
+followed	O
+by	O
+a	O
+return	O
+of	O
+sodium	O
+excretion	O
+to	O
+control	O
+values	O
+.	O
+
+The	O
+amounts	O
+of	O
+alphaENaC	O
+,	O
+betaENaC	O
+and	O
+gammaENaC	O
+proteins	O
+were	O
+not	O
+increased	O
+during	O
+PAN	O
+-	O
+induced	O
+sodium	O
+retention	O
+.	O
+
+In	O
+conclusion	O
+,	O
+ENaC	O
+mRNA	O
+expression	O
+,	O
+especially	O
+alphaENaC	O
+,	O
+is	O
+increased	O
+in	O
+the	O
+very	O
+early	O
+phase	O
+of	O
+the	O
+experimental	O
+model	O
+of	O
+PAN	O
+-	O
+induced	O
+nephrotic	B
+syndrome	I
+in	O
+rats	O
+,	O
+but	O
+appears	O
+to	O
+escape	O
+from	O
+the	O
+regulation	O
+by	O
+aldosterone	O
+after	O
+day	O
+3	O
+.	O
+
+Sub	O
+-	O
+chronic	O
+low	O
+dose	O
+gamma	O
+-	O
+vinyl	O
+GABA	O
+(	O
+vigabatrin	O
+)	O
+inhibits	O
+cocaine	O
+-	O
+induced	O
+increases	O
+in	O
+nucleus	O
+accumbens	O
+dopamine	O
+.	O
+
+RATIONALE	O
+:	O
+gamma	O
+-	O
+Vinyl	O
+GABA	O
+(	O
+GVG	O
+)	O
+irreversibly	O
+inhibits	O
+GABA	O
+-	O
+transaminase	O
+.	O
+
+This	O
+non	O
+-	O
+receptor	O
+mediated	O
+inhibition	O
+requires	O
+de	O
+novo	O
+synthesis	O
+for	O
+restoration	O
+of	O
+functional	O
+GABA	O
+catabolism	O
+.	O
+
+OBJECTIVES	O
+:	O
+Given	O
+its	O
+preclinical	O
+success	O
+for	O
+treating	O
+substance	B
+abuse	I
+and	O
+the	O
+increased	O
+risk	O
+of	O
+visual	B
+field	I
+defects	I
+(	O
+VFD	B
+)	O
+associated	O
+with	O
+cumulative	O
+lifetime	O
+exposure	O
+,	O
+we	O
+explored	O
+the	O
+effects	O
+of	O
+sub	O
+-	O
+chronic	O
+low	O
+dose	O
+GVG	O
+on	O
+cocaine	O
+-	O
+induced	O
+increases	O
+in	O
+nucleus	O
+accumbens	O
+(	O
+NAcc	O
+)	O
+dopamine	O
+(	O
+DA	O
+)	O
+.	O
+
+METHODS	O
+:	O
+Using	O
+in	O
+vivo	O
+microdialysis	O
+,	O
+we	O
+compared	O
+acute	O
+exposure	O
+(	O
+450	O
+mg	O
+/	O
+kg	O
+)	O
+to	O
+an	O
+identical	O
+sub	O
+-	O
+chronic	O
+exposure	O
+(	O
+150	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+for	O
+3	O
+days	O
+)	O
+,	O
+followed	O
+by	O
+1	O
+-	O
+or	O
+3	O
+-	O
+day	O
+washout	O
+.	O
+
+Finally	O
+,	O
+we	O
+examined	O
+the	O
+low	O
+dose	O
+of	O
+150	O
+mg	O
+/	O
+kg	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+)	O
+using	O
+a	O
+similar	O
+washout	O
+period	O
+.	O
+
+RESULTS	O
+:	O
+Sub	O
+-	O
+chronic	O
+GVG	O
+exposure	O
+inhibited	O
+the	O
+effect	O
+of	O
+cocaine	O
+for	O
+3	O
+days	O
+,	O
+which	O
+exceeded	O
+in	O
+magnitude	O
+and	O
+duration	O
+the	O
+identical	O
+acute	O
+dose	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Sub	O
+-	O
+chronic	O
+low	O
+dose	O
+GVG	O
+potentiates	O
+and	O
+extends	O
+the	O
+inhibition	O
+of	O
+cocaine	O
+-	O
+induced	O
+increases	O
+in	O
+dopamine	O
+,	O
+effectively	O
+reducing	O
+cumulative	O
+exposures	O
+and	O
+the	O
+risk	O
+for	O
+VFDS	O
+.	O
+
+MR	O
+imaging	O
+with	O
+quantitative	O
+diffusion	O
+mapping	O
+of	O
+tacrolimus	O
+-	O
+induced	O
+neurotoxicity	B
+in	O
+organ	O
+transplant	O
+patients	O
+.	O
+
+Our	O
+objective	O
+was	O
+to	O
+investigate	O
+brain	O
+MR	O
+imaging	O
+findings	O
+and	O
+the	O
+utility	O
+of	O
+diffusion	O
+-	O
+weighted	O
+(	O
+DW	O
+)	O
+imaging	O
+in	O
+organ	O
+transplant	O
+patients	O
+who	O
+developed	O
+neurologic	O
+symptoms	O
+during	O
+tacrolimus	O
+therapy	O
+.	O
+
+Brain	O
+MR	O
+studies	O
+,	O
+including	O
+DW	O
+imaging	O
+,	O
+were	O
+prospectively	O
+performed	O
+in	O
+14	O
+organ	O
+transplant	O
+patients	O
+receiving	O
+tacrolimus	O
+who	O
+developed	O
+neurologic	B
+complications	I
+.	O
+
+In	O
+each	O
+patient	O
+who	O
+had	O
+abnormalities	O
+on	O
+the	O
+initial	O
+MR	O
+study	O
+,	O
+a	O
+follow	O
+-	O
+up	O
+MR	O
+study	O
+was	O
+performed	O
+1	O
+month	O
+later	O
+.	O
+
+Apparent	O
+diffusion	O
+coefficient	O
+(	O
+ADC	O
+)	O
+values	O
+on	O
+the	O
+initial	O
+MR	O
+study	O
+were	O
+correlated	O
+with	O
+reversibility	O
+of	O
+the	O
+lesions	O
+.	O
+
+Of	O
+the	O
+14	O
+patients	O
+,	O
+5	O
+(	O
+35	O
+.	O
+7	O
+%	O
+)	O
+had	O
+white	B
+matter	I
+abnormalities	I
+,	O
+1	O
+(	O
+7	O
+.	O
+1	O
+%	O
+)	O
+had	O
+putaminal	B
+hemorrhage	I
+,	O
+and	O
+8	O
+(	O
+57	O
+.	O
+1	O
+%	O
+)	O
+had	O
+normal	O
+findings	O
+on	O
+initial	O
+MR	O
+images	O
+.	O
+
+Among	O
+the	O
+5	O
+patients	O
+with	O
+white	B
+matter	I
+abnormalities	I
+,	O
+4	O
+patients	O
+(	O
+80	O
+.	O
+0	O
+%	O
+)	O
+showed	O
+higher	O
+than	O
+normal	O
+ADC	O
+values	O
+on	O
+initial	O
+MR	O
+images	O
+,	O
+and	O
+all	O
+showed	O
+complete	O
+resolution	O
+on	O
+follow	O
+-	O
+up	O
+images	O
+.	O
+
+The	O
+remaining	O
+1	O
+patient	O
+(	O
+20	O
+.	O
+0	O
+%	O
+)	O
+showed	O
+lower	O
+than	O
+normal	O
+ADC	O
+value	O
+and	O
+showed	O
+incomplete	O
+resolution	O
+with	O
+cortical	B
+laminar	I
+necrosis	I
+.	O
+
+Diffusion	O
+-	O
+weighted	O
+imaging	O
+may	O
+be	O
+useful	O
+in	O
+predicting	O
+the	O
+outcomes	O
+of	O
+the	O
+lesions	O
+of	O
+tacrolimus	O
+-	O
+induced	O
+neurotoxicity	B
+.	O
+
+L	O
+-	O
+arginine	O
+transport	O
+in	O
+humans	O
+with	O
+cortisol	O
+-	O
+induced	O
+hypertension	B
+.	O
+
+A	O
+deficient	O
+L	O
+-	O
+arginine	O
+-	O
+nitric	O
+oxide	O
+system	O
+is	O
+implicated	O
+in	O
+cortisol	O
+-	O
+induced	O
+hypertension	B
+.	O
+
+We	O
+investigate	O
+whether	O
+abnormalities	O
+in	O
+L	O
+-	O
+arginine	O
+uptake	O
+contribute	O
+to	O
+this	O
+deficiency	O
+.	O
+
+Eight	O
+healthy	O
+men	O
+were	O
+recruited	O
+.	O
+
+Hydrocortisone	O
+acetate	O
+(	O
+50	O
+mg	O
+)	O
+was	O
+given	O
+orally	O
+every	O
+6	O
+hours	O
+for	O
+24	O
+hours	O
+after	O
+a	O
+5	O
+-	O
+day	O
+fixed	O
+-	O
+salt	O
+diet	O
+(	O
+150	O
+mmol	O
+/	O
+d	O
+)	O
+.	O
+
+Crossover	O
+studies	O
+were	O
+performed	O
+2	O
+weeks	O
+apart	O
+.	O
+
+Thirty	O
+milliliters	O
+of	O
+blood	O
+was	O
+obtained	O
+for	O
+isolation	O
+of	O
+peripheral	O
+blood	O
+mononuclear	O
+cells	O
+after	O
+each	O
+treatment	O
+period	O
+.	O
+
+L	O
+-	O
+arginine	O
+uptake	O
+was	O
+assessed	O
+in	O
+mononuclear	O
+cells	O
+incubated	O
+with	O
+L	O
+-	O
+arginine	O
+(	O
+1	O
+to	O
+300	O
+micromol	O
+/	O
+L	O
+)	O
+,	O
+incorporating	O
+100	O
+nmol	O
+/	O
+L	O
+[	O
+3H	O
+]	O
+-	O
+l	O
+-	O
+arginine	O
+for	O
+a	O
+period	O
+of	O
+5	O
+minutes	O
+at	O
+37	O
+degrees	O
+C	O
+.	O
+
+Forearm	O
+[	O
+3H	O
+]	O
+-	O
+L	O
+-	O
+arginine	O
+extraction	O
+was	O
+calculated	O
+after	O
+infusion	O
+of	O
+[	O
+3H	O
+]	O
+-	O
+L	O
+-	O
+arginine	O
+into	O
+the	O
+brachial	O
+artery	O
+at	O
+a	O
+rate	O
+of	O
+100	O
+nCi	O
+/	O
+min	O
+for	O
+80	O
+minutes	O
+.	O
+
+Deep	O
+forearm	O
+venous	O
+samples	O
+were	O
+collected	O
+for	O
+determination	O
+of	O
+L	O
+-	O
+arginine	O
+extraction	O
+.	O
+
+Plasma	O
+cortisol	O
+concentrations	O
+were	O
+significantly	O
+raised	O
+during	O
+the	O
+active	O
+phase	O
+(	O
+323	O
++	O
+/	O
+-	O
+43	O
+to	O
+1082	O
++	O
+/	O
+-	O
+245	O
+mmol	O
+/	O
+L	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Systolic	O
+blood	O
+pressure	O
+was	O
+elevated	O
+by	O
+an	O
+average	O
+of	O
+7	O
+mm	O
+Hg	O
+.	O
+
+Neither	O
+L	O
+-	O
+arginine	O
+transport	O
+into	O
+mononuclear	O
+cells	O
+(	O
+placebo	O
+vs	O
+active	O
+,	O
+26	O
+.	O
+3	O
++	O
+/	O
+-	O
+3	O
+.	O
+6	O
+vs	O
+29	O
+.	O
+0	O
++	O
+/	O
+-	O
+2	O
+.	O
+1	O
+pmol	O
+/	O
+10	O
+000	O
+cells	O
+per	O
+5	O
+minutes	O
+,	O
+respectively	O
+,	O
+at	O
+an	O
+l	O
+-	O
+arginine	O
+concentration	O
+of	O
+300	O
+micromol	O
+/	O
+L	O
+)	O
+nor	O
+L	O
+-	O
+arginine	O
+extraction	O
+in	O
+the	O
+forearm	O
+(	O
+at	O
+80	O
+minutes	O
+,	O
+placebo	O
+vs	O
+active	O
+,	O
+1	O
+868	O
+904	O
++	O
+/	O
+-	O
+434	O
+962	O
+vs	O
+2	O
+013	O
+910	O
++	O
+/	O
+-	O
+770	O
+619	O
+disintegrations	O
+per	O
+minute	O
+)	O
+was	O
+affected	O
+by	O
+cortisol	O
+treatment	O
+;	O
+ie	O
+,	O
+that	O
+L	O
+-	O
+arginine	O
+uptake	O
+is	O
+not	O
+affected	O
+by	O
+short	O
+-	O
+term	O
+cortisol	O
+treatment	O
+.	O
+
+We	O
+conclude	O
+that	O
+cortisol	O
+-	O
+induced	O
+increases	B
+in	I
+blood	I
+pressure	I
+are	O
+not	O
+associated	O
+with	O
+abnormalities	O
+in	O
+the	O
+l	O
+-	O
+arginine	O
+transport	O
+system	O
+.	O
+
+Amount	O
+of	O
+bleeding	B
+and	O
+hematoma	B
+size	O
+in	O
+the	O
+collagenase	O
+-	O
+induced	O
+intracerebral	B
+hemorrhage	I
+rat	O
+model	O
+.	O
+
+The	O
+aggravated	O
+risk	O
+on	O
+intracerebral	B
+hemorrhage	I
+(	O
+ICH	B
+)	O
+with	O
+drugs	O
+used	O
+for	O
+stroke	B
+patients	O
+should	O
+be	O
+estimated	O
+carefully	O
+.	O
+
+We	O
+therefore	O
+established	O
+sensitive	O
+quantification	O
+methods	O
+and	O
+provided	O
+a	O
+rat	O
+ICH	B
+model	O
+for	O
+detection	O
+of	O
+ICH	B
+deterioration	O
+.	O
+
+In	O
+ICH	B
+intrastriatally	O
+induced	O
+by	O
+0	O
+.	O
+014	O
+-	O
+unit	O
+,	O
+0	O
+.	O
+070	O
+-	O
+unit	O
+,	O
+and	O
+0	O
+.	O
+350	O
+-	O
+unit	O
+collagenase	O
+,	O
+the	O
+amount	O
+of	O
+bleeding	B
+was	O
+measured	O
+using	O
+a	O
+hemoglobin	O
+assay	O
+developed	O
+in	O
+the	O
+present	O
+study	O
+and	O
+was	O
+compared	O
+with	O
+the	O
+morphologically	O
+determined	O
+hematoma	B
+volume	O
+.	O
+
+The	O
+blood	O
+amounts	O
+and	O
+hematoma	B
+volumes	O
+were	O
+significantly	O
+correlated	O
+,	O
+and	O
+the	O
+hematoma	B
+induced	O
+by	O
+0	O
+.	O
+014	O
+-	O
+unit	O
+collagenase	O
+was	O
+adequate	O
+to	O
+detect	O
+ICH	B
+deterioration	O
+.	O
+
+In	O
+ICH	B
+induction	O
+using	O
+0	O
+.	O
+014	O
+-	O
+unit	O
+collagenase	O
+,	O
+heparin	O
+enhanced	O
+the	O
+hematoma	B
+volume	O
+3	O
+.	O
+4	O
+-	O
+fold	O
+over	O
+that	O
+seen	O
+in	O
+control	O
+ICH	B
+animals	O
+and	O
+the	O
+bleeding	B
+7	O
+.	O
+6	O
+-	O
+fold	O
+.	O
+
+Data	O
+suggest	O
+that	O
+this	O
+sensitive	O
+hemoglobin	O
+assay	O
+is	O
+useful	O
+for	O
+ICH	B
+detection	O
+,	O
+and	O
+that	O
+a	O
+model	O
+with	O
+a	O
+small	O
+ICH	B
+induced	O
+with	O
+a	O
+low	O
+-	O
+dose	O
+collagenase	O
+should	O
+be	O
+used	O
+for	O
+evaluation	O
+of	O
+drugs	O
+that	O
+may	O
+affect	O
+ICH	B
+.	O
+
+Estradiol	O
+reduces	O
+seizure	B
+-	O
+induced	O
+hippocampal	B
+injury	I
+in	O
+ovariectomized	O
+female	O
+but	O
+not	O
+in	O
+male	O
+rats	O
+.	O
+
+Estrogens	O
+protect	O
+ovariectomized	O
+rats	O
+from	O
+hippocampal	B
+injury	I
+induced	O
+by	O
+kainic	O
+acid	O
+-	O
+induced	O
+status	B
+epilepticus	I
+(	O
+SE	B
+)	O
+.	O
+
+We	O
+compared	O
+the	O
+effects	O
+of	O
+17beta	O
+-	O
+estradiol	O
+in	O
+adult	O
+male	O
+and	O
+ovariectomized	O
+female	O
+rats	O
+subjected	O
+to	O
+lithium	O
+-	O
+pilocarpine	O
+-	O
+induced	O
+SE	B
+.	O
+
+Rats	O
+received	O
+subcutaneous	O
+injections	O
+of	O
+17beta	O
+-	O
+estradiol	O
+(	O
+2	O
+microg	O
+/	O
+rat	O
+)	O
+or	O
+oil	O
+once	O
+daily	O
+for	O
+four	O
+consecutive	O
+days	O
+.	O
+
+SE	B
+was	O
+induced	O
+20	O
+h	O
+following	O
+the	O
+second	O
+injection	O
+and	O
+terminated	O
+3	O
+h	O
+later	O
+.	O
+
+The	O
+extent	O
+of	O
+silver	O
+-	O
+stained	O
+CA3	O
+and	O
+CA1	O
+hippocampal	O
+neurons	O
+was	O
+evaluated	O
+2	O
+days	O
+after	O
+SE	B
+.	O
+
+17beta	O
+-	O
+Estradiol	O
+did	O
+not	O
+alter	O
+the	O
+onset	O
+of	O
+first	O
+clonus	O
+in	O
+ovariectomized	O
+rats	O
+but	O
+accelerated	O
+it	O
+in	O
+males	O
+.	O
+
+17beta	O
+-	O
+Estradiol	O
+reduced	O
+the	O
+argyrophilic	O
+neurons	O
+in	O
+the	O
+CA1	O
+and	O
+CA3	O
+-	O
+C	O
+sectors	O
+of	O
+ovariectomized	O
+rats	O
+.	O
+
+In	O
+males	O
+,	O
+estradiol	O
+increased	O
+the	O
+total	O
+damage	O
+score	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+the	O
+effects	O
+of	O
+estradiol	O
+on	O
+seizure	B
+threshold	O
+and	O
+damage	O
+may	O
+be	O
+altered	O
+by	O
+sex	O
+-	O
+related	O
+differences	O
+in	O
+the	O
+hormonal	O
+environment	O
+.	O
+
+Pseudoacromegaly	B
+induced	O
+by	O
+the	O
+long	O
+-	O
+term	O
+use	O
+of	O
+minoxidil	O
+.	O
+
+Acromegaly	B
+is	O
+an	O
+endocrine	B
+disorder	I
+caused	O
+by	O
+chronic	O
+excessive	O
+growth	O
+hormone	O
+secretion	O
+from	O
+the	O
+anterior	O
+pituitary	O
+gland	O
+.	O
+
+Significant	O
+disfiguring	O
+changes	O
+occur	O
+as	O
+a	O
+result	O
+of	O
+bone	O
+,	O
+cartilage	O
+,	O
+and	O
+soft	O
+tissue	O
+hypertrophy	B
+,	O
+including	O
+the	O
+thickening	O
+of	O
+the	O
+skin	O
+,	O
+coarsening	O
+of	O
+facial	O
+features	O
+,	O
+and	O
+cutis	B
+verticis	I
+gyrata	I
+.	O
+
+Pseudoacromegaly	B
+,	O
+on	O
+the	O
+other	O
+hand	O
+,	O
+is	O
+the	O
+presence	O
+of	O
+similar	O
+acromegaloid	O
+features	O
+in	O
+the	O
+absence	O
+of	O
+elevated	O
+growth	O
+hormone	O
+or	O
+insulin	O
+-	O
+like	O
+growth	O
+factor	O
+levels	O
+.	O
+
+We	O
+present	O
+a	O
+patient	O
+with	O
+pseudoacromegaly	B
+that	O
+resulted	O
+from	O
+the	O
+long	O
+-	O
+term	O
+use	O
+of	O
+minoxidil	O
+at	O
+an	O
+unusually	O
+high	O
+dose	O
+.	O
+
+This	O
+is	O
+the	O
+first	O
+case	O
+report	O
+of	O
+pseudoacromegaly	B
+as	O
+a	O
+side	O
+effect	O
+of	O
+minoxidil	O
+use	O
+.	O
+
+Combined	O
+androgen	O
+blockade	O
+-	O
+induced	O
+anemia	B
+in	O
+prostate	B
+cancer	I
+patients	O
+without	O
+bone	O
+involvement	O
+.	O
+
+BACKGROUND	O
+:	O
+To	O
+determine	O
+the	O
+onset	O
+and	O
+extent	O
+of	O
+combined	O
+androgen	O
+blockade	O
+(	O
+CAB	O
+)	O
+-	O
+induced	O
+anemia	B
+in	O
+prostate	B
+cancer	I
+patients	O
+without	O
+bone	O
+involvement	O
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+Forty	O
+-	O
+two	O
+patients	O
+with	O
+biopsy	O
+-	O
+proven	O
+prostatic	B
+adenocarcinoma	I
+[	O
+26	O
+with	O
+stage	O
+C	O
+(	O
+T3N0M0	O
+)	O
+and	O
+16	O
+with	O
+stage	O
+D1	O
+(	O
+T3N1M0	O
+)	O
+]	O
+were	O
+included	O
+in	O
+this	O
+study	O
+.	O
+
+All	O
+patients	O
+received	O
+CAB	O
+[	O
+leuprolide	O
+acetate	O
+(	O
+LHRH	O
+-	O
+A	O
+)	O
+3	O
+.	O
+75	O
+mg	O
+,	O
+intramuscularly	O
+,	O
+every	O
+28	O
+days	O
+plus	O
+250	O
+mg	O
+flutamide	O
+,	O
+tid	O
+,	O
+per	O
+Os	O
+]	O
+and	O
+were	O
+evaluated	O
+for	O
+anemia	B
+by	O
+physical	O
+examination	O
+and	O
+laboratory	O
+tests	O
+at	O
+baseline	O
+and	O
+4	O
+subsequent	O
+intervals	O
+(	O
+1	O
+,	O
+2	O
+,	O
+3	O
+and	O
+6	O
+months	O
+post	O
+-	O
+CAB	O
+)	O
+.	O
+
+Hb	O
+,	O
+PSA	O
+and	O
+Testosterone	O
+measurements	O
+were	O
+recorded	O
+.	O
+
+Patients	O
+with	O
+stage	O
+D2	O
+-	O
+3	O
+disease	O
+,	O
+abnormal	O
+hemoglobin	O
+level	O
+or	O
+renal	O
+and	O
+liver	O
+function	O
+tests	O
+that	O
+were	O
+higher	O
+than	O
+the	O
+upper	O
+limits	O
+were	O
+excluded	O
+from	O
+the	O
+study	O
+.	O
+
+The	O
+duration	O
+of	O
+the	O
+study	O
+was	O
+six	O
+months	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+mean	O
+hemoglobin	O
+(	O
+Hb	O
+)	O
+levels	O
+were	O
+significantly	O
+declined	O
+in	O
+all	O
+patients	O
+from	O
+baseline	O
+of	O
+14	O
+.	O
+2	O
+g	O
+/	O
+dl	O
+to	O
+14	O
+.	O
+0	O
+g	O
+/	O
+dl	O
+,	O
+13	O
+.	O
+5	O
+g	O
+/	O
+dl	O
+,	O
+13	O
+.	O
+2	O
+g	O
+/	O
+dl	O
+and	O
+12	O
+.	O
+7	O
+g	O
+/	O
+dl	O
+at	O
+1	O
+,	O
+2	O
+,	O
+3	O
+and	O
+6	O
+months	O
+post	O
+-	O
+CAB	O
+,	O
+respectively	O
+.	O
+
+Severe	O
+and	O
+clinically	O
+evident	O
+anemia	B
+of	O
+Hb	O
+<	O
+11	O
+g	O
+/	O
+dl	O
+with	O
+clinical	O
+symptoms	O
+was	O
+detected	O
+in	O
+6	O
+patients	O
+(	O
+14	O
+.	O
+3	O
+%	O
+)	O
+.	O
+
+This	O
+CAB	O
+-	O
+induced	O
+anemia	B
+was	O
+normochromic	O
+and	O
+normocytic	O
+.	O
+
+At	O
+six	O
+months	O
+post	O
+-	O
+CAB	O
+,	O
+patients	O
+with	O
+severe	O
+anemia	B
+had	O
+a	O
+Hb	O
+mean	O
+value	O
+of	O
+10	O
+.	O
+2	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+g	O
+/	O
+dl	O
+(	O
+X	O
++	O
+/	O
+-	O
+SE	O
+)	O
+,	O
+whereas	O
+the	O
+other	O
+patients	O
+had	O
+mild	O
+anemia	B
+with	O
+Hb	O
+mean	O
+value	O
+of	O
+13	O
+.	O
+2	O
++	O
+/	O
+-	O
+0	O
+.	O
+17	O
+(	O
+X	O
++	O
+/	O
+-	O
+SE	O
+)	O
+.	O
+
+The	O
+development	O
+of	O
+severe	O
+anemia	B
+at	O
+6	O
+months	O
+post	O
+-	O
+CAB	O
+was	O
+predictable	O
+by	O
+the	O
+reduction	O
+of	O
+Hb	O
+baseline	O
+value	O
+of	O
+more	O
+than	O
+2	O
+.	O
+5	O
+g	O
+/	O
+dl	O
+after	O
+3	O
+months	O
+of	O
+CAB	O
+(	O
+p	O
+=	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+The	O
+development	O
+of	O
+severe	O
+CAB	O
+-	O
+induced	O
+anemia	B
+in	O
+prostate	B
+cancer	I
+patients	O
+did	O
+not	O
+correlate	O
+with	O
+T	O
+baseline	O
+values	O
+(	O
+T	O
+<	O
+3	O
+ng	O
+/	O
+ml	O
+versus	O
+T	O
+>	O
+or	O
+=	O
+3	O
+ng	O
+/	O
+ml	O
+)	O
+,	O
+with	O
+age	O
+(	O
+<	O
+76	O
+yrs	O
+versus	O
+>	O
+or	O
+=	O
+76	O
+yrs	O
+)	O
+,	O
+and	O
+clinical	O
+stage	O
+(	O
+stage	O
+C	O
+versus	O
+stage	O
+D1	O
+)	O
+.	O
+
+Severe	O
+and	O
+clinically	O
+evident	O
+anemia	B
+was	O
+easily	O
+corrected	O
+by	O
+subcutaneous	O
+injections	O
+(	O
+3	O
+times	O
+/	O
+week	O
+for	O
+1	O
+month	O
+)	O
+of	O
+recombinant	O
+erythropoietin	O
+(	O
+rHuEPO	O
+-	O
+beta	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+Our	O
+data	O
+suggest	O
+that	O
+rHuEPO	O
+-	O
+beta	O
+correctable	O
+CAB	O
+-	O
+induced	O
+anemia	B
+occurs	O
+in	O
+14	O
+.	O
+3	O
+%	O
+of	O
+prostate	B
+cancer	I
+patients	O
+after	O
+6	O
+months	O
+of	O
+therapy	O
+.	O
+
+Delirium	B
+during	O
+clozapine	O
+treatment	O
+:	O
+incidence	O
+and	O
+associated	O
+risk	O
+factors	O
+.	O
+
+BACKGROUND	O
+:	O
+Incidence	O
+and	O
+risk	O
+factors	O
+for	O
+delirium	B
+during	O
+clozapine	O
+treatment	O
+require	O
+further	O
+clarification	O
+.	O
+
+METHODS	O
+:	O
+We	O
+used	O
+computerized	O
+pharmacy	O
+records	O
+to	O
+identify	O
+all	O
+adult	O
+psychiatric	B
+inpatients	O
+treated	O
+with	O
+clozapine	O
+(	O
+1995	O
+-	O
+96	O
+)	O
+,	O
+reviewed	O
+their	O
+medical	O
+records	O
+to	O
+score	O
+incidence	O
+and	O
+severity	O
+of	O
+delirium	B
+,	O
+and	O
+tested	O
+associations	O
+with	O
+potential	O
+risk	O
+factors	O
+.	O
+
+RESULTS	O
+:	O
+Subjects	O
+(	O
+n	O
+=	O
+139	O
+)	O
+were	O
+72	O
+women	O
+and	O
+67	O
+men	O
+,	O
+aged	O
+40	O
+.	O
+8	O
++	O
+/	O
+-	O
+12	O
+.	O
+1	O
+years	O
+,	O
+hospitalized	O
+for	O
+24	O
+.	O
+9	O
++	O
+/	O
+-	O
+23	O
+.	O
+3	O
+days	O
+,	O
+and	O
+given	O
+clozapine	O
+,	O
+gradually	O
+increased	O
+to	O
+an	O
+average	O
+daily	O
+dose	O
+of	O
+282	O
++	O
+/	O
+-	O
+203	O
+mg	O
+(	O
+3	O
+.	O
+45	O
++	O
+/	O
+-	O
+2	O
+.	O
+45	O
+mg	O
+/	O
+kg	O
+)	O
+for	O
+18	O
+.	O
+9	O
++	O
+/	O
+-	O
+16	O
+.	O
+4	O
+days	O
+.	O
+
+Delirium	B
+was	O
+diagnosed	O
+in	O
+14	O
+(	O
+10	O
+.	O
+1	O
+%	O
+incidence	O
+,	O
+or	O
+1	O
+.	O
+48	O
+cases	O
+/	O
+person	O
+-	O
+years	O
+of	O
+exposure	O
+)	O
+;	O
+71	O
+.	O
+4	O
+%	O
+of	O
+cases	O
+were	O
+moderate	O
+or	O
+severe	O
+.	O
+
+Associated	O
+factors	O
+were	O
+co	O
+-	O
+treatment	O
+with	O
+other	O
+centrally	O
+antimuscarinic	O
+agents	O
+,	O
+poor	O
+clinical	O
+outcome	O
+,	O
+older	O
+age	O
+,	O
+and	O
+longer	O
+hospitalization	O
+(	O
+by	O
+17	O
+.	O
+5	O
+days	O
+,	O
+increasing	O
+cost	O
+)	O
+;	O
+sex	O
+,	O
+diagnosis	O
+or	O
+medical	O
+co	O
+-	O
+morbidity	O
+,	O
+and	O
+daily	O
+clozapine	O
+dose	O
+,	O
+which	O
+fell	O
+with	O
+age	O
+,	O
+were	O
+unrelated	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Delirium	B
+was	O
+found	O
+in	O
+10	O
+%	O
+of	O
+clozapine	O
+-	O
+treated	O
+inpatients	O
+,	O
+particularly	O
+in	O
+older	O
+patients	O
+exposed	O
+to	O
+other	O
+central	O
+anticholinergics	O
+.	O
+
+Delirium	B
+was	O
+inconsistently	O
+recognized	O
+clinically	O
+in	O
+milder	O
+cases	O
+and	O
+was	O
+associated	O
+with	O
+increased	O
+length	O
+-	O
+of	O
+-	O
+stay	O
+and	O
+higher	O
+costs	O
+,	O
+and	O
+inferior	O
+clinical	O
+outcome	O
+.	O
+
+Neuroprotective	O
+action	O
+of	O
+MPEP	O
+,	O
+a	O
+selective	O
+mGluR5	O
+antagonist	O
+,	O
+in	O
+methamphetamine	O
+-	O
+induced	O
+dopaminergic	O
+neurotoxicity	B
+is	O
+associated	O
+with	O
+a	O
+decrease	O
+in	O
+dopamine	O
+outflow	O
+and	O
+inhibition	O
+of	O
+hyperthermia	B
+in	O
+rats	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+examine	O
+the	O
+role	O
+of	O
+metabotropic	O
+glutamate	O
+receptor	O
+5	O
+(	O
+mGluR5	O
+)	O
+in	O
+the	O
+toxic	O
+action	O
+of	O
+methamphetamine	O
+on	O
+dopaminergic	O
+neurones	O
+in	O
+rats	O
+.	O
+
+Methamphetamine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+sc	O
+)	O
+,	O
+administered	O
+five	O
+times	O
+,	O
+reduced	O
+the	O
+levels	O
+of	O
+dopamine	O
+and	O
+its	O
+metabolites	O
+in	O
+striatal	O
+tissue	O
+when	O
+measured	O
+72	O
+h	O
+after	O
+the	O
+last	O
+injection	O
+.	O
+
+A	O
+selective	O
+antagonist	O
+of	O
+mGluR5	O
+,	O
+2	O
+-	O
+methyl	O
+-	O
+6	O
+-	O
+(	O
+phenylethynyl	O
+)	O
+pyridine	O
+(	O
+MPEP	O
+;	O
+5	O
+mg	O
+/	O
+kg	O
+ip	O
+)	O
+,	O
+when	O
+administered	O
+five	O
+times	O
+immediately	O
+before	O
+each	O
+methamphetamine	O
+injection	O
+reversed	O
+the	O
+above	O
+-	O
+mentioned	O
+methamphetamine	O
+effects	O
+.	O
+
+A	O
+single	O
+MPEP	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+ip	O
+)	O
+injection	O
+reduced	O
+the	O
+basal	O
+extracellular	O
+dopamine	O
+level	O
+in	O
+the	O
+striatum	O
+,	O
+as	O
+well	O
+as	O
+dopamine	O
+release	O
+stimulated	O
+either	O
+by	O
+methamphetamine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+sc	O
+)	O
+or	O
+by	O
+intrastriatally	O
+administered	O
+veratridine	O
+(	O
+100	O
+microM	O
+)	O
+.	O
+
+Moreover	O
+,	O
+it	O
+transiently	O
+diminished	O
+the	O
+methamphetamine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+sc	O
+)	O
+-	O
+induced	O
+hyperthermia	B
+and	O
+reduced	O
+basal	O
+body	O
+temperature	O
+.	O
+
+MPEP	O
+administered	O
+into	O
+the	O
+striatum	O
+at	O
+high	O
+concentrations	O
+(	O
+500	O
+microM	O
+)	O
+increased	O
+extracellular	O
+dopamine	O
+levels	O
+,	O
+while	O
+lower	O
+concentrations	O
+(	O
+50	O
+-	O
+100	O
+microM	O
+)	O
+were	O
+devoid	O
+of	O
+any	O
+effect	O
+.	O
+
+The	O
+results	O
+of	O
+this	O
+study	O
+suggest	O
+that	O
+the	O
+blockade	O
+of	O
+mGluR5	O
+by	O
+MPEP	O
+may	O
+protect	O
+dopaminergic	O
+neurones	O
+against	O
+methamphetamine	O
+-	O
+induced	O
+toxicity	B
+.	O
+
+Neuroprotection	O
+rendered	O
+by	O
+MPEP	O
+may	O
+be	O
+associated	O
+with	O
+the	O
+reduction	O
+of	O
+the	O
+methamphetamine	O
+-	O
+induced	O
+dopamine	O
+efflux	O
+in	O
+the	O
+striatum	O
+due	O
+to	O
+the	O
+blockade	O
+of	O
+extrastriatal	O
+mGluR5	O
+,	O
+and	O
+with	O
+a	O
+decrease	O
+in	O
+hyperthermia	B
+.	O
+
+Protective	O
+efficacy	O
+of	O
+neuroactive	O
+steroids	O
+against	O
+cocaine	O
+kindled	O
+-	O
+seizures	B
+in	O
+mice	O
+.	O
+
+Neuroactive	O
+steroids	O
+demonstrate	O
+pharmacological	O
+actions	O
+that	O
+have	O
+relevance	O
+for	O
+a	O
+host	O
+of	O
+neurological	B
+and	I
+psychiatric	I
+disorders	I
+.	O
+
+They	O
+offer	O
+protection	O
+against	O
+seizures	B
+in	O
+a	O
+range	O
+of	O
+models	O
+and	O
+seem	O
+to	O
+inhibit	O
+certain	O
+stages	O
+of	O
+drug	B
+dependence	I
+in	O
+preclinical	O
+assessments	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+evaluate	O
+two	O
+endogenous	O
+and	O
+one	O
+synthetic	O
+neuroactive	O
+steroid	O
+that	O
+positively	O
+modulate	O
+the	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+(	O
+GABA	O
+(	O
+A	O
+)	O
+)	O
+receptor	O
+against	O
+the	O
+increase	O
+in	O
+sensitivity	O
+to	O
+the	O
+convulsant	O
+effects	O
+of	O
+cocaine	O
+engendered	O
+by	O
+repeated	O
+cocaine	O
+administration	O
+(	O
+seizure	B
+kindling	O
+)	O
+.	O
+
+Allopregnanolone	O
+(	O
+3alpha	O
+-	O
+hydroxy	O
+-	O
+5alpha	O
+-	O
+pregnan	O
+-	O
+20	O
+-	O
+one	O
+)	O
+,	O
+pregnanolone	O
+(	O
+3alpha	O
+-	O
+hydroxy	O
+-	O
+5beta	O
+-	O
+pregnan	O
+-	O
+20	O
+-	O
+one	O
+)	O
+and	O
+ganaxolone	O
+(	O
+a	O
+synthetic	O
+derivative	O
+of	O
+allopregnanolone	O
+3alpha	O
+-	O
+hydroxy	O
+-	O
+3beta	O
+-	O
+methyl	O
+-	O
+5alpha	O
+-	O
+pregnan	O
+-	O
+20	O
+-	O
+one	O
+)	O
+were	O
+tested	O
+for	O
+their	O
+ability	O
+to	O
+suppress	O
+the	O
+expression	O
+(	O
+anticonvulsant	O
+effect	O
+)	O
+and	O
+development	O
+(	O
+antiepileptogenic	O
+effect	O
+)	O
+of	O
+cocaine	O
+-	O
+kindled	O
+seizures	B
+in	O
+male	O
+,	O
+Swiss	O
+-	O
+Webster	O
+mice	O
+.	O
+
+Kindled	O
+seizures	B
+were	O
+induced	O
+by	O
+daily	O
+administration	O
+of	O
+60	O
+mg	O
+/	O
+kg	O
+cocaine	O
+for	O
+5	O
+days	O
+.	O
+
+All	O
+of	O
+these	O
+positive	O
+GABA	O
+(	O
+A	O
+)	O
+modulators	O
+suppressed	O
+the	O
+expression	O
+of	O
+kindled	O
+seizures	B
+,	O
+whereas	O
+only	O
+allopregnanolone	O
+and	O
+ganaxolone	O
+inhibited	O
+the	O
+development	O
+of	O
+kindling	O
+.	O
+
+Allopregnanolone	O
+and	O
+pregnanolone	O
+,	O
+but	O
+not	O
+ganaxolone	O
+,	O
+also	O
+reduced	O
+cumulative	O
+lethality	O
+associated	O
+with	O
+kindling	O
+.	O
+
+These	O
+findings	O
+demonstrate	O
+that	O
+some	O
+neuroactive	O
+steroids	O
+attenuate	O
+convulsant	O
+and	O
+sensitizing	O
+properties	O
+of	O
+cocaine	O
+and	O
+add	O
+to	O
+a	O
+growing	O
+literature	O
+on	O
+their	O
+potential	O
+use	O
+in	O
+the	O
+modulation	O
+of	O
+effects	O
+of	O
+drugs	O
+of	O
+abuse	O
+.	O
+
+Effect	O
+of	O
+humoral	O
+modulators	O
+of	O
+morphine	O
+-	O
+induced	O
+increase	B
+in	I
+locomotor	I
+activity	I
+of	O
+mice	O
+.	O
+
+The	O
+effect	O
+of	O
+humoral	O
+modulators	O
+on	O
+the	O
+morphine	O
+-	O
+induced	O
+increase	B
+in	I
+locomotor	I
+activity	I
+of	O
+mice	O
+was	O
+studied	O
+.	O
+
+The	O
+subcutaneous	O
+administration	O
+of	O
+10	O
+mg	O
+/	O
+kg	O
+of	O
+morphine	O
+-	O
+HC1	O
+produced	O
+a	O
+marked	O
+increase	B
+in	I
+locomotor	I
+activity	I
+in	O
+mice	O
+.	O
+
+The	O
+morphine	O
+-	O
+induced	O
+hyperactivity	B
+was	O
+potentiated	O
+by	O
+scopolamine	O
+and	O
+attenuated	O
+by	O
+physostigmine	O
+.	O
+
+In	O
+contrast	O
+,	O
+both	O
+methscopolamine	O
+and	O
+neostigmine	O
+,	O
+which	O
+do	O
+not	O
+penetrate	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+,	O
+had	O
+no	O
+effect	O
+on	O
+the	O
+hyperactivity	B
+produced	O
+by	O
+morphine	O
+.	O
+
+Pretreatment	O
+of	O
+mice	O
+with	O
+alpha	O
+-	O
+methyltyrosine	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+,	O
+one	O
+hour	O
+)	O
+,	O
+an	O
+inhibitor	O
+of	O
+tyrosine	O
+hydroxylase	O
+,	O
+significantly	O
+decreased	O
+the	O
+activity	O
+-	O
+increasing	O
+effects	O
+of	O
+morphine	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+pretreatment	O
+with	O
+p	O
+-	O
+chlorophenylalamine	O
+(	O
+3	O
+X	O
+320	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+,	O
+24	O
+hr	O
+)	O
+,	O
+a	O
+serotonin	O
+depletor	O
+,	O
+caused	O
+no	O
+significant	O
+change	O
+in	O
+the	O
+hyperactivity	B
+.	O
+
+The	O
+study	O
+suggests	O
+that	O
+the	O
+activity	O
+-	O
+increasing	O
+effects	O
+of	O
+morphine	O
+are	O
+mediated	O
+by	O
+the	O
+release	O
+of	O
+catecholamines	O
+from	O
+adrenergic	O
+neurons	O
+in	O
+the	O
+brain	O
+.	O
+
+And	O
+the	O
+results	O
+are	O
+consistent	O
+with	O
+the	O
+hypothesis	O
+that	O
+morphine	O
+acts	O
+by	O
+retarding	O
+the	O
+release	O
+of	O
+acetylcholine	O
+at	O
+some	O
+central	O
+cholinergic	O
+synapses	O
+.	O
+
+It	O
+is	O
+also	O
+suggested	O
+from	O
+collected	O
+evidence	O
+that	O
+the	O
+activity	O
+-	O
+increasing	O
+effects	O
+of	O
+morphine	O
+in	O
+mice	O
+are	O
+mediated	O
+by	O
+mechanisms	O
+different	O
+from	O
+those	O
+which	O
+mediate	O
+the	O
+activity	O
+-	O
+increasing	O
+effects	O
+of	O
+morphine	O
+in	O
+rats	O
+.	O
+
+Effects	O
+of	O
+uninephrectomy	O
+and	O
+high	O
+protein	O
+feeding	O
+on	O
+lithium	O
+-	O
+induced	O
+chronic	B
+renal	I
+failure	I
+in	O
+rats	O
+.	O
+
+Rats	O
+with	O
+lithium	O
+-	O
+induced	O
+nephropathy	B
+were	O
+subjected	O
+to	O
+high	O
+protein	O
+(	O
+HP	O
+)	O
+feeding	O
+,	O
+uninephrectomy	O
+(	O
+NX	O
+)	O
+or	O
+a	O
+combination	O
+of	O
+these	O
+,	O
+in	O
+an	O
+attempt	O
+to	O
+induce	O
+glomerular	O
+hyperfiltration	O
+and	O
+further	O
+progression	O
+of	O
+renal	B
+failure	I
+.	O
+
+Newborn	O
+female	O
+Wistar	O
+rats	O
+were	O
+fed	O
+a	O
+lithium	O
+-	O
+containing	O
+diet	O
+(	O
+50	O
+mmol	O
+/	O
+kg	O
+)	O
+for	O
+8	O
+weeks	O
+and	O
+then	O
+randomized	O
+to	O
+normal	O
+diet	O
+,	O
+HP	O
+diet	O
+(	O
+40	O
+vs	O
+.	O
+19	O
+%	O
+)	O
+,	O
+NX	O
+or	O
+HP	O
++	O
+NX	O
+for	O
+another	O
+8	O
+weeks	O
+.	O
+
+Corresponding	O
+non	O
+-	O
+lithium	O
+pretreated	O
+groups	O
+were	O
+generated	O
+.	O
+
+When	O
+comparing	O
+all	O
+lithium	O
+treated	O
+versus	O
+non	O
+-	O
+lithium	O
+-	O
+treated	O
+groups	O
+,	O
+lithium	O
+caused	O
+a	O
+reduction	O
+in	O
+glomerular	O
+filtration	O
+rate	O
+(	O
+GFR	O
+)	O
+without	O
+significant	O
+changes	O
+in	O
+effective	O
+renal	O
+plasma	O
+flow	O
+(	O
+as	O
+determined	O
+by	O
+a	O
+marker	O
+secreted	O
+into	O
+the	O
+proximal	O
+tubules	O
+)	O
+or	O
+lithium	O
+clearance	O
+.	O
+
+Consequently	O
+,	O
+lithium	O
+pretreatment	O
+caused	O
+a	O
+fall	O
+in	O
+filtration	O
+fraction	O
+and	O
+an	O
+increase	O
+in	O
+fractional	O
+Li	O
+excretion	O
+.	O
+
+Lithium	O
+also	O
+caused	O
+proteinuria	B
+and	O
+systolic	O
+hypertension	B
+in	O
+absence	O
+of	O
+glomerulosclerosis	B
+.	O
+
+HP	O
+failed	O
+to	O
+accentuante	O
+progression	O
+of	O
+renal	B
+failure	I
+and	O
+in	O
+fact	O
+tended	O
+to	O
+increase	O
+GFR	O
+and	O
+decrease	O
+plasma	O
+creatinine	O
+levels	O
+in	O
+lithium	O
+pretreated	O
+rats	O
+.	O
+
+NX	O
+caused	O
+an	O
+additive	O
+deterioration	O
+in	O
+GFR	O
+which	O
+,	O
+however	O
+,	O
+was	O
+ameliorated	O
+by	O
+HP	O
+.	O
+
+NX	O
++	O
+HP	O
+caused	O
+a	O
+further	O
+rise	O
+in	O
+blood	O
+pressure	O
+in	O
+Li	O
+-	O
+pretreated	O
+rats	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+Li	O
+-	O
+induced	O
+nephropathy	B
+,	O
+even	O
+when	O
+the	O
+GFR	O
+is	O
+only	O
+modestly	O
+reduced	O
+,	O
+is	O
+associated	O
+with	O
+proteinuria	B
+and	O
+arterial	O
+systolic	O
+hypertension	B
+.	O
+
+In	O
+this	O
+model	O
+of	O
+chronic	B
+renal	I
+failure	I
+the	O
+decline	O
+in	O
+GFR	O
+is	O
+not	O
+accompanied	O
+by	O
+a	O
+corresponding	O
+fall	O
+in	O
+effective	O
+renal	O
+plasma	O
+flow	O
+,	O
+which	O
+may	O
+be	O
+the	O
+functional	O
+expression	O
+of	O
+the	O
+formation	O
+of	O
+nonfiltrating	O
+atubular	O
+glomeruli	O
+.	O
+
+The	O
+fractional	O
+reabsorption	O
+of	O
+tubular	O
+fluid	O
+by	O
+the	O
+proximal	O
+tubules	O
+is	O
+reduced	O
+,	O
+leaving	O
+the	O
+distal	O
+delivery	O
+unchanged	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Treatment	O
+of	O
+Crohn	B
+'	I
+s	I
+disease	I
+with	O
+fusidic	O
+acid	O
+:	O
+an	O
+antibiotic	O
+with	O
+immunosuppressive	O
+properties	O
+similar	O
+to	O
+cyclosporin	O
+.	O
+
+Fusidic	O
+acid	O
+is	O
+an	O
+antibiotic	O
+with	O
+T	O
+-	O
+cell	O
+specific	O
+immunosuppressive	O
+effects	O
+similar	O
+to	O
+those	O
+of	O
+cyclosporin	O
+.	O
+
+Because	O
+of	O
+the	O
+need	O
+for	O
+the	O
+development	O
+of	O
+new	O
+treatments	O
+for	O
+Crohn	B
+'	I
+s	I
+disease	I
+,	O
+a	O
+pilot	O
+study	O
+was	O
+undertaken	O
+to	O
+estimate	O
+the	O
+pharmacodynamics	O
+and	O
+tolerability	O
+of	O
+fusidic	O
+acid	O
+treatment	O
+in	O
+chronic	O
+active	O
+,	O
+therapy	O
+-	O
+resistant	O
+patients	O
+.	O
+
+Eight	O
+Crohn	B
+'	I
+s	I
+disease	I
+patients	O
+were	O
+included	O
+.	O
+
+Fusidic	O
+acid	O
+was	O
+administered	O
+orally	O
+in	O
+a	O
+dose	O
+of	O
+500	O
+mg	O
+t	O
+.	O
+d	O
+.	O
+s	O
+.	O
+and	O
+the	O
+treatment	O
+was	O
+planned	O
+to	O
+last	O
+8	O
+weeks	O
+.	O
+
+The	O
+disease	O
+activity	O
+was	O
+primarily	O
+measured	O
+by	O
+a	O
+modified	O
+individual	O
+grading	O
+score	O
+.	O
+
+Five	O
+of	O
+8	O
+patients	O
+(	O
+63	O
+%	O
+)	O
+improved	O
+during	O
+fusidic	O
+acid	O
+treatment	O
+:	O
+3	O
+at	O
+two	O
+weeks	O
+and	O
+2	O
+after	O
+four	O
+weeks	O
+.	O
+
+There	O
+were	O
+no	O
+serious	O
+clinical	O
+side	O
+effects	O
+,	O
+but	O
+dose	O
+reduction	O
+was	O
+required	O
+in	O
+two	O
+patients	O
+because	O
+of	O
+nausea	B
+.	O
+
+Biochemically	O
+,	O
+an	O
+increase	O
+in	O
+alkaline	O
+phosphatases	O
+was	O
+noted	O
+in	O
+5	O
+of	O
+8	O
+cases	O
+(	O
+63	O
+%	O
+)	O
+,	O
+and	O
+the	O
+greatest	O
+increases	O
+were	O
+seen	O
+in	O
+those	O
+who	O
+had	O
+elevated	O
+levels	O
+prior	O
+to	O
+treatment	O
+.	O
+
+All	O
+reversed	O
+to	O
+pre	O
+-	O
+treatment	O
+levels	O
+after	O
+cessation	O
+of	O
+treatment	O
+.	O
+
+The	O
+results	O
+of	O
+this	O
+pilot	O
+study	O
+suggest	O
+that	O
+fusidic	O
+acid	O
+may	O
+be	O
+of	O
+benefit	O
+in	O
+selected	O
+chronic	O
+active	O
+Crohn	B
+'	I
+s	I
+disease	I
+patients	O
+in	O
+whom	O
+conventional	O
+treatment	O
+is	O
+ineffective	O
+.	O
+
+Because	O
+there	O
+seems	O
+to	O
+exist	O
+a	O
+scientific	O
+rationale	O
+for	O
+the	O
+use	O
+of	O
+fusidic	O
+acid	O
+at	O
+the	O
+cytokine	O
+level	O
+in	O
+inflammatory	B
+bowel	I
+disease	I
+,	O
+we	O
+suggest	O
+that	O
+the	O
+role	O
+of	O
+this	O
+treatment	O
+should	O
+be	O
+further	O
+investigated	O
+.	O
+
+Changes	O
+in	O
+depressive	B
+status	O
+associated	O
+with	O
+topical	O
+beta	O
+-	O
+blockers	O
+.	O
+
+Depression	B
+and	O
+sexual	B
+dysfunction	I
+have	O
+been	O
+related	O
+to	O
+side	O
+effects	O
+of	O
+topical	O
+beta	O
+-	O
+blockers	O
+.	O
+
+We	O
+performed	O
+a	O
+preliminary	O
+study	O
+in	O
+order	O
+to	O
+determine	O
+any	O
+difference	O
+between	O
+a	O
+non	O
+selective	O
+beta	O
+-	O
+blocker	O
+(	O
+timolol	O
+)	O
+and	O
+a	O
+selective	O
+beta	O
+-	O
+blocker	O
+(	O
+betaxolol	O
+)	O
+regarding	O
+CNS	O
+side	O
+effects	O
+.	O
+
+Eight	O
+glaucomatous	B
+patients	O
+chronically	O
+treated	O
+with	O
+timolol	O
+0	O
+.	O
+5	O
+%	O
+/	O
+12h	O
+,	O
+suffering	O
+from	O
+depression	B
+diagnosed	O
+through	O
+DMS	O
+-	O
+III	O
+-	O
+R	O
+criteria	O
+,	O
+were	O
+included	O
+in	O
+the	O
+study	O
+.	O
+
+During	O
+the	O
+six	O
+-	O
+month	O
+follow	O
+up	O
+,	O
+depression	B
+was	O
+quantified	O
+through	O
+the	O
+Beck	O
+and	O
+Zung	O
+-	O
+Conde	O
+scales	O
+every	O
+two	O
+months	O
+.	O
+
+In	O
+a	O
+double	O
+blind	O
+cross	O
+-	O
+over	O
+study	O
+with	O
+control	O
+group	O
+,	O
+the	O
+patients	O
+under	O
+timolol	O
+treatment	O
+presented	O
+higher	O
+depression	B
+values	O
+measured	O
+through	O
+the	O
+Beck	O
+and	O
+the	O
+Zung	O
+-	O
+Conde	O
+scales	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+vs	O
+control	O
+)	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+betaxolol	O
+could	O
+be	O
+less	O
+of	O
+a	O
+depression	B
+-	O
+inducer	O
+than	O
+timolol	O
+in	O
+predisposed	O
+patients	O
+.	O
+
+Protection	O
+against	O
+amphetamine	O
+-	O
+induced	O
+neurotoxicity	B
+toward	O
+striatal	O
+dopamine	O
+neurons	O
+in	O
+rodents	O
+by	O
+LY274614	O
+,	O
+an	O
+excitatory	O
+amino	O
+acid	O
+antagonist	O
+.	O
+
+LY274614	O
+,	O
+3SR	O
+,	O
+4aRS	O
+,	O
+6SR	O
+,	O
+8aRS	O
+-	O
+6	O
+-	O
+[	O
+phosphonomethyl	O
+]	O
+decahydr	O
+oisoquinoline	O
+-	O
+3	O
+-	O
+carboxylic	O
+acid	O
+,	O
+has	O
+been	O
+described	O
+as	O
+a	O
+potent	O
+antagonist	O
+of	O
+the	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+subtype	O
+of	O
+glutamate	O
+receptor	O
+.	O
+
+Here	O
+its	O
+ability	O
+to	O
+antagonize	O
+the	O
+prolonged	O
+depletion	O
+of	O
+dopamine	O
+in	O
+the	O
+striatum	O
+by	O
+amphetamine	O
+in	O
+iprindole	O
+-	O
+treated	O
+rats	O
+is	O
+reported	O
+.	O
+
+A	O
+single	O
+18	O
+.	O
+4	O
+mg	O
+/	O
+kg	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+dose	O
+of	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+amphetamine	O
+hemisulfate	O
+,	O
+given	O
+to	O
+rats	O
+pretreated	O
+with	O
+iprindole	O
+,	O
+resulted	O
+in	O
+persistent	O
+depletion	O
+of	O
+dopamine	O
+in	O
+the	O
+striatum	O
+1	O
+week	O
+later	O
+.	O
+
+This	O
+prolonged	O
+depletion	O
+of	O
+dopamine	O
+in	O
+the	O
+striatum	O
+was	O
+antagonized	O
+by	O
+dizocilpine	O
+(	O
+MK	O
+-	O
+801	O
+,	O
+a	O
+non	O
+-	O
+competitive	O
+antagonist	O
+of	O
+NMDA	O
+receptors	O
+)	O
+or	O
+by	O
+LY274614	O
+(	O
+a	O
+competitive	O
+antagonist	O
+of	O
+NMDA	O
+receptors	O
+)	O
+.	O
+
+The	O
+protective	O
+effect	O
+of	O
+LY274614	O
+was	O
+dose	O
+-	O
+dependent	O
+,	O
+being	O
+maximum	O
+at	O
+10	O
+-	O
+40	O
+mgkg	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+A	O
+10	O
+mg	O
+/	O
+kg	O
+dose	O
+of	O
+LY274614	O
+was	O
+effective	O
+in	O
+antagonizing	O
+the	O
+depletion	O
+of	O
+dopamine	O
+in	O
+the	O
+striatum	O
+,	O
+when	O
+given	O
+as	O
+long	O
+as	O
+8	O
+hr	O
+prior	O
+to	O
+amphetamine	O
+but	O
+not	O
+when	O
+given	O
+24	O
+hr	O
+prior	O
+to	O
+amphetamine	O
+.	O
+
+Depletion	O
+of	O
+dopamine	O
+in	O
+the	O
+striatum	O
+was	O
+also	O
+antagonized	O
+when	O
+LY274614	O
+was	O
+given	O
+after	O
+the	O
+injection	O
+of	O
+amphetamine	O
+;	O
+LY274614	O
+protected	O
+when	O
+given	O
+up	O
+to	O
+4	O
+hr	O
+after	O
+but	O
+not	O
+when	O
+given	O
+8	O
+or	O
+24	O
+hr	O
+after	O
+amphetamine	O
+.	O
+
+The	O
+prolonged	O
+depletion	O
+of	O
+dopamine	O
+in	O
+the	O
+striatum	O
+in	O
+mice	O
+,	O
+given	O
+multiple	O
+injections	O
+of	O
+methamphetamine	O
+,	O
+was	O
+also	O
+antagonized	O
+dose	O
+-	O
+dependently	O
+and	O
+completely	O
+by	O
+LY274614	O
+.	O
+
+The	O
+data	O
+strengthen	O
+the	O
+evidence	O
+that	O
+the	O
+neurotoxic	B
+effect	O
+of	O
+amphetamine	O
+and	O
+related	O
+compounds	O
+toward	O
+nigrostriatal	O
+dopamine	O
+neurons	O
+involves	O
+NMDA	O
+receptors	O
+and	O
+that	O
+LY274614	O
+is	O
+an	O
+NMDA	O
+receptor	O
+antagonist	O
+with	O
+long	O
+-	O
+lasting	O
+in	O
+vivo	O
+effects	O
+in	O
+rats	O
+.	O
+
+Ketoconazole	O
+-	O
+induced	O
+neurologic	B
+sequelae	I
+.	O
+
+A	O
+77	O
+-	O
+y	O
+-	O
+old	O
+patient	O
+developed	O
+weakness	B
+of	I
+extremities	I
+,	O
+legs	B
+paralysis	I
+,	O
+dysarthria	B
+and	O
+tremor	B
+1	O
+h	O
+after	O
+ingestion	O
+of	O
+200	O
+mg	O
+ketoconazole	O
+for	O
+the	O
+first	O
+time	O
+in	O
+his	O
+life	O
+.	O
+
+All	O
+complaints	O
+faded	O
+away	O
+within	O
+24	O
+h	O
+.	O
+
+Few	O
+days	O
+later	O
+,	O
+the	O
+patient	O
+used	O
+another	O
+200	O
+mg	O
+ketoconazole	O
+tablet	O
+,	O
+and	O
+within	O
+an	O
+hour	O
+experienced	O
+a	O
+similar	O
+clinical	O
+picture	O
+,	O
+which	O
+resolved	O
+again	O
+spontaneously	O
+within	O
+hours	O
+.	O
+
+Laboratory	O
+evaluations	O
+,	O
+including	O
+head	O
+CT	O
+scan	O
+,	O
+were	O
+normal	O
+.	O
+
+This	O
+case	O
+illustrates	O
+the	O
+need	O
+for	O
+close	O
+vigilance	O
+in	O
+adverse	B
+drug	I
+reactions	I
+,	O
+particularly	O
+in	O
+the	O
+elderly	O
+.	O
+
+Development	O
+of	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+in	O
+parkinsonian	B
+monkeys	O
+may	O
+depend	O
+upon	O
+rate	O
+of	O
+symptom	O
+onset	O
+and	O
+/	O
+or	O
+duration	O
+of	O
+symptoms	O
+.	O
+
+Levodopa	O
+-	O
+induced	O
+dyskinesias	B
+(	O
+LIDs	B
+)	O
+present	O
+a	O
+major	O
+problem	O
+for	O
+the	O
+long	O
+-	O
+term	O
+management	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+patients	O
+.	O
+
+Due	O
+to	O
+the	O
+interdependence	O
+of	O
+risk	O
+factors	O
+in	O
+clinical	O
+populations	O
+,	O
+it	O
+is	O
+difficult	O
+to	O
+independently	O
+examine	O
+factors	O
+that	O
+may	O
+influence	O
+the	O
+development	O
+of	O
+LIDs	B
+.	O
+
+Using	O
+macaque	O
+monkeys	O
+with	O
+different	O
+types	O
+of	O
+MPTP	O
+-	O
+induced	O
+parkinsonism	B
+,	O
+the	O
+current	O
+study	O
+evaluated	O
+the	O
+degree	O
+to	O
+which	O
+rate	O
+of	O
+symptom	O
+progression	O
+,	O
+symptom	O
+severity	O
+,	O
+and	O
+response	O
+to	O
+and	O
+duration	O
+of	O
+levodopa	O
+therapy	O
+may	O
+be	O
+involved	O
+in	O
+the	O
+development	O
+of	O
+LIDs	B
+.	O
+
+Monkeys	O
+with	O
+acute	O
+(	O
+short	O
+-	O
+term	O
+)	O
+MPTP	O
+exposure	O
+,	O
+rapid	O
+symptom	O
+onset	O
+and	O
+short	O
+symptom	O
+duration	O
+prior	O
+to	O
+initiation	O
+of	O
+levodopa	O
+therapy	O
+developed	O
+dyskinesia	B
+between	O
+11	O
+and	O
+24	O
+days	O
+of	O
+daily	O
+levodopa	O
+administration	O
+.	O
+
+In	O
+contrast	O
+,	O
+monkeys	O
+with	O
+long	O
+-	O
+term	O
+MPTP	O
+exposure	O
+,	O
+slow	O
+symptom	O
+progression	O
+and	O
+/	O
+or	O
+long	O
+symptom	O
+duration	O
+prior	O
+to	O
+initiation	O
+of	O
+levodopa	O
+therapy	O
+were	O
+more	O
+resistant	O
+to	O
+developing	O
+LIDs	B
+(	O
+e	O
+.	O
+g	O
+.	O
+,	O
+dyskinesia	B
+developed	O
+no	O
+sooner	O
+than	O
+146	O
+days	O
+of	O
+chronic	O
+levodopa	O
+administration	O
+)	O
+.	O
+
+All	O
+animals	O
+were	O
+similarly	O
+symptomatic	O
+at	O
+the	O
+start	O
+of	O
+levodopa	O
+treatment	O
+and	O
+had	O
+similar	O
+therapeutic	O
+responses	O
+to	O
+the	O
+drug	O
+.	O
+
+These	O
+data	O
+suggest	O
+distinct	O
+differences	O
+in	O
+the	O
+propensity	O
+to	O
+develop	O
+LIDs	B
+in	O
+monkeys	O
+with	O
+different	O
+rates	O
+of	O
+symptom	O
+progression	O
+or	O
+symptom	O
+durations	O
+prior	O
+to	O
+levodopa	O
+and	O
+demonstrate	O
+the	O
+value	O
+of	O
+these	O
+models	O
+for	O
+further	O
+studying	O
+the	O
+pathophysiology	O
+of	O
+LIDs	B
+.	O
+
+A	O
+diet	O
+promoting	O
+sugar	B
+dependency	I
+causes	O
+behavioral	B
+cross	I
+-	I
+sensitization	I
+to	O
+a	O
+low	O
+dose	O
+of	O
+amphetamine	O
+.	O
+
+Previous	O
+research	O
+in	O
+this	O
+laboratory	O
+has	O
+shown	O
+that	O
+a	O
+diet	O
+of	O
+intermittent	O
+excessive	O
+sugar	O
+consumption	O
+produces	O
+a	O
+state	O
+with	O
+neurochemical	O
+and	O
+behavioral	O
+similarities	O
+to	O
+drug	B
+dependency	I
+.	O
+
+The	O
+present	O
+study	O
+examined	O
+whether	O
+female	O
+rats	O
+on	O
+various	O
+regimens	O
+of	O
+sugar	O
+access	O
+would	O
+show	O
+behavioral	B
+cross	I
+-	I
+sensitization	I
+to	O
+a	O
+low	O
+dose	O
+of	O
+amphetamine	O
+.	O
+
+After	O
+a	O
+30	O
+-	O
+min	O
+baseline	O
+measure	O
+of	O
+locomotor	O
+activity	O
+(	O
+day	O
+0	O
+)	O
+,	O
+animals	O
+were	O
+maintained	O
+on	O
+a	O
+cyclic	O
+diet	O
+of	O
+12	O
+-	O
+h	O
+deprivation	O
+followed	O
+by	O
+12	O
+-	O
+h	O
+access	O
+to	O
+10	O
+%	O
+sucrose	O
+solution	O
+and	O
+chow	O
+pellets	O
+(	O
+12	O
+h	O
+access	O
+starting	O
+4	O
+h	O
+after	O
+onset	O
+of	O
+the	O
+dark	O
+period	O
+)	O
+for	O
+21	O
+days	O
+.	O
+
+Locomotor	O
+activity	O
+was	O
+measured	O
+again	O
+for	O
+30	O
+min	O
+at	O
+the	O
+beginning	O
+of	O
+days	O
+1	O
+and	O
+21	O
+of	O
+sugar	O
+access	O
+.	O
+
+Beginning	O
+on	O
+day	O
+22	O
+,	O
+all	O
+rats	O
+were	O
+maintained	O
+on	O
+ad	O
+libitum	O
+chow	O
+.	O
+
+Nine	O
+days	O
+later	O
+locomotor	O
+activity	O
+was	O
+measured	O
+in	O
+response	O
+to	O
+a	O
+single	O
+low	O
+dose	O
+of	O
+amphetamine	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+The	O
+animals	O
+that	O
+had	O
+experienced	O
+cyclic	O
+sucrose	O
+and	O
+chow	O
+were	O
+hyperactive	B
+in	O
+response	O
+to	O
+amphetamine	O
+compared	O
+with	O
+four	O
+control	O
+groups	O
+(	O
+ad	O
+libitum	O
+10	O
+%	O
+sucrose	O
+and	O
+chow	O
+followed	O
+by	O
+amphetamine	O
+injection	O
+,	O
+cyclic	O
+chow	O
+followed	O
+by	O
+amphetamine	O
+injection	O
+,	O
+ad	O
+libitum	O
+chow	O
+with	O
+amphetamine	O
+,	O
+or	O
+cyclic	O
+10	O
+%	O
+sucrose	O
+and	O
+chow	O
+with	O
+a	O
+saline	O
+injection	O
+)	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+a	O
+diet	O
+comprised	O
+of	O
+alternating	O
+deprivation	O
+and	O
+access	O
+to	O
+a	O
+sugar	O
+solution	O
+and	O
+chow	O
+produces	O
+bingeing	O
+on	O
+sugar	O
+that	O
+leads	O
+to	O
+a	O
+long	O
+lasting	O
+state	O
+of	O
+increased	O
+sensitivity	O
+to	O
+amphetamine	O
+,	O
+possibly	O
+due	O
+to	O
+a	O
+lasting	O
+alteration	O
+in	O
+the	O
+dopamine	O
+system	O
+.	O
+
+Reversible	O
+dilated	B
+cardiomyopathy	I
+related	O
+to	O
+amphotericin	O
+B	O
+therapy	O
+.	O
+
+We	O
+describe	O
+a	O
+patient	O
+who	O
+developed	O
+dilated	B
+cardiomyopathy	I
+and	O
+clinical	O
+congestive	O
+heart	B
+failure	I
+after	O
+2	O
+months	O
+of	O
+therapy	O
+with	O
+amphotericin	O
+B	O
+(	O
+AmB	O
+)	O
+for	O
+disseminated	O
+coccidioidomycosis	B
+.	O
+
+His	O
+echocardiographic	O
+abnormalities	O
+and	O
+heart	B
+failure	I
+resolved	O
+after	O
+posaconazole	O
+was	O
+substituted	O
+for	O
+AmB	O
+.	O
+
+It	O
+is	O
+important	O
+to	O
+recognize	O
+the	O
+rare	O
+and	O
+potentially	O
+reversible	O
+toxicity	B
+of	O
+AmB	O
+.	O
+
+NO	O
+-	O
+induced	O
+migraine	B
+attack	O
+:	O
+strong	O
+increase	O
+in	O
+plasma	O
+calcitonin	O
+gene	O
+-	O
+related	O
+peptide	O
+(	O
+CGRP	O
+)	O
+concentration	O
+and	O
+negative	O
+correlation	O
+with	O
+platelet	O
+serotonin	O
+release	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+investigate	O
+changes	O
+in	O
+the	O
+plasma	O
+calcitonin	O
+gene	O
+-	O
+related	O
+peptide	O
+(	O
+CGRP	O
+)	O
+concentration	O
+and	O
+platelet	O
+serotonin	O
+(	O
+5	O
+-	O
+hydroxytriptamine	O
+,	O
+5	O
+-	O
+HT	O
+)	O
+content	O
+during	O
+the	O
+immediate	O
+headache	B
+and	O
+the	O
+delayed	O
+genuine	O
+migraine	B
+attack	O
+provoked	O
+by	O
+nitroglycerin	O
+.	O
+
+Fifteen	O
+female	O
+migraineurs	B
+(	I
+without	I
+aura	I
+)	I
+and	O
+eight	O
+controls	O
+participated	O
+in	O
+the	O
+study	O
+.	O
+
+Sublingual	O
+nitroglycerin	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+)	O
+was	O
+administered	O
+.	O
+
+Blood	O
+was	O
+collected	O
+from	O
+the	O
+antecubital	O
+vein	O
+four	O
+times	O
+:	O
+60	O
+min	O
+before	O
+and	O
+after	O
+the	O
+nitroglycerin	O
+application	O
+,	O
+and	O
+60	O
+and	O
+120	O
+min	O
+after	O
+the	O
+beginning	O
+of	O
+the	O
+migraine	B
+attack	O
+(	O
+mean	O
+344	O
+and	O
+404	O
+min	O
+;	O
+12	O
+subjects	O
+)	O
+.	O
+
+In	O
+those	O
+subjects	O
+who	O
+had	O
+no	O
+migraine	B
+attack	O
+(	O
+11	O
+subjects	O
+)	O
+a	O
+similar	O
+time	O
+schedule	O
+was	O
+used	O
+.	O
+
+Plasma	O
+CGRP	O
+concentration	O
+increased	O
+significantly	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+during	O
+the	O
+migraine	B
+attack	O
+and	O
+returned	O
+to	O
+baseline	O
+after	O
+the	O
+cessation	O
+of	O
+the	O
+migraine	B
+.	O
+
+In	O
+addition	O
+,	O
+both	O
+change	O
+and	O
+peak	O
+,	O
+showed	O
+significant	O
+positive	O
+correlations	O
+with	O
+migraine	B
+headache	B
+intensity	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+However	O
+,	O
+plasma	O
+CGRP	O
+concentrations	O
+failed	O
+to	O
+change	O
+during	O
+immediate	O
+headache	B
+and	O
+in	O
+the	O
+subjects	O
+with	O
+no	O
+migraine	B
+attack	O
+.	O
+
+Basal	O
+CGRP	O
+concentration	O
+was	O
+significantly	O
+higher	O
+and	O
+platelet	O
+5	O
+-	O
+HT	O
+content	O
+tended	O
+to	O
+be	O
+lower	O
+in	O
+subjects	O
+who	O
+experienced	O
+a	O
+migraine	B
+attack	O
+.	O
+
+Platelet	O
+serotonin	O
+content	O
+decreased	O
+significantly	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+after	O
+nitroglycerin	O
+in	O
+subjects	O
+with	O
+no	O
+migraine	B
+attack	O
+but	O
+no	O
+consistent	O
+change	O
+was	O
+observed	O
+in	O
+patients	O
+with	O
+migraine	B
+attack	O
+.	O
+
+In	O
+conclusion	O
+,	O
+the	O
+fact	O
+that	O
+plasma	O
+CGRP	O
+concentration	O
+correlates	O
+with	O
+the	O
+timing	O
+and	O
+severity	O
+of	O
+a	O
+migraine	B
+headache	B
+suggests	O
+a	O
+direct	O
+relationship	O
+between	O
+CGRP	O
+and	O
+migraine	B
+.	O
+
+In	O
+contrast	O
+,	O
+serotonin	O
+release	O
+from	O
+platelets	O
+does	O
+not	O
+provoke	O
+migraine	B
+,	O
+it	O
+may	O
+even	O
+counteract	O
+the	O
+headache	B
+and	O
+the	O
+concomitant	O
+CGRP	O
+release	O
+in	O
+this	O
+model	O
+.	O
+
+Hyperbaric	O
+oxygen	O
+therapy	O
+for	O
+control	O
+of	O
+intractable	O
+cyclophosphamide	O
+-	O
+induced	O
+hemorrhagic	B
+cystitis	I
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+intractable	O
+hemorrhagic	B
+cystitis	I
+due	O
+to	O
+cyclophosphamide	O
+therapy	O
+for	O
+Wegener	B
+'	I
+s	I
+granulomatosis	I
+.	O
+
+Conservative	O
+treatment	O
+,	O
+including	O
+bladder	O
+irrigation	O
+with	O
+physiological	O
+saline	O
+and	O
+instillation	O
+of	O
+prostaglandin	O
+F2	O
+alpha	O
+,	O
+failed	O
+to	O
+totally	O
+control	O
+hemorrhage	B
+.	O
+
+We	O
+then	O
+used	O
+hyperbaric	O
+oxygen	O
+at	O
+an	O
+absolute	O
+pressure	O
+of	O
+2	O
+atm	O
+,	O
+5	O
+days	O
+a	O
+week	O
+for	O
+8	O
+consecutive	O
+weeks	O
+.	O
+
+The	O
+bleeding	B
+ceased	O
+completely	O
+by	O
+the	O
+end	O
+of	O
+treatment	O
+and	O
+the	O
+patient	O
+remained	O
+free	O
+of	O
+hematuria	B
+thereafter	O
+.	O
+
+No	O
+side	O
+effect	O
+was	O
+noted	O
+during	O
+the	O
+course	O
+of	O
+therapy	O
+.	O
+
+In	O
+future	O
+,	O
+this	O
+form	O
+of	O
+therapy	O
+can	O
+offer	O
+a	O
+safe	O
+alternative	O
+in	O
+the	O
+treatment	O
+of	O
+cyclophosphamide	O
+-	O
+induced	O
+hemorrhagic	B
+cystitis	I
+.	O
+
+Acute	B
+psychosis	I
+due	O
+to	O
+treatment	O
+with	O
+phenytoin	O
+in	O
+a	O
+nonepileptic	O
+patient	O
+.	O
+
+The	O
+development	O
+of	O
+psychosis	B
+related	O
+to	O
+antiepileptic	O
+drug	O
+treatment	O
+is	O
+usually	O
+attributed	O
+to	O
+the	O
+interaction	O
+between	O
+the	O
+epileptic	B
+brain	O
+substratum	O
+and	O
+the	O
+antiepileptic	O
+drugs	O
+.	O
+
+The	O
+case	O
+of	O
+a	O
+nonepileptic	O
+patient	O
+who	O
+developed	O
+psychosis	B
+following	O
+phenytoin	O
+treatment	O
+for	O
+trigeminal	B
+neuralgia	I
+is	O
+described	O
+.	O
+
+This	O
+case	O
+suggests	O
+that	O
+the	O
+psychotic	B
+symptoms	I
+that	O
+occur	O
+following	O
+phenytoin	O
+treatment	O
+in	O
+some	O
+epileptic	B
+patients	O
+may	O
+be	O
+the	O
+direct	O
+result	O
+of	O
+medication	O
+,	O
+unrelated	O
+to	O
+seizures	B
+.	O
+
+Risks	O
+of	O
+the	O
+consumption	O
+of	O
+beverages	O
+containing	O
+quinine	O
+.	O
+
+Although	O
+the	O
+United	O
+States	O
+Food	O
+and	O
+Drug	O
+Administration	O
+banned	O
+its	O
+use	O
+for	O
+nocturnal	B
+leg	I
+cramps	I
+due	O
+to	O
+lack	O
+of	O
+safety	O
+and	O
+efficacy	O
+,	O
+quinine	O
+is	O
+widely	O
+available	O
+in	O
+beverages	O
+including	O
+tonic	O
+water	O
+and	O
+bitter	O
+lemon	O
+.	O
+
+Numerous	O
+anecdotal	O
+reports	O
+suggest	O
+that	O
+products	O
+containing	O
+quinine	O
+may	O
+produce	O
+neurological	B
+complications	I
+,	O
+including	O
+confusion	B
+,	O
+altered	O
+mental	O
+status	O
+,	O
+seizures	B
+,	O
+and	O
+coma	B
+,	O
+particularly	O
+in	O
+older	O
+women	O
+.	O
+
+Psychologists	O
+need	O
+to	O
+inquire	O
+about	O
+consumption	O
+of	O
+quinine	O
+-	O
+containing	O
+beverages	O
+as	O
+part	O
+of	O
+an	O
+evaluation	O
+process	O
+.	O
+
+Transient	O
+platypnea	B
+-	I
+orthodeoxia	I
+-	I
+like	I
+syndrome	I
+induced	O
+by	O
+propafenone	O
+overdose	B
+in	O
+a	O
+young	O
+woman	O
+with	O
+Ebstein	B
+'	I
+s	I
+anomaly	I
+.	O
+
+In	O
+this	O
+report	O
+we	O
+describe	O
+the	O
+case	O
+of	O
+a	O
+37	O
+-	O
+year	O
+-	O
+old	O
+white	O
+woman	O
+with	O
+Ebstein	B
+'	I
+s	I
+anomaly	I
+,	O
+who	O
+developed	O
+a	O
+rare	O
+syndrome	O
+called	O
+platypnea	B
+-	I
+orthodeoxia	I
+,	O
+characterized	O
+by	O
+massive	O
+right	O
+-	O
+to	O
+-	O
+left	O
+interatrial	O
+shunting	O
+with	O
+transient	O
+profound	O
+hypoxia	B
+and	O
+cyanosis	B
+.	O
+
+This	O
+shunt	O
+of	O
+blood	O
+via	O
+a	O
+patent	B
+foramen	I
+ovale	I
+occurred	O
+in	O
+the	O
+presence	O
+of	O
+a	O
+normal	O
+pulmonary	O
+artery	O
+pressure	O
+,	O
+and	O
+was	O
+probably	O
+precipitated	O
+by	O
+a	O
+propafenone	O
+overdose	B
+.	O
+
+This	O
+drug	O
+caused	O
+biventricular	B
+dysfunction	I
+,	O
+due	O
+to	O
+its	O
+negative	O
+inotropic	O
+effect	O
+,	O
+and	O
+hypotension	B
+,	O
+due	O
+to	O
+its	O
+peripheral	O
+vasodilatory	O
+effect	O
+.	O
+
+These	O
+effects	O
+gave	O
+rise	O
+to	O
+an	O
+increase	O
+in	O
+the	O
+right	O
+atrial	O
+pressure	O
+and	O
+a	O
+decrease	O
+in	O
+the	O
+left	O
+one	O
+with	O
+a	O
+consequent	O
+stretching	O
+of	O
+the	O
+foramen	O
+ovale	O
+and	O
+the	O
+creation	O
+of	O
+massive	O
+right	O
+-	O
+to	O
+-	O
+left	O
+shunting	O
+.	O
+
+In	O
+our	O
+case	O
+this	O
+interatrial	O
+shunt	O
+was	O
+very	O
+accurately	O
+detected	O
+at	O
+bubble	O
+contrast	O
+echocardiography	O
+.	O
+
+Noxious	O
+chemical	O
+stimulation	O
+of	O
+rat	O
+facial	O
+mucosa	O
+increases	O
+intracranial	O
+blood	O
+flow	O
+through	O
+a	O
+trigemino	O
+-	O
+parasympathetic	O
+reflex	O
+-	O
+-	O
+an	O
+experimental	O
+model	O
+for	O
+vascular	B
+dysfunctions	I
+in	O
+cluster	B
+headache	I
+.	O
+
+Cluster	B
+headache	I
+is	O
+characterized	O
+by	O
+typical	O
+autonomic	O
+dysfunctions	O
+including	O
+facial	O
+and	O
+intracranial	B
+vascular	I
+disturbances	I
+.	O
+
+Both	O
+the	O
+trigeminal	O
+and	O
+the	O
+cranial	O
+parasympathetic	O
+systems	O
+may	O
+be	O
+involved	O
+in	O
+mediating	O
+these	O
+dysfunctions	O
+.	O
+
+An	O
+experimental	O
+model	O
+was	O
+developed	O
+in	O
+the	O
+rat	O
+to	O
+measure	O
+changes	O
+in	O
+lacrimation	O
+and	O
+intracranial	O
+blood	O
+flow	O
+following	O
+noxious	O
+chemical	O
+stimulation	O
+of	O
+facial	O
+mucosa	O
+.	O
+
+Blood	O
+flow	O
+was	O
+monitored	O
+in	O
+arteries	O
+of	O
+the	O
+exposed	O
+cranial	O
+dura	O
+mater	O
+and	O
+the	O
+parietal	O
+cortex	O
+using	O
+laser	O
+Doppler	O
+flowmetry	O
+.	O
+
+Capsaicin	O
+(	O
+0	O
+.	O
+01	O
+-	O
+1	O
+mm	O
+)	O
+applied	O
+to	O
+oral	O
+or	O
+nasal	O
+mucosa	O
+induced	O
+increases	B
+in	I
+dural	I
+and	I
+cortical	I
+blood	I
+flow	I
+and	O
+provoked	O
+lacrimation	O
+.	O
+
+These	O
+responses	O
+were	O
+blocked	O
+by	O
+systemic	O
+pre	O
+-	O
+administration	O
+of	O
+hexamethonium	O
+chloride	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+The	O
+evoked	O
+increases	B
+in	I
+dural	I
+blood	I
+flow	I
+were	O
+also	O
+abolished	O
+by	O
+topical	O
+pre	O
+-	O
+administration	O
+of	O
+atropine	O
+(	O
+1	O
+mm	O
+)	O
+and	O
+[	O
+Lys1	O
+,	O
+Pro2	O
+,	O
+5	O
+,	O
+Arg3	O
+,	O
+4	O
+,	O
+Tyr6	O
+]	O
+-	O
+VIP	O
+(	O
+0	O
+.	O
+1	O
+mm	O
+)	O
+,	O
+a	O
+vasoactive	O
+intestinal	O
+polypeptide	O
+(	O
+VIP	O
+)	O
+antagonist	O
+,	O
+onto	O
+the	O
+exposed	O
+dura	O
+mater	O
+.	O
+
+We	O
+conclude	O
+that	O
+noxious	O
+stimulation	O
+of	O
+facial	O
+mucosa	O
+increases	O
+intracranial	O
+blood	O
+flow	O
+and	O
+lacrimation	O
+via	O
+a	O
+trigemino	O
+-	O
+parasympathetic	O
+reflex	O
+.	O
+
+The	O
+blood	O
+flow	O
+responses	O
+seem	O
+to	O
+be	O
+mediated	O
+by	O
+the	O
+release	O
+of	O
+acetylcholine	O
+and	O
+VIP	O
+within	O
+the	O
+meninges	O
+.	O
+
+Similar	O
+mechanisms	O
+may	O
+be	O
+involved	O
+in	O
+the	O
+pathogenesis	O
+of	O
+cluster	B
+headache	I
+.	O
+
+Organophosphate	O
+-	O
+induced	O
+convulsions	B
+and	O
+prevention	O
+of	O
+neuropathological	B
+damages	I
+.	O
+
+Such	O
+organophosphorus	O
+(	O
+OP	O
+)	O
+compounds	O
+as	O
+diisopropylfluorophosphate	O
+(	O
+DFP	O
+)	O
+,	O
+sarin	O
+and	O
+soman	O
+are	O
+potent	O
+inhibitors	O
+of	O
+acetylcholinesterases	O
+(	O
+AChEs	O
+)	O
+and	O
+butyrylcholinesterases	O
+(	O
+BChEs	O
+)	O
+.	O
+
+The	O
+acute	O
+toxicity	B
+of	O
+OPs	O
+is	O
+the	O
+result	O
+of	O
+their	O
+irreversible	O
+binding	O
+with	O
+AChEs	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+,	O
+which	O
+elevates	O
+acetylcholine	O
+(	O
+ACh	O
+)	O
+levels	O
+.	O
+
+The	O
+protective	O
+action	O
+of	O
+subcutaneously	O
+(	O
+SC	O
+)	O
+administered	O
+antidotes	O
+or	O
+their	O
+combinations	O
+in	O
+DFP	O
+(	O
+2	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+BW	O
+)	O
+intoxication	O
+was	O
+studied	O
+in	O
+9	O
+-	O
+10	O
+-	O
+weeks	O
+-	O
+old	O
+Han	O
+-	O
+Wistar	O
+male	O
+rats	O
+.	O
+
+The	O
+rats	O
+received	O
+AChE	O
+reactivator	O
+pralidoxime	O
+-	O
+2	O
+-	O
+chloride	O
+(	O
+2PAM	O
+)	O
+(	O
+30	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+BW	O
+)	O
+,	O
+anticonvulsant	O
+diazepam	O
+(	O
+2	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+BW	O
+)	O
+,	O
+A	O
+(	O
+1	O
+)	O
+-	O
+adenosine	O
+receptor	O
+agonist	O
+N	O
+(	O
+6	O
+)	O
+-	O
+cyclopentyl	O
+adenosine	O
+(	O
+CPA	O
+)	O
+(	O
+2	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+BW	O
+)	O
+,	O
+NMDA	O
+-	O
+receptor	O
+antagonist	O
+dizocilpine	O
+maleate	O
+(	O
++	O
+-	O
+MK801	O
+hydrogen	O
+maleate	O
+)	O
+(	O
+2	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+BW	O
+)	O
+or	O
+their	O
+combinations	O
+with	O
+cholinolytic	O
+drug	O
+atropine	O
+sulfate	O
+(	O
+50	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+BW	O
+)	O
+immediately	O
+or	O
+30	O
+min	O
+after	O
+the	O
+single	O
+SC	O
+injection	O
+of	O
+DFP	O
+.	O
+
+The	O
+control	O
+rats	O
+received	O
+atropine	O
+sulfate	O
+,	O
+but	O
+also	O
+saline	O
+and	O
+olive	O
+oil	O
+instead	O
+of	O
+other	O
+antidotes	O
+and	O
+DFP	O
+,	O
+respectively	O
+.	O
+
+All	O
+rats	O
+were	O
+terminated	O
+either	O
+24	O
+h	O
+or	O
+3	O
+weeks	O
+after	O
+the	O
+DFP	O
+injection	O
+.	O
+
+The	O
+rats	O
+treated	O
+with	O
+DFP	O
+-	O
+atropine	O
+showed	O
+severe	O
+typical	O
+OP	O
+-	O
+induced	O
+toxicity	B
+signs	O
+.	O
+
+When	O
+CPA	O
+,	O
+diazepam	O
+or	O
+2PAM	O
+was	O
+given	O
+immediately	O
+after	O
+DFP	O
+-	O
+atropine	O
+,	O
+these	O
+treatments	O
+prevented	O
+,	O
+delayed	O
+or	O
+shortened	O
+the	O
+occurrence	O
+of	O
+serious	O
+signs	O
+of	O
+poisoning	B
+.	O
+
+Atropine	O
+-	O
+MK801	O
+did	O
+not	O
+offer	O
+any	O
+additional	O
+protection	O
+against	O
+DFP	O
+toxicity	B
+.	O
+
+In	O
+conclusion	O
+,	O
+CPA	O
+,	O
+diazepam	O
+and	O
+2PAM	O
+in	O
+combination	O
+with	O
+atropine	O
+prevented	O
+the	O
+occurrence	O
+of	O
+serious	O
+signs	O
+of	O
+poisoning	B
+and	O
+thus	O
+reduced	O
+the	O
+toxicity	B
+of	O
+DFP	O
+in	O
+rat	O
+.	O
+
+A	O
+pyridoxine	O
+-	O
+dependent	O
+behavioral	B
+disorder	I
+unmasked	O
+by	O
+isoniazid	O
+.	O
+
+A	O
+3	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+had	O
+behavioral	B
+deterioration	I
+,	O
+with	O
+hyperkinesis	B
+,	O
+irritability	B
+,	O
+and	O
+sleeping	B
+difficulties	I
+after	O
+the	O
+therapeutic	O
+administration	O
+of	O
+isoniazid	O
+.	O
+
+The	O
+administration	O
+of	O
+pharmacologic	O
+doses	O
+of	O
+pyridoxine	O
+hydrochloride	O
+led	O
+to	O
+a	O
+disappearance	O
+of	O
+symptoms	O
+.	O
+
+After	O
+discontinuing	O
+isoniazid	O
+therapy	O
+a	O
+similar	O
+pattern	O
+of	O
+behavior	O
+was	O
+noted	O
+that	O
+was	O
+controlled	O
+by	O
+pyridoxine	O
+.	O
+
+A	O
+placebo	O
+had	O
+no	O
+effect	O
+,	O
+but	O
+niacinamide	O
+was	O
+as	O
+effective	O
+as	O
+pyridoxine	O
+.	O
+
+Periodic	O
+withdrawal	O
+of	O
+pyridoxine	O
+was	O
+associated	O
+with	O
+return	O
+of	O
+the	O
+hyperkinesis	B
+.	O
+
+The	O
+level	O
+of	O
+pyridoxal	O
+in	O
+the	O
+blood	O
+was	O
+normal	O
+during	O
+the	O
+periods	O
+of	O
+relapse	O
+.	O
+
+Metabolic	O
+studies	O
+suggested	O
+a	O
+block	O
+in	O
+the	O
+kynurenine	O
+pathway	O
+of	O
+tryptophan	O
+metabolism	O
+.	O
+
+The	O
+patient	O
+has	O
+been	O
+followed	O
+for	O
+six	O
+years	O
+and	O
+has	O
+required	O
+pharmacologic	O
+doses	O
+of	O
+pyridoxine	O
+to	O
+control	O
+her	O
+behavior	O
+.	O
+
+Recurrent	O
+excitation	O
+in	O
+the	O
+dentate	O
+gyrus	O
+of	O
+a	O
+murine	O
+model	O
+of	O
+temporal	B
+lobe	I
+epilepsy	I
+.	O
+
+Similar	O
+to	O
+rats	O
+,	O
+systemic	O
+pilocarpine	O
+injection	O
+causes	O
+status	B
+epilepticus	I
+(	O
+SE	B
+)	O
+and	O
+the	O
+eventual	O
+development	O
+of	O
+spontaneous	O
+seizures	B
+and	O
+mossy	O
+fiber	O
+sprouting	O
+in	O
+C57BL	O
+/	O
+6	O
+and	O
+CD1	O
+mice	O
+,	O
+but	O
+the	O
+physiological	O
+correlates	O
+of	O
+these	O
+events	O
+have	O
+not	O
+been	O
+identified	O
+in	O
+mice	O
+.	O
+
+Population	O
+responses	O
+in	O
+granule	O
+cells	O
+of	O
+the	O
+dentate	O
+gyrus	O
+were	O
+examined	O
+in	O
+transverse	O
+slices	O
+of	O
+the	O
+ventral	O
+hippocampus	O
+from	O
+pilocarpine	O
+-	O
+treated	O
+and	O
+untreated	O
+mice	O
+.	O
+
+In	O
+Mg	O
+(	O
+2	O
++	O
+)	O
+-	O
+free	O
+bathing	O
+medium	O
+containing	O
+bicuculline	O
+,	O
+conditions	O
+designed	O
+to	O
+increase	O
+excitability	O
+in	O
+the	O
+slices	O
+,	O
+electrical	O
+stimulation	O
+of	O
+the	O
+hilus	O
+resulted	O
+in	O
+a	O
+single	O
+population	O
+spike	O
+in	O
+granule	O
+cells	O
+from	O
+control	O
+mice	O
+and	O
+pilocarpine	O
+-	O
+treated	O
+mice	O
+that	O
+did	O
+not	O
+experience	O
+SE	B
+.	O
+
+In	O
+SE	B
+survivors	O
+,	O
+similar	O
+stimulation	O
+resulted	O
+in	O
+a	O
+population	O
+spike	O
+followed	O
+,	O
+at	O
+a	O
+variable	O
+latency	O
+,	O
+by	O
+negative	O
+DC	O
+shifts	O
+and	O
+repetitive	O
+afterdischarges	O
+of	O
+3	O
+-	O
+60	O
+s	O
+duration	O
+,	O
+which	O
+were	O
+blocked	O
+by	O
+ionotropic	O
+glutamate	O
+receptor	O
+antagonists	O
+.	O
+
+Focal	O
+glutamate	O
+photostimulation	O
+of	O
+the	O
+granule	O
+cell	O
+layer	O
+at	O
+sites	O
+distant	O
+from	O
+the	O
+recording	O
+pipette	O
+resulted	O
+in	O
+population	O
+responses	O
+of	O
+1	O
+-	O
+30	O
+s	O
+duration	O
+in	O
+slices	O
+from	O
+SE	B
+survivors	O
+but	O
+not	O
+other	O
+groups	O
+.	O
+
+These	O
+data	O
+support	O
+the	O
+hypothesis	O
+that	O
+SE	B
+-	O
+induced	O
+mossy	O
+fiber	O
+sprouting	O
+and	O
+synaptic	O
+reorganization	O
+are	O
+relevant	O
+characteristics	O
+of	O
+seizure	B
+development	O
+in	O
+these	O
+murine	O
+strains	O
+,	O
+resembling	O
+rat	O
+models	O
+of	O
+human	O
+temporal	B
+lobe	I
+epilepsy	I
+.	O
+
+Urinary	B
+bladder	I
+cancer	I
+in	O
+Wegener	B
+'	I
+s	I
+granulomatosis	I
+:	O
+risks	O
+and	O
+relation	O
+to	O
+cyclophosphamide	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+assess	O
+and	O
+characterise	O
+the	O
+risk	O
+of	O
+bladder	B
+cancer	I
+,	O
+and	O
+its	O
+relation	O
+to	O
+cyclophosphamide	O
+,	O
+in	O
+patients	O
+with	O
+Wegener	B
+'	I
+s	I
+granulomatosis	I
+.	O
+
+METHODS	O
+:	O
+In	O
+the	O
+population	O
+based	O
+,	O
+nationwide	O
+Swedish	O
+Inpatient	O
+Register	O
+a	O
+cohort	O
+of	O
+1065	O
+patients	O
+with	O
+Wegener	B
+'	I
+s	I
+granulomatosis	I
+,	O
+1969	O
+-	O
+95	O
+,	O
+was	O
+identified	O
+.	O
+
+Through	O
+linkage	O
+with	O
+the	O
+Swedish	O
+Cancer	B
+Register	O
+,	O
+all	O
+subjects	O
+in	O
+this	O
+cohort	O
+diagnosed	O
+with	O
+bladder	B
+cancer	I
+were	O
+identified	O
+.	O
+
+Nested	O
+within	O
+the	O
+cohort	O
+,	O
+a	O
+matched	O
+case	O
+-	O
+control	O
+study	O
+was	O
+performed	O
+to	O
+estimate	O
+the	O
+association	O
+between	O
+cyclophosphamide	O
+and	O
+bladder	B
+cancer	I
+using	O
+odds	O
+ratios	O
+(	O
+ORs	O
+)	O
+as	O
+relative	O
+risk	O
+.	O
+
+In	O
+the	O
+cohort	O
+the	O
+cumulative	O
+risk	O
+of	O
+bladder	B
+cancer	I
+after	O
+Wegener	B
+'	I
+s	I
+granulomatosis	I
+,	O
+and	O
+the	O
+relative	O
+prevalence	O
+of	O
+a	O
+history	O
+of	O
+bladder	B
+cancer	I
+at	O
+the	O
+time	O
+of	O
+diagnosis	O
+of	O
+Wegener	B
+'	I
+s	I
+granulomatosis	I
+,	O
+were	O
+also	O
+estimated	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+median	O
+cumulative	O
+doses	O
+of	O
+cyclophosphamide	O
+among	O
+cases	O
+(	O
+n	O
+=	O
+11	O
+)	O
+and	O
+controls	O
+(	O
+n	O
+=	O
+25	O
+)	O
+were	O
+113	O
+g	O
+and	O
+25	O
+g	O
+,	O
+respectively	O
+.	O
+
+The	O
+risk	O
+of	O
+bladder	B
+cancer	I
+doubled	O
+for	O
+every	O
+10	O
+g	O
+increment	O
+in	O
+cyclophosphamide	O
+(	O
+OR	O
+=	O
+2	O
+.	O
+0	O
+,	O
+95	O
+%	O
+confidence	O
+interval	O
+(	O
+CI	O
+)	O
+0	O
+.	O
+8	O
+to	O
+4	O
+.	O
+9	O
+)	O
+.	O
+
+Treatment	O
+duration	O
+longer	O
+than	O
+1	O
+year	O
+was	O
+associated	O
+with	O
+an	O
+eightfold	O
+increased	O
+risk	O
+(	O
+OR	O
+=	O
+7	O
+.	O
+7	O
+,	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+9	O
+to	O
+69	O
+)	O
+.	O
+
+The	O
+absolute	O
+risk	O
+for	O
+bladder	B
+cancer	I
+in	O
+the	O
+cohort	O
+reached	O
+10	O
+%	O
+16	O
+years	O
+after	O
+diagnosis	O
+of	O
+Wegener	B
+'	I
+s	I
+granulomatosis	I
+,	O
+and	O
+a	O
+history	O
+of	O
+bladder	B
+cancer	I
+was	O
+(	O
+non	O
+-	O
+significantly	O
+)	O
+twice	O
+as	O
+common	O
+as	O
+expected	O
+at	O
+the	O
+time	O
+of	O
+diagnosis	O
+of	O
+Wegener	B
+'	I
+s	I
+granulomatosis	I
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+results	O
+indicate	O
+a	O
+dose	O
+-	O
+response	O
+relationship	O
+between	O
+cyclophosphamide	O
+and	O
+the	O
+risk	O
+of	O
+bladder	B
+cancer	I
+,	O
+high	O
+cumulative	O
+risks	O
+in	O
+the	O
+entire	O
+cohort	O
+,	O
+and	O
+also	O
+the	O
+possibility	O
+of	O
+risk	O
+factors	O
+operating	O
+even	O
+before	O
+Wegener	B
+'	I
+s	I
+granulomatosis	I
+.	O
+
+Differential	O
+modulation	O
+by	O
+estrogen	O
+of	O
+alpha2	O
+-	O
+adrenergic	O
+and	O
+I1	O
+-	O
+imidazoline	O
+receptor	O
+-	O
+mediated	O
+hypotension	B
+in	O
+female	O
+rats	O
+.	O
+
+We	O
+have	O
+recently	O
+shown	O
+that	O
+estrogen	O
+negatively	O
+modulates	O
+the	O
+hypotensive	B
+effect	O
+of	O
+clonidine	O
+(	O
+mixed	O
+alpha2	O
+-	O
+/	O
+I1	O
+-	O
+receptor	O
+agonist	O
+)	O
+in	O
+female	O
+rats	O
+and	O
+implicates	O
+the	O
+cardiovascular	O
+autonomic	O
+control	O
+in	O
+this	O
+interaction	O
+.	O
+
+The	O
+present	O
+study	O
+investigated	O
+whether	O
+this	O
+effect	O
+of	O
+estrogen	O
+involves	O
+interaction	O
+with	O
+alpha2	O
+-	O
+and	O
+/	O
+or	O
+I1	O
+-	O
+receptors	O
+.	O
+
+Changes	O
+evoked	O
+by	O
+a	O
+single	O
+intraperitoneal	O
+injection	O
+of	O
+rilmenidine	O
+(	O
+600	O
+microg	O
+/	O
+kg	O
+)	O
+or	O
+alpha	O
+-	O
+methyldopa	O
+(	O
+100	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+selective	O
+I1	O
+-	O
+and	O
+alpha2	O
+-	O
+receptor	O
+agonists	O
+,	O
+respectively	O
+,	O
+in	O
+blood	O
+pressure	O
+,	O
+hemodynamic	O
+variability	O
+,	O
+and	O
+locomotor	O
+activity	O
+were	O
+assessed	O
+in	O
+radiotelemetered	O
+sham	O
+-	O
+operated	O
+and	O
+ovariectomized	O
+(	O
+Ovx	O
+)	O
+Sprague	O
+-	O
+Dawley	O
+female	O
+rats	O
+with	O
+or	O
+without	O
+12	O
+-	O
+wk	O
+estrogen	O
+replacement	O
+.	O
+
+Three	O
+time	O
+domain	O
+indexes	O
+of	O
+hemodynamic	O
+variability	O
+were	O
+employed	O
+:	O
+the	O
+standard	O
+deviation	O
+of	O
+mean	O
+arterial	O
+pressure	O
+as	O
+a	O
+measure	O
+of	O
+blood	O
+pressure	O
+variability	O
+and	O
+the	O
+standard	O
+deviation	O
+of	O
+beat	O
+-	O
+to	O
+-	O
+beat	O
+intervals	O
+(	O
+SDRR	O
+)	O
+and	O
+the	O
+root	O
+mean	O
+square	O
+of	O
+successive	O
+differences	O
+in	O
+R	O
+-	O
+wave	O
+-	O
+to	O
+-	O
+R	O
+-	O
+wave	O
+intervals	O
+as	O
+measures	O
+of	O
+heart	O
+rate	O
+variability	O
+.	O
+
+In	O
+sham	O
+-	O
+operated	O
+rats	O
+,	O
+rilmenidine	O
+or	O
+alpha	O
+-	O
+methyldopa	O
+elicited	O
+similar	O
+hypotension	B
+that	O
+lasted	O
+at	O
+least	O
+5	O
+h	O
+and	O
+was	O
+associated	O
+with	O
+reductions	O
+in	O
+standard	O
+deviation	O
+of	O
+mean	O
+arterial	O
+pressure	O
+.	O
+
+SDRR	O
+was	O
+reduced	O
+only	O
+by	O
+alpha	O
+-	O
+methyldopa	O
+.	O
+
+Ovx	O
+significantly	O
+enhanced	O
+the	O
+hypotensive	B
+response	O
+to	O
+alpha	O
+-	O
+methyldopa	O
+,	O
+in	O
+contrast	O
+to	O
+no	O
+effect	O
+on	O
+rilmenidine	O
+hypotension	B
+.	O
+
+The	O
+enhanced	O
+alpha	O
+-	O
+methyldopa	O
+hypotension	B
+in	O
+Ovx	O
+rats	O
+was	O
+paralleled	O
+with	O
+further	O
+reduction	O
+in	O
+SDRR	O
+and	O
+a	B
+reduced	I
+locomotor	I
+activity	I
+.	O
+
+Estrogen	O
+replacement	O
+(	O
+17beta	O
+-	O
+estradiol	O
+subcutaneous	O
+pellet	O
+,	O
+14	O
+.	O
+2	O
+microg	O
+/	O
+day	O
+,	O
+12	O
+wk	O
+)	O
+of	O
+Ovx	O
+rats	O
+restored	O
+the	O
+hemodynamic	O
+and	O
+locomotor	O
+effects	O
+of	O
+alpha	O
+-	O
+methyldopa	O
+to	O
+sham	O
+-	O
+operated	O
+levels	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+estrogen	O
+downregulates	O
+alpha2	O
+-	O
+but	O
+not	O
+I1	O
+-	O
+receptor	O
+-	O
+mediated	O
+hypotension	B
+and	O
+highlight	O
+a	O
+role	O
+for	O
+the	O
+cardiac	O
+autonomic	O
+control	O
+in	O
+alpha	O
+-	O
+methyldopa	O
+-	O
+estrogen	O
+interaction	O
+.	O
+
+Severe	O
+reversible	O
+left	B
+ventricular	I
+systolic	I
+and	I
+diastolic	I
+dysfunction	I
+due	O
+to	O
+accidental	O
+iatrogenic	O
+epinephrine	O
+overdose	B
+.	O
+
+Catecholamine	O
+-	O
+induced	O
+cardiomyopathy	B
+due	O
+to	O
+chronic	O
+excess	O
+of	O
+endogenous	O
+catecholamines	O
+has	O
+been	O
+recognized	O
+for	O
+decades	O
+as	O
+a	O
+clinical	O
+phenomenon	O
+.	O
+
+In	O
+contrast	O
+,	O
+reports	O
+of	O
+myocardial	B
+dysfunction	I
+due	O
+to	O
+acute	O
+iatrogenic	O
+overdose	B
+are	O
+rare	O
+.	O
+
+A	O
+35	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+whose	O
+cervix	O
+uteri	O
+was	O
+inadvertently	O
+injected	O
+with	O
+8	O
+mg	O
+of	O
+epinephrine	O
+developed	O
+myocardial	B
+stunning	I
+that	O
+was	O
+characterized	O
+by	O
+severe	O
+hemodynamic	O
+compromise	O
+,	O
+profound	O
+,	O
+albeit	O
+transient	O
+,	O
+left	B
+ventricular	I
+systolic	I
+and	I
+diastolic	I
+dysfunction	I
+,	O
+and	O
+only	O
+modestly	O
+elevated	O
+biochemical	O
+markers	O
+of	O
+myocardial	B
+necrosis	I
+.	O
+
+Our	O
+case	O
+illustrates	O
+the	O
+serious	O
+consequences	O
+of	O
+medical	O
+errors	O
+that	O
+can	O
+be	O
+avoided	O
+through	O
+improved	O
+medication	O
+labeling	O
+and	O
+staff	O
+supervision	O
+.	O
+
+Cardioprotective	O
+effect	O
+of	O
+tincture	O
+of	O
+Crataegus	O
+on	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+in	O
+rats	O
+.	O
+
+Tincture	O
+of	O
+Crataegus	O
+(	O
+TCR	O
+)	O
+,	O
+an	O
+alcoholic	O
+extract	O
+of	O
+the	O
+berries	O
+of	O
+hawthorn	O
+(	O
+Crataegus	O
+oxycantha	O
+)	O
+,	O
+is	O
+used	O
+in	O
+herbal	O
+and	O
+homeopathic	O
+medicine	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+done	O
+to	O
+investigate	O
+the	O
+protective	O
+effect	O
+of	O
+TCR	O
+on	O
+experimentally	O
+induced	O
+myocardial	B
+infarction	I
+in	O
+rats	O
+.	O
+
+Pretreatment	O
+of	O
+TCR	O
+,	O
+at	O
+a	O
+dose	O
+of	O
+0	O
+.	O
+5	O
+mL	O
+/	O
+100	O
+g	O
+bodyweight	O
+per	O
+day	O
+,	O
+orally	O
+for	O
+30	O
+days	O
+,	O
+prevented	O
+the	O
+increase	O
+in	O
+lipid	O
+peroxidation	O
+and	O
+activity	O
+of	O
+marker	O
+enzymes	O
+observed	O
+in	O
+isoproterenol	O
+-	O
+induced	O
+rats	O
+(	O
+85	O
+mg	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+s	O
+.	O
+c	O
+.	O
+for	O
+2	O
+days	O
+at	O
+an	O
+interval	O
+of	O
+24	O
+h	O
+)	O
+.	O
+
+TCR	O
+prevented	O
+the	O
+isoproterenol	O
+-	O
+induced	O
+decrease	O
+in	O
+antioxidant	O
+enzymes	O
+in	O
+the	O
+heart	O
+and	O
+increased	O
+the	O
+rate	O
+of	O
+ADP	O
+-	O
+stimulated	O
+oxygen	O
+uptake	O
+and	O
+respiratory	O
+coupling	O
+ratio	O
+.	O
+
+TCR	O
+protected	O
+against	O
+pathological	O
+changes	O
+induced	O
+by	O
+isoproterenol	O
+in	O
+rat	O
+heart	O
+.	O
+
+The	O
+results	O
+show	O
+that	O
+pretreatment	O
+with	O
+TCR	O
+may	O
+be	O
+useful	O
+in	O
+preventing	O
+the	O
+damage	O
+induced	O
+by	O
+isoproterenol	O
+in	O
+rat	O
+heart	O
+.	O
+
+Treatment	O
+of	O
+tinnitus	B
+by	O
+intratympanic	O
+instillation	O
+of	O
+lignocaine	O
+(	O
+lidocaine	O
+)	O
+2	O
+per	O
+cent	O
+through	O
+ventilation	O
+tubes	O
+.	O
+
+Idiopathic	B
+subjective	I
+tinnitus	I
+(	O
+IST	B
+)	O
+is	O
+one	O
+of	O
+the	O
+most	O
+obscure	O
+otological	O
+pathologies	O
+.	O
+
+This	O
+paper	O
+presents	O
+the	O
+results	O
+of	O
+treating	O
+IST	B
+by	O
+intratympanic	O
+instillation	O
+of	O
+lignocaine	O
+(	O
+lidocaine	O
+)	O
+2	O
+per	O
+cent	O
+through	O
+a	O
+grommet	O
+,	O
+for	O
+five	O
+weekly	O
+courses	O
+.	O
+
+Fifty	O
+-	O
+two	O
+patients	O
+suffering	O
+from	O
+intractable	O
+tinnitus	B
+entered	O
+this	O
+therapeutic	O
+trial	O
+,	O
+but	O
+only	O
+nine	O
+finished	O
+all	O
+five	O
+courses	O
+.	O
+
+In	O
+one	O
+patient	O
+,	O
+the	O
+tinnitus	B
+was	O
+almost	O
+completely	O
+abolished	O
+,	O
+but	O
+in	O
+all	O
+the	O
+nine	O
+patients	O
+the	O
+decompensated	O
+tinnitus	B
+changed	O
+to	O
+a	O
+compensated	O
+one	O
+.	O
+
+We	O
+suggest	O
+this	O
+mode	O
+of	O
+treatment	O
+for	O
+patients	O
+that	O
+were	O
+previously	O
+treated	O
+by	O
+drugs	O
+,	O
+acupuncture	O
+and	O
+biofeedback	O
+,	O
+with	O
+disappointing	O
+results	O
+.	O
+
+Patients	O
+should	O
+be	O
+warned	O
+about	O
+the	O
+side	O
+effects	O
+of	O
+vertigo	B
+and	O
+vomiting	B
+,	O
+which	O
+subsides	O
+gradually	O
+with	O
+every	O
+new	O
+instillation	O
+,	O
+and	O
+that	O
+the	O
+tinnitus	B
+may	O
+not	O
+disappear	O
+but	O
+will	O
+be	O
+alleviated	O
+,	O
+enabling	O
+them	O
+to	O
+cope	O
+more	O
+easily	O
+with	O
+the	O
+disease	O
+and	O
+lead	O
+a	O
+more	O
+normal	O
+life	O
+.	O
+
+The	O
+alpha3	O
+and	O
+beta4	O
+nicotinic	O
+acetylcholine	O
+receptor	O
+subunits	O
+are	O
+necessary	O
+for	O
+nicotine	O
+-	O
+induced	O
+seizures	B
+and	O
+hypolocomotion	B
+in	O
+mice	O
+.	O
+
+Binding	O
+of	O
+nicotine	O
+to	O
+nicotinic	O
+acetylcholine	O
+receptors	O
+(	O
+nAChRs	O
+)	O
+elicits	O
+a	O
+series	O
+of	O
+dose	O
+-	O
+dependent	O
+behaviors	O
+that	O
+go	O
+from	O
+altered	O
+exploration	O
+,	O
+sedation	O
+,	O
+and	O
+tremors	B
+,	O
+to	O
+seizures	B
+and	O
+death	B
+.	O
+
+nAChRs	O
+are	O
+pentameric	O
+ion	O
+channels	O
+usually	O
+composed	O
+of	O
+alpha	O
+and	O
+beta	O
+subunits	O
+.	O
+
+A	O
+gene	O
+cluster	O
+comprises	O
+the	O
+alpha3	O
+,	O
+alpha5	O
+and	O
+beta4	O
+subunits	O
+,	O
+which	O
+coassemble	O
+to	O
+form	O
+functional	O
+receptors	O
+.	O
+
+We	O
+examined	O
+the	O
+role	O
+of	O
+the	O
+beta4	O
+subunits	O
+in	O
+nicotine	O
+-	O
+induced	O
+seizures	B
+and	O
+hypolocomotion	B
+in	O
+beta4	O
+homozygous	O
+null	O
+(	O
+beta4	O
+-	O
+/	O
+-	O
+)	O
+and	O
+alpha3	O
+heterozygous	O
+(	O
++	O
+/	O
+-	O
+)	O
+mice	O
+.	O
+
+beta4	O
+-	O
+/	O
+-	O
+mice	O
+were	O
+less	O
+sensitive	O
+to	O
+the	O
+effects	O
+of	O
+nicotine	O
+both	O
+at	O
+low	O
+doses	O
+,	O
+measured	O
+as	O
+decreased	O
+exploration	O
+in	O
+an	O
+open	O
+field	O
+,	O
+and	O
+at	O
+high	O
+doses	O
+,	O
+measured	O
+as	O
+sensitivity	O
+to	O
+nicotine	O
+-	O
+induced	O
+seizures	B
+.	O
+
+Using	O
+in	O
+situ	O
+hybridization	O
+probes	O
+for	O
+the	O
+alpha3	O
+and	O
+alpha5	O
+subunits	O
+,	O
+we	O
+showed	O
+that	O
+alpha5	O
+mRNA	O
+levels	O
+are	O
+unchanged	O
+,	O
+whereas	O
+alpha3	O
+mRNA	O
+levels	O
+are	O
+selectively	O
+decreased	O
+in	O
+the	O
+mitral	O
+cell	O
+layer	O
+of	O
+the	O
+olfactory	O
+bulb	O
+,	O
+and	O
+the	O
+inferior	O
+and	O
+the	O
+superior	O
+colliculus	O
+of	O
+beta4	O
+-	O
+/	O
+-	O
+brains	O
+.	O
+
+alpha3	O
++	O
+/	O
+-	O
+mice	O
+were	O
+partially	O
+resistant	O
+to	O
+nicotine	O
+-	O
+induced	O
+seizures	B
+when	O
+compared	O
+to	O
+wild	O
+-	O
+type	O
+littermates	O
+.	O
+
+mRNA	O
+levels	O
+for	O
+the	O
+alpha5	O
+and	O
+the	O
+beta4	O
+subunits	O
+were	O
+unchanged	O
+in	O
+alpha3	O
++	O
+/	O
+-	O
+brains	O
+.	O
+
+Together	O
+,	O
+these	O
+results	O
+suggest	O
+that	O
+the	O
+beta4	O
+and	O
+the	O
+alpha3	O
+subunits	O
+are	O
+mediators	O
+of	O
+nicotine	O
+-	O
+induced	O
+seizures	B
+and	O
+hypolocomotion	B
+.	O
+
+The	O
+effects	O
+of	O
+sevoflurane	O
+on	O
+lidocaine	O
+-	O
+induced	O
+convulsions	B
+.	O
+
+The	O
+influence	O
+of	O
+sevoflurane	O
+on	O
+lidocaine	O
+-	O
+induced	O
+convulsions	B
+was	O
+studied	O
+in	O
+cats	O
+.	O
+
+The	O
+convulsive	B
+threshold	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+)	O
+was	O
+41	O
+.	O
+4	O
++	O
+/	O
+-	O
+6	O
+.	O
+5	O
+mg	O
+.	O
+
+l	O
+(	O
+-	O
+1	O
+)	O
+with	O
+lidocaine	O
+infusion	O
+(	O
+6	O
+mg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+min	O
+(	O
+-	O
+1	O
+)	O
+)	O
+,	O
+increasing	O
+significantly	O
+to	O
+66	O
+.	O
+6	O
++	O
+/	O
+-	O
+10	O
+.	O
+9	O
+mg	O
+.	O
+
+l	O
+(	O
+-	O
+1	O
+)	O
+when	O
+the	O
+end	O
+-	O
+tidal	O
+concentration	O
+of	O
+sevoflurane	O
+was	O
+0	O
+.	O
+8	O
+%	O
+.	O
+
+However	O
+,	O
+the	O
+threshold	O
+(	O
+61	O
+.	O
+6	O
++	O
+/	O
+-	O
+8	O
+.	O
+7	O
+mg	O
+.	O
+l	O
+(	O
+-	O
+1	O
+)	O
+)	O
+during	O
+1	O
+.	O
+6	O
+%	O
+sevoflurane	O
+was	O
+not	O
+significant	O
+from	O
+that	O
+during	O
+0	O
+.	O
+8	O
+%	O
+sevoflurane	O
+,	O
+indicating	O
+a	O
+celling	O
+effect	O
+.	O
+
+There	O
+was	O
+no	O
+significant	O
+difference	O
+in	O
+the	O
+convulsive	B
+threshold	O
+between	O
+sevoflurane	O
+and	O
+enflurane	O
+.	O
+
+The	O
+rise	O
+in	O
+blood	O
+pressure	O
+became	O
+less	O
+marked	O
+when	O
+higher	O
+concentrations	O
+of	O
+sevoflurane	O
+or	O
+enflurane	O
+were	O
+administered	O
+and	O
+the	O
+blood	O
+pressure	O
+at	O
+convulsions	B
+decreased	O
+significantly	O
+in	O
+1	O
+.	O
+6	O
+%	O
+sevoflurane	O
+,	O
+and	O
+in	O
+0	O
+.	O
+8	O
+%	O
+and	O
+1	O
+.	O
+6	O
+%	O
+enflurane	O
+.	O
+
+However	O
+,	O
+there	O
+was	O
+no	O
+significant	O
+difference	O
+in	O
+the	O
+lidocaine	O
+concentrations	O
+measured	O
+when	O
+the	O
+systolic	O
+blood	O
+pressure	O
+became	O
+70	O
+mmHg	O
+.	O
+
+Apamin	O
+,	O
+a	O
+selective	O
+blocker	O
+of	O
+calcium	O
+-	O
+dependent	O
+potassium	O
+channels	O
+,	O
+was	O
+administered	O
+intracerebroventricularly	O
+in	O
+rats	O
+anesthetized	O
+with	O
+0	O
+.	O
+8	O
+%	O
+sevoflurane	O
+to	O
+investigate	O
+the	O
+mechanism	O
+of	O
+the	O
+anticonvulsive	O
+effects	O
+.	O
+
+Apamin	O
+(	O
+10	O
+ng	O
+)	O
+had	O
+a	O
+tendency	O
+to	O
+decrease	O
+the	O
+convulsive	B
+threshold	O
+(	O
+21	O
+.	O
+6	O
++	O
+/	O
+-	O
+2	O
+.	O
+2	O
+to	O
+19	O
+.	O
+9	O
++	O
+/	O
+-	O
+2	O
+.	O
+5	O
+mg	O
+.	O
+l	O
+(	O
+-	O
+1	O
+)	O
+)	O
+but	O
+this	O
+was	O
+not	O
+statistically	O
+significant	O
+.	O
+
+It	O
+is	O
+suggested	O
+that	O
+sevoflurane	O
+reduces	O
+the	O
+convulsive	B
+effect	O
+of	O
+lidocaine	O
+toxicity	B
+but	O
+carries	O
+some	O
+risk	O
+due	O
+to	O
+circulatory	O
+depression	B
+.	O
+
+Cardiac	B
+toxicity	I
+observed	O
+in	O
+association	O
+with	O
+high	O
+-	O
+dose	O
+cyclophosphamide	O
+-	O
+based	O
+chemotherapy	O
+for	O
+metastatic	O
+breast	B
+cancer	I
+.	O
+
+INTRODUCTION	O
+:	O
+Cyclophosphamide	O
+is	O
+an	O
+alkylating	O
+agent	O
+given	O
+frequently	O
+as	O
+a	O
+component	O
+of	O
+many	O
+conditioning	O
+regimens	O
+.	O
+
+In	O
+high	O
+doses	O
+,	O
+its	O
+nonhematological	O
+dose	O
+-	O
+limiting	O
+toxicity	B
+is	O
+cardiomyopathy	B
+.	O
+
+STUDY	O
+DESIGN	O
+:	O
+We	O
+combined	O
+paclitaxel	O
+,	O
+melphalan	O
+and	O
+high	O
+-	O
+dose	O
+cyclophosphamide	O
+,	O
+thiotepa	O
+,	O
+and	O
+carboplatin	O
+in	O
+a	O
+triple	O
+sequential	O
+high	O
+-	O
+dose	O
+regimen	O
+for	O
+patients	O
+with	O
+metastatic	O
+breast	B
+cancer	I
+.	O
+
+Analysis	O
+was	O
+performed	O
+on	O
+61	O
+women	O
+with	O
+chemotherapy	O
+-	O
+responsive	O
+metastatic	O
+breast	B
+cancer	I
+receiving	O
+96	O
+-	O
+h	O
+infusional	O
+cyclophosphamide	O
+as	O
+part	O
+of	O
+a	O
+triple	O
+sequential	O
+high	O
+-	O
+dose	O
+regimen	O
+to	O
+assess	O
+association	O
+between	O
+presence	O
+of	O
+peritransplant	O
+congestive	B
+heart	I
+failure	I
+(	O
+CHF	B
+)	O
+and	O
+the	O
+following	O
+pretreatment	O
+characteristics	O
+:	O
+presence	O
+of	O
+electrocardiogram	O
+(	O
+EKG	O
+)	O
+abnormalities	O
+,	O
+age	O
+,	O
+hypertension	B
+,	O
+prior	O
+cardiac	O
+history	O
+,	O
+smoking	O
+,	O
+diabetes	B
+mellitus	I
+,	O
+prior	O
+use	O
+of	O
+anthracyclines	O
+,	O
+and	O
+left	O
+-	O
+sided	O
+chest	O
+irradiation	O
+.	O
+
+RESULTS	O
+:	O
+Six	O
+of	O
+61	O
+women	O
+(	O
+10	O
+%	O
+)	O
+developed	O
+clinically	O
+reversible	O
+grade	O
+3	O
+CHF	B
+following	O
+infusional	O
+cyclophosphamide	O
+with	O
+a	O
+median	O
+percent	O
+decline	O
+in	O
+ejection	O
+fraction	O
+of	O
+31	O
+%	O
+.	O
+
+Incidence	O
+of	O
+transient	O
+cyclophosphamide	O
+-	O
+related	O
+cardiac	B
+toxicity	I
+(	O
+10	O
+%	O
+)	O
+is	O
+comparable	O
+to	O
+previous	O
+recorded	O
+literature	O
+.	O
+
+Older	O
+age	O
+was	O
+significantly	O
+correlated	O
+with	O
+the	O
+CHF	B
+development	O
+;	O
+with	O
+median	O
+ages	O
+for	O
+the	O
+entire	O
+group	O
+and	O
+for	O
+patients	O
+developing	O
+CHF	B
+of	O
+45	O
+and	O
+59	O
+,	O
+respectively	O
+.	O
+
+No	O
+association	O
+was	O
+found	O
+with	O
+other	O
+pretreatment	O
+characteristics	O
+.	O
+
+CONCLUSIONS	O
+:	O
+As	O
+a	O
+result	O
+of	O
+these	O
+findings	O
+,	O
+oncologists	O
+should	O
+carefully	O
+monitor	O
+fluid	O
+balance	O
+in	O
+older	O
+patients	O
+.	O
+
+Routine	O
+EKG	O
+monitoring	O
+during	O
+infusional	O
+cyclophosphamide	O
+did	O
+not	O
+predict	O
+CHF	B
+development	O
+.	O
+
+Tremor	B
+side	O
+effects	O
+of	O
+salbutamol	O
+,	O
+quantified	O
+by	O
+a	O
+laser	O
+pointer	O
+technique	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+study	O
+tremor	B
+side	O
+effects	O
+of	O
+salbutamol	O
+an	O
+easily	O
+applicable	O
+,	O
+quick	O
+and	O
+low	O
+-	O
+priced	O
+method	O
+is	O
+needed	O
+.	O
+
+A	O
+new	O
+method	O
+using	O
+a	O
+commercially	O
+available	O
+,	O
+pen	O
+-	O
+shaped	O
+laser	O
+pointer	O
+was	O
+developed	O
+.	O
+
+Aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+determine	O
+sensitivity	O
+,	O
+reproducibility	O
+,	O
+reference	O
+values	O
+and	O
+the	O
+agreement	O
+with	O
+a	O
+questionnaire	O
+.	O
+
+METHODS	O
+:	O
+Tremor	B
+was	O
+measured	O
+using	O
+a	O
+laser	O
+pointer	O
+technique	O
+.	O
+
+To	O
+determine	O
+sensitivity	O
+we	O
+assessed	O
+tremor	B
+in	O
+44	O
+patients	O
+with	O
+obstructive	B
+lung	I
+disease	I
+after	O
+administration	O
+of	O
+cumulative	O
+doses	O
+of	O
+salbutamol	O
+.	O
+
+Subjects	O
+were	O
+asked	O
+to	O
+aim	O
+at	O
+the	O
+centre	O
+of	O
+a	O
+target	O
+,	O
+subdivided	O
+in	O
+concentric	O
+circles	O
+,	O
+from	O
+5	O
+m	O
+distance	O
+.	O
+
+The	O
+circle	O
+in	O
+which	O
+the	O
+participant	O
+succeeded	O
+to	O
+aim	O
+was	O
+recorded	O
+in	O
+millimetres	O
+radius	O
+.	O
+
+In	O
+another	O
+series	O
+of	O
+measurements	O
+,	O
+reproducibility	O
+and	O
+reference	O
+values	O
+of	O
+the	O
+tremor	B
+was	O
+assessed	O
+in	O
+65	O
+healthy	O
+subjects	O
+in	O
+three	O
+sessions	O
+,	O
+at	O
+9	O
+a	O
+.	O
+m	O
+.	O
+,	O
+4	O
+p	O
+.	O
+m	O
+.	O
+and	O
+9	O
+a	O
+.	O
+m	O
+.	O
+,	O
+respectively	O
+,	O
+1	O
+week	O
+later	O
+.	O
+
+Postural	O
+tremor	B
+was	O
+measured	O
+with	O
+the	O
+arm	O
+horizontally	O
+outstretched	O
+rest	O
+tremor	B
+with	O
+the	O
+arm	O
+supported	O
+by	O
+an	O
+armrest	O
+and	O
+finally	O
+tremor	B
+was	O
+measured	O
+after	O
+holding	O
+a	O
+2	O
+-	O
+kg	O
+weight	O
+until	O
+exhaustion	O
+.	O
+
+Inter	O
+-	O
+observer	O
+variability	O
+was	O
+measured	O
+in	O
+a	O
+series	O
+of	O
+10	O
+healthy	O
+subjects	O
+.	O
+
+Tremor	B
+was	O
+measured	O
+simultaneously	O
+by	O
+two	O
+independent	O
+observers	O
+.	O
+
+RESULTS	O
+:	O
+Salbutamol	O
+significantly	O
+increased	O
+tremor	B
+severity	O
+in	O
+patients	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+way	O
+.	O
+
+Within	O
+healthy	O
+adults	O
+no	O
+age	O
+-	O
+dependency	O
+could	O
+be	O
+found	O
+(	O
+b	O
+=	O
+0	O
+.	O
+262	O
+mm	O
+/	O
+year	O
+;	O
+P	O
+=	O
+0	O
+.	O
+72	O
+)	O
+.	O
+
+There	O
+was	O
+no	O
+agreement	O
+between	O
+the	O
+questionnaire	O
+and	O
+tremor	B
+severity	O
+(	O
+r	O
+=	O
+0	O
+.	O
+093	O
+;	O
+P	O
+=	O
+0	O
+.	O
+53	O
+)	O
+.	O
+
+Postural	O
+tremor	B
+showed	O
+no	O
+significant	O
+difference	O
+between	O
+the	O
+first	O
+and	O
+third	O
+session	O
+(	O
+P	O
+=	O
+0	O
+.	O
+07	O
+)	O
+.	O
+
+Support	O
+of	O
+the	O
+arm	O
+decreased	O
+tremor	B
+severity	O
+,	O
+exhaustion	O
+increased	O
+tremor	B
+severity	O
+significantly	O
+.	O
+
+A	O
+good	O
+agreement	O
+was	O
+found	O
+between	O
+two	O
+independent	O
+observers	O
+(	O
+interclass	O
+correlation	O
+coefficient	O
+0	O
+.	O
+72	O
+)	O
+.	O
+
+DISCUSSION	O
+:	O
+Quantifying	O
+tremor	B
+by	O
+using	O
+an	O
+inexpensive	O
+laser	O
+pointer	O
+is	O
+,	O
+with	O
+the	O
+exception	O
+of	O
+children	O
+(	O
+<	O
+12	O
+years	O
+)	O
+a	O
+sensitive	O
+and	O
+reproducible	O
+method	O
+.	O
+
+Safety	O
+and	O
+adverse	O
+effects	O
+associated	O
+with	O
+raloxifene	O
+:	O
+multiple	O
+outcomes	O
+of	O
+raloxifene	O
+evaluation	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+examine	O
+the	O
+effect	O
+of	O
+raloxifene	O
+on	O
+major	O
+adverse	O
+events	O
+that	O
+occur	O
+with	O
+postmenopausal	O
+estrogen	O
+therapy	O
+or	O
+tamoxifen	O
+.	O
+
+METHODS	O
+:	O
+The	O
+Multiple	O
+Outcomes	O
+of	O
+Raloxifene	O
+Evaluation	O
+,	O
+a	O
+multicenter	O
+,	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+trial	O
+,	O
+enrolled	O
+7	O
+,	O
+705	O
+postmenopausal	O
+women	O
+with	O
+osteoporosis	B
+.	O
+
+Women	O
+were	O
+randomly	O
+assigned	O
+to	O
+raloxifene	O
+60	O
+mg	O
+/	O
+d	O
+or	O
+120	O
+mg	O
+/	O
+d	O
+or	O
+placebo	O
+.	O
+
+Outcomes	O
+included	O
+venous	B
+thromboembolism	I
+,	O
+cataracts	B
+,	O
+gallbladder	B
+disease	I
+,	O
+and	O
+endometrial	B
+hyperplasia	I
+or	I
+cancer	I
+.	O
+
+RESULTS	O
+:	O
+During	O
+a	O
+mean	O
+follow	O
+-	O
+up	O
+of	O
+3	O
+.	O
+3	O
+years	O
+,	O
+raloxifene	O
+was	O
+associated	O
+with	O
+an	O
+increased	O
+risk	O
+for	O
+venous	B
+thromboembolism	I
+(	O
+relative	O
+risk	O
+[	O
+RR	O
+]	O
+2	O
+.	O
+1	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+1	O
+.	O
+2	O
+-	O
+3	O
+.	O
+8	O
+)	O
+.	O
+
+The	O
+excess	O
+event	O
+rate	O
+was	O
+1	O
+.	O
+8	O
+per	O
+1	O
+,	O
+000	O
+woman	O
+-	O
+years	O
+(	O
+95	O
+%	O
+CI	O
+-	O
+0	O
+.	O
+5	O
+-	O
+4	O
+.	O
+1	O
+)	O
+,	O
+and	O
+the	O
+number	O
+needed	O
+to	O
+treat	O
+to	O
+cause	O
+1	O
+event	O
+was	O
+170	O
+(	O
+95	O
+%	O
+CI	O
+100	O
+-	O
+582	O
+)	O
+over	O
+3	O
+.	O
+3	O
+years	O
+.	O
+
+Risk	O
+in	O
+the	O
+raloxifene	O
+group	O
+was	O
+higher	O
+than	O
+in	O
+the	O
+placebo	O
+group	O
+for	O
+the	O
+first	O
+2	O
+years	O
+,	O
+but	O
+decreased	O
+to	O
+about	O
+the	O
+same	O
+rate	O
+as	O
+in	O
+the	O
+placebo	O
+group	O
+thereafter	O
+.	O
+
+Raloxifene	O
+did	O
+not	O
+increase	O
+risk	O
+for	O
+cataracts	B
+(	O
+RR	O
+0	O
+.	O
+9	O
+;	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+8	O
+-	O
+1	O
+.	O
+1	O
+)	O
+,	O
+gallbladder	B
+disease	I
+(	O
+RR	O
+1	O
+.	O
+0	O
+;	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+7	O
+-	O
+1	O
+.	O
+3	O
+)	O
+,	O
+endometrial	B
+hyperplasia	I
+(	O
+RR	O
+1	O
+.	O
+3	O
+;	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+4	O
+-	O
+5	O
+.	O
+1	O
+)	O
+,	O
+or	O
+endometrial	B
+cancer	I
+(	O
+RR	O
+0	O
+.	O
+9	O
+;	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+3	O
+-	O
+2	O
+.	O
+7	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+Raloxifene	O
+was	O
+associated	O
+with	O
+an	O
+increased	O
+risk	O
+for	O
+venous	B
+thromboembolism	I
+,	O
+but	O
+there	O
+was	O
+no	O
+increased	O
+risk	O
+for	O
+cataracts	B
+,	O
+gallbladder	B
+disease	I
+,	O
+endometrial	B
+hyperplasia	I
+,	O
+or	O
+endometrial	B
+cancer	I
+.	O
+
+LEVEL	O
+OF	O
+EVIDENCE	O
+:	O
+I	O
+
+Optimization	O
+of	O
+levodopa	O
+therapy	O
+.	O
+
+While	O
+there	O
+is	O
+no	O
+single	O
+correct	O
+starting	O
+dose	O
+for	O
+levodopa	O
+therapy	O
+,	O
+many	O
+individuals	O
+can	O
+be	O
+started	O
+on	O
+either	O
+the	O
+25	O
+/	O
+100	O
+or	O
+controlled	O
+-	O
+release	O
+formula	O
+,	O
+following	O
+the	O
+general	O
+rule	O
+not	O
+to	O
+attempt	O
+to	O
+titrate	O
+carbidopa	O
+-	O
+levodopa	O
+to	O
+the	O
+point	O
+of	O
+"	O
+normality	O
+,	O
+"	O
+which	O
+can	O
+lead	O
+to	O
+toxicity	B
+.	O
+
+The	O
+physician	O
+should	O
+also	O
+determine	O
+the	O
+proper	O
+use	O
+of	O
+any	O
+adjunctive	O
+medications	O
+;	O
+such	O
+combined	O
+therapy	O
+has	O
+become	O
+the	O
+standard	O
+approach	O
+to	O
+treatment	O
+.	O
+
+Following	O
+the	O
+initial	O
+period	O
+of	O
+therapy	O
+,	O
+emerging	O
+difficulties	O
+require	O
+a	O
+reassessment	O
+of	O
+therapeutic	O
+approaches	O
+,	O
+such	O
+as	O
+dosage	O
+adjustment	O
+or	O
+introduction	O
+of	O
+a	O
+dopamine	O
+agonist	O
+.	O
+
+Other	O
+possible	O
+adverse	O
+effects	O
+-	O
+-	O
+such	O
+as	O
+gastrointestinal	B
+disorders	I
+,	O
+orthostatic	B
+hypotension	I
+,	O
+levodopa	O
+-	O
+induced	O
+psychosis	B
+,	O
+sleep	B
+disturbances	I
+or	O
+parasomnias	B
+,	O
+or	O
+drug	O
+interactions	O
+-	O
+-	O
+also	O
+require	O
+carefully	O
+monitored	O
+individual	O
+treatment	O
+.	O
+
+Nonpharmacologic	O
+concerns	O
+can	O
+help	O
+the	O
+Parkinson	B
+'	I
+s	I
+disease	I
+patient	O
+achieve	O
+and	O
+maintain	O
+optimal	O
+functioning	O
+,	O
+including	O
+daily	O
+exercise	O
+,	O
+physical	O
+therapy	O
+,	O
+and	O
+involvement	O
+with	O
+support	O
+groups	O
+.	O
+
+Long	O
+term	O
+audiological	O
+evaluation	O
+of	O
+beta	B
+-	I
+thalassemic	I
+patients	O
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+identify	O
+the	O
+incidence	O
+and	O
+to	O
+monitor	O
+the	O
+progression	O
+of	O
+hearing	B
+loss	I
+in	O
+children	O
+and	O
+young	O
+adults	O
+with	O
+beta	B
+-	I
+thalassemia	I
+major	O
+.	O
+
+METHODS	O
+:	O
+One	O
+hundred	O
+and	O
+four	O
+(	O
+104	O
+)	O
+patients	O
+aged	O
+6	O
+-	O
+35	O
+years	O
+(	O
+mean	O
+17	O
+,	O
+2	O
+years	O
+)	O
+participated	O
+in	O
+the	O
+study	O
+.	O
+
+All	O
+patients	O
+were	O
+on	O
+a	O
+regular	O
+transfusion	O
+-	O
+chelation	O
+program	O
+maintaining	O
+a	O
+mean	O
+hemoglobin	O
+level	O
+of	O
+9	O
+.	O
+5	O
+gr	O
+/	O
+dl	O
+.	O
+
+Subjects	O
+were	O
+receiving	O
+desferrioxamine	O
+(	O
+DFO	O
+)	O
+chelation	O
+treatment	O
+with	O
+a	O
+mean	O
+daily	O
+dose	O
+of	O
+50	O
+-	O
+60	O
+mg	O
+/	O
+kg	O
+,	O
+5	O
+-	O
+6	O
+days	O
+a	O
+week	O
+during	O
+the	O
+first	O
+six	O
+years	O
+of	O
+the	O
+study	O
+,	O
+which	O
+was	O
+then	O
+reduced	O
+to	O
+40	O
+-	O
+50	O
+mg	O
+/	O
+kg	O
+for	O
+the	O
+following	O
+eight	O
+years	O
+.	O
+
+Patients	O
+were	O
+followed	O
+for	O
+8	O
+-	O
+14	O
+years	O
+.	O
+
+RESULTS	O
+:	O
+Overall	O
+,	O
+21	O
+out	O
+of	O
+104	O
+patients	O
+(	O
+20	O
+.	O
+2	O
+%	O
+)	O
+presented	O
+with	O
+high	O
+frequency	O
+sensorineural	B
+hearing	I
+loss	I
+(	O
+SNHL	B
+)	O
+,	O
+either	O
+unilateral	O
+or	O
+bilateral	O
+.	O
+
+No	O
+ototoxic	B
+factor	O
+,	O
+other	O
+than	O
+DFO	O
+,	O
+was	O
+present	O
+in	O
+any	O
+of	O
+the	O
+patients	O
+.	O
+
+Patients	O
+with	O
+SNHL	B
+presented	O
+with	O
+relatively	O
+lower	O
+serum	O
+ferritin	O
+levels	O
+than	O
+those	O
+with	O
+normal	O
+hearing	O
+,	O
+however	O
+,	O
+no	O
+statistically	O
+significant	O
+difference	O
+was	O
+observed	O
+.	O
+
+Subjects	O
+with	O
+SNHL	B
+were	O
+submitted	O
+to	O
+DFO	O
+reduction	O
+or	O
+temporary	O
+withdrawal	O
+.	O
+
+Following	O
+intervention	O
+,	O
+7	O
+out	O
+of	O
+21	O
+affected	O
+patients	O
+recovered	O
+,	O
+10	O
+remained	O
+stable	O
+and	O
+4	O
+demonstrated	O
+aggravation	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+findings	O
+are	O
+indicative	O
+of	O
+DFO	O
+'	O
+s	O
+contributing	O
+role	O
+in	O
+the	O
+development	O
+of	O
+hearing	B
+impairment	I
+.	O
+
+Regular	O
+audiologic	O
+evaluation	O
+is	O
+imperative	O
+in	O
+all	O
+thalassemic	B
+patients	O
+so	O
+that	O
+early	O
+changes	O
+may	O
+be	O
+recognized	O
+and	O
+treatment	O
+may	O
+be	O
+judiciously	O
+adjusted	O
+in	O
+order	O
+to	O
+prevent	O
+or	O
+reverse	O
+hearing	B
+impairment	I
+.	O
+
+Individual	O
+differences	O
+in	O
+renal	O
+ACE	O
+activity	O
+in	O
+healthy	O
+rats	O
+predict	O
+susceptibility	O
+to	O
+adriamycin	O
+-	O
+induced	O
+renal	B
+damage	I
+.	O
+
+BACKGROUND	O
+:	O
+In	O
+man	O
+,	O
+differences	O
+in	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+levels	O
+,	O
+related	O
+to	O
+ACE	O
+(	O
+I	O
+/	O
+D	O
+)	O
+genotype	O
+,	O
+are	O
+associated	O
+with	O
+renal	O
+prognosis	O
+.	O
+
+This	O
+raises	O
+the	O
+hypothesis	O
+that	O
+individual	O
+differences	O
+in	O
+renal	O
+ACE	O
+activity	O
+are	O
+involved	O
+in	O
+renal	O
+susceptibility	O
+to	O
+inflicted	O
+damage	O
+.	O
+
+Therefore	O
+,	O
+we	O
+studied	O
+the	O
+predictive	O
+effect	O
+of	O
+renal	O
+ACE	O
+activity	O
+for	O
+the	O
+severity	O
+of	O
+renal	B
+damage	I
+induced	O
+by	O
+a	O
+single	O
+injection	O
+of	O
+adriamycin	O
+in	O
+rats	O
+.	O
+
+METHODS	O
+:	O
+Renal	O
+ACE	O
+activity	O
+(	O
+Hip	O
+-	O
+His	O
+-	O
+Leu	O
+cleavage	O
+by	O
+cortical	O
+homogenates	O
+)	O
+was	O
+determined	O
+by	O
+renal	O
+biopsy	O
+in	O
+27	O
+adult	O
+male	O
+Wistar	O
+rats	O
+.	O
+
+After	O
+1	O
+week	O
+of	O
+recovery	O
+,	O
+proteinuria	B
+was	O
+induced	O
+by	O
+adriamycin	O
+[	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+intravenously	O
+(	O
+i	O
+.	O
+v	O
+.	O
+)	O
+n	O
+=	O
+18	O
+;	O
+controls	O
+,	O
+saline	O
+i	O
+.	O
+v	O
+.	O
+n	O
+=	O
+9	O
+]	O
+.	O
+
+Proteinuria	B
+was	O
+measured	O
+every	O
+2	O
+weeks	O
+.	O
+
+After	O
+12	O
+weeks	O
+,	O
+rats	O
+were	O
+sacrificed	O
+and	O
+their	O
+kidneys	O
+harvested	O
+.	O
+
+RESULTS	O
+:	O
+As	O
+anticipated	O
+,	O
+adriamycin	O
+elicited	O
+nephrotic	B
+range	O
+proteinuria	B
+,	O
+renal	B
+interstitial	I
+damage	I
+and	O
+mild	O
+focal	B
+glomerulosclerosis	I
+.	O
+
+Baseline	O
+renal	O
+ACE	O
+positively	O
+correlated	O
+with	O
+the	O
+relative	O
+rise	O
+in	O
+proteinuria	B
+after	O
+adriamycin	O
+(	O
+r	O
+=	O
+0	O
+.	O
+62	O
+,	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+,	O
+renal	O
+interstitial	O
+alpha	O
+-	O
+smooth	O
+muscle	O
+actin	O
+(	O
+r	O
+=	O
+0	O
+.	O
+49	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+,	O
+interstitial	O
+macrophage	O
+influx	O
+(	O
+r	O
+=	O
+0	O
+.	O
+56	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+,	O
+interstitial	O
+collagen	O
+III	O
+(	O
+r	O
+=	O
+0	O
+.	O
+53	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+,	O
+glomerular	O
+alpha	O
+-	O
+smooth	O
+muscle	O
+actin	O
+(	O
+r	O
+=	O
+0	O
+.	O
+74	O
+,	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+and	O
+glomerular	O
+desmin	O
+(	O
+r	O
+=	O
+0	O
+.	O
+48	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Baseline	O
+renal	O
+ACE	O
+did	O
+not	O
+correlate	O
+with	O
+focal	B
+glomerulosclerosis	I
+(	O
+r	O
+=	O
+0	O
+.	O
+22	O
+,	O
+NS	O
+)	O
+.	O
+
+In	O
+controls	O
+,	O
+no	O
+predictive	O
+values	O
+for	O
+renal	O
+parameters	O
+were	O
+observed	O
+.	O
+
+CONCLUSION	O
+:	O
+Individual	O
+differences	O
+in	O
+renal	O
+ACE	O
+activity	O
+predict	O
+the	O
+severity	O
+of	O
+adriamycin	O
+-	O
+induced	O
+renal	B
+damage	I
+in	O
+this	O
+outbred	O
+rat	O
+strain	O
+.	O
+
+This	O
+supports	O
+the	O
+assumption	O
+that	O
+differences	O
+in	O
+renal	O
+ACE	O
+activity	O
+predispose	O
+to	O
+a	O
+less	O
+favourable	O
+course	O
+of	O
+renal	B
+damage	I
+.	O
+
+Recurrent	O
+acute	O
+interstitial	B
+nephritis	I
+induced	O
+by	O
+azithromycin	O
+.	O
+
+A	O
+14	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+is	O
+reported	O
+with	O
+recurrent	O
+,	O
+azithromycin	O
+-	O
+induced	O
+,	O
+acute	O
+interstitial	B
+nephritis	I
+.	O
+
+The	O
+second	O
+episode	O
+was	O
+more	O
+severe	O
+than	O
+the	O
+first	O
+;	O
+and	O
+although	O
+both	O
+were	O
+treated	O
+with	O
+intensive	O
+corticosteroid	O
+therapy	O
+,	O
+renal	O
+function	O
+remained	O
+impaired	O
+.	O
+
+Although	O
+most	O
+cases	O
+of	O
+antibiotic	O
+induced	O
+acute	O
+interstitial	B
+nephritis	I
+are	O
+benign	O
+and	O
+self	O
+-	O
+limited	O
+,	O
+some	O
+patients	O
+are	O
+at	O
+risk	O
+for	O
+permanent	O
+renal	B
+injury	I
+.	O
+
+Spironolactone	O
+-	O
+induced	O
+renal	B
+insufficiency	I
+and	O
+hyperkalemia	B
+in	O
+patients	O
+with	O
+heart	B
+failure	I
+.	O
+
+BACKGROUND	O
+:	O
+A	O
+previous	O
+randomized	O
+controlled	O
+trial	O
+evaluating	O
+the	O
+use	O
+of	O
+spironolactone	O
+in	O
+heart	B
+failure	I
+patients	O
+reported	O
+a	O
+low	O
+risk	O
+of	O
+hyperkalemia	B
+(	O
+2	O
+%	O
+)	O
+and	O
+renal	B
+insufficiency	I
+(	O
+0	O
+%	O
+)	O
+.	O
+
+Because	O
+treatments	O
+for	O
+heart	B
+failure	I
+have	O
+changed	O
+since	O
+the	O
+benefits	O
+of	O
+spironolactone	O
+were	O
+reported	O
+,	O
+the	O
+prevalence	O
+of	O
+these	O
+complications	O
+may	O
+differ	O
+in	O
+current	O
+clinical	O
+practice	O
+.	O
+
+We	O
+therefore	O
+sought	O
+to	O
+determine	O
+the	O
+prevalence	O
+and	O
+clinical	O
+associations	O
+of	O
+hyperkalemia	B
+and	O
+renal	B
+insufficiency	I
+in	O
+heart	B
+failure	I
+patients	O
+treated	O
+with	O
+spironolactone	O
+.	O
+
+METHODS	O
+:	O
+We	O
+performed	O
+a	O
+case	O
+control	O
+study	O
+of	O
+heart	B
+failure	I
+patients	O
+treated	O
+with	O
+spironolactone	O
+in	O
+our	O
+clinical	O
+practice	O
+.	O
+
+Cases	O
+were	O
+patients	O
+who	O
+developed	O
+hyperkalemia	B
+(	O
+K	O
+(	O
++	O
+)	O
+>	O
+5	O
+.	O
+0	O
+mEq	O
+/	O
+L	O
+)	O
+or	O
+renal	B
+insufficiency	I
+(	O
+Cr	O
+>	O
+or	O
+=	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+dL	O
+)	O
+,	O
+and	O
+they	O
+were	O
+compared	O
+to	O
+2	O
+randomly	O
+selected	O
+controls	O
+per	O
+case	O
+.	O
+
+Clinical	O
+characteristics	O
+,	O
+medications	O
+,	O
+and	O
+serum	O
+chemistries	O
+at	O
+baseline	O
+and	O
+follow	O
+-	O
+up	O
+time	O
+periods	O
+were	O
+compared	O
+.	O
+
+RESULTS	O
+:	O
+Sixty	O
+-	O
+seven	O
+of	O
+926	O
+patients	O
+(	O
+7	O
+.	O
+2	O
+%	O
+)	O
+required	O
+discontinuation	O
+of	O
+spironolactone	O
+due	O
+to	O
+hyperkalemia	B
+(	O
+n	O
+=	O
+33	O
+)	O
+or	O
+renal	B
+failure	I
+(	O
+n	O
+=	O
+34	O
+)	O
+.	O
+
+Patients	O
+who	O
+developed	O
+hyperkalemia	B
+were	O
+older	O
+and	O
+more	O
+likely	O
+to	O
+have	O
+diabetes	B
+,	O
+had	O
+higher	O
+baseline	O
+serum	O
+potassium	O
+levels	O
+and	O
+lower	O
+baseline	O
+potassium	O
+supplement	O
+doses	O
+,	O
+and	O
+were	O
+more	O
+likely	O
+to	O
+be	O
+treated	O
+with	O
+beta	O
+-	O
+blockers	O
+than	O
+controls	O
+(	O
+n	O
+=	O
+134	O
+)	O
+.	O
+
+Patients	O
+who	O
+developed	O
+renal	B
+insufficiency	I
+had	O
+lower	O
+baseline	O
+body	O
+weight	O
+and	O
+higher	O
+baseline	O
+serum	O
+creatinine	O
+,	O
+required	O
+higher	O
+doses	O
+of	O
+loop	O
+diuretics	O
+,	O
+and	O
+were	O
+more	O
+likely	O
+to	O
+be	O
+treated	O
+with	O
+thiazide	O
+diuretics	O
+than	O
+controls	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Spironolactone	O
+-	O
+induced	O
+hyperkalemia	B
+and	O
+renal	B
+insufficiency	I
+are	O
+more	O
+common	O
+in	O
+our	O
+clinical	O
+experience	O
+than	O
+reported	O
+previously	O
+.	O
+
+This	O
+difference	O
+is	O
+explained	O
+by	O
+patient	O
+comorbidities	O
+and	O
+more	O
+frequent	O
+use	O
+of	O
+beta	O
+-	O
+blockers	O
+.	O
+
+Acute	O
+reserpine	O
+and	O
+subchronic	O
+haloperidol	O
+treatments	O
+change	O
+synaptosomal	O
+brain	O
+glutamate	O
+uptake	O
+and	O
+elicit	O
+orofacial	B
+dyskinesia	I
+in	O
+rats	O
+.	O
+
+Reserpine	O
+-	O
+and	O
+haloperidol	O
+-	O
+induced	O
+orofacial	B
+dyskinesia	I
+are	O
+putative	O
+animal	O
+models	O
+of	O
+tardive	B
+dyskinesia	I
+(	O
+TD	B
+)	O
+whose	O
+pathophysiology	O
+has	O
+been	O
+related	O
+to	O
+free	O
+radical	O
+generation	O
+and	O
+oxidative	O
+stress	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+the	O
+authors	O
+induced	O
+orofacial	B
+dyskinesia	I
+by	O
+acute	O
+reserpine	O
+and	O
+subchronic	O
+haloperidol	O
+administration	O
+to	O
+rats	O
+.	O
+
+Reserpine	O
+injection	O
+(	O
+one	O
+dose	O
+of	O
+1	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+every	O
+other	O
+day	O
+for	O
+3	O
+days	O
+caused	O
+a	O
+significant	O
+increase	O
+in	O
+vacuous	O
+chewing	O
+,	O
+tongue	O
+protrusion	O
+and	O
+duration	O
+of	O
+facial	O
+twitching	O
+,	O
+compared	O
+to	O
+the	O
+control	O
+.	O
+
+Haloperidol	O
+administration	O
+(	O
+one	O
+dose	O
+of	O
+12	O
+mg	O
+/	O
+kg	O
+once	O
+a	O
+week	O
+s	O
+.	O
+c	O
+.	O
+)	O
+for	O
+4	O
+weeks	O
+caused	O
+an	O
+increase	O
+in	O
+vacuous	O
+chewing	O
+,	O
+tongue	O
+protrusion	O
+and	O
+duration	O
+of	O
+facial	O
+twitching	O
+observed	O
+in	O
+four	O
+weekly	O
+evaluations	O
+.	O
+
+After	O
+the	O
+treatments	O
+and	O
+behavioral	O
+observation	O
+,	O
+glutamate	O
+uptake	O
+by	O
+segments	O
+of	O
+the	O
+brain	O
+was	O
+analyzed	O
+.	O
+
+A	O
+decreased	O
+glutamate	O
+uptake	O
+was	O
+observed	O
+in	O
+the	O
+subcortical	O
+parts	O
+of	O
+animals	O
+treated	O
+with	O
+reserpine	O
+and	O
+haloperidol	O
+,	O
+compared	O
+to	O
+the	O
+control	O
+.	O
+
+Importantly	O
+,	O
+a	O
+decrease	O
+in	O
+glutamate	O
+uptake	O
+correlates	O
+negatively	O
+with	O
+an	O
+increase	O
+in	O
+the	O
+incidence	O
+of	O
+orofacial	B
+diskinesia	I
+.	O
+
+These	O
+results	O
+indicate	O
+that	O
+early	O
+changes	O
+in	O
+glutamate	O
+transport	O
+may	O
+be	O
+related	O
+to	O
+the	O
+development	O
+of	O
+vacuous	O
+chewing	O
+movements	O
+in	O
+rats	O
+.	O
+
+Ceftriaxone	O
+-	O
+associated	O
+biliary	B
+pseudolithiasis	I
+in	O
+paediatric	O
+surgical	O
+patients	O
+.	O
+
+It	O
+is	O
+well	O
+known	O
+that	O
+ceftriaxone	O
+leads	O
+to	O
+pseudolithiasis	B
+in	O
+some	O
+patients	O
+.	O
+
+Clinical	O
+and	O
+experimental	O
+studies	O
+also	O
+suggest	O
+that	O
+situations	O
+causing	O
+gallbladder	B
+dysfunction	I
+,	O
+such	O
+as	O
+fasting	O
+,	O
+may	O
+have	O
+a	O
+role	O
+for	O
+the	O
+development	O
+of	O
+pseudolithiasis	B
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+prospectively	O
+evaluated	O
+the	O
+incidence	O
+and	O
+clinical	O
+importance	O
+of	O
+pseudolithiasis	B
+in	O
+paediatric	O
+surgical	O
+patients	O
+receiving	O
+ceftriaxone	O
+treatment	O
+,	O
+who	O
+often	O
+had	O
+to	O
+fast	O
+in	O
+the	O
+post	O
+-	O
+operative	O
+period	O
+.	O
+
+Fifty	O
+children	O
+who	O
+were	O
+given	O
+ceftriaxone	O
+were	O
+evaluated	O
+by	O
+serial	O
+abdominal	O
+sonograms	O
+.	O
+
+Of	O
+those	O
+,	O
+13	O
+(	O
+26	O
+%	O
+)	O
+developed	O
+biliary	O
+pathology	O
+.	O
+
+Comparison	O
+of	O
+the	O
+patients	O
+with	O
+or	O
+without	O
+pseudolithiasis	B
+revealed	O
+no	O
+significant	O
+difference	O
+with	O
+respect	O
+to	O
+age	O
+,	O
+sex	O
+,	O
+duration	O
+of	O
+the	O
+treatment	O
+and	O
+starvation	O
+variables	O
+.	O
+
+After	O
+cessation	O
+of	O
+the	O
+treatment	O
+,	O
+pseudolithiasis	B
+resolved	O
+spontaneously	O
+within	O
+a	O
+short	O
+period	O
+.	O
+
+The	O
+incidence	O
+of	O
+pseudolithiasis	B
+is	O
+not	O
+affected	O
+by	O
+fasting	O
+.	O
+
+Coronary	B
+aneurysm	I
+after	O
+implantation	O
+of	O
+a	O
+paclitaxel	O
+-	O
+eluting	O
+stent	O
+.	O
+
+Formation	O
+of	O
+coronary	B
+aneurysm	I
+is	O
+a	O
+rare	O
+complication	O
+of	O
+stenting	O
+with	O
+bare	O
+metal	O
+stents	O
+,	O
+but	O
+based	O
+on	O
+experimental	O
+studies	O
+drug	O
+-	O
+eluting	O
+stents	O
+may	O
+induce	O
+toxic	O
+effects	O
+on	O
+the	O
+vessel	O
+wall	O
+with	O
+incomplete	O
+stent	O
+apposition	O
+,	O
+aneurysm	B
+formation	O
+and	O
+with	O
+the	O
+potential	O
+of	O
+stent	O
+thrombosis	B
+or	O
+vessel	B
+rupture	I
+.	O
+
+We	O
+present	O
+a	O
+43	O
+-	O
+year	O
+-	O
+old	O
+man	O
+who	O
+developed	O
+a	O
+coronary	B
+aneurysm	I
+in	O
+the	O
+right	O
+coronary	O
+artery	O
+6	O
+months	O
+after	O
+receiving	O
+a	O
+paclitaxel	O
+-	O
+eluting	O
+stent	O
+.	O
+
+The	O
+patient	O
+was	O
+asymptomatic	O
+and	O
+the	O
+aneurysm	B
+was	O
+detected	O
+in	O
+a	O
+routine	O
+control	O
+.	O
+
+Angiography	O
+and	O
+intracoronary	O
+ultrasound	O
+demonstrated	O
+lack	O
+of	O
+contact	O
+between	O
+stent	O
+and	O
+vessel	O
+wall	O
+in	O
+a	O
+15	O
+-	O
+mm	O
+long	O
+segment	O
+with	O
+maximal	O
+aneurysm	B
+diameter	O
+of	O
+6	O
+.	O
+0	O
+mm	O
+.	O
+
+The	O
+patient	O
+was	O
+successfully	O
+treated	O
+with	O
+a	O
+graft	O
+stent	O
+.	O
+
+Causes	O
+of	O
+acute	O
+thrombotic	B
+microangiopathy	I
+in	O
+patients	O
+receiving	O
+kidney	O
+transplantation	O
+.	O
+
+OBJECTIVES	O
+:	O
+Thrombotic	B
+microangiopathy	I
+is	O
+a	O
+well	O
+-	O
+known	O
+problem	O
+in	O
+patients	O
+following	O
+renal	O
+transplantation	O
+.	O
+
+In	O
+postrenal	O
+transplantation	O
+,	O
+thrombotic	B
+microangiopathy	I
+is	O
+often	O
+a	O
+reflection	O
+of	O
+hemolytic	B
+uremic	I
+syndrome	I
+.	O
+
+We	O
+aimed	O
+to	O
+determine	O
+the	O
+causes	O
+of	O
+thrombotic	B
+microangiopathy	I
+in	O
+a	O
+population	O
+of	O
+renal	O
+transplantation	O
+recipients	O
+and	O
+discuss	O
+the	O
+literature	O
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+We	O
+investigated	O
+the	O
+causes	O
+of	O
+thrombotic	B
+microangiopathy	I
+during	O
+a	O
+1	O
+-	O
+year	O
+period	O
+,	O
+from	O
+June	O
+2003	O
+to	O
+June	O
+2004	O
+,	O
+at	O
+the	O
+King	O
+Fahad	O
+National	O
+Guard	O
+Hospital	O
+in	O
+Riyadh	O
+,	O
+Saudi	O
+Arabia	O
+,	O
+by	O
+reviewing	O
+the	O
+slides	O
+of	O
+all	O
+transplant	O
+biopsies	O
+(	O
+n	O
+=	O
+25	O
+)	O
+performed	O
+during	O
+this	O
+interval	O
+.	O
+
+Pre	O
+-	O
+and	O
+posttransplant	O
+crossmatching	O
+was	O
+done	O
+when	O
+possible	O
+.	O
+
+RESULTS	O
+:	O
+Five	O
+cases	O
+of	O
+thrombotic	B
+microangiopathy	I
+were	O
+found	O
+.	O
+
+Three	O
+of	O
+these	O
+cases	O
+were	O
+from	O
+the	O
+25	O
+transplantations	O
+performed	O
+at	O
+King	O
+Fahad	O
+National	O
+Guard	O
+Hospital	O
+,	O
+while	O
+the	O
+other	O
+2	O
+transplantations	O
+had	O
+been	O
+performed	O
+abroad	O
+and	O
+were	O
+referred	O
+to	O
+us	O
+for	O
+follow	O
+-	O
+up	O
+.	O
+
+Three	O
+cases	O
+were	O
+related	O
+to	O
+cyclosporine	O
+,	O
+and	O
+1	O
+case	O
+was	O
+secondary	O
+to	O
+both	O
+cyclosporine	O
+and	O
+tacrolimus	O
+.	O
+
+The	O
+fifth	O
+case	O
+had	O
+features	O
+of	O
+thrombotic	B
+microangiopathy	I
+related	O
+to	O
+an	O
+antiphospholipid	B
+syndrome	I
+in	O
+a	O
+patient	O
+with	O
+systemic	B
+lupus	I
+erythematosus	I
+.	O
+
+CONCLUSIONS	O
+:	O
+In	O
+the	O
+literature	O
+,	O
+the	O
+most	O
+-	O
+frequent	O
+cause	O
+of	O
+hemolytic	B
+uremic	I
+syndrome	I
+in	O
+patients	O
+following	O
+renal	O
+transplantation	O
+is	O
+recurrence	O
+of	O
+the	O
+hemolytic	B
+uremic	I
+syndrome	I
+.	O
+
+Other	O
+causes	O
+include	O
+drug	O
+-	O
+related	O
+(	O
+cyclosporine	O
+,	O
+tacrolimus	O
+)	O
+toxicity	B
+,	O
+procoagulant	O
+status	O
+,	O
+and	O
+antibody	O
+-	O
+mediated	O
+rejection	O
+.	O
+
+We	O
+found	O
+that	O
+the	O
+most	O
+-	O
+frequent	O
+cause	O
+of	O
+thrombotic	B
+microangiopathy	I
+was	O
+drug	O
+related	O
+,	O
+secondary	O
+mainly	O
+to	O
+cyclosporine	O
+.	O
+
+In	O
+the	O
+current	O
+study	O
+,	O
+the	O
+frequency	O
+of	O
+thrombotic	B
+microangiopathy	I
+was	O
+similar	O
+to	O
+the	O
+percentage	O
+reported	O
+in	O
+the	O
+literature	O
+(	O
+20	O
+%	O
+)	O
+.	O
+
+Comparison	O
+of	O
+developmental	O
+toxicity	B
+of	O
+selective	O
+and	O
+non	O
+-	O
+selective	O
+cyclooxygenase	O
+-	O
+2	O
+inhibitors	O
+in	O
+CRL	O
+:	O
+(	O
+WI	O
+)	O
+WUBR	O
+Wistar	O
+rats	O
+-	O
+-	O
+DFU	O
+and	O
+piroxicam	O
+study	O
+.	O
+
+BACKGROUND	O
+:	O
+Cyclooxygenase	O
+(	O
+COX	O
+)	O
+inhibitors	O
+are	O
+one	O
+of	O
+the	O
+most	O
+often	O
+ingested	O
+drugs	O
+during	O
+pregnancy	O
+.	O
+
+Unlike	O
+general	O
+toxicity	B
+data	O
+,	O
+their	O
+prenatal	O
+toxic	O
+effects	O
+were	O
+not	O
+extensively	O
+studied	O
+before	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+experiment	O
+was	O
+to	O
+evaluate	O
+the	O
+developmental	O
+toxicity	B
+of	O
+the	O
+non	O
+-	O
+selective	O
+(	O
+piroxicam	O
+)	O
+and	O
+selective	O
+(	O
+DFU	O
+;	O
+5	O
+,	O
+5	O
+-	O
+dimethyl	O
+-	O
+3	O
+-	O
+(	O
+3	O
+-	O
+fluorophenyl	O
+)	O
+-	O
+4	O
+-	O
+(	O
+4	O
+-	O
+methylsulphonyl	O
+)	O
+phenyl	O
+-	O
+2	O
+(	O
+5H	O
+)	O
+-	O
+furanon	O
+)	O
+COX	O
+-	O
+2	O
+inhibitors	O
+.	O
+
+METHODS	O
+:	O
+Drugs	O
+were	O
+separately	O
+,	O
+orally	O
+once	O
+daily	O
+dosed	O
+to	O
+pregnant	O
+rats	O
+from	O
+day	O
+8	O
+to	O
+21	O
+(	O
+GD1	O
+=	O
+plug	O
+day	O
+)	O
+.	O
+
+Doses	O
+were	O
+set	O
+at	O
+0	O
+.	O
+3	O
+,	O
+3	O
+.	O
+0	O
+and	O
+30	O
+.	O
+0mg	O
+/	O
+kg	O
+for	O
+piroxicam	O
+and	O
+0	O
+.	O
+2	O
+,	O
+2	O
+.	O
+0	O
+and	O
+20	O
+.	O
+0mg	O
+/	O
+kg	O
+for	O
+DFU	O
+.	O
+
+Fetuses	O
+were	O
+delivered	O
+on	O
+GD	O
+21	O
+and	O
+routinely	O
+examined	O
+.	O
+
+Comprehensive	O
+clinical	O
+and	O
+developmental	O
+measurements	O
+were	O
+done	O
+.	O
+
+The	O
+pooled	O
+statistical	O
+analysis	O
+for	O
+ventricular	B
+septal	I
+(	I
+VSD	I
+)	I
+and	I
+midline	I
+(	I
+MD	I
+)	I
+defects	I
+was	O
+performed	O
+for	O
+rat	O
+fetuses	O
+exposed	O
+to	O
+piroxicam	O
+,	O
+selective	O
+and	O
+non	O
+-	O
+selective	O
+COX	O
+-	O
+2	O
+inhibitor	O
+based	O
+on	O
+present	O
+and	O
+historic	O
+data	O
+.	O
+
+RESULTS	O
+:	O
+Maternal	O
+toxicity	B
+,	O
+intrauterine	B
+growth	I
+retardation	I
+,	O
+and	O
+increase	B
+of	I
+external	I
+and	I
+skeletal	I
+variations	I
+were	O
+found	O
+in	O
+rats	O
+treated	O
+with	O
+the	O
+highest	O
+dose	O
+of	O
+piroxicam	O
+.	O
+
+Decrease	O
+of	O
+fetal	O
+length	O
+was	O
+the	O
+only	O
+signs	O
+of	O
+the	O
+DFU	O
+developmental	O
+toxicity	B
+observed	O
+in	O
+pups	O
+exposed	O
+to	O
+the	O
+highest	O
+compound	O
+dose	O
+.	O
+
+Lack	O
+of	O
+teratogenicity	O
+was	O
+found	O
+in	O
+piroxicam	O
+and	O
+DFU	O
+-	O
+exposed	O
+groups	O
+.	O
+
+Prenatal	O
+exposure	O
+to	O
+non	O
+-	O
+selective	O
+COX	O
+inhibitors	O
+increases	O
+the	O
+risk	O
+of	O
+VSD	O
+and	O
+MD	O
+when	O
+compared	O
+to	O
+historic	O
+control	O
+but	O
+not	O
+with	O
+selective	O
+COX	O
+-	O
+2	O
+inhibitors	O
+.	O
+
+CONCLUSION	O
+:	O
+Both	O
+selective	O
+and	O
+non	O
+-	O
+selective	O
+COX	O
+-	O
+2	O
+inhibitors	O
+were	O
+toxic	O
+for	O
+rats	O
+fetuses	O
+when	O
+administered	O
+in	O
+the	O
+highest	O
+dose	O
+.	O
+
+Unlike	O
+DFU	O
+,	O
+piroxicam	O
+was	O
+also	O
+highly	O
+toxic	O
+to	O
+the	O
+dams	O
+.	O
+
+Prenatal	O
+exposure	O
+to	O
+selective	O
+COX	O
+-	O
+2	O
+inhibitors	O
+does	O
+not	O
+increase	O
+the	O
+risk	O
+of	O
+ventricular	B
+septal	I
+and	I
+midline	I
+defects	I
+in	O
+rat	O
+when	O
+compared	O
+to	O
+non	O
+-	O
+selective	O
+drugs	O
+and	O
+historic	O
+control	O
+.	O
+
+Lone	O
+atrial	B
+fibrillation	I
+associated	O
+with	O
+creatine	O
+monohydrate	O
+supplementation	O
+.	O
+
+Atrial	B
+fibrillation	I
+in	O
+young	O
+patients	O
+without	O
+structural	O
+heart	B
+disease	I
+is	O
+rare	O
+.	O
+
+Therefore	O
+,	O
+when	O
+the	O
+arrhythmia	B
+is	O
+present	O
+in	O
+this	O
+population	O
+,	O
+reversible	O
+causes	O
+must	O
+be	O
+identified	O
+and	O
+resolved	O
+.	O
+
+Thyroid	B
+disorders	I
+,	O
+illicit	O
+drug	O
+or	O
+stimulant	O
+use	O
+,	O
+and	O
+acute	B
+alcohol	I
+intoxication	I
+are	O
+among	O
+these	O
+causes	O
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+30	O
+-	O
+year	O
+-	O
+old	O
+Caucasian	O
+man	O
+who	O
+came	O
+to	O
+the	O
+emergency	O
+department	O
+in	O
+atrial	B
+fibrillation	I
+with	O
+rapid	O
+ventricular	O
+response	O
+.	O
+
+His	O
+medical	O
+history	O
+was	O
+unremarkable	O
+,	O
+except	O
+for	O
+minor	O
+fractures	B
+of	O
+the	O
+fingers	O
+and	O
+foot	O
+.	O
+
+Thyroid	O
+-	O
+stimulating	O
+hormone	O
+,	O
+magnesium	O
+,	O
+and	O
+potassium	O
+levels	O
+were	O
+within	O
+normal	O
+limits	O
+,	O
+urine	O
+drug	O
+screen	O
+was	O
+negative	O
+,	O
+and	O
+alcohol	O
+use	O
+was	O
+denied	O
+.	O
+
+However	O
+,	O
+when	O
+the	O
+patient	O
+was	O
+questioned	O
+about	O
+use	O
+of	O
+herbal	O
+products	O
+and	O
+supplements	O
+,	O
+the	O
+use	O
+of	O
+creatine	O
+monohydrate	O
+was	O
+revealed	O
+.	O
+
+The	O
+patient	O
+was	O
+admitted	O
+to	O
+the	O
+hospital	O
+,	O
+anticoagulated	O
+with	O
+unfractionated	O
+heparin	O
+,	O
+and	O
+given	O
+intravenous	O
+diltiazem	O
+for	O
+rate	O
+control	O
+and	O
+intravenous	O
+amiodarone	O
+for	O
+rate	O
+and	O
+rhythm	O
+control	O
+.	O
+
+When	O
+discharged	O
+less	O
+than	O
+24	O
+hours	O
+later	O
+,	O
+he	O
+was	O
+receiving	O
+metoprolol	O
+and	O
+aspirin	O
+,	O
+with	O
+follow	O
+-	O
+up	O
+plans	O
+for	O
+echocardiography	O
+and	O
+nuclear	O
+imaging	O
+to	O
+assess	O
+perfusion	O
+.	O
+
+Exogenous	O
+creatine	O
+is	O
+used	O
+by	O
+athletes	O
+to	O
+theoretically	O
+improve	O
+exercise	O
+performance	O
+.	O
+
+Vegetarians	O
+may	O
+also	O
+take	O
+creatine	O
+to	O
+replace	O
+what	O
+they	O
+are	O
+not	O
+consuming	O
+from	O
+meat	O
+,	O
+fish	O
+,	O
+and	O
+other	O
+animal	O
+products	O
+.	O
+
+Previous	O
+anecdotal	O
+reports	O
+have	O
+linked	O
+creatine	O
+to	O
+the	O
+development	O
+of	O
+arrhythmia	B
+.	O
+
+Clinicians	O
+must	O
+be	O
+diligent	O
+when	O
+interviewing	O
+patients	O
+about	O
+their	O
+drug	O
+therapy	O
+histories	O
+and	O
+include	O
+questions	O
+about	O
+their	O
+use	O
+of	O
+herbal	O
+products	O
+and	O
+dietary	O
+supplements	O
+.	O
+
+In	O
+addition	O
+,	O
+it	O
+is	O
+important	O
+to	O
+report	O
+adverse	O
+effects	O
+associated	O
+with	O
+frequently	O
+consumed	O
+supplements	O
+and	O
+herbal	O
+products	O
+to	O
+the	O
+Food	O
+and	O
+Drug	O
+Administration	O
+and	O
+in	O
+the	O
+literature	O
+.	O
+
+Seizures	B
+induced	O
+by	O
+the	O
+cocaine	O
+metabolite	O
+benzoylecgonine	O
+in	O
+rats	O
+.	O
+
+The	O
+half	O
+-	O
+life	O
+(	O
+t1	O
+/	O
+2	O
+)	O
+of	O
+cocaine	O
+is	O
+relatively	O
+short	O
+,	O
+but	O
+some	O
+of	O
+the	O
+consequences	O
+of	O
+its	O
+use	O
+,	O
+such	O
+as	O
+seizures	B
+and	O
+strokes	B
+,	O
+can	O
+occur	O
+hours	O
+after	O
+exposure	O
+.	O
+
+This	O
+led	O
+us	O
+to	O
+hypothesize	O
+that	O
+a	O
+metabolite	O
+of	O
+cocaine	O
+may	O
+be	O
+responsible	O
+for	O
+some	O
+of	O
+those	O
+delayed	O
+sequelae	O
+.	O
+
+We	O
+evaluated	O
+the	O
+potential	O
+of	O
+the	O
+major	O
+metabolite	O
+of	O
+cocaine	O
+,	O
+benzoylecgonine	O
+(	O
+BE	O
+)	O
+,	O
+to	O
+cause	O
+seizures	B
+.	O
+
+Two	O
+separate	O
+equimolar	O
+doses	O
+(	O
+0	O
+.	O
+2	O
+and	O
+0	O
+.	O
+4	O
+mumol	O
+)	O
+of	O
+either	O
+cocaine	O
+or	O
+BE	O
+were	O
+injected	O
+ventricularly	O
+in	O
+unanesthetized	O
+juvenile	O
+rats	O
+.	O
+
+Treated	O
+rats	O
+were	O
+then	O
+evaluated	O
+for	O
+incidence	O
+,	O
+latency	O
+,	O
+and	O
+seizure	B
+pattern	O
+or	O
+for	O
+locomotor	O
+activity	O
+in	O
+animals	O
+without	O
+seizures	B
+.	O
+
+BE	O
+-	O
+Induced	O
+seizures	B
+occurred	O
+more	O
+frequently	O
+and	O
+had	O
+significantly	O
+longer	O
+latencies	O
+than	O
+those	O
+induced	O
+by	O
+equimolar	O
+amounts	O
+of	O
+cocaine	O
+.	O
+
+Whereas	O
+cocaine	O
+-	O
+induced	O
+seizures	B
+were	O
+best	O
+characterized	O
+as	O
+brief	O
+,	O
+generalized	O
+,	O
+and	O
+tonic	O
+and	O
+resulted	O
+in	O
+death	B
+,	O
+those	O
+induced	O
+by	O
+BE	O
+were	O
+prolonged	O
+,	O
+often	O
+multiple	O
+and	O
+mixed	O
+in	O
+type	O
+,	O
+and	O
+rarely	O
+resulted	O
+in	O
+death	B
+.	O
+
+Electrical	O
+recordings	O
+from	O
+the	O
+hippocampus	O
+showed	O
+a	O
+rhythmic	O
+progression	O
+in	O
+EEG	O
+frequency	O
+and	O
+voltage	O
+with	O
+clinical	O
+seizure	B
+expression	O
+.	O
+
+BE	O
+-	O
+Injected	O
+rats	O
+that	O
+did	O
+not	O
+have	O
+seizures	B
+had	O
+significantly	O
+more	O
+locomotor	O
+activity	O
+than	O
+cocaine	O
+-	O
+injected	O
+animals	O
+without	O
+seizures	B
+.	O
+
+The	O
+finding	O
+that	O
+cocaine	O
+-	O
+and	O
+BE	O
+-	O
+induced	O
+seizures	B
+differ	O
+in	O
+several	O
+respects	O
+suggests	O
+more	O
+than	O
+one	O
+mechanism	O
+for	O
+cocaine	O
+-	O
+induced	O
+seizures	B
+and	O
+emphasizes	O
+the	O
+importance	O
+of	O
+a	O
+cocaine	O
+metabolite	O
+,	O
+BE	O
+.	O
+
+The	O
+selective	O
+5	O
+-	O
+HT6	O
+receptor	O
+antagonist	O
+Ro4368554	O
+restores	O
+memory	O
+performance	O
+in	O
+cholinergic	O
+and	O
+serotonergic	O
+models	O
+of	O
+memory	B
+deficiency	I
+in	O
+the	O
+rat	O
+.	O
+
+Antagonists	O
+at	O
+serotonin	O
+type	O
+6	O
+(	O
+5	O
+-	O
+HT	O
+(	O
+6	O
+)	O
+)	O
+receptors	O
+show	O
+activity	O
+in	O
+models	O
+of	O
+learning	O
+and	O
+memory	O
+.	O
+
+Although	O
+the	O
+underlying	O
+mechanism	O
+(	O
+s	O
+)	O
+are	O
+not	O
+well	O
+understood	O
+,	O
+these	O
+effects	O
+may	O
+involve	O
+an	O
+increase	O
+in	O
+acetylcholine	O
+(	O
+ACh	O
+)	O
+levels	O
+.	O
+
+The	O
+present	O
+study	O
+sought	O
+to	O
+characterize	O
+the	O
+cognitive	O
+-	O
+enhancing	O
+effects	O
+of	O
+the	O
+5	O
+-	O
+HT	O
+(	O
+6	O
+)	O
+antagonist	O
+Ro4368554	O
+(	O
+3	O
+-	O
+benzenesulfonyl	O
+-	O
+7	O
+-	O
+(	O
+4	O
+-	O
+methyl	O
+-	O
+piperazin	O
+-	O
+1	O
+-	O
+yl	O
+)	O
+1H	O
+-	O
+indole	O
+)	O
+in	O
+a	O
+rat	O
+object	O
+recognition	O
+task	O
+employing	O
+a	O
+cholinergic	O
+(	O
+scopolamine	O
+pretreatment	O
+)	O
+and	O
+a	O
+serotonergic	O
+-	O
+(	O
+tryptophan	O
+(	O
+TRP	O
+)	O
+depletion	O
+)	O
+deficient	O
+model	O
+,	O
+and	O
+compared	O
+its	O
+pattern	O
+of	O
+action	O
+with	O
+that	O
+of	O
+the	O
+acetylcholinesterase	O
+inhibitor	O
+metrifonate	O
+.	O
+
+Initial	O
+testing	O
+in	O
+a	O
+time	O
+-	O
+dependent	O
+forgetting	O
+task	O
+employing	O
+a	O
+24	O
+-	O
+h	O
+delay	O
+between	O
+training	O
+and	O
+testing	O
+showed	O
+that	O
+metrifonate	O
+improved	O
+object	O
+recognition	O
+(	O
+at	O
+10	O
+and	O
+30	O
+mg	O
+/	O
+kg	O
+,	O
+p	O
+.	O
+o	O
+.	O
+)	O
+,	O
+whereas	O
+Ro4368554	O
+was	O
+inactive	O
+.	O
+
+Both	O
+,	O
+Ro4368554	O
+(	O
+3	O
+and	O
+10	O
+mg	O
+/	O
+kg	O
+,	O
+intraperitoneally	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+)	O
+and	O
+metrifonate	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+,	O
+p	O
+.	O
+o	O
+.	O
+,	O
+respectively	O
+)	O
+reversed	O
+memory	B
+deficits	I
+induced	O
+by	O
+scopolamine	O
+and	O
+TRP	O
+depletion	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+,	O
+and	O
+3	O
+mg	O
+/	O
+kg	O
+,	O
+p	O
+.	O
+o	O
+.	O
+,	O
+respectively	O
+)	O
+.	O
+
+In	O
+conclusion	O
+,	O
+although	O
+Ro4368554	O
+did	O
+not	O
+improve	O
+a	O
+time	O
+-	O
+related	O
+retention	O
+deficit	O
+,	O
+it	O
+reversed	O
+a	O
+cholinergic	O
+and	O
+a	O
+serotonergic	O
+memory	B
+deficit	I
+,	O
+suggesting	O
+that	O
+both	O
+mechanisms	O
+may	O
+be	O
+involved	O
+in	O
+the	O
+facilitation	O
+of	O
+object	O
+memory	O
+by	O
+Ro4368554	O
+and	O
+,	O
+possibly	O
+,	O
+other	O
+5	O
+-	O
+HT	O
+(	O
+6	O
+)	O
+receptor	O
+antagonists	O
+.	O
+
+Evaluation	O
+of	O
+the	O
+anticocaine	O
+monoclonal	O
+antibody	O
+GNC92H2	O
+as	O
+an	O
+immunotherapy	O
+for	O
+cocaine	B
+overdose	I
+.	O
+
+The	O
+illicit	O
+use	O
+of	O
+cocaine	O
+continues	O
+in	O
+epidemic	O
+proportions	O
+and	O
+treatment	O
+for	O
+cocaine	B
+overdose	I
+remains	O
+elusive	O
+.	O
+
+Current	O
+protein	O
+-	O
+based	O
+technology	O
+offers	O
+a	O
+new	O
+therapeutic	O
+venue	O
+by	O
+which	O
+antibodies	O
+bind	O
+the	O
+drug	O
+in	O
+the	O
+blood	O
+stream	O
+,	O
+inactivating	O
+its	O
+toxic	O
+effects	O
+.	O
+
+The	O
+therapeutic	O
+potential	O
+of	O
+the	O
+anticocaine	O
+antibody	O
+GNC92H2	O
+was	O
+examined	O
+using	O
+a	O
+model	O
+of	O
+cocaine	B
+overdose	I
+.	O
+
+Swiss	O
+albino	O
+mice	O
+prepared	O
+with	O
+intrajugular	O
+catheters	O
+were	O
+tested	O
+in	O
+photocell	O
+cages	O
+after	O
+administration	O
+of	O
+93	O
+mg	O
+/	O
+kg	O
+(	O
+LD50	O
+)	O
+of	O
+cocaine	O
+and	O
+GNC92H2	O
+infusions	O
+ranging	O
+from	O
+30	O
+to	O
+190	O
+mg	O
+/	O
+kg	O
+.	O
+
+GNC92H2	O
+was	O
+delivered	O
+30	O
+min	O
+before	O
+,	O
+concomitantly	O
+or	O
+3	O
+min	O
+after	O
+cocaine	O
+treatment	O
+.	O
+
+Significant	O
+blockade	O
+of	O
+cocaine	O
+toxicity	B
+was	O
+observed	O
+with	O
+the	O
+higher	O
+dose	O
+of	O
+GNC92H2	O
+(	O
+190	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+where	O
+premorbid	O
+behaviors	O
+were	O
+reduced	O
+up	O
+to	O
+40	O
+%	O
+,	O
+seizures	B
+up	O
+to	O
+77	O
+%	O
+and	O
+death	B
+by	O
+72	O
+%	O
+.	O
+
+Importantly	O
+,	O
+GNC92H2	O
+prevented	O
+death	B
+even	O
+post	O
+-	O
+cocaine	O
+injection	O
+.	O
+
+The	O
+results	O
+support	O
+the	O
+important	O
+potential	O
+of	O
+GNC92H2	O
+as	O
+a	O
+therapeutic	O
+tool	O
+against	O
+cocaine	B
+overdose	I
+.	O
+
+Electrocardiographic	O
+evidence	O
+of	O
+myocardial	B
+injury	I
+in	O
+psychiatrically	O
+hospitalized	O
+cocaine	O
+abusers	O
+.	O
+
+The	O
+electrocardiograms	O
+(	O
+ECG	O
+)	O
+of	O
+99	O
+cocaine	O
+-	O
+abusing	O
+patients	O
+were	O
+compared	O
+with	O
+the	O
+ECGs	O
+of	O
+50	O
+schizophrenic	B
+controls	O
+.	O
+
+Eleven	O
+of	O
+the	O
+cocaine	O
+abusers	O
+and	O
+none	O
+of	O
+the	O
+controls	O
+had	O
+ECG	O
+evidence	O
+of	O
+significant	O
+myocardial	B
+injury	I
+defined	O
+as	O
+myocardial	B
+infarction	I
+,	O
+ischemia	B
+,	O
+and	O
+bundle	B
+branch	I
+block	I
+.	O
+
+Behavioral	O
+effects	O
+of	O
+urotensin	O
+-	O
+II	O
+centrally	O
+administered	O
+in	O
+mice	O
+.	O
+
+Urotensin	O
+-	O
+II	O
+(	O
+U	O
+-	O
+II	O
+)	O
+receptors	O
+are	O
+widely	O
+distributed	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+.	O
+
+Intracerebroventricular	O
+(	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+injection	O
+of	O
+U	O
+-	O
+II	O
+causes	O
+hypertension	B
+and	O
+bradycardia	B
+and	O
+stimulates	O
+prolactin	O
+and	O
+thyrotropin	O
+secretion	O
+.	O
+
+However	O
+,	O
+the	O
+behavioral	O
+effects	O
+of	O
+centrally	O
+administered	O
+U	O
+-	O
+II	O
+have	O
+received	O
+little	O
+attention	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+we	O
+tested	O
+the	O
+effects	O
+of	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+injections	O
+of	O
+U	O
+-	O
+II	O
+on	O
+behavioral	O
+,	O
+metabolic	O
+,	O
+and	O
+endocrine	O
+responses	O
+in	O
+mice	O
+.	O
+
+Administration	O
+of	O
+graded	O
+doses	O
+of	O
+U	O
+-	O
+II	O
+(	O
+1	O
+-	O
+10	O
+,	O
+000	O
+ng	O
+/	O
+mouse	O
+)	O
+provoked	O
+:	O
+(	O
+1	O
+)	O
+a	O
+dose	O
+-	O
+dependent	O
+reduction	O
+in	O
+the	O
+number	O
+of	O
+head	O
+dips	O
+in	O
+the	O
+hole	O
+-	O
+board	O
+test	O
+;	O
+(	O
+2	O
+)	O
+a	O
+dose	O
+-	O
+dependent	O
+reduction	O
+in	O
+the	O
+number	O
+of	O
+entries	O
+in	O
+the	O
+white	O
+chamber	O
+in	O
+the	O
+black	O
+-	O
+and	O
+-	O
+white	O
+compartment	O
+test	O
+,	O
+and	O
+in	O
+the	O
+number	O
+of	O
+entries	O
+in	O
+the	O
+central	O
+platform	O
+and	O
+open	O
+arms	O
+in	O
+the	O
+plus	O
+-	O
+maze	O
+test	O
+;	O
+and	O
+(	O
+3	O
+)	O
+a	O
+dose	O
+-	O
+dependent	O
+increase	O
+in	O
+the	O
+duration	O
+of	O
+immobility	O
+in	O
+the	O
+forced	O
+-	O
+swimming	O
+test	O
+and	O
+tail	O
+suspension	O
+test	O
+.	O
+
+Intracerebroventricular	O
+injection	O
+of	O
+U	O
+-	O
+II	O
+also	O
+caused	O
+an	O
+increase	O
+in	O
+:	O
+food	O
+intake	O
+at	O
+doses	O
+of	O
+100	O
+and	O
+1	O
+,	O
+000	O
+ng	O
+/	O
+mouse	O
+,	O
+water	O
+intake	O
+at	O
+doses	O
+of	O
+100	O
+-	O
+10	O
+,	O
+000	O
+ng	O
+/	O
+mouse	O
+,	O
+and	O
+horizontal	O
+locomotion	O
+activity	O
+at	O
+a	O
+dose	O
+of	O
+10	O
+,	O
+000	O
+ng	O
+/	O
+mouse	O
+.	O
+
+Whatever	O
+was	O
+the	O
+dose	O
+,	O
+the	O
+central	O
+administration	O
+of	O
+U	O
+-	O
+II	O
+had	O
+no	O
+effect	O
+on	O
+body	O
+temperature	O
+,	O
+nociception	O
+,	O
+apomorphine	O
+-	O
+induced	O
+penile	B
+erection	I
+and	O
+climbing	O
+behavior	O
+,	O
+and	O
+stress	O
+-	O
+induced	O
+plasma	O
+corticosterone	O
+level	O
+.	O
+
+Taken	O
+together	O
+,	O
+the	O
+present	O
+study	O
+demonstrates	O
+that	O
+the	O
+central	O
+injection	O
+of	O
+U	O
+-	O
+II	O
+at	O
+doses	O
+of	O
+1	O
+-	O
+10	O
+,	O
+000	O
+ng	O
+/	O
+mouse	O
+induces	O
+anxiogenic	O
+-	O
+and	O
+depressant	O
+-	O
+like	O
+effects	O
+in	O
+mouse	O
+.	O
+
+These	O
+data	O
+suggest	O
+that	O
+U	O
+-	O
+II	O
+may	O
+be	O
+involved	O
+in	O
+some	O
+aspects	O
+of	O
+psychiatric	B
+disorders	I
+.	O
+
+Learning	O
+of	O
+rats	O
+under	O
+amnesia	B
+caused	O
+by	O
+pentobarbital	O
+.	O
+
+Dissociated	O
+learning	O
+of	O
+rats	O
+in	O
+the	O
+normal	O
+state	O
+and	O
+the	O
+state	O
+of	O
+amnesia	B
+produced	O
+by	O
+pentobarbital	O
+(	O
+15	O
+mg	O
+/	O
+kg	O
+,	O
+ip	O
+)	O
+was	O
+carried	O
+out	O
+.	O
+
+Rats	O
+were	O
+trained	O
+to	O
+approach	O
+a	O
+shelf	O
+where	O
+they	O
+received	O
+food	O
+reinforcement	O
+.	O
+
+In	O
+Group	O
+1	O
+the	O
+rats	O
+were	O
+trained	O
+under	O
+the	O
+influence	O
+of	O
+pentobarbital	O
+to	O
+run	O
+to	O
+the	O
+same	O
+shelf	O
+as	O
+in	O
+the	O
+normal	O
+state	O
+.	O
+
+In	O
+Group	O
+2	O
+the	O
+rats	O
+were	O
+trained	O
+to	O
+approach	O
+different	O
+shelves	O
+in	O
+different	O
+drug	O
+states	O
+.	O
+
+It	O
+was	O
+shown	O
+that	O
+memory	B
+dissociation	I
+occurred	O
+in	O
+both	O
+groups	O
+.	O
+
+Differences	O
+in	O
+the	O
+parameters	O
+of	O
+training	O
+under	O
+the	O
+influence	O
+of	O
+pentobarbital	O
+between	O
+Groups	O
+1	O
+and	O
+2	O
+were	O
+revealed	O
+.	O
+
+These	O
+findings	O
+show	O
+that	O
+the	O
+brain	O
+-	O
+dissociated	O
+state	O
+induced	O
+by	O
+pentobarbital	O
+is	O
+formed	O
+with	O
+the	O
+participation	O
+of	O
+the	O
+mechanisms	O
+of	O
+information	O
+perception	O
+.	O
+
+The	O
+effects	O
+of	O
+short	O
+-	O
+term	O
+raloxifene	O
+therapy	O
+on	O
+fibrinolysis	O
+markers	O
+:	O
+TAFI	O
+,	O
+tPA	O
+,	O
+and	O
+PAI	O
+-	O
+1	O
+.	O
+
+BACKGROUND	O
+:	O
+Markers	O
+of	O
+fibrinolysis	O
+,	O
+thrombin	O
+-	O
+activatable	O
+fibrinolysis	O
+inhibitor	O
+(	O
+TAFI	O
+)	O
+,	O
+tissue	O
+-	O
+type	O
+plasminogen	O
+activator	O
+(	O
+tPA	O
+)	O
+,	O
+and	O
+plasminogen	O
+activator	O
+inhibitor	O
+-	O
+1	O
+(	O
+PAI	O
+-	O
+1	O
+)	O
+levels	O
+were	O
+studied	O
+for	O
+the	O
+evaluation	O
+of	O
+short	O
+-	O
+term	O
+effects	O
+of	O
+raloxifene	O
+administration	O
+in	O
+postmenopausal	O
+women	O
+.	O
+
+METHODS	O
+:	O
+Thirty	O
+-	O
+nine	O
+postmenopausal	O
+women	O
+with	O
+osteopenia	B
+or	O
+osteoporosis	B
+were	O
+included	O
+in	O
+this	O
+prospective	O
+,	O
+controlled	O
+clinical	O
+study	O
+.	O
+
+Twenty	O
+-	O
+five	O
+women	O
+were	O
+given	O
+raloxifene	O
+hydrochloride	O
+(	O
+60	O
+mg	O
+/	O
+day	O
+)	O
+plus	O
+calcium	O
+(	O
+500	O
+mg	O
+/	O
+day	O
+)	O
+.	O
+
+Age	O
+-	O
+matched	O
+controls	O
+(	O
+n	O
+=	O
+14	O
+)	O
+were	O
+given	O
+only	O
+calcium	O
+.	O
+
+Plasma	O
+TAFI	O
+,	O
+tPA	O
+,	O
+and	O
+PAI	O
+-	O
+1	O
+antigen	O
+levels	O
+were	O
+measured	O
+at	O
+baseline	O
+and	O
+after	O
+3	O
+months	O
+of	O
+treatment	O
+by	O
+commercially	O
+available	O
+ELISA	O
+kits	O
+.	O
+
+Variations	O
+of	O
+individuals	O
+were	O
+assessed	O
+by	O
+Wilcoxon	O
+'	O
+s	O
+test	O
+.	O
+
+Relationship	O
+between	O
+those	O
+markers	O
+and	O
+demographic	O
+characteristics	O
+were	O
+investigated	O
+.	O
+
+RESULTS	O
+:	O
+Three	O
+months	O
+of	O
+raloxifene	O
+treatment	O
+was	O
+associated	O
+with	O
+a	O
+significant	O
+decrease	O
+in	O
+the	O
+plasma	O
+TAFI	O
+antigen	O
+concentrations	O
+(	O
+16	O
+%	O
+change	O
+,	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+,	O
+and	O
+a	O
+significant	O
+increase	O
+in	O
+tPA	O
+antigen	O
+concentrations	O
+(	O
+25	O
+%	O
+change	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+A	O
+significant	O
+correlation	O
+was	O
+found	O
+between	O
+baseline	O
+TAFI	O
+antigen	O
+concentrations	O
+and	O
+the	O
+duration	O
+of	O
+amenorrhea	B
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+;	O
+r	O
+=	O
+0	O
+.	O
+33	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+We	O
+suggest	O
+that	O
+the	O
+increased	O
+risk	O
+of	O
+venous	B
+thromboembolism	I
+due	O
+to	O
+raloxifene	O
+treatment	O
+may	O
+be	O
+related	O
+to	O
+increased	O
+tPA	O
+levels	O
+,	O
+but	O
+not	O
+TAFI	O
+levels	O
+.	O
+
+Valproate	O
+-	O
+induced	O
+encephalopathy	B
+.	O
+
+Valproate	O
+-	O
+induced	O
+encephalopathy	B
+is	O
+a	O
+rare	O
+syndrome	O
+that	O
+may	O
+manifest	O
+in	O
+otherwise	O
+normal	O
+epileptic	B
+individuals	O
+.	O
+
+It	O
+may	O
+even	O
+present	O
+in	O
+patients	O
+who	O
+have	O
+tolerated	O
+this	O
+medicine	O
+well	O
+in	O
+the	O
+past	O
+.	O
+
+It	O
+is	O
+usually	O
+but	O
+not	O
+necessarily	O
+associated	O
+with	O
+hyperammonemia	B
+.	O
+
+The	O
+EEG	O
+shows	O
+characteristic	O
+triphasic	O
+waves	O
+in	O
+most	O
+patients	O
+with	O
+this	O
+complication	O
+.	O
+
+A	O
+case	O
+of	O
+valproate	O
+-	O
+induced	O
+encephalopathy	B
+is	O
+presented	O
+.	O
+
+The	O
+problems	O
+in	O
+diagnosing	O
+this	O
+condition	O
+are	O
+subsequently	O
+discussed	O
+.	O
+
+Recurrent	O
+dysphonia	B
+and	O
+acitretin	O
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+woman	O
+complaining	O
+of	O
+dysphonia	B
+while	O
+she	O
+was	O
+treated	O
+by	O
+acitretin	O
+.	O
+
+Her	O
+symptoms	O
+totally	O
+regressed	O
+after	O
+drug	O
+withdrawal	O
+and	O
+reappeared	O
+when	O
+acitretin	O
+was	O
+reintroduced	O
+.	O
+
+To	O
+our	O
+knowledge	O
+,	O
+this	O
+is	O
+the	O
+first	O
+case	O
+of	O
+acitretin	O
+-	O
+induced	O
+dysphonia	B
+.	O
+
+This	O
+effect	O
+may	O
+be	O
+related	O
+to	O
+the	O
+pharmacological	O
+effect	O
+of	O
+this	O
+drug	O
+on	O
+mucous	O
+membranes	O
+.	O
+
+Nitro	O
+-	O
+L	O
+-	O
+arginine	O
+methyl	O
+ester	O
+:	O
+a	O
+potential	O
+protector	O
+against	O
+gentamicin	O
+ototoxicity	B
+.	O
+
+The	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+inhibitor	O
+nitro	O
+-	O
+L	O
+-	O
+arginine	O
+methyl	O
+ester	O
+(	O
+L	O
+-	O
+NAME	O
+)	O
+may	O
+act	O
+as	O
+an	O
+otoprotectant	O
+against	O
+high	B
+-	I
+frequency	I
+hearing	I
+loss	I
+caused	O
+by	O
+gentamicin	O
+,	O
+but	O
+further	O
+studies	O
+are	O
+needed	O
+to	O
+confirm	O
+this	O
+.	O
+Aminoglycoside	O
+antibiotics	O
+are	O
+still	O
+widely	O
+used	O
+by	O
+virtue	O
+of	O
+their	O
+efficacy	O
+and	O
+low	O
+cost	O
+.	O
+
+Their	O
+ototoxicity	B
+is	O
+a	O
+serious	O
+health	O
+problem	O
+and	O
+,	O
+as	O
+their	O
+ototoxic	B
+mechanism	O
+involves	O
+the	O
+production	O
+of	O
+NO	O
+,	O
+we	O
+need	O
+to	O
+assess	O
+the	O
+use	O
+of	O
+NO	O
+inhibitors	O
+for	O
+the	O
+prevention	O
+of	O
+aminoglycoside	O
+-	O
+induced	O
+sensorineural	B
+hearing	I
+loss	I
+.	O
+
+In	O
+this	O
+experimental	O
+study	O
+we	O
+used	O
+30	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+,	O
+27	O
+of	O
+which	O
+had	O
+gentamicin	O
+instilled	O
+into	O
+the	O
+middle	O
+ear	O
+.	O
+
+The	O
+otoprotectant	O
+L	O
+-	O
+NAME	O
+was	O
+administered	O
+topically	O
+to	O
+12	O
+/	O
+27	O
+animals	O
+.	O
+
+Its	O
+effect	O
+was	O
+determined	O
+in	O
+terms	O
+of	O
+attenuation	O
+of	O
+hearing	B
+loss	I
+,	O
+measured	O
+by	O
+shifts	O
+in	O
+the	O
+auditory	O
+brainstem	O
+response	O
+threshold	O
+.	O
+
+L	O
+-	O
+NAME	O
+reduced	O
+gentamicin	O
+-	O
+induced	O
+hearing	B
+loss	I
+in	O
+the	O
+high	O
+-	O
+frequency	O
+range	O
+,	O
+but	O
+gave	O
+no	O
+protection	O
+in	O
+the	O
+middle	O
+or	O
+low	O
+frequencies	O
+.	O
+
+Safety	O
+profile	O
+of	O
+a	O
+nicotine	O
+lozenge	O
+compared	O
+with	O
+that	O
+of	O
+nicotine	O
+gum	O
+in	O
+adult	O
+smokers	O
+with	O
+underlying	O
+medical	O
+conditions	O
+:	O
+a	O
+12	O
+-	O
+week	O
+,	O
+randomized	O
+,	O
+open	O
+-	O
+label	O
+study	O
+.	O
+
+BACKGROUND	O
+:	O
+Nicotine	O
+polacrilex	O
+lozenges	O
+deliver	O
+25	O
+%	O
+to	O
+27	O
+%	O
+more	O
+nicotine	O
+compared	O
+with	O
+equivalent	O
+doses	O
+of	O
+nicotine	O
+polacrilex	O
+gum	O
+.	O
+
+The	O
+increased	O
+nicotine	O
+exposure	O
+from	O
+the	O
+lozenge	O
+has	O
+raised	O
+questions	O
+about	O
+the	O
+relative	O
+safety	O
+of	O
+the	O
+lozenge	O
+and	O
+gum	O
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+compare	O
+the	O
+safety	O
+profiles	O
+of	O
+the	O
+4	O
+-	O
+mg	O
+nicotine	O
+lozenge	O
+and	O
+4	O
+-	O
+mg	O
+nicotine	O
+gum	O
+in	O
+smokers	O
+with	O
+selected	O
+label	O
+-	O
+restricted	O
+diseases	O
+.	O
+
+METHODS	O
+:	O
+This	O
+was	O
+a	O
+multicenter	O
+,	O
+randomized	O
+,	O
+open	O
+-	O
+label	O
+study	O
+in	O
+adult	O
+smokers	O
+with	O
+heart	B
+disease	I
+,	O
+hypertension	B
+not	O
+controlled	O
+by	O
+medication	O
+,	O
+and	O
+/	O
+or	O
+diabetes	B
+mellitus	I
+.	O
+
+Patients	O
+were	O
+randomized	O
+in	O
+a	O
+1	O
+:	O
+1	O
+ratio	O
+to	O
+receive	O
+the	O
+4	O
+-	O
+mg	O
+nicotine	O
+lozenge	O
+or	O
+4	O
+-	O
+mg	O
+nicotine	O
+gum	O
+.	O
+
+Safety	O
+assessments	O
+were	O
+made	O
+at	O
+baseline	O
+and	O
+at	O
+2	O
+,	O
+4	O
+,	O
+6	O
+,	O
+and	O
+12	O
+weeks	O
+after	O
+the	O
+start	O
+of	O
+product	O
+use	O
+.	O
+
+RESULTS	O
+:	O
+Nine	O
+hundred	O
+one	O
+patients	O
+were	O
+randomized	O
+to	O
+treatment	O
+,	O
+447	O
+who	O
+received	O
+the	O
+lozenge	O
+and	O
+454	O
+who	O
+received	O
+the	O
+gum	O
+(	O
+safety	O
+population	O
+)	O
+.	O
+
+The	O
+majority	O
+were	O
+women	O
+(	O
+52	O
+.	O
+7	O
+%	O
+)	O
+.	O
+
+Patients	O
+'	O
+mean	O
+age	O
+was	O
+53	O
+.	O
+9	O
+years	O
+,	O
+their	O
+mean	O
+weight	O
+was	O
+193	O
+.	O
+9	O
+pounds	O
+,	O
+and	O
+they	O
+smoked	O
+a	O
+mean	O
+of	O
+25	O
+.	O
+2	O
+cigarettes	O
+per	O
+day	O
+at	O
+baseline	O
+.	O
+
+Five	O
+hundred	O
+fifty	O
+-	O
+three	O
+patients	O
+,	O
+264	O
+taking	O
+the	O
+lozenge	O
+and	O
+289	O
+taking	O
+the	O
+gum	O
+,	O
+used	O
+the	O
+study	O
+product	O
+for	O
+>	O
+or	O
+=	O
+4	O
+days	O
+per	O
+week	O
+during	O
+the	O
+first	O
+2	O
+weeks	O
+(	O
+evaluable	O
+population	O
+)	O
+.	O
+
+The	O
+nicotine	O
+lozenge	O
+and	O
+nicotine	O
+gum	O
+were	O
+equally	O
+well	O
+tolerated	O
+,	O
+despite	O
+increased	O
+nicotine	O
+exposure	O
+from	O
+the	O
+lozenge	O
+.	O
+
+The	O
+incidence	O
+of	O
+adverse	O
+events	O
+in	O
+the	O
+2	O
+groups	O
+was	O
+similar	O
+during	O
+the	O
+first	O
+2	O
+weeks	O
+of	O
+product	O
+use	O
+(	O
+evaluation	O
+population	O
+:	O
+55	O
+.	O
+3	O
+%	O
+lozenge	O
+,	O
+54	O
+.	O
+7	O
+%	O
+gum	O
+)	O
+,	O
+as	O
+well	O
+as	O
+during	O
+the	O
+entire	O
+study	O
+(	O
+safety	O
+population	O
+:	O
+63	O
+.	O
+8	O
+%	O
+and	O
+58	O
+.	O
+6	O
+%	O
+,	O
+respectively	O
+)	O
+.	O
+
+Stratification	O
+of	O
+patients	O
+by	O
+sex	O
+,	O
+age	O
+,	O
+extent	O
+of	O
+concurrent	O
+smoking	O
+,	O
+extent	O
+of	O
+product	O
+use	O
+,	O
+and	O
+severity	O
+of	O
+adverse	O
+events	O
+revealed	O
+no	O
+clinically	O
+significant	O
+differences	O
+between	O
+the	O
+lozenge	O
+and	O
+gum	O
+.	O
+
+The	O
+most	O
+common	O
+adverse	O
+events	O
+were	O
+nausea	B
+(	O
+17	O
+.	O
+2	O
+%	O
+and	O
+16	O
+.	O
+1	O
+%	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+-	O
+3	O
+.	O
+7	O
+to	O
+6	O
+.	O
+0	O
+)	O
+,	O
+hiccups	B
+(	O
+10	O
+.	O
+7	O
+%	O
+and	O
+6	O
+.	O
+6	O
+%	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+0	O
+.	O
+5	O
+to	O
+7	O
+.	O
+8	O
+)	O
+,	O
+and	O
+headache	B
+(	O
+8	O
+.	O
+7	O
+%	O
+and	O
+9	O
+.	O
+9	O
+%	O
+;	O
+95	O
+%	O
+Cl	O
+,	O
+-	O
+5	O
+.	O
+0	O
+to	O
+2	O
+.	O
+6	O
+)	O
+.	O
+
+Serious	O
+adverse	O
+events	O
+were	O
+reported	O
+in	O
+11	O
+and	O
+13	O
+patients	O
+in	O
+the	O
+respective	O
+groups	O
+.	O
+
+Fewer	O
+than	O
+6	O
+%	O
+of	O
+patients	O
+in	O
+either	O
+group	O
+were	O
+considered	O
+by	O
+the	O
+investigator	O
+to	O
+have	O
+a	O
+worsening	O
+of	O
+their	O
+overall	O
+disease	O
+condition	O
+during	O
+the	O
+study	O
+.	O
+
+The	O
+majority	O
+of	O
+patients	O
+(	O
+>	O
+60	O
+%	O
+)	O
+experienced	O
+no	O
+change	O
+in	O
+their	O
+disease	O
+status	O
+from	O
+baseline	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+4	O
+-	O
+mg	O
+nicotine	O
+lozenge	O
+and	O
+4	O
+-	O
+mg	O
+nicotine	O
+gum	O
+had	O
+comparable	O
+safety	O
+profiles	O
+in	O
+these	O
+patients	O
+with	O
+label	O
+-	O
+restricted	O
+medical	O
+conditions	O
+.	O
+
+Pharmacological	O
+modulation	O
+of	O
+pain	B
+-	O
+related	O
+brain	O
+activity	O
+during	O
+normal	O
+and	O
+central	O
+sensitization	O
+states	O
+in	O
+humans	O
+.	O
+
+Abnormal	O
+processing	O
+of	O
+somatosensory	O
+inputs	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+(	O
+central	O
+sensitization	O
+)	O
+is	O
+the	O
+mechanism	O
+accounting	O
+for	O
+the	O
+enhanced	O
+pain	B
+sensitivity	O
+in	O
+the	O
+skin	O
+surrounding	O
+tissue	B
+injury	I
+(	O
+secondary	B
+hyperalgesia	I
+)	O
+.	O
+
+Secondary	B
+hyperalgesia	I
+shares	O
+clinical	O
+characteristics	O
+with	O
+neurogenic	B
+hyperalgesia	I
+in	O
+patients	O
+with	O
+neuropathic	B
+pain	I
+.	O
+
+Abnormal	O
+brain	O
+responses	O
+to	O
+somatosensory	O
+stimuli	O
+have	O
+been	O
+found	O
+in	O
+patients	O
+with	O
+hyperalgesia	B
+as	O
+well	O
+as	O
+in	O
+normal	O
+subjects	O
+during	O
+experimental	O
+central	O
+sensitization	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+assess	O
+the	O
+effects	O
+of	O
+gabapentin	O
+,	O
+a	O
+drug	O
+effective	O
+in	O
+neuropathic	B
+pain	I
+patients	O
+,	O
+on	O
+brain	O
+processing	O
+of	O
+nociceptive	O
+information	O
+in	O
+normal	O
+and	O
+central	O
+sensitization	O
+states	O
+.	O
+
+Using	O
+functional	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+fMRI	O
+)	O
+in	O
+normal	O
+volunteers	O
+,	O
+we	O
+studied	O
+the	O
+gabapentin	O
+-	O
+induced	O
+modulation	O
+of	O
+brain	O
+activity	O
+in	O
+response	O
+to	O
+nociceptive	O
+mechanical	O
+stimulation	O
+of	O
+normal	O
+skin	O
+and	O
+capsaicin	O
+-	O
+induced	O
+secondary	B
+hyperalgesia	I
+.	O
+
+The	O
+dose	O
+of	O
+gabapentin	O
+was	O
+1	O
+,	O
+800	O
+mg	O
+per	O
+os	O
+,	O
+in	O
+a	O
+single	O
+administration	O
+.	O
+
+We	O
+found	O
+that	O
+(	O
+i	O
+)	O
+gabapentin	O
+reduced	O
+the	O
+activations	O
+in	O
+the	O
+bilateral	O
+operculoinsular	O
+cortex	O
+,	O
+independently	O
+of	O
+the	O
+presence	O
+of	O
+central	O
+sensitization	O
+;	O
+(	O
+ii	O
+)	O
+gabapentin	O
+reduced	O
+the	O
+activation	O
+in	O
+the	O
+brainstem	O
+,	O
+only	O
+during	O
+central	O
+sensitization	O
+;	O
+(	O
+iii	O
+)	O
+gabapentin	O
+suppressed	O
+stimulus	O
+-	O
+induced	O
+deactivations	O
+,	O
+only	O
+during	O
+central	O
+sensitization	O
+;	O
+this	O
+effect	O
+was	O
+more	O
+robust	O
+than	O
+the	O
+effect	O
+on	O
+brain	O
+activation	O
+.	O
+
+The	O
+observed	O
+drug	O
+-	O
+induced	O
+effects	O
+were	O
+not	O
+due	O
+to	O
+changes	O
+in	O
+the	O
+baseline	O
+fMRI	O
+signal	O
+.	O
+
+These	O
+findings	O
+indicate	O
+that	O
+gabapentin	O
+has	O
+a	O
+measurable	O
+antinociceptive	O
+effect	O
+and	O
+a	O
+stronger	O
+antihyperalgesic	O
+effect	O
+most	O
+evident	O
+in	O
+the	O
+brain	O
+areas	O
+undergoing	O
+deactivation	O
+,	O
+thus	O
+supporting	O
+the	O
+concept	O
+that	O
+gabapentin	O
+is	O
+more	O
+effective	O
+in	O
+modulating	O
+nociceptive	O
+transmission	O
+when	O
+central	O
+sensitization	O
+is	O
+present	O
+.	O
+
+Investigation	O
+of	O
+mitochondrial	O
+involvement	O
+in	O
+the	O
+experimental	O
+model	O
+of	O
+epilepsy	B
+induced	O
+by	O
+pilocarpine	O
+.	O
+
+Mitochondrial	B
+abnormalities	I
+have	O
+been	O
+associated	O
+with	O
+several	O
+aspects	O
+of	O
+epileptogenesis	O
+,	O
+such	O
+as	O
+energy	O
+generation	O
+,	O
+control	O
+of	O
+cell	O
+death	B
+,	O
+neurotransmitter	O
+synthesis	O
+,	O
+and	O
+free	O
+radical	O
+(	O
+FR	O
+)	O
+production	O
+.	O
+
+Increased	O
+production	O
+of	O
+FRs	O
+may	O
+cause	O
+mtDNA	O
+damage	O
+leading	O
+to	O
+decreased	O
+activities	O
+of	O
+oxidative	O
+phosphorylation	O
+complexes	O
+containing	O
+mtDNA	O
+-	O
+encoded	O
+subunits	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+investigated	O
+whether	O
+increased	O
+generation	O
+of	O
+FR	O
+during	O
+status	B
+epilepticus	I
+would	O
+be	O
+sufficient	O
+to	O
+provoke	O
+abnormalities	O
+in	O
+mtDNA	O
+and	O
+in	O
+the	O
+expression	O
+and	O
+activity	O
+of	O
+cytochrome	O
+c	O
+oxidase	O
+(	O
+CCO	O
+)	O
+,	O
+complex	O
+IV	O
+of	O
+the	O
+respiratory	O
+chain	O
+,	O
+in	O
+the	O
+chronic	O
+phase	O
+of	O
+the	O
+pilocarpine	O
+model	O
+of	O
+temporal	B
+lobe	I
+epilepsy	I
+.	O
+
+DNA	O
+analysis	O
+revealed	O
+low	O
+amounts	O
+of	O
+a	O
+4	O
+.	O
+8	O
+kb	O
+mtDNA	O
+deletion	O
+but	O
+with	O
+no	O
+differences	O
+in	O
+frequency	O
+or	O
+quantity	O
+in	O
+the	O
+control	O
+and	O
+experimental	O
+groups	O
+.	O
+
+We	O
+did	O
+not	O
+find	O
+abnormalities	O
+in	O
+the	O
+expression	O
+and	O
+distribution	O
+of	O
+an	O
+mtDNA	O
+-	O
+encoded	O
+subunit	O
+of	O
+CCO	O
+(	O
+CCO	O
+-	O
+I	O
+)	O
+or	O
+a	O
+relative	O
+decrease	O
+in	O
+CCO	O
+-	O
+I	O
+when	O
+compared	O
+with	O
+nuclear	O
+-	O
+encoded	O
+subunits	O
+(	O
+CCO	O
+-	O
+IV	O
+and	O
+SDH	O
+-	O
+fp	O
+)	O
+.	O
+
+No	O
+abnormality	O
+in	O
+CCO	O
+activity	O
+was	O
+observed	O
+through	O
+histochemistry	O
+.	O
+
+Although	O
+evidences	O
+of	O
+mitochondrial	B
+abnormalities	I
+were	O
+found	O
+in	O
+previously	O
+published	O
+studies	O
+,	O
+our	O
+results	O
+do	O
+not	O
+suggest	O
+that	O
+the	O
+FRs	O
+,	O
+generated	O
+during	O
+the	O
+acute	O
+phase	O
+,	O
+determined	O
+important	O
+abnormalities	O
+in	O
+mtDNA	O
+,	O
+in	O
+expression	O
+of	O
+CCO	O
+-	O
+I	O
+,	O
+and	O
+in	O
+CCO	O
+activity	O
+.	O
+
+Adverse	O
+effect	O
+of	O
+the	O
+calcium	O
+channel	O
+blocker	O
+nitrendipine	O
+on	O
+nephrosclerosis	B
+in	O
+rats	O
+with	O
+renovascular	B
+hypertension	I
+.	O
+
+The	O
+effect	O
+of	O
+a	O
+6	O
+-	O
+week	O
+treatment	O
+with	O
+the	O
+calcium	O
+channel	O
+blocker	O
+nitrendipine	O
+or	O
+the	O
+angiotensin	O
+converting	O
+enzyme	O
+inhibitor	O
+enalapril	O
+on	O
+blood	O
+pressure	O
+,	O
+albuminuria	B
+,	O
+renal	O
+hemodynamics	O
+,	O
+and	O
+morphology	O
+of	O
+the	O
+nonclipped	O
+kidney	O
+was	O
+studied	O
+in	O
+rats	O
+with	O
+two	O
+-	O
+kidney	O
+,	O
+one	O
+clip	O
+renovascular	B
+hypertension	I
+.	O
+
+Six	O
+weeks	O
+after	O
+clipping	O
+of	O
+one	O
+renal	O
+artery	O
+,	O
+hypertensive	B
+rats	O
+(	O
+178	O
++	O
+/	O
+-	O
+4	O
+mm	O
+Hg	O
+)	O
+were	O
+randomly	O
+assigned	O
+to	O
+three	O
+groups	O
+:	O
+untreated	O
+hypertensive	B
+controls	O
+(	O
+n	O
+=	O
+8	O
+)	O
+,	O
+enalapril	O
+-	O
+treated	O
+(	O
+n	O
+=	O
+8	O
+)	O
+,	O
+or	O
+nitrendipine	O
+-	O
+treated	O
+(	O
+n	O
+=	O
+10	O
+)	O
+.	O
+
+Sham	O
+-	O
+operated	O
+rats	O
+served	O
+as	O
+normotensive	O
+controls	O
+(	O
+128	O
++	O
+/	O
+-	O
+3	O
+mm	O
+Hg	O
+,	O
+n	O
+=	O
+8	O
+)	O
+.	O
+
+After	O
+6	O
+weeks	O
+of	O
+treatment	O
+,	O
+renal	O
+hemodynamics	O
+(	O
+glomerular	O
+filtration	O
+rate	O
+and	O
+renal	O
+plasma	O
+flow	O
+)	O
+were	O
+measured	O
+in	O
+the	O
+anesthetized	O
+rats	O
+.	O
+
+Renal	O
+tissue	O
+was	O
+obtained	O
+for	O
+determination	O
+of	O
+glomerular	O
+size	O
+and	O
+sclerosis	O
+.	O
+
+Enalapril	O
+but	O
+not	O
+nitrendipine	O
+reduced	O
+blood	O
+pressure	O
+significantly	O
+.	O
+
+After	O
+6	O
+weeks	O
+of	O
+therapy	O
+,	O
+glomerular	O
+filtration	O
+rate	O
+was	O
+not	O
+different	O
+among	O
+the	O
+studied	O
+groups	O
+.	O
+
+Renal	O
+plasma	O
+flow	O
+increased	O
+,	O
+but	O
+albumin	O
+excretion	O
+and	O
+glomerulosclerosis	B
+did	O
+not	O
+change	O
+after	O
+enalapril	O
+treatment	O
+.	O
+
+In	O
+contrast	O
+,	O
+in	O
+the	O
+nitrendipine	O
+-	O
+treated	O
+group	O
+albuminuria	B
+increased	O
+from	O
+12	O
+.	O
+8	O
++	O
+/	O
+-	O
+2	O
+progressively	O
+to	O
+163	O
++	O
+/	O
+-	O
+55	O
+compared	O
+with	O
+19	O
+.	O
+2	O
++	O
+/	O
+-	O
+9	O
+mg	O
+/	O
+24	O
+hr	O
+in	O
+the	O
+hypertensive	B
+controls	O
+.	O
+
+Furthermore	O
+,	O
+glomerulosclerosis	B
+index	O
+was	O
+significantly	O
+increased	O
+in	O
+the	O
+nitrendipine	O
+-	O
+treated	O
+group	O
+compared	O
+with	O
+the	O
+hypertensive	B
+controls	O
+(	O
+0	O
+.	O
+38	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+versus	O
+0	O
+.	O
+13	O
++	O
+/	O
+-	O
+0	O
+.	O
+04	O
+)	O
+.	O
+
+In	O
+addition	O
+,	O
+glomerular	O
+size	O
+was	O
+higher	O
+in	O
+the	O
+nitrendipine	O
+-	O
+treated	O
+group	O
+(	O
+14	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+17	O
+10	O
+(	O
+-	O
+3	O
+)	O
+mm2	O
+)	O
+but	O
+lower	O
+in	O
+the	O
+enalapril	O
+-	O
+treated	O
+group	O
+(	O
+11	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+15	O
+10	O
+(	O
+-	O
+3	O
+)	O
+mm2	O
+)	O
+compared	O
+with	O
+the	O
+hypertensive	B
+controls	O
+(	O
+12	O
+.	O
+1	O
++	O
+/	O
+-	O
+0	O
+.	O
+17	O
+10	O
+(	O
+-	O
+3	O
+)	O
+mm2	O
+)	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Ketoconazole	O
+induced	O
+torsades	B
+de	I
+pointes	I
+without	O
+concomitant	O
+use	O
+of	O
+QT	O
+interval	O
+-	O
+prolonging	O
+drug	O
+.	O
+
+Ketoconazole	O
+is	O
+not	O
+known	O
+to	O
+be	O
+proarrhythmic	O
+without	O
+concomitant	O
+use	O
+of	O
+QT	O
+interval	O
+-	O
+prolonging	O
+drugs	O
+.	O
+
+We	O
+report	O
+a	O
+woman	O
+with	O
+coronary	B
+artery	I
+disease	I
+who	O
+developed	O
+a	O
+markedly	O
+prolonged	B
+QT	I
+interval	I
+and	O
+torsades	B
+de	I
+pointes	I
+(	O
+TdP	B
+)	O
+after	O
+taking	O
+ketoconazole	O
+for	O
+treatment	O
+of	O
+fungal	B
+infection	I
+.	O
+
+Her	O
+QT	O
+interval	O
+returned	O
+to	O
+normal	O
+upon	O
+withdrawal	O
+of	O
+ketoconazole	O
+.	O
+
+Genetic	O
+study	O
+did	O
+not	O
+find	O
+any	O
+mutation	O
+in	O
+her	O
+genes	O
+that	O
+encode	O
+cardiac	O
+IKr	O
+channel	O
+proteins	O
+.	O
+
+We	O
+postulate	O
+that	O
+by	O
+virtue	O
+of	O
+its	O
+direct	O
+blocking	O
+action	O
+on	O
+IKr	O
+,	O
+ketoconazole	O
+alone	O
+may	O
+prolong	O
+QT	O
+interval	O
+and	O
+induce	O
+TdP	B
+.	O
+
+This	O
+calls	O
+for	O
+attention	O
+when	O
+ketoconazole	O
+is	O
+administered	O
+to	O
+patients	O
+with	O
+risk	O
+factors	O
+for	O
+acquired	O
+long	B
+QT	I
+syndrome	I
+.	O
+
+Cerebral	B
+vasculitis	I
+following	O
+oral	O
+methylphenidate	O
+intake	O
+in	O
+an	O
+adult	O
+:	O
+a	O
+case	O
+report	O
+.	O
+
+Methylphenidate	O
+is	O
+structurally	O
+and	O
+functionally	O
+similar	O
+to	O
+amphetamine	O
+.	O
+
+Cerebral	B
+vasculitis	I
+associated	O
+with	O
+amphetamine	B
+abuse	I
+is	O
+well	O
+documented	O
+,	O
+and	O
+in	O
+rare	O
+cases	O
+ischaemic	B
+stroke	I
+has	O
+been	O
+reported	O
+after	O
+methylphenidate	O
+intake	O
+in	O
+children	O
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+63	O
+-	O
+year	O
+-	O
+old	O
+female	O
+who	O
+was	O
+treated	O
+with	O
+methylphenidate	O
+due	O
+to	O
+hyperactivity	B
+and	O
+suffered	O
+from	O
+multiple	O
+ischaemic	B
+strokes	I
+.	O
+
+We	O
+consider	O
+drug	O
+-	O
+induced	O
+cerebral	B
+vasculitis	I
+as	O
+the	O
+most	O
+likely	O
+cause	O
+of	O
+recurrent	O
+ischaemic	B
+strokes	I
+in	O
+the	O
+absence	O
+of	O
+any	O
+pathological	O
+findings	O
+during	O
+the	O
+diagnostic	O
+work	O
+-	O
+up	O
+.	O
+
+We	O
+conclude	O
+that	O
+methylphenidate	O
+mediated	O
+vasculitis	B
+should	O
+be	O
+considered	O
+in	O
+patients	O
+with	O
+neurological	O
+symptoms	O
+and	O
+a	O
+history	O
+of	O
+methylphenidate	O
+therapy	O
+.	O
+
+This	O
+potential	O
+side	O
+-	O
+effect	O
+,	O
+though	O
+very	O
+rare	O
+,	O
+represents	O
+one	O
+more	O
+reason	O
+to	O
+be	O
+very	O
+restrictive	O
+in	O
+the	O
+use	O
+of	O
+methylphenidate	O
+.	O
+
+MDMA	O
+polydrug	O
+users	O
+show	O
+process	O
+-	O
+specific	O
+central	O
+executive	O
+impairments	O
+coupled	O
+with	O
+impaired	B
+social	I
+and	I
+emotional	I
+judgement	I
+processes	I
+.	O
+
+In	O
+recent	O
+years	O
+working	O
+memory	B
+deficits	I
+have	O
+been	O
+reported	O
+in	O
+users	O
+of	O
+MDMA	O
+(	O
+3	O
+,	O
+4	O
+-	O
+methylenedioxymethamphetamine	O
+,	O
+ecstasy	O
+)	O
+.	O
+
+The	O
+current	O
+study	O
+aimed	O
+to	O
+assess	O
+the	O
+impact	O
+of	O
+MDMA	O
+use	O
+on	O
+three	O
+separate	O
+central	O
+executive	O
+processes	O
+(	O
+set	O
+shifting	O
+,	O
+inhibition	O
+and	O
+memory	O
+updating	O
+)	O
+and	O
+also	O
+on	O
+"	O
+prefrontal	O
+"	O
+mediated	O
+social	O
+and	O
+emotional	O
+judgement	O
+processes	O
+.	O
+
+Fifteen	O
+polydrug	O
+ecstasy	O
+users	O
+and	O
+15	O
+polydrug	O
+non	O
+-	O
+ecstasy	O
+user	O
+controls	O
+completed	O
+a	O
+general	O
+drug	O
+use	O
+questionnaire	O
+,	O
+the	O
+Brixton	O
+Spatial	O
+Anticipation	O
+task	O
+(	O
+set	O
+shifting	O
+)	O
+,	O
+Backward	O
+Digit	O
+Span	O
+procedure	O
+(	O
+memory	O
+updating	O
+)	O
+,	O
+Inhibition	O
+of	O
+Return	O
+(	O
+inhibition	O
+)	O
+,	O
+an	O
+emotional	O
+intelligence	O
+scale	O
+,	O
+the	O
+Tromso	O
+Social	O
+Intelligence	O
+Scale	O
+and	O
+the	O
+Dysexecutive	O
+Questionnaire	O
+(	O
+DEX	O
+)	O
+.	O
+
+Compared	O
+with	O
+MDMA	O
+-	O
+free	O
+polydrug	O
+controls	O
+,	O
+MDMA	O
+polydrug	O
+users	O
+showed	O
+impairments	O
+in	O
+set	O
+shifting	O
+and	O
+memory	O
+updating	O
+,	O
+and	O
+also	O
+in	O
+social	O
+and	O
+emotional	O
+judgement	O
+processes	O
+.	O
+
+The	O
+latter	O
+two	O
+deficits	O
+remained	O
+significant	O
+after	O
+controlling	O
+for	O
+other	O
+drug	O
+use	O
+.	O
+
+These	O
+data	O
+lend	O
+further	O
+support	O
+to	O
+the	O
+proposal	O
+that	O
+cognitive	O
+processes	O
+mediated	O
+by	O
+the	O
+prefrontal	O
+cortex	O
+may	O
+be	O
+impaired	O
+by	O
+recreational	O
+ecstasy	O
+use	O
+.	O
+
+Phase	O
+II	O
+study	O
+of	O
+the	O
+amsacrine	O
+analogue	O
+CI	O
+-	O
+921	O
+(	O
+NSC	O
+343499	O
+)	O
+in	O
+non	B
+-	I
+small	I
+cell	I
+lung	I
+cancer	I
+.	O
+
+CI	O
+-	O
+921	O
+(	O
+NSC	O
+343499	O
+;	O
+9	O
+-	O
+[	O
+[	O
+2	O
+-	O
+methoxy	O
+-	O
+4	O
+-	O
+[	O
+(	O
+methylsulphonyl	O
+)	O
+amino	O
+]	O
+phenyl	O
+]	O
+amino	O
+]	O
+-	O
+N	O
+,	O
+5	O
+-	O
+dimethyl	O
+-	O
+4	O
+-	O
+acridinecarboxamide	O
+)	O
+is	O
+a	O
+topoisomerase	O
+II	O
+poison	O
+with	O
+high	O
+experimental	O
+antitumour	O
+activity	O
+.	O
+
+It	O
+was	O
+administered	O
+by	O
+15	O
+min	O
+infusion	O
+to	O
+16	O
+evaluable	O
+patients	O
+with	O
+non	B
+-	I
+small	I
+cell	I
+lung	I
+cancer	I
+(	O
+NSCLC	B
+)	O
+(	O
+7	O
+with	O
+no	O
+prior	O
+treatment	O
+,	O
+9	O
+patients	O
+in	O
+relapse	O
+following	O
+surgery	O
+/	O
+radiotherapy	O
+)	O
+at	O
+a	O
+dose	O
+(	O
+648	O
+mg	O
+/	O
+m2	O
+divided	O
+over	O
+3	O
+days	O
+,	O
+repeated	O
+every	O
+3	O
+weeks	O
+)	O
+determined	O
+by	O
+phase	O
+I	O
+trial	O
+.	O
+
+Patients	O
+had	O
+a	O
+median	O
+performance	O
+status	O
+of	O
+1	O
+(	O
+WHO	O
+)	O
+,	O
+and	O
+median	O
+age	O
+of	O
+61	O
+years	O
+.	O
+
+The	O
+histology	O
+comprised	O
+squamous	B
+carcinoma	I
+(	O
+11	O
+)	O
+,	O
+adenocarcinoma	B
+(	O
+1	O
+)	O
+,	O
+mixed	O
+histology	O
+(	O
+2	O
+)	O
+,	O
+bronchio	B
+-	I
+alveolar	I
+carcinoma	I
+(	O
+1	O
+)	O
+and	O
+large	O
+cell	O
+undifferentiated	B
+carcinoma	I
+(	O
+1	O
+)	O
+.	O
+
+Neutropenia	B
+grade	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+3	O
+was	O
+seen	O
+in	O
+15	O
+patients	O
+,	O
+infections	B
+with	O
+recovery	O
+in	O
+3	O
+,	O
+and	O
+grand	O
+mal	O
+seizures	B
+in	O
+1	O
+patient	O
+.	O
+
+Grade	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+2	O
+nausea	B
+and	O
+vomiting	B
+occurred	O
+in	O
+66	O
+%	O
+courses	O
+and	O
+phlebitis	B
+in	O
+the	O
+infusion	O
+arm	O
+in	O
+37	O
+%	O
+.	O
+
+1	O
+patient	O
+with	O
+squamous	B
+cell	I
+carcinoma	I
+achieved	O
+a	O
+partial	O
+response	O
+lasting	O
+5	O
+months	O
+.	O
+
+Further	O
+testing	O
+in	O
+this	O
+and	O
+other	O
+tumour	B
+types	O
+using	O
+multiple	O
+daily	O
+schedules	O
+is	O
+warranted	O
+.	O
+
+Pharmacokinetics	O
+of	O
+desipramine	O
+HCl	O
+when	O
+administered	O
+with	O
+cinacalcet	O
+HCl	O
+.	O
+
+OBJECTIVE	O
+:	O
+In	O
+vitro	O
+work	O
+has	O
+demonstrated	O
+that	O
+cinacalcet	O
+is	O
+a	O
+strong	O
+inhibitor	O
+of	O
+cytochrome	O
+P450	O
+isoenzyme	O
+(	O
+CYP	O
+)	O
+2D6	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+evaluate	O
+the	O
+effect	O
+of	O
+cinacalcet	O
+on	O
+CYP2D6	O
+activity	O
+,	O
+using	O
+desipramine	O
+as	O
+a	O
+probe	O
+substrate	O
+,	O
+in	O
+healthy	O
+subjects	O
+.	O
+
+METHODS	O
+:	O
+Seventeen	O
+subjects	O
+who	O
+were	O
+genotyped	O
+as	O
+CYP2D6	O
+extensive	O
+metabolizers	O
+were	O
+enrolled	O
+in	O
+this	O
+randomized	O
+,	O
+open	O
+-	O
+label	O
+,	O
+crossover	O
+study	O
+to	O
+receive	O
+a	O
+single	O
+oral	O
+dose	O
+of	O
+desipramine	O
+(	O
+50	O
+mg	O
+)	O
+on	O
+two	O
+separate	O
+occasions	O
+,	O
+once	O
+alone	O
+and	O
+once	O
+after	O
+multiple	O
+doses	O
+of	O
+cinacalcet	O
+(	O
+90	O
+mg	O
+for	O
+7	O
+days	O
+)	O
+.	O
+
+Blood	O
+samples	O
+were	O
+obtained	O
+predose	O
+and	O
+up	O
+to	O
+72	O
+h	O
+postdose	O
+.	O
+
+RESULTS	O
+:	O
+Fourteen	O
+subjects	O
+completed	O
+both	O
+treatment	O
+arms	O
+.	O
+
+Relative	O
+to	O
+desipramine	O
+alone	O
+,	O
+mean	O
+AUC	O
+and	O
+C	O
+(	O
+max	O
+)	O
+of	O
+desipramine	O
+increased	O
+3	O
+.	O
+6	O
+-	O
+and	O
+1	O
+.	O
+8	O
+-	O
+fold	O
+when	O
+coadministered	O
+with	O
+cinacalcet	O
+.	O
+
+The	O
+t	O
+(	O
+1	O
+/	O
+2	O
+,	O
+z	O
+)	O
+of	O
+desipramine	O
+was	O
+longer	O
+when	O
+desipramine	O
+was	O
+coadministered	O
+with	O
+cinacalcet	O
+(	O
+21	O
+.	O
+0	O
+versus	O
+43	O
+.	O
+3	O
+hs	O
+)	O
+.	O
+
+The	O
+t	O
+(	O
+max	O
+)	O
+was	O
+similar	O
+between	O
+the	O
+regimens	O
+.	O
+
+Fewer	O
+subjects	O
+reported	O
+adverse	O
+events	O
+following	O
+treatment	O
+with	O
+desipramine	O
+alone	O
+than	O
+when	O
+receiving	O
+desipramine	O
+with	O
+cinacalcet	O
+(	O
+33	O
+versus	O
+86	O
+%	O
+)	O
+,	O
+the	O
+most	O
+frequent	O
+of	O
+which	O
+(	O
+nausea	B
+and	O
+headache	B
+)	O
+have	O
+been	O
+reported	O
+for	O
+patients	O
+treated	O
+with	O
+either	O
+desipramine	O
+or	O
+cinacalcet	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+study	O
+demonstrates	O
+that	O
+cinacalcet	O
+is	O
+a	O
+strong	O
+inhibitor	O
+of	O
+CYP2D6	O
+.	O
+
+These	O
+data	O
+suggest	O
+that	O
+during	O
+concomitant	O
+treatment	O
+with	O
+cinacalcet	O
+,	O
+dose	O
+adjustment	O
+may	O
+be	O
+necessary	O
+for	O
+drugs	O
+that	O
+demonstrate	O
+a	O
+narrow	O
+therapeutic	O
+index	O
+and	O
+are	O
+metabolized	O
+by	O
+CYP2D6	O
+.	O
+
+Case	O
+report	O
+:	O
+acute	O
+unintentional	O
+carbachol	O
+intoxication	O
+.	O
+
+INTRODUCTION	O
+:	O
+Intoxications	O
+with	O
+carbachol	O
+,	O
+a	O
+muscarinic	O
+cholinergic	O
+receptor	O
+agonist	O
+are	O
+rare	O
+.	O
+
+We	O
+report	O
+an	O
+interesting	O
+case	O
+investigating	O
+a	O
+(	O
+near	O
+)	O
+fatal	O
+poisoning	B
+.	O
+
+METHODS	O
+:	O
+The	O
+son	O
+of	O
+an	O
+84	O
+-	O
+year	O
+-	O
+old	O
+male	O
+discovered	O
+a	O
+newspaper	O
+report	O
+stating	O
+clinical	O
+success	O
+with	O
+plant	O
+extracts	O
+in	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+.	O
+
+The	O
+mode	O
+of	O
+action	O
+was	O
+said	O
+to	O
+be	O
+comparable	O
+to	O
+that	O
+of	O
+the	O
+synthetic	O
+compound	O
+'	O
+carbamylcholin	O
+'	O
+;	O
+that	O
+is	O
+,	O
+carbachol	O
+.	O
+
+He	O
+bought	O
+25	O
+g	O
+of	O
+carbachol	O
+as	O
+pure	O
+substance	O
+in	O
+a	O
+pharmacy	O
+,	O
+and	O
+the	O
+father	O
+was	O
+administered	O
+400	O
+to	O
+500	O
+mg	O
+.	O
+
+Carbachol	O
+concentrations	O
+in	O
+serum	O
+and	O
+urine	O
+on	O
+day	O
+1	O
+and	O
+2	O
+of	O
+hospital	O
+admission	O
+were	O
+analysed	O
+by	O
+HPLC	O
+-	O
+mass	O
+spectrometry	O
+.	O
+
+RESULTS	O
+:	O
+Minutes	O
+after	O
+oral	O
+administration	O
+,	O
+the	O
+patient	O
+developed	O
+nausea	B
+,	O
+sweating	O
+and	O
+hypotension	B
+,	O
+and	O
+finally	O
+collapsed	O
+.	O
+
+Bradycardia	B
+,	O
+cholinergic	O
+symptoms	O
+and	O
+asystole	B
+occurred	O
+.	O
+
+Initial	O
+cardiopulmonary	O
+resuscitation	O
+and	O
+immediate	O
+treatment	O
+with	O
+adrenaline	O
+(	O
+epinephrine	O
+)	O
+,	O
+atropine	O
+and	O
+furosemide	O
+was	O
+successful	O
+.	O
+
+On	O
+hospital	O
+admission	O
+,	O
+blood	O
+pressure	O
+of	O
+the	O
+intubated	O
+,	O
+bradyarrhythmic	O
+patient	O
+was	O
+100	O
+/	O
+65	O
+mmHg	O
+.	O
+
+Further	O
+signs	O
+were	O
+hyperhidrosis	B
+,	O
+hypersalivation	B
+,	O
+bronchorrhoea	B
+,	O
+and	O
+severe	O
+miosis	B
+;	O
+the	O
+electrocardiographic	O
+finding	O
+was	O
+atrio	B
+-	I
+ventricular	I
+dissociation	I
+.	O
+
+High	O
+doses	O
+of	O
+atropine	O
+(	O
+up	O
+to	O
+50	O
+mg	O
+per	O
+24	O
+hours	O
+)	O
+,	O
+adrenaline	O
+and	O
+dopamine	O
+were	O
+necessary	O
+.	O
+
+The	O
+patient	O
+was	O
+extubated	O
+1	O
+week	O
+later	O
+.	O
+
+However	O
+,	O
+increased	O
+dyspnoea	B
+and	O
+bronchospasm	B
+necessitated	O
+reintubation	O
+.	O
+
+Respiratory	B
+insufficiency	I
+was	O
+further	O
+worsened	O
+by	O
+Proteus	B
+mirabilis	I
+infection	I
+and	O
+severe	O
+bronchoconstriction	O
+.	O
+
+One	O
+week	O
+later	O
+,	O
+the	O
+patient	O
+was	O
+again	O
+extubated	O
+and	O
+3	O
+days	O
+later	O
+was	O
+transferred	O
+to	O
+a	O
+peripheral	O
+ward	O
+.	O
+
+On	O
+the	O
+next	O
+day	O
+he	O
+died	O
+,	O
+probably	O
+as	O
+a	O
+result	O
+of	O
+heart	B
+failure	I
+.	O
+
+Serum	O
+samples	O
+from	O
+the	O
+first	O
+and	O
+second	O
+days	O
+contained	O
+3	O
+.	O
+6	O
+and	O
+1	O
+.	O
+9	O
+mg	O
+/	O
+l	O
+carbachol	O
+,	O
+respectively	O
+.	O
+
+The	O
+corresponding	O
+urine	O
+concentrations	O
+amounted	O
+to	O
+374	O
+and	O
+554	O
+mg	O
+/	O
+l	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+case	O
+started	O
+with	O
+a	O
+media	O
+report	O
+in	O
+a	O
+popular	O
+newspaper	O
+,	O
+initiated	O
+by	O
+published	O
+,	O
+peer	O
+-	O
+reviewed	O
+research	O
+on	O
+herbals	O
+,	O
+and	O
+involved	O
+human	O
+failure	O
+in	O
+a	O
+case	O
+history	O
+,	O
+medical	O
+examination	O
+and	O
+clinical	O
+treatment	O
+.	O
+
+For	O
+the	O
+first	O
+time	O
+,	O
+an	O
+analytical	O
+method	O
+for	O
+the	O
+determination	O
+of	O
+carbachol	O
+in	O
+plasma	O
+and	O
+urine	O
+has	O
+been	O
+developed	O
+.	O
+
+The	O
+analysed	O
+carbachol	O
+concentration	O
+exceeded	O
+the	O
+supposed	O
+serum	O
+level	O
+resulting	O
+from	O
+a	O
+therapeutic	O
+dose	O
+by	O
+a	O
+factor	O
+of	O
+130	O
+to	O
+260	O
+.	O
+
+Especially	O
+in	O
+old	O
+patients	O
+,	O
+intensivists	O
+should	O
+consider	O
+intoxications	O
+(	O
+with	O
+cholinergics	O
+)	O
+as	O
+a	O
+cause	O
+of	O
+acute	B
+cardiovascular	I
+failure	I
+.	O
+
+Pharmacological	O
+evidence	O
+for	O
+the	O
+potential	O
+of	O
+Daucus	O
+carota	O
+in	O
+the	O
+management	O
+of	O
+cognitive	B
+dysfunctions	I
+.	O
+
+The	O
+present	O
+study	O
+was	O
+aimed	O
+at	O
+investigating	O
+the	O
+effects	O
+of	O
+Daucus	O
+carota	O
+seeds	O
+on	O
+cognitive	O
+functions	O
+,	O
+total	O
+serum	O
+cholesterol	O
+levels	O
+and	O
+brain	O
+cholinesterase	O
+activity	O
+in	O
+mice	O
+.	O
+
+The	O
+ethanolic	O
+extract	O
+of	O
+Daucus	O
+carota	O
+seeds	O
+(	O
+DCE	O
+)	O
+was	O
+administered	O
+orally	O
+in	O
+three	O
+doses	O
+(	O
+100	O
+,	O
+200	O
+,	O
+400	O
+mg	O
+/	O
+kg	O
+)	O
+for	O
+seven	O
+successive	O
+days	O
+to	O
+different	O
+groups	O
+of	O
+young	O
+and	O
+aged	O
+mice	O
+.	O
+
+Elevated	O
+plus	O
+maze	O
+and	O
+passive	O
+avoidance	O
+apparatus	O
+served	O
+as	O
+the	O
+exteroceptive	O
+behavioral	O
+models	O
+for	O
+testing	O
+memory	O
+.	O
+
+Diazepam	O
+-	O
+,	O
+scopolamine	O
+-	O
+and	O
+ageing	O
+-	O
+induced	O
+amnesia	B
+served	O
+as	O
+the	O
+interoceptive	O
+behavioral	O
+models	O
+.	O
+
+DCE	O
+(	O
+200	O
+,	O
+400	O
+mg	O
+/	O
+kg	O
+,	O
+p	O
+.	O
+o	O
+.	O
+)	O
+showed	O
+significant	O
+improvement	O
+in	O
+memory	O
+scores	O
+of	O
+young	O
+and	O
+aged	O
+mice	O
+.	O
+
+The	O
+extent	O
+of	O
+memory	O
+improvement	O
+evoked	O
+by	O
+DCE	O
+was	O
+23	O
+%	O
+at	O
+the	O
+dose	O
+of	O
+200	O
+mg	O
+/	O
+kg	O
+and	O
+35	O
+%	O
+at	O
+the	O
+dose	O
+of	O
+400	O
+mg	O
+/	O
+kg	O
+in	O
+young	O
+mice	O
+using	O
+elevated	O
+plus	O
+maze	O
+.	O
+
+Similarly	O
+,	O
+significant	O
+improvements	O
+in	O
+memory	O
+scores	O
+were	O
+observed	O
+using	O
+passive	O
+avoidance	O
+apparatus	O
+and	O
+aged	O
+mice	O
+.	O
+
+Furthermore	O
+,	O
+DCE	O
+reversed	O
+the	O
+amnesia	B
+induced	O
+by	O
+scopolamine	O
+(	O
+0	O
+.	O
+4	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+and	O
+diazepam	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+Daucus	O
+carota	O
+extract	O
+(	O
+200	O
+,	O
+400	O
+mg	O
+/	O
+kg	O
+,	O
+p	O
+.	O
+o	O
+.	O
+)	O
+reduced	O
+significantly	O
+the	O
+brain	O
+acetylcholinesterase	O
+activity	O
+and	O
+cholesterol	O
+levels	O
+in	O
+young	O
+and	O
+aged	O
+mice	O
+.	O
+
+The	O
+extent	O
+of	O
+inhibition	O
+of	O
+brain	O
+cholinesterase	O
+activity	O
+evoked	O
+by	O
+DCE	O
+at	O
+the	O
+dose	O
+of	O
+400	O
+mg	O
+/	O
+kg	O
+was	O
+22	O
+%	O
+in	O
+young	O
+and	O
+19	O
+%	O
+in	O
+aged	O
+mice	O
+.	O
+
+There	O
+was	O
+a	O
+remarkable	O
+reduction	O
+in	O
+total	O
+cholesterol	O
+level	O
+as	O
+well	O
+,	O
+to	O
+the	O
+extent	O
+of	O
+23	O
+%	O
+in	O
+young	O
+and	O
+21	O
+%	O
+in	O
+aged	O
+animals	O
+with	O
+this	O
+dose	O
+of	O
+DCE	O
+.	O
+
+Therefore	O
+,	O
+DCE	O
+may	O
+prove	O
+to	O
+be	O
+a	O
+useful	O
+remedy	O
+for	O
+the	O
+management	O
+of	O
+cognitive	B
+dysfunctions	I
+on	O
+account	O
+of	O
+its	O
+multifarious	O
+beneficial	O
+effects	O
+such	O
+as	O
+,	O
+memory	O
+improving	O
+property	O
+,	O
+cholesterol	O
+lowering	O
+property	O
+and	O
+anticholinesterase	O
+activity	O
+.	O
+
+Valproic	O
+acid	O
+induced	O
+encephalopathy	B
+-	O
+-	O
+19	O
+new	O
+cases	O
+in	O
+Germany	O
+from	O
+1994	O
+to	O
+2003	O
+-	O
+-	O
+a	O
+side	O
+effect	O
+associated	O
+to	O
+VPA	O
+-	O
+therapy	O
+not	O
+only	O
+in	O
+young	O
+children	O
+.	O
+
+Valproic	O
+acid	O
+(	O
+VPA	O
+)	O
+is	O
+a	O
+broad	O
+-	O
+spectrum	O
+antiepileptic	O
+drug	O
+and	O
+is	O
+usually	O
+well	O
+-	O
+tolerated	O
+.	O
+
+Rare	O
+serious	O
+complications	O
+may	O
+occur	O
+in	O
+some	O
+patients	O
+,	O
+including	O
+haemorrhagic	O
+pancreatitis	B
+,	O
+bone	B
+marrow	I
+suppression	I
+,	O
+VPA	O
+-	O
+induced	O
+hepatotoxicity	B
+and	O
+VPA	O
+-	O
+induced	O
+encephalopathy	B
+.	O
+
+The	O
+typical	O
+signs	O
+of	O
+VPA	O
+-	O
+induced	O
+encephalopathy	B
+are	O
+impaired	B
+consciousness	I
+,	O
+sometimes	O
+marked	O
+EEG	O
+background	O
+slowing	O
+,	O
+increased	O
+seizure	B
+frequency	O
+,	O
+with	O
+or	O
+without	O
+hyperammonemia	B
+.	O
+
+There	O
+is	O
+still	O
+no	O
+proof	O
+of	O
+causative	O
+effect	O
+of	O
+VPA	O
+in	O
+patients	O
+with	O
+encephalopathy	B
+,	O
+but	O
+only	O
+of	O
+an	O
+association	O
+with	O
+an	O
+assumed	O
+causal	O
+relation	O
+.	O
+
+We	O
+report	O
+19	O
+patients	O
+with	O
+VPA	O
+-	O
+associated	O
+encephalopathy	B
+in	O
+Germany	O
+from	O
+the	O
+years	O
+1994	O
+to	O
+2003	O
+,	O
+none	O
+of	O
+whom	O
+had	O
+been	O
+published	O
+previously	O
+.	O
+
+Cerebral	B
+haemorrhage	I
+induced	O
+by	O
+warfarin	O
+-	O
+the	O
+influence	O
+of	O
+drug	O
+-	O
+drug	O
+interactions	O
+.	O
+
+PURPOSE	O
+:	O
+To	O
+evaluate	O
+the	O
+frequency	O
+,	O
+severity	O
+and	O
+preventability	O
+of	O
+warfarin	O
+-	O
+induced	O
+cerebral	B
+haemorrhages	I
+due	O
+to	O
+warfarin	O
+and	O
+warfarin	O
+-	O
+drug	O
+interactions	O
+in	O
+patients	O
+living	O
+in	O
+the	O
+county	O
+of	O
+Osterg	O
+tland	O
+,	O
+Sweden	O
+.	O
+
+METHODS	O
+:	O
+All	O
+patients	O
+with	O
+a	O
+diagnosed	O
+cerebral	B
+haemorrhage	I
+at	O
+three	O
+hospitals	O
+during	O
+the	O
+period	O
+2000	O
+-	O
+2002	O
+were	O
+identified	O
+.	O
+
+Medical	O
+records	O
+were	O
+studied	O
+retrospectively	O
+to	O
+evaluate	O
+whether	O
+warfarin	O
+and	O
+warfarin	O
+-	O
+drug	O
+interactions	O
+could	O
+have	O
+caused	O
+the	O
+cerebral	B
+haemorrhage	I
+.	O
+
+The	O
+proportion	O
+of	O
+possibly	O
+avoidable	O
+cases	O
+due	O
+to	O
+drug	O
+interactions	O
+was	O
+estimated	O
+.	O
+
+RESULTS	O
+:	O
+Among	O
+593	O
+patients	O
+with	O
+cerebral	B
+haemorrhage	I
+,	O
+59	O
+(	O
+10	O
+%	O
+)	O
+were	O
+assessed	O
+as	O
+related	O
+to	O
+warfarin	O
+treatment	O
+.	O
+
+This	O
+imply	O
+an	O
+incidence	O
+of	O
+1	O
+.	O
+7	O
+/	O
+100	O
+,	O
+000	O
+treatment	O
+years	O
+.	O
+
+Of	O
+the	O
+59	O
+cases	O
+,	O
+26	O
+(	O
+44	O
+%	O
+)	O
+had	O
+a	O
+fatal	O
+outcome	O
+,	O
+compared	O
+to	O
+136	O
+(	O
+25	O
+%	O
+)	O
+among	O
+the	O
+non	O
+-	O
+warfarin	O
+patients	O
+(	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+A	O
+warfarin	O
+-	O
+drug	O
+interaction	O
+could	O
+have	O
+contributed	O
+to	O
+the	O
+haemorrhage	B
+in	O
+24	O
+(	O
+41	O
+%	O
+)	O
+of	O
+the	O
+warfarin	O
+patients	O
+and	O
+in	O
+7	O
+of	O
+these	O
+(	O
+12	O
+%	O
+)	O
+the	O
+bleeding	B
+complication	O
+was	O
+considered	O
+being	O
+possible	O
+to	O
+avoid	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Warfarin	O
+-	O
+induced	O
+cerebral	B
+haemorrhages	I
+are	O
+a	O
+major	O
+clinical	O
+problem	O
+with	O
+a	O
+high	O
+fatality	O
+rate	O
+.	O
+
+Almost	O
+half	O
+of	O
+the	O
+cases	O
+was	O
+related	O
+to	O
+a	O
+warfarin	O
+-	O
+drug	O
+interaction	O
+.	O
+
+A	O
+significant	O
+proportion	O
+of	O
+warfarin	O
+-	O
+related	O
+cerebral	B
+haemorrhages	I
+might	O
+have	O
+been	O
+prevented	O
+if	O
+greater	O
+caution	O
+had	O
+been	O
+taken	O
+when	O
+prescribing	O
+drugs	O
+known	O
+to	O
+interact	O
+with	O
+warfarin	O
+.	O
+
+Antipsychotic	O
+-	O
+like	O
+profile	O
+of	O
+thioperamide	O
+,	O
+a	O
+selective	O
+H3	O
+-	O
+receptor	O
+antagonist	O
+in	O
+mice	O
+.	O
+
+Experimental	O
+and	O
+clinical	O
+evidence	O
+points	O
+to	O
+a	O
+role	O
+of	O
+central	O
+histaminergic	O
+system	O
+in	O
+the	O
+pathogenesis	O
+of	O
+schizophrenia	B
+.	O
+
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+study	O
+the	O
+effect	O
+of	O
+histamine	O
+H	O
+(	O
+3	O
+)	O
+-	O
+receptor	O
+ligands	O
+on	O
+neuroleptic	O
+-	O
+induced	O
+catalepsy	B
+,	O
+apomorphine	O
+-	O
+induced	O
+climbing	O
+behavior	O
+and	O
+amphetamine	O
+-	O
+induced	O
+locomotor	O
+activities	O
+in	O
+mice	O
+.	O
+
+Catalepsy	B
+was	O
+induced	O
+by	O
+haloperidol	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+)	O
+,	O
+while	O
+apomorphine	O
+(	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+and	O
+amphetamine	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+were	O
+used	O
+for	O
+studying	O
+climbing	O
+behavior	O
+and	O
+locomotor	O
+activities	O
+,	O
+respectively	O
+.	O
+
+(	O
+R	O
+)	O
+-	O
+alpha	O
+-	O
+methylhistamine	O
+(	O
+RAMH	O
+)	O
+(	O
+5	O
+microg	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+and	O
+thioperamide	O
+(	O
+THP	O
+)	O
+(	O
+15	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+,	O
+per	O
+se	O
+did	O
+not	O
+cause	O
+catalepsy	B
+.	O
+
+Administration	O
+of	O
+THP	O
+(	O
+3	O
+.	O
+75	O
+,	O
+7	O
+.	O
+5	O
+and	O
+15	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+1	O
+h	O
+prior	O
+to	O
+haloperidol	O
+resulted	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+increase	O
+in	O
+the	O
+catalepsy	B
+times	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+However	O
+,	O
+pretreatment	O
+with	O
+RAMH	O
+significantly	O
+reversed	O
+such	O
+an	O
+effect	O
+of	O
+THP	O
+(	O
+15	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+RAMH	O
+per	O
+se	O
+showed	O
+significant	O
+reduction	O
+in	O
+locomotor	O
+time	O
+,	O
+distance	O
+traveled	O
+and	O
+average	O
+speed	O
+but	O
+THP	O
+(	O
+15	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+per	O
+se	O
+had	O
+no	O
+effect	O
+on	O
+these	O
+parameters	O
+.	O
+
+On	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B
+,	O
+THP	O
+(	O
+3	O
+.	O
+75	O
+and	O
+7	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+reduced	O
+locomotor	O
+time	O
+,	O
+distance	O
+traveled	O
+and	O
+average	O
+speed	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Pretreatment	O
+with	O
+RAMH	O
+(	O
+5	O
+microg	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+could	O
+partially	O
+reverse	O
+such	O
+effects	O
+of	O
+THP	O
+(	O
+3	O
+.	O
+75	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+Climbing	O
+behavior	O
+induced	O
+by	O
+apomorphine	O
+was	O
+reduced	O
+in	O
+animals	O
+treated	O
+with	O
+THP	O
+.	O
+
+Such	O
+an	O
+effect	O
+was	O
+,	O
+however	O
+,	O
+reversed	O
+in	O
+presence	O
+of	O
+RAMH	O
+.	O
+
+THP	O
+exhibited	O
+an	O
+antipsychotic	O
+-	O
+like	O
+profile	O
+by	O
+potentiating	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+,	O
+reducing	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B
+and	O
+reducing	O
+apomorphine	O
+-	O
+induced	O
+climbing	O
+in	O
+mice	O
+.	O
+
+Such	O
+effects	O
+of	O
+THP	O
+were	O
+reversed	O
+by	O
+RAMH	O
+indicating	O
+the	O
+involvement	O
+of	O
+histamine	O
+H	O
+(	O
+3	O
+)	O
+-	O
+receptors	O
+.	O
+
+Findings	O
+suggest	O
+a	O
+potential	O
+for	O
+H	O
+(	O
+3	O
+)	O
+-	O
+receptor	O
+antagonists	O
+in	O
+improving	O
+the	O
+refractory	O
+cases	O
+of	O
+schizophrenia	B
+.	O
+
+Cauda	B
+equina	I
+syndrome	I
+after	O
+epidural	O
+steroid	O
+injection	O
+:	O
+a	O
+case	O
+report	O
+.	O
+
+OBJECTIVE	O
+:	O
+Conventional	O
+treatment	O
+methods	O
+of	O
+lumbusacral	O
+radiculopathy	B
+are	O
+physical	O
+therapy	O
+,	O
+epidural	O
+steroid	O
+injections	O
+,	O
+oral	O
+medications	O
+,	O
+and	O
+spinal	O
+manipulative	O
+therapy	O
+.	O
+
+Cauda	B
+equina	I
+syndrome	I
+is	O
+a	O
+rare	O
+complication	O
+of	O
+epidural	O
+anesthesia	O
+.	O
+
+The	O
+following	O
+case	O
+is	O
+a	O
+report	O
+of	O
+cauda	B
+equina	I
+syndrome	I
+possibly	O
+caused	O
+by	O
+epidural	O
+injection	O
+of	O
+triamcinolone	O
+and	O
+bupivacaine	O
+.	O
+
+CLINICAL	O
+FEATURES	O
+:	O
+A	O
+50	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+low	B
+back	I
+and	I
+right	I
+leg	I
+pain	I
+was	O
+scheduled	O
+for	O
+epidural	O
+steroid	O
+injection	O
+.	O
+
+INTERVENTION	O
+AND	O
+OUTCOME	O
+:	O
+An	O
+18	O
+-	O
+gauge	O
+Touhy	O
+needle	O
+was	O
+inserted	O
+until	O
+loss	O
+of	O
+resistance	O
+occurred	O
+at	O
+the	O
+L4	O
+-	O
+5	O
+level	O
+.	O
+
+Spread	O
+of	O
+the	O
+contrast	O
+medium	O
+within	O
+the	O
+epidural	O
+space	O
+was	O
+determined	O
+by	O
+radiographic	O
+imaging	O
+.	O
+
+After	O
+verifying	O
+the	O
+epidural	O
+space	O
+,	O
+bupivacaine	O
+and	O
+triamcinolone	O
+diacetate	O
+were	O
+injected	O
+.	O
+
+After	O
+the	O
+injection	O
+,	O
+there	O
+was	O
+a	O
+reduction	O
+in	O
+radicular	O
+symptoms	O
+.	O
+
+Three	O
+hours	O
+later	O
+,	O
+she	O
+complained	O
+of	O
+perineal	O
+numbness	B
+and	O
+lower	B
+extremity	I
+weakness	I
+.	O
+
+The	O
+neurologic	O
+evaluation	O
+revealed	O
+loss	B
+of	I
+sensation	I
+in	O
+the	O
+saddle	O
+area	O
+and	O
+medial	O
+aspect	O
+of	O
+her	O
+right	O
+leg	O
+.	O
+
+There	O
+was	O
+a	O
+decrease	O
+in	O
+the	O
+perception	O
+of	O
+pinprick	O
+test	O
+.	O
+
+Deep	O
+-	O
+tendon	O
+reflexes	O
+were	O
+decreased	O
+especially	O
+in	O
+the	O
+right	O
+leg	O
+.	O
+
+She	O
+was	O
+unable	O
+to	O
+urinate	O
+.	O
+
+The	O
+patient	O
+'	O
+s	O
+symptoms	O
+improved	O
+slightly	O
+over	O
+the	O
+next	O
+few	O
+hours	O
+.	O
+
+She	O
+had	O
+a	O
+gradual	O
+return	O
+of	O
+motor	O
+function	O
+and	O
+ability	O
+of	O
+feeling	O
+Foley	O
+catheter	O
+.	O
+
+All	O
+of	O
+the	O
+symptoms	O
+were	O
+completely	O
+resolved	O
+over	O
+the	O
+next	O
+8	O
+hours	O
+.	O
+
+CONCLUSION	O
+:	O
+Complications	O
+associated	O
+with	O
+epidural	O
+steroid	O
+injections	O
+are	O
+rare	O
+.	O
+
+Clinical	O
+examination	O
+and	O
+continued	O
+vigilance	O
+for	O
+neurologic	B
+deterioration	I
+after	O
+epidural	O
+steroid	O
+injections	O
+is	O
+important	O
+.	O
+
+High	O
+-	O
+dose	O
+testosterone	O
+is	O
+associated	O
+with	O
+atherosclerosis	B
+in	O
+postmenopausal	O
+women	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+study	O
+the	O
+long	O
+-	O
+term	O
+effects	O
+of	O
+androgen	O
+treatment	O
+on	O
+atherosclerosis	B
+in	O
+postmenopausal	O
+women	O
+.	O
+
+METHODS	O
+:	O
+In	O
+a	O
+population	O
+-	O
+based	O
+study	O
+in	O
+513	O
+naturally	O
+postmenopausal	O
+women	O
+aged	O
+54	O
+-	O
+67	O
+years	O
+,	O
+we	O
+studied	O
+the	O
+association	O
+between	O
+self	O
+-	O
+reported	O
+intramuscularly	O
+administered	O
+high	O
+-	O
+dose	O
+estrogen	O
+-	O
+testosterone	O
+therapy	O
+(	O
+estradiol	O
+-	O
+and	O
+testosterone	O
+esters	O
+)	O
+and	O
+aortic	O
+atherosclerosis	B
+.	O
+
+Aortic	O
+atherosclerosis	B
+was	O
+diagnosed	O
+by	O
+radiographic	O
+detection	O
+of	O
+calcified	O
+deposits	O
+in	O
+the	O
+abdominal	O
+aorta	O
+,	O
+which	O
+have	O
+been	O
+shown	O
+to	O
+reflect	O
+intima	O
+atherosclerosis	B
+.	O
+
+Hormone	O
+therapy	O
+users	O
+were	O
+compared	O
+with	O
+never	O
+users	O
+.	O
+
+RESULTS	O
+:	O
+Intramuscular	O
+hormone	O
+therapy	O
+use	O
+for	O
+1	O
+year	O
+or	O
+longer	O
+was	O
+reported	O
+by	O
+25	O
+women	O
+.	O
+
+In	O
+almost	O
+half	O
+of	O
+these	O
+women	O
+severe	O
+atherosclerosis	B
+of	O
+the	O
+aorta	O
+was	O
+present	O
+(	O
+n	O
+=	O
+11	O
+)	O
+,	O
+while	O
+in	O
+women	O
+without	O
+hormone	O
+use	O
+severe	O
+atherosclerosis	B
+of	O
+the	O
+aorta	O
+was	O
+present	O
+in	O
+less	O
+than	O
+20	O
+%	O
+(	O
+OR	O
+3	O
+.	O
+1	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+1	O
+-	O
+8	O
+.	O
+5	O
+,	O
+adjusted	O
+for	O
+age	O
+,	O
+years	O
+since	O
+menopause	O
+,	O
+smoking	O
+,	O
+and	O
+body	O
+mass	O
+index	O
+)	O
+.	O
+
+The	O
+association	O
+remained	O
+after	O
+additional	O
+adjustment	O
+for	O
+diabetes	B
+,	O
+cholesterol	O
+level	O
+,	O
+systolic	O
+blood	O
+pressure	O
+,	O
+or	O
+alcohol	O
+use	O
+.	O
+
+No	O
+association	O
+was	O
+found	O
+for	O
+hormone	O
+use	O
+less	O
+than	O
+1	O
+year	O
+.	O
+
+CONCLUSION	O
+:	O
+Our	O
+results	O
+suggest	O
+that	O
+high	O
+-	O
+dose	O
+testosterone	O
+therapy	O
+may	O
+adversely	O
+affect	O
+atherosclerosis	B
+in	O
+postmenopausal	O
+women	O
+and	O
+indicate	O
+that	O
+androgen	O
+replacement	O
+in	O
+these	O
+women	O
+may	O
+not	O
+be	O
+harmless	O
+.	O
+
+Optimising	O
+stroke	B
+prevention	O
+in	O
+non	O
+-	O
+valvular	O
+atrial	B
+fibrillation	I
+.	O
+
+Atrial	B
+fibrillation	I
+is	O
+associated	O
+with	O
+substantial	O
+morbidity	O
+and	O
+mortality	O
+.	O
+
+Pooled	O
+data	O
+from	O
+trials	O
+comparing	O
+antithrombotic	O
+treatment	O
+with	O
+placebo	O
+have	O
+shown	O
+that	O
+warfarin	O
+reduces	O
+the	O
+risk	O
+of	O
+stroke	B
+by	O
+62	O
+%	O
+,	O
+and	O
+that	O
+aspirin	O
+alone	O
+reduces	O
+the	O
+risk	O
+by	O
+22	O
+%	O
+.	O
+
+Overall	O
+,	O
+in	O
+high	O
+-	O
+risk	O
+patients	O
+,	O
+warfarin	O
+is	O
+superior	O
+to	O
+aspirin	O
+in	O
+preventing	O
+strokes	B
+,	O
+with	O
+a	O
+relative	O
+risk	O
+reduction	O
+of	O
+36	O
+%	O
+.	O
+
+Ximelagatran	O
+,	O
+an	O
+oral	O
+direct	O
+thrombin	O
+inhibitor	O
+,	O
+was	O
+found	O
+to	O
+be	O
+as	O
+efficient	O
+as	O
+vitamin	O
+K	O
+antagonist	O
+drugs	O
+in	O
+the	O
+prevention	O
+of	O
+embolic	B
+events	I
+,	O
+but	O
+has	O
+been	O
+recently	O
+withdrawn	O
+because	O
+of	O
+abnormal	B
+liver	I
+function	I
+tests	O
+.	O
+
+The	O
+ACTIVE	O
+-	O
+W	O
+(	O
+Atrial	B
+Fibrillation	I
+Clopidogrel	O
+Trial	O
+with	O
+Irbesartan	O
+for	O
+Prevention	O
+of	O
+Vascular	O
+Events	O
+)	O
+study	O
+has	O
+demonstrated	O
+that	O
+warfarin	O
+is	O
+superior	O
+to	O
+platelet	O
+therapy	O
+(	O
+clopidogrel	O
+plus	O
+aspirin	O
+)	O
+in	O
+the	O
+prevention	O
+af	O
+embolic	B
+events	I
+.	O
+
+Idraparinux	O
+,	O
+a	O
+Factor	O
+Xa	O
+inhibitor	O
+,	O
+is	O
+being	O
+evaluated	O
+in	O
+patients	O
+with	O
+atrial	B
+fibrillation	I
+.	O
+
+Angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitors	O
+and	O
+angiotensin	O
+II	O
+receptor	O
+-	O
+blocking	O
+drugs	O
+hold	O
+promise	O
+in	O
+atrial	B
+fibrillation	I
+through	O
+cardiac	B
+remodelling	I
+.	O
+
+Preliminary	O
+studies	O
+suggest	O
+that	O
+statins	O
+could	O
+interfere	O
+with	O
+the	O
+risk	O
+of	O
+recurrence	O
+after	O
+electrical	O
+cardioversion	O
+.	O
+
+Finally	O
+,	O
+percutaneous	O
+methods	O
+for	O
+the	O
+exclusion	O
+of	O
+left	O
+atrial	O
+appendage	O
+are	O
+under	O
+investigation	O
+in	O
+high	O
+-	O
+risk	O
+patients	O
+.	O
+
+Anti	O
+-	O
+oxidant	O
+effects	O
+of	O
+atorvastatin	O
+in	O
+dexamethasone	O
+-	O
+induced	O
+hypertension	B
+in	O
+the	O
+rat	O
+.	O
+
+1	O
+.	O
+
+Dexamethasone	O
+(	O
+Dex	O
+)	O
+-	O
+induced	O
+hypertension	B
+is	O
+characterized	O
+by	O
+endothelial	O
+dysfunction	O
+associated	O
+with	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+deficiency	O
+and	O
+increased	O
+superoxide	O
+(	O
+O2	O
+-	O
+)	O
+production	O
+.	O
+
+Atorvastatin	O
+(	O
+Ato	O
+)	O
+possesses	O
+pleiotropic	O
+properties	O
+that	O
+have	O
+been	O
+reported	O
+to	O
+improve	O
+endothelial	O
+function	O
+through	O
+increased	O
+availability	O
+of	O
+NO	O
+and	O
+reduced	O
+O2	O
+-	O
+production	O
+in	O
+various	O
+forms	O
+of	O
+hypertension	B
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+we	O
+investigated	O
+whether	O
+50	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+,	O
+p	O
+.	O
+o	O
+.	O
+,	O
+Ato	O
+could	O
+prevent	O
+endothelial	O
+NO	O
+synthase	O
+(	O
+eNOS	O
+)	O
+downregulation	O
+and	O
+the	O
+increase	O
+in	O
+O2	O
+-	O
+in	O
+Sprague	O
+-	O
+Dawley	O
+(	O
+SD	O
+)	O
+rats	O
+,	O
+thereby	O
+reducing	O
+blood	O
+pressure	O
+.	O
+
+2	O
+.	O
+
+Male	O
+SD	O
+rats	O
+(	O
+n	O
+=	O
+30	O
+)	O
+were	O
+treated	O
+with	O
+Ato	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+in	O
+drinking	O
+water	O
+)	O
+or	O
+tap	O
+water	O
+for	O
+15	O
+days	O
+.	O
+
+Dexamethasone	O
+(	O
+10	O
+microg	O
+/	O
+kg	O
+per	O
+day	O
+,	O
+s	O
+.	O
+c	O
+.	O
+)	O
+or	O
+saline	O
+was	O
+started	O
+after	O
+4	O
+days	O
+in	O
+Ato	O
+-	O
+treated	O
+and	O
+non	O
+-	O
+treated	O
+rats	O
+and	O
+continued	O
+for	O
+11	O
+-	O
+13	O
+days	O
+.	O
+
+Systolic	O
+blood	O
+pressure	O
+(	O
+SBP	O
+)	O
+was	O
+measured	O
+on	O
+alternate	O
+days	O
+using	O
+the	O
+tail	O
+-	O
+cuff	O
+method	O
+.	O
+
+Endothelial	O
+function	O
+was	O
+assessed	O
+by	O
+acetylcholine	O
+-	O
+induced	O
+vasorelaxation	O
+and	O
+phenylephrine	O
+-	O
+induced	O
+vasoconstriction	O
+in	O
+aortic	O
+segments	O
+.	O
+
+Vascular	O
+eNOS	O
+mRNA	O
+was	O
+assessed	O
+by	O
+semi	O
+-	O
+quantitative	O
+reverse	O
+transcription	O
+-	O
+polymerase	O
+chain	O
+reaction	O
+.	O
+
+3	O
+.	O
+
+In	O
+rats	O
+treated	O
+with	O
+Dex	O
+alone	O
+,	O
+SBP	O
+was	O
+increased	O
+from	O
+109	O
++	O
+/	O
+-	O
+2	O
+to	O
+133	O
++	O
+/	O
+-	O
+2	O
+mmHg	O
+on	O
+Days	O
+4	O
+and	O
+Day	O
+14	O
+,	O
+respectively	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+In	O
+the	O
+Ato	O
++	O
+Dex	O
+group	O
+,	O
+SBP	O
+was	O
+increased	O
+from	O
+113	O
++	O
+/	O
+-	O
+2	O
+to	O
+119	O
++	O
+/	O
+-	O
+2	O
+mmHg	O
+on	O
+Days	O
+4	O
+to	O
+14	O
+,	O
+respectively	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+,	O
+but	O
+was	O
+significantly	O
+lower	O
+than	O
+SBP	O
+in	O
+the	O
+group	O
+treated	O
+with	O
+Dex	O
+alone	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Endothelial	O
+-	O
+dependent	O
+relaxation	O
+and	O
+eNOS	O
+mRNA	O
+expression	O
+were	O
+greater	O
+in	O
+the	O
+Dex	O
++	O
+Ato	O
+group	O
+than	O
+in	O
+the	O
+Dex	O
+only	O
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+and	O
+P	O
+<	O
+0	O
+.	O
+0001	O
+,	O
+respectively	O
+)	O
+.	O
+
+Aortic	O
+superoxide	O
+production	O
+was	O
+lower	O
+in	O
+the	O
+Dex	O
++	O
+Ato	O
+group	O
+compared	O
+with	O
+the	O
+group	O
+treated	O
+with	O
+Dex	O
+alone	O
+(	O
+P	O
+<	O
+0	O
+.	O
+0001	O
+)	O
+.	O
+
+4	O
+.	O
+
+Treatment	O
+with	O
+Ato	O
+improved	O
+endothelial	O
+function	O
+,	O
+reduced	O
+superoxide	O
+production	O
+and	O
+reduced	O
+SBP	O
+in	O
+Dex	O
+-	O
+treated	O
+SD	O
+rats	O
+.	O
+
+Severe	O
+citrate	O
+toxicity	B
+complicating	O
+volunteer	O
+apheresis	O
+platelet	O
+donation	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+severe	O
+citrate	O
+toxicity	B
+during	O
+volunteer	O
+donor	O
+apheresis	O
+platelet	O
+collection	O
+.	O
+
+The	O
+donor	O
+was	O
+a	O
+40	O
+-	O
+year	O
+-	O
+old	O
+female	O
+,	O
+first	O
+-	O
+time	O
+apheresis	O
+platelet	O
+donor	O
+.	O
+
+Past	O
+medical	O
+history	O
+was	O
+remarkable	O
+for	O
+hypertension	B
+,	O
+hyperlipidemia	B
+,	O
+and	O
+depression	B
+.	O
+
+Reported	O
+medications	O
+included	O
+bumetanide	O
+,	O
+pravastatin	O
+,	O
+and	O
+paroxetine	O
+.	O
+
+Thirty	O
+minutes	O
+from	O
+the	O
+start	O
+of	O
+the	O
+procedure	O
+,	O
+the	O
+donor	O
+noted	O
+tingling	O
+around	O
+the	O
+mouth	O
+,	O
+hands	O
+,	O
+and	O
+feet	O
+.	O
+
+She	O
+then	O
+very	O
+rapidly	O
+developed	O
+acute	O
+onset	O
+of	O
+severe	O
+facial	O
+and	O
+extremity	O
+tetany	B
+.	O
+
+Empirical	O
+treatment	O
+with	O
+intravenous	O
+calcium	O
+gluconate	O
+was	O
+initiated	O
+,	O
+and	O
+muscle	B
+contractions	I
+slowly	O
+subsided	O
+over	O
+approximately	O
+10	O
+to	O
+15	O
+minutes	O
+.	O
+
+The	O
+events	O
+are	O
+consistent	O
+with	O
+a	O
+severe	O
+reaction	O
+to	O
+calcium	O
+chelation	O
+by	O
+sodium	O
+citrate	O
+anticoagulant	O
+resulting	O
+in	O
+symptomatic	O
+systemic	O
+hypocalcemia	B
+.	O
+
+Upon	O
+additional	O
+retrospective	O
+analysis	O
+,	O
+it	O
+was	O
+noted	O
+that	O
+bumetanide	O
+is	O
+a	O
+loop	O
+diuretic	O
+that	O
+may	O
+cause	O
+significant	O
+hypocalcemia	B
+.	O
+
+We	O
+conclude	O
+that	O
+careful	O
+screening	O
+for	O
+medications	O
+and	O
+underlying	O
+conditions	O
+predisposing	O
+to	O
+hypocalcemia	B
+is	O
+recommended	O
+to	O
+help	O
+prevent	O
+severe	O
+reactions	O
+due	O
+to	O
+citrate	O
+toxicity	B
+.	O
+
+Laboratory	O
+measurement	O
+of	O
+pre	O
+-	O
+procedure	O
+serum	O
+calcium	O
+levels	O
+in	O
+selected	O
+donors	O
+may	O
+identify	O
+cases	O
+requiring	O
+heightened	O
+vigilance	O
+.	O
+
+The	O
+case	O
+also	O
+illustrates	O
+the	O
+importance	O
+of	O
+maintaining	O
+preparedness	O
+for	O
+managing	O
+rare	O
+but	O
+serious	O
+reactions	O
+in	O
+volunteer	O
+apheresis	O
+blood	O
+donors	O
+.	O
+
+Sirolimus	O
+-	O
+associated	O
+proteinuria	B
+and	O
+renal	B
+dysfunction	I
+.	O
+
+Sirolimus	O
+is	O
+a	O
+novel	O
+immunosuppressant	O
+with	O
+potent	O
+antiproliferative	O
+actions	O
+through	O
+its	O
+ability	O
+to	O
+inhibit	O
+the	O
+raptor	O
+-	O
+containing	O
+mammalian	O
+target	O
+of	O
+rapamycin	O
+protein	O
+kinase	O
+.	O
+
+Sirolimus	O
+represents	O
+a	O
+major	O
+therapeutic	O
+advance	O
+in	O
+the	O
+prevention	O
+of	O
+acute	O
+renal	O
+allograft	O
+rejection	O
+and	O
+chronic	O
+allograft	O
+nephropathy	B
+.	O
+
+Its	O
+role	O
+in	O
+the	O
+therapy	O
+of	O
+glomerulonephritis	B
+,	O
+autoimmunity	B
+,	O
+cystic	B
+renal	I
+diseases	I
+and	O
+renal	B
+cancer	I
+is	O
+under	O
+investigation	O
+.	O
+
+Because	O
+sirolimus	O
+does	O
+not	O
+share	O
+the	O
+vasomotor	O
+renal	O
+adverse	O
+effects	O
+exhibited	O
+by	O
+calcineurin	O
+inhibitors	O
+,	O
+it	O
+has	O
+been	O
+designated	O
+a	O
+'	O
+non	O
+-	O
+nephrotoxic	B
+drug	O
+'	O
+.	O
+
+However	O
+,	O
+clinical	O
+reports	O
+suggest	O
+that	O
+,	O
+under	O
+some	O
+circumstances	O
+,	O
+sirolimus	O
+is	O
+associated	O
+with	O
+proteinuria	B
+and	O
+acute	B
+renal	I
+dysfunction	I
+.	O
+
+A	O
+common	O
+risk	O
+factor	O
+appears	O
+to	O
+be	O
+presence	O
+of	O
+pre	O
+-	O
+existing	O
+chronic	B
+renal	I
+damage	I
+.	O
+
+The	O
+mechanisms	O
+of	O
+sirolimus	O
+-	O
+associated	O
+proteinuria	B
+are	O
+multifactorial	O
+and	O
+may	O
+be	O
+due	O
+to	O
+an	O
+increase	O
+in	O
+glomerular	O
+capillary	O
+pressure	O
+following	O
+calcineurin	O
+inhibitor	O
+withdrawal	O
+.	O
+
+It	O
+has	O
+also	O
+been	O
+suggested	O
+that	O
+sirolimus	O
+directly	O
+causes	O
+increased	O
+glomerular	O
+permeability	O
+/	O
+injury	O
+,	O
+but	O
+evidence	O
+for	O
+this	O
+mechanism	O
+is	O
+currently	O
+inconclusive	O
+.	O
+
+The	O
+acute	B
+renal	I
+dysfunction	I
+associated	O
+with	O
+sirolimus	O
+(	O
+such	O
+as	O
+in	O
+delayed	O
+graft	O
+function	O
+)	O
+may	O
+be	O
+due	O
+to	O
+suppression	O
+of	O
+compensatory	O
+renal	O
+cell	O
+proliferation	O
+and	O
+survival	O
+/	O
+repair	O
+processes	O
+.	O
+
+Although	O
+these	O
+adverse	O
+effects	O
+occur	O
+in	O
+some	O
+patients	O
+,	O
+their	O
+occurrence	O
+could	O
+be	O
+minimised	O
+by	O
+knowledge	O
+of	O
+the	O
+molecular	O
+effects	O
+of	O
+sirolimus	O
+on	O
+the	O
+kidney	O
+,	O
+the	O
+use	O
+of	O
+sirolimus	O
+in	O
+appropriate	O
+patient	O
+populations	O
+,	O
+close	O
+monitoring	O
+of	O
+proteinuria	B
+and	O
+renal	O
+function	O
+,	O
+use	O
+of	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitors	O
+or	O
+angiotensin	O
+II	O
+receptor	O
+blockers	O
+if	O
+proteinuria	B
+occurs	O
+and	O
+withdrawal	O
+if	O
+needed	O
+.	O
+
+Further	O
+long	O
+-	O
+term	O
+analysis	O
+of	O
+renal	O
+allograft	O
+studies	O
+using	O
+sirolimus	O
+as	O
+de	O
+novo	O
+immunosuppression	O
+along	O
+with	O
+clinical	O
+and	O
+laboratory	O
+studies	O
+will	O
+refine	O
+these	O
+issues	O
+in	O
+the	O
+future	O
+.	O
+
+Proteinuria	B
+after	O
+conversion	O
+to	O
+sirolimus	O
+in	O
+renal	O
+transplant	O
+recipients	O
+.	O
+
+Sirolimus	O
+(	O
+SRL	O
+)	O
+is	O
+a	O
+new	O
+,	O
+potent	O
+immunosuppressive	O
+agent	O
+.	O
+
+More	O
+recently	O
+,	O
+proteinuria	B
+has	O
+been	O
+reported	O
+as	O
+a	O
+consequence	O
+of	O
+sirolimus	O
+therapy	O
+,	O
+although	O
+the	O
+mechanism	O
+has	O
+remained	O
+unclear	O
+.	O
+
+We	O
+retrospectively	O
+examined	O
+the	O
+records	O
+of	O
+25	O
+renal	O
+transplant	O
+patients	O
+,	O
+who	O
+developed	O
+or	O
+displayed	O
+increased	O
+proteinuria	B
+after	O
+SRL	O
+conversion	O
+.	O
+
+The	O
+patient	O
+cohort	O
+(	O
+14	O
+men	O
+,	O
+11	O
+women	O
+)	O
+was	O
+treated	O
+with	O
+SRL	O
+as	O
+conversion	O
+therapy	O
+,	O
+due	O
+to	O
+chronic	B
+allograft	I
+nephropathy	I
+(	O
+CAN	B
+)	O
+(	O
+n	O
+=	O
+15	O
+)	O
+neoplasia	B
+(	O
+n	O
+=	O
+8	O
+)	O
+;	O
+Kaposi	B
+'	I
+s	I
+sarcoma	I
+,	O
+Four	O
+skin	B
+cancers	I
+,	O
+One	O
+intestinal	B
+tumors	I
+,	O
+One	O
+renal	B
+cell	I
+carsinom	I
+)	O
+or	O
+BK	O
+virus	O
+nephropathy	B
+(	O
+n	O
+=	O
+2	O
+)	O
+.	O
+
+SRL	O
+was	O
+started	O
+at	O
+a	O
+mean	O
+of	O
+78	O
++	O
+/	O
+-	O
+42	O
+(	O
+15	O
+to	O
+163	O
+)	O
+months	O
+after	O
+transplantation	O
+.	O
+
+Mean	O
+follow	O
+-	O
+up	O
+on	O
+SRL	O
+therapy	O
+was	O
+20	O
++	O
+/	O
+-	O
+12	O
+(	O
+6	O
+to	O
+43	O
+)	O
+months	O
+.	O
+
+Proteinuria	B
+increased	O
+from	O
+0	O
+.	O
+445	O
+(	O
+0	O
+to	O
+1	O
+.	O
+5	O
+)	O
+g	O
+/	O
+d	O
+before	O
+conversion	O
+to	O
+3	O
+.	O
+2	O
+g	O
+/	O
+dL	O
+(	O
+0	O
+.	O
+2	O
+to	O
+12	O
+)	O
+after	O
+conversion	O
+(	O
+P	O
+=	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Before	O
+conversion	O
+8	O
+(	O
+32	O
+%	O
+)	O
+patients	O
+had	O
+no	O
+proteinuria	B
+,	O
+whereas	O
+afterwards	O
+all	O
+patients	O
+had	O
+proteinuria	B
+.	O
+
+In	O
+28	O
+%	O
+of	O
+patients	O
+proteinuria	B
+remained	O
+unchanged	O
+,	O
+whereas	O
+it	O
+increased	O
+in	O
+68	O
+%	O
+of	O
+patients	O
+.	O
+
+In	O
+40	O
+%	O
+it	O
+increased	O
+by	O
+more	O
+than	O
+100	O
+%	O
+.	O
+
+Twenty	O
+-	O
+eight	O
+percent	O
+of	O
+patients	O
+showed	O
+increased	O
+proteinuria	B
+to	O
+the	O
+nephrotic	B
+range	O
+.	O
+
+Biopsies	O
+performed	O
+in	O
+five	O
+patients	O
+revealed	O
+new	O
+pathological	O
+changes	O
+:	O
+One	O
+membranoproliferative	B
+glomerulopathy	I
+and	O
+interstitial	B
+nephritis	I
+.	O
+
+These	O
+patients	O
+showed	O
+persistently	O
+good	O
+graft	O
+function	O
+.	O
+
+Serum	O
+creatinine	O
+values	O
+did	O
+not	O
+change	O
+significantly	O
+:	O
+1	O
+.	O
+98	O
++	O
+/	O
+-	O
+0	O
+.	O
+8	O
+mg	O
+/	O
+dL	O
+before	O
+SRL	O
+therapy	O
+and	O
+2	O
+.	O
+53	O
++	O
+/	O
+-	O
+1	O
+.	O
+9	O
+mg	O
+/	O
+dL	O
+at	O
+last	O
+follow	O
+-	O
+up	O
+(	O
+P	O
+=	O
+.	O
+14	O
+)	O
+.	O
+
+Five	O
+grafts	O
+were	O
+lost	O
+and	O
+the	O
+patients	O
+returned	O
+to	O
+dialysis	O
+.	O
+
+Five	O
+patients	O
+displayed	O
+CAN	B
+and	O
+Kaposi	B
+'	I
+s	I
+sarcoma	I
+.	O
+
+Mean	O
+urinary	O
+protein	O
+of	O
+patients	O
+who	O
+returned	O
+to	O
+dialysis	O
+was	O
+1	O
+.	O
+26	O
+(	O
+0	O
+.	O
+5	O
+to	O
+3	O
+.	O
+5	O
+)	O
+g	O
+/	O
+d	O
+before	O
+and	O
+4	O
+.	O
+7	O
+(	O
+3	O
+to	O
+12	O
+)	O
+g	O
+/	O
+d	O
+after	O
+conversion	O
+(	O
+P	O
+=	O
+.	O
+01	O
+)	O
+.	O
+
+Mean	O
+serum	O
+creatinine	O
+level	O
+before	O
+conversion	O
+was	O
+2	O
+.	O
+21	O
+mg	O
+/	O
+dL	O
+and	O
+thereafter	O
+,	O
+4	O
+.	O
+93	O
+mg	O
+/	O
+dL	O
+(	O
+P	O
+=	O
+.	O
+02	O
+)	O
+.	O
+
+Heavy	O
+proteinuria	B
+was	O
+common	O
+after	O
+the	O
+use	O
+of	O
+SRL	O
+as	O
+rescue	O
+therapy	O
+for	O
+renal	O
+transplantation	O
+.	O
+
+Therefore	O
+,	O
+conversion	O
+should	O
+be	O
+considered	O
+for	O
+patients	O
+who	O
+have	O
+not	O
+developed	O
+advanced	O
+CAN	B
+and	O
+proteinuria	B
+.	O
+
+The	O
+possibility	O
+of	O
+de	O
+novo	O
+glomerular	O
+pathology	O
+under	O
+SRL	O
+treatment	O
+requires	O
+further	O
+investigation	O
+by	O
+renal	O
+biopsy	O
+.	O
+
+Long	O
+-	O
+term	O
+follow	O
+-	O
+up	O
+of	O
+ifosfamide	O
+renal	B
+toxicity	I
+in	O
+children	O
+treated	O
+for	O
+malignant	B
+mesenchymal	I
+tumors	I
+:	O
+an	O
+International	O
+Society	O
+of	O
+Pediatric	O
+Oncology	O
+report	O
+.	O
+
+The	O
+renal	O
+function	O
+of	O
+74	O
+children	O
+with	O
+malignant	B
+mesenchymal	I
+tumors	I
+in	O
+complete	O
+remission	O
+and	O
+who	O
+have	O
+received	O
+the	O
+same	O
+ifosfamide	O
+chemotherapy	O
+protocol	O
+(	O
+International	O
+Society	O
+of	O
+Pediatric	O
+Oncology	O
+Malignant	B
+Mesenchymal	I
+Tumor	I
+Study	O
+84	O
+[	O
+SIOP	O
+MMT	O
+84	O
+]	O
+)	O
+were	O
+studied	O
+1	O
+year	O
+after	O
+the	O
+completion	O
+of	O
+treatment	O
+.	O
+
+Total	O
+cumulative	O
+doses	O
+were	O
+36	O
+or	O
+60	O
+g	O
+/	O
+m2	O
+of	O
+ifosfamide	O
+(	O
+six	O
+or	O
+10	O
+cycles	O
+of	O
+ifosfamide	O
+,	O
+vincristine	O
+,	O
+and	O
+dactinomycin	O
+[	O
+IVA	O
+]	O
+)	O
+.	O
+
+None	O
+of	O
+them	O
+had	O
+received	O
+cisplatin	O
+chemotherapy	O
+.	O
+
+Ages	O
+ranged	O
+from	O
+4	O
+months	O
+to	O
+17	O
+years	O
+;	O
+58	O
+patients	O
+were	O
+males	O
+and	O
+42	O
+females	O
+.	O
+
+The	O
+most	O
+common	O
+primary	O
+tumor	B
+site	O
+was	O
+the	O
+head	O
+and	O
+neck	O
+.	O
+
+Renal	O
+function	O
+was	O
+investigated	O
+by	O
+measuring	O
+plasma	O
+and	O
+urinary	O
+electrolytes	O
+,	O
+glucosuria	B
+,	O
+proteinuria	B
+,	O
+aminoaciduria	B
+,	O
+urinary	O
+pH	O
+,	O
+osmolarity	O
+,	O
+creatinine	O
+clearance	O
+,	O
+phosphate	O
+tubular	O
+reabsorption	O
+,	O
+beta	O
+2	O
+microglobulinuria	O
+,	O
+and	O
+lysozymuria	O
+.	O
+
+Fifty	O
+-	O
+eight	O
+patients	O
+(	O
+78	O
+%	O
+)	O
+had	O
+normal	O
+renal	O
+tests	O
+,	O
+whereas	O
+16	O
+patients	O
+(	O
+22	O
+%	O
+)	O
+had	O
+renal	B
+abnormalities	I
+.	O
+
+Two	O
+subsets	O
+of	O
+patients	O
+were	O
+identified	O
+from	O
+this	O
+latter	O
+group	O
+:	O
+the	O
+first	O
+included	O
+four	O
+patients	O
+(	O
+5	O
+%	O
+of	O
+the	O
+total	O
+population	O
+)	O
+who	O
+developed	O
+major	O
+toxicity	B
+resulting	O
+in	O
+Fanconi	B
+'	I
+s	I
+syndrome	I
+(	O
+TDFS	B
+)	O
+;	O
+and	O
+the	O
+second	O
+group	O
+included	O
+five	O
+patients	O
+with	O
+elevated	O
+beta	O
+2	O
+microglobulinuria	O
+and	O
+low	O
+phosphate	O
+reabsorption	O
+.	O
+
+The	O
+remaining	O
+seven	O
+patients	O
+had	O
+isolated	O
+beta	O
+2	O
+microglobulinuria	O
+.	O
+
+Severe	O
+toxicity	B
+was	O
+correlated	O
+with	O
+the	O
+higher	O
+cumulative	O
+dose	O
+of	O
+60	O
+g	O
+/	O
+m2	O
+of	O
+ifosfamide	O
+,	O
+a	O
+younger	O
+age	O
+(	O
+less	O
+than	O
+2	O
+1	O
+/	O
+2	O
+years	O
+old	O
+)	O
+,	O
+and	O
+a	O
+predominance	O
+of	O
+vesicoprostatic	O
+tumor	B
+involvement	O
+.	O
+
+This	O
+low	O
+percentage	O
+(	O
+5	O
+%	O
+)	O
+of	O
+TDFS	O
+must	O
+be	O
+evaluated	O
+with	O
+respect	O
+to	O
+the	O
+efficacy	O
+of	O
+ifosfamide	O
+in	O
+the	O
+treatment	O
+of	O
+mesenchymal	B
+tumors	I
+in	O
+children	O
+.	O
+
+Progressive	O
+myopathy	B
+with	O
+up	O
+-	O
+regulation	O
+of	O
+MHC	O
+-	O
+I	O
+associated	O
+with	O
+statin	O
+therapy	O
+.	O
+
+Statins	O
+can	O
+cause	O
+a	O
+necrotizing	O
+myopathy	B
+and	O
+hyperCKaemia	B
+which	O
+is	O
+reversible	O
+on	O
+cessation	O
+of	O
+the	O
+drug	O
+.	O
+
+What	O
+is	O
+less	O
+well	O
+known	O
+is	O
+a	O
+phenomenon	O
+whereby	O
+statins	O
+may	O
+induce	O
+a	O
+myopathy	B
+,	O
+which	O
+persists	O
+or	O
+may	O
+progress	O
+after	O
+stopping	O
+the	O
+drug	O
+.	O
+
+We	O
+investigated	O
+the	O
+muscle	O
+pathology	O
+in	O
+8	O
+such	O
+cases	O
+.	O
+
+All	O
+had	O
+myofibre	O
+necrosis	B
+but	O
+only	O
+3	O
+had	O
+an	O
+inflammatory	O
+infiltrate	O
+.	O
+
+In	O
+all	O
+cases	O
+there	O
+was	O
+diffuse	O
+or	O
+multifocal	O
+up	O
+-	O
+regulation	O
+of	O
+MHC	O
+-	O
+I	O
+expression	O
+even	O
+in	O
+non	O
+-	O
+necrotic	B
+fibres	O
+.	O
+
+Progressive	O
+improvement	O
+occurred	O
+in	O
+7	O
+cases	O
+after	O
+commencement	O
+of	O
+prednisolone	O
+and	O
+methotrexate	O
+,	O
+and	O
+in	O
+one	O
+case	O
+spontaneously	O
+.	O
+
+These	O
+observations	O
+suggest	O
+that	O
+statins	O
+may	O
+initiate	O
+an	O
+immune	O
+-	O
+mediated	O
+myopathy	B
+that	O
+persists	O
+after	O
+withdrawal	O
+of	O
+the	O
+drug	O
+and	O
+responds	O
+to	O
+immunosuppressive	O
+therapy	O
+.	O
+
+The	O
+mechanism	O
+of	O
+this	O
+myopathy	B
+is	O
+uncertain	O
+but	O
+may	O
+involve	O
+the	O
+induction	O
+by	O
+statins	O
+of	O
+an	O
+endoplasmic	O
+reticulum	O
+stress	O
+response	O
+with	O
+associated	O
+up	O
+-	O
+regulation	O
+of	O
+MHC	O
+-	O
+I	O
+expression	O
+and	O
+antigen	O
+presentation	O
+by	O
+muscle	O
+fibres	O
+.	O
+
+Use	O
+of	O
+chromosome	O
+substitution	O
+strains	O
+to	O
+identify	O
+seizure	B
+susceptibility	O
+loci	O
+in	O
+mice	O
+.	O
+
+Seizure	B
+susceptibility	O
+varies	O
+among	O
+inbred	O
+mouse	O
+strains	O
+.	O
+
+Chromosome	O
+substitution	O
+strains	O
+(	O
+CSS	O
+)	O
+,	O
+in	O
+which	O
+a	O
+single	O
+chromosome	O
+from	O
+one	O
+inbred	O
+strain	O
+(	O
+donor	O
+)	O
+has	O
+been	O
+transferred	O
+onto	O
+a	O
+second	O
+strain	O
+(	O
+host	O
+)	O
+by	O
+repeated	O
+backcrossing	O
+,	O
+may	O
+be	O
+used	O
+to	O
+identify	O
+quantitative	O
+trait	O
+loci	O
+(	O
+QTLs	O
+)	O
+that	O
+contribute	O
+to	O
+seizure	B
+susceptibility	O
+.	O
+
+QTLs	O
+for	O
+susceptibility	O
+to	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+,	O
+a	O
+model	O
+of	O
+temporal	B
+lobe	I
+epilepsy	I
+,	O
+have	O
+not	O
+been	O
+reported	O
+,	O
+and	O
+CSS	O
+have	O
+not	O
+previously	O
+been	O
+used	O
+to	O
+localize	O
+seizure	B
+susceptibility	O
+genes	O
+.	O
+
+We	O
+report	O
+QTLs	O
+identified	O
+using	O
+a	O
+B6	O
+(	O
+host	O
+)	O
+x	O
+A	O
+/	O
+J	O
+(	O
+donor	O
+)	O
+CSS	O
+panel	O
+to	O
+localize	O
+genes	O
+involved	O
+in	O
+susceptibility	O
+to	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+.	O
+
+Three	O
+hundred	O
+fifty	O
+-	O
+five	O
+adult	O
+male	O
+CSS	O
+mice	O
+,	O
+58	O
+B6	O
+,	O
+and	O
+39	O
+A	O
+/	O
+J	O
+were	O
+tested	O
+for	O
+susceptibility	O
+to	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+.	O
+
+Highest	O
+stage	O
+reached	O
+and	O
+latency	O
+to	O
+each	O
+stage	O
+were	O
+recorded	O
+for	O
+all	O
+mice	O
+.	O
+
+B6	O
+mice	O
+were	O
+resistant	O
+to	O
+seizures	B
+and	O
+slower	O
+to	O
+reach	O
+stages	O
+compared	O
+to	O
+A	O
+/	O
+J	O
+mice	O
+.	O
+
+The	O
+CSS	O
+for	O
+Chromosomes	O
+10	O
+and	O
+18	O
+progressed	O
+to	O
+the	O
+most	O
+severe	O
+stages	O
+,	O
+diverging	O
+dramatically	O
+from	O
+the	O
+B6	O
+phenotype	O
+.	O
+
+Latencies	O
+to	O
+stages	O
+were	O
+also	O
+significantly	O
+shorter	O
+for	O
+CSS10	O
+and	O
+CSS18	O
+mice	O
+.	O
+
+CSS	O
+mapping	O
+suggests	O
+seizure	B
+susceptibility	O
+loci	O
+on	O
+mouse	O
+Chromosomes	O
+10	O
+and	O
+18	O
+.	O
+
+This	O
+approach	O
+provides	O
+a	O
+framework	O
+for	O
+identifying	O
+potentially	O
+novel	O
+homologous	O
+candidate	O
+genes	O
+for	O
+human	O
+temporal	B
+lobe	I
+epilepsy	I
+.	O
+
+In	O
+vitro	O
+characterization	O
+of	O
+parasympathetic	O
+and	O
+sympathetic	O
+responses	O
+in	O
+cyclophosphamide	O
+-	O
+induced	O
+cystitis	B
+in	O
+the	O
+rat	O
+.	O
+
+In	O
+cyclophosphamide	O
+-	O
+induced	O
+cystitis	B
+in	O
+the	O
+rat	O
+,	O
+detrusor	O
+function	O
+is	O
+impaired	O
+and	O
+the	O
+expression	O
+and	O
+effects	O
+of	O
+muscarinic	O
+receptors	O
+altered	O
+.	O
+
+Whether	O
+or	O
+not	O
+the	O
+neuronal	O
+transmission	O
+may	O
+be	O
+affected	O
+by	O
+cystitis	B
+was	O
+presently	O
+investigated	O
+.	O
+
+Responses	O
+of	O
+urinary	O
+strip	O
+preparations	O
+from	O
+control	O
+and	O
+cyclophosphamide	O
+-	O
+pretreated	O
+rats	O
+to	O
+electrical	O
+field	O
+stimulation	O
+and	O
+to	O
+agonists	O
+were	O
+assessed	O
+in	O
+the	O
+absence	O
+and	O
+presence	O
+of	O
+muscarinic	O
+,	O
+adrenergic	O
+and	O
+purinergic	O
+receptor	O
+antagonists	O
+.	O
+
+Generally	O
+,	O
+atropine	O
+reduced	O
+contractions	O
+,	O
+but	O
+in	O
+contrast	O
+to	O
+controls	O
+,	O
+it	O
+also	O
+reduced	O
+responses	O
+to	O
+low	O
+electrical	O
+field	O
+stimulation	O
+intensity	O
+(	O
+1	O
+-	O
+5	O
+Hz	O
+)	O
+in	O
+inflamed	O
+preparations	O
+.	O
+
+In	O
+both	O
+types	O
+,	O
+purinoceptor	O
+desensitization	O
+with	O
+alpha	O
+,	O
+beta	O
+-	O
+methylene	O
+adenosine	O
+-	O
+5	O
+'	O
+-	O
+triphosphate	O
+(	O
+alpha	O
+,	O
+beta	O
+-	O
+meATP	O
+)	O
+caused	O
+further	O
+reductions	O
+at	O
+low	O
+frequencies	O
+(	O
+<	O
+10	O
+Hz	O
+)	O
+.	O
+
+The	O
+muscarinic	O
+receptor	O
+antagonists	O
+atropine	O
+,	O
+4	O
+-	O
+diphenylacetoxy	O
+-	O
+N	O
+-	O
+methylpiperidine	O
+(	O
+4	O
+-	O
+DAMP	O
+)	O
+(	O
+'	O
+M	O
+(	O
+1	O
+)	O
+/	O
+M	O
+(	O
+3	O
+)	O
+/	O
+M	O
+(	O
+5	O
+)	O
+-	O
+selective	O
+'	O
+)	O
+,	O
+methoctramine	O
+(	O
+'	O
+M	O
+(	O
+2	O
+)	O
+-	O
+selective	O
+'	O
+)	O
+and	O
+pirenzepine	O
+(	O
+'	O
+M	O
+(	O
+1	O
+)	O
+-	O
+selective	O
+'	O
+)	O
+antagonized	O
+the	O
+tonic	O
+component	O
+of	O
+the	O
+electrical	O
+field	O
+stimulation	O
+-	O
+evoked	O
+contractile	O
+response	O
+more	O
+potently	O
+than	O
+the	O
+phasic	O
+component	O
+.	O
+
+4	O
+-	O
+DAMP	O
+inhibited	O
+the	O
+tonic	O
+contractions	O
+in	O
+controls	O
+more	O
+potently	O
+than	O
+methoctramine	O
+and	O
+pirenzepine	O
+.	O
+
+In	O
+inflamed	O
+preparations	O
+,	O
+the	O
+muscarinic	O
+receptor	O
+antagonism	O
+on	O
+the	O
+phasic	O
+component	O
+of	O
+the	O
+electrical	O
+field	O
+stimulation	O
+-	O
+evoked	O
+contraction	O
+was	O
+decreased	O
+and	O
+the	O
+pirenzepine	O
+and	O
+4	O
+-	O
+DAMP	O
+antagonism	O
+on	O
+the	O
+tonic	O
+component	O
+was	O
+much	O
+less	O
+efficient	O
+than	O
+in	O
+controls	O
+.	O
+
+In	O
+contrast	O
+to	O
+controls	O
+,	O
+methoctramine	O
+increased	O
+-	O
+-	O
+instead	O
+of	O
+decreased	O
+-	O
+-	O
+the	O
+tonic	O
+responses	O
+at	O
+high	O
+frequencies	O
+.	O
+
+While	O
+contractions	O
+to	O
+carbachol	O
+and	O
+ATP	O
+were	O
+the	O
+same	O
+in	O
+inflamed	O
+and	O
+in	O
+control	O
+strips	O
+when	O
+related	O
+to	O
+a	O
+reference	O
+potassium	O
+response	O
+,	O
+isoprenaline	O
+-	O
+induced	O
+relaxations	O
+were	O
+smaller	O
+in	O
+inflamed	O
+strips	O
+.	O
+
+Thus	O
+,	O
+in	O
+cystitis	B
+substantial	O
+changes	O
+of	O
+the	O
+efferent	O
+functional	O
+responses	O
+occur	O
+.	O
+
+While	O
+postjunctional	O
+beta	O
+-	O
+adrenoceptor	O
+-	O
+mediated	O
+relaxations	O
+are	O
+reduced	O
+,	O
+effects	O
+by	O
+prejunctional	O
+inhibitory	O
+muscarinic	O
+receptors	O
+may	O
+be	O
+increased	O
+.	O
+
+Direct	O
+inhibition	O
+of	O
+cardiac	O
+hyperpolarization	O
+-	O
+activated	O
+cyclic	O
+nucleotide	O
+-	O
+gated	O
+pacemaker	O
+channels	O
+by	O
+clonidine	O
+.	O
+
+BACKGROUND	O
+:	O
+Inhibition	O
+of	O
+cardiac	O
+sympathetic	O
+tone	O
+represents	O
+an	O
+important	O
+strategy	O
+for	O
+treatment	O
+of	O
+cardiovascular	B
+disease	I
+,	O
+including	O
+arrhythmia	B
+,	O
+coronary	B
+heart	I
+disease	I
+,	O
+and	O
+chronic	O
+heart	B
+failure	I
+.	O
+
+Activation	O
+of	O
+presynaptic	O
+alpha2	O
+-	O
+adrenoceptors	O
+is	O
+the	O
+most	O
+widely	O
+accepted	O
+mechanism	O
+of	O
+action	O
+of	O
+the	O
+antisympathetic	O
+drug	O
+clonidine	O
+;	O
+however	O
+,	O
+other	O
+target	O
+proteins	O
+have	O
+been	O
+postulated	O
+to	O
+contribute	O
+to	O
+the	O
+in	O
+vivo	O
+actions	O
+of	O
+clonidine	O
+.	O
+
+METHODS	O
+AND	O
+RESULTS	O
+:	O
+To	O
+test	O
+whether	O
+clonidine	O
+elicits	O
+pharmacological	O
+effects	O
+independent	O
+of	O
+alpha2	O
+-	O
+adrenoceptors	O
+,	O
+we	O
+have	O
+generated	O
+mice	O
+with	O
+a	O
+targeted	O
+deletion	O
+of	O
+all	O
+3	O
+alpha2	O
+-	O
+adrenoceptor	O
+subtypes	O
+(	O
+alpha2ABC	O
+-	O
+/	O
+-	O
+)	O
+.	O
+
+Alpha2ABC	O
+-	O
+/	O
+-	O
+mice	O
+were	O
+completely	O
+unresponsive	O
+to	O
+the	O
+analgesic	O
+and	O
+hypnotic	O
+effects	O
+of	O
+clonidine	O
+;	O
+however	O
+,	O
+clonidine	O
+significantly	O
+lowered	O
+heart	O
+rate	O
+in	O
+alpha2ABC	O
+-	O
+/	O
+-	O
+mice	O
+by	O
+up	O
+to	O
+150	O
+bpm	O
+.	O
+
+Clonidine	O
+-	O
+induced	O
+bradycardia	B
+in	O
+conscious	O
+alpha2ABC	O
+-	O
+/	O
+-	O
+mice	O
+was	O
+32	O
+.	O
+3	O
+%	O
+(	O
+10	O
+microg	O
+/	O
+kg	O
+)	O
+and	O
+26	O
+.	O
+6	O
+%	O
+(	O
+100	O
+microg	O
+/	O
+kg	O
+)	O
+of	O
+the	O
+effect	O
+in	O
+wild	O
+-	O
+type	O
+mice	O
+.	O
+
+A	O
+similar	O
+bradycardic	O
+effect	O
+of	O
+clonidine	O
+was	O
+observed	O
+in	O
+isolated	O
+spontaneously	O
+beating	O
+right	O
+atria	O
+from	O
+alpha2ABC	O
+-	O
+knockout	O
+and	O
+wild	O
+-	O
+type	O
+mice	O
+.	O
+
+Clonidine	O
+inhibited	O
+the	O
+native	O
+pacemaker	O
+current	O
+(	O
+I	O
+(	O
+f	O
+)	O
+)	O
+in	O
+isolated	O
+sinoatrial	O
+node	O
+pacemaker	O
+cells	O
+and	O
+the	O
+I	O
+(	O
+f	O
+)	O
+-	O
+generating	O
+hyperpolarization	O
+-	O
+activated	O
+cyclic	O
+nucleotide	O
+-	O
+gated	O
+(	O
+HCN	O
+)	O
+2	O
+and	O
+HCN4	O
+channels	O
+in	O
+transfected	O
+HEK293	O
+cells	O
+.	O
+
+As	O
+a	O
+consequence	O
+of	O
+blocking	O
+I	O
+(	O
+f	O
+)	O
+,	O
+clonidine	O
+reduced	O
+the	O
+slope	O
+of	O
+the	O
+diastolic	O
+depolarization	O
+and	O
+the	O
+frequency	O
+of	O
+pacemaker	O
+potentials	O
+in	O
+sinoatrial	O
+node	O
+cells	O
+from	O
+wild	O
+-	O
+type	O
+and	O
+alpha2ABC	O
+-	O
+knockout	O
+mice	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Direct	O
+inhibition	O
+of	O
+cardiac	O
+HCN	O
+pacemaker	O
+channels	O
+contributes	O
+to	O
+the	O
+bradycardic	O
+effects	O
+of	O
+clonidine	O
+gene	O
+-	O
+targeted	O
+mice	O
+in	O
+vivo	O
+,	O
+and	O
+thus	O
+,	O
+clonidine	O
+-	O
+like	O
+drugs	O
+represent	O
+novel	O
+structures	O
+for	O
+future	O
+HCN	O
+channel	O
+inhibitors	O
+.	O
+
+Granulomatous	B
+hepatitis	I
+due	O
+to	O
+combination	O
+of	O
+amoxicillin	O
+and	O
+clavulanic	O
+acid	O
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+patient	O
+with	O
+amoxicillin	O
+-	O
+clavulanic	O
+acid	O
+-	O
+induced	O
+hepatitis	B
+with	O
+histologic	O
+multiple	O
+granulomas	B
+.	O
+
+This	O
+type	O
+of	O
+lesion	O
+broadens	O
+the	O
+spectrum	O
+of	O
+liver	B
+injury	I
+due	O
+to	O
+this	O
+drug	O
+combination	O
+,	O
+mainly	O
+represented	O
+by	O
+a	O
+benign	O
+cholestatic	B
+syndrome	I
+.	O
+
+The	O
+association	O
+of	O
+granulomas	B
+and	O
+eosinophilia	B
+favor	O
+an	O
+immunoallergic	O
+mechanism	O
+.	O
+
+As	O
+penicillin	O
+derivatives	O
+and	O
+amoxicillin	O
+alone	O
+are	O
+known	O
+to	O
+induce	O
+such	O
+types	O
+of	O
+lesions	O
+,	O
+the	O
+amoxicillin	O
+component	O
+,	O
+with	O
+or	O
+without	O
+a	O
+potentiating	O
+effect	O
+of	O
+clavulanic	O
+acid	O
+,	O
+might	O
+have	O
+a	O
+major	O
+role	O
+.	O
+
+Dobutamine	O
+stress	O
+echocardiography	O
+:	O
+a	O
+sensitive	O
+indicator	O
+of	O
+diminished	O
+myocardial	O
+function	O
+in	O
+asymptomatic	O
+doxorubicin	O
+-	O
+treated	O
+long	O
+-	O
+term	O
+survivors	O
+of	O
+childhood	O
+cancer	B
+.	O
+
+Doxorubicin	O
+is	O
+an	O
+effective	O
+anticancer	O
+chemotherapeutic	O
+agent	O
+known	O
+to	O
+cause	O
+acute	O
+and	O
+chronic	O
+cardiomyopathy	B
+.	O
+
+To	O
+develop	O
+a	O
+more	O
+sensitive	O
+echocardiographic	O
+screening	O
+test	O
+for	O
+cardiac	B
+damage	I
+due	O
+to	O
+doxorubicin	O
+,	O
+a	O
+cohort	O
+study	O
+was	O
+performed	O
+using	O
+dobutamine	O
+infusion	O
+to	O
+differentiate	O
+asymptomatic	O
+long	O
+-	O
+term	O
+survivors	O
+of	O
+childhood	O
+cancer	B
+treated	O
+with	O
+doxorubicin	O
+from	O
+healthy	O
+control	O
+subjects	O
+.	O
+
+Echocardiographic	O
+data	O
+from	O
+the	O
+experimental	O
+group	O
+of	O
+21	O
+patients	O
+(	O
+mean	O
+age	O
+16	O
++	O
+/	O
+-	O
+5	O
+years	O
+)	O
+treated	O
+from	O
+1	O
+.	O
+6	O
+to	O
+14	O
+.	O
+3	O
+years	O
+(	O
+median	O
+5	O
+.	O
+3	O
+)	O
+before	O
+this	O
+study	O
+with	O
+27	O
+to	O
+532	O
+mg	O
+/	O
+m2	O
+of	O
+doxorubicin	O
+(	O
+mean	O
+196	O
+)	O
+were	O
+compared	O
+with	O
+echocardiographic	O
+data	O
+from	O
+12	O
+normal	O
+age	O
+-	O
+matched	O
+control	O
+subjects	O
+.	O
+
+Graded	O
+dobutamine	O
+infusions	O
+of	O
+0	O
+.	O
+5	O
+,	O
+2	O
+.	O
+5	O
+,	O
+5	O
+and	O
+10	O
+micrograms	O
+/	O
+kg	O
+per	O
+min	O
+were	O
+administered	O
+.	O
+
+Echocardiographic	O
+Doppler	O
+studies	O
+were	O
+performed	O
+before	O
+infusion	O
+and	O
+after	O
+15	O
+min	O
+of	O
+infusion	O
+at	O
+each	O
+rate	O
+.	O
+
+Dobutamine	O
+infusion	O
+at	O
+10	O
+micrograms	O
+/	O
+kg	O
+per	O
+min	O
+was	O
+discontinued	O
+after	O
+six	O
+studies	O
+secondary	O
+to	O
+a	O
+50	O
+%	O
+incidence	O
+rate	O
+of	O
+adverse	O
+symptoms	O
+.	O
+
+The	O
+most	O
+important	O
+findings	O
+were	O
+that	O
+compared	O
+with	O
+values	O
+in	O
+control	O
+subjects	O
+,	O
+end	O
+-	O
+systolic	O
+left	O
+ventricular	O
+posterior	O
+wall	O
+dimension	O
+and	O
+percent	O
+of	O
+left	O
+ventricular	O
+posterior	O
+wall	O
+thickening	O
+in	O
+doxorubicin	O
+-	O
+treated	O
+patients	O
+were	O
+decreased	O
+at	O
+baseline	O
+study	O
+and	O
+these	O
+findings	O
+were	O
+more	O
+clearly	O
+delineated	O
+with	O
+dobutamine	O
+stimulation	O
+.	O
+
+End	O
+-	O
+systolic	O
+left	O
+ventricular	O
+posterior	O
+wall	O
+dimension	O
+at	O
+baseline	O
+for	O
+the	O
+doxorubicin	O
+-	O
+treated	O
+group	O
+was	O
+11	O
++	O
+/	O
+-	O
+1	O
+.	O
+9	O
+mm	O
+versus	O
+13	O
+.	O
+1	O
++	O
+/	O
+-	O
+1	O
+.	O
+5	O
+mm	O
+for	O
+control	O
+subjects	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+End	O
+-	O
+systolic	O
+left	O
+ventricular	O
+posterior	O
+wall	O
+dimension	O
+at	O
+the	O
+5	O
+-	O
+micrograms	O
+/	O
+kg	O
+per	O
+min	O
+dobutamine	O
+infusion	O
+for	O
+the	O
+doxorubicin	O
+-	O
+treated	O
+group	O
+was	O
+14	O
+.	O
+1	O
++	O
+/	O
+-	O
+2	O
+.	O
+4	O
+mm	O
+versus	O
+19	O
+.	O
+3	O
++	O
+/	O
+-	O
+2	O
+.	O
+6	O
+mm	O
+for	O
+control	O
+subjects	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Influence	O
+of	O
+smoking	O
+on	O
+developing	O
+cochlea	O
+.	O
+
+Does	O
+smoking	O
+during	O
+pregnancy	O
+affect	O
+the	O
+amplitudes	O
+of	O
+transient	O
+evoked	O
+otoacoustic	O
+emissions	O
+in	O
+newborns	O
+?	O
+
+OBJECTIVE	O
+:	O
+Maternal	O
+tobacco	O
+smoking	O
+has	O
+negative	O
+effects	O
+on	O
+fetal	O
+growth	O
+.	O
+
+The	O
+influence	O
+of	O
+smoking	O
+during	O
+pregnancy	O
+on	O
+the	O
+developing	O
+cochlea	O
+has	O
+not	O
+been	O
+estimated	O
+,	O
+although	O
+smoking	O
+has	O
+been	O
+positively	O
+associated	O
+with	O
+hearing	B
+loss	I
+in	O
+adults	O
+.	O
+
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+effects	O
+of	O
+maternal	O
+smoking	O
+on	O
+transient	O
+evoked	O
+otoacoustic	O
+emissions	O
+(	O
+TEOAEs	O
+)	O
+of	O
+healthy	O
+neonates	O
+.	O
+
+METHODS	O
+:	O
+This	O
+study	O
+was	O
+undertaken	O
+as	O
+part	O
+of	O
+neonatal	O
+screening	O
+for	O
+hearing	B
+impairment	I
+and	O
+involved	O
+both	O
+ears	O
+of	O
+200	O
+newborns	O
+.	O
+
+Newborns	O
+whose	O
+mothers	O
+reported	O
+smoking	O
+during	O
+pregnancy	O
+(	O
+n	O
+=	O
+200	O
+ears	O
+)	O
+were	O
+compared	O
+to	O
+a	O
+control	O
+group	O
+of	O
+newborns	O
+(	O
+n	O
+=	O
+200	O
+ears	O
+)	O
+,	O
+whose	O
+mothers	O
+were	O
+non	O
+-	O
+smokers	O
+.	O
+
+Exposure	O
+to	O
+tobacco	O
+was	O
+characterized	O
+as	O
+low	O
+(	O
+<	O
+5	O
+cigarettes	O
+per	O
+day	O
+,	O
+n	O
+=	O
+88	O
+ears	O
+)	O
+,	O
+moderate	O
+(	O
+5	O
+<	O
+or	O
+=	O
+cigarettes	O
+per	O
+day	O
+<	O
+10	O
+,	O
+n	O
+=	O
+76	O
+)	O
+or	O
+high	O
+(	O
+>	O
+or	O
+=	O
+10	O
+cigarettes	O
+per	O
+day	O
+,	O
+n	O
+=	O
+36	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+In	O
+exposed	O
+neonates	O
+,	O
+TEOAEs	O
+mean	O
+response	O
+(	O
+across	O
+frequency	O
+)	O
+and	O
+mean	O
+amplitude	O
+at	O
+4000Hz	O
+was	O
+significantly	O
+lower	O
+than	O
+in	O
+non	O
+-	O
+exposed	O
+neonates	O
+.	O
+
+Comparisons	O
+between	O
+exposed	O
+newborns	O
+'	O
+subgroups	O
+revealed	O
+no	O
+significant	O
+differences	O
+.	O
+
+However	O
+,	O
+by	O
+comparing	O
+each	O
+subgroup	O
+to	O
+control	O
+group	O
+,	O
+we	O
+found	O
+statistically	O
+significant	O
+decreases	B
+of	I
+TEOAEs	I
+amplitudes	I
+at	O
+4000Hz	O
+for	O
+all	O
+three	O
+groups	O
+.	O
+
+Mean	O
+TEOAEs	O
+responses	O
+of	O
+highly	O
+exposed	O
+newborns	O
+were	O
+also	O
+significantly	O
+lower	O
+in	O
+comparison	O
+to	O
+our	O
+control	O
+group	O
+.	O
+
+CONCLUSION	O
+:	O
+In	O
+utero	O
+,	O
+exposure	O
+to	O
+tobacco	O
+smoking	O
+seems	O
+to	O
+have	O
+a	O
+small	O
+impact	O
+on	O
+outer	O
+hair	O
+cells	O
+.	O
+
+These	O
+effects	O
+seem	O
+to	O
+be	O
+equally	O
+true	O
+for	O
+all	O
+exposed	O
+newborns	O
+,	O
+regardless	O
+of	O
+the	O
+degree	O
+of	O
+exposure	O
+.	O
+
+Further	O
+studies	O
+are	O
+needed	O
+in	O
+order	O
+to	O
+establish	O
+a	O
+potential	O
+negative	O
+effect	O
+of	O
+maternal	O
+smoking	O
+on	O
+the	O
+neonate	O
+'	O
+s	O
+hearing	O
+acuity	O
+.	O
+
+Simvastatin	O
+-	O
+induced	O
+bilateral	O
+leg	O
+compartment	B
+syndrome	I
+and	O
+myonecrosis	B
+associated	O
+with	O
+hypothyroidism	B
+.	O
+
+A	O
+54	O
+-	O
+year	O
+-	O
+old	O
+hypothyroid	B
+male	O
+taking	O
+thyroxine	O
+and	O
+simvastatin	O
+presented	O
+with	O
+bilateral	O
+leg	O
+compartment	B
+syndrome	I
+and	O
+myonecrosis	B
+.	O
+
+Urgent	O
+fasciotomies	O
+were	O
+performed	O
+and	O
+the	O
+patient	O
+made	O
+an	O
+uneventful	O
+recovery	O
+with	O
+the	O
+withdrawal	O
+of	O
+simvastatin	O
+.	O
+
+It	O
+is	O
+likely	O
+that	O
+this	O
+complication	O
+will	O
+be	O
+seen	O
+more	O
+often	O
+with	O
+the	O
+increased	O
+worldwide	O
+use	O
+of	O
+this	O
+drug	O
+and	O
+its	O
+approval	O
+for	O
+all	O
+arteriopathic	B
+patients	O
+.	O
+
+Neuroinflammation	B
+and	O
+behavioral	B
+abnormalities	I
+after	O
+neonatal	O
+terbutaline	O
+treatment	O
+in	O
+rats	O
+:	O
+implications	O
+for	O
+autism	B
+.	O
+
+Autism	B
+is	O
+a	O
+neurodevelopmental	B
+disorder	I
+presenting	O
+before	O
+3	O
+years	O
+of	O
+age	O
+with	O
+deficits	B
+in	I
+communication	I
+and	I
+social	I
+skills	I
+and	O
+repetitive	B
+behaviors	I
+.	O
+
+In	O
+addition	O
+to	O
+genetic	O
+influences	O
+,	O
+recent	O
+studies	O
+suggest	O
+that	O
+prenatal	O
+drug	O
+or	O
+chemical	O
+exposures	O
+are	O
+risk	O
+factors	O
+for	O
+autism	B
+.	O
+
+Terbutaline	O
+,	O
+a	O
+beta2	O
+-	O
+adrenoceptor	O
+agonist	O
+used	O
+to	O
+arrest	O
+preterm	B
+labor	I
+,	O
+has	O
+been	O
+associated	O
+with	O
+increased	O
+concordance	O
+for	O
+autism	B
+in	O
+dizygotic	O
+twins	O
+.	O
+
+We	O
+studied	O
+the	O
+effects	O
+of	O
+terbutaline	O
+on	O
+microglial	O
+activation	O
+in	O
+different	O
+brain	O
+regions	O
+and	O
+behavioral	O
+outcomes	O
+in	O
+developing	O
+rats	O
+.	O
+
+Newborn	O
+rats	O
+were	O
+given	O
+terbutaline	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+daily	O
+on	O
+postnatal	O
+days	O
+(	O
+PN	O
+)	O
+2	O
+to	O
+5	O
+or	O
+PN	O
+11	O
+to	O
+14	O
+and	O
+examined	O
+24	O
+h	O
+after	O
+the	O
+last	O
+dose	O
+and	O
+at	O
+PN	O
+30	O
+.	O
+
+Immunohistochemical	O
+studies	O
+showed	O
+that	O
+administration	O
+of	O
+terbutaline	O
+on	O
+PN	O
+2	O
+to	O
+5	O
+produced	O
+a	O
+robust	O
+increase	O
+in	O
+microglial	O
+activation	O
+on	O
+PN	O
+30	O
+in	O
+the	O
+cerebral	O
+cortex	O
+,	O
+as	O
+well	O
+as	O
+in	O
+cerebellar	O
+and	O
+cerebrocortical	O
+white	O
+matter	O
+.	O
+
+None	O
+of	O
+these	O
+effects	O
+occurred	O
+in	O
+animals	O
+given	O
+terbutaline	O
+on	O
+PN	O
+11	O
+to	O
+14	O
+.	O
+
+In	O
+behavioral	O
+tests	O
+,	O
+animals	O
+treated	O
+with	O
+terbutaline	O
+on	O
+PN	O
+2	O
+to	O
+5	O
+showed	O
+consistent	O
+patterns	O
+of	O
+hyper	O
+-	O
+reactivity	O
+to	O
+novelty	O
+and	O
+aversive	O
+stimuli	O
+when	O
+assessed	O
+in	O
+a	O
+novel	O
+open	O
+field	O
+,	O
+as	O
+well	O
+as	O
+in	O
+the	O
+acoustic	O
+startle	O
+response	O
+test	O
+.	O
+
+Our	O
+findings	O
+indicate	O
+that	O
+beta2	O
+-	O
+adrenoceptor	O
+overstimulation	O
+during	O
+an	O
+early	O
+critical	O
+period	O
+results	O
+in	O
+microglial	O
+activation	O
+associated	O
+with	O
+innate	O
+neuroinflammatory	O
+pathways	O
+and	O
+behavioral	B
+abnormalities	I
+,	O
+similar	O
+to	O
+those	O
+described	O
+in	O
+autism	B
+.	O
+
+This	O
+study	O
+provides	O
+a	O
+useful	O
+animal	O
+model	O
+for	O
+understanding	O
+the	O
+neuropathological	O
+processes	O
+underlying	O
+autism	B
+spectrum	I
+disorders	I
+.	O
+
+Upregulation	O
+of	O
+brain	O
+expression	O
+of	O
+P	O
+-	O
+glycoprotein	O
+in	O
+MRP2	O
+-	O
+deficient	O
+TR	O
+(	O
+-	O
+)	O
+rats	O
+resembles	O
+seizure	B
+-	O
+induced	O
+up	O
+-	O
+regulation	O
+of	O
+this	O
+drug	O
+efflux	O
+transporter	O
+in	O
+normal	O
+rats	O
+.	O
+
+PURPOSE	O
+:	O
+The	O
+multidrug	O
+resistance	O
+protein	O
+2	O
+(	O
+MRP2	O
+)	O
+is	O
+a	O
+drug	O
+efflux	O
+transporter	O
+that	O
+is	O
+expressed	O
+predominantly	O
+at	O
+the	O
+apical	O
+domain	O
+of	O
+hepatocytes	O
+but	O
+seems	O
+also	O
+to	O
+be	O
+expressed	O
+at	O
+the	O
+apical	O
+membrane	O
+of	O
+brain	O
+capillary	O
+endothelial	O
+cells	O
+that	O
+form	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+(	O
+BBB	O
+)	O
+.	O
+
+MRP2	O
+is	O
+absent	O
+in	O
+the	O
+transport	O
+-	O
+deficient	O
+(	O
+TR	O
+(	O
+-	O
+)	O
+)	O
+Wistar	O
+rat	O
+mutant	O
+,	O
+so	O
+that	O
+this	O
+rat	O
+strain	O
+was	O
+very	O
+helpful	O
+in	O
+defining	O
+substrates	O
+of	O
+MRP2	O
+by	O
+comparing	O
+tissue	O
+concentrations	O
+or	O
+functional	O
+activities	O
+of	O
+compounds	O
+in	O
+MRP2	O
+-	O
+deficient	O
+rats	O
+with	O
+those	O
+in	O
+transport	O
+-	O
+competent	O
+Wistar	O
+rats	O
+.	O
+
+By	O
+using	O
+this	O
+strategy	O
+to	O
+study	O
+the	O
+involvement	O
+of	O
+MRP2	O
+in	O
+brain	O
+access	O
+of	O
+antiepileptic	O
+drugs	O
+(	O
+AEDs	O
+)	O
+,	O
+we	O
+recently	O
+reported	O
+that	O
+phenytoin	O
+is	O
+a	O
+substrate	O
+for	O
+MRP2	O
+in	O
+the	O
+BBB	O
+.	O
+
+However	O
+,	O
+one	O
+drawback	O
+of	O
+such	O
+studies	O
+in	O
+genetically	O
+deficient	O
+rats	O
+is	O
+the	O
+fact	O
+that	O
+compensatory	O
+changes	O
+with	O
+upregulation	O
+of	O
+other	O
+transporters	O
+can	O
+occur	O
+.	O
+
+This	O
+prompted	O
+us	O
+to	O
+study	O
+the	O
+brain	O
+expression	O
+of	O
+P	O
+-	O
+glycoprotein	O
+(	O
+Pgp	O
+)	O
+,	O
+a	O
+major	O
+drug	O
+efflux	O
+transporter	O
+in	O
+many	O
+tissues	O
+,	O
+including	O
+the	O
+BBB	O
+,	O
+in	O
+TR	O
+(	O
+-	O
+)	O
+rats	O
+compared	O
+with	O
+nonmutant	O
+(	O
+wild	O
+-	O
+type	O
+)	O
+Wistar	O
+rats	O
+.	O
+
+METHODS	O
+:	O
+The	O
+expression	O
+of	O
+MRP2	O
+and	O
+Pgp	O
+in	O
+brain	O
+and	O
+liver	O
+sections	O
+of	O
+TR	O
+(	O
+-	O
+)	O
+rats	O
+and	O
+normal	O
+Wistar	O
+rats	O
+was	O
+determined	O
+with	O
+immunohistochemistry	O
+,	O
+by	O
+using	O
+a	O
+novel	O
+,	O
+highly	O
+selective	O
+monoclonal	O
+MRP2	O
+antibody	O
+and	O
+the	O
+monoclonal	O
+Pgp	O
+antibody	O
+C219	O
+,	O
+respectively	O
+.	O
+
+RESULTS	O
+:	O
+Immunofluorescence	O
+staining	O
+with	O
+the	O
+MRP2	O
+antibody	O
+was	O
+found	O
+to	O
+label	O
+a	O
+high	O
+number	O
+of	O
+microvessels	O
+throughout	O
+the	O
+brain	O
+in	O
+normal	O
+Wistar	O
+rats	O
+,	O
+whereas	O
+such	O
+labeling	O
+was	O
+absent	O
+in	O
+TR	O
+(	O
+-	O
+)	O
+rats	O
+.	O
+
+TR	O
+(	O
+-	O
+)	O
+rats	O
+exhibited	O
+a	O
+significant	O
+up	O
+-	O
+regulation	O
+of	O
+Pgp	O
+in	O
+brain	O
+capillary	O
+endothelial	O
+cells	O
+compared	O
+with	O
+wild	O
+-	O
+type	O
+controls	O
+.	O
+
+No	O
+such	O
+obvious	O
+upregulation	O
+of	O
+Pgp	O
+was	O
+observed	O
+in	O
+liver	O
+sections	O
+.	O
+
+A	O
+comparable	O
+overexpression	O
+of	O
+Pgp	O
+in	O
+the	O
+BBB	O
+was	O
+obtained	O
+after	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+in	O
+wild	O
+-	O
+type	O
+Wistar	O
+rats	O
+.	O
+
+Experiments	O
+with	O
+systemic	O
+administration	O
+of	O
+the	O
+Pgp	O
+substrate	O
+phenobarbital	O
+and	O
+the	O
+selective	O
+Pgp	O
+inhibitor	O
+tariquidar	O
+in	O
+TR	O
+(	O
+-	O
+)	O
+rats	O
+substantiated	O
+that	O
+Pgp	O
+is	O
+functional	O
+and	O
+compensates	O
+for	O
+the	O
+lack	O
+of	O
+MRP2	O
+in	O
+the	O
+BBB	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+data	O
+on	O
+TR	O
+(	O
+-	O
+)	O
+rats	O
+indicate	O
+that	O
+Pgp	O
+plays	O
+an	O
+important	O
+role	O
+in	O
+the	O
+compensation	O
+of	O
+MRP2	O
+deficiency	O
+in	O
+the	O
+BBB	O
+.	O
+
+Because	O
+such	O
+a	O
+compensatory	O
+mechanism	O
+most	O
+likely	O
+occurs	O
+to	O
+reduce	O
+injury	B
+to	I
+the	I
+brain	I
+from	O
+cytotoxic	O
+compounds	O
+,	O
+the	O
+present	O
+data	O
+substantiate	O
+the	O
+concept	O
+that	O
+MRP2	O
+performs	O
+a	O
+protective	O
+role	O
+in	O
+the	O
+BBB	O
+.	O
+
+Furthermore	O
+,	O
+our	O
+data	O
+suggest	O
+that	O
+TR	O
+(	O
+-	O
+)	O
+rats	O
+are	O
+an	O
+interesting	O
+tool	O
+to	O
+study	O
+consequences	O
+of	O
+overexpression	O
+of	O
+Pgp	O
+in	O
+the	O
+BBB	O
+on	O
+access	O
+of	O
+drugs	O
+in	O
+the	O
+brain	O
+,	O
+without	O
+the	O
+need	O
+of	O
+inducing	O
+seizures	B
+or	O
+other	O
+Pgp	O
+-	O
+enhancing	O
+events	O
+for	O
+this	O
+purpose	O
+.	O
+
+Role	O
+of	O
+xanthine	O
+oxidase	O
+in	O
+dexamethasone	O
+-	O
+induced	O
+hypertension	B
+in	O
+rats	O
+.	O
+
+1	O
+.	O
+
+Glucocorticoid	O
+-	O
+induced	O
+hypertension	B
+(	O
+GC	O
+-	O
+HT	B
+)	O
+in	O
+the	O
+rat	O
+is	O
+associated	O
+with	O
+nitric	O
+oxide	O
+-	O
+redox	O
+imbalance	O
+.	O
+
+2	O
+.	O
+
+We	O
+studied	O
+the	O
+role	O
+of	O
+xanthine	O
+oxidase	O
+(	O
+XO	O
+)	O
+,	O
+which	O
+is	O
+implicated	O
+in	O
+the	O
+production	O
+of	O
+reactive	O
+oxygen	O
+species	O
+,	O
+in	O
+dexamethasone	O
+-	O
+induced	O
+hypertension	B
+(	O
+dex	O
+-	O
+HT	B
+)	O
+.	O
+
+3	O
+.	O
+
+Thirty	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+were	O
+divided	O
+randomly	O
+into	O
+four	O
+treatment	O
+groups	O
+:	O
+saline	O
+,	O
+dexamethasone	O
+(	O
+dex	O
+)	O
+,	O
+allopurinol	O
+plus	O
+saline	O
+,	O
+and	O
+allopurinol	O
+plus	O
+dex	O
+.	O
+
+4	O
+.	O
+
+Systolic	O
+blood	O
+pressures	O
+(	O
+SBP	O
+)	O
+and	O
+bodyweights	O
+were	O
+recorded	O
+each	O
+alternate	O
+day	O
+.	O
+
+Thymus	O
+weight	O
+was	O
+used	O
+as	O
+a	O
+marker	O
+of	O
+glucocorticoid	O
+activity	O
+,	O
+and	O
+serum	O
+urate	O
+to	O
+assess	O
+XO	O
+inhibition	O
+.	O
+
+5	O
+.	O
+
+Dex	O
+increased	B
+SBP	I
+(	O
+110	O
++	O
+/	O
+-	O
+2	O
+-	O
+126	O
++	O
+/	O
+-	O
+3	O
+mmHg	O
+;	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+and	O
+decreased	B
+thymus	I
+(	I
+P	I
+<	I
+0	I
+.	I
+001	I
+)	I
+and	I
+bodyweights	I
+(	O
+P	O
+"	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+Allopurinol	O
+decreased	O
+serum	O
+urate	O
+from	O
+76	O
++	O
+/	O
+-	O
+5	O
+to	O
+30	O
++	O
+/	O
+-	O
+3	O
+micromol	O
+/	O
+L	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+in	O
+saline	O
+and	O
+from	O
+84	O
++	O
+/	O
+-	O
+13	O
+to	O
+28	O
++	O
+/	O
+-	O
+2	O
+micromol	O
+/	O
+L	O
+in	O
+dex	O
+-	O
+treated	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+groups	O
+.	O
+
+6	O
+.	O
+
+Allopurinol	O
+did	O
+not	O
+prevent	O
+dex	O
+-	O
+HT	B
+.	O
+
+This	O
+,	O
+together	O
+with	O
+our	O
+previous	O
+findings	O
+that	O
+allopurinol	O
+failed	O
+to	O
+prevent	O
+adrenocorticotrophic	O
+hormone	O
+induced	O
+hypertension	B
+,	O
+suggests	O
+that	O
+XO	O
+activity	O
+is	O
+not	O
+a	O
+major	O
+determinant	O
+of	O
+GC	O
+-	O
+HT	B
+in	O
+the	O
+rat	O
+.	O
+
+Side	O
+effects	O
+of	O
+postoperative	O
+administration	O
+of	O
+methylprednisolone	O
+and	O
+gentamicin	O
+into	O
+the	O
+posterior	O
+sub	O
+-	O
+Tenon	O
+'	O
+s	O
+space	O
+.	O
+
+PURPOSE	O
+:	O
+To	O
+assess	O
+the	O
+incidence	O
+of	O
+postoperative	O
+emetic	O
+side	O
+effects	O
+after	O
+the	O
+administration	O
+of	O
+methylprednisolone	O
+and	O
+gentamicin	O
+into	O
+the	O
+posterior	O
+sub	O
+-	O
+Tenon	O
+'	O
+s	O
+space	O
+at	O
+the	O
+end	O
+of	O
+routine	O
+cataract	B
+surgery	O
+.	O
+
+SETTING	O
+:	O
+St	O
+.	O
+
+Luke	O
+'	O
+s	O
+Hospital	O
+,	O
+Gwardamangia	O
+,	O
+Malta	O
+.	O
+
+METHODS	O
+:	O
+A	O
+double	O
+-	O
+blind	O
+double	O
+-	O
+armed	O
+prospective	O
+study	O
+comprised	O
+40	O
+patients	O
+who	O
+had	O
+uneventful	O
+sutureless	O
+phacoemulsification	O
+under	O
+sub	O
+-	O
+Tenon	O
+'	O
+s	O
+local	O
+infiltration	O
+of	O
+3	O
+mL	O
+of	O
+plain	O
+lignocaine	O
+.	O
+
+At	O
+the	O
+end	O
+of	O
+the	O
+procedure	O
+,	O
+Group	O
+A	O
+(	O
+n	O
+=	O
+20	O
+)	O
+had	O
+20	O
+mg	O
+/	O
+0	O
+.	O
+5	O
+mL	O
+of	O
+methylprednisolone	O
+and	O
+10	O
+mg	O
+/	O
+0	O
+.	O
+5	O
+mL	O
+of	O
+gentamicin	O
+injected	O
+into	O
+the	O
+posterior	O
+sub	O
+-	O
+Tenon	O
+'	O
+s	O
+space	O
+and	O
+Group	O
+B	O
+(	O
+n	O
+=	O
+20	O
+)	O
+had	O
+the	O
+same	O
+combination	O
+injected	O
+into	O
+the	O
+anterior	O
+sub	O
+-	O
+Tenon	O
+'	O
+s	O
+space	O
+.	O
+
+Postoperatively	O
+,	O
+all	O
+patients	O
+were	O
+assessed	O
+for	O
+symptoms	O
+of	O
+nausea	B
+,	I
+vomiting	I
+,	O
+and	O
+headache	B
+.	O
+
+A	O
+chi	O
+-	O
+square	O
+test	O
+was	O
+used	O
+to	O
+assess	O
+the	O
+statistical	O
+significance	O
+of	O
+results	O
+.	O
+
+RESULTS	O
+:	O
+Sixty	O
+percent	O
+in	O
+Group	O
+A	O
+developed	O
+postoperative	B
+emetic	I
+symptoms	I
+,	O
+headache	B
+,	O
+or	O
+both	O
+;	O
+1	O
+patient	O
+in	O
+Group	O
+B	O
+developed	O
+symptoms	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+administration	O
+of	O
+methylprednisolone	O
+and	O
+gentamicin	O
+in	O
+the	O
+posterior	O
+sub	O
+-	O
+Tenon	O
+'	O
+s	O
+space	O
+was	O
+related	O
+to	O
+a	O
+high	O
+incidence	O
+of	O
+side	O
+effects	O
+including	O
+nausea	B
+,	I
+vomiting	I
+,	O
+and	O
+headache	B
+.	O
+
+All	O
+adverse	O
+effects	O
+were	O
+self	O
+-	O
+limiting	O
+.	O
+
+Assessment	O
+of	O
+a	O
+new	O
+non	O
+-	O
+invasive	O
+index	O
+of	O
+cardiac	O
+performance	O
+for	O
+detection	O
+of	O
+dobutamine	O
+-	O
+induced	O
+myocardial	B
+ischemia	I
+.	O
+
+BACKGROUND	O
+:	O
+Electrocardiography	O
+has	O
+a	O
+very	O
+low	O
+sensitivity	O
+in	O
+detecting	O
+dobutamine	O
+-	O
+induced	O
+myocardial	B
+ischemia	I
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+assess	O
+the	O
+added	O
+diagnostic	O
+value	O
+of	O
+a	O
+new	O
+cardiac	O
+performance	O
+index	O
+(	O
+dP	O
+/	O
+dtejc	O
+)	O
+measurement	O
+,	O
+based	O
+on	O
+brachial	O
+artery	O
+flow	O
+changes	O
+,	O
+as	O
+compared	O
+to	O
+standard	O
+12	O
+-	O
+lead	O
+ECG	O
+,	O
+for	O
+detecting	O
+dobutamine	O
+-	O
+induced	O
+myocardial	B
+ischemia	I
+,	O
+using	O
+Tc99m	O
+-	O
+Sestamibi	O
+single	O
+-	O
+photon	O
+emission	O
+computed	O
+tomography	O
+as	O
+the	O
+gold	O
+standard	O
+of	O
+comparison	O
+to	O
+assess	O
+the	O
+presence	O
+or	O
+absence	O
+of	O
+ischemia	B
+.	O
+
+METHODS	O
+:	O
+The	O
+study	O
+group	O
+comprised	O
+40	O
+patients	O
+undergoing	O
+Sestamibi	O
+-	O
+SPECT	O
+/	O
+dobutamine	O
+stress	O
+test	O
+.	O
+
+Simultaneous	O
+measurements	O
+of	O
+ECG	O
+and	O
+brachial	O
+artery	O
+dP	O
+/	O
+dtejc	O
+were	O
+performed	O
+at	O
+each	O
+dobutamine	O
+level	O
+.	O
+
+In	O
+19	O
+of	O
+the	O
+40	O
+patients	O
+perfusion	O
+defects	O
+compatible	O
+with	O
+ischemia	B
+were	O
+detected	O
+on	O
+SPECT	O
+.	O
+
+The	O
+increase	O
+in	O
+dP	O
+/	O
+dtejc	O
+during	O
+infusion	O
+of	O
+dobutamine	O
+in	O
+this	O
+group	O
+was	O
+severely	O
+impaired	O
+as	O
+compared	O
+to	O
+the	O
+non	O
+-	O
+ischemic	O
+group	O
+.	O
+
+dP	O
+/	O
+dtejc	O
+outcome	O
+was	O
+combined	O
+with	O
+the	O
+ECG	O
+results	O
+,	O
+giving	O
+an	O
+ECG	O
+-	O
+enhanced	O
+value	O
+,	O
+and	O
+compared	O
+to	O
+ECG	O
+alone	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+sensitivity	O
+improved	O
+dramatically	O
+from	O
+16	O
+%	O
+to	O
+79	O
+%	O
+,	O
+positive	O
+predictive	O
+value	O
+increased	O
+from	O
+60	O
+%	O
+to	O
+68	O
+%	O
+and	O
+negative	O
+predictive	O
+value	O
+from	O
+54	O
+%	O
+to	O
+78	O
+%	O
+,	O
+and	O
+specificity	O
+decreased	O
+from	O
+90	O
+%	O
+to	O
+67	O
+%	O
+.	O
+
+CONCLUSIONS	O
+:	O
+If	O
+ECG	O
+alone	O
+is	O
+used	O
+for	O
+specificity	O
+,	O
+the	O
+combination	O
+with	O
+dP	O
+/	O
+dtejc	O
+improved	O
+the	O
+sensitivity	O
+of	O
+the	O
+test	O
+and	O
+could	O
+be	O
+a	O
+cost	O
+-	O
+savings	O
+alternative	O
+to	O
+cardiac	O
+imaging	O
+or	O
+perfusion	O
+studies	O
+to	O
+detect	O
+myocardial	B
+ischemia	I
+,	O
+especially	O
+in	O
+patients	O
+unable	O
+to	O
+exercise	O
+.	O
+
+Cocaine	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+:	O
+clinical	O
+observations	O
+and	O
+pathogenetic	O
+considerations	O
+.	O
+
+Clinical	O
+and	O
+experimental	O
+data	O
+published	O
+to	O
+date	O
+suggest	O
+several	O
+possible	O
+mechanisms	O
+by	O
+which	O
+cocaine	O
+may	O
+result	O
+in	O
+acute	B
+myocardial	I
+infarction	I
+.	O
+
+In	O
+individuals	O
+with	O
+preexisting	O
+,	O
+high	O
+-	O
+grade	O
+coronary	O
+arterial	O
+narrowing	O
+,	O
+acute	B
+myocardial	I
+infarction	I
+may	O
+result	O
+from	O
+an	O
+increase	O
+in	O
+myocardial	O
+oxygen	O
+demand	O
+associated	O
+with	O
+cocaine	O
+-	O
+induced	O
+increase	O
+in	O
+rate	O
+-	O
+pressure	O
+product	O
+.	O
+
+In	O
+other	O
+individuals	O
+with	O
+no	O
+underlying	O
+atherosclerotic	B
+obstruction	I
+,	O
+coronary	B
+occlusion	I
+may	O
+be	O
+due	O
+to	O
+spasm	B
+,	O
+thrombus	B
+,	O
+or	O
+both	O
+.	O
+
+With	O
+regard	O
+to	O
+spasm	B
+,	O
+the	O
+clinical	O
+findings	O
+are	O
+largely	O
+circumstantial	O
+,	O
+and	O
+the	O
+locus	O
+of	O
+cocaine	O
+-	O
+induced	O
+vasoconstriction	O
+remains	O
+speculative	O
+.	O
+
+Although	O
+certain	O
+clinical	O
+and	O
+experimental	O
+findings	O
+support	O
+the	O
+hypothesis	O
+that	O
+spasm	B
+involves	O
+the	O
+epicardial	O
+,	O
+medium	O
+-	O
+size	O
+vessels	O
+,	O
+other	O
+data	O
+suggest	O
+intramural	O
+vasoconstriction	O
+.	O
+
+Diffuse	O
+intramural	O
+vasoconstriction	O
+is	O
+not	O
+consistent	O
+with	O
+reports	O
+of	O
+segmental	O
+,	O
+discrete	O
+infarction	B
+.	O
+
+Whereas	O
+certain	O
+in	O
+vivo	O
+data	O
+suggest	O
+that	O
+these	O
+effects	O
+are	O
+alpha	O
+-	O
+mediated	O
+,	O
+other	O
+in	O
+vitro	O
+data	O
+suggest	O
+the	O
+opposite	O
+.	O
+
+The	O
+finding	O
+of	O
+cocaine	O
+-	O
+induced	O
+vasoconstriction	O
+in	O
+segments	O
+of	O
+(	O
+noninnervated	O
+)	O
+human	O
+umbilical	O
+artery	O
+suggests	O
+that	O
+the	O
+presence	O
+or	O
+absence	O
+of	O
+intact	O
+innervation	O
+is	O
+not	O
+sufficient	O
+to	O
+explain	O
+the	O
+discrepant	O
+data	O
+involving	O
+the	O
+possibility	O
+of	O
+alpha	O
+-	O
+mediated	O
+effects	O
+.	O
+
+Finally	O
+,	O
+the	O
+contribution	O
+of	O
+a	O
+primary	O
+,	O
+thrombotic	B
+effect	O
+of	O
+cocaine	O
+has	O
+not	O
+been	O
+excluded	O
+.	O
+
+Proteomic	O
+analysis	O
+of	O
+striatal	O
+proteins	O
+in	O
+the	O
+rat	O
+model	O
+of	O
+L	O
+-	O
+DOPA	O
+-	O
+induced	O
+dyskinesia	B
+.	O
+
+L	O
+-	O
+DOPA	O
+-	O
+induced	O
+dyskinesia	B
+(	O
+LID	B
+)	O
+is	O
+among	O
+the	O
+motor	O
+complications	O
+that	O
+arise	O
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+patients	O
+after	O
+a	O
+prolonged	O
+treatment	O
+with	O
+L	O
+-	O
+DOPA	O
+.	O
+
+To	O
+this	O
+day	O
+,	O
+transcriptome	O
+analysis	O
+has	O
+been	O
+performed	O
+in	O
+a	O
+rat	O
+model	O
+of	O
+LID	B
+[	O
+Neurobiol	O
+.	O
+Dis	O
+.	O
+,	O
+17	O
+(	O
+2004	O
+)	O
+,	O
+219	O
+]	O
+but	O
+information	O
+regarding	O
+the	O
+proteome	O
+is	O
+still	O
+lacking	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+we	O
+investigated	O
+the	O
+changes	O
+occurring	O
+at	O
+the	O
+protein	O
+level	O
+in	O
+striatal	O
+samples	O
+obtained	O
+from	O
+the	O
+unilaterally	O
+6	O
+-	O
+hydroxydopamine	O
+-	O
+lesion	O
+rat	O
+model	O
+of	O
+PD	B
+treated	O
+with	O
+saline	O
+,	O
+L	O
+-	O
+DOPA	O
+or	O
+bromocriptine	O
+using	O
+two	O
+-	O
+dimensional	O
+difference	O
+gel	O
+electrophoresis	O
+and	O
+mass	O
+spectrometry	O
+(	O
+MS	O
+)	O
+.	O
+
+Rats	O
+treated	O
+with	O
+L	O
+-	O
+DOPA	O
+were	O
+allocated	O
+to	O
+two	O
+groups	O
+based	O
+on	O
+the	O
+presence	O
+or	O
+absence	O
+of	O
+LID	B
+.	O
+
+Among	O
+the	O
+2000	O
+spots	O
+compared	O
+for	O
+statistical	O
+difference	O
+,	O
+67	O
+spots	O
+were	O
+significantly	O
+changed	O
+in	O
+abundance	O
+and	O
+identified	O
+using	O
+matrix	O
+-	O
+assisted	O
+laser	O
+desorption	O
+/	O
+ionization	O
+time	O
+-	O
+of	O
+-	O
+flight	O
+MS	O
+,	O
+atmospheric	O
+pressure	O
+matrix	O
+-	O
+assisted	O
+laser	O
+desorption	O
+/	O
+ionization	O
+and	O
+HPLC	O
+coupled	O
+tandem	O
+MS	O
+(	O
+LC	O
+/	O
+MS	O
+/	O
+MS	O
+)	O
+.	O
+
+Out	O
+of	O
+these	O
+67	O
+proteins	O
+,	O
+LID	B
+significantly	O
+changed	O
+the	O
+expression	O
+level	O
+of	O
+five	O
+proteins	O
+:	O
+alphabeta	O
+-	O
+crystalin	O
+,	O
+gamma	O
+-	O
+enolase	O
+,	O
+guanidoacetate	O
+methyltransferase	O
+,	O
+vinculin	O
+,	O
+and	O
+proteasome	O
+alpha	O
+-	O
+2	O
+subunit	O
+.	O
+
+Complementary	O
+techniques	O
+such	O
+as	O
+western	O
+immunoblotting	O
+and	O
+immunohistochemistry	O
+were	O
+performed	O
+to	O
+investigate	O
+the	O
+validity	O
+of	O
+the	O
+data	O
+obtained	O
+using	O
+the	O
+proteomic	O
+approach	O
+.	O
+
+In	O
+conclusion	O
+,	O
+this	O
+study	O
+provides	O
+new	O
+insights	O
+into	O
+the	O
+protein	O
+changes	O
+occurring	O
+in	O
+LID	B
+.	O
+
+Cardiac	O
+Angiography	O
+in	O
+Renally	O
+Impaired	O
+Patients	O
+(	O
+CARE	O
+)	O
+study	O
+:	O
+a	O
+randomized	O
+double	O
+-	O
+blind	O
+trial	O
+of	O
+contrast	O
+-	O
+induced	O
+nephropathy	B
+in	O
+patients	O
+with	O
+chronic	B
+kidney	I
+disease	I
+.	O
+
+BACKGROUND	O
+:	O
+No	O
+direct	O
+comparisons	O
+exist	O
+of	O
+the	O
+renal	O
+tolerability	O
+of	O
+the	O
+low	O
+-	O
+osmolality	O
+contrast	O
+medium	O
+iopamidol	O
+with	O
+that	O
+of	O
+the	O
+iso	O
+-	O
+osmolality	O
+contrast	O
+medium	O
+iodixanol	O
+in	O
+high	O
+-	O
+risk	O
+patients	O
+.	O
+
+METHODS	O
+AND	O
+RESULTS	O
+:	O
+The	O
+present	O
+study	O
+is	O
+a	O
+multicenter	O
+,	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+comparison	O
+of	O
+iopamidol	O
+and	O
+iodixanol	O
+in	O
+patients	O
+with	O
+chronic	B
+kidney	I
+disease	I
+(	O
+estimated	O
+glomerular	O
+filtration	O
+rate	O
+,	O
+20	O
+to	O
+59	O
+mL	O
+/	O
+min	O
+)	O
+who	O
+underwent	O
+cardiac	O
+angiography	O
+or	O
+percutaneous	O
+coronary	O
+interventions	O
+.	O
+
+Serum	O
+creatinine	O
+(	O
+SCr	O
+)	O
+levels	O
+and	O
+estimated	O
+glomerular	O
+filtration	O
+rate	O
+were	O
+assessed	O
+at	O
+baseline	O
+and	O
+2	O
+to	O
+5	O
+days	O
+after	O
+receiving	O
+medications	O
+.	O
+
+The	O
+primary	O
+outcome	O
+was	O
+a	O
+postdose	O
+SCr	O
+increase	O
+>	O
+or	O
+=	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+dL	O
+(	O
+44	O
+.	O
+2	O
+micromol	O
+/	O
+L	O
+)	O
+over	O
+baseline	O
+.	O
+
+Secondary	O
+outcomes	O
+were	O
+a	O
+postdose	O
+SCr	O
+increase	O
+>	O
+or	O
+=	O
+25	O
+%	O
+,	O
+a	O
+postdose	O
+estimated	O
+glomerular	O
+filtration	O
+rate	O
+decrease	O
+of	O
+>	O
+or	O
+=	O
+25	O
+%	O
+,	O
+and	O
+the	O
+mean	O
+peak	O
+change	O
+in	O
+SCr	O
+.	O
+
+In	O
+414	O
+patients	O
+,	O
+contrast	O
+volume	O
+,	O
+presence	O
+of	O
+diabetes	B
+mellitus	I
+,	O
+use	O
+of	O
+N	O
+-	O
+acetylcysteine	O
+,	O
+mean	O
+baseline	O
+SCr	O
+,	O
+and	O
+estimated	O
+glomerular	O
+filtration	O
+rate	O
+were	O
+comparable	O
+in	O
+the	O
+2	O
+groups	O
+.	O
+
+SCr	O
+increases	O
+>	O
+or	O
+=	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+dL	O
+occurred	O
+in	O
+4	O
+.	O
+4	O
+%	O
+(	O
+9	O
+of	O
+204	O
+patients	O
+)	O
+after	O
+iopamidol	O
+and	O
+6	O
+.	O
+7	O
+%	O
+(	O
+14	O
+of	O
+210	O
+patients	O
+)	O
+after	O
+iodixanol	O
+(	O
+P	O
+=	O
+0	O
+.	O
+39	O
+)	O
+,	O
+whereas	O
+rates	O
+of	O
+SCr	O
+increases	O
+>	O
+or	O
+=	O
+25	O
+%	O
+were	O
+9	O
+.	O
+8	O
+%	O
+and	O
+12	O
+.	O
+4	O
+%	O
+,	O
+respectively	O
+(	O
+P	O
+=	O
+0	O
+.	O
+44	O
+)	O
+.	O
+
+In	O
+patients	O
+with	O
+diabetes	B
+,	O
+SCr	O
+increases	O
+>	O
+or	O
+=	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+dL	O
+were	O
+5	O
+.	O
+1	O
+%	O
+(	O
+4	O
+of	O
+78	O
+patients	O
+)	O
+with	O
+iopamidol	O
+and	O
+13	O
+.	O
+0	O
+%	O
+(	O
+12	O
+of	O
+92	O
+patients	O
+)	O
+with	O
+iodixanol	O
+(	O
+P	O
+=	O
+0	O
+.	O
+11	O
+)	O
+,	O
+whereas	O
+SCr	O
+increases	O
+>	O
+or	O
+=	O
+25	O
+%	O
+were	O
+10	O
+.	O
+3	O
+%	O
+and	O
+15	O
+.	O
+2	O
+%	O
+,	O
+respectively	O
+(	O
+P	O
+=	O
+0	O
+.	O
+37	O
+)	O
+.	O
+
+Mean	O
+post	O
+-	O
+SCr	O
+increases	O
+were	O
+significantly	O
+less	O
+with	O
+iopamidol	O
+(	O
+all	O
+patients	O
+:	O
+0	O
+.	O
+07	O
+versus	O
+0	O
+.	O
+12	O
+mg	O
+/	O
+dL	O
+,	O
+6	O
+.	O
+2	O
+versus	O
+10	O
+.	O
+6	O
+micromol	O
+/	O
+L	O
+,	O
+P	O
+=	O
+0	O
+.	O
+03	O
+;	O
+patients	O
+with	O
+diabetes	B
+:	O
+0	O
+.	O
+07	O
+versus	O
+0	O
+.	O
+16	O
+mg	O
+/	O
+dL	O
+,	O
+6	O
+.	O
+2	O
+versus	O
+14	O
+.	O
+1	O
+micromol	O
+/	O
+L	O
+,	O
+P	O
+=	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+rate	O
+of	O
+contrast	O
+-	O
+induced	O
+nephropathy	B
+,	O
+defined	O
+by	O
+multiple	O
+end	O
+points	O
+,	O
+is	O
+not	O
+statistically	O
+different	O
+after	O
+the	O
+intraarterial	O
+administration	O
+of	O
+iopamidol	O
+or	O
+iodixanol	O
+to	O
+high	O
+-	O
+risk	O
+patients	O
+,	O
+with	O
+or	O
+without	O
+diabetes	B
+mellitus	I
+.	O
+
+Any	O
+true	O
+difference	O
+between	O
+the	O
+agents	O
+is	O
+small	O
+and	O
+not	O
+likely	O
+to	O
+be	O
+clinically	O
+significant	O
+.	O
+
+A	O
+novel	O
+compound	O
+,	O
+maltolyl	O
+p	O
+-	O
+coumarate	O
+,	O
+attenuates	O
+cognitive	B
+deficits	I
+and	O
+shows	O
+neuroprotective	O
+effects	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+dementia	B
+models	O
+.	O
+
+To	O
+develop	O
+a	O
+novel	O
+and	O
+effective	O
+drug	O
+that	O
+could	O
+enhance	O
+cognitive	O
+function	O
+and	O
+neuroprotection	O
+,	O
+we	O
+newly	O
+synthesized	O
+maltolyl	O
+p	O
+-	O
+coumarate	O
+by	O
+the	O
+esterification	O
+of	O
+maltol	O
+and	O
+p	O
+-	O
+coumaric	O
+acid	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+we	O
+investigated	O
+whether	O
+maltolyl	O
+p	O
+-	O
+coumarate	O
+could	O
+improve	O
+cognitive	B
+decline	I
+in	O
+scopolamine	O
+-	O
+injected	O
+rats	O
+and	O
+in	O
+amyloid	O
+beta	O
+peptide	O
+(	O
+1	O
+-	O
+42	O
+)	O
+-	O
+infused	O
+rats	O
+.	O
+
+Maltolyl	O
+p	O
+-	O
+coumarate	O
+was	O
+found	O
+to	O
+attenuate	O
+cognitive	B
+deficits	I
+in	O
+both	O
+rat	O
+models	O
+using	O
+passive	O
+avoidance	O
+test	O
+and	O
+to	O
+reduce	O
+apoptotic	O
+cell	O
+death	O
+observed	O
+in	O
+the	O
+hippocampus	O
+of	O
+the	O
+amyloid	O
+beta	O
+peptide	O
+(	O
+1	O
+-	O
+42	O
+)	O
+-	O
+infused	O
+rats	O
+.	O
+
+We	O
+also	O
+examined	O
+the	O
+neuroprotective	O
+effects	O
+of	O
+maltolyl	O
+p	O
+-	O
+coumarate	O
+in	O
+vitro	O
+using	O
+SH	O
+-	O
+SY5Y	O
+cells	O
+.	O
+
+Cells	O
+were	O
+pretreated	O
+with	O
+maltolyl	O
+p	O
+-	O
+coumarate	O
+,	O
+before	O
+exposed	O
+to	O
+amyloid	O
+beta	O
+peptide	O
+(	O
+1	O
+-	O
+42	O
+)	O
+,	O
+glutamate	O
+or	O
+H2O2	O
+.	O
+
+We	O
+found	O
+that	O
+maltolyl	O
+p	O
+-	O
+coumarate	O
+significantly	O
+decreased	O
+apoptotic	O
+cell	O
+death	O
+and	O
+reduced	O
+reactive	O
+oxygen	O
+species	O
+,	O
+cytochrome	O
+c	O
+release	O
+,	O
+and	O
+caspase	O
+3	O
+activation	O
+.	O
+
+Taking	O
+these	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+results	O
+together	O
+,	O
+our	O
+study	O
+suggests	O
+that	O
+maltolyl	O
+p	O
+-	O
+coumarate	O
+is	O
+a	O
+potentially	O
+effective	O
+candidate	O
+against	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+that	O
+is	O
+characterized	O
+by	O
+wide	O
+spread	O
+neuronal	B
+death	I
+and	O
+progressive	O
+decline	B
+of	I
+cognitive	I
+function	I
+.	O
+
+Attenuation	O
+of	O
+methamphetamine	O
+-	O
+induced	O
+nigrostriatal	O
+dopaminergic	O
+neurotoxicity	B
+in	O
+mice	O
+by	O
+lipopolysaccharide	O
+pretreatment	O
+.	O
+
+Immunological	O
+activation	O
+has	O
+been	O
+proposed	O
+to	O
+play	O
+a	O
+role	O
+in	O
+methamphetamine	O
+-	O
+induced	O
+dopaminergic	B
+terminal	I
+damage	I
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+examined	O
+the	O
+roles	O
+of	O
+lipopolysaccharide	O
+,	O
+a	O
+pro	O
+-	O
+inflammatory	O
+and	O
+inflammatory	O
+factor	O
+,	O
+treatment	O
+in	O
+modulating	O
+the	O
+methamphetamine	O
+-	O
+induced	O
+nigrostriatal	O
+dopamine	O
+neurotoxicity	B
+.	O
+
+Lipopolysaccharide	O
+pretreatment	O
+did	O
+not	O
+affect	O
+the	O
+basal	O
+body	O
+temperature	O
+or	O
+methamphetamine	O
+-	O
+elicited	O
+hyperthermia	B
+three	O
+days	O
+later	O
+.	O
+
+Such	O
+systemic	O
+lipopolysaccharide	O
+treatment	O
+mitigated	O
+methamphetamine	O
+-	O
+induced	O
+striatal	O
+dopamine	O
+and	O
+3	O
+,	O
+4	O
+-	O
+dihydroxyphenylacetic	O
+acid	O
+depletions	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+.	O
+
+As	O
+the	O
+most	O
+potent	O
+dose	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+of	O
+lipopolysaccharide	O
+was	O
+administered	O
+two	O
+weeks	O
+,	O
+one	O
+day	O
+before	O
+or	O
+after	O
+the	O
+methamphetamine	O
+dosing	O
+regimen	O
+,	O
+methamphetamine	O
+-	O
+induced	O
+striatal	O
+dopamine	O
+and	O
+3	O
+,	O
+4	O
+-	O
+dihydroxyphenylacetic	O
+acid	O
+depletions	O
+remained	O
+unaltered	O
+.	O
+
+Moreover	O
+,	O
+systemic	O
+lipopolysaccharide	O
+pretreatment	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+attenuated	O
+local	O
+methamphetamine	O
+infusion	O
+-	O
+produced	O
+dopamine	O
+and	O
+3	O
+,	O
+4	O
+-	O
+dihydroxyphenylacetic	O
+acid	O
+depletions	O
+in	O
+the	O
+striatum	O
+,	O
+indicating	O
+that	O
+the	O
+protective	O
+effect	O
+of	O
+lipopolysaccharide	O
+is	O
+less	O
+likely	O
+due	O
+to	O
+interrupted	O
+peripheral	O
+distribution	O
+or	O
+metabolism	O
+of	O
+methamphetamine	O
+.	O
+
+We	O
+concluded	O
+a	O
+critical	O
+time	O
+window	O
+for	O
+systemic	O
+lipopolysaccharide	O
+pretreatment	O
+in	O
+exerting	O
+effective	O
+protection	O
+against	O
+methamphetamine	O
+-	O
+induced	O
+nigrostriatal	O
+dopamine	O
+neurotoxicity	B
+.	O
+
+Acute	O
+myocarditis	B
+associated	O
+with	O
+clozapine	O
+.	O
+
+OBJECTIVE	O
+:	O
+A	O
+case	O
+of	O
+acute	O
+myocarditis	B
+associated	O
+with	O
+the	O
+commencement	O
+of	O
+clozapine	O
+is	O
+described	O
+,	O
+highlighting	O
+the	O
+onset	O
+,	O
+course	O
+and	O
+possible	O
+contributing	O
+factors	O
+.	O
+
+There	O
+is	O
+an	O
+urgent	O
+need	O
+to	O
+raise	O
+awareness	O
+about	O
+this	O
+potentially	O
+fatal	O
+complication	O
+of	O
+clozapine	O
+use	O
+.	O
+
+RESULTS	O
+:	O
+A	O
+20	O
+-	O
+year	O
+-	O
+old	O
+male	O
+with	O
+schizophrenia	B
+developed	O
+a	O
+sudden	O
+onset	O
+of	O
+myocarditis	B
+after	O
+commencement	O
+of	O
+clozapine	O
+.	O
+
+The	O
+patient	O
+recovered	O
+with	O
+intensive	O
+medical	O
+support	O
+.	O
+
+The	O
+symptoms	O
+occurred	O
+around	O
+2	O
+weeks	O
+after	O
+starting	O
+clozapine	O
+in	O
+an	O
+inpatient	O
+setting	O
+.	O
+
+Possible	O
+contributing	O
+factors	O
+may	O
+have	O
+been	O
+concomitant	O
+antidepressant	O
+use	O
+and	O
+unaccustomed	O
+physical	O
+activity	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Myocarditis	B
+is	O
+an	O
+increasingly	O
+recognized	O
+complication	O
+associated	O
+with	O
+the	O
+use	O
+of	O
+clozapine	O
+.	O
+
+It	O
+can	O
+be	O
+fatal	O
+if	O
+not	O
+recognized	O
+and	O
+treated	O
+early	O
+.	O
+
+Considering	O
+that	O
+clozapine	O
+remains	O
+the	O
+gold	O
+standard	O
+in	O
+treatment	O
+of	O
+resistant	O
+psychosis	B
+,	O
+there	O
+is	O
+an	O
+urgent	O
+need	O
+to	O
+raise	O
+awareness	O
+among	O
+medical	O
+and	O
+paramedical	O
+staff	O
+involved	O
+in	O
+the	O
+care	O
+of	O
+these	O
+patients	O
+.	O
+
+There	O
+are	O
+also	O
+implications	O
+for	O
+recommendations	O
+and	O
+regulations	O
+regarding	O
+the	O
+use	O
+of	O
+clozapine	O
+.	O
+
+Severe	O
+rhabdomyolysis	B
+and	O
+acute	B
+renal	I
+failure	I
+secondary	O
+to	O
+concomitant	O
+use	O
+of	O
+simvastatin	O
+,	O
+amiodarone	O
+,	O
+and	O
+atazanavir	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+a	O
+severe	O
+interaction	O
+between	O
+simvastatin	O
+,	O
+amiodarone	O
+,	O
+and	O
+atazanavir	O
+resulting	O
+in	O
+rhabdomyolysis	B
+and	O
+acute	B
+renal	I
+failure	I
+.	O
+
+BACKGROUND	O
+:	O
+A	O
+72	O
+-	O
+year	O
+-	O
+old	O
+white	O
+man	O
+with	O
+underlying	O
+human	B
+immunodeficiency	I
+virus	I
+,	O
+atrial	B
+fibrillation	I
+,	O
+coronary	B
+artery	I
+disease	I
+,	O
+and	O
+hyperlipidemia	B
+presented	O
+with	O
+generalized	O
+pain	B
+,	O
+fatigue	B
+,	O
+and	O
+dark	O
+orange	O
+urine	O
+for	O
+3	O
+days	O
+.	O
+
+The	O
+patient	O
+was	O
+taking	O
+80	O
+mg	O
+simvastatin	O
+at	O
+bedtime	O
+(	O
+initiated	O
+27	O
+days	O
+earlier	O
+)	O
+;	O
+amiodarone	O
+at	O
+a	O
+dose	O
+of	O
+400	O
+mg	O
+daily	O
+for	O
+7	O
+days	O
+,	O
+then	O
+200	O
+mg	O
+daily	O
+(	O
+initiated	O
+19	O
+days	O
+earlier	O
+)	O
+;	O
+and	O
+400	O
+mg	O
+atazanavir	O
+daily	O
+(	O
+initiated	O
+at	O
+least	O
+2	O
+years	O
+previously	O
+)	O
+.	O
+
+Laboratory	O
+evaluation	O
+revealed	O
+66	O
+,	O
+680	O
+U	O
+/	O
+L	O
+creatine	O
+kinase	O
+,	O
+93	O
+mg	O
+/	O
+dL	O
+blood	O
+urea	O
+nitrogen	O
+,	O
+4	O
+.	O
+6	O
+mg	O
+/	O
+dL	O
+creatinine	O
+,	O
+1579	O
+U	O
+/	O
+L	O
+aspartate	O
+aminotransferase	O
+,	O
+and	O
+738	O
+U	O
+/	O
+L	O
+alanine	O
+aminotransferase	O
+.	O
+
+Simvastatin	O
+,	O
+amiodarone	O
+,	O
+and	O
+the	O
+patient	O
+'	O
+s	O
+human	B
+immunodeficiency	I
+virus	I
+medications	O
+were	O
+all	O
+temporarily	O
+discontinued	O
+and	O
+the	O
+patient	O
+was	O
+given	O
+forced	O
+alkaline	O
+diuresis	O
+and	O
+started	O
+on	O
+dialysis	O
+.	O
+
+Nine	O
+days	O
+later	O
+the	O
+patient	O
+'	O
+s	O
+creatine	O
+kinase	O
+had	O
+dropped	O
+to	O
+1695	O
+U	O
+/	O
+L	O
+and	O
+creatinine	O
+was	O
+3	O
+.	O
+3	O
+mg	O
+/	O
+dL	O
+.	O
+
+The	O
+patient	O
+was	O
+discharged	O
+and	O
+continued	O
+outpatient	O
+dialysis	O
+for	O
+1	O
+month	O
+until	O
+his	O
+renal	O
+function	O
+recovered	O
+.	O
+
+DISCUSSION	O
+:	O
+The	O
+risk	O
+of	O
+rhabdomyolysis	B
+is	O
+increased	O
+in	O
+the	O
+presence	O
+of	O
+concomitant	O
+drugs	O
+that	O
+inhibit	O
+simvastatin	O
+metabolism	O
+.	O
+
+Simvastatin	O
+is	O
+metabolized	O
+by	O
+CYP3A4	O
+.	O
+
+Amiodarone	O
+and	O
+atazanavir	O
+are	O
+recognized	O
+CYP3A4	O
+inhibitors	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Pharmacokinetic	O
+differences	O
+in	O
+statins	O
+are	O
+an	O
+important	O
+consideration	O
+for	O
+assessing	O
+the	O
+risk	O
+of	O
+potential	O
+drug	O
+interactions	O
+.	O
+
+In	O
+patients	O
+requiring	O
+the	O
+concurrent	O
+use	O
+of	O
+statins	O
+and	O
+CYP3A4	O
+inhibitors	O
+,	O
+pravastatin	O
+,	O
+fluvastatin	O
+,	O
+and	O
+rosuvastatin	O
+carry	O
+the	O
+lowest	O
+risk	O
+of	O
+drug	O
+interactions	O
+;	O
+atorvastatin	O
+carries	O
+moderate	O
+risk	O
+,	O
+whereas	O
+simvastatin	O
+and	O
+lovastatin	O
+have	O
+the	O
+highest	O
+risk	O
+and	O
+should	O
+be	O
+avoided	O
+in	O
+patients	O
+taking	O
+concomitant	O
+CYP3A4	O
+inhibitors	O
+.	O
+
+Interaction	O
+between	O
+warfarin	O
+and	O
+levofloxacin	O
+:	O
+case	O
+series	O
+.	O
+
+Warfarin	O
+is	O
+the	O
+most	O
+widely	O
+used	O
+oral	O
+anticoagulant	O
+and	O
+is	O
+indicated	O
+for	O
+many	O
+clinical	O
+conditions	O
+.	O
+
+Levofloxacin	O
+,	O
+a	O
+fluoroquinolone	O
+,	O
+is	O
+one	O
+of	O
+the	O
+most	O
+commonly	O
+prescribed	O
+antibiotics	O
+in	O
+clinical	O
+practice	O
+and	O
+is	O
+effective	O
+against	O
+Gram	O
+-	O
+positive	O
+,	O
+Gram	O
+-	O
+negative	O
+,	O
+and	O
+atypical	O
+bacteria	O
+.	O
+
+While	O
+small	O
+prospective	O
+studies	O
+have	O
+not	O
+revealed	O
+any	O
+significant	O
+drug	O
+-	O
+drug	O
+interaction	O
+between	O
+warfarin	O
+and	O
+levofloxacin	O
+,	O
+several	O
+case	O
+reports	O
+have	O
+indicated	O
+that	O
+levofloxacin	O
+may	O
+significantly	O
+potentiate	O
+the	O
+anticoagulation	O
+effect	O
+of	O
+warfarin	O
+.	O
+
+We	O
+report	O
+3	O
+cases	O
+of	O
+serious	O
+bleeding	B
+complications	O
+that	O
+appear	O
+to	O
+be	O
+the	O
+result	O
+of	O
+the	O
+interaction	O
+between	O
+warfarin	O
+and	O
+levofloxacin	O
+.	O
+
+Physicians	O
+should	O
+be	O
+aware	O
+of	O
+this	O
+potential	O
+interaction	O
+and	O
+use	O
+caution	O
+when	O
+prescribing	O
+levofloxacin	O
+to	O
+patients	O
+taking	O
+warfarin	O
+.	O
+
+Mutations	O
+associated	O
+with	O
+lamivudine	O
+-	O
+resistance	O
+in	O
+therapy	O
+-	O
+na	O
+ve	O
+hepatitis	B
+B	I
+virus	I
+(	I
+HBV	I
+)	I
+infected	I
+patients	O
+with	O
+and	O
+without	O
+HIV	B
+co	I
+-	I
+infection	I
+:	O
+implications	O
+for	O
+antiretroviral	O
+therapy	O
+in	O
+HBV	B
+and	I
+HIV	I
+co	I
+-	I
+infected	I
+South	O
+African	O
+patients	O
+.	O
+
+This	O
+was	O
+an	O
+exploratory	O
+study	O
+to	O
+investigate	O
+lamivudine	O
+-	O
+resistant	O
+hepatitis	B
+B	I
+virus	O
+(	O
+HBV	O
+)	O
+strains	O
+in	O
+selected	O
+lamivudine	O
+-	O
+na	O
+ve	O
+HBV	O
+carriers	O
+with	O
+and	O
+without	O
+human	B
+immunodeficiency	I
+virus	I
+(	I
+HIV	I
+)	I
+co	I
+-	I
+infection	I
+in	O
+South	O
+African	O
+patients	O
+.	O
+
+Thirty	O
+-	O
+five	O
+lamivudine	O
+-	O
+na	O
+ve	O
+HBV	B
+infected	I
+patients	O
+with	O
+or	O
+without	O
+HIV	B
+co	I
+-	I
+infection	I
+were	O
+studied	O
+:	O
+15	O
+chronic	O
+HBV	B
+mono	I
+-	I
+infected	I
+patients	O
+and	O
+20	O
+HBV	B
+-	I
+HIV	I
+co	I
+-	I
+infected	I
+patients	O
+.	O
+
+The	O
+latter	O
+group	O
+was	O
+further	O
+sub	O
+-	O
+divided	O
+into	O
+13	O
+occult	O
+HBV	O
+(	O
+HBsAg	O
+-	O
+negative	O
+)	O
+and	O
+7	O
+overt	O
+HBV	O
+(	O
+HBsAg	O
+-	O
+positive	O
+)	O
+patients	O
+.	O
+
+HBsAg	O
+,	O
+anti	O
+-	O
+HBs	O
+,	O
+anti	O
+-	O
+HBc	O
+,	O
+and	O
+anti	O
+-	O
+HIV	O
+1	O
+/	O
+2	O
+were	O
+determined	O
+as	O
+part	O
+of	O
+routine	O
+diagnosis	O
+using	O
+Axsym	O
+assays	O
+(	O
+Abbott	O
+Laboratories	O
+,	O
+North	O
+Chicago	O
+,	O
+IL	O
+)	O
+.	O
+
+Serum	O
+samples	O
+were	O
+PCR	O
+amplified	O
+with	O
+HBV	O
+reverse	O
+transcriptase	O
+(	O
+RT	O
+)	O
+primers	O
+,	O
+followed	O
+by	O
+direct	O
+sequencing	O
+across	O
+the	O
+tyrosine	O
+-	O
+methionine	O
+-	O
+aspartate	O
+-	O
+aspartate	O
+(	O
+YMDD	O
+)	O
+motif	O
+of	O
+the	O
+major	O
+catalytic	O
+region	O
+in	O
+the	O
+C	O
+domain	O
+of	O
+the	O
+HBV	O
+RT	O
+enzyme	O
+.	O
+
+HBV	O
+viral	O
+load	O
+was	O
+performed	O
+with	O
+Amplicor	O
+HBV	O
+Monitor	O
+test	O
+v2	O
+.	O
+0	O
+(	O
+Roche	O
+Diagnostics	O
+,	O
+Penzberg	O
+,	O
+Germany	O
+)	O
+.	O
+
+HBV	O
+lamivudine	O
+-	O
+resistant	O
+strains	O
+were	O
+detected	O
+in	O
+3	O
+of	O
+15	O
+mono	O
+-	O
+infected	O
+chronic	O
+hepatitis	B
+B	I
+patients	O
+and	O
+10	O
+of	O
+20	O
+HBV	B
+-	I
+HIV	I
+co	I
+-	I
+infected	I
+patients	O
+.	O
+
+To	O
+the	O
+best	O
+of	O
+our	O
+knowledge	O
+,	O
+this	O
+constitutes	O
+the	O
+first	O
+report	O
+of	O
+HBV	O
+lamivudine	O
+-	O
+resistant	O
+strains	O
+in	O
+therapy	O
+-	O
+na	O
+ve	O
+HBV	B
+-	I
+HIV	I
+co	I
+-	I
+infected	I
+patients	O
+.	O
+
+The	O
+HBV	O
+viral	O
+loads	O
+for	O
+mono	O
+-	O
+infected	O
+and	O
+co	O
+-	O
+infected	O
+patients	O
+ranged	O
+from	O
+3	O
+.	O
+32	O
+x	O
+10	O
+(	O
+2	O
+)	O
+to	O
+3	O
+.	O
+82	O
+x	O
+10	O
+(	O
+7	O
+)	O
+and	O
+<	O
+200	O
+to	O
+4	O
+.	O
+40	O
+x	O
+10	O
+(	O
+3	O
+)	O
+copies	O
+/	O
+ml	O
+,	O
+respectively	O
+.	O
+
+It	O
+remains	O
+to	O
+be	O
+seen	O
+whether	O
+such	O
+pre	O
+-	O
+existing	O
+antiviral	O
+mutations	O
+could	O
+result	O
+in	O
+widespread	O
+emergence	O
+of	O
+HBV	O
+resistant	O
+strains	O
+when	O
+lamivudine	O
+-	O
+containing	O
+highly	O
+active	O
+antiretroviral	O
+(	O
+ARV	O
+)	O
+treatment	O
+(	O
+HAART	O
+)	O
+regimens	O
+become	O
+widely	O
+applied	O
+in	O
+South	O
+Africa	O
+,	O
+as	O
+this	O
+is	O
+likely	O
+to	O
+have	O
+potential	O
+implications	O
+in	O
+the	O
+management	O
+of	O
+HBV	B
+-	I
+HIV	I
+co	I
+-	I
+infected	I
+patients	O
+.	O
+
+Rabbit	B
+syndrome	I
+,	O
+antidepressant	O
+use	O
+,	O
+and	O
+cerebral	O
+perfusion	O
+SPECT	O
+scan	O
+findings	O
+.	O
+
+The	O
+rabbit	B
+syndrome	I
+is	O
+an	O
+extrapyramidal	O
+side	O
+effect	O
+associated	O
+with	O
+chronic	O
+neuroleptic	O
+therapy	O
+.	O
+
+Its	O
+occurrence	O
+in	O
+a	O
+patient	O
+being	O
+treated	O
+with	O
+imipramine	O
+is	O
+described	O
+,	O
+representing	O
+the	O
+first	O
+reported	O
+case	O
+of	O
+this	O
+syndrome	O
+in	O
+conjunction	O
+with	O
+antidepressants	O
+.	O
+
+Repeated	O
+cerebral	O
+perfusion	O
+SPECT	O
+scans	O
+revealed	O
+decreased	B
+basal	I
+ganglia	I
+perfusion	I
+while	O
+the	O
+movement	B
+disorder	I
+was	O
+present	O
+,	O
+and	O
+a	O
+return	O
+to	O
+normal	O
+perfusion	O
+when	O
+the	O
+rabbit	B
+syndrome	I
+resolved	O
+.	O
+
+Estrogen	O
+prevents	O
+cholesteryl	O
+ester	O
+accumulation	O
+in	O
+macrophages	O
+induced	O
+by	O
+the	O
+HIV	O
+protease	O
+inhibitor	O
+ritonavir	O
+.	O
+
+Individuals	O
+with	O
+HIV	O
+can	O
+now	O
+live	O
+long	O
+lives	O
+with	O
+drug	O
+therapy	O
+that	O
+often	O
+includes	O
+protease	O
+inhibitors	O
+such	O
+as	O
+ritonavir	O
+.	O
+
+Many	O
+patients	O
+,	O
+however	O
+,	O
+develop	O
+negative	O
+long	O
+-	O
+term	O
+side	O
+effects	O
+such	O
+as	O
+premature	B
+atherosclerosis	I
+.	O
+
+We	O
+have	O
+previously	O
+demonstrated	O
+that	O
+ritonavir	O
+treatment	O
+increases	O
+atherosclerotic	B
+lesion	I
+formation	O
+in	O
+male	O
+mice	O
+to	O
+a	O
+greater	O
+extent	O
+than	O
+in	O
+female	O
+mice	O
+.	O
+
+Furthermore	O
+,	O
+peripheral	O
+blood	O
+monocytes	O
+isolated	O
+from	O
+ritonavir	O
+-	O
+treated	O
+females	O
+had	O
+less	O
+cholesteryl	O
+ester	O
+accumulation	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+we	O
+have	O
+investigated	O
+the	O
+molecular	O
+mechanisms	O
+by	O
+which	O
+female	O
+hormones	O
+influence	O
+cholesterol	O
+metabolism	O
+in	O
+macrophages	O
+in	O
+response	O
+to	O
+the	O
+HIV	O
+protease	O
+inhibitor	O
+ritonavir	O
+.	O
+
+We	O
+have	O
+utilized	O
+the	O
+human	O
+monocyte	O
+cell	O
+line	O
+,	O
+THP	O
+-	O
+1	O
+as	O
+a	O
+model	O
+to	O
+address	O
+this	O
+question	O
+.	O
+
+Briefly	O
+,	O
+cells	O
+were	O
+differentiated	O
+for	O
+72	O
+h	O
+with	O
+100	O
+nM	O
+PMA	O
+to	O
+obtain	O
+a	O
+macrophage	O
+-	O
+like	O
+phenotype	O
+in	O
+the	O
+presence	O
+or	O
+absence	O
+of	O
+1	O
+nM	O
+17beta	O
+-	O
+estradiol	O
+(	O
+E2	O
+)	O
+,	O
+100	O
+nM	O
+progesterone	O
+or	O
+vehicle	O
+(	O
+0	O
+.	O
+01	O
+%	O
+ethanol	O
+)	O
+.	O
+
+Cells	O
+were	O
+then	O
+treated	O
+with	O
+30	O
+ng	O
+/	O
+ml	O
+ritonavir	O
+or	O
+vehicle	O
+in	O
+the	O
+presence	O
+of	O
+aggregated	O
+LDL	O
+for	O
+24	O
+h	O
+.	O
+
+Cell	O
+extracts	O
+were	O
+harvested	O
+,	O
+and	O
+lipid	O
+or	O
+total	O
+RNA	O
+was	O
+isolated	O
+.	O
+
+E2	O
+decreased	O
+the	O
+accumulation	O
+of	O
+cholesteryl	O
+esters	O
+in	O
+macrophages	O
+following	O
+ritonavir	O
+treatment	O
+.	O
+
+Ritonavir	O
+increased	O
+the	O
+expression	O
+of	O
+the	O
+scavenger	O
+receptor	O
+,	O
+CD36	O
+mRNA	O
+,	O
+responsible	O
+for	O
+the	O
+uptake	O
+of	O
+LDL	O
+.	O
+
+Additionally	O
+,	O
+ritonavir	O
+treatment	O
+selectively	O
+increased	O
+the	O
+relative	O
+levels	O
+of	O
+PPARgamma	O
+mRNA	O
+,	O
+a	O
+transcription	O
+factor	O
+responsible	O
+for	O
+the	O
+regulation	O
+of	O
+CD36	O
+mRNA	O
+expression	O
+.	O
+
+Treatment	O
+with	O
+E2	O
+,	O
+however	O
+,	O
+failed	O
+to	O
+prevent	O
+these	O
+increases	O
+at	O
+the	O
+mRNA	O
+level	O
+.	O
+
+E2	O
+did	O
+,	O
+however	O
+,	O
+significantly	O
+suppress	O
+CD36	O
+protein	O
+levels	O
+as	O
+measured	O
+by	O
+fluorescent	O
+immunocytochemistry	O
+.	O
+
+This	O
+data	O
+suggests	O
+that	O
+E2	O
+modifies	O
+the	O
+expression	O
+of	O
+CD36	O
+at	O
+the	O
+level	O
+of	O
+protein	O
+expression	O
+in	O
+monocyte	O
+-	O
+derived	O
+macrophages	O
+resulting	O
+in	O
+reduced	O
+cholesteryl	O
+ester	O
+accumulation	O
+following	O
+ritonavir	O
+treatment	O
+.	O
+
+Acute	O
+hepatitis	B
+attack	O
+after	O
+exposure	O
+to	O
+telithromycin	O
+.	O
+
+INTRODUCTION	O
+:	O
+Antibiotic	O
+-	O
+associated	O
+hepatotoxicity	B
+is	O
+rare	O
+.	O
+
+With	O
+widespread	O
+use	O
+of	O
+antimicrobial	O
+agents	O
+,	O
+however	O
+,	O
+hepatic	B
+injury	I
+occurs	O
+frequently	O
+,	O
+and	O
+among	O
+adverse	B
+drug	I
+reactions	I
+,	O
+idiosyncratic	O
+reactions	O
+are	O
+the	O
+most	O
+serious	O
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+25	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+,	O
+with	O
+a	O
+height	O
+of	O
+175	O
+cm	O
+and	O
+weight	O
+of	O
+72	O
+kg	O
+presented	O
+to	O
+Marmara	O
+University	O
+Hospital	O
+Emergency	O
+Department	O
+,	O
+Istanbul	O
+,	O
+Turkey	O
+,	O
+with	O
+5	O
+days	O
+'	O
+history	O
+of	O
+jaundice	B
+,	O
+malaise	O
+,	O
+nausea	B
+,	O
+and	O
+vomiting	B
+.	O
+
+He	O
+had	O
+been	O
+prescribed	O
+telithromycin	O
+400	O
+mg	O
+/	O
+d	O
+PO	O
+to	O
+treat	O
+an	O
+upper	B
+respiratory	I
+tract	I
+infection	I
+7	O
+days	O
+prior	O
+.	O
+
+Admission	O
+laboratory	O
+tests	O
+were	O
+as	O
+follows	O
+:	O
+alanine	O
+aminotransferase	O
+,	O
+67	O
+U	O
+/	O
+L	O
+(	O
+reference	O
+range	O
+,	O
+10	O
+-	O
+37	O
+U	O
+/	O
+L	O
+)	O
+;	O
+aspartate	O
+aminotransferase	O
+,	O
+98	O
+U	O
+/	O
+L	O
+(	O
+10	O
+-	O
+40	O
+U	O
+/	O
+L	O
+)	O
+;	O
+alkaline	O
+phosphatase	O
+,	O
+513	O
+U	O
+/	O
+L	O
+(	O
+0	O
+-	O
+270	O
+U	O
+/	O
+L	O
+)	O
+;	O
+gamma	O
+-	O
+glutamyltransferase	O
+,	O
+32	O
+U	O
+/	O
+L	O
+(	O
+7	O
+-	O
+49	O
+U	O
+/	O
+L	O
+)	O
+;	O
+amylase	O
+,	O
+46	O
+U	O
+/	O
+L	O
+(	O
+0	O
+-	O
+220	O
+U	O
+/	O
+L	O
+)	O
+;	O
+total	O
+bilirubin	O
+,	O
+20	O
+.	O
+1	O
+mg	O
+/	O
+dL	O
+(	O
+0	O
+.	O
+2	O
+-	O
+1	O
+.	O
+0	O
+mg	O
+/	O
+dL	O
+)	O
+;	O
+direct	O
+bilirubin	O
+,	O
+14	O
+.	O
+8	O
+mg	O
+/	O
+dL	O
+(	O
+0	O
+-	O
+0	O
+.	O
+3	O
+mg	O
+/	O
+dL	O
+)	O
+;	O
+and	O
+albumin	O
+,	O
+4	O
+.	O
+7	O
+mg	O
+/	O
+dL	O
+(	O
+3	O
+.	O
+5	O
+-	O
+5	O
+.	O
+4	O
+mg	O
+/	O
+dL	O
+)	O
+.	O
+
+No	O
+toxin	O
+,	O
+alcohol	O
+,	O
+or	O
+other	O
+drugs	O
+were	O
+reported	O
+.	O
+
+The	O
+patient	O
+had	O
+suffered	O
+a	O
+previous	O
+episode	O
+of	O
+"	O
+acute	O
+hepatitis	B
+of	O
+unknown	O
+origin	O
+,	O
+"	O
+that	O
+occurred	O
+after	O
+telithromycin	O
+usage	O
+.	O
+
+Both	O
+incidents	O
+occurred	O
+within	O
+a	O
+year	O
+.	O
+
+DISCUSSION	O
+:	O
+Telithromycin	O
+is	O
+the	O
+first	O
+of	O
+the	O
+ketolide	O
+antibacterials	O
+to	O
+receive	O
+US	O
+Food	O
+and	O
+Drug	O
+Administration	O
+approval	O
+for	O
+clinical	O
+use	O
+.	O
+
+It	O
+has	O
+been	O
+associated	O
+with	O
+infrequent	O
+and	O
+usually	O
+reversible	O
+severe	O
+hepatic	B
+dysfunction	I
+.	O
+
+Based	O
+on	O
+a	O
+score	O
+of	O
+8	O
+on	O
+the	O
+Naranjo	O
+adverse	B
+drug	I
+reaction	I
+probability	O
+scale	O
+,	O
+telithromycin	O
+was	O
+the	O
+probable	O
+cause	O
+of	O
+acute	O
+hepatitis	B
+in	O
+this	O
+patient	O
+,	O
+and	O
+pathological	O
+findings	O
+suggested	O
+drug	O
+-	O
+induced	O
+toxic	B
+hepatitis	I
+.	O
+
+Recurrence	O
+of	O
+hepatitis	B
+attack	O
+might	O
+have	O
+been	O
+avoided	O
+if	O
+the	O
+initial	O
+incident	O
+had	O
+been	O
+communicated	O
+to	O
+the	O
+attending	O
+physician	O
+who	O
+prescribed	O
+telithromycin	O
+the	O
+second	O
+time	O
+.	O
+
+CONCLUSION	O
+:	O
+Here	O
+we	O
+report	O
+a	O
+case	O
+of	O
+acute	O
+hepatitis	B
+probably	O
+associated	O
+with	O
+the	O
+administration	O
+of	O
+telithromycin	O
+.	O
+
+A	O
+study	O
+on	O
+the	O
+effect	O
+of	O
+the	O
+duration	O
+of	O
+subcutaneous	O
+heparin	O
+injection	O
+on	O
+bruising	B
+and	O
+pain	B
+.	O
+
+AIM	O
+:	O
+This	O
+study	O
+was	O
+carried	O
+out	O
+to	O
+determine	O
+the	O
+effect	O
+of	O
+injection	O
+duration	O
+on	O
+bruising	B
+and	O
+pain	B
+following	O
+the	O
+administration	O
+of	O
+the	O
+subcutaneous	O
+injection	O
+of	O
+heparin	O
+.	O
+
+BACKGROUND	O
+:	O
+Although	O
+different	O
+methods	O
+to	O
+prevent	O
+bruising	B
+and	O
+pain	B
+following	O
+the	O
+subcutaneous	O
+injection	O
+of	O
+heparin	O
+have	O
+been	O
+widely	O
+studied	O
+and	O
+described	O
+,	O
+the	O
+effect	O
+of	O
+injection	O
+duration	O
+on	O
+the	O
+occurrence	O
+of	O
+bruising	B
+and	O
+pain	B
+is	O
+little	O
+documented	O
+.	O
+
+DESIGN	O
+:	O
+This	O
+study	O
+was	O
+designed	O
+as	O
+within	O
+-	O
+subject	O
+,	O
+quasi	O
+-	O
+experimental	O
+research	O
+.	O
+
+METHOD	O
+:	O
+The	O
+sample	O
+for	O
+the	O
+study	O
+consisted	O
+of	O
+50	O
+patients	O
+to	O
+whom	O
+subcutaneous	O
+heparin	O
+was	O
+administered	O
+.	O
+
+Heparin	O
+was	O
+injected	O
+over	O
+10	O
+seconds	O
+on	O
+the	O
+right	O
+abdominal	O
+site	O
+and	O
+30	O
+seconds	O
+on	O
+the	O
+left	O
+abdominal	O
+site	O
+.	O
+
+Injections	O
+areas	O
+were	O
+assessed	O
+for	O
+the	O
+presence	O
+of	O
+bruising	B
+at	O
+48	O
+and	O
+72	O
+hours	O
+after	O
+each	O
+injection	O
+.	O
+
+Dimensions	O
+of	O
+the	O
+bruising	B
+on	O
+the	O
+heparin	O
+applied	O
+areas	O
+were	O
+measured	O
+using	O
+transparent	O
+millimetric	O
+measuring	O
+paper	O
+.	O
+
+The	O
+visual	O
+analog	O
+scale	O
+(	O
+VAS	O
+)	O
+was	O
+used	O
+to	O
+measure	O
+pain	B
+intensity	O
+and	O
+a	O
+stop	O
+-	O
+watch	O
+was	O
+used	O
+to	O
+time	O
+the	O
+pain	B
+period	O
+.	O
+
+Data	O
+were	O
+analysed	O
+using	O
+chi	O
+-	O
+square	O
+test	O
+,	O
+Mann	O
+-	O
+Whitney	O
+U	O
+,	O
+Wilcoxon	O
+signed	O
+ranks	O
+tests	O
+and	O
+correlation	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+percentage	O
+of	O
+bruising	B
+occurrence	O
+was	O
+64	O
+%	O
+with	O
+the	O
+injection	O
+of	O
+10	O
+seconds	O
+duration	O
+and	O
+42	O
+%	O
+in	O
+the	O
+30	O
+-	O
+second	O
+injection	O
+.	O
+
+It	O
+was	O
+determined	O
+that	O
+the	O
+size	O
+of	O
+the	O
+bruising	B
+was	O
+smaller	O
+in	O
+the	O
+30	O
+-	O
+second	O
+injection	O
+.	O
+
+Pain	B
+intensity	O
+and	O
+pain	B
+period	O
+were	O
+statistically	O
+significantly	O
+lower	O
+for	O
+the	O
+30	O
+-	O
+second	O
+injection	O
+than	O
+for	O
+the	O
+10	O
+-	O
+second	O
+injection	O
+.	O
+
+CONCLUSIONS	O
+:	O
+It	O
+was	O
+determined	O
+that	O
+injection	O
+duration	O
+had	O
+an	O
+effect	O
+on	O
+bruising	B
+and	O
+pain	B
+following	O
+the	O
+subcutaneous	O
+administration	O
+of	O
+heparin	O
+.	O
+
+This	O
+study	O
+should	O
+be	O
+repeated	O
+on	O
+a	O
+larger	O
+sample	O
+.	O
+
+RELEVANCE	O
+TO	O
+CLINICAL	O
+PRACTICE	O
+:	O
+When	O
+administering	O
+subcutaneous	O
+heparin	O
+injections	O
+,	O
+it	O
+is	O
+important	O
+to	O
+extend	O
+the	O
+duration	O
+of	O
+the	O
+injection	O
+.	O
+
+Acute	B
+liver	I
+failure	I
+in	O
+two	O
+patients	O
+with	O
+regular	O
+alcohol	O
+consumption	O
+ingesting	O
+paracetamol	O
+at	O
+therapeutic	O
+dosage	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+possible	O
+role	O
+of	O
+alcohol	O
+in	O
+the	O
+development	O
+of	O
+hepatotoxicity	B
+associated	O
+with	O
+therapeutic	O
+doses	O
+of	O
+paracetamol	O
+(	O
+acetaminophen	O
+)	O
+is	O
+currently	O
+debated	O
+.	O
+
+CASE	O
+REPORT	O
+:	O
+We	O
+describe	O
+2	O
+patients	O
+who	O
+were	O
+regular	O
+consumers	O
+of	O
+alcohol	O
+and	O
+who	O
+developed	O
+liver	B
+failure	I
+within	O
+3	O
+-	O
+5	O
+days	O
+after	O
+hospitalization	O
+and	O
+stopping	O
+alcohol	O
+consumption	O
+while	O
+being	O
+treated	O
+with	O
+4	O
+g	O
+paracetamol	O
+/	O
+day	O
+.	O
+
+A	O
+paracetamol	O
+serum	O
+level	O
+obtained	O
+in	O
+one	O
+of	O
+these	O
+patients	O
+was	O
+not	O
+in	O
+the	O
+toxic	O
+range	O
+.	O
+
+Possible	O
+risk	O
+factors	O
+for	O
+the	O
+development	O
+of	O
+hepatotoxicity	B
+in	O
+patients	O
+treated	O
+with	O
+therapeutic	O
+doses	O
+of	O
+paracetamol	O
+are	O
+discussed	O
+.	O
+
+CONCLUSION	O
+:	O
+In	O
+patients	O
+with	O
+risk	O
+factors	O
+,	O
+e	O
+.	O
+g	O
+.	O
+regular	O
+consumption	O
+of	O
+alcohol	O
+,	O
+liver	B
+failure	I
+is	O
+possible	O
+when	O
+therapeutic	O
+doses	O
+are	O
+ingested	O
+.	O
+
+We	O
+propose	O
+that	O
+the	O
+paracetamol	O
+dose	O
+should	O
+not	O
+exceed	O
+2	O
+g	O
+/	O
+day	O
+in	O
+such	O
+patients	O
+and	O
+that	O
+their	O
+liver	O
+function	O
+should	O
+be	O
+monitored	O
+closely	O
+while	O
+being	O
+treated	O
+with	O
+paracetamol	O
+.	O
+
+Associations	O
+between	O
+use	O
+of	O
+benzodiazepines	O
+or	O
+related	O
+drugs	O
+and	O
+health	O
+,	O
+physical	O
+abilities	O
+and	O
+cognitive	O
+function	O
+:	O
+a	O
+non	O
+-	O
+randomised	O
+clinical	O
+study	O
+in	O
+the	O
+elderly	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+describe	O
+associations	O
+between	O
+the	O
+use	O
+of	O
+benzodiazepines	O
+or	O
+related	O
+drugs	O
+(	O
+BZDs	O
+/	O
+RDs	O
+)	O
+and	O
+health	O
+,	O
+functional	O
+abilities	O
+and	O
+cognitive	O
+function	O
+in	O
+the	O
+elderly	O
+.	O
+
+METHODS	O
+:	O
+A	O
+non	O
+-	O
+randomised	O
+clinical	O
+study	O
+of	O
+patients	O
+aged	O
+>	O
+or	O
+=	O
+65	O
+years	O
+admitted	O
+to	O
+acute	O
+hospital	O
+wards	O
+during	O
+1	O
+month	O
+.	O
+
+164	O
+patients	O
+(	O
+mean	O
+age	O
++	O
+/	O
+-	O
+standard	O
+deviation	O
+[	O
+SD	O
+]	O
+81	O
+.	O
+6	O
++	O
+/	O
+-	O
+6	O
+.	O
+8	O
+years	O
+)	O
+were	O
+admitted	O
+.	O
+
+Of	O
+these	O
+,	O
+nearly	O
+half	O
+(	O
+n	O
+=	O
+78	O
+)	O
+had	O
+used	O
+BZDs	O
+/	O
+RDs	O
+before	O
+admission	O
+,	O
+and	O
+the	O
+remainder	O
+(	O
+n	O
+=	O
+86	O
+)	O
+were	O
+non	O
+-	O
+users	O
+.	O
+
+Cognitive	O
+ability	O
+was	O
+assessed	O
+by	O
+the	O
+Mini	O
+-	O
+Mental	O
+State	O
+Examination	O
+(	O
+MMSE	O
+)	O
+.	O
+
+Patients	O
+scoring	O
+>	O
+or	O
+=	O
+20	O
+MMSE	O
+sum	O
+points	O
+were	O
+interviewed	O
+(	O
+n	O
+=	O
+79	O
+)	O
+and	O
+questioned	O
+regarding	O
+symptoms	O
+and	O
+functional	O
+abilities	O
+during	O
+the	O
+week	O
+prior	O
+to	O
+admission	O
+.	O
+
+Data	O
+on	O
+use	O
+of	O
+BZDs	O
+/	O
+RDs	O
+before	O
+admission	O
+,	O
+current	O
+medications	O
+and	O
+discharge	O
+diagnoses	O
+were	O
+collected	O
+from	O
+medical	O
+records	O
+.	O
+
+Health	O
+,	O
+physical	O
+abilities	O
+and	O
+cognitive	O
+function	O
+were	O
+compared	O
+between	O
+BZD	O
+/	O
+RD	O
+users	O
+and	O
+non	O
+-	O
+users	O
+,	O
+and	O
+adjustments	O
+were	O
+made	O
+for	O
+confounding	O
+variables	O
+.	O
+
+The	O
+residual	O
+serum	O
+concentrations	O
+of	O
+oxazepam	O
+,	O
+temazepam	O
+and	O
+zopiclone	O
+were	O
+analysed	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+duration	O
+of	O
+BZD	O
+/	O
+RD	O
+use	O
+was	O
+7	O
++	O
+/	O
+-	O
+7	O
+years	O
+(	O
+range	O
+1	O
+-	O
+31	O
+)	O
+.	O
+
+Two	O
+or	O
+three	O
+BZDs	O
+/	O
+RDs	O
+were	O
+concomitantly	O
+taken	O
+by	O
+26	O
+%	O
+of	O
+users	O
+(	O
+n	O
+=	O
+20	O
+)	O
+.	O
+
+Long	O
+-	O
+term	O
+use	O
+of	O
+these	O
+drugs	O
+was	O
+associated	O
+with	O
+female	O
+sex	O
+and	O
+use	O
+of	O
+a	O
+higher	O
+number	O
+of	O
+drugs	O
+with	O
+effects	O
+on	O
+the	O
+CNS	O
+,	O
+which	O
+tended	O
+to	O
+be	O
+related	O
+to	O
+diagnosed	O
+dementia	B
+.	O
+
+After	O
+adjustment	O
+for	O
+these	O
+variables	O
+as	O
+confounders	O
+,	O
+use	O
+of	O
+BZDs	O
+/	O
+RDs	O
+was	O
+not	O
+associated	O
+with	O
+cognitive	O
+function	O
+as	O
+measured	O
+by	O
+the	O
+MMSE	O
+.	O
+
+However	O
+,	O
+use	O
+of	O
+BZDs	O
+/	O
+RDs	O
+was	O
+associated	O
+with	O
+dizziness	B
+,	O
+inability	B
+to	I
+sleep	I
+after	O
+awaking	O
+at	O
+night	O
+and	O
+tiredness	B
+in	O
+the	O
+mornings	O
+during	O
+the	O
+week	O
+prior	O
+to	O
+admission	O
+and	O
+with	O
+stronger	O
+depressive	B
+symptoms	I
+measured	O
+at	O
+the	O
+beginning	O
+of	O
+the	O
+hospital	O
+stay	O
+.	O
+
+Use	O
+of	O
+BZDs	O
+/	O
+RDs	O
+tended	O
+to	O
+be	O
+associated	O
+with	O
+a	O
+reduced	O
+ability	O
+to	O
+walk	O
+and	O
+shorter	O
+night	O
+-	O
+time	O
+sleep	O
+during	O
+the	O
+week	O
+prior	O
+to	O
+admission	O
+.	O
+
+A	O
+higher	O
+residual	O
+serum	O
+concentration	O
+of	O
+temazepam	O
+correlated	O
+with	O
+a	O
+lower	O
+MMSE	O
+sum	O
+score	O
+after	O
+adjustment	O
+for	O
+confounding	O
+variables	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Long	O
+-	O
+term	O
+use	O
+and	O
+concomitant	O
+use	O
+of	O
+more	O
+than	O
+one	O
+BZD	O
+/	O
+RD	O
+were	O
+common	O
+in	O
+elderly	O
+patients	O
+hospitalised	O
+because	O
+of	O
+acute	O
+illnesses	O
+.	O
+
+Long	O
+-	O
+term	O
+use	O
+was	O
+associated	O
+with	O
+daytime	O
+and	O
+night	O
+-	O
+time	O
+symptoms	O
+indicative	O
+of	O
+poorer	O
+health	O
+and	O
+potentially	O
+caused	O
+by	O
+the	O
+adverse	O
+effects	O
+of	O
+these	O
+drugs	O
+.	O
+
+Acute	O
+vocal	B
+fold	I
+palsy	I
+after	O
+acute	O
+disulfiram	O
+intoxication	O
+.	O
+
+Acute	O
+peripheral	B
+neuropathy	I
+caused	O
+by	O
+a	O
+disulfiram	O
+overdose	B
+is	O
+very	O
+rare	O
+and	O
+there	O
+is	O
+no	O
+report	O
+of	O
+it	O
+leading	O
+to	O
+vocal	B
+fold	I
+palsy	I
+.	O
+
+A	O
+49	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+was	O
+transferred	O
+to	O
+our	O
+department	O
+because	O
+of	O
+quadriparesis	B
+,	O
+lancinating	O
+pain	B
+,	O
+sensory	B
+loss	I
+,	O
+and	O
+paresthesia	B
+of	O
+the	O
+distal	O
+limbs	O
+.	O
+
+One	O
+month	O
+previously	O
+,	O
+she	O
+had	O
+taken	O
+a	O
+single	O
+high	O
+dose	O
+of	O
+disulfiram	O
+(	O
+130	O
+tablets	O
+of	O
+ALCOHOL	O
+STOP	O
+TAB	O
+,	O
+Shin	O
+-	O
+Poong	O
+Pharm	O
+.	O
+Co	O
+.	O
+,	O
+Ansan	O
+,	O
+Korea	O
+)	O
+in	O
+a	O
+suicide	O
+attempt	O
+.	O
+
+She	O
+was	O
+not	O
+an	O
+alcoholic	O
+.	O
+
+For	O
+the	O
+first	O
+few	O
+days	O
+after	O
+ingestion	O
+,	O
+she	O
+was	O
+in	O
+a	O
+confused	O
+state	O
+and	O
+had	O
+mild	O
+to	O
+moderate	O
+ataxia	B
+and	O
+giddiness	B
+.	O
+
+She	O
+noticed	O
+hoarseness	B
+and	O
+distally	O
+accentuated	O
+motor	O
+and	O
+sensory	O
+dysfunction	O
+after	O
+she	O
+had	O
+recovered	O
+from	O
+this	O
+state	O
+.	O
+
+A	O
+nerve	O
+conduction	O
+study	O
+was	O
+consistent	O
+with	O
+severe	O
+sensorimotor	O
+axonal	O
+polyneuropathy	B
+.	O
+
+Laryngeal	O
+electromyography	O
+(	O
+thyroarytenoid	O
+muscle	O
+)	O
+showed	O
+ample	O
+denervation	O
+potentials	O
+.	O
+
+Laryngoscopy	O
+revealed	O
+asymmetric	O
+vocal	O
+fold	O
+movements	O
+during	O
+phonation	O
+.	O
+
+Her	O
+vocal	O
+change	O
+and	O
+weakness	O
+began	O
+to	O
+improve	O
+spontaneously	O
+about	O
+3	O
+weeks	O
+after	O
+transfer	O
+.	O
+
+This	O
+was	O
+a	O
+case	O
+of	O
+acute	O
+palsy	B
+of	O
+the	O
+recurrent	O
+laryngeal	O
+nerve	O
+and	O
+superimposed	O
+severe	O
+acute	O
+sensorimotor	O
+axonal	O
+polyneuropathy	B
+caused	O
+by	O
+high	O
+-	O
+dose	O
+disulfiram	O
+intoxication	O
+.	O
+
+Encephalopathy	B
+induced	O
+by	O
+levetiracetam	O
+added	O
+to	O
+valproate	O
+.	O
+
+BACKGROUND	O
+:	O
+We	O
+report	O
+on	O
+the	O
+manifestation	O
+of	O
+a	O
+levetiracetam	O
+(	O
+LEV	O
+)	O
+-	O
+induced	O
+encephalopathy	B
+.	O
+
+FINDINGS	O
+:	O
+A	O
+28	O
+-	O
+year	O
+-	O
+old	O
+man	O
+suffering	O
+from	O
+idiopathic	B
+epilepsy	I
+with	O
+generalized	O
+seizures	B
+was	O
+treated	O
+with	O
+LEV	O
+(	O
+3000	O
+mg	O
+)	O
+added	O
+to	O
+valproate	O
+(	O
+VPA	O
+)	O
+(	O
+2000	O
+mg	O
+)	O
+.	O
+
+Frequency	O
+of	O
+generalized	O
+tonic	B
+-	I
+clonic	I
+seizures	I
+increased	O
+from	O
+one	O
+per	O
+6	O
+months	O
+to	O
+two	O
+per	O
+month	O
+.	O
+
+Neuropsychological	O
+testing	O
+showed	O
+impaired	B
+word	I
+fluency	I
+,	I
+psychomotor	I
+speed	I
+and	I
+working	I
+memory	I
+.	O
+
+The	O
+interictal	O
+electroencephalogram	O
+(	O
+EEG	O
+)	O
+showed	O
+a	O
+generalized	O
+slowing	O
+to	O
+5	O
+per	O
+second	O
+theta	O
+rhythms	O
+with	O
+bilateral	O
+generalized	O
+high	O
+-	O
+amplitude	O
+discharges	O
+.	O
+
+OUTCOME	O
+:	O
+Following	O
+discontinuation	O
+of	O
+LEV	O
+,	O
+EEG	O
+and	O
+neuropsychological	O
+findings	O
+improved	O
+and	O
+seizure	B
+frequency	O
+decreased	O
+.	O
+
+Norepinephrine	O
+signaling	O
+through	O
+beta	O
+-	O
+adrenergic	O
+receptors	O
+is	O
+critical	O
+for	O
+expression	O
+of	O
+cocaine	O
+-	O
+induced	O
+anxiety	B
+.	O
+
+BACKGROUND	O
+:	O
+Cocaine	O
+is	O
+a	O
+widely	O
+abused	O
+psychostimulant	O
+that	O
+has	O
+both	O
+rewarding	O
+and	O
+aversive	O
+properties	O
+.	O
+
+While	O
+the	O
+mechanisms	O
+underlying	O
+cocaine	O
+'	O
+s	O
+rewarding	O
+effects	O
+have	O
+been	O
+studied	O
+extensively	O
+,	O
+less	O
+attention	O
+has	O
+been	O
+paid	O
+to	O
+the	O
+unpleasant	O
+behavioral	O
+states	O
+induced	O
+by	O
+cocaine	O
+,	O
+such	O
+as	O
+anxiety	B
+.	O
+
+METHODS	O
+:	O
+In	O
+this	O
+study	O
+,	O
+we	O
+evaluated	O
+the	O
+performance	O
+of	O
+dopamine	O
+beta	O
+-	O
+hydroxylase	O
+knockout	O
+(	O
+Dbh	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+,	O
+which	O
+lack	O
+norepinephrine	O
+(	O
+NE	O
+)	O
+,	O
+in	O
+the	O
+elevated	O
+plus	O
+maze	O
+(	O
+EPM	O
+)	O
+to	O
+examine	O
+the	O
+contribution	O
+of	O
+noradrenergic	O
+signaling	O
+to	O
+cocaine	O
+-	O
+induced	O
+anxiety	B
+.	O
+
+RESULTS	O
+:	O
+We	O
+found	O
+that	O
+cocaine	O
+dose	O
+-	O
+dependently	O
+increased	O
+anxiety	B
+-	O
+like	O
+behavior	O
+in	O
+control	O
+(	O
+Dbh	O
++	O
+/	O
+-	O
+)	O
+mice	O
+,	O
+as	O
+measured	O
+by	O
+a	O
+decrease	O
+in	O
+open	O
+arm	O
+exploration	O
+.	O
+
+The	O
+Dbh	O
+-	O
+/	O
+-	O
+mice	O
+had	O
+normal	O
+baseline	O
+performance	O
+in	O
+the	O
+EPM	O
+but	O
+were	O
+completely	O
+resistant	O
+to	O
+the	O
+anxiogenic	O
+effects	O
+of	O
+cocaine	O
+.	O
+
+Cocaine	O
+-	O
+induced	O
+anxiety	B
+was	O
+also	O
+attenuated	O
+in	O
+Dbh	O
++	O
+/	O
+-	O
+mice	O
+following	O
+administration	O
+of	O
+disulfiram	O
+,	O
+a	O
+dopamine	O
+beta	O
+-	O
+hydroxylase	O
+(	O
+DBH	O
+)	O
+inhibitor	O
+.	O
+
+In	O
+experiments	O
+using	O
+specific	O
+adrenergic	O
+antagonists	O
+,	O
+we	O
+found	O
+that	O
+pretreatment	O
+with	O
+the	O
+beta	O
+-	O
+adrenergic	O
+receptor	O
+antagonist	O
+propranolol	O
+blocked	O
+cocaine	O
+-	O
+induced	O
+anxiety	B
+-	O
+like	O
+behavior	O
+in	O
+Dbh	O
++	O
+/	O
+-	O
+and	O
+wild	O
+-	O
+type	O
+C57BL6	O
+/	O
+J	O
+mice	O
+,	O
+while	O
+the	O
+alpha	O
+(	O
+1	O
+)	O
+antagonist	O
+prazosin	O
+and	O
+the	O
+alpha	O
+(	O
+2	O
+)	O
+antagonist	O
+yohimbine	O
+had	O
+no	O
+effect	O
+.	O
+
+CONCLUSIONS	O
+:	O
+These	O
+results	O
+indicate	O
+that	O
+noradrenergic	O
+signaling	O
+via	O
+beta	O
+-	O
+adrenergic	O
+receptors	O
+is	O
+required	O
+for	O
+cocaine	O
+-	O
+induced	O
+anxiety	B
+in	O
+mice	O
+.	O
+
+Hypothalamic	O
+prolactin	O
+receptor	O
+messenger	O
+ribonucleic	O
+acid	O
+levels	O
+,	O
+prolactin	O
+signaling	O
+,	O
+and	O
+hyperprolactinemic	B
+inhibition	O
+of	O
+pulsatile	O
+luteinizing	O
+hormone	O
+secretion	O
+are	O
+dependent	O
+on	O
+estradiol	O
+.	O
+
+Hyperprolactinemia	B
+can	O
+reduce	O
+fertility	O
+and	O
+libido	O
+.	O
+
+Although	O
+central	O
+prolactin	O
+actions	O
+are	O
+thought	O
+to	O
+contribute	O
+to	O
+this	O
+,	O
+the	O
+mechanisms	O
+are	O
+poorly	O
+understood	O
+.	O
+
+We	O
+first	O
+tested	O
+whether	O
+chronic	O
+hyperprolactinemia	B
+inhibited	O
+two	O
+neuroendocrine	O
+parameters	O
+necessary	O
+for	O
+female	O
+fertility	O
+:	O
+pulsatile	O
+LH	O
+secretion	O
+and	O
+the	O
+estrogen	O
+-	O
+induced	O
+LH	O
+surge	O
+.	O
+
+Chronic	O
+hyperprolactinemia	B
+induced	O
+by	O
+the	O
+dopamine	O
+antagonist	O
+sulpiride	O
+caused	O
+a	O
+40	O
+%	O
+reduction	O
+LH	O
+pulse	O
+frequency	O
+in	O
+ovariectomized	O
+rats	O
+,	O
+but	O
+only	O
+in	O
+the	O
+presence	O
+of	O
+chronic	O
+low	O
+levels	O
+of	O
+estradiol	O
+.	O
+
+Sulpiride	O
+did	O
+not	O
+affect	O
+the	O
+magnitude	O
+of	O
+a	O
+steroid	O
+-	O
+induced	O
+LH	O
+surge	O
+or	O
+the	O
+percentage	O
+of	O
+GnRH	O
+neurons	O
+activated	O
+during	O
+the	O
+surge	O
+.	O
+
+Estradiol	O
+is	O
+known	O
+to	O
+influence	O
+expression	O
+of	O
+the	O
+long	O
+form	O
+of	O
+prolactin	O
+receptors	O
+(	O
+PRL	O
+-	O
+R	O
+)	O
+and	O
+components	O
+of	O
+prolactin	O
+'	O
+s	O
+signaling	O
+pathway	O
+.	O
+
+To	O
+test	O
+the	O
+hypothesis	O
+that	O
+estrogen	O
+increases	O
+PRL	O
+-	O
+R	O
+expression	O
+and	O
+sensitivity	O
+to	O
+prolactin	O
+,	O
+we	O
+next	O
+demonstrated	O
+that	O
+estradiol	O
+greatly	O
+augments	O
+prolactin	O
+-	O
+induced	O
+STAT5	O
+activation	O
+.	O
+
+Lastly	O
+,	O
+we	O
+measured	O
+PRL	O
+-	O
+R	O
+and	O
+suppressor	O
+of	O
+cytokine	O
+signaling	O
+(	O
+SOCS	O
+-	O
+1	O
+and	O
+-	O
+3	O
+and	O
+CIS	O
+,	O
+which	O
+reflect	O
+the	O
+level	O
+of	O
+prolactin	O
+signaling	O
+)	O
+mRNAs	O
+in	O
+response	O
+to	O
+sulpiride	O
+and	O
+estradiol	O
+.	O
+
+Sulpiride	O
+induced	O
+only	O
+SOCS	O
+-	O
+1	O
+in	O
+the	O
+medial	O
+preoptic	O
+area	O
+,	O
+where	O
+GnRH	O
+neurons	O
+are	O
+regulated	O
+,	O
+but	O
+in	O
+the	O
+arcuate	O
+nucleus	O
+and	O
+choroid	O
+plexus	O
+,	O
+PRL	O
+-	O
+R	O
+,	O
+SOCS	O
+-	O
+3	O
+,	O
+and	O
+CIS	O
+mRNA	O
+levels	O
+were	O
+also	O
+induced	O
+.	O
+
+Estradiol	O
+enhanced	O
+these	O
+effects	O
+on	O
+SOCS	O
+-	O
+3	O
+and	O
+CIS	O
+.	O
+
+Interestingly	O
+,	O
+estradiol	O
+also	O
+induced	O
+PRL	O
+-	O
+R	O
+,	O
+SOCS	O
+-	O
+3	O
+,	O
+and	O
+CIS	O
+mRNA	O
+levels	O
+independently	O
+.	O
+
+These	O
+data	O
+show	O
+that	O
+GnRH	O
+pulse	O
+frequency	O
+is	O
+inhibited	O
+by	O
+chronic	O
+hyperprolactinemia	B
+in	O
+a	O
+steroid	O
+-	O
+dependent	O
+manner	O
+.	O
+
+They	O
+also	O
+provide	O
+evidence	O
+for	O
+estradiol	O
+-	O
+dependent	O
+and	O
+brain	O
+region	O
+-	O
+specific	O
+regulation	O
+of	O
+PRL	O
+-	O
+R	O
+expression	O
+and	O
+signaling	O
+responses	O
+by	O
+prolactin	O
+.	O
+
+Clonidine	O
+for	O
+attention	B
+-	I
+deficit	I
+/	I
+hyperactivity	I
+disorder	I
+:	O
+II	O
+.	O
+
+ECG	O
+changes	O
+and	O
+adverse	O
+events	O
+analysis	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+examine	O
+the	O
+safety	O
+and	O
+tolerability	O
+of	O
+clonidine	O
+used	O
+alone	O
+or	O
+with	O
+methylphenidate	O
+in	O
+children	O
+with	O
+attention	B
+-	I
+deficit	I
+/	I
+hyperactivity	I
+disorder	I
+(	O
+ADHD	B
+)	O
+.	O
+
+METHOD	O
+:	O
+In	O
+a	O
+16	O
+-	O
+week	O
+multicenter	O
+,	O
+double	O
+-	O
+blind	O
+trial	O
+,	O
+122	O
+children	O
+with	O
+ADHD	B
+were	O
+randomly	O
+assigned	O
+to	O
+clonidine	O
+(	O
+n	O
+=	O
+31	O
+)	O
+,	O
+methylphenidate	O
+(	O
+n	O
+=	O
+29	O
+)	O
+,	O
+clonidine	O
+and	O
+methylphenidate	O
+(	O
+n	O
+=	O
+32	O
+)	O
+,	O
+or	O
+placebo	O
+(	O
+n	O
+=	O
+30	O
+)	O
+.	O
+
+Doses	O
+were	O
+flexibly	O
+titrated	O
+up	O
+to	O
+0	O
+.	O
+6	O
+mg	O
+/	O
+day	O
+for	O
+clonidine	O
+and	O
+60	O
+mg	O
+/	O
+day	O
+for	O
+methylphenidate	O
+(	O
+both	O
+with	O
+divided	O
+dosing	O
+)	O
+.	O
+
+Groups	O
+were	O
+compared	O
+regarding	O
+adverse	O
+events	O
+and	O
+changes	O
+from	O
+baseline	O
+to	O
+week	O
+16	O
+in	O
+electrocardiograms	O
+and	O
+vital	O
+signs	O
+.	O
+
+RESULTS	O
+:	O
+There	O
+were	O
+more	O
+incidents	O
+of	O
+bradycardia	B
+in	O
+subjects	O
+treated	O
+with	O
+clonidine	O
+compared	O
+with	O
+those	O
+not	O
+treated	O
+with	O
+clonidine	O
+(	O
+17	O
+.	O
+5	O
+%	O
+versus	O
+3	O
+.	O
+4	O
+%	O
+;	O
+p	O
+=	O
+.	O
+02	O
+)	O
+,	O
+but	O
+no	O
+other	O
+significant	O
+group	O
+differences	O
+regarding	O
+electrocardiogram	O
+and	O
+other	O
+cardiovascular	O
+outcomes	O
+.	O
+
+There	O
+were	O
+no	O
+suggestions	O
+of	O
+interactions	O
+between	O
+clonidine	O
+and	O
+methylphenidate	O
+regarding	O
+cardiovascular	O
+outcomes	O
+.	O
+
+Moderate	O
+or	O
+severe	O
+adverse	O
+events	O
+were	O
+more	O
+common	O
+in	O
+subjects	O
+on	O
+clonidine	O
+(	O
+79	O
+.	O
+4	O
+%	O
+versus	O
+49	O
+.	O
+2	O
+%	O
+;	O
+p	O
+=	O
+.	O
+0006	O
+)	O
+but	O
+not	O
+associated	O
+with	O
+higher	O
+rates	O
+of	O
+early	O
+study	O
+withdrawal	O
+.	O
+
+Drowsiness	B
+was	O
+common	O
+on	O
+clonidine	O
+,	O
+but	O
+generally	O
+resolved	O
+by	O
+6	O
+to	O
+8	O
+weeks	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Clonidine	O
+,	O
+used	O
+alone	O
+or	O
+with	O
+methylphenidate	O
+,	O
+appears	O
+safe	O
+and	O
+well	O
+tolerated	O
+in	O
+childhood	O
+ADHD	B
+.	O
+
+Physicians	O
+prescribing	O
+clonidine	O
+should	O
+monitor	O
+for	O
+bradycardia	B
+and	O
+advise	O
+patients	O
+about	O
+the	O
+high	O
+likelihood	O
+of	O
+initial	O
+drowsiness	B
+.	O
+
+Renal	B
+Fanconi	I
+syndrome	I
+and	O
+myopathy	B
+after	O
+liver	O
+transplantation	O
+:	O
+drug	O
+-	O
+related	O
+mitochondrial	B
+cytopathy	I
+?	O
+
+Advances	O
+in	O
+the	O
+field	O
+of	O
+transplantation	O
+provide	O
+a	O
+better	O
+quality	O
+of	O
+life	O
+and	O
+allow	O
+more	O
+favorable	O
+conditions	O
+for	O
+growth	O
+and	O
+development	O
+in	O
+children	O
+.	O
+
+However	O
+,	O
+combinations	O
+of	O
+different	O
+therapeutic	O
+regimens	O
+require	O
+consideration	O
+of	O
+potential	O
+adverse	O
+reactions	O
+.	O
+
+We	O
+describe	O
+a	O
+15	O
+-	O
+yr	O
+-	O
+old	O
+girl	O
+who	O
+had	O
+orthotopic	O
+liver	O
+transplantation	O
+because	O
+of	O
+Wilson	B
+'	I
+s	I
+disease	I
+.	O
+
+Tacrolimus	O
+,	O
+MMF	O
+,	O
+and	O
+steroids	O
+were	O
+given	O
+as	O
+immunosuppressant	O
+.	O
+
+Lamivudine	O
+was	O
+added	O
+because	O
+of	O
+de	O
+nova	O
+hepatitis	B
+B	I
+infection	I
+during	O
+her	O
+follow	O
+-	O
+up	O
+.	O
+
+Three	O
+yr	O
+after	O
+transplantation	O
+she	O
+developed	O
+renal	B
+Fanconi	I
+syndrome	I
+with	O
+severe	O
+metabolic	B
+acidosis	I
+,	O
+hypophosphatemia	B
+,	O
+glycosuria	B
+,	O
+and	O
+aminoaciduria	B
+.	O
+
+Although	O
+tacrolimus	O
+was	O
+suspected	O
+to	O
+be	O
+the	O
+cause	O
+of	O
+late	O
+post	O
+-	O
+transplant	O
+renal	O
+acidosis	B
+and	O
+was	O
+replaced	O
+by	O
+sirolimus	O
+,	O
+acidosis	B
+,	O
+and	O
+electrolyte	O
+imbalance	O
+got	O
+worse	O
+.	O
+
+Proximal	O
+muscle	B
+weakness	I
+has	O
+developed	O
+during	O
+her	O
+follow	O
+-	O
+up	O
+.	O
+
+Fanconi	B
+syndrome	I
+,	O
+as	O
+well	O
+as	O
+myopathy	B
+,	O
+is	O
+well	O
+recognized	O
+in	O
+patients	O
+with	O
+mitochondrial	B
+disorders	I
+and	O
+caused	O
+by	O
+depletion	O
+of	O
+mtDNA	O
+.	O
+
+We	O
+suggest	O
+that	O
+our	O
+patient	O
+'	O
+s	O
+tubular	B
+dysfunction	I
+and	O
+myopathy	B
+may	O
+have	O
+resulted	O
+from	O
+mitochondrial	B
+dysfunction	I
+which	O
+is	O
+triggered	O
+by	O
+tacrolimus	O
+and	O
+augmented	O
+by	O
+lamivudine	O
+.	O
+
+Higher	O
+optical	O
+density	O
+of	O
+an	O
+antigen	O
+assay	O
+predicts	O
+thrombosis	B
+in	O
+patients	O
+with	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+correlate	O
+optical	O
+density	O
+and	O
+percent	O
+inhibition	O
+of	O
+a	O
+two	O
+-	O
+step	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+(	O
+HIT	B
+)	O
+antigen	O
+assay	O
+with	O
+thrombosis	B
+;	O
+the	O
+assay	O
+utilizes	O
+reaction	O
+inhibition	O
+characteristics	O
+of	O
+a	O
+high	O
+heparin	O
+concentration	O
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+Patients	O
+with	O
+more	O
+than	O
+50	O
+%	O
+decrease	O
+in	O
+platelet	O
+count	O
+or	O
+thrombocytopenia	B
+(	O
+<	O
+150	O
+x	O
+10	O
+(	O
+9	O
+)	O
+/	O
+L	O
+)	O
+after	O
+exposure	O
+to	O
+heparin	O
+,	O
+who	O
+had	O
+a	O
+positive	O
+two	O
+-	O
+step	O
+antigen	O
+assay	O
+[	O
+optical	O
+density	O
+(	O
+OD	O
+)	O
+>	O
+0	O
+.	O
+4	O
+and	O
+>	O
+50	O
+inhibition	O
+with	O
+high	O
+concentration	O
+of	O
+heparin	O
+]	O
+were	O
+included	O
+in	O
+the	O
+study	O
+.	O
+
+RESULTS	O
+:	O
+Forty	O
+of	O
+94	O
+HIT	B
+patients	O
+had	O
+thrombosis	B
+at	O
+diagnosis	O
+;	O
+54	O
+/	O
+94	O
+had	O
+isolated	O
+-	O
+HIT	B
+without	O
+thrombosis	B
+.	O
+
+Eight	O
+of	O
+the	O
+isolated	O
+-	O
+HIT	B
+patients	O
+developed	O
+thrombosis	B
+within	O
+the	O
+next	O
+30	O
+d	O
+;	O
+thus	O
+,	O
+a	O
+total	O
+of	O
+48	O
+patients	O
+had	O
+thrombosis	B
+at	O
+day	O
+30	O
+.	O
+
+At	O
+diagnosis	O
+there	O
+was	O
+no	O
+significant	O
+difference	O
+in	O
+OD	O
+between	O
+HIT	B
+patients	O
+with	O
+thrombosis	B
+and	O
+those	O
+with	O
+isolated	O
+-	O
+HIT	B
+.	O
+
+However	O
+,	O
+OD	O
+was	O
+significantly	O
+higher	O
+in	O
+all	O
+patients	O
+with	O
+thrombosis	B
+(	O
+n	O
+=	O
+48	O
+,	O
+1	O
+.	O
+34	O
++	O
+/	O
+-	O
+0	O
+.	O
+89	O
+)	O
+,	O
+including	O
+isolated	O
+-	O
+HIT	B
+patients	O
+who	O
+later	O
+developed	O
+thrombosis	B
+within	O
+30	O
+d	O
+(	O
+n	O
+=	O
+8	O
+,	O
+1	O
+.	O
+84	O
++	O
+/	O
+-	O
+0	O
+.	O
+64	O
+)	O
+as	O
+compared	O
+to	O
+isolated	O
+-	O
+HIT	B
+patients	O
+who	O
+did	O
+not	O
+develop	O
+thrombosis	B
+(	O
+0	O
+.	O
+96	O
++	O
+/	O
+-	O
+0	O
+.	O
+75	O
+;	O
+P	O
+=	O
+0	O
+.	O
+011	O
+and	O
+P	O
+=	O
+0	O
+.	O
+008	O
+)	O
+.	O
+
+The	O
+Receiver	O
+Operative	O
+Characteristic	O
+Curve	O
+showed	O
+that	O
+OD	O
+>	O
+1	O
+.	O
+27	O
+in	O
+the	O
+isolated	O
+-	O
+HIT	B
+group	O
+had	O
+a	O
+significantly	O
+higher	O
+chance	O
+of	O
+developing	O
+thrombosis	B
+by	O
+day	O
+30	O
+.	O
+
+None	O
+of	O
+these	O
+groups	O
+showed	O
+significant	O
+difference	O
+in	O
+percent	O
+inhibition	O
+.	O
+
+Multivariate	O
+analysis	O
+showed	O
+a	O
+2	O
+.	O
+8	O
+-	O
+fold	O
+increased	O
+risk	O
+of	O
+thrombosis	B
+in	O
+females	O
+.	O
+
+Similarly	O
+,	O
+thrombotic	B
+risk	O
+increased	O
+with	O
+age	O
+and	O
+OD	O
+values	O
+.	O
+
+CONCLUSION	O
+:	O
+Higher	O
+OD	O
+is	O
+associated	O
+with	O
+significant	O
+risk	O
+of	O
+subsequent	O
+thrombosis	B
+in	O
+patients	O
+with	O
+isolated	O
+-	O
+HIT	B
+;	O
+percent	O
+inhibition	O
+,	O
+however	O
+,	O
+was	O
+not	O
+predictive	O
+.	O
+
+Thalidomide	O
+has	O
+limited	O
+single	O
+-	O
+agent	O
+activity	O
+in	O
+relapsed	O
+or	O
+refractory	O
+indolent	O
+non	B
+-	I
+Hodgkin	I
+lymphomas	I
+:	O
+a	O
+phase	O
+II	O
+trial	O
+of	O
+the	O
+Cancer	B
+and	O
+Leukemia	B
+Group	O
+B	O
+.	O
+
+Thalidomide	O
+is	O
+an	O
+immunomodulatory	O
+agent	O
+with	O
+demonstrated	O
+activity	O
+in	O
+multiple	B
+myeloma	I
+,	O
+mantle	B
+cell	I
+lymphoma	I
+and	O
+lymphoplasmacytic	B
+lymphoma	I
+.	O
+
+Its	O
+activity	O
+is	O
+believed	O
+to	O
+be	O
+due	O
+modulation	O
+of	O
+the	O
+tumour	B
+milieu	O
+,	O
+including	O
+downregulation	O
+of	O
+angiogenesis	O
+and	O
+inflammatory	O
+cytokines	O
+.	O
+
+Between	O
+July	O
+2001	O
+and	O
+April	O
+2004	O
+,	O
+24	O
+patients	O
+with	O
+relapsed	O
+/	O
+refractory	O
+indolent	O
+lymphomas	B
+received	O
+thalidomide	O
+200	O
+mg	O
+daily	O
+with	O
+escalation	O
+by	O
+100	O
+mg	O
+daily	O
+every	O
+1	O
+-	O
+2	O
+weeks	O
+as	O
+tolerated	O
+,	O
+up	O
+to	O
+a	O
+maximum	O
+of	O
+800	O
+mg	O
+daily	O
+.	O
+
+Patients	O
+had	O
+received	O
+a	O
+median	O
+of	O
+2	O
+(	O
+range	O
+,	O
+1	O
+-	O
+4	O
+)	O
+prior	O
+regimens	O
+.	O
+
+Of	O
+24	O
+evaluable	O
+patients	O
+,	O
+two	O
+achieved	O
+a	O
+complete	O
+remission	O
+and	O
+one	O
+achieved	O
+a	O
+partial	O
+remission	O
+for	O
+an	O
+overall	O
+response	O
+rate	O
+of	O
+12	O
+.	O
+5	O
+%	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+:	O
+2	O
+.	O
+6	O
+-	O
+32	O
+.	O
+4	O
+%	O
+)	O
+.	O
+
+Eleven	O
+patients	O
+progressed	O
+during	O
+therapy	O
+.	O
+
+Grade	O
+3	O
+-	O
+4	O
+adverse	O
+effects	O
+included	O
+myelosuppression	B
+,	O
+fatigue	B
+,	O
+somnolence	B
+/	O
+depressed	B
+mood	I
+,	O
+neuropathy	B
+and	O
+dyspnea	B
+.	O
+
+Of	O
+concern	O
+was	O
+the	O
+occurrence	O
+of	O
+four	O
+thromboembolic	B
+events	O
+.	O
+
+Our	O
+results	O
+failed	O
+to	O
+demonstrate	O
+an	O
+important	O
+response	O
+rate	O
+to	O
+single	O
+agent	O
+thalidomide	O
+in	O
+indolent	O
+lymphomas	B
+and	O
+contrast	O
+with	O
+the	O
+higher	O
+activity	O
+level	O
+reported	O
+with	O
+the	O
+second	O
+generation	O
+immunomodulatory	O
+agent	O
+,	O
+lenalidomide	O
+.	O
+
+Sex	O
+differences	O
+in	O
+NMDA	O
+antagonist	O
+enhancement	O
+of	O
+morphine	O
+antihyperalgesia	O
+in	O
+a	O
+capsaicin	O
+model	O
+of	O
+persistent	O
+pain	B
+:	O
+comparisons	O
+to	O
+two	O
+models	O
+of	O
+acute	B
+pain	I
+.	O
+
+In	O
+acute	B
+pain	I
+models	O
+,	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+antagonists	O
+enhance	O
+the	O
+antinociceptive	O
+effects	O
+of	O
+morphine	O
+to	O
+a	O
+greater	O
+extent	O
+in	O
+males	O
+than	O
+females	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+investigation	O
+was	O
+to	O
+extend	O
+these	O
+findings	O
+to	O
+a	O
+persistent	O
+pain	B
+model	O
+which	O
+could	O
+be	O
+distinguished	O
+from	O
+acute	B
+pain	I
+models	O
+on	O
+the	O
+basis	O
+of	O
+the	O
+nociceptive	O
+fibers	O
+activated	O
+,	O
+neurochemical	O
+substrates	O
+,	O
+and	O
+duration	O
+of	O
+the	O
+nociceptive	O
+stimulus	O
+.	O
+
+To	O
+this	O
+end	O
+,	O
+persistent	O
+hyperalgesia	B
+was	O
+induced	O
+by	O
+administration	O
+of	O
+capsaicin	O
+in	O
+the	O
+tail	O
+of	O
+gonadally	O
+intact	O
+F344	O
+rats	O
+,	O
+following	O
+which	O
+the	O
+tail	O
+was	O
+immersed	O
+in	O
+a	O
+mildly	O
+noxious	O
+thermal	O
+stimulus	O
+,	O
+and	O
+tail	O
+-	O
+withdrawal	O
+latencies	O
+measured	O
+.	O
+
+For	O
+comparison	O
+,	O
+tests	O
+were	O
+conducted	O
+in	O
+two	O
+acute	B
+pain	I
+models	O
+,	O
+the	O
+hotplate	O
+and	O
+warm	O
+water	O
+tail	O
+-	O
+withdrawal	O
+procedures	O
+.	O
+
+In	O
+males	O
+,	O
+the	O
+non	O
+-	O
+competitive	O
+NMDA	O
+antagonist	O
+dextromethorphan	O
+enhanced	O
+the	O
+antihyperalgesic	O
+effect	O
+of	O
+low	O
+to	O
+moderate	O
+doses	O
+of	O
+morphine	O
+in	O
+a	O
+dose	O
+-	O
+and	O
+time	O
+-	O
+dependent	O
+manner	O
+.	O
+
+Across	O
+the	O
+doses	O
+and	O
+pretreatment	O
+times	O
+examined	O
+,	O
+enhancement	O
+was	O
+not	O
+observed	O
+in	O
+females	O
+.	O
+
+Enhancement	O
+of	O
+morphine	O
+antinociception	O
+by	O
+dextromethorphan	O
+was	O
+seen	O
+in	O
+both	O
+males	O
+and	O
+females	O
+in	O
+the	O
+acute	B
+pain	I
+models	O
+,	O
+with	O
+the	O
+magnitude	O
+of	O
+this	O
+effect	O
+being	O
+greater	O
+in	O
+males	O
+.	O
+
+These	O
+findings	O
+demonstrate	O
+a	O
+sexually	O
+-	O
+dimorphic	O
+interaction	O
+between	O
+NMDA	O
+antagonists	O
+and	O
+morphine	O
+in	O
+a	O
+persistent	O
+pain	B
+model	O
+that	O
+can	O
+be	O
+distinguished	O
+from	O
+those	O
+observed	O
+in	O
+acute	B
+pain	I
+models	O
+.	O
+
+Development	O
+of	O
+proteinuria	B
+after	O
+switch	O
+to	O
+sirolimus	O
+-	O
+based	O
+immunosuppression	O
+in	O
+long	O
+-	O
+term	O
+cardiac	O
+transplant	O
+patients	O
+.	O
+
+Calcineurin	O
+-	O
+inhibitor	O
+therapy	O
+can	O
+lead	O
+to	O
+renal	B
+dysfunction	I
+in	O
+heart	O
+transplantation	O
+patients	O
+.	O
+
+The	O
+novel	O
+immunosuppressive	O
+(	O
+IS	O
+)	O
+drug	O
+sirolmus	O
+(	O
+Srl	O
+)	O
+lacks	O
+nephrotoxic	B
+effects	O
+;	O
+however	O
+,	O
+proteinuria	B
+associated	O
+with	O
+Srl	O
+has	O
+been	O
+reported	O
+following	O
+renal	O
+transplantation	O
+.	O
+
+In	O
+cardiac	O
+transplantation	O
+,	O
+the	O
+incidence	O
+of	O
+proteinuria	B
+associated	O
+with	O
+Srl	O
+is	O
+unknown	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+long	O
+-	O
+term	O
+cardiac	O
+transplant	O
+patients	O
+were	O
+switched	O
+from	O
+cyclosporine	O
+to	O
+Srl	O
+-	O
+based	O
+IS	O
+.	O
+
+Concomitant	O
+IS	O
+consisted	O
+of	O
+mycophenolate	O
+mofetil	O
++	O
+/	O
+-	O
+steroids	O
+.	O
+
+Proteinuria	O
+increased	O
+significantly	O
+from	O
+a	O
+median	O
+of	O
+0	O
+.	O
+13	O
+g	O
+/	O
+day	O
+(	O
+range	O
+0	O
+-	O
+5	O
+.	O
+7	O
+)	O
+preswitch	O
+to	O
+0	O
+.	O
+23	O
+g	O
+/	O
+day	O
+(	O
+0	O
+-	O
+9	O
+.	O
+88	O
+)	O
+at	O
+24	O
+months	O
+postswitch	O
+(	O
+p	O
+=	O
+0	O
+.	O
+0024	O
+)	O
+.	O
+
+Before	O
+the	O
+switch	O
+,	O
+11	O
+.	O
+5	O
+%	O
+of	O
+patients	O
+had	O
+high	O
+-	O
+grade	O
+proteinuria	B
+(	O
+>	O
+1	O
+.	O
+0	O
+g	O
+/	O
+day	O
+)	O
+;	O
+this	O
+increased	O
+to	O
+22	O
+.	O
+9	O
+%	O
+postswitch	O
+(	O
+p	O
+=	O
+0	O
+.	O
+006	O
+)	O
+.	O
+
+ACE	O
+inhibitor	O
+and	O
+angiotensin	O
+-	O
+releasing	O
+blocker	O
+(	O
+ARB	O
+)	O
+therapy	O
+reduced	O
+proteinuria	B
+development	O
+.	O
+
+Patients	O
+without	O
+proteinuria	B
+had	O
+increased	O
+renal	O
+function	O
+(	O
+median	O
+42	O
+.	O
+5	O
+vs	O
+.	O
+64	O
+.	O
+1	O
+,	O
+p	O
+=	O
+0	O
+.	O
+25	O
+)	O
+,	O
+whereas	O
+patients	O
+who	O
+developed	O
+high	O
+-	O
+grade	O
+proteinuria	B
+showed	O
+decreased	O
+renal	O
+function	O
+at	O
+the	O
+end	O
+of	O
+follow	O
+-	O
+up	O
+(	O
+median	O
+39	O
+.	O
+6	O
+vs	O
+.	O
+29	O
+.	O
+2	O
+,	O
+p	O
+=	O
+0	O
+.	O
+125	O
+)	O
+.	O
+
+Thus	O
+,	O
+proteinuria	B
+may	O
+develop	O
+in	O
+cardiac	O
+transplant	O
+patients	O
+after	O
+switch	O
+to	O
+Srl	O
+,	O
+which	O
+may	O
+have	O
+an	O
+adverse	O
+effect	O
+on	O
+renal	O
+function	O
+in	O
+these	O
+patients	O
+.	O
+
+Srl	O
+should	O
+be	O
+used	O
+with	O
+ACEi	O
+/	O
+ARB	O
+therapy	O
+and	O
+patients	O
+monitored	O
+for	O
+proteinuria	B
+and	O
+increased	O
+renal	B
+dysfunction	I
+.	O
+
+Ginsenoside	O
+Rg1	O
+restores	O
+the	O
+impairment	B
+of	I
+learning	I
+induced	O
+by	O
+chronic	O
+morphine	O
+administration	O
+in	O
+rats	O
+.	O
+
+Rg1	O
+,	O
+as	O
+a	O
+ginsenoside	O
+extracted	O
+from	O
+Panax	O
+ginseng	O
+,	O
+could	O
+ameliorate	O
+spatial	O
+learning	B
+impairment	I
+.	O
+
+Previous	O
+studies	O
+have	O
+demonstrated	O
+that	O
+Rg1	O
+might	O
+be	O
+a	O
+useful	O
+agent	O
+for	O
+the	O
+prevention	O
+and	O
+treatment	O
+of	O
+the	O
+adverse	O
+effects	O
+of	O
+morphine	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+effect	O
+of	O
+Rg1	O
+on	O
+learning	B
+impairment	I
+by	O
+chronic	O
+morphine	O
+administration	O
+and	O
+the	O
+mechanism	O
+responsible	O
+for	O
+this	O
+effect	O
+.	O
+
+Male	O
+rats	O
+were	O
+subcutaneously	O
+injected	O
+with	O
+morphine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+twice	O
+a	O
+day	O
+at	O
+12	O
+hour	O
+intervals	O
+for	O
+10	O
+days	O
+,	O
+and	O
+Rg1	O
+(	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+intraperitoneally	O
+injected	O
+2	O
+hours	O
+after	O
+the	O
+second	O
+injection	O
+of	O
+morphine	O
+once	O
+a	O
+day	O
+for	O
+10	O
+days	O
+.	O
+
+Spatial	O
+learning	O
+capacity	O
+was	O
+assessed	O
+in	O
+the	O
+Morris	O
+water	O
+maze	O
+.	O
+
+The	O
+results	O
+showed	O
+that	O
+rats	O
+treated	O
+with	O
+Morphine	O
+/	O
+Rg1	O
+decreased	O
+escape	O
+latency	O
+and	O
+increased	O
+the	O
+time	O
+spent	O
+in	O
+platform	O
+quadrant	O
+and	O
+entering	O
+frequency	O
+.	O
+
+By	O
+implantation	O
+of	O
+electrodes	O
+and	O
+electrophysiological	O
+recording	O
+in	O
+vivo	O
+,	O
+the	O
+results	O
+showed	O
+that	O
+Rg1	O
+restored	O
+the	O
+long	O
+-	O
+term	O
+potentiation	O
+(	O
+LTP	O
+)	O
+impaired	O
+by	O
+morphine	O
+in	O
+both	O
+freely	O
+moving	O
+and	O
+anaesthetised	O
+rats	O
+.	O
+
+The	O
+electrophysiological	O
+recording	O
+in	O
+vitro	O
+showed	O
+that	O
+Rg1	O
+restored	O
+the	O
+LTP	O
+in	O
+slices	O
+from	O
+the	O
+rats	O
+treated	O
+with	O
+morphine	O
+,	O
+but	O
+not	O
+changed	O
+LTP	O
+in	O
+the	O
+slices	O
+from	O
+normal	O
+saline	O
+-	O
+or	O
+morphine	O
+/	O
+Rg1	O
+-	O
+treated	O
+rats	O
+;	O
+this	O
+restoration	O
+could	O
+be	O
+inhibited	O
+by	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+receptor	O
+antagonist	O
+MK801	O
+.	O
+
+We	O
+conclude	O
+that	O
+Rg1	O
+may	O
+significantly	O
+improve	O
+the	O
+spatial	O
+learning	O
+capacity	O
+impaired	O
+by	O
+chonic	O
+morphine	O
+administration	O
+and	O
+restore	O
+the	O
+morphine	O
+-	O
+inhibited	O
+LTP	O
+.	O
+
+This	O
+effect	O
+is	O
+NMDA	O
+receptor	O
+dependent	O
+.	O
+
+Synthesis	O
+of	O
+N	O
+-	O
+pyrimidinyl	O
+-	O
+2	O
+-	O
+phenoxyacetamides	O
+as	O
+adenosine	O
+A2A	O
+receptor	O
+antagonists	O
+.	O
+
+A	O
+series	O
+of	O
+N	O
+-	O
+pyrimidinyl	O
+-	O
+2	O
+-	O
+phenoxyacetamide	O
+adenosine	O
+A	O
+(	O
+2A	O
+)	O
+antagonists	O
+is	O
+described	O
+.	O
+
+SAR	O
+studies	O
+led	O
+to	O
+compound	O
+14	O
+with	O
+excellent	O
+potency	O
+(	O
+K	O
+(	O
+i	O
+)	O
+=	O
+0	O
+.	O
+4	O
+nM	O
+)	O
+,	O
+selectivity	O
+(	O
+A	O
+(	O
+1	O
+)	O
+/	O
+A	O
+(	O
+2A	O
+)	O
+>	O
+100	O
+)	O
+,	O
+and	O
+efficacy	O
+(	O
+MED	O
+10	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+)	O
+in	O
+the	O
+rat	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+model	O
+for	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+Evidence	O
+for	O
+an	O
+involvement	O
+of	O
+D1	O
+and	O
+D2	O
+dopamine	O
+receptors	O
+in	O
+mediating	O
+nicotine	O
+-	O
+induced	O
+hyperactivity	B
+in	O
+rats	O
+.	O
+
+Previous	O
+studies	O
+have	O
+suggested	O
+that	O
+repeated	O
+exposure	O
+of	O
+rats	O
+to	O
+the	O
+drug	O
+or	O
+to	O
+the	O
+experimental	O
+environment	O
+is	O
+necessary	O
+to	O
+observe	O
+nicotine	O
+-	O
+induced	O
+locomotor	O
+stimulation	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+the	O
+role	O
+of	O
+habituation	O
+to	O
+the	O
+experimental	O
+environment	O
+on	O
+the	O
+stimulant	O
+effect	O
+of	O
+nicotine	O
+in	O
+rats	O
+was	O
+examined	O
+.	O
+
+In	O
+addition	O
+,	O
+the	O
+role	O
+of	O
+dopamine	O
+receptors	O
+in	O
+mediating	O
+nicotine	O
+-	O
+induced	O
+locomotor	O
+stimulation	O
+was	O
+investigated	O
+by	O
+examining	O
+the	O
+effects	O
+of	O
+selective	O
+D1	O
+and	O
+D2	O
+dopamine	O
+receptor	O
+antagonists	O
+on	O
+activity	O
+induced	O
+by	O
+nicotine	O
+.	O
+
+Locomotor	O
+activity	O
+was	O
+assessed	O
+in	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+tested	O
+in	O
+photocell	O
+cages	O
+.	O
+
+Nicotine	O
+(	O
+1	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+)	O
+caused	O
+a	O
+significant	O
+increase	B
+in	I
+locomotor	I
+activity	I
+in	O
+rats	O
+that	O
+were	O
+habituated	O
+to	O
+the	O
+test	O
+environment	O
+,	O
+but	O
+had	O
+only	O
+a	O
+weak	O
+and	O
+delayed	O
+stimulant	O
+action	O
+in	O
+rats	O
+that	O
+were	O
+unfamiliar	O
+with	O
+the	O
+test	O
+environment	O
+.	O
+
+The	O
+stimulant	O
+action	O
+of	O
+nicotine	O
+was	O
+blocked	O
+by	O
+the	O
+central	O
+nicotinic	O
+antagonist	O
+mecamylamine	O
+but	O
+not	O
+by	O
+the	O
+peripheral	O
+nicotinic	O
+blocker	O
+hexamethonium	O
+,	O
+indicating	O
+that	O
+the	O
+response	O
+is	O
+probably	O
+mediated	O
+by	O
+central	O
+nicotinic	O
+receptors	O
+.	O
+
+Nicotine	O
+-	O
+induced	O
+hyperactivity	B
+was	O
+blocked	O
+by	O
+the	O
+selective	O
+D1	O
+antagonist	O
+SCH	O
+23390	O
+,	O
+the	O
+selective	O
+D2	O
+antagonist	O
+raclopride	O
+and	O
+the	O
+D1	O
+/	O
+D2	O
+antagonist	O
+fluphenazine	O
+.	O
+
+Pretreatment	O
+with	O
+the	O
+D2	O
+agonist	O
+PHNO	O
+enhanced	O
+nicotine	O
+-	O
+induced	O
+hyperactivity	B
+,	O
+whereas	O
+the	O
+D1	O
+agonist	O
+SKF	O
+38393	O
+had	O
+no	O
+effect	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+acute	O
+nicotine	O
+injection	O
+induces	O
+a	O
+pronounced	O
+hyperactivity	B
+in	O
+rats	O
+habituated	O
+to	O
+the	O
+test	O
+environment	O
+.	O
+
+The	O
+effect	O
+appears	O
+to	O
+be	O
+mediated	O
+by	O
+central	O
+nicotine	O
+receptors	O
+,	O
+possibly	O
+located	O
+on	O
+dopaminergic	O
+neurons	O
+,	O
+and	O
+also	O
+requires	O
+the	O
+activation	O
+of	O
+both	O
+D1	O
+and	O
+D2	O
+dopamine	O
+receptors	O
+.	O
+
+Central	O
+retinal	B
+vein	I
+occlusion	I
+associated	O
+with	O
+clomiphene	O
+-	O
+induced	O
+ovulation	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+central	O
+retinal	B
+vein	I
+occlusion	I
+associated	O
+with	O
+clomiphene	O
+citrate	O
+(	O
+CC	O
+)	O
+.	O
+
+DESIGN	O
+:	O
+Case	O
+study	O
+.	O
+
+SETTING	O
+:	O
+Ophthalmology	O
+clinic	O
+of	O
+an	O
+academic	O
+hospital	O
+.	O
+
+PATIENT	O
+(	O
+S	O
+)	O
+:	O
+A	O
+36	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+referred	O
+from	O
+the	O
+infertility	B
+clinic	O
+for	O
+blurred	B
+vision	I
+.	O
+
+INTERVENTION	O
+(	O
+S	O
+)	O
+:	O
+Ophthalmic	O
+examination	O
+after	O
+CC	O
+therapy	O
+.	O
+
+MAIN	O
+OUTCOME	O
+MEASURE	O
+(	O
+S	O
+)	O
+:	O
+Central	O
+retinal	B
+vein	I
+occlusion	I
+after	O
+ovulation	O
+induction	O
+with	O
+CC	O
+.	O
+
+RESULT	O
+(	O
+S	O
+)	O
+:	O
+A	O
+36	O
+-	O
+year	O
+-	O
+old	O
+Chinese	O
+woman	O
+developed	O
+central	O
+retinal	B
+vein	I
+occlusion	I
+after	O
+eight	O
+courses	O
+of	O
+CC	O
+.	O
+
+A	O
+search	O
+of	O
+the	O
+literature	O
+on	O
+the	O
+thromboembolic	B
+complications	O
+of	O
+CC	O
+does	O
+not	O
+include	O
+this	O
+severe	O
+ophthalmic	O
+complication	O
+,	O
+although	O
+mild	O
+visual	B
+disturbance	I
+after	O
+CC	O
+intake	O
+is	O
+not	O
+uncommon	O
+.	O
+
+CONCLUSION	O
+(	O
+S	O
+)	O
+:	O
+This	O
+is	O
+the	O
+first	O
+reported	O
+case	O
+of	O
+central	O
+retinal	B
+vein	I
+occlusion	I
+after	O
+treatment	O
+with	O
+CC	O
+.	O
+
+Extra	O
+caution	O
+is	O
+warranted	O
+in	O
+treating	O
+infertility	B
+patients	O
+with	O
+CC	O
+,	O
+and	O
+patients	O
+should	O
+be	O
+well	O
+informed	O
+of	O
+this	O
+side	O
+effect	O
+before	O
+commencement	O
+of	O
+therapy	O
+.	O
+
+Acute	O
+bronchodilating	O
+effects	O
+of	O
+ipratropium	O
+bromide	O
+and	O
+theophylline	O
+in	O
+chronic	B
+obstructive	I
+pulmonary	I
+disease	I
+.	O
+
+The	O
+bronchodilator	O
+effects	O
+of	O
+a	O
+single	O
+dose	O
+of	O
+ipratropium	O
+bromide	O
+aerosol	O
+(	O
+36	O
+micrograms	O
+)	O
+and	O
+short	O
+-	O
+acting	O
+theophylline	O
+tablets	O
+(	O
+dose	O
+titrated	O
+to	O
+produce	O
+serum	O
+levels	O
+of	O
+10	O
+-	O
+20	O
+micrograms	O
+/	O
+mL	O
+)	O
+were	O
+compared	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+crossover	O
+study	O
+in	O
+21	O
+patients	O
+with	O
+stable	O
+,	O
+chronic	B
+obstructive	I
+pulmonary	I
+disease	I
+.	O
+
+Mean	O
+peak	O
+forced	O
+expiratory	O
+volume	O
+in	O
+1	O
+second	O
+(	O
+FEV1	O
+)	O
+increases	O
+over	O
+baseline	O
+and	O
+the	O
+proportion	O
+of	O
+patients	O
+attaining	O
+at	O
+least	O
+a	O
+15	O
+%	O
+increase	O
+in	O
+the	O
+FEV1	O
+(	O
+responders	O
+)	O
+were	O
+31	O
+%	O
+and	O
+90	O
+%	O
+,	O
+respectively	O
+,	O
+for	O
+ipratropium	O
+and	O
+17	O
+%	O
+and	O
+50	O
+%	O
+,	O
+respectively	O
+,	O
+for	O
+theophylline	O
+.	O
+
+The	O
+average	O
+FEV1	O
+increases	O
+during	O
+the	O
+6	O
+-	O
+hour	O
+observation	O
+period	O
+were	O
+18	O
+%	O
+for	O
+ipratropium	O
+and	O
+8	O
+%	O
+for	O
+theophylline	O
+.	O
+
+The	O
+mean	O
+duration	O
+of	O
+action	O
+was	O
+3	O
+.	O
+8	O
+hours	O
+with	O
+ipratropium	O
+and	O
+2	O
+.	O
+4	O
+hours	O
+with	O
+theophylline	O
+.	O
+
+While	O
+side	O
+effects	O
+were	O
+rare	O
+,	O
+those	O
+experienced	O
+after	O
+theophylline	O
+use	O
+did	O
+involve	O
+the	O
+cardiovascular	B
+and	I
+gastrointestinal	I
+systems	I
+.	O
+
+These	O
+results	O
+show	O
+that	O
+ipratropium	O
+is	O
+a	O
+more	O
+potent	O
+bronchodilator	O
+than	O
+oral	O
+theophylline	O
+in	O
+patients	O
+with	O
+chronic	B
+airflow	I
+obstruction	I
+.	O
+
+Methamphetamine	O
+-	O
+induced	O
+neurotoxicity	B
+and	O
+microglial	O
+activation	O
+are	O
+not	O
+mediated	O
+by	O
+fractalkine	O
+receptor	O
+signaling	O
+.	O
+
+Methamphetamine	O
+(	O
+METH	O
+)	O
+damages	O
+dopamine	O
+(	O
+DA	O
+)	O
+nerve	O
+endings	O
+by	O
+a	O
+process	O
+that	O
+has	O
+been	O
+linked	O
+to	O
+microglial	O
+activation	O
+but	O
+the	O
+signaling	O
+pathways	O
+that	O
+mediate	O
+this	O
+response	O
+have	O
+not	O
+yet	O
+been	O
+delineated	O
+.	O
+
+Cardona	O
+et	O
+al	O
+.	O
+
+[	O
+Nat	O
+.	O
+Neurosci	O
+.	O
+9	O
+(	O
+2006	O
+)	O
+,	O
+917	O
+]	O
+recently	O
+identified	O
+the	O
+microglial	O
+-	O
+specific	O
+fractalkine	O
+receptor	O
+(	O
+CX3CR1	O
+)	O
+as	O
+an	O
+important	O
+mediator	O
+of	O
+MPTP	O
+-	O
+induced	O
+neurodegeneration	B
+of	O
+DA	O
+neurons	O
+.	O
+
+Because	O
+the	O
+CNS	B
+damage	I
+caused	O
+by	O
+METH	O
+and	O
+MPTP	O
+is	O
+highly	O
+selective	O
+for	O
+the	O
+DA	O
+neuronal	O
+system	O
+in	O
+mouse	O
+models	O
+of	O
+neurotoxicity	B
+,	O
+we	O
+hypothesized	O
+that	O
+the	O
+CX3CR1	O
+plays	O
+a	O
+role	O
+in	O
+METH	O
+-	O
+induced	O
+neurotoxicity	B
+and	O
+microglial	O
+activation	O
+.	O
+
+Mice	O
+in	O
+which	O
+the	O
+CX3CR1	O
+gene	O
+has	O
+been	O
+deleted	O
+and	O
+replaced	O
+with	O
+a	O
+cDNA	O
+encoding	O
+enhanced	O
+green	O
+fluorescent	O
+protein	O
+(	O
+eGFP	O
+)	O
+were	O
+treated	O
+with	O
+METH	O
+and	O
+examined	O
+for	O
+striatal	O
+neurotoxicity	B
+.	O
+
+METH	O
+depleted	O
+DA	O
+,	O
+caused	O
+microglial	O
+activation	O
+,	O
+and	O
+increased	O
+body	O
+temperature	O
+in	O
+CX3CR1	O
+knockout	O
+mice	O
+to	O
+the	O
+same	O
+extent	O
+and	O
+over	O
+the	O
+same	O
+time	O
+course	O
+seen	O
+in	O
+wild	O
+-	O
+type	O
+controls	O
+.	O
+
+The	O
+effects	O
+of	O
+METH	O
+in	O
+CX3CR1	O
+knockout	O
+mice	O
+were	O
+not	O
+gender	O
+-	O
+dependent	O
+and	O
+did	O
+not	O
+extend	O
+beyond	O
+the	O
+striatum	O
+.	O
+
+Striatal	O
+microglia	O
+expressing	O
+eGFP	O
+constitutively	O
+show	O
+morphological	O
+changes	O
+after	O
+METH	O
+that	O
+are	O
+characteristic	O
+of	O
+activation	O
+.	O
+
+This	O
+response	O
+was	O
+restricted	O
+to	O
+the	O
+striatum	O
+and	O
+contrasted	O
+sharply	O
+with	O
+unresponsive	O
+eGFP	O
+-	O
+microglia	O
+in	O
+surrounding	O
+brain	O
+areas	O
+that	O
+are	O
+not	O
+damaged	O
+by	O
+METH	O
+.	O
+
+We	O
+conclude	O
+from	O
+these	O
+studies	O
+that	O
+CX3CR1	O
+signaling	O
+does	O
+not	O
+modulate	O
+METH	O
+neurotoxicity	B
+or	O
+microglial	O
+activation	O
+.	O
+
+Furthermore	O
+,	O
+it	O
+appears	O
+that	O
+striatal	O
+-	O
+resident	O
+microglia	O
+respond	O
+to	O
+METH	O
+with	O
+an	O
+activation	O
+cascade	O
+and	O
+then	O
+return	O
+to	O
+a	O
+surveying	O
+state	O
+without	O
+undergoing	O
+apoptosis	O
+or	O
+migration	O
+.	O
+
+Nicotine	O
+-	O
+induced	O
+nystagmus	B
+correlates	O
+with	O
+midpontine	O
+activation	O
+.	O
+
+The	O
+pathomechanism	O
+of	O
+nicotine	O
+-	O
+induced	O
+nystagmus	B
+(	O
+NIN	B
+)	O
+is	O
+unknown	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+delineate	O
+brain	O
+structures	O
+that	O
+are	O
+involved	O
+in	O
+NIN	B
+generation	O
+.	O
+
+Eight	O
+healthy	O
+volunteers	O
+inhaled	O
+nicotine	O
+in	O
+darkness	O
+during	O
+a	O
+functional	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+fMRI	O
+)	O
+experiment	O
+;	O
+eye	O
+movements	O
+were	O
+registered	O
+using	O
+video	O
+-	O
+oculography	O
+.	O
+
+NIN	B
+correlated	O
+with	O
+blood	O
+oxygen	O
+level	O
+-	O
+dependent	O
+(	O
+BOLD	O
+)	O
+activity	O
+levels	O
+in	O
+a	O
+midpontine	O
+site	O
+in	O
+the	O
+posterior	O
+basis	O
+pontis	O
+.	O
+
+NIN	B
+-	O
+induced	O
+midpontine	O
+activation	O
+may	O
+correspond	O
+to	O
+activation	O
+of	O
+the	O
+dorsomedial	O
+pontine	O
+nuclei	O
+and	O
+the	O
+nucleus	O
+reticularis	O
+tegmenti	O
+pontis	O
+,	O
+structures	O
+known	O
+to	O
+participate	O
+in	O
+the	O
+generation	O
+of	O
+multidirectional	O
+saccades	O
+and	O
+smooth	O
+pursuit	O
+eye	O
+movements	O
+.	O
+
+Acute	O
+effects	O
+of	O
+N	O
+-	O
+(	O
+2	O
+-	O
+propylpentanoyl	O
+)	O
+urea	O
+on	O
+hippocampal	O
+amino	O
+acid	O
+neurotransmitters	O
+in	O
+pilocarpine	O
+-	O
+induced	O
+seizure	B
+in	O
+rats	O
+.	O
+
+The	O
+present	O
+study	O
+aimed	O
+to	O
+investigate	O
+the	O
+anticonvulsant	O
+activity	O
+as	O
+well	O
+as	O
+the	O
+effects	O
+on	O
+the	O
+level	O
+of	O
+hippocampal	O
+amino	O
+acid	O
+neurotransmitters	O
+(	O
+glutamate	O
+,	O
+aspartate	O
+,	O
+glycine	O
+and	O
+GABA	O
+)	O
+of	O
+N	O
+-	O
+(	O
+2	O
+-	O
+propylpentanoyl	O
+)	O
+urea	O
+(	O
+VPU	O
+)	O
+in	O
+comparison	O
+to	O
+its	O
+parent	O
+compound	O
+,	O
+valproic	O
+acid	O
+(	O
+VPA	O
+)	O
+.	O
+
+VPU	O
+was	O
+more	O
+potent	O
+than	O
+VPA	O
+,	O
+exhibiting	O
+the	O
+median	O
+effective	O
+dose	O
+(	O
+ED	O
+(	O
+50	O
+)	O
+)	O
+of	O
+49	O
+mg	O
+/	O
+kg	O
+in	O
+protecting	O
+rats	O
+against	O
+pilocarpine	O
+-	O
+induced	O
+seizure	B
+whereas	O
+the	O
+corresponding	O
+value	O
+for	O
+VPA	O
+was	O
+322	O
+mg	O
+/	O
+kg	O
+.	O
+
+In	O
+vivo	O
+microdialysis	O
+demonstrated	O
+that	O
+an	O
+intraperitoneal	O
+administration	O
+of	O
+pilocarpine	O
+induced	O
+a	O
+pronounced	O
+increment	O
+of	O
+hippocampal	O
+glutamate	O
+and	O
+aspartate	O
+whereas	O
+no	O
+significant	O
+change	O
+was	O
+observed	O
+on	O
+the	O
+level	O
+of	O
+glycine	O
+and	O
+GABA	O
+.	O
+
+Pretreatment	O
+with	O
+either	O
+VPU	O
+(	O
+50	O
+and	O
+100	O
+mg	O
+/	O
+kg	O
+)	O
+or	O
+VPA	O
+(	O
+300	O
+and	O
+600	O
+mg	O
+/	O
+kg	O
+)	O
+completely	O
+abolished	O
+pilocarpine	O
+-	O
+evoked	O
+increases	O
+in	O
+extracellular	O
+glutamate	O
+and	O
+aspartate	O
+.	O
+
+In	O
+addition	O
+,	O
+a	O
+statistically	O
+significant	O
+reduction	O
+was	O
+also	O
+observed	O
+on	O
+the	O
+level	O
+of	O
+GABA	O
+and	O
+glycine	O
+but	O
+less	O
+than	O
+a	O
+drastic	O
+reduction	O
+of	O
+glutamate	O
+and	O
+aspartate	O
+level	O
+.	O
+
+Based	O
+on	O
+the	O
+finding	O
+that	O
+VPU	O
+and	O
+VPA	O
+could	O
+protect	O
+the	O
+animals	O
+against	O
+pilocarpine	O
+-	O
+induced	O
+seizure	B
+it	O
+is	O
+suggested	O
+that	O
+the	O
+reduction	O
+of	O
+inhibitory	O
+amino	O
+acid	O
+neurotransmitters	O
+was	O
+comparatively	O
+minor	O
+and	O
+offset	O
+by	O
+a	O
+pronounced	O
+reduction	O
+of	O
+glutamate	O
+and	O
+aspartate	O
+.	O
+
+Therefore	O
+,	O
+like	O
+VPA	O
+,	O
+the	O
+finding	O
+that	O
+VPU	O
+could	O
+drastically	O
+reduce	O
+pilocarpine	O
+-	O
+induced	O
+increases	O
+in	O
+glutamate	O
+and	O
+aspartate	O
+should	O
+account	O
+,	O
+at	O
+least	O
+partly	O
+,	O
+for	O
+its	O
+anticonvulsant	O
+activity	O
+observed	O
+in	O
+pilocarpine	O
+-	O
+induced	O
+seizure	B
+in	O
+experimental	O
+animals	O
+.	O
+
+Some	O
+other	O
+mechanism	O
+than	O
+those	O
+being	O
+reported	O
+herein	O
+should	O
+be	O
+further	O
+investigated	O
+.	O
+
+Protective	O
+effect	O
+of	O
+verapamil	O
+on	O
+gastric	B
+hemorrhagic	I
+ulcers	B
+in	O
+severe	O
+atherosclerotic	B
+rats	O
+.	O
+
+Studies	O
+concerning	O
+with	O
+pathogenesis	O
+of	O
+gastric	B
+hemorrhage	I
+and	O
+mucosal	O
+ulceration	O
+produced	O
+in	O
+atherosclerotic	B
+rats	O
+are	O
+lacking	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+is	O
+to	O
+examine	O
+the	O
+role	O
+of	O
+gastric	O
+acid	O
+back	O
+-	O
+diffusion	O
+,	O
+mast	O
+cell	O
+histamine	O
+release	O
+,	O
+lipid	O
+peroxide	O
+(	O
+LPO	O
+)	O
+generation	O
+and	O
+mucosal	O
+microvascular	O
+permeability	O
+in	O
+modulating	O
+gastric	B
+hemorrhage	I
+and	O
+ulcer	B
+in	O
+rats	O
+with	O
+atherosclerosis	B
+induced	O
+by	O
+coadministration	O
+of	O
+vitamin	O
+D2	O
+and	O
+cholesterol	O
+.	O
+
+Additionally	O
+,	O
+the	O
+protective	O
+effect	O
+of	O
+verapamil	O
+on	O
+this	O
+ulcer	B
+model	O
+was	O
+evaluated	O
+.	O
+
+Male	O
+Wistar	O
+rats	O
+were	O
+challenged	O
+intragastrically	O
+once	O
+daily	O
+for	O
+9	O
+days	O
+with	O
+1	O
+.	O
+0	O
+ml	O
+/	O
+kg	O
+of	O
+corn	O
+oil	O
+containing	O
+vitamin	O
+D2	O
+and	O
+cholesterol	O
+to	O
+induce	O
+atherosclerosis	B
+.	O
+
+Control	O
+rats	O
+received	O
+corn	O
+oil	O
+only	O
+.	O
+
+After	O
+gastric	O
+surgery	O
+,	O
+rat	O
+stomachs	O
+were	O
+irrigated	O
+for	O
+3	O
+h	O
+with	O
+either	O
+simulated	O
+gastric	O
+juice	O
+or	O
+normal	O
+saline	O
+.	O
+
+Gastric	O
+acid	O
+back	O
+-	O
+diffusion	O
+,	O
+mucosal	O
+LPO	O
+generation	O
+,	O
+histamine	O
+concentration	O
+,	O
+microvascular	O
+permeability	O
+,	O
+luminal	O
+hemoglobin	O
+content	O
+and	O
+ulcer	B
+areas	O
+were	O
+determined	O
+.	O
+
+Elevated	O
+atherosclerotic	B
+parameters	O
+,	O
+such	O
+as	O
+serum	O
+calcium	O
+,	O
+total	O
+cholesterol	O
+and	O
+low	O
+-	O
+density	O
+lipoprotein	O
+concentration	O
+were	O
+obtained	O
+in	O
+atherosclerotic	B
+rats	O
+.	O
+
+Severe	O
+gastric	O
+ulcers	B
+accompanied	O
+with	O
+increased	O
+ulcerogenic	O
+factors	O
+,	O
+including	O
+gastric	O
+acid	O
+back	O
+-	O
+diffusion	O
+,	O
+histamine	O
+release	O
+,	O
+LPO	O
+generation	O
+and	O
+luminal	O
+hemoglobin	O
+content	O
+were	O
+also	O
+observed	O
+in	O
+these	O
+rats	O
+.	O
+
+Moreover	O
+,	O
+a	O
+positive	O
+correlation	O
+of	O
+histamine	O
+to	O
+gastric	B
+hemorrhage	I
+and	O
+to	O
+ulcer	B
+was	O
+found	O
+in	O
+those	O
+atherosclerotic	B
+rats	O
+.	O
+
+This	O
+hemorrhagic	B
+ulcer	B
+and	O
+various	O
+ulcerogenic	O
+parameters	O
+were	O
+dose	O
+-	O
+dependently	O
+ameliorated	O
+by	O
+daily	O
+intragastric	O
+verapamil	O
+.	O
+
+Atherosclerosis	B
+could	O
+produce	O
+gastric	B
+hemorrhagic	I
+ulcer	B
+via	O
+aggravation	O
+of	O
+gastric	O
+acid	O
+back	O
+-	O
+diffusion	O
+,	O
+LPO	O
+generation	O
+,	O
+histamine	O
+release	O
+and	O
+microvascular	O
+permeability	O
+that	O
+could	O
+be	O
+ameliorated	O
+by	O
+verapamil	O
+in	O
+rats	O
+.	O
+
+Lamivudine	O
+for	O
+the	O
+prevention	O
+of	O
+hepatitis	B
+B	I
+virus	O
+reactivation	O
+in	O
+hepatitis	O
+-	O
+B	O
+surface	O
+antigen	O
+(	O
+HBSAG	O
+)	O
+seropositive	O
+cancer	B
+patients	O
+undergoing	O
+cytotoxic	O
+chemotherapy	O
+.	O
+
+Hepatitis	B
+B	I
+virus	O
+(	O
+HBV	O
+)	O
+is	O
+one	O
+of	O
+the	O
+major	O
+causes	O
+of	O
+chronic	O
+liver	B
+disease	I
+worldwide	O
+.	O
+
+Cancer	B
+patients	O
+who	O
+are	O
+chronic	O
+carriers	O
+of	O
+HBV	O
+have	O
+a	O
+higher	O
+hepatic	B
+complication	I
+rate	O
+while	O
+receiving	O
+cytotoxic	O
+chemotherapy	O
+(	O
+CT	O
+)	O
+and	O
+this	O
+has	O
+mainly	O
+been	O
+attributed	O
+to	O
+HBV	O
+reactivation	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+cancer	B
+patients	O
+who	O
+have	O
+solid	O
+and	O
+hematological	B
+malignancies	I
+with	O
+chronic	O
+HBV	B
+infection	I
+received	O
+the	O
+antiviral	O
+agent	O
+lamivudine	O
+prior	O
+and	O
+during	O
+CT	O
+compared	O
+with	O
+historical	O
+control	O
+group	O
+who	O
+did	O
+not	O
+receive	O
+lamivudine	O
+.	O
+
+The	O
+objectives	O
+were	O
+to	O
+assess	O
+the	O
+efficacy	O
+of	O
+lamivudine	O
+in	O
+reducing	O
+the	O
+incidence	O
+of	O
+HBV	O
+reactivation	O
+,	O
+and	O
+diminishing	O
+morbidity	O
+and	O
+mortality	O
+during	O
+CT	O
+.	O
+
+Two	O
+groups	O
+were	O
+compared	O
+in	O
+this	O
+study	O
+.	O
+
+The	O
+prophylactic	O
+lamivudin	O
+group	O
+consisted	O
+of	O
+37	O
+patients	O
+who	O
+received	O
+prophylactic	O
+lamivudine	O
+treatment	O
+.	O
+
+The	O
+historical	O
+controls	O
+consisted	O
+of	O
+50	O
+consecutive	O
+patients	O
+who	O
+underwent	O
+CT	O
+without	O
+prophylactic	O
+lamivudine	O
+.	O
+
+They	O
+were	O
+followed	O
+up	O
+during	O
+and	O
+for	O
+8	O
+weeks	O
+after	O
+CT	O
+.	O
+
+The	O
+outcomes	O
+were	O
+compared	O
+for	O
+both	O
+groups	O
+.	O
+
+Of	O
+our	O
+control	O
+group	O
+(	O
+n	O
+=	O
+50	O
+)	O
+,	O
+21	O
+patients	O
+(	O
+42	O
+%	O
+)	O
+were	O
+established	O
+hepatitis	B
+.	O
+
+Twelve	O
+(	O
+24	O
+%	O
+)	O
+of	O
+them	O
+were	O
+evaluated	O
+as	O
+severe	O
+hepatitis	B
+.	O
+
+In	O
+the	O
+prophylactic	O
+lamivudine	O
+group	O
+severe	O
+hepatitis	B
+were	O
+observed	O
+only	O
+in	O
+1	O
+patient	O
+(	O
+2	O
+.	O
+7	O
+%	O
+)	O
+of	O
+37	O
+patients	O
+(	O
+p	O
+<	O
+0	O
+.	O
+006	O
+)	O
+.	O
+
+Comparison	O
+of	O
+the	O
+mean	O
+ALT	O
+values	O
+revealed	O
+significantly	O
+higher	O
+mean	O
+alanine	O
+aminotransferase	O
+(	O
+ALT	O
+)	O
+values	O
+in	O
+the	O
+control	O
+group	O
+than	O
+the	O
+prophylactic	O
+lamivudine	O
+group	O
+;	O
+154	O
+:	O
+64	O
+(	O
+p	O
+<	O
+0	O
+.	O
+32	O
+)	O
+.	O
+
+Our	O
+study	O
+suggests	O
+that	O
+prophylactic	O
+lamivudine	O
+significantly	O
+decreases	O
+the	O
+incidence	O
+of	O
+HBV	O
+reactivation	O
+and	O
+overall	O
+morbidity	O
+in	O
+cancer	B
+patients	O
+during	O
+and	O
+after	O
+immunosuppressive	O
+therapy	O
+.	O
+
+Further	O
+studies	O
+are	O
+needed	O
+to	O
+determine	O
+the	O
+most	O
+appropriate	O
+nucleoside	O
+or	O
+nucleotide	O
+analogue	O
+for	O
+antiviral	O
+prophylaxis	O
+during	O
+CT	O
+and	O
+the	O
+optimal	O
+duration	O
+of	O
+administration	O
+after	O
+completion	O
+of	O
+CT	O
+.	O
+
+Recovery	O
+of	O
+tacrolimus	O
+-	O
+associated	O
+brachial	B
+neuritis	I
+after	O
+conversion	O
+to	O
+everolimus	O
+in	O
+a	O
+pediatric	O
+renal	O
+transplant	O
+recipient	O
+-	O
+-	O
+case	O
+report	O
+and	O
+review	O
+of	O
+the	O
+literature	O
+.	O
+
+TAC	O
+has	O
+been	O
+shown	O
+to	O
+be	O
+a	O
+potent	O
+immunosuppressive	O
+agent	O
+for	O
+solid	O
+organ	O
+transplantation	O
+in	O
+pediatrics	O
+.	O
+
+Neurotoxicity	B
+is	O
+a	O
+potentially	O
+serious	O
+toxic	O
+effect	O
+.	O
+
+It	O
+is	O
+characterized	O
+by	O
+encephalopathy	B
+,	O
+headaches	B
+,	O
+seizures	B
+,	O
+or	O
+neurological	B
+deficits	I
+.	O
+
+Here	O
+,	O
+we	O
+describe	O
+an	O
+eight	O
+-	O
+and	O
+-	O
+a	O
+-	O
+half	O
+-	O
+yr	O
+-	O
+old	O
+male	O
+renal	O
+transplant	O
+recipient	O
+with	O
+right	O
+BN	O
+.	O
+
+MRI	O
+demonstrated	O
+hyperintense	O
+T2	O
+signals	O
+in	O
+the	O
+cervical	O
+cord	O
+and	O
+right	O
+brachial	O
+plexus	O
+roots	O
+indicative	O
+of	O
+both	O
+myelitis	B
+and	O
+right	O
+brachial	B
+plexitis	I
+.	O
+
+Symptoms	O
+persisted	O
+for	O
+three	O
+months	O
+despite	O
+TAC	O
+dose	O
+reduction	O
+,	O
+administration	O
+of	O
+IVIG	O
+and	O
+four	O
+doses	O
+of	O
+methylprednisolone	O
+pulse	O
+therapy	O
+.	O
+
+Improvement	O
+and	O
+eventually	O
+full	O
+recovery	O
+only	O
+occurred	O
+after	O
+TAC	O
+was	O
+completely	O
+discontinued	O
+and	O
+successfully	O
+replaced	O
+by	O
+everolimus	O
+.	O
+
+Omitting	O
+fentanyl	O
+reduces	O
+nausea	B
+and	O
+vomiting	B
+,	O
+without	O
+increasing	O
+pain	B
+,	O
+after	O
+sevoflurane	O
+for	O
+day	O
+surgery	O
+.	O
+
+BACKGROUND	O
+AND	O
+OBJECTIVE	O
+:	O
+Despite	O
+advantages	O
+of	O
+induction	O
+and	O
+maintenance	O
+of	O
+anaesthesia	O
+with	O
+sevoflurane	O
+,	O
+postoperative	B
+nausea	I
+and	I
+vomiting	I
+occurs	O
+frequently	O
+.	O
+
+Fentanyl	O
+is	O
+a	O
+commonly	O
+used	O
+supplement	O
+that	O
+may	O
+contribute	O
+to	O
+this	O
+,	O
+although	O
+it	O
+may	O
+also	O
+improve	O
+analgesia	O
+.	O
+
+METHODS	O
+:	O
+This	O
+double	O
+-	O
+blind	O
+study	O
+examined	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+postoperative	B
+nausea	I
+and	I
+vomiting	I
+and	O
+pain	B
+in	O
+the	O
+first	O
+24	O
+h	O
+after	O
+sevoflurane	O
+anaesthesia	O
+in	O
+216	O
+adult	O
+day	O
+surgery	O
+patients	O
+.	O
+
+Patients	O
+were	O
+randomly	O
+allocated	O
+to	O
+either	O
+receive	O
+or	O
+not	O
+receive	O
+1	O
+1	O
+fentanyl	O
+,	O
+while	O
+a	O
+third	O
+group	O
+received	O
+dexamethasone	O
+in	O
+addition	O
+to	O
+fentanyl	O
+.	O
+
+RESULTS	O
+:	O
+Omission	O
+of	O
+fentanyl	O
+did	O
+not	O
+reduce	O
+the	O
+overall	O
+incidence	O
+of	O
+postoperative	B
+nausea	I
+and	I
+vomiting	I
+,	O
+but	O
+did	O
+reduce	O
+the	O
+incidence	O
+of	O
+vomiting	B
+and	O
+/	O
+or	O
+moderate	O
+to	O
+severe	O
+nausea	B
+prior	O
+to	O
+discharge	O
+from	O
+20	O
+%	O
+and	O
+17	O
+%	O
+with	O
+fentanyl	O
+and	O
+fentanyl	O
+-	O
+dexamethasone	O
+,	O
+respectively	O
+,	O
+to	O
+5	O
+%	O
+(	O
+P	O
+=	O
+0	O
+.	O
+013	O
+)	O
+.	O
+
+Antiemetic	O
+requirements	O
+were	O
+reduced	O
+from	O
+24	O
+%	O
+and	O
+31	O
+%	O
+to	O
+7	O
+%	O
+(	O
+P	O
+=	O
+0	O
+.	O
+0012	O
+)	O
+.	O
+
+Dexamethasone	O
+had	O
+no	O
+significant	O
+effect	O
+on	O
+the	O
+incidence	O
+or	O
+severity	O
+of	O
+postoperative	B
+nausea	I
+and	I
+vomiting	I
+.	O
+
+Combining	O
+the	O
+two	O
+fentanyl	O
+groups	O
+revealed	O
+further	O
+significant	O
+benefits	O
+from	O
+the	O
+avoidance	O
+of	O
+opioids	O
+,	O
+reducing	O
+postoperative	B
+nausea	I
+and	I
+vomiting	I
+and	O
+nausea	B
+prior	O
+to	O
+discharge	O
+from	O
+35	O
+%	O
+and	O
+33	O
+%	O
+to	O
+22	O
+%	O
+and	O
+19	O
+%	O
+(	O
+P	O
+=	O
+0	O
+.	O
+049	O
+and	O
+P	O
+=	O
+0	O
+.	O
+035	O
+)	O
+,	O
+respectively	O
+,	O
+while	O
+nausea	B
+in	O
+the	O
+first	O
+24	O
+h	O
+was	O
+decreased	O
+from	O
+42	O
+%	O
+to	O
+27	O
+%	O
+(	O
+P	O
+=	O
+0	O
+.	O
+034	O
+)	O
+.	O
+
+Pain	B
+severity	O
+and	O
+analgesic	O
+requirements	O
+were	O
+unaffected	O
+by	O
+the	O
+omission	O
+of	O
+fentanyl	O
+.	O
+
+Fentanyl	O
+did	O
+reduce	O
+minor	O
+intraoperative	O
+movement	O
+but	O
+had	O
+no	O
+sevoflurane	O
+-	O
+sparing	O
+effect	O
+and	O
+increased	O
+respiratory	B
+depression	I
+,	O
+hypotension	B
+and	O
+bradycardia	B
+.	O
+
+CONCLUSION	O
+:	O
+As	O
+fentanyl	O
+exacerbated	O
+postoperative	B
+nausea	I
+and	I
+vomiting	I
+without	O
+an	O
+improvement	O
+in	O
+postoperative	B
+pain	I
+and	O
+also	O
+had	O
+adverse	O
+cardiorespiratory	O
+effects	O
+,	O
+it	O
+appears	O
+to	O
+be	O
+an	O
+unnecessary	O
+and	O
+possibly	O
+detrimental	O
+supplement	O
+to	O
+sevoflurane	O
+in	O
+day	O
+surgery	O
+.	O
+
+Valvular	B
+heart	I
+disease	I
+in	O
+patients	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+treated	O
+with	O
+pergolide	O
+.	O
+
+Course	O
+following	O
+treatment	O
+modifications	O
+.	O
+
+Valvular	B
+heart	I
+abnormalities	I
+have	O
+been	O
+reported	O
+in	O
+patients	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+treated	O
+with	O
+pergolide	O
+.	O
+
+However	O
+,	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+these	O
+abnormalities	O
+vary	O
+from	O
+study	O
+to	O
+study	O
+and	O
+their	O
+course	O
+after	O
+drug	O
+withdrawal	O
+has	O
+not	O
+been	O
+systematically	O
+assessed	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+estimate	O
+the	O
+frequency	O
+and	O
+severity	O
+of	O
+valvular	B
+heart	I
+abnormality	I
+and	O
+its	O
+possible	O
+reversibility	O
+after	O
+drug	O
+withdrawal	O
+in	O
+a	O
+case	O
+-	O
+control	O
+study	O
+.	O
+
+METHODS	O
+:	O
+All	O
+PD	B
+patients	O
+in	O
+the	O
+Amiens	O
+area	O
+treated	O
+with	O
+pergolide	O
+were	O
+invited	O
+to	O
+attend	O
+a	O
+cardiologic	O
+assessment	O
+including	O
+transthoracic	O
+echocardiography	O
+.	O
+
+Thirty	O
+PD	B
+patients	O
+participated	O
+in	O
+the	O
+study	O
+.	O
+
+A	O
+second	O
+echocardiography	O
+was	O
+performed	O
+(	O
+median	O
+interval	O
+:	O
+13	O
+months	O
+)	O
+after	O
+pergolide	O
+withdrawal	O
+(	O
+n	O
+=	O
+10	O
+patients	O
+)	O
+.	O
+
+Controls	O
+were	O
+age	O
+-	O
+and	O
+sex	O
+-	O
+matched	O
+non	O
+-	O
+PD	B
+patients	O
+referred	O
+to	O
+the	O
+cardiology	O
+department	O
+.	O
+
+RESULTS	O
+:	O
+Compared	O
+to	O
+controls	O
+,	O
+aortic	B
+regurgitation	I
+(	O
+OR	O
+:	O
+3	O
+.	O
+1	O
+;	O
+95	O
+%	O
+IC	O
+:	O
+1	O
+.	O
+1	O
+-	O
+8	O
+.	O
+8	O
+)	O
+and	O
+mitral	B
+regurgitation	I
+(	O
+OR	O
+:	O
+10	O
+.	O
+7	O
+;	O
+95	O
+%	O
+IC	O
+:	O
+2	O
+.	O
+1	O
+-	O
+53	O
+)	O
+were	O
+more	O
+frequent	O
+in	O
+PD	B
+patients	O
+(	O
+tricuspid	O
+:	O
+NS	O
+)	O
+.	O
+
+The	O
+number	O
+of	O
+affected	O
+valves	O
+(	O
+n	O
+=	O
+2	O
+.	O
+4	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+)	O
+and	O
+the	O
+sum	O
+of	O
+regurgitation	O
+grades	O
+(	O
+n	O
+=	O
+2	O
+.	O
+8	O
++	O
+/	O
+-	O
+1	O
+.	O
+09	O
+)	O
+were	O
+higher	O
+(	O
+p	O
+=	O
+0	O
+.	O
+008	O
+and	O
+p	O
+=	O
+0	O
+.	O
+006	O
+,	O
+respectively	O
+)	O
+in	O
+the	O
+pergolide	O
+group	O
+.	O
+
+Severity	O
+of	O
+regurgitation	O
+was	O
+not	O
+correlated	O
+with	O
+pergolide	O
+cumulative	O
+dose	O
+.	O
+
+A	O
+restrictive	O
+pattern	O
+of	O
+valvular	B
+regurgitation	I
+,	O
+suggestive	O
+of	O
+the	O
+role	O
+of	O
+pergolide	O
+,	O
+was	O
+observed	O
+in	O
+12	O
+/	O
+30	O
+(	O
+40	O
+%	O
+)	O
+patients	O
+including	O
+two	O
+with	O
+heart	B
+failure	I
+.	O
+
+Pergolide	O
+was	O
+discontinued	O
+in	O
+10	O
+patients	O
+with	O
+valvular	B
+heart	I
+disease	I
+,	O
+resulting	O
+in	O
+a	O
+lower	O
+regurgitation	O
+grade	O
+(	O
+p	O
+=	O
+0	O
+.	O
+01	O
+)	O
+at	O
+the	O
+second	O
+transthoracic	O
+echocardiography	O
+and	O
+the	O
+two	O
+patients	O
+with	O
+heart	B
+failure	I
+returned	O
+to	O
+nearly	O
+normal	O
+clinical	O
+examination	O
+.	O
+
+This	O
+study	O
+supports	O
+the	O
+high	O
+frequency	O
+of	O
+restrictive	O
+valve	B
+regurgitation	I
+in	O
+PD	B
+patients	O
+treated	O
+with	O
+pergolide	O
+and	O
+reveals	O
+that	O
+a	O
+significant	O
+improvement	O
+is	O
+usual	O
+when	O
+the	O
+treatment	O
+is	O
+converted	O
+to	O
+non	O
+-	O
+ergot	O
+dopamine	O
+agonists	O
+.	O
+
+Adriamycin	O
+-	O
+induced	O
+autophagic	O
+cardiomyocyte	O
+death	B
+plays	O
+a	O
+pathogenic	O
+role	O
+in	O
+a	O
+rat	O
+model	O
+of	O
+heart	B
+failure	I
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+mechanisms	O
+underlying	O
+heart	B
+failure	I
+induced	O
+by	O
+adriamycin	O
+are	O
+very	O
+complicated	O
+and	O
+still	O
+unclear	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+investigate	O
+whether	O
+autophagy	O
+was	O
+involved	O
+in	O
+the	O
+progression	O
+of	O
+heart	B
+failure	I
+induced	O
+by	O
+adriamycin	O
+,	O
+so	O
+that	O
+we	O
+can	O
+develop	O
+a	O
+novel	O
+treatment	O
+strategy	O
+for	O
+heart	B
+failure	I
+.	O
+
+METHODS	O
+:	O
+3	O
+-	O
+methyladenine	O
+(	O
+3MA	O
+)	O
+,	O
+a	O
+specific	O
+inhibitor	O
+on	O
+autophagy	O
+was	O
+used	O
+in	O
+a	O
+heart	B
+failure	I
+model	O
+of	O
+rats	O
+induced	O
+by	O
+adriamycin	O
+.	O
+
+Neonatal	O
+cardiomyocytes	O
+were	O
+isolated	O
+from	O
+Sprague	O
+-	O
+Dawley	O
+rat	O
+hearts	O
+and	O
+randomly	O
+divided	O
+into	O
+controls	O
+,	O
+an	O
+adriamycin	O
+-	O
+treated	O
+group	O
+,	O
+and	O
+a	O
+3MA	O
+plus	O
+adriamycin	O
+-	O
+treated	O
+group	O
+.	O
+
+We	O
+then	O
+examined	O
+the	O
+morphology	O
+,	O
+expression	O
+of	O
+beclin	O
+1	O
+gene	O
+,	O
+mitochondrial	O
+permeability	O
+transition	O
+(	O
+MPT	O
+)	O
+,	O
+and	O
+Na	O
++	O
+-	O
+K	O
++	O
+ATPase	O
+activity	O
+in	O
+vivo	O
+.	O
+
+We	O
+also	O
+assessed	O
+cell	O
+viability	O
+,	O
+mitochondrial	O
+membrane	O
+potential	O
+changes	O
+and	O
+counted	O
+autophagic	O
+vacuoles	O
+in	O
+cultured	O
+cardiomyocytes	O
+.	O
+
+In	O
+addition	O
+,	O
+we	O
+analyzed	O
+the	O
+expression	O
+of	O
+autophagy	O
+associated	O
+gene	O
+,	O
+beclin	O
+1	O
+using	O
+RT	O
+-	O
+PCR	O
+and	O
+Western	O
+blotting	O
+in	O
+an	O
+animal	O
+model	O
+.	O
+
+RESULTS	O
+:	O
+3MA	O
+significantly	O
+improved	O
+cardiac	O
+function	O
+and	O
+reduced	O
+mitochondrial	O
+injury	O
+.	O
+
+Furthermore	O
+,	O
+adriamycin	O
+induced	O
+the	O
+formation	O
+of	O
+autophagic	O
+vacuoles	O
+,	O
+and	O
+3MA	O
+strongly	O
+downregulated	O
+the	O
+expression	O
+of	O
+beclin	O
+1	O
+in	O
+adriamycin	O
+-	O
+induced	O
+failing	O
+heart	O
+and	O
+inhibited	O
+the	O
+formation	O
+of	O
+autophagic	O
+vacuoles	O
+.	O
+
+CONCLUSION	O
+:	O
+Autophagic	O
+cardiomyocyte	O
+death	B
+plays	O
+an	O
+important	O
+role	O
+in	O
+the	O
+pathogenesis	O
+of	O
+heart	B
+failure	I
+in	O
+rats	O
+induced	O
+by	O
+adriamycin	O
+.	O
+
+Mitochondrial	O
+injury	O
+may	O
+be	O
+involved	O
+in	O
+the	O
+progression	O
+of	O
+heart	B
+failure	I
+caused	O
+by	O
+adriamycin	O
+via	O
+the	O
+autophagy	O
+pathway	O
+.	O
+
+mToR	O
+inhibitors	O
+-	O
+induced	O
+proteinuria	B
+:	O
+mechanisms	O
+,	O
+significance	O
+,	O
+and	O
+management	O
+.	O
+
+Massive	O
+urinary	O
+protein	O
+excretion	O
+has	O
+been	O
+observed	O
+after	O
+conversion	O
+from	O
+calcineurin	O
+inhibitors	O
+to	O
+mammalian	O
+target	O
+of	O
+rapamycin	O
+(	O
+mToR	O
+)	O
+inhibitors	O
+,	O
+especially	O
+sirolimus	O
+,	O
+in	O
+renal	O
+transplant	O
+recipients	O
+with	O
+chronic	B
+allograft	I
+nephropathy	I
+.	O
+
+Because	O
+proteinuria	B
+is	O
+a	O
+major	O
+predictive	O
+factor	O
+of	O
+poor	O
+transplantation	O
+outcome	O
+,	O
+many	O
+studies	O
+focused	O
+on	O
+this	O
+adverse	O
+event	O
+during	O
+the	O
+past	O
+years	O
+.	O
+
+Whether	O
+proteinuria	B
+was	O
+due	O
+to	O
+sirolimus	O
+or	O
+only	O
+a	O
+consequence	O
+of	O
+calcineurin	O
+inhibitors	O
+withdrawal	O
+remained	O
+unsolved	O
+until	O
+high	O
+range	O
+proteinuria	B
+has	O
+been	O
+observed	O
+during	O
+sirolimus	O
+therapy	O
+in	O
+islet	O
+transplantation	O
+and	O
+in	O
+patients	O
+who	O
+received	O
+sirolimus	O
+de	O
+novo	O
+.	O
+
+Podocyte	O
+injury	O
+and	O
+focal	O
+segmental	O
+glomerulosclerosis	B
+have	O
+been	O
+related	O
+to	O
+mToR	O
+inhibition	O
+in	O
+some	O
+patients	O
+,	O
+but	O
+the	O
+pathways	O
+underlying	O
+these	O
+lesions	O
+remain	O
+hypothetic	O
+.	O
+
+We	O
+discuss	O
+herein	O
+the	O
+possible	O
+mechanisms	O
+and	O
+the	O
+significance	O
+of	O
+mToR	O
+blockade	O
+-	O
+induced	O
+proteinuria	B
+.	O
+
+Neuropsychiatric	O
+side	O
+effects	O
+after	O
+the	O
+use	O
+of	O
+mefloquine	O
+.	O
+
+This	O
+study	O
+describes	O
+neuropsychiatric	O
+side	O
+effects	O
+in	O
+patients	O
+after	O
+treatment	O
+with	O
+mefloquine	O
+.	O
+
+Reactions	O
+consisted	O
+mainly	O
+of	O
+seizures	B
+,	O
+acute	O
+psychoses	B
+,	O
+anxiety	B
+neurosis	I
+,	O
+and	O
+major	O
+disturbances	B
+of	I
+sleep	I
+-	I
+wake	I
+rhythm	I
+.	O
+
+Side	O
+effects	O
+occurred	O
+after	O
+both	O
+therapeutic	O
+and	O
+prophylactic	O
+intake	O
+and	O
+were	O
+graded	O
+from	O
+moderate	O
+to	O
+severe	O
+.	O
+
+In	O
+a	O
+risk	O
+analysis	O
+of	O
+neuropsychiatric	O
+side	O
+effects	O
+in	O
+Germany	O
+,	O
+it	O
+is	O
+estimated	O
+that	O
+one	O
+of	O
+8	O
+,	O
+000	O
+mefloquine	O
+users	O
+suffers	O
+from	O
+such	O
+reactions	O
+.	O
+
+The	O
+incidence	O
+calculation	O
+revealed	O
+that	O
+one	O
+of	O
+215	O
+therapeutic	O
+users	O
+had	O
+reactions	O
+,	O
+compared	O
+with	O
+one	O
+of	O
+13	O
+,	O
+000	O
+in	O
+the	O
+prophylaxis	O
+group	O
+,	O
+making	O
+the	O
+risk	O
+of	O
+neuropsychiatric	O
+reactions	O
+after	O
+mefloquine	O
+treatment	O
+60	O
+times	O
+higher	O
+than	O
+after	O
+prophylaxis	O
+.	O
+
+Therefore	O
+,	O
+certain	O
+limitations	O
+for	O
+malaria	B
+prophylaxis	O
+and	O
+treatment	O
+with	O
+mefloquine	O
+are	O
+recommended	O
+.	O
+
+Prenatal	O
+protein	O
+deprivation	O
+alters	O
+dopamine	O
+-	O
+mediated	O
+behaviors	O
+and	O
+dopaminergic	O
+and	O
+glutamatergic	O
+receptor	O
+binding	O
+.	O
+
+Epidemiological	O
+evidence	O
+indicates	O
+that	O
+prenatal	O
+nutritional	O
+deprivation	O
+may	O
+increase	O
+the	O
+risk	O
+of	O
+schizophrenia	B
+.	O
+
+The	O
+goal	O
+of	O
+these	O
+studies	O
+was	O
+to	O
+use	O
+an	O
+animal	O
+model	O
+to	O
+examine	O
+the	O
+effects	O
+of	O
+prenatal	O
+protein	O
+deprivation	O
+on	O
+behaviors	O
+and	O
+receptor	O
+binding	O
+with	O
+relevance	O
+to	O
+schizophrenia	B
+.	O
+
+We	O
+report	O
+that	O
+prenatally	O
+protein	O
+deprived	O
+(	O
+PD	O
+)	O
+female	O
+rats	O
+showed	O
+an	O
+increased	O
+stereotypic	O
+response	O
+to	O
+apomorphine	O
+and	O
+an	O
+increased	O
+locomotor	O
+response	O
+to	O
+amphetamine	O
+in	O
+adulthood	O
+.	O
+
+These	O
+differences	O
+were	O
+not	O
+observed	O
+during	O
+puberty	O
+.	O
+
+No	O
+changes	O
+in	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+or	O
+MK	O
+-	O
+801	O
+-	O
+induced	O
+locomotion	O
+were	O
+seen	O
+following	O
+PD	O
+.	O
+
+In	O
+addition	O
+,	O
+PD	O
+female	O
+rats	O
+showed	O
+increased	O
+(	O
+3	O
+)	O
+H	O
+-	O
+MK	O
+-	O
+801	O
+binding	O
+in	O
+the	O
+striatum	O
+and	O
+hippocampus	O
+,	O
+but	O
+not	O
+in	O
+the	O
+cortex	O
+.	O
+
+PD	O
+female	O
+rats	O
+also	O
+showed	O
+increased	O
+(	O
+3	O
+)	O
+H	O
+-	O
+haloperidol	O
+binding	O
+and	O
+decreased	O
+dopamine	O
+transporter	O
+binding	O
+in	O
+striatum	O
+.	O
+
+No	O
+statistically	O
+significant	O
+changes	O
+in	O
+behavior	O
+or	O
+receptor	O
+binding	O
+were	O
+found	O
+in	O
+PD	O
+males	O
+with	O
+the	O
+exception	O
+of	O
+increased	O
+(	O
+3	O
+)	O
+H	O
+-	O
+MK	O
+-	O
+801	O
+binding	O
+in	O
+cortex	O
+.	O
+
+This	O
+animal	O
+model	O
+may	O
+be	O
+useful	O
+to	O
+explore	O
+the	O
+mechanisms	O
+by	O
+which	O
+prenatal	O
+nutritional	B
+deficiency	I
+enhances	O
+risk	O
+for	O
+schizophrenia	B
+in	O
+humans	O
+and	O
+may	O
+also	O
+have	O
+implications	O
+for	O
+developmental	O
+processes	O
+leading	O
+to	O
+differential	O
+sensitivity	O
+to	O
+drugs	O
+of	O
+abuse	O
+.	O
+
+Adverse	O
+effects	O
+of	O
+topical	O
+papaverine	O
+on	O
+auditory	O
+nerve	O
+function	O
+.	O
+
+BACKGROUND	O
+:	O
+Papaverine	O
+hydrochloride	O
+is	O
+a	O
+direct	O
+-	O
+acting	O
+vasodilator	O
+used	O
+to	O
+manage	O
+vasospasm	B
+during	O
+various	O
+neurosurgical	O
+operations	O
+.	O
+
+Transient	O
+cranial	B
+nerve	I
+dysfunction	I
+has	O
+been	O
+described	O
+in	O
+a	O
+few	O
+cases	O
+with	O
+topical	O
+papaverine	O
+.	O
+
+This	O
+study	O
+supports	O
+previous	O
+reports	O
+and	O
+provides	O
+neurophysiological	O
+evidence	O
+of	O
+an	O
+adverse	O
+effect	O
+on	O
+the	O
+auditory	O
+nerve	O
+.	O
+
+METHODS	O
+:	O
+We	O
+conducted	O
+a	O
+retrospective	O
+review	O
+of	O
+70	O
+consecutive	O
+microvascular	O
+decompression	O
+operations	O
+and	O
+studied	O
+those	O
+patients	O
+who	O
+received	O
+topical	O
+papaverine	O
+for	O
+vasospasm	B
+.	O
+
+Topical	O
+papaverine	O
+was	O
+used	O
+as	O
+a	O
+direct	O
+therapeutic	O
+action	O
+to	O
+manage	O
+vasospasm	B
+in	O
+a	O
+total	O
+of	O
+11	O
+patients	O
+.	O
+
+The	O
+timing	O
+of	O
+papaverine	O
+application	O
+and	O
+ongoing	O
+operative	O
+events	O
+was	O
+reviewed	O
+relative	O
+to	O
+changes	O
+in	O
+neurophysiological	O
+recordings	O
+.	O
+
+Brainstem	O
+auditory	O
+evoked	O
+potentials	O
+(	O
+BAEPs	O
+)	O
+were	O
+routinely	O
+used	O
+to	O
+monitor	O
+cochlear	O
+nerve	O
+function	O
+during	O
+these	O
+operations	O
+.	O
+
+FINDINGS	O
+:	O
+A	O
+temporal	O
+relationship	O
+was	O
+found	O
+between	O
+topical	O
+papaverine	O
+and	O
+BAEP	O
+changes	O
+leading	O
+to	O
+complete	O
+waveform	O
+loss	O
+.	O
+
+The	O
+average	O
+temporal	O
+delay	O
+between	O
+papaverine	O
+and	O
+the	O
+onset	O
+of	O
+an	O
+adverse	O
+BAEP	O
+change	O
+was	O
+5	O
+min	O
+.	O
+
+In	O
+10	O
+of	O
+11	O
+patients	O
+,	O
+BAEP	O
+waves	O
+II	O
+/	O
+III	O
+-	O
+V	O
+completely	O
+disappeared	O
+within	O
+2	O
+to	O
+25	O
+min	O
+after	O
+papaverine	O
+.	O
+
+Eight	O
+of	O
+these	O
+10	O
+patients	O
+had	O
+complete	O
+loss	O
+of	O
+BAEP	O
+waveforms	O
+within	O
+10	O
+min	O
+.	O
+
+One	O
+patient	O
+showed	O
+no	O
+recovery	O
+of	O
+later	O
+waves	O
+and	O
+a	O
+delayed	O
+profound	O
+sensorineural	B
+hearing	I
+loss	I
+.	O
+
+The	O
+average	O
+recovery	O
+time	O
+of	O
+BAEP	O
+waveforms	O
+to	O
+pre	O
+-	O
+papaverine	O
+baseline	O
+values	O
+was	O
+39	O
+min	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Topical	O
+papaverine	O
+for	O
+the	O
+treatment	O
+of	O
+vasospasm	B
+was	O
+associated	O
+with	O
+the	O
+onset	O
+of	O
+a	O
+transient	O
+disturbance	O
+in	O
+neurophysiological	O
+function	O
+of	O
+the	O
+ascending	O
+auditory	O
+brainstem	O
+pathway	O
+.	O
+
+The	O
+complete	O
+disappearance	O
+of	O
+BAEP	O
+waveforms	O
+with	O
+a	O
+consistent	O
+temporal	O
+delay	O
+suggests	O
+a	O
+possible	O
+adverse	B
+effect	I
+on	I
+the	I
+proximal	I
+eighth	I
+nerve	I
+.	O
+
+Recommendations	O
+to	O
+avoid	O
+potential	O
+cranial	B
+nerve	I
+deficits	I
+from	O
+papaverine	O
+are	O
+provided	O
+.	O
+
+Simvastatin	O
+-	O
+ezetimibe	O
+-	O
+induced	O
+hepatic	B
+failure	I
+necessitating	O
+liver	O
+transplantation	O
+.	O
+
+Abstract	O
+Serum	O
+aminotransferase	O
+elevations	O
+are	O
+a	O
+commonly	O
+known	O
+adverse	O
+effect	O
+of	O
+3	O
+-	O
+hydroxy	O
+-	O
+3	O
+-	O
+methylglutaryl	O
+coenzyme	O
+A	O
+reductase	O
+inhibitor	O
+(	O
+statin	O
+)	O
+therapy	O
+.	O
+
+However	O
+,	O
+hepatotoxic	B
+events	O
+have	O
+not	O
+been	O
+widely	O
+published	O
+with	O
+ezetimibe	O
+or	O
+the	O
+combination	O
+agent	O
+simvastatin	O
+-	O
+ezetimibe	O
+.	O
+
+We	O
+describe	O
+a	O
+70	O
+-	O
+year	O
+-	O
+old	O
+Hispanic	O
+woman	O
+who	O
+developed	O
+fulminant	B
+hepatic	I
+failure	I
+necessitating	O
+liver	O
+transplantation	O
+10	O
+weeks	O
+after	O
+conversion	O
+from	O
+simvastatin	O
+40	O
+mg	O
+/	O
+day	O
+to	O
+simvastatin	O
+10	O
+mg	O
+-	O
+ezetimibe	O
+40	O
+mg	O
+/	O
+day	O
+.	O
+
+The	O
+patient	O
+'	O
+s	O
+lipid	O
+panel	O
+had	O
+been	O
+maintained	O
+with	O
+simvastatin	O
+for	O
+18	O
+months	O
+before	O
+the	O
+conversion	O
+without	O
+evidence	O
+of	O
+hepatotoxicity	B
+.	O
+
+A	O
+routine	O
+laboratory	O
+work	O
+-	O
+up	O
+10	O
+weeks	O
+after	O
+conversion	O
+revealed	O
+elevated	O
+serum	O
+aminotransferase	O
+levels	O
+.	O
+
+Simvastatinezetimibe	O
+and	O
+escitalopram	O
+(	O
+which	O
+she	O
+was	O
+taking	O
+for	O
+depression	B
+)	O
+were	O
+discontinued	O
+,	O
+and	O
+other	O
+potential	O
+causes	O
+of	O
+hepatotoxicity	B
+were	O
+excluded	O
+.	O
+
+A	O
+repeat	O
+work	O
+-	O
+up	O
+revealed	O
+further	O
+elevations	O
+in	O
+aminotransferase	O
+levels	O
+,	O
+and	O
+liver	O
+biopsy	O
+revealed	O
+evidence	O
+of	O
+moderate	O
+-	O
+to	O
+-	O
+severe	O
+drug	B
+toxicity	I
+.	O
+
+She	O
+underwent	O
+liver	O
+transplantation	O
+with	O
+an	O
+uneventful	O
+postoperative	O
+course	O
+.	O
+
+Her	O
+aminotransferase	O
+levels	O
+returned	O
+to	O
+normal	O
+by	O
+postoperative	O
+day	O
+23	O
+,	O
+and	O
+her	O
+2	O
+-	O
+year	O
+follow	O
+-	O
+up	O
+showed	O
+no	O
+adverse	O
+events	O
+.	O
+
+Ezetimibe	O
+undergoes	O
+extensive	O
+glucuronidation	O
+by	O
+uridine	O
+diphosphate	O
+glucoronosyltransferases	O
+(	O
+UGT	O
+)	O
+in	O
+the	O
+intestine	O
+and	O
+liver	O
+and	O
+may	O
+have	O
+inhibited	O
+the	O
+glucuronidation	O
+of	O
+simvastatin	O
+hydroxy	O
+acid	O
+,	O
+resulting	O
+in	O
+increased	O
+simvastatin	O
+exposure	O
+and	O
+subsequent	O
+hepatotoxicity	B
+.	O
+
+To	O
+our	O
+knowledge	O
+,	O
+this	O
+is	O
+the	O
+first	O
+case	O
+report	O
+of	O
+simvastatin	O
+-	O
+ezetimibe	O
+-	O
+induced	O
+liver	B
+failure	I
+that	O
+resulted	O
+in	O
+liver	O
+transplantation	O
+.	O
+
+We	O
+postulate	O
+that	O
+the	O
+mechanism	O
+of	O
+the	O
+simvastatinezetimibe	O
+-	O
+induced	O
+hepatotoxicity	B
+is	O
+the	O
+increased	O
+simvastatin	O
+exposure	O
+by	O
+ezetimibe	O
+inhibition	O
+of	O
+UGT	O
+enzymes	O
+.	O
+
+Clinicians	O
+should	O
+be	O
+aware	O
+of	O
+potential	O
+hepatotoxicity	B
+with	O
+simvastatin	O
+-	O
+ezetimibe	O
+especially	O
+in	O
+elderly	O
+patients	O
+and	O
+should	O
+carefully	O
+monitor	O
+serum	O
+aminotransferase	O
+levels	O
+when	O
+starting	O
+therapy	O
+and	O
+titrating	O
+the	O
+dosage	O
+.	O
+
+Massive	O
+proteinuria	B
+and	O
+acute	B
+renal	I
+failure	I
+after	O
+oral	O
+bisphosphonate	O
+(	O
+alendronate	O
+)	O
+administration	O
+in	O
+a	O
+patient	O
+with	O
+focal	B
+segmental	I
+glomerulosclerosis	I
+.	O
+
+A	O
+61	O
+-	O
+year	O
+-	O
+old	O
+Japanese	O
+man	O
+with	O
+nephrotic	B
+syndrome	I
+due	O
+to	O
+focal	B
+segmental	I
+glomerulosclerosis	I
+was	O
+initially	O
+responding	O
+well	O
+to	O
+steroid	O
+therapy	O
+.	O
+
+The	O
+amount	O
+of	O
+daily	O
+urinary	O
+protein	O
+decreased	O
+from	O
+15	O
+.	O
+6	O
+to	O
+2	O
+.	O
+8	O
+g	O
+.	O
+
+Within	O
+14	O
+days	O
+of	O
+the	O
+oral	O
+bisphosphonate	O
+(	O
+alendronate	O
+sodium	O
+)	O
+administration	O
+,	O
+the	O
+amount	O
+of	O
+daily	O
+urinary	O
+protein	O
+increased	O
+rapidly	O
+up	O
+to	O
+12	O
+.	O
+8	O
+g	O
+with	O
+acute	B
+renal	I
+failure	I
+.	O
+
+After	O
+discontinuing	O
+the	O
+oral	O
+alendronate	O
+,	O
+the	O
+patient	O
+underwent	O
+six	O
+cycles	O
+of	O
+hemodialysis	O
+and	O
+four	O
+cycles	O
+of	O
+LDL	O
+apheresis	O
+.	O
+
+Urinary	O
+volume	O
+and	O
+serum	O
+creatinine	O
+levels	O
+recovered	O
+to	O
+the	O
+normal	O
+range	O
+,	O
+with	O
+urinary	O
+protein	O
+disappearing	O
+completely	O
+within	O
+40	O
+days	O
+.	O
+
+This	O
+report	O
+demonstrates	O
+that	O
+not	O
+only	O
+intravenous	O
+,	O
+but	O
+also	O
+oral	O
+bisphosphonates	O
+can	O
+aggravate	O
+proteinuria	B
+and	O
+acute	B
+renal	I
+failure	I
+.	O
+
+Serum	O
+-	O
+and	O
+glucocorticoid	O
+-	O
+inducible	O
+kinase	O
+1	O
+in	O
+doxorubicin	O
+-	O
+induced	O
+nephrotic	B
+syndrome	I
+.	O
+
+Doxorubicin	O
+-	O
+induced	O
+nephropathy	B
+leads	O
+to	O
+epithelial	O
+sodium	O
+channel	O
+(	O
+ENaC	O
+)	O
+-	O
+dependent	O
+volume	B
+retention	I
+and	O
+renal	O
+fibrosis	B
+.	O
+
+The	O
+aldosterone	O
+-	O
+sensitive	O
+serum	O
+-	O
+and	O
+glucocorticoid	O
+-	O
+inducible	O
+kinase	O
+SGK1	O
+has	O
+been	O
+shown	O
+to	O
+participate	O
+in	O
+the	O
+stimulation	O
+of	O
+ENaC	O
+and	O
+to	O
+mediate	O
+renal	O
+fibrosis	B
+following	O
+mineralocorticoid	O
+and	O
+salt	O
+excess	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+performed	O
+to	O
+elucidate	O
+the	O
+role	O
+of	O
+SGK1	O
+in	O
+the	O
+volume	B
+retention	I
+and	O
+fibrosis	B
+during	O
+nephrotic	B
+syndrome	I
+.	O
+
+To	O
+this	O
+end	O
+,	O
+doxorubicin	O
+(	O
+15	O
+mug	O
+/	O
+g	O
+body	O
+wt	O
+)	O
+was	O
+injected	O
+intravenously	O
+into	O
+gene	O
+-	O
+targeted	O
+mice	O
+lacking	O
+SGK1	O
+(	O
+sgk1	O
+(	O
+-	O
+/	O
+-	O
+)	O
+)	O
+and	O
+their	O
+wild	O
+-	O
+type	O
+littermates	O
+(	O
+sgk1	O
+(	O
++	O
+/	O
++	O
+)	O
+)	O
+.	O
+
+Doxorubicin	O
+treatment	O
+resulted	O
+in	O
+heavy	O
+proteinuria	B
+(	O
+>	O
+100	O
+mg	O
+protein	O
+/	O
+mg	O
+crea	O
+)	O
+in	O
+15	O
+/	O
+44	O
+of	O
+sgk1	O
+(	O
++	O
+/	O
++	O
+)	O
+and	O
+15	O
+/	O
+44	O
+of	O
+sgk1	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+leading	O
+to	O
+severe	O
+nephrotic	B
+syndrome	I
+with	O
+ascites	B
+,	O
+lipidemia	B
+,	O
+and	O
+hypoalbuminemia	B
+in	O
+both	O
+genotypes	O
+.	O
+
+Plasma	O
+aldosterone	O
+levels	O
+increased	O
+in	O
+nephrotic	B
+mice	O
+of	O
+both	O
+genotypes	O
+and	O
+was	O
+followed	O
+by	O
+increased	O
+SGK1	O
+protein	O
+expression	O
+in	O
+sgk1	O
+(	O
++	O
+/	O
++	O
+)	O
+mice	O
+.	O
+
+Urinary	O
+sodium	O
+excretion	O
+reached	O
+signficantly	O
+lower	O
+values	O
+in	O
+sgk1	O
+(	O
++	O
+/	O
++	O
+)	O
+mice	O
+(	O
+15	O
++	O
+/	O
+-	O
+5	O
+mumol	O
+/	O
+mg	O
+crea	O
+)	O
+than	O
+in	O
+sgk1	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+(	O
+35	O
++	O
+/	O
+-	O
+5	O
+mumol	O
+/	O
+mg	O
+crea	O
+)	O
+and	O
+was	O
+associated	O
+with	O
+a	O
+significantly	O
+higher	O
+body	O
+weight	B
+gain	I
+in	O
+sgk1	O
+(	O
++	O
+/	O
++	O
+)	O
+compared	O
+with	O
+sgk1	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+(	O
++	O
+6	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+vs	O
+.	O
++	O
+4	O
+.	O
+1	O
++	O
+/	O
+-	O
+0	O
+.	O
+8	O
+g	O
+)	O
+.	O
+
+During	O
+the	O
+course	O
+of	O
+nephrotic	B
+syndrome	I
+,	O
+serum	O
+urea	O
+concentrations	O
+increased	O
+significantly	O
+faster	O
+in	O
+sgk1	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+than	O
+in	O
+sgk1	O
+(	O
++	O
+/	O
++	O
+)	O
+mice	O
+leading	O
+to	O
+uremia	B
+and	O
+a	O
+reduced	O
+median	O
+survival	O
+in	O
+sgk1	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+(	O
+29	O
+vs	O
+.	O
+40	O
+days	O
+in	O
+sgk1	O
+(	O
++	O
+/	O
++	O
+)	O
+mice	O
+)	O
+.	O
+
+In	O
+conclusion	O
+,	O
+gene	O
+-	O
+targeted	O
+mice	O
+lacking	O
+SGK1	O
+showed	O
+blunted	O
+volume	B
+retention	I
+,	O
+yet	O
+were	O
+not	O
+protected	O
+against	O
+renal	O
+fibrosis	B
+during	O
+experimental	O
+nephrotic	B
+syndrome	I
+.	O
+
+Severe	O
+thrombocytopenia	B
+and	O
+haemolytic	B
+anaemia	I
+associated	O
+with	O
+ciprofloxacin	O
+:	O
+a	O
+case	O
+report	O
+with	O
+fatal	O
+outcome	O
+.	O
+
+Haematological	O
+adverse	O
+reactions	O
+associated	O
+with	O
+fatal	O
+outcome	O
+are	O
+rare	O
+during	O
+treatment	O
+with	O
+ciprofloxacin	O
+.	O
+
+A	O
+30	O
+-	O
+year	O
+old	O
+Caucasian	O
+man	O
+reported	O
+with	O
+abdominal	B
+pain	I
+and	O
+jaundice	B
+after	O
+3	O
+-	O
+day	O
+administration	O
+of	O
+oral	O
+ciprofloxacin	O
+for	O
+a	O
+suspect	O
+of	O
+urinary	B
+tract	I
+infection	I
+.	O
+
+Clinical	O
+evaluations	O
+suggested	O
+an	O
+initial	O
+diagnosis	O
+of	O
+severe	O
+thrombocytopenia	B
+and	O
+haemolysis	B
+.	O
+
+The	O
+patient	O
+progressively	O
+developed	O
+petechiae	B
+and	O
+purpura	B
+on	O
+thorax	O
+and	O
+lower	O
+limbs	O
+.	O
+
+Despite	O
+pharmacological	O
+and	O
+supportive	O
+interventions	O
+,	O
+laboratory	O
+parameters	O
+worsened	O
+and	O
+the	O
+patient	O
+died	O
+17	O
+hours	O
+after	O
+admission	O
+.	O
+
+An	O
+accurate	O
+autopsy	O
+revealed	O
+most	O
+organs	O
+with	O
+diffuse	O
+petechial	O
+haemorrhages	B
+.	O
+
+No	O
+signs	O
+of	O
+bone	B
+marrow	I
+depression	I
+were	O
+found	O
+.	O
+
+No	O
+thrombi	B
+or	O
+signs	O
+of	O
+microangiopathies	B
+were	O
+observed	O
+in	O
+arterial	O
+vessels	O
+.	O
+
+Blood	O
+and	O
+urine	O
+cultures	O
+did	O
+not	O
+show	O
+any	O
+bacterial	O
+growth	O
+.	O
+
+This	O
+case	O
+report	O
+shows	O
+that	O
+ciprofloxacin	O
+may	O
+precipitate	O
+life	O
+-	O
+threatening	O
+thrombocytopenia	B
+and	O
+haemolytic	B
+anaemia	I
+,	O
+even	O
+in	O
+the	O
+early	O
+phases	O
+of	O
+treatment	O
+and	O
+without	O
+apparent	O
+previous	O
+exposures	O
+.	O
+
+Alpha	O
+-	O
+lipoic	O
+acid	O
+prevents	O
+mitochondrial	B
+damage	I
+and	O
+neurotoxicity	B
+in	O
+experimental	O
+chemotherapy	O
+neuropathy	B
+.	O
+
+The	O
+study	O
+investigates	O
+if	O
+alpha	O
+-	O
+lipoic	O
+acid	O
+is	O
+neuroprotective	O
+against	O
+chemotherapy	O
+induced	O
+neurotoxicity	B
+,	O
+if	O
+mitochondrial	B
+damage	I
+plays	O
+a	O
+critical	O
+role	O
+in	O
+toxic	B
+neurodegenerative	I
+cascade	I
+,	O
+and	O
+if	O
+neuroprotective	O
+effects	O
+of	O
+alpha	O
+-	O
+lipoic	O
+acid	O
+depend	O
+on	O
+mitochondria	O
+protection	O
+.	O
+
+We	O
+used	O
+an	O
+in	O
+vitro	O
+model	O
+of	O
+chemotherapy	O
+induced	O
+peripheral	B
+neuropathy	I
+that	O
+closely	O
+mimic	O
+the	O
+in	O
+vivo	O
+condition	O
+by	O
+exposing	O
+primary	O
+cultures	O
+of	O
+dorsal	O
+root	O
+ganglion	O
+(	O
+DRG	O
+)	O
+sensory	O
+neurons	O
+to	O
+paclitaxel	O
+and	O
+cisplatin	O
+,	O
+two	O
+widely	O
+used	O
+and	O
+highly	O
+effective	O
+chemotherapeutic	O
+drugs	O
+.	O
+
+This	O
+approach	O
+allowed	O
+investigating	O
+the	O
+efficacy	O
+of	O
+alpha	O
+-	O
+lipoic	O
+acid	O
+in	O
+preventing	O
+axonal	B
+damage	I
+and	O
+apoptosis	O
+and	O
+the	O
+function	O
+and	O
+ultrastructural	O
+morphology	O
+of	O
+mitochondria	O
+after	O
+exposure	O
+to	O
+toxic	O
+agents	O
+and	O
+alpha	O
+-	O
+lipoic	O
+acid	O
+.	O
+
+Our	O
+results	O
+demonstrate	O
+that	O
+both	O
+cisplatin	O
+and	O
+paclitaxel	O
+cause	O
+early	O
+mitochondrial	B
+impairment	I
+with	O
+loss	O
+of	O
+membrane	O
+potential	O
+and	O
+induction	O
+of	O
+autophagic	O
+vacuoles	O
+in	O
+neurons	O
+.	O
+
+Alpha	O
+-	O
+lipoic	O
+acid	O
+exerts	O
+neuroprotective	O
+effects	O
+against	O
+chemotherapy	O
+induced	O
+neurotoxicity	B
+in	O
+sensory	O
+neurons	O
+:	O
+it	O
+rescues	O
+the	O
+mitochondrial	B
+toxicity	I
+and	O
+induces	O
+the	O
+expression	O
+of	O
+frataxin	O
+,	O
+an	O
+essential	O
+mitochondrial	O
+protein	O
+with	O
+anti	O
+-	O
+oxidant	O
+and	O
+chaperone	O
+properties	O
+.	O
+
+In	O
+conclusion	O
+mitochondrial	B
+toxicity	I
+is	O
+an	O
+early	O
+common	O
+event	O
+both	O
+in	O
+paclitaxel	O
+and	O
+cisplatin	O
+induced	O
+neurotoxicity	B
+.	O
+
+Alpha	O
+-	O
+lipoic	O
+acid	O
+protects	O
+sensory	O
+neurons	O
+through	O
+its	O
+anti	O
+-	O
+oxidant	O
+and	O
+mitochondrial	O
+regulatory	O
+functions	O
+,	O
+possibly	O
+inducing	O
+the	O
+expression	O
+of	O
+frataxin	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+alpha	O
+-	O
+lipoic	O
+acid	O
+might	O
+reduce	O
+the	O
+risk	O
+of	O
+developing	O
+peripheral	B
+nerve	I
+toxicity	I
+in	O
+patients	O
+undergoing	O
+chemotherapy	O
+and	O
+encourage	O
+further	O
+confirmatory	O
+clinical	O
+trials	O
+.	O
+
+Toxicity	B
+in	O
+rhesus	O
+monkeys	O
+following	O
+administration	O
+of	O
+the	O
+8	O
+-	O
+aminoquinoline	O
+8	O
+-	O
+[	O
+(	O
+4	O
+-	O
+amino	O
+-	O
+l	O
+-	O
+methylbutyl	O
+)	O
+amino	O
+]	O
+-	O
+5	O
+-	O
+(	O
+l	O
+-	O
+hexyloxy	O
+)	O
+-	O
+6	O
+-	O
+methoxy	O
+-	O
+4	O
+-	O
+methylquinoline	O
+(	O
+WR242511	O
+)	O
+.	O
+
+INTRODUCTION	O
+:	O
+Many	O
+substances	O
+that	O
+form	O
+methemoglobin	O
+(	O
+MHb	O
+)	O
+effectively	O
+counter	O
+cyanide	O
+(	O
+CN	O
+)	O
+toxicity	B
+.	O
+
+Although	O
+MHb	O
+formers	O
+are	O
+generally	O
+applied	O
+as	O
+treatments	O
+for	O
+CN	O
+poisoning	B
+,	O
+it	O
+has	O
+been	O
+proposed	O
+that	O
+a	O
+stable	O
+,	O
+long	O
+-	O
+acting	O
+MHb	O
+former	O
+could	O
+serve	O
+as	O
+a	O
+CN	O
+pretreatment	O
+.	O
+
+Using	O
+this	O
+rationale	O
+,	O
+the	O
+8	O
+-	O
+aminoquinoline	O
+WR242511	O
+,	O
+a	O
+potent	O
+long	O
+-	O
+lasting	O
+MHb	O
+former	O
+in	O
+rodents	O
+and	O
+beagle	O
+dogs	O
+,	O
+was	O
+studied	O
+in	O
+the	O
+rhesus	O
+monkey	O
+for	O
+advanced	O
+development	O
+as	O
+a	O
+potential	O
+CN	O
+pretreatment	O
+.	O
+
+METHODS	O
+:	O
+In	O
+this	O
+study	O
+,	O
+WR242511	O
+was	O
+administered	O
+intravenously	O
+(	O
+IV	O
+)	O
+in	O
+2	O
+female	O
+and	O
+4	O
+male	O
+rhesus	O
+monkeys	O
+in	O
+doses	O
+of	O
+3	O
+.	O
+5	O
+and	O
+/	O
+or	O
+7	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+;	O
+a	O
+single	O
+male	O
+also	O
+received	O
+WR242511	O
+orally	O
+(	O
+PO	O
+)	O
+at	O
+7	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+.	O
+
+Health	O
+status	O
+and	O
+MHb	O
+levels	O
+were	O
+monitored	O
+following	O
+exposure	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+selected	O
+doses	O
+of	O
+WR242511	O
+,	O
+which	O
+produced	O
+significant	O
+methemoglobinemia	B
+in	O
+beagle	O
+dogs	O
+in	O
+earlier	O
+studies	O
+conducted	O
+elsewhere	O
+,	O
+produced	O
+very	O
+little	O
+MHb	O
+(	O
+mean	O
+<	O
+2	O
+.	O
+0	O
+%	O
+)	O
+in	O
+the	O
+rhesus	O
+monkey	O
+.	O
+
+Furthermore	O
+,	O
+transient	O
+hemoglobinuria	B
+was	O
+noted	O
+approximately	O
+60	O
+minutes	O
+postinjection	O
+of	O
+WR242511	O
+(	O
+3	O
+.	O
+5	O
+or	O
+7	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+and	O
+2	O
+lethalities	O
+occurred	O
+(	O
+one	O
+IV	O
+and	O
+one	O
+PO	O
+)	O
+following	O
+the	O
+7	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+dose	O
+.	O
+
+Myoglobinuria	B
+was	O
+also	O
+observed	O
+following	O
+the	O
+7	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+dose	O
+.	O
+
+Histopathology	O
+analyses	O
+in	O
+the	O
+2	O
+animals	O
+that	O
+died	O
+revealed	O
+liver	B
+and	I
+kidney	I
+toxicity	I
+,	O
+with	O
+greater	O
+severity	O
+in	O
+the	O
+orally	O
+-	O
+treated	O
+animal	O
+.	O
+
+CONCLUSIONS	O
+:	O
+These	O
+data	O
+demonstrate	O
+direct	O
+and	O
+/	O
+or	O
+indirect	O
+drug	O
+-	O
+induced	O
+toxicity	B
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+WR242511	O
+should	O
+not	O
+be	O
+pursued	O
+as	O
+a	O
+pretreatment	O
+for	O
+CN	O
+poisoning	B
+unless	O
+the	O
+anti	O
+-	O
+CN	O
+characteristics	O
+of	O
+this	O
+compound	O
+can	O
+be	O
+successfully	O
+dissociated	O
+from	O
+those	O
+producing	O
+undesirable	O
+toxicity	B
+.	O
+
+Repetitive	O
+transcranial	O
+magnetic	O
+stimulation	O
+for	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+In	O
+a	O
+placebo	O
+-	O
+controlled	O
+,	O
+single	O
+-	O
+blinded	O
+,	O
+crossover	O
+study	O
+,	O
+we	O
+assessed	O
+the	O
+effect	O
+of	O
+"	O
+real	O
+"	O
+repetitive	O
+transcranial	O
+magnetic	O
+stimulation	O
+(	O
+rTMS	O
+)	O
+versus	O
+"	O
+sham	O
+"	O
+rTMS	O
+(	O
+placebo	O
+)	O
+on	O
+peak	O
+dose	O
+dyskinesias	B
+in	O
+patients	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+.	O
+
+Ten	O
+patients	O
+with	O
+PD	B
+and	O
+prominent	O
+dyskinesias	B
+had	O
+rTMS	O
+(	O
+1	O
+,	O
+800	O
+pulses	O
+;	O
+1	O
+Hz	O
+rate	O
+)	O
+delivered	O
+over	O
+the	O
+motor	O
+cortex	O
+for	O
+4	O
+consecutive	O
+days	O
+twice	O
+,	O
+once	O
+real	O
+stimuli	O
+and	O
+once	O
+sham	O
+stimulation	O
+were	O
+used	O
+;	O
+evaluations	O
+were	O
+done	O
+at	O
+the	O
+baseline	O
+and	O
+1	O
+day	O
+after	O
+the	O
+end	O
+of	O
+each	O
+of	O
+the	O
+treatment	O
+series	O
+.	O
+
+Direct	O
+comparison	O
+between	O
+sham	O
+and	O
+real	O
+rTMS	O
+effects	O
+showed	O
+no	O
+significant	O
+difference	O
+in	O
+clinician	O
+-	O
+assessed	O
+dyskinesia	B
+severity	O
+.	O
+
+However	O
+,	O
+comparison	O
+with	O
+the	O
+baseline	O
+showed	O
+small	O
+but	O
+significant	O
+reduction	O
+in	O
+dyskinesia	B
+severity	O
+following	O
+real	O
+rTMS	O
+but	O
+not	O
+placebo	O
+.	O
+
+The	O
+major	O
+effect	O
+was	O
+on	O
+dystonia	B
+subscore	O
+.	O
+
+Similarly	O
+,	O
+in	O
+patient	O
+diaries	O
+,	O
+although	O
+both	O
+treatments	O
+caused	O
+reduction	O
+in	O
+subjective	O
+dyskinesia	B
+scores	O
+during	O
+the	O
+days	O
+of	O
+intervention	O
+,	O
+the	O
+effect	O
+was	O
+sustained	O
+for	O
+3	O
+days	O
+after	O
+the	O
+intervention	O
+for	O
+the	O
+real	O
+rTMS	O
+only	O
+.	O
+
+Following	O
+rTMS	O
+,	O
+no	O
+side	O
+effects	O
+and	O
+no	O
+adverse	O
+effects	O
+on	O
+motor	O
+function	O
+and	O
+PD	B
+symptoms	O
+were	O
+noted	O
+.	O
+
+The	O
+results	O
+suggest	O
+the	O
+existence	O
+of	O
+residual	O
+beneficial	O
+clinical	O
+aftereffects	O
+of	O
+consecutive	O
+daily	O
+applications	O
+of	O
+low	O
+-	O
+frequency	O
+rTMS	O
+on	O
+dyskinesias	B
+in	O
+PD	B
+.	O
+
+The	O
+effects	O
+may	O
+be	O
+further	O
+exploited	O
+for	O
+potential	O
+therapeutic	O
+uses	O
+.	O
+
+Intracavernous	O
+epinephrine	O
+:	O
+a	O
+minimally	O
+invasive	O
+treatment	O
+for	O
+priapism	B
+in	O
+the	O
+emergency	O
+department	O
+.	O
+
+Priapism	B
+is	O
+the	O
+prolonged	O
+erection	O
+of	O
+the	O
+penis	O
+in	O
+the	O
+absence	O
+of	O
+sexual	O
+arousal	O
+.	O
+
+A	O
+45	O
+-	O
+year	O
+-	O
+old	O
+man	O
+,	O
+an	O
+admitted	O
+frequent	O
+cocaine	O
+user	O
+,	O
+presented	O
+to	O
+the	O
+Emergency	O
+Department	O
+(	O
+ED	O
+)	O
+on	O
+two	O
+separate	O
+occasions	O
+with	O
+a	O
+history	O
+of	O
+priapism	B
+after	O
+cocaine	O
+use	O
+.	O
+
+The	O
+management	O
+options	O
+in	O
+the	O
+ED	O
+,	O
+as	O
+exemplified	O
+by	O
+four	O
+individual	O
+case	O
+reports	O
+,	O
+in	O
+particular	O
+the	O
+use	O
+of	O
+a	O
+minimally	O
+invasive	O
+method	O
+of	O
+intracorporal	O
+epinephrine	O
+instillation	O
+,	O
+are	O
+discussed	O
+.	O
+
+Prophylactic	O
+use	O
+of	O
+lamivudine	O
+with	O
+chronic	O
+immunosuppressive	O
+therapy	O
+for	O
+rheumatologic	B
+disorders	I
+.	O
+
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+report	O
+our	O
+experience	O
+concerning	O
+the	O
+effectiveness	O
+of	O
+the	O
+prophylactic	O
+administration	O
+of	O
+lamivudine	O
+in	O
+hepatitis	O
+B	O
+virus	O
+surface	O
+antigen	O
+(	O
+HBs	O
+Ag	O
+)	O
+positive	O
+patients	O
+with	O
+rheumatologic	B
+disease	I
+.	O
+
+From	O
+June	O
+2004	O
+to	O
+October	O
+2006	O
+,	O
+11	O
+HBs	O
+Ag	O
+positive	O
+patients	O
+with	O
+rheumatologic	B
+diseases	I
+,	O
+who	O
+were	O
+on	O
+both	O
+immunosuppressive	O
+and	O
+prophylactic	O
+lamivudine	O
+therapies	O
+,	O
+were	O
+retrospectively	O
+assessed	O
+.	O
+
+Liver	O
+function	O
+tests	O
+,	O
+hepatitis	B
+B	I
+virus	O
+(	O
+HBV	O
+)	O
+serologic	O
+markers	O
+,	O
+and	O
+HBV	O
+DNA	O
+levels	O
+of	O
+the	O
+patients	O
+during	O
+follow	O
+-	O
+up	O
+were	O
+obtained	O
+from	O
+hospital	O
+file	O
+records	O
+.	O
+
+Eleven	O
+patients	O
+(	O
+six	O
+male	O
+)	O
+with	O
+median	O
+age	O
+47	O
+years	O
+(	O
+range	O
+27	O
+-	O
+73	O
+)	O
+,	O
+median	O
+disease	O
+duration	O
+50	O
+months	O
+(	O
+range	O
+9	O
+-	O
+178	O
+)	O
+and	O
+median	O
+follow	O
+-	O
+up	O
+period	O
+of	O
+patients	O
+13	O
+.	O
+8	O
+months	O
+(	O
+range	O
+5	O
+-	O
+27	O
+)	O
+were	O
+enrolled	O
+in	O
+this	O
+study	O
+.	O
+
+Lamivudine	O
+therapy	O
+was	O
+started	O
+3	O
+-	O
+7	O
+days	O
+prior	O
+to	O
+immunosuppressive	O
+therapy	O
+in	O
+all	O
+patients	O
+.	O
+
+Baseline	O
+,	O
+liver	O
+function	O
+tests	O
+were	O
+elevated	O
+in	O
+two	O
+patients	O
+(	O
+fourth	O
+patient	O
+:	O
+ALT	O
+:	O
+122	O
+IU	O
+/	O
+l	O
+,	O
+AST	O
+:	O
+111	O
+IU	O
+/	O
+l	O
+,	O
+tenth	O
+patient	O
+:	O
+ALT	O
+:	O
+294	O
+IU	O
+/	O
+l	O
+,	O
+AST	O
+:	O
+274	O
+IU	O
+/	O
+l	O
+,	O
+with	O
+minimal	O
+changes	O
+in	O
+the	O
+liver	O
+biopsy	O
+in	O
+both	O
+)	O
+.	O
+
+Shortly	O
+after	O
+treatment	O
+their	O
+tests	O
+normalized	O
+and	O
+during	O
+follow	O
+-	O
+up	O
+period	O
+none	O
+of	O
+the	O
+patients	O
+had	O
+abnormal	B
+liver	I
+function	I
+tests	O
+.	O
+
+In	O
+four	O
+patients	O
+HBV	O
+DNA	O
+levels	O
+were	O
+higher	O
+than	O
+normal	O
+at	O
+baseline	O
+.	O
+
+Two	O
+of	O
+these	O
+normalized	O
+and	O
+the	O
+others	O
+increased	O
+later	O
+.	O
+
+In	O
+three	O
+additional	O
+patients	O
+,	O
+HBV	O
+DNA	O
+levels	O
+were	O
+increased	O
+during	O
+follow	O
+-	O
+up	O
+.	O
+
+None	O
+of	O
+the	O
+patients	O
+had	O
+significant	O
+clinical	O
+sings	O
+of	O
+HBV	O
+activation	O
+.	O
+
+Lamivudine	O
+was	O
+well	O
+tolerated	O
+and	O
+was	O
+continued	O
+in	O
+all	O
+patients	O
+.	O
+
+Prophylactic	O
+administration	O
+of	O
+lamivudine	O
+in	O
+patients	O
+who	O
+required	O
+immunosuppressive	O
+therapy	O
+seems	O
+to	O
+be	O
+safe	O
+,	O
+well	O
+tolerated	O
+and	O
+effective	O
+in	O
+preventing	O
+HBV	O
+reactivation	O
+.	O
+
+Effect	O
+of	O
+green	O
+tea	O
+and	O
+vitamin	O
+E	O
+combination	O
+in	O
+isoproterenol	O
+induced	O
+myocardial	B
+infarction	I
+in	O
+rats	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+aimed	O
+to	O
+investigate	O
+the	O
+combined	O
+effects	O
+of	O
+green	O
+tea	O
+and	O
+vitamin	O
+E	O
+on	O
+heart	O
+weight	O
+,	O
+body	O
+weight	O
+,	O
+serum	O
+marker	O
+enzymes	O
+,	O
+lipid	O
+peroxidation	O
+,	O
+endogenous	O
+antioxidants	O
+and	O
+membrane	O
+bound	O
+ATPases	O
+in	O
+isoproterenol	O
+(	O
+ISO	O
+)	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+in	O
+rats	O
+.	O
+
+Adult	O
+male	O
+albino	O
+rats	O
+,	O
+treated	O
+with	O
+ISO	O
+(	O
+200	O
+mg	O
+/	O
+kg	O
+,	O
+s	O
+.	O
+c	O
+.	O
+)	O
+for	O
+2	O
+days	O
+at	O
+an	O
+interval	O
+of	O
+24	O
+h	O
+caused	O
+a	O
+significant	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+elevation	O
+of	O
+heart	O
+weight	O
+,	O
+serum	O
+marker	O
+enzymes	O
+,	O
+lipid	O
+peroxidation	O
+and	O
+Ca	O
++	O
+2	O
+ATPase	O
+level	O
+whereas	O
+there	O
+was	O
+a	O
+significant	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+decrease	O
+in	O
+body	O
+weight	O
+,	O
+endogenous	O
+antioxidants	O
+,	O
+Na	O
++	O
+/	O
+K	O
++	O
+ATPase	O
+and	O
+Mg	O
++	O
+2	O
+ATPase	O
+levels	O
+.	O
+
+Administration	O
+of	O
+green	O
+tea	O
+(	O
+100	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+,	O
+p	O
+.	O
+o	O
+.	O
+)	O
+and	O
+vitamin	O
+E	O
+(	O
+100	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+,	O
+p	O
+.	O
+o	O
+.	O
+)	O
+together	O
+for	O
+30	O
+consecutive	O
+days	O
+and	O
+challenged	O
+with	O
+ISO	O
+on	O
+the	O
+day	O
+29th	O
+and	O
+30th	O
+,	O
+showed	O
+a	O
+significant	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+decrease	O
+in	O
+heart	O
+weight	O
+,	O
+serum	O
+marker	O
+enzymes	O
+,	O
+lipid	O
+peroxidation	O
+,	O
+Ca	O
++	O
+2	O
+ATPase	O
+and	O
+a	O
+significant	O
+increase	O
+in	O
+the	O
+body	O
+weight	O
+,	O
+endogenous	O
+antioxidants	O
+,	O
+Na	O
++	O
+/	O
+K	O
++	O
+ATPase	O
+and	O
+Mg	O
++	O
+2	O
+ATPase	O
+when	O
+compared	O
+with	O
+ISO	O
+treated	O
+group	O
+and	O
+green	O
+tea	O
+or	O
+vitamin	O
+E	O
+alone	O
+treated	O
+groups	O
+.	O
+
+These	O
+findings	O
+indicate	O
+the	O
+synergistic	O
+protective	O
+effect	O
+of	O
+green	O
+tea	O
+and	O
+vitamin	O
+E	O
+during	O
+ISO	O
+induced	O
+myocardial	B
+infarction	I
+in	O
+rats	O
+.	O
+
+Irreversible	O
+damage	O
+to	O
+the	O
+medullary	O
+interstitium	O
+in	O
+experimental	O
+analgesic	O
+nephropathy	B
+in	O
+F344	O
+rats	O
+.	O
+
+Renal	B
+papillary	I
+necrosis	I
+(	O
+RPN	B
+)	O
+and	O
+a	O
+decreased	O
+urinary	O
+concentrating	O
+ability	O
+developed	O
+during	O
+continuous	O
+long	O
+-	O
+term	O
+treatment	O
+with	O
+aspirin	O
+and	O
+paracetamol	O
+in	O
+female	O
+Fischer	O
+344	O
+rats	O
+.	O
+
+Renal	O
+structure	O
+and	O
+concentrating	O
+ability	O
+were	O
+examined	O
+after	O
+a	O
+recovery	O
+period	O
+of	O
+up	O
+to	O
+18	O
+weeks	O
+,	O
+when	O
+no	O
+analgesics	O
+were	O
+given	O
+,	O
+to	O
+investigate	O
+whether	O
+the	O
+analgesic	O
+-	O
+induced	O
+changes	O
+were	O
+reversible	O
+.	O
+
+There	O
+was	O
+no	O
+evidence	O
+of	O
+repair	O
+to	O
+the	O
+damaged	O
+medullary	O
+interstitial	O
+matrix	O
+,	O
+or	O
+proliferation	O
+of	O
+remaining	O
+undamaged	O
+type	O
+1	O
+medullary	O
+interstitial	O
+cells	O
+after	O
+the	O
+recovery	O
+period	O
+following	O
+analgesic	O
+treatment	O
+.	O
+
+The	O
+recovery	O
+of	O
+urinary	O
+concentrating	O
+ability	O
+was	O
+related	O
+to	O
+the	O
+length	O
+of	O
+analgesic	O
+treatment	O
+and	O
+the	O
+extent	O
+of	O
+the	O
+resulting	O
+inner	O
+medullary	O
+structural	O
+damage	O
+.	O
+
+During	O
+the	O
+early	O
+stages	O
+of	O
+analgesic	O
+treatment	O
+,	O
+the	O
+changes	O
+in	O
+urinary	O
+concentrating	O
+ability	O
+were	O
+reversible	O
+,	O
+but	O
+after	O
+prolonged	O
+analgesic	O
+treatment	O
+,	O
+maximum	O
+urinary	O
+concentrating	O
+ability	O
+failed	O
+to	O
+recover	O
+.	O
+
+This	O
+study	O
+shows	O
+that	O
+prolonged	O
+analgesic	O
+treatment	O
+in	O
+Fischer	O
+344	O
+rats	O
+causes	O
+progressive	O
+and	O
+irreversible	O
+damage	O
+to	O
+the	O
+interstitial	O
+matrix	O
+and	O
+type	O
+1	O
+interstitial	O
+cells	O
+leading	O
+to	O
+RPN	B
+.	O
+
+The	O
+associated	O
+urinary	O
+concentrating	O
+defect	O
+is	O
+reversible	O
+only	O
+during	O
+the	O
+early	O
+stages	O
+of	O
+structural	O
+damage	O
+to	O
+the	O
+inner	O
+medulla	O
+.	O
+
+Testosterone	O
+-	O
+dependent	O
+hypertension	B
+and	O
+upregulation	O
+of	O
+intrarenal	O
+angiotensinogen	O
+in	O
+Dahl	O
+salt	O
+-	O
+sensitive	O
+rats	O
+.	O
+
+Blood	O
+pressure	O
+(	O
+BP	O
+)	O
+is	O
+more	O
+salt	O
+sensitive	O
+in	O
+men	O
+than	O
+in	O
+premenopausal	O
+women	O
+.	O
+
+In	O
+Dahl	O
+salt	O
+-	O
+sensitive	O
+rats	O
+(	O
+DS	O
+)	O
+,	O
+high	O
+-	O
+salt	O
+(	O
+HS	O
+)	O
+diet	O
+increases	O
+BP	O
+more	O
+in	O
+males	O
+than	O
+females	O
+.	O
+
+In	O
+contrast	O
+to	O
+the	O
+systemic	O
+renin	O
+-	O
+angiotensin	O
+system	O
+,	O
+which	O
+is	O
+suppressed	O
+in	O
+response	O
+to	O
+HS	O
+in	O
+male	O
+DS	O
+,	O
+intrarenal	O
+angiotensinogen	O
+expression	O
+is	O
+increased	O
+,	O
+and	O
+intrarenal	O
+levels	O
+of	O
+ANG	O
+II	O
+are	O
+not	O
+suppressed	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+the	O
+hypothesis	O
+was	O
+tested	O
+that	O
+there	O
+is	O
+a	O
+sexual	O
+dimorphism	O
+in	O
+HS	O
+-	O
+induced	O
+upregulation	O
+of	O
+intrarenal	O
+angiotensinogen	O
+mediated	O
+by	O
+testosterone	O
+that	O
+also	O
+causes	O
+increases	O
+in	O
+BP	O
+and	O
+renal	B
+injury	I
+.	O
+
+On	O
+a	O
+low	O
+-	O
+salt	O
+(	O
+LS	O
+)	O
+diet	O
+,	O
+male	O
+DS	O
+had	O
+higher	O
+levels	O
+of	O
+intrarenal	O
+angiotensinogen	O
+mRNA	O
+than	O
+females	O
+.	O
+
+HS	O
+diet	O
+for	O
+4	O
+wk	O
+increased	O
+renal	O
+cortical	O
+angiotensinogen	O
+mRNA	O
+and	O
+protein	O
+only	O
+in	O
+male	O
+DS	O
+,	O
+which	O
+was	O
+prevented	O
+by	O
+castration	O
+.	O
+
+Ovariectomy	O
+of	O
+female	O
+DS	O
+had	O
+no	O
+effect	O
+on	O
+intrarenal	O
+angiotensinogen	O
+expression	O
+on	O
+either	O
+diet	O
+.	O
+
+Radiotelemetric	O
+BP	O
+was	O
+similar	O
+between	O
+males	O
+and	O
+castrated	O
+rats	O
+on	O
+LS	O
+diet	O
+.	O
+
+HS	O
+diet	O
+for	O
+4	O
+wk	O
+caused	O
+a	O
+progressive	O
+increase	O
+in	O
+BP	O
+,	O
+protein	O
+and	O
+albumin	O
+excretion	O
+,	O
+and	O
+glomerular	B
+sclerosis	I
+in	O
+male	O
+DS	O
+rats	O
+,	O
+which	O
+were	O
+attenuated	O
+by	O
+castration	O
+.	O
+
+Testosterone	O
+replacement	O
+in	O
+castrated	O
+DS	O
+rats	O
+increased	O
+BP	O
+,	O
+renal	B
+injury	I
+,	O
+and	O
+upregulation	O
+of	O
+renal	O
+angiotensinogen	O
+associated	O
+with	O
+HS	O
+diet	O
+.	O
+
+Testosterone	O
+contributes	O
+to	O
+the	O
+development	O
+of	O
+hypertension	B
+and	O
+renal	B
+injury	I
+in	O
+male	O
+DS	O
+rats	O
+on	O
+HS	O
+diet	O
+possibly	O
+through	O
+upregulation	O
+of	O
+the	O
+intrarenal	O
+renin	O
+-	O
+angiotensin	O
+system	O
+.	O
+
+Explicit	O
+episodic	O
+memory	O
+for	O
+sensory	O
+-	O
+discriminative	O
+components	O
+of	O
+capsaicin	O
+-	O
+induced	O
+pain	B
+:	O
+immediate	O
+and	O
+delayed	O
+ratings	O
+.	O
+
+Pain	B
+memory	O
+is	O
+thought	O
+to	O
+affect	O
+future	O
+pain	B
+sensitivity	O
+and	O
+thus	O
+contribute	O
+to	O
+clinical	O
+pain	B
+conditions	O
+.	O
+
+Systematic	O
+investigations	O
+of	O
+the	O
+human	O
+capacity	O
+to	O
+remember	O
+sensory	O
+features	O
+of	O
+experimental	O
+pain	B
+are	O
+sparse	O
+.	O
+
+In	O
+order	O
+to	O
+address	O
+long	O
+-	O
+term	O
+pain	B
+memory	O
+,	O
+nine	O
+healthy	O
+male	O
+volunteers	O
+received	O
+intradermal	O
+injections	O
+of	O
+three	O
+doses	O
+of	O
+capsaicin	O
+(	O
+0	O
+.	O
+05	O
+,	O
+1	O
+and	O
+20	O
+microg	O
+,	O
+separated	O
+by	O
+15	O
+min	O
+breaks	O
+)	O
+,	O
+each	O
+given	O
+three	O
+times	O
+in	O
+a	O
+balanced	O
+design	O
+across	O
+three	O
+sessions	O
+at	O
+one	O
+week	O
+intervals	O
+.	O
+
+Pain	B
+rating	O
+was	O
+performed	O
+using	O
+a	O
+computerized	O
+visual	O
+analogue	O
+scale	O
+(	O
+0	O
+-	O
+100	O
+)	O
+digitized	O
+at	O
+1	O
+/	O
+s	O
+,	O
+either	O
+immediately	O
+online	O
+or	O
+one	O
+hour	O
+or	O
+one	O
+day	O
+after	O
+injection	O
+.	O
+
+Subjects	O
+also	O
+recalled	O
+their	O
+pains	B
+one	O
+week	O
+later	O
+.	O
+
+Capsaicin	O
+injection	O
+reliably	O
+induced	O
+a	O
+dose	O
+-	O
+dependent	O
+flare	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+without	O
+any	O
+difference	O
+within	O
+or	O
+across	O
+sessions	O
+.	O
+
+The	O
+strong	O
+burning	O
+pain	B
+decayed	O
+exponentially	O
+within	O
+a	O
+few	O
+minutes	O
+.	O
+
+Subjects	O
+were	O
+able	O
+to	O
+reliably	O
+discriminate	O
+pain	B
+magnitude	O
+and	O
+duration	O
+across	O
+capsaicin	O
+doses	O
+(	O
+both	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+,	O
+regardless	O
+of	O
+whether	O
+first	O
+-	O
+time	O
+ratings	O
+were	O
+requested	O
+immediately	O
+,	O
+after	O
+one	O
+hour	O
+or	O
+after	O
+one	O
+day	O
+.	O
+
+Pain	B
+recall	O
+after	O
+one	O
+week	O
+was	O
+similarly	O
+precise	O
+(	O
+magnitude	O
+:	O
+p	O
+<	O
+0	O
+.	O
+01	O
+,	O
+duration	O
+:	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Correlation	O
+with	O
+rating	O
+recall	O
+after	O
+one	O
+week	O
+was	O
+best	O
+when	O
+first	O
+-	O
+time	O
+ratings	O
+were	O
+requested	O
+as	O
+late	O
+as	O
+one	O
+day	O
+after	O
+injection	O
+(	O
+R	O
+(	O
+2	O
+)	O
+=	O
+0	O
+.	O
+79	O
+)	O
+indicating	O
+that	O
+both	O
+rating	O
+retrievals	O
+utilized	O
+similar	O
+memory	O
+traces	O
+.	O
+
+These	O
+results	O
+indicate	O
+a	O
+reliable	O
+memory	O
+for	O
+magnitude	O
+and	O
+duration	O
+of	O
+experimentally	O
+induced	O
+pain	B
+.	O
+
+The	O
+data	O
+further	O
+suggest	O
+that	O
+the	O
+consolidation	O
+of	O
+this	O
+memory	O
+is	O
+an	O
+important	O
+interim	O
+stage	O
+,	O
+and	O
+may	O
+take	O
+up	O
+to	O
+one	O
+day	O
+.	O
+
+Severe	O
+and	O
+long	O
+lasting	O
+cholestasis	B
+after	O
+high	O
+-	O
+dose	O
+co	O
+-	O
+trimoxazole	O
+treatment	O
+for	O
+Pneumocystis	B
+pneumonia	I
+in	O
+HIV	B
+-	I
+infected	I
+patients	O
+-	O
+-	O
+a	O
+report	O
+of	O
+two	O
+cases	O
+.	O
+
+Pneumocystis	B
+pneumonia	I
+(	O
+PCP	B
+)	O
+,	O
+a	O
+common	O
+opportunistic	B
+infection	I
+in	O
+HIV	B
+-	I
+infected	I
+individuals	O
+,	O
+is	O
+generally	O
+treated	O
+with	O
+high	O
+doses	O
+of	O
+co	O
+-	O
+trimoxazole	O
+.	O
+
+However	O
+,	O
+treatment	O
+is	O
+often	O
+limited	O
+by	O
+adverse	O
+effects	O
+.	O
+
+Here	O
+,	O
+we	O
+report	O
+two	O
+cases	O
+of	O
+severely	O
+immunocompromised	O
+HIV	B
+-	I
+infected	I
+patients	O
+who	O
+developed	O
+severe	O
+intrahepatic	B
+cholestasis	I
+,	O
+and	O
+in	O
+one	O
+patient	O
+lesions	O
+mimicking	O
+liver	B
+abscess	I
+formation	O
+on	O
+radiologic	O
+exams	O
+,	O
+during	O
+co	O
+-	O
+trimoxazole	O
+treatment	O
+for	O
+PCP	B
+.	O
+
+Whereas	O
+patient	O
+1	O
+showed	O
+lesions	O
+of	O
+up	O
+to	O
+1	O
+cm	O
+readily	O
+detectable	O
+on	O
+magnetic	O
+resonance	O
+imaging	O
+under	O
+prolonged	O
+co	O
+-	O
+trimoxazole	O
+treatment	O
+,	O
+therapy	O
+of	O
+patient	O
+2	O
+was	O
+switched	O
+early	O
+.	O
+
+Bradykinin	O
+receptors	O
+antagonists	O
+and	O
+nitric	O
+oxide	O
+synthase	O
+inhibitors	O
+in	O
+vincristine	O
+and	O
+streptozotocin	O
+induced	O
+hyperalgesia	B
+in	O
+chemotherapy	O
+and	O
+diabetic	B
+neuropathy	I
+rat	O
+model	O
+.	O
+
+PURPOSE	O
+:	O
+The	O
+influence	O
+of	O
+an	O
+irreversible	O
+inhibitor	O
+of	O
+constitutive	O
+NO	O
+synthase	O
+(	O
+L	O
+-	O
+NOArg	O
+;	O
+1	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+ip	O
+)	O
+,	O
+a	O
+relatively	O
+selective	O
+inhibitor	O
+of	O
+inducible	O
+NO	O
+synthase	O
+(	O
+L	O
+-	O
+NIL	O
+;	O
+1	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+ip	O
+)	O
+and	O
+a	O
+relatively	O
+specific	O
+inhibitor	O
+of	O
+neuronal	O
+NO	O
+synthase	O
+(	O
+7	O
+-	O
+NI	O
+;	O
+0	O
+.	O
+1	O
+mg	O
+/	O
+kg	O
+ip	O
+)	O
+,	O
+on	O
+antihyperalgesic	O
+action	O
+of	O
+selective	O
+antagonists	O
+of	O
+B2	O
+and	O
+B1	O
+receptors	O
+:	O
+D	O
+-	O
+Arg	O
+-	O
+[	O
+Hyp3	O
+,	O
+Thi5	O
+,	O
+D	O
+-	O
+Tic7	O
+,	O
+Oic8	O
+]	O
+bradykinin	O
+(	O
+HOE	O
+140	O
+;	O
+70	O
+nmol	O
+/	O
+kg	O
+ip	O
+)	O
+or	O
+des	O
+Arg10	O
+HOE	O
+140	O
+(	O
+70	O
+nmol	O
+/	O
+kg	O
+ip	O
+)	O
+respectively	O
+,	O
+in	O
+model	O
+of	O
+diabetic	B
+(	I
+streptozotocin	I
+-	I
+induced	I
+)	I
+and	I
+toxic	I
+(	I
+vincristine	I
+-	I
+induced	I
+)	I
+neuropathy	I
+was	O
+investigated	O
+.	O
+
+METHODS	O
+:	O
+The	O
+changes	O
+in	O
+pain	B
+thresholds	O
+were	O
+determined	O
+using	O
+mechanical	O
+stimuli	O
+-	O
+-	O
+the	O
+modification	O
+of	O
+the	O
+classic	O
+paw	O
+withdrawal	O
+test	O
+described	O
+by	O
+Randall	O
+-	O
+Selitto	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+results	O
+of	O
+this	O
+paper	O
+confirm	O
+that	O
+inhibition	O
+of	O
+bradykinin	O
+receptors	O
+and	O
+inducible	O
+NO	O
+synthase	O
+but	O
+not	O
+neuronal	O
+NO	O
+synthase	O
+activity	O
+reduces	O
+diabetic	B
+hyperalgesia	I
+.	O
+
+Pretreatment	O
+with	O
+L	O
+-	O
+NOArg	O
+and	O
+L	O
+-	O
+NIL	O
+but	O
+not	O
+7	O
+-	O
+NI	O
+,	O
+significantly	O
+increases	O
+antihyperalgesic	O
+activity	O
+both	O
+HOE	O
+140	O
+and	O
+des	O
+Arg10	O
+HOE	O
+140	O
+.	O
+
+It	O
+was	O
+also	O
+shown	O
+that	O
+both	O
+products	O
+of	O
+inducible	O
+NO	O
+synthase	O
+and	O
+neuronal	O
+NO	O
+synthase	O
+activation	O
+as	O
+well	O
+as	O
+bradykinin	O
+are	O
+involved	O
+in	O
+hyperalgesia	B
+produced	O
+by	O
+vincristine	O
+.	O
+
+Moreover	O
+,	O
+L	O
+-	O
+NOArg	O
+and	O
+7	O
+-	O
+NI	O
+but	O
+not	O
+L	O
+-	O
+NIL	O
+intensify	O
+antihyperalgesic	O
+activity	O
+of	O
+HOE	O
+140	O
+or	O
+des	O
+-	O
+Arg10HOE	O
+140	O
+in	O
+toxic	B
+neuropathy	I
+.	O
+
+CONCLUSIONS	O
+:	O
+Results	O
+of	O
+these	O
+studies	O
+suggest	O
+that	O
+B1	O
+and	O
+B2	O
+receptors	O
+are	O
+engaged	O
+in	O
+transmission	O
+of	O
+nociceptive	O
+stimuli	O
+in	O
+both	O
+diabetic	B
+and	I
+toxic	I
+neuropathy	I
+.	O
+
+In	O
+streptozotocin	O
+-	O
+induced	O
+hyperalgesia	B
+,	O
+inducible	O
+NO	O
+synthase	O
+participates	O
+in	O
+pronociceptive	O
+activity	O
+of	O
+bradykinin	O
+,	O
+whereas	O
+in	O
+vincristine	O
+-	O
+induced	O
+hyperalgesia	B
+bradykinin	O
+seemed	O
+to	O
+activate	O
+neuronal	O
+NO	O
+synthase	O
+pathway	O
+.	O
+
+Therefore	O
+,	O
+concomitant	O
+administration	O
+of	O
+small	O
+doses	O
+of	O
+bradykinin	O
+receptor	O
+antagonists	O
+and	O
+NO	O
+synthase	O
+inhibitors	O
+can	O
+be	O
+effective	O
+in	O
+alleviation	O
+of	O
+neuropathic	B
+pain	I
+,	O
+even	O
+in	O
+hospital	O
+care	O
+.	O
+
+Confusion	B
+,	O
+a	O
+rather	O
+serious	O
+adverse	O
+drug	O
+reaction	O
+with	O
+valproic	O
+acid	O
+:	O
+a	O
+review	O
+of	O
+the	O
+French	O
+Pharmacovigilance	O
+database	O
+.	O
+
+INTRODUCTION	O
+:	O
+Confusion	B
+is	O
+an	O
+adverse	O
+drug	O
+reaction	O
+frequently	O
+observed	O
+with	O
+valproic	O
+acid	O
+.	O
+
+Some	O
+case	O
+reports	O
+are	O
+published	O
+in	O
+the	O
+literature	O
+but	O
+no	O
+systematic	O
+study	O
+from	O
+a	O
+sample	O
+of	O
+patients	O
+has	O
+been	O
+published	O
+.	O
+
+We	O
+performed	O
+this	O
+study	O
+in	O
+order	O
+to	O
+describe	O
+the	O
+main	O
+characteristics	O
+of	O
+this	O
+adverse	O
+drug	O
+reaction	O
+.	O
+
+METHODS	O
+:	O
+Using	O
+the	O
+French	O
+Pharmacovigilance	O
+database	O
+,	O
+we	O
+selected	O
+the	O
+cases	O
+of	O
+confusion	B
+reported	O
+since	O
+1985	O
+with	O
+valproic	O
+acid	O
+.	O
+
+RESULTS	O
+:	O
+272	O
+cases	O
+of	O
+confusion	B
+were	O
+reported	O
+with	O
+valproic	O
+acid	O
+:	O
+153	O
+women	O
+and	O
+119	O
+men	O
+.	O
+
+Confusion	B
+mostly	O
+occurred	O
+during	O
+the	O
+two	O
+first	O
+weeks	O
+following	O
+valproic	O
+acid	O
+exposure	O
+(	O
+39	O
+.	O
+7	O
+%	O
+)	O
+.	O
+
+It	O
+was	O
+"	O
+serious	O
+"	O
+for	O
+almost	O
+2	O
+/	O
+3	O
+of	O
+the	O
+patients	O
+(	O
+62	O
+.	O
+5	O
+%	O
+)	O
+and	O
+its	O
+outcome	O
+favourable	O
+in	O
+most	O
+of	O
+the	O
+cases	O
+(	O
+82	O
+%	O
+)	O
+.	O
+
+The	O
+occurrence	O
+of	O
+this	O
+ADR	O
+was	O
+more	O
+frequent	O
+in	O
+patients	O
+aged	O
+between	O
+61	O
+and	O
+80	O
+years	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+work	O
+shows	O
+that	O
+confusion	B
+with	O
+valproic	O
+acid	O
+is	O
+a	O
+serious	O
+,	O
+rather	O
+frequent	O
+but	O
+reversible	O
+adverse	O
+drug	O
+reaction	O
+.	O
+
+It	O
+occurs	O
+especially	O
+in	O
+older	O
+patients	O
+and	O
+during	O
+the	O
+first	O
+two	O
+weeks	O
+of	O
+treatment	O
+.	O
+
+Reversible	O
+inferior	B
+colliculus	I
+lesion	I
+in	O
+metronidazole	O
+-	O
+induced	O
+encephalopathy	B
+:	O
+magnetic	O
+resonance	O
+findings	O
+on	O
+diffusion	O
+-	O
+weighted	O
+and	O
+fluid	O
+attenuated	O
+inversion	O
+recovery	O
+imaging	O
+.	O
+
+OBJECTIVE	O
+:	O
+This	O
+is	O
+to	O
+present	O
+reversible	O
+inferior	B
+colliculus	I
+lesions	I
+in	O
+metronidazole	O
+-	O
+induced	O
+encephalopathy	B
+,	O
+to	O
+focus	O
+on	O
+the	O
+diffusion	O
+-	O
+weighted	O
+imaging	O
+(	O
+DWI	O
+)	O
+and	O
+fluid	O
+attenuated	O
+inversion	O
+recovery	O
+(	O
+FLAIR	O
+)	O
+imaging	O
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+From	O
+November	O
+2005	O
+to	O
+September	O
+2007	O
+,	O
+8	O
+patients	O
+(	O
+5	O
+men	O
+and	O
+3	O
+women	O
+)	O
+were	O
+diagnosed	O
+as	O
+having	O
+metronidazole	O
+-	O
+induced	O
+encephalopathy	B
+(	O
+age	O
+range	O
+;	O
+43	O
+-	O
+78	O
+years	O
+)	O
+.	O
+
+They	O
+had	O
+been	O
+taking	O
+metronidazole	O
+(	O
+total	O
+dosage	O
+,	O
+45	O
+-	O
+120	O
+g	O
+;	O
+duration	O
+,	O
+30	O
+days	O
+to	O
+2	O
+months	O
+)	O
+to	O
+treat	O
+the	O
+infection	B
+in	O
+various	O
+organs	O
+.	O
+
+Initial	O
+brain	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+were	O
+obtained	O
+after	O
+the	O
+hospitalization	O
+,	O
+including	O
+DWI	O
+(	O
+8	O
+/	O
+8	O
+)	O
+,	O
+apparent	O
+diffusion	O
+coefficient	O
+(	O
+ADC	O
+)	O
+map	O
+(	O
+4	O
+/	O
+8	O
+)	O
+,	O
+FLAIR	O
+(	O
+7	O
+/	O
+8	O
+)	O
+,	O
+and	O
+T2	O
+-	O
+weighted	O
+image	O
+(	O
+8	O
+/	O
+8	O
+)	O
+.	O
+
+Follow	O
+-	O
+up	O
+MRIs	O
+were	O
+performed	O
+on	O
+5	O
+patients	O
+from	O
+third	O
+to	O
+14th	O
+days	O
+after	O
+discontinuation	O
+of	O
+metronidazole	O
+administration	O
+.	O
+
+Findings	O
+of	O
+initial	O
+and	O
+follow	O
+-	O
+up	O
+MRIs	O
+were	O
+retrospectively	O
+evaluated	O
+by	O
+2	O
+neuroradiologists	O
+by	O
+consensus	O
+,	O
+to	O
+analyze	O
+the	O
+presence	O
+of	O
+abnormal	O
+signal	O
+intensities	O
+,	O
+their	O
+locations	O
+,	O
+and	O
+signal	O
+changes	O
+on	O
+follow	O
+-	O
+up	O
+images	O
+.	O
+
+RESULTS	O
+:	O
+Initial	O
+MRIs	O
+showed	O
+abnormal	O
+high	O
+signal	O
+intensities	O
+on	O
+DWI	O
+and	O
+FLAIR	O
+(	O
+or	O
+T2	O
+-	O
+weighted	O
+image	O
+)	O
+at	O
+the	O
+dentate	O
+nucleus	O
+(	O
+8	O
+/	O
+8	O
+)	O
+,	O
+inferior	O
+colliculus	O
+(	O
+6	O
+/	O
+8	O
+)	O
+,	O
+corpus	O
+callosum	O
+(	O
+2	O
+/	O
+8	O
+)	O
+,	O
+pons	O
+(	O
+2	O
+/	O
+8	O
+)	O
+,	O
+medulla	O
+(	O
+1	O
+/	O
+8	O
+)	O
+,	O
+and	O
+bilateral	O
+cerebral	O
+white	O
+matter	O
+(	O
+1	O
+/	O
+8	O
+)	O
+.	O
+
+High	O
+-	O
+signal	O
+intensity	O
+lesions	O
+on	O
+DWI	O
+tended	O
+to	O
+show	O
+low	O
+signal	O
+intensity	O
+on	O
+ADC	O
+map	O
+(	O
+3	O
+/	O
+4	O
+)	O
+,	O
+but	O
+in	O
+one	O
+patient	O
+,	O
+high	O
+signal	O
+intensity	O
+was	O
+shown	O
+at	O
+bilateral	O
+dentate	O
+nuclei	O
+on	O
+not	O
+only	O
+DWI	O
+but	O
+also	O
+ADC	O
+map	O
+.	O
+
+All	O
+the	O
+lesions	O
+in	O
+dentate	O
+,	O
+inferior	O
+colliculus	O
+,	O
+pons	O
+,	O
+and	O
+medullas	O
+had	O
+been	O
+resolved	O
+completely	O
+on	O
+follow	O
+-	O
+up	O
+MRIs	O
+in	O
+5	O
+patients	O
+,	O
+but	O
+in	O
+1	O
+patient	O
+of	O
+them	O
+,	O
+corpus	O
+callosal	B
+lesion	I
+persisted	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Reversible	O
+inferior	B
+colliculus	I
+lesions	I
+could	O
+be	O
+considered	O
+as	O
+the	O
+characteristic	O
+for	O
+metronidazole	O
+-	O
+induced	O
+encephalopathy	B
+,	O
+next	O
+to	O
+the	O
+dentate	O
+nucleus	O
+involvement	O
+.	O
+
+Clinically	O
+significant	O
+proteinuria	B
+following	O
+the	O
+administration	O
+of	O
+sirolimus	O
+to	O
+renal	O
+transplant	O
+recipients	O
+.	O
+
+BACKGROUND	O
+:	O
+Sirolimus	O
+is	O
+the	O
+latest	O
+immunosuppressive	O
+agent	O
+used	O
+to	O
+prevent	O
+rejection	O
+,	O
+and	O
+may	O
+have	O
+less	O
+nephrotoxicity	B
+than	O
+calcineurin	O
+inhibitor	O
+(	O
+CNI	O
+)	O
+-	O
+based	O
+regimens	O
+.	O
+
+To	O
+date	O
+there	O
+has	O
+been	O
+little	O
+documentation	O
+of	O
+clinically	O
+significant	O
+proteinuria	B
+linked	O
+with	O
+the	O
+use	O
+of	O
+sirolimus	O
+.	O
+
+We	O
+have	O
+encountered	O
+several	O
+patients	O
+who	O
+developed	O
+substantial	O
+proteinuria	B
+associated	O
+with	O
+sirolimus	O
+use	O
+.	O
+
+In	O
+each	O
+patient	O
+,	O
+the	O
+close	O
+temporal	O
+association	O
+between	O
+the	O
+commencement	O
+of	O
+sirolimus	O
+therapy	O
+and	O
+proteinuria	B
+implicated	O
+sirolimus	O
+as	O
+the	O
+most	O
+likely	O
+etiology	O
+of	O
+the	O
+proteinuria	B
+.	O
+
+METHODS	O
+:	O
+We	O
+analyzed	O
+the	O
+clinical	O
+and	O
+laboratory	O
+information	O
+available	O
+for	O
+all	O
+119	O
+patients	O
+transplanted	O
+at	O
+the	O
+Washington	O
+Hospital	O
+Center	O
+between	O
+1999	O
+-	O
+2003	O
+for	O
+whom	O
+sirolimus	O
+was	O
+a	O
+component	O
+of	O
+their	O
+immunosuppressant	O
+regimen	O
+.	O
+
+In	O
+these	O
+patients	O
+,	O
+the	O
+magnitude	O
+of	O
+proteinuria	B
+was	O
+assessed	O
+on	O
+morning	O
+urine	O
+samples	O
+by	O
+turbidometric	O
+measurement	O
+or	O
+random	O
+urine	O
+protein	O
+:	O
+creatinine	O
+ratios	O
+,	O
+an	O
+estimate	O
+of	O
+grams	O
+of	O
+proteinuria	B
+/	O
+day	O
+.	O
+
+Laboratory	O
+results	O
+were	O
+compared	O
+between	O
+prior	O
+,	O
+during	O
+and	O
+following	O
+sirolimus	O
+use	O
+.	O
+
+RESULTS	O
+:	O
+Twenty	O
+-	O
+eight	O
+patients	O
+(	O
+24	O
+%	O
+)	O
+developed	O
+increased	O
+proteinuria	B
+from	O
+baseline	O
+during	O
+their	O
+post	O
+-	O
+transplantation	O
+course	O
+.	O
+
+In	O
+21	O
+patients	O
+an	O
+alternative	O
+cause	O
+of	O
+proteinuria	B
+was	O
+either	O
+obvious	O
+or	O
+insufficient	O
+data	O
+was	O
+available	O
+to	O
+be	O
+conclusive	O
+.	O
+
+In	O
+7	O
+of	O
+the	O
+28	O
+patients	O
+there	O
+was	O
+a	O
+striking	O
+temporal	O
+association	O
+between	O
+the	O
+initiation	O
+of	O
+sirolimus	O
+and	O
+the	O
+development	O
+of	O
+nephrotic	B
+-	O
+range	O
+proteinuria	B
+.	O
+
+Proteinuria	B
+correlated	O
+most	O
+strongly	O
+with	O
+sirolimus	O
+therapy	O
+when	O
+compared	O
+to	O
+other	O
+demographic	O
+and	O
+clinical	O
+variables	O
+.	O
+
+In	O
+most	O
+patients	O
+,	O
+discontinuation	O
+of	O
+sirolimus	O
+resulted	O
+in	O
+a	O
+decrease	O
+,	O
+but	O
+not	O
+resolution	O
+,	O
+of	O
+proteinuria	B
+.	O
+
+CONCLUSIONS	O
+:	O
+Sirolimus	O
+induces	O
+or	O
+aggravates	O
+pre	O
+-	O
+existing	O
+proteinuria	B
+in	O
+an	O
+unpredictable	O
+subset	O
+of	O
+renal	O
+allograft	O
+recipients	O
+.	O
+
+Proteinuria	B
+may	O
+improve	O
+,	O
+but	O
+does	O
+not	O
+resolve	O
+,	O
+when	O
+sirolimus	O
+is	O
+withdrawn	O
+.	O
+
+Components	O
+of	O
+lemon	O
+essential	O
+oil	O
+attenuate	O
+dementia	B
+induced	O
+by	O
+scopolamine	O
+.	O
+
+The	O
+anti	O
+-	O
+dementia	B
+effects	O
+of	O
+s	O
+-	O
+limonene	O
+and	O
+s	O
+-	O
+perillyl	O
+alcohol	O
+were	O
+observed	O
+using	O
+the	O
+passive	O
+avoidance	O
+test	O
+(	O
+PA	O
+)	O
+and	O
+the	O
+open	O
+field	O
+habituation	O
+test	O
+(	O
+OFH	O
+)	O
+.	O
+
+These	O
+lemon	O
+essential	O
+oils	O
+showed	O
+strong	O
+ability	O
+to	O
+improve	O
+memory	B
+impaired	I
+by	O
+scopolamine	O
+;	O
+however	O
+,	O
+s	O
+-	O
+perillyl	O
+alcohol	O
+relieved	O
+the	O
+deficit	B
+of	I
+associative	I
+memory	I
+in	O
+PA	O
+only	O
+,	O
+and	O
+did	O
+not	O
+improve	O
+non	O
+-	O
+associative	O
+memory	O
+significantly	O
+in	O
+OFH	O
+.	O
+
+Analysis	O
+of	O
+neurotransmitter	O
+concentration	O
+in	O
+some	O
+brain	O
+regions	O
+on	O
+the	O
+test	O
+day	O
+showed	O
+that	O
+dopamine	O
+concentration	O
+of	O
+the	O
+vehicle	O
+/	O
+scopolamine	O
+group	O
+was	O
+significantly	O
+lower	O
+than	O
+that	O
+of	O
+the	O
+vehicle	O
+/	O
+vehicle	O
+group	O
+,	O
+but	O
+this	O
+phenomenon	O
+was	O
+reversed	O
+when	O
+s	O
+-	O
+limonene	O
+or	O
+s	O
+-	O
+perillyl	O
+alcohol	O
+were	O
+administered	O
+before	O
+the	O
+injection	O
+of	O
+scopolamine	O
+.	O
+
+Simultaneously	O
+,	O
+we	O
+found	O
+that	O
+these	O
+two	O
+lemon	O
+essential	O
+oil	O
+components	O
+could	O
+inhibit	O
+acetylcholinesterase	O
+activity	O
+in	O
+vitro	O
+using	O
+the	O
+Ellman	O
+method	O
+.	O
+
+Attentional	O
+modulation	O
+of	O
+perceived	O
+pain	B
+intensity	O
+in	O
+capsaicin	O
+-	O
+induced	O
+secondary	O
+hyperalgesia	B
+.	O
+
+Perceived	O
+pain	B
+intensity	O
+is	O
+modulated	O
+by	O
+attention	O
+.	O
+
+However	O
+,	O
+it	O
+is	O
+not	O
+known	O
+that	O
+how	O
+pain	B
+intensity	O
+ratings	O
+are	O
+affected	O
+by	O
+attention	O
+in	O
+capsaicin	O
+-	O
+induced	O
+secondary	O
+hyperalgesia	B
+.	O
+
+Here	O
+we	O
+show	O
+that	O
+perceived	O
+pain	B
+intensity	O
+in	O
+secondary	O
+hyperalgesia	B
+is	O
+decreased	O
+when	O
+attention	O
+is	O
+distracted	O
+away	O
+from	O
+the	O
+painful	O
+pinprick	O
+stimulus	O
+with	O
+a	O
+visual	O
+task	O
+.	O
+
+Furthermore	O
+,	O
+it	O
+was	O
+found	O
+that	O
+the	O
+magnitude	O
+of	O
+attentional	O
+modulation	O
+in	O
+secondary	O
+hyperalgesia	B
+is	O
+very	O
+similar	O
+to	O
+that	O
+of	O
+capsaicin	O
+-	O
+untreated	O
+,	O
+control	O
+condition	O
+.	O
+
+Our	O
+findings	O
+,	O
+showing	O
+no	O
+interaction	O
+between	O
+capsaicin	O
+treatment	O
+and	O
+attentional	O
+modulation	O
+suggest	O
+that	O
+capsaicin	O
+-	O
+induced	O
+secondary	O
+hyperalgesia	B
+and	O
+attention	O
+might	O
+affect	O
+mechanical	O
+pain	B
+through	O
+independent	O
+mechanisms	O
+.	O
+
+Cardioprotective	O
+effect	O
+of	O
+salvianolic	O
+acid	O
+A	O
+on	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+in	O
+rats	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+evaluate	O
+the	O
+cardioprotective	O
+potential	O
+of	O
+salvianolic	O
+acid	O
+A	O
+on	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+in	O
+rats	O
+.	O
+
+Hemodynamic	O
+parameters	O
+and	O
+lead	O
+II	O
+electrocardiograph	O
+were	O
+monitored	O
+and	O
+recorded	O
+continuously	O
+.	O
+
+Cardiac	O
+marker	O
+enzymes	O
+and	O
+antioxidative	O
+parameters	O
+in	O
+serum	O
+and	O
+heart	O
+tissues	O
+were	O
+measured	O
+.	O
+
+Assay	O
+for	O
+mitochondrial	O
+respiratory	O
+function	O
+and	O
+histopathological	O
+examination	O
+of	O
+heart	O
+tissues	O
+were	O
+performed	O
+.	O
+
+Isoproterenol	O
+-	O
+treated	O
+rats	O
+showed	O
+significant	O
+increases	O
+in	O
+the	O
+levels	O
+of	O
+lactate	O
+dehydrogenase	O
+,	O
+aspartate	O
+transaminase	O
+,	O
+creatine	O
+kinase	O
+and	O
+malondialdehyde	O
+and	O
+significant	O
+decreases	O
+in	O
+the	O
+activities	O
+of	O
+superoxide	O
+dismutase	O
+,	O
+catalase	O
+and	O
+glutathione	O
+peroxidase	O
+in	O
+serum	O
+and	O
+heart	O
+.	O
+
+These	O
+rats	O
+also	O
+showed	O
+declines	O
+in	O
+left	O
+ventricular	O
+systolic	O
+pressure	O
+,	O
+maximum	O
+and	O
+minimum	O
+rate	O
+of	O
+developed	O
+left	O
+ventricular	O
+pressure	O
+,	O
+and	O
+elevation	O
+of	O
+left	O
+ventricular	O
+end	O
+-	O
+diastolic	O
+pressure	O
+and	O
+ST	O
+-	O
+segment	O
+.	O
+
+In	O
+addition	O
+,	O
+mitochondrial	O
+respiratory	B
+dysfunction	I
+characterized	O
+by	O
+decreased	O
+respiratory	O
+control	O
+ratio	O
+and	O
+ADP	O
+/	O
+O	O
+was	O
+observed	O
+in	O
+isoproterenol	O
+-	O
+treated	O
+rats	O
+.	O
+
+Administration	O
+of	O
+salvianolic	O
+acid	O
+A	O
+for	O
+a	O
+period	O
+of	O
+8	O
+days	O
+significantly	O
+attenuated	O
+isoproterenol	O
+-	O
+induced	O
+cardiac	B
+dysfunction	I
+and	O
+myocardial	B
+injury	I
+and	O
+improved	O
+mitochondrial	O
+respiratory	O
+function	O
+.	O
+
+The	O
+protective	O
+role	O
+of	O
+salvianolic	O
+acid	O
+A	O
+against	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+damage	I
+was	O
+further	O
+confirmed	O
+by	O
+histopathological	O
+examination	O
+.	O
+
+The	O
+results	O
+of	O
+our	O
+study	O
+suggest	O
+that	O
+salvianolic	O
+acid	O
+A	O
+possessing	O
+antioxidant	O
+activity	O
+has	O
+a	O
+significant	O
+protective	O
+effect	O
+against	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+.	O
+
+Long	O
+-	O
+term	O
+glutamate	O
+supplementation	O
+failed	O
+to	O
+protect	O
+against	O
+peripheral	B
+neurotoxicity	I
+of	O
+paclitaxel	O
+.	O
+
+Toxic	O
+peripheral	B
+neuropathy	I
+is	O
+still	O
+a	O
+significant	O
+limiting	O
+factor	O
+for	O
+chemotherapy	O
+with	O
+paclitaxel	O
+(	O
+PAC	O
+)	O
+,	O
+although	O
+glutamate	O
+and	O
+its	O
+closely	O
+related	O
+amino	O
+acid	O
+glutamine	O
+were	O
+claimed	O
+to	O
+ameliorate	O
+PAC	O
+neurotoxicity	B
+.	O
+
+This	O
+pilot	O
+trial	O
+aimed	O
+to	O
+evaluate	O
+the	O
+role	O
+of	O
+glutamate	O
+supplementation	O
+for	O
+preventing	O
+PAC	O
+-	O
+induced	O
+peripheral	B
+neuropathy	I
+in	O
+a	O
+randomized	O
+,	O
+placebo	O
+-	O
+controlled	O
+,	O
+double	O
+-	O
+blinded	O
+clinical	O
+and	O
+electro	O
+-	O
+diagnostic	O
+study	O
+.	O
+
+Forty	O
+-	O
+three	O
+ovarian	B
+cancer	I
+patients	O
+were	O
+available	O
+for	O
+analysis	O
+following	O
+six	O
+cycles	O
+of	O
+the	O
+same	O
+PAC	O
+-	O
+containing	O
+regimen	O
+:	O
+23	O
+had	O
+been	O
+supplemented	O
+by	O
+glutamate	O
+all	O
+along	O
+the	O
+treatment	O
+period	O
+,	O
+at	O
+a	O
+daily	O
+dose	O
+of	O
+three	O
+times	O
+500	O
+mg	O
+(	O
+group	O
+G	O
+)	O
+,	O
+and	O
+20	O
+had	O
+received	O
+a	O
+placebo	O
+(	O
+group	O
+P	O
+)	O
+.	O
+
+Patients	O
+were	O
+evaluated	O
+by	O
+neurological	O
+examinations	O
+,	O
+questionnaires	O
+and	O
+sensory	O
+-	O
+motor	O
+nerve	O
+conduction	O
+studies	O
+.	O
+
+There	O
+was	O
+no	O
+significant	O
+difference	O
+in	O
+the	O
+frequency	O
+of	O
+signs	O
+or	O
+symptoms	O
+between	O
+the	O
+two	O
+groups	O
+although	O
+neurotoxicity	B
+symptoms	O
+presented	O
+mostly	O
+with	O
+lower	O
+scores	O
+of	O
+severity	O
+in	O
+group	O
+G	O
+.	O
+
+However	O
+,	O
+this	O
+difference	O
+reached	O
+statistical	O
+significance	O
+only	O
+with	O
+regard	O
+to	O
+reported	O
+pain	B
+sensation	O
+(	O
+P	O
+=	O
+0	O
+.	O
+011	O
+)	O
+.	O
+
+Also	O
+the	O
+frequency	O
+of	O
+abnormal	O
+electro	O
+-	O
+diagnostic	O
+findings	O
+showed	O
+similarity	O
+between	O
+the	O
+two	O
+groups	O
+(	O
+G	O
+:	O
+7	O
+/	O
+23	O
+=	O
+30	O
+.	O
+4	O
+%	O
+;	O
+P	O
+:	O
+6	O
+/	O
+20	O
+=	O
+30	O
+%	O
+)	O
+.	O
+
+This	O
+pilot	O
+study	O
+leads	O
+to	O
+the	O
+conclusion	O
+that	O
+glutamate	O
+supplementation	O
+at	O
+the	O
+chosen	O
+regimen	O
+fails	O
+to	O
+protect	O
+against	O
+peripheral	B
+neurotoxicity	I
+of	O
+PAC	O
+.	O
+
+Development	O
+of	O
+ocular	B
+myasthenia	I
+during	O
+pegylated	O
+interferon	O
+and	O
+ribavirin	O
+treatment	O
+for	O
+chronic	B
+hepatitis	I
+C	I
+.	O
+
+A	O
+63	O
+-	O
+year	O
+-	O
+old	O
+male	O
+experienced	O
+sudden	O
+diplopia	B
+after	O
+9	O
+weeks	O
+of	O
+administration	O
+of	O
+pegylated	O
+interferon	O
+(	O
+IFN	O
+)	O
+alpha	O
+-	O
+2b	O
+and	O
+ribavirin	O
+for	O
+chronic	B
+hepatitis	I
+C	I
+(	O
+CHC	B
+)	O
+.	O
+
+Ophthalmologic	O
+examinations	O
+showed	O
+ptosis	B
+on	I
+the	I
+right	I
+upper	I
+lid	I
+and	O
+restricted	B
+right	I
+eye	I
+movement	I
+without	O
+any	O
+other	O
+neurological	O
+signs	O
+.	O
+
+A	O
+brain	O
+imaging	O
+study	O
+and	O
+repetitive	O
+nerve	O
+stimulation	O
+test	O
+indicated	O
+no	O
+abnormality	O
+.	O
+
+The	O
+acetylcholine	O
+receptor	O
+antibody	O
+titer	O
+and	O
+response	O
+to	O
+acetylcholinesterase	O
+inhibitors	O
+were	O
+negative	O
+,	O
+and	O
+the	O
+results	O
+of	O
+thyroid	O
+function	O
+tests	O
+were	O
+normal	O
+.	O
+
+The	O
+patient	O
+'	O
+s	O
+ophthalmological	O
+symptoms	O
+improved	O
+rapidly	O
+3	O
+weeks	O
+after	O
+discontinuation	O
+of	O
+pegylated	O
+IFN	O
+alpha	O
+-	O
+2b	O
+and	O
+ribavirin	O
+.	O
+
+The	O
+ocular	B
+myasthenia	I
+associated	O
+with	O
+combination	O
+therapy	O
+of	O
+pegylated	O
+IFN	O
+alpha	O
+-	O
+2b	O
+and	O
+ribavirin	O
+for	O
+CHC	B
+is	O
+very	O
+rarely	O
+reported	O
+;	O
+therefore	O
+,	O
+we	O
+present	O
+this	O
+case	O
+with	O
+a	O
+review	O
+of	O
+the	O
+various	O
+eye	O
+complications	O
+of	O
+IFN	O
+therapy	O
+.	O
+
+Learning	B
+and	I
+memory	I
+deficits	I
+in	O
+ecstasy	O
+users	O
+and	O
+their	O
+neural	O
+correlates	O
+during	O
+a	O
+face	O
+-	O
+learning	O
+task	O
+.	O
+
+It	O
+has	O
+been	O
+consistently	O
+shown	O
+that	O
+ecstasy	O
+users	O
+display	O
+impairments	B
+in	I
+learning	I
+and	I
+memory	I
+performance	O
+.	O
+
+In	O
+addition	O
+,	O
+working	O
+memory	O
+processing	O
+in	O
+ecstasy	O
+users	O
+has	O
+been	O
+shown	O
+to	O
+be	O
+associated	O
+with	O
+neural	O
+alterations	O
+in	O
+hippocampal	O
+and	O
+/	O
+or	O
+cortical	O
+regions	O
+as	O
+measured	O
+by	O
+functional	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+fMRI	O
+)	O
+.	O
+
+Using	O
+functional	O
+imaging	O
+and	O
+a	O
+face	O
+-	O
+learning	O
+task	O
+,	O
+we	O
+investigated	O
+neural	O
+correlates	O
+of	O
+encoding	O
+and	O
+recalling	O
+face	O
+-	O
+name	O
+associations	O
+in	O
+20	O
+recreational	O
+drug	O
+users	O
+whose	O
+predominant	O
+drug	O
+use	O
+was	O
+ecstasy	O
+and	O
+20	O
+controls	O
+.	O
+
+To	O
+address	O
+the	O
+potential	O
+confounding	O
+effects	O
+of	O
+the	O
+cannabis	O
+use	O
+of	O
+the	O
+ecstasy	O
+using	O
+group	O
+,	O
+a	O
+second	O
+analysis	O
+included	O
+14	O
+previously	O
+tested	O
+cannabis	O
+users	O
+(	O
+Nestor	O
+,	O
+L	O
+.	O
+,	O
+Roberts	O
+,	O
+G	O
+.	O
+,	O
+Garavan	O
+,	O
+H	O
+.	O
+,	O
+Hester	O
+,	O
+R	O
+.	O
+,	O
+2008	O
+.	O
+Deficits	B
+in	I
+learning	I
+and	I
+memory	I
+:	O
+parahippocampal	O
+hyperactivity	B
+and	O
+frontocortical	O
+hypoactivity	O
+in	O
+cannabis	O
+users	O
+.	O
+Neuroimage	O
+40	O
+,	O
+1328	O
+-	O
+1339	O
+)	O
+.	O
+
+Ecstasy	O
+users	O
+performed	O
+significantly	O
+worse	O
+in	O
+learning	O
+and	O
+memory	O
+compared	O
+to	O
+controls	O
+and	O
+cannabis	O
+users	O
+.	O
+
+A	O
+conjunction	O
+analysis	O
+of	O
+the	O
+encode	O
+and	O
+recall	O
+phases	O
+of	O
+the	O
+task	O
+revealed	O
+ecstasy	O
+-	O
+specific	O
+hyperactivity	B
+in	O
+bilateral	O
+frontal	O
+regions	O
+,	O
+left	O
+temporal	O
+,	O
+right	O
+parietal	O
+,	O
+bilateral	O
+temporal	O
+,	O
+and	O
+bilateral	O
+occipital	O
+brain	O
+regions	O
+.	O
+
+Ecstasy	O
+-	O
+specific	O
+hypoactivity	O
+was	O
+evident	O
+in	O
+the	O
+right	O
+dorsal	O
+anterior	O
+cingulated	O
+cortex	O
+(	O
+ACC	O
+)	O
+and	O
+left	O
+posterior	O
+cingulated	O
+cortex	O
+.	O
+
+In	O
+both	O
+ecstasy	O
+and	O
+cannabis	O
+groups	O
+brain	O
+activation	O
+was	O
+decreased	O
+in	O
+the	O
+right	O
+medial	O
+frontal	O
+gyrus	O
+,	O
+left	O
+parahippocampal	O
+gyrus	O
+,	O
+left	O
+dorsal	O
+cingulate	O
+gyrus	O
+,	O
+and	O
+left	O
+caudate	O
+.	O
+
+These	O
+results	O
+elucidated	O
+ecstasy	O
+-	O
+related	O
+deficits	O
+,	O
+only	O
+some	O
+of	O
+which	O
+might	O
+be	O
+attributed	O
+to	O
+cannabis	O
+use	O
+.	O
+
+These	O
+ecstasy	O
+-	O
+specific	O
+effects	O
+may	O
+be	O
+related	O
+to	O
+the	O
+vulnerability	O
+of	O
+isocortical	O
+and	O
+allocortical	O
+regions	O
+to	O
+the	O
+neurotoxic	B
+effects	O
+of	O
+ecstasy	O
+.	O
+
+Disulfiram	O
+-	O
+like	O
+syndrome	O
+after	O
+hydrogen	O
+cyanamide	O
+professional	O
+skin	O
+exposure	O
+:	O
+two	O
+case	O
+reports	O
+in	O
+France	O
+.	O
+
+Hydrogen	O
+cyanamide	O
+is	O
+a	O
+plant	O
+growth	O
+regulator	O
+used	O
+in	O
+agriculture	O
+to	O
+induce	O
+bud	O
+break	O
+in	O
+fruit	O
+trees	O
+.	O
+
+Contact	O
+with	O
+the	O
+skin	O
+can	O
+result	O
+in	O
+percutaneous	O
+absorption	O
+of	O
+the	O
+substance	O
+that	O
+inhibits	O
+aldehyde	O
+dehydrogenase	O
+and	O
+can	O
+induce	O
+acetaldehyde	O
+syndrome	O
+in	O
+case	O
+of	O
+alcohol	O
+use	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+report	O
+is	O
+to	O
+describe	O
+two	O
+cases	O
+of	O
+a	O
+disulfiram	O
+-	O
+like	O
+syndrome	O
+following	O
+occupational	O
+exposure	O
+to	O
+hydrogen	O
+cyanamide	O
+.	O
+
+The	O
+first	O
+case	O
+involved	O
+a	O
+59	O
+-	O
+year	O
+-	O
+old	O
+man	O
+who	O
+used	O
+Dormex	O
+,	O
+which	O
+contains	O
+hydrogen	O
+cyanamide	O
+,	O
+without	O
+protection	O
+after	O
+consuming	O
+a	O
+large	O
+amount	O
+of	O
+alcohol	O
+during	O
+a	O
+meal	O
+.	O
+
+In	O
+less	O
+than	O
+1	O
+hour	O
+after	O
+the	O
+ingestion	O
+of	O
+alcohol	O
+,	O
+he	O
+developed	O
+malaise	O
+with	O
+flushing	B
+of	I
+the	I
+face	I
+,	O
+tachycardia	B
+,	O
+and	O
+dyspnea	B
+.	O
+
+Manifestations	O
+regressed	O
+spontaneously	O
+under	O
+surveillance	O
+in	O
+the	O
+hospital	O
+.	O
+
+The	O
+second	O
+case	O
+occurred	O
+in	O
+a	O
+55	O
+-	O
+year	O
+-	O
+old	O
+farmer	O
+following	O
+cutaneous	O
+contact	O
+with	O
+Dormex	O
+.	O
+
+Five	O
+hours	O
+after	O
+exposure	O
+,	O
+he	O
+developed	O
+disulfiram	O
+-	O
+like	O
+syndrome	O
+with	O
+flushing	B
+,	O
+tachycardia	B
+,	O
+and	O
+arterial	B
+hypotension	I
+after	O
+consuming	O
+three	O
+glasses	O
+of	O
+wine	O
+.	O
+
+The	O
+patient	O
+recovered	O
+spontaneously	O
+in	O
+3	O
+hours	O
+under	O
+surveillance	O
+in	O
+the	O
+hospital	O
+.	O
+
+These	O
+cases	O
+confirm	O
+the	O
+necessity	O
+of	O
+avoiding	O
+alcohol	O
+consumption	O
+as	O
+recommended	O
+in	O
+the	O
+instructions	O
+for	O
+use	O
+of	O
+Dormex	O
+and	O
+of	O
+preventing	O
+cutaneous	O
+contact	O
+during	O
+use	O
+.	O
+
+Sulpiride	O
+-	O
+induced	O
+tardive	B
+dystonia	I
+.	O
+
+Sulpiride	O
+is	O
+a	O
+selective	O
+D2	O
+-	O
+receptor	O
+antagonist	O
+with	O
+antipsychotic	O
+and	O
+antidepressant	O
+properties	O
+.	O
+
+Although	O
+initially	O
+thought	O
+to	O
+be	O
+free	O
+of	O
+extrapyramidal	O
+side	O
+effects	O
+,	O
+sulpiride	O
+-	O
+induced	O
+tardive	B
+dyskinesia	I
+and	O
+parkinsonism	B
+have	O
+been	O
+reported	O
+occasionally	O
+.	O
+
+We	O
+studied	O
+a	O
+37	O
+-	O
+year	O
+-	O
+old	O
+man	O
+who	O
+developed	O
+persistent	O
+segmental	O
+dystonia	B
+within	O
+2	O
+months	O
+after	O
+starting	O
+sulpiride	O
+therapy	O
+.	O
+
+We	O
+could	O
+not	O
+find	O
+any	O
+previous	O
+reports	O
+of	O
+sulpiride	O
+-	O
+induced	O
+tardive	B
+dystonia	I
+.	O
+
+Comparative	O
+cognitive	O
+and	O
+subjective	O
+side	O
+effects	O
+of	O
+immediate	O
+-	O
+release	O
+oxycodone	O
+in	O
+healthy	O
+middle	O
+-	O
+aged	O
+and	O
+older	O
+adults	O
+.	O
+
+This	O
+study	O
+measured	O
+the	O
+objective	O
+and	O
+subjective	O
+neurocognitive	O
+effects	O
+of	O
+a	O
+single	O
+10	O
+-	O
+mg	O
+dose	O
+of	O
+immediate	O
+-	O
+release	O
+oxycodone	O
+in	O
+healthy	O
+,	O
+older	O
+(	O
+>	O
+65	O
+years	O
+)	O
+,	O
+and	O
+middle	O
+-	O
+aged	O
+(	O
+35	O
+to	O
+55	O
+years	O
+)	O
+adults	O
+who	O
+were	O
+not	O
+suffering	O
+from	O
+chronic	O
+or	O
+significant	O
+daily	O
+pain	B
+.	O
+
+Seventy	O
+-	O
+one	O
+participants	O
+completed	O
+2	O
+separate	O
+study	O
+days	O
+and	O
+were	O
+blind	O
+to	O
+medication	O
+condition	O
+(	O
+placebo	O
+,	O
+10	O
+-	O
+mg	O
+oxycodone	O
+)	O
+.	O
+
+Plasma	O
+oxycodone	O
+concentration	O
+peaked	O
+between	O
+60	O
+and	O
+90	O
+minutes	O
+postdose	O
+(	O
+P	O
+<	O
+.	O
+01	O
+)	O
+and	O
+pupil	O
+size	O
+,	O
+an	O
+indication	O
+of	O
+physiological	O
+effects	O
+of	O
+the	O
+medication	O
+,	O
+peaked	O
+at	O
+approximately	O
+90	O
+to	O
+120	O
+minutes	O
+postdose	O
+(	O
+P	O
+<	O
+.	O
+01	O
+)	O
+.	O
+
+Significant	O
+declines	B
+in	I
+simple	I
+and	I
+sustained	I
+attention	I
+,	I
+working	I
+memory	I
+,	I
+and	I
+verbal	I
+memory	I
+were	O
+observed	O
+at	O
+1	O
+hour	O
+postdose	O
+compared	O
+to	O
+baseline	O
+for	O
+both	O
+age	O
+groups	O
+with	O
+a	O
+trend	O
+toward	O
+return	O
+to	O
+baseline	O
+by	O
+5	O
+hours	O
+postdose	O
+.	O
+
+For	O
+almost	O
+all	O
+cognitive	O
+measures	O
+,	O
+there	O
+were	O
+no	O
+medication	O
+by	O
+age	O
+-	O
+interaction	O
+effects	O
+,	O
+which	O
+indicates	O
+that	O
+the	O
+2	O
+age	O
+groups	O
+exhibited	O
+similar	O
+responses	O
+to	O
+the	O
+medication	O
+challenge	O
+.	O
+
+This	O
+study	O
+suggests	O
+that	O
+for	O
+healthy	O
+older	O
+adults	O
+who	O
+are	O
+not	O
+suffering	O
+from	O
+chronic	B
+pain	I
+,	O
+neurocognitive	O
+and	O
+pharmacodynamic	O
+changes	O
+in	O
+response	O
+to	O
+a	O
+10	O
+-	O
+mg	O
+dose	O
+of	O
+immediate	O
+-	O
+release	O
+oxycodone	O
+are	O
+similar	O
+to	O
+those	O
+observed	O
+for	O
+middle	O
+-	O
+aged	O
+adults	O
+.	O
+
+PERSPECTIVE	O
+:	O
+Study	O
+findings	O
+indicate	O
+that	O
+the	O
+metabolism	O
+,	O
+neurocognitive	O
+effects	O
+,	O
+and	O
+physical	O
+side	O
+effects	O
+of	O
+oral	O
+oxycodone	O
+are	O
+similar	O
+for	O
+healthy	O
+middle	O
+-	O
+aged	O
+and	O
+older	O
+adults	O
+.	O
+
+Therefore	O
+,	O
+clinicians	O
+should	O
+not	O
+avoid	O
+prescribing	O
+oral	O
+opioids	O
+to	O
+older	O
+adults	O
+based	O
+on	O
+the	O
+belief	O
+that	O
+older	O
+adults	O
+are	O
+at	O
+higher	O
+risk	O
+for	O
+side	O
+effects	O
+than	O
+younger	O
+adults	O
+.	O
+
+The	O
+glycine	O
+transporter	O
+-	O
+1	O
+inhibitor	O
+SSR103800	O
+displays	O
+a	O
+selective	O
+and	O
+specific	O
+antipsychotic	O
+-	O
+like	O
+profile	O
+in	O
+normal	O
+and	O
+transgenic	O
+mice	O
+.	O
+
+Schizophrenia	B
+has	O
+been	O
+initially	O
+associated	O
+with	O
+dysfunction	O
+in	O
+dopamine	O
+neurotransmission	O
+.	O
+
+However	O
+,	O
+the	O
+observation	O
+that	O
+antagonists	O
+of	O
+the	O
+glutamate	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+receptor	O
+produce	O
+schizophrenic	B
+-	O
+like	O
+symptoms	O
+in	O
+humans	O
+has	O
+led	O
+to	O
+the	O
+idea	O
+of	O
+a	O
+dysfunctioning	O
+of	O
+the	O
+glutamatergic	O
+system	O
+via	O
+its	O
+NMDA	O
+receptor	O
+.	O
+
+As	O
+a	O
+result	O
+,	O
+there	O
+is	O
+a	O
+growing	O
+interest	O
+in	O
+the	O
+development	O
+of	O
+pharmacological	O
+agents	O
+with	O
+potential	O
+antipsychotic	O
+properties	O
+that	O
+enhance	O
+the	O
+activity	O
+of	O
+the	O
+glutamatergic	O
+system	O
+via	O
+a	O
+modulation	O
+of	O
+the	O
+NMDA	O
+receptor	O
+.	O
+
+Among	O
+them	O
+are	O
+glycine	O
+transporter	O
+-	O
+1	O
+(	O
+GlyT1	O
+)	O
+inhibitors	O
+such	O
+as	O
+SSR103800	O
+,	O
+which	O
+indirectly	O
+enhance	O
+NMDA	O
+receptor	O
+function	O
+by	O
+increasing	O
+the	O
+glycine	O
+(	O
+a	O
+co	O
+-	O
+agonist	O
+for	O
+the	O
+NMDA	O
+receptor	O
+)	O
+levels	O
+in	O
+the	O
+synapse	O
+.	O
+
+This	O
+study	O
+aimed	O
+at	O
+investigating	O
+the	O
+potential	O
+antipsychotic	O
+-	O
+like	O
+properties	O
+of	O
+SSR103800	O
+,	O
+with	O
+a	O
+particular	O
+focus	O
+on	O
+models	O
+of	O
+hyperactivity	B
+,	O
+involving	O
+either	O
+drug	O
+challenge	O
+(	O
+ie	O
+,	O
+amphetamine	O
+and	O
+MK	O
+-	O
+801	O
+)	O
+or	O
+transgenic	O
+mice	O
+(	O
+ie	O
+,	O
+NMDA	O
+Nr1	O
+(	O
+neo	O
+-	O
+/	O
+-	O
+)	O
+and	O
+DAT	O
+(	O
+-	O
+/	O
+-	O
+)	O
+)	O
+.	O
+
+Results	O
+showed	O
+that	O
+SSR103800	O
+(	O
+10	O
+-	O
+30	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+)	O
+blocked	O
+hyperactivity	B
+induced	O
+by	O
+the	O
+non	O
+-	O
+competitive	O
+NMDA	O
+receptor	O
+antagonist	O
+,	O
+MK	O
+-	O
+801	O
+and	O
+partially	O
+reversed	O
+spontaneous	O
+hyperactivity	B
+of	O
+NMDA	O
+Nr1	O
+(	O
+neo	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+.	O
+
+In	O
+contrast	O
+,	O
+SSR103800	O
+failed	O
+to	O
+affect	O
+hyperactivity	B
+induced	O
+by	O
+amphetamine	O
+or	O
+naturally	O
+observed	O
+in	O
+dopamine	O
+transporter	O
+(	O
+DAT	O
+(	O
+-	O
+/	O
+-	O
+)	O
+)	O
+knockout	O
+mice	O
+(	O
+10	O
+-	O
+30	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+)	O
+.	O
+
+Importantly	O
+,	O
+both	O
+classical	O
+(	O
+haloperidol	O
+)	O
+and	O
+atypical	O
+(	O
+olanzapine	O
+,	O
+clozapine	O
+and	O
+aripiprazole	O
+)	O
+antipsychotics	O
+were	O
+effective	O
+in	O
+all	O
+these	O
+models	O
+of	O
+hyperactivity	B
+.	O
+
+However	O
+,	O
+unlike	O
+these	O
+latter	O
+,	O
+SSR103800	O
+did	O
+not	O
+produce	O
+catalepsy	B
+(	O
+retention	O
+on	O
+the	O
+bar	O
+test	O
+)	O
+up	O
+to	O
+30	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+
+Together	O
+these	O
+findings	O
+show	O
+that	O
+the	O
+GlyT1	O
+inhibitor	O
+,	O
+SSR103800	O
+,	O
+produces	O
+antipsychotic	O
+-	O
+like	O
+effects	O
+,	O
+which	O
+differ	O
+from	O
+those	O
+observed	O
+with	O
+compounds	O
+primarily	O
+targeting	O
+the	O
+dopaminergic	O
+system	O
+,	O
+and	O
+has	O
+a	O
+reduced	O
+side	O
+-	O
+effect	O
+potential	O
+as	O
+compared	O
+with	O
+these	O
+latter	O
+drugs	O
+.	O
+
+Pyrrolidine	O
+dithiocarbamate	O
+protects	O
+the	O
+piriform	O
+cortex	O
+in	O
+the	O
+pilocarpine	O
+status	B
+epilepticus	I
+model	O
+.	O
+
+Pyrrolidine	O
+dithiocarbamate	O
+(	O
+PDTC	O
+)	O
+has	O
+a	O
+dual	O
+mechanism	O
+of	O
+action	O
+as	O
+an	O
+antioxidant	O
+and	O
+an	O
+inhibitor	O
+of	O
+the	O
+transcription	O
+factor	O
+kappa	O
+-	O
+beta	O
+.	O
+
+Both	O
+,	O
+production	O
+of	O
+reactive	O
+oxygen	O
+species	O
+as	O
+well	O
+as	O
+activation	O
+of	O
+NF	O
+-	O
+kappaB	O
+have	O
+been	O
+implicated	O
+in	O
+severe	O
+neuronal	B
+damage	I
+in	O
+different	O
+sub	O
+-	O
+regions	O
+of	O
+the	O
+hippocampus	O
+as	O
+well	O
+as	O
+in	O
+the	O
+surrounding	O
+cortices	O
+.	O
+
+The	O
+effect	O
+of	O
+PDTC	O
+on	O
+status	B
+epilepticus	I
+-	O
+associated	O
+cell	O
+loss	O
+in	O
+the	O
+hippocampus	O
+and	O
+piriform	O
+cortex	O
+was	O
+evaluated	O
+in	O
+the	O
+rat	O
+fractionated	O
+pilocarpine	O
+model	O
+.	O
+
+Treatment	O
+with	O
+150	O
+mg	O
+/	O
+kg	O
+PDTC	O
+before	O
+and	O
+following	O
+status	B
+epilepticus	I
+significantly	O
+increased	O
+the	O
+mortality	O
+rate	O
+to	O
+100	O
+%	O
+.	O
+
+Administration	O
+of	O
+50	O
+mg	O
+/	O
+kg	O
+PDTC	O
+(	O
+low	O
+-	O
+dose	O
+)	O
+did	O
+not	O
+exert	O
+major	O
+effects	O
+on	O
+the	O
+development	O
+of	O
+a	O
+status	B
+epilepticus	I
+or	O
+the	O
+mortality	O
+rate	O
+.	O
+
+In	O
+vehicle	O
+-	O
+treated	O
+rats	O
+,	O
+status	B
+epilepticus	I
+caused	O
+pronounced	O
+neuronal	B
+damage	I
+in	O
+the	O
+piriform	O
+cortex	O
+comprising	O
+both	O
+pyramidal	O
+cells	O
+and	O
+interneurons	O
+.	O
+
+Low	O
+-	O
+dose	O
+PDTC	O
+treatment	O
+almost	O
+completely	O
+protected	O
+from	O
+lesions	O
+in	O
+the	O
+piriform	O
+cortex	O
+.	O
+
+A	O
+significant	O
+decrease	O
+in	O
+neuronal	O
+density	O
+of	O
+the	O
+hippocampal	O
+hilar	O
+formation	O
+was	O
+identified	O
+in	O
+vehicle	O
+-	O
+and	O
+PDTC	O
+-	O
+treated	O
+rats	O
+following	O
+status	B
+epilepticus	I
+.	O
+
+In	O
+conclusion	O
+,	O
+the	O
+NF	O
+-	O
+kappaB	O
+inhibitor	O
+and	O
+antioxidant	O
+PDTC	O
+protected	O
+the	O
+piriform	O
+cortex	O
+,	O
+whereas	O
+it	O
+did	O
+not	O
+affect	O
+hilar	O
+neuronal	B
+loss	I
+.	O
+
+These	O
+data	O
+might	O
+indicate	O
+that	O
+the	O
+generation	O
+of	O
+reactive	O
+oxygen	O
+species	O
+and	O
+activation	O
+of	O
+NF	O
+-	O
+kappaB	O
+plays	O
+a	O
+more	O
+central	O
+role	O
+in	O
+seizure	B
+-	O
+associated	O
+neuronal	B
+damage	I
+in	O
+the	O
+temporal	O
+cortex	O
+as	O
+compared	O
+to	O
+the	O
+hippocampal	O
+hilus	O
+.	O
+
+However	O
+,	O
+future	O
+investigations	O
+are	O
+necessary	O
+to	O
+exactly	O
+analyze	O
+the	O
+biochemical	O
+mechanisms	O
+by	O
+which	O
+PDTC	O
+exerted	O
+its	O
+beneficial	O
+effects	O
+in	O
+the	O
+piriform	O
+cortex	O
+.	O
+
+Anaesthetists	O
+'	O
+nightmare	O
+:	O
+masseter	B
+spasm	I
+after	O
+induction	O
+in	O
+an	O
+undiagnosed	O
+case	O
+of	O
+myotonia	B
+congenita	I
+.	O
+
+We	O
+report	O
+an	O
+undiagnosed	O
+case	O
+of	O
+myotonia	B
+congenita	I
+in	O
+a	O
+24	O
+-	O
+year	O
+-	O
+old	O
+previously	O
+healthy	O
+primigravida	O
+,	O
+who	O
+developed	O
+life	O
+threatening	O
+masseter	B
+spasm	I
+following	O
+a	O
+standard	O
+dose	O
+of	O
+intravenous	O
+suxamethonium	O
+for	O
+induction	O
+of	O
+anaesthesia	O
+.	O
+
+Neither	O
+the	O
+patient	O
+nor	O
+the	O
+anaesthetist	O
+was	O
+aware	O
+of	O
+the	O
+diagnosis	O
+before	O
+this	O
+potentially	O
+lethal	O
+complication	O
+occurred	O
+.	O
+
+Twin	O
+preterm	O
+neonates	O
+with	O
+cardiac	B
+toxicity	I
+related	O
+to	O
+lopinavir	O
+/	O
+ritonavir	O
+therapy	O
+.	O
+
+We	O
+report	O
+twin	O
+neonates	O
+who	O
+were	O
+born	O
+prematurely	O
+at	O
+32	O
+weeks	O
+of	O
+gestation	O
+to	O
+a	O
+mother	O
+with	O
+human	B
+immunodeficiency	I
+virus	I
+infection	I
+.	O
+
+One	O
+of	O
+the	O
+twins	O
+developed	O
+complete	O
+heart	B
+block	I
+and	O
+dilated	B
+cardiomyopathy	I
+related	O
+to	O
+lopinavir	O
+/	O
+ritonavir	O
+therapy	O
+,	O
+a	O
+boosted	O
+protease	O
+-	O
+inhibitor	O
+agent	O
+,	O
+while	O
+the	O
+other	O
+twin	O
+developed	O
+mild	O
+bradycardia	B
+.	O
+
+We	O
+recommend	O
+caution	O
+in	O
+the	O
+use	O
+of	O
+lopinavir	O
+/	O
+ritonavir	O
+in	O
+the	O
+immediate	O
+neonatal	O
+period	O
+.	O
+
+When	O
+drugs	O
+disappear	O
+from	O
+the	O
+patient	O
+:	O
+elimination	O
+of	O
+intravenous	O
+medication	O
+by	O
+hemodiafiltration	O
+.	O
+
+Twenty	O
+-	O
+three	O
+hours	O
+after	O
+heart	O
+transplantation	O
+,	O
+life	O
+-	O
+threatening	O
+acute	O
+right	B
+heart	I
+failure	I
+was	O
+diagnosed	O
+in	O
+a	O
+patient	O
+requiring	O
+continuous	O
+venovenous	O
+hemodiafiltration	O
+(	O
+CVVHDF	O
+)	O
+.	O
+
+Increasing	O
+doses	O
+of	O
+catecholamines	O
+,	O
+sedatives	O
+,	O
+and	O
+muscle	O
+relaxants	O
+administered	O
+through	O
+a	O
+central	O
+venous	O
+catheter	O
+were	O
+ineffective	O
+.	O
+
+However	O
+,	O
+a	O
+bolus	O
+of	O
+epinephrine	O
+injected	O
+through	O
+an	O
+alternative	O
+catheter	O
+provoked	O
+a	O
+hypertensive	B
+crisis	O
+.	O
+
+Thus	O
+,	O
+interference	O
+with	O
+the	O
+central	O
+venous	O
+infusion	O
+by	O
+the	O
+dialysis	O
+catheter	O
+was	O
+suspected	O
+.	O
+
+The	O
+catheters	O
+were	O
+changed	O
+,	O
+and	O
+hemodynamics	O
+stabilized	O
+at	O
+lower	O
+catecholamine	O
+doses	O
+.	O
+
+When	O
+the	O
+effects	O
+of	O
+IV	O
+drugs	O
+are	O
+inadequate	O
+in	O
+patients	O
+receiving	O
+CVVHDF	O
+,	O
+interference	O
+with	O
+adjacent	O
+catheters	O
+resulting	O
+in	O
+elimination	O
+of	O
+the	O
+drug	O
+by	O
+CVVHDF	O
+should	O
+be	O
+suspected	O
+.	O
+
+Less	O
+frequent	O
+lithium	O
+administration	O
+and	O
+lower	O
+urine	O
+volume	O
+.	O
+
+OBJECTIVE	O
+:	O
+This	O
+study	O
+was	O
+designed	O
+to	O
+determine	O
+whether	O
+patients	O
+maintained	O
+on	O
+a	O
+regimen	O
+of	O
+lithium	O
+on	O
+a	O
+once	O
+-	O
+per	O
+-	O
+day	O
+schedule	O
+have	O
+lower	O
+urine	O
+volumes	O
+than	O
+do	O
+patients	O
+receiving	O
+multiple	O
+doses	O
+per	O
+day	O
+.	O
+
+METHOD	O
+:	O
+This	O
+was	O
+a	O
+cross	O
+-	O
+sectional	O
+study	O
+of	O
+85	O
+patients	O
+from	O
+a	O
+lithium	O
+clinic	O
+who	O
+received	O
+different	O
+dose	O
+schedules	O
+.	O
+
+Patients	O
+were	O
+admitted	O
+to	O
+the	O
+hospital	O
+for	O
+measurement	O
+of	O
+lithium	O
+level	O
+,	O
+creatinine	O
+clearance	O
+,	O
+urine	O
+volume	O
+,	O
+and	O
+maximum	O
+osmolality	O
+.	O
+
+RESULTS	O
+:	O
+Multiple	O
+daily	O
+doses	O
+of	O
+lithium	O
+were	O
+associated	O
+with	O
+higher	O
+urine	O
+volumes	O
+.	O
+
+The	O
+dosing	O
+schedule	O
+,	O
+duration	O
+of	O
+lithium	O
+treatment	O
+,	O
+and	O
+daily	O
+dose	O
+of	O
+lithium	O
+did	O
+not	O
+affect	O
+maximum	O
+osmolality	O
+or	O
+creatinine	O
+clearance	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Urine	O
+volume	O
+can	O
+be	O
+reduced	O
+by	O
+giving	O
+lithium	O
+once	O
+daily	O
+and	O
+/	O
+or	O
+by	O
+lowering	O
+the	O
+total	O
+daily	O
+dose	O
+.	O
+
+Lithium	O
+-	O
+induced	O
+polyuria	B
+seems	O
+to	O
+be	O
+related	O
+to	O
+extrarenal	O
+as	O
+well	O
+as	O
+to	O
+renal	O
+effects	O
+.	O
+
+Antibacterial	O
+medication	O
+use	O
+during	O
+pregnancy	O
+and	O
+risk	O
+of	O
+birth	B
+defects	I
+:	O
+National	O
+Birth	B
+Defects	I
+Prevention	O
+Study	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+estimate	O
+the	O
+association	O
+between	O
+antibacterial	O
+medications	O
+and	O
+selected	O
+birth	B
+defects	I
+.	O
+
+DESIGN	O
+,	O
+SETTING	O
+,	O
+AND	O
+PARTICIPANTS	O
+:	O
+Population	O
+-	O
+based	O
+,	O
+multisite	O
+,	O
+case	O
+-	O
+control	O
+study	O
+of	O
+women	O
+who	O
+had	O
+pregnancies	O
+affected	O
+by	O
+1	O
+of	O
+more	O
+than	O
+30	O
+eligible	O
+major	O
+birth	B
+defects	I
+identified	O
+via	O
+birth	B
+defect	I
+surveillance	O
+programs	O
+in	O
+10	O
+states	O
+(	O
+n	O
+=	O
+13	O
+155	O
+)	O
+and	O
+control	O
+women	O
+randomly	O
+selected	O
+from	O
+the	O
+same	O
+geographical	O
+regions	O
+(	O
+n	O
+=	O
+4941	O
+)	O
+.	O
+
+MAIN	O
+EXPOSURE	O
+:	O
+Reported	O
+maternal	O
+use	O
+of	O
+antibacterials	O
+(	O
+1	O
+month	O
+before	O
+pregnancy	O
+through	O
+the	O
+end	O
+of	O
+the	O
+first	O
+trimester	O
+)	O
+.	O
+
+MAIN	O
+OUTCOME	O
+MEASURE	O
+:	O
+Odds	O
+ratios	O
+(	O
+ORs	O
+)	O
+measuring	O
+the	O
+association	O
+between	O
+antibacterial	O
+use	O
+and	O
+selected	O
+birth	B
+defects	I
+adjusted	O
+for	O
+potential	O
+confounders	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+reported	O
+use	O
+of	O
+antibacterials	O
+increased	O
+during	O
+pregnancy	O
+,	O
+peaking	O
+during	O
+the	O
+third	O
+month	O
+.	O
+
+Sulfonamides	O
+were	O
+associated	O
+with	O
+anencephaly	B
+(	O
+adjusted	O
+OR	O
+[	O
+AOR	O
+]	O
+=	O
+3	O
+.	O
+4	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+,	O
+1	O
+.	O
+3	O
+-	O
+8	O
+.	O
+8	O
+)	O
+,	O
+hypoplastic	B
+left	I
+heart	I
+syndrome	I
+(	O
+AOR	O
+=	O
+3	O
+.	O
+2	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+3	O
+-	O
+7	O
+.	O
+6	O
+)	O
+,	O
+coarctation	B
+of	I
+the	I
+aorta	I
+(	O
+AOR	O
+=	O
+2	O
+.	O
+7	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+3	O
+-	O
+5	O
+.	O
+6	O
+)	O
+,	O
+choanal	B
+atresia	I
+(	O
+AOR	O
+=	O
+8	O
+.	O
+0	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+2	O
+.	O
+7	O
+-	O
+23	O
+.	O
+5	O
+)	O
+,	O
+transverse	B
+limb	I
+deficiency	I
+(	O
+AOR	O
+=	O
+2	O
+.	O
+5	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+0	O
+-	O
+5	O
+.	O
+9	O
+)	O
+,	O
+and	O
+diaphragmatic	B
+hernia	I
+(	O
+AOR	O
+=	O
+2	O
+.	O
+4	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+1	O
+-	O
+5	O
+.	O
+4	O
+)	O
+.	O
+
+Nitrofurantoins	O
+were	O
+associated	O
+with	O
+anophthalmia	B
+or	O
+microphthalmos	B
+(	O
+AOR	O
+=	O
+3	O
+.	O
+7	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+1	O
+-	O
+12	O
+.	O
+2	O
+)	O
+,	O
+hypoplastic	B
+left	I
+heart	I
+syndrome	I
+(	O
+AOR	O
+=	O
+4	O
+.	O
+2	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+9	O
+-	O
+9	O
+.	O
+1	O
+)	O
+,	O
+atrial	B
+septal	I
+defects	I
+(	O
+AOR	O
+=	O
+1	O
+.	O
+9	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+1	O
+-	O
+3	O
+.	O
+4	O
+)	O
+,	O
+and	O
+cleft	B
+lip	I
+with	O
+cleft	B
+palate	I
+(	O
+AOR	O
+=	O
+2	O
+.	O
+1	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1	O
+.	O
+2	O
+-	O
+3	O
+.	O
+9	O
+)	O
+.	O
+
+Other	O
+antibacterial	O
+agents	O
+that	O
+showed	O
+associations	O
+included	O
+erythromycins	O
+(	O
+2	O
+defects	O
+)	O
+,	O
+penicillins	O
+(	O
+1	O
+defect	O
+)	O
+,	O
+cephalosporins	O
+(	O
+1	O
+defect	O
+)	O
+,	O
+and	O
+quinolones	O
+(	O
+1	O
+defect	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Reassuringly	O
+,	O
+penicillins	O
+,	O
+erythromycins	O
+,	O
+and	O
+cephalosporins	O
+,	O
+although	O
+used	O
+commonly	O
+by	O
+pregnant	O
+women	O
+,	O
+were	O
+not	O
+associated	O
+with	O
+many	O
+birth	B
+defects	I
+.	O
+
+Sulfonamides	O
+and	O
+nitrofurantoins	O
+were	O
+associated	O
+with	O
+several	O
+birth	B
+defects	I
+,	O
+indicating	O
+a	O
+need	O
+for	O
+additional	O
+scrutiny	O
+.	O
+
+Differential	O
+impact	O
+of	O
+immune	O
+escape	O
+mutations	O
+G145R	O
+and	O
+P120T	O
+on	O
+the	O
+replication	O
+of	O
+lamivudine	O
+-	O
+resistant	O
+hepatitis	O
+B	O
+virus	O
+e	O
+antigen	O
+-	O
+positive	O
+and	O
+-	O
+negative	O
+strains	O
+.	O
+
+Immune	O
+escape	O
+variants	O
+of	O
+the	O
+hepatitis	B
+B	I
+virus	O
+(	O
+HBV	O
+)	O
+represent	O
+an	O
+emerging	O
+clinical	O
+challenge	O
+,	O
+because	O
+they	O
+can	O
+be	O
+associated	O
+with	O
+vaccine	O
+escape	O
+,	O
+HBV	O
+reactivation	O
+,	O
+and	O
+failure	O
+of	O
+diagnostic	O
+tests	O
+.	O
+
+Recent	O
+data	O
+suggest	O
+a	O
+preferential	O
+selection	O
+of	O
+immune	O
+escape	O
+mutants	O
+in	O
+distinct	O
+peripheral	O
+blood	O
+leukocyte	O
+compartments	O
+of	O
+infected	O
+individuals	O
+.	O
+
+We	O
+therefore	O
+systematically	O
+analyzed	O
+the	O
+functional	O
+impact	O
+of	O
+the	O
+most	O
+prevalent	O
+immune	O
+escape	O
+variants	O
+,	O
+the	O
+sG145R	O
+and	O
+sP120T	O
+mutants	O
+,	O
+on	O
+the	O
+viral	O
+replication	O
+efficacy	O
+and	O
+antiviral	O
+drug	O
+susceptibility	O
+of	O
+common	O
+treatment	O
+-	O
+associated	O
+mutants	O
+with	O
+resistance	O
+to	O
+lamivudine	O
+(	O
+LAM	O
+)	O
+and	O
+/	O
+or	O
+HBeAg	O
+negativity	O
+.	O
+
+Replication	O
+-	O
+competent	O
+HBV	O
+strains	O
+with	O
+sG145R	O
+or	O
+sP120T	O
+and	O
+LAM	O
+resistance	O
+(	O
+rtM204I	O
+or	O
+rtL180M	O
+/	O
+rtM204V	O
+)	O
+were	O
+generated	O
+on	O
+an	O
+HBeAg	O
+-	O
+positive	O
+and	O
+an	O
+HBeAg	O
+-	O
+negative	O
+background	O
+with	O
+precore	O
+(	O
+PC	O
+)	O
+and	O
+basal	O
+core	O
+promoter	O
+(	O
+BCP	O
+)	O
+mutants	O
+.	O
+
+The	O
+sG145R	O
+mutation	O
+strongly	O
+reduced	O
+HBsAg	O
+levels	O
+and	O
+was	O
+able	O
+to	O
+fully	O
+restore	O
+the	O
+impaired	O
+replication	O
+of	O
+LAM	O
+-	O
+resistant	O
+HBV	O
+mutants	O
+to	O
+the	O
+levels	O
+of	O
+wild	O
+-	O
+type	O
+HBV	O
+,	O
+and	O
+PC	O
+or	O
+BCP	O
+mutations	O
+further	O
+enhanced	O
+viral	O
+replication	O
+.	O
+
+Although	O
+the	O
+sP120T	O
+substitution	O
+also	O
+impaired	O
+HBsAg	O
+secretion	O
+,	O
+it	O
+did	O
+not	O
+enhance	O
+the	O
+replication	O
+of	O
+LAM	O
+-	O
+resistant	O
+clones	O
+.	O
+
+However	O
+,	O
+the	O
+concomitant	O
+occurrence	O
+of	O
+HBeAg	O
+negativity	O
+(	O
+PC	O
+/	O
+BCP	O
+)	O
+,	O
+sP120T	O
+,	O
+and	O
+LAM	O
+resistance	O
+resulted	O
+in	O
+the	O
+restoration	O
+of	O
+replication	O
+to	O
+levels	O
+of	O
+wild	O
+-	O
+type	O
+HBV	O
+.	O
+
+In	O
+all	O
+clones	O
+with	O
+combined	O
+immune	O
+escape	O
+and	O
+LAM	O
+resistance	O
+mutations	O
+,	O
+the	O
+nucleotide	O
+analogues	O
+adefovir	O
+and	O
+tenofovir	O
+remained	O
+effective	O
+in	O
+suppressing	O
+viral	O
+replication	O
+in	O
+vitro	O
+.	O
+
+These	O
+findings	O
+reveal	O
+the	O
+differential	O
+impact	O
+of	O
+immune	O
+escape	O
+variants	O
+on	O
+the	O
+replication	O
+and	O
+drug	O
+susceptibility	O
+of	O
+complex	O
+HBV	O
+mutants	O
+,	O
+supporting	O
+the	O
+need	O
+of	O
+close	O
+surveillance	O
+and	O
+treatment	O
+adjustment	O
+in	O
+response	O
+to	O
+the	O
+selection	O
+of	O
+distinct	O
+mutational	O
+patterns	O
+.	O
+
+Hemolytic	B
+anemia	I
+associated	O
+with	O
+the	O
+use	O
+of	O
+omeprazole	O
+.	O
+
+Omeprazole	O
+is	O
+the	O
+first	O
+drug	O
+designed	O
+to	O
+block	O
+the	O
+final	O
+step	O
+in	O
+the	O
+acid	O
+secretory	O
+process	O
+within	O
+the	O
+parietal	O
+cell	O
+.	O
+
+It	O
+has	O
+been	O
+shown	O
+to	O
+be	O
+extremely	O
+effective	O
+in	O
+the	O
+treatment	O
+of	O
+peptic	B
+ulcer	I
+disease	I
+,	O
+reflux	B
+esophagitis	I
+,	O
+and	O
+the	O
+Zollinger	B
+-	I
+Ellison	I
+syndrome	I
+.	O
+
+Although	O
+clinical	O
+experience	O
+with	O
+omeprazole	O
+is	O
+still	O
+limited	O
+,	O
+many	O
+controlled	O
+studies	O
+have	O
+established	O
+the	O
+short	O
+-	O
+term	O
+safety	O
+of	O
+this	O
+drug	O
+.	O
+
+We	O
+report	O
+the	O
+first	O
+case	O
+of	O
+a	O
+serious	O
+short	O
+-	O
+term	O
+adverse	O
+reaction	O
+with	O
+the	O
+use	O
+of	O
+omeprazole	O
+:	O
+hemolytic	B
+anemia	I
+.	O
+
+The	O
+patient	O
+developed	O
+weakness	O
+,	O
+lethargy	B
+,	O
+and	O
+shortness	B
+of	I
+breath	I
+2	O
+days	O
+after	O
+starting	O
+therapy	O
+with	O
+omeprazole	O
+.	O
+
+Two	O
+weeks	O
+after	O
+the	O
+initiation	O
+of	O
+therapy	O
+,	O
+her	O
+hematocrit	O
+had	O
+decreased	O
+from	O
+44	O
+.	O
+1	O
+%	O
+to	O
+20	O
+.	O
+4	O
+%	O
+,	O
+and	O
+she	O
+had	O
+a	O
+positive	O
+direct	O
+Coombs	O
+antiglobulin	O
+test	O
+and	O
+an	O
+elevated	O
+indirect	O
+bilirubin	O
+.	O
+
+After	O
+she	O
+discontinued	O
+the	O
+omeprazole	O
+,	O
+her	O
+hemoglobin	O
+and	O
+hematocrit	O
+gradually	O
+returned	O
+to	O
+normal	O
+.	O
+
+The	O
+mechanism	O
+by	O
+which	O
+omeprazole	O
+caused	O
+the	O
+patient	O
+'	O
+s	O
+hemolytic	B
+anemia	I
+is	O
+uncertain	O
+,	O
+but	O
+physicians	O
+should	O
+be	O
+alerted	O
+to	O
+this	O
+possible	O
+adverse	O
+effect	O
+.	O
+
+Phenylephrine	O
+but	O
+not	O
+ephedrine	O
+reduces	B
+frontal	I
+lobe	I
+oxygenation	I
+following	O
+anesthesia	O
+-	O
+induced	O
+hypotension	B
+.	O
+
+BACKGROUND	O
+:	O
+Vasopressor	O
+agents	O
+are	O
+used	O
+to	O
+correct	O
+anesthesia	O
+-	O
+induced	O
+hypotension	B
+.	O
+
+We	O
+describe	O
+the	O
+effect	O
+of	O
+phenylephrine	O
+and	O
+ephedrine	O
+on	O
+frontal	O
+lobe	O
+oxygenation	O
+(	O
+S	O
+(	O
+c	O
+)	O
+O	O
+(	O
+2	O
+)	O
+)	O
+following	O
+anesthesia	O
+-	O
+induced	O
+hypotension	B
+.	O
+
+METHODS	O
+:	O
+Following	O
+induction	O
+of	O
+anesthesia	O
+by	O
+fentanyl	O
+(	O
+0	O
+.	O
+15	O
+mg	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+)	O
+and	O
+propofol	O
+(	O
+2	O
+.	O
+0	O
+mg	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+)	O
+,	O
+13	O
+patients	O
+received	O
+phenylephrine	O
+(	O
+0	O
+.	O
+1	O
+mg	O
+iv	O
+)	O
+and	O
+12	O
+patients	O
+received	O
+ephedrine	O
+(	O
+10	O
+mg	O
+iv	O
+)	O
+to	O
+restore	O
+mean	O
+arterial	O
+pressure	O
+(	O
+MAP	O
+)	O
+.	O
+
+Heart	O
+rate	O
+(	O
+HR	O
+)	O
+,	O
+MAP	O
+,	O
+stroke	B
+volume	O
+(	O
+SV	O
+)	O
+,	O
+cardiac	O
+output	O
+(	O
+CO	O
+)	O
+,	O
+and	O
+frontal	O
+lobe	O
+oxygenation	O
+(	O
+S	O
+(	O
+c	O
+)	O
+O	O
+(	O
+2	O
+)	O
+)	O
+were	O
+registered	O
+.	O
+
+RESULTS	O
+:	O
+Induction	O
+of	O
+anesthesia	O
+was	O
+followed	O
+by	O
+a	B
+decrease	I
+in	I
+MAP	I
+,	I
+HR	I
+,	I
+SV	I
+,	I
+and	I
+CO	I
+concomitant	O
+with	O
+an	O
+elevation	O
+in	O
+S	O
+(	O
+c	O
+)	O
+O	O
+(	O
+2	O
+)	O
+.	O
+
+After	O
+administration	O
+of	O
+phenylephrine	O
+,	O
+MAP	O
+increased	O
+(	O
+51	O
++	O
+/	O
+-	O
+12	O
+to	O
+81	O
++	O
+/	O
+-	O
+13	O
+mmHg	O
+;	O
+P	O
+<	O
+0	O
+.	O
+001	O
+;	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+)	O
+.	O
+
+However	O
+,	O
+a	O
+14	O
+%	O
+(	O
+from	O
+70	O
++	O
+/	O
+-	O
+8	O
+%	O
+to	O
+60	O
++	O
+/	O
+-	O
+7	O
+%	O
+)	O
+reduction	O
+in	O
+S	O
+(	O
+c	O
+)	O
+O	O
+(	O
+2	O
+)	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+followed	O
+with	O
+no	O
+change	O
+in	O
+CO	O
+(	O
+3	O
+.	O
+7	O
++	O
+/	O
+-	O
+1	O
+.	O
+1	O
+to	O
+3	O
+.	O
+4	O
++	O
+/	O
+-	O
+0	O
+.	O
+9	O
+l	O
+min	O
+(	O
+-	O
+1	O
+)	O
+)	O
+.	O
+
+The	O
+administration	O
+of	O
+ephedrine	O
+led	O
+to	O
+a	O
+similar	O
+increase	O
+in	O
+MAP	O
+(	O
+53	O
++	O
+/	O
+-	O
+9	O
+to	O
+79	O
++	O
+/	O
+-	O
+8	O
+mmHg	O
+;	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+,	O
+restored	O
+CO	O
+(	O
+3	O
+.	O
+2	O
++	O
+/	O
+-	O
+1	O
+.	O
+2	O
+to	O
+5	O
+.	O
+0	O
++	O
+/	O
+-	O
+1	O
+.	O
+3	O
+l	O
+min	O
+(	O
+-	O
+1	O
+)	O
+)	O
+,	O
+and	O
+preserved	O
+S	O
+(	O
+c	O
+)	O
+O	O
+(	O
+2	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+utilization	O
+of	O
+phenylephrine	O
+to	O
+correct	O
+hypotension	B
+induced	O
+by	O
+anesthesia	O
+has	O
+a	O
+negative	O
+impact	O
+on	O
+S	O
+(	O
+c	O
+)	O
+O	O
+(	O
+2	O
+)	O
+while	O
+ephedrine	O
+maintains	O
+frontal	O
+lobe	O
+oxygenation	O
+potentially	O
+related	O
+to	O
+an	O
+increase	O
+in	O
+CO	O
+.	O
+
+Prolonged	O
+elevation	O
+of	O
+plasma	O
+argatroban	O
+in	O
+a	O
+cardiac	O
+transplant	O
+patient	O
+with	O
+a	O
+suspected	O
+history	O
+of	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+with	O
+thrombosis	B
+.	O
+
+BACKGROUND	O
+:	O
+Direct	O
+thrombin	O
+inhibitors	O
+(	O
+DTIs	O
+)	O
+provide	O
+an	O
+alternative	O
+method	O
+of	O
+anticoagulation	O
+for	O
+patients	O
+with	O
+a	O
+history	O
+of	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+(	O
+HIT	B
+)	O
+or	O
+HIT	B
+with	O
+thrombosis	B
+(	O
+HITT	B
+)	O
+undergoing	O
+cardiopulmonary	O
+bypass	O
+(	O
+CPB	O
+)	O
+.	O
+
+In	O
+the	O
+following	O
+report	O
+,	O
+a	O
+65	O
+-	O
+year	O
+-	O
+old	O
+critically	B
+ill	I
+patient	O
+with	O
+a	O
+suspected	O
+history	O
+of	O
+HITT	B
+was	O
+administered	O
+argatroban	O
+for	O
+anticoagulation	O
+on	O
+bypass	O
+during	O
+heart	O
+transplantation	O
+.	O
+
+The	O
+patient	O
+required	O
+massive	O
+transfusion	O
+support	O
+(	O
+55	O
+units	O
+of	O
+red	O
+blood	O
+cells	O
+,	O
+42	O
+units	O
+of	O
+fresh	O
+-	O
+frozen	O
+plasma	O
+,	O
+40	O
+units	O
+of	O
+cryoprecipitate	O
+,	O
+40	O
+units	O
+of	O
+platelets	O
+,	O
+and	O
+three	O
+doses	O
+of	O
+recombinant	O
+Factor	O
+VIIa	O
+)	O
+for	O
+severe	O
+intraoperative	B
+and	I
+postoperative	I
+bleeding	I
+.	O
+
+STUDY	O
+DESIGN	O
+AND	O
+METHODS	O
+:	O
+Plasma	O
+samples	O
+from	O
+before	O
+and	O
+after	O
+CPB	O
+were	O
+analyzed	O
+postoperatively	O
+for	O
+argatroban	O
+concentration	O
+using	O
+a	O
+modified	O
+ecarin	O
+clotting	O
+time	O
+(	O
+ECT	O
+)	O
+assay	O
+.	O
+
+RESULTS	O
+:	O
+Unexpectedly	O
+high	O
+concentrations	O
+of	O
+argatroban	O
+were	O
+measured	O
+in	O
+these	O
+samples	O
+(	O
+range	O
+,	O
+0	O
+-	O
+32	O
+microg	O
+/	O
+mL	O
+)	O
+,	O
+and	O
+a	O
+prolonged	O
+plasma	O
+argatroban	O
+half	O
+life	O
+(	O
+t	O
+(	O
+1	O
+/	O
+2	O
+)	O
+)	O
+of	O
+514	O
+minutes	O
+was	O
+observed	O
+(	O
+published	O
+elimination	O
+t	O
+(	O
+1	O
+/	O
+2	O
+)	O
+is	O
+39	O
+-	O
+51	O
+minutes	O
+[	O
+<	O
+or	O
+=	O
+181	O
+minutes	O
+with	O
+hepatic	B
+impairment	I
+]	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Correlation	O
+of	O
+plasma	O
+argatroban	O
+concentration	O
+versus	O
+the	O
+patient	O
+'	O
+s	O
+coagulation	O
+variables	O
+and	O
+clinical	O
+course	O
+suggest	O
+that	O
+prolonged	O
+elevated	O
+levels	O
+of	O
+plasma	O
+argatroban	O
+may	O
+have	O
+contributed	O
+to	O
+the	O
+patient	O
+'	O
+s	O
+extended	O
+coagulopathy	B
+.	O
+
+Because	O
+DTIs	O
+do	O
+not	O
+have	O
+reversal	O
+agents	O
+,	O
+surgical	O
+teams	O
+and	O
+transfusion	O
+services	O
+should	O
+remain	O
+aware	O
+of	O
+the	O
+possibility	O
+of	O
+massive	O
+transfusion	O
+events	O
+during	O
+anticoagulation	O
+with	O
+these	O
+agents	O
+.	O
+
+This	O
+is	O
+the	O
+first	O
+report	O
+to	O
+measure	O
+plasma	O
+argatroban	O
+concentration	O
+in	O
+the	O
+context	O
+of	O
+CPB	O
+and	O
+extended	O
+coagulopathy	B
+.	O
+
+The	O
+effects	O
+of	O
+the	O
+adjunctive	O
+bupropion	O
+on	O
+male	O
+sexual	B
+dysfunction	I
+induced	O
+by	O
+a	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitor	O
+:	O
+a	O
+double	O
+-	O
+blind	O
+placebo	O
+-	O
+controlled	O
+and	O
+randomized	O
+study	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+determine	O
+the	O
+safety	O
+and	O
+efficacy	O
+of	O
+adjunctive	O
+bupropion	O
+sustained	O
+-	O
+release	O
+(	O
+SR	O
+)	O
+on	O
+male	O
+sexual	B
+dysfunction	I
+(	O
+SD	B
+)	O
+induced	O
+by	O
+a	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitor	O
+(	O
+SSRI	O
+)	O
+,	O
+as	O
+SD	B
+is	O
+a	O
+common	O
+side	O
+-	O
+effect	O
+of	O
+SSRIs	O
+and	O
+the	O
+most	O
+effective	O
+treatments	O
+have	O
+yet	O
+to	O
+be	O
+determined	O
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+The	O
+randomized	O
+sample	O
+consisted	O
+of	O
+234	O
+euthymic	O
+men	O
+who	O
+were	O
+receiving	O
+some	O
+type	O
+of	O
+SSRI	O
+.	O
+
+The	O
+men	O
+were	O
+randomly	O
+assigned	O
+to	O
+bupropion	O
+SR	O
+(	O
+150	O
+mg	O
+twice	O
+daily	O
+,	O
+117	O
+)	O
+or	O
+placebo	O
+(	O
+twice	O
+daily	O
+,	O
+117	O
+)	O
+for	O
+12	O
+weeks	O
+.	O
+
+Efficacy	O
+was	O
+evaluated	O
+using	O
+the	O
+Clinical	O
+Global	O
+Impression	O
+-	O
+Sexual	O
+Function	O
+(	O
+CGI	O
+-	O
+SF	O
+;	O
+the	O
+primary	O
+outcome	O
+measure	O
+)	O
+,	O
+the	O
+International	O
+Index	O
+of	O
+Erectile	O
+Function	O
+(	O
+IIEF	O
+)	O
+,	O
+Arizona	O
+Sexual	O
+Experience	O
+Scale	O
+(	O
+ASEX	O
+)	O
+,	O
+and	O
+Erectile	B
+Dysfunction	I
+Inventory	O
+of	O
+Treatment	O
+Satisfaction	O
+(	O
+EDITS	O
+)	O
+(	O
+secondary	O
+outcome	O
+measures	O
+)	O
+.	O
+
+Participants	O
+were	O
+followed	O
+biweekly	O
+during	O
+study	O
+period	O
+.	O
+
+RESULTS	O
+:	O
+After	O
+12	O
+weeks	O
+of	O
+treatment	O
+,	O
+the	O
+mean	O
+(	O
+sd	O
+)	O
+scores	O
+for	O
+CGI	O
+-	O
+SF	O
+were	O
+significantly	O
+lower	O
+,	O
+i	O
+.	O
+e	O
+.	O
+better	O
+,	O
+in	O
+patients	O
+on	O
+bupropion	O
+SR	O
+,	O
+at	O
+2	O
+.	O
+4	O
+(	O
+1	O
+.	O
+2	O
+)	O
+,	O
+than	O
+in	O
+the	O
+placebo	O
+group	O
+,	O
+at	O
+3	O
+.	O
+9	O
+(	O
+1	O
+.	O
+1	O
+)	O
+(	O
+P	O
+=	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+Men	O
+who	O
+received	O
+bupropion	O
+had	O
+a	O
+significant	O
+increase	O
+in	O
+the	O
+total	O
+IIEF	O
+score	O
+(	O
+54	O
+.	O
+4	O
+%	O
+vs	O
+1	O
+.	O
+2	O
+%	O
+;	O
+P	O
+=	O
+0	O
+.	O
+003	O
+)	O
+,	O
+and	O
+in	O
+the	O
+five	O
+different	O
+domains	O
+of	O
+the	O
+IIEF	O
+.	O
+
+Total	O
+ASEX	O
+scores	O
+were	O
+significantly	O
+lower	O
+,	O
+i	O
+.	O
+e	O
+.	O
+better	O
+,	O
+among	O
+men	O
+who	O
+received	O
+bupropion	O
+than	O
+placebo	O
+,	O
+at	O
+15	O
+.	O
+5	O
+(	O
+4	O
+.	O
+3	O
+)	O
+vs	O
+21	O
+.	O
+5	O
+(	O
+4	O
+.	O
+7	O
+)	O
+(	O
+P	O
+=	O
+0	O
+.	O
+002	O
+)	O
+.	O
+
+The	O
+EDITS	O
+scores	O
+were	O
+67	O
+.	O
+4	O
+(	O
+10	O
+.	O
+2	O
+)	O
+for	O
+the	O
+bupropion	O
+and	O
+36	O
+.	O
+3	O
+(	O
+11	O
+.	O
+7	O
+)	O
+for	O
+the	O
+placebo	O
+group	O
+(	O
+P	O
+=	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+The	O
+ASEX	O
+score	O
+and	O
+CGI	O
+-	O
+SF	O
+score	O
+were	O
+correlated	O
+(	O
+P	O
+=	O
+0	O
+.	O
+003	O
+)	O
+.	O
+
+In	O
+linear	O
+regression	O
+analyses	O
+the	O
+CGI	O
+-	O
+SF	O
+score	O
+was	O
+not	O
+affected	O
+significantly	O
+by	O
+the	O
+duration	O
+of	O
+SD	B
+,	O
+type	O
+of	O
+SSRI	O
+used	O
+and	O
+age	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Bupropion	O
+is	O
+an	O
+effective	O
+treatment	O
+for	O
+male	O
+SD	B
+induced	O
+by	O
+SSRIs	O
+.	O
+
+These	O
+results	O
+provide	O
+empirical	O
+support	O
+for	O
+conducting	O
+a	O
+further	O
+study	O
+of	O
+bupropion	O
+.	O
+
+Prevention	O
+of	O
+seizures	B
+and	O
+reorganization	O
+of	O
+hippocampal	O
+functions	O
+by	O
+transplantation	O
+of	O
+bone	O
+marrow	O
+cells	O
+in	O
+the	O
+acute	O
+phase	O
+of	O
+experimental	O
+epilepsy	B
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+investigated	O
+the	O
+therapeutic	O
+potential	O
+of	O
+bone	O
+marrow	O
+mononuclear	O
+cells	O
+(	O
+BMCs	O
+)	O
+in	O
+a	O
+model	O
+of	O
+epilepsy	B
+induced	O
+by	O
+pilocarpine	O
+in	O
+rats	O
+.	O
+
+BMCs	O
+obtained	O
+from	O
+green	O
+fluorescent	O
+protein	O
+(	O
+GFP	O
+)	O
+transgenic	O
+mice	O
+or	O
+rats	O
+were	O
+transplanted	O
+intravenously	O
+after	O
+induction	O
+of	O
+status	B
+epilepticus	I
+(	O
+SE	B
+)	O
+.	O
+
+Spontaneous	B
+recurrent	I
+seizures	I
+(	O
+SRS	B
+)	O
+were	O
+monitored	O
+using	O
+Racine	O
+'	O
+s	O
+seizure	B
+severity	O
+scale	O
+.	O
+
+All	O
+of	O
+the	O
+rats	O
+in	O
+the	O
+saline	O
+-	O
+treated	O
+epileptic	B
+control	O
+group	O
+developed	O
+SRS	B
+,	O
+whereas	O
+none	O
+of	O
+the	O
+BMC	O
+-	O
+treated	O
+epileptic	B
+animals	O
+had	O
+seizures	B
+in	O
+the	O
+short	O
+term	O
+(	O
+15	O
+days	O
+after	O
+transplantation	O
+)	O
+,	O
+regardless	O
+of	O
+the	O
+BMC	O
+source	O
+.	O
+
+Over	O
+the	O
+long	O
+-	O
+term	O
+chronic	O
+phase	O
+(	O
+120	O
+days	O
+after	O
+transplantation	O
+)	O
+,	O
+only	O
+25	O
+%	O
+of	O
+BMC	O
+-	O
+treated	O
+epileptic	B
+animals	O
+had	O
+seizures	B
+,	O
+but	O
+with	O
+a	O
+lower	O
+frequency	O
+and	O
+duration	O
+compared	O
+to	O
+the	O
+epileptic	B
+control	O
+group	O
+.	O
+
+The	O
+density	O
+of	O
+hippocampal	O
+neurons	O
+in	O
+the	O
+brains	O
+of	O
+animals	O
+treated	O
+with	O
+BMCs	O
+was	O
+markedly	O
+preserved	O
+.	O
+
+At	O
+hippocampal	O
+Schaeffer	O
+collateral	O
+-	O
+CA1	O
+synapses	O
+,	O
+long	O
+-	O
+term	O
+potentiation	O
+was	O
+preserved	O
+in	O
+BMC	O
+-	O
+transplanted	O
+rats	O
+compared	O
+to	O
+epileptic	B
+controls	O
+.	O
+
+The	O
+donor	O
+-	O
+derived	O
+GFP	O
+(	O
++	O
+)	O
+cells	O
+were	O
+rarely	O
+found	O
+in	O
+the	O
+brains	O
+of	O
+transplanted	O
+epileptic	B
+rats	O
+.	O
+
+In	O
+conclusion	O
+,	O
+treatment	O
+with	O
+BMCs	O
+can	O
+prevent	O
+the	O
+development	O
+of	O
+chronic	O
+seizures	B
+,	O
+reduce	O
+neuronal	B
+loss	I
+,	O
+and	O
+influence	O
+the	O
+reorganization	O
+of	O
+the	O
+hippocampal	O
+neuronal	O
+network	O
+.	O
+
+Normalizing	O
+effects	O
+of	O
+modafinil	O
+on	O
+sleep	O
+in	O
+chronic	O
+cocaine	O
+users	O
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+purpose	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+effect	O
+of	O
+morning	O
+-	O
+dosed	O
+modafinil	O
+on	O
+sleep	O
+and	O
+daytime	B
+sleepiness	I
+in	O
+chronic	O
+cocaine	O
+users	O
+.	O
+
+METHOD	O
+:	O
+Twenty	O
+cocaine	O
+-	O
+dependent	O
+participants	O
+were	O
+randomly	O
+assigned	O
+to	O
+receive	O
+modafinil	O
+,	O
+400	O
+mg	O
+(	O
+N	O
+=	O
+10	O
+)	O
+,	O
+or	O
+placebo	O
+(	O
+N	O
+=	O
+10	O
+)	O
+every	O
+morning	O
+at	O
+7	O
+:	O
+30	O
+a	O
+.	O
+m	O
+.	O
+for	O
+16	O
+days	O
+in	O
+an	O
+inpatient	O
+,	O
+double	O
+-	O
+blind	O
+randomized	O
+trial	O
+.	O
+
+Participants	O
+underwent	O
+polysomnographic	O
+sleep	O
+recordings	O
+on	O
+days	O
+1	O
+to	O
+3	O
+,	O
+7	O
+to	O
+9	O
+,	O
+and	O
+14	O
+to	O
+16	O
+(	O
+first	O
+,	O
+second	O
+,	O
+and	O
+third	O
+weeks	O
+of	O
+abstinence	O
+)	O
+.	O
+
+The	O
+Multiple	O
+Sleep	O
+Latency	O
+Test	O
+was	O
+performed	O
+at	O
+11	O
+:	O
+30	O
+a	O
+.	O
+m	O
+.	O
+,	O
+2	O
+:	O
+00	O
+p	O
+.	O
+m	O
+.	O
+,	O
+and	O
+4	O
+:	O
+30	O
+p	O
+.	O
+m	O
+.	O
+on	O
+days	O
+2	O
+,	O
+8	O
+,	O
+and	O
+15	O
+.	O
+
+For	O
+comparison	O
+of	O
+sleep	O
+architecture	O
+variables	O
+,	O
+12	O
+healthy	O
+comparison	O
+participants	O
+underwent	O
+a	O
+single	O
+night	O
+of	O
+experimental	O
+polysomnography	O
+that	O
+followed	O
+1	O
+night	O
+of	O
+accommodation	O
+polysomnography	O
+.	O
+
+RESULTS	O
+:	O
+Progressive	O
+abstinence	O
+from	O
+cocaine	O
+was	O
+associated	O
+with	O
+worsening	O
+of	O
+all	O
+measured	O
+polysomnographic	O
+sleep	O
+outcomes	O
+.	O
+
+Compared	O
+with	O
+placebo	O
+,	O
+modafinil	O
+decreased	O
+nighttime	O
+sleep	O
+latency	O
+and	O
+increased	O
+slow	O
+-	O
+wave	O
+sleep	O
+time	O
+in	O
+cocaine	O
+-	O
+dependent	O
+participants	O
+.	O
+
+The	O
+effect	O
+of	O
+modafinil	O
+interacted	O
+with	O
+the	O
+abstinence	O
+week	O
+and	O
+was	O
+associated	O
+with	O
+longer	O
+total	O
+sleep	O
+time	O
+and	O
+shorter	O
+REM	O
+sleep	O
+latency	O
+in	O
+the	O
+third	O
+week	O
+of	O
+abstinence	O
+.	O
+
+Comparison	O
+of	O
+slow	O
+-	O
+wave	O
+sleep	O
+time	O
+,	O
+total	O
+sleep	O
+time	O
+,	O
+and	O
+sleep	O
+latency	O
+in	O
+cocaine	O
+-	O
+dependent	O
+and	O
+healthy	O
+participants	O
+revealed	O
+a	O
+normalizing	O
+effect	O
+of	O
+modafinil	O
+in	O
+cocaine	O
+-	O
+dependent	O
+participants	O
+.	O
+
+Modafinil	O
+was	O
+associated	O
+with	O
+increased	O
+daytime	O
+sleep	O
+latency	O
+,	O
+as	O
+measured	O
+by	O
+the	O
+Multiple	O
+Sleep	O
+Latency	O
+Test	O
+,	O
+and	O
+a	O
+nearly	O
+significant	O
+decrease	O
+in	O
+subjective	O
+daytime	B
+sleepiness	I
+.	O
+
+CONCLUSIONS	O
+:	O
+Morning	O
+-	O
+dosed	O
+modafinil	O
+promotes	O
+nocturnal	O
+sleep	O
+,	O
+normalizes	O
+sleep	O
+architecture	O
+,	O
+and	O
+decreases	O
+daytime	B
+sleepiness	I
+in	O
+abstinent	O
+cocaine	O
+users	O
+.	O
+
+These	O
+effects	O
+may	O
+be	O
+relevant	O
+in	O
+the	O
+treatment	O
+of	O
+cocaine	O
+dependence	O
+.	O
+
+Safety	O
+of	O
+transesophageal	O
+echocardiography	O
+in	O
+adults	O
+:	O
+study	O
+in	O
+a	O
+multidisciplinary	O
+hospital	O
+.	O
+
+BACKGROUND	O
+:	O
+TEE	O
+is	O
+a	O
+semi	O
+-	O
+invasive	O
+tool	O
+broadly	O
+used	O
+and	O
+its	O
+utilization	O
+associated	O
+to	O
+sedatives	O
+drugs	O
+might	O
+to	O
+affect	O
+the	O
+procedure	O
+safety	O
+.	O
+
+OBJECTIVE	O
+:	O
+to	O
+analyze	O
+aspects	O
+of	O
+TEE	O
+safety	O
+associated	O
+to	O
+the	O
+use	O
+of	O
+Midazolan	O
+(	O
+MZ	O
+)	O
+and	O
+Flumazenil	O
+(	O
+FL	O
+)	O
+and	O
+the	O
+influence	O
+of	O
+the	O
+clinical	O
+variables	O
+on	O
+the	O
+event	O
+rate	O
+.	O
+
+METHOD	O
+:	O
+prospective	O
+study	O
+with	O
+137	O
+patients	O
+that	O
+underwent	O
+TEE	O
+with	O
+MZ	O
+associated	O
+to	O
+moderate	O
+sedation	O
+.	O
+
+We	O
+analyzed	O
+the	O
+following	O
+events	O
+:	O
+complications	O
+related	O
+with	O
+the	O
+topical	O
+anesthesia	O
+,	O
+with	O
+MZ	O
+use	O
+and	O
+with	O
+the	O
+procedure	O
+.	O
+
+Uni	O
+-	O
+and	O
+multivariate	O
+analyses	O
+were	O
+used	O
+to	O
+test	O
+the	O
+influence	O
+of	O
+the	O
+clinical	O
+variables	O
+:	O
+age	O
+,	O
+sex	O
+,	O
+stroke	B
+,	O
+myocardiopathy	B
+(	O
+MP	B
+)	O
+,	O
+duration	O
+of	O
+the	O
+test	O
+,	O
+mitral	B
+regurgitation	I
+(	O
+MR	B
+)	O
+and	O
+the	O
+MZ	O
+dose	O
+.	O
+
+RESULTS	O
+:	O
+All	O
+patients	O
+(	O
+65	O
++	O
+/	O
+-	O
+16	O
+yrs	O
+;	O
+58	O
+%	O
+males	O
+)	O
+finished	O
+the	O
+examination	O
+.	O
+
+The	O
+mean	O
+doses	O
+of	O
+MZ	O
+and	O
+FL	O
+were	O
+4	O
+.	O
+3	O
++	O
+/	O
+-	O
+1	O
+.	O
+9	O
+mg	O
+and	O
+0	O
+.	O
+28	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+mg	O
+,	O
+respectively	O
+.	O
+
+The	O
+duration	O
+of	O
+the	O
+examination	O
+and	O
+the	O
+mean	O
+ejection	O
+fraction	O
+(	O
+EF	O
+)	O
+were	O
+16	O
+.	O
+4	O
++	O
+/	O
+-	O
+6	O
+.	O
+1	O
+minutes	O
+and	O
+60	O
++	O
+/	O
+-	O
+9	O
+%	O
+,	O
+respectively	O
+.	O
+
+Mild	O
+hypoxia	B
+(	O
+SO2	O
+<	O
+90	O
+%	O
+)	O
+was	O
+the	O
+most	O
+common	O
+event	O
+(	O
+11	O
+patients	O
+)	O
+;	O
+3	O
+patients	O
+(	O
+2	O
+%	O
+)	O
+presented	O
+transient	O
+hypoxia	B
+due	O
+to	O
+upper	O
+airway	B
+obstruction	I
+by	O
+probe	O
+introduction	O
+and	O
+8	O
+(	O
+5	O
+.	O
+8	O
+%	O
+)	O
+due	O
+to	O
+hypoxia	B
+caused	O
+by	O
+MZ	O
+use	O
+.	O
+
+Transient	O
+hypotension	B
+(	O
+SAP	O
+<	O
+90mmHg	O
+)	O
+occurred	O
+in	O
+1	O
+patient	O
+(	O
+0	O
+.	O
+7	O
+%	O
+)	O
+.	O
+
+The	O
+multivariate	O
+analysis	O
+showed	O
+that	O
+severe	O
+MR	B
+,	O
+MP	B
+(	O
+EF	O
+<	O
+45	O
+%	O
+)	O
+and	O
+high	O
+doses	O
+of	O
+MZ	O
+(	O
+>	O
+5mg	O
+)	O
+were	O
+associated	O
+with	O
+events	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+The	O
+EF	O
+was	O
+40	O
+%	O
+,	O
+in	O
+the	O
+group	O
+with	O
+MP	B
+and	O
+44	O
+%	O
+in	O
+the	O
+group	O
+with	O
+severe	O
+MR	B
+and	O
+it	O
+can	O
+be	O
+a	O
+factor	O
+associated	O
+with	O
+clinical	O
+events	O
+in	O
+the	O
+last	O
+group	O
+.	O
+
+CONCLUSION	O
+:	O
+TEE	O
+with	O
+sedation	O
+presents	O
+a	O
+low	O
+rate	O
+of	O
+events	O
+.	O
+
+There	O
+were	O
+no	O
+severe	O
+events	O
+and	O
+there	O
+was	O
+no	O
+need	O
+to	O
+interrupt	O
+the	O
+examinations	O
+.	O
+
+Effect	O
+of	O
+direct	O
+intracoronary	O
+administration	O
+of	O
+methylergonovine	O
+in	O
+patients	O
+with	O
+and	O
+without	O
+variant	B
+angina	I
+.	O
+
+The	O
+effects	O
+of	O
+intracoronary	O
+administration	O
+of	O
+methylergonovine	O
+were	O
+studied	O
+in	O
+21	O
+patients	O
+with	O
+variant	B
+angina	I
+and	O
+22	O
+patients	O
+with	O
+atypical	O
+chest	B
+pain	I
+and	O
+in	O
+others	O
+without	O
+angina	B
+pectoris	I
+(	O
+control	O
+group	O
+)	O
+.	O
+
+Methylergonovine	O
+was	O
+administered	O
+continuously	O
+at	O
+a	O
+rate	O
+of	O
+10	O
+micrograms	O
+/	O
+min	O
+up	O
+to	O
+50	O
+micrograms	O
+.	O
+
+In	O
+all	O
+patients	O
+with	O
+variant	B
+angina	I
+,	O
+coronary	B
+spasm	I
+was	O
+provoked	O
+at	O
+a	O
+mean	O
+dose	O
+of	O
+28	O
++	O
+/	O
+-	O
+13	O
+micrograms	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+)	O
+.	O
+
+In	O
+the	O
+control	O
+group	O
+neither	O
+ischemic	O
+ST	O
+change	O
+nor	O
+localized	O
+spasm	B
+occurred	O
+.	O
+
+The	O
+basal	O
+tone	O
+of	O
+the	O
+right	O
+coronary	O
+artery	O
+was	O
+significantly	O
+lower	O
+than	O
+that	O
+of	O
+the	O
+left	O
+coronary	O
+artery	O
+.	O
+
+The	O
+percentage	O
+of	O
+vasoconstriction	O
+of	O
+the	O
+right	O
+coronary	O
+artery	O
+was	O
+significantly	O
+higher	O
+than	O
+that	O
+of	O
+the	O
+left	O
+coronary	O
+artery	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+spasm	B
+provocation	O
+tests	O
+,	O
+which	O
+use	O
+an	O
+intracoronary	O
+injection	O
+of	O
+a	O
+relatively	O
+low	O
+dose	O
+of	O
+methylergonovine	O
+,	O
+have	O
+a	O
+high	O
+sensitivity	O
+in	O
+variant	B
+angina	I
+and	O
+the	O
+vasoreactivity	O
+of	O
+the	O
+right	O
+coronary	O
+artery	O
+may	O
+be	O
+greater	O
+than	O
+that	O
+of	O
+the	O
+other	O
+coronary	O
+arteries	O
+.	O
+
+Oral	O
+manifestations	O
+of	O
+"	O
+meth	B
+mouth	I
+"	O
+:	O
+a	O
+case	O
+report	O
+.	O
+
+AIM	O
+:	O
+The	O
+aim	O
+of	O
+the	O
+documentation	O
+of	O
+this	O
+clinical	O
+case	O
+is	O
+to	O
+make	O
+clinicians	O
+aware	O
+of	O
+"	O
+meth	B
+mouth	I
+"	O
+and	O
+the	O
+medical	O
+risks	O
+associated	O
+with	O
+this	O
+serious	O
+condition	O
+.	O
+
+BACKGROUND	O
+:	O
+Methamphetamine	O
+is	O
+a	O
+very	O
+addictive	O
+,	O
+powerful	O
+stimulant	O
+that	O
+increases	O
+wakefulness	O
+and	O
+physical	O
+activity	O
+and	O
+can	O
+produce	O
+other	O
+effects	O
+such	O
+as	O
+cardiac	B
+dysrhythmias	I
+,	O
+hypertension	B
+,	O
+hallucinations	B
+,	O
+and	O
+violent	B
+behavior	I
+.	O
+
+Dental	O
+patients	O
+abusing	O
+methamphetamine	O
+can	O
+present	O
+with	O
+poor	O
+oral	O
+hygiene	O
+,	O
+xerostomia	B
+,	O
+rampant	O
+caries	B
+(	O
+"	O
+meth	B
+mouth	I
+"	O
+)	O
+,	O
+and	O
+excessive	O
+tooth	B
+wear	I
+.	O
+
+Oral	O
+rehabilitation	O
+of	O
+patients	O
+using	O
+methamphetamine	O
+can	O
+be	O
+challenging	O
+.	O
+
+CASE	O
+DESCRIPTION	O
+:	O
+A	O
+30	O
+-	O
+year	O
+-	O
+old	O
+Caucasian	O
+woman	O
+presented	O
+with	O
+dental	O
+pain	B
+,	O
+bad	B
+breath	I
+,	O
+and	O
+self	O
+-	O
+reported	O
+poor	O
+esthetics	O
+.	O
+
+A	O
+comprehensive	O
+examination	O
+including	O
+her	O
+medical	O
+history	O
+,	O
+panoramic	O
+radiograph	O
+,	O
+and	O
+intraoral	O
+examination	O
+revealed	O
+19	O
+carious	B
+lesions	I
+,	O
+which	O
+is	O
+not	O
+very	O
+common	O
+for	O
+a	O
+healthy	O
+adult	O
+.	O
+
+She	O
+reported	O
+her	O
+use	O
+of	O
+methamphetamine	O
+for	O
+five	O
+years	O
+and	O
+had	O
+not	O
+experienced	O
+any	O
+major	O
+carious	B
+episodes	I
+before	O
+she	O
+started	O
+using	O
+the	O
+drug	O
+.	O
+
+SUMMARY	O
+:	O
+The	O
+patient	O
+'	O
+s	O
+medical	O
+and	O
+dental	O
+histories	O
+along	O
+with	O
+radiographic	O
+and	O
+clinical	O
+findings	O
+lead	O
+to	O
+a	O
+diagnosis	O
+of	O
+"	O
+meth	B
+mouth	I
+.	O
+"	O
+Although	O
+three	O
+different	O
+dental	O
+treatment	O
+modalities	O
+(	O
+either	O
+conventional	O
+or	O
+implant	O
+-	O
+supported	O
+)	O
+have	O
+been	O
+offered	O
+to	O
+the	O
+patient	O
+since	O
+August	O
+2007	O
+,	O
+the	O
+patient	O
+has	O
+yet	O
+to	O
+initiate	O
+any	O
+treatment	O
+.	O
+
+CLINICAL	O
+SIGNIFICANCE	O
+:	O
+This	O
+clinical	O
+case	O
+showing	O
+oral	O
+manifestations	O
+of	O
+meth	B
+mouth	I
+was	O
+presented	O
+to	O
+help	O
+dental	O
+practitioners	O
+recognize	O
+and	O
+manage	O
+patients	O
+who	O
+may	O
+be	O
+abusing	O
+methamphetamines	O
+.	O
+
+Dental	O
+practitioners	O
+also	O
+may	O
+be	O
+skeptical	O
+about	O
+the	O
+reliability	O
+of	O
+appointment	O
+keeping	O
+by	O
+these	O
+patients	O
+,	O
+as	O
+they	O
+frequently	O
+miss	O
+their	O
+appointments	O
+without	O
+reasonable	O
+justification	O
+.	O
+
+Antituberculosis	O
+therapy	O
+-	O
+induced	O
+acute	B
+liver	I
+failure	I
+:	O
+magnitude	O
+,	O
+profile	O
+,	O
+prognosis	O
+,	O
+and	O
+predictors	O
+of	O
+outcome	O
+.	O
+
+Antituberculosis	O
+therapy	O
+(	O
+ATT	O
+)	O
+-	O
+associated	O
+acute	B
+liver	I
+failure	I
+(	O
+ATT	O
+-	O
+ALF	B
+)	O
+is	O
+the	O
+commonest	O
+drug	O
+-	O
+induced	O
+ALF	B
+in	O
+South	O
+Asia	O
+.	O
+
+Prospective	O
+studies	O
+on	O
+ATT	O
+-	O
+ALF	B
+are	O
+lacking	O
+.	O
+
+The	O
+current	O
+study	O
+prospectively	O
+evaluated	O
+the	O
+magnitude	O
+,	O
+clinical	O
+course	O
+,	O
+outcome	O
+,	O
+and	O
+prognostic	O
+factors	O
+in	O
+ATT	O
+-	O
+ALF	B
+.	O
+
+From	O
+January	O
+1986	O
+to	O
+January	O
+2009	O
+,	O
+1223	O
+consecutive	O
+ALF	B
+patients	O
+were	O
+evaluated	O
+:	O
+ATT	O
+alone	O
+was	O
+the	O
+cause	O
+in	O
+70	O
+(	O
+5	O
+.	O
+7	O
+%	O
+)	O
+patients	O
+.	O
+
+Another	O
+15	O
+(	O
+1	O
+.	O
+2	O
+%	O
+)	O
+had	O
+ATT	O
+and	O
+simultaneous	O
+hepatitis	B
+virus	I
+infection	I
+.	O
+
+In	O
+44	O
+(	O
+62	O
+.	O
+8	O
+%	O
+)	O
+patients	O
+,	O
+ATT	O
+was	O
+prescribed	O
+empirically	O
+without	O
+definitive	O
+evidence	O
+of	O
+tuberculosis	B
+.	O
+
+ATT	O
+-	O
+ALF	B
+patients	O
+were	O
+younger	O
+(	O
+32	O
+.	O
+87	O
+[	O
++	O
+/	O
+-	O
+15	O
+.	O
+8	O
+]	O
+years	O
+)	O
+,	O
+and	O
+49	O
+(	O
+70	O
+%	O
+)	O
+of	O
+them	O
+were	O
+women	O
+.	O
+
+Most	O
+had	O
+hyperacute	O
+presentation	O
+;	O
+the	O
+median	O
+icterus	B
+encephalopathy	B
+interval	O
+was	O
+4	O
+.	O
+5	O
+(	O
+0	O
+-	O
+30	O
+)	O
+days	O
+.	O
+
+The	O
+median	O
+duration	O
+of	O
+ATT	O
+before	O
+ALF	B
+was	O
+30	O
+(	O
+7	O
+-	O
+350	O
+)	O
+days	O
+.	O
+
+At	O
+presentation	O
+,	O
+advanced	O
+encephalopathy	B
+and	O
+cerebral	B
+edema	I
+were	O
+present	O
+in	O
+51	O
+(	O
+76	O
+%	O
+)	O
+and	O
+29	O
+(	O
+41	O
+.	O
+4	O
+%	O
+)	O
+patients	O
+,	O
+respectively	O
+.	O
+
+Gastrointestinal	B
+bleed	I
+,	O
+seizures	B
+,	O
+infection	B
+,	O
+and	O
+acute	B
+renal	I
+failure	I
+were	O
+documented	O
+in	O
+seven	O
+(	O
+10	O
+%	O
+)	O
+,	O
+five	O
+(	O
+7	O
+.	O
+1	O
+%	O
+)	O
+,	O
+26	O
+(	O
+37	O
+.	O
+1	O
+%	O
+)	O
+,	O
+and	O
+seven	O
+(	O
+10	O
+%	O
+)	O
+patients	O
+,	O
+respectively	O
+.	O
+
+Compared	O
+with	O
+hepatitis	B
+E	I
+virus	O
+(	O
+HEV	O
+)	O
+and	O
+non	O
+-	O
+A	O
+non	O
+-	O
+E	O
+-	O
+induced	O
+ALF	B
+,	O
+ATT	O
+-	O
+ALF	B
+patients	O
+had	O
+nearly	O
+similar	O
+presentations	O
+except	O
+for	O
+older	O
+age	O
+and	O
+less	O
+elevation	O
+of	O
+liver	O
+enzymes	O
+.	O
+
+The	O
+mortality	O
+rate	O
+among	O
+patients	O
+with	O
+ATT	O
+-	O
+ALF	B
+was	O
+high	O
+(	O
+67	O
+.	O
+1	O
+%	O
+,	O
+n	O
+=	O
+47	O
+)	O
+,	O
+and	O
+only	O
+23	O
+(	O
+32	O
+.	O
+9	O
+%	O
+)	O
+patients	O
+recovered	O
+with	O
+medical	O
+treatment	O
+.	O
+
+In	O
+multivariate	O
+analysis	O
+,	O
+three	O
+factors	O
+independently	O
+predicted	O
+mortality	O
+:	O
+serum	O
+bilirubin	O
+(	O
+>	O
+or	O
+=	O
+10	O
+.	O
+8	O
+mg	O
+/	O
+dL	O
+)	O
+,	O
+prothrombin	O
+time	O
+(	O
+PT	O
+)	O
+prolongation	O
+(	O
+>	O
+or	O
+=	O
+26	O
+seconds	O
+)	O
+,	O
+and	O
+grade	O
+III	O
+/	O
+IV	O
+encephalopathy	B
+at	O
+presentation	O
+.	O
+
+CONCLUSION	O
+:	O
+ATT	O
+-	O
+ALF	B
+constituted	O
+5	O
+.	O
+7	O
+%	O
+of	O
+ALF	B
+at	O
+our	O
+center	O
+and	O
+had	O
+a	O
+high	O
+mortality	O
+rate	O
+.	O
+
+Because	O
+the	O
+mortality	O
+rate	O
+is	O
+so	O
+high	O
+,	O
+determining	O
+which	O
+factors	O
+are	O
+predictors	O
+is	O
+less	O
+important	O
+.	O
+
+A	O
+high	O
+proportion	O
+of	O
+patients	O
+had	O
+consumed	O
+ATT	O
+empirically	O
+,	O
+which	O
+could	O
+have	O
+been	O
+prevented	O
+.	O
+
+Design	O
+and	O
+analysis	O
+of	O
+the	O
+HYPREN	O
+-	O
+trial	O
+:	O
+safety	O
+of	O
+enalapril	O
+and	O
+prazosin	O
+in	O
+the	O
+initial	O
+treatment	O
+phase	O
+of	O
+patients	O
+with	O
+congestive	B
+heart	I
+failure	I
+.	O
+
+Since	O
+the	O
+introduction	O
+of	O
+angiotensin	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+inhibitors	O
+into	O
+the	O
+adjunctive	O
+treatment	O
+of	O
+patients	O
+with	O
+congestive	B
+heart	I
+failure	I
+,	O
+cases	O
+of	O
+severe	O
+hypotension	B
+,	O
+especially	O
+on	O
+the	O
+first	O
+day	O
+of	O
+treatment	O
+,	O
+have	O
+occasionally	O
+been	O
+reported	O
+.	O
+
+To	O
+assess	O
+the	O
+safety	O
+of	O
+the	O
+ACE	O
+inhibitor	O
+enalapril	O
+a	O
+multicenter	O
+,	O
+randomized	O
+,	O
+prazosin	O
+-	O
+controlled	O
+trial	O
+was	O
+designed	O
+that	O
+compared	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+symptomatic	O
+hypotension	B
+on	O
+the	O
+first	O
+day	O
+of	O
+treatment	O
+.	O
+
+Trial	O
+medication	O
+was	O
+2	O
+.	O
+5	O
+mg	O
+enalapril	O
+or	O
+0	O
+.	O
+5	O
+prazosin	O
+.	O
+
+Subjects	O
+were	O
+1210	O
+inpatients	O
+with	O
+New	O
+York	O
+Heart	O
+Association	O
+(	O
+NYHA	O
+)	O
+functional	O
+class	O
+II	O
+and	O
+III	O
+.	O
+
+Patients	O
+who	O
+received	O
+enalapril	O
+experienced	O
+clinically	O
+and	O
+statistically	O
+significantly	O
+less	O
+symptomatic	O
+hypotension	B
+(	O
+5	O
+.	O
+2	O
+%	O
+)	O
+than	O
+the	O
+patients	O
+who	O
+received	O
+prazosin	O
+(	O
+12	O
+.	O
+9	O
+%	O
+)	O
+.	O
+
+All	O
+patients	O
+recovered	O
+.	O
+
+It	O
+was	O
+concluded	O
+that	O
+treatment	O
+with	O
+enalapril	O
+was	O
+well	O
+tolerated	O
+and	O
+it	O
+is	O
+,	O
+therefore	O
+,	O
+unreasonable	O
+to	O
+restrict	O
+the	O
+initiation	O
+of	O
+treatment	O
+with	O
+enalapril	O
+to	O
+inpatients	O
+.	O
+
+Central	B
+nervous	I
+system	I
+complications	I
+during	O
+treatment	O
+of	O
+acute	B
+lymphoblastic	I
+leukemia	I
+in	O
+a	O
+single	O
+pediatric	O
+institution	O
+.	O
+
+Central	B
+nervous	I
+system	I
+(	I
+CNS	I
+)	I
+complications	I
+during	O
+treatment	O
+of	O
+childhood	O
+acute	B
+lymphoblastic	I
+leukemia	I
+(	O
+ALL	B
+)	O
+remain	O
+a	O
+challenging	O
+clinical	O
+problem	O
+.	O
+
+Outcome	O
+improvement	O
+with	O
+more	O
+intensive	O
+chemotherapy	O
+has	O
+significantly	O
+increased	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+adverse	O
+events	O
+.	O
+
+This	O
+study	O
+analyzed	O
+the	O
+incidence	O
+of	O
+neurological	B
+complications	I
+during	O
+ALL	B
+treatment	O
+in	O
+a	O
+single	O
+pediatric	O
+institution	O
+,	O
+focusing	O
+on	O
+clinical	O
+,	O
+radiological	O
+,	O
+and	O
+electrophysiological	O
+findings	O
+.	O
+
+Exclusion	O
+criteria	O
+included	O
+CNS	O
+leukemic	B
+infiltration	I
+at	O
+diagnosis	O
+,	O
+therapy	O
+-	O
+related	O
+peripheral	B
+neuropathy	I
+,	O
+late	O
+-	O
+onset	O
+encephalopathy	B
+,	O
+or	O
+long	O
+-	O
+term	O
+neurocognitive	B
+defects	I
+.	O
+
+During	O
+a	O
+9	O
+-	O
+year	O
+period	O
+,	O
+we	O
+retrospectively	O
+collected	O
+27	O
+neurological	O
+events	O
+(	O
+11	O
+%	O
+)	O
+in	O
+as	O
+many	O
+patients	O
+,	O
+from	O
+253	O
+children	O
+enrolled	O
+in	O
+the	O
+ALL	B
+front	O
+-	O
+line	O
+protocol	O
+.	O
+
+CNS	O
+complications	O
+included	O
+posterior	O
+reversible	O
+leukoencephalopathy	B
+syndrome	O
+(	O
+n	O
+=	O
+10	O
+)	O
+,	O
+stroke	B
+(	O
+n	O
+=	O
+5	O
+)	O
+,	O
+temporal	B
+lobe	I
+epilepsy	I
+(	O
+n	O
+=	O
+2	O
+)	O
+,	O
+high	O
+-	O
+dose	O
+methotrexate	O
+toxicity	B
+(	O
+n	O
+=	O
+2	O
+)	O
+,	O
+syndrome	O
+of	O
+inappropriate	B
+antidiuretic	I
+hormone	I
+secretion	I
+(	O
+n	O
+=	O
+1	O
+)	O
+,	O
+and	O
+other	O
+unclassified	O
+events	O
+(	O
+n	O
+=	O
+7	O
+)	O
+.	O
+
+In	O
+conclusion	O
+,	O
+CNS	O
+complications	O
+are	O
+frequent	O
+events	O
+during	O
+ALL	B
+therapy	O
+,	O
+and	O
+require	O
+rapid	O
+detection	O
+and	O
+prompt	O
+treatment	O
+to	O
+limit	O
+permanent	O
+damage	O
+.	O
+
+Cocaine	O
+causes	O
+memory	B
+and	I
+learning	I
+impairments	I
+in	O
+rats	O
+:	O
+involvement	O
+of	O
+nuclear	O
+factor	O
+kappa	O
+B	O
+and	O
+oxidative	O
+stress	O
+,	O
+and	O
+prevention	O
+by	O
+topiramate	O
+.	O
+
+Different	O
+mechanisms	O
+have	O
+been	O
+suggested	O
+for	O
+cocaine	O
+toxicity	B
+including	O
+an	O
+increase	O
+in	O
+oxidative	O
+stress	O
+but	O
+the	O
+association	O
+between	O
+oxidative	O
+status	O
+in	O
+the	O
+brain	O
+and	O
+cocaine	O
+induced	O
+-	O
+behaviour	O
+is	O
+poorly	O
+understood	O
+.	O
+
+Nuclear	O
+factor	O
+kappa	O
+B	O
+(	O
+NFkappaB	O
+)	O
+is	O
+a	O
+sensor	O
+of	O
+oxidative	O
+stress	O
+and	O
+participates	O
+in	O
+memory	O
+formation	O
+that	O
+could	O
+be	O
+involved	O
+in	O
+drug	O
+toxicity	B
+and	O
+addiction	O
+mechanisms	O
+.	O
+
+Therefore	O
+NFkappaB	O
+activity	O
+,	O
+oxidative	O
+stress	O
+,	O
+neuronal	O
+nitric	O
+oxide	O
+synthase	O
+(	O
+nNOS	O
+)	O
+activity	O
+,	O
+spatial	O
+learning	O
+and	O
+memory	O
+as	O
+well	O
+as	O
+the	O
+effect	O
+of	O
+topiramate	O
+,	O
+a	O
+previously	O
+proposed	O
+therapy	O
+for	O
+cocaine	B
+addiction	I
+,	O
+were	O
+evaluated	O
+in	O
+an	O
+experimental	O
+model	O
+of	O
+cocaine	O
+administration	O
+in	O
+rats	O
+.	O
+
+NFkappaB	O
+activity	O
+was	O
+decreased	O
+in	O
+the	O
+frontal	O
+cortex	O
+of	O
+cocaine	O
+treated	O
+rats	O
+,	O
+as	O
+well	O
+as	O
+GSH	O
+concentration	O
+and	O
+glutathione	O
+peroxidase	O
+activity	O
+in	O
+the	O
+hippocampus	O
+,	O
+whereas	O
+nNOS	O
+activity	O
+in	O
+the	O
+hippocampus	O
+was	O
+increased	O
+.	O
+
+Memory	O
+retrieval	O
+of	O
+experiences	O
+acquired	O
+prior	O
+to	O
+cocaine	O
+administration	O
+was	O
+impaired	O
+and	O
+negatively	O
+correlated	O
+with	O
+NFkappaB	O
+activity	O
+in	O
+the	O
+frontal	O
+cortex	O
+.	O
+
+In	O
+contrast	O
+,	O
+learning	O
+of	O
+new	O
+tasks	O
+was	O
+enhanced	O
+and	O
+correlated	O
+with	O
+the	O
+increase	O
+of	O
+nNOS	O
+activity	O
+and	O
+the	O
+decrease	O
+of	O
+glutathione	O
+peroxidase	O
+.	O
+
+These	O
+results	O
+provide	O
+evidence	O
+for	O
+a	O
+possible	O
+mechanistic	O
+role	O
+of	O
+oxidative	O
+and	O
+nitrosative	O
+stress	O
+and	O
+NFkappaB	O
+in	O
+the	O
+alterations	O
+induced	O
+by	O
+cocaine	O
+.	O
+
+Topiramate	O
+prevented	O
+all	O
+the	O
+alterations	O
+observed	O
+,	O
+showing	O
+novel	O
+neuroprotective	O
+properties	O
+.	O
+
+Efficacy	O
+and	O
+safety	O
+of	O
+asenapine	O
+in	O
+a	O
+placebo	O
+-	O
+and	O
+haloperidol	O
+-	O
+controlled	O
+trial	O
+in	O
+patients	O
+with	O
+acute	O
+exacerbation	O
+of	O
+schizophrenia	B
+.	O
+
+Asenapine	O
+is	O
+approved	O
+by	O
+the	O
+Food	O
+and	O
+Drugs	O
+Administration	O
+in	O
+adults	O
+for	O
+acute	O
+treatment	O
+of	O
+schizophrenia	B
+or	O
+of	O
+manic	B
+or	O
+mixed	O
+episodes	O
+associated	O
+with	O
+bipolar	B
+I	I
+disorder	I
+with	O
+or	O
+without	O
+psychotic	B
+features	O
+.	O
+
+In	O
+a	O
+double	O
+-	O
+blind	O
+6	O
+-	O
+week	O
+trial	O
+,	O
+458	O
+patients	O
+with	O
+acute	O
+schizophrenia	B
+were	O
+randomly	O
+assigned	O
+to	O
+fixed	O
+-	O
+dose	O
+treatment	O
+with	O
+asenapine	O
+at	O
+5	O
+mg	O
+twice	O
+daily	O
+(	O
+BID	O
+)	O
+,	O
+asenapine	O
+at	O
+10	O
+mg	O
+BID	O
+,	O
+placebo	O
+,	O
+or	O
+haloperidol	O
+at	O
+4	O
+mg	O
+BID	O
+(	O
+to	O
+verify	O
+assay	O
+sensitivity	O
+)	O
+.	O
+
+With	O
+last	O
+observations	O
+carried	O
+forward	O
+(	O
+LOCF	O
+)	O
+,	O
+mean	O
+Positive	O
+and	O
+Negative	O
+Syndrome	O
+Scale	O
+total	O
+score	O
+reductions	O
+from	O
+baseline	O
+to	O
+endpoint	O
+were	O
+significantly	O
+greater	O
+with	O
+asenapine	O
+at	O
+5	O
+mg	O
+BID	O
+(	O
+-	O
+16	O
+.	O
+2	O
+)	O
+and	O
+haloperidol	O
+(	O
+-	O
+15	O
+.	O
+4	O
+)	O
+than	O
+placebo	O
+(	O
+-	O
+10	O
+.	O
+7	O
+;	O
+both	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+;	O
+using	O
+mixed	O
+model	O
+for	O
+repeated	O
+measures	O
+(	O
+MMRM	O
+)	O
+,	O
+changes	O
+at	O
+day	O
+42	O
+were	O
+significantly	O
+greater	O
+with	O
+asenapine	O
+at	O
+5	O
+and	O
+10	O
+mg	O
+BID	O
+(	O
+-	O
+21	O
+.	O
+3	O
+and	O
+-	O
+19	O
+.	O
+4	O
+,	O
+respectively	O
+)	O
+and	O
+haloperidol	O
+(	O
+-	O
+20	O
+.	O
+0	O
+)	O
+than	O
+placebo	O
+(	O
+-	O
+14	O
+.	O
+6	O
+;	O
+all	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+On	O
+the	O
+Positive	O
+and	O
+Negative	O
+Syndrome	O
+Scale	O
+positive	O
+subscale	O
+,	O
+all	O
+treatments	O
+were	O
+superior	O
+to	O
+placebo	O
+with	O
+LOCF	O
+and	O
+MMRM	O
+;	O
+asenapine	O
+at	O
+5	O
+mg	O
+BID	O
+was	O
+superior	O
+to	O
+placebo	O
+on	O
+the	O
+negative	O
+subscale	O
+with	O
+MMRM	O
+and	O
+on	O
+the	O
+general	O
+psychopathology	O
+subscale	O
+with	O
+LOCF	O
+and	O
+MMRM	O
+.	O
+
+Treatment	O
+-	O
+related	O
+adverse	O
+events	O
+(	O
+AEs	O
+)	O
+occurred	O
+in	O
+44	O
+%	O
+and	O
+52	O
+%	O
+,	O
+57	O
+%	O
+,	O
+and	O
+41	O
+%	O
+of	O
+the	O
+asenapine	O
+at	O
+5	O
+and	O
+10	O
+mg	O
+BID	O
+,	O
+haloperidol	O
+,	O
+and	O
+placebo	O
+groups	O
+,	O
+respectively	O
+.	O
+
+Extrapyramidal	B
+symptoms	I
+reported	O
+as	O
+AEs	O
+occurred	O
+in	O
+15	O
+%	O
+and	O
+18	O
+%	O
+,	O
+34	O
+%	O
+,	O
+and	O
+10	O
+%	O
+of	O
+the	O
+asenapine	O
+at	O
+5	O
+and	O
+10	O
+mg	O
+BID	O
+,	O
+haloperidol	O
+,	O
+and	O
+placebo	O
+groups	O
+,	O
+respectively	O
+.	O
+
+Across	O
+all	O
+groups	O
+,	O
+no	O
+more	O
+than	O
+5	O
+%	O
+of	O
+patients	O
+had	O
+clinically	O
+significant	O
+weight	O
+change	O
+.	O
+
+Post	O
+hoc	O
+analyses	O
+indicated	O
+that	O
+efficacy	O
+was	O
+similar	O
+with	O
+asenapine	O
+and	O
+haloperidol	O
+;	O
+greater	O
+contrasts	O
+were	O
+seen	O
+in	O
+AEs	O
+,	O
+especially	O
+extrapyramidal	B
+symptoms	I
+.	O
+
+Salvage	O
+therapy	O
+with	O
+nelarabine	O
+,	O
+etoposide	O
+,	O
+and	O
+cyclophosphamide	O
+in	O
+relapsed	O
+/	O
+refractory	O
+paediatric	O
+T	B
+-	I
+cell	I
+lymphoblastic	I
+leukaemia	I
+and	I
+lymphoma	I
+.	O
+
+A	O
+combination	O
+of	O
+5	O
+d	O
+of	O
+nelarabine	O
+(	O
+AraG	O
+)	O
+with	O
+5	O
+d	O
+of	O
+etoposide	O
+(	O
+VP	O
+)	O
+and	O
+cyclophosphamide	O
+(	O
+CPM	O
+)	O
+and	O
+prophylactic	O
+intrathecal	O
+chemotherapy	O
+was	O
+used	O
+as	O
+salvage	O
+therapy	O
+in	O
+seven	O
+children	O
+with	O
+refractory	O
+or	O
+relapsed	O
+T	B
+-	I
+cell	I
+leukaemia	I
+or	I
+lymphoma	I
+.	O
+
+The	O
+most	O
+common	O
+side	O
+effects	O
+attributable	O
+to	O
+the	O
+AraG	O
+included	O
+Grade	O
+2	O
+and	O
+3	O
+sensory	O
+and	O
+motor	O
+neuropathy	B
+and	O
+musculoskeletal	B
+pain	I
+.	O
+
+Haematological	B
+toxicity	I
+was	O
+greater	O
+for	O
+the	O
+combination	O
+than	O
+AraG	O
+alone	O
+,	O
+although	O
+median	O
+time	O
+to	O
+neutrophil	O
+and	O
+platelet	O
+recovery	O
+was	O
+consistent	O
+with	O
+other	O
+salvage	O
+therapies	O
+.	O
+
+All	O
+patients	O
+had	O
+some	O
+response	O
+to	O
+the	O
+combined	O
+therapy	O
+and	O
+five	O
+of	O
+the	O
+seven	O
+went	O
+into	O
+complete	O
+remission	O
+after	O
+one	O
+or	O
+two	O
+courses	O
+of	O
+AraG	O
+/	O
+VP	O
+/	O
+CPM	O
+.	O
+
+Our	O
+experience	O
+supports	O
+the	O
+safety	O
+of	O
+giving	O
+AraG	O
+as	O
+salvage	O
+therapy	O
+in	O
+synchrony	O
+with	O
+etoposide	O
+and	O
+cyclophosphamide	O
+,	O
+although	O
+neurological	B
+toxicity	I
+must	O
+be	O
+closely	O
+monitored	O
+.	O
+
+Effect	O
+of	O
+adriamycin	O
+combined	O
+with	O
+whole	O
+body	O
+hyperthermia	B
+on	O
+tumor	B
+and	O
+normal	O
+tissues	O
+.	O
+
+Thermal	O
+enhancement	O
+of	O
+Adriamycin	O
+-	O
+mediated	O
+antitumor	O
+activity	O
+and	O
+normal	O
+tissue	O
+toxicities	B
+by	O
+whole	O
+body	O
+hyperthermia	B
+were	O
+compared	O
+using	O
+a	O
+F344	O
+rat	O
+model	O
+.	O
+
+Antitumor	O
+activity	O
+was	O
+studied	O
+using	O
+a	O
+tumor	B
+growth	O
+delay	O
+assay	O
+.	O
+
+Acute	O
+normal	O
+tissue	O
+toxicities	B
+(	O
+i	O
+.	O
+e	O
+.	O
+,	O
+leukopenia	B
+and	O
+thrombocytopenia	B
+)	O
+and	O
+late	O
+normal	O
+tissue	O
+toxicities	B
+(	O
+i	O
+.	O
+e	O
+.	O
+,	O
+myocardial	B
+and	I
+kidney	I
+injury	I
+)	O
+were	O
+evaluated	O
+by	O
+functional	O
+/	O
+physiological	O
+assays	O
+and	O
+by	O
+morphological	O
+techniques	O
+.	O
+
+Whole	O
+body	O
+hyperthermia	B
+(	O
+120	O
+min	O
+at	O
+41	O
+.	O
+5	O
+degrees	O
+C	O
+)	O
+enhanced	O
+both	O
+Adriamycin	O
+-	O
+mediated	O
+antitumor	O
+activity	O
+and	O
+toxic	O
+side	O
+effects	O
+.	O
+
+The	O
+thermal	O
+enhancement	O
+ratio	O
+calculated	O
+for	O
+antitumor	O
+activity	O
+was	O
+1	O
+.	O
+6	O
+.	O
+
+Thermal	O
+enhancement	O
+ratios	O
+estimated	O
+for	O
+"	O
+acute	O
+"	O
+hematological	O
+changes	O
+were	O
+1	O
+.	O
+3	O
+,	O
+whereas	O
+those	O
+estimated	O
+for	O
+"	O
+late	O
+"	O
+damage	O
+(	O
+based	O
+on	O
+morphological	O
+cardiac	B
+and	I
+renal	I
+lesions	I
+)	O
+varied	O
+between	O
+2	O
+.	O
+4	O
+and	O
+4	O
+.	O
+3	O
+.	O
+
+Thus	O
+,	O
+while	O
+whole	O
+body	O
+hyperthermia	B
+enhances	O
+Adriamycin	O
+-	O
+mediated	O
+antitumor	O
+effect	O
+,	O
+normal	O
+tissue	O
+toxicity	B
+is	O
+also	O
+increased	O
+,	O
+and	O
+the	O
+potential	O
+therapeutic	O
+gain	O
+of	O
+the	O
+combined	O
+modality	O
+treatment	O
+is	O
+eroded	O
+.	O
+
+Permeability	O
+,	O
+ultrastructural	O
+changes	O
+,	O
+and	O
+distribution	O
+of	O
+novel	O
+proteins	O
+in	O
+the	O
+glomerular	O
+barrier	O
+in	O
+early	O
+puromycin	O
+aminonucleoside	O
+nephrosis	B
+.	O
+
+BACKGROUND	O
+/	O
+AIMS	O
+:	O
+It	O
+is	O
+still	O
+unclear	O
+what	O
+happens	O
+in	O
+the	O
+glomerulus	O
+when	O
+proteinuria	B
+starts	O
+.	O
+
+Using	O
+puromycin	O
+aminonucleoside	O
+nephrosis	B
+(	O
+PAN	O
+)	O
+rats	O
+,	O
+we	O
+studied	O
+early	O
+ultrastructural	O
+and	O
+permeability	O
+changes	O
+in	O
+relation	O
+to	O
+the	O
+expression	O
+of	O
+the	O
+podocyte	O
+-	O
+associated	O
+molecules	O
+nephrin	O
+,	O
+a	O
+-	O
+actinin	O
+,	O
+dendrin	O
+,	O
+and	O
+plekhh2	O
+,	O
+the	O
+last	O
+two	O
+of	O
+which	O
+were	O
+only	O
+recently	O
+discovered	O
+in	O
+podocytes	O
+.	O
+
+METHODS	O
+:	O
+Using	O
+immune	O
+stainings	O
+,	O
+semiquantitative	O
+measurement	O
+was	O
+performed	O
+under	O
+the	O
+electron	O
+microscope	O
+.	O
+
+Permeability	O
+was	O
+assessed	O
+using	O
+isolated	O
+kidney	O
+perfusion	O
+with	O
+tracers	O
+.	O
+
+Possible	O
+effects	O
+of	O
+ACE	O
+inhibition	O
+were	O
+tested	O
+.	O
+
+RESULTS	O
+:	O
+By	O
+day	O
+2	O
+,	O
+some	O
+patchy	O
+foot	O
+process	O
+effacement	O
+,	O
+but	O
+no	O
+proteinuria	B
+,	O
+appeared	O
+.	O
+
+The	O
+amount	O
+of	O
+nephrin	O
+was	O
+reduced	O
+in	O
+both	O
+diseased	O
+and	O
+normal	O
+areas	O
+.	O
+
+The	O
+other	O
+proteins	O
+showed	O
+few	O
+changes	O
+,	O
+which	O
+were	O
+limited	O
+to	O
+diseased	O
+areas	O
+.	O
+
+By	O
+day	O
+4	O
+,	O
+foot	O
+process	O
+effacement	O
+was	O
+complete	O
+and	O
+proteinuria	B
+appeared	O
+in	O
+parallel	O
+with	O
+signs	O
+of	O
+size	O
+barrier	O
+damage	O
+.	O
+
+Nephrin	O
+decreased	O
+further	O
+,	O
+while	O
+dendrin	O
+and	O
+plekhh2	O
+also	O
+decreased	O
+but	O
+a	O
+-	O
+actinin	O
+remained	O
+unchanged	O
+.	O
+
+ACE	O
+inhibition	O
+had	O
+no	O
+significant	O
+protective	O
+effect	O
+.	O
+
+CONCLUSIONS	O
+:	O
+PAN	O
+glomeruli	O
+already	O
+showed	O
+significant	O
+pathology	O
+by	O
+day	O
+4	O
+,	O
+despite	O
+relatively	O
+mild	O
+proteinuria	B
+.	O
+
+This	O
+was	O
+preceded	O
+by	O
+altered	O
+nephrin	O
+expression	O
+,	O
+supporting	O
+its	O
+pivotal	O
+role	O
+in	O
+podocyte	O
+morphology	O
+.	O
+
+The	O
+novel	O
+proteins	O
+dendrin	O
+and	O
+plekhh2	O
+were	O
+both	O
+reduced	O
+,	O
+suggesting	O
+roles	O
+in	O
+PAN	O
+,	O
+whereas	O
+a	O
+-	O
+actinin	O
+was	O
+unchanged	O
+.	O
+
+A	O
+novel	O
+,	O
+multiple	O
+symptom	O
+model	O
+of	O
+obsessive	B
+-	I
+compulsive	I
+-	I
+like	I
+behaviors	I
+in	O
+animals	O
+.	O
+
+BACKGROUND	O
+:	O
+Current	O
+animal	O
+models	O
+of	O
+obsessive	B
+-	I
+compulsive	I
+disorder	I
+(	O
+OCD	B
+)	O
+typically	O
+involve	O
+acute	O
+,	O
+drug	O
+-	O
+induced	O
+symptom	O
+provocation	O
+or	O
+a	O
+genetic	O
+association	O
+with	O
+stereotypies	O
+or	O
+anxiety	B
+.	O
+
+None	O
+of	O
+these	O
+current	O
+models	O
+demonstrate	O
+multiple	O
+OCD	B
+-	O
+like	O
+behaviors	O
+.	O
+
+METHODS	O
+:	O
+Neonatal	O
+rats	O
+were	O
+treated	O
+with	O
+the	O
+tricyclic	O
+antidepressant	O
+clomipramine	O
+or	O
+vehicle	O
+between	O
+days	O
+9	O
+and	O
+16	O
+twice	O
+daily	O
+and	O
+behaviorally	O
+tested	O
+in	O
+adulthood	O
+.	O
+
+RESULTS	O
+:	O
+Clomipramine	O
+exposure	O
+in	O
+immature	O
+rats	O
+produced	O
+significant	O
+behavioral	O
+and	O
+biochemical	O
+changes	O
+that	O
+include	O
+enhanced	O
+anxiety	B
+(	O
+elevated	O
+plus	O
+maze	O
+and	O
+marble	O
+burying	O
+)	O
+,	O
+behavioral	B
+inflexibility	I
+(	O
+perseveration	O
+in	O
+the	O
+spontaneous	O
+alternation	O
+task	O
+and	O
+impaired	O
+reversal	O
+learning	O
+)	O
+,	O
+working	O
+memory	B
+impairment	I
+(	O
+e	O
+.	O
+g	O
+.	O
+,	O
+win	O
+-	O
+shift	O
+paradigm	O
+)	O
+,	O
+hoarding	B
+,	O
+and	O
+corticostriatal	B
+dysfunction	I
+.	O
+
+Dopamine	O
+D2	O
+receptors	O
+were	O
+elevated	O
+in	O
+the	O
+striatum	O
+,	O
+whereas	O
+serotonin	O
+2C	O
+,	O
+but	O
+not	O
+serotonin	O
+1A	O
+,	O
+receptors	O
+were	O
+elevated	O
+in	O
+the	O
+orbital	O
+frontal	O
+cortex	O
+.	O
+
+CONCLUSIONS	O
+:	O
+This	O
+is	O
+the	O
+first	O
+demonstration	O
+of	O
+multiple	O
+symptoms	O
+consistent	O
+with	O
+an	O
+OCD	B
+-	O
+like	O
+profile	O
+in	O
+animals	O
+.	O
+
+Moreover	O
+,	O
+these	O
+behaviors	O
+are	O
+accompanied	O
+by	O
+biochemical	O
+changes	O
+in	O
+brain	O
+regions	O
+previously	O
+identified	O
+as	O
+relevant	O
+to	O
+OCD	B
+.	O
+
+This	O
+novel	O
+model	O
+of	O
+OCD	B
+demonstrates	O
+that	O
+drug	O
+exposure	O
+during	O
+a	O
+sensitive	O
+period	O
+can	O
+program	O
+disease	O
+-	O
+like	O
+systems	O
+permanently	O
+,	O
+which	O
+could	O
+have	O
+implications	O
+for	O
+current	O
+and	O
+future	O
+therapeutic	O
+strategies	O
+for	O
+this	O
+and	O
+other	O
+psychiatric	B
+disorders	I
+.	O
+
+Elevation	O
+of	O
+ADAM10	O
+,	O
+ADAM17	O
+,	O
+MMP	O
+-	O
+2	O
+and	O
+MMP	O
+-	O
+9	O
+expression	O
+with	O
+media	O
+degeneration	O
+features	O
+CaCl2	O
+-	O
+induced	O
+thoracic	B
+aortic	I
+aneurysm	I
+in	O
+a	O
+rat	O
+model	O
+.	O
+
+PURPOSE	O
+:	O
+This	O
+study	O
+was	O
+designed	O
+to	O
+establish	O
+a	O
+rat	O
+model	O
+of	O
+thoracic	B
+aortic	I
+aneurysm	I
+(	O
+TAA	B
+)	O
+by	O
+calcium	O
+chloride	O
+(	O
+CaCl	O
+(	O
+2	O
+)	O
+)	O
+-	O
+induced	O
+arterial	B
+injury	I
+and	O
+to	O
+explore	O
+the	O
+potential	O
+role	O
+of	O
+a	O
+disintegrin	O
+and	O
+metalloproteinase	O
+(	O
+ADAM	O
+)	O
+,	O
+matrix	O
+metalloproteinases	O
+(	O
+MMPs	O
+)	O
+and	O
+their	O
+endogenous	O
+inhibitors	O
+(	O
+TIMPs	O
+)	O
+in	O
+TAA	B
+formation	O
+.	O
+
+METHODS	O
+:	O
+Thoracic	O
+aorta	O
+of	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+was	O
+exposed	O
+to	O
+0	O
+.	O
+5M	O
+CaCl	O
+(	O
+2	O
+)	O
+or	O
+normal	O
+saline	O
+(	O
+NaCl	O
+)	O
+.	O
+
+After	O
+12weeks	O
+,	O
+animals	O
+were	O
+euthanized	O
+,	O
+and	O
+CaCl	O
+(	O
+2	O
+)	O
+-	O
+treated	O
+,	O
+CaCl	O
+(	O
+2	O
+)	O
+-	O
+untreated	O
+(	O
+n	O
+=	O
+12	O
+)	O
+and	O
+NaCl	O
+-	O
+treated	O
+aortic	O
+segments	O
+(	O
+n	O
+=	O
+12	O
+)	O
+were	O
+collected	O
+for	O
+histological	O
+and	O
+molecular	O
+assessments	O
+.	O
+
+MMP	O
+-	O
+TIMP	O
+and	O
+ADAM	O
+mRNAs	O
+were	O
+semi	O
+-	O
+quantitatively	O
+analyzed	O
+and	O
+protein	O
+expressions	O
+were	O
+determined	O
+by	O
+immunohistochemistry	O
+.	O
+
+RESULTS	O
+:	O
+Despite	O
+similar	O
+external	O
+diameters	O
+among	O
+CaCl	O
+(	O
+2	O
+)	O
+-	O
+treated	O
+,	O
+non	O
+-	O
+CaCl	O
+(	O
+2	O
+)	O
+-	O
+treated	O
+and	O
+NaCl	O
+-	O
+treated	O
+segments	O
+,	O
+aneurymal	O
+alteration	O
+(	O
+n	O
+=	O
+6	O
+,	O
+50	O
+%	O
+)	O
+,	O
+media	O
+degeneration	O
+with	O
+regional	O
+disruption	O
+,	O
+fragmentation	O
+of	O
+elastic	O
+fiber	O
+,	O
+and	O
+increased	O
+collagen	O
+deposition	O
+(	O
+n	O
+=	O
+12	O
+,	O
+100	O
+%	O
+)	O
+were	O
+demonstrated	O
+in	O
+CaCl	O
+(	O
+2	O
+)	O
+-	O
+treated	O
+segments	O
+.	O
+
+MMP	O
+-	O
+2	O
+,	O
+MMP	O
+-	O
+9	O
+,	O
+ADAM	O
+-	O
+10	O
+and	O
+ADAM	O
+-	O
+17	O
+mRNA	O
+levels	O
+were	O
+increased	O
+in	O
+CaCl	O
+(	O
+2	O
+)	O
+-	O
+treated	O
+segments	O
+(	O
+all	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+,	O
+with	O
+trends	O
+of	O
+elevation	O
+in	O
+CaCl	O
+(	O
+2	O
+)	O
+-	O
+untreated	O
+segments	O
+,	O
+as	O
+compared	O
+with	O
+NaCl	O
+-	O
+treated	O
+segments	O
+.	O
+
+Immunohistochemistry	O
+displayed	O
+significantly	O
+increased	O
+expressions	O
+of	O
+MMP	O
+-	O
+2	O
+,	O
+MMP	O
+-	O
+9	O
+,	O
+ADAM	O
+-	O
+10	O
+and	O
+ADAM	O
+-	O
+17	O
+(	O
+all	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+in	O
+intima	O
+and	O
+media	O
+for	O
+CaCl	O
+(	O
+2	O
+)	O
+-	O
+treated	O
+segments	O
+.	O
+
+TIMP	O
+mRNA	O
+and	O
+tissue	O
+levels	O
+did	O
+not	O
+differ	O
+obviously	O
+among	O
+the	O
+three	O
+aortic	O
+segments	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+study	O
+establishes	O
+a	O
+TAA	B
+model	O
+by	O
+periarterial	O
+CaCl	O
+(	O
+2	O
+)	O
+exposure	O
+in	O
+rats	O
+,	O
+and	O
+demonstrates	O
+a	O
+significant	O
+elevation	O
+of	O
+expression	O
+of	O
+MMP	O
+-	O
+2	O
+,	O
+MMP	O
+-	O
+9	O
+,	O
+ADAM10	O
+and	O
+ADAM17	O
+in	O
+the	O
+pathogenesis	O
+of	O
+vascular	O
+remodeling	O
+.	O
+
+Suxamethonium	O
+induced	O
+prolonged	O
+apnea	B
+in	O
+a	O
+patient	O
+receiving	O
+electroconvulsive	O
+therapy	O
+.	O
+
+Suxamethonium	O
+causes	O
+prolonged	O
+apnea	B
+in	O
+patients	O
+in	O
+whom	O
+pseudocholinesterase	O
+enzyme	O
+gets	O
+deactivated	O
+by	O
+organophosphorus	O
+(	O
+OP	O
+)	O
+poisons	O
+.	O
+
+Here	O
+,	O
+we	O
+present	O
+a	O
+similar	O
+incident	O
+in	O
+a	O
+severely	O
+depressed	B
+patient	O
+who	O
+received	O
+electroconvulsive	O
+therapy	O
+(	O
+ECT	O
+)	O
+.	O
+
+Prolonged	O
+apnea	B
+in	O
+our	O
+case	O
+ensued	O
+because	O
+the	O
+information	O
+about	O
+suicidal	O
+attempt	O
+by	O
+OP	O
+compound	O
+was	O
+concealed	O
+from	O
+the	O
+treating	O
+team	O
+.	O
+
+Curcumin	O
+ameliorates	O
+cognitive	B
+dysfunction	I
+and	O
+oxidative	O
+damage	O
+in	O
+phenobarbitone	O
+and	O
+carbamazepine	O
+administered	O
+rats	O
+.	O
+
+The	O
+antiepileptic	O
+drugs	O
+,	O
+phenobarbitone	O
+and	O
+carbamazepine	O
+are	O
+well	O
+known	O
+to	O
+cause	O
+cognitive	B
+impairment	I
+on	O
+chronic	O
+use	O
+.	O
+
+The	O
+increase	O
+in	O
+free	O
+radical	O
+generation	O
+has	O
+been	O
+implicated	O
+as	O
+one	O
+of	O
+the	O
+important	O
+mechanisms	O
+of	O
+cognitive	B
+impairment	I
+by	O
+antiepileptic	O
+drugs	O
+.	O
+
+Curcumin	O
+has	O
+shown	O
+antioxidant	O
+,	O
+anti	O
+-	O
+inflammatory	O
+and	O
+neuro	O
+-	O
+protective	O
+properties	O
+.	O
+
+Therefore	O
+,	O
+the	O
+present	O
+study	O
+was	O
+carried	O
+out	O
+to	O
+investigate	O
+the	O
+effect	O
+of	O
+chronic	O
+curcumin	O
+administration	O
+on	O
+phenobarbitone	O
+-	O
+and	O
+carbamazepine	O
+-	O
+induced	O
+cognitive	B
+impairment	I
+and	O
+oxidative	O
+stress	O
+in	O
+rats	O
+.	O
+
+Pharmacokinetic	O
+interactions	O
+of	O
+curcumin	O
+with	O
+phenobarbitone	O
+and	O
+carbamazepine	O
+were	O
+also	O
+studied	O
+.	O
+
+Vehicle	O
+/	O
+drugs	O
+were	O
+administered	O
+daily	O
+for	O
+21days	O
+to	O
+male	O
+Wistar	O
+rats	O
+.	O
+
+Passive	O
+avoidance	O
+paradigm	O
+and	O
+elevated	O
+plus	O
+maze	O
+test	O
+were	O
+used	O
+to	O
+assess	O
+cognitive	O
+function	O
+.	O
+
+At	O
+the	O
+end	O
+of	O
+study	O
+period	O
+,	O
+serum	O
+phenobarbitone	O
+and	O
+carbamazepine	O
+,	O
+whole	O
+brain	O
+malondialdehyde	O
+and	O
+reduced	O
+glutathione	O
+levels	O
+were	O
+estimated	O
+.	O
+
+The	O
+administration	O
+of	O
+phenobarbitone	O
+and	O
+carbamazepine	O
+for	O
+21days	O
+caused	O
+a	O
+significant	O
+impairment	B
+of	I
+learning	I
+and	I
+memory	I
+as	O
+well	O
+as	O
+an	O
+increased	O
+oxidative	O
+stress	O
+.	O
+
+Concomitant	O
+curcumin	O
+administration	O
+prevented	O
+the	O
+cognitive	B
+impairment	I
+and	O
+decreased	O
+the	O
+increased	O
+oxidative	O
+stress	O
+induced	O
+by	O
+these	O
+antiepileptic	O
+drugs	O
+.	O
+
+Curcumin	O
+co	O
+-	O
+administration	O
+did	O
+not	O
+cause	O
+any	O
+significant	O
+alteration	O
+in	O
+the	O
+serum	O
+concentrations	O
+of	O
+both	O
+phenobarbitone	O
+as	O
+well	O
+as	O
+carbamazepine	O
+.	O
+
+These	O
+results	O
+show	O
+that	O
+curcumin	O
+has	O
+beneficial	O
+effect	O
+in	O
+mitigating	O
+the	O
+deterioration	B
+of	I
+cognitive	I
+functions	I
+and	O
+oxidative	O
+damage	O
+in	O
+rats	O
+treated	O
+with	O
+phenobarbitone	O
+and	O
+carbamazepine	O
+without	O
+significantly	O
+altering	O
+their	O
+serum	O
+concentrations	O
+.	O
+
+The	O
+findings	O
+suggest	O
+that	O
+curcumin	O
+can	O
+be	O
+considered	O
+as	O
+a	O
+potential	O
+safe	O
+and	O
+effective	O
+adjuvant	O
+to	O
+phenobarbitone	O
+and	O
+carbamazepine	O
+therapy	O
+in	O
+preventing	O
+cognitive	B
+impairment	I
+associated	O
+with	O
+these	O
+drugs	O
+.	O
+
+Can	O
+angiogenesis	O
+be	O
+a	O
+target	O
+of	O
+treatment	O
+for	O
+ribavirin	O
+associated	O
+hemolytic	B
+anemia	I
+?	O
+
+BACKGROUND	O
+/	O
+AIMS	O
+:	O
+Recently	O
+ribavirin	O
+has	O
+been	O
+found	O
+to	O
+inhibit	O
+angiogenesis	O
+and	O
+a	O
+number	O
+of	O
+angiogenesis	O
+inhibitors	O
+such	O
+as	O
+sunitinib	O
+and	O
+sorafenib	O
+have	O
+been	O
+found	O
+to	O
+cause	O
+acute	O
+hemolysis	B
+.	O
+
+We	O
+aimed	O
+to	O
+investigate	O
+whether	O
+there	O
+is	O
+a	O
+relation	O
+between	O
+hemoglobin	O
+,	O
+haptoglobin	O
+and	O
+angiogenesis	O
+soluble	O
+markers	O
+which	O
+are	O
+modifiable	O
+and	O
+can	O
+help	O
+in	O
+developing	O
+strategies	O
+against	O
+anemia	B
+.	O
+
+METHODS	O
+:	O
+Fourteen	O
+patients	O
+chronically	B
+infected	I
+with	I
+hepatitis	I
+C	I
+virus	I
+were	O
+treated	O
+by	O
+pegylated	O
+interferon	O
+alpha	O
+2a	O
+and	O
+ribavirin	O
+.	O
+
+Serum	O
+hemoglobin	O
+,	O
+haptoglobin	O
+and	O
+angiogenesis	O
+markers	O
+of	O
+vascular	O
+endothelial	O
+growth	O
+factor	O
+and	O
+angiopoetin	O
+-	O
+2	O
+were	O
+investigated	O
+before	O
+and	O
+after	O
+therapy	O
+.	O
+
+RESULTS	O
+:	O
+We	O
+observed	O
+a	O
+significant	O
+decrease	O
+in	O
+haptoglobin	O
+levels	O
+at	O
+the	O
+end	O
+of	O
+the	O
+treatment	O
+period	O
+.	O
+
+Hemoglobin	O
+levels	O
+also	O
+decreased	O
+but	O
+insignificantly	O
+by	O
+treatment	O
+.	O
+
+In	O
+contrast	O
+with	O
+the	O
+literature	O
+,	O
+serum	O
+levels	O
+of	O
+angiogenesis	O
+factors	O
+did	O
+not	O
+change	O
+significantly	O
+by	O
+pegylated	O
+interferon	O
+and	O
+ribavirin	O
+therapy	O
+.	O
+
+We	O
+found	O
+no	O
+correlation	O
+of	O
+angiogenesis	O
+soluble	O
+markers	O
+with	O
+either	O
+hemoglobin	O
+or	O
+haptoglobin	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+is	O
+the	O
+first	O
+study	O
+in	O
+the	O
+literature	O
+investigating	O
+a	O
+link	O
+between	O
+angiogenesis	O
+soluble	O
+markers	O
+and	O
+ribavirin	O
+induced	O
+anemia	B
+in	O
+patients	O
+with	O
+hepatitis	B
+C	I
+and	O
+we	O
+could	O
+not	O
+find	O
+any	O
+relation	O
+.	O
+
+Future	O
+research	O
+with	O
+larger	O
+number	O
+of	O
+patients	O
+is	O
+needed	O
+to	O
+find	O
+out	O
+modifiable	O
+factors	O
+that	O
+will	O
+improve	O
+the	O
+safety	O
+of	O
+ribavirin	O
+therapy	O
+.	O
+
+Reduction	O
+in	O
+injection	O
+pain	B
+using	O
+buffered	O
+lidocaine	O
+as	O
+a	O
+local	O
+anesthetic	O
+before	O
+cardiac	O
+catheterization	O
+.	O
+
+Previous	O
+reports	O
+have	O
+suggested	O
+that	O
+pain	B
+associated	O
+with	O
+the	O
+injection	O
+of	O
+lidocaine	O
+is	O
+related	O
+to	O
+the	O
+acidic	O
+pH	O
+of	O
+the	O
+solution	O
+.	O
+
+To	O
+determine	O
+if	O
+the	O
+addition	O
+of	O
+a	O
+buffering	O
+solution	O
+to	O
+adjust	O
+the	O
+pH	O
+of	O
+lidocaine	O
+into	O
+the	O
+physiologic	O
+range	O
+would	O
+reduce	O
+pain	B
+during	O
+injection	O
+,	O
+we	O
+performed	O
+a	O
+blinded	O
+randomized	O
+study	O
+in	O
+patients	O
+undergoing	O
+cardiac	O
+catheterization	O
+.	O
+
+Twenty	O
+patients	O
+were	O
+asked	O
+to	O
+quantify	O
+the	O
+severity	O
+of	O
+pain	B
+after	O
+receiving	O
+standard	O
+lidocaine	O
+in	O
+one	O
+femoral	O
+area	O
+and	O
+buffered	O
+lidocaine	O
+in	O
+the	O
+opposite	O
+femoral	O
+area	O
+.	O
+
+The	O
+mean	O
+pain	B
+score	O
+for	O
+buffered	O
+lidocaine	O
+was	O
+significantly	O
+lower	O
+than	O
+the	O
+mean	O
+score	O
+for	O
+standard	O
+lidocaine	O
+(	O
+2	O
+.	O
+7	O
++	O
+/	O
+-	O
+1	O
+.	O
+9	O
+vs	O
+.	O
+3	O
+.	O
+8	O
++	O
+/	O
+-	O
+2	O
+.	O
+2	O
+,	O
+P	O
+=	O
+0	O
+.	O
+03	O
+)	O
+.	O
+
+The	O
+pH	O
+adjustment	O
+of	O
+standard	O
+lidocaine	O
+can	O
+be	O
+accomplished	O
+easily	O
+in	O
+the	O
+catheterization	O
+laboratory	O
+before	O
+injection	O
+and	O
+results	O
+in	O
+a	O
+reduction	O
+of	O
+the	O
+pain	B
+occurring	O
+during	O
+the	O
+infiltration	O
+of	O
+tissues	O
+.	O
+
+Effect	O
+of	O
+L	O
+-	O
+alpha	O
+-	O
+glyceryl	O
+-	O
+phosphorylcholine	O
+on	O
+amnesia	B
+caused	O
+by	O
+scopolamine	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+carried	O
+out	O
+to	O
+test	O
+the	O
+effects	O
+of	O
+L	O
+-	O
+alpha	O
+-	O
+glycerylphosphorylcholine	O
+(	O
+L	O
+-	O
+alpha	O
+-	O
+GFC	O
+)	O
+on	O
+memory	B
+impairment	I
+induced	O
+by	O
+scopolamine	O
+in	O
+man	O
+.	O
+
+Thirty	O
+-	O
+two	O
+healthy	O
+young	O
+volunteers	O
+were	O
+randomly	O
+allocated	O
+to	O
+four	O
+different	O
+groups	O
+.	O
+
+They	O
+were	O
+given	O
+a	O
+ten	O
+day	O
+pretreatment	O
+with	O
+either	O
+L	O
+-	O
+alpha	O
+-	O
+GFC	O
+or	O
+placebo	O
+,	O
+p	O
+.	O
+o	O
+.	O
+,	O
+and	O
+on	O
+the	O
+eleventh	O
+day	O
+either	O
+scopolamine	O
+or	O
+placebo	O
+,	O
+i	O
+.	O
+m	O
+.	O
+
+Before	O
+and	O
+0	O
+.	O
+5	O
+,	O
+1	O
+,	O
+2	O
+,	O
+3	O
+,	O
+and	O
+6	O
+h	O
+after	O
+injection	O
+the	O
+subjects	O
+were	O
+given	O
+attention	O
+and	O
+mnemonic	O
+tests	O
+.	O
+
+The	O
+findings	O
+of	O
+this	O
+study	O
+indicate	O
+that	O
+the	O
+drug	O
+is	O
+able	O
+to	O
+antagonize	O
+impairment	B
+of	I
+attention	I
+and	I
+memory	I
+induced	O
+by	O
+scopolamine	O
+.	O
+
+Safety	O
+of	O
+capecitabine	O
+:	O
+a	O
+review	O
+.	O
+
+IMPORTANCE	O
+OF	O
+THE	O
+FIELD	O
+:	O
+Fluoropyrimidines	O
+,	O
+in	O
+particular	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+,	O
+have	O
+been	O
+the	O
+mainstay	O
+of	O
+treatment	O
+for	O
+several	O
+solid	O
+tumors	B
+,	O
+including	O
+colorectal	B
+,	I
+breast	I
+and	I
+head	I
+and	I
+neck	I
+cancers	I
+,	O
+for	O
+>	O
+40	O
+years	O
+.	O
+
+AREAS	O
+COVERED	O
+IN	O
+THIS	O
+REVIEW	O
+:	O
+This	O
+article	O
+reviews	O
+the	O
+pharmacology	O
+and	O
+efficacy	O
+of	O
+capecitabine	O
+with	O
+a	O
+special	O
+emphasis	O
+on	O
+its	O
+safety	O
+.	O
+
+WHAT	O
+THE	O
+READER	O
+WILL	O
+GAIN	O
+:	O
+The	O
+reader	O
+will	O
+gain	O
+better	O
+insight	O
+into	O
+the	O
+safety	O
+of	O
+capecitabine	O
+in	O
+special	O
+populations	O
+such	O
+as	O
+patients	O
+with	O
+advanced	O
+age	O
+,	O
+renal	B
+and	I
+kidney	I
+disease	I
+.	O
+
+We	O
+also	O
+explore	O
+different	O
+dosing	O
+and	O
+schedules	O
+of	O
+capecitabine	O
+administration	O
+.	O
+
+TAKE	O
+HOME	O
+MESSAGE	O
+:	O
+Capecitabine	O
+is	O
+an	O
+oral	O
+prodrug	O
+of	O
+5	O
+-	O
+FU	O
+and	O
+was	O
+developed	O
+to	O
+fulfill	O
+the	O
+need	O
+for	O
+a	O
+more	O
+convenient	O
+therapy	O
+and	O
+provide	O
+an	O
+improved	O
+safety	O
+/	O
+efficacy	O
+profile	O
+.	O
+
+It	O
+has	O
+shown	O
+promising	O
+results	O
+alone	O
+or	O
+in	O
+combination	O
+with	O
+other	O
+chemotherapeutic	O
+agents	O
+in	O
+colorectal	B
+,	I
+breast	I
+,	I
+pancreaticobiliary	I
+,	I
+gastric	I
+,	I
+renal	I
+cell	I
+and	I
+head	I
+and	I
+neck	I
+cancers	I
+.	O
+
+The	O
+most	O
+commonly	O
+reported	O
+toxic	O
+effects	O
+of	O
+capecitabine	O
+are	O
+diarrhea	B
+,	O
+nausea	B
+,	O
+vomiting	B
+,	O
+stomatitis	B
+and	O
+hand	B
+-	I
+foot	I
+syndrome	I
+.	O
+
+Capecitabine	O
+has	O
+a	O
+well	O
+-	O
+established	O
+safety	O
+profile	O
+and	O
+can	O
+be	O
+given	O
+safely	O
+to	O
+patients	O
+with	O
+advanced	O
+age	O
+,	O
+hepatic	B
+and	I
+renal	I
+dysfunctions	I
+.	O
+
+Levodopa	O
+-	O
+induced	O
+dyskinesias	B
+in	O
+patients	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+:	O
+filling	O
+the	O
+bench	O
+-	O
+to	O
+-	O
+bedside	O
+gap	O
+.	O
+
+Levodopa	O
+is	O
+the	O
+most	O
+effective	O
+drug	O
+for	O
+the	O
+treatment	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+However	O
+,	O
+the	O
+long	O
+-	O
+term	O
+use	O
+of	O
+this	O
+dopamine	O
+precursor	O
+is	O
+complicated	O
+by	O
+highly	O
+disabling	O
+fluctuations	O
+and	O
+dyskinesias	B
+.	O
+
+Although	O
+preclinical	O
+and	O
+clinical	O
+findings	O
+suggest	O
+pulsatile	O
+stimulation	O
+of	O
+striatal	O
+postsynaptic	O
+receptors	O
+as	O
+a	O
+key	O
+mechanism	O
+underlying	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+,	O
+their	O
+pathogenesis	O
+is	O
+still	O
+unclear	O
+.	O
+
+In	O
+recent	O
+years	O
+,	O
+evidence	O
+from	O
+animal	O
+models	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+has	O
+provided	O
+important	O
+information	O
+to	O
+understand	O
+the	O
+effect	O
+of	O
+specific	O
+receptor	O
+and	O
+post	O
+-	O
+receptor	O
+molecular	O
+mechanisms	O
+underlying	O
+the	O
+development	O
+of	O
+dyskinetic	B
+movements	I
+.	O
+
+Recent	O
+preclinical	O
+and	O
+clinical	O
+data	O
+from	O
+promising	O
+lines	O
+of	O
+research	O
+focus	O
+on	O
+the	O
+differential	O
+role	O
+of	O
+presynaptic	O
+versus	O
+postsynaptic	O
+mechanisms	O
+,	O
+dopamine	O
+receptor	O
+subtypes	O
+,	O
+ionotropic	O
+and	O
+metabotropic	O
+glutamate	O
+receptors	O
+,	O
+and	O
+non	O
+-	O
+dopaminergic	O
+neurotransmitter	O
+systems	O
+in	O
+the	O
+pathophysiology	O
+of	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+.	O
+
+Effects	O
+of	O
+pallidal	O
+neurotensin	O
+on	O
+haloperidol	O
+-	O
+induced	O
+parkinsonian	B
+catalepsy	I
+:	O
+behavioral	O
+and	O
+electrophysiological	O
+studies	O
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+globus	O
+pallidus	O
+plays	O
+a	O
+critical	O
+role	O
+in	O
+movement	O
+regulation	O
+.	O
+
+Previous	O
+studies	O
+have	O
+indicated	O
+that	O
+the	O
+globus	O
+pallidus	O
+receives	O
+neurotensinergic	O
+innervation	O
+from	O
+the	O
+striatum	O
+,	O
+and	O
+systemic	O
+administration	O
+of	O
+a	O
+neurotensin	O
+analog	O
+could	O
+produce	O
+antiparkinsonian	O
+effects	O
+.	O
+
+The	O
+present	O
+study	O
+aimed	O
+to	O
+investigate	O
+the	O
+effects	O
+of	O
+pallidal	O
+neurotensin	O
+on	O
+haloperidol	O
+-	O
+induced	O
+parkinsonian	B
+symptoms	I
+.	O
+
+METHODS	O
+:	O
+Behavioral	O
+experiments	O
+and	O
+electrophysiological	O
+recordings	O
+were	O
+performed	O
+in	O
+the	O
+present	O
+study	O
+.	O
+
+RESULTS	O
+:	O
+Bilateral	O
+infusions	O
+of	O
+neurotensin	O
+into	O
+the	O
+globus	O
+pallidus	O
+reversed	O
+haloperidol	O
+-	O
+induced	O
+parkinsonian	B
+catalepsy	I
+in	O
+rats	O
+.	O
+
+Electrophysiological	O
+recordings	O
+showed	O
+that	O
+microinjection	O
+of	O
+neurotensin	O
+induced	O
+excitation	O
+of	O
+pallidal	O
+neurons	O
+in	O
+the	O
+presence	O
+of	O
+systemic	O
+haloperidol	O
+administration	O
+.	O
+
+The	O
+neurotensin	O
+type	O
+-	O
+1	O
+receptor	O
+antagonist	O
+SR48692	O
+blocked	O
+both	O
+the	O
+behavioral	O
+and	O
+the	O
+electrophysiological	O
+effects	O
+induced	O
+by	O
+neurotensin	O
+.	O
+
+CONCLUSION	O
+:	O
+Activation	O
+of	O
+pallidal	O
+neurotensin	O
+receptors	O
+may	O
+be	O
+involved	O
+in	O
+neurotensin	O
+-	O
+induced	O
+antiparkinsonian	O
+effects	O
+.	O
+
+Carmofur	O
+-	O
+induced	O
+organic	B
+mental	I
+disorders	I
+.	O
+
+Organic	B
+mental	I
+disorder	I
+was	O
+observed	O
+in	O
+a	O
+29	O
+-	O
+year	O
+-	O
+old	O
+female	O
+in	O
+the	O
+prognostic	O
+period	O
+after	O
+the	O
+onset	O
+of	O
+carmofur	O
+-	O
+induced	O
+leukoencephalopathy	B
+.	O
+
+Symptoms	O
+such	O
+as	O
+euphoria	O
+,	O
+emotional	O
+lability	O
+and	O
+puerile	O
+attitude	O
+noted	O
+in	O
+the	O
+patient	O
+were	O
+diagnosed	O
+as	O
+organic	B
+personality	I
+syndrome	I
+according	O
+to	O
+the	O
+criteria	O
+defined	O
+in	O
+the	O
+DSM	O
+-	O
+III	O
+-	O
+R	O
+.	O
+
+It	O
+is	O
+referred	O
+to	O
+as	O
+a	O
+frontal	B
+lobe	I
+syndrome	I
+.	O
+
+Brain	O
+CT	O
+revealed	O
+a	O
+periventricular	O
+low	O
+density	O
+area	O
+in	O
+the	O
+frontal	O
+white	O
+matter	O
+and	O
+moderate	O
+dilatation	O
+of	O
+the	O
+lateral	O
+ventricles	O
+especially	O
+at	O
+the	O
+bilateral	O
+anterior	O
+horns	O
+.	O
+
+Consequently	O
+,	O
+carmofur	O
+-	O
+induced	O
+leukoencephalopathy	B
+may	O
+uncommonly	O
+result	O
+in	O
+organic	B
+personality	I
+syndrome	I
+in	O
+the	O
+residual	O
+state	O
+.	O
+
+It	O
+may	O
+be	O
+attributed	O
+to	O
+the	O
+structural	B
+damage	I
+to	I
+the	I
+frontal	I
+lobe	I
+.	O
+
+Butyrylcholinesterase	O
+gene	O
+mutations	O
+in	O
+patients	O
+with	O
+prolonged	O
+apnea	B
+after	O
+succinylcholine	O
+for	O
+electroconvulsive	O
+therapy	O
+.	O
+
+BACKGROUND	O
+:	O
+patients	O
+undergoing	O
+electroconvulsive	O
+therapy	O
+(	O
+ECT	O
+)	O
+often	O
+receive	O
+succinylcholine	O
+as	O
+part	O
+of	O
+the	O
+anesthetic	O
+procedure	O
+.	O
+
+The	O
+duration	O
+of	O
+action	O
+may	O
+be	O
+prolonged	O
+in	O
+patients	O
+with	O
+genetic	O
+variants	O
+of	O
+the	O
+butyrylcholinesterase	O
+enzyme	O
+(	O
+BChE	O
+)	O
+,	O
+the	O
+most	O
+common	O
+being	O
+the	O
+K	O
+-	O
+and	O
+the	O
+A	O
+-	O
+variants	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+assess	O
+the	O
+clinical	O
+significance	O
+of	O
+genetic	O
+variants	O
+in	O
+butyrylcholinesterase	O
+gene	O
+(	O
+BCHE	O
+)	O
+in	O
+patients	O
+with	O
+a	O
+suspected	O
+prolonged	O
+duration	O
+of	O
+action	O
+of	O
+succinylcholine	O
+after	O
+ECT	O
+.	O
+
+METHODS	O
+:	O
+a	O
+total	O
+of	O
+13	O
+patients	O
+were	O
+referred	O
+to	O
+the	O
+Danish	O
+Cholinesterase	O
+Research	O
+Unit	O
+after	O
+ECT	O
+during	O
+38	O
+months	O
+.	O
+
+We	O
+determined	O
+the	O
+BChE	O
+activity	O
+and	O
+the	O
+BCHE	O
+genotype	O
+using	O
+molecular	O
+genetic	O
+methods	O
+,	O
+the	O
+duration	O
+of	O
+apnea	B
+,	O
+time	O
+to	O
+sufficient	O
+spontaneous	O
+ventilation	O
+and	O
+whether	O
+neuromuscular	O
+monitoring	O
+was	O
+used	O
+.	O
+
+The	O
+duration	O
+of	O
+apnea	B
+was	O
+compared	O
+with	O
+published	O
+data	O
+on	O
+normal	O
+subjects	O
+.	O
+
+RESULTS	O
+:	O
+in	O
+11	O
+patients	O
+,	O
+mutations	O
+were	O
+found	O
+in	O
+the	O
+BCHE	O
+gene	O
+,	O
+the	O
+K	O
+-	O
+variant	O
+being	O
+the	O
+most	O
+frequent	O
+.	O
+
+The	O
+duration	O
+of	O
+apnea	B
+was	O
+5	O
+-	O
+15	O
+min	O
+compared	O
+with	O
+3	O
+-	O
+5	O
+.	O
+3	O
+min	O
+from	O
+the	O
+literature	O
+.	O
+
+Severe	O
+distress	O
+was	O
+noted	O
+in	O
+the	O
+recovery	O
+phase	O
+in	O
+two	O
+patients	O
+.	O
+
+Neuromuscular	O
+monitoring	O
+was	O
+used	O
+in	O
+two	O
+patients	O
+.	O
+
+CONCLUSION	O
+:	O
+eleven	O
+of	O
+13	O
+patients	O
+with	O
+a	O
+prolonged	O
+duration	O
+of	O
+action	O
+of	O
+succinylcholine	O
+had	O
+mutations	O
+in	O
+BCHE	O
+,	O
+indicating	O
+that	O
+this	O
+is	O
+the	O
+possible	O
+reason	O
+for	O
+a	O
+prolonged	O
+period	O
+of	O
+apnea	B
+.	O
+
+We	O
+recommend	O
+objective	O
+neuromuscular	O
+monitoring	O
+during	O
+the	O
+first	O
+ECT	O
+.	O
+
+Perhexiline	O
+maleate	O
+and	O
+peripheral	B
+neuropathy	I
+.	O
+
+Peripheral	B
+neuropathy	I
+has	O
+been	O
+noted	O
+as	O
+a	O
+complication	O
+of	O
+therapy	O
+with	O
+perhexiline	O
+maleate	O
+,	O
+a	O
+drug	O
+widely	O
+used	O
+in	O
+France	O
+(	O
+and	O
+in	O
+clinical	O
+trials	O
+in	O
+the	O
+United	O
+States	O
+)	O
+for	O
+the	O
+prophylactic	O
+treatment	O
+of	O
+angina	B
+pectoris	I
+.	O
+
+In	O
+24	O
+patients	O
+with	O
+this	O
+complication	O
+,	O
+the	O
+marked	O
+slowing	O
+of	O
+motor	O
+nerve	O
+conduction	O
+velocity	O
+and	O
+the	O
+electromyographic	O
+changes	O
+imply	O
+mainly	O
+a	O
+demyelinating	B
+disorder	I
+.	O
+
+Improvement	O
+was	O
+noted	O
+with	O
+cessation	O
+of	O
+therapy	O
+.	O
+
+In	O
+a	O
+few	O
+cases	O
+the	O
+presence	O
+of	O
+active	O
+denervation	O
+signified	O
+a	O
+poor	O
+prognosis	O
+,	O
+with	O
+only	O
+slight	O
+improvement	O
+.	O
+
+The	O
+underlying	O
+mechanism	O
+causing	O
+the	O
+neuropathy	B
+is	O
+not	O
+yet	O
+fully	O
+known	O
+,	O
+although	O
+some	O
+evidence	O
+indicates	O
+that	O
+it	O
+may	O
+be	O
+a	O
+lipid	O
+storage	O
+process	O
+.	O
+
+A	O
+phase	O
+I	O
+study	O
+of	O
+4	O
+'	O
+-	O
+0	O
+-	O
+tetrahydropyranyladriamycin	O
+.	O
+
+Clinical	O
+pharmacology	O
+and	O
+pharmacokinetics	O
+.	O
+
+A	O
+Phase	O
+I	O
+study	O
+of	O
+intravenous	O
+(	O
+IV	O
+)	O
+bolus	O
+4	O
+'	O
+-	O
+0	O
+-	O
+tetrahydropyranyladriamycin	O
+(	O
+Pirarubicin	O
+)	O
+was	O
+done	O
+in	O
+55	O
+patients	O
+in	O
+good	O
+performance	O
+status	O
+with	O
+refractory	O
+tumors	B
+.	O
+
+Twenty	O
+-	O
+six	O
+had	O
+minimal	O
+prior	O
+therapy	O
+(	O
+good	O
+risk	O
+)	O
+,	O
+23	O
+had	O
+extensive	O
+prior	O
+therapy	O
+(	O
+poor	O
+risk	O
+)	O
+,	O
+and	O
+six	O
+had	O
+renal	B
+and	I
+/	I
+or	I
+hepatic	I
+dysfunction	I
+.	O
+
+A	O
+total	O
+of	O
+167	O
+courses	O
+at	O
+doses	O
+of	O
+15	O
+to	O
+70	O
+mg	O
+/	O
+m2	O
+were	O
+evaluable	O
+.	O
+
+Maximum	O
+tolerated	O
+dose	O
+in	O
+good	O
+-	O
+risk	O
+patients	O
+was	O
+70	O
+mg	O
+/	O
+m2	O
+,	O
+and	O
+in	O
+poor	O
+-	O
+risk	O
+patients	O
+,	O
+60	O
+mg	O
+/	O
+m2	O
+.	O
+
+The	O
+dose	O
+-	O
+limiting	O
+toxic	O
+effect	O
+was	O
+transient	O
+noncumulative	O
+granulocytopenia	B
+.	O
+
+Granulocyte	O
+nadir	O
+was	O
+on	O
+day	O
+14	O
+(	O
+range	O
+,	O
+4	O
+-	O
+22	O
+)	O
+.	O
+
+Less	O
+frequent	O
+toxic	O
+effects	O
+included	O
+thrombocytopenia	B
+,	O
+anemia	B
+,	O
+nausea	B
+,	O
+mild	O
+alopecia	B
+,	O
+phlebitis	B
+,	O
+and	O
+mucositis	B
+.	O
+
+Myelosuppression	B
+was	O
+more	O
+in	O
+patients	O
+with	O
+hepatic	B
+dysfunction	I
+.	O
+
+Pharmacokinetic	O
+analyses	O
+in	O
+21	O
+patients	O
+revealed	O
+Pirarubicin	O
+plasma	O
+T	O
+1	O
+/	O
+2	O
+alpha	O
+(	O
++	O
+/	O
+-	O
+SE	O
+)	O
+of	O
+2	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+85	O
+minutes	O
+,	O
+T	O
+beta	O
+1	O
+/	O
+2	O
+of	O
+25	O
+.	O
+6	O
++	O
+/	O
+-	O
+6	O
+.	O
+5	O
+minutes	O
+,	O
+and	O
+T	O
+1	O
+/	O
+2	O
+gamma	O
+of	O
+23	O
+.	O
+6	O
++	O
+/	O
+-	O
+7	O
+.	O
+6	O
+hours	O
+.	O
+
+The	O
+area	O
+under	O
+the	O
+curve	O
+was	O
+537	O
++	O
+/	O
+-	O
+149	O
+ng	O
+/	O
+ml	O
+x	O
+hours	O
+,	O
+volume	O
+of	O
+distribution	O
+(	O
+Vd	O
+)	O
+3504	O
++	O
+/	O
+-	O
+644	O
+l	O
+/	O
+m2	O
+,	O
+and	O
+total	O
+clearance	O
+(	O
+ClT	O
+)	O
+was	O
+204	O
++	O
+39	O
+.	O
+3	O
+l	O
+/	O
+hour	O
+/	O
+m2	O
+.	O
+
+Adriamycinol	O
+,	O
+doxorubicin	O
+,	O
+adriamycinone	O
+,	O
+and	O
+tetrahydropyranyladriamycinol	O
+were	O
+the	O
+metabolites	O
+detected	O
+in	O
+plasma	O
+and	O
+the	O
+amount	O
+of	O
+doxorubicin	O
+was	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+10	O
+%	O
+of	O
+the	O
+total	O
+metabolites	O
+.	O
+
+Urinary	O
+excretion	O
+of	O
+Pirarubicin	O
+in	O
+the	O
+first	O
+24	O
+hours	O
+was	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+10	O
+%	O
+.	O
+
+Activity	O
+was	O
+noted	O
+in	O
+mesothelioma	B
+,	O
+leiomyosarcoma	B
+,	O
+and	O
+basal	B
+cell	I
+carcinoma	I
+.	O
+
+The	O
+recommended	O
+starting	O
+dose	O
+for	O
+Phase	O
+II	O
+trials	O
+is	O
+60	O
+mg	O
+/	O
+m2	O
+IV	O
+bolus	O
+every	O
+3	O
+weeks	O
+.	O
+
+Ocular	B
+and	I
+auditory	I
+toxicity	I
+in	O
+hemodialyzed	O
+patients	O
+receiving	O
+desferrioxamine	O
+.	O
+
+During	O
+an	O
+18	O
+-	O
+month	O
+period	O
+of	O
+study	O
+41	O
+hemodialyzed	O
+patients	O
+receiving	O
+desferrioxamine	O
+(	O
+10	O
+-	O
+40	O
+mg	O
+/	O
+kg	O
+BW	O
+/	O
+3	O
+times	O
+weekly	O
+)	O
+for	O
+the	O
+first	O
+time	O
+were	O
+monitored	O
+for	O
+detection	O
+of	O
+audiovisual	B
+toxicity	I
+.	O
+
+6	O
+patients	O
+presented	O
+clinical	O
+symptoms	O
+of	O
+visual	B
+or	I
+auditory	I
+toxicity	I
+.	O
+
+Moreover	O
+,	O
+detailed	O
+ophthalmologic	O
+and	O
+audiologic	O
+studies	O
+disclosed	O
+abnormalities	O
+in	O
+7	O
+more	O
+asymptomatic	O
+patients	O
+.	O
+
+Visual	B
+toxicity	I
+was	O
+of	O
+retinal	O
+origin	O
+and	O
+was	O
+characterized	O
+by	O
+a	O
+tritan	O
+-	O
+type	O
+dyschromatopsy	B
+,	O
+sometimes	O
+associated	O
+with	O
+a	B
+loss	I
+of	I
+visual	I
+acuity	I
+and	O
+pigmentary	B
+retinal	I
+deposits	I
+.	O
+
+Auditory	B
+toxicity	I
+was	O
+characterized	O
+by	O
+a	O
+mid	O
+-	O
+to	O
+high	O
+-	O
+frequency	O
+neurosensorial	B
+hearing	I
+loss	I
+and	O
+the	O
+lesion	O
+was	O
+of	O
+the	O
+cochlear	O
+type	O
+.	O
+
+Desferrioxamine	O
+withdrawal	O
+resulted	O
+in	O
+a	O
+complete	O
+recovery	O
+of	O
+visual	O
+function	O
+in	O
+1	O
+patient	O
+and	O
+partial	O
+recovery	O
+in	O
+3	O
+,	O
+and	O
+a	O
+complete	O
+reversal	O
+of	O
+hearing	B
+loss	I
+in	O
+3	O
+patients	O
+and	O
+partial	O
+recovery	O
+in	O
+3	O
+.	O
+
+This	O
+toxicity	B
+appeared	O
+in	O
+patients	O
+receiving	O
+the	O
+higher	O
+doses	O
+of	O
+desferrioxamine	O
+or	O
+coincided	O
+with	O
+the	O
+normalization	O
+of	O
+ferritin	O
+or	O
+aluminium	O
+serum	O
+levels	O
+.	O
+
+The	O
+data	O
+indicate	O
+that	O
+audiovisual	B
+toxicity	I
+is	O
+not	O
+an	O
+infrequent	O
+complication	O
+in	O
+hemodialyzed	O
+patients	O
+receiving	O
+desferrioxamine	O
+.	O
+
+Periodical	O
+audiovisual	O
+monitoring	O
+should	O
+be	O
+performed	O
+on	O
+hemodialyzed	O
+patients	O
+receiving	O
+the	O
+drug	O
+in	O
+order	O
+to	O
+detect	O
+adverse	O
+effects	O
+as	O
+early	O
+as	O
+possible	O
+.	O
+
+Serial	O
+epilepsy	B
+caused	O
+by	O
+levodopa	O
+/	O
+carbidopa	O
+administration	O
+in	O
+two	O
+patients	O
+on	O
+hemodialysis	O
+.	O
+
+Two	O
+patients	O
+with	O
+similar	O
+clinical	O
+features	O
+are	O
+presented	O
+:	O
+both	O
+patients	O
+had	O
+chronic	B
+renal	I
+failure	I
+,	O
+on	O
+hemodialysis	O
+for	O
+many	O
+years	O
+but	O
+recently	O
+begun	O
+on	O
+a	O
+high	O
+-	O
+flux	O
+dialyzer	O
+;	O
+both	O
+had	O
+been	O
+receiving	O
+a	O
+carbidopa	O
+/	O
+levodopa	O
+preparation	O
+;	O
+and	O
+both	O
+had	O
+the	O
+onset	O
+of	O
+hallucinosis	B
+and	O
+recurrent	O
+seizures	B
+,	O
+which	O
+were	O
+refractory	O
+to	O
+anticonvulsants	O
+.	O
+
+The	O
+first	O
+patient	O
+died	O
+without	O
+a	O
+diagnosis	O
+;	O
+the	O
+second	O
+patient	O
+had	O
+a	O
+dramatic	O
+recovery	O
+following	O
+the	O
+administration	O
+of	O
+vitamin	O
+B6	O
+.	O
+
+Neither	O
+patient	O
+was	O
+considered	O
+to	O
+have	O
+a	O
+renal	O
+state	O
+sufficiently	O
+severe	O
+enough	O
+to	O
+explain	O
+their	O
+presentation	O
+.	O
+
+Randomized	O
+,	O
+double	O
+-	O
+blind	O
+trial	O
+of	O
+mazindol	O
+in	O
+Duchenne	B
+dystrophy	I
+.	O
+
+There	O
+is	O
+evidence	O
+that	O
+growth	O
+hormone	O
+may	O
+be	O
+related	O
+to	O
+the	O
+progression	O
+of	O
+weakness	B
+in	O
+Duchenne	B
+dystrophy	I
+.	O
+
+We	O
+conducted	O
+a	O
+12	O
+-	O
+month	O
+controlled	O
+trial	O
+of	O
+mazindol	O
+,	O
+a	O
+putative	O
+growth	O
+hormone	O
+secretion	O
+inhibitor	O
+,	O
+in	O
+83	O
+boys	O
+with	O
+Duchenne	B
+dystrophy	I
+.	O
+
+Muscle	O
+strength	O
+,	O
+contractures	O
+,	O
+functional	O
+ability	O
+and	O
+pulmonary	O
+function	O
+were	O
+tested	O
+at	O
+baseline	O
+,	O
+and	O
+6	O
+and	O
+12	O
+months	O
+after	O
+treatment	O
+with	O
+mazindol	O
+(	O
+3	O
+mg	O
+/	O
+d	O
+)	O
+or	O
+placebo	O
+.	O
+
+The	O
+study	O
+was	O
+designed	O
+to	O
+have	O
+a	O
+power	O
+of	O
+greater	O
+than	O
+0	O
+.	O
+90	O
+to	O
+detect	O
+a	O
+slowing	O
+to	O
+25	O
+%	O
+of	O
+the	O
+expected	O
+rate	O
+of	O
+progression	O
+of	O
+weakness	B
+at	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+.	O
+
+Mazindol	O
+did	O
+not	O
+benefit	O
+strength	O
+at	O
+any	O
+point	O
+in	O
+the	O
+study	O
+.	O
+
+Side	O
+effects	O
+attributable	O
+to	O
+mazindol	O
+included	O
+decreased	B
+appetite	I
+(	O
+36	O
+%	O
+)	O
+,	O
+dry	B
+mouth	I
+(	O
+10	O
+%	O
+)	O
+,	O
+behavioral	O
+change	O
+(	O
+22	O
+%	O
+)	O
+,	O
+and	O
+gastrointestinal	B
+symptoms	I
+(	O
+18	O
+%	O
+)	O
+;	O
+mazindol	O
+dosage	O
+was	O
+reduced	O
+in	O
+43	O
+%	O
+of	O
+patients	O
+.	O
+
+The	O
+effect	O
+of	O
+mazindol	O
+on	O
+GH	O
+secretion	O
+was	O
+estimated	O
+indirectly	O
+by	O
+comparing	O
+the	O
+postabsorptive	O
+IGF	O
+-	O
+I	O
+levels	O
+obtained	O
+following	O
+3	O
+,	O
+6	O
+,	O
+9	O
+,	O
+and	O
+12	O
+months	O
+in	O
+the	O
+mazindol	O
+treated	O
+to	O
+those	O
+in	O
+the	O
+placebo	O
+groups	O
+.	O
+
+Although	O
+mazindol	O
+-	O
+treated	O
+patients	O
+gained	O
+less	O
+weight	O
+and	O
+height	O
+than	O
+placebo	O
+-	O
+treated	O
+patients	O
+,	O
+no	O
+significant	O
+effect	O
+on	O
+IGF	O
+-	O
+I	O
+levels	O
+was	O
+observed	O
+.	O
+
+Mazindol	O
+doses	O
+not	O
+slow	O
+the	O
+progression	O
+of	O
+weakness	B
+in	O
+Duchenne	B
+dystrophy	I
+.	O
+
+Facilitation	O
+of	O
+memory	O
+retrieval	O
+by	O
+pre	O
+-	O
+test	O
+morphine	O
+and	O
+its	O
+state	O
+dependency	O
+in	O
+the	O
+step	O
+-	O
+through	O
+type	O
+passive	O
+avoidance	O
+learning	O
+test	O
+in	O
+mice	O
+.	O
+
+Amnesia	B
+produced	O
+by	O
+scopolamine	O
+and	O
+cycloheximide	O
+were	O
+reversed	O
+by	O
+morphine	O
+given	O
+30	O
+min	O
+before	O
+the	O
+test	O
+trial	O
+(	O
+pre	O
+-	O
+test	O
+)	O
+,	O
+and	O
+pre	O
+-	O
+test	O
+morphine	O
+also	O
+facilitated	O
+the	O
+memory	O
+retrieval	O
+in	O
+the	O
+animals	O
+administered	O
+naloxone	O
+during	O
+the	O
+training	O
+trial	O
+.	O
+
+Similarly	O
+,	O
+pre	O
+-	O
+test	O
+scopolamine	O
+partially	O
+reversed	O
+the	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+,	O
+but	O
+not	O
+significantly	O
+;	O
+and	O
+pre	O
+-	O
+test	O
+cycloheximide	O
+failed	O
+to	O
+reverse	O
+the	O
+cycloheximide	O
+-	O
+induced	O
+amnesia	B
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+the	O
+facilitation	O
+of	O
+memory	O
+retrieval	O
+by	O
+pre	O
+-	O
+test	O
+morphine	O
+might	O
+be	O
+the	O
+direct	O
+action	O
+of	O
+morphine	O
+rather	O
+than	O
+a	O
+state	O
+dependent	O
+effect	O
+.	O
+
+Naloxone	O
+reverses	O
+the	O
+antihypertensive	O
+effect	O
+of	O
+clonidine	O
+.	O
+
+In	O
+unanesthetized	O
+,	O
+spontaneously	O
+hypertensive	B
+rats	O
+the	O
+decrease	O
+in	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+produced	O
+by	O
+intravenous	O
+clonidine	O
+,	O
+5	O
+to	O
+20	O
+micrograms	O
+/	O
+kg	O
+,	O
+was	O
+inhibited	O
+or	O
+reversed	O
+by	O
+nalozone	O
+,	O
+0	O
+.	O
+2	O
+to	O
+2	O
+mg	O
+/	O
+kg	O
+.	O
+
+The	O
+hypotensive	B
+effect	O
+of	O
+100	O
+mg	O
+/	O
+kg	O
+alpha	O
+-	O
+methyldopa	O
+was	O
+also	O
+partially	O
+reversed	O
+by	O
+naloxone	O
+.	O
+
+Naloxone	O
+alone	O
+did	O
+not	O
+affect	O
+either	O
+blood	O
+pressure	O
+or	O
+heart	O
+rate	O
+.	O
+
+In	O
+brain	O
+membranes	O
+from	O
+spontaneously	O
+hypertensive	B
+rats	O
+clonidine	O
+,	O
+10	O
+(	O
+-	O
+8	O
+)	O
+to	O
+10	O
+(	O
+-	O
+5	O
+)	O
+M	O
+,	O
+did	O
+not	O
+influence	O
+stereoselective	O
+binding	O
+of	O
+[	O
+3H	O
+]	O
+-	O
+naloxone	O
+(	O
+8	O
+nM	O
+)	O
+,	O
+and	O
+naloxone	O
+,	O
+10	O
+(	O
+-	O
+8	O
+)	O
+to	O
+10	O
+(	O
+-	O
+4	O
+)	O
+M	O
+,	O
+did	O
+not	O
+influence	O
+clonidine	O
+-	O
+suppressible	O
+binding	O
+of	O
+[	O
+3H	O
+]	O
+-	O
+dihydroergocryptine	O
+(	O
+1	O
+nM	O
+)	O
+.	O
+
+These	O
+findings	O
+indicate	O
+that	O
+in	O
+spontaneously	O
+hypertensive	B
+rats	O
+the	O
+effects	O
+of	O
+central	O
+alpha	O
+-	O
+adrenoceptor	O
+stimulation	O
+involve	O
+activation	O
+of	O
+opiate	O
+receptors	O
+.	O
+
+As	O
+naloxone	O
+and	O
+clonidine	O
+do	O
+not	O
+appear	O
+to	O
+interact	O
+with	O
+the	O
+same	O
+receptor	O
+site	O
+,	O
+the	O
+observed	O
+functional	O
+antagonism	O
+suggests	O
+the	O
+release	O
+of	O
+an	O
+endogenous	O
+opiate	O
+by	O
+clonidine	O
+or	O
+alpha	O
+-	O
+methyldopa	O
+and	O
+the	O
+possible	O
+role	O
+of	O
+the	O
+opiate	O
+in	O
+the	O
+central	O
+control	O
+of	O
+sympathetic	O
+tone	O
+.	O
+
+Neurotoxicity	B
+of	O
+halogenated	O
+hydroxyquinolines	O
+:	O
+clinical	O
+analysis	O
+of	O
+cases	O
+reported	O
+outside	O
+Japan	O
+.	O
+
+An	O
+analysis	O
+is	O
+presented	O
+of	O
+220	O
+cases	O
+of	O
+possible	O
+neurotoxic	B
+reactions	O
+to	O
+halogenated	O
+hydroxyquinolines	O
+reported	O
+from	O
+outside	O
+Japan	O
+.	O
+
+In	O
+80	O
+cases	O
+insufficient	O
+information	O
+was	O
+available	O
+for	O
+adequate	O
+comment	O
+and	O
+in	O
+29	O
+a	O
+relationship	O
+to	O
+the	O
+administration	O
+of	O
+clioquinol	O
+could	O
+be	O
+excluded	O
+.	O
+
+Of	O
+the	O
+remainder	O
+,	O
+a	O
+relationship	O
+to	O
+clioquinol	O
+was	O
+considered	O
+probable	O
+in	O
+42	O
+and	O
+possible	O
+in	O
+69	O
+cases	O
+.	O
+
+In	O
+six	O
+of	O
+the	O
+probable	O
+cases	O
+the	O
+neurological	B
+disturbance	I
+consisted	O
+of	O
+an	O
+acute	O
+reversible	O
+encephalopathy	B
+usually	O
+related	O
+to	O
+the	O
+ingestion	O
+of	O
+a	O
+high	O
+dose	O
+of	O
+clioquinol	O
+over	O
+a	O
+short	O
+period	O
+.	O
+
+The	O
+most	O
+common	O
+manifestation	O
+,	O
+observed	O
+in	O
+15	O
+further	O
+cases	O
+,	O
+was	O
+isolated	O
+optic	B
+atrophy	I
+.	O
+
+This	O
+was	O
+most	O
+frequently	O
+found	O
+in	O
+children	O
+,	O
+many	O
+of	O
+whom	O
+had	O
+received	O
+clioquinol	O
+as	O
+treatment	O
+for	O
+acrodermatitis	B
+enteropathica	I
+.	O
+
+In	O
+the	O
+remaining	O
+cases	O
+,	O
+a	O
+combination	O
+of	O
+myelopathy	B
+,	O
+visual	B
+disturbance	I
+,	O
+and	O
+peripheral	B
+neuropathy	I
+was	O
+the	O
+most	O
+common	O
+manifestation	O
+.	O
+
+Isolated	O
+myelopathy	B
+or	O
+peripheral	B
+neuropathy	I
+,	O
+or	O
+these	O
+manifestations	O
+occurring	O
+together	O
+,	O
+were	O
+infrequent	O
+.	O
+
+The	O
+onset	O
+of	O
+all	O
+manifestations	O
+(	O
+except	O
+toxic	O
+encephalopathy	B
+)	O
+was	O
+usually	O
+subacute	O
+,	O
+with	O
+subsequent	O
+partial	O
+recovery	O
+.	O
+
+Older	O
+subjects	O
+tended	O
+to	O
+display	O
+more	O
+side	O
+effects	O
+.	O
+
+The	O
+full	O
+syndrome	O
+of	O
+subacute	O
+myelo	B
+-	I
+optic	I
+neuropathy	I
+was	O
+more	O
+frequent	O
+in	O
+women	O
+,	O
+but	O
+they	O
+tended	O
+to	O
+have	O
+taken	O
+greater	O
+quantities	O
+of	O
+the	O
+drug	O
+.	O
+
+Prazosin	O
+-	O
+induced	O
+stress	B
+incontinence	I
+.	O
+
+A	O
+case	O
+of	O
+genuine	O
+stress	B
+incontinence	I
+due	O
+to	O
+prazosin	O
+,	O
+a	O
+common	O
+antihypertensive	O
+drug	O
+,	O
+is	O
+presented	O
+.	O
+
+Prazosin	O
+exerts	O
+its	O
+antihypertensive	O
+effects	O
+through	O
+vasodilatation	O
+caused	O
+by	O
+selective	O
+blockade	O
+of	O
+postsynaptic	O
+alpha	O
+-	O
+1	O
+adrenergic	O
+receptors	O
+.	O
+
+As	O
+an	O
+alpha	O
+-	O
+blocker	O
+,	O
+it	O
+also	O
+exerts	O
+a	O
+significant	O
+relaxant	O
+effect	O
+on	O
+the	O
+bladder	O
+neck	O
+and	O
+urethra	O
+.	O
+
+The	O
+patient	O
+'	O
+s	O
+clinical	O
+course	O
+is	O
+described	O
+and	O
+correlated	O
+with	O
+initial	O
+urodynamic	O
+studies	O
+while	O
+on	O
+prazosin	O
+and	O
+subsequent	O
+studies	O
+while	O
+taking	O
+verapamil	O
+.	O
+
+Her	O
+incontinence	B
+resolved	O
+with	O
+the	O
+change	O
+of	O
+medication	O
+.	O
+
+The	O
+restoration	O
+of	O
+continence	O
+was	O
+accompanied	O
+by	O
+a	O
+substantial	O
+rise	O
+in	O
+maximum	O
+urethral	O
+pressure	O
+,	O
+maximum	O
+urethral	O
+closure	O
+pressure	O
+,	O
+and	O
+functional	O
+urethral	O
+length	O
+.	O
+
+Patients	O
+who	O
+present	O
+with	O
+stress	B
+incontinence	I
+while	O
+taking	O
+prazosin	O
+should	O
+change	O
+their	O
+antihypertensive	O
+medication	O
+before	O
+considering	O
+surgery	O
+,	O
+because	O
+their	O
+incontinence	B
+may	O
+resolve	O
+spontaneously	O
+with	O
+a	O
+change	O
+in	O
+drug	O
+therapy	O
+.	O
+
+Myocardial	B
+infarction	I
+following	O
+sublingual	O
+administration	O
+of	O
+isosorbide	O
+dinitrate	O
+.	O
+
+A	O
+78	O
+-	O
+year	O
+-	O
+old	O
+with	O
+healed	O
+septal	O
+necrosis	B
+suffered	O
+a	O
+recurrent	O
+myocardial	B
+infarction	I
+of	O
+the	O
+anterior	O
+wall	O
+following	O
+the	O
+administration	O
+of	O
+isosorbide	O
+dinitrate	O
+5	O
+mg	O
+sublingually	O
+.	O
+
+After	O
+detailing	O
+the	O
+course	O
+of	O
+events	O
+,	O
+we	O
+discuss	O
+the	O
+role	O
+of	O
+paradoxical	O
+coronary	O
+spasm	B
+and	O
+hypotension	B
+-	O
+mediated	O
+myocardial	B
+ischemia	I
+occurring	O
+downstream	O
+to	O
+significant	O
+coronary	B
+arterial	I
+stenosis	I
+in	O
+the	O
+pathophysiology	O
+of	O
+acute	B
+coronary	I
+insufficiency	I
+.	O
+
+Comparison	O
+of	O
+the	O
+respiratory	O
+effects	O
+of	O
+i	O
+.	O
+v	O
+.	O
+infusions	O
+of	O
+morphine	O
+and	O
+regional	O
+analgesia	O
+by	O
+extradural	O
+block	O
+.	O
+
+The	O
+incidence	O
+of	O
+postoperative	O
+respiratory	O
+apnoea	B
+was	O
+compared	O
+between	O
+five	O
+patients	O
+receiving	O
+a	O
+continuous	O
+i	O
+.	O
+v	O
+.	O
+infusion	O
+of	O
+morphine	O
+(	O
+mean	O
+73	O
+.	O
+6	O
+mg	O
+)	O
+and	O
+five	O
+patients	O
+receiving	O
+a	O
+continuous	O
+extradural	O
+infusion	O
+of	O
+0	O
+.	O
+25	O
+%	O
+bupivacaine	O
+(	O
+mean	O
+192	O
+mg	O
+)	O
+in	O
+the	O
+24	O
+-	O
+h	O
+period	O
+following	O
+upper	O
+abdominal	O
+surgery	O
+.	O
+
+Monitoring	O
+consisted	O
+of	O
+airflow	O
+detection	O
+by	O
+a	O
+carbon	O
+dioxide	O
+analyser	O
+,	O
+chest	O
+wall	O
+movement	O
+detected	O
+by	O
+pneumatic	O
+capsules	O
+,	O
+and	O
+continuous	O
+electrocardiograph	O
+recorded	O
+with	O
+a	O
+Holter	O
+ambulatory	O
+monitor	O
+.	O
+
+Both	O
+obstructive	B
+(	I
+P	I
+less	I
+than	I
+0	I
+.	I
+05	I
+)	I
+and	I
+central	I
+apnoea	I
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+occurred	O
+more	O
+frequently	O
+in	O
+patients	O
+who	O
+had	O
+a	O
+morphine	O
+infusion	O
+.	O
+
+There	O
+was	O
+also	O
+a	O
+higher	O
+incidence	O
+of	O
+tachyarrhythmias	B
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+and	O
+ventricular	B
+ectopic	I
+beats	I
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+in	O
+the	O
+morphine	O
+infusion	O
+group	O
+.	O
+
+Effects	O
+of	O
+aminophylline	O
+on	O
+the	O
+threshold	O
+for	O
+initiating	O
+ventricular	B
+fibrillation	I
+during	O
+respiratory	B
+failure	I
+.	O
+
+Cardiac	B
+arrhythmias	I
+have	O
+frequently	O
+been	O
+reported	O
+in	O
+association	O
+with	O
+respiratory	B
+failure	I
+.	O
+
+The	O
+possible	O
+additive	O
+role	O
+of	O
+pharmacologic	O
+agents	O
+in	O
+precipitating	O
+cardiac	B
+disturbances	I
+in	O
+patients	O
+with	O
+respiratory	B
+failure	I
+has	O
+only	O
+recently	O
+been	O
+emphasized	O
+.	O
+
+The	O
+effects	O
+of	O
+aminophylline	O
+on	O
+the	O
+ventricular	B
+fibrillation	I
+threshold	O
+during	O
+normal	O
+acid	O
+-	O
+base	O
+conditions	O
+and	O
+during	O
+respiratory	B
+failure	I
+were	O
+studied	O
+in	O
+anesthetized	O
+open	O
+chest	O
+dogs	O
+.	O
+
+The	O
+ventricular	B
+fibrillation	I
+threshold	O
+was	O
+measured	O
+by	O
+passing	O
+a	O
+gated	O
+train	O
+of	O
+12	O
+constant	O
+current	O
+pulses	O
+through	O
+the	O
+ventricular	O
+myocardium	O
+during	O
+the	O
+vulnerable	O
+period	O
+of	O
+the	O
+cardiac	O
+cycle	O
+.	O
+
+During	O
+the	O
+infusion	O
+of	O
+aminophylline	O
+,	O
+the	O
+ventricular	B
+fibrillation	I
+threshold	O
+was	O
+reduced	O
+by	O
+30	O
+to	O
+40	O
+percent	O
+of	O
+the	O
+control	O
+when	O
+pH	O
+and	O
+partial	O
+pressures	O
+of	O
+oxygen	O
+(	O
+PO2	O
+)	O
+and	O
+carbon	O
+dioxide	O
+(	O
+CO2	O
+)	O
+were	O
+kept	O
+within	O
+normal	O
+limits	O
+.	O
+
+When	O
+respiratory	B
+failure	I
+was	O
+produced	O
+by	O
+hypoventilation	B
+(	O
+pH	O
+7	O
+.	O
+05	O
+to	O
+7	O
+.	O
+25	O
+;	O
+PC02	O
+70	O
+to	O
+100	O
+mm	O
+Hg	O
+:	O
+P02	O
+20	O
+to	O
+40	O
+mm	O
+Hg	O
+)	O
+,	O
+infusion	O
+of	O
+aminophylline	O
+resulted	O
+in	O
+an	O
+even	O
+greater	O
+decrease	O
+in	O
+ventricular	B
+fibrillation	I
+threshold	O
+to	O
+60	O
+percent	O
+of	O
+the	O
+control	O
+level	O
+.	O
+
+These	O
+experiments	O
+suggest	O
+that	O
+although	O
+many	O
+factors	O
+may	O
+contribute	O
+to	O
+the	O
+increased	O
+incidence	O
+of	O
+ventricular	B
+arrhythmias	I
+in	O
+respiratory	B
+failure	I
+,	O
+pharmacologic	O
+agents	O
+,	O
+particularly	O
+aminophylline	O
+,	O
+may	O
+play	O
+a	O
+significant	O
+role	O
+.	O
+
+Pentoxifylline	O
+(	O
+Trental	O
+)	O
+does	O
+not	O
+inhibit	O
+dipyridamole	O
+-	O
+induced	O
+coronary	O
+hyperemia	B
+:	O
+implications	O
+for	O
+dipyridamole	O
+-	O
+thallium	O
+-	O
+201	O
+myocardial	O
+imaging	O
+.	O
+
+Dipyridamole	O
+-	O
+thallium	O
+-	O
+201	O
+imaging	O
+is	O
+often	O
+performed	O
+in	O
+patients	O
+unable	O
+to	O
+exercise	O
+because	O
+of	O
+peripheral	B
+vascular	I
+disease	I
+.	O
+
+Many	O
+of	O
+these	O
+patients	O
+are	O
+taking	O
+pentoxifylline	O
+(	O
+Trental	O
+)	O
+,	O
+a	O
+methylxanthine	O
+derivative	O
+which	O
+may	O
+improve	O
+intermittent	B
+claudication	I
+.	O
+
+Whether	O
+pentoxifylline	O
+inhibits	O
+dipyridamole	O
+-	O
+induced	O
+coronary	O
+hyperemia	B
+like	O
+other	O
+methylxanthines	O
+such	O
+as	O
+theophylline	O
+and	O
+should	O
+be	O
+stopped	O
+prior	O
+to	O
+dipyridamole	O
+-	O
+thallium	O
+-	O
+201	O
+imaging	O
+is	O
+unknown	O
+.	O
+
+Therefore	O
+,	O
+we	O
+studied	O
+the	O
+hyperemic	O
+response	O
+to	O
+dipyridamole	O
+in	O
+seven	O
+open	O
+-	O
+chest	O
+anesthetized	O
+dogs	O
+after	O
+pretreatment	O
+with	O
+either	O
+pentoxifylline	O
+(	O
+0	O
+,	O
+7	O
+.	O
+5	O
+,	O
+or	O
+15	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+or	O
+theophylline	O
+(	O
+3	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+.	O
+
+Baseline	O
+circumflex	O
+coronary	O
+blood	O
+flows	O
+did	O
+not	O
+differ	O
+significantly	O
+among	O
+treatment	O
+groups	O
+.	O
+
+Dipyridamole	O
+significantly	O
+increased	O
+coronary	O
+blood	O
+flow	O
+before	O
+and	O
+after	O
+7	O
+.	O
+5	O
+or	O
+15	O
+mm	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+pentoxifylline	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+002	O
+)	O
+.	O
+
+Neither	O
+dose	O
+of	O
+pentoxifylline	O
+significantly	O
+decreased	O
+the	O
+dipyridamole	O
+-	O
+induced	O
+hyperemia	B
+,	O
+while	O
+peak	O
+coronary	O
+blood	O
+flow	O
+was	O
+significantly	O
+lower	O
+after	O
+theophylline	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+We	O
+conclude	O
+that	O
+pentoxyifylline	O
+does	O
+not	O
+inhibit	O
+dipyridamole	O
+-	O
+induced	O
+coronary	O
+hyperemia	B
+even	O
+at	O
+high	O
+doses	O
+.	O
+
+Cause	O
+of	O
+death	B
+among	O
+patients	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+:	O
+a	O
+rare	O
+mortality	O
+due	O
+to	O
+cerebral	B
+haemorrhage	I
+.	O
+
+Causes	O
+of	O
+death	B
+,	O
+with	O
+special	O
+reference	O
+to	O
+cerebral	B
+haemorrhage	I
+,	O
+among	O
+240	O
+patients	O
+with	O
+pathologically	O
+verified	O
+Parkinson	B
+'	I
+s	I
+disease	I
+were	O
+investigated	O
+using	O
+the	O
+Annuals	O
+of	O
+the	O
+Pathological	O
+Autopsy	O
+Cases	O
+in	O
+Japan	O
+from	O
+1981	O
+to	O
+1985	O
+.	O
+
+The	O
+leading	O
+causes	O
+of	O
+death	B
+were	O
+pneumonia	B
+and	O
+bronchitis	B
+(	O
+44	O
+.	O
+1	O
+%	O
+)	O
+,	O
+malignant	O
+neoplasms	B
+(	O
+11	O
+.	O
+6	O
+%	O
+)	O
+,	O
+heart	B
+diseases	I
+(	O
+4	O
+.	O
+1	O
+%	O
+)	O
+,	O
+cerebral	B
+infarction	I
+(	O
+3	O
+.	O
+7	O
+%	O
+)	O
+and	O
+septicaemia	B
+(	O
+3	O
+.	O
+3	O
+%	O
+)	O
+.	O
+
+Cerebral	B
+haemorrhage	I
+was	O
+the	O
+11th	O
+most	O
+frequent	O
+cause	O
+of	O
+death	B
+,	O
+accounting	O
+for	O
+only	O
+0	O
+.	O
+8	O
+%	O
+of	O
+deaths	B
+among	O
+the	O
+patients	O
+,	O
+whereas	O
+it	O
+was	O
+the	O
+5th	O
+most	O
+common	O
+cause	O
+of	O
+death	B
+among	O
+the	O
+Japanese	O
+general	O
+population	O
+in	O
+1985	O
+.	O
+
+The	O
+low	O
+incidence	O
+of	O
+cerebral	B
+haemorrhage	I
+as	O
+a	O
+cause	O
+of	O
+death	B
+in	O
+patients	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+may	O
+reflect	O
+the	O
+hypotensive	B
+effect	O
+of	O
+levodopa	O
+and	O
+a	O
+hypotensive	B
+mechanism	O
+due	O
+to	O
+reduced	O
+noradrenaline	O
+levels	O
+in	O
+the	O
+parkinsonian	B
+brain	O
+.	O
+
+Possible	O
+intramuscular	O
+midazolam	O
+-	O
+associated	O
+cardiorespiratory	B
+arrest	I
+and	O
+death	B
+.	O
+
+Midazolam	O
+hydrochloride	O
+is	O
+commonly	O
+used	O
+for	O
+dental	O
+or	O
+endoscopic	O
+procedures	O
+.	O
+
+Although	O
+generally	O
+consisted	O
+safe	O
+when	O
+given	O
+intramuscularly	O
+,	O
+intravenous	O
+administration	O
+is	O
+known	O
+to	O
+cause	O
+respiratory	B
+and	I
+cardiovascular	I
+depression	I
+.	O
+
+This	O
+report	O
+describes	O
+the	O
+first	O
+published	O
+case	O
+of	O
+cardiorespiratory	B
+arrest	I
+and	O
+death	B
+associated	O
+with	O
+intramuscular	O
+administration	O
+of	O
+midazolam	O
+.	O
+
+Information	O
+regarding	O
+midazolam	O
+use	O
+is	O
+reviewed	O
+to	O
+provide	O
+recommendation	O
+for	O
+safe	O
+administration	O
+.	O
+
+Myasthenia	B
+gravis	I
+presenting	O
+as	O
+weakness	O
+after	O
+magnesium	O
+administration	O
+.	O
+
+We	O
+studied	O
+a	O
+patient	O
+with	O
+no	O
+prior	O
+history	O
+of	O
+neuromuscular	B
+disease	I
+who	O
+became	O
+virtually	O
+quadriplegic	B
+after	O
+parenteral	O
+magnesium	O
+administration	O
+for	O
+preeclampsia	B
+.	O
+
+The	O
+serum	O
+magnesium	O
+concentration	O
+was	O
+3	O
+.	O
+0	O
+mEq	O
+/	O
+L	O
+,	O
+which	O
+is	O
+usually	O
+well	O
+tolerated	O
+.	O
+
+The	O
+magnesium	O
+was	O
+stopped	O
+and	O
+she	O
+recovered	O
+over	O
+a	O
+few	O
+days	O
+.	O
+
+While	O
+she	O
+was	O
+weak	O
+,	O
+2	O
+-	O
+Hz	O
+repetitive	O
+stimulation	O
+revealed	O
+a	O
+decrement	O
+without	O
+significant	O
+facilitation	O
+at	O
+rapid	O
+rates	O
+or	O
+after	O
+exercise	O
+,	O
+suggesting	O
+postsynaptic	B
+neuromuscular	I
+blockade	I
+.	O
+
+After	O
+her	O
+strength	O
+returned	O
+,	O
+repetitive	O
+stimulation	O
+was	O
+normal	O
+,	O
+but	O
+single	O
+fiber	O
+EMG	O
+revealed	O
+increased	O
+jitter	O
+and	O
+blocking	O
+.	O
+
+Her	O
+acetylcholine	O
+receptor	O
+antibody	O
+level	O
+was	O
+markedly	O
+elevated	O
+.	O
+
+Although	O
+paralysis	B
+after	O
+magnesium	O
+administration	O
+has	O
+been	O
+described	O
+in	O
+patients	O
+with	O
+known	O
+myasthenia	B
+gravis	I
+,	O
+it	O
+has	O
+not	O
+previously	O
+been	O
+reported	O
+to	O
+be	O
+the	O
+initial	O
+or	O
+only	O
+manifestation	O
+of	O
+the	O
+disease	O
+.	O
+
+Patients	O
+who	O
+are	O
+unusually	O
+sensitive	O
+to	O
+the	O
+neuromuscular	O
+effects	O
+of	O
+magnesium	O
+should	O
+be	O
+suspected	O
+of	O
+having	O
+an	O
+underlying	O
+disorder	B
+of	I
+neuromuscular	I
+transmission	I
+.	O
+
+No	O
+enhancement	O
+by	O
+phenobarbital	O
+of	O
+the	O
+hepatocarcinogenicity	O
+of	O
+a	O
+choline	O
+-	O
+devoid	O
+diet	O
+in	O
+the	O
+rat	O
+.	O
+
+An	O
+experiment	O
+was	O
+performed	O
+to	O
+test	O
+whether	O
+inclusion	O
+of	O
+phenobarbital	O
+in	O
+a	O
+choline	O
+-	O
+devoid	O
+diet	O
+would	O
+increase	O
+the	O
+hepatocarcinogenicity	O
+of	O
+the	O
+diet	O
+.	O
+
+Groups	O
+of	O
+5	O
+-	O
+week	O
+old	O
+male	O
+Fischer	O
+-	O
+344	O
+rats	O
+were	O
+fed	O
+for	O
+7	O
+-	O
+25	O
+months	O
+semipurified	O
+choline	O
+-	O
+devoid	O
+or	O
+choline	O
+-	O
+supplemented	O
+diets	O
+,	O
+containing	O
+or	O
+not	O
+0	O
+.	O
+06	O
+%	O
+phenobarbital	O
+.	O
+
+No	O
+hepatic	O
+preneoplastic	O
+nodules	O
+or	O
+hepatocellular	B
+carcinomas	I
+developed	O
+in	O
+rats	O
+fed	O
+the	O
+plain	O
+choline	O
+-	O
+supplemented	O
+diet	O
+,	O
+while	O
+one	O
+preneoplastic	O
+nodule	O
+and	O
+one	O
+hepatocellular	B
+carcinoma	I
+developed	O
+in	O
+two	O
+rats	O
+fed	O
+the	O
+same	O
+diet	O
+containing	O
+phenobarbital	O
+.	O
+
+The	O
+incidence	O
+of	O
+preneoplastic	O
+nodules	O
+and	O
+of	O
+hepatocellular	B
+carcinomas	I
+was	O
+10	O
+%	O
+and	O
+37	O
+%	O
+,	O
+respectively	O
+,	O
+in	O
+rats	O
+fed	O
+the	O
+plain	O
+choline	O
+-	O
+devoid	O
+diet	O
+,	O
+and	O
+17	O
+%	O
+and	O
+30	O
+%	O
+,	O
+in	O
+rats	O
+fed	O
+the	O
+phenobarbital	O
+-	O
+containing	O
+choline	O
+-	O
+devoid	O
+diet	O
+.	O
+
+The	O
+results	O
+evinced	O
+no	O
+enhancement	O
+of	O
+the	O
+hepatocarcinogenicity	O
+of	O
+the	O
+choline	O
+-	O
+devoid	O
+diet	O
+by	O
+phenobarbital	O
+.	O
+
+Sporadic	O
+neoplastic	O
+lesions	O
+were	O
+observed	O
+in	O
+organs	O
+other	O
+than	O
+the	O
+liver	O
+of	O
+some	O
+of	O
+the	O
+animals	O
+,	O
+irrespective	O
+of	O
+the	O
+diet	O
+fed	O
+.	O
+
+On	O
+two	O
+paradoxical	O
+side	O
+-	O
+effects	O
+of	O
+prednisolone	O
+in	O
+rats	O
+,	O
+ribosomal	O
+RNA	O
+biosyntheses	O
+,	O
+and	O
+a	O
+mechanism	O
+of	O
+action	O
+.	O
+
+Liver	B
+enlargement	I
+and	O
+muscle	B
+wastage	I
+occurred	O
+in	O
+Wistar	O
+rats	O
+following	O
+the	O
+subcutaneous	O
+administration	O
+of	O
+prednisolone	O
+.	O
+
+In	O
+the	O
+liver	O
+both	O
+the	O
+content	O
+of	O
+RNA	O
+and	O
+the	O
+biosynthesis	O
+of	O
+ribosomal	O
+RNA	O
+increased	O
+while	O
+both	O
+the	O
+RNA	O
+content	O
+and	O
+ribosomal	O
+RNA	O
+biosynthesis	O
+were	O
+reduced	O
+in	O
+the	O
+gastrocnemius	O
+muscle	O
+.	O
+
+It	O
+is	O
+suggested	O
+that	O
+the	O
+drug	O
+acted	O
+in	O
+a	O
+selective	O
+and	O
+tissue	O
+-	O
+specific	O
+manner	O
+to	O
+enhance	O
+ribosomal	O
+RNA	O
+synthesis	O
+in	O
+the	O
+liver	O
+and	O
+depress	O
+such	O
+synthesis	O
+in	O
+the	O
+muscle	O
+.	O
+
+This	O
+view	O
+supports	O
+the	O
+contention	O
+that	O
+the	O
+liver	O
+and	O
+muscle	O
+are	O
+independent	O
+sites	O
+of	O
+prednisolone	O
+action	O
+.	O
+
+Differential	O
+effects	O
+of	O
+gamma	O
+-	O
+hexachlorocyclohexane	O
+(	O
+lindane	O
+)	O
+on	O
+pharmacologically	O
+-	O
+induced	O
+seizures	B
+.	O
+
+Gamma	O
+-	O
+hexachlorocyclohexane	O
+(	O
+gamma	O
+-	O
+HCH	O
+)	O
+,	O
+the	O
+active	O
+ingredient	O
+of	O
+the	O
+insecticide	O
+lindane	O
+,	O
+has	O
+been	O
+shown	O
+to	O
+decrease	O
+seizure	B
+threshold	O
+to	O
+pentylenetrazol	O
+(	O
+PTZ	O
+)	O
+3	O
+h	O
+after	O
+exposure	O
+to	O
+gamma	O
+-	O
+HCH	O
+and	O
+conversely	O
+increase	O
+threshold	O
+to	O
+PTZ	O
+-	O
+induced	O
+seizures	B
+24	O
+h	O
+after	O
+exposure	O
+to	O
+gamma	O
+-	O
+HCH	O
+(	O
+Vohland	O
+et	O
+al	O
+.	O
+1981	O
+)	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+the	O
+severity	O
+of	O
+response	O
+to	O
+other	O
+seizure	B
+-	O
+inducing	O
+agents	O
+was	O
+tested	O
+in	O
+mice	O
+1	O
+and	O
+24	O
+h	O
+after	O
+intraperitoneal	O
+administration	O
+of	O
+80	O
+mg	O
+/	O
+kg	O
+gamma	O
+-	O
+HCH	O
+.	O
+
+One	O
+hour	O
+after	O
+the	O
+administration	O
+of	O
+gamma	O
+-	O
+HCH	O
+,	O
+the	O
+activity	O
+of	O
+seizure	B
+-	O
+inducing	O
+agents	O
+was	O
+increased	O
+,	O
+regardless	O
+of	O
+their	O
+mechanism	O
+,	O
+while	O
+24	O
+h	O
+after	O
+gamma	O
+-	O
+HCH	O
+a	O
+differential	O
+response	O
+was	O
+observed	O
+.	O
+
+Seizure	B
+activity	O
+due	O
+to	O
+PTZ	O
+and	O
+picrotoxin	O
+(	O
+PTX	O
+)	O
+was	O
+significantly	O
+decreased	O
+;	O
+however	O
+,	O
+seizure	B
+activity	O
+due	O
+to	O
+3	O
+-	O
+mercaptopropionic	O
+acid	O
+(	O
+MPA	O
+)	O
+,	O
+bicuculline	O
+(	O
+BCC	O
+)	O
+,	O
+methyl	O
+6	O
+,	O
+7	O
+-	O
+dimethoxy	O
+-	O
+4	O
+-	O
+ethyl	O
+-	O
+B	O
+-	O
+carboline	O
+-	O
+3	O
+-	O
+carboxylate	O
+(	O
+DMCM	O
+)	O
+,	O
+or	O
+strychnine	O
+(	O
+STR	O
+)	O
+was	O
+not	O
+different	O
+from	O
+control	O
+.	O
+
+In	O
+vitro	O
+,	O
+gamma	O
+-	O
+HCH	O
+,	O
+pentylenetetrazol	O
+and	O
+picrotoxin	O
+were	O
+shown	O
+to	O
+inhibit	O
+3H	O
+-	O
+TBOB	O
+binding	O
+in	O
+mouse	O
+whole	O
+brain	O
+,	O
+with	O
+IC50	O
+values	O
+of	O
+4	O
+.	O
+6	O
+,	O
+404	O
+and	O
+9	O
+.	O
+4	O
+microM	O
+,	O
+respectively	O
+.	O
+
+MPA	O
+,	O
+BCC	O
+,	O
+DMCM	O
+,	O
+and	O
+STR	O
+showed	O
+no	O
+inhibition	O
+of	O
+3H	O
+-	O
+TBOB	O
+(	O
+t	O
+-	O
+butyl	O
+bicyclo	O
+-	O
+orthobenzoate	O
+)	O
+binding	O
+at	O
+concentrations	O
+of	O
+100	O
+micron	O
+.	O
+
+The	O
+pharmacological	O
+challenge	O
+data	O
+suggest	O
+that	O
+tolerance	O
+may	O
+occur	O
+to	O
+seizure	B
+activity	O
+induced	O
+by	O
+PTZ	O
+and	O
+PTX	O
+24	O
+h	O
+after	O
+gamma	O
+-	O
+HCH	O
+,	O
+since	O
+the	O
+response	O
+to	O
+only	O
+these	O
+two	O
+seizure	B
+-	O
+inducing	O
+agents	O
+is	O
+decreased	O
+.	O
+
+The	O
+in	O
+vitro	O
+data	O
+suggest	O
+that	O
+the	O
+site	O
+responsible	O
+for	O
+the	O
+decrease	O
+in	O
+seizure	B
+activity	O
+24	O
+h	O
+after	O
+gamma	O
+-	O
+HCH	O
+may	O
+be	O
+the	O
+GABA	O
+-	O
+A	O
+receptor	O
+-	O
+linked	O
+chloride	O
+channel	O
+.	O
+
+Tolerance	O
+and	O
+antiviral	O
+effect	O
+of	O
+ribavirin	O
+in	O
+patients	O
+with	O
+Argentine	B
+hemorrhagic	I
+fever	I
+.	O
+
+Tolerance	O
+and	O
+antiviral	O
+effect	O
+of	O
+ribavirin	O
+was	O
+studied	O
+in	O
+6	O
+patients	O
+with	O
+Argentine	B
+hemorrhagic	I
+fever	I
+(	O
+AHF	B
+)	O
+of	O
+more	O
+than	O
+8	O
+days	O
+of	O
+evolution	O
+.	O
+
+Administration	O
+of	O
+ribavirin	O
+resulted	O
+in	O
+a	O
+neutralization	O
+of	O
+viremia	B
+and	O
+a	O
+drop	O
+of	O
+endogenous	O
+interferon	O
+titers	O
+.	O
+
+The	O
+average	O
+time	O
+of	O
+death	B
+was	O
+delayed	O
+.	O
+
+A	O
+reversible	O
+anemia	B
+was	O
+the	O
+only	O
+adverse	O
+effect	O
+observed	O
+.	O
+
+From	O
+these	O
+results	O
+,	O
+we	O
+conclude	O
+that	O
+ribavirin	O
+has	O
+an	O
+antiviral	O
+effect	O
+in	O
+advanced	O
+cases	O
+of	O
+AHF	B
+,	O
+and	O
+that	O
+anemia	B
+,	O
+the	O
+only	O
+secondary	O
+reaction	O
+observed	O
+,	O
+can	O
+be	O
+easily	O
+managed	O
+.	O
+
+The	O
+possible	O
+beneficial	O
+effect	O
+of	O
+ribavirin	O
+during	O
+the	O
+initial	O
+days	O
+of	O
+AHF	B
+is	O
+discussed	O
+.	O
+
+Is	O
+the	O
+treatment	O
+of	O
+scabies	B
+hazardous	O
+?	O
+
+Treatment	O
+for	O
+scabies	B
+is	O
+usually	O
+initiated	O
+by	O
+general	O
+practitioners	O
+;	O
+most	O
+consider	O
+lindane	O
+(	O
+gamma	O
+benzene	O
+hexachloride	O
+)	O
+the	O
+treatment	O
+of	O
+choice	O
+.	O
+
+Lindane	O
+is	O
+also	O
+widely	O
+used	O
+as	O
+an	O
+agricultural	O
+and	O
+industrial	O
+pesticide	O
+,	O
+and	O
+as	O
+a	O
+result	O
+the	O
+toxic	O
+profile	O
+of	O
+this	O
+insecticide	O
+is	O
+well	O
+understood	O
+.	O
+
+Evidence	O
+is	O
+accumulating	O
+that	O
+lindane	O
+can	O
+be	O
+toxic	B
+to	I
+the	I
+central	I
+nervous	I
+system	I
+and	O
+may	O
+be	O
+associated	O
+with	O
+aplastic	B
+anaemia	I
+.	O
+
+Preparations	O
+containing	O
+lindane	O
+continue	O
+to	O
+be	O
+sold	O
+over	O
+the	O
+counter	O
+and	O
+may	O
+represent	O
+a	O
+hazard	O
+to	O
+poorly	O
+informed	O
+patients	O
+.	O
+
+This	O
+literature	O
+review	O
+suggests	O
+that	O
+general	O
+practitioners	O
+should	O
+prescribe	O
+scabicides	O
+with	O
+increased	O
+caution	O
+for	O
+certain	O
+at	O
+-	O
+risk	O
+groups	O
+,	O
+and	O
+give	O
+adequate	O
+warnings	O
+regarding	O
+potential	O
+toxicity	B
+.	O
+
+Mouse	O
+strain	O
+-	O
+dependent	O
+effect	O
+of	O
+amantadine	O
+on	O
+motility	O
+and	O
+brain	O
+biogenic	O
+amines	O
+.	O
+
+The	O
+effect	O
+of	O
+amantadine	O
+hydrochloride	O
+,	O
+injected	O
+i	O
+.	O
+p	O
+.	O
+in	O
+6	O
+increments	O
+of	O
+100	O
+mg	O
+/	O
+kg	O
+each	O
+over	O
+30	O
+hr	O
+,	O
+on	O
+mouse	O
+motility	O
+and	O
+whole	O
+brain	O
+content	O
+of	O
+selected	O
+biogenic	O
+amines	O
+and	O
+major	O
+metabolites	O
+was	O
+studied	O
+in	O
+4	O
+strains	O
+of	O
+mice	O
+.	O
+
+These	O
+were	O
+the	O
+albino	O
+Sprague	O
+-	O
+Dawley	O
+ICR	O
+and	O
+BALB	O
+/	O
+C	O
+,	O
+the	O
+black	O
+C57BL	O
+/	O
+6	O
+and	O
+the	O
+brown	O
+CDF	O
+-	O
+I	O
+mouse	O
+strains	O
+.	O
+
+Amantadine	O
+treatment	O
+produced	O
+a	O
+biphasic	O
+effect	O
+on	O
+mouse	O
+motility	O
+.	O
+
+The	O
+initial	O
+dose	O
+of	O
+amantadine	O
+depressed	B
+locomotor	O
+activity	O
+in	O
+all	O
+mouse	O
+strains	O
+studied	O
+with	O
+the	O
+BALB	O
+/	O
+C	O
+mice	O
+being	O
+the	O
+most	O
+sensitive	O
+.	O
+
+Subsequent	O
+amantadine	O
+treatments	O
+produced	O
+enhancement	O
+of	O
+motility	O
+from	O
+corresponding	O
+control	O
+in	O
+all	O
+mouse	O
+strains	O
+with	O
+the	O
+BALB	O
+/	O
+C	O
+mice	O
+being	O
+the	O
+least	O
+sensitive	O
+.	O
+
+The	O
+locomotor	O
+activity	O
+was	O
+decreased	O
+from	O
+corresponding	O
+controls	O
+in	O
+all	O
+strains	O
+studied	O
+,	O
+except	O
+for	O
+the	O
+ICR	O
+mice	O
+,	O
+during	O
+an	O
+overnight	O
+drug	O
+-	O
+free	O
+period	O
+following	O
+the	O
+fourth	O
+amantadine	O
+treatment	O
+.	O
+
+Readministration	O
+of	O
+amantadine	O
+,	O
+after	O
+a	O
+drug	O
+-	O
+free	O
+overnight	O
+period	O
+,	O
+increased	O
+motility	O
+from	O
+respective	O
+saline	O
+control	O
+in	O
+all	O
+strains	O
+with	O
+exception	O
+of	O
+the	O
+BALB	O
+/	O
+C	O
+mice	O
+where	O
+suppression	B
+of	I
+motility	I
+occurred	O
+.	O
+
+Treatment	O
+with	O
+amantadine	O
+did	O
+not	O
+alter	O
+whole	O
+brain	O
+dopamine	O
+levels	O
+but	O
+decreased	O
+the	O
+amounts	O
+of	O
+3	O
+,	O
+4	O
+-	O
+dihydroxyphenylacetic	O
+acid	O
+in	O
+the	O
+BALB	O
+/	O
+C	O
+mice	O
+compared	O
+to	O
+saline	O
+control	O
+.	O
+
+Conversely	O
+,	O
+brain	O
+normetanephrine	O
+concentration	O
+was	O
+increased	O
+from	O
+saline	O
+control	O
+by	O
+amantadine	O
+in	O
+the	O
+BALB	O
+/	O
+C	O
+mice	O
+.	O
+
+The	O
+results	O
+suggest	O
+a	O
+strain	O
+-	O
+dependent	O
+effect	O
+of	O
+amantadine	O
+on	O
+motility	O
+and	O
+indicate	O
+a	O
+differential	O
+response	O
+to	O
+the	O
+acute	O
+and	O
+multiple	O
+dose	O
+regimens	O
+used	O
+.	O
+
+The	O
+BALB	O
+/	O
+C	O
+mouse	O
+was	O
+the	O
+most	O
+sensitive	O
+strain	O
+and	O
+could	O
+serve	O
+as	O
+the	O
+strain	O
+of	O
+choice	O
+for	O
+evaluating	O
+the	O
+side	O
+effects	O
+of	O
+amantadine	O
+.	O
+
+The	O
+biochemical	O
+results	O
+of	O
+brain	O
+biogenic	O
+amines	O
+of	O
+BALB	O
+/	O
+C	O
+mouse	O
+strain	O
+suggest	O
+a	O
+probable	O
+decrease	O
+of	O
+catecholamine	O
+turnover	O
+rate	O
+and	O
+/	O
+or	O
+metabolism	O
+by	O
+monoamine	O
+oxidase	O
+and	O
+a	O
+resulting	O
+increase	O
+in	O
+O	O
+-	O
+methylation	O
+of	O
+norepinephrine	O
+which	O
+may	O
+account	O
+for	O
+a	O
+behavioral	B
+depression	I
+caused	O
+by	O
+amantadine	O
+in	O
+the	O
+BALB	O
+/	O
+C	O
+mice	O
+.	O
+
+Chloroacetaldehyde	O
+and	O
+its	O
+contribution	O
+to	O
+urotoxicity	O
+during	O
+treatment	O
+with	O
+cyclophosphamide	O
+or	O
+ifosfamide	O
+.	O
+
+An	O
+experimental	O
+study	O
+/	O
+short	O
+communication	O
+.	O
+
+Based	O
+on	O
+clinical	O
+data	O
+,	O
+indicating	O
+that	O
+chloroacetaldehyde	O
+(	O
+CAA	O
+)	O
+is	O
+an	O
+important	O
+metabolite	O
+of	O
+oxazaphosphorine	O
+cytostatics	O
+,	O
+an	O
+experimental	O
+study	O
+was	O
+carried	O
+out	O
+in	O
+order	O
+to	O
+elucidate	O
+the	O
+role	O
+of	O
+CAA	O
+in	O
+the	O
+development	O
+of	O
+hemorrhagic	B
+cystitis	I
+.	O
+
+The	O
+data	O
+demonstrate	O
+that	O
+CAA	O
+after	O
+i	O
+.	O
+v	O
+.	O
+administration	O
+does	O
+not	O
+contribute	O
+to	O
+bladder	B
+damage	I
+.	O
+
+When	O
+instilled	O
+directly	O
+into	O
+the	O
+bladder	O
+,	O
+CAA	O
+exerts	O
+urotoxic	O
+effects	O
+,	O
+it	O
+is	O
+,	O
+however	O
+,	O
+susceptible	O
+to	O
+detoxification	O
+with	O
+mesna	O
+.	O
+
+Source	O
+of	O
+pain	B
+and	O
+primitive	O
+dysfunction	O
+in	O
+migraine	B
+:	O
+an	O
+identical	O
+site	O
+?	O
+
+Twenty	O
+common	O
+migraine	B
+patients	O
+received	O
+a	O
+one	O
+sided	O
+frontotemporal	O
+application	O
+of	O
+nitroglycerin	O
+(	O
+10	O
+patients	O
+)	O
+or	O
+placebo	O
+ointment	O
+(	O
+10	O
+patients	O
+)	O
+in	O
+a	O
+double	O
+blind	O
+study	O
+.	O
+
+Early	O
+onset	O
+migraine	B
+attacks	O
+were	O
+induced	O
+by	O
+nitroglycerin	O
+in	O
+seven	O
+out	O
+of	O
+10	O
+patients	O
+versus	O
+no	O
+patient	O
+in	O
+the	O
+placebo	O
+group	O
+.	O
+
+Subsequently	O
+20	O
+migraine	B
+patients	O
+,	O
+who	O
+developed	O
+an	O
+early	O
+onset	O
+attack	O
+with	O
+frontotemporal	O
+nitroglycerin	O
+,	O
+received	O
+the	O
+drug	O
+in	O
+a	O
+second	O
+induction	O
+test	O
+at	O
+other	O
+body	O
+areas	O
+.	O
+
+No	O
+early	O
+onset	O
+migraine	B
+was	O
+observed	O
+.	O
+
+Thus	O
+the	O
+migraine	B
+-	O
+inducing	O
+effect	O
+of	O
+nitroglycerin	O
+seems	O
+to	O
+depend	O
+on	O
+direct	O
+stimulation	O
+of	O
+the	O
+habitual	O
+site	O
+of	O
+pain	B
+,	O
+suggesting	O
+that	O
+the	O
+frontotemporal	O
+region	O
+is	O
+of	O
+crucial	O
+importance	O
+in	O
+the	O
+development	O
+of	O
+a	O
+migraine	B
+crisis	O
+.	O
+
+This	O
+is	O
+not	O
+consistent	O
+with	O
+a	O
+CNS	O
+origin	O
+of	O
+migraine	B
+attack	O
+.	O
+
+Hypersensitivity	B
+to	O
+carbamazepine	O
+presenting	O
+with	O
+a	O
+leukemoid	B
+reaction	I
+,	O
+eosinophilia	B
+,	O
+erythroderma	B
+,	O
+and	O
+renal	B
+failure	I
+.	O
+
+We	O
+report	O
+a	O
+patient	O
+in	O
+whom	O
+hypersensitivity	B
+to	O
+carbamazepine	O
+presented	O
+with	O
+generalized	O
+erythroderma	B
+,	O
+a	O
+severe	O
+leukemoid	B
+reaction	I
+,	O
+eosinophilia	B
+,	O
+hyponatremia	B
+,	O
+and	O
+renal	B
+failure	I
+.	O
+
+This	O
+is	O
+the	O
+first	O
+report	O
+of	O
+such	O
+an	O
+unusual	O
+reaction	O
+to	O
+carbamazepine	O
+.	O
+
+Fluoxetine	O
+-	O
+induced	O
+akathisia	B
+:	O
+clinical	O
+and	O
+theoretical	O
+implications	O
+.	O
+
+Five	O
+patients	O
+receiving	O
+fluoxetine	O
+for	O
+the	O
+treatment	O
+of	O
+obsessive	B
+compulsive	I
+disorder	I
+or	O
+major	B
+depression	I
+developed	O
+akathisia	B
+.	O
+
+The	O
+typical	O
+fluoxetine	O
+-	O
+induced	O
+symptoms	O
+of	O
+restlessness	O
+,	O
+constant	O
+pacing	O
+,	O
+purposeless	O
+movements	O
+of	O
+the	O
+feet	O
+and	O
+legs	O
+,	O
+and	O
+marked	O
+anxiety	B
+were	O
+indistinguishable	O
+from	O
+those	O
+of	O
+neuroleptic	O
+-	O
+induced	O
+akathisia	B
+.	O
+
+Three	O
+patients	O
+who	O
+had	O
+experienced	O
+neuroleptic	O
+-	O
+induced	O
+akathisia	B
+in	O
+the	O
+past	O
+reported	O
+that	O
+the	O
+symptoms	O
+of	O
+fluoxetine	O
+-	O
+induced	O
+akathisia	B
+were	O
+identical	O
+,	O
+although	O
+somewhat	O
+milder	O
+.	O
+
+Akathisia	B
+appeared	O
+to	O
+be	O
+a	O
+common	O
+side	O
+effect	O
+of	O
+fluoxetine	O
+and	O
+generally	O
+responded	O
+well	O
+to	O
+treatment	O
+with	O
+the	O
+beta	O
+-	O
+adrenergic	O
+antagonist	O
+propranolol	O
+,	O
+dose	O
+reduction	O
+,	O
+or	O
+both	O
+.	O
+
+The	O
+authors	O
+suggest	O
+that	O
+fluoxetine	O
+-	O
+induced	O
+akathisia	B
+may	O
+be	O
+caused	O
+by	O
+serotonergically	O
+mediated	O
+inhibition	O
+of	O
+dopaminergic	O
+neurotransmission	O
+and	O
+that	O
+the	O
+pathophysiology	O
+of	O
+fluoxetine	O
+-	O
+induced	O
+akathisia	B
+and	O
+tricyclic	O
+antidepressant	O
+-	O
+induced	O
+"	O
+jitteriness	O
+"	O
+may	O
+be	O
+identical	O
+.	O
+
+Effect	O
+of	O
+converting	O
+enzyme	O
+inhibition	O
+on	O
+the	O
+course	O
+of	O
+adriamycin	O
+-	O
+induced	O
+nephropathy	B
+.	O
+
+The	O
+effect	O
+of	O
+the	O
+converting	O
+enzyme	O
+inhibitor	O
+(	O
+CEI	O
+)	O
+enalapril	O
+was	O
+assessed	O
+in	O
+Munich	O
+-	O
+Wistar	O
+rats	O
+with	O
+established	O
+adriamycin	O
+nephrosis	B
+.	O
+
+Rats	O
+were	O
+given	O
+a	O
+single	O
+dose	O
+of	O
+adriamycin	O
+and	O
+one	O
+month	O
+later	O
+divided	O
+into	O
+four	O
+groups	O
+matched	O
+for	O
+albuminuria	B
+,	O
+blood	O
+pressure	O
+,	O
+and	O
+plasma	O
+albumin	O
+concentration	O
+.	O
+
+Groups	O
+1	O
+and	O
+3	O
+remained	O
+untreated	O
+while	O
+groups	O
+2	O
+and	O
+4	O
+received	O
+enalapril	O
+.	O
+
+Groups	O
+1	O
+and	O
+2	O
+underwent	O
+micropuncture	O
+studies	O
+after	O
+10	O
+days	O
+.	O
+
+These	O
+short	O
+-	O
+term	O
+studies	O
+showed	O
+that	O
+enalapril	O
+reduced	O
+arterial	O
+blood	O
+pressure	O
+(	O
+101	O
++	O
+/	O
+-	O
+2	O
+vs	O
+.	O
+124	O
++	O
+/	O
+-	O
+3	O
+mm	O
+Hg	O
+,	O
+group	O
+2	O
+vs	O
+.	O
+1	O
+,	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+and	O
+glomerular	O
+capillary	O
+pressure	O
+(	O
+54	O
++	O
+/	O
+-	O
+1	O
+vs	O
+.	O
+61	O
++	O
+/	O
+-	O
+2	O
+mm	O
+Hg	O
+,	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+without	O
+reducing	O
+albuminuria	B
+(	O
+617	O
++	O
+/	O
+-	O
+50	O
+vs	O
+.	O
+570	O
++	O
+/	O
+-	O
+47	O
+mg	O
+/	O
+day	O
+)	O
+or	O
+GFR	O
+(	O
+1	O
+.	O
+03	O
++	O
+/	O
+-	O
+0	O
+.	O
+04	O
+vs	O
+.	O
+1	O
+.	O
+04	O
++	O
+/	O
+-	O
+0	O
+.	O
+11	O
+ml	O
+/	O
+min	O
+)	O
+.	O
+
+Groups	O
+3	O
+and	O
+4	O
+were	O
+studied	O
+at	O
+four	O
+and	O
+at	O
+six	O
+months	O
+to	O
+assess	O
+the	O
+effect	O
+of	O
+enalapril	O
+on	O
+progression	O
+of	O
+renal	B
+injury	I
+in	O
+adriamycin	O
+nephrosis	B
+.	O
+
+Chronic	O
+enalapril	O
+treatment	O
+reduced	O
+blood	O
+pressure	O
+without	O
+reducing	O
+albuminuria	B
+in	O
+group	O
+4	O
+.	O
+
+Untreated	O
+group	O
+3	O
+rats	O
+exhibited	O
+a	O
+progressive	O
+reduction	O
+in	O
+GFR	O
+(	O
+0	O
+.	O
+35	O
++	O
+/	O
+-	O
+0	O
+.	O
+08	O
+ml	O
+/	O
+min	O
+at	O
+4	O
+months	O
+,	O
+0	O
+.	O
+27	O
++	O
+/	O
+-	O
+0	O
+.	O
+07	O
+ml	O
+/	O
+min	O
+at	O
+6	O
+months	O
+)	O
+.	O
+
+Enalapril	O
+treatment	O
+blunted	O
+but	O
+did	O
+not	O
+prevent	O
+reduction	O
+in	O
+GFR	O
+in	O
+group	O
+4	O
+(	O
+0	O
+.	O
+86	O
++	O
+/	O
+-	O
+0	O
+.	O
+15	O
+ml	O
+/	O
+min	O
+at	O
+4	O
+months	O
+,	O
+0	O
+.	O
+69	O
++	O
+/	O
+-	O
+0	O
+.	O
+13	O
+ml	O
+/	O
+min	O
+at	O
+6	O
+months	O
+,	O
+both	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+vs	O
+.	O
+group	O
+3	O
+)	O
+.	O
+
+Reduction	O
+in	O
+GFR	O
+was	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+glomerular	B
+sclerosis	I
+in	O
+both	O
+treated	O
+and	O
+untreated	O
+rats	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Clotiazepam	O
+-	O
+induced	O
+acute	O
+hepatitis	B
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+patient	O
+who	O
+developed	O
+acute	O
+hepatitis	B
+with	O
+extensive	B
+hepatocellular	I
+necrosis	I
+,	O
+7	O
+months	O
+after	O
+the	O
+onset	O
+of	O
+administration	O
+of	O
+clotiazepam	O
+,	O
+a	O
+thienodiazepine	O
+derivative	O
+.	O
+
+Clotiazepam	O
+withdrawal	O
+was	O
+followed	O
+by	O
+prompt	O
+recovery	O
+.	O
+
+The	O
+administration	O
+of	O
+several	O
+benzodiazepines	O
+,	O
+chemically	O
+related	O
+to	O
+clotiazepam	O
+,	O
+did	O
+not	O
+interfere	O
+with	O
+recovery	O
+and	O
+did	O
+not	O
+induce	O
+any	O
+relapse	O
+of	O
+hepatitis	B
+.	O
+
+This	O
+observation	O
+shows	O
+that	O
+clotiazepam	O
+can	O
+induce	O
+acute	O
+hepatitis	B
+and	O
+suggests	O
+that	O
+there	O
+is	O
+no	O
+cross	O
+hepatotoxicity	B
+between	O
+clotiazepam	O
+and	O
+several	O
+benzodiazepines	O
+.	O
+
+5	O
+-	O
+azacytidine	O
+potentiates	O
+initiation	B
+induced	I
+by	I
+carcinogens	I
+in	O
+rat	O
+liver	O
+.	O
+
+To	O
+test	O
+the	O
+validity	O
+of	O
+the	O
+hypothesis	O
+that	O
+hypomethylation	O
+of	O
+DNA	O
+plays	O
+an	O
+important	O
+role	O
+in	O
+the	O
+initiation	B
+of	I
+carcinogenic	I
+process	I
+,	O
+5	O
+-	O
+azacytidine	O
+(	O
+5	O
+-	O
+AzC	O
+)	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+an	O
+inhibitor	O
+of	O
+DNA	O
+methylation	O
+,	O
+was	O
+given	O
+to	O
+rats	O
+during	O
+the	O
+phase	O
+of	O
+repair	O
+synthesis	O
+induced	O
+by	O
+the	O
+three	O
+carcinogens	O
+,	O
+benzo	O
+[	O
+a	O
+]	O
+-	O
+pyrene	O
+(	O
+200	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+N	O
+-	O
+methyl	O
+-	O
+N	O
+-	O
+nitrosourea	O
+(	O
+60	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+1	O
+,	O
+2	O
+-	O
+dimethylhydrazine	O
+(	O
+1	O
+,	O
+2	O
+-	O
+DMH	O
+)	O
+(	O
+100	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+The	O
+initiated	O
+hepatocytes	O
+in	O
+the	O
+liver	O
+were	O
+assayed	O
+as	O
+the	O
+gamma	O
+-	O
+glutamyltransferase	O
+(	O
+gamma	O
+-	O
+GT	O
+)	O
+positive	O
+foci	O
+formed	O
+following	O
+a	O
+2	O
+-	O
+week	O
+selection	O
+regimen	O
+consisting	O
+of	O
+dietary	O
+0	O
+.	O
+02	O
+%	O
+2	O
+-	O
+acetylaminofluorene	O
+coupled	O
+with	O
+a	O
+necrogenic	O
+dose	O
+of	O
+CCl4	O
+.	O
+
+The	O
+results	O
+obtained	O
+indicate	O
+that	O
+with	O
+all	O
+three	O
+carcinogens	O
+,	O
+administration	O
+of	O
+5	O
+-	O
+AzC	O
+during	O
+repair	O
+synthesis	O
+increased	O
+the	O
+incidence	O
+of	O
+initiated	O
+hepatocytes	O
+,	O
+for	O
+example	O
+10	O
+-	O
+20	O
+foci	O
+/	O
+cm2	O
+in	O
+5	O
+-	O
+AzC	O
+and	O
+carcinogen	O
+-	O
+treated	O
+rats	O
+compared	O
+with	O
+3	O
+-	O
+5	O
+foci	O
+/	O
+cm2	O
+in	O
+rats	O
+treated	O
+with	O
+carcinogen	O
+only	O
+.	O
+
+Administration	O
+of	O
+[	O
+3H	O
+]	O
+-	O
+5	O
+-	O
+azadeoxycytidine	O
+during	O
+the	O
+repair	O
+synthesis	O
+induced	O
+by	O
+1	O
+,	O
+2	O
+-	O
+DMH	O
+further	O
+showed	O
+that	O
+0	O
+.	O
+019	O
+mol	O
+%	O
+of	O
+cytosine	O
+residues	O
+in	O
+DNA	O
+were	O
+substituted	O
+by	O
+the	O
+analogue	O
+,	O
+indicating	O
+that	O
+incorporation	O
+of	O
+5	O
+-	O
+AzC	O
+occurs	O
+during	O
+repair	O
+synthesis	O
+.	O
+
+In	O
+the	O
+absence	O
+of	O
+the	O
+carcinogen	O
+,	O
+5	O
+-	O
+AzC	O
+given	O
+after	O
+a	O
+two	O
+thirds	O
+partial	O
+hepatectomy	O
+,	O
+when	O
+its	O
+incorporation	O
+should	O
+be	O
+maximum	O
+,	O
+failed	O
+to	O
+induce	O
+any	O
+gamma	O
+-	O
+GT	O
+positive	O
+foci	O
+.	O
+
+The	O
+results	O
+suggest	O
+that	O
+hypomethylation	O
+of	O
+DNA	O
+per	O
+se	O
+may	O
+not	O
+be	O
+sufficient	O
+for	O
+initiation	O
+.	O
+
+Perhaps	O
+two	O
+events	O
+might	O
+be	O
+necessary	O
+for	O
+initiation	O
+,	O
+the	O
+first	O
+caused	O
+by	O
+the	O
+carcinogen	O
+and	O
+a	O
+second	O
+involving	O
+hypomethylation	O
+of	O
+DNA	O
+.	O
+
+Antihypertensive	O
+drugs	O
+and	O
+depression	B
+:	O
+a	O
+reappraisal	O
+.	O
+
+Eighty	O
+-	O
+nine	O
+new	O
+referral	O
+hypertensive	B
+out	O
+-	O
+patients	O
+and	O
+46	O
+new	O
+referral	O
+non	O
+-	O
+hypertensive	B
+chronically	O
+physically	O
+ill	O
+out	O
+-	O
+patients	O
+completed	O
+a	O
+mood	O
+rating	O
+scale	O
+at	O
+regular	O
+intervals	O
+for	O
+one	O
+year	O
+.	O
+
+The	O
+results	O
+showed	O
+a	O
+high	O
+prevalence	O
+of	O
+depression	B
+in	O
+both	O
+groups	O
+of	O
+patients	O
+,	O
+with	O
+no	O
+preponderance	O
+in	O
+the	O
+hypertensive	B
+group	O
+.	O
+
+Hypertensive	B
+patients	O
+with	O
+psychiatric	B
+histories	O
+had	O
+a	O
+higher	O
+prevalence	O
+of	O
+depression	B
+than	O
+the	O
+comparison	O
+patients	O
+.	O
+
+This	O
+was	O
+accounted	O
+for	O
+by	O
+a	O
+significant	O
+number	O
+of	O
+depressions	B
+occurring	O
+in	O
+methyl	O
+dopa	O
+treated	O
+patients	O
+with	O
+psychiatric	B
+histories	O
+.	O
+
+Chronic	B
+active	I
+hepatitis	I
+associated	O
+with	O
+diclofenac	O
+sodium	O
+therapy	O
+.	O
+
+Diclofenac	O
+sodium	O
+(	O
+Voltarol	O
+,	O
+Geigy	O
+Pharmaceuticals	O
+)	O
+is	O
+a	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+derivative	O
+of	O
+phenylacetic	O
+acid	O
+.	O
+
+Although	O
+generally	O
+well	O
+-	O
+tolerated	O
+,	O
+asymptomatic	O
+abnormalities	B
+of	I
+liver	I
+function	I
+have	O
+been	O
+recorded	O
+and	O
+,	O
+less	O
+commonly	O
+,	O
+severe	O
+hepatitis	B
+induced	O
+by	O
+diclofenac	O
+.	O
+
+The	O
+patient	O
+described	O
+developed	O
+chronic	B
+active	I
+hepatitis	I
+after	O
+six	O
+months	O
+therapy	O
+with	O
+diclofenac	O
+sodium	O
+which	O
+progressed	O
+despite	O
+the	O
+withdrawal	O
+of	O
+the	O
+drug	O
+,	O
+a	O
+finding	O
+not	O
+previously	O
+reported	O
+.	O
+
+Arterial	O
+hypertension	B
+as	O
+a	O
+complication	O
+of	O
+prolonged	O
+ketoconazole	O
+treatment	O
+.	O
+
+Two	O
+of	O
+14	O
+patients	O
+with	O
+Cushing	B
+'	I
+s	I
+syndrome	I
+treated	O
+on	O
+a	O
+long	O
+-	O
+term	O
+basis	O
+with	O
+ketoconazole	O
+developed	O
+sustained	O
+hypertension	B
+.	O
+
+In	O
+both	O
+cases	O
+normal	O
+plasma	O
+and	O
+urinary	O
+free	O
+cortisol	O
+levels	O
+had	O
+been	O
+achieved	O
+following	O
+ketoconazole	O
+therapy	O
+,	O
+yet	O
+continuous	O
+blood	O
+pressure	O
+monitoring	O
+demonstrated	O
+hypertension	B
+31	O
+(	O
+patient	O
+1	O
+)	O
+and	O
+52	O
+weeks	O
+(	O
+patient	O
+2	O
+)	O
+after	O
+treatment	O
+.	O
+
+In	O
+patient	O
+1	O
+,	O
+plasma	O
+levels	O
+of	O
+deoxycorticosterone	O
+and	O
+11	O
+-	O
+deoxycortisol	O
+were	O
+elevated	O
+.	O
+
+In	O
+patient	O
+2	O
+,	O
+in	O
+addition	O
+to	O
+an	O
+increase	O
+in	O
+both	O
+deoxycorticosterone	O
+and	O
+11	O
+-	O
+deoxycortisol	O
+levels	O
+,	O
+plasma	O
+aldosterone	O
+values	O
+were	O
+raised	O
+,	O
+with	O
+a	O
+concomitant	O
+suppression	O
+of	O
+renin	O
+levels	O
+.	O
+
+Our	O
+findings	O
+show	O
+that	O
+long	O
+-	O
+term	O
+treatment	O
+with	O
+high	O
+doses	O
+of	O
+ketoconazole	O
+may	O
+induce	O
+enzyme	O
+blockade	O
+leading	O
+to	O
+mineralocorticoid	O
+-	O
+related	O
+hypertension	B
+.	O
+
+Effects	O
+of	O
+an	O
+inhibitor	O
+of	O
+angiotensin	O
+converting	O
+enzyme	O
+(	O
+Captopril	O
+)	O
+on	O
+pulmonary	B
+and	I
+renal	I
+insufficiency	I
+due	O
+to	O
+intravascular	B
+coagulation	I
+in	O
+the	O
+rat	O
+.	O
+
+Induction	O
+of	O
+intravascular	B
+coagulation	I
+and	O
+inhibition	O
+of	O
+fibrinolysis	O
+by	O
+injection	O
+of	O
+thrombin	O
+and	O
+tranexamic	O
+acid	O
+(	O
+AMCA	O
+)	O
+in	O
+the	O
+rat	O
+gives	O
+rise	O
+to	O
+pulmonary	B
+and	I
+renal	I
+insufficiency	I
+resembling	O
+that	O
+occurring	O
+after	O
+trauma	B
+or	O
+sepsis	B
+in	O
+man	O
+.	O
+
+Injection	O
+of	O
+Captopril	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+an	O
+inhibitor	O
+of	O
+angiotensin	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+,	O
+reduced	O
+both	O
+pulmonary	B
+and	I
+renal	I
+insufficiency	I
+in	O
+this	O
+rat	O
+model	O
+.	O
+
+The	O
+lung	O
+weights	O
+were	O
+lower	O
+and	O
+PaO2	O
+was	O
+improved	O
+in	O
+rats	O
+given	O
+this	O
+enzyme	O
+-	O
+blocking	O
+agent	O
+.	O
+
+The	O
+contents	O
+of	O
+albumin	O
+in	O
+the	O
+lungs	O
+were	O
+not	O
+changed	O
+,	O
+indicating	O
+that	O
+Captopril	O
+did	O
+not	O
+influence	O
+the	O
+extravasation	O
+of	O
+protein	O
+.	O
+
+Renal	B
+damage	I
+as	O
+reflected	O
+by	O
+an	O
+increase	O
+in	O
+serum	O
+urea	O
+and	O
+in	O
+kidney	O
+weight	O
+was	O
+prevented	O
+by	O
+Captopril	O
+.	O
+
+The	O
+amount	O
+of	O
+fibrin	O
+in	O
+the	O
+kidneys	O
+was	O
+also	O
+considerably	O
+lower	O
+than	O
+in	O
+animals	O
+which	O
+received	O
+thrombin	O
+and	O
+AMCA	O
+alone	O
+.	O
+
+It	O
+is	O
+suggested	O
+that	O
+the	O
+effects	O
+of	O
+Captopril	O
+on	O
+the	O
+lungs	O
+may	O
+be	O
+attributable	O
+to	O
+a	O
+vasodilatory	O
+effect	O
+due	O
+to	O
+a	O
+reduction	O
+in	O
+the	O
+circulating	O
+level	O
+of	O
+Angiotension	O
+II	O
+and	O
+an	O
+increase	O
+in	O
+prostacyclin	O
+(	O
+secondary	O
+to	O
+an	O
+increase	O
+in	O
+bradykinin	O
+)	O
+.	O
+
+Captopril	O
+may	O
+,	O
+by	O
+the	O
+same	O
+mechanism	O
+,	O
+reduce	O
+the	O
+increase	O
+in	O
+glomerular	O
+filtration	O
+that	O
+is	O
+known	O
+to	O
+occur	O
+after	O
+an	O
+injection	O
+of	O
+thrombin	O
+,	O
+thereby	O
+diminishing	O
+the	O
+aggregation	O
+of	O
+fibrin	O
+monomers	O
+in	O
+the	O
+glomeruli	O
+,	O
+with	O
+the	O
+result	O
+that	O
+less	O
+fibrin	O
+will	O
+be	O
+deposited	O
+and	O
+thus	O
+less	O
+kidney	B
+damage	I
+will	O
+be	O
+produced	O
+.	O
+
+Stroke	B
+associated	O
+with	O
+cocaine	O
+use	O
+.	O
+
+We	O
+describe	O
+eight	O
+patients	O
+in	O
+whom	O
+cocaine	O
+use	O
+was	O
+related	O
+to	O
+stroke	B
+and	O
+review	O
+39	O
+cases	O
+from	O
+the	O
+literature	O
+.	O
+
+Among	O
+these	O
+47	O
+patients	O
+the	O
+mean	O
+(	O
++	O
+/	O
+-	O
+SD	O
+)	O
+age	O
+was	O
+32	O
+.	O
+5	O
++	O
+/	O
+-	O
+12	O
+.	O
+1	O
+years	O
+;	O
+76	O
+%	O
+(	O
+34	O
+/	O
+45	O
+)	O
+were	O
+men	O
+.	O
+
+Stroke	B
+followed	O
+cocaine	O
+use	O
+by	O
+inhalation	O
+,	O
+intranasal	O
+,	O
+intravenous	O
+,	O
+and	O
+intramuscular	O
+routes	O
+.	O
+
+Intracranial	B
+aneurysms	I
+or	O
+arteriovenous	B
+malformations	I
+were	O
+present	O
+in	O
+17	O
+of	O
+32	O
+patients	O
+studied	O
+angiographically	O
+or	O
+at	O
+autopsy	O
+;	O
+cerebral	B
+vasculitis	I
+was	O
+present	O
+in	O
+two	O
+patients	O
+.	O
+
+Cerebral	B
+infarction	I
+occurred	O
+in	O
+10	O
+patients	O
+(	O
+22	O
+%	O
+)	O
+,	O
+intracerebral	B
+hemorrhage	I
+in	O
+22	O
+(	O
+49	O
+%	O
+)	O
+,	O
+and	O
+subarachnoid	B
+hemorrhage	I
+in	O
+13	O
+(	O
+29	O
+%	O
+)	O
+.	O
+
+These	O
+data	O
+indicate	O
+that	O
+(	O
+1	O
+)	O
+the	O
+apparent	O
+incidence	O
+of	O
+stroke	B
+related	O
+to	O
+cocaine	O
+use	O
+is	O
+increasing	O
+;	O
+(	O
+2	O
+)	O
+cocaine	O
+-	O
+associated	O
+stroke	B
+occurs	O
+primarily	O
+in	O
+young	O
+adults	O
+;	O
+(	O
+3	O
+)	O
+stroke	B
+may	O
+follow	O
+any	O
+route	O
+of	O
+cocaine	O
+administration	O
+;	O
+(	O
+4	O
+)	O
+stroke	B
+after	O
+cocaine	O
+use	O
+is	O
+frequently	O
+associated	O
+with	O
+intracranial	B
+aneurysms	I
+and	O
+arteriovenous	B
+malformations	I
+;	O
+and	O
+(	O
+5	O
+)	O
+in	O
+cocaine	O
+-	O
+associated	O
+stroke	B
+,	O
+the	O
+frequency	O
+of	O
+intracranial	B
+hemorrhage	I
+exceeds	O
+that	O
+of	O
+cerebral	B
+infarction	I
+.	O
+
+A	O
+randomized	O
+comparison	O
+of	O
+labetalol	O
+and	O
+nitroprusside	O
+for	O
+induced	O
+hypotension	B
+.	O
+
+In	O
+a	O
+randomized	O
+study	O
+,	O
+labetalol	O
+-	O
+induced	O
+hypotension	B
+and	O
+nitroprusside	O
+-	O
+induced	O
+hypotension	B
+were	O
+compared	O
+in	O
+20	O
+patients	O
+(	O
+10	O
+in	O
+each	O
+group	O
+)	O
+scheduled	O
+for	O
+major	O
+orthopedic	O
+procedures	O
+.	O
+
+Each	O
+patient	O
+was	O
+subjected	O
+to	O
+an	O
+identical	O
+anesthetic	O
+protocol	O
+and	O
+similar	O
+drug	O
+-	O
+induced	O
+reductions	B
+in	I
+mean	I
+arterial	I
+blood	I
+pressure	I
+(	O
+BP	O
+)	O
+(	O
+50	O
+to	O
+55	O
+mmHg	O
+)	O
+.	O
+
+Nitroprusside	O
+infusion	O
+was	O
+associated	O
+with	O
+a	O
+significant	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+increase	B
+in	I
+heart	I
+rate	I
+and	I
+cardiac	I
+output	I
+;	O
+rebound	O
+hypertension	B
+was	O
+observed	O
+in	O
+three	O
+patients	O
+after	O
+discontinuation	O
+of	O
+nitroprusside	O
+.	O
+
+Labetalol	O
+administration	O
+was	O
+not	O
+associated	O
+with	O
+any	O
+of	O
+these	O
+findings	O
+.	O
+
+Arterial	O
+PO2	O
+decreased	O
+in	O
+both	O
+groups	O
+.	O
+
+It	O
+was	O
+concluded	O
+that	O
+labetalol	O
+offers	O
+advantages	O
+over	O
+nitroprusside	O
+.	O
+
+Sodium	O
+status	O
+influences	O
+chronic	O
+amphotericin	O
+B	O
+nephrotoxicity	B
+in	O
+rats	O
+.	O
+
+The	O
+nephrotoxic	B
+potential	O
+of	O
+amphotericin	O
+B	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+intraperitoneally	O
+for	O
+3	O
+weeks	O
+)	O
+has	O
+been	O
+investigated	O
+in	O
+salt	O
+-	O
+depleted	O
+,	O
+normal	O
+-	O
+salt	O
+,	O
+and	O
+salt	O
+-	O
+loaded	O
+rats	O
+.	O
+
+In	O
+salt	O
+-	O
+depleted	O
+rats	O
+,	O
+amphotericin	O
+B	O
+decreased	O
+creatinine	O
+clearance	O
+linearly	O
+with	O
+time	O
+,	O
+with	O
+an	O
+85	O
+%	O
+reduction	O
+by	O
+week	O
+3	O
+.	O
+
+In	O
+contrast	O
+,	O
+in	O
+normal	O
+-	O
+salt	O
+rats	O
+creatinine	O
+clearance	O
+was	O
+decreased	O
+but	O
+to	O
+a	O
+lesser	O
+extent	O
+at	O
+week	O
+2	O
+and	O
+3	O
+,	O
+and	O
+in	O
+salt	O
+-	O
+loaded	O
+rats	O
+creatinine	O
+clearance	O
+did	O
+not	O
+change	O
+for	O
+2	O
+weeks	O
+and	O
+was	O
+decreased	O
+by	O
+43	O
+%	O
+at	O
+week	O
+3	O
+.	O
+
+All	O
+rats	O
+in	O
+the	O
+sodium	O
+-	O
+depleted	O
+group	O
+had	O
+histopathological	O
+evidence	O
+of	O
+patchy	O
+tubular	O
+cytoplasmic	O
+degeneration	O
+in	O
+tubules	O
+that	O
+was	O
+not	O
+observed	O
+in	O
+any	O
+normal	O
+-	O
+salt	O
+or	O
+salt	O
+-	O
+loaded	O
+rat	O
+.	O
+
+Concentrations	O
+of	O
+amphotericin	O
+B	O
+in	O
+plasma	O
+were	O
+not	O
+significantly	O
+different	O
+among	O
+the	O
+three	O
+groups	O
+at	O
+any	O
+time	O
+during	O
+the	O
+study	O
+.	O
+
+However	O
+,	O
+at	O
+the	O
+end	O
+of	O
+3	O
+weeks	O
+,	O
+amphotericin	O
+B	O
+levels	O
+in	O
+the	O
+kidneys	O
+and	O
+liver	O
+were	O
+significantly	O
+higher	O
+in	O
+salt	O
+-	O
+depleted	O
+and	O
+normal	O
+-	O
+salt	O
+rats	O
+than	O
+those	O
+in	O
+salt	O
+-	O
+loaded	O
+rats	O
+,	O
+with	O
+plasma	O
+/	O
+kidney	O
+ratios	O
+of	O
+21	O
+,	O
+14	O
+,	O
+and	O
+8	O
+in	O
+salt	O
+-	O
+depleted	O
+,	O
+normal	O
+-	O
+salt	O
+,	O
+and	O
+salt	O
+-	O
+loaded	O
+rats	O
+,	O
+respectively	O
+.	O
+
+In	O
+conclusion	O
+,	O
+reductions	O
+in	O
+creatinine	O
+clearance	O
+and	O
+renal	O
+amphotericin	O
+B	O
+accumulation	O
+after	O
+chronic	O
+amphotericin	O
+B	O
+administration	O
+were	O
+enhanced	O
+by	O
+salt	O
+depletion	O
+and	O
+attenuated	O
+by	O
+sodium	O
+loading	O
+in	O
+rats	O
+.	O
+
+Flestolol	O
+:	O
+an	O
+ultra	O
+-	O
+short	O
+-	O
+acting	O
+beta	O
+-	O
+adrenergic	O
+blocking	O
+agent	O
+.	O
+
+Flestolol	O
+(	O
+ACC	O
+-	O
+9089	O
+)	O
+is	O
+a	O
+nonselective	O
+,	O
+competitive	O
+,	O
+ultra	O
+-	O
+short	O
+-	O
+acting	O
+beta	O
+-	O
+adrenergic	O
+blocking	O
+agent	O
+,	O
+without	O
+any	O
+intrinsic	O
+sympathomimetic	O
+activity	O
+.	O
+
+Flestolol	O
+is	O
+metabolized	O
+by	O
+plasma	O
+esterases	O
+and	O
+has	O
+an	O
+elimination	O
+half	O
+-	O
+life	O
+of	O
+approximately	O
+6	O
+.	O
+5	O
+minutes	O
+.	O
+
+This	O
+agent	O
+was	O
+well	O
+tolerated	O
+in	O
+healthy	O
+volunteers	O
+at	O
+doses	O
+up	O
+to	O
+100	O
+micrograms	O
+/	O
+kg	O
+/	O
+min	O
+.	O
+
+In	O
+long	O
+-	O
+term	O
+infusion	O
+studies	O
+,	O
+flestolol	O
+was	O
+well	O
+tolerated	O
+at	O
+the	O
+effective	O
+beta	O
+-	O
+blocking	O
+dose	O
+(	O
+5	O
+micrograms	O
+/	O
+kg	O
+/	O
+min	O
+)	O
+for	O
+up	O
+to	O
+seven	O
+days	O
+.	O
+
+Flestolol	O
+blood	O
+concentrations	O
+increased	O
+linearly	O
+with	O
+increasing	O
+dose	O
+and	O
+good	O
+correlation	O
+exists	O
+between	O
+blood	O
+concentrations	O
+of	O
+flestolol	O
+and	O
+beta	O
+-	O
+adrenergic	O
+blockade	O
+.	O
+
+Flestolol	O
+produced	O
+a	O
+dose	O
+-	O
+dependent	O
+attenuation	O
+of	O
+isoproterenol	O
+-	O
+induced	O
+tachycardia	B
+.	O
+
+Electrophysiologic	O
+and	O
+hemodynamic	O
+effects	O
+of	O
+flestolol	O
+are	O
+similar	O
+to	O
+those	O
+of	O
+other	O
+beta	O
+blockers	O
+.	O
+
+In	O
+contrast	O
+with	O
+other	O
+beta	O
+blockers	O
+,	O
+flestolol	O
+-	O
+induced	O
+effects	O
+reverse	O
+rapidly	O
+(	O
+within	O
+30	O
+minutes	O
+)	O
+following	O
+discontinuation	O
+because	O
+of	O
+its	O
+short	O
+half	O
+-	O
+life	O
+.	O
+
+Flestolol	O
+effectively	O
+reduced	O
+heart	O
+rate	O
+in	O
+patients	O
+with	O
+supraventricular	B
+tachyarrhythmia	I
+.	O
+
+In	O
+patients	O
+with	O
+unstable	B
+angina	I
+,	O
+flestolol	O
+infusion	O
+was	O
+found	O
+to	O
+be	O
+safe	O
+and	O
+effective	O
+in	O
+controlling	O
+chest	B
+pain	I
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+flestolol	O
+is	O
+a	O
+potent	O
+,	O
+well	O
+-	O
+tolerated	O
+,	O
+ultra	O
+-	O
+short	O
+-	O
+acting	O
+beta	O
+-	O
+adrenergic	O
+blocking	O
+agent	O
+.	O
+
+Use	O
+of	O
+flestolol	O
+in	O
+the	O
+critical	O
+care	O
+setting	O
+is	O
+currently	O
+undergoing	O
+investigation	O
+.	O
+
+Immunohistochemical	O
+,	O
+electron	O
+microscopic	O
+and	O
+morphometric	O
+studies	O
+of	O
+estrogen	O
+-	O
+induced	O
+rat	O
+prolactinomas	B
+after	O
+bromocriptine	O
+treatment	O
+.	O
+
+To	O
+clarify	O
+the	O
+effects	O
+of	O
+bromocriptine	O
+on	O
+prolactinoma	B
+cells	O
+in	O
+vivo	O
+,	O
+immunohistochemical	O
+,	O
+ultrastructural	O
+and	O
+morphometrical	O
+analyses	O
+were	O
+applied	O
+to	O
+estrogen	O
+-	O
+induced	O
+rat	O
+prolactinoma	B
+cells	O
+1	O
+h	O
+and	O
+6	O
+h	O
+after	O
+injection	O
+of	O
+bromocriptine	O
+(	O
+3	O
+mg	O
+/	O
+kg	O
+of	O
+body	O
+weight	O
+)	O
+.	O
+
+One	O
+h	O
+after	O
+treatment	O
+,	O
+serum	O
+prolactin	O
+levels	O
+decreased	O
+markedly	O
+.	O
+
+Electron	O
+microscopy	O
+disclosed	O
+many	O
+secretory	O
+granules	O
+,	O
+slightly	O
+distorted	O
+rough	O
+endoplasmic	O
+reticulum	O
+,	O
+and	O
+partially	O
+dilated	O
+Golgi	O
+cisternae	O
+in	O
+the	O
+prolactinoma	B
+cells	O
+.	O
+
+Morphometric	O
+analysis	O
+revealed	O
+that	O
+the	O
+volume	O
+density	O
+of	O
+secretory	O
+granules	O
+increased	O
+,	O
+while	O
+the	O
+volume	O
+density	O
+of	O
+cytoplasmic	O
+microtubules	O
+decreased	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+lowered	O
+serum	O
+prolactin	O
+levels	O
+in	O
+the	O
+early	O
+phase	O
+of	O
+bromocriptine	O
+treatment	O
+may	O
+result	O
+from	O
+an	O
+impaired	O
+secretion	O
+of	O
+prolactin	O
+due	O
+to	O
+decreasing	O
+numbers	O
+of	O
+cytoplasmic	O
+microtubules	O
+.	O
+
+At	O
+6	O
+h	O
+after	O
+injection	O
+,	O
+serum	O
+prolactin	O
+levels	O
+were	O
+still	O
+considerably	O
+lower	O
+than	O
+in	O
+controls	O
+.	O
+
+The	O
+prolactinoma	B
+cells	O
+at	O
+this	O
+time	O
+were	O
+well	O
+granulated	O
+,	O
+with	O
+vesiculated	O
+rough	O
+endoplasmic	O
+reticulum	O
+and	O
+markedly	O
+dilated	O
+Golgi	O
+cisternae	O
+.	O
+
+Electron	O
+microscopical	O
+immunohistochemistry	O
+revealed	O
+positive	O
+reaction	O
+products	O
+noted	O
+on	O
+the	O
+secretory	O
+granules	O
+,	O
+Golgi	O
+cisternae	O
+,	O
+and	O
+endoplasmic	O
+reticulum	O
+of	O
+the	O
+untreated	O
+rat	O
+prolactinoma	B
+cells	O
+.	O
+
+However	O
+,	O
+only	O
+secretory	O
+granules	O
+showed	O
+the	O
+positive	O
+reaction	O
+products	O
+for	O
+prolactin	O
+6	O
+h	O
+after	O
+bromocriptine	O
+treatment	O
+of	O
+the	O
+adenoma	B
+cells	O
+.	O
+
+An	O
+increase	O
+in	O
+the	O
+volume	O
+density	O
+of	O
+secretory	O
+granules	O
+and	O
+a	O
+decrease	O
+in	O
+the	O
+volume	O
+densities	O
+of	O
+rough	O
+endoplasmic	O
+reticulum	O
+and	O
+microtubules	O
+was	O
+determined	O
+by	O
+morphometric	O
+analysis	O
+,	O
+suggesting	O
+that	O
+bromocriptine	O
+inhibits	O
+protein	O
+synthesis	O
+as	O
+well	O
+as	O
+bringing	O
+about	O
+a	O
+disturbance	O
+of	O
+the	O
+prolactin	O
+secretion	O
+.	O
+
+Sulfasalazine	O
+-	O
+induced	O
+lupus	B
+erythematosus	I
+.	O
+
+Pneumonitis	B
+,	O
+bilateral	O
+pleural	B
+effusions	I
+,	O
+echocardiographic	O
+evidence	O
+of	O
+cardiac	B
+tamponade	I
+,	O
+and	O
+positive	O
+autoantibodies	O
+developed	O
+in	O
+a	O
+43	O
+-	O
+year	O
+-	O
+old	O
+man	O
+,	O
+who	O
+was	O
+receiving	O
+long	O
+-	O
+term	O
+sulfasalazine	O
+therapy	O
+for	O
+chronic	O
+ulcerative	B
+colitis	I
+.	O
+
+After	O
+cessation	O
+of	O
+the	O
+sulfasalazine	O
+and	O
+completion	O
+of	O
+a	O
+six	O
+-	O
+week	O
+course	O
+of	O
+corticosteroids	O
+,	O
+these	O
+problems	O
+resolved	O
+over	O
+a	O
+period	O
+of	O
+four	O
+to	O
+six	O
+months	O
+.	O
+
+It	O
+is	O
+suggested	O
+that	O
+the	O
+patient	O
+had	O
+sulfasalazine	O
+-	O
+induced	O
+lupus	B
+,	O
+which	O
+manifested	O
+with	O
+serositis	B
+and	O
+pulmonary	O
+parenchymal	O
+involvement	O
+in	O
+the	O
+absence	O
+of	O
+joint	O
+symptoms	O
+.	O
+
+Physicians	O
+who	O
+use	O
+sulfasalazine	O
+to	O
+treat	O
+patients	O
+with	O
+inflammatory	B
+bowel	I
+disease	I
+should	O
+be	O
+aware	O
+of	O
+the	O
+signs	O
+of	O
+sulfasalazine	O
+-	O
+induced	O
+lupus	B
+syndrome	I
+.	O
+
+Chronic	O
+carbamazepine	O
+treatment	O
+in	O
+the	O
+rat	O
+:	O
+efficacy	O
+,	O
+toxicity	B
+,	O
+and	O
+effect	O
+on	O
+plasma	O
+and	O
+tissue	O
+folate	O
+concentrations	O
+.	O
+
+Folate	O
+depletion	O
+has	O
+often	O
+been	O
+a	O
+problem	O
+in	O
+chronic	O
+antiepileptic	O
+drug	O
+(	O
+AED	O
+)	O
+therapy	O
+.	O
+
+Carbamazepine	O
+(	O
+CBZ	O
+)	O
+,	O
+a	O
+commonly	O
+used	O
+AED	O
+,	O
+has	O
+been	O
+implicated	O
+in	O
+some	O
+clinical	O
+studies	O
+.	O
+
+A	O
+rat	O
+model	O
+was	O
+developed	O
+to	O
+examine	O
+the	O
+effects	O
+of	O
+chronic	O
+CBZ	O
+treatment	O
+on	O
+folate	O
+concentrations	O
+in	O
+the	O
+rat	O
+.	O
+
+In	O
+the	O
+course	O
+of	O
+developing	O
+this	O
+model	O
+,	O
+a	O
+common	O
+vehicle	O
+,	O
+propylene	O
+glycol	O
+,	O
+by	O
+itself	O
+in	O
+high	O
+doses	O
+,	O
+was	O
+found	O
+to	O
+exhibit	O
+protective	O
+properties	O
+against	O
+induced	O
+seizures	B
+and	O
+inhibited	O
+weight	B
+gain	I
+.	O
+
+Seizures	B
+induced	O
+by	O
+hexafluorodiethyl	O
+ether	O
+(	O
+HFDE	O
+)	O
+were	O
+also	O
+found	O
+to	O
+be	O
+a	O
+more	O
+sensitive	O
+measure	O
+of	O
+protection	O
+by	O
+CBZ	O
+than	O
+seizures	B
+induced	O
+by	O
+maximal	O
+electroshock	O
+(	O
+MES	O
+)	O
+.	O
+
+Oral	O
+administration	O
+of	O
+CBZ	O
+as	O
+an	O
+aqueous	O
+suspension	O
+every	O
+8	O
+h	O
+at	O
+a	O
+dose	O
+of	O
+250	O
+mg	O
+/	O
+kg	O
+was	O
+continuously	O
+protective	O
+against	O
+HFDE	O
+-	O
+induced	O
+seizures	B
+and	O
+was	O
+minimally	O
+toxic	O
+as	O
+measured	O
+by	O
+weight	B
+gain	I
+over	O
+8	O
+weeks	O
+of	O
+treatment	O
+.	O
+
+The	O
+CBZ	O
+levels	O
+measured	O
+in	O
+plasma	O
+and	O
+brain	O
+of	O
+these	O
+animals	O
+,	O
+however	O
+,	O
+were	O
+below	O
+those	O
+normally	O
+considered	O
+protective	O
+.	O
+
+This	O
+treatment	O
+with	O
+CBZ	O
+had	O
+no	O
+apparent	O
+adverse	O
+effect	O
+on	O
+folate	O
+concentrations	O
+in	O
+the	O
+rat	O
+,	O
+and	O
+,	O
+indeed	O
+,	O
+the	O
+folate	O
+concentration	O
+increased	O
+in	O
+liver	O
+after	O
+6	O
+weeks	O
+of	O
+treatment	O
+and	O
+in	O
+plasma	O
+at	O
+8	O
+weeks	O
+of	O
+treatment	O
+.	O
+
+Dipyridamole	O
+-	O
+induced	O
+myocardial	B
+ischemia	I
+.	O
+
+Angina	B
+and	O
+ischemic	O
+electrocardiographic	O
+changes	O
+occurred	O
+after	O
+administration	O
+of	O
+oral	O
+dipyridamole	O
+in	O
+four	O
+patients	O
+awaiting	O
+urgent	O
+myocardial	O
+revascularization	O
+procedures	O
+.	O
+
+To	O
+our	O
+knowledge	O
+,	O
+this	O
+has	O
+not	O
+previously	O
+been	O
+reported	O
+as	O
+a	O
+side	O
+effect	O
+of	O
+preoperative	O
+dipyridamole	O
+therapy	O
+,	O
+although	O
+dipyridamole	O
+-	O
+induced	O
+myocardial	B
+ischemia	I
+has	O
+been	O
+demonstrated	O
+to	O
+occur	O
+in	O
+animals	O
+and	O
+humans	O
+with	O
+coronary	B
+artery	I
+disease	I
+.	O
+
+Epicardial	O
+coronary	O
+collateral	O
+vessels	O
+were	O
+demonstrated	O
+in	O
+all	O
+four	O
+patients	O
+;	O
+a	O
+coronary	O
+"	O
+steal	O
+"	O
+phenomenon	O
+may	O
+be	O
+the	O
+mechanism	O
+of	O
+the	O
+dipyridamole	O
+-	O
+induced	O
+ischemia	B
+observed	O
+.	O
+
+Inhibition	O
+of	O
+sympathoadrenal	O
+activity	O
+by	O
+atrial	O
+natriuretic	O
+factor	O
+in	O
+dogs	O
+.	O
+
+In	O
+six	O
+conscious	O
+,	O
+trained	O
+dogs	O
+,	O
+maintained	O
+on	O
+a	O
+normal	O
+sodium	O
+intake	O
+of	O
+2	O
+to	O
+4	O
+mEq	O
+/	O
+kg	O
+/	O
+day	O
+,	O
+sympathetic	O
+activity	O
+was	O
+assessed	O
+as	O
+the	O
+release	O
+rate	O
+of	O
+norepinephrine	O
+and	O
+epinephrine	O
+during	O
+15	O
+-	O
+minute	O
+i	O
+.	O
+v	O
+.	O
+infusions	O
+of	O
+human	O
+alpha	O
+-	O
+atrial	O
+natriuretic	O
+factor	O
+.	O
+
+Mean	O
+arterial	O
+pressure	O
+(	O
+as	O
+a	O
+percentage	O
+of	O
+control	O
++	O
+/	O
+-	O
+SEM	O
+)	O
+during	O
+randomized	O
+infusions	O
+of	O
+0	O
+.	O
+03	O
+,	O
+0	O
+.	O
+1	O
+,	O
+0	O
+.	O
+3	O
+,	O
+or	O
+1	O
+.	O
+0	O
+microgram	O
+/	O
+kg	O
+/	O
+min	O
+was	O
+99	O
++	O
+/	O
+-	O
+1	O
+,	O
+95	O
++	O
+/	O
+-	O
+1	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+,	O
+93	O
++	O
+/	O
+-	O
+1	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+,	O
+or	O
+79	O
++	O
+/	O
+-	O
+6	O
+%	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+,	O
+respectively	O
+,	O
+but	O
+no	O
+tachycardia	B
+and	O
+no	O
+augmentation	O
+of	O
+the	O
+norepinephrine	O
+release	O
+rate	O
+(	O
+up	O
+to	O
+0	O
+.	O
+3	O
+microgram	O
+/	O
+kg	O
+/	O
+min	O
+)	O
+were	O
+observed	O
+,	O
+which	O
+is	O
+in	O
+contrast	O
+to	O
+comparable	O
+hypotension	B
+induced	O
+by	O
+hydralazine	O
+or	O
+nitroglycerin	O
+.	O
+
+The	O
+release	O
+rate	O
+of	O
+epinephrine	O
+(	O
+control	O
+,	O
+6	O
+.	O
+7	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+ng	O
+/	O
+kg	O
+/	O
+min	O
+)	O
+declined	O
+immediately	O
+during	O
+infusions	O
+of	O
+atrial	O
+natriuretic	O
+factor	O
+to	O
+a	O
+minimum	O
+of	O
+49	O
++	O
+/	O
+-	O
+5	O
+%	O
+of	O
+control	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+during	O
+0	O
+.	O
+1	O
+microgram	O
+/	O
+kg	O
+/	O
+min	O
+and	O
+to	O
+63	O
++	O
+/	O
+-	O
+5	O
+%	O
+(	O
+0	O
+.	O
+1	O
+greater	O
+than	O
+p	O
+greater	O
+than	O
+0	O
+.	O
+05	O
+)	O
+or	O
+95	O
++	O
+/	O
+-	O
+13	O
+%	O
+(	O
+not	O
+significant	O
+)	O
+during	O
+0	O
+.	O
+3	O
+or	O
+1	O
+.	O
+0	O
+microgram	O
+/	O
+kg	O
+/	O
+min	O
+.	O
+
+Steady	O
+state	O
+arterial	O
+plasma	O
+concentrations	O
+of	O
+atrial	O
+natriuretic	O
+factor	O
+were	O
+39	O
++	O
+/	O
+-	O
+10	O
+pg	O
+/	O
+ml	O
+(	O
+n	O
+=	O
+6	O
+)	O
+during	O
+infusions	O
+of	O
+saline	O
+and	O
+284	O
++	O
+/	O
+-	O
+24	O
+pg	O
+/	O
+ml	O
+(	O
+n	O
+=	O
+6	O
+)	O
+and	O
+1520	O
++	O
+/	O
+-	O
+300	O
+pg	O
+/	O
+ml	O
+(	O
+n	O
+=	O
+9	O
+)	O
+during	O
+0	O
+.	O
+03	O
+and	O
+0	O
+.	O
+1	O
+microgram	O
+/	O
+kg	O
+/	O
+min	O
+infusions	O
+of	O
+the	O
+factor	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Inhibition	O
+of	O
+immunoreactive	O
+corticotropin	O
+-	O
+releasing	O
+factor	O
+secretion	O
+into	O
+the	O
+hypophysial	O
+-	O
+portal	O
+circulation	O
+by	O
+delayed	O
+glucocorticoid	O
+feedback	O
+.	O
+
+Nitroprusside	O
+-	O
+induced	O
+hypotension	B
+evokes	O
+ACTH	O
+secretion	O
+which	O
+is	O
+primarily	O
+mediated	O
+by	O
+enhanced	O
+secretion	O
+of	O
+immunoreactive	O
+corticotropin	O
+-	O
+releasing	O
+factor	O
+(	O
+irCRF	O
+)	O
+into	O
+the	O
+hypophysial	O
+-	O
+portal	O
+circulation	O
+.	O
+
+Portal	O
+plasma	O
+concentrations	O
+of	O
+neither	O
+arginine	O
+vasopressin	O
+nor	O
+oxytocin	O
+are	O
+significantly	O
+altered	O
+in	O
+this	O
+paradigm	O
+.	O
+
+Application	O
+of	O
+a	O
+delayed	O
+feedback	O
+signal	O
+,	O
+in	O
+the	O
+form	O
+of	O
+a	O
+2	O
+-	O
+h	O
+systemic	O
+corticosterone	O
+infusion	O
+in	O
+urethane	O
+-	O
+anesthetized	O
+rats	O
+with	O
+pharmacological	O
+blockade	O
+of	O
+glucocorticoid	O
+synthesis	O
+,	O
+is	O
+without	O
+effect	O
+on	O
+the	O
+resting	O
+secretion	O
+of	O
+arginine	O
+vasopressin	O
+and	O
+oxytocin	O
+at	O
+any	O
+corticosterone	O
+feedback	O
+dose	O
+tested	O
+.	O
+
+Resting	O
+irCRF	O
+levels	O
+are	O
+suppressed	O
+only	O
+at	O
+the	O
+highest	O
+corticosterone	O
+infusion	O
+rate	O
+,	O
+which	O
+resulted	O
+in	O
+systemic	O
+corticosterone	O
+levels	O
+of	O
+40	O
+micrograms	O
+/	O
+dl	O
+.	O
+
+Suppression	O
+of	O
+irCRF	O
+secretion	O
+in	O
+response	O
+to	O
+nitroprusside	O
+-	O
+induced	O
+hypotension	B
+is	O
+observed	O
+and	O
+occurs	O
+at	O
+a	O
+plasma	O
+corticosterone	O
+level	O
+between	O
+8	O
+-	O
+12	O
+micrograms	O
+/	O
+dl	O
+.	O
+
+These	O
+studies	O
+provide	O
+further	O
+evidence	O
+for	O
+a	O
+strong	O
+central	O
+component	O
+of	O
+the	O
+delayed	O
+feedback	O
+process	O
+which	O
+is	O
+mediated	O
+by	O
+modulation	O
+of	O
+irCRF	O
+release	O
+.	O
+
+Noradrenergic	O
+involvement	O
+in	O
+catalepsy	B
+induced	O
+by	O
+delta	O
+9	O
+-	O
+tetrahydrocannabinol	O
+.	O
+
+In	O
+order	O
+to	O
+elucidate	O
+the	O
+role	O
+of	O
+the	O
+catecholaminergic	O
+system	O
+in	O
+the	O
+cataleptogenic	O
+effect	O
+of	O
+delta	O
+9	O
+-	O
+tetrahydrocannabinol	O
+(	O
+THC	O
+)	O
+,	O
+the	O
+effect	O
+of	O
+pretreatment	O
+with	O
+6	O
+-	O
+hydroxydopamine	O
+(	O
+6	O
+-	O
+OHDA	O
+)	O
+or	O
+with	O
+desipramine	O
+and	O
+6	O
+-	O
+OHDA	O
+and	O
+lesions	O
+of	O
+the	O
+locus	O
+coeruleus	O
+were	O
+investigated	O
+in	O
+rats	O
+.	O
+
+The	O
+cataleptogenic	O
+effect	O
+of	O
+THC	O
+was	O
+significantly	O
+reduced	O
+in	O
+rats	O
+treated	O
+with	O
+6	O
+-	O
+OHDA	O
+and	O
+in	O
+rats	O
+with	O
+lesions	O
+of	O
+the	O
+locus	O
+coeruleus	O
+but	O
+not	O
+in	O
+rats	O
+treated	O
+with	O
+desipramine	O
+and	O
+6	O
+-	O
+OHDA	O
+,	O
+as	O
+compared	O
+with	O
+control	O
+rats	O
+.	O
+
+On	O
+the	O
+contrary	O
+,	O
+the	O
+cataleptogenic	O
+effect	O
+of	O
+haloperidol	O
+was	O
+significantly	O
+reduced	O
+in	O
+rats	O
+treated	O
+with	O
+desipramine	O
+and	O
+6	O
+-	O
+OHDA	O
+but	O
+not	O
+in	O
+rats	O
+treated	O
+with	O
+6	O
+-	O
+OHDA	O
+or	O
+in	O
+rats	O
+with	O
+lesions	O
+of	O
+the	O
+locus	O
+coeruleus	O
+.	O
+
+These	O
+results	O
+indicate	O
+that	O
+noradrenergic	O
+neurons	O
+have	O
+an	O
+important	O
+role	O
+in	O
+the	O
+manifestation	O
+of	O
+catalepsy	B
+induced	O
+by	O
+THC	O
+,	O
+whereas	O
+dopaminergic	O
+neurons	O
+are	O
+important	O
+in	O
+catalepsy	B
+induced	O
+by	O
+haloperidol	O
+.	O
+
+Reversibility	O
+of	O
+captopril	O
+-	O
+induced	O
+renal	B
+insufficiency	I
+after	O
+prolonged	O
+use	O
+in	O
+an	O
+unusual	O
+case	O
+of	O
+renovascular	B
+hypertension	I
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+severe	O
+hypertension	B
+with	O
+an	O
+occluded	O
+renal	O
+artery	O
+to	O
+a	O
+solitary	O
+kidney	O
+,	O
+who	O
+developed	O
+sudden	B
+deterioration	I
+of	I
+renal	I
+function	I
+following	O
+treatment	O
+with	O
+captopril	O
+.	O
+
+His	O
+renal	O
+function	O
+remained	O
+impaired	O
+but	O
+stable	O
+during	O
+2	O
+years	O
+'	O
+treatment	O
+with	O
+captopril	O
+but	O
+returned	O
+to	O
+pre	O
+-	O
+treatment	O
+levels	O
+soon	O
+after	O
+cessation	O
+of	O
+the	O
+drug	O
+.	O
+
+This	O
+indicates	O
+reversibility	O
+in	O
+captopril	O
+-	O
+induced	O
+renal	B
+failure	I
+even	O
+after	O
+its	O
+prolonged	O
+use	O
+and	O
+suggests	O
+that	O
+no	O
+organic	O
+damage	O
+occurs	O
+to	O
+glomerular	O
+arterioles	O
+following	O
+chronic	O
+ACE	O
+inhibition	O
+.	O
+
+HMG	O
+CoA	O
+reductase	O
+inhibitors	O
+.	O
+
+Current	O
+clinical	O
+experience	O
+.	O
+
+Lovastatin	O
+and	O
+simvastatin	O
+are	O
+the	O
+2	O
+best	O
+-	O
+known	O
+members	O
+of	O
+the	O
+class	O
+of	O
+hypolipidaemic	O
+agents	O
+known	O
+as	O
+HMG	O
+CoA	O
+reductase	O
+inhibitors	O
+.	O
+
+Clinical	O
+experience	O
+with	O
+lovastatin	O
+includes	O
+over	O
+5000	O
+patients	O
+,	O
+700	O
+of	O
+whom	O
+have	O
+been	O
+treated	O
+for	O
+2	O
+years	O
+or	O
+more	O
+,	O
+and	O
+experience	O
+with	O
+simvastatin	O
+includes	O
+over	O
+3500	O
+patients	O
+,	O
+of	O
+whom	O
+350	O
+have	O
+been	O
+treated	O
+for	O
+18	O
+months	O
+or	O
+more	O
+.	O
+
+Lovastatin	O
+has	O
+been	O
+marketed	O
+in	O
+the	O
+United	O
+States	O
+for	O
+over	O
+6	O
+months	O
+.	O
+
+Both	O
+agents	O
+show	O
+substantial	O
+clinical	O
+efficacy	O
+,	O
+with	O
+reductions	O
+in	O
+total	O
+cholesterol	O
+of	O
+over	O
+30	O
+%	O
+and	O
+in	O
+LDL	O
+-	O
+cholesterol	O
+of	O
+40	O
+%	O
+in	O
+clinical	O
+studies	O
+.	O
+
+Modest	O
+increases	O
+in	O
+HDL	O
+-	O
+cholesterol	O
+levels	O
+of	O
+about	O
+10	O
+%	O
+are	O
+also	O
+reported	O
+.	O
+
+Clinical	O
+tolerability	O
+of	O
+both	O
+agents	O
+has	O
+been	O
+good	O
+,	O
+with	O
+fewer	O
+than	O
+3	O
+%	O
+of	O
+patients	O
+withdrawn	O
+from	O
+treatment	O
+because	O
+of	O
+clinical	O
+adverse	O
+experiences	O
+.	O
+
+Ophthalmological	O
+examinations	O
+in	O
+over	O
+1100	O
+patients	O
+treated	O
+with	O
+one	O
+or	O
+the	O
+other	O
+agent	O
+have	O
+revealed	O
+no	O
+evidence	O
+of	O
+significant	O
+short	O
+term	O
+(	O
+up	O
+to	O
+2	O
+years	O
+)	O
+cataractogenic	O
+potential	O
+.	O
+
+One	O
+to	O
+2	O
+%	O
+of	O
+patients	O
+have	O
+elevations	O
+of	O
+serum	O
+transaminases	O
+to	O
+greater	O
+than	O
+3	O
+times	O
+the	O
+upper	O
+limit	O
+of	O
+normal	O
+.	O
+
+These	O
+episodes	O
+are	O
+asymptomatic	O
+and	O
+reversible	O
+when	O
+therapy	O
+is	O
+discontinued	O
+.	O
+
+Minor	O
+elevations	O
+of	O
+creatine	O
+kinase	O
+levels	O
+are	O
+reported	O
+in	O
+about	O
+5	O
+%	O
+of	O
+patients	O
+.	O
+
+Myopathy	B
+,	O
+associated	O
+in	O
+some	O
+cases	O
+with	O
+myoglobinuria	B
+,	O
+and	O
+in	O
+2	O
+cases	O
+with	O
+transient	O
+renal	B
+failure	I
+,	O
+has	O
+been	O
+rarely	O
+reported	O
+with	O
+lovastatin	O
+,	O
+especially	O
+in	O
+patients	O
+concomitantly	O
+treated	O
+with	O
+cyclosporin	O
+,	O
+gemfibrozil	O
+or	O
+niacin	O
+.	O
+
+Lovastatin	O
+and	O
+simvastatin	O
+are	O
+both	O
+effective	O
+and	O
+well	O
+-	O
+tolerated	O
+agents	O
+for	O
+lowering	O
+elevated	O
+levels	O
+of	O
+serum	O
+cholesterol	O
+.	O
+
+As	O
+wider	O
+use	O
+confirms	O
+their	O
+safety	O
+profile	O
+,	O
+they	O
+will	O
+gain	O
+increasing	O
+importance	O
+in	O
+the	O
+therapeutic	O
+approach	O
+to	O
+hypercholesterolaemia	B
+and	O
+its	O
+consequences	O
+.	O
+
+Hepatic	O
+reactions	O
+associated	O
+with	O
+ketoconazole	O
+in	O
+the	O
+United	O
+Kingdom	O
+.	O
+
+Ketoconazole	O
+was	O
+introduced	O
+in	O
+the	O
+United	O
+Kingdom	O
+in	O
+1981	O
+.	O
+
+By	O
+November	O
+1984	O
+the	O
+Committee	O
+on	O
+Safety	O
+of	O
+Medicines	O
+had	O
+received	O
+82	O
+reports	O
+of	O
+possible	O
+hepatotoxicity	B
+associated	O
+with	O
+the	O
+drug	O
+,	O
+including	O
+five	O
+deaths	B
+.	O
+
+An	O
+analysis	O
+of	O
+the	O
+75	O
+cases	O
+that	O
+had	O
+been	O
+adequately	O
+followed	O
+up	O
+suggested	O
+that	O
+16	O
+,	O
+including	O
+three	O
+deaths	B
+,	O
+were	O
+probably	O
+related	O
+to	O
+treatment	O
+with	O
+the	O
+drug	O
+.	O
+
+Of	O
+the	O
+remainder	O
+,	O
+48	O
+were	O
+possibly	O
+related	O
+to	O
+treatment	O
+,	O
+five	O
+were	O
+unlikely	O
+to	O
+be	O
+so	O
+,	O
+and	O
+six	O
+were	O
+unclassifiable	O
+.	O
+
+The	O
+mean	O
+age	O
+of	O
+patients	O
+in	O
+the	O
+16	O
+probable	O
+cases	O
+was	O
+57	O
+.	O
+9	O
+,	O
+with	O
+hepatotoxicity	B
+being	O
+more	O
+common	O
+in	O
+women	O
+.	O
+
+The	O
+average	O
+duration	O
+of	O
+treatment	O
+before	O
+the	O
+onset	O
+of	O
+jaundice	B
+was	O
+61	O
+days	O
+.	O
+
+None	O
+of	O
+these	O
+well	O
+validated	O
+cases	O
+occurred	O
+within	O
+the	O
+first	O
+10	O
+days	O
+after	O
+treatment	O
+.	O
+
+The	O
+results	O
+of	O
+serum	O
+liver	O
+function	O
+tests	O
+suggested	O
+hepatocellular	B
+injury	I
+in	O
+10	O
+(	O
+63	O
+%	O
+)	O
+;	O
+the	O
+rest	O
+showed	O
+a	O
+mixed	O
+pattern	O
+.	O
+
+In	O
+contrast	O
+,	O
+the	O
+results	O
+of	O
+histological	O
+examination	O
+of	O
+the	O
+liver	O
+often	O
+showed	O
+evidence	O
+of	O
+cholestasis	B
+.	O
+
+The	O
+characteristics	O
+of	O
+the	O
+48	O
+patients	O
+in	O
+the	O
+possible	O
+cases	O
+were	O
+similar	O
+.	O
+
+Allergic	O
+manifestations	O
+such	O
+as	O
+rash	B
+and	O
+eosinophilia	B
+were	O
+rare	O
+.	O
+
+Hepatitis	B
+was	O
+usually	O
+reversible	O
+when	O
+treatment	O
+was	O
+stopped	O
+,	O
+with	O
+the	O
+results	O
+of	O
+liver	O
+function	O
+tests	O
+returning	O
+to	O
+normal	O
+after	O
+an	O
+average	O
+of	O
+3	O
+.	O
+1	O
+months	O
+.	O
+
+In	O
+two	O
+of	O
+the	O
+three	O
+deaths	B
+probably	O
+associated	O
+with	O
+ketoconazole	O
+treatment	O
+the	O
+drug	O
+had	O
+been	O
+continued	O
+after	O
+the	O
+onset	O
+of	O
+jaundice	B
+and	O
+other	O
+symptoms	O
+of	O
+hepatitis	B
+.	O
+
+Clinical	O
+and	O
+biochemical	O
+monitoring	O
+at	O
+regular	O
+intervals	O
+for	O
+evidence	O
+of	O
+hepatitis	B
+is	O
+advised	O
+during	O
+long	O
+term	O
+treatment	O
+with	O
+ketoconazole	O
+to	O
+prevent	O
+possible	O
+serious	O
+hepatic	B
+injury	I
+.	O
+
+Glyburide	O
+-	O
+induced	O
+hepatitis	B
+.	O
+
+Drug	O
+-	O
+induced	O
+hepatotoxicity	B
+,	O
+although	O
+common	O
+,	O
+has	O
+been	O
+reported	O
+only	O
+infrequently	O
+with	O
+sulfonylureas	O
+.	O
+
+For	O
+glyburide	O
+,	O
+a	O
+second	O
+-	O
+generation	O
+sulfonylurea	O
+,	O
+only	O
+two	O
+brief	O
+reports	O
+of	O
+hepatotoxicity	B
+exist	O
+.	O
+
+Two	O
+patients	O
+with	O
+type	B
+II	I
+diabetes	I
+mellitus	I
+developed	O
+an	O
+acute	B
+hepatitis	I
+-	I
+like	I
+syndrome	I
+soon	O
+after	O
+initiation	O
+of	O
+glyburide	O
+therapy	O
+.	O
+
+There	O
+was	O
+no	O
+serologic	O
+evidence	O
+of	O
+viral	B
+infection	I
+,	O
+and	O
+a	O
+liver	O
+biopsy	O
+sample	O
+showed	O
+a	O
+histologic	O
+pattern	O
+consistent	O
+with	O
+drug	B
+-	I
+induced	I
+hepatitis	I
+.	O
+
+Both	O
+patients	O
+recovered	O
+quickly	O
+after	O
+stopping	O
+glyburide	O
+therapy	O
+and	O
+have	O
+remained	O
+well	O
+for	O
+a	O
+follow	O
+-	O
+up	O
+period	O
+of	O
+1	O
+year	O
+.	O
+
+Glyburide	O
+can	O
+produce	O
+an	O
+acute	B
+hepatitis	I
+-	I
+like	I
+illness	I
+in	O
+some	O
+persons	O
+.	O
+
+Intracranial	O
+pressure	O
+increases	O
+during	O
+alfentanil	O
+-	O
+induced	O
+rigidity	B
+.	O
+
+Intracranial	O
+pressure	O
+(	O
+ICP	O
+)	O
+was	O
+measured	O
+during	O
+alfentanil	O
+-	O
+induced	O
+rigidity	B
+in	O
+rats	O
+.	O
+
+Ten	O
+rats	O
+had	O
+arterial	O
+,	O
+central	O
+venous	O
+(	O
+CVP	O
+)	O
+,	O
+and	O
+subdural	O
+cannulae	O
+inserted	O
+under	O
+halothane	O
+anesthesia	O
+.	O
+
+The	O
+animals	O
+were	O
+mechanically	O
+ventilated	O
+to	O
+achieve	O
+normocarbia	O
+(	O
+PCO2	O
+=	O
+42	O
++	O
+/	O
+-	O
+1	O
+mmHg	O
+,	O
+mean	O
++	O
+/	O
+-	O
+SE	O
+)	O
+.	O
+
+Following	O
+instrumentation	O
+,	O
+halothane	O
+was	O
+discontinued	O
+and	O
+alfentanil	O
+(	O
+125	O
+mu	O
+/	O
+kg	O
+)	O
+administered	O
+iv	O
+during	O
+emergence	O
+from	O
+halothane	O
+anesthesia	O
+.	O
+
+In	O
+the	O
+five	O
+rats	O
+that	O
+developed	O
+somatic	B
+rigidity	I
+,	O
+ICP	O
+and	O
+CVP	O
+increased	O
+significantly	O
+above	O
+baseline	O
+(	O
+delta	O
+ICP	O
+7	O
+.	O
+5	O
++	O
+/	O
+-	O
+1	O
+.	O
+0	O
+mmHg	O
+,	O
+delta	O
+CVP	O
+5	O
+.	O
+9	O
++	O
+/	O
+-	O
+1	O
+.	O
+3	O
+mmHg	O
+)	O
+.	O
+
+These	O
+variables	O
+returned	O
+to	O
+baseline	O
+when	O
+rigidity	B
+was	O
+abolished	O
+with	O
+metocurine	O
+.	O
+
+In	O
+five	O
+rats	O
+that	O
+did	O
+not	O
+become	O
+rigid	O
+,	O
+ICP	O
+and	O
+CVP	O
+did	O
+not	O
+change	O
+following	O
+alfentanil	O
+.	O
+
+These	O
+observations	O
+suggest	O
+that	O
+rigidity	B
+should	O
+be	O
+prevented	O
+when	O
+alfentanil	O
+,	O
+and	O
+,	O
+presumably	O
+,	O
+other	O
+opiates	O
+,	O
+are	O
+used	O
+in	O
+the	O
+anesthetic	O
+management	O
+of	O
+patients	O
+with	O
+ICP	O
+problems	O
+.	O
+
+Verapamil	O
+withdrawal	O
+as	O
+a	O
+possible	O
+cause	O
+of	O
+myocardial	B
+infarction	I
+in	O
+a	O
+hypertensive	B
+woman	O
+with	O
+a	O
+normal	O
+coronary	O
+angiogram	O
+.	O
+
+Verapamil	O
+is	O
+an	O
+effective	O
+and	O
+relatively	O
+-	O
+safe	O
+antihypertensive	O
+drug	O
+.	O
+
+Serious	O
+adverse	O
+effects	O
+are	O
+uncommon	O
+and	O
+mainly	O
+have	O
+been	O
+related	O
+to	O
+the	O
+depression	B
+of	O
+cardiac	O
+contractility	O
+and	O
+conduction	O
+,	O
+especially	O
+when	O
+the	O
+drug	O
+is	O
+combined	O
+with	O
+beta	O
+-	O
+blocking	O
+agents	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+in	O
+which	O
+myocardial	B
+infarction	I
+coincided	O
+with	O
+the	O
+introduction	O
+of	O
+captopril	O
+and	O
+the	O
+withdrawal	O
+of	O
+verapamil	O
+in	O
+a	O
+previously	O
+asymptomatic	O
+woman	O
+with	O
+severe	O
+hypertension	B
+.	O
+
+Possible	O
+mechanisms	O
+that	O
+involve	O
+a	O
+verapamil	O
+-	O
+related	O
+increase	O
+in	O
+platelet	O
+and	O
+/	O
+or	O
+vascular	O
+alpha	O
+2	O
+-	O
+adrenoreceptor	O
+affinity	O
+for	O
+catecholamines	O
+are	O
+discussed	O
+.	O
+
+Haemolytic	B
+-	I
+uraemic	I
+syndrome	I
+after	O
+treatment	O
+with	O
+metronidazole	O
+.	O
+
+This	O
+paper	O
+describes	O
+the	O
+clinical	O
+features	O
+of	O
+six	O
+children	O
+who	O
+developed	O
+the	O
+haemolytic	B
+-	I
+uraemic	I
+syndrome	I
+after	O
+treatment	O
+with	O
+metronidazole	O
+.	O
+
+These	O
+children	O
+were	O
+older	O
+and	O
+were	O
+more	O
+likely	O
+to	O
+have	O
+undergone	O
+recent	O
+bowel	O
+surgery	O
+than	O
+are	O
+other	O
+children	O
+with	O
+this	O
+condition	O
+.	O
+
+While	O
+the	O
+involvement	O
+of	O
+metronidazole	O
+in	O
+the	O
+aetiology	O
+of	O
+the	O
+haemolytic	B
+-	I
+uraemic	I
+syndrome	I
+is	O
+not	O
+established	O
+firmly	O
+,	O
+the	O
+action	O
+of	O
+this	O
+drug	O
+in	O
+sensitizing	O
+tissues	O
+to	O
+oxidation	O
+injury	O
+and	O
+the	O
+reported	O
+evidence	O
+of	O
+oxidation	O
+changes	O
+in	O
+the	O
+haemolytic	B
+-	I
+uraemic	I
+syndrome	I
+suggest	O
+a	O
+possible	O
+link	O
+between	O
+metronidazole	O
+treatment	O
+and	O
+some	O
+cases	O
+of	O
+the	O
+haemolytic	B
+-	I
+uraemic	I
+syndrome	I
+.	O
+
+Adverse	O
+cardiac	O
+effects	O
+during	O
+induction	O
+chemotherapy	O
+treatment	O
+with	O
+cis	O
+-	O
+platin	O
+and	O
+5	O
+-	O
+fluorouracil	O
+.	O
+
+Survival	O
+for	O
+patients	O
+with	O
+advanced	O
+head	B
+and	I
+neck	I
+carcinoma	I
+and	O
+esophageal	B
+carcinoma	I
+is	O
+poor	O
+with	O
+radiotherapy	O
+and	O
+/	O
+or	O
+surgery	O
+.	O
+
+Obviously	O
+,	O
+there	O
+is	O
+a	O
+need	O
+for	O
+effective	O
+chemotherapy	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+cis	O
+-	O
+platin	O
+(	O
+80	O
+-	O
+120	O
+mg	O
+/	O
+m2BSA	O
+)	O
+and	O
+5	O
+-	O
+FU	O
+(	O
+1000	O
+mg	O
+/	O
+m2BSA	O
+daily	O
+as	O
+a	O
+continuous	O
+infusion	O
+during	O
+5	O
+days	O
+)	O
+were	O
+given	O
+to	O
+76	O
+patients	O
+before	O
+radiotherapy	O
+and	O
+surgery	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+clarify	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+adverse	O
+cardiac	O
+effects	O
+to	O
+this	O
+treatment	O
+.	O
+
+Before	O
+treatment	O
+all	O
+patients	O
+had	O
+a	O
+cardiac	O
+evaluation	O
+and	O
+during	O
+treatment	O
+serial	O
+ECG	O
+recordings	O
+were	O
+performed	O
+.	O
+
+In	O
+the	O
+pre	O
+-	O
+treatment	O
+evaluation	O
+,	O
+signs	O
+of	O
+cardiovascular	B
+disease	I
+were	O
+found	O
+in	O
+33	O
+patients	O
+(	O
+43	O
+%	O
+)	O
+.	O
+
+During	O
+treatment	O
+,	O
+adverse	O
+cardiac	O
+effects	O
+were	O
+observed	O
+in	O
+14	O
+patients	O
+(	O
+18	O
+%	O
+)	O
+.	O
+
+The	O
+mean	O
+age	O
+of	O
+these	O
+patients	O
+was	O
+the	O
+same	O
+as	O
+for	O
+the	O
+entire	O
+group	O
+,	O
+64	O
+years	O
+.	O
+
+The	O
+incidence	O
+of	O
+cardiotoxicity	B
+was	O
+not	O
+higher	O
+in	O
+patients	O
+with	O
+signs	O
+of	O
+cardiovascular	B
+disease	I
+than	O
+in	O
+those	O
+without	O
+in	O
+the	O
+pre	O
+-	O
+treatment	O
+evaluation	O
+.	O
+
+The	O
+most	O
+common	O
+signs	O
+of	O
+cardiotoxicity	B
+were	O
+chest	B
+pain	I
+,	O
+ST	O
+-	O
+T	O
+wave	O
+changes	O
+and	O
+atrial	B
+fibrillation	I
+.	O
+
+This	O
+was	O
+followed	O
+by	O
+ventricular	B
+fibrillation	I
+in	O
+one	O
+patient	O
+and	O
+sudden	B
+death	I
+in	O
+another	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+patients	O
+on	O
+5	O
+-	O
+FU	O
+treatment	O
+should	O
+be	O
+under	O
+close	O
+supervision	O
+and	O
+that	O
+the	O
+treatment	O
+should	O
+be	O
+discontinued	O
+if	O
+chest	B
+pain	I
+or	O
+tachyarrhythmia	B
+is	O
+observed	O
+.	O
+
+Death	B
+from	O
+chemotherapy	O
+in	O
+gestational	B
+trophoblastic	I
+disease	I
+.	O
+
+Multiple	O
+cytotoxic	O
+drug	O
+administration	O
+is	O
+the	O
+generally	O
+accepted	O
+treatment	O
+of	O
+patients	O
+with	O
+a	O
+high	O
+-	O
+risk	O
+stage	O
+of	O
+choriocarcinoma	B
+.	O
+
+Based	O
+on	O
+this	O
+principle	O
+a	O
+27	O
+-	O
+year	O
+old	O
+woman	O
+,	O
+classified	O
+as	O
+being	O
+in	O
+the	O
+high	O
+-	O
+risk	O
+group	O
+(	O
+Goldstein	O
+and	O
+Berkowitz	O
+score	O
+:	O
+11	O
+)	O
+,	O
+was	O
+treated	O
+with	O
+multiple	O
+cytotoxic	O
+drugs	O
+.	O
+
+The	O
+multiple	O
+drug	O
+schema	O
+consisted	O
+of	O
+:	O
+Etoposide	O
+16	O
+.	O
+213	O
+,	O
+Methotrexate	O
+,	O
+Cyclophosphamide	O
+,	O
+Actomycin	O
+-	O
+D	O
+,	O
+and	O
+Cisplatin	O
+.	O
+
+On	O
+the	O
+first	O
+day	O
+of	O
+the	O
+schedule	O
+,	O
+moderate	O
+high	O
+doses	O
+of	O
+Methotrexate	O
+,	O
+Etoposide	O
+and	O
+Cyclophosphamide	O
+were	O
+administered	O
+.	O
+
+Within	O
+8	O
+hours	O
+after	O
+initiation	O
+of	O
+therapy	O
+the	O
+patient	O
+died	O
+with	O
+a	O
+clinical	O
+picture	O
+resembling	O
+massive	O
+pulmonary	B
+obstruction	I
+due	O
+to	O
+choriocarcinomic	O
+tissue	O
+plugs	O
+,	O
+probably	O
+originating	O
+from	O
+the	O
+uterus	O
+.	O
+
+Formation	O
+of	O
+these	O
+plugs	O
+was	O
+probably	O
+due	O
+to	O
+extensive	O
+tumor	B
+necrosis	B
+at	O
+the	O
+level	O
+of	O
+the	O
+walls	O
+of	O
+the	O
+major	O
+uterine	O
+veins	O
+,	O
+which	O
+resulted	O
+in	O
+an	O
+open	O
+exchange	O
+of	O
+tumor	B
+plugs	O
+to	O
+the	O
+vascular	O
+spaces	O
+;	O
+decrease	O
+in	O
+tumor	B
+tissue	O
+coherence	O
+secondary	O
+to	O
+chemotherapy	O
+may	O
+have	O
+further	O
+contributed	O
+to	O
+the	O
+formation	O
+of	O
+tumor	B
+emboli	O
+.	O
+
+In	O
+view	O
+of	O
+the	O
+close	O
+time	O
+association	O
+between	O
+the	O
+start	O
+of	O
+chemotherapy	O
+and	O
+the	O
+acute	O
+onset	O
+of	O
+massive	O
+embolism	B
+other	O
+explanations	O
+,	O
+such	O
+as	O
+spontaneous	O
+necrosis	B
+,	O
+must	O
+be	O
+considered	O
+less	O
+likely	O
+.	O
+
+Patients	O
+with	O
+large	O
+pelvic	B
+tumor	I
+loads	O
+are	O
+,	O
+according	O
+to	O
+existing	O
+classifications	O
+,	O
+at	O
+high	O
+risk	O
+to	O
+die	O
+and	O
+to	O
+develop	O
+drug	O
+resistance	O
+.	O
+
+Notwithstanding	O
+these	O
+facts	O
+our	O
+findings	O
+suggest	O
+that	O
+these	O
+patients	O
+might	O
+benefit	O
+from	O
+relatively	O
+mild	O
+initial	O
+treatment	O
+,	O
+especially	O
+true	O
+for	O
+patients	O
+not	O
+previously	O
+exposed	O
+to	O
+this	O
+drug	O
+.	O
+
+Close	O
+observation	O
+of	O
+the	O
+response	O
+status	O
+both	O
+clinically	O
+and	O
+with	O
+beta	O
+-	O
+hCG	O
+values	O
+may	O
+indicate	O
+whether	O
+and	O
+when	O
+more	O
+agressive	O
+combination	O
+chemotherapy	O
+should	O
+be	O
+started	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Pulmonary	O
+shunt	O
+and	O
+cardiovascular	O
+responses	O
+to	O
+CPAP	O
+during	O
+nitroprusside	O
+-	O
+induced	O
+hypotension	B
+.	O
+
+The	O
+effects	O
+of	O
+continuous	O
+positive	O
+airway	O
+pressure	O
+(	O
+CPAP	O
+)	O
+on	O
+cardiovascular	O
+dynamics	O
+and	O
+pulmonary	O
+shunt	O
+(	O
+QS	O
+/	O
+QT	O
+)	O
+were	O
+investigated	O
+in	O
+12	O
+dogs	O
+before	O
+and	O
+during	O
+sodium	O
+nitroprusside	O
+infusion	O
+that	O
+decreased	O
+mean	O
+arterial	O
+blood	O
+pressure	O
+40	O
+-	O
+50	O
+per	O
+cent	O
+.	O
+
+Before	O
+nitroprusside	O
+infusion	O
+,	O
+5	O
+cm	O
+H2O	O
+CPAP	O
+significantly	O
+,	O
+P	O
+less	O
+than	O
+.	O
+05	O
+,	O
+decreased	O
+arterial	O
+blood	O
+pressure	O
+,	O
+but	O
+did	O
+not	O
+significantly	O
+alter	O
+heart	O
+rate	O
+,	O
+cardiac	O
+output	O
+,	O
+systemic	O
+vascular	O
+resistance	O
+,	O
+or	O
+QS	O
+/	O
+QT	O
+.	O
+
+Ten	O
+cm	O
+H2O	O
+CPAP	O
+before	O
+nitroprusside	O
+infusion	O
+produced	O
+a	O
+further	O
+decrease	B
+in	I
+arterial	I
+blood	I
+pressure	I
+and	O
+significantly	O
+increased	O
+heart	O
+rate	O
+and	O
+decreased	B
+cardiac	I
+output	I
+and	O
+QS	O
+/	O
+QT	O
+.	O
+
+Nitroprusside	O
+caused	O
+significant	O
+decreases	B
+in	I
+arterial	I
+blood	I
+pressure	I
+and	O
+systemic	O
+vascular	O
+resistance	O
+and	O
+increases	O
+in	O
+heart	O
+rate	O
+,	O
+but	O
+did	O
+not	O
+change	O
+cardiac	O
+output	O
+or	O
+QS	O
+/	O
+QT	O
+.	O
+
+Five	O
+cm	O
+H2O	O
+CPAP	O
+during	O
+nitroprusside	O
+did	O
+not	O
+further	O
+alter	O
+any	O
+of	O
+the	O
+above	O
+-	O
+mentioned	O
+variables	O
+.	O
+
+However	O
+,	O
+10	O
+cm	O
+H2O	O
+CPAP	O
+decreased	O
+arterial	O
+blood	O
+pressure	O
+,	O
+cardiac	O
+output	O
+,	O
+and	O
+QS	O
+/	O
+QT	O
+.	O
+
+These	O
+data	O
+indicate	O
+that	O
+nitroprusside	O
+infusion	O
+rates	O
+that	O
+decrease	O
+mean	O
+arterial	O
+blood	O
+pressure	O
+by	O
+40	O
+-	O
+50	O
+per	O
+cent	O
+do	O
+not	O
+change	O
+cardiac	O
+output	O
+or	O
+QS	O
+/	O
+QT	O
+.	O
+
+During	O
+nitroprusside	O
+infusion	O
+low	O
+levels	O
+of	O
+CPAP	O
+do	O
+not	O
+markedly	O
+alter	O
+cardiovascular	O
+dynamics	O
+,	O
+but	O
+high	O
+levels	O
+of	O
+CPAP	O
+(	O
+10	O
+cm	O
+H2O	O
+)	O
+,	O
+while	O
+decreasing	O
+QS	O
+/	O
+QT	O
+,	O
+produce	O
+marked	O
+decreases	B
+in	I
+arterial	I
+blood	I
+pressure	I
+and	I
+cardiac	I
+output	I
+.	O
+
+Systolic	O
+pressure	O
+variation	O
+is	O
+greater	O
+during	O
+hemorrhage	B
+than	O
+during	O
+sodium	O
+nitroprusside	O
+-	O
+induced	O
+hypotension	B
+in	O
+ventilated	O
+dogs	O
+.	O
+
+The	O
+systolic	O
+pressure	O
+variation	O
+(	O
+SPV	O
+)	O
+,	O
+which	O
+is	O
+the	O
+difference	O
+between	O
+the	O
+maximal	O
+and	O
+minimal	O
+values	O
+of	O
+the	O
+systolic	O
+blood	O
+pressure	O
+(	O
+SBP	O
+)	O
+after	O
+one	O
+positive	O
+-	O
+pressure	O
+breath	O
+,	O
+was	O
+studied	O
+in	O
+ventilated	O
+dogs	O
+subjected	O
+to	O
+hypotension	B
+.	O
+
+Mean	O
+arterial	O
+pressure	O
+was	O
+decreased	O
+to	O
+50	O
+mm	O
+Hg	O
+for	O
+30	O
+minutes	O
+either	O
+by	O
+hemorrhage	B
+(	O
+HEM	B
+,	O
+n	O
+=	O
+7	O
+)	O
+or	O
+by	O
+continuous	O
+infusion	O
+of	O
+sodium	O
+nitroprusside	O
+(	O
+SNP	O
+,	O
+n	O
+=	O
+7	O
+)	O
+.	O
+
+During	O
+HEM	B
+-	O
+induced	O
+hypotension	B
+the	O
+cardiac	O
+output	O
+was	O
+significantly	O
+lower	O
+and	O
+systemic	O
+vascular	O
+resistance	O
+higher	O
+compared	O
+with	O
+that	O
+in	O
+the	O
+SNP	O
+group	O
+.	O
+
+The	O
+systemic	O
+,	O
+central	O
+venous	O
+,	O
+pulmonary	O
+capillary	O
+wedge	O
+pressures	O
+,	O
+and	O
+heart	O
+rates	O
+,	O
+were	O
+similar	O
+in	O
+the	O
+two	O
+groups	O
+.	O
+
+Analysis	O
+of	O
+the	O
+respiratory	O
+changes	O
+in	O
+the	O
+arterial	O
+pressure	O
+waveform	O
+enabled	O
+differentiation	O
+between	O
+the	O
+two	O
+groups	O
+.	O
+
+The	O
+SPV	O
+during	O
+hypotension	B
+was	O
+15	O
+.	O
+7	O
++	O
+/	O
+-	O
+6	O
+.	O
+7	O
+mm	O
+Hg	O
+in	O
+the	O
+HEM	B
+group	O
+,	O
+compared	O
+with	O
+9	O
+.	O
+1	O
++	O
+/	O
+-	O
+2	O
+.	O
+0	O
+mm	O
+Hg	O
+in	O
+the	O
+SNP	O
+group	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+02	O
+)	O
+.	O
+
+The	O
+delta	O
+down	O
+,	O
+which	O
+is	O
+the	O
+measure	O
+of	O
+decrease	O
+of	O
+SBP	O
+after	O
+a	O
+mechanical	O
+breath	O
+,	O
+was	O
+20	O
+.	O
+3	O
++	O
+/	O
+-	O
+8	O
+.	O
+4	O
+and	O
+10	O
+.	O
+1	O
++	O
+/	O
+-	O
+3	O
+.	O
+8	O
+mm	O
+Hg	O
+in	O
+the	O
+HEM	B
+and	O
+SNP	O
+groups	O
+,	O
+respectively	O
+,	O
+during	O
+hypotension	B
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+02	O
+)	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+increases	O
+in	O
+the	O
+SPV	O
+and	O
+the	O
+delta	O
+down	O
+are	O
+characteristic	O
+of	O
+a	O
+hypotensive	B
+state	O
+due	O
+to	O
+a	O
+predominant	O
+decrease	O
+in	O
+preload	O
+.	O
+
+They	O
+are	O
+thus	O
+more	O
+important	O
+during	O
+absolute	O
+hypovolemia	B
+than	O
+during	O
+deliberate	O
+hypotension	B
+.	O
+
+Ventricular	B
+tachyarrhythmias	I
+during	O
+cesarean	O
+section	O
+after	O
+ritodrine	O
+therapy	O
+:	O
+interaction	O
+with	O
+anesthetics	O
+.	O
+
+This	O
+case	O
+illustrates	O
+that	O
+patients	O
+receiving	O
+ritodrine	O
+for	O
+preterm	B
+labor	I
+may	O
+risk	O
+interactions	O
+between	O
+the	O
+residual	O
+betamimetic	O
+effects	O
+of	O
+ritodrine	O
+and	O
+the	O
+effects	O
+of	O
+anesthetics	O
+during	O
+cesarean	O
+section	O
+.	O
+
+Such	O
+interactions	O
+may	O
+result	O
+in	O
+serious	O
+cardiovascular	B
+complications	I
+even	O
+after	O
+cessation	O
+of	O
+an	O
+infusion	O
+of	O
+ritodrine	O
+.	O
+
+Preoperative	O
+assessment	O
+should	O
+focus	O
+on	O
+cardiovascular	O
+status	O
+and	O
+serum	O
+potassium	O
+level	O
+.	O
+
+Delaying	O
+induction	O
+of	O
+anesthesia	O
+should	O
+be	O
+considered	O
+whenever	O
+possible	O
+.	O
+
+Careful	O
+fluid	O
+administration	O
+and	O
+cautious	O
+use	O
+of	O
+titrated	O
+doses	O
+of	O
+ephedrine	O
+are	O
+advised	O
+.	O
+
+After	O
+delivery	O
+of	O
+the	O
+infant	O
+,	O
+there	O
+should	O
+be	O
+no	O
+contraindication	O
+to	O
+the	O
+use	O
+of	O
+an	O
+alpha	O
+-	O
+adrenergic	O
+vasopressor	O
+such	O
+as	O
+phenylephrine	O
+to	O
+treat	O
+hypotensive	B
+patients	O
+with	O
+tachycardia	B
+.	O
+
+Verapamil	O
+-	O
+induced	O
+carbamazepine	O
+neurotoxicity	B
+.	O
+
+A	O
+report	O
+of	O
+two	O
+cases	O
+.	O
+
+Two	O
+patients	O
+with	O
+signs	O
+of	O
+carbamazepine	O
+neurotoxicity	B
+after	O
+combined	O
+treatment	O
+with	O
+verapamil	O
+showed	O
+complete	O
+recovery	O
+after	O
+discontinuation	O
+of	O
+the	O
+calcium	O
+entry	O
+blocker	O
+.	O
+
+Use	O
+of	O
+verapamil	O
+in	O
+combination	O
+with	O
+carbamazepine	O
+should	O
+either	O
+be	O
+avoided	O
+or	O
+prescribed	O
+only	O
+with	O
+appropriate	O
+adjustment	O
+of	O
+the	O
+carbamazepine	O
+dose	O
+(	O
+usually	O
+reduction	O
+of	O
+the	O
+carbamazepine	O
+dose	O
+by	O
+one	O
+half	O
+)	O
+.	O
+
+Paracetamol	O
+-	O
+associated	O
+coma	B
+,	O
+metabolic	B
+acidosis	I
+,	O
+renal	B
+and	I
+hepatic	I
+failure	I
+.	O
+
+A	O
+case	O
+of	O
+metabolic	B
+acidosis	I
+,	O
+acute	B
+renal	I
+failure	I
+and	I
+hepatic	I
+failure	I
+following	O
+paracetamol	O
+ingestion	O
+is	O
+presented	O
+.	O
+
+The	O
+diagnostic	O
+difficulty	O
+at	O
+presentation	O
+is	O
+highlighted	O
+.	O
+
+Continuous	O
+arteriovenous	O
+haemofiltration	O
+proved	O
+a	O
+valuable	O
+means	O
+of	O
+maintaining	O
+fluid	O
+and	O
+electrolyte	O
+balance	O
+.	O
+
+The	O
+patient	O
+recovered	O
+.	O
+
+Sexual	B
+dysfunction	I
+among	O
+patients	O
+with	O
+arthritis	B
+.	O
+
+The	O
+relationship	O
+of	O
+arthritis	B
+and	O
+sexual	B
+dysfunction	I
+was	O
+investigated	O
+among	O
+169	O
+patients	O
+with	O
+rheumatoid	B
+arthritis	I
+,	O
+osteoarthritis	B
+and	O
+spondyloarthropathy	B
+,	O
+130	O
+of	O
+whom	O
+were	O
+pair	O
+-	O
+matched	O
+to	O
+controls	O
+.	O
+
+Assessments	O
+of	O
+marital	O
+happiness	O
+and	O
+depressed	B
+mood	I
+were	O
+also	O
+made	O
+using	O
+the	O
+CES	O
+-	O
+D	O
+and	O
+the	O
+Azrin	O
+Marital	O
+Happiness	O
+Scale	O
+(	O
+AMHS	O
+)	O
+.	O
+
+Sexual	B
+dysfunctions	I
+were	O
+found	O
+to	O
+be	O
+common	O
+among	O
+patients	O
+and	O
+controls	O
+,	O
+the	O
+majority	O
+in	O
+both	O
+groups	O
+reporting	O
+one	O
+or	O
+more	O
+dysfunctions	O
+.	O
+
+Impotence	B
+was	O
+more	O
+common	O
+among	O
+male	O
+patients	O
+than	O
+controls	O
+and	O
+was	O
+found	O
+to	O
+be	O
+associated	O
+with	O
+co	O
+-	O
+morbidity	O
+and	O
+the	O
+taking	O
+of	O
+methotrexate	O
+.	O
+
+Depressed	B
+mood	I
+was	O
+more	O
+common	O
+among	O
+patients	O
+and	O
+was	O
+associated	O
+with	O
+certain	O
+sexual	O
+difficulties	O
+,	O
+but	O
+not	O
+with	O
+impotence	B
+.	O
+
+Marital	O
+unhappiness	O
+,	O
+as	O
+indicated	O
+by	O
+AMHS	O
+scores	O
+,	O
+was	O
+not	O
+associated	O
+with	O
+arthritis	B
+but	O
+was	O
+associated	O
+with	O
+sexual	B
+dysfunction	I
+,	O
+sexual	O
+dissatisfaction	O
+and	O
+being	O
+female	O
+.	O
+
+Does	O
+paracetamol	O
+cause	O
+urothelial	B
+cancer	I
+or	O
+renal	B
+papillary	I
+necrosis	I
+?	O
+
+The	O
+risk	O
+of	O
+developing	O
+renal	B
+papillary	I
+necrosis	I
+or	O
+cancer	B
+of	I
+the	I
+renal	I
+pelvis	I
+,	I
+ureter	I
+or	I
+bladder	I
+associated	O
+with	O
+consumption	O
+of	O
+either	O
+phenacetin	O
+or	O
+paracetamol	O
+was	O
+calculated	O
+from	O
+data	O
+acquired	O
+by	O
+questionnaire	O
+from	O
+381	O
+cases	O
+and	O
+808	O
+controls	O
+.	O
+
+The	O
+risk	O
+of	O
+renal	B
+papillary	I
+necrosis	I
+was	O
+increased	O
+nearly	O
+20	O
+-	O
+fold	O
+by	O
+consumption	O
+of	O
+phenacetin	O
+,	O
+which	O
+also	O
+increased	O
+the	O
+risk	O
+for	O
+cancer	B
+of	I
+the	I
+renal	I
+pelvis	I
+and	I
+bladder	I
+but	O
+not	O
+for	O
+ureteric	B
+cancer	I
+.	O
+
+By	O
+contrast	O
+,	O
+we	O
+were	O
+unable	O
+to	O
+substantiate	O
+an	O
+increased	O
+risk	O
+from	O
+paracetamol	O
+consumption	O
+for	O
+renal	B
+papillary	I
+necrosis	I
+or	O
+any	O
+of	O
+these	O
+cancers	B
+although	O
+there	O
+was	O
+a	O
+suggestion	O
+of	O
+an	O
+association	O
+with	O
+cancer	B
+of	I
+the	I
+ureter	I
+.	O
+
+Dapsone	O
+-	O
+associated	O
+Heinz	O
+body	O
+hemolytic	B
+anemia	I
+in	O
+a	O
+Cambodian	O
+woman	O
+with	O
+hemoglobin	O
+E	O
+trait	O
+.	O
+
+A	O
+Cambodian	O
+woman	O
+with	O
+hemoglobin	O
+E	O
+trait	O
+(	O
+AE	O
+)	O
+and	O
+leprosy	B
+developed	O
+a	O
+Heinz	O
+body	O
+hemolytic	B
+anemia	I
+while	O
+taking	O
+a	O
+dose	O
+of	O
+dapsone	O
+(	O
+50	O
+mg	O
+/	O
+day	O
+)	O
+not	O
+usually	O
+associated	O
+with	O
+clinical	O
+hemolysis	B
+.	O
+
+Her	O
+red	O
+blood	O
+cells	O
+(	O
+RBCs	O
+)	O
+had	O
+increased	O
+incubated	O
+Heinz	O
+body	O
+formation	O
+,	O
+decreased	O
+reduced	O
+glutathione	O
+(	O
+GSH	O
+)	O
+,	O
+and	O
+decreased	O
+GSH	O
+stability	O
+.	O
+
+The	O
+pentose	O
+phosphate	O
+shunt	O
+activity	O
+of	O
+the	O
+dapsone	O
+-	O
+exposed	O
+AE	O
+RBCs	O
+was	O
+increased	O
+compared	O
+to	O
+normal	O
+RBCs	O
+.	O
+
+Although	O
+the	O
+AE	O
+RBCs	O
+from	O
+an	O
+individual	O
+not	O
+taking	O
+dapsone	O
+had	O
+increased	O
+incubated	O
+Heinz	O
+body	O
+formation	O
+,	O
+the	O
+GSH	O
+content	O
+and	O
+GSH	O
+stability	O
+were	O
+normal	O
+.	O
+
+The	O
+pentose	O
+phosphate	O
+shunt	O
+activity	O
+of	O
+the	O
+non	O
+-	O
+dapsone	O
+-	O
+exposed	O
+AE	O
+RBCs	O
+was	O
+decreased	O
+compared	O
+to	O
+normal	O
+RBCs	O
+.	O
+
+Thus	O
+,	O
+AE	O
+RBCs	O
+appear	O
+to	O
+have	O
+an	O
+increased	O
+sensitivity	O
+to	O
+oxidant	O
+stress	O
+both	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+,	O
+since	O
+dapsone	O
+does	O
+not	O
+cause	O
+hemolytic	B
+anemia	I
+at	O
+this	O
+dose	O
+in	O
+hematologically	O
+normal	O
+individuals	O
+.	O
+
+Given	O
+the	O
+influx	O
+of	O
+Southeast	O
+Asians	O
+into	O
+the	O
+United	O
+States	O
+,	O
+oxidant	O
+medications	O
+should	O
+be	O
+used	O
+with	O
+caution	O
+,	O
+especially	O
+if	O
+an	O
+infection	B
+is	O
+present	O
+,	O
+in	O
+individuals	O
+of	O
+ethnic	O
+backgrounds	O
+that	O
+have	O
+an	O
+increased	O
+prevalence	O
+of	O
+hemoglobin	O
+E	O
+.	O
+
+Severe	O
+complications	O
+of	O
+antianginal	O
+drug	O
+therapy	O
+in	O
+a	O
+patient	O
+identified	O
+as	O
+a	O
+poor	O
+metabolizer	O
+of	O
+metoprolol	O
+,	O
+propafenone	O
+,	O
+diltiazem	O
+,	O
+and	O
+sparteine	O
+.	O
+
+A	O
+47	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+suffering	O
+from	O
+coronary	B
+artery	I
+disease	I
+was	O
+admitted	O
+to	O
+the	O
+CCU	O
+in	O
+shock	B
+with	O
+III	O
+.	O
+
+AV	B
+block	I
+,	O
+severe	O
+hypotension	B
+,	O
+and	O
+impairment	B
+of	I
+ventricular	I
+function	I
+.	O
+
+One	O
+week	O
+prior	O
+to	O
+admission	O
+a	O
+therapy	O
+with	O
+standard	O
+doses	O
+of	O
+metoprolol	O
+(	O
+100	O
+mg	O
+t	O
+.	O
+i	O
+.	O
+d	O
+.	O
+and	O
+then	O
+100	O
+mg	O
+b	O
+.	O
+i	O
+.	O
+d	O
+.	O
+)	O
+had	O
+been	O
+initiated	O
+.	O
+
+Two	O
+days	O
+before	O
+admission	O
+diltiazem	O
+(	O
+60	O
+mg	O
+b	O
+.	O
+i	O
+.	O
+d	O
+.	O
+)	O
+was	O
+prescribed	O
+in	O
+addition	O
+.	O
+
+Analyses	O
+of	O
+a	O
+blood	O
+sample	O
+revealed	O
+unusually	O
+high	O
+plasma	O
+concentrations	O
+of	O
+metoprolol	O
+(	O
+greater	O
+than	O
+3000	O
+ng	O
+/	O
+ml	O
+)	O
+and	O
+diltiazem	O
+(	O
+526	O
+ng	O
+/	O
+ml	O
+)	O
+.	O
+
+The	O
+patient	O
+recovered	O
+within	O
+1	O
+week	O
+following	O
+discontinuation	O
+of	O
+antianginal	O
+therapy	O
+.	O
+
+Three	O
+months	O
+later	O
+the	O
+patient	O
+was	O
+exposed	O
+to	O
+a	O
+single	O
+dose	O
+of	O
+metoprolol	O
+,	O
+diltiazem	O
+,	O
+propafenone	O
+(	O
+since	O
+he	O
+had	O
+received	O
+this	O
+drug	O
+in	O
+the	O
+past	O
+)	O
+,	O
+and	O
+sparteine	O
+(	O
+as	O
+a	O
+probe	O
+for	O
+the	O
+debrisoquine	O
+/	O
+sparteine	O
+type	O
+polymorphism	O
+of	O
+oxidative	O
+drug	O
+metabolism	O
+)	O
+.	O
+
+It	O
+was	O
+found	O
+that	O
+he	O
+was	O
+a	O
+poor	O
+metabolizer	O
+of	O
+all	O
+four	O
+drugs	O
+,	O
+indicating	O
+that	O
+their	O
+metabolism	O
+is	O
+under	O
+the	O
+same	O
+genetic	O
+control	O
+.	O
+
+Therefore	O
+,	O
+patients	O
+belonging	O
+to	O
+the	O
+poor	O
+-	O
+metabolizer	O
+phenotype	O
+of	O
+sparteine	O
+/	O
+debrisoquine	O
+polymorphism	O
+in	O
+drug	O
+metabolism	O
+,	O
+which	O
+constitutes	O
+6	O
+.	O
+4	O
+%	O
+of	O
+the	O
+German	O
+population	O
+,	O
+may	O
+experience	O
+adverse	B
+drug	I
+reactions	I
+when	O
+treated	O
+with	O
+standard	O
+doses	O
+of	O
+one	O
+of	O
+these	O
+drugs	O
+alone	O
+.	O
+
+Moreover	O
+,	O
+the	O
+coadministration	O
+of	O
+these	O
+frequently	O
+used	O
+drugs	O
+is	O
+expected	O
+to	O
+be	O
+especially	O
+harmful	O
+in	O
+this	O
+subgroup	O
+of	O
+patients	O
+.	O
+
+Clinical	O
+experiences	O
+in	O
+an	O
+open	O
+and	O
+a	O
+double	O
+-	O
+blind	O
+trial	O
+.	O
+
+A	O
+total	O
+of	O
+sixty	O
+patients	O
+were	O
+trated	O
+with	O
+bromperidol	O
+first	O
+in	O
+open	O
+conditions	O
+(	O
+20	O
+patients	O
+)	O
+,	O
+then	O
+on	O
+a	O
+double	O
+blind	O
+basis	O
+(	O
+40	O
+patients	O
+)	O
+with	O
+haloperidol	O
+as	O
+the	O
+reference	O
+substance	O
+.	O
+
+The	O
+open	O
+study	O
+lasted	O
+for	O
+four	O
+weeks	O
+;	O
+the	O
+drug	O
+was	O
+administrated	O
+in	O
+the	O
+form	O
+of	O
+1	O
+mg	O
+tablets	O
+.	O
+
+The	O
+daily	O
+dose	O
+(	O
+initial	O
+dose	O
+:	O
+1	O
+mg	O
+;	O
+mean	O
+dose	O
+at	O
+the	O
+end	O
+of	O
+the	O
+trial	O
+:	O
+4	O
+.	O
+47	O
+mg	O
+)	O
+was	O
+always	O
+administered	O
+in	O
+one	O
+single	O
+dose	O
+.	O
+
+Nineteen	O
+patients	O
+finished	O
+the	O
+trial	O
+,	O
+and	O
+in	O
+18	O
+cases	O
+the	O
+therapeutic	O
+result	O
+was	O
+considered	O
+very	O
+good	O
+to	O
+good	O
+.	O
+
+These	O
+results	O
+were	O
+confirmed	O
+by	O
+statistical	O
+analysis	O
+.	O
+
+Nine	O
+patients	O
+exhibited	O
+mild	O
+to	O
+moderate	O
+extrapyramidal	B
+concomitant	I
+symptoms	I
+;	O
+no	O
+other	O
+side	O
+effects	O
+were	O
+observed	O
+.	O
+
+The	O
+results	O
+of	O
+detailed	O
+laboratory	O
+tests	O
+and	O
+evaluations	O
+of	O
+various	O
+quantitative	O
+and	O
+qualitative	O
+tolerability	O
+parameters	O
+were	O
+not	O
+indicative	O
+of	O
+toxic	O
+effects	O
+.	O
+
+In	O
+the	O
+double	O
+blind	O
+study	O
+with	O
+haloperidol	O
+,	O
+both	O
+substances	O
+were	O
+found	O
+to	O
+be	O
+highly	O
+effective	O
+in	O
+the	O
+treatment	O
+of	O
+psychotic	B
+syndromes	I
+belonging	I
+predominantly	I
+to	I
+the	I
+schizophrenia	I
+group	I
+.	O
+
+Certain	O
+clues	O
+,	O
+including	O
+the	O
+onset	O
+of	O
+action	O
+,	O
+seem	O
+to	O
+be	O
+indicative	O
+of	O
+the	O
+superiority	O
+of	O
+bromperidol	O
+.	O
+
+No	O
+differences	O
+were	O
+observed	O
+with	O
+respect	O
+to	O
+side	O
+effects	O
+and	O
+general	O
+tolerability	O
+.	O
+
+Prolonged	O
+cholestasis	B
+after	O
+troleandomycin	O
+-	O
+induced	O
+acute	O
+hepatitis	B
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+patient	O
+in	O
+whom	O
+troleandomycin	O
+-	O
+induced	O
+hepatitis	B
+was	O
+followed	O
+by	O
+prolonged	O
+anicteric	O
+cholestasis	B
+.	O
+
+Jaundice	B
+occurred	O
+after	O
+administration	O
+of	O
+troleandomycin	O
+for	O
+7	O
+days	O
+and	O
+was	O
+associated	O
+with	O
+hypereosinophilia	B
+.	O
+
+Jaundice	B
+disappeared	O
+within	O
+3	O
+months	O
+but	O
+was	O
+followed	O
+by	O
+prolonged	O
+anicteric	O
+cholestasis	B
+marked	O
+by	O
+pruritus	B
+and	O
+high	O
+levels	O
+of	O
+alkaline	O
+phosphatase	O
+and	O
+gammaglutamyltransferase	O
+activities	O
+.	O
+
+Finally	O
+,	O
+pruritus	B
+disappeared	O
+within	O
+19	O
+months	O
+,	O
+and	O
+liver	O
+tests	O
+returned	O
+to	O
+normal	O
+27	O
+months	O
+after	O
+the	O
+onset	O
+of	O
+hepatitis	B
+.	O
+
+This	O
+observation	O
+demonstrates	O
+that	O
+prolonged	O
+cholestasis	B
+can	O
+follow	O
+troleandomycin	O
+-	O
+induced	O
+acute	O
+hepatitis	B
+.	O
+
+Serial	O
+studies	O
+of	O
+auditory	B
+neurotoxicity	I
+in	O
+patients	O
+receiving	O
+deferoxamine	O
+therapy	O
+.	O
+
+Visual	B
+and	I
+auditory	I
+neurotoxicity	I
+was	O
+previously	O
+documented	O
+in	O
+42	O
+of	O
+89	O
+patients	O
+with	O
+transfusion	O
+-	O
+dependent	O
+anemia	B
+who	O
+were	O
+receiving	O
+iron	O
+chelation	O
+therapy	O
+with	O
+daily	O
+subcutaneous	O
+deferoxamine	O
+.	O
+
+Twenty	O
+-	O
+two	O
+patients	O
+in	O
+the	O
+affected	O
+group	O
+had	O
+abnormal	B
+audiograms	I
+with	I
+deficits	I
+mostly	I
+in	I
+the	I
+high	I
+frequency	I
+range	I
+of	I
+4	I
+,	I
+000	I
+to	I
+8	I
+,	I
+000	I
+Hz	I
+and	O
+in	O
+the	O
+hearing	O
+threshold	O
+levels	O
+of	O
+30	O
+to	O
+100	O
+decibels	O
+.	O
+
+When	O
+deferoxamine	O
+therapy	O
+was	O
+discontinued	O
+and	O
+serial	O
+studies	O
+were	O
+performed	O
+,	O
+audiograms	O
+in	O
+seven	O
+cases	O
+reverted	O
+to	O
+normal	O
+or	O
+near	O
+normal	O
+within	O
+two	O
+to	O
+three	O
+weeks	O
+,	O
+and	O
+nine	O
+of	O
+13	O
+patients	O
+with	O
+symptoms	O
+became	O
+asymptomatic	O
+.	O
+
+Audiograms	O
+from	O
+15	O
+patients	O
+remained	O
+abnormal	O
+and	O
+four	O
+patients	O
+required	O
+hearing	O
+aids	O
+because	O
+of	O
+permanent	B
+disability	I
+.	O
+
+Since	O
+18	O
+of	O
+the	O
+22	O
+patients	O
+were	O
+initially	O
+receiving	O
+deferoxamine	O
+doses	O
+in	O
+excess	O
+of	O
+the	O
+commonly	O
+recommended	O
+50	O
+mg	O
+/	O
+kg	O
+per	O
+dose	O
+,	O
+therapy	O
+was	O
+restarted	O
+with	O
+lower	O
+doses	O
+,	O
+usually	O
+50	O
+mg	O
+/	O
+kg	O
+per	O
+dose	O
+or	O
+less	O
+depending	O
+on	O
+the	O
+degree	O
+of	O
+auditory	B
+abnormality	I
+,	O
+and	O
+with	O
+the	O
+exception	O
+of	O
+two	O
+cases	O
+no	O
+further	O
+toxicity	B
+was	O
+demonstrated	O
+.	O
+
+Auditory	O
+deterioration	O
+and	O
+improvement	O
+,	O
+demonstrated	O
+serially	O
+in	O
+individual	O
+patients	O
+receiving	O
+and	O
+not	O
+receiving	O
+deferoxamine	O
+,	O
+respectively	O
+,	O
+provided	O
+convincing	O
+evidence	O
+for	O
+a	O
+cause	O
+-	O
+and	O
+-	O
+effect	O
+relation	O
+between	O
+deferoxamine	O
+administration	O
+and	O
+ototoxicity	B
+.	O
+
+Based	O
+on	O
+these	O
+data	O
+,	O
+a	O
+plan	O
+of	O
+management	O
+was	O
+developed	O
+that	O
+allows	O
+effective	O
+yet	O
+safe	O
+administration	O
+of	O
+deferoxamine	O
+.	O
+
+A	O
+dose	O
+of	O
+50	O
+mg	O
+/	O
+kg	O
+is	O
+recommended	O
+in	O
+those	O
+without	O
+audiogram	O
+abnormalities	O
+.	O
+
+With	O
+mild	O
+toxicity	B
+,	O
+a	O
+reduction	O
+to	O
+30	O
+or	O
+40	O
+mg	O
+/	O
+kg	O
+per	O
+dose	O
+should	O
+result	O
+in	O
+a	O
+reversal	O
+of	O
+the	O
+abnormal	O
+results	O
+to	O
+normal	O
+within	O
+four	O
+weeks	O
+.	O
+
+Moderate	O
+abnormalities	O
+require	O
+a	O
+reduction	O
+of	O
+deferoxamine	O
+to	O
+25	O
+mg	O
+/	O
+kg	O
+per	O
+dose	O
+with	O
+careful	O
+monitoring	O
+.	O
+
+In	O
+those	O
+with	O
+symptoms	O
+of	O
+hearing	B
+loss	I
+,	O
+the	O
+drug	O
+should	O
+be	O
+stopped	O
+for	O
+four	O
+weeks	O
+,	O
+and	O
+when	O
+the	O
+audiogram	O
+is	O
+stable	O
+or	O
+improved	O
+,	O
+therapy	O
+should	O
+be	O
+restarted	O
+at	O
+10	O
+to	O
+25	O
+mg	O
+/	O
+kg	O
+per	O
+dose	O
+.	O
+
+Serial	O
+audiograms	O
+should	O
+be	O
+performed	O
+every	O
+six	O
+months	O
+in	O
+those	O
+without	O
+problems	O
+and	O
+more	O
+frequently	O
+in	O
+young	O
+patients	O
+with	O
+normal	O
+serum	O
+ferritin	O
+values	O
+and	O
+in	O
+those	O
+with	O
+auditory	B
+dysfunction	I
+.	O
+
+Lidocaine	O
+-	O
+induced	O
+cardiac	B
+asystole	I
+.	O
+
+Intravenous	O
+administration	O
+of	O
+a	O
+single	O
+50	O
+-	O
+mg	O
+bolus	O
+of	O
+lidocaine	O
+in	O
+a	O
+67	O
+-	O
+year	O
+-	O
+old	O
+man	O
+resulted	O
+in	O
+profound	O
+depression	B
+of	O
+the	O
+activity	O
+of	O
+the	O
+sinoatrial	O
+and	O
+atrioventricular	O
+nodal	O
+pacemakers	O
+.	O
+
+The	O
+patient	O
+had	O
+no	O
+apparent	O
+associated	O
+conditions	O
+which	O
+might	O
+have	O
+predisposed	O
+him	O
+to	O
+the	O
+development	O
+of	O
+bradyarrhythmias	B
+;	O
+and	O
+,	O
+thus	O
+,	O
+this	O
+probably	O
+represented	O
+a	O
+true	O
+idiosyncrasy	O
+to	O
+lidocaine	O
+.	O
+
+Flurbiprofen	O
+in	O
+the	O
+treatment	O
+of	O
+juvenile	B
+rheumatoid	I
+arthritis	I
+.	O
+
+Thirty	O
+-	O
+four	O
+patients	O
+with	O
+juvenile	B
+rheumatoid	I
+arthritis	I
+,	O
+who	O
+were	O
+treated	O
+with	O
+flurbiprofen	O
+at	O
+a	O
+maximum	O
+dose	O
+of	O
+4	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+,	O
+had	O
+statistically	O
+significant	O
+decreases	O
+from	O
+baseline	O
+in	O
+6	O
+arthritis	B
+indices	O
+after	O
+12	O
+weeks	O
+of	O
+treatment	O
+.	O
+
+Improvements	O
+were	O
+seen	O
+in	O
+the	O
+number	O
+of	O
+tender	B
+joints	I
+,	O
+the	O
+severity	O
+of	O
+swelling	B
+and	O
+tenderness	B
+,	O
+the	O
+time	O
+of	O
+walk	O
+50	O
+feet	O
+,	O
+the	O
+duration	O
+of	O
+morning	B
+stiffness	I
+and	O
+the	O
+circumference	O
+of	O
+the	O
+left	O
+knee	O
+.	O
+
+The	O
+most	O
+frequently	O
+observed	O
+side	O
+effect	O
+was	O
+fecal	B
+occult	I
+blood	I
+(	O
+25	O
+%	O
+of	O
+patients	O
+)	O
+;	O
+however	O
+,	O
+there	O
+was	O
+no	O
+other	O
+evidence	O
+of	O
+gastrointestinal	B
+(	I
+GI	I
+)	I
+bleeding	I
+in	O
+these	O
+patients	O
+.	O
+
+One	O
+patient	O
+was	O
+prematurely	O
+discontinued	O
+from	O
+the	O
+study	O
+for	O
+severe	O
+headache	B
+and	O
+abdominal	B
+pain	I
+.	O
+
+Most	O
+side	O
+effects	O
+were	O
+mild	O
+and	O
+related	O
+to	O
+the	O
+GI	O
+tract	O
+.	O
+
+Hyperkalemia	B
+associated	O
+with	O
+sulindac	O
+therapy	O
+.	O
+
+Hyperkalemia	B
+has	O
+recently	O
+been	O
+recognized	O
+as	O
+a	O
+complication	O
+of	O
+nonsteroidal	O
+antiinflammatory	O
+agents	O
+(	O
+NSAID	O
+)	O
+such	O
+as	O
+indomethacin	O
+.	O
+
+Several	O
+recent	O
+studies	O
+have	O
+stressed	O
+the	O
+renal	O
+sparing	O
+features	O
+of	O
+sulindac	O
+,	O
+owing	O
+to	O
+its	O
+lack	O
+of	O
+interference	O
+with	O
+renal	O
+prostacyclin	O
+synthesis	O
+.	O
+
+We	O
+describe	O
+4	O
+patients	O
+in	O
+whom	O
+hyperkalemia	B
+ranging	O
+from	O
+6	O
+.	O
+1	O
+to	O
+6	O
+.	O
+9	O
+mEq	O
+/	O
+l	O
+developed	O
+within	O
+3	O
+to	O
+8	O
+days	O
+of	O
+sulindac	O
+administration	O
+.	O
+
+In	O
+all	O
+of	O
+them	O
+normal	O
+serum	O
+potassium	O
+levels	O
+reached	O
+within	O
+2	O
+to	O
+4	O
+days	O
+of	O
+stopping	O
+sulindac	O
+.	O
+
+As	O
+no	O
+other	O
+medications	O
+known	O
+to	O
+effect	O
+serum	O
+potassium	O
+had	O
+been	O
+given	O
+concomitantly	O
+,	O
+this	O
+course	O
+of	O
+events	O
+is	O
+suggestive	O
+of	O
+a	O
+cause	O
+-	O
+and	O
+-	O
+effect	O
+relationship	O
+between	O
+sulindac	O
+and	O
+hyperkalemia	B
+.	O
+
+These	O
+observations	O
+indicate	O
+that	O
+initial	O
+hopes	O
+that	O
+sulindac	O
+may	O
+not	O
+be	O
+associated	O
+with	O
+the	O
+adverse	O
+renal	O
+effects	O
+of	O
+other	O
+NSAID	O
+are	O
+probably	O
+not	O
+justified	O
+.	O
+
+Drug	O
+-	O
+induced	O
+arterial	O
+spasm	B
+relieved	O
+by	O
+lidocaine	O
+.	O
+
+Case	O
+report	O
+.	O
+
+Following	O
+major	O
+intracranial	O
+surgery	O
+in	O
+a	O
+35	O
+-	O
+year	O
+-	O
+old	O
+man	O
+,	O
+sodium	O
+pentothal	O
+was	O
+intravenously	O
+infused	O
+to	O
+minimize	O
+cerebral	B
+ischaemia	I
+.	O
+
+Intense	O
+vasospasm	B
+with	O
+threatened	O
+gangrene	B
+arose	O
+in	O
+the	O
+arm	O
+used	O
+for	O
+the	O
+infusion	O
+.	O
+
+Since	O
+the	O
+cranial	O
+condition	O
+precluded	O
+use	O
+of	O
+more	O
+usual	O
+methods	O
+,	O
+lidocaine	O
+was	O
+given	O
+intra	O
+-	O
+arterially	O
+,	O
+with	O
+careful	O
+cardiovascular	O
+monitoring	O
+,	O
+to	O
+counteract	O
+the	O
+vasospasm	B
+.	O
+
+The	O
+treatment	O
+was	O
+rapidly	O
+successful	O
+.	O
+
+Regional	O
+localization	O
+of	O
+the	O
+antagonism	O
+of	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B
+by	O
+intracerebral	O
+calcitonin	O
+injections	O
+.	O
+
+Calcitonin	O
+receptors	O
+are	O
+found	O
+in	O
+the	O
+brain	O
+,	O
+and	O
+intracerebral	O
+infusions	O
+of	O
+calcitonin	O
+can	O
+produce	O
+behavioral	O
+effects	O
+.	O
+
+Among	O
+these	O
+behavioral	O
+effects	O
+are	O
+decreases	O
+in	O
+food	O
+intake	O
+and	O
+decreases	O
+in	O
+amphetamine	O
+-	O
+induced	O
+locomotor	O
+activity	O
+.	O
+
+In	O
+previous	O
+experiments	O
+we	O
+found	O
+that	O
+decreases	O
+in	O
+food	O
+intake	O
+were	O
+induced	O
+by	O
+local	O
+administration	O
+of	O
+calcitonin	O
+into	O
+several	O
+hypothalamic	O
+sites	O
+and	O
+into	O
+the	O
+nucleus	O
+accumbens	O
+.	O
+
+In	O
+the	O
+present	O
+experiment	O
+calcitonin	O
+decreased	O
+locomotor	O
+activity	O
+when	O
+locally	O
+injected	O
+into	O
+the	O
+same	O
+sites	O
+where	O
+it	O
+decreases	O
+food	O
+intake	O
+.	O
+
+The	O
+areas	O
+where	O
+calcitonin	O
+is	O
+most	O
+effective	O
+in	O
+decreasing	O
+locomotor	O
+activity	O
+are	O
+located	O
+in	O
+the	O
+hypothalamus	O
+and	O
+nucleus	O
+accumbens	O
+,	O
+suggesting	O
+that	O
+these	O
+areas	O
+are	O
+the	O
+major	O
+sites	O
+of	O
+action	O
+of	O
+calcitonin	O
+in	O
+inhibiting	O
+amphetamine	O
+-	O
+induced	O
+locomotor	O
+activity	O
+.	O
+
+The	O
+hematologic	O
+effects	O
+of	O
+cefonicid	O
+and	O
+cefazedone	O
+in	O
+the	O
+dog	O
+:	O
+a	O
+potential	O
+model	O
+of	O
+cephalosporin	O
+hematotoxicity	B
+in	O
+man	O
+.	O
+
+Cephalosporin	O
+antibiotics	O
+cause	O
+a	O
+variety	O
+of	O
+hematologic	B
+disturbances	I
+in	O
+man	O
+,	O
+the	O
+pathogeneses	O
+and	O
+hematopathology	O
+of	O
+which	O
+remain	O
+poorly	O
+characterized	O
+.	O
+
+There	O
+is	O
+a	O
+need	O
+for	O
+a	O
+well	O
+-	O
+defined	O
+animal	O
+model	O
+in	O
+which	O
+these	O
+blood	B
+dyscrasias	I
+can	O
+be	O
+studied	O
+.	O
+
+In	O
+four	O
+subacute	O
+toxicity	B
+studies	O
+,	O
+the	O
+intravenous	O
+administration	O
+of	O
+cefonicid	O
+or	O
+cefazedone	O
+to	O
+beagle	O
+dogs	O
+caused	O
+a	O
+dose	O
+-	O
+dependent	O
+incidence	O
+of	O
+anemia	B
+,	O
+neutropenia	B
+,	O
+and	O
+thrombocytopenia	B
+after	O
+1	O
+-	O
+3	O
+months	O
+of	O
+treatment	O
+.	O
+
+A	O
+nonregenerative	O
+anemia	B
+was	O
+the	O
+most	O
+compromising	O
+of	O
+the	O
+cytopenias	B
+and	O
+occurred	O
+in	O
+approximately	O
+50	O
+%	O
+of	O
+dogs	O
+receiving	O
+400	O
+-	O
+500	O
+mg	O
+/	O
+kg	O
+cefonicid	O
+or	O
+540	O
+-	O
+840	O
+mg	O
+/	O
+kg	O
+cefazedone	O
+.	O
+
+All	O
+three	O
+cytopenias	B
+were	O
+completely	O
+reversible	O
+following	O
+cessation	O
+of	O
+treatment	O
+;	O
+the	O
+time	O
+required	O
+for	O
+recovery	O
+of	O
+the	O
+erythron	O
+(	O
+approximately	O
+1	O
+month	O
+)	O
+was	O
+considerably	O
+longer	O
+than	O
+that	O
+of	O
+the	O
+granulocytes	O
+and	O
+platelets	O
+(	O
+hours	O
+to	O
+a	O
+few	O
+days	O
+)	O
+.	O
+
+Upon	O
+rechallenge	O
+with	O
+either	O
+cephalosporin	O
+,	O
+the	O
+hematologic	B
+syndrome	I
+was	O
+reproduced	O
+in	O
+most	O
+dogs	O
+tested	O
+;	O
+cefonicid	O
+(	O
+but	O
+not	O
+cefazedone	O
+)	O
+-	O
+treated	O
+dogs	O
+showed	O
+a	O
+substantially	O
+reduced	O
+induction	O
+period	O
+(	O
+15	O
++	O
+/	O
+-	O
+5	O
+days	O
+)	O
+compared	O
+to	O
+that	O
+of	O
+the	O
+first	O
+exposure	O
+to	O
+the	O
+drug	O
+(	O
+61	O
++	O
+/	O
+-	O
+24	O
+days	O
+)	O
+.	O
+
+This	O
+observation	O
+,	O
+along	O
+with	O
+the	O
+rapid	O
+rate	O
+of	O
+decline	O
+in	O
+red	O
+cell	O
+mass	O
+parameters	O
+of	O
+affected	O
+dogs	O
+,	O
+suggests	O
+that	O
+a	O
+hemolytic	B
+component	O
+complicated	O
+the	O
+red	O
+cell	O
+production	O
+problem	O
+and	O
+that	O
+multiple	O
+toxicologic	O
+mechanisms	O
+contributed	O
+to	O
+the	O
+cytopenia	B
+.	O
+
+We	O
+conclude	O
+that	O
+the	O
+administration	O
+of	O
+high	O
+doses	O
+of	O
+cefonicid	O
+or	O
+cefazedone	O
+to	O
+dogs	O
+can	O
+induce	O
+hematotoxicity	B
+similar	O
+to	O
+the	O
+cephalosporin	O
+-	O
+induced	O
+blood	B
+dyscrasias	I
+described	O
+in	O
+man	O
+and	O
+thus	O
+provides	O
+a	O
+useful	O
+model	O
+for	O
+studying	O
+the	O
+mechanisms	O
+of	O
+these	O
+disorders	O
+.	O
+
+Cerebral	O
+blood	O
+flow	O
+and	O
+metabolism	O
+during	O
+isoflurane	O
+-	O
+induced	O
+hypotension	B
+in	O
+patients	O
+subjected	O
+to	O
+surgery	O
+for	O
+cerebral	B
+aneurysms	I
+.	O
+
+Cerebral	O
+blood	O
+flow	O
+and	O
+cerebral	O
+metabolic	O
+rate	O
+for	O
+oxygen	O
+were	O
+measured	O
+during	O
+isoflurane	O
+-	O
+induced	O
+hypotension	B
+in	O
+10	O
+patients	O
+subjected	O
+to	O
+craniotomy	O
+for	O
+clipping	O
+of	O
+a	O
+cerebral	B
+aneurysm	I
+.	O
+
+Flow	O
+and	O
+metabolism	O
+were	O
+measured	O
+5	O
+-	O
+13	O
+days	O
+after	O
+the	O
+subarachnoid	B
+haemorrhage	I
+by	O
+a	O
+modification	O
+of	O
+the	O
+classical	O
+Kety	O
+-	O
+Schmidt	O
+technique	O
+using	O
+xenon	O
+-	O
+133	O
+i	O
+.	O
+v	O
+.	O
+Anaesthesia	O
+was	O
+maintained	O
+with	O
+an	O
+inspired	O
+isoflurane	O
+concentration	O
+of	O
+0	O
+.	O
+75	O
+%	O
+(	O
+plus	O
+67	O
+%	O
+nitrous	O
+oxide	O
+in	O
+oxygen	O
+)	O
+,	O
+during	O
+which	O
+CBF	O
+and	O
+CMRO2	O
+were	O
+34	O
+.	O
+3	O
++	O
+/	O
+-	O
+2	O
+.	O
+1	O
+ml	O
+/	O
+100	O
+g	O
+min	O
+-	O
+1	O
+and	O
+2	O
+.	O
+32	O
++	O
+/	O
+-	O
+0	O
+.	O
+16	O
+ml	O
+/	O
+100	O
+g	O
+min	O
+-	O
+1	O
+at	O
+PaCO2	O
+4	O
+.	O
+1	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+kPa	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SEM	O
+)	O
+.	O
+
+Controlled	O
+hypotension	B
+to	O
+an	O
+average	O
+MAP	O
+of	O
+50	O
+-	O
+55	O
+mm	O
+Hg	O
+was	O
+induced	O
+by	O
+increasing	O
+the	O
+dose	O
+of	O
+isoflurane	O
+,	O
+and	O
+maintained	O
+at	O
+an	O
+inspired	O
+concentration	O
+of	O
+2	O
+.	O
+2	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+%	O
+.	O
+
+This	O
+resulted	O
+in	O
+a	O
+significant	O
+decrease	O
+in	O
+CMRO2	O
+(	O
+to	O
+1	O
+.	O
+73	O
++	O
+/	O
+-	O
+0	O
+.	O
+16	O
+ml	O
+/	O
+100	O
+g	O
+min	O
+-	O
+1	O
+)	O
+,	O
+while	O
+CBF	O
+was	O
+unchanged	O
+.	O
+
+After	O
+the	O
+clipping	O
+of	O
+the	O
+aneurysm	B
+the	O
+isoflurane	O
+concentration	O
+was	O
+reduced	O
+to	O
+0	O
+.	O
+75	O
+%	O
+.	O
+
+There	O
+was	O
+a	O
+significant	O
+increase	O
+in	O
+CBF	O
+,	O
+although	O
+CMRO2	O
+was	O
+unchanged	O
+,	O
+compared	O
+with	O
+pre	O
+-	O
+hypotensive	B
+values	O
+.	O
+
+These	O
+changes	O
+might	O
+offer	O
+protection	O
+to	O
+brain	O
+tissue	O
+during	O
+periods	O
+of	O
+induced	O
+hypotension	B
+.	O
+
+Triazolam	O
+-	O
+induced	O
+brief	O
+episodes	O
+of	O
+secondary	O
+mania	B
+in	O
+a	O
+depressed	B
+patient	O
+.	O
+
+Large	O
+doses	O
+of	O
+triazolam	O
+repeatedly	O
+induced	O
+brief	O
+episodes	O
+of	O
+mania	B
+in	O
+a	O
+depressed	B
+elderly	O
+woman	O
+.	O
+
+Features	O
+of	O
+organic	B
+mental	I
+disorder	I
+(	O
+delirium	B
+)	O
+were	O
+not	O
+present	O
+.	O
+
+Manic	B
+excitement	O
+was	O
+coincident	O
+with	O
+the	O
+duration	O
+of	O
+action	O
+of	O
+triazolam	O
+.	O
+
+The	O
+possible	O
+contribution	O
+of	O
+the	O
+triazolo	O
+group	O
+to	O
+changes	O
+in	O
+affective	O
+status	O
+is	O
+discussed	O
+.	O
+
+The	O
+correlation	O
+between	O
+neurotoxic	B
+esterase	O
+inhibition	O
+and	O
+mipafox	O
+-	O
+induced	O
+neuropathic	B
+damage	I
+in	O
+rats	O
+.	O
+
+The	O
+correlation	O
+between	O
+neuropathic	B
+damage	I
+and	O
+inhibition	O
+of	O
+neurotoxic	B
+esterase	O
+or	O
+neuropathy	B
+target	O
+enzyme	O
+(	O
+NTE	O
+)	O
+was	O
+examined	O
+in	O
+rats	O
+acutely	O
+exposed	O
+to	O
+Mipafox	O
+(	O
+N	O
+,	O
+N	O
+'	O
+-	O
+diisopropylphosphorodiamidofluoridate	O
+)	O
+,	O
+a	O
+neurotoxic	B
+organophosphate	O
+.	O
+
+Brain	O
+and	O
+spinal	O
+cord	O
+NTE	O
+activities	O
+were	O
+measured	O
+in	O
+Long	O
+-	O
+Evans	O
+male	O
+rats	O
+1	O
+hr	O
+post	O
+-	O
+exposure	O
+to	O
+various	O
+dosages	O
+of	O
+Mipafox	O
+(	O
+ip	O
+,	O
+1	O
+-	O
+15	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+These	O
+data	O
+were	O
+correlated	O
+with	O
+histologically	O
+scored	O
+cervical	O
+cord	B
+damage	I
+in	O
+a	O
+separate	O
+group	O
+of	O
+similarly	O
+dosed	O
+rats	O
+sampled	O
+14	O
+-	O
+21	O
+days	O
+post	O
+-	O
+exposure	O
+.	O
+
+Those	O
+dosages	O
+(	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+that	O
+inhibited	O
+mean	O
+NTE	O
+activity	O
+in	O
+the	O
+spinal	O
+cord	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+73	O
+%	O
+and	O
+brain	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+67	O
+%	O
+of	O
+control	O
+values	O
+produced	O
+severe	O
+(	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+3	O
+)	O
+cervical	O
+cord	O
+pathology	O
+in	O
+85	O
+%	O
+of	O
+the	O
+rats	O
+.	O
+
+In	O
+contrast	O
+,	O
+dosages	O
+of	O
+Mipafox	O
+(	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+which	O
+inhibited	O
+mean	O
+NTE	O
+activity	O
+in	O
+spinal	O
+cord	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+61	O
+%	O
+and	O
+brain	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+60	O
+%	O
+produced	O
+this	O
+degree	O
+of	O
+cord	B
+damage	I
+in	O
+only	O
+9	O
+%	O
+of	O
+the	O
+animals	O
+.	O
+
+These	O
+data	O
+indicate	O
+that	O
+a	O
+critical	O
+percentage	O
+of	O
+NTE	O
+inhibition	O
+in	O
+brain	O
+and	O
+spinal	O
+cord	O
+sampled	O
+shortly	O
+after	O
+Mipafox	O
+exposure	O
+can	O
+predict	O
+neuropathic	B
+damage	I
+in	O
+rats	O
+several	O
+weeks	O
+later	O
+.	O
+
+Allergic	B
+reaction	I
+to	O
+5	O
+-	O
+fluorouracil	O
+infusion	O
+.	O
+
+An	O
+allergic	B
+reaction	I
+consisting	O
+of	O
+angioneurotic	B
+edema	I
+secondary	O
+to	O
+continuous	O
+infusion	O
+5	O
+-	O
+fluorouracil	O
+occurred	O
+in	O
+a	O
+patient	O
+with	O
+recurrent	O
+carcinoma	B
+of	I
+the	I
+oral	I
+cavity	I
+,	O
+cirrhosis	B
+,	O
+and	O
+cisplatin	O
+-	O
+induced	O
+impaired	B
+renal	I
+function	I
+.	O
+
+This	O
+reaction	O
+occurred	O
+during	O
+the	O
+sixth	O
+and	O
+seventh	O
+courses	O
+of	O
+infusional	O
+chemotherapy	O
+.	O
+
+Oral	O
+diphenhydramine	O
+and	O
+prednisone	O
+were	O
+ineffective	O
+in	O
+preventing	O
+the	O
+recurrence	O
+of	O
+the	O
+allergic	B
+reaction	I
+.	O
+
+Discontinuance	O
+of	O
+effective	O
+chemotherapy	O
+in	O
+this	O
+patient	O
+during	O
+partial	O
+remission	O
+resulted	O
+in	O
+fatal	O
+disease	O
+progression	O
+.	O
+
+Myasthenia	B
+gravis	I
+caused	O
+by	O
+penicillamine	O
+and	O
+chloroquine	O
+therapy	O
+for	O
+rheumatoid	B
+arthritis	I
+.	O
+
+We	O
+have	O
+described	O
+a	O
+unique	O
+patient	O
+who	O
+had	O
+reversible	O
+and	O
+dose	O
+-	O
+related	O
+myasthenia	B
+gravis	I
+after	O
+penicillamine	O
+and	O
+chloroquine	O
+therapy	O
+for	O
+rheumatoid	B
+arthritis	I
+.	O
+
+Although	O
+acetylcholine	O
+receptor	O
+antibodies	O
+were	O
+not	O
+detectable	O
+,	O
+the	O
+time	O
+course	O
+was	O
+consistent	O
+with	O
+an	O
+autoimmune	O
+process	O
+.	O
+
+On	O
+the	O
+mechanisms	O
+of	O
+the	O
+development	O
+of	O
+tolerance	O
+to	O
+the	O
+muscular	B
+rigidity	I
+produced	O
+by	O
+morphine	O
+in	O
+rats	O
+.	O
+
+The	O
+development	O
+of	O
+tolerance	O
+to	O
+the	O
+muscular	B
+rigidity	I
+produced	O
+by	O
+morphine	O
+was	O
+studied	O
+in	O
+rats	O
+.	O
+
+Saline	O
+-	O
+pretreated	O
+controls	O
+given	O
+a	O
+test	O
+dose	O
+of	O
+morphine	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+showed	O
+a	O
+pronounced	O
+rigidity	B
+recorded	O
+as	O
+tonic	O
+activity	O
+in	O
+the	O
+electromyogram	O
+.	O
+
+Rats	O
+treated	O
+for	O
+11	O
+days	O
+with	O
+morphine	O
+and	O
+withdrawn	O
+for	O
+36	O
+-	O
+40	O
+h	O
+showed	O
+differences	O
+in	O
+the	O
+development	O
+of	O
+tolerance	O
+:	O
+about	O
+half	O
+of	O
+the	O
+animals	O
+showed	O
+a	O
+rigidity	B
+after	O
+the	O
+test	O
+dose	O
+of	O
+morphine	O
+that	O
+was	O
+not	O
+significantly	O
+less	O
+than	O
+in	O
+the	O
+controls	O
+and	O
+were	O
+akinetic	B
+(	O
+A	O
+group	O
+)	O
+.	O
+
+The	O
+other	O
+rats	O
+showed	O
+a	O
+strong	O
+decrease	O
+in	O
+the	O
+rigidity	B
+and	O
+the	O
+occurrence	O
+of	O
+stereotyped	O
+(	O
+S	O
+)	O
+licking	O
+and	O
+/	O
+or	O
+gnawing	O
+in	O
+presence	O
+of	O
+akinetic	B
+or	O
+hyperkinetic	B
+(	O
+K	O
+)	O
+behaviour	O
+(	O
+AS	O
+/	O
+KS	O
+group	O
+)	O
+,	O
+suggesting	O
+signs	O
+of	O
+dopaminergic	O
+activation	O
+.	O
+
+The	O
+rigidity	B
+was	O
+considerably	O
+decreased	O
+in	O
+both	O
+groups	O
+after	O
+20	O
+days	O
+'	O
+treatment	O
+.	O
+
+In	O
+a	O
+further	O
+series	O
+of	O
+experiments	O
+,	O
+haloperidol	O
+(	O
+0	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+was	O
+used	O
+in	O
+order	O
+to	O
+block	O
+the	O
+dopaminergic	O
+activation	O
+and	O
+to	O
+estimate	O
+the	O
+real	O
+degree	O
+of	O
+the	O
+tolerance	O
+to	O
+the	O
+rigidity	B
+without	O
+any	O
+dopaminergic	O
+interference	O
+.	O
+
+Haloperidol	O
+enhanced	O
+the	O
+rigidity	B
+in	O
+the	O
+A	O
+group	O
+.	O
+
+However	O
+,	O
+the	O
+level	O
+in	O
+the	O
+AS	O
+/	O
+KS	O
+group	O
+remained	O
+considerably	O
+lower	O
+than	O
+in	O
+the	O
+A	O
+group	O
+.	O
+
+The	O
+results	O
+suggest	O
+that	O
+rigidity	B
+,	O
+which	O
+is	O
+assumed	O
+to	O
+be	O
+due	O
+to	O
+an	O
+action	O
+of	O
+morphine	O
+in	O
+the	O
+striatum	O
+,	O
+can	O
+be	O
+antagonized	O
+by	O
+another	O
+process	O
+leading	O
+to	O
+dopaminergic	O
+activation	O
+in	O
+the	O
+striatum	O
+.	O
+
+Nevertheless	O
+,	O
+there	O
+occurs	O
+some	O
+real	O
+tolerance	O
+to	O
+this	O
+effect	O
+.	O
+
+The	O
+rapid	O
+alternations	O
+of	O
+rigidity	B
+and	O
+the	O
+signs	O
+of	O
+dopaminergic	O
+activation	O
+observed	O
+in	O
+the	O
+animals	O
+of	O
+the	O
+AS	O
+/	O
+KS	O
+group	O
+might	O
+be	O
+due	O
+to	O
+rapid	O
+shifts	O
+in	O
+the	O
+predominance	O
+of	O
+various	O
+DA	O
+-	O
+innervated	O
+structures	O
+.	O
+
+A	O
+case	O
+of	O
+massive	O
+rhabdomyolysis	B
+following	O
+molindone	O
+administration	O
+.	O
+
+Rhabdomyolysis	B
+is	O
+a	O
+potentially	O
+lethal	O
+syndrome	O
+that	O
+psychiatric	B
+patients	O
+seem	O
+predisposed	O
+to	O
+develop	O
+.	O
+
+The	O
+clinical	O
+signs	O
+and	O
+symptoms	O
+,	O
+typical	O
+laboratory	O
+features	O
+,	O
+and	O
+complications	O
+of	O
+rhabdomyolysis	B
+are	O
+presented	O
+.	O
+
+The	O
+case	O
+of	O
+a	O
+schizophrenic	B
+patient	O
+is	O
+reported	O
+to	O
+illustrate	O
+massive	O
+rhabdomyolysis	B
+and	O
+subsequent	O
+acute	B
+renal	I
+failure	I
+following	O
+molindone	O
+administration	O
+.	O
+
+Physicians	O
+who	O
+prescribe	O
+molindone	O
+should	O
+be	O
+aware	O
+of	O
+this	O
+reaction	O
+.	O
+
+Compression	B
+neuropathy	I
+of	I
+the	I
+radial	I
+nerve	I
+due	O
+to	O
+pentazocine	O
+-	O
+induced	O
+fibrous	B
+myopathy	I
+.	O
+
+Fibrous	B
+myopathy	I
+is	O
+a	O
+common	O
+,	O
+well	O
+-	O
+known	O
+side	O
+effect	O
+of	O
+repeated	O
+pentazocine	O
+injection	O
+.	O
+
+However	O
+,	O
+compression	B
+neuropathy	I
+due	O
+to	O
+fibrotic	O
+muscle	O
+affected	O
+by	O
+pentazocine	O
+-	O
+induced	O
+myopathy	B
+has	O
+not	O
+previously	O
+been	O
+reported	O
+.	O
+
+In	O
+a	O
+37	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+documented	O
+pentazocine	O
+-	O
+induced	O
+fibrous	B
+myopathy	I
+of	O
+triceps	O
+and	O
+deltoid	O
+muscles	O
+bilaterally	O
+and	O
+a	O
+three	O
+-	O
+week	O
+history	O
+of	O
+right	O
+wrist	O
+drop	O
+,	O
+electrodiagnostic	O
+examination	O
+showed	O
+a	O
+severe	O
+but	O
+partial	O
+lesion	O
+of	O
+the	O
+right	O
+radial	O
+nerve	O
+distal	O
+to	O
+the	O
+branches	O
+to	O
+the	O
+triceps	O
+,	O
+in	O
+addition	O
+to	O
+the	O
+fibrous	B
+myopathy	I
+.	O
+
+Surgery	O
+revealed	O
+the	O
+right	O
+radial	O
+nerve	O
+to	O
+be	O
+severely	O
+compressed	O
+by	O
+the	O
+densely	O
+fibrotic	O
+lateral	O
+head	O
+of	O
+the	O
+triceps	O
+.	O
+
+Decompression	O
+and	O
+neurolysis	O
+were	O
+performed	O
+with	O
+good	O
+subsequent	O
+recovery	O
+of	O
+function	O
+.	O
+
+Recurrent	O
+reversible	O
+acute	B
+renal	I
+failure	I
+from	O
+amphotericin	O
+.	O
+
+A	O
+patient	O
+with	O
+cryptogenic	O
+cirrhosis	B
+and	O
+disseminated	O
+sporotrichosis	B
+developed	O
+acute	B
+renal	I
+failure	I
+immediately	O
+following	O
+the	O
+administration	O
+of	O
+amphotericin	O
+B	O
+on	O
+four	O
+separate	O
+occasions	O
+.	O
+
+The	O
+abruptness	O
+of	O
+the	O
+renal	B
+failure	I
+and	O
+its	O
+reversibility	O
+within	O
+days	O
+suggests	O
+that	O
+there	O
+was	O
+a	O
+functional	O
+component	O
+to	O
+the	O
+renal	B
+dysfunction	I
+.	O
+
+We	O
+propose	O
+that	O
+amphotericin	O
+,	O
+in	O
+the	O
+setting	O
+of	O
+reduced	O
+effective	O
+arterial	O
+volume	O
+,	O
+may	O
+activate	O
+tubuloglomerular	O
+feedback	O
+,	O
+thereby	O
+contributing	O
+to	O
+acute	B
+renal	I
+failure	I
+.	O
+
+Cerebral	B
+infarction	I
+with	O
+a	O
+single	O
+oral	O
+dose	O
+of	O
+phenylpropanolamine	O
+.	O
+
+Phenylpropanolamine	O
+(	O
+PPA	O
+)	O
+,	O
+a	O
+synthetic	O
+sympathomimetic	O
+that	O
+is	O
+structurally	O
+similar	O
+to	O
+amphetamine	O
+,	O
+is	O
+available	O
+over	O
+the	O
+counter	O
+in	O
+anorectics	O
+,	O
+nasal	O
+congestants	O
+,	O
+and	O
+cold	O
+preparations	O
+.	O
+
+Its	O
+prolonged	O
+use	O
+or	O
+overuse	O
+has	O
+been	O
+associated	O
+with	O
+seizures	B
+,	O
+intracerebral	B
+hemorrhage	I
+,	O
+neuropsychiatric	B
+symptoms	I
+,	O
+and	O
+nonhemorrhagic	O
+cerebral	B
+infarction	I
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+young	O
+woman	O
+who	O
+suffered	O
+a	O
+cerebral	B
+infarction	I
+after	O
+taking	O
+a	O
+single	O
+oral	O
+dose	O
+of	O
+PPA	O
+.	O
+
+Remission	O
+induction	O
+of	O
+meningeal	B
+leukemia	I
+with	O
+high	O
+-	O
+dose	O
+intravenous	O
+methotrexate	O
+.	O
+
+Twenty	O
+children	O
+with	O
+acute	B
+lymphoblastic	I
+leukemia	I
+who	O
+developed	O
+meningeal	B
+disease	I
+were	O
+treated	O
+with	O
+a	O
+high	O
+-	O
+dose	O
+intravenous	O
+methotrexate	O
+regimen	O
+that	O
+was	O
+designed	O
+to	O
+achieve	O
+and	O
+maintain	O
+CSF	O
+methotrexate	O
+concentrations	O
+of	O
+10	O
+(	O
+-	O
+5	O
+)	O
+mol	O
+/	O
+L	O
+without	O
+the	O
+need	O
+for	O
+concomitant	O
+intrathecal	O
+dosing	O
+.	O
+
+The	O
+methotrexate	O
+was	O
+administered	O
+as	O
+a	O
+loading	O
+dose	O
+of	O
+6	O
+,	O
+000	O
+mg	O
+/	O
+m2	O
+for	O
+a	O
+period	O
+of	O
+one	O
+hour	O
+followed	O
+by	O
+an	O
+infusion	O
+of	O
+1	O
+,	O
+200	O
+mg	O
+/	O
+m2	O
+/	O
+h	O
+for	O
+23	O
+hours	O
+.	O
+
+Leucovorin	O
+rescue	O
+was	O
+initiated	O
+12	O
+hours	O
+after	O
+the	O
+end	O
+of	O
+the	O
+infusion	O
+with	O
+a	O
+loading	O
+dose	O
+of	O
+200	O
+mg	O
+/	O
+m2	O
+followed	O
+by	O
+12	O
+mg	O
+/	O
+m2	O
+every	O
+three	O
+hours	O
+for	O
+six	O
+doses	O
+and	O
+then	O
+every	O
+six	O
+hours	O
+until	O
+the	O
+plasma	O
+methotrexate	O
+level	O
+decreased	O
+to	O
+less	O
+than	O
+1	O
+X	O
+10	O
+(	O
+-	O
+7	O
+)	O
+mol	O
+/	O
+L	O
+.	O
+
+The	O
+mean	O
+steady	O
+-	O
+state	O
+plasma	O
+and	O
+CSF	O
+methotrexate	O
+concentrations	O
+achieved	O
+were	O
+1	O
+.	O
+1	O
+X	O
+10	O
+(	O
+-	O
+3	O
+)	O
+mol	O
+/	O
+L	O
+and	O
+3	O
+.	O
+6	O
+X	O
+10	O
+(	O
+-	O
+5	O
+)	O
+mol	O
+/	O
+L	O
+,	O
+respectively	O
+.	O
+
+All	O
+20	O
+patients	O
+responded	O
+to	O
+this	O
+regimen	O
+,	O
+16	O
+/	O
+20	O
+(	O
+80	O
+%	O
+)	O
+achieved	O
+a	O
+complete	O
+remission	O
+,	O
+and	O
+20	O
+%	O
+obtained	O
+a	O
+partial	O
+remission	O
+.	O
+
+The	O
+most	O
+common	O
+toxicities	B
+encountered	O
+were	O
+transient	O
+serum	O
+transaminase	O
+and	O
+bilirubin	O
+elevations	O
+,	O
+neutropenia	B
+,	O
+and	O
+mucositis	B
+.	O
+
+One	O
+patient	O
+had	O
+focal	O
+seizures	B
+and	O
+transient	B
+hemiparesis	I
+but	O
+recovered	O
+completely	O
+.	O
+
+High	O
+-	O
+dose	O
+intravenous	O
+methotrexate	O
+is	O
+an	O
+effective	O
+treatment	O
+for	O
+the	O
+induction	O
+of	O
+remission	O
+after	O
+meningeal	O
+relapse	O
+in	O
+acute	B
+lymphoblastic	I
+leukemia	I
+.	O
+
+Interaction	O
+of	O
+cyclosporin	O
+A	O
+with	O
+antineoplastic	O
+agents	O
+.	O
+
+A	O
+synergistic	O
+effect	O
+of	O
+etoposide	O
+and	O
+cyclosporin	O
+A	O
+was	O
+observed	O
+in	O
+a	O
+patient	O
+with	O
+acute	B
+T	I
+-	I
+lymphocytic	I
+leukemia	I
+in	O
+relapse	O
+.	O
+
+The	O
+concomitant	O
+administration	O
+of	O
+etoposide	O
+and	O
+cyclosporin	O
+A	O
+resulted	O
+in	O
+eradication	O
+of	O
+hitherto	O
+refractory	O
+leukemic	B
+infiltration	I
+of	O
+bone	O
+marrow	O
+.	O
+
+Severe	O
+side	O
+effects	O
+in	O
+terms	O
+of	O
+mental	O
+confusion	B
+and	O
+progressive	O
+hyperbilirubinemia	B
+,	O
+however	O
+,	O
+point	O
+to	O
+an	O
+enhancement	O
+not	O
+only	O
+of	O
+antineoplastic	O
+effects	O
+but	O
+also	O
+of	O
+toxicity	B
+in	O
+normal	O
+tissues	O
+.	O
+
+This	O
+report	O
+demonstrates	O
+for	O
+the	O
+first	O
+time	O
+that	O
+the	O
+pharmacodynamic	O
+properties	O
+of	O
+cyclosporin	O
+A	O
+may	O
+not	O
+be	O
+confined	O
+strictly	O
+to	O
+suppression	O
+of	O
+normal	O
+T	O
+-	O
+cell	O
+functions	O
+.	O
+
+Incidence	O
+of	O
+neoplasms	B
+in	O
+patients	O
+with	O
+rheumatoid	B
+arthritis	I
+exposed	O
+to	O
+different	O
+treatment	O
+regimens	O
+.	O
+
+Immunosuppressive	O
+drugs	O
+have	O
+been	O
+used	O
+during	O
+the	O
+last	O
+30	O
+years	O
+in	O
+treatment	O
+of	O
+patients	O
+with	O
+severe	O
+rheumatoid	B
+arthritis	I
+.	O
+
+The	O
+drugs	O
+commonly	O
+used	O
+are	O
+cyclophosphamide	O
+and	O
+chlorambucil	O
+(	O
+alkylating	O
+agents	O
+)	O
+,	O
+azathioprine	O
+(	O
+purine	O
+analogue	O
+)	O
+,	O
+and	O
+methotrexate	O
+(	O
+folic	O
+acid	O
+analogue	O
+)	O
+.	O
+
+There	O
+is	O
+evidence	O
+that	O
+all	O
+four	O
+immunosuppressive	O
+drugs	O
+can	O
+reduce	O
+synovitis	B
+,	O
+but	O
+disease	O
+activity	O
+almost	O
+always	O
+recurs	O
+after	O
+therapy	O
+is	O
+stopped	O
+.	O
+
+Since	O
+adverse	O
+reactions	O
+are	O
+frequent	O
+,	O
+less	O
+than	O
+50	O
+percent	O
+of	O
+patients	O
+are	O
+able	O
+to	O
+continue	O
+a	O
+particular	O
+drug	O
+for	O
+more	O
+than	O
+one	O
+year	O
+.	O
+
+Since	O
+it	O
+takes	O
+three	O
+to	O
+12	O
+months	O
+to	O
+achieve	O
+maximal	O
+effects	O
+,	O
+those	O
+patients	O
+who	O
+are	O
+unable	O
+to	O
+continue	O
+the	O
+drug	O
+receive	O
+little	O
+benefit	O
+from	O
+it	O
+.	O
+
+Patients	O
+treated	O
+with	O
+alkylating	O
+agents	O
+have	O
+an	O
+increased	O
+risk	O
+of	O
+development	O
+of	O
+acute	B
+nonlymphocytic	I
+leukemia	I
+,	O
+and	O
+both	O
+alkylating	O
+agents	O
+and	O
+azathioprine	O
+are	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+non	B
+-	I
+Hodgkin	I
+'	I
+s	I
+lymphoma	I
+.	O
+
+Cyclophosphamide	O
+therapy	O
+increases	O
+the	O
+risk	O
+of	O
+carcinoma	B
+of	I
+the	I
+bladder	I
+.	O
+
+There	O
+have	O
+been	O
+several	O
+long	O
+-	O
+term	O
+studies	O
+of	O
+patients	O
+with	O
+rheumatoid	B
+arthritis	I
+treated	O
+with	O
+azathioprine	O
+and	O
+cyclophosphamide	O
+and	O
+the	O
+incidence	O
+of	O
+most	O
+of	O
+the	O
+common	O
+cancers	B
+is	O
+not	O
+increased	O
+.	O
+
+Data	O
+on	O
+the	O
+possible	O
+increased	O
+risk	O
+of	O
+malignancy	B
+in	O
+rheumatoid	B
+arthritis	I
+are	O
+still	O
+being	O
+collected	O
+,	O
+and	O
+until	O
+further	O
+information	O
+is	O
+available	O
+,	O
+the	O
+use	O
+of	O
+immunosuppressive	O
+drugs	O
+,	O
+particularly	O
+alkylating	O
+agents	O
+,	O
+in	O
+the	O
+treatment	O
+of	O
+rheumatoid	B
+arthritis	I
+should	O
+be	O
+reserved	O
+for	O
+patients	O
+with	O
+severe	O
+progressive	O
+disease	O
+or	O
+life	O
+-	O
+threatening	O
+complications	O
+.	O
+
+Warfarin	O
+-	O
+induced	O
+iliopsoas	O
+hemorrhage	B
+with	O
+subsequent	O
+femoral	B
+nerve	I
+palsy	I
+.	O
+
+We	O
+present	O
+the	O
+case	O
+of	O
+a	O
+28	O
+-	O
+year	O
+-	O
+old	O
+man	O
+on	O
+chronic	O
+warfarin	O
+therapy	O
+who	O
+sustained	O
+a	O
+minor	O
+muscle	B
+tear	I
+and	O
+developed	O
+increasing	O
+pain	B
+and	O
+a	O
+flexure	O
+contracture	B
+of	O
+the	O
+right	O
+hip	O
+.	O
+
+Surgical	O
+exploration	O
+revealed	O
+an	O
+iliopsoas	O
+hematoma	B
+and	O
+femoral	O
+nerve	B
+entrapment	I
+,	O
+resulting	O
+in	O
+a	O
+femoral	B
+nerve	I
+palsy	I
+and	O
+partial	B
+loss	I
+of	I
+quadriceps	I
+functions	I
+.	O
+
+Anticoagulant	O
+-	O
+induced	O
+femoral	B
+nerve	I
+palsy	I
+represents	O
+the	O
+most	O
+common	O
+form	O
+of	O
+warfarin	O
+-	O
+induced	O
+peripheral	B
+neuropathy	I
+;	O
+it	O
+is	O
+characterized	O
+by	O
+severe	O
+pain	B
+in	O
+the	O
+inguinal	O
+region	O
+,	O
+varying	O
+degrees	O
+of	O
+motor	B
+and	I
+sensory	I
+impairment	I
+,	O
+and	O
+flexure	O
+contracture	B
+of	O
+the	O
+involved	O
+extremity	O
+.	O
+
+Pneumonitis	O
+with	O
+pleural	B
+and	I
+pericardial	I
+effusion	I
+and	O
+neuropathy	B
+during	O
+amiodarone	O
+therapy	O
+.	O
+
+A	O
+patient	O
+with	O
+sinuatrial	B
+disease	I
+and	O
+implanted	O
+pacemaker	O
+was	O
+treated	O
+with	O
+amiodarone	O
+(	O
+maximum	O
+dose	O
+1000	O
+mg	O
+,	O
+maintenance	O
+dose	O
+800	O
+mg	O
+daily	O
+)	O
+for	O
+10	O
+months	O
+,	O
+for	O
+control	O
+of	O
+supraventricular	B
+tachyarrhythmias	I
+.	O
+
+He	O
+developed	O
+pneumonitis	B
+,	O
+pleural	B
+and	I
+pericardial	I
+effusions	I
+,	O
+and	O
+a	O
+predominantly	O
+proximal	B
+motor	I
+neuropathy	I
+.	O
+
+Immediate	O
+but	O
+gradual	O
+improvement	O
+followed	O
+withdrawal	O
+of	O
+amiodarone	O
+and	O
+treatment	O
+with	O
+prednisolone	O
+.	O
+
+Review	O
+of	O
+this	O
+and	O
+previously	O
+reported	O
+cases	O
+indicates	O
+the	O
+need	O
+for	O
+early	O
+diagnosis	O
+of	O
+amiodarone	O
+pneumonitis	B
+,	O
+immediate	O
+withdrawal	O
+of	O
+amiodarone	O
+,	O
+and	O
+prompt	O
+but	O
+continued	O
+steroid	O
+therapy	O
+to	O
+ensure	O
+full	O
+recovery	O
+.	O
+
+Amiodarone	O
+-	O
+induced	O
+sinoatrial	B
+block	I
+.	O
+
+We	O
+observed	O
+sinoatrial	B
+block	I
+due	O
+to	O
+chronic	O
+amiodarone	O
+administration	O
+in	O
+a	O
+5	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+with	O
+primary	B
+cardiomyopathy	I
+,	O
+Wolff	B
+-	I
+Parkinson	I
+-	I
+White	I
+syndrome	I
+and	O
+supraventricular	B
+tachycardia	I
+.	O
+
+Reduction	O
+in	O
+the	O
+dosage	O
+of	O
+amiodarone	O
+resulted	O
+in	O
+the	O
+disappearance	O
+of	O
+the	O
+sinoatrial	B
+block	I
+and	O
+the	O
+persistence	O
+of	O
+asymptomatic	O
+sinus	B
+bradycardia	I
+.	O
+
+Desipramine	O
+-	O
+induced	O
+delirium	B
+at	O
+"	O
+subtherapeutic	O
+"	O
+concentrations	O
+:	O
+a	O
+case	O
+report	O
+.	O
+
+An	O
+elderly	O
+patient	O
+treated	O
+with	O
+low	O
+dose	O
+Desipramine	O
+developed	O
+a	O
+delirium	B
+while	O
+her	O
+plasma	O
+level	O
+was	O
+in	O
+the	O
+"	O
+subtherapeutic	O
+"	O
+range	O
+.	O
+
+Delirium	B
+,	O
+which	O
+may	O
+be	O
+induced	O
+by	O
+tricyclic	O
+drug	O
+therapy	O
+in	O
+the	O
+elderly	O
+,	O
+can	O
+be	O
+caused	O
+by	O
+tricyclics	O
+with	O
+low	O
+anticholinergic	O
+potency	O
+.	O
+
+Therapeutic	O
+ranges	O
+for	O
+antidepressants	O
+that	O
+have	O
+been	O
+derived	O
+from	O
+general	O
+adult	O
+population	O
+studies	O
+may	O
+not	O
+be	O
+appropriate	O
+for	O
+the	O
+elderly	O
+.	O
+
+Further	O
+studies	O
+of	O
+specifically	O
+elderly	O
+patients	O
+are	O
+now	O
+required	O
+to	O
+establish	O
+safer	O
+and	O
+more	O
+appropriate	O
+guidelines	O
+for	O
+drug	O
+therapy	O
+.	O
+
+Indomethacin	O
+-	O
+induced	O
+renal	B
+insufficiency	I
+:	O
+recurrence	O
+on	O
+rechallenge	O
+.	O
+
+We	O
+have	O
+reported	O
+a	O
+case	O
+of	O
+acute	O
+oliguric	O
+renal	B
+failure	I
+with	O
+hyperkalemia	B
+in	O
+a	O
+patient	O
+with	O
+cirrhosis	B
+,	O
+ascites	B
+,	O
+and	O
+cor	B
+pulmonale	I
+after	O
+indomethacin	O
+therapy	O
+.	O
+
+Prompt	O
+restoration	O
+of	O
+renal	O
+function	O
+followed	O
+drug	O
+withdrawal	O
+,	O
+while	O
+re	O
+-	O
+exposure	O
+to	O
+a	O
+single	O
+dose	O
+of	O
+indomethacin	O
+caused	O
+recurrence	O
+of	O
+acute	O
+reversible	O
+oliguria	B
+.	O
+
+Our	O
+case	O
+supports	O
+the	O
+hypothesis	O
+that	O
+endogenous	O
+renal	O
+prostaglandins	O
+play	O
+a	O
+role	O
+in	O
+the	O
+maintenance	O
+of	O
+renal	O
+blood	O
+flow	O
+when	O
+circulating	O
+plasma	O
+volume	O
+is	O
+diminished	O
+.	O
+
+Since	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+agents	O
+interfere	O
+with	O
+this	O
+compensatory	O
+mechanism	O
+and	O
+may	O
+cause	O
+acute	B
+renal	I
+failure	I
+,	O
+they	O
+should	O
+be	O
+used	O
+with	O
+caution	O
+in	O
+such	O
+patients	O
+.	O
+
+Patterns	O
+of	O
+hepatic	B
+injury	I
+induced	O
+by	O
+methyldopa	O
+.	O
+
+Twelve	O
+patients	O
+with	O
+liver	B
+disease	I
+related	O
+to	O
+methyldopa	O
+were	O
+seen	O
+between	O
+1967	O
+and	O
+1977	O
+.	O
+
+Illness	O
+occurred	O
+within	O
+1	O
+-	O
+-	O
+9	O
+weeks	O
+of	O
+commencement	O
+of	O
+therapy	O
+in	O
+9	O
+patients	O
+,	O
+the	O
+remaining	O
+3	O
+patients	O
+having	O
+received	O
+the	O
+drug	O
+for	O
+13	O
+months	O
+,	O
+15	O
+months	O
+and	O
+7	O
+years	O
+before	O
+experiencing	O
+symptoms	O
+.	O
+
+Jaundice	B
+with	O
+tender	O
+hepatomegaly	B
+,	O
+usually	O
+preceded	O
+by	O
+symptoms	O
+of	O
+malaise	O
+,	O
+anorexia	B
+,	O
+nausea	B
+and	O
+vomiting	B
+,	O
+and	O
+associated	O
+with	O
+upper	O
+abdominal	B
+pain	I
+,	O
+was	O
+an	O
+invariable	O
+finding	O
+in	O
+all	O
+patients	O
+.	O
+
+Biochemical	O
+liver	O
+function	O
+tests	O
+indicated	O
+hepatocellular	O
+necrosis	B
+and	O
+correlated	O
+with	O
+histopathological	O
+evidence	O
+of	O
+hepatic	B
+injury	I
+,	O
+the	O
+spectrum	O
+of	O
+which	O
+ranged	O
+from	O
+fatty	B
+change	I
+and	O
+focal	O
+hepatocellular	O
+necrosis	B
+to	O
+massive	B
+hepatic	I
+necrosis	I
+.	O
+
+Most	O
+patients	O
+showed	O
+moderate	O
+to	O
+severe	O
+acute	B
+hepatitis	I
+or	O
+chronic	B
+active	I
+hepatitis	I
+with	O
+associated	O
+cholestasis	B
+.	O
+
+The	O
+drug	O
+was	O
+withdrawn	O
+on	O
+presentation	O
+to	O
+hospital	O
+in	O
+11	O
+patients	O
+,	O
+with	O
+rapid	O
+clinical	O
+improvement	O
+in	O
+9	O
+.	O
+
+One	O
+patient	O
+died	O
+,	O
+having	O
+presented	O
+in	O
+hepatic	B
+failure	I
+,	O
+and	O
+another	O
+,	O
+who	O
+had	O
+been	O
+taking	O
+methyldopa	O
+for	O
+7	O
+years	O
+,	O
+showed	O
+slower	O
+clinical	O
+and	O
+biochemical	O
+resolution	O
+over	O
+a	O
+period	O
+of	O
+several	O
+months	O
+.	O
+
+The	O
+remaining	O
+patient	O
+in	O
+the	O
+series	O
+developed	O
+fulminant	B
+hepatitis	I
+when	O
+the	O
+drug	O
+was	O
+accidentally	O
+recommenced	O
+1	O
+year	O
+after	O
+a	O
+prior	O
+episode	O
+of	O
+methyldopa	O
+-	O
+induced	O
+hepatitis	B
+.	O
+
+In	O
+this	O
+latter	O
+patient	O
+,	O
+and	O
+in	O
+2	O
+others	O
+,	O
+the	O
+causal	O
+relationship	O
+between	O
+methyldopa	O
+and	O
+hepatic	B
+dysfunction	I
+was	O
+proved	O
+with	O
+the	O
+recurrence	O
+of	O
+hepatitis	B
+within	O
+2	O
+weeks	O
+of	O
+re	O
+-	O
+exposure	O
+to	O
+the	O
+drug	O
+.	O
+
+Suxamethonium	O
+infusion	O
+rate	O
+and	O
+observed	O
+fasciculations	B
+.	O
+
+A	O
+dose	O
+-	O
+response	O
+study	O
+.	O
+
+Suxamethonium	O
+chloride	O
+(	O
+Sch	O
+)	O
+was	O
+administered	O
+i	O
+.	O
+v	O
+.	O
+to	O
+36	O
+adult	O
+males	O
+at	O
+six	O
+rates	O
+:	O
+0	O
+.	O
+25	O
+mg	O
+s	O
+-	O
+1	O
+to	O
+20	O
+mg	O
+s	O
+-	O
+1	O
+.	O
+
+The	O
+infusion	O
+was	O
+discontinued	O
+either	O
+when	O
+there	O
+was	O
+no	O
+muscular	O
+response	O
+to	O
+tetanic	B
+stimulation	O
+of	O
+the	O
+ulnar	O
+nerve	O
+or	O
+when	O
+Sch	O
+120	O
+mg	O
+was	O
+exceeded	O
+.	O
+
+Six	O
+additional	O
+patients	O
+received	O
+a	O
+30	O
+-	O
+mg	O
+i	O
+.	O
+v	O
+.	O
+bolus	O
+dose	O
+.	O
+
+Fasciculations	B
+in	O
+six	O
+areas	O
+of	O
+the	O
+body	O
+were	O
+scored	O
+from	O
+0	O
+to	O
+3	O
+and	O
+summated	O
+as	O
+a	O
+total	O
+fasciculation	B
+score	O
+.	O
+
+The	O
+times	O
+to	O
+first	O
+fasciculation	B
+,	O
+twitch	B
+suppression	O
+and	O
+tetanus	B
+suppression	O
+were	O
+inversely	O
+related	O
+to	O
+the	O
+infusion	O
+rates	O
+.	O
+
+Fasciculations	B
+in	O
+the	O
+six	O
+areas	O
+and	O
+the	O
+total	O
+fasciculation	B
+score	O
+were	O
+related	O
+directly	O
+to	O
+the	O
+rate	O
+of	O
+infusion	O
+.	O
+
+Total	O
+fasciculation	B
+scores	O
+in	O
+the	O
+30	O
+-	O
+mg	O
+bolus	O
+group	O
+and	O
+the	O
+5	O
+-	O
+mg	O
+s	O
+-	O
+1	O
+and	O
+20	O
+-	O
+mg	O
+s	O
+-	O
+1	O
+infusion	O
+groups	O
+were	O
+not	O
+significantly	O
+different	O
+.	O
+
+Treatment	O
+of	O
+psoriasis	B
+with	O
+azathioprine	O
+.	O
+
+Azathioprine	O
+treatment	O
+benefited	O
+19	O
+(	O
+66	O
+%	O
+)	O
+out	O
+of	O
+29	O
+patients	O
+suffering	O
+from	O
+severe	O
+psoriasis	B
+.	O
+
+Haematological	O
+complications	O
+were	O
+not	O
+troublesome	O
+and	O
+results	O
+of	O
+biochemical	O
+liver	O
+function	O
+tests	O
+remained	O
+normal	O
+.	O
+
+Minimal	O
+cholestasis	B
+was	O
+seen	O
+in	O
+two	O
+cases	O
+and	O
+portal	O
+fibrosis	B
+of	O
+a	O
+reversible	O
+degree	O
+in	O
+eight	O
+.	O
+
+Liver	O
+biopsies	O
+should	O
+be	O
+undertaken	O
+at	O
+regular	O
+intervals	O
+if	O
+azathioprine	O
+therapy	O
+is	O
+continued	O
+so	O
+that	O
+structural	O
+liver	B
+damage	I
+may	O
+be	O
+detected	O
+at	O
+an	O
+early	O
+and	O
+reversible	O
+stage	O
+.	O
+
+Angiosarcoma	B
+of	I
+the	I
+liver	I
+associated	O
+with	O
+diethylstilbestrol	O
+.	O
+
+Angiosarcoma	B
+of	I
+the	I
+liver	I
+occurred	O
+in	O
+a	O
+76	O
+-	O
+year	O
+-	O
+old	O
+man	O
+who	O
+had	O
+been	O
+treated	O
+for	O
+a	O
+well	O
+-	O
+differentiated	O
+adenocarcinoma	B
+of	I
+the	I
+liver	I
+with	O
+diethylstilbestrol	O
+for	O
+13	O
+years	O
+.	O
+
+Angiosarcoma	B
+was	O
+also	O
+present	O
+within	O
+pulmonary	O
+and	O
+renal	O
+arteries	O
+.	O
+
+The	O
+possibility	O
+that	O
+the	O
+intraarterial	B
+lesions	I
+might	O
+represent	O
+independent	O
+primary	O
+tumors	B
+is	O
+considered	O
+.	O
+
+Galanthamine	O
+hydrobromide	O
+,	O
+a	O
+longer	O
+acting	O
+anticholinesterase	O
+drug	O
+,	O
+in	O
+the	O
+treatment	O
+of	O
+the	O
+central	O
+effects	O
+of	O
+scopolamine	O
+(	O
+Hyoscine	O
+)	O
+.	O
+
+Galanthamine	O
+hydrobromide	O
+,	O
+an	O
+anticholinesterase	O
+drug	O
+capable	O
+of	O
+penetrating	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+,	O
+was	O
+used	O
+in	O
+a	O
+patient	O
+demonstrating	O
+central	O
+effects	O
+of	O
+scopolamine	O
+(	O
+hyoscine	O
+)	O
+overdosage	B
+.	O
+
+It	O
+is	O
+longer	O
+acting	O
+than	O
+physostigmine	O
+and	O
+is	O
+used	O
+in	O
+anaesthesia	O
+to	O
+reverse	O
+the	O
+non	O
+-	O
+depolarizing	O
+neuromuscular	O
+block	O
+.	O
+
+However	O
+,	O
+studies	O
+into	O
+the	O
+dose	O
+necessary	O
+to	O
+combating	O
+scopolamine	O
+intoxication	O
+are	O
+indicated	O
+.	O
+
+Comparison	O
+of	O
+the	O
+subjective	O
+effects	O
+and	O
+plasma	O
+concentrations	O
+following	O
+oral	O
+and	O
+i	O
+.	O
+m	O
+.	O
+administration	O
+of	O
+flunitrazepam	O
+in	O
+volunteers	O
+.	O
+
+Flunitrazepam	O
+0	O
+.	O
+5	O
+,	O
+1	O
+.	O
+0	O
+or	O
+2	O
+.	O
+0	O
+mg	O
+was	O
+given	O
+by	O
+the	O
+oral	O
+or	O
+i	O
+.	O
+m	O
+.	O
+routes	O
+to	O
+groups	O
+of	O
+volunteers	O
+and	O
+its	O
+effects	O
+compared	O
+.	O
+
+Plasma	O
+concentrations	O
+of	O
+the	O
+drug	O
+were	O
+estimated	O
+by	O
+gas	O
+-	O
+liquid	O
+chromatography	O
+,	O
+in	O
+a	O
+smaller	O
+number	O
+of	O
+the	O
+subjects	O
+.	O
+
+The	O
+most	O
+striking	O
+effect	O
+was	O
+sedation	O
+which	O
+increased	O
+with	O
+the	O
+dose	O
+,	O
+2	O
+mg	O
+producing	O
+deep	O
+sleep	O
+although	O
+the	O
+subjects	O
+could	O
+still	O
+be	O
+aroused	O
+.	O
+
+The	O
+effects	O
+of	O
+i	O
+.	O
+m	O
+.	O
+administration	O
+were	O
+apparent	O
+earlier	O
+and	O
+sometimes	O
+lasted	O
+longer	O
+than	O
+those	O
+following	O
+oral	O
+administration	O
+.	O
+
+Dizziness	B
+was	O
+less	O
+marked	O
+than	O
+sedation	O
+,	O
+but	O
+increased	O
+with	O
+the	O
+dose	O
+.	O
+
+There	O
+was	O
+pain	B
+on	O
+i	O
+.	O
+m	O
+.	O
+injection	O
+of	O
+flunitrazepam	O
+significantly	O
+more	O
+often	O
+than	O
+with	O
+isotonic	O
+saline	O
+.	O
+
+Plasma	O
+concentrations	O
+varied	O
+with	O
+dose	O
+and	O
+route	O
+and	O
+corresponded	O
+qualitatively	O
+with	O
+the	O
+subjective	O
+effects	O
+.	O
+
+The	O
+drug	O
+was	O
+still	O
+present	O
+in	O
+measurable	O
+quantities	O
+after	O
+24	O
+h	O
+even	O
+with	O
+the	O
+smallest	O
+dose	O
+.	O
+
+Possible	O
+teratogenicity	O
+of	O
+sulphasalazine	O
+.	O
+
+Three	O
+infants	O
+,	O
+born	O
+of	O
+two	O
+mothers	O
+with	O
+inflammatory	B
+bowel	I
+disease	I
+who	O
+received	O
+treatment	O
+with	O
+sulphasalazine	O
+throughout	O
+pregnancy	O
+,	O
+were	O
+found	O
+to	O
+have	O
+major	O
+congenital	B
+anomalies	I
+.	O
+
+In	O
+the	O
+singleton	O
+pregnancy	O
+,	O
+the	O
+mother	O
+had	O
+ulcerative	B
+colitis	I
+,	O
+and	O
+the	O
+infant	O
+,	O
+a	O
+male	O
+,	O
+had	O
+coarctation	B
+of	I
+the	I
+aorta	I
+and	O
+a	O
+ventricular	B
+septal	I
+defect	I
+.	O
+
+In	O
+the	O
+twin	O
+pregnancy	O
+,	O
+the	O
+mother	O
+had	O
+Crohn	B
+'	I
+s	I
+disease	I
+.	O
+
+The	O
+first	O
+twin	O
+,	O
+a	O
+female	O
+,	O
+had	O
+a	O
+left	O
+Potter	B
+-	I
+type	I
+IIa	I
+polycystic	I
+kidney	I
+and	O
+a	O
+rudimentary	B
+left	I
+uterine	I
+cornu	I
+.	O
+
+The	O
+second	O
+twin	O
+,	O
+a	O
+male	O
+,	O
+had	O
+some	O
+features	O
+of	O
+Potter	B
+'	I
+s	I
+facies	I
+,	O
+hypoplastic	B
+lungs	I
+,	O
+absent	B
+kidneys	I
+and	I
+ureters	I
+,	O
+and	O
+talipes	B
+equinovarus	I
+.	O
+
+Despite	O
+reports	O
+to	O
+the	O
+contrary	O
+,	O
+it	O
+is	O
+suggested	O
+that	O
+sulphasalazine	O
+may	O
+be	O
+teratogenic	O
+.	O
+
+Thrombotic	B
+microangiopathy	I
+and	O
+renal	B
+failure	I
+associated	O
+with	O
+antineoplastic	O
+chemotherapy	O
+.	O
+
+Five	O
+patients	O
+with	O
+carcinoma	B
+developed	O
+thrombotic	B
+microangiopathy	I
+(	O
+characterized	O
+by	O
+renal	B
+insufficiency	I
+,	O
+microangiopathic	B
+hemolytic	I
+anemia	I
+,	O
+and	O
+usually	O
+thrombocytopenia	B
+)	O
+after	O
+treatment	O
+with	O
+cisplatin	O
+,	O
+bleomycin	O
+,	O
+and	O
+a	O
+vinca	O
+alkaloid	O
+.	O
+
+One	O
+patient	O
+had	O
+thrombotic	B
+thrombocytopenic	I
+purpura	I
+,	O
+three	O
+the	O
+hemolytic	B
+-	I
+uremic	I
+syndrome	I
+,	O
+and	O
+one	O
+an	O
+apparent	O
+forme	O
+fruste	O
+of	O
+one	O
+of	O
+these	O
+disorders	O
+.	O
+
+Histologic	O
+examination	O
+of	O
+the	O
+renal	O
+tissue	O
+showed	O
+evidence	O
+of	O
+intravascular	B
+coagulation	I
+,	O
+primarily	O
+affecting	O
+the	O
+small	O
+arteries	O
+,	O
+arterioles	O
+,	O
+and	O
+glomeruli	O
+.	O
+
+Because	O
+each	O
+patient	O
+was	O
+tumor	B
+-	O
+free	O
+or	O
+had	O
+only	O
+a	O
+small	O
+tumor	B
+at	O
+the	O
+onset	O
+of	O
+this	O
+syndrome	O
+,	O
+the	O
+thrombotic	B
+microangiopathy	I
+may	O
+have	O
+been	O
+induced	O
+by	O
+chemotherapy	O
+.	O
+
+Diagnosis	O
+of	O
+this	O
+potentially	O
+fatal	O
+complication	O
+may	O
+be	O
+delayed	O
+or	O
+missed	O
+if	O
+renal	O
+tissue	O
+or	O
+the	O
+peripheral	O
+blood	O
+smear	O
+is	O
+not	O
+examined	O
+,	O
+because	O
+renal	B
+failure	I
+may	O
+be	O
+ascribed	O
+to	O
+cisplatin	O
+nephrotoxicity	B
+and	O
+the	O
+anemia	B
+and	O
+thrombocytopenia	B
+to	O
+drug	O
+-	O
+induced	O
+bone	B
+marrow	I
+suppression	I
+.	O
+
+International	O
+mexiletine	O
+and	O
+placebo	O
+antiarrhythmic	O
+coronary	O
+trial	O
+:	O
+I	O
+.	O
+
+Report	O
+on	O
+arrhythmia	B
+and	O
+other	O
+findings	O
+.	O
+
+Impact	O
+Research	O
+Group	O
+.	O
+
+The	O
+antiarrhythmic	O
+effects	O
+of	O
+the	O
+sustained	O
+release	O
+form	O
+of	O
+mexiletine	O
+(	O
+Mexitil	O
+-	O
+Perlongets	O
+)	O
+were	O
+evaluated	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+placebo	O
+trial	O
+in	O
+630	O
+patients	O
+with	O
+recent	O
+documented	O
+myocardial	B
+infarction	I
+.	O
+
+The	O
+primary	O
+response	O
+variable	O
+was	O
+based	O
+on	O
+central	O
+reading	O
+of	O
+24	O
+hour	O
+ambulatory	O
+electrocardiographic	O
+recordings	O
+and	O
+was	O
+defined	O
+as	O
+the	O
+occurrence	O
+of	O
+30	O
+or	O
+more	O
+single	O
+premature	O
+ventricular	O
+complexes	O
+in	O
+any	O
+two	O
+consecutive	O
+30	O
+minute	O
+blocks	O
+or	O
+one	O
+or	O
+more	O
+runs	O
+of	O
+two	O
+or	O
+more	O
+premature	O
+ventricular	O
+complexes	O
+in	O
+the	O
+entire	O
+24	O
+hour	O
+electrocardiographic	O
+recording	O
+.	O
+
+Large	O
+differences	O
+,	O
+regarded	O
+as	O
+statistically	O
+significant	O
+,	O
+between	O
+the	O
+mexiletine	O
+and	O
+placebo	O
+groups	O
+were	O
+noted	O
+in	O
+that	O
+end	O
+point	O
+at	O
+months	O
+1	O
+and	O
+4	O
+,	O
+but	O
+only	O
+trends	O
+were	O
+observed	O
+at	O
+month	O
+12	O
+.	O
+
+These	O
+differences	O
+were	O
+observed	O
+even	O
+though	O
+the	O
+serum	O
+mexiletine	O
+levels	O
+obtained	O
+in	O
+this	O
+study	O
+were	O
+generally	O
+lower	O
+than	O
+those	O
+observed	O
+in	O
+studies	O
+that	O
+have	O
+used	O
+the	O
+regular	O
+form	O
+of	O
+the	O
+drug	O
+.	O
+
+There	O
+were	O
+more	O
+deaths	B
+in	O
+the	O
+mexiletine	O
+group	O
+(	O
+7	O
+.	O
+6	O
+%	O
+)	O
+than	O
+in	O
+the	O
+placebo	O
+group	O
+(	O
+4	O
+.	O
+8	O
+%	O
+)	O
+;	O
+the	O
+difference	O
+was	O
+not	O
+statistically	O
+significant	O
+.	O
+
+The	O
+incidence	O
+of	O
+coronary	O
+events	O
+was	O
+similar	O
+in	O
+both	O
+groups	O
+.	O
+
+Previously	O
+recognized	O
+side	O
+effects	O
+,	O
+particularly	O
+tremor	B
+and	O
+gastrointestinal	B
+problems	I
+,	O
+were	O
+more	O
+frequent	O
+in	O
+the	O
+mexiletine	O
+group	O
+than	O
+in	O
+the	O
+placebo	O
+group	O
+.	O
+
+Changes	O
+in	O
+heart	O
+size	O
+during	O
+long	O
+-	O
+term	O
+timolol	O
+treatment	O
+after	O
+myocardial	B
+infarction	I
+.	O
+
+The	O
+effect	O
+of	O
+long	O
+-	O
+term	O
+timolol	O
+treatment	O
+on	O
+heart	O
+size	O
+after	O
+myocardial	B
+infarction	I
+was	O
+evaluated	O
+by	O
+X	O
+-	O
+ray	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+study	O
+including	O
+241	O
+patients	O
+(	O
+placebo	O
+126	O
+,	O
+timolol	O
+115	O
+)	O
+.	O
+
+The	O
+follow	O
+-	O
+up	O
+period	O
+was	O
+12	O
+months	O
+.	O
+
+The	O
+timolol	O
+-	O
+treated	O
+patients	O
+showed	O
+a	O
+small	O
+but	O
+significant	O
+increase	O
+in	O
+heart	O
+size	O
+from	O
+baseline	O
+in	O
+contrast	O
+to	O
+a	O
+decrease	O
+in	O
+the	O
+placebo	O
+group	O
+.	O
+
+These	O
+differences	O
+may	O
+be	O
+caused	O
+by	O
+timolol	O
+-	O
+induced	O
+bradycardia	B
+and	O
+a	O
+compensatory	O
+increase	O
+in	O
+end	O
+-	O
+diastolic	O
+volume	O
+.	O
+
+The	O
+timolol	O
+-	O
+related	O
+increase	O
+in	O
+heart	O
+size	O
+was	O
+observed	O
+only	O
+in	O
+patients	O
+with	O
+normal	O
+and	O
+borderline	O
+heart	O
+size	O
+.	O
+
+In	O
+patients	O
+with	O
+cardiomegaly	B
+,	O
+the	O
+increase	O
+in	O
+heart	O
+size	O
+was	O
+similar	O
+in	O
+both	O
+groups	O
+.	O
+
+After	O
+re	O
+-	O
+infarction	B
+,	O
+heart	O
+size	O
+increased	O
+in	O
+the	O
+placebo	O
+group	O
+and	O
+remained	O
+unchanged	O
+in	O
+the	O
+timolol	O
+group	O
+.	O
+
+Vitamin	O
+D3	O
+toxicity	B
+in	O
+dairy	O
+cows	O
+.	O
+
+Large	O
+parenteral	O
+doses	O
+of	O
+vitamin	O
+D3	O
+(	O
+15	O
+to	O
+17	O
+.	O
+5	O
+x	O
+10	O
+(	O
+6	O
+)	O
+IU	O
+vitamin	O
+D3	O
+)	O
+were	O
+associated	O
+with	O
+prolonged	O
+hypercalcemia	B
+,	O
+hyperphosphatemia	B
+,	O
+and	O
+large	O
+increases	O
+of	O
+vitamin	O
+D3	O
+and	O
+its	O
+metabolites	O
+in	O
+the	O
+blood	O
+plasma	O
+of	O
+nonlactating	O
+nonpregnant	O
+and	O
+pregnant	O
+Jersey	O
+cows	O
+.	O
+
+Calcium	O
+concentrations	O
+1	O
+day	O
+postpartum	O
+were	O
+higher	O
+in	O
+cows	O
+treated	O
+with	O
+vitamin	O
+D3	O
+about	O
+32	O
+days	O
+prepartum	O
+(	O
+8	O
+.	O
+8	O
+mg	O
+/	O
+100	O
+ml	O
+)	O
+than	O
+in	O
+control	O
+cows	O
+(	O
+5	O
+.	O
+5	O
+mg	O
+/	O
+100	O
+ml	O
+)	O
+.	O
+
+None	O
+of	O
+the	O
+cows	O
+treated	O
+with	O
+vitamin	O
+D3	O
+showed	O
+signs	O
+of	O
+milk	B
+fever	I
+during	O
+the	O
+peripartal	O
+period	O
+;	O
+however	O
+,	O
+22	O
+%	O
+of	O
+the	O
+control	O
+cows	O
+developed	O
+clinical	O
+signs	O
+of	O
+milk	B
+fever	I
+during	O
+this	O
+period	O
+.	O
+
+Signs	O
+of	O
+vitamin	O
+D3	O
+toxicity	B
+were	O
+not	O
+observed	O
+in	O
+nonlactating	O
+nonpregnant	O
+cows	O
+;	O
+however	O
+,	O
+pregnant	O
+cows	O
+commonly	O
+developed	O
+severe	O
+signs	O
+of	O
+vitamin	O
+D3	O
+toxicity	B
+and	O
+10	O
+of	O
+17	O
+cows	O
+died	O
+.	O
+
+There	O
+was	O
+widespread	O
+metastatic	O
+calcification	O
+in	O
+the	O
+cows	O
+that	O
+died	O
+.	O
+
+Because	O
+of	O
+the	O
+extreme	O
+toxicity	B
+of	O
+vitamin	O
+D3	O
+in	O
+pregnant	O
+Jersey	O
+cows	O
+and	O
+the	O
+low	O
+margin	O
+of	O
+safety	O
+between	O
+doses	O
+of	O
+vitamin	O
+D3	O
+that	O
+prevent	O
+milk	B
+fever	I
+and	O
+doses	O
+that	O
+induce	O
+milk	B
+fever	I
+,	O
+we	O
+concluded	O
+that	O
+vitamin	O
+D3	O
+cannot	O
+be	O
+used	O
+practically	O
+to	O
+prevent	O
+milk	B
+fever	I
+when	O
+injected	O
+several	O
+weeks	O
+prepartum	O
+.	O
+
+Diseases	B
+of	I
+peripheral	I
+nerves	I
+as	O
+seen	O
+in	O
+the	O
+Nigerian	O
+African	O
+.	O
+
+The	O
+anatomical	O
+and	O
+aetiological	O
+diagnoses	O
+of	O
+peripheral	B
+nerve	I
+disease	I
+excluding	O
+its	O
+primary	O
+benign	O
+and	O
+malignant	O
+disorders	O
+,	O
+as	O
+seen	O
+in	O
+358	O
+Nigerians	O
+are	O
+presented	O
+.	O
+
+There	O
+is	O
+a	O
+male	O
+preponderance	O
+and	O
+the	O
+peak	O
+incidence	O
+is	O
+in	O
+the	O
+fourth	O
+decade	O
+.	O
+
+Sensori	B
+-	I
+motor	I
+neuropathy	I
+was	O
+the	O
+commonest	O
+presentation	O
+(	O
+50	O
+%	O
+)	O
+.	O
+
+Guillain	B
+-	I
+Barr	I
+syndrome	I
+was	O
+the	O
+commonest	O
+identifiable	O
+cause	O
+(	O
+15	O
+.	O
+6	O
+%	O
+)	O
+,	O
+accounting	O
+for	O
+half	O
+of	O
+the	O
+cases	O
+with	O
+motor	B
+neuropathy	I
+.	O
+
+Peripheral	B
+neuropathy	I
+due	O
+to	O
+nutritional	B
+deficiency	I
+of	O
+thiamine	O
+and	O
+riboflavin	O
+was	O
+common	O
+(	O
+10	O
+.	O
+1	O
+%	O
+)	O
+and	O
+presented	O
+mainly	O
+as	O
+sensory	O
+and	O
+sensori	B
+-	I
+motor	I
+neuropathy	I
+.	O
+
+Diabetes	B
+mellitus	I
+was	O
+the	O
+major	O
+cause	O
+of	O
+autonomic	B
+neuropathy	I
+.	O
+
+Isoniazid	O
+was	O
+the	O
+most	O
+frequent	O
+agent	O
+in	O
+drug	O
+-	O
+induced	O
+neuropathy	B
+.	O
+
+Migraine	B
+(	O
+20	O
+%	O
+)	O
+was	O
+not	O
+an	O
+uncommon	O
+cause	O
+of	O
+cranial	B
+neuropathy	I
+although	O
+malignancies	B
+arising	O
+from	O
+the	O
+reticuloendothelial	O
+system	O
+or	O
+related	O
+structures	O
+of	O
+the	O
+head	O
+and	O
+neck	O
+were	O
+more	O
+frequent	O
+(	O
+26	O
+%	O
+)	O
+.	O
+
+In	O
+26	O
+.	O
+5	O
+%	O
+of	O
+all	O
+the	O
+cases	O
+,	O
+the	O
+aetiology	O
+of	O
+the	O
+neuropathy	B
+was	O
+undetermined	O
+.	O
+
+Heredofamilial	O
+and	O
+connective	B
+tissue	I
+disorders	I
+were	O
+rare	O
+.	O
+
+Some	O
+of	O
+the	O
+factors	O
+related	O
+to	O
+the	O
+clinical	O
+presentation	O
+and	O
+pathogenesis	O
+of	O
+the	O
+neuropathies	B
+are	O
+briefly	O
+discussed	O
+.	O
+
+Reduction	O
+in	O
+caffeine	O
+toxicity	B
+by	O
+acetaminophen	O
+.	O
+
+A	O
+patient	O
+who	O
+allegedly	O
+consumed	O
+100	O
+tablets	O
+of	O
+an	O
+over	O
+-	O
+the	O
+-	O
+counter	O
+analgesic	O
+containing	O
+sodium	O
+acetylsalicylate	O
+,	O
+caffeine	O
+,	O
+and	O
+acetaminophen	O
+displayed	O
+no	O
+significant	O
+CNS	O
+stimulation	O
+despite	O
+the	O
+presence	O
+of	O
+175	O
+micrograms	O
+of	O
+caffeine	O
+per	O
+mL	O
+of	O
+serum	O
+.	O
+
+Because	O
+salicylates	O
+have	O
+been	O
+reported	O
+to	O
+augment	O
+the	O
+stimulatory	O
+effects	O
+of	O
+caffeine	O
+on	O
+the	O
+CNS	O
+,	O
+attention	O
+was	O
+focused	O
+on	O
+the	O
+possibility	O
+that	O
+the	O
+presence	O
+of	O
+acetaminophen	O
+(	O
+52	O
+micrograms	O
+/	O
+mL	O
+)	O
+reduced	O
+the	O
+CNS	O
+toxicity	B
+of	O
+caffeine	O
+.	O
+
+Studies	O
+in	O
+DBA	O
+/	O
+2J	O
+mice	O
+showed	O
+that	O
+:	O
+1	O
+)	O
+pretreatment	O
+with	O
+acetaminophen	O
+(	O
+100	O
+mg	O
+/	O
+kg	O
+)	O
+increased	O
+the	O
+interval	O
+between	O
+the	O
+administration	O
+of	O
+caffeine	O
+(	O
+300	O
+to	O
+450	O
+mg	O
+/	O
+kg	O
+IP	O
+)	O
+and	O
+the	O
+onset	O
+of	O
+fatal	O
+convulsions	B
+by	O
+a	O
+factor	O
+of	O
+about	O
+two	O
+;	O
+and	O
+2	O
+)	O
+pretreatment	O
+with	O
+acetaminophen	O
+(	O
+75	O
+mg	O
+/	O
+kg	O
+)	O
+reduced	O
+the	O
+incidence	O
+of	O
+audiogenic	O
+seizures	B
+produced	O
+in	O
+the	O
+presence	O
+of	O
+caffeine	O
+(	O
+12	O
+.	O
+5	O
+to	O
+75	O
+mg	O
+/	O
+kg	O
+IP	O
+)	O
+.	O
+
+The	O
+frequency	O
+of	O
+sound	O
+-	O
+induced	O
+seizures	B
+after	O
+12	O
+.	O
+5	O
+or	O
+25	O
+mg	O
+/	O
+kg	O
+caffeine	O
+was	O
+reduced	O
+from	O
+50	O
+to	O
+5	O
+%	O
+by	O
+acetaminophen	O
+.	O
+
+In	O
+the	O
+absence	O
+of	O
+caffeine	O
+,	O
+acetaminophen	O
+(	O
+up	O
+to	O
+300	O
+mg	O
+/	O
+kg	O
+)	O
+did	O
+not	O
+modify	O
+the	O
+seizures	B
+induced	O
+by	O
+maximal	O
+electroshock	O
+and	O
+did	O
+not	O
+alter	O
+the	O
+convulsant	O
+dose	O
+of	O
+pentylenetetrezol	O
+in	O
+mice	O
+(	O
+tests	O
+performed	O
+by	O
+the	O
+Anticonvulsant	O
+Screening	O
+Project	O
+of	O
+NINCDS	O
+)	O
+.	O
+
+Acetaminophen	O
+(	O
+up	O
+to	O
+150	O
+micrograms	O
+/	O
+mL	O
+)	O
+did	O
+not	O
+retard	O
+the	O
+incorporation	O
+of	O
+radioactive	O
+adenosine	O
+into	O
+ATP	O
+in	O
+slices	O
+of	O
+rat	O
+cerebral	O
+cortex	O
+.	O
+
+Thus	O
+the	O
+mechanism	O
+by	O
+which	O
+acetaminophen	O
+antagonizes	O
+the	O
+actions	O
+of	O
+caffeine	O
+in	O
+the	O
+CNS	O
+remains	O
+unknown	O
+.	O
+
+A	O
+double	O
+-	O
+blind	O
+study	O
+of	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+dothiepin	O
+hydrochloride	O
+in	O
+the	O
+treatment	O
+of	O
+major	O
+depressive	B
+disorder	I
+.	O
+
+In	O
+a	O
+6	O
+-	O
+week	O
+double	O
+-	O
+blind	O
+parallel	O
+treatment	O
+study	O
+,	O
+dothiepin	O
+and	O
+amitriptyline	O
+were	O
+compared	O
+to	O
+placebo	O
+in	O
+the	O
+treatment	O
+of	O
+33	O
+depressed	B
+outpatients	O
+.	O
+
+Dothiepin	O
+and	O
+amitriptyline	O
+were	O
+equally	O
+effective	O
+in	O
+alleviating	O
+the	O
+symptoms	O
+of	O
+depressive	B
+illness	I
+,	O
+and	O
+both	O
+were	O
+significantly	O
+superior	O
+to	O
+placebo	O
+.	O
+
+The	O
+overall	O
+incidence	O
+of	O
+side	O
+effects	O
+and	O
+the	O
+frequency	O
+and	O
+severity	O
+of	O
+blurred	B
+vision	I
+,	O
+dry	B
+mouth	I
+,	O
+and	O
+drowsiness	O
+were	O
+significantly	O
+less	O
+with	O
+dothiepin	O
+than	O
+with	O
+amitriptyline	O
+.	O
+
+Dothiepin	O
+also	O
+produced	O
+fewer	O
+CNS	O
+and	O
+cardiovascular	O
+effects	O
+.	O
+
+There	O
+were	O
+no	O
+clinically	O
+important	O
+changes	O
+in	O
+laboratory	O
+parameters	O
+.	O
+
+Dothiepin	O
+thus	O
+was	O
+found	O
+to	O
+be	O
+an	O
+effective	O
+antidepressant	O
+drug	O
+associated	O
+with	O
+fewer	O
+side	O
+effects	O
+than	O
+amitriptyline	O
+in	O
+the	O
+treatment	O
+of	O
+depressed	B
+outpatients	O
+.	O
+
+Behavioral	O
+effects	O
+of	O
+diazepam	O
+and	O
+propranolol	O
+in	O
+patients	O
+with	O
+panic	B
+disorder	I
+and	O
+agoraphobia	B
+.	O
+
+The	O
+effects	O
+of	O
+oral	O
+doses	O
+of	O
+diazepam	O
+(	O
+single	O
+dose	O
+of	O
+10	O
+mg	O
+and	O
+a	O
+median	O
+dose	O
+of	O
+30	O
+mg	O
+/	O
+day	O
+for	O
+2	O
+weeks	O
+)	O
+and	O
+propranolol	O
+(	O
+single	O
+dose	O
+of	O
+80	O
+mg	O
+and	O
+a	O
+median	O
+dose	O
+of	O
+240	O
+mg	O
+/	O
+day	O
+for	O
+2	O
+weeks	O
+)	O
+on	O
+psychological	O
+performance	O
+of	O
+patients	O
+with	O
+panic	B
+disorders	I
+and	O
+agoraphobia	B
+were	O
+investigated	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+,	O
+randomized	O
+and	O
+crossover	O
+design	O
+.	O
+
+Both	O
+drugs	O
+impaired	B
+immediate	I
+free	I
+recall	I
+but	O
+the	O
+decrease	O
+was	O
+greater	O
+for	O
+diazepam	O
+than	O
+propranolol	O
+.	O
+
+Delayed	B
+free	I
+recall	I
+was	I
+also	I
+impaired	I
+but	O
+the	O
+two	O
+drugs	O
+did	O
+not	O
+differ	O
+.	O
+
+Patients	O
+tapped	O
+faster	O
+after	O
+propranolol	O
+than	O
+diazepam	O
+and	O
+they	O
+were	O
+more	O
+sedated	O
+after	O
+diazepam	O
+than	O
+propranolol	O
+.	O
+
+After	O
+2	O
+weeks	O
+of	O
+treatment	O
+,	O
+patients	O
+tested	O
+5	O
+-	O
+8	O
+h	O
+after	O
+the	O
+last	O
+dose	O
+of	O
+medication	O
+did	O
+not	O
+show	O
+any	O
+decrement	O
+of	O
+performance	O
+.	O
+
+These	O
+results	O
+are	O
+similar	O
+to	O
+those	O
+previously	O
+found	O
+in	O
+healthy	O
+subjects	O
+.	O
+
+Accumulation	O
+of	O
+drugs	O
+was	O
+not	O
+reflected	O
+in	O
+prolonged	O
+behavioral	B
+impairment	I
+.	O
+
+Comparison	O
+of	O
+i	O
+.	O
+v	O
+.	O
+glycopyrrolate	O
+and	O
+atropine	O
+in	O
+the	O
+prevention	O
+of	O
+bradycardia	B
+and	O
+arrhythmias	B
+following	O
+repeated	O
+doses	O
+of	O
+suxamethonium	O
+in	O
+children	O
+.	O
+
+The	O
+effectiveness	O
+of	O
+administration	O
+of	O
+glycopyrrolate	O
+5	O
+and	O
+10	O
+micrograms	O
+kg	O
+-	O
+1	O
+and	O
+atropine	O
+10	O
+and	O
+20	O
+micrograms	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+v	O
+.	O
+immediately	O
+before	O
+the	O
+induction	O
+of	O
+anaesthesia	O
+,	O
+to	O
+prevent	O
+arrhythmia	B
+and	O
+bradycardia	B
+following	O
+repeated	O
+doses	O
+of	O
+suxamethonium	O
+in	O
+children	O
+,	O
+was	O
+studied	O
+.	O
+
+A	O
+control	O
+group	O
+was	O
+included	O
+for	O
+comparison	O
+with	O
+the	O
+lower	O
+dose	O
+range	O
+of	O
+glycopyrrolate	O
+and	O
+atropine	O
+.	O
+
+A	O
+frequency	O
+of	O
+bradycardia	B
+of	O
+50	O
+%	O
+was	O
+noted	O
+in	O
+the	O
+control	O
+group	O
+,	O
+but	O
+this	O
+was	O
+not	O
+significantly	O
+different	O
+from	O
+the	O
+frequency	O
+with	O
+the	O
+active	O
+drugs	O
+.	O
+
+Bradycardia	B
+(	O
+defined	O
+as	O
+a	O
+decrease	O
+in	O
+heart	O
+rate	O
+to	O
+less	O
+than	O
+50	O
+beat	O
+min	O
+-	O
+1	O
+)	O
+was	O
+prevented	O
+when	O
+the	O
+larger	O
+dose	O
+of	O
+either	O
+active	O
+drug	O
+was	O
+used	O
+.	O
+
+It	O
+is	O
+recommended	O
+that	O
+either	O
+glycopyrrolate	O
+10	O
+micrograms	O
+kg	O
+-	O
+1	O
+or	O
+atropine	O
+20	O
+micrograms	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+v	O
+.	O
+should	O
+immediately	O
+precede	O
+induction	O
+of	O
+anaesthesia	O
+,	O
+in	O
+children	O
+,	O
+if	O
+the	O
+repeated	O
+administration	O
+of	O
+suxamethonium	O
+is	O
+anticipated	O
+.	O
+
+Veno	B
+-	I
+occlusive	I
+liver	I
+disease	I
+after	O
+dacarbazine	O
+therapy	O
+(	O
+DTIC	O
+)	O
+for	O
+melanoma	B
+.	O
+
+A	O
+case	O
+of	O
+veno	B
+-	I
+occlusive	I
+disease	I
+of	I
+the	I
+liver	I
+with	O
+fatal	O
+outcome	O
+after	O
+dacarbazine	O
+(	O
+DTIC	O
+)	O
+therapy	O
+for	O
+melanoma	B
+is	O
+reported	O
+.	O
+
+There	O
+was	O
+a	O
+fulminant	O
+clinical	O
+course	O
+from	O
+start	O
+of	O
+symptoms	O
+until	O
+death	B
+.	O
+
+At	O
+autopsy	O
+the	O
+liver	O
+was	O
+enlarged	O
+and	O
+firm	O
+with	O
+signs	O
+of	O
+venous	B
+congestion	I
+.	O
+
+Small	O
+-	O
+and	O
+medium	O
+-	O
+sized	O
+hepatic	O
+veins	O
+were	O
+blocked	O
+by	O
+thrombosis	B
+.	O
+
+Eosinophilic	O
+infiltrations	O
+were	O
+found	O
+around	O
+the	O
+vessels	O
+.	O
+
+Published	O
+cases	O
+from	O
+the	O
+literature	O
+are	O
+reviewed	O
+and	O
+pertinent	O
+features	O
+discussed	O
+.	O
+
+Maternal	O
+lithium	O
+and	O
+neonatal	O
+Ebstein	B
+'	I
+s	I
+anomaly	I
+:	O
+evaluation	O
+with	O
+cross	O
+-	O
+sectional	O
+echocardiography	O
+.	O
+
+Cross	O
+-	O
+sectional	O
+echocardiography	O
+was	O
+used	O
+to	O
+evaluate	O
+two	O
+neonates	O
+whose	O
+mothers	O
+ingested	O
+lithium	O
+during	O
+pregnancy	O
+.	O
+
+In	O
+one	O
+infant	O
+,	O
+Ebstein	B
+'	I
+s	I
+anomaly	I
+of	O
+the	O
+tricuspid	O
+valve	O
+was	O
+identified	O
+.	O
+
+In	O
+the	O
+other	O
+infant	O
+cross	O
+-	O
+sectional	O
+echocardiography	O
+provided	O
+reassurance	O
+that	O
+the	O
+infant	O
+did	O
+not	O
+have	O
+Ebstein	B
+'	I
+s	I
+anomaly	I
+.	O
+
+Cross	O
+-	O
+sectional	O
+echocardiographic	O
+screening	O
+of	O
+newborns	O
+exposed	O
+to	O
+lithium	O
+during	O
+gestation	O
+can	O
+provide	O
+highly	O
+accurate	O
+,	O
+noninvasive	O
+assessment	O
+of	O
+the	O
+presence	O
+or	O
+absence	O
+of	O
+lithium	O
+-	O
+induced	O
+cardiac	B
+malformations	I
+.	O
+
+Effects	O
+of	O
+training	O
+on	O
+the	O
+extent	O
+of	O
+experimental	O
+myocardial	B
+infarction	I
+in	O
+aging	O
+rats	O
+.	O
+
+The	O
+effects	O
+of	O
+exercise	O
+on	O
+the	O
+severity	O
+of	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+were	O
+studied	O
+in	O
+female	O
+albino	O
+rats	O
+of	O
+20	O
+,	O
+40	O
+,	O
+60	O
+and	O
+80	O
+weeks	O
+of	O
+age	O
+.	O
+
+The	O
+rats	O
+were	O
+trained	O
+to	O
+swim	O
+for	O
+a	O
+specific	O
+duration	O
+and	O
+for	O
+a	O
+particular	O
+period	O
+.	O
+
+The	O
+occurrence	O
+of	O
+infarcts	B
+were	O
+confirmed	O
+by	O
+histological	O
+methods	O
+.	O
+
+Elevations	O
+in	O
+the	O
+serum	O
+GOT	O
+and	O
+GPT	O
+were	O
+maximum	O
+in	O
+the	O
+sedentary	O
+-	O
+isoproterenols	O
+and	O
+minimum	O
+in	O
+the	O
+exercise	O
+-	O
+controls	O
+.	O
+
+These	O
+changes	O
+in	O
+the	O
+serum	O
+transaminases	O
+were	O
+associated	O
+with	O
+corresponding	O
+depletions	O
+in	O
+the	O
+cardiac	O
+GOT	O
+and	O
+GPT	O
+.	O
+
+However	O
+,	O
+age	O
+was	O
+seen	O
+to	O
+interfere	O
+with	O
+the	O
+responses	O
+exhibited	O
+by	O
+the	O
+young	O
+and	O
+old	O
+rats	O
+.	O
+
+Studies	O
+dealing	O
+with	O
+myocardial	B
+infarction	I
+are	O
+more	O
+informative	O
+when	O
+dealt	O
+with	O
+age	O
+.	O
+
+Effect	O
+of	O
+polyethylene	O
+glycol	O
+400	O
+on	O
+adriamycin	O
+toxicity	B
+in	O
+mice	O
+.	O
+
+The	O
+effect	O
+of	O
+a	O
+widely	O
+used	O
+organic	O
+solvent	O
+,	O
+polyethylene	O
+glycol	O
+400	O
+(	O
+PEG	O
+400	O
+)	O
+,	O
+on	O
+the	O
+toxic	O
+action	O
+of	O
+an	O
+acute	O
+or	O
+chronic	O
+treatment	O
+with	O
+adriamycin	O
+(	O
+ADR	O
+)	O
+was	O
+evaluated	O
+in	O
+mice	O
+.	O
+
+PEG	O
+400	O
+impressively	O
+decreased	O
+both	O
+acute	O
+high	O
+-	O
+dose	O
+and	O
+chronic	O
+low	O
+-	O
+dose	O
+-	O
+ADR	O
+-	O
+associated	O
+lethality	O
+.	O
+
+Light	O
+microscopic	O
+analysis	O
+showed	O
+a	O
+significant	O
+protection	O
+against	O
+ADR	O
+-	O
+induced	O
+cardiac	B
+morphological	I
+alterations	I
+.	O
+
+Such	O
+treatment	O
+did	O
+not	O
+diminish	O
+the	O
+ADR	O
+antitumor	O
+activity	O
+in	O
+L1210	B
+leukemia	I
+and	O
+in	O
+Ehrlich	B
+ascites	I
+tumor	I
+.	O
+
+Sublingual	O
+absorption	O
+of	O
+the	O
+quaternary	O
+ammonium	O
+antiarrhythmic	O
+agent	O
+,	O
+UM	O
+-	O
+272	O
+.	O
+
+UM	O
+-	O
+272	O
+(	O
+N	O
+,	O
+N	O
+-	O
+dimethylpropranolol	O
+)	O
+,	O
+a	O
+quaternary	O
+antiarrhythmic	O
+agent	O
+,	O
+was	O
+administered	O
+sublingually	O
+to	O
+dogs	O
+with	O
+ouabain	O
+-	O
+induced	O
+ventricular	B
+tachycardias	I
+.	O
+
+Both	O
+anti	O
+-	O
+arrhythmic	O
+efficacy	O
+and	O
+bioavailability	O
+were	O
+compared	O
+to	O
+oral	O
+drug	O
+.	O
+
+Sublingual	O
+UM	O
+-	O
+272	O
+converted	O
+ventricular	B
+tachycardia	I
+to	O
+sinus	O
+rhythm	O
+in	O
+all	O
+5	O
+dogs	O
+.	O
+
+The	O
+area	O
+under	O
+the	O
+plasma	O
+concentration	O
+time	O
+curve	O
+at	O
+90	O
+min	O
+was	O
+4	O
+-	O
+12	O
+times	O
+greater	O
+than	O
+for	O
+oral	O
+drug	O
+,	O
+suggesting	O
+the	O
+existence	O
+of	O
+an	O
+absorption	O
+-	O
+limiting	O
+process	O
+in	O
+the	O
+intestine	O
+,	O
+and	O
+providing	O
+an	O
+alternate	O
+form	O
+of	O
+administration	O
+for	O
+quaternary	O
+drugs	O
+.	O
+
+Early	O
+adjuvant	O
+adriamycin	O
+in	O
+superficial	O
+bladder	B
+carcinoma	I
+.	O
+
+A	O
+multicenter	O
+study	O
+was	O
+performed	O
+in	O
+110	O
+patients	O
+with	O
+superficial	O
+transitional	O
+cell	O
+carcinoma	B
+of	I
+the	I
+bladder	I
+.	O
+
+Adriamycin	O
+(	O
+50	O
+mg	O
+/	O
+50	O
+ml	O
+)	O
+was	O
+administered	O
+intravesically	O
+within	O
+24	O
+h	O
+after	O
+transurethral	O
+resection	O
+of	O
+TA	O
+-	O
+T1	O
+(	O
+O	O
+-	O
+A	O
+)	O
+bladder	B
+tumors	I
+.	O
+
+Instillation	O
+was	O
+repeated	O
+twice	O
+during	O
+the	O
+first	O
+week	O
+,	O
+then	O
+weekly	O
+during	O
+the	O
+first	O
+month	O
+and	O
+afterwards	O
+monthly	O
+for	O
+1	O
+year	O
+.	O
+
+The	O
+tolerance	O
+was	O
+evaluated	O
+in	O
+these	O
+110	O
+patients	O
+,	O
+and	O
+29	O
+patients	O
+presented	O
+with	O
+local	O
+side	O
+-	O
+effects	O
+.	O
+
+In	O
+24	O
+of	O
+these	O
+patients	O
+chemical	O
+cystitis	B
+was	O
+severe	O
+enough	O
+for	O
+them	O
+to	O
+drop	O
+out	O
+of	O
+the	O
+study	O
+.	O
+
+No	O
+systemic	O
+side	O
+-	O
+effects	O
+were	O
+observed	O
+.	O
+
+Recurrence	O
+was	O
+studied	O
+in	O
+82	O
+evaluable	O
+patients	O
+after	O
+1	O
+year	O
+of	O
+follow	O
+-	O
+up	O
+and	O
+in	O
+72	O
+patients	O
+followed	O
+for	O
+2	O
+-	O
+3	O
+years	O
+(	O
+mean	O
+32	O
+months	O
+)	O
+.	O
+
+Of	O
+the	O
+82	O
+patients	O
+studied	O
+after	O
+1	O
+year	O
+,	O
+23	O
+had	O
+primary	O
+and	O
+59	O
+recurrent	O
+disease	O
+.	O
+
+Of	O
+the	O
+82	O
+evaluable	O
+patients	O
+,	O
+50	O
+did	O
+not	O
+show	O
+any	O
+recurrence	O
+after	O
+1	O
+year	O
+(	O
+61	O
+%	O
+)	O
+,	O
+while	O
+32	O
+presented	O
+with	O
+one	O
+or	O
+more	O
+recurrences	O
+(	O
+39	O
+%	O
+)	O
+.	O
+
+Of	O
+these	O
+recurrences	O
+,	O
+27	O
+were	O
+T1	O
+tumors	B
+while	O
+five	O
+progressed	O
+to	O
+more	O
+highly	O
+invasive	O
+lesions	O
+.	O
+
+In	O
+patients	O
+that	O
+were	O
+free	O
+of	O
+recurrence	O
+during	O
+the	O
+first	O
+year	O
+,	O
+80	O
+%	O
+remained	O
+tumor	B
+-	O
+free	O
+during	O
+the	O
+2	O
+-	O
+to	O
+3	O
+-	O
+year	O
+follow	O
+-	O
+up	O
+period	O
+.	O
+
+Of	O
+the	O
+patients	O
+developing	O
+one	O
+or	O
+more	O
+recurrences	O
+during	O
+the	O
+first	O
+year	O
+,	O
+only	O
+50	O
+%	O
+presented	O
+with	O
+further	O
+recurrence	O
+once	O
+the	O
+instillations	O
+were	O
+stopped	O
+.	O
+
+The	O
+beneficial	O
+effect	O
+of	O
+Adriamycin	O
+appears	O
+obvious	O
+and	O
+might	O
+be	O
+related	O
+to	O
+the	O
+drug	O
+itself	O
+,	O
+the	O
+early	O
+and	O
+repeated	O
+instillations	O
+after	O
+TUR	O
+,	O
+or	O
+both	O
+.	O
+
+D	O
+-	O
+penicillamine	O
+-	O
+induced	O
+angiopathy	B
+in	O
+rats	O
+.	O
+
+The	O
+effect	O
+of	O
+high	O
+dose	O
+D	O
+-	O
+penicillamine	O
+treatment	O
+on	O
+aortic	O
+permeability	O
+to	O
+albumin	O
+and	O
+on	O
+the	O
+ultrastructure	O
+of	O
+the	O
+vessel	O
+.	O
+
+Male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+were	O
+treated	O
+with	O
+D	O
+-	O
+penicillamine	O
+(	O
+D	O
+-	O
+pen	O
+)	O
+500	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+for	O
+10	O
+or	O
+42	O
+days	O
+.	O
+
+Pair	O
+fed	O
+rats	O
+served	O
+as	O
+controls	O
+.	O
+
+Changes	O
+in	O
+aortic	O
+morphology	O
+were	O
+examined	O
+by	O
+light	O
+-	O
+and	O
+transmission	O
+-	O
+electron	O
+microscopy	O
+(	O
+TEM	O
+)	O
+.	O
+
+In	O
+addition	O
+,	O
+the	O
+endothelial	O
+permeability	O
+and	O
+the	O
+penetration	O
+through	O
+the	O
+aortic	O
+wall	O
+of	O
+albumin	O
+were	O
+studied	O
+10	O
+minutes	O
+,	O
+24	O
+and	O
+48	O
+hours	O
+after	O
+i	O
+.	O
+v	O
+.	O
+injection	O
+of	O
+human	O
+serum	O
+131I	O
+-	O
+albumin	O
+(	O
+131I	O
+-	O
+HSA	O
+)	O
+.	O
+
+TEM	O
+revealed	O
+extensive	O
+elastolysis	O
+in	O
+the	O
+arterial	O
+wall	O
+of	O
+D	O
+-	O
+pen	O
+-	O
+treated	O
+rats	O
+,	O
+consistent	O
+with	O
+an	O
+inhibitory	O
+effect	O
+on	O
+crosslink	O
+formation	O
+.	O
+
+In	O
+experimental	O
+animals	O
+excess	O
+deposition	O
+of	O
+collagen	O
+and	O
+glycoaminoglycans	O
+was	O
+observed	O
+in	O
+the	O
+subendothelial	O
+and	O
+medial	O
+layer	O
+of	O
+the	O
+aortic	O
+wall	O
+,	O
+together	O
+with	O
+prominent	O
+basal	O
+membrane	O
+substance	O
+around	O
+aortic	O
+smooth	O
+muscle	O
+cells	O
+.	O
+
+The	O
+aorta	O
+/	O
+serum	O
+-	O
+ratio	O
+and	O
+the	O
+radioactive	O
+build	O
+-	O
+up	O
+24	O
+and	O
+48	O
+hours	O
+after	O
+injection	O
+of	O
+131I	O
+-	O
+HSA	O
+was	O
+reduced	O
+in	O
+animals	O
+treated	O
+with	O
+D	O
+-	O
+pen	O
+for	O
+42	O
+days	O
+,	O
+indicating	O
+an	O
+impeded	O
+transmural	O
+transport	O
+of	O
+tracer	O
+which	O
+may	O
+be	O
+caused	O
+by	O
+a	O
+steric	O
+exclusion	O
+effect	O
+of	O
+abundant	O
+hyaluronate	O
+.	O
+
+The	O
+endothelial	O
+ultrastructure	O
+was	O
+unaffected	O
+by	O
+D	O
+-	O
+pen	O
+,	O
+and	O
+no	O
+differences	O
+in	O
+aortic	O
+131I	O
+-	O
+HSA	O
+radioactivity	O
+or	O
+aorta	O
+/	O
+serum	O
+-	O
+ratio	O
+were	O
+recorded	O
+between	O
+experimental	O
+and	O
+control	O
+groups	O
+10	O
+minutes	O
+after	O
+tracer	O
+injection	O
+,	O
+indicating	O
+that	O
+the	O
+permeability	O
+of	O
+the	O
+endothelial	O
+barrier	O
+to	O
+albumin	O
+remained	O
+unaffected	O
+by	O
+D	O
+-	O
+pen	O
+treatment	O
+.	O
+
+These	O
+observations	O
+support	O
+the	O
+hypothesis	O
+that	O
+treatment	O
+with	O
+high	O
+doses	O
+of	O
+D	O
+-	O
+pen	O
+may	O
+induce	O
+a	O
+fibroproliferative	O
+response	O
+in	O
+rat	O
+aorta	O
+,	O
+possibly	O
+by	O
+an	O
+inhibitory	O
+effect	O
+on	O
+the	O
+cross	O
+-	O
+linking	O
+of	O
+collagen	O
+and	O
+elastin	O
+.	O
+
+Effect	O
+of	O
+aspirin	O
+on	O
+N	O
+-	O
+[	O
+4	O
+-	O
+(	O
+5	O
+-	O
+nitro	O
+-	O
+2	O
+-	O
+furyl	O
+)	O
+-	O
+2	O
+-	O
+thiazolyl	O
+]	O
+-	O
+formamide	O
+-	O
+induced	O
+epithelial	O
+proliferation	O
+in	O
+the	O
+urinary	O
+bladder	O
+and	O
+forestomach	O
+of	O
+the	O
+rat	O
+.	O
+
+The	O
+co	O
+-	O
+administration	O
+of	O
+aspirin	O
+with	O
+N	O
+-	O
+[	O
+4	O
+-	O
+(	O
+5	O
+-	O
+nitro	O
+-	O
+2	O
+-	O
+furyl	O
+)	O
+-	O
+2	O
+-	O
+thiazolyl	O
+]	O
+-	O
+formamide	O
+(	O
+FANFT	O
+)	O
+to	O
+rats	O
+resulted	O
+in	O
+a	O
+reduced	O
+incidence	O
+of	O
+FANFT	O
+-	O
+induced	O
+bladder	B
+carcinomas	I
+but	O
+a	O
+concomitant	O
+induction	O
+of	O
+forestomach	B
+tumors	I
+.	O
+
+An	O
+autoradiographic	O
+study	O
+was	O
+performed	O
+on	O
+male	O
+F	O
+-	O
+344	O
+rats	O
+fed	O
+diet	O
+containing	O
+FANFT	O
+at	O
+a	O
+level	O
+of	O
+0	O
+.	O
+2	O
+%	O
+and	O
+/	O
+or	O
+aspirin	O
+at	O
+a	O
+level	O
+of	O
+0	O
+.	O
+5	O
+%	O
+to	O
+evaluate	O
+the	O
+effect	O
+of	O
+aspirin	O
+on	O
+the	O
+increased	O
+cell	O
+proliferation	O
+induced	O
+by	O
+FANFT	O
+in	O
+the	O
+forestomach	O
+and	O
+bladder	O
+.	O
+
+FANFT	O
+-	O
+induced	O
+cell	O
+proliferation	O
+in	O
+the	O
+bladder	O
+was	O
+significantly	O
+suppressed	O
+by	O
+aspirin	O
+co	O
+-	O
+administration	O
+after	O
+4	O
+weeks	O
+but	O
+not	O
+after	O
+12	O
+weeks	O
+.	O
+
+In	O
+the	O
+forestomach	O
+,	O
+and	O
+also	O
+in	O
+the	O
+liver	O
+,	O
+aspirin	O
+did	O
+not	O
+affect	O
+the	O
+FANFT	O
+-	O
+induced	O
+increase	O
+in	O
+labeling	O
+index	O
+.	O
+
+The	O
+present	O
+results	O
+are	O
+consistent	O
+with	O
+the	O
+carcinogenicity	O
+experiment	O
+suggesting	O
+that	O
+different	O
+mechanisms	O
+are	O
+involved	O
+in	O
+FANFT	O
+carcinogenesis	B
+in	O
+the	O
+bladder	O
+and	O
+forestomach	O
+,	O
+and	O
+that	O
+aspirin	O
+'	O
+s	O
+effect	O
+on	O
+FANFT	O
+in	O
+the	O
+forestomach	O
+is	O
+not	O
+due	O
+to	O
+an	O
+irritant	O
+effect	O
+associated	O
+with	O
+increased	O
+cell	O
+proliferation	O
+.	O
+
+Also	O
+,	O
+there	O
+appears	O
+to	O
+be	O
+an	O
+adaptation	O
+by	O
+the	O
+rats	O
+to	O
+the	O
+chronic	O
+ingestion	O
+of	O
+aspirin	O
+.	O
+
+A	O
+case	O
+of	O
+tardive	B
+dyskinesia	I
+caused	O
+by	O
+metoclopramide	O
+.	O
+
+Abnormal	B
+involuntary	I
+movements	I
+appeared	O
+in	O
+the	O
+mouth	O
+,	O
+tongue	O
+,	O
+neck	O
+and	O
+abdomen	O
+of	O
+a	O
+64	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+after	O
+he	O
+took	O
+metoclopramide	O
+for	O
+gastrointestinal	B
+disorder	I
+in	O
+a	O
+regimen	O
+of	O
+30	O
+mg	O
+per	O
+day	O
+for	O
+a	O
+total	O
+of	O
+about	O
+260	O
+days	O
+.	O
+
+The	O
+symptoms	O
+exacerbated	O
+to	O
+a	O
+maximum	O
+in	O
+a	O
+month	O
+.	O
+
+When	O
+the	O
+metoclopramide	O
+administration	O
+was	O
+discontinued	O
+,	O
+the	O
+abnormal	B
+movements	I
+gradually	O
+improved	O
+to	O
+a	O
+considerable	O
+extent	O
+.	O
+
+Attention	O
+to	O
+the	O
+possible	O
+induction	O
+of	O
+specific	O
+tardive	B
+dyskinesia	I
+is	O
+called	O
+for	O
+in	O
+the	O
+use	O
+of	O
+this	O
+drug	O
+.	O
+
+Intra	O
+-	O
+arterial	O
+BCNU	O
+chemotherapy	O
+for	O
+treatment	O
+of	O
+malignant	B
+gliomas	I
+of	O
+the	O
+central	O
+nervous	O
+system	O
+.	O
+
+Because	O
+of	O
+the	O
+rapid	O
+systemic	O
+clearance	O
+of	O
+BCNU	O
+(	O
+1	O
+,	O
+3	O
+-	O
+bis	O
+-	O
+(	O
+2	O
+-	O
+chloroethyl	O
+)	O
+-	O
+1	O
+-	O
+nitrosourea	O
+)	O
+,	O
+intra	O
+-	O
+arterial	O
+administration	O
+should	O
+provide	O
+a	O
+substantial	O
+advantage	O
+over	O
+intravenous	O
+administration	O
+for	O
+the	O
+treatment	O
+of	O
+malignant	B
+gliomas	I
+.	O
+
+Thirty	O
+-	O
+six	O
+patients	O
+were	O
+treated	O
+with	O
+BCNU	O
+every	O
+6	O
+to	O
+8	O
+weeks	O
+,	O
+either	O
+by	O
+transfemoral	O
+catheterization	O
+of	O
+the	O
+internal	O
+carotid	O
+or	O
+vertebral	O
+artery	O
+or	O
+through	O
+a	O
+fully	O
+implantable	O
+intracarotid	O
+drug	O
+delivery	O
+system	O
+,	O
+beginning	O
+with	O
+a	O
+dose	O
+of	O
+200	O
+mg	O
+/	O
+sq	O
+m	O
+body	O
+surface	O
+area	O
+.	O
+
+Twelve	O
+patients	O
+with	O
+Grade	O
+III	O
+or	O
+IV	O
+astrocytomas	B
+were	O
+treated	O
+after	O
+partial	O
+resection	O
+of	O
+the	O
+tumor	B
+without	O
+prior	O
+radiation	O
+therapy	O
+.	O
+
+After	O
+two	O
+to	O
+seven	O
+cycles	O
+of	O
+chemotherapy	O
+,	O
+nine	O
+patients	O
+showed	O
+a	O
+decrease	O
+in	O
+tumor	B
+size	O
+and	O
+surrounding	O
+edema	B
+on	O
+contrast	O
+-	O
+enhanced	O
+computerized	O
+tomography	O
+scans	O
+.	O
+
+In	O
+the	O
+nine	O
+responders	O
+,	O
+median	O
+duration	O
+of	O
+chemotherapy	O
+response	O
+from	O
+the	O
+time	O
+of	O
+operation	O
+was	O
+25	O
+weeks	O
+(	O
+range	O
+12	O
+to	O
+more	O
+than	O
+91	O
+weeks	O
+)	O
+.	O
+
+The	O
+median	O
+duration	O
+of	O
+survival	O
+in	O
+the	O
+12	O
+patients	O
+was	O
+54	O
+weeks	O
+(	O
+range	O
+21	O
+to	O
+more	O
+than	O
+156	O
+weeks	O
+)	O
+,	O
+with	O
+an	O
+18	O
+-	O
+month	O
+survival	O
+rate	O
+of	O
+42	O
+%	O
+.	O
+
+Twenty	O
+-	O
+four	O
+patients	O
+with	O
+recurrent	O
+Grade	O
+I	O
+to	O
+IV	O
+astrocytomas	B
+,	O
+whose	O
+resection	O
+and	O
+irradiation	O
+therapy	O
+had	O
+failed	O
+,	O
+received	O
+two	O
+to	O
+eight	O
+courses	O
+of	O
+intra	O
+-	O
+arterial	O
+BCNU	O
+therapy	O
+.	O
+
+Seventeen	O
+of	O
+these	O
+had	O
+a	O
+response	O
+or	O
+were	O
+stable	O
+for	O
+a	O
+median	O
+of	O
+20	O
+weeks	O
+(	O
+range	O
+6	O
+to	O
+more	O
+than	O
+66	O
+weeks	O
+)	O
+.	O
+
+The	O
+catheterization	O
+procedure	O
+is	O
+safe	O
+,	O
+with	O
+no	O
+immediate	O
+complication	O
+in	O
+111	O
+infusions	O
+of	O
+BCNU	O
+.	O
+
+A	O
+delayed	O
+complication	O
+in	O
+nine	O
+patients	O
+has	O
+been	O
+unilateral	O
+loss	B
+of	I
+vision	I
+secondary	O
+to	O
+a	O
+retinal	B
+vasculitis	I
+.	O
+
+The	O
+frequency	O
+of	O
+visual	B
+loss	I
+decreased	O
+after	O
+the	O
+concentration	O
+of	O
+the	O
+ethanol	O
+diluent	O
+was	O
+lowered	O
+.	O
+
+Provocation	O
+of	O
+postural	O
+hypotension	B
+by	O
+nitroglycerin	O
+in	O
+diabetic	B
+autonomic	I
+neuropathy	I
+?	O
+
+The	O
+effect	O
+of	O
+nitroglycerin	O
+on	O
+heart	O
+rate	O
+and	O
+systolic	O
+blood	O
+pressure	O
+was	O
+compared	O
+in	O
+5	O
+normal	O
+subjects	O
+,	O
+12	O
+diabetic	B
+subjects	O
+without	O
+autonomic	B
+neuropathy	I
+,	O
+and	O
+5	O
+diabetic	B
+subjects	O
+with	O
+autonomic	B
+neuropathy	I
+.	O
+
+The	O
+magnitude	O
+and	O
+time	O
+course	O
+of	O
+the	O
+increase	O
+in	O
+heart	O
+rate	O
+and	O
+the	O
+decrease	O
+in	O
+systolic	O
+blood	O
+pressure	O
+after	O
+nitroglycerin	O
+were	O
+similar	O
+in	O
+the	O
+normal	O
+and	O
+diabetic	B
+subjects	O
+without	O
+autonomic	B
+neuropathy	I
+,	O
+whereas	O
+a	O
+lesser	O
+increase	O
+in	O
+heart	O
+rate	O
+and	O
+a	O
+greater	O
+decrease	O
+in	O
+systolic	O
+blood	O
+pressure	O
+occurred	O
+in	O
+the	O
+diabetic	B
+subjects	O
+with	O
+autonomic	B
+neuropathy	I
+.	O
+
+It	O
+is	O
+therefore	O
+suggested	O
+that	O
+caution	O
+should	O
+be	O
+exercised	O
+when	O
+prescribing	O
+vasodilator	O
+drugs	O
+in	O
+diabetic	B
+patients	O
+,	O
+particularly	O
+those	O
+with	O
+autonomic	B
+neuropathy	I
+.	O
+
+Blood	O
+pressure	O
+response	O
+to	O
+chronic	O
+low	O
+-	O
+dose	O
+intrarenal	O
+noradrenaline	O
+infusion	O
+in	O
+conscious	O
+rats	O
+.	O
+
+Sodium	O
+chloride	O
+solution	O
+(	O
+0	O
+.	O
+9	O
+%	O
+)	O
+or	O
+noradrenaline	O
+in	O
+doses	O
+of	O
+4	O
+,	O
+12	O
+and	O
+36	O
+micrograms	O
+h	O
+-	O
+1	O
+kg	O
+-	O
+1	O
+was	O
+infused	O
+for	O
+five	O
+consecutive	O
+days	O
+,	O
+either	O
+intrarenally	O
+(	O
+by	O
+a	O
+new	O
+technique	O
+)	O
+or	O
+intravenously	O
+into	O
+rats	O
+with	O
+one	O
+kidney	O
+removed	O
+.	O
+
+Intrarenal	O
+infusion	O
+of	O
+noradrenaline	O
+caused	O
+hypertension	B
+at	O
+doses	O
+which	O
+did	O
+not	O
+do	O
+so	O
+when	O
+infused	O
+intravenously	O
+.	O
+
+Intrarenal	O
+compared	O
+with	O
+intravenous	O
+infusion	O
+of	O
+noradrenaline	O
+caused	O
+higher	O
+plasma	O
+noradrenaline	O
+concentrations	O
+and	O
+a	O
+shift	O
+of	O
+the	O
+plasma	O
+noradrenaline	O
+concentration	O
+-	O
+blood	O
+pressure	O
+effect	O
+curve	O
+towards	O
+lower	O
+plasma	O
+noradrenaline	O
+levels	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+hypertension	B
+after	O
+chronic	O
+intrarenal	O
+noradrenaline	O
+infusion	O
+is	O
+produced	O
+by	O
+relatively	O
+higher	O
+levels	O
+of	O
+circulating	O
+noradrenaline	O
+and	O
+by	O
+triggering	O
+of	O
+an	O
+additional	O
+intrarenal	O
+pressor	O
+mechanism	O
+.	O
+
+Characterization	O
+of	O
+estrogen	O
+-	O
+induced	O
+adenohypophyseal	B
+tumors	I
+in	O
+the	O
+Fischer	O
+344	O
+rat	O
+.	O
+
+Pituitary	B
+tumors	I
+were	O
+induced	O
+in	O
+F344	O
+female	O
+rats	O
+by	O
+chronic	O
+treatment	O
+with	O
+diethylstilbestrol	O
+(	O
+DES	O
+,	O
+8	O
+-	O
+10	O
+mg	O
+)	O
+implanted	O
+subcutaneously	O
+in	O
+silastic	O
+capsules	O
+.	O
+
+Over	O
+a	O
+range	O
+of	O
+1	O
+-	O
+150	O
+days	O
+of	O
+DES	O
+treatment	O
+,	O
+pairs	O
+of	O
+control	O
+and	O
+DES	O
+-	O
+treated	O
+rats	O
+were	O
+sacrificed	O
+,	O
+and	O
+their	O
+pituitaries	O
+dissociated	O
+enzymatically	O
+into	O
+single	O
+-	O
+cell	O
+preparations	O
+.	O
+
+The	O
+cell	O
+populations	O
+were	O
+examined	O
+regarding	O
+total	O
+cell	O
+recovery	O
+correlated	O
+with	O
+gland	O
+weight	O
+,	O
+intracellular	O
+prolactin	O
+(	O
+PRL	O
+)	O
+content	O
+and	O
+subsequent	O
+release	O
+in	O
+primary	O
+culture	O
+,	O
+immunocytochemical	O
+PRL	O
+staining	O
+,	O
+density	O
+and	O
+/	O
+or	O
+size	O
+alterations	O
+via	O
+separation	O
+on	O
+Ficoll	O
+-	O
+Hypaque	O
+and	O
+by	O
+unit	O
+gravity	O
+sedimentation	O
+,	O
+and	O
+cell	O
+cycle	O
+analysis	O
+,	O
+after	O
+acriflavine	O
+DNA	O
+staining	O
+,	O
+by	O
+laser	O
+flow	O
+cytometry	O
+.	O
+
+Total	O
+cell	O
+yields	O
+from	O
+DES	O
+-	O
+treated	O
+pituitaries	O
+increased	O
+from	O
+1	O
+.	O
+3	O
+times	O
+control	O
+yields	O
+at	O
+8	O
+days	O
+of	O
+treatment	O
+to	O
+58	O
+.	O
+9	O
+times	O
+control	O
+values	O
+by	O
+day	O
+150	O
+.	O
+
+Intracellular	O
+PRL	O
+content	O
+ranged	O
+from	O
+1	O
+.	O
+9	O
+to	O
+9	O
+.	O
+4	O
+times	O
+control	O
+levels	O
+,	O
+and	O
+PRL	O
+release	O
+in	O
+vitro	O
+was	O
+significantly	O
+and	O
+consistently	O
+higher	O
+than	O
+controls	O
+,	O
+after	O
+at	O
+least	O
+8	O
+days	O
+of	O
+DES	O
+exposure	O
+.	O
+
+Beyond	O
+8	O
+days	O
+of	O
+DES	O
+exposure	O
+,	O
+the	O
+immunochemically	O
+PRL	O
+-	O
+positive	O
+proportion	O
+of	O
+cells	O
+increased	O
+to	O
+over	O
+50	O
+%	O
+of	O
+the	O
+total	O
+population	O
+.	O
+
+Increased	O
+density	O
+and	O
+/	O
+or	O
+size	O
+and	O
+PRL	O
+content	O
+were	O
+indicated	O
+for	O
+the	O
+majority	O
+of	O
+the	O
+PRL	O
+cell	O
+population	O
+in	O
+both	O
+types	O
+of	O
+separation	O
+protocols	O
+.	O
+
+All	O
+these	O
+effects	O
+of	O
+DES	O
+were	O
+more	O
+pronounced	O
+among	O
+previously	O
+ovariectomized	O
+animals	O
+.	O
+
+The	O
+data	O
+extend	O
+the	O
+findings	O
+of	O
+other	O
+investigators	O
+,	O
+further	O
+establishing	O
+the	O
+DES	O
+-	O
+induced	O
+tumor	B
+as	O
+a	O
+model	O
+for	O
+study	O
+of	O
+PRL	O
+cellular	O
+control	O
+mechanisms	O
+.	O
+
+Age	O
+and	O
+renal	O
+clearance	O
+of	O
+cimetidine	O
+.	O
+
+In	O
+35	O
+patients	O
+(	O
+ages	O
+20	O
+to	O
+86	O
+yr	O
+)	O
+receiving	O
+cimetidine	O
+therapeutically	O
+two	O
+serum	O
+samples	O
+and	O
+all	O
+urine	O
+formed	O
+in	O
+the	O
+interim	O
+were	O
+collected	O
+for	O
+analysis	O
+of	O
+cimetidine	O
+by	O
+high	O
+-	O
+pressure	O
+liquid	O
+chromatography	O
+and	O
+for	O
+creatinine	O
+.	O
+
+Cimetidine	O
+clearance	O
+decreased	O
+with	O
+age	O
+.	O
+
+The	O
+extrapolated	O
+6	O
+-	O
+hr	O
+serum	O
+concentration	O
+of	O
+cimetidine	O
+per	O
+unit	O
+dose	O
+,	O
+after	O
+intravenous	O
+cimetidine	O
+,	O
+increased	O
+with	O
+age	O
+of	O
+the	O
+patients	O
+.	O
+
+The	O
+ratio	O
+of	O
+cimetidine	O
+clearance	O
+to	O
+creatinine	O
+clearance	O
+(	O
+Rc	O
+)	O
+averaged	O
+4	O
+.	O
+8	O
++	O
+/	O
+-	O
+2	O
+.	O
+0	O
+,	O
+indicating	O
+net	O
+tubular	O
+secretion	O
+for	O
+cimetidine	O
+.	O
+
+Rc	O
+seemed	O
+to	O
+be	O
+independent	O
+of	O
+age	O
+and	O
+decreased	O
+with	O
+increasing	O
+serum	O
+concentration	O
+of	O
+cimetidine	O
+,	O
+suggesting	O
+that	O
+secretion	O
+of	O
+cimetidine	O
+is	O
+a	O
+saturable	O
+process	O
+.	O
+
+There	O
+was	O
+only	O
+one	O
+case	O
+of	O
+dementia	B
+possibly	O
+due	O
+to	O
+cimetidine	O
+(	O
+with	O
+a	O
+drug	O
+level	O
+of	O
+1	O
+.	O
+9	O
+microgram	O
+/	O
+ml	O
+6	O
+hr	O
+after	O
+a	O
+dose	O
+)	O
+in	O
+a	O
+group	O
+of	O
+13	O
+patients	O
+without	O
+liver	B
+or	I
+kidney	I
+disease	I
+who	O
+had	O
+cimetidine	O
+levels	O
+above	O
+1	O
+.	O
+25	O
+microgram	O
+/	O
+ml	O
+.	O
+
+Thus	O
+,	O
+high	O
+cimetidine	O
+levels	O
+alone	O
+do	O
+not	O
+always	O
+induce	O
+dementia	B
+.	O
+
+Further	O
+observations	O
+on	O
+the	O
+electrophysiologic	O
+effects	O
+of	O
+oral	O
+amiodarone	O
+therapy	O
+.	O
+
+A	O
+case	O
+is	O
+presented	O
+of	O
+a	O
+reversible	O
+intra	B
+-	I
+Hisian	I
+block	I
+occurring	O
+under	O
+amiodarone	O
+treatment	O
+for	O
+atrial	B
+tachycardia	I
+in	O
+a	O
+patient	O
+without	O
+clear	O
+intraventricular	B
+conduction	I
+abnormalities	I
+.	O
+
+His	O
+bundle	O
+recordings	O
+showed	O
+an	O
+atrial	B
+tachycardia	I
+with	O
+intermittent	O
+exit	O
+block	O
+and	O
+greatly	O
+prolonged	O
+BH	O
+and	O
+HV	O
+intervals	O
+(	O
+40	O
+and	O
+100	O
+msec	O
+,	O
+respectively	O
+)	O
+.	O
+
+Thirty	O
+days	O
+after	O
+amiodarone	O
+discontinuation	O
+,	O
+His	O
+bundle	O
+electrograms	O
+showed	O
+atrial	B
+flutter	I
+without	O
+intra	O
+-	O
+Hisian	O
+or	O
+infra	O
+-	O
+Hisian	O
+delay	O
+.	O
+
+Amiodarone	O
+should	O
+be	O
+used	O
+with	O
+caution	O
+during	O
+long	O
+-	O
+term	O
+oral	O
+therapy	O
+in	O
+patients	O
+with	O
+or	O
+without	O
+clear	O
+intraventricular	O
+conduction	O
+defects	O
+.	O
+
+Development	O
+of	O
+clear	B
+cell	I
+adenocarcinoma	I
+in	O
+DES	O
+-	O
+exposed	O
+offspring	O
+under	O
+observation	O
+.	O
+
+Two	O
+cases	O
+of	O
+clear	B
+cell	I
+adenocarcinoma	I
+of	I
+the	I
+vagina	I
+detected	O
+at	O
+follow	O
+-	O
+up	O
+in	O
+young	O
+women	O
+exposed	O
+in	O
+utero	O
+to	O
+diethylstilbestrol	O
+are	O
+reported	O
+.	O
+
+One	O
+patient	O
+,	O
+aged	O
+23	O
+,	O
+had	O
+been	O
+followed	O
+for	O
+2	O
+years	O
+before	O
+carcinoma	B
+was	O
+diagnosed	O
+;	O
+the	O
+second	O
+patient	O
+,	O
+aged	O
+22	O
+,	O
+had	O
+been	O
+seen	O
+on	O
+a	O
+regular	O
+basis	O
+for	O
+5	O
+years	O
+,	O
+8	O
+months	O
+.	O
+
+In	O
+both	O
+instances	O
+,	O
+suspicion	O
+of	O
+the	O
+presence	O
+of	O
+carcinoma	B
+was	O
+aroused	O
+by	O
+the	O
+palpation	O
+of	O
+a	O
+small	O
+nodule	O
+in	O
+the	O
+vaginal	O
+fornix	O
+.	O
+
+Hysterosalpingography	O
+was	O
+performed	O
+on	O
+both	O
+patients	O
+and	O
+,	O
+in	O
+1	O
+instance	O
+,	O
+an	O
+abnormal	O
+x	O
+-	O
+ray	O
+film	O
+was	O
+reflected	O
+by	O
+the	O
+gross	O
+appearance	O
+of	O
+the	O
+uterine	O
+cavity	O
+found	O
+in	O
+the	O
+surgical	O
+specimen	O
+.	O
+
+Neurologic	O
+effects	O
+of	O
+subarachnoid	O
+administration	O
+of	O
+2	O
+-	O
+chloroprocaine	O
+-	O
+CE	O
+,	O
+bupivacaine	O
+,	O
+and	O
+low	O
+pH	O
+normal	O
+saline	O
+in	O
+dogs	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+evaluate	O
+the	O
+neurologic	O
+consequences	O
+of	O
+deliberate	O
+subarachnoid	O
+injection	O
+of	O
+large	O
+volumes	O
+of	O
+2	O
+-	O
+chloroprocaine	O
+-	O
+CE	O
+in	O
+experimental	O
+animals	O
+.	O
+
+The	O
+possible	O
+role	O
+of	O
+low	O
+pH	O
+as	O
+well	O
+as	O
+total	O
+volume	O
+as	O
+potential	O
+factors	O
+in	O
+causing	O
+neurotoxicity	B
+was	O
+evaluated	O
+.	O
+
+The	O
+65	O
+dogs	O
+in	O
+the	O
+study	O
+received	O
+injections	O
+in	O
+the	O
+subarachnoid	O
+space	O
+as	O
+follows	O
+:	O
+6	O
+to	O
+8	O
+ml	O
+of	O
+bupivacaine	O
+(	O
+N	O
+=	O
+15	O
+)	O
+,	O
+2	O
+-	O
+chloroprocaine	O
+-	O
+CE	O
+(	O
+N	O
+=	O
+20	O
+)	O
+,	O
+low	O
+pH	O
+normal	O
+saline	O
+(	O
+pH	O
+3	O
+.	O
+0	O
+)	O
+(	O
+N	O
+=	O
+20	O
+)	O
+,	O
+or	O
+normal	O
+saline	O
+(	O
+N	O
+=	O
+10	O
+)	O
+.	O
+
+Of	O
+the	O
+20	O
+animals	O
+that	O
+received	O
+subarachnoid	O
+injection	O
+of	O
+2	O
+-	O
+chloroprocaine	O
+-	O
+CE	O
+seven	O
+(	O
+35	O
+%	O
+)	O
+developed	O
+hind	O
+-	O
+limb	O
+paralysis	B
+.	O
+
+None	O
+of	O
+the	O
+animals	O
+that	O
+received	O
+bupivacaine	O
+,	O
+normal	O
+saline	O
+,	O
+or	O
+normal	O
+saline	O
+titrated	O
+to	O
+a	O
+pH	O
+3	O
+.	O
+0	O
+developed	O
+hind	O
+-	O
+limb	O
+paralysis	B
+.	O
+
+Of	O
+the	O
+15	O
+spinal	O
+cords	O
+of	O
+the	O
+animals	O
+that	O
+received	O
+2	O
+-	O
+chloroprocaine	O
+-	O
+CE	O
+,	O
+13	O
+showed	O
+subpial	B
+necrosis	I
+;	O
+the	O
+nerve	O
+roots	O
+and	O
+subarachnoid	O
+vessels	O
+were	O
+normal	O
+.	O
+
+The	O
+spinal	O
+cords	O
+of	O
+the	O
+animals	O
+that	O
+received	O
+bupivacaine	O
+,	O
+low	O
+pH	O
+normal	O
+saline	O
+(	O
+pH	O
+3	O
+.	O
+0	O
+)	O
+,	O
+or	O
+normal	O
+saline	O
+did	O
+not	O
+show	O
+abnormal	O
+findings	O
+.	O
+
+Procainamide	O
+-	O
+induced	O
+polymorphous	O
+ventricular	B
+tachycardia	I
+.	O
+
+Seven	O
+cases	O
+of	O
+procainamide	O
+-	O
+induced	O
+polymorphous	O
+ventricular	B
+tachycardia	I
+are	O
+presented	O
+.	O
+
+In	O
+four	O
+patients	O
+,	O
+polymorphous	O
+ventricular	B
+tachycardia	I
+appeared	O
+after	O
+intravenous	O
+administration	O
+of	O
+200	O
+to	O
+400	O
+mg	O
+of	O
+procainamide	O
+for	O
+the	O
+treatment	O
+of	O
+sustained	O
+ventricular	B
+tachycardia	I
+.	O
+
+In	O
+the	O
+remaining	O
+three	O
+patients	O
+,	O
+procainamide	O
+was	O
+administered	O
+orally	O
+for	O
+treatment	O
+of	O
+chronic	O
+premature	B
+ventricular	I
+contractions	I
+or	O
+atrial	B
+flutter	I
+.	O
+
+These	O
+patients	O
+had	O
+Q	B
+-	I
+T	I
+prolongation	I
+and	O
+recurrent	O
+syncope	B
+due	O
+to	O
+polymorphous	O
+ventricular	B
+tachycardia	I
+.	O
+
+In	O
+four	O
+patients	O
+,	O
+the	O
+arrhythmia	B
+was	O
+rapidly	O
+diagnosed	O
+and	O
+treated	O
+with	O
+disappearance	O
+of	O
+further	O
+episodes	O
+of	O
+the	O
+arrhythmia	B
+.	O
+
+In	O
+two	O
+patients	O
+,	O
+the	O
+arrhythmia	B
+degenerated	O
+into	O
+irreversible	O
+ventricular	B
+fibrillation	I
+and	O
+both	O
+patients	O
+died	O
+.	O
+
+In	O
+the	O
+seventh	O
+patient	O
+,	O
+a	O
+permanent	O
+ventricular	O
+pacemaker	O
+was	O
+inserted	O
+and	O
+,	O
+despite	O
+continuation	O
+of	O
+procainamide	O
+therapy	O
+,	O
+polymorphous	O
+ventricular	B
+tachycardia	I
+did	O
+not	O
+reoccur	O
+.	O
+
+These	O
+seven	O
+cases	O
+demonstrate	O
+that	O
+procainamide	O
+can	O
+produce	O
+an	O
+acquired	O
+prolonged	B
+Q	I
+-	I
+T	I
+syndrome	I
+with	O
+polymorphous	O
+ventricular	B
+tachycardia	I
+.	O
+
+Phenobarbitone	O
+-	O
+induced	O
+enlargement	B
+of	I
+the	I
+liver	I
+in	O
+the	O
+rat	O
+:	O
+its	O
+relationship	O
+to	O
+carbon	O
+tetrachloride	O
+-	O
+induced	O
+cirrhosis	B
+.	O
+
+The	O
+yield	O
+of	O
+severe	O
+cirrhosis	B
+of	I
+the	I
+liver	I
+(	O
+defined	O
+as	O
+a	O
+shrunken	O
+finely	O
+nodular	O
+liver	O
+with	O
+micronodular	O
+histology	O
+,	O
+ascites	B
+greater	O
+than	O
+30	O
+ml	O
+,	O
+plasma	O
+albumin	O
+less	O
+than	O
+2	O
+.	O
+2	O
+g	O
+/	O
+dl	O
+,	O
+splenomegaly	B
+2	O
+-	O
+3	O
+times	O
+normal	O
+,	O
+and	O
+testicular	O
+atrophy	B
+approximately	O
+half	O
+normal	O
+weight	O
+)	O
+after	O
+12	O
+doses	O
+of	O
+carbon	O
+tetrachloride	O
+given	O
+intragastrically	O
+in	O
+the	O
+phenobarbitone	O
+-	O
+primed	O
+rat	O
+was	O
+increased	O
+from	O
+25	O
+%	O
+to	O
+56	O
+%	O
+by	O
+giving	O
+the	O
+initial	O
+"	O
+calibrating	O
+"	O
+dose	O
+of	O
+carbon	O
+tetrachloride	O
+at	O
+the	O
+peak	O
+of	O
+the	O
+phenobarbitone	O
+-	O
+induced	O
+enlargement	B
+of	I
+the	I
+liver	I
+.	O
+
+At	O
+this	O
+point	O
+it	O
+was	O
+assumed	O
+that	O
+the	O
+cytochrome	O
+P450	O
+/	O
+CCl4	O
+toxic	O
+state	O
+was	O
+both	O
+maximal	O
+and	O
+stable	O
+.	O
+
+The	O
+optimal	O
+rat	O
+size	O
+to	O
+begin	O
+phenobarbitone	O
+was	O
+determined	O
+as	O
+100	O
+g	O
+,	O
+and	O
+this	O
+size	O
+as	O
+a	O
+group	O
+had	O
+a	O
+mean	O
+maximum	O
+relative	O
+liver	O
+weight	O
+increase	O
+47	O
+%	O
+greater	O
+than	O
+normal	O
+rats	O
+of	O
+the	O
+same	O
+body	O
+weight	O
+.	O
+
+The	O
+optimal	O
+time	O
+for	O
+the	O
+initial	O
+dose	O
+of	O
+carbon	O
+tetrachloride	O
+was	O
+after	O
+14	O
+days	O
+on	O
+phenobarbitone	O
+.	O
+
+Triamterene	O
+nephrolithiasis	B
+complicating	O
+dyazide	O
+therapy	O
+.	O
+
+A	O
+case	O
+of	O
+triamterene	O
+nephrolithiasis	B
+is	O
+reported	O
+in	O
+a	O
+man	O
+after	O
+4	O
+years	O
+of	O
+hydrochlorothiazide	O
+-	O
+triamterene	O
+therapy	O
+for	O
+hypertension	B
+.	O
+
+The	O
+stone	O
+passed	O
+spontaneously	O
+and	O
+was	O
+found	O
+to	O
+contain	O
+a	O
+triamterene	O
+metabolite	O
+admixed	O
+with	O
+uric	O
+acid	O
+salts	O
+.	O
+
+Factors	O
+affecting	O
+triamterene	O
+nephrolithiasis	B
+are	O
+discussed	O
+and	O
+2	O
+previously	O
+reported	O
+cases	O
+are	O
+reviewed	O
+.	O
+
+Busulfan	O
+-	O
+induced	O
+hemorrhagic	B
+cystitis	I
+.	O
+
+A	O
+case	O
+of	O
+a	O
+busulfan	O
+-	O
+induced	O
+hemorrhage	B
+cystitis	I
+is	O
+reported	O
+.	O
+
+Spontaneous	O
+resolution	O
+occurred	O
+following	O
+cessation	O
+of	O
+the	O
+drug	O
+.	O
+
+The	O
+similarity	O
+between	O
+the	O
+histologic	O
+appearances	O
+of	O
+busulfan	O
+cystitis	B
+and	O
+both	O
+radiation	O
+and	O
+cyclophosphamide	O
+-	O
+induced	O
+cystitis	B
+is	O
+discussed	O
+and	O
+the	O
+world	O
+literature	O
+reviewed	O
+.	O
+
+In	O
+view	O
+of	O
+the	O
+known	O
+tendency	O
+of	O
+busulfan	O
+to	O
+induce	O
+cellular	O
+atypia	O
+and	O
+carcinoma	B
+in	O
+other	O
+sites	O
+,	O
+periodic	O
+urinary	O
+cytology	O
+is	O
+suggested	O
+in	O
+patients	O
+on	O
+long	O
+-	O
+term	O
+therapy	O
+.	O
+
+Variant	O
+ventricular	B
+tachycardia	I
+in	O
+desipramine	O
+toxicity	B
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+variant	O
+ventricular	B
+tachycardia	I
+induced	O
+by	O
+desipramine	O
+toxicity	B
+.	O
+
+Unusual	O
+features	O
+of	O
+the	O
+arrhythmia	B
+are	O
+repetitive	O
+group	O
+beating	O
+,	O
+progressive	O
+shortening	O
+of	O
+the	O
+R	O
+-	O
+R	O
+interval	O
+,	O
+progressive	O
+widening	O
+of	O
+the	O
+QRS	O
+complex	O
+with	O
+eventual	O
+failure	O
+of	O
+intraventricular	O
+conduction	O
+,	O
+and	O
+changes	O
+in	O
+direction	O
+of	O
+the	O
+QRS	O
+axis	O
+.	O
+
+Recognition	O
+of	O
+variant	O
+ventricular	B
+tachycardia	I
+is	O
+important	O
+because	O
+therapy	O
+differs	O
+from	O
+that	O
+of	O
+classic	O
+ventricular	B
+tachycardia	I
+.	O
+
+Rebound	O
+hypertensive	B
+after	O
+sodium	O
+nitroprusside	O
+prevented	O
+by	O
+saralasin	O
+in	O
+rats	O
+.	O
+
+The	O
+role	O
+of	O
+the	O
+renin	O
+-	O
+-	O
+angiotensin	O
+system	O
+in	O
+the	O
+maintenance	O
+of	O
+blood	O
+pressure	O
+during	O
+halothane	O
+anesthesia	O
+and	O
+sodium	O
+nitroprusside	O
+(	O
+SNP	O
+)	O
+-	O
+induced	O
+hypotension	B
+was	O
+evaluated	O
+.	O
+
+Control	O
+rats	O
+received	O
+halothane	O
+anesthesia	O
+(	O
+1	O
+MAC	O
+)	O
+for	O
+one	O
+hour	O
+,	O
+followed	O
+by	O
+SNP	O
+infusion	O
+,	O
+40	O
+microgram	O
+/	O
+kg	O
+/	O
+min	O
+,	O
+for	O
+30	O
+min	O
+,	O
+followed	O
+by	O
+a	O
+30	O
+-	O
+min	O
+recovery	O
+period	O
+.	O
+
+A	O
+second	O
+group	O
+of	O
+rats	O
+was	O
+treated	O
+identically	O
+and	O
+,	O
+in	O
+addition	O
+,	O
+received	O
+an	O
+infusion	O
+of	O
+saralasin	O
+(	O
+a	O
+competitive	O
+inhibitor	O
+of	O
+angiotensin	O
+II	O
+)	O
+throughout	O
+the	O
+experimental	O
+period	O
+.	O
+
+In	O
+each	O
+group	O
+,	O
+SNP	O
+infusion	O
+resulted	O
+in	O
+an	O
+initial	O
+decrease	O
+in	O
+blood	O
+pressure	O
+from	O
+86	O
+torr	O
+and	O
+83	O
+torr	O
+,	O
+respectively	O
+,	O
+to	O
+48	O
+torr	O
+.	O
+
+During	O
+the	O
+SNP	O
+infusion	O
+the	O
+control	O
+animals	O
+demonstrated	O
+a	O
+progressive	O
+increase	B
+in	I
+blood	I
+pressure	I
+to	O
+61	O
+torr	O
+,	O
+whereas	O
+the	O
+saralasin	O
+-	O
+treated	O
+animals	O
+showed	O
+no	O
+change	O
+.	O
+
+Following	O
+discontinuation	O
+of	O
+SNP	O
+,	O
+blood	O
+pressure	O
+in	O
+the	O
+control	O
+animals	O
+rebounded	O
+to	O
+94	O
+torr	O
+,	O
+as	O
+compared	O
+with	O
+78	O
+torr	O
+in	O
+the	O
+saralasin	O
+-	O
+treated	O
+rats	O
+.	O
+
+This	O
+study	O
+indicates	O
+that	O
+with	O
+stable	O
+halothane	O
+anesthesia	O
+,	O
+the	O
+partial	O
+recovery	O
+of	O
+blood	O
+pressure	O
+during	O
+SNP	O
+infusion	O
+and	O
+the	O
+post	O
+-	O
+SNP	O
+rebound	O
+of	O
+blood	O
+pressure	O
+can	O
+be	O
+completely	O
+blocked	O
+by	O
+saralasin	O
+.	O
+
+This	O
+demonstrates	O
+the	O
+participation	O
+of	O
+the	O
+renin	O
+-	O
+-	O
+angiotensin	O
+system	O
+in	O
+antagonizing	O
+the	O
+combined	O
+hypotensive	B
+effects	O
+of	O
+halothane	O
+and	O
+SNP	O
+.	O
+
+Clinical	O
+nephrotoxicity	B
+of	O
+tobramycin	O
+and	O
+gentamicin	O
+.	O
+
+A	O
+prospective	O
+study	O
+.	O
+
+Nearly	O
+3	O
+.	O
+2	O
+million	O
+people	O
+in	O
+this	O
+country	O
+receive	O
+aminoglycoside	O
+antibiotics	O
+annually	O
+.	O
+
+Gentamicin	O
+sulfate	O
+and	O
+tobramycin	O
+sulfate	O
+continue	O
+to	O
+demonstrate	O
+ototoxicity	B
+and	O
+nephrotoxicity	B
+in	O
+both	O
+animal	O
+and	O
+clinical	O
+studies	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+62	O
+patients	O
+with	O
+confirmed	O
+initial	O
+normal	O
+renal	O
+function	O
+and	O
+treated	O
+with	O
+2	O
+to	O
+5	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+of	O
+gentamicin	O
+sulfate	O
+or	O
+tobramycin	O
+sulfate	O
+for	O
+a	O
+minimum	O
+of	O
+seven	O
+days	O
+were	O
+followed	O
+up	O
+prospectively	O
+for	O
+the	O
+development	O
+of	O
+aminoglycoside	O
+-	O
+related	O
+renal	B
+failure	I
+,	O
+defined	O
+as	O
+at	O
+least	O
+a	O
+one	O
+-	O
+third	O
+reduction	O
+in	O
+renal	O
+function	O
+.	O
+
+In	O
+these	O
+62	O
+patients	O
+,	O
+no	O
+other	O
+causes	O
+for	O
+renal	B
+failure	I
+could	O
+be	O
+identified	O
+.	O
+
+Five	O
+of	O
+33	O
+(	O
+15	O
+%	O
+)	O
+of	O
+the	O
+tobramycin	O
+-	O
+treated	O
+patients	O
+and	O
+16	O
+of	O
+29	O
+(	O
+55	O
+.	O
+2	O
+%	O
+)	O
+of	O
+the	O
+gentamicin	O
+-	O
+treated	O
+patients	O
+had	O
+renal	B
+failure	I
+.	O
+
+Thus	O
+,	O
+gentamicin	O
+was	O
+associated	O
+with	O
+renal	B
+failure	I
+more	O
+than	O
+three	O
+times	O
+as	O
+often	O
+as	O
+was	O
+tobramycin	O
+.	O
+
+Metabolic	O
+involvement	O
+in	O
+adriamycin	O
+cardiotoxicity	B
+.	O
+
+The	O
+cardiotoxic	B
+effects	O
+of	O
+adriamycin	O
+were	O
+studied	O
+in	O
+mammalian	O
+myocardial	O
+cells	O
+in	O
+culture	O
+as	O
+a	O
+model	O
+system	O
+.	O
+
+Adriamycin	O
+inhibited	O
+cell	O
+growth	O
+and	O
+the	O
+rhythmic	O
+contractions	O
+characteristic	O
+of	O
+myocardial	O
+cells	O
+in	O
+culture	O
+.	O
+
+A	O
+possible	O
+involvement	O
+of	O
+energy	O
+metabolism	O
+was	O
+suggested	O
+previously	O
+,	O
+and	O
+in	O
+this	O
+study	O
+the	O
+adenylate	O
+energy	O
+charge	O
+and	O
+phosphorylcreatine	O
+mole	O
+fraction	O
+were	O
+determined	O
+in	O
+the	O
+adriamycin	O
+-	O
+treated	O
+cells	O
+.	O
+
+The	O
+adenylate	O
+energy	O
+charge	O
+was	O
+found	O
+to	O
+be	O
+significantly	O
+decreased	O
+,	O
+while	O
+the	O
+phophorylcreatine	O
+mole	O
+fraction	O
+was	O
+unchanged	O
+.	O
+
+Such	O
+disparity	O
+suggests	O
+an	O
+inhibition	O
+of	O
+creatine	O
+phosphokinase	O
+.	O
+
+The	O
+addition	O
+of	O
+1	O
+mM	O
+adenosine	O
+to	O
+the	O
+myocardial	O
+cell	O
+cultures	O
+markedly	O
+increases	O
+the	O
+ATP	O
+concentration	O
+through	O
+a	O
+pathway	O
+reportedly	O
+leading	O
+to	O
+a	O
+compartmentalized	O
+ATP	O
+pool	O
+.	O
+
+In	O
+the	O
+adriamycin	O
+-	O
+treated	O
+cells	O
+,	O
+the	O
+addition	O
+of	O
+adenosine	O
+increased	O
+the	O
+adenylate	O
+charge	O
+and	O
+,	O
+concomitant	O
+with	O
+this	O
+inrcease	O
+,	O
+the	O
+cells	O
+'	O
+functional	O
+integrity	O
+,	O
+in	O
+terms	O
+of	O
+percentage	O
+of	O
+beating	O
+cells	O
+and	O
+rate	O
+of	O
+contractions	O
+,	O
+was	O
+maintained	O
+.	O
+
+Age	O
+-	O
+dependent	O
+sensitivity	O
+of	O
+the	O
+rat	O
+to	O
+neurotoxic	B
+effects	O
+of	O
+streptomycin	O
+.	O
+
+Streptomycin	O
+sulfate	O
+(	O
+300	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+was	O
+injected	O
+for	O
+various	O
+periods	O
+into	O
+preweanling	O
+rats	O
+and	O
+for	O
+3	O
+weeks	O
+into	O
+weanling	O
+rats	O
+.	O
+
+Beginning	O
+at	O
+8	O
+days	O
+of	O
+age	O
+,	O
+body	O
+movement	O
+and	O
+hearing	O
+were	O
+examined	O
+for	O
+6	O
+and	O
+up	O
+to	O
+17	O
+weeks	O
+,	O
+respectively	O
+.	O
+
+Abnormal	B
+movements	I
+and	O
+deafness	B
+occurred	O
+only	O
+in	O
+rats	O
+treated	O
+during	O
+the	O
+preweaning	O
+period	O
+;	O
+within	O
+this	O
+period	O
+the	O
+greatest	O
+sensitivities	O
+for	O
+these	O
+abnormalities	O
+occurred	O
+from	O
+2	O
+to	O
+11	O
+-	O
+17	O
+and	O
+5	O
+to	O
+11	O
+days	O
+of	O
+age	O
+,	O
+respectively	O
+,	O
+indicating	O
+that	O
+the	O
+cochlea	O
+is	O
+more	O
+sensitive	O
+to	O
+streptomycin	O
+than	O
+the	O
+site	O
+(	O
+vestibular	O
+or	O
+central	O
+)	O
+responsible	O
+for	O
+the	O
+dyskinesias	B
+.	O
+
+Late	O
+,	O
+late	O
+doxorubicin	O
+cardiotoxicity	B
+.	O
+
+Cardiac	B
+toxicity	I
+is	O
+a	O
+major	O
+complication	O
+which	O
+limits	O
+the	O
+use	O
+of	O
+adriamycin	O
+as	O
+a	O
+chemotherapeutic	O
+agent	O
+.	O
+
+Cardiomyopathy	B
+is	O
+frequent	O
+when	O
+the	O
+total	O
+dose	O
+exceeds	O
+600	O
+mg	O
+/	O
+m2	O
+and	O
+occurs	O
+within	O
+one	O
+to	O
+six	O
+months	O
+after	O
+cessation	O
+of	O
+therapy	O
+.	O
+
+A	O
+patient	O
+is	O
+reported	O
+who	O
+developed	O
+progressive	O
+cardiomyopathy	B
+two	O
+and	O
+one	O
+-	O
+half	O
+years	O
+after	O
+receiving	O
+580	O
+mg	O
+/	O
+m2	O
+which	O
+apparently	O
+represents	O
+late	O
+,	O
+late	O
+cardiotoxicity	B
+.	O
+
+Attenuation	O
+of	O
+the	O
+lithium	O
+-	O
+induced	O
+diabetes	B
+-	I
+insipidus	I
+-	I
+like	I
+syndrome	I
+by	O
+amiloride	O
+in	O
+rats	O
+.	O
+
+The	O
+effect	O
+of	O
+amiloride	O
+on	O
+lithium	O
+-	O
+induced	O
+polydipsia	B
+and	O
+polyuria	B
+and	O
+on	O
+the	O
+lithium	O
+concentration	O
+in	O
+the	O
+plasma	O
+,	O
+brain	O
+,	O
+kidney	O
+,	O
+thyroid	O
+and	O
+red	O
+blood	O
+cells	O
+was	O
+investigated	O
+in	O
+rats	O
+,	O
+chronically	O
+treated	O
+with	O
+LiCl	O
+.	O
+
+Amiloride	O
+reduced	O
+the	O
+drinking	O
+and	O
+urine	O
+volume	O
+of	O
+rats	O
+in	O
+an	O
+acute	O
+(	O
+6	O
+or	O
+12	O
+h	O
+)	O
+and	O
+a	O
+subacute	O
+(	O
+3	O
+days	O
+)	O
+experiment	O
+.	O
+
+6	O
+h	O
+after	O
+the	O
+administration	O
+of	O
+amiloride	O
+,	O
+a	O
+reduction	O
+was	O
+observed	O
+in	O
+the	O
+lithium	O
+content	O
+of	O
+the	O
+renal	O
+medulla	O
+but	O
+not	O
+in	O
+the	O
+other	O
+organs	O
+studied	O
+.	O
+
+At	O
+12	O
+h	O
+,	O
+all	O
+the	O
+tissues	O
+showed	O
+a	O
+slight	O
+increase	O
+in	O
+lithium	O
+levels	O
+.	O
+
+After	O
+3	O
+days	O
+of	O
+combined	O
+treatment	O
+,	O
+a	O
+marked	O
+elevation	O
+in	O
+plasma	O
+and	O
+tissue	O
+lithium	O
+levels	O
+accompanied	O
+a	O
+reduction	O
+in	O
+water	O
+intake	O
+.	O
+
+In	O
+all	O
+the	O
+experiments	O
+,	O
+the	O
+attenuation	O
+of	O
+the	O
+lithium	O
+-	O
+induced	O
+diabetes	B
+-	I
+insipidus	I
+-	I
+like	I
+syndrome	I
+by	O
+amiloride	O
+was	O
+accompanied	O
+by	O
+a	O
+reduction	O
+of	O
+the	O
+ratio	O
+between	O
+the	O
+lithium	O
+concentration	O
+in	O
+the	O
+renal	O
+medulla	O
+and	O
+its	O
+levels	O
+in	O
+the	O
+blood	O
+and	O
+an	O
+elevation	O
+in	O
+the	O
+plasma	O
+potassium	O
+level	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+acute	O
+amiloride	O
+administration	O
+to	O
+lithium	O
+-	O
+treated	O
+patients	O
+suffering	O
+from	O
+polydipsia	B
+and	O
+polyuria	B
+might	O
+relieve	O
+these	O
+patients	O
+but	O
+prolonged	O
+amiloride	O
+supplementation	O
+would	O
+result	O
+in	O
+elevated	O
+lithium	O
+levels	O
+and	O
+might	O
+be	O
+hazardous	O
+.	O
+
+Cardiovascular	B
+complications	I
+associated	O
+with	O
+terbutaline	O
+treatment	O
+for	O
+preterm	B
+labor	I
+.	O
+
+Severe	O
+cardiovascular	B
+complications	I
+occurred	O
+in	O
+eight	O
+of	O
+160	O
+patients	O
+treated	O
+with	O
+terbutaline	O
+for	O
+preterm	B
+labor	I
+.	O
+
+Associated	O
+corticosteroid	O
+therapy	O
+and	O
+twin	O
+gestations	O
+appear	O
+to	O
+be	O
+predisposing	O
+factors	O
+.	O
+
+Potential	O
+mechanisms	O
+of	O
+the	O
+pathophysiology	O
+are	O
+briefly	O
+discussed	O
+.	O
+
+Toxic	B
+hepatitis	I
+induced	O
+by	O
+antithyroid	O
+drugs	O
+:	O
+four	O
+cases	O
+including	O
+one	O
+with	O
+cross	O
+-	O
+reactivity	O
+between	O
+carbimazole	O
+and	O
+benzylthiouracil	O
+.	O
+
+OBJECTIVE	O
+:	O
+This	O
+study	O
+was	O
+conducted	O
+to	O
+assess	O
+the	O
+occurrence	O
+of	O
+hepatic	B
+adverse	I
+effects	I
+encountered	O
+with	O
+antithyroid	O
+drugs	O
+.	O
+
+METHODS	O
+:	O
+Retrospective	O
+review	O
+of	O
+medical	O
+records	O
+of	O
+236	O
+patients	O
+with	O
+hyperthyroidism	B
+admitted	O
+in	O
+our	O
+department	O
+(	O
+in	O
+-	O
+or	O
+out	O
+-	O
+patients	O
+)	O
+from	O
+1986	O
+to	O
+1992	O
+.	O
+
+RESULTS	O
+:	O
+Four	O
+patients	O
+(	O
+1	O
+.	O
+7	O
+%	O
+)	O
+were	O
+identified	O
+with	O
+toxic	B
+hepatitis	I
+which	O
+could	O
+reasonably	O
+be	O
+attributed	O
+to	O
+the	O
+use	O
+of	O
+antithyroid	O
+agent	O
+.	O
+
+Two	O
+patients	O
+had	O
+a	O
+cholestatic	B
+hepatitis	I
+induced	O
+by	O
+carbimazole	O
+(	O
+N	O
+omercazole	O
+)	O
+.	O
+
+Two	O
+others	O
+had	O
+a	O
+mixed	O
+(	O
+cholestatic	B
+and	O
+cytolytic	O
+)	O
+hepatitis	B
+following	O
+carbimazole	O
+.	O
+
+One	O
+of	O
+the	O
+latter	O
+two	O
+patients	O
+further	O
+experienced	O
+a	O
+cytolytic	O
+hepatitis	B
+which	O
+appeared	O
+after	O
+Benzylthiouracil	O
+(	O
+Basd	O
+ne	O
+)	O
+had	O
+replaced	O
+carbimazole	O
+.	O
+
+Biological	O
+features	O
+of	O
+hepatitis	B
+disappeared	O
+in	O
+all	O
+cases	O
+after	O
+cessation	O
+of	O
+the	O
+incriminated	O
+drug	O
+,	O
+while	O
+biliary	O
+,	O
+viral	O
+and	O
+immunological	O
+searches	O
+were	O
+negative	O
+.	O
+
+Only	O
+2	O
+patients	O
+of	O
+our	O
+retrospective	O
+study	O
+experienced	O
+a	O
+mild	O
+or	O
+severe	O
+neutropenia	B
+.	O
+
+CONCLUSION	O
+:	O
+Toxic	B
+hepatitis	I
+is	O
+a	O
+potential	O
+adverse	O
+effect	O
+of	O
+antithyroid	O
+drugs	O
+which	O
+warrants	O
+,	O
+as	O
+for	O
+haematological	O
+disturbances	O
+,	O
+a	O
+pre	O
+-	O
+therapeutic	O
+determination	O
+and	O
+a	O
+careful	O
+follow	O
+-	O
+up	O
+of	O
+relevant	O
+biological	O
+markers	O
+.	O
+
+Moreover	O
+,	O
+hepatotoxicity	B
+may	O
+not	O
+be	O
+restricted	O
+to	O
+one	O
+class	O
+of	O
+antithyroid	O
+agents	O
+.	O
+
+Interactive	O
+effects	O
+of	O
+variations	O
+in	O
+[	O
+Na	O
+]	O
+o	O
+and	O
+[	O
+Ca	O
+]	O
+o	O
+on	O
+rat	O
+atrial	O
+spontaneous	O
+frequency	O
+.	O
+
+The	O
+effects	O
+of	O
+varying	O
+the	O
+extracellular	O
+concentrations	O
+of	O
+Na	O
+and	O
+Ca	O
+(	O
+[	O
+Na	O
+]	O
+o	O
+and	O
+[	O
+Ca	O
+]	O
+o	O
+)	O
+on	O
+both	O
+,	O
+the	O
+spontaneous	O
+beating	O
+and	O
+the	O
+negative	O
+chronotropic	O
+action	O
+of	O
+verapamil	O
+,	O
+were	O
+studied	O
+in	O
+the	O
+isolated	O
+rat	O
+atria	O
+.	O
+
+Basal	O
+frequency	O
+(	O
+BF	O
+)	O
+evaluated	O
+by	O
+surface	O
+electrogram	O
+was	O
+223	O
++	O
+/	O
+-	O
+4	O
+beats	O
+/	O
+min	O
+.	O
+in	O
+control	O
+Krebs	O
+-	O
+Ringer	O
+containing	O
+137	O
+mM	O
+Na	O
+and	O
+1	O
+.	O
+35	O
+mM	O
+Ca	O
+(	O
+N	O
+)	O
+.	O
+
+It	O
+decreased	O
+by	O
+16	O
++	O
+/	O
+-	O
+3	O
+%	O
+by	O
+lowering	O
+[	O
+Na	O
+]	O
+o	O
+to	O
+78	O
+mM	O
+(	O
+LNa	O
+)	O
+,	O
+23	O
++	O
+/	O
+-	O
+2	O
+%	O
+by	O
+lowering	O
+simultaneously	O
+[	O
+Na	O
+]	O
+o	O
+to	O
+78	O
+mM	O
+and	O
+[	O
+Ca	O
+]	O
+o	O
+to	O
+0	O
+.	O
+675	O
+mM	O
+(	O
+LNa	O
++	O
+LCa	O
+)	O
+and	O
+31	O
++	O
+/	O
+-	O
+5	O
+%	O
+by	O
+lowering	O
+[	O
+Na	O
+]	O
+o	O
+to	O
+78	O
+mM	O
+plus	O
+increasing	O
+[	O
+Ca	O
+]	O
+o	O
+to	O
+3	O
+.	O
+6	O
+mM	O
+(	O
+LNa	O
++	O
+HCa	O
+)	O
+.	O
+
+At	O
+normal	O
+[	O
+Na	O
+]	O
+o	O
+,	O
+decrease	O
+(	O
+0	O
+.	O
+675	O
+mM	O
+)	O
+or	O
+increase	O
+(	O
+3	O
+.	O
+6	O
+mM	O
+)	O
+of	O
+[	O
+Ca	O
+]	O
+o	O
+did	O
+not	O
+modify	O
+BF	O
+;	O
+a	O
+reduction	O
+of	O
+ten	O
+times	O
+(	O
+0	O
+.	O
+135	O
+mM	O
+of	O
+normal	O
+[	O
+Ca	O
+]	O
+o	O
+was	O
+effective	O
+to	O
+reduce	O
+BF	O
+by	O
+40	O
++	O
+/	O
+-	O
+13	O
+%	O
+.	O
+
+All	O
+negative	O
+chronotropic	O
+effects	O
+were	O
+BF	O
+-	O
+dependent	O
+.	O
+
+Dose	O
+-	O
+dependent	O
+bradycardia	B
+induced	O
+by	O
+verapamil	O
+was	O
+potentiated	O
+by	O
+LNa	O
+,	O
+LCa	O
+,	O
+and	O
+HCa	O
+.	O
+
+Independent	O
+but	O
+not	O
+additive	O
+effects	O
+of	O
+Na	O
+and	O
+Ca	O
+are	O
+shown	O
+by	O
+decreases	O
+in	O
+the	O
+values	O
+of	O
+[	O
+verapamil	O
+]	O
+o	O
+needed	O
+to	O
+reduce	O
+BF	O
+by	O
+30	O
+%	O
+(	O
+IC30	O
+)	O
+with	O
+the	O
+following	O
+order	O
+of	O
+inhibitory	O
+potency	O
+:	O
+LNa	O
+>	O
+LCa	O
+>	O
+HCa	O
+>	O
+N	O
+,	O
+resulting	O
+LNa	O
++	O
+HCa	O
+similar	O
+to	O
+LNa	O
+.	O
+
+The	O
+[	O
+verapamil	O
+]	O
+o	O
+that	O
+arrested	O
+atrial	O
+beating	O
+(	O
+AC	O
+)	O
+was	O
+also	O
+potentiated	O
+with	O
+the	O
+order	O
+LNa	O
+=	O
+LNa	O
++	O
+LCa	O
+=	O
+LNa	O
++	O
+HCa	O
+=	O
+LCa	O
+>	O
+HCa	O
+=	O
+N	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+rat	O
+atrial	O
+spontaneous	O
+beating	O
+is	O
+more	O
+dependent	O
+on	O
+[	O
+Na	O
+]	O
+o	O
+than	O
+on	O
+[	O
+Ca	O
+]	O
+o	O
+in	O
+a	O
+range	O
+of	O
++	O
+/	O
+-	O
+50	O
+%	O
+of	O
+their	O
+normal	O
+concentration	O
+.	O
+
+Also	O
+the	O
+enhancement	O
+of	O
+verapamil	O
+effects	O
+on	O
+atrial	O
+beating	O
+was	O
+more	O
+pronounced	O
+at	O
+LNa	O
+than	O
+at	O
+LCa	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Pseudo	O
+-	O
+allergic	B
+reactions	I
+to	O
+corticosteroids	O
+:	O
+diagnosis	O
+and	O
+alternatives	O
+.	O
+
+Two	O
+patients	O
+treated	O
+with	O
+parenteral	O
+paramethasone	O
+(	O
+Triniol	O
+)	O
+and	O
+dexamethasone	O
+(	O
+Sedionbel	O
+)	O
+are	O
+described	O
+.	O
+
+A	O
+few	O
+minutes	O
+after	O
+administration	O
+of	O
+the	O
+drugs	O
+,	O
+they	O
+presented	O
+urticaria	B
+(	O
+patients	O
+1	O
+and	O
+2	O
+)	O
+and	O
+conjunctivitis	B
+(	O
+patient	O
+1	O
+)	O
+.	O
+
+The	O
+purpose	O
+of	O
+our	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+cause	O
+of	O
+the	O
+patients	O
+'	O
+reactions	O
+,	O
+the	O
+immunological	O
+mechanisms	O
+involved	O
+and	O
+whether	O
+these	O
+patients	O
+would	O
+be	O
+able	O
+to	O
+tolerate	O
+any	O
+kind	O
+of	O
+corticoid	O
+.	O
+
+Clinical	O
+examinations	O
+and	O
+skin	O
+,	O
+oral	O
+and	O
+parenteral	O
+challenges	O
+with	O
+different	O
+corticosteroids	O
+and	O
+ELISA	O
+tests	O
+were	O
+performed	O
+.	O
+
+In	O
+the	O
+two	O
+patients	O
+,	O
+skin	O
+and	O
+ELISA	O
+tests	O
+with	O
+paramethasone	O
+were	O
+negative	O
+,	O
+as	O
+was	O
+the	O
+prick	O
+test	O
+with	O
+each	O
+of	O
+its	O
+excipients	O
+.	O
+
+A	O
+single	O
+-	O
+blind	O
+parenteral	O
+challenge	O
+with	O
+Triniol	O
+was	O
+positive	O
+in	O
+both	O
+patients	O
+after	O
+the	O
+administration	O
+of	O
+1	O
+ml	O
+of	O
+the	O
+drug	O
+,	O
+and	O
+negative	O
+with	O
+its	O
+excipients	O
+.	O
+
+We	O
+also	O
+carried	O
+out	O
+oral	O
+and	O
+parenteral	O
+challenges	O
+with	O
+other	O
+corticosteroids	O
+and	O
+found	O
+intolerance	O
+to	O
+some	O
+of	O
+them	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+paramethasone	O
+caused	O
+pseudoallergic	O
+reactions	O
+in	O
+our	O
+patients	O
+.	O
+
+Corticosteroids	O
+different	O
+from	O
+paramethasone	O
+also	O
+produced	O
+hypersensitivity	B
+reactions	O
+in	O
+these	O
+patients	O
+;	O
+however	O
+,	O
+a	O
+few	O
+of	O
+them	O
+were	O
+tolerated	O
+.	O
+
+The	O
+basic	O
+mechanisms	O
+of	O
+those	O
+reactions	O
+are	O
+not	O
+yet	O
+fully	O
+understood	O
+.	O
+
+To	O
+our	O
+knowledge	O
+,	O
+this	O
+is	O
+the	O
+first	O
+report	O
+of	O
+a	O
+pseudo	O
+-	O
+allergy	B
+caused	O
+by	O
+paramethasone	O
+.	O
+
+Study	O
+of	O
+the	O
+role	O
+of	O
+vitamin	O
+B12	O
+and	O
+folinic	O
+acid	O
+supplementation	O
+in	O
+preventing	O
+hematologic	O
+toxicity	B
+of	O
+zidovudine	O
+.	O
+
+A	O
+prospective	O
+,	O
+randomized	O
+study	O
+was	O
+conducted	O
+to	O
+evaluate	O
+the	O
+role	O
+of	O
+vitamin	O
+B12	O
+and	O
+folinic	O
+acid	O
+supplementation	O
+in	O
+preventing	O
+zidovudine	O
+(	O
+ZDV	O
+)	O
+-	O
+induced	O
+bone	B
+marrow	I
+suppression	I
+.	O
+
+Seventy	O
+-	O
+five	O
+human	B
+immunodeficiency	I
+virus	I
+(	I
+HIV	I
+)	I
+-	I
+infected	I
+patients	O
+with	O
+CD4	O
++	O
+cell	O
+counts	O
+<	O
+500	O
+/	O
+mm3	O
+were	O
+randomized	O
+to	O
+receive	O
+either	O
+ZDV	O
+(	O
+500	O
+mg	O
+daily	O
+)	O
+alone	O
+(	O
+group	O
+I	O
+,	O
+n	O
+=	O
+38	O
+)	O
+or	O
+in	O
+combination	O
+with	O
+folinic	O
+acid	O
+(	O
+15	O
+mg	O
+daily	O
+)	O
+and	O
+intramascular	O
+vitamin	O
+B12	O
+(	O
+1000	O
+micrograms	O
+monthly	O
+)	O
+(	O
+group	O
+II	O
+,	O
+n	O
+=	O
+37	O
+)	O
+.	O
+
+Finally	O
+,	O
+15	O
+patients	O
+were	O
+excluded	O
+from	O
+the	O
+study	O
+(	O
+noncompliance	O
+14	O
+,	O
+death	B
+1	O
+)	O
+;	O
+thus	O
+,	O
+60	O
+patients	O
+(	O
+31	O
+in	O
+group	O
+I	O
+and	O
+29	O
+in	O
+group	O
+II	O
+)	O
+were	O
+eligible	O
+for	O
+analysis	O
+.	O
+
+No	O
+significant	O
+differences	O
+between	O
+groups	O
+were	O
+found	O
+at	O
+enrollment	O
+.	O
+
+During	O
+the	O
+study	O
+,	O
+vitamin	O
+B12	O
+and	O
+folate	O
+levels	O
+were	O
+significantly	O
+higher	O
+in	O
+group	O
+II	O
+patients	O
+;	O
+however	O
+,	O
+no	O
+differences	O
+in	O
+hemoglobin	O
+,	O
+hematocrit	O
+,	O
+mean	O
+corpuscular	O
+volume	O
+,	O
+and	O
+white	O
+-	O
+cell	O
+,	O
+neutrophil	O
+and	O
+platelet	O
+counts	O
+were	O
+observed	O
+between	O
+groups	O
+at	O
+3	O
+,	O
+6	O
+,	O
+9	O
+and	O
+12	O
+months	O
+.	O
+
+Severe	O
+hematologic	O
+toxicity	B
+(	O
+neutrophil	O
+count	O
+<	O
+1000	O
+/	O
+mm3	O
+and	O
+/	O
+or	O
+hemoglobin	O
+<	O
+8	O
+g	O
+/	O
+dl	O
+)	O
+occurred	O
+in	O
+4	O
+patients	O
+assigned	O
+to	O
+group	O
+I	O
+and	O
+7	O
+assigned	O
+to	O
+group	O
+II	O
+.	O
+
+There	O
+was	O
+no	O
+correlation	O
+between	O
+vitamin	O
+B12	O
+or	O
+folate	O
+levels	O
+and	O
+development	O
+of	O
+myelosuppression	B
+.	O
+
+Vitamin	O
+B12	O
+and	O
+folinic	O
+acid	O
+supplementation	O
+of	O
+ZDV	O
+therapy	O
+does	O
+not	O
+seem	O
+useful	O
+in	O
+preventing	O
+or	O
+reducing	O
+ZDV	O
+-	O
+induced	O
+myelotoxicity	B
+in	O
+the	O
+overall	O
+treated	O
+population	O
+,	O
+although	O
+a	O
+beneficial	O
+effect	O
+in	O
+certain	O
+subgroups	O
+of	O
+patients	O
+cannot	O
+be	O
+excluded	O
+.	O
+
+Safety	O
+and	O
+side	O
+-	O
+effects	O
+of	O
+alprazolam	O
+.	O
+
+Controlled	O
+study	O
+in	O
+agoraphobia	B
+with	O
+panic	B
+disorder	I
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+widespread	O
+use	O
+of	O
+benzodiazepines	O
+has	O
+led	O
+to	O
+increasing	O
+recognition	O
+of	O
+their	O
+unwanted	O
+effects	O
+.	O
+
+The	O
+efficacy	O
+of	O
+alprazolam	O
+and	O
+placebo	O
+in	O
+panic	B
+disorder	I
+with	O
+agoraphobia	B
+,	O
+and	O
+the	O
+side	O
+-	O
+effect	O
+and	O
+adverse	O
+effect	O
+profiles	O
+of	O
+both	O
+drug	O
+groups	O
+were	O
+measured	O
+.	O
+
+METHOD	O
+:	O
+In	O
+London	O
+and	O
+Toronto	O
+154	O
+patients	O
+who	O
+met	O
+DSM	O
+-	O
+III	O
+criteria	O
+for	O
+panic	B
+disorder	I
+with	O
+agoraphobia	B
+were	O
+randomised	O
+to	O
+alprazolam	O
+or	O
+placebo	O
+.	O
+
+Subjects	O
+in	O
+each	O
+drug	O
+group	O
+also	O
+received	O
+either	O
+exposure	O
+or	O
+relaxation	O
+.	O
+
+Treatment	O
+was	O
+from	O
+weeks	O
+0	O
+to	O
+8	O
+and	O
+was	O
+then	O
+tapered	O
+from	O
+weeks	O
+8	O
+to	O
+16	O
+.	O
+
+RESULTS	O
+:	O
+Mean	O
+alprazolam	O
+dose	O
+was	O
+5	O
+mg	O
+daily	O
+.	O
+
+Compared	O
+with	O
+placebo	O
+subjects	O
+,	O
+alprazolam	O
+patients	O
+developed	O
+more	O
+adverse	O
+reactions	O
+(	O
+21	O
+%	O
+v	O
+.	O
+0	O
+%	O
+)	O
+of	O
+depression	B
+,	O
+enuresis	B
+,	O
+disinhibition	O
+and	O
+aggression	B
+;	O
+and	O
+more	O
+side	O
+-	O
+effects	O
+,	O
+particularly	O
+sedation	O
+,	O
+irritability	B
+,	O
+impaired	B
+memory	I
+,	O
+weight	B
+loss	I
+and	O
+ataxia	B
+.	O
+
+Side	O
+-	O
+effects	O
+tended	O
+to	O
+diminish	O
+during	O
+treatment	O
+but	O
+remained	O
+significant	O
+at	O
+week	O
+8	O
+.	O
+
+Despite	O
+this	O
+,	O
+the	O
+drop	O
+-	O
+out	O
+rate	O
+was	O
+low	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Alprazolam	O
+caused	O
+side	O
+-	O
+effects	O
+and	O
+adverse	O
+effects	O
+during	O
+treatment	O
+but	O
+many	O
+patients	O
+were	O
+willing	O
+to	O
+accept	O
+these	O
+.	O
+
+Crescentic	O
+fibrillary	O
+glomerulonephritis	B
+associated	O
+with	O
+intermittent	O
+rifampin	O
+therapy	O
+for	O
+pulmonary	B
+tuberculosis	I
+.	O
+
+This	O
+case	O
+study	O
+reveals	O
+an	O
+unusual	O
+finding	O
+of	O
+rapidly	O
+proliferative	O
+crescentic	O
+glomerulonephritis	B
+in	O
+a	O
+patient	O
+treated	O
+with	O
+rifampin	O
+who	O
+had	O
+no	O
+other	O
+identifiable	O
+causes	O
+for	O
+developing	O
+this	O
+disease	O
+.	O
+
+This	O
+patient	O
+underwent	O
+a	O
+10	O
+-	O
+month	O
+regimen	O
+of	O
+rifampin	O
+and	O
+isoniazid	O
+for	O
+pulmonary	B
+tuberculosis	I
+and	O
+was	O
+discovered	O
+to	O
+have	O
+developed	O
+signs	O
+of	O
+severe	O
+renal	B
+failure	I
+five	O
+weeks	O
+after	O
+completion	O
+of	O
+therapy	O
+.	O
+
+Renal	O
+biopsy	O
+revealed	O
+severe	O
+glomerulonephritis	B
+with	O
+crescents	O
+,	O
+electron	O
+dense	O
+fibrillar	O
+deposits	O
+and	O
+moderate	O
+lymphocytic	O
+interstitial	O
+infiltrate	O
+.	O
+
+Other	O
+possible	O
+causes	O
+of	O
+rapidly	O
+progressive	O
+glomerulonephritis	B
+were	O
+investigated	O
+and	O
+ruled	O
+out	O
+.	O
+
+This	O
+report	O
+documents	O
+the	O
+unusual	O
+occurrence	O
+of	O
+rapidly	O
+progressive	O
+glomerulonephritis	B
+with	O
+crescents	O
+and	O
+fibrillar	O
+glomerulonephritis	B
+in	O
+a	O
+patient	O
+treated	O
+with	O
+rifampin	O
+.	O
+
+Acute	O
+confusion	B
+induced	O
+by	O
+a	O
+high	O
+-	O
+dose	O
+infusion	O
+of	O
+5	O
+-	O
+fluorouracil	O
+and	O
+folinic	O
+acid	O
+.	O
+
+A	O
+61	O
+-	O
+year	O
+-	O
+old	O
+man	O
+was	O
+treated	O
+with	O
+combination	O
+chemotherapy	O
+incorporating	O
+cisplatinum	O
+,	O
+etoposide	O
+,	O
+high	O
+-	O
+dose	O
+5	O
+-	O
+fluorouracil	O
+(	O
+2	O
+,	O
+250	O
+mg	O
+/	O
+m2	O
+/	O
+24	O
+hours	O
+)	O
+and	O
+folinic	O
+acid	O
+for	O
+an	O
+inoperable	O
+gastric	B
+adenocarcinoma	I
+.	O
+
+He	O
+developed	O
+acute	O
+neurologic	O
+symptoms	O
+of	O
+mental	O
+confusion	B
+,	O
+disorientation	B
+and	O
+irritability	B
+,	O
+and	O
+then	O
+lapsed	O
+into	O
+a	O
+deep	O
+coma	B
+,	O
+lasting	O
+for	O
+approximately	O
+40	O
+hours	O
+during	O
+the	O
+first	O
+dose	O
+(	O
+day	O
+2	O
+)	O
+of	O
+5	O
+-	O
+fluorouracil	O
+and	O
+folinic	O
+acid	O
+infusion	O
+.	O
+
+This	O
+complication	O
+reappeared	O
+on	O
+day	O
+25	O
+during	O
+the	O
+second	O
+dose	O
+of	O
+5	O
+-	O
+fluorouracil	O
+and	O
+folinic	O
+acid	O
+,	O
+which	O
+were	O
+then	O
+the	O
+only	O
+drugs	O
+given	O
+.	O
+
+Because	O
+folinic	O
+acid	O
+was	O
+unlikely	O
+to	O
+be	O
+associated	O
+with	O
+this	O
+condition	O
+,	O
+neurotoxicity	B
+due	O
+to	O
+high	O
+-	O
+dose	O
+5	O
+-	O
+fluorouracil	O
+was	O
+highly	O
+suspected	O
+.	O
+
+The	O
+pathogenesis	O
+of	O
+5	O
+-	O
+fluorouracil	O
+neurotoxicity	B
+may	O
+be	O
+due	O
+to	O
+a	O
+Krebs	O
+cycle	O
+blockade	O
+by	O
+fluoroacetate	O
+and	O
+fluorocitrate	O
+,	O
+thiamine	O
+deficiency	O
+,	O
+or	O
+dihydrouracil	O
+dehydrogenase	O
+deficiency	O
+.	O
+
+High	O
+-	O
+dose	O
+5	O
+-	O
+fluorouracil	O
+/	O
+folinic	O
+acid	O
+infusion	O
+therapy	O
+has	O
+recently	O
+become	O
+a	O
+popular	O
+regimen	O
+for	O
+various	O
+cancers	B
+.	O
+
+It	O
+is	O
+necessary	O
+that	O
+both	O
+oncologists	O
+and	O
+neurologists	O
+be	O
+fully	O
+aware	O
+of	O
+this	O
+unusual	O
+complication	O
+.	O
+
+Effect	O
+of	O
+switching	O
+carbamazepine	O
+to	O
+oxcarbazepine	O
+on	O
+the	O
+plasma	O
+levels	O
+of	O
+neuroleptics	O
+.	O
+
+A	O
+case	O
+report	O
+.	O
+
+Carbamazepine	O
+was	O
+switched	O
+to	O
+its	O
+10	O
+-	O
+keto	O
+analogue	O
+oxcarbazepine	O
+among	O
+six	O
+difficult	O
+-	O
+to	O
+-	O
+treat	O
+schizophrenic	B
+or	O
+organic	B
+psychotic	I
+patients	O
+using	O
+concomitantly	O
+haloperidol	O
+,	O
+chlorpromazine	O
+or	O
+clozapine	O
+.	O
+
+This	O
+change	O
+resulted	O
+within	O
+2	O
+-	O
+4	O
+weeks	O
+in	O
+the	O
+50	O
+-	O
+200	O
+%	O
+increase	O
+in	O
+the	O
+plasma	O
+levels	O
+of	O
+these	O
+neuroleptics	O
+and	O
+the	O
+appearance	O
+of	O
+extrapyramidal	B
+symptoms	I
+.	O
+
+None	O
+of	O
+the	O
+patients	O
+showed	O
+any	O
+clinical	O
+deteriotation	O
+during	O
+the	O
+following	O
+3	O
+-	O
+6	O
+months	O
+.	O
+
+The	O
+results	O
+of	O
+this	O
+case	O
+report	O
+support	O
+the	O
+idea	O
+that	O
+in	O
+contrast	O
+with	O
+carbamazepine	O
+oxcarbazepine	O
+does	O
+not	O
+induce	O
+the	O
+hepatic	O
+microsomal	O
+enzyme	O
+systems	O
+regulating	O
+the	O
+inactivation	O
+of	O
+antipsychotic	O
+drugs	O
+.	O
+
+Time	O
+course	O
+of	O
+lipid	O
+peroxidation	O
+in	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+nephropathy	B
+.	O
+
+Reactive	O
+oxygen	O
+species	O
+have	O
+been	O
+implicated	O
+in	O
+the	O
+pathogenesis	O
+of	O
+acute	O
+puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+)	O
+-	O
+induced	O
+nephropathy	B
+,	O
+with	O
+antioxidants	O
+significantly	O
+reducing	O
+the	O
+proteinuria	B
+.	O
+
+The	O
+temporal	O
+relationship	O
+between	O
+lipid	O
+peroxidation	O
+in	O
+the	O
+kidney	O
+and	O
+proteinuria	B
+was	O
+examined	O
+in	O
+this	O
+study	O
+.	O
+
+Rats	O
+were	O
+treated	O
+with	O
+a	O
+single	O
+IV	O
+injection	O
+of	O
+puromycin	O
+aminonucleoside	O
+,	O
+(	O
+PAN	O
+,	O
+7	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+24	O
+hour	O
+urine	O
+samples	O
+were	O
+obtained	O
+prior	O
+to	O
+sacrifice	O
+on	O
+days	O
+3	O
+,	O
+5	O
+,	O
+7	O
+,	O
+10	O
+,	O
+17	O
+,	O
+27	O
+,	O
+41	O
+(	O
+N	O
+=	O
+5	O
+-	O
+10	O
+per	O
+group	O
+)	O
+.	O
+
+The	O
+kidneys	O
+were	O
+removed	O
+,	O
+flushed	O
+with	O
+ice	O
+cold	O
+TRIS	O
+buffer	O
+.	O
+
+Kidney	O
+cortices	O
+from	O
+each	O
+animal	O
+were	O
+used	O
+to	O
+prepare	O
+homogenates	O
+.	O
+
+Tissue	O
+lipid	O
+peroxidation	O
+was	O
+measured	O
+in	O
+whole	O
+homogenates	O
+as	O
+well	O
+as	O
+in	O
+lipid	O
+extracts	O
+from	O
+homogenates	O
+as	O
+thiobarbituric	O
+acid	O
+reactive	O
+substances	O
+.	O
+
+Proteinuria	B
+was	O
+evident	O
+at	O
+day	O
+5	O
+,	O
+peaked	O
+at	O
+day	O
+7	O
+and	O
+persisted	O
+to	O
+day	O
+27	O
+.	O
+
+Lipid	O
+peroxidation	O
+in	O
+homogenates	O
+was	O
+maximal	O
+at	O
+day	O
+3	O
+and	O
+declined	O
+rapidly	O
+to	O
+control	O
+levels	O
+by	O
+day	O
+17	O
+.	O
+
+This	O
+study	O
+supports	O
+the	O
+role	O
+of	O
+lipid	O
+peroxidation	O
+in	O
+mediating	O
+the	O
+proteinuric	B
+injury	I
+in	O
+PAN	O
+nephropathy	B
+.	O
+
+Composition	O
+of	O
+gall	B
+bladder	I
+stones	I
+associated	O
+with	O
+octreotide	O
+:	O
+response	O
+to	O
+oral	O
+ursodeoxycholic	O
+acid	O
+.	O
+
+Octreotide	O
+,	O
+an	O
+effective	O
+treatment	O
+for	O
+acromegaly	B
+,	O
+induces	O
+gall	B
+bladder	I
+stones	I
+in	O
+13	O
+-	O
+60	O
+%	O
+of	O
+patients	O
+.	O
+
+Because	O
+knowledge	O
+of	O
+stone	O
+composition	O
+is	O
+essential	O
+for	O
+studies	O
+of	O
+their	O
+pathogenesis	O
+,	O
+treatment	O
+,	O
+and	O
+prevention	O
+,	O
+this	O
+was	O
+investigated	O
+by	O
+direct	O
+and	O
+indirect	O
+methods	O
+in	O
+14	O
+octreotide	O
+treated	O
+acromegalic	B
+patients	O
+with	O
+gall	B
+stones	I
+.	O
+
+Chemical	O
+analysis	O
+of	O
+gall	B
+stones	I
+retrieved	O
+at	O
+cholecystectomy	O
+from	O
+two	O
+patients	O
+,	O
+showed	O
+that	O
+they	O
+contained	O
+71	O
+%	O
+and	O
+87	O
+%	O
+cholesterol	O
+by	O
+weight	O
+.	O
+
+In	O
+the	O
+remaining	O
+12	O
+patients	O
+,	O
+localised	O
+computed	O
+tomography	O
+of	O
+the	O
+gall	O
+bladder	O
+showed	O
+that	O
+eight	O
+had	O
+stones	O
+with	O
+maximum	O
+attenuation	O
+scores	O
+of	O
+<	O
+100	O
+Hounsfield	O
+units	O
+(	O
+values	O
+of	O
+<	O
+100	O
+HU	O
+predict	O
+cholesterol	O
+rich	O
+,	O
+dissolvable	O
+stones	O
+)	O
+.	O
+
+Gall	O
+bladder	O
+bile	O
+was	O
+obtained	O
+by	O
+ultrasound	O
+guided	O
+,	O
+fine	O
+needle	O
+puncture	O
+from	O
+six	O
+patients	O
+.	O
+
+All	O
+six	O
+patients	O
+had	O
+supersaturated	O
+bile	O
+(	O
+mean	O
+(	O
+SEM	O
+)	O
+cholesterol	O
+saturation	O
+index	O
+of	O
+1	O
+.	O
+19	O
+(	O
+0	O
+.	O
+08	O
+)	O
+(	O
+range	O
+1	O
+.	O
+01	O
+-	O
+1	O
+.	O
+53	O
+)	O
+)	O
+and	O
+all	O
+had	O
+abnormally	O
+rapid	O
+cholesterol	O
+microcrystal	O
+nucleation	O
+times	O
+(	O
+<	O
+4	O
+days	O
+(	O
+range	O
+1	O
+-	O
+4	O
+)	O
+)	O
+,	O
+whilst	O
+in	O
+four	O
+,	O
+the	O
+bile	O
+contained	O
+cholesterol	O
+microcrystals	O
+immediately	O
+after	O
+sampling	O
+.	O
+
+Of	O
+the	O
+12	O
+patients	O
+considered	O
+for	O
+oral	O
+ursodeoxycholic	O
+acid	O
+(	O
+UDCA	O
+)	O
+treatment	O
+,	O
+two	O
+had	O
+a	O
+blocked	O
+cystic	O
+duct	O
+and	O
+were	O
+not	O
+started	O
+on	O
+UDCA	O
+while	O
+one	O
+was	O
+lost	O
+to	O
+follow	O
+up	O
+.	O
+
+After	O
+one	O
+year	O
+of	O
+treatment	O
+,	O
+five	O
+of	O
+the	O
+remaining	O
+nine	O
+patients	O
+showed	O
+either	O
+partial	O
+(	O
+n	O
+=	O
+3	O
+)	O
+or	O
+complete	O
+(	O
+n	O
+=	O
+2	O
+)	O
+gall	B
+stone	I
+dissolution	O
+,	O
+suggesting	O
+that	O
+their	O
+stones	O
+were	O
+cholesterol	O
+rich	O
+.	O
+
+This	O
+corresponds	O
+,	O
+by	O
+actuarial	O
+(	O
+life	O
+table	O
+)	O
+analysis	O
+,	O
+to	O
+a	O
+combined	O
+gall	B
+stone	I
+dissolution	O
+rate	O
+of	O
+58	O
+.	O
+3	O
+(	O
+15	O
+.	O
+9	O
+%	O
+)	O
+.	O
+
+In	O
+conclusion	O
+,	O
+octreotide	O
+induced	O
+gall	B
+stones	I
+are	O
+generally	O
+small	O
+,	O
+multiple	O
+,	O
+and	O
+cholesterol	O
+rich	O
+although	O
+,	O
+in	O
+common	O
+with	O
+spontaneous	O
+gall	B
+stone	I
+disease	I
+,	O
+at	O
+presentation	O
+some	O
+patients	O
+will	O
+have	O
+a	O
+blocked	O
+cystic	O
+duct	O
+and	O
+some	O
+gall	B
+stones	I
+containing	O
+calcium	O
+.	O
+
+Erythema	B
+multiforme	I
+and	O
+hypersensitivity	B
+myocarditis	I
+caused	O
+by	O
+ampicillin	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+erythema	B
+multiforme	I
+and	O
+hypersensitivity	B
+myocarditis	I
+caused	O
+by	O
+ampicillin	O
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+13	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+was	O
+treated	O
+with	O
+ampicillin	O
+and	O
+gentamicin	O
+because	O
+of	O
+suspected	O
+septicemia	B
+.	O
+
+Medications	O
+were	O
+discontinued	O
+when	O
+erythema	B
+multiforme	I
+and	O
+congestive	B
+heart	I
+failure	I
+caused	O
+by	O
+myocarditis	B
+occurred	O
+.	O
+
+The	O
+patient	O
+was	O
+treated	O
+with	O
+methylprednisolone	O
+and	O
+gradually	O
+improved	O
+.	O
+
+Macrophage	O
+-	O
+migration	O
+inhibition	O
+(	O
+MIF	O
+)	O
+test	O
+with	O
+ampicillin	O
+was	O
+positive	O
+.	O
+
+DISCUSSION	O
+:	O
+After	O
+most	O
+infections	B
+causing	O
+erythema	B
+multiforme	I
+and	O
+myocarditis	B
+were	O
+ruled	O
+out	O
+,	O
+a	O
+drug	B
+-	I
+induced	I
+allergic	I
+reaction	I
+was	O
+suspected	O
+.	O
+
+Positive	O
+MIF	O
+test	O
+for	O
+ampicillin	O
+showed	O
+sensitization	O
+of	O
+the	O
+patient	O
+'	O
+s	O
+lymphocytes	O
+to	O
+ampicillin	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Hypersensitivity	B
+myocarditis	I
+is	O
+a	O
+rare	O
+and	O
+dangerous	O
+manifestation	O
+of	O
+allergy	B
+to	O
+penicillins	O
+.	O
+
+Clomipramine	O
+-	O
+induced	O
+sleep	B
+disturbance	I
+does	O
+not	O
+impair	O
+its	O
+prolactin	O
+-	O
+releasing	O
+action	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+undertaken	O
+to	O
+examine	O
+the	O
+role	O
+of	O
+sleep	B
+disturbance	I
+,	O
+induced	O
+by	O
+clomipramine	O
+administration	O
+,	O
+on	O
+the	O
+secretory	O
+rate	O
+of	O
+prolactin	O
+(	O
+PRL	O
+)	O
+in	O
+addition	O
+to	O
+the	O
+direct	O
+drug	O
+effect	O
+.	O
+
+Two	O
+groups	O
+of	O
+supine	O
+subjects	O
+were	O
+studied	O
+under	O
+placebo	O
+-	O
+controlled	O
+conditions	O
+,	O
+one	O
+during	O
+the	O
+night	O
+,	O
+when	O
+sleeping	O
+(	O
+n	O
+=	O
+7	O
+)	O
+and	O
+the	O
+other	O
+at	O
+daytime	O
+,	O
+when	O
+awake	O
+(	O
+n	O
+=	O
+6	O
+)	O
+.	O
+
+Each	O
+subject	O
+received	O
+a	O
+single	O
+50	O
+mg	O
+dose	O
+of	O
+clomipramine	O
+given	O
+orally	O
+2	O
+hours	O
+before	O
+blood	O
+collection	O
+.	O
+
+Plasma	O
+PRL	O
+concentrations	O
+were	O
+analysed	O
+at	O
+10	O
+min	O
+intervals	O
+and	O
+underlying	O
+secretory	O
+rates	O
+calculated	O
+by	O
+a	O
+deconvolution	O
+procedure	O
+.	O
+
+For	O
+both	O
+experiments	O
+the	O
+drug	O
+intake	O
+led	O
+to	O
+significant	O
+increases	O
+in	O
+PRL	O
+secretion	O
+,	O
+acting	O
+preferentially	O
+on	O
+tonic	O
+secretion	O
+as	O
+pulse	O
+amplitude	O
+and	O
+frequency	O
+did	O
+not	O
+differ	O
+significantly	O
+from	O
+corresponding	O
+control	O
+values	O
+.	O
+
+During	O
+the	O
+night	O
+clomipramine	O
+ingestion	O
+altered	O
+the	O
+complete	O
+sleep	O
+architecture	O
+in	O
+that	O
+it	O
+suppressed	O
+REM	O
+sleep	O
+and	O
+the	O
+sleep	O
+cycles	O
+and	O
+induced	O
+increased	O
+wakefulness	O
+.	O
+
+As	O
+the	O
+relative	O
+increase	O
+in	O
+PRL	O
+secretion	O
+expressed	O
+as	O
+a	O
+percentage	O
+of	O
+the	O
+mean	O
+did	O
+not	O
+significantly	O
+differ	O
+between	O
+the	O
+night	O
+and	O
+day	O
+time	O
+studies	O
+(	O
+46	O
++	O
+/	O
+-	O
+19	O
+%	O
+vs	O
+34	O
++	O
+/	O
+-	O
+10	O
+%	O
+)	O
+,	O
+it	O
+can	O
+be	O
+concluded	O
+that	O
+the	O
+observed	O
+sleep	B
+disturbance	I
+did	O
+not	O
+interfere	O
+with	O
+the	O
+drug	O
+action	O
+per	O
+se	O
+.	O
+
+The	O
+presence	O
+of	O
+REM	O
+sleep	O
+was	O
+shown	O
+not	O
+to	O
+be	O
+a	O
+determining	O
+factor	O
+either	O
+for	O
+secretory	O
+pulse	O
+amplitude	O
+and	O
+frequency	O
+,	O
+as	O
+,	O
+for	O
+both	O
+,	O
+mean	O
+nocturnal	O
+values	O
+were	O
+similar	O
+with	O
+and	O
+without	O
+prior	O
+clomipramine	O
+ingestion	O
+.	O
+
+Survey	O
+of	O
+complications	O
+of	O
+indocyanine	O
+green	O
+angiography	O
+in	O
+Japan	O
+.	O
+
+PURPOSE	O
+:	O
+We	O
+evaluated	O
+the	O
+safety	O
+of	O
+indocyanine	O
+green	O
+for	O
+use	O
+in	O
+fundus	O
+angiography	O
+.	O
+
+METHODS	O
+:	O
+We	O
+sent	O
+a	O
+questionnaire	O
+concerning	O
+complications	O
+of	O
+indocyanine	O
+green	O
+to	O
+32	O
+institutions	O
+in	O
+Japan	O
+,	O
+which	O
+were	O
+selected	O
+on	O
+the	O
+basis	O
+of	O
+the	O
+client	O
+list	O
+from	O
+the	O
+Topcon	O
+Company	O
+,	O
+which	O
+manufactures	O
+the	O
+indocyanine	O
+green	O
+fundus	O
+camera	O
+.	O
+
+RESULTS	O
+:	O
+Ophthalmologists	O
+at	O
+15	O
+institutions	O
+responded	O
+,	O
+reporting	O
+a	O
+total	O
+of	O
+3	O
+,	O
+774	O
+indocyanine	O
+green	O
+angiograms	O
+performed	O
+on	O
+2	O
+,	O
+820	O
+patients	O
+between	O
+June	O
+1984	O
+and	O
+September	O
+1992	O
+.	O
+
+Before	O
+angiography	O
+,	O
+intradermal	O
+or	O
+intravenous	O
+indocyanine	O
+green	O
+testing	O
+,	O
+or	O
+both	O
+was	O
+performed	O
+at	O
+13	O
+of	O
+15	O
+institutions	O
+.	O
+
+For	O
+three	O
+patients	O
+,	O
+the	O
+decision	O
+was	O
+made	O
+not	O
+to	O
+proceed	O
+with	O
+angiography	O
+after	O
+positive	O
+preangiographic	O
+testing	O
+.	O
+
+The	O
+dosage	O
+of	O
+indocyanine	O
+green	O
+used	O
+for	O
+angiography	O
+varied	O
+from	O
+25	O
+to	O
+75	O
+mg	O
+,	O
+depending	O
+upon	O
+the	O
+institution	O
+.	O
+
+There	O
+were	O
+13	O
+cases	O
+of	O
+adverse	O
+reactions	O
+(	O
+0	O
+.	O
+34	O
+%	O
+)	O
+,	O
+ten	O
+of	O
+which	O
+were	O
+mild	O
+reactions	O
+such	O
+as	O
+nausea	B
+,	O
+exanthema	B
+,	O
+urtication	B
+,	O
+itchiness	B
+,	O
+and	O
+urgency	O
+to	O
+defecate	O
+,	O
+and	O
+did	O
+not	O
+require	O
+treatment	O
+.	O
+
+Also	O
+recorded	O
+were	O
+one	O
+case	O
+of	O
+pain	B
+of	O
+the	O
+vein	O
+,	O
+which	O
+required	O
+treatment	O
+,	O
+and	O
+two	O
+cases	O
+of	O
+hypotension	B
+.	O
+
+The	O
+two	O
+hypotensive	B
+patients	O
+required	O
+treatment	O
+for	O
+shock	B
+.	O
+
+CONCLUSIONS	O
+:	O
+A	O
+comparison	O
+of	O
+frequency	O
+of	O
+adverse	O
+reactions	O
+to	O
+indocyanine	O
+green	O
+with	O
+the	O
+previously	O
+reported	O
+frequency	O
+of	O
+such	O
+reactions	O
+to	O
+fluorescein	O
+sodium	O
+indicated	O
+that	O
+indocyanine	O
+green	O
+is	O
+a	O
+safe	O
+as	O
+fluorescein	O
+for	O
+use	O
+in	O
+angiography	O
+.	O
+
+Angioedema	B
+following	O
+the	O
+intravenous	O
+administration	O
+of	O
+metoprolol	O
+.	O
+
+A	O
+72	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+was	O
+admitted	O
+to	O
+the	O
+hospital	O
+with	O
+"	O
+flash	O
+"	O
+pulmonary	B
+edema	I
+,	O
+preceded	O
+by	O
+chest	B
+pain	I
+,	O
+requiring	O
+intubation	O
+.	O
+
+Her	O
+medical	O
+history	O
+included	O
+coronary	B
+artery	I
+disease	I
+with	O
+previous	O
+myocardial	B
+infarctions	I
+,	O
+hypertension	B
+,	O
+and	O
+diabetes	B
+mellitus	I
+.	O
+
+A	O
+history	O
+of	O
+angioedema	B
+secondary	O
+to	O
+lisinopril	O
+therapy	O
+was	O
+elicited	O
+.	O
+
+Current	O
+medications	O
+did	O
+not	O
+include	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitors	O
+or	O
+beta	O
+-	O
+blockers	O
+.	O
+
+She	O
+had	O
+no	O
+previous	O
+beta	O
+-	O
+blocking	O
+drug	O
+exposure	O
+.	O
+
+During	O
+the	O
+first	O
+day	O
+of	O
+hospitalization	O
+(	O
+while	O
+intubated	O
+)	O
+,	O
+intravenous	O
+metoprolol	O
+was	O
+given	O
+,	O
+resulting	O
+in	O
+severe	O
+angioedema	B
+.	O
+
+The	O
+angioedema	B
+resolved	O
+after	O
+therapy	O
+with	O
+intravenous	O
+steroids	O
+and	O
+diphenhydramine	O
+hydrochloride	O
+.	O
+
+Effect	O
+of	O
+coniine	O
+on	O
+the	O
+developing	O
+chick	O
+embryo	O
+.	O
+
+Coniine	O
+,	O
+an	O
+alkaloid	O
+from	O
+Conium	O
+maculatum	O
+(	O
+poison	O
+hemlock	O
+)	O
+,	O
+has	O
+been	O
+shown	O
+to	O
+be	O
+teratogenic	O
+in	O
+livestock	O
+.	O
+
+The	O
+major	O
+teratogenic	O
+outcome	O
+is	O
+arthrogryposis	B
+,	O
+presumably	O
+due	O
+to	O
+nicotinic	O
+receptor	O
+blockade	O
+.	O
+
+However	O
+,	O
+coniine	O
+has	O
+failed	O
+to	O
+produce	O
+arthrogryposis	B
+in	O
+rats	O
+or	O
+mice	O
+and	O
+is	O
+only	O
+weakly	O
+teratogenic	O
+in	O
+rabbits	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+evaluate	O
+and	O
+compare	O
+the	O
+effects	O
+of	O
+coniine	O
+and	O
+nicotine	O
+in	O
+the	O
+developing	O
+chick	O
+.	O
+
+Concentrations	O
+of	O
+coniine	O
+and	O
+nicotine	O
+sulfate	O
+were	O
+0	O
+.	O
+015	O
+%	O
+,	O
+0	O
+.	O
+03	O
+%	O
+,	O
+0	O
+.	O
+075	O
+%	O
+,	O
+0	O
+.	O
+15	O
+%	O
+,	O
+0	O
+.	O
+75	O
+%	O
+,	O
+1	O
+.	O
+5	O
+%	O
+,	O
+3	O
+%	O
+,	O
+and	O
+6	O
+%	O
+and	O
+1	O
+%	O
+,	O
+5	O
+%	O
+,	O
+and	O
+10	O
+%	O
+,	O
+respectively	O
+.	O
+
+Both	O
+compounds	O
+caused	O
+deformations	B
+and	O
+lethality	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+.	O
+
+All	O
+concentrations	O
+of	O
+nicotine	O
+sulfate	O
+caused	O
+some	O
+lethality	O
+but	O
+a	O
+no	O
+effect	O
+level	O
+for	O
+coniine	O
+lethality	O
+was	O
+0	O
+.	O
+75	O
+%	O
+.	O
+
+The	O
+deformations	B
+caused	O
+by	O
+both	O
+coniine	O
+and	O
+nicotine	O
+sulfate	O
+were	O
+excessive	B
+flexion	I
+or	I
+extension	I
+of	I
+one	I
+or	I
+more	I
+toes	I
+.	O
+
+No	O
+histopathological	O
+alterations	O
+or	O
+differences	O
+in	O
+bone	O
+formation	O
+were	O
+seen	O
+in	O
+the	O
+limbs	O
+or	O
+toes	O
+of	O
+any	O
+chicks	O
+from	O
+any	O
+group	O
+;	O
+however	O
+,	O
+extensive	O
+cranial	B
+hemorrhage	I
+occurred	O
+in	O
+all	O
+nicotine	O
+sulfate	O
+-	O
+treated	O
+chicks	O
+.	O
+
+There	O
+was	O
+a	O
+statistically	O
+significant	O
+(	O
+P	O
+<	O
+or	O
+=	O
+0	O
+.	O
+01	O
+)	O
+decrease	O
+in	O
+movement	O
+in	O
+coniine	O
+and	O
+nicotine	O
+sulfate	O
+treated	O
+chicks	O
+as	O
+determined	O
+by	O
+ultrasound	O
+.	O
+
+Control	O
+chicks	O
+were	O
+in	O
+motion	O
+an	O
+average	O
+of	O
+33	O
+.	O
+67	O
+%	O
+of	O
+the	O
+time	O
+,	O
+while	O
+coniine	O
+-	O
+treated	O
+chicks	O
+were	O
+only	O
+moving	O
+8	O
+.	O
+95	O
+%	O
+of	O
+a	O
+5	O
+-	O
+min	O
+interval	O
+,	O
+and	O
+no	O
+movement	O
+was	O
+observed	O
+for	O
+nicotine	O
+sulfate	O
+treated	O
+chicks	O
+.	O
+
+In	O
+summary	O
+,	O
+the	O
+chick	O
+embryo	O
+provides	O
+a	O
+reliable	O
+and	O
+simple	O
+experimental	O
+animal	O
+model	O
+of	O
+coniine	O
+-	O
+induced	O
+arthrogryposis	B
+.	O
+
+Data	O
+from	O
+this	O
+model	O
+support	O
+a	O
+mechanism	O
+involving	O
+nicotinic	O
+receptor	O
+blockade	O
+with	O
+subsequent	O
+decreased	O
+fetal	O
+movement	O
+.	O
+
+Immediate	O
+allergic	B
+reactions	I
+to	O
+amoxicillin	O
+.	O
+
+A	O
+large	O
+group	O
+of	O
+patients	O
+with	O
+suspected	O
+allergic	B
+reactions	I
+to	O
+beta	O
+-	O
+lactam	O
+antibiotics	O
+was	O
+evaluated	O
+.	O
+
+A	O
+detailed	O
+clinical	O
+history	O
+,	O
+together	O
+with	O
+skin	O
+tests	O
+,	O
+RAST	O
+(	O
+radioallergosorbent	O
+test	O
+)	O
+,	O
+and	O
+controlled	O
+challenge	O
+tests	O
+,	O
+was	O
+used	O
+to	O
+establish	O
+whether	O
+patients	O
+allergic	B
+to	O
+beta	O
+-	O
+lactam	O
+antibiotics	O
+had	O
+selective	O
+immediate	O
+allergic	B
+responses	O
+to	O
+amoxicillin	O
+(	O
+AX	O
+)	O
+or	O
+were	O
+cross	O
+-	O
+reacting	O
+with	O
+other	O
+penicillin	O
+derivatives	O
+.	O
+
+Skin	O
+tests	O
+were	O
+performed	O
+with	O
+benzylpenicilloyl	O
+-	O
+poly	O
+-	O
+L	O
+-	O
+lysine	O
+(	O
+BPO	O
+-	O
+PLL	O
+)	O
+,	O
+benzylpenicilloate	O
+,	O
+benzylpenicillin	O
+(	O
+PG	O
+)	O
+,	O
+ampicillin	O
+(	O
+AMP	O
+)	O
+,	O
+and	O
+AX	O
+.	O
+
+RAST	O
+for	O
+BPO	O
+-	O
+PLL	O
+and	O
+AX	O
+-	O
+PLL	O
+was	O
+done	O
+.	O
+
+When	O
+both	O
+skin	O
+test	O
+and	O
+RAST	O
+for	O
+BPO	O
+were	O
+negative	O
+,	O
+single	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+challenge	O
+tests	O
+were	O
+done	O
+to	O
+ensure	O
+tolerance	O
+of	O
+PG	O
+or	O
+sensitivity	O
+to	O
+AX	O
+.	O
+
+A	O
+total	O
+of	O
+177	O
+patients	O
+were	O
+diagnosed	O
+as	O
+allergic	B
+to	O
+beta	O
+-	O
+lactam	O
+antibiotics	O
+.	O
+
+We	O
+selected	O
+the	O
+54	O
+(	O
+30	O
+.	O
+5	O
+%	O
+)	O
+cases	O
+of	O
+immediate	O
+AX	O
+allergy	B
+with	O
+good	O
+tolerance	O
+of	O
+PG	O
+.	O
+
+Anaphylaxis	B
+was	O
+seen	O
+in	O
+37	O
+patients	O
+(	O
+69	O
+%	O
+)	O
+,	O
+the	O
+other	O
+17	O
+(	O
+31	O
+%	O
+)	O
+having	O
+urticaria	B
+and	O
+/	O
+or	O
+angioedema	B
+.	O
+
+All	O
+the	O
+patients	O
+were	O
+skin	O
+test	O
+negative	O
+to	O
+BPO	O
+;	O
+49	O
+of	O
+51	O
+(	O
+96	O
+%	O
+)	O
+were	O
+also	O
+negative	O
+to	O
+MDM	B
+,	O
+and	O
+44	O
+of	O
+46	O
+(	O
+96	O
+%	O
+)	O
+to	O
+PG	O
+.	O
+
+Skin	O
+tests	O
+with	O
+AX	O
+were	O
+positive	O
+in	O
+34	O
+(	O
+63	O
+%	O
+)	O
+patients	O
+.	O
+
+RAST	O
+was	O
+positive	O
+for	O
+AX	O
+in	O
+22	O
+patients	O
+(	O
+41	O
+%	O
+)	O
+and	O
+to	O
+BPO	O
+in	O
+just	O
+5	O
+(	O
+9	O
+%	O
+)	O
+.	O
+
+None	O
+of	O
+the	O
+sera	O
+with	O
+negative	O
+RAST	O
+for	O
+AX	O
+were	O
+positive	O
+to	O
+BPO	O
+.	O
+
+Challenge	O
+tests	O
+with	O
+AX	O
+were	O
+performed	O
+in	O
+23	O
+subjects	O
+(	O
+43	O
+%	O
+)	O
+to	O
+establish	O
+the	O
+diagnosis	O
+of	O
+immediate	O
+allergic	B
+reaction	I
+to	O
+AX	O
+,	O
+and	O
+in	O
+15	O
+cases	O
+(	O
+28	O
+%	O
+)	O
+both	O
+skin	O
+test	O
+and	O
+RAST	O
+for	O
+AX	O
+were	O
+negative	O
+.	O
+
+PG	O
+was	O
+well	O
+tolerated	O
+by	O
+all	O
+54	O
+patients	O
+.	O
+
+We	O
+describe	O
+the	O
+largest	O
+group	O
+of	O
+AX	O
+-	O
+allergic	B
+patients	O
+who	O
+have	O
+tolerated	O
+PG	O
+reported	O
+so	O
+far	O
+.	O
+
+Diagnosis	O
+of	O
+these	O
+patients	O
+can	O
+be	O
+achieved	O
+only	O
+if	O
+specific	O
+AX	O
+-	O
+related	O
+reagents	O
+are	O
+employed	O
+.	O
+
+Further	O
+studies	O
+are	O
+necessary	O
+to	O
+determine	O
+the	O
+exact	O
+extent	O
+of	O
+this	O
+problem	O
+and	O
+to	O
+improve	O
+the	O
+efficacy	O
+of	O
+diagnostic	O
+methods	O
+.	O
+
+Reversal	O
+by	O
+phenylephrine	O
+of	O
+the	O
+beneficial	O
+effects	O
+of	O
+intravenous	O
+nitroglycerin	O
+in	O
+patients	O
+with	O
+acute	B
+myocardial	I
+infarction	I
+.	O
+
+Nitroglycerin	O
+has	O
+been	O
+shown	O
+to	O
+reduce	O
+ST	O
+-	O
+segment	O
+elevation	O
+during	O
+acute	B
+myocardial	I
+infarction	I
+,	O
+an	O
+effect	O
+potentiated	O
+in	O
+the	O
+dog	O
+by	O
+agents	O
+that	O
+reverse	O
+nitroglycerin	O
+-	O
+induced	O
+hypotension	B
+.	O
+
+Our	O
+study	O
+was	O
+designed	O
+to	O
+determine	O
+the	O
+effects	O
+of	O
+combined	O
+nitroglycerin	O
+and	O
+phenylephrine	O
+therapy	O
+.	O
+
+Ten	O
+patients	O
+with	O
+acute	O
+transmural	O
+myocardial	B
+infarctions	I
+received	O
+intravenous	O
+nitroglycerin	O
+,	O
+sufficient	O
+to	O
+reduce	O
+mean	O
+arterial	O
+pressure	O
+from	O
+107	O
++	O
+/	O
+-	O
+6	O
+to	O
+85	O
++	O
+/	O
+-	O
+6	O
+mm	O
+Hg	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+,	O
+for	O
+60	O
+minutes	O
+.	O
+
+Left	O
+ventricular	O
+filling	O
+pressure	O
+decreased	O
+from	O
+19	O
++	O
+/	O
+-	O
+2	O
+to	O
+11	O
++	O
+/	O
+-	O
+2	O
+mm	O
+Hg	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+SigmaST	O
+,	O
+the	O
+sum	O
+of	O
+ST	O
+-	O
+segment	O
+elevations	O
+in	O
+16	O
+precordial	O
+leads	O
+,	O
+decreased	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+02	O
+)	O
+with	O
+intravenous	O
+nitroglycerin	O
+.	O
+
+Subsequent	O
+addition	O
+of	O
+phenylephrine	O
+infusion	O
+,	O
+sufficient	O
+to	O
+re	O
+-	O
+elevate	O
+mean	O
+arterial	O
+pressure	O
+to	O
+106	O
++	O
+/	O
+-	O
+4	O
+mm	O
+Hg	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+for	O
+30	O
+minutes	O
+,	O
+increased	O
+left	O
+ventricular	O
+filling	O
+pressure	O
+to	O
+17	O
++	O
+/	O
+-	O
+2	O
+mm	O
+Hg	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+and	O
+also	O
+significantly	O
+increased	O
+sigmaST	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Our	O
+results	O
+suggest	O
+that	O
+addition	O
+of	O
+phenylephrine	O
+to	O
+nitroglycerin	O
+is	O
+not	O
+beneficial	O
+in	O
+the	O
+treatment	O
+of	O
+patients	O
+with	O
+acute	B
+myocardial	I
+infarction	I
+.	O
+
+Acetazolamide	O
+-	O
+induced	O
+nephrolithiasis	B
+:	O
+implications	O
+for	O
+treatment	O
+of	O
+neuromuscular	B
+disorders	I
+.	O
+
+Carbonic	O
+anhydrase	O
+inhibitors	O
+can	O
+cause	O
+nephrolithiasis	B
+.	O
+
+We	O
+studied	O
+20	O
+patients	O
+receiving	O
+long	O
+-	O
+term	O
+carbonic	O
+anhydrase	O
+inhibitor	O
+treatment	O
+for	O
+periodic	O
+paralysis	B
+and	O
+myotonia	B
+.	O
+
+Three	O
+patients	O
+on	O
+acetazolamide	O
+(	O
+15	O
+%	O
+)	O
+developed	O
+renal	B
+calculi	I
+.	O
+
+Extracorporeal	O
+lithotripsy	O
+successfully	O
+removed	O
+a	O
+renal	B
+calculus	I
+in	O
+one	O
+patient	O
+and	O
+surgery	O
+removed	O
+a	O
+staghorn	O
+calculus	B
+in	O
+another	O
+,	O
+permitting	O
+continued	O
+treatment	O
+.	O
+
+Renal	O
+function	O
+remained	O
+normal	O
+in	O
+all	O
+patients	O
+.	O
+
+Nephrolithiasis	B
+is	O
+a	O
+complication	O
+of	O
+acetazolamide	O
+but	O
+does	O
+not	O
+preclude	O
+its	O
+use	O
+.	O
+
+Effects	O
+of	O
+calcium	O
+channel	O
+blockers	O
+on	O
+bupivacaine	O
+-	O
+induced	O
+toxicity	B
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+influence	O
+of	O
+calcium	O
+channel	O
+blockers	O
+on	O
+bupivacaine	O
+-	O
+induced	O
+acute	O
+toxicity	B
+.	O
+
+For	O
+each	O
+of	O
+the	O
+three	O
+tested	O
+calcium	O
+channel	O
+blockers	O
+(	O
+diltiazem	O
+,	O
+verapamil	O
+and	O
+bepridil	O
+)	O
+6	O
+groups	O
+of	O
+mice	O
+were	O
+treated	O
+by	O
+two	O
+different	O
+doses	O
+,	O
+i	O
+.	O
+e	O
+.	O
+2	O
+and	O
+10	O
+mg	O
+/	O
+kg	O
+/	O
+i	O
+.	O
+p	O
+.	O
+,	O
+or	O
+an	O
+equal	O
+volume	O
+of	O
+saline	O
+for	O
+the	O
+control	O
+group	O
+(	O
+n	O
+=	O
+20	O
+)	O
+;	O
+15	O
+minutes	O
+later	O
+,	O
+all	O
+the	O
+animals	O
+were	O
+injected	O
+with	O
+a	O
+single	O
+50	O
+mg	O
+/	O
+kg	O
+/	O
+i	O
+.	O
+p	O
+.	O
+dose	O
+of	O
+bupivacaine	O
+.	O
+
+The	O
+convulsant	O
+activity	O
+,	O
+the	O
+time	O
+of	O
+latency	O
+to	O
+convulse	O
+and	O
+the	O
+mortality	O
+rate	O
+were	O
+assessed	O
+in	O
+each	O
+group	O
+.	O
+
+The	O
+local	O
+anesthetic	O
+-	O
+induced	O
+mortality	O
+was	O
+significantly	O
+increased	O
+by	O
+the	O
+three	O
+different	O
+calcium	O
+channel	O
+blockers	O
+.	O
+
+The	O
+convulsant	O
+activity	O
+of	O
+bupivacaine	O
+was	O
+not	O
+significantly	O
+modified	O
+but	O
+calcium	O
+channel	O
+blockers	O
+decreased	O
+the	O
+time	O
+of	O
+latency	O
+to	O
+obtain	O
+bupivacaine	O
+-	O
+induced	O
+convulsions	B
+;	O
+this	O
+effect	O
+was	O
+less	O
+pronounced	O
+with	O
+bepridil	O
+.	O
+
+Epidural	O
+blood	O
+flow	O
+during	O
+prostaglandin	O
+E1	O
+or	O
+trimethaphan	O
+induced	O
+hypotension	B
+.	O
+
+To	O
+evaluate	O
+the	O
+effect	O
+of	O
+prostaglandin	O
+E1	O
+(	O
+PGE1	O
+)	O
+or	O
+trimethaphan	O
+(	O
+TMP	O
+)	O
+induced	O
+hypotension	B
+on	O
+epidural	O
+blood	O
+flow	O
+(	O
+EBF	O
+)	O
+during	O
+spinal	O
+surgery	O
+,	O
+EBF	O
+was	O
+measured	O
+using	O
+the	O
+heat	O
+clearance	O
+method	O
+in	O
+30	O
+patients	O
+who	O
+underwent	O
+postero	O
+-	O
+lateral	O
+interbody	O
+fusion	O
+under	O
+isoflurane	O
+anaesthesia	O
+.	O
+
+An	O
+initial	O
+dose	O
+of	O
+0	O
+.	O
+1	O
+microgram	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+of	O
+PGE1	O
+(	O
+15	O
+patients	O
+)	O
+,	O
+or	O
+10	O
+micrograms	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+of	O
+TMP	O
+(	O
+15	O
+patients	O
+)	O
+was	O
+administered	O
+intravenously	O
+after	O
+the	O
+dural	O
+opening	O
+and	O
+the	O
+dose	O
+was	O
+adjusted	O
+to	O
+maintain	O
+the	O
+mean	O
+arterial	O
+blood	O
+pressure	O
+(	O
+MAP	O
+)	O
+at	O
+about	O
+60	O
+mmHg	O
+.	O
+
+The	O
+hypotensive	B
+drug	O
+was	O
+discontinued	O
+at	O
+the	O
+completion	O
+of	O
+the	O
+operative	O
+procedure	O
+.	O
+
+After	O
+starting	O
+PGE1	O
+or	O
+TMP	O
+,	O
+MAP	O
+and	O
+rate	O
+pressure	O
+product	O
+(	O
+RPP	O
+)	O
+decreased	O
+significantly	O
+compared	O
+with	O
+preinfusion	O
+values	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+,	O
+and	O
+the	O
+degree	O
+of	O
+hypotension	B
+due	O
+to	O
+PGE1	O
+remained	O
+constant	O
+until	O
+60	O
+min	O
+after	O
+its	O
+discontinuation	O
+.	O
+
+Heart	O
+rate	O
+(	O
+HR	O
+)	O
+did	O
+not	O
+change	O
+in	O
+either	O
+group	O
+.	O
+
+EBFF	O
+did	O
+not	O
+change	O
+during	O
+PGE1	O
+infusion	O
+whereas	O
+in	O
+the	O
+TMP	O
+group	O
+,	O
+EBF	O
+decreased	O
+significantly	O
+at	O
+30	O
+and	O
+60	O
+min	O
+after	O
+the	O
+start	O
+of	O
+TMP	O
+(	O
+preinfusion	O
+:	O
+45	O
+.	O
+9	O
++	O
+/	O
+-	O
+13	O
+.	O
+9	O
+ml	O
+/	O
+100g	O
+/	O
+min	O
+.	O
+30	O
+min	O
+:	O
+32	O
+.	O
+3	O
++	O
+/	O
+-	O
+9	O
+.	O
+9	O
+ml	O
+/	O
+100	O
+g	O
+/	O
+min	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+60	O
+min	O
+:	O
+30	O
++	O
+/	O
+-	O
+7	O
+.	O
+5	O
+ml	O
+/	O
+100	O
+g	O
+/	O
+min	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+)	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+PGE1	O
+may	O
+be	O
+preferable	O
+to	O
+TMP	O
+for	O
+hypotensive	B
+anaesthesia	O
+in	O
+spinal	O
+surgery	O
+because	O
+TMP	O
+decreased	O
+EBF	O
+.	O
+
+Dup	O
+753	O
+prevents	O
+the	O
+development	O
+of	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+nephrosis	B
+.	O
+
+The	O
+appearance	O
+of	O
+nephrotic	B
+syndromes	I
+such	O
+as	O
+proteinuria	B
+,	O
+hypoalbuminemia	B
+,	O
+hypercholesterolemia	B
+and	O
+increase	O
+in	O
+blood	O
+nitrogen	O
+urea	O
+,	O
+induced	O
+in	O
+rats	O
+by	O
+injection	O
+of	O
+puromycin	O
+aminonucleoside	O
+was	O
+markedly	O
+inhibited	O
+by	O
+oral	O
+administration	O
+of	O
+Dup	O
+753	O
+(	O
+losartan	O
+)	O
+,	O
+a	O
+novel	O
+angiotensin	O
+II	O
+receptor	O
+antagonist	O
+,	O
+at	O
+a	O
+dose	O
+of	O
+1	O
+or	O
+2	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+.	O
+
+The	O
+results	O
+suggest	O
+a	O
+possible	O
+involvement	O
+of	O
+the	O
+renin	O
+-	O
+angiotensin	O
+system	O
+in	O
+the	O
+development	O
+of	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+nephrosis	B
+.	O
+
+Neuroplasticity	O
+of	O
+the	O
+adult	O
+primate	O
+auditory	O
+cortex	O
+following	O
+cochlear	O
+hearing	B
+loss	I
+.	O
+
+Tonotopic	O
+organization	O
+is	O
+an	O
+essential	O
+feature	O
+of	O
+the	O
+primary	O
+auditory	O
+area	O
+(	O
+A1	O
+)	O
+of	O
+primate	O
+cortex	O
+.	O
+
+In	O
+A1	O
+of	O
+macaque	O
+monkeys	O
+,	O
+low	O
+frequencies	O
+are	O
+represented	O
+rostrolaterally	O
+and	O
+high	O
+frequencies	O
+are	O
+represented	O
+caudomedially	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+if	O
+changes	O
+occur	O
+in	O
+this	O
+tonotopic	O
+organization	O
+following	O
+cochlear	O
+hearing	B
+loss	I
+.	O
+
+Under	O
+anesthesia	O
+,	O
+the	O
+superior	O
+temporal	O
+gyrus	O
+of	O
+adult	O
+macaque	O
+monkeys	O
+was	O
+exposed	O
+,	O
+and	O
+the	O
+tonotopic	O
+organization	O
+of	O
+A1	O
+was	O
+mapped	O
+using	O
+conventional	O
+microelectrode	O
+recording	O
+techniques	O
+.	O
+
+Following	O
+recovery	O
+,	O
+the	O
+monkeys	O
+were	O
+selectively	O
+deafened	O
+for	O
+high	O
+frequencies	O
+using	O
+kanamycin	O
+and	O
+furosemide	O
+.	O
+
+The	O
+actual	O
+frequencies	O
+deafened	O
+were	O
+determined	O
+by	O
+the	O
+loss	O
+of	O
+tone	O
+-	O
+burst	O
+elicited	O
+auditory	O
+brainstem	O
+responses	O
+.	O
+
+Three	O
+months	O
+after	O
+deafening	O
+,	O
+A1	O
+was	O
+remapped	O
+.	O
+
+Postmortem	O
+cytoarchitectural	O
+features	O
+identifying	O
+A1	O
+were	O
+correlated	O
+with	O
+the	O
+electrophysiologic	O
+data	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+the	O
+deprived	O
+area	O
+of	O
+A1	O
+undergoes	O
+extensive	O
+reorganization	O
+and	O
+becomes	O
+responsive	O
+to	O
+intact	O
+cochlear	O
+frequencies	O
+.	O
+
+The	O
+region	O
+of	O
+cortex	O
+that	O
+represents	O
+the	O
+low	O
+frequencies	O
+was	O
+not	O
+obviously	O
+affected	O
+by	O
+the	O
+cochlear	O
+hearing	B
+loss	I
+.	O
+
+Sodium	O
+bicarbonate	O
+alleviates	O
+penile	B
+pain	I
+induced	O
+by	O
+intracavernous	O
+injections	O
+for	O
+erectile	B
+dysfunction	I
+.	O
+
+In	O
+an	O
+attempt	O
+to	O
+determine	O
+whether	O
+penile	B
+pain	I
+associated	O
+with	O
+intracorporeal	O
+injections	O
+could	O
+be	O
+due	O
+to	O
+the	O
+acidity	O
+of	O
+the	O
+medication	O
+,	O
+we	O
+performed	O
+a	O
+randomized	O
+study	O
+comparing	O
+the	O
+incidence	O
+of	O
+penile	B
+pain	I
+following	O
+intracorporeal	O
+injections	O
+with	O
+or	O
+without	O
+the	O
+addition	O
+of	O
+sodium	O
+bicarbonate	O
+to	O
+the	O
+intracorporeal	O
+medications	O
+.	O
+
+A	O
+total	O
+of	O
+38	O
+consecutive	O
+patients	O
+who	O
+presented	O
+to	O
+our	O
+clinic	O
+with	O
+impotence	B
+received	O
+0	O
+.	O
+2	O
+ml	O
+.	O
+of	O
+a	O
+combination	O
+of	O
+3	O
+drugs	O
+:	O
+6	O
+mg	O
+.	O
+papaverine	O
+,	O
+100	O
+micrograms	O
+.	O
+phentolamine	O
+and	O
+10	O
+micrograms	O
+.	O
+prostaglandin	O
+E1	O
+with	O
+(	O
+pH	O
+7	O
+.	O
+05	O
+)	O
+or	O
+without	O
+(	O
+pH	O
+4	O
+.	O
+17	O
+)	O
+the	O
+addition	O
+of	O
+sodium	O
+bicarbonate	O
+(	O
+0	O
+.	O
+03	O
+mEq	O
+.	O
+)	O
+.	O
+
+Of	O
+the	O
+19	O
+patients	O
+without	O
+sodium	O
+bicarbonate	O
+added	O
+to	O
+the	O
+medication	O
+11	O
+(	O
+58	O
+%	O
+)	O
+complained	O
+of	O
+penile	B
+pain	I
+due	O
+to	O
+the	O
+medication	O
+,	O
+while	O
+only	O
+1	O
+of	O
+the	O
+19	O
+men	O
+(	O
+5	O
+%	O
+)	O
+who	O
+received	O
+sodium	O
+bicarbonate	O
+complained	O
+of	O
+penile	B
+pain	I
+.	O
+
+From	O
+these	O
+data	O
+we	O
+conclude	O
+that	O
+the	O
+penile	B
+pain	I
+following	O
+intracorporeal	O
+injections	O
+is	O
+most	O
+likely	O
+due	O
+to	O
+the	O
+acidity	O
+of	O
+the	O
+medication	O
+,	O
+which	O
+can	O
+be	O
+overcome	O
+by	O
+elevating	O
+the	O
+pH	O
+to	O
+a	O
+neutral	O
+level	O
+.	O
+
+The	O
+use	O
+and	O
+toxicity	B
+of	O
+didanosine	O
+(	O
+ddI	O
+)	O
+in	O
+HIV	B
+antibody	I
+-	I
+positive	I
+individuals	O
+intolerant	O
+to	O
+zidovudine	O
+(	O
+AZT	O
+)	O
+
+One	O
+hundred	O
+and	O
+fifty	O
+-	O
+one	O
+patients	O
+intolerant	O
+to	O
+zidovudine	O
+(	O
+AZT	O
+)	O
+received	O
+didanosine	O
+(	O
+ddI	O
+)	O
+to	O
+a	O
+maximum	O
+dose	O
+of	O
+12	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+.	O
+
+Patient	O
+response	O
+was	O
+assessed	O
+using	O
+changes	O
+in	O
+CD4	O
++	O
+lymphocyte	O
+subset	O
+count	O
+,	O
+HIV	O
+p24	O
+antigen	O
+,	O
+weight	O
+,	O
+and	O
+quality	O
+of	O
+life	O
+.	O
+
+Seventy	O
+patients	O
+developed	O
+major	O
+opportunistic	B
+infections	I
+whilst	O
+on	O
+therapy	O
+;	O
+this	O
+was	O
+the	O
+first	O
+AIDS	B
+diagnosis	O
+in	O
+17	O
+.	O
+
+Only	O
+minor	O
+changes	O
+in	O
+CD4	O
++	O
+lymphocyte	O
+subset	O
+count	O
+were	O
+observed	O
+in	O
+AIDS	B
+patients	O
+,	O
+although	O
+a	O
+more	O
+significant	O
+rise	O
+occurred	O
+in	O
+those	O
+with	O
+earlier	O
+stages	O
+of	O
+disease	O
+.	O
+
+Of	O
+those	O
+positive	O
+for	O
+p24	O
+antigen	O
+at	O
+the	O
+commencement	O
+of	O
+the	O
+study	O
+67	O
+%	O
+showed	O
+a	O
+positive	O
+response	O
+,	O
+and	O
+this	O
+was	O
+most	O
+likely	O
+in	O
+those	O
+with	O
+CD4	O
++	O
+lymphocyte	O
+subset	O
+counts	O
+above	O
+100	O
+mm3	O
+.	O
+
+A	O
+positive	O
+weight	O
+response	O
+was	O
+seen	O
+in	O
+16	O
+%	O
+of	O
+patients	O
+.	O
+
+Most	O
+patients	O
+showed	O
+improvement	O
+in	O
+individual	O
+parameters	O
+and	O
+global	O
+score	O
+of	O
+quality	O
+of	O
+life	O
+.	O
+
+Adverse	O
+reactions	O
+possibly	O
+attributable	O
+to	O
+didanosine	O
+were	O
+common	O
+.	O
+
+The	O
+most	O
+common	O
+side	O
+-	O
+effect	O
+was	O
+diarrhoea	B
+,	O
+which	O
+resulted	O
+in	O
+cessation	O
+of	O
+therapy	O
+in	O
+19	O
+individuals	O
+.	O
+
+Peripheral	B
+neuropathy	I
+occurred	O
+in	O
+12	O
+patients	O
+and	O
+pancreatitis	B
+in	O
+six	O
+.	O
+
+Thirteen	O
+patients	O
+developed	O
+a	O
+raised	O
+serum	O
+amylase	O
+without	O
+abdominal	B
+pain	I
+.	O
+
+Seven	O
+patients	O
+developed	O
+glucose	B
+tolerance	I
+curves	I
+characteristic	O
+of	O
+diabetes	B
+but	O
+these	O
+were	O
+mild	O
+,	O
+did	O
+not	O
+require	O
+treatment	O
+and	O
+returned	O
+to	O
+normal	O
+on	O
+ceasing	O
+didanosine	O
+.	O
+
+Immunohistochemical	O
+studies	O
+with	O
+antibodies	O
+to	O
+neurofilament	O
+proteins	O
+on	O
+axonal	B
+damage	I
+in	O
+experimental	O
+focal	O
+lesions	O
+in	O
+rat	O
+.	O
+
+Immunohistochemistry	O
+with	O
+monoclonal	O
+antibodies	O
+against	O
+neurofilament	O
+(	O
+NF	O
+)	O
+proteins	O
+of	O
+middle	O
+and	O
+high	O
+molecular	O
+weight	O
+class	O
+,	O
+NF	O
+-	O
+M	O
+and	O
+NF	O
+-	O
+H	O
+,	O
+was	O
+used	O
+to	O
+study	O
+axonal	B
+injury	I
+in	O
+the	O
+borderzone	O
+of	O
+focal	O
+lesions	O
+in	O
+rats	O
+.	O
+
+Focal	O
+injury	B
+in	I
+the	I
+cortex	I
+was	O
+produced	O
+by	O
+infusion	O
+of	O
+lactate	O
+at	O
+acid	O
+pH	O
+or	O
+by	O
+stab	O
+caused	O
+by	O
+needle	O
+insertion	O
+.	O
+
+Infarcts	B
+in	I
+substantia	I
+nigra	I
+pars	I
+reticulata	I
+were	O
+evoked	O
+by	O
+prolonged	O
+pilocarpine	O
+-	O
+induced	O
+status	B
+epilepticus	I
+.	O
+
+Immunohistochemical	O
+staining	O
+for	O
+NFs	O
+showed	O
+characteristic	O
+terminal	O
+clubs	O
+of	O
+axons	O
+in	O
+the	O
+borderzone	O
+of	O
+lesions	O
+.	O
+
+Differences	O
+in	O
+the	O
+labelling	O
+pattern	O
+occurred	O
+with	O
+different	O
+antibodies	O
+which	O
+apparently	O
+depended	O
+on	O
+molecular	O
+weight	O
+class	O
+of	O
+NFs	O
+and	O
+phosphorylation	O
+state	O
+.	O
+
+These	O
+immunohistochemical	O
+changes	O
+of	O
+NFs	O
+can	O
+serve	O
+as	O
+a	O
+marker	O
+for	O
+axonal	B
+damage	I
+in	O
+various	O
+experimental	O
+traumatic	B
+or	O
+ischemic	O
+lesions	O
+.	O
+
+Pharmacokinetic	O
+and	O
+clinical	O
+studies	O
+in	O
+patients	O
+with	O
+cimetidine	O
+-	O
+associated	O
+mental	O
+confusion	B
+.	O
+
+15	O
+cases	O
+of	O
+cimetidine	O
+-	O
+associated	O
+mental	O
+confusion	B
+have	O
+been	O
+reported	O
+.	O
+
+In	O
+order	O
+that	O
+this	O
+syndrome	O
+might	O
+be	O
+investigated	O
+changes	O
+in	O
+mental	O
+status	O
+(	O
+M	O
+.	O
+S	O
+.	O
+)	O
+were	O
+correlated	O
+with	O
+serum	O
+concentrations	O
+and	O
+renal	O
+and	O
+hepatic	O
+function	O
+in	O
+36	O
+patients	O
+,	O
+30	O
+patients	O
+had	O
+no	O
+M	O
+.	O
+S	O
+.	O
+change	O
+on	O
+cimetidine	O
+and	O
+6	O
+had	O
+moderate	O
+to	O
+severe	O
+changes	O
+.	O
+
+These	O
+6	O
+patients	O
+had	O
+both	O
+renal	B
+and	I
+liver	I
+dysfunction	I
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+,	O
+as	O
+well	O
+as	O
+cimetidine	O
+trough	O
+-	O
+concentrations	O
+of	O
+more	O
+than	O
+1	O
+.	O
+25	O
+microgram	O
+/	O
+ml	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+severity	O
+of	O
+M	O
+.	O
+S	O
+.	O
+changes	O
+increased	O
+as	O
+trough	O
+-	O
+concentrations	O
+rose	O
+,	O
+5	O
+patients	O
+had	O
+lumbar	O
+puncture	O
+.	O
+
+The	O
+cerebrospinal	O
+fluid	O
+:	O
+serum	O
+ratio	O
+of	O
+cimetidine	O
+concentrations	O
+was	O
+0	O
+.	O
+24	O
+:	O
+1	O
+and	O
+indicates	O
+that	O
+cimetidine	O
+passes	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+;	O
+it	O
+also	O
+raises	O
+the	O
+possibility	O
+that	O
+M	O
+.	O
+S	O
+.	O
+changes	O
+are	O
+due	O
+to	O
+blockade	O
+of	O
+histamine	O
+H2	O
+-	O
+receptors	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+.	O
+
+Patients	O
+likely	O
+to	O
+have	O
+both	O
+raised	O
+trough	O
+-	O
+concentrations	O
+and	O
+mental	O
+confusion	B
+are	O
+those	O
+with	O
+both	O
+severe	O
+renal	B
+and	I
+hepatic	I
+dysfunction	I
+.	O
+
+They	O
+should	O
+be	O
+closely	O
+observed	O
+and	O
+should	O
+be	O
+given	O
+reduced	O
+doses	O
+of	O
+cimetidine	O
+.	O
+
+Prospective	O
+study	O
+of	O
+the	O
+long	O
+-	O
+term	O
+effects	O
+of	O
+somatostatin	O
+analog	O
+(	O
+octreotide	O
+)	O
+on	O
+gallbladder	O
+function	O
+and	O
+gallstone	B
+formation	O
+in	O
+Chinese	O
+acromegalic	B
+patients	O
+.	O
+
+This	O
+article	O
+reports	O
+the	O
+changes	O
+in	O
+gallbladder	O
+function	O
+examined	O
+by	O
+ultrasonography	O
+in	O
+20	O
+Chinese	O
+patients	O
+with	O
+active	O
+acromegaly	B
+treated	O
+with	O
+sc	O
+injection	O
+of	O
+the	O
+somatostatin	O
+analog	O
+octreotide	O
+in	O
+dosages	O
+of	O
+300	O
+-	O
+1500	O
+micrograms	O
+/	O
+day	O
+for	O
+a	O
+mean	O
+of	O
+24	O
+.	O
+2	O
++	O
+/	O
+-	O
+13	O
+.	O
+9	O
+months	O
+.	O
+
+During	O
+treatment	O
+with	O
+octreotide	O
+,	O
+17	O
+patients	O
+developed	O
+sludge	O
+,	O
+10	O
+had	O
+gallstones	B
+,	O
+and	O
+1	O
+developed	O
+acute	B
+cholecystitis	I
+requiring	O
+surgery	O
+.	O
+
+In	O
+all	O
+of	O
+7	O
+patients	O
+examined	O
+acutely	O
+,	O
+gallbladder	O
+contractility	O
+was	O
+inhibited	O
+after	O
+a	O
+single	O
+100	O
+-	O
+micrograms	O
+injection	O
+.	O
+
+In	O
+8	O
+patients	O
+followed	O
+for	O
+24	O
+weeks	O
+,	O
+gallbladder	O
+contractility	O
+remained	O
+depressed	B
+throughout	O
+therapy	O
+.	O
+
+After	O
+withdrawal	O
+of	O
+octreotide	O
+in	O
+10	O
+patients	O
+without	O
+gallstones	B
+,	O
+8	O
+patients	O
+assessed	O
+had	O
+return	O
+of	O
+normal	O
+gallbladder	O
+contractility	O
+within	O
+1	O
+month	O
+.	O
+
+In	O
+8	O
+of	O
+the	O
+remaining	O
+10	O
+patients	O
+who	O
+developed	O
+gallstones	B
+during	O
+treatment	O
+,	O
+gallbladder	O
+contractility	O
+normalized	O
+in	O
+5	O
+patients	O
+(	O
+3	O
+of	O
+whom	O
+has	O
+disappearance	O
+of	O
+their	O
+stones	O
+within	O
+3	O
+weeks	O
+)	O
+,	O
+and	O
+remained	O
+depressed	B
+in	O
+3	O
+(	O
+2	O
+of	O
+whom	O
+had	O
+stones	O
+present	O
+at	O
+6	O
+months	O
+)	O
+.	O
+
+Our	O
+results	O
+suggest	O
+that	O
+the	O
+suppression	O
+of	O
+gallbladder	O
+contractility	O
+is	O
+the	O
+cause	O
+of	O
+the	O
+successive	O
+formation	O
+of	O
+bile	O
+sludge	O
+,	O
+gallstones	B
+,	O
+and	O
+cholecystitis	B
+during	O
+octreotide	O
+therapy	O
+in	O
+Chinese	O
+acromegalic	B
+patients	O
+.	O
+
+It	O
+is	O
+therefore	O
+very	O
+important	O
+to	O
+follow	O
+the	O
+changes	O
+of	O
+gallbladder	O
+function	O
+during	O
+long	O
+-	O
+term	O
+octreotide	O
+therapy	O
+of	O
+acromegalic	B
+patients	O
+.	O
+
+Increase	O
+of	O
+Parkinson	B
+disability	I
+after	O
+fluoxetine	O
+medication	O
+.	O
+
+Depression	B
+is	O
+a	O
+major	O
+clinical	O
+feature	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+We	O
+report	O
+the	O
+increased	O
+amount	O
+of	O
+motor	B
+disability	I
+in	O
+four	O
+patients	O
+with	O
+idiopathic	B
+Parkinson	I
+'	I
+s	I
+disease	I
+after	O
+exposure	O
+to	O
+the	O
+antidepressant	O
+fluoxetine	O
+.	O
+
+The	O
+possibility	O
+of	O
+a	O
+clinically	O
+relevant	O
+dopamine	O
+-	O
+antagonistic	O
+capacity	O
+of	O
+fluoxetine	O
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+patients	O
+must	O
+be	O
+considered	O
+.	O
+
+Sinus	B
+arrest	I
+associated	O
+with	O
+continuous	O
+-	O
+infusion	O
+cimetidine	O
+.	O
+
+The	O
+administration	O
+of	O
+intermittent	O
+intravenous	O
+infusions	O
+of	O
+cimetidine	O
+is	O
+infrequently	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+bradyarrhythmias	B
+.	O
+
+A	O
+40	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+leukemia	B
+and	O
+no	O
+history	O
+of	O
+cardiac	B
+disease	I
+developed	O
+recurrent	O
+,	O
+brief	O
+episodes	O
+of	O
+apparent	O
+sinus	B
+arrest	I
+while	O
+receiving	O
+continuous	O
+-	O
+infusion	O
+cimetidine	O
+50	O
+mg	O
+/	O
+hour	O
+.	O
+
+The	O
+arrhythmias	B
+were	O
+temporally	O
+related	O
+to	O
+cimetidine	O
+administration	O
+,	O
+disappeared	O
+after	O
+dechallenge	O
+,	O
+and	O
+did	O
+not	O
+recur	O
+during	O
+ranitidine	O
+treatment	O
+.	O
+
+This	O
+is	O
+the	O
+first	O
+reported	O
+case	O
+of	O
+sinus	B
+arrest	I
+associated	O
+with	O
+continuous	O
+-	O
+infusion	O
+cimetidine	O
+.	O
+
+Phase	O
+II	O
+trial	O
+of	O
+vinorelbine	O
+in	O
+metastatic	O
+squamous	B
+cell	I
+esophageal	I
+carcinoma	I
+.	O
+
+European	O
+Organization	O
+for	O
+Research	O
+and	O
+Treatment	O
+of	O
+Cancer	B
+Gastrointestinal	O
+Treat	O
+Cancer	B
+Cooperative	O
+Group	O
+.	O
+
+PURPOSE	O
+:	O
+To	O
+evaluate	O
+the	O
+response	O
+rate	O
+and	O
+toxic	O
+effects	O
+of	O
+vinorelbine	O
+(	O
+VNB	O
+)	O
+administered	O
+as	O
+a	O
+single	O
+agent	O
+in	O
+metastatic	O
+squamous	B
+cell	I
+esophageal	I
+carcinoma	I
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+Forty	O
+-	O
+six	O
+eligible	O
+patients	O
+with	O
+measurable	O
+lesions	O
+were	O
+included	O
+and	O
+were	O
+stratified	O
+according	O
+to	O
+previous	O
+chemotherapy	O
+.	O
+
+Thirty	O
+patients	O
+without	O
+prior	O
+chemotherapy	O
+and	O
+16	O
+pretreated	O
+with	O
+cisplatin	O
+-	O
+based	O
+chemotherapy	O
+were	O
+assessable	O
+for	O
+toxicity	B
+and	O
+response	O
+.	O
+
+VNB	O
+was	O
+administered	O
+weekly	O
+as	O
+a	O
+25	O
+-	O
+mg	O
+/	O
+m2	O
+short	O
+intravenous	O
+(	O
+i	O
+.	O
+v	O
+.	O
+)	O
+infusion	O
+.	O
+
+RESULTS	O
+:	O
+Six	O
+of	O
+30	O
+patients	O
+(	O
+20	O
+%	O
+)	O
+without	O
+prior	O
+chemotherapy	O
+achieved	O
+a	O
+partial	O
+response	O
+(	O
+PR	O
+)	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+,	O
+8	O
+%	O
+to	O
+39	O
+%	O
+)	O
+.	O
+
+The	O
+median	O
+duration	O
+of	O
+response	O
+was	O
+21	O
+weeks	O
+(	O
+range	O
+,	O
+17	O
+to	O
+28	O
+)	O
+.	O
+
+One	O
+of	O
+16	O
+patients	O
+(	O
+6	O
+%	O
+)	O
+with	O
+prior	O
+chemotherapy	O
+had	O
+a	O
+complete	O
+response	O
+(	O
+CR	O
+)	O
+of	O
+31	O
+weeks	O
+'	O
+duration	O
+(	O
+95	O
+%	O
+CI	O
+,	O
+0	O
+%	O
+to	O
+30	O
+%	O
+)	O
+.	O
+
+The	O
+overall	O
+response	O
+rate	O
+(	O
+World	O
+Health	O
+Organization	O
+[	O
+WHO	O
+]	O
+criteria	O
+)	O
+was	O
+15	O
+%	O
+(	O
+CR	O
+,	O
+2	O
+%	O
+;	O
+PR	O
+13	O
+%	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+6	O
+%	O
+to	O
+29	O
+%	O
+)	O
+.	O
+
+The	O
+median	O
+dose	O
+-	O
+intensity	O
+(	O
+DI	O
+)	O
+was	O
+20	O
+mg	O
+/	O
+m2	O
+/	O
+wk	O
+.	O
+
+VNB	O
+was	O
+well	O
+tolerated	O
+and	O
+zero	O
+instances	O
+of	O
+WHO	O
+grade	O
+4	O
+nonhematologic	O
+toxicity	B
+occurred	O
+.	O
+
+At	O
+least	O
+one	O
+episode	O
+of	O
+grade	O
+3	O
+or	O
+4	O
+granulocytopenia	B
+was	O
+seen	O
+in	O
+59	O
+%	O
+of	O
+patients	O
+.	O
+
+A	O
+grade	O
+2	O
+or	O
+3	O
+infection	B
+occurred	O
+in	O
+16	O
+%	O
+of	O
+patients	O
+,	O
+but	O
+no	O
+toxic	O
+deaths	B
+occurred	O
+.	O
+
+Other	O
+side	O
+effects	O
+were	O
+rare	O
+,	O
+and	O
+peripheral	B
+neurotoxicity	I
+has	O
+been	O
+minor	O
+(	O
+26	O
+%	O
+grade	O
+1	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+These	O
+data	O
+indicate	O
+that	O
+VNB	O
+is	O
+an	O
+active	O
+agent	O
+in	O
+metastatic	O
+esophageal	B
+squamous	I
+cell	I
+carcinoma	I
+.	O
+
+Given	O
+its	O
+excellent	O
+tolerance	O
+profile	O
+and	O
+low	O
+toxicity	B
+,	O
+further	O
+evaluation	O
+of	O
+VNB	O
+in	O
+combination	O
+therapy	O
+is	O
+warranted	O
+.	O
+
+Evaluation	O
+of	O
+adverse	O
+reactions	O
+of	O
+aponidine	O
+hydrochloride	O
+ophthalmic	O
+solution	O
+.	O
+
+We	O
+prospectively	O
+evaluated	O
+the	O
+adverse	O
+reactions	O
+of	O
+apraclonidine	O
+in	O
+20	O
+normal	O
+volunteers	O
+by	O
+instilling	O
+a	O
+single	O
+drop	O
+of	O
+1	O
+%	O
+apraclonidine	O
+in	O
+their	O
+right	O
+eyes	O
+.	O
+
+Examinations	O
+,	O
+including	O
+blood	O
+pressure	O
+,	O
+pulse	O
+rate	O
+,	O
+conjunctiva	O
+and	O
+cornea	O
+,	O
+intraocular	O
+pressure	O
+(	O
+IOP	O
+)	O
+,	O
+pupil	O
+diameter	O
+,	O
+basal	O
+tear	O
+secretion	O
+and	O
+margin	O
+reflex	O
+distance	O
+of	O
+both	O
+upper	O
+and	O
+lower	O
+eyelids	O
+,	O
+were	O
+performed	O
+prior	O
+to	O
+entry	O
+and	O
+at	O
+1	O
+,	O
+3	O
+,	O
+5	O
+and	O
+7	O
+hours	O
+after	O
+instillation	O
+.	O
+
+The	O
+ocular	B
+hypotensive	I
+effects	O
+were	O
+statistically	O
+significant	O
+for	O
+apraclonidine	O
+-	O
+treated	O
+eyes	O
+throughout	O
+the	O
+study	O
+and	O
+also	O
+statistically	O
+significant	O
+for	O
+contralateral	O
+eyes	O
+from	O
+three	O
+hours	O
+after	O
+topical	O
+administration	O
+of	O
+1	O
+%	O
+apraclonidine	O
+.	O
+
+Decreases	B
+in	I
+systolic	I
+blood	I
+pressure	I
+were	O
+statistically	O
+,	O
+but	O
+not	O
+clinically	O
+,	O
+significant	O
+.	O
+
+No	O
+significant	O
+changes	O
+in	O
+diastolic	O
+blood	O
+pressure	O
+,	O
+pulse	O
+rate	O
+and	O
+basal	O
+tear	O
+secretion	O
+were	O
+noted	O
+.	O
+
+Conjunctival	B
+blanching	I
+and	O
+mydriasis	B
+were	O
+commonly	O
+found	O
+.	O
+
+Upper	O
+lid	O
+retraction	O
+was	O
+frequently	O
+noted	O
+.	O
+
+While	O
+the	O
+elevations	O
+of	O
+the	O
+upper	O
+lid	O
+margin	O
+in	O
+most	O
+subjects	O
+were	O
+not	O
+more	O
+than	O
+2	O
+mm	O
+and	O
+did	O
+not	O
+cause	O
+noticeable	O
+change	O
+in	O
+appearance	O
+,	O
+one	O
+subject	O
+suffered	O
+from	O
+mechanical	O
+entropion	B
+and	O
+marked	O
+corneal	B
+abrasion	I
+3	O
+hours	O
+after	O
+instillation	O
+of	O
+the	O
+medication	O
+.	O
+
+This	O
+may	O
+well	O
+be	O
+a	O
+particularly	O
+notable	O
+finding	O
+in	O
+Asian	O
+people	O
+.	O
+
+Thiopentone	O
+pretreatment	O
+for	O
+propofol	O
+injection	O
+pain	B
+in	O
+ambulatory	O
+patients	O
+.	O
+
+This	O
+study	O
+investigated	O
+propofol	O
+injection	O
+pain	B
+in	O
+patients	O
+undergoing	O
+ambulatory	O
+anaesthesia	O
+.	O
+
+In	O
+a	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+trial	O
+,	O
+90	O
+women	O
+were	O
+allocated	O
+to	O
+receive	O
+one	O
+of	O
+three	O
+treatments	O
+prior	O
+to	O
+induction	O
+of	O
+anaesthesia	O
+with	O
+propofol	O
+.	O
+
+Patients	O
+in	O
+Group	O
+C	O
+received	O
+2	O
+ml	O
+normal	O
+saline	O
+,	O
+Group	O
+L	O
+,	O
+2	O
+ml	O
+,	O
+lidocaine	O
+2	O
+%	O
+(	O
+40	O
+mg	O
+)	O
+and	O
+Group	O
+T	O
+,	O
+2	O
+ml	O
+thiopentone	O
+2	O
+.	O
+5	O
+%	O
+(	O
+50	O
+mg	O
+)	O
+.	O
+
+Venous	O
+discomfort	O
+was	O
+assessed	O
+with	O
+a	O
+visual	O
+analogue	O
+scale	O
+(	O
+VAS	O
+)	O
+5	O
+-	O
+15	O
+sec	O
+after	O
+commencing	O
+propofol	O
+administration	O
+using	O
+an	O
+infusion	O
+pump	O
+(	O
+rate	O
+1000	O
+micrograms	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+)	O
+.	O
+
+Loss	B
+of	I
+consciousness	I
+occurred	O
+in	O
+60	O
+-	O
+90	O
+sec	O
+.	O
+
+Visual	O
+analogue	O
+scores	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+)	O
+during	O
+induction	O
+were	O
+lower	O
+in	O
+Groups	O
+L	O
+(	O
+3	O
+.	O
+3	O
++	O
+/	O
+-	O
+2	O
+.	O
+5	O
+)	O
+and	O
+T	O
+(	O
+4	O
+.	O
+1	O
++	O
+/	O
+-	O
+2	O
+.	O
+7	O
+)	O
+than	O
+in	O
+Group	O
+C	O
+(	O
+5	O
+.	O
+6	O
++	O
+/	O
+-	O
+2	O
+.	O
+3	O
+)	O
+;	O
+P	O
+=	O
+0	O
+.	O
+0031	O
+.	O
+
+The	O
+incidence	O
+of	O
+venous	O
+discomfort	O
+was	O
+lower	O
+in	O
+Group	O
+L	O
+(	O
+76	O
+.	O
+6	O
+%	O
+;	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+than	O
+in	O
+Group	O
+C	O
+(	O
+100	O
+%	O
+)	O
+but	O
+not	O
+different	O
+from	O
+Group	O
+T	O
+(	O
+90	O
+%	O
+)	O
+.	O
+
+The	O
+VAS	O
+scores	O
+for	O
+recall	O
+of	O
+pain	B
+in	O
+the	O
+recovery	O
+room	O
+were	O
+correlated	O
+with	O
+the	O
+VAS	O
+scores	O
+during	O
+induction	O
+(	O
+r	O
+=	O
+0	O
+.	O
+7045	O
+;	O
+P	O
+<	O
+0	O
+.	O
+0001	O
+)	O
+.	O
+
+Recovery	O
+room	O
+discharge	O
+times	O
+were	O
+similar	O
+:	O
+C	O
+(	O
+75	O
+.	O
+9	O
++	O
+/	O
+-	O
+19	O
+.	O
+4	O
+min	O
+)	O
+;	O
+L	O
+73	O
+.	O
+6	O
++	O
+/	O
+-	O
+21	O
+.	O
+6	O
+min	O
+)	O
+;	O
+T	O
+(	O
+77	O
+.	O
+1	O
++	O
+/	O
+-	O
+18	O
+.	O
+9	O
+min	O
+)	O
+.	O
+
+Assessing	O
+their	O
+overall	O
+satisfaction	O
+,	O
+89	O
+.	O
+7	O
+%	O
+would	O
+choose	O
+propofol	O
+anaesthesia	O
+again	O
+.	O
+
+We	O
+conclude	O
+that	O
+lidocaine	O
+reduces	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+propofol	O
+injection	O
+pain	B
+in	O
+ambulatory	O
+patients	O
+whereas	O
+thiopentone	O
+only	O
+reduces	O
+its	O
+severity	O
+.	O
+
+Persistent	O
+paralysis	B
+after	O
+prolonged	O
+use	O
+of	O
+atracurium	O
+in	O
+the	O
+absence	O
+of	O
+corticosteroids	O
+.	O
+
+Neuromuscular	O
+blocking	O
+agents	O
+(	O
+NMBAs	O
+)	O
+are	O
+often	O
+used	O
+for	O
+patients	O
+requiring	O
+prolonged	O
+mechanical	O
+ventilation	O
+.	O
+
+Reports	O
+of	O
+persistent	O
+paralysis	B
+after	O
+the	O
+discontinuance	O
+of	O
+these	O
+drugs	O
+have	O
+most	O
+often	O
+involved	O
+aminosteroid	O
+-	O
+based	O
+NMBAs	O
+such	O
+as	O
+vecuronium	O
+bromide	O
+,	O
+especially	O
+when	O
+used	O
+in	O
+conjunction	O
+with	O
+corticosteroids	O
+.	O
+
+Atracurium	O
+besylate	O
+,	O
+a	O
+short	O
+-	O
+acting	O
+benzylisoquinolinium	O
+NMBA	O
+that	O
+is	O
+eliminated	O
+independently	O
+of	O
+renal	O
+or	O
+hepatic	O
+function	O
+,	O
+has	O
+also	O
+been	O
+associated	O
+with	O
+persistent	O
+paralysis	B
+,	O
+but	O
+only	O
+when	O
+used	O
+with	O
+corticosteroids	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+atracurium	O
+-	O
+related	O
+paralysis	B
+persisting	O
+for	O
+approximately	O
+50	O
+hours	O
+in	O
+a	O
+patient	O
+who	O
+was	O
+not	O
+treated	O
+with	O
+corticosteroids	O
+.	O
+
+A	O
+phase	O
+I	O
+/	O
+II	O
+study	O
+of	O
+paclitaxel	O
+plus	O
+cisplatin	O
+as	O
+first	O
+-	O
+line	O
+therapy	O
+for	O
+head	B
+and	I
+neck	I
+cancers	I
+:	O
+preliminary	O
+results	O
+.	O
+
+Improved	O
+outcomes	O
+among	O
+patients	O
+with	O
+head	B
+and	I
+neck	I
+carcinomas	I
+require	O
+investigations	O
+of	O
+new	O
+drugs	O
+for	O
+induction	O
+therapy	O
+.	O
+
+Preliminary	O
+results	O
+of	O
+an	O
+Eastern	O
+Cooperative	O
+Oncology	O
+Group	O
+study	O
+of	O
+single	O
+-	O
+agent	O
+paclitaxel	O
+(	O
+Taxol	O
+;	O
+Bristol	O
+-	O
+Myers	O
+Squibb	O
+Company	O
+,	O
+Princeton	O
+,	O
+NJ	O
+)	O
+reported	O
+a	O
+37	O
+%	O
+response	O
+rate	O
+in	O
+patients	O
+with	O
+head	B
+and	I
+neck	I
+cancer	I
+,	O
+and	O
+the	O
+paclitaxel	O
+/	O
+cisplatin	O
+combination	O
+has	O
+been	O
+used	O
+successfully	O
+and	O
+has	O
+significantly	O
+improved	O
+median	O
+response	O
+duration	O
+in	O
+ovarian	B
+cancer	I
+patients	O
+.	O
+
+We	O
+initiated	O
+a	O
+phase	O
+I	O
+/	O
+II	O
+trial	O
+to	O
+determine	O
+the	O
+response	O
+and	O
+toxicity	B
+of	O
+escalating	O
+paclitaxel	O
+doses	O
+combined	O
+with	O
+fixed	O
+-	O
+dose	O
+cisplatin	O
+with	O
+granulocyte	O
+colony	O
+-	O
+stimulating	O
+factor	O
+support	O
+in	O
+patients	O
+with	O
+untreated	O
+locally	O
+advanced	O
+inoperable	O
+head	B
+and	I
+neck	I
+carcinoma	I
+.	O
+
+To	O
+date	O
+,	O
+23	O
+men	O
+with	O
+a	O
+median	O
+age	O
+of	O
+50	O
+years	O
+and	O
+good	O
+performance	O
+status	O
+have	O
+entered	O
+the	O
+trial	O
+.	O
+
+Primary	O
+tumor	B
+sites	O
+were	O
+oropharynx	O
+,	O
+10	O
+patients	O
+;	O
+hypopharynx	O
+,	O
+four	O
+;	O
+larynx	O
+,	O
+two	O
+;	O
+oral	O
+cavity	O
+,	O
+three	O
+;	O
+unknown	O
+primary	O
+,	O
+two	O
+;	O
+and	O
+nasal	O
+cavity	O
+and	O
+parotid	O
+gland	O
+,	O
+one	O
+each	O
+.	O
+
+Of	O
+20	O
+patients	O
+evaluable	O
+for	O
+toxicity	B
+,	O
+four	O
+had	O
+stage	O
+III	O
+and	O
+16	O
+had	O
+stage	O
+IV	O
+disease	O
+.	O
+
+Treatment	O
+,	O
+given	O
+every	O
+21	O
+days	O
+for	O
+a	O
+maximum	O
+of	O
+three	O
+cycles	O
+,	O
+consisted	O
+of	O
+paclitaxel	O
+by	O
+3	O
+-	O
+hour	O
+infusion	O
+followed	O
+the	O
+next	O
+day	O
+by	O
+a	O
+fixed	O
+dose	O
+of	O
+cisplatin	O
+(	O
+75	O
+mg	O
+/	O
+m2	O
+)	O
+.	O
+
+The	O
+dose	O
+levels	O
+incorporate	O
+escalating	O
+paclitaxel	O
+doses	O
+,	O
+and	O
+intrapatient	O
+escalations	O
+within	O
+a	O
+given	O
+dose	O
+level	O
+are	O
+permitted	O
+if	O
+toxicity	B
+permits	O
+.	O
+
+At	O
+the	O
+time	O
+of	O
+this	O
+writing	O
+,	O
+dose	O
+level	O
+4	O
+(	O
+260	O
+,	O
+270	O
+,	O
+and	O
+280	O
+mg	O
+/	O
+m2	O
+)	O
+is	O
+being	O
+evaluated	O
+;	O
+three	O
+patients	O
+from	O
+this	O
+level	O
+are	O
+evaluable	O
+.	O
+
+With	O
+paclitaxel	O
+doses	O
+of	O
+200	O
+mg	O
+/	O
+m2	O
+and	O
+higher	O
+,	O
+granulocyte	O
+colony	O
+-	O
+stimulating	O
+factor	O
+5	O
+micrograms	O
+/	O
+kg	O
+/	O
+d	O
+is	O
+given	O
+(	O
+days	O
+4	O
+through	O
+12	O
+)	O
+.	O
+
+Of	O
+18	O
+patients	O
+evaluable	O
+for	O
+response	O
+,	O
+seven	O
+(	O
+39	O
+%	O
+)	O
+achieved	O
+a	O
+complete	O
+response	O
+and	O
+six	O
+(	O
+33	O
+%	O
+)	O
+achieved	O
+a	O
+partial	O
+response	O
+.	O
+
+Three	O
+patients	O
+had	O
+no	O
+change	O
+and	O
+disease	O
+progressed	O
+in	O
+two	O
+.	O
+
+The	O
+overall	O
+response	O
+rate	O
+is	O
+72	O
+%	O
+.	O
+
+Eleven	O
+responding	O
+patients	O
+had	O
+subsequent	O
+surgery	O
+/	O
+radiotherapy	O
+or	O
+radical	O
+radiotherapy	O
+.	O
+
+Two	O
+pathologic	O
+complete	O
+responses	O
+were	O
+observed	O
+in	O
+patients	O
+who	O
+had	O
+achieved	O
+clinical	O
+complete	O
+responses	O
+.	O
+
+Alopecia	B
+,	O
+paresthesias	B
+,	O
+and	O
+arthralgias	B
+/	O
+myalgias	B
+have	O
+occurred	O
+frequently	O
+,	O
+but	O
+with	O
+one	O
+exception	O
+(	O
+a	O
+grade	O
+3	O
+myalgia	B
+)	O
+they	O
+have	O
+been	O
+grade	O
+1	O
+or	O
+2	O
+.	O
+
+No	O
+dose	O
+-	O
+limiting	O
+hematologic	O
+toxicity	B
+has	O
+been	O
+seen	O
+.	O
+
+Paclitaxel	O
+/	O
+cisplatin	O
+is	O
+an	O
+effective	O
+first	O
+-	O
+line	O
+regimen	O
+for	O
+locoregionally	O
+advanced	O
+head	B
+and	I
+neck	I
+cancer	I
+and	O
+continued	O
+study	O
+is	O
+warranted	O
+.	O
+
+Results	O
+thus	O
+far	O
+suggest	O
+no	O
+dose	O
+-	O
+response	O
+effect	O
+for	O
+paclitaxel	O
+doses	O
+above	O
+200	O
+mg	O
+/	O
+m2	O
+.	O
+
+Improvement	O
+of	O
+levodopa	O
+-	O
+induced	O
+dyskinesia	B
+by	O
+propranolol	O
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+Seven	O
+patients	O
+suffering	O
+from	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+with	O
+severely	O
+disabling	O
+dyskinesia	B
+received	O
+low	O
+-	O
+dose	O
+propranolol	O
+as	O
+an	O
+adjunct	O
+to	O
+the	O
+currently	O
+used	O
+medical	O
+treatment	O
+.	O
+
+There	O
+was	O
+a	O
+significant	O
+40	O
+%	O
+improvement	O
+in	O
+the	O
+dyskinesia	B
+score	O
+without	O
+increase	O
+of	O
+parkinsonian	B
+motor	B
+disability	I
+.	O
+
+Ballistic	O
+and	O
+choreic	O
+dyskinesia	B
+were	O
+markedly	O
+ameliorated	O
+,	O
+whereas	O
+dystonia	B
+was	O
+not	O
+.	O
+
+This	O
+study	O
+suggests	O
+that	O
+administration	O
+of	O
+low	O
+doses	O
+of	O
+beta	O
+-	O
+blockers	O
+may	O
+improve	O
+levodopa	O
+-	O
+induced	O
+ballistic	O
+and	O
+choreic	O
+dyskinesia	B
+in	O
+PD	B
+.	O
+
+Habitual	O
+use	O
+of	O
+acetaminophen	O
+as	O
+a	O
+risk	O
+factor	O
+for	O
+chronic	B
+renal	I
+failure	I
+:	O
+a	O
+comparison	O
+with	O
+phenacetin	O
+.	O
+
+Six	O
+epidemiologic	O
+studies	O
+in	O
+the	O
+United	O
+States	O
+and	O
+Europe	O
+indicate	O
+that	O
+habitual	O
+use	O
+of	O
+phenacetin	O
+is	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+chronic	B
+renal	I
+failure	I
+and	O
+end	B
+-	I
+stage	I
+renal	I
+disease	I
+(	O
+ESRD	B
+)	O
+,	O
+with	O
+a	O
+relative	O
+risk	O
+in	O
+the	O
+range	O
+of	O
+4	O
+to	O
+19	O
+.	O
+
+As	O
+a	O
+result	O
+of	O
+these	O
+and	O
+other	O
+studies	O
+,	O
+phenacetin	O
+has	O
+now	O
+been	O
+withdrawn	O
+from	O
+the	O
+market	O
+in	O
+most	O
+countries	O
+.	O
+
+However	O
+,	O
+three	O
+case	O
+control	O
+studies	O
+,	O
+one	O
+each	O
+in	O
+North	O
+Carolina	O
+,	O
+northern	O
+Maryland	O
+,	O
+and	O
+West	O
+Berlin	O
+,	O
+Germany	O
+,	O
+showed	O
+that	O
+habitual	O
+use	O
+of	O
+acetaminophen	O
+is	O
+also	O
+associated	O
+with	O
+chronic	B
+renal	I
+failure	I
+and	O
+ESRD	B
+,	O
+with	O
+a	O
+relative	O
+risk	O
+in	O
+the	O
+range	O
+of	O
+2	O
+to	O
+4	O
+.	O
+
+These	O
+studies	O
+suggest	O
+that	O
+both	O
+phenacetin	O
+and	O
+acetaminophen	O
+may	O
+contribute	O
+to	O
+the	O
+burden	O
+of	O
+ESRD	B
+,	O
+with	O
+the	O
+risk	O
+of	O
+the	O
+latter	O
+being	O
+somewhat	O
+less	O
+than	O
+that	O
+of	O
+the	O
+former	O
+.	O
+
+This	O
+apparent	O
+difference	O
+in	O
+risk	O
+may	O
+not	O
+be	O
+due	O
+to	O
+differences	O
+in	O
+nephrotoxic	B
+potential	O
+of	O
+the	O
+drugs	O
+themselves	O
+.	O
+
+A	O
+lower	O
+relative	O
+risk	O
+would	O
+be	O
+expected	O
+for	O
+acetaminophen	O
+if	O
+the	O
+risk	O
+of	O
+both	O
+drugs	O
+in	O
+combination	O
+with	O
+other	O
+analgesics	O
+was	O
+higher	O
+than	O
+the	O
+risk	O
+of	O
+either	O
+agent	O
+alone	O
+.	O
+
+Thus	O
+,	O
+acetaminophen	O
+has	O
+been	O
+used	O
+both	O
+as	O
+a	O
+single	O
+agent	O
+and	O
+in	O
+combination	O
+with	O
+other	O
+analgesics	O
+,	O
+whereas	O
+phenacetin	O
+was	O
+available	O
+only	O
+in	O
+combinations	O
+.	O
+
+The	O
+possibility	O
+that	O
+habitual	O
+use	O
+of	O
+acetaminophen	O
+alone	O
+increases	O
+the	O
+risk	O
+of	O
+ESRD	B
+has	O
+not	O
+been	O
+clearly	O
+demonstrated	O
+,	O
+but	O
+cannot	O
+be	O
+dismissed	O
+.	O
+
+Acetaminophen	O
+-	O
+induced	O
+hypotension	B
+.	O
+
+Through	O
+30	O
+years	O
+of	O
+widespread	O
+use	O
+,	O
+acetaminophen	O
+has	O
+been	O
+shown	O
+to	O
+be	O
+a	O
+remarkably	O
+safe	O
+medication	O
+in	O
+therapeutic	O
+dosages	O
+.	O
+
+The	O
+potential	O
+for	O
+acetaminophen	O
+to	O
+produce	O
+cardiovascular	B
+toxicities	I
+is	O
+very	O
+low	O
+.	O
+
+However	O
+,	O
+acetaminophen	O
+has	O
+been	O
+demonstrated	O
+to	O
+produce	O
+symptoms	O
+of	O
+anaphylaxis	B
+,	O
+including	O
+hypotension	B
+,	O
+in	O
+sensitive	O
+individuals	O
+.	O
+
+This	O
+article	O
+describes	O
+two	O
+critically	B
+ill	I
+patients	O
+in	O
+whom	O
+transient	O
+episodes	O
+of	O
+hypotension	B
+reproducibly	O
+developed	O
+after	O
+administration	O
+of	O
+acetaminophen	O
+.	O
+
+Other	O
+symptoms	O
+of	O
+allergic	B
+reactions	I
+were	O
+not	O
+clinically	O
+detectable	O
+.	O
+
+The	O
+hypotensive	B
+episodes	O
+were	O
+severe	O
+enough	O
+to	O
+require	O
+vasopressor	O
+administration	O
+.	O
+
+The	O
+reports	O
+illustrate	O
+the	O
+need	O
+for	O
+clinicians	O
+to	O
+consider	O
+acetaminophen	O
+in	O
+patients	O
+with	O
+hypotension	B
+of	O
+unknown	O
+origin	O
+.	O
+
+Reduction	O
+of	O
+heparan	O
+sulphate	O
+-	O
+associated	O
+anionic	O
+sites	O
+in	O
+the	O
+glomerular	O
+basement	O
+membrane	O
+of	O
+rats	O
+with	O
+streptozotocin	O
+-	O
+induced	O
+diabetic	B
+nephropathy	I
+.	O
+
+Heparan	O
+sulphate	O
+-	O
+associated	O
+anionic	O
+sites	O
+in	O
+the	O
+glomerular	O
+basement	O
+membrane	O
+were	O
+studied	O
+in	O
+rats	O
+8	O
+months	O
+after	O
+induction	O
+of	O
+diabetes	B
+by	O
+streptozotocin	O
+and	O
+in	O
+age	O
+-	O
+adn	O
+sex	O
+-	O
+matched	O
+control	O
+rats	O
+,	O
+employing	O
+the	O
+cationic	O
+dye	O
+cuprolinic	O
+blue	O
+.	O
+
+Morphometric	O
+analysis	O
+at	O
+the	O
+ultrastructural	O
+level	O
+was	O
+performed	O
+using	O
+a	O
+computerized	O
+image	O
+processor	O
+.	O
+
+The	O
+heparan	O
+sulphate	O
+specificity	O
+of	O
+the	O
+cuprolinic	O
+blue	O
+staining	O
+was	O
+demonstrated	O
+by	O
+glycosaminoglycan	O
+-	O
+degrading	O
+enzymes	O
+,	O
+showing	O
+that	O
+pretreatment	O
+of	O
+the	O
+sections	O
+with	O
+heparitinase	O
+abolished	O
+all	O
+staining	O
+,	O
+whereas	O
+chondroitinase	O
+ABC	O
+had	O
+no	O
+effect	O
+.	O
+
+The	O
+majority	O
+of	O
+anionic	O
+sites	O
+(	O
+74	O
+%	O
+in	O
+diabetic	B
+and	O
+81	O
+%	O
+in	O
+control	O
+rats	O
+)	O
+were	O
+found	O
+within	O
+the	O
+lamina	O
+rara	O
+externa	O
+of	O
+the	O
+glomerular	O
+basement	O
+membrane	O
+.	O
+
+A	O
+minority	O
+of	O
+anionic	O
+sites	O
+were	O
+scattered	O
+throughout	O
+the	O
+lamina	O
+densa	O
+and	O
+lamina	O
+rara	O
+interna	O
+,	O
+and	O
+were	O
+significantly	O
+smaller	O
+than	O
+those	O
+in	O
+the	O
+lamina	O
+rara	O
+externa	O
+of	O
+the	O
+glomerular	O
+basement	O
+membrane	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+and	O
+p	O
+<	O
+0	O
+.	O
+01	O
+for	O
+diabetic	B
+and	O
+control	O
+rats	O
+,	O
+respectively	O
+)	O
+.	O
+
+Diabetic	B
+rats	O
+progressively	O
+developed	O
+albuminuria	B
+reaching	O
+40	O
+.	O
+3	O
+(	O
+32	O
+.	O
+2	O
+-	O
+62	O
+.	O
+0	O
+)	O
+mg	O
+/	O
+24	O
+h	O
+after	O
+8	O
+months	O
+in	O
+contrast	O
+to	O
+the	O
+control	O
+animals	O
+(	O
+0	O
+.	O
+8	O
+(	O
+0	O
+.	O
+2	O
+-	O
+0	O
+.	O
+9	O
+)	O
+mg	O
+/	O
+24	O
+h	O
+,	O
+p	O
+<	O
+0	O
+.	O
+002	O
+)	O
+.	O
+
+At	O
+the	O
+same	O
+time	O
+,	O
+the	O
+number	O
+of	O
+heparan	O
+sulphate	O
+anionic	O
+sites	O
+and	O
+the	O
+total	O
+anionic	O
+site	O
+surface	O
+(	O
+number	O
+of	O
+anionic	O
+sites	O
+x	O
+mean	O
+anionic	O
+site	O
+surface	O
+)	O
+in	O
+the	O
+lamina	O
+rara	O
+externa	O
+of	O
+the	O
+glomerular	O
+basement	O
+membrane	O
+was	O
+reduced	O
+by	O
+19	O
+%	O
+(	O
+p	O
+<	O
+0	O
+.	O
+021	O
+)	O
+and	O
+by	O
+26	O
+%	O
+(	O
+p	O
+<	O
+0	O
+.	O
+02	O
+)	O
+,	O
+respectively	O
+.	O
+
+Number	O
+and	O
+total	O
+anionic	O
+site	O
+surface	O
+in	O
+the	O
+remaining	O
+part	O
+of	O
+the	O
+glomerular	O
+basement	O
+membrane	O
+(	O
+lamina	O
+densa	O
+and	O
+lamina	O
+rara	O
+interna	O
+)	O
+were	O
+not	O
+significantly	O
+changed	O
+.	O
+
+We	O
+conclude	O
+that	O
+in	O
+streptozotocin	O
+-	O
+diabetic	B
+rats	O
+with	O
+an	O
+increased	O
+urinary	O
+albumin	O
+excretion	O
+,	O
+a	O
+reduced	O
+heparan	O
+sulphate	O
+charge	O
+barrier	O
+/	O
+density	O
+is	O
+found	O
+at	O
+the	O
+lamina	O
+rara	O
+externa	O
+of	O
+the	O
+glomerular	O
+basement	O
+membrane	O
+.	O
+
+Mediation	O
+of	O
+enhanced	O
+reflex	O
+vagal	O
+bradycardia	B
+by	O
+L	O
+-	O
+dopa	O
+via	O
+central	O
+dopamine	O
+formation	O
+in	O
+dogs	O
+.	O
+
+L	O
+-	O
+Dopa	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+decreased	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+after	O
+extracerebral	O
+decarboxylase	O
+inhibition	O
+with	O
+MK	O
+-	O
+486	O
+(	O
+25	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+in	O
+anesthetize	O
+MAO	O
+-	O
+inhibited	O
+dogs	O
+.	O
+
+In	O
+addition	O
+,	O
+reflex	O
+bradycardia	B
+caused	O
+by	O
+injected	O
+norepinephrine	O
+was	O
+significantly	O
+enhanced	O
+by	O
+L	O
+-	O
+dopa	O
+,	O
+DL	O
+-	O
+Threo	O
+-	O
+dihydroxyphenylserine	O
+had	O
+no	O
+effect	O
+on	O
+blood	O
+pressure	O
+,	O
+heart	O
+rate	O
+or	O
+reflex	O
+responses	O
+to	O
+norepinephrine	O
+.	O
+
+FLA	O
+-	O
+63	O
+,	O
+a	O
+dopamine	O
+-	O
+beta	O
+-	O
+oxidase	O
+inhibitor	O
+,	O
+did	O
+not	O
+have	O
+any	O
+effect	O
+on	O
+the	O
+hypotension	B
+,	O
+bradycardia	B
+or	O
+reflex	O
+-	O
+enhancing	O
+effect	O
+of	O
+L	O
+-	O
+dopa	O
+.	O
+
+Pimozide	O
+did	O
+not	O
+affect	O
+the	O
+actions	O
+of	O
+L	O
+-	O
+dopa	O
+on	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+but	O
+completely	O
+blocked	O
+the	O
+enhancement	O
+of	O
+reflexes	O
+.	O
+
+Removal	O
+of	O
+the	O
+carotid	O
+sinuses	O
+caused	O
+an	O
+elevation	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+and	O
+abolished	O
+the	O
+negative	O
+chronotropic	O
+effect	O
+of	O
+norepinephrine	O
+.	O
+
+However	O
+,	O
+L	O
+-	O
+dopa	O
+restored	O
+the	O
+bradycardia	B
+caused	O
+by	O
+norepinephrine	O
+in	O
+addition	O
+to	O
+decreasing	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+.	O
+
+5	O
+-	O
+HTP	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+decreased	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+and	O
+decreased	O
+the	O
+reflex	O
+bradycardia	B
+to	O
+norepinephrine	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+L	O
+-	O
+dopa	O
+enhances	O
+reflex	O
+bradycardia	B
+through	O
+central	O
+alpha	O
+-	O
+receptor	O
+stimulation	O
+.	O
+
+Furthermore	O
+,	O
+the	O
+effects	O
+are	O
+mediated	O
+through	O
+dopamine	O
+rather	O
+than	O
+norepinephrine	O
+and	O
+do	O
+not	O
+require	O
+the	O
+carotid	O
+sinus	O
+baroreceptors	O
+.	O
+
+Microangiopathic	B
+hemolytic	I
+anemia	I
+complicating	O
+FK506	O
+(	O
+tacrolimus	O
+)	O
+therapy	O
+.	O
+
+We	O
+describe	O
+3	O
+episodes	O
+of	O
+microangiopathic	B
+hemolytic	I
+anemia	I
+(	O
+MAHA	B
+)	O
+in	O
+2	O
+solid	O
+organ	O
+recipients	O
+under	O
+FK506	O
+(	O
+tacrolimus	O
+)	O
+therapy	O
+.	O
+
+In	O
+both	O
+cases	O
+,	O
+discontinuation	O
+of	O
+FK506	O
+and	O
+treatment	O
+with	O
+plasma	O
+exchange	O
+,	O
+fresh	O
+frozen	O
+plasma	O
+replacement	O
+,	O
+corticosteroids	O
+,	O
+aspirin	O
+,	O
+and	O
+dipyridamole	O
+led	O
+to	O
+resolution	O
+of	O
+MAHA	B
+.	O
+
+In	O
+one	O
+patient	O
+,	O
+reintroduction	O
+of	O
+FK506	O
+led	O
+to	O
+rapid	O
+recurrence	O
+of	O
+MAHA	B
+.	O
+
+FK506	O
+-	O
+associated	O
+MAHA	B
+is	O
+probably	O
+rare	O
+but	O
+physicians	O
+must	O
+be	O
+aware	O
+of	O
+this	O
+severe	O
+complication	O
+.	O
+
+In	O
+our	O
+experience	O
+and	O
+according	O
+to	O
+the	O
+literature	O
+,	O
+FK506	O
+does	O
+not	O
+seem	O
+to	O
+cross	O
+-	O
+react	O
+with	O
+cyclosporin	O
+A	O
+(	O
+CyA	O
+)	O
+,	O
+an	O
+immuno	O
+-	O
+suppressive	O
+drug	O
+already	O
+known	O
+to	O
+induce	O
+MAHA	B
+.	O
+
+Effect	O
+of	O
+some	O
+anticancer	O
+drugs	O
+and	O
+combined	O
+chemotherapy	O
+on	O
+renal	B
+toxicity	I
+.	O
+
+The	O
+nephrotoxic	B
+action	O
+of	O
+anticancer	O
+drugs	O
+such	O
+as	O
+nitrogranulogen	O
+(	O
+NG	O
+)	O
+,	O
+methotrexate	O
+(	O
+MTX	O
+)	O
+,	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+and	O
+cyclophosphamide	O
+(	O
+CY	O
+)	O
+administered	O
+alone	O
+or	O
+in	O
+combination	O
+[	O
+MTX	O
++	O
+5	O
+-	O
+FU	O
++	O
+CY	O
+(	O
+CMF	O
+)	O
+]	O
+was	O
+evaluated	O
+in	O
+experiments	O
+on	O
+Wistar	O
+rats	O
+.	O
+
+After	O
+drug	O
+administration	O
+,	O
+creatinine	O
+concentrations	O
+in	O
+the	O
+plasma	O
+and	O
+in	O
+the	O
+urine	O
+of	O
+the	O
+rats	O
+were	O
+determined	O
+,	O
+as	O
+well	O
+as	O
+creatinine	O
+clearance	O
+.	O
+
+Histopathologic	O
+evaluation	O
+of	O
+the	O
+kidneys	O
+was	O
+also	O
+performed	O
+.	O
+
+After	O
+MTX	O
+administration	O
+a	O
+significant	O
+increase	O
+(	O
+p	O
+=	O
+0	O
+.	O
+0228	O
+)	O
+in	O
+the	O
+plasma	O
+creatinine	O
+concentration	O
+and	O
+a	O
+significant	O
+(	O
+p	O
+=	O
+0	O
+.	O
+0001	O
+)	O
+decrease	O
+in	O
+creatinine	O
+clearance	O
+was	O
+noted	O
+compared	O
+to	O
+controls	O
+.	O
+
+After	O
+the	O
+administration	O
+of	O
+NG	O
+,	O
+5	O
+-	O
+FU	O
+and	O
+CY	O
+neither	O
+a	O
+statistically	O
+significant	O
+increase	O
+in	O
+creatinine	O
+concentration	O
+nor	O
+an	O
+increase	O
+in	O
+creatinine	O
+clearance	O
+was	O
+observed	O
+compared	O
+to	O
+the	O
+group	O
+receiving	O
+no	O
+cytostatics	O
+.	O
+
+Following	O
+polytherapy	O
+according	O
+to	O
+the	O
+CMF	O
+regimen	O
+,	O
+a	O
+statistically	O
+significant	O
+decrease	O
+(	O
+p	O
+=	O
+0	O
+.	O
+0343	O
+)	O
+in	O
+creatinine	O
+clearance	O
+was	O
+found	O
+,	O
+but	O
+creatinine	O
+concentration	O
+did	O
+not	O
+increase	O
+significantly	O
+compared	O
+to	O
+controls	O
+.	O
+
+CY	O
+caused	O
+hemorrhagic	B
+cystitis	I
+in	O
+40	O
+%	O
+of	O
+rats	O
+,	O
+but	O
+it	O
+did	O
+not	O
+cause	O
+this	O
+complication	O
+when	O
+combined	O
+with	O
+5	O
+-	O
+FU	O
+and	O
+MTX	O
+.	O
+
+Histologic	O
+changes	O
+were	O
+found	O
+in	O
+rat	O
+kidneys	O
+after	O
+administration	O
+of	O
+MTX	O
+,	O
+CY	O
+and	O
+NG	O
+,	O
+while	O
+no	O
+such	O
+change	O
+was	O
+observed	O
+after	O
+5	O
+-	O
+FU	O
+and	O
+joint	O
+administration	O
+of	O
+MTX	O
++	O
+5	O
+-	O
+FU	O
++	O
+CY	O
+compared	O
+to	O
+controls	O
+.	O
+
+Our	O
+studies	O
+indicate	O
+that	O
+nephrotoxicity	B
+of	O
+MTX	O
++	O
+5	O
+-	O
+FU	O
++	O
+CY	O
+administered	O
+jointly	O
+is	O
+lower	O
+than	O
+in	O
+monotherapy	O
+.	O
+
+The	O
+interpeduncular	O
+nucleus	O
+regulates	O
+nicotine	O
+'	O
+s	O
+effects	O
+on	O
+free	O
+-	O
+field	O
+activity	O
+.	O
+
+Partial	O
+lesions	O
+were	O
+made	O
+with	O
+kainic	O
+acid	O
+in	O
+the	O
+interpeduncular	O
+nucleus	O
+of	O
+the	O
+ventral	O
+midbrain	O
+of	O
+the	O
+rat	O
+.	O
+
+Compared	O
+with	O
+sham	O
+-	O
+operated	O
+controls	O
+,	O
+lesions	O
+significantly	O
+(	O
+p	O
+<	O
+0	O
+.	O
+25	O
+)	O
+blunted	O
+the	O
+early	O
+(	O
+<	O
+60	O
+min	O
+)	O
+free	O
+-	O
+field	O
+locomotor	B
+hypoactivity	I
+caused	O
+by	O
+nicotine	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+,	O
+i	O
+.	O
+m	O
+.	O
+)	O
+,	O
+enhanced	O
+the	O
+later	O
+(	O
+60	O
+-	O
+120	O
+min	O
+)	O
+nicotine	O
+-	O
+induced	O
+hyperactivity	B
+,	O
+and	O
+raised	O
+spontaneous	O
+nocturnal	O
+activity	O
+.	O
+
+Lesions	O
+reduced	O
+the	O
+extent	O
+of	O
+immunohistological	O
+staining	O
+for	O
+choline	O
+acetyltransferase	O
+in	O
+the	O
+interpeduncular	O
+nucleus	O
+(	O
+p	O
+<	O
+0	O
+.	O
+025	O
+)	O
+,	O
+but	O
+not	O
+for	O
+tyrosine	O
+hydroxylase	O
+in	O
+the	O
+surrounding	O
+catecholaminergic	O
+A10	O
+region	O
+.	O
+
+We	O
+conclude	O
+that	O
+the	O
+interpeduncular	O
+nucleus	O
+mediates	O
+nicotinic	O
+depression	B
+of	O
+locomotor	O
+activity	O
+and	O
+dampens	O
+nicotinic	O
+arousal	O
+mechanisms	O
+located	O
+elsewhere	O
+in	O
+the	O
+brain	O
+.	O
+
+Lithium	O
+-	O
+associated	O
+cognitive	B
+and	I
+functional	I
+deficits	I
+reduced	O
+by	O
+a	O
+switch	O
+to	O
+divalproex	O
+sodium	O
+:	O
+a	O
+case	O
+series	O
+.	O
+
+BACKGROUND	O
+:	O
+Lithium	O
+remains	O
+a	O
+first	O
+-	O
+line	O
+treatment	O
+for	O
+the	O
+acute	O
+and	O
+maintenance	O
+treatment	O
+of	O
+bipolar	B
+disorder	I
+.	O
+
+Although	O
+much	O
+has	O
+been	O
+written	O
+about	O
+the	O
+management	O
+of	O
+the	O
+more	O
+common	O
+adverse	O
+effects	O
+of	O
+lithium	O
+,	O
+such	O
+as	O
+polyuria	B
+and	O
+tremor	B
+,	O
+more	O
+subtle	O
+lithium	O
+side	O
+effects	O
+such	O
+as	O
+cognitive	B
+deficits	I
+,	O
+loss	B
+of	I
+creativity	I
+,	O
+and	O
+functional	B
+impairments	I
+remain	O
+understudied	O
+.	O
+
+This	O
+report	O
+summarizes	O
+our	O
+experience	O
+in	O
+switching	O
+bipolar	B
+patients	O
+from	O
+lithium	O
+to	O
+divalproex	O
+sodium	O
+to	O
+alleviate	O
+such	O
+cognitive	B
+and	I
+functional	I
+impairments	I
+.	O
+
+METHOD	O
+:	O
+Open	O
+,	O
+case	O
+series	O
+design	O
+.	O
+
+RESULTS	O
+:	O
+We	O
+report	O
+seven	O
+cases	O
+where	O
+substitution	O
+of	O
+lithium	O
+,	O
+either	O
+fully	O
+or	O
+partially	O
+,	O
+with	O
+divalproex	O
+sodium	O
+was	O
+extremely	O
+helpful	O
+in	O
+reducing	O
+the	O
+cognitive	B
+,	I
+motivational	I
+,	I
+or	I
+creative	I
+deficits	I
+attributed	O
+to	O
+lithium	O
+in	O
+our	O
+bipolar	B
+patients	O
+.	O
+
+CONCLUSION	O
+:	O
+In	O
+this	O
+preliminary	O
+report	O
+,	O
+divalproex	O
+sodium	O
+was	O
+a	O
+superior	O
+alternative	O
+to	O
+lithium	O
+in	O
+bipolar	B
+patients	O
+experiencing	O
+cognitive	B
+deficits	I
+,	O
+loss	B
+of	I
+creativity	I
+,	O
+and	O
+functional	B
+impairments	I
+.	O
+
+Effect	O
+of	O
+nifedipine	O
+on	O
+renal	O
+function	O
+in	O
+liver	O
+transplant	O
+recipients	O
+receiving	O
+tacrolimus	O
+.	O
+
+The	O
+effect	O
+of	O
+nifedipine	O
+on	O
+renal	O
+function	O
+in	O
+liver	O
+transplant	O
+recipients	O
+who	O
+were	O
+receiving	O
+tacrolimus	O
+was	O
+evaluated	O
+between	O
+January	O
+1992	O
+and	O
+January	O
+1996	O
+.	O
+
+Two	O
+groups	O
+of	O
+patients	O
+receiving	O
+tacrolimus	O
+were	O
+compared	O
+over	O
+a	O
+period	O
+of	O
+1	O
+year	O
+,	O
+one	O
+group	O
+comprising	O
+hypertensive	B
+patients	O
+who	O
+were	O
+receiving	O
+nifedipine	O
+,	O
+and	O
+the	O
+other	O
+comprising	O
+nonhypertensive	O
+patients	O
+not	O
+receiving	O
+nifedipine	O
+.	O
+
+The	O
+time	O
+from	O
+transplant	O
+to	O
+baseline	O
+was	O
+similar	O
+in	O
+all	O
+patients	O
+.	O
+
+Nifedipine	O
+significantly	O
+improved	O
+kidney	O
+function	O
+as	O
+indicated	O
+by	O
+a	O
+significant	O
+lowering	O
+of	O
+serum	O
+creatinine	O
+levels	O
+at	O
+6	O
+and	O
+12	O
+months	O
+.	O
+
+The	O
+observed	O
+positive	O
+impact	O
+of	O
+nifedipine	O
+on	O
+reducing	O
+the	O
+nephrotoxicity	B
+associated	O
+with	O
+tacrolimus	O
+in	O
+liver	O
+transplant	O
+recipients	O
+should	O
+be	O
+an	O
+important	O
+factor	O
+in	O
+selecting	O
+an	O
+agent	O
+to	O
+treat	O
+hypertension	B
+in	O
+this	O
+population	O
+.	O
+
+Alpha	O
+and	O
+beta	O
+coma	B
+in	O
+drug	O
+intoxication	O
+uncomplicated	O
+by	O
+cerebral	B
+hypoxia	I
+.	O
+
+Four	O
+patients	O
+who	O
+were	O
+rendered	O
+comatose	B
+or	O
+stuporous	B
+by	O
+drug	O
+intoxication	O
+,	O
+but	O
+who	O
+were	O
+not	O
+hypoxic	O
+,	O
+are	O
+described	O
+.	O
+
+Three	O
+patients	O
+received	O
+high	O
+doses	O
+of	O
+chlormethiazole	O
+for	O
+alcohol	O
+withdrawal	B
+symptoms	I
+,	O
+and	O
+one	O
+took	O
+a	O
+suicidal	O
+overdose	B
+of	O
+nitrazepam	O
+.	O
+
+The	O
+patient	O
+with	O
+nitrazepam	O
+overdose	B
+and	O
+two	O
+of	O
+those	O
+with	O
+chlormethiazole	O
+intoxication	O
+conformed	O
+to	O
+the	O
+criteria	O
+of	O
+'	O
+alpha	O
+coma	B
+'	O
+,	O
+showing	O
+non	O
+-	O
+reactive	O
+generalized	O
+or	O
+frontally	O
+predominant	O
+alpha	O
+activity	O
+in	O
+the	O
+EEG	O
+.	O
+
+The	O
+fourth	O
+patient	O
+who	O
+was	O
+unconscious	O
+after	O
+chlormethiazole	O
+administration	O
+exhibite	O
+generalized	O
+non	O
+-	O
+reactive	O
+activity	O
+in	O
+the	O
+slow	O
+beta	O
+range	O
+.	O
+
+All	O
+four	O
+recovered	O
+completely	O
+without	O
+neurological	B
+sequelae	I
+following	O
+the	O
+withdrawal	O
+of	O
+the	O
+offending	O
+agents	O
+.	O
+
+The	O
+similarities	O
+between	O
+the	O
+effects	O
+of	O
+structural	O
+lesions	O
+and	O
+pharmacological	O
+depression	B
+of	O
+the	O
+brain	O
+stem	O
+reticular	O
+formation	O
+are	O
+discussed	O
+.	O
+
+It	O
+is	O
+suggested	O
+that	O
+in	O
+both	O
+situations	O
+disturbed	O
+reticulo	O
+-	O
+thalamic	O
+interactions	O
+are	O
+important	O
+in	O
+the	O
+pathogenesis	O
+of	O
+alpha	O
+coma	B
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+when	O
+this	O
+electroencephalographic	O
+and	O
+behavioural	O
+picture	O
+is	O
+seen	O
+in	O
+drug	O
+intoxication	O
+,	O
+in	O
+the	O
+absence	O
+of	O
+significant	O
+hypoxaemia	B
+,	O
+a	O
+favourable	O
+outcome	O
+may	O
+be	O
+anticipated	O
+.	O
+
+Magnetic	O
+resonance	O
+volumetry	O
+of	O
+the	O
+cerebellum	O
+in	O
+epileptic	B
+patients	O
+after	O
+phenytoin	O
+overdosages	B
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+evaluate	O
+the	O
+relationship	O
+between	O
+phenytoin	O
+medication	O
+and	O
+cerebellar	B
+atrophy	I
+in	O
+patients	O
+who	O
+had	O
+experienced	O
+clinical	O
+intoxication	O
+.	O
+
+Five	O
+females	O
+and	O
+6	O
+males	O
+,	O
+21	O
+-	O
+59	O
+years	O
+of	O
+age	O
+,	O
+were	O
+examined	O
+with	O
+a	O
+1	O
+.	O
+5	O
+-	O
+T	O
+whole	O
+-	O
+body	O
+system	O
+using	O
+a	O
+circular	O
+polarized	O
+head	O
+coil	O
+.	O
+
+Conventional	O
+spin	O
+echo	O
+images	O
+were	O
+acquired	O
+in	O
+the	O
+sagittal	O
+and	O
+transverse	O
+orientation	O
+.	O
+
+In	O
+addition	O
+,	O
+we	O
+performed	O
+a	O
+high	O
+-	O
+resolution	O
+3D	O
+gradient	O
+echo	O
+,	O
+T1	O
+-	O
+weighted	O
+sequences	O
+at	O
+a	O
+1	O
+-	O
+mm	O
+slice	O
+thickness	O
+.	O
+
+The	O
+images	O
+were	O
+subsequently	O
+processed	O
+to	O
+obtain	O
+volumetric	O
+data	O
+for	O
+the	O
+cerebellum	O
+.	O
+
+Cerebellar	O
+volume	O
+for	O
+the	O
+patient	O
+group	O
+ranged	O
+between	O
+67	O
+.	O
+66	O
+and	O
+131	O
+.	O
+08	O
+ml	O
+(	O
+mean	O
+108	O
+.	O
+9	O
+ml	O
+)	O
+.	O
+
+In	O
+addition	O
+3D	O
+gradient	O
+echo	O
+data	O
+sets	O
+from	O
+10	O
+healthy	O
+male	O
+and	O
+10	O
+healthy	O
+female	O
+age	O
+-	O
+matched	O
+volunteers	O
+were	O
+used	O
+to	O
+compare	O
+cerebellar	O
+volumes	O
+.	O
+
+Using	O
+linear	O
+regression	O
+we	O
+found	O
+that	O
+no	O
+correlation	O
+exists	O
+between	O
+seizure	B
+duration	O
+,	O
+elevation	O
+of	O
+phenytoin	O
+serum	O
+levels	O
+and	O
+cerebellar	O
+volume	O
+.	O
+
+However	O
+,	O
+multiple	O
+regression	O
+for	O
+the	O
+daily	O
+dosage	O
+,	O
+duration	O
+of	O
+phenytoin	O
+treatment	O
+and	O
+cerebellar	O
+volume	O
+revealed	O
+a	O
+correlation	O
+of	O
+these	O
+parameters	O
+.	O
+
+We	O
+conclude	O
+that	O
+phenytoin	O
+overdosage	B
+does	O
+not	O
+necessarily	O
+result	O
+in	O
+cerebellar	B
+atrophy	I
+and	O
+it	O
+is	O
+unlikely	O
+that	O
+phenytoin	O
+medication	O
+was	O
+the	O
+only	O
+cause	O
+of	O
+cerebellar	B
+atrophy	I
+in	O
+the	O
+remaining	O
+patients	O
+.	O
+
+Quantitative	O
+morphometric	O
+studies	O
+of	O
+the	O
+cerebellum	O
+provide	O
+valuable	O
+insights	O
+into	O
+the	O
+pathogenesis	O
+of	O
+cerebellar	B
+disorders	I
+.	O
+
+Late	O
+recovery	O
+of	O
+renal	O
+function	O
+in	O
+a	O
+woman	O
+with	O
+the	O
+hemolytic	B
+uremic	I
+syndrome	I
+.	O
+
+A	O
+case	O
+is	O
+reported	O
+of	O
+the	O
+hemolytic	B
+uremic	I
+syndrome	I
+(	O
+HUS	B
+)	O
+in	O
+a	O
+woman	O
+taking	O
+oral	O
+contraceptives	O
+.	O
+
+She	O
+was	O
+treated	O
+with	O
+heparin	O
+,	O
+dipyridamole	O
+and	O
+hemodialysis	O
+;	O
+and	O
+after	O
+more	O
+than	O
+three	O
+months	O
+,	O
+her	O
+urinary	O
+output	O
+rose	O
+above	O
+500	O
+ml	O
+;	O
+and	O
+six	O
+months	O
+after	O
+the	O
+onset	O
+of	O
+anuria	B
+,	O
+dialysis	O
+treatment	O
+was	O
+stopped	O
+.	O
+
+This	O
+case	O
+emphasizes	O
+the	O
+possibility	O
+that	O
+HUS	B
+in	O
+adults	O
+is	O
+not	O
+invariably	O
+irreversible	O
+and	O
+that	O
+,	O
+despite	O
+prolonged	O
+oliguria	B
+,	O
+recovery	O
+of	O
+renal	O
+function	O
+can	O
+be	O
+obtained	O
+.	O
+
+Therefore	O
+,	O
+in	O
+adult	O
+patients	O
+affected	O
+by	O
+HUS	B
+,	O
+dialysis	O
+should	O
+not	O
+be	O
+discontinued	O
+prematurely	O
+;	O
+moreover	O
+,	O
+bilateral	O
+nephrectomy	O
+,	O
+for	O
+treatment	O
+of	O
+severe	O
+hypertension	B
+and	O
+microangiopathic	B
+hemolytic	I
+anemia	I
+,	O
+should	O
+be	O
+performed	O
+with	O
+caution	O
+.	O
+
+Morphological	O
+features	O
+of	O
+encephalopathy	B
+after	O
+chronic	O
+administration	O
+of	O
+the	O
+antiepileptic	O
+drug	O
+valproate	O
+to	O
+rats	O
+.	O
+
+A	O
+transmission	O
+electron	O
+microscopic	O
+study	O
+of	O
+capillaries	O
+in	O
+the	O
+cerebellar	O
+cortex	O
+.	O
+
+Long	O
+-	O
+term	O
+intragastric	O
+application	O
+of	O
+the	O
+antiepileptic	O
+drug	O
+sodium	O
+valproate	O
+(	O
+Vupral	O
+"	O
+Polfa	O
+"	O
+)	O
+at	O
+the	O
+effective	O
+dose	O
+of	O
+200	O
+mg	O
+/	O
+kg	O
+b	O
+.	O
+
+w	O
+.	O
+once	O
+daily	O
+to	O
+rats	O
+for	O
+1	O
+,	O
+3	O
+,	O
+6	O
+,	O
+9	O
+and	O
+12	O
+months	O
+revealed	O
+neurological	B
+disorders	I
+indicating	O
+cerebellum	B
+damage	I
+(	O
+"	O
+valproate	O
+encephalopathy	B
+"	O
+)	O
+.	O
+
+The	O
+first	O
+ultrastructural	O
+changes	O
+in	O
+structural	O
+elements	O
+of	O
+the	O
+blood	O
+-	O
+brain	O
+-	O
+barrier	O
+(	O
+BBB	O
+)	O
+in	O
+the	O
+cerebellar	O
+cortex	O
+were	O
+detectable	O
+after	O
+3	O
+months	O
+of	O
+the	O
+experiment	O
+.	O
+
+They	O
+became	O
+more	O
+severe	O
+in	O
+the	O
+later	O
+months	O
+of	O
+the	O
+experiment	O
+,	O
+and	O
+were	O
+most	O
+severe	O
+after	O
+12	O
+months	O
+,	O
+located	O
+mainly	O
+in	O
+the	O
+molecular	O
+layer	O
+of	O
+the	O
+cerebellar	O
+cortex	O
+.	O
+
+Lesions	O
+of	O
+the	O
+capillary	O
+included	O
+necrosis	B
+of	O
+endothelial	O
+cells	O
+.	O
+
+Organelles	O
+of	O
+these	O
+cells	O
+,	O
+in	O
+particular	O
+the	O
+mitochondria	O
+(	O
+increased	O
+number	O
+and	O
+size	O
+,	O
+distinct	O
+degeneration	O
+of	O
+their	O
+matrix	O
+and	O
+cristae	O
+)	O
+and	O
+Golgi	O
+apparatus	O
+were	O
+altered	O
+.	O
+
+Reduced	O
+size	O
+of	O
+capillary	O
+lumen	O
+and	O
+occlusion	O
+were	O
+caused	O
+by	O
+swollen	O
+endothelial	O
+cells	O
+which	O
+had	O
+luminal	O
+protrusions	O
+and	O
+swollen	O
+microvilli	O
+.	O
+
+Pressure	O
+on	O
+the	O
+vessel	O
+wall	O
+was	O
+produced	O
+by	O
+enlarged	O
+perivascular	O
+astrocytic	O
+processes	O
+.	O
+
+Fragments	O
+of	O
+necrotic	B
+endothelial	O
+cells	O
+were	O
+in	O
+the	O
+vascular	O
+lumens	O
+and	O
+in	O
+these	O
+there	O
+was	O
+loosening	O
+and	O
+breaking	O
+of	O
+tight	O
+cellular	O
+junctions	O
+.	O
+
+Damage	O
+to	O
+the	O
+vascular	O
+basement	O
+lamina	O
+was	O
+also	O
+observed	O
+.	O
+
+Damage	O
+to	O
+the	O
+capillary	O
+was	O
+accompanied	O
+by	O
+marked	O
+damage	O
+to	O
+neuroglial	O
+cells	O
+,	O
+mainly	O
+to	O
+perivascular	O
+processes	O
+of	O
+astrocytes	O
+.	O
+
+The	O
+proliferation	O
+of	O
+astrocytes	O
+(	O
+Bergmann	O
+'	O
+s	O
+in	O
+particular	O
+)	O
+and	O
+occasionally	O
+of	O
+oligodendrocytes	O
+was	O
+found	O
+.	O
+
+Alterations	O
+in	O
+the	O
+structural	O
+elements	O
+of	O
+the	O
+BBB	O
+coexisted	O
+with	O
+marked	O
+lesions	O
+of	O
+neurons	O
+of	O
+the	O
+cerebellum	O
+(	O
+Purkinje	O
+cells	O
+are	O
+earliest	O
+)	O
+.	O
+
+In	O
+electron	O
+micrographs	O
+both	O
+luminal	O
+and	O
+antiluminal	O
+sides	O
+of	O
+the	O
+BBB	O
+of	O
+the	O
+cerebellar	O
+cortex	O
+had	O
+similar	O
+lesions	O
+.	O
+
+The	O
+possible	O
+influence	O
+of	O
+the	O
+hepatic	B
+damage	I
+,	O
+mainly	O
+hyperammonemia	B
+,	O
+upon	O
+the	O
+development	O
+of	O
+valproate	O
+encephalopathy	B
+is	O
+discussed	O
+.	O
+
+Fatal	O
+intracranial	B
+bleeding	I
+associated	O
+with	O
+prehospital	O
+use	O
+of	O
+epinephrine	O
+.	O
+
+We	O
+present	O
+a	O
+case	O
+of	O
+paramedic	O
+misjudgment	O
+in	O
+the	O
+execution	O
+of	O
+a	O
+protocol	O
+for	O
+the	O
+treatment	O
+of	O
+allergic	B
+reaction	I
+in	O
+a	O
+case	O
+of	O
+pulmonary	B
+edema	I
+with	O
+wheezing	B
+.	O
+
+The	O
+sudden	O
+onset	O
+of	O
+respiratory	B
+distress	I
+,	O
+rash	B
+,	O
+and	O
+a	O
+history	O
+of	O
+a	O
+new	O
+medicine	O
+led	O
+the	O
+two	O
+paramedics	O
+on	O
+the	O
+scene	O
+to	O
+administer	O
+subcutaneous	O
+epinephrine	O
+.	O
+
+Subsequently	O
+,	O
+acute	O
+cardiac	B
+arrest	I
+and	O
+fatal	O
+subarachnoid	B
+hemorrhage	I
+occurred	O
+.	O
+
+Epinephrine	O
+has	O
+a	O
+proven	O
+role	O
+in	O
+cardiac	B
+arrest	I
+in	O
+prehospital	O
+care	O
+;	O
+however	O
+,	O
+use	O
+by	O
+paramedics	O
+in	O
+patients	O
+with	O
+suspected	O
+allergic	B
+reaction	I
+and	O
+severe	O
+hypertension	B
+should	O
+be	O
+viewed	O
+with	O
+caution	O
+.	O
+
+Role	O
+of	O
+activation	O
+of	O
+bradykinin	O
+B2	O
+receptors	O
+in	O
+disruption	O
+of	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+during	O
+acute	O
+hypertension	B
+.	O
+
+Cellular	O
+mechanisms	O
+which	O
+account	O
+for	O
+disruption	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+during	O
+acute	O
+hypertension	B
+are	O
+not	O
+clear	O
+.	O
+
+The	O
+goal	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+role	O
+of	O
+synthesis	O
+/	O
+release	O
+of	O
+bradykinin	O
+to	O
+activate	O
+B2	O
+receptors	O
+in	O
+disruption	O
+of	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+during	O
+acute	O
+hypertension	B
+.	O
+
+Permeability	O
+of	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+was	O
+quantitated	O
+by	O
+clearance	O
+of	O
+fluorescent	O
+-	O
+labeled	O
+dextran	O
+before	O
+and	O
+during	O
+phenylephrine	O
+-	O
+induced	O
+acute	O
+hypertension	B
+in	O
+rats	O
+treated	O
+with	O
+vehicle	O
+and	O
+Hoe	O
+-	O
+140	O
+(	O
+0	O
+.	O
+1	O
+microM	O
+)	O
+.	O
+
+Phenylephrine	O
+infusion	O
+increased	O
+arterial	O
+pressure	O
+,	O
+arteriolar	O
+diameter	O
+and	O
+clearance	O
+of	O
+fluorescent	O
+dextran	O
+by	O
+a	O
+similar	O
+magnitude	O
+in	O
+both	O
+groups	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+disruption	O
+of	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+during	O
+acute	O
+hypertension	B
+is	O
+not	O
+related	O
+to	O
+the	O
+synthesis	O
+/	O
+release	O
+of	O
+bradykinin	O
+to	O
+activate	O
+B2	O
+receptors	O
+.	O
+
+Risk	O
+factors	O
+of	O
+sensorineural	B
+hearing	I
+loss	I
+in	O
+preterm	O
+infants	O
+.	O
+
+Among	O
+547	O
+preterm	O
+infants	O
+of	O
+<	O
+or	O
+=	O
+34	O
+weeks	O
+gestation	O
+born	O
+between	O
+1987	O
+and	O
+1991	O
+,	O
+8	O
+children	O
+(	O
+1	O
+.	O
+46	O
+%	O
+)	O
+developed	O
+severe	O
+progressive	O
+and	O
+bilateral	O
+sensorineural	B
+hearing	I
+loss	I
+.	O
+
+Perinatal	O
+risk	O
+factors	O
+of	O
+infants	O
+with	O
+hearing	B
+loss	I
+were	O
+compared	O
+with	O
+those	O
+of	O
+two	O
+control	O
+groups	O
+matched	O
+for	O
+gestation	O
+and	O
+birth	O
+weight	O
+and	O
+for	O
+perinatal	O
+complications	O
+.	O
+
+Our	O
+observations	O
+demonstrated	O
+an	O
+association	O
+of	O
+hearing	B
+loss	I
+with	O
+a	O
+higher	O
+incidence	O
+of	O
+perinatal	O
+complications	O
+.	O
+
+Ototoxicity	B
+appeared	O
+closely	O
+related	O
+to	O
+a	O
+prolonged	O
+administration	O
+and	O
+higher	O
+total	O
+dose	O
+of	O
+ototoxic	B
+drugs	O
+,	O
+particularly	O
+aminoglycosides	O
+and	O
+furosemide	O
+.	O
+
+Finally	O
+,	O
+we	O
+strongly	O
+recommend	O
+to	O
+prospectively	O
+and	O
+regularly	O
+perform	O
+audiologic	O
+assessment	O
+in	O
+sick	O
+preterm	O
+children	O
+as	O
+hearing	B
+loss	I
+is	O
+of	O
+delayed	O
+onset	O
+and	O
+in	O
+most	O
+cases	O
+bilateral	O
+and	O
+severe	O
+.	O
+
+Seizure	B
+resulting	O
+from	O
+a	O
+venlafaxine	O
+overdose	B
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+venlafaxine	O
+overdose	B
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+40	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+major	B
+depression	I
+took	O
+an	O
+overdose	B
+of	O
+venlafaxine	O
+in	O
+an	O
+apparent	O
+suicide	O
+attempt	O
+.	O
+
+After	O
+the	O
+ingestion	O
+of	O
+26	O
+venlafaxine	O
+50	O
+-	O
+mg	O
+tablets	O
+,	O
+the	O
+patient	O
+experienced	O
+a	O
+witnessed	O
+generalized	O
+seizure	B
+.	O
+
+She	O
+was	O
+admitted	O
+to	O
+the	O
+medical	O
+intensive	O
+care	O
+unit	O
+,	O
+venlafaxine	O
+was	O
+discontinued	O
+,	O
+and	O
+no	O
+further	O
+sequelae	O
+were	O
+seen	O
+.	O
+
+DISCUSSION	O
+:	O
+To	O
+our	O
+knowledge	O
+,	O
+this	O
+is	O
+the	O
+first	O
+reported	O
+case	O
+of	O
+venlafaxine	O
+overdose	B
+that	O
+resulted	O
+in	O
+a	O
+generalized	O
+seizure	B
+.	O
+
+Based	O
+on	O
+nonoverdose	O
+pharmacokinetics	O
+and	O
+pharmacodynamics	O
+of	O
+venlafaxine	O
+and	O
+the	O
+potential	O
+risks	O
+of	O
+available	O
+interventions	O
+,	O
+no	O
+emergent	O
+therapy	O
+was	O
+instituted	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+venlafaxine	O
+overdose	B
+in	O
+our	O
+patient	O
+resulted	O
+in	O
+a	O
+single	O
+episode	O
+of	O
+generalized	O
+seizure	B
+but	O
+elicited	O
+no	O
+further	O
+sequelae	O
+.	O
+
+Combined	O
+effects	O
+of	O
+prolonged	O
+prostaglandin	O
+E1	O
+-	O
+induced	O
+hypotension	B
+and	O
+haemodilution	B
+on	O
+human	O
+hepatic	O
+function	O
+.	O
+
+Combined	O
+effects	O
+of	O
+prolonged	O
+prostaglandin	O
+E1	O
+(	O
+PGE1	O
+)	O
+-	O
+induced	O
+hypotension	B
+and	O
+haemodilution	B
+on	O
+hepatic	O
+function	O
+were	O
+studied	O
+in	O
+30	O
+patients	O
+undergoing	O
+hip	O
+surgery	O
+.	O
+
+The	O
+patients	O
+were	O
+randomly	O
+allocated	O
+to	O
+one	O
+of	O
+three	O
+groups	O
+;	O
+those	O
+in	O
+group	O
+A	O
+(	O
+n	O
+=	O
+10	O
+)	O
+were	O
+subjected	O
+to	O
+controlled	O
+hypotension	B
+alone	O
+,	O
+those	O
+in	O
+group	O
+B	O
+(	O
+n	O
+=	O
+10	O
+)	O
+to	O
+haemodilution	B
+alone	O
+and	O
+those	O
+in	O
+group	O
+C	O
+(	O
+n	O
+=	O
+10	O
+)	O
+to	O
+both	O
+controlled	O
+hypotension	B
+and	O
+haemodilution	B
+.	O
+
+Haemodilution	B
+in	O
+groups	O
+B	O
+and	O
+C	O
+was	O
+produced	O
+by	O
+withdrawing	O
+approximately	O
+1000	O
+mL	O
+of	O
+blood	O
+and	O
+replacing	O
+it	O
+with	O
+the	O
+same	O
+amount	O
+of	O
+dextran	O
+solution	O
+,	O
+and	O
+final	O
+haematocrit	O
+values	O
+were	O
+21	O
+or	O
+22	O
+%	O
+.	O
+
+Controlled	O
+hypotension	B
+in	O
+groups	O
+A	O
+and	O
+C	O
+was	O
+induced	O
+with	O
+PGE1	O
+to	O
+maintain	O
+mean	O
+arterial	O
+blood	O
+pressure	O
+at	O
+55	O
+mmHg	O
+for	O
+180	O
+min	O
+.	O
+
+Measurements	O
+included	O
+arterial	O
+ketone	O
+body	O
+ratio	O
+(	O
+AKBR	O
+,	O
+aceto	O
+-	O
+acetate	O
+/	O
+3	O
+-	O
+hydroxybutyrate	O
+)	O
+and	O
+clinical	O
+hepatic	O
+function	O
+parameters	O
+.	O
+
+AKBR	O
+and	O
+biological	O
+hepatic	O
+function	O
+tests	O
+showed	O
+no	O
+change	O
+throughout	O
+the	O
+time	O
+course	O
+in	O
+groups	O
+A	O
+and	O
+B	O
+.	O
+
+In	O
+group	O
+C	O
+,	O
+AKBR	O
+showed	O
+a	O
+significant	O
+decrease	O
+at	O
+120	O
+min	O
+(	O
+-	O
+40	O
+%	O
+)	O
+and	O
+at	O
+180	O
+min	O
+(	O
+-	O
+49	O
+%	O
+)	O
+after	O
+the	O
+start	O
+of	O
+hypotension	B
+and	O
+at	O
+60	O
+min	O
+(	O
+-	O
+32	O
+%	O
+)	O
+after	O
+recovery	O
+of	O
+normotension	O
+,	O
+and	O
+SGOT	O
+,	O
+SGPT	O
+,	O
+LDH	O
+and	O
+total	O
+bilirubin	O
+showed	O
+significant	O
+increases	O
+after	O
+operation	O
+.	O
+
+The	O
+results	O
+suggest	O
+that	O
+a	O
+prolonged	O
+combination	O
+of	O
+more	O
+than	O
+120	O
+min	O
+of	O
+PGE1	O
+-	O
+induced	O
+hypotension	B
+and	O
+moderate	O
+haemodilution	B
+would	O
+cause	O
+impairment	B
+of	I
+hepatic	I
+function	I
+.	O
+
+Cardiovascular	B
+alterations	I
+in	O
+rat	O
+fetuses	O
+exposed	O
+to	O
+calcium	O
+channel	O
+blockers	O
+.	O
+
+Preclinical	O
+toxicologic	O
+investigation	O
+suggested	O
+that	O
+a	O
+new	O
+calcium	O
+channel	O
+blocker	O
+,	O
+Ro	O
+40	O
+-	O
+5967	O
+,	O
+induced	O
+cardiovascular	B
+alterations	I
+in	O
+rat	O
+fetuses	O
+exposed	O
+to	O
+this	O
+agent	O
+during	O
+organogenesis	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+investigate	O
+the	O
+hypothesis	O
+that	O
+calcium	O
+channel	O
+blockers	O
+in	O
+general	O
+induce	O
+cardiovascular	B
+malformations	I
+indicating	O
+a	O
+pharmacologic	O
+class	O
+effect	O
+.	O
+
+We	O
+studied	O
+three	O
+calcium	O
+channel	O
+blockers	O
+of	O
+different	O
+structure	O
+,	O
+nifedipine	O
+,	O
+diltiazem	O
+,	O
+and	O
+verapamil	O
+,	O
+along	O
+with	O
+the	O
+new	O
+agent	O
+.	O
+
+Pregnant	O
+rats	O
+were	O
+administered	O
+one	O
+of	O
+these	O
+calcium	O
+channel	O
+blockers	O
+during	O
+the	O
+period	O
+of	O
+cardiac	O
+morphogenesis	O
+and	O
+the	O
+offspring	O
+examined	O
+on	O
+day	O
+20	O
+of	O
+gestation	O
+for	O
+cardiovascular	B
+malformations	I
+.	O
+
+A	O
+low	O
+incidence	O
+of	O
+cardiovascular	B
+malformations	I
+was	O
+observed	O
+after	O
+exposure	O
+to	O
+each	O
+of	O
+the	O
+four	O
+calcium	O
+channel	O
+blockers	O
+,	O
+but	O
+this	O
+incidence	O
+was	O
+statistically	O
+significant	O
+only	O
+for	O
+verapamil	O
+and	O
+nifedipine	O
+.	O
+
+All	O
+four	O
+agents	O
+were	O
+associated	O
+with	O
+aortic	O
+arch	O
+branching	O
+variants	O
+,	O
+although	O
+significantly	O
+increased	O
+only	O
+for	O
+Ro	O
+40	O
+-	O
+5967	O
+and	O
+verapamil	O
+.	O
+
+The	O
+site	O
+of	O
+common	O
+side	O
+effects	O
+of	O
+sumatriptan	O
+.	O
+
+Atypical	B
+sensations	I
+following	O
+the	O
+use	O
+of	O
+subcutaneous	O
+sumatriptan	O
+are	O
+common	O
+,	O
+but	O
+of	O
+uncertain	O
+origin	O
+.	O
+
+They	O
+are	O
+almost	O
+always	O
+benign	O
+,	O
+but	O
+can	O
+be	O
+mistaken	O
+for	O
+a	O
+serious	O
+adverse	O
+event	O
+by	O
+the	O
+patient	O
+.	O
+
+Two	O
+patients	O
+are	O
+presented	O
+with	O
+tingling	B
+or	I
+burning	I
+sensations	I
+limited	O
+to	O
+areas	O
+of	O
+heat	O
+exposure	O
+or	O
+sunburn	B
+.	O
+
+In	O
+these	O
+individuals	O
+,	O
+side	O
+effects	O
+are	O
+most	O
+likely	O
+generated	O
+superficially	O
+in	O
+the	O
+skin	O
+.	O
+
+Macula	O
+toxicity	B
+after	O
+intravitreal	O
+amikacin	O
+.	O
+
+BACKGROUND	O
+:	O
+Although	O
+intravitreal	O
+aminoglycosides	O
+have	O
+substantially	O
+improved	O
+visual	O
+prognosis	O
+in	O
+endophthalmitis	B
+,	O
+macular	O
+infarction	B
+may	O
+impair	O
+full	O
+visual	O
+recovery	O
+.	O
+
+METHODS	O
+:	O
+We	O
+present	O
+a	O
+case	O
+of	O
+presumed	O
+amikacin	O
+retinal	B
+toxicity	I
+following	O
+treatment	O
+with	O
+amikacin	O
+and	O
+vancomycin	O
+for	O
+alpha	O
+-	O
+haemolytic	O
+streptococcal	B
+endophthalmitis	I
+.	O
+
+RESULTS	O
+:	O
+Endophthalmitis	B
+resolved	O
+with	O
+improvement	O
+in	O
+visual	O
+acuity	O
+to	O
+6	O
+/	O
+24	O
+at	O
+three	O
+months	O
+.	O
+
+Fundus	O
+fluorescein	O
+angiography	O
+confirmed	O
+macular	O
+capillary	O
+closure	O
+and	O
+telangiectasis	B
+.	O
+
+CONCLUSIONS	O
+:	O
+Currently	O
+accepted	O
+intravitreal	O
+antibiotic	O
+regimens	O
+may	O
+cause	O
+retinal	B
+toxicity	I
+and	O
+macular	O
+ischaemia	B
+.	O
+
+Treatment	O
+strategies	O
+aimed	O
+at	O
+avoiding	O
+retinal	B
+toxicity	I
+are	O
+discussed	O
+.	O
+
+The	O
+role	O
+of	O
+nicotine	O
+in	O
+smoking	O
+-	O
+related	O
+cardiovascular	B
+disease	I
+.	O
+
+Nicotine	O
+activates	O
+the	O
+sympathetic	O
+nervous	O
+system	O
+and	O
+in	O
+this	O
+way	O
+could	O
+contribute	O
+to	O
+cardiovascular	B
+disease	I
+.	O
+
+Animal	O
+studies	O
+and	O
+mechanistic	O
+studies	O
+indicate	O
+that	O
+nicotine	O
+could	O
+play	O
+a	O
+role	O
+in	O
+accelerating	O
+atherosclerosis	B
+,	O
+but	O
+evidence	O
+among	O
+humans	O
+is	O
+too	O
+inadequate	O
+to	O
+be	O
+definitive	O
+about	O
+such	O
+an	O
+effect	O
+.	O
+
+Almost	O
+certainly	O
+,	O
+nicotine	O
+via	O
+its	O
+hemodynamic	O
+effects	O
+contributes	O
+to	O
+acute	O
+cardiovascular	O
+events	O
+,	O
+although	O
+current	O
+evidence	O
+suggests	O
+that	O
+the	O
+effects	O
+of	O
+nicotine	O
+are	O
+much	O
+less	O
+important	O
+than	O
+are	O
+the	O
+prothrombotic	O
+effects	O
+of	O
+cigarette	O
+smoking	O
+or	O
+the	O
+effects	O
+of	O
+carbon	O
+monoxide	O
+.	O
+
+Nicotine	O
+does	O
+not	O
+appear	O
+to	O
+enhance	O
+thrombosis	B
+among	O
+humans	O
+.	O
+
+Clinical	O
+studies	O
+of	O
+pipe	O
+smokers	O
+and	O
+people	O
+using	O
+transdermal	O
+nicotine	O
+support	O
+the	O
+idea	O
+that	O
+toxins	O
+other	O
+than	O
+nicotine	O
+are	O
+the	O
+most	O
+important	O
+causes	O
+of	O
+acute	O
+cardiovascular	O
+events	O
+.	O
+
+Finally	O
+,	O
+the	O
+dose	O
+response	O
+for	O
+cardiovascular	O
+events	O
+of	O
+nicotine	O
+appears	O
+to	O
+be	O
+flat	O
+,	O
+suggesting	O
+that	O
+if	O
+nicotine	O
+is	O
+involved	O
+,	O
+adverse	O
+effects	O
+might	O
+be	O
+seen	O
+with	O
+relatively	O
+low	O
+-	O
+level	O
+cigarette	O
+exposures	O
+.	O
+
+Iatrogenically	O
+induced	O
+intractable	O
+atrioventricular	B
+reentrant	I
+tachycardia	I
+after	O
+verapamil	O
+and	O
+catheter	O
+ablation	O
+in	O
+a	O
+patient	O
+with	O
+Wolff	B
+-	I
+Parkinson	I
+-	I
+White	I
+syndrome	I
+and	O
+idiopathic	B
+dilated	I
+cardiomyopathy	I
+.	O
+
+In	O
+a	O
+patient	O
+with	O
+WPW	B
+syndrome	I
+and	O
+idiopathic	B
+dilated	I
+cardiomyopathy	I
+,	O
+intractable	O
+atrioventricular	B
+reentrant	I
+tachycardia	I
+(	O
+AVRT	B
+)	O
+was	O
+iatrogenically	O
+induced	O
+.	O
+
+QRS	O
+without	O
+preexcitation	O
+,	O
+caused	O
+by	O
+junctional	O
+escape	O
+beats	O
+after	O
+verapamil	O
+or	O
+unidirectional	O
+antegrade	O
+block	O
+of	O
+accessory	O
+pathway	O
+after	O
+catheter	O
+ablation	O
+,	O
+established	O
+frequent	O
+AVRT	B
+attack	O
+.	O
+
+Epidemic	O
+of	O
+liver	B
+disease	I
+caused	O
+by	O
+hydrochlorofluorocarbons	O
+used	O
+as	O
+ozone	O
+-	O
+sparing	O
+substitutes	O
+of	O
+chlorofluorocarbons	O
+.	O
+
+BACKGROUND	O
+:	O
+Hydrochlorofluorocarbons	O
+(	O
+HCFCs	O
+)	O
+are	O
+used	O
+increasingly	O
+in	O
+industry	O
+as	O
+substitutes	O
+for	O
+ozone	O
+-	O
+depleting	O
+chlorofluorocarbons	O
+(	O
+CFCs	O
+)	O
+.	O
+
+Limited	O
+studies	O
+in	O
+animals	O
+indicate	O
+potential	O
+hepatotoxicity	B
+of	O
+some	O
+of	O
+these	O
+compounds	O
+.	O
+
+We	O
+investigated	O
+an	O
+epidemic	O
+of	O
+liver	B
+disease	I
+in	O
+nine	O
+industrial	O
+workers	O
+who	O
+had	O
+had	O
+repeated	O
+accidental	O
+exposure	O
+to	O
+a	O
+mixture	O
+of	O
+1	O
+,	O
+1	O
+-	O
+dichloro	O
+-	O
+2	O
+,	O
+2	O
+,	O
+2	O
+-	O
+trifluoroethane	O
+(	O
+HCFC	O
+123	O
+)	O
+and	O
+1	O
+-	O
+chloro	O
+-	O
+1	O
+,	O
+2	O
+,	O
+2	O
+,	O
+2	O
+-	O
+tetrafluoroethane	O
+(	O
+HCFC	O
+124	O
+)	O
+.	O
+
+All	O
+nine	O
+exposed	O
+workers	O
+were	O
+affected	O
+to	O
+various	O
+degrees	O
+.	O
+
+Both	O
+compounds	O
+are	O
+metabolised	O
+in	O
+the	O
+same	O
+way	O
+as	O
+1	O
+-	O
+bromo	O
+-	O
+1	O
+-	O
+chloro	O
+-	O
+2	O
+,	O
+2	O
+,	O
+2	O
+-	O
+trifluoroethane	O
+(	O
+halothane	O
+)	O
+to	O
+form	O
+reactive	O
+trifluoroacetyl	O
+halide	O
+intermediates	O
+,	O
+which	O
+have	O
+been	O
+implicated	O
+in	O
+the	O
+hepatotoxicity	B
+of	O
+halothane	O
+.	O
+
+We	O
+aimed	O
+to	O
+test	O
+whether	O
+HCFCs	O
+123	O
+and	O
+124	O
+can	O
+result	O
+in	O
+serious	O
+liver	B
+disease	I
+.	O
+
+METHODS	O
+:	O
+For	O
+one	O
+severely	O
+affected	O
+worker	O
+liver	O
+biopsy	O
+and	O
+immunohistochemical	O
+stainings	O
+for	O
+the	O
+presence	O
+of	O
+trifluoroacetyl	O
+protein	O
+adducts	O
+were	O
+done	O
+.	O
+
+The	O
+serum	O
+of	O
+six	O
+affected	O
+workers	O
+and	O
+five	O
+controls	O
+was	O
+tested	O
+for	O
+autoantibodies	O
+that	O
+react	O
+with	O
+human	O
+liver	O
+cytochrome	O
+-	O
+P450	O
+2E1	O
+(	O
+P450	O
+2E1	O
+)	O
+and	O
+P58	O
+protein	O
+disulphide	O
+isomerase	O
+isoform	O
+(	O
+P58	O
+)	O
+.	O
+
+FINDINGS	O
+:	O
+The	O
+liver	O
+biopsy	O
+sample	O
+showed	O
+hepatocellular	O
+necrosis	B
+which	O
+was	O
+prominent	O
+in	O
+perivenular	O
+zone	O
+three	O
+and	O
+extended	O
+focally	O
+from	O
+portal	O
+tracts	O
+to	O
+portal	O
+tracts	O
+and	O
+centrilobular	O
+areas	O
+(	O
+bridging	O
+necrosis	B
+)	O
+.	O
+
+Trifluoroacetyl	O
+-	O
+adducted	O
+proteins	O
+were	O
+detected	O
+in	O
+surviving	O
+hepatocytes	O
+.	O
+
+Autoantibodies	O
+against	O
+P450	O
+2E1	O
+or	O
+P58	O
+,	O
+previously	O
+associated	O
+with	O
+halothane	B
+hepatitis	I
+,	O
+were	O
+detected	O
+in	O
+the	O
+serum	O
+of	O
+five	O
+affected	O
+workers	O
+.	O
+
+INTERPRETATION	O
+:	O
+Repeated	O
+exposure	O
+of	O
+human	O
+beings	O
+to	O
+HCFCs	O
+123	O
+and	O
+124	O
+can	O
+result	O
+in	O
+serious	O
+liver	B
+injury	I
+in	O
+a	O
+large	O
+proportion	O
+of	O
+the	O
+exposed	O
+population	O
+.	O
+
+Although	O
+the	O
+exact	O
+mechanism	O
+of	O
+hepatotoxicity	B
+of	O
+these	O
+agents	O
+is	O
+not	O
+known	O
+,	O
+the	O
+results	O
+suggest	O
+that	O
+trifluoroacetyl	O
+-	O
+altered	O
+liver	O
+proteins	O
+are	O
+involved	O
+.	O
+
+In	O
+view	O
+of	O
+the	O
+potentially	O
+widespread	O
+use	O
+of	O
+these	O
+compounds	O
+,	O
+there	O
+is	O
+an	O
+urgent	O
+need	O
+to	O
+develop	O
+safer	O
+alternatives	O
+.	O
+
+Bile	B
+duct	I
+hamartoma	I
+occurring	O
+in	O
+association	O
+with	O
+long	O
+-	O
+term	O
+treatment	O
+with	O
+danazol	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+bile	B
+duct	I
+hamartoma	I
+which	O
+developed	O
+in	O
+a	O
+patient	O
+who	O
+had	O
+been	O
+on	O
+long	O
+-	O
+term	O
+danazol	O
+treatment	O
+.	O
+
+Such	O
+patients	O
+should	O
+be	O
+under	O
+close	O
+follow	O
+-	O
+up	O
+,	O
+preferably	O
+with	O
+periodic	O
+ultrasound	O
+examination	O
+of	O
+the	O
+liver	O
+.	O
+
+If	O
+the	O
+patient	O
+develops	O
+a	O
+liver	B
+mass	I
+,	O
+because	O
+of	O
+non	O
+-	O
+specific	O
+clinical	O
+features	O
+and	O
+imaging	O
+appearances	O
+,	O
+biopsy	O
+may	O
+be	O
+the	O
+only	O
+way	O
+to	O
+achieve	O
+a	O
+definitive	O
+diagnosis	O
+.	O
+
+Endocrine	O
+screening	O
+in	O
+1	O
+,	O
+022	O
+men	O
+with	O
+erectile	B
+dysfunction	I
+:	O
+clinical	O
+significance	O
+and	O
+cost	O
+-	O
+effective	O
+strategy	O
+.	O
+
+PURPOSE	O
+:	O
+We	O
+reviewed	O
+the	O
+results	O
+of	O
+serum	O
+testosterone	O
+and	O
+prolactin	O
+determination	O
+in	O
+1	O
+,	O
+022	O
+patients	O
+referred	O
+because	O
+of	O
+erectile	B
+dysfunction	I
+and	O
+compared	O
+the	O
+data	O
+with	O
+history	O
+,	O
+results	O
+of	O
+physical	O
+examination	O
+,	O
+other	O
+etiological	O
+investigations	O
+and	O
+effects	O
+of	O
+endocrine	O
+therapy	O
+to	O
+refine	O
+the	O
+rules	O
+of	O
+cost	O
+-	O
+effective	O
+endocrine	O
+screening	O
+and	O
+to	O
+pinpoint	O
+actual	O
+responsibility	O
+for	O
+hormonal	O
+abnormalities	O
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+Testosterone	O
+and	O
+prolactin	O
+were	O
+determined	O
+by	O
+radioimmunoassay	O
+.	O
+
+Every	O
+patient	O
+was	O
+screened	O
+for	O
+testosterone	O
+and	O
+451	O
+were	O
+screened	O
+for	O
+prolactin	O
+on	O
+the	O
+basis	O
+of	O
+low	B
+sexual	I
+desire	I
+,	O
+gynecomastia	B
+or	O
+testosterone	O
+less	O
+than	O
+4	O
+ng	O
+.	O
+/	O
+ml	O
+.	O
+
+Determination	O
+was	O
+repeated	O
+in	O
+case	O
+of	O
+abnormal	O
+first	O
+results	O
+.	O
+
+Prolactin	O
+results	O
+were	O
+compared	O
+with	O
+those	O
+of	O
+a	O
+previous	O
+personal	O
+cohort	O
+of	O
+1	O
+,	O
+340	O
+patients	O
+with	O
+erectile	B
+dysfunction	I
+and	O
+systematic	O
+prolactin	O
+determination	O
+.	O
+
+Main	O
+clinical	O
+criteria	O
+tested	O
+regarding	O
+efficiency	O
+in	O
+hormone	O
+determination	O
+were	O
+low	B
+sexual	I
+desire	I
+,	O
+small	O
+testes	O
+and	O
+gynecomastia	B
+.	O
+
+Endocrine	O
+therapy	O
+consisted	O
+of	O
+testosterone	O
+heptylate	O
+or	O
+human	O
+chorionic	O
+gonadotropin	O
+for	O
+hypogonadism	B
+and	O
+bromocriptine	O
+for	O
+hyperprolactinemia	B
+.	O
+
+RESULTS	O
+:	O
+Testosterone	O
+was	O
+less	O
+than	O
+3	O
+ng	O
+.	O
+/	O
+ml	O
+.	O
+in	O
+107	O
+patients	O
+but	O
+normal	O
+in	O
+40	O
+%	O
+at	O
+repeat	O
+determination	O
+.	O
+
+The	O
+prevalence	O
+of	O
+repeatedly	O
+low	O
+testosterone	O
+increased	O
+with	O
+age	O
+(	O
+4	O
+%	O
+before	O
+age	O
+50	O
+years	O
+and	O
+9	O
+%	O
+50	O
+years	O
+or	O
+older	O
+)	O
+.	O
+
+Two	O
+pituitary	B
+tumors	I
+were	O
+discovered	O
+after	O
+testosterone	O
+determination	O
+.	O
+
+Most	O
+of	O
+the	O
+other	O
+low	O
+testosterone	O
+levels	O
+seemed	O
+to	O
+result	O
+from	O
+nonorganic	O
+hypothalamic	B
+dysfunction	I
+because	O
+of	O
+normal	O
+serum	O
+luteinizing	O
+hormone	O
+and	O
+prolactin	O
+and	O
+to	O
+have	O
+only	O
+a	O
+small	O
+role	O
+in	O
+erectile	B
+dysfunction	I
+(	O
+definite	O
+improvement	O
+in	O
+only	O
+16	O
+of	O
+44	O
+[	O
+36	O
+%	O
+]	O
+after	O
+androgen	O
+therapy	O
+,	O
+normal	O
+morning	O
+or	O
+nocturnal	O
+erections	O
+in	O
+30	O
+%	O
+and	O
+definite	O
+vasculogenic	O
+contributions	O
+in	O
+42	O
+%	O
+)	O
+.	O
+
+Determining	O
+testosterone	O
+only	O
+in	O
+cases	O
+of	O
+low	B
+sexual	I
+desire	I
+or	O
+abnormal	O
+physical	O
+examination	O
+would	O
+have	O
+missed	O
+40	O
+%	O
+of	O
+the	O
+cases	O
+with	O
+low	O
+testosterone	O
+,	O
+including	O
+37	O
+%	O
+of	O
+those	O
+subsequently	O
+improved	O
+by	O
+androgen	O
+therapy	O
+.	O
+
+Prolactin	O
+exceeded	O
+20	O
+ng	O
+.	O
+/	O
+ml	O
+.	O
+in	O
+5	O
+men	O
+and	O
+was	O
+normal	O
+in	O
+2	O
+at	O
+repeat	O
+determination	O
+.	O
+
+Only	O
+1	O
+prolactinoma	B
+was	O
+discovered	O
+.	O
+
+These	O
+data	O
+are	O
+lower	O
+than	O
+those	O
+we	O
+found	O
+during	O
+the	O
+last	O
+2	O
+decades	O
+(	O
+overall	O
+prolactin	O
+greater	O
+than	O
+20	O
+ng	O
+.	O
+/	O
+ml	O
+.	O
+in	O
+1	O
+.	O
+86	O
+%	O
+of	O
+1	O
+,	O
+821	O
+patients	O
+,	O
+prolactinomas	B
+in	O
+7	O
+,	O
+0	O
+.	O
+38	O
+%	O
+)	O
+.	O
+
+Bromocriptine	O
+was	O
+definitely	O
+effective	O
+in	O
+cases	O
+with	O
+prolactin	O
+greater	O
+than	O
+35	O
+ng	O
+.	O
+/	O
+ml	O
+.	O
+
+(	O
+8	O
+of	O
+12	O
+compared	O
+to	O
+only	O
+9	O
+of	O
+22	O
+cases	O
+with	O
+prolactin	O
+between	O
+20	O
+and	O
+35	O
+ng	O
+.	O
+/	O
+ml	O
+.	O
+)	O
+.	O
+
+Testosterone	O
+was	O
+low	O
+in	O
+less	O
+than	O
+50	O
+%	O
+of	O
+cases	O
+with	O
+prolactin	O
+greater	O
+than	O
+35	O
+ng	O
+.	O
+/	O
+ml	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Low	O
+prevalences	O
+and	O
+effects	O
+of	O
+low	O
+testosterone	O
+and	O
+high	O
+prolactin	O
+in	O
+erectile	B
+dysfunction	I
+cannot	O
+justify	O
+their	O
+routine	O
+determination	O
+.	O
+
+However	O
+,	O
+cost	O
+-	O
+effective	O
+screening	O
+strategies	O
+recommended	O
+so	O
+far	O
+missed	O
+40	O
+to	O
+50	O
+%	O
+of	O
+cases	O
+improved	O
+with	O
+endocrine	O
+therapy	O
+and	O
+the	O
+pituitary	B
+tumors	I
+.	O
+
+We	O
+now	O
+advocate	O
+that	O
+before	O
+age	O
+50	O
+years	O
+testosterone	O
+be	O
+determined	O
+only	O
+in	O
+cases	O
+of	O
+low	B
+sexual	I
+desire	I
+and	O
+abnormal	O
+physical	O
+examination	O
+but	O
+that	O
+it	O
+be	O
+measured	O
+in	O
+all	O
+men	O
+older	O
+than	O
+50	O
+years	O
+.	O
+
+Prolactin	O
+should	O
+be	O
+determined	O
+only	O
+in	O
+cases	O
+of	O
+low	B
+sexual	I
+desire	I
+,	O
+gynecomastia	B
+and	O
+/	O
+or	O
+testosterone	O
+less	O
+than	O
+4	O
+ng	O
+.	O
+/	O
+ml	O
+.	O
+
+Extrapyramidal	O
+side	O
+effects	O
+with	O
+risperidone	O
+and	O
+haloperidol	O
+at	O
+comparable	O
+D2	O
+receptor	O
+occupancy	O
+levels	O
+.	O
+
+Risperidone	O
+is	O
+an	O
+antipsychotic	O
+drug	O
+with	O
+high	O
+affinity	O
+at	O
+dopamine	O
+D2	O
+and	O
+serotonin	O
+5	O
+-	O
+HT2	O
+receptors	O
+.	O
+
+Previous	O
+clinical	O
+studies	O
+have	O
+proposed	O
+that	O
+risperidone	O
+'	O
+s	O
+pharmacologic	O
+profile	O
+may	O
+produce	O
+improved	O
+efficacy	O
+for	O
+negative	O
+psychotic	B
+symptoms	I
+and	O
+decreased	O
+propensity	O
+for	O
+extrapyramidal	O
+side	O
+effects	O
+;	O
+features	O
+shared	O
+by	O
+so	O
+-	O
+called	O
+'	O
+atypical	O
+'	O
+neuroleptics	O
+.	O
+
+To	O
+determine	O
+if	O
+routine	O
+risperidone	O
+treatment	O
+is	O
+associated	O
+with	O
+a	O
+unique	O
+degree	O
+of	O
+D2	O
+receptor	O
+occupancy	O
+and	O
+pattern	O
+of	O
+clinical	O
+effects	O
+,	O
+we	O
+used	O
+[	O
+123I	O
+]	O
+IBZM	O
+SPECT	O
+to	O
+determine	O
+D2	O
+occupancy	O
+in	O
+subjects	O
+treated	O
+with	O
+routine	O
+clinical	O
+doses	O
+of	O
+risperidone	O
+(	O
+n	O
+=	O
+12	O
+)	O
+or	O
+haloperidol	O
+(	O
+n	O
+=	O
+7	O
+)	O
+.	O
+
+Both	O
+risperidone	O
+and	O
+haloperidol	O
+produced	O
+D2	O
+occupancy	O
+levels	O
+between	O
+approximately	O
+60	O
+and	O
+90	O
+%	O
+at	O
+standard	O
+clinical	O
+doses	O
+.	O
+
+There	O
+was	O
+no	O
+significant	O
+difference	O
+between	O
+occupancy	O
+levels	O
+obtained	O
+with	O
+haloperidol	O
+or	O
+risperidone	O
+.	O
+
+Drug	B
+-	I
+induced	I
+parkinsonism	I
+was	O
+observed	O
+in	O
+subjects	O
+treated	O
+with	O
+risperidone	O
+(	O
+42	O
+%	O
+)	O
+and	O
+haloperidol	O
+(	O
+29	O
+%	O
+)	O
+and	O
+was	O
+observed	O
+at	O
+occupancy	O
+levels	O
+above	O
+60	O
+%	O
+.	O
+
+Based	O
+on	O
+these	O
+observations	O
+,	O
+it	O
+is	O
+concluded	O
+that	O
+5	O
+-	O
+HT2	O
+blockade	O
+obtained	O
+with	O
+risperidone	O
+at	O
+D2	O
+occupancy	O
+rates	O
+of	O
+60	O
+%	O
+and	O
+above	O
+does	O
+not	O
+appear	O
+to	O
+protect	O
+against	O
+the	O
+risk	O
+for	O
+extrapyramidal	O
+side	O
+effects	O
+.	O
+
+Treatment	O
+of	O
+previously	O
+treated	O
+metastatic	O
+breast	B
+cancer	I
+by	O
+mitoxantrone	O
+and	O
+48	O
+-	O
+hour	O
+continuous	O
+infusion	O
+of	O
+high	O
+-	O
+dose	O
+5	O
+-	O
+FU	O
+and	O
+leucovorin	O
+(	O
+MFL	O
+)	O
+:	O
+low	O
+palliative	O
+benefit	O
+and	O
+high	O
+treatment	O
+-	O
+related	O
+toxicity	B
+.	O
+
+For	O
+previously	O
+treated	O
+advanced	O
+breast	B
+cancer	I
+,	O
+there	O
+is	O
+no	O
+standard	O
+second	O
+-	O
+line	O
+therapy	O
+.	O
+
+Combination	O
+chemotherapy	O
+with	O
+mitoxantrone	O
+,	O
+high	O
+-	O
+dose	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+and	O
+leucovorin	O
+(	O
+MFL	O
+regimen	O
+)	O
+had	O
+been	O
+reported	O
+as	O
+an	O
+effective	O
+and	O
+well	O
+tolerated	O
+regimen	O
+.	O
+
+From	O
+October	O
+1993	O
+to	O
+November	O
+1995	O
+,	O
+we	O
+treated	O
+13	O
+patients	O
+with	O
+previously	O
+chemotherapy	O
+-	O
+treated	O
+metastatic	O
+breast	B
+cancer	I
+by	O
+mitoxantrone	O
+,	O
+12	O
+mg	O
+/	O
+m2	O
+,	O
+on	O
+day	O
+1	O
+and	O
+continuous	O
+infusion	O
+of	O
+5	O
+-	O
+FU	O
+,	O
+3000	O
+mg	O
+/	O
+m2	O
+,	O
+together	O
+with	O
+leucovorin	O
+,	O
+300	O
+mg	O
+/	O
+m2	O
+,	O
+for	O
+48	O
+h	O
+from	O
+day	O
+1	O
+to	O
+2	O
+.	O
+
+Each	O
+course	O
+of	O
+chemotherapy	O
+was	O
+given	O
+every	O
+4	O
+weeks	O
+.	O
+
+Most	O
+of	O
+these	O
+patients	O
+had	O
+more	O
+than	O
+two	O
+metastatic	O
+sites	O
+,	O
+with	O
+lung	O
+metastasis	O
+predominant	O
+.	O
+
+Seven	O
+patients	O
+had	O
+been	O
+treated	O
+with	O
+anthracycline	O
+.	O
+
+Seven	O
+patients	O
+had	O
+previously	O
+received	O
+radiotherapy	O
+and	O
+seven	O
+had	O
+received	O
+hormone	O
+therapy	O
+.	O
+
+Median	O
+number	O
+of	O
+courses	O
+of	O
+MFL	O
+regimen	O
+given	O
+was	O
+six	O
+and	O
+the	O
+median	O
+cumulative	O
+dose	O
+of	O
+mitoxantrone	O
+was	O
+68	O
+.	O
+35	O
+mg	O
+/	O
+m2	O
+.	O
+
+One	O
+patient	O
+had	O
+complete	O
+response	O
+,	O
+seven	O
+had	O
+stable	O
+disease	O
+,	O
+none	O
+had	O
+partial	O
+response	O
+and	O
+five	O
+had	O
+progressive	O
+disease	O
+.	O
+
+The	O
+overall	O
+objective	O
+response	O
+rate	O
+was	O
+7	O
+.	O
+6	O
+%	O
+.	O
+
+The	O
+median	O
+follow	O
+-	O
+up	O
+period	O
+was	O
+14	O
+months	O
+.	O
+
+Median	O
+survival	O
+was	O
+16	O
+months	O
+.	O
+
+Median	O
+progression	O
+-	O
+free	O
+survival	O
+was	O
+5	O
+months	O
+.	O
+
+A	O
+complete	O
+responder	O
+had	O
+relapse	O
+-	O
+free	O
+survival	O
+up	O
+to	O
+17	O
+months	O
+.	O
+
+Major	O
+toxicities	B
+were	O
+cardiotoxicity	B
+and	O
+leukopenia	B
+.	O
+
+Eight	O
+patients	O
+were	O
+dead	O
+in	O
+the	O
+last	O
+follow	O
+-	O
+up	O
+;	O
+two	O
+of	O
+them	O
+died	O
+of	O
+treatment	O
+-	O
+related	O
+toxicity	B
+.	O
+
+The	O
+MFL	O
+regimen	O
+achieves	O
+little	O
+palliative	O
+benefit	O
+and	O
+induces	O
+severe	O
+toxicity	B
+at	O
+a	O
+fairly	O
+high	O
+rate	O
+.	O
+
+Administration	O
+of	O
+this	O
+regimen	O
+to	O
+breast	B
+cancer	I
+patients	O
+who	O
+have	O
+been	O
+treated	O
+by	O
+chemotherapy	O
+and	O
+those	O
+with	O
+impaired	B
+heart	I
+function	I
+requires	O
+careful	O
+attention	O
+.	O
+
+Ticlopidine	O
+-	O
+induced	O
+aplastic	B
+anemia	I
+:	O
+report	O
+of	O
+three	O
+Chinese	O
+patients	O
+and	O
+review	O
+of	O
+the	O
+literature	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+three	O
+Chinese	O
+patients	O
+with	O
+ticlopidine	O
+-	O
+induced	O
+aplastic	B
+anemia	I
+were	O
+reported	O
+and	O
+another	O
+13	O
+patients	O
+in	O
+the	O
+English	O
+literature	O
+were	O
+reviewed	O
+.	O
+
+We	O
+attempted	O
+to	O
+find	O
+underlying	O
+similarities	O
+,	O
+evaluate	O
+the	O
+risk	O
+factors	O
+,	O
+and	O
+identify	O
+appropriate	O
+treatment	O
+for	O
+this	O
+complication	O
+.	O
+
+All	O
+but	O
+one	O
+of	O
+the	O
+patients	O
+were	O
+over	O
+60	O
+years	O
+old	O
+,	O
+and	O
+the	O
+6	O
+who	O
+died	O
+were	O
+all	O
+older	O
+than	O
+65	O
+.	O
+
+Therefore	O
+,	O
+old	O
+age	O
+may	O
+be	O
+a	O
+risk	O
+factor	O
+for	O
+developing	O
+this	O
+complication	O
+.	O
+
+Agranulocytosis	B
+occurred	O
+3	O
+-	O
+20	O
+weeks	O
+after	O
+initiation	O
+of	O
+ticlopidine	O
+,	O
+so	O
+frequent	O
+examination	O
+of	O
+white	O
+cell	O
+count	O
+during	O
+treatment	O
+is	O
+recommended	O
+.	O
+
+There	O
+seemed	O
+to	O
+be	O
+no	O
+direct	O
+correlation	O
+between	O
+the	O
+dose	O
+or	O
+duration	O
+used	O
+and	O
+the	O
+severity	O
+of	O
+bone	B
+marrow	I
+suppression	I
+.	O
+
+Treatment	O
+for	O
+ticlopidine	O
+-	O
+induced	O
+aplastic	B
+anemia	I
+with	O
+colony	O
+-	O
+stimulating	O
+factors	O
+seemed	O
+to	O
+have	O
+little	O
+effect	O
+.	O
+
+The	O
+fact	O
+that	O
+5	O
+of	O
+the	O
+6	O
+patients	O
+who	O
+received	O
+concurrent	O
+calcium	O
+channel	O
+blockers	O
+died	O
+,	O
+should	O
+alert	O
+clinicians	O
+to	O
+be	O
+more	O
+cautious	O
+when	O
+using	O
+these	O
+two	O
+drugs	O
+simultaneously	O
+.	O
+
+Upregulation	O
+of	O
+the	O
+expression	O
+of	O
+vasopressin	O
+gene	O
+in	O
+the	O
+paraventricular	O
+and	O
+supraoptic	O
+nuclei	O
+of	O
+the	O
+lithium	O
+-	O
+induced	O
+diabetes	B
+insipidus	I
+rat	O
+.	O
+
+The	O
+expression	O
+of	O
+arginine	O
+vasopressin	O
+(	O
+AVP	O
+)	O
+gene	O
+in	O
+the	O
+paraventricular	O
+(	O
+PVN	O
+)	O
+and	O
+supraoptic	O
+nuclei	O
+(	O
+SON	O
+)	O
+was	O
+investigated	O
+in	O
+rats	O
+with	O
+lithium	O
+(	O
+Li	O
+)	O
+-	O
+induced	O
+polyuria	B
+,	O
+using	O
+in	O
+situ	O
+hybridization	O
+histochemistry	O
+and	O
+radioimmunoassay	O
+.	O
+
+The	O
+male	O
+Wistar	O
+rats	O
+consuming	O
+a	O
+diet	O
+that	O
+contained	O
+LiCl	O
+(	O
+60	O
+mmol	O
+/	O
+kg	O
+)	O
+for	O
+4	O
+weeks	O
+developed	O
+marked	O
+polyuria	B
+.	O
+
+The	O
+Li	O
+-	O
+treated	O
+rats	O
+produced	O
+a	O
+large	O
+volume	O
+of	O
+hypotonic	O
+urine	O
+with	O
+low	O
+ionic	O
+concentrations	O
+.	O
+
+Plasma	O
+sodium	O
+concentrations	O
+were	O
+found	O
+to	O
+be	O
+slightly	O
+increased	O
+in	O
+the	O
+Li	O
+-	O
+treated	O
+rats	O
+compared	O
+with	O
+those	O
+in	O
+controls	O
+.	O
+
+Plasma	O
+concentration	O
+of	O
+AVP	O
+and	O
+transcripts	O
+of	O
+AVP	O
+gene	O
+in	O
+the	O
+PVN	O
+and	O
+SON	O
+were	O
+significantly	O
+increased	O
+in	O
+the	O
+Li	O
+-	O
+treated	O
+rats	O
+compared	O
+with	O
+controls	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+dehydration	B
+and	O
+/	O
+or	O
+the	O
+activation	O
+of	O
+visceral	O
+afferent	O
+inputs	O
+may	O
+contribute	O
+to	O
+the	O
+elevation	O
+of	O
+plasma	O
+AVP	O
+and	O
+the	O
+upregulation	O
+of	O
+AVP	O
+gene	O
+expression	O
+in	O
+the	O
+PVN	O
+and	O
+the	O
+SON	O
+of	O
+the	O
+Li	O
+-	O
+induced	O
+diabetes	B
+insipidus	I
+rat	O
+.	O
+
+Antinociceptive	O
+and	O
+antiamnesic	O
+properties	O
+of	O
+the	O
+presynaptic	O
+cholinergic	O
+amplifier	O
+PG	O
+-	O
+9	O
+.	O
+
+The	O
+antinociceptive	O
+effect	O
+of	O
+3	O
+alpha	O
+-	O
+tropyl	O
+2	O
+-	O
+(	O
+p	O
+-	O
+bromophenyl	O
+)	O
+propionate	O
+[	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+PG	O
+-	O
+9	O
+]	O
+(	O
+10	O
+-	O
+40	O
+mg	O
+kg	O
+-	O
+1	O
+s	O
+.	O
+c	O
+.	O
+;	O
+30	O
+-	O
+60	O
+mg	O
+kg	O
+-	O
+1	O
+p	O
+.	O
+o	O
+.	O
+;	O
+10	O
+-	O
+30	O
+mg	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+v	O
+.	O
+;	O
+10	O
+-	O
+30	O
+micrograms	O
+/	O
+mouse	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+was	O
+examined	O
+in	O
+mice	O
+,	O
+rats	O
+and	O
+guinea	O
+pigs	O
+by	O
+use	O
+of	O
+the	O
+hot	O
+-	O
+plate	O
+,	O
+abdominal	O
+-	O
+constriction	O
+,	O
+tail	O
+-	O
+flick	O
+and	O
+paw	O
+-	O
+pressure	O
+tests	O
+.	O
+
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+PG	O
+-	O
+9	O
+antinociception	O
+peaked	O
+15	O
+min	O
+after	O
+injection	O
+and	O
+then	O
+slowly	O
+diminished	O
+.	O
+
+The	O
+antinociception	O
+produced	O
+by	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+PG	O
+-	O
+9	O
+was	O
+prevented	O
+by	O
+the	O
+unselective	O
+muscarinic	O
+antagonist	O
+atropine	O
+,	O
+the	O
+M1	O
+-	O
+selective	O
+antagonists	O
+pirenzepine	O
+and	O
+dicyclomine	O
+and	O
+the	O
+acetylcholine	O
+depletor	O
+hemicholinium	O
+-	O
+3	O
+,	O
+but	O
+not	O
+by	O
+the	O
+opioid	O
+antagonist	O
+naloxone	O
+,	O
+the	O
+gamma	O
+-	O
+aminobutyric	O
+acidB	O
+antagonist	O
+3	O
+-	O
+aminopropyl	O
+-	O
+diethoxy	O
+-	O
+methyl	O
+-	O
+phosphinic	O
+acid	O
+,	O
+the	O
+H3	O
+agonist	O
+R	O
+-	O
+(	O
+alpha	O
+)	O
+-	O
+methylhistamine	O
+,	O
+the	O
+D2	O
+antagonist	O
+quinpirole	O
+,	O
+the	O
+5	O
+-	O
+hydroxytryptamine4	O
+antagonist	O
+2	O
+-	O
+methoxy	O
+-	O
+4	O
+-	O
+amino	O
+-	O
+5	O
+-	O
+chlorobenzoic	O
+acid	O
+2	O
+-	O
+(	O
+diethylamino	O
+)	O
+ethyl	O
+ester	O
+hydrochloride	O
+,	O
+the	O
+5	O
+-	O
+hydroxytryptamin1A	O
+antagonist	O
+1	O
+-	O
+(	O
+2	O
+-	O
+methoxyphenyl	O
+)	O
+-	O
+4	O
+-	O
+[	O
+4	O
+-	O
+(	O
+2	O
+-	O
+phthalimido	O
+)	O
+butyl	O
+]	O
+piperazine	O
+hydrobromide	O
+and	O
+the	O
+polyamines	O
+depletor	O
+reserpine	O
+.	O
+
+Based	O
+on	O
+these	O
+data	O
+,	O
+it	O
+can	O
+be	O
+postulated	O
+that	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+PG	O
+-	O
+9	O
+exerted	O
+an	O
+antinociceptive	O
+effect	O
+mediated	O
+by	O
+a	O
+central	O
+potentiation	O
+of	O
+cholinergic	O
+transmission	O
+.	O
+
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+PG	O
+-	O
+9	O
+(	O
+10	O
+-	O
+40	O
+mg	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+p	O
+.	O
+)	O
+was	O
+able	O
+to	O
+prevent	O
+amnesia	B
+induced	O
+by	O
+scopolamine	O
+(	O
+1	O
+mg	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+p	O
+.	O
+)	O
+and	O
+dicyclomine	O
+(	O
+2	O
+mg	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+p	O
+.	O
+)	O
+in	O
+the	O
+mouse	O
+passive	O
+-	O
+avoidance	O
+test	O
+.	O
+
+Affinity	O
+profiles	O
+of	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+PG	O
+-	O
+9	O
+for	O
+muscarinic	O
+receptor	O
+subtypes	O
+,	O
+determined	O
+by	O
+functional	O
+studies	O
+(	O
+rabbit	O
+vas	O
+deferens	O
+for	O
+M1	O
+,	O
+guinea	O
+pig	O
+atrium	O
+for	O
+M2	O
+,	O
+guinea	O
+pig	O
+ileum	O
+for	O
+M3	O
+and	O
+immature	O
+guinea	O
+pig	O
+uterus	O
+for	O
+putative	O
+M4	O
+)	O
+,	O
+have	O
+shown	O
+an	O
+M4	O
+/	O
+M1	O
+selectivity	O
+ratio	O
+of	O
+10	O
+.	O
+2	O
+that	O
+might	O
+be	O
+responsible	O
+for	O
+the	O
+antinociception	O
+and	O
+the	O
+anti	O
+-	O
+amnesic	B
+effect	O
+induced	O
+by	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+PG	O
+-	O
+9	O
+through	O
+an	O
+increase	O
+in	O
+acetylcholine	O
+extracellular	O
+levels	O
+.	O
+
+In	O
+the	O
+antinociceptive	O
+and	O
+antiamnesic	O
+dose	O
+range	O
+,	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+PG	O
+-	O
+9	O
+did	O
+not	O
+impair	O
+mouse	O
+performance	O
+evaluated	O
+by	O
+the	O
+rota	O
+-	O
+rod	O
+test	O
+and	O
+Animex	O
+apparatus	O
+.	O
+
+The	O
+effect	O
+of	O
+different	O
+anaesthetic	O
+agents	O
+in	O
+hearing	B
+loss	I
+following	O
+spinal	O
+anaesthesia	O
+.	O
+
+The	O
+cause	O
+of	O
+hearing	B
+loss	I
+after	O
+spinal	O
+anaesthesia	O
+is	O
+unknown	O
+.	O
+
+Up	O
+until	O
+now	O
+,	O
+the	O
+only	O
+factor	O
+studied	O
+has	O
+been	O
+the	O
+effect	O
+of	O
+the	O
+diameter	O
+of	O
+the	O
+spinal	O
+needle	O
+on	O
+post	O
+-	O
+operative	O
+sensorineural	B
+hearing	I
+loss	I
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+describe	O
+this	O
+hearing	B
+loss	I
+and	O
+to	O
+investigate	O
+other	O
+factors	O
+influencing	O
+the	O
+degree	O
+of	O
+hearing	B
+loss	I
+.	O
+
+Two	O
+groups	O
+of	O
+22	O
+similar	O
+patients	O
+were	O
+studied	O
+:	O
+one	O
+group	O
+received	O
+6	O
+mL	O
+prilocaine	O
+2	O
+%	O
+;	O
+and	O
+the	O
+other	O
+received	O
+3	O
+mL	O
+bupivacaine	O
+0	O
+.	O
+5	O
+%	O
+.	O
+
+Patients	O
+given	O
+prilocaine	O
+were	O
+more	O
+likely	O
+to	O
+develop	O
+hearing	B
+loss	I
+(	O
+10	O
+out	O
+of	O
+22	O
+)	O
+than	O
+those	O
+given	O
+bupivacaine	O
+(	O
+4	O
+out	O
+of	O
+22	O
+)	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+average	O
+hearing	B
+loss	I
+for	O
+speech	O
+frequencies	O
+was	O
+about	O
+10	O
+dB	O
+after	O
+prilocaine	O
+and	O
+15	O
+dB	O
+after	O
+bupivacaine	O
+.	O
+
+None	O
+of	O
+the	O
+patients	O
+complained	O
+of	O
+subjective	O
+hearing	B
+loss	I
+.	O
+
+Long	O
+-	O
+term	O
+follow	O
+-	O
+up	O
+of	O
+the	O
+patients	O
+was	O
+not	O
+possible	O
+.	O
+
+A	O
+transient	O
+neurological	B
+deficit	I
+following	O
+intrathecal	O
+injection	O
+of	O
+1	O
+%	O
+hyperbaric	O
+bupivacaine	O
+for	O
+unilateral	O
+spinal	O
+anaesthesia	O
+.	O
+
+We	O
+describe	O
+a	O
+case	O
+of	O
+transient	O
+neurological	B
+deficit	I
+that	O
+occurred	O
+after	O
+unilateral	O
+spinal	O
+anaesthesia	O
+with	O
+8	O
+mg	O
+of	O
+1	O
+%	O
+hyperbaric	O
+bupivacaine	O
+slowly	O
+injected	O
+through	O
+a	O
+25	O
+-	O
+gauge	O
+pencil	O
+-	O
+point	O
+spinal	O
+needle	O
+.	O
+
+The	O
+surgery	O
+and	O
+anaesthesia	O
+were	O
+uneventful	O
+,	O
+but	O
+3	O
+days	O
+after	O
+surgery	O
+,	O
+the	O
+patient	O
+reported	O
+an	O
+area	O
+of	O
+hypoaesthesia	O
+over	O
+L3	O
+-	O
+L4	O
+dermatomes	O
+of	O
+the	O
+leg	O
+which	O
+had	O
+been	O
+operated	O
+on	O
+(	O
+loss	B
+of	I
+pinprick	I
+sensation	I
+)	O
+without	O
+reduction	O
+in	O
+muscular	O
+strength	O
+.	O
+
+Sensation	O
+in	O
+this	O
+area	O
+returned	O
+to	O
+normal	O
+over	O
+the	O
+following	O
+2	O
+weeks	O
+.	O
+
+Prospective	O
+multicentre	O
+studies	O
+with	O
+a	O
+large	O
+population	O
+and	O
+a	O
+long	O
+follow	O
+-	O
+up	O
+should	O
+be	O
+performed	O
+in	O
+order	O
+to	O
+evaluate	O
+the	O
+incidence	O
+of	O
+this	O
+unusual	O
+side	O
+effect	O
+.	O
+
+However	O
+,	O
+we	O
+suggest	O
+that	O
+a	O
+low	O
+solution	O
+concentration	O
+should	O
+be	O
+preferred	O
+for	O
+unilateral	O
+spinal	O
+anaesthesia	O
+with	O
+a	O
+hyperbaric	O
+anaesthetic	O
+solution	O
+(	O
+if	O
+pencil	O
+-	O
+point	O
+needle	O
+and	O
+slow	O
+injection	O
+rate	O
+are	O
+employed	O
+)	O
+,	O
+in	O
+order	O
+to	O
+minimize	O
+the	O
+risk	O
+of	O
+a	O
+localized	O
+high	O
+peak	O
+anaesthetic	O
+concentration	O
+,	O
+which	O
+might	O
+lead	O
+to	O
+a	O
+transient	O
+neurological	B
+deficit	I
+.	O
+
+Transient	B
+neurologic	I
+symptoms	I
+after	O
+spinal	O
+anesthesia	O
+:	O
+a	O
+lower	O
+incidence	O
+with	O
+prilocaine	O
+and	O
+bupivacaine	O
+than	O
+with	O
+lidocaine	O
+.	O
+
+BACKGROUND	O
+:	O
+Recent	O
+evidence	O
+suggests	O
+that	O
+transient	B
+neurologic	I
+symptoms	I
+(	O
+TNSs	B
+)	O
+frequently	O
+follow	O
+lidocaine	O
+spinal	O
+anesthesia	O
+but	O
+are	O
+infrequent	O
+with	O
+bupivacaine	O
+.	O
+
+However	O
+,	O
+identification	O
+of	O
+a	O
+short	O
+-	O
+acting	O
+local	O
+anesthetic	O
+to	O
+substitute	O
+for	O
+lidocaine	O
+for	O
+brief	O
+surgical	O
+procedures	O
+remains	O
+an	O
+important	O
+goal	O
+.	O
+
+Prilocaine	O
+is	O
+an	O
+amide	O
+local	O
+anesthetic	O
+with	O
+a	O
+duration	O
+of	O
+action	O
+similar	O
+to	O
+that	O
+of	O
+lidocaine	O
+.	O
+
+Accordingly	O
+,	O
+the	O
+present	O
+,	O
+prospective	O
+double	O
+-	O
+blind	O
+study	O
+compares	O
+prilocaine	O
+with	O
+lidocaine	O
+and	O
+bupivacaine	O
+with	O
+respect	O
+to	O
+duration	O
+of	O
+action	O
+and	O
+relative	O
+risk	O
+of	O
+TNSs	B
+.	O
+
+METHODS	O
+:	O
+Ninety	O
+patients	O
+classified	O
+as	O
+American	O
+Society	O
+of	O
+Anesthesiologists	O
+physical	O
+status	O
+I	O
+or	O
+II	O
+who	O
+were	O
+scheduled	O
+for	O
+short	O
+gynecologic	O
+procedures	O
+under	O
+spinal	O
+anesthesia	O
+were	O
+randomly	O
+allocated	O
+to	O
+receive	O
+2	O
+.	O
+5	O
+ml	O
+2	O
+%	O
+lidocaine	O
+in	O
+7	O
+.	O
+5	O
+%	O
+glucose	O
+,	O
+2	O
+%	O
+prilocaine	O
+in	O
+7	O
+.	O
+5	O
+%	O
+glucose	O
+,	O
+or	O
+0	O
+.	O
+5	O
+%	O
+bupivacaine	O
+in	O
+7	O
+.	O
+5	O
+%	O
+glucose	O
+.	O
+
+All	O
+solutions	O
+were	O
+provided	O
+in	O
+blinded	O
+vials	O
+by	O
+the	O
+hospital	O
+pharmacy	O
+.	O
+
+Details	O
+of	O
+spinal	O
+puncture	O
+,	O
+extension	O
+and	O
+regression	O
+of	O
+spinal	O
+block	O
+,	O
+and	O
+the	O
+times	O
+to	O
+reach	O
+discharge	O
+criteria	O
+were	O
+noted	O
+.	O
+
+In	O
+the	O
+evening	O
+of	O
+postoperative	O
+day	O
+1	O
+,	O
+patients	O
+were	O
+evaluated	O
+for	O
+TNSs	B
+by	O
+a	O
+physician	O
+unaware	O
+of	O
+the	O
+drug	O
+administered	O
+and	O
+the	O
+details	O
+of	O
+the	O
+anesthetic	O
+procedure	O
+.	O
+
+RESULTS	O
+:	O
+Nine	O
+of	O
+30	O
+patients	O
+receiving	O
+lidocaine	O
+experienced	O
+TNSs	B
+,	O
+1	O
+of	O
+30	O
+patients	O
+receiving	O
+prilocaine	O
+(	O
+P	O
+=	O
+0	O
+.	O
+03	O
+)	O
+had	O
+them	O
+,	O
+and	O
+none	O
+of	O
+30	O
+patients	O
+receiving	O
+bupivacaine	O
+had	O
+TNSs	B
+.	O
+
+Times	O
+to	O
+ambulate	O
+and	O
+to	O
+void	O
+were	O
+similar	O
+after	O
+lidocaine	O
+and	O
+prilocaine	O
+(	O
+150	O
+vs	O
+.	O
+165	O
+min	O
+and	O
+238	O
+vs	O
+.	O
+253	O
+min	O
+,	O
+respectively	O
+)	O
+but	O
+prolonged	O
+after	O
+bupivacaine	O
+(	O
+200	O
+and	O
+299	O
+min	O
+,	O
+respectively	O
+;	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Prilocaine	O
+may	O
+be	O
+preferable	O
+to	O
+lidocaine	O
+for	O
+short	O
+surgical	O
+procedures	O
+because	O
+it	O
+has	O
+a	O
+similar	O
+duration	O
+of	O
+action	O
+but	O
+a	O
+lower	O
+incidence	O
+of	O
+TNSs	B
+.	O
+
+Suxamethonium	O
+-	O
+induced	O
+cardiac	B
+arrest	I
+and	O
+death	B
+following	O
+5	O
+days	O
+of	O
+immobilization	O
+.	O
+
+The	O
+present	O
+report	O
+describes	O
+a	O
+case	O
+of	O
+cardiac	B
+arrest	I
+and	O
+subsequent	O
+death	B
+as	O
+a	O
+result	O
+of	O
+hyperkalaemia	B
+following	O
+the	O
+use	O
+of	O
+suxamethonium	O
+in	O
+a	O
+23	O
+-	O
+year	O
+-	O
+old	O
+Malawian	O
+woman	O
+.	O
+
+Five	O
+days	O
+after	O
+the	O
+onset	O
+of	O
+the	O
+symptoms	O
+of	O
+meningitis	B
+,	O
+the	O
+patient	O
+aspirated	O
+stomach	O
+contents	O
+and	O
+needed	O
+endotracheal	O
+intubation	O
+.	O
+
+Forty	O
+seconds	O
+after	O
+injection	O
+of	O
+suxamethonium	O
+,	O
+bradycardia	B
+and	O
+cardiac	B
+arrest	I
+occurred	O
+.	O
+
+Attempts	O
+to	O
+resuscitate	O
+the	O
+patient	O
+were	O
+not	O
+successful	O
+.	O
+
+The	O
+serum	O
+level	O
+of	O
+potassium	O
+was	O
+observed	O
+to	O
+be	O
+8	O
+.	O
+4	O
+mequiv	O
+L	O
+-	O
+1	O
+.	O
+
+Apart	O
+from	O
+the	O
+reduction	O
+in	O
+the	O
+patient	O
+'	O
+s	O
+level	O
+of	O
+consciousness	O
+,	O
+there	O
+were	O
+no	O
+signs	O
+of	O
+motor	O
+neurone	O
+damage	O
+or	O
+of	O
+any	O
+of	O
+the	O
+other	O
+known	O
+predisposing	O
+conditions	O
+for	O
+hyperkalaemia	B
+following	O
+the	O
+administration	O
+of	O
+suxamethonium	O
+.	O
+
+It	O
+is	O
+postulated	O
+that	O
+her	O
+death	B
+was	O
+caused	O
+by	O
+hypersensitivity	B
+to	O
+suxamethonium	O
+,	O
+associated	O
+with	O
+her	O
+5	O
+-	O
+day	O
+immobilization	O
+.	O
+
+Acute	O
+hepatitis	B
+,	O
+autoimmune	B
+hemolytic	I
+anemia	I
+,	O
+and	O
+erythroblastocytopenia	B
+induced	O
+by	O
+ceftriaxone	O
+.	O
+
+An	O
+80	O
+-	O
+yr	O
+-	O
+old	O
+man	O
+developed	O
+acute	O
+hepatitis	B
+shortly	O
+after	O
+ingesting	O
+oral	O
+ceftriaxone	O
+.	O
+
+Although	O
+the	O
+transaminases	O
+gradually	O
+returned	O
+to	O
+baseline	O
+after	O
+withholding	O
+the	O
+beta	O
+lactam	O
+antibiotic	O
+,	O
+there	O
+was	O
+a	O
+gradual	O
+increase	O
+in	O
+serum	O
+bilirubin	O
+and	O
+a	O
+decrease	O
+in	O
+hemoglobin	O
+concentration	O
+caused	O
+by	O
+an	O
+autoimmune	B
+hemolytic	I
+anemia	I
+and	O
+erythroblastocytopenia	B
+.	O
+
+These	O
+responded	O
+to	O
+systemic	O
+steroids	O
+and	O
+immunoglobulins	O
+.	O
+
+Despite	O
+the	O
+widespread	O
+use	O
+of	O
+these	O
+agents	O
+this	O
+triad	O
+of	O
+side	O
+effects	O
+has	O
+not	O
+previously	O
+been	O
+reported	O
+in	O
+connection	O
+with	O
+beta	O
+lactam	O
+antibiotics	O
+.	O
+
+Thyroxine	O
+abuse	O
+:	O
+an	O
+unusual	O
+case	O
+of	O
+thyrotoxicosis	B
+in	O
+pregnancy	O
+.	O
+
+Eating	B
+disorders	I
+and	O
+the	O
+associated	O
+behavioural	O
+problems	O
+and	O
+drug	B
+abuse	I
+are	O
+uncommon	O
+in	O
+pregnancy	O
+.	O
+
+When	O
+they	O
+do	O
+occur	O
+they	O
+are	O
+often	O
+unrecognized	O
+because	O
+of	O
+denial	O
+but	O
+when	O
+significant	O
+may	O
+pose	O
+a	O
+risk	O
+to	O
+both	O
+the	O
+mother	O
+and	O
+her	O
+fetus	O
+.	O
+
+This	O
+case	O
+illustrates	O
+a	O
+number	O
+of	O
+problems	O
+that	O
+may	O
+be	O
+encountered	O
+in	O
+women	O
+with	O
+eating	B
+disorders	I
+in	O
+pregnancy	O
+,	O
+including	O
+prolonged	O
+and	O
+recurrent	O
+metabolic	O
+disturbances	O
+and	O
+diuretic	O
+abuse	O
+.	O
+
+In	O
+particular	O
+it	O
+illustrates	O
+the	O
+derangements	O
+of	O
+thyroid	O
+function	O
+seen	O
+in	O
+pregnant	O
+women	O
+with	O
+eating	B
+disorders	I
+and	O
+reminds	O
+us	O
+that	O
+when	O
+a	O
+cause	O
+for	O
+thyrotoxicosis	B
+remains	O
+obscure	O
+,	O
+thyroxine	O
+abuse	O
+should	O
+be	O
+considered	O
+and	O
+explored	O
+.	O
+
+Repeated	O
+trimipramine	O
+induces	O
+dopamine	O
+D2	O
+/	O
+D3	O
+and	O
+alpha1	O
+-	O
+adrenergic	O
+up	O
+-	O
+regulation	O
+.	O
+
+Trimipramine	O
+(	O
+TRI	O
+)	O
+,	O
+which	O
+shows	O
+a	O
+clinical	O
+antidepressant	O
+activity	O
+,	O
+is	O
+chemically	O
+related	O
+to	O
+imipramine	O
+but	O
+does	O
+not	O
+inhibit	O
+the	O
+reuptake	O
+of	O
+noradrenaline	O
+and	O
+5	O
+-	O
+hydroxytryptamine	O
+,	O
+nor	O
+does	O
+it	O
+induce	O
+beta	O
+-	O
+adrenergic	O
+down	O
+-	O
+regulation	O
+.	O
+
+The	O
+mechanism	O
+of	O
+its	O
+antidepressant	O
+activity	O
+is	O
+still	O
+unknown	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+find	O
+out	O
+whether	O
+TRI	O
+given	O
+repeatedly	O
+was	O
+able	O
+to	O
+induce	O
+adaptive	O
+changes	O
+in	O
+the	O
+dopaminergic	O
+and	O
+alpha1	O
+-	O
+adrenergic	O
+systems	O
+,	O
+demonstrated	O
+by	O
+us	O
+previously	O
+for	O
+various	O
+antidepressants	O
+.	O
+
+TRI	O
+was	O
+given	O
+to	O
+male	O
+Wistar	O
+rats	O
+and	O
+male	O
+Albino	O
+Swiss	O
+mice	O
+perorally	O
+twice	O
+daily	O
+for	O
+14	O
+days	O
+.	O
+
+In	O
+the	O
+acute	O
+experiment	O
+TRI	O
+(	O
+given	O
+i	O
+.	O
+p	O
+.	O
+)	O
+does	O
+not	O
+antagonize	O
+the	O
+reserpine	O
+hypothermia	B
+in	O
+mice	O
+and	O
+does	O
+not	O
+potentiate	O
+the	O
+5	O
+-	O
+hydroxytryptophan	O
+head	O
+twitches	O
+in	O
+rats	O
+.	O
+
+TRI	O
+given	O
+repeatedly	O
+to	O
+rats	O
+increases	O
+the	O
+locomotor	O
+hyperactivity	B
+induced	O
+by	O
+d	O
+-	O
+amphetamine	O
+,	O
+quinpirole	O
+and	O
+(	O
++	O
+)	O
+-	O
+7	O
+-	O
+hydroxy	O
+-	O
+dipropyloaminotetralin	O
+(	O
+dopamine	O
+D2	O
+and	O
+D3	O
+effects	O
+)	O
+.	O
+
+The	O
+stereotypies	O
+induced	O
+by	O
+d	O
+-	O
+amphetamine	O
+or	O
+apomorphine	O
+are	O
+not	O
+potentiated	O
+by	O
+TRI	O
+.	O
+
+It	O
+increases	O
+the	O
+behaviour	O
+stimulation	O
+evoked	O
+by	O
+phenylephrine	O
+(	O
+given	O
+intraventricularly	O
+)	O
+in	O
+rats	O
+,	O
+evaluated	O
+in	O
+the	O
+open	O
+field	O
+test	O
+as	O
+well	O
+as	O
+the	O
+aggressiveness	B
+evoked	O
+by	O
+clonidine	O
+in	O
+mice	O
+,	O
+both	O
+these	O
+effects	O
+being	O
+mediated	O
+by	O
+an	O
+alpha1	O
+-	O
+adrenergic	O
+receptor	O
+.	O
+
+It	O
+may	O
+be	O
+concluded	O
+that	O
+,	O
+like	O
+other	O
+tricyclic	O
+antidepressants	O
+studied	O
+previously	O
+,	O
+TRI	O
+given	O
+repeatedly	O
+increases	O
+the	O
+responsiveness	O
+of	O
+brain	O
+dopamine	O
+D2	O
+and	O
+D3	O
+(	O
+locomotor	O
+activity	O
+but	O
+not	O
+stereotypy	O
+)	O
+as	O
+well	O
+as	O
+alpha1	O
+-	O
+adrenergic	O
+receptors	O
+to	O
+their	O
+agonists	O
+.	O
+
+A	O
+question	O
+arises	O
+whether	O
+the	O
+reuptake	O
+inhibition	O
+is	O
+of	O
+any	O
+importance	O
+to	O
+the	O
+adaptive	O
+changes	O
+induced	O
+by	O
+repeated	O
+antidepressants	O
+,	O
+suggested	O
+to	O
+be	O
+responsible	O
+for	O
+the	O
+antidepressant	O
+activity	O
+.	O
+
+Pethidine	O
+-	O
+associated	O
+seizure	B
+in	O
+a	O
+healthy	O
+adolescent	O
+receiving	O
+pethidine	O
+for	O
+postoperative	B
+pain	I
+control	O
+.	O
+
+A	O
+healthy	O
+17	O
+-	O
+year	O
+-	O
+old	O
+male	O
+received	O
+standard	O
+intermittent	O
+doses	O
+of	O
+pethidine	O
+via	O
+a	O
+patient	O
+-	O
+controlled	O
+analgesia	O
+(	O
+PCA	O
+)	O
+pump	O
+for	O
+management	O
+of	O
+postoperative	B
+pain	I
+control	O
+.	O
+
+Twenty	O
+-	O
+three	O
+h	O
+postoperatively	O
+he	O
+developed	O
+a	O
+brief	O
+self	O
+-	O
+limited	O
+seizure	B
+.	O
+
+Both	O
+plasma	O
+pethidine	O
+and	O
+norpethidine	O
+were	O
+elevated	O
+in	O
+the	O
+range	O
+associated	O
+with	O
+clinical	O
+manifestations	O
+of	O
+central	O
+nervous	O
+system	O
+excitation	O
+.	O
+
+No	O
+other	O
+risk	O
+factors	O
+for	O
+CNS	O
+toxicity	B
+were	O
+identified	O
+.	O
+
+This	O
+method	O
+allowed	O
+frequent	O
+self	O
+-	O
+dosing	O
+of	O
+pethidine	O
+at	O
+short	O
+time	O
+intervals	O
+and	O
+rapid	O
+accumulation	O
+of	O
+pethidine	O
+and	O
+norpethidine	O
+.	O
+
+The	O
+routine	O
+use	O
+of	O
+pethidine	O
+via	O
+PCA	O
+even	O
+for	O
+a	O
+brief	O
+postoperative	O
+analgesia	O
+should	O
+be	O
+reconsidered	O
+.	O
+
+An	O
+unusual	O
+toxic	O
+reaction	O
+to	O
+axillary	O
+block	O
+by	O
+mepivacaine	O
+with	O
+adrenaline	O
+.	O
+
+An	O
+increase	B
+in	I
+blood	I
+pressure	I
+,	O
+accompanied	O
+by	O
+atrial	B
+fibrillation	I
+,	O
+agitation	B
+,	O
+incomprehensible	B
+shouts	I
+and	O
+loss	B
+of	I
+consciousness	I
+,	O
+was	O
+observed	O
+in	O
+an	O
+elderly	O
+,	O
+ASA	O
+classification	O
+group	O
+II	O
+,	O
+cardiovascularly	O
+medicated	O
+male	O
+,	O
+12	O
+min	O
+after	O
+performance	O
+of	O
+axillary	O
+block	O
+with	O
+mepivacaine	O
+850	O
+mg	O
+containing	O
+adrenaline	O
+0	O
+.	O
+225	O
+mg	O
+,	O
+for	O
+correction	O
+of	O
+Dupuytren	B
+'	I
+s	I
+contracture	I
+.	O
+
+After	O
+intravenous	O
+administration	O
+of	O
+labetalol	O
+,	O
+metoprolol	O
+and	O
+midazolam	O
+the	O
+patient	O
+'	O
+s	O
+condition	O
+improved	O
+,	O
+and	O
+15	O
+min	O
+later	O
+he	O
+woke	O
+up	O
+.	O
+
+The	O
+block	O
+was	O
+successful	O
+and	O
+surgery	O
+was	O
+conducted	O
+as	O
+scheduled	O
+despite	O
+persisting	O
+atrial	B
+fibrillation	I
+.	O
+
+Postoperatively	O
+,	O
+the	O
+patient	O
+refused	O
+DC	O
+cardioversion	O
+and	O
+was	O
+treated	O
+medically	O
+.	O
+
+Both	O
+the	O
+temporal	O
+relationship	O
+of	O
+events	O
+and	O
+the	O
+response	O
+to	O
+treatment	O
+suggest	O
+that	O
+a	O
+rapid	O
+systemic	O
+absorption	O
+of	O
+mepivacaine	O
+with	O
+adrenaline	O
+and	O
+/	O
+or	O
+interaction	O
+of	O
+these	O
+drugs	O
+with	O
+the	O
+patient	O
+'	O
+s	O
+cardiovascular	O
+medications	O
+were	O
+responsible	O
+for	O
+the	O
+perioperative	O
+complications	O
+.	O
+
+Drug	O
+-	O
+associated	O
+acute	O
+-	O
+onset	O
+vanishing	B
+bile	I
+duct	I
+and	O
+Stevens	B
+-	I
+Johnson	I
+syndromes	I
+in	O
+a	O
+child	O
+.	O
+
+Acute	O
+vanishing	B
+bile	I
+duct	I
+syndrome	O
+is	O
+a	O
+rare	O
+but	O
+established	O
+cause	O
+of	O
+progressive	O
+cholestasis	B
+in	O
+adults	O
+,	O
+is	O
+most	O
+often	O
+drug	O
+or	O
+toxin	O
+related	O
+,	O
+and	O
+is	O
+of	O
+unknown	O
+pathogenesis	O
+.	O
+
+It	O
+has	O
+not	O
+been	O
+reported	O
+previously	O
+in	O
+children	O
+.	O
+
+Stevens	B
+-	I
+Johnson	I
+syndrome	I
+is	O
+a	O
+well	O
+-	O
+recognized	O
+immune	O
+complex	O
+-	O
+mediated	O
+hypersensitivity	B
+reaction	O
+that	O
+affects	O
+all	O
+age	O
+groups	O
+,	O
+is	O
+drug	O
+or	O
+infection	B
+induced	O
+,	O
+and	O
+has	O
+classic	O
+systemic	O
+,	O
+mucosal	O
+,	O
+and	O
+dermatologic	O
+manifestations	O
+.	O
+
+A	O
+previously	O
+healthy	O
+child	O
+who	O
+developed	O
+acute	O
+,	O
+severe	O
+,	O
+rapidly	O
+progressive	O
+vanishing	B
+bile	I
+duct	I
+syndrome	I
+shortly	O
+after	O
+Stevens	B
+-	I
+Johnson	I
+syndrome	I
+is	O
+described	O
+;	O
+this	O
+was	O
+temporally	O
+associated	O
+with	O
+ibuprofen	O
+use	O
+.	O
+
+Despite	O
+therapy	O
+with	O
+ursodeoxycholic	O
+acid	O
+,	O
+prednisone	O
+,	O
+and	O
+then	O
+tacrolimus	O
+,	O
+her	O
+cholestatic	B
+disease	I
+was	O
+unrelenting	O
+,	O
+with	O
+cirrhosis	B
+shown	O
+by	O
+biopsy	O
+6	O
+months	O
+after	O
+presentation	O
+.	O
+
+This	O
+case	O
+documents	O
+acute	O
+drug	O
+-	O
+related	O
+vanishing	B
+bile	I
+duct	I
+syndrome	I
+in	O
+the	O
+pediatric	O
+age	O
+group	O
+and	O
+suggests	O
+shared	O
+immune	O
+mechanisms	O
+in	O
+the	O
+pathogenesis	O
+of	O
+both	O
+Stevens	B
+-	I
+Johnson	I
+syndrome	I
+and	O
+vanishing	B
+bile	I
+duct	I
+syndrome	I
+.	O
+
+High	O
+incidence	O
+of	O
+primary	B
+pulmonary	I
+hypertension	I
+associated	O
+with	O
+appetite	O
+suppressants	O
+in	O
+Belgium	O
+.	O
+
+Primary	B
+pulmonary	I
+hypertension	I
+is	O
+a	O
+rare	O
+,	O
+progressive	O
+and	O
+incurable	O
+disease	O
+,	O
+which	O
+has	O
+been	O
+associated	O
+with	O
+the	O
+intake	O
+of	O
+appetite	O
+suppressant	O
+drugs	O
+.	O
+
+The	O
+importance	O
+of	O
+this	O
+association	O
+was	O
+evaluated	O
+in	O
+Belgium	O
+while	O
+this	O
+country	O
+still	O
+had	O
+no	O
+restriction	O
+on	O
+the	O
+prescription	O
+of	O
+appetite	O
+suppressants	O
+.	O
+
+Thirty	O
+-	O
+five	O
+patients	O
+with	O
+primary	B
+pulmonary	I
+hypertension	I
+and	O
+85	O
+matched	O
+controls	O
+were	O
+recruited	O
+over	O
+32	O
+months	O
+(	O
+1992	O
+-	O
+1994	O
+)	O
+in	O
+Belgium	O
+.	O
+
+Exposure	O
+to	O
+appetite	O
+-	O
+suppressants	O
+was	O
+assessed	O
+on	O
+the	O
+basis	O
+of	O
+hospital	O
+records	O
+and	O
+standardized	O
+interview	O
+.	O
+
+Twenty	O
+-	O
+three	O
+of	O
+the	O
+patients	O
+had	O
+previously	O
+taken	O
+appetite	O
+suppressants	O
+,	O
+mainly	O
+fenfluramines	O
+,	O
+as	O
+compared	O
+with	O
+only	O
+5	O
+of	O
+the	O
+controls	O
+(	O
+66	O
+versus	O
+6	O
+%	O
+,	O
+p	O
+<	O
+0	O
+.	O
+0001	O
+)	O
+.	O
+
+Five	O
+patients	O
+died	O
+before	O
+the	O
+interview	O
+,	O
+all	O
+of	O
+them	O
+had	O
+taken	O
+appetite	O
+suppressants	O
+.	O
+
+In	O
+8	O
+patients	O
+the	O
+diagnosis	O
+of	O
+primary	B
+pulmonary	I
+hypertension	I
+was	O
+uncertain	O
+,	O
+5	O
+of	O
+them	O
+had	O
+taken	O
+appetite	O
+suppressants	O
+.	O
+
+The	O
+patients	O
+who	O
+had	O
+been	O
+exposed	O
+to	O
+appetite	O
+suppressants	O
+tended	O
+to	O
+be	O
+on	O
+average	O
+more	O
+severely	O
+ill	O
+,	O
+and	O
+to	O
+have	O
+a	O
+shorter	O
+median	O
+delay	O
+between	O
+onset	O
+of	O
+symptoms	O
+and	O
+diagnosis	O
+.	O
+
+A	O
+policy	O
+of	O
+unrestricted	O
+prescription	O
+of	O
+appetite	O
+suppressants	O
+may	O
+lead	O
+to	O
+a	O
+high	O
+incidence	O
+of	O
+associated	O
+primary	B
+pulmonary	I
+hypertension	I
+.	O
+
+Intake	O
+of	O
+appetite	O
+suppressants	O
+may	O
+accelerate	O
+the	O
+progression	O
+of	O
+the	O
+disease	O
+.	O
+
+Inappropriate	O
+use	O
+of	O
+carbamazepine	O
+and	O
+vigabatrin	O
+in	O
+typical	O
+absence	B
+seizures	I
+.	O
+
+Carbamazepine	O
+and	O
+vigabatrin	O
+are	O
+contraindicated	O
+in	O
+typical	O
+absence	B
+seizures	I
+.	O
+
+Of	O
+18	O
+consecutive	O
+referrals	O
+of	O
+children	O
+with	O
+resistant	O
+typical	O
+absences	O
+only	O
+,	O
+eight	O
+were	O
+erroneously	O
+treated	O
+with	O
+carbamazepine	O
+either	O
+as	O
+monotherapy	O
+or	O
+as	O
+an	O
+add	O
+-	O
+on	O
+.	O
+
+Vigabatrin	O
+was	O
+also	O
+used	O
+in	O
+the	O
+treatment	O
+of	O
+two	O
+children	O
+.	O
+
+Frequency	O
+of	O
+absences	O
+increased	O
+in	O
+four	O
+children	O
+treated	O
+with	O
+carbamazepine	O
+and	O
+two	O
+of	O
+these	O
+developed	O
+myoclonic	B
+jerks	I
+,	O
+which	O
+resolved	O
+on	O
+withdrawal	O
+of	O
+carbamazepine	O
+.	O
+
+Absences	O
+were	O
+aggravated	O
+in	O
+both	O
+cases	O
+where	O
+vigabatrin	O
+was	O
+added	O
+on	O
+to	O
+concurrent	O
+treatment	O
+.	O
+
+Optimal	O
+control	O
+of	O
+the	O
+absences	O
+was	O
+achieved	O
+with	O
+sodium	O
+valproate	O
+,	O
+lamotrigine	O
+,	O
+or	O
+ethosuximide	O
+alone	O
+or	O
+in	O
+combination	O
+.	O
+
+Choreoathetoid	B
+movements	I
+associated	O
+with	O
+rapid	O
+adjustment	O
+to	O
+methadone	O
+.	O
+
+Choreatiform	B
+hyperkinesias	I
+are	O
+known	O
+to	O
+be	O
+occasional	O
+movement	B
+abnormalities	I
+during	O
+intoxications	O
+with	O
+cocaine	O
+but	O
+not	O
+opiates	O
+.	O
+
+This	O
+is	O
+a	O
+case	O
+report	O
+of	O
+euphoria	O
+and	O
+choreoathetoid	B
+movements	I
+both	O
+transiently	O
+induced	O
+by	O
+rapid	O
+adjustment	O
+to	O
+the	O
+selective	O
+mu	O
+-	O
+opioid	O
+receptor	O
+agonist	O
+methadone	O
+in	O
+an	O
+inpatient	O
+previously	O
+abusing	O
+heroine	O
+and	O
+cocaine	O
+.	O
+
+In	O
+addition	O
+,	O
+minor	O
+EEG	O
+abnormalities	O
+occurred	O
+.	O
+
+Possible	O
+underlying	O
+neurobiological	O
+phenomena	O
+are	O
+discussed	O
+.	O
+
+Adverse	O
+effects	O
+of	O
+the	O
+atypical	O
+antipsychotics	O
+.	O
+
+Collaborative	O
+Working	O
+Group	O
+on	O
+Clinical	O
+Trial	O
+Evaluations	O
+.	O
+
+Adverse	O
+effects	O
+of	O
+antipsychotics	O
+often	O
+lead	O
+to	O
+noncompliance	O
+.	O
+
+Thus	O
+,	O
+clinicians	O
+should	O
+address	O
+patients	O
+'	O
+concerns	O
+about	O
+adverse	O
+effects	O
+and	O
+attempt	O
+to	O
+choose	O
+medications	O
+that	O
+will	O
+improve	O
+their	O
+patients	O
+'	O
+quality	O
+of	O
+life	O
+as	O
+well	O
+as	O
+overall	O
+health	O
+.	O
+
+The	O
+side	O
+effect	O
+profiles	O
+of	O
+the	O
+atypical	O
+antipsychotics	O
+are	O
+more	O
+advantageous	O
+than	O
+those	O
+of	O
+the	O
+conventional	O
+neuroleptics	O
+.	O
+
+Conventional	O
+agents	O
+are	O
+associated	O
+with	O
+unwanted	O
+central	O
+nervous	O
+system	O
+effects	O
+,	O
+including	O
+extrapyramidal	B
+symptoms	I
+(	O
+EPS	B
+)	O
+,	O
+tardive	B
+dyskinesia	I
+,	O
+sedation	O
+,	O
+and	O
+possible	O
+impairment	O
+of	O
+some	O
+cognitive	O
+measures	O
+,	O
+as	O
+well	O
+as	O
+cardiac	O
+effects	O
+,	O
+orthostatic	B
+hypotension	I
+,	O
+hepatic	O
+changes	O
+,	O
+anticholinergic	O
+side	O
+effects	O
+,	O
+sexual	B
+dysfunction	I
+,	O
+and	O
+weight	B
+gain	I
+.	O
+
+The	O
+newer	O
+atypical	O
+agents	O
+have	O
+a	O
+lower	O
+risk	O
+of	O
+EPS	B
+,	O
+but	O
+are	O
+associated	O
+in	O
+varying	O
+degrees	O
+with	O
+sedation	O
+,	O
+cardiovascular	O
+effects	O
+,	O
+anticholinergic	O
+effects	O
+,	O
+weight	B
+gain	I
+,	O
+sexual	B
+dysfunction	I
+,	O
+hepatic	O
+effects	O
+,	O
+lowered	O
+seizure	B
+threshold	O
+(	O
+primarily	O
+clozapine	O
+)	O
+,	O
+and	O
+agranulocytosis	B
+(	O
+clozapine	O
+only	O
+)	O
+.	O
+
+Since	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+specific	O
+adverse	O
+effects	O
+differ	O
+among	O
+the	O
+various	O
+atypicals	O
+,	O
+the	O
+clinician	O
+should	O
+carefully	O
+consider	O
+which	O
+side	O
+effects	O
+are	O
+most	O
+likely	O
+to	O
+lead	O
+to	O
+the	O
+individual	O
+'	O
+s	O
+dissatisfaction	O
+and	O
+noncompliance	O
+before	O
+choosing	O
+an	O
+antipsychotic	O
+for	O
+a	O
+particular	O
+patient	O
+.	O
+
+A	O
+randomized	O
+,	O
+placebo	O
+-	O
+controlled	O
+dose	O
+-	O
+comparison	O
+trial	O
+of	O
+haloperidol	O
+for	O
+psychosis	B
+and	O
+disruptive	B
+behaviors	I
+in	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+goal	O
+of	O
+this	O
+study	O
+was	O
+to	O
+compare	O
+the	O
+efficacy	O
+and	O
+side	O
+effects	O
+of	O
+two	O
+doses	O
+of	O
+haloperidol	O
+and	O
+placebo	O
+in	O
+the	O
+treatment	O
+of	O
+psychosis	B
+and	O
+disruptive	B
+behaviors	I
+in	O
+patients	O
+with	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+.	O
+
+METHOD	O
+:	O
+In	O
+a	O
+6	O
+-	O
+week	O
+random	O
+-	O
+assignment	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+trial	O
+(	O
+phase	O
+A	O
+)	O
+,	O
+haloperidol	O
+,	O
+2	O
+-	O
+3	O
+mg	O
+/	O
+day	O
+(	O
+standard	O
+dose	O
+)	O
+,	O
+and	O
+haloperidol	O
+,	O
+0	O
+.	O
+50	O
+-	O
+0	O
+.	O
+75	O
+mg	O
+/	O
+day	O
+(	O
+low	O
+dose	O
+)	O
+,	O
+were	O
+compared	O
+in	O
+71	O
+outpatients	O
+with	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+.	O
+
+For	O
+the	O
+subsequent	O
+6	O
+-	O
+week	O
+double	O
+-	O
+blind	O
+crossover	O
+phase	O
+(	O
+phase	O
+B	O
+)	O
+,	O
+patients	O
+taking	O
+standard	O
+-	O
+or	O
+low	O
+-	O
+dose	O
+haloperidol	O
+were	O
+switched	O
+to	O
+placebo	O
+,	O
+and	O
+patients	O
+taking	O
+placebo	O
+were	O
+randomly	O
+assigned	O
+to	O
+standard	O
+-	O
+or	O
+low	O
+-	O
+dose	O
+haloperidol	O
+.	O
+
+RESULTS	O
+:	O
+For	O
+the	O
+60	O
+patients	O
+who	O
+completed	O
+phase	O
+A	O
+,	O
+standard	O
+-	O
+dose	O
+haloperidol	O
+was	O
+efficacious	O
+and	O
+superior	O
+to	O
+both	O
+low	O
+-	O
+dose	O
+haloperidol	O
+and	O
+placebo	O
+for	O
+scores	O
+on	O
+the	O
+Brief	O
+Psychiatric	O
+Rating	O
+Scale	O
+psychosis	B
+factor	O
+and	O
+on	O
+psychomotor	B
+agitation	I
+.	O
+
+Response	O
+rates	O
+according	O
+to	O
+three	O
+sets	O
+of	O
+criteria	O
+were	O
+greater	O
+with	O
+the	O
+standard	O
+dose	O
+(	O
+55	O
+%	O
+-	O
+60	O
+%	O
+)	O
+than	O
+the	O
+low	O
+dose	O
+(	O
+25	O
+%	O
+-	O
+35	O
+%	O
+)	O
+and	O
+placebo	O
+(	O
+25	O
+%	O
+-	O
+30	O
+%	O
+)	O
+.	O
+
+The	O
+advantage	O
+of	O
+standard	O
+dose	O
+over	O
+low	O
+dose	O
+was	O
+replicated	O
+in	O
+phase	O
+B	O
+.	O
+
+In	O
+phase	O
+A	O
+,	O
+extrapyramidal	B
+signs	I
+tended	O
+to	O
+be	O
+greater	O
+with	O
+the	O
+standard	O
+dose	O
+than	O
+in	O
+the	O
+other	O
+two	O
+conditions	O
+,	O
+primarily	O
+because	O
+of	O
+a	O
+subgroup	O
+(	O
+20	O
+%	O
+)	O
+who	O
+developed	O
+moderate	O
+to	O
+severe	O
+signs	O
+.	O
+
+Low	O
+-	O
+dose	O
+haloperidol	O
+did	O
+not	O
+differ	O
+from	O
+placebo	O
+on	O
+any	O
+measure	O
+of	O
+efficacy	O
+or	O
+side	O
+effects	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+results	O
+indicated	O
+a	O
+favorable	O
+therapeutic	O
+profile	O
+for	O
+haloperidol	O
+in	O
+doses	O
+of	O
+2	O
+-	O
+3	O
+mg	O
+/	O
+day	O
+,	O
+although	O
+a	O
+subgroup	O
+developed	O
+moderate	O
+to	O
+severe	O
+extrapyramidal	B
+signs	I
+.	O
+
+A	O
+starting	O
+dose	O
+of	O
+1	O
+mg	O
+/	O
+day	O
+with	O
+gradual	O
+,	O
+upward	O
+dose	O
+titration	O
+is	O
+recommended	O
+.	O
+
+The	O
+narrow	O
+therapeutic	O
+window	O
+observed	O
+with	O
+haloperidol	O
+may	O
+also	O
+apply	O
+to	O
+other	O
+neuroleptics	O
+used	O
+in	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+patients	O
+with	O
+psychosis	B
+and	O
+disruptive	B
+behaviors	I
+.	O
+
+Effects	O
+of	O
+acetylsalicylic	O
+acid	O
+,	O
+dipyridamole	O
+,	O
+and	O
+hydrocortisone	O
+on	O
+epinephrine	O
+-	O
+induced	O
+myocardial	B
+injury	I
+in	O
+dogs	O
+.	O
+
+A	O
+reproducible	O
+model	O
+for	O
+producing	O
+diffuse	O
+myocardial	B
+injury	I
+(	O
+epinephrine	O
+infusion	O
+)	O
+has	O
+been	O
+developed	O
+to	O
+study	O
+the	O
+cardioprotective	O
+effects	O
+of	O
+agents	O
+or	O
+maneuvers	O
+which	O
+might	O
+alter	O
+the	O
+evolution	O
+of	O
+acute	O
+myocardial	B
+infarction	I
+.	O
+
+Infusions	O
+of	O
+epinephrine	O
+(	O
+4	O
+mug	O
+per	O
+kilogram	O
+per	O
+minute	O
+for	O
+6	O
+hours	O
+)	O
+increased	O
+radiocalcium	O
+uptakes	O
+into	O
+intact	O
+myocardium	O
+and	O
+each	O
+of	O
+its	O
+subcellular	O
+components	O
+with	O
+the	O
+mitochondrial	O
+fraction	O
+showing	O
+the	O
+most	O
+consistent	O
+changes	O
+when	O
+compared	O
+to	O
+saline	O
+-	O
+infused	O
+control	O
+animals	O
+(	O
+4	O
+,	O
+957	O
+vs	O
+.	O
+827	O
+counts	O
+per	O
+minute	O
+per	O
+gram	O
+of	O
+dried	O
+tissue	O
+or	O
+fraction	O
+)	O
+.	O
+
+Myocardial	O
+concentrations	O
+of	O
+calcium	O
+also	O
+increased	O
+significantly	O
+(	O
+12	O
+.	O
+0	O
+vs	O
+.	O
+5	O
+.	O
+0	O
+mg	O
+.	O
+per	O
+100	O
+Gm	O
+.	O
+of	O
+fat	O
+-	O
+free	O
+dry	O
+weight	O
+)	O
+.	O
+
+Infusions	O
+of	O
+calcium	O
+chloride	O
+sufficient	O
+to	O
+raise	O
+serum	O
+calcium	O
+concentrations	O
+2	O
+mEq	O
+.	O
+per	O
+liter	O
+failed	O
+to	O
+increase	O
+calcium	O
+influx	O
+into	O
+the	O
+myocardial	O
+cell	O
+.	O
+
+Mitochondrial	O
+radiocalcium	O
+uptakes	O
+were	O
+significantly	O
+decreased	O
+in	O
+animals	O
+pretreated	O
+with	O
+acetylsalicylic	O
+acid	O
+or	O
+dipyridamole	O
+or	O
+when	O
+hydrocortisone	O
+was	O
+added	O
+to	O
+the	O
+epinephrine	O
+infusion	O
+(	O
+2	O
+,	O
+682	O
+,	O
+2	O
+,	O
+803	O
+,	O
+and	O
+3	O
+,	O
+424	O
+counts	O
+per	O
+minute	O
+per	O
+gram	O
+of	O
+dried	O
+fraction	O
+,	O
+respectively	O
+)	O
+.	O
+
+Myocardial	O
+calcium	O
+concentrations	O
+also	O
+were	O
+decreased	O
+(	O
+11	O
+.	O
+2	O
+,	O
+8	O
+.	O
+3	O
+,	O
+and	O
+8	O
+.	O
+9	O
+mg	O
+.	O
+per	O
+100	O
+Gm	O
+.	O
+of	O
+fat	O
+-	O
+free	O
+dry	O
+weight	O
+,	O
+respectively	O
+)	O
+in	O
+the	O
+three	O
+treatment	O
+groups	O
+,	O
+being	O
+significantly	O
+decreased	O
+only	O
+in	O
+the	O
+last	O
+two	O
+.	O
+
+Evidence	O
+of	O
+microscopic	O
+damage	O
+was	O
+graded	O
+as	O
+less	O
+severe	O
+in	O
+the	O
+three	O
+treatment	O
+groups	O
+.	O
+
+Acetylsalicylic	O
+acid	O
+,	O
+dipyridamole	O
+,	O
+and	O
+hydrocortisone	O
+all	O
+appear	O
+to	O
+have	O
+cardioprotective	O
+effects	O
+when	O
+tested	O
+in	O
+this	O
+model	O
+.	O
+
+Clinical	O
+and	O
+histopathologic	O
+examination	O
+of	O
+renal	O
+allografts	O
+treated	O
+with	O
+tacrolimus	O
+(	O
+FK506	O
+)	O
+for	O
+at	O
+least	O
+one	O
+year	O
+.	O
+
+BACKGROUND	O
+:	O
+We	O
+clinically	O
+and	O
+pathologically	O
+analyzed	O
+renal	O
+allografts	O
+from	O
+1	O
+9	O
+renal	O
+transplant	O
+patients	O
+treated	O
+with	O
+tacrolimus	O
+(	O
+FK506	O
+)	O
+for	O
+more	O
+than	O
+1	O
+year	O
+.	O
+
+METHODS	O
+:	O
+Twenty	O
+-	O
+six	O
+renal	O
+allograft	O
+biopsy	O
+specimens	O
+from	O
+1	O
+9	O
+renal	O
+transplant	O
+patients	O
+who	O
+underwent	O
+transplantations	O
+between	O
+1991	O
+and	O
+1993	O
+were	O
+evaluated	O
+.	O
+
+Thirteen	O
+biopsies	O
+were	O
+performed	O
+from	O
+stable	O
+functioning	O
+renal	O
+allografts	O
+with	O
+informed	O
+consent	O
+(	O
+nonepisode	O
+biopsy	O
+)	O
+and	O
+the	O
+other	O
+13	O
+were	O
+from	O
+dysfunctional	O
+renal	O
+allografts	O
+with	O
+a	O
+clinical	O
+indication	O
+for	O
+biopsy	O
+(	O
+episode	O
+biopsy	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+main	O
+pathologic	O
+diagnoses	O
+(	O
+some	O
+overlap	O
+)	O
+were	O
+acute	O
+rejection	O
+(	O
+AR	O
+;	O
+n	O
+=	O
+4	O
+)	O
+,	O
+chronic	O
+rejection	O
+(	O
+CR	O
+;	O
+n	O
+=	O
+5	O
+)	O
+,	O
+AR	O
++	O
+CR	O
+(	O
+n	O
+=	O
+4	O
+)	O
+,	O
+recurrent	O
+IgA	B
+nephropathy	I
+(	O
+n	O
+=	O
+5	O
+)	O
+,	O
+normal	O
+findings	O
+(	O
+n	O
+=	O
+2	O
+)	O
+,	O
+minimal	O
+-	O
+type	O
+chronic	O
+FK506	O
+nephropathy	B
+(	O
+n	O
+=	O
+9	O
+)	O
+,	O
+and	O
+mild	O
+-	O
+type	O
+FK506	O
+nephropathy	B
+(	O
+n	O
+=	O
+11	O
+)	O
+.	O
+
+Of	O
+the	O
+nonepisode	O
+biopsies	O
+,	O
+7	O
+and	O
+4	O
+biopsies	O
+showed	O
+minimal	O
+-	O
+type	O
+and	O
+mild	O
+-	O
+type	O
+chronic	O
+FK506	O
+nephropathy	B
+,	O
+respectively	O
+.	O
+
+Chronic	O
+FK506	O
+nephropathy	B
+consisted	O
+of	O
+rough	O
+and	O
+foamy	O
+tubular	O
+vacuolization	O
+(	O
+5	O
+biopsies	O
+)	O
+,	O
+arteriolopathy	O
+(	O
+angiodegeneration	O
+of	O
+the	O
+arteriolar	O
+wall	O
+;	O
+20	O
+biopsies	O
+)	O
+,	O
+focal	B
+segmental	I
+glomerulosclerosis	I
+(	O
+4	O
+biopsies	O
+)	O
+and	O
+the	O
+striped	O
+form	O
+of	O
+interstitial	B
+fibrosis	I
+(	O
+11	O
+biopsies	O
+)	O
+.	O
+
+The	O
+serum	O
+creatinine	O
+levels	O
+of	O
+patients	O
+in	O
+the	O
+mild	O
+-	O
+type	O
+chronic	O
+FK506	O
+nephropathy	B
+group	O
+,	O
+which	O
+included	O
+7	O
+episode	O
+biopsies	O
+,	O
+were	O
+statistically	O
+higher	O
+than	O
+those	O
+in	O
+the	O
+minimum	O
+-	O
+type	O
+chronic	O
+FK506	O
+-	O
+nephropathy	B
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+This	O
+study	O
+demonstrates	O
+that	O
+chronic	O
+FK506	O
+nephropathy	B
+consists	O
+primarily	O
+of	O
+arteriolopathy	O
+manifesting	O
+as	O
+insudative	O
+hyalinosis	O
+of	O
+the	O
+arteriolar	O
+wall	O
+,	O
+and	O
+suggests	O
+that	O
+mild	O
+-	O
+type	O
+chronic	O
+FK506	O
+nephropathy	B
+is	O
+a	O
+condition	O
+which	O
+may	O
+lead	O
+to	O
+deterioration	O
+of	O
+renal	O
+allograft	O
+function	O
+.	O
+
+Different	O
+lobular	O
+distributions	O
+of	O
+altered	O
+hepatocyte	O
+tight	O
+junctions	O
+in	O
+rat	O
+models	O
+of	O
+intrahepatic	B
+and	I
+extrahepatic	I
+cholestasis	I
+.	O
+
+Hepatocyte	O
+tight	O
+junctions	O
+(	O
+TJs	O
+)	O
+,	O
+the	O
+only	O
+intercellular	O
+barrier	O
+between	O
+the	O
+sinusoidal	O
+and	O
+the	O
+canalicular	O
+spaces	O
+,	O
+play	O
+a	O
+key	O
+role	O
+in	O
+bile	O
+formation	O
+.	O
+
+Although	O
+hepatocyte	O
+TJs	O
+are	O
+impaired	O
+in	O
+cholestasis	B
+,	O
+attempts	O
+to	O
+localize	O
+the	O
+precise	O
+site	O
+of	O
+hepatocyte	O
+TJ	O
+damage	O
+by	O
+freeze	O
+-	O
+fracture	O
+electron	O
+microscopy	O
+have	O
+produced	O
+limited	O
+information	O
+.	O
+
+Recently	O
+,	O
+several	O
+TJ	O
+-	O
+associated	O
+proteins	O
+like	O
+ZO	O
+-	O
+1	O
+and	O
+7H6	O
+have	O
+been	O
+identified	O
+and	O
+characterized	O
+.	O
+
+Immunolocalization	O
+of	O
+7H6	O
+appears	O
+to	O
+closely	O
+correlate	O
+with	O
+paracellular	O
+permeability	O
+.	O
+
+We	O
+used	O
+rat	O
+models	O
+of	O
+intrahepatic	B
+cholestasis	I
+by	O
+ethinyl	O
+estradiol	O
+(	O
+EE	O
+)	O
+treatment	O
+and	O
+extrahepatic	B
+cholestasis	I
+by	O
+bile	O
+duct	O
+ligation	O
+(	O
+BDL	O
+)	O
+to	O
+precisely	O
+determine	O
+the	O
+site	O
+of	O
+TJ	O
+damage	O
+.	O
+
+Alterations	O
+in	O
+hepatocyte	O
+TJs	O
+were	O
+assessed	O
+by	O
+double	O
+-	O
+immunolabeling	O
+for	O
+7H6	O
+and	O
+ZO	O
+-	O
+1	O
+using	O
+a	O
+confocal	O
+laser	O
+scanning	O
+microscope	O
+.	O
+
+In	O
+control	O
+rats	O
+,	O
+immunostaining	O
+for	O
+7H6	O
+and	O
+ZO	O
+-	O
+1	O
+colocalized	O
+to	O
+outline	O
+bile	O
+canaliculi	O
+in	O
+a	O
+continuous	O
+fashion	O
+.	O
+
+In	O
+contrast	O
+,	O
+7H6	O
+and	O
+ZO	O
+-	O
+1	O
+immunostaining	O
+was	O
+more	O
+discontinuous	O
+,	O
+outlining	O
+the	O
+bile	O
+canaliculi	O
+after	O
+BDL	O
+.	O
+
+Immunostaining	O
+for	O
+7H6	O
+,	O
+not	O
+ZO	O
+-	O
+1	O
+,	O
+decreased	O
+and	O
+predominantly	O
+appeared	O
+as	O
+discrete	O
+signals	O
+in	O
+the	O
+submembranous	O
+cytoplasm	O
+of	O
+periportal	O
+hepatocytes	O
+after	O
+BDL	O
+.	O
+
+After	O
+EE	O
+treatment	O
+,	O
+changes	O
+in	O
+immunostaining	O
+for	O
+7H6	O
+and	O
+ZO	O
+-	O
+1	O
+were	O
+similar	O
+to	O
+those	O
+seen	O
+in	O
+periportal	O
+hepatocytes	O
+after	O
+BDL	O
+,	O
+but	O
+distributed	O
+more	O
+diffusely	O
+throughout	O
+the	O
+lobule	O
+.	O
+
+This	O
+study	O
+is	O
+the	O
+first	O
+to	O
+demonstrate	O
+that	O
+impairment	O
+of	O
+hepatocyte	O
+TJs	O
+occurs	O
+heterogenously	O
+in	O
+the	O
+liver	O
+lobule	O
+after	O
+BDL	O
+and	O
+suggests	O
+that	O
+BDL	O
+and	O
+EE	O
+treatments	O
+produce	O
+different	O
+lobular	O
+distributions	O
+of	O
+increased	O
+paracellular	O
+permeability	O
+.	O
+
+Memory	O
+facilitation	O
+and	O
+stimulation	O
+of	O
+endogenous	O
+nerve	O
+growth	O
+factor	O
+synthesis	O
+by	O
+the	O
+acetylcholine	O
+releaser	O
+PG	O
+-	O
+9	O
+.	O
+
+The	O
+effects	O
+of	O
+PG	O
+-	O
+9	O
+(	O
+3alpha	O
+-	O
+tropyl	O
+2	O
+-	O
+(	O
+p	O
+-	O
+bromophenyl	O
+)	O
+propionate	O
+)	O
+,	O
+the	O
+acetylcholine	O
+releaser	O
+,	O
+on	O
+memory	O
+processes	O
+and	O
+nerve	O
+growth	O
+factor	O
+(	O
+NGF	O
+)	O
+synthesis	O
+were	O
+evaluated	O
+.	O
+
+In	O
+the	O
+mouse	O
+passive	O
+-	O
+avoidance	O
+test	O
+,	O
+PG	O
+-	O
+9	O
+(	O
+10	O
+-	O
+30	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+,	O
+administered	O
+20	O
+min	O
+before	O
+the	O
+training	O
+session	O
+,	O
+prevented	O
+amnesia	B
+induced	O
+by	O
+both	O
+the	O
+non	O
+selective	O
+antimuscarinic	O
+drug	O
+scopolamine	O
+and	O
+the	O
+M1	O
+-	O
+selective	O
+antagonist	O
+S	O
+-	O
+(	O
+-	O
+)	O
+-	O
+ET	O
+-	O
+126	O
+.	O
+
+In	O
+the	O
+same	O
+experimental	O
+conditions	O
+,	O
+PG	O
+-	O
+9	O
+(	O
+5	O
+-	O
+20	O
+microg	O
+per	O
+mouse	O
+,	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+was	O
+also	O
+able	O
+to	O
+prevent	O
+antimuscarine	O
+-	O
+induced	O
+amnesia	B
+,	O
+demonstrating	O
+a	O
+central	O
+localization	O
+of	O
+the	O
+activity	O
+.	O
+
+At	O
+the	O
+highest	O
+effective	O
+doses	O
+,	O
+PG	O
+-	O
+9	O
+did	O
+not	O
+produce	O
+any	O
+collateral	O
+symptoms	O
+as	O
+revealed	O
+by	O
+the	O
+Irwin	O
+test	O
+,	O
+and	O
+it	O
+did	O
+not	O
+modify	O
+spontaneous	O
+motility	O
+and	O
+inspection	O
+activity	O
+,	O
+as	O
+revealed	O
+by	O
+the	O
+hole	O
+-	O
+board	O
+test	O
+.	O
+
+PG	O
+-	O
+9	O
+was	O
+also	O
+able	O
+to	O
+increase	O
+the	O
+amount	O
+of	O
+NGF	O
+secreted	O
+in	O
+vitro	O
+by	O
+astrocytes	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+.	O
+
+The	O
+maximal	O
+NGF	O
+contents	O
+obtained	O
+by	O
+PG	O
+-	O
+9	O
+were	O
+17	O
+.	O
+6	O
+-	O
+fold	O
+of	O
+the	O
+control	O
+value	O
+.	O
+
+During	O
+culture	O
+,	O
+no	O
+morphological	O
+changes	O
+were	O
+found	O
+at	O
+effective	O
+concentrations	O
+of	O
+PG	O
+-	O
+9	O
+.	O
+
+The	O
+current	O
+work	O
+indicates	O
+the	O
+ability	O
+of	O
+PG	O
+-	O
+9	O
+to	O
+induce	O
+beneficial	O
+effects	O
+on	O
+cognitive	O
+processes	O
+and	O
+stimulate	O
+activity	O
+of	O
+NGF	O
+synthesis	O
+in	O
+astroglial	O
+cells	O
+.	O
+
+Therefore	O
+,	O
+PG	O
+-	O
+9	O
+could	O
+represent	O
+a	O
+potential	O
+useful	O
+drug	O
+able	O
+to	O
+improve	O
+the	O
+function	O
+of	O
+impaired	O
+cognitive	O
+processes	O
+.	O
+
+Mechanisms	O
+of	O
+FK	O
+506	O
+-	O
+induced	O
+hypertension	B
+in	O
+the	O
+rat	O
+.	O
+
+-	O
+Tacrolimus	O
+(	O
+FK	O
+506	O
+)	O
+is	O
+a	O
+powerful	O
+,	O
+widely	O
+used	O
+immunosuppressant	O
+.	O
+
+The	O
+clinical	O
+utility	O
+of	O
+FK	O
+506	O
+is	O
+complicated	O
+by	O
+substantial	O
+hypertension	B
+and	O
+nephrotoxicity	B
+.	O
+
+To	O
+clarify	O
+the	O
+mechanisms	O
+of	O
+FK	O
+506	O
+-	O
+induced	O
+hypertension	B
+,	O
+we	O
+studied	O
+the	O
+chronic	O
+effects	O
+of	O
+FK	O
+506	O
+on	O
+the	O
+synthesis	O
+of	O
+endothelin	O
+-	O
+1	O
+(	O
+ET	O
+-	O
+1	O
+)	O
+,	O
+the	O
+expression	O
+of	O
+mRNA	O
+of	O
+ET	O
+-	O
+1	O
+and	O
+endothelin	O
+-	O
+converting	O
+enzyme	O
+-	O
+1	O
+(	O
+ECE	O
+-	O
+1	O
+)	O
+,	O
+the	O
+endothelial	O
+nitric	O
+oxide	O
+synthase	O
+(	O
+eNOS	O
+)	O
+activity	O
+,	O
+and	O
+the	O
+expression	O
+of	O
+mRNA	O
+of	O
+eNOS	O
+and	O
+C	O
+-	O
+type	O
+natriuretic	O
+peptide	O
+(	O
+CNP	O
+)	O
+in	O
+rat	O
+blood	O
+vessels	O
+.	O
+
+In	O
+addition	O
+,	O
+the	O
+effect	O
+of	O
+the	O
+specific	O
+endothelin	O
+type	O
+A	O
+receptor	O
+antagonist	O
+FR	O
+139317	O
+on	O
+FK	O
+506	O
+-	O
+induced	O
+hypertension	B
+in	O
+rats	O
+was	O
+studied	O
+.	O
+
+FK	O
+506	O
+,	O
+5	O
+mg	O
+.	O
+
+kg	O
+-	O
+1	O
+.	O
+
+d	O
+-	O
+1	O
+given	O
+for	O
+4	O
+weeks	O
+,	O
+elevated	O
+blood	O
+pressure	O
+from	O
+102	O
++	O
+/	O
+-	O
+13	O
+to	O
+152	O
++	O
+/	O
+-	O
+15	O
+mm	O
+Hg	O
+and	O
+increased	O
+the	O
+synthesis	O
+of	O
+ET	O
+-	O
+1	O
+and	O
+the	O
+levels	O
+of	O
+ET	O
+-	O
+1	O
+mRNA	O
+in	O
+the	O
+mesenteric	O
+artery	O
+(	O
+240	O
+%	O
+and	O
+230	O
+%	O
+,	O
+respectively	O
+)	O
+.	O
+
+Little	O
+change	O
+was	O
+observed	O
+in	O
+the	O
+expression	O
+of	O
+ECE	O
+-	O
+1	O
+mRNA	O
+and	O
+CNP	O
+mRNA	O
+.	O
+
+FK	O
+506	O
+decreased	O
+eNOS	O
+activity	O
+and	O
+the	O
+levels	O
+of	O
+eNOS	O
+mRNA	O
+in	O
+the	O
+aorta	O
+(	O
+48	O
+%	O
+and	O
+55	O
+%	O
+,	O
+respectively	O
+)	O
+.	O
+
+The	O
+administration	O
+of	O
+FR	O
+139317	O
+(	O
+10	O
+mg	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+d	O
+-	O
+1	O
+)	O
+prevented	O
+FK	O
+506	O
+-	O
+induced	O
+hypertension	B
+in	O
+rats	O
+.	O
+
+These	O
+results	O
+indicate	O
+that	O
+FK	O
+506	O
+may	O
+increase	O
+blood	O
+pressure	O
+not	O
+only	O
+by	O
+increasing	O
+ET	O
+-	O
+1	O
+production	O
+but	O
+also	O
+by	O
+decreasing	O
+NO	O
+synthesis	O
+in	O
+the	O
+vasculature	O
+.	O
+
+22	O
+-	O
+oxacalcitriol	O
+suppresses	O
+secondary	B
+hyperparathyroidism	I
+without	O
+inducing	O
+low	B
+bone	I
+turnover	I
+in	O
+dogs	O
+with	O
+renal	B
+failure	I
+.	O
+
+BACKGROUND	O
+:	O
+Calcitriol	O
+therapy	O
+suppresses	O
+serum	O
+levels	O
+of	O
+parathyroid	O
+hormone	O
+(	O
+PTH	O
+)	O
+in	O
+patients	O
+with	O
+renal	B
+failure	I
+but	O
+has	O
+several	O
+drawbacks	O
+,	O
+including	O
+hypercalcemia	B
+and	O
+/	O
+or	O
+marked	O
+suppression	B
+of	I
+bone	I
+turnover	I
+,	O
+which	O
+may	O
+lead	O
+to	O
+adynamic	B
+bone	I
+disease	I
+.	O
+
+A	O
+new	O
+vitamin	O
+D	O
+analogue	O
+,	O
+22	O
+-	O
+oxacalcitriol	O
+(	O
+OCT	O
+)	O
+,	O
+has	O
+been	O
+shown	O
+to	O
+have	O
+promising	O
+characteristics	O
+.	O
+
+This	O
+study	O
+was	O
+undertaken	O
+to	O
+determine	O
+the	O
+effects	O
+of	O
+OCT	O
+on	O
+serum	O
+PTH	O
+levels	O
+and	O
+bone	O
+turnover	O
+in	O
+states	O
+of	O
+normal	O
+or	O
+impaired	B
+renal	I
+function	I
+.	O
+
+METHODS	O
+:	O
+Sixty	O
+dogs	O
+were	O
+either	O
+nephrectomized	O
+(	O
+Nx	O
+,	O
+N	O
+=	O
+38	O
+)	O
+or	O
+sham	O
+-	O
+operated	O
+(	O
+Sham	O
+,	O
+N	O
+=	O
+22	O
+)	O
+.	O
+
+The	O
+animals	O
+received	O
+supplemental	O
+phosphate	O
+to	O
+enhance	O
+PTH	O
+secretion	O
+.	O
+
+Fourteen	O
+weeks	O
+after	O
+the	O
+start	O
+of	O
+phosphate	O
+supplementation	O
+,	O
+half	O
+of	O
+the	O
+Nx	O
+and	O
+Sham	O
+dogs	O
+received	O
+doses	O
+of	O
+OCT	O
+(	O
+three	O
+times	O
+per	O
+week	O
+)	O
+;	O
+the	O
+other	O
+half	O
+were	O
+given	O
+vehicle	O
+for	O
+60	O
+weeks	O
+.	O
+
+Thereafter	O
+,	O
+the	O
+treatment	O
+modalities	O
+for	O
+a	O
+subset	O
+of	O
+animals	O
+were	O
+crossed	O
+over	O
+for	O
+an	O
+additional	O
+eight	O
+months	O
+.	O
+
+Biochemical	O
+and	O
+hormonal	O
+indices	O
+of	O
+calcium	O
+and	O
+bone	O
+metabolism	O
+were	O
+measured	O
+throughout	O
+the	O
+study	O
+,	O
+and	O
+bone	O
+biopsies	O
+were	O
+done	O
+at	O
+baseline	O
+,	O
+60	O
+weeks	O
+after	O
+OCT	O
+or	O
+vehicle	O
+treatment	O
+,	O
+and	O
+at	O
+the	O
+end	O
+of	O
+the	O
+crossover	O
+period	O
+.	O
+
+RESULTS	O
+:	O
+In	O
+Nx	O
+dogs	O
+,	O
+OCT	O
+significantly	O
+decreased	O
+serum	O
+PTH	O
+levels	O
+soon	O
+after	O
+the	O
+induction	O
+of	O
+renal	B
+insufficiency	I
+.	O
+
+In	O
+long	O
+-	O
+standing	O
+secondary	B
+hyperparathyroidism	I
+,	O
+OCT	O
+(	O
+0	O
+.	O
+03	O
+microg	O
+/	O
+kg	O
+)	O
+stabilized	O
+serum	O
+PTH	O
+levels	O
+during	O
+the	O
+first	O
+months	O
+.	O
+
+Serum	O
+PTH	O
+levels	O
+rose	O
+thereafter	O
+,	O
+but	O
+the	O
+rise	O
+was	O
+less	O
+pronounced	O
+compared	O
+with	O
+baseline	O
+than	O
+the	O
+rise	O
+seen	O
+in	O
+Nx	O
+control	O
+.	O
+
+These	O
+effects	O
+were	O
+accompanied	O
+by	O
+episodes	O
+of	O
+hypercalcemia	B
+and	O
+hyperphosphatemia	B
+.	O
+
+In	O
+animals	O
+with	O
+normal	O
+renal	O
+function	O
+,	O
+OCT	O
+induced	O
+a	O
+transient	O
+decrease	O
+in	O
+serum	O
+PTH	O
+levels	O
+at	O
+a	O
+dose	O
+of	O
+0	O
+.	O
+1	O
+microg	O
+/	O
+kg	O
+,	O
+which	O
+was	O
+not	O
+sustained	O
+with	O
+lowering	O
+of	O
+the	O
+doses	O
+.	O
+
+In	O
+Nx	O
+dogs	O
+,	O
+OCT	O
+reversed	O
+abnormal	O
+bone	O
+formation	O
+,	O
+such	O
+as	O
+woven	B
+osteoid	I
+and	O
+fibrosis	B
+,	O
+but	O
+did	O
+not	O
+significantly	O
+alter	O
+the	O
+level	O
+of	O
+bone	O
+turnover	O
+.	O
+
+In	O
+addition	O
+,	O
+OCT	O
+improved	O
+mineralization	O
+lag	O
+time	O
+,	O
+(	O
+that	O
+is	O
+,	O
+the	O
+rate	O
+at	O
+which	O
+osteoid	O
+mineralizes	O
+)	O
+in	O
+both	O
+Nx	O
+and	O
+Sham	O
+dogs	O
+.	O
+
+CONCLUSIONS	O
+:	O
+These	O
+results	O
+indicate	O
+that	O
+even	O
+though	O
+OCT	O
+does	O
+not	O
+completely	O
+prevent	O
+the	O
+occurrence	O
+of	O
+hypercalcemia	B
+in	O
+experimental	O
+dogs	O
+with	O
+renal	B
+insufficiency	I
+,	O
+it	O
+may	O
+be	O
+of	O
+use	O
+in	O
+the	O
+management	O
+of	O
+secondary	B
+hyperparathyroidism	I
+because	O
+it	O
+does	O
+not	O
+induce	O
+low	B
+bone	I
+turnover	I
+and	O
+,	O
+therefore	O
+,	O
+does	O
+not	O
+increase	O
+the	O
+risk	O
+of	O
+adynamic	B
+bone	I
+disease	I
+.	O
+
+Hypotension	B
+,	O
+bradycardia	B
+,	O
+and	O
+asystole	B
+after	O
+high	O
+-	O
+dose	O
+intravenous	O
+methylprednisolone	O
+in	O
+a	O
+monitored	O
+patient	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+hypotension	B
+,	O
+bradycardia	B
+,	O
+and	O
+asystole	B
+after	O
+intravenous	O
+administration	O
+of	O
+high	O
+-	O
+dose	O
+methylprednisolone	O
+in	O
+a	O
+73	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+who	O
+underwent	O
+electrocardiographic	O
+(	O
+ECG	O
+)	O
+monitoring	O
+throughout	O
+the	O
+episode	O
+.	O
+
+There	O
+was	O
+a	O
+history	O
+of	O
+ischemic	B
+cardiac	B
+disease	I
+9	O
+years	O
+earlier	O
+.	O
+
+The	O
+patient	O
+was	O
+admitted	O
+with	O
+a	O
+pulmonary	B
+-	I
+renal	I
+syndrome	I
+with	O
+hemoptysis	B
+,	O
+rapidly	O
+progressive	O
+renal	B
+failure	I
+,	O
+and	O
+hypoxemia	B
+that	O
+required	O
+mechanical	O
+ventilation	O
+in	O
+the	O
+intensive	O
+care	O
+unit	O
+.	O
+
+After	O
+receiving	O
+advanced	O
+cardiopulmonary	O
+resuscitation	O
+,	O
+the	O
+patient	O
+recovered	O
+cardiac	O
+rhythm	O
+.	O
+
+The	O
+ECG	O
+showed	O
+a	O
+junctional	O
+rhythm	O
+without	O
+ventricular	B
+arrhythmia	I
+.	O
+
+This	O
+study	O
+reviews	O
+the	O
+current	O
+proposed	O
+mechanisms	O
+of	O
+sudden	B
+death	I
+after	O
+a	O
+high	O
+dose	O
+of	O
+intravenous	O
+methylprednisolone	O
+(	O
+IVMP	O
+)	O
+.	O
+
+These	O
+mechanisms	O
+are	O
+not	O
+well	O
+understood	O
+because	O
+,	O
+in	O
+most	O
+cases	O
+,	O
+the	O
+patients	O
+were	O
+not	O
+monitored	O
+at	O
+the	O
+moment	O
+of	O
+the	O
+event	O
+.	O
+
+Rapid	O
+infusion	O
+and	O
+underlying	O
+cardiac	B
+disease	I
+were	O
+important	O
+risk	O
+factors	O
+in	O
+the	O
+case	O
+reported	O
+here	O
+,	O
+and	O
+the	O
+authors	O
+discount	O
+ventricular	B
+arrhythmia	I
+as	O
+the	O
+main	O
+mechanism	O
+.	O
+
+Worsening	O
+of	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+by	O
+motor	O
+and	O
+mental	O
+tasks	O
+.	O
+
+Ten	O
+patients	O
+who	O
+had	O
+Parkinson	B
+'	I
+s	I
+disease	I
+with	O
+disabling	O
+dyskinesia	B
+were	O
+included	O
+in	O
+this	O
+study	O
+to	O
+evaluate	O
+the	O
+role	O
+of	O
+mental	O
+(	O
+mental	O
+calculation	O
+)	O
+and	O
+motor	O
+(	O
+flexion	O
+/	O
+extension	O
+of	O
+right	O
+fingers	O
+,	O
+flexion	O
+/	O
+extension	O
+of	O
+left	O
+fingers	O
+,	O
+flexion	O
+/	O
+extension	O
+of	O
+the	O
+neck	O
+,	O
+speaking	O
+aloud	O
+)	O
+tasks	O
+on	O
+the	O
+worsening	O
+of	O
+peak	O
+-	O
+dose	O
+dyskinesia	B
+following	O
+administration	O
+of	O
+an	O
+effective	O
+single	O
+dose	O
+of	O
+apomorphine	O
+.	O
+
+Compared	O
+with	O
+the	O
+score	O
+at	O
+rest	O
+(	O
+1	O
+.	O
+3	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+)	O
+,	O
+a	O
+significant	O
+aggravation	O
+of	O
+the	O
+dyskinesia	B
+score	O
+was	O
+observed	O
+during	O
+speaking	O
+aloud	O
+(	O
+5	O
+.	O
+2	O
++	O
+/	O
+-	O
+1	O
+.	O
+1	O
+,	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+,	O
+movements	O
+of	O
+right	O
+(	O
+4	O
+.	O
+5	O
++	O
+/	O
+-	O
+1	O
+.	O
+0	O
+,	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+and	O
+left	O
+(	O
+3	O
+.	O
+7	O
++	O
+/	O
+-	O
+0	O
+.	O
+8	O
+,	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+fingers	O
+,	O
+movements	O
+of	O
+the	O
+neck	O
+(	O
+5	O
+.	O
+1	O
++	O
+/	O
+-	O
+1	O
+.	O
+0	O
+,	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+,	O
+and	O
+mental	O
+calculation	O
+(	O
+3	O
+.	O
+1	O
++	O
+/	O
+-	O
+1	O
+.	O
+0	O
+,	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+activation	O
+tasks	O
+such	O
+as	O
+"	O
+speaking	O
+aloud	O
+"	O
+could	O
+be	O
+used	O
+for	O
+objective	O
+assessment	O
+of	O
+dyskinesia	B
+severity	O
+.	O
+
+Urine	O
+N	O
+-	O
+acetyl	O
+-	O
+beta	O
+-	O
+D	O
+-	O
+glucosaminidase	O
+-	O
+-	O
+a	O
+marker	O
+of	O
+tubular	O
+damage	O
+?	O
+
+BACKGROUND	O
+:	O
+Although	O
+an	O
+indicator	O
+of	O
+renal	B
+tubular	I
+dysfunction	I
+,	O
+an	O
+increased	O
+urinary	O
+N	O
+-	O
+acetyl	O
+-	O
+beta	O
+-	O
+D	O
+-	O
+glucosaminidase	O
+(	O
+NAG	O
+)	O
+activity	O
+might	O
+reflect	O
+increased	O
+lysosomal	O
+activity	O
+in	O
+renal	O
+tubular	O
+cells	O
+.	O
+
+METHODS	O
+:	O
+Puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+)	O
+was	O
+administered	O
+to	O
+Sprague	O
+Dawley	O
+rats	O
+to	O
+induce	O
+proteinuria	B
+.	O
+
+Total	O
+protein	O
+,	O
+albumin	O
+,	O
+NAG	O
+activity	O
+and	O
+protein	O
+electrophoretic	O
+pattern	O
+were	O
+assessed	O
+in	O
+daily	O
+urine	O
+samples	O
+for	O
+33	O
+days	O
+.	O
+
+The	O
+morphological	O
+appearance	O
+of	O
+the	O
+kidneys	O
+was	O
+examined	O
+on	O
+days	O
+three	O
+,	O
+four	O
+,	O
+six	O
+,	O
+eight	O
+and	O
+thirty	O
+three	O
+and	O
+the	O
+NAG	O
+isoenzyme	O
+patterns	O
+on	O
+days	O
+zero	O
+,	O
+four	O
+,	O
+eight	O
+and	O
+thirty	O
+three	O
+.	O
+
+RESULTS	O
+:	O
+Following	O
+intravenous	O
+PAN	O
+urine	O
+volume	O
+and	O
+urine	O
+NAG	O
+activity	O
+increased	O
+significantly	O
+by	O
+day	O
+two	O
+,	O
+but	O
+returned	O
+to	O
+normal	O
+by	O
+day	O
+four	O
+.	O
+
+After	O
+day	O
+four	O
+all	O
+treated	O
+animals	O
+exhibited	O
+a	O
+marked	O
+rise	O
+in	O
+urine	O
+albumin	O
+,	O
+total	O
+protein	O
+excretion	O
+and	O
+NAG	O
+activity	O
+.	O
+
+Electrophoresis	O
+showed	O
+a	O
+generalised	O
+increase	O
+in	O
+middle	O
+and	O
+high	O
+molecular	O
+weight	O
+urine	O
+proteins	O
+from	O
+day	O
+four	O
+onwards	O
+.	O
+
+Protein	O
+droplets	O
+first	O
+appeared	O
+prominent	O
+in	O
+tubular	O
+cells	O
+on	O
+day	O
+four	O
+.	O
+
+Peak	O
+urine	O
+NAG	O
+activity	O
+and	O
+a	O
+change	O
+in	O
+NAG	O
+isoenzyme	O
+pattern	O
+coincided	O
+with	O
+both	O
+the	O
+peak	O
+proteinuria	B
+and	O
+the	O
+reduction	O
+in	O
+intracellular	O
+protein	O
+and	O
+NAG	O
+droplets	O
+(	O
+day	O
+six	O
+onwards	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+This	O
+animal	O
+model	O
+demonstrates	O
+that	O
+an	O
+increase	O
+in	O
+lysosomal	O
+turnover	O
+and	O
+hence	O
+urine	O
+NAG	O
+activity	O
+,	O
+occurs	O
+when	O
+increased	O
+protein	O
+is	O
+presented	O
+to	O
+the	O
+tubular	O
+cells	O
+.	O
+
+Urine	O
+NAG	O
+activity	O
+is	O
+thus	O
+a	O
+measure	O
+of	O
+altered	O
+function	O
+in	O
+the	O
+renal	O
+tubules	O
+and	O
+not	O
+simply	O
+an	O
+indicator	O
+of	O
+damage	O
+.	O
+
+Cauda	B
+equina	I
+syndrome	I
+after	O
+spinal	O
+anaesthesia	O
+with	O
+hyperbaric	O
+5	O
+%	O
+lignocaine	O
+:	O
+a	O
+review	O
+of	O
+six	O
+cases	O
+of	O
+cauda	B
+equina	I
+syndrome	I
+reported	O
+to	O
+the	O
+Swedish	O
+Pharmaceutical	O
+Insurance	O
+1993	O
+-	O
+1997	O
+.	O
+
+Six	O
+cases	O
+of	O
+cauda	B
+equina	I
+syndrome	I
+with	O
+varying	O
+severity	O
+were	O
+reported	O
+to	O
+the	O
+Swedish	O
+Pharmaceutical	O
+Insurance	O
+during	O
+the	O
+period	O
+1993	O
+-	O
+1997	O
+.	O
+
+All	O
+were	O
+associated	O
+with	O
+spinal	O
+anaesthesia	O
+using	O
+hyperbaric	O
+5	O
+%	O
+lignocaine	O
+.	O
+
+Five	O
+cases	O
+had	O
+single	O
+-	O
+shot	O
+spinal	O
+anaesthesia	O
+and	O
+one	O
+had	O
+a	O
+repeat	O
+spinal	O
+anaesthetic	O
+due	O
+to	O
+inadequate	O
+block	O
+.	O
+
+The	O
+dose	O
+of	O
+hyperbaric	O
+5	O
+%	O
+lignocaine	O
+administered	O
+ranged	O
+from	O
+60	O
+to	O
+120	O
+mg	O
+.	O
+
+Three	O
+of	O
+the	O
+cases	O
+were	O
+most	O
+likely	O
+caused	O
+by	O
+direct	O
+neurotoxicity	B
+of	O
+hyperbaric	O
+5	O
+%	O
+lignocaine	O
+.	O
+
+In	O
+the	O
+other	O
+3	O
+cases	O
+,	O
+direct	O
+neurotoxicity	B
+was	O
+also	O
+probable	O
+,	O
+but	O
+unfortunately	O
+radiological	O
+investigations	O
+were	O
+not	O
+done	O
+to	O
+definitely	O
+exclude	O
+a	O
+compressive	O
+aetiology	O
+.	O
+
+All	O
+cases	O
+sustained	O
+permanent	O
+neurological	B
+deficits	I
+.	O
+
+We	O
+recommend	O
+that	O
+hyperbaric	O
+lignocaine	O
+should	O
+be	O
+administered	O
+in	O
+concentrations	O
+not	O
+greater	O
+than	O
+2	O
+%	O
+and	O
+at	O
+a	O
+total	O
+dose	O
+preferably	O
+not	O
+exceeding	O
+60	O
+mg	O
+.	O
+
+Systemic	O
+toxicity	B
+following	O
+administration	O
+of	O
+sirolimus	O
+(	O
+formerly	O
+rapamycin	O
+)	O
+for	O
+psoriasis	B
+:	O
+association	O
+of	O
+capillary	B
+leak	I
+syndrome	I
+with	O
+apoptosis	O
+of	O
+lesional	O
+lymphocytes	O
+.	O
+
+BACKGROUND	O
+:	O
+Sirolimus	O
+(	O
+formerly	O
+rapamycin	O
+)	O
+is	O
+an	O
+immunosuppressive	O
+agent	O
+that	O
+interferes	O
+with	O
+T	O
+-	O
+cell	O
+activation	O
+.	O
+
+After	O
+2	O
+individuals	O
+with	O
+psoriasis	B
+developed	O
+a	O
+capillary	B
+leak	I
+syndrome	I
+following	O
+treatment	O
+with	O
+oral	O
+sirolimus	O
+lesional	O
+skin	O
+cells	O
+and	O
+activated	O
+peripheral	O
+blood	O
+cells	O
+were	O
+analyzed	O
+for	O
+induction	O
+of	O
+apoptosis	O
+.	O
+
+OBSERVATIONS	O
+:	O
+A	O
+keratome	O
+skin	O
+specimen	O
+from	O
+1	O
+patient	O
+with	O
+sirolimus	O
+-	O
+induced	O
+capillary	B
+leak	I
+syndrome	I
+had	O
+a	O
+2	O
+.	O
+3	O
+-	O
+fold	O
+increase	O
+in	O
+percentage	O
+of	O
+apoptotic	O
+cells	O
+(	O
+to	O
+48	O
+%	O
+)	O
+compared	O
+with	O
+an	O
+unaffected	O
+sirolimus	O
+-	O
+treated	O
+patient	O
+with	O
+psoriasis	B
+(	O
+21	O
+%	O
+)	O
+.	O
+
+Activated	O
+peripheral	O
+blood	O
+T	O
+cells	O
+from	O
+patients	O
+with	O
+psoriasis	B
+tended	O
+to	O
+exhibit	O
+greater	O
+spontaneous	O
+or	O
+dexamethasone	O
+-	O
+induced	O
+apoptosis	O
+than	O
+did	O
+normal	O
+T	O
+cells	O
+,	O
+particularly	O
+in	O
+the	O
+presence	O
+of	O
+sirolimus	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Severe	O
+adverse	O
+effects	O
+of	O
+sirolimus	O
+include	O
+fever	B
+,	O
+anemia	B
+,	O
+and	O
+capillary	B
+leak	I
+syndrome	I
+.	O
+
+These	O
+symptoms	O
+may	O
+be	O
+the	O
+result	O
+of	O
+drug	O
+-	O
+induced	O
+apoptosis	O
+of	O
+lesional	O
+leukocytes	O
+,	O
+especially	O
+activated	O
+T	O
+lymphocytes	O
+,	O
+and	O
+possibly	O
+release	O
+of	O
+inflammatory	O
+mediators	O
+.	O
+
+Because	O
+patients	O
+with	O
+severe	O
+psoriasis	B
+may	O
+develop	O
+capillary	B
+leak	I
+from	O
+various	O
+systemic	O
+therapies	O
+,	O
+clinical	O
+monitoring	O
+is	O
+advisable	O
+for	O
+patients	O
+with	O
+inflammatory	B
+diseases	I
+who	O
+are	O
+treated	O
+with	O
+immune	O
+modulators	O
+.	O
+
+Effect	O
+of	O
+lithium	O
+maintenance	O
+therapy	O
+on	O
+thyroid	O
+and	O
+parathyroid	O
+function	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+assess	O
+changes	O
+induced	O
+by	O
+lithium	O
+maintenance	O
+therapy	O
+on	O
+the	O
+incidence	O
+of	O
+thyroid	O
+,	O
+parathyroid	O
+and	O
+ion	O
+alterations	O
+.	O
+
+These	O
+were	O
+evaluated	O
+with	O
+respect	O
+to	O
+the	O
+duration	O
+of	O
+lithium	O
+therapy	O
+,	O
+age	O
+,	O
+sex	O
+,	O
+and	O
+family	O
+history	O
+(	O
+whether	O
+or	O
+not	O
+the	O
+patient	O
+had	O
+a	O
+first	O
+-	O
+degree	O
+relative	O
+with	O
+thyroid	B
+disease	I
+)	O
+.	O
+
+DESIGN	O
+:	O
+Prospective	O
+study	O
+.	O
+
+SETTING	O
+:	O
+Affective	O
+Disorders	O
+Clinic	O
+at	O
+St	O
+.	O
+
+Mary	O
+'	O
+s	O
+Hospital	O
+,	O
+Montreal	O
+.	O
+
+PATIENTS	O
+:	O
+One	O
+hundred	O
+and	O
+one	O
+patients	O
+(	O
+28	O
+men	O
+and	O
+73	O
+women	O
+)	O
+with	O
+bipolar	B
+disorder	I
+receiving	O
+lithium	O
+maintenance	O
+therapy	O
+ranging	O
+from	O
+1	O
+year	O
+'	O
+s	O
+to	O
+32	O
+years	O
+'	O
+duration	O
+.	O
+
+The	O
+control	O
+group	O
+consisted	O
+of	O
+82	O
+patients	O
+with	O
+no	O
+psychiatric	B
+or	O
+endocrinological	O
+diagnoses	O
+from	O
+the	O
+hospital	O
+'	O
+s	O
+out	O
+-	O
+patient	O
+clinics	O
+.	O
+
+OUTCOME	O
+MEASURES	O
+:	O
+Laboratory	O
+analyses	O
+of	O
+calcium	O
+,	O
+magnesium	O
+and	O
+thyroid	O
+-	O
+stimulating	O
+hormone	O
+levels	O
+performed	O
+before	O
+beginning	O
+lithium	O
+therapy	O
+and	O
+at	O
+biannual	O
+follow	O
+-	O
+up	O
+.	O
+
+RESULTS	O
+:	O
+Hypothyroidism	B
+developed	O
+in	O
+40	O
+patients	O
+,	O
+excluding	O
+8	O
+patients	O
+who	O
+were	O
+hypothyroid	B
+at	O
+baseline	O
+.	O
+
+All	O
+patients	O
+having	O
+first	O
+-	O
+degree	O
+relatives	O
+affected	O
+by	O
+thyroid	B
+illness	I
+had	O
+accelerated	O
+onset	O
+of	O
+hypothyroidism	B
+(	O
+3	O
+.	O
+7	O
+years	O
+after	O
+onset	O
+of	O
+lithium	O
+therapy	O
+)	O
+compared	O
+with	O
+patients	O
+without	O
+a	O
+family	O
+history	O
+(	O
+8	O
+.	O
+6	O
+years	O
+after	O
+onset	O
+of	O
+lithium	O
+therapy	O
+)	O
+.	O
+
+Women	O
+over	O
+60	O
+years	O
+of	O
+age	O
+were	O
+more	O
+often	O
+affected	O
+by	O
+hypothyroidism	B
+than	O
+women	O
+under	O
+60	O
+years	O
+of	O
+age	O
+(	O
+34	O
+.	O
+6	O
+%	O
+versus	O
+31	O
+.	O
+9	O
+%	O
+)	O
+.	O
+
+Magnesium	O
+levels	O
+in	O
+patients	O
+on	O
+lithium	O
+treatment	O
+were	O
+unchanged	O
+from	O
+baseline	O
+levels	O
+.	O
+
+After	O
+lithium	O
+treatment	O
+,	O
+calcium	O
+levels	O
+were	O
+higher	O
+than	O
+either	O
+baseline	O
+levels	O
+or	O
+control	O
+levels	O
+.	O
+
+Thus	O
+,	O
+lithium	O
+treatment	O
+counteracted	O
+the	O
+decrease	O
+in	O
+plasma	O
+calcium	O
+levels	O
+associated	O
+with	O
+aging	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Familial	O
+thyroid	B
+illness	I
+is	O
+a	O
+risk	O
+factor	O
+for	O
+hypothyroidism	B
+and	O
+hypercalcemia	B
+during	O
+lithium	O
+therapy	O
+.	O
+
+Severe	O
+immune	O
+hemolytic	B
+anemia	I
+associated	O
+with	O
+prophylactic	O
+use	O
+of	O
+cefotetan	O
+in	O
+obstetric	O
+and	O
+gynecologic	O
+procedures	O
+.	O
+
+Second	O
+-	O
+and	O
+third	O
+-	O
+generation	O
+cephalosporins	O
+,	O
+especially	O
+cefotetan	O
+,	O
+are	O
+increasingly	O
+associated	O
+with	O
+severe	O
+,	O
+sometimes	O
+fatal	O
+immune	O
+hemolytic	B
+anemia	I
+.	O
+
+We	O
+noticed	O
+that	O
+10	O
+of	O
+our	O
+35	O
+cases	O
+of	O
+cefotetan	O
+-	O
+induced	O
+hemolytic	B
+anemias	I
+were	O
+in	O
+patients	O
+who	O
+had	O
+received	O
+cefotetan	O
+prophylactically	O
+for	O
+obstetric	O
+and	O
+gynecologic	O
+procedures	O
+.	O
+
+Eight	O
+of	O
+these	O
+cases	O
+of	O
+severe	O
+immune	O
+hemolytic	B
+anemia	I
+are	O
+described	O
+.	O
+
+Effects	O
+of	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+on	O
+hemostasis	O
+in	O
+patients	O
+with	O
+aneurysmal	B
+subarachnoid	I
+hemorrhage	I
+.	O
+
+Platelet	O
+function	O
+is	O
+impaired	O
+by	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+(	O
+NSAIDs	O
+)	O
+with	O
+prominent	O
+anti	O
+-	O
+inflammatory	O
+properties	O
+.	O
+
+Their	O
+safety	O
+in	O
+patients	O
+undergoing	O
+intracranial	O
+surgery	O
+is	O
+under	O
+debate	O
+.	O
+
+Patients	O
+with	O
+aneurysmal	B
+subarachnoid	I
+hemorrhage	I
+(	O
+SAH	B
+)	O
+were	O
+randomized	O
+to	O
+receive	O
+either	O
+ketoprofen	O
+,	O
+100	O
+mg	O
+,	O
+three	O
+times	O
+a	O
+day	O
+(	O
+ketoprofen	O
+group	O
+,	O
+n	O
+=	O
+9	O
+)	O
+or	O
+a	O
+weak	O
+NSAID	O
+,	O
+acetaminophen	O
+,	O
+1	O
+g	O
+,	O
+three	O
+times	O
+a	O
+day	O
+(	O
+acetaminophen	O
+group	O
+,	O
+n	O
+=	O
+9	O
+)	O
+starting	O
+immediately	O
+after	O
+the	O
+diagnosis	O
+of	O
+aneurysmal	B
+SAH	B
+.	O
+
+Treatment	O
+was	O
+continued	O
+for	O
+3	O
+days	O
+postoperatively	O
+.	O
+
+Test	O
+blood	O
+samples	O
+were	O
+taken	O
+before	O
+treatment	O
+and	O
+surgery	O
+as	O
+well	O
+as	O
+on	O
+the	O
+first	O
+,	O
+third	O
+,	O
+and	O
+fifth	O
+postoperative	O
+mornings	O
+.	O
+
+Maximal	O
+platelet	B
+aggregation	I
+induced	O
+by	O
+6	O
+microM	O
+of	O
+adenosine	O
+diphosphate	O
+decreased	O
+after	O
+administration	O
+of	O
+ketoprofen	O
+.	O
+
+Aggregation	O
+was	O
+lower	O
+(	O
+P	O
+<	O
+.	O
+05	O
+)	O
+in	O
+the	O
+ketoprofen	O
+group	O
+than	O
+in	O
+the	O
+acetaminophen	O
+group	O
+just	O
+before	O
+surgery	O
+and	O
+on	O
+the	O
+third	O
+postoperative	O
+day	O
+.	O
+
+In	O
+contrast	O
+,	O
+maximal	O
+platelet	B
+aggregation	I
+increased	O
+in	O
+the	O
+acetaminophen	O
+group	O
+on	O
+the	O
+third	O
+postoperative	O
+day	O
+as	O
+compared	O
+with	O
+the	O
+pretreatment	O
+platelet	B
+aggregation	I
+results	O
+(	O
+P	O
+<	O
+.	O
+05	O
+)	O
+.	O
+
+One	O
+patient	O
+in	O
+the	O
+ketoprofen	O
+group	O
+developed	O
+a	O
+postoperative	O
+intracranial	O
+hematoma	B
+.	O
+
+Coagulation	O
+(	O
+prothrombin	O
+time	O
+[	O
+PT	O
+]	O
+,	O
+activated	O
+partial	O
+thromboplastin	O
+time	O
+[	O
+APPT	O
+]	O
+,	O
+fibrinogen	O
+concentration	O
+,	O
+and	O
+antithrombin	O
+III	O
+[	O
+AT	O
+III	O
+]	O
+)	O
+was	O
+comparable	O
+between	O
+the	O
+two	O
+groups	O
+.	O
+
+Ketoprofen	O
+but	O
+not	O
+acetaminophen	O
+impaired	O
+platelet	O
+function	O
+in	O
+patients	O
+with	O
+SAH	B
+.	O
+
+If	O
+ketoprofen	O
+is	O
+used	O
+before	O
+surgery	O
+on	O
+cerebral	O
+artery	B
+aneurysms	I
+,	O
+it	O
+may	O
+pose	O
+an	O
+additional	O
+risk	O
+factor	O
+for	O
+hemorrhage	B
+.	O
+
+Nitric	O
+oxide	O
+synthase	O
+expression	O
+in	O
+the	O
+course	O
+of	O
+lead	O
+-	O
+induced	O
+hypertension	B
+.	O
+
+We	O
+recently	O
+showed	O
+elevated	O
+reactive	O
+oxygen	O
+species	O
+(	O
+ROS	O
+)	O
+,	O
+reduced	O
+urinary	O
+excretion	O
+of	O
+NO	O
+metabolites	O
+(	O
+NOx	O
+)	O
+,	O
+and	O
+increased	O
+NO	O
+sequestration	O
+as	O
+nitrotyrosine	O
+in	O
+various	O
+tissues	O
+in	O
+rats	O
+with	O
+lead	O
+-	O
+induced	O
+hypertension	B
+.	O
+
+This	O
+study	O
+was	O
+designed	O
+to	O
+discern	O
+whether	O
+the	O
+reduction	O
+in	O
+urinary	O
+NOx	O
+in	O
+lead	O
+-	O
+induced	O
+hypertension	B
+is	O
+,	O
+in	O
+part	O
+,	O
+due	O
+to	O
+depressed	O
+NO	O
+synthase	O
+(	O
+NOS	O
+)	O
+expression	O
+.	O
+
+Male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+were	O
+randomly	O
+assigned	O
+to	O
+a	O
+lead	O
+-	O
+treated	O
+group	O
+(	O
+given	O
+lead	O
+acetate	O
+,	O
+100	O
+ppm	O
+,	O
+in	O
+drinking	O
+water	O
+and	O
+regular	O
+rat	O
+chow	O
+)	O
+,	O
+a	O
+group	O
+given	O
+lead	O
+and	O
+vitamin	O
+E	O
+-	O
+fortified	O
+chow	O
+,	O
+or	O
+a	O
+normal	O
+control	O
+group	O
+given	O
+either	O
+regular	O
+food	O
+and	O
+water	O
+or	O
+vitamin	O
+E	O
+-	O
+fortified	O
+food	O
+for	O
+12	O
+weeks	O
+.	O
+
+Tail	O
+blood	O
+pressure	O
+,	O
+urinary	O
+NOx	O
+excretion	O
+,	O
+plasma	O
+malondialdehyde	O
+(	O
+MDA	O
+)	O
+,	O
+and	O
+endothelial	O
+and	O
+inducible	O
+NOS	O
+(	O
+eNOS	O
+and	O
+iNOS	O
+)	O
+isotypes	O
+in	O
+the	O
+aorta	O
+and	O
+kidney	O
+were	O
+measured	O
+.	O
+
+The	O
+lead	O
+-	O
+treated	O
+group	O
+exhibited	O
+a	O
+rise	O
+in	O
+blood	O
+pressure	O
+and	O
+plasma	O
+MDA	O
+concentration	O
+,	O
+a	O
+fall	O
+in	O
+urinary	O
+NOx	O
+excretion	O
+,	O
+and	O
+a	O
+paradoxical	O
+rise	O
+in	O
+vascular	O
+and	O
+renal	O
+tissue	O
+eNOS	O
+and	O
+iNOS	O
+expression	O
+.	O
+
+Vitamin	O
+E	O
+supplementation	O
+ameliorated	O
+hypertension	B
+,	O
+lowered	O
+plasma	O
+MDA	O
+concentration	O
+,	O
+and	O
+raised	O
+urinary	O
+NOx	O
+excretion	O
+while	O
+significantly	O
+lowering	O
+vascular	O
+,	O
+but	O
+not	O
+renal	O
+,	O
+tissue	O
+eNOS	O
+and	O
+iNOS	O
+expression	O
+.	O
+
+Vitamin	O
+E	O
+supplementation	O
+had	O
+no	O
+effect	O
+on	O
+either	O
+blood	O
+pressure	O
+,	O
+plasma	O
+MDA	O
+,	O
+or	O
+NOS	O
+expression	O
+in	O
+the	O
+control	O
+group	O
+.	O
+
+The	O
+study	O
+also	O
+revealed	O
+significant	O
+inhibition	O
+of	O
+NOS	O
+enzymatic	O
+activity	O
+by	O
+lead	O
+in	O
+cell	O
+-	O
+free	O
+preparations	O
+.	O
+
+In	O
+conclusion	O
+,	O
+lead	O
+-	O
+induced	O
+hypertension	B
+in	O
+this	O
+model	O
+was	O
+associated	O
+with	O
+a	O
+compensatory	O
+upregulation	O
+of	O
+renal	O
+and	O
+vascular	O
+eNOS	O
+and	O
+iNOS	O
+expression	O
+.	O
+
+This	O
+is	O
+,	O
+in	O
+part	O
+,	O
+due	O
+to	O
+ROS	O
+-	O
+mediated	O
+NO	O
+inactivation	O
+,	O
+lead	O
+-	O
+associated	O
+inhibition	O
+of	O
+NOS	O
+activity	O
+,	O
+and	O
+perhaps	O
+stimulatory	O
+actions	O
+of	O
+increased	O
+shear	O
+stress	O
+associated	O
+with	O
+hypertension	B
+.	O
+
+Glyceryl	O
+trinitrate	O
+induces	O
+attacks	O
+of	O
+migraine	B
+without	I
+aura	I
+in	O
+sufferers	O
+of	O
+migraine	B
+with	I
+aura	I
+.	O
+
+Migraine	B
+with	I
+aura	I
+and	O
+migraine	B
+without	I
+aura	I
+have	O
+the	O
+same	O
+pain	B
+phase	O
+,	O
+thus	O
+indicating	O
+that	O
+migraine	B
+with	I
+aura	I
+and	O
+migraine	B
+without	I
+aura	I
+share	O
+a	O
+common	O
+pathway	O
+of	O
+nociception	O
+.	O
+
+In	O
+recent	O
+years	O
+,	O
+increasing	O
+evidence	O
+has	O
+suggested	O
+that	O
+the	O
+messenger	O
+molecule	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+is	O
+involved	O
+in	O
+pain	B
+mechanisms	O
+of	O
+migraine	B
+without	I
+aura	I
+.	O
+
+In	O
+order	O
+to	O
+clarify	O
+whether	O
+the	O
+same	O
+is	O
+true	O
+for	O
+migraine	B
+with	I
+aura	I
+,	O
+in	O
+the	O
+present	O
+study	O
+we	O
+examined	O
+the	O
+headache	B
+response	O
+to	O
+intravenous	O
+infusion	O
+of	O
+glyceryl	O
+trinitrate	O
+(	O
+GTN	O
+)	O
+(	O
+0	O
+.	O
+5	O
+microg	O
+/	O
+kg	O
+/	O
+min	O
+for	O
+20	O
+min	O
+)	O
+in	O
+12	O
+sufferers	O
+of	O
+migraine	B
+with	I
+aura	I
+.	O
+
+The	O
+specific	O
+aim	O
+was	O
+to	O
+elucidate	O
+whether	O
+an	O
+aura	O
+and	O
+/	O
+or	O
+an	O
+attack	O
+of	O
+migraine	B
+without	I
+aura	I
+could	O
+be	O
+induced	O
+.	O
+
+Fourteen	O
+healthy	O
+subjects	O
+served	O
+as	O
+controls	O
+.	O
+
+Aura	O
+symptoms	O
+were	O
+not	O
+elicited	O
+in	O
+any	O
+subject	O
+.	O
+
+Headache	B
+was	O
+more	O
+severe	O
+in	O
+migraineurs	B
+than	O
+in	O
+the	O
+controls	O
+during	O
+and	O
+immediately	O
+after	O
+GTN	O
+infusion	O
+(	O
+p	O
+=	O
+0	O
+.	O
+037	O
+)	O
+as	O
+well	O
+as	O
+during	O
+the	O
+following	O
+11	O
+h	O
+(	O
+p	O
+=	O
+0	O
+.	O
+008	O
+)	O
+.	O
+
+In	O
+the	O
+controls	O
+,	O
+the	O
+GTN	O
+-	O
+induced	O
+headache	B
+gradually	O
+disappeared	O
+,	O
+whereas	O
+in	O
+migraineurs	B
+peak	O
+headache	B
+intensity	O
+occurred	O
+at	O
+a	O
+mean	O
+time	O
+of	O
+240	O
+min	O
+post	O
+-	O
+infusion	O
+.	O
+
+At	O
+this	O
+time	O
+the	O
+induced	O
+headache	B
+in	O
+6	O
+of	O
+12	O
+migraineurs	B
+fulfilled	O
+the	O
+diagnostic	O
+criteria	O
+for	O
+migraine	B
+without	I
+aura	I
+of	O
+the	O
+International	O
+Headache	B
+Society	O
+.	O
+
+The	O
+results	O
+therefore	O
+suggest	O
+that	O
+NO	O
+is	O
+involved	O
+in	O
+the	O
+pain	B
+mechanisms	O
+of	O
+migraine	B
+with	I
+aura	I
+.	O
+
+Since	O
+cortical	O
+spreading	O
+depression	B
+has	O
+been	O
+shown	O
+to	O
+liberate	O
+NO	O
+in	O
+animals	O
+,	O
+this	O
+finding	O
+may	O
+help	O
+our	O
+understanding	O
+of	O
+the	O
+coupling	O
+between	O
+cortical	O
+spreading	O
+depression	B
+and	O
+headache	B
+in	O
+migraine	B
+with	I
+aura	I
+.	O
+
+Rapid	O
+reversal	O
+of	O
+life	O
+-	O
+threatening	O
+diltiazem	O
+-	O
+induced	O
+tetany	B
+with	O
+calcium	O
+chloride	O
+.	O
+
+We	O
+describe	O
+a	O
+patient	O
+who	O
+developed	O
+tetany	B
+with	O
+sudden	O
+respiratory	B
+arrest	I
+after	O
+the	O
+infusion	O
+of	O
+intravenous	O
+diltiazem	O
+.	O
+
+The	O
+administration	O
+of	O
+calcium	O
+chloride	O
+rapidly	O
+resolved	O
+the	O
+patient	O
+'	O
+s	O
+tetany	B
+with	O
+prompt	O
+recovery	O
+of	O
+respiratory	O
+function	O
+,	O
+averting	O
+the	O
+need	O
+for	O
+more	O
+aggressive	O
+airway	O
+management	O
+and	O
+ventilatory	O
+support	O
+.	O
+
+The	O
+emergency	O
+physician	O
+should	O
+be	O
+aware	O
+that	O
+life	O
+-	O
+threatening	O
+tetany	B
+may	O
+accompany	O
+the	O
+administration	O
+of	O
+intravenous	O
+diltiazem	O
+and	O
+that	O
+calcium	O
+chloride	O
+may	O
+be	O
+a	O
+rapid	O
+and	O
+effective	O
+remedy	O
+.	O
+
+Predictors	O
+of	O
+decreased	B
+renal	I
+function	I
+in	O
+patients	O
+with	O
+heart	B
+failure	I
+during	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitor	O
+therapy	O
+:	O
+results	O
+from	O
+the	O
+studies	O
+of	O
+left	B
+ventricular	I
+dysfunction	I
+(	O
+SOLVD	O
+)	O
+
+BACKGROUND	O
+:	O
+Although	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitor	O
+therapy	O
+reduces	O
+mortality	O
+rates	O
+in	O
+patients	O
+with	O
+congestive	B
+heart	I
+failure	I
+(	O
+CHF	B
+)	O
+,	O
+it	O
+may	O
+also	O
+cause	O
+decreased	B
+renal	I
+function	I
+.	O
+
+Little	O
+information	O
+is	O
+available	O
+to	O
+predict	O
+which	O
+patients	O
+are	O
+at	O
+highest	O
+risk	O
+for	O
+this	O
+complication	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+quantify	O
+specific	O
+clinical	O
+predictors	O
+of	O
+reduction	B
+in	I
+renal	I
+function	I
+in	O
+patients	O
+with	O
+CHF	B
+who	O
+are	O
+prescribed	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitor	O
+therapy	O
+.	O
+
+METHOD	O
+:	O
+We	O
+analyzed	O
+data	O
+from	O
+the	O
+Studies	O
+of	O
+Left	B
+Ventricular	I
+Dysfunction	I
+(	O
+SOLVD	O
+)	O
+,	O
+a	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+trial	O
+of	O
+enalapril	O
+for	O
+the	O
+treatment	O
+of	O
+CHF	B
+.	O
+
+There	O
+were	O
+3379	O
+patients	O
+randomly	O
+assigned	O
+to	O
+enalapril	O
+with	O
+a	O
+median	O
+follow	O
+-	O
+up	O
+of	O
+974	O
+days	O
+and	O
+3379	O
+patients	O
+randomly	O
+assigned	O
+to	O
+placebo	O
+with	O
+a	O
+mean	O
+follow	O
+-	O
+up	O
+of	O
+967	O
+days	O
+.	O
+
+Decreased	B
+renal	I
+function	I
+was	O
+defined	O
+as	O
+a	O
+rise	O
+in	O
+serum	O
+creatinine	O
+>	O
+/	O
+=	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+dL	O
+(	O
+44	O
+micromol	O
+/	O
+L	O
+)	O
+from	O
+baseline	O
+.	O
+
+We	O
+used	O
+time	O
+-	O
+to	O
+-	O
+event	O
+analysis	O
+to	O
+identify	O
+potential	O
+predictors	O
+of	O
+decrease	O
+in	O
+renal	O
+function	O
+including	O
+age	O
+,	O
+baseline	O
+ejection	O
+fraction	O
+,	O
+baseline	O
+creatinine	O
+,	O
+low	O
+systolic	O
+blood	O
+pressure	O
+(	O
+<	O
+100	O
+mm	O
+Hg	O
+)	O
+,	O
+history	O
+of	O
+hypertension	B
+,	O
+diabetes	B
+,	O
+and	O
+use	O
+of	O
+antiplatelet	O
+,	O
+diuretic	O
+,	O
+and	O
+beta	O
+-	O
+blocker	O
+therapy	O
+.	O
+
+RESULTS	O
+:	O
+Patients	O
+randomly	O
+assigned	O
+to	O
+enalapril	O
+had	O
+a	O
+33	O
+%	O
+greater	O
+likelihood	O
+of	O
+decreased	B
+renal	I
+function	I
+than	O
+controls	O
+(	O
+P	O
+=	O
+.	O
+003	O
+)	O
+.	O
+
+By	O
+multivariate	O
+analysis	O
+,	O
+in	O
+both	O
+the	O
+placebo	O
+and	O
+enalapril	O
+groups	O
+older	O
+age	O
+,	O
+diuretic	O
+therapy	O
+,	O
+and	O
+diabetes	B
+were	O
+associated	O
+with	O
+decreased	B
+renal	I
+function	I
+,	O
+whereas	O
+beta	O
+-	O
+blocker	O
+therapy	O
+and	O
+higher	O
+ejection	O
+fraction	O
+were	O
+renoprotective	O
+.	O
+
+Older	O
+age	O
+was	O
+associated	O
+with	O
+a	O
+greater	O
+risk	O
+of	O
+developing	O
+decreased	B
+renal	I
+function	I
+in	O
+both	O
+groups	O
+,	O
+but	O
+significantly	O
+more	O
+so	O
+in	O
+the	O
+enalapril	O
+group	O
+(	O
+enalapril	O
+:	O
+risk	O
+ratio	O
+[	O
+RR	O
+]	O
+1	O
+.	O
+42	O
+per	O
+10	O
+years	O
+,	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+1	O
+.	O
+32	O
+-	O
+1	O
+.	O
+52	O
+with	O
+enalapril	O
+;	O
+placebo	O
+:	O
+RR	O
+1	O
+.	O
+18	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+12	O
+-	O
+1	O
+.	O
+25	O
+)	O
+.	O
+
+Diuretic	O
+therapy	O
+was	O
+likewise	O
+associated	O
+with	O
+a	O
+greater	O
+risk	O
+of	O
+decreased	B
+renal	I
+function	I
+in	O
+the	O
+enalapril	O
+group	O
+(	O
+RR	O
+1	O
+.	O
+89	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+70	O
+-	O
+2	O
+.	O
+08	O
+)	O
+than	O
+in	O
+the	O
+placebo	O
+group	O
+(	O
+RR	O
+1	O
+.	O
+35	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+09	O
+-	O
+1	O
+.	O
+66	O
+)	O
+.	O
+
+Conversely	O
+,	O
+enalapril	O
+had	O
+a	O
+relative	O
+renoprotective	O
+effect	O
+(	O
+RR	O
+1	O
+.	O
+33	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+13	O
+-	O
+1	O
+.	O
+53	O
+)	O
+compared	O
+with	O
+placebo	O
+(	O
+RR	O
+1	O
+.	O
+96	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+57	O
+-	O
+2	O
+.	O
+44	O
+)	O
+in	O
+patients	O
+with	O
+diabetes	B
+.	O
+
+A	O
+lower	O
+risk	O
+of	O
+renal	B
+impairment	I
+was	O
+seen	O
+in	O
+both	O
+groups	O
+with	O
+beta	O
+-	O
+blocker	O
+therapy	O
+(	O
+RR	O
+0	O
+.	O
+70	O
+,	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+57	O
+-	O
+0	O
+.	O
+85	O
+)	O
+and	O
+higher	O
+baseline	O
+ejection	O
+fraction	O
+(	O
+RR	O
+0	O
+.	O
+93	O
+per	O
+5	O
+%	O
+increment	O
+,	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+91	O
+-	O
+0	O
+.	O
+96	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Enalapril	O
+use	O
+caused	O
+a	O
+33	O
+%	O
+increase	O
+in	O
+the	O
+risk	O
+of	O
+decreased	B
+renal	I
+function	I
+in	O
+patients	O
+with	O
+CHF	B
+.	O
+
+Diuretic	O
+use	O
+and	O
+advanced	O
+age	O
+increased	O
+this	O
+risk	O
+.	O
+
+Diabetes	B
+was	O
+associated	O
+with	O
+an	O
+increased	O
+risk	O
+of	O
+renal	B
+impairment	I
+in	O
+all	O
+patients	O
+with	O
+CHF	B
+,	O
+but	O
+this	O
+risk	O
+was	O
+reduced	O
+in	O
+the	O
+enalapril	O
+group	O
+compared	O
+with	O
+the	O
+placebo	O
+group	O
+.	O
+
+beta	O
+-	O
+Blocker	O
+therapy	O
+and	O
+higher	O
+ejection	O
+fraction	O
+were	O
+renoprotective	O
+in	O
+all	O
+patients	O
+regardless	O
+of	O
+therapy	O
+.	O
+
+Hypomania	B
+-	O
+like	O
+syndrome	O
+induced	O
+by	O
+olanzapine	O
+.	O
+
+We	O
+report	O
+a	O
+female	O
+patient	O
+with	O
+a	O
+diagnosis	O
+of	O
+a	O
+not	O
+otherwise	O
+specified	O
+psychotic	B
+disorder	I
+(	O
+DSM	O
+-	O
+IV	O
+)	O
+who	O
+developed	O
+hypomania	B
+shortly	O
+after	O
+the	O
+introduction	O
+of	O
+olanzapine	O
+treatment	O
+.	O
+
+Acetazolamide	O
+-	O
+induced	O
+Gerstmann	B
+syndrome	I
+.	O
+
+Acute	O
+confusion	B
+induced	O
+by	O
+acetazolamide	O
+is	O
+a	O
+well	O
+known	O
+adverse	O
+drug	O
+reaction	O
+in	O
+patients	O
+with	O
+renal	B
+impairment	I
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+acetazolamide	O
+-	O
+induced	O
+Gerstmann	B
+syndrome	I
+in	O
+a	O
+patient	O
+with	O
+normal	O
+renal	O
+function	O
+,	O
+to	O
+highlight	O
+predisposing	O
+factors	O
+that	O
+are	O
+frequently	O
+overlooked	O
+.	O
+
+Vasopressin	O
+in	O
+the	O
+treatment	O
+of	O
+milrinone	O
+-	O
+induced	O
+hypotension	B
+in	O
+severe	O
+heart	B
+failure	I
+.	O
+
+The	O
+use	O
+of	O
+phosphodiesterase	O
+inhibitors	O
+such	O
+as	O
+milrinone	O
+in	O
+the	O
+treatment	O
+of	O
+severe	O
+heart	B
+failure	I
+is	O
+frequently	O
+restricted	O
+because	O
+they	O
+cause	O
+vasodilation	O
+and	O
+hypotension	B
+.	O
+
+In	O
+patients	O
+with	O
+decompensated	O
+heart	B
+failure	I
+with	O
+hypotension	B
+after	O
+treatment	O
+with	O
+milrinone	O
+,	O
+low	O
+doses	O
+of	O
+vasopressin	O
+restored	O
+blood	O
+pressure	O
+without	O
+inhibiting	O
+the	O
+inotropic	O
+effect	O
+of	O
+milrinone	O
+.	O
+
+Treatment	O
+of	O
+tacrolimus	O
+-	O
+related	O
+adverse	O
+effects	O
+by	O
+conversion	O
+to	O
+cyclosporine	O
+in	O
+liver	O
+transplant	O
+recipients	O
+.	O
+
+When	O
+tacrolimus	O
+side	O
+effects	O
+persist	O
+despite	O
+dose	O
+reduction	O
+,	O
+conversion	O
+to	O
+cyclosporine	O
+-	O
+based	O
+immunosuppression	O
+(	O
+CyA	O
+)	O
+is	O
+necessary	O
+.	O
+
+We	O
+characterized	O
+tacrolimus	O
+side	O
+effects	O
+that	O
+warranted	O
+discontinuation	O
+of	O
+the	O
+drug	O
+,	O
+and	O
+outcomes	O
+after	O
+conversion	O
+.	O
+
+Of	O
+388	O
+liver	O
+recipients	O
+who	O
+received	O
+tacrolimus	O
+as	O
+primary	O
+immunosuppression	O
+,	O
+70	O
+required	O
+conversion	O
+to	O
+CyA	O
+.	O
+
+We	O
+recorded	O
+indication	O
+for	O
+conversion	O
+,	O
+whether	O
+conversion	O
+was	O
+early	O
+or	O
+late	O
+after	O
+transplantation	O
+,	O
+tacrolimus	O
+dose	O
+and	O
+trough	O
+blood	O
+level	O
+at	O
+conversion	O
+,	O
+and	O
+incidence	O
+of	O
+rejection	O
+after	O
+conversion	O
+.	O
+
+Conversion	O
+was	O
+early	O
+in	O
+29	O
+patients	O
+(	O
+41	O
+.	O
+4	O
+%	O
+)	O
+and	O
+late	O
+in	O
+41	O
+(	O
+58	O
+.	O
+6	O
+%	O
+)	O
+.	O
+
+Indications	O
+for	O
+early	O
+conversion	O
+were	O
+neurotoxicity	B
+(	O
+20	O
+)	O
+,	O
+(	B
+insulin	I
+-	I
+dependent	I
+)	I
+diabetes	I
+mellitus	I
+(	O
+IDDM	B
+)	O
+(	O
+5	O
+)	O
+,	O
+nephrotoxicity	B
+(	O
+3	O
+)	O
+,	O
+gastrointestinal	B
+(	I
+GI	I
+)	I
+toxicity	I
+(	O
+6	O
+)	O
+,	O
+and	O
+cardiomyopathy	B
+(	O
+1	O
+)	O
+,	O
+and	O
+for	O
+late	O
+conversion	O
+were	O
+neurotoxicity	B
+(	O
+15	O
+)	O
+,	O
+IDDM	B
+(	O
+12	O
+)	O
+,	O
+nephrotoxicity	B
+(	O
+3	O
+)	O
+,	O
+GI	B
+toxicity	I
+(	O
+5	O
+)	O
+,	O
+hepatotoxicity	B
+(	O
+6	O
+)	O
+,	O
+post	B
+-	I
+transplant	I
+lmphoproliferate	I
+disease	I
+(	O
+PTLD	B
+)	O
+(	O
+2	O
+)	O
+,	O
+cardiomyopathy	B
+(	O
+1	O
+)	O
+,	O
+hemolytic	B
+anemia	I
+(	O
+1	O
+)	O
+,	O
+and	O
+pruritus	B
+(	O
+1	O
+)	O
+.	O
+
+All	O
+early	O
+-	O
+conversion	O
+patients	O
+showed	O
+improvement	O
+/	O
+resolution	O
+of	O
+symptoms	O
+.	O
+
+Among	O
+late	O
+-	O
+conversion	O
+patients	O
+,	O
+37	O
+(	O
+90	O
+.	O
+2	O
+%	O
+)	O
+had	O
+improvement	O
+/	O
+resolution	O
+;	O
+in	O
+4	O
+(	O
+9	O
+.	O
+8	O
+%	O
+)	O
+,	O
+adverse	O
+effects	O
+persisted	O
+.	O
+
+The	O
+overall	O
+rejection	O
+rate	O
+was	O
+30	O
+%	O
+.	O
+
+Sixty	O
+-	O
+two	O
+patients	O
+(	O
+88	O
+.	O
+6	O
+%	O
+)	O
+are	O
+alive	O
+with	O
+functioning	O
+grafts	O
+686	O
++	O
+/	O
+-	O
+362	O
+days	O
+(	O
+range	O
+,	O
+154	O
+-	O
+1433	O
+days	O
+)	O
+after	O
+conversion	O
+.	O
+
+When	O
+tacrolimus	O
+side	O
+effects	O
+are	O
+unresponsive	O
+to	O
+dose	O
+reduction	O
+,	O
+conversion	O
+to	O
+CyA	O
+can	O
+be	O
+accomplished	O
+safely	O
+,	O
+with	O
+no	O
+increased	O
+risk	O
+of	O
+rejection	O
+and	O
+excellent	O
+long	O
+-	O
+term	O
+outcome	O
+.	O
+
+Ocular	O
+manifestations	O
+of	O
+juvenile	B
+rheumatoid	I
+arthritis	I
+.	O
+
+We	O
+followed	O
+210	O
+cases	O
+of	O
+juvenile	B
+rheumatoid	I
+arthritis	I
+closely	O
+for	O
+eleven	O
+years	O
+.	O
+
+Thirty	O
+-	O
+six	O
+of	O
+the	O
+210	O
+patients	O
+(	O
+17	O
+.	O
+2	O
+%	O
+)	O
+developed	O
+iridocyclitis	B
+.	O
+
+Iridocyclitis	B
+was	O
+seen	O
+most	O
+frequently	O
+in	O
+young	O
+female	O
+patients	O
+(	O
+0	O
+to	O
+4	O
+years	O
+)	O
+with	O
+the	O
+monoarticular	O
+or	O
+pauciatricular	O
+form	O
+of	O
+the	O
+arthritis	B
+.	O
+
+However	O
+,	O
+30	O
+%	O
+of	O
+the	O
+patients	O
+developed	O
+uveitis	B
+after	O
+16	O
+years	O
+of	O
+age	O
+.	O
+
+Although	O
+61	O
+%	O
+of	O
+patients	O
+had	O
+a	O
+noncontributory	O
+ocular	O
+history	O
+on	O
+entry	O
+,	O
+42	O
+%	O
+had	O
+active	O
+uveitis	B
+on	O
+entry	O
+.	O
+
+Our	O
+approach	O
+was	O
+effective	O
+in	O
+detecting	O
+uveitis	B
+in	O
+new	O
+cases	O
+and	O
+exacerbations	O
+of	O
+uveitis	B
+in	O
+established	O
+cases	O
+.	O
+
+Forty	O
+-	O
+four	O
+percent	O
+of	O
+patients	O
+with	O
+uveitis	B
+had	O
+one	O
+or	O
+more	O
+identifiable	O
+signs	O
+or	O
+symptoms	O
+,	O
+such	O
+as	O
+red	O
+eye	O
+,	O
+ocular	B
+pain	I
+,	O
+decreased	B
+visual	I
+acuity	I
+,	O
+or	O
+photophobia	B
+,	O
+in	O
+order	O
+of	O
+decreasing	O
+frequency	O
+.	O
+
+Even	O
+after	O
+early	O
+detection	O
+and	O
+prompt	O
+treatment	O
+,	O
+41	O
+%	O
+of	O
+cases	O
+of	O
+uveitis	B
+did	O
+not	O
+respond	O
+to	O
+more	O
+than	O
+six	O
+months	O
+of	O
+intensive	O
+topical	O
+treatment	O
+with	O
+corticosteroids	O
+and	O
+mydriatics	O
+.	O
+
+Despite	O
+this	O
+,	O
+there	O
+was	O
+a	O
+dramatic	O
+decrease	O
+in	O
+the	O
+50	O
+%	O
+incidence	O
+of	O
+blinding	O
+complications	O
+of	O
+uveitis	B
+cited	O
+in	O
+earlier	O
+studies	O
+.	O
+
+Cataract	B
+and	O
+band	B
+keratopathy	I
+occurred	O
+in	O
+only	O
+22	O
+and	O
+13	O
+%	O
+of	O
+our	O
+group	O
+,	O
+respectively	O
+.	O
+
+We	O
+used	O
+chloroquine	O
+or	O
+hydroxychloroquine	O
+in	O
+173	O
+of	O
+210	O
+cases	O
+and	O
+found	O
+only	O
+one	O
+case	O
+of	O
+chorioretinopathy	B
+attributable	O
+to	O
+these	O
+drugs	O
+.	O
+
+Systemically	O
+administered	O
+corticosteroids	O
+were	O
+used	O
+in	O
+75	O
+of	O
+210	O
+cases	O
+;	O
+a	O
+significant	O
+number	O
+of	O
+posterior	O
+subcapsular	O
+cataracts	B
+was	O
+found	O
+.	O
+
+Typical	O
+keratoconjunctivitis	B
+sicca	O
+developed	O
+in	O
+three	O
+of	O
+the	O
+uveitis	B
+cases	O
+.	O
+
+This	O
+association	O
+with	O
+uveitis	B
+and	O
+JRA	O
+was	O
+not	O
+noted	O
+previously	O
+.	O
+
+Surgical	O
+treatment	O
+of	O
+cataracts	B
+,	O
+band	B
+keratopathy	I
+,	O
+and	O
+glaucoma	B
+achieved	O
+uniformly	O
+discouraging	O
+results	O
+.	O
+
+Cyclophosphamide	O
+-	O
+induced	O
+cystitis	B
+in	O
+freely	O
+-	O
+moving	O
+conscious	O
+rats	O
+:	O
+behavioral	O
+approach	O
+to	O
+a	O
+new	O
+model	O
+of	O
+visceral	B
+pain	I
+.	O
+
+PURPOSE	O
+:	O
+To	O
+develop	O
+a	O
+model	O
+of	O
+visceral	B
+pain	I
+in	O
+rats	O
+using	O
+a	O
+behavioral	O
+approach	O
+.	O
+
+Cyclophosphamide	O
+(	O
+CP	O
+)	O
+,	O
+an	O
+antitumoral	O
+agent	O
+known	O
+to	O
+produce	O
+toxic	O
+effects	O
+on	O
+the	O
+bladder	O
+wall	O
+through	O
+its	O
+main	O
+toxic	O
+metabolite	O
+acrolein	O
+,	O
+was	O
+used	O
+to	O
+induce	O
+cystitis	B
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+CP	O
+was	O
+administered	O
+at	O
+doses	O
+of	O
+50	O
+,	O
+100	O
+and	O
+200	O
+mg	O
+.	O
+/	O
+kg	O
+.	O
+
+i	O
+.	O
+p	O
+.	O
+to	O
+male	O
+rats	O
+,	O
+and	O
+their	O
+behavior	O
+observed	O
+and	O
+scored	O
+.	O
+
+The	O
+effects	O
+of	O
+morphine	O
+(	O
+0	O
+.	O
+5	O
+to	O
+4	O
+mg	O
+.	O
+/	O
+kg	O
+.	O
+i	O
+.	O
+v	O
+.	O
+)	O
+on	O
+CP	O
+-	O
+induced	O
+behavioral	O
+modifications	O
+were	O
+tested	O
+administered	O
+alone	O
+and	O
+after	O
+naloxone	O
+(	O
+1	O
+mg	O
+.	O
+/	O
+kg	O
+.	O
+s	O
+.	O
+c	O
+.	O
+)	O
+.	O
+
+In	O
+addition	O
+,	O
+90	O
+minutes	O
+after	O
+CP	O
+injection	O
+,	O
+that	O
+is	O
+,	O
+at	O
+the	O
+time	O
+of	O
+administration	O
+of	O
+morphine	O
+,	O
+the	O
+bladder	O
+was	O
+removed	O
+in	O
+some	O
+rats	O
+for	O
+histological	O
+examination	O
+.	O
+
+Finally	O
+,	O
+to	O
+show	O
+that	O
+the	O
+bladder	O
+is	O
+essential	O
+for	O
+the	O
+CP	O
+-	O
+induced	O
+behavioral	O
+modifications	O
+,	O
+female	O
+rats	O
+also	O
+received	O
+CP	O
+at	O
+doses	O
+of	O
+200	O
+mg	O
+.	O
+/	O
+kg	O
+.	O
+
+i	O
+.	O
+p	O
+.	O
+and	O
+of	O
+20	O
+mg	O
+.	O
+by	O
+the	O
+intravesical	O
+route	O
+,	O
+and	O
+acrolein	O
+at	O
+doses	O
+of	O
+0	O
+.	O
+5	O
+mg	O
+.	O
+by	O
+the	O
+intravesical	O
+route	O
+and	O
+of	O
+5	O
+mg	O
+.	O
+/	O
+kg	O
+.	O
+
+i	O
+.	O
+v	O
+.	O
+RESULTS	O
+:	O
+CP	O
+dose	O
+-	O
+relatedly	O
+induced	O
+marked	O
+behavioral	O
+modifications	O
+in	O
+male	O
+rats	O
+:	O
+breathing	O
+rate	O
+decrease	O
+,	O
+closing	O
+of	O
+the	O
+eyes	O
+and	O
+occurrence	O
+of	O
+specific	O
+postures	O
+.	O
+
+Morphine	O
+dose	O
+-	O
+dependently	O
+reversed	O
+these	O
+behavioral	B
+disorders	I
+.	O
+
+A	O
+dose	O
+of	O
+0	O
+.	O
+5	O
+mg	O
+.	O
+/	O
+kg	O
+.	O
+produced	O
+a	O
+reduction	O
+of	O
+almost	O
+50	O
+%	O
+of	O
+the	O
+behavioral	O
+score	O
+induced	O
+by	O
+CP	O
+200	O
+mg	O
+.	O
+/	O
+kg	O
+.	O
+
+This	O
+effect	O
+was	O
+completely	O
+prevented	O
+by	O
+pretreatment	O
+with	O
+naloxone	O
+.	O
+
+At	O
+the	O
+time	O
+of	O
+administration	O
+of	O
+morphine	O
+,	O
+histological	O
+modifications	O
+of	O
+the	O
+bladder	O
+wall	O
+,	O
+such	O
+as	O
+chorionic	O
+and	O
+muscle	O
+layer	O
+edema	B
+,	O
+were	O
+observed	O
+.	O
+
+In	O
+female	O
+rats	O
+,	O
+CP	O
+200	O
+mg	O
+.	O
+/	O
+kg	O
+.	O
+
+i	O
+.	O
+p	O
+.	O
+produced	O
+the	O
+same	O
+marked	O
+behavioral	O
+modifications	O
+as	O
+those	O
+observed	O
+in	O
+male	O
+rats	O
+.	O
+
+Administered	O
+at	O
+the	O
+dose	O
+of	O
+20	O
+mg	O
+.	O
+intravesically	O
+,	O
+CP	O
+did	O
+not	O
+produce	O
+any	O
+behavioral	O
+effects	O
+,	O
+whereas	O
+acrolein	O
+at	O
+0	O
+.	O
+5	O
+mg	O
+.	O
+intravesically	O
+induced	O
+behavioral	O
+modifications	O
+identical	O
+to	O
+those	O
+under	O
+CP	O
+200	O
+mg	O
+.	O
+/	O
+kg	O
+.	O
+
+i	O
+.	O
+p	O
+.	O
+,	O
+with	O
+the	O
+same	O
+maximal	O
+levels	O
+.	O
+
+Conversely	O
+,	O
+acrolein	O
+5	O
+mg	O
+.	O
+/	O
+kg	O
+.	O
+
+i	O
+.	O
+v	O
+.	O
+did	O
+not	O
+produce	O
+any	O
+behavioral	O
+effects	O
+at	O
+all	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Overall	O
+,	O
+these	O
+results	O
+indicate	O
+that	O
+this	O
+experimental	O
+model	O
+of	O
+CP	O
+-	O
+induced	O
+cystitis	B
+may	O
+be	O
+an	O
+interesting	O
+new	O
+behavioral	O
+model	O
+of	O
+inflammatory	O
+visceral	B
+pain	I
+,	O
+allowing	O
+a	O
+better	O
+understanding	O
+of	O
+these	O
+painful	B
+syndromes	I
+and	O
+thus	O
+a	O
+better	O
+therapeutic	O
+approach	O
+to	O
+them	O
+.	O
+
+Prednisolone	O
+-	O
+induced	O
+muscle	B
+dysfunction	I
+is	O
+caused	O
+more	O
+by	O
+atrophy	B
+than	O
+by	O
+altered	O
+acetylcholine	O
+receptor	O
+expression	O
+.	O
+
+Large	O
+doses	O
+of	O
+glucocorticoids	O
+can	O
+alter	O
+muscle	O
+physiology	O
+and	O
+susceptibility	O
+to	O
+neuromuscular	O
+blocking	O
+drugs	O
+by	O
+mechanisms	O
+not	O
+clearly	O
+understood	O
+.	O
+
+We	O
+investigated	O
+the	O
+effects	O
+of	O
+moderate	O
+and	O
+large	O
+doses	O
+of	O
+prednisolone	O
+on	O
+muscle	O
+function	O
+and	O
+pharmacology	O
+,	O
+and	O
+their	O
+relationship	O
+to	O
+changes	O
+in	O
+muscle	O
+size	O
+and	O
+acetylcholine	O
+receptor	O
+(	O
+AChR	O
+)	O
+expression	O
+.	O
+
+With	O
+institutional	O
+approval	O
+,	O
+35	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+were	O
+randomly	O
+allocated	O
+to	O
+receive	O
+daily	O
+subcutaneous	O
+doses	O
+of	O
+10	O
+mg	O
+/	O
+kg	O
+prednisolone	O
+(	O
+P10	O
+group	O
+)	O
+,	O
+100	O
+mg	O
+/	O
+kg	O
+prednisolone	O
+(	O
+P100	O
+group	O
+)	O
+,	O
+or	O
+an	O
+equal	O
+volume	O
+of	O
+saline	O
+(	O
+S	O
+group	O
+)	O
+for	O
+7	O
+days	O
+.	O
+
+A	O
+fourth	O
+group	O
+of	O
+rats	O
+was	O
+pair	O
+fed	O
+(	O
+food	O
+restricted	O
+)	O
+with	O
+the	O
+P100	O
+rats	O
+for	O
+7	O
+days	O
+(	O
+FR	O
+group	O
+)	O
+.	O
+
+On	O
+Day	O
+8	O
+,	O
+the	O
+nerve	O
+-	O
+evoked	O
+peak	O
+twitch	O
+tensions	O
+,	O
+tetanic	B
+tensions	O
+,	O
+and	O
+fatigability	O
+,	O
+and	O
+the	O
+dose	O
+-	O
+response	O
+curves	O
+of	O
+d	O
+-	O
+tubocurarine	O
+in	O
+the	O
+tibialis	O
+cranialis	O
+muscle	O
+were	O
+measured	O
+in	O
+vivo	O
+and	O
+related	O
+to	O
+muscle	O
+mass	O
+or	O
+expression	O
+of	O
+AChRs	O
+.	O
+
+Rate	O
+of	O
+body	O
+weight	O
+gain	O
+was	O
+depressed	O
+in	O
+the	O
+P100	O
+,	O
+FR	O
+,	O
+and	O
+P10	O
+groups	O
+compared	O
+with	O
+the	O
+S	O
+group	O
+.	O
+
+Tibialis	O
+muscle	O
+mass	O
+was	O
+smaller	O
+in	O
+the	O
+P100	O
+group	O
+than	O
+in	O
+the	O
+P10	O
+or	O
+S	O
+groups	O
+.	O
+
+The	O
+evoked	O
+peak	O
+twitch	O
+and	O
+tetanic	B
+tensions	O
+were	O
+less	O
+in	O
+the	O
+P100	O
+group	O
+than	O
+in	O
+the	O
+P10	O
+or	O
+S	O
+groups	O
+,	O
+however	O
+,	O
+tension	O
+per	O
+milligram	O
+of	O
+muscle	O
+mass	O
+was	O
+greater	O
+in	O
+the	O
+P100	O
+group	O
+than	O
+in	O
+the	O
+S	O
+group	O
+.	O
+
+The	O
+50	O
+%	O
+effective	O
+dose	O
+of	O
+d	O
+-	O
+tubocurarine	O
+(	O
+microg	O
+/	O
+kg	O
+)	O
+in	O
+the	O
+tibialis	O
+muscle	O
+was	O
+smaller	O
+in	O
+the	O
+P10	O
+(	O
+33	O
+.	O
+6	O
++	O
+/	O
+-	O
+5	O
+.	O
+4	O
+)	O
+than	O
+in	O
+the	O
+S	O
+(	O
+61	O
+.	O
+9	O
++	O
+/	O
+-	O
+5	O
+.	O
+0	O
+)	O
+or	O
+the	O
+P100	O
+(	O
+71	O
+.	O
+3	O
++	O
+/	O
+-	O
+9	O
+.	O
+6	O
+)	O
+groups	O
+.	O
+
+AChR	O
+expression	O
+was	O
+less	O
+in	O
+the	O
+P10	O
+group	O
+than	O
+in	O
+the	O
+S	O
+group	O
+.	O
+
+The	O
+evoked	O
+tensions	O
+correlated	O
+with	O
+muscle	O
+mass	O
+(	O
+r	O
+(	O
+2	O
+)	O
+=	O
+0	O
+.	O
+32	O
+,	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+,	O
+however	O
+,	O
+not	O
+with	O
+expression	O
+of	O
+AChR	O
+.	O
+
+The	O
+50	O
+%	O
+effective	O
+dose	O
+of	O
+d	O
+-	O
+tubocurarine	O
+did	O
+not	O
+correlate	O
+with	O
+muscle	O
+mass	O
+or	O
+AChR	O
+expression	O
+.	O
+
+Our	O
+results	O
+suggest	O
+that	O
+the	O
+neuromuscular	B
+dysfunction	I
+after	O
+prednisolone	O
+is	O
+dose	O
+-	O
+dependent	O
+,	O
+and	O
+derives	O
+primarily	O
+from	O
+muscle	B
+atrophy	I
+and	O
+derives	O
+less	O
+so	O
+from	O
+changes	O
+in	O
+AChR	O
+expression	O
+.	O
+
+IMPLICATIONS	O
+:	O
+The	O
+mechanisms	O
+by	O
+which	O
+chronic	O
+glucocorticoid	O
+therapy	O
+alters	O
+neuromuscular	O
+physiology	O
+and	O
+pharmacology	O
+are	O
+unclear	O
+.	O
+
+We	O
+suggest	O
+that	O
+the	O
+observed	O
+effects	O
+are	O
+dose	O
+-	O
+dependent	O
+and	O
+derive	O
+primarily	O
+from	O
+muscle	B
+atrophy	I
+and	O
+derive	O
+less	O
+from	O
+changes	O
+in	O
+acetylcholine	O
+receptor	O
+expression	O
+.	O
+
+Apomorphine	O
+:	O
+an	O
+underutilized	O
+therapy	O
+for	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+Apomorphine	O
+was	O
+the	O
+first	O
+dopaminergic	O
+drug	O
+ever	O
+used	O
+to	O
+treat	O
+symptoms	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+While	O
+powerful	O
+antiparkinsonian	O
+effects	O
+had	O
+been	O
+observed	O
+as	O
+early	O
+as	O
+1951	O
+,	O
+the	O
+potential	O
+of	O
+treating	O
+fluctuating	O
+Parkinson	B
+'	I
+s	I
+disease	I
+by	O
+subcutaneous	O
+administration	O
+of	O
+apomorphine	O
+has	O
+only	O
+recently	O
+become	O
+the	O
+subject	O
+of	O
+systematic	O
+study	O
+.	O
+
+A	O
+number	O
+of	O
+small	O
+scale	O
+clinical	O
+trials	O
+have	O
+unequivocally	O
+shown	O
+that	O
+intermittent	O
+subcutaneous	O
+apomorphine	O
+injections	O
+produce	O
+antiparkinsonian	O
+benefit	O
+close	O
+if	O
+not	O
+identical	O
+to	O
+that	O
+seen	O
+with	O
+levodopa	O
+and	O
+that	O
+apomorphine	O
+rescue	O
+injections	O
+can	O
+reliably	O
+revert	O
+off	O
+-	O
+periods	O
+even	O
+in	O
+patients	O
+with	O
+complex	O
+on	O
+-	O
+off	O
+motor	O
+swings	O
+.	O
+
+Continuous	O
+subcutaneous	O
+apomorphine	O
+infusions	O
+can	O
+reduce	O
+daily	O
+off	O
+-	O
+time	O
+by	O
+more	O
+than	O
+50	O
+%	O
+in	O
+this	O
+group	O
+of	O
+patients	O
+,	O
+which	O
+appears	O
+to	O
+be	O
+a	O
+stronger	O
+effect	O
+than	O
+that	O
+generally	O
+seen	O
+with	O
+add	O
+-	O
+on	O
+therapy	O
+with	O
+oral	O
+dopamine	O
+agonists	O
+or	O
+COMT	O
+inhibitors	O
+.	O
+
+Extended	O
+follow	O
+-	O
+up	O
+studies	O
+of	O
+up	O
+to	O
+8	O
+years	O
+have	O
+demonstrated	O
+long	O
+-	O
+term	O
+persistence	O
+of	O
+apomorphine	O
+efficacy	O
+.	O
+
+In	O
+addition	O
+,	O
+there	O
+is	O
+convincing	O
+clinical	O
+evidence	O
+that	O
+monotherapy	O
+with	O
+continuous	O
+subcutaneous	O
+apomorphine	O
+infusions	O
+is	O
+associated	O
+with	O
+marked	O
+reductions	O
+of	O
+preexisting	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+.	O
+
+The	O
+main	O
+side	O
+effects	O
+of	O
+subcutaneous	O
+apomorphine	O
+treatment	O
+are	O
+related	O
+to	O
+cutaneous	O
+tolerability	O
+problems	O
+,	O
+whereas	O
+sedation	O
+and	O
+psychiatric	B
+complications	O
+play	O
+a	O
+lesser	O
+role	O
+.	O
+
+Given	O
+the	O
+marked	O
+degree	O
+of	O
+efficacy	O
+of	O
+subcutaneous	O
+apomorphine	O
+treatment	O
+in	O
+fluctuating	O
+Parkinson	B
+'	I
+s	I
+disease	I
+,	O
+this	O
+approach	O
+seems	O
+to	O
+deserve	O
+more	O
+widespread	O
+clinical	O
+use	O
+.	O
+
+Probing	O
+peripheral	O
+and	O
+central	O
+cholinergic	O
+system	O
+responses	O
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+pharmacological	O
+response	O
+to	O
+drugs	O
+that	O
+act	O
+on	O
+the	O
+cholinergic	O
+system	O
+of	O
+the	O
+iris	O
+has	O
+been	O
+used	O
+to	O
+predict	O
+deficits	O
+in	O
+central	O
+cholinergic	O
+functioning	O
+due	O
+to	O
+diseases	O
+such	O
+as	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+,	O
+yet	O
+correlations	O
+between	O
+central	O
+and	O
+peripheral	O
+responses	O
+have	O
+not	O
+been	O
+properly	O
+studied	O
+.	O
+
+This	O
+study	O
+assessed	O
+the	O
+effect	O
+of	O
+normal	O
+aging	O
+on	O
+(	O
+1	O
+)	O
+the	O
+tropicamide	O
+-	O
+induced	O
+increase	O
+in	O
+pupil	O
+diameter	O
+,	O
+and	O
+(	O
+2	O
+)	O
+the	O
+reversal	O
+of	O
+this	O
+effect	O
+with	O
+pilocarpine	O
+.	O
+
+Scopolamine	O
+was	O
+used	O
+as	O
+a	O
+positive	O
+control	O
+to	O
+detect	O
+age	O
+-	O
+dependent	O
+changes	O
+in	O
+central	O
+cholinergic	O
+functioning	O
+in	O
+the	O
+elderly	O
+.	O
+
+DESIGN	O
+:	O
+Randomized	O
+double	O
+-	O
+blind	O
+controlled	O
+trial	O
+.	O
+
+PARTICIPANTS	O
+:	O
+Ten	O
+healthy	O
+elderly	O
+(	O
+mean	O
+age	O
+70	O
+)	O
+and	O
+9	O
+young	O
+(	O
+mean	O
+age	O
+33	O
+)	O
+volunteers	O
+.	O
+
+INTERVENTIONS	O
+:	O
+Pupil	O
+diameter	O
+was	O
+monitored	O
+using	O
+a	O
+computerized	O
+infrared	O
+pupillometer	O
+over	O
+4	O
+hours	O
+.	O
+
+The	O
+study	O
+involved	O
+4	O
+sessions	O
+.	O
+
+In	O
+1	O
+session	O
+,	O
+tropicamide	O
+(	O
+20	O
+microL	O
+,	O
+0	O
+.	O
+01	O
+%	O
+)	O
+was	O
+administered	O
+to	O
+one	O
+eye	O
+and	O
+placebo	O
+to	O
+the	O
+other	O
+.	O
+
+In	O
+another	O
+session	O
+,	O
+tropicamide	O
+(	O
+20	O
+microL	O
+,	O
+0	O
+.	O
+01	O
+%	O
+)	O
+was	O
+administered	O
+to	O
+both	O
+eyes	O
+,	O
+followed	O
+23	O
+minutes	O
+later	O
+by	O
+the	O
+application	O
+of	O
+pilocarpine	O
+(	O
+20	O
+microL	O
+,	O
+0	O
+.	O
+1	O
+%	O
+)	O
+to	O
+one	O
+eye	O
+and	O
+placebo	O
+to	O
+the	O
+other	O
+.	O
+
+All	O
+eye	O
+drops	O
+were	O
+given	O
+in	O
+a	O
+randomized	O
+order	O
+.	O
+
+In	O
+2	O
+separate	O
+sessions	O
+,	O
+a	O
+single	O
+dose	O
+of	O
+scopolamine	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+,	O
+intravenously	O
+)	O
+or	O
+placebo	O
+was	O
+administered	O
+,	O
+and	O
+the	O
+effects	O
+on	O
+word	O
+recall	O
+were	O
+measured	O
+using	O
+the	O
+Buschke	O
+Selective	O
+Reminding	O
+Test	O
+over	O
+2	O
+hours	O
+.	O
+
+OUTCOME	O
+MEASURES	O
+:	O
+Pupil	O
+size	O
+at	O
+time	O
+points	O
+after	O
+administration	O
+of	O
+tropicamide	O
+and	O
+pilocarpine	O
+;	O
+scopolamine	O
+-	O
+induced	O
+impairment	B
+in	I
+word	I
+recall	I
+.	O
+
+RESULTS	O
+:	O
+There	O
+was	O
+no	O
+significant	O
+difference	O
+between	O
+elderly	O
+and	O
+young	O
+volunteers	O
+in	O
+pupillary	O
+response	O
+to	O
+tropicamide	O
+at	O
+any	O
+time	O
+point	O
+(	O
+p	O
+>	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+elderly	O
+group	O
+had	O
+a	O
+significantly	O
+greater	O
+pilocarpine	O
+-	O
+induced	O
+net	O
+decrease	O
+in	O
+pupil	O
+size	O
+85	O
+,	O
+125	O
+,	O
+165	O
+and	O
+215	O
+minutes	O
+after	O
+administration	O
+,	O
+compared	O
+with	O
+the	O
+young	O
+group	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Compared	O
+with	O
+the	O
+young	O
+group	O
+,	O
+the	O
+elderly	O
+group	O
+had	O
+greater	O
+scopolamine	O
+-	O
+induced	O
+impairment	B
+in	I
+word	I
+recall	I
+60	O
+,	O
+90	O
+and	O
+120	O
+minutes	O
+after	O
+administration	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+There	O
+is	O
+an	O
+age	O
+-	O
+related	O
+pupillary	O
+response	O
+to	O
+pilocarpine	O
+that	O
+is	O
+not	O
+found	O
+with	O
+tropicamide	O
+.	O
+
+Thus	O
+,	O
+pilocarpine	O
+may	O
+be	O
+useful	O
+to	O
+assess	O
+variations	O
+in	O
+central	O
+cholinergic	O
+function	O
+in	O
+elderly	O
+patients	O
+.	O
+
+Pain	B
+responses	O
+in	O
+methadone	O
+-	O
+maintained	O
+opioid	O
+abusers	O
+.	O
+
+Providing	O
+pain	B
+management	O
+for	O
+known	O
+opioid	O
+abusers	O
+is	O
+a	O
+challenging	O
+clinical	O
+task	O
+,	O
+in	O
+part	O
+because	O
+little	O
+is	O
+known	O
+about	O
+their	O
+pain	B
+experience	O
+and	O
+analgesic	O
+requirements	O
+.	O
+
+This	O
+study	O
+was	O
+designed	O
+to	O
+describe	O
+pain	B
+tolerance	O
+and	O
+analgesic	O
+response	O
+in	O
+a	O
+sample	O
+of	O
+opioid	B
+addicts	I
+stabilized	O
+in	O
+methadone	O
+-	O
+maintenance	O
+(	O
+MM	O
+)	O
+treatment	O
+(	O
+n	O
+=	O
+60	O
+)	O
+in	O
+comparison	O
+to	O
+matched	O
+nondependent	O
+control	O
+subjects	O
+(	O
+n	O
+=	O
+60	O
+)	O
+.	O
+
+By	O
+using	O
+a	O
+placebo	O
+-	O
+controlled	O
+,	O
+two	O
+-	O
+way	O
+factorial	O
+design	O
+,	O
+tolerance	O
+to	O
+cold	O
+-	O
+pressor	O
+(	O
+CP	O
+)	O
+pain	B
+was	O
+examined	O
+,	O
+both	O
+before	O
+and	O
+after	O
+oral	O
+administration	O
+of	O
+therapeutic	O
+doses	O
+of	O
+common	O
+opioid	O
+(	O
+hydromorphone	O
+2	O
+mg	O
+)	O
+and	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+(	O
+ketorolac	O
+10	O
+mg	O
+)	O
+analgesic	O
+agents	O
+.	O
+
+Results	O
+showed	O
+that	O
+MM	O
+individuals	O
+were	O
+significantly	O
+less	O
+tolerant	O
+of	O
+CP	O
+pain	B
+than	O
+control	O
+subjects	O
+,	O
+replicating	O
+previous	O
+work	O
+.	O
+
+Analgesic	O
+effects	O
+were	O
+significant	O
+neither	O
+for	O
+medication	O
+nor	O
+group	O
+.	O
+
+These	O
+data	O
+indicate	O
+that	O
+MM	O
+opioid	O
+abusers	O
+represent	O
+a	O
+pain	B
+-	I
+intolerant	I
+subset	O
+of	O
+clinical	O
+patients	O
+.	O
+
+Their	O
+complaints	O
+of	O
+pain	B
+should	O
+be	O
+evaluated	O
+seriously	O
+and	O
+managed	O
+aggressively	O
+.	O
+
+High	O
+-	O
+dose	O
+methylprednisolone	O
+may	O
+do	O
+more	O
+harm	O
+for	O
+spinal	B
+cord	I
+injury	I
+.	O
+
+Because	O
+of	O
+the	O
+National	O
+Acute	O
+Spinal	B
+Cord	I
+Injury	I
+Studies	O
+(	O
+NASCIS	O
+)	O
+,	O
+high	O
+-	O
+dose	O
+methylprednisolone	O
+became	O
+the	O
+standard	O
+of	O
+care	O
+for	O
+the	O
+acute	O
+spinal	B
+cord	I
+injury	I
+.	O
+
+In	O
+the	O
+NASCIS	O
+,	O
+there	O
+was	O
+no	O
+mention	O
+regarding	O
+the	O
+possibility	O
+of	O
+acute	O
+corticosteroid	O
+myopathy	B
+that	O
+high	O
+-	O
+dose	O
+methylprednisolone	O
+may	O
+cause	O
+.	O
+
+The	O
+dosage	O
+of	O
+methylprednisolone	O
+recommended	O
+by	O
+the	O
+NASCIS	O
+3	O
+is	O
+the	O
+highest	O
+dose	O
+of	O
+steroids	O
+ever	O
+being	O
+used	O
+during	O
+a	O
+2	O
+-	O
+day	O
+period	O
+for	O
+any	O
+clinical	O
+condition	O
+.	O
+
+We	O
+hypothesize	O
+that	O
+it	O
+may	O
+cause	O
+some	O
+damage	B
+to	I
+the	I
+muscle	I
+of	O
+spinal	B
+cord	I
+injury	I
+patients	O
+.	O
+
+Further	O
+,	O
+steroid	O
+myopathy	B
+recovers	O
+naturally	O
+and	O
+the	O
+neurological	O
+improvement	O
+shown	O
+in	O
+the	O
+NASCIS	O
+may	O
+be	O
+just	O
+a	O
+recording	O
+of	O
+this	O
+natural	O
+motor	O
+recovery	O
+from	O
+the	O
+steroid	O
+myopathy	B
+,	O
+instead	O
+of	O
+any	O
+protection	O
+that	O
+methylprednisolone	O
+offers	O
+to	O
+the	O
+spinal	B
+cord	I
+injury	I
+.	O
+
+To	O
+our	O
+knowledge	O
+,	O
+this	O
+is	O
+the	O
+first	O
+discussion	O
+considering	O
+the	O
+possibility	O
+that	O
+the	O
+methylprednisolone	O
+recommended	O
+by	O
+NASCIS	O
+may	O
+cause	O
+acute	O
+corticosteroid	O
+myopathy	B
+.	O
+
+Conversion	O
+to	O
+rapamycin	O
+immunosuppression	O
+in	O
+renal	O
+transplant	O
+recipients	O
+:	O
+report	O
+of	O
+an	O
+initial	O
+experience	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+aim	O
+of	O
+this	O
+study	O
+is	O
+to	O
+evaluate	O
+the	O
+effects	O
+of	O
+RAPA	O
+conversion	O
+in	O
+patients	O
+undergoing	O
+cyclosporine	O
+(	O
+CsA	O
+)	O
+or	O
+tacrolimus	O
+(	O
+Tac	O
+)	O
+toxicity	B
+.	O
+
+METHODS	O
+:	O
+Twenty	O
+renal	O
+transplant	O
+recipients	O
+were	O
+switched	O
+to	O
+fixed	O
+dose	O
+rapamycin	O
+(	O
+RAPA	O
+)	O
+(	O
+5	O
+mg	O
+/	O
+day	O
+)	O
+0	O
+to	O
+204	O
+months	O
+posttransplant	O
+.	O
+
+Drug	O
+monitoring	O
+was	O
+not	O
+initially	O
+used	O
+to	O
+adjust	O
+doses	O
+.	O
+
+The	O
+indications	O
+for	O
+switch	O
+were	O
+chronic	O
+CsA	O
+or	O
+Tac	O
+nephrotoxicity	B
+(	O
+12	O
+)	O
+,	O
+acute	O
+CsA	O
+or	O
+Tac	O
+toxicity	B
+(	O
+3	O
+)	O
+,	O
+severe	O
+facial	B
+dysmorphism	I
+(	O
+2	O
+)	O
+,	O
+posttransplant	B
+lymphoproliferative	I
+disorder	I
+(	O
+PTLD	B
+)	O
+in	O
+remission	O
+(	O
+2	O
+)	O
+,	O
+and	O
+hepatotoxicity	B
+in	O
+1	O
+.	O
+
+Follow	O
+-	O
+up	O
+is	O
+7	O
+to	O
+24	O
+months	O
+.	O
+
+RESULTS	O
+:	O
+In	O
+the	O
+12	O
+patients	O
+switched	O
+because	O
+of	O
+chronic	O
+nephrotoxicity	B
+there	O
+was	O
+a	O
+significant	O
+decrease	O
+in	O
+serum	O
+creatinine	O
+[	O
+233	O
++	O
+/	O
+-	O
+34	O
+to	O
+210	O
++	O
+/	O
+-	O
+56	O
+micromol	O
+/	O
+liter	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+at	O
+6	O
+months	O
+]	O
+.	O
+
+Facial	B
+dysmorphism	I
+improved	O
+in	O
+two	O
+patients	O
+.	O
+
+No	O
+relapse	O
+of	O
+PTLD	B
+was	O
+observed	O
+.	O
+
+Five	O
+patients	O
+developed	O
+pneumonia	B
+(	O
+two	O
+Pneumocystis	B
+carinii	I
+pneumonia	I
+,	O
+one	O
+infectious	B
+mononucleosis	I
+with	O
+polyclonal	O
+PTLD	B
+lung	O
+infiltrate	O
+)	O
+and	O
+two	O
+had	O
+bronchiolitis	B
+obliterans	I
+.	O
+
+There	O
+were	O
+no	O
+deaths	O
+.	O
+
+RAPA	O
+was	O
+discontinued	O
+in	O
+four	O
+patients	O
+,	O
+because	O
+of	O
+pneumonia	B
+in	O
+two	O
+,	O
+PTLD	B
+in	O
+one	O
+,	O
+and	O
+oral	O
+aphtous	B
+ulcers	I
+in	O
+one	O
+.	O
+
+RAPA	O
+levels	O
+were	O
+high	O
+(	O
+>	O
+15	O
+ng	O
+/	O
+ml	O
+)	O
+in	O
+7	O
+of	O
+13	O
+(	O
+54	O
+%	O
+)	O
+patients	O
+.	O
+
+CONCLUSIONS	O
+:	O
+RAPA	O
+conversion	O
+provides	O
+adequate	O
+immunosuppression	O
+to	O
+enable	O
+CsA	O
+withdrawal	O
+.	O
+
+However	O
+,	O
+when	O
+converting	O
+patients	O
+to	O
+RAPA	O
+drug	O
+levels	O
+should	O
+be	O
+monitored	O
+to	O
+avoid	O
+over	O
+-	O
+immunosuppression	O
+and	O
+adequate	O
+antiviral	O
+and	O
+Pneumocystis	B
+carinii	I
+pneumonia	I
+prophylaxis	O
+should	O
+be	O
+given	O
+.	O
+
+Electro	O
+-	O
+oculography	O
+,	O
+electroretinography	O
+,	O
+visual	O
+evoked	O
+potentials	O
+,	O
+and	O
+multifocal	O
+electroretinography	O
+in	O
+patients	O
+with	O
+vigabatrin	O
+-	O
+attributed	O
+visual	B
+field	I
+constriction	I
+.	O
+
+PURPOSE	O
+:	O
+Symptomatic	O
+visual	B
+field	I
+constriction	I
+thought	O
+to	O
+be	O
+associated	O
+with	O
+vigabatrin	O
+has	O
+been	O
+reported	O
+.	O
+
+The	O
+current	O
+study	O
+investigated	O
+the	O
+visual	O
+fields	O
+and	O
+visual	O
+electrophysiology	O
+of	O
+eight	O
+patients	O
+with	O
+known	O
+vigabatrin	O
+-	O
+attributed	O
+visual	B
+field	I
+loss	I
+,	O
+three	O
+of	O
+whom	O
+were	O
+reported	O
+previously	O
+.	O
+
+Six	O
+of	O
+the	O
+patients	O
+were	O
+no	O
+longer	O
+receiving	O
+vigabatrin	O
+.	O
+
+METHODS	O
+:	O
+The	O
+central	O
+and	O
+peripheral	O
+fields	O
+were	O
+examined	O
+with	O
+the	O
+Humphrey	O
+Visual	O
+Field	O
+Analyzer	O
+.	O
+
+Full	O
+visual	O
+electrophysiology	O
+,	O
+including	O
+flash	O
+electroretinography	O
+(	O
+ERG	O
+)	O
+,	O
+pattern	O
+electroretinography	O
+,	O
+multifocal	O
+ERG	O
+using	O
+the	O
+VERIS	O
+system	O
+,	O
+electro	O
+-	O
+oculography	O
+,	O
+and	O
+flash	O
+and	O
+pattern	O
+visual	O
+evoked	O
+potentials	O
+,	O
+was	O
+undertaken	O
+.	O
+
+RESULTS	O
+:	O
+Seven	O
+patients	O
+showed	O
+marked	O
+visual	B
+field	I
+constriction	I
+with	O
+some	O
+sparing	O
+of	O
+the	O
+temporal	O
+visual	O
+field	O
+.	O
+
+The	O
+eighth	O
+exhibited	O
+concentric	O
+constriction	O
+.	O
+
+Most	O
+electrophysiological	O
+responses	O
+were	O
+usually	O
+just	O
+within	O
+normal	O
+limits	O
+;	O
+two	O
+patients	O
+had	O
+subnormal	O
+Arden	O
+electro	O
+-	O
+oculography	O
+indices	O
+;	O
+and	O
+one	O
+patient	O
+showed	O
+an	O
+abnormally	O
+delayed	O
+photopic	O
+b	O
+wave	O
+.	O
+
+However	O
+,	O
+five	O
+patients	O
+showed	O
+delayed	O
+30	O
+-	O
+Hz	O
+flicker	O
+b	O
+waves	O
+,	O
+and	O
+seven	O
+patients	O
+showed	O
+delayed	O
+oscillatory	O
+potentials	O
+.	O
+
+Multifocal	O
+ERG	O
+showed	O
+abnormalities	O
+that	O
+sometimes	O
+correlated	O
+with	O
+the	O
+visual	O
+field	O
+appearance	O
+and	O
+confirmed	O
+that	O
+the	O
+deficit	O
+occurs	O
+at	O
+the	O
+retinal	O
+level	O
+.	O
+
+CONCLUSION	O
+:	O
+Marked	O
+visual	B
+field	I
+constriction	I
+appears	O
+to	O
+be	O
+associated	O
+with	O
+vigabatrin	O
+therapy	O
+.	O
+
+The	O
+field	O
+defects	O
+and	O
+some	O
+electrophysiological	O
+abnormalities	O
+persist	O
+when	O
+vigabatrin	O
+therapy	O
+is	O
+withdrawn	O
+.	O
+
+Myocardial	B
+ischemia	I
+due	O
+to	O
+coronary	B
+artery	I
+spasm	I
+during	O
+dobutamine	O
+stress	O
+echocardiography	O
+.	O
+
+Dobutamine	O
+stress	O
+echocardiography	O
+(	O
+DSE	O
+)	O
+is	O
+a	O
+useful	O
+and	O
+safe	O
+provocation	O
+test	O
+for	O
+myocardial	B
+ischemia	I
+.	O
+
+Until	O
+now	O
+,	O
+the	O
+test	O
+has	O
+been	O
+focused	O
+only	O
+on	O
+the	O
+organic	O
+lesion	O
+in	O
+the	O
+coronary	O
+artery	O
+,	O
+and	O
+positive	O
+DSE	O
+has	O
+indicated	O
+the	O
+presence	O
+of	O
+significant	O
+fixed	O
+coronary	B
+artery	I
+stenosis	I
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+is	O
+to	O
+examine	O
+whether	O
+myocardial	B
+ischemia	I
+due	O
+to	O
+coronary	B
+spasm	I
+is	O
+induced	O
+by	O
+dobutamine	O
+.	O
+
+We	O
+performed	O
+DSE	O
+on	O
+51	O
+patients	O
+with	O
+coronary	B
+spastic	I
+angina	I
+but	O
+without	O
+significant	O
+fixed	O
+coronary	B
+artery	I
+stenosis	I
+.	O
+
+All	O
+patients	O
+had	O
+anginal	B
+attacks	O
+at	O
+rest	O
+with	O
+ST	O
+elevation	O
+on	O
+the	O
+electrocardiogram	O
+(	O
+variant	B
+angina	I
+)	O
+.	O
+
+Coronary	O
+spasm	O
+was	O
+induced	O
+by	O
+intracoronary	O
+injection	O
+of	O
+acetylcholine	O
+,	O
+and	O
+no	O
+fixed	O
+coronary	B
+artery	I
+stenosis	I
+was	O
+documented	O
+on	O
+angiograms	O
+in	O
+all	O
+patients	O
+.	O
+
+DSE	O
+was	O
+performed	O
+with	O
+intravenous	O
+dobutamine	O
+infusion	O
+with	O
+an	O
+incremental	O
+doses	O
+of	O
+5	O
+,	O
+10	O
+,	O
+20	O
+,	O
+30	O
+,	O
+and	O
+40	O
+microg	O
+/	O
+kg	O
+/	O
+min	O
+every	O
+5	O
+minutes	O
+.	O
+
+Of	O
+the	O
+51	O
+patients	O
+,	O
+7	O
+patients	O
+showed	O
+asynergy	O
+with	O
+ST	O
+elevation	O
+.	O
+
+All	O
+7	O
+patients	O
+(	O
+13	O
+.	O
+7	O
+%	O
+)	O
+had	O
+chest	B
+pain	I
+during	O
+asynergy	O
+,	O
+and	O
+both	O
+chest	B
+pain	I
+and	O
+electrocardiographic	O
+changes	O
+were	O
+preceded	O
+by	O
+asynergy	O
+.	O
+
+These	O
+findings	O
+indicate	O
+that	O
+dobutamine	O
+can	O
+provoke	O
+coronary	B
+spasm	I
+in	O
+some	O
+patients	O
+with	O
+coronary	B
+spastic	I
+angina	I
+.	O
+
+When	O
+DSE	O
+is	O
+performed	O
+to	O
+evaluate	O
+coronary	B
+artery	I
+disease	I
+,	O
+not	O
+only	O
+fixed	O
+coronary	B
+stenosis	I
+,	O
+but	O
+also	O
+coronary	B
+spasm	I
+should	O
+be	O
+considered	O
+as	O
+a	O
+genesis	O
+of	O
+asynergy	O
+.	O
+
+Effect	O
+of	O
+intravenous	O
+metoprolol	O
+or	O
+intravenous	O
+metoprolol	O
+plus	O
+glucagon	O
+on	O
+dobutamine	O
+-	O
+induced	O
+myocardial	B
+ischemia	I
+.	O
+
+STUDY	O
+OBJECTIVE	O
+:	O
+To	O
+determine	O
+the	O
+effect	O
+of	O
+metoprolol	O
+on	O
+dobutamine	O
+stress	O
+testing	O
+with	O
+technetium	O
+-	O
+99m	O
+sestamibi	O
+single	O
+-	O
+photon	O
+emission	O
+computed	O
+tomography	O
+imaging	O
+and	O
+ST	O
+-	O
+segment	O
+monitoring	O
+,	O
+and	O
+to	O
+assess	O
+the	O
+impact	O
+of	O
+intravenous	O
+glucagon	O
+on	O
+metoprolol	O
+'	O
+s	O
+effects	O
+.	O
+
+DESIGN	O
+:	O
+Randomized	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+trial	O
+.	O
+
+SETTING	O
+:	O
+Community	O
+hospital	O
+.	O
+
+PATIENTS	O
+:	O
+Twenty	O
+-	O
+two	O
+patients	O
+with	O
+known	O
+reversible	O
+perfusion	O
+defects	O
+.	O
+
+INTERVENTION	O
+:	O
+Patients	O
+underwent	O
+dobutamine	O
+stress	O
+tests	O
+per	O
+standard	O
+protocol	O
+.	O
+
+Before	O
+dobutamine	O
+was	O
+begun	O
+,	O
+no	O
+therapy	O
+was	O
+given	O
+during	O
+the	O
+first	O
+visit	O
+,	O
+and	O
+patients	O
+were	O
+randomized	O
+on	O
+subsequent	O
+visits	O
+to	O
+receive	O
+metoprolol	O
+or	O
+metoprolol	O
+plus	O
+glucagon	O
+1	O
+mg	O
+.	O
+
+Metoprolol	O
+was	O
+dosed	O
+to	O
+achieve	O
+a	O
+resting	O
+predobutamine	O
+heart	O
+rate	O
+below	O
+65	O
+beats	O
+/	O
+minute	O
+or	O
+a	O
+total	O
+intravenous	O
+dose	O
+of	O
+20	O
+mg	O
+.	O
+
+MEASUREMENTS	O
+AND	O
+MAIN	O
+RESULTS	O
+:	O
+Metoprolol	O
+reduced	O
+maximum	O
+heart	O
+rate	O
+31	O
+%	O
+,	O
+summed	O
+stress	O
+scores	O
+29	O
+%	O
+,	O
+and	O
+summed	O
+difference	O
+scores	O
+43	O
+%	O
+versus	O
+control	O
+.	O
+
+Metoprolol	O
+plus	O
+glucagon	O
+also	O
+reduced	O
+the	O
+maximum	O
+heart	O
+rate	O
+29	O
+%	O
+versus	O
+control	O
+.	O
+
+Summed	O
+stress	O
+and	O
+summed	O
+difference	O
+scores	O
+were	O
+not	O
+significantly	O
+reduced	O
+,	O
+although	O
+they	O
+were	O
+18	O
+%	O
+and	O
+30	O
+%	O
+lower	O
+,	O
+respectively	O
+,	O
+than	O
+control	O
+.	O
+
+No	O
+significant	O
+differences	O
+were	O
+found	O
+in	O
+any	O
+parameter	O
+between	O
+metoprolol	O
+and	O
+metoprolol	O
+-	O
+glucagon	O
+.	O
+
+CONCLUSION	O
+:	O
+During	O
+dobutamine	O
+stress	O
+testing	O
+,	O
+metoprolol	O
+attenuates	O
+or	O
+eliminates	O
+evidence	O
+of	O
+myocardial	B
+ischemia	I
+.	O
+
+Glucagon	O
+1	O
+mg	O
+,	O
+although	O
+somewhat	O
+effective	O
+,	O
+does	O
+not	O
+correct	O
+this	O
+effect	O
+to	O
+the	O
+extent	O
+that	O
+it	O
+can	O
+be	O
+administered	O
+clinically	O
+.	O
+
+Evidence	O
+of	O
+functional	O
+somatotopy	O
+in	O
+GPi	O
+from	O
+results	O
+of	O
+pallidotomy	O
+.	O
+
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+explore	O
+the	O
+functional	O
+anatomy	O
+of	O
+the	O
+globus	O
+pallidus	O
+internus	O
+(	O
+GPi	O
+)	O
+by	O
+studying	O
+the	O
+effects	O
+of	O
+unilateral	O
+pallidotomy	O
+on	O
+parkinsonian	B
+'	O
+off	O
+'	O
+signs	O
+and	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+(	O
+LID	B
+)	O
+.	O
+
+We	O
+found	O
+significant	O
+positive	O
+correlations	O
+between	O
+the	O
+preoperative	O
+levodopa	O
+responsiveness	O
+of	O
+motor	O
+signs	O
+and	O
+the	O
+levodopa	O
+responsiveness	O
+of	O
+scores	O
+in	O
+timed	O
+tests	O
+(	O
+Core	O
+Assessment	O
+Program	O
+for	O
+Intracerebral	O
+Transplantations	O
+)	O
+in	O
+the	O
+contralateral	O
+limbs	O
+and	O
+the	O
+improvement	O
+in	O
+these	O
+scores	O
+after	O
+surgery	O
+,	O
+whereas	O
+there	O
+was	O
+no	O
+correlation	O
+with	O
+the	O
+improvement	O
+in	O
+LID	B
+.	O
+
+We	O
+also	O
+found	O
+a	O
+highly	O
+significant	O
+correlation	O
+(	O
+P	O
+:	O
+<	O
+0	O
+.	O
+0001	O
+,	O
+r	O
+=	O
+0	O
+.	O
+8	O
+)	O
+between	O
+the	O
+volume	O
+of	O
+the	O
+ventral	O
+lesion	O
+in	O
+the	O
+GPi	O
+and	O
+the	O
+improvement	O
+in	O
+LID	B
+in	O
+the	O
+contralateral	O
+limbs	O
+,	O
+whereas	O
+there	O
+was	O
+no	O
+correlation	O
+between	O
+the	O
+ventral	O
+volume	O
+and	O
+the	O
+improvement	O
+in	O
+parkinsonian	B
+'	O
+off	O
+'	O
+signs	O
+.	O
+
+The	O
+volumes	O
+of	O
+the	O
+total	O
+lesion	O
+cylinder	O
+and	O
+the	O
+dorsal	O
+lesion	O
+did	O
+not	O
+correlate	O
+with	O
+the	O
+outcome	O
+of	O
+either	O
+dyskinesias	B
+or	O
+parkinsonian	B
+'	O
+off	O
+'	O
+signs	O
+.	O
+
+The	O
+differential	O
+predictive	O
+value	O
+of	O
+levodopa	O
+responsiveness	O
+for	O
+the	O
+outcome	O
+of	O
+parkinsonian	B
+'	O
+off	O
+'	O
+signs	O
+and	O
+LID	B
+and	O
+the	O
+different	O
+correlations	O
+of	O
+ventral	O
+lesion	O
+volume	O
+with	O
+dyskinesias	B
+and	O
+parkinsonian	B
+'	O
+off	O
+'	O
+signs	O
+indicate	O
+that	O
+different	O
+anatomical	O
+or	O
+pathophysiological	O
+substrates	O
+may	O
+be	O
+responsible	O
+for	O
+the	O
+generation	O
+of	O
+parkinsonian	B
+'	O
+off	O
+'	O
+signs	O
+and	O
+dyskinesias	B
+.	O
+
+Whereas	O
+cells	O
+in	O
+a	O
+wider	O
+area	O
+of	O
+the	O
+GPi	O
+may	O
+be	O
+implicated	O
+in	O
+parkinsonism	B
+,	O
+the	O
+ventral	O
+GPi	O
+seems	O
+to	O
+be	O
+crucial	O
+for	O
+the	O
+manifestation	O
+of	O
+LID	B
+.	O
+
+We	O
+suggest	O
+that	O
+our	O
+observations	O
+are	O
+additional	O
+proof	O
+of	O
+the	O
+functional	O
+somatotopy	O
+of	O
+the	O
+systems	O
+within	O
+the	O
+GPi	O
+that	O
+mediate	O
+parkinsonism	B
+and	O
+dyskinesias	B
+,	O
+especially	O
+along	O
+the	O
+dorsoventral	O
+trajectory	O
+used	O
+in	O
+pallidotomy	O
+.	O
+
+The	O
+outcome	O
+of	O
+pallidotomy	O
+in	O
+which	O
+the	O
+lesion	O
+involves	O
+the	O
+ventral	O
+and	O
+dorsal	O
+GPi	O
+could	O
+be	O
+the	O
+net	O
+effect	O
+of	O
+alteration	O
+in	O
+the	O
+activity	O
+of	O
+pathways	O
+which	O
+mediate	O
+different	O
+symptoms	O
+,	O
+and	O
+hence	O
+could	O
+be	O
+variable	O
+.	O
+
+Screening	O
+for	O
+stimulant	O
+use	O
+in	O
+adult	O
+emergency	O
+department	O
+seizure	B
+patients	O
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+prevalence	O
+of	O
+positive	O
+plasma	O
+drug	O
+screening	O
+for	O
+cocaine	O
+or	O
+amphetamine	O
+in	O
+adult	O
+emergency	O
+department	O
+seizure	B
+patients	O
+.	O
+
+METHODS	O
+:	O
+This	O
+prospective	O
+study	O
+evaluated	O
+consecutive	O
+eligible	O
+seizure	B
+patients	O
+who	O
+had	O
+a	O
+plasma	O
+sample	O
+collected	O
+as	O
+part	O
+of	O
+their	O
+clinical	O
+evaluation	O
+.	O
+
+Plasma	O
+was	O
+tested	O
+for	O
+amphetamine	O
+and	O
+the	O
+cocaine	O
+metabolite	O
+benzoylecgonine	O
+using	O
+enzyme	O
+-	O
+mediated	O
+immunoassay	O
+methodology	O
+.	O
+
+Plasma	O
+samples	O
+with	O
+benzoylecgonine	O
+greater	O
+than	O
+150	O
+ng	O
+/	O
+mL	O
+or	O
+an	O
+amphetamine	O
+greater	O
+than	O
+500	O
+ng	O
+/	O
+mL	O
+were	O
+defined	O
+as	O
+positive	O
+.	O
+
+Patient	O
+demographics	O
+,	O
+history	O
+of	O
+underlying	O
+drug	O
+or	O
+alcohol	O
+-	O
+related	O
+seizure	B
+disorder	O
+,	O
+estimated	O
+time	O
+from	O
+seizure	B
+to	O
+sample	O
+collection	O
+,	O
+history	O
+or	O
+suspicion	O
+of	O
+cocaine	B
+or	I
+amphetamine	I
+abuse	I
+,	O
+results	O
+of	O
+clinical	O
+urine	O
+testing	O
+for	O
+drugs	O
+of	O
+abuse	O
+,	O
+and	O
+assay	O
+results	O
+were	O
+recorded	O
+without	O
+patient	O
+identifiers	O
+.	O
+
+RESULTS	O
+:	O
+Fourteen	O
+of	O
+248	O
+(	O
+5	O
+.	O
+6	O
+%	O
+,	O
+95	O
+%	O
+CI	O
+2	O
+.	O
+7	O
+%	O
+-	O
+8	O
+.	O
+5	O
+%	O
+)	O
+plasma	O
+samples	O
+were	O
+positive	O
+by	O
+immunoassay	O
+testing	O
+for	O
+benzoylecgonine	O
+and	O
+no	O
+samples	O
+(	O
+0	O
+%	O
+,	O
+95	O
+%	O
+CI	O
+0	O
+-	O
+1	O
+.	O
+2	O
+%	O
+)	O
+were	O
+positive	O
+for	O
+amphetamine	O
+.	O
+
+Positive	O
+test	O
+results	O
+were	O
+more	O
+common	O
+in	O
+patient	O
+visits	O
+where	O
+there	O
+was	O
+a	O
+history	O
+or	O
+suspicion	O
+of	O
+cocaine	B
+or	I
+amphetamine	I
+abuse	I
+(	O
+p	O
+<	O
+0	O
+.	O
+0005	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+During	O
+this	O
+study	O
+period	O
+,	O
+routine	O
+plasma	O
+screening	O
+for	O
+cocaine	O
+and	O
+amphetamines	O
+in	O
+adult	O
+seizure	B
+patients	O
+had	O
+a	O
+low	O
+yield	O
+.	O
+
+As	O
+a	O
+result	O
+,	O
+routine	O
+plasma	O
+screening	O
+would	O
+yield	O
+few	O
+cases	O
+of	O
+stimulant	O
+drug	O
+in	O
+which	O
+there	O
+was	O
+neither	O
+a	O
+history	O
+nor	O
+suspicion	O
+of	O
+drug	B
+abuse	I
+in	O
+this	O
+population	O
+.	O
+
+Contribution	O
+of	O
+sodium	O
+valproate	O
+to	O
+the	O
+syndrome	B
+of	I
+inappropriate	I
+secretion	I
+of	I
+antidiuretic	I
+hormone	I
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+62	O
+-	O
+year	O
+-	O
+old	O
+man	O
+who	O
+was	O
+administered	O
+sodium	O
+valproate	O
+(	O
+VPA	O
+)	O
+and	O
+who	O
+subsequently	O
+developed	O
+the	O
+syndrome	B
+of	I
+inappropriate	I
+secretion	I
+of	I
+antidiuretic	I
+hormone	I
+(	O
+SIADH	B
+)	O
+.	O
+
+He	O
+had	O
+been	O
+taking	O
+VPA	O
+for	O
+treatment	O
+of	O
+idiopathic	O
+generalized	O
+tonic	B
+-	I
+clonic	I
+convulsions	I
+since	O
+he	O
+was	O
+56	O
+years	O
+old	O
+.	O
+
+After	O
+substituting	O
+VPA	O
+with	O
+zonisamide	O
+,	O
+the	O
+serum	O
+sodium	O
+level	O
+returned	O
+to	O
+normal	O
+.	O
+
+We	O
+consider	O
+this	O
+episode	O
+of	O
+SIADH	B
+to	O
+be	O
+the	O
+result	O
+of	O
+a	O
+combination	O
+of	O
+factors	O
+including	O
+a	O
+weakness	B
+of	I
+the	I
+central	I
+nervous	I
+system	I
+and	O
+the	O
+long	O
+-	O
+term	O
+administration	O
+of	O
+VPA	O
+.	O
+
+Association	O
+of	O
+nitric	O
+oxide	O
+production	O
+and	O
+apoptosis	O
+in	O
+a	O
+model	O
+of	O
+experimental	O
+nephropathy	B
+.	O
+
+BACKGROUND	O
+:	O
+In	O
+recent	O
+studies	O
+increased	O
+amounts	O
+of	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+and	O
+apoptosis	O
+have	O
+been	O
+implicated	O
+in	O
+various	O
+pathological	O
+conditions	O
+in	O
+the	O
+kidney	O
+.	O
+
+We	O
+have	O
+studied	O
+the	O
+role	O
+of	O
+NO	O
+and	O
+its	O
+association	O
+with	O
+apoptosis	O
+in	O
+an	O
+experimental	O
+model	O
+of	O
+nephrotic	B
+syndrome	I
+induced	O
+by	O
+a	O
+single	O
+injection	O
+of	O
+adriamycin	O
+(	O
+ADR	O
+)	O
+.	O
+
+METHODS	O
+:	O
+The	O
+alteration	O
+in	O
+the	O
+NO	O
+pathway	O
+was	O
+assessed	O
+by	O
+measuring	O
+nitrite	O
+levels	O
+in	O
+serum	O
+/	O
+urine	O
+and	O
+by	O
+evaluating	O
+the	O
+changes	O
+in	O
+vascular	O
+reactivity	O
+of	O
+the	O
+isolated	O
+perfused	O
+rat	O
+kidney	O
+(	O
+IPRK	O
+)	O
+system	O
+.	O
+
+Rats	O
+were	O
+stratified	O
+into	O
+control	O
+groups	O
+and	O
+ADR	O
+-	O
+induced	O
+nephropathy	B
+groups	O
+.	O
+
+These	O
+two	O
+groups	O
+were	O
+then	O
+divided	O
+into	O
+:	O
+group	O
+1	O
+,	O
+animals	O
+receiving	O
+saline	O
+;	O
+and	O
+group	O
+2	O
+,	O
+animals	O
+receiving	O
+aminoguanidine	O
+(	O
+AG	O
+)	O
+which	O
+is	O
+a	O
+specific	O
+inhibitor	O
+of	O
+inducible	O
+-	O
+NO	O
+synthase	O
+.	O
+
+On	O
+day	O
+21	O
+,	O
+rats	O
+were	O
+sacrificed	O
+after	O
+obtaining	O
+material	O
+for	O
+biochemical	O
+analysis	O
+.	O
+
+RESULTS	O
+:	O
+Histopathological	O
+examination	O
+of	O
+the	O
+kidneys	O
+of	O
+rats	O
+treated	O
+with	O
+ADR	O
+revealed	O
+focal	O
+areas	O
+of	O
+mesangial	B
+proliferation	I
+and	O
+mild	O
+tubulointerstitial	B
+inflammation	I
+.	O
+
+They	O
+also	O
+had	O
+significantly	O
+higher	O
+levels	O
+of	O
+proteinuria	B
+compared	O
+with	O
+control	O
+and	O
+treatment	O
+groups	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Urine	O
+nitrite	O
+levels	O
+were	O
+significantly	O
+increased	O
+in	O
+the	O
+ADR	O
+-	O
+nephropathy	B
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+In	O
+the	O
+IPRK	O
+phenylephrine	O
+and	O
+acetylcholine	O
+related	O
+responses	O
+were	O
+significantly	O
+impaired	O
+in	O
+the	O
+ADR	O
+-	O
+nephropathy	B
+group	O
+.	O
+
+Apoptosis	O
+was	O
+not	O
+detected	O
+in	O
+controls	O
+.	O
+
+However	O
+,	O
+in	O
+the	O
+ADR	O
+-	O
+nephropathy	B
+group	O
+,	O
+numerous	O
+apoptotic	O
+cells	O
+were	O
+identified	O
+in	O
+the	O
+tubulointerstitial	O
+areas	O
+.	O
+
+Double	O
+staining	O
+revealed	O
+numerous	O
+interstitial	O
+apoptotic	O
+cells	O
+to	O
+stain	O
+for	O
+ED1	O
+,	O
+a	O
+marker	O
+for	O
+monocytes	O
+/	O
+macrophages	O
+.	O
+
+Treatment	O
+with	O
+AG	O
+prevented	O
+the	O
+impairment	O
+of	O
+renal	O
+vascular	O
+bed	O
+responses	O
+and	O
+reduced	O
+both	O
+urine	O
+nitrite	O
+levels	O
+and	O
+apoptosis	O
+to	O
+control	O
+levels	O
+.	O
+
+CONCLUSION	O
+:	O
+We	O
+suggest	O
+that	O
+interactions	O
+between	O
+NO	O
+and	O
+apoptosis	O
+are	O
+important	O
+in	O
+the	O
+pathogenesis	O
+of	O
+the	O
+ADR	O
+-	O
+induced	O
+nephrosis	B
+.	O
+
+Dual	O
+effects	O
+of	O
+melatonin	O
+on	O
+barbiturate	O
+-	O
+induced	O
+narcosis	B
+in	O
+rats	O
+.	O
+
+Melatonin	O
+affects	O
+the	O
+circadian	O
+sleep	O
+/	O
+wake	O
+cycle	O
+,	O
+but	O
+it	O
+is	O
+not	O
+clear	O
+whether	O
+it	O
+may	O
+influence	O
+drug	O
+-	O
+induced	O
+narcosis	B
+.	O
+
+Sodium	O
+thiopenthal	O
+was	O
+administered	O
+intraperitoneally	O
+into	O
+male	O
+rats	O
+pre	O
+-	O
+treated	O
+with	O
+melatonin	O
+(	O
+0	O
+.	O
+05	O
+,	O
+0	O
+.	O
+5	O
+,	O
+5	O
+and	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+Melatonin	O
+pre	O
+-	O
+treatment	O
+affected	O
+in	O
+a	O
+dual	O
+manner	O
+barbiturate	O
+narcosis	B
+,	O
+however	O
+,	O
+no	O
+dose	O
+-	O
+effect	O
+correlation	O
+was	O
+found	O
+.	O
+
+In	O
+particular	O
+,	O
+low	O
+doses	O
+reduced	O
+the	O
+latency	O
+to	O
+and	O
+prolonged	O
+the	O
+duration	O
+of	O
+barbiturate	O
+narcosis	B
+.	O
+
+In	O
+contrast	O
+,	O
+the	O
+highest	O
+dose	O
+of	O
+melatonin	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+caused	O
+a	O
+paradoxical	O
+increase	O
+in	O
+the	O
+latency	O
+and	O
+produced	O
+a	O
+sustained	O
+reduction	O
+of	O
+the	O
+duration	O
+of	O
+narcosis	B
+,	O
+and	O
+a	O
+reduction	O
+in	O
+mortality	O
+rate	O
+.	O
+
+Melatonin	O
+0	O
+.	O
+5	O
+and	O
+5	O
+mg	O
+/	O
+kg	O
+influenced	O
+the	O
+duration	O
+but	O
+not	O
+the	O
+latency	O
+of	O
+ketamine	O
+-	O
+or	O
+diazepam	O
+-	O
+induced	O
+narcosis	B
+.	O
+
+Thus	O
+,	O
+the	O
+dual	O
+action	O
+of	O
+melatonin	O
+on	O
+pharmacological	O
+narcosis	B
+seems	O
+to	O
+be	O
+specific	O
+for	O
+the	O
+barbiturate	O
+mechanism	O
+of	O
+action	O
+.	O
+
+Reduced	O
+cardiotoxicity	B
+and	O
+preserved	O
+antitumor	O
+efficacy	O
+of	O
+liposome	O
+-	O
+encapsulated	O
+doxorubicin	O
+and	O
+cyclophosphamide	O
+compared	O
+with	O
+conventional	O
+doxorubicin	O
+and	O
+cyclophosphamide	O
+in	O
+a	O
+randomized	O
+,	O
+multicenter	O
+trial	O
+of	O
+metastatic	O
+breast	B
+cancer	I
+.	O
+
+PURPOSE	O
+:	O
+To	O
+determine	O
+whether	O
+Myocet	O
+(	O
+liposome	O
+-	O
+encapsulated	O
+doxorubicin	O
+;	O
+The	O
+Liposome	O
+Company	O
+,	O
+Elan	O
+Corporation	O
+,	O
+Princeton	O
+,	O
+NJ	O
+)	O
+in	O
+combination	O
+with	O
+cyclophosphamide	O
+significantly	O
+reduces	O
+doxorubicin	O
+cardiotoxicity	B
+while	O
+providing	O
+comparable	O
+antitumor	O
+efficacy	O
+in	O
+first	O
+-	O
+line	O
+treatment	O
+of	O
+metastatic	O
+breast	B
+cancer	I
+(	O
+MBC	B
+)	O
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+Two	O
+hundred	O
+ninety	O
+-	O
+seven	O
+patients	O
+with	O
+MBC	B
+and	O
+no	O
+prior	O
+chemotherapy	O
+for	O
+metastatic	O
+disease	O
+were	O
+randomized	O
+to	O
+receive	O
+either	O
+60	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+of	O
+Myocet	O
+(	O
+M	O
+)	O
+or	O
+conventional	O
+doxorubicin	O
+(	O
+A	O
+)	O
+,	O
+in	O
+combination	O
+with	O
+600	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+of	O
+cyclophosphamide	O
+(	O
+C	O
+)	O
+,	O
+every	O
+3	O
+weeks	O
+until	O
+disease	O
+progression	O
+or	O
+unacceptable	O
+toxicity	B
+.	O
+
+Cardiotoxicity	B
+was	O
+defined	O
+by	O
+reductions	O
+in	O
+left	O
+-	O
+ventricular	O
+ejection	O
+fraction	O
+,	O
+assessed	O
+by	O
+serial	O
+multigated	O
+radionuclide	O
+angiography	O
+scans	O
+,	O
+or	O
+congestive	B
+heart	I
+failure	I
+(	O
+CHF	B
+)	O
+.	O
+
+Antitumor	O
+efficacy	O
+was	O
+assessed	O
+by	O
+objective	O
+tumor	B
+response	O
+rates	O
+(	O
+World	O
+Health	O
+Organization	O
+criteria	O
+)	O
+,	O
+time	O
+to	O
+progression	O
+,	O
+and	O
+survival	O
+.	O
+
+RESULTS	O
+:	O
+Six	O
+percent	O
+of	O
+MC	O
+patients	O
+versus	O
+21	O
+%	O
+(	O
+including	O
+five	O
+cases	O
+of	O
+CHF	B
+)	O
+of	O
+AC	O
+patients	O
+developed	O
+cardiotoxicity	B
+(	O
+P	O
+=	O
+.	O
+0002	O
+)	O
+.	O
+
+Median	O
+cumulative	O
+doxorubicin	O
+dose	O
+at	O
+onset	O
+was	O
+more	O
+than	O
+2	O
+,	O
+220	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+for	O
+MC	O
+versus	O
+480	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+for	O
+AC	O
+(	O
+P	O
+=	O
+.	O
+0001	O
+,	O
+hazard	O
+ratio	O
+,	O
+5	O
+.	O
+04	O
+)	O
+.	O
+
+MC	O
+patients	O
+also	O
+experienced	O
+less	O
+grade	O
+4	O
+neutropenia	B
+.	O
+
+Antitumor	O
+efficacy	O
+of	O
+MC	O
+versus	O
+AC	O
+was	O
+comparable	O
+:	O
+objective	O
+response	O
+rates	O
+,	O
+43	O
+%	O
+versus	O
+43	O
+%	O
+;	O
+median	O
+time	O
+to	O
+progression	O
+,	O
+5	O
+.	O
+1	O
+%	O
+versus	O
+5	O
+.	O
+5	O
+months	O
+;	O
+median	O
+time	O
+to	O
+treatment	O
+failure	O
+,	O
+4	O
+.	O
+6	O
+versus	O
+4	O
+.	O
+4	O
+months	O
+;	O
+and	O
+median	O
+survival	O
+,	O
+19	O
+versus	O
+16	O
+months	O
+.	O
+
+CONCLUSION	O
+:	O
+Myocet	O
+improves	O
+the	O
+therapeutic	O
+index	O
+of	O
+doxorubicin	O
+by	O
+significantly	O
+reducing	O
+cardiotoxicity	B
+and	O
+grade	O
+4	O
+neutropenia	B
+and	O
+provides	O
+comparable	O
+antitumor	O
+efficacy	O
+,	O
+when	O
+used	O
+in	O
+combination	O
+with	O
+cyclophosphamide	O
+as	O
+first	O
+-	O
+line	O
+therapy	O
+for	O
+MBC	B
+.	O
+
+The	O
+role	O
+of	O
+nitrergic	O
+system	O
+in	O
+lidocaine	O
+-	O
+induced	O
+convulsion	B
+in	O
+the	O
+mouse	O
+.	O
+
+The	O
+effects	O
+of	O
+N	O
+-	O
+nitro	O
+-	O
+L	O
+-	O
+arginine	O
+-	O
+methyl	O
+ester	O
+(	O
+L	O
+-	O
+NAME	O
+)	O
+a	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+synthase	O
+inhibitor	O
+and	O
+L	O
+-	O
+arginine	O
+,	O
+a	O
+NO	O
+precursor	O
+,	O
+were	O
+investigated	O
+on	O
+lidocaine	O
+-	O
+induced	O
+convulsions	B
+.	O
+
+In	O
+the	O
+first	O
+experiment	O
+,	O
+four	O
+groups	O
+of	O
+mice	O
+received	O
+physiological	O
+saline	O
+(	O
+0	O
+.	O
+9	O
+%	O
+)	O
+,	O
+L	O
+-	O
+arginine	O
+(	O
+300	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+,	O
+L	O
+-	O
+NAME	O
+(	O
+100	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+and	O
+diazepam	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+respectively	O
+.	O
+
+Thirty	O
+minutes	O
+after	O
+these	O
+injections	O
+,	O
+all	O
+mice	O
+received	O
+lidocaine	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+In	O
+the	O
+second	O
+experiment	O
+,	O
+four	O
+groups	O
+of	O
+mice	O
+received	O
+similar	O
+treatment	O
+in	O
+the	O
+first	O
+experiment	O
+,	O
+and	O
+30	O
+min	O
+after	O
+these	O
+injections	O
+,	O
+all	O
+mice	O
+received	O
+a	O
+higher	O
+dose	O
+of	O
+lidocaine	O
+(	O
+80	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+L	O
+-	O
+NAME	O
+(	O
+100	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+and	O
+diazepam	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+)	O
+significantly	O
+decreased	O
+the	O
+incidence	O
+of	O
+lidocaine	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+-	O
+induced	O
+convulsions	B
+.	O
+
+In	O
+contrast	O
+,	O
+the	O
+L	O
+-	O
+arginine	O
+treatment	O
+increased	O
+the	O
+incidence	O
+of	O
+lidocaine	O
+(	O
+80	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+-	O
+induced	O
+convulsions	B
+significantly	O
+.	O
+
+These	O
+results	O
+may	O
+suggest	O
+that	O
+NO	O
+is	O
+a	O
+proconvulsant	O
+mediator	O
+in	O
+lidocaine	O
+-	O
+induced	O
+convulsions	B
+.	O
+
+Erythropoietin	O
+restores	O
+the	O
+anemia	B
+-	O
+induced	O
+reduction	O
+in	O
+cyclophosphamide	O
+cytotoxicity	B
+in	O
+rat	O
+tumors	B
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+examine	O
+the	O
+impact	O
+of	O
+anemia	B
+prevention	O
+by	O
+recombinant	O
+human	O
+erythropoietin	O
+(	O
+rHuEPO	O
+)	O
+treatment	O
+on	O
+the	O
+cytotoxicity	B
+of	O
+cyclophosphamide	O
+in	O
+solid	O
+experimental	O
+tumors	B
+.	O
+
+Anemia	B
+was	O
+induced	O
+using	O
+a	O
+single	O
+dose	O
+of	O
+carboplatin	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+resulting	O
+in	O
+a	O
+long	O
+-	O
+lasting	O
+reduction	O
+(	O
+30	O
+%	O
+)	O
+of	O
+the	O
+hemoglobin	O
+concentration	O
+.	O
+
+In	O
+a	O
+second	O
+group	O
+,	O
+the	O
+development	O
+of	O
+anemia	B
+was	O
+prevented	O
+by	O
+rHuEPO	O
+(	O
+1000	O
+IU	O
+/	O
+kg	O
+)	O
+administered	O
+s	O
+.	O
+c	O
+.	O
+three	O
+times	O
+/	O
+week	O
+starting	O
+7	O
+days	O
+before	O
+carboplatin	O
+application	O
+.	O
+
+Four	O
+days	O
+after	O
+carboplatin	O
+treatment	O
+,	O
+tumors	B
+(	O
+DS	O
+-	O
+sarcoma	B
+of	O
+the	O
+rat	O
+)	O
+were	O
+implanted	O
+s	O
+.	O
+c	O
+.	O
+onto	O
+the	O
+hind	O
+food	O
+dorsum	O
+.	O
+
+Neither	O
+carboplatin	O
+nor	O
+rHuEPO	O
+treatment	O
+influenced	O
+tumor	B
+growth	O
+rate	O
+per	O
+se	O
+.	O
+
+When	O
+tumors	B
+were	O
+treated	O
+with	O
+a	O
+single	O
+dose	O
+of	O
+cyclophosphamide	O
+(	O
+60	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+5	O
+days	O
+after	O
+implantation	O
+,	O
+a	O
+growth	O
+delay	O
+with	O
+a	O
+subsequent	O
+regrowth	O
+of	O
+the	O
+tumors	B
+was	O
+observed	O
+.	O
+
+In	O
+the	O
+anemia	B
+group	O
+,	O
+the	O
+growth	O
+delay	O
+was	O
+significantly	O
+shorter	O
+compared	O
+with	O
+nonanemic	O
+controls	O
+(	O
+13	O
+.	O
+3	O
+days	O
+versus	O
+8	O
+.	O
+6	O
+days	O
+)	O
+.	O
+
+In	O
+the	O
+group	O
+where	O
+anemia	B
+was	O
+prevented	O
+by	O
+rHuEPO	O
+treatment	O
+,	O
+growth	O
+delay	O
+was	O
+comparable	O
+with	O
+that	O
+of	O
+nonanemic	O
+controls	O
+(	O
+13	O
+.	O
+3	O
+days	O
+)	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+chemotherapy	O
+-	O
+induced	O
+anemia	B
+reduces	O
+cytotoxicity	B
+of	O
+cyclophosphamide	O
+in	O
+tumors	B
+,	O
+whereas	O
+correction	O
+of	O
+anemia	B
+by	O
+rHuEPO	O
+treatment	O
+(	O
+epoetin	O
+alpha	O
+)	O
+increases	O
+the	O
+sensitivity	O
+,	O
+probably	O
+as	O
+a	O
+result	O
+of	O
+an	O
+improved	O
+oxygen	O
+supply	O
+to	O
+tumor	B
+tissue	O
+.	O
+
+Fatal	O
+haemorrhagic	B
+myocarditis	I
+secondary	O
+to	O
+cyclophosphamide	O
+therapy	O
+.	O
+
+Haemorrhagic	B
+myocarditis	I
+is	O
+a	O
+rare	O
+but	O
+important	O
+complication	O
+of	O
+cyclophosphamide	O
+therapy	O
+.	O
+
+Echocardiographic	O
+identification	O
+of	O
+the	O
+disorder	O
+can	O
+be	O
+made	O
+.	O
+
+We	O
+believe	O
+that	O
+the	O
+ultrasound	O
+features	O
+of	O
+this	O
+disorder	O
+have	O
+not	O
+been	O
+previously	O
+reported	O
+.	O
+
+Effects	O
+of	O
+verapamil	O
+on	O
+atrial	B
+fibrillation	I
+and	O
+its	O
+electrophysiological	O
+determinants	O
+in	O
+dogs	O
+.	O
+
+BACKGROUND	O
+:	O
+Atrial	B
+tachycardia	I
+-	O
+induced	O
+remodeling	O
+promotes	O
+the	O
+occurrence	O
+and	O
+maintenance	O
+of	O
+atrial	B
+fibrillation	I
+(	O
+AF	B
+)	O
+and	O
+decreases	O
+L	O
+-	O
+type	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+current	O
+.	O
+
+There	O
+is	O
+also	O
+a	O
+clinical	O
+suggestion	O
+that	O
+acute	O
+L	O
+-	O
+type	O
+Ca	O
+(	O
+2	O
+)	O
+channel	O
+blockade	O
+can	O
+promote	O
+AF	B
+,	O
+consistent	O
+with	O
+an	O
+AF	B
+promoting	O
+effect	O
+of	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+channel	O
+inhibition	O
+.	O
+
+METHODS	O
+:	O
+To	O
+evaluate	O
+the	O
+potential	O
+mechanisms	O
+of	O
+AF	B
+promotion	O
+by	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+channel	O
+blockers	O
+,	O
+we	O
+administered	O
+verapamil	O
+to	O
+morphine	O
+-	O
+chloralose	O
+anesthetized	O
+dogs	O
+.	O
+
+Diltiazem	O
+was	O
+used	O
+as	O
+a	O
+comparison	O
+drug	O
+and	O
+autonomic	O
+blockade	O
+with	O
+atropine	O
+and	O
+nadolol	O
+was	O
+applied	O
+in	O
+some	O
+experiments	O
+.	O
+
+Epicardial	O
+mapping	O
+with	O
+240	O
+epicardial	O
+electrodes	O
+was	O
+used	O
+to	O
+evaluate	O
+activation	O
+during	O
+AF	B
+.	O
+
+RESULTS	O
+:	O
+Verapamil	O
+caused	O
+AF	B
+promotion	O
+in	O
+six	O
+dogs	O
+,	O
+increasing	O
+mean	O
+duration	O
+of	O
+AF	B
+induced	O
+by	O
+burst	O
+pacing	O
+,	O
+from	O
+8	O
++	O
+/	O
+-	O
+4	O
+s	O
+(	O
+mean	O
++	O
+/	O
+-	O
+S	O
+.	O
+E	O
+.	O
+)	O
+to	O
+95	O
++	O
+/	O
+-	O
+39	O
+s	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+vs	O
+.	O
+control	O
+)	O
+at	O
+a	O
+loading	O
+dose	O
+of	O
+0	O
+.	O
+1	O
+mg	O
+/	O
+kg	O
+and	O
+228	O
++	O
+/	O
+-	O
+101	O
+s	O
+(	O
+P	O
+<	O
+0	O
+.	O
+0005	O
+vs	O
+.	O
+control	O
+)	O
+at	O
+a	O
+dose	O
+of	O
+0	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+.	O
+
+Underlying	O
+electrophysiological	O
+mechanisms	O
+were	O
+studied	O
+in	O
+detail	O
+in	O
+five	O
+additional	O
+dogs	O
+under	O
+control	O
+conditions	O
+and	O
+in	O
+the	O
+presence	O
+of	O
+the	O
+higher	O
+dose	O
+of	O
+verapamil	O
+.	O
+
+In	O
+these	O
+experiments	O
+,	O
+verapamil	O
+shortened	O
+mean	O
+effective	O
+refractory	O
+period	O
+(	O
+ERP	O
+)	O
+from	O
+122	O
++	O
+/	O
+-	O
+5	O
+to	O
+114	O
++	O
+/	O
+-	O
+4	O
+ms	O
+(	O
+P	O
+<	O
+0	O
+.	O
+02	O
+)	O
+at	O
+a	O
+cycle	O
+length	O
+of	O
+300	O
+ms	O
+,	O
+decreased	O
+ERP	O
+heterogeneity	O
+(	O
+from	O
+15	O
++	O
+/	O
+-	O
+1	O
+to	O
+10	O
++	O
+/	O
+-	O
+1	O
+%	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+,	O
+heterogeneously	O
+accelerated	O
+atrial	O
+conduction	O
+and	O
+decreased	O
+the	O
+cycle	O
+length	O
+of	O
+AF	B
+(	O
+94	O
++	O
+/	O
+-	O
+4	O
+to	O
+84	O
++	O
+/	O
+-	O
+3	O
+ms	O
+,	O
+P	O
+<	O
+0	O
+.	O
+005	O
+)	O
+.	O
+
+Diltiazem	O
+did	O
+not	O
+affect	O
+ERP	O
+,	O
+AF	B
+cycle	O
+length	O
+or	O
+AF	B
+duration	O
+,	O
+but	O
+produced	O
+conduction	O
+acceleration	O
+similar	O
+to	O
+that	O
+caused	O
+by	O
+verapamil	O
+(	O
+n	O
+=	O
+5	O
+)	O
+.	O
+
+In	O
+the	O
+presence	O
+of	O
+autonomic	O
+blockade	O
+,	O
+verapamil	O
+failed	O
+to	O
+promote	O
+AF	B
+and	O
+increased	O
+,	O
+rather	O
+than	O
+decreasing	O
+,	O
+refractoriness	O
+.	O
+
+Neither	O
+verapamil	O
+nor	O
+diltiazem	O
+affected	O
+atrial	O
+conduction	O
+in	O
+the	O
+presence	O
+of	O
+autonomic	O
+blockade	O
+.	O
+
+Epicardial	O
+mapping	O
+suggested	O
+that	O
+verapamil	O
+promoted	O
+AF	B
+by	O
+increasing	O
+the	O
+number	O
+of	O
+simultaneous	O
+wavefronts	O
+reflected	O
+by	O
+separate	O
+zones	O
+of	O
+reactivation	O
+in	O
+each	O
+cycle	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Verapamil	O
+promotes	O
+AF	B
+in	O
+normal	O
+dogs	O
+by	O
+promoting	O
+multiple	O
+circuit	O
+reentry	O
+,	O
+an	O
+effect	O
+dependent	O
+on	O
+intact	O
+autonomic	O
+tone	O
+and	O
+not	O
+shared	O
+by	O
+diltiazem	O
+.	O
+
+Calcitonin	O
+gene	O
+-	O
+related	O
+peptide	O
+levels	O
+during	O
+nitric	O
+oxide	O
+-	O
+induced	O
+headache	B
+in	O
+patients	O
+with	O
+chronic	O
+tension	B
+-	I
+type	I
+headache	I
+.	O
+
+It	O
+has	O
+been	O
+proposed	O
+that	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+induced	O
+headache	B
+in	O
+primary	B
+headaches	I
+may	O
+be	O
+associated	O
+with	O
+release	O
+of	O
+calcitonin	O
+gene	O
+-	O
+related	O
+peptide	O
+(	O
+CGRP	O
+)	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+we	O
+aimed	O
+to	O
+investigate	O
+plasma	O
+levels	O
+of	O
+CGRP	O
+during	O
+headache	B
+induced	O
+by	O
+the	O
+NO	O
+donor	O
+glyceryl	O
+trinitrate	O
+(	O
+GTN	O
+)	O
+in	O
+16	O
+patients	O
+with	O
+chronic	O
+tension	B
+-	I
+type	I
+headache	I
+and	O
+16	O
+healthy	O
+controls	O
+.	O
+
+The	O
+subjects	O
+were	O
+randomly	O
+allocated	O
+to	O
+receive	O
+0	O
+.	O
+5	O
+microg	O
+/	O
+kg	O
+/	O
+min	O
+GTN	O
+or	O
+placebo	O
+over	O
+20	O
+min	O
+on	O
+two	O
+headache	B
+-	O
+free	O
+days	O
+.	O
+
+Blood	O
+samples	O
+were	O
+collected	O
+at	O
+baseline	O
+,	O
+10	O
+,	O
+20	O
+and	O
+60	O
+min	O
+after	O
+start	O
+of	O
+infusion	O
+.	O
+
+Both	O
+patients	O
+and	O
+controls	O
+developed	O
+significantly	O
+stronger	O
+immediate	O
+headache	B
+on	O
+the	O
+GTN	O
+day	O
+than	O
+on	O
+the	O
+placebo	O
+day	O
+and	O
+the	O
+headache	B
+was	O
+significantly	O
+more	O
+pronounced	O
+in	O
+patients	O
+than	O
+in	O
+controls	O
+.	O
+
+There	O
+was	O
+no	O
+difference	O
+between	O
+the	O
+area	O
+under	O
+the	O
+CGRP	O
+curve	O
+(	O
+AUCCGRP	O
+)	O
+on	O
+GTN	O
+vs	O
+.	O
+placebo	O
+day	O
+in	O
+either	O
+patients	O
+(	O
+P	O
+=	O
+0	O
+.	O
+65	O
+)	O
+or	O
+controls	O
+(	O
+P	O
+=	O
+0	O
+.	O
+48	O
+)	O
+.	O
+
+The	O
+AUCCGRP	O
+recorded	O
+on	O
+the	O
+GTN	O
+day	O
+did	O
+not	O
+differ	O
+between	O
+patients	O
+and	O
+controls	O
+(	O
+P	O
+=	O
+0	O
+.	O
+36	O
+)	O
+.	O
+
+Both	O
+in	O
+patients	O
+and	O
+controls	O
+,	O
+CGRP	O
+levels	O
+changed	O
+significantly	O
+over	O
+time	O
+,	O
+on	O
+both	O
+the	O
+GTN	O
+and	O
+placebo	O
+days	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+present	O
+study	O
+indicates	O
+that	O
+NO	O
+-	O
+induced	O
+immediate	O
+headache	B
+is	O
+not	O
+associated	O
+with	O
+release	O
+of	O
+CGRP	O
+.	O
+
+Fluconazole	O
+-	O
+induced	O
+torsade	B
+de	I
+pointes	I
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+present	O
+a	O
+case	O
+of	O
+fluconazole	O
+-	O
+associated	O
+torsade	B
+de	I
+pointes	I
+(	O
+TDP	B
+)	O
+and	O
+discuss	O
+fluconazole	O
+'	O
+s	O
+role	O
+in	O
+causing	O
+TDP	B
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+68	O
+-	O
+year	O
+-	O
+old	O
+white	O
+woman	O
+with	O
+Candida	O
+glabrata	O
+isolated	O
+from	O
+a	O
+presacral	O
+abscess	O
+developed	O
+TDP	B
+eight	O
+days	O
+after	O
+commencing	O
+oral	O
+fluconazole	O
+The	O
+patient	O
+had	O
+no	O
+other	O
+risk	O
+factors	O
+for	O
+TDP	B
+,	O
+including	O
+coronary	B
+artery	I
+disease	I
+,	O
+cardiomyopathy	B
+,	O
+congestive	B
+heart	I
+failure	I
+,	O
+and	O
+electrolyte	O
+abnormalities	O
+There	O
+was	O
+a	O
+temporal	O
+association	O
+between	O
+the	O
+initiation	O
+of	O
+fluconazole	O
+and	O
+TDP	B
+.	O
+
+The	O
+TDP	B
+resolved	O
+when	O
+fluconazole	O
+was	O
+discontinued	O
+;	O
+however	O
+,	O
+the	O
+patient	O
+continued	O
+to	O
+have	O
+premature	B
+ventricular	I
+contractions	I
+and	O
+nonsustained	O
+ventricular	B
+tachycardia	I
+(	O
+NSVT	B
+)	O
+until	O
+six	O
+days	O
+after	O
+drug	O
+cessation	O
+DISCUSSION	O
+:	O
+Use	O
+of	O
+the	O
+Naranjo	O
+probability	O
+scale	O
+indicates	O
+a	O
+probable	O
+relationship	O
+between	O
+the	O
+use	O
+of	O
+fluconazole	O
+and	O
+the	O
+development	O
+of	O
+TDP	B
+.	O
+
+The	O
+possible	O
+mechanism	O
+is	O
+depression	B
+of	O
+rapidly	O
+activating	O
+delayed	O
+rectifier	O
+potassium	O
+currents	O
+.	O
+
+In	O
+our	O
+patient	O
+,	O
+there	O
+was	O
+no	O
+other	O
+etiology	O
+identified	O
+that	O
+could	O
+explain	O
+QT	B
+prolongation	I
+or	O
+TDP	B
+The	O
+complete	O
+disappearance	O
+of	O
+NSVT	B
+and	O
+premature	B
+ventricular	I
+contractions	I
+followed	O
+by	O
+normalization	O
+of	O
+QT	O
+interval	O
+after	O
+the	O
+drug	O
+was	O
+stopped	O
+strongly	O
+suggests	O
+fluconazole	O
+as	O
+the	O
+etiology	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Clinicians	O
+should	O
+be	O
+aware	O
+that	O
+fluconazole	O
+,	O
+even	O
+at	O
+low	O
+doses	O
+,	O
+may	O
+cause	O
+prolongation	B
+of	I
+the	I
+QT	I
+interval	I
+,	O
+leading	O
+to	O
+TDP	B
+.	O
+
+Serial	O
+electrocardiographic	O
+monitoring	O
+may	O
+be	O
+considered	O
+when	O
+fluconazole	O
+is	O
+administered	O
+in	O
+patients	O
+who	O
+are	O
+at	O
+risk	O
+for	O
+ventricular	B
+arrhythmias	I
+.	O
+
+Cutaneous	B
+leucocytoclastic	I
+vasculitis	I
+associated	O
+with	O
+oxacillin	O
+.	O
+
+A	O
+67	O
+-	O
+year	O
+-	O
+old	O
+man	O
+who	O
+was	O
+treated	O
+with	O
+oxacillin	O
+for	O
+one	O
+week	O
+because	O
+of	O
+Staphylococcus	B
+aureus	I
+bacteremia	I
+,	O
+developed	O
+renal	B
+failure	I
+and	O
+diffuse	O
+,	O
+symmetric	O
+,	O
+palpable	O
+purpuric	B
+lesions	I
+on	O
+his	O
+feet	O
+.	O
+
+Necrotic	B
+blisters	I
+were	O
+noted	O
+on	O
+his	O
+fingers	O
+.	O
+
+Skin	O
+biopsies	O
+showed	O
+findings	O
+diagnostic	O
+of	O
+leucocytoclastic	B
+vasculitis	I
+.	O
+
+Oxacillin	O
+was	O
+discontinued	O
+and	O
+patient	O
+was	O
+treated	O
+with	O
+corticosteroids	O
+.	O
+
+The	O
+rash	B
+disappeared	O
+after	O
+three	O
+weeks	O
+and	O
+renal	O
+function	O
+returned	O
+to	O
+normal	O
+.	O
+
+Leucocytoclastic	B
+vasculitis	I
+presents	O
+as	O
+palpable	O
+purpura	B
+of	O
+the	O
+lower	O
+extremities	O
+often	O
+accompanied	O
+by	O
+abdominal	B
+pain	I
+,	O
+arthralgia	B
+,	O
+and	O
+renal	B
+involvement	I
+.	O
+
+Etiologic	O
+factors	O
+or	O
+associated	O
+disorders	O
+include	O
+infections	B
+,	O
+medications	O
+,	O
+collagen	B
+vascular	I
+disease	I
+and	O
+neoplasia	B
+.	O
+
+However	O
+,	O
+in	O
+half	O
+of	O
+the	O
+cases	O
+no	O
+etiologic	O
+factor	O
+is	O
+identified	O
+.	O
+
+Usually	O
+it	O
+is	O
+a	O
+self	O
+-	O
+limited	O
+disorder	O
+,	O
+but	O
+corticosteroid	O
+therapy	O
+may	O
+be	O
+needed	O
+in	O
+life	O
+-	O
+threatening	O
+cases	O
+since	O
+early	O
+treatment	O
+with	O
+corticosteroids	O
+in	O
+severe	O
+cases	O
+can	O
+prevent	O
+complications	O
+.	O
+
+Oxacillin	O
+should	O
+be	O
+included	O
+among	O
+the	O
+drugs	O
+that	O
+can	O
+cause	O
+leucocytoclastic	B
+vasculitis	I
+.	O
+
+The	O
+renal	O
+pathology	O
+in	O
+a	O
+case	O
+of	O
+lithium	O
+-	O
+induced	O
+diabetes	B
+insipidus	I
+.	O
+
+A	O
+case	O
+of	O
+lithium	O
+-	O
+induced	O
+diabetes	B
+insipidus	I
+is	O
+reported	O
+.	O
+
+At	O
+necropsy	O
+microscopy	O
+shoed	O
+unique	O
+and	O
+extensive	O
+damage	O
+to	O
+cells	O
+lining	O
+the	O
+distal	O
+nephron	O
+.	O
+
+It	O
+is	O
+suggested	O
+that	O
+these	O
+changes	O
+represent	O
+a	O
+specific	O
+toxic	O
+effect	O
+of	O
+lithium	O
+,	O
+reported	O
+here	O
+for	O
+the	O
+first	O
+time	O
+in	O
+man	O
+.	O
+
+Cholestatic	B
+jaundice	I
+associated	O
+with	O
+the	O
+use	O
+of	O
+metformin	O
+.	O
+
+We	O
+report	O
+a	O
+patient	O
+who	O
+developed	O
+cholestatic	B
+jaundice	I
+shortly	O
+after	O
+initiation	O
+of	O
+treatment	O
+with	O
+metformin	O
+hydrochloride	O
+.	O
+
+Ultrasound	O
+of	O
+the	O
+liver	O
+and	O
+abdominal	O
+CT	O
+were	O
+normal	O
+.	O
+
+An	O
+ERCP	O
+showed	O
+normal	O
+biliary	O
+anatomy	O
+.	O
+
+A	O
+percutaneous	O
+liver	O
+biopsy	O
+was	O
+obtained	O
+showing	O
+marked	O
+cholestasis	B
+,	O
+with	O
+portal	O
+edema	B
+,	O
+ductular	O
+proliferation	O
+,	O
+and	O
+acute	O
+inflammation	B
+.	O
+
+Metformin	O
+hydrochloride	O
+was	O
+discontinued	O
+,	O
+and	O
+the	O
+patient	O
+'	O
+s	O
+jaundice	B
+resolved	O
+slowly	O
+over	O
+a	O
+period	O
+of	O
+several	O
+months	O
+.	O
+
+Given	O
+the	O
+onset	O
+of	O
+his	O
+jaundice	B
+2	O
+wk	O
+after	O
+the	O
+initiation	O
+of	O
+metformin	O
+,	O
+we	O
+believe	O
+that	O
+this	O
+case	O
+represents	O
+an	O
+example	O
+of	O
+metformin	O
+-	O
+associated	O
+hepatotoxicity	B
+,	O
+the	O
+first	O
+such	O
+case	O
+reported	O
+.	O
+
+Systemic	O
+toxicity	B
+and	O
+resuscitation	O
+in	O
+bupivacaine	O
+-	O
+,	O
+levobupivacaine	O
+-	O
+,	O
+or	O
+ropivacaine	O
+-	O
+infused	O
+rats	O
+.	O
+
+We	O
+compared	O
+the	O
+systemic	O
+toxicity	B
+of	O
+bupivacaine	O
+,	O
+levobupivacaine	O
+,	O
+and	O
+ropivacaine	O
+in	O
+anesthetized	O
+rats	O
+.	O
+
+We	O
+also	O
+compared	O
+the	O
+ability	O
+to	O
+resuscitate	O
+rats	O
+after	O
+lethal	O
+doses	O
+of	O
+these	O
+local	O
+anesthetics	O
+.	O
+
+Bupivacaine	O
+,	O
+levobupivacaine	O
+,	O
+or	O
+ropivacaine	O
+was	O
+infused	O
+at	O
+a	O
+rate	O
+of	O
+2	O
+mg	O
+.	O
+
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+
+min	O
+(	O
+-	O
+1	O
+)	O
+while	O
+electrocardiogram	O
+,	O
+electroencephalogram	O
+,	O
+and	O
+arterial	O
+pressure	O
+were	O
+continuously	O
+monitored	O
+.	O
+
+When	O
+asystole	B
+was	O
+recorded	O
+,	O
+drug	O
+infusion	O
+was	O
+stopped	O
+and	O
+a	O
+resuscitation	O
+sequence	O
+was	O
+begun	O
+.	O
+
+Epinephrine	O
+0	O
+.	O
+01	O
+mg	O
+/	O
+kg	O
+was	O
+administered	O
+at	O
+1	O
+-	O
+min	O
+intervals	O
+while	O
+external	O
+cardiac	O
+compressions	O
+were	O
+applied	O
+.	O
+
+Resuscitation	O
+was	O
+considered	O
+successful	O
+when	O
+a	O
+systolic	O
+arterial	O
+pressure	O
+>	O
+or	O
+=	O
+100	O
+mm	O
+Hg	O
+was	O
+achieved	O
+within	O
+5	O
+min	O
+.	O
+
+The	O
+cumulative	O
+doses	O
+of	O
+levobupivacaine	O
+and	O
+ropivacaine	O
+that	O
+produced	O
+seizures	B
+were	O
+similar	O
+and	O
+were	O
+larger	O
+than	O
+those	O
+of	O
+bupivacaine	O
+.	O
+
+The	O
+cumulative	O
+doses	O
+of	O
+levobupivacaine	O
+that	O
+produced	O
+dysrhythmias	B
+and	O
+asystole	B
+were	O
+smaller	O
+than	O
+the	O
+corresponding	O
+doses	O
+of	O
+ropivacaine	O
+,	O
+but	O
+they	O
+were	O
+larger	O
+than	O
+those	O
+of	O
+bupivacaine	O
+.	O
+
+The	O
+number	O
+of	O
+successful	O
+resuscitations	O
+did	O
+not	O
+differ	O
+among	O
+groups	O
+.	O
+
+However	O
+,	O
+a	O
+smaller	O
+dose	O
+of	O
+epinephrine	O
+was	O
+required	O
+in	O
+the	O
+Ropivacaine	O
+group	O
+than	O
+in	O
+the	O
+other	O
+groups	O
+.	O
+
+We	O
+conclude	O
+that	O
+the	O
+systemic	O
+toxicity	B
+of	O
+levobupivacaine	O
+is	O
+intermediate	O
+between	O
+that	O
+of	O
+ropivacaine	O
+and	O
+bupivacaine	O
+when	O
+administered	O
+at	O
+the	O
+same	O
+rate	O
+and	O
+that	O
+ropivacaine	O
+-	O
+induced	O
+cardiac	B
+arrest	I
+appears	O
+to	O
+be	O
+more	O
+susceptible	O
+to	O
+treatment	O
+than	O
+that	O
+induced	O
+by	O
+bupivacaine	O
+or	O
+levobupivacaine	O
+.	O
+
+Amphotericin	O
+B	O
+-	O
+induced	O
+seizures	B
+in	O
+a	O
+patient	O
+with	O
+AIDS	B
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+multiple	O
+episodes	O
+of	O
+seizure	B
+activity	O
+in	O
+an	O
+AIDS	B
+patent	O
+following	O
+amphotericin	O
+B	O
+infusion	O
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+46	O
+-	O
+year	O
+-	O
+old	O
+African	O
+-	O
+American	O
+man	O
+experienced	O
+recurrent	O
+grand	B
+mal	I
+seizures	I
+during	O
+intravenous	O
+infusion	O
+of	O
+amphotericin	O
+B	O
+,	O
+then	O
+petit	O
+mal	O
+seizures	B
+as	O
+the	O
+infusion	O
+was	O
+stopped	O
+and	O
+the	O
+drug	O
+concentrations	O
+decreased	O
+with	O
+time	O
+.	O
+
+The	O
+patients	O
+concurrent	O
+medications	O
+included	O
+didanosine	O
+,	O
+hydroxyzine	O
+,	O
+promethazine	O
+,	O
+hydrocortisone	O
+,	O
+and	O
+prochlorperazine	O
+.	O
+
+Despite	O
+administration	O
+of	O
+phenytoin	O
+and	O
+lorazepam	O
+,	O
+the	O
+seizures	B
+persisted	O
+and	O
+occurred	O
+only	O
+during	O
+amphotercin	O
+B	O
+administration	O
+.	O
+
+DISCUSSION	O
+:	O
+AIDS	B
+and	O
+cryptococcal	B
+meningitis	I
+,	O
+both	O
+of	O
+which	O
+the	O
+patient	O
+had	O
+,	O
+can	O
+potentially	O
+cause	O
+seizures	B
+.	O
+
+The	O
+patient	O
+had	O
+a	O
+history	O
+of	O
+alcohol	B
+abuse	I
+;	O
+alcohol	O
+intake	O
+as	O
+well	O
+as	O
+withdrawal	O
+can	O
+also	O
+cause	O
+seizures	B
+.	O
+
+Didanosine	O
+also	O
+has	O
+a	O
+potential	O
+for	O
+inducing	O
+seizures	B
+.	O
+
+However	O
+,	O
+these	O
+other	O
+potential	O
+causes	O
+of	O
+seizure	B
+were	O
+ruled	O
+out	O
+.	O
+
+The	O
+time	O
+course	O
+of	O
+events	O
+suggested	O
+that	O
+amphotericin	O
+B	O
+was	O
+the	O
+cause	O
+of	O
+the	O
+seizures	B
+in	O
+this	O
+AIDS	B
+patient	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Amphotericin	O
+B	O
+seems	O
+to	O
+be	O
+the	O
+probable	O
+cause	O
+of	O
+the	O
+seizures	B
+.	O
+
+To	O
+date	O
+,	O
+only	O
+three	O
+cases	O
+of	O
+seizures	B
+associated	O
+with	O
+amphotericin	O
+B	O
+have	O
+been	O
+reported	O
+in	O
+the	O
+literature	O
+,	O
+but	O
+healthcare	O
+providers	O
+should	O
+be	O
+aware	O
+of	O
+the	O
+potential	O
+for	O
+this	O
+rare	O
+adverse	O
+effect	O
+.	O
+
+Sirolimus	O
+and	O
+mycophenolate	O
+mofetil	O
+for	O
+calcineurin	O
+-	O
+free	O
+immunosuppression	O
+in	O
+renal	O
+transplant	O
+recipients	O
+.	O
+
+Calcineurin	O
+inhibitors	O
+,	O
+such	O
+as	O
+cyclosporine	O
+and	O
+tacrolimus	O
+,	O
+have	O
+been	O
+available	O
+for	O
+almost	O
+20	O
+years	O
+.	O
+
+Although	O
+these	O
+drugs	O
+are	O
+highly	O
+effective	O
+and	O
+represent	O
+the	O
+mainstay	O
+of	O
+transplant	O
+immunosuppression	O
+,	O
+they	O
+are	O
+associated	O
+with	O
+acute	O
+and	O
+chronic	O
+nephrotoxicity	B
+.	O
+
+Acute	O
+nephrotoxicity	B
+,	O
+which	O
+occurs	O
+in	O
+the	O
+early	O
+period	O
+after	O
+transplantation	O
+,	O
+leads	O
+to	O
+a	O
+higher	O
+rate	O
+of	O
+dialysis	O
+,	O
+and	O
+chronic	O
+nephrotoxicity	B
+may	O
+eventually	O
+result	O
+in	O
+graft	O
+loss	O
+.	O
+
+Acute	O
+and	O
+chronic	O
+nephrotoxicity	B
+is	O
+becoming	O
+more	O
+common	O
+as	O
+the	O
+use	O
+of	O
+marginal	O
+kidneys	O
+for	O
+transplantation	O
+increases	O
+.	O
+
+Two	O
+recently	O
+available	O
+immunosuppressive	O
+agents	O
+,	O
+mycophenolate	O
+mofetil	O
+and	O
+sirolimus	O
+(	O
+rapamycin	O
+)	O
+,	O
+have	O
+no	O
+nephrotoxicity	B
+.	O
+
+The	O
+use	O
+of	O
+these	O
+drugs	O
+in	O
+combination	O
+with	O
+other	O
+agents	O
+has	O
+led	O
+to	O
+the	O
+development	O
+of	O
+new	O
+paradigms	O
+of	O
+immunosuppressive	O
+therapy	O
+.	O
+
+This	O
+paper	O
+reviews	O
+the	O
+results	O
+of	O
+clinical	O
+trials	O
+that	O
+have	O
+investigated	O
+these	O
+new	O
+approaches	O
+to	O
+immunosuppression	O
+in	O
+renal	O
+transplant	O
+recipients	O
+.	O
+
+Tolerability	O
+of	O
+nimesulide	O
+and	O
+paracetamol	O
+in	O
+patients	O
+with	O
+NSAID	O
+-	O
+induced	O
+urticaria	B
+/	O
+angioedema	B
+.	O
+
+Previous	O
+studies	O
+evaluated	O
+the	O
+tolerance	O
+of	O
+nimesulide	O
+and	O
+paracetamol	O
+in	O
+subjects	O
+with	O
+cutaneous	O
+,	O
+respiratory	O
+and	O
+anaphylactoid	O
+reactions	O
+induced	O
+by	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+(	O
+NSAIDs	O
+)	O
+.	O
+
+In	O
+this	O
+study	O
+we	O
+investigated	O
+tolerability	O
+and	O
+reliability	O
+of	O
+nimesulide	O
+and	O
+paracetamol	O
+in	O
+a	O
+very	O
+large	O
+number	O
+of	O
+patients	O
+with	O
+an	O
+exclusive	O
+well	O
+-	O
+documented	O
+history	O
+of	O
+NSAID	O
+-	O
+induced	O
+urticaria	B
+/	O
+angioedema	B
+.	O
+
+Furthermore	O
+,	O
+we	O
+evaluated	O
+whether	O
+some	O
+factors	O
+have	O
+the	O
+potential	O
+to	O
+increase	O
+the	O
+risk	O
+of	O
+reaction	O
+to	O
+paracetamol	O
+and	O
+nimesulide	O
+.	O
+
+A	O
+single	O
+-	O
+placebo	O
+-	O
+controlled	O
+oral	O
+challenge	O
+procedure	O
+with	O
+nimesulide	O
+or	O
+paracetamol	O
+was	O
+applied	O
+to	O
+829	O
+patients	O
+with	O
+a	O
+history	O
+of	O
+NSAID	O
+-	O
+induced	O
+urticaria	B
+/	O
+angioedema	B
+.	O
+
+A	O
+total	O
+of	O
+75	O
+/	O
+829	O
+(	O
+9	O
+.	O
+4	O
+%	O
+)	O
+patients	O
+experienced	O
+reactions	O
+to	O
+nimesulide	O
+or	O
+paracetamol	O
+.	O
+
+Of	O
+the	O
+715	O
+patients	O
+tested	O
+with	O
+nimesulide	O
+62	O
+(	O
+8	O
+.	O
+6	O
+%	O
+)	O
+showed	O
+a	O
+positive	O
+test	O
+,	O
+while	O
+of	O
+114	O
+subjects	O
+submitted	O
+to	O
+the	O
+challenge	O
+with	O
+paracetamol	O
+,	O
+13	O
+(	O
+9	O
+.	O
+6	O
+%	O
+)	O
+did	O
+not	O
+tolerate	O
+this	O
+drug	O
+.	O
+
+Furthermore	O
+,	O
+18	O
+.	O
+28	O
+%	O
+of	O
+patients	O
+with	O
+a	O
+history	O
+of	O
+chronic	O
+urticaria	B
+and	O
+11	O
+.	O
+8	O
+%	O
+of	O
+subjects	O
+with	O
+an	O
+history	O
+of	O
+NSAID	O
+-	O
+induced	O
+urticaria	B
+/	O
+angioedema	B
+or	O
+angioedema	B
+alone	O
+(	O
+with	O
+or	O
+without	O
+chronic	O
+urticaria	B
+)	O
+resulted	O
+to	O
+be	O
+intolerant	O
+to	O
+alternative	O
+drugs	O
+.	O
+
+Taken	O
+together	O
+,	O
+our	O
+results	O
+confirm	O
+the	O
+good	O
+tolerability	O
+of	O
+nimesulide	O
+and	O
+paracetamol	O
+in	O
+patients	O
+who	O
+experienced	O
+urticaria	B
+/	O
+angioedema	B
+caused	O
+by	O
+NSAIDs	O
+.	O
+
+However	O
+,	O
+the	O
+risk	O
+of	O
+reaction	O
+to	O
+these	O
+alternative	O
+study	O
+drugs	O
+is	O
+statistically	O
+increased	O
+by	O
+a	O
+history	O
+of	O
+chronic	O
+urticaria	B
+and	O
+,	O
+above	O
+all	O
+,	O
+by	O
+a	O
+history	O
+of	O
+NSAID	O
+-	O
+induced	O
+angioedema	B
+.	O
+
+Comparison	O
+of	O
+aqueous	O
+and	O
+gellan	O
+ophthalmic	O
+timolol	O
+with	O
+placebo	O
+on	O
+the	O
+24	O
+-	O
+hour	O
+heart	O
+rate	O
+response	O
+in	O
+patients	O
+on	O
+treatment	O
+for	O
+glaucoma	B
+.	O
+
+PURPOSE	O
+:	O
+Topical	O
+beta	O
+-	O
+blocker	O
+treatment	O
+is	O
+routine	O
+therapy	O
+in	O
+the	O
+management	O
+of	O
+patients	O
+with	O
+glaucoma	B
+.	O
+
+Therapy	O
+results	O
+in	O
+systemic	O
+absorption	O
+,	O
+however	O
+,	O
+the	O
+degree	O
+of	O
+reduction	O
+of	O
+resting	O
+and	O
+peak	O
+heart	O
+rate	O
+has	O
+not	O
+been	O
+quantified	O
+.	O
+
+DESIGN	O
+:	O
+This	O
+trial	O
+evaluated	O
+the	O
+effect	O
+of	O
+placebo	O
+,	O
+0	O
+.	O
+5	O
+%	O
+aqueous	O
+timolol	O
+(	O
+timolol	O
+solution	O
+)	O
+and	O
+a	O
+0	O
+.	O
+5	O
+%	O
+timolol	O
+suspension	O
+that	O
+forms	O
+a	O
+gel	O
+on	O
+application	O
+to	O
+the	O
+conjunctiva	O
+(	O
+timolol	O
+gellan	O
+)	O
+on	O
+the	O
+24	O
+-	O
+hour	O
+heart	O
+rate	O
+in	O
+patients	O
+currently	O
+being	O
+treated	O
+for	O
+glaucoma	B
+to	O
+quantify	O
+the	O
+reduction	O
+in	O
+mean	O
+heart	O
+rate	O
+.	O
+
+METHODS	O
+:	O
+Forty	O
+-	O
+three	O
+Caucasian	O
+patients	O
+with	O
+primary	O
+open	B
+-	I
+angle	I
+glaucoma	I
+or	O
+ocular	B
+hypertension	I
+with	O
+a	O
+mean	O
+(	O
++	O
+/	O
+-	O
+SD	O
+)	O
+age	O
+of	O
+63	O
+(	O
++	O
+/	O
+-	O
+8	O
+)	O
+years	O
+were	O
+randomized	O
+and	O
+crossed	O
+over	O
+in	O
+a	O
+double	O
+-	O
+masked	O
+manner	O
+to	O
+14	O
+days	O
+of	O
+treatment	O
+with	O
+placebo	O
+(	O
+morning	O
+and	O
+evening	O
+in	O
+both	O
+eyes	O
+)	O
+,	O
+timolol	O
+solution	O
+(	O
+morning	O
+and	O
+evening	O
+in	O
+both	O
+eyes	O
+)	O
+,	O
+or	O
+timolol	O
+gellan	O
+(	O
+morning	O
+in	O
+both	O
+eyes	O
+with	O
+placebo	O
+in	O
+the	O
+evening	O
+)	O
+.	O
+
+On	O
+the	O
+13th	O
+day	O
+of	O
+each	O
+period	O
+,	O
+heart	O
+rate	O
+was	O
+recorded	O
+continuously	O
+during	O
+a	O
+typical	O
+,	O
+ambulant	O
+24	O
+-	O
+hour	O
+period	O
+.	O
+
+RESULTS	O
+:	O
+Both	O
+timolol	O
+solution	O
+and	O
+timolol	O
+gellan	O
+reduced	O
+the	O
+mean	O
+24	O
+-	O
+hour	O
+heart	O
+rate	O
+compared	O
+with	O
+placebo	O
+(	O
+P	O
+<	O
+or	O
+=	O
+.	O
+001	O
+)	O
+,	O
+and	O
+this	O
+reduction	O
+was	O
+most	O
+pronounced	O
+during	O
+the	O
+daytime	O
+(	O
+-	O
+7	O
+.	O
+5	O
+%	O
+change	O
+in	O
+mean	O
+heart	O
+rate	O
+,	O
+-	O
+5	O
+.	O
+7	O
+beats	O
+/	O
+min	O
+)	O
+.	O
+
+Timolol	O
+gellan	O
+showed	O
+a	O
+numerically	O
+but	O
+not	O
+significantly	O
+smaller	O
+reduction	O
+in	O
+24	O
+-	O
+hour	O
+heart	O
+rate	O
+,	O
+compared	O
+with	O
+timolol	O
+solution	O
+.	O
+
+During	O
+the	O
+night	O
+,	O
+the	O
+mean	O
+12	O
+-	O
+hour	O
+heart	O
+rate	O
+on	O
+placebo	O
+and	O
+timolol	O
+gellan	O
+were	O
+both	O
+significantly	O
+less	O
+than	O
+on	O
+timolol	O
+solution	O
+;	O
+the	O
+difference	O
+between	O
+solution	O
+and	O
+gellan	O
+treatments	O
+was	O
+statistically	O
+significant	O
+(	O
+P	O
+=	O
+.	O
+01	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Both	O
+timolol	O
+solution	O
+and	O
+timolol	O
+gellan	O
+decrease	O
+the	O
+mean	O
+24	O
+-	O
+hour	O
+heart	O
+rate	O
+compared	O
+with	O
+placebo	O
+.	O
+
+This	O
+response	O
+was	O
+most	O
+pronounced	O
+during	O
+the	O
+active	O
+daytime	O
+period	O
+.	O
+
+These	O
+data	O
+quantify	O
+the	O
+modest	O
+bradycardia	B
+associated	O
+with	O
+ophthalmic	O
+beta	O
+-	O
+blocker	O
+therapy	O
+in	O
+a	O
+typical	O
+patient	O
+population	O
+on	O
+therapy	O
+for	O
+glaucoma	B
+.	O
+
+Although	O
+exercise	O
+performance	O
+was	O
+not	O
+assessed	O
+in	O
+this	O
+trial	O
+,	O
+reductions	O
+of	O
+this	O
+magnitude	O
+should	O
+not	O
+have	O
+substantial	O
+clinical	O
+consequences	O
+.	O
+
+Management	O
+strategies	O
+for	O
+ribavirin	O
+-	O
+induced	O
+hemolytic	B
+anemia	I
+in	O
+the	O
+treatment	O
+of	O
+hepatitis	B
+C	I
+:	O
+clinical	O
+and	O
+economic	O
+implications	O
+.	O
+
+OBJECTIVES	O
+:	O
+Recently	O
+published	O
+studies	O
+have	O
+demonstrated	O
+increased	O
+efficacy	O
+and	O
+cost	O
+-	O
+effectiveness	O
+of	O
+combination	O
+therapy	O
+with	O
+interferon	O
+and	O
+alpha	O
+-	O
+2b	O
+/	O
+ribavirin	O
+compared	O
+with	O
+interferon	O
+-	O
+alpha	O
+monotherapy	O
+in	O
+the	O
+treatment	O
+of	O
+chronic	B
+hepatitis	I
+C	I
+(	O
+CHC	B
+)	O
+.	O
+
+Combination	O
+therapy	O
+is	O
+associated	O
+with	O
+a	O
+clinically	O
+important	O
+adverse	O
+effect	O
+:	O
+ribavirin	O
+-	O
+induced	O
+hemolytic	B
+anemia	I
+(	O
+RIHA	B
+)	O
+.	O
+
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+evaluate	O
+the	O
+direct	O
+health	O
+-	O
+care	O
+costs	O
+and	O
+management	O
+of	O
+RIHA	B
+during	O
+treatment	O
+of	O
+CHC	B
+in	O
+a	O
+clinical	O
+trial	O
+setting	O
+.	O
+
+METHODS	O
+:	O
+A	O
+systematic	O
+literature	O
+review	O
+was	O
+conducted	O
+to	O
+synthesize	O
+information	O
+on	O
+the	O
+incidence	O
+and	O
+management	O
+of	O
+RIHA	B
+.	O
+
+Decision	O
+-	O
+analytic	O
+techniques	O
+were	O
+used	O
+to	O
+estimate	O
+the	O
+cost	O
+of	O
+treating	O
+RIHA	B
+.	O
+
+Uncertainty	O
+was	O
+evaluated	O
+using	O
+sensitivity	O
+analyses	O
+.	O
+
+RESULTS	O
+:	O
+RIHA	B
+,	O
+defined	O
+as	O
+a	O
+reduction	O
+in	O
+hemoglobin	O
+to	O
+less	O
+than	O
+100	O
+g	O
+/	O
+L	O
+,	O
+occurs	O
+in	O
+approximately	O
+7	O
+%	O
+to	O
+9	O
+%	O
+of	O
+patients	O
+treated	O
+with	O
+combination	O
+therapy	O
+.	O
+
+The	O
+standard	O
+of	O
+care	O
+for	O
+management	O
+of	O
+RIHA	B
+is	O
+reduction	O
+or	O
+discontinuation	O
+of	O
+the	O
+ribavirin	O
+dosage	O
+.	O
+
+We	O
+estimated	O
+the	O
+direct	O
+cost	O
+of	O
+treating	O
+clinically	O
+significant	O
+RIHA	B
+to	O
+be	O
+170	O
+per	O
+patient	O
+receiving	O
+combination	O
+therapy	O
+per	O
+48	O
+-	O
+week	O
+treatment	O
+course	O
+(	O
+range	O
+68	O
+-	O
+692	O
+)	O
+.	O
+
+The	O
+results	O
+of	O
+the	O
+one	O
+-	O
+way	O
+sensitivity	O
+analyses	O
+ranged	O
+from	O
+57	O
+to	O
+317	O
+.	O
+
+In	O
+comparison	O
+,	O
+the	O
+cost	O
+of	O
+48	O
+weeks	O
+of	O
+combination	O
+therapy	O
+is	O
+16	O
+,	O
+459	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+direct	O
+cost	O
+of	O
+treating	O
+clinically	O
+significant	O
+RIHA	B
+is	O
+1	O
+%	O
+(	O
+170	O
+/	O
+16	O
+,	O
+459	O
+)	O
+of	O
+drug	O
+treatment	O
+costs	O
+.	O
+
+Questions	O
+remain	O
+about	O
+the	O
+optimal	O
+dose	O
+of	O
+ribavirin	O
+and	O
+the	O
+incidence	O
+of	O
+RIHA	B
+in	O
+a	O
+real	O
+-	O
+world	O
+population	O
+.	O
+
+Despite	O
+these	O
+uncertainties	O
+,	O
+this	O
+initial	O
+evaluation	O
+of	O
+the	O
+direct	O
+cost	O
+of	O
+treating	O
+RIHA	B
+provides	O
+an	O
+estimate	O
+of	O
+the	O
+cost	O
+and	O
+management	O
+implications	O
+of	O
+this	O
+clinically	O
+important	O
+adverse	O
+effect	O
+.	O
+
+Preliminary	O
+efficacy	O
+assessment	O
+of	O
+intrathecal	O
+injection	O
+of	O
+an	O
+American	O
+formulation	O
+of	O
+adenosine	O
+in	O
+humans	O
+.	O
+
+BACKGROUND	O
+:	O
+Preclinical	O
+studies	O
+of	O
+intrathecal	O
+adenosine	O
+suggest	O
+it	O
+may	O
+be	O
+effective	O
+in	O
+the	O
+treatment	O
+of	O
+acute	B
+and	I
+chronic	I
+pain	I
+in	O
+humans	O
+,	O
+and	O
+preliminary	O
+studies	O
+in	O
+volunteers	O
+and	O
+patients	O
+with	O
+a	O
+Swedish	O
+formulation	O
+of	O
+adenosine	O
+suggests	O
+it	O
+may	O
+be	O
+effective	O
+in	O
+hypersensitivity	B
+states	O
+but	O
+not	O
+with	O
+acute	O
+noxious	O
+stimulation	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+screen	O
+for	O
+efficacy	O
+of	O
+a	O
+different	O
+formulation	O
+of	O
+adenosine	O
+marketed	O
+in	O
+the	O
+US	O
+,	O
+using	O
+both	O
+acute	O
+noxious	O
+stimulation	O
+and	O
+capsaicin	O
+-	O
+evoked	O
+mechanical	O
+hypersensitivity	B
+.	O
+
+METHODS	O
+:	O
+Following	O
+Food	O
+and	O
+Drug	O
+Administration	O
+and	O
+institutional	O
+review	O
+board	O
+approval	O
+and	O
+written	O
+informed	O
+consent	O
+,	O
+65	O
+volunteers	O
+were	O
+studied	O
+in	O
+two	O
+trials	O
+:	O
+an	O
+open	O
+-	O
+label	O
+,	O
+dose	O
+-	O
+escalating	O
+trial	O
+with	O
+intrathecal	O
+adenosine	O
+doses	O
+of	O
+0	O
+.	O
+25	O
+-	O
+2	O
+.	O
+0	O
+mg	O
+and	O
+a	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+trial	O
+of	O
+adenosine	O
+,	O
+2	O
+mg	O
+.	O
+
+Cerebrospinal	O
+fluid	O
+was	O
+obtained	O
+for	O
+pharmacokinetic	O
+analysis	O
+,	O
+and	O
+pain	B
+ratings	O
+in	O
+response	O
+to	O
+acute	O
+heat	O
+stimuli	O
+and	O
+areas	O
+of	O
+mechanical	B
+hyperalgesia	I
+and	O
+allodynia	B
+after	O
+intradermal	O
+capsaicin	O
+injection	O
+were	O
+determined	O
+.	O
+
+RESULTS	O
+:	O
+Adenosine	O
+produced	O
+no	O
+effect	O
+on	O
+pain	B
+report	O
+to	O
+acute	O
+noxious	O
+thermal	O
+or	O
+chemical	O
+stimulation	O
+but	O
+reduced	O
+mechanical	B
+hyperalgesia	I
+and	O
+allodynia	B
+from	O
+intradermal	O
+capsaicin	O
+injection	O
+for	O
+at	O
+least	O
+24	O
+h	O
+.	O
+
+In	O
+contrast	O
+,	O
+residence	O
+time	O
+of	O
+adenosine	O
+in	O
+cerebrospinal	O
+fluid	O
+was	O
+short	O
+(	O
+<	O
+4	O
+h	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+These	O
+results	O
+show	O
+selective	O
+inhibition	O
+by	O
+intrathecal	O
+adenosine	O
+of	O
+hypersensitivity	B
+,	O
+presumed	O
+to	O
+reflect	O
+central	O
+sensitization	O
+in	O
+humans	O
+after	O
+peripheral	O
+capsaicin	O
+injection	O
+.	O
+
+The	O
+long	O
+-	O
+lasting	O
+effect	O
+is	O
+consistent	O
+with	O
+that	O
+observed	O
+in	O
+preliminary	O
+reports	O
+of	O
+patients	O
+with	O
+chronic	O
+neuropathic	B
+pain	I
+and	O
+is	O
+not	O
+due	O
+to	O
+prolonged	O
+residence	O
+of	O
+adenosine	O
+in	O
+cerebrospinal	O
+fluid	O
+.	O
+
+Delayed	O
+-	O
+onset	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+.	O
+
+BACKGROUND	O
+:	O
+Heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+presents	O
+5	O
+to	O
+12	O
+days	O
+after	O
+heparin	O
+exposure	O
+,	O
+with	O
+or	O
+without	O
+arterial	B
+or	I
+venous	I
+thromboemboli	I
+.	O
+
+Delayed	O
+recognition	O
+and	O
+treatment	O
+of	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+contribute	O
+to	O
+poor	O
+patient	O
+outcomes	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+describe	O
+and	O
+increase	O
+awareness	O
+of	O
+a	O
+clinical	O
+scenario	O
+in	O
+which	O
+the	O
+onset	O
+or	O
+manifestations	O
+of	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+are	O
+delayed	O
+.	O
+
+DESIGN	O
+:	O
+Retrospective	O
+case	O
+series	O
+.	O
+
+SETTING	O
+:	O
+Three	O
+large	O
+urban	O
+hospitals	O
+(	O
+with	O
+active	O
+cardiovascular	O
+surgery	O
+programs	O
+)	O
+.	O
+
+PATIENTS	O
+:	O
+14	O
+patients	O
+seen	O
+over	O
+a	O
+3	O
+-	O
+year	O
+period	O
+in	O
+whom	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+became	O
+apparent	O
+on	O
+delayed	O
+presentation	O
+with	O
+thromboembolic	B
+complications	O
+.	O
+
+MEASUREMENTS	O
+:	O
+Platelet	O
+counts	O
+,	O
+onset	O
+of	O
+objectively	O
+determined	O
+thromboembolism	B
+,	O
+results	O
+of	O
+heparin	O
+-	O
+induced	O
+platelet	O
+factor	O
+4	O
+antibody	O
+tests	O
+,	O
+and	O
+outcomes	O
+.	O
+
+RESULTS	O
+:	O
+Patients	O
+went	O
+home	O
+after	O
+hospitalizations	O
+that	O
+had	O
+included	O
+heparin	O
+exposure	O
+-	O
+-	O
+in	O
+most	O
+cases	O
+,	O
+with	O
+no	O
+thrombocytopenia	B
+recognized	O
+-	O
+-	O
+only	O
+to	O
+return	O
+to	O
+the	O
+hospital	O
+(	O
+median	O
+,	O
+day	O
+14	O
+)	O
+with	O
+thromboembolic	B
+complications	O
+.	O
+
+Thromboemboli	B
+were	O
+venous	O
+(	O
+12	O
+patients	O
+,	O
+7	O
+with	O
+pulmonary	B
+emboli	I
+)	O
+or	O
+arterial	O
+(	O
+4	O
+patients	O
+)	O
+or	O
+both	O
+.	O
+
+Platelet	O
+counts	O
+were	O
+mildly	O
+decreased	O
+in	O
+all	O
+but	O
+2	O
+patients	O
+on	O
+second	O
+presentation	O
+.	O
+
+On	O
+readmission	O
+,	O
+11	O
+patients	O
+received	O
+therapeutic	O
+heparin	O
+,	O
+which	O
+worsened	O
+the	O
+patients	O
+'	O
+clinical	O
+condition	O
+and	O
+,	O
+in	O
+all	O
+11	O
+cases	O
+,	O
+decreased	O
+the	O
+platelet	O
+count	O
+(	O
+mean	O
+at	O
+readmission	O
+,	O
+143	O
+x	O
+10	O
+(	O
+9	O
+)	O
+cells	O
+/	O
+L	O
+;	O
+mean	O
+nadir	O
+after	O
+heparin	O
+re	O
+-	O
+exposure	O
+,	O
+39	O
+x	O
+10	O
+(	O
+9	O
+)	O
+cells	O
+/	O
+L	O
+)	O
+.	O
+
+Results	O
+of	O
+serologic	O
+tests	O
+for	O
+heparin	O
+-	O
+induced	O
+antibodies	O
+were	O
+positive	O
+in	O
+all	O
+patients	O
+.	O
+
+Subsequent	O
+treatments	O
+included	O
+alternative	O
+anticoagulants	O
+(	O
+11	O
+patients	O
+)	O
+,	O
+thrombolytic	O
+drugs	O
+(	O
+3	O
+patients	O
+)	O
+,	O
+inferior	O
+vena	O
+cava	O
+filters	O
+(	O
+3	O
+patients	O
+)	O
+and	O
+,	O
+eventually	O
+,	O
+warfarin	O
+(	O
+11	O
+patients	O
+)	O
+.	O
+
+Three	O
+patients	O
+died	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Delayed	O
+-	O
+onset	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+is	O
+increasingly	O
+being	O
+recognized	O
+.	O
+
+To	O
+avoid	O
+disastrous	O
+outcomes	O
+,	O
+physicians	O
+must	O
+consider	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+whenever	O
+a	O
+recently	O
+hospitalized	O
+patient	O
+returns	O
+with	O
+thromboembolism	B
+;	O
+therapy	O
+with	O
+alternative	O
+anticoagulants	O
+,	O
+not	O
+heparin	O
+,	O
+should	O
+be	O
+initiated	O
+.	O
+
+Treatment	O
+of	O
+risperidone	O
+-	O
+induced	O
+hyperprolactinemia	B
+with	O
+a	O
+dopamine	O
+agonist	O
+in	O
+children	O
+.	O
+
+BACKGROUND	O
+:	O
+Risperidone	O
+,	O
+a	O
+potent	O
+antagonist	O
+of	O
+both	O
+serotonergic	O
+(	O
+5HT2A	O
+)	O
+and	O
+dopaminergic	O
+D2	O
+receptors	O
+is	O
+associated	O
+with	O
+hyperprolactinemia	B
+in	O
+adults	O
+and	O
+children	O
+.	O
+
+Chronically	O
+elevated	O
+prolactin	O
+levels	O
+in	O
+children	O
+with	O
+prolactinomas	B
+may	O
+be	O
+associated	O
+with	O
+arrested	O
+growth	O
+and	O
+development	O
+resulting	O
+in	O
+either	O
+delayed	B
+puberty	I
+or	O
+short	O
+stature	O
+.	O
+
+These	O
+possibilities	O
+stress	O
+the	O
+importance	O
+of	O
+developing	O
+a	O
+safe	O
+and	O
+effective	O
+approach	O
+to	O
+drug	O
+-	O
+induced	O
+hyperprolactinemia	B
+in	O
+youth	O
+.	O
+
+We	O
+report	O
+the	O
+successful	O
+treatment	O
+of	O
+risperidone	O
+-	O
+induced	O
+hyperprolactinemia	B
+with	O
+cabergoline	O
+in	O
+youth	O
+.	O
+
+METHODS	O
+:	O
+We	O
+undertook	O
+a	O
+retrospective	O
+case	O
+review	O
+of	O
+four	O
+children	O
+with	O
+risperidone	O
+-	O
+induced	O
+hyperprolactinemia	B
+treated	O
+with	O
+cabergoline	O
+.	O
+
+RESULTS	O
+:	O
+Four	O
+males	O
+(	O
+age	O
+6	O
+-	O
+11	O
+years	O
+)	O
+with	O
+Diagnostic	O
+and	O
+Statistical	O
+Manual	O
+of	O
+Mental	B
+Disorders	I
+(	O
+fourth	O
+edition	O
+)	O
+bipolar	B
+disorder	I
+or	O
+psychoses	B
+,	O
+with	O
+risperidone	O
+-	O
+induced	O
+elevations	O
+in	O
+serum	O
+prolactin	O
+levels	O
+(	O
+57	O
+.	O
+5	O
+-	O
+129	O
+ng	O
+/	O
+mL	O
+,	O
+normal	O
+5	O
+-	O
+15	O
+ng	O
+/	O
+mL	O
+)	O
+,	O
+were	O
+treated	O
+with	O
+cabergoline	O
+(	O
+mean	O
+dose	O
+2	O
+.	O
+13	O
++	O
+/	O
+-	O
+0	O
+.	O
+09	O
+mg	O
+/	O
+week	O
+)	O
+.	O
+
+When	O
+serum	O
+prolactin	O
+levels	O
+normalized	O
+in	O
+all	O
+four	O
+subjects	O
+(	O
+mean	O
+11	O
+.	O
+2	O
++	O
+/	O
+-	O
+10	O
+.	O
+9	O
+ng	O
+/	O
+mL	O
+)	O
+,	O
+the	O
+cabergoline	O
+dose	O
+was	O
+reduced	O
+to	O
+1	O
+mg	O
+/	O
+week	O
+in	O
+three	O
+of	O
+four	O
+subjects	O
+.	O
+
+The	O
+mean	O
+duration	O
+of	O
+therapy	O
+with	O
+cabergoline	O
+was	O
+523	O
+.	O
+5	O
++	O
+/	O
+-	O
+129	O
+.	O
+7	O
+days	O
+,	O
+and	O
+the	O
+mean	O
+duration	O
+of	O
+therapy	O
+with	O
+risperidone	O
+was	O
+788	O
+.	O
+5	O
++	O
+/	O
+-	O
+162	O
+.	O
+5	O
+days	O
+.	O
+
+Cabergoline	O
+was	O
+well	O
+tolerated	O
+without	O
+adverse	O
+effects	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Cabergoline	O
+may	O
+be	O
+useful	O
+for	O
+the	O
+treatment	O
+of	O
+risperidone	O
+-	O
+induced	O
+hyperprolactinemia	B
+in	O
+youth	O
+;	O
+however	O
+,	O
+further	O
+research	O
+is	O
+needed	O
+.	O
+
+Acute	O
+cholestatic	B
+hepatitis	I
+after	O
+exposure	O
+to	O
+isoflurane	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+acute	O
+cholestatic	B
+hepatitis	I
+following	O
+exposure	O
+to	O
+the	O
+inhalational	O
+anesthetic	O
+isoflurane	O
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+70	O
+-	O
+year	O
+-	O
+old	O
+healthy	O
+woman	O
+from	O
+Iraq	O
+developed	O
+acute	O
+cholestatic	B
+hepatitis	I
+3	O
+weeks	O
+following	O
+repair	O
+of	O
+the	O
+right	O
+rotator	O
+cuff	O
+under	O
+general	O
+anesthesia	O
+.	O
+
+There	O
+was	O
+no	O
+evidence	O
+for	O
+viral	O
+,	O
+autoimmune	O
+,	O
+or	O
+metabolic	O
+causes	O
+of	O
+hepatitis	B
+.	O
+
+No	O
+other	O
+medications	O
+were	O
+involved	O
+except	O
+for	O
+dipyrone	O
+for	O
+analgesia	B
+.	O
+
+The	O
+alanine	O
+aminotransferase	O
+was	O
+elevated	O
+to	O
+a	O
+peak	O
+concentration	O
+of	O
+1533	O
+U	O
+/	O
+L	O
+and	O
+the	O
+serum	O
+bilirubin	O
+reached	O
+a	O
+peak	O
+of	O
+17	O
+.	O
+0	O
+mg	O
+/	O
+dL	O
+.	O
+
+There	O
+was	O
+slow	O
+improvement	O
+over	O
+4	O
+months	O
+.	O
+
+Accidental	O
+reexposure	O
+by	O
+the	O
+patient	O
+to	O
+dipyrone	O
+was	O
+uneventful	O
+.	O
+
+DISCUSSION	O
+:	O
+The	O
+clinical	O
+and	O
+histologic	O
+picture	O
+of	O
+this	O
+case	O
+resembles	O
+halothane	B
+hepatitis	I
+,	O
+which	O
+has	O
+a	O
+significant	O
+mortality	O
+rate	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Isoflurane	O
+,	O
+a	O
+common	O
+anesthetic	O
+agent	O
+,	O
+can	O
+cause	O
+severe	O
+cholestatic	B
+hepatitis	I
+.	O
+
+Torsade	B
+de	I
+pointes	I
+induced	O
+by	O
+metoclopramide	O
+in	O
+an	O
+elderly	O
+woman	O
+with	O
+preexisting	O
+complete	O
+left	B
+bundle	I
+branch	I
+block	I
+.	O
+
+There	O
+is	O
+a	O
+growing	O
+list	O
+of	O
+drugs	O
+implicated	O
+in	O
+acquired	O
+long	B
+QT	I
+syndrome	I
+and	O
+torsade	B
+de	I
+pointes	I
+.	O
+
+However	O
+,	O
+the	O
+torsadogenic	O
+potential	O
+of	O
+metoclopramide	O
+,	O
+a	O
+commonly	O
+used	O
+antiemetic	O
+and	O
+prokinetic	O
+drug	O
+,	O
+has	O
+not	O
+been	O
+reported	O
+in	O
+the	O
+literature	O
+,	O
+despite	O
+its	O
+chemical	O
+similarity	O
+to	O
+procainamide	O
+.	O
+
+We	O
+report	O
+on	O
+a	O
+92	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+preexisting	O
+complete	O
+left	B
+bundle	I
+branch	I
+block	I
+who	O
+developed	O
+torsade	B
+de	I
+pointes	I
+after	O
+intravenous	O
+and	O
+oral	O
+administration	O
+of	O
+metoclopramide	O
+.	O
+
+This	O
+patient	O
+also	O
+developed	O
+torsade	B
+de	I
+pointes	I
+when	O
+cisapride	O
+and	O
+erythromycin	O
+were	O
+given	O
+simultaneously	O
+.	O
+
+These	O
+two	O
+episodes	O
+were	O
+suppressed	O
+successfully	O
+after	O
+discontinuing	O
+the	O
+offending	O
+drugs	O
+and	O
+administering	O
+class	O
+IB	O
+drugs	O
+.	O
+
+This	O
+is	O
+the	O
+first	O
+documentation	O
+that	O
+metoclopramide	O
+provokes	O
+torsade	B
+de	I
+pointes	I
+clinically	O
+.	O
+
+Metoclopramide	O
+should	O
+be	O
+used	O
+cautiously	O
+in	O
+patients	O
+with	O
+a	O
+risk	O
+of	O
+torsade	B
+de	I
+pointes	I
+.	O
+
+Dopamine	O
+D2	O
+receptor	O
+signaling	O
+controls	O
+neuronal	O
+cell	O
+death	O
+induced	O
+by	O
+muscarinic	O
+and	O
+glutamatergic	O
+drugs	O
+.	O
+
+Dopamine	O
+(	O
+DA	O
+)	O
+,	O
+through	O
+D1	O
+/	O
+D2	O
+receptor	O
+-	O
+mediated	O
+signaling	O
+,	O
+plays	O
+a	O
+major	O
+role	O
+in	O
+the	O
+control	O
+of	O
+epileptic	B
+seizures	I
+arising	O
+in	O
+the	O
+limbic	O
+system	O
+.	O
+
+Excitotoxicity	B
+leading	O
+to	O
+neuronal	O
+cell	O
+death	O
+in	O
+the	O
+affected	O
+areas	O
+is	O
+a	O
+major	O
+consequence	O
+of	O
+seizures	B
+at	O
+the	O
+cellular	O
+level	O
+.	O
+
+In	O
+this	O
+respect	O
+,	O
+little	O
+is	O
+known	O
+about	O
+the	O
+role	O
+of	O
+DA	O
+receptors	O
+in	O
+the	O
+occurrence	O
+of	O
+epilepsy	B
+-	O
+induced	O
+neuronal	O
+cell	O
+death	O
+.	O
+
+Here	O
+we	O
+analyze	O
+the	O
+occurrence	O
+of	O
+seizures	B
+and	O
+neurotoxicity	B
+in	O
+D2R	O
+-	O
+/	O
+-	O
+mice	O
+treated	O
+with	O
+the	O
+cholinergic	O
+agonist	O
+pilocarpine	O
+.	O
+
+We	O
+compared	O
+these	O
+results	O
+with	O
+those	O
+previously	O
+obtained	O
+with	O
+kainic	O
+acid	O
+(	O
+KA	O
+)	O
+,	O
+a	O
+potent	O
+glutamate	O
+agonist	O
+.	O
+
+Importantly	O
+,	O
+D2R	O
+-	O
+/	O
+-	O
+mice	O
+develop	O
+seizures	B
+at	O
+doses	O
+of	O
+both	O
+drugs	O
+that	O
+are	O
+not	O
+epileptogenic	O
+for	O
+WT	O
+littermates	O
+and	O
+show	O
+greater	O
+neurotoxicity	B
+.	O
+
+However	O
+,	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+result	O
+in	O
+a	O
+more	O
+widespread	O
+neuronal	O
+death	O
+in	O
+both	O
+WT	O
+and	O
+D2R	O
+-	O
+/	O
+-	O
+brains	O
+in	O
+comparison	O
+to	O
+KA	O
+.	O
+
+Thus	O
+,	O
+the	O
+absence	O
+of	O
+D2R	O
+lowers	O
+the	O
+threshold	O
+for	O
+seizures	B
+induced	O
+by	O
+both	O
+glutamate	O
+and	O
+acetylcholine	O
+.	O
+
+Moreover	O
+,	O
+the	O
+dopaminergic	O
+control	O
+of	O
+epilepsy	B
+-	O
+induced	O
+neurodegeneration	B
+seems	O
+to	O
+be	O
+mediated	O
+by	O
+distinct	O
+interactions	O
+of	O
+D2R	O
+signaling	O
+with	O
+these	O
+two	O
+neurotransmitters	O
+.	O
+
+Steroid	O
+structure	O
+and	O
+pharmacological	O
+properties	O
+determine	O
+the	O
+anti	O
+-	O
+amnesic	B
+effects	O
+of	O
+pregnenolone	O
+sulphate	O
+in	O
+the	O
+passive	O
+avoidance	O
+task	O
+in	O
+rats	O
+.	O
+
+Pregnenolone	O
+sulphate	O
+(	O
+PREGS	O
+)	O
+has	O
+generated	O
+interest	O
+as	O
+one	O
+of	O
+the	O
+most	O
+potent	O
+memory	O
+-	O
+enhancing	O
+neurosteroids	O
+to	O
+be	O
+examined	O
+in	O
+rodent	O
+learning	O
+studies	O
+,	O
+with	O
+particular	O
+importance	O
+in	O
+the	O
+ageing	O
+process	O
+.	O
+
+The	O
+mechanism	O
+by	O
+which	O
+this	O
+endogenous	O
+steroid	O
+enhances	O
+memory	O
+formation	O
+is	O
+hypothesized	O
+to	O
+involve	O
+actions	O
+on	O
+glutamatergic	O
+and	O
+GABAergic	O
+systems	O
+.	O
+
+This	O
+hypothesis	O
+stems	O
+from	O
+findings	O
+that	O
+PREGS	O
+is	O
+a	O
+potent	O
+positive	O
+modulator	O
+of	O
+N	O
+-	O
+methyl	O
+-	O
+d	O
+-	O
+aspartate	O
+receptors	O
+(	O
+NMDARs	O
+)	O
+and	O
+a	O
+negative	O
+modulator	O
+of	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+(	O
+A	O
+)	O
+receptors	O
+(	O
+GABA	O
+(	O
+A	O
+)	O
+Rs	O
+)	O
+.	O
+
+Moreover	O
+,	O
+PREGS	O
+is	O
+able	O
+to	O
+reverse	O
+the	O
+amnesic	B
+-	O
+like	O
+effects	O
+of	O
+NMDAR	O
+and	O
+GABA	O
+(	O
+A	O
+)	O
+R	O
+ligands	O
+.	O
+
+To	O
+investigate	O
+this	O
+hypothesis	O
+,	O
+the	O
+present	O
+study	O
+in	O
+rats	O
+examined	O
+the	O
+memory	O
+-	O
+altering	O
+abilities	O
+of	O
+structural	O
+analogs	O
+of	O
+PREGS	O
+,	O
+which	O
+differ	O
+in	O
+their	O
+modulation	O
+of	O
+NMDAR	O
+and	O
+/	O
+or	O
+GABA	O
+(	O
+A	O
+)	O
+R	O
+function	O
+.	O
+
+The	O
+analogs	O
+tested	O
+were	O
+:	O
+11	O
+-	O
+ketopregnenolone	O
+sulphate	O
+(	O
+an	O
+agent	O
+that	O
+is	O
+inactive	O
+at	O
+GABA	O
+(	O
+A	O
+)	O
+Rs	O
+and	O
+NMDARs	O
+)	O
+,	O
+epipregnanolone	O
+(	O
+[	O
+3beta	O
+-	O
+hydroxy	O
+-	O
+5beta	O
+-	O
+pregnan	O
+-	O
+20	O
+-	O
+one	O
+]	O
+sulphate	O
+,	O
+an	O
+inhibitor	O
+of	O
+both	O
+GABA	O
+(	O
+A	O
+)	O
+Rs	O
+and	O
+NMDARs	O
+)	O
+,	O
+and	O
+a	O
+newly	O
+synthesized	O
+(	O
+-	O
+)	O
+PREGS	O
+enantiomer	O
+(	O
+which	O
+is	O
+identical	O
+to	O
+PREGS	O
+in	O
+effects	O
+on	O
+GABA	O
+(	O
+A	O
+)	O
+Rs	O
+and	O
+NMDARs	O
+)	O
+.	O
+
+The	O
+memory	O
+-	O
+enhancing	O
+effects	O
+of	O
+PREGS	O
+and	O
+its	O
+analogs	O
+were	O
+tested	O
+in	O
+the	O
+passive	O
+avoidance	O
+task	O
+using	O
+the	O
+model	O
+of	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+.	O
+
+Both	O
+PREGS	O
+and	O
+its	O
+(	O
+-	O
+)	O
+enantiomer	O
+blocked	O
+the	O
+effects	O
+of	O
+scopolamine	O
+.	O
+
+The	O
+results	O
+show	O
+that	O
+,	O
+unlike	O
+PREGS	O
+,	O
+11	O
+-	O
+ketopregnenolone	O
+sulphate	O
+and	O
+epipregnanolone	O
+sulphate	O
+failed	O
+to	O
+block	O
+the	O
+effect	O
+of	O
+scopolamine	O
+,	O
+suggesting	O
+that	O
+altering	O
+the	O
+modulation	O
+of	O
+NMDA	O
+receptors	O
+diminishes	O
+the	O
+memory	O
+-	O
+enhancing	O
+effects	O
+of	O
+PREGS	O
+.	O
+
+Moreover	O
+,	O
+enantioselectivity	O
+was	O
+demonstrated	O
+by	O
+the	O
+ability	O
+of	O
+natural	O
+PREGS	O
+to	O
+be	O
+an	O
+order	O
+of	O
+magnitude	O
+more	O
+effective	O
+than	O
+its	O
+synthetic	O
+enantiomer	O
+in	O
+reversing	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+.	O
+
+These	O
+results	O
+identify	O
+a	O
+novel	O
+neuropharmacological	O
+site	O
+for	O
+the	O
+modulation	O
+of	O
+memory	O
+processes	O
+by	O
+neuroactive	O
+steroids	O
+.	O
+
+Activation	O
+of	O
+poly	O
+(	O
+ADP	O
+-	O
+ribose	O
+)	O
+polymerase	O
+contributes	O
+to	O
+development	O
+of	O
+doxorubicin	O
+-	O
+induced	O
+heart	B
+failure	I
+.	O
+
+Activation	O
+of	O
+the	O
+nuclear	O
+enzyme	O
+poly	O
+(	O
+ADP	O
+-	O
+ribose	O
+)	O
+polymerase	O
+(	O
+PARP	O
+)	O
+by	O
+oxidant	O
+-	O
+mediated	O
+DNA	O
+damage	O
+is	O
+an	O
+important	O
+pathway	O
+of	O
+cell	O
+dysfunction	O
+and	O
+tissue	O
+injury	O
+in	O
+conditions	O
+associated	O
+with	O
+oxidative	O
+stress	O
+.	O
+
+Increased	O
+oxidative	O
+stress	O
+is	O
+a	O
+major	O
+factor	O
+implicated	O
+in	O
+the	O
+cardiotoxicity	B
+of	O
+doxorubicin	O
+(	O
+DOX	O
+)	O
+,	O
+a	O
+widely	O
+used	O
+antitumor	O
+anthracycline	O
+antibiotic	O
+.	O
+
+Thus	O
+,	O
+we	O
+hypothesized	O
+that	O
+the	O
+activation	O
+of	O
+PARP	O
+may	O
+contribute	O
+to	O
+the	O
+DOX	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+Using	O
+a	O
+dual	O
+approach	O
+of	O
+PARP	O
+-	O
+1	O
+suppression	O
+,	O
+by	O
+genetic	O
+deletion	O
+or	O
+pharmacological	O
+inhibition	O
+with	O
+the	O
+phenanthridinone	O
+PARP	O
+inhibitor	O
+PJ34	O
+,	O
+we	O
+now	O
+demonstrate	O
+the	O
+role	O
+of	O
+PARP	O
+in	O
+the	O
+development	O
+of	O
+cardiac	B
+dysfunction	I
+induced	O
+by	O
+DOX	O
+.	O
+
+PARP	O
+-	O
+1	O
++	O
+/	O
++	O
+and	O
+PARP	O
+-	O
+1	O
+-	O
+/	O
+-	O
+mice	O
+received	O
+a	O
+single	O
+injection	O
+of	O
+DOX	O
+(	O
+25	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+)	O
+.	O
+
+Five	O
+days	O
+after	O
+DOX	O
+administration	O
+,	O
+left	O
+ventricular	O
+performance	O
+was	O
+significantly	O
+depressed	O
+in	O
+PARP	O
+-	O
+1	O
++	O
+/	O
++	O
+mice	O
+,	O
+but	O
+only	O
+to	O
+a	O
+smaller	O
+extent	O
+in	O
+PARP	O
+-	O
+1	O
+-	O
+/	O
+-	O
+ones	O
+.	O
+
+Similar	O
+experiments	O
+were	O
+conducted	O
+in	O
+BALB	O
+/	O
+c	O
+mice	O
+treated	O
+with	O
+PJ34	O
+or	O
+vehicle	O
+.	O
+
+Treatment	O
+with	O
+a	O
+PJ34	O
+significantly	O
+improved	O
+cardiac	B
+dysfunction	I
+and	O
+increased	O
+the	O
+survival	O
+of	O
+the	O
+animals	O
+.	O
+
+In	O
+addition	O
+PJ34	O
+significantly	O
+reduced	O
+the	O
+DOX	O
+-	O
+induced	O
+increase	O
+in	O
+the	O
+serum	O
+lactate	O
+dehydrogenase	O
+and	O
+creatine	O
+kinase	O
+activities	O
+but	O
+not	O
+metalloproteinase	O
+activation	O
+in	O
+the	O
+heart	O
+.	O
+
+Thus	O
+,	O
+PARP	O
+activation	O
+contributes	O
+to	O
+the	O
+cardiotoxicity	B
+of	O
+DOX	O
+.	O
+
+PARP	O
+inhibitors	O
+may	O
+exert	O
+protective	O
+effects	O
+against	O
+the	O
+development	O
+of	O
+severe	O
+cardiac	B
+complications	I
+associated	O
+with	O
+the	O
+DOX	O
+treatment	O
+.	O
+
+Spironolactone	O
+:	O
+is	O
+it	O
+a	O
+novel	O
+drug	O
+for	O
+the	O
+prevention	O
+of	O
+amphotericin	O
+B	O
+-	O
+related	O
+hypokalemia	B
+in	O
+cancer	B
+patients	O
+?	O
+
+OBJECTIVE	O
+:	O
+Nephrotoxicity	B
+is	O
+the	O
+major	O
+adverse	O
+effect	O
+of	O
+amphotericin	O
+B	O
+(	O
+AmB	O
+)	O
+,	O
+often	O
+limiting	O
+administration	O
+of	O
+full	O
+dosage	O
+.	O
+
+Selective	O
+distal	O
+tubular	O
+epithelial	O
+toxicity	B
+seems	O
+to	O
+be	O
+responsible	O
+for	O
+the	O
+profound	O
+potassium	O
+wasting	O
+that	O
+is	O
+a	O
+major	O
+clinical	O
+side	O
+effect	O
+of	O
+treatment	O
+with	O
+AmB	O
+.	O
+
+Potassium	O
+depletion	O
+also	O
+potentiates	O
+the	O
+tubular	O
+toxicity	B
+of	O
+AmB	O
+.	O
+
+This	O
+study	O
+was	O
+designed	O
+to	O
+assess	O
+the	O
+ability	O
+of	O
+spironolactone	O
+to	O
+reduce	O
+potassium	O
+requirements	O
+and	O
+to	O
+prevent	O
+hypokalemia	B
+in	O
+neutropenic	B
+patients	O
+on	O
+AmB	O
+treatment	O
+.	O
+
+METHODS	O
+:	O
+In	O
+this	O
+study	O
+26	O
+patients	O
+with	O
+various	O
+hematological	B
+disorders	I
+were	O
+randomized	O
+to	O
+receive	O
+either	O
+intravenous	O
+AmB	O
+alone	O
+or	O
+AmB	O
+and	O
+oral	O
+spironolactone	O
+100	O
+mg	O
+twice	O
+daily	O
+when	O
+developing	O
+a	O
+proven	O
+or	O
+suspected	O
+fungal	B
+infection	I
+.	O
+
+RESULTS	O
+:	O
+Patients	O
+receiving	O
+concomitant	O
+AmB	O
+and	O
+spironolactone	O
+had	O
+significantly	O
+higher	O
+plasma	O
+potassium	O
+levels	O
+than	O
+those	O
+receiving	O
+AmB	O
+alone	O
+(	O
+P	O
+=	O
+0	O
+.	O
+0027	O
+)	O
+.	O
+
+Those	O
+patients	O
+receiving	O
+AmB	O
+and	O
+spironolactone	O
+required	O
+significantly	O
+less	O
+potassium	O
+supplementation	O
+to	O
+maintain	O
+their	O
+plasma	O
+potassium	O
+within	O
+the	O
+normal	O
+range	O
+(	O
+P	O
+=	O
+0	O
+.	O
+022	O
+)	O
+.	O
+
+Moreover	O
+,	O
+urinary	O
+potassium	O
+losses	O
+were	O
+significantly	O
+less	O
+in	O
+patients	O
+receiving	O
+AmB	O
+and	O
+spironolactone	O
+than	O
+those	O
+receiving	O
+AmB	O
+alone	O
+(	O
+P	O
+=	O
+0	O
+.	O
+040	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+study	O
+showed	O
+that	O
+spironolactone	O
+can	O
+reduce	O
+potassium	O
+requirements	O
+and	O
+prevent	O
+hypokalemia	B
+by	O
+reducing	O
+urinary	O
+potassium	O
+loss	O
+in	O
+neutropenic	B
+patients	O
+on	O
+AmB	O
+treatment	O
+.	O
+
+Erectile	B
+dysfunction	I
+occurs	O
+following	O
+substantia	O
+nigra	O
+lesions	O
+in	O
+the	O
+rat	O
+.	O
+
+Erectile	O
+function	O
+was	O
+assessed	O
+6	O
+weeks	O
+following	O
+uni	O
+-	O
+and	O
+bilateral	O
+injections	O
+of	O
+6	O
+-	O
+hydroxydopamine	O
+in	O
+the	O
+substantia	O
+nigra	O
+nucleus	O
+of	O
+the	O
+brain	O
+.	O
+
+Behavioral	O
+apomorphine	O
+-	O
+induced	O
+penile	O
+erections	O
+were	O
+reduced	O
+(	O
+5	O
+/	O
+8	O
+)	O
+and	O
+increased	O
+(	O
+3	O
+/	O
+8	O
+)	O
+in	O
+uni	O
+-	O
+and	O
+bilateral	O
+lesioned	O
+animals	O
+.	O
+
+Intracavernous	O
+pressures	O
+,	O
+following	O
+electrical	O
+stimulation	O
+of	O
+the	O
+cavernous	O
+nerve	O
+,	O
+decreased	O
+in	O
+lesioned	O
+animals	O
+.	O
+
+Lesions	O
+of	O
+the	O
+substantia	O
+nigra	O
+were	O
+confirmed	O
+by	O
+histology	O
+.	O
+
+Concentration	O
+of	O
+dopamine	O
+and	O
+its	O
+metabolites	O
+were	O
+decreased	O
+in	O
+the	O
+striatum	O
+of	O
+substantia	O
+nigra	O
+lesioned	O
+rats	O
+.	O
+
+Lesions	O
+of	O
+the	O
+substantia	O
+nigra	O
+are	O
+therefore	O
+associated	O
+with	O
+erectile	B
+dysfunction	I
+in	O
+rats	O
+and	O
+may	O
+serve	O
+as	O
+a	O
+model	O
+to	O
+study	O
+erectile	B
+dysfunction	I
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+Nicotine	O
+potentiation	O
+of	O
+morphine	O
+-	O
+induced	O
+catalepsy	B
+in	O
+mice	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+effects	O
+of	O
+nicotine	O
+on	O
+catalepsy	B
+induced	O
+by	O
+morphine	O
+in	O
+mice	O
+have	O
+been	O
+investigated	O
+.	O
+
+Morphine	O
+but	O
+not	O
+nicotine	O
+induced	O
+a	O
+dose	O
+-	O
+dependent	O
+catalepsy	B
+.	O
+
+The	O
+response	O
+of	O
+morphine	O
+was	O
+potentiated	O
+by	O
+nicotine	O
+.	O
+
+Intraperitoneal	O
+administration	O
+of	O
+atropine	O
+,	O
+naloxone	O
+,	O
+mecamylamine	O
+,	O
+and	O
+hexamethonium	O
+to	O
+mice	O
+reduced	O
+catalepsy	B
+induced	O
+by	O
+a	O
+combination	O
+of	O
+morphine	O
+with	O
+nicotine	O
+.	O
+
+Intracerebroventricular	O
+injection	O
+of	O
+atropine	O
+,	O
+hexamethonium	O
+,	O
+and	O
+naloxone	O
+also	O
+decreased	O
+catalepsy	B
+induced	O
+by	O
+morphine	O
+plus	O
+nicotine	O
+.	O
+
+Intraperitoneal	O
+administration	O
+of	O
+atropine	O
+,	O
+but	O
+not	O
+intraperitoneal	O
+or	O
+intracerebroventricular	O
+injection	O
+of	O
+hexamethonium	O
+,	O
+decreased	O
+the	O
+effect	O
+of	O
+a	O
+single	O
+dose	O
+of	O
+morphine	O
+.	O
+
+It	O
+was	O
+concluded	O
+that	O
+morphine	O
+catalepsy	B
+can	O
+be	O
+elicited	O
+by	O
+opioid	O
+and	O
+cholinergic	O
+receptors	O
+,	O
+and	O
+the	O
+potentiation	O
+of	O
+morphine	O
+induced	O
+by	O
+nicotine	O
+may	O
+also	O
+be	O
+mediated	O
+through	O
+cholinergic	O
+receptor	O
+mechanisms	O
+.	O
+
+Force	O
+overflow	O
+and	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+We	O
+assessed	O
+force	O
+coordination	O
+of	O
+the	O
+hand	O
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+and	O
+its	O
+relationship	O
+to	O
+motor	O
+complications	O
+of	O
+levodopa	O
+therapy	O
+,	O
+particularly	O
+to	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+(	O
+LID	B
+)	O
+.	O
+
+We	O
+studied	O
+two	O
+groups	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+patients	O
+with	O
+(	O
+Parkinson	B
+'	I
+s	I
+disease	I
++	O
+LID	B
+,	O
+n	O
+=	O
+23	O
+)	O
+and	O
+without	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+(	O
+Parkinson	B
+'	I
+s	I
+disease	I
+-	O
+LID	B
+,	O
+n	O
+=	O
+10	O
+)	O
+,	O
+and	O
+age	O
+-	O
+matched	O
+healthy	O
+controls	O
+.	O
+
+The	O
+motor	O
+score	O
+of	O
+the	O
+Unified	O
+Parkinson	B
+'	I
+s	I
+Disease	I
+Rating	O
+Scale	O
+,	O
+a	O
+dyskinesia	B
+score	O
+and	O
+force	O
+in	O
+a	O
+grip	O
+-	O
+lift	O
+paradigm	O
+were	O
+assessed	O
+ON	O
+and	O
+OFF	O
+levodopa	O
+.	O
+
+A	O
+pathological	O
+increase	O
+of	O
+forces	O
+was	O
+seen	O
+in	O
+ON	O
+-	O
+state	O
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
++	O
+LID	B
+only	O
+.	O
+
+In	O
+Parkinson	B
+'	I
+s	I
+disease	I
++	O
+LID	B
+,	O
+the	O
+force	O
+involved	O
+in	O
+pressing	O
+down	O
+the	O
+object	O
+before	O
+lifting	O
+was	O
+significantly	O
+increased	O
+by	O
+levodopa	O
+(	O
+by	O
+61	O
+%	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+An	O
+overshooting	O
+of	O
+peak	O
+grip	O
+force	O
+by	O
+51	O
+%	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+and	O
+of	O
+static	O
+grip	O
+force	O
+by	O
+45	O
+%	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+was	O
+observed	O
+in	O
+the	O
+ON	O
+-	O
+compared	O
+with	O
+the	O
+OFF	O
+-	O
+drug	O
+condition	O
+.	O
+
+In	O
+contrast	O
+,	O
+no	O
+excessive	O
+force	O
+was	O
+found	O
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+-	O
+LID	B
+.	O
+
+Peak	O
+grip	O
+force	O
+in	O
+ON	O
+-	O
+state	O
+was	O
+140	O
+%	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+higher	O
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
++	O
+LID	B
+than	O
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+-	O
+LID	B
+,	O
+while	O
+static	O
+grip	O
+force	O
+was	O
+increased	O
+by	O
+138	O
+%	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+between	O
+groups	O
+.	O
+
+Severity	O
+of	O
+peak	O
+-	O
+dose	O
+dyskinesias	B
+was	O
+strongly	O
+correlated	O
+with	O
+grip	O
+force	O
+in	O
+ON	O
+-	O
+state	O
+(	O
+r	O
+=	O
+0	O
+.	O
+79	O
+with	O
+peak	O
+force	O
+,	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+No	O
+correlation	O
+was	O
+observed	O
+between	O
+forces	O
+and	O
+the	O
+motor	O
+score	O
+as	O
+well	O
+as	O
+with	O
+the	O
+daily	O
+dose	O
+of	O
+dopaminergic	O
+medication	O
+.	O
+
+Force	O
+excess	O
+was	O
+only	O
+observed	O
+in	O
+patients	O
+with	O
+LID	B
+and	O
+motor	O
+fluctuations	O
+.	O
+
+A	O
+close	O
+relationship	O
+was	O
+seen	O
+between	O
+the	O
+overshooting	O
+of	O
+forces	O
+and	O
+dyskinesias	B
+in	O
+the	O
+ON	O
+-	O
+drug	O
+condition	O
+.	O
+
+We	O
+postulate	O
+that	O
+both	O
+LID	B
+and	O
+grip	O
+force	O
+excess	O
+share	O
+common	O
+pathophysiological	O
+mechanisms	O
+related	O
+to	O
+motor	O
+fluctuations	O
+.	O
+
+Behavioral	O
+effects	O
+of	O
+MK	O
+-	O
+801	O
+on	O
+reserpine	O
+-	O
+treated	O
+mice	O
+.	O
+
+The	O
+effects	O
+of	O
+dizocilpine	O
+(	O
+MK	O
+-	O
+801	O
+)	O
+,	O
+a	O
+noncompetitive	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+receptor	O
+antagonist	O
+,	O
+were	O
+studied	O
+on	O
+dopamine	O
+-	O
+related	O
+behaviors	O
+induced	O
+by	O
+reserpine	O
+treatments	O
+.	O
+
+This	O
+study	O
+focuses	O
+on	O
+behavioral	O
+syndromes	O
+that	O
+may	O
+used	O
+as	O
+models	O
+for	O
+Parkinson	B
+'	I
+s	I
+disease	I
+,	O
+or	O
+tardive	B
+dyskinesia	I
+,	O
+and	O
+its	O
+response	O
+after	O
+glutamatergic	O
+blockage	O
+.	O
+
+Reserpine	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+administered	O
+once	O
+every	O
+other	O
+day	O
+for	O
+4	O
+days	O
+,	O
+produced	O
+increases	O
+in	O
+orofacial	B
+dyskinesia	I
+,	O
+tongue	O
+protrusion	O
+and	O
+vacuous	O
+chewing	O
+in	O
+mice	O
+,	O
+which	O
+are	O
+signs	O
+indicative	O
+of	O
+tardive	B
+dyskinesia	I
+.	O
+
+Reserpine	O
+also	O
+produced	O
+tremor	B
+and	O
+catalepsy	B
+,	O
+which	O
+are	O
+signs	O
+suggestive	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+MK	O
+-	O
+801	O
+(	O
+0	O
+.	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+administered	O
+30	O
+min	O
+before	O
+the	O
+observation	O
+test	O
+,	O
+prevented	O
+the	O
+vacuous	O
+chewing	O
+movements	O
+,	O
+tongue	O
+protrusions	O
+and	O
+catalepsy	B
+induced	O
+by	O
+reserpine	O
+.	O
+
+However	O
+,	O
+MK	O
+-	O
+801	O
+injection	O
+produced	O
+a	O
+significant	O
+increase	O
+of	O
+tremor	B
+in	O
+reserpine	O
+-	O
+treated	O
+mice	O
+.	O
+
+Reserpine	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+administered	O
+90	O
+min	O
+before	O
+the	O
+test	O
+and	O
+followed	O
+by	O
+apomophine	O
+injection	O
+(	O
+0	O
+.	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+5	O
+min	O
+before	O
+the	O
+test	O
+,	O
+did	O
+not	O
+produce	O
+oral	B
+dyskinesia	I
+in	O
+mice	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+reserpine	O
+induced	O
+increases	O
+in	O
+tremor	B
+and	O
+catalepsy	B
+compared	O
+to	O
+control	O
+mice	O
+.	O
+
+MK	O
+-	O
+801	O
+(	O
+0	O
+.	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+administration	O
+attenuated	O
+the	O
+catalepsy	B
+and	O
+tremor	B
+induced	O
+by	O
+reserpine	O
+.	O
+
+Pretreatment	O
+with	O
+reserpine	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+24	O
+h	O
+before	O
+the	O
+observation	O
+test	O
+produced	O
+increases	O
+in	O
+vacuous	O
+chewing	O
+movements	O
+and	O
+tongue	O
+protrusion	O
+,	O
+as	O
+well	O
+as	O
+increases	O
+in	O
+tremor	B
+and	O
+catalepsy	B
+,	O
+whereas	O
+MK	O
+-	O
+801	O
+(	O
+0	O
+.	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+injection	O
+90	O
+min	O
+before	O
+the	O
+test	O
+reversed	O
+the	O
+effects	O
+of	O
+reserpine	O
+.	O
+
+These	O
+results	O
+show	O
+that	O
+reserpine	O
+produces	O
+different	O
+and	O
+abnormal	B
+movements	I
+,	O
+which	O
+are	O
+related	O
+to	O
+dose	O
+and	O
+schedule	O
+employed	O
+and	O
+can	O
+be	O
+considered	O
+as	O
+parkinsonian	B
+-	O
+like	O
+and	O
+tardive	B
+dsykinesia	I
+signs	O
+.	O
+
+The	O
+glutamatergic	O
+blockage	O
+produced	O
+by	O
+NMDA	O
+can	O
+restore	O
+these	O
+signs	O
+,	O
+such	O
+as	O
+vacuous	O
+chewing	O
+movements	O
+,	O
+tongue	O
+protrusions	O
+,	O
+catalepsy	B
+and	O
+tremor	B
+according	O
+to	O
+the	O
+employed	O
+model	O
+.	O
+
+Risperidone	O
+-	O
+associated	O
+,	O
+benign	O
+transient	O
+visual	B
+disturbances	I
+in	O
+schizophrenic	B
+patients	O
+with	O
+a	O
+past	O
+history	O
+of	O
+LSD	O
+abuse	O
+.	O
+
+Two	O
+schizophrenic	B
+patients	O
+,	O
+who	O
+had	O
+a	O
+prior	O
+history	O
+of	O
+LSD	O
+abuse	O
+and	O
+who	O
+had	O
+previously	O
+developed	O
+EPS	B
+with	O
+classic	O
+antipsychotics	O
+,	O
+were	O
+successfully	O
+treated	O
+with	O
+risperidone	O
+.	O
+
+They	O
+both	O
+reported	O
+short	O
+episodes	O
+of	O
+transient	O
+visual	B
+disturbances	I
+,	O
+which	O
+appeared	O
+immediately	O
+after	O
+starting	O
+treatment	O
+with	O
+risperidone	O
+.	O
+
+This	O
+imagery	O
+resembled	O
+visual	B
+disturbances	I
+previously	O
+experienced	O
+as	O
+"	O
+flashbacks	O
+"	O
+related	O
+to	O
+prior	O
+LSD	O
+consumption	O
+.	O
+
+Risperidone	O
+administration	O
+was	O
+continued	O
+and	O
+the	O
+visual	B
+disturbances	I
+gradually	O
+wore	O
+off	O
+.	O
+
+During	O
+a	O
+six	O
+-	O
+month	O
+follow	O
+-	O
+up	O
+period	O
+,	O
+there	O
+was	O
+no	O
+recurrence	O
+of	O
+visual	B
+disturbances	I
+.	O
+
+This	O
+phenomenon	O
+may	O
+be	O
+interpreted	O
+as	O
+a	O
+benign	O
+,	O
+short	O
+-	O
+term	O
+and	O
+self	O
+-	O
+limiting	O
+side	O
+effect	O
+which	O
+does	O
+not	O
+contraindicate	O
+the	O
+use	O
+of	O
+risperidone	O
+or	O
+interfere	O
+with	O
+treatment	O
+.	O
+
+Conclusions	O
+based	O
+on	O
+two	O
+case	O
+reports	O
+should	O
+be	O
+taken	O
+with	O
+appropriate	O
+caution	O
+.	O
+
+Topiramate	O
+-	O
+induced	O
+nephrolithiasis	B
+.	O
+
+Topiramate	O
+is	O
+a	O
+recently	O
+developed	O
+antiepileptic	O
+medication	O
+that	O
+is	O
+becoming	O
+more	O
+widely	O
+prescribed	O
+because	O
+of	O
+its	O
+efficacy	O
+in	O
+treating	O
+refractory	B
+seizures	I
+.	O
+
+Urologists	O
+should	O
+be	O
+aware	O
+that	O
+this	O
+medication	O
+can	O
+cause	O
+metabolic	B
+acidosis	I
+in	O
+patients	O
+secondary	O
+to	O
+inhibition	O
+of	O
+carbonic	O
+anhydrase	O
+.	O
+
+In	O
+addition	O
+,	O
+a	O
+distal	O
+tubular	O
+acidification	O
+defect	O
+may	O
+result	O
+,	O
+thus	O
+impairing	O
+the	O
+normal	O
+compensatory	O
+drop	O
+in	O
+urine	O
+pH	O
+.	O
+
+These	O
+factors	O
+can	O
+lead	O
+to	O
+the	O
+development	O
+of	O
+calcium	O
+phosphate	O
+nephrolithiasis	B
+.	O
+
+We	O
+report	O
+the	O
+first	O
+two	O
+cases	O
+of	O
+topiramate	O
+-	O
+induced	O
+nephrolithiasis	B
+in	O
+the	O
+urologic	O
+literature	O
+.	O
+
+Ketamine	O
+in	O
+war	O
+/	O
+tropical	O
+surgery	O
+(	O
+a	O
+final	O
+tribute	O
+to	O
+the	O
+racemic	O
+mixture	O
+)	O
+.	O
+
+A	O
+technique	O
+of	O
+continuous	O
+intravenous	O
+anaesthesia	O
+with	O
+ketamine	O
+was	O
+used	O
+successfully	O
+during	O
+the	O
+Somalia	O
+civil	O
+war	O
+in	O
+1994	O
+and	O
+in	O
+north	O
+Uganda	O
+in	O
+1999	O
+for	O
+64	O
+operations	O
+in	O
+62	O
+patients	O
+,	O
+aged	O
+from	O
+6	O
+weeks	O
+to	O
+70	O
+years	O
+,	O
+undergoing	O
+limb	O
+and	O
+abdominal	O
+surgery	O
+including	O
+caesarian	O
+sections	O
+and	O
+interventions	O
+in	O
+neonates	O
+.	O
+
+Operations	O
+lasting	O
+up	O
+to	O
+2h	O
+could	O
+be	O
+performed	O
+in	O
+the	O
+absence	O
+of	O
+sophisticated	O
+equipment	O
+such	O
+as	O
+pulse	O
+oximeters	O
+or	O
+ventilators	O
+in	O
+patients	O
+on	O
+spontaneous	O
+ventilation	O
+breathing	O
+air	O
+/	O
+oxygen	O
+only	O
+.	O
+
+After	O
+premedication	O
+with	O
+diazepam	O
+,	O
+glycopyrrolate	O
+and	O
+local	O
+anaesthesia	O
+,	O
+and	O
+induction	O
+with	O
+standard	O
+doses	O
+of	O
+ketamine	O
+,	O
+a	O
+maintenance	O
+dose	O
+of	O
+10	O
+-	O
+20	O
+microg	O
+/	O
+kg	O
+/	O
+min	O
+of	O
+ketamine	O
+proved	O
+safe	O
+and	O
+effective	O
+.	O
+
+Emphasis	O
+was	O
+placed	O
+on	O
+bedside	O
+clinical	O
+monitoring	O
+,	O
+relying	O
+heavily	O
+on	O
+the	O
+heart	O
+rate	O
+.	O
+
+Diazepam	O
+,	O
+unless	O
+contraindicated	O
+or	O
+risky	O
+,	O
+remains	O
+the	O
+only	O
+necessary	O
+complementary	O
+drug	O
+to	O
+ketamine	O
+as	O
+it	O
+buffers	O
+its	O
+cardiovascular	O
+response	O
+and	O
+decreases	O
+the	O
+duration	O
+and	O
+intensity	O
+of	O
+operative	O
+and	O
+postoperative	O
+hallucinations	B
+.	O
+
+Local	O
+anaesthetic	O
+blocks	O
+were	O
+useful	O
+in	O
+decreasing	O
+the	O
+requirement	O
+for	O
+postoperative	O
+analgesia	B
+.	O
+
+An	O
+antisialogue	O
+was	O
+usually	O
+unnecessary	O
+in	O
+operations	O
+lasting	O
+up	O
+to	O
+2	O
+h	O
+,	O
+glycopyrrolate	O
+being	O
+the	O
+best	O
+choice	O
+for	O
+its	O
+lowest	O
+psychotropic	O
+and	O
+chronotropic	O
+effects	O
+,	O
+especially	O
+in	O
+a	O
+hot	O
+climate	O
+.	O
+
+Experience	O
+in	O
+war	O
+/	O
+tropical	O
+settings	O
+suggests	O
+this	O
+technique	O
+could	O
+be	O
+useful	O
+in	O
+civilian	O
+contexts	O
+such	O
+as	O
+outdoor	O
+life	O
+-	O
+saving	O
+emergency	O
+surgery	O
+or	O
+in	O
+mass	O
+casualties	O
+where	O
+,	O
+e	O
+.	O
+g	O
+.	O
+amputation	O
+and	O
+rapid	O
+extrication	O
+were	O
+required	O
+.	O
+
+Intravenous	O
+ribavirin	O
+treatment	O
+for	O
+severe	O
+adenovirus	B
+disease	I
+in	O
+immunocompromised	O
+children	O
+.	O
+
+BACKGROUND	O
+:	O
+Adenovirus	O
+is	O
+an	O
+important	O
+cause	O
+of	O
+morbidity	O
+and	O
+mortality	O
+in	O
+the	O
+immunocompromised	O
+host	O
+.	O
+
+The	O
+incidence	O
+of	O
+severe	O
+adenovirus	B
+disease	I
+in	O
+pediatrics	O
+is	O
+increasing	O
+in	O
+association	O
+with	O
+growing	O
+numbers	O
+of	O
+immunocompromised	O
+children	O
+,	O
+where	O
+case	O
+fatality	O
+rates	O
+as	O
+high	O
+as	O
+50	O
+%	O
+to	O
+80	O
+%	O
+have	O
+been	O
+reported	O
+.	O
+
+There	O
+are	O
+no	O
+approved	O
+antiviral	O
+agents	O
+with	O
+proven	O
+efficacy	O
+for	O
+the	O
+treatment	O
+of	O
+severe	O
+adenovirus	B
+disease	I
+,	O
+nor	O
+are	O
+there	O
+any	O
+prospective	O
+randomized	O
+,	O
+controlled	O
+trials	O
+of	O
+potentially	O
+useful	O
+anti	O
+-	O
+adenovirus	O
+therapies	O
+.	O
+
+Apparent	O
+clinical	O
+success	O
+in	O
+the	O
+treatment	O
+of	O
+severe	O
+adenovirus	B
+disease	I
+is	O
+limited	O
+to	O
+a	O
+few	O
+case	O
+reports	O
+and	O
+small	O
+series	O
+.	O
+
+Experience	O
+is	O
+greatest	O
+with	O
+intravenous	O
+ribavirin	O
+and	O
+cidofovir	O
+.	O
+
+Ribavirin	O
+,	O
+a	O
+guanosine	O
+analogue	O
+,	O
+has	O
+broad	O
+antiviral	O
+activity	O
+against	O
+both	O
+RNA	O
+and	O
+DNA	O
+viruses	O
+,	O
+including	O
+documented	O
+activity	O
+against	O
+adenovirus	O
+in	O
+vitro	O
+.	O
+
+Ribavirin	O
+is	O
+licensed	O
+in	O
+aerosol	O
+form	O
+for	O
+the	O
+treatment	O
+of	O
+respiratory	B
+syncytial	I
+virus	I
+infection	I
+,	O
+and	O
+orally	O
+in	O
+combination	O
+with	O
+interferon	O
+to	O
+treat	O
+hepatitis	B
+C	I
+.	O
+
+Intravenous	O
+ribavirin	O
+is	O
+the	O
+treatment	O
+of	O
+choice	O
+for	O
+infection	B
+with	I
+hemorrhagic	I
+fever	I
+viruses	I
+.	O
+
+The	O
+most	O
+common	O
+adverse	O
+effect	O
+of	O
+intravenous	O
+ribavirin	O
+is	O
+reversible	O
+mild	O
+anemia	B
+.	O
+
+The	O
+use	O
+of	O
+cidofovir	O
+in	O
+severe	O
+adenovirus	B
+infection	I
+has	O
+been	O
+limited	O
+by	O
+adverse	O
+effects	O
+,	O
+the	O
+most	O
+significant	O
+of	O
+which	O
+is	O
+nephrotoxicity	B
+.	O
+
+OBJECTIVE	O
+:	O
+We	O
+report	O
+our	O
+experience	O
+with	O
+intravenous	O
+ribavirin	O
+therapy	O
+for	O
+severe	O
+adenovirus	B
+disease	I
+in	O
+a	O
+series	O
+of	O
+immunocompromised	O
+children	O
+and	O
+review	O
+the	O
+literature	O
+.	O
+
+DESIGN	O
+/	O
+METHODS	O
+:	O
+We	O
+retrospectively	O
+reviewed	O
+the	O
+medical	O
+records	O
+of	O
+5	O
+children	O
+treated	O
+with	O
+intravenous	O
+ribavirin	O
+for	O
+documented	O
+severe	O
+adenovirus	B
+disease	I
+.	O
+
+Two	O
+patients	O
+developed	O
+adenovirus	O
+hemorrhagic	B
+cystitis	I
+after	O
+cardiac	O
+and	O
+bone	O
+marrow	O
+transplants	O
+,	O
+respectively	O
+.	O
+
+The	O
+bone	O
+marrow	O
+transplant	O
+patient	O
+also	O
+received	O
+intravenous	O
+cidofovir	O
+for	O
+progressive	O
+disseminated	O
+disease	O
+.	O
+
+An	O
+additional	O
+3	O
+children	O
+developed	O
+adenovirus	B
+pneumonia	I
+;	O
+2	O
+were	O
+neonates	O
+,	O
+1	O
+of	O
+whom	O
+had	O
+partial	O
+DiGeorge	B
+syndrome	I
+.	O
+
+The	O
+remaining	O
+infant	O
+had	O
+recently	O
+undergone	O
+a	O
+cardiac	O
+transplant	O
+.	O
+
+Intravenous	O
+ribavirin	O
+was	O
+administered	O
+on	O
+a	O
+compassionate	O
+-	O
+use	O
+protocol	O
+.	O
+
+RESULTS	O
+:	O
+Complete	O
+clinical	O
+recovery	O
+followed	O
+later	O
+by	O
+viral	O
+clearance	O
+was	O
+observed	O
+in	O
+2	O
+children	O
+:	O
+the	O
+cardiac	O
+transplant	O
+recipient	O
+with	O
+adenovirus	O
+hemorrhagic	B
+cystitis	I
+and	O
+the	O
+immunocompetent	O
+neonate	O
+with	O
+adenovirus	B
+pneumonia	I
+.	O
+
+The	O
+remaining	O
+3	O
+children	O
+died	O
+of	O
+adenovirus	B
+disease	I
+.	O
+
+Intravenous	O
+ribavirin	O
+therapy	O
+was	O
+well	O
+tolerated	O
+.	O
+
+Use	O
+of	O
+cidofovir	O
+in	O
+1	O
+child	O
+was	O
+associated	O
+with	O
+progressive	B
+renal	I
+failure	I
+and	O
+neutropenia	B
+.	O
+
+DISCUSSION	O
+:	O
+Our	O
+series	O
+of	O
+patients	O
+is	O
+representative	O
+of	O
+the	O
+spectrum	O
+of	O
+immunocompromised	O
+children	O
+at	O
+greatest	O
+risk	O
+for	O
+severe	O
+adenovirus	B
+disease	I
+,	O
+namely	O
+solid	O
+-	O
+organ	O
+and	O
+bone	O
+marrow	O
+transplant	O
+recipients	O
+,	O
+neonates	O
+,	O
+and	O
+children	O
+with	O
+immunodeficiency	B
+.	O
+
+Although	O
+intravenous	O
+ribavirin	O
+was	O
+not	O
+effective	O
+for	O
+all	O
+children	O
+with	O
+severe	O
+adenovirus	B
+disease	I
+in	O
+this	O
+series	O
+or	O
+in	O
+the	O
+literature	O
+,	O
+therapy	O
+is	O
+unlikely	O
+to	O
+be	O
+of	O
+benefit	O
+if	O
+begun	O
+late	O
+in	O
+the	O
+course	O
+of	O
+the	O
+infection	B
+.	O
+
+Early	O
+identification	O
+,	O
+eg	O
+by	O
+polymerase	O
+chain	O
+reaction	O
+of	O
+those	O
+patients	O
+at	O
+risk	O
+of	O
+disseminated	O
+adenovirus	B
+disease	I
+may	O
+permit	O
+earlier	O
+antiviral	O
+treatment	O
+and	O
+better	O
+evaluation	O
+of	O
+therapeutic	O
+response	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Two	O
+of	O
+5	O
+children	O
+with	O
+severe	O
+adenovirus	B
+disease	I
+treated	O
+with	O
+intravenous	O
+ribavirin	O
+recovered	O
+.	O
+
+The	O
+availability	O
+of	O
+newer	O
+rapid	O
+diagnostic	O
+techniques	O
+,	O
+such	O
+as	O
+polymerase	O
+chain	O
+reaction	O
+,	O
+may	O
+make	O
+earlier	O
+,	O
+more	O
+effective	O
+treatment	O
+of	O
+adenovirus	B
+infection	I
+possible	O
+.	O
+
+Given	O
+the	O
+seriousness	O
+and	O
+increasing	O
+prevalence	O
+of	O
+adenovirus	B
+disease	I
+in	O
+certain	O
+hosts	O
+,	O
+especially	O
+children	O
+,	O
+a	O
+large	O
+,	O
+multicenter	O
+clinical	O
+trial	O
+of	O
+potentially	O
+useful	O
+anti	O
+-	O
+adenoviral	O
+therapies	O
+,	O
+such	O
+as	O
+intravenous	O
+ribavirin	O
+,	O
+is	O
+clearly	O
+required	O
+to	O
+demonstrate	O
+the	O
+most	O
+effective	O
+and	O
+least	O
+toxic	O
+therapy	O
+.	O
+
+Delayed	O
+asystolic	B
+cardiac	B
+arrest	I
+after	O
+diltiazem	O
+overdose	B
+;	O
+resuscitation	O
+with	O
+high	O
+dose	O
+intravenous	O
+calcium	O
+.	O
+
+A	O
+51	O
+year	O
+old	O
+man	O
+took	O
+a	O
+mixed	O
+overdose	B
+including	O
+1	O
+.	O
+8	O
+-	O
+3	O
+.	O
+6	O
+g	O
+of	O
+diltiazem	O
+,	O
+paracetamol	O
+,	O
+aspirin	O
+,	O
+isosorbide	O
+nitrate	O
+,	O
+and	O
+alcohol	O
+.	O
+
+He	O
+initially	O
+presented	O
+to	O
+hospital	O
+after	O
+six	O
+hours	O
+with	O
+mild	O
+hypotension	B
+and	O
+was	O
+treated	O
+with	O
+activated	O
+charcoal	O
+and	O
+intravenous	O
+fluids	O
+.	O
+
+Eighteen	O
+hours	O
+after	O
+the	O
+overdose	B
+he	O
+had	O
+two	O
+generalised	O
+tonic	B
+-	I
+clonic	I
+seizures	I
+.	O
+
+The	O
+patient	O
+remained	O
+unresponsive	O
+with	O
+junctional	O
+bradycardia	B
+,	O
+unrecordable	O
+blood	O
+pressure	O
+,	O
+and	O
+then	O
+became	O
+asystolic	B
+.	O
+
+He	O
+was	O
+resuscitated	O
+with	O
+high	O
+dose	O
+(	O
+13	O
+.	O
+5	O
+g	O
+)	O
+intravenous	O
+calcium	O
+and	O
+adrenaline	O
+(	O
+epinephrine	O
+)	O
+.	O
+
+He	O
+required	O
+inotropic	O
+support	O
+and	O
+temporary	O
+pacing	O
+over	O
+the	O
+next	O
+48	O
+hours	O
+.	O
+
+This	O
+case	O
+suggests	O
+there	O
+is	O
+a	O
+role	O
+for	O
+aggressive	O
+high	O
+dose	O
+intravenous	O
+calcium	O
+therapy	O
+in	O
+severe	O
+diltiazem	O
+overdose	B
+,	O
+particularly	O
+with	O
+the	O
+onset	O
+of	O
+asystole	B
+.	O
+
+It	O
+should	O
+be	O
+considered	O
+early	O
+in	O
+cases	O
+of	O
+cardiac	B
+arrest	I
+after	O
+diltiazem	O
+overdose	B
+.	O
+
+The	O
+case	O
+also	O
+highlights	O
+the	O
+problems	O
+with	O
+delayed	O
+toxicity	B
+when	O
+whole	O
+bowel	O
+irrigation	O
+is	O
+not	O
+administered	O
+.	O
+
+Low	O
+-	O
+molecular	O
+-	O
+weight	O
+heparin	O
+for	O
+the	O
+treatment	O
+of	O
+patients	O
+with	O
+mechanical	O
+heart	O
+valves	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+interruption	O
+of	O
+oral	O
+anticoagulant	O
+(	O
+OAC	O
+)	O
+administration	O
+is	O
+sometimes	O
+indicated	O
+in	O
+patients	O
+with	O
+mechanical	O
+heart	O
+valves	O
+,	O
+mainly	O
+before	O
+noncardiac	O
+surgery	O
+,	O
+non	O
+-	O
+surgical	O
+interventions	O
+,	O
+and	O
+pregnancy	O
+.	O
+
+Unfractionated	O
+heparin	O
+(	O
+UH	O
+)	O
+is	O
+currently	O
+the	O
+substitute	O
+for	O
+selected	O
+patients	O
+.	O
+
+Low	O
+-	O
+molecular	O
+-	O
+weight	O
+heparin	O
+(	O
+LMWH	O
+)	O
+offers	O
+theoretical	O
+advantages	O
+over	O
+UH	O
+,	O
+but	O
+is	O
+not	O
+currently	O
+considered	O
+in	O
+clinical	O
+guidelines	O
+as	O
+an	O
+alternative	O
+to	O
+UH	O
+in	O
+patients	O
+with	O
+prosthetic	O
+valves	O
+.	O
+
+HYPOTHESIS	O
+:	O
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+review	O
+the	O
+data	O
+accumulated	O
+so	O
+far	O
+on	O
+the	O
+use	O
+of	O
+LMWH	O
+in	O
+this	O
+patient	O
+population	O
+and	O
+to	O
+discuss	O
+its	O
+applicability	O
+in	O
+common	O
+practice	O
+.	O
+
+METHODS	O
+:	O
+For	O
+this	O
+paper	O
+,	O
+the	O
+current	O
+medical	O
+literature	O
+on	O
+LMWH	O
+in	O
+patients	O
+with	O
+mechanical	O
+heart	O
+valves	O
+was	O
+extensively	O
+reviewed	O
+.	O
+
+RESULTS	O
+:	O
+There	O
+were	O
+eight	O
+series	O
+and	O
+six	O
+case	O
+reports	O
+.	O
+
+None	O
+of	O
+the	O
+studies	O
+was	O
+randomized	O
+,	O
+and	O
+only	O
+one	O
+was	O
+prospective	O
+.	O
+
+Data	O
+to	O
+establish	O
+the	O
+thromboembolic	B
+risk	O
+were	O
+incomplete	O
+.	O
+
+After	O
+excluding	O
+case	O
+reports	O
+,	O
+the	O
+following	O
+groups	O
+were	O
+constructed	O
+:	O
+(	O
+a	O
+)	O
+short	O
+-	O
+term	O
+administration	O
+,	O
+after	O
+valve	O
+insertion	O
+(	O
+n	O
+=	O
+212	O
+)	O
+;	O
+(	O
+b	O
+)	O
+short	O
+-	O
+term	O
+,	O
+perioperative	O
+(	O
+noncardiac	O
+)	O
+/	O
+periprocedural	O
+(	O
+n	O
+=	O
+114	O
+)	O
+;	O
+(	O
+c	O
+)	O
+long	O
+-	O
+term	O
+,	O
+due	O
+to	O
+intolerance	O
+to	O
+OAC	O
+(	O
+n	O
+=	O
+16	O
+)	O
+;	O
+(	O
+d	O
+)	O
+long	O
+-	O
+term	O
+,	O
+in	O
+pregnancy	O
+(	O
+n	O
+=	O
+10	O
+)	O
+.	O
+
+The	O
+incidence	O
+rate	O
+of	O
+thromboembolism	B
+was	O
+0	O
+.	O
+9	O
+%	O
+for	O
+all	O
+the	O
+studies	O
+and	O
+0	O
+.	O
+5	O
+,	O
+0	O
+,	O
+20	O
+,	O
+and	O
+0	O
+%	O
+in	O
+groups	O
+a	O
+,	O
+b	O
+,	O
+c	O
+,	O
+and	O
+d	O
+,	O
+respectively	O
+;	O
+for	O
+hemorrhage	B
+,	O
+the	O
+overall	O
+rate	O
+was	O
+3	O
+.	O
+4	O
+%	O
+(	O
+3	O
+.	O
+8	O
+,	O
+2	O
+.	O
+6	O
+,	O
+10	O
+,	O
+and	O
+0	O
+%	O
+for	O
+the	O
+respective	O
+groups	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+In	O
+patients	O
+with	O
+mechanical	O
+heart	O
+valves	O
+,	O
+short	O
+-	O
+term	O
+LMWH	O
+therapy	O
+compares	O
+favorably	O
+with	O
+UH	O
+.	O
+
+Data	O
+on	O
+mid	O
+-	O
+and	O
+long	O
+-	O
+term	O
+LMWH	O
+administration	O
+in	O
+these	O
+patients	O
+are	O
+sparse	O
+.	O
+
+Further	O
+randomized	O
+studies	O
+are	O
+needed	O
+to	O
+confirm	O
+the	O
+safety	O
+and	O
+precise	O
+indications	O
+for	O
+the	O
+use	O
+of	O
+LMWH	O
+in	O
+patients	O
+with	O
+mechanical	O
+heart	O
+valves	O
+.	O
+
+Cardiac	B
+arrest	I
+after	O
+intravenous	O
+metoclopramide	O
+-	O
+a	O
+case	O
+of	O
+five	O
+repeated	O
+injections	O
+of	O
+metoclopramide	O
+causing	O
+five	O
+episodes	O
+of	O
+cardiac	B
+arrest	I
+.	O
+
+We	O
+describe	O
+a	O
+patient	O
+where	O
+intravenous	O
+injection	O
+of	O
+metoclopramide	O
+was	O
+immediately	O
+followed	O
+by	O
+asystole	B
+repeatedly	O
+.	O
+
+The	O
+patient	O
+received	O
+metoclopramide	O
+10	O
+mg	O
+i	O
+.	O
+v	O
+.	O
+five	O
+times	O
+during	O
+48	O
+h	O
+.	O
+
+After	O
+interviewing	O
+the	O
+attending	O
+nurses	O
+and	O
+reviewing	O
+the	O
+written	O
+documentation	O
+,	O
+it	O
+is	O
+clear	O
+that	O
+every	O
+administration	O
+of	O
+metoclopramide	O
+was	O
+immediately	O
+(	O
+within	O
+s	O
+)	O
+followed	O
+by	O
+asystole	B
+.	O
+
+The	O
+asystole	B
+lasted	O
+15	O
+-	O
+30	O
+s	O
+on	O
+four	O
+occasions	O
+,	O
+on	O
+one	O
+occasion	O
+it	O
+lasted	O
+2	O
+min	O
+.	O
+
+The	O
+patient	O
+received	O
+atropine	O
+0	O
+.	O
+5	O
+-	O
+1	O
+mg	O
+and	O
+chest	O
+compressions	O
+,	O
+before	O
+sinus	O
+rhythm	O
+again	O
+took	O
+over	O
+.	O
+
+We	O
+interpret	O
+this	O
+as	O
+episodes	O
+of	O
+cardiac	B
+arrest	I
+caused	O
+by	O
+metoclopramide	O
+.	O
+
+The	O
+rapid	O
+injection	O
+via	O
+the	O
+central	O
+venous	O
+route	O
+and	O
+the	O
+concomitant	O
+tapering	O
+of	O
+dopamine	O
+infusion	O
+might	O
+have	O
+contributed	O
+in	O
+precipitating	O
+the	O
+adverse	O
+drug	O
+reaction	O
+.	O
+
+Immunohistochemical	O
+study	O
+on	O
+inducible	O
+type	O
+of	O
+nitric	O
+oxide	O
+(	O
+iNOS	O
+)	O
+,	O
+basic	O
+fibroblast	O
+growth	O
+factor	O
+(	O
+bFGF	O
+)	O
+and	O
+tumor	B
+growth	O
+factor	O
+-	O
+beta1	O
+(	O
+TGF	O
+-	O
+beta1	O
+)	O
+in	O
+arteritis	B
+induced	O
+in	O
+rats	O
+by	O
+fenoldopam	O
+and	O
+theophylline	O
+,	O
+vasodilators	O
+.	O
+
+Arteritis	B
+induced	O
+in	O
+rats	O
+by	O
+vasodilators	O
+,	O
+fenoldopam	O
+and	O
+theophylline	O
+,	O
+was	O
+examined	O
+immunohistochemically	O
+for	O
+expressions	O
+of	O
+inducible	O
+type	O
+of	O
+nitric	O
+oxide	O
+synthase	O
+(	O
+iNOS	O
+)	O
+,	O
+basic	O
+fibroblast	O
+growth	O
+factor	O
+(	O
+bFGF	O
+)	O
+and	O
+tumor	B
+growth	O
+factor	O
+-	O
+beta1	O
+(	O
+TGF	O
+-	O
+beta1	O
+)	O
+.	O
+
+Rats	O
+were	O
+administered	O
+fenoldopam	O
+for	O
+24	O
+hours	O
+by	O
+intravenous	O
+infusion	O
+with	O
+or	O
+without	O
+following	O
+repeated	O
+daily	O
+oral	O
+administrations	O
+of	O
+theophylline	O
+.	O
+
+Irrespective	O
+of	O
+theophylline	O
+administration	O
+,	O
+iNOS	O
+antigens	O
+were	O
+remarkably	O
+abundant	O
+in	O
+ED	O
+-	O
+1	O
+-	O
+positive	O
+cells	O
+on	O
+day	O
+5	O
+and	O
+8	O
+post	O
+-	O
+fenoldopam	O
+-	O
+infusion	O
+(	O
+DPI	O
+)	O
+;	O
+bFGF	O
+antigens	O
+were	O
+remarkably	O
+abundant	O
+in	O
+ED	O
+-	O
+1	O
+-	O
+positive	O
+cells	O
+on	O
+1	O
+and	O
+3	O
+DPI	O
+;	O
+TGF	O
+-	O
+beta1	O
+antigens	O
+were	O
+observed	O
+in	O
+ED	O
+-	O
+1	O
+-	O
+positive	O
+cells	O
+on	O
+and	O
+after	O
+5	O
+DPI	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+the	O
+peak	O
+expression	O
+of	O
+iNOS	O
+antigen	O
+was	O
+followed	O
+by	O
+that	O
+of	O
+bFGF	O
+antigen	O
+,	O
+and	O
+bFGF	O
+may	O
+have	O
+a	O
+suppressive	O
+effect	O
+on	O
+iNOS	O
+expression	O
+in	O
+these	O
+rat	O
+arteritis	B
+models	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+TGF	O
+-	O
+beta1	O
+was	O
+not	O
+considered	O
+to	O
+have	O
+a	O
+suppressive	O
+effect	O
+on	O
+iNOS	O
+expression	O
+in	O
+these	O
+models	O
+.	O
+
+The	O
+striatum	O
+as	O
+a	O
+target	O
+for	O
+anti	O
+-	O
+rigor	O
+effects	O
+of	O
+an	O
+antagonist	O
+of	O
+mGluR1	O
+,	O
+but	O
+not	O
+an	O
+agonist	O
+of	O
+group	O
+II	O
+metabotropic	O
+glutamate	O
+receptors	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+find	O
+out	O
+whether	O
+the	O
+metabotropic	O
+receptor	O
+1	O
+(	O
+mGluR1	O
+)	O
+and	O
+group	O
+II	O
+mGluRs	O
+,	O
+localized	O
+in	O
+the	O
+striatum	O
+,	O
+are	O
+involved	O
+in	O
+antiparkinsonian	O
+-	O
+like	O
+effects	O
+in	O
+rats	O
+.	O
+
+Haloperidol	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+ip	O
+)	O
+induced	O
+parkinsonian	B
+-	O
+like	O
+muscle	B
+rigidity	I
+,	O
+measured	O
+as	O
+an	O
+increased	O
+resistance	O
+of	O
+a	O
+rat	O
+'	O
+s	O
+hind	O
+foot	O
+to	O
+passive	O
+flexion	O
+and	O
+extension	O
+at	O
+the	O
+ankle	O
+joint	O
+.	O
+
+(	O
+RS	O
+)	O
+-	O
+1	O
+-	O
+aminoindan	O
+-	O
+1	O
+,	O
+5	O
+-	O
+dicarboxylic	O
+acid	O
+(	O
+AIDA	O
+;	O
+0	O
+.	O
+5	O
+-	O
+15	O
+microg	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+)	O
+,	O
+a	O
+potent	O
+and	O
+selective	O
+mGluR1	O
+antagonist	O
+,	O
+or	O
+(	O
+2R	O
+,	O
+4R	O
+)	O
+-	O
+4	O
+-	O
+aminopyrrolidine	O
+-	O
+2	O
+,	O
+4	O
+-	O
+dicarboxylate	O
+(	O
+2R	O
+,	O
+4R	O
+-	O
+APDC	O
+;	O
+7	O
+.	O
+5	O
+-	O
+15	O
+microg	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+)	O
+,	O
+a	O
+selective	O
+group	O
+II	O
+agonist	O
+,	O
+was	O
+injected	O
+bilaterally	O
+into	O
+the	O
+striatum	O
+of	O
+haloperidol	O
+-	O
+treated	O
+animals	O
+.	O
+
+AIDA	O
+in	O
+doses	O
+of	O
+7	O
+.	O
+5	O
+-	O
+15	O
+microg	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+diminished	O
+the	O
+haloperidol	O
+-	O
+induced	O
+muscle	B
+rigidity	I
+.	O
+
+In	O
+contrast	O
+,	O
+2R	O
+,	O
+4R	O
+-	O
+APDC	O
+injections	O
+were	O
+ineffective	O
+.	O
+
+The	O
+present	O
+results	O
+may	O
+suggest	O
+that	O
+the	O
+blockade	O
+of	O
+striatal	O
+mGluR1	O
+,	O
+but	O
+not	O
+the	O
+stimulation	O
+of	O
+group	O
+II	O
+mGluRs	O
+,	O
+may	O
+ameliorate	O
+parkinsonian	B
+muscle	B
+rigidity	I
+.	O
+
+A	O
+phase	O
+II	O
+study	O
+of	O
+thalidomide	O
+in	O
+advanced	O
+metastatic	O
+renal	B
+cell	I
+carcinoma	I
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+evaluate	O
+the	O
+toxicity	B
+and	O
+activity	O
+of	O
+thalidomide	O
+in	O
+patients	O
+with	O
+advanced	O
+metastatic	O
+renal	B
+cell	I
+cancer	I
+and	O
+to	O
+measure	O
+changes	O
+of	O
+one	O
+angiogenic	O
+factor	O
+,	O
+vascular	O
+endothelial	O
+growth	O
+factor	O
+(	O
+VEGF	O
+)	O
+165	O
+,	O
+with	O
+therapy	O
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+29	O
+patients	O
+were	O
+enrolled	O
+on	O
+a	O
+study	O
+of	O
+thalidomide	O
+using	O
+an	O
+intra	O
+-	O
+patient	O
+dose	O
+escalation	O
+schedule	O
+.	O
+
+Patients	O
+began	O
+thalidomide	O
+at	O
+400	O
+mg	O
+/	O
+d	O
+and	O
+escalated	O
+as	O
+tolerated	O
+to	O
+1200	O
+mg	O
+/	O
+d	O
+by	O
+day	O
+54	O
+.	O
+
+Fifty	O
+-	O
+nine	O
+per	O
+cent	O
+of	O
+patients	O
+had	O
+had	O
+previous	O
+therapy	O
+with	O
+IL	O
+-	O
+2	O
+and	O
+52	O
+%	O
+were	O
+performance	O
+status	O
+2	O
+or	O
+3	O
+.	O
+
+Systemic	O
+plasma	O
+VEGF165	O
+levels	O
+were	O
+measured	O
+by	O
+dual	O
+monoclonal	O
+ELISA	O
+in	O
+8	O
+patients	O
+.	O
+
+RESULTS	O
+:	O
+24	O
+patients	O
+were	O
+evaluable	O
+for	O
+response	O
+with	O
+one	O
+partial	O
+response	O
+of	O
+11	O
+months	O
+duration	O
+of	O
+a	O
+patient	O
+with	O
+hepatic	O
+and	O
+pulmonary	O
+metastases	B
+(	O
+4	O
+%	O
+)	O
+,	O
+one	O
+minor	O
+response	O
+,	O
+and	O
+2	O
+patients	O
+stable	O
+for	O
+over	O
+6	O
+months	O
+.	O
+
+Somnolence	B
+and	O
+constipation	B
+were	O
+prominent	O
+toxicities	B
+and	O
+most	O
+patients	O
+could	O
+not	O
+tolerate	O
+the	O
+1200	O
+mg	O
+/	O
+day	O
+dose	O
+level	O
+.	O
+
+Systemic	O
+plasma	O
+VEGF165	O
+levels	O
+did	O
+not	O
+change	O
+with	O
+therapy	O
+.	O
+
+CONCLUSION	O
+:	O
+These	O
+results	O
+are	O
+consistent	O
+with	O
+a	O
+low	O
+level	O
+of	O
+activity	O
+of	O
+thalidomide	O
+in	O
+renal	B
+cell	I
+carcinoma	I
+.	O
+
+Administration	O
+of	O
+doses	O
+over	O
+800	O
+mg	O
+/	O
+day	O
+was	O
+difficult	O
+to	O
+achieve	O
+in	O
+this	O
+patient	O
+population	O
+,	O
+however	O
+lower	O
+doses	O
+were	O
+practical	O
+.	O
+
+The	O
+dose	O
+-	O
+response	O
+relationship	O
+,	O
+if	O
+any	O
+,	O
+of	O
+thalidomide	O
+for	O
+renal	B
+cell	I
+carcinoma	I
+is	O
+unclear	O
+.	O
+
+Can	O
+lidocaine	O
+reduce	O
+succinylcholine	O
+induced	O
+postoperative	B
+myalgia	I
+?	O
+
+This	O
+study	O
+was	O
+undertaken	O
+to	O
+determine	O
+the	O
+effect	O
+of	O
+lidocaine	O
+pretreatment	O
+on	O
+reduction	O
+of	O
+succinylcholine	O
+-	O
+induced	O
+myalgia	B
+in	O
+patients	O
+undergoing	O
+general	O
+anesthesia	O
+for	O
+gynecological	O
+surgery	O
+.	O
+
+One	O
+hundred	O
+and	O
+thirty	O
+-	O
+five	O
+patients	O
+were	O
+assigned	O
+to	O
+one	O
+of	O
+three	O
+groups	O
+in	O
+a	O
+prospective	O
+,	O
+double	O
+blind	O
+,	O
+randomized	O
+manner	O
+.	O
+
+Group	O
+PS	O
+,	O
+the	O
+control	O
+group	O
+,	O
+received	O
+normal	O
+saline	O
+and	O
+succinylcholine	O
+1	O
+.	O
+5	O
+mg	O
+x	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+;	O
+Group	O
+LS	O
+,	O
+lidocaine	O
+1	O
+.	O
+5	O
+mg	O
+x	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+and	O
+succinylcholine	O
+1	O
+.	O
+5	O
+mg	O
+x	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+;	O
+Group	O
+PR	O
+,	O
+normal	O
+saline	O
+and	O
+rocuronium	O
+0	O
+.	O
+6	O
+mg	O
+x	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+
+Morphine	O
+0	O
+.	O
+1	O
+mg	O
+x	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+iv	O
+was	O
+given	O
+for	O
+premedication	O
+and	O
+all	O
+patients	O
+were	O
+monitored	O
+with	O
+a	O
+noninvasive	O
+blood	O
+pressure	O
+monitor	O
+,	O
+ECG	O
+and	O
+pulse	O
+oximetry	O
+.	O
+
+Anesthesia	O
+was	O
+induced	O
+with	O
+5	O
+mg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+thiopental	O
+iv	O
+.	O
+followed	O
+by	O
+succinylcholine	O
+(	O
+Group	O
+PS	O
+,	O
+LS	O
+)	O
+or	O
+rocuronium	O
+(	O
+Group	O
+PR	O
+)	O
+for	O
+tracheal	O
+intubation	O
+.	O
+
+Following	O
+administration	O
+of	O
+these	O
+agents	O
+,	O
+the	O
+presence	O
+,	O
+and	O
+degree	O
+of	O
+fasciculation	B
+were	O
+assessed	O
+visually	O
+on	O
+a	O
+four	O
+point	O
+scale	O
+by	O
+one	O
+investigator	O
+who	O
+was	O
+blinded	O
+to	O
+the	O
+drug	O
+administered	O
+.	O
+
+The	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+of	O
+each	O
+patient	O
+were	O
+monitored	O
+on	O
+nine	O
+occasions	O
+.	O
+
+Twenty	O
+-	O
+four	O
+hours	O
+later	O
+,	O
+any	O
+myalgia	B
+experienced	O
+was	O
+assessed	O
+according	O
+to	O
+a	O
+structured	O
+questionaire	O
+and	O
+graded	O
+by	O
+a	O
+four	O
+point	O
+scale	O
+by	O
+one	O
+investigator	O
+blinded	O
+to	O
+the	O
+intraoperative	O
+management	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+muscle	B
+fasciculation	I
+was	O
+not	O
+found	O
+in	O
+Group	O
+PR	O
+while	O
+the	O
+patients	O
+in	O
+Group	O
+LS	O
+had	O
+a	O
+lower	O
+incidence	O
+of	O
+muscle	B
+fasciculation	I
+than	O
+those	O
+in	O
+Group	O
+PS	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+At	O
+24	O
+h	O
+,	O
+the	O
+incidence	O
+of	O
+myalgia	B
+was	O
+higher	O
+in	O
+Group	O
+PS	O
+than	O
+in	O
+Group	O
+LS	O
+and	O
+PR	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+A	O
+correlation	O
+was	O
+not	O
+found	O
+between	O
+the	O
+incidence	O
+of	O
+myalgia	B
+and	O
+the	O
+occurrence	O
+of	O
+muscle	B
+fasciculation	I
+.	O
+
+The	O
+changes	O
+in	O
+systolic	O
+and	O
+diastolic	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+were	O
+not	O
+significant	O
+among	O
+the	O
+three	O
+groups	O
+.	O
+
+In	O
+conclusion	O
+,	O
+where	O
+succinylcholine	O
+is	O
+used	O
+,	O
+lidocaine	O
+is	O
+proven	O
+to	O
+be	O
+the	O
+useful	O
+pretreatment	O
+agent	O
+for	O
+the	O
+reduction	O
+of	O
+postoperative	B
+myalgia	I
+.	O
+
+Reduced	O
+sodium	O
+channel	O
+density	O
+,	O
+altered	O
+voltage	O
+dependence	O
+of	O
+inactivation	O
+,	O
+and	O
+increased	O
+susceptibility	O
+to	O
+seizures	B
+in	O
+mice	O
+lacking	O
+sodium	O
+channel	O
+beta	O
+2	O
+-	O
+subunits	O
+.	O
+
+Sodium	O
+channel	O
+beta	O
+-	O
+subunits	O
+modulate	O
+channel	O
+gating	O
+,	O
+assembly	O
+,	O
+and	O
+cell	O
+surface	O
+expression	O
+in	O
+heterologous	O
+cell	O
+systems	O
+.	O
+
+We	O
+generated	O
+beta2	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+to	O
+investigate	O
+the	O
+role	O
+of	O
+beta2	O
+in	O
+control	O
+of	O
+sodium	O
+channel	O
+density	O
+,	O
+localization	O
+,	O
+and	O
+function	O
+in	O
+neurons	O
+in	O
+vivo	O
+.	O
+
+Measurements	O
+of	O
+[	O
+(	O
+3	O
+)	O
+H	O
+]	O
+saxitoxin	O
+(	O
+STX	O
+)	O
+binding	O
+showed	O
+a	O
+significant	O
+reduction	O
+in	O
+the	O
+level	O
+of	O
+plasma	O
+membrane	O
+sodium	O
+channels	O
+in	O
+beta2	O
+(	O
+-	O
+/	O
+-	O
+)	O
+neurons	O
+.	O
+
+The	O
+loss	O
+of	O
+beta2	O
+resulted	O
+in	O
+negative	O
+shifts	O
+in	O
+the	O
+voltage	O
+dependence	O
+of	O
+inactivation	O
+as	O
+well	O
+as	O
+significant	O
+decreases	O
+in	O
+sodium	O
+current	O
+density	O
+in	O
+acutely	O
+dissociated	O
+hippocampal	O
+neurons	O
+.	O
+
+The	O
+integral	O
+of	O
+the	O
+compound	O
+action	O
+potential	O
+in	O
+optic	O
+nerve	O
+was	O
+significantly	O
+reduced	O
+,	O
+and	O
+the	O
+threshold	O
+for	O
+action	O
+potential	O
+generation	O
+was	O
+increased	O
+,	O
+indicating	O
+a	O
+reduction	O
+in	O
+the	O
+level	O
+of	O
+functional	O
+plasma	O
+membrane	O
+sodium	O
+channels	O
+.	O
+
+In	O
+contrast	O
+,	O
+the	O
+conduction	O
+velocity	O
+,	O
+the	O
+number	O
+and	O
+size	O
+of	O
+axons	O
+in	O
+the	O
+optic	O
+nerve	O
+,	O
+and	O
+the	O
+specific	O
+localization	O
+of	O
+Na	O
+(	O
+v	O
+)	O
+1	O
+.	O
+6	O
+channels	O
+in	O
+the	O
+nodes	O
+of	O
+Ranvier	O
+were	O
+unchanged	O
+.	O
+
+beta2	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+displayed	O
+increased	O
+susceptibility	O
+to	O
+seizures	B
+,	O
+as	O
+indicated	O
+by	O
+reduced	O
+latency	O
+and	O
+threshold	O
+for	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+,	O
+but	O
+seemed	O
+normal	O
+in	O
+other	O
+neurological	O
+tests	O
+.	O
+
+Our	O
+observations	O
+show	O
+that	O
+beta2	O
+-	O
+subunits	O
+play	O
+an	O
+important	O
+role	O
+in	O
+the	O
+regulation	O
+of	O
+sodium	O
+channel	O
+density	O
+and	O
+function	O
+in	O
+neurons	O
+in	O
+vivo	O
+and	O
+are	O
+required	O
+for	O
+normal	O
+action	O
+potential	O
+generation	O
+and	O
+control	O
+of	O
+excitability	O
+.	O
+
+Acute	B
+liver	I
+failure	I
+with	O
+concurrent	O
+bupropion	O
+and	O
+carbimazole	O
+therapy	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+fatal	O
+liver	B
+failure	I
+possibly	O
+associated	O
+with	O
+concurrent	O
+use	O
+of	O
+bupropion	O
+and	O
+carbimazole	O
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+41	O
+-	O
+year	O
+-	O
+old	O
+Chinese	O
+man	O
+with	O
+a	O
+history	O
+of	O
+hyperthyroidism	B
+had	O
+been	O
+treated	O
+with	O
+carbimazole	O
+and	O
+propranolol	O
+for	O
+the	O
+past	O
+5	O
+years	O
+.	O
+
+He	O
+received	O
+a	O
+10	O
+-	O
+day	O
+course	O
+of	O
+bupropion	O
+as	O
+an	O
+aid	O
+for	O
+smoking	O
+cessation	O
+10	O
+weeks	O
+prior	O
+to	O
+presentation	O
+.	O
+
+He	O
+developed	O
+acute	B
+liver	I
+failure	I
+with	O
+rapid	O
+deterioration	O
+of	O
+renal	O
+function	O
+.	O
+
+Liver	O
+biopsy	O
+showed	O
+evidence	O
+of	O
+nonspecific	O
+drug	B
+-	I
+induced	I
+acute	I
+liver	I
+injury	I
+.	O
+
+His	O
+condition	O
+was	O
+further	O
+complicated	O
+by	O
+sepsis	B
+and	O
+coagulopathy	B
+.	O
+
+Death	O
+resulted	O
+19	O
+days	O
+after	O
+the	O
+onset	O
+of	O
+symptoms	O
+.	O
+
+The	O
+likelihood	O
+that	O
+bupropion	O
+induced	O
+hepatotoxicity	B
+in	O
+our	O
+patient	O
+was	O
+possible	O
+,	O
+based	O
+on	O
+the	O
+Naranjo	O
+probability	O
+scale	O
+.	O
+
+DISCUSSION	O
+:	O
+Although	O
+there	O
+is	O
+increasing	O
+evidence	O
+of	O
+hepatotoxicity	B
+induced	O
+by	O
+bupropion	O
+,	O
+this	O
+is	O
+the	O
+first	O
+case	O
+of	O
+fatality	O
+that	O
+could	O
+have	O
+resulted	O
+from	O
+acute	B
+liver	I
+failure	I
+in	O
+a	O
+patient	O
+receiving	O
+bupropion	O
+while	O
+on	O
+concomitant	O
+treatment	O
+with	O
+carbimazole	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Clinicians	O
+should	O
+be	O
+aware	O
+of	O
+the	O
+possibility	O
+of	O
+acute	B
+liver	I
+insult	I
+induced	O
+by	O
+bupropion	O
+given	O
+concurrently	O
+with	O
+other	O
+hepatotoxic	B
+drugs	O
+.	O
+
+Pyeloureteral	O
+filling	O
+defects	O
+associated	O
+with	O
+systemic	O
+anticoagulation	O
+:	O
+a	O
+case	O
+report	O
+.	O
+
+The	O
+etiology	O
+of	O
+pyeloureteritis	B
+cystica	I
+has	O
+long	O
+been	O
+attributed	O
+to	O
+chronic	O
+infection	B
+and	O
+inflammation	B
+.	O
+
+A	O
+case	O
+is	O
+presented	O
+that	O
+is	O
+unique	O
+in	O
+that	O
+the	O
+acute	O
+onset	O
+and	O
+the	O
+rapid	O
+resolution	O
+of	O
+pyeloureteral	O
+filling	O
+defects	O
+in	O
+this	O
+patient	O
+were	O
+documented	O
+by	O
+radiography	O
+.	O
+
+There	O
+is	O
+no	O
+evidence	O
+of	O
+antecedent	O
+or	O
+concurrent	O
+infection	B
+in	O
+this	O
+patient	O
+.	O
+
+The	O
+disease	O
+occurred	O
+subsequent	O
+to	O
+the	O
+initiation	O
+of	O
+heparin	O
+therapy	O
+for	O
+suspected	O
+pelvic	O
+thrombophlebitis	B
+and	O
+cleared	O
+rapidly	O
+subsequent	O
+to	O
+its	O
+discontinuation	O
+.	O
+
+The	O
+rate	O
+of	O
+resolution	O
+of	O
+the	O
+radiographic	O
+findings	O
+may	O
+be	O
+helpful	O
+in	O
+distinguishing	O
+between	O
+true	O
+pyeloureteritis	B
+cystica	I
+and	O
+submucosal	B
+hemorrhage	I
+.	O
+
+Nephrotoxic	B
+effects	O
+in	O
+high	O
+-	O
+risk	O
+patients	O
+undergoing	O
+angiography	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+use	O
+of	O
+iodinated	O
+contrast	O
+medium	O
+can	O
+result	O
+in	O
+nephropathy	B
+.	O
+
+Whether	O
+iso	O
+-	O
+osmolar	O
+contrast	O
+medium	O
+is	O
+less	O
+nephrotoxic	B
+than	O
+low	O
+-	O
+osmolar	O
+contrast	O
+medium	O
+in	O
+high	O
+-	O
+risk	O
+patients	O
+is	O
+uncertain	O
+.	O
+
+METHODS	O
+:	O
+We	O
+conducted	O
+a	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+prospective	O
+,	O
+multicenter	O
+study	O
+comparing	O
+the	O
+nephrotoxic	B
+effects	O
+of	O
+an	O
+iso	O
+-	O
+osmolar	O
+,	O
+dimeric	O
+,	O
+nonionic	O
+contrast	O
+medium	O
+,	O
+iodixanol	O
+,	O
+with	O
+those	O
+of	O
+a	O
+low	O
+-	O
+osmolar	O
+,	O
+nonionic	O
+,	O
+monomeric	O
+contrast	O
+medium	O
+,	O
+iohexol	O
+.	O
+
+The	O
+study	O
+involved	O
+129	O
+patients	O
+with	O
+diabetes	B
+with	O
+serum	O
+creatinine	O
+concentrations	O
+of	O
+1	O
+.	O
+5	O
+to	O
+3	O
+.	O
+5	O
+mg	O
+per	O
+deciliter	O
+who	O
+underwent	O
+coronary	O
+or	O
+aortofemoral	O
+angiography	O
+.	O
+
+The	O
+primary	O
+end	O
+point	O
+was	O
+the	O
+peak	O
+increase	O
+from	O
+base	O
+line	O
+in	O
+the	O
+creatinine	O
+concentration	O
+during	O
+the	O
+three	O
+days	O
+after	O
+angiography	O
+.	O
+
+Other	O
+end	O
+points	O
+were	O
+an	O
+increase	O
+in	O
+the	O
+creatinine	O
+concentration	O
+of	O
+0	O
+.	O
+5	O
+mg	O
+per	O
+deciliter	O
+or	O
+more	O
+,	O
+an	O
+increase	O
+of	O
+1	O
+.	O
+0	O
+mg	O
+per	O
+deciliter	O
+or	O
+more	O
+,	O
+and	O
+a	O
+change	O
+in	O
+the	O
+creatinine	O
+concentration	O
+from	O
+day	O
+0	O
+to	O
+day	O
+7	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+creatinine	O
+concentration	O
+increased	O
+significantly	O
+less	O
+in	O
+patients	O
+who	O
+received	O
+iodixanol	O
+.	O
+
+From	O
+day	O
+0	O
+to	O
+day	O
+3	O
+,	O
+the	O
+mean	O
+peak	O
+increase	O
+in	O
+creatinine	O
+was	O
+0	O
+.	O
+13	O
+mg	O
+per	O
+deciliter	O
+in	O
+the	O
+iodixanol	O
+group	O
+and	O
+0	O
+.	O
+55	O
+mg	O
+per	O
+deciliter	O
+in	O
+the	O
+iohexol	O
+group	O
+(	O
+P	O
+=	O
+0	O
+.	O
+001	O
+;	O
+the	O
+increase	O
+with	O
+iodixanol	O
+minus	O
+the	O
+increase	O
+with	O
+iohexol	O
+,	O
+-	O
+0	O
+.	O
+42	O
+mg	O
+per	O
+deciliter	O
+[	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+-	O
+0	O
+.	O
+73	O
+to	O
+-	O
+0	O
+.	O
+22	O
+]	O
+)	O
+.	O
+
+Two	O
+of	O
+the	O
+64	O
+patients	O
+in	O
+the	O
+iodixanol	O
+group	O
+(	O
+3	O
+percent	O
+)	O
+had	O
+an	O
+increase	O
+in	O
+the	O
+creatinine	O
+concentration	O
+of	O
+0	O
+.	O
+5	O
+mg	O
+per	O
+deciliter	O
+or	O
+more	O
+,	O
+as	O
+compared	O
+with	O
+17	O
+of	O
+the	O
+65	O
+patients	O
+in	O
+the	O
+iohexol	O
+group	O
+(	O
+26	O
+percent	O
+)	O
+(	O
+P	O
+=	O
+0	O
+.	O
+002	O
+;	O
+odds	O
+ratio	O
+for	O
+such	O
+an	O
+increase	O
+in	O
+the	O
+iodixanol	O
+group	O
+,	O
+0	O
+.	O
+09	O
+[	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+0	O
+.	O
+02	O
+to	O
+0	O
+.	O
+41	O
+]	O
+)	O
+.	O
+
+No	O
+patient	O
+receiving	O
+iodixanol	O
+had	O
+an	O
+increase	O
+of	O
+1	O
+.	O
+0	O
+mg	O
+per	O
+deciliter	O
+or	O
+more	O
+,	O
+but	O
+10	O
+patients	O
+in	O
+the	O
+iohexol	O
+group	O
+(	O
+15	O
+percent	O
+)	O
+did	O
+.	O
+
+The	O
+mean	O
+change	O
+in	O
+the	O
+creatinine	O
+concentration	O
+from	O
+day	O
+0	O
+to	O
+day	O
+7	O
+was	O
+0	O
+.	O
+07	O
+mg	O
+per	O
+deciliter	O
+in	O
+the	O
+iodixanol	O
+group	O
+and	O
+0	O
+.	O
+24	O
+mg	O
+per	O
+deciliter	O
+in	O
+the	O
+iohexol	O
+group	O
+(	O
+P	O
+=	O
+0	O
+.	O
+003	O
+;	O
+value	O
+in	O
+the	O
+iodixanol	O
+group	O
+minus	O
+the	O
+value	O
+in	O
+the	O
+iohexol	O
+group	O
+,	O
+-	O
+0	O
+.	O
+17	O
+mg	O
+per	O
+deciliter	O
+[	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+-	O
+0	O
+.	O
+34	O
+to	O
+-	O
+0	O
+.	O
+07	O
+]	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Nephropathy	B
+induced	O
+by	O
+contrast	O
+medium	O
+may	O
+be	O
+less	O
+likely	O
+to	O
+develop	O
+in	O
+high	O
+-	O
+risk	O
+patients	O
+when	O
+iodixanol	O
+is	O
+used	O
+rather	O
+than	O
+a	O
+low	O
+-	O
+osmolar	O
+,	O
+nonionic	O
+contrast	O
+medium	O
+.	O
+
+Protective	O
+effect	O
+of	O
+edaravone	O
+against	O
+streptomycin	O
+-	O
+induced	O
+vestibulotoxicity	B
+in	O
+the	O
+guinea	O
+pig	O
+.	O
+
+This	O
+study	O
+investigated	O
+alleviation	O
+of	O
+streptomycin	O
+-	O
+induced	O
+vestibulotoxicity	B
+by	O
+edaravone	O
+in	O
+guinea	O
+pigs	O
+.	O
+
+Edaravone	O
+,	O
+a	O
+free	O
+radical	O
+scavenger	O
+,	O
+has	O
+potent	O
+free	O
+radical	O
+quenching	O
+action	O
+and	O
+is	O
+used	O
+in	O
+clinical	O
+practice	O
+to	O
+treat	O
+cerebral	B
+infarction	I
+.	O
+
+Streptomycin	O
+was	O
+administered	O
+to	O
+the	O
+inner	O
+ear	O
+by	O
+osmotic	O
+pump	O
+for	O
+24	O
+h	O
+,	O
+and	O
+edaravone	O
+(	O
+n	O
+=	O
+8	O
+)	O
+or	O
+saline	O
+(	O
+n	O
+=	O
+6	O
+)	O
+was	O
+intraperitoneally	O
+injected	O
+once	O
+a	O
+day	O
+for	O
+7	O
+days	O
+.	O
+
+We	O
+observed	O
+horizontal	O
+vestibulo	O
+-	O
+ocular	O
+reflex	O
+as	O
+a	O
+marker	O
+of	O
+postoperative	O
+vestibular	O
+function	O
+.	O
+
+Animals	O
+injected	O
+with	O
+saline	O
+showed	O
+statistically	O
+smaller	O
+gains	O
+than	O
+those	O
+injected	O
+with	O
+edaravone	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+edaravone	O
+suppresses	O
+streptomycin	O
+-	O
+induced	O
+vestibulotoxicity	B
+.	O
+
+Levodopa	O
+-	O
+induced	O
+oromandibular	O
+dystonia	B
+in	O
+progressive	B
+supranuclear	I
+palsy	I
+.	O
+
+Levodopa	O
+-	O
+induced	O
+dyskinesias	B
+have	O
+been	O
+reported	O
+in	O
+Parkinson	B
+'	I
+s	I
+disease	I
+and	O
+multiple	B
+system	I
+atrophy	I
+.	O
+
+Cranial	O
+dystonias	B
+are	O
+rare	O
+in	O
+patients	O
+with	O
+progressive	B
+supranuclear	I
+palsy	I
+(	O
+PSP	B
+)	O
+.	O
+
+In	O
+this	O
+report	O
+we	O
+describe	O
+an	O
+unusual	O
+case	O
+of	O
+reversible	O
+levodopa	O
+-	O
+induced	O
+Oromandibular	B
+dystonia	I
+(	O
+OMD	B
+)	O
+in	O
+a	O
+PSP	B
+patient	O
+to	O
+highlight	O
+the	O
+importance	O
+of	O
+recognizing	O
+this	O
+drug	O
+related	O
+complication	O
+in	O
+the	O
+management	O
+of	O
+PSP	B
+,	O
+and	O
+discuss	O
+the	O
+possible	O
+underlying	O
+pathophysiology	O
+.	O
+
+Case	O
+report	O
+:	O
+Dexatrim	O
+(	O
+Phenylpropanolamine	O
+)	O
+as	O
+a	O
+cause	O
+of	O
+myocardial	B
+infarction	I
+.	O
+
+Phenylpropanolamine	O
+(	O
+PPA	O
+)	O
+is	O
+a	O
+sympathetic	O
+amine	O
+used	O
+in	O
+over	O
+-	O
+the	O
+-	O
+counter	O
+cold	O
+remedies	O
+and	O
+weight	O
+-	O
+control	O
+preparations	O
+worldwide	O
+.	O
+
+Its	O
+use	O
+has	O
+been	O
+associated	O
+with	O
+hypertensive	B
+episodes	O
+and	O
+hemorrhagic	B
+strokes	I
+in	O
+younger	O
+women	O
+.	O
+
+Several	O
+reports	O
+have	O
+linked	O
+the	O
+abuse	O
+of	O
+PPA	O
+with	O
+myocardial	B
+injury	I
+,	O
+especially	O
+when	O
+overdose	B
+is	O
+involved	O
+.	O
+
+We	O
+report	O
+here	O
+the	O
+first	O
+case	O
+of	O
+Dexatrim	O
+(	O
+PPA	O
+)	O
+-	O
+induced	O
+myocardial	B
+injury	I
+in	O
+a	O
+young	O
+woman	O
+who	O
+was	O
+using	O
+it	O
+at	O
+recommended	O
+doses	O
+for	O
+weight	O
+control	O
+.	O
+
+In	O
+addition	O
+,	O
+we	O
+review	O
+the	O
+7	O
+other	O
+cases	O
+of	O
+PPA	O
+related	O
+myocardial	B
+injury	I
+that	O
+have	O
+been	O
+reported	O
+so	O
+far	O
+.	O
+
+Physicians	O
+and	O
+patients	O
+should	O
+be	O
+alert	O
+to	O
+the	O
+potential	O
+cardiac	O
+risk	O
+associated	O
+with	O
+the	O
+use	O
+of	O
+PPA	O
+,	O
+even	O
+at	O
+doses	O
+generally	O
+considered	O
+to	O
+be	O
+safe	O
+.	O
+
+Differential	O
+diagnosis	O
+of	O
+high	O
+serum	O
+creatine	O
+kinase	O
+levels	O
+in	O
+systemic	B
+lupus	I
+erythematosus	I
+.	O
+
+We	O
+report	O
+the	O
+clinical	O
+and	O
+bioptic	O
+findings	O
+for	O
+a	O
+57	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+severe	O
+chloroquine	O
+-	O
+induced	O
+myopathy	B
+.	O
+
+Since	O
+1989	O
+,	O
+she	O
+had	O
+been	O
+suffering	O
+from	O
+systemic	B
+lupus	I
+erythematosus	I
+(	O
+SLE	B
+)	O
+with	O
+renal	B
+involvement	I
+and	O
+undergone	O
+periods	O
+of	O
+treatment	O
+with	O
+azathioprine	O
+and	O
+cyclophosphamide	O
+.	O
+
+Additional	O
+therapy	O
+with	O
+chloroquine	O
+(	O
+CQ	O
+)	O
+was	O
+started	O
+because	O
+of	O
+arthralgia	B
+.	O
+
+At	O
+the	O
+same	O
+time	O
+,	O
+slightly	O
+increased	O
+creatine	O
+kinase	O
+(	O
+CK	O
+)	O
+levels	O
+were	O
+noted	O
+.	O
+
+Myositis	B
+was	O
+suspected	O
+,	O
+and	O
+the	O
+patient	O
+was	O
+treated	O
+with	O
+steroids	O
+.	O
+
+The	O
+CK	O
+increase	O
+persisted	O
+,	O
+however	O
+,	O
+and	O
+she	O
+developed	O
+progressive	O
+muscular	B
+weakness	I
+and	O
+muscular	B
+atrophy	I
+.	O
+
+Routine	O
+controls	O
+revealed	O
+markedly	O
+elevated	O
+CK	O
+levels	O
+of	O
+1	O
+,	O
+700	O
+U	O
+/	O
+l	O
+.	O
+
+The	O
+neurological	O
+and	O
+electrophysiological	O
+findings	O
+were	O
+not	O
+typical	O
+of	O
+myositis	B
+.	O
+
+Thus	O
+,	O
+muscle	O
+biopsy	O
+of	O
+the	O
+deltoid	O
+muscle	O
+was	O
+performed	O
+in	O
+order	O
+to	O
+exclude	O
+polymyositis	B
+or	O
+toxic	O
+myopathy	B
+.	O
+
+As	O
+it	O
+revealed	O
+chloroquine	O
+-	O
+induced	O
+myopathy	B
+,	O
+medication	O
+was	O
+stopped	O
+.	O
+
+Discriminating	O
+between	O
+primary	O
+SLE	B
+-	O
+induced	O
+affection	B
+of	I
+the	I
+musculoskeletal	I
+system	I
+and	O
+drug	O
+-	O
+induced	O
+side	O
+effects	O
+is	O
+important	O
+for	O
+appropriate	O
+treatment	O
+of	O
+SLE	B
+patients	O
+.	O
+
+Seizure	B
+associated	O
+with	O
+sleep	B
+deprivation	I
+and	O
+sustained	O
+-	O
+release	O
+bupropion	O
+.	O
+
+This	O
+case	O
+report	O
+describes	O
+a	O
+generalized	O
+seizure	B
+associated	O
+with	O
+sustained	O
+-	O
+release	O
+bupropion	O
+use	O
+and	O
+sleep	B
+deprivation	I
+.	O
+
+The	O
+subject	O
+,	O
+a	O
+31	O
+-	O
+year	O
+-	O
+old	O
+female	O
+smoker	O
+,	O
+was	O
+participating	O
+in	O
+a	O
+clinical	O
+trial	O
+evaluating	O
+an	O
+investigational	O
+medication	O
+for	O
+smoking	O
+cessation	O
+that	O
+used	O
+sustained	O
+-	O
+release	O
+bupropion	O
+as	O
+an	O
+active	O
+control	O
+.	O
+
+After	O
+5	O
+weeks	O
+of	O
+bupropion	O
+use	O
+,	O
+the	O
+subject	O
+experienced	O
+a	O
+generalized	O
+tonic	O
+clonic	O
+seizure	B
+after	O
+staying	O
+up	O
+nearly	O
+all	O
+night	O
+packing	O
+and	O
+moving	O
+to	O
+a	O
+new	O
+residence	O
+.	O
+
+The	O
+patient	O
+had	O
+no	O
+other	O
+risk	O
+factors	O
+for	O
+seizures	B
+.	O
+
+We	O
+suggest	O
+that	O
+sleep	B
+deprivation	I
+may	O
+add	O
+to	O
+the	O
+risk	O
+of	O
+bupropion	O
+-	O
+associated	O
+seizures	B
+.	O
+
+Postoperative	B
+myalgia	I
+after	O
+succinylcholine	O
+:	O
+no	O
+evidence	O
+for	O
+an	O
+inflammatory	O
+origin	O
+.	O
+
+A	O
+common	O
+side	O
+effect	O
+associated	O
+with	O
+succinylcholine	O
+is	O
+postoperative	B
+myalgia	I
+.	O
+
+The	O
+pathogenesis	O
+of	O
+this	O
+myalgia	B
+is	O
+still	O
+unclear	O
+;	O
+inflammation	B
+has	O
+been	O
+suggested	O
+but	O
+without	O
+convincing	O
+evidence	O
+.	O
+
+We	O
+designed	O
+the	O
+present	O
+study	O
+to	O
+investigate	O
+whether	O
+an	O
+inflammatory	O
+reaction	O
+contributes	O
+to	O
+this	O
+myalgia	B
+.	O
+
+The	O
+incidence	O
+and	O
+severity	O
+of	O
+succinylcholine	O
+-	O
+associated	O
+myalgia	B
+was	O
+determined	O
+in	O
+64	O
+patients	O
+pretreated	O
+with	O
+saline	O
+or	O
+dexamethasone	O
+before	O
+succinylcholine	O
+(	O
+n	O
+=	O
+32	O
+for	O
+each	O
+)	O
+.	O
+
+Incidence	O
+and	O
+severity	O
+of	O
+myalgia	B
+did	O
+not	O
+differ	O
+significantly	O
+between	O
+the	O
+two	O
+groups	O
+:	O
+15	O
+patients	O
+in	O
+the	O
+dexamethasone	O
+group	O
+complained	O
+of	O
+myalgia	B
+compared	O
+with	O
+18	O
+patients	O
+in	O
+the	O
+saline	O
+group	O
+,	O
+and	O
+severe	O
+myalgia	B
+was	O
+reported	O
+by	O
+five	O
+patients	O
+and	O
+three	O
+patients	O
+,	O
+respectively	O
+(	O
+not	O
+significant	O
+)	O
+.	O
+
+At	O
+48	O
+h	O
+after	O
+surgery	O
+,	O
+12	O
+patients	O
+in	O
+both	O
+groups	O
+still	O
+suffered	O
+from	O
+myalgia	B
+(	O
+not	O
+significant	O
+)	O
+.	O
+
+In	O
+addition	O
+,	O
+interleukin	O
+-	O
+6	O
+(	O
+IL	O
+-	O
+6	O
+)	O
+as	O
+an	O
+early	O
+marker	O
+of	O
+inflammation	B
+was	O
+assessed	O
+in	O
+a	O
+subgroup	O
+of	O
+10	O
+patients	O
+pretreated	O
+with	O
+saline	O
+.	O
+
+We	O
+found	O
+an	O
+increase	O
+of	O
+IL	O
+-	O
+6	O
+for	O
+only	O
+three	O
+patients	O
+,	O
+but	O
+only	O
+one	O
+patient	O
+reported	O
+myalgia	B
+;	O
+no	O
+relationship	O
+between	O
+myalgia	B
+and	O
+the	O
+increase	O
+of	O
+IL	O
+-	O
+6	O
+was	O
+found	O
+.	O
+
+In	O
+conclusion	O
+,	O
+there	O
+is	O
+no	O
+evidence	O
+for	O
+an	O
+inflammatory	O
+origin	O
+of	O
+succinylcholine	O
+-	O
+associated	O
+myalgia	B
+.	O
+
+IMPLICATIONS	O
+:	O
+Administration	O
+of	O
+dexamethasone	O
+before	O
+succinylcholine	O
+was	O
+not	O
+effective	O
+in	O
+decreasing	O
+the	O
+incidence	O
+or	O
+the	O
+severity	O
+of	O
+succinylcholine	O
+-	O
+induced	O
+postoperative	B
+myalgia	I
+.	O
+
+Furthermore	O
+,	O
+there	O
+was	O
+no	O
+significant	O
+relationship	O
+between	O
+postoperative	B
+myalgia	I
+and	O
+time	O
+course	O
+of	O
+interleukin	O
+-	O
+6	O
+concentrations	O
+,	O
+a	O
+marker	O
+of	O
+inflammation	B
+.	O
+
+Pretreatment	O
+with	O
+dexamethasone	O
+is	O
+not	O
+justified	O
+to	O
+prevent	O
+postoperative	B
+myalgia	I
+after	O
+succinylcholine	O
+.	O
+
+Effect	O
+of	O
+lindane	O
+on	O
+hepatic	O
+and	O
+brain	O
+cytochrome	O
+P450s	O
+and	O
+influence	O
+of	O
+P450	O
+modulation	O
+in	O
+lindane	O
+induced	O
+neurotoxicity	B
+.	O
+
+Oral	O
+administration	O
+of	O
+lindane	O
+(	O
+2	O
+.	O
+5	O
+,	O
+5	O
+,	O
+10	O
+and	O
+15	O
+mg	O
+/	O
+kg	O
+,	O
+body	O
+weight	O
+)	O
+for	O
+5	O
+days	O
+was	O
+found	O
+to	O
+produce	O
+a	O
+dose	O
+-	O
+dependent	O
+increase	O
+in	O
+the	O
+activity	O
+of	O
+P450	O
+dependent	O
+7	O
+-	O
+ethoxyresorufin	O
+-	O
+O	O
+-	O
+deethylase	O
+(	O
+EROD	O
+)	O
+,	O
+7	O
+-	O
+pentoxyresorufin	O
+-	O
+O	O
+-	O
+dealkylase	O
+(	O
+PROD	O
+)	O
+and	O
+N	O
+-	O
+nitrosodimethylamine	O
+demethylase	O
+(	O
+NDMA	O
+-	O
+d	O
+)	O
+in	O
+rat	O
+brain	O
+and	O
+liver	O
+.	O
+
+A	O
+significant	O
+increase	O
+in	O
+the	O
+hepatic	O
+and	O
+brain	O
+P450	O
+monooxygenases	O
+was	O
+also	O
+observed	O
+when	O
+the	O
+duration	O
+of	O
+exposure	O
+of	O
+low	O
+dose	O
+(	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+of	O
+lindane	O
+was	O
+increased	O
+from	O
+5	O
+days	O
+to	O
+15	O
+or	O
+21	O
+days	O
+.	O
+
+As	O
+observed	O
+with	O
+different	O
+doses	O
+,	O
+the	O
+magnitude	O
+of	O
+induction	O
+in	O
+the	O
+activity	O
+of	O
+P450	O
+monooxygenases	O
+was	O
+several	O
+fold	O
+higher	O
+in	O
+liver	O
+microsomes	O
+when	O
+compared	O
+with	O
+the	O
+brain	O
+.	O
+
+Western	O
+blotting	O
+studies	O
+have	O
+indicated	O
+that	O
+the	O
+increase	O
+in	O
+the	O
+P450	O
+enzymes	O
+could	O
+be	O
+due	O
+to	O
+the	O
+increase	O
+in	O
+the	O
+expression	O
+of	O
+P450	O
+1A1	O
+/	O
+1A2	O
+,	O
+2B1	O
+/	O
+2B2	O
+and	O
+2E1	O
+isoenzymes	O
+.	O
+
+In	O
+vitro	O
+studies	O
+using	O
+organic	O
+inhibitors	O
+specific	O
+for	O
+individual	O
+P450	O
+isoenzymes	O
+and	O
+antibody	O
+inhibition	O
+experiments	O
+have	O
+further	O
+demonstrated	O
+that	O
+the	O
+increase	O
+in	O
+the	O
+activity	O
+of	O
+PROD	O
+,	O
+EROD	O
+and	O
+NDMA	O
+-	O
+d	O
+are	O
+due	O
+to	O
+the	O
+increase	O
+in	O
+the	O
+levels	O
+of	O
+P450	O
+2B1	O
+/	O
+2B2	O
+,	O
+1A1	O
+/	O
+1A2	O
+and	O
+2E1	O
+isoenzymes	O
+,	O
+respectively	O
+.	O
+
+Induction	O
+studies	O
+have	O
+further	O
+shown	O
+that	O
+while	O
+pretreatment	O
+of	O
+3	O
+-	O
+methylcholanthrene	O
+(	O
+MC	O
+)	O
+,	O
+an	O
+inducer	O
+of	O
+P4501A1	O
+/	O
+1A2	O
+,	O
+did	O
+not	O
+produce	O
+any	O
+significant	O
+effect	O
+in	O
+the	O
+incidence	O
+of	O
+lindane	O
+induced	O
+convulsions	B
+,	O
+pretreatment	O
+with	O
+phenobarbital	O
+(	O
+PB	O
+)	O
+,	O
+an	O
+inducer	O
+of	O
+P450	O
+2B1	O
+/	O
+2B2	O
+or	O
+ethanol	O
+,	O
+an	O
+inducer	O
+of	O
+P450	O
+2E1	O
+catalysed	O
+reactions	O
+,	O
+significantly	O
+increased	O
+the	O
+incidence	O
+of	O
+lindane	O
+induced	O
+convulsions	B
+.	O
+
+Similarly	O
+,	O
+when	O
+the	O
+P450	O
+-	O
+mediated	O
+metabolism	O
+of	O
+lindane	O
+was	O
+blocked	O
+by	O
+cobalt	O
+chloride	O
+incidence	O
+of	O
+convulsions	B
+was	O
+increased	O
+in	O
+animals	O
+treated	O
+with	O
+lindane	O
+indicating	O
+that	O
+lindane	O
+per	O
+se	O
+or	O
+its	O
+metabolites	O
+formed	O
+by	O
+PB	O
+or	O
+ethanol	O
+inducible	O
+P450	O
+isoenzymes	O
+are	O
+involved	O
+in	O
+its	O
+neurobehavioral	O
+toxicity	B
+.	O
+
+Absolute	O
+and	O
+attributable	O
+risk	O
+of	O
+venous	B
+thromboembolism	I
+in	O
+women	O
+on	O
+combined	O
+cyproterone	O
+acetate	O
+and	O
+ethinylestradiol	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+achieve	O
+absolute	O
+risk	O
+estimates	O
+of	O
+venous	B
+thromboembolism	I
+(	O
+VTE	B
+)	O
+among	O
+women	O
+on	O
+cyproterone	O
+acetate	O
+plus	O
+ethinylestradiol	O
+(	O
+CPA	O
+/	O
+EE	O
+)	O
+,	O
+and	O
+among	O
+women	O
+on	O
+combined	O
+oral	O
+contraceptives	O
+(	O
+COCs	O
+)	O
+.	O
+
+METHODS	O
+:	O
+From	O
+the	O
+Danish	O
+National	O
+Register	O
+of	O
+Patients	O
+(	O
+NRP	O
+)	O
+,	O
+1996	O
+to	O
+1998	O
+,	O
+the	O
+records	O
+of	O
+1	O
+.	O
+1	O
+million	O
+Danish	O
+women	O
+,	O
+ages	O
+15	O
+to	O
+44	O
+years	O
+,	O
+were	O
+searched	O
+for	O
+evidence	O
+of	O
+VTE	B
+.	O
+
+COC	O
+use	O
+was	O
+ascertained	O
+through	O
+mailed	O
+questionnaires	O
+.	O
+
+Sales	O
+statistics	O
+of	O
+COCs	O
+and	O
+CPA	O
+/	O
+EE	O
+were	O
+provided	O
+through	O
+Danish	O
+Drug	O
+Statistics	O
+.	O
+
+RESULTS	O
+:	O
+During	O
+the	O
+time	O
+frame	O
+of	O
+the	O
+study	O
+,	O
+330	O
+women	O
+were	O
+found	O
+to	O
+have	O
+had	O
+VTE	B
+while	O
+on	O
+COCs	O
+.	O
+
+Of	O
+these	O
+women	O
+,	O
+67	O
+were	O
+on	O
+levonorgestrel	O
+-	O
+containing	O
+COCs	O
+.	O
+
+Eleven	O
+were	O
+on	O
+CPA	O
+/	O
+EE	O
+.	O
+
+The	O
+corresponding	O
+absolute	O
+risk	O
+of	O
+VTE	B
+was	O
+3	O
+.	O
+4	O
+(	O
+range	O
+,	O
+3	O
+.	O
+1	O
+-	O
+3	O
+.	O
+8	O
+)	O
+per	O
+10	O
+000	O
+women	O
+years	O
+among	O
+the	O
+women	O
+on	O
+COCs	O
+,	O
+4	O
+.	O
+2	O
+(	O
+range	O
+,	O
+3	O
+.	O
+2	O
+-	O
+5	O
+.	O
+2	O
+)	O
+per	O
+10	O
+000	O
+women	O
+years	O
+among	O
+women	O
+on	O
+levonorgestrel	O
+-	O
+containing	O
+COCs	O
+,	O
+and	O
+3	O
+.	O
+1	O
+(	O
+range	O
+,	O
+1	O
+.	O
+3	O
+-	O
+4	O
+.	O
+9	O
+)	O
+per	O
+10	O
+000	O
+women	O
+years	O
+among	O
+the	O
+women	O
+on	O
+CPA	O
+/	O
+EE	O
+.	O
+
+CONCLUSION	O
+:	O
+Our	O
+results	O
+suggest	O
+the	O
+absolute	O
+risk	O
+of	O
+VTE	B
+among	O
+Danish	O
+women	O
+on	O
+COCs	O
+is	O
+similar	O
+to	O
+that	O
+among	O
+women	O
+taking	O
+CPA	O
+/	O
+EE	O
+.	O
+
+Comparison	O
+of	O
+developmental	O
+toxicology	O
+of	O
+aspirin	O
+(	O
+acetylsalicylic	O
+acid	O
+)	O
+in	O
+rats	O
+using	O
+selected	O
+dosing	O
+paradigms	O
+.	O
+
+BACKGROUND	O
+:	O
+Analysis	O
+of	O
+the	O
+literature	O
+for	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+(	O
+NSAIDs	O
+)	O
+suggests	O
+that	O
+a	O
+low	O
+incidence	O
+of	O
+developmental	B
+anomalies	I
+occurs	O
+in	O
+rats	O
+given	O
+NSAIDs	O
+on	O
+specific	O
+days	O
+during	O
+organogenesis	O
+.	O
+
+Aspirin	O
+(	O
+acetylsalicylic	O
+acid	O
+[	O
+ASA	O
+]	O
+)	O
+,	O
+an	O
+irreversible	O
+cyclooxygenase	O
+1	O
+and	O
+2	O
+inhibitor	O
+,	O
+induces	O
+developmental	B
+anomalies	I
+when	O
+administered	O
+to	O
+Wistar	O
+rats	O
+on	O
+gestational	O
+day	O
+(	O
+GD	O
+)	O
+9	O
+,	O
+10	O
+,	O
+or	O
+11	O
+(	O
+Kimmel	O
+CA	O
+,	O
+Wilson	O
+JG	O
+,	O
+Schumacher	O
+HJ	O
+.	O
+Teratology	O
+4	O
+:	O
+15	O
+-	O
+24	O
+,	O
+1971	O
+)	O
+.	O
+
+There	O
+are	O
+no	O
+published	O
+ASA	O
+studies	O
+using	O
+the	O
+multiple	O
+dosing	O
+paradigm	O
+of	O
+GDs	O
+6	O
+to	O
+17	O
+.	O
+
+Objectives	O
+of	O
+the	O
+current	O
+study	O
+were	O
+to	O
+compare	O
+results	O
+between	O
+Sprague	O
+-	O
+Dawley	O
+(	O
+SD	O
+)	O
+and	O
+Wistar	O
+strains	O
+when	O
+ASA	O
+is	O
+administered	O
+on	O
+GD	O
+9	O
+,	O
+10	O
+,	O
+or	O
+11	O
+;	O
+to	O
+compare	O
+the	O
+malformation	O
+patterns	O
+following	O
+single	O
+and	O
+multiple	O
+dosings	O
+during	O
+organogenesis	O
+in	O
+SD	O
+rats	O
+;	O
+and	O
+to	O
+test	O
+the	O
+hypothesis	O
+that	O
+maternal	O
+gastrointestinal	B
+toxicity	I
+confounds	O
+the	O
+detection	O
+of	O
+low	O
+incidence	O
+malformations	B
+with	O
+ASA	O
+when	O
+a	O
+multiple	O
+dosing	O
+paradigm	O
+is	O
+used	O
+.	O
+
+METHODS	O
+:	O
+ASA	O
+was	O
+administered	O
+as	O
+a	O
+single	O
+dose	O
+on	O
+GD	O
+9	O
+(	O
+0	O
+,	O
+250	O
+,	O
+500	O
+,	O
+or	O
+625	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+10	O
+(	O
+0	O
+,	O
+500	O
+,	O
+625	O
+,	O
+or	O
+750	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+or	O
+11	O
+(	O
+0	O
+,	O
+500	O
+,	O
+750	O
+,	O
+or	O
+1000	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+from	O
+GD	O
+6	O
+to	O
+GD	O
+17	O
+(	O
+0	O
+,	O
+50	O
+,	O
+125	O
+,	O
+or	O
+250	O
+mg	O
+/	O
+kg	O
+a	O
+day	O
+)	O
+in	O
+the	O
+multiple	O
+dose	O
+study	O
+to	O
+SD	O
+rats	O
+.	O
+
+Animals	O
+were	O
+killed	O
+on	O
+GD	O
+21	O
+,	O
+and	O
+fetuses	O
+were	O
+examined	O
+viscerally	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+literature	O
+evaluation	O
+suggested	O
+that	O
+NSAIDs	O
+induce	O
+ventricular	B
+septal	I
+defects	I
+(	O
+VSDs	B
+)	O
+and	O
+midline	B
+defects	I
+(	O
+MDs	B
+)	O
+in	O
+rats	O
+and	O
+diaphragmatic	B
+hernia	I
+(	O
+DH	B
+)	O
+,	O
+MDs	B
+,	O
+and	O
+VSDs	B
+in	O
+rabbits	O
+(	O
+Cook	O
+JC	O
+et	O
+al	O
+.	O
+,	O
+2003	O
+)	O
+;	O
+hence	O
+,	O
+the	O
+present	O
+study	O
+focused	O
+on	O
+these	O
+malformations	B
+,	O
+even	O
+though	O
+ASA	O
+induces	O
+several	O
+other	O
+low	O
+-	O
+incidence	O
+malformations	B
+.	O
+
+In	O
+single	O
+dose	O
+studies	O
+,	O
+DH	B
+,	O
+MD	B
+,	O
+and	O
+VSD	B
+were	O
+induced	O
+on	O
+GDs	O
+9	O
+and	O
+10	O
+.	O
+
+VSD	B
+also	O
+was	O
+noted	O
+following	O
+treatment	O
+on	O
+GD	O
+11	O
+.	O
+
+In	O
+contrast	O
+,	O
+DH	B
+and	O
+MD	B
+were	O
+noted	O
+in	O
+the	O
+multiple	O
+dose	O
+study	O
+design	O
+only	O
+in	O
+the	O
+high	O
+-	O
+dose	O
+group	O
+,	O
+and	O
+VSD	B
+was	O
+noted	O
+across	O
+all	O
+dose	O
+groups	O
+.	O
+
+CONCLUSIONS	O
+:	O
+High	O
+concordance	O
+in	O
+major	O
+developmental	B
+anomalies	I
+between	O
+Wistar	O
+and	O
+SD	O
+rats	O
+were	O
+noted	O
+with	O
+the	O
+exception	O
+of	O
+VSD	B
+in	O
+the	O
+SD	O
+rats	O
+and	O
+hydrocephalus	B
+in	O
+the	O
+Wistar	O
+rats	O
+.	O
+
+Variations	O
+and	O
+malformations	B
+were	O
+similar	O
+when	O
+ASA	O
+was	O
+administered	O
+as	O
+a	O
+single	O
+dose	O
+or	O
+during	O
+the	O
+period	O
+of	O
+organogenesis	O
+(	O
+GDs	O
+6	O
+to	O
+17	O
+)	O
+.	O
+
+It	O
+was	O
+also	O
+evident	O
+that	O
+,	O
+by	O
+titrating	O
+the	O
+dose	O
+to	O
+achieve	O
+a	O
+maximum	O
+tolerated	O
+dose	O
+,	O
+malformations	B
+that	O
+normally	O
+occur	O
+at	O
+low	O
+incidence	O
+,	O
+as	O
+reported	O
+from	O
+previous	O
+single	O
+dose	O
+studies	O
+,	O
+could	O
+also	O
+be	O
+induced	O
+with	O
+ASA	O
+given	O
+at	O
+multiple	O
+doses	O
+.	O
+
+Reversal	O
+of	O
+central	O
+benzodiazepine	O
+effects	O
+by	O
+flumazenil	O
+after	O
+intravenous	O
+conscious	O
+sedation	O
+with	O
+diazepam	O
+and	O
+opioids	O
+:	O
+report	O
+of	O
+a	O
+double	O
+-	O
+blind	O
+multicenter	O
+study	O
+.	O
+
+The	O
+Flumazenil	O
+in	O
+Intravenous	O
+Conscious	O
+Sedation	O
+with	O
+Diazepam	O
+Multicenter	O
+Study	O
+Group	O
+II	O
+.	O
+
+The	O
+efficacy	O
+and	O
+safety	O
+of	O
+a	O
+new	O
+benzodiazepine	O
+antagonist	O
+,	O
+flumazenil	O
+,	O
+were	O
+assessed	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+multicenter	O
+study	O
+.	O
+
+Flumazenil	O
+(	O
+mean	O
+dose	O
+,	O
+0	O
+.	O
+76	O
+mg	O
+)	O
+or	O
+placebo	O
+(	O
+mean	O
+dose	O
+,	O
+8	O
+.	O
+9	O
+ml	O
+)	O
+was	O
+administered	O
+intravenously	O
+to	O
+130	O
+and	O
+67	O
+patients	O
+,	O
+respectively	O
+,	O
+who	O
+had	O
+been	O
+given	O
+diazepam	O
+in	O
+conjunction	O
+with	O
+an	O
+opioid	O
+(	O
+fentanyl	O
+,	O
+meperidine	O
+,	O
+or	O
+morphine	O
+)	O
+for	O
+the	O
+induction	O
+and	O
+maintenance	O
+of	O
+intravenous	O
+conscious	O
+sedation	O
+for	O
+diagnostic	O
+or	O
+therapeutic	O
+surgical	O
+procedures	O
+.	O
+
+The	O
+group	O
+assessable	O
+for	O
+efficacy	O
+comprised	O
+122	O
+patients	O
+treated	O
+with	O
+flumazenil	O
+and	O
+64	O
+patients	O
+given	O
+placebo	O
+.	O
+
+After	O
+5	O
+minutes	O
+,	O
+80	O
+/	O
+115	O
+(	O
+70	O
+%	O
+)	O
+flumazenil	O
+-	O
+treated	O
+patients	O
+,	O
+compared	O
+with	O
+21	O
+/	O
+63	O
+(	O
+33	O
+%	O
+)	O
+placebo	O
+-	O
+treated	O
+patients	O
+,	O
+were	O
+completely	O
+awake	O
+and	O
+alert	O
+,	O
+as	O
+indicated	O
+by	O
+a	O
+score	O
+of	O
+5	O
+on	O
+the	O
+Observer	O
+'	O
+s	O
+Assessment	O
+of	O
+Alertness	O
+/	O
+Sedation	O
+Scale	O
+.	O
+
+Ninety	O
+-	O
+five	O
+percent	O
+of	O
+patients	O
+in	O
+each	O
+group	O
+who	O
+attained	O
+a	O
+score	O
+of	O
+5	O
+at	O
+the	O
+5	O
+-	O
+minute	O
+assessment	O
+showed	O
+no	O
+loss	O
+of	O
+alertness	O
+throughout	O
+the	O
+180	O
+-	O
+minute	O
+assessment	O
+period	O
+.	O
+
+Flumazenil	O
+-	O
+treated	O
+patients	O
+also	O
+performed	O
+significantly	O
+better	O
+on	O
+the	O
+Finger	O
+-	O
+to	O
+-	O
+Nose	O
+Test	O
+and	O
+the	O
+recall	O
+of	O
+pictures	O
+shown	O
+at	O
+the	O
+5	O
+-	O
+minute	O
+assessment	O
+.	O
+
+Flumazenil	O
+was	O
+well	O
+tolerated	O
+,	O
+with	O
+no	O
+serious	O
+adverse	O
+effects	O
+reported	O
+.	O
+
+Thirty	O
+-	O
+nine	O
+(	O
+30	O
+%	O
+)	O
+of	O
+flumazenil	O
+-	O
+treated	O
+patients	O
+,	O
+compared	O
+with	O
+17	O
+(	O
+25	O
+%	O
+)	O
+of	O
+placebo	O
+-	O
+treated	O
+patients	O
+had	O
+one	O
+or	O
+more	O
+drug	O
+-	O
+related	O
+adverse	O
+experiences	O
+.	O
+
+The	O
+most	O
+common	O
+adverse	O
+effects	O
+were	O
+nausea	B
+and	O
+vomiting	B
+in	O
+the	O
+flumazenil	O
+group	O
+and	O
+nausea	B
+and	O
+injection	O
+-	O
+site	O
+pain	B
+in	O
+the	O
+placebo	O
+group	O
+.	O
+
+Flumazenil	O
+was	O
+found	O
+to	O
+promptly	O
+reverse	O
+sedation	O
+induced	O
+by	O
+diazepam	O
+in	O
+the	O
+presence	O
+of	O
+opioids	O
+.	O
+
+Methylphenidate	O
+-	O
+induced	O
+obsessive	B
+-	I
+compulsive	I
+symptoms	I
+in	O
+an	O
+elderly	O
+man	O
+.	O
+
+An	O
+82	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+treatment	B
+-	I
+resistant	I
+depression	I
+and	O
+early	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+was	O
+started	O
+on	O
+methylphenidate	O
+.	O
+
+Significant	O
+obsessive	B
+-	I
+compulsive	I
+behavior	I
+ensued	O
+but	O
+diminished	O
+over	O
+several	O
+weeks	O
+when	O
+methylphenidate	O
+was	O
+replaced	O
+by	O
+fluvoxamine	O
+.	O
+
+The	O
+patient	O
+had	O
+no	O
+prior	O
+psychiatric	B
+history	O
+,	O
+but	O
+he	O
+had	O
+a	O
+sister	O
+with	O
+obsessive	B
+-	I
+compulsive	I
+disorder	I
+.	O
+
+It	O
+appears	O
+that	O
+methylphenidate	O
+precipitated	O
+the	O
+patient	O
+'	O
+s	O
+pathological	O
+behavior	O
+.	O
+
+Ciprofloxacin	O
+-	O
+induced	O
+acute	O
+interstitial	B
+nephritis	I
+and	O
+autoimmune	B
+hemolytic	I
+anemia	I
+.	O
+
+Ciprofloxacin	O
+has	O
+been	O
+associated	O
+with	O
+several	O
+side	O
+effects	O
+including	O
+interstitial	B
+nephritis	I
+and	O
+hemolytic	B
+anemia	I
+.	O
+
+The	O
+combination	O
+of	O
+both	O
+side	O
+effects	O
+is	O
+extremely	O
+rare	O
+.	O
+
+In	O
+this	O
+report	O
+,	O
+we	O
+describe	O
+a	O
+case	O
+of	O
+ciprofloxacin	O
+-	O
+induced	O
+interstitial	B
+nephritis	I
+and	O
+autoimmune	B
+hemolytic	I
+anemia	I
+.	O
+
+Hemolytic	B
+anemia	I
+improved	O
+after	O
+stopping	O
+the	O
+drug	O
+and	O
+initiation	O
+of	O
+steroid	O
+therapy	O
+.	O
+
+Unfortunately	O
+,	O
+acute	O
+interstitial	B
+nephritis	I
+was	O
+irreversible	O
+and	O
+the	O
+patient	O
+developed	O
+end	B
+-	I
+stage	I
+renal	I
+disease	I
+.	O
+
+Potential	O
+deleterious	O
+effect	O
+of	O
+furosemide	O
+in	O
+radiocontrast	O
+nephropathy	B
+.	O
+
+The	O
+purpose	O
+of	O
+the	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+efficacy	O
+of	O
+furosemide	O
+in	O
+addition	O
+to	O
+intravenous	O
+fluids	O
+in	O
+the	O
+prevention	O
+of	O
+radiocontrast	O
+nephropathy	B
+.	O
+
+18	O
+patients	O
+,	O
+referred	O
+to	O
+a	O
+radiocontrast	O
+study	O
+,	O
+considered	O
+at	O
+risk	O
+because	O
+of	O
+preexisting	O
+renal	B
+insufficiency	I
+,	O
+were	O
+enrolled	O
+in	O
+a	O
+prospective	O
+,	O
+randomized	O
+,	O
+controlled	O
+trial	O
+,	O
+performed	O
+at	O
+the	O
+secondary	O
+care	O
+center	O
+of	O
+a	O
+1	O
+,	O
+100	O
+-	O
+bed	O
+private	O
+university	O
+hospital	O
+.	O
+
+In	O
+addition	O
+to	O
+fluids	O
+,	O
+the	O
+treatment	O
+group	O
+received	O
+furosemide	O
+(	O
+mean	O
+dose	O
+110	O
+mg	O
+)	O
+intravenously	O
+30	O
+min	O
+prior	O
+to	O
+the	O
+injection	O
+of	O
+contrast	O
+material	O
+.	O
+
+The	O
+control	O
+group	O
+received	O
+fluids	O
+(	O
+mean	O
+3	O
+liters	O
+)	O
+.	O
+
+Radiological	O
+studies	O
+were	O
+mostly	O
+angiographies	O
+performed	O
+with	O
+both	O
+ionic	O
+and	O
+non	O
+-	O
+ionic	O
+contrast	O
+material	O
+,	O
+at	O
+an	O
+average	O
+dose	O
+of	O
+245	O
+ml	O
+.	O
+
+Renal	B
+function	I
+significantly	I
+deteriorated	I
+in	O
+the	O
+group	O
+pretreated	O
+with	O
+furosemide	O
+(	O
+p	O
+<	O
+0	O
+.	O
+005	O
+by	O
+ANOVA	O
+)	O
+,	O
+with	O
+a	O
+rise	O
+in	O
+serum	O
+creatinine	O
+from	O
+145	O
++	O
+/	O
+-	O
+13	O
+to	O
+182	O
++	O
+/	O
+-	O
+16	O
+mumol	O
+/	O
+l	O
+at	O
+24	O
+h	O
+,	O
+while	O
+no	O
+change	O
+occurred	O
+in	O
+the	O
+control	O
+group	O
+(	O
+from	O
+141	O
++	O
+/	O
+-	O
+6	O
+to	O
+142	O
++	O
+/	O
+-	O
+7	O
+mumol	O
+/	O
+l	O
+)	O
+.	O
+
+Renal	B
+failure	I
+was	O
+associated	O
+with	O
+weight	B
+loss	I
+in	O
+the	O
+furosemide	O
+-	O
+treated	O
+group	O
+.	O
+
+Furosemide	O
+may	O
+be	O
+deleterious	O
+in	O
+the	O
+prevention	O
+of	O
+radiocontrast	O
+nephropathy	B
+.	O
+
+Progestational	O
+agents	O
+and	O
+blood	B
+coagulation	I
+.	O
+
+VII	O
+.	O
+
+Thromboembolic	B
+and	O
+other	O
+complications	O
+of	O
+oral	O
+contraceptive	O
+therapy	O
+in	O
+relationship	O
+to	O
+pretreatment	O
+levels	O
+of	O
+blood	B
+coagulation	I
+factors	O
+:	O
+summary	O
+report	O
+of	O
+a	O
+ten	O
+-	O
+year	O
+study	O
+.	O
+
+During	O
+a	O
+ten	O
+-	O
+year	O
+period	O
+,	O
+348	O
+women	O
+were	O
+studied	O
+for	O
+a	O
+total	O
+of	O
+5	O
+,	O
+877	O
+patient	O
+months	O
+in	O
+four	O
+separate	O
+studies	O
+relating	O
+oral	O
+contraceptives	O
+to	O
+changes	O
+in	O
+hematologic	O
+parameters	O
+.	O
+
+Significant	O
+increases	O
+in	O
+certain	O
+factors	O
+of	O
+the	O
+blood	B
+coagulation	I
+and	O
+fibrinolysin	O
+systems	O
+(	O
+factors	O
+I	O
+,	O
+II	O
+,	O
+VII	O
+,	O
+VIII	O
+,	O
+IX	O
+,	O
+and	O
+X	O
+and	O
+plasminogen	O
+)	O
+were	O
+observed	O
+in	O
+the	O
+treated	O
+groups	O
+.	O
+
+Severe	O
+complications	O
+developed	O
+in	O
+four	O
+patients	O
+.	O
+
+All	O
+four	O
+had	O
+an	O
+abnormal	O
+blood	B
+coagulation	I
+profile	O
+,	O
+suggesting	O
+"	O
+hypercoagulability	B
+"	O
+before	O
+initiation	O
+of	O
+therapy	O
+.	O
+
+Some	O
+of	O
+these	O
+findings	O
+represented	O
+the	O
+most	O
+extreme	O
+abnormalities	O
+seen	O
+in	O
+the	O
+entire	O
+group	O
+of	O
+patients	O
+;	O
+some	O
+increased	O
+further	O
+during	O
+therapy	O
+.	O
+
+One	O
+of	O
+these	O
+patients	O
+developed	O
+a	O
+myocardial	B
+infarction	I
+before	O
+receiving	O
+any	O
+medication	O
+,	O
+shortly	O
+after	O
+the	O
+base	O
+-	O
+line	O
+values	O
+were	O
+obtained	O
+.	O
+
+One	O
+patient	O
+developed	O
+retinopathy	B
+19	O
+months	O
+after	O
+she	O
+began	O
+therapy	O
+,	O
+and	O
+another	O
+developed	O
+thrombophlebitis	B
+after	O
+27	O
+months	O
+of	O
+therapy	O
+.	O
+
+The	O
+fourth	O
+patient	O
+developed	O
+thrombophlebitis	B
+14	O
+days	O
+after	O
+initiation	O
+of	O
+contraceptive	O
+therapy	O
+.	O
+
+All	O
+four	O
+patients	O
+were	O
+of	O
+the	O
+A	O
+or	O
+AB	O
+blood	O
+group	O
+.	O
+
+Previous	O
+studies	O
+suggested	O
+the	O
+possiblility	O
+of	O
+increased	O
+propensity	O
+for	O
+thromboembolic	B
+episodes	I
+in	O
+patients	O
+possessing	O
+the	O
+A	O
+antigen	O
+.	O
+
+It	O
+appears	O
+from	O
+these	O
+data	O
+that	O
+hematologic	O
+work	O
+-	O
+ups	O
+may	O
+be	O
+useful	O
+in	O
+women	O
+who	O
+are	O
+about	O
+to	O
+start	O
+long	O
+-	O
+term	O
+oral	O
+contraceptive	O
+therapy	O
+.	O
+
+Orthostatic	B
+hypotension	I
+occurs	O
+following	O
+alpha	O
+2	O
+-	O
+adrenoceptor	O
+blockade	O
+in	O
+chronic	O
+prazosin	O
+-	O
+pretreated	O
+conscious	O
+spontaneously	O
+hypertensive	B
+rats	O
+.	O
+
+1	O
+.	O
+
+Studies	O
+were	O
+performed	O
+to	O
+evaluate	O
+whether	O
+chronic	O
+prazosin	O
+treatment	O
+alters	O
+the	O
+alpha	O
+2	O
+-	O
+adrenoceptor	O
+function	O
+for	O
+orthostatic	O
+control	O
+of	O
+arterial	O
+blood	O
+pressure	O
+in	O
+conscious	O
+spontaneously	O
+hypertensive	B
+rats	O
+(	O
+SHR	O
+)	O
+.	O
+
+2	O
+.	O
+
+Conscious	O
+SHR	O
+(	O
+male	O
+300	O
+-	O
+350	O
+g	O
+)	O
+were	O
+subjected	O
+to	O
+90	O
+degrees	O
+head	O
+-	O
+up	O
+tilts	O
+for	O
+60	O
+s	O
+following	O
+acute	O
+administration	O
+of	O
+prazosin	O
+(	O
+0	O
+.	O
+1	O
+mg	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+p	O
+.	O
+)	O
+or	O
+rauwolscine	O
+(	O
+3	O
+mg	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+v	O
+.	O
+)	O
+.	O
+
+Orthostatic	B
+hypotension	I
+was	O
+determined	O
+by	O
+the	O
+average	O
+decrease	O
+(	O
+%	O
+)	O
+in	O
+mean	O
+arterial	O
+pressure	O
+(	O
+MAP	O
+femoral	O
+)	O
+over	O
+the	O
+60	O
+-	O
+s	O
+tilt	O
+period	O
+.	O
+
+The	O
+basal	O
+MAP	O
+of	O
+conscious	O
+SHR	O
+was	O
+reduced	O
+to	O
+a	O
+similar	O
+extent	O
+by	O
+prazosin	O
+(	O
+-	O
+23	O
+%	O
+(	O
+-	O
+)	O
+-	O
+26	O
+%	O
+MAP	O
+)	O
+and	O
+rauwolscine	O
+(	O
+-	O
+16	O
+%	O
+(	O
+-	O
+)	O
+-	O
+33	O
+%	O
+MAP	O
+)	O
+.	O
+
+However	O
+,	O
+the	O
+head	O
+-	O
+up	O
+tilt	O
+induced	O
+orthostatic	B
+hypotension	I
+in	O
+the	O
+SHR	O
+treated	O
+with	O
+prazosin	O
+(	O
+-	O
+16	O
+%	O
+MAP	O
+,	O
+n	O
+=	O
+6	O
+)	O
+,	O
+but	O
+not	O
+in	O
+the	O
+SHR	O
+treated	O
+with	O
+rauwolscine	O
+(	O
+less	O
+than	O
++	O
+2	O
+%	O
+MAP	O
+,	O
+n	O
+=	O
+6	O
+)	O
+.	O
+
+3	O
+.	O
+
+Conscious	O
+SHR	O
+were	O
+treated	O
+for	O
+4	O
+days	O
+with	O
+prazosin	O
+at	O
+2	O
+mg	O
+kg	O
+-	O
+1	O
+day	O
+-	O
+1	O
+i	O
+.	O
+p	O
+.	O
+for	O
+chronic	O
+alpha	O
+1	O
+-	O
+adrenoceptor	O
+blockade	O
+.	O
+
+MAP	O
+in	O
+conscious	O
+SHR	O
+after	O
+chronic	O
+prazosin	O
+treatment	O
+was	O
+14	O
+%	O
+lower	O
+than	O
+in	O
+the	O
+untreated	O
+SHR	O
+(	O
+n	O
+=	O
+8	O
+)	O
+.	O
+
+Head	O
+-	O
+up	O
+tilts	O
+in	O
+these	O
+rats	O
+did	O
+not	O
+produce	O
+orthostatic	B
+hypotension	I
+when	O
+performed	O
+either	O
+prior	O
+to	O
+or	O
+after	O
+acute	O
+dosing	O
+of	O
+prazosin	O
+(	O
+0	O
+.	O
+1	O
+mg	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+Conversely	O
+,	O
+administration	O
+of	O
+rauwolscine	O
+(	O
+3	O
+mg	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+v	O
+.	O
+)	O
+in	O
+chronic	O
+prazosin	O
+treated	O
+SHR	O
+decreased	O
+the	O
+basal	O
+MAP	O
+by	O
+12	O
+-	O
+31	O
+%	O
+(	O
+n	O
+=	O
+4	O
+)	O
+,	O
+and	O
+subsequent	O
+tilts	O
+induced	O
+further	O
+drops	O
+of	O
+MAP	O
+by	O
+19	O
+-	O
+23	O
+%	O
+in	O
+these	O
+rats	O
+.	O
+
+4	O
+.	O
+
+The	O
+pressor	O
+responses	O
+and	O
+bradycardia	B
+to	O
+the	O
+alpha	O
+1	O
+-	O
+agonist	O
+cirazoline	O
+(	O
+0	O
+.	O
+6	O
+and	O
+2	O
+micrograms	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+v	O
+.	O
+)	O
+,	O
+the	O
+alpha	O
+2	O
+-	O
+agonist	O
+Abbott	O
+-	O
+53693	O
+(	O
+1	O
+and	O
+3	O
+micrograms	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+v	O
+.	O
+)	O
+,	O
+and	O
+noradrenaline	O
+(	O
+0	O
+.	O
+1	O
+and	O
+1	O
+.	O
+0	O
+micrograms	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+v	O
+.	O
+)	O
+were	O
+determined	O
+in	O
+conscious	O
+SHR	O
+with	O
+and	O
+without	O
+chronic	O
+prazosin	O
+pretreatment	O
+.	O
+
+Both	O
+the	O
+pressor	O
+and	O
+bradycardia	B
+effects	O
+of	O
+cirazoline	O
+were	O
+abolished	O
+in	O
+chronic	O
+prazosin	O
+treated	O
+SHR	O
+(	O
+n	O
+=	O
+4	O
+)	O
+as	O
+compared	O
+to	O
+the	O
+untreated	O
+SHR	O
+(	O
+n	O
+=	O
+4	O
+)	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+the	O
+pressor	O
+effects	O
+of	O
+Abbott	O
+-	O
+53693	O
+were	O
+similar	O
+in	O
+both	O
+groups	O
+of	O
+SHR	O
+,	O
+but	O
+the	O
+accompanying	O
+bradycardia	B
+was	O
+greater	O
+in	O
+SHR	O
+with	O
+chronic	O
+prazosin	O
+treatment	O
+than	O
+without	O
+such	O
+treatment	O
+.	O
+
+Furthermore	O
+,	O
+the	O
+bradycardia	B
+that	O
+accompanied	O
+the	O
+noradrenaline	O
+-	O
+induced	O
+pressor	O
+effect	O
+in	O
+SHR	O
+was	O
+similar	O
+with	O
+and	O
+without	O
+chronic	O
+prazosin	O
+treatment	O
+despite	O
+a	O
+47	O
+-	O
+71	O
+%	O
+reduction	O
+of	O
+the	O
+pressor	O
+effect	O
+in	O
+chronic	O
+alpha	O
+1	O
+-	O
+receptor	O
+blocked	O
+SHR	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+400	O
+WORDS	O
+)	O
+
+Hemolytic	B
+-	I
+uremic	I
+syndrome	I
+associated	O
+with	O
+ingestion	O
+of	O
+quinine	O
+.	O
+
+Hemolytic	B
+-	I
+uremic	I
+syndrome	I
+following	O
+quinine	O
+ingestion	O
+is	O
+a	O
+newly	O
+described	O
+phenomenon	O
+,	O
+with	O
+just	O
+two	O
+previous	O
+descriptions	O
+of	O
+4	O
+cases	O
+in	O
+the	O
+literature	O
+.	O
+
+We	O
+describe	O
+a	O
+5th	O
+case	O
+.	O
+
+The	O
+reaction	O
+may	O
+be	O
+mediated	O
+by	O
+the	O
+presence	O
+of	O
+antibodies	O
+reactive	O
+against	O
+platelets	O
+in	O
+the	O
+presence	O
+of	O
+quinine	O
+.	O
+
+Treatment	O
+has	O
+included	O
+use	O
+of	O
+plasma	O
+exchange	O
+,	O
+prednisone	O
+,	O
+aspirin	O
+,	O
+and	O
+dipyridamole	O
+.	O
+
+The	O
+patients	O
+have	O
+all	O
+regained	O
+some	O
+degree	O
+of	O
+renal	O
+function	O
+.	O
+
+However	O
+,	O
+it	O
+is	O
+unclear	O
+whether	O
+pharmacological	O
+treatment	O
+or	O
+spontaneous	O
+resolution	O
+is	O
+responsible	O
+for	O
+the	O
+improvement	O
+.	O
+
+Quinine	O
+-	O
+associated	O
+hemolytic	B
+-	I
+uremic	I
+syndrome	I
+probably	O
+occurs	O
+more	O
+often	O
+than	O
+is	O
+recognized	O
+.	O
+
+It	O
+is	O
+important	O
+to	O
+recognize	O
+this	O
+reaction	O
+when	O
+it	O
+occurs	O
+and	O
+to	O
+avoid	O
+further	O
+quinine	O
+exposure	O
+,	O
+since	O
+the	O
+reaction	O
+seems	O
+to	O
+be	O
+recurrent	O
+.	O
+
+Amnestic	B
+syndrome	I
+associated	O
+with	O
+propranolol	O
+toxicity	B
+:	O
+a	O
+case	O
+report	O
+.	O
+
+An	O
+elderly	O
+woman	O
+developed	O
+an	O
+Alzheimer	B
+-	O
+like	O
+subacute	O
+dementia	B
+as	O
+a	O
+result	O
+of	O
+propranolol	O
+toxicity	B
+.	O
+
+Analysis	O
+of	O
+the	O
+manifestations	O
+showed	O
+that	O
+severe	O
+impairment	O
+of	O
+memory	O
+accounted	O
+for	O
+virtually	O
+all	O
+of	O
+the	O
+abnormalities	O
+.	O
+
+There	O
+is	O
+evidence	O
+that	O
+cerebral	O
+reactions	O
+to	O
+drug	O
+toxicity	B
+can	O
+exhibit	O
+patterns	O
+that	O
+suggest	O
+highly	O
+selective	O
+involvement	O
+of	O
+functional	O
+subdivisions	O
+of	O
+the	O
+brain	O
+.	O
+
+Cefotetan	O
+-	O
+induced	O
+immune	O
+hemolytic	B
+anemia	I
+.	O
+
+Immune	O
+hemolytic	B
+anemia	I
+due	O
+to	O
+a	O
+drug	O
+-	O
+adsorption	O
+mechanism	O
+has	O
+been	O
+described	O
+primarily	O
+in	O
+patients	O
+receiving	O
+penicillins	O
+and	O
+first	O
+-	O
+generation	O
+cephalosporins	O
+.	O
+
+We	O
+describe	O
+a	O
+patient	O
+who	O
+developed	O
+anemia	B
+while	O
+receiving	O
+intravenous	O
+cefotetan	O
+.	O
+
+Cefotetan	O
+-	O
+dependent	O
+antibodies	O
+were	O
+detected	O
+in	O
+the	O
+patient	O
+'	O
+s	O
+serum	O
+and	O
+in	O
+an	O
+eluate	O
+prepared	O
+from	O
+his	O
+red	O
+blood	O
+cells	O
+.	O
+
+The	O
+eluate	O
+also	O
+reacted	O
+weakly	O
+with	O
+red	O
+blood	O
+cells	O
+in	O
+the	O
+absence	O
+of	O
+cefotetan	O
+,	O
+suggesting	O
+the	O
+concomitant	O
+formation	O
+of	O
+warm	O
+-	O
+reactive	O
+autoantibodies	O
+.	O
+
+These	O
+observations	O
+,	O
+in	O
+conjunction	O
+with	O
+clinical	O
+and	O
+laboratory	O
+evidence	O
+of	O
+extravascular	O
+hemolysis	B
+,	O
+are	O
+consistent	O
+with	O
+drug	O
+-	O
+induced	O
+hemolytic	B
+anemia	I
+,	O
+possibly	O
+involving	O
+both	O
+drug	O
+-	O
+adsorption	O
+and	O
+autoantibody	O
+formation	O
+mechanisms	O
+.	O
+
+This	O
+case	O
+emphasizes	O
+the	O
+need	O
+for	O
+increased	O
+awareness	O
+of	O
+hemolytic	O
+reactions	O
+to	O
+all	O
+cephalosporins	O
+.	O
+
+Use	O
+of	O
+dexamethasone	O
+with	O
+mesna	O
+for	O
+the	O
+prevention	O
+of	O
+ifosfamide	O
+-	O
+induced	O
+hemorrhagic	B
+cystitis	I
+.	O
+
+AIM	O
+:	O
+Hemorrhagic	B
+cystitis	I
+(	O
+HC	B
+)	O
+is	O
+a	O
+limiting	O
+side	O
+-	O
+effect	O
+of	O
+chemotherapy	O
+with	O
+ifosfamide	O
+(	O
+IFS	O
+)	O
+.	O
+
+In	O
+the	O
+study	O
+presented	O
+here	O
+,	O
+we	O
+investigated	O
+the	O
+use	O
+of	O
+dexamethasone	O
+in	O
+combination	O
+with	O
+mesna	O
+for	O
+the	O
+prevention	O
+of	O
+IFS	O
+-	O
+induced	O
+HC	B
+.	O
+
+METHODS	O
+:	O
+Male	O
+Wistar	O
+rats	O
+(	O
+150	O
+-	O
+200	O
+g	O
+;	O
+6	O
+rats	O
+per	O
+group	O
+)	O
+were	O
+treated	O
+with	O
+saline	O
+or	O
+mesna	O
+5	O
+min	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+before	O
+and	O
+2	O
+and	O
+6	O
+h	O
+after	O
+(	O
+v	O
+.	O
+o	O
+.	O
+)	O
+administration	O
+of	O
+IFS	O
+.	O
+
+One	O
+,	O
+two	O
+or	O
+three	O
+doses	O
+of	O
+mesna	O
+were	O
+replaced	O
+with	O
+dexamethasone	O
+alone	O
+or	O
+with	O
+dexamethasone	O
+plus	O
+mesna	O
+.	O
+
+Cystitis	B
+was	O
+evaluated	O
+24	O
+h	O
+after	O
+its	O
+induction	O
+by	O
+the	O
+changes	O
+in	O
+bladder	O
+wet	O
+weight	O
+and	O
+by	O
+macroscopic	O
+and	O
+microscopic	O
+analysis	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+replacement	O
+of	O
+the	O
+last	O
+dose	O
+or	O
+the	O
+last	O
+two	O
+doses	O
+of	O
+mesna	O
+with	O
+dexamethasone	O
+reduced	O
+the	O
+increase	O
+in	O
+bladder	O
+wet	O
+weight	O
+induced	O
+by	O
+IFS	O
+by	O
+84	O
+.	O
+79	O
+%	O
+and	O
+89	O
+.	O
+13	O
+%	O
+,	O
+respectively	O
+.	O
+
+In	O
+addition	O
+,	O
+it	O
+almost	O
+abolished	O
+the	O
+macroscopic	O
+and	O
+microscopic	O
+alterations	O
+induced	O
+by	O
+IFS	O
+.	O
+
+Moreover	O
+,	O
+the	O
+addition	O
+of	O
+dexamethasone	O
+to	O
+the	O
+last	O
+two	O
+doses	O
+of	O
+mesna	O
+was	O
+more	O
+efficient	O
+than	O
+three	O
+doses	O
+of	O
+mesna	O
+alone	O
+when	O
+evaluated	O
+microscopically	O
+.	O
+
+CONCLUSION	O
+:	O
+Dexamethasone	O
+in	O
+combination	O
+with	O
+mesna	O
+was	O
+efficient	O
+in	O
+blocking	O
+IFS	O
+-	O
+induced	O
+HC	B
+.	O
+
+However	O
+,	O
+the	O
+replacement	O
+of	O
+last	O
+two	O
+doses	O
+of	O
+mesna	O
+with	O
+saline	O
+or	O
+all	O
+of	O
+the	O
+mesna	O
+doses	O
+with	O
+dexamethasone	O
+did	O
+not	O
+prevent	O
+HC	B
+.	O
+
+All	O
+-	O
+trans	O
+-	O
+retinoic	O
+acid	O
+-	O
+induced	O
+erythema	B
+nodosum	I
+in	O
+patients	O
+with	O
+acute	B
+promyelocytic	I
+leukemia	I
+.	O
+
+Erythema	B
+nodosum	I
+associated	O
+with	O
+all	O
+-	O
+trans	O
+-	O
+retinoic	O
+acid	O
+(	O
+ATRA	O
+)	O
+for	O
+acute	B
+promyelocytic	I
+leukemia	I
+(	O
+APL	B
+)	O
+is	O
+very	O
+rare	O
+.	O
+
+We	O
+describe	O
+four	O
+patients	O
+with	O
+classic	O
+APL	B
+who	O
+developed	O
+erythema	B
+nodosum	I
+during	O
+ATRA	O
+therapy	O
+.	O
+
+Fever	B
+and	O
+subsequent	O
+multiple	O
+painful	B
+erythematous	B
+nodules	I
+over	O
+extremities	O
+developed	O
+on	O
+D11	O
+,	O
+D16	O
+,	O
+D17	O
+,	O
+and	O
+D19	O
+,	O
+respectively	O
+,	O
+after	O
+ATRA	O
+therapy	O
+.	O
+
+The	O
+skin	O
+biopsy	O
+taken	O
+from	O
+each	O
+patient	O
+was	O
+consistent	O
+with	O
+erythema	B
+nodosum	I
+.	O
+
+All	O
+patients	O
+received	O
+short	O
+course	O
+of	O
+steroids	O
+.	O
+
+Fever	B
+subsided	O
+rapidly	O
+and	O
+the	O
+skin	O
+lesions	O
+regressed	O
+completely	O
+.	O
+
+All	O
+patients	O
+achieved	O
+complete	O
+remission	O
+without	O
+withdrawal	O
+of	O
+ATRA	O
+.	O
+
+ATRA	O
+seemed	O
+to	O
+be	O
+the	O
+most	O
+possible	O
+etiology	O
+of	O
+erythema	B
+nodosum	I
+in	O
+our	O
+patients	O
+.	O
+
+Short	O
+-	O
+term	O
+use	O
+of	O
+steroid	O
+is	O
+very	O
+effective	O
+in	O
+ATRA	O
+-	O
+induced	O
+erythema	B
+nodosum	I
+.	O
+
+Effect	O
+of	O
+some	O
+convulsants	O
+on	O
+the	O
+protective	O
+activity	O
+of	O
+loreclezole	O
+and	O
+its	O
+combinations	O
+with	O
+valproate	O
+or	O
+clonazepam	O
+in	O
+amygdala	O
+-	O
+kindled	O
+rats	O
+.	O
+
+Loreclezole	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+exerted	O
+a	O
+significant	O
+protective	O
+action	O
+in	O
+amygdala	O
+-	O
+kindled	O
+rats	O
+,	O
+reducing	O
+both	O
+seizure	B
+and	O
+afterdischarge	O
+durations	O
+.	O
+
+The	O
+combinations	O
+of	O
+loreclezole	O
+(	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+with	O
+valproate	O
+,	O
+clonazepam	O
+,	O
+or	O
+carbamazepine	O
+(	O
+applied	O
+at	O
+their	O
+subprotective	O
+doses	O
+)	O
+also	O
+exhibited	O
+antiseizure	O
+effect	O
+in	O
+this	O
+test	O
+.	O
+
+However	O
+,	O
+only	O
+two	O
+first	O
+combinations	O
+occurred	O
+to	O
+be	O
+of	O
+pharmacodynamic	O
+nature	O
+.	O
+
+Among	O
+several	O
+chemoconvulsants	O
+,	O
+bicuculline	O
+,	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartic	O
+acid	O
+and	O
+BAY	O
+k	O
+-	O
+8644	O
+(	O
+the	O
+opener	O
+of	O
+L	O
+-	O
+type	O
+calcium	O
+channels	O
+)	O
+reversed	O
+the	O
+protective	O
+activity	O
+of	O
+loreclezole	O
+alone	O
+and	O
+its	O
+combination	O
+with	O
+valproate	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+bicuculline	O
+,	O
+aminophylline	O
+and	O
+BAY	O
+k	O
+-	O
+8644	O
+inhibited	O
+the	O
+anticonvulsive	O
+action	O
+of	O
+loreclezole	O
+combined	O
+with	O
+clonazepam	O
+.	O
+
+The	O
+results	O
+support	O
+the	O
+hypothesis	O
+that	O
+the	O
+protective	O
+activity	O
+of	O
+loreclezole	O
+and	O
+its	O
+combinations	O
+with	O
+other	O
+antiepileptics	O
+may	O
+involve	O
+potentiation	O
+of	O
+GABAergic	O
+neurotransmission	O
+and	O
+blockade	O
+of	O
+L	O
+-	O
+type	O
+of	O
+calcium	O
+channels	O
+.	O
+
+Mitochondrial	O
+DNA	O
+and	O
+its	O
+respiratory	O
+chain	O
+products	O
+are	O
+defective	O
+in	O
+doxorubicin	O
+nephrosis	B
+.	O
+
+BACKGROUND	O
+:	O
+Doxorubicin	O
+induces	O
+a	O
+self	O
+-	O
+perpetuating	O
+nephropathy	B
+characterized	O
+by	O
+early	O
+glomerular	B
+and	I
+late	I
+-	I
+onset	I
+tubular	I
+lesions	I
+in	O
+rats	O
+.	O
+
+We	O
+investigated	O
+the	O
+potential	O
+role	O
+of	O
+mitochondrial	B
+injury	I
+in	O
+the	O
+onset	O
+of	O
+these	O
+lesions	O
+.	O
+
+METHODS	O
+:	O
+Rats	O
+were	O
+treated	O
+with	O
+intravenous	O
+doxorubicin	O
+(	O
+1	O
+mg	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+week	O
+(	O
+-	O
+1	O
+)	O
+)	O
+for	O
+7	O
+weeks	O
+and	O
+were	O
+sacrificed	O
+either	O
+1	O
+week	O
+(	O
+'	O
+short	O
+-	O
+term	O
+'	O
+)	O
+or	O
+30	O
+weeks	O
+(	O
+'	O
+long	O
+-	O
+term	O
+'	O
+)	O
+following	O
+the	O
+last	O
+dose	O
+.	O
+
+Additional	O
+rats	O
+received	O
+a	O
+single	O
+dose	O
+either	O
+6	O
+days	O
+or	O
+2	O
+h	O
+prior	O
+to	O
+euthanasia	O
+.	O
+
+All	O
+rats	O
+were	O
+killed	O
+at	O
+48	O
+weeks	O
+of	O
+age	O
+.	O
+
+Glomerular	B
+and	I
+tubular	I
+injury	I
+was	O
+monitored	O
+and	O
+correlated	O
+to	O
+the	O
+activity	O
+or	O
+expression	O
+of	O
+respiratory	O
+chain	O
+components	O
+.	O
+
+Finally	O
+,	O
+we	O
+quantified	O
+both	O
+nuclear	O
+and	O
+mitochondrial	O
+DNA	O
+(	O
+mtDNA	O
+)	O
+as	O
+well	O
+as	O
+superoxide	O
+production	O
+and	O
+the	O
+4834	O
+base	O
+pair	O
+'	O
+common	O
+'	O
+mtDNA	O
+deletion	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+'	O
+long	O
+-	O
+term	O
+'	O
+group	O
+had	O
+significant	O
+glomerular	B
+and	I
+tubular	I
+lesions	I
+,	O
+depressed	O
+activities	O
+of	O
+mtDNA	O
+-	O
+encoded	O
+NADH	O
+dehydrogenase	O
+and	O
+cytochrome	O
+-	O
+c	O
+oxidase	O
+(	O
+COX	O
+)	O
+and	O
+increased	O
+citrate	O
+synthase	O
+activity	O
+.	O
+
+In	O
+addition	O
+,	O
+expression	O
+of	O
+the	O
+mtDNA	O
+-	O
+encoded	O
+COX	O
+subunit	O
+I	O
+was	O
+reduced	O
+and	O
+mtDNA	O
+levels	O
+were	O
+decreased	O
+.	O
+
+In	O
+'	O
+short	O
+-	O
+term	O
+'	O
+rats	O
+,	O
+there	O
+were	O
+fewer	O
+tubular	B
+lesions	I
+,	O
+but	O
+similar	O
+numbers	O
+of	O
+glomerular	B
+lesions	I
+activity	O
+.	O
+
+Among	O
+all	O
+animals	O
+,	O
+glomerular	B
+and	I
+tubular	I
+injury	I
+were	O
+inversely	O
+correlated	O
+with	O
+mtDNA	O
+levels	O
+,	O
+mtDNA	O
+-	O
+encoded	O
+respiratory	O
+chain	O
+activities	O
+and	O
+with	O
+the	O
+expression	O
+of	O
+the	O
+mtDNA	O
+-	O
+encoded	O
+respiratory	O
+chain	O
+subunit	O
+COX	O
+-	O
+I	O
+.	O
+
+Injury	O
+was	O
+positively	O
+correlated	O
+with	O
+superoxide	O
+production	O
+and	O
+the	O
+activities	O
+of	O
+nucleus	O
+-	O
+encoded	O
+mitochondrial	O
+or	O
+cytoplasmic	O
+enzymes	O
+.	O
+
+Kidneys	O
+from	O
+the	O
+'	O
+long	O
+-	O
+term	O
+'	O
+group	O
+showed	O
+more	O
+mtDNA	O
+deletions	O
+than	O
+in	O
+'	O
+short	O
+-	O
+term	O
+'	O
+animals	O
+and	O
+these	O
+were	O
+not	O
+observed	O
+in	O
+the	O
+other	O
+groups	O
+.	O
+
+CONCLUSIONS	O
+:	O
+These	O
+results	O
+suggest	O
+an	O
+important	O
+role	O
+for	O
+quantitative	O
+and	O
+qualitative	O
+mtDNA	O
+alterations	O
+through	O
+the	O
+reduction	O
+of	O
+mtDNA	O
+-	O
+encoded	O
+respiratory	O
+chain	O
+function	O
+and	O
+induction	O
+of	O
+superoxide	O
+in	O
+doxorubicin	O
+-	O
+induced	O
+renal	B
+lesions	I
+.	O
+
+A	O
+randomized	O
+,	O
+placebo	O
+-	O
+controlled	O
+,	O
+crossover	O
+study	O
+of	O
+ephedrine	O
+for	O
+SSRI	O
+-	O
+induced	O
+female	O
+sexual	B
+dysfunction	I
+.	O
+
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+whether	O
+ephedrine	O
+,	O
+an	O
+alpha	O
+-	O
+and	O
+beta	O
+-	O
+adrenergic	O
+agonist	O
+previously	O
+shown	O
+to	O
+enhance	O
+genital	O
+blood	O
+flow	O
+in	O
+women	O
+,	O
+has	O
+beneficial	O
+effects	O
+in	O
+reversing	O
+antidepressant	O
+-	O
+induced	O
+sexual	B
+dysfunction	I
+.	O
+
+Nineteen	O
+sexually	B
+dysfunctional	I
+women	O
+receiving	O
+either	O
+fluoxetine	O
+,	O
+sertraline	O
+,	O
+or	O
+paroxetine	O
+participated	O
+in	O
+an	O
+eight	O
+-	O
+week	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+,	O
+cross	O
+-	O
+over	O
+study	O
+of	O
+the	O
+effects	O
+of	O
+ephedrine	O
+(	O
+50	O
+mg	O
+)	O
+on	O
+self	O
+-	O
+report	O
+measures	O
+of	O
+sexual	O
+desire	O
+,	O
+arousal	O
+,	O
+orgasm	O
+,	O
+and	O
+sexual	O
+satisfaction	O
+.	O
+
+Although	O
+there	O
+were	O
+significant	O
+improvements	O
+relative	O
+to	O
+baseline	O
+in	O
+sexual	O
+desire	O
+and	O
+orgasm	O
+intensity	O
+/	O
+pleasure	O
+on	O
+50	O
+mg	O
+ephedrine	O
+1	O
+-	O
+hr	O
+prior	O
+to	O
+sexual	O
+activity	O
+,	O
+significant	O
+improvements	O
+in	O
+these	O
+measures	O
+,	O
+as	O
+well	O
+as	O
+in	O
+sexual	O
+arousal	O
+and	O
+orgasmic	O
+ability	O
+also	O
+were	O
+noted	O
+with	O
+placebo	O
+.	O
+
+These	O
+findings	O
+highlight	O
+the	O
+importance	O
+of	O
+conducting	O
+placebo	O
+-	O
+controlled	O
+trials	O
+for	O
+this	O
+condition	O
+.	O
+
+Does	O
+hormone	O
+therapy	O
+for	O
+the	O
+treatment	O
+of	O
+breast	B
+cancer	I
+have	O
+a	O
+detrimental	B
+effect	I
+on	I
+memory	I
+and	I
+cognition	I
+?	O
+
+A	O
+pilot	O
+study	O
+.	O
+
+This	O
+pilot	O
+study	O
+examines	O
+whether	O
+hormone	O
+therapy	O
+for	O
+breast	B
+cancer	I
+affects	O
+cognition	O
+.	O
+
+Patients	O
+participating	O
+in	O
+a	O
+randomised	O
+trial	O
+of	O
+anastrozole	O
+,	O
+tamoxifen	O
+alone	O
+or	O
+combined	O
+(	O
+ATAC	O
+)	O
+(	O
+n	O
+=	O
+94	O
+)	O
+and	O
+a	O
+group	O
+of	O
+women	O
+without	O
+breast	B
+cancer	I
+(	O
+n	O
+=	O
+35	O
+)	O
+completed	O
+a	O
+battery	O
+of	O
+neuropsychological	O
+measures	O
+.	O
+
+Compared	O
+with	O
+the	O
+control	O
+group	O
+,	O
+the	O
+patients	O
+were	O
+impaired	O
+on	O
+a	O
+processing	O
+speed	O
+task	O
+(	O
+p	O
+=	O
+0	O
+.	O
+032	O
+)	O
+and	O
+on	O
+a	O
+measure	O
+of	O
+immediate	O
+verbal	O
+memory	O
+(	O
+p	O
+=	O
+0	O
+.	O
+026	O
+)	O
+after	O
+controlling	O
+for	O
+the	O
+use	O
+of	O
+hormone	O
+replacement	O
+therapy	O
+in	O
+both	O
+groups	O
+.	O
+
+Patient	O
+group	O
+performance	O
+was	O
+not	O
+significantly	O
+related	O
+to	O
+length	O
+of	O
+treatment	O
+or	O
+measures	O
+of	O
+psychological	O
+morbidity	O
+.	O
+
+The	O
+results	O
+showed	O
+specific	O
+impairments	O
+in	O
+processing	O
+speed	O
+and	O
+verbal	O
+memory	O
+in	O
+women	O
+receiving	O
+hormonal	O
+therapy	O
+for	O
+the	O
+treatment	O
+of	O
+breast	B
+cancer	I
+.	O
+
+Verbal	O
+memory	O
+may	O
+be	O
+especially	O
+sensitive	O
+to	O
+changes	O
+in	O
+oestrogen	O
+levels	O
+,	O
+a	O
+finding	O
+commonly	O
+reported	O
+in	O
+studies	O
+of	O
+hormone	O
+replacement	O
+therapy	O
+in	O
+healthy	O
+women	O
+.	O
+
+In	O
+view	O
+of	O
+the	O
+increased	O
+use	O
+of	O
+hormone	O
+therapies	O
+in	O
+an	O
+adjuvant	O
+and	O
+preventative	O
+setting	O
+their	O
+impact	O
+on	O
+cognitive	O
+functioning	O
+should	O
+be	O
+investigated	O
+more	O
+thoroughly	O
+.	O
+
+Expression	O
+of	O
+p300	O
+protects	O
+cardiac	O
+myocytes	O
+from	O
+apoptosis	O
+in	O
+vivo	O
+.	O
+
+Doxorubicin	O
+is	O
+an	O
+anti	O
+-	O
+tumor	B
+agent	O
+that	O
+represses	O
+cardiac	O
+-	O
+specific	O
+gene	O
+expression	O
+and	O
+induces	O
+myocardial	O
+cell	O
+apoptosis	O
+.	O
+
+Doxorubicin	O
+depletes	O
+cardiac	O
+p300	O
+,	O
+a	O
+transcriptional	O
+coactivator	O
+that	O
+is	O
+required	O
+for	O
+the	O
+maintenance	O
+of	O
+the	O
+differentiated	O
+phenotype	O
+of	O
+cardiac	O
+myocytes	O
+.	O
+
+However	O
+,	O
+the	O
+role	O
+of	O
+p300	O
+in	O
+protection	O
+against	O
+doxorubicin	O
+-	O
+induced	O
+apoptosis	O
+is	O
+unknown	O
+.	O
+
+Transgenic	O
+mice	O
+overexpressing	O
+p300	O
+in	O
+the	O
+heart	O
+and	O
+wild	O
+-	O
+type	O
+mice	O
+were	O
+subjected	O
+to	O
+doxorubicin	O
+treatment	O
+.	O
+
+Compared	O
+with	O
+wild	O
+-	O
+type	O
+mice	O
+,	O
+transgenic	O
+mice	O
+exhibited	O
+higher	O
+survival	O
+rate	O
+as	O
+well	O
+as	O
+more	O
+preserved	O
+left	O
+ventricular	O
+function	O
+and	O
+cardiac	O
+expression	O
+of	O
+alpha	O
+-	O
+sarcomeric	O
+actin	O
+.	O
+
+Doxorubicin	O
+induced	O
+myocardial	O
+cell	O
+apoptosis	O
+in	O
+wild	O
+-	O
+type	O
+mice	O
+but	O
+not	O
+in	O
+transgenic	O
+mice	O
+.	O
+
+Expression	O
+of	O
+p300	O
+increased	O
+the	O
+cardiac	O
+level	O
+of	O
+bcl	O
+-	O
+2	O
+and	O
+mdm	O
+-	O
+2	O
+,	O
+but	O
+not	O
+that	O
+of	O
+p53	O
+or	O
+other	O
+members	O
+of	O
+the	O
+bcl	O
+-	O
+2	O
+family	O
+.	O
+
+These	O
+findings	O
+demonstrate	O
+that	O
+overexpression	O
+of	O
+p300	O
+protects	O
+cardiac	O
+myocytes	O
+from	O
+doxorubicin	O
+-	O
+induced	O
+apoptosis	O
+and	O
+reduces	O
+the	O
+extent	O
+of	O
+acute	O
+heart	B
+failure	I
+in	O
+adult	O
+mice	O
+in	O
+vivo	O
+.	O
+
+Methimazole	O
+-	O
+induced	O
+cholestatic	B
+jaundice	I
+.	O
+
+Methimazole	O
+is	O
+a	O
+widely	O
+used	O
+and	O
+generally	O
+well	O
+-	O
+tolerated	O
+antithyroid	O
+agent	O
+.	O
+
+A	O
+43	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+had	O
+severe	O
+jaundice	B
+and	O
+itching	B
+1	O
+month	O
+after	O
+receiving	O
+methimazole	O
+(	O
+10	O
+mg	O
+tid	O
+)	O
+and	O
+propranolol	O
+(	O
+20	O
+mg	O
+tid	O
+)	O
+for	O
+treatment	O
+of	O
+hyperthyroidism	B
+.	O
+
+The	O
+patient	O
+continued	O
+treatment	O
+for	O
+another	O
+4	O
+days	O
+after	O
+the	O
+appearance	O
+of	O
+jaundice	B
+until	O
+she	O
+finished	O
+both	O
+medications	O
+.	O
+
+When	O
+seen	O
+at	O
+the	O
+emergency	O
+department	O
+2	O
+weeks	O
+later	O
+,	O
+she	O
+still	O
+had	O
+severe	O
+icterus	B
+,	O
+pruritus	B
+,	O
+and	O
+hyperbilirubinemia	B
+,	O
+formed	O
+mainly	O
+of	O
+the	O
+conjugated	O
+fraction	O
+.	O
+
+Methimazole	O
+-	O
+induced	O
+cholestasis	B
+was	O
+diagnosed	O
+,	O
+and	O
+propranolol	O
+therapy	O
+was	O
+resumed	O
+.	O
+
+Over	O
+the	O
+following	O
+9	O
+days	O
+,	O
+the	O
+symptoms	O
+improved	O
+and	O
+plasma	O
+bilirubin	O
+levels	O
+were	O
+normal	O
+after	O
+12	O
+weeks	O
+without	O
+methimazole	O
+.	O
+
+In	O
+rare	O
+cases	O
+within	O
+the	O
+first	O
+few	O
+weeks	O
+of	O
+therapy	O
+,	O
+this	O
+drug	O
+can	O
+cause	O
+severe	O
+and	O
+reversible	O
+cholestatic	B
+jaundice	I
+.	O
+
+Physicians	O
+and	O
+patients	O
+should	O
+be	O
+aware	O
+of	O
+this	O
+adverse	O
+effect	O
+so	O
+that	O
+,	O
+upon	O
+occurrence	O
+,	O
+they	O
+can	O
+discontinue	O
+methimazole	O
+therapy	O
+and	O
+avoid	O
+unnecessary	O
+invasive	O
+procedures	O
+.	O
+
+Atrial	B
+fibrillation	I
+following	O
+chemotherapy	O
+for	O
+stage	O
+IIIE	O
+diffuse	O
+large	O
+B	O
+-	O
+cell	O
+gastric	B
+lymphoma	I
+in	O
+a	O
+patient	O
+with	O
+myotonic	B
+dystrophy	I
+(	O
+Steinert	B
+'	I
+s	I
+disease	I
+)	O
+.	O
+
+The	O
+authors	O
+describe	O
+the	O
+unusual	O
+association	O
+between	O
+diffuse	O
+B	O
+-	O
+cell	O
+gastric	B
+lymphoma	I
+and	O
+myotonic	B
+dystrophy	I
+,	O
+the	O
+most	O
+common	O
+form	O
+of	O
+adult	O
+muscular	B
+dystrophy	I
+,	O
+and	O
+sudden	O
+atrial	B
+fibrillation	I
+following	O
+one	O
+cycle	O
+of	O
+doxorubicin	O
+-	O
+based	O
+chemotherapy	O
+in	O
+the	O
+same	O
+patient	O
+.	O
+
+Atrial	B
+fibrillation	I
+or	O
+other	O
+cardiac	B
+arrhythmias	I
+are	O
+unusual	O
+complications	O
+in	O
+patients	O
+treated	O
+with	O
+chemotherapy	O
+.	O
+
+The	O
+cardiac	B
+toxicity	I
+intrinsically	O
+associated	O
+with	O
+the	O
+aggressive	O
+chemotherapy	O
+employed	O
+could	O
+function	O
+as	O
+a	O
+triggering	O
+factor	O
+for	O
+the	O
+arrhythmia	B
+in	O
+the	O
+predisposed	O
+myocardium	O
+of	O
+this	O
+patient	O
+.	O
+
+Hypersensitivity	B
+immune	O
+reaction	O
+as	O
+a	O
+mechanism	O
+for	O
+dilevalol	O
+-	O
+associated	O
+hepatitis	B
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+assess	O
+lymphocyte	O
+reactivity	O
+to	O
+dilevalol	O
+and	O
+to	O
+serum	O
+containing	O
+putative	O
+ex	O
+vivo	O
+dilevalol	O
+antigens	O
+or	O
+metabolites	O
+in	O
+a	O
+case	O
+of	O
+dilevalol	O
+-	O
+induced	O
+liver	B
+injury	I
+.	O
+
+PATIENT	O
+:	O
+A	O
+58	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+a	O
+clinical	O
+diagnosis	O
+of	O
+dilevalol	O
+-	O
+induced	O
+liver	B
+injury	I
+.	O
+
+METHODS	O
+:	O
+Peripheral	O
+blood	O
+mononuclear	O
+cells	O
+collected	O
+from	O
+the	O
+patient	O
+were	O
+cultured	O
+in	O
+the	O
+presence	O
+of	O
+a	O
+solution	O
+of	O
+dilevalol	O
+and	O
+also	O
+with	O
+sera	O
+collected	O
+from	O
+a	O
+volunteer	O
+before	O
+and	O
+after	O
+dilevalol	O
+intake	O
+.	O
+
+A	O
+similar	O
+protocol	O
+was	O
+performed	O
+with	O
+lymphocytes	O
+from	O
+a	O
+healthy	O
+subject	O
+.	O
+
+RESULTS	O
+:	O
+No	O
+lymphocyte	O
+proliferation	O
+was	O
+observed	O
+either	O
+in	O
+the	O
+patient	O
+or	O
+in	O
+the	O
+healthy	O
+volunteer	O
+in	O
+the	O
+presence	O
+of	O
+dilevalol	O
+solutions	O
+.	O
+
+A	O
+significant	O
+proliferative	O
+response	O
+to	O
+serum	O
+collected	O
+after	O
+dilevalol	O
+intake	O
+was	O
+observed	O
+in	O
+the	O
+case	O
+of	O
+the	O
+patient	O
+compared	O
+with	O
+the	O
+proliferative	O
+response	O
+to	O
+the	O
+serum	O
+collected	O
+before	O
+the	O
+drug	O
+intake	O
+.	O
+
+No	O
+reactivity	O
+was	O
+found	O
+when	O
+lymphocytes	O
+from	O
+the	O
+healthy	O
+subject	O
+were	O
+tested	O
+under	O
+similar	O
+conditions	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+methodology	O
+used	O
+allowed	O
+the	O
+detection	O
+of	O
+lymphocyte	O
+sensitization	O
+to	O
+sera	O
+containing	O
+ex	O
+vivo	O
+-	O
+prepared	O
+dilevalol	O
+antigens	O
+,	O
+suggesting	O
+the	O
+involvement	O
+of	O
+an	O
+immunologic	O
+mechanism	O
+in	O
+dilevalol	O
+-	O
+induced	O
+liver	B
+injury	I
+.	O
+
+Increased	O
+expression	O
+and	O
+apical	O
+targeting	O
+of	O
+renal	O
+ENaC	O
+subunits	O
+in	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+nephrotic	B
+syndrome	I
+in	O
+rats	O
+.	O
+
+Nephrotic	B
+syndrome	I
+is	O
+often	O
+accompanied	O
+by	O
+sodium	O
+retention	O
+and	O
+generalized	O
+edema	B
+.	O
+
+However	O
+,	O
+the	O
+molecular	O
+basis	O
+for	O
+the	O
+decreased	O
+renal	O
+sodium	O
+excretion	O
+remains	O
+undefined	O
+.	O
+
+We	O
+hypothesized	O
+that	O
+epithelial	O
+Na	O
+channel	O
+(	O
+ENaC	O
+)	O
+subunit	O
+dysregulation	O
+may	O
+be	O
+responsible	O
+for	O
+the	O
+increased	O
+sodium	O
+retention	O
+.	O
+
+An	O
+experimental	O
+group	O
+of	O
+rats	O
+was	O
+treated	O
+with	O
+puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+;	O
+180	O
+mg	O
+/	O
+kg	O
+iv	O
+)	O
+,	O
+whereas	O
+the	O
+control	O
+group	O
+received	O
+only	O
+vehicle	O
+.	O
+
+After	O
+7	O
+days	O
+,	O
+PAN	O
+treatment	O
+induced	O
+significant	O
+proteinuria	B
+,	O
+hypoalbuminemia	B
+,	O
+decreased	O
+urinary	O
+sodium	O
+excretion	O
+,	O
+and	O
+extensive	O
+ascites	B
+.	O
+
+The	O
+protein	O
+abundance	O
+of	O
+alpha	O
+-	O
+ENaC	O
+and	O
+beta	O
+-	O
+ENaC	O
+was	O
+increased	O
+in	O
+the	O
+inner	O
+stripe	O
+of	O
+the	O
+outer	O
+medulla	O
+(	O
+ISOM	O
+)	O
+and	O
+in	O
+the	O
+inner	O
+medulla	O
+(	O
+IM	O
+)	O
+but	O
+was	O
+not	O
+altered	O
+in	O
+the	O
+cortex	O
+.	O
+
+gamma	O
+-	O
+ENaC	O
+abundance	O
+was	O
+increased	O
+in	O
+the	O
+cortex	O
+,	O
+ISOM	O
+,	O
+and	O
+IM	O
+.	O
+
+Immunoperoxidase	O
+brightfield	O
+-	O
+and	O
+laser	O
+-	O
+scanning	O
+confocal	O
+fluorescence	O
+microscopy	O
+demonstrated	O
+increased	O
+targeting	O
+of	O
+alpha	O
+-	O
+ENaC	O
+,	O
+beta	O
+-	O
+ENaC	O
+,	O
+and	O
+gamma	O
+-	O
+ENaC	O
+subunits	O
+to	O
+the	O
+apical	O
+plasma	O
+membrane	O
+in	O
+the	O
+distal	O
+convoluted	O
+tubule	O
+(	O
+DCT2	O
+)	O
+,	O
+connecting	O
+tubule	O
+,	O
+and	O
+cortical	O
+and	O
+medullary	O
+collecting	O
+duct	O
+segments	O
+.	O
+
+Immunoelectron	O
+microscopy	O
+further	O
+revealed	O
+an	O
+increased	O
+labeling	O
+of	O
+alpha	O
+-	O
+ENaC	O
+in	O
+the	O
+apical	O
+plasma	O
+membrane	O
+of	O
+cortical	O
+collecting	O
+duct	O
+principal	O
+cells	O
+of	O
+PAN	O
+-	O
+treated	O
+rats	O
+,	O
+indicating	O
+enhanced	O
+apical	O
+targeting	O
+of	O
+alpha	O
+-	O
+ENaC	O
+subunits	O
+.	O
+
+In	O
+contrast	O
+,	O
+the	O
+protein	O
+abundances	O
+of	O
+Na	O
+(	O
++	O
+)	O
+/	O
+H	O
+(	O
++	O
+)	O
+exchanger	O
+type	O
+3	O
+(	O
+NHE3	O
+)	O
+,	O
+Na	O
+(	O
++	O
+)	O
+-	O
+K	O
+(	O
++	O
+)	O
+-	O
+2Cl	O
+(	O
+-	O
+)	O
+cotransporter	O
+(	O
+BSC	O
+-	O
+1	O
+)	O
+,	O
+and	O
+thiazide	O
+-	O
+sensitive	O
+Na	O
+(	O
++	O
+)	O
+-	O
+Cl	O
+(	O
+-	O
+)	O
+cotransporter	O
+(	O
+TSC	O
+)	O
+were	O
+decreased	O
+.	O
+
+Moreover	O
+,	O
+the	O
+abundance	O
+of	O
+the	O
+alpha	O
+(	O
+1	O
+)	O
+-	O
+subunit	O
+of	O
+the	O
+Na	O
+-	O
+K	O
+-	O
+ATPase	O
+was	O
+decreased	O
+in	O
+the	O
+cortex	O
+and	O
+ISOM	O
+,	O
+but	O
+it	O
+remained	O
+unchanged	O
+in	O
+the	O
+IM	O
+.	O
+
+In	O
+conclusion	O
+,	O
+the	O
+increased	O
+or	O
+sustained	O
+expression	O
+of	O
+ENaC	O
+subunits	O
+combined	O
+with	O
+increased	O
+apical	O
+targeting	O
+in	O
+the	O
+DCT2	O
+,	O
+connecting	O
+tubule	O
+,	O
+and	O
+collecting	O
+duct	O
+are	O
+likely	O
+to	O
+play	O
+a	O
+role	O
+in	O
+the	O
+sodium	O
+retention	O
+associated	O
+with	O
+PAN	O
+-	O
+induced	O
+nephrotic	B
+syndrome	I
+.	O
+
+The	O
+decreased	O
+abundance	O
+of	O
+NHE3	O
+,	O
+BSC	O
+-	O
+1	O
+,	O
+TSC	O
+,	O
+and	O
+Na	O
+-	O
+K	O
+-	O
+ATPase	O
+may	O
+play	O
+a	O
+compensatory	O
+role	O
+to	O
+promote	O
+sodium	O
+excretion	O
+.	O
+
+Pallidal	O
+stimulation	O
+:	O
+an	O
+alternative	O
+to	O
+pallidotomy	O
+?	O
+
+A	O
+resurgence	O
+of	O
+interest	O
+in	O
+the	O
+surgical	O
+treatment	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+came	O
+with	O
+the	O
+rediscovery	O
+of	O
+posteroventral	O
+pallidotomy	O
+by	O
+Laitinen	O
+in	O
+1985	O
+.	O
+
+Laitinen	O
+'	O
+s	O
+procedure	O
+improved	O
+most	O
+symptoms	O
+in	O
+drug	O
+-	O
+resistant	O
+PD	B
+,	O
+which	O
+engendered	O
+wide	O
+interest	O
+in	O
+the	O
+neurosurgical	O
+community	O
+.	O
+
+Another	O
+lesioning	O
+procedure	O
+,	O
+ventrolateral	O
+thalamotomy	O
+,	O
+has	O
+become	O
+a	O
+powerful	O
+alternative	O
+to	O
+stimulate	O
+the	O
+nucleus	O
+ventralis	O
+intermedius	O
+,	O
+producing	O
+high	O
+long	O
+-	O
+term	O
+success	O
+rates	O
+and	O
+low	O
+morbidity	O
+rates	O
+.	O
+
+Pallidal	O
+stimulation	O
+has	O
+not	O
+met	O
+with	O
+the	O
+same	O
+success	O
+.	O
+
+According	O
+to	O
+the	O
+literature	O
+pallidotomy	O
+improves	O
+the	O
+"	O
+on	O
+"	O
+symptoms	O
+of	O
+PD	B
+,	O
+such	O
+as	O
+dyskinesias	B
+,	O
+as	O
+well	O
+as	O
+the	O
+"	O
+off	O
+"	O
+symptoms	O
+,	O
+such	O
+as	O
+rigidity	B
+,	O
+bradykinesia	B
+,	O
+and	O
+on	O
+-	O
+off	O
+fluctuations	O
+.	O
+
+Pallidal	O
+stimulation	O
+improves	O
+bradykinesia	B
+and	O
+rigidity	B
+to	O
+a	O
+minor	O
+extent	O
+;	O
+however	O
+,	O
+its	O
+strength	O
+seems	O
+to	O
+be	O
+in	O
+improving	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+.	O
+
+Stimulation	O
+often	O
+produces	O
+an	O
+improvement	O
+in	O
+the	O
+hyper	B
+-	I
+or	I
+dyskinetic	I
+upper	O
+limbs	O
+,	O
+but	O
+increases	O
+the	O
+"	O
+freezing	O
+"	O
+phenomenon	O
+in	O
+the	O
+lower	O
+limbs	O
+at	O
+the	O
+same	O
+time	O
+.	O
+
+Considering	O
+the	O
+small	O
+increase	O
+in	O
+the	O
+patient	O
+'	O
+s	O
+independence	O
+,	O
+the	O
+high	O
+costs	O
+of	O
+bilateral	O
+implants	O
+,	O
+and	O
+the	O
+difficulty	O
+most	O
+patients	O
+experience	O
+in	O
+handling	O
+the	O
+devices	O
+,	O
+the	O
+question	O
+arises	O
+as	O
+to	O
+whether	O
+bilateral	O
+pallidal	O
+stimulation	O
+is	O
+a	O
+real	O
+alternative	O
+to	O
+pallidotomy	O
+.	O
+
+Effects	O
+of	O
+the	O
+cyclooxygenase	O
+-	O
+2	O
+specific	O
+inhibitor	O
+valdecoxib	O
+versus	O
+nonsteroidal	O
+antiinflammatory	O
+agents	O
+and	O
+placebo	O
+on	O
+cardiovascular	O
+thrombotic	B
+events	O
+in	O
+patients	O
+with	O
+arthritis	B
+.	O
+
+There	O
+have	O
+been	O
+concerns	O
+that	O
+the	O
+risk	O
+of	O
+cardiovascular	O
+thrombotic	B
+events	O
+may	O
+be	O
+higher	O
+with	O
+cyclooxygenase	O
+(	O
+COX	O
+)	O
+-	O
+2	O
+-	O
+specific	O
+inhibitors	O
+than	O
+nonselective	O
+nonsteroidal	O
+antiinflammatory	O
+drugs	O
+(	O
+NSAIDs	O
+)	O
+.	O
+
+We	O
+evaluated	O
+cardiovascular	O
+event	O
+data	O
+for	O
+valdecoxib	O
+,	O
+a	O
+new	O
+COX	O
+-	O
+2	O
+-	O
+specific	O
+inhibitor	O
+in	O
+approximately	O
+8000	O
+patients	O
+with	O
+osteoarthritis	B
+and	O
+rheumatoid	B
+arthritis	I
+treated	O
+with	O
+this	O
+agent	O
+in	O
+randomized	O
+clinical	O
+trials	O
+.	O
+
+The	O
+incidence	O
+of	O
+cardiovascular	O
+thrombotic	B
+events	O
+(	O
+cardiac	O
+,	O
+cerebrovascular	O
+and	O
+peripheral	O
+vascular	O
+,	O
+or	O
+arterial	O
+thrombotic	B
+)	O
+was	O
+determined	O
+by	O
+analyzing	O
+pooled	O
+valdecoxib	O
+(	O
+10	O
+-	O
+80	O
+mg	O
+daily	O
+)	O
+,	O
+nonselective	O
+NSAID	O
+(	O
+diclofenac	O
+75	O
+mg	O
+bid	O
+,	O
+ibuprofen	O
+800	O
+mg	O
+tid	O
+,	O
+or	O
+naproxen	O
+500	O
+mg	O
+bid	O
+)	O
+and	O
+placebo	O
+data	O
+from	O
+10	O
+randomized	O
+osteoarthritis	B
+and	O
+rheumatoid	B
+arthritis	I
+trials	O
+that	O
+were	O
+6	O
+-	O
+52	O
+weeks	O
+in	O
+duration	O
+.	O
+
+The	O
+incidence	O
+rates	O
+of	O
+events	O
+were	O
+determined	O
+in	O
+all	O
+patients	O
+(	O
+n	O
+=	O
+7934	O
+)	O
+and	O
+in	O
+users	O
+of	O
+low	O
+-	O
+dose	O
+(	O
+<	O
+or	O
+=	O
+325	O
+mg	O
+daily	O
+)	O
+aspirin	O
+(	O
+n	O
+=	O
+1051	O
+)	O
+and	O
+nonusers	O
+of	O
+aspirin	O
+(	O
+n	O
+=	O
+6883	O
+)	O
+.	O
+
+Crude	O
+and	O
+exposure	O
+-	O
+adjusted	O
+incidences	O
+of	O
+thrombotic	B
+events	O
+were	O
+similar	O
+for	O
+valdecoxib	O
+,	O
+NSAIDs	O
+,	O
+and	O
+placebo	O
+.	O
+
+The	O
+risk	O
+of	O
+serious	O
+thrombotic	B
+events	O
+was	O
+also	O
+similar	O
+for	O
+each	O
+valdecoxib	O
+dose	O
+.	O
+
+Thrombotic	B
+risk	O
+was	O
+consistently	O
+higher	O
+for	O
+users	O
+of	O
+aspirin	O
+users	O
+than	O
+nonusers	O
+of	O
+aspirin	O
+(	O
+placebo	O
+,	O
+1	O
+.	O
+4	O
+%	O
+vs	O
+.	O
+0	O
+%	O
+;	O
+valdecoxib	O
+,	O
+1	O
+.	O
+7	O
+%	O
+vs	O
+.	O
+0	O
+.	O
+2	O
+%	O
+;	O
+NSAIDs	O
+,	O
+1	O
+.	O
+9	O
+%	O
+vs	O
+.	O
+0	O
+.	O
+5	O
+%	O
+)	O
+.	O
+
+The	O
+rates	O
+of	O
+events	O
+in	O
+users	O
+of	O
+aspirin	O
+were	O
+similar	O
+for	O
+all	O
+3	O
+treatment	O
+groups	O
+and	O
+across	O
+valdecoxib	O
+doses	O
+.	O
+
+Short	O
+-	O
+and	O
+intermediate	O
+-	O
+term	O
+treatment	O
+with	O
+therapeutic	O
+(	O
+10	O
+or	O
+20	O
+mg	O
+daily	O
+)	O
+and	O
+supratherapeutic	O
+(	O
+40	O
+or	O
+80	O
+mg	O
+daily	O
+)	O
+valdecoxib	O
+doses	O
+was	O
+not	O
+associated	O
+with	O
+an	O
+increased	O
+incidence	O
+of	O
+thrombotic	B
+events	O
+relative	O
+to	O
+nonselective	O
+NSAIDs	O
+or	O
+placebo	O
+in	O
+osteoarthritis	B
+and	O
+rheumatoid	B
+arthritis	I
+patients	O
+in	O
+controlled	O
+clinical	O
+trials	O
+.	O
+
+Hypersensitivity	B
+myocarditis	B
+complicating	O
+hypertrophic	B
+cardiomyopathy	I
+heart	O
+.	O
+
+The	O
+present	O
+report	O
+describes	O
+a	O
+case	O
+of	O
+eosinophilic	B
+myocarditis	I
+complicating	O
+hypertrophic	B
+cardiomyopathy	I
+.	O
+
+The	O
+47	O
+-	O
+year	O
+-	O
+old	O
+female	O
+patient	O
+,	O
+known	O
+to	O
+have	O
+hypertrophic	B
+cardiomyopathy	I
+,	O
+was	O
+admitted	O
+with	O
+biventricular	B
+failure	I
+and	O
+managed	O
+aggressively	O
+with	O
+dobutamine	O
+infusion	O
+and	O
+other	O
+drugs	O
+while	O
+being	O
+assessed	O
+for	O
+heart	O
+transplantation	O
+.	O
+
+On	O
+transthoracic	O
+echocardiogram	O
+,	O
+she	O
+had	O
+moderate	O
+left	B
+ventricular	I
+dysfunction	I
+with	O
+regional	O
+variability	O
+and	O
+moderate	O
+mitral	B
+regurgitation	I
+.	O
+
+The	O
+recipient	O
+'	O
+s	O
+heart	O
+showed	O
+the	O
+features	O
+of	O
+apical	O
+hypertrophic	B
+cardiomyopathy	I
+and	O
+myocarditis	B
+with	O
+abundant	O
+eosinophils	O
+.	O
+
+Myocarditis	B
+is	O
+rare	O
+and	O
+eosinophilic	B
+myocarditis	I
+is	O
+rarer	O
+.	O
+
+It	O
+is	O
+likely	O
+that	O
+the	O
+hypersensitivity	B
+(	O
+eosinophilic	B
+)	O
+myocarditis	B
+was	O
+related	O
+to	O
+dobutamine	O
+infusion	O
+therapy	O
+.	O
+
+Eosinophilic	B
+myocarditis	I
+has	O
+been	O
+reported	O
+with	O
+an	O
+incidence	O
+of	O
+2	O
+.	O
+4	O
+%	O
+to	O
+7	O
+.	O
+2	O
+%	O
+in	O
+explanted	O
+hearts	O
+and	O
+may	O
+be	O
+related	O
+to	O
+multidrug	O
+therapy	O
+.	O
+
+Time	O
+trends	O
+in	O
+warfarin	O
+-	O
+associated	O
+hemorrhage	B
+.	O
+
+The	O
+annual	O
+incidence	O
+of	O
+warfarin	O
+-	O
+related	O
+bleeding	B
+at	O
+Brigham	O
+and	O
+Women	O
+'	O
+s	O
+Hospital	O
+increased	O
+from	O
+0	O
+.	O
+97	O
+/	O
+1	O
+,	O
+000	O
+patient	O
+admissions	O
+in	O
+the	O
+first	O
+time	O
+period	O
+(	O
+January	O
+1995	O
+to	O
+October	O
+1998	O
+)	O
+to	O
+1	O
+.	O
+19	O
+/	O
+1	O
+,	O
+000	O
+patient	O
+admissions	O
+in	O
+the	O
+second	O
+time	O
+period	O
+(	O
+November	O
+1998	O
+to	O
+August	O
+2002	O
+)	O
+of	O
+this	O
+study	O
+.	O
+
+The	O
+proportion	O
+of	O
+patients	O
+with	O
+major	O
+and	O
+intracranial	B
+bleeding	I
+increased	O
+from	O
+20	O
+.	O
+2	O
+%	O
+and	O
+1	O
+.	O
+9	O
+%	O
+,	O
+respectively	O
+,	O
+in	O
+the	O
+first	O
+time	O
+period	O
+,	O
+to	O
+33	O
+.	O
+3	O
+%	O
+and	O
+7	O
+.	O
+8	O
+%	O
+,	O
+respectively	O
+,	O
+in	O
+the	O
+second	O
+.	O
+
+Yohimbine	O
+treatment	O
+of	O
+sexual	B
+side	I
+effects	I
+induced	O
+by	O
+serotonin	O
+reuptake	O
+blockers	O
+.	O
+
+BACKGROUND	O
+:	O
+Preclinical	O
+and	O
+clinical	O
+studies	O
+suggest	O
+that	O
+yohimbine	O
+facilitates	O
+sexual	O
+behavior	O
+and	O
+may	O
+be	O
+helpful	O
+in	O
+the	O
+treatment	O
+of	O
+male	B
+impotence	I
+.	O
+
+A	O
+single	O
+case	O
+report	O
+suggests	O
+that	O
+yohimbine	O
+may	O
+be	O
+used	O
+to	O
+treat	O
+the	O
+sexual	B
+side	I
+effects	I
+of	O
+clomipramine	O
+.	O
+
+This	O
+study	O
+evaluated	O
+yohimbine	O
+as	O
+a	O
+treatment	O
+for	O
+the	O
+sexual	B
+side	I
+effects	I
+caused	O
+by	O
+serotonin	O
+reuptake	O
+blockers	O
+.	O
+
+METHOD	O
+:	O
+Six	O
+patients	O
+with	O
+either	O
+obsessive	B
+compulsive	I
+disorder	I
+,	O
+trichotillomania	B
+,	O
+anxiety	B
+,	O
+or	O
+affective	B
+disorders	I
+who	O
+suffered	O
+sexual	B
+side	I
+effects	I
+after	O
+treatment	O
+with	O
+serotonin	O
+reuptake	O
+blockers	O
+were	O
+given	O
+yohimbine	O
+on	O
+a	O
+p	O
+.	O
+r	O
+.	O
+n	O
+.	O
+basis	O
+in	O
+an	O
+open	O
+clinical	O
+trial	O
+.	O
+
+Various	O
+doses	O
+of	O
+yohimbine	O
+were	O
+used	O
+to	O
+determine	O
+the	O
+ideal	O
+dose	O
+for	O
+each	O
+patient	O
+.	O
+
+RESULTS	O
+:	O
+Five	O
+of	O
+the	O
+six	O
+patients	O
+experienced	O
+improved	O
+sexual	O
+functioning	O
+after	O
+taking	O
+yohimbine	O
+.	O
+
+One	O
+patient	O
+who	O
+failed	O
+to	O
+comply	O
+with	O
+yohimbine	O
+treatment	O
+had	O
+no	O
+therapeutic	O
+effects	O
+.	O
+
+Side	O
+effects	O
+of	O
+yohimbine	O
+included	O
+excessive	O
+sweating	O
+,	O
+increased	O
+anxiety	B
+,	O
+and	O
+a	O
+wound	O
+-	O
+up	O
+feeling	O
+in	O
+some	O
+patients	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+results	O
+of	O
+this	O
+study	O
+indicate	O
+that	O
+yohimbine	O
+may	O
+be	O
+an	O
+effective	O
+treatment	O
+for	O
+the	O
+sexual	B
+side	I
+effects	I
+caused	O
+by	O
+serotonin	O
+reuptake	O
+blockers	O
+.	O
+
+Future	O
+controlled	O
+studies	O
+are	O
+needed	O
+to	O
+further	O
+investigate	O
+the	O
+effectiveness	O
+and	O
+safety	O
+of	O
+yohimbine	O
+for	O
+this	O
+indication	O
+.	O
+
+Hemorrhagic	B
+cystitis	I
+complicating	O
+bone	O
+marrow	O
+transplantation	O
+.	O
+
+Hemorrhagic	B
+cystitis	I
+is	O
+a	O
+potentially	O
+serious	O
+complication	O
+of	O
+high	O
+-	O
+dose	O
+cyclophosphamide	O
+therapy	O
+administered	O
+before	O
+bone	O
+marrow	O
+transplantation	O
+.	O
+
+As	O
+standard	O
+practice	O
+at	O
+our	O
+institution	O
+,	O
+patients	O
+who	O
+are	O
+scheduled	O
+to	O
+receive	O
+a	O
+bone	O
+marrow	O
+transplant	O
+are	O
+treated	O
+prophylactically	O
+with	O
+forced	O
+hydration	O
+and	O
+bladder	O
+irrigation	O
+.	O
+
+In	O
+an	O
+attempt	O
+to	O
+obviate	O
+the	O
+inconvenience	O
+of	O
+bladder	O
+irrigation	O
+,	O
+we	O
+conducted	O
+a	O
+feasibility	O
+trial	O
+of	O
+uroprophylaxis	O
+with	O
+mesna	O
+,	O
+which	O
+neutralizes	O
+the	O
+hepatic	O
+metabolite	O
+of	O
+cyclophosphamide	O
+that	O
+causes	O
+hemorrhagic	B
+cystitis	I
+.	O
+
+Of	O
+97	O
+patients	O
+who	O
+received	O
+standard	O
+prophylaxis	O
+,	O
+4	O
+had	O
+symptomatic	O
+hemorrhagic	B
+cystitis	I
+.	O
+
+In	O
+contrast	O
+,	O
+two	O
+of	O
+four	O
+consecutive	O
+patients	O
+who	O
+received	O
+mesna	O
+uroprophylaxis	O
+before	O
+allogeneic	O
+bone	O
+marrow	O
+transplantation	O
+had	O
+severe	O
+hemorrhagic	B
+cystitis	I
+for	O
+at	O
+least	O
+2	O
+weeks	O
+.	O
+
+Because	O
+of	O
+this	O
+suboptimal	O
+result	O
+,	O
+we	O
+resumed	O
+the	O
+use	O
+of	O
+bladder	O
+irrigation	O
+and	O
+forced	O
+hydration	O
+to	O
+minimize	O
+the	O
+risk	O
+of	O
+hemorrhagic	B
+cystitis	I
+.	O
+
+Consensus	O
+statement	O
+concerning	O
+cardiotoxicity	B
+occurring	O
+during	O
+haematopoietic	O
+stem	O
+cell	O
+transplantation	O
+in	O
+the	O
+treatment	O
+of	O
+autoimmune	B
+diseases	I
+,	O
+with	O
+special	O
+reference	O
+to	O
+systemic	B
+sclerosis	I
+and	O
+multiple	B
+sclerosis	I
+.	O
+
+Autologous	O
+haematopoietic	O
+stem	O
+cell	O
+transplantation	O
+is	O
+now	O
+a	O
+feasible	O
+and	O
+effective	O
+treatment	O
+for	O
+selected	O
+patients	O
+with	O
+severe	O
+autoimmune	B
+diseases	I
+.	O
+
+Worldwide	O
+,	O
+over	O
+650	O
+patients	O
+have	O
+been	O
+transplanted	O
+in	O
+the	O
+context	O
+of	O
+phase	O
+I	O
+and	O
+II	O
+clinical	O
+trials	O
+.	O
+
+The	O
+results	O
+are	O
+encouraging	O
+enough	O
+to	O
+begin	O
+randomised	O
+phase	O
+III	O
+trials	O
+.	O
+
+However	O
+,	O
+as	O
+predicted	O
+,	O
+significant	O
+transplant	O
+-	O
+related	O
+morbidity	O
+and	O
+mortality	O
+have	O
+been	O
+observed	O
+.	O
+
+This	O
+is	O
+primarily	O
+due	O
+to	O
+complications	O
+related	O
+to	O
+either	O
+the	O
+stage	O
+of	O
+the	O
+disease	O
+at	O
+transplant	O
+or	O
+due	O
+to	O
+infections	B
+.	O
+
+The	O
+number	O
+of	O
+deaths	O
+related	O
+to	O
+cardiac	B
+toxicity	I
+is	O
+low	O
+.	O
+
+However	O
+,	O
+caution	O
+is	O
+required	O
+when	O
+cyclophosphamide	O
+or	O
+anthracyclines	O
+such	O
+as	O
+mitoxantrone	O
+are	O
+used	O
+in	O
+patients	O
+with	O
+a	O
+possible	O
+underlying	O
+heart	B
+damage	I
+,	O
+for	O
+example	O
+,	O
+systemic	B
+sclerosis	I
+patients	O
+.	O
+
+In	O
+November	O
+2002	O
+,	O
+a	O
+meeting	O
+was	O
+held	O
+in	O
+Florence	O
+,	O
+bringing	O
+together	O
+a	O
+number	O
+of	O
+experts	O
+in	O
+various	O
+fields	O
+,	O
+including	O
+rheumatology	O
+,	O
+cardiology	O
+,	O
+neurology	O
+,	O
+pharmacology	O
+and	O
+transplantation	O
+medicine	O
+.	O
+
+The	O
+object	O
+of	O
+the	O
+meeting	O
+was	O
+to	O
+analyse	O
+existing	O
+data	O
+,	O
+both	O
+published	O
+or	O
+available	O
+,	O
+in	O
+the	O
+European	O
+Group	O
+for	O
+Blood	O
+and	O
+Marrow	O
+Transplantation	O
+autoimmune	B
+disease	I
+database	O
+,	O
+and	O
+to	O
+propose	O
+a	O
+safe	O
+approach	O
+to	O
+such	O
+patients	O
+.	O
+
+A	O
+full	O
+cardiological	O
+assessment	O
+before	O
+and	O
+during	O
+the	O
+transplant	O
+emerged	O
+as	O
+the	O
+major	O
+recommendation	O
+.	O
+
+Does	O
+supplemental	O
+vitamin	O
+C	O
+increase	O
+cardiovascular	B
+disease	I
+risk	O
+in	O
+women	O
+with	O
+diabetes	B
+?	O
+
+BACKGROUND	O
+:	O
+Vitamin	O
+C	O
+acts	O
+as	O
+a	O
+potent	O
+antioxidant	O
+;	O
+however	O
+,	O
+it	O
+can	O
+also	O
+be	O
+a	O
+prooxidant	O
+and	O
+glycate	O
+protein	O
+under	O
+certain	O
+circumstances	O
+in	O
+vitro	O
+.	O
+
+These	O
+observations	O
+led	O
+us	O
+to	O
+hypothesize	O
+that	O
+a	O
+high	O
+intake	O
+of	O
+vitamin	O
+C	O
+in	O
+diabetic	B
+persons	O
+might	O
+promote	O
+atherosclerosis	B
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+objective	O
+was	O
+to	O
+examine	O
+the	O
+relation	O
+between	O
+vitamin	O
+C	O
+intake	O
+and	O
+mortality	O
+from	O
+cardiovascular	B
+disease	I
+.	O
+
+DESIGN	O
+:	O
+We	O
+studied	O
+the	O
+relation	O
+between	O
+vitamin	O
+C	O
+intake	O
+and	O
+mortality	O
+from	O
+total	O
+cardiovascular	B
+disease	I
+(	O
+n	O
+=	O
+281	O
+)	O
+,	O
+coronary	B
+artery	I
+disease	I
+(	O
+n	O
+=	O
+175	O
+)	O
+,	O
+and	O
+stroke	B
+(	O
+n	O
+=	O
+57	O
+)	O
+in	O
+1923	O
+postmenopausal	O
+women	O
+who	O
+reported	O
+being	O
+diabetic	B
+at	O
+baseline	O
+.	O
+
+Diet	O
+was	O
+assessed	O
+with	O
+a	O
+food	O
+-	O
+frequency	O
+questionnaire	O
+at	O
+baseline	O
+,	O
+and	O
+subjects	O
+initially	O
+free	O
+of	O
+coronary	B
+artery	I
+disease	I
+were	O
+prospectively	O
+followed	O
+for	O
+15	O
+y	O
+.	O
+
+RESULTS	O
+:	O
+After	O
+adjustment	O
+for	O
+cardiovascular	B
+disease	I
+risk	O
+factors	O
+,	O
+type	O
+of	O
+diabetes	B
+medication	O
+used	O
+,	O
+duration	O
+of	O
+diabetes	B
+,	O
+and	O
+intakes	O
+of	O
+folate	O
+,	O
+vitamin	O
+E	O
+,	O
+and	O
+beta	O
+-	O
+carotene	O
+,	O
+the	O
+adjusted	O
+relative	O
+risks	O
+of	O
+total	O
+cardiovascular	B
+disease	I
+mortality	O
+were	O
+1	O
+.	O
+0	O
+,	O
+0	O
+.	O
+97	O
+,	O
+1	O
+.	O
+11	O
+,	O
+1	O
+.	O
+47	O
+,	O
+and	O
+1	O
+.	O
+84	O
+(	O
+P	O
+for	O
+trend	O
+<	O
+0	O
+.	O
+01	O
+)	O
+across	O
+quintiles	O
+of	O
+total	O
+vitamin	O
+C	O
+intake	O
+from	O
+food	O
+and	O
+supplements	O
+.	O
+
+Adjusted	O
+relative	O
+risks	O
+of	O
+coronary	B
+artery	I
+disease	I
+were	O
+1	O
+.	O
+0	O
+,	O
+0	O
+.	O
+81	O
+,	O
+0	O
+.	O
+99	O
+,	O
+1	O
+.	O
+26	O
+,	O
+and	O
+1	O
+.	O
+91	O
+(	O
+P	O
+for	O
+trend	O
+=	O
+0	O
+.	O
+01	O
+)	O
+and	O
+of	O
+stroke	B
+were	O
+1	O
+.	O
+0	O
+,	O
+0	O
+.	O
+52	O
+,	O
+1	O
+.	O
+23	O
+,	O
+2	O
+.	O
+22	O
+,	O
+and	O
+2	O
+.	O
+57	O
+(	O
+P	O
+for	O
+trend	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+When	O
+dietary	O
+and	O
+supplemental	O
+vitamin	O
+C	O
+were	O
+analyzed	O
+separately	O
+,	O
+only	O
+supplemental	O
+vitamin	O
+C	O
+showed	O
+a	O
+positive	O
+association	O
+with	O
+mortality	O
+endpoints	O
+.	O
+
+Vitamin	O
+C	O
+intake	O
+was	O
+unrelated	O
+to	O
+mortality	O
+from	O
+cardiovascular	B
+disease	I
+in	O
+the	O
+nondiabetic	O
+subjects	O
+at	O
+baseline	O
+.	O
+
+CONCLUSION	O
+:	O
+A	O
+high	O
+vitamin	O
+C	O
+intake	O
+from	O
+supplements	O
+is	O
+associated	O
+with	O
+an	O
+increased	O
+risk	O
+of	O
+cardiovascular	B
+disease	I
+mortality	O
+in	O
+postmenopausal	O
+women	O
+with	O
+diabetes	B
+.	O
+
+Optical	O
+coherence	O
+tomography	O
+can	O
+measure	O
+axonal	O
+loss	O
+in	O
+patients	O
+with	O
+ethambutol	O
+-	O
+induced	O
+optic	B
+neuropathy	I
+.	O
+
+PURPOSE	O
+:	O
+To	O
+map	O
+and	O
+identify	O
+the	O
+pattern	O
+,	O
+in	O
+vivo	O
+,	O
+of	O
+axonal	B
+degeneration	I
+in	O
+ethambutol	O
+-	O
+induced	O
+optic	B
+neuropathy	I
+using	O
+optical	O
+coherence	O
+tomography	O
+(	O
+OCT	O
+)	O
+.	O
+
+Ethambutol	O
+is	O
+an	O
+antimycobacterial	O
+agent	O
+often	O
+used	O
+to	O
+treat	O
+tuberculosis	B
+.	O
+
+A	O
+serious	O
+complication	O
+of	O
+ethambutol	O
+is	O
+an	O
+optic	B
+neuropathy	I
+that	O
+impairs	O
+visual	O
+acuity	O
+,	O
+contrast	O
+sensitivity	O
+,	O
+and	O
+color	O
+vision	O
+.	O
+
+However	O
+,	O
+early	O
+on	O
+,	O
+when	O
+the	O
+toxic	O
+optic	B
+neuropathy	I
+is	O
+mild	O
+and	O
+partly	O
+reversible	O
+,	O
+the	O
+funduscopic	O
+findings	O
+are	O
+often	O
+subtle	O
+and	O
+easy	O
+to	O
+miss	O
+.	O
+
+METHODS	O
+:	O
+Three	O
+subjects	O
+with	O
+a	O
+history	O
+of	O
+ethambutol	O
+(	O
+EMB	O
+)	O
+-	O
+induced	O
+optic	B
+neuropathy	I
+of	O
+short	O
+-	O
+,	O
+intermediate	O
+-	O
+,	O
+and	O
+long	O
+-	O
+term	O
+visual	B
+deficits	I
+were	O
+administered	O
+a	O
+full	O
+neuro	O
+-	O
+ophthalmologic	O
+examination	O
+including	O
+visual	O
+acuity	O
+,	O
+color	O
+vision	O
+,	O
+contrast	O
+sensitivity	O
+,	O
+and	O
+fundus	O
+examination	O
+.	O
+
+In	O
+addition	O
+,	O
+OCT	O
+(	O
+OCT	O
+3000	O
+,	O
+Humphrey	O
+-	O
+Zeiss	O
+,	O
+Dublin	O
+,	O
+CA	O
+)	O
+was	O
+performed	O
+on	O
+both	O
+eyes	O
+of	O
+each	O
+subject	O
+using	O
+the	O
+retinal	O
+nerve	O
+fiber	O
+layer	O
+(	O
+RNFL	O
+)	O
+analysis	O
+protocol	O
+.	O
+
+OCT	O
+interpolates	O
+data	O
+from	O
+100	O
+points	O
+around	O
+the	O
+optic	O
+nerve	O
+to	O
+effectively	O
+map	O
+out	O
+the	O
+RNFL	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+results	O
+were	O
+compared	O
+to	O
+the	O
+calculated	O
+average	O
+RNFL	O
+of	O
+normal	O
+eyes	O
+accumulated	O
+from	O
+four	O
+prior	O
+studies	O
+using	O
+OCT	O
+,	O
+n	O
+=	O
+661	O
+.	O
+
+In	O
+all	O
+subjects	O
+with	O
+history	O
+of	O
+EMB	O
+-	O
+induced	O
+optic	B
+neuropathy	I
+,	O
+there	O
+was	O
+a	O
+mean	O
+loss	O
+of	O
+72	O
+%	O
+nerve	O
+fiber	O
+layer	O
+thickness	O
+in	O
+the	O
+temporal	O
+quadrant	O
+(	O
+patient	O
+A	O
+,	O
+with	O
+eventual	O
+recovery	O
+of	O
+visual	O
+acuity	O
+and	O
+fields	O
+,	O
+58	O
+%	O
+loss	O
+;	O
+patient	O
+B	O
+,	O
+with	O
+intermediate	O
+visual	B
+deficits	I
+,	O
+68	O
+%	O
+loss	O
+;	O
+patient	O
+C	O
+,	O
+with	O
+chronic	O
+visual	B
+deficits	I
+,	O
+90	O
+%	O
+loss	O
+)	O
+,	O
+with	O
+an	O
+average	O
+mean	O
+optic	O
+nerve	O
+thickness	O
+of	O
+26	O
++	O
+/	O
+-	O
+16	O
+microm	O
+.	O
+
+There	O
+was	O
+a	O
+combined	O
+mean	O
+loss	O
+of	O
+46	O
+%	O
+of	O
+fibers	O
+from	O
+the	O
+superior	O
+,	O
+inferior	O
+,	O
+and	O
+nasal	O
+quadrants	O
+in	O
+the	O
+(	O
+six	O
+)	O
+eyes	O
+of	O
+all	O
+three	O
+subjects	O
+(	O
+mean	O
+average	O
+thickness	O
+of	O
+55	O
++	O
+/	O
+-	O
+29	O
+microm	O
+)	O
+.	O
+
+In	O
+both	O
+sets	O
+(	O
+four	O
+)	O
+of	O
+eyes	O
+of	O
+the	O
+subjects	O
+with	O
+persistent	O
+visual	B
+deficits	I
+(	O
+patients	O
+B	O
+and	O
+C	O
+)	O
+,	O
+there	O
+was	O
+an	O
+average	O
+loss	O
+of	O
+79	O
+%	O
+of	O
+nerve	O
+fiber	O
+thickness	O
+in	O
+the	O
+temporal	O
+quadrant	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+OCT	O
+results	O
+in	O
+these	O
+patients	O
+with	O
+EMB	O
+-	O
+induced	O
+optic	B
+neuropathy	I
+show	O
+considerable	O
+loss	O
+especially	O
+of	O
+the	O
+temporal	O
+fibers	O
+.	O
+
+This	O
+is	O
+consistent	O
+with	O
+prior	O
+histopathological	O
+studies	O
+that	O
+show	O
+predominant	O
+loss	O
+of	O
+parvo	O
+-	O
+cellular	O
+axons	O
+(	O
+or	O
+small	O
+-	O
+caliber	O
+axons	O
+)	O
+within	O
+the	O
+papillo	O
+-	O
+macular	O
+bundle	O
+in	O
+toxic	O
+or	O
+hereditary	O
+optic	B
+neuropathies	I
+.	O
+
+OCT	O
+can	O
+be	O
+a	O
+valuable	O
+tool	O
+in	O
+the	O
+quantitative	O
+analysis	O
+of	O
+optic	B
+neuropathies	I
+.	O
+
+Additionally	O
+,	O
+in	O
+terms	O
+of	O
+management	O
+of	O
+EMB	O
+-	O
+induced	O
+optic	B
+neuropathy	I
+,	O
+it	O
+is	O
+important	O
+to	O
+properly	O
+manage	O
+ethambutol	O
+dosing	O
+in	O
+patients	O
+with	O
+renal	B
+impairment	I
+and	O
+to	O
+achieve	O
+proper	O
+transition	O
+to	O
+a	O
+maintenance	O
+dose	O
+once	O
+an	O
+appropriate	O
+loading	O
+dose	O
+has	O
+been	O
+reached	O
+.	O
+
+Hypoxia	B
+in	O
+renal	B
+disease	I
+with	O
+proteinuria	B
+and	O
+/	O
+or	O
+glomerular	O
+hypertension	B
+.	O
+
+Despite	O
+the	O
+increasing	O
+need	O
+to	O
+identify	O
+and	O
+quantify	O
+tissue	O
+oxygenation	O
+at	O
+the	O
+cellular	O
+level	O
+,	O
+relatively	O
+few	O
+methods	O
+have	O
+been	O
+available	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+developed	O
+a	O
+new	O
+hypoxia	B
+-	O
+responsive	O
+reporter	O
+vector	O
+using	O
+a	O
+hypoxia	B
+-	O
+responsive	O
+element	O
+of	O
+the	O
+5	O
+'	O
+vascular	O
+endothelial	O
+growth	O
+factor	O
+untranslated	O
+region	O
+and	O
+generated	O
+a	O
+novel	O
+hypoxia	B
+-	O
+sensing	O
+transgenic	O
+rat	O
+.	O
+
+We	O
+then	O
+applied	O
+this	O
+animal	O
+model	O
+to	O
+the	O
+detection	O
+of	O
+tubulointerstitial	O
+hypoxia	B
+in	O
+the	O
+diseased	B
+kidney	I
+.	O
+
+With	O
+this	O
+model	O
+,	O
+we	O
+were	O
+able	O
+to	O
+identify	O
+diffuse	O
+cortical	O
+hypoxia	B
+in	O
+the	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+nephrotic	B
+syndrome	I
+and	O
+focal	O
+and	O
+segmental	O
+hypoxia	B
+in	O
+the	O
+remnant	O
+kidney	O
+model	O
+.	O
+
+Expression	O
+of	O
+the	O
+hypoxia	B
+-	O
+responsive	O
+transgene	O
+increased	O
+throughout	O
+the	O
+observation	O
+period	O
+,	O
+reaching	O
+2	O
+.	O
+2	O
+-	O
+fold	O
+at	O
+2	O
+weeks	O
+in	O
+the	O
+puromycin	O
+aminonucleoside	O
+model	O
+and	O
+2	O
+.	O
+6	O
+-	O
+fold	O
+at	O
+4	O
+weeks	O
+in	O
+the	O
+remnant	O
+kidney	O
+model	O
+,	O
+whereas	O
+that	O
+of	O
+vascular	O
+endothelial	O
+growth	O
+factor	O
+showed	O
+a	O
+mild	O
+decrease	O
+,	O
+reflecting	O
+distinct	O
+behaviors	O
+of	O
+the	O
+two	O
+genes	O
+.	O
+
+The	O
+degree	O
+of	O
+hypoxia	B
+showed	O
+a	O
+positive	O
+correlation	O
+with	O
+microscopic	O
+tubulointerstitial	B
+injury	I
+in	O
+both	O
+models	O
+.	O
+
+Finally	O
+,	O
+we	O
+identified	O
+the	O
+localization	O
+of	O
+proliferating	O
+cell	O
+nuclear	O
+antigen	O
+-	O
+positive	O
+,	O
+ED	O
+-	O
+1	O
+-	O
+positive	O
+,	O
+and	O
+terminal	O
+dUTP	O
+nick	O
+-	O
+end	O
+labeled	O
+-	O
+positive	O
+cells	O
+in	O
+the	O
+hypoxic	B
+cortical	O
+area	O
+in	O
+the	O
+remnant	O
+kidney	O
+model	O
+.	O
+
+We	O
+propose	O
+here	O
+a	O
+possible	O
+pathological	O
+tie	O
+between	O
+chronic	O
+tubulointerstitial	O
+hypoxia	B
+and	O
+progressive	O
+glomerular	B
+diseases	I
+.	O
+
+Adequate	O
+timing	O
+of	O
+ribavirin	O
+reduction	O
+in	O
+patients	O
+with	O
+hemolysis	B
+during	O
+combination	O
+therapy	O
+of	O
+interferon	O
+and	O
+ribavirin	O
+for	O
+chronic	B
+hepatitis	I
+C	I
+.	O
+
+BACKGROUND	O
+:	O
+Hemolytic	B
+anemia	I
+is	O
+one	O
+of	O
+the	O
+major	O
+adverse	O
+events	O
+of	O
+the	O
+combination	O
+therapy	O
+of	O
+interferon	O
+and	O
+ribavirin	O
+.	O
+
+Because	O
+of	O
+ribavirin	O
+-	O
+related	O
+hemolytic	B
+anemia	I
+,	O
+dose	O
+reduction	O
+is	O
+a	O
+common	O
+event	O
+in	O
+this	O
+therapy	O
+.	O
+
+In	O
+this	O
+clinical	O
+retrospective	O
+cohort	O
+study	O
+we	O
+have	O
+examined	O
+the	O
+suitable	O
+timing	O
+of	O
+ribavirin	O
+reduction	O
+in	O
+patients	O
+with	O
+hemolysis	B
+during	O
+combination	O
+therapy	O
+.	O
+
+METHODS	O
+:	O
+Thirty	O
+-	O
+seven	O
+of	O
+160	O
+patients	O
+who	O
+had	O
+HCV	O
+-	O
+genotype	O
+1b	O
+,	O
+had	O
+high	O
+virus	O
+load	O
+,	O
+and	O
+received	O
+24	O
+-	O
+week	O
+combination	O
+therapy	O
+developed	O
+anemia	B
+with	O
+hemoglobin	O
+level	O
+<	O
+10	O
+g	O
+/	O
+dl	O
+or	O
+anemia	B
+-	O
+related	O
+signs	O
+during	O
+therapy	O
+.	O
+
+After	O
+that	O
+,	O
+these	O
+37	O
+patients	O
+were	O
+reduced	O
+one	O
+tablet	O
+of	O
+ribavirin	O
+(	O
+200	O
+mg	O
+)	O
+per	O
+day	O
+.	O
+
+After	O
+reduction	O
+of	O
+ribavirin	O
+,	O
+27	O
+of	O
+37	O
+patients	O
+could	O
+continue	O
+combination	O
+therapy	O
+for	O
+a	O
+total	O
+of	O
+24	O
+weeks	O
+(	O
+group	O
+A	O
+)	O
+.	O
+
+However	O
+,	O
+10	O
+of	O
+37	O
+patients	O
+with	O
+reduction	O
+of	O
+ribavirin	O
+could	O
+not	O
+continue	O
+combination	O
+therapy	O
+because	O
+their	O
+<	O
+8	O
+.	O
+5	O
+g	O
+/	O
+dl	O
+hemoglobin	O
+values	O
+decreased	O
+to	O
+or	O
+anemia	B
+-	O
+related	O
+severe	O
+side	O
+effects	O
+occurred	O
+(	O
+group	O
+B	O
+)	O
+.	O
+
+We	O
+assessed	O
+the	O
+final	O
+efficacy	O
+and	O
+safety	O
+after	O
+reduction	O
+of	O
+ribavirin	O
+in	O
+groups	O
+A	O
+and	O
+B	O
+.	O
+
+RESULTS	O
+:	O
+A	O
+sustained	O
+virological	O
+response	O
+(	O
+SVR	O
+)	O
+was	O
+29	O
+.	O
+6	O
+%	O
+(	O
+8	O
+/	O
+27	O
+)	O
+in	O
+group	O
+A	O
+and	O
+10	O
+%	O
+(	O
+1	O
+/	O
+10	O
+)	O
+in	O
+group	O
+B	O
+,	O
+respectively	O
+.	O
+
+A	O
+34	O
+.	O
+4	O
+%	O
+(	O
+12	O
+/	O
+27	O
+)	O
+of	O
+SVR	O
++	O
+biological	O
+response	O
+in	O
+group	O
+A	O
+was	O
+higher	O
+than	O
+10	O
+%	O
+(	O
+1	O
+/	O
+10	O
+)	O
+in	O
+group	O
+B	O
+(	O
+P	O
+=	O
+0	O
+.	O
+051	O
+)	O
+,	O
+with	O
+slight	O
+significance	O
+.	O
+
+With	O
+respect	O
+to	O
+hemoglobin	O
+level	O
+at	O
+the	O
+time	O
+of	O
+ribavirin	O
+reduction	O
+,	O
+a	O
+rate	O
+of	O
+continuation	O
+of	O
+therapy	O
+in	O
+patients	O
+with	O
+>	O
+or	O
+=	O
+10	O
+g	O
+/	O
+dl	O
+hemoglobin	O
+was	O
+higher	O
+than	O
+that	O
+in	O
+patients	O
+with	O
+<	O
+10	O
+g	O
+/	O
+dl	O
+(	O
+P	O
+=	O
+0	O
+.	O
+036	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Reduction	O
+of	O
+ribavirin	O
+at	O
+hemoglobin	O
+level	O
+>	O
+or	O
+=	O
+10	O
+g	O
+/	O
+dl	O
+is	O
+suitable	O
+in	O
+terms	O
+of	O
+efficacy	O
+and	O
+side	O
+effects	O
+.	O
+
+Aging	O
+process	O
+of	O
+epithelial	O
+cells	O
+of	O
+the	O
+rat	O
+prostate	O
+lateral	O
+lobe	O
+in	O
+experimental	O
+hyperprolactinemia	B
+induced	O
+by	O
+haloperidol	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+examine	O
+the	O
+influence	O
+of	O
+hyperprolactinemia	B
+,	O
+induced	O
+by	O
+haloperidol	O
+(	O
+HAL	O
+)	O
+on	O
+age	O
+related	O
+morphology	O
+and	O
+function	O
+changes	O
+of	O
+epithelial	O
+cells	O
+in	O
+rat	O
+prostate	O
+lateral	O
+lobe	O
+.	O
+
+The	O
+study	O
+was	O
+performed	O
+on	O
+sexually	O
+mature	O
+male	O
+rats	O
+.	O
+
+Serum	O
+concentrations	O
+of	O
+prolactin	O
+(	O
+PRL	O
+)	O
+and	O
+testosterone	O
+(	O
+T	O
+)	O
+were	O
+measured	O
+.	O
+
+Tissue	O
+sections	O
+were	O
+evaluated	O
+with	O
+light	O
+and	O
+electron	O
+microscopy	O
+.	O
+
+Immunohistochemical	O
+reactions	O
+for	O
+Anti	O
+-	O
+Proliferating	O
+Cell	O
+Nuclear	O
+Antigen	O
+(	O
+PCNA	O
+)	O
+were	O
+performed	O
+.	O
+
+In	O
+rats	O
+of	O
+the	O
+experimental	O
+group	O
+,	O
+the	O
+mean	O
+concentration	O
+of	O
+:	O
+PRL	O
+was	O
+more	O
+than	O
+twice	O
+higher	O
+,	O
+whereas	O
+T	O
+concentration	O
+was	O
+almost	O
+twice	O
+lower	O
+than	O
+that	O
+in	O
+the	O
+control	O
+group	O
+.	O
+
+Light	O
+microscopy	O
+visualized	O
+the	O
+following	O
+:	O
+hypertrophy	B
+and	O
+epithelium	O
+hyperplasia	B
+of	O
+the	O
+glandular	O
+ducts	O
+,	O
+associated	O
+with	O
+increased	O
+PCNA	O
+expression	O
+.	O
+
+Electron	O
+microscopy	O
+revealed	O
+changes	O
+in	O
+columnar	O
+epithelial	O
+cells	O
+,	O
+concerning	O
+organelles	O
+,	O
+engaged	O
+in	O
+protein	O
+synthesis	O
+and	O
+secretion	O
+.	O
+
+Relation	O
+of	O
+perfusion	O
+defects	O
+observed	O
+with	O
+myocardial	O
+contrast	O
+echocardiography	O
+to	O
+the	O
+severity	O
+of	O
+coronary	B
+stenosis	I
+:	O
+correlation	O
+with	O
+thallium	O
+-	O
+201	O
+single	O
+-	O
+photon	O
+emission	O
+tomography	O
+.	O
+
+It	O
+has	O
+been	O
+previously	O
+shown	O
+that	O
+myocardial	O
+contrast	O
+echocardiography	O
+is	O
+a	O
+valuable	O
+technique	O
+for	O
+delineating	O
+regions	O
+of	O
+myocardial	O
+underperfusion	O
+secondary	O
+to	O
+coronary	B
+occlusion	I
+and	O
+to	O
+critical	O
+coronary	B
+stenoses	I
+in	O
+the	O
+presence	O
+of	O
+hyperemic	B
+stimulation	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+whether	O
+myocardial	O
+contrast	O
+echocardiography	O
+performed	O
+with	O
+a	O
+stable	O
+solution	O
+of	O
+sonicated	O
+albumin	O
+could	O
+detect	O
+regions	O
+of	O
+myocardial	O
+underperfusion	O
+resulting	O
+from	O
+various	O
+degrees	O
+of	O
+coronary	B
+stenosis	I
+.	O
+
+The	O
+perfusion	O
+defect	O
+produced	O
+in	O
+16	O
+open	O
+chest	O
+dogs	O
+was	O
+compared	O
+with	O
+the	O
+anatomic	O
+area	O
+at	O
+risk	O
+measured	O
+by	O
+the	O
+postmortem	O
+dual	O
+-	O
+perfusion	O
+technique	O
+and	O
+with	O
+thallium	O
+-	O
+201	O
+single	O
+-	O
+photon	O
+emission	O
+tomography	O
+(	O
+SPECT	O
+)	O
+.	O
+
+During	O
+a	O
+transient	O
+(	O
+20	O
+-	O
+s	O
+)	O
+coronary	B
+occlusion	I
+,	O
+a	O
+perfusion	O
+defect	O
+was	O
+observed	O
+with	O
+contrast	O
+echocardiography	O
+in	O
+14	O
+of	O
+the	O
+15	O
+dogs	O
+in	O
+which	O
+the	O
+occlusion	O
+was	O
+produced	O
+.	O
+
+The	O
+perfusion	O
+defect	O
+correlated	O
+significantly	O
+with	O
+the	O
+anatomic	O
+area	O
+at	O
+risk	O
+(	O
+r	O
+=	O
+0	O
+.	O
+74	O
+;	O
+p	O
+less	O
+than	O
+0	O
+.	O
+002	O
+)	O
+.	O
+
+During	O
+dipyridamole	O
+-	O
+induced	O
+hyperemia	B
+,	O
+12	O
+of	O
+the	O
+16	O
+dogs	O
+with	O
+a	O
+partial	O
+coronary	B
+stenosis	I
+had	O
+a	O
+visible	O
+area	O
+of	O
+hypoperfusion	O
+by	O
+contrast	O
+echocardiography	O
+.	O
+
+The	O
+four	O
+dogs	O
+without	O
+a	O
+perfusion	O
+defect	O
+had	O
+a	O
+stenosis	O
+that	O
+resulted	O
+in	O
+a	O
+mild	O
+(	O
+0	O
+%	O
+to	O
+50	O
+%	O
+)	O
+reduction	O
+in	O
+dipyridamole	O
+-	O
+induced	O
+hyperemia	B
+.	O
+
+The	O
+size	O
+of	O
+the	O
+perfusion	O
+defect	O
+during	O
+stenosis	O
+correlated	O
+significantly	O
+with	O
+the	O
+anatomic	O
+area	O
+at	O
+risk	O
+(	O
+r	O
+=	O
+0	O
+.	O
+61	O
+;	O
+p	O
+=	O
+0	O
+.	O
+02	O
+)	O
+.	O
+
+Thallium	O
+-	O
+201	O
+SPECT	O
+demonstrated	O
+a	O
+perfusion	O
+defect	O
+in	O
+all	O
+14	O
+dogs	O
+analyzed	O
+during	O
+dipyridamole	O
+-	O
+induced	O
+hyperemia	B
+;	O
+the	O
+size	O
+of	O
+the	O
+perfusion	O
+defect	O
+correlated	O
+with	O
+the	O
+anatomic	O
+area	O
+at	O
+risk	O
+(	O
+r	O
+=	O
+0	O
+.	O
+58	O
+;	O
+p	O
+less	O
+than	O
+0	O
+.	O
+03	O
+)	O
+and	O
+with	O
+the	O
+perfusion	O
+defect	O
+by	O
+contrast	O
+echocardiography	O
+(	O
+r	O
+=	O
+0	O
+.	O
+58	O
+;	O
+p	O
+less	O
+than	O
+0	O
+.	O
+03	O
+)	O
+.	O
+
+Thus	O
+,	O
+myocardial	O
+contrast	O
+echocardiography	O
+can	O
+be	O
+used	O
+to	O
+visualize	O
+and	O
+quantitate	O
+the	O
+amount	O
+of	O
+jeopardized	O
+myocardium	O
+during	O
+moderate	O
+to	O
+severe	O
+degrees	O
+of	O
+coronary	B
+stenosis	I
+.	O
+
+The	O
+results	O
+obtained	O
+show	O
+a	O
+correlation	O
+with	O
+the	O
+anatomic	O
+area	O
+at	O
+risk	O
+similar	O
+to	O
+that	O
+obtained	O
+with	O
+thallium	O
+-	O
+201	O
+SPECT	O
+.	O
+
+The	O
+activation	O
+of	O
+spinal	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+receptors	O
+may	O
+contribute	O
+to	O
+degeneration	O
+of	O
+spinal	O
+motor	O
+neurons	O
+induced	O
+by	O
+neuraxial	O
+morphine	O
+after	O
+a	O
+noninjurious	O
+interval	O
+of	O
+spinal	B
+cord	I
+ischemia	I
+.	O
+
+We	O
+investigated	O
+the	O
+relationship	O
+between	O
+the	O
+degeneration	O
+of	O
+spinal	O
+motor	O
+neurons	O
+and	O
+activation	O
+of	O
+N	O
+-	O
+methyl	O
+-	O
+d	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+receptors	O
+after	O
+neuraxial	O
+morphine	O
+following	O
+a	O
+noninjurious	O
+interval	O
+of	O
+aortic	B
+occlusion	I
+in	O
+rats	O
+.	O
+
+Spinal	B
+cord	I
+ischemia	I
+was	O
+induced	O
+by	O
+aortic	B
+occlusion	I
+for	O
+6	O
+min	O
+with	O
+a	O
+balloon	O
+catheter	O
+.	O
+
+In	O
+a	O
+microdialysis	O
+study	O
+,	O
+10	O
+muL	O
+of	O
+saline	O
+(	O
+group	O
+C	O
+;	O
+n	O
+=	O
+8	O
+)	O
+or	O
+30	O
+mug	O
+of	O
+morphine	O
+(	O
+group	O
+M	O
+;	O
+n	O
+=	O
+8	O
+)	O
+was	O
+injected	O
+intrathecally	O
+(	O
+IT	O
+)	O
+0	O
+.	O
+5	O
+h	O
+after	O
+reflow	O
+,	O
+and	O
+30	O
+mug	O
+of	O
+morphine	O
+(	O
+group	O
+SM	O
+;	O
+n	O
+=	O
+8	O
+)	O
+or	O
+10	O
+muL	O
+of	O
+saline	O
+(	O
+group	O
+SC	O
+;	O
+n	O
+=	O
+8	O
+)	O
+was	O
+injected	O
+IT	O
+0	O
+.	O
+5	O
+h	O
+after	O
+sham	O
+operation	O
+.	O
+
+Microdialysis	O
+samples	O
+were	O
+collected	O
+preischemia	O
+,	O
+before	O
+IT	O
+injection	O
+,	O
+and	O
+at	O
+2	O
+,	O
+4	O
+,	O
+8	O
+,	O
+24	O
+,	O
+and	O
+48	O
+h	O
+of	O
+reperfusion	O
+(	O
+after	O
+IT	O
+injection	O
+)	O
+.	O
+
+Second	O
+,	O
+we	O
+investigated	O
+the	O
+effect	O
+of	O
+IT	O
+MK	O
+-	O
+801	O
+(	O
+30	O
+mug	O
+)	O
+on	O
+the	O
+histopathologic	O
+changes	O
+in	O
+the	O
+spinal	O
+cord	O
+after	O
+morphine	O
+-	O
+induced	O
+spastic	B
+paraparesis	I
+.	O
+
+After	O
+IT	O
+morphine	O
+,	O
+the	O
+cerebrospinal	O
+fluid	O
+(	O
+CSF	O
+)	O
+glutamate	O
+concentration	O
+was	O
+increased	O
+in	O
+group	O
+M	O
+relative	O
+to	O
+both	O
+baseline	O
+and	O
+group	O
+C	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+This	O
+increase	O
+persisted	O
+for	O
+8	O
+hrs	O
+.	O
+
+IT	O
+MK	O
+-	O
+801	O
+significantly	O
+reduced	O
+the	O
+number	O
+of	O
+dark	O
+-	O
+stained	O
+alpha	O
+-	O
+motoneurons	O
+after	O
+morphine	O
+-	O
+induced	O
+spastic	B
+paraparesis	I
+compared	O
+with	O
+the	O
+saline	O
+group	O
+.	O
+
+These	O
+data	O
+indicate	O
+that	O
+IT	O
+morphine	O
+induces	O
+spastic	B
+paraparesis	I
+with	O
+a	O
+concomitant	O
+increase	O
+in	O
+CSF	O
+glutamate	O
+,	O
+which	O
+is	O
+involved	O
+in	O
+NMDA	O
+receptor	O
+activation	O
+.	O
+
+We	O
+suggest	O
+that	O
+opioids	O
+may	O
+be	O
+neurotoxic	B
+in	O
+the	O
+setting	O
+of	O
+spinal	B
+cord	I
+ischemia	I
+via	O
+NMDA	O
+receptor	O
+activation	O
+.	O
+
+Acute	O
+low	B
+back	I
+pain	I
+during	O
+intravenous	O
+administration	O
+of	O
+amiodarone	O
+:	O
+a	O
+report	O
+of	O
+two	O
+cases	O
+.	O
+
+Amiodarone	O
+represents	O
+an	O
+effective	O
+antiarrhythmic	O
+drug	O
+for	O
+cardioversion	O
+of	O
+recent	O
+-	O
+onset	O
+atrial	B
+fibrillation	I
+(	O
+AF	B
+)	O
+and	O
+maintenance	O
+of	O
+sinus	O
+rhythm	O
+.	O
+
+We	O
+briefly	O
+describe	O
+two	O
+patients	O
+suffering	O
+from	O
+recent	O
+-	O
+onset	O
+atrial	B
+fibrillation	I
+,	O
+who	O
+experienced	O
+an	O
+acute	O
+devastating	O
+low	B
+back	I
+pain	I
+a	O
+few	O
+minutes	O
+after	O
+initiation	O
+of	O
+intravenous	O
+amiodarone	O
+loading	O
+.	O
+
+Notably	O
+,	O
+this	O
+side	O
+effect	O
+has	O
+not	O
+been	O
+ever	O
+reported	O
+in	O
+the	O
+medical	O
+literature	O
+.	O
+
+Clinicians	O
+should	O
+be	O
+aware	O
+of	O
+this	O
+reaction	O
+since	O
+prompt	O
+termination	O
+of	O
+parenteral	O
+administration	O
+leads	O
+to	O
+complete	O
+resolution	O
+.	O
+
+Quantitative	O
+drug	O
+levels	O
+in	O
+stimulant	O
+psychosis	B
+:	O
+relationship	O
+to	O
+symptom	O
+severity	O
+,	O
+catecholamines	O
+and	O
+hyperkinesia	B
+.	O
+
+To	O
+examine	O
+the	O
+relationship	O
+between	O
+quantitative	O
+stimulant	O
+drug	O
+levels	O
+,	O
+catecholamines	O
+,	O
+and	O
+psychotic	B
+symptoms	I
+,	O
+nineteen	O
+patients	O
+in	O
+a	O
+psychiatric	B
+emergency	O
+service	O
+with	O
+a	O
+diagnosis	O
+of	O
+amphetamine	O
+-	O
+or	O
+cocaine	O
+-	O
+induced	O
+psychosis	B
+were	O
+interviewed	O
+,	O
+and	O
+plasma	O
+and	O
+urine	O
+were	O
+collected	O
+for	O
+quantitative	O
+assays	O
+of	O
+stimulant	O
+drug	O
+and	O
+catecholamine	O
+metabolite	O
+levels	O
+.	O
+
+Methamphetamine	O
+or	O
+amphetamine	O
+levels	O
+were	O
+related	O
+to	O
+several	O
+psychopathology	O
+scores	O
+and	O
+the	O
+global	O
+hyperkinesia	B
+rating	O
+.	O
+
+HVA	O
+levels	O
+were	O
+related	O
+to	O
+global	O
+hyperkinesia	B
+but	O
+not	O
+to	O
+psychopathology	O
+ratings	O
+.	O
+
+Although	O
+many	O
+other	O
+factors	O
+such	O
+as	O
+sensitization	O
+may	O
+play	O
+a	O
+role	O
+,	O
+intensity	O
+of	O
+stimulant	O
+-	O
+induced	O
+psychotic	B
+symptoms	I
+and	O
+stereotypies	B
+appears	O
+to	O
+be	O
+at	O
+least	O
+in	O
+part	O
+dose	O
+-	O
+related	O
+.	O
+
+Pheochromocytoma	B
+unmasked	O
+by	O
+amisulpride	O
+and	O
+tiapride	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+describe	O
+the	O
+unmasking	O
+of	O
+pheochromocytoma	B
+in	O
+a	O
+patient	O
+treated	O
+with	O
+amisulpride	O
+and	O
+tiapride	O
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+42	O
+-	O
+year	O
+-	O
+old	O
+white	O
+man	O
+developed	O
+acute	O
+hypertension	B
+with	O
+severe	O
+headache	B
+and	O
+vomiting	B
+2	O
+hours	O
+after	O
+the	O
+first	O
+doses	O
+of	O
+amisulpride	O
+100	O
+mg	O
+and	O
+tiapride	O
+100	O
+mg	O
+.	O
+
+Both	O
+drugs	O
+were	O
+immediately	O
+discontinued	O
+,	O
+and	O
+the	O
+patient	O
+recovered	O
+after	O
+subsequent	O
+nicardipine	O
+and	O
+verapamil	O
+treatment	O
+.	O
+
+Abdominal	O
+ultrasound	O
+showed	O
+an	O
+adrenal	O
+mass	O
+,	O
+and	O
+postoperative	O
+histologic	O
+examination	O
+confirmed	O
+the	O
+diagnosis	O
+of	O
+pheochromocytoma	B
+.	O
+
+DISCUSSION	O
+:	O
+Drug	O
+-	O
+induced	O
+symptoms	O
+of	O
+pheochromocytoma	B
+are	O
+often	O
+associated	O
+with	O
+the	O
+use	O
+of	O
+substituted	O
+benzamide	O
+drugs	O
+,	O
+but	O
+the	O
+underlying	O
+mechanism	O
+is	O
+unknown	O
+.	O
+
+In	O
+our	O
+case	O
+,	O
+use	O
+of	O
+the	O
+Naranjo	O
+probability	O
+scale	O
+indicated	O
+a	O
+possible	O
+relationship	O
+between	O
+the	O
+hypertensive	B
+crisis	O
+and	O
+amisulpride	O
+and	O
+tiapride	O
+therapy	O
+.	O
+
+CONCLUSIONS	O
+:	O
+As	O
+of	O
+March	O
+24	O
+,	O
+2005	O
+,	O
+this	O
+is	O
+the	O
+first	O
+reported	O
+case	O
+of	O
+amisulpride	O
+-	O
+and	O
+tiapride	O
+-	O
+induced	O
+hypertensive	B
+crisis	O
+in	O
+a	O
+patient	O
+with	O
+pheochromocytoma	B
+.	O
+
+Physicians	O
+and	O
+other	O
+healthcare	O
+professionals	O
+should	O
+be	O
+aware	O
+of	O
+this	O
+potential	O
+adverse	O
+effect	O
+of	O
+tiapride	O
+and	O
+amisulpride	O
+.	O
+
+Minor	O
+neurological	B
+dysfunction	I
+,	O
+cognitive	O
+development	O
+,	O
+and	O
+somatic	O
+development	O
+at	O
+the	O
+age	O
+of	O
+3	O
+to	O
+7	O
+years	O
+after	O
+dexamethasone	O
+treatment	O
+in	O
+very	O
+-	O
+low	O
+birth	O
+-	O
+weight	O
+infants	O
+.	O
+
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+assess	O
+minor	O
+neurological	B
+dysfunction	I
+,	O
+cognitive	O
+development	O
+,	O
+and	O
+somatic	O
+development	O
+after	O
+dexamethasone	O
+therapy	O
+in	O
+very	O
+-	O
+low	O
+-	O
+birthweight	O
+infants	O
+.	O
+
+Thirty	O
+-	O
+three	O
+children	O
+after	O
+dexamethasone	O
+treatment	O
+were	O
+matched	O
+to	O
+33	O
+children	O
+without	O
+dexamethasone	O
+treatment	O
+.	O
+
+Data	O
+were	O
+assessed	O
+at	O
+the	O
+age	O
+of	O
+3	O
+-	O
+7	O
+years	O
+.	O
+
+Dexamethasone	O
+was	O
+started	O
+between	O
+the	O
+7th	O
+and	O
+the	O
+28th	O
+day	O
+of	O
+life	O
+over	O
+7	O
+days	O
+with	O
+a	O
+total	O
+dose	O
+of	O
+2	O
+.	O
+35	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+.	O
+
+Exclusion	O
+criteria	O
+were	O
+asphyxia	B
+,	O
+malformations	B
+,	O
+major	O
+surgical	O
+interventions	O
+,	O
+small	O
+for	O
+gestational	O
+age	O
+,	O
+intraventricular	O
+haemorrhage	B
+grades	O
+III	O
+and	O
+IV	O
+,	O
+periventricular	B
+leukomalacia	I
+,	O
+and	O
+severe	O
+psychomotor	B
+retardation	I
+.	O
+
+Each	O
+child	O
+was	O
+examined	O
+by	O
+a	O
+neuropediatrician	O
+for	O
+minor	O
+neurological	B
+dysfunctions	I
+and	O
+tested	O
+by	O
+a	O
+psychologist	O
+for	O
+cognitive	O
+development	O
+with	O
+a	O
+Kaufman	O
+Assessment	O
+Battery	O
+for	O
+Children	O
+and	O
+a	O
+Draw	O
+-	O
+a	O
+-	O
+Man	O
+Test	O
+.	O
+
+There	O
+were	O
+no	O
+differences	O
+in	O
+demographic	O
+data	O
+,	O
+growth	O
+,	O
+and	O
+socio	O
+-	O
+economic	O
+status	O
+between	O
+the	O
+two	O
+groups	O
+.	O
+
+Fine	O
+motor	O
+skills	O
+and	O
+gross	O
+motor	O
+function	O
+were	O
+significantly	O
+better	O
+in	O
+the	O
+control	O
+group	O
+(	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+In	O
+the	O
+Draw	O
+-	O
+a	O
+-	O
+Man	O
+Test	O
+,	O
+the	O
+control	O
+group	O
+showed	O
+better	O
+results	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+There	O
+were	O
+no	O
+differences	O
+in	O
+development	O
+of	O
+speech	O
+,	O
+social	O
+development	O
+,	O
+and	O
+the	O
+Kaufman	O
+Assessment	O
+Battery	O
+for	O
+Children	O
+.	O
+
+After	O
+dexamethasone	O
+treatment	O
+,	O
+children	O
+showed	O
+a	O
+higher	O
+rate	O
+of	O
+minor	O
+neurological	B
+dysfunctions	I
+.	O
+
+Neurological	O
+development	O
+was	O
+affected	O
+even	O
+without	O
+neurological	O
+diagnosis	O
+.	O
+
+Further	O
+long	O
+-	O
+term	O
+follow	O
+-	O
+up	O
+studies	O
+will	O
+be	O
+necessary	O
+to	O
+fully	O
+evaluate	O
+the	O
+impact	O
+of	O
+dexamethasone	O
+on	O
+neurological	O
+and	O
+cognitive	O
+development	O
+.	O
+
+Valproic	O
+acid	O
+I	O
+:	O
+time	O
+course	O
+of	O
+lipid	O
+peroxidation	O
+biomarkers	O
+,	O
+liver	B
+toxicity	I
+,	O
+and	O
+valproic	O
+acid	O
+metabolite	O
+levels	O
+in	O
+rats	O
+.	O
+
+A	O
+single	O
+dose	O
+of	O
+valproic	O
+acid	O
+(	O
+VPA	O
+)	O
+,	O
+which	O
+is	O
+a	O
+widely	O
+used	O
+antiepileptic	O
+drug	O
+,	O
+is	O
+associated	O
+with	O
+oxidative	O
+stress	O
+in	O
+rats	O
+,	O
+as	O
+recently	O
+demonstrated	O
+by	O
+elevated	O
+levels	O
+of	O
+15	O
+-	O
+F	O
+(	O
+2t	O
+)	O
+-	O
+isoprostane	O
+(	O
+15	O
+-	O
+F	O
+(	O
+2t	O
+)	O
+-	O
+IsoP	O
+)	O
+.	O
+
+To	O
+determine	O
+whether	O
+there	O
+was	O
+a	O
+temporal	O
+relationship	O
+between	O
+VPA	O
+-	O
+associated	O
+oxidative	O
+stress	O
+and	O
+hepatotoxicity	B
+,	O
+adult	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+were	O
+treated	O
+ip	O
+with	O
+VPA	O
+(	O
+500	O
+mg	O
+/	O
+kg	O
+)	O
+or	O
+0	O
+.	O
+9	O
+%	O
+saline	O
+(	O
+vehicle	O
+)	O
+once	O
+daily	O
+for	O
+2	O
+,	O
+4	O
+,	O
+7	O
+,	O
+10	O
+,	O
+or	O
+14	O
+days	O
+.	O
+
+Oxidative	O
+stress	O
+was	O
+assessed	O
+by	O
+determining	O
+plasma	O
+and	O
+liver	O
+levels	O
+of	O
+15	O
+-	O
+F	O
+(	O
+2t	O
+)	O
+-	O
+IsoP	O
+,	O
+lipid	O
+hydroperoxides	O
+(	O
+LPO	O
+)	O
+,	O
+and	O
+thiobarbituric	O
+acid	O
+reactive	O
+substances	O
+(	O
+TBARs	O
+)	O
+.	O
+
+Plasma	O
+and	O
+liver	O
+15	O
+-	O
+F	O
+(	O
+2t	O
+)	O
+-	O
+IsoP	O
+were	O
+elevated	O
+and	O
+reached	O
+a	O
+plateau	O
+after	O
+day	O
+2	O
+of	O
+VPA	O
+treatment	O
+compared	O
+to	O
+control	O
+.	O
+
+Liver	O
+LPO	O
+levels	O
+were	O
+not	O
+elevated	O
+until	O
+day	O
+7	O
+of	O
+treatment	O
+(	O
+1	O
+.	O
+8	O
+-	O
+fold	O
+versus	O
+control	O
+,	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Liver	O
+and	O
+plasma	O
+TBARs	O
+were	O
+not	O
+increased	O
+until	O
+14	O
+days	O
+(	O
+2	O
+-	O
+fold	O
+vs	O
+.	O
+control	O
+,	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Liver	B
+toxicity	I
+was	O
+evaluated	O
+based	O
+on	O
+serum	O
+levels	O
+of	O
+alpha	O
+-	O
+glutathione	O
+S	O
+-	O
+transferase	O
+(	O
+alpha	O
+-	O
+GST	O
+)	O
+and	O
+by	O
+histology	O
+.	O
+
+Serum	O
+alpha	O
+-	O
+GST	O
+levels	O
+were	O
+significantly	O
+elevated	O
+by	O
+day	O
+4	O
+,	O
+which	O
+corresponded	O
+to	O
+hepatotoxicity	B
+as	O
+shown	O
+by	O
+the	O
+increasing	O
+incidence	O
+of	O
+inflammation	B
+of	O
+the	O
+liver	O
+capsule	O
+,	O
+necrosis	B
+,	O
+and	O
+steatosis	B
+throughout	O
+the	O
+study	O
+.	O
+
+The	O
+liver	O
+levels	O
+of	O
+beta	O
+-	O
+oxidation	O
+metabolites	O
+of	O
+VPA	O
+were	O
+decreased	O
+by	O
+day	O
+14	O
+,	O
+while	O
+the	O
+levels	O
+of	O
+4	O
+-	O
+ene	O
+-	O
+VPA	O
+and	O
+(	O
+E	O
+)	O
+-	O
+2	O
+,	O
+4	O
+-	O
+diene	O
+-	O
+VPA	O
+were	O
+not	O
+elevated	O
+throughout	O
+the	O
+study	O
+.	O
+
+Overall	O
+,	O
+these	O
+findings	O
+indicate	O
+that	O
+VPA	O
+treatment	O
+results	O
+in	O
+oxidative	O
+stress	O
+,	O
+as	O
+measured	O
+by	O
+levels	O
+of	O
+15	O
+-	O
+F	O
+(	O
+2t	O
+)	O
+-	O
+IsoP	O
+,	O
+which	O
+precedes	O
+the	O
+onset	O
+of	O
+necrosis	B
+,	O
+steatosis	B
+,	O
+and	O
+elevated	O
+levels	O
+of	O
+serum	O
+alpha	O
+-	O
+GST	O
+.	O
+
+Assessment	O
+of	O
+perinatal	O
+hepatitis	B
+B	I
+and	O
+rubella	B
+prevention	O
+in	O
+New	O
+Hampshire	O
+delivery	O
+hospitals	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+evaluate	O
+current	O
+performance	O
+on	O
+recommended	O
+perinatal	O
+hepatitis	B
+B	I
+and	O
+rubella	B
+prevention	O
+practices	O
+in	O
+New	O
+Hampshire	O
+.	O
+
+METHODS	O
+:	O
+Data	O
+were	O
+extracted	O
+from	O
+2021	O
+paired	O
+mother	O
+-	O
+infant	O
+records	O
+for	O
+the	O
+year	O
+2000	O
+birth	O
+cohort	O
+in	O
+New	O
+Hampshire	O
+'	O
+s	O
+25	O
+delivery	O
+hospitals	O
+.	O
+
+Assessment	O
+was	O
+done	O
+on	O
+the	O
+following	O
+:	O
+prenatal	O
+screening	O
+for	O
+hepatitis	B
+B	I
+and	O
+rubella	B
+,	O
+administration	O
+of	O
+the	O
+hepatitis	B
+B	I
+vaccine	O
+birth	O
+dose	O
+to	O
+all	O
+infants	O
+,	O
+administration	O
+of	O
+hepatitis	B
+B	I
+immune	O
+globulin	O
+to	O
+infants	O
+who	O
+were	O
+born	O
+to	O
+hepatitis	O
+B	O
+surface	O
+antigen	O
+-	O
+positive	O
+mothers	O
+,	O
+rubella	B
+immunity	O
+,	O
+and	O
+administration	O
+of	O
+in	O
+-	O
+hospital	O
+postpartum	O
+rubella	B
+vaccine	O
+to	O
+rubella	B
+nonimmune	O
+women	O
+.	O
+
+RESULTS	O
+:	O
+Prenatal	O
+screening	O
+rates	O
+for	O
+hepatitis	B
+B	I
+(	O
+98	O
+.	O
+8	O
+%	O
+)	O
+and	O
+rubella	B
+(	O
+99	O
+.	O
+4	O
+%	O
+)	O
+were	O
+high	O
+.	O
+
+Hepatitis	B
+B	I
+vaccine	O
+birth	O
+dose	O
+was	O
+administered	O
+to	O
+76	O
+.	O
+2	O
+%	O
+of	O
+all	O
+infants	O
+.	O
+
+All	O
+infants	O
+who	O
+were	O
+born	O
+to	O
+hepatitis	O
+B	O
+surface	O
+antigen	O
+-	O
+positive	O
+mothers	O
+also	O
+received	O
+hepatitis	B
+B	I
+immune	O
+globulin	O
+.	O
+
+Multivariate	O
+logistic	O
+regression	O
+showed	O
+that	O
+the	O
+month	O
+of	O
+delivery	O
+and	O
+infant	O
+birth	O
+weight	O
+were	O
+independent	O
+predictors	O
+of	O
+hepatitis	B
+B	I
+vaccination	O
+.	O
+
+The	O
+proportion	O
+of	O
+infants	O
+who	O
+were	O
+vaccinated	O
+in	O
+January	O
+and	O
+February	O
+2000	O
+(	O
+48	O
+.	O
+5	O
+%	O
+and	O
+67	O
+.	O
+5	O
+%	O
+,	O
+respectively	O
+)	O
+was	O
+less	O
+than	O
+any	O
+other	O
+months	O
+,	O
+whereas	O
+the	O
+proportion	O
+who	O
+were	O
+vaccinated	O
+in	O
+December	O
+2000	O
+(	O
+88	O
+.	O
+2	O
+%	O
+)	O
+was	O
+the	O
+highest	O
+.	O
+
+Women	O
+who	O
+were	O
+born	O
+between	O
+1971	O
+and	O
+1975	O
+had	O
+the	O
+highest	O
+rate	O
+of	O
+rubella	B
+nonimmunity	O
+(	O
+9	O
+.	O
+5	O
+%	O
+)	O
+.	O
+
+In	O
+-	O
+hospital	O
+postpartum	O
+rubella	B
+vaccine	O
+administration	O
+was	O
+documented	O
+for	O
+75	O
+.	O
+6	O
+%	O
+of	O
+nonimmune	O
+women	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+study	O
+documents	O
+good	O
+compliance	O
+in	O
+New	O
+Hampshire	O
+'	O
+s	O
+birthing	O
+hospitals	O
+with	O
+national	O
+guidelines	O
+for	O
+perinatal	O
+hepatitis	B
+B	I
+and	O
+rubella	B
+prevention	O
+and	O
+highlights	O
+potential	O
+areas	O
+for	O
+improvement	O
+.	O
+
+Succinylcholine	O
+-	O
+induced	O
+masseter	B
+muscle	I
+rigidity	I
+during	O
+bronchoscopic	O
+removal	O
+of	O
+a	O
+tracheal	O
+foreign	O
+body	O
+.	O
+
+Masseter	B
+muscle	I
+rigidity	I
+during	O
+general	O
+anesthesia	O
+is	O
+considered	O
+an	O
+early	O
+warning	O
+sign	O
+of	O
+a	O
+possible	O
+episode	O
+of	O
+malignant	B
+hyperthermia	I
+.	O
+
+The	O
+decision	O
+whether	O
+to	O
+continue	O
+or	O
+discontinue	O
+the	O
+procedure	O
+depends	O
+on	O
+the	O
+urgency	O
+of	O
+the	O
+surgery	O
+and	O
+severity	O
+of	O
+masseter	B
+muscle	I
+rigidity	I
+.	O
+
+Here	O
+,	O
+we	O
+describe	O
+a	O
+case	O
+of	O
+severe	O
+masseter	B
+muscle	I
+rigidity	I
+(	O
+jaw	B
+of	I
+steel	I
+)	O
+after	O
+succinylcholine	O
+(	O
+Sch	O
+)	O
+administration	O
+during	O
+general	O
+anesthetic	O
+management	O
+for	O
+rigid	O
+bronchoscopic	O
+removal	O
+of	O
+a	O
+tracheal	O
+foreign	O
+body	O
+.	O
+
+Anesthesia	O
+was	O
+continued	O
+uneventfully	O
+with	O
+propofol	O
+infusion	O
+while	O
+all	O
+facilities	O
+were	O
+available	O
+to	O
+detect	O
+and	O
+treat	O
+malignant	B
+hyperthermia	I
+.	O
+
+Dexrazoxane	O
+protects	O
+against	O
+myelosuppression	B
+from	O
+the	O
+DNA	O
+cleavage	O
+-	O
+enhancing	O
+drugs	O
+etoposide	O
+and	O
+daunorubicin	O
+but	O
+not	O
+doxorubicin	O
+.	O
+
+PURPOSE	O
+:	O
+The	O
+anthracyclines	O
+daunorubicin	O
+and	O
+doxorubicin	O
+and	O
+the	O
+epipodophyllotoxin	O
+etoposide	O
+are	O
+potent	O
+DNA	O
+cleavage	O
+-	O
+enhancing	O
+drugs	O
+that	O
+are	O
+widely	O
+used	O
+in	O
+clinical	O
+oncology	O
+;	O
+however	O
+,	O
+myelosuppression	B
+and	O
+cardiac	B
+toxicity	I
+limit	O
+their	O
+use	O
+.	O
+
+Dexrazoxane	O
+(	O
+ICRF	O
+-	O
+187	O
+)	O
+is	O
+recommended	O
+for	O
+protection	O
+against	O
+anthracycline	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+EXPERIMENTAL	O
+DESIGN	O
+:	O
+Because	O
+of	O
+their	O
+widespread	O
+use	O
+,	O
+the	O
+hematologic	B
+toxicity	I
+following	O
+coadministration	O
+of	O
+dexrazoxane	O
+and	O
+these	O
+three	O
+structurally	O
+different	O
+DNA	O
+cleavage	O
+enhancers	O
+was	O
+investigated	O
+:	O
+Sensitivity	O
+of	O
+human	O
+and	O
+murine	O
+blood	O
+progenitor	O
+cells	O
+to	O
+etoposide	O
+,	O
+daunorubicin	O
+,	O
+and	O
+doxorubicin	O
++	O
+/	O
+-	O
+dexrazoxane	O
+was	O
+determined	O
+in	O
+granulocyte	O
+-	O
+macrophage	O
+colony	O
+forming	O
+assays	O
+.	O
+
+Likewise	O
+,	O
+in	O
+vivo	O
+,	O
+B6D2F1	O
+mice	O
+were	O
+treated	O
+with	O
+etoposide	O
+,	O
+daunorubicin	O
+,	O
+and	O
+doxorubicin	O
+,	O
+with	O
+or	O
+without	O
+dexrazoxane	O
+over	O
+a	O
+wide	O
+range	O
+of	O
+doses	O
+:	O
+posttreatment	O
+,	O
+a	O
+full	O
+hematologic	O
+evaluation	O
+was	O
+done	O
+.	O
+
+RESULTS	O
+:	O
+Nontoxic	O
+doses	O
+of	O
+dexrazoxane	O
+reduced	O
+myelosuppression	B
+and	O
+weight	B
+loss	I
+from	O
+daunorubicin	O
+and	O
+etoposide	O
+in	O
+mice	O
+and	O
+antagonized	O
+their	O
+antiproliferative	O
+effects	O
+in	O
+the	O
+colony	O
+assay	O
+;	O
+however	O
+,	O
+dexrazoxane	O
+neither	O
+reduced	O
+myelosuppression	B
+,	O
+weight	B
+loss	I
+,	O
+nor	O
+the	O
+in	O
+vitro	O
+cytotoxicity	B
+from	O
+doxorubicin	O
+.	O
+
+CONCLUSION	O
+:	O
+Although	O
+our	O
+findings	O
+support	O
+the	O
+observation	O
+that	O
+dexrazoxane	O
+reduces	O
+neither	O
+hematologic	O
+activity	O
+nor	O
+antitumor	O
+activity	O
+from	O
+doxorubicin	O
+clinically	O
+,	O
+the	O
+potent	O
+antagonism	O
+of	O
+daunorubicin	O
+activity	O
+raises	O
+concern	O
+;	O
+a	O
+possible	O
+interference	O
+with	O
+anticancer	O
+efficacy	O
+certainly	O
+would	O
+call	O
+for	O
+renewed	O
+attention	O
+.	O
+
+Our	O
+data	O
+also	O
+suggest	O
+that	O
+significant	O
+etoposide	O
+dose	O
+escalation	O
+is	O
+perhaps	O
+possible	O
+by	O
+the	O
+use	O
+of	O
+dexrazoxane	O
+.	O
+
+Clinical	O
+trials	O
+in	O
+patients	O
+with	O
+brain	O
+metastases	B
+combining	O
+dexrazoxane	O
+and	O
+high	O
+doses	O
+of	O
+etoposide	O
+is	O
+ongoing	O
+with	O
+the	O
+aim	O
+of	O
+improving	O
+efficacy	O
+without	O
+aggravating	O
+hematologic	B
+toxicity	I
+.	O
+
+If	O
+successful	O
+,	O
+this	O
+represents	O
+an	O
+exciting	O
+mechanism	O
+for	O
+pharmacologic	O
+regulation	O
+of	O
+side	O
+effects	O
+from	O
+cytotoxic	O
+chemotherapy	O
+.	O
+
+Assessment	O
+of	O
+the	O
+onset	O
+and	O
+persistence	O
+of	O
+amnesia	B
+during	O
+procedural	O
+sedation	O
+with	O
+propofol	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+assess	O
+patients	O
+'	O
+ability	O
+to	O
+repeat	O
+and	O
+recall	O
+words	O
+presented	O
+to	O
+them	O
+while	O
+undergoing	O
+procedural	O
+sedation	O
+with	O
+propofol	O
+,	O
+and	O
+correlate	O
+their	O
+recall	O
+with	O
+their	O
+level	O
+of	O
+awareness	O
+as	O
+measured	O
+by	O
+bispectral	O
+index	O
+(	O
+BIS	O
+)	O
+monitoring	O
+.	O
+
+METHODS	O
+:	O
+This	O
+was	O
+a	O
+prospective	O
+,	O
+single	O
+-	O
+intervention	O
+study	O
+of	O
+consenting	O
+adult	O
+patients	O
+undergoing	O
+procedural	O
+sedation	O
+with	O
+propofol	O
+between	O
+December	O
+28	O
+,	O
+2002	O
+,	O
+and	O
+October	O
+31	O
+,	O
+2003	O
+.	O
+
+BIS	O
+monitoring	O
+was	O
+initiated	O
+starting	O
+3	O
+minutes	O
+before	O
+the	O
+procedure	O
+and	O
+continuing	O
+until	O
+the	O
+patient	O
+had	O
+regained	O
+baseline	O
+mental	O
+status	O
+.	O
+
+At	O
+1	O
+-	O
+minute	O
+intervals	O
+during	O
+the	O
+procedural	O
+sedation	O
+,	O
+until	O
+the	O
+patient	O
+regained	O
+baseline	O
+mental	O
+status	O
+at	O
+the	O
+end	O
+of	O
+the	O
+procedure	O
+,	O
+a	O
+word	O
+from	O
+a	O
+standardized	O
+list	O
+was	O
+read	O
+aloud	O
+,	O
+and	O
+the	O
+patient	O
+was	O
+asked	O
+to	O
+immediately	O
+repeat	O
+the	O
+word	O
+to	O
+the	O
+investigator	O
+.	O
+
+The	O
+BIS	O
+score	O
+at	O
+the	O
+time	O
+the	O
+word	O
+was	O
+read	O
+and	O
+the	O
+patient	O
+'	O
+s	O
+ability	O
+to	O
+repeat	O
+the	O
+word	O
+were	O
+recorded	O
+.	O
+
+After	O
+the	O
+procedure	O
+,	O
+the	O
+patient	O
+was	O
+asked	O
+to	O
+state	O
+all	O
+of	O
+the	O
+words	O
+from	O
+the	O
+list	O
+that	O
+he	O
+or	O
+she	O
+could	O
+recall	O
+,	O
+and	O
+to	O
+identify	O
+the	O
+last	O
+word	O
+recalled	O
+from	O
+prior	O
+to	O
+the	O
+start	O
+of	O
+the	O
+procedure	O
+and	O
+the	O
+first	O
+word	O
+recalled	O
+from	O
+after	O
+the	O
+procedure	O
+was	O
+completed	O
+.	O
+
+RESULTS	O
+:	O
+Seventy	O
+-	O
+five	O
+consenting	O
+patients	O
+were	O
+enrolled	O
+;	O
+one	O
+patient	O
+was	O
+excluded	O
+from	O
+data	O
+analysis	O
+for	O
+a	O
+protocol	O
+violation	O
+.	O
+
+No	O
+serious	O
+adverse	O
+events	O
+were	O
+noted	O
+during	O
+the	O
+procedural	O
+sedations	O
+.	O
+
+The	O
+mean	O
+(	O
++	O
+/	O
+-	O
+standard	O
+deviation	O
+)	O
+time	O
+of	O
+data	O
+collection	O
+was	O
+16	O
+.	O
+4	O
+minutes	O
+(	O
++	O
+/	O
+-	O
+7	O
+.	O
+1	O
+;	O
+range	O
+5	O
+to	O
+34	O
+minutes	O
+)	O
+.	O
+
+The	O
+mean	O
+initial	O
+(	O
+preprocedure	O
+)	O
+BIS	O
+score	O
+was	O
+97	O
+.	O
+1	O
+(	O
++	O
+/	O
+-	O
+2	O
+.	O
+3	O
+;	O
+range	O
+92	O
+to	O
+99	O
+)	O
+.	O
+
+The	O
+mean	O
+lowest	O
+BIS	O
+score	O
+occurring	O
+during	O
+these	O
+procedural	O
+sedations	O
+was	O
+66	O
+.	O
+9	O
+(	O
++	O
+/	O
+-	O
+14	O
+.	O
+4	O
+;	O
+range	O
+33	O
+to	O
+91	O
+)	O
+.	O
+
+The	O
+mean	O
+lowest	O
+BIS	O
+score	O
+corresponding	O
+to	O
+the	O
+ability	O
+of	O
+the	O
+patient	O
+to	O
+immediately	O
+repeat	O
+words	O
+read	O
+from	O
+the	O
+list	O
+was	O
+77	O
+.	O
+1	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+74	O
+.	O
+3	O
+to	O
+80	O
+.	O
+0	O
+)	O
+.	O
+
+The	O
+mean	O
+highest	O
+BIS	O
+score	O
+corresponding	O
+to	O
+the	O
+inability	B
+to	I
+repeat	I
+words	I
+was	O
+81	O
+.	O
+5	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+78	O
+.	O
+1	O
+to	O
+84	O
+.	O
+8	O
+)	O
+.	O
+
+The	O
+mean	O
+BIS	O
+score	O
+corresponding	O
+to	O
+the	O
+last	O
+word	O
+recalled	O
+from	O
+prior	O
+to	O
+the	O
+initiation	O
+of	O
+the	O
+sedation	O
+was	O
+96	O
+.	O
+7	O
+(	O
++	O
+/	O
+-	O
+2	O
+.	O
+4	O
+;	O
+range	O
+84	O
+to	O
+98	O
+)	O
+.	O
+
+The	O
+mean	O
+BIS	O
+score	O
+corresponding	O
+to	O
+the	O
+first	O
+word	O
+recalled	O
+after	O
+the	O
+procedure	O
+was	O
+completed	O
+was	O
+91	O
+.	O
+2	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+88	O
+.	O
+1	O
+to	O
+94	O
+.	O
+3	O
+)	O
+.	O
+
+All	O
+patients	O
+recalled	O
+at	O
+least	O
+one	O
+word	O
+that	O
+had	O
+been	O
+read	O
+to	O
+them	O
+during	O
+the	O
+protocol	O
+.	O
+
+The	O
+mean	O
+lowest	O
+BIS	O
+score	O
+for	O
+any	O
+recalled	O
+word	O
+was	O
+91	O
+.	O
+5	O
+(	O
++	O
+/	O
+-	O
+11	O
+.	O
+1	O
+;	O
+range	O
+79	O
+to	O
+98	O
+)	O
+,	O
+and	O
+no	O
+words	O
+were	O
+recalled	O
+when	O
+the	O
+corresponding	O
+BIS	O
+score	O
+was	O
+less	O
+than	O
+90	O
+.	O
+
+CONCLUSIONS	O
+:	O
+There	O
+is	O
+a	O
+range	O
+of	O
+BIS	O
+scores	O
+during	O
+which	O
+sedated	O
+patients	O
+are	O
+able	O
+to	O
+repeat	O
+words	O
+read	O
+to	O
+them	O
+but	O
+are	O
+not	O
+able	O
+to	O
+subsequently	O
+recall	O
+these	O
+words	O
+.	O
+
+Furthermore	O
+,	O
+patients	O
+had	O
+no	O
+recall	O
+of	O
+words	O
+repeated	O
+prior	O
+to	O
+procedural	O
+sedation	O
+in	O
+BIS	O
+ranges	O
+associated	O
+with	O
+recall	O
+after	O
+procedural	O
+sedation	O
+,	O
+suggestive	O
+of	O
+retrograde	B
+amnesia	I
+.	O
+
+Amiodarone	O
+pulmonary	B
+toxicity	I
+.	O
+
+Amiodarone	O
+is	O
+an	O
+effective	O
+antiarrhythmic	O
+agent	O
+whose	O
+utility	O
+is	O
+limited	O
+by	O
+many	O
+side	O
+-	O
+effects	O
+,	O
+the	O
+most	O
+problematic	O
+being	O
+pneumonitis	B
+.	O
+
+The	O
+pulmonary	B
+toxicity	I
+of	O
+amiodarone	O
+is	O
+thought	O
+to	O
+result	O
+from	O
+direct	O
+injury	O
+related	O
+to	O
+the	O
+intracellular	O
+accumulation	O
+of	O
+phospholipid	O
+and	O
+T	O
+cell	O
+-	O
+mediated	O
+hypersensitivity	B
+pneumonitis	I
+.	O
+
+The	O
+clinical	O
+and	O
+radiographic	O
+features	O
+of	O
+amiodarone	O
+-	O
+induced	O
+pulmonary	B
+toxicity	I
+are	O
+characteristic	O
+but	O
+nonspecific	O
+.	O
+
+The	O
+diagnosis	O
+depends	O
+on	O
+exclusion	O
+of	O
+other	O
+entities	O
+,	O
+such	O
+as	O
+heart	B
+failure	I
+,	O
+infection	B
+,	O
+and	O
+malignancy	B
+.	O
+
+While	O
+withdrawal	O
+of	O
+amiodarone	O
+leads	O
+to	O
+clinical	O
+improvement	O
+in	O
+majority	O
+of	O
+cases	O
+,	O
+this	O
+is	O
+not	O
+always	O
+possible	O
+or	O
+advisable	O
+.	O
+
+Dose	O
+reduction	O
+or	O
+concomitant	O
+steroid	O
+therapy	O
+may	O
+have	O
+a	O
+role	O
+in	O
+selected	O
+patients	O
+.	O
+
+Two	O
+prodrugs	O
+of	O
+potent	O
+and	O
+selective	O
+GluR5	O
+kainate	O
+receptor	O
+antagonists	O
+actives	O
+in	O
+three	O
+animal	O
+models	O
+of	O
+pain	B
+.	O
+
+Amino	O
+acids	O
+5	O
+and	O
+7	O
+,	O
+two	O
+potent	O
+and	O
+selective	O
+competitive	O
+GluR5	O
+KA	O
+receptor	O
+antagonists	O
+,	O
+exhibited	O
+high	O
+GluR5	O
+receptor	O
+affinity	O
+over	O
+other	O
+glutamate	O
+receptors	O
+.	O
+
+Their	O
+ester	O
+prodrugs	O
+6	O
+and	O
+8	O
+were	O
+orally	O
+active	O
+in	O
+three	O
+models	O
+of	O
+pain	B
+:	O
+reversal	O
+of	O
+formalin	O
+-	O
+induced	O
+paw	O
+licking	O
+,	O
+carrageenan	O
+-	O
+induced	O
+thermal	B
+hyperalgesia	I
+,	O
+and	O
+capsaicin	O
+-	O
+induced	O
+mechanical	B
+hyperalgesia	I
+.	O
+
+Possible	O
+azithromycin	O
+-	O
+associated	O
+hiccups	B
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+persistent	O
+hiccups	B
+associated	O
+by	O
+azithromycin	O
+therapy	O
+.	O
+
+CASE	O
+SUMMARY	O
+:	O
+A	O
+76	O
+-	O
+year	O
+-	O
+old	O
+man	O
+presented	O
+with	O
+persistent	O
+hiccups	B
+after	O
+beginning	O
+azithromycin	O
+for	O
+the	O
+treatment	O
+of	O
+pharyngitis	B
+.	O
+
+Hiccups	B
+were	O
+persistent	O
+and	O
+exhausting	O
+.	O
+
+Discontinuation	O
+of	O
+azithromycin	O
+and	O
+therapy	O
+with	O
+baclofen	O
+finally	O
+resolved	O
+hiccups	B
+.	O
+
+No	O
+organic	O
+cause	O
+of	O
+hiccups	B
+was	O
+identified	O
+despite	O
+extensive	O
+investigation	O
+.	O
+
+DISCUSSION	O
+:	O
+Pharmacotherapeutic	O
+agents	O
+have	O
+been	O
+uncommonly	O
+associated	O
+with	O
+hiccups	B
+.	O
+
+Corticosteroids	O
+(	O
+dexamethasone	O
+and	O
+methylprednisolone	O
+)	O
+,	O
+benzodiazepines	O
+(	O
+midazolam	O
+)	O
+and	O
+general	O
+anaesthesia	O
+have	O
+been	O
+the	O
+specific	O
+agents	O
+mentioned	O
+most	O
+frequently	O
+in	O
+the	O
+literature	O
+as	O
+being	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+hiccups	B
+.	O
+
+Few	O
+cases	O
+of	O
+drug	O
+-	O
+induced	O
+hiccups	B
+have	O
+been	O
+reported	O
+related	O
+to	O
+macrolide	O
+antimicrobials	O
+.	O
+
+Using	O
+the	O
+Naranjo	O
+adverse	O
+effect	O
+reaction	O
+probability	O
+scale	O
+this	O
+event	O
+could	O
+be	O
+classified	O
+as	O
+possible	O
+(	O
+score	O
+5	O
+points	O
+)	O
+,	O
+mostly	O
+because	O
+of	O
+the	O
+close	O
+temporal	O
+sequence	O
+,	O
+previous	O
+reports	O
+on	O
+this	O
+reaction	O
+with	O
+other	O
+macrolides	O
+and	O
+the	O
+absence	O
+of	O
+any	O
+alternative	O
+explanation	O
+for	O
+hiccups	B
+.	O
+
+Our	O
+hypothesis	O
+is	O
+that	O
+a	O
+vagal	O
+mechanism	O
+mediated	O
+by	O
+azithromycin	O
+could	O
+be	O
+the	O
+pathogenesis	O
+of	O
+hiccups	B
+in	O
+our	O
+patient	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Diagnosis	O
+of	O
+drug	O
+-	O
+induced	O
+hiccups	B
+is	O
+difficult	O
+and	O
+often	O
+achieved	O
+only	O
+by	O
+a	O
+process	O
+of	O
+elimination	O
+.	O
+
+However	O
+,	O
+macrolide	O
+antimicrobials	O
+have	O
+been	O
+reported	O
+to	O
+be	O
+associated	O
+with	O
+hiccups	B
+and	O
+vagal	O
+mechanism	O
+could	O
+explain	O
+the	O
+development	O
+of	O
+this	O
+side	O
+-	O
+effect	O
+.	O
+
+Calcium	O
+carbonate	O
+toxicity	B
+:	O
+the	O
+updated	O
+milk	B
+-	I
+alkali	I
+syndrome	I
+;	O
+report	O
+of	O
+3	O
+cases	O
+and	O
+review	O
+of	O
+the	O
+literature	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+describe	O
+3	O
+patients	O
+with	O
+calcium	O
+carbonate	O
+-	O
+induced	O
+hypercalcemia	B
+and	O
+gain	O
+insights	O
+into	O
+the	O
+cause	O
+and	O
+management	O
+of	O
+the	O
+milk	B
+-	I
+alkali	I
+syndrome	I
+.	O
+
+METHODS	O
+:	O
+We	O
+report	O
+the	O
+clinical	O
+and	O
+laboratory	O
+data	O
+in	O
+3	O
+patients	O
+who	O
+presented	O
+with	O
+severe	O
+hypercalcemia	B
+(	O
+corrected	O
+serum	O
+calcium	O
+>	O
+or	O
+=	O
+14	O
+mg	O
+/	O
+dL	O
+)	O
+and	O
+review	O
+the	O
+pertinent	O
+literature	O
+on	O
+milk	B
+-	I
+alkali	I
+syndrome	I
+.	O
+
+RESULTS	O
+:	O
+The	O
+3	O
+patients	O
+had	O
+acute	B
+renal	I
+insufficiency	I
+,	O
+relative	O
+metabolic	B
+alkalosis	I
+,	O
+and	O
+low	O
+parathyroid	O
+hormone	O
+(	O
+PTH	O
+)	O
+,	O
+PTH	O
+-	O
+related	O
+peptide	O
+,	O
+and	O
+1	O
+,	O
+25	O
+-	O
+dihydroxyvitamin	O
+D	O
+concentrations	O
+.	O
+
+No	O
+malignant	O
+lesion	O
+was	O
+found	O
+.	O
+
+Treatment	O
+included	O
+aggressive	O
+hydration	O
+and	O
+varied	O
+amounts	O
+of	O
+furosemide	O
+.	O
+
+The	O
+2	O
+patients	O
+with	O
+the	O
+higher	O
+serum	O
+calcium	O
+concentrations	O
+received	O
+pamidronate	O
+intravenously	O
+(	O
+60	O
+and	O
+30	O
+mg	O
+,	O
+respectively	O
+)	O
+,	O
+which	O
+caused	O
+severe	O
+hypocalcemia	B
+.	O
+
+Of	O
+the	O
+3	O
+patients	O
+,	O
+2	O
+were	O
+ingesting	O
+acceptable	O
+doses	O
+of	O
+elemental	O
+calcium	O
+(	O
+1	O
+g	O
+and	O
+2	O
+g	O
+daily	O
+,	O
+respectively	O
+)	O
+in	O
+the	O
+form	O
+of	O
+calcium	O
+carbonate	O
+.	O
+
+In	O
+addition	O
+to	O
+our	O
+highlighted	O
+cases	O
+,	O
+we	O
+review	O
+the	O
+history	O
+,	O
+classification	O
+,	O
+pathophysiologic	O
+features	O
+,	O
+and	O
+treatment	O
+of	O
+milk	B
+-	I
+alkali	I
+syndrome	I
+and	O
+summarize	O
+the	O
+cases	O
+reported	O
+from	O
+early	O
+1995	O
+to	O
+November	O
+2003	O
+.	O
+
+CONCLUSION	O
+:	O
+Milk	B
+-	I
+alkali	I
+syndrome	I
+may	O
+be	O
+a	O
+common	O
+cause	O
+of	O
+unexplained	O
+hypercalcemia	B
+and	O
+can	O
+be	O
+precipitated	O
+by	O
+small	O
+amounts	O
+of	O
+orally	O
+ingested	O
+calcium	O
+carbonate	O
+in	O
+susceptible	O
+persons	O
+.	O
+
+Treatment	O
+with	O
+hydration	O
+,	O
+furosemide	O
+,	O
+and	O
+discontinuation	O
+of	O
+the	O
+calcium	O
+and	O
+vitamin	O
+D	O
+source	O
+is	O
+adequate	O
+.	O
+
+Pamidronate	O
+treatment	O
+is	O
+associated	O
+with	O
+considerable	O
+risk	O
+for	O
+hypocalcemia	B
+,	O
+even	O
+in	O
+cases	O
+of	O
+initially	O
+severe	O
+hypercalcemia	B
+.	O
+
+Warfarin	O
+-	O
+induced	O
+leukocytoclastic	B
+vasculitis	I
+.	O
+
+Skin	O
+reactions	O
+associated	O
+with	O
+oral	O
+coumarin	O
+-	O
+derived	O
+anticoagulants	O
+are	O
+an	O
+uncommon	O
+occurrence	O
+.	O
+
+Leukocytoclastic	B
+vasculitis	I
+(	O
+LV	B
+)	O
+is	O
+primarily	O
+a	O
+cutaneous	B
+small	I
+vessel	I
+vasculitis	I
+,	O
+though	O
+systemic	O
+involvement	O
+may	O
+be	O
+encountered	O
+.	O
+
+We	O
+report	O
+4	O
+patients	O
+with	O
+late	O
+-	O
+onset	O
+LV	B
+probably	O
+due	O
+to	O
+warfarin	O
+.	O
+
+All	O
+4	O
+patients	O
+presented	O
+with	O
+skin	B
+eruptions	I
+that	O
+developed	O
+after	O
+receiving	O
+warfarin	O
+for	O
+several	O
+years	O
+.	O
+
+The	O
+results	O
+of	O
+skin	B
+lesion	I
+biopsies	O
+were	O
+available	O
+in	O
+3	O
+patients	O
+,	O
+confirming	O
+LV	B
+Cutaneous	I
+lesions	I
+resolved	O
+in	O
+all	O
+patients	O
+after	O
+warfarin	O
+was	O
+discontinued	O
+.	O
+
+In	O
+2	O
+of	O
+the	O
+4	O
+patients	O
+,	O
+rechallenge	O
+with	O
+warfarin	O
+led	O
+to	O
+recurrence	O
+of	O
+the	O
+lesions	O
+.	O
+
+LV	B
+may	O
+be	O
+a	O
+late	O
+-	O
+onset	O
+adverse	O
+reaction	O
+associated	O
+with	O
+warfarin	O
+therapy	O
+.	O
+
+Cocaine	O
+-	O
+induced	O
+brainstem	O
+seizures	B
+and	O
+behavior	O
+.	O
+
+A	O
+variety	O
+of	O
+abnormal	O
+sensory	O
+/	O
+motor	O
+behaviors	O
+associated	O
+with	O
+electrical	O
+discharges	O
+recorded	O
+from	O
+the	O
+bilateral	O
+brainstem	O
+were	O
+induced	O
+in	O
+adult	O
+WKY	O
+rats	O
+by	O
+mechanical	O
+(	O
+electrode	O
+implants	O
+)	O
+and	O
+DC	O
+electrical	O
+current	O
+stimulations	O
+and	O
+by	O
+acute	O
+and	O
+chronic	O
+administration	O
+of	O
+cocaine	O
+.	O
+
+The	O
+electrode	O
+implant	O
+implicated	O
+one	O
+side	O
+or	O
+the	O
+other	O
+of	O
+the	O
+reticular	O
+system	O
+of	O
+the	O
+brainstem	O
+but	O
+subjects	O
+were	O
+not	O
+incapacitated	O
+by	O
+the	O
+stimulations	O
+.	O
+
+Cocaine	O
+(	O
+40	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+injected	O
+subcutaneously	O
+for	O
+an	O
+acute	O
+experiment	O
+and	O
+subsequent	O
+20	O
+mg	O
+/	O
+kg	O
+doses	O
+twice	O
+daily	O
+for	O
+3	O
+days	O
+in	O
+a	O
+chronic	O
+study	O
+.	O
+
+Cocaine	O
+generated	O
+more	O
+abnormal	O
+behaviors	O
+in	O
+the	O
+brainstem	O
+perturbation	O
+group	O
+,	O
+especially	O
+the	O
+electrically	O
+perturbated	O
+subjects	O
+.	O
+
+The	O
+abnormal	O
+behaviors	O
+were	O
+yawning	O
+,	O
+retrocollis	O
+,	O
+hyperactivity	B
+,	O
+hypersensitivity	B
+,	O
+"	O
+beating	O
+drum	O
+"	O
+behavior	O
+,	O
+squealing	O
+,	O
+head	O
+bobbing	O
+,	O
+circling	O
+,	O
+sniffing	O
+,	O
+abnormal	O
+posturing	O
+,	O
+and	O
+facial	O
+twitching	O
+.	O
+
+Shifts	O
+in	O
+the	O
+power	O
+frequency	O
+spectra	O
+of	O
+the	O
+discharge	O
+patterns	O
+were	O
+noted	O
+between	O
+quiet	O
+and	O
+pacing	O
+behavioral	O
+states	O
+.	O
+
+Hypersensitivity	B
+to	O
+various	O
+auditory	O
+,	O
+tactile	O
+,	O
+and	O
+visual	O
+stimulation	O
+was	O
+present	O
+and	O
+shifts	O
+in	O
+the	O
+brainstem	O
+ambient	O
+power	O
+spectral	O
+frequency	O
+occurred	O
+in	O
+response	O
+to	O
+tactile	O
+stimulation	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+the	O
+brainstem	O
+generates	O
+and	O
+propagates	O
+pathological	O
+discharges	O
+that	O
+can	O
+be	O
+elicited	O
+by	O
+mechanical	O
+and	O
+DC	O
+electrical	O
+perturbation	O
+.	O
+
+Cocaine	O
+was	O
+found	O
+to	O
+activate	O
+the	O
+discharge	O
+system	O
+and	O
+thus	O
+induce	O
+abnormal	O
+behaviors	O
+that	O
+are	O
+generated	O
+at	O
+the	O
+discharge	O
+site	O
+and	O
+at	O
+distant	O
+sites	O
+to	O
+which	O
+the	O
+discharge	O
+propagates	O
+.	O
+
+Cognitive	O
+functions	O
+may	O
+also	O
+be	O
+involved	O
+since	O
+dopaminergic	O
+and	O
+serotonergic	O
+cellular	O
+elements	O
+at	O
+the	O
+brainstem	O
+level	O
+are	O
+also	O
+implicated	O
+.	O
+
+rTMS	O
+of	O
+supplementary	O
+motor	O
+area	O
+modulates	O
+therapy	O
+-	O
+induced	O
+dyskinesias	B
+in	O
+Parkinson	B
+disease	I
+.	O
+
+The	O
+neural	O
+mechanisms	O
+and	O
+circuitry	O
+involved	O
+in	O
+levodopa	O
+-	O
+induced	O
+dyskinesia	B
+are	O
+unclear	O
+.	O
+
+Using	O
+repetitive	O
+transcranial	O
+magnetic	O
+stimulation	O
+(	O
+rTMS	O
+)	O
+over	O
+the	O
+supplementary	O
+motor	O
+area	O
+(	O
+SMA	O
+)	O
+in	O
+a	O
+group	O
+of	O
+patients	O
+with	O
+advanced	O
+Parkinson	B
+disease	I
+,	O
+the	O
+authors	O
+investigated	O
+whether	O
+modulation	O
+of	O
+SMA	O
+excitability	O
+may	O
+result	O
+in	O
+a	O
+modification	O
+of	O
+a	O
+dyskinetic	B
+state	O
+induced	O
+by	O
+continuous	O
+apomorphine	O
+infusion	O
+.	O
+
+rTMS	O
+at	O
+1	O
+Hz	O
+was	O
+observed	O
+to	O
+markedly	O
+reduce	O
+drug	B
+-	I
+induced	I
+dyskinesias	I
+,	O
+whereas	O
+5	O
+-	O
+Hz	O
+rTMS	O
+induced	O
+a	O
+slight	O
+but	O
+not	O
+significant	O
+increase	O
+.	O
+
+Intracavitary	O
+chemotherapy	O
+(	O
+paclitaxel	O
+/	O
+carboplatin	O
+liquid	O
+crystalline	O
+cubic	O
+phases	O
+)	O
+for	O
+recurrent	O
+glioblastoma	B
+-	O
+-	O
+clinical	O
+observations	O
+.	O
+
+Human	O
+malignant	O
+brain	B
+tumors	I
+have	O
+a	O
+poor	O
+prognosis	O
+in	O
+spite	O
+of	O
+surgery	O
+and	O
+radiation	O
+therapy	O
+.	O
+
+Cubic	O
+phases	O
+consist	O
+of	O
+curved	O
+biocontinuous	O
+lipid	O
+bilayers	O
+,	O
+separating	O
+two	O
+congruent	O
+networks	O
+of	O
+water	O
+channels	O
+.	O
+
+Used	O
+as	O
+a	O
+host	O
+for	O
+cytotoxic	O
+drugs	O
+,	O
+the	O
+gel	O
+-	O
+like	O
+matrix	O
+can	O
+easily	O
+be	O
+applied	O
+to	O
+the	O
+walls	O
+of	O
+a	O
+surgical	O
+resection	O
+cavity	O
+.	O
+
+For	O
+human	O
+glioblastoma	B
+recurrences	O
+,	O
+the	O
+feasibility	O
+,	O
+safety	O
+,	O
+and	O
+short	O
+-	O
+term	O
+effects	O
+of	O
+a	O
+surgical	O
+intracavitary	O
+application	O
+of	O
+paclitaxel	O
+and	O
+carboplatin	O
+encapsulated	O
+by	O
+liquid	O
+crystalline	O
+cubic	O
+phases	O
+are	O
+examined	O
+in	O
+a	O
+pilot	O
+study	O
+.	O
+
+A	O
+total	O
+of	O
+12	O
+patients	O
+with	O
+a	O
+recurrence	O
+of	O
+a	O
+glioblastoma	B
+multiforme	O
+underwent	O
+re	O
+-	O
+resection	O
+and	O
+received	O
+an	O
+intracavitary	O
+application	O
+of	O
+paclitaxel	O
+and	O
+carboplatin	O
+cubic	O
+phases	O
+in	O
+different	O
+dosages	O
+.	O
+
+Six	O
+of	O
+the	O
+patients	O
+received	O
+more	O
+than	O
+15	O
+mg	O
+paclitaxel	O
+and	O
+suffered	O
+from	O
+moderate	O
+to	O
+severe	O
+brain	B
+edema	I
+,	O
+while	O
+the	O
+remaining	O
+patients	O
+received	O
+only	O
+a	O
+total	O
+of	O
+15	O
+mg	O
+paclitaxel	O
+.	O
+
+In	O
+the	O
+latter	O
+group	O
+,	O
+brain	B
+edema	I
+was	O
+markedly	O
+reduced	O
+and	O
+dealt	O
+medically	O
+.	O
+
+Intracavitary	O
+chemotherapy	O
+in	O
+recurrent	O
+glioblastoma	B
+using	O
+cubic	O
+phases	O
+is	O
+feasible	O
+and	O
+safe	O
+,	O
+yet	O
+the	O
+clinical	O
+benefit	O
+remains	O
+to	O
+be	O
+examined	O
+in	O
+a	O
+clinical	O
+phase	O
+II	O
+study	O
+.	O
+
+Lamotrigine	O
+associated	O
+with	O
+exacerbation	O
+or	O
+de	O
+novo	O
+myoclonus	B
+in	O
+idiopathic	B
+generalized	I
+epilepsies	I
+.	O
+
+Five	O
+patients	O
+with	O
+idiopathic	B
+generalized	I
+epilepsies	I
+(	O
+IGE	B
+)	O
+treated	O
+with	O
+lamotrigine	O
+(	O
+LTG	O
+)	O
+experienced	O
+exacerbation	O
+or	O
+de	O
+novo	O
+appearance	O
+of	O
+myoclonic	B
+jerks	I
+(	O
+MJ	B
+)	O
+.	O
+
+In	O
+three	O
+patients	O
+,	O
+LTG	O
+exacerbated	O
+MJ	B
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+with	O
+early	O
+aggravation	O
+during	O
+titration	O
+.	O
+
+MJ	B
+disappeared	O
+when	O
+LTG	O
+dose	O
+was	O
+decreased	O
+by	O
+25	O
+to	O
+50	O
+%	O
+.	O
+
+In	O
+two	O
+patients	O
+,	O
+LTG	O
+exacerbated	O
+MJ	B
+in	O
+a	O
+delayed	O
+but	O
+more	O
+severe	O
+manner	O
+,	O
+with	O
+myoclonic	B
+status	I
+that	O
+only	O
+ceased	O
+after	O
+LTG	O
+withdrawal	O
+.	O
+
+Absence	O
+of	O
+acute	O
+cerebral	O
+vasoconstriction	O
+after	O
+cocaine	O
+-	O
+associated	O
+subarachnoid	B
+hemorrhage	I
+.	O
+
+INTRODUCTION	O
+:	O
+Cocaine	O
+use	O
+has	O
+been	O
+associated	O
+with	O
+neurovascular	B
+complications	I
+,	O
+including	O
+arterial	O
+vasoconstriction	O
+and	O
+vasculitis	B
+.	O
+
+However	O
+,	O
+there	O
+are	O
+few	O
+studies	O
+of	O
+angiographic	O
+effects	O
+of	O
+cocaine	O
+on	O
+human	O
+cerebral	O
+arteries	O
+.	O
+
+Information	O
+on	O
+these	O
+effects	O
+could	O
+be	O
+obtained	O
+from	O
+angiograms	O
+of	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+subarachnoid	B
+hemorrhage	I
+(	O
+SAH	B
+)	O
+who	O
+underwent	O
+angiography	O
+shortly	O
+after	O
+cocaine	O
+use	O
+.	O
+
+METHODS	O
+:	O
+We	O
+screened	O
+patients	O
+with	O
+SAH	B
+retrospectively	O
+and	O
+identified	O
+those	O
+with	O
+positive	O
+urine	O
+toxicology	O
+for	O
+cocaine	O
+or	O
+its	O
+metabolites	O
+.	O
+
+Quantitative	O
+arterial	O
+diameter	O
+measurements	O
+from	O
+angiograms	O
+of	O
+these	O
+patients	O
+were	O
+compared	O
+to	O
+measurements	O
+from	O
+control	O
+patients	O
+with	O
+SAH	B
+who	O
+were	O
+matched	O
+for	O
+factors	O
+known	O
+to	O
+influence	O
+arterial	O
+diameter	O
+.	O
+
+Qualitative	O
+comparisons	O
+of	O
+small	O
+artery	O
+changes	O
+also	O
+were	O
+made	O
+.	O
+
+RESULTS	O
+:	O
+Thirteen	O
+patients	O
+with	O
+positive	O
+cocaine	O
+toxicology	O
+were	O
+compared	O
+to	O
+26	O
+controls	O
+.	O
+
+There	O
+were	O
+no	O
+significant	O
+differences	O
+between	O
+groups	O
+in	O
+the	O
+mean	O
+diameters	O
+of	O
+the	O
+intradural	O
+internal	O
+carotid	O
+,	O
+sphenoidal	O
+segment	O
+of	O
+the	O
+middle	O
+cerebral	O
+,	O
+precommunicating	O
+segment	O
+of	O
+the	O
+anterior	O
+cerebral	O
+,	O
+or	O
+basilar	O
+arteries	O
+(	O
+p	O
+greater	O
+than	O
+0	O
+.	O
+05	O
+for	O
+all	O
+comparisons	O
+,	O
+unpaired	O
+t	O
+-	O
+tests	O
+)	O
+.	O
+
+There	O
+also	O
+were	O
+no	O
+significant	O
+differences	O
+between	O
+groups	O
+when	O
+expressing	O
+diameters	O
+as	O
+the	O
+sum	O
+of	O
+the	O
+precommunicating	O
+segment	O
+of	O
+the	O
+anterior	O
+cerebral	O
++	O
+sphenoidal	O
+segment	O
+of	O
+the	O
+middle	O
+cerebral	O
++	O
+supraclinoid	O
+internal	O
+carotid	O
+artery	O
++	O
+basilar	O
+artery	O
+divided	O
+by	O
+the	O
+diameter	O
+of	O
+the	O
+petrous	O
+internal	O
+carotid	O
+artery	O
+(	O
+p	O
+greater	O
+than	O
+0	O
+.	O
+05	O
+,	O
+unpaired	O
+t	O
+-	O
+tests	O
+)	O
+.	O
+
+Qualitative	O
+assessments	O
+showed	O
+two	O
+arterial	O
+irregularities	O
+in	O
+the	O
+distal	O
+vasculature	O
+in	O
+each	O
+group	O
+.	O
+
+CONCLUSION	O
+:	O
+No	O
+quantitative	O
+evidence	O
+for	O
+narrowing	O
+of	O
+large	O
+cerebral	O
+arteries	O
+or	O
+qualitative	O
+angiographic	O
+evidence	O
+for	O
+distal	O
+narrowing	O
+or	O
+vasculitis	B
+could	O
+be	O
+found	O
+in	O
+patients	O
+who	O
+underwent	O
+angiography	O
+after	O
+aneurysmal	B
+SAH	B
+associated	O
+with	O
+cocaine	O
+use	O
+.	O
+
+Methamphetamine	O
+causes	O
+alterations	O
+in	O
+the	O
+MAP	O
+kinase	O
+-	O
+related	O
+pathways	O
+in	O
+the	O
+brains	O
+of	O
+mice	O
+that	O
+display	O
+increased	O
+aggressiveness	B
+.	O
+
+Aggressive	B
+behaviors	I
+have	O
+been	O
+reported	O
+in	O
+patients	O
+who	O
+suffer	O
+from	O
+some	O
+psychiatric	B
+disorders	I
+,	O
+and	O
+are	O
+common	O
+in	O
+methamphetamine	O
+(	O
+METH	O
+)	O
+abusers	O
+.	O
+
+Herein	O
+,	O
+we	O
+report	O
+that	O
+multiple	O
+(	O
+but	O
+not	O
+single	O
+)	O
+injections	O
+of	O
+METH	O
+significantly	O
+increased	O
+aggressiveness	B
+in	O
+male	O
+CD	O
+-	O
+1	O
+mice	O
+.	O
+
+This	O
+increase	O
+in	O
+aggressiveness	B
+was	O
+not	O
+secondary	O
+to	O
+METH	O
+-	O
+induced	O
+hyperactivity	B
+.	O
+
+Analysis	O
+of	O
+protein	O
+expression	O
+using	O
+antibody	O
+microarrays	O
+and	O
+Western	O
+blotting	O
+revealed	O
+differential	O
+changes	O
+in	O
+MAP	O
+kinase	O
+-	O
+related	O
+pathways	O
+after	O
+multiple	O
+and	O
+single	O
+METH	O
+injections	O
+.	O
+
+There	O
+were	O
+statistically	O
+significant	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+decreases	O
+in	O
+MEK1	O
+,	O
+Erk2p	O
+,	O
+GSK3alpha	O
+,	O
+14	O
+-	O
+3	O
+-	O
+3e	O
+,	O
+and	O
+MEK7	O
+in	O
+the	O
+striata	O
+of	O
+mice	O
+after	O
+multiple	O
+injections	O
+of	O
+METH	O
+.	O
+
+MEK1	O
+was	O
+significantly	O
+decreased	O
+also	O
+after	O
+a	O
+single	O
+injection	O
+of	O
+METH	O
+,	O
+but	O
+to	O
+a	O
+much	O
+lesser	O
+degree	O
+than	O
+after	O
+multiple	O
+injections	O
+of	O
+METH	O
+.	O
+
+In	O
+the	O
+frontal	O
+cortex	O
+,	O
+there	O
+was	O
+a	O
+statistically	O
+significant	O
+decrease	O
+in	O
+GSK3alpha	O
+after	O
+multiple	O
+(	O
+but	O
+not	O
+single	O
+)	O
+injections	O
+of	O
+METH	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+alterations	O
+in	O
+MAP	O
+kinase	O
+-	O
+related	O
+pathways	O
+in	O
+the	O
+prefronto	O
+-	O
+striatal	O
+circuitries	O
+might	O
+be	O
+involved	O
+in	O
+the	O
+manifestation	O
+of	O
+aggressive	B
+behaviors	I
+in	O
+mice	O
+.	O
+
+Amisulpride	O
+related	O
+tic	B
+-	I
+like	I
+symptoms	I
+in	O
+an	O
+adolescent	O
+schizophrenic	B
+.	O
+
+Tic	B
+disorders	I
+can	O
+be	O
+effectively	O
+treated	O
+by	O
+atypical	O
+antipsychotics	O
+such	O
+as	O
+risperidone	O
+,	O
+olanzapine	O
+and	O
+ziprasidone	O
+.	O
+
+However	O
+,	O
+there	O
+are	O
+two	O
+case	O
+reports	O
+that	O
+show	O
+tic	B
+-	I
+like	I
+symptoms	I
+,	O
+including	O
+motor	O
+and	O
+phonic	O
+variants	O
+,	O
+occurring	O
+during	O
+treatment	O
+with	O
+quetiapine	O
+or	O
+clozapine	O
+.	O
+
+We	O
+present	O
+a	O
+15	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+schizophrenic	B
+who	O
+developed	O
+frequent	O
+involuntary	B
+eye	I
+-	I
+blinking	I
+movements	I
+after	O
+5	O
+months	O
+of	O
+amisulpride	O
+treatment	O
+(	O
+1000	O
+mg	O
+per	O
+day	O
+)	O
+.	O
+
+The	O
+tic	B
+-	I
+like	I
+symptoms	I
+resolved	O
+completely	O
+after	O
+we	O
+reduced	O
+the	O
+dose	O
+of	O
+amisulpride	O
+down	O
+to	O
+800	O
+mg	O
+per	O
+day	O
+.	O
+
+However	O
+,	O
+her	O
+psychosis	B
+recurred	O
+after	O
+the	O
+dose	O
+reduction	O
+.	O
+
+We	O
+then	O
+placed	O
+her	O
+on	O
+an	O
+additional	O
+100	O
+mg	O
+per	O
+day	O
+of	O
+quetiapine	O
+.	O
+
+She	O
+has	O
+been	O
+in	O
+complete	O
+remission	O
+under	O
+the	O
+combined	O
+medications	O
+for	O
+more	O
+than	O
+one	O
+year	O
+and	O
+maintains	O
+a	O
+fair	O
+role	O
+function	O
+.	O
+
+No	O
+more	O
+tic	B
+-	I
+like	I
+symptoms	I
+or	O
+other	O
+side	O
+effects	O
+have	O
+been	O
+reported	O
+.	O
+
+Together	O
+with	O
+previously	O
+reported	O
+cases	O
+,	O
+our	O
+patient	O
+suggests	O
+that	O
+tic	B
+-	I
+like	I
+symptoms	I
+might	O
+occur	O
+in	O
+certain	O
+vulnerable	O
+individuals	O
+during	O
+treatment	O
+with	O
+atypical	O
+antipsychotics	O
+such	O
+as	O
+quetiapine	O
+,	O
+clozapine	O
+,	O
+or	O
+amisulpride	O
+.	O
+
+Chloroquine	O
+related	O
+complete	O
+heart	B
+block	I
+with	O
+blindness	B
+:	O
+case	O
+report	O
+.	O
+
+A	O
+27	O
+-	O
+year	O
+old	O
+African	O
+woman	O
+with	O
+history	O
+of	O
+regular	O
+chloroquine	O
+ingestion	O
+presented	O
+with	O
+progressive	O
+deterioration	B
+of	I
+vision	I
+,	O
+easy	O
+fatiguability	B
+,	O
+dyspnoea	B
+,	O
+dizziness	B
+progressing	O
+to	O
+syncopal	B
+attacks	I
+.	O
+
+Ophthalmological	O
+assessment	O
+revealed	O
+features	O
+of	O
+chloroquine	O
+retinopathy	B
+,	O
+cardiac	O
+assessment	O
+revealed	O
+features	O
+of	O
+heart	B
+failure	I
+and	O
+a	O
+complete	O
+heart	B
+block	I
+with	O
+right	B
+bundle	I
+branch	I
+block	I
+pattern	O
+.	O
+
+The	O
+heart	B
+block	I
+was	O
+treated	O
+by	O
+pacemaker	O
+insertion	O
+and	O
+the	O
+heart	B
+failure	I
+resolved	O
+spontaneously	O
+following	O
+chloroquine	O
+discontinuation	O
+.	O
+
+She	O
+however	O
+remains	O
+blind	B
+.	O
+
+Effects	O
+of	O
+suprofen	O
+on	O
+the	O
+isolated	O
+perfused	O
+rat	O
+kidney	O
+.	O
+
+Although	O
+suprofen	O
+has	O
+been	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+acute	B
+renal	I
+failure	I
+in	O
+greater	O
+than	O
+100	O
+subjects	O
+,	O
+the	O
+mechanism	O
+of	O
+damage	O
+remains	O
+unclear	O
+.	O
+
+The	O
+direct	O
+nephrotoxic	B
+effects	O
+of	O
+a	O
+single	O
+dose	O
+of	O
+15	O
+mg	O
+of	O
+suprofen	O
+were	O
+compared	O
+in	O
+the	O
+recirculating	O
+isolated	O
+rat	O
+kidney	O
+perfused	O
+with	O
+cell	O
+-	O
+free	O
+buffer	O
+with	O
+or	O
+without	O
+the	O
+addition	O
+of	O
+5	O
+mg	O
+/	O
+dL	O
+of	O
+uric	O
+acid	O
+.	O
+
+There	O
+were	O
+no	O
+significant	O
+differences	O
+in	O
+renal	O
+sodium	O
+excretion	O
+,	O
+oxygen	O
+consumption	O
+,	O
+or	O
+urinary	O
+flow	O
+rates	O
+in	O
+kidneys	O
+perfused	O
+with	O
+suprofen	O
+compared	O
+with	O
+the	O
+drug	O
+-	O
+free	O
+control	O
+groups	O
+.	O
+
+In	O
+contrast	O
+,	O
+a	O
+significant	O
+decline	O
+in	O
+glomerular	O
+filtration	O
+rate	O
+was	O
+found	O
+after	O
+the	O
+introduction	O
+of	O
+suprofen	O
+to	O
+the	O
+kidney	O
+perfused	O
+with	O
+uric	O
+acid	O
+;	O
+no	O
+changes	O
+were	O
+found	O
+with	O
+suprofen	O
+in	O
+the	O
+absence	O
+of	O
+uric	O
+acid	O
+.	O
+
+A	O
+significant	O
+decrease	O
+in	O
+the	O
+baseline	O
+excretion	O
+rate	O
+of	O
+uric	O
+acid	O
+was	O
+found	O
+in	O
+rats	O
+given	O
+suprofen	O
+,	O
+compared	O
+with	O
+drug	O
+-	O
+free	O
+controls	O
+.	O
+
+However	O
+,	O
+the	O
+fractional	O
+excretion	O
+of	O
+uric	O
+acid	O
+was	O
+unchanged	O
+between	O
+the	O
+groups	O
+over	O
+the	O
+experimental	O
+period	O
+.	O
+
+In	O
+summary	O
+,	O
+suprofen	O
+causes	O
+acute	B
+declines	I
+in	I
+renal	I
+function	I
+,	O
+most	O
+likely	O
+by	O
+directly	O
+altering	O
+the	O
+intrarenal	O
+distribution	O
+of	O
+uric	O
+acid	O
+.	O
+
+Microinjection	O
+of	O
+ritanserin	O
+into	O
+the	O
+CA1	O
+region	O
+of	O
+hippocampus	O
+improves	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+in	O
+adult	O
+male	O
+rats	O
+.	O
+
+The	O
+effect	O
+of	O
+ritanserin	O
+(	O
+5	O
+-	O
+HT2	O
+antagonist	O
+)	O
+on	O
+scopolamine	O
+(	O
+muscarinic	O
+cholinergic	O
+antagonist	O
+)	O
+-	O
+induced	O
+amnesia	B
+in	O
+Morris	O
+water	O
+maze	O
+(	O
+MWM	O
+)	O
+was	O
+investigated	O
+.	O
+
+Rats	O
+were	O
+divided	O
+into	O
+eight	O
+groups	O
+and	O
+bilaterally	O
+cannulated	O
+into	O
+CA1	O
+region	O
+of	O
+the	O
+hippocampus	O
+.	O
+
+One	O
+week	O
+later	O
+,	O
+they	O
+received	O
+repeatedly	O
+vehicles	O
+(	O
+saline	O
+,	O
+DMSO	O
+,	O
+saline	O
++	O
+DMSO	O
+)	O
+,	O
+scopolamine	O
+(	O
+2	O
+microg	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+saline	O
+/	O
+side	O
+;	O
+30	O
+min	O
+before	O
+training	O
+)	O
+,	O
+ritanserin	O
+(	O
+2	O
+,	O
+4	O
+and	O
+8	O
+microg	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+DMSO	O
+/	O
+side	O
+;	O
+20	O
+min	O
+before	O
+training	O
+)	O
+and	O
+scopolamine	O
+(	O
+2	O
+microg	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+;	O
+30	O
+min	O
+before	O
+ritanserin	O
+injection	O
+)	O
++	O
+ritanserin	O
+(	O
+4	O
+microg	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+DMSO	O
+)	O
+through	O
+cannulae	O
+each	O
+day	O
+.	O
+
+Animals	O
+were	O
+tested	O
+for	O
+four	O
+consecutive	O
+days	O
+(	O
+4	O
+trial	O
+/	O
+day	O
+)	O
+in	O
+MWM	O
+during	O
+which	O
+the	O
+position	O
+of	O
+hidden	O
+platform	O
+was	O
+unchanged	O
+.	O
+
+In	O
+the	O
+fifth	O
+day	O
+,	O
+the	O
+platform	O
+was	O
+elevated	O
+above	O
+the	O
+water	O
+surface	O
+in	O
+another	O
+position	O
+to	O
+evaluate	O
+the	O
+function	O
+of	O
+motor	O
+,	O
+motivational	O
+and	O
+visual	O
+systems	O
+.	O
+
+The	O
+results	O
+showed	O
+a	O
+significant	O
+increase	O
+in	O
+escape	O
+latencies	O
+and	O
+traveled	O
+distances	O
+to	O
+find	O
+platform	O
+in	O
+scopolamine	O
+-	O
+treated	O
+group	O
+as	O
+compared	O
+to	O
+saline	O
+group	O
+.	O
+
+Ritanserin	O
+-	O
+treated	O
+rats	O
+(	O
+4	O
+microg	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+/	O
+side	O
+)	O
+showed	O
+a	O
+significant	O
+decrease	O
+in	O
+the	O
+mentioned	O
+parameters	O
+as	O
+compared	O
+to	O
+DMSO	O
+-	O
+treated	O
+group	O
+.	O
+
+However	O
+,	O
+scopolamine	O
+and	O
+ritanserin	O
+co	O
+-	O
+administration	O
+resulted	O
+in	O
+a	O
+significant	O
+decrease	O
+in	O
+escape	O
+latencies	O
+and	O
+traveled	O
+distances	O
+as	O
+compared	O
+to	O
+the	O
+scopolamine	O
+-	O
+treated	O
+rats	O
+.	O
+
+Our	O
+findings	O
+show	O
+that	O
+microinjection	O
+of	O
+ritanserin	O
+into	O
+the	O
+CA1	O
+region	O
+of	O
+the	O
+hippocampus	O
+improves	O
+the	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+.	O
+
+PTU	O
+-	O
+associated	O
+vasculitis	B
+in	O
+a	O
+girl	O
+with	O
+Turner	B
+Syndrome	I
+and	O
+Graves	B
+'	I
+disease	I
+.	O
+
+Palpable	O
+purpura	B
+is	O
+a	O
+concerning	O
+clinical	O
+finding	O
+in	O
+pediatric	O
+patients	O
+and	O
+can	O
+have	O
+many	O
+causes	O
+,	O
+including	O
+infectious	O
+and	O
+autoimmune	O
+processes	O
+.	O
+
+A	O
+rare	O
+cause	O
+,	O
+drug	O
+-	O
+induced	O
+vasculitis	B
+,	O
+may	O
+result	O
+from	O
+the	O
+production	O
+of	O
+antineutrophil	O
+cytoplasmic	O
+antibodies	O
+(	O
+ANCAs	O
+)	O
+in	O
+response	O
+to	O
+a	O
+medication	O
+.	O
+
+We	O
+report	O
+a	O
+girl	O
+with	O
+Turner	B
+syndrome	I
+and	O
+Graves	B
+'	I
+disease	I
+who	O
+presented	O
+with	O
+palpable	O
+purpuric	B
+lesions	I
+.	O
+
+The	O
+diagnosis	O
+of	O
+propylthiouracil	O
+(	O
+PTU	O
+)	O
+-	O
+associated	O
+vasculitis	B
+was	O
+made	O
+by	O
+observation	O
+of	O
+consistent	O
+clinical	O
+features	O
+,	O
+the	O
+detection	O
+of	O
+elevated	O
+ANA	O
+and	O
+ANCA	O
+in	O
+the	O
+blood	O
+,	O
+and	O
+the	O
+observed	O
+clinical	O
+resolution	O
+of	O
+symptoms	O
+following	O
+withdrawal	O
+of	O
+PTU	O
+.	O
+
+Subsequent	O
+treatment	O
+of	O
+persistent	O
+hyperthyroidism	B
+with	O
+radioablation	O
+did	O
+not	O
+result	O
+in	O
+an	O
+exacerbation	O
+of	O
+the	O
+vasculitis	B
+,	O
+a	O
+complication	O
+described	O
+in	O
+prior	O
+case	O
+reports	O
+.	O
+
+Daidzein	O
+activates	O
+choline	O
+acetyltransferase	O
+from	O
+MC	O
+-	O
+IXC	O
+cells	O
+and	O
+improves	O
+drug	O
+-	O
+induced	O
+amnesia	B
+.	O
+
+The	O
+choline	O
+acetyltransferase	O
+(	O
+ChAT	O
+)	O
+activator	O
+,	O
+which	O
+enhances	O
+cholinergic	O
+transmission	O
+via	O
+an	O
+augmentation	O
+of	O
+the	O
+enzymatic	O
+production	O
+of	O
+acetylcholine	O
+(	O
+ACh	O
+)	O
+,	O
+is	O
+an	O
+important	O
+factor	O
+in	O
+the	O
+treatment	O
+of	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+(	O
+AD	B
+)	O
+.	O
+
+Methanolic	O
+extracts	O
+from	O
+Pueraria	O
+thunbergiana	O
+exhibited	O
+an	O
+activation	O
+effect	O
+(	O
+46	O
+%	O
+)	O
+on	O
+ChAT	O
+in	O
+vitro	O
+.	O
+
+Via	O
+the	O
+sequential	O
+isolation	O
+of	O
+Pueraria	O
+thunbergiana	O
+,	O
+the	O
+active	O
+component	O
+was	O
+ultimately	O
+identified	O
+as	O
+daidzein	O
+(	O
+4	O
+'	O
+,	O
+7	O
+-	O
+dihydroxy	O
+-	O
+isoflavone	O
+)	O
+.	O
+
+In	O
+order	O
+to	O
+investigate	O
+the	O
+effects	O
+of	O
+daidzein	O
+from	O
+Pueraria	O
+thunbergiana	O
+on	O
+scopolamine	O
+-	O
+induced	O
+impairments	B
+of	I
+learning	I
+and	I
+memory	I
+,	O
+we	O
+conducted	O
+a	O
+series	O
+of	O
+in	O
+vivo	O
+tests	O
+.	O
+
+Administration	O
+of	O
+daidzein	O
+(	O
+4	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+)	O
+to	O
+mice	O
+was	O
+shown	O
+significantly	O
+to	O
+reverse	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+,	O
+according	O
+to	O
+the	O
+results	O
+of	O
+a	O
+Y	O
+-	O
+maze	O
+test	O
+.	O
+
+Injections	O
+of	O
+scopolamine	O
+into	O
+mice	O
+resulted	O
+in	O
+impaired	O
+performance	O
+on	O
+Y	O
+-	O
+maze	O
+tests	O
+(	O
+a	O
+37	O
+%	O
+decreases	O
+in	O
+alternation	O
+behavior	O
+)	O
+.	O
+
+By	O
+way	O
+of	O
+contrast	O
+,	O
+mice	O
+treated	O
+with	O
+daidzein	O
+prior	O
+to	O
+the	O
+scopolamine	O
+injections	O
+were	O
+noticeably	O
+protected	O
+from	O
+this	O
+performance	O
+impairment	O
+(	O
+an	O
+approximately	O
+12	O
+%	O
+-	O
+21	O
+%	O
+decrease	O
+in	O
+alternation	O
+behavior	O
+)	O
+.	O
+
+These	O
+results	O
+indicate	O
+that	O
+daidzein	O
+might	O
+play	O
+a	O
+role	O
+in	O
+acetylcholine	O
+biosynthesis	O
+as	O
+a	O
+ChAT	O
+activator	O
+,	O
+and	O
+that	O
+it	O
+also	O
+ameliorates	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+.	O
+
+Urinary	O
+symptoms	O
+and	O
+quality	O
+of	O
+life	O
+changes	O
+in	O
+Thai	O
+women	O
+with	O
+overactive	B
+bladder	I
+after	O
+tolterodine	O
+treatment	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+study	O
+the	O
+urinary	O
+symptoms	O
+and	O
+quality	O
+of	O
+life	O
+changes	O
+in	O
+Thai	O
+women	O
+with	O
+overactive	B
+bladder	I
+(	O
+OAB	B
+)	O
+after	O
+tolterodine	O
+treatment	O
+.	O
+
+MATERIAL	O
+AND	O
+METHOD	O
+:	O
+Thirty	O
+women	O
+(	O
+aged	O
+30	O
+-	O
+77	O
+years	O
+)	O
+diagnosed	O
+as	O
+having	O
+OAB	B
+at	O
+the	O
+Gynecology	O
+Clinic	O
+,	O
+King	O
+Chulalongkorn	O
+Memorial	O
+Hospital	O
+from	O
+January	O
+to	O
+April	O
+2004	O
+were	O
+included	O
+in	O
+the	O
+present	O
+study	O
+.	O
+
+Tolterodine	O
+2	O
+mg	O
+,	O
+twice	O
+daily	O
+was	O
+given	O
+.	O
+
+After	O
+8	O
+weeks	O
+treatment	O
+,	O
+changes	O
+in	O
+micturition	O
+diary	O
+variables	O
+and	O
+tolerability	O
+were	O
+determined	O
+.	O
+
+Short	O
+form	O
+36	O
+(	O
+SF36	O
+)	O
+questionaires	O
+(	O
+Thai	O
+version	O
+)	O
+were	O
+given	O
+before	O
+and	O
+after	O
+8	O
+weeks	O
+of	O
+treatment	O
+.	O
+
+RESULTS	O
+:	O
+At	O
+8	O
+weeks	O
+,	O
+all	O
+micturition	O
+per	O
+day	O
+decreased	O
+from	O
+16	O
+.	O
+
+7	O
++	O
+/	O
+-	O
+5	O
+.	O
+
+3	O
+to	O
+6	O
+.	O
+
+7	O
++	O
+/	O
+-	O
+2	O
+.	O
+4	O
+times	O
+per	O
+day	O
+.	O
+
+The	O
+number	O
+of	O
+nocturia	B
+episodes	O
+decreased	O
+from	O
+5	O
+.	O
+4	O
++	O
+/	O
+-	O
+4	O
+.	O
+2	O
+to	O
+1	O
+.	O
+1	O
++	O
+/	O
+-	O
+1	O
+.	O
+0	O
+times	O
+per	O
+night	O
+.	O
+
+The	O
+most	O
+common	O
+side	O
+effect	O
+was	O
+dry	B
+month	I
+in	O
+5	O
+cases	O
+(	O
+16	O
+.	O
+7	O
+%	O
+)	O
+with	O
+2	O
+cases	O
+reporting	O
+a	O
+moderate	O
+degree	O
+and	O
+1	O
+case	O
+with	O
+severe	O
+degree	O
+.	O
+
+Only	O
+one	O
+case	O
+(	O
+3	O
+.	O
+3	O
+%	O
+)	O
+withdrew	O
+from	O
+the	O
+present	O
+study	O
+due	O
+to	O
+a	O
+severe	O
+dry	B
+mouth	I
+.	O
+
+The	O
+SF	O
+-	O
+36	O
+scores	O
+changed	O
+significantly	O
+in	O
+the	O
+domains	O
+of	O
+physical	O
+functioning	O
+,	O
+role	O
+function	O
+emotional	O
+,	O
+social	O
+function	O
+and	O
+mental	O
+heath	O
+.	O
+
+CONCLUSION	O
+:	O
+Tolterodine	O
+was	O
+well	O
+tolerated	O
+and	O
+its	O
+effects	O
+improved	O
+the	O
+quality	O
+of	O
+life	O
+in	O
+Thai	O
+women	O
+with	O
+OAB	B
+.	O
+
+Remifentanil	O
+pretreatment	O
+reduces	O
+myoclonus	B
+after	O
+etomidate	O
+.	O
+
+STUDY	O
+OBJECTIVE	O
+:	O
+The	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+compare	O
+the	O
+effect	O
+of	O
+pretreatment	O
+with	O
+remifentanil	O
+1	O
+microg	O
+/	O
+kg	O
+and	O
+the	O
+effect	O
+of	O
+gender	O
+on	O
+the	O
+incidence	O
+of	O
+myoclonus	B
+after	O
+anesthesia	O
+induction	O
+with	O
+etomidate	O
+.	O
+
+DESIGN	O
+:	O
+This	O
+was	O
+a	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+study	O
+.	O
+
+SETTING	O
+:	O
+The	O
+study	O
+was	O
+conducted	O
+at	O
+a	O
+university	O
+hospital	O
+.	O
+
+PATIENTS	O
+:	O
+Sixty	O
+patients	O
+were	O
+pretreated	O
+in	O
+a	O
+randomized	O
+double	O
+-	O
+blinded	O
+fashion	O
+with	O
+remifentanil	O
+1	O
+microg	O
+/	O
+kg	O
+or	O
+placebo	O
+.	O
+
+Two	O
+minutes	O
+after	O
+remifentanil	O
+or	O
+placebo	O
+injection	O
+,	O
+etomidate	O
+0	O
+.	O
+3	O
+mg	O
+/	O
+kg	O
+was	O
+given	O
+.	O
+
+MEASUREMENTS	O
+:	O
+Myoclonus	B
+was	O
+recorded	O
+with	O
+a	O
+scale	O
+of	O
+0	O
+to	O
+3	O
+.	O
+
+The	O
+grade	O
+of	O
+sedation	O
+(	O
+none	O
+,	O
+mild	O
+,	O
+moderate	O
+,	O
+severe	O
+)	O
+,	O
+nausea	B
+,	O
+pruritus	B
+,	O
+and	O
+apnea	B
+were	O
+recorded	O
+after	O
+injection	O
+of	O
+both	O
+drugs	O
+.	O
+
+MAIN	O
+RESULTS	O
+:	O
+The	O
+incidence	O
+of	O
+myoclonus	B
+was	O
+significantly	O
+lower	O
+in	O
+the	O
+remifentanil	O
+group	O
+(	O
+6	O
+.	O
+7	O
+%	O
+)	O
+than	O
+in	O
+the	O
+placebo	O
+group	O
+(	O
+70	O
+%	O
+)	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+None	O
+of	O
+the	O
+patients	O
+experienced	O
+sedation	O
+,	O
+apnea	B
+,	O
+nausea	B
+,	O
+or	O
+pruritus	B
+after	O
+injection	O
+of	O
+both	O
+drugs	O
+.	O
+
+In	O
+the	O
+placebo	O
+group	O
+,	O
+male	O
+patients	O
+were	O
+associated	O
+with	O
+significantly	O
+increased	O
+incidence	O
+of	O
+myoclonus	B
+after	O
+etomidate	O
+administration	O
+.	O
+
+CONCLUSION	O
+:	O
+Pretreatment	O
+with	O
+remifentanil	O
+1	O
+microg	O
+/	O
+kg	O
+reduced	O
+myoclonus	B
+after	O
+etomidate	O
+induction	O
+without	O
+side	O
+effects	O
+such	O
+as	O
+sedation	O
+,	O
+apnea	B
+,	O
+nausea	B
+,	O
+or	O
+pruritus	B
+.	O
+
+Men	O
+experience	O
+increased	O
+incidence	O
+of	O
+myoclonus	B
+than	O
+women	O
+after	O
+etomidate	O
+administration	O
+.	O
+
+Memory	O
+function	O
+and	O
+serotonin	O
+transporter	O
+promoter	O
+gene	O
+polymorphism	O
+in	O
+ecstasy	O
+(	O
+MDMA	O
+)	O
+users	O
+.	O
+
+Although	O
+3	O
+,	O
+4	O
+-	O
+methylenedioxymethamphetamine	O
+(	O
+MDMA	O
+or	O
+ecstasy	O
+)	O
+has	O
+been	O
+shown	O
+to	O
+damage	O
+brain	O
+serotonin	O
+(	O
+5	O
+-	O
+HT	O
+)	O
+neurons	O
+in	O
+animals	O
+and	O
+possibly	O
+humans	O
+,	O
+little	O
+is	O
+known	O
+about	O
+the	O
+long	O
+-	O
+term	O
+consequences	O
+of	O
+MDMA	O
+-	O
+induced	O
+5	O
+-	O
+HT	O
+neurotoxic	B
+lesions	I
+on	O
+functions	O
+in	O
+which	O
+5	O
+-	O
+HT	O
+is	O
+involved	O
+,	O
+such	O
+as	O
+cognitive	O
+function	O
+.	O
+
+Because	O
+5	O
+-	O
+HT	O
+transporters	O
+play	O
+a	O
+key	O
+element	O
+in	O
+the	O
+regulation	O
+of	O
+synaptic	O
+5	O
+-	O
+HT	O
+transmission	O
+it	O
+may	O
+be	O
+important	O
+to	O
+control	O
+for	O
+the	O
+potential	O
+covariance	O
+effect	O
+of	O
+a	O
+polymorphism	O
+in	O
+the	O
+5	O
+-	O
+HT	O
+transporter	O
+promoter	O
+gene	O
+region	O
+(	O
+5	O
+-	O
+HTTLPR	O
+)	O
+when	O
+studying	O
+the	O
+effects	O
+of	O
+MDMA	O
+as	O
+well	O
+as	O
+cognitive	O
+functioning	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+effects	O
+of	O
+moderate	O
+and	O
+heavy	O
+MDMA	O
+use	O
+on	O
+cognitive	O
+function	O
+,	O
+as	O
+well	O
+as	O
+the	O
+effects	O
+of	O
+long	O
+-	O
+term	O
+abstention	O
+from	O
+MDMA	O
+,	O
+in	O
+subjects	O
+genotyped	O
+for	O
+5	O
+-	O
+HTTLPR	O
+.	O
+
+A	O
+second	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+determine	O
+whether	O
+these	O
+effects	O
+differ	O
+for	O
+females	O
+and	O
+males	O
+.	O
+
+Fifteen	O
+moderate	O
+MDMA	O
+users	O
+(	O
+<	O
+55	O
+lifetime	O
+tablets	O
+)	O
+,	O
+22	O
+heavy	O
+MDMA	O
++	O
+users	O
+(	O
+>	O
+55	O
+lifetime	O
+tablets	O
+)	O
+,	O
+16	O
+ex	O
+-	O
+MDMA	O
++	O
+users	O
+(	O
+last	O
+tablet	O
+>	O
+1	O
+year	O
+ago	O
+)	O
+and	O
+13	O
+controls	O
+were	O
+compared	O
+on	O
+a	O
+battery	O
+of	O
+neuropsychological	O
+tests	O
+.	O
+
+DNA	O
+from	O
+peripheral	O
+nuclear	O
+blood	O
+cells	O
+was	O
+genotyped	O
+for	O
+5	O
+-	O
+HTTLPR	O
+using	O
+standard	O
+polymerase	O
+chain	O
+reaction	O
+methods	O
+.	O
+A	O
+significant	O
+group	O
+effect	O
+was	O
+observed	O
+only	O
+on	O
+memory	O
+function	O
+tasks	O
+(	O
+p	O
+=	O
+0	O
+.	O
+04	O
+)	O
+but	O
+not	O
+on	O
+reaction	O
+times	O
+(	O
+p	O
+=	O
+0	O
+.	O
+61	O
+)	O
+or	O
+attention	O
+/	O
+executive	O
+functioning	O
+(	O
+p	O
+=	O
+0	O
+.	O
+59	O
+)	O
+.	O
+
+Heavy	O
+and	O
+ex	O
+-	O
+MDMA	O
++	O
+users	O
+performed	O
+significantly	O
+poorer	O
+on	O
+memory	O
+tasks	O
+than	O
+controls	O
+.	O
+
+In	O
+contrast	O
+,	O
+no	O
+evidence	O
+of	O
+memory	B
+impairment	I
+was	O
+observed	O
+in	O
+moderate	O
+MDMA	O
+users	O
+.	O
+
+No	O
+significant	O
+effect	O
+of	O
+5	O
+-	O
+HTTLPR	O
+or	O
+gender	O
+was	O
+observed	O
+.	O
+
+While	O
+the	O
+use	O
+of	O
+MDMA	O
+in	O
+quantities	O
+that	O
+may	O
+be	O
+considered	O
+"	O
+moderate	O
+"	O
+is	O
+not	O
+associated	O
+with	O
+impaired	B
+memory	I
+functioning	I
+,	O
+heavy	O
+use	O
+of	O
+MDMA	O
+use	O
+may	O
+lead	O
+to	O
+long	O
+lasting	O
+memory	B
+impairments	I
+.	O
+
+No	O
+effect	O
+of	O
+5	O
+-	O
+HTTLPR	O
+or	O
+gender	O
+on	O
+memory	O
+function	O
+or	O
+MDMA	O
+use	O
+was	O
+observed	O
+.	O
+
+Role	O
+of	O
+mangiferin	O
+on	O
+biochemical	O
+alterations	O
+and	O
+antioxidant	O
+status	O
+in	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+in	O
+rats	O
+.	O
+
+The	O
+current	O
+study	O
+dealt	O
+with	O
+the	O
+protective	O
+role	O
+of	O
+mangiferin	O
+,	O
+a	O
+polyphenol	O
+from	O
+Mangifera	O
+indica	O
+Linn	O
+.	O
+
+(	O
+Anacardiaceae	O
+)	O
+,	O
+on	O
+isoproterenol	O
+(	O
+ISPH	O
+)	O
+-	O
+induced	O
+myocardial	B
+infarction	I
+(	O
+MI	B
+)	O
+in	O
+rats	O
+through	O
+its	O
+antioxidative	O
+mechanism	O
+.	O
+
+Subcutaneous	O
+injection	O
+of	O
+ISPH	O
+(	O
+200	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+in	O
+1	O
+ml	O
+saline	O
+)	O
+to	O
+rats	O
+for	O
+2	O
+consecutive	O
+days	O
+caused	O
+myocardial	B
+damage	I
+in	O
+rat	O
+heart	O
+,	O
+which	O
+was	O
+determined	O
+by	O
+the	O
+increased	O
+activity	O
+of	O
+serum	O
+lactate	O
+dehydrogenase	O
+(	O
+LDH	O
+)	O
+and	O
+creatine	O
+phosphokinase	O
+isoenzymes	O
+(	O
+CK	O
+-	O
+MB	O
+)	O
+,	O
+increased	O
+uric	O
+acid	O
+level	O
+and	O
+reduced	O
+plasma	O
+iron	O
+binding	O
+capacity	O
+.	O
+
+The	O
+protective	O
+role	O
+of	O
+mangiferin	O
+was	O
+analyzed	O
+by	O
+triphenyl	O
+tetrazolium	O
+chloride	O
+(	O
+TTC	O
+)	O
+test	O
+used	O
+for	O
+macroscopic	O
+enzyme	O
+mapping	O
+assay	O
+of	O
+the	O
+ischemic	B
+myocardium	I
+.	O
+
+The	O
+heart	O
+tissue	O
+antioxidant	O
+enzymes	O
+such	O
+as	O
+superoxide	O
+dismutase	O
+,	O
+catalase	O
+,	O
+glutathione	O
+peroxidase	O
+,	O
+glutathione	O
+transferase	O
+and	O
+glutathione	O
+reductase	O
+activities	O
+,	O
+non	O
+-	O
+enzymic	O
+antioxidants	O
+such	O
+as	O
+cerruloplasmin	O
+,	O
+Vitamin	O
+C	O
+,	O
+Vitamin	O
+E	O
+and	O
+glutathione	O
+levels	O
+were	O
+altered	O
+in	O
+MI	B
+rats	O
+.	O
+
+Upon	O
+pretreatment	O
+with	O
+mangiferin	O
+(	O
+100	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+suspended	O
+in	O
+2	O
+ml	O
+of	O
+dimethyl	O
+sulphoxide	O
+)	O
+given	O
+intraperitoneally	O
+for	O
+28	O
+days	O
+to	O
+MI	B
+rats	O
+protected	O
+the	O
+above	O
+-	O
+mentioned	O
+parameters	O
+to	O
+fall	O
+from	O
+the	O
+normal	O
+levels	O
+.	O
+
+Activities	O
+of	O
+heart	O
+tissue	O
+enzymic	O
+antioxidants	O
+and	O
+serum	O
+non	O
+-	O
+enzymic	O
+antioxidants	O
+levels	O
+rose	O
+significantly	O
+upon	O
+mangiferin	O
+administration	O
+as	O
+compared	O
+to	O
+ISPH	O
+-	O
+induced	O
+MI	B
+rats	O
+.	O
+
+From	O
+the	O
+present	O
+study	O
+it	O
+is	O
+concluded	O
+that	O
+mangiferin	O
+exerts	O
+a	O
+beneficial	O
+effect	O
+against	O
+ISPH	O
+-	O
+induced	O
+MI	B
+due	O
+to	O
+its	O
+antioxidant	O
+potential	O
+,	O
+which	O
+regulated	O
+the	O
+tissues	O
+defense	O
+system	O
+against	O
+cardiac	B
+damage	I
+.	O
+
+Cardiovascular	O
+risk	O
+with	O
+cyclooxygenase	O
+inhibitors	O
+:	O
+general	O
+problem	O
+with	O
+substance	O
+specific	O
+differences	O
+?	O
+
+Randomised	O
+clinical	O
+trials	O
+and	O
+observational	O
+studies	O
+have	O
+shown	O
+an	O
+increased	O
+risk	O
+of	O
+myocardial	B
+infarction	I
+,	O
+stroke	B
+,	O
+hypertension	B
+and	O
+heart	B
+failure	I
+during	O
+treatment	O
+with	O
+cyclooxygenase	O
+inhibitors	O
+.	O
+
+Adverse	O
+cardiovascular	O
+effects	O
+occurred	O
+mainly	O
+,	O
+but	O
+not	O
+exclusively	O
+,	O
+in	O
+patients	O
+with	O
+concomitant	O
+risk	O
+factors	O
+.	O
+
+Cyclooxygenase	O
+inhibitors	O
+cause	O
+complex	O
+changes	O
+in	O
+renal	O
+,	O
+vascular	O
+and	O
+cardiac	O
+prostanoid	O
+profiles	O
+thereby	O
+increasing	O
+vascular	O
+resistance	O
+and	O
+fluid	O
+retention	O
+.	O
+
+The	O
+incidence	O
+of	O
+cardiovascular	O
+adverse	O
+events	O
+tends	O
+to	O
+increase	O
+with	O
+the	O
+daily	O
+dose	O
+and	O
+total	O
+exposure	O
+time	O
+.	O
+
+A	O
+comparison	O
+of	O
+individual	O
+selective	O
+and	O
+unselective	O
+cyclooxygenase	O
+inhibitors	O
+suggests	O
+substance	O
+-	O
+specific	O
+differences	O
+,	O
+which	O
+may	O
+depend	O
+on	O
+differences	O
+in	O
+pharmacokinetic	O
+parameters	O
+or	O
+inhibitory	O
+potency	O
+and	O
+may	O
+be	O
+contributed	O
+by	O
+prostaglandin	O
+-	O
+independent	O
+effects	O
+.	O
+
+Diagnostic	O
+markers	O
+such	O
+as	O
+N	O
+-	O
+terminal	O
+pro	O
+brain	O
+natriuretic	O
+peptide	O
+(	O
+NT	O
+-	O
+proBNP	O
+)	O
+or	O
+high	O
+-	O
+sensitive	O
+C	O
+-	O
+reactive	O
+protein	O
+might	O
+help	O
+in	O
+the	O
+early	O
+identification	O
+of	O
+patients	O
+at	O
+risk	O
+,	O
+thus	O
+avoiding	O
+the	O
+occurrence	O
+of	O
+serious	O
+cardiovascular	B
+toxicity	I
+.	O
+
+Pilocarpine	O
+seizures	B
+cause	O
+age	O
+-	O
+dependent	O
+impairment	B
+in	I
+auditory	I
+location	I
+discrimination	I
+.	O
+
+Children	O
+who	O
+have	O
+status	B
+epilepticus	I
+have	O
+continuous	O
+or	O
+rapidly	O
+repeating	O
+seizures	B
+that	O
+may	O
+be	O
+life	O
+-	O
+threatening	O
+and	O
+may	O
+cause	O
+life	O
+-	O
+long	O
+changes	O
+in	O
+brain	O
+and	O
+behavior	O
+.	O
+
+The	O
+extent	O
+to	O
+which	O
+status	B
+epilepticus	I
+causes	O
+deficits	B
+in	I
+auditory	I
+discrimination	I
+is	O
+unknown	O
+.	O
+
+A	O
+naturalistic	O
+auditory	O
+location	O
+discrimination	O
+method	O
+was	O
+used	O
+to	O
+evaluate	O
+this	O
+question	O
+using	O
+an	O
+animal	O
+model	O
+of	O
+status	B
+epilepticus	I
+.	O
+
+Male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+were	O
+injected	O
+with	O
+saline	O
+on	O
+postnatal	O
+day	O
+(	O
+P	O
+)	O
+20	O
+,	O
+or	O
+a	O
+convulsant	O
+dose	O
+of	O
+pilocarpine	O
+on	O
+P20	O
+or	O
+P45	O
+.	O
+
+Pilocarpine	O
+on	O
+either	O
+day	O
+induced	O
+status	B
+epilepticus	I
+;	O
+status	B
+epilepticus	I
+at	O
+P45	O
+resulted	O
+in	O
+CA3	O
+cell	O
+loss	O
+and	O
+spontaneous	O
+seizures	B
+,	O
+whereas	O
+P20	O
+rats	O
+had	O
+no	O
+cell	O
+loss	O
+or	O
+spontaneous	O
+seizures	B
+.	O
+
+Mature	O
+rats	O
+were	O
+trained	O
+with	O
+sound	O
+-	O
+source	O
+location	O
+and	O
+sound	O
+-	O
+silence	O
+discriminations	O
+.	O
+
+Control	O
+(	O
+saline	O
+P20	O
+)	O
+rats	O
+acquired	O
+both	O
+discriminations	O
+immediately	O
+.	O
+
+In	O
+status	B
+epilepticus	I
+(	O
+P20	O
+)	O
+rats	O
+,	O
+acquisition	O
+of	O
+the	O
+sound	O
+-	O
+source	O
+location	O
+discrimination	O
+was	O
+moderately	O
+impaired	O
+.	O
+
+Status	B
+epilepticus	I
+(	O
+P45	O
+)	O
+rats	O
+failed	O
+to	O
+acquire	O
+either	O
+sound	O
+-	O
+source	O
+location	O
+or	O
+sound	O
+-	O
+silence	O
+discriminations	O
+.	O
+
+Status	B
+epilepticus	I
+in	O
+rat	O
+causes	O
+an	O
+age	O
+-	O
+dependent	O
+,	O
+long	O
+-	O
+term	O
+impairment	B
+in	I
+auditory	I
+discrimination	I
+.	O
+
+This	O
+impairment	O
+may	O
+explain	O
+one	O
+cause	O
+of	O
+impaired	B
+auditory	I
+location	I
+discrimination	I
+in	O
+humans	O
+.	O
+
+Nerve	O
+growth	O
+factor	O
+and	O
+prostaglandins	O
+in	O
+the	O
+urine	O
+of	O
+female	O
+patients	O
+with	O
+overactive	B
+bladder	I
+.	O
+
+PURPOSE	O
+:	O
+NGF	O
+and	O
+PGs	O
+in	O
+the	O
+bladder	O
+can	O
+be	O
+affected	O
+by	O
+pathological	O
+changes	O
+in	O
+the	O
+bladder	O
+and	O
+these	O
+changes	O
+can	O
+be	O
+detected	O
+in	O
+urine	O
+.	O
+
+We	O
+investigated	O
+changes	O
+in	O
+urinary	O
+NGF	O
+and	O
+PGs	O
+in	O
+women	O
+with	O
+OAB	B
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+The	O
+study	O
+groups	O
+included	O
+65	O
+women	O
+with	O
+OAB	B
+and	O
+20	O
+without	O
+bladder	O
+symptoms	O
+who	O
+served	O
+as	O
+controls	O
+.	O
+
+Evaluation	O
+included	O
+patient	O
+history	O
+,	O
+urinalysis	O
+,	O
+a	O
+voiding	O
+diary	O
+and	O
+urodynamic	O
+studies	O
+.	O
+
+Urine	O
+samples	O
+were	O
+collected	O
+.	O
+
+NGF	O
+,	O
+PGE2	O
+,	O
+PGF2alpha	O
+and	O
+PGI2	O
+were	O
+measured	O
+using	O
+enzyme	O
+-	O
+linked	O
+immunosorbent	O
+assay	O
+and	O
+compared	O
+between	O
+the	O
+groups	O
+.	O
+
+In	O
+addition	O
+,	O
+correlations	O
+between	O
+urinary	O
+NGF	O
+and	O
+PG	O
+,	O
+and	O
+urodynamic	O
+parameters	O
+in	O
+patients	O
+with	O
+OAB	B
+were	O
+examined	O
+.	O
+
+RESULTS	O
+:	O
+Urinary	O
+NGF	O
+,	O
+PGE2	O
+and	O
+PGF2alpha	O
+were	O
+significantly	O
+increased	O
+in	O
+patients	O
+with	O
+OAB	B
+compared	O
+with	O
+controls	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+However	O
+,	O
+urinary	O
+PGI2	O
+was	O
+not	O
+different	O
+between	O
+controls	O
+and	O
+patients	O
+with	O
+OAB	B
+.	O
+
+In	O
+patients	O
+with	O
+OAB	B
+urinary	O
+PGE2	O
+positively	O
+correlated	O
+with	O
+volume	O
+at	O
+first	O
+desire	O
+to	O
+void	O
+and	O
+maximum	O
+cystometric	O
+capacity	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Urinary	O
+NGF	O
+,	O
+PGF2alpha	O
+and	O
+PGI2	O
+did	O
+not	O
+correlate	O
+with	O
+urodynamic	O
+parameters	O
+in	O
+patients	O
+with	O
+OAB	B
+.	O
+
+CONCLUSIONS	O
+:	O
+NGF	O
+and	O
+PGs	O
+have	O
+important	O
+roles	O
+in	O
+the	O
+development	O
+of	O
+OAB	B
+symptoms	O
+in	O
+female	O
+patients	O
+.	O
+
+Urinary	O
+levels	O
+of	O
+these	O
+factors	O
+may	O
+be	O
+used	O
+as	O
+markers	O
+to	O
+evaluate	O
+OAB	B
+symptoms	O
+.	O
+
+Definition	O
+and	O
+management	O
+of	O
+anemia	B
+in	O
+patients	O
+infected	B
+with	I
+hepatitis	I
+C	I
+virus	I
+.	O
+
+Chronic	B
+infection	I
+with	I
+hepatitis	I
+C	I
+virus	I
+(	O
+HCV	O
+)	O
+can	O
+progress	O
+to	O
+cirrhosis	B
+,	O
+hepatocellular	B
+carcinoma	I
+,	O
+and	O
+end	B
+-	I
+stage	I
+liver	I
+disease	I
+.	O
+
+The	O
+current	O
+best	O
+treatment	O
+for	O
+HCV	B
+infection	I
+is	O
+combination	O
+therapy	O
+with	O
+pegylated	O
+interferon	O
+and	O
+ribavirin	O
+.	O
+
+Although	O
+this	O
+regimen	O
+produces	O
+sustained	O
+virologic	O
+responses	O
+(	O
+SVRs	O
+)	O
+in	O
+approximately	O
+50	O
+%	O
+of	O
+patients	O
+,	O
+it	O
+can	O
+be	O
+associated	O
+with	O
+a	O
+potentially	O
+dose	O
+-	O
+limiting	O
+hemolytic	B
+anemia	I
+.	O
+
+Hemoglobin	O
+concentrations	O
+decrease	O
+mainly	O
+as	O
+a	O
+result	O
+of	O
+ribavirin	O
+-	O
+induced	O
+hemolysis	B
+,	O
+and	O
+this	O
+anemia	B
+can	O
+be	O
+problematic	O
+in	O
+patients	O
+with	O
+HCV	B
+infection	I
+,	O
+especially	O
+those	O
+who	O
+have	O
+comorbid	O
+renal	B
+or	I
+cardiovascular	I
+disorders	I
+.	O
+
+In	O
+general	O
+,	O
+anemia	B
+can	O
+increase	O
+the	O
+risk	O
+of	O
+morbidity	O
+and	O
+mortality	O
+,	O
+and	O
+may	O
+have	O
+negative	O
+effects	O
+on	O
+cerebral	O
+function	O
+and	O
+quality	O
+of	O
+life	O
+.	O
+
+Although	O
+ribavirin	O
+-	O
+associated	O
+anemia	B
+can	O
+be	O
+reversed	O
+by	O
+dose	O
+reduction	O
+or	O
+discontinuation	O
+,	O
+this	O
+approach	O
+compromises	O
+outcomes	O
+by	O
+significantly	O
+decreasing	O
+SVR	O
+rates	O
+.	O
+
+Recombinant	O
+human	O
+erythropoietin	O
+has	O
+been	O
+used	O
+to	O
+manage	O
+ribavirin	O
+-	O
+associated	O
+anemia	B
+but	O
+has	O
+other	O
+potential	O
+disadvantages	O
+.	O
+
+Viramidine	O
+,	O
+a	O
+liver	O
+-	O
+targeting	O
+prodrug	O
+of	O
+ribavirin	O
+,	O
+has	O
+the	O
+potential	O
+to	O
+maintain	O
+the	O
+virologic	O
+efficacy	O
+of	O
+ribavirin	O
+while	O
+decreasing	O
+the	O
+risk	O
+of	O
+hemolytic	B
+anemia	I
+in	O
+patients	O
+with	O
+chronic	B
+hepatitis	I
+C	I
+.	O
+
+Impact	O
+of	O
+alcohol	O
+exposure	O
+after	O
+pregnancy	O
+recognition	O
+on	O
+ultrasonographic	O
+fetal	O
+growth	O
+measures	O
+.	O
+
+BACKGROUND	O
+:	O
+More	O
+than	O
+3	O
+decades	O
+after	O
+Jones	O
+and	O
+Smith	O
+(	O
+1973	O
+)	O
+reported	O
+on	O
+the	O
+devastation	O
+caused	O
+by	O
+alcohol	O
+exposure	O
+on	O
+fetal	O
+development	O
+,	O
+the	O
+rates	O
+of	O
+heavy	O
+drinking	O
+during	O
+pregnancy	O
+remain	O
+relatively	O
+unchanged	O
+.	O
+
+Early	O
+identification	O
+of	O
+fetal	O
+alcohol	O
+exposure	O
+and	O
+maternal	O
+abstinence	O
+led	O
+to	O
+better	O
+infant	O
+outcomes	O
+.	O
+
+This	O
+study	O
+examined	O
+the	O
+utility	O
+of	O
+biometry	O
+for	O
+detecting	O
+alcohol	O
+-	O
+related	O
+fetal	O
+growth	B
+impairment	I
+.	O
+
+METHODS	O
+:	O
+We	O
+obtained	O
+fetal	O
+ultrasound	O
+measures	O
+from	O
+routine	O
+ultrasound	O
+examinations	O
+for	O
+167	O
+pregnant	O
+hazardous	O
+drinkers	O
+who	O
+were	O
+enrolled	O
+in	O
+a	O
+brief	O
+alcohol	O
+intervention	O
+study	O
+.	O
+
+The	O
+fetal	O
+measures	O
+for	O
+women	O
+who	O
+quit	O
+after	O
+learning	O
+of	O
+their	O
+pregnancies	O
+were	O
+compared	O
+with	O
+measures	O
+for	O
+women	O
+who	O
+continued	O
+some	O
+drinking	O
+throughout	O
+the	O
+course	O
+of	O
+their	O
+pregnancies	O
+.	O
+
+Because	O
+intensity	O
+of	O
+alcohol	O
+consumption	O
+is	O
+associated	O
+with	O
+poorer	O
+fetal	O
+outcomes	O
+,	O
+separate	O
+analyses	O
+were	O
+conducted	O
+for	O
+the	O
+heavy	O
+(	O
+average	O
+of	O
+>	O
+or	O
+=	O
+5	O
+drinks	O
+per	O
+drinking	O
+day	O
+)	O
+alcohol	O
+consumers	O
+.	O
+
+Fetal	O
+measures	O
+from	O
+the	O
+heavy	O
+-	O
+exposed	O
+fetuses	O
+were	O
+also	O
+compared	O
+with	O
+measures	O
+from	O
+a	O
+nondrinking	O
+group	O
+that	O
+was	O
+representative	O
+of	O
+normal	O
+,	O
+uncomplicated	O
+pregnancies	O
+from	O
+our	O
+clinics	O
+.	O
+
+Analyses	O
+of	O
+covariance	O
+were	O
+used	O
+to	O
+determine	O
+whether	O
+there	O
+were	O
+differences	O
+between	O
+groups	O
+after	O
+controlling	O
+for	O
+influences	O
+of	O
+gestational	O
+age	O
+and	O
+drug	B
+abuse	I
+.	O
+
+RESULTS	O
+:	O
+Nearly	O
+half	O
+of	O
+the	O
+pregnant	O
+drinkers	O
+abstained	O
+after	O
+learning	O
+of	O
+their	O
+pregnancies	O
+.	O
+
+When	O
+women	O
+reportedly	O
+quit	O
+drinking	O
+early	O
+in	O
+their	O
+pregnancies	O
+,	O
+fetal	O
+growth	O
+measures	O
+were	O
+not	O
+significantly	O
+different	O
+from	O
+a	O
+non	O
+-	O
+alcohol	O
+-	O
+exposed	O
+group	O
+,	O
+regardless	O
+of	O
+prior	O
+drinking	O
+patterns	O
+.	O
+
+Any	O
+alcohol	O
+consumption	O
+postpregnancy	O
+recognition	O
+among	O
+the	O
+heavy	O
+drinkers	O
+resulted	O
+in	O
+reduced	B
+cerebellar	I
+growth	I
+as	O
+well	O
+as	O
+decreased	B
+cranial	I
+to	I
+body	I
+growth	I
+in	O
+comparison	O
+with	O
+women	O
+who	O
+either	O
+quit	O
+drinking	O
+or	O
+who	O
+were	O
+nondrinkers	O
+.	O
+
+Amphetamine	O
+abuse	O
+was	O
+predictive	O
+of	O
+larger	O
+cranial	O
+to	O
+body	O
+growth	O
+ratios	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Alterations	O
+in	O
+fetal	O
+biometric	O
+measurements	O
+were	O
+observed	O
+among	O
+the	O
+heavy	O
+drinkers	O
+only	O
+when	O
+they	O
+continued	O
+drinking	O
+after	O
+becoming	O
+aware	O
+of	O
+their	O
+pregnancies	O
+.	O
+
+Although	O
+the	O
+reliance	O
+on	O
+self	O
+-	O
+reported	O
+drinking	O
+is	O
+a	O
+limitation	O
+in	O
+this	O
+study	O
+,	O
+these	O
+findings	O
+support	O
+the	O
+benefits	O
+of	O
+early	O
+abstinence	O
+and	O
+the	O
+potential	O
+for	O
+ultrasound	O
+examinations	O
+in	O
+the	O
+detection	O
+of	O
+fetal	O
+alcohol	O
+effects	O
+.	O
+
+Ethambutol	O
+-	O
+associated	O
+optic	B
+neuropathy	I
+.	O
+
+INTRODUCTION	O
+:	O
+Ethambutol	O
+is	O
+used	O
+in	O
+the	O
+treatment	O
+of	O
+tuberculosis	B
+,	O
+which	O
+is	O
+still	O
+prevalent	O
+in	O
+Southeast	O
+Asia	O
+,	O
+and	O
+can	O
+be	O
+associated	O
+with	O
+permanent	O
+visual	B
+loss	I
+.	O
+
+We	O
+report	O
+3	O
+cases	O
+which	O
+presented	O
+with	O
+bitemporal	B
+hemianopia	I
+.	O
+
+CLINICAL	O
+PICTURE	O
+:	O
+Three	O
+patients	O
+with	O
+ethambutol	O
+-	O
+associated	O
+toxic	O
+optic	B
+neuropathy	I
+are	O
+described	O
+.	O
+
+All	O
+3	O
+patients	O
+had	O
+loss	B
+of	I
+central	I
+visual	I
+acuity	I
+,	I
+colour	I
+vision	I
+(	I
+Ishihara	I
+)	I
+and	I
+visual	I
+field	I
+.	O
+
+The	O
+visual	B
+field	I
+loss	I
+had	O
+a	O
+bitemporal	O
+flavour	O
+,	O
+suggesting	O
+involvement	O
+of	O
+the	O
+optic	O
+chiasm	O
+.	O
+
+TREATMENT	O
+:	O
+Despite	O
+stopping	O
+ethambutol	O
+on	O
+diagnosis	O
+,	O
+visual	O
+function	O
+continued	O
+to	O
+deteriorate	O
+for	O
+a	O
+few	O
+months	O
+.	O
+
+Subsequent	O
+improvement	O
+was	O
+mild	O
+in	O
+2	O
+cases	O
+.	O
+
+In	O
+the	O
+third	O
+case	O
+,	O
+visual	O
+acuity	O
+and	O
+colour	O
+vision	O
+normalised	O
+but	O
+the	O
+optic	O
+discs	O
+were	O
+pale	O
+.	O
+
+OUTCOME	O
+:	O
+All	O
+3	O
+patients	O
+had	O
+some	O
+permanent	O
+loss	B
+of	I
+visual	I
+function	I
+.	O
+
+CONCLUSIONS	O
+:	O
+Ethambutol	O
+usage	O
+is	O
+associated	O
+with	O
+permanent	O
+visual	B
+loss	I
+and	O
+should	O
+be	O
+avoided	O
+if	O
+possible	O
+or	O
+used	O
+with	O
+caution	O
+and	O
+proper	O
+ophthalmological	O
+follow	O
+-	O
+up	O
+.	O
+
+The	O
+author	O
+postulates	O
+that	O
+in	O
+cases	O
+of	O
+ethambutol	O
+associated	O
+chiasmopathy	O
+,	O
+ethambutol	O
+may	O
+initially	O
+affect	O
+the	O
+optic	O
+nerves	O
+and	O
+subsequently	O
+progress	O
+to	O
+involve	O
+the	O
+optic	O
+chiasm	O
+.	O
+
+Possible	O
+neuroleptic	B
+malignant	I
+syndrome	I
+related	O
+to	O
+concomitant	O
+treatment	O
+with	O
+paroxetine	O
+and	O
+alprazolam	O
+.	O
+
+A	O
+74	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+depressive	B
+symptoms	I
+was	O
+admitted	O
+to	O
+a	O
+psychiatric	B
+hospital	O
+due	O
+to	O
+insomnia	B
+,	O
+loss	B
+of	I
+appetite	I
+,	O
+exhaustion	O
+,	O
+and	O
+agitation	B
+.	O
+
+Medical	O
+treatment	O
+was	O
+initiated	O
+at	O
+a	O
+daily	O
+dose	O
+of	O
+20	O
+mg	O
+paroxetine	O
+and	O
+1	O
+.	O
+2	O
+mg	O
+alprazolam	O
+.	O
+
+On	O
+the	O
+10th	O
+day	O
+of	O
+paroxetine	O
+and	O
+alprazolam	O
+treatment	O
+,	O
+the	O
+patient	O
+exhibited	O
+marked	O
+psychomotor	B
+retardation	I
+,	O
+disorientation	O
+,	O
+and	O
+severe	O
+muscle	B
+rigidity	I
+with	O
+tremors	B
+.	O
+
+The	O
+patient	O
+had	O
+a	O
+fever	B
+(	O
+38	O
+.	O
+2	O
+degrees	O
+C	O
+)	O
+,	O
+fluctuating	O
+blood	O
+pressure	O
+(	O
+between	O
+165	O
+/	O
+90	O
+and	O
+130	O
+/	O
+70	O
+mg	O
+mm	O
+Hg	O
+)	O
+,	O
+and	O
+severe	O
+extrapyramidal	B
+symptoms	I
+.	O
+
+Laboratory	O
+tests	O
+showed	O
+an	O
+elevation	O
+of	O
+creatine	O
+phosphokinase	O
+(	O
+2218	O
+IU	O
+/	O
+L	O
+)	O
+,	O
+aspartate	O
+aminotransferase	O
+(	O
+134	O
+IU	O
+/	O
+L	O
+)	O
+,	O
+alanine	O
+aminotransferase	O
+(	O
+78	O
+IU	O
+/	O
+L	O
+)	O
+,	O
+and	O
+BUN	O
+(	O
+27	O
+.	O
+9	O
+mg	O
+/	O
+ml	O
+)	O
+levels	O
+.	O
+
+The	O
+patient	O
+received	O
+bromocriptine	O
+and	O
+diazepam	O
+to	O
+treat	O
+his	O
+symptoms	O
+.	O
+
+7	O
+days	O
+later	O
+,	O
+the	O
+fever	B
+disappeared	O
+and	O
+the	O
+patient	O
+'	O
+s	O
+serum	O
+CPK	O
+levels	O
+were	O
+normalized	O
+(	O
+175	O
+IU	O
+/	O
+L	O
+)	O
+.	O
+
+This	O
+patient	O
+presented	O
+with	O
+symptoms	O
+of	O
+neuroleptic	B
+malignant	I
+syndrome	I
+(	O
+NMS	B
+)	O
+,	O
+thus	O
+demonstrating	O
+that	O
+NMS	B
+-	O
+like	O
+symptoms	O
+can	O
+occur	O
+after	O
+combined	O
+paroxetine	O
+and	O
+alprazolam	O
+treatment	O
+.	O
+
+The	O
+adverse	O
+drug	O
+reaction	O
+score	O
+obtained	O
+by	O
+the	O
+Naranjo	O
+algorithm	O
+was	O
+6	O
+in	O
+our	O
+case	O
+,	O
+indicating	O
+a	O
+probable	O
+relationship	O
+between	O
+the	O
+patient	O
+'	O
+s	O
+NMS	B
+-	O
+like	O
+adverse	O
+symptoms	O
+and	O
+the	O
+combined	O
+treatment	O
+used	O
+in	O
+this	O
+case	O
+.	O
+
+The	O
+involvement	O
+of	O
+physiologic	O
+and	O
+environmental	O
+aspects	O
+specific	O
+to	O
+this	O
+patient	O
+was	O
+suspected	O
+.	O
+
+Several	O
+risk	O
+factors	O
+for	O
+NMS	B
+should	O
+be	O
+noted	O
+in	O
+elderly	O
+depressive	B
+patients	O
+whose	O
+symptoms	O
+often	O
+include	O
+dehydration	B
+,	O
+agitation	B
+,	O
+malnutrition	B
+,	O
+and	O
+exhaustion	O
+.	O
+
+Careful	O
+therapeutic	O
+intervention	O
+is	O
+necessary	O
+in	O
+cases	O
+involving	O
+elderly	O
+patients	O
+who	O
+suffer	O
+from	O
+depression	B
+.	O
+
+Down	O
+-	O
+regulation	O
+of	O
+norepinephrine	O
+transporter	O
+function	O
+induced	O
+by	O
+chronic	O
+administration	O
+of	O
+desipramine	O
+linking	O
+to	O
+the	O
+alteration	O
+of	O
+sensitivity	O
+of	O
+local	O
+-	O
+anesthetics	O
+-	O
+induced	O
+convulsions	B
+and	O
+the	O
+counteraction	O
+by	O
+co	O
+-	O
+administration	O
+with	O
+local	O
+anesthetics	O
+.	O
+
+Alterations	O
+of	O
+norepinephrine	O
+transporter	O
+(	O
+NET	O
+)	O
+function	O
+by	O
+chronic	O
+inhibition	O
+of	O
+NET	O
+in	O
+relation	O
+to	O
+sensitization	O
+to	O
+seizures	B
+induce	O
+by	O
+cocaine	O
+and	O
+local	O
+anesthetics	O
+were	O
+studied	O
+in	O
+mice	O
+.	O
+
+Daily	O
+administration	O
+of	O
+desipramine	O
+,	O
+an	O
+inhibitor	O
+of	O
+the	O
+NET	O
+,	O
+for	O
+5	O
+days	O
+decreased	O
+[	O
+(	O
+3	O
+)	O
+H	O
+]	O
+norepinephrine	O
+uptake	O
+in	O
+the	O
+P2	O
+fractions	O
+of	O
+hippocampus	O
+but	O
+not	O
+cortex	O
+,	O
+striatum	O
+or	O
+amygdalae	O
+.	O
+
+Co	O
+-	O
+administration	O
+of	O
+lidocaine	O
+,	O
+bupivacaine	O
+or	O
+tricaine	O
+with	O
+desipramine	O
+reversed	O
+this	O
+effect	O
+.	O
+
+Daily	O
+treatment	O
+of	O
+cocaine	O
+increased	O
+[	O
+(	O
+3	O
+)	O
+H	O
+]	O
+norepinephrine	O
+uptake	O
+into	O
+the	O
+hippocampus	O
+.	O
+
+Daily	O
+administration	O
+of	O
+desipramine	O
+increased	O
+the	O
+incidence	O
+of	O
+appearance	O
+of	O
+lidocaine	O
+-	O
+induced	O
+convulsions	B
+and	O
+decreased	O
+that	O
+of	O
+cocaine	O
+-	O
+induced	O
+convulsions	B
+.	O
+
+Co	O
+-	O
+administration	O
+of	O
+lidocaine	O
+with	O
+desipramine	O
+reversed	O
+the	O
+changes	O
+of	O
+convulsive	B
+activity	O
+of	O
+lidocaine	O
+and	O
+cocaine	O
+induced	O
+by	O
+repeated	O
+administration	O
+of	O
+desipramine	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+down	O
+-	O
+regulation	O
+of	O
+hippocampal	O
+NET	O
+induced	O
+by	O
+chronic	O
+administration	O
+of	O
+desipramine	O
+may	O
+be	O
+relevant	O
+to	O
+desipramine	O
+-	O
+induced	O
+sensitization	O
+of	O
+lidocaine	O
+convulsions	B
+.	O
+
+Inhibition	O
+of	O
+Na	O
+(	O
++	O
+)	O
+channels	O
+by	O
+local	O
+anesthetics	O
+may	O
+regulate	O
+desipramine	O
+-	O
+induced	O
+down	O
+-	O
+regulation	O
+of	O
+NET	O
+function	O
+.	O
+
+Repeated	O
+administration	O
+of	O
+cocaine	O
+induces	O
+up	O
+-	O
+regulation	O
+of	O
+hippocampal	O
+NET	O
+function	O
+.	O
+
+Desipramine	O
+-	O
+induced	O
+sensitization	O
+of	O
+lidocaine	O
+seizures	B
+may	O
+have	O
+a	O
+mechanism	O
+distinct	O
+from	O
+kindling	O
+resulting	O
+from	O
+repeated	O
+administration	O
+of	O
+cocaine	O
+.	O
+
+Atorvastatin	O
+prevented	O
+and	O
+reversed	O
+dexamethasone	O
+-	O
+induced	O
+hypertension	B
+in	O
+the	O
+rat	O
+.	O
+
+To	O
+assess	O
+the	O
+antioxidant	O
+effects	O
+of	O
+atorvastatin	O
+(	O
+atorva	O
+)	O
+on	O
+dexamethasone	O
+(	O
+dex	O
+)	O
+-	O
+induced	O
+hypertension	B
+,	O
+60	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+were	O
+treated	O
+with	O
+atorva	O
+30	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+or	O
+tap	O
+water	O
+for	O
+15	O
+days	O
+.	O
+
+Dex	O
+increased	O
+systolic	O
+blood	O
+pressure	O
+(	O
+SBP	O
+)	O
+from	O
+109	O
++	O
+/	O
+-	O
+1	O
+.	O
+8	O
+to	O
+135	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+mmHg	O
+and	O
+plasma	O
+superoxide	O
+(	O
+5711	O
++	O
+/	O
+-	O
+284	O
+.	O
+9	O
+saline	O
+,	O
+7931	O
++	O
+/	O
+-	O
+392	O
+.	O
+8	O
+U	O
+/	O
+ml	O
+dex	O
+,	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+In	O
+this	O
+prevention	O
+study	O
+,	O
+SBP	O
+in	O
+the	O
+atorva	O
++	O
+dex	O
+group	O
+was	O
+increased	O
+from	O
+115	O
++	O
+/	O
+-	O
+0	O
+.	O
+4	O
+to	O
+124	O
++	O
+/	O
+-	O
+1	O
+.	O
+5	O
+mmHg	O
+,	O
+but	O
+this	O
+was	O
+significantly	O
+lower	O
+than	O
+in	O
+the	O
+dex	O
+-	O
+only	O
+group	O
+(	O
+P	O
+'	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Atorva	O
+reversed	O
+dex	O
+-	O
+induced	O
+hypertension	B
+(	O
+129	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+mmHg	O
+,	O
+vs	O
+.	O
+135	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+mmHg	O
+P	O
+'	O
+<	O
+0	O
+.	O
+05	O
+)	O
+and	O
+decreased	O
+plasma	O
+superoxide	O
+(	O
+7931	O
++	O
+/	O
+-	O
+392	O
+.	O
+8	O
+dex	O
+,	O
+1187	O
++	O
+/	O
+-	O
+441	O
+.	O
+2	O
+atorva	O
++	O
+dex	O
+,	O
+P	O
+<	O
+0	O
+.	O
+0001	O
+)	O
+.	O
+
+Plasma	O
+nitrate	O
+/	O
+nitrite	O
+(	O
+NOx	O
+)	O
+was	O
+decreased	O
+in	O
+dex	O
+-	O
+treated	O
+rats	O
+compared	O
+to	O
+saline	O
+-	O
+treated	O
+rats	O
+(	O
+11	O
+.	O
+2	O
++	O
+/	O
+-	O
+1	O
+.	O
+08	O
+microm	O
+,	O
+15	O
+.	O
+3	O
++	O
+/	O
+-	O
+1	O
+.	O
+17	O
+microm	O
+,	O
+respectively	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Atorva	O
+affected	O
+neither	O
+plasma	O
+NOx	O
+nor	O
+thymus	O
+weight	O
+.	O
+
+Thus	O
+,	O
+atorvastatin	O
+prevented	O
+and	O
+reversed	O
+dexamethasone	O
+-	O
+induced	O
+hypertension	B
+in	O
+the	O
+rat	O
+.	O
+
+Peripheral	B
+neuropathy	I
+caused	O
+by	O
+high	O
+-	O
+dose	O
+cytosine	O
+arabinoside	O
+treatment	O
+in	O
+a	O
+patient	O
+with	O
+acute	B
+myeloid	I
+leukemia	I
+.	O
+
+The	O
+central	O
+nervous	O
+system	O
+toxicity	B
+of	O
+high	O
+-	O
+dose	O
+cytosine	O
+arabinoside	O
+is	O
+well	O
+recognized	O
+,	O
+but	O
+the	O
+toxicity	B
+of	O
+cytosine	O
+arabinoside	O
+in	O
+the	O
+peripheral	O
+nervous	O
+system	O
+has	O
+been	O
+infrequently	O
+reported	O
+.	O
+
+A	O
+49	O
+-	O
+year	O
+-	O
+old	O
+Japanese	O
+man	O
+was	O
+diagnosed	O
+with	O
+acute	B
+myeloid	I
+leukemia	I
+.	O
+
+After	O
+he	O
+achieved	O
+complete	O
+remission	O
+,	O
+he	O
+received	O
+high	O
+-	O
+dose	O
+cytosine	O
+arabinoside	O
+treatment	O
+(	O
+2	O
+g	O
+/	O
+m2	O
+twice	O
+a	O
+day	O
+for	O
+5	O
+days	O
+;	O
+total	O
+,	O
+20	O
+g	O
+/	O
+m2	O
+)	O
+as	O
+consolidation	O
+therapy	O
+.	O
+
+The	O
+first	O
+course	O
+of	O
+high	O
+-	O
+dose	O
+cytosine	O
+arabinoside	O
+resulted	O
+in	O
+no	O
+unusual	O
+symptoms	O
+,	O
+but	O
+on	O
+day	O
+21	O
+of	O
+the	O
+second	O
+course	O
+of	O
+treatment	O
+,	O
+the	O
+patient	O
+complained	O
+of	O
+numbness	B
+in	O
+his	O
+right	O
+foot	O
+.	O
+
+Electromyogram	O
+and	O
+nerve	O
+-	O
+conduction	O
+studies	O
+showed	O
+peripheral	B
+neuropathy	I
+in	O
+both	O
+peroneal	O
+nerves	O
+.	O
+
+This	O
+neuropathy	B
+was	O
+gradually	O
+resolving	O
+;	O
+however	O
+,	O
+after	O
+the	O
+patient	O
+received	O
+allogeneic	O
+bone	O
+marrow	O
+transplantation	O
+,	O
+the	O
+symptoms	O
+worsened	O
+,	O
+with	O
+the	O
+development	O
+of	O
+graft	B
+-	I
+versus	I
+-	I
+host	I
+disease	I
+,	O
+and	O
+the	O
+symptoms	O
+subsequently	O
+responded	O
+to	O
+methylprednisolone	O
+.	O
+
+Although	O
+the	O
+mechanisms	O
+of	O
+peripheral	B
+neuropathy	I
+are	O
+still	O
+unclear	O
+,	O
+high	O
+-	O
+dose	O
+cytosine	O
+arabinoside	O
+is	O
+a	O
+therapy	O
+that	O
+is	O
+potentially	O
+toxic	O
+to	O
+the	O
+peripheral	O
+nervous	O
+system	O
+,	O
+and	O
+auto	O
+/	O
+alloimmunity	O
+may	O
+play	O
+an	O
+important	O
+role	O
+in	O
+these	O
+mechanisms	O
+.	O
+
+Effect	O
+of	O
+alpha	O
+-	O
+tocopherol	O
+and	O
+deferoxamine	O
+on	O
+methamphetamine	O
+-	O
+induced	O
+neurotoxicity	B
+.	O
+
+Methamphetamine	O
+(	O
+MA	O
+)	O
+-	O
+induced	O
+dopaminergic	O
+neurotoxicity	B
+is	O
+believed	O
+to	O
+be	O
+associated	O
+with	O
+the	O
+increased	O
+formation	O
+of	O
+free	O
+radicals	O
+.	O
+
+This	O
+study	O
+examined	O
+the	O
+effect	O
+of	O
+alpha	O
+-	O
+tocopherol	O
+(	O
+alpha	O
+-	O
+TC	O
+)	O
+,	O
+a	O
+scavenger	O
+of	O
+reactive	O
+oxygen	O
+species	O
+,	O
+and	O
+deferoxamine	O
+(	O
+DFO	O
+)	O
+,	O
+an	O
+iron	O
+chelator	O
+,	O
+on	O
+the	O
+MA	O
+-	O
+induced	O
+neurotoxicity	B
+.	O
+
+Male	O
+rats	O
+were	O
+treated	O
+with	O
+MA	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+,	O
+every	O
+2	O
+h	O
+for	O
+four	O
+injections	O
+)	O
+.	O
+
+The	O
+rat	O
+received	O
+either	O
+alpha	O
+-	O
+TC	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+)	O
+intraperitoneally	O
+for	O
+3	O
+days	O
+and	O
+30	O
+min	O
+prior	O
+to	O
+MA	O
+administration	O
+or	O
+DFO	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+subcutaneously	O
+30	O
+min	O
+before	O
+MA	O
+administration	O
+.	O
+
+The	O
+concentrations	O
+of	O
+dopamine	O
+(	O
+DA	O
+)	O
+,	O
+serotonin	O
+and	O
+their	O
+metabolites	O
+decreased	O
+significantly	O
+after	O
+MA	O
+administration	O
+,	O
+which	O
+was	O
+inhibited	O
+by	O
+the	O
+alpha	O
+-	O
+TC	O
+and	O
+DFO	O
+pretreatment	O
+.	O
+
+alpha	O
+-	O
+TC	O
+and	O
+DFO	O
+attenuated	O
+the	O
+MA	O
+-	O
+induced	O
+hyperthermia	B
+as	O
+well	O
+as	O
+the	O
+alterations	O
+in	O
+the	O
+locomotor	O
+activity	O
+.	O
+
+The	O
+level	O
+of	O
+lipid	O
+peroxidation	O
+was	O
+higher	O
+and	O
+the	O
+reduced	O
+glutathione	O
+concentration	O
+was	O
+lower	O
+in	O
+the	O
+MA	O
+-	O
+treated	O
+rats	O
+.	O
+
+These	O
+changes	O
+were	O
+significantly	O
+attenuated	O
+by	O
+alpha	O
+-	O
+TC	O
+and	O
+DFO	O
+.	O
+
+This	O
+suggests	O
+that	O
+alpha	O
+-	O
+TC	O
+and	O
+DFO	O
+ameliorate	O
+the	O
+MA	O
+-	O
+induced	O
+neuronal	B
+damage	I
+by	O
+decreasing	O
+the	O
+level	O
+of	O
+oxidative	O
+stress	O
+.	O
+
+Blockade	O
+of	O
+both	O
+D	O
+-	O
+1	O
+and	O
+D	O
+-	O
+2	O
+dopamine	O
+receptors	O
+may	O
+induce	O
+catalepsy	B
+in	O
+mice	O
+.	O
+
+1	O
+.	O
+
+The	O
+catalepsy	B
+induced	O
+by	O
+dopamine	O
+antagonists	O
+has	O
+been	O
+tested	O
+and	O
+the	O
+possible	O
+dopamine	O
+subtypes	O
+involved	O
+in	O
+catalepsy	B
+was	O
+determined	O
+.	O
+
+2	O
+.	O
+
+Dopamine	O
+antagonist	O
+fluphenazine	O
+,	O
+D	O
+-	O
+1	O
+antagonist	O
+SCH	O
+23390	O
+or	O
+D	O
+-	O
+2	O
+antagonist	O
+sulpiride	O
+induced	O
+catalepsy	B
+.	O
+
+The	O
+effect	O
+of	O
+fluphenazine	O
+and	O
+sulpiride	O
+was	O
+dose	O
+-	O
+dependent	O
+.	O
+
+Combination	O
+of	O
+SCH	O
+23390	O
+with	O
+sulpiride	O
+did	O
+not	O
+induce	O
+catalepsy	B
+potentiation	O
+.	O
+
+3	O
+.	O
+
+D	O
+-	O
+1	O
+agonist	O
+SKF	O
+38393	O
+or	O
+D	O
+-	O
+2	O
+agonist	O
+quinpirole	O
+decreased	O
+the	O
+catalepsy	B
+induced	O
+by	O
+fluphenazine	O
+,	O
+SCH	O
+23390	O
+or	O
+sulpiride	O
+.	O
+
+4	O
+.	O
+
+Combination	O
+of	O
+SKF	O
+38393	O
+with	O
+quinpirole	O
+did	O
+not	O
+cause	O
+potentiated	O
+inhibitory	O
+effect	O
+on	O
+catalepsy	B
+induced	O
+by	O
+dopamine	O
+antagonists	O
+.	O
+
+5	O
+.	O
+
+The	O
+data	O
+may	O
+indicate	O
+that	O
+although	O
+D	O
+-	O
+2	O
+receptor	O
+blockade	O
+is	O
+involved	O
+in	O
+catalepsy	B
+,	O
+the	O
+D	O
+-	O
+1	O
+receptor	O
+may	O
+plan	O
+a	O
+role	O
+.	O
+
+Sustained	O
+clinical	O
+improvement	O
+of	O
+a	O
+patient	O
+with	O
+decompensated	O
+hepatitis	B
+B	I
+virus	O
+-	O
+related	O
+cirrhosis	B
+after	O
+treatment	O
+with	O
+lamivudine	O
+monotherapy	O
+.	O
+
+Hepatitis	B
+B	I
+virus	I
+(	I
+HBV	I
+)	I
+infection	I
+,	O
+which	O
+causes	O
+liver	B
+cirrhosis	I
+and	O
+hepatocellular	B
+carcinoma	I
+,	O
+remains	O
+a	O
+major	O
+health	O
+problem	O
+in	O
+Asian	O
+countries	O
+.	O
+
+Recent	O
+development	O
+of	O
+vaccine	O
+for	O
+prevention	O
+is	O
+reported	O
+to	O
+be	O
+successful	O
+in	O
+reducing	O
+the	O
+size	O
+of	O
+chronically	O
+infected	O
+carriers	O
+,	O
+although	O
+the	O
+standard	O
+medical	O
+therapies	O
+have	O
+not	O
+been	O
+established	O
+up	O
+to	O
+now	O
+.	O
+
+In	O
+this	O
+report	O
+,	O
+we	O
+encountered	O
+a	O
+patient	O
+with	O
+decompensated	O
+HBV	O
+-	O
+related	O
+cirrhosis	B
+who	O
+exhibited	O
+the	O
+dramatic	O
+improvements	O
+after	O
+antiviral	O
+therapy	O
+.	O
+
+The	O
+patient	O
+was	O
+a	O
+50	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+.	O
+
+Previous	O
+conventional	O
+medical	O
+treatments	O
+were	O
+not	O
+effective	O
+for	O
+this	O
+patient	O
+,	O
+thus	O
+this	O
+patient	O
+had	O
+been	O
+referred	O
+to	O
+our	O
+hospital	O
+.	O
+
+However	O
+,	O
+the	O
+administration	O
+of	O
+lamivudine	O
+,	O
+a	O
+reverse	O
+transcriptase	O
+inhibitor	O
+,	O
+for	O
+23	O
+months	O
+dramatically	O
+improved	O
+her	O
+liver	O
+severity	O
+.	O
+
+During	O
+this	O
+period	O
+,	O
+no	O
+drug	O
+resistant	O
+mutant	O
+HBV	O
+emerged	O
+,	O
+and	O
+the	O
+serum	O
+HBV	O
+-	O
+DNA	O
+level	O
+was	O
+continuously	O
+suppressed	O
+.	O
+
+These	O
+virological	O
+responses	O
+were	O
+also	O
+maintained	O
+even	O
+after	O
+the	O
+antiviral	O
+therapy	O
+was	O
+discontinued	O
+.	O
+
+Moreover	O
+,	O
+both	O
+hepatitis	O
+B	O
+surface	O
+antigen	O
+and	O
+e	O
+antigen	O
+were	O
+observed	O
+to	O
+have	O
+disappeared	O
+in	O
+this	O
+patient	O
+.	O
+
+The	O
+administration	O
+of	O
+lamivudine	O
+to	O
+patients	O
+with	O
+HBV	O
+-	O
+related	O
+cirrhosis	B
+,	O
+like	O
+our	O
+present	O
+case	O
+,	O
+should	O
+be	O
+considered	O
+as	O
+an	O
+initial	O
+medical	O
+therapeutic	O
+option	O
+,	O
+especially	O
+in	O
+countries	O
+where	O
+liver	O
+transplantation	O
+is	O
+not	O
+reliably	O
+available	O
+.	O
+
+Antiarrhythmic	O
+effects	O
+of	O
+optical	O
+isomers	O
+of	O
+cibenzoline	O
+on	O
+canine	O
+ventricular	B
+arrhythmias	I
+.	O
+
+Antiarrhythmic	O
+effects	O
+of	O
+(	O
++	O
+)	O
+-	O
+cibenzoline	O
+and	O
+(	O
+-	O
+)	O
+-	O
+cibenzoline	O
+were	O
+examined	O
+using	O
+two	O
+canine	O
+ventricular	B
+arrhythmia	I
+models	O
+.	O
+
+Digitalis	O
+arrhythmia	B
+,	O
+which	O
+is	O
+suppressed	O
+by	O
+Na	O
+channel	O
+blockers	O
+,	O
+was	O
+induced	O
+by	O
+intermittent	O
+intravenous	O
+(	O
+i	O
+.	O
+v	O
+.	O
+)	O
+injection	O
+of	O
+ouabain	O
+in	O
+pentobarbital	O
+-	O
+anesthetized	O
+dogs	O
+.	O
+
+Adrenaline	B
+arrhythmia	I
+,	O
+which	O
+is	O
+suppressed	O
+by	O
+Ca	O
+channel	O
+blockers	O
+,	O
+was	O
+induced	O
+by	O
+adrenaline	O
+infusion	O
+in	O
+halothane	O
+-	O
+anesthetized	O
+dogs	O
+.	O
+
+Ten	O
+and	O
+5	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+(	O
++	O
+)	O
+-	O
+cibenzoline	O
+suppressed	O
+digitalis	O
+-	O
+and	O
+adrenaline	O
+-	O
+induced	O
+arrhythmias	B
+,	O
+respectively	O
+.	O
+
+The	O
+minimum	O
+effective	O
+plasma	O
+concentrations	O
+of	O
+(	O
++	O
+)	O
+-	O
+cibenzoline	O
+for	O
+digitalis	O
+-	O
+and	O
+adrenaline	O
+-	O
+induced	O
+arrhythmias	B
+were	O
+1	O
+.	O
+4	O
++	O
+/	O
+-	O
+0	O
+.	O
+4	O
+and	O
+2	O
+.	O
+0	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+micrograms	O
+/	O
+ml	O
+,	O
+respectively	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+,	O
+n	O
+=	O
+6	O
+)	O
+.	O
+
+A	O
+lower	O
+dose	O
+of	O
+1	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+of	O
+(	O
+-	O
+)	O
+-	O
+cibenzoline	O
+suppressed	O
+the	O
+digitalis	O
+-	O
+induced	O
+arrhythmia	B
+,	O
+whereas	O
+5	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+was	O
+needed	O
+to	O
+suppress	O
+adrenaline	O
+-	O
+induced	O
+arrhythmias	B
+.	O
+
+The	O
+minimum	O
+effective	O
+plasma	O
+concentrations	O
+of	O
+(	O
+-	O
+)	O
+-	O
+cibenzoline	O
+for	O
+digitalis	O
+-	O
+and	O
+adrenaline	O
+-	O
+induced	O
+arrhythmia	B
+were	O
+0	O
+.	O
+06	O
++	O
+/	O
+-	O
+0	O
+.	O
+04	O
+and	O
+0	O
+.	O
+7	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+micrograms	O
+/	O
+ml	O
+,	O
+respectively	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+,	O
+n	O
+=	O
+6	O
+)	O
+.	O
+
+The	O
+stronger	O
+antiarrhythmic	O
+effect	O
+of	O
+(	O
+-	O
+)	O
+-	O
+cibenzoline	O
+indicates	O
+that	O
+(	O
+-	O
+)	O
+-	O
+isomer	O
+may	O
+have	O
+an	O
+effect	O
+nearly	O
+5	O
+-	O
+20	O
+times	O
+stronger	O
+in	O
+suppressing	O
+Na	O
+channels	O
+,	O
+but	O
+effects	O
+of	O
+both	O
+drugs	O
+on	O
+Ca	O
+channels	O
+may	O
+be	O
+almost	O
+equipotent	O
+.	O
+
+Passage	O
+of	O
+mannitol	O
+into	O
+the	O
+brain	O
+around	O
+gliomas	B
+:	O
+a	O
+potential	O
+cause	O
+of	O
+rebound	O
+phenomenon	O
+.	O
+
+A	O
+study	O
+on	O
+21	O
+patients	O
+.	O
+
+AIM	O
+:	O
+Widespread	O
+use	O
+of	O
+mannitol	O
+to	O
+reduce	O
+brain	B
+edema	I
+and	O
+lower	O
+elevated	B
+ICP	I
+in	O
+brain	B
+tumor	I
+patients	O
+continues	O
+to	O
+be	O
+afflicted	O
+by	O
+the	O
+so	O
+-	O
+called	O
+rebound	O
+phenomenon	O
+.	O
+
+Leakage	O
+of	O
+mannitol	O
+into	O
+the	O
+brain	O
+parenchyma	O
+through	O
+an	O
+altered	O
+BBB	O
+and	O
+secondary	O
+reversal	O
+of	O
+osmotic	O
+gradient	O
+is	O
+considered	O
+the	O
+major	O
+cause	O
+of	O
+rebound	O
+.	O
+
+This	O
+has	O
+only	O
+been	O
+demonstrated	O
+experimentally	O
+in	O
+animals	O
+.	O
+
+As	O
+a	O
+contribution	O
+to	O
+this	O
+issue	O
+we	O
+decided	O
+to	O
+research	O
+the	O
+possible	O
+passage	O
+of	O
+mannitol	O
+into	O
+the	O
+brain	O
+after	O
+administration	O
+to	O
+21	O
+brain	B
+tumor	I
+patients	O
+.	O
+
+METHODS	O
+:	O
+Mannitol	O
+(	O
+18	O
+%	O
+solution	O
+;	O
+1	O
+g	O
+/	O
+kg	O
+)	O
+was	O
+administered	O
+as	O
+a	O
+bolus	O
+to	O
+patients	O
+(	O
+ten	O
+had	O
+malignant	B
+glioma	I
+,	O
+seven	O
+brain	O
+metastases	B
+and	O
+four	O
+meningioma	B
+)	O
+about	O
+30	O
+minutes	O
+before	O
+craniotomy	O
+.	O
+
+During	O
+resection	O
+,	O
+a	O
+sample	O
+of	O
+the	O
+surrounding	O
+edematous	B
+white	O
+matter	O
+was	O
+taken	O
+at	O
+the	O
+same	O
+time	O
+as	O
+a	O
+10	O
+ml	O
+venous	O
+blood	O
+sample	O
+.	O
+
+Mannitol	O
+concentrations	O
+were	O
+measured	O
+in	O
+plasma	O
+and	O
+white	O
+matter	O
+by	O
+a	O
+modified	O
+version	O
+of	O
+the	O
+enzyme	O
+assay	O
+of	O
+Blonquist	O
+et	O
+al	O
+.	O
+
+RESULTS	O
+:	O
+In	O
+most	O
+glioma	B
+patients	O
+,	O
+mannitol	O
+concentrations	O
+in	O
+white	O
+matter	O
+were	O
+2	O
+to	O
+6	O
+times	O
+higher	O
+than	O
+in	O
+plasma	O
+(	O
+mean	O
+3	O
+.	O
+5	O
+times	O
+)	O
+.	O
+
+In	O
+meningioma	B
+and	O
+metastases	B
+patients	O
+plasma	O
+concentrations	O
+of	O
+mannitol	O
+were	O
+higher	O
+than	O
+white	O
+matter	O
+concentrations	O
+except	O
+in	O
+three	O
+cases	O
+with	O
+infiltration	O
+by	O
+neoplastic	O
+cells	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+results	O
+of	O
+our	O
+study	O
+show	O
+that	O
+even	O
+after	O
+a	O
+single	O
+bolus	O
+,	O
+mannitol	O
+may	O
+leak	O
+through	O
+the	O
+altered	O
+BBB	O
+near	O
+gliomas	B
+,	O
+reversing	O
+the	O
+initial	O
+plasma	O
+-	O
+to	O
+-	O
+blood	O
+osmotic	O
+gradient	O
+,	O
+aggravating	O
+peritumoral	O
+edema	B
+and	O
+promoting	O
+rebound	O
+of	O
+ICP	O
+.	O
+
+Placebo	O
+-	O
+level	O
+incidence	O
+of	O
+extrapyramidal	B
+symptoms	I
+(	O
+EPS	B
+)	O
+with	O
+quetiapine	O
+in	O
+controlled	O
+studies	O
+of	O
+patients	O
+with	O
+bipolar	B
+mania	I
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+evaluate	O
+extrapyramidal	B
+symptoms	I
+(	O
+EPS	B
+)	O
+,	O
+including	O
+akathisia	B
+,	O
+with	O
+quetiapine	O
+in	O
+patients	O
+with	O
+bipolar	B
+mania	I
+.	O
+
+METHODS	O
+:	O
+Data	O
+were	O
+analyzed	O
+from	O
+four	O
+similarly	O
+designed	O
+,	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+3	O
+-	O
+to	O
+12	O
+-	O
+week	O
+studies	O
+.	O
+
+Two	O
+studies	O
+evaluated	O
+quetiapine	O
+monotherapy	O
+(	O
+up	O
+to	O
+800	O
+mg	O
+/	O
+day	O
+)	O
+(	O
+n	O
+=	O
+209	O
+)	O
+versus	O
+placebo	O
+(	O
+n	O
+=	O
+198	O
+)	O
+,	O
+with	O
+lithium	O
+or	O
+haloperidol	O
+monotherapy	O
+as	O
+respective	O
+active	O
+controls	O
+.	O
+
+Two	O
+studies	O
+evaluated	O
+quetiapine	O
+(	O
+up	O
+to	O
+800	O
+mg	O
+/	O
+day	O
+)	O
+in	O
+combination	O
+with	O
+a	O
+mood	O
+stabilizer	O
+(	O
+lithium	O
+or	O
+divalproex	O
+,	O
+QTP	O
++	O
+Li	O
+/	O
+DVP	O
+)	O
+(	O
+n	O
+=	O
+196	O
+)	O
+compared	O
+to	O
+placebo	O
+and	O
+mood	O
+stabilizer	O
+(	O
+PBO	O
++	O
+Li	O
+/	O
+DVP	O
+)	O
+(	O
+n	O
+=	O
+203	O
+)	O
+.	O
+
+Extrapyramidal	B
+symptoms	I
+were	O
+evaluated	O
+using	O
+the	O
+Simpson	O
+-	O
+Angus	O
+Scale	O
+(	O
+SAS	O
+)	O
+,	O
+the	O
+Barnes	O
+Akathisia	O
+Rating	O
+Scale	O
+(	O
+BARS	O
+)	O
+,	O
+adverse	O
+event	O
+reports	O
+and	O
+anticholinergic	O
+drug	O
+usage	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+incidence	O
+of	O
+EPS	B
+-	O
+related	O
+adverse	O
+events	O
+,	O
+including	O
+akathisia	B
+,	O
+was	O
+no	O
+different	O
+with	O
+quetiapine	O
+monotherapy	O
+(	O
+12	O
+.	O
+9	O
+%	O
+)	O
+than	O
+with	O
+placebo	O
+(	O
+13	O
+.	O
+1	O
+%	O
+)	O
+.	O
+
+Similarly	O
+,	O
+EPS	B
+-	O
+related	O
+adverse	O
+events	O
+with	O
+QTP	O
++	O
+Li	O
+/	O
+DVP	O
+(	O
+21	O
+.	O
+4	O
+%	O
+)	O
+were	O
+no	O
+different	O
+than	O
+with	O
+PBO	O
++	O
+Li	O
+/	O
+DVP	O
+(	O
+19	O
+.	O
+2	O
+%	O
+)	O
+.	O
+
+Adverse	O
+events	O
+related	O
+to	O
+EPS	B
+occurred	O
+in	O
+59	O
+.	O
+6	O
+%	O
+of	O
+patients	O
+treated	O
+with	O
+haloperidol	O
+(	O
+n	O
+=	O
+99	O
+)	O
+monotherapy	O
+,	O
+whereas	O
+26	O
+.	O
+5	O
+%	O
+of	O
+patients	O
+treated	O
+with	O
+lithium	O
+(	O
+n	O
+=	O
+98	O
+)	O
+monotherapy	O
+experienced	O
+adverse	O
+events	O
+related	O
+to	O
+EPS	B
+.	O
+
+The	O
+incidence	O
+of	O
+akathisia	B
+was	O
+low	O
+and	O
+similar	O
+with	O
+quetiapine	O
+monotherapy	O
+(	O
+3	O
+.	O
+3	O
+%	O
+)	O
+and	O
+placebo	O
+(	O
+6	O
+.	O
+1	O
+%	O
+)	O
+,	O
+and	O
+with	O
+QTP	O
++	O
+Li	O
+/	O
+DVP	O
+(	O
+3	O
+.	O
+6	O
+%	O
+)	O
+and	O
+PBO	O
++	O
+Li	O
+/	O
+DVP	O
+(	O
+4	O
+.	O
+9	O
+%	O
+)	O
+.	O
+
+Lithium	O
+was	O
+associated	O
+with	O
+a	O
+significantly	O
+higher	O
+incidence	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+of	O
+tremor	B
+(	O
+18	O
+.	O
+4	O
+%	O
+)	O
+than	O
+quetiapine	O
+(	O
+5	O
+.	O
+6	O
+%	O
+)	O
+;	O
+cerebellar	O
+tremor	B
+,	O
+which	O
+is	O
+a	O
+known	O
+adverse	O
+effect	O
+of	O
+lithium	O
+,	O
+may	O
+have	O
+contributed	O
+to	O
+the	O
+elevated	O
+rate	O
+of	O
+tremor	B
+in	O
+patients	O
+receiving	O
+lithium	O
+therapy	O
+.	O
+
+Haloperidol	O
+induced	O
+a	O
+significantly	O
+higher	O
+incidence	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+of	O
+akathisia	B
+(	O
+33	O
+.	O
+3	O
+%	O
+versus	O
+5	O
+.	O
+9	O
+%	O
+)	O
+,	O
+tremor	B
+(	O
+30	O
+.	O
+3	O
+%	O
+versus	O
+7	O
+.	O
+8	O
+%	O
+)	O
+,	O
+and	O
+extrapyramidal	B
+syndrome	I
+(	O
+35	O
+.	O
+4	O
+%	O
+versus	O
+5	O
+.	O
+9	O
+%	O
+)	O
+than	O
+quetiapine	O
+.	O
+
+No	O
+significant	O
+differences	O
+were	O
+observed	O
+between	O
+quetiapine	O
+and	O
+placebo	O
+on	O
+SAS	O
+and	O
+BARS	O
+scores	O
+.	O
+
+Anticholinergic	O
+use	O
+was	O
+low	O
+and	O
+similar	O
+with	O
+quetiapine	O
+or	O
+placebo	O
+.	O
+
+CONCLUSIONS	O
+:	O
+In	O
+bipolar	B
+mania	I
+,	O
+the	O
+incidence	O
+of	O
+EPS	B
+,	O
+including	O
+akathisia	B
+,	O
+with	O
+quetiapine	O
+therapy	O
+is	O
+similar	O
+to	O
+that	O
+with	O
+placebo	O
+.	O
+
+Is	O
+phenytoin	O
+administration	O
+safe	O
+in	O
+a	O
+hypothermic	B
+child	O
+?	O
+
+A	O
+male	O
+neonate	O
+with	O
+a	O
+Chiari	B
+malformation	I
+and	O
+a	O
+leaking	O
+myelomeningocoele	O
+underwent	O
+ventriculoperitoneal	O
+shunt	O
+insertion	O
+followed	O
+by	O
+repair	O
+of	O
+myelomeningocoele	O
+.	O
+
+During	O
+anaesthesia	O
+and	O
+surgery	O
+,	O
+he	O
+inadvertently	O
+became	O
+moderately	O
+hypothermic	B
+.	O
+
+Intravenous	O
+phenytoin	O
+was	O
+administered	O
+during	O
+the	O
+later	O
+part	O
+of	O
+the	O
+surgery	O
+for	O
+seizure	B
+prophylaxis	O
+.	O
+
+Following	O
+phenytoin	O
+administration	O
+,	O
+the	O
+patient	O
+developed	O
+acute	O
+severe	O
+bradycardia	B
+,	O
+refractory	O
+to	O
+atropine	O
+and	O
+adrenaline	O
+.	O
+
+The	O
+cardiac	O
+depressant	O
+actions	O
+of	O
+phenytoin	O
+and	O
+hypothermia	B
+can	O
+be	O
+additive	O
+.	O
+
+Administration	O
+of	O
+phenytoin	O
+in	O
+the	O
+presence	O
+of	O
+hypothermia	B
+may	O
+lead	O
+to	O
+an	O
+adverse	O
+cardiac	O
+event	O
+in	O
+children	O
+.	O
+
+As	O
+phenytoin	O
+is	O
+a	O
+commonly	O
+used	O
+drug	O
+,	O
+clinicians	O
+need	O
+to	O
+be	O
+aware	O
+of	O
+this	O
+interaction	O
+.	O
+
+Valproate	O
+-	O
+induced	O
+chorea	B
+and	O
+encephalopathy	B
+in	O
+atypical	O
+nonketotic	B
+hyperglycinemia	I
+.	O
+
+Nonketotic	B
+hyperglycinemia	I
+is	O
+a	O
+disorder	B
+of	I
+amino	I
+acid	I
+metabolism	I
+in	O
+which	O
+a	O
+defect	O
+in	O
+the	O
+glycine	O
+cleavage	O
+system	O
+leads	O
+to	O
+an	O
+accumulation	O
+of	O
+glycine	O
+in	O
+the	O
+brain	O
+and	O
+other	O
+body	O
+compartments	O
+.	O
+
+In	O
+the	O
+classical	O
+form	O
+it	O
+presents	O
+as	O
+neonatal	O
+apnea	B
+,	O
+intractable	O
+seizures	B
+,	O
+and	O
+hypotonia	B
+,	O
+followed	O
+by	O
+significant	O
+psychomotor	B
+retardation	I
+.	O
+
+An	O
+important	O
+subset	O
+of	O
+children	O
+with	O
+nonketotic	B
+hyperglycinemia	I
+are	O
+atypical	O
+variants	O
+who	O
+present	O
+in	O
+a	O
+heterogeneous	O
+manner	O
+.	O
+
+This	O
+report	O
+describes	O
+a	O
+patient	O
+with	O
+mild	O
+language	B
+delay	I
+and	O
+mental	B
+retardation	I
+,	O
+who	O
+was	O
+found	O
+to	O
+have	O
+nonketotic	B
+hyperglycinemia	I
+following	O
+her	O
+presentation	O
+with	O
+acute	O
+encephalopathy	B
+and	O
+chorea	B
+shortly	O
+after	O
+initiation	O
+of	O
+valproate	O
+therapy	O
+.	O
+
+Delayed	O
+institution	O
+of	O
+hypertension	B
+during	O
+focal	O
+cerebral	B
+ischemia	I
+:	O
+effect	O
+on	O
+brain	B
+edema	I
+.	O
+
+The	O
+effect	O
+of	O
+induced	O
+hypertension	B
+instituted	O
+after	O
+a	O
+2	O
+-	O
+h	O
+delay	O
+following	O
+middle	B
+cerebral	I
+artery	I
+occlusion	I
+(	O
+MCAO	B
+)	O
+on	O
+brain	B
+edema	I
+formation	O
+and	O
+histochemical	O
+injury	O
+was	O
+studied	O
+.	O
+
+Under	O
+isoflurane	O
+anesthesia	O
+,	O
+the	O
+MCA	O
+of	O
+14	O
+spontaneously	O
+hypertensive	B
+rats	O
+was	O
+occluded	O
+.	O
+
+In	O
+the	O
+control	O
+group	O
+(	O
+n	O
+=	O
+7	O
+)	O
+,	O
+the	O
+mean	O
+arterial	O
+pressure	O
+(	O
+MAP	O
+)	O
+was	O
+not	O
+manipulated	O
+.	O
+
+In	O
+the	O
+hypertensive	B
+group	O
+(	O
+n	O
+=	O
+7	O
+)	O
+,	O
+the	O
+MAP	O
+was	O
+elevated	O
+by	O
+25	O
+-	O
+30	O
+mm	O
+Hg	O
+beginning	O
+2	O
+h	O
+after	O
+MCAO	B
+.	O
+
+Four	O
+hours	O
+after	O
+MCAO	B
+,	O
+the	O
+rats	O
+were	O
+killed	O
+and	O
+the	O
+brains	O
+harvested	O
+.	O
+
+The	O
+brains	O
+were	O
+sectioned	O
+along	O
+coronal	O
+planes	O
+spanning	O
+the	O
+distribution	O
+of	O
+ischemia	B
+produced	O
+by	O
+MCAO	B
+.	O
+
+Specific	O
+gravity	O
+(	O
+SG	O
+)	O
+was	O
+determined	O
+in	O
+the	O
+subcortex	O
+and	O
+in	O
+two	O
+sites	O
+in	O
+the	O
+cortex	O
+(	O
+core	O
+and	O
+periphery	O
+of	O
+the	O
+ischemic	B
+territory	O
+)	O
+.	O
+
+The	O
+extent	O
+of	O
+neuronal	B
+injury	I
+was	O
+determined	O
+by	O
+2	O
+,	O
+3	O
+,	O
+5	O
+-	O
+triphenyltetrazolium	O
+staining	O
+.	O
+
+In	O
+the	O
+ischemic	B
+core	O
+,	O
+there	O
+was	O
+no	O
+difference	O
+in	O
+SG	O
+in	O
+the	O
+subcortex	O
+and	O
+cortex	O
+in	O
+the	O
+two	O
+groups	O
+.	O
+
+In	O
+the	O
+periphery	O
+of	O
+the	O
+ischemic	B
+territory	O
+,	O
+SG	O
+in	O
+the	O
+cortex	O
+was	O
+greater	O
+(	O
+less	O
+edema	B
+accumulation	O
+)	O
+in	O
+the	O
+hypertensive	B
+group	O
+(	O
+1	O
+.	O
+041	O
++	O
+/	O
+-	O
+0	O
+.	O
+001	O
+vs	O
+1	O
+.	O
+039	O
++	O
+/	O
+-	O
+0	O
+.	O
+001	O
+,	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+area	O
+of	O
+histochemical	O
+injury	O
+(	O
+as	O
+a	O
+percent	O
+of	O
+the	O
+cross	O
+-	O
+sectional	O
+area	O
+of	O
+the	O
+hemisphere	O
+)	O
+was	O
+less	O
+in	O
+the	O
+hypertensive	B
+group	O
+(	O
+33	O
++	O
+/	O
+-	O
+3	O
+%	O
+vs	O
+21	O
++	O
+/	O
+-	O
+2	O
+%	O
+,	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+data	O
+indicate	O
+that	O
+phenylephrine	O
+-	O
+induced	O
+hypertension	B
+instituted	O
+2	O
+h	O
+after	O
+MCAO	B
+does	O
+not	O
+aggravate	O
+edema	B
+in	O
+the	O
+ischemic	B
+core	O
+,	O
+that	O
+it	O
+improves	O
+edema	B
+in	O
+the	O
+periphery	O
+of	O
+the	O
+ischemic	B
+territory	O
+,	O
+and	O
+that	O
+it	O
+reduces	O
+the	O
+area	O
+of	O
+histochemical	O
+neuronal	B
+dysfunction	I
+.	O
+
+Behavioral	O
+effects	O
+of	O
+pubertal	O
+anabolic	O
+androgenic	O
+steroid	O
+exposure	O
+in	O
+male	O
+rats	O
+with	O
+low	O
+serotonin	O
+.	O
+
+The	O
+goal	O
+of	O
+this	O
+study	O
+was	O
+to	O
+assess	O
+the	O
+interactive	O
+effects	O
+of	O
+chronic	O
+anabolic	O
+androgenic	O
+steroid	O
+(	O
+AAS	O
+)	O
+exposure	O
+and	O
+brain	O
+serotonin	O
+(	O
+5	O
+-	O
+hydroxytryptamine	O
+,	O
+5	O
+-	O
+HT	O
+)	O
+depletion	O
+on	O
+behavior	O
+of	O
+pubertal	O
+male	O
+rats	O
+.	O
+
+Serotonin	O
+was	O
+depleted	O
+beginning	O
+on	O
+postnatal	O
+day	O
+26	O
+with	O
+parachlorophenylalanine	O
+(	O
+PCPA	O
+100	O
+mg	O
+/	O
+kg	O
+,	O
+every	O
+other	O
+day	O
+)	O
+;	O
+controls	O
+received	O
+saline	O
+.	O
+
+At	O
+puberty	O
+(	O
+P40	O
+)	O
+,	O
+half	O
+the	O
+PCPA	O
+-	O
+treated	O
+rats	O
+and	O
+half	O
+the	O
+saline	O
+-	O
+treated	O
+rats	O
+began	O
+treatment	O
+with	O
+testosterone	O
+(	O
+T	O
+,	O
+5	O
+mg	O
+/	O
+kg	O
+,	O
+5	O
+days	O
+/	O
+week	O
+)	O
+.	O
+
+Behavioral	O
+measures	O
+included	O
+locomotion	O
+,	O
+irritability	B
+,	O
+copulation	O
+,	O
+partner	O
+preference	O
+,	O
+and	O
+aggression	B
+.	O
+
+Animals	O
+were	O
+tested	O
+for	O
+aggression	B
+in	O
+their	O
+home	O
+cage	O
+,	O
+both	O
+with	O
+and	O
+without	O
+physical	O
+provocation	O
+(	O
+mild	O
+tail	O
+pinch	O
+)	O
+.	O
+
+Brain	O
+levels	O
+of	O
+5	O
+-	O
+HT	O
+and	O
+its	O
+metabolite	O
+,	O
+5	O
+-	O
+hydroxyindoleacetic	O
+acid	O
+(	O
+5	O
+-	O
+HIAA	O
+)	O
+,	O
+were	O
+determined	O
+using	O
+HPLC	O
+.	O
+
+PCPA	O
+significantly	O
+and	O
+substantially	O
+depleted	O
+5	O
+-	O
+HT	O
+and	O
+5	O
+-	O
+HIAA	O
+in	O
+all	O
+brain	O
+regions	O
+examined	O
+.	O
+
+Chronic	O
+T	O
+treatment	O
+significantly	O
+decreased	O
+5	O
+-	O
+HT	O
+and	O
+5	O
+-	O
+HIAA	O
+in	O
+certain	O
+brain	O
+areas	O
+,	O
+but	O
+to	O
+a	O
+much	O
+lesser	O
+extent	O
+than	O
+PCPA	O
+.	O
+
+Chronic	O
+exposure	O
+to	O
+PCPA	O
+alone	O
+significantly	O
+decreased	O
+locomotor	O
+activity	O
+and	O
+increased	O
+irritability	B
+but	O
+had	O
+no	O
+effect	O
+on	O
+sexual	O
+behavior	O
+,	O
+partner	O
+preference	O
+,	O
+or	O
+aggression	B
+.	O
+
+T	O
+alone	O
+had	O
+no	O
+effect	O
+on	O
+locomotion	O
+,	O
+irritability	B
+,	O
+or	O
+sexual	O
+behavior	O
+but	O
+increased	O
+partner	O
+preference	O
+and	O
+aggression	B
+.	O
+
+The	O
+most	O
+striking	O
+effect	O
+of	O
+combining	O
+T	O
++	O
+PCPA	O
+was	O
+a	O
+significant	O
+increase	O
+in	O
+attack	O
+frequency	O
+as	O
+well	O
+as	O
+a	O
+significant	O
+decrease	O
+in	O
+the	O
+latency	O
+to	O
+attack	O
+,	O
+particularly	O
+following	O
+physical	O
+provocation	O
+.	O
+
+Based	O
+on	O
+these	O
+data	O
+,	O
+it	O
+can	O
+be	O
+speculated	O
+that	O
+pubertal	O
+AAS	O
+users	O
+with	O
+low	O
+central	O
+5	O
+-	O
+HT	O
+may	O
+be	O
+especially	O
+prone	O
+to	O
+exhibit	O
+aggressive	B
+behavior	I
+.	O
+
+Effects	O
+of	O
+UMB24	O
+and	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+SM	O
+21	O
+,	O
+putative	O
+sigma2	O
+-	O
+preferring	O
+antagonists	O
+,	O
+on	O
+behavioral	O
+toxic	O
+and	O
+stimulant	O
+effects	O
+of	O
+cocaine	O
+in	O
+mice	O
+.	O
+
+Earlier	O
+studies	O
+have	O
+demonstrated	O
+that	O
+antagonism	O
+of	O
+sigma1	O
+receptors	O
+attenuates	O
+the	O
+convulsive	B
+,	O
+lethal	O
+,	O
+locomotor	O
+stimulatory	O
+and	O
+rewarding	O
+actions	O
+of	O
+cocaine	O
+in	O
+mice	O
+.	O
+
+In	O
+contrast	O
+,	O
+the	O
+contribution	O
+of	O
+sigma2	O
+receptors	O
+is	O
+unclear	O
+because	O
+experimental	O
+tools	O
+to	O
+selectively	O
+target	O
+this	O
+subtype	O
+are	O
+unavailable	O
+.	O
+
+To	O
+begin	O
+addressing	O
+this	O
+need	O
+,	O
+we	O
+characterized	O
+UMB24	O
+(	O
+1	O
+-	O
+(	O
+2	O
+-	O
+phenethyl	O
+)	O
+-	O
+4	O
+-	O
+(	O
+2	O
+-	O
+pyridyl	O
+)	O
+-	O
+piperazine	O
+)	O
+and	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+SM	O
+21	O
+(	O
+3alpha	O
+-	O
+tropanyl	O
+-	O
+2	O
+-	O
+(	O
+4	O
+-	O
+chorophenoxy	O
+)	O
+butyrate	O
+)	O
+in	O
+receptor	O
+binding	O
+and	O
+behavioral	O
+studies	O
+.	O
+
+Receptor	O
+binding	O
+studies	O
+confirmed	O
+that	O
+UMB24	O
+and	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+SM	O
+21	O
+display	O
+preferential	O
+affinity	O
+for	O
+sigma2	O
+over	O
+sigma1	O
+receptors	O
+.	O
+
+In	O
+behavioral	O
+studies	O
+,	O
+pretreatment	O
+of	O
+Swiss	O
+Webster	O
+mice	O
+with	O
+UMB24	O
+or	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+SM	O
+21	O
+significantly	O
+attenuated	O
+cocaine	O
+-	O
+induced	O
+convulsions	B
+and	O
+locomotor	O
+activity	O
+,	O
+but	O
+not	O
+lethality	O
+.	O
+
+When	O
+administered	O
+alone	O
+,	O
+(	O
++	O
+/	O
+-	O
+)	O
+-	O
+SM	O
+21	O
+produced	O
+no	O
+significant	O
+effects	O
+compared	O
+to	O
+control	O
+injections	O
+of	O
+saline	O
+,	O
+but	O
+UMB24	O
+had	O
+locomotor	O
+depressant	O
+actions	O
+.	O
+
+Together	O
+,	O
+the	O
+data	O
+suggest	O
+that	O
+sigma2	O
+receptor	O
+antagonists	O
+have	O
+the	O
+potential	O
+to	O
+attenuate	O
+some	O
+of	O
+the	O
+behavioral	O
+effects	O
+of	O
+cocaine	O
+,	O
+and	O
+further	O
+development	O
+of	O
+more	O
+selective	O
+,	O
+high	O
+affinity	O
+ligands	O
+are	O
+warranted	O
+.	O
+
+Cardiac	B
+arrest	I
+in	O
+a	O
+child	O
+with	O
+cerebral	B
+palsy	I
+undergoing	O
+sevoflurane	O
+induction	O
+of	O
+anesthesia	O
+after	O
+preoperative	O
+clonidine	O
+.	O
+
+Clonidine	O
+is	O
+a	O
+frequently	O
+administered	O
+alpha2	O
+-	O
+adrenergic	O
+agonist	O
+which	O
+can	O
+decrease	O
+heart	O
+rate	O
+and	O
+blood	O
+pressure	O
+.	O
+
+We	O
+present	O
+a	O
+case	O
+of	O
+a	O
+5	O
+-	O
+year	O
+-	O
+old	O
+child	O
+with	O
+cerebral	B
+palsy	I
+and	O
+seizure	B
+disorder	I
+,	O
+receiving	O
+clonidine	O
+for	O
+restlessness	B
+,	O
+who	O
+presented	O
+for	O
+placement	O
+of	O
+a	O
+baclofen	O
+pump	O
+.	O
+
+Without	O
+the	O
+knowledge	O
+of	O
+the	O
+medical	O
+personnel	O
+,	O
+the	O
+patient	O
+'	O
+s	O
+mother	O
+administered	O
+three	O
+doses	O
+of	O
+clonidine	O
+during	O
+the	O
+evening	O
+before	O
+and	O
+morning	O
+of	O
+surgery	O
+to	O
+reduce	O
+anxiety	B
+.	O
+
+During	O
+induction	O
+of	O
+anesthesia	O
+,	O
+the	O
+patient	O
+developed	O
+bradycardia	B
+and	O
+hypotension	B
+requiring	O
+cardiac	O
+resuscitation	O
+.	O
+
+There	O
+are	O
+no	O
+previous	O
+reports	O
+of	O
+clonidine	O
+-	O
+associated	O
+cardiac	B
+arrest	I
+in	O
+a	O
+child	O
+undergoing	O
+induction	O
+of	O
+anesthesia	O
+.	O
+
+Angiotensin	O
+-	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+inhibitor	O
+-	O
+associated	O
+angioedema	B
+of	O
+the	O
+stomach	O
+and	O
+small	O
+intestine	O
+:	O
+a	O
+case	O
+report	O
+.	O
+
+This	O
+is	O
+a	O
+case	O
+report	O
+on	O
+a	O
+45	O
+-	O
+year	O
+old	O
+African	O
+-	O
+American	O
+female	O
+with	O
+newly	O
+diagnosed	O
+hypertension	B
+,	O
+who	O
+was	O
+started	O
+on	O
+a	O
+combination	O
+pill	O
+of	O
+amlodipine	O
+/	O
+benazapril	O
+10	O
+/	O
+5	O
+mg	O
+.	O
+
+The	O
+very	O
+next	O
+day	O
+,	O
+she	O
+presented	O
+at	O
+the	O
+emergency	O
+room	O
+(	O
+ER	O
+)	O
+with	O
+abdominal	B
+pain	I
+,	O
+nausea	B
+and	O
+vomiting	B
+.	O
+
+Physical	O
+exam	O
+,	O
+complete	O
+metabolic	O
+panel	O
+,	O
+and	O
+hemogram	O
+were	O
+in	O
+the	O
+normal	O
+range	O
+.	O
+
+She	O
+was	O
+discharged	O
+from	O
+the	O
+ER	O
+after	O
+a	O
+few	O
+hours	O
+of	O
+treatment	O
+with	O
+fluid	O
+and	O
+analgesics	O
+.	O
+
+However	O
+,	O
+she	O
+returned	O
+to	O
+the	O
+ER	O
+the	O
+next	O
+day	O
+with	O
+the	O
+same	O
+complaints	O
+.	O
+
+This	O
+time	O
+the	O
+physical	O
+exam	O
+was	O
+significant	O
+for	O
+a	O
+distended	O
+abdomen	O
+with	O
+dullness	O
+to	O
+percussion	O
+.	O
+
+CT	O
+scan	O
+of	O
+the	O
+abdomen	O
+revealed	O
+markedly	O
+thickened	O
+antrum	O
+of	O
+the	O
+stomach	O
+,	O
+duodenum	O
+and	O
+jejunum	O
+,	O
+along	O
+with	O
+fluid	O
+in	O
+the	O
+abdominal	O
+and	O
+pelvic	O
+cavity	O
+.	O
+
+Angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitor	O
+(	O
+ACEI	O
+)	O
+-	O
+induced	O
+angioedema	B
+was	O
+suspected	O
+,	O
+and	O
+anti	O
+-	O
+hypertensive	B
+medications	O
+were	O
+discontinued	O
+.	O
+
+Her	O
+symptoms	O
+improved	O
+within	O
+the	O
+next	O
+24	O
+hours	O
+,	O
+and	O
+repeat	O
+CT	O
+after	O
+72	O
+hours	O
+revealed	O
+marked	O
+improvement	O
+in	O
+stomach	O
+and	O
+small	O
+bowel	O
+thickening	O
+and	O
+resolution	O
+of	O
+ascites	B
+.	O
+
+The	O
+recognition	O
+of	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+and	O
+angiotensin	O
+receptor	O
+blocker	O
+(	O
+ARB	O
+)	O
+intestinal	B
+angioedema	I
+constitutes	O
+a	O
+challenge	O
+to	O
+primary	O
+care	O
+physicians	O
+,	O
+internists	O
+,	O
+emergency	O
+room	O
+personal	O
+and	O
+surgeons	O
+.	O
+
+Carbamazepine	O
+-	O
+induced	O
+cardiac	B
+dysfunction	I
+.	O
+
+Characterization	O
+of	O
+two	O
+distinct	O
+clinical	O
+syndromes	O
+.	O
+
+A	O
+patient	O
+with	O
+sinus	O
+bradycardia	B
+and	O
+atrioventricular	B
+block	I
+,	O
+induced	O
+by	O
+carbamazepine	O
+,	O
+prompted	O
+an	O
+extensive	O
+literature	O
+review	O
+of	O
+all	O
+previously	O
+reported	O
+cases	O
+.	O
+
+From	O
+the	O
+analysis	O
+of	O
+these	O
+cases	O
+,	O
+two	O
+distinct	O
+forms	O
+of	O
+carbamazepine	O
+-	O
+associated	O
+cardiac	B
+dysfunction	I
+emerged	O
+.	O
+
+One	O
+patient	O
+group	O
+developed	O
+sinus	B
+tachycardias	I
+in	O
+the	O
+setting	O
+of	O
+a	O
+massive	O
+carbamazepine	O
+overdose	B
+.	O
+
+The	O
+second	O
+group	O
+consisted	O
+almost	O
+exclusively	O
+of	O
+elderly	O
+women	O
+who	O
+developed	O
+potentially	O
+life	O
+-	O
+threatening	O
+bradyarrhythmias	B
+or	O
+atrioventricular	B
+conduction	I
+delay	I
+,	O
+associated	O
+with	O
+either	O
+therapeutic	O
+or	O
+modestly	O
+elevated	O
+carbamazepine	O
+serum	O
+levels	O
+.	O
+
+Because	O
+carbamazepine	O
+is	O
+widely	O
+used	O
+in	O
+the	O
+treatment	O
+of	O
+many	O
+neurologic	O
+and	O
+psychiatric	B
+conditions	O
+,	O
+the	O
+recognition	O
+of	O
+the	O
+latter	O
+syndrome	O
+has	O
+important	O
+implications	O
+for	O
+the	O
+use	O
+of	O
+this	O
+drug	O
+in	O
+elderly	O
+patients	O
+.	O
+
+Detection	O
+of	O
+abnormal	O
+cardiac	O
+adrenergic	O
+neuron	O
+activity	O
+in	O
+adriamycin	O
+-	O
+induced	O
+cardiomyopathy	B
+with	O
+iodine	O
+-	O
+125	O
+-	O
+metaiodobenzylguanidine	O
+.	O
+
+Radiolabeled	O
+metaiodobenzylguanidine	O
+(	O
+MIBG	O
+)	O
+,	O
+an	O
+analog	O
+of	O
+norepinephrine	O
+(	O
+NE	O
+)	O
+,	O
+serves	O
+as	O
+an	O
+index	O
+of	O
+adrenergic	O
+neuron	O
+integrity	O
+and	O
+function	O
+.	O
+
+Using	O
+a	O
+rat	O
+model	O
+of	O
+adriamycin	O
+-	O
+induced	O
+cardiomyopathy	B
+,	O
+we	O
+tested	O
+the	O
+hypothesis	O
+that	O
+abnormal	O
+cardiac	O
+adrenergic	O
+neuron	O
+activity	O
+may	O
+appear	O
+and	O
+be	O
+exacerbated	O
+dose	O
+-	O
+dependently	O
+in	O
+adriamycin	O
+cardiomyopathy	B
+.	O
+
+The	O
+degree	O
+of	O
+vacuolar	B
+degeneration	I
+of	I
+myocardial	I
+cells	I
+was	O
+analyzed	O
+in	O
+relation	O
+to	O
+the	O
+duration	O
+of	O
+adriamycin	O
+treatment	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+,	O
+once	O
+a	O
+week	O
+)	O
+.	O
+
+There	O
+were	O
+no	O
+abnormalities	O
+or	O
+only	O
+isolated	O
+degeneration	O
+in	O
+the	O
+1	O
+-	O
+or	O
+2	O
+-	O
+wk	O
+treatment	O
+groups	O
+,	O
+isolated	O
+or	O
+scattered	O
+degeneration	O
+in	O
+half	O
+of	O
+the	O
+3	O
+-	O
+wk	O
+group	O
+,	O
+frequent	O
+scattered	O
+degeneration	O
+in	O
+the	O
+4	O
+-	O
+wk	O
+group	O
+,	O
+scattered	O
+or	O
+focal	O
+degeneration	O
+in	O
+the	O
+5	O
+-	O
+wk	O
+group	O
+,	O
+and	O
+extensive	O
+degeneration	O
+in	O
+the	O
+8	O
+-	O
+wk	O
+group	O
+.	O
+
+Myocardial	O
+accumulation	O
+of	O
+[	O
+125I	O
+]	O
+MIBG	O
+4	O
+hr	O
+after	O
+intravenous	O
+injection	O
+did	O
+not	O
+differ	O
+between	O
+the	O
+controls	O
+and	O
+the	O
+groups	O
+treated	O
+3	O
+wk	O
+or	O
+less	O
+.	O
+
+However	O
+,	O
+the	O
+4	O
+-	O
+wk	O
+group	O
+had	O
+a	O
+slightly	O
+lower	O
+accumulation	O
+in	O
+the	O
+right	O
+ventricular	O
+wall	O
+(	O
+82	O
+%	O
+of	O
+the	O
+control	O
+)	O
+and	O
+significantly	O
+lower	O
+accumulation	O
+in	O
+the	O
+left	O
+ventricular	O
+wall	O
+(	O
+about	O
+66	O
+%	O
+of	O
+the	O
+control	O
+:	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+In	O
+the	O
+5	O
+-	O
+wk	O
+group	O
+,	O
+MIBG	O
+accumulation	O
+in	O
+the	O
+right	O
+and	O
+left	O
+ventricular	O
+wall	O
+was	O
+35	O
+%	O
+and	O
+27	O
+%	O
+of	O
+that	O
+in	O
+controls	O
+,	O
+respectively	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+In	O
+the	O
+8	O
+-	O
+wk	O
+group	O
+,	O
+MIBG	O
+accumulation	O
+in	O
+the	O
+right	O
+and	O
+left	O
+ventricular	O
+wall	O
+was	O
+18	O
+%	O
+and	O
+14	O
+%	O
+of	O
+that	O
+in	O
+controls	O
+,	O
+respectively	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Thus	O
+,	O
+MIBG	O
+accumulation	O
+in	O
+the	O
+myocardium	O
+decreased	O
+in	O
+an	O
+adriamycin	O
+dose	O
+-	O
+dependent	O
+manner	O
+.	O
+
+The	O
+appearance	O
+of	O
+impaired	O
+cardiac	O
+adrenergic	O
+neuron	O
+activity	O
+in	O
+the	O
+presence	O
+of	O
+slight	O
+myocardial	B
+impairment	I
+(	O
+scattered	O
+or	O
+focal	O
+vacuolar	B
+degeneration	I
+)	O
+indicates	O
+that	O
+MIBG	O
+scintigraphy	O
+may	O
+be	O
+a	O
+useful	O
+method	O
+for	O
+detection	O
+of	O
+adriamycin	O
+-	O
+induced	O
+cardiomyopathy	B
+.	O
+
+Syncope	B
+and	O
+QT	B
+prolongation	I
+among	O
+patients	O
+treated	O
+with	O
+methadone	O
+for	O
+heroin	O
+dependence	O
+in	O
+the	O
+city	O
+of	O
+Copenhagen	O
+.	O
+
+BACKGROUND	O
+:	O
+Methadone	O
+is	O
+prescribed	O
+to	O
+heroin	O
+addicts	O
+to	O
+decrease	O
+illicit	O
+opioid	O
+use	O
+.	O
+
+Prolongation	O
+of	O
+the	O
+QT	O
+interval	O
+in	O
+the	O
+ECG	O
+of	O
+patients	O
+with	O
+torsade	B
+de	I
+pointes	I
+(	O
+TdP	B
+)	O
+has	O
+been	O
+reported	O
+in	O
+methadone	O
+users	O
+.	O
+
+As	O
+heroin	O
+addicts	O
+sometimes	O
+faint	O
+while	O
+using	O
+illicit	O
+drugs	O
+,	O
+doctors	O
+might	O
+attribute	O
+too	O
+many	O
+episodes	O
+of	O
+syncope	B
+to	O
+illicit	O
+drug	O
+use	O
+and	O
+thereby	O
+underestimate	O
+the	O
+incidence	O
+of	O
+TdP	B
+in	O
+this	O
+special	O
+population	O
+,	O
+and	O
+the	O
+high	O
+mortality	O
+in	O
+this	O
+population	O
+may	O
+,	O
+in	O
+part	O
+,	O
+be	O
+caused	O
+by	O
+the	O
+proarrhythmic	O
+effect	O
+of	O
+methadone	O
+.	O
+
+METHODS	O
+:	O
+In	O
+this	O
+cross	O
+-	O
+sectional	O
+study	O
+interview	O
+,	O
+ECGs	O
+and	O
+blood	O
+samples	O
+were	O
+collected	O
+in	O
+a	O
+population	O
+of	O
+adult	O
+heroin	O
+addicts	O
+treated	O
+with	O
+methadone	O
+or	O
+buprenorphine	O
+on	O
+a	O
+daily	O
+basis	O
+.	O
+
+Of	O
+the	O
+patients	O
+at	O
+the	O
+Drug	O
+Addiction	O
+Service	O
+in	O
+the	O
+municipal	O
+of	O
+Copenhagen	O
+,	O
+450	O
+(	O
+approximately	O
+52	O
+%	O
+)	O
+were	O
+included	O
+.	O
+
+The	O
+QT	O
+interval	O
+was	O
+estimated	O
+from	O
+12	O
+lead	O
+ECGs	O
+.	O
+
+All	O
+participants	O
+were	O
+interviewed	O
+about	O
+any	O
+experience	O
+of	O
+syncope	B
+.	O
+
+The	O
+association	O
+between	O
+opioid	O
+dose	O
+and	O
+QT	O
+,	O
+and	O
+methadone	O
+dose	O
+and	O
+reporting	O
+of	O
+syncope	B
+was	O
+assessed	O
+using	O
+multivariate	O
+linear	O
+regression	O
+and	O
+logistic	O
+regression	O
+,	O
+respectively	O
+.	O
+
+RESULTS	O
+:	O
+Methadone	O
+dose	O
+was	O
+associated	O
+with	O
+longer	O
+QT	O
+interval	O
+of	O
+0	O
+.	O
+140	O
+ms	O
+/	O
+mg	O
+(	O
+p	O
+=	O
+0	O
+.	O
+002	O
+)	O
+.	O
+
+No	O
+association	O
+between	O
+buprenorphine	O
+and	O
+QTc	O
+was	O
+found	O
+.	O
+
+Among	O
+the	O
+subjects	O
+treated	O
+with	O
+methadone	O
+,	O
+28	O
+%	O
+men	O
+and	O
+32	O
+%	O
+women	O
+had	O
+prolonged	B
+QTc	I
+interval	I
+.	O
+
+None	O
+of	O
+the	O
+subjects	O
+treated	O
+with	O
+buprenorphine	O
+had	O
+QTc	O
+interval	O
+>	O
+0	O
+.	O
+440	O
+s	O
+(	O
+(	O
+1	O
+/	O
+2	O
+)	O
+)	O
+.	O
+
+A	O
+50	O
+mg	O
+higher	O
+methadone	O
+dose	O
+was	O
+associated	O
+with	O
+a	O
+1	O
+.	O
+2	O
+(	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+1	O
+to	O
+1	O
+.	O
+4	O
+)	O
+times	O
+higher	O
+odds	O
+for	O
+syncope	B
+.	O
+
+CONCLUSIONS	O
+:	O
+Methadone	O
+is	O
+associated	O
+with	O
+QT	B
+prolongation	I
+and	O
+higher	O
+reporting	O
+of	O
+syncope	B
+in	O
+a	O
+population	O
+of	O
+heroin	O
+addicts	O
+.	O
+
+Neuroleptic	B
+malignant	I
+syndrome	I
+induced	O
+by	O
+ziprasidone	O
+on	O
+the	O
+second	O
+day	O
+of	O
+treatment	O
+.	O
+
+Neuroleptic	B
+malignant	I
+syndrome	I
+(	O
+NMS	B
+)	O
+is	O
+the	O
+rarest	O
+and	O
+most	O
+serious	O
+of	O
+the	O
+neuroleptic	O
+-	O
+induced	O
+movement	B
+disorders	I
+.	O
+
+We	O
+describe	O
+a	O
+case	O
+of	O
+neuroleptic	B
+malignant	I
+syndrome	I
+(	O
+NMS	B
+)	O
+associated	O
+with	O
+the	O
+use	O
+of	O
+ziprasidone	O
+.	O
+
+Although	O
+conventional	O
+neuroleptics	O
+are	O
+more	O
+frequently	O
+associated	O
+with	O
+NMS	B
+,	O
+atypical	O
+antipsychotic	O
+drugs	O
+like	O
+ziprasidone	O
+may	O
+also	O
+be	O
+a	O
+cause	O
+.	O
+
+The	O
+patient	O
+is	O
+a	O
+24	O
+-	O
+year	O
+-	O
+old	O
+male	O
+with	O
+a	O
+history	O
+of	O
+schizophrenia	B
+who	O
+developed	O
+signs	O
+and	O
+symptoms	O
+of	O
+NMS	B
+after	O
+2	O
+days	O
+of	O
+treatment	O
+with	O
+an	O
+80	O
+-	O
+mg	O
+/	O
+day	O
+dose	O
+of	O
+orally	O
+administrated	O
+ziprasidone	O
+.	O
+
+This	O
+case	O
+is	O
+the	O
+earliest	O
+(	O
+second	O
+day	O
+of	O
+treatment	O
+)	O
+NMS	B
+due	O
+to	O
+ziprasidone	O
+reported	O
+in	O
+the	O
+literature	O
+.	O
+
+Peripheral	O
+iron	O
+dextran	O
+induced	O
+degeneration	B
+of	I
+dopaminergic	I
+neurons	I
+in	O
+rat	O
+substantia	O
+nigra	O
+.	O
+
+Iron	O
+accumulation	O
+is	O
+considered	O
+to	O
+be	O
+involved	O
+in	O
+the	O
+pathogenesis	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+To	O
+demonstrate	O
+the	O
+relationship	O
+between	O
+peripheral	O
+iron	O
+overload	O
+and	O
+dopaminergic	O
+neuron	O
+loss	O
+in	O
+rat	O
+substantia	O
+nigra	O
+(	O
+SN	O
+)	O
+,	O
+in	O
+the	O
+present	O
+study	O
+we	O
+used	O
+fast	O
+cyclic	O
+voltammetry	O
+,	O
+tyrosine	O
+hydroxylase	O
+(	O
+TH	O
+)	O
+immunohistochemistry	O
+,	O
+Perls	O
+'	O
+iron	O
+staining	O
+,	O
+and	O
+high	O
+performance	O
+liquid	O
+chromatography	O
+-	O
+electrochemical	O
+detection	O
+to	O
+study	O
+the	O
+degeneration	B
+of	I
+dopaminergic	I
+neurons	I
+and	O
+increased	O
+iron	O
+content	O
+in	O
+the	O
+SN	O
+of	O
+iron	O
+dextran	O
+overloaded	O
+animals	O
+.	O
+
+The	O
+findings	O
+showed	O
+that	O
+peripheral	O
+iron	O
+dextran	O
+overload	O
+increased	O
+the	O
+iron	O
+staining	O
+positive	O
+cells	O
+and	O
+reduced	O
+the	O
+number	O
+of	O
+TH	O
+-	O
+immunoreactive	O
+neurons	O
+in	O
+the	O
+SN	O
+.	O
+
+As	O
+a	O
+result	O
+,	O
+dopamine	O
+release	O
+and	O
+content	O
+,	O
+as	O
+well	O
+as	O
+its	O
+metabolites	O
+contents	O
+were	O
+decreased	O
+in	O
+caudate	O
+putamen	O
+.	O
+
+Even	O
+more	O
+dramatic	O
+changes	O
+were	O
+found	O
+in	O
+chronic	O
+overload	O
+group	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+peripheral	O
+iron	O
+dextran	O
+can	O
+increase	O
+the	O
+iron	O
+level	O
+in	O
+the	O
+SN	O
+,	O
+where	O
+excessive	O
+iron	O
+causes	O
+the	O
+degeneration	B
+of	I
+dopaminergic	I
+neurons	I
+.	O
+
+The	O
+chronic	O
+iron	O
+overload	O
+may	O
+be	O
+more	O
+destructive	O
+to	O
+dopaminergic	O
+neurons	O
+than	O
+the	O
+acute	O
+iron	O
+overload	O
+.	O
+
+Attenuated	O
+disruption	O
+of	O
+prepulse	O
+inhibition	O
+by	O
+dopaminergic	O
+stimulation	O
+after	O
+maternal	O
+deprivation	O
+and	O
+adolescent	O
+corticosterone	O
+treatment	O
+in	O
+rats	O
+.	O
+
+The	O
+development	O
+of	O
+schizophrenia	B
+may	O
+include	O
+an	O
+early	O
+neurodevelopmental	O
+stress	O
+component	O
+which	O
+increases	O
+vulnerability	O
+to	O
+later	O
+stressful	O
+life	O
+events	O
+,	O
+in	O
+combination	O
+leading	O
+to	O
+overt	O
+disease	O
+.	O
+
+We	O
+investigated	O
+the	O
+effect	O
+of	O
+an	O
+early	O
+stress	O
+,	O
+in	O
+the	O
+form	O
+of	O
+maternal	O
+deprivation	O
+,	O
+combined	O
+with	O
+a	O
+later	O
+stress	O
+,	O
+simulated	O
+by	O
+chronic	O
+periadolescent	O
+corticosterone	O
+treatment	O
+,	O
+on	O
+behaviour	O
+in	O
+rats	O
+.	O
+
+Acute	O
+treatment	O
+with	O
+apomorphine	O
+caused	O
+disruption	O
+of	O
+prepulse	O
+inhibition	O
+(	O
+PPI	O
+)	O
+in	O
+controls	O
+and	O
+in	O
+rats	O
+that	O
+had	O
+undergone	O
+either	O
+maternal	O
+deprivation	O
+or	O
+corticosterone	O
+treatment	O
+,	O
+but	O
+was	O
+surprisingly	O
+absent	O
+in	O
+rats	O
+that	O
+had	O
+undergone	O
+the	O
+combined	O
+early	O
+and	O
+late	O
+stress	O
+.	O
+
+Amphetamine	O
+treatment	O
+significantly	O
+disrupted	O
+PPI	O
+in	O
+both	O
+non	O
+-	O
+deprived	O
+groups	O
+,	O
+but	O
+was	O
+absent	O
+in	O
+both	O
+maternally	O
+deprived	O
+groups	O
+.	O
+
+The	O
+serotonin	O
+-	O
+1A	O
+receptor	O
+agonist	O
+,	O
+8	O
+-	O
+OH	O
+-	O
+DPAT	O
+,	O
+induced	O
+a	O
+significant	O
+disruption	O
+of	O
+PPI	O
+in	O
+all	O
+groups	O
+.	O
+
+Amphetamine	O
+-	O
+induced	O
+locomotor	B
+hyperactivity	I
+was	O
+similar	O
+in	O
+all	O
+groups	O
+.	O
+
+These	O
+results	O
+show	O
+an	O
+inhibitory	O
+interaction	O
+of	O
+early	O
+stress	O
+,	O
+caused	O
+by	O
+maternal	O
+deprivation	O
+,	O
+combined	O
+with	O
+'	O
+adolescent	O
+'	O
+stress	O
+,	O
+simulated	O
+by	O
+corticosterone	O
+treatment	O
+,	O
+on	O
+dopaminergic	O
+regulation	O
+of	O
+PPI	O
+.	O
+
+The	O
+altered	O
+effects	O
+of	O
+apomorphine	O
+and	O
+amphetamine	O
+could	O
+indicate	O
+differential	O
+changes	O
+in	O
+dopamine	O
+receptor	O
+signalling	O
+leading	O
+to	O
+functional	O
+desensitisation	O
+,	O
+or	O
+altered	O
+modulation	O
+of	O
+sensory	O
+gating	O
+in	O
+the	O
+nucleus	O
+accumbens	O
+by	O
+limbic	O
+structures	O
+such	O
+as	O
+the	O
+hippocampus	O
+.	O
+
+An	O
+extremely	O
+rare	O
+case	O
+of	O
+delusional	B
+parasitosis	I
+in	O
+a	O
+chronic	B
+hepatitis	I
+C	I
+patient	O
+during	O
+pegylated	O
+interferon	O
+alpha	O
+-	O
+2b	O
+and	O
+ribavirin	O
+treatment	O
+.	O
+
+During	O
+treatment	O
+of	O
+chronic	B
+hepatitis	I
+C	I
+patients	O
+with	O
+interferon	O
+and	O
+ribavirin	O
+,	O
+a	O
+lot	O
+of	O
+side	O
+effects	O
+are	O
+described	O
+.	O
+
+Twenty	O
+-	O
+three	O
+percent	O
+to	O
+44	O
+%	O
+of	O
+patients	O
+develop	O
+depression	B
+.	O
+
+A	O
+minority	O
+of	O
+patients	O
+evolve	O
+to	O
+psychosis	B
+.	O
+
+To	O
+the	O
+best	O
+of	O
+our	O
+knowledge	O
+,	O
+no	O
+cases	O
+of	O
+psychogenic	B
+parasitosis	I
+occurring	O
+during	O
+interferon	O
+therapy	O
+have	O
+been	O
+described	O
+in	O
+the	O
+literature	O
+.	O
+
+We	O
+present	O
+a	O
+49	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+who	O
+developed	O
+a	O
+delusional	B
+parasitosis	I
+during	O
+treatment	O
+with	O
+pegylated	O
+interferon	O
+alpha	O
+-	O
+2b	O
+weekly	O
+and	O
+ribavirin	O
+.	O
+
+She	O
+complained	O
+of	O
+seeing	O
+parasites	O
+and	O
+the	O
+larvae	O
+of	O
+fleas	O
+in	O
+her	O
+stools	O
+.	O
+
+This	O
+could	O
+not	O
+be	O
+confirmed	O
+by	O
+any	O
+technical	O
+examination	O
+.	O
+
+All	O
+the	O
+complaints	O
+disappeared	O
+after	O
+stopping	O
+pegylated	O
+interferon	O
+alpha	O
+-	O
+2b	O
+and	O
+reappeared	O
+after	O
+restarting	O
+it	O
+.	O
+
+She	O
+had	O
+a	O
+complete	O
+sustained	O
+viral	O
+response	O
+.	O
+
+Hepatonecrosis	B
+and	O
+cholangitis	B
+related	O
+to	O
+long	O
+-	O
+term	O
+phenobarbital	O
+therapy	O
+:	O
+an	O
+autopsy	O
+report	O
+of	O
+two	O
+patients	O
+.	O
+
+Phenobarbital	O
+(	O
+PB	O
+)	O
+has	O
+a	O
+reputation	O
+for	O
+safety	O
+,	O
+and	O
+it	O
+is	O
+commonly	O
+believed	O
+that	O
+PB	O
+-	O
+related	O
+increases	O
+in	O
+serum	O
+aminotransferase	O
+levels	O
+do	O
+not	O
+indicate	O
+or	O
+predict	O
+the	O
+development	O
+of	O
+significant	O
+chronic	O
+liver	B
+disease	I
+.	O
+
+Here	O
+we	O
+report	O
+of	O
+two	O
+adult	O
+patients	O
+with	O
+a	O
+long	O
+history	O
+of	O
+epilepsy	B
+treated	O
+with	O
+PB	O
+who	O
+died	O
+suddenly	O
+:	O
+one	O
+as	O
+consequence	O
+of	O
+cardiac	B
+arrest	I
+,	O
+the	O
+other	O
+of	O
+acute	O
+bronchopneumonia	B
+.	O
+
+At	O
+autopsy	O
+,	O
+analysis	O
+of	O
+liver	O
+parenchyma	O
+revealed	O
+rich	O
+portal	O
+inflammatory	O
+infiltrate	O
+,	O
+which	O
+consisted	O
+of	O
+mixed	O
+eosinophil	O
+and	O
+monocyte	O
+cells	O
+,	O
+associated	O
+with	O
+several	O
+foci	O
+of	O
+necrosis	B
+surrounded	O
+by	O
+a	O
+hard	O
+ring	O
+of	O
+non	O
+-	O
+specific	O
+granulomatous	O
+tissue	O
+.	O
+
+Inflammatory	O
+reactions	O
+of	O
+internal	O
+and	O
+external	O
+hepatic	O
+biliary	O
+ducts	O
+were	O
+also	O
+seen	O
+.	O
+
+Our	O
+findings	O
+illustrate	O
+that	O
+PB	O
+may	O
+be	O
+associated	O
+with	O
+chronic	O
+liver	B
+damage	I
+,	O
+which	O
+may	O
+lead	O
+to	O
+more	O
+serious	O
+and	O
+deleterious	O
+consequences	O
+.	O
+
+For	O
+this	O
+reason	O
+,	O
+each	O
+clinician	O
+should	O
+recognize	O
+this	O
+entity	O
+in	O
+the	O
+differential	O
+diagnosis	O
+of	O
+PB	O
+-	O
+related	O
+asymptomatic	O
+chronic	B
+hepatic	I
+enzyme	I
+dysfunction	I
+.	O
+
+Delayed	O
+leukoencephalopathy	B
+with	O
+stroke	B
+-	O
+like	O
+presentation	O
+in	O
+chemotherapy	O
+recipients	O
+.	O
+
+BACKGROUND	O
+:	O
+A	O
+transient	O
+leukoencephalopathy	B
+mimicking	O
+cerebrovascular	B
+accident	I
+has	O
+been	O
+described	O
+as	O
+a	O
+complication	O
+of	O
+chemotherapy	O
+,	O
+most	O
+commonly	O
+in	O
+recipients	O
+of	O
+intrathecal	O
+methotrexate	O
+for	O
+childhood	O
+leukaemia	B
+.	O
+
+Recently	O
+published	O
+neuroimaging	O
+data	O
+suggest	O
+a	O
+common	O
+pathophysiology	O
+associated	O
+with	O
+a	O
+variety	O
+of	O
+chemotherapy	O
+agents	O
+and	O
+modes	O
+of	O
+administration	O
+.	O
+
+METHODS	O
+:	O
+We	O
+reviewed	O
+the	O
+medical	O
+literature	O
+for	O
+single	O
+reports	O
+and	O
+case	O
+series	O
+of	O
+patients	O
+presenting	O
+with	O
+stroke	B
+-	O
+like	O
+episodes	O
+while	O
+receiving	O
+systemic	O
+or	O
+intrathecal	O
+chemotherapy	O
+.	O
+
+We	O
+only	O
+included	O
+studies	O
+providing	O
+detailed	O
+neuroimaging	O
+data	O
+.	O
+
+Patients	O
+with	O
+cerebrovascular	B
+accidents	I
+were	O
+excluded	O
+.	O
+
+RESULTS	O
+:	O
+We	O
+identified	O
+27	O
+reports	O
+of	O
+toxic	O
+leukoencephalopathy	B
+in	O
+patients	O
+treated	O
+with	O
+methotrexate	O
+(	O
+intrathecal	O
+,	O
+systemic	O
+)	O
+,	O
+5	O
+-	O
+fluorouracil	O
+and	O
+its	O
+derivative	O
+carmofur	O
+,	O
+and	O
+capecitabine	O
+.	O
+
+Diffusion	O
+weighted	O
+imaging	O
+(	O
+DWI	O
+)	O
+of	O
+all	O
+patients	O
+revealed	O
+well	O
+demarcated	O
+hyperintense	O
+lesions	B
+within	I
+the	I
+subcortical	I
+white	I
+matter	I
+of	O
+the	O
+cerebral	O
+hemispheres	O
+and	O
+the	O
+corpus	O
+callosum	O
+,	O
+corresponding	O
+to	O
+areas	O
+of	O
+decreased	O
+proton	O
+diffusion	O
+on	O
+apparent	O
+diffusion	O
+coefficient	O
+(	O
+ADC	O
+)	O
+maps	O
+(	O
+available	O
+in	O
+21	O
+/	O
+27	O
+patients	O
+)	O
+.	O
+
+Lesions	O
+exceeded	O
+the	O
+confines	O
+of	O
+adjacent	O
+vascular	O
+territories	O
+.	O
+
+Complete	O
+resolution	O
+of	O
+symptoms	O
+within	O
+1	O
+-	O
+4	O
+days	O
+was	O
+accompanied	O
+by	O
+normalisation	O
+of	O
+ADC	O
+abnormalities	O
+.	O
+
+However	O
+,	O
+fluid	O
+attenuated	O
+inversion	O
+recovery	O
+(	O
+FLAIR	O
+)	O
+sequences	O
+frequently	O
+revealed	O
+persistent	O
+white	B
+matter	I
+abnormalities	I
+.	O
+
+CONCLUSIONS	O
+:	O
+Several	O
+pathophysiological	O
+models	O
+of	O
+delayed	O
+leukoencephalopathy	B
+after	O
+exposure	O
+to	O
+intrathecal	O
+or	O
+systemic	O
+chemotherapy	O
+have	O
+been	O
+proposed	O
+.	O
+
+DWI	O
+findings	O
+in	O
+this	O
+cohort	O
+are	O
+indicative	O
+of	O
+cytotoxic	B
+oedema	I
+within	I
+cerebral	I
+white	I
+matter	I
+and	O
+lend	O
+support	O
+to	O
+an	O
+at	O
+least	O
+partially	O
+reversible	O
+metabolic	O
+derangement	O
+as	O
+the	O
+basis	O
+for	O
+this	O
+syndrome	O
+.	O
+
+Prenatal	O
+exposure	O
+to	O
+fluoxetine	O
+induces	O
+fetal	B
+pulmonary	I
+hypertension	I
+in	O
+the	O
+rat	O
+.	O
+
+RATIONALE	O
+:	O
+Fluoxetine	O
+is	O
+a	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitor	O
+antidepressant	O
+widely	O
+used	O
+by	O
+pregnant	O
+women	O
+.	O
+
+Epidemiological	O
+data	O
+suggest	O
+that	O
+fluoxetine	O
+exposure	O
+prenatally	O
+increases	O
+the	O
+prevalence	O
+of	O
+persistent	O
+pulmonary	B
+hypertension	I
+syndrome	I
+of	O
+the	O
+newborn	O
+.	O
+
+The	O
+mechanism	O
+responsible	O
+for	O
+this	O
+effect	O
+is	O
+unclear	O
+and	O
+paradoxical	O
+,	O
+considering	O
+the	O
+current	O
+evidence	O
+of	O
+a	O
+pulmonary	B
+hypertension	I
+protective	O
+fluoxetine	O
+effect	O
+in	O
+adult	O
+rodents	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+evaluate	O
+the	O
+fluoxetine	O
+effect	O
+on	O
+fetal	O
+rat	O
+pulmonary	O
+vascular	O
+smooth	O
+muscle	O
+mechanical	O
+properties	O
+and	O
+cell	O
+proliferation	O
+rate	O
+.	O
+
+METHODS	O
+:	O
+Pregnant	O
+rats	O
+were	O
+treated	O
+with	O
+fluoxetine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+from	O
+Day	O
+11	O
+through	O
+Day	O
+21	O
+of	O
+gestation	O
+.	O
+
+MEASUREMENTS	O
+AND	O
+MAIN	O
+RESULTS	O
+:	O
+Fetuses	O
+were	O
+delivered	O
+by	O
+cesarean	O
+section	O
+.	O
+
+As	O
+compared	O
+with	O
+controls	O
+,	O
+fluoxetine	O
+exposure	O
+resulted	O
+in	O
+fetal	B
+pulmonary	I
+hypertension	I
+as	O
+evidenced	O
+by	O
+an	O
+increase	O
+in	O
+the	O
+weight	O
+ratio	O
+of	O
+the	O
+right	O
+ventricle	O
+to	O
+the	O
+left	O
+ventricle	O
+plus	O
+septum	O
+(	O
+P	O
+=	O
+0	O
+.	O
+02	O
+)	O
+and	O
+by	O
+an	O
+increase	O
+in	O
+pulmonary	O
+arterial	O
+medial	O
+thickness	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+Postnatal	O
+mortality	O
+was	O
+increased	O
+among	O
+experimental	O
+animals	O
+,	O
+and	O
+arterial	O
+oxygen	O
+saturation	O
+was	O
+96	O
++	O
+/	O
+-	O
+1	O
+%	O
+in	O
+1	O
+-	O
+day	O
+-	O
+old	O
+control	O
+animals	O
+and	O
+significantly	O
+lower	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+in	O
+fluoxetine	O
+-	O
+exposed	O
+pups	O
+(	O
+79	O
++	O
+/	O
+-	O
+2	O
+%	O
+)	O
+.	O
+
+In	O
+vitro	O
+,	O
+fluoxetine	O
+induced	O
+pulmonary	O
+arterial	O
+muscle	O
+contraction	O
+in	O
+fetal	O
+,	O
+but	O
+not	O
+adult	O
+,	O
+animals	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+and	O
+reduced	O
+serotonin	O
+-	O
+induced	O
+contraction	O
+at	O
+both	O
+ages	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+After	O
+in	O
+utero	O
+exposure	O
+to	O
+a	O
+low	O
+fluoxetine	O
+concentration	O
+the	O
+pulmonary	O
+arterial	O
+smooth	O
+muscle	O
+cell	O
+proliferation	O
+rate	O
+was	O
+significantly	O
+increased	O
+in	O
+fetal	O
+,	O
+but	O
+not	O
+adult	O
+,	O
+cells	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+In	O
+contrast	O
+to	O
+the	O
+adult	O
+,	O
+fluoxetine	O
+exposure	O
+in	O
+utero	O
+induces	O
+pulmonary	B
+hypertension	I
+in	O
+the	O
+fetal	O
+rat	O
+as	O
+a	O
+result	O
+of	O
+a	O
+developmentally	O
+regulated	O
+increase	O
+in	O
+pulmonary	O
+vascular	O
+smooth	O
+muscle	O
+proliferation	O
+.	O
+
+Disulfiram	O
+-	O
+induced	O
+transient	O
+optic	B
+and	I
+peripheral	I
+neuropathy	I
+:	O
+a	O
+case	O
+report	O
+.	O
+
+AIM	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+optic	B
+and	I
+peripheral	I
+neuropathy	I
+after	O
+chronic	O
+use	O
+of	O
+disulfiram	O
+for	O
+alcohol	B
+dependence	I
+management	O
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+A	O
+case	O
+report	O
+.	O
+
+RESULTS	O
+:	O
+A	O
+57	O
+-	O
+year	O
+-	O
+old	O
+male	O
+presented	O
+with	O
+gradual	O
+loss	B
+of	I
+vision	I
+in	O
+both	O
+eyes	O
+with	O
+intermittent	O
+headaches	B
+for	O
+2	O
+months	O
+.	O
+
+He	O
+also	O
+complained	O
+of	O
+paraesthesia	B
+with	O
+numbness	B
+in	O
+both	O
+feet	O
+.	O
+
+His	O
+vision	O
+was	O
+6	O
+/	O
+15	O
+and	O
+2	O
+/	O
+60	O
+in	O
+the	O
+right	O
+and	O
+left	O
+eyes	O
+,	O
+respectively	O
+.	O
+
+Fundoscopy	O
+revealed	O
+bilaterally	O
+swollen	O
+optic	O
+nerve	O
+heads	O
+.	O
+
+Visual	O
+field	O
+testing	O
+confirmed	O
+bilateral	O
+central	O
+-	O
+caecal	O
+scotomata	B
+.	O
+
+He	O
+had	O
+been	O
+taking	O
+disulfiram	O
+for	O
+alcohol	B
+dependence	I
+for	O
+the	O
+preceding	O
+3	O
+years	O
+.	O
+
+Disulfiram	O
+discontinuation	O
+lead	O
+to	O
+an	O
+immediate	O
+symptomatic	O
+improvement	O
+.	O
+
+CONCLUSION	O
+:	O
+Physicians	O
+initiating	O
+long	O
+-	O
+term	O
+disulfiram	O
+therapy	O
+should	O
+be	O
+aware	O
+of	O
+these	O
+adverse	O
+effects	O
+.	O
+
+They	O
+should	O
+recommend	O
+annual	O
+ophthalmic	O
+reviews	O
+with	O
+visual	O
+field	O
+testing	O
+.	O
+
+Patients	O
+should	O
+be	O
+reassured	O
+with	O
+respect	O
+to	O
+the	O
+reversibility	O
+of	O
+these	O
+adverse	O
+effects	O
+.	O
+
+Intraocular	O
+pressure	O
+in	O
+patients	O
+with	O
+uveitis	B
+treated	O
+with	O
+fluocinolone	O
+acetonide	O
+implants	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+report	O
+the	O
+incidence	O
+and	O
+management	O
+of	O
+elevated	B
+intraocular	I
+pressure	I
+(	O
+IOP	O
+)	O
+in	O
+patients	O
+with	O
+uveitis	B
+treated	O
+with	O
+the	O
+fluocinolone	O
+acetonide	O
+(	O
+FA	O
+)	O
+intravitreal	O
+implant	O
+.	O
+
+DESIGN	O
+:	O
+Pooled	O
+data	O
+from	O
+3	O
+multicenter	O
+,	O
+double	O
+-	O
+masked	O
+,	O
+randomized	O
+,	O
+controlled	O
+,	O
+phase	O
+2b	O
+/	O
+3	O
+clinical	O
+trials	O
+evaluating	O
+the	O
+safety	O
+and	O
+efficacy	O
+of	O
+the	O
+0	O
+.	O
+59	O
+-	O
+mg	O
+or	O
+2	O
+.	O
+1	O
+-	O
+mg	O
+FA	O
+intravitreal	O
+implant	O
+or	O
+standard	O
+therapy	O
+were	O
+analyzed	O
+.	O
+
+RESULTS	O
+:	O
+During	O
+the	O
+3	O
+-	O
+year	O
+follow	O
+-	O
+up	O
+,	O
+71	O
+.	O
+0	O
+%	O
+of	O
+implanted	O
+eyes	O
+had	O
+an	O
+IOP	O
+increase	O
+of	O
+10	O
+mm	O
+Hg	O
+or	O
+more	O
+than	O
+baseline	O
+and	O
+55	O
+.	O
+1	O
+%	O
+,	O
+24	O
+.	O
+7	O
+%	O
+,	O
+and	O
+6	O
+.	O
+2	O
+%	O
+of	O
+eyes	O
+reached	O
+an	O
+IOP	O
+of	O
+30	O
+mm	O
+Hg	O
+or	O
+more	O
+,	O
+40	O
+mm	O
+Hg	O
+or	O
+more	O
+,	O
+and	O
+50	O
+mm	O
+Hg	O
+or	O
+more	O
+,	O
+respectively	O
+.	O
+
+Topical	O
+IOP	O
+-	O
+lowering	O
+medication	O
+was	O
+administered	O
+in	O
+74	O
+.	O
+8	O
+%	O
+of	O
+implanted	O
+eyes	O
+,	O
+and	O
+IOP	O
+-	O
+lowering	O
+surgeries	O
+,	O
+most	O
+of	O
+which	O
+were	O
+trabeculectomies	O
+(	O
+76	O
+.	O
+2	O
+%	O
+)	O
+,	O
+were	O
+performed	O
+on	O
+36	O
+.	O
+6	O
+%	O
+of	O
+implanted	O
+eyes	O
+.	O
+
+Intraocular	O
+pressure	O
+-	O
+lowering	O
+surgeries	O
+were	O
+considered	O
+a	O
+success	O
+(	O
+postoperative	O
+IOP	O
+of	O
+6	O
+-	O
+21	O
+mm	O
+Hg	O
+with	O
+or	O
+without	O
+additional	O
+IOP	O
+-	O
+lowering	O
+medication	O
+)	O
+in	O
+85	O
+.	O
+1	O
+%	O
+of	O
+eyes	O
+at	O
+1	O
+year	O
+.	O
+
+The	O
+rate	O
+of	O
+hypotony	B
+(	O
+IOP	O
+<	O
+/	O
+=	O
+5	O
+mm	O
+Hg	O
+)	O
+following	O
+IOP	O
+-	O
+lowering	O
+surgery	O
+(	O
+42	O
+.	O
+5	O
+%	O
+)	O
+was	O
+not	O
+different	O
+from	O
+that	O
+of	O
+implanted	O
+eyes	O
+not	O
+subjected	O
+to	O
+surgery	O
+(	O
+35	O
+.	O
+4	O
+%	O
+)	O
+(	O
+P	O
+=	O
+.	O
+09	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+Elevated	O
+IOP	O
+is	O
+a	O
+significant	O
+complication	O
+with	O
+the	O
+FA	O
+intravitreal	O
+implant	O
+but	O
+may	O
+be	O
+controlled	O
+with	O
+medication	O
+and	O
+surgery	O
+.	O
+
+Myocardial	O
+Fas	O
+ligand	O
+expression	O
+increases	O
+susceptibility	O
+to	O
+AZT	O
+-	O
+induced	O
+cardiomyopathy	B
+.	O
+
+BACKGROUND	O
+:	O
+Dilated	B
+cardiomyopathy	I
+(	O
+DCM	B
+)	O
+and	O
+myocarditis	B
+occur	O
+in	O
+many	O
+HIV	B
+-	I
+infected	I
+individuals	O
+,	O
+resulting	O
+in	O
+symptomatic	O
+heart	B
+failure	I
+in	O
+up	O
+to	O
+5	O
+%	O
+of	O
+patients	O
+.	O
+
+Highly	O
+active	O
+antiretroviral	O
+therapy	O
+(	O
+HAART	O
+)	O
+has	O
+significantly	O
+reduced	O
+morbidity	O
+and	O
+mortality	O
+of	O
+acquired	B
+immunodeficiency	I
+syndrome	I
+(	O
+AIDS	B
+)	O
+,	O
+but	O
+has	O
+resulted	O
+in	O
+an	O
+increase	O
+in	O
+cardiac	B
+and	I
+skeletal	I
+myopathies	I
+.	O
+
+METHODS	O
+AND	O
+RESULTS	O
+:	O
+In	O
+order	O
+to	O
+investigate	O
+whether	O
+the	O
+HAART	O
+component	O
+zidovudine	O
+(	O
+3	O
+'	O
+-	O
+azido	O
+-	O
+2	O
+'	O
+,	O
+3	O
+'	O
+-	O
+deoxythymidine	O
+;	O
+AZT	O
+)	O
+triggers	O
+the	O
+Fas	O
+-	O
+dependent	O
+cell	O
+-	O
+death	O
+pathway	O
+and	O
+cause	O
+cytoskeletal	O
+disruption	O
+in	O
+a	O
+murine	O
+model	O
+of	O
+DCM	B
+,	O
+8	O
+-	O
+week	O
+-	O
+old	O
+transgenic	O
+(	O
+expressing	O
+Fas	O
+ligand	O
+in	O
+the	O
+myocardium	O
+:	O
+FasL	O
+Tg	O
+)	O
+and	O
+non	O
+-	O
+transgenic	O
+(	O
+NTg	O
+)	O
+mice	O
+received	O
+water	O
+ad	O
+libitum	O
+containing	O
+different	O
+concentrations	O
+of	O
+AZT	O
+(	O
+0	O
+,	O
+0	O
+.	O
+07	O
+,	O
+0	O
+.	O
+2	O
+,	O
+and	O
+0	O
+.	O
+7	O
+mg	O
+/	O
+ml	O
+)	O
+.	O
+
+After	O
+6	O
+weeks	O
+,	O
+cardiac	O
+function	O
+was	O
+assessed	O
+by	O
+echocardiography	O
+and	O
+morphology	O
+was	O
+assessed	O
+by	O
+histopathologic	O
+and	O
+immunohistochemical	O
+methods	O
+.	O
+
+NTg	O
+and	O
+untreated	O
+FasL	O
+Tg	O
+mice	O
+showed	O
+little	O
+or	O
+no	O
+change	O
+in	O
+cardiac	O
+structure	O
+or	O
+function	O
+.	O
+
+In	O
+contrast	O
+,	O
+AZT	O
+-	O
+treated	O
+FasL	O
+Tg	O
+mice	O
+developed	O
+cardiac	B
+dilation	I
+and	O
+depressed	O
+cardiac	O
+function	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+,	O
+with	O
+concomitant	O
+inflammatory	O
+infiltration	O
+of	O
+both	O
+ventricles	O
+.	O
+
+These	O
+changes	O
+were	O
+associated	O
+with	O
+an	O
+increased	O
+sarcolemmal	O
+expression	O
+of	O
+Fas	O
+and	O
+FasL	O
+,	O
+as	O
+well	O
+as	O
+increased	O
+activation	O
+of	O
+caspase	O
+3	O
+,	O
+translocation	O
+of	O
+calpain	O
+1	O
+to	O
+the	O
+sarcolemma	O
+and	O
+sarcomere	O
+,	O
+and	O
+increased	O
+numbers	O
+of	O
+cells	O
+undergoing	O
+apoptosis	O
+.	O
+
+These	O
+were	O
+associated	O
+with	O
+changes	O
+in	O
+dystrophin	O
+and	O
+cardiac	O
+troponin	O
+I	O
+localization	O
+,	O
+as	O
+well	O
+as	O
+loss	O
+of	O
+sarcolemmal	O
+integrity	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+expression	O
+of	O
+Fas	O
+ligand	O
+in	O
+the	O
+myocardium	O
+,	O
+as	O
+identified	O
+in	O
+HIV	O
+-	O
+positive	O
+patients	O
+,	O
+might	O
+increase	O
+the	O
+susceptibility	O
+to	O
+HAART	O
+-	O
+induced	O
+cardiomyopathy	B
+due	O
+to	O
+activation	O
+of	O
+apoptotic	O
+pathways	O
+,	O
+resulting	O
+in	O
+cardiac	B
+dilation	I
+and	I
+dysfunction	I
+.	O
+
+Gastrointestinal	O
+tolerability	O
+of	O
+etoricoxib	O
+in	O
+rheumatoid	B
+arthritis	I
+patients	O
+:	O
+results	O
+of	O
+the	O
+etoricoxib	O
+vs	O
+diclofenac	O
+sodium	O
+gastrointestinal	O
+tolerability	O
+and	O
+effectiveness	O
+trial	O
+(	O
+EDGE	O
+-	O
+II	O
+)	O
+.	O
+
+OBJECTIVE	O
+:	O
+A	O
+randomised	O
+,	O
+double	O
+-	O
+blind	O
+study	O
+to	O
+compare	O
+the	O
+gastrointestinal	O
+(	O
+GI	O
+)	O
+tolerability	O
+,	O
+safety	O
+and	O
+efficacy	O
+of	O
+etoricoxib	O
+and	O
+diclofenac	O
+in	O
+patients	O
+with	O
+rheumatoid	B
+arthritis	I
+(	O
+RA	B
+)	O
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+A	O
+total	O
+of	O
+4086	O
+patients	O
+(	O
+mean	O
+age	O
+60	O
+.	O
+8	O
+years	O
+)	O
+diagnosed	O
+with	O
+RA	B
+were	O
+enrolled	O
+and	O
+received	O
+etoricoxib	O
+90	O
+mg	O
+daily	O
+(	O
+n	O
+=	O
+2032	O
+)	O
+or	O
+diclofenac	O
+75	O
+mg	O
+twice	O
+daily	O
+(	O
+n	O
+=	O
+2054	O
+)	O
+.	O
+
+Use	O
+of	O
+gastroprotective	O
+agents	O
+and	O
+low	O
+-	O
+dose	O
+aspirin	O
+was	O
+allowed	O
+.	O
+
+The	O
+prespecified	O
+primary	O
+end	O
+point	O
+consisted	O
+of	O
+the	O
+cumulative	O
+rate	O
+of	O
+patient	O
+discontinuations	O
+due	O
+to	O
+clinical	O
+and	O
+laboratory	O
+GI	O
+adverse	O
+experiences	O
+(	O
+AEs	O
+)	O
+.	O
+
+General	O
+safety	O
+was	O
+also	O
+assessed	O
+,	O
+including	O
+adjudicated	O
+thrombotic	B
+cardiovascular	I
+event	O
+data	O
+.	O
+
+Efficacy	O
+was	O
+evaluated	O
+using	O
+the	O
+Patient	O
+Global	O
+Assessment	O
+of	O
+Disease	O
+Status	O
+(	O
+PGADS	O
+;	O
+0	O
+-	O
+4	O
+point	O
+scale	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+Mean	O
+(	O
+SD	O
+;	O
+maximum	O
+)	O
+duration	O
+of	O
+treatment	O
+was	O
+19	O
+.	O
+3	O
+(	O
+10	O
+.	O
+3	O
+;	O
+32	O
+.	O
+9	O
+)	O
+and	O
+19	O
+.	O
+1	O
+(	O
+10	O
+.	O
+4	O
+;	O
+33	O
+.	O
+1	O
+)	O
+months	O
+in	O
+the	O
+etoricoxib	O
+and	O
+diclofenac	O
+groups	O
+,	O
+respectively	O
+.	O
+
+The	O
+cumulative	O
+discontinuation	O
+rate	O
+due	O
+to	O
+GI	B
+AEs	I
+was	O
+significantly	O
+lower	O
+with	O
+etoricoxib	O
+than	O
+diclofenac	O
+(	O
+5	O
+.	O
+2	O
+vs	O
+8	O
+.	O
+5	O
+events	O
+per	O
+100	O
+patient	O
+-	O
+years	O
+,	O
+respectively	O
+;	O
+hazard	O
+ratio	O
+0	O
+.	O
+62	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+0	O
+.	O
+47	O
+,	O
+0	O
+.	O
+81	O
+;	O
+p	O
+<	O
+or	O
+=	O
+0	O
+.	O
+001	O
+)	O
+)	O
+.	O
+
+The	O
+incidence	O
+of	O
+discontinuations	O
+for	O
+hypertension	B
+-	O
+related	O
+and	O
+oedema	B
+-	O
+related	O
+AEs	O
+were	O
+significantly	O
+higher	O
+with	O
+etoricoxib	O
+(	O
+2	O
+.	O
+5	O
+%	O
+and	O
+1	O
+.	O
+1	O
+%	O
+respectively	O
+)	O
+compared	O
+with	O
+diclofenac	O
+(	O
+1	O
+.	O
+5	O
+%	O
+and	O
+0	O
+.	O
+4	O
+%	O
+respectively	O
+;	O
+p	O
+<	O
+0	O
+.	O
+001	O
+for	O
+hypertension	B
+and	O
+p	O
+<	O
+0	O
+.	O
+01	O
+for	O
+oedema	B
+)	O
+.	O
+
+Etoricoxib	O
+and	O
+diclofenac	O
+treatment	O
+resulted	O
+in	O
+similar	O
+efficacy	O
+(	O
+PGADS	O
+mean	O
+changes	O
+from	O
+baseline	O
+-	O
+0	O
+.	O
+62	O
+vs	O
+-	O
+0	O
+.	O
+58	O
+,	O
+respectively	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Etoricoxib	O
+90	O
+mg	O
+demonstrated	O
+a	O
+significantly	O
+lower	O
+risk	O
+for	O
+discontinuing	O
+treatment	O
+due	O
+to	O
+GI	B
+AEs	I
+compared	O
+with	O
+diclofenac	O
+150	O
+mg	O
+.	O
+
+Discontinuations	O
+from	O
+renovascular	O
+AEs	O
+,	O
+although	O
+less	O
+common	O
+than	O
+discontinuations	O
+from	O
+GI	B
+AEs	I
+,	O
+were	O
+significantly	O
+higher	O
+with	O
+etoricoxib	O
+.	O
+
+Anxiogenic	O
+potential	O
+of	O
+ciprofloxacin	O
+and	O
+norfloxacin	O
+in	O
+rats	O
+.	O
+
+INTRODUCTION	O
+:	O
+The	O
+possible	O
+anxiogenic	O
+effects	O
+of	O
+fluoroquinolones	O
+,	O
+namely	O
+ciprofloxacin	O
+and	O
+norfloxacin	O
+,	O
+were	O
+investigated	O
+in	O
+adult	O
+Charles	O
+Foster	O
+albino	O
+rats	O
+of	O
+either	O
+sex	O
+,	O
+weighing	O
+150	O
+-	O
+200	O
+g	O
+.	O
+
+METHODS	O
+:	O
+The	O
+drugs	O
+were	O
+given	O
+orally	O
+,	O
+in	O
+doses	O
+of	O
+50	O
+mg	O
+/	O
+kg	O
+for	O
+five	O
+consecutive	O
+days	O
+and	O
+the	O
+experiments	O
+were	O
+performed	O
+on	O
+the	O
+fifth	O
+day	O
+.	O
+
+The	O
+tests	O
+included	O
+open	O
+-	O
+field	O
+exploratory	O
+behaviour	O
+,	O
+elevated	O
+plus	O
+maze	O
+and	O
+elevated	O
+zero	O
+maze	O
+,	O
+social	O
+interaction	O
+and	O
+novelty	O
+-	O
+suppressed	O
+feeding	O
+latency	O
+behaviour	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+results	O
+indicate	O
+that	O
+ciprofloxacin	O
+-	O
+and	O
+norfloxacin	O
+-	O
+treated	O
+rats	O
+showed	O
+anxious	B
+behaviour	I
+in	O
+comparison	O
+to	O
+control	O
+rats	O
+in	O
+all	O
+the	O
+parameters	O
+studied	O
+.	O
+
+However	O
+,	O
+ciprofloxacin	O
+-	O
+and	O
+norfloxacin	O
+-	O
+treated	O
+rats	O
+did	O
+not	O
+differ	O
+significantly	O
+from	O
+each	O
+other	O
+in	O
+various	O
+behavioural	O
+parameters	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+present	O
+experimental	O
+findings	O
+substantiate	O
+the	O
+clinically	O
+observed	O
+anxiogenic	O
+potential	O
+of	O
+ciprofloxacin	O
+and	O
+norfloxacin	O
+.	O
+
+Reduction	O
+of	O
+pain	B
+during	O
+induction	O
+with	O
+target	O
+-	O
+controlled	O
+propofol	O
+and	O
+remifentanil	O
+.	O
+
+BACKGROUND	O
+:	O
+Pain	B
+on	O
+injection	O
+of	O
+propofol	O
+is	O
+unpleasant	O
+.	O
+
+We	O
+hypothesized	O
+that	O
+propofol	O
+infusion	O
+pain	B
+might	O
+be	O
+prevented	O
+by	O
+infusing	O
+remifentanil	O
+before	O
+starting	O
+the	O
+propofol	O
+infusion	O
+in	O
+a	O
+clinical	O
+setting	O
+where	O
+target	O
+-	O
+controlled	O
+infusions	O
+(	O
+TCI	O
+)	O
+of	O
+both	O
+drugs	O
+were	O
+used	O
+.	O
+
+A	O
+prospective	O
+,	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+trial	O
+was	O
+performed	O
+to	O
+determine	O
+the	O
+effect	O
+-	O
+site	O
+concentration	O
+(	O
+Ce	O
+)	O
+of	O
+remifentanil	O
+to	O
+prevent	O
+the	O
+pain	B
+without	O
+producing	O
+complications	O
+.	O
+
+METHODS	O
+:	O
+A	O
+total	O
+of	O
+128	O
+patients	O
+undergoing	O
+general	O
+surgery	O
+were	O
+randomly	O
+allocated	O
+to	O
+receive	O
+normal	O
+saline	O
+(	O
+control	O
+)	O
+or	O
+remifentanil	O
+to	O
+a	O
+target	O
+Ce	O
+of	O
+2	O
+ng	O
+ml	O
+(	O
+-	O
+1	O
+)	O
+(	O
+R2	O
+)	O
+,	O
+4	O
+ng	O
+ml	O
+(	O
+-	O
+1	O
+)	O
+(	O
+R4	O
+)	O
+,	O
+or	O
+6	O
+ng	O
+ml	O
+(	O
+-	O
+1	O
+)	O
+(	O
+R6	O
+)	O
+administered	O
+via	O
+TCI	O
+.	O
+
+After	O
+the	O
+target	O
+Ce	O
+was	O
+achieved	O
+,	O
+the	O
+infusion	O
+of	O
+propofol	O
+was	O
+started	O
+.	O
+
+Remifentanil	O
+-	O
+related	O
+complications	O
+were	O
+assessed	O
+during	O
+the	O
+remifentanil	O
+infusion	O
+,	O
+and	O
+pain	B
+caused	O
+by	O
+propofol	O
+was	O
+evaluated	O
+using	O
+a	O
+four	O
+-	O
+point	O
+scale	O
+during	O
+the	O
+propofol	O
+infusion	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+incidence	O
+of	O
+pain	B
+was	O
+significantly	O
+lower	O
+in	O
+Groups	O
+R4	O
+and	O
+R6	O
+than	O
+in	O
+the	O
+control	O
+and	O
+R2	O
+groups	O
+(	O
+12	O
+/	O
+32	O
+and	O
+6	O
+/	O
+31	O
+vs	O
+26	O
+/	O
+31	O
+and	O
+25	O
+/	O
+32	O
+,	O
+respectively	O
+,	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Pain	B
+was	O
+less	O
+severe	O
+in	O
+Groups	O
+R4	O
+and	O
+R6	O
+than	O
+in	O
+the	O
+control	O
+and	O
+R2	O
+groups	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+However	O
+,	O
+both	O
+incidence	O
+and	O
+severity	O
+of	O
+pain	B
+were	O
+not	O
+different	O
+between	O
+Groups	O
+R4	O
+and	O
+R6	O
+.	O
+
+No	O
+significant	O
+complications	O
+were	O
+observed	O
+during	O
+the	O
+study	O
+.	O
+
+CONCLUSIONS	O
+:	O
+During	O
+induction	O
+of	O
+anaesthesia	O
+with	O
+TCI	O
+of	O
+propofol	O
+and	O
+remifentanil	O
+,	O
+a	O
+significant	O
+reduction	O
+in	O
+propofol	O
+infusion	O
+pain	B
+was	O
+achieved	O
+without	O
+significant	O
+complications	O
+by	O
+prior	O
+administration	O
+of	O
+remifentanil	O
+at	O
+a	O
+target	O
+Ce	O
+of	O
+4	O
+ng	O
+ml	O
+(	O
+-	O
+1	O
+)	O
+.	O
+
+Dexmedetomidine	O
+and	O
+cardiac	O
+protection	O
+for	O
+non	O
+-	O
+cardiac	O
+surgery	O
+:	O
+a	O
+meta	O
+-	O
+analysis	O
+of	O
+randomised	O
+controlled	O
+trials	O
+.	O
+
+We	O
+conducted	O
+a	O
+systematic	O
+review	O
+of	O
+the	O
+effects	O
+of	O
+dexmedetomidine	O
+on	O
+cardiac	O
+outcomes	O
+following	O
+non	O
+-	O
+cardiac	O
+surgery	O
+.	O
+
+We	O
+included	O
+prospective	O
+,	O
+randomised	O
+peri	O
+-	O
+operative	O
+studies	O
+of	O
+dexmedetomidine	O
+that	O
+reported	O
+mortality	O
+,	O
+cardiac	O
+morbidity	O
+or	O
+adverse	O
+drug	O
+events	O
+.	O
+
+A	O
+PubMed	O
+Central	O
+and	O
+EMBASE	O
+search	O
+was	O
+conducted	O
+up	O
+to	O
+July	O
+2007	O
+.	O
+
+The	O
+reference	O
+lists	O
+of	O
+identified	O
+papers	O
+were	O
+examined	O
+for	O
+further	O
+trials	O
+.	O
+
+Of	O
+425	O
+studies	O
+identified	O
+,	O
+20	O
+were	O
+included	O
+in	O
+the	O
+meta	O
+-	O
+analysis	O
+(	O
+840	O
+patients	O
+)	O
+.	O
+
+Dexmedetomidine	O
+was	O
+associated	O
+with	O
+a	O
+trend	O
+towards	O
+improved	O
+cardiac	O
+outcomes	O
+;	O
+all	O
+-	O
+cause	O
+mortality	O
+(	O
+OR	O
+0	O
+.	O
+27	O
+,	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+01	O
+-	O
+7	O
+.	O
+13	O
+,	O
+p	O
+=	O
+0	O
+.	O
+44	O
+)	O
+,	O
+non	O
+-	O
+fatal	O
+myocardial	B
+infarction	I
+(	O
+OR	O
+0	O
+.	O
+26	O
+,	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+04	O
+-	O
+1	O
+.	O
+60	O
+,	O
+p	O
+=	O
+0	O
+.	O
+14	O
+)	O
+,	O
+and	O
+myocardial	B
+ischaemia	I
+(	O
+OR	O
+0	O
+.	O
+65	O
+,	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+26	O
+-	O
+1	O
+.	O
+63	O
+,	O
+p	O
+=	O
+0	O
+.	O
+36	O
+)	O
+.	O
+
+Peri	O
+-	O
+operative	O
+hypotension	B
+(	O
+26	O
+%	O
+,	O
+OR	O
+3	O
+.	O
+80	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+91	O
+-	O
+7	O
+.	O
+54	O
+,	O
+p	O
+=	O
+0	O
+.	O
+0001	O
+)	O
+and	O
+bradycardia	B
+(	O
+17	O
+%	O
+,	O
+OR	O
+5	O
+.	O
+45	O
+,	O
+95	O
+%	O
+CI	O
+2	O
+.	O
+98	O
+-	O
+9	O
+.	O
+95	O
+,	O
+p	O
+<	O
+0	O
+.	O
+00001	O
+)	O
+were	O
+significantly	O
+increased	O
+.	O
+
+An	O
+anticholinergic	O
+did	O
+not	O
+reduce	O
+the	O
+incidence	O
+of	O
+bradycardia	B
+(	O
+p	O
+=	O
+0	O
+.	O
+43	O
+)	O
+.	O
+
+A	O
+randomised	O
+placebo	O
+-	O
+controlled	O
+trial	O
+of	O
+dexmedetomidine	O
+is	O
+warranted	O
+.	O
+
+Myocardial	B
+infarction	I
+in	O
+pregnancy	O
+associated	O
+with	O
+clomiphene	O
+citrate	O
+for	O
+ovulation	O
+induction	O
+:	O
+a	O
+case	O
+report	O
+.	O
+
+BACKGROUND	O
+:	O
+Clomiphene	O
+citrate	O
+(	O
+CC	O
+)	O
+is	O
+commonly	O
+prescribed	O
+for	O
+ovulation	O
+induction	O
+.	O
+
+It	O
+is	O
+considered	O
+safe	O
+,	O
+with	O
+minimal	O
+side	O
+effects	O
+.	O
+
+Thromboembolism	B
+is	O
+a	O
+rare	O
+but	O
+life	O
+-	O
+threatening	O
+complication	O
+that	O
+has	O
+been	O
+reported	O
+after	O
+ovulation	O
+induction	O
+with	O
+CC	O
+.	O
+
+Spontaneous	O
+coronary	B
+thrombosis	I
+or	O
+thromboembolism	B
+with	O
+subsequent	O
+clot	O
+lysis	O
+has	O
+been	O
+suggested	O
+as	O
+one	O
+of	O
+the	O
+most	O
+common	O
+causes	O
+of	O
+myocardial	B
+infarction	I
+(	O
+MI	B
+)	O
+during	O
+pregnancy	O
+,	O
+with	O
+a	O
+subsequently	O
+normal	O
+coronary	O
+angiogram	O
+.	O
+
+CASE	O
+:	O
+A	O
+33	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+a	O
+5	O
+-	O
+week	O
+gestation	O
+had	O
+recently	O
+received	O
+CC	O
+for	O
+ovulation	O
+induction	O
+and	O
+presented	O
+with	O
+chest	B
+pain	I
+.	O
+
+An	O
+electrocardiogram	O
+showed	O
+a	O
+lateral	O
+and	O
+anterior	O
+wall	O
+myocardial	B
+infarction	I
+.	O
+
+Cardiac	O
+enzymes	O
+showed	O
+a	O
+peak	O
+rise	O
+in	O
+troponin	O
+I	O
+to	O
+9	O
+.	O
+10	O
+ng	O
+/	O
+mL	O
+.	O
+
+An	O
+initial	O
+exercise	O
+stress	O
+test	O
+was	O
+normal	O
+.	O
+
+At	O
+the	O
+time	O
+of	O
+admission	O
+,	O
+the	O
+patient	O
+was	O
+at	O
+high	O
+risk	O
+of	O
+radiation	B
+injury	I
+to	O
+the	O
+fetus	O
+,	O
+so	O
+a	O
+coronary	O
+angiogram	O
+was	O
+postponed	O
+until	O
+the	O
+second	O
+trimester	O
+.	O
+
+It	O
+showed	O
+normal	O
+coronary	O
+vessels	O
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+appears	O
+to	O
+be	O
+the	O
+first	O
+reported	O
+case	O
+documenting	O
+a	O
+possible	O
+association	O
+between	O
+CC	O
+and	O
+myocardial	B
+infarction	I
+.	O
+
+Thrombosis	B
+might	O
+be	O
+a	O
+rare	O
+but	O
+hazardous	O
+complication	O
+of	O
+CC	O
+.	O
+
+Given	O
+this	O
+life	O
+-	O
+threatening	O
+complication	O
+,	O
+appropriate	O
+prophylactic	O
+measures	O
+should	O
+be	O
+used	O
+in	O
+high	O
+-	O
+risk	O
+woman	O
+undergoing	O
+ovarian	O
+stimulation	O
+.	O
+
+Reverse	O
+or	O
+inverted	O
+left	B
+ventricular	I
+apical	I
+ballooning	I
+syndrome	I
+(	O
+reverse	O
+Takotsubo	B
+cardiomyopathy	I
+)	O
+in	O
+a	O
+young	O
+woman	O
+in	O
+the	O
+setting	O
+of	O
+amphetamine	O
+use	O
+.	O
+
+Transient	O
+left	B
+ventricular	I
+apical	I
+ballooning	I
+syndrome	I
+was	O
+first	O
+described	O
+in	O
+Japan	O
+as	O
+"	O
+Takotsubo	B
+cardiomyopathy	I
+.	O
+"	O
+This	O
+syndrome	O
+has	O
+been	O
+identified	O
+in	O
+many	O
+other	O
+countries	O
+.	O
+
+Many	O
+variations	O
+of	O
+this	O
+syndrome	O
+have	O
+been	O
+recently	O
+described	O
+in	O
+the	O
+literature	O
+.	O
+
+One	O
+of	O
+the	O
+rarest	O
+is	O
+the	O
+reverse	O
+type	O
+of	O
+this	O
+syndrome	O
+,	O
+with	O
+hyperdynamic	O
+apex	O
+and	O
+complete	O
+akinesia	B
+of	O
+the	O
+base	O
+(	O
+as	O
+opposed	O
+to	O
+the	O
+classic	O
+apical	B
+ballooning	I
+)	O
+.	O
+
+In	O
+this	O
+article	O
+,	O
+we	O
+report	O
+an	O
+interesting	O
+case	O
+of	O
+a	O
+young	O
+woman	O
+who	O
+presented	O
+with	O
+this	O
+rare	O
+type	O
+of	O
+reverse	O
+apical	B
+ballooning	I
+syndrome	I
+occurring	O
+after	O
+amphetamine	O
+use	O
+.	O
+
+This	O
+report	O
+is	O
+followed	O
+by	O
+review	O
+of	O
+the	O
+literature	O
+.	O
+
+Results	O
+of	O
+a	O
+comparative	O
+,	O
+phase	O
+III	O
+,	O
+12	O
+-	O
+week	O
+,	O
+multicenter	O
+,	O
+prospective	O
+,	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+assessment	O
+of	O
+the	O
+efficacy	O
+and	O
+tolerability	O
+of	O
+a	O
+fixed	O
+-	O
+dose	O
+combination	O
+of	O
+telmisartan	O
+and	O
+amlodipine	O
+versus	O
+amlodipine	O
+monotherapy	O
+in	O
+Indian	O
+adults	O
+with	O
+stage	O
+II	O
+hypertension	B
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+evaluate	O
+the	O
+efficacy	O
+and	O
+tolerability	O
+of	O
+a	O
+new	O
+fixed	O
+-	O
+dose	O
+combination	O
+(	O
+FDC	O
+)	O
+of	O
+telmisartan	O
+40	O
+mg	O
++	O
+amlodipine	O
+5	O
+mg	O
+(	O
+T	O
++	O
+A	O
+)	O
+compared	O
+with	O
+amlodipine	O
+5	O
+-	O
+mg	O
+monotherapy	O
+(	O
+A	O
+)	O
+in	O
+adult	O
+Indian	O
+patients	O
+with	O
+stage	O
+II	O
+hypertension	B
+.	O
+
+METHODS	O
+:	O
+This	O
+comparative	O
+,	O
+Phase	O
+III	O
+,	O
+12	O
+-	O
+week	O
+,	O
+multicenter	O
+,	O
+prospective	O
+,	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+study	O
+was	O
+conducted	O
+in	O
+Indian	O
+patients	O
+aged	O
+18	O
+to	O
+65	O
+years	O
+with	O
+established	O
+stage	O
+II	O
+hypertension	B
+.	O
+
+Patients	O
+were	O
+treated	O
+with	O
+oral	O
+FDC	O
+of	O
+T	O
++	O
+A	O
+or	O
+A	O
+QD	O
+before	O
+breakfast	O
+for	O
+12	O
+weeks	O
+;	O
+blood	O
+pressure	O
+(	O
+BP	O
+)	O
+and	O
+heart	O
+rate	O
+were	O
+measured	O
+in	O
+the	O
+sitting	O
+position	O
+.	O
+
+Primary	O
+efficacy	O
+end	O
+points	O
+were	O
+reduction	O
+in	O
+clinical	O
+systolic	O
+BP	O
+(	O
+SBP	O
+)	O
+/	O
+diastolic	O
+BP	O
+(	O
+DBP	O
+)	O
+from	O
+baseline	O
+to	O
+study	O
+end	O
+and	O
+number	O
+of	O
+responders	O
+(	O
+ie	O
+,	O
+patients	O
+who	O
+achieved	O
+target	O
+SBP	O
+/	O
+DBP	O
+<	O
+130	O
+/	O
+<	O
+80	O
+mm	O
+Hg	O
+)	O
+at	O
+end	O
+of	O
+study	O
+.	O
+
+Tolerability	O
+was	O
+assessed	O
+by	O
+treatment	O
+-	O
+emergent	O
+adverse	O
+events	O
+,	O
+identified	O
+using	O
+physical	O
+examination	O
+,	O
+laboratory	O
+analysis	O
+,	O
+and	O
+electrocardiography	O
+.	O
+
+RESULTS	O
+:	O
+A	O
+total	O
+of	O
+210	O
+patients	O
+were	O
+enrolled	O
+in	O
+the	O
+study	O
+;	O
+203	O
+patients	O
+(	O
+143	O
+men	O
+,	O
+60	O
+women	O
+)	O
+completed	O
+the	O
+study	O
+while	O
+7	O
+were	O
+lost	O
+to	O
+follow	O
+-	O
+up	O
+(	O
+4	O
+patients	O
+in	O
+the	O
+T	O
++	O
+A	O
+group	O
+and	O
+3	O
+in	O
+the	O
+A	O
+group	O
+)	O
+and	O
+considered	O
+with	O
+-	O
+drawn	O
+.	O
+
+At	O
+study	O
+end	O
+,	O
+statistically	O
+significant	O
+percentage	O
+reductions	O
+from	O
+baseline	O
+within	O
+groups	O
+and	O
+between	O
+groups	O
+were	O
+observed	O
+in	O
+SBP	O
+(	O
+T	O
++	O
+A	O
+[	O
+-	O
+27	O
+.	O
+4	O
+%	O
+]	O
+;	O
+A	O
+[	O
+-	O
+16	O
+.	O
+6	O
+%	O
+]	O
+)	O
+and	O
+DBP	O
+(	O
+T	O
++	O
+A	O
+[	O
+-	O
+20	O
+.	O
+1	O
+%	O
+]	O
+;	O
+A	O
+[	O
+-	O
+13	O
+.	O
+3	O
+%	O
+]	O
+)	O
+(	O
+all	O
+,	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Response	O
+rates	O
+were	O
+87	O
+.	O
+3	O
+%	O
+(	O
+89	O
+/	O
+102	O
+)	O
+in	O
+the	O
+T	O
++	O
+A	O
+group	O
+and	O
+69	O
+.	O
+3	O
+%	O
+(	O
+70	O
+/	O
+101	O
+)	O
+in	O
+the	O
+A	O
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+prevalences	O
+of	O
+adverse	O
+events	O
+were	O
+not	O
+significantly	O
+different	O
+between	O
+the	O
+2	O
+treatment	O
+groups	O
+(	O
+T	O
++	O
+A	O
+,	O
+16	O
+.	O
+0	O
+%	O
+[	O
+17	O
+/	O
+106	O
+]	O
+;	O
+A	O
+,	O
+15	O
+.	O
+4	O
+%	O
+[	O
+16	O
+/	O
+104	O
+]	O
+)	O
+.	O
+
+Peripheral	O
+edema	B
+was	O
+reported	O
+in	O
+8	O
+.	O
+5	O
+%	O
+patients	O
+(	O
+9	O
+/	O
+106	O
+)	O
+in	O
+the	O
+T	O
++	O
+A	O
+group	O
+compared	O
+with	O
+13	O
+.	O
+5	O
+%	O
+(	O
+14	O
+/	O
+104	O
+)	O
+in	O
+the	O
+A	O
+group	O
+,	O
+and	O
+cough	B
+was	O
+reported	O
+in	O
+3	O
+.	O
+8	O
+%	O
+patients	O
+(	O
+4	O
+/	O
+106	O
+)	O
+in	O
+the	O
+T	O
++	O
+A	O
+group	O
+and	O
+1	O
+.	O
+0	O
+%	O
+(	O
+1	O
+/	O
+104	O
+)	O
+patients	O
+in	O
+the	O
+A	O
+group	O
+;	O
+these	O
+differences	O
+did	O
+not	O
+reach	O
+statistical	O
+significance	O
+.	O
+
+The	O
+incidences	O
+of	O
+headache	B
+,	O
+dizziness	B
+,	O
+and	O
+diarrhea	B
+were	O
+similar	O
+between	O
+the	O
+2	O
+groups	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Among	O
+these	O
+Indian	O
+patients	O
+with	O
+stage	O
+II	O
+hypertension	B
+,	O
+the	O
+FDC	O
+of	O
+T	O
++	O
+A	O
+was	O
+found	O
+to	O
+be	O
+significantly	O
+more	O
+effective	O
+,	O
+with	O
+regard	O
+to	O
+BP	O
+reductions	O
+,	O
+than	O
+A	O
+,	O
+and	O
+both	O
+treatments	O
+were	O
+well	O
+tolerated	O
+.	O
+
+Increased	O
+mental	B
+slowing	I
+associated	O
+with	O
+the	O
+APOE	O
+epsilon4	O
+allele	O
+after	O
+trihexyphenidyl	O
+oral	O
+anticholinergic	O
+challenge	O
+in	O
+healthy	O
+elderly	O
+.	O
+
+OBJECTIVES	O
+:	O
+The	O
+objectives	O
+of	O
+this	O
+study	O
+were	O
+to	O
+examine	O
+the	O
+relationship	O
+between	O
+APOE	O
+epsilon4	O
+and	O
+subjective	O
+effects	O
+of	O
+trihexyphenidyl	O
+on	O
+measures	O
+reflecting	O
+sedation	O
+and	O
+confusion	B
+and	O
+to	O
+investigate	O
+the	O
+relationship	O
+between	O
+trihexyphenidyl	O
+-	O
+induced	O
+subjective	O
+effects	O
+and	O
+objective	O
+memory	O
+performance	O
+.	O
+
+METHODS	O
+:	O
+This	O
+study	O
+comprised	O
+24	O
+cognitively	O
+intact	O
+,	O
+health	O
+elderly	O
+adults	O
+(	O
+12	O
+APOE	O
+epsilon4	O
+carriers	O
+)	O
+at	O
+an	O
+outpatient	O
+geriatric	O
+psychiatry	O
+research	O
+clinic	O
+.	O
+
+This	O
+was	O
+a	O
+randomized	O
+,	O
+double	O
+blind	O
+,	O
+placebo	O
+-	O
+controlled	O
+,	O
+three	O
+-	O
+way	O
+,	O
+crossover	O
+experimental	O
+design	O
+.	O
+
+All	O
+participants	O
+received	O
+1	O
+.	O
+0	O
+mg	O
+or	O
+2	O
+.	O
+0	O
+mg	O
+trihexyphenidyl	O
+or	O
+placebo	O
+administered	O
+in	O
+counterbalanced	O
+sequences	O
+over	O
+a	O
+period	O
+of	O
+three	O
+consecutive	O
+weeks	O
+.	O
+
+Bond	O
+and	O
+Lader	O
+'	O
+s	O
+visual	O
+analog	O
+scales	O
+and	O
+alternate	O
+versions	O
+of	O
+the	O
+Buschke	O
+Selective	O
+Reminding	O
+Test	O
+were	O
+administered	O
+in	O
+a	O
+repeated	O
+measures	O
+design	O
+at	O
+baseline	O
+,	O
+1	O
+,	O
+2	O
+.	O
+5	O
+,	O
+and	O
+5	O
+hours	O
+postdrug	O
+administration	O
+.	O
+
+RESULTS	O
+:	O
+A	O
+2	O
+.	O
+0	O
+-	O
+mg	O
+oral	O
+dose	O
+of	O
+trihexyphenidyl	O
+resulted	O
+in	O
+increased	O
+subjective	O
+ratings	O
+of	O
+mental	B
+slowness	I
+in	O
+carriers	O
+of	O
+the	O
+APOE	O
+epsilon4	O
+allele	O
+only	O
+.	O
+
+Drug	O
+effects	O
+as	O
+determined	O
+by	O
+difference	O
+scores	O
+between	O
+2	O
+.	O
+0	O
+mg	O
+trihexyphenidyl	O
+and	O
+placebo	O
+on	O
+ratings	O
+of	O
+mental	B
+slowness	I
+significantly	O
+correlated	O
+with	O
+total	O
+and	O
+delayed	O
+recall	O
+on	O
+the	O
+Buschke	O
+Selective	O
+Reminding	O
+Test	O
+in	O
+carriers	O
+of	O
+the	O
+APOE	O
+epsilon4	O
+allele	O
+only	O
+.	O
+
+However	O
+,	O
+no	O
+significant	O
+effects	O
+were	O
+found	O
+with	O
+other	O
+visual	O
+analog	O
+scales	O
+reflecting	O
+subjective	O
+sedation	O
+and	O
+clear	O
+-	O
+headedness	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+epsilon4	O
+allele	O
+in	O
+healthy	O
+elderly	O
+was	O
+associated	O
+with	O
+increased	O
+subjective	O
+mental	B
+slowing	I
+after	O
+trihexyphenidyl	O
+anticholinergic	O
+challenge	O
+.	O
+
+An	O
+evaluation	O
+of	O
+amikacin	O
+nephrotoxicity	B
+in	O
+the	O
+hematology	O
+/	O
+oncology	O
+population	O
+.	O
+
+Amikacin	O
+is	O
+an	O
+aminoglycoside	O
+commonly	O
+used	O
+to	O
+provide	O
+empirical	O
+double	O
+gram	O
+-	O
+negative	O
+treatment	O
+for	O
+febrile	B
+neutropenia	I
+and	O
+other	O
+suspected	O
+infections	B
+.	O
+
+Strategies	O
+of	O
+extended	O
+-	O
+interval	O
+and	O
+conventional	O
+dosing	O
+have	O
+been	O
+utilized	O
+extensively	O
+in	O
+the	O
+general	O
+medical	O
+population	O
+;	O
+however	O
+,	O
+data	O
+are	O
+lacking	O
+to	O
+support	O
+a	O
+dosing	O
+strategy	O
+in	O
+the	O
+hematology	O
+/	O
+oncology	O
+population	O
+.	O
+
+To	O
+evaluate	O
+amikacin	O
+-	O
+associated	O
+nephrotoxicity	B
+in	O
+an	O
+adult	O
+hematology	O
+/	O
+oncology	O
+population	O
+,	O
+a	O
+prospective	O
+,	O
+randomized	O
+,	O
+open	O
+-	O
+label	O
+trial	O
+was	O
+conducted	O
+at	O
+a	O
+university	O
+-	O
+affiliated	O
+medical	O
+center	O
+.	O
+
+Forty	O
+patients	O
+with	O
+a	O
+diagnosis	O
+consistent	O
+with	O
+a	O
+hematologic	B
+/	I
+oncologic	I
+disorder	I
+that	O
+required	O
+treatment	O
+with	O
+an	O
+aminoglycoside	O
+were	O
+randomized	O
+to	O
+either	O
+conventional	O
+or	O
+extended	O
+-	O
+interval	O
+amikacin	O
+.	O
+
+The	O
+occurrence	O
+of	O
+nephrotoxicity	B
+by	O
+means	O
+of	O
+an	O
+increase	O
+in	O
+serum	O
+creatinine	O
+and	O
+evaluation	O
+of	O
+efficacy	O
+via	O
+amikacin	O
+serum	O
+concentrations	O
+with	O
+respective	O
+pathogens	O
+were	O
+assessed	O
+.	O
+
+The	O
+occurrence	O
+of	O
+nephrotoxicity	B
+was	O
+similar	O
+between	O
+the	O
+conventional	O
+and	O
+extended	O
+-	O
+interval	O
+groups	O
+,	O
+at	O
+10	O
+%	O
+and	O
+5	O
+%	O
+,	O
+respectively	O
+(	O
+P	O
+=	O
+1	O
+.	O
+00	O
+)	O
+.	O
+
+Six	O
+patients	O
+in	O
+the	O
+conventional	O
+group	O
+had	O
+a	O
+positive	O
+culture	O
+,	O
+compared	O
+with	O
+none	O
+in	O
+the	O
+extended	O
+-	O
+interval	O
+group	O
+(	O
+P	O
+=	O
+0	O
+.	O
+002	O
+)	O
+.	O
+
+The	O
+occurrence	O
+of	O
+nephrotoxicity	B
+was	O
+similar	O
+between	O
+the	O
+two	O
+dosing	O
+regimens	O
+,	O
+but	O
+the	O
+distribution	O
+of	O
+risk	O
+factors	O
+was	O
+variable	O
+between	O
+the	O
+two	O
+groups	O
+.	O
+
+Efficacy	O
+could	O
+not	O
+be	O
+assessed	O
+.	O
+
+High	O
+dose	O
+dexmedetomidine	O
+as	O
+the	O
+sole	O
+sedative	O
+for	O
+pediatric	O
+MRI	O
+.	O
+
+OBJECTIVE	O
+:	O
+This	O
+large	O
+-	O
+scale	O
+retrospective	O
+review	O
+evaluates	O
+the	O
+sedation	O
+profile	O
+of	O
+dexmedetomidine	O
+.	O
+
+AIM	O
+:	O
+To	O
+determine	O
+the	O
+hemodynamic	O
+responses	O
+,	O
+efficacy	O
+and	O
+adverse	O
+events	O
+associated	O
+with	O
+the	O
+use	O
+of	O
+high	O
+dose	O
+dexmedetomidine	O
+as	O
+the	O
+sole	O
+sedative	O
+for	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+studies	O
+.	O
+
+BACKGROUND	O
+:	O
+Dexmedetomidine	O
+has	O
+been	O
+used	O
+at	O
+our	O
+institution	O
+since	O
+2005	O
+to	O
+provide	O
+sedation	O
+for	O
+pediatric	O
+radiological	O
+imaging	O
+studies	O
+.	O
+
+Over	O
+time	O
+,	O
+an	O
+effective	O
+protocol	O
+utilizing	O
+high	O
+dose	O
+dexmedetomidine	O
+as	O
+the	O
+sole	O
+sedative	O
+agent	O
+has	O
+evolved	O
+.	O
+
+METHODS	O
+/	O
+MATERIALS	O
+:	O
+As	O
+part	O
+of	O
+the	O
+ongoing	O
+Quality	O
+Assurance	O
+process	O
+,	O
+data	O
+on	O
+all	O
+sedations	O
+are	O
+reviewed	O
+monthly	O
+and	O
+protocols	O
+modified	O
+as	O
+needed	O
+.	O
+
+Data	O
+were	O
+analyzed	O
+from	O
+all	O
+747	O
+consecutive	O
+patients	O
+who	O
+received	O
+dexmedetomidine	O
+for	O
+MRI	O
+sedation	O
+from	O
+April	O
+2005	O
+to	O
+April	O
+2007	O
+.	O
+
+RESULTS	O
+:	O
+Since	O
+2005	O
+,	O
+the	O
+10	O
+-	O
+min	O
+loading	O
+dose	O
+of	O
+our	O
+dexmedetomidine	O
+protocol	O
+increased	O
+from	O
+2	O
+to	O
+3	O
+microg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+,	O
+and	O
+the	O
+infusion	O
+rate	O
+increased	O
+from	O
+1	O
+to	O
+1	O
+.	O
+5	O
+to	O
+2	O
+microg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+h	O
+(	O
+-	O
+1	O
+)	O
+.	O
+
+The	O
+current	O
+sedation	O
+protocol	O
+progressively	O
+increased	O
+the	O
+rate	O
+of	O
+successful	O
+sedation	O
+(	O
+able	O
+to	O
+complete	O
+the	O
+imaging	O
+study	O
+)	O
+when	O
+using	O
+dexmedetomidine	O
+alone	O
+from	O
+91	O
+.	O
+8	O
+%	O
+to	O
+97	O
+.	O
+6	O
+%	O
+(	O
+P	O
+=	O
+0	O
+.	O
+009	O
+)	O
+,	O
+reducing	O
+the	O
+requirement	O
+for	O
+adjuvant	O
+pentobarbital	O
+in	O
+the	O
+event	O
+of	O
+sedation	O
+failure	O
+with	O
+dexmedetomidine	O
+alone	O
+and	O
+decreased	O
+the	O
+mean	O
+recovery	O
+time	O
+by	O
+10	O
+min	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Although	O
+dexmedetomidine	O
+sedation	O
+was	O
+associated	O
+with	O
+a	O
+16	O
+%	O
+incidence	O
+of	O
+bradycardia	B
+,	O
+all	O
+concomitant	O
+mean	O
+arterial	O
+blood	O
+pressures	O
+were	O
+within	O
+20	O
+%	O
+of	O
+age	O
+-	O
+adjusted	O
+normal	O
+range	O
+and	O
+oxygen	O
+saturations	O
+were	O
+95	O
+%	O
+or	O
+higher	O
+.	O
+
+CONCLUSION	O
+:	O
+Dexmedetomidine	O
+in	O
+high	O
+doses	O
+provides	O
+adequate	O
+sedation	O
+for	O
+pediatric	O
+MRI	O
+studies	O
+.	O
+
+While	O
+use	O
+of	O
+high	O
+dose	O
+dexmedetomidine	O
+is	O
+associated	O
+with	O
+decreases	O
+in	O
+heart	O
+rate	O
+and	O
+blood	O
+pressure	O
+outside	O
+the	O
+established	O
+'	O
+awake	O
+'	O
+norms	O
+,	O
+this	O
+deviation	O
+is	O
+generally	O
+within	O
+20	O
+%	O
+of	O
+norms	O
+,	O
+and	O
+is	O
+not	O
+associated	O
+with	O
+adverse	O
+sequelae	O
+.	O
+
+Dexmedetomidine	O
+is	O
+useful	O
+as	O
+the	O
+sole	O
+sedative	O
+for	O
+pediatric	O
+MRI	O
+.	O
+
+Hepatotoxicity	B
+associated	O
+with	O
+sulfasalazine	O
+in	O
+inflammatory	O
+arthritis	B
+:	O
+A	O
+case	O
+series	O
+from	O
+a	O
+local	O
+surveillance	O
+of	O
+serious	O
+adverse	O
+events	O
+.	O
+
+BACKGROUND	O
+:	O
+Spontaneous	O
+reporting	O
+systems	O
+for	O
+adverse	O
+drug	O
+reactions	O
+(	O
+ADRs	O
+)	O
+are	O
+handicapped	O
+by	O
+under	O
+-	O
+reporting	O
+and	O
+limited	O
+detail	O
+on	O
+individual	O
+cases	O
+.	O
+
+We	O
+report	O
+an	O
+investigation	O
+from	O
+a	O
+local	O
+surveillance	O
+for	O
+serious	O
+adverse	O
+drug	O
+reactions	O
+associated	O
+with	O
+disease	O
+modifying	O
+anti	O
+-	O
+rheumatic	O
+drugs	O
+that	O
+was	O
+triggered	O
+by	O
+the	O
+occurrence	O
+of	O
+liver	B
+failure	I
+in	O
+two	O
+of	O
+our	O
+patients	O
+.	O
+
+METHODS	O
+:	O
+Serious	O
+ADR	O
+reports	O
+have	O
+been	O
+solicited	O
+from	O
+local	O
+clinicians	O
+by	O
+regular	O
+postcards	O
+over	O
+the	O
+past	O
+seven	O
+years	O
+.	O
+
+Patients	O
+'	O
+,	O
+who	O
+had	O
+hepatotoxicity	B
+on	O
+sulfasalazine	O
+and	O
+met	O
+a	O
+definition	O
+of	O
+a	O
+serious	O
+ADR	O
+,	O
+were	O
+identified	O
+.	O
+
+Two	O
+clinicians	O
+reviewed	O
+structured	O
+case	O
+reports	O
+and	O
+assessed	O
+causality	O
+by	O
+consensus	O
+and	O
+by	O
+using	O
+a	O
+causality	O
+assessment	O
+instrument	O
+.	O
+
+The	O
+likely	O
+frequency	O
+of	O
+hepatotoxicity	B
+with	O
+sulfasalazine	O
+was	O
+estimated	O
+by	O
+making	O
+a	O
+series	O
+of	O
+conservative	O
+assumptions	O
+.	O
+
+RESULTS	O
+:	O
+Ten	O
+cases	O
+were	O
+identified	O
+:	O
+eight	O
+occurred	O
+during	O
+surveillance	O
+.	O
+
+Eight	O
+patients	O
+were	O
+hospitalised	O
+,	O
+two	O
+in	O
+hepatic	B
+failure	I
+-	O
+one	O
+died	O
+after	O
+a	O
+liver	O
+transplant	O
+.	O
+
+All	O
+but	O
+one	O
+event	O
+occurred	O
+within	O
+6	O
+weeks	O
+of	O
+treatment	O
+.	O
+
+Seven	O
+patients	O
+had	O
+a	O
+skin	B
+rash	I
+,	O
+three	O
+eosinophilia	B
+and	O
+one	O
+interstitial	B
+nephritis	I
+.	O
+
+Five	O
+patients	O
+were	O
+of	O
+Black	O
+British	O
+of	O
+African	O
+or	O
+Caribbean	O
+descent	O
+.	O
+
+Liver	O
+enzymes	O
+showed	O
+a	O
+hepatocellular	O
+pattern	O
+in	O
+four	O
+cases	O
+and	O
+a	O
+mixed	O
+pattern	O
+in	O
+six	O
+.	O
+
+Drug	O
+-	O
+related	O
+hepatotoxicity	B
+was	O
+judged	O
+probable	O
+or	O
+highly	O
+probable	O
+in	O
+8	O
+patients	O
+.	O
+
+The	O
+likely	O
+frequency	O
+of	O
+serious	O
+hepatotoxicity	B
+with	O
+sulfasalazine	O
+was	O
+estimated	O
+at	O
+0	O
+.	O
+4	O
+%	O
+of	O
+treated	O
+patients	O
+.	O
+
+CONCLUSION	O
+:	O
+Serious	O
+hepatotoxicity	B
+associated	O
+with	O
+sulfasalazine	O
+appears	O
+to	O
+be	O
+under	O
+-	O
+appreciated	O
+and	O
+intensive	O
+monitoring	O
+and	O
+vigilance	O
+in	O
+the	O
+first	O
+6	O
+weeks	O
+of	O
+treatment	O
+is	O
+especially	O
+important	O
+.	O
+
+Complete	O
+atrioventricular	B
+block	I
+secondary	O
+to	O
+lithium	O
+therapy	O
+.	O
+
+Sinus	B
+node	I
+dysfunction	I
+has	O
+been	O
+reported	O
+most	O
+frequently	O
+among	O
+the	O
+adverse	O
+cardiovascular	O
+effects	O
+of	O
+lithium	O
+.	O
+
+In	O
+the	O
+present	O
+case	O
+,	O
+complete	O
+atrioventricular	B
+(	I
+AV	I
+)	I
+block	I
+with	O
+syncopal	B
+attacks	I
+developed	O
+secondary	O
+to	O
+lithium	O
+therapy	O
+,	O
+necessitating	O
+permanent	O
+pacemaker	O
+implantation	O
+.	O
+
+Serum	O
+lithium	O
+levels	O
+remained	O
+under	O
+or	O
+within	O
+the	O
+therapeutic	O
+range	O
+during	O
+the	O
+syncopal	B
+attacks	I
+.	O
+
+Lithium	O
+should	O
+be	O
+used	O
+with	O
+extreme	O
+caution	O
+,	O
+especially	O
+in	O
+patients	O
+with	O
+mild	O
+disturbance	O
+of	O
+AV	O
+conduction	O
+.	O
+
+Exaggerated	O
+expression	O
+of	O
+inflammatory	O
+mediators	O
+in	O
+vasoactive	O
+intestinal	O
+polypeptide	O
+knockout	O
+(	O
+VIP	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+with	O
+cyclophosphamide	O
+(	O
+CYP	O
+)	O
+-	O
+induced	O
+cystitis	B
+.	O
+
+Vasoactive	O
+intestinal	O
+polypeptide	O
+(	O
+VIP	O
+)	O
+is	O
+an	O
+immunomodulatory	O
+neuropeptide	O
+distributed	O
+in	O
+micturition	O
+pathways	O
+.	O
+
+VIP	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+exhibit	O
+altered	O
+bladder	O
+function	O
+and	O
+neurochemical	O
+properties	O
+in	O
+micturition	O
+pathways	O
+after	O
+cyclophosphamide	O
+(	O
+CYP	O
+)	O
+-	O
+induced	O
+cystitis	B
+.	O
+
+Given	O
+VIP	O
+'	O
+s	O
+role	O
+as	O
+an	O
+anti	O
+-	O
+inflammatory	O
+mediator	O
+,	O
+we	O
+hypothesized	O
+that	O
+VIP	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+would	O
+exhibit	O
+enhanced	O
+inflammatory	O
+mediator	O
+expression	O
+after	O
+cystitis	B
+.	O
+
+A	O
+mouse	O
+inflammatory	O
+cytokine	O
+and	O
+receptor	O
+RT2	O
+profiler	O
+array	O
+was	O
+used	O
+to	O
+determine	O
+regulated	O
+transcripts	O
+in	O
+the	O
+urinary	O
+bladder	O
+of	O
+wild	O
+type	O
+(	O
+WT	O
+)	O
+and	O
+VIP	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+with	O
+or	O
+without	O
+CYP	O
+-	O
+induced	O
+cystitis	B
+(	O
+150	O
+mg	O
+/	O
+kg	O
+;	O
+i	O
+.	O
+p	O
+.	O
+;	O
+48	O
+h	O
+)	O
+.	O
+
+Four	O
+binary	O
+comparisons	O
+were	O
+made	O
+:	O
+WT	O
+control	O
+versus	O
+CYP	O
+treatment	O
+(	O
+48	O
+h	O
+)	O
+,	O
+VIP	O
+(	O
+-	O
+/	O
+-	O
+)	O
+control	O
+versus	O
+CYP	O
+treatment	O
+(	O
+48	O
+h	O
+)	O
+,	O
+WT	O
+control	O
+versus	O
+VIP	O
+(	O
+-	O
+/	O
+-	O
+)	O
+control	O
+,	O
+and	O
+WT	O
+with	O
+CYP	O
+treatment	O
+(	O
+48	O
+h	O
+)	O
+versus	O
+VIP	O
+(	O
+-	O
+/	O
+-	O
+)	O
+with	O
+CYP	O
+treatment	O
+(	O
+48	O
+h	O
+)	O
+.	O
+
+The	O
+genes	O
+presented	O
+represent	O
+(	O
+1	O
+)	O
+greater	O
+than	O
+1	O
+.	O
+5	O
+-	O
+fold	O
+change	O
+in	O
+either	O
+direction	O
+and	O
+(	O
+2	O
+)	O
+the	O
+p	O
+value	O
+is	O
+less	O
+than	O
+0	O
+.	O
+05	O
+for	O
+the	O
+comparison	O
+being	O
+made	O
+.	O
+
+Several	O
+regulated	O
+genes	O
+were	O
+validated	O
+using	O
+enzyme	O
+-	O
+linked	O
+immunoassays	O
+including	O
+IL	O
+-	O
+1beta	O
+and	O
+CXCL1	O
+.	O
+
+CYP	O
+treatment	O
+significantly	O
+(	O
+p	O
+<	O
+or	O
+=	O
+0	O
+.	O
+001	O
+)	O
+increased	O
+expression	O
+of	O
+CXCL1	O
+and	O
+IL	O
+-	O
+1beta	O
+in	O
+the	O
+urinary	O
+bladder	O
+of	O
+WT	O
+and	O
+VIP	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+,	O
+but	O
+expression	O
+in	O
+VIP	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+with	O
+CYP	O
+treatment	O
+was	O
+significantly	O
+(	O
+p	O
+<	O
+or	O
+=	O
+0	O
+.	O
+001	O
+)	O
+greater	O
+(	O
+4	O
+.	O
+2	O
+-	O
+to	O
+13	O
+-	O
+fold	O
+increase	O
+)	O
+than	O
+that	O
+observed	O
+in	O
+WT	O
+urinary	O
+bladder	O
+(	O
+3	O
+.	O
+6	O
+-	O
+to	O
+5	O
+-	O
+fold	O
+increase	O
+)	O
+.	O
+
+The	O
+data	O
+suggest	O
+that	O
+in	O
+VIP	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+with	O
+bladder	B
+inflammation	I
+,	O
+inflammatory	O
+mediators	O
+are	O
+increased	O
+above	O
+that	O
+observed	O
+in	O
+WT	O
+with	O
+CYP	O
+.	O
+
+This	O
+shift	O
+in	O
+balance	O
+may	O
+contribute	O
+to	O
+increased	O
+bladder	B
+dysfunction	I
+in	O
+VIP	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+with	O
+bladder	B
+inflammation	I
+and	O
+altered	O
+neurochemical	O
+expression	O
+in	O
+micturition	O
+pathways	O
+.	O
+
+Debrisoquine	O
+phenotype	O
+and	O
+the	O
+pharmacokinetics	O
+and	O
+beta	O
+-	O
+2	O
+receptor	O
+pharmacodynamics	O
+of	O
+metoprolol	O
+and	O
+its	O
+enantiomers	O
+.	O
+
+The	O
+metabolism	O
+of	O
+the	O
+cardioselective	O
+beta	O
+-	O
+blocker	O
+metoprolol	O
+is	O
+under	O
+genetic	O
+control	O
+of	O
+the	O
+debrisoquine	O
+/	O
+sparteine	O
+type	O
+.	O
+
+The	O
+two	O
+metabolic	O
+phenotypes	O
+,	O
+extensive	O
+(	O
+EM	O
+)	O
+and	O
+poor	O
+metabolizers	O
+(	O
+PM	O
+)	O
+,	O
+show	O
+different	O
+stereoselective	O
+metabolism	O
+,	O
+resulting	O
+in	O
+apparently	O
+higher	O
+beta	O
+-	O
+1	O
+adrenoceptor	O
+antagonistic	O
+potency	O
+of	O
+racemic	O
+metoprolol	O
+in	O
+EMs	O
+.	O
+
+We	O
+investigated	O
+if	O
+the	O
+latter	O
+also	O
+applies	O
+to	O
+the	O
+beta	O
+-	O
+2	O
+adrenoceptor	O
+antagonism	O
+by	O
+metoprolol	O
+.	O
+
+The	O
+drug	O
+effect	O
+studied	O
+was	O
+the	O
+antagonism	O
+by	O
+metoprolol	O
+of	O
+terbutaline	O
+-	O
+induced	O
+hypokalemia	B
+.	O
+
+By	O
+using	O
+pharmacokinetic	O
+pharmacodynamic	O
+modeling	O
+the	O
+pharmacodynamics	O
+of	O
+racemic	O
+metoprolol	O
+and	O
+the	O
+active	O
+S	O
+-	O
+isomer	O
+,	O
+were	O
+quantitated	O
+in	O
+EMs	O
+and	O
+PMs	O
+in	O
+terms	O
+of	O
+IC50	O
+values	O
+,	O
+representing	O
+metoprolol	O
+plasma	O
+concentrations	O
+resulting	O
+in	O
+half	O
+-	O
+maximum	O
+receptor	O
+occupancy	O
+.	O
+
+Six	O
+EMs	O
+received	O
+0	O
+.	O
+5	O
+mg	O
+of	O
+terbutaline	O
+s	O
+.	O
+c	O
+.	O
+on	O
+two	O
+different	O
+occasions	O
+:	O
+1	O
+)	O
+1	O
+hr	O
+after	O
+administration	O
+of	O
+a	O
+placebo	O
+and	O
+2	O
+)	O
+1	O
+hr	O
+after	O
+150	O
+mg	O
+of	O
+metoprolol	O
+p	O
+.	O
+o	O
+.	O
+
+Five	O
+PMs	O
+were	O
+studied	O
+according	O
+to	O
+the	O
+same	O
+protocol	O
+,	O
+except	O
+for	O
+a	O
+higher	O
+terbutaline	O
+dose	O
+(	O
+0	O
+.	O
+75	O
+mg	O
+)	O
+on	O
+day	O
+2	O
+.	O
+
+Blood	O
+samples	O
+for	O
+the	O
+analysis	O
+of	O
+plasma	O
+potassium	O
+,	O
+terbutaline	O
+,	O
+metoprolol	O
+(	O
+racemic	O
+,	O
+R	O
+-	O
+and	O
+S	O
+-	O
+isomer	O
+)	O
+,	O
+and	O
+alpha	O
+-	O
+hydroxymetoprolol	O
+concentrations	O
+were	O
+taken	O
+at	O
+regular	O
+time	O
+intervals	O
+,	O
+during	O
+8	O
+hr	O
+after	O
+metoprolol	O
+.	O
+
+In	O
+PMs	O
+,	O
+metoprolol	O
+increased	O
+the	O
+terbutaline	O
+area	O
+under	O
+the	O
+plasma	O
+concentration	O
+vs	O
+.	O
+time	O
+curve	O
+(	O
++	O
+67	O
+%	O
+)	O
+.	O
+
+Higher	O
+metoprolol	O
+/	O
+alpha	O
+-	O
+hydroxymetoprolol	O
+ratios	O
+in	O
+PMs	O
+were	O
+predictive	O
+for	O
+higher	O
+R	O
+-	O
+/	O
+S	O
+-	O
+isomer	O
+ratios	O
+of	O
+unchanged	O
+drug	O
+.	O
+
+There	O
+was	O
+a	O
+difference	O
+in	O
+metoprolol	O
+potency	O
+with	O
+higher	O
+racemic	O
+metoprolol	O
+IC50	O
+values	O
+in	O
+PMs	O
+(	O
+72	O
++	O
+/	O
+-	O
+7	O
+ng	O
+.	O
+ml	O
+-	O
+1	O
+)	O
+than	O
+EMs	O
+(	O
+42	O
++	O
+/	O
+-	O
+8	O
+ng	O
+.	O
+ml	O
+-	O
+1	O
+,	O
+P	O
+less	O
+than	O
+.	O
+001	O
+)	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+The	O
+hemodynamics	O
+of	O
+oxytocin	O
+and	O
+other	O
+vasoactive	O
+agents	O
+during	O
+neuraxial	O
+anesthesia	O
+for	O
+cesarean	O
+delivery	O
+:	O
+findings	O
+in	O
+six	O
+cases	O
+.	O
+
+Oxytocin	O
+is	O
+a	O
+commonly	O
+used	O
+uterotonic	O
+that	O
+can	O
+cause	O
+significant	O
+and	O
+even	O
+fatal	O
+hypotension	B
+,	O
+particularly	O
+when	O
+given	O
+as	O
+a	O
+bolus	O
+.	O
+
+The	O
+resulting	O
+hypotension	B
+can	O
+be	O
+produced	O
+by	O
+a	O
+decrease	O
+in	O
+systemic	O
+vascular	O
+resistance	O
+or	O
+cardiac	O
+output	O
+through	O
+a	O
+decrease	O
+in	O
+venous	O
+return	O
+.	O
+
+Parturients	O
+with	O
+normal	O
+volume	O
+status	O
+,	O
+heart	O
+valves	O
+and	O
+pulmonary	O
+vasculature	O
+most	O
+often	O
+respond	O
+to	O
+this	O
+hypotension	B
+with	O
+a	O
+compensatory	O
+increase	O
+in	O
+heart	O
+rate	O
+and	O
+stroke	B
+volume	O
+.	O
+
+Oxytocin	O
+-	O
+induced	O
+hypotension	B
+at	O
+cesarean	O
+delivery	O
+may	O
+be	O
+incorrectly	O
+attributed	O
+to	O
+blood	B
+loss	I
+.	O
+
+Pulse	O
+power	O
+analysis	O
+(	O
+also	O
+called	O
+"	O
+pulse	O
+contour	O
+analysis	O
+"	O
+)	O
+of	O
+an	O
+arterial	O
+pressure	O
+wave	O
+form	O
+allows	O
+continuous	O
+evaluation	O
+of	O
+systemic	O
+vascular	O
+resistance	O
+and	O
+cardiac	O
+output	O
+in	O
+real	O
+time	O
+,	O
+thereby	O
+elucidating	O
+the	O
+causative	O
+factors	O
+behind	O
+changes	O
+in	O
+blood	O
+pressure	O
+.	O
+
+Pulse	O
+power	O
+analysis	O
+was	O
+conducted	O
+in	O
+six	O
+cases	O
+of	O
+cesarean	O
+delivery	O
+performed	O
+under	O
+neuraxial	O
+anesthesia	O
+.	O
+
+Hypotension	B
+in	O
+response	O
+to	O
+oxytocin	O
+was	O
+associated	O
+with	O
+a	O
+decrease	O
+in	O
+systemic	O
+vascular	O
+resistance	O
+and	O
+a	O
+compensatory	O
+increase	O
+in	O
+stroke	B
+volume	O
+,	O
+heart	O
+rate	O
+and	O
+cardiac	O
+output	O
+.	O
+
+Pulse	O
+power	O
+analysis	O
+may	O
+be	O
+helpful	O
+in	O
+determining	O
+the	O
+etiology	O
+of	O
+and	O
+treating	O
+hypotension	B
+during	O
+cesarean	O
+delivery	O
+under	O
+neuraxial	O
+anesthesia	O
+.	O
+
+Protective	O
+effects	O
+of	O
+antithrombin	O
+on	O
+puromycin	O
+aminonucleoside	O
+nephrosis	B
+in	O
+rats	O
+.	O
+
+We	O
+investigated	O
+the	O
+effects	O
+of	O
+antithrombin	O
+,	O
+a	O
+plasma	O
+inhibitor	O
+of	O
+coagulation	O
+factors	O
+,	O
+in	O
+rats	O
+with	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+nephrosis	B
+,	O
+which	O
+is	O
+an	O
+experimental	O
+model	O
+of	O
+human	O
+nephrotic	B
+syndrome	I
+.	O
+
+Antithrombin	O
+(	O
+50	O
+or	O
+500	O
+IU	O
+/	O
+kg	O
+/	O
+i	O
+.	O
+v	O
+.	O
+)	O
+was	O
+administered	O
+to	O
+rats	O
+once	O
+a	O
+day	O
+for	O
+10	O
+days	O
+immediately	O
+after	O
+the	O
+injection	O
+of	O
+puromycin	O
+aminonucleoside	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+/	O
+i	O
+.	O
+v	O
+.	O
+)	O
+.	O
+
+Treatment	O
+with	O
+antithrombin	O
+attenuated	O
+the	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+hematological	B
+abnormalities	I
+.	O
+
+Puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+renal	B
+dysfunction	I
+and	O
+hyperlipidemia	B
+were	O
+also	O
+suppressed	O
+.	O
+
+Histopathological	O
+examination	O
+revealed	O
+severe	O
+renal	B
+damage	I
+such	O
+as	O
+proteinaceous	O
+casts	O
+in	O
+tubuli	O
+and	O
+tubular	O
+expansion	O
+in	O
+the	O
+kidney	O
+of	O
+control	O
+rats	O
+,	O
+while	O
+an	O
+improvement	O
+of	O
+the	O
+damage	O
+was	O
+seen	O
+in	O
+antithrombin	O
+-	O
+treated	O
+rats	O
+.	O
+
+In	O
+addition	O
+,	O
+antithrombin	O
+treatment	O
+markedly	O
+suppressed	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+apoptosis	O
+of	O
+renal	O
+tubular	O
+epithelial	O
+cells	O
+.	O
+
+Furthermore	O
+,	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+increases	O
+in	O
+renal	O
+cytokine	O
+content	O
+were	O
+also	O
+decreased	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+thrombin	O
+plays	O
+an	O
+important	O
+role	O
+in	O
+the	O
+pathogenesis	O
+of	O
+puromycin	O
+aminonucleoside	O
+-	O
+induced	O
+nephrotic	B
+syndrome	I
+.	O
+
+Treatment	O
+with	O
+antithrombin	O
+may	O
+be	O
+clinically	O
+effective	O
+in	O
+patients	O
+with	O
+nephrotic	B
+syndrome	I
+.	O
+
+Heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+after	O
+liver	O
+transplantation	O
+.	O
+
+BACKGROUND	O
+:	O
+Unfractionated	O
+heparin	O
+sodium	O
+(	O
+UFH	O
+)	O
+or	O
+low	O
+-	O
+molecular	O
+weight	O
+heparin	O
+(	O
+LMWH	O
+)	O
+is	O
+used	O
+in	O
+anticoagulant	O
+protocols	O
+at	O
+several	O
+institutions	O
+to	O
+prevent	O
+thrombosis	B
+after	O
+liver	O
+transplantation	O
+.	O
+
+Heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+(	O
+HIT	B
+)	O
+is	O
+an	O
+adverse	O
+immune	O
+-	O
+mediated	O
+reaction	O
+to	O
+heparin	O
+,	O
+resulting	O
+in	O
+platelet	O
+count	O
+decreases	O
+of	O
+more	O
+than	O
+50	O
+%	O
+.	O
+
+The	O
+frequencies	O
+of	O
+HIT	B
+after	O
+liver	O
+transplantation	O
+and	O
+platelet	O
+factor	O
+4	O
+/	O
+heparin	O
+-	O
+reactive	O
+antibody	O
+(	O
+HIT	B
+antibody	O
+)	O
+positivity	O
+in	O
+liver	O
+transplantation	O
+patients	O
+,	O
+however	O
+,	O
+are	O
+unknown	O
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+The	O
+32	O
+men	O
+and	O
+20	O
+women	O
+underwent	O
+living	O
+donor	O
+liver	O
+transplantation	O
+.	O
+
+We	O
+started	O
+LMWH	O
+(	O
+25	O
+IU	O
+/	O
+kg	O
+/	O
+h	O
+)	O
+on	O
+postoperative	O
+day	O
+(	O
+POD	O
+)	O
+1	O
+,	O
+switching	O
+to	O
+UFH	O
+(	O
+5000	O
+U	O
+/	O
+d	O
+)	O
+on	O
+POD	O
+2	O
+or	O
+3	O
+.	O
+
+The	O
+dose	O
+of	O
+UFH	O
+was	O
+changed	O
+according	O
+to	O
+the	O
+activated	O
+clotting	O
+time	O
+level	O
+.	O
+
+HIT	B
+antibody	O
+levels	O
+were	O
+measured	O
+the	O
+day	O
+before	O
+surgery	O
+and	O
+on	O
+POD	O
+7	O
+and	O
+14	O
+.	O
+
+Platelet	O
+count	O
+was	O
+measured	O
+daily	O
+for	O
+3	O
+weeks	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+average	O
+platelet	O
+counts	O
+preoperatively	O
+,	O
+and	O
+on	O
+POD	O
+7	O
+,	O
+14	O
+,	O
+and	O
+21	O
+were	O
+65	O
+,	O
+88	O
+,	O
+149	O
+,	O
+and	O
+169	O
+x	O
+10	O
+(	O
+9	O
+)	O
+/	O
+L	O
+,	O
+respectively	O
+.	O
+
+Two	O
+patients	O
+developed	O
+hepatic	O
+artery	O
+thrombosis	B
+on	O
+POD	O
+11	O
+and	O
+19	O
+,	O
+respectively	O
+,	O
+although	O
+they	O
+were	O
+HIT	B
+antibody	O
+-	O
+negative	O
+and	O
+their	O
+platelet	O
+counts	O
+were	O
+stable	O
+.	O
+
+In	O
+2	O
+other	O
+patients	O
+,	O
+the	O
+platelet	O
+count	O
+decreased	O
+suddenly	O
+from	O
+107	O
+x	O
+10	O
+(	O
+9	O
+)	O
+/	O
+L	O
+on	O
+POD	O
+4	O
+to	O
+65	O
+x	O
+10	O
+(	O
+9	O
+)	O
+/	O
+L	O
+on	O
+POD	O
+6	O
+and	O
+from	O
+76	O
+x	O
+10	O
+(	O
+9	O
+)	O
+/	O
+L	O
+on	O
+POD	O
+7	O
+to	O
+33	O
+x	O
+10	O
+(	O
+9	O
+)	O
+/	O
+L	O
+on	O
+POD	O
+9	O
+,	O
+respectively	O
+.	O
+
+The	O
+heparin	O
+-	O
+induced	O
+platelet	B
+aggregation	I
+test	O
+was	O
+negative	O
+in	O
+these	O
+patients	O
+.	O
+
+The	O
+percentage	O
+of	O
+HIT	B
+antibody	O
+-	O
+positive	O
+patients	O
+was	O
+0	O
+.	O
+5	O
+%	O
+preoperatively	O
+,	O
+5	O
+.	O
+6	O
+%	O
+on	O
+POD	O
+7	O
+,	O
+and	O
+5	O
+.	O
+6	O
+%	O
+on	O
+POD	O
+14	O
+.	O
+
+None	O
+of	O
+the	O
+subjects	O
+/	O
+patients	O
+developed	O
+UFH	O
+-	O
+related	O
+HIT	B
+.	O
+
+CONCLUSIONS	O
+:	O
+In	O
+our	O
+series	O
+,	O
+the	O
+occurrence	O
+of	O
+HIT	B
+after	O
+liver	O
+transplantation	O
+was	O
+uncommon	O
+.	O
+
+Doxorubicin	O
+cardiomyopathy	B
+-	O
+induced	O
+inflammation	B
+and	O
+apoptosis	O
+are	O
+attenuated	O
+by	O
+gene	O
+deletion	O
+of	O
+the	O
+kinin	O
+B1	O
+receptor	O
+.	O
+
+Clinical	O
+use	O
+of	O
+the	O
+anthracycline	O
+doxorubicin	O
+(	O
+DOX	O
+)	O
+is	O
+limited	O
+by	O
+its	O
+cardiotoxic	B
+effects	O
+,	O
+which	O
+are	O
+attributed	O
+to	O
+the	O
+induction	O
+of	O
+apoptosis	O
+.	O
+
+To	O
+elucidate	O
+the	O
+possible	O
+role	O
+of	O
+the	O
+kinin	O
+B1	O
+receptor	O
+(	O
+B1R	O
+)	O
+during	O
+the	O
+development	O
+of	O
+DOX	O
+cardiomyopathy	B
+,	O
+we	O
+studied	O
+B1R	O
+knockout	O
+mice	O
+(	O
+B1R	O
+(	O
+-	O
+/	O
+-	O
+)	O
+)	O
+by	O
+investigating	O
+cardiac	O
+inflammation	B
+and	O
+apoptosis	O
+after	O
+induction	O
+of	O
+DOX	O
+-	O
+induced	O
+cardiomyopathy	B
+.	O
+
+DOX	O
+control	O
+mice	O
+showed	O
+cardiac	B
+dysfunction	I
+measured	O
+by	O
+pressure	O
+-	O
+volume	O
+loops	O
+in	O
+vivo	O
+.	O
+
+This	O
+was	O
+associated	O
+with	O
+a	O
+reduced	O
+activation	O
+state	O
+of	O
+AKT	O
+,	O
+as	O
+well	O
+as	O
+an	O
+increased	O
+bax	O
+/	O
+bcl2	O
+ratio	O
+in	O
+Western	O
+blots	O
+,	O
+indicating	O
+cardiac	B
+apoptosis	I
+.	O
+
+Furthermore	O
+,	O
+mRNA	O
+levels	O
+of	O
+the	O
+proinflammatory	O
+cytokine	O
+interleukin	O
+6	O
+were	O
+increased	O
+in	O
+the	O
+cardiac	O
+tissue	O
+.	O
+
+In	O
+DOX	O
+B1R	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+,	O
+cardiac	B
+dysfunction	I
+was	O
+improved	O
+compared	O
+to	O
+DOX	O
+control	O
+mice	O
+,	O
+which	O
+was	O
+associated	O
+with	O
+normalization	O
+of	O
+the	O
+bax	O
+/	O
+bcl	O
+-	O
+2	O
+ratio	O
+and	O
+interleukin	O
+6	O
+,	O
+as	O
+well	O
+as	O
+AKT	O
+activation	O
+state	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+B1R	O
+is	O
+detrimental	O
+in	O
+DOX	O
+cardiomyopathy	B
+in	O
+that	O
+it	O
+mediates	O
+the	O
+inflammatory	O
+response	O
+and	O
+apoptosis	O
+.	O
+
+These	O
+insights	O
+might	O
+have	O
+useful	O
+implications	O
+for	O
+future	O
+studies	O
+utilizing	O
+B1R	O
+antagonists	O
+for	O
+treatment	O
+of	O
+human	O
+DOX	O
+cardiomyopathy	B
+.	O
+
+Detailed	O
+spectral	O
+profile	O
+analysis	O
+of	O
+penicillin	O
+-	O
+induced	O
+epileptiform	B
+activity	I
+in	O
+anesthetized	O
+rats	O
+.	O
+
+Penicillin	O
+model	O
+is	O
+a	O
+widely	O
+used	O
+experimental	O
+model	O
+for	O
+epilepsy	B
+research	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+we	O
+aimed	O
+to	O
+portray	O
+a	O
+detailed	O
+spectral	O
+analysis	O
+of	O
+penicillin	O
+-	O
+induced	O
+epileptiform	B
+activity	I
+in	O
+comparison	O
+with	O
+basal	O
+brain	O
+activity	O
+in	O
+anesthetized	O
+Wistar	O
+rats	O
+.	O
+
+Male	O
+Wistar	O
+rats	O
+were	O
+anesthetized	O
+with	O
+i	O
+.	O
+p	O
+.	O
+urethane	O
+and	O
+connected	O
+to	O
+an	O
+electrocorticogram	O
+setup	O
+.	O
+
+After	O
+a	O
+short	O
+period	O
+of	O
+basal	O
+activity	O
+recording	O
+,	O
+epileptic	B
+focus	O
+was	O
+induced	O
+by	O
+injecting	O
+400IU	O
+/	O
+2	O
+microl	O
+penicillin	O
+-	O
+G	O
+potassium	O
+into	O
+the	O
+left	O
+lateral	O
+ventricle	O
+while	O
+the	O
+cortical	O
+activity	O
+was	O
+continuously	O
+recorded	O
+.	O
+
+Basal	O
+activity	O
+,	O
+latent	O
+period	O
+and	O
+the	O
+penicillin	O
+-	O
+induced	O
+epileptiform	B
+activity	I
+periods	O
+were	O
+then	O
+analyzed	O
+using	O
+both	O
+conventional	O
+methods	O
+and	O
+spectral	O
+analysis	O
+.	O
+
+Spectral	O
+analyses	O
+were	O
+conducted	O
+by	O
+dividing	O
+the	O
+whole	O
+spectrum	O
+into	O
+different	O
+frequency	O
+bands	O
+including	O
+delta	O
+,	O
+theta	O
+(	O
+slow	O
+and	O
+fast	O
+)	O
+,	O
+alpha	O
+-	O
+sigma	O
+,	O
+beta	O
+(	O
+1	O
+and	O
+2	O
+)	O
+and	O
+gamma	O
+(	O
+1	O
+and	O
+2	O
+)	O
+bands	O
+.	O
+
+Our	O
+results	O
+show	O
+that	O
+the	O
+most	O
+affected	O
+frequency	O
+bands	O
+were	O
+delta	O
+,	O
+theta	O
+,	O
+beta	O
+-	O
+2	O
+and	O
+gamma	O
+-	O
+2	O
+bands	O
+during	O
+the	O
+epileptiform	B
+activity	I
+and	O
+there	O
+were	O
+marked	O
+differences	O
+in	O
+terms	O
+of	O
+spectral	O
+densities	O
+between	O
+three	O
+investigated	O
+episodes	O
+(	O
+basal	O
+activity	O
+,	O
+latent	O
+period	O
+and	O
+epileptiform	B
+activity	I
+)	O
+.	O
+
+Our	O
+results	O
+may	O
+help	O
+to	O
+analyze	O
+novel	O
+data	O
+obtained	O
+using	O
+similar	O
+experimental	O
+models	O
+and	O
+the	O
+simple	O
+analysis	O
+method	O
+described	O
+here	O
+can	O
+be	O
+used	O
+in	O
+similar	O
+studies	O
+to	O
+investigate	O
+the	O
+basic	O
+neuronal	O
+mechanism	O
+of	O
+this	O
+or	O
+other	O
+types	O
+of	O
+experimental	O
+epilepsies	B
+.	O
+
+High	O
+fat	O
+diet	O
+-	O
+fed	O
+obese	B
+rats	O
+are	O
+highly	O
+sensitive	O
+to	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+Often	O
+,	O
+chemotherapy	O
+by	O
+doxorubicin	O
+(	O
+Adriamycin	O
+)	O
+is	O
+limited	O
+due	O
+to	O
+life	O
+threatening	O
+cardiotoxicity	B
+in	O
+patients	O
+during	O
+and	O
+posttherapy	O
+.	O
+
+Recently	O
+,	O
+we	O
+have	O
+shown	O
+that	O
+moderate	O
+diet	O
+restriction	O
+remarkably	O
+protects	O
+against	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+This	O
+cardioprotection	O
+is	O
+accompanied	O
+by	O
+decreased	O
+cardiac	O
+oxidative	O
+stress	O
+and	O
+triglycerides	O
+and	O
+increased	O
+cardiac	O
+fatty	O
+-	O
+acid	O
+oxidation	O
+,	O
+ATP	O
+synthesis	O
+,	O
+and	O
+upregulated	O
+JAK	O
+/	O
+STAT3	O
+pathway	O
+.	O
+
+In	O
+the	O
+current	O
+study	O
+,	O
+we	O
+investigated	O
+whether	O
+a	O
+physiological	O
+intervention	O
+by	O
+feeding	O
+40	O
+%	O
+high	O
+fat	O
+diet	O
+(	O
+HFD	O
+)	O
+,	O
+which	O
+induces	O
+obesity	B
+in	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+(	O
+250	O
+-	O
+275	O
+g	O
+)	O
+,	O
+sensitizes	O
+to	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B
+.	O
+
+A	O
+LD	O
+(	O
+10	O
+)	O
+dose	O
+(	O
+8	O
+mg	O
+doxorubicin	O
+/	O
+kg	O
+,	O
+ip	O
+)	O
+administered	O
+on	O
+day	O
+43	O
+of	O
+the	O
+HFD	O
+feeding	O
+regimen	O
+led	O
+to	O
+higher	O
+cardiotoxicity	B
+,	O
+cardiac	B
+dysfunction	I
+,	O
+lipid	O
+peroxidation	O
+,	O
+and	O
+80	O
+%	O
+mortality	O
+in	O
+the	O
+obese	B
+(	O
+OB	B
+)	O
+rats	O
+in	O
+the	O
+absence	O
+of	O
+any	O
+significant	O
+renal	B
+or	I
+hepatic	I
+toxicity	I
+.	O
+
+Doxorubicin	O
+toxicokinetics	O
+studies	O
+revealed	O
+no	O
+change	O
+in	O
+accumulation	O
+of	O
+doxorubicin	O
+and	O
+doxorubicinol	O
+(	O
+toxic	O
+metabolite	O
+)	O
+in	O
+the	O
+normal	O
+diet	O
+-	O
+fed	O
+(	O
+ND	O
+)	O
+and	O
+OB	B
+hearts	O
+.	O
+
+Mechanistic	O
+studies	O
+revealed	O
+that	O
+OB	B
+rats	O
+are	O
+sensitized	O
+due	O
+to	O
+:	O
+(	O
+1	O
+)	O
+higher	O
+oxyradical	O
+stress	O
+leading	O
+to	O
+upregulation	O
+of	O
+uncoupling	O
+proteins	O
+2	O
+and	O
+3	O
+,	O
+(	O
+2	O
+)	O
+downregulation	O
+of	O
+cardiac	O
+peroxisome	O
+proliferators	O
+activated	O
+receptor	O
+-	O
+alpha	O
+,	O
+(	O
+3	O
+)	O
+decreased	O
+plasma	O
+adiponectin	O
+levels	O
+,	O
+(	O
+4	O
+)	O
+decreased	O
+cardiac	O
+fatty	O
+-	O
+acid	O
+oxidation	O
+(	O
+666	O
+.	O
+9	O
++	O
+/	O
+-	O
+14	O
+.	O
+0	O
+nmol	O
+/	O
+min	O
+/	O
+g	O
+heart	O
+in	O
+ND	O
+versus	O
+400	O
+.	O
+2	O
++	O
+/	O
+-	O
+11	O
+.	O
+8	O
+nmol	O
+/	O
+min	O
+/	O
+g	O
+heart	O
+in	O
+OB	B
+)	O
+,	O
+(	O
+5	O
+)	O
+decreased	O
+mitochondrial	O
+AMP	O
+-	O
+alpha2	O
+protein	O
+kinase	O
+,	O
+and	O
+(	O
+6	O
+)	O
+86	O
+%	O
+drop	O
+in	O
+cardiac	O
+ATP	O
+levels	O
+accompanied	O
+by	O
+decreased	O
+ATP	O
+/	O
+ADP	O
+ratio	O
+after	O
+doxorubicin	O
+administration	O
+.	O
+
+Decreased	O
+cardiac	O
+erythropoietin	O
+and	O
+increased	O
+SOCS3	O
+further	O
+downregulated	O
+the	O
+cardioprotective	O
+JAK	O
+/	O
+STAT3	O
+pathway	O
+.	O
+
+In	O
+conclusion	O
+,	O
+HFD	O
+-	O
+induced	O
+obese	B
+rats	O
+are	O
+highly	O
+sensitized	O
+to	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B
+by	O
+substantially	O
+downregulating	O
+cardiac	O
+mitochondrial	O
+ATP	O
+generation	O
+,	O
+increasing	O
+oxidative	O
+stress	O
+and	O
+downregulating	O
+the	O
+JAK	O
+/	O
+STAT3	O
+pathway	O
+.	O
+
+Isoproterenol	O
+induces	O
+primary	O
+loss	O
+of	O
+dystrophin	O
+in	O
+rat	O
+hearts	O
+:	O
+correlation	O
+with	O
+myocardial	B
+injury	I
+.	O
+
+The	O
+mechanism	O
+of	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B
+damage	I
+is	O
+unknown	O
+,	O
+but	O
+a	O
+mismatch	O
+of	O
+oxygen	O
+supply	O
+vs	O
+.	O
+demand	O
+following	O
+coronary	O
+hypotension	B
+and	O
+myocardial	B
+hyperactivity	I
+is	O
+the	O
+best	O
+explanation	O
+for	O
+the	O
+complex	O
+morphological	O
+alterations	O
+observed	O
+.	O
+
+Severe	O
+alterations	O
+in	O
+the	O
+structural	O
+integrity	O
+of	O
+the	O
+sarcolemma	O
+of	O
+cardiomyocytes	O
+have	O
+been	O
+demonstrated	O
+to	O
+be	O
+caused	O
+by	O
+isoproterenol	O
+.	O
+
+Taking	O
+into	O
+account	O
+that	O
+the	O
+sarcolemmal	O
+integrity	O
+is	O
+stabilized	O
+by	O
+the	O
+dystrophin	O
+-	O
+glycoprotein	O
+complex	O
+(	O
+DGC	O
+)	O
+that	O
+connects	O
+actin	O
+and	O
+laminin	O
+in	O
+contractile	O
+machinery	O
+and	O
+extracellular	O
+matrix	O
+and	O
+by	O
+integrins	O
+,	O
+this	O
+study	O
+tests	O
+the	O
+hypothesis	O
+that	O
+isoproterenol	O
+affects	O
+sarcolemmal	O
+stability	O
+through	O
+changes	O
+in	O
+the	O
+DGC	O
+and	O
+integrins	O
+.	O
+
+We	O
+found	O
+different	O
+sensitivity	O
+of	O
+the	O
+DGC	O
+and	O
+integrin	O
+to	O
+isoproterenol	O
+subcutaneous	O
+administration	O
+.	O
+
+Immunofluorescent	O
+staining	O
+revealed	O
+that	O
+dystrophin	O
+is	O
+the	O
+most	O
+sensitive	O
+among	O
+the	O
+structures	O
+connecting	O
+the	O
+actin	O
+in	O
+the	O
+cardiomyocyte	O
+cytoskeleton	O
+and	O
+the	O
+extracellular	O
+matrix	O
+.	O
+
+The	O
+sarcomeric	O
+actin	O
+dissolution	O
+occurred	O
+after	O
+the	O
+reduction	O
+or	O
+loss	O
+of	O
+dystrophin	O
+.	O
+
+Subsequently	O
+,	O
+after	O
+lysis	O
+of	O
+myofilaments	O
+,	O
+gamma	O
+-	O
+sarcoglycan	O
+,	O
+beta	O
+-	O
+dystroglycan	O
+,	O
+beta1	O
+-	O
+integrin	O
+,	O
+and	O
+laminin	O
+alpha	O
+-	O
+2	O
+expressions	O
+were	O
+reduced	O
+followed	O
+by	O
+their	O
+breakdown	O
+,	O
+as	O
+epiphenomena	O
+of	O
+the	O
+myocytolytic	O
+process	O
+.	O
+
+In	O
+conclusion	O
+,	O
+administration	O
+of	O
+isoproterenol	O
+to	O
+rats	O
+results	O
+in	O
+primary	O
+loss	O
+of	O
+dystrophin	O
+,	O
+the	O
+most	O
+sensitive	O
+among	O
+the	O
+structural	O
+proteins	O
+that	O
+form	O
+the	O
+DGC	O
+that	O
+connects	O
+the	O
+extracellular	O
+matrix	O
+and	O
+the	O
+cytoskeleton	O
+in	O
+cardiomyocyte	O
+.	O
+
+These	O
+changes	O
+,	O
+related	O
+to	O
+ischaemic	B
+injury	I
+,	O
+explain	O
+the	O
+severe	O
+alterations	O
+in	O
+the	O
+structural	O
+integrity	O
+of	O
+the	O
+sarcolemma	O
+of	O
+cardiomyocytes	O
+and	O
+hence	O
+severe	O
+and	O
+irreversible	O
+injury	O
+induced	O
+by	O
+isoproterenol	O
+.	O
+
+Etiologic	O
+factors	O
+in	O
+the	O
+pathogenesis	O
+of	O
+liver	B
+tumors	I
+associated	O
+with	O
+oral	O
+contraceptives	O
+.	O
+
+Within	O
+the	O
+last	O
+several	O
+years	O
+,	O
+previously	O
+rare	O
+liver	B
+tumors	I
+have	O
+been	O
+seen	O
+in	O
+young	O
+women	O
+using	O
+oral	O
+contraceptive	O
+steroids	O
+.	O
+
+The	O
+Registry	O
+for	O
+Liver	B
+Tumors	I
+Associated	O
+with	O
+Oral	O
+Contraceptives	O
+at	O
+the	O
+University	O
+of	O
+California	O
+,	O
+Irvine	O
+,	O
+has	O
+clearly	O
+identified	O
+27	O
+cases	O
+.	O
+
+The	O
+recent	O
+literature	O
+contains	O
+44	O
+case	O
+reports	O
+.	O
+
+Common	O
+to	O
+these	O
+71	O
+cases	O
+has	O
+been	O
+a	O
+histopathologic	O
+diagnosis	O
+of	O
+focal	B
+nodular	I
+hyperplasia	I
+,	O
+adenoma	B
+,	O
+hamartoma	B
+,	O
+and	O
+hepatoma	B
+.	O
+
+Significant	O
+statistical	O
+etiologic	O
+factors	O
+include	O
+prolonged	O
+uninterrupted	O
+usage	O
+of	O
+oral	O
+contraceptive	O
+steroids	O
+.	O
+
+Eight	O
+deaths	O
+and	O
+liver	O
+rupture	B
+in	O
+18	O
+patients	O
+attest	O
+to	O
+the	O
+seriousness	O
+of	O
+this	O
+new	O
+potentially	O
+lethal	O
+adverse	O
+phenomenon	O
+.	O
+
+Ifosfamide	O
+continuous	O
+infusion	O
+without	O
+mesna	O
+.	O
+
+A	O
+phase	O
+I	O
+trial	O
+of	O
+a	O
+14	O
+-	O
+day	O
+cycle	O
+.	O
+
+Twenty	O
+patients	O
+received	O
+27	O
+courses	O
+of	O
+ifosfamide	O
+administered	O
+as	O
+a	O
+24	O
+-	O
+hour	O
+continuous	O
+infusion	O
+for	O
+14	O
+days	O
+without	O
+Mesna	O
+.	O
+
+The	O
+goal	O
+of	O
+the	O
+study	O
+was	O
+to	O
+deliver	O
+a	O
+dose	O
+rate	O
+and	O
+total	O
+cumulative	O
+dose	O
+of	O
+ifosfamide	O
+that	O
+would	O
+be	O
+comparable	O
+to	O
+standard	O
+bolus	O
+or	O
+short	O
+-	O
+term	O
+infusions	O
+administered	O
+with	O
+Mesna	O
+.	O
+
+Dose	O
+escalations	O
+proceeded	O
+from	O
+200	O
+to	O
+300	O
+,	O
+400	O
+,	O
+450	O
+,	O
+500	O
+,	O
+and	O
+550	O
+mg	O
+/	O
+m2	O
+/	O
+d	O
+.	O
+
+Four	O
+patients	O
+developed	O
+transient	O
+microscopic	O
+hematuria	B
+at	O
+400	O
+,	O
+450	O
+,	O
+and	O
+500	O
+mg	O
+/	O
+m2	O
+/	O
+d	O
+.	O
+
+There	O
+were	O
+no	O
+instances	O
+of	O
+macroscopic	O
+hematuria	B
+.	O
+
+At	O
+550	O
+mg	O
+/	O
+m2	O
+/	O
+d	O
+,	O
+three	O
+patients	O
+experienced	O
+nonurologic	O
+toxicity	B
+;	O
+confusion	B
+(	O
+1	O
+)	O
+,	O
+nausea	B
+(	O
+1	O
+)	O
+,	O
+and	O
+Grade	O
+2	O
+leukopenia	B
+(	O
+1	O
+)	O
+.	O
+
+The	O
+recommended	O
+dose	O
+of	O
+500	O
+mg	O
+/	O
+m2	O
+/	O
+d	O
+delivers	O
+a	O
+total	O
+dose	O
+of	O
+7	O
+g	O
+/	O
+m2	O
+per	O
+cycle	O
+,	O
+which	O
+is	O
+comparable	O
+to	O
+that	O
+delivered	O
+in	O
+clinical	O
+practice	O
+for	O
+bolus	O
+or	O
+short	O
+-	O
+term	O
+infusion	O
+.	O
+
+Because	O
+few	O
+patients	O
+received	O
+multiple	O
+courses	O
+over	O
+time	O
+,	O
+the	O
+cumulative	O
+effects	O
+are	O
+indeterminate	O
+in	O
+the	O
+present	O
+trial	O
+.	O
+
+The	O
+frequency	O
+and	O
+predictability	O
+of	O
+hematuria	B
+are	O
+not	O
+precise	O
+,	O
+and	O
+at	O
+least	O
+daily	O
+monitoring	O
+by	O
+urine	O
+Hematest	O
+is	O
+essential	O
+,	O
+adding	O
+Mesna	O
+to	O
+the	O
+infusate	O
+in	O
+patients	O
+with	O
+persistent	O
+hematuria	B
+.	O
+
+The	O
+protracted	O
+infusion	O
+schedule	O
+for	O
+ifosfamide	O
+permits	O
+convenient	O
+outpatient	O
+administration	O
+without	O
+Mesna	O
+and	O
+reduces	O
+the	O
+drug	O
+cost	O
+of	O
+clinical	O
+usage	O
+of	O
+this	O
+agent	O
+by	O
+up	O
+to	O
+890	O
+per	O
+cycle	O
+.	O
+
+Clinical	O
+activity	O
+was	O
+demonstrated	O
+in	O
+a	O
+single	O
+patient	O
+,	O
+but	O
+a	O
+comparative	O
+trial	O
+of	O
+standard	O
+bolus	O
+schedules	O
+with	O
+the	O
+protracted	O
+infusion	O
+schedule	O
+will	O
+be	O
+necessary	O
+to	O
+determine	O
+if	O
+the	O
+clinical	O
+effectiveness	O
+of	O
+the	O
+drug	O
+is	O
+maintained	O
+.	O
+
+A	O
+case	O
+of	O
+ventricular	B
+tachycardia	I
+related	O
+to	O
+caffeine	O
+pretreatment	O
+.	O
+
+Suboptimal	O
+seizure	B
+duration	O
+is	O
+commonly	O
+encountered	O
+in	O
+electroconvulsive	O
+therapy	O
+practice	O
+,	O
+especially	O
+in	O
+older	O
+patients	O
+with	O
+higher	O
+seizure	B
+thresholds	O
+.	O
+
+Intravenous	O
+caffeine	O
+is	O
+commonly	O
+used	O
+to	O
+improve	O
+seizure	B
+duration	O
+and	O
+quality	O
+in	O
+such	O
+patients	O
+and	O
+is	O
+generally	O
+well	O
+tolerated	O
+aside	O
+from	O
+occasional	O
+reports	O
+of	O
+relatively	O
+benign	O
+ventricular	B
+ectopy	I
+.	O
+
+We	O
+describe	O
+a	O
+patient	O
+with	O
+no	O
+previous	O
+history	O
+of	O
+cardiac	B
+disease	I
+or	O
+arrhythmia	B
+who	O
+developed	O
+sustained	O
+bigeminy	O
+and	O
+2	O
+brief	O
+runs	O
+of	O
+ventricular	B
+tachycardia	I
+after	O
+caffeine	O
+administration	O
+.	O
+
+Although	O
+intravenous	O
+caffeine	O
+is	O
+generally	O
+well	O
+tolerated	O
+,	O
+the	O
+clinician	O
+should	O
+be	O
+aware	O
+of	O
+the	O
+potential	O
+for	O
+unpredictable	O
+and	O
+serious	O
+ventricular	B
+arrhythmias	I
+.	O
+
+Fatal	O
+haemopericardium	B
+and	O
+gastrointestinal	B
+haemorrhage	I
+due	O
+to	O
+possible	O
+interaction	O
+of	O
+cranberry	O
+juice	O
+with	O
+warfarin	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+fatal	O
+internal	O
+haemorrhage	B
+in	O
+an	O
+elderly	O
+man	O
+who	O
+consumed	O
+only	O
+cranberry	O
+juice	O
+for	O
+two	O
+weeks	O
+while	O
+maintaining	O
+his	O
+usual	O
+dosage	O
+of	O
+warfarin	O
+.	O
+
+We	O
+propose	O
+that	O
+naturally	O
+occurring	O
+compounds	O
+such	O
+as	O
+flavonoids	O
+,	O
+which	O
+are	O
+present	O
+in	O
+fruit	O
+juices	O
+,	O
+may	O
+increase	O
+the	O
+potency	O
+of	O
+warfarin	O
+by	O
+competing	O
+for	O
+the	O
+enzymes	O
+that	O
+normally	O
+inactivate	O
+warfarin	O
+.	O
+
+While	O
+traditionally	O
+regarded	O
+as	O
+foodstuffs	O
+,	O
+consumption	O
+of	O
+fruit	O
+juices	O
+should	O
+be	O
+considered	O
+when	O
+patients	O
+develop	O
+adverse	O
+drug	O
+reactions	O
+.	O
+
+Effect	O
+of	O
+increasing	O
+intraperitoneal	O
+infusion	O
+rates	O
+on	O
+bupropion	O
+hydrochloride	O
+-	O
+induced	O
+seizures	B
+in	O
+mice	O
+.	O
+
+BACKGROUND	O
+:	O
+It	O
+is	O
+not	O
+known	O
+if	O
+there	O
+is	O
+a	O
+relationship	O
+between	O
+input	O
+rate	O
+and	O
+incidence	O
+of	O
+bupropion	O
+-	O
+induced	O
+seizures	B
+.	O
+
+This	O
+is	O
+important	O
+,	O
+since	O
+different	O
+controlled	O
+release	O
+formulations	O
+of	O
+bupropion	O
+release	O
+the	O
+active	O
+drug	O
+at	O
+different	O
+rates	O
+.	O
+
+METHODS	O
+:	O
+We	O
+investigated	O
+the	O
+effect	O
+of	O
+varying	O
+the	O
+intraperitoneal	O
+infusion	O
+rates	O
+of	O
+bupropion	O
+HCl	O
+120	O
+mg	O
+/	O
+kg	O
+,	O
+a	O
+known	O
+convulsive	B
+dose	O
+50	O
+(	O
+CD50	O
+)	O
+,	O
+on	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+bupropion	O
+-	O
+induced	O
+convulsions	B
+in	O
+the	O
+Swiss	O
+albino	O
+mice	O
+.	O
+
+A	O
+total	O
+of	O
+69	O
+mice	O
+,	O
+approximately	O
+7	O
+weeks	O
+of	O
+age	O
+,	O
+and	O
+weighing	O
+21	O
+.	O
+0	O
+to	O
+29	O
+.	O
+1	O
+g	O
+were	O
+randomly	O
+assigned	O
+to	O
+bupropion	O
+HCl	O
+120	O
+mg	O
+/	O
+kg	O
+treatment	O
+by	O
+intraperitoneal	O
+(	O
+IP	O
+)	O
+administration	O
+in	O
+7	O
+groups	O
+(	O
+9	O
+to	O
+10	O
+animals	O
+per	O
+group	O
+)	O
+.	O
+
+Bupropion	O
+HCl	O
+was	O
+infused	O
+through	O
+a	O
+surgically	O
+implanted	O
+IP	O
+dosing	O
+catheter	O
+with	O
+infusions	O
+in	O
+each	O
+group	O
+of	O
+0	O
+min	O
+,	O
+15	O
+min	O
+,	O
+30	O
+min	O
+,	O
+60	O
+min	O
+,	O
+90	O
+min	O
+,	O
+120	O
+min	O
+,	O
+and	O
+240	O
+min	O
+.	O
+
+The	O
+number	O
+,	O
+time	O
+of	O
+onset	O
+,	O
+duration	O
+and	O
+the	O
+intensity	O
+of	O
+the	O
+convulsions	B
+or	O
+absence	O
+of	O
+convulsions	B
+were	O
+recorded	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+results	O
+showed	O
+that	O
+IP	O
+administration	O
+of	O
+bupropion	O
+HCl	O
+120	O
+mg	O
+/	O
+kg	O
+by	O
+bolus	O
+injection	O
+induced	O
+convulsions	B
+in	O
+6	O
+out	O
+of	O
+10	O
+mice	O
+(	O
+60	O
+%	O
+of	O
+convulsing	O
+mice	O
+)	O
+in	O
+group	O
+1	O
+.	O
+
+Logistic	O
+regression	O
+analysis	O
+revealed	O
+that	O
+infusion	O
+time	O
+was	O
+significant	O
+(	O
+p	O
+=	O
+0	O
+.	O
+0004	O
+;	O
+odds	O
+ratio	O
+=	O
+0	O
+.	O
+974	O
+)	O
+and	O
+increasing	O
+the	O
+IP	O
+infusion	O
+time	O
+of	O
+bupropion	O
+HCl	O
+120	O
+mg	O
+/	O
+kg	O
+was	O
+associated	O
+with	O
+a	O
+91	O
+%	O
+reduced	O
+odds	O
+of	O
+convulsions	B
+at	O
+infusion	O
+times	O
+of	O
+15	O
+to	O
+90	O
+min	O
+compared	O
+to	O
+bolus	O
+injection	O
+.	O
+
+Further	O
+increase	O
+in	O
+infusion	O
+time	O
+resulted	O
+in	O
+further	O
+reduction	O
+in	O
+the	O
+odds	O
+of	O
+convulsions	B
+to	O
+99	O
+.	O
+8	O
+%	O
+reduction	O
+at	O
+240	O
+min	O
+.	O
+
+CONCLUSION	O
+:	O
+In	O
+conclusion	O
+,	O
+the	O
+demonstration	O
+of	O
+an	O
+inverse	O
+relationship	O
+between	O
+infusion	O
+time	O
+of	O
+a	O
+fixed	O
+and	O
+convulsive	B
+dose	O
+of	O
+bupropion	O
+and	O
+the	O
+risk	O
+of	O
+convulsions	B
+in	O
+a	O
+prospective	O
+study	O
+is	O
+novel	O
+.	O
+
+Graft	B
+-	I
+versus	I
+-	I
+host	I
+disease	I
+prophylaxis	O
+with	O
+everolimus	O
+and	O
+tacrolimus	O
+is	O
+associated	O
+with	O
+a	O
+high	O
+incidence	O
+of	O
+sinusoidal	B
+obstruction	I
+syndrome	I
+and	O
+microangiopathy	B
+:	O
+results	O
+of	O
+the	O
+EVTAC	O
+trial	O
+.	O
+
+A	O
+calcineurin	O
+inhibitor	O
+combined	O
+with	O
+methotrexate	O
+is	O
+the	O
+standard	O
+prophylaxis	O
+for	O
+graft	B
+-	I
+versus	I
+-	I
+host	I
+disease	I
+(	O
+GVHD	B
+)	O
+after	O
+allogeneic	O
+hematopoietic	O
+stem	O
+cell	O
+transplantation	O
+(	O
+HSCT	O
+)	O
+.	O
+
+Everolimus	O
+,	O
+a	O
+derivative	O
+of	O
+sirolimus	O
+,	O
+seems	O
+to	O
+mediate	O
+antileukemia	O
+effects	O
+.	O
+
+We	O
+report	O
+on	O
+a	O
+combination	O
+of	O
+everolimus	O
+and	O
+tacrolimus	O
+in	O
+24	O
+patients	O
+(	O
+median	O
+age	O
+,	O
+62	O
+years	O
+)	O
+with	O
+either	O
+myelodysplastic	B
+syndrome	I
+(	O
+MDS	B
+;	O
+n	O
+=	O
+17	O
+)	O
+or	O
+acute	B
+myeloid	I
+leukemia	I
+(	O
+AML	B
+;	O
+n	O
+=	O
+7	O
+)	O
+undergoing	O
+intensive	O
+conditioning	O
+followed	O
+by	O
+HSCT	O
+from	O
+related	O
+(	O
+n	O
+=	O
+4	O
+)	O
+or	O
+unrelated	O
+(	O
+n	O
+=	O
+20	O
+)	O
+donors	O
+.	O
+
+All	O
+patients	O
+engrafted	O
+,	O
+and	O
+only	O
+1	O
+patient	O
+experienced	O
+grade	O
+IV	O
+mucositis	B
+.	O
+
+Nine	O
+patients	O
+(	O
+37	O
+%	O
+)	O
+developed	O
+acute	O
+grade	O
+II	O
+-	O
+IV	O
+GVHD	B
+,	O
+and	O
+11	O
+of	O
+17	O
+evaluable	O
+patients	O
+(	O
+64	O
+%	O
+)	O
+developed	O
+chronic	O
+extensive	O
+GVHD	B
+.	O
+
+Transplantation	B
+-	I
+associated	I
+microangiopathy	I
+(	O
+TMA	B
+)	O
+occurred	O
+in	O
+7	O
+patients	O
+(	O
+29	O
+%	O
+)	O
+,	O
+with	O
+2	O
+cases	O
+of	O
+acute	B
+renal	I
+failure	I
+.	O
+
+The	O
+study	O
+was	O
+terminated	O
+prematurely	O
+because	O
+an	O
+additional	O
+6	O
+patients	O
+(	O
+25	O
+%	O
+)	O
+developed	O
+sinusoidal	B
+obstruction	I
+syndrome	I
+(	O
+SOS	B
+)	O
+,	O
+which	O
+was	O
+fatal	O
+in	O
+2	O
+cases	O
+.	O
+
+With	O
+a	O
+median	O
+follow	O
+-	O
+up	O
+of	O
+26	O
+months	O
+,	O
+the	O
+2	O
+-	O
+year	O
+overall	O
+survival	O
+rate	O
+was	O
+47	O
+%	O
+.	O
+
+Although	O
+this	O
+new	O
+combination	O
+appears	O
+to	O
+be	O
+effective	O
+as	O
+a	O
+prophylactic	O
+regimen	O
+for	O
+acute	O
+GVHD	B
+,	O
+the	O
+incidence	O
+of	O
+TMA	B
+and	O
+SOS	B
+is	O
+considerably	O
+higher	O
+than	O
+seen	O
+with	O
+other	O
+regimens	O
+.	O
+
+Longitudinal	O
+assessment	O
+of	O
+air	O
+conduction	O
+audiograms	O
+in	O
+a	O
+phase	O
+III	O
+clinical	O
+trial	O
+of	O
+difluoromethylornithine	O
+and	O
+sulindac	O
+for	O
+prevention	O
+of	O
+sporadic	O
+colorectal	B
+adenomas	I
+.	O
+
+A	O
+phase	O
+III	O
+clinical	O
+trial	O
+assessed	O
+the	O
+recurrence	O
+of	O
+adenomatous	B
+polyps	I
+after	O
+treatment	O
+for	O
+36	O
+months	O
+with	O
+difluoromethylornithine	O
+(	O
+DFMO	O
+)	O
+plus	O
+sulindac	O
+or	O
+matched	O
+placebos	O
+.	O
+
+Temporary	O
+hearing	B
+loss	I
+is	O
+a	O
+known	O
+toxicity	B
+of	O
+treatment	O
+with	O
+DFMO	O
+,	O
+thus	O
+a	O
+comprehensive	O
+approach	O
+was	O
+developed	O
+to	O
+analyze	O
+serial	O
+air	O
+conduction	O
+audiograms	O
+.	O
+
+The	O
+generalized	O
+estimating	O
+equation	O
+method	O
+estimated	O
+the	O
+mean	O
+difference	O
+between	O
+treatment	O
+arms	O
+with	O
+regard	O
+to	O
+change	O
+in	O
+air	O
+conduction	O
+pure	O
+tone	O
+thresholds	O
+while	O
+accounting	O
+for	O
+within	O
+-	O
+subject	O
+correlation	O
+due	O
+to	O
+repeated	O
+measurements	O
+at	O
+frequencies	O
+.	O
+
+Based	O
+on	O
+290	O
+subjects	O
+,	O
+there	O
+was	O
+an	O
+average	O
+difference	O
+of	O
+0	O
+.	O
+50	O
+dB	O
+between	O
+subjects	O
+treated	O
+with	O
+DFMO	O
+plus	O
+sulindac	O
+compared	O
+with	O
+those	O
+treated	O
+with	O
+placebo	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+-	O
+0	O
+.	O
+64	O
+to	O
+1	O
+.	O
+63	O
+dB	O
+;	O
+P	O
+=	O
+0	O
+.	O
+39	O
+)	O
+,	O
+adjusted	O
+for	O
+baseline	O
+values	O
+,	O
+age	O
+,	O
+and	O
+frequencies	O
+.	O
+
+In	O
+the	O
+normal	O
+speech	O
+range	O
+of	O
+500	O
+to	O
+3	O
+,	O
+000	O
+Hz	O
+,	O
+an	O
+estimated	O
+difference	O
+of	O
+0	O
+.	O
+99	O
+dB	O
+(	O
+-	O
+0	O
+.	O
+17	O
+to	O
+2	O
+.	O
+14	O
+dB	O
+;	O
+P	O
+=	O
+0	O
+.	O
+09	O
+)	O
+was	O
+detected	O
+.	O
+
+Dose	O
+intensity	O
+did	O
+not	O
+add	O
+information	O
+to	O
+models	O
+.	O
+
+There	O
+were	O
+14	O
+of	O
+151	O
+(	O
+9	O
+.	O
+3	O
+%	O
+)	O
+in	O
+the	O
+DFMO	O
+plus	O
+sulindac	O
+group	O
+and	O
+4	O
+of	O
+139	O
+(	O
+2	O
+.	O
+9	O
+%	O
+)	O
+in	O
+the	O
+placebo	O
+group	O
+who	O
+experienced	O
+at	O
+least	O
+15	O
+dB	O
+hearing	O
+reduction	O
+from	O
+baseline	O
+in	O
+2	O
+or	O
+more	O
+consecutive	O
+frequencies	O
+across	O
+the	O
+entire	O
+range	O
+tested	O
+(	O
+P	O
+=	O
+0	O
+.	O
+02	O
+)	O
+.	O
+
+Follow	O
+-	O
+up	O
+air	O
+conduction	O
+done	O
+at	O
+least	O
+6	O
+months	O
+after	O
+end	O
+of	O
+treatment	O
+showed	O
+an	O
+adjusted	O
+mean	O
+difference	O
+in	O
+hearing	O
+thresholds	O
+of	O
+1	O
+.	O
+08	O
+dB	O
+(	O
+-	O
+0	O
+.	O
+81	O
+to	O
+2	O
+.	O
+96	O
+dB	O
+;	O
+P	O
+=	O
+0	O
+.	O
+26	O
+)	O
+between	O
+treatment	O
+arms	O
+.	O
+
+There	O
+was	O
+no	O
+significant	O
+difference	O
+in	O
+the	O
+proportion	O
+of	O
+subjects	O
+in	O
+the	O
+DFMO	O
+plus	O
+sulindac	O
+group	O
+who	O
+experienced	O
+clinically	O
+significant	O
+hearing	B
+loss	I
+compared	O
+with	O
+the	O
+placebo	O
+group	O
+.	O
+
+The	O
+estimated	O
+attributable	O
+risk	O
+of	O
+ototoxicity	B
+from	O
+exposure	O
+to	O
+the	O
+drug	O
+is	O
+8	O
+.	O
+4	O
+%	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+-	O
+2	O
+.	O
+0	O
+%	O
+to	O
+18	O
+.	O
+8	O
+%	O
+;	O
+P	O
+=	O
+0	O
+.	O
+12	O
+)	O
+.	O
+
+There	O
+is	O
+a	O
+<	O
+2	O
+dB	O
+difference	O
+in	O
+mean	O
+threshold	O
+for	O
+patients	O
+treated	O
+with	O
+DFMO	O
+plus	O
+sulindac	O
+compared	O
+with	O
+those	O
+treated	O
+with	O
+placebo	O
+.	O
+
+Proteinase	O
+3	O
+-	O
+antineutrophil	O
+cytoplasmic	O
+antibody	O
+-	O
+(	O
+PR3	O
+-	O
+ANCA	O
+)	O
+positive	O
+necrotizing	O
+glomerulonephritis	B
+after	O
+restarting	O
+sulphasalazine	O
+treatment	O
+.	O
+
+A	O
+59	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+ulcerative	B
+colitis	I
+developed	O
+red	B
+eyes	I
+,	O
+pleural	B
+effusion	I
+,	O
+eosinophilia	B
+and	O
+urinary	B
+abnormalities	I
+after	O
+restarting	O
+of	O
+sulphasalazine	O
+treatment	O
+.	O
+
+Light	O
+microscopy	O
+of	O
+a	O
+kidney	O
+biopsy	O
+revealed	O
+segmental	B
+necrotizing	I
+glomerulonephritis	I
+without	O
+deposition	O
+of	O
+immunoglobulin	O
+or	O
+complement	O
+.	O
+
+Proteinase	O
+3	O
+-	O
+antineutrophil	O
+cytoplasmic	O
+antibody	O
+(	O
+PR3	O
+-	O
+ANCA	O
+)	O
+titer	O
+was	O
+elevated	O
+at	O
+183	O
+ELISA	O
+units	O
+(	O
+EU	O
+)	O
+in	O
+sera	O
+(	O
+normal	O
+range	O
+less	O
+than	O
+10	O
+EU	O
+)	O
+,	O
+myeloperoxidase	O
+-	O
+ANCA	O
+was	O
+negative	O
+.	O
+
+PR3	O
+-	O
+ANCA	O
+titer	O
+was	O
+250	O
+and	O
+1	O
+,	O
+070	O
+EU	O
+in	O
+pleural	B
+effusions	I
+on	O
+right	O
+and	O
+left	O
+side	O
+,	O
+respectively	O
+.	O
+
+Although	O
+cessation	O
+of	O
+sulphasalazine	O
+treatment	O
+resulted	O
+in	O
+improvements	O
+in	O
+fever	B
+,	O
+red	B
+eyes	I
+,	O
+chest	B
+pain	I
+,	O
+titer	O
+of	O
+C	O
+-	O
+reactive	O
+protein	O
+and	O
+volume	O
+of	O
+the	O
+pleural	B
+effusions	I
+,	O
+we	O
+initiated	O
+steroid	O
+therapy	O
+,	O
+because	O
+PR3	O
+-	O
+ANCA	O
+titer	O
+rose	O
+to	O
+320	O
+EU	O
+,	O
+eosinophil	O
+count	O
+increased	O
+to	O
+1	O
+,	O
+100	O
+cells	O
+/	O
+microl	O
+,	O
+and	O
+the	O
+pleural	B
+effusion	I
+remained	O
+.	O
+
+One	O
+month	O
+after	O
+steroid	O
+therapy	O
+,	O
+the	O
+pleural	B
+effusion	I
+disappeared	O
+,	O
+and	O
+PR3	O
+-	O
+ANCA	O
+titer	O
+normalized	O
+3	O
+months	O
+later	O
+.	O
+
+This	O
+case	O
+suggests	O
+that	O
+sulphasalazine	O
+can	O
+induce	O
+PR3	O
+-	O
+ANCA	O
+-	O
+positive	O
+necrotizing	O
+glomerulonephritis	B
+.	O
+
+Comparison	O
+of	O
+unilateral	O
+pallidotomy	O
+and	O
+subthalamotomy	O
+findings	O
+in	O
+advanced	O
+idiopathic	B
+Parkinson	I
+'	I
+s	I
+disease	I
+.	O
+
+A	O
+prospective	O
+,	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+pilot	O
+study	O
+to	O
+compare	O
+the	O
+results	O
+of	O
+stereotactic	O
+unilateral	O
+pallidotomy	O
+and	O
+subthalamotomy	O
+in	O
+advanced	O
+idiopathic	B
+Parkinson	I
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+refractory	O
+to	O
+medical	O
+treatment	O
+was	O
+designed	O
+.	O
+
+Ten	O
+consecutive	O
+patients	O
+(	O
+mean	O
+age	O
+,	O
+58	O
+.	O
+4	O
++	O
+/	O
+-	O
+6	O
+.	O
+8	O
+years	O
+;	O
+7	O
+men	O
+,	O
+3	O
+women	O
+)	O
+with	O
+similar	O
+characteristics	O
+at	O
+the	O
+duration	O
+of	O
+disease	O
+(	O
+mean	O
+disease	O
+time	O
+,	O
+8	O
+.	O
+4	O
++	O
+/	O
+-	O
+3	O
+.	O
+5	O
+years	O
+)	O
+,	O
+disabling	O
+motor	O
+fluctuations	O
+(	O
+Hoehn	O
+_	O
+Yahr	O
+stage	O
+3	O
+-	O
+5	O
+in	O
+off	O
+-	O
+drug	O
+phases	O
+)	O
+and	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+were	O
+selected	O
+.	O
+
+All	O
+patients	O
+had	O
+bilateral	O
+symptoms	O
+and	O
+their	O
+levodopa	O
+equivalent	O
+dosing	O
+were	O
+analysed	O
+.	O
+
+Six	O
+patients	O
+were	O
+operated	O
+on	O
+in	O
+the	O
+globus	O
+pallidus	O
+interna	O
+(	O
+GPi	O
+)	O
+and	O
+four	O
+in	O
+the	O
+subthalamic	O
+nucleus	O
+(	O
+STN	O
+)	O
+.	O
+
+Clinical	O
+evaluation	O
+included	O
+the	O
+use	O
+of	O
+the	O
+Unified	O
+Parkinson	B
+'	I
+s	I
+Disease	I
+Rating	O
+Scale	O
+(	O
+UPDRS	O
+)	O
+,	O
+Hoehn	O
+_	O
+Yahr	O
+score	O
+and	O
+Schwab	O
+England	O
+activities	O
+of	O
+daily	O
+living	O
+(	O
+ADL	O
+)	O
+score	O
+in	O
+'	O
+on	O
+'	O
+-	O
+and	O
+'	O
+off	O
+'	O
+-	O
+drug	O
+conditions	O
+before	O
+surgery	O
+and	O
+6	O
+months	O
+after	O
+surgery	O
+.	O
+
+There	O
+was	O
+statistically	O
+significant	O
+improvement	O
+in	O
+all	O
+contralateral	O
+major	O
+parkinsonian	B
+motor	O
+signs	O
+in	O
+all	O
+patients	O
+followed	O
+for	O
+6	O
+months	O
+.	O
+
+Levodopa	O
+equivalent	O
+daily	O
+intake	O
+was	O
+significantly	O
+reduced	O
+in	O
+the	O
+STN	O
+group	O
+.	O
+
+Changes	O
+in	O
+UPDRS	O
+,	O
+Hoehn	O
+_	O
+Yahr	O
+and	O
+Schwab	O
+England	O
+ADL	O
+scores	O
+were	O
+similar	O
+in	O
+both	O
+groups	O
+.	O
+
+Cognitive	O
+functions	O
+were	O
+unchanged	O
+in	O
+both	O
+groups	O
+.	O
+
+Complications	O
+were	O
+observed	O
+in	O
+two	O
+patients	O
+:	O
+one	O
+had	O
+a	O
+left	O
+homonymous	B
+hemianopsia	I
+after	O
+pallidotomy	O
+and	O
+another	O
+one	O
+developed	O
+left	O
+hemiballistic	O
+movements	O
+3	O
+days	O
+after	O
+subthalamotomy	O
+which	O
+partly	O
+improved	O
+within	O
+1	O
+month	O
+with	O
+Valproate	O
+1000	O
+mg	O
+/	O
+day	O
+.	O
+
+The	O
+findings	O
+of	O
+this	O
+study	O
+suggest	O
+that	O
+lesions	O
+of	O
+the	O
+unilateral	O
+STN	O
+and	O
+GPi	O
+are	O
+equally	O
+effective	O
+treatment	O
+for	O
+patients	O
+with	O
+advanced	O
+PD	B
+refractory	O
+to	O
+medical	O
+treatment	O
+.	O
+
+DSMM	O
+XI	O
+study	O
+:	O
+dose	O
+definition	O
+for	O
+intravenous	O
+cyclophosphamide	O
+in	O
+combination	O
+with	O
+bortezomib	O
+/	O
+dexamethasone	O
+for	O
+remission	O
+induction	O
+in	O
+patients	O
+with	O
+newly	O
+diagnosed	O
+myeloma	B
+.	O
+
+A	O
+clinical	O
+trial	O
+was	O
+initiated	O
+to	O
+evaluate	O
+the	O
+recommended	O
+dose	O
+of	O
+cyclophosphamide	O
+in	O
+combination	O
+with	O
+bortezomib	O
+and	O
+dexamethasone	O
+as	O
+induction	O
+treatment	O
+before	O
+stem	O
+cell	O
+transplantation	O
+for	O
+younger	O
+patients	O
+with	O
+newly	O
+diagnosed	O
+multiple	B
+myeloma	I
+(	O
+MM	B
+)	O
+.	O
+
+Thirty	O
+patients	O
+were	O
+treated	O
+with	O
+three	O
+21	O
+-	O
+day	O
+cycles	O
+of	O
+bortezomib	O
+1	O
+.	O
+3	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+on	O
+days	O
+1	O
+,	O
+4	O
+,	O
+8	O
+,	O
+and	O
+11	O
+plus	O
+dexamethasone	O
+40	O
+mg	O
+on	O
+the	O
+day	O
+of	O
+bortezomib	O
+injection	O
+and	O
+the	O
+day	O
+after	O
+plus	O
+cyclophosphamide	O
+at	O
+900	O
+,	O
+1	O
+,	O
+200	O
+,	O
+or	O
+1	O
+,	O
+500	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+on	O
+day	O
+1	O
+.	O
+
+The	O
+maximum	O
+tolerated	O
+dose	O
+of	O
+cyclophosphamide	O
+was	O
+defined	O
+as	O
+900	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+.	O
+
+At	O
+this	O
+dose	O
+level	O
+,	O
+92	O
+%	O
+of	O
+patients	O
+achieved	O
+at	O
+least	O
+a	O
+partial	O
+response	O
+.	O
+
+The	O
+overall	O
+response	O
+rate	O
+[	O
+complete	O
+response	O
+(	O
+CR	O
+)	O
+plus	O
+partial	O
+response	O
+(	O
+PR	O
+)	O
+]	O
+across	O
+all	O
+dose	O
+levels	O
+was	O
+77	O
+%	O
+,	O
+with	O
+a	O
+10	O
+%	O
+CR	O
+rate	O
+.	O
+
+No	O
+patient	O
+experienced	O
+progressive	O
+disease	O
+.	O
+
+The	O
+most	O
+frequent	O
+adverse	O
+events	O
+were	O
+hematological	B
+and	I
+gastrointestinal	I
+toxicities	I
+as	O
+well	O
+as	O
+neuropathy	B
+.	O
+
+The	O
+results	O
+suggest	O
+that	O
+bortezomib	O
+in	O
+combination	O
+with	O
+cyclophosphamide	O
+at	O
+900	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+and	O
+dexamethasone	O
+is	O
+an	O
+effective	O
+induction	O
+treatment	O
+for	O
+patients	O
+with	O
+newly	O
+diagnosed	O
+MM	B
+that	O
+warrants	O
+further	O
+investigation	O
+.	O
+
+Naloxone	O
+reversal	O
+of	O
+hypotension	B
+due	O
+to	O
+captopril	O
+overdose	B
+.	O
+
+The	O
+hemodynamic	O
+effects	O
+of	O
+captopril	O
+and	O
+other	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitors	O
+may	O
+be	O
+mediated	O
+by	O
+the	O
+endogenous	O
+opioid	O
+system	O
+.	O
+
+The	O
+opioid	O
+antagonist	O
+naloxone	O
+has	O
+been	O
+shown	O
+to	O
+block	O
+or	O
+reverse	O
+the	O
+hypotensive	B
+actions	O
+of	O
+captopril	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+an	O
+intentional	O
+captopril	O
+overdose	B
+,	O
+manifested	O
+by	O
+marked	O
+hypotension	B
+,	O
+that	O
+resolved	O
+promptly	O
+with	O
+the	O
+administration	O
+of	O
+naloxone	O
+.	O
+
+To	O
+our	O
+knowledge	O
+,	O
+this	O
+is	O
+the	O
+first	O
+reported	O
+case	O
+of	O
+captopril	O
+-	O
+induced	O
+hypotension	B
+treated	O
+with	O
+naloxone	O
+.	O
+
+Our	O
+experience	O
+demonstrates	O
+a	O
+possible	O
+role	O
+of	O
+naloxone	O
+in	O
+the	O
+reversal	O
+of	O
+hypotension	B
+resulting	O
+from	O
+captopril	O
+.	O
+
+Identification	O
+of	O
+a	O
+simple	O
+and	O
+sensitive	O
+microplate	O
+method	O
+for	O
+the	O
+detection	O
+of	O
+oversulfated	O
+chondroitin	O
+sulfate	O
+in	O
+heparin	O
+products	O
+.	O
+
+Heparin	O
+is	O
+a	O
+commonly	O
+implemented	O
+anticoagulant	O
+used	O
+to	O
+treat	O
+critically	O
+ill	O
+patients	O
+.	O
+
+Recently	O
+,	O
+a	O
+number	O
+of	O
+commercial	O
+lots	O
+of	O
+heparin	O
+products	O
+were	O
+found	O
+to	O
+be	O
+contaminated	O
+with	O
+an	O
+oversulfated	O
+chondroitin	O
+sulfate	O
+(	O
+OSCS	O
+)	O
+derivative	O
+that	O
+could	O
+elicit	O
+a	O
+hypotensive	B
+response	O
+in	O
+pigs	O
+following	O
+a	O
+single	O
+high	O
+-	O
+dose	O
+infusion	O
+.	O
+
+Using	O
+both	O
+contaminated	O
+heparin	O
+products	O
+and	O
+the	O
+synthetically	O
+produced	O
+derivative	O
+,	O
+we	O
+showed	O
+that	O
+the	O
+OSCS	O
+produces	O
+dose	O
+-	O
+dependent	O
+hypotension	B
+in	O
+pigs	O
+.	O
+
+The	O
+no	O
+observed	O
+effect	O
+level	O
+(	O
+NOEL	O
+)	O
+for	O
+this	O
+contaminant	O
+appears	O
+to	O
+be	O
+approximately	O
+1mg	O
+/	O
+kg	O
+,	O
+corresponding	O
+to	O
+a	O
+contamination	O
+level	O
+of	O
+approximately	O
+3	O
+%	O
+.	O
+
+We	O
+also	O
+demonstrated	O
+that	O
+OSCS	O
+can	O
+be	O
+identified	O
+in	O
+heparin	O
+products	O
+using	O
+a	O
+simple	O
+,	O
+inexpensive	O
+,	O
+commercially	O
+available	O
+heparin	O
+enzyme	O
+immunoassay	O
+(	O
+EIA	O
+)	O
+kit	O
+that	O
+has	O
+a	O
+limit	O
+of	O
+detection	O
+of	O
+approximately	O
+0	O
+.	O
+1	O
+%	O
+,	O
+well	O
+below	O
+the	O
+NOEL	O
+.	O
+
+This	O
+kit	O
+may	O
+provide	O
+a	O
+useful	O
+method	O
+to	O
+test	O
+heparin	O
+products	O
+for	O
+contamination	O
+with	O
+oversulfated	O
+GAG	O
+derivatives	O
+.	O
+
+5	O
+flourouracil	O
+-	O
+induced	O
+apical	B
+ballooning	I
+syndrome	I
+:	O
+a	O
+case	O
+report	O
+.	O
+
+The	O
+apical	B
+ballooning	I
+syndrome	I
+(	O
+ABS	B
+)	O
+is	O
+a	O
+recently	O
+described	O
+stress	O
+-	O
+mediated	O
+acute	B
+cardiac	I
+syndrome	I
+characterized	O
+by	O
+transient	O
+wall	O
+-	O
+motion	O
+abnormalities	O
+involving	O
+the	O
+apex	O
+and	O
+midventricle	O
+with	O
+hyperkinesis	B
+of	O
+the	O
+basal	O
+left	O
+ventricular	O
+(	O
+LV	O
+)	O
+segments	O
+without	O
+obstructive	O
+epicardial	B
+coronary	I
+disease	I
+.	O
+
+Cardiotoxicity	B
+is	O
+not	O
+an	O
+uncommon	O
+adverse	O
+effect	O
+of	O
+chemotherapeutic	O
+agents	O
+.	O
+
+However	O
+,	O
+there	O
+are	O
+no	O
+reports	O
+of	O
+ABS	B
+secondary	O
+to	O
+chemotherapeutic	O
+agents	O
+.	O
+
+We	O
+describe	O
+the	O
+case	O
+of	O
+a	O
+woman	O
+who	O
+developed	O
+the	O
+syndrome	O
+after	O
+chemotherapy	O
+for	O
+metastatic	O
+cancer	B
+.	O
+
+A	O
+79	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+presented	O
+with	O
+typical	O
+ischemic	B
+chest	B
+pain	I
+,	O
+elevated	O
+cardiac	O
+enzymes	O
+with	O
+significant	O
+ST	O
+-	O
+segment	O
+abnormalities	O
+on	O
+her	O
+electrocardiogram	O
+.	O
+
+She	O
+underwent	O
+recent	O
+chemotherapy	O
+with	O
+fluorouracil	O
+for	O
+metastatic	O
+colorectal	B
+cancer	I
+.	O
+
+Echocardiography	O
+revealed	O
+a	O
+wall	O
+-	O
+motion	O
+abnormality	O
+involving	O
+the	O
+apical	O
+and	O
+periapical	O
+segments	O
+which	O
+appeared	O
+akinetic	B
+.	O
+
+Coronary	O
+angiography	O
+revealed	O
+no	O
+obstructive	O
+coronary	O
+lesions	O
+.	O
+
+The	O
+patient	O
+was	O
+stabilized	O
+with	O
+medical	O
+therapy	O
+.	O
+
+Four	O
+weeks	O
+later	O
+she	O
+remained	O
+completely	O
+asymptomatic	O
+.	O
+
+Echocardiogram	O
+revealed	O
+a	O
+normal	O
+ejection	O
+fraction	O
+and	O
+a	O
+resolution	O
+of	O
+the	O
+apical	O
+akinesis	B
+.	O
+
+Pathogenetic	O
+mechanisms	O
+of	O
+cardiac	B
+complications	I
+in	O
+cancer	B
+patients	O
+undergoing	O
+chemotherapy	O
+include	O
+coronary	B
+vasospasm	I
+,	O
+endothelial	O
+damage	O
+and	O
+consequent	O
+thrombus	B
+formation	O
+.	O
+
+In	O
+our	O
+patient	O
+,	O
+both	O
+supraphysiologic	O
+levels	O
+of	O
+plasma	O
+catecholamines	O
+and	O
+stress	O
+related	O
+neuropeptides	O
+caused	O
+by	O
+cancer	B
+diagnosis	O
+as	O
+well	O
+as	O
+chemotherapy	O
+may	O
+have	O
+contributed	O
+the	O
+development	O
+of	O
+ABS	B
+.	O
+
+Rapid	O
+reversal	O
+of	O
+anticoagulation	O
+reduces	O
+hemorrhage	B
+volume	O
+in	O
+a	O
+mouse	O
+model	O
+of	O
+warfarin	O
+-	O
+associated	O
+intracerebral	B
+hemorrhage	I
+.	O
+
+Warfarin	O
+-	O
+associated	O
+intracerebral	B
+hemorrhage	I
+(	O
+W	O
+-	O
+ICH	B
+)	O
+is	O
+a	O
+severe	O
+type	O
+of	O
+stroke	B
+.	O
+
+There	O
+is	O
+no	O
+consensus	O
+on	O
+the	O
+optimal	O
+treatment	O
+for	O
+W	O
+-	O
+ICH	B
+.	O
+
+Using	O
+a	O
+mouse	O
+model	O
+,	O
+we	O
+tested	O
+whether	O
+the	O
+rapid	O
+reversal	O
+of	O
+anticoagulation	O
+using	O
+human	O
+prothrombin	O
+complex	O
+concentrate	O
+(	O
+PCC	O
+)	O
+can	O
+reduce	O
+hemorrhagic	O
+blood	O
+volume	O
+.	O
+
+Male	O
+CD	O
+-	O
+1	O
+mice	O
+were	O
+treated	O
+with	O
+warfarin	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+over	O
+24	O
+h	O
+)	O
+,	O
+resulting	O
+in	O
+a	O
+mean	O
+(	O
++	O
+/	O
+-	O
+s	O
+.	O
+d	O
+.	O
+)	O
+International	O
+Normalized	O
+Ratio	O
+of	O
+3	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+9	O
+.	O
+
+First	O
+,	O
+we	O
+showed	O
+that	O
+an	O
+intravenous	O
+administration	O
+of	O
+human	O
+PCC	O
+rapidly	O
+reversed	O
+anticoagulation	O
+in	O
+mice	O
+.	O
+
+Second	O
+,	O
+a	O
+stereotactic	O
+injection	O
+of	O
+collagenase	O
+was	O
+administered	O
+to	O
+induce	O
+hemorrhage	B
+in	O
+the	O
+right	O
+striatum	O
+.	O
+
+Forty	O
+-	O
+five	O
+minutes	O
+later	O
+,	O
+the	O
+animals	O
+were	O
+randomly	O
+treated	O
+with	O
+PCC	O
+(	O
+100	O
+U	O
+/	O
+kg	O
+)	O
+or	O
+saline	O
+i	O
+.	O
+v	O
+.	O
+(	O
+n	O
+=	O
+12	O
+per	O
+group	O
+)	O
+.	O
+
+Twenty	O
+-	O
+four	O
+hours	O
+after	O
+hemorrhage	B
+induction	O
+,	O
+hemorrhagic	O
+blood	O
+volume	O
+was	O
+quantified	O
+using	O
+a	O
+photometric	O
+hemoglobin	O
+assay	O
+.	O
+
+The	O
+mean	O
+hemorrhagic	O
+blood	O
+volume	O
+was	O
+reduced	O
+in	O
+PCC	O
+-	O
+treated	O
+animals	O
+(	O
+6	O
+.	O
+5	O
++	O
+/	O
+-	O
+3	O
+.	O
+1	O
+microL	O
+)	O
+compared	O
+with	O
+saline	O
+controls	O
+(	O
+15	O
+.	O
+3	O
++	O
+/	O
+-	O
+11	O
+.	O
+2	O
+microL	O
+,	O
+P	O
+=	O
+0	O
+.	O
+015	O
+)	O
+.	O
+
+In	O
+the	O
+saline	O
+group	O
+,	O
+45	O
+%	O
+of	O
+the	O
+mice	O
+developed	O
+large	O
+hematomas	B
+(	O
+i	O
+.	O
+e	O
+.	O
+,	O
+>	O
+15	O
+microL	O
+)	O
+.	O
+
+In	O
+contrast	O
+,	O
+such	O
+extensive	O
+lesions	O
+were	O
+never	O
+found	O
+in	O
+the	O
+PCC	O
+group	O
+.	O
+
+We	O
+provide	O
+experimental	O
+data	O
+suggesting	O
+PCC	O
+to	O
+be	O
+an	O
+effective	O
+acute	O
+treatment	O
+for	O
+W	O
+-	O
+ICH	B
+in	O
+terms	O
+of	O
+reducing	O
+hemorrhagic	O
+blood	O
+volume	O
+.	O
+
+Future	O
+studies	O
+are	O
+needed	O
+to	O
+assess	O
+the	O
+therapeutic	O
+potential	O
+emerging	O
+from	O
+our	O
+finding	O
+for	O
+human	O
+W	O
+-	O
+ICH	B
+.	O
+
+Long	O
+term	O
+hormone	O
+therapy	O
+for	O
+perimenopausal	O
+and	O
+postmenopausal	O
+women	O
+.	O
+
+BACKGROUND	O
+:	O
+Hormone	O
+therapy	O
+(	O
+HT	O
+)	O
+is	O
+widely	O
+used	O
+for	O
+controlling	O
+menopausal	O
+symptoms	O
+and	O
+has	O
+also	O
+been	O
+used	O
+for	O
+the	O
+management	O
+and	O
+prevention	O
+of	O
+cardiovascular	B
+disease	I
+,	O
+osteoporosis	B
+and	O
+dementia	B
+in	O
+older	O
+women	O
+.	O
+
+This	O
+is	O
+an	O
+updated	O
+version	O
+of	O
+the	O
+original	O
+Cochrane	O
+review	O
+first	O
+published	O
+in	O
+2005	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+assess	O
+the	O
+effect	O
+of	O
+long	O
+-	O
+term	O
+HT	O
+on	O
+mortality	O
+,	O
+cardiovascular	O
+outcomes	O
+,	O
+cancer	B
+,	O
+gallbladder	B
+disease	I
+,	O
+cognition	O
+,	O
+fractures	B
+and	O
+quality	O
+of	O
+life	O
+.	O
+
+SEARCH	O
+STRATEGY	O
+:	O
+We	O
+searched	O
+the	O
+following	O
+databases	O
+to	O
+November	O
+2007	O
+:	O
+Trials	O
+Register	O
+of	O
+the	O
+Cochrane	O
+Menstrual	B
+Disorders	I
+and	O
+Subfertility	O
+Group	O
+,	O
+Cochrane	O
+Central	O
+Register	O
+of	O
+Controlled	O
+Trials	O
+,	O
+MEDLINE	O
+,	O
+EMBASE	O
+,	O
+Biological	O
+Abstracts	O
+.	O
+
+Also	O
+relevant	O
+non	O
+-	O
+indexed	O
+journals	O
+and	O
+conference	O
+abstracts	O
+.	O
+
+SELECTION	O
+CRITERIA	O
+:	O
+Randomised	O
+double	O
+-	O
+blind	O
+trials	O
+of	O
+HT	O
+versus	O
+placebo	O
+,	O
+taken	O
+for	O
+at	O
+least	O
+one	O
+year	O
+by	O
+perimenopausal	O
+or	O
+postmenopausal	O
+women	O
+.	O
+
+HT	O
+included	O
+oestrogens	O
+,	O
+with	O
+or	O
+without	O
+progestogens	O
+,	O
+via	O
+oral	O
+,	O
+transdermal	O
+,	O
+subcutaneous	O
+or	O
+transnasal	O
+routes	O
+.	O
+
+DATA	O
+COLLECTION	O
+AND	O
+ANALYSIS	O
+:	O
+Two	O
+authors	O
+independently	O
+assessed	O
+trial	O
+quality	O
+and	O
+extracted	O
+data	O
+.	O
+
+MAIN	O
+RESULTS	O
+:	O
+Nineteen	O
+trials	O
+involving	O
+41	O
+,	O
+904	O
+women	O
+were	O
+included	O
+.	O
+
+In	O
+relatively	O
+healthy	O
+women	O
+,	O
+combined	O
+continuous	O
+HT	O
+significantly	O
+increased	O
+the	O
+risk	O
+of	O
+venous	B
+thrombo	I
+-	I
+embolism	I
+or	O
+coronary	O
+event	O
+(	O
+after	O
+one	O
+year	O
+'	O
+s	O
+use	O
+)	O
+,	O
+stroke	B
+(	O
+after	O
+three	O
+years	O
+)	O
+,	O
+breast	B
+cancer	I
+and	O
+gallbladder	B
+disease	I
+.	O
+
+Long	O
+-	O
+term	O
+oestrogen	O
+-	O
+only	O
+HT	O
+significantly	O
+increased	O
+the	O
+risk	O
+of	O
+venous	B
+thrombo	I
+-	I
+embolism	I
+,	O
+stroke	B
+and	O
+gallbladder	B
+disease	I
+(	O
+after	O
+one	O
+to	O
+two	O
+years	O
+,	O
+three	O
+years	O
+and	O
+seven	O
+years	O
+'	O
+use	O
+respectively	O
+)	O
+,	O
+but	O
+did	O
+not	O
+significantly	O
+increase	O
+the	O
+risk	O
+of	O
+breast	B
+cancer	I
+.	O
+
+The	O
+only	O
+statistically	O
+significant	O
+benefits	O
+of	O
+HT	O
+were	O
+a	O
+decreased	O
+incidence	O
+of	O
+fractures	B
+and	O
+(	O
+for	O
+combined	O
+HT	O
+)	O
+colon	B
+cancer	I
+,	O
+with	O
+long	O
+-	O
+term	O
+use	O
+.	O
+
+Among	O
+women	O
+aged	O
+over	O
+65	O
+who	O
+were	O
+relatively	O
+healthy	O
+(	O
+i	O
+.	O
+e	O
+.	O
+generally	O
+fit	O
+,	O
+without	O
+overt	O
+disease	O
+)	O
+and	O
+taking	O
+continuous	O
+combined	O
+HT	O
+,	O
+there	O
+was	O
+a	O
+statistically	O
+significant	O
+increase	O
+in	O
+the	O
+incidence	O
+of	O
+dementia	B
+.	O
+
+Among	O
+women	O
+with	O
+cardiovascular	B
+disease	I
+,	O
+long	O
+-	O
+term	O
+use	O
+of	O
+combined	O
+continuous	O
+HT	O
+significantly	O
+increased	O
+the	O
+risk	O
+of	O
+venous	B
+thrombo	I
+-	I
+embolism	I
+.	O
+One	O
+trial	O
+analysed	O
+subgroups	O
+of	O
+2839	O
+relatively	O
+healthy	O
+50	O
+to	O
+59	O
+year	O
+old	O
+women	O
+taking	O
+combined	O
+continuous	O
+HT	O
+and	O
+1637	O
+taking	O
+oestrogen	O
+-	O
+only	O
+HT	O
+,	O
+versus	O
+similar	O
+-	O
+sized	O
+placebo	O
+groups	O
+.	O
+
+The	O
+only	O
+significantly	O
+increased	O
+risk	O
+reported	O
+was	O
+for	O
+venous	B
+thrombo	I
+-	I
+embolism	I
+in	O
+women	O
+taking	O
+combined	O
+continuous	O
+HT	O
+:	O
+their	O
+absolute	O
+risk	O
+remained	O
+low	O
+,	O
+at	O
+less	O
+than	O
+1	O
+/	O
+500	O
+.	O
+
+However	O
+,	O
+this	O
+study	O
+was	O
+not	O
+powered	O
+to	O
+detect	O
+differences	O
+between	O
+groups	O
+of	O
+younger	O
+women	O
+.	O
+
+AUTHORS	O
+'	O
+CONCLUSIONS	O
+:	O
+HT	O
+is	O
+not	O
+indicated	O
+for	O
+the	O
+routine	O
+management	O
+of	O
+chronic	O
+disease	O
+.	O
+
+We	O
+need	O
+more	O
+evidence	O
+on	O
+the	O
+safety	O
+of	O
+HT	O
+for	O
+menopausal	O
+symptom	O
+control	O
+,	O
+though	O
+short	O
+-	O
+term	O
+use	O
+appears	O
+to	O
+be	O
+relatively	O
+safe	O
+for	O
+healthy	O
+younger	O
+women	O
+.	O
+
+Acute	B
+renal	I
+failure	I
+in	O
+patients	O
+with	O
+AIDS	B
+on	O
+tenofovir	O
+while	O
+receiving	O
+prolonged	O
+vancomycin	O
+course	O
+for	O
+osteomyelitis	B
+.	O
+
+Renal	B
+failure	I
+developed	O
+after	O
+a	O
+prolonged	O
+course	O
+of	O
+vancomycin	O
+therapy	O
+in	O
+2	O
+patients	O
+who	O
+were	O
+receiving	O
+tenofovir	O
+disoproxil	O
+fumarate	O
+as	O
+part	O
+of	O
+an	O
+antiretroviral	O
+regimen	O
+.	O
+
+Tenofovir	O
+has	O
+been	O
+implicated	O
+in	O
+the	O
+development	O
+of	O
+Fanconi	B
+syndrome	I
+and	O
+renal	B
+insufficiency	I
+because	O
+of	O
+its	O
+effects	O
+on	O
+the	O
+proximal	O
+renal	O
+tubule	O
+.	O
+
+Vancomycin	O
+nephrotoxicity	B
+is	O
+infrequent	O
+but	O
+may	O
+result	O
+from	O
+coadministration	O
+with	O
+a	O
+nephrotoxic	B
+agent	O
+.	O
+
+Clinicians	O
+should	O
+be	O
+aware	O
+that	O
+tenofovir	O
+may	O
+raise	O
+the	O
+risk	O
+of	O
+renal	B
+failure	I
+during	O
+prolonged	O
+administration	O
+of	O
+vancomycin	O
+.	O
+
+Recurrent	O
+dysosmia	B
+induced	O
+by	O
+pyrazinamide	O
+.	O
+
+Pyrazinamide	O
+can	O
+have	O
+adverse	O
+effects	O
+such	O
+as	O
+hepatic	B
+toxicity	I
+,	O
+hyperuricemia	B
+or	O
+digestive	O
+disorders	O
+.	O
+
+In	O
+rare	O
+cases	O
+,	O
+alterations	O
+in	O
+taste	O
+and	O
+smell	O
+function	O
+have	O
+been	O
+reported	O
+for	O
+pyrazinamide	O
+when	O
+combined	O
+with	O
+other	O
+drugs	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+reversible	O
+olfactory	B
+disorder	I
+related	O
+to	O
+pyrazinamide	O
+in	O
+a	O
+woman	O
+,	O
+with	O
+a	O
+positive	O
+rechallenge	O
+.	O
+
+The	O
+patient	O
+presented	O
+every	O
+day	O
+a	O
+sensation	O
+of	O
+smelling	O
+something	O
+burning	O
+15	O
+min	O
+after	O
+drug	O
+intake	O
+.	O
+
+Dysosmia	B
+disappeared	O
+completely	O
+after	O
+pyrazinamide	O
+withdrawal	O
+and	O
+recurred	O
+after	O
+its	O
+rechallenge	O
+.	O
+
+The	O
+case	O
+was	O
+reported	O
+to	O
+the	O
+Tunisian	O
+Centre	O
+of	O
+Pharmacovigilance	O
+.	O
+
+Mice	O
+lacking	O
+mPGES	O
+-	O
+1	O
+are	O
+resistant	O
+to	O
+lithium	O
+-	O
+induced	O
+polyuria	B
+.	O
+
+Cyclooxygenase	O
+-	O
+2	O
+activity	O
+is	O
+required	O
+for	O
+the	O
+development	O
+of	O
+lithium	O
+-	O
+induced	O
+polyuria	B
+.	O
+
+However	O
+,	O
+the	O
+involvement	O
+of	O
+a	O
+specific	O
+,	O
+terminal	O
+prostaglandin	O
+(	O
+PG	O
+)	O
+isomerase	O
+has	O
+not	O
+been	O
+evaluated	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+undertaken	O
+to	O
+assess	O
+lithium	O
+-	O
+induced	O
+polyuria	B
+in	O
+mice	O
+deficient	O
+in	O
+microsomal	O
+prostaglandin	O
+E	O
+synthase	O
+-	O
+1	O
+(	O
+mPGES	O
+-	O
+1	O
+)	O
+.	O
+
+A	O
+2	O
+-	O
+wk	O
+administration	O
+of	O
+LiCl	O
+(	O
+4	O
+mmol	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+day	O
+(	O
+-	O
+1	O
+)	O
+ip	O
+)	O
+in	O
+mPGES	O
+-	O
+1	O
++	O
+/	O
++	O
+mice	O
+led	O
+to	O
+a	O
+marked	O
+polyuria	B
+with	O
+hyposmotic	O
+urine	O
+.	O
+
+This	O
+was	O
+associated	O
+with	O
+elevated	O
+renal	O
+mPGES	O
+-	O
+1	O
+protein	O
+expression	O
+and	O
+increased	O
+urine	O
+PGE	O
+(	O
+2	O
+)	O
+excretion	O
+.	O
+
+In	O
+contrast	O
+,	O
+mPGES	O
+-	O
+1	O
+-	O
+/	O
+-	O
+mice	O
+were	O
+largely	O
+resistant	O
+to	O
+lithium	O
+-	O
+induced	O
+polyuria	B
+and	O
+a	O
+urine	O
+concentrating	O
+defect	O
+,	O
+accompanied	O
+by	O
+nearly	O
+complete	O
+blockade	O
+of	O
+high	O
+urine	O
+PGE	O
+(	O
+2	O
+)	O
+and	O
+cAMP	O
+output	O
+.	O
+
+Immunoblotting	O
+,	O
+immunohistochemistry	O
+,	O
+and	O
+quantitative	O
+(	O
+q	O
+)	O
+RT	O
+-	O
+PCR	O
+consistently	O
+detected	O
+a	O
+significant	O
+decrease	O
+in	O
+aquaporin	O
+-	O
+2	O
+(	O
+AQP2	O
+)	O
+protein	O
+expression	O
+in	O
+both	O
+the	O
+renal	O
+cortex	O
+and	O
+medulla	O
+of	O
+lithium	O
+-	O
+treated	O
++	O
+/	O
++	O
+mice	O
+.	O
+
+This	O
+decrease	O
+was	O
+significantly	O
+attenuated	O
+in	O
+the	O
+-	O
+/	O
+-	O
+mice	O
+.	O
+
+qRT	O
+-	O
+PCR	O
+detected	O
+similar	O
+patterns	O
+of	O
+changes	O
+in	O
+AQP2	O
+mRNA	O
+in	O
+the	O
+medulla	O
+but	O
+not	O
+in	O
+the	O
+cortex	O
+.	O
+
+Similarly	O
+,	O
+the	O
+total	O
+protein	O
+abundance	O
+of	O
+the	O
+Na	O
+-	O
+K	O
+-	O
+2Cl	O
+cotransporter	O
+(	O
+NKCC2	O
+)	O
+in	O
+the	O
+medulla	O
+but	O
+not	O
+in	O
+the	O
+cortex	O
+of	O
+the	O
++	O
+/	O
++	O
+mice	O
+was	O
+significantly	O
+reduced	O
+by	O
+lithium	O
+treatment	O
+.	O
+
+In	O
+contrast	O
+,	O
+the	O
+dowregulation	O
+of	O
+renal	O
+medullary	O
+NKCC2	O
+expression	O
+was	O
+significantly	O
+attenuated	O
+in	O
+the	O
+-	O
+/	O
+-	O
+mice	O
+.	O
+
+We	O
+conclude	O
+that	O
+mPGES	O
+-	O
+1	O
+-	O
+derived	O
+PGE	O
+(	O
+2	O
+)	O
+mediates	O
+lithium	O
+-	O
+induced	O
+polyuria	B
+likely	O
+via	O
+inhibition	O
+of	O
+AQP2	O
+and	O
+NKCC2	O
+expression	O
+.	O
+
+Preservation	O
+of	O
+renal	O
+blood	O
+flow	O
+during	O
+hypotension	B
+induced	O
+with	O
+fenoldopam	O
+in	O
+dogs	O
+.	O
+
+The	O
+introduction	O
+of	O
+drugs	O
+that	O
+could	O
+induce	O
+hypotension	B
+with	O
+different	O
+pharmacological	O
+actions	O
+would	O
+be	O
+advantageous	O
+because	O
+side	O
+effects	O
+unique	O
+to	O
+a	O
+specific	O
+drug	O
+could	O
+be	O
+minimized	O
+by	O
+selecting	O
+appropriate	O
+therapy	O
+.	O
+
+Specific	O
+dopamine	O
+-	O
+1	O
+,	O
+(	O
+DA1	O
+)	O
+and	O
+dopamine	O
+-	O
+2	O
+(	O
+DA2	O
+)	O
+receptor	O
+agonists	O
+are	O
+now	O
+under	O
+clinical	O
+investigation	O
+.	O
+
+Fenoldopam	O
+mesylate	O
+is	O
+a	O
+specific	O
+DA1	O
+receptor	O
+agonist	O
+that	O
+lowers	O
+blood	O
+pressure	O
+by	O
+vasodilatation	O
+.	O
+
+The	O
+hypothesis	O
+that	O
+fenoldopam	O
+could	O
+be	O
+used	O
+to	O
+induce	O
+hypotension	B
+and	O
+preserve	O
+blood	O
+flow	O
+to	O
+the	O
+kidney	O
+was	O
+tested	O
+.	O
+
+Systemic	O
+aortic	O
+blood	O
+pressure	O
+and	O
+renal	O
+blood	O
+flow	O
+were	O
+measured	O
+continuously	O
+with	O
+a	O
+carotid	O
+arterial	O
+catheter	O
+and	O
+an	O
+electromagnetic	O
+flow	O
+probe	O
+respectively	O
+,	O
+in	O
+order	O
+to	O
+compare	O
+the	O
+cardiovascular	O
+and	O
+renal	O
+vascular	O
+effects	O
+of	O
+fenoldopam	O
+and	O
+sodium	O
+nitroprusside	O
+in	O
+ten	O
+dogs	O
+under	O
+halothane	O
+general	O
+anaesthesia	O
+.	O
+
+Mean	O
+arterial	O
+pressure	O
+was	O
+decreased	O
+30	O
++	O
+/	O
+-	O
+8	O
+per	O
+cent	O
+from	O
+control	O
+with	O
+infusion	O
+of	O
+fenoldopam	O
+(	O
+3	O
+.	O
+4	O
++	O
+/	O
+-	O
+2	O
+.	O
+0	O
+micrograms	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+)	O
+and	O
+34	O
++	O
+/	O
+-	O
+4	O
+per	O
+cent	O
+with	O
+infusion	O
+of	O
+sodium	O
+nitroprusside	O
+(	O
+5	O
+.	O
+9	O
+micrograms	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+)	O
+(	O
+NS	O
+)	O
+.	O
+
+Renal	O
+blood	O
+flow	O
+(	O
+RBF	O
+)	O
+increased	O
+during	O
+fenoldopam	O
+-	O
+induced	O
+hypotension	B
+11	O
++	O
+/	O
+-	O
+7	O
+per	O
+cent	O
+and	O
+decreased	O
+21	O
++	O
+/	O
+-	O
+8	O
+per	O
+cent	O
+during	O
+sodium	O
+nitroprusside	O
+-	O
+induced	O
+hypotension	B
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+Sodium	O
+nitroprusside	O
+is	O
+a	O
+non	O
+-	O
+selective	O
+arteriolar	O
+and	O
+venous	O
+vasodilator	O
+that	O
+can	O
+produce	O
+redistribution	O
+of	O
+blood	O
+flow	O
+away	O
+from	O
+the	O
+kidney	O
+during	O
+induced	O
+hypotension	B
+.	O
+
+Fenoldopam	O
+is	O
+a	O
+selective	O
+dopamine	O
+-	O
+1	O
+(	O
+DA1	O
+)	O
+receptor	O
+agonist	O
+that	O
+causes	O
+vasodilatation	O
+to	O
+the	O
+kidney	O
+and	O
+other	O
+organs	O
+with	O
+DA1	O
+receptors	O
+and	O
+preserves	O
+blood	O
+flow	O
+to	O
+the	O
+kidney	O
+during	O
+induced	O
+hypotension	B
+.	O
+
+Seizures	B
+associated	O
+with	O
+levofloxacin	O
+:	O
+case	O
+presentation	O
+and	O
+literature	O
+review	O
+.	O
+
+PURPOSE	O
+:	O
+We	O
+present	O
+a	O
+case	O
+of	O
+a	O
+patient	O
+who	O
+developed	O
+seizures	B
+shortly	O
+after	O
+initiating	O
+treatment	O
+with	O
+levofloxacin	O
+and	O
+to	O
+discuss	O
+the	O
+potential	O
+drug	O
+-	O
+drug	O
+interactions	O
+related	O
+to	O
+the	O
+inhibition	O
+of	O
+cytochrome	O
+P450	O
+(	O
+CYP	O
+)	O
+1A2	O
+in	O
+this	O
+case	O
+,	O
+as	O
+well	O
+as	O
+in	O
+other	O
+cases	O
+,	O
+of	O
+levofloxacin	O
+-	O
+induced	O
+seizures	B
+.	O
+
+METHODS	O
+:	O
+Several	O
+biomedical	O
+databases	O
+were	O
+searched	O
+including	O
+MEDLINE	O
+,	O
+Cochrane	O
+and	O
+Ovid	O
+.	O
+
+The	O
+main	O
+search	O
+terms	O
+utilized	O
+were	O
+case	O
+report	O
+and	O
+levofloxacin	O
+.	O
+
+The	O
+search	O
+was	O
+limited	O
+to	O
+studies	O
+published	O
+in	O
+English	O
+.	O
+
+RESULTS	O
+:	O
+Six	O
+cases	O
+of	O
+levofloxacin	O
+-	O
+induced	O
+seizures	B
+have	O
+been	O
+reported	O
+in	O
+the	O
+literature	O
+.	O
+
+Drug	O
+-	O
+drug	O
+interactions	O
+related	O
+to	O
+the	O
+inhibition	O
+of	O
+CYP1A2	O
+by	O
+levofloxacin	O
+are	O
+likely	O
+involved	O
+in	O
+the	O
+clinical	O
+outcome	O
+of	O
+these	O
+cases	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Clinicians	O
+are	O
+exhorted	O
+to	O
+pay	O
+close	O
+attention	O
+when	O
+initiating	O
+levofloxacin	O
+therapy	O
+in	O
+patients	O
+taking	O
+medications	O
+with	O
+epileptogenic	O
+properties	O
+that	O
+are	O
+CYP1A2	O
+substrates	O
+.	O
+
+Dextran	O
+-	O
+etodolac	O
+conjugates	O
+:	O
+synthesis	O
+,	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+evaluation	O
+.	O
+
+Etodolac	O
+(	O
+E	O
+)	O
+,	O
+is	O
+a	O
+non	O
+-	O
+narcotic	O
+analgesic	O
+and	O
+antiinflammatory	O
+drug	O
+.	O
+
+A	O
+biodegradable	O
+polymer	O
+dextran	O
+has	O
+been	O
+utilized	O
+as	O
+a	O
+carrier	O
+for	O
+synthesis	O
+of	O
+etodolac	O
+-	O
+dextran	O
+conjugates	O
+(	O
+ED	O
+)	O
+to	O
+improve	O
+its	O
+aqueous	O
+solubility	O
+and	O
+reduce	O
+gastrointestinal	O
+side	O
+effects	O
+.	O
+
+An	O
+activated	O
+moiety	O
+,	O
+i	O
+.	O
+e	O
+.	O
+N	O
+-	O
+acylimidazole	O
+derivative	O
+of	O
+etodolac	O
+(	O
+EAI	O
+)	O
+,	O
+was	O
+condensed	O
+with	O
+the	O
+polysaccharide	O
+polymer	O
+dextran	O
+of	O
+different	O
+molecular	O
+weights	O
+(	O
+40000	O
+,	O
+60000	O
+,	O
+110000	O
+and	O
+200000	O
+)	O
+.	O
+
+IR	O
+spectral	O
+data	O
+confirmed	O
+formation	O
+of	O
+ester	O
+bonding	O
+in	O
+the	O
+conjugates	O
+.	O
+
+Etodolac	O
+contents	O
+were	O
+evaluated	O
+by	O
+UV	O
+-	O
+spectrophotometric	O
+analysis	O
+.	O
+
+The	O
+molecular	O
+weights	O
+were	O
+determined	O
+by	O
+measuring	O
+viscosity	O
+using	O
+the	O
+Mark	O
+-	O
+Howink	O
+-	O
+Sakurada	O
+equation	O
+.	O
+
+In	O
+vitro	O
+hydrolysis	O
+of	O
+ED	O
+was	O
+done	O
+in	O
+aqueous	O
+buffers	O
+(	O
+pH	O
+1	O
+.	O
+2	O
+,	O
+7	O
+.	O
+4	O
+,	O
+9	O
+)	O
+and	O
+in	O
+80	O
+%	O
+(	O
+v	O
+/	O
+v	O
+)	O
+human	O
+plasma	O
+(	O
+pH	O
+7	O
+.	O
+4	O
+)	O
+.	O
+
+At	O
+pH	O
+9	O
+,	O
+a	O
+higher	O
+rate	O
+of	O
+etodolac	O
+release	O
+from	O
+ED	O
+was	O
+observed	O
+as	O
+compared	O
+to	O
+aqueous	O
+buffer	O
+of	O
+pH	O
+7	O
+.	O
+4	O
+and	O
+80	O
+%	O
+human	O
+plasma	O
+(	O
+pH	O
+7	O
+.	O
+4	O
+)	O
+,	O
+following	O
+first	O
+-	O
+order	O
+kinetics	O
+.	O
+
+In	O
+vivo	O
+investigations	O
+were	O
+performed	O
+in	O
+animals	O
+.	O
+
+Acute	O
+analgesic	O
+and	O
+antiinflammatory	O
+activities	O
+were	O
+ascertained	O
+using	O
+acetic	O
+acid	O
+induced	O
+writhing	B
+model	O
+(	O
+mice	O
+)	O
+and	O
+carrageenan	O
+-	O
+induced	O
+rat	O
+paw	O
+edema	B
+model	O
+,	O
+respectively	O
+.	O
+
+In	O
+comparison	O
+to	O
+control	O
+,	O
+E	O
+and	O
+ED1	O
+-	O
+ED4	O
+showed	O
+highly	O
+significant	O
+analgesic	O
+and	O
+antiinflammatory	O
+activities	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Biological	O
+evaluation	O
+suggested	O
+that	O
+conjugates	O
+(	O
+ED1	O
+-	O
+ED4	O
+)	O
+retained	O
+comparable	O
+analgesic	O
+and	O
+antiinflammatory	O
+activities	O
+with	O
+remarkably	O
+reduced	O
+ulcerogenicity	O
+as	O
+compared	O
+to	O
+their	O
+parent	O
+drug	O
+-	O
+-	O
+etodolac	O
+.	O
+
+The	O
+antiarrhythmic	O
+effect	O
+and	O
+possible	O
+ionic	O
+mechanisms	O
+of	O
+pilocarpine	O
+on	O
+animal	O
+models	O
+.	O
+
+This	O
+study	O
+was	O
+designed	O
+to	O
+evaluate	O
+the	O
+effects	O
+of	O
+pilocarpine	O
+and	O
+explore	O
+the	O
+underlying	O
+ionic	O
+mechanism	O
+,	O
+using	O
+both	O
+aconitine	O
+-	O
+induced	O
+rat	O
+and	O
+ouabain	O
+-	O
+induced	O
+guinea	O
+pig	O
+arrhythmia	B
+models	O
+.	O
+
+Confocal	O
+microscopy	O
+was	O
+used	O
+to	O
+measure	O
+intracellular	O
+free	O
+-	O
+calcium	O
+concentrations	O
+(	O
+[	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+]	O
+(	O
+i	O
+)	O
+)	O
+in	O
+isolated	O
+myocytes	O
+.	O
+
+The	O
+current	O
+data	O
+showed	O
+that	O
+pilocarpine	O
+significantly	O
+delayed	O
+onset	O
+of	O
+arrhythmias	B
+,	O
+decreased	O
+the	O
+time	O
+course	O
+of	O
+ventricular	B
+tachycardia	I
+and	I
+fibrillation	I
+,	O
+reduced	O
+arrhythmia	B
+score	O
+,	O
+and	O
+increased	O
+the	O
+survival	O
+time	O
+of	O
+arrhythmic	B
+rats	O
+and	O
+guinea	O
+pigs	O
+.	O
+
+[	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+]	O
+(	O
+i	O
+)	O
+overload	O
+induced	O
+by	O
+aconitine	O
+or	O
+ouabain	O
+was	O
+reduced	O
+in	O
+isolated	O
+myocytes	O
+pretreated	O
+with	O
+pilocarpine	O
+.	O
+
+Moreover	O
+,	O
+M	O
+(	O
+3	O
+)	O
+-	O
+muscarinic	O
+acetylcholine	O
+receptor	O
+(	O
+mAChR	O
+)	O
+antagonist	O
+4	O
+-	O
+DAMP	O
+(	O
+4	O
+-	O
+diphenylacetoxy	O
+-	O
+N	O
+-	O
+methylpiperidine	O
+-	O
+methiodide	O
+)	O
+partially	O
+abolished	O
+the	O
+beneficial	O
+effects	O
+of	O
+pilocarpine	O
+.	O
+
+These	O
+data	O
+suggest	O
+that	O
+pilocarpine	O
+produced	O
+antiarrhythmic	O
+actions	O
+on	O
+arrhythmic	B
+rat	O
+and	O
+guinea	O
+pig	O
+models	O
+induced	O
+by	O
+aconitine	O
+or	O
+ouabain	O
+via	O
+stimulating	O
+the	O
+cardiac	O
+M	O
+(	O
+3	O
+)	O
+-	O
+mAChR	O
+.	O
+
+The	O
+mechanism	O
+may	O
+be	O
+related	O
+to	O
+the	O
+improvement	O
+of	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+handling	O
+.	O
+
+Effect	O
+of	O
+Hibiscus	O
+rosa	O
+sinensis	O
+on	O
+reserpine	O
+-	O
+induced	O
+neurobehavioral	O
+and	O
+biochemical	O
+alterations	O
+in	O
+rats	O
+.	O
+
+Effect	O
+of	O
+methanolic	O
+extract	O
+of	O
+Hibiscus	O
+rosa	O
+sinensis	O
+(	O
+100	O
+-	O
+300	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+studied	O
+on	O
+reserpine	O
+-	O
+induced	O
+orofacial	O
+dyskinesia	B
+and	O
+neurochemical	O
+alterations	O
+.	O
+
+The	O
+rats	O
+were	O
+treated	O
+with	O
+intraperitoneal	O
+reserpine	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+,	O
+ip	O
+)	O
+for	O
+3	O
+days	O
+every	O
+other	O
+day	O
+.	O
+
+On	O
+day	O
+5	O
+,	O
+vacuous	O
+chewing	O
+movements	O
+and	O
+tongue	O
+protrusions	O
+were	O
+counted	O
+for	O
+5	O
+min	O
+.	O
+
+Reserpine	O
+treated	O
+rats	O
+significantly	O
+developed	O
+vacuous	O
+chewing	O
+movements	O
+and	O
+tongue	O
+protrusions	O
+however	O
+,	O
+coadministration	O
+of	O
+Hibiscus	O
+rosa	O
+sinensis	O
+roots	O
+extract	O
+(	O
+100	O
+,	O
+200	O
+and	O
+300	O
+mg	O
+/	O
+kg	O
+,	O
+per	O
+orally	O
+)	O
+attenuated	O
+the	O
+effects	O
+.	O
+
+Biochemical	O
+analysis	O
+of	O
+brain	O
+revealed	O
+that	O
+the	O
+reserpine	O
+treatment	O
+significantly	O
+increased	O
+lipid	O
+peroxidation	O
+and	O
+decreased	O
+levels	O
+of	O
+superoxide	O
+dismutase	O
+(	O
+SOD	O
+)	O
+,	O
+catalase	O
+(	O
+CAT	O
+)	O
+and	O
+glutathione	O
+reductase	O
+(	O
+GSH	O
+)	O
+,	O
+an	O
+index	O
+of	O
+oxidative	O
+stress	O
+process	O
+.	O
+
+Coadministration	O
+of	O
+extract	O
+significantly	O
+reduced	O
+the	O
+lipid	O
+peroxidation	O
+and	O
+reversed	O
+the	O
+decrease	O
+in	O
+brain	O
+SOD	O
+,	O
+CAT	O
+and	O
+GSH	O
+levels	O
+.	O
+
+The	O
+results	O
+of	O
+the	O
+present	O
+study	O
+suggested	O
+that	O
+Hibiscus	O
+rosa	O
+sinensis	O
+had	O
+a	O
+protective	O
+role	O
+against	O
+reserpine	O
+-	O
+induced	O
+orofacial	O
+dyskinesia	B
+and	O
+oxidative	O
+stress	O
+.	O
+
+Dynamic	O
+response	O
+of	O
+blood	O
+vessel	O
+in	O
+acute	B
+renal	I
+failure	I
+.	O
+
+In	O
+this	O
+study	O
+we	O
+postulated	O
+that	O
+during	O
+acute	B
+renal	I
+failure	I
+induced	O
+by	O
+gentamicin	O
+the	O
+transient	O
+or	O
+dynamic	O
+response	O
+of	O
+blood	O
+vessels	O
+could	O
+be	O
+affected	O
+,	O
+and	O
+that	O
+antioxidants	O
+can	O
+prevent	O
+the	O
+changes	O
+in	O
+dynamic	O
+responses	O
+of	O
+blood	O
+vessels	O
+.	O
+
+The	O
+new	O
+approach	O
+to	O
+ex	O
+vivo	O
+blood	O
+vessel	O
+experiments	O
+in	O
+which	O
+not	O
+only	O
+the	O
+end	O
+points	O
+of	O
+vessels	O
+response	O
+within	O
+the	O
+time	O
+interval	O
+is	O
+considered	O
+,	O
+but	O
+also	O
+dynamics	O
+of	O
+this	O
+response	O
+,	O
+was	O
+used	O
+in	O
+this	O
+paper	O
+.	O
+
+Our	O
+results	O
+confirm	O
+the	O
+alteration	O
+in	O
+dynamic	O
+response	O
+of	O
+blood	O
+vessels	O
+during	O
+the	O
+change	O
+of	O
+pressure	O
+in	O
+gentamicin	O
+-	O
+treated	O
+animals	O
+.	O
+
+The	O
+beneficial	O
+effects	O
+of	O
+vitamin	O
+C	O
+administration	O
+to	O
+gentamicin	O
+-	O
+treated	O
+animals	O
+are	O
+also	O
+confirmed	O
+through	O
+:	O
+lower	O
+level	O
+of	O
+blood	O
+urea	O
+and	O
+creatinine	O
+and	O
+higher	O
+level	O
+of	O
+potassium	O
+.	O
+
+The	O
+pressure	O
+dynamic	O
+responses	O
+of	O
+isolated	O
+blood	O
+vessels	O
+show	O
+a	O
+faster	O
+pressure	O
+change	O
+in	O
+gentamicin	O
+-	O
+treated	O
+animals	O
+(	O
+8	O
+.	O
+07	O
++	O
+/	O
+-	O
+1	O
+.	O
+7	O
+s	O
+vs	O
+.	O
+5	O
+.	O
+64	O
++	O
+/	O
+-	O
+0	O
+.	O
+18	O
+s	O
+)	O
+.	O
+
+Vitamin	O
+C	O
+administration	O
+induced	O
+slowdown	O
+of	O
+pressure	O
+change	O
+back	O
+to	O
+the	O
+control	O
+values	O
+.	O
+
+The	O
+pressure	O
+dynamic	O
+properties	O
+,	O
+quantitatively	O
+defined	O
+by	O
+comparative	O
+pressure	O
+dynamic	O
+and	O
+total	O
+pressure	O
+dynamic	O
+,	O
+confirm	O
+the	O
+alteration	O
+in	O
+dynamic	O
+response	O
+of	O
+blood	O
+vessels	O
+during	O
+the	O
+change	O
+of	O
+pressure	O
+in	O
+gentamicin	O
+-	O
+treated	O
+animals	O
+and	O
+beneficial	O
+effects	O
+of	O
+vitamin	O
+C	O
+administration	O
+.	O
+
+Reversible	O
+myocardial	B
+hypertrophy	I
+induced	O
+by	O
+tacrolimus	O
+in	O
+a	O
+pediatric	O
+heart	O
+transplant	O
+recipient	O
+:	O
+case	O
+report	O
+.	O
+
+Tacrolimus	O
+is	O
+a	O
+potent	O
+immunosuppressant	O
+that	O
+is	O
+frequently	O
+used	O
+in	O
+organ	O
+transplantation	O
+.	O
+
+However	O
+,	O
+adverse	O
+effects	O
+include	O
+cardiac	B
+toxicity	I
+.	O
+
+Herein	O
+we	O
+describe	O
+transient	O
+myocardial	B
+hypertrophy	I
+induced	O
+by	O
+tacrolimus	O
+after	O
+heart	O
+transplantation	O
+.	O
+
+The	O
+hypertrophy	B
+caused	O
+no	O
+clinical	O
+symptoms	O
+but	O
+was	O
+noted	O
+because	O
+of	O
+elevation	O
+of	O
+plasma	O
+brain	O
+natriuretic	O
+peptide	O
+concentration	O
+and	O
+confirmed	O
+at	O
+echocardiography	O
+.	O
+
+Initially	O
+,	O
+allograft	O
+rejection	O
+was	O
+feared	O
+;	O
+however	O
+,	O
+myocardial	O
+biopsy	O
+samples	O
+revealed	O
+only	O
+interstitial	O
+edema	B
+and	O
+mild	O
+myocardial	B
+hypertrophy	I
+;	O
+neither	O
+cellular	O
+nor	O
+humoral	O
+rejection	O
+was	O
+detected	O
+.	O
+
+The	O
+blood	O
+tacrolimus	O
+concentration	O
+was	O
+higher	O
+than	O
+usual	O
+at	O
+that	O
+time	O
+;	O
+thus	O
+,	O
+tacrolimus	O
+dosage	O
+was	O
+reduced	O
+.	O
+
+Myocardial	B
+hypertrophy	I
+completely	O
+resolved	O
+upon	O
+reducing	O
+the	O
+target	O
+concentration	O
+of	O
+tacrolimus	O
+and	O
+did	O
+not	O
+recur	O
+,	O
+as	O
+confirmed	O
+at	O
+echocardiography	O
+and	O
+myocardial	O
+biopsy	O
+.	O
+
+Thus	O
+,	O
+we	O
+conclude	O
+that	O
+tacrolimus	O
+induces	O
+reversible	O
+myocardial	B
+hypertrophy	I
+.	O
+
+In	O
+patients	O
+receiving	O
+tacrolimus	O
+therapy	O
+,	O
+blood	O
+concentration	O
+should	O
+be	O
+carefully	O
+controlled	O
+and	O
+extreme	O
+attention	O
+paid	O
+to	O
+cardiac	O
+involvement	O
+.	O
+
+Nimodipine	O
+prevents	O
+memory	B
+impairment	I
+caused	O
+by	O
+nitroglycerin	O
+-	O
+induced	O
+hypotension	B
+in	O
+adult	O
+mice	O
+.	O
+
+BACKGROUND	O
+:	O
+Hypotension	B
+and	O
+a	O
+resultant	O
+decrease	O
+in	O
+cerebral	O
+blood	O
+flow	O
+have	O
+been	O
+implicated	O
+in	O
+the	O
+development	O
+of	O
+cognitive	B
+dysfunction	I
+.	O
+
+We	O
+tested	O
+the	O
+hypothesis	O
+that	O
+nimodipine	O
+(	O
+NIMO	O
+)	O
+administered	O
+at	O
+the	O
+onset	O
+of	O
+nitroglycerin	O
+(	O
+NTG	O
+)	O
+-	O
+induced	O
+hypotension	B
+would	O
+preserve	O
+long	O
+-	O
+term	O
+associative	O
+memory	O
+.	O
+
+METHODS	O
+:	O
+The	O
+passive	O
+avoidance	O
+(	O
+PA	O
+)	O
+paradigm	O
+was	O
+used	O
+to	O
+assess	O
+memory	O
+retention	O
+.	O
+
+For	O
+PA	O
+training	O
+,	O
+latencies	O
+(	O
+seconds	O
+)	O
+were	O
+recorded	O
+for	O
+entry	O
+from	O
+a	O
+suspended	O
+platform	O
+into	O
+a	O
+Plexiglas	O
+tube	O
+where	O
+a	O
+shock	O
+was	O
+automatically	O
+delivered	O
+.	O
+
+Latencies	O
+were	O
+recorded	O
+48	O
+h	O
+later	O
+for	O
+a	O
+testing	O
+trial	O
+.	O
+
+Ninety	O
+-	O
+six	O
+Swiss	O
+-	O
+Webster	O
+mice	O
+(	O
+30	O
+-	O
+35	O
+g	O
+,	O
+6	O
+-	O
+8	O
+wk	O
+)	O
+,	O
+were	O
+randomized	O
+into	O
+6	O
+groups	O
+1	O
+)	O
+saline	O
+(	O
+control	O
+)	O
+,	O
+2	O
+)	O
+NTG	O
+immediately	O
+after	O
+learning	O
+,	O
+3	O
+)	O
+NTG	O
+3	O
+h	O
+after	O
+learning	O
+,	O
+4	O
+)	O
+NTG	O
+and	O
+NIMO	O
+,	O
+5	O
+)	O
+vehicle	O
+,	O
+and	O
+6	O
+)	O
+NIMO	O
+alone	O
+.	O
+
+The	O
+extent	O
+of	O
+hypotension	B
+and	O
+changes	O
+in	O
+brain	O
+tissue	O
+oxygenation	O
+(	O
+PbtO	O
+(	O
+2	O
+)	O
+)	O
+and	O
+in	O
+cerebral	O
+blood	O
+flow	O
+were	O
+studied	O
+in	O
+a	O
+separate	O
+group	O
+of	O
+animals	O
+.	O
+
+RESULTS	O
+:	O
+All	O
+groups	O
+exhibited	O
+similar	O
+training	O
+latencies	O
+(	O
+17	O
+.	O
+0	O
++	O
+/	O
+-	O
+4	O
+.	O
+6	O
+s	O
+)	O
+.	O
+
+Mice	O
+subjected	O
+to	O
+hypotensive	B
+episodes	O
+showed	O
+a	O
+significant	O
+decrease	O
+in	O
+latency	O
+time	O
+(	O
+178	O
++	O
+/	O
+-	O
+156	O
+s	O
+)	O
+compared	O
+with	O
+those	O
+injected	O
+with	O
+saline	O
+,	O
+NTG	O
++	O
+NIMO	O
+,	O
+or	O
+delayed	O
+NTG	O
+(	O
+580	O
++	O
+/	O
+-	O
+81	O
+s	O
+,	O
+557	O
++	O
+/	O
+-	O
+67	O
+s	O
+,	O
+and	O
+493	O
++	O
+/	O
+-	O
+146	O
+s	O
+,	O
+respectively	O
+)	O
+.	O
+
+A	O
+Kruskal	O
+-	O
+Wallis	O
+1	O
+-	O
+way	O
+analysis	O
+of	O
+variance	O
+indicated	O
+a	O
+significant	O
+difference	O
+among	O
+the	O
+4	O
+treatment	O
+groups	O
+(	O
+H	O
+=	O
+15	O
+.	O
+34	O
+;	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+In	O
+a	O
+separate	O
+group	O
+of	O
+mice	O
+not	O
+subjected	O
+to	O
+behavioral	O
+studies	O
+,	O
+the	O
+same	O
+dose	O
+of	O
+NTG	O
+(	O
+n	O
+=	O
+3	O
+)	O
+and	O
+NTG	O
++	O
+NIMO	O
+(	O
+n	O
+=	O
+3	O
+)	O
+caused	O
+mean	O
+arterial	O
+blood	O
+pressure	O
+to	O
+decrease	O
+from	O
+85	O
+.	O
+9	O
++	O
+/	O
+-	O
+3	O
+.	O
+8	O
+mm	O
+Hg	O
+sem	O
+to	O
+31	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+8	O
+mm	O
+Hg	O
+sem	O
+and	O
+from	O
+86	O
+.	O
+2	O
++	O
+/	O
+-	O
+3	O
+.	O
+7	O
+mm	O
+Hg	O
+sem	O
+to	O
+32	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+mm	O
+Hg	O
+sem	O
+,	O
+respectively	O
+.	O
+
+Mean	O
+arterial	O
+blood	O
+pressure	O
+in	O
+mice	O
+treated	O
+with	O
+NIMO	O
+alone	O
+decreased	O
+from	O
+88	O
+.	O
+1	O
++	O
+/	O
+-	O
+3	O
+.	O
+8	O
+mm	O
+Hg	O
+to	O
+80	O
+.	O
+0	O
++	O
+/	O
+-	O
+2	O
+.	O
+9	O
+mm	O
+Hg	O
+.	O
+
+The	O
+intergroup	O
+difference	O
+was	O
+statistically	O
+significant	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+PbtO	O
+(	O
+2	O
+)	O
+decreased	O
+from	O
+51	O
+.	O
+7	O
++	O
+/	O
+-	O
+4	O
+.	O
+5	O
+mm	O
+Hg	O
+sem	O
+to	O
+33	O
+.	O
+8	O
++	O
+/	O
+-	O
+5	O
+.	O
+2	O
+mm	O
+Hg	O
+sem	O
+in	O
+the	O
+NTG	O
+group	O
+and	O
+from	O
+38	O
+.	O
+6	O
++	O
+/	O
+-	O
+6	O
+.	O
+1	O
+mm	O
+Hg	O
+sem	O
+to	O
+25	O
+.	O
+4	O
++	O
+/	O
+-	O
+2	O
+.	O
+0	O
+mm	O
+Hg	O
+sem	O
+in	O
+the	O
+NTG	O
++	O
+NIMO	O
+groups	O
+,	O
+respectively	O
+.	O
+
+There	O
+were	O
+no	O
+significant	O
+differences	O
+among	O
+groups	O
+.	O
+
+CONCLUSION	O
+:	O
+In	O
+a	O
+PA	O
+retention	O
+paradigm	O
+,	O
+the	O
+injection	O
+of	O
+NTG	O
+immediately	O
+after	O
+learning	O
+produced	O
+a	O
+significant	O
+impairment	O
+of	O
+long	O
+-	O
+term	O
+associative	O
+memory	O
+in	O
+mice	O
+,	O
+whereas	O
+delayed	O
+induced	O
+hypotension	B
+had	O
+no	O
+effect	O
+.	O
+
+NIMO	O
+attenuated	O
+the	O
+disruption	O
+in	O
+consolidation	O
+of	O
+long	O
+-	O
+term	O
+memory	O
+caused	O
+by	O
+NTG	O
+but	O
+did	O
+not	O
+improve	O
+latency	O
+in	O
+the	O
+absence	O
+of	O
+hypotension	B
+.	O
+
+The	O
+observed	O
+effect	O
+of	O
+NIMO	O
+may	O
+have	O
+been	O
+attributable	O
+to	O
+the	O
+preservation	O
+of	O
+calcium	O
+homeostasis	O
+during	O
+hypotension	B
+,	O
+because	O
+there	O
+were	O
+no	O
+differences	O
+in	O
+the	O
+PbtO	O
+(	O
+2	O
+)	O
+indices	O
+among	O
+groups	O
+.	O
+
+Metabotropic	O
+glutamate	O
+7	O
+receptor	O
+subtype	O
+modulates	O
+motor	O
+symptoms	O
+in	O
+rodent	O
+models	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+Metabotropic	O
+glutamate	O
+(	O
+mGlu	O
+)	O
+receptors	O
+modulate	O
+synaptic	O
+transmission	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+and	O
+represent	O
+promising	O
+therapeutic	O
+targets	O
+for	O
+symptomatic	O
+treatment	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+.	O
+
+Among	O
+the	O
+eight	O
+mGlu	O
+receptor	O
+subtypes	O
+,	O
+mGlu7	O
+receptor	O
+is	O
+prominently	O
+expressed	O
+in	O
+the	O
+basal	O
+ganglia	O
+,	O
+but	O
+its	O
+role	O
+in	O
+restoring	O
+motor	O
+function	O
+in	O
+animal	O
+models	O
+of	O
+PD	B
+is	O
+not	O
+known	O
+.	O
+
+The	O
+effects	O
+of	O
+N	O
+,	O
+N	O
+'	O
+-	O
+dibenzhydrylethane	O
+-	O
+1	O
+,	O
+2	O
+-	O
+diamine	O
+dihydrochloride	O
+(	O
+AMN082	O
+)	O
+,	O
+the	O
+first	O
+selective	O
+allosteric	O
+activator	O
+of	O
+mGlu7	O
+receptors	O
+,	O
+were	O
+thus	O
+tested	O
+in	O
+different	O
+rodent	O
+models	O
+of	O
+PD	B
+.	O
+
+Here	O
+,	O
+we	O
+show	O
+that	O
+oral	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+or	O
+intrastriatal	O
+administration	O
+(	O
+0	O
+.	O
+1	O
+and	O
+0	O
+.	O
+5	O
+nmol	O
+)	O
+of	O
+AMN082	O
+reverses	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+in	O
+rats	O
+.	O
+
+AMN082	O
+(	O
+2	O
+.	O
+5	O
+and	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+reduces	O
+apomorphine	O
+-	O
+induced	O
+rotations	O
+in	O
+unilateral	O
+6	O
+-	O
+hydroxydopamine	O
+(	O
+6	O
+-	O
+OHDA	O
+)	O
+-	O
+lesioned	O
+rats	O
+.	O
+
+In	O
+a	O
+more	O
+complex	O
+task	O
+commonly	O
+used	O
+to	O
+evaluate	O
+major	O
+akinetic	B
+symptoms	O
+of	O
+PD	B
+patients	O
+,	O
+5	O
+mg	O
+/	O
+kg	O
+AMN082	O
+reverses	O
+the	O
+increased	O
+reaction	O
+time	O
+to	O
+respond	O
+to	O
+a	O
+cue	O
+of	O
+bilateral	O
+6	O
+-	O
+OHDA	O
+-	O
+lesioned	O
+rats	O
+.	O
+
+In	O
+addition	O
+,	O
+AMN082	O
+reduces	O
+the	O
+duration	O
+of	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+in	O
+a	O
+mGlu7	O
+receptor	O
+-	O
+dependent	O
+manner	O
+in	O
+wild	O
+-	O
+type	O
+but	O
+not	O
+mGlu7	O
+receptor	O
+knockout	O
+mice	O
+.	O
+
+Higher	O
+doses	O
+of	O
+AMN082	O
+(	O
+10	O
+and	O
+20	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+)	O
+have	O
+no	O
+effect	O
+on	O
+the	O
+same	O
+models	O
+of	O
+PD	B
+.	O
+
+Overall	O
+these	O
+findings	O
+suggest	O
+that	O
+mGlu7	O
+receptor	O
+activation	O
+can	O
+reverse	O
+motor	O
+dysfunction	O
+associated	O
+with	O
+reduced	O
+dopamine	O
+activity	O
+.	O
+
+Selective	O
+ligands	O
+of	O
+mGlu7	O
+receptor	O
+subtypes	O
+may	O
+thus	O
+be	O
+considered	O
+as	O
+promising	O
+compounds	O
+for	O
+the	O
+development	O
+of	O
+antiparkinsonian	O
+therapeutic	O
+strategies	O
+.	O
+
+Sorafenib	O
+-	O
+induced	O
+acute	O
+myocardial	B
+infarction	I
+due	O
+to	O
+coronary	B
+artery	I
+spasm	I
+.	O
+
+A	O
+65	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+advanced	O
+renal	B
+cell	I
+carcinoma	I
+was	O
+admitted	O
+due	O
+to	O
+continuing	O
+chest	B
+pain	I
+at	O
+rest	O
+.	O
+
+Two	O
+weeks	O
+before	O
+his	O
+admission	O
+,	O
+sorafenib	O
+had	O
+been	O
+started	O
+.	O
+
+He	O
+was	O
+diagnosed	O
+with	O
+non	O
+-	O
+ST	O
+-	O
+elevation	O
+myocardial	B
+infarction	I
+by	O
+laboratory	O
+data	O
+and	O
+electrocardiogram	O
+.	O
+
+Enhanced	O
+heart	O
+magnetic	O
+resonance	O
+imaging	O
+also	O
+showed	O
+subendocardial	B
+infarction	I
+.	O
+
+However	O
+,	O
+there	O
+was	O
+no	O
+stenosis	O
+in	O
+coronary	O
+arteries	O
+on	O
+angiography	O
+.	O
+
+Coronary	B
+artery	I
+spasm	I
+was	O
+induced	O
+by	O
+a	O
+provocative	O
+test	O
+.	O
+
+Cessation	O
+of	O
+sorafenib	O
+and	O
+administration	O
+of	O
+Ca	O
+-	O
+channel	O
+blocker	O
+and	O
+nitrates	O
+ameliorated	O
+his	O
+symptoms	O
+,	O
+but	O
+relapse	O
+occurred	O
+after	O
+resumption	O
+of	O
+sorafenib	O
+.	O
+
+Addition	O
+of	O
+oral	O
+nicorandil	O
+reduced	O
+his	O
+symptoms	O
+and	O
+maintained	O
+stable	B
+angina	I
+status	O
+.	O
+
+We	O
+report	O
+the	O
+first	O
+case	O
+of	O
+sorafenib	O
+-	O
+induced	O
+coronary	B
+artery	I
+spasm	I
+.	O
+
+Sorafenib	O
+is	O
+a	O
+multikinase	O
+inhibitor	O
+that	O
+targets	O
+signaling	O
+pathways	O
+necessary	O
+for	O
+cellular	O
+proliferation	O
+and	O
+survival	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+the	O
+Rho	O
+/	O
+ROCK	O
+pathway	O
+has	O
+an	O
+important	O
+role	O
+in	O
+the	O
+pathogenesis	O
+of	O
+coronary	B
+artery	I
+spasm	I
+.	O
+
+Our	O
+report	O
+may	O
+show	O
+an	O
+adverse	O
+effect	O
+on	O
+the	O
+Rho	O
+/	O
+ROCK	O
+pathway	O
+by	O
+sorafenib	O
+use	O
+.	O
+
+A	O
+novel	O
+animal	O
+model	O
+to	O
+evaluate	O
+the	O
+ability	O
+of	O
+a	O
+drug	O
+delivery	O
+system	O
+to	O
+promote	O
+the	O
+passage	O
+through	O
+the	O
+BBB	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+investigation	O
+was	O
+to	O
+explore	O
+the	O
+potentiality	O
+of	O
+a	O
+novel	O
+animal	O
+model	O
+to	O
+be	O
+used	O
+for	O
+the	O
+in	O
+vivo	O
+evaluation	O
+of	O
+the	O
+ability	O
+of	O
+a	O
+drug	O
+delivery	O
+system	O
+to	O
+promote	O
+the	O
+passage	O
+through	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+(	O
+BBB	O
+)	O
+and	O
+/	O
+or	O
+to	O
+improve	O
+the	O
+brain	O
+localization	O
+of	O
+a	O
+bioactive	O
+compound	O
+.	O
+
+A	O
+Tween	O
+80	O
+-	O
+coated	O
+poly	O
+-	O
+L	O
+-	O
+lactid	O
+acid	O
+nanoparticles	O
+was	O
+used	O
+as	O
+a	O
+model	O
+of	O
+colloidal	O
+drug	O
+delivery	O
+system	O
+,	O
+able	O
+to	O
+trespass	O
+the	O
+BBB	O
+.	O
+
+Tacrine	O
+,	O
+administered	O
+in	O
+LiCl	O
+pre	O
+-	O
+treated	O
+rats	O
+,	O
+induces	O
+electrocorticographic	O
+seizures	B
+and	O
+delayed	O
+hippocampal	B
+damage	I
+.	O
+
+The	O
+toxic	O
+effects	O
+of	O
+tacrine	O
+-	O
+loaded	O
+poly	O
+-	O
+L	O
+-	O
+lactid	O
+acid	O
+nanoparticles	O
+(	O
+5mg	O
+/	O
+kg	O
+)	O
+,	O
+a	O
+saline	O
+solution	O
+of	O
+tacrine	O
+(	O
+5mg	O
+/	O
+kg	O
+)	O
+and	O
+an	O
+empty	O
+colloidal	O
+nanoparticle	O
+suspension	O
+were	O
+compared	O
+following	O
+i	O
+.	O
+p	O
+.	O
+administration	O
+in	O
+LiCl	O
+-	O
+pre	O
+-	O
+treated	O
+Wistar	O
+rats	O
+.	O
+
+All	O
+the	O
+animals	O
+treated	O
+with	O
+tacrine	O
+-	O
+loaded	O
+nanoparticles	O
+showed	O
+an	O
+earlier	O
+outcome	O
+of	O
+CNS	O
+adverse	O
+symptoms	O
+,	O
+i	O
+.	O
+e	O
+.	O
+epileptic	B
+onset	O
+,	O
+with	O
+respect	O
+to	O
+those	O
+animals	O
+treated	O
+with	O
+the	O
+free	O
+compound	O
+(	O
+10	O
+min	O
+vs	O
+.	O
+22	O
+min	O
+respectively	O
+)	O
+.	O
+
+In	O
+addition	O
+,	O
+tacrine	O
+-	O
+loaded	O
+nanoparticles	O
+administration	O
+induced	O
+damage	B
+of	I
+neuronal	I
+cells	I
+in	O
+CA1	O
+field	O
+of	O
+the	O
+hippocampus	O
+in	O
+all	O
+treated	O
+animals	O
+,	O
+while	O
+the	O
+saline	O
+solution	O
+of	O
+tacrine	O
+only	O
+in	O
+60	O
+%	O
+of	O
+animals	O
+.	O
+
+Empty	O
+nanoparticles	O
+provided	O
+similar	O
+results	O
+to	O
+control	O
+(	O
+saline	O
+-	O
+treated	O
+)	O
+group	O
+of	O
+animals	O
+.	O
+
+In	O
+conclusion	O
+,	O
+the	O
+evaluation	O
+of	O
+time	O
+-	O
+to	O
+-	O
+onset	O
+of	O
+symptoms	O
+and	O
+the	O
+severity	O
+of	O
+neurodegenerative	O
+processes	O
+induced	O
+by	O
+the	O
+tacrine	O
+-	O
+lithium	O
+model	O
+of	O
+epilepsy	B
+in	O
+the	O
+rat	O
+,	O
+could	O
+be	O
+used	O
+to	O
+evaluate	O
+preliminarily	O
+the	O
+capability	O
+of	O
+a	O
+drug	O
+delivery	O
+system	O
+to	O
+trespass	O
+(	O
+or	O
+not	O
+)	O
+the	O
+BBB	O
+in	O
+vivo	O
+.	O
+
+High	O
+-	O
+dose	O
+tranexamic	O
+Acid	O
+is	O
+associated	O
+with	O
+nonischemic	O
+clinical	O
+seizures	B
+in	O
+cardiac	O
+surgical	O
+patients	O
+.	O
+
+BACKGROUND	O
+:	O
+In	O
+2	O
+separate	O
+centers	O
+,	O
+we	O
+observed	O
+a	O
+notable	O
+increase	O
+in	O
+the	O
+incidence	O
+of	O
+postoperative	O
+convulsive	B
+seizures	B
+from	O
+1	O
+.	O
+3	O
+%	O
+to	O
+3	O
+.	O
+8	O
+%	O
+in	O
+patients	O
+having	O
+undergone	O
+major	O
+cardiac	O
+surgical	O
+procedures	O
+.	O
+
+These	O
+events	O
+were	O
+temporally	O
+coincident	O
+with	O
+the	O
+initial	O
+use	O
+of	O
+high	O
+-	O
+dose	O
+tranexamic	O
+acid	O
+(	O
+TXA	O
+)	O
+therapy	O
+after	O
+withdrawal	O
+of	O
+aprotinin	O
+from	O
+general	O
+clinical	O
+usage	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+review	O
+was	O
+to	O
+perform	O
+a	O
+retrospective	O
+analysis	O
+to	O
+examine	O
+whether	O
+there	O
+was	O
+a	O
+relation	O
+between	O
+TXA	O
+usage	O
+and	O
+seizures	B
+after	O
+cardiac	O
+surgery	O
+.	O
+
+METHODS	O
+:	O
+An	O
+in	O
+-	O
+depth	O
+chart	O
+review	O
+was	O
+undertaken	O
+in	O
+all	O
+24	O
+patients	O
+who	O
+developed	O
+perioperative	O
+seizures	B
+.	O
+
+Electroencephalographic	O
+activity	O
+was	O
+recorded	O
+in	O
+11	O
+of	O
+these	O
+patients	O
+,	O
+and	O
+all	O
+patients	O
+had	O
+a	O
+formal	O
+neurological	O
+evaluation	O
+and	O
+brain	O
+imaging	O
+studies	O
+.	O
+
+RESULTS	O
+:	O
+Twenty	O
+-	O
+one	O
+of	O
+the	O
+24	O
+patients	O
+did	O
+not	O
+have	O
+evidence	O
+of	O
+new	O
+cerebral	B
+ischemic	I
+injury	I
+,	O
+but	O
+seizures	B
+were	O
+likely	O
+due	O
+to	O
+ischemic	B
+brain	I
+injury	I
+in	O
+3	O
+patients	O
+.	O
+
+All	O
+patients	O
+with	O
+seizures	B
+did	O
+not	O
+have	O
+permanent	O
+neurological	B
+abnormalities	I
+.	O
+
+All	O
+24	O
+patients	O
+with	O
+seizures	B
+received	O
+high	O
+doses	O
+of	O
+TXA	O
+intraoperatively	O
+ranging	O
+from	O
+61	O
+to	O
+259	O
+mg	O
+/	O
+kg	O
+,	O
+had	O
+a	O
+mean	O
+age	O
+of	O
+69	O
+.	O
+9	O
+years	O
+,	O
+and	O
+21	O
+of	O
+24	O
+had	O
+undergone	O
+open	O
+chamber	O
+rather	O
+than	O
+coronary	O
+bypass	O
+procedures	O
+.	O
+
+All	O
+but	O
+one	O
+patient	O
+were	O
+managed	O
+using	O
+cardiopulmonary	O
+bypass	O
+.	O
+
+No	O
+evidence	O
+of	O
+brain	B
+ischemic	I
+,	O
+metabolic	O
+,	O
+or	O
+hyperthermia	B
+-	O
+induced	O
+causes	O
+for	O
+their	O
+seizures	B
+was	O
+apparent	O
+.	O
+
+CONCLUSION	O
+:	O
+Our	O
+results	O
+suggest	O
+that	O
+use	O
+of	O
+high	O
+-	O
+dose	O
+TXA	O
+in	O
+older	O
+patients	O
+in	O
+conjunction	O
+with	O
+cardiopulmonary	O
+bypass	O
+and	O
+open	O
+-	O
+chamber	O
+cardiac	O
+surgery	O
+is	O
+associated	O
+with	O
+clinical	O
+seizures	B
+in	O
+susceptible	O
+patients	O
+.	O
+
+Electrocardiographic	O
+changes	O
+and	O
+cardiac	B
+arrhythmias	I
+in	O
+patients	O
+receiving	O
+psychotropic	O
+drugs	O
+.	O
+
+Eight	O
+patients	O
+had	O
+cardiac	O
+manifestations	O
+that	O
+were	O
+life	O
+-	O
+threatening	O
+in	O
+five	O
+while	O
+taking	O
+psychotropic	O
+drugs	O
+,	O
+either	O
+phenothiazines	O
+or	O
+tricyclic	O
+antidepressants	O
+.	O
+
+Although	O
+most	O
+patients	O
+were	O
+receiving	O
+several	O
+drugs	O
+,	O
+Mellaril	O
+(	O
+thioridazine	O
+)	O
+appeared	O
+to	O
+be	O
+responsible	O
+for	O
+five	O
+cases	O
+of	O
+ventricular	B
+tachycardia	I
+,	O
+one	O
+of	O
+which	O
+was	O
+fatal	O
+in	O
+a	O
+35	O
+year	O
+old	O
+woman	O
+.	O
+
+Supraventricular	B
+tachycardia	I
+developed	O
+in	O
+one	O
+patient	O
+receiving	O
+Thorazine	O
+(	O
+chlorpromazine	O
+)	O
+.	O
+
+Aventyl	O
+(	O
+nortriptyline	O
+)	O
+and	O
+Elavil	O
+(	O
+amitriptyline	O
+)	O
+each	O
+produced	O
+left	B
+bundle	I
+branch	I
+block	I
+in	O
+a	O
+73	O
+year	O
+old	O
+woman	O
+.	O
+
+Electrocardiographic	O
+T	O
+and	O
+U	O
+wave	O
+abnormalities	O
+were	O
+present	O
+in	O
+most	O
+patients	O
+.	O
+
+The	O
+ventricular	B
+arrhythmias	I
+responded	O
+to	O
+intravenous	O
+administration	O
+of	O
+lidocaine	O
+and	O
+to	O
+direct	O
+current	O
+electric	O
+shock	O
+;	O
+ventricular	O
+pacing	O
+was	O
+required	O
+in	O
+some	O
+instances	O
+and	O
+intravenous	O
+administration	O
+of	O
+propranolol	O
+combined	O
+with	O
+ventricular	O
+pacing	O
+in	O
+one	O
+.	O
+
+The	O
+tachyarrhythmias	B
+generally	O
+subsided	O
+within	O
+48	O
+hours	O
+after	O
+administration	O
+of	O
+the	O
+drugs	O
+was	O
+stopped	O
+.	O
+
+Five	O
+of	O
+the	O
+eight	O
+patients	O
+were	O
+50	O
+years	O
+of	O
+age	O
+or	O
+younger	O
+;	O
+only	O
+one	O
+clearly	O
+had	O
+antecedent	O
+heart	B
+disease	I
+.	O
+
+Major	O
+cardiac	B
+arrhythmias	I
+are	O
+a	O
+potential	O
+hazard	O
+in	O
+patients	O
+without	O
+heart	B
+disease	I
+who	O
+are	O
+receiving	O
+customary	O
+therapeutic	O
+doses	O
+of	O
+psychotropic	O
+drugs	O
+.	O
+
+A	O
+prospective	O
+clinical	O
+trial	O
+is	O
+suggested	O
+to	O
+quantify	O
+the	O
+risk	O
+of	O
+cardiac	B
+complications	I
+to	O
+patients	O
+receiving	O
+phenothiazines	O
+or	O
+tricyclic	O
+antidepressant	O
+drugs	O
+.	O
+
+Sensitivity	O
+of	O
+erythroid	O
+progenitor	O
+colonies	O
+to	O
+erythropoietin	O
+in	O
+azidothymidine	O
+treated	O
+immunodeficient	B
+mice	O
+.	O
+
+The	O
+anaemia	B
+induced	O
+by	O
+3	O
+'	O
+-	O
+azido	O
+-	O
+3	O
+'	O
+dideoxythymidine	O
+(	O
+AZT	O
+)	O
+is	O
+poorly	O
+understood	O
+.	O
+
+We	O
+have	O
+used	O
+a	O
+murine	O
+model	O
+of	O
+AIDS	B
+,	O
+infection	B
+of	O
+female	O
+C57BL	O
+/	O
+6	O
+mice	O
+with	O
+LP	O
+-	O
+BM5	O
+murine	O
+leukaemia	B
+(	O
+MuLV	O
+)	O
+virus	O
+,	O
+to	O
+determine	O
+if	O
+AZT	O
+-	O
+induced	O
+anaemia	B
+is	O
+due	O
+,	O
+in	O
+part	O
+,	O
+to	O
+decreased	O
+responsiveness	O
+of	O
+erythropoietic	O
+precursors	O
+(	O
+BFU	O
+-	O
+e	O
+)	O
+to	O
+erythropoietin	O
+(	O
+EPO	O
+)	O
+.	O
+
+Mice	O
+in	O
+the	O
+early	O
+stage	O
+of	O
+LP	O
+-	O
+BM5	O
+MuLV	O
+disease	O
+were	O
+given	O
+AZT	O
+in	O
+their	O
+drinking	O
+water	O
+at	O
+1	O
+.	O
+0	O
+and	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+ml	O
+.	O
+
+AZT	O
+produced	O
+anaemia	B
+in	O
+both	O
+groups	O
+,	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+fashion	O
+.	O
+
+Despite	O
+the	O
+anaemia	B
+,	O
+the	O
+number	O
+of	O
+splenic	O
+and	O
+bone	O
+marrow	O
+BFU	O
+-	O
+e	O
+in	O
+AZT	O
+treated	O
+mice	O
+increased	O
+up	O
+to	O
+five	O
+-	O
+fold	O
+over	O
+levels	O
+observed	O
+in	O
+infected	O
+untreated	O
+animals	O
+after	O
+15	O
+d	O
+of	O
+treatment	O
+.	O
+
+Colony	O
+formation	O
+by	O
+splenic	O
+and	O
+bone	O
+marrow	O
+BFUe	O
+was	O
+stimulated	O
+at	O
+lower	O
+concentrations	O
+of	O
+EPO	O
+in	O
+mice	O
+receiving	O
+AZT	O
+for	O
+15	O
+d	O
+than	O
+for	O
+infected	O
+,	O
+untreated	O
+mice	O
+.	O
+
+By	O
+day	O
+30	O
+,	O
+sensitivity	O
+of	O
+both	O
+splenic	O
+and	O
+bone	O
+marrow	O
+BFU	O
+-	O
+e	O
+of	O
+treated	O
+animals	O
+returned	O
+to	O
+that	O
+observed	O
+from	O
+cells	O
+of	O
+infected	O
+untreated	O
+animals	O
+.	O
+
+The	O
+mean	O
+plasma	O
+levels	O
+of	O
+EPO	O
+observed	O
+in	O
+AZT	O
+treated	O
+mice	O
+were	O
+appropriate	O
+for	O
+the	O
+degree	O
+of	O
+anaemia	B
+observed	O
+when	O
+compared	O
+with	O
+phenylhydrazine	O
+(	O
+PHZ	O
+)	O
+treated	O
+mice	O
+.	O
+
+The	O
+numbers	O
+of	O
+BFU	O
+-	O
+e	O
+and	O
+the	O
+percentage	O
+of	O
+bone	O
+marrow	O
+erythroblasts	O
+observed	O
+were	O
+comparable	O
+in	O
+AZT	O
+and	O
+PHZ	O
+treated	O
+mice	O
+with	O
+similar	O
+degrees	O
+of	O
+anaemia	B
+.	O
+
+However	O
+,	O
+reticulocytosis	B
+was	O
+inappropriate	O
+for	O
+the	O
+degree	O
+of	O
+anaemia	B
+observed	O
+in	O
+AZT	O
+treated	O
+infected	O
+mice	O
+.	O
+
+AZT	O
+-	O
+induced	O
+peripheral	O
+anaemia	B
+in	O
+the	O
+face	O
+of	O
+increased	O
+numbers	O
+of	O
+BFU	O
+-	O
+e	O
+and	O
+increased	O
+levels	O
+of	O
+plasma	O
+EPO	O
+suggest	O
+a	O
+lesion	O
+in	O
+terminal	O
+differentiation	O
+.	O
+
+Sedation	O
+depth	O
+during	O
+spinal	O
+anesthesia	O
+and	O
+the	O
+development	O
+of	O
+postoperative	B
+delirium	I
+in	O
+elderly	O
+patients	O
+undergoing	O
+hip	B
+fracture	I
+repair	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+determine	O
+whether	O
+limiting	O
+intraoperative	O
+sedation	O
+depth	O
+during	O
+spinal	O
+anesthesia	O
+for	O
+hip	B
+fracture	I
+repair	O
+in	O
+elderly	O
+patients	O
+can	O
+decrease	O
+the	O
+prevalence	O
+of	O
+postoperative	B
+delirium	I
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+We	O
+performed	O
+a	O
+double	O
+-	O
+blind	O
+,	O
+randomized	O
+controlled	O
+trial	O
+at	O
+an	O
+academic	O
+medical	O
+center	O
+of	O
+elderly	O
+patients	O
+(	O
+>	O
+or	O
+=	O
+65	O
+years	O
+)	O
+without	O
+preoperative	O
+delirium	B
+or	O
+severe	O
+dementia	B
+who	O
+underwent	O
+hip	B
+fracture	I
+repair	O
+under	O
+spinal	O
+anesthesia	O
+with	O
+propofol	O
+sedation	O
+.	O
+
+Sedation	O
+depth	O
+was	O
+titrated	O
+using	O
+processed	O
+electroencephalography	O
+with	O
+the	O
+bispectral	O
+index	O
+(	O
+BIS	O
+)	O
+,	O
+and	O
+patients	O
+were	O
+randomized	O
+to	O
+receive	O
+either	O
+deep	O
+(	O
+BIS	O
+,	O
+approximately	O
+50	O
+)	O
+or	O
+light	O
+(	O
+BIS	O
+,	O
+>	O
+or	O
+=	O
+80	O
+)	O
+sedation	O
+.	O
+
+Postoperative	B
+delirium	I
+was	O
+assessed	O
+as	O
+defined	O
+by	O
+Diagnostic	O
+and	O
+Statistical	O
+Manual	O
+of	O
+Mental	B
+Disorders	I
+(	O
+Third	O
+Edition	O
+Revised	O
+)	O
+criteria	O
+using	O
+the	O
+Confusion	O
+Assessment	O
+Method	O
+beginning	O
+at	O
+any	O
+time	O
+from	O
+the	O
+second	O
+day	O
+after	O
+surgery	O
+.	O
+
+RESULTS	O
+:	O
+From	O
+April	O
+2	O
+,	O
+2005	O
+,	O
+through	O
+October	O
+30	O
+,	O
+2008	O
+,	O
+a	O
+total	O
+of	O
+114	O
+patients	O
+were	O
+randomized	O
+.	O
+
+The	O
+prevalence	O
+of	O
+postoperative	B
+delirium	I
+was	O
+significantly	O
+lower	O
+in	O
+the	O
+light	O
+sedation	O
+group	O
+(	O
+11	O
+/	O
+57	O
+[	O
+19	O
+%	O
+]	O
+vs	O
+23	O
+/	O
+57	O
+[	O
+40	O
+%	O
+]	O
+in	O
+the	O
+deep	O
+sedation	O
+group	O
+;	O
+P	O
+=	O
+.	O
+02	O
+)	O
+,	O
+indicating	O
+that	O
+1	O
+incident	O
+of	O
+delirium	B
+will	O
+be	O
+prevented	O
+for	O
+every	O
+4	O
+.	O
+7	O
+patients	O
+treated	O
+with	O
+light	O
+sedation	O
+.	O
+
+The	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+number	O
+of	O
+days	O
+of	O
+delirium	B
+during	O
+hospitalization	O
+was	O
+lower	O
+in	O
+the	O
+light	O
+sedation	O
+group	O
+than	O
+in	O
+the	O
+deep	O
+sedation	O
+group	O
+(	O
+0	O
+.	O
+5	O
++	O
+/	O
+-	O
+1	O
+.	O
+5	O
+days	O
+vs	O
+1	O
+.	O
+4	O
++	O
+/	O
+-	O
+4	O
+.	O
+0	O
+days	O
+;	O
+P	O
+=	O
+.	O
+01	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+use	O
+of	O
+light	O
+propofol	O
+sedation	O
+decreased	O
+the	O
+prevalence	O
+of	O
+postoperative	B
+delirium	I
+by	O
+50	O
+%	O
+compared	O
+with	O
+deep	O
+sedation	O
+.	O
+
+Limiting	O
+depth	O
+of	O
+sedation	O
+during	O
+spinal	O
+anesthesia	O
+is	O
+a	O
+simple	O
+,	O
+safe	O
+,	O
+and	O
+cost	O
+-	O
+effective	O
+intervention	O
+for	O
+preventing	O
+postoperative	B
+delirium	I
+in	O
+elderly	O
+patients	O
+that	O
+could	O
+be	O
+widely	O
+and	O
+readily	O
+adopted	O
+.	O
+
+The	O
+protective	O
+role	O
+of	O
+Nrf2	O
+in	O
+streptozotocin	O
+-	O
+induced	O
+diabetic	B
+nephropathy	I
+.	O
+
+OBJECTIVE	O
+:	O
+Diabetic	B
+nephropathy	I
+is	O
+one	O
+of	O
+the	O
+major	O
+causes	O
+of	O
+renal	B
+failure	I
+,	O
+which	O
+is	O
+accompanied	O
+by	O
+the	O
+production	O
+of	O
+reactive	O
+oxygen	O
+species	O
+(	O
+ROS	O
+)	O
+.	O
+
+Nrf2	O
+is	O
+the	O
+primary	O
+transcription	O
+factor	O
+that	O
+controls	O
+the	O
+antioxidant	O
+response	O
+essential	O
+for	O
+maintaining	O
+cellular	O
+redox	O
+homeostasis	O
+.	O
+
+Here	O
+,	O
+we	O
+report	O
+our	O
+findings	O
+demonstrating	O
+a	O
+protective	O
+role	O
+of	O
+Nrf2	O
+against	O
+diabetic	B
+nephropathy	I
+.	O
+
+RESEARCH	O
+DESIGN	O
+AND	O
+METHODS	O
+:	O
+We	O
+explore	O
+the	O
+protective	O
+role	O
+of	O
+Nrf2	O
+against	O
+diabetic	B
+nephropathy	I
+using	O
+human	O
+kidney	O
+biopsy	O
+tissues	O
+from	O
+diabetic	B
+nephropathy	I
+patients	O
+,	O
+a	O
+streptozotocin	O
+-	O
+induced	O
+diabetic	B
+nephropathy	I
+model	O
+in	O
+Nrf2	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+,	O
+and	O
+cultured	O
+human	O
+mesangial	O
+cells	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+glomeruli	O
+of	O
+human	O
+diabetic	B
+nephropathy	I
+patients	O
+were	O
+under	O
+oxidative	O
+stress	O
+and	O
+had	O
+elevated	O
+Nrf2	O
+levels	O
+.	O
+
+In	O
+the	O
+animal	O
+study	O
+,	O
+Nrf2	O
+was	O
+demonstrated	O
+to	O
+be	O
+crucial	O
+in	O
+ameliorating	O
+streptozotocin	O
+-	O
+induced	O
+renal	B
+damage	I
+.	O
+
+This	O
+is	O
+evident	O
+by	O
+Nrf2	O
+(	O
+-	O
+/	O
+-	O
+)	O
+mice	O
+having	O
+higher	O
+ROS	O
+production	O
+and	O
+suffering	O
+from	O
+greater	O
+oxidative	O
+DNA	O
+damage	O
+and	O
+renal	B
+injury	I
+compared	O
+with	O
+Nrf2	O
+(	O
++	O
+/	O
++	O
+)	O
+mice	O
+.	O
+
+Mechanistic	O
+studies	O
+in	O
+both	O
+in	O
+vivo	O
+and	O
+in	O
+vitro	O
+systems	O
+showed	O
+that	O
+the	O
+Nrf2	O
+-	O
+mediated	O
+protection	O
+against	O
+diabetic	B
+nephropathy	I
+is	O
+,	O
+at	O
+least	O
+,	O
+partially	O
+through	O
+inhibition	O
+of	O
+transforming	O
+growth	O
+factor	O
+-	O
+beta1	O
+(	O
+TGF	O
+-	O
+beta1	O
+)	O
+and	O
+reduction	O
+of	O
+extracellular	O
+matrix	O
+production	O
+.	O
+
+In	O
+human	O
+renal	O
+mesangial	O
+cells	O
+,	O
+high	O
+glucose	O
+induced	O
+ROS	O
+production	O
+and	O
+activated	O
+expression	O
+of	O
+Nrf2	O
+and	O
+its	O
+downstream	O
+genes	O
+.	O
+
+Furthermore	O
+,	O
+activation	O
+or	O
+overexpression	O
+of	O
+Nrf2	O
+inhibited	O
+the	O
+promoter	O
+activity	O
+of	O
+TGF	O
+-	O
+beta1	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+,	O
+whereas	O
+knockdown	O
+of	O
+Nrf2	O
+by	O
+siRNA	O
+enhanced	O
+TGF	O
+-	O
+beta1	O
+transcription	O
+and	O
+fibronectin	O
+production	O
+.	O
+
+CONCLUSIONS	O
+:	O
+This	O
+work	O
+clearly	O
+indicates	O
+a	O
+protective	O
+role	O
+of	O
+Nrf2	O
+in	O
+diabetic	B
+nephropathy	I
+,	O
+suggesting	O
+that	O
+dietary	O
+or	O
+therapeutic	O
+activation	O
+of	O
+Nrf2	O
+could	O
+be	O
+used	O
+as	O
+a	O
+strategy	O
+to	O
+prevent	O
+or	O
+slow	O
+down	O
+the	O
+progression	O
+of	O
+diabetic	B
+nephropathy	I
+.	O
+
+Metformin	O
+prevents	O
+experimental	O
+gentamicin	O
+-	O
+induced	O
+nephropathy	B
+by	O
+a	O
+mitochondria	O
+-	O
+dependent	O
+pathway	O
+.	O
+
+The	O
+antidiabetic	O
+drug	O
+metformin	O
+can	O
+diminish	O
+apoptosis	O
+induced	O
+by	O
+oxidative	O
+stress	O
+in	O
+endothelial	O
+cells	O
+and	O
+prevent	O
+vascular	B
+dysfunction	I
+even	O
+in	O
+nondiabetic	O
+patients	O
+.	O
+
+Here	O
+we	O
+tested	O
+whether	O
+it	O
+has	O
+a	O
+beneficial	O
+effect	O
+in	O
+a	O
+rat	O
+model	O
+of	O
+gentamicin	O
+toxicity	B
+.	O
+
+Mitochondrial	O
+analysis	O
+,	O
+respiration	O
+intensity	O
+,	O
+levels	O
+of	O
+reactive	O
+oxygen	O
+species	O
+,	O
+permeability	O
+transition	O
+,	O
+and	O
+cytochrome	O
+c	O
+release	O
+were	O
+assessed	O
+3	O
+and	O
+6	O
+days	O
+after	O
+gentamicin	O
+administration	O
+.	O
+
+Metformin	O
+treatment	O
+fully	O
+blocked	O
+gentamicin	O
+-	O
+mediated	O
+acute	B
+renal	I
+failure	I
+.	O
+
+This	O
+was	O
+accompanied	O
+by	O
+a	O
+lower	O
+activity	O
+of	O
+N	O
+-	O
+acetyl	O
+-	O
+beta	O
+-	O
+D	O
+-	O
+glucosaminidase	O
+,	O
+together	O
+with	O
+a	O
+decrease	O
+of	O
+lipid	O
+peroxidation	O
+and	O
+increase	O
+of	O
+antioxidant	O
+systems	O
+.	O
+
+Metformin	O
+also	O
+protected	O
+the	O
+kidney	O
+from	O
+histological	O
+damage	O
+6	O
+days	O
+after	O
+gentamicin	O
+administration	O
+.	O
+
+These	O
+in	O
+vivo	O
+markers	O
+of	O
+kidney	B
+dysfunction	I
+and	O
+their	O
+correction	O
+by	O
+metformin	O
+were	O
+complemented	O
+by	O
+in	O
+vitro	O
+studies	O
+of	O
+mitochondrial	O
+function	O
+.	O
+
+We	O
+found	O
+that	O
+gentamicin	O
+treatment	O
+depleted	O
+respiratory	O
+components	O
+(	O
+cytochrome	O
+c	O
+,	O
+NADH	O
+)	O
+,	O
+probably	O
+due	O
+to	O
+the	O
+opening	O
+of	O
+mitochondrial	O
+transition	O
+pores	O
+.	O
+
+These	O
+injuries	O
+,	O
+partly	O
+mediated	O
+by	O
+a	O
+rise	O
+in	O
+reactive	O
+oxygen	O
+species	O
+from	O
+the	O
+electron	O
+transfer	O
+chain	O
+,	O
+were	O
+significantly	O
+decreased	O
+by	O
+metformin	O
+.	O
+
+Thus	O
+,	O
+our	O
+study	O
+suggests	O
+that	O
+pleiotropic	O
+effects	O
+of	O
+metformin	O
+can	O
+lessen	O
+gentamicin	O
+nephrotoxicity	B
+and	O
+improve	O
+mitochondrial	O
+homeostasis	O
+.	O
+
+Risk	O
+of	O
+nephropathy	B
+after	O
+consumption	O
+of	O
+nonionic	O
+contrast	O
+media	O
+by	O
+children	O
+undergoing	O
+cardiac	O
+angiography	O
+:	O
+a	O
+prospective	O
+study	O
+.	O
+
+Despite	O
+increasing	O
+reports	O
+on	O
+nonionic	O
+contrast	O
+media	O
+-	O
+induced	O
+nephropathy	B
+(	O
+CIN	B
+)	O
+in	O
+hospitalized	O
+adult	O
+patients	O
+during	O
+cardiac	O
+procedures	O
+,	O
+the	O
+studies	O
+in	O
+pediatrics	O
+are	O
+limited	O
+,	O
+with	O
+even	O
+less	O
+focus	O
+on	O
+possible	O
+predisposing	O
+factors	O
+and	O
+preventive	O
+measures	O
+for	O
+patients	O
+undergoing	O
+cardiac	O
+angiography	O
+.	O
+
+This	O
+prospective	O
+study	O
+determined	O
+the	O
+incidence	O
+of	O
+CIN	B
+for	O
+two	O
+nonionic	O
+contrast	O
+media	O
+(	O
+CM	O
+)	O
+,	O
+iopromide	O
+and	O
+iohexol	O
+,	O
+among	O
+80	O
+patients	O
+younger	O
+than	O
+18	O
+years	O
+and	O
+compared	O
+the	O
+rates	O
+for	O
+this	O
+complication	O
+in	O
+relation	O
+to	O
+the	O
+type	O
+and	O
+dosage	O
+of	O
+CM	O
+and	O
+the	O
+presence	O
+of	O
+cyanosis	B
+.	O
+
+The	O
+80	O
+patients	O
+in	O
+the	O
+study	O
+consecutively	O
+received	O
+either	O
+iopromide	O
+(	O
+group	O
+A	O
+,	O
+n	O
+=	O
+40	O
+)	O
+or	O
+iohexol	O
+(	O
+group	O
+B	O
+,	O
+n	O
+=	O
+40	O
+)	O
+.	O
+
+Serum	O
+sodium	O
+(	O
+Na	O
+)	O
+,	O
+potassium	O
+(	O
+K	O
+)	O
+,	O
+and	O
+creatinine	O
+(	O
+Cr	O
+)	O
+were	O
+measured	O
+24	O
+h	O
+before	O
+angiography	O
+as	O
+baseline	O
+values	O
+,	O
+then	O
+measured	O
+again	O
+at	O
+12	O
+-	O
+,	O
+24	O
+-	O
+,	O
+and	O
+48	O
+-	O
+h	O
+intervals	O
+after	O
+CM	O
+use	O
+.	O
+
+Urine	O
+samples	O
+for	O
+Na	O
+and	O
+Cr	O
+also	O
+were	O
+checked	O
+at	O
+the	O
+same	O
+intervals	O
+.	O
+
+Risk	O
+of	O
+renal	B
+failure	I
+,	O
+Injury	B
+to	I
+the	I
+kidney	I
+,	O
+Failure	B
+of	I
+kidney	I
+function	I
+,	O
+Loss	B
+of	I
+kidney	I
+function	I
+,	O
+and	O
+End	O
+-	O
+stage	O
+renal	B
+damage	I
+(	O
+RIFLE	O
+criteria	O
+)	O
+were	O
+used	O
+to	O
+define	O
+CIN	B
+and	O
+its	O
+incidence	O
+in	O
+the	O
+study	O
+population	O
+.	O
+
+Accordingly	O
+,	O
+among	O
+the	O
+15	O
+CIN	B
+patients	O
+(	O
+18	O
+.	O
+75	O
+%	O
+)	O
+,	O
+7	O
+.	O
+5	O
+%	O
+of	O
+the	O
+patients	O
+in	O
+group	O
+A	O
+had	O
+increased	O
+risk	O
+and	O
+3	O
+.	O
+75	O
+%	O
+had	O
+renal	B
+injury	I
+,	O
+whereas	O
+5	O
+%	O
+of	O
+group	O
+B	O
+had	O
+increased	O
+risk	O
+and	O
+2	O
+.	O
+5	O
+%	O
+had	O
+renal	B
+injury	I
+.	O
+
+Whereas	O
+33	O
+.	O
+3	O
+%	O
+of	O
+the	O
+patients	O
+with	O
+CIN	B
+were	O
+among	O
+those	O
+who	O
+received	O
+the	O
+proper	O
+dosage	O
+of	O
+CM	O
+,	O
+the	O
+percentage	O
+increased	O
+to	O
+66	O
+.	O
+6	O
+%	O
+among	O
+those	O
+who	O
+received	O
+larger	O
+doses	O
+,	O
+with	O
+a	O
+significant	O
+difference	O
+in	O
+the	O
+incidence	O
+of	O
+CIN	B
+related	O
+to	O
+the	O
+different	O
+dosages	O
+of	O
+CM	O
+(	O
+p	O
+=	O
+0	O
+.	O
+014	O
+)	O
+.	O
+
+Among	O
+the	O
+15	O
+patients	O
+with	O
+CIN	B
+,	O
+6	O
+had	O
+cyanotic	O
+congenital	B
+heart	I
+diseases	I
+,	O
+but	O
+the	O
+incidence	O
+did	O
+not	O
+differ	O
+significantly	O
+from	O
+that	O
+for	O
+the	O
+noncyanotic	O
+patients	O
+(	O
+p	O
+=	O
+0	O
+.	O
+243	O
+)	O
+.	O
+
+Although	O
+clinically	O
+silent	O
+,	O
+CIN	B
+is	O
+not	O
+rare	O
+in	O
+pediatrics	O
+.	O
+
+The	O
+incidence	O
+depends	O
+on	O
+dosage	O
+but	O
+not	O
+on	O
+the	O
+type	O
+of	O
+consumed	O
+nonionic	O
+CM	O
+,	O
+nor	O
+on	O
+the	O
+presence	O
+of	O
+cyanosis	B
+,	O
+and	O
+although	O
+CIN	B
+usually	O
+is	O
+reversible	O
+,	O
+more	O
+concern	O
+is	O
+needed	O
+for	O
+the	O
+prevention	O
+of	O
+such	O
+a	O
+complication	O
+in	O
+children	O
+.	O
+
+Renal	O
+function	O
+and	O
+hemodynamics	O
+during	O
+prolonged	O
+isoflurane	O
+-	O
+induced	O
+hypotension	B
+in	O
+humans	O
+.	O
+
+The	O
+effect	O
+of	O
+isoflurane	O
+-	O
+induced	O
+hypotension	B
+on	O
+glomerular	O
+function	O
+and	O
+renal	O
+blood	O
+flow	O
+was	O
+investigated	O
+in	O
+20	O
+human	O
+subjects	O
+.	O
+
+Glomerular	O
+filtration	O
+rate	O
+(	O
+GFR	O
+)	O
+and	O
+effective	O
+renal	O
+plasma	O
+flow	O
+(	O
+ERPF	O
+)	O
+were	O
+measured	O
+by	O
+inulin	O
+and	O
+para	O
+-	O
+aminohippurate	O
+(	O
+PAH	O
+)	O
+clearance	O
+,	O
+respectively	O
+.	O
+
+Anesthesia	O
+was	O
+maintained	O
+with	O
+fentanyl	O
+,	O
+nitrous	O
+oxide	O
+,	O
+oxygen	O
+,	O
+and	O
+isoflurane	O
+.	O
+
+Hypotension	B
+was	O
+induced	O
+for	O
+236	O
+.	O
+9	O
++	O
+/	O
+-	O
+15	O
+.	O
+1	O
+min	O
+by	O
+increasing	O
+the	O
+isoflurane	O
+inspired	O
+concentration	O
+to	O
+maintain	O
+a	O
+mean	O
+arterial	O
+pressure	O
+of	O
+59	O
+.	O
+8	O
++	O
+/	O
+-	O
+0	O
+.	O
+4	O
+mmHg	O
+.	O
+
+GFR	O
+and	O
+ERPF	O
+decreased	O
+with	O
+the	O
+induction	O
+of	O
+anesthesia	O
+but	O
+not	O
+significantly	O
+more	O
+during	O
+hypotension	B
+.	O
+
+Postoperatively	O
+,	O
+ERPF	O
+returned	O
+to	O
+preoperative	O
+values	O
+,	O
+whereas	O
+GFR	O
+was	O
+higher	O
+than	O
+preoperative	O
+values	O
+.	O
+
+Renal	O
+vascular	O
+resistance	O
+increased	O
+during	O
+anesthesia	O
+but	O
+decreased	O
+when	O
+hypotension	B
+was	O
+induced	O
+,	O
+allowing	O
+the	O
+maintenance	O
+of	O
+renal	O
+blood	O
+flow	O
+.	O
+
+We	O
+conclude	O
+that	O
+renal	O
+compensatory	O
+mechanisms	O
+are	O
+preserved	O
+during	O
+isoflurane	O
+-	O
+induced	O
+hypotension	B
+and	O
+that	O
+renal	O
+function	O
+and	O
+hemodynamics	O
+quickly	O
+return	O
+to	O
+normal	O
+when	O
+normotension	O
+is	O
+resumed	O
+.	O
+
+Brainstem	B
+dysgenesis	I
+in	O
+an	O
+infant	O
+prenatally	O
+exposed	O
+to	O
+cocaine	O
+.	O
+
+Many	O
+authors	O
+described	O
+the	O
+effects	O
+on	O
+the	O
+fetus	O
+of	O
+maternal	O
+cocaine	B
+abuse	I
+during	O
+pregnancy	O
+.	O
+
+Vasoconstriction	O
+appears	O
+to	O
+be	O
+the	O
+common	O
+mechanism	O
+of	O
+action	O
+leading	O
+to	O
+a	O
+wide	O
+range	O
+of	O
+fetal	B
+anomalies	I
+.	O
+
+We	O
+report	O
+on	O
+an	O
+infant	O
+with	O
+multiple	B
+cranial	I
+-	I
+nerve	I
+involvement	I
+attributable	O
+to	O
+brainstem	B
+dysgenesis	I
+,	O
+born	O
+to	O
+a	O
+cocaine	B
+-	I
+addicted	I
+mother	O
+.	O
+
+A	O
+cross	O
+-	O
+sectional	O
+evaluation	O
+of	O
+the	O
+effect	O
+of	O
+risperidone	O
+and	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitors	O
+on	O
+bone	O
+mineral	O
+density	O
+in	O
+boys	O
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+effect	O
+of	O
+risperidone	O
+-	O
+induced	O
+hyperprolactinemia	B
+on	O
+trabecular	O
+bone	O
+mineral	O
+density	O
+(	O
+BMD	O
+)	O
+in	O
+children	O
+and	O
+adolescents	O
+.	O
+
+METHOD	O
+:	O
+Medically	O
+healthy	O
+7	O
+-	O
+to	O
+17	O
+-	O
+year	O
+-	O
+old	O
+males	O
+chronically	O
+treated	O
+,	O
+in	O
+a	O
+naturalistic	O
+setting	O
+,	O
+with	O
+risperidone	O
+were	O
+recruited	O
+for	O
+this	O
+cross	O
+-	O
+sectional	O
+study	O
+through	O
+child	O
+psychiatry	O
+outpatient	O
+clinics	O
+between	O
+November	O
+2005	O
+and	O
+June	O
+2007	O
+.	O
+
+Anthropometric	O
+measurements	O
+and	O
+laboratory	O
+testing	O
+were	O
+conducted	O
+.	O
+
+The	O
+clinical	O
+diagnoses	O
+were	O
+based	O
+on	O
+chart	O
+review	O
+,	O
+and	O
+developmental	O
+and	O
+treatment	O
+history	O
+was	O
+obtained	O
+from	O
+the	O
+medical	O
+record	O
+.	O
+
+Volumetric	O
+BMD	O
+of	O
+the	O
+ultradistal	O
+radius	O
+was	O
+measured	O
+using	O
+peripheral	O
+quantitative	O
+computed	O
+tomography	O
+,	O
+and	O
+areal	O
+BMD	O
+of	O
+the	O
+lumbar	O
+spine	O
+was	O
+estimated	O
+using	O
+dual	O
+-	O
+energy	O
+x	O
+-	O
+ray	O
+absorptiometry	O
+.	O
+
+RESULTS	O
+:	O
+Hyperprolactinemia	B
+was	O
+present	O
+in	O
+49	O
+%	O
+of	O
+83	O
+boys	O
+(	O
+n	O
+=	O
+41	O
+)	O
+treated	O
+with	O
+risperidone	O
+for	O
+a	O
+mean	O
+of	O
+2	O
+.	O
+9	O
+years	O
+.	O
+
+Serum	O
+testosterone	O
+concentration	O
+increased	O
+with	O
+pubertal	O
+status	O
+but	O
+was	O
+not	O
+affected	O
+by	O
+hyperprolactinemia	B
+.	O
+
+As	O
+expected	O
+,	O
+bone	O
+mineral	O
+content	O
+and	O
+BMD	O
+increased	O
+with	O
+sexual	O
+maturity	O
+.	O
+
+After	O
+adjusting	O
+for	O
+the	O
+stage	O
+of	O
+sexual	O
+development	O
+and	O
+height	O
+and	O
+BMI	O
+z	O
+scores	O
+,	O
+serum	O
+prolactin	O
+was	O
+negatively	O
+associated	O
+with	O
+trabecular	O
+volumetric	O
+BMD	O
+at	O
+the	O
+ultradistal	O
+radius	O
+(	O
+P	O
+<	O
+.	O
+03	O
+)	O
+.	O
+
+Controlling	O
+for	O
+relevant	O
+covariates	O
+,	O
+we	O
+also	O
+found	O
+treatment	O
+with	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitors	O
+(	O
+SSRIs	O
+)	O
+to	O
+be	O
+associated	O
+with	O
+lower	O
+trabecular	O
+BMD	O
+at	O
+the	O
+radius	O
+(	O
+P	O
+=	O
+.	O
+03	O
+)	O
+and	O
+BMD	O
+z	O
+score	O
+at	O
+the	O
+lumbar	O
+spine	O
+(	O
+P	O
+<	O
+.	O
+05	O
+)	O
+.	O
+
+These	O
+findings	O
+became	O
+more	O
+marked	O
+when	O
+the	O
+analysis	O
+was	O
+restricted	O
+to	O
+non	O
+-	O
+Hispanic	O
+white	O
+patients	O
+.	O
+
+Of	O
+13	O
+documented	O
+fractures	B
+,	O
+3	O
+occurred	O
+after	O
+risperidone	O
+and	O
+SSRIs	O
+were	O
+started	O
+,	O
+and	O
+none	O
+occurred	O
+in	O
+patients	O
+with	O
+hyperprolactinemia	B
+.	O
+
+CONCLUSIONS	O
+:	O
+This	O
+is	O
+the	O
+first	O
+study	O
+to	O
+link	O
+risperidone	O
+-	O
+induced	O
+hyperprolactinemia	B
+and	O
+SSRI	O
+treatment	O
+to	O
+lower	O
+BMD	O
+in	O
+children	O
+and	O
+adolescents	O
+.	O
+
+Future	O
+research	O
+should	O
+evaluate	O
+the	O
+longitudinal	O
+course	O
+of	O
+this	O
+adverse	O
+event	O
+to	O
+determine	O
+its	O
+temporal	O
+stability	O
+and	O
+whether	O
+a	O
+higher	O
+fracture	O
+rate	O
+ensues	O
+.	O
+
+Fear	O
+-	O
+potentiated	O
+startle	B
+,	O
+but	O
+not	O
+light	O
+-	O
+enhanced	O
+startle	B
+,	O
+is	O
+enhanced	O
+by	O
+anxiogenic	O
+drugs	O
+.	O
+
+RATIONALE	O
+AND	O
+OBJECTIVES	O
+:	O
+The	O
+light	O
+-	O
+enhanced	O
+startle	B
+paradigm	O
+(	O
+LES	O
+)	O
+is	O
+suggested	O
+to	O
+model	O
+anxiety	B
+,	O
+because	O
+of	O
+the	O
+non	O
+-	O
+specific	O
+cue	O
+and	O
+the	O
+long	O
+-	O
+term	O
+effect	O
+.	O
+
+In	O
+contrast	O
+,	O
+the	O
+fear	O
+-	O
+potentiated	O
+startle	B
+(	O
+FPS	O
+)	O
+is	O
+suggested	O
+to	O
+model	O
+conditioned	O
+fear	O
+.	O
+
+However	O
+,	O
+the	O
+pharmacological	O
+profiles	O
+of	O
+these	O
+two	O
+paradigms	O
+are	O
+very	O
+similar	O
+.	O
+
+The	O
+present	O
+study	O
+investigated	O
+the	O
+effects	O
+of	O
+putative	O
+anxiogenic	O
+drugs	O
+on	O
+LES	O
+and	O
+FPS	O
+and	O
+aimed	O
+at	O
+determining	O
+the	O
+sensitivity	O
+of	O
+LES	O
+for	O
+anxiogenic	O
+drugs	O
+and	O
+to	O
+potentially	O
+showing	O
+a	O
+pharmacological	O
+differentiation	O
+between	O
+these	O
+two	O
+paradigms	O
+.	O
+
+METHODS	O
+:	O
+Male	O
+Wistar	O
+rats	O
+received	O
+each	O
+dose	O
+of	O
+the	O
+alpha	O
+(	O
+2	O
+)	O
+-	O
+adrenoceptor	O
+antagonist	O
+yohimbine	O
+(	O
+0	O
+.	O
+25	O
+-	O
+1	O
+.	O
+0mg	O
+/	O
+kg	O
+)	O
+,	O
+the	O
+5	O
+-	O
+HT	O
+(	O
+2C	O
+)	O
+receptor	O
+agonist	O
+m	O
+-	O
+chlorophenylpiperazine	O
+(	O
+mCPP	O
+,	O
+0	O
+.	O
+5	O
+-	O
+2	O
+.	O
+0mg	O
+/	O
+kg	O
+)	O
+or	O
+the	O
+GABA	O
+(	O
+A	O
+)	O
+inverse	O
+receptor	O
+agonist	O
+pentylenetetrazole	O
+(	O
+PTZ	O
+,	O
+3	O
+-	O
+30mg	O
+/	O
+kg	O
+)	O
+and	O
+were	O
+subsequently	O
+tested	O
+in	O
+either	O
+LES	O
+or	O
+FPS	O
+.	O
+
+RESULTS	O
+:	O
+None	O
+of	O
+the	O
+drugs	O
+enhanced	O
+LES	O
+,	O
+whereas	O
+mCPP	O
+increased	O
+percentage	O
+FPS	O
+and	O
+yohimbine	O
+increased	O
+absolute	O
+FPS	O
+values	O
+.	O
+
+Furthermore	O
+,	O
+yohimbine	O
+increased	O
+baseline	O
+startle	B
+amplitude	O
+in	O
+the	O
+LES	O
+,	O
+while	O
+mCPP	O
+suppressed	O
+baseline	O
+startle	B
+in	O
+both	O
+the	O
+LES	O
+and	O
+FPS	O
+and	O
+PTZ	O
+suppressed	O
+baseline	O
+startle	B
+in	O
+the	O
+FPS	O
+.	O
+
+CONCLUSIONS	O
+:	O
+In	O
+contrast	O
+to	O
+findings	O
+in	O
+the	O
+FPS	O
+paradigm	O
+,	O
+none	O
+of	O
+the	O
+drugs	O
+were	O
+able	O
+to	O
+exacerbate	O
+the	O
+LES	O
+response	O
+.	O
+
+Thus	O
+,	O
+a	O
+clear	O
+pharmacological	O
+differentiation	O
+was	O
+found	O
+between	O
+LES	O
+and	O
+FPS	O
+.	O
+
+Rosaceiform	O
+dermatitis	B
+associated	O
+with	O
+topical	O
+tacrolimus	O
+treatment	O
+.	O
+
+We	O
+describe	O
+herein	O
+3	O
+patients	O
+who	O
+developed	O
+rosacea	B
+-	O
+like	O
+dermatitis	B
+eruptions	B
+while	O
+using	O
+0	O
+.	O
+03	O
+%	O
+or	O
+0	O
+.	O
+1	O
+%	O
+tacrolimus	O
+ointment	O
+for	O
+facial	B
+dermatitis	I
+.	O
+
+Skin	O
+biopsy	O
+specimens	O
+showed	O
+telangiectasia	B
+and	O
+noncaseating	O
+epithelioid	O
+granulomatous	O
+tissue	O
+formation	O
+in	O
+the	O
+papillary	O
+to	O
+mid	O
+dermis	O
+.	O
+
+Continuous	O
+topical	O
+use	O
+of	O
+immunomodulators	O
+such	O
+as	O
+tacrolimus	O
+or	O
+pimecrolimus	O
+should	O
+be	O
+regarded	O
+as	O
+a	O
+potential	O
+cause	O
+of	O
+rosaceiform	O
+dermatitis	B
+,	O
+although	O
+many	O
+cases	O
+have	O
+not	O
+been	O
+reported	O
+.	O
+
+Coenzyme	O
+Q10	O
+treatment	O
+ameliorates	O
+acute	O
+cisplatin	O
+nephrotoxicity	B
+in	O
+mice	O
+.	O
+
+The	O
+nephroprotective	O
+effect	O
+of	O
+coenzyme	O
+Q10	O
+was	O
+investigated	O
+in	O
+mice	O
+with	O
+acute	B
+renal	I
+injury	I
+induced	O
+by	O
+a	O
+single	O
+i	O
+.	O
+p	O
+.	O
+injection	O
+of	O
+cisplatin	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+Coenzyme	O
+Q10	O
+treatment	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+was	O
+applied	O
+for	O
+6	O
+consecutive	O
+days	O
+,	O
+starting	O
+1	O
+day	O
+before	O
+cisplatin	O
+administration	O
+.	O
+
+Coenzyme	O
+Q10	O
+significantly	O
+reduced	O
+blood	O
+urea	O
+nitrogen	O
+and	O
+serum	O
+creatinine	O
+levels	O
+which	O
+were	O
+increased	O
+by	O
+cisplatin	O
+.	O
+
+Coenzyme	O
+Q10	O
+significantly	O
+compensated	O
+deficits	O
+in	O
+the	O
+antioxidant	O
+defense	O
+mechanisms	O
+(	O
+reduced	O
+glutathione	O
+level	O
+and	O
+superoxide	O
+dismutase	O
+activity	O
+)	O
+,	O
+suppressed	O
+lipid	O
+peroxidation	O
+,	O
+decreased	O
+the	O
+elevations	O
+of	O
+tumor	B
+necrosis	B
+factor	O
+-	O
+alpha	O
+,	O
+nitric	O
+oxide	O
+and	O
+platinum	O
+ion	O
+concentration	O
+,	O
+and	O
+attenuated	O
+the	O
+reductions	O
+of	O
+selenium	O
+and	O
+zinc	O
+ions	O
+in	O
+renal	O
+tissue	O
+resulted	O
+from	O
+cisplatin	O
+administration	O
+.	O
+
+Also	O
+,	O
+histopathological	O
+renal	B
+tissue	I
+damage	I
+mediated	O
+by	O
+cisplatin	O
+was	O
+ameliorated	O
+by	O
+coenzyme	O
+Q10	O
+treatment	O
+.	O
+
+Immunohistochemical	O
+analysis	O
+revealed	O
+that	O
+coenzyme	O
+Q10	O
+significantly	O
+decreased	O
+the	O
+cisplatin	O
+-	O
+induced	O
+overexpression	O
+of	O
+inducible	O
+nitric	O
+oxide	O
+synthase	O
+,	O
+nuclear	O
+factor	O
+-	O
+kappaB	O
+,	O
+caspase	O
+-	O
+3	O
+and	O
+p53	O
+in	O
+renal	O
+tissue	O
+.	O
+
+It	O
+was	O
+concluded	O
+that	O
+coenzyme	O
+Q10	O
+represents	O
+a	O
+potential	O
+therapeutic	O
+option	O
+to	O
+protect	O
+against	O
+acute	O
+cisplatin	O
+nephrotoxicity	B
+commonly	O
+encountered	O
+in	O
+clinical	O
+practice	O
+.	O
+
+Reversible	O
+cholestasis	B
+with	O
+bile	B
+duct	I
+injury	I
+following	O
+azathioprine	O
+therapy	O
+.	O
+
+A	O
+case	O
+report	O
+.	O
+
+A	O
+67	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+,	O
+with	O
+primary	O
+polymyositis	B
+and	O
+without	O
+previous	O
+evidence	O
+of	O
+liver	B
+disease	I
+,	O
+developed	O
+clinical	O
+and	O
+biochemical	O
+features	O
+of	O
+severe	O
+cholestasis	B
+3	O
+months	O
+after	O
+initiation	O
+of	O
+azathioprine	O
+therapy	O
+.	O
+
+Liver	O
+biopsy	O
+showed	O
+cholestasis	B
+with	O
+both	O
+cytological	O
+and	O
+architectural	O
+alterations	O
+of	O
+interlobular	O
+bile	O
+ducts	O
+.	O
+
+Azathioprine	O
+withdrawal	O
+resulted	O
+after	O
+7	O
+weeks	O
+in	O
+the	O
+resolution	O
+of	O
+clinical	O
+and	O
+biochemical	O
+abnormalities	O
+.	O
+
+It	O
+is	O
+believed	O
+that	O
+this	O
+is	O
+the	O
+first	O
+reported	O
+case	O
+of	O
+reversible	O
+azathioprine	O
+-	O
+induced	O
+cholestasis	B
+associated	O
+with	O
+histological	O
+evidence	O
+of	O
+bile	B
+duct	I
+injury	I
+.	O
+
+Dopamine	O
+is	O
+not	O
+essential	O
+for	O
+the	O
+development	O
+of	O
+methamphetamine	O
+-	O
+induced	O
+neurotoxicity	B
+.	O
+
+It	O
+is	O
+widely	O
+believed	O
+that	O
+dopamine	O
+(	O
+DA	O
+)	O
+mediates	O
+methamphetamine	O
+(	O
+METH	O
+)	O
+-	O
+induced	O
+toxicity	B
+to	O
+brain	O
+dopaminergic	O
+neurons	O
+,	O
+because	O
+drugs	O
+that	O
+interfere	O
+with	O
+DA	O
+neurotransmission	O
+decrease	O
+toxicity	B
+,	O
+whereas	O
+drugs	O
+that	O
+increase	O
+DA	O
+neurotransmission	O
+enhance	O
+toxicity	B
+.	O
+
+However	O
+,	O
+temperature	O
+effects	O
+of	O
+drugs	O
+that	O
+have	O
+been	O
+used	O
+to	O
+manipulate	O
+brain	O
+DA	O
+neurotransmission	O
+confound	O
+interpretation	O
+of	O
+the	O
+data	O
+.	O
+
+Here	O
+we	O
+show	O
+that	O
+the	O
+recently	O
+reported	O
+ability	O
+of	O
+L	O
+-	O
+dihydroxyphenylalanine	O
+to	O
+reverse	O
+the	O
+protective	O
+effect	O
+of	O
+alpha	O
+-	O
+methyl	O
+-	O
+para	O
+-	O
+tyrosine	O
+on	O
+METH	O
+-	O
+induced	O
+DA	O
+neurotoxicity	B
+is	O
+also	O
+confounded	O
+by	O
+drug	O
+effects	O
+on	O
+body	O
+temperature	O
+.	O
+
+Further	O
+,	O
+we	O
+show	O
+that	O
+mice	O
+genetically	O
+engineered	O
+to	O
+be	O
+deficient	O
+in	O
+brain	O
+DA	O
+develop	O
+METH	O
+neurotoxicity	B
+,	O
+as	O
+long	O
+as	O
+the	O
+thermic	O
+effects	O
+of	O
+METH	O
+are	O
+preserved	O
+.	O
+
+In	O
+addition	O
+,	O
+we	O
+demonstrate	O
+that	O
+mice	O
+genetically	O
+engineered	O
+to	O
+have	O
+unilateral	O
+brain	O
+DA	O
+deficits	O
+develop	O
+METH	O
+-	O
+induced	O
+dopaminergic	B
+deficits	I
+that	O
+are	O
+of	O
+comparable	O
+magnitude	O
+on	O
+both	O
+sides	O
+of	O
+the	O
+brain	O
+.	O
+
+Taken	O
+together	O
+,	O
+these	O
+findings	O
+demonstrate	O
+that	O
+DA	O
+is	O
+not	O
+essential	O
+for	O
+the	O
+development	O
+of	O
+METH	O
+-	O
+induced	O
+dopaminergic	O
+neurotoxicity	B
+and	O
+suggest	O
+that	O
+mechanisms	O
+independent	O
+of	O
+DA	O
+warrant	O
+more	O
+intense	O
+investigation	O
+.	O
+
+Swallowing	O
+-	O
+induced	O
+atrial	B
+tachyarrhythmia	I
+triggered	O
+by	O
+salbutamol	O
+:	O
+case	O
+report	O
+and	O
+review	O
+of	O
+the	O
+literature	O
+.	O
+
+CASE	O
+:	O
+A	O
+49	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+experienced	O
+chest	O
+discomfort	O
+while	O
+swallowing	O
+.	O
+
+On	O
+electrocardiogram	O
+,	O
+episodes	O
+of	O
+atrial	B
+tachyarrhythmia	I
+were	O
+recorded	O
+immediately	O
+after	O
+swallowing	O
+;	O
+24	O
+-	O
+hour	O
+Holter	O
+monitoring	O
+recorded	O
+several	O
+events	O
+.	O
+
+The	O
+arrhythmia	B
+resolved	O
+after	O
+therapy	O
+with	O
+atenolol	O
+,	O
+but	O
+recurred	O
+a	O
+year	O
+later	O
+.	O
+
+The	O
+patient	O
+noticed	O
+that	O
+before	O
+these	O
+episodes	O
+he	O
+had	O
+been	O
+using	O
+an	O
+inhalator	O
+of	O
+salbutamol	O
+.	O
+
+After	O
+stopping	O
+the	O
+beta	O
+-	O
+agonist	O
+,	O
+and	O
+after	O
+a	O
+week	O
+with	O
+the	O
+atenolol	O
+,	O
+the	O
+arrhythmia	B
+disappeared	O
+.	O
+
+DISCUSSION	O
+:	O
+Swallowing	O
+-	O
+induced	O
+atrial	B
+tachyarrhythmia	I
+(	O
+SIAT	B
+)	O
+is	O
+a	O
+rare	O
+phenomenon	O
+.	O
+
+Fewer	O
+than	O
+50	O
+cases	O
+of	O
+SIAT	B
+have	O
+been	O
+described	O
+in	O
+the	O
+literature	O
+.	O
+
+This	O
+article	O
+summarizes	O
+all	O
+the	O
+cases	O
+published	O
+,	O
+creating	O
+a	O
+comprehensive	O
+review	O
+of	O
+the	O
+current	O
+knowledge	O
+and	O
+approach	O
+to	O
+SIAT	B
+.	O
+
+It	O
+discusses	O
+demographics	O
+,	O
+clinical	O
+characteristics	O
+and	O
+types	O
+of	O
+arrhythmia	B
+,	O
+postulated	O
+mechanisms	O
+of	O
+SIAT	B
+,	O
+and	O
+different	O
+treatment	O
+possibilities	O
+such	O
+as	O
+medications	O
+,	O
+surgery	O
+,	O
+and	O
+radiofrequency	O
+catheter	O
+ablation	O
+(	O
+RFCA	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+Salbutamol	O
+is	O
+presented	O
+here	O
+as	O
+a	O
+possible	O
+trigger	O
+for	O
+SIAT	B
+.	O
+
+Although	O
+it	O
+is	O
+difficult	O
+to	O
+define	O
+causality	O
+in	O
+a	O
+case	O
+report	O
+,	O
+it	O
+is	O
+logical	O
+to	O
+think	O
+that	O
+a	O
+beta	O
+-	O
+agonist	O
+like	O
+salbutamol	O
+(	O
+known	O
+to	O
+induce	O
+tachycardia	B
+)	O
+may	O
+be	O
+the	O
+trigger	O
+of	O
+adrenergic	O
+reflexes	O
+originating	O
+in	O
+the	O
+esophagus	O
+while	O
+swallowing	O
+and	O
+that	O
+a	O
+beta	O
+-	O
+blocker	O
+such	O
+as	O
+atenolol	O
+(	O
+that	O
+blocks	O
+the	O
+adrenergic	O
+activity	O
+)	O
+may	O
+relieve	O
+it	O
+.	O
+
+The	O
+ability	O
+of	O
+insulin	O
+treatment	O
+to	O
+reverse	O
+or	O
+prevent	O
+the	O
+changes	O
+in	O
+urinary	O
+bladder	O
+function	O
+caused	O
+by	O
+streptozotocin	O
+-	O
+induced	O
+diabetes	B
+mellitus	I
+.	O
+
+1	O
+.	O
+
+The	O
+effects	O
+of	O
+insulin	O
+treatment	O
+on	O
+in	O
+vivo	O
+and	O
+in	O
+vitro	O
+urinary	O
+bladder	O
+function	O
+in	O
+streptozotocin	O
+-	O
+diabetic	B
+rats	O
+were	O
+investigated	O
+.	O
+
+2	O
+.	O
+
+Diabetes	B
+of	O
+2	O
+months	O
+duration	O
+resulted	O
+in	O
+decreases	O
+in	O
+body	O
+weight	O
+and	O
+increases	O
+in	O
+fluid	O
+consumption	O
+,	O
+urine	O
+volume	O
+,	O
+frequency	O
+of	O
+micturition	O
+,	O
+and	O
+average	O
+volume	O
+per	O
+micturition	O
+;	O
+effects	O
+which	O
+were	O
+prevented	O
+by	O
+insulin	O
+treatment	O
+.	O
+
+3	O
+.	O
+
+Insulin	O
+treatment	O
+also	O
+prevented	O
+the	O
+increases	O
+in	O
+contractile	O
+responses	O
+of	O
+bladder	O
+body	O
+strips	O
+from	O
+diabetic	B
+rats	O
+to	O
+nerve	O
+stimulation	O
+,	O
+ATP	O
+,	O
+and	O
+bethanechol	O
+.	O
+
+4	O
+.	O
+
+Diabetes	B
+of	O
+4	O
+months	O
+duration	O
+also	O
+resulted	O
+in	O
+decreases	O
+in	O
+body	O
+weight	O
+,	O
+and	O
+increases	O
+in	O
+fluid	O
+consumption	O
+,	O
+urine	O
+volume	O
+,	O
+frequency	O
+of	O
+micturition	O
+,	O
+and	O
+average	O
+volume	O
+per	O
+micturition	O
+,	O
+effects	O
+which	O
+were	O
+reversed	O
+by	O
+insulin	O
+treatment	O
+for	O
+the	O
+final	O
+2	O
+months	O
+of	O
+the	O
+study	O
+.	O
+
+5	O
+.	O
+
+Insulin	O
+treatment	O
+reversed	O
+the	O
+increases	O
+in	O
+contractile	O
+responses	O
+of	O
+bladder	O
+body	O
+strips	O
+from	O
+diabetic	B
+rats	O
+to	O
+nerve	O
+stimulation	O
+,	O
+ATP	O
+,	O
+and	O
+bethanechol	O
+.	O
+
+6	O
+.	O
+
+The	O
+data	O
+indicate	O
+that	O
+the	O
+effects	O
+of	O
+streptozotocin	O
+-	O
+induced	O
+diabetes	B
+on	O
+urinary	O
+bladder	O
+function	O
+are	O
+both	O
+prevented	O
+and	O
+reversed	O
+by	O
+insulin	O
+treatment	O
+.	O
+
+Glutamatergic	O
+neurotransmission	O
+mediated	O
+by	O
+NMDA	O
+receptors	O
+in	O
+the	O
+inferior	O
+colliculus	O
+can	O
+modulate	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+.	O
+
+The	O
+inferior	O
+colliculus	O
+(	O
+IC	O
+)	O
+is	O
+primarily	O
+involved	O
+in	O
+the	O
+processing	O
+of	O
+auditory	O
+information	O
+,	O
+but	O
+it	O
+is	O
+distinguished	O
+from	O
+other	O
+auditory	O
+nuclei	O
+in	O
+the	O
+brainstem	O
+by	O
+its	O
+connections	O
+with	O
+structures	O
+of	O
+the	O
+motor	O
+system	O
+.	O
+
+Functional	O
+evidence	O
+relating	O
+the	O
+IC	O
+to	O
+motor	O
+behavior	O
+derives	O
+from	O
+experiments	O
+showing	O
+that	O
+activation	O
+of	O
+the	O
+IC	O
+by	O
+electrical	O
+stimulation	O
+or	O
+excitatory	O
+amino	O
+acid	O
+microinjection	O
+causes	O
+freezing	O
+,	O
+escape	O
+-	O
+like	O
+behavior	O
+,	O
+and	O
+immobility	O
+.	O
+
+However	O
+,	O
+the	O
+nature	O
+of	O
+this	O
+immobility	O
+is	O
+still	O
+unclear	O
+.	O
+
+The	O
+present	O
+study	O
+examined	O
+the	O
+influence	O
+of	O
+excitatory	O
+amino	O
+acid	O
+-	O
+mediated	O
+mechanisms	O
+in	O
+the	O
+IC	O
+on	O
+the	O
+catalepsy	B
+induced	O
+by	O
+the	O
+dopamine	O
+receptor	O
+blocker	O
+haloperidol	O
+administered	O
+systemically	O
+(	O
+1	O
+or	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+in	O
+rats	O
+.	O
+
+Haloperidol	O
+-	O
+induced	O
+catalepsy	B
+was	O
+challenged	O
+with	O
+prior	O
+intracollicular	O
+microinjections	O
+of	O
+glutamate	O
+NMDA	O
+receptor	O
+antagonists	O
+,	O
+MK	O
+-	O
+801	O
+(	O
+15	O
+or	O
+30	O
+mmol	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+)	O
+and	O
+AP7	O
+(	O
+10	O
+or	O
+20	O
+nmol	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+)	O
+,	O
+or	O
+of	O
+the	O
+NMDA	O
+receptor	O
+agonist	O
+N	O
+-	O
+methyl	O
+-	O
+d	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+,	O
+20	O
+or	O
+30	O
+nmol	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+)	O
+.	O
+
+The	O
+results	O
+showed	O
+that	O
+intracollicular	O
+microinjection	O
+of	O
+MK	O
+-	O
+801	O
+and	O
+AP7	O
+previous	O
+to	O
+systemic	O
+injections	O
+of	O
+haloperidol	O
+significantly	O
+attenuated	O
+the	O
+catalepsy	B
+,	O
+as	O
+indicated	O
+by	O
+a	O
+reduced	O
+latency	O
+to	O
+step	O
+down	O
+from	O
+a	O
+horizontal	O
+bar	O
+.	O
+
+Accordingly	O
+,	O
+intracollicular	O
+microinjection	O
+of	O
+NMDA	O
+increased	O
+the	O
+latency	O
+to	O
+step	O
+down	O
+the	O
+bar	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+glutamate	O
+-	O
+mediated	O
+mechanisms	O
+in	O
+the	O
+neural	O
+circuits	O
+at	O
+the	O
+IC	O
+level	O
+influence	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+and	O
+participate	O
+in	O
+the	O
+regulation	O
+of	O
+motor	O
+activity	O
+.	O
+
+Severe	O
+congestive	B
+heart	I
+failure	I
+patient	O
+on	O
+amiodarone	O
+presenting	O
+with	O
+myxedemic	B
+coma	I
+:	O
+a	O
+case	O
+report	O
+.	O
+
+This	O
+is	O
+a	O
+case	O
+report	O
+of	O
+myxedema	B
+coma	I
+secondary	O
+to	O
+amiodarone	O
+-	O
+induced	O
+hypothyroidism	B
+in	O
+a	O
+patient	O
+with	O
+severe	O
+congestive	B
+heart	I
+failure	I
+(	O
+CHF	B
+)	O
+.	O
+
+To	O
+our	O
+knowledge	O
+and	O
+after	O
+reviewing	O
+the	O
+literature	O
+there	O
+is	O
+one	O
+case	O
+report	O
+of	O
+myxedema	B
+coma	I
+during	O
+long	O
+term	O
+amiodarone	O
+therapy	O
+.	O
+
+Myxedema	B
+coma	I
+is	O
+a	O
+life	O
+threatening	O
+condition	O
+that	O
+carries	O
+a	O
+mortality	O
+reaching	O
+as	O
+high	O
+as	O
+20	O
+%	O
+with	O
+treatment	O
+.	O
+
+The	O
+condition	O
+is	O
+treated	O
+with	O
+intravenous	O
+thyroxine	O
+(	O
+T4	O
+)	O
+or	O
+intravenous	O
+tri	O
+-	O
+iodo	O
+-	O
+thyronine	O
+(	O
+T3	O
+)	O
+.	O
+
+Patients	O
+with	O
+CHF	B
+on	O
+amiodarone	O
+may	O
+suffer	O
+serious	O
+morbidity	O
+and	O
+mortality	O
+from	O
+hypothyroidism	B
+,	O
+and	O
+thus	O
+may	O
+deserve	O
+closer	O
+follow	O
+up	O
+for	O
+thyroid	O
+stimulating	O
+hormone	O
+(	O
+TSH	O
+)	O
+levels	O
+.	O
+
+This	O
+case	O
+report	O
+carries	O
+an	O
+important	O
+clinical	O
+application	O
+given	O
+the	O
+frequent	O
+usage	O
+of	O
+amiodarone	O
+among	O
+CHF	B
+patients	O
+.	O
+
+The	O
+myriad	O
+clinical	O
+presentation	O
+of	O
+myxedema	B
+coma	I
+and	O
+its	O
+serious	O
+morbidity	O
+and	O
+mortality	O
+stresses	O
+the	O
+need	O
+to	O
+suspect	O
+this	O
+clinical	O
+syndrome	O
+among	O
+CHF	B
+patients	O
+presenting	O
+with	O
+hypotension	B
+,	O
+weakness	B
+or	O
+other	O
+unexplained	O
+symptoms	O
+.	O
+
+Effects	O
+of	O
+active	O
+constituents	O
+of	O
+Crocus	O
+sativus	O
+L	O
+.	O
+,	O
+crocin	O
+on	O
+streptozocin	O
+-	O
+induced	O
+model	O
+of	O
+sporadic	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+in	O
+male	O
+rats	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+involvement	O
+of	O
+water	O
+-	O
+soluble	O
+carotenoids	O
+,	O
+crocins	O
+,	O
+as	O
+the	O
+main	O
+and	O
+active	O
+components	O
+of	O
+Crocus	O
+sativus	O
+L	O
+.	O
+extract	O
+in	O
+learning	O
+and	O
+memory	O
+processes	O
+has	O
+been	O
+proposed	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+the	O
+effect	O
+of	O
+crocins	O
+on	O
+sporadic	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+induced	O
+by	O
+intracerebroventricular	O
+(	O
+icv	O
+)	O
+streptozocin	O
+(	O
+STZ	O
+)	O
+in	O
+male	O
+rats	O
+was	O
+investigated	O
+.	O
+
+METHODS	O
+:	O
+Male	O
+adult	O
+Wistar	O
+rats	O
+(	O
+n	O
+=	O
+90	O
+and	O
+260	O
+-	O
+290	O
+g	O
+)	O
+were	O
+divided	O
+into	O
+1	O
+,	O
+control	O
+;	O
+2	O
+and	O
+3	O
+,	O
+crocins	O
+(	O
+15	O
+and	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+;	O
+4	O
+,	O
+STZ	O
+;	O
+5	O
+and	O
+6	O
+,	O
+STZ	O
++	O
+crocins	O
+(	O
+15	O
+and	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+groups	O
+.	O
+
+In	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+groups	O
+,	O
+rats	O
+were	O
+injected	O
+with	O
+STZ	O
+-	O
+icv	O
+bilaterally	O
+(	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+in	O
+first	O
+day	O
+and	O
+3	O
+days	O
+later	O
+,	O
+a	O
+similar	O
+STZ	O
+-	O
+icv	O
+application	O
+was	O
+repeated	O
+.	O
+
+In	O
+STZ	O
++	O
+crocin	O
+animal	O
+groups	O
+,	O
+crocin	O
+was	O
+applied	O
+in	O
+doses	O
+of	O
+15	O
+and	O
+30	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+,	O
+one	O
+day	O
+pre	O
+-	O
+surgery	O
+and	O
+continued	O
+for	O
+three	O
+weeks	O
+.	O
+
+Prescription	O
+of	O
+crocin	O
+in	O
+each	O
+dose	O
+was	O
+repeated	O
+once	O
+for	O
+two	O
+days	O
+.	O
+
+However	O
+,	O
+the	O
+learning	O
+and	O
+memory	O
+performance	O
+was	O
+assessed	O
+using	O
+passive	O
+avoidance	O
+paradigm	O
+,	O
+and	O
+for	O
+spatial	O
+cognition	O
+evaluation	O
+,	O
+Y	O
+-	O
+maze	O
+task	O
+was	O
+used	O
+.	O
+
+RESULTS	O
+:	O
+It	O
+was	O
+found	O
+out	O
+that	O
+crocin	O
+(	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+-	O
+treated	O
+STZ	O
+-	O
+injected	O
+rats	O
+show	O
+higher	O
+correct	O
+choices	O
+and	O
+lower	O
+errors	O
+in	O
+Y	O
+-	O
+maze	O
+than	O
+vehicle	O
+-	O
+treated	O
+STZ	O
+-	O
+injected	O
+rats	O
+.	O
+
+In	O
+addition	O
+,	O
+crocin	O
+in	O
+the	O
+mentioned	O
+dose	O
+could	O
+significantly	O
+attenuated	O
+learning	B
+and	I
+memory	I
+impairment	I
+in	O
+treated	O
+STZ	O
+-	O
+injected	O
+group	O
+in	O
+passive	O
+avoidance	O
+test	O
+.	O
+
+CONCLUSION	O
+:	O
+Therefore	O
+,	O
+these	O
+results	O
+demonstrate	O
+the	O
+effectiveness	O
+of	O
+crocin	O
+(	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+in	O
+antagonizing	O
+the	O
+cognitive	B
+deficits	I
+caused	O
+by	O
+STZ	O
+-	O
+icv	O
+in	O
+rats	O
+and	O
+its	O
+potential	O
+in	O
+the	O
+treatment	O
+of	O
+neurodegenerative	B
+diseases	I
+such	O
+as	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+.	O
+
+Serotonin	O
+6	O
+receptor	O
+gene	O
+is	O
+associated	O
+with	O
+methamphetamine	O
+-	O
+induced	O
+psychosis	B
+in	O
+a	O
+Japanese	O
+population	O
+.	O
+
+BACKGROUND	O
+:	O
+Altered	O
+serotonergic	O
+neural	O
+transmission	O
+is	O
+hypothesized	O
+to	O
+be	O
+a	O
+susceptibility	O
+factor	O
+for	O
+psychotic	B
+disorders	I
+such	O
+as	O
+schizophrenia	B
+.	O
+
+The	O
+serotonin	O
+6	O
+(	O
+5	O
+-	O
+HT6	O
+)	O
+receptor	O
+is	O
+therapeutically	O
+targeted	O
+by	O
+several	O
+second	O
+generation	O
+antipsychotics	O
+,	O
+such	O
+as	O
+clozapine	O
+and	O
+olanzapine	O
+,	O
+and	O
+d	O
+-	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B
+in	O
+rats	O
+is	O
+corrected	O
+with	O
+the	O
+use	O
+of	O
+a	O
+selective	O
+5	O
+-	O
+HT6	O
+receptor	O
+antagonist	O
+.	O
+
+In	O
+addition	O
+,	O
+the	O
+disrupted	O
+prepulse	O
+inhibition	O
+induced	O
+by	O
+d	O
+-	O
+amphetamine	O
+or	O
+phencyclidine	O
+was	O
+restored	O
+by	O
+5	O
+-	O
+HT6	O
+receptor	O
+antagonist	O
+in	O
+an	O
+animal	O
+study	O
+using	O
+rats	O
+.	O
+
+These	O
+animal	O
+models	O
+were	O
+considered	O
+to	O
+reflect	O
+the	O
+positive	O
+symptoms	O
+of	O
+schizophrenia	B
+,	O
+and	O
+the	O
+above	O
+evidence	O
+suggests	O
+that	O
+altered	O
+5	O
+-	O
+HT6	O
+receptors	O
+are	O
+involved	O
+in	O
+the	O
+pathophysiology	O
+of	O
+psychotic	B
+disorders	I
+.	O
+
+The	O
+symptoms	O
+of	O
+methamphetamine	O
+(	O
+METH	O
+)	O
+-	O
+induced	O
+psychosis	B
+are	O
+similar	O
+to	O
+those	O
+of	O
+paranoid	B
+type	I
+schizophrenia	I
+.	O
+
+Therefore	O
+,	O
+we	O
+conducted	O
+an	O
+analysis	O
+of	O
+the	O
+association	O
+of	O
+the	O
+5	O
+-	O
+HT6	O
+gene	O
+(	O
+HTR6	O
+)	O
+with	O
+METH	O
+-	O
+induced	O
+psychosis	B
+.	O
+
+METHOD	O
+:	O
+Using	O
+five	O
+tagging	O
+SNPs	O
+(	O
+rs6693503	O
+,	O
+rs1805054	O
+,	O
+rs4912138	O
+,	O
+rs3790757	O
+and	O
+rs9659997	O
+)	O
+,	O
+we	O
+conducted	O
+a	O
+genetic	O
+association	O
+analysis	O
+of	O
+case	O
+-	O
+control	O
+samples	O
+(	O
+197	O
+METH	O
+-	O
+induced	O
+psychosis	B
+patients	O
+and	O
+337	O
+controls	O
+)	O
+in	O
+the	O
+Japanese	O
+population	O
+.	O
+
+The	O
+age	O
+and	O
+sex	O
+of	O
+the	O
+control	O
+subjects	O
+did	O
+not	O
+differ	O
+from	O
+those	O
+of	O
+the	O
+methamphetamine	O
+dependence	O
+patients	O
+.	O
+
+RESULTS	O
+:	O
+rs6693503	O
+was	O
+associated	O
+with	O
+METH	O
+-	O
+induced	O
+psychosis	B
+patients	O
+in	O
+the	O
+allele	O
+/	O
+genotype	O
+-	O
+wise	O
+analysis	O
+.	O
+
+Moreover	O
+,	O
+this	O
+association	O
+remained	O
+significant	O
+after	O
+Bonferroni	O
+correction	O
+.	O
+
+In	O
+the	O
+haplotype	O
+-	O
+wise	O
+analysis	O
+,	O
+we	O
+detected	O
+an	O
+association	O
+between	O
+two	O
+markers	O
+(	O
+rs6693503	O
+and	O
+rs1805054	O
+)	O
+and	O
+three	O
+markers	O
+(	O
+rs6693503	O
+,	O
+rs1805054	O
+and	O
+rs4912138	O
+)	O
+in	O
+HTR6	O
+and	O
+METH	O
+-	O
+induced	O
+psychosis	B
+patients	O
+,	O
+respectively	O
+.	O
+
+CONCLUSION	O
+:	O
+HTR6	O
+may	O
+play	O
+an	O
+important	O
+role	O
+in	O
+the	O
+pathophysiology	O
+of	O
+METH	O
+-	O
+induced	O
+psychosis	B
+in	O
+the	O
+Japanese	O
+population	O
+.	O
+
+Neural	O
+correlates	O
+of	O
+S	O
+-	O
+ketamine	O
+induced	O
+psychosis	B
+during	O
+overt	O
+continuous	O
+verbal	O
+fluency	O
+.	O
+
+The	O
+glutamatergic	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+receptor	O
+has	O
+been	O
+implicated	O
+in	O
+the	O
+pathophysiology	O
+of	O
+schizophrenia	B
+.	O
+
+Administered	O
+to	O
+healthy	O
+volunteers	O
+,	O
+a	O
+subanesthetic	O
+dose	O
+of	O
+the	O
+non	O
+-	O
+competitive	O
+NMDA	O
+receptor	O
+antagonist	O
+ketamine	O
+leads	O
+to	O
+psychopathological	O
+symptoms	O
+similar	O
+to	O
+those	O
+observed	O
+in	O
+schizophrenia	B
+.	O
+
+In	O
+patients	O
+with	O
+schizophrenia	B
+,	O
+ketamine	O
+exacerbates	O
+the	O
+core	O
+symptoms	O
+of	O
+illness	O
+,	O
+supporting	O
+the	O
+hypothesis	O
+of	O
+a	O
+glutamatergic	B
+dysfunction	I
+.	O
+
+In	O
+a	O
+counterbalanced	O
+,	O
+placebo	O
+-	O
+controlled	O
+,	O
+double	O
+-	O
+blind	O
+study	O
+design	O
+,	O
+healthy	O
+subjects	O
+were	O
+administered	O
+a	O
+continuous	O
+subanesthetic	O
+S	O
+-	O
+ketamine	O
+infusion	O
+while	O
+differences	O
+in	O
+BOLD	O
+responses	O
+measured	O
+with	O
+fMRI	O
+were	O
+detected	O
+.	O
+
+During	O
+the	O
+scanning	O
+period	O
+,	O
+subjects	O
+performed	O
+continuous	O
+overt	O
+verbal	O
+fluency	O
+tasks	O
+(	O
+phonological	O
+,	O
+lexical	O
+and	O
+semantic	O
+)	O
+.	O
+
+Ketamine	O
+-	O
+induced	O
+psychopathological	O
+symptoms	O
+were	O
+assessed	O
+with	O
+the	O
+Positive	O
+and	O
+Negative	O
+Syndrome	O
+Scale	O
+(	O
+PANSS	O
+)	O
+.	O
+
+Ketamine	O
+elicited	O
+psychosis	B
+like	O
+psychopathology	O
+.	O
+
+Post	O
+-	O
+hoc	O
+t	O
+-	O
+tests	O
+revealed	O
+significant	O
+differences	O
+between	O
+placebo	O
+and	O
+ketamine	O
+for	O
+the	O
+amounts	O
+of	O
+words	O
+generated	O
+during	O
+lexical	O
+and	O
+semantic	O
+verbal	O
+fluency	O
+,	O
+while	O
+the	O
+phonological	O
+domain	O
+remained	O
+unaffected	O
+.	O
+
+Ketamine	O
+led	O
+to	O
+enhanced	O
+cortical	O
+activations	O
+in	O
+supramarginal	O
+and	O
+frontal	O
+brain	O
+regions	O
+for	O
+phonological	O
+and	O
+lexical	O
+verbal	O
+fluency	O
+,	O
+but	O
+not	O
+for	O
+semantic	O
+verbal	O
+fluency	O
+.	O
+
+Ketamine	O
+induces	O
+activation	O
+changes	O
+in	O
+healthy	O
+subjects	O
+similar	O
+to	O
+those	O
+observed	O
+in	O
+patients	O
+with	O
+schizophrenia	B
+,	O
+particularly	O
+in	O
+frontal	O
+and	O
+temporal	O
+brain	O
+regions	O
+.	O
+
+Our	O
+results	O
+provide	O
+further	O
+support	O
+for	O
+the	O
+hypothesis	O
+of	O
+an	O
+NMDA	O
+receptor	O
+dysfunction	O
+in	O
+the	O
+pathophysiology	O
+of	O
+schizophrenia	B
+.	O
+
+Long	O
+-	O
+term	O
+prognosis	O
+for	O
+transplant	O
+-	O
+free	O
+survivors	O
+of	O
+paracetamol	O
+-	O
+induced	O
+acute	B
+liver	I
+failure	I
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+prognosis	O
+for	O
+transplant	O
+-	O
+free	O
+survivors	O
+of	O
+paracetamol	O
+-	O
+induced	O
+acute	B
+liver	I
+failure	I
+remains	O
+unknown	O
+.	O
+
+AIM	O
+:	O
+To	O
+examine	O
+whether	O
+paracetamol	O
+-	O
+induced	O
+acute	B
+liver	I
+failure	I
+increases	O
+long	O
+-	O
+term	O
+mortality	O
+.	O
+
+METHODS	O
+:	O
+We	O
+followed	O
+up	O
+all	O
+transplant	O
+-	O
+free	O
+survivors	O
+of	O
+paracetamol	O
+-	O
+induced	O
+acute	B
+liver	I
+injury	I
+,	O
+hospitalized	O
+in	O
+a	O
+Danish	O
+national	O
+referral	O
+centre	O
+during	O
+1984	O
+-	O
+2004	O
+.	O
+
+We	O
+compared	O
+age	O
+-	O
+specific	O
+mortality	O
+rates	O
+from	O
+1	O
+year	O
+post	O
+-	O
+discharge	O
+through	O
+2008	O
+between	O
+those	O
+in	O
+whom	O
+the	O
+liver	B
+injury	I
+led	O
+to	O
+an	O
+acute	B
+liver	I
+failure	I
+and	O
+those	O
+in	O
+whom	O
+it	O
+did	O
+not	O
+.	O
+
+RESULTS	O
+:	O
+We	O
+included	O
+641	O
+patients	O
+.	O
+
+On	O
+average	O
+,	O
+age	O
+-	O
+specific	O
+mortality	O
+rates	O
+were	O
+slightly	O
+higher	O
+for	O
+the	O
+101	O
+patients	O
+whose	O
+paracetamol	O
+-	O
+induced	O
+liver	B
+injury	I
+had	O
+caused	O
+an	O
+acute	B
+liver	I
+failure	I
+(	O
+adjusted	O
+mortality	O
+rate	O
+ratio	O
+=	O
+1	O
+.	O
+70	O
+,	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+02	O
+-	O
+2	O
+.	O
+85	O
+)	O
+,	O
+but	O
+the	O
+association	O
+was	O
+age	O
+-	O
+dependent	O
+,	O
+and	O
+no	O
+survivors	O
+of	O
+acute	B
+liver	I
+failure	I
+died	O
+of	O
+liver	B
+disease	I
+,	O
+whereas	O
+suicides	O
+were	O
+frequent	O
+in	O
+both	O
+groups	O
+.	O
+
+These	O
+observations	O
+speak	O
+against	O
+long	O
+-	O
+term	O
+effects	O
+of	O
+acute	B
+liver	I
+failure	I
+.	O
+
+More	O
+likely	O
+,	O
+the	O
+elevated	O
+mortality	O
+rate	O
+ratio	O
+resulted	O
+from	O
+incomplete	O
+adjustment	O
+for	O
+the	O
+greater	O
+prevalence	O
+of	O
+substance	B
+abuse	I
+among	O
+survivors	O
+of	O
+acute	B
+liver	I
+failure	I
+.	O
+
+CONCLUSIONS	O
+:	O
+Paracetamol	O
+-	O
+induced	O
+acute	B
+liver	I
+failure	I
+did	O
+not	O
+affect	O
+long	O
+-	O
+term	O
+mortality	O
+.	O
+
+Clinical	O
+follow	O
+-	O
+up	O
+may	O
+be	O
+justified	O
+by	O
+the	O
+cause	O
+of	O
+the	O
+liver	B
+failure	I
+,	O
+but	O
+not	O
+by	O
+the	O
+liver	B
+failure	I
+itself	O
+.	O
+
+In	O
+vivo	O
+characterization	O
+of	O
+a	O
+dual	O
+adenosine	O
+A2A	O
+/	O
+A1	O
+receptor	O
+antagonist	O
+in	O
+animal	O
+models	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+The	O
+in	O
+vivo	O
+characterization	O
+of	O
+a	O
+dual	O
+adenosine	O
+A	O
+(	O
+2A	O
+)	O
+/	O
+A	O
+(	O
+1	O
+)	O
+receptor	O
+antagonist	O
+in	O
+several	O
+animal	O
+models	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+is	O
+described	O
+.	O
+
+Discovery	O
+and	O
+scale	O
+-	O
+up	O
+syntheses	O
+of	O
+compound	O
+1	O
+are	O
+described	O
+in	O
+detail	O
+,	O
+highlighting	O
+optimization	O
+steps	O
+that	O
+increased	O
+the	O
+overall	O
+yield	O
+of	O
+1	O
+from	O
+10	O
+.	O
+0	O
+%	O
+to	O
+30	O
+.	O
+5	O
+%	O
+.	O
+
+Compound	O
+1	O
+is	O
+a	O
+potent	O
+A	O
+(	O
+2A	O
+)	O
+/	O
+A	O
+(	O
+1	O
+)	O
+receptor	O
+antagonist	O
+in	O
+vitro	O
+(	O
+A	O
+(	O
+2A	O
+)	O
+K	O
+(	O
+i	O
+)	O
+=	O
+4	O
+.	O
+1	O
+nM	O
+;	O
+A	O
+(	O
+1	O
+)	O
+K	O
+(	O
+i	O
+)	O
+=	O
+17	O
+.	O
+0	O
+nM	O
+)	O
+that	O
+has	O
+excellent	O
+activity	O
+,	O
+after	O
+oral	O
+administration	O
+,	O
+across	O
+a	O
+number	O
+of	O
+animal	O
+models	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+including	O
+mouse	O
+and	O
+rat	O
+models	O
+of	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+,	O
+mouse	O
+model	O
+of	O
+reserpine	O
+-	O
+induced	O
+akinesia	B
+,	O
+rat	O
+6	O
+-	O
+hydroxydopamine	O
+(	O
+6	O
+-	O
+OHDA	O
+)	O
+lesion	O
+model	O
+of	O
+drug	O
+-	O
+induced	O
+rotation	O
+,	O
+and	O
+MPTP	O
+-	O
+treated	O
+non	O
+-	O
+human	O
+primate	O
+model	O
+.	O
+
+Effects	O
+of	O
+the	O
+hippocampal	O
+deep	O
+brain	O
+stimulation	O
+on	O
+cortical	O
+epileptic	B
+discharges	O
+in	O
+penicillin	O
+-	O
+induced	O
+epilepsy	B
+model	O
+in	O
+rats	O
+.	O
+
+AIM	O
+:	O
+Experimental	O
+and	O
+clinical	O
+studies	O
+have	O
+revealed	O
+that	O
+hippocampal	O
+DBS	O
+can	O
+control	O
+epileptic	B
+activity	O
+,	O
+but	O
+the	O
+mechanism	O
+of	O
+action	O
+is	O
+obscure	O
+and	O
+optimal	O
+stimulation	O
+parameters	O
+are	O
+not	O
+clearly	O
+defined	O
+.	O
+
+The	O
+aim	O
+was	O
+to	O
+evaluate	O
+the	O
+effects	O
+of	O
+high	O
+frequency	O
+hippocampal	O
+stimulation	O
+on	O
+cortical	O
+epileptic	B
+activity	O
+in	O
+penicillin	O
+-	O
+induced	O
+epilepsy	B
+model	O
+.	O
+
+MATERIAL	O
+AND	O
+METHODS	O
+:	O
+Twenty	O
+-	O
+five	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+were	O
+implanted	O
+DBS	O
+electrodes	O
+.	O
+
+In	O
+group	O
+-	O
+1	O
+(	O
+n	O
+=	O
+10	O
+)	O
+hippocampal	O
+DBS	O
+was	O
+off	O
+and	O
+in	O
+the	O
+group	O
+-	O
+2	O
+(	O
+n	O
+=	O
+10	O
+)	O
+hippocampal	O
+DBS	O
+was	O
+on	O
+(	O
+185	O
+Hz	O
+,	O
+0	O
+.	O
+5V	O
+,	O
+1V	O
+,	O
+2V	O
+,	O
+and	O
+5V	O
+for	O
+60	O
+sec	O
+)	O
+following	O
+penicillin	O
+G	O
+injection	O
+intracortically	O
+.	O
+
+In	O
+the	O
+control	O
+group	O
+hippocampal	O
+DBS	O
+was	O
+on	O
+following	O
+8	O
+l	O
+saline	O
+injection	O
+intracortically	O
+.	O
+
+EEG	O
+recordings	O
+were	O
+obtained	O
+before	O
+and	O
+15	O
+minutes	O
+following	O
+penicillin	O
+-	O
+G	O
+injection	O
+,	O
+and	O
+at	O
+10th	O
+minutes	O
+following	O
+each	O
+stimulus	O
+for	O
+analysis	O
+in	O
+terms	O
+of	O
+frequency	O
+,	O
+amplitude	O
+,	O
+and	O
+power	O
+spectrum	O
+.	O
+
+RESULTS	O
+:	O
+High	O
+frequency	O
+hippocampal	O
+DBS	O
+suppressed	O
+the	O
+acute	O
+penicillin	O
+-	O
+induced	O
+cortical	O
+epileptic	B
+activity	O
+independent	O
+from	O
+stimulus	O
+intensity	O
+.	O
+
+In	O
+the	O
+control	O
+group	O
+,	O
+hippocampal	O
+stimulation	O
+alone	O
+lead	O
+only	O
+to	O
+diffuse	O
+slowing	O
+of	O
+cerebral	O
+bioelectrical	O
+activity	O
+at	O
+5V	O
+stimulation	O
+.	O
+
+CONCLUSION	O
+:	O
+Our	O
+results	O
+revealed	O
+that	O
+continuous	O
+high	O
+frequency	O
+stimulation	O
+of	O
+the	O
+hippocampus	O
+suppressed	O
+acute	O
+cortical	O
+epileptic	B
+activity	O
+effectively	O
+without	O
+causing	O
+secondary	O
+epileptic	B
+discharges	O
+.	O
+
+These	O
+results	O
+are	O
+important	O
+in	O
+terms	O
+of	O
+defining	O
+the	O
+optimal	O
+parameters	O
+of	O
+hippocampal	O
+DBS	O
+in	O
+patients	O
+with	O
+epilepsy	B
+.	O
+
+CCNU	O
+(	O
+lomustine	O
+)	O
+toxicity	B
+in	O
+dogs	O
+:	O
+a	O
+retrospective	O
+study	O
+(	O
+2002	O
+-	O
+07	O
+)	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+describe	O
+the	O
+incidence	O
+of	O
+haematological	B
+,	I
+renal	I
+,	I
+hepatic	I
+and	I
+gastrointestinal	I
+toxicities	I
+in	O
+tumour	O
+-	O
+bearing	O
+dogs	O
+receiving	O
+1	O
+-	O
+(	O
+2	O
+-	O
+chloroethyl	O
+)	O
+-	O
+3	O
+-	O
+cyclohexyl	O
+-	O
+1	O
+-	O
+nitrosourea	O
+(	O
+CCNU	O
+)	O
+.	O
+
+DESIGN	O
+:	O
+The	O
+medical	O
+records	O
+of	O
+206	O
+dogs	O
+that	O
+were	O
+treated	O
+with	O
+CCNU	O
+at	O
+the	O
+Melbourne	O
+Veterinary	O
+Specialist	O
+Centre	O
+between	O
+February	O
+2002	O
+and	O
+December	O
+2007	O
+were	O
+retrospectively	O
+evaluated	O
+.	O
+
+RESULTS	O
+:	O
+Of	O
+the	O
+206	O
+dogs	O
+treated	O
+with	O
+CCNU	O
+,	O
+185	O
+met	O
+the	O
+inclusion	O
+criteria	O
+for	O
+at	O
+least	O
+one	O
+class	O
+of	O
+toxicity	B
+.	O
+
+CCNU	O
+was	O
+used	O
+most	O
+commonly	O
+in	O
+the	O
+treatment	O
+of	O
+lymphoma	B
+,	O
+mast	B
+cell	I
+tumour	I
+,	O
+brain	B
+tumour	I
+,	O
+histiocytic	B
+tumours	I
+and	O
+epitheliotropic	B
+lymphoma	I
+.	O
+
+Throughout	O
+treatment	O
+,	O
+56	O
+.	O
+9	O
+%	O
+of	O
+dogs	O
+experienced	O
+neutropenia	B
+,	O
+34	O
+.	O
+2	O
+%	O
+experienced	O
+anaemia	B
+and	O
+14	O
+.	O
+2	O
+%	O
+experienced	O
+thrombocytopenia	B
+.	O
+
+Gastrointestinal	B
+toxicosis	I
+was	O
+detected	O
+in	O
+37	O
+.	O
+8	O
+%	O
+of	O
+dogs	O
+,	O
+the	O
+most	O
+common	O
+sign	O
+of	O
+which	O
+was	O
+vomiting	B
+(	O
+24	O
+.	O
+3	O
+%	O
+)	O
+.	O
+
+Potential	O
+renal	O
+toxicity	B
+and	O
+elevated	O
+alanine	O
+transaminase	O
+(	O
+ALT	O
+)	O
+concentration	O
+were	O
+reported	O
+in	O
+12	O
+.	O
+2	O
+%	O
+and	O
+48	O
+.	O
+8	O
+%	O
+of	O
+dogs	O
+,	O
+respectively	O
+.	O
+
+The	O
+incidence	O
+of	O
+hepatic	B
+failure	I
+was	O
+1	O
+.	O
+2	O
+%	O
+.	O
+
+CONCLUSIONS	O
+:	O
+CCNU	O
+-	O
+associated	O
+toxicity	B
+in	O
+dogs	O
+is	O
+common	O
+,	O
+but	O
+is	O
+usually	O
+not	O
+life	O
+threatening	O
+.	O
+
+Central	O
+vein	B
+thrombosis	I
+and	O
+topical	O
+dipivalyl	O
+epinephrine	O
+.	O
+
+A	O
+report	O
+is	O
+given	O
+on	O
+an	O
+83	O
+-	O
+year	O
+-	O
+old	O
+female	O
+who	O
+acquired	O
+central	O
+vein	B
+thrombosis	I
+in	O
+her	O
+seeing	O
+eye	O
+one	O
+day	O
+after	O
+having	O
+started	O
+topical	O
+medication	O
+with	O
+dipivalyl	O
+epinephrine	O
+for	O
+advanced	O
+glaucoma	B
+discovered	O
+in	O
+the	O
+other	O
+eye	O
+.	O
+
+From	O
+present	O
+knowledge	O
+about	O
+the	O
+effects	O
+of	O
+adrenergic	O
+eye	O
+drops	O
+on	O
+ocular	O
+blood	O
+circulation	O
+,	O
+it	O
+is	O
+difficult	O
+to	O
+suggest	O
+an	O
+association	O
+between	O
+the	O
+two	O
+events	O
+,	O
+which	O
+may	O
+be	O
+coincidental	O
+only	O
+.	O
+
+Benzylacyclouridine	O
+reverses	O
+azidothymidine	O
+-	O
+induced	O
+marrow	B
+suppression	I
+without	O
+impairment	O
+of	O
+anti	O
+-	O
+human	O
+immunodeficiency	B
+virus	O
+activity	O
+.	O
+
+Increased	O
+extracellular	O
+concentrations	O
+of	O
+uridine	O
+(	O
+Urd	O
+)	O
+have	O
+been	O
+reported	O
+to	O
+reduce	O
+,	O
+in	O
+vitro	O
+,	O
+azidothymidine	O
+(	O
+AZT	O
+)	O
+-	O
+induced	O
+inhibition	O
+of	O
+human	O
+granulocyte	O
+-	O
+macrophage	O
+progenitor	O
+cells	O
+without	O
+impairment	O
+of	O
+its	O
+antihuman	O
+immunodeficiency	B
+virus	O
+(	O
+HIV	O
+)	O
+activity	O
+.	O
+
+Because	O
+of	O
+the	O
+clinical	O
+toxicities	B
+associated	O
+with	O
+chronic	O
+Urd	O
+administration	O
+,	O
+the	O
+ability	O
+of	O
+benzylacyclouridine	O
+(	O
+BAU	O
+)	O
+to	O
+effect	O
+,	O
+in	O
+vivo	O
+,	O
+AZT	O
+-	O
+induced	O
+anemia	B
+and	O
+leukopenia	B
+was	O
+assessed	O
+.	O
+
+This	O
+agent	O
+inhibits	O
+Urd	O
+catabolism	O
+and	O
+,	O
+in	O
+vivo	O
+,	O
+increases	O
+the	O
+plasma	O
+concentration	O
+of	O
+Urd	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+,	O
+without	O
+Urd	O
+-	O
+related	O
+toxicity	B
+.	O
+
+In	O
+mice	O
+rendered	O
+anemic	B
+and	O
+leukopenic	B
+by	O
+the	O
+administration	O
+of	O
+AZT	O
+for	O
+28	O
+days	O
+in	O
+drinking	O
+water	O
+(	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+mL	O
+)	O
+,	O
+the	O
+continued	O
+administration	O
+of	O
+AZT	O
+plus	O
+daily	O
+BAU	O
+(	O
+300	O
+mg	O
+/	O
+kg	O
+,	O
+orally	O
+)	O
+partially	O
+reversed	O
+AZT	O
+-	O
+induced	O
+anemia	B
+and	O
+leukopenia	B
+(	O
+P	O
+less	O
+than	O
+.	O
+05	O
+)	O
+,	O
+increased	O
+peripheral	O
+reticulocytes	O
+(	O
+to	O
+4	O
+.	O
+9	O
+%	O
+,	O
+P	O
+less	O
+than	O
+.	O
+01	O
+)	O
+,	O
+increased	O
+cellularity	O
+in	O
+the	O
+marrow	O
+,	O
+and	O
+improved	O
+megaloblastosis	B
+.	O
+
+When	O
+coadministered	O
+with	O
+AZT	O
+from	O
+the	O
+onset	O
+of	O
+drug	O
+administration	O
+,	O
+BAU	O
+reduced	O
+AZT	O
+-	O
+induced	O
+marrow	B
+toxicity	I
+.	O
+
+In	O
+vitro	O
+,	O
+at	O
+a	O
+concentration	O
+of	O
+100	O
+mumol	O
+/	O
+L	O
+,	O
+BAU	O
+possesses	O
+minimal	O
+anti	O
+-	O
+HIV	O
+activity	O
+and	O
+has	O
+no	O
+effect	O
+on	O
+the	O
+ability	O
+of	O
+AZT	O
+to	O
+reverse	O
+the	O
+HIV	O
+-	O
+induced	O
+cytopathic	O
+effect	O
+in	O
+MT4	O
+cells	O
+.	O
+
+The	O
+clinical	O
+and	O
+biochemical	O
+implications	O
+of	O
+these	O
+findings	O
+are	O
+discussed	O
+.	O
+
+Lethal	O
+anuria	B
+complicating	O
+high	O
+dose	O
+ifosfamide	O
+chemotherapy	O
+in	O
+a	O
+breast	B
+cancer	I
+patient	O
+with	O
+an	O
+impaired	B
+renal	I
+function	I
+.	O
+
+A	O
+sixty	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+advanced	O
+breast	B
+cancer	I
+,	O
+previously	O
+treated	O
+with	O
+cisplatin	O
+,	O
+developed	O
+an	O
+irreversible	O
+lethal	O
+renal	B
+failure	I
+with	O
+anuria	B
+,	O
+the	O
+day	O
+after	O
+5	O
+g	O
+/	O
+m2	O
+bolus	O
+ifosfamide	O
+.	O
+
+Postrenal	B
+failure	I
+was	O
+excluded	O
+by	O
+echography	O
+.	O
+
+A	O
+prerenal	O
+component	O
+could	O
+have	O
+contributed	O
+to	O
+renal	B
+failure	I
+because	O
+of	O
+a	O
+transient	O
+hypotension	B
+,	O
+due	O
+to	O
+an	O
+increasing	O
+ascitis	O
+,	O
+occurring	O
+just	O
+before	O
+anuria	B
+.	O
+
+However	O
+,	O
+correction	O
+of	O
+the	O
+hemodynamic	O
+parameters	O
+did	O
+not	O
+improve	O
+renal	O
+function	O
+.	O
+
+Ifosfamide	O
+is	O
+a	O
+known	O
+nephrotoxic	B
+drug	O
+with	O
+demonstrated	O
+tubulopathies	B
+.	O
+
+We	O
+strongly	O
+suspect	O
+that	O
+this	O
+lethal	O
+anuria	B
+was	O
+mainly	O
+due	O
+to	O
+ifosfamide	O
+,	O
+occurring	O
+in	O
+a	O
+patient	O
+having	O
+received	O
+previous	O
+cisplatin	O
+chemotherapy	O
+and	O
+with	O
+poor	O
+kidney	O
+perfusion	O
+due	O
+to	O
+transient	O
+hypotension	B
+.	O
+
+We	O
+recommend	O
+careful	O
+use	O
+of	O
+ifosfamide	O
+in	O
+patients	O
+pretreated	O
+with	O
+nephrotoxic	B
+chemotherapy	O
+and	O
+inadequate	O
+renal	O
+perfusion	O
+.	O
+
+Nociceptive	O
+effects	O
+induced	O
+by	O
+intrathecal	O
+administration	O
+of	O
+prostaglandin	O
+D2	O
+,	O
+E2	O
+,	O
+or	O
+F2	O
+alpha	O
+to	O
+conscious	O
+mice	O
+.	O
+
+The	O
+effects	O
+of	O
+intrathecal	O
+administration	O
+of	O
+prostaglandins	O
+on	O
+pain	B
+responses	O
+in	O
+conscious	O
+mice	O
+were	O
+evaluated	O
+by	O
+using	O
+hot	O
+plate	O
+and	O
+acetic	O
+acid	O
+writhing	O
+tests	O
+.	O
+
+Prostaglandin	O
+D2	O
+(	O
+0	O
+.	O
+5	O
+-	O
+3	O
+ng	O
+/	O
+mouse	O
+)	O
+had	O
+a	O
+hyperalgesic	B
+action	O
+on	O
+the	O
+response	O
+to	O
+a	O
+hot	O
+plate	O
+during	O
+a	O
+3	O
+-	O
+60	O
+min	O
+period	O
+after	O
+injection	O
+.	O
+
+Prostaglandin	O
+E2	O
+showed	O
+a	O
+hyperalgesic	B
+effect	O
+at	O
+doses	O
+of	O
+1	O
+pg	O
+to	O
+10	O
+ng	O
+/	O
+mouse	O
+,	O
+but	O
+the	O
+effect	O
+lasted	O
+shorter	O
+(	O
+3	O
+-	O
+30	O
+min	O
+)	O
+than	O
+that	O
+of	O
+prostaglandin	O
+D2	O
+.	O
+
+Similar	O
+results	O
+were	O
+obtained	O
+by	O
+acetic	O
+acid	O
+writhing	O
+tests	O
+.	O
+
+The	O
+hyperalgesic	B
+effect	O
+of	O
+prostaglandin	O
+D2	O
+was	O
+blocked	O
+by	O
+simultaneous	O
+injection	O
+of	O
+a	O
+substance	O
+P	O
+antagonist	O
+(	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+100	O
+ng	O
+)	O
+but	O
+not	O
+by	O
+AH6809	O
+,	O
+a	O
+prostanoid	O
+EP1	O
+-	O
+receptor	O
+antagonist	O
+.	O
+
+Conversely	O
+,	O
+prostaglandin	O
+E2	O
+-	O
+induced	O
+hyperalgesia	B
+was	O
+blocked	O
+by	O
+AH6809	O
+(	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+500	O
+ng	O
+)	O
+but	O
+not	O
+by	O
+the	O
+substance	O
+P	O
+antagonist	O
+.	O
+
+Prostaglandin	O
+F2	O
+alpha	O
+had	O
+little	O
+effect	O
+on	O
+pain	B
+responses	O
+.	O
+
+These	O
+results	O
+demonstrate	O
+that	O
+both	O
+prostaglandin	O
+D2	O
+and	O
+prostaglandin	O
+E2	O
+exert	O
+hyperalgesia	B
+in	O
+the	O
+spinal	O
+cord	O
+,	O
+but	O
+in	O
+different	O
+ways	O
+.	O
+
+D	O
+-	O
+penicillamine	O
+in	O
+the	O
+treatment	O
+of	O
+localized	B
+scleroderma	I
+.	O
+
+Localized	B
+scleroderma	I
+has	O
+no	O
+recognized	O
+internal	O
+organ	O
+involvement	O
+but	O
+may	O
+be	O
+disfiguring	O
+and	O
+disabling	O
+when	O
+the	O
+cutaneous	O
+lesions	O
+are	O
+extensive	O
+or	O
+affect	O
+children	O
+.	O
+
+There	O
+is	O
+no	O
+accepted	O
+or	O
+proven	O
+treatment	O
+for	O
+localized	B
+scleroderma	I
+.	O
+
+Case	O
+reports	O
+of	O
+11	O
+patients	O
+with	O
+severe	O
+,	O
+extensive	O
+localized	B
+scleroderma	I
+who	O
+were	O
+treated	O
+with	O
+D	O
+-	O
+penicillamine	O
+are	O
+summarized	O
+in	O
+this	O
+article	O
+.	O
+
+This	O
+drug	O
+was	O
+judged	O
+to	O
+have	O
+a	O
+favorable	O
+effect	O
+on	O
+the	O
+disease	O
+course	O
+in	O
+7	O
+(	O
+64	O
+%	O
+)	O
+of	O
+11	O
+patients	O
+.	O
+
+Improvement	O
+began	O
+within	O
+3	O
+to	O
+6	O
+months	O
+and	O
+consisted	O
+of	O
+cessation	O
+of	O
+active	O
+cutaneous	O
+lesions	O
+in	O
+all	O
+7	O
+patients	O
+,	O
+skin	O
+softening	O
+in	O
+5	O
+,	O
+and	O
+more	O
+normal	O
+growth	O
+of	O
+the	O
+affected	O
+limb	O
+in	O
+2	O
+of	O
+3	O
+children	O
+.	O
+
+Joint	O
+stiffness	O
+and	O
+contractures	B
+also	O
+improved	O
+.	O
+
+The	O
+dose	O
+of	O
+D	O
+-	O
+penicillamine	O
+associated	O
+with	O
+a	O
+favorable	O
+response	O
+was	O
+as	O
+low	O
+as	O
+2	O
+to	O
+5	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+given	O
+over	O
+a	O
+period	O
+ranging	O
+from	O
+15	O
+to	O
+53	O
+months	O
+.	O
+
+D	O
+-	O
+Penicillamine	O
+caused	O
+nephrotic	B
+syndrome	I
+in	O
+1	O
+patient	O
+and	O
+milder	O
+reversible	O
+proteinuria	B
+in	O
+3	O
+other	O
+patients	O
+;	O
+none	O
+developed	O
+renal	B
+insufficiency	I
+.	O
+
+These	O
+data	O
+suggest	O
+that	O
+D	O
+-	O
+penicillamine	O
+may	O
+be	O
+effective	O
+in	O
+severe	O
+cases	O
+of	O
+localized	B
+scleroderma	I
+.	O
+
+Cerebral	B
+sinus	I
+thrombosis	I
+as	O
+a	O
+potential	O
+hazard	O
+of	O
+antifibrinolytic	O
+treatment	O
+in	O
+menorrhagia	B
+.	O
+
+We	O
+describe	O
+a	O
+42	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+who	O
+developed	O
+superior	O
+sagittal	B
+and	I
+left	I
+transverse	I
+sinus	I
+thrombosis	I
+associated	O
+with	O
+prolonged	O
+epsilon	O
+-	O
+aminocaproic	O
+acid	O
+therapy	O
+for	O
+menorrhagia	B
+.	O
+
+This	O
+antifibrinolytic	O
+agent	O
+has	O
+been	O
+used	O
+in	O
+women	O
+with	O
+menorrhagia	B
+to	O
+promote	O
+clotting	O
+and	O
+reduce	O
+blood	B
+loss	I
+.	O
+
+Although	O
+increased	O
+risk	O
+of	O
+thromboembolic	B
+disease	I
+has	O
+been	O
+reported	O
+during	O
+treatment	O
+with	O
+epsilon	O
+-	O
+aminocaproic	O
+acid	O
+,	O
+cerebral	B
+sinus	I
+thrombosis	I
+has	O
+not	O
+been	O
+previously	O
+described	O
+.	O
+
+Careful	O
+use	O
+of	O
+epsilon	O
+-	O
+aminocaproic	O
+acid	O
+therapy	O
+is	O
+recommended	O
+.	O
+
+Seizure	B
+activity	O
+with	O
+imipenem	O
+therapy	O
+:	O
+incidence	O
+and	O
+risk	O
+factors	O
+.	O
+
+Two	O
+elderly	O
+patients	O
+with	O
+a	O
+history	O
+of	O
+either	O
+cerebral	B
+vascular	I
+accident	I
+(	O
+CVA	B
+)	O
+or	O
+head	B
+trauma	I
+and	O
+no	O
+evidence	O
+of	O
+renal	B
+disease	I
+developed	O
+seizures	B
+while	O
+receiving	O
+maximum	O
+doses	O
+of	O
+imipenem	O
+/	O
+cilastatin	O
+.	O
+
+Neither	O
+patient	O
+had	O
+reported	O
+previous	O
+seizures	B
+or	O
+seizure	B
+-	O
+like	O
+activity	O
+nor	O
+was	O
+receiving	O
+anticonvulsant	O
+agents	O
+.	O
+
+All	O
+seizures	B
+were	O
+controlled	O
+with	O
+therapeutic	O
+doses	O
+of	O
+phenytoin	O
+.	O
+
+Both	O
+patients	O
+had	O
+received	O
+maximum	O
+doses	O
+of	O
+other	O
+beta	O
+-	O
+lactam	O
+antibiotics	O
+without	O
+evidence	O
+of	O
+seizure	B
+activity	O
+.	O
+
+Midline	O
+B3	O
+serotonin	O
+nerves	O
+in	O
+rat	O
+medulla	O
+are	O
+involved	O
+in	O
+hypotensive	B
+effect	O
+of	O
+methyldopa	O
+.	O
+
+Previous	O
+experiments	O
+in	O
+this	O
+laboratory	O
+have	O
+shown	O
+that	O
+microinjection	O
+of	O
+methyldopa	O
+onto	O
+the	O
+ventrolateral	O
+cells	O
+of	O
+the	O
+B3	O
+serotonin	O
+neurons	O
+in	O
+the	O
+medulla	O
+elicits	O
+a	O
+hypotensive	B
+response	O
+mediated	O
+by	O
+a	O
+projection	O
+descending	O
+into	O
+the	O
+spinal	O
+cord	O
+.	O
+
+The	O
+present	O
+experiments	O
+were	O
+designed	O
+to	O
+investigate	O
+the	O
+role	O
+of	O
+the	O
+midline	O
+cells	O
+of	O
+the	O
+B3	O
+serotonin	O
+neurons	O
+in	O
+the	O
+medulla	O
+,	O
+coinciding	O
+with	O
+the	O
+raphe	O
+magnus	O
+.	O
+
+In	O
+spontaneously	O
+hypertensive	B
+,	O
+stroke	B
+-	O
+prone	O
+rats	O
+,	O
+microinjection	O
+of	O
+methyldopa	O
+into	O
+the	O
+area	O
+of	O
+the	O
+midline	O
+B3	O
+serotonin	O
+cell	O
+group	O
+in	O
+the	O
+ventral	O
+medulla	O
+caused	O
+a	O
+potent	O
+hypotension	B
+of	O
+30	O
+-	O
+40	O
+mm	O
+Hg	O
+,	O
+which	O
+was	O
+maximal	O
+2	O
+-	O
+3	O
+h	O
+after	O
+administration	O
+and	O
+was	O
+abolished	O
+by	O
+the	O
+serotonin	O
+neurotoxin	O
+5	O
+,	O
+7	O
+-	O
+dihydroxytryptamine	O
+(	O
+5	O
+,	O
+7	O
+-	O
+DHT	O
+)	O
+injected	O
+intracerebroventricularly	O
+.	O
+
+However	O
+,	O
+intraspinal	O
+injection	O
+of	O
+5	O
+,	O
+7	O
+-	O
+DHT	O
+to	O
+produce	O
+a	O
+more	O
+selective	O
+lesion	O
+of	O
+only	O
+descending	O
+serotonin	O
+projections	O
+in	O
+the	O
+spinal	O
+cord	O
+did	O
+not	O
+affect	O
+this	O
+hypotension	B
+.	O
+
+Further	O
+,	O
+5	O
+,	O
+7	O
+-	O
+DHT	O
+lesion	O
+of	O
+serotonin	O
+nerves	O
+travelling	O
+in	O
+the	O
+median	O
+forebrain	O
+bundle	O
+,	O
+one	O
+of	O
+the	O
+main	O
+ascending	O
+pathways	O
+from	O
+the	O
+B3	O
+serotonin	O
+cells	O
+,	O
+did	O
+not	O
+affect	O
+the	O
+fall	O
+in	O
+blood	O
+pressure	O
+associated	O
+with	O
+a	O
+midline	O
+B3	O
+serotonin	O
+methyldopa	O
+injection	O
+.	O
+
+It	O
+is	O
+concluded	O
+therefore	O
+that	O
+,	O
+unlike	O
+the	O
+ventrolateral	O
+B3	O
+cells	O
+which	O
+mediate	O
+a	O
+methyldopa	O
+-	O
+induced	O
+hypotension	B
+via	O
+descending	O
+projections	O
+,	O
+the	O
+midline	O
+serotonin	O
+B3	O
+cells	O
+in	O
+the	O
+medulla	O
+contribute	O
+to	O
+the	O
+hypotensive	B
+action	O
+of	O
+methyldopa	O
+,	O
+either	O
+by	O
+way	O
+of	O
+an	O
+ascending	O
+projection	O
+which	O
+does	O
+not	O
+pass	O
+through	O
+the	O
+median	O
+forebrain	O
+bundle	O
+,	O
+or	O
+through	O
+a	O
+projection	O
+restricted	O
+to	O
+the	O
+caudal	O
+brainstem	O
+.	O
+
+Antiarrhythmic	O
+plasma	O
+concentrations	O
+of	O
+cibenzoline	O
+on	O
+canine	O
+ventricular	B
+arrhythmias	I
+.	O
+
+Using	O
+two	O
+-	O
+stage	O
+coronary	O
+ligation	O
+-	O
+,	O
+digitalis	O
+-	O
+,	O
+and	O
+adrenaline	O
+-	O
+induced	O
+canine	O
+ventricular	B
+arrhythmias	I
+,	O
+antiarrhythmic	O
+effects	O
+of	O
+cibenzoline	O
+were	O
+examined	O
+and	O
+the	O
+minimum	O
+effective	O
+plasma	O
+concentration	O
+for	O
+each	O
+arrhythmia	B
+model	O
+was	O
+determined	O
+.	O
+
+Cibenzoline	O
+suppressed	O
+all	O
+the	O
+arrhythmias	B
+,	O
+and	O
+the	O
+minimum	O
+effective	O
+plasma	O
+concentrations	O
+for	O
+arrhythmias	B
+induced	O
+by	O
+24	O
+-	O
+h	O
+coronary	O
+ligation	O
+,	O
+48	O
+-	O
+h	O
+coronary	O
+ligation	O
+,	O
+digitalis	O
+,	O
+and	O
+adrenaline	O
+were	O
+1	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+9	O
+(	O
+by	O
+8	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+,	O
+1	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+(	O
+by	O
+8	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+,	O
+0	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+(	O
+by	O
+2	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+,	O
+and	O
+3	O
+.	O
+5	O
++	O
+/	O
+-	O
+1	O
+.	O
+3	O
+(	O
+by	O
+5	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+micrograms	O
+/	O
+ml	O
+,	O
+respectively	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SDM	O
+,	O
+n	O
+=	O
+6	O
+-	O
+7	O
+)	O
+.	O
+
+The	O
+concentration	O
+for	O
+adrenaline	O
+-	O
+induced	O
+arrhythmia	B
+was	O
+significantly	O
+higher	O
+than	O
+those	O
+for	O
+the	O
+other	O
+types	O
+of	O
+arrhythmias	B
+.	O
+
+This	O
+pharmacological	O
+profile	O
+is	O
+similar	O
+to	O
+those	O
+of	O
+mexiletine	O
+and	O
+tocainide	O
+,	O
+and	O
+all	O
+three	O
+drugs	O
+have	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+stimulant	O
+action	O
+.	O
+
+Because	O
+cibenzoline	O
+had	O
+only	O
+weak	O
+hypotensive	B
+and	O
+sinus	O
+node	O
+depressive	B
+effects	O
+and	O
+was	O
+found	O
+to	O
+be	O
+orally	O
+active	O
+when	O
+given	O
+to	O
+coronary	O
+ligation	O
+arrhythmia	B
+dogs	O
+,	O
+its	O
+clinical	O
+usefulness	O
+is	O
+expected	O
+.	O
+
+Continuous	O
+ambulatory	O
+ECG	O
+monitoring	O
+during	O
+fluorouracil	O
+therapy	O
+:	O
+a	O
+prospective	O
+study	O
+.	O
+
+Although	O
+there	O
+have	O
+been	O
+anecdotal	O
+reports	O
+of	O
+cardiac	B
+toxicity	I
+associated	O
+with	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+therapy	O
+,	O
+this	O
+phenomenon	O
+has	O
+not	O
+been	O
+studied	O
+in	O
+a	O
+systematic	O
+fashion	O
+.	O
+
+We	O
+prospectively	O
+performed	O
+continuous	O
+ambulatory	O
+ECG	O
+monitoring	O
+on	O
+25	O
+patients	O
+undergoing	O
+5	O
+-	O
+FU	O
+infusion	O
+for	O
+treatment	O
+of	O
+solid	O
+tumors	B
+in	O
+order	O
+to	O
+assess	O
+the	O
+incidence	O
+of	O
+ischemic	B
+ST	O
+changes	O
+.	O
+
+Patients	O
+were	O
+monitored	O
+for	O
+23	O
++	O
+/	O
+-	O
+4	O
+hours	O
+before	O
+5	O
+-	O
+FU	O
+infusion	O
+,	O
+and	O
+98	O
++	O
+/	O
+-	O
+9	O
+hours	O
+during	O
+5	O
+-	O
+FU	O
+infusion	O
+.	O
+
+Anginal	B
+episodes	O
+were	O
+rare	O
+:	O
+only	O
+one	O
+patient	O
+had	O
+angina	B
+(	O
+during	O
+5	O
+-	O
+FU	O
+infusion	O
+)	O
+.	O
+
+However	O
+,	O
+asymptomatic	O
+ST	O
+changes	O
+(	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+1	O
+mm	O
+ST	O
+deviation	O
+)	O
+were	O
+common	O
+:	O
+six	O
+of	O
+25	O
+patients	O
+(	O
+24	O
+%	O
+)	O
+had	O
+ST	O
+changes	O
+before	O
+5	O
+-	O
+FU	O
+infusion	O
+v	O
+17	O
+(	O
+68	O
+%	O
+)	O
+during	O
+5	O
+-	O
+FU	O
+infusion	O
+(	O
+P	O
+less	O
+than	O
+.	O
+002	O
+)	O
+.	O
+
+The	O
+incidence	O
+of	O
+ischemic	B
+episodes	O
+per	O
+patient	O
+per	O
+hour	O
+was	O
+0	O
+.	O
+05	O
++	O
+/	O
+-	O
+0	O
+.	O
+02	O
+prior	O
+to	O
+5	O
+-	O
+FU	O
+infusion	O
+v	O
+0	O
+.	O
+13	O
++	O
+/	O
+-	O
+0	O
+.	O
+03	O
+during	O
+5	O
+-	O
+FU	O
+infusion	O
+(	O
+P	O
+less	O
+than	O
+.	O
+001	O
+)	O
+;	O
+the	O
+duration	O
+of	O
+ECG	O
+changes	O
+was	O
+0	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+minutes	O
+per	O
+patient	O
+per	O
+hour	O
+before	O
+5	O
+-	O
+FU	O
+v	O
+1	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+minutes	O
+per	O
+patient	O
+per	O
+hour	O
+during	O
+5	O
+-	O
+FU	O
+(	O
+P	O
+less	O
+than	O
+.	O
+01	O
+)	O
+.	O
+
+ECG	O
+changes	O
+were	O
+more	O
+common	O
+among	O
+patients	O
+with	O
+known	O
+coronary	B
+artery	I
+disease	I
+.	O
+
+There	O
+were	O
+two	O
+cases	O
+of	O
+sudden	B
+death	I
+,	O
+both	O
+of	O
+which	O
+occurred	O
+at	O
+the	O
+end	O
+of	O
+the	O
+chemotherapy	O
+course	O
+.	O
+
+We	O
+conclude	O
+that	O
+5	O
+-	O
+FU	O
+infusion	O
+is	O
+associated	O
+with	O
+a	O
+significant	O
+increase	O
+in	O
+silent	O
+ST	O
+segment	O
+deviation	O
+suggestive	O
+of	O
+ischemia	B
+,	O
+particularly	O
+among	O
+patients	O
+with	O
+coronary	B
+artery	I
+disease	I
+.	O
+
+The	O
+mechanism	O
+and	O
+clinical	O
+significance	O
+of	O
+these	O
+ECG	O
+changes	O
+remain	O
+to	O
+be	O
+determined	O
+.	O
+
+Nature	O
+,	O
+time	O
+course	O
+and	O
+dose	O
+dependence	O
+of	O
+zidovudine	O
+-	O
+related	O
+side	O
+effects	O
+:	O
+results	O
+from	O
+the	O
+Multicenter	O
+Canadian	O
+Azidothymidine	O
+Trial	O
+.	O
+
+To	O
+characterize	O
+the	O
+nature	O
+,	O
+time	O
+course	O
+and	O
+dose	O
+dependency	O
+of	O
+zidovudine	O
+-	O
+related	O
+side	O
+effects	O
+,	O
+we	O
+undertook	O
+a	O
+multicenter	O
+,	O
+prospective	O
+,	O
+dose	O
+-	O
+range	O
+finding	O
+study	O
+.	O
+
+Our	O
+study	O
+group	O
+consisted	O
+of	O
+74	O
+HIV	O
+-	O
+positive	O
+homosexual	O
+men	O
+belonging	O
+to	O
+groups	O
+II	O
+B	O
+,	O
+III	O
+and	O
+IV	O
+C2	O
+from	O
+the	O
+Centers	O
+for	O
+Disease	O
+Control	O
+(	O
+CDC	O
+)	O
+classification	O
+of	O
+HIV	B
+disease	I
+.	O
+
+Following	O
+a	O
+3	O
+-	O
+week	O
+observation	O
+period	O
+,	O
+volunteers	O
+were	O
+treated	O
+with	O
+zidovudine	O
+600	O
+mg	O
+/	O
+day	O
+for	O
+18	O
+weeks	O
+,	O
+900	O
+mg	O
+/	O
+day	O
+for	O
+9	O
+weeks	O
+and	O
+1200	O
+mg	O
+/	O
+day	O
+for	O
+9	O
+weeks	O
+,	O
+followed	O
+by	O
+a	O
+washout	O
+period	O
+of	O
+6	O
+weeks	O
+after	O
+which	O
+they	O
+were	O
+re	O
+-	O
+started	O
+on	O
+1200	O
+mg	O
+/	O
+day	O
+or	O
+the	O
+highest	O
+tolerated	O
+dose	O
+at	O
+8	O
+-	O
+hourly	O
+intervals	O
+.	O
+
+Subjects	O
+were	O
+randomly	O
+assigned	O
+to	O
+4	O
+-	O
+hourly	O
+or	O
+8	O
+-	O
+hourly	O
+regimens	O
+within	O
+CDC	O
+groups	O
+while	O
+taking	O
+600	O
+and	O
+1200	O
+mg	O
+/	O
+day	O
+.	O
+
+Clinical	O
+and	O
+laboratory	O
+evaluations	O
+were	O
+performed	O
+at	O
+3	O
+-	O
+week	O
+intervals	O
+.	O
+
+Symptomatic	O
+adverse	O
+effects	O
+were	O
+present	O
+in	O
+96	O
+%	O
+of	O
+subjects	O
+,	O
+most	O
+commonly	O
+nausea	B
+(	O
+64	O
+%	O
+)	O
+,	O
+fatigue	B
+(	O
+55	O
+%	O
+)	O
+and	O
+headache	B
+(	O
+49	O
+%	O
+)	O
+.	O
+
+These	O
+were	O
+generally	O
+self	O
+-	O
+limited	O
+,	O
+reappearing	O
+briefly	O
+at	O
+each	O
+dose	O
+increment	O
+.	O
+
+A	O
+decrease	O
+in	O
+hemoglobin	O
+occurred	O
+shortly	O
+after	O
+initiation	O
+of	O
+therapy	O
+.	O
+
+This	O
+was	O
+not	O
+dose	O
+dependent	O
+and	O
+reversed	O
+rapidly	O
+upon	O
+discontinuation	O
+of	O
+treatment	O
+.	O
+
+A	O
+red	O
+blood	O
+cell	O
+count	O
+decrease	O
+,	O
+a	O
+mean	O
+cell	O
+volume	O
+increase	O
+and	O
+a	O
+granulocyte	O
+count	O
+decrease	O
+developed	O
+early	O
+in	O
+a	O
+dose	O
+-	O
+independent	O
+fashion	O
+,	O
+reverting	O
+at	O
+least	O
+partially	O
+during	O
+the	O
+washout	O
+phase	O
+.	O
+
+The	O
+decrease	O
+in	O
+reticulocyte	O
+count	O
+was	O
+dose	O
+related	O
+between	O
+600	O
+and	O
+900	O
+mg	O
+/	O
+day	O
+with	O
+no	O
+further	O
+change	O
+when	O
+the	O
+dose	O
+was	O
+escalated	O
+to	O
+1200	O
+mg	O
+/	O
+day	O
+.	O
+
+Bone	O
+marrow	O
+changes	O
+occurred	O
+rapidly	O
+as	O
+demonstrated	O
+by	O
+megaloblastosis	B
+in	O
+95	O
+%	O
+of	O
+65	O
+specimens	O
+at	O
+week	O
+18	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+National	O
+project	O
+on	O
+the	O
+prevention	O
+of	O
+mother	O
+-	O
+to	O
+-	O
+infant	O
+infection	B
+by	I
+hepatitis	I
+B	I
+virus	I
+in	O
+Japan	O
+.	O
+
+In	O
+Japan	O
+,	O
+a	O
+nationwide	O
+prevention	O
+program	O
+against	O
+mother	O
+-	O
+to	O
+-	O
+infant	O
+infection	B
+by	I
+hepatitis	I
+B	I
+virus	I
+(	O
+HBV	O
+)	O
+started	O
+in	O
+1985	O
+.	O
+
+This	O
+program	O
+consists	O
+of	O
+double	O
+screenings	O
+of	O
+pregnant	O
+women	O
+and	O
+prophylactic	O
+treatment	O
+to	O
+the	O
+infants	O
+born	O
+to	O
+both	O
+hepatitis	O
+B	O
+surface	O
+antigen	O
+(	O
+HBsAg	O
+)	O
+and	O
+hepatitis	O
+B	O
+e	O
+antigen	O
+(	O
+HBeAg	O
+)	O
+positive	O
+mothers	O
+.	O
+
+These	O
+infants	O
+are	O
+treated	O
+with	O
+two	O
+injections	O
+of	O
+hepatitis	B
+B	I
+immune	O
+globulin	O
+(	O
+HBIG	O
+)	O
+and	O
+at	O
+least	O
+three	O
+injections	O
+of	O
+plasma	O
+derived	O
+hepatitis	O
+B	O
+vaccine	O
+.	O
+
+We	O
+sent	O
+questionnaires	O
+about	O
+the	O
+numbers	O
+of	O
+each	O
+procedure	O
+or	O
+examination	O
+during	O
+nine	O
+months	O
+of	O
+investigation	O
+period	O
+to	O
+each	O
+local	O
+government	O
+in	O
+1986	O
+and	O
+1987	O
+.	O
+
+93	O
+.	O
+4	O
+%	O
+pregnant	O
+women	O
+had	O
+the	O
+chance	O
+to	O
+be	O
+examined	O
+for	O
+HBsAg	O
+,	O
+and	O
+the	O
+positive	O
+rate	O
+was	O
+1	O
+.	O
+4	O
+to	O
+1	O
+.	O
+5	O
+%	O
+.	O
+
+The	O
+HBeAg	O
+positive	O
+rate	O
+in	O
+HBsAg	O
+positive	O
+was	O
+23	O
+to	O
+26	O
+%	O
+.	O
+
+The	O
+HBsAg	O
+positive	O
+rate	O
+in	O
+neonates	O
+and	O
+in	O
+infants	O
+before	O
+two	O
+months	O
+were	O
+3	O
+%	O
+and	O
+2	O
+%	O
+respectively	O
+.	O
+
+Some	O
+problems	O
+may	O
+arise	O
+,	O
+because	O
+27	O
+to	O
+30	O
+%	O
+of	O
+infants	O
+need	O
+the	O
+fourth	O
+vaccination	O
+in	O
+some	O
+restricted	O
+areas	O
+.	O
+
+Involvement	O
+of	O
+the	O
+mu	O
+-	O
+opiate	O
+receptor	O
+in	O
+peripheral	O
+analgesia	B
+.	O
+
+The	O
+intradermal	O
+injection	O
+of	O
+mu	O
+(	O
+morphine	O
+,	O
+Tyr	O
+-	O
+D	O
+-	O
+Ala	O
+-	O
+Gly	O
+-	O
+NMe	O
+-	O
+Phe	O
+-	O
+Gly	O
+-	O
+ol	O
+and	O
+morphiceptin	O
+)	O
+,	O
+kappa	O
+(	O
+trans	O
+-	O
+3	O
+,	O
+4	O
+-	O
+dichloro	O
+-	O
+N	O
+-	O
+methyl	O
+-	O
+N	O
+[	O
+2	O
+-	O
+(	O
+1	O
+-	O
+pyrrolidinyl	O
+)	O
+cyclohexyl	O
+]	O
+benzeneactemide	O
+)	O
+and	O
+delta	O
+(	O
+[	O
+D	O
+-	O
+Pen2	O
+.	O
+5	O
+]	O
+-	O
+enkephalin	O
+and	O
+[	O
+D	O
+-	O
+Ser2	O
+]	O
+-	O
+[	O
+Leu	O
+]	O
+enkephalin	O
+-	O
+Thr	O
+)	O
+selective	O
+opioid	O
+-	O
+agonists	O
+,	O
+by	O
+themselves	O
+,	O
+did	O
+not	O
+significantly	O
+affect	O
+the	O
+mechanical	O
+nociceptive	O
+threshold	O
+in	O
+the	O
+hindpaw	O
+of	O
+the	O
+rat	O
+.	O
+
+Intradermal	O
+injection	O
+of	O
+mu	O
+,	O
+but	O
+not	O
+delta	O
+or	O
+kappa	O
+opioid	O
+-	O
+agonists	O
+,	O
+however	O
+,	O
+produced	O
+dose	O
+-	O
+dependent	O
+inhibition	O
+of	O
+prostaglandin	O
+E2	O
+-	O
+induced	O
+hyperalgesia	B
+.	O
+
+The	O
+analgesic	O
+effect	O
+of	O
+the	O
+mu	O
+-	O
+agonist	O
+morphine	O
+was	O
+dose	O
+-	O
+dependently	O
+antagonized	O
+by	O
+naloxone	O
+and	O
+prevented	O
+by	O
+co	O
+-	O
+injection	O
+of	O
+pertussis	O
+toxin	O
+.	O
+
+Morphine	O
+did	O
+not	O
+,	O
+however	O
+,	O
+alter	O
+the	O
+hyperalgesia	B
+induced	O
+by	O
+8	O
+-	O
+bromo	O
+cyclic	O
+adenosine	O
+monophosphate	O
+.	O
+
+We	O
+conclude	O
+that	O
+the	O
+analgesic	O
+action	O
+of	O
+opioids	O
+on	O
+the	O
+peripheral	O
+terminals	O
+of	O
+primary	O
+afferents	O
+is	O
+via	O
+a	O
+binding	O
+site	O
+with	O
+characteristics	O
+of	O
+the	O
+mu	O
+-	O
+opioid	O
+receptor	O
+and	O
+that	O
+this	O
+action	O
+is	O
+mediated	O
+by	O
+inhibition	O
+of	O
+the	O
+cyclic	O
+adenosine	O
+monophosphate	O
+second	O
+messenger	O
+system	O
+.	O
+
+Involvement	O
+of	O
+locus	O
+coeruleus	O
+and	O
+noradrenergic	O
+neurotransmission	O
+in	O
+fentanyl	O
+-	O
+induced	O
+muscular	B
+rigidity	I
+in	O
+the	O
+rat	O
+.	O
+
+Whereas	O
+muscular	B
+rigidity	I
+is	O
+a	O
+well	O
+-	O
+known	O
+side	O
+effect	O
+that	O
+is	O
+associated	O
+with	O
+high	O
+-	O
+dose	O
+fentanyl	O
+anesthesia	O
+,	O
+a	O
+paucity	O
+of	O
+information	O
+exists	O
+with	O
+regard	O
+to	O
+its	O
+underlying	O
+mechanism	O
+(	O
+s	O
+)	O
+.	O
+
+We	O
+investigated	O
+in	O
+this	O
+study	O
+the	O
+possible	O
+engagement	O
+of	O
+locus	O
+coeruleus	O
+of	O
+the	O
+pons	O
+in	O
+this	O
+phenomenon	O
+,	O
+using	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+anesthetized	O
+with	O
+ketamine	O
+.	O
+
+Under	O
+proper	O
+control	O
+of	O
+respiration	O
+,	O
+body	O
+temperature	O
+and	O
+end	O
+-	O
+tidal	O
+CO2	O
+,	O
+intravenous	O
+administration	O
+of	O
+fentanyl	O
+(	O
+50	O
+or	O
+100	O
+micrograms	O
+/	O
+kg	O
+)	O
+consistently	O
+promoted	O
+an	O
+increase	O
+in	O
+electromyographic	O
+activity	O
+recorded	O
+from	O
+the	O
+gastrocnemius	O
+and	O
+abdominal	O
+rectus	O
+muscles	O
+.	O
+
+Such	O
+an	O
+induced	O
+muscular	B
+rigidity	I
+by	O
+the	O
+narcotic	O
+agent	O
+was	O
+significantly	O
+antagonized	O
+or	O
+even	O
+reduced	O
+by	O
+prior	O
+electrolytic	O
+lesions	O
+of	O
+the	O
+locus	O
+coeruleus	O
+or	O
+pretreatment	O
+with	O
+the	O
+alpha	O
+-	O
+adrenoceptor	O
+blocker	O
+,	O
+prazosin	O
+.	O
+
+Microinjection	O
+of	O
+fentanyl	O
+(	O
+2	O
+.	O
+5	O
+micrograms	O
+/	O
+50	O
+nl	O
+)	O
+directly	O
+into	O
+this	O
+pontine	O
+nucleus	O
+,	O
+on	O
+the	O
+other	O
+hand	O
+,	O
+elicited	O
+discernible	O
+electromyographic	O
+excitation	O
+.	O
+
+It	O
+is	O
+speculated	O
+that	O
+the	O
+induction	O
+of	O
+muscular	B
+rigidity	I
+by	O
+fentanyl	O
+may	O
+involve	O
+the	O
+coerulospinal	O
+noradrenergic	O
+fibers	O
+to	O
+the	O
+spinal	O
+motoneurons	O
+.	O
+
+Dexmedetomidine	O
+,	O
+acting	O
+through	O
+central	O
+alpha	O
+-	O
+2	O
+adrenoceptors	O
+,	O
+prevents	O
+opiate	O
+-	O
+induced	O
+muscle	B
+rigidity	I
+in	O
+the	O
+rat	O
+.	O
+
+The	O
+highly	O
+-	O
+selective	O
+alpha	O
+-	O
+2	O
+adrenergic	O
+agonist	O
+dexmedetomidine	O
+(	O
+D	O
+-	O
+MED	O
+)	O
+is	O
+capable	O
+of	O
+inducing	O
+muscle	B
+flaccidity	I
+and	O
+anesthesia	O
+in	O
+rats	O
+and	O
+dogs	O
+.	O
+
+Intense	O
+generalized	O
+muscle	B
+rigidity	I
+is	O
+an	O
+undesirable	O
+side	O
+effect	O
+of	O
+potent	O
+opiate	O
+agonists	O
+.	O
+
+Although	O
+the	O
+neurochemistry	O
+of	O
+opiate	O
+-	O
+induced	O
+rigidity	B
+has	O
+yet	O
+to	O
+be	O
+fully	O
+elucidated	O
+,	O
+recent	O
+work	O
+suggests	O
+a	O
+role	O
+for	O
+a	O
+central	O
+adrenergic	O
+mechanism	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+the	O
+authors	O
+determined	O
+if	O
+treatment	O
+with	O
+D	O
+-	O
+MED	O
+prevents	O
+the	O
+muscle	B
+rigidity	I
+caused	O
+by	O
+high	O
+-	O
+dose	O
+alfentanil	O
+anesthesia	O
+in	O
+the	O
+rat	O
+.	O
+
+Animals	O
+(	O
+n	O
+=	O
+42	O
+)	O
+were	O
+treated	O
+intraperitoneally	O
+with	O
+one	O
+of	O
+the	O
+following	O
+six	O
+regimens	O
+:	O
+1	O
+)	O
+L	O
+-	O
+MED	O
+(	O
+the	O
+inactive	O
+L	O
+-	O
+isomer	O
+of	O
+medetomidine	O
+)	O
+,	O
+30	O
+micrograms	O
+/	O
+kg	O
+;	O
+2	O
+)	O
+D	O
+-	O
+MED	O
+,	O
+10	O
+micrograms	O
+/	O
+kg	O
+;	O
+3	O
+)	O
+D	O
+-	O
+MED	O
+,	O
+30	O
+micrograms	O
+/	O
+kg	O
+;	O
+4	O
+)	O
+D	O
+-	O
+MED	O
+[	O
+30	O
+micrograms	O
+/	O
+kg	O
+]	O
+and	O
+the	O
+central	O
+-	O
+acting	O
+alpha	O
+-	O
+2	O
+antagonist	O
+,	O
+idazoxan	O
+[	O
+10	O
+mg	O
+/	O
+kg	O
+]	O
+;	O
+5	O
+)	O
+D	O
+-	O
+MED	O
+[	O
+30	O
+micrograms	O
+/	O
+kg	O
+]	O
+and	O
+the	O
+peripheral	O
+-	O
+acting	O
+alpha	O
+-	O
+2	O
+antagonist	O
+DG	O
+-	O
+5128	O
+[	O
+10	O
+mg	O
+/	O
+kg	O
+]	O
+,	O
+or	O
+;	O
+6	O
+)	O
+saline	O
+.	O
+
+Baseline	O
+electromyographic	O
+activity	O
+was	O
+recorded	O
+from	O
+the	O
+gastrocnemius	O
+muscle	O
+before	O
+and	O
+after	O
+drug	O
+treatment	O
+.	O
+
+Each	O
+rat	O
+was	O
+then	O
+injected	O
+with	O
+alfentanil	O
+(	O
+ALF	O
+,	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+sc	O
+)	O
+.	O
+
+ALF	O
+injection	O
+resulted	O
+in	O
+a	O
+marked	O
+increase	O
+in	O
+hindlimb	O
+EMG	O
+activity	O
+in	O
+the	O
+L	O
+-	O
+MED	O
+treatment	O
+group	O
+which	O
+was	O
+indistinguishable	O
+from	O
+that	O
+seen	O
+in	O
+animals	O
+treated	O
+with	O
+saline	O
+.	O
+
+In	O
+contrast	O
+,	O
+D	O
+-	O
+MED	O
+prevented	O
+alfentanil	O
+-	O
+induced	O
+muscle	B
+rigidity	I
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+fashion	O
+.	O
+
+The	O
+small	O
+EMG	O
+values	O
+obtained	O
+in	O
+the	O
+high	O
+-	O
+dose	O
+D	O
+-	O
+MED	O
+group	O
+were	O
+comparable	O
+with	O
+those	O
+recorded	O
+in	O
+earlier	O
+studies	O
+from	O
+control	O
+animals	O
+not	O
+given	O
+any	O
+opiate	O
+.	O
+
+The	O
+high	O
+-	O
+dose	O
+D	O
+-	O
+MED	O
+animals	O
+were	O
+flaccid	O
+,	O
+akinetic	B
+,	O
+and	O
+lacked	O
+a	O
+startle	B
+response	O
+during	O
+the	O
+entire	O
+experimental	O
+period	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Some	O
+central	O
+effects	O
+of	O
+repeated	O
+treatment	O
+with	O
+fluvoxamine	O
+.	O
+
+We	O
+investigated	O
+the	O
+effect	O
+of	O
+repeated	O
+treatment	O
+with	O
+fluvoxamine	O
+,	O
+a	O
+selective	O
+serotonin	O
+uptake	O
+inhibitor	O
+,	O
+on	O
+behavioral	O
+effects	O
+of	O
+dopaminomimetics	O
+and	O
+methoxamine	O
+and	O
+on	O
+the	O
+animal	O
+behavior	O
+in	O
+the	O
+"	O
+behavioral	O
+despair	O
+"	O
+test	O
+.	O
+
+A	O
+repeated	O
+treatment	O
+with	O
+fluvoxamine	O
+(	O
+twice	O
+daily	O
+for	O
+14	O
+days	O
+)	O
+potentiated	O
+in	O
+mice	O
+and	O
+in	O
+rats	O
+(	O
+weaker	O
+)	O
+the	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B
+.	O
+
+The	O
+hyperactivity	B
+induced	O
+by	O
+nomifensine	O
+in	O
+mice	O
+remained	O
+unaffected	O
+by	O
+fluvoxamine	O
+.	O
+
+The	O
+stimulation	O
+of	O
+locomotor	O
+activity	O
+by	O
+intracerebroventricularly	O
+administered	O
+methoxamine	O
+was	O
+not	O
+affected	O
+by	O
+repeated	O
+treatment	O
+with	O
+fluvoxamine	O
+.	O
+
+Given	O
+three	O
+times	O
+fluvoxamine	O
+had	O
+no	O
+effect	O
+on	O
+the	O
+immobilization	O
+time	O
+in	O
+the	O
+"	O
+behavioral	O
+despair	O
+"	O
+test	O
+in	O
+rats	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+fluvoxamine	O
+given	O
+repeatedly	O
+acts	O
+differently	O
+than	O
+citalopram	O
+,	O
+another	O
+selective	O
+serotonin	O
+uptake	O
+inhibitor	O
+,	O
+and	O
+differs	O
+also	O
+from	O
+other	O
+antidepressant	O
+drugs	O
+.	O
+
+Protective	O
+effect	O
+of	O
+a	O
+specific	O
+platelet	O
+-	O
+activating	O
+factor	O
+antagonist	O
+,	O
+BN	O
+52021	O
+,	O
+on	O
+bupivacaine	O
+-	O
+induced	O
+cardiovascular	B
+impairments	I
+in	O
+rats	O
+.	O
+
+Administration	O
+of	O
+the	O
+local	O
+anaesthetic	O
+bupivacaine	O
+(	O
+1	O
+.	O
+5	O
+or	O
+2	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+v	O
+.	O
+)	O
+to	O
+rats	O
+elicited	O
+a	O
+marked	O
+decrease	B
+of	I
+mean	I
+arterial	I
+blood	I
+pressure	I
+(	I
+MBP	I
+)	I
+and	I
+heart	I
+rate	I
+(	I
+HR	I
+)	I
+leading	O
+to	O
+death	O
+(	O
+in	O
+67	O
+%	O
+or	O
+90	O
+%	O
+of	O
+animals	O
+respectively	O
+)	O
+.	O
+
+Intravenous	O
+injection	O
+of	O
+the	O
+specific	O
+platelet	O
+-	O
+activating	O
+factor	O
+(	O
+PAF	O
+)	O
+antagonist	O
+BN	O
+52021	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+30	O
+min	O
+before	O
+bupivacaine	O
+administration	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+suppressed	O
+both	O
+the	O
+decrease	B
+of	I
+MBP	I
+and	I
+HR	I
+.	O
+
+In	O
+contrast	O
+,	O
+doses	O
+of	O
+1	O
+mg	O
+/	O
+kg	O
+BN	O
+52021	O
+given	O
+30	O
+min	O
+before	O
+or	O
+10	O
+mg	O
+/	O
+kg	O
+administered	O
+5	O
+min	O
+before	O
+i	O
+.	O
+v	O
+.	O
+injection	O
+of	O
+bupivacaine	O
+were	O
+ineffective	O
+.	O
+
+When	O
+BN	O
+52021	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+was	O
+injected	O
+immediately	O
+after	O
+bupivacaine	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+a	O
+partial	O
+reversion	O
+of	O
+the	O
+decrease	B
+of	I
+MBP	I
+and	I
+HR	I
+was	O
+observed	O
+,	O
+whereas	O
+the	O
+dose	O
+of	O
+10	O
+mg	O
+/	O
+kg	O
+was	O
+ineffective	O
+.	O
+
+A	O
+partial	O
+recovery	O
+of	O
+bupivacaine	O
+-	O
+induced	O
+ECG	O
+alterations	O
+was	O
+observed	O
+after	O
+pretreatment	O
+of	O
+the	O
+rats	O
+with	O
+BN	O
+52021	O
+.	O
+
+Since	O
+the	O
+administration	O
+of	O
+BN	O
+52021	O
+,	O
+at	O
+all	O
+doses	O
+studied	O
+,	O
+did	O
+not	O
+alter	O
+MBP	O
+and	O
+HR	O
+at	O
+the	O
+doses	O
+used	O
+,	O
+the	O
+bulk	O
+of	O
+these	O
+results	O
+clearly	O
+demonstrate	O
+a	O
+protective	O
+action	O
+of	O
+BN	O
+52021	O
+,	O
+a	O
+specific	O
+antagonist	O
+of	O
+PAF	O
+,	O
+against	O
+bupivacaine	O
+-	O
+induced	O
+cardiovascular	B
+toxicity	I
+.	O
+
+Thus	O
+,	O
+consistent	O
+with	O
+its	O
+direct	O
+effect	O
+on	O
+heart	O
+,	O
+PAF	O
+appears	O
+to	O
+be	O
+implicated	O
+in	O
+bupivacaine	O
+-	O
+induced	O
+cardiovascular	B
+alterations	I
+.	O
+
+The	O
+epidemiology	O
+of	O
+the	O
+acute	O
+flank	B
+pain	I
+syndrome	O
+from	O
+suprofen	O
+.	O
+
+Suprofen	O
+,	O
+a	O
+new	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drug	O
+,	O
+was	O
+marketed	O
+in	O
+early	O
+1986	O
+as	O
+an	O
+analgesic	O
+agent	O
+.	O
+
+Until	O
+physicians	O
+began	O
+reporting	O
+an	O
+unusual	O
+acute	O
+flank	B
+pain	I
+syndrome	O
+to	O
+the	O
+spontaneous	O
+reporting	O
+system	O
+,	O
+700	O
+,	O
+000	O
+persons	O
+used	O
+the	O
+drug	O
+in	O
+the	O
+United	O
+States	O
+.	O
+
+Through	O
+August	O
+1986	O
+,	O
+a	O
+total	O
+of	O
+163	O
+cases	O
+of	O
+this	O
+syndrome	O
+were	O
+reported	O
+.	O
+
+To	O
+elucidate	O
+the	O
+epidemiology	O
+of	O
+the	O
+syndrome	O
+,	O
+a	O
+case	O
+-	O
+control	O
+study	O
+was	O
+performed	O
+,	O
+comparing	O
+62	O
+of	O
+the	O
+case	O
+patients	O
+who	O
+had	O
+been	O
+reported	O
+to	O
+the	O
+spontaneous	O
+reporting	O
+system	O
+to	O
+185	O
+suprofen	O
+-	O
+exposed	O
+control	O
+subjects	O
+who	O
+did	O
+not	O
+have	O
+the	O
+syndrome	O
+.	O
+
+Case	O
+patients	O
+were	O
+more	O
+likely	O
+to	O
+be	O
+men	O
+(	O
+odds	O
+ratio	O
+,	O
+3	O
+.	O
+8	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+1	O
+.	O
+2	O
+-	O
+12	O
+.	O
+1	O
+)	O
+,	O
+suffer	O
+from	O
+hay	B
+fever	I
+and	O
+asthma	B
+(	O
+odds	O
+ratio	O
+,	O
+3	O
+.	O
+4	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+1	O
+.	O
+0	O
+-	O
+11	O
+.	O
+9	O
+)	O
+;	O
+to	O
+participate	O
+in	O
+regular	O
+exercise	O
+(	O
+odds	O
+ratio	O
+,	O
+5	O
+.	O
+9	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+1	O
+.	O
+1	O
+-	O
+30	O
+.	O
+7	O
+)	O
+,	O
+especially	O
+in	O
+the	O
+use	O
+of	O
+Nautilus	O
+equipment	O
+(	O
+p	O
+=	O
+0	O
+.	O
+02	O
+)	O
+;	O
+and	O
+to	O
+use	O
+alcohol	O
+(	O
+odds	O
+ratio	O
+,	O
+4	O
+.	O
+4	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+1	O
+.	O
+1	O
+-	O
+17	O
+.	O
+5	O
+)	O
+.	O
+
+Possible	O
+risk	O
+factors	O
+included	O
+young	O
+age	O
+,	O
+concurrent	O
+use	O
+of	O
+other	O
+analgesic	O
+agents	O
+(	O
+especially	O
+ibuprofen	O
+)	O
+,	O
+preexisting	O
+renal	B
+disease	I
+,	O
+a	O
+history	O
+of	O
+kidney	B
+stones	I
+,	O
+a	O
+history	O
+of	O
+gout	B
+,	O
+a	O
+recent	O
+increase	O
+in	O
+activity	O
+,	O
+a	O
+recent	O
+increase	O
+in	O
+sun	O
+exposure	O
+,	O
+and	O
+residence	O
+in	O
+the	O
+Sunbelt	O
+.	O
+
+These	O
+were	O
+findings	O
+that	O
+were	O
+suggestive	O
+but	O
+did	O
+not	O
+reach	O
+conventional	O
+statistical	O
+significance	O
+.	O
+
+These	O
+findings	O
+are	O
+consistent	O
+with	O
+the	O
+postulated	O
+mechanism	O
+for	O
+this	O
+unusual	O
+syndrome	O
+:	O
+acute	O
+diffuse	O
+crystallization	O
+of	O
+uric	O
+acid	O
+in	O
+renal	O
+tubules	O
+.	O
+
+Phlorizin	O
+-	O
+induced	O
+glycosuria	B
+does	O
+not	O
+prevent	O
+gentamicin	O
+nephrotoxicity	B
+in	O
+rats	O
+.	O
+
+Because	O
+rats	O
+with	O
+streptozotocin	O
+-	O
+induced	O
+diabetes	B
+mellitus	I
+(	O
+DM	B
+)	O
+have	O
+a	O
+high	O
+solute	O
+diuresis	O
+(	O
+glycosuria	B
+of	O
+10	O
+to	O
+12	O
+g	O
+/	O
+day	O
+)	O
+,	O
+we	O
+have	O
+suggested	O
+that	O
+this	O
+may	O
+in	O
+part	O
+be	O
+responsible	O
+for	O
+their	O
+resistance	O
+to	O
+gentamicin	O
+-	O
+induced	O
+acute	B
+renal	I
+failure	I
+(	O
+ARF	B
+)	O
+.	O
+
+The	O
+protection	O
+from	O
+gentamicin	O
+nephrotoxicity	B
+was	O
+studied	O
+in	O
+non	O
+-	O
+diabetic	B
+rats	O
+with	O
+chronic	O
+solute	O
+diuresis	O
+induced	O
+by	O
+blockage	O
+of	O
+tubular	O
+glucose	O
+reabsorption	O
+with	O
+phlorizin	O
+(	O
+P	O
+)	O
+.	O
+
+DM	B
+rats	O
+with	O
+mild	O
+glycosuria	B
+(	O
+similar	O
+in	O
+degree	O
+to	O
+that	O
+of	O
+the	O
+P	O
+treated	O
+animals	O
+)	O
+were	O
+also	O
+studied	O
+.	O
+
+Unanesthetized	O
+adult	O
+female	O
+,	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+were	O
+divided	O
+in	O
+four	O
+groups	O
+and	O
+studied	O
+for	O
+15	O
+days	O
+.	O
+
+Group	O
+1	O
+(	O
+P	O
+alone	O
+)	O
+received	O
+P	O
+,	O
+360	O
+mg	O
+/	O
+day	O
+,	O
+for	O
+15	O
+days	O
+;	O
+Group	O
+II	O
+(	O
+P	O
++	O
+gentamicin	O
+)	O
+;	O
+Group	O
+III	O
+(	O
+gentamicin	O
+alone	O
+)	O
+and	O
+Group	O
+IV	O
+(	O
+mild	O
+DM	B
++	O
+gentamicin	O
+)	O
+.	O
+
+Nephrotoxic	B
+doses	O
+(	O
+40	O
+mg	O
+/	O
+kg	O
+body	O
+wt	O
+/	O
+day	O
+)	O
+of	O
+gentamicin	O
+were	O
+injected	O
+during	O
+the	O
+last	O
+nine	O
+days	O
+of	O
+study	O
+to	O
+the	O
+animals	O
+of	O
+groups	O
+II	O
+to	O
+IV	O
+.	O
+
+In	O
+Group	O
+I	O
+,	O
+P	O
+induced	O
+a	O
+moderate	O
+and	O
+stable	O
+glycosuria	B
+(	O
+3	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+g	O
+/	O
+day	O
+,	O
+SE	O
+)	O
+,	O
+and	O
+no	O
+functional	O
+or	O
+morphologic	O
+evidence	O
+of	O
+renal	B
+dysfunction	I
+(	O
+baseline	O
+CCr	O
+2	O
+.	O
+1	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+ml	O
+/	O
+min	O
+,	O
+undetectable	O
+lysozymuria	O
+)	O
+or	O
+damage	O
+(	O
+tubular	B
+necrosis	I
+score	O
+[	O
+maximum	O
+4	O
+]	O
+,	O
+zero	O
+)	O
+.	O
+
+In	O
+Group	O
+II	O
+,	O
+P	O
+did	O
+not	O
+prevent	O
+gentamicin	O
+-	O
+ARF	B
+(	O
+maximal	O
+decrease	O
+in	O
+CCr	O
+at	O
+day	O
+9	O
+.	O
+89	O
+%	O
+,	O
+P	O
+less	O
+than	O
+0	O
+.	O
+001	O
+;	O
+peak	O
+lysozymuria	O
+,	O
+1863	O
++	O
+/	O
+-	O
+321	O
+micrograms	O
+/	O
+day	O
+;	O
+and	O
+tubular	B
+necrosis	I
+score	O
+,	O
+3	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+)	O
+.	O
+
+These	O
+values	O
+were	O
+not	O
+different	O
+from	O
+those	O
+of	O
+Group	O
+III	O
+:	O
+maximal	O
+decrease	O
+in	O
+CCr	O
+73	O
+%	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+;	O
+lysozymuria	O
+,	O
+2147	O
++	O
+/	O
+-	O
+701	O
+micrograms	O
+/	O
+day	O
+;	O
+tubular	B
+necrosis	I
+score	O
+,	O
+3	O
+.	O
+8	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Catalepsy	B
+induced	O
+by	O
+combinations	O
+of	O
+ketamine	O
+and	O
+morphine	O
+:	O
+potentiation	O
+,	O
+antagonism	O
+,	O
+tolerance	O
+and	O
+cross	O
+-	O
+tolerance	O
+in	O
+the	O
+rat	O
+.	O
+
+Previous	O
+studies	O
+demonstrated	O
+that	O
+both	O
+ketamine	O
+and	O
+morphine	O
+induced	O
+analgesia	B
+and	O
+catalepsy	B
+in	O
+the	O
+rat	O
+.	O
+
+Pre	O
+-	O
+treatment	O
+with	O
+ketamine	O
+produced	O
+cross	O
+-	O
+tolerance	O
+to	O
+morphine	O
+,	O
+whereas	O
+pretreatment	O
+with	O
+morphine	O
+did	O
+not	O
+induce	O
+cross	O
+-	O
+tolerance	O
+to	O
+ketamine	O
+but	O
+rather	O
+augmented	O
+the	O
+cataleptic	B
+response	O
+;	O
+this	O
+augmentation	O
+was	O
+attributed	O
+to	O
+residual	O
+morphine	O
+in	O
+the	O
+brain	O
+.	O
+
+The	O
+present	O
+studies	O
+explored	O
+the	O
+duration	O
+of	O
+the	O
+loss	O
+of	O
+righting	O
+reflex	O
+induced	O
+by	O
+sub	O
+-	O
+effective	O
+doses	O
+of	O
+ketamine	O
+and	O
+morphine	O
+,	O
+administered	O
+simultaneously	O
+.	O
+
+There	O
+was	O
+mutual	O
+potentiation	O
+between	O
+sub	O
+-	O
+effective	O
+doses	O
+of	O
+ketamine	O
+and	O
+morphine	O
+,	O
+but	O
+sub	O
+-	O
+effective	O
+doses	O
+of	O
+ketamine	O
+partly	O
+antagonized	O
+fully	O
+-	O
+effective	O
+doses	O
+of	O
+morphine	O
+.	O
+
+Latency	O
+to	O
+the	O
+loss	O
+of	O
+righting	O
+reflex	O
+,	O
+rigidity	B
+and	O
+behavior	O
+on	O
+recovery	O
+,	O
+reflected	O
+the	O
+relative	O
+predominance	O
+of	O
+ketamine	O
+or	O
+morphine	O
+in	O
+each	O
+combination	O
+.	O
+
+Naloxone	O
+inhibited	O
+the	O
+induced	O
+cataleptic	B
+effects	O
+.	O
+
+The	O
+degree	O
+and	O
+time	O
+course	O
+of	O
+development	O
+of	O
+tolerance	O
+to	O
+daily	O
+administration	O
+of	O
+sub	O
+-	O
+effective	O
+dose	O
+combinations	O
+of	O
+ketamine	O
+and	O
+morphine	O
+were	O
+similar	O
+.	O
+
+Rats	O
+,	O
+tolerant	O
+to	O
+ketamine	O
+-	O
+dominant	O
+combinations	O
+,	O
+were	O
+cross	O
+-	O
+tolerant	O
+to	O
+both	O
+drugs	O
+,	O
+while	O
+those	O
+tolerant	O
+to	O
+morphine	O
+-	O
+dominant	O
+combinations	O
+were	O
+cross	O
+-	O
+tolerant	O
+to	O
+morphine	O
+but	O
+showed	O
+either	O
+no	O
+cross	O
+-	O
+tolerance	O
+or	O
+an	O
+augmented	O
+response	O
+to	O
+ketamine	O
+.	O
+
+While	O
+the	O
+mutual	O
+potentiation	O
+,	O
+antagonism	O
+and	O
+tolerance	O
+suggest	O
+common	O
+mechanisms	O
+for	O
+the	O
+induced	O
+catalepsy	B
+,	O
+differences	O
+in	O
+latency	O
+,	O
+rigidity	B
+and	O
+behavior	O
+,	O
+asymmetry	O
+of	O
+cross	O
+-	O
+tolerance	O
+and	O
+a	O
+widely	O
+-	O
+different	O
+ID50	O
+for	O
+naloxone	O
+would	O
+argue	O
+against	O
+an	O
+action	O
+at	O
+a	O
+single	O
+opioid	O
+site	O
+.	O
+
+Hydrocortisone	O
+-	O
+induced	O
+hypertension	B
+in	O
+humans	O
+:	O
+pressor	O
+responsiveness	O
+and	O
+sympathetic	O
+function	O
+.	O
+
+Oral	O
+hydrocortisone	O
+increases	O
+blood	O
+pressure	O
+and	O
+enhances	O
+pressor	O
+responsiveness	O
+in	O
+normal	O
+human	O
+subjects	O
+.	O
+
+We	O
+studied	O
+the	O
+effects	O
+of	O
+1	O
+week	O
+of	O
+oral	O
+hydrocortisone	O
+(	O
+200	O
+mg	O
+/	O
+day	O
+)	O
+on	O
+blood	O
+pressure	O
+,	O
+cardiac	O
+output	O
+,	O
+total	O
+peripheral	O
+resistance	O
+,	O
+forearm	O
+vascular	O
+resistance	O
+,	O
+and	O
+norepinephrine	O
+spillover	O
+to	O
+plasma	O
+in	O
+eight	O
+healthy	O
+male	O
+volunteers	O
+.	O
+
+Although	O
+diastolic	O
+blood	O
+pressure	O
+remained	O
+unchanged	O
+,	O
+systolic	O
+blood	O
+pressure	O
+increased	O
+from	O
+119	O
+to	O
+135	O
+mm	O
+Hg	O
+(	O
+SED	O
++	O
+/	O
+-	O
+3	O
+.	O
+4	O
+,	O
+p	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+,	O
+associated	O
+with	O
+an	O
+increased	B
+cardiac	I
+output	I
+(	O
+5	O
+.	O
+85	O
+-	O
+7	O
+.	O
+73	O
+l	O
+/	O
+min	O
+,	O
+SED	O
++	O
+/	O
+-	O
+0	O
+.	O
+46	O
+,	O
+p	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+Total	O
+peripheral	O
+vascular	O
+resistance	O
+fell	O
+from	O
+15	O
+.	O
+1	O
+to	O
+12	O
+.	O
+2	O
+mm	O
+Hg	O
+/	O
+l	O
+/	O
+min	O
+(	O
+SED	O
++	O
+/	O
+-	O
+1	O
+.	O
+03	O
+,	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Resting	O
+forearm	O
+vascular	O
+resistance	O
+remained	O
+unchanged	O
+,	O
+but	O
+the	O
+reflex	O
+response	O
+to	O
+the	O
+cold	O
+pressor	O
+test	O
+was	O
+accentuated	O
+,	O
+the	O
+rise	O
+in	O
+resistance	O
+increasing	O
+from	O
+10	O
+.	O
+5	O
+mm	O
+Hg	O
+/	O
+ml	O
+/	O
+100	O
+ml	O
+/	O
+min	O
+(	O
+R	O
+units	O
+)	O
+before	O
+treatment	O
+to	O
+32	O
+.	O
+6	O
+R	O
+units	O
+after	O
+treatment	O
+(	O
+SED	O
++	O
+/	O
+-	O
+6	O
+.	O
+4	O
+,	O
+p	O
+less	O
+than	O
+0	O
+.	O
+025	O
+)	O
+.	O
+
+The	O
+rise	O
+in	O
+forearm	O
+vascular	O
+resistance	O
+accompanying	O
+intra	O
+-	O
+arterial	O
+norepinephrine	O
+(	O
+25	O
+,	O
+50	O
+,	O
+and	O
+100	O
+ng	O
+/	O
+min	O
+)	O
+was	O
+also	O
+significantly	O
+greater	O
+after	O
+hydrocortisone	O
+,	O
+increasing	O
+from	O
+an	O
+average	O
+of	O
+14	O
+.	O
+9	O
++	O
+/	O
+-	O
+2	O
+.	O
+4	O
+R	O
+units	O
+before	O
+treatment	O
+to	O
+35	O
+.	O
+1	O
++	O
+/	O
+-	O
+5	O
+.	O
+5	O
+R	O
+units	O
+after	O
+hydrocortisone	O
+(	O
+SED	O
++	O
+/	O
+-	O
+6	O
+.	O
+0	O
+,	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+A	O
+shift	O
+to	O
+the	O
+left	O
+in	O
+the	O
+dose	O
+-	O
+response	O
+relation	O
+and	O
+fall	O
+in	O
+threshold	O
+suggested	O
+increased	O
+sensitivity	O
+to	O
+norepinephrine	O
+after	O
+treatment	O
+.	O
+
+Measurement	O
+of	O
+resting	O
+norepinephrine	O
+spillover	O
+rate	O
+to	O
+plasma	O
+and	O
+norepinephrine	O
+uptake	O
+indicated	O
+that	O
+overall	O
+resting	O
+sympathetic	O
+nervous	O
+system	O
+activity	O
+was	O
+not	O
+increased	O
+.	O
+
+The	O
+rise	B
+in	I
+resting	I
+blood	I
+pressure	I
+with	O
+hydrocortisone	O
+is	O
+associated	O
+with	O
+an	O
+increased	B
+cardiac	I
+output	I
+(	O
+presumably	O
+due	O
+to	O
+increased	O
+blood	O
+volume	O
+)	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Neuromuscular	B
+blockade	I
+with	O
+magnesium	O
+sulfate	O
+and	O
+nifedipine	O
+.	O
+
+A	O
+patient	O
+who	O
+received	O
+tocolysis	O
+with	O
+nifedipine	O
+developed	O
+neuromuscular	B
+blockade	I
+after	O
+500	O
+mg	O
+of	O
+magnesium	O
+sulfate	O
+was	O
+administered	O
+.	O
+
+This	O
+reaction	O
+demonstrates	O
+that	O
+nifedipine	O
+can	O
+seriously	O
+potentiate	O
+the	O
+toxicity	B
+of	O
+magnesium	O
+.	O
+
+Caution	O
+should	O
+be	O
+exercised	O
+when	O
+these	O
+two	O
+tocolytics	O
+are	O
+combined	O
+.	O
+
+Chronic	O
+carbamazepine	O
+inhibits	O
+the	O
+development	O
+of	O
+local	O
+anesthetic	O
+seizures	B
+kindled	O
+by	O
+cocaine	O
+and	O
+lidocaine	O
+.	O
+
+The	O
+effects	O
+of	O
+carbamazepine	O
+(	O
+CBZ	O
+)	O
+treatment	O
+on	O
+local	O
+anesthetic	O
+-	O
+kindled	O
+seizures	B
+and	O
+lethality	O
+were	O
+evaluated	O
+in	O
+different	O
+stages	O
+of	O
+the	O
+kindling	O
+process	O
+and	O
+under	O
+different	O
+methods	O
+of	O
+CBZ	O
+administration	O
+.	O
+
+Chronic	O
+oral	O
+CBZ	O
+inhibited	O
+the	O
+development	O
+of	O
+both	O
+lidocaine	O
+-	O
+and	O
+cocaine	O
+-	O
+induced	O
+seizures	B
+,	O
+but	O
+had	O
+little	O
+effect	O
+on	O
+the	O
+fully	O
+developed	O
+local	O
+anesthetic	O
+seizures	B
+.	O
+
+Chronic	O
+CBZ	O
+also	O
+decreased	O
+the	O
+incidence	O
+of	O
+seizure	B
+-	O
+related	O
+mortality	O
+in	O
+the	O
+cocaine	O
+-	O
+injected	O
+rats	O
+.	O
+
+Acute	O
+CBZ	O
+over	O
+a	O
+range	O
+of	O
+doses	O
+(	O
+15	O
+-	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+had	O
+no	O
+effect	O
+on	O
+completed	O
+lidocaine	O
+-	O
+kindled	O
+or	O
+acute	O
+cocaine	O
+-	O
+induced	O
+seizures	B
+.	O
+
+Repeated	O
+i	O
+.	O
+p	O
+.	O
+injection	O
+of	O
+CBZ	O
+(	O
+15	O
+mg	O
+/	O
+kg	O
+)	O
+also	O
+was	O
+without	O
+effect	O
+on	O
+the	O
+development	O
+of	O
+lidocaine	O
+-	O
+or	O
+cocaine	O
+-	O
+kindled	O
+seizures	B
+.	O
+
+The	O
+differential	O
+effects	O
+of	O
+CBZ	O
+depending	O
+upon	O
+stage	O
+of	O
+seizure	B
+development	O
+suggest	O
+that	O
+distinct	O
+mechanisms	O
+underlie	O
+the	O
+development	O
+versus	O
+maintenance	O
+of	O
+local	O
+anesthetic	O
+-	O
+kindled	O
+seizures	B
+.	O
+
+The	O
+effectiveness	O
+of	O
+chronic	O
+but	O
+not	O
+repeated	O
+,	O
+intermittent	O
+injections	O
+of	O
+CBZ	O
+suggests	O
+that	O
+different	O
+biochemical	O
+consequences	O
+result	O
+from	O
+the	O
+different	O
+treatment	O
+regimens	O
+.	O
+
+The	O
+possible	O
+utility	O
+of	O
+chronic	O
+CBZ	O
+in	O
+preventing	O
+the	O
+development	O
+of	O
+toxic	O
+side	O
+effects	O
+in	O
+human	O
+cocaine	O
+users	O
+is	O
+suggested	O
+by	O
+these	O
+data	O
+,	O
+but	O
+remains	O
+to	O
+be	O
+directly	O
+evaluated	O
+.	O
+
+Magnetic	O
+resonance	O
+imaging	O
+of	O
+cerebral	O
+venous	B
+thrombosis	I
+secondary	O
+to	O
+"	O
+low	O
+-	O
+dose	O
+"	O
+birth	O
+control	O
+pills	O
+.	O
+
+The	O
+clinical	O
+and	O
+radiographic	O
+features	O
+of	O
+cerebral	O
+deep	B
+venous	I
+thrombosis	I
+in	O
+a	O
+21	O
+-	O
+year	O
+-	O
+old	O
+white	O
+woman	O
+are	O
+presented	O
+.	O
+
+This	O
+nulliparous	O
+patient	O
+presented	O
+with	O
+relatively	O
+mild	O
+clinical	O
+symptoms	O
+and	O
+progressing	O
+mental	O
+status	O
+changes	O
+.	O
+
+The	O
+only	O
+known	O
+risk	O
+factor	O
+was	O
+"	O
+low	O
+-	O
+dose	O
+"	O
+oral	O
+contraceptive	O
+pills	O
+.	O
+
+The	O
+magnetic	O
+resonance	O
+image	O
+(	O
+MRI	O
+)	O
+showed	O
+increased	O
+signal	O
+intensity	O
+from	O
+the	O
+internal	O
+cerebral	O
+veins	O
+,	O
+vein	O
+of	O
+Galen	O
+,	O
+and	O
+straight	O
+sinus	O
+.	O
+
+The	O
+diagnosis	O
+was	O
+confirmed	O
+by	O
+arterial	O
+angiography	O
+.	O
+
+Beta	O
+-	O
+2	O
+-	O
+adrenoceptor	O
+-	O
+mediated	O
+hypokalemia	B
+and	O
+its	O
+abolishment	O
+by	O
+oxprenolol	O
+.	O
+
+The	O
+time	O
+course	O
+and	O
+concentration	O
+-	O
+effect	O
+relationship	O
+of	O
+terbutaline	O
+-	O
+induced	O
+hypokalemia	B
+was	O
+studied	O
+,	O
+using	O
+computer	O
+-	O
+aided	O
+pharmacokinetic	O
+-	O
+dynamic	O
+modeling	O
+.	O
+
+Subsequently	O
+we	O
+investigated	O
+the	O
+efficacy	O
+of	O
+oxprenolol	O
+in	O
+antagonizing	O
+such	O
+hypokalemia	B
+,	O
+together	O
+with	O
+the	O
+pharmacokinetic	O
+interaction	O
+between	O
+both	O
+drugs	O
+.	O
+
+Six	O
+healthy	O
+subjects	O
+were	O
+given	O
+a	O
+0	O
+.	O
+5	O
+mg	O
+subcutaneous	O
+dose	O
+of	O
+terbutaline	O
+on	O
+two	O
+occasions	O
+:	O
+1	O
+hour	O
+after	O
+oral	O
+administration	O
+of	O
+a	O
+placebo	O
+and	O
+1	O
+hour	O
+after	O
+80	O
+mg	O
+oxprenolol	O
+orally	O
+.	O
+
+In	O
+the	O
+7	O
+-	O
+hour	O
+period	O
+after	O
+terbutaline	O
+administration	O
+,	O
+plasma	O
+samples	O
+were	O
+taken	O
+for	O
+determination	O
+of	O
+plasma	O
+potassium	O
+levels	O
+and	O
+drug	O
+concentrations	O
+.	O
+
+The	O
+sigmoid	O
+Emax	O
+model	O
+offered	O
+a	O
+good	O
+description	O
+of	O
+the	O
+relation	O
+between	O
+terbutaline	O
+concentrations	O
+and	O
+potassium	O
+effects	O
+.	O
+
+Oxprenolol	O
+caused	O
+decreases	O
+of	O
+65	O
+%	O
+and	O
+56	O
+%	O
+of	O
+terbutaline	O
+volume	O
+of	O
+distribution	O
+and	O
+clearance	O
+,	O
+respectively	O
+,	O
+and	O
+an	O
+increase	O
+of	O
+130	O
+%	O
+of	O
+its	O
+AUC	O
+.	O
+
+In	O
+spite	O
+of	O
+higher	O
+terbutaline	O
+concentrations	O
+after	O
+oxprenolol	O
+pretreatment	O
+,	O
+the	O
+hypokalemia	B
+was	O
+almost	O
+completely	O
+antagonized	O
+by	O
+the	O
+beta	O
+2	O
+-	O
+blocking	O
+action	O
+.	O
+
+A	O
+dystonia	B
+-	O
+like	O
+syndrome	O
+after	O
+neuropeptide	O
+(	O
+MSH	O
+/	O
+ACTH	O
+)	O
+stimulation	O
+of	O
+the	O
+rat	O
+locus	O
+ceruleus	O
+.	O
+
+The	O
+movement	B
+disorder	I
+investigated	O
+in	O
+these	O
+studies	O
+has	O
+some	O
+features	O
+in	O
+common	O
+with	O
+human	O
+idiopathic	O
+dystonia	B
+,	O
+and	O
+information	O
+obtained	O
+in	O
+these	O
+studies	O
+may	O
+be	O
+of	O
+potential	O
+clinical	O
+benefit	O
+.	O
+
+The	O
+present	O
+experimental	O
+results	O
+indicated	O
+that	O
+peptidergic	O
+stimulation	O
+of	O
+the	O
+LC	O
+resulted	O
+in	O
+a	O
+NE	O
+-	O
+mediated	O
+inhibition	O
+of	O
+cerebellar	O
+Purkinje	O
+cells	O
+located	O
+at	O
+terminals	O
+of	O
+the	O
+ceruleo	O
+-	O
+cerebellar	O
+pathway	O
+.	O
+
+However	O
+,	O
+it	O
+is	O
+not	O
+certain	O
+as	O
+to	O
+the	O
+following	O
+:	O
+(	O
+a	O
+)	O
+what	O
+receptors	O
+were	O
+stimulated	O
+by	O
+the	O
+ACTH	O
+N	O
+-	O
+terminal	O
+fragments	O
+at	O
+the	O
+LC	O
+that	O
+resulted	O
+in	O
+this	O
+disorder	O
+;	O
+(	O
+b	O
+)	O
+whether	O
+NE	O
+,	O
+released	O
+onto	O
+Purkinje	O
+cell	O
+synapses	O
+located	O
+at	O
+terminals	O
+of	O
+the	O
+ceruleo	O
+-	O
+cerebellar	O
+pathway	O
+,	O
+did	O
+indeed	O
+cause	O
+the	O
+long	O
+-	O
+term	O
+depression	B
+at	O
+Purkinje	O
+cell	O
+synapses	O
+(	O
+previously	O
+described	O
+by	O
+others	O
+)	O
+that	O
+resulted	O
+in	O
+the	O
+long	O
+duration	O
+of	O
+the	O
+movement	B
+disorder	I
+;	O
+(	O
+c	O
+)	O
+whether	O
+the	O
+inhibition	O
+of	O
+inhibitory	O
+Purkinje	O
+cells	O
+resulted	O
+in	O
+disinhibition	O
+or	O
+increased	O
+excitability	O
+of	O
+the	O
+unilateral	O
+cerebellar	O
+fastigial	O
+or	O
+interpositus	O
+nuclei	O
+,	O
+the	O
+output	O
+targets	O
+of	O
+the	O
+Purkinje	O
+cell	O
+axons	O
+,	O
+that	O
+may	O
+have	O
+been	O
+an	O
+important	O
+contributing	O
+factor	O
+to	O
+this	O
+disorder	O
+.	O
+
+These	O
+questions	O
+are	O
+currently	O
+being	O
+investigated	O
+.	O
+
+Enhanced	O
+stimulus	O
+-	O
+induced	O
+neurotransmitter	O
+overflow	O
+in	O
+epinephrine	O
+-	O
+induced	O
+hypertensive	B
+rats	O
+is	O
+not	O
+mediated	O
+by	O
+prejunctional	O
+beta	O
+-	O
+adrenoceptor	O
+activation	O
+.	O
+
+The	O
+present	O
+study	O
+examines	O
+the	O
+effect	O
+of	O
+6	O
+-	O
+day	O
+epinephrine	O
+treatment	O
+(	O
+100	O
+micrograms	O
+/	O
+kg	O
+per	O
+h	O
+,	O
+s	O
+.	O
+c	O
+.	O
+)	O
+on	O
+stimulus	O
+-	O
+induced	O
+(	O
+1	O
+Hz	O
+)	O
+endogenous	O
+neurotransmitter	O
+overflow	O
+from	O
+the	O
+isolated	O
+perfused	O
+kidney	O
+of	O
+vehicle	O
+-	O
+and	O
+epinephrine	O
+-	O
+treated	O
+rats	O
+.	O
+
+Renal	O
+catecholamine	O
+stores	O
+and	O
+stimulus	O
+-	O
+induced	O
+overflow	O
+in	O
+the	O
+vehicle	O
+-	O
+treated	O
+group	O
+consisted	O
+of	O
+norepinephrine	O
+only	O
+.	O
+
+However	O
+,	O
+epinephrine	O
+treatment	O
+resulted	O
+in	O
+the	O
+incorporation	O
+of	O
+epinephrine	O
+into	O
+renal	O
+catecholamine	O
+stores	O
+such	O
+that	O
+approximately	O
+40	O
+%	O
+of	O
+the	O
+catecholamine	O
+present	O
+was	O
+epinephrine	O
+while	O
+the	O
+norepinephrine	O
+content	O
+was	O
+reduced	O
+by	O
+a	O
+similar	O
+degree	O
+.	O
+
+Total	O
+tissue	O
+catecholamine	O
+content	O
+of	O
+the	O
+kidney	O
+on	O
+a	O
+molar	O
+basis	O
+was	O
+unchanged	O
+.	O
+
+Stimulus	O
+-	O
+induced	O
+fractional	O
+overflow	O
+of	O
+neurotransmitter	O
+from	O
+the	O
+epinephrine	O
+-	O
+treated	O
+kidneys	O
+was	O
+approximately	O
+twice	O
+normal	O
+and	O
+consisted	O
+of	O
+both	O
+norepinephrine	O
+and	O
+epinephrine	O
+in	O
+proportions	O
+similar	O
+to	O
+those	O
+found	O
+in	O
+the	O
+kidney	O
+.	O
+
+This	O
+difference	O
+in	O
+fractional	O
+overflow	O
+between	O
+groups	O
+was	O
+not	O
+affected	O
+by	O
+neuronal	O
+and	O
+extraneuronal	O
+uptake	O
+blockade	O
+.	O
+
+Propranolol	O
+had	O
+no	O
+effect	O
+on	O
+stimulus	O
+-	O
+induced	O
+overflow	O
+in	O
+either	O
+group	O
+.	O
+
+Phentolamine	O
+increased	O
+stimulus	O
+-	O
+induced	O
+overflow	O
+in	O
+both	O
+groups	O
+although	O
+the	O
+increment	O
+in	O
+overflow	O
+was	O
+greater	O
+in	O
+the	O
+epinephrine	O
+-	O
+treated	O
+group	O
+.	O
+
+In	O
+conclusion	O
+,	O
+chronic	O
+epinephrine	O
+treatment	O
+results	O
+in	O
+enhanced	O
+fractional	O
+neurotransmitter	O
+overflow	O
+.	O
+
+However	O
+,	O
+neither	O
+alterations	O
+in	O
+prejunctional	O
+beta	O
+-	O
+adrenoceptor	O
+influences	O
+nor	O
+alterations	O
+in	O
+neuronal	O
+and	O
+extraneuronal	O
+uptake	O
+mechanisms	O
+appear	O
+to	O
+be	O
+responsible	O
+for	O
+this	O
+alteration	O
+.	O
+
+Furthermore	O
+,	O
+data	O
+obtained	O
+with	O
+phentolamine	O
+alone	O
+do	O
+not	O
+suggest	O
+alpha	O
+-	O
+adrenoceptor	O
+desensitization	O
+as	O
+the	O
+cause	O
+of	O
+the	O
+enhanced	O
+neurotransmitter	O
+overflow	O
+after	O
+epinephrine	O
+treatment	O
+.	O
+
+GABA	O
+involvement	O
+in	O
+naloxone	O
+induced	O
+reversal	O
+of	O
+respiratory	B
+paralysis	I
+produced	O
+by	O
+thiopental	O
+.	O
+
+No	O
+agent	O
+is	O
+yet	O
+available	O
+to	O
+reverse	O
+respiratory	B
+paralysis	I
+produced	O
+by	O
+CNS	O
+depressants	O
+,	O
+such	O
+as	O
+general	O
+anesthetics	O
+.	O
+
+In	O
+this	O
+study	O
+naloxone	O
+reversed	O
+respiratory	B
+paralysis	I
+induced	O
+by	O
+thiopental	O
+in	O
+rats	O
+.	O
+
+25	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+v	O
+.	O
+thiopental	O
+produced	O
+anesthesia	O
+without	O
+altering	O
+respiratory	O
+rate	O
+,	O
+increased	O
+GABA	O
+,	O
+decreased	O
+glutamate	O
+,	O
+and	O
+had	O
+no	O
+effect	O
+on	O
+aspartate	O
+or	O
+glycine	O
+levels	O
+compared	O
+to	O
+controls	O
+in	O
+rat	O
+cortex	O
+and	O
+brain	O
+stem	O
+.	O
+
+Pretreatment	O
+of	O
+rats	O
+with	O
+thiosemicarbazide	O
+for	O
+30	O
+minutes	O
+abolished	O
+the	O
+anesthetic	O
+action	O
+as	O
+well	O
+as	O
+the	O
+respiratory	O
+depressant	O
+action	O
+of	O
+thiopental	O
+.	O
+
+50	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+v	O
+.	O
+thiopental	O
+produced	O
+respiratory	B
+arrest	I
+with	O
+further	O
+increase	O
+in	O
+GABA	O
+and	O
+decrease	O
+in	O
+glutamate	O
+again	O
+in	O
+cortex	O
+and	O
+brain	O
+stem	O
+without	O
+affecting	O
+any	O
+of	O
+the	O
+amino	O
+acids	O
+studied	O
+in	O
+four	O
+regions	O
+of	O
+rat	O
+brain	O
+.	O
+
+Naloxone	O
+(	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+v	O
+.	O
+)	O
+reversed	O
+respiratory	B
+paralysis	I
+,	O
+glutamate	O
+and	O
+GABA	O
+levels	O
+to	O
+control	O
+values	O
+in	O
+brain	O
+stem	O
+and	O
+cortex	O
+with	O
+no	O
+changes	O
+in	O
+caudate	O
+or	O
+cerebellum	O
+.	O
+
+These	O
+data	O
+suggest	O
+naloxone	O
+reverses	O
+respiratory	B
+paralysis	I
+produced	O
+by	O
+thiopental	O
+and	O
+involves	O
+GABA	O
+in	O
+its	O
+action	O
+.	O
+
+Diazepam	O
+facilitates	O
+reflex	O
+bradycardia	B
+in	O
+conscious	O
+rats	O
+.	O
+
+The	O
+effects	O
+of	O
+diazepam	O
+on	O
+cardiovascular	O
+function	O
+were	O
+assessed	O
+in	O
+conscious	O
+rats	O
+.	O
+
+Intravenous	O
+administration	O
+of	O
+diazepam	O
+(	O
+1	O
+-	O
+30	O
+mg	O
+kg	O
+-	O
+1	O
+)	O
+produced	O
+a	O
+dose	O
+-	O
+dependent	O
+decrease	O
+in	O
+both	O
+the	O
+mean	O
+arterial	O
+pressure	O
+and	O
+the	O
+heart	O
+rate	O
+.	O
+
+Also	O
+,	O
+reflex	O
+bradycardia	B
+was	O
+produced	O
+in	O
+rats	O
+by	O
+intravenous	O
+infusion	O
+of	O
+adrenaline	O
+(	O
+1	O
+.	O
+25	O
+-	O
+2	O
+.	O
+5	O
+micrograms	O
+kg	O
+-	O
+1	O
+)	O
+.	O
+
+Intravenous	O
+pretreatment	O
+of	O
+the	O
+rats	O
+with	O
+diazepam	O
+,	O
+although	O
+causing	O
+no	O
+change	O
+in	O
+the	O
+adrenaline	O
+-	O
+induced	O
+pressor	O
+effect	O
+,	O
+did	O
+enhance	O
+the	O
+adrenaline	O
+-	O
+induced	O
+reflex	O
+bradycardia	B
+.	O
+
+However	O
+,	O
+the	O
+diazepam	O
+enhancement	O
+of	O
+adrenaline	O
+-	O
+induced	O
+reflex	O
+bradycardia	B
+was	O
+antagonized	O
+by	O
+pretreatment	O
+of	O
+rats	O
+with	O
+an	O
+intravenous	O
+dose	O
+of	O
+picrotoxin	O
+(	O
+an	O
+agent	O
+blocks	O
+chloride	O
+channels	O
+by	O
+binding	O
+to	O
+sites	O
+associated	O
+with	O
+the	O
+benzodiazepine	O
+-	O
+GABA	O
+-	O
+chloride	O
+channel	O
+macromolecular	O
+complex	O
+)	O
+.	O
+
+The	O
+data	O
+indicate	O
+that	O
+diazepam	O
+acts	O
+through	O
+the	O
+benzodiazepine	O
+-	O
+GABA	O
+-	O
+chloride	O
+channel	O
+macromolecular	O
+complex	O
+within	O
+the	O
+central	O
+nervous	O
+system	O
+to	O
+facilitate	O
+reflex	O
+bradycardia	B
+mediated	O
+through	O
+baroreceptor	O
+reflexes	O
+in	O
+response	O
+to	O
+an	O
+acute	O
+increase	O
+in	O
+arterial	O
+pressure	O
+.	O
+
+Initial	O
+potassium	O
+loss	O
+and	O
+hypokalaemia	B
+during	O
+chlorthalidone	O
+administration	O
+in	O
+patients	O
+with	O
+essential	O
+hypertension	B
+:	O
+the	O
+influence	O
+of	O
+dietary	O
+sodium	O
+restriction	O
+.	O
+
+To	O
+investigate	O
+the	O
+initial	O
+potassium	O
+loss	O
+and	O
+development	O
+of	O
+hypokalaemia	B
+during	O
+the	O
+administration	O
+of	O
+an	O
+oral	O
+diuretic	O
+,	O
+metabolic	O
+balance	O
+studies	O
+were	O
+performed	O
+in	O
+ten	O
+patients	O
+with	O
+essential	O
+hypertension	B
+who	O
+had	O
+shown	O
+hypokalaemia	B
+under	O
+prior	O
+oral	O
+diuretic	O
+treatment	O
+.	O
+
+Chlorthalidone	O
+(	O
+50	O
+mg	O
+daily	O
+)	O
+was	O
+given	O
+for	O
+14	O
+days	O
+.	O
+
+Six	O
+patients	O
+received	O
+a	O
+normal	O
+-	O
+sodium	O
+diet	O
+and	O
+four	O
+a	O
+low	O
+-	O
+sodium	O
+(	O
+17	O
+mmol	O
+/	O
+day	O
+)	O
+diet	O
+.	O
+
+All	O
+patients	O
+had	O
+a	O
+normal	O
+initial	O
+total	O
+body	O
+potassium	O
+(	O
+40K	O
+)	O
+.	O
+
+The	O
+electrolyte	O
+balances	O
+,	O
+weight	O
+,	O
+bromide	O
+space	O
+,	O
+plasma	O
+renin	O
+activity	O
+,	O
+and	O
+aldosterone	O
+secretion	O
+rate	O
+were	O
+measured	O
+.	O
+
+In	O
+both	O
+groups	O
+a	O
+potassium	O
+deficit	O
+developed	O
+,	O
+with	O
+proportionally	O
+larger	O
+losses	O
+from	O
+the	O
+extracellular	O
+than	O
+from	O
+the	O
+intracellular	O
+compartment	O
+.	O
+
+In	O
+the	O
+normal	O
+-	O
+sodium	O
+group	O
+the	O
+highest	O
+mean	O
+potassium	O
+deficit	O
+was	O
+176	O
+mmol	O
+on	O
+day	O
+9	O
+,	O
+after	O
+which	O
+some	O
+potassium	O
+was	O
+regained	O
+;	O
+in	O
+the	O
+low	O
+-	O
+sodium	O
+group	O
+the	O
+highest	O
+deficit	O
+was	O
+276	O
+mmol	O
+on	O
+day	O
+13	O
+.	O
+
+The	O
+normal	O
+-	O
+sodium	O
+group	O
+showed	O
+an	O
+immediate	O
+but	O
+temporary	O
+rise	O
+of	O
+the	O
+renin	O
+and	O
+aldosterone	O
+levels	O
+;	O
+in	O
+the	O
+low	O
+-	O
+sodium	O
+group	O
+renin	O
+and	O
+aldosterone	O
+increased	O
+more	O
+slowly	O
+but	O
+remained	O
+elevated	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+dietary	O
+sodium	O
+restriction	O
+increases	O
+diuretic	O
+-	O
+induced	O
+potassium	O
+loss	O
+,	O
+presumably	O
+by	O
+an	O
+increased	O
+activity	O
+of	O
+the	O
+renin	O
+-	O
+angiotensin	O
+-	O
+aldosterone	O
+system	O
+,	O
+while	O
+sodium	O
+delivery	O
+to	O
+the	O
+distal	O
+renal	O
+tubules	O
+remains	O
+sufficiently	O
+high	O
+to	O
+allow	O
+increased	O
+potassium	O
+secretion	O
+.	O
+
+Reversal	O
+of	O
+neuroleptic	O
+-	O
+induced	O
+catalepsy	B
+by	O
+novel	O
+aryl	O
+-	O
+piperazine	O
+anxiolytic	O
+drugs	O
+.	O
+
+The	O
+novel	O
+anxiolytic	O
+drug	O
+,	O
+buspirone	O
+,	O
+reverses	O
+catalepsy	B
+induced	O
+by	O
+haloperidol	O
+.	O
+
+A	O
+series	O
+of	O
+aryl	O
+-	O
+piperazine	O
+analogues	O
+of	O
+buspirone	O
+and	O
+other	O
+5	O
+-	O
+hydroxytryptaminergic	O
+agonists	O
+were	O
+tested	O
+for	O
+their	O
+ability	O
+to	O
+reverse	O
+haloperidol	O
+induced	O
+catalepsy	B
+.	O
+
+Those	O
+drugs	O
+with	O
+strong	O
+affinity	O
+for	O
+5	O
+-	O
+hydroxytryptamine1a	O
+receptors	O
+were	O
+able	O
+to	O
+reverse	O
+catalepsy	B
+.	O
+
+Drugs	O
+with	O
+affinity	O
+for	O
+other	O
+5	O
+-	O
+HT	O
+receptors	O
+or	O
+weak	O
+affinity	O
+were	O
+ineffective	O
+.	O
+
+However	O
+,	O
+inhibition	O
+of	O
+postsynaptic	O
+5	O
+-	O
+HT	O
+receptors	O
+neither	O
+inhibited	O
+nor	O
+potentiated	O
+reversal	O
+of	O
+catalepsy	B
+and	O
+leaves	O
+open	O
+the	O
+question	O
+as	O
+to	O
+the	O
+site	O
+or	O
+mechanism	O
+for	O
+this	O
+effect	O
+.	O
+
+Glycopyrronium	O
+requirements	O
+for	O
+antagonism	O
+of	O
+the	O
+muscarinic	O
+side	O
+effects	O
+of	O
+edrophonium	O
+.	O
+
+We	O
+have	O
+compared	O
+,	O
+in	O
+60	O
+adult	O
+patients	O
+,	O
+the	O
+cardiovascular	O
+effects	O
+of	O
+glycopyrronium	O
+5	O
+micrograms	O
+kg	O
+-	O
+1	O
+and	O
+10	O
+micrograms	O
+kg	O
+-	O
+1	O
+given	O
+either	O
+simultaneously	O
+or	O
+1	O
+min	O
+before	O
+edrophonium	O
+1	O
+mg	O
+kg	O
+-	O
+1	O
+.	O
+
+Significant	O
+differences	O
+between	O
+the	O
+four	O
+groups	O
+were	O
+detected	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Both	O
+groups	O
+receiving	O
+10	O
+micrograms	O
+kg	O
+-	O
+1	O
+showed	O
+increases	O
+in	O
+heart	O
+rate	O
+of	O
+up	O
+to	O
+30	O
+beat	O
+min	O
+-	O
+1	O
+(	O
+95	O
+%	O
+confidence	O
+limits	O
+28	O
+-	O
+32	O
+beat	O
+min	O
+-	O
+1	O
+)	O
+.	O
+
+Use	O
+of	O
+glycopyrronium	O
+5	O
+micrograms	O
+kg	O
+-	O
+1	O
+provided	O
+greater	O
+cardiovascular	O
+stability	O
+and	O
+,	O
+given	O
+1	O
+min	O
+before	O
+the	O
+edrophonium	O
+,	O
+was	O
+sufficient	O
+to	O
+minimize	O
+early	O
+,	O
+edrophonium	O
+-	O
+induced	O
+bradycardias	B
+.	O
+
+This	O
+low	O
+dose	O
+of	O
+glycopyrronium	O
+provided	O
+good	O
+control	O
+of	O
+oropharyngeal	O
+secretions	O
+.	O
+
+Selective	O
+injection	O
+of	O
+iopentol	O
+,	O
+iohexol	O
+and	O
+metrizoate	O
+into	O
+the	O
+left	O
+coronary	O
+artery	O
+of	O
+the	O
+dog	O
+.	O
+
+Induction	O
+of	O
+ventricular	B
+fibrillation	I
+and	O
+decrease	O
+of	O
+aortic	O
+pressure	O
+.	O
+
+In	O
+twenty	O
+beagle	O
+dogs	O
+selective	O
+injections	O
+were	O
+made	O
+into	O
+the	O
+left	O
+coronary	O
+artery	O
+with	O
+iopentol	O
+,	O
+iohexol	O
+and	O
+metrizoate	O
+in	O
+doses	O
+of	O
+4	O
+ml	O
+,	O
+8	O
+ml	O
+and	O
+16	O
+ml	O
+.	O
+
+Thirty	O
+-	O
+six	O
+iopentol	O
+injections	O
+,	O
+35	O
+iohexol	O
+injections	O
+and	O
+37	O
+metrizoate	O
+injections	O
+were	O
+made	O
+.	O
+
+Frequencies	O
+of	O
+ventricular	B
+fibrillation	I
+were	O
+significantly	O
+lower	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+after	O
+iopentol	O
+(	O
+0	O
+%	O
+)	O
+and	O
+iohexol	O
+(	O
+3	O
+%	O
+)	O
+than	O
+after	O
+metrizoate	O
+(	O
+22	O
+%	O
+)	O
+.	O
+
+Iopentol	O
+and	O
+iohexol	O
+also	O
+produced	O
+significantly	O
+less	O
+decrease	O
+in	O
+aortic	O
+blood	O
+pressure	O
+than	O
+metrizoate	O
+at	O
+the	O
+different	O
+doses	O
+.	O
+
+Thyroid	O
+function	O
+and	O
+urine	O
+-	O
+concentrating	O
+ability	O
+during	O
+lithium	O
+treatment	O
+.	O
+
+It	O
+has	O
+been	O
+suggested	O
+that	O
+adenylate	O
+cyclase	O
+inhibition	O
+may	O
+be	O
+important	O
+in	O
+the	O
+development	O
+of	O
+both	O
+nephrogenic	B
+diabetes	I
+insipidus	I
+and	O
+hypothyroidism	B
+during	O
+lithium	O
+treatment	O
+.	O
+
+We	O
+measured	O
+serum	O
+thyroxine	O
+and	O
+urine	O
+-	O
+concentrating	O
+ability	O
+(	O
+Umax	O
+)	O
+in	O
+response	O
+to	O
+desmopressin	O
+(	O
+DDAVP	O
+)	O
+in	O
+85	O
+patients	O
+receiving	O
+lithium	O
+.	O
+
+Hypothyroidism	B
+developed	O
+in	O
+eight	O
+patients	O
+while	O
+they	O
+were	O
+taking	O
+lithium	O
+.	O
+
+Impaired	O
+Umax	O
+was	O
+found	O
+in	O
+both	O
+euthyroid	O
+and	O
+hypothyroid	B
+patients	O
+while	O
+some	O
+hypothyroid	B
+patients	O
+concentrated	O
+their	O
+urine	O
+well	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+the	O
+dominant	O
+mechanisms	O
+by	O
+which	O
+lithium	O
+exerts	O
+these	O
+two	O
+effects	O
+are	O
+different	O
+.	O
+
+Remodelling	O
+of	O
+nerve	O
+structure	O
+in	O
+experimental	O
+isoniazid	O
+neuropathy	B
+in	O
+the	O
+rat	O
+.	O
+
+The	O
+neuropathy	B
+caused	O
+by	O
+a	O
+single	O
+dose	O
+of	O
+isoniazid	O
+in	O
+rats	O
+was	O
+studied	O
+with	O
+a	O
+computer	O
+-	O
+assisted	O
+morphometric	O
+method	O
+.	O
+
+Scatter	O
+diagrams	O
+of	O
+the	O
+g	O
+ratio	O
+(	O
+quotient	O
+fibre	O
+diameter	O
+/	O
+axon	O
+diameter	O
+)	O
+define	O
+regenerating	O
+fibres	O
+as	O
+a	O
+distinct	O
+population	O
+,	O
+distinguishable	O
+from	O
+the	O
+surviving	O
+fibres	O
+by	O
+reduced	O
+sheath	O
+thickness	O
+and	O
+reduced	O
+axon	O
+calibre	O
+.	O
+
+There	O
+was	O
+also	O
+evidence	O
+of	O
+a	O
+subtle	O
+direct	O
+toxic	O
+effect	O
+on	O
+the	O
+entire	O
+fibre	O
+population	O
+,	O
+causing	O
+axon	O
+shrinkage	O
+masked	O
+by	O
+readjustment	O
+of	O
+the	O
+myelin	O
+sheath	O
+.	O
+
+Multicenter	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+multiple	O
+-	O
+dose	O
+,	O
+parallel	O
+-	O
+groups	O
+efficacy	O
+and	O
+safety	O
+trial	O
+of	O
+azelastine	O
+,	O
+chlorpheniramine	O
+,	O
+and	O
+placebo	O
+in	O
+the	O
+treatment	O
+of	O
+spring	B
+allergic	I
+rhinitis	I
+.	O
+
+Azelastine	O
+,	O
+a	O
+novel	O
+antiallergic	O
+medication	O
+,	O
+was	O
+compared	O
+with	O
+chlorpheniramine	O
+maleate	O
+and	O
+placebo	O
+for	O
+efficacy	O
+and	O
+safety	O
+in	O
+the	O
+treatment	O
+of	O
+spring	B
+allergic	I
+rhinitis	I
+in	O
+a	O
+multicenter	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+multiple	O
+-	O
+dose	O
+,	O
+parallel	O
+-	O
+groups	O
+study	O
+.	O
+
+One	O
+hundred	O
+fifty	O
+-	O
+five	O
+subjects	O
+participated	O
+.	O
+
+Subjects	O
+ranged	O
+in	O
+age	O
+from	O
+18	O
+to	O
+60	O
+years	O
+of	O
+age	O
+and	O
+had	O
+at	O
+least	O
+a	O
+2	O
+-	O
+year	O
+history	O
+of	O
+spring	B
+allergic	I
+rhinitis	I
+,	O
+confirmed	O
+by	O
+positive	O
+skin	O
+test	O
+to	O
+spring	O
+aeroallergens	O
+.	O
+
+Medications	O
+were	O
+given	O
+four	O
+times	O
+daily	O
+;	O
+the	O
+azelastine	O
+groups	O
+received	O
+0	O
+.	O
+5	O
+,	O
+1	O
+.	O
+0	O
+,	O
+or	O
+2	O
+.	O
+0	O
+mg	O
+in	O
+the	O
+morning	O
+and	O
+evening	O
+with	O
+placebo	O
+in	O
+the	O
+early	O
+and	O
+late	O
+afternoon	O
+;	O
+the	O
+chlorpheniramine	O
+group	O
+received	O
+4	O
+.	O
+0	O
+mg	O
+four	O
+times	O
+daily	O
+.	O
+
+Daily	O
+subject	O
+symptom	O
+cards	O
+were	O
+completed	O
+during	O
+a	O
+screening	O
+period	O
+to	O
+assess	O
+pretreatment	O
+symptoms	O
+and	O
+during	O
+a	O
+4	O
+-	O
+week	O
+treatment	O
+period	O
+while	O
+subjects	O
+received	O
+study	O
+medications	O
+.	O
+
+Individual	O
+symptoms	O
+,	O
+total	O
+symptoms	O
+,	O
+and	O
+major	O
+symptoms	O
+were	O
+compared	O
+to	O
+determine	O
+efficacy	O
+of	O
+medication	O
+.	O
+
+Elicited	O
+,	O
+volunteered	O
+,	O
+and	O
+observed	O
+adverse	O
+experiences	O
+were	O
+recorded	O
+for	O
+each	O
+subject	O
+and	O
+compared	O
+among	O
+groups	O
+.	O
+
+Vital	O
+signs	O
+,	O
+body	O
+weights	O
+,	O
+serum	O
+chemistry	O
+values	O
+,	O
+complete	O
+blood	O
+cell	O
+counts	O
+,	O
+urine	O
+studies	O
+,	O
+and	O
+electrocardiograms	O
+were	O
+obtained	O
+for	O
+each	O
+subject	O
+and	O
+compared	O
+among	O
+groups	O
+.	O
+
+Symptoms	O
+relief	O
+in	O
+the	O
+group	O
+receiving	O
+the	O
+highest	O
+concentration	O
+of	O
+azelastine	O
+(	O
+2	O
+.	O
+0	O
+mg	O
+twice	O
+daily	O
+)	O
+was	O
+statistically	O
+greater	O
+than	O
+in	O
+the	O
+placebo	O
+group	O
+during	O
+all	O
+weeks	O
+of	O
+the	O
+study	O
+.	O
+
+Lower	O
+doses	O
+of	O
+azelastine	O
+were	O
+statistically	O
+more	O
+effective	O
+than	O
+placebo	O
+only	O
+during	O
+portions	O
+of	O
+the	O
+first	O
+3	O
+weeks	O
+of	O
+the	O
+study	O
+.	O
+
+In	O
+contrast	O
+,	O
+although	O
+the	O
+chlorpheniramine	O
+group	O
+did	O
+have	O
+fewer	O
+symptoms	O
+than	O
+the	O
+placebo	O
+group	O
+during	O
+the	O
+study	O
+,	O
+the	O
+difference	O
+never	O
+reached	O
+statistical	O
+significance	O
+during	O
+any	O
+week	O
+of	O
+the	O
+study	O
+.	O
+
+There	O
+were	O
+no	O
+serious	O
+side	O
+effects	O
+in	O
+any	O
+of	O
+the	O
+treatment	O
+groups	O
+.	O
+
+Drowsiness	B
+and	O
+altered	B
+taste	I
+perception	I
+were	O
+increased	O
+significantly	O
+over	O
+placebo	O
+only	O
+in	O
+the	O
+high	O
+-	O
+dose	O
+azelastine	O
+group	O
+.	O
+
+Azelastine	O
+appears	O
+to	O
+be	O
+a	O
+safe	O
+,	O
+efficacious	O
+medication	O
+for	O
+seasonal	B
+allergic	I
+rhinitis	I
+.	O
+
+Toxicity	B
+due	O
+to	O
+remission	O
+inducing	O
+drugs	O
+in	O
+rheumatoid	B
+arthritis	I
+.	O
+
+Association	O
+with	O
+HLA	O
+-	O
+B35	O
+and	O
+Cw4	O
+antigens	O
+.	O
+
+Twenty	O
+-	O
+five	O
+patients	O
+with	O
+rheumatoid	B
+arthritis	I
+(	O
+RA	B
+)	O
+who	O
+developed	O
+toxicity	B
+while	O
+taking	O
+remission	O
+inducing	O
+drugs	O
+and	O
+30	O
+without	O
+toxicity	B
+were	O
+studied	O
+for	O
+possible	O
+associations	O
+with	O
+class	O
+I	O
+and	O
+II	O
+HLA	O
+antigens	O
+.	O
+
+A	O
+strong	O
+association	O
+has	O
+been	O
+found	O
+between	O
+nephritis	B
+and	O
+dermatitis	B
+due	O
+to	O
+Tiopronin	O
+(	O
+a	O
+D	O
+-	O
+Penicillamine	O
+like	O
+compound	O
+)	O
+and	O
+class	O
+I	O
+antigens	O
+B35	O
+-	O
+Cw4	O
+,	O
+and	O
+between	O
+dermatitis	B
+due	O
+to	O
+gold	O
+thiosulphate	O
+and	O
+B35	O
+.	O
+
+Compared	O
+to	O
+healthy	O
+controls	O
+a	O
+lower	O
+DR5	O
+frequency	O
+was	O
+observed	O
+in	O
+patients	O
+with	O
+RA	B
+except	O
+for	O
+the	O
+Tiopronin	O
+related	O
+nephritis	B
+group	O
+.	O
+
+Transient	O
+contralateral	B
+rotation	I
+following	O
+unilateral	O
+substantia	B
+nigra	I
+lesion	I
+reflects	O
+susceptibility	O
+of	O
+the	O
+nigrostriatal	O
+system	O
+to	O
+exhaustion	O
+by	O
+amphetamine	O
+.	O
+
+Following	O
+unilateral	O
+6	O
+-	O
+OHDA	O
+induced	O
+SN	B
+lesion	I
+,	O
+a	O
+transient	O
+period	O
+of	O
+contralateral	B
+rotation	I
+has	O
+been	O
+reported	O
+to	O
+precede	O
+the	O
+predominant	O
+ipsilateral	B
+circling	I
+.	O
+
+In	O
+order	O
+to	O
+clarify	O
+the	O
+nature	O
+of	O
+this	O
+initial	O
+contralateral	B
+rotation	I
+we	O
+examined	O
+the	O
+effect	O
+of	O
+the	O
+duration	O
+of	O
+recovery	O
+period	O
+after	O
+the	O
+lesion	O
+,	O
+on	O
+amphetamine	O
+-	O
+induced	O
+rotational	B
+behavior	I
+.	O
+
+Three	O
+days	O
+post	O
+lesion	O
+,	O
+most	O
+rats	O
+circled	O
+predominantly	O
+contralaterally	O
+to	O
+the	O
+lesion	O
+.	O
+
+Such	O
+contralateral	B
+rotation	I
+may	O
+result	O
+from	O
+either	O
+degeneration	O
+-	O
+induced	O
+breakdown	O
+of	O
+the	O
+DA	O
+pool	O
+,	O
+or	O
+lesion	O
+-	O
+induced	O
+increase	O
+of	O
+DA	O
+turnover	O
+in	O
+the	O
+spared	O
+neurons	O
+.	O
+
+A	O
+substantial	O
+degree	O
+of	O
+contralateral	O
+preference	O
+was	O
+still	O
+evident	O
+when	O
+amphetamine	O
+was	O
+administered	O
+for	O
+the	O
+first	O
+time	O
+24	O
+days	O
+after	O
+lesioning	O
+,	O
+indicating	O
+involvement	O
+of	O
+spared	O
+cells	O
+in	O
+the	O
+contralateral	B
+rotation	I
+.	O
+
+However	O
+,	O
+regardless	O
+of	O
+the	O
+duration	O
+of	O
+recovery	O
+(	O
+and	O
+irrespective	O
+of	O
+either	O
+lesion	O
+volume	O
+,	O
+amphetamine	O
+dose	O
+,	O
+or	O
+post	O
+-	O
+lesion	O
+motor	O
+exercise	O
+)	O
+,	O
+amphetamine	O
+-	O
+induced	O
+rotation	B
+tended	O
+to	O
+become	O
+gradually	O
+more	O
+ipsilateral	O
+as	O
+the	O
+observation	O
+session	O
+progressed	O
+,	O
+and	O
+all	O
+rats	O
+circled	O
+ipsilaterally	O
+to	O
+the	O
+lesion	O
+in	O
+response	O
+to	O
+further	O
+amphetamine	O
+injections	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+amphetamine	O
+has	O
+an	O
+irreversible	O
+effect	O
+on	O
+the	O
+post	O
+-	O
+lesion	O
+DA	O
+pool	O
+contributing	O
+to	O
+contralateral	B
+rotation	I
+.	O
+
+Mitomycin	O
+C	O
+associated	O
+hemolytic	B
+uremic	I
+syndrome	I
+.	O
+
+Mitomycin	O
+C	O
+associated	O
+Hemolytic	B
+Uremic	I
+Syndrome	I
+(	O
+HUS	B
+)	O
+is	O
+a	O
+potentially	O
+fatal	O
+but	O
+uncommon	O
+condition	O
+that	O
+is	O
+not	O
+yet	O
+widely	O
+recognised	O
+.	O
+
+It	O
+consists	O
+of	O
+microangiopathic	O
+hemolytic	B
+anemia	I
+,	O
+thrombocytopenia	B
+and	O
+progressive	O
+renal	B
+failure	I
+associated	O
+with	O
+mitomycin	O
+C	O
+treatment	O
+and	O
+affects	O
+about	O
+10	O
+%	O
+of	O
+patients	O
+treated	O
+with	O
+this	O
+agent	O
+.	O
+
+The	O
+renal	B
+failure	I
+usually	O
+develops	O
+about	O
+8	O
+-	O
+10	O
+mth	O
+after	O
+start	O
+of	O
+mitomycin	O
+C	O
+treatment	O
+and	O
+the	O
+mortality	O
+is	O
+approximately	O
+60	O
+%	O
+from	O
+renal	B
+failure	I
+or	O
+pulmonary	B
+edema	I
+.	O
+
+Renal	B
+lesions	I
+are	O
+similar	O
+to	O
+those	O
+seen	O
+in	O
+idiopathic	O
+HUS	B
+and	O
+include	O
+arteriolar	O
+fibrin	O
+thrombi	B
+,	O
+expanded	O
+subendothelial	O
+zones	O
+in	O
+glomerular	O
+capillary	O
+walls	O
+,	O
+ischemic	B
+wrinkling	O
+of	O
+glomerular	O
+basement	O
+membranes	O
+and	O
+mesangiolysis	O
+.	O
+
+The	O
+mechanism	O
+of	O
+action	O
+is	O
+postulated	O
+as	O
+mitomycin	O
+C	O
+-	O
+induced	O
+endothelial	O
+cell	O
+damage	O
+.	O
+
+We	O
+describe	O
+the	O
+clinical	O
+course	O
+and	O
+pathological	O
+findings	O
+in	O
+a	O
+65	O
+yr	O
+-	O
+old	O
+man	O
+with	O
+gastric	B
+adenocarcinoma	I
+who	O
+developed	O
+renal	B
+failure	I
+and	O
+thrombocytopenia	B
+while	O
+on	O
+treatment	O
+with	O
+mitomycin	O
+C	O
+and	O
+died	O
+in	O
+pulmonary	B
+edema	I
+.	O
+
+Ketanserin	O
+pretreatment	O
+reverses	O
+alfentanil	O
+-	O
+induced	O
+muscle	B
+rigidity	I
+.	O
+
+Systemic	O
+pretreatment	O
+with	O
+ketanserin	O
+,	O
+a	O
+relatively	O
+specific	O
+type	O
+-	O
+2	O
+serotonin	O
+receptor	O
+antagonist	O
+,	O
+significantly	O
+attenuated	O
+the	O
+muscle	B
+rigidity	I
+produced	O
+in	O
+rats	O
+by	O
+the	O
+potent	O
+short	O
+-	O
+acting	O
+opiate	O
+agonist	O
+alfentanil	O
+.	O
+
+Following	O
+placement	O
+of	O
+subcutaneous	O
+electrodes	O
+in	O
+each	O
+animal	O
+'	O
+s	O
+left	O
+gastrocnemius	O
+muscle	O
+,	O
+rigidity	B
+was	O
+assessed	O
+by	O
+analyzing	O
+root	O
+-	O
+mean	O
+-	O
+square	O
+electromyographic	O
+activity	O
+.	O
+
+Intraperitoneal	O
+ketanserin	O
+administration	O
+at	O
+doses	O
+of	O
+0	O
+.	O
+63	O
+and	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+prevented	O
+the	O
+alfentanil	O
+-	O
+induced	O
+increase	O
+in	O
+electromyographic	O
+activity	O
+compared	O
+with	O
+animals	O
+pretreated	O
+with	O
+saline	O
+.	O
+
+Chlordiazepoxide	O
+at	O
+doses	O
+up	O
+to	O
+10	O
+mg	O
+/	O
+kg	O
+failed	O
+to	O
+significantly	O
+influence	O
+the	O
+rigidity	B
+produced	O
+by	O
+alfentanil	O
+.	O
+
+Despite	O
+the	O
+absence	O
+of	O
+rigidity	B
+,	O
+animals	O
+that	O
+received	O
+ketanserin	O
+(	O
+greater	O
+than	O
+0	O
+.	O
+31	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+followed	O
+by	O
+alfentanil	O
+were	O
+motionless	O
+,	O
+flaccid	O
+,	O
+and	O
+less	O
+responsive	O
+to	O
+external	O
+stimuli	O
+than	O
+were	O
+animals	O
+receiving	O
+alfentanil	O
+alone	O
+.	O
+
+Rats	O
+that	O
+received	O
+ketanserin	O
+and	O
+alfentanil	O
+exhibited	O
+less	O
+rearing	O
+and	O
+exploratory	O
+behavior	O
+at	O
+the	O
+end	O
+of	O
+the	O
+60	O
+-	O
+min	O
+recording	O
+period	O
+than	O
+did	O
+animals	O
+that	O
+received	O
+ketanserin	O
+alone	O
+.	O
+
+These	O
+results	O
+,	O
+in	O
+combination	O
+with	O
+previous	O
+work	O
+,	O
+suggest	O
+that	O
+muscle	B
+rigidity	I
+,	O
+a	O
+clinically	O
+relevant	O
+side	O
+-	O
+effect	O
+of	O
+parenteral	O
+narcotic	O
+administration	O
+,	O
+may	O
+be	O
+partly	O
+mediated	O
+via	O
+serotonergic	O
+pathways	O
+.	O
+
+Pretreatment	O
+with	O
+type	O
+-	O
+2	O
+serotonin	O
+antagonists	O
+may	O
+be	O
+clinically	O
+useful	O
+in	O
+attenuating	O
+opiate	O
+-	O
+induced	O
+rigidity	B
+,	O
+although	O
+further	O
+studies	O
+will	O
+be	O
+necessary	O
+to	O
+assess	O
+the	O
+interaction	O
+of	O
+possibly	O
+enhanced	O
+CNS	O
+,	O
+cardiovascular	B
+,	I
+and	I
+respiratory	I
+depression	I
+.	O
+
+Antagonism	O
+of	O
+diazepam	O
+-	O
+induced	O
+sedative	O
+effects	O
+by	O
+Ro15	O
+-	O
+1788	O
+in	O
+patients	O
+after	O
+surgery	O
+under	O
+lumbar	O
+epidural	O
+block	O
+.	O
+
+A	O
+double	O
+-	O
+blind	O
+placebo	O
+-	O
+controlled	O
+investigation	O
+of	O
+efficacy	O
+and	O
+safety	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+assess	O
+the	O
+efficacy	O
+of	O
+Ro15	O
+-	O
+1788	O
+and	O
+a	O
+placebo	O
+in	O
+reversing	O
+diazepam	O
+-	O
+induced	O
+effects	O
+after	O
+surgery	O
+under	O
+epidural	O
+block	O
+,	O
+and	O
+to	O
+evaluate	O
+the	O
+local	O
+tolerance	O
+and	O
+general	O
+safety	O
+of	O
+Ro15	O
+-	O
+1788	O
+.	O
+
+Fifty	O
+-	O
+seven	O
+patients	O
+were	O
+sedated	O
+with	O
+diazepam	O
+for	O
+surgery	O
+under	O
+epidural	O
+anaesthesia	O
+.	O
+
+Antagonism	O
+of	O
+diazepam	O
+-	O
+induced	O
+effects	O
+by	O
+Ro15	O
+-	O
+1788	O
+was	O
+investigated	O
+postoperatively	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+placebo	O
+-	O
+controlled	O
+trial	O
+.	O
+
+The	O
+patient	O
+'	O
+s	O
+subjective	O
+assessment	O
+of	O
+mood	O
+rating	O
+,	O
+an	O
+objective	O
+test	O
+of	O
+performance	O
+,	O
+a	O
+test	O
+for	O
+amnesia	B
+,	O
+and	O
+vital	O
+signs	O
+were	O
+recorded	O
+for	O
+up	O
+to	O
+300	O
+min	O
+after	O
+administration	O
+of	O
+the	O
+trial	O
+drug	O
+.	O
+
+No	O
+significant	O
+differences	O
+between	O
+the	O
+two	O
+groups	O
+were	O
+observed	O
+for	O
+mood	O
+rating	O
+,	O
+amnesia	B
+,	O
+or	O
+vital	O
+signs	O
+.	O
+
+The	O
+Ro15	O
+-	O
+1788	O
+group	O
+showed	O
+a	O
+significant	O
+improvement	O
+in	O
+the	O
+performance	O
+test	O
+up	O
+to	O
+120	O
+min	O
+after	O
+administration	O
+of	O
+the	O
+drug	O
+.	O
+
+There	O
+was	O
+no	O
+evidence	O
+of	O
+reaction	O
+at	O
+the	O
+injection	O
+site	O
+.	O
+
+Chorea	B
+associated	O
+with	O
+oral	O
+contraception	O
+.	O
+
+Three	O
+patients	O
+developed	O
+chorea	B
+while	O
+receiving	O
+oral	O
+contraceptives	O
+.	O
+
+Two	O
+were	O
+young	O
+patients	O
+whose	O
+chorea	B
+developed	O
+long	O
+after	O
+treatment	O
+had	O
+been	O
+started	O
+and	O
+disappeared	O
+soon	O
+after	O
+it	O
+had	O
+been	O
+discontinued	O
+.	O
+
+The	O
+third	O
+patient	O
+had	O
+acute	O
+amphetamine	O
+-	O
+induced	O
+chorea	B
+after	O
+prolonged	O
+oral	O
+contraception	O
+.	O
+
+Prolonged	O
+administration	O
+of	O
+female	O
+sex	O
+hormones	O
+is	O
+a	O
+possible	O
+cause	O
+of	O
+chorea	B
+in	O
+women	O
+who	O
+have	O
+not	O
+previously	O
+had	O
+chorea	B
+or	O
+rheumatic	B
+fever	I
+.	O
+
+Co	O
+-	O
+carcinogenic	B
+effect	O
+of	O
+retinyl	O
+acetate	O
+on	O
+forestomach	B
+carcinogenesis	I
+of	O
+male	O
+F344	O
+rats	O
+induced	O
+with	O
+butylated	O
+hydroxyanisole	O
+.	O
+
+The	O
+potential	O
+modifying	O
+effect	O
+of	O
+retinyl	O
+acetate	O
+(	O
+RA	O
+)	O
+on	O
+butylated	O
+hydroxyanisole	O
+(	O
+BHA	O
+)	O
+-	O
+induced	O
+rat	O
+forestomach	B
+tumorigenesis	I
+was	O
+examined	O
+.	O
+
+Male	O
+F344	O
+rats	O
+,	O
+5	O
+weeks	O
+of	O
+age	O
+,	O
+were	O
+maintained	O
+on	O
+diet	O
+containing	O
+1	O
+%	O
+or	O
+2	O
+%	O
+BHA	O
+by	O
+weight	O
+and	O
+simultaneously	O
+on	O
+drinking	O
+water	O
+supplemented	O
+with	O
+RA	O
+at	O
+various	O
+concentrations	O
+(	O
+w	O
+/	O
+v	O
+)	O
+for	O
+52	O
+weeks	O
+.	O
+
+In	O
+groups	O
+given	O
+2	O
+%	O
+BHA	O
+,	O
+although	O
+marked	O
+hyperplastic	O
+changes	O
+of	O
+the	O
+forestomach	O
+epithelium	O
+were	O
+observed	O
+in	O
+all	O
+animals	O
+,	O
+co	O
+-	O
+administration	O
+of	O
+0	O
+.	O
+25	O
+%	O
+RA	O
+significantly	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+increased	O
+the	O
+incidence	O
+of	O
+forestomach	B
+tumors	I
+(	O
+squamous	B
+cell	I
+papilloma	I
+and	O
+carcinoma	B
+)	O
+to	O
+60	O
+%	O
+(	O
+9	O
+/	O
+15	O
+,	O
+2	O
+rats	O
+with	O
+carcinoma	B
+)	O
+from	O
+15	O
+%	O
+(	O
+3	O
+/	O
+20	O
+,	O
+one	O
+rat	O
+with	O
+carcinoma	B
+)	O
+in	O
+the	O
+group	O
+given	O
+RA	O
+-	O
+free	O
+water	O
+.	O
+
+In	O
+rats	O
+given	O
+1	O
+%	O
+BHA	O
+,	O
+RA	O
+co	O
+-	O
+administered	O
+at	O
+a	O
+dose	O
+of	O
+0	O
+.	O
+05	O
+,	O
+0	O
+.	O
+1	O
+,	O
+0	O
+.	O
+2	O
+or	O
+0	O
+.	O
+25	O
+%	O
+showed	O
+a	O
+dose	O
+-	O
+dependent	O
+enhancing	O
+effect	O
+on	O
+the	O
+development	O
+of	O
+the	O
+BHA	O
+-	O
+induced	O
+epithelial	B
+hyperplasia	I
+.	O
+
+Tumors	B
+,	O
+all	O
+papillomas	B
+,	O
+were	O
+induced	O
+in	O
+3	O
+rats	O
+(	O
+17	O
+%	O
+)	O
+with	O
+0	O
+.	O
+25	O
+%	O
+RA	O
+and	O
+in	O
+one	O
+rat	O
+(	O
+10	O
+%	O
+)	O
+with	O
+0	O
+.	O
+05	O
+%	O
+RA	O
+co	O
+-	O
+administration	O
+.	O
+
+RA	O
+alone	O
+did	O
+not	O
+induce	O
+hyperplastic	O
+changes	O
+in	O
+the	O
+forestomach	O
+.	O
+
+These	O
+findings	O
+indicate	O
+that	O
+RA	O
+acted	O
+as	O
+a	O
+co	O
+-	O
+carcinogen	O
+in	O
+the	O
+BHA	O
+forestomach	B
+carcinogenesis	I
+of	O
+the	O
+rat	O
+.	O
+
+A	O
+prospective	O
+study	O
+on	O
+the	O
+dose	O
+dependency	O
+of	O
+cardiotoxicity	B
+induced	O
+by	O
+mitomycin	O
+C	O
+.	O
+
+Since	O
+1975	O
+mitomycin	O
+C	O
+(	O
+MMC	O
+)	O
+has	O
+been	O
+suggested	O
+to	O
+be	O
+cardiotoxic	B
+,	O
+especially	O
+when	O
+combined	O
+with	O
+or	O
+given	O
+following	O
+doxorubicin	O
+.	O
+
+Data	O
+on	O
+dose	O
+dependency	O
+or	O
+incidence	O
+concerning	O
+this	O
+side	O
+effect	O
+were	O
+not	O
+known	O
+.	O
+
+We	O
+have	O
+initiated	O
+a	O
+prospective	O
+study	O
+to	O
+obtain	O
+some	O
+more	O
+data	O
+on	O
+these	O
+subjects	O
+.	O
+
+Forty	O
+-	O
+four	O
+MMC	O
+-	O
+treated	O
+patients	O
+were	O
+studied	O
+,	O
+37	O
+of	O
+them	O
+could	O
+be	O
+evaluated	O
+.	O
+
+All	O
+patients	O
+were	O
+studied	O
+by	O
+repeated	O
+physical	O
+examinations	O
+,	O
+chest	O
+X	O
+-	O
+rays	O
+,	O
+electro	O
+-	O
+and	O
+echocardiography	O
+and	O
+radionuclide	O
+left	O
+ventricular	O
+ejection	O
+fraction	O
+(	O
+EF	O
+)	O
+determinations	O
+.	O
+
+The	O
+results	O
+were	O
+evaluated	O
+per	O
+cumulative	O
+dose	O
+level	O
+.	O
+
+One	O
+of	O
+the	O
+patients	O
+developed	O
+cardiac	B
+failure	I
+after	O
+30	O
+mg	O
+m	O
+-	O
+2	O
+MMC	O
+and	O
+only	O
+150	O
+mg	O
+m	O
+-	O
+2	O
+doxorubicin	O
+.	O
+
+The	O
+cardiac	B
+failure	I
+was	O
+predicted	O
+by	O
+a	O
+drop	O
+in	O
+EF	O
+determined	O
+during	O
+a	O
+cold	O
+pressor	O
+test	O
+.	O
+
+None	O
+of	O
+the	O
+other	O
+patients	O
+developed	O
+clinical	O
+cardiotoxicity	B
+,	O
+nor	O
+did	O
+the	O
+studied	O
+parameters	O
+change	O
+.	O
+
+The	O
+literature	O
+on	O
+this	O
+subject	O
+was	O
+also	O
+reviewed	O
+.	O
+
+Based	O
+on	O
+the	O
+combined	O
+data	O
+from	O
+the	O
+present	O
+study	O
+and	O
+the	O
+literature	O
+,	O
+we	O
+suggest	O
+that	O
+MMC	O
+-	O
+related	O
+cardiotoxicity	B
+is	O
+dose	O
+dependent	O
+,	O
+occurring	O
+at	O
+cumulative	O
+dose	O
+levels	O
+of	O
+30	O
+mg	O
+m	O
+-	O
+2	O
+or	O
+more	O
+,	O
+mainly	O
+in	O
+patients	O
+also	O
+(	O
+previously	O
+or	O
+simultaneously	O
+)	O
+treated	O
+with	O
+doxorubicin	O
+.	O
+
+The	O
+incidence	O
+is	O
+likely	O
+to	O
+be	O
+less	O
+than	O
+10	O
+%	O
+even	O
+for	O
+this	O
+risk	O
+group	O
+.	O
+
+Reversible	O
+cerebral	B
+lesions	I
+associated	O
+with	O
+tiazofurin	O
+usage	O
+:	O
+MR	O
+demonstration	O
+.	O
+
+Tiazofurin	O
+is	O
+an	O
+experimental	O
+chemotherapeutic	O
+agent	O
+currently	O
+undergoing	O
+clinical	O
+evaluation	O
+.	O
+
+We	O
+report	O
+our	O
+results	O
+with	O
+magnetic	O
+resonance	O
+(	O
+MR	O
+)	O
+in	O
+demonstrating	O
+reversible	O
+cerebral	B
+abnormalities	I
+concurrent	O
+with	O
+the	O
+use	O
+of	O
+this	O
+drug	O
+.	O
+
+The	O
+abnormalities	O
+on	O
+MR	O
+were	O
+correlated	O
+with	O
+findings	O
+on	O
+CT	O
+as	O
+well	O
+as	O
+with	O
+cerebral	O
+angiography	O
+.	O
+
+The	O
+utility	O
+of	O
+MR	O
+in	O
+the	O
+evaluation	O
+of	O
+patients	O
+receiving	O
+this	O
+new	O
+agent	O
+is	O
+illustrated	O
+.	O
+
+Receptor	O
+mechanisms	O
+of	O
+nicotine	O
+-	O
+induced	O
+locomotor	B
+hyperactivity	I
+in	O
+chronic	O
+nicotine	O
+-	O
+treated	O
+rats	O
+.	O
+
+Rats	O
+were	O
+pretreated	O
+with	O
+saline	O
+or	O
+nicotine	O
+(	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+)	O
+by	O
+subcutaneously	O
+implanting	O
+each	O
+animal	O
+with	O
+an	O
+Alzet	O
+osmotic	O
+mini	O
+-	O
+pump	O
+which	O
+continuously	O
+released	O
+saline	O
+or	O
+nicotine	O
+for	O
+1	O
+,	O
+5	O
+and	O
+14	O
+days	O
+.	O
+
+At	O
+the	O
+end	O
+of	O
+each	O
+pretreatment	O
+period	O
+,	O
+animals	O
+were	O
+used	O
+for	O
+(	O
+i	O
+)	O
+determining	O
+their	O
+locomotor	O
+response	O
+to	O
+acutely	O
+injected	O
+nicotine	O
+(	O
+0	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+,	O
+s	O
+.	O
+c	O
+.	O
+)	O
+and	O
+(	O
+ii	O
+)	O
+measuring	O
+the	O
+density	O
+of	O
+L	O
+-	O
+[	O
+3H	O
+]	O
+nicotine	O
+and	O
+[	O
+3H	O
+]	O
+spiperone	O
+binding	O
+sites	O
+in	O
+the	O
+striatum	O
+.	O
+
+We	O
+observed	O
+no	O
+changes	O
+in	O
+nicotine	O
+-	O
+induced	O
+locomotor	O
+response	O
+,	O
+striatal	O
+L	O
+-	O
+[	O
+3H	O
+]	O
+nicotine	O
+and	O
+[	O
+3H	O
+]	O
+spiperone	O
+binding	O
+in	O
+the	O
+animals	O
+pretreated	O
+with	O
+nicotine	O
+for	O
+1	O
+day	O
+.	O
+
+In	O
+rats	O
+which	O
+were	O
+pretreated	O
+with	O
+nicotine	O
+for	O
+5	O
+days	O
+,	O
+there	O
+was	O
+a	O
+significant	O
+increase	O
+in	O
+the	O
+nicotine	O
+-	O
+stimulated	O
+locomotor	O
+response	O
+which	O
+was	O
+associated	O
+with	O
+an	O
+increase	O
+in	O
+the	O
+number	O
+of	O
+L	O
+-	O
+[	O
+3H	O
+]	O
+nicotine	O
+binding	O
+sites	O
+and	O
+also	O
+with	O
+an	O
+elevated	O
+dopamine	O
+(	O
+DA	O
+)	O
+level	O
+in	O
+the	O
+striatum	O
+.	O
+
+The	O
+number	O
+of	O
+striatal	O
+[	O
+3H	O
+]	O
+spiperone	O
+binding	O
+sites	O
+was	O
+not	O
+affected	O
+.	O
+
+In	O
+animals	O
+pretreated	O
+with	O
+nicotine	O
+for	O
+14	O
+days	O
+,	O
+the	O
+nicotine	O
+-	O
+induced	O
+locomotor	O
+response	O
+remained	O
+to	O
+be	O
+potentiated	O
+.	O
+
+However	O
+,	O
+this	O
+response	O
+was	O
+correlated	O
+with	O
+an	O
+elevated	O
+number	O
+of	O
+striatal	O
+[	O
+3H	O
+]	O
+spiperone	O
+binding	O
+sites	O
+,	O
+whereas	O
+the	O
+number	O
+of	O
+striatal	O
+L	O
+-	O
+[	O
+3H	O
+]	O
+nicotine	O
+binding	O
+sites	O
+and	O
+the	O
+striatal	O
+DA	O
+level	O
+were	O
+normal	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+chronic	O
+nicotine	O
+-	O
+treated	O
+rats	O
+develop	O
+locomotor	B
+hyperactivity	I
+in	O
+response	O
+to	O
+nicotine	O
+initially	O
+due	O
+to	O
+increases	O
+of	O
+both	O
+the	O
+density	O
+of	O
+nicotinic	O
+receptors	O
+and	O
+DA	O
+concentration	O
+,	O
+followed	O
+by	O
+inducing	O
+DA	O
+receptor	O
+supersensitivity	O
+in	O
+the	O
+striatum	O
+.	O
+
+Amelioration	O
+of	O
+bendrofluazide	O
+-	O
+induced	O
+hypokalemia	B
+by	O
+timolol	O
+.	O
+
+The	O
+beta	O
+adrenergic	O
+blocking	O
+drug	O
+,	O
+timolol	O
+,	O
+tended	O
+to	O
+correct	O
+the	O
+hypokalemia	B
+of	O
+short	O
+-	O
+term	O
+bendrofluazide	O
+treatment	O
+in	O
+6	O
+healthy	O
+male	O
+subjects	O
+and	O
+although	O
+the	O
+effect	O
+was	O
+small	O
+it	O
+was	O
+significant	O
+.	O
+
+Timolol	O
+also	O
+reduced	O
+the	O
+rise	O
+in	O
+plasma	O
+aldosterone	O
+and	O
+urine	O
+potassium	O
+excretion	O
+following	O
+bendrofluazide	O
+and	O
+increased	O
+the	O
+urine	O
+sodium	O
+/	O
+potassium	O
+ratio	O
+.	O
+
+There	O
+was	O
+no	O
+evidence	O
+of	O
+a	O
+shift	O
+of	O
+potassium	O
+from	O
+the	O
+intracellular	O
+to	O
+the	O
+extracellular	O
+space	O
+.	O
+
+St	B
+.	I
+
+Anthony	B
+'	I
+s	I
+fire	I
+,	O
+then	O
+and	O
+now	O
+:	O
+a	O
+case	O
+report	O
+and	O
+historical	O
+review	O
+.	O
+
+A	O
+rare	O
+case	O
+of	O
+morbid	O
+vasospasm	B
+,	O
+together	O
+with	O
+striking	O
+angiographic	O
+findings	O
+,	O
+is	O
+described	O
+secondary	O
+to	O
+the	O
+ingestion	O
+of	O
+methysergide	O
+by	O
+a	O
+48	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+.	O
+
+A	O
+brief	O
+review	O
+of	O
+the	O
+literature	O
+on	O
+similar	O
+cases	O
+is	O
+presented	O
+.	O
+
+A	O
+discussion	O
+of	O
+the	O
+history	O
+of	O
+ergot	O
+includes	O
+its	O
+original	O
+discovery	O
+,	O
+the	O
+epidemics	O
+of	O
+gangrene	B
+that	O
+it	O
+has	O
+caused	O
+through	O
+the	O
+ages	O
+and	O
+its	O
+past	O
+and	O
+present	O
+role	O
+in	O
+the	O
+management	O
+of	O
+migraine	B
+headache	I
+.	O
+
+Despite	O
+the	O
+advent	O
+of	O
+calcium	O
+channel	O
+blockers	O
+and	O
+beta	O
+-	O
+adrenergic	O
+antagonists	O
+,	O
+ergot	O
+preparations	O
+continue	O
+to	O
+play	O
+a	O
+major	O
+role	O
+in	O
+migraine	B
+therapy	O
+,	O
+so	O
+that	O
+the	O
+danger	O
+of	O
+St	B
+.	I
+
+Anthony	B
+'	I
+s	I
+fire	I
+persists	O
+.	O
+
+Cardiac	O
+transplantation	O
+:	O
+improved	O
+quality	O
+of	O
+survival	O
+with	O
+a	O
+modified	O
+immunosuppressive	O
+protocol	O
+.	O
+
+The	O
+effects	O
+on	O
+renal	O
+function	O
+on	O
+two	O
+different	O
+immunosuppressive	O
+protocols	O
+were	O
+evaluated	O
+retrospectively	O
+in	O
+two	O
+subsequent	O
+groups	O
+of	O
+heart	O
+transplant	O
+recipients	O
+.	O
+
+In	O
+group	O
+I	O
+,	O
+cyclosporine	O
+was	O
+given	O
+before	O
+the	O
+procedure	O
+at	O
+a	O
+loading	O
+dose	O
+of	O
+17	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+and	O
+then	O
+continued	O
+after	O
+the	O
+procedure	O
+to	O
+keep	O
+a	O
+whole	O
+blood	O
+level	O
+about	O
+1000	O
+ng	O
+/	O
+ml	O
+.	O
+
+In	O
+group	O
+II	O
+,	O
+cyclosporine	O
+was	O
+started	O
+only	O
+after	O
+the	O
+procedure	O
+at	O
+a	O
+lower	O
+dosage	O
+and	O
+was	O
+complemented	O
+by	O
+azathioprine	O
+,	O
+which	O
+was	O
+used	O
+for	O
+the	O
+first	O
+postoperative	O
+week	O
+.	O
+
+Group	O
+II	O
+showed	O
+a	O
+better	O
+perioperative	O
+renal	O
+function	O
+as	O
+determined	O
+by	O
+serum	O
+blood	O
+urea	O
+nitrogen	O
+and	O
+serum	O
+creatinine	O
+levels	O
+.	O
+
+Group	O
+II	O
+also	O
+showed	O
+a	O
+significant	O
+decrease	O
+of	O
+chronic	O
+nephrotoxicity	B
+secondary	O
+to	O
+long	O
+-	O
+term	O
+therapy	O
+with	O
+cyclosporine	O
+.	O
+
+Despite	O
+this	O
+improvement	O
+in	O
+late	O
+renal	O
+function	O
+,	O
+group	O
+II	O
+still	O
+shows	O
+a	O
+slow	O
+rise	O
+in	O
+serum	O
+creatinine	O
+.	O
+
+We	O
+think	O
+that	O
+even	O
+these	O
+lower	O
+dosages	O
+of	O
+cyclosporine	O
+can	O
+cause	O
+chronic	O
+nephrotoxicity	B
+and	O
+that	O
+further	O
+modification	O
+of	O
+the	O
+immunosuppressive	O
+regimen	O
+is	O
+required	O
+to	O
+completely	O
+abolish	O
+this	O
+toxic	O
+side	O
+effect	O
+.	O
+
+Ethopropazine	O
+and	O
+benztropine	O
+in	O
+neuroleptic	O
+-	O
+induced	O
+parkinsonism	B
+.	O
+
+In	O
+a	O
+12	O
+-	O
+week	O
+controlled	O
+study	O
+ethopropazine	O
+was	O
+compared	O
+to	O
+benztropine	O
+in	O
+the	O
+treatment	O
+of	O
+parkinsonism	B
+induced	O
+by	O
+fluphenazine	O
+enanthate	O
+in	O
+60	O
+schizophrenic	B
+outpatients	O
+.	O
+
+Ethopropazine	O
+and	O
+benztropine	O
+were	O
+found	O
+to	O
+be	O
+equally	O
+effective	O
+in	O
+controlling	O
+parkinsonian	B
+symptoms	I
+and	O
+were	O
+as	O
+efficacious	O
+as	O
+procyclidine	O
+,	O
+their	O
+previous	O
+antiparkinsonian	O
+drug	O
+.	O
+
+However	O
+,	O
+benztropine	O
+treated	O
+patients	O
+had	O
+a	O
+significant	O
+increase	O
+in	O
+tardive	B
+dyskinesia	I
+compared	O
+to	O
+their	O
+condition	O
+during	O
+procyclindine	O
+treatment	O
+,	O
+and	O
+significantly	O
+more	O
+anxiety	B
+and	O
+depression	B
+than	O
+ethopropazine	O
+treated	O
+patients	O
+.	O
+
+This	O
+suggests	O
+that	O
+benztropine	O
+is	O
+not	O
+the	O
+anticholinergic	O
+drug	O
+of	O
+choice	O
+in	O
+the	O
+treatment	O
+of	O
+neuroleptic	O
+-	O
+induced	O
+parkinsonian	B
+symptoms	I
+,	O
+because	O
+of	O
+its	O
+more	O
+toxic	O
+central	O
+and	O
+peripheral	O
+atropinic	O
+effect	O
+.	O
+
+Quinidine	O
+phenylethylbarbiturate	O
+-	O
+induced	O
+fulminant	O
+hepatitis	B
+in	O
+a	O
+pregnant	O
+woman	O
+.	O
+
+A	O
+case	O
+report	O
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+19	O
+-	O
+year	O
+-	O
+old	O
+Laotian	O
+patient	O
+affected	O
+by	O
+fulminant	O
+hepatitis	B
+during	O
+the	O
+third	O
+trimester	O
+of	O
+her	O
+pregnancy	O
+after	O
+a	O
+1	O
+-	O
+month	O
+administration	O
+of	O
+quinidine	O
+phenylethylbarbiturate	O
+.	O
+
+After	O
+delivery	O
+,	O
+the	O
+patient	O
+underwent	O
+orthotopic	O
+liver	O
+transplantation	O
+.	O
+
+The	O
+patient	O
+was	O
+in	O
+good	O
+condition	O
+16	O
+months	O
+after	O
+liver	O
+transplantation	O
+.	O
+
+Quinidine	O
+itself	O
+or	O
+phenylethylbarbiturate	O
+may	O
+be	O
+responsible	O
+for	O
+fulminant	O
+hepatitis	B
+in	O
+this	O
+patient	O
+.	O
+
+Mechanisms	O
+of	O
+myocardial	B
+ischemia	I
+induced	O
+by	O
+epinephrine	O
+:	O
+comparison	O
+with	O
+exercise	O
+-	O
+induced	O
+ischemia	B
+.	O
+
+The	O
+role	O
+of	O
+epinephrine	O
+in	O
+eliciting	O
+myocardial	B
+ischemia	I
+was	O
+examined	O
+in	O
+patients	O
+with	O
+coronary	B
+artery	I
+disease	I
+.	O
+
+Objective	O
+signs	O
+of	O
+ischemia	B
+and	O
+factors	O
+increasing	O
+myocardial	O
+oxygen	O
+consumption	O
+were	O
+compared	O
+during	O
+epinephrine	O
+infusion	O
+and	O
+supine	O
+bicycle	O
+exercise	O
+.	O
+
+Both	O
+epinephrine	O
+and	O
+exercise	O
+produced	O
+myocardial	B
+ischemia	I
+as	O
+evidenced	O
+by	O
+ST	O
+segment	O
+depression	B
+and	O
+angina	B
+.	O
+
+However	O
+,	O
+the	O
+mechanisms	O
+of	O
+myocardial	B
+ischemia	I
+induced	O
+by	O
+epinephrine	O
+were	O
+significantly	O
+different	O
+from	O
+those	O
+of	O
+exercise	O
+.	O
+
+Exercise	O
+-	O
+induced	O
+myocardial	B
+ischemia	I
+was	O
+marked	O
+predominantly	O
+by	O
+increased	O
+heart	O
+rate	O
+and	O
+rate	O
+-	O
+pressure	O
+product	O
+with	O
+a	O
+minor	O
+contribution	O
+of	O
+end	O
+-	O
+diastolic	O
+volume	O
+,	O
+while	O
+epinephrine	O
+-	O
+induced	O
+ischemia	B
+was	O
+characterized	O
+by	O
+a	O
+marked	O
+increase	O
+in	O
+contractility	O
+and	O
+a	O
+less	O
+pronounced	O
+increase	O
+in	O
+heart	O
+rate	O
+and	O
+rate	O
+-	O
+pressure	O
+product	O
+.	O
+
+These	O
+findings	O
+indicate	O
+that	O
+ischemia	B
+produced	O
+by	O
+epinephrine	O
+,	O
+as	O
+may	O
+occur	O
+during	O
+states	O
+of	O
+emotional	O
+distress	O
+,	O
+has	O
+a	O
+mechanism	O
+distinct	O
+from	O
+that	O
+due	O
+to	O
+physical	O
+exertion	O
+.	O
+
+Recent	O
+preclinical	O
+and	O
+clinical	O
+studies	O
+with	O
+the	O
+thymidylate	O
+synthase	O
+inhibitor	O
+N10	O
+-	O
+propargyl	O
+-	O
+5	O
+,	O
+8	O
+-	O
+dideazafolic	O
+acid	O
+(	O
+CB	O
+3717	O
+)	O
+.	O
+
+CB	O
+3717	O
+,	O
+N10	O
+-	O
+propargyl	O
+-	O
+5	O
+,	O
+8	O
+-	O
+dideazafolic	O
+acid	O
+,	O
+is	O
+a	O
+tight	O
+-	O
+binding	O
+inhibitor	O
+of	O
+thymidylate	O
+synthase	O
+(	O
+TS	O
+)	O
+whose	O
+cytotoxicity	B
+is	O
+mediated	O
+solely	O
+through	O
+the	O
+inhibition	O
+of	O
+this	O
+enzyme	O
+.	O
+
+Recent	O
+preclinical	O
+studies	O
+have	O
+focused	O
+on	O
+the	O
+intracellular	O
+formation	O
+of	O
+CB	O
+3717	O
+polyglutamates	O
+.	O
+
+Following	O
+a	O
+12	O
+-	O
+hour	O
+exposure	O
+of	O
+L1210	O
+cells	O
+to	O
+50	O
+microM	O
+[	O
+3H	O
+]	O
+CB	O
+3717	O
+,	O
+30	O
+%	O
+of	O
+the	O
+extractable	O
+radioactivity	O
+could	O
+be	O
+accounted	O
+for	O
+as	O
+CB	O
+3717	O
+tetra	O
+-	O
+and	O
+pentaglutamate	O
+,	O
+as	O
+determined	O
+by	O
+high	O
+-	O
+pressure	O
+liquid	O
+chromatography	O
+(	O
+HPLC	O
+)	O
+analyses	O
+.	O
+
+As	O
+inhibitors	O
+of	O
+isolated	O
+L1210	O
+TS	O
+,	O
+CB	O
+3717	O
+di	O
+-	O
+,	O
+tri	O
+-	O
+,	O
+tetra	O
+-	O
+and	O
+pentaglutamate	O
+are	O
+26	O
+-	O
+,	O
+87	O
+-	O
+,	O
+119	O
+-	O
+and	O
+114	O
+-	O
+fold	O
+more	O
+potent	O
+than	O
+CB	O
+3717	O
+,	O
+respectively	O
+,	O
+and	O
+their	O
+formation	O
+may	O
+,	O
+therefore	O
+,	O
+be	O
+an	O
+important	O
+determinant	O
+of	O
+CB	O
+3717	O
+cytotoxicity	B
+.	O
+
+In	O
+early	O
+clinical	O
+studies	O
+with	O
+CB	O
+3717	O
+,	O
+activity	O
+has	O
+been	O
+seen	O
+in	O
+breast	B
+cancer	I
+,	O
+ovarian	B
+cancer	I
+,	O
+hepatoma	B
+,	O
+and	O
+mesothelioma	B
+.	O
+
+Toxicities	B
+included	O
+hepatotoxicity	B
+,	O
+malaise	B
+,	O
+and	O
+dose	O
+-	O
+limiting	O
+nephrotoxicity	B
+.	O
+
+This	O
+latter	O
+effect	O
+is	O
+thought	O
+to	O
+be	O
+due	O
+to	O
+drug	O
+precipitation	O
+within	O
+the	O
+renal	O
+tubule	O
+as	O
+a	O
+result	O
+of	O
+the	O
+poor	O
+solubility	O
+of	O
+CB	O
+3717	O
+under	O
+acidic	O
+conditions	O
+.	O
+
+In	O
+an	O
+attempt	O
+to	O
+overcome	O
+this	O
+problem	O
+,	O
+a	O
+clinical	O
+trial	O
+of	O
+CB	O
+3717	O
+administered	O
+with	O
+alkaline	O
+diuresis	O
+is	O
+under	O
+way	O
+.	O
+
+Preliminary	O
+results	O
+at	O
+400	O
+and	O
+500	O
+mg	O
+/	O
+m2	O
+suggest	O
+that	O
+a	O
+reduction	O
+in	O
+nephrotoxicity	B
+may	O
+have	O
+been	O
+achieved	O
+with	O
+only	O
+1	O
+instance	O
+of	O
+renal	B
+toxicity	I
+in	O
+10	O
+patients	O
+.	O
+
+Hepatotoxicity	B
+and	O
+malaise	B
+are	O
+again	O
+the	O
+most	O
+frequent	O
+side	O
+effects	O
+.	O
+
+Evidence	O
+of	O
+antitumor	O
+activity	O
+has	O
+been	O
+seen	O
+in	O
+3	O
+patients	O
+.	O
+
+Pharmacokinetic	O
+investigations	O
+have	O
+shown	O
+that	O
+alkaline	O
+diuresis	O
+does	O
+not	O
+alter	O
+CB	O
+3717	O
+plasma	O
+levels	O
+or	O
+urinary	O
+excretion	O
+and	O
+that	O
+satisfactory	O
+urinary	O
+alkalinization	O
+can	O
+be	O
+readily	O
+achieved	O
+.	O
+
+Type	B
+B	I
+hepatitis	I
+after	O
+needle	O
+-	O
+stick	O
+exposure	O
+:	O
+prevention	O
+with	O
+hepatitis	B
+B	I
+immune	O
+globulin	O
+.	O
+
+Final	O
+report	O
+of	O
+the	O
+Veterans	O
+Administration	O
+Cooperative	O
+Study	O
+.	O
+
+Hepatitis	B
+B	I
+immune	O
+globulin	O
+(	O
+HBIG	O
+)	O
+and	O
+immune	O
+serum	O
+globulin	O
+(	O
+ISG	O
+)	O
+were	O
+examined	O
+in	O
+a	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+trial	O
+to	O
+assess	O
+their	O
+relative	O
+efficacies	O
+in	O
+preventing	O
+type	B
+B	I
+hepatitis	I
+after	O
+needle	O
+-	O
+stick	O
+exposure	O
+to	O
+hepatitis	O
+B	O
+surface	O
+antigen	O
+(	O
+HBsAG	O
+)	O
+-	O
+positive	O
+donors	O
+.	O
+
+Clinical	O
+hepatitis	B
+developed	O
+in	O
+1	O
+.	O
+4	O
+%	O
+of	O
+HBIG	O
+and	O
+in	O
+5	O
+.	O
+9	O
+%	O
+of	O
+ISG	O
+recipients	O
+(	O
+P	O
+=	O
+0	O
+.	O
+016	O
+)	O
+,	O
+and	O
+seroconversion	O
+(	O
+anti	O
+-	O
+HBs	O
+)	O
+occurred	O
+in	O
+5	O
+.	O
+6	O
+%	O
+and	O
+20	O
+.	O
+7	O
+%	O
+of	O
+them	O
+respectively	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Mild	O
+and	O
+transient	O
+side	O
+-	O
+effects	O
+were	O
+noted	O
+in	O
+3	O
+.	O
+0	O
+%	O
+of	O
+ISG	O
+and	O
+in	O
+3	O
+.	O
+2	O
+%	O
+of	O
+HBIG	O
+recipients	O
+.	O
+
+Available	O
+donor	O
+sera	O
+were	O
+examined	O
+for	O
+DNA	O
+polymerase	O
+(	O
+DNAP	O
+)	O
+and	O
+e	O
+antigen	O
+and	O
+antibody	O
+(	O
+HBeAg	O
+;	O
+anti	O
+-	O
+HBE	O
+)	O
+.	O
+
+Both	O
+DNAP	O
+and	O
+HBeAg	O
+showed	O
+a	O
+highly	O
+statistically	O
+significant	O
+correlation	O
+with	O
+the	O
+infectivity	O
+of	O
+HBsAg	O
+-	O
+positive	O
+donors	O
+.	O
+
+Hepatitis	B
+B	I
+immune	O
+globulin	O
+remained	O
+significantly	O
+superior	O
+to	O
+ISG	O
+in	O
+preventing	O
+type	B
+B	I
+hepatitis	I
+even	O
+when	O
+the	O
+analysis	O
+was	O
+confined	O
+to	O
+these	O
+two	O
+high	O
+-	O
+risk	O
+subgroups	O
+.	O
+
+The	O
+efficacy	O
+of	O
+ISG	O
+in	O
+preventing	O
+type	B
+B	I
+hepatitis	I
+cannot	O
+be	O
+ascertained	O
+because	O
+a	O
+true	O
+placebo	O
+group	O
+was	O
+not	O
+included	O
+.	O
+
+Production	O
+of	O
+autochthonous	O
+prostate	B
+cancer	I
+in	O
+Lobund	O
+-	O
+Wistar	O
+rats	O
+by	O
+treatments	O
+with	O
+N	O
+-	O
+nitroso	O
+-	O
+N	O
+-	O
+methylurea	O
+and	O
+testosterone	O
+.	O
+
+More	O
+than	O
+50	O
+%	O
+of	O
+Lobund	O
+-	O
+Wistar	O
+(	O
+L	O
+-	O
+W	O
+)	O
+strain	O
+rats	O
+developed	O
+large	O
+,	O
+palpable	O
+prostate	B
+adenocarcinomas	I
+(	O
+PAs	B
+)	O
+following	O
+treatments	O
+with	O
+N	O
+-	O
+nitroso	O
+-	O
+N	O
+-	O
+methylurea	O
+(	O
+CAS	O
+:	O
+684	O
+-	O
+93	O
+-	O
+5	O
+)	O
+and	O
+testosterone	O
+propionate	O
+[	O
+(	O
+TP	O
+)	O
+CAS	O
+:	O
+57	O
+-	O
+85	O
+-	O
+2	O
+]	O
+,	O
+and	O
+most	O
+of	O
+the	O
+tumor	B
+-	O
+bearing	O
+rats	O
+manifested	O
+metastatic	O
+lesions	O
+.	O
+
+The	O
+incubation	O
+periods	O
+averaged	O
+10	O
+.	O
+6	O
+months	O
+.	O
+
+Within	O
+the	O
+same	O
+timeframe	O
+,	O
+no	O
+L	O
+-	O
+W	O
+rat	O
+developed	O
+a	O
+similar	O
+palpable	O
+PA	B
+when	O
+treated	O
+only	O
+with	O
+TP	O
+.	O
+
+In	O
+L	O
+-	O
+W	O
+rats	O
+,	O
+TP	O
+acted	O
+as	O
+a	O
+tumor	B
+enhancement	O
+agent	O
+,	O
+with	O
+primary	O
+emphasis	O
+on	O
+the	O
+development	O
+of	O
+prostate	B
+cancer	I
+.	O
+
+Relative	O
+efficacy	O
+and	O
+toxicity	B
+of	O
+netilmicin	O
+and	O
+tobramycin	O
+in	O
+oncology	O
+patients	O
+.	O
+
+We	O
+prospectively	O
+compared	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+netilmicin	O
+sulfate	O
+or	O
+tobramycin	O
+sulfate	O
+in	O
+conjunction	O
+with	O
+piperacillin	O
+sodium	O
+in	O
+118	O
+immunocompromised	O
+patients	O
+with	O
+presumed	O
+severe	O
+infections	B
+.	O
+
+The	O
+two	O
+treatment	O
+regimens	O
+were	O
+equally	O
+efficacious	O
+.	O
+
+Nephrotoxicity	B
+occurred	O
+in	O
+a	O
+similar	O
+proportion	O
+in	O
+patients	O
+treated	O
+with	O
+netilmicin	O
+and	O
+tobramycin	O
+(	O
+17	O
+%	O
+vs	O
+11	O
+%	O
+)	O
+.	O
+
+Ototoxicity	B
+occurred	O
+in	O
+four	O
+(	O
+9	O
+.	O
+5	O
+%	O
+)	O
+of	O
+42	O
+netilmicin	O
+and	O
+piperacillin	O
+and	O
+in	O
+12	O
+(	O
+22	O
+%	O
+)	O
+of	O
+54	O
+tobramycin	O
+and	O
+piperacillin	O
+-	O
+treated	O
+patients	O
+.	O
+
+Of	O
+those	O
+evaluated	O
+with	O
+posttherapy	O
+audiograms	O
+,	O
+three	O
+of	O
+four	O
+netilmicin	O
+and	O
+piperacillin	O
+-	O
+treated	O
+patients	O
+had	O
+auditory	O
+thresholds	O
+return	O
+to	O
+baseline	O
+compared	O
+with	O
+one	O
+of	O
+nine	O
+tobramycin	O
+and	O
+piperacillin	O
+-	O
+treated	O
+patients	O
+.	O
+
+The	O
+number	O
+of	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+15	O
+-	O
+dB	O
+increases	O
+in	O
+auditory	O
+threshold	O
+as	O
+a	O
+proportion	O
+of	O
+total	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+15	O
+-	O
+dB	O
+changes	O
+(	O
+increases	O
+and	O
+decreases	O
+)	O
+was	O
+significantly	O
+lower	O
+in	O
+netilmicin	O
+and	O
+piperacillin	O
+-	O
+vs	O
+tobramycin	O
+and	O
+piperacillin	O
+-	O
+treated	O
+patients	O
+(	O
+18	O
+of	O
+78	O
+vs	O
+67	O
+of	O
+115	O
+)	O
+.	O
+
+We	O
+conclude	O
+that	O
+aminoglycoside	O
+-	O
+associated	O
+ototoxicity	B
+was	O
+less	O
+severe	O
+and	O
+more	O
+often	O
+reversible	O
+with	O
+netilmicin	O
+than	O
+with	O
+tobramycin	O
+.	O
+
+Urinary	O
+enzymes	O
+and	O
+protein	O
+patterns	O
+as	O
+indicators	O
+of	O
+injury	B
+to	I
+different	I
+regions	I
+of	I
+the	I
+kidney	I
+.	O
+
+Acute	B
+experimental	I
+models	I
+of	I
+renal	I
+damage	I
+to	O
+the	O
+proximal	O
+tubular	O
+,	O
+glomerular	O
+,	O
+and	O
+papillary	O
+regions	O
+of	O
+the	O
+rat	O
+were	O
+produced	O
+by	O
+administration	O
+of	O
+hexachloro	O
+-	O
+1	O
+:	O
+3	O
+-	O
+butadiene	O
+(	O
+HCBD	O
+)	O
+,	O
+puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+)	O
+,	O
+and	O
+2	O
+-	O
+bromoethylamine	O
+(	O
+BEA	O
+)	O
+,	O
+respectively	O
+.	O
+
+Several	O
+routine	O
+indicators	O
+of	O
+nephrotoxicity	B
+,	O
+the	O
+enzymes	O
+alkaline	O
+phosphatase	O
+and	O
+N	O
+-	O
+acetyl	O
+-	O
+beta	O
+-	O
+glucosaminidase	O
+,	O
+and	O
+the	O
+molecular	O
+weight	O
+of	O
+protein	B
+excretion	I
+were	O
+determined	O
+on	O
+urine	O
+samples	O
+.	O
+
+Tubular	O
+damage	O
+produced	O
+by	O
+HCBD	O
+or	O
+BEA	O
+was	O
+discriminated	O
+both	O
+quantitatively	O
+and	O
+qualitatively	O
+from	O
+glomerular	B
+damage	I
+produced	O
+by	O
+PAN	O
+.	O
+
+The	O
+latter	O
+was	O
+characterized	O
+by	O
+a	O
+pronounced	O
+increase	O
+in	O
+protein	B
+excretion	I
+,	O
+especially	O
+proteins	O
+with	O
+molecular	O
+weight	O
+greater	O
+than	O
+40	O
+,	O
+000	O
+Da	O
+.	O
+
+In	O
+contrast	O
+,	O
+protein	B
+excretion	I
+in	O
+tubular	O
+damage	O
+was	O
+raised	O
+only	O
+slightly	O
+and	O
+characterized	O
+by	O
+excretion	B
+of	I
+proteins	I
+of	O
+a	O
+wide	O
+range	O
+of	O
+molecular	O
+weights	O
+.	O
+
+Proximal	O
+tubular	O
+damage	O
+caused	O
+by	O
+HCBD	O
+and	O
+papillary	O
+damage	O
+caused	O
+by	O
+BEA	O
+were	O
+distinguished	O
+both	O
+by	O
+conventional	O
+urinalysis	O
+(	O
+volume	O
+and	O
+specific	O
+gravity	O
+)	O
+and	O
+by	O
+measurement	O
+of	O
+the	O
+two	O
+urinary	O
+enzymes	O
+.	O
+
+Alkaline	O
+phosphatase	O
+and	O
+glucose	O
+were	O
+markedly	O
+and	O
+transiently	O
+elevated	O
+in	O
+proximal	O
+tubular	O
+damage	O
+and	O
+N	O
+-	O
+acetyl	O
+-	O
+beta	O
+-	O
+glucosaminidase	O
+showed	O
+a	O
+sustained	O
+elevation	O
+in	O
+papillary	O
+damage	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+both	O
+selective	O
+urinary	O
+enzymes	O
+and	O
+the	O
+molecular	O
+weight	O
+pattern	O
+of	O
+urinary	O
+proteins	O
+can	O
+be	O
+used	O
+to	O
+provide	O
+diagnostic	O
+information	O
+about	O
+the	O
+possible	O
+site	O
+of	O
+renal	B
+damage	I
+.	O
+
+A	O
+catch	O
+in	O
+the	O
+Reye	B
+.	O
+
+Twenty	O
+-	O
+six	O
+cases	O
+of	O
+Reye	B
+syndrome	I
+from	O
+The	O
+Children	O
+'	O
+s	O
+Hospital	O
+,	O
+Camperdown	O
+,	O
+Australia	O
+,	O
+occurring	O
+between	O
+1973	O
+and	O
+1982	O
+were	O
+reviewed	O
+.	O
+
+Of	O
+these	O
+,	O
+20	O
+cases	O
+met	O
+the	O
+US	O
+Public	O
+Health	O
+Service	O
+Centers	O
+for	O
+Disease	O
+Control	O
+criteria	O
+for	O
+the	O
+diagnosis	O
+of	O
+Reye	B
+syndrome	I
+.	O
+
+Aspirin	O
+or	O
+salicylate	O
+ingestion	O
+had	O
+occurred	O
+in	O
+only	O
+one	O
+of	O
+the	O
+20	O
+cases	O
+(	O
+5	O
+%	O
+)	O
+,	O
+and	O
+paracetamol	O
+(	O
+acetaminophen	O
+)	O
+had	O
+been	O
+administered	O
+in	O
+only	O
+six	O
+of	O
+the	O
+cases	O
+(	O
+30	O
+%	O
+)	O
+.	O
+
+Pathologic	O
+confirmation	O
+of	O
+the	O
+diagnosis	O
+of	O
+Reye	B
+syndrome	I
+was	O
+accomplished	O
+in	O
+90	O
+%	O
+of	O
+the	O
+cases	O
+.	O
+
+The	O
+incidence	O
+of	O
+Reye	B
+syndrome	I
+in	O
+New	O
+South	O
+Wales	O
+,	O
+Australia	O
+,	O
+is	O
+estimated	O
+from	O
+this	O
+study	O
+to	O
+be	O
+approximately	O
+nine	O
+cases	O
+per	O
+1	O
+million	O
+children	O
+compared	O
+with	O
+recent	O
+US	O
+data	O
+of	O
+ten	O
+to	O
+20	O
+cases	O
+per	O
+1	O
+million	O
+children	O
+and	O
+three	O
+to	O
+seven	O
+cases	O
+per	O
+1	O
+million	O
+children	O
+in	O
+Great	O
+Britain	O
+.	O
+
+The	O
+mortality	O
+for	O
+these	O
+Reye	B
+syndrome	I
+cases	O
+in	O
+Australia	O
+was	O
+45	O
+%	O
+as	O
+compared	O
+with	O
+a	O
+32	O
+%	O
+case	O
+-	O
+fatality	O
+rate	O
+in	O
+the	O
+United	O
+States	O
+.	O
+
+In	O
+Australia	O
+,	O
+the	O
+pediatric	O
+usage	O
+of	O
+aspirin	O
+has	O
+been	O
+extremely	O
+low	O
+for	O
+the	O
+past	O
+25	O
+years	O
+(	O
+less	O
+than	O
+1	O
+%	O
+of	O
+total	O
+dosage	O
+units	O
+sold	O
+)	O
+,	O
+with	O
+paracetamol	O
+(	O
+acetaminophen	O
+)	O
+dominating	O
+the	O
+pediatric	O
+analgesic	O
+and	O
+antipyretic	O
+market	O
+.	O
+
+Reye	B
+syndrome	I
+may	O
+be	O
+disappearing	O
+from	O
+Australia	O
+despite	O
+a	O
+total	O
+lack	O
+of	O
+association	O
+with	O
+salicylates	O
+or	O
+aspirin	O
+ingestion	O
+,	O
+since	O
+there	O
+were	O
+no	O
+cases	O
+found	O
+at	O
+The	O
+Children	O
+'	O
+s	O
+Hospital	O
+in	O
+1983	O
+,	O
+1984	O
+,	O
+or	O
+1985	O
+.	O
+
+Postpartum	O
+psychosis	B
+induced	O
+by	O
+bromocriptine	O
+.	O
+
+Two	O
+multigravida	O
+patients	O
+with	O
+no	O
+prior	O
+psychiatric	B
+history	O
+were	O
+seen	O
+with	O
+postpartum	O
+psychosis	B
+,	O
+having	O
+received	O
+bromocriptine	O
+for	O
+inhibition	B
+of	I
+lactation	I
+.	O
+
+Bromocriptine	O
+given	O
+in	O
+high	O
+doses	O
+has	O
+been	O
+associated	O
+with	O
+psychosis	B
+in	O
+patients	O
+receiving	O
+the	O
+drug	O
+for	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+These	O
+cases	O
+demonstrate	O
+that	O
+bromocriptine	O
+may	O
+cause	O
+psychosis	B
+even	O
+when	O
+given	O
+in	O
+low	O
+doses	O
+.	O
+
+Hyperglycemic	B
+acidotic	I
+coma	I
+and	O
+death	O
+in	O
+Kearns	B
+-	I
+Sayre	I
+syndrome	I
+.	O
+
+This	O
+paper	O
+presents	O
+the	O
+clinical	O
+and	O
+metabolic	O
+findings	O
+in	O
+two	O
+young	O
+boys	O
+with	O
+long	O
+-	O
+standing	O
+Kearns	B
+-	I
+Sayre	I
+syndrome	I
+.	O
+
+Following	O
+short	O
+exposure	O
+to	O
+oral	O
+prednisone	O
+,	O
+both	O
+boys	O
+developed	O
+lethargy	B
+,	O
+increasing	O
+somnolence	B
+,	O
+polydipsia	B
+,	O
+polyphagia	B
+,	O
+and	O
+polyuria	B
+.	O
+
+Both	O
+presented	O
+in	O
+the	O
+emergency	O
+room	O
+with	O
+profound	O
+coma	B
+,	O
+hypotension	B
+,	O
+severe	O
+hyperglycemia	B
+,	O
+and	O
+acidosis	B
+.	O
+
+Nonketotic	O
+lactic	B
+acidosis	I
+was	O
+present	O
+in	O
+one	O
+and	O
+ketosis	B
+without	O
+a	O
+known	O
+serum	O
+lactate	O
+level	O
+was	O
+present	O
+in	O
+the	O
+other	O
+.	O
+
+Respiratory	B
+failure	I
+rapidly	O
+ensued	O
+and	O
+both	O
+patients	O
+expired	O
+in	O
+spite	O
+of	O
+efforts	O
+at	O
+resuscitation	O
+.	O
+
+We	O
+believe	O
+these	O
+two	O
+cases	O
+represent	O
+a	O
+newly	O
+described	O
+and	O
+catastrophic	O
+metabolic	B
+-	I
+endocrine	I
+failure	I
+in	O
+the	O
+Kearns	B
+-	I
+Sayre	I
+syndrome	I
+.	O
+
+Experimental	O
+cyclosporine	O
+nephrotoxicity	B
+:	O
+risk	O
+of	O
+concomitant	O
+chemotherapy	O
+.	O
+
+The	O
+role	O
+of	O
+cyclosporine	O
+(	O
+CSA	O
+)	O
+alone	O
+or	O
+in	O
+combination	O
+with	O
+various	O
+chemotherapeutics	O
+in	O
+the	O
+development	O
+of	O
+renal	B
+toxicity	I
+was	O
+evaluated	O
+in	O
+rats	O
+.	O
+
+Administration	O
+of	O
+20	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+CSA	O
+for	O
+4	O
+weeks	O
+caused	O
+renal	O
+functional	O
+and	O
+structural	O
+changes	O
+similar	O
+to	O
+those	O
+reported	O
+in	O
+man	O
+.	O
+
+The	O
+combined	O
+administration	O
+of	O
+CSA	O
+and	O
+various	O
+chemotherapeutic	O
+drugs	O
+with	O
+a	O
+nephrotoxic	B
+potential	O
+,	O
+such	O
+as	O
+gentamicin	O
+(	O
+at	O
+therapeutic	O
+doses	O
+)	O
+,	O
+amphothericin	O
+B	O
+and	O
+ketoconazole	O
+,	O
+which	O
+are	O
+frequently	O
+used	O
+in	O
+immunosuppressed	O
+patients	O
+,	O
+did	O
+not	O
+aggravate	O
+the	O
+CSA	O
+induced	O
+toxicity	B
+in	O
+the	O
+rat	O
+model	O
+.	O
+
+Gentamicin	O
+at	O
+toxic	O
+doses	O
+,	O
+however	O
+,	O
+increased	O
+CSA	O
+nephrotoxicity	B
+.	O
+
+Thus	O
+,	O
+the	O
+nephrotoxicity	B
+induced	O
+by	O
+CSA	O
+has	O
+a	O
+different	O
+pathogenetic	O
+mechanism	O
+.	O
+
+Diuretics	O
+,	O
+potassium	O
+and	O
+arrhythmias	B
+in	O
+hypertensive	B
+coronary	B
+disease	I
+.	O
+
+It	O
+has	O
+been	O
+proposed	O
+that	O
+modest	O
+changes	O
+in	O
+plasma	O
+potassium	O
+can	O
+alter	O
+the	O
+tendency	O
+towards	O
+cardiac	B
+arrhythmias	I
+.	O
+
+If	O
+this	O
+were	O
+so	O
+,	O
+patients	O
+with	O
+coronary	B
+artery	I
+disease	I
+might	O
+be	O
+especially	O
+susceptible	O
+.	O
+
+Thus	O
+,	O
+myocardial	O
+electrical	O
+excitability	O
+was	O
+measured	O
+in	O
+patients	O
+with	O
+mild	O
+essential	O
+hypertension	B
+and	O
+known	O
+coronary	B
+artery	I
+disease	I
+after	O
+8	O
+weeks	O
+of	O
+treatment	O
+with	O
+a	O
+potassium	O
+-	O
+conserving	O
+diuretic	O
+(	O
+amiloride	O
+)	O
+and	O
+a	O
+similar	O
+period	O
+on	O
+a	O
+potassium	O
+-	O
+losing	O
+diuretic	O
+(	O
+chlorthalidone	O
+)	O
+in	O
+a	O
+randomised	O
+study	O
+.	O
+
+Plasma	O
+potassium	O
+concentrations	O
+were	O
+on	O
+average	O
+1	O
+mmol	O
+/	O
+L	O
+lower	O
+during	O
+the	O
+chlorthalidone	O
+phase	O
+compared	O
+to	O
+amiloride	O
+therapy	O
+.	O
+
+Blood	O
+pressure	O
+and	O
+volume	O
+states	O
+as	O
+assessed	O
+by	O
+bodyweight	O
+,	O
+plasma	O
+renin	O
+and	O
+noradrenaline	O
+(	O
+norepinephrine	O
+)	O
+concentrations	O
+were	O
+similar	O
+on	O
+the	O
+2	O
+regimens	O
+.	O
+
+Compared	O
+to	O
+amiloride	O
+treatment	O
+,	O
+the	O
+chlorthalidone	O
+phase	O
+was	O
+associated	O
+with	O
+an	O
+increased	O
+frequency	O
+of	O
+ventricular	B
+ectopic	I
+beats	I
+(	O
+24	O
+-	O
+hour	O
+Holter	O
+monitoring	O
+)	O
+and	O
+a	O
+higher	O
+Lown	O
+grading	O
+,	O
+increased	O
+upslope	O
+and	O
+duration	O
+of	O
+the	O
+monophasic	O
+action	O
+potential	O
+,	O
+prolonged	O
+ventricular	O
+effective	O
+refractory	O
+period	O
+,	O
+and	O
+increased	O
+electrical	O
+instability	O
+during	O
+programmed	O
+ventricular	O
+stimulation	O
+.	O
+
+The	O
+above	O
+results	O
+indicate	O
+that	O
+because	O
+potassium	O
+-	O
+losing	O
+diuretic	O
+therapy	O
+can	O
+increase	O
+myocardial	O
+electrical	O
+excitability	O
+in	O
+patients	O
+with	O
+ischaemic	B
+heart	I
+disease	I
+,	O
+even	O
+minor	O
+falls	O
+in	O
+plasma	O
+potassium	O
+concentrations	O
+are	O
+probably	O
+best	O
+avoided	O
+in	O
+such	O
+patients	O
+.	O
+
+Transketolase	O
+abnormality	O
+in	O
+tolazamide	O
+-	O
+induced	O
+Wernicke	B
+'	I
+s	I
+encephalopathy	I
+.	O
+
+We	O
+studied	O
+a	O
+thiamine	O
+-	O
+dependent	O
+enzyme	O
+,	O
+transketolase	O
+,	O
+from	O
+fibroblasts	O
+of	O
+a	O
+diabetic	B
+patient	O
+who	O
+developed	O
+Wernicke	B
+'	I
+s	I
+encephalopathy	I
+when	O
+treated	O
+with	O
+tolazamide	O
+,	O
+in	O
+order	O
+to	O
+delineate	O
+if	O
+this	O
+patient	O
+also	O
+had	O
+transketolase	O
+abnormality	O
+[	O
+high	O
+Km	O
+for	O
+thiamine	O
+pyrophosphate	O
+(	O
+TPP	O
+)	O
+]	O
+,	O
+as	O
+previously	O
+reported	O
+in	O
+postalcoholic	O
+Wernicke	B
+-	I
+Korsakoff	I
+syndrome	I
+.	O
+
+In	O
+addition	O
+to	O
+this	O
+patient	O
+,	O
+we	O
+also	O
+studied	O
+this	O
+enzyme	O
+from	O
+three	O
+diabetic	B
+kindreds	O
+without	O
+any	O
+history	O
+of	O
+Wernicke	B
+'	I
+s	I
+encephalopathy	I
+and	O
+from	O
+four	O
+normal	O
+controls	O
+.	O
+
+We	O
+found	O
+that	O
+the	O
+above	O
+-	O
+mentioned	O
+patient	O
+and	O
+one	O
+of	O
+the	O
+diabetic	B
+kindreds	O
+with	O
+no	O
+history	O
+of	O
+Wernicke	B
+'	I
+s	I
+encephalopathy	I
+had	O
+abnormal	O
+transketolase	O
+as	O
+determined	O
+by	O
+its	O
+Km	O
+for	O
+TPP	O
+.	O
+
+These	O
+data	O
+suggest	O
+a	O
+similarity	O
+between	O
+postalcoholic	O
+Wernicke	B
+-	I
+Korsakoff	I
+syndrome	I
+and	O
+the	O
+patient	O
+with	O
+tolazamide	O
+-	O
+induced	O
+Wernicke	B
+'	I
+s	I
+encephalopathy	I
+from	O
+the	O
+standpoint	O
+of	O
+transketolase	O
+abnormality	O
+.	O
+
+Bradycardia	B
+due	O
+to	O
+trihexyphenidyl	O
+hydrochloride	O
+.	O
+
+A	O
+chronic	O
+schizophrenic	B
+patient	O
+was	O
+treated	O
+with	O
+an	O
+anticholinergic	O
+drug	O
+,	O
+trihexyphenidyl	O
+hydrochloride	O
+.	O
+
+The	O
+patient	O
+developed	O
+,	O
+paradoxically	O
+,	O
+sinus	O
+bradycardia	B
+.	O
+
+The	O
+reaction	O
+was	O
+specific	O
+to	O
+trihexyphenidyl	O
+and	O
+not	O
+to	O
+other	O
+anticholinergic	O
+drugs	O
+.	O
+
+This	O
+antidyskinetic	O
+drug	O
+is	O
+widely	O
+used	O
+in	O
+clinical	O
+psychiatric	B
+practice	O
+and	O
+physicians	O
+should	O
+be	O
+aware	O
+of	O
+this	O
+side	O
+effect	O
+.	O
+
+Post	O
+-	O
+operative	O
+rigidity	B
+after	O
+fentanyl	O
+administration	O
+.	O
+
+A	O
+case	O
+of	O
+thoraco	O
+-	O
+abdominal	O
+rigidity	B
+leading	O
+to	O
+respiratory	B
+failure	I
+is	O
+described	O
+in	O
+the	O
+post	O
+-	O
+operative	O
+period	O
+in	O
+an	O
+elderly	O
+patient	O
+who	O
+received	O
+a	O
+moderate	O
+dose	O
+of	O
+fentanyl	O
+.	O
+
+This	O
+was	O
+successfully	O
+reversed	O
+by	O
+naloxone	O
+.	O
+
+The	O
+mechanisms	O
+possibly	O
+implicated	O
+in	O
+this	O
+accident	O
+are	O
+discussed	O
+.	O
+
+Anti	O
+-	O
+carcinogenic	B
+action	O
+of	O
+phenobarbital	O
+given	O
+simultaneously	O
+with	O
+diethylnitrosamine	O
+in	O
+the	O
+rat	O
+.	O
+
+The	O
+present	O
+work	O
+has	O
+been	O
+planned	O
+in	O
+order	O
+to	O
+elucidate	O
+the	O
+effect	O
+of	O
+phenobarbital	O
+(	O
+PB	O
+:	O
+15	O
+mg	O
+per	O
+rat	O
+of	O
+ingested	O
+dose	O
+)	O
+on	O
+carcinogenesis	B
+when	O
+it	O
+is	O
+administered	O
+simultaneously	O
+with	O
+diethylnitrosamine	O
+(	O
+DEN	O
+:	O
+10	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+)	O
+.	O
+
+Wistar	O
+rats	O
+(	O
+180	O
+g	O
+)	O
+were	O
+treated	O
+by	O
+DEN	O
+alone	O
+or	O
+by	O
+DEN	O
++	O
+PB	O
+during	O
+2	O
+,	O
+4	O
+and	O
+6	O
+weeks	O
+according	O
+to	O
+our	O
+schedule	O
+for	O
+hepatocarcinogenesis	B
+.	O
+
+After	O
+the	O
+end	O
+of	O
+the	O
+treatment	O
+,	O
+the	O
+number	O
+and	O
+the	O
+size	O
+of	O
+induced	O
+PAS	O
+positive	O
+preneoplastic	B
+foci	I
+was	O
+significantly	O
+reduced	O
+when	O
+PB	O
+was	O
+given	O
+simultaneously	O
+with	O
+DEN	O
+for	O
+4	O
+and	O
+6	O
+weeks	O
+.	O
+
+The	O
+mitotic	O
+inhibition	O
+and	O
+the	O
+production	O
+of	O
+micronuclei	O
+normally	O
+observed	O
+after	O
+partial	O
+hepatectomy	O
+in	O
+DEN	O
+treated	O
+rats	O
+were	O
+also	O
+significantly	O
+decreased	O
+in	O
+DEN	O
++	O
+PB	O
+treated	O
+rats	O
+.	O
+
+When	O
+the	O
+treatment	O
+last	O
+only	O
+2	O
+weeks	O
+,	O
+the	O
+presence	O
+of	O
+PB	O
+did	O
+not	O
+change	O
+significantly	O
+the	O
+last	O
+parameters	O
+.	O
+
+In	O
+DEN	O
++	O
+PB	O
+treated	O
+rats	O
+,	O
+the	O
+survival	O
+was	O
+prolonged	O
+and	O
+the	O
+tumor	B
+incidence	O
+decreased	O
+as	O
+compared	O
+with	O
+the	O
+results	O
+obtained	O
+by	O
+DEN	O
+alone	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+PB	O
+,	O
+which	O
+promotes	O
+carcinogenesis	B
+when	O
+administered	O
+after	O
+the	O
+DEN	O
+treatment	O
+,	O
+reduces	O
+the	O
+carcinogen	O
+effect	O
+when	O
+given	O
+simultaneously	O
+with	O
+DEN	O
+.	O
+
+This	O
+'	O
+anti	O
+-	O
+carcinogen	O
+'	O
+effect	O
+acts	O
+on	O
+the	O
+initiation	O
+as	O
+well	O
+as	O
+on	O
+the	O
+promotion	O
+of	O
+the	O
+precancerous	B
+lesions	I
+.	O
+
+Biochemical	O
+investigations	O
+are	O
+in	O
+progress	O
+to	O
+obtain	O
+more	O
+information	O
+about	O
+this	O
+'	O
+paradoxical	O
+'	O
+PB	O
+effect	O
+.	O
+
+Bilateral	B
+optic	I
+neuropathy	I
+due	O
+to	O
+combined	O
+ethambutol	O
+and	O
+isoniazid	O
+treatment	O
+.	O
+
+The	O
+case	O
+of	O
+a	O
+40	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+who	O
+underwent	O
+an	O
+unsuccessful	O
+cadaver	O
+kidney	O
+transplantation	O
+and	O
+was	O
+treated	O
+with	O
+ethambutol	O
+and	O
+isoniazid	O
+is	O
+reported	O
+.	O
+
+A	O
+bilateral	B
+retrobulbar	I
+neuropathy	I
+with	O
+an	O
+unusual	O
+central	O
+bitemporal	O
+hemianopic	O
+scotoma	B
+was	O
+found	O
+.	O
+
+Ethambutol	O
+was	O
+stopped	O
+and	O
+only	O
+small	O
+improvement	O
+of	O
+the	O
+visual	O
+acuity	O
+followed	O
+.	O
+
+Isoniazid	O
+was	O
+discontinued	O
+later	O
+,	O
+followed	O
+by	O
+a	O
+dramatic	O
+improvement	O
+in	O
+the	O
+visual	O
+acuity	O
+.	O
+
+The	O
+hazards	O
+of	O
+optic	O
+nerve	O
+toxicity	B
+due	O
+to	O
+ethambutol	O
+are	O
+known	O
+.	O
+
+We	O
+emphasize	O
+the	O
+potential	O
+danger	O
+in	O
+the	O
+use	O
+of	O
+ethambutol	O
+and	O
+isoniazid	O
+.	O
+
+A	O
+prospective	O
+study	O
+of	O
+adverse	O
+reactions	O
+associated	O
+with	O
+vancomycin	O
+therapy	O
+.	O
+
+A	O
+prospective	O
+evaluation	O
+of	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+vancomycin	O
+was	O
+conducted	O
+in	O
+54	O
+consecutive	O
+patients	O
+over	O
+a	O
+16	O
+-	O
+month	O
+period	O
+.	O
+
+Vancomycin	O
+was	O
+curative	O
+in	O
+95	O
+%	O
+of	O
+43	O
+patients	O
+with	O
+proven	O
+infection	B
+.	O
+
+Drugs	O
+were	O
+ceased	O
+in	O
+six	O
+patients	O
+because	O
+of	O
+adverse	O
+reactions	O
+;	O
+in	O
+three	O
+of	O
+these	O
+vancomycin	O
+was	O
+considered	O
+the	O
+likely	O
+cause	O
+.	O
+
+Reactions	O
+included	O
+thrombophlebitis	B
+(	O
+20	O
+of	O
+54	O
+patients	O
+)	O
+,	O
+rash	B
+(	O
+4	O
+of	O
+54	O
+)	O
+,	O
+nephrotoxicity	B
+(	O
+4	O
+of	O
+50	O
+)	O
+,	O
+proteinuria	B
+(	O
+1	O
+of	O
+50	O
+)	O
+and	O
+ototoxicity	B
+(	O
+1	O
+of	O
+11	O
+patients	O
+tested	O
+by	O
+audiometry	O
+)	O
+.	O
+
+Thrombophlebitis	B
+occurred	O
+only	O
+with	O
+infusion	O
+through	O
+peripheral	O
+cannulae	O
+;	O
+nephrotoxicity	B
+and	O
+ototoxicity	B
+were	O
+confined	O
+to	O
+patients	O
+receiving	O
+an	O
+aminoglycoside	O
+plus	O
+vancomycin	O
+.	O
+
+We	O
+conclude	O
+that	O
+vancomycin	O
+,	O
+administered	O
+appropriately	O
+,	O
+constitutes	O
+safe	O
+,	O
+effective	O
+therapy	O
+for	O
+infections	B
+caused	O
+by	O
+susceptible	O
+bacteria	O
+.	O
+
+Factors	O
+associated	O
+with	O
+nephrotoxicity	B
+and	O
+clinical	O
+outcome	O
+in	O
+patients	O
+receiving	O
+amikacin	O
+.	O
+
+Data	O
+from	O
+60	O
+patients	O
+treated	O
+with	O
+amikacin	O
+were	O
+analyzed	O
+for	O
+factors	O
+associated	O
+with	O
+nephrotoxicity	B
+.	O
+
+In	O
+42	O
+of	O
+these	O
+patients	O
+,	O
+data	O
+were	O
+examined	O
+for	O
+factors	O
+associated	O
+with	O
+clinical	O
+outcome	O
+.	O
+
+Variables	O
+evaluated	O
+included	O
+patient	O
+weight	O
+,	O
+age	O
+,	O
+sex	O
+,	O
+serum	O
+creatinine	O
+level	O
+,	O
+creatinine	O
+clearance	O
+,	O
+duration	O
+of	O
+therapy	O
+,	O
+total	O
+dose	O
+,	O
+mean	O
+daily	O
+dose	O
+,	O
+organism	O
+minimum	O
+inhibitory	O
+concentration	O
+(	O
+MIC	O
+)	O
+,	O
+mean	O
+peak	O
+levels	O
+,	O
+mean	O
+trough	O
+levels	O
+,	O
+mean	O
+area	O
+under	O
+the	O
+serum	O
+concentration	O
+-	O
+time	O
+curve	O
+(	O
+AUC	O
+)	O
+,	O
+total	O
+AUC	O
+,	O
+mean	O
+AUC	O
+greater	O
+than	O
+MIC	O
+,	O
+total	O
+AUC	O
+greater	O
+than	O
+MIC	O
+,	O
+mean	O
+Schumacher	O
+'	O
+s	O
+intensity	O
+factor	O
+(	O
+IF	O
+)	O
+,	O
+total	O
+IF	O
+,	O
+In	O
+(	O
+mean	O
+maximum	O
+concentration	O
+[	O
+Cmax	O
+]	O
+/	O
+MIC	O
+)	O
+.	O
+
+Model	O
+-	O
+dependent	O
+pharmacokinetic	O
+parameters	O
+were	O
+calculated	O
+by	O
+computer	O
+based	O
+on	O
+a	O
+one	O
+-	O
+compartment	O
+model	O
+.	O
+
+When	O
+the	O
+parameters	O
+were	O
+examined	O
+individually	O
+,	O
+duration	O
+of	O
+therapy	O
+and	O
+total	O
+AUC	O
+correlated	O
+significantly	O
+(	O
+P	O
+less	O
+than	O
+.	O
+05	O
+)	O
+with	O
+nephrotoxicity	B
+.	O
+
+In	O
+contrast	O
+,	O
+a	O
+stepwise	O
+discriminant	O
+function	O
+analysis	O
+identified	O
+only	O
+duration	O
+of	O
+therapy	O
+(	O
+P	O
+less	O
+than	O
+.	O
+001	O
+)	O
+as	O
+an	O
+important	O
+factor	O
+.	O
+
+Based	O
+on	O
+this	O
+model	O
+and	O
+on	O
+Bayes	O
+'	O
+theorem	O
+,	O
+the	O
+predictive	O
+accuracy	O
+of	O
+identifying	O
+"	O
+nephrotoxic	B
+"	O
+patients	O
+increased	O
+from	O
+0	O
+.	O
+17	O
+to	O
+0	O
+.	O
+39	O
+.	O
+
+When	O
+examined	O
+individually	O
+,	O
+mean	O
+IF	O
+,	O
+MIC	O
+,	O
+total	O
+dose	O
+,	O
+mean	O
+daily	O
+dose	O
+,	O
+and	O
+ln	O
+(	O
+mean	O
+Cmax	O
+/	O
+MIC	O
+)	O
+correlated	O
+significantly	O
+(	O
+P	O
+less	O
+than	O
+.	O
+05	O
+)	O
+with	O
+cure	O
+.	O
+
+In	O
+contrast	O
+,	O
+a	O
+simultaneous	O
+multivariable	O
+analysis	O
+identified	O
+IF	O
+,	O
+MIC	O
+,	O
+and	O
+total	O
+dose	O
+according	O
+to	O
+one	O
+model	O
+and	O
+ln	O
+(	O
+mean	O
+Cmax	O
+/	O
+MIC	O
+)	O
+according	O
+to	O
+a	O
+second	O
+statistical	O
+model	O
+of	O
+parameters	O
+selected	O
+to	O
+have	O
+the	O
+greatest	O
+prospective	O
+value	O
+.	O
+
+Based	O
+on	O
+Bayes	O
+'	O
+theorem	O
+and	O
+the	O
+first	O
+model	O
+,	O
+the	O
+predictive	O
+accuracy	O
+of	O
+identifying	O
+patients	O
+not	O
+cured	O
+increased	O
+from	O
+0	O
+.	O
+19	O
+to	O
+0	O
+.	O
+83	O
+.	O
+
+For	O
+the	O
+second	O
+model	O
+,	O
+the	O
+predictive	O
+accuracy	O
+increased	O
+from	O
+0	O
+.	O
+19	O
+to	O
+0	O
+.	O
+50	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Cardiac	B
+toxicity	I
+of	O
+5	O
+-	O
+fluorouracil	O
+.	O
+
+Report	O
+of	O
+a	O
+case	O
+of	O
+spontaneous	O
+angina	B
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+a	O
+patient	O
+with	O
+colon	B
+carcinoma	I
+and	O
+liver	O
+metastasis	B
+who	O
+presented	O
+chest	B
+pain	I
+after	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+administration	O
+.	O
+
+Clinical	O
+electrocardiographic	O
+evolution	O
+was	O
+similar	O
+to	O
+that	O
+observed	O
+in	O
+Prinzmetal	B
+'	I
+s	I
+angina	I
+,	O
+and	O
+chest	B
+pain	I
+promptly	O
+resolved	O
+with	O
+nifedipine	O
+.	O
+
+These	O
+data	O
+suggest	O
+that	O
+coronary	B
+spasm	I
+may	O
+be	O
+the	O
+cause	O
+of	O
+cardiotoxicity	B
+due	O
+to	O
+5	O
+-	O
+FU	O
+,	O
+and	O
+that	O
+calcium	O
+antagonists	O
+may	O
+probably	O
+be	O
+used	O
+in	O
+the	O
+prevention	O
+or	O
+treatment	O
+of	O
+5	O
+-	O
+FU	O
+cardiotoxicity	B
+.	O
+
+Dose	O
+-	O
+related	O
+beneficial	O
+and	O
+adverse	O
+effects	O
+of	O
+dietary	O
+corticosterone	O
+on	O
+organophosphorus	O
+-	O
+induced	O
+delayed	O
+neuropathy	B
+in	O
+chickens	O
+.	O
+
+Tri	O
+-	O
+ortho	O
+-	O
+tolyl	O
+phosphate	O
+(	O
+TOTP	O
+)	O
+,	O
+360	O
+mg	O
+/	O
+kg	O
+,	O
+po	O
+,	O
+and	O
+0	O
+,	O
+0	O
+'	O
+-	O
+diisopropyl	O
+phosphorofluoridate	O
+(	O
+DFP	O
+)	O
+,	O
+1	O
+mg	O
+/	O
+kg	O
+sc	O
+,	O
+were	O
+administered	O
+to	O
+adult	O
+White	O
+Leghorn	O
+chickens	O
+24	O
+hr	O
+after	O
+they	O
+were	O
+placed	O
+on	O
+diets	O
+containing	O
+0	O
+to	O
+300	O
+ppm	O
+corticosterone	O
+.	O
+
+Supplemented	O
+diets	O
+were	O
+continued	O
+until	O
+clinical	O
+signs	O
+and	O
+lesions	O
+of	O
+delayed	O
+neuropathy	B
+appeared	O
+.	O
+
+Although	O
+low	O
+concentrations	O
+(	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+50	O
+ppm	O
+)	O
+of	O
+corticosterone	O
+had	O
+beneficial	O
+effects	O
+on	O
+TOTP	O
+-	O
+induced	O
+neuropathy	B
+,	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+200	O
+ppm	O
+exacerbated	O
+clinical	O
+signs	O
+in	O
+chickens	O
+given	O
+either	O
+TOTP	O
+or	O
+DFP	O
+.	O
+
+Neurotoxic	B
+esterase	O
+activities	O
+24	O
+hr	O
+after	O
+TOTP	O
+or	O
+DFP	O
+were	O
+less	O
+than	O
+20	O
+%	O
+of	O
+values	O
+measured	O
+in	O
+chickens	O
+not	O
+given	O
+organophosphorous	O
+compounds	O
+.	O
+
+Chickens	O
+given	O
+200	O
+ppm	O
+corticosterone	O
+without	O
+TOTP	O
+or	O
+DFP	O
+had	O
+significantly	O
+elevated	O
+activity	O
+of	O
+plasma	O
+cholinesterase	O
+and	O
+significantly	O
+inhibited	O
+activity	O
+of	O
+liver	O
+carboxylesterase	O
+.	O
+
+Degenerating	B
+myelinated	I
+fibers	I
+were	O
+also	O
+evident	O
+in	O
+distal	O
+levels	O
+of	O
+the	O
+peripheral	O
+nerves	O
+of	O
+chickens	O
+given	O
+TOTP	O
+or	O
+DFP	O
+.	O
+
+Hepatotoxicity	B
+of	O
+amiodarone	O
+.	O
+
+Amiodarone	O
+has	O
+proved	O
+very	O
+effective	O
+in	O
+the	O
+treatment	O
+of	O
+otherwise	O
+resistant	O
+cardiac	O
+tachyarrhythmias	B
+.	O
+
+The	O
+use	O
+of	O
+amiodarone	O
+has	O
+,	O
+however	O
+,	O
+been	O
+limited	O
+due	O
+to	O
+its	O
+serious	O
+side	O
+-	O
+effects	O
+.	O
+
+A	O
+patient	O
+with	O
+cholestatic	B
+hepatitis	I
+due	O
+to	O
+amiodarone	O
+treatment	O
+is	O
+presented	O
+below	O
+and	O
+a	O
+review	O
+of	O
+the	O
+hepatotoxicity	B
+of	O
+amiodarone	O
+is	O
+given	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+solid	O
+evidence	O
+exists	O
+of	O
+hepatic	B
+injury	I
+due	O
+to	O
+amiodarone	O
+treatment	O
+,	O
+including	O
+steatosis	B
+,	O
+alterations	O
+resembling	O
+alcoholic	B
+hepatitis	I
+,	O
+cholestatic	B
+hepatitis	I
+and	O
+micronodular	O
+cirrhosis	B
+of	I
+the	I
+liver	I
+.	O
+
+Patients	O
+receiving	O
+amiodarone	O
+should	O
+be	O
+regularly	O
+screened	O
+with	O
+respect	O
+to	O
+hepatic	O
+enzyme	O
+levels	O
+.	O
+
+Therapy	O
+should	O
+be	O
+discontinued	O
+on	O
+the	O
+suspicion	O
+of	O
+cholestatic	B
+injury	I
+or	O
+hepatomegaly	B
+.	O
+
+Promotional	O
+effects	O
+of	O
+testosterone	O
+and	O
+dietary	O
+fat	O
+on	O
+prostate	O
+carcinogenesis	B
+in	O
+genetically	O
+susceptible	O
+rats	O
+.	O
+
+Germfree	O
+(	O
+GF	O
+)	O
+Lobund	O
+strain	O
+Wistar	O
+(	O
+LW	O
+)	O
+rats	O
+,	O
+fed	O
+vegetable	O
+diet	O
+L	O
+-	O
+485	O
+,	O
+have	O
+developed	O
+prostate	B
+adenocarcinomas	I
+spontaneously	O
+(	O
+10	O
+%	O
+incidence	O
+)	O
+at	O
+average	O
+age	O
+34	O
+months	O
+.	O
+
+Conventional	O
+LW	O
+rats	O
+,	O
+implanted	O
+with	O
+testosterone	O
+at	O
+age	O
+4	O
+months	O
+,	O
+developed	O
+a	O
+higher	O
+incidence	O
+of	O
+prostate	B
+cancer	I
+after	O
+an	O
+average	O
+interval	O
+of	O
+14	O
+months	O
+:	O
+24	O
+%	O
+had	O
+developed	O
+gross	O
+tumors	B
+,	O
+and	O
+40	O
+%	O
+when	O
+it	O
+included	O
+microscopic	O
+tumors	B
+.	O
+
+Preliminary	O
+results	O
+indicate	O
+that	O
+testosterone	O
+-	O
+treated	O
+LW	O
+rats	O
+that	O
+were	O
+fed	O
+the	O
+same	O
+diet	O
+,	O
+which	O
+was	O
+supplemented	O
+with	O
+corn	O
+oil	O
+up	O
+to	O
+20	O
+%	O
+fat	O
+,	O
+developed	O
+prostate	B
+cancer	I
+after	O
+intervals	O
+of	O
+6	O
+-	O
+12	O
+months	O
+.	O
+
+Aged	O
+GF	O
+Sprague	O
+-	O
+Dawley	O
+(	O
+SD	O
+)	O
+rats	O
+have	O
+not	O
+developed	O
+prostate	B
+cancer	I
+spontaneously	O
+.	O
+
+Conventional	O
+SD	O
+rats	O
+fed	O
+diet	O
+L	O
+-	O
+485	O
+and	O
+treated	O
+with	O
+testosterone	O
+developed	O
+only	O
+prostatitis	B
+.	O
+
+Experimental	O
+designs	O
+should	O
+consider	O
+genetic	O
+susceptibility	O
+as	O
+a	O
+basic	O
+prerequisite	O
+for	O
+studies	O
+on	O
+experimental	O
+prostate	B
+cancer	I
+.	O
+
+Time	O
+course	O
+alterations	O
+of	O
+QTC	O
+interval	O
+due	O
+to	O
+hypaque	O
+76	O
+.	O
+
+Sequential	O
+measurement	O
+of	O
+QT	O
+interval	O
+during	O
+left	O
+ventricular	O
+angiography	O
+was	O
+made	O
+30	O
+seconds	O
+and	O
+one	O
+,	O
+three	O
+,	O
+five	O
+and	O
+ten	O
+minutes	O
+after	O
+injection	O
+of	O
+hypaque	O
+76	O
+.	O
+
+The	O
+subjects	O
+were	O
+ten	O
+patients	O
+found	O
+to	O
+have	O
+normal	O
+left	O
+ventricles	O
+and	O
+coronary	O
+arteries	O
+.	O
+
+Significant	O
+QTC	B
+prolongation	I
+occurred	O
+in	O
+30	O
+seconds	O
+to	O
+one	O
+minute	O
+in	O
+association	O
+with	O
+marked	O
+hypotension	B
+and	O
+elevation	O
+of	O
+cardiac	O
+output	O
+.	O
+
+Rat	O
+extraocular	O
+muscle	O
+regeneration	O
+.	O
+
+Repair	O
+of	O
+local	O
+anesthetic	O
+-	O
+induced	O
+damage	O
+.	O
+
+Local	O
+anesthetics	O
+that	O
+are	O
+commonly	O
+used	O
+in	O
+ophthalmic	O
+surgery	O
+(	O
+0	O
+.	O
+75	O
+%	O
+bupivacaine	O
+hydrochloride	O
+,	O
+2	O
+.	O
+0	O
+%	O
+mepivacaine	O
+hydrochloride	O
+,	O
+and	O
+2	O
+.	O
+0	O
+%	O
+lidocaine	O
+hydrochloride	O
+plus	O
+1	O
+:	O
+100	O
+,	O
+000	O
+epinephrine	O
+)	O
+were	O
+injected	O
+into	O
+the	O
+retrobulbar	O
+area	O
+of	O
+rat	O
+eyes	O
+.	O
+
+Controls	O
+were	O
+injected	O
+with	O
+physiological	O
+saline	O
+.	O
+
+All	O
+three	O
+anesthetics	O
+produced	O
+massive	O
+degeneration	O
+of	O
+the	O
+extraocular	O
+muscles	O
+.	O
+
+Muscle	B
+degeneration	I
+is	O
+followed	O
+by	O
+regeneration	O
+of	O
+the	O
+damaged	O
+muscle	O
+fibers	O
+.	O
+
+In	O
+addition	O
+to	O
+muscle	B
+damage	I
+,	O
+severe	O
+damage	O
+was	O
+also	O
+seen	O
+in	O
+harderian	O
+glands	O
+,	O
+especially	O
+after	O
+exposure	O
+to	O
+mepivacaine	O
+and	O
+lidocaine	O
+plus	O
+epinephrine	O
+.	O
+
+With	O
+these	O
+findings	O
+in	O
+rats	O
+,	O
+it	O
+is	O
+hypothesized	O
+that	O
+the	O
+temporary	O
+diplopia	B
+sometimes	O
+seen	O
+in	O
+patients	O
+after	O
+ophthalmic	O
+surgery	O
+might	O
+be	O
+due	O
+to	O
+anesthetic	O
+-	O
+induced	O
+damage	O
+to	O
+the	O
+extraocular	O
+muscles	O
+.	O
+
+Gentamicin	O
+nephropathy	B
+in	O
+a	O
+neonate	O
+.	O
+
+The	O
+clinical	O
+and	O
+autopsy	O
+findings	O
+in	O
+a	O
+premature	O
+baby	O
+who	O
+died	O
+of	O
+acute	B
+renal	I
+failure	I
+after	O
+therapy	O
+with	O
+gentamicin	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+)	O
+and	O
+penicillin	O
+are	O
+presented	O
+.	O
+
+The	O
+serum	O
+gentamicin	O
+concentration	O
+had	O
+reached	O
+toxic	O
+levels	O
+when	O
+anuria	B
+developed	O
+.	O
+
+Numerous	O
+periodic	O
+acid	O
+Schiff	O
+(	O
+PAS	O
+)	O
+positive	O
+,	O
+diastase	O
+resistant	O
+cytoplasmic	O
+inclusion	O
+bodies	O
+which	O
+appeared	O
+as	O
+myelin	O
+figures	O
+in	O
+cytosegresomes	O
+under	O
+the	O
+electron	O
+microscope	O
+were	O
+identified	O
+in	O
+the	O
+proximal	O
+convoluted	O
+tubules	O
+.	O
+
+The	O
+pathological	O
+changes	O
+induced	O
+by	O
+gentamicin	O
+in	O
+the	O
+human	O
+neonatal	O
+kidneys	O
+have	O
+not	O
+been	O
+previously	O
+reported	O
+.	O
+
+Induction	O
+by	O
+paracetamol	O
+of	O
+bladder	B
+and	I
+liver	I
+tumours	I
+in	O
+the	O
+rat	O
+.	O
+
+Effects	O
+on	O
+hepatocyte	O
+fine	O
+structure	O
+.	O
+
+Groups	O
+of	O
+male	O
+and	O
+female	O
+inbred	O
+Leeds	O
+strain	O
+rats	O
+were	O
+fed	O
+diets	O
+containing	O
+either	O
+0	O
+.	O
+5	O
+%	O
+or	O
+1	O
+.	O
+0	O
+%	O
+paracetamol	O
+by	O
+weight	O
+for	O
+up	O
+to	O
+18	O
+months	O
+.	O
+
+At	O
+the	O
+1	O
+.	O
+0	O
+%	O
+dosage	O
+level	O
+,	O
+20	O
+%	O
+of	O
+rats	O
+of	O
+both	O
+sexes	O
+developed	O
+neoplastic	O
+nodules	O
+of	O
+the	O
+liver	O
+,	O
+a	O
+statistically	O
+significant	O
+incidence	O
+.	O
+
+These	O
+rats	O
+also	O
+showed	O
+gross	O
+enlargement	O
+of	O
+their	O
+livers	O
+and	O
+an	O
+increase	O
+in	O
+foci	O
+of	O
+cellular	O
+alteration	O
+,	O
+the	O
+latter	O
+also	O
+being	O
+observed	O
+in	O
+the	O
+low	O
+dosage	O
+male	O
+rats	O
+.	O
+
+Papillomas	B
+of	O
+the	O
+transitional	O
+epithelium	O
+of	O
+the	O
+bladder	O
+developed	O
+in	O
+all	O
+paracetamol	O
+-	O
+treated	O
+groups	O
+,	O
+and	O
+three	O
+rats	O
+bore	O
+bladder	B
+carcinomas	I
+.	O
+
+However	O
+,	O
+significant	O
+yields	O
+of	O
+bladder	B
+tumours	I
+were	O
+only	O
+obtained	O
+from	O
+low	O
+dosage	O
+females	O
+and	O
+high	O
+dosage	O
+males	O
+.	O
+
+Additionally	O
+,	O
+20	O
+to	O
+25	O
+%	O
+of	O
+paracetamol	O
+-	O
+treated	O
+rats	O
+developed	O
+hyperplasia	B
+of	O
+the	O
+bladder	O
+epithelium	O
+,	O
+which	O
+was	O
+not	O
+coincident	O
+with	O
+the	O
+presence	O
+of	O
+bladder	B
+calculi	I
+.	O
+
+A	O
+low	O
+yield	O
+of	O
+tumours	B
+at	O
+various	O
+other	O
+sites	O
+also	O
+arose	O
+following	O
+paracetamol	O
+feeding	O
+.	O
+
+An	O
+electron	O
+microscope	O
+study	O
+of	O
+the	O
+livers	O
+of	O
+paracetamol	O
+-	O
+treated	O
+rats	O
+revealed	O
+ultrastructural	O
+changes	O
+in	O
+the	O
+hepatocytes	O
+that	O
+resemble	O
+those	O
+that	O
+result	O
+from	O
+exposure	O
+to	O
+a	O
+variety	O
+of	O
+known	O
+hepatocarcinogens	B
+.	O
+
+Transient	O
+hemiparesis	B
+:	O
+a	O
+rare	O
+manifestation	O
+of	O
+diphenylhydantoin	O
+toxicity	B
+.	O
+
+Report	O
+of	O
+two	O
+cases	O
+.	O
+
+Among	O
+the	O
+common	O
+side	O
+effects	O
+of	O
+diphenylhydantoin	O
+(	O
+DPH	O
+)	O
+overdose	B
+,	O
+the	O
+most	O
+frequently	O
+encountered	O
+neurological	O
+signs	O
+are	O
+those	O
+of	O
+cerebellar	B
+dysfunction	I
+.	O
+
+Very	O
+rarely	O
+,	O
+the	O
+toxic	O
+neurological	O
+manifestations	O
+of	O
+this	O
+drug	O
+are	O
+of	O
+cerebral	O
+origin	O
+.	O
+
+Two	O
+patients	O
+are	O
+presented	O
+who	O
+suffered	O
+progressive	O
+hemiparesis	B
+due	O
+to	O
+DPH	O
+overdose	B
+.	O
+
+Both	O
+had	O
+brain	O
+surgery	O
+before	O
+DPH	O
+treatment	O
+.	O
+
+It	O
+is	O
+assumed	O
+that	O
+patients	O
+with	O
+some	O
+cerebral	B
+damage	I
+are	O
+liable	O
+to	O
+manifest	O
+DPH	O
+toxicity	B
+as	O
+focal	O
+neurological	O
+signs	O
+.	O
+
+Tiapride	O
+in	O
+levodopa	O
+-	O
+induced	O
+involuntary	B
+movements	I
+.	O
+
+Tiapride	O
+,	O
+a	O
+substituted	O
+benzamide	O
+derivative	O
+closely	O
+related	O
+to	O
+metoclopramide	O
+,	O
+reduced	O
+levodopa	O
+-	O
+induced	O
+peak	O
+dose	O
+involuntary	B
+movements	I
+in	O
+16	O
+patients	O
+with	O
+idiopathic	B
+Parkinson	I
+'	I
+s	I
+disease	I
+.	O
+
+However	O
+,	O
+an	O
+unacceptable	O
+increase	O
+in	O
+disability	O
+from	O
+Parkinsonism	B
+with	O
+aggravation	O
+of	O
+end	O
+-	O
+of	O
+-	O
+dose	O
+akinesia	B
+led	O
+to	O
+its	O
+cessation	O
+in	O
+14	O
+patients	O
+.	O
+
+Tiapride	O
+had	O
+no	O
+effect	O
+on	O
+levodopa	O
+-	O
+induced	O
+early	O
+morning	O
+of	O
+"	O
+off	O
+-	O
+period	O
+"	O
+segmental	O
+dystonia	B
+.	O
+
+These	O
+results	O
+fail	O
+to	O
+support	O
+the	O
+notion	O
+that	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+are	O
+caused	O
+by	O
+overstimulation	O
+of	O
+a	O
+separate	O
+group	O
+of	O
+dopamine	O
+receptors	O
+.	O
+
+Quinidine	O
+hepatitis	B
+.	O
+
+Long	O
+-	O
+term	O
+administration	O
+of	O
+quinidine	O
+was	O
+associated	O
+with	O
+persistent	O
+elevation	O
+of	O
+serum	O
+concentrations	O
+of	O
+SGOT	O
+,	O
+lactic	O
+acid	O
+dehydrogenase	O
+,	O
+and	O
+alkaline	O
+phosphatase	O
+.	O
+
+Liver	O
+biopsy	O
+showed	O
+active	O
+hepatitis	B
+.	O
+
+Discontinuance	O
+of	O
+quinidine	O
+therapy	O
+led	O
+to	O
+normalization	O
+of	O
+liver	O
+function	O
+tests	O
+.	O
+
+A	O
+challenge	O
+dose	O
+of	O
+quinidine	O
+caused	O
+clinical	O
+symptoms	O
+and	O
+abrupt	O
+elevation	O
+of	O
+SGOT	O
+,	O
+alkaline	O
+phosphatase	O
+,	O
+and	O
+lactic	O
+acid	O
+dehydrogenase	O
+values	O
+.	O
+
+We	O
+concluded	O
+that	O
+this	O
+patient	O
+had	O
+quinidine	O
+hepatotoxicity	B
+and	O
+believe	O
+that	O
+this	O
+is	O
+the	O
+first	O
+case	O
+reported	O
+with	O
+liver	O
+biopsy	O
+documentation	O
+.	O
+
+This	O
+report	O
+also	O
+suggests	O
+that	O
+,	O
+even	O
+after	O
+long	O
+-	O
+term	O
+administration	O
+,	O
+the	O
+hepatic	B
+toxicity	I
+is	O
+reversible	O
+.	O
+
+Arterial	O
+thromboembolism	B
+in	O
+patients	O
+receiving	O
+systemic	O
+heparin	O
+therapy	O
+:	O
+a	O
+complication	O
+associated	O
+with	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+.	O
+
+Arterial	O
+thromboembolism	B
+is	O
+a	O
+recognized	O
+complication	O
+of	O
+systemic	O
+heparin	O
+therapy	O
+.	O
+
+Characteristic	O
+of	O
+the	O
+entity	O
+is	O
+arterial	B
+occlusion	I
+by	O
+platelet	O
+-	O
+fibrin	O
+thrombi	B
+with	O
+distal	O
+ischemia	B
+occurring	O
+four	O
+to	O
+twenty	O
+days	O
+after	O
+the	O
+initiation	O
+of	O
+heparin	O
+therapy	O
+,	O
+preceded	O
+by	O
+profound	O
+thrombocytopenia	B
+with	O
+platelet	O
+counts	O
+in	O
+the	O
+range	O
+of	O
+30	O
+,	O
+000	O
+to	O
+40	O
+,	O
+000	O
+per	O
+cubic	O
+millimeter	O
+.	O
+
+The	O
+clinically	O
+apparent	O
+occlusion	O
+may	O
+be	O
+preceded	O
+by	O
+gastrointestinal	B
+and	I
+musculoskeletal	I
+symptoms	I
+that	O
+appear	O
+to	O
+be	O
+ischemic	B
+in	O
+origin	O
+,	O
+and	O
+might	O
+serve	O
+to	O
+warn	O
+the	O
+clinician	O
+of	O
+these	O
+complications	O
+.	O
+
+Previous	O
+reports	O
+of	O
+these	O
+phenomena	O
+as	O
+well	O
+as	O
+recent	O
+studies	O
+of	O
+the	O
+effect	O
+of	O
+heparin	O
+are	O
+reviewed	O
+.	O
+
+The	O
+common	O
+factor	O
+relating	O
+thromboembolism	B
+and	O
+thrombocytopenia	B
+is	O
+heparin	O
+-	O
+induced	O
+platelet	B
+aggregation	I
+.	O
+
+Appropriate	O
+treatment	O
+consists	O
+of	O
+discontinuation	O
+of	O
+heparin	O
+,	O
+and	O
+anticoagulation	O
+with	O
+sodium	O
+warfarin	O
+if	O
+necessary	O
+.	O
+
+Vascular	O
+procedures	O
+are	O
+performed	O
+as	O
+indicated	O
+.	O
+
+Pharmacology	O
+of	O
+GYKI	O
+-	O
+41	O
+099	O
+(	O
+chlorpropanol	O
+,	O
+Tobanum	O
+)	O
+a	O
+new	O
+potent	O
+beta	O
+-	O
+adrenergic	O
+antagonist	O
+.	O
+
+The	O
+compound	O
+GYKI	O
+-	O
+41	O
+099	O
+,	O
+as	O
+a	O
+beta	O
+-	O
+adrenergic	O
+antagonist	O
+,	O
+is	O
+3	O
+-	O
+8	O
+times	O
+more	O
+potent	O
+than	O
+propranolol	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+.	O
+
+Its	O
+antiarrhythmic	O
+effectiveness	O
+surpasses	O
+that	O
+of	O
+propranolol	O
+and	O
+pindolol	O
+inhibiting	O
+the	O
+ouabain	O
+arrhythmia	B
+in	O
+dogs	O
+and	O
+cats	O
+.	O
+
+GYKI	O
+-	O
+41	O
+900	O
+has	O
+a	O
+negligible	O
+cardiodepressant	O
+activity	O
+;	O
+it	O
+is	O
+not	O
+cardioselective	O
+.	O
+
+The	O
+compound	O
+shows	O
+a	O
+rapid	O
+and	O
+long	O
+lasting	O
+effect	O
+.	O
+
+There	O
+was	O
+a	O
+prolonged	O
+elimination	O
+of	O
+the	O
+radioactivity	O
+after	O
+the	O
+injection	O
+of	O
+14C	O
+-	O
+41	O
+099	O
+to	O
+rats	O
+and	O
+dogs	O
+.	O
+
+The	O
+half	O
+life	O
+of	O
+the	O
+unlabeled	O
+substance	O
+in	O
+humans	O
+was	O
+more	O
+than	O
+10	O
+hours	O
+.	O
+
+Adverse	O
+reactions	O
+to	O
+bendrofluazide	O
+and	O
+propranolol	O
+for	O
+the	O
+treatment	O
+of	O
+mild	O
+hypertension	B
+.	O
+
+Report	O
+of	O
+Medical	O
+Research	O
+Council	O
+Working	O
+Party	O
+on	O
+Mild	O
+to	O
+Moderate	O
+Hypertension	B
+.	O
+
+Participants	O
+in	O
+the	O
+Medical	O
+Research	O
+Council	O
+treatment	O
+trial	O
+for	O
+mild	O
+hypertension	B
+are	O
+randomly	O
+allocated	O
+to	O
+one	O
+of	O
+four	O
+treatment	O
+groups	O
+:	O
+bendrofluazide	O
+,	O
+propranolol	O
+,	O
+or	O
+a	O
+placebo	O
+for	O
+either	O
+of	O
+these	O
+drugs	O
+.	O
+
+The	O
+trial	O
+is	O
+single	O
+-	O
+blind	O
+.	O
+
+23	O
+582	O
+patient	O
+-	O
+years	O
+of	O
+observation	O
+have	O
+been	O
+completed	O
+so	O
+far	O
+,	O
+10	O
+684	O
+on	O
+active	O
+drugs	O
+and	O
+12	O
+898	O
+on	O
+placebos	O
+.	O
+
+The	O
+results	O
+show	O
+an	O
+association	O
+between	O
+bendrofluazide	O
+treatment	O
+and	O
+impotence	B
+,	O
+and	O
+impotence	B
+also	O
+occurred	O
+more	O
+frequently	O
+in	O
+patients	O
+taking	O
+propranolol	O
+than	O
+in	O
+those	O
+taking	O
+placebos	O
+.	O
+
+Other	O
+adverse	O
+reactions	O
+significantly	O
+linked	O
+with	O
+active	O
+drugs	O
+include	O
+impaired	B
+glucose	I
+tolerance	I
+in	O
+men	O
+and	O
+women	O
+and	O
+gout	B
+in	O
+men	O
+,	O
+associated	O
+with	O
+bendrofluazide	O
+treatment	O
+,	O
+and	O
+Raynaud	B
+'	I
+s	I
+phenomenon	I
+and	O
+dyspnoea	B
+in	O
+men	O
+and	O
+women	O
+taking	O
+propranolol	O
+.	O
+
+No	O
+corneal	B
+disease	I
+is	O
+known	O
+to	O
+have	O
+occurred	O
+in	O
+the	O
+propranolol	O
+group	O
+.	O
+
+Mean	O
+serum	O
+potassium	O
+level	O
+fell	O
+,	O
+and	O
+urea	O
+and	O
+uric	O
+acid	O
+levels	O
+rose	O
+,	O
+in	O
+men	O
+and	O
+women	O
+taking	O
+bendrofluazide	O
+.	O
+
+In	O
+the	O
+propranolol	O
+group	O
+,	O
+serum	O
+potassium	O
+and	O
+uric	O
+acid	O
+levels	O
+rose	O
+in	O
+both	O
+sexes	O
+,	O
+but	O
+the	O
+urea	O
+level	O
+rose	O
+significantly	O
+in	O
+women	O
+only	O
+.	O
+
+Serotonergic	O
+drugs	O
+,	O
+benzodiazepines	O
+and	O
+baclofen	O
+block	O
+muscimol	O
+-	O
+induced	O
+myoclonic	B
+jerks	I
+in	O
+a	O
+strain	O
+of	O
+mice	O
+.	O
+
+In	O
+male	O
+Swiss	O
+mice	O
+,	O
+muscimol	O
+produced	O
+myoclonic	B
+jerks	I
+.	O
+
+A	O
+3	O
+mg	O
+/	O
+kg	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+dose	O
+induced	O
+this	O
+response	O
+in	O
+all	O
+of	O
+the	O
+mice	O
+tested	O
+and	O
+the	O
+peak	O
+response	O
+of	O
+73	O
+jerks	O
+per	O
+min	O
+was	O
+observed	O
+between	O
+27	O
+and	O
+45	O
+min	O
+.	O
+
+Increasing	O
+the	O
+brain	O
+serotonin	O
+levels	O
+by	O
+the	O
+administration	O
+of	O
+5	O
+-	O
+hydroxytryptophan	O
+(	O
+80	O
+-	O
+160	O
+mg	O
+/	O
+kg	O
+)	O
+in	O
+combination	O
+with	O
+a	O
+peripheral	O
+decarboxylase	O
+inhibitor	O
+resulted	O
+in	O
+an	O
+inhibition	O
+of	O
+the	O
+muscimol	O
+effect	O
+.	O
+
+However	O
+,	O
+in	O
+a	O
+similar	O
+experiment	O
+l	O
+-	O
+dopa	O
+(	O
+80	O
+-	O
+160	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+without	O
+effect	O
+.	O
+
+In	O
+doses	O
+of	O
+3	O
+-	O
+10	O
+mg	O
+/	O
+kg	O
+,	O
+the	O
+serotonin	O
+receptor	O
+agonist	O
+MK	O
+-	O
+212	O
+caused	O
+a	O
+dose	O
+-	O
+dependent	O
+blockade	O
+of	O
+the	O
+response	O
+of	O
+muscimol	O
+.	O
+
+Of	O
+the	O
+benzodiazepines	O
+,	O
+clonazepam	O
+(	O
+0	O
+.	O
+1	O
+-	O
+0	O
+.	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+found	O
+to	O
+be	O
+several	O
+fold	O
+more	O
+potent	O
+than	O
+diazepam	O
+(	O
+0	O
+.	O
+3	O
+-	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+in	O
+blocking	O
+the	O
+myoclonic	B
+jerks	I
+.	O
+
+While	O
+(	O
+-	O
+)	O
+-	O
+baclofen	O
+(	O
+1	O
+-	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+proved	O
+to	O
+be	O
+an	O
+effective	O
+antagonist	O
+of	O
+muscimol	O
+,	O
+its	O
+(	O
++	O
+)	O
+-	O
+isomer	O
+(	O
+5	O
+-	O
+20	O
+mg	O
+/	O
+kg	O
+)	O
+lacked	O
+this	O
+property	O
+.	O
+
+Considering	O
+the	O
+fact	O
+that	O
+5	O
+-	O
+HTP	O
+and	O
+the	O
+benzodiazepines	O
+have	O
+been	O
+found	O
+to	O
+be	O
+beneficial	O
+in	O
+the	O
+management	O
+of	O
+clinical	O
+myoclonus	B
+,	O
+the	O
+muscimol	O
+-	O
+induced	O
+myoclonus	B
+seems	O
+to	O
+be	O
+a	O
+satisfactory	O
+animal	O
+model	O
+that	O
+may	O
+prove	O
+useful	O
+for	O
+the	O
+development	O
+of	O
+new	O
+drug	O
+treatments	O
+for	O
+this	O
+condition	O
+.	O
+
+Our	O
+present	O
+study	O
+indicated	O
+the	O
+possible	O
+value	O
+of	O
+MK	O
+-	O
+212	O
+and	O
+(	O
+-	O
+)	O
+-	O
+baclofen	O
+in	O
+the	O
+management	O
+of	O
+clinical	O
+myoclonus	B
+.	O
+
+Adverse	O
+interaction	O
+between	O
+beta	O
+-	O
+adrenergic	O
+blocking	O
+drugs	O
+and	O
+verapamil	O
+-	O
+-	O
+report	O
+of	O
+three	O
+cases	O
+.	O
+
+Three	O
+patients	O
+with	O
+ischaemic	B
+heart	I
+disease	I
+developed	O
+profound	O
+cardiac	B
+failure	I
+,	O
+hypotension	B
+and	O
+bradycardia	B
+during	O
+combined	O
+therapy	O
+with	O
+verapamil	O
+and	O
+beta	O
+-	O
+adrenergic	O
+blocking	O
+drugs	O
+.	O
+
+This	O
+clinical	O
+picture	O
+resolved	O
+completely	O
+with	O
+cessation	O
+of	O
+the	O
+combined	O
+therapy	O
+.	O
+
+Baseline	O
+left	O
+ventricular	O
+function	O
+,	O
+assessed	O
+by	O
+cardiac	O
+catheterisation	O
+or	O
+nuclear	O
+angiography	O
+,	O
+was	O
+normal	O
+in	O
+two	O
+patients	O
+and	O
+only	O
+mildly	O
+reduced	O
+in	O
+the	O
+other	O
+.	O
+
+Simultaneously	O
+administration	O
+of	O
+beta	O
+-	O
+adrenergic	O
+blocking	O
+drugs	O
+and	O
+verapamil	O
+may	O
+result	O
+in	O
+profound	O
+adverse	O
+interactions	O
+and	O
+should	O
+only	O
+be	O
+administered	O
+with	O
+great	O
+caution	O
+.	O
+
+Comparison	O
+of	O
+the	O
+effectiveness	O
+of	O
+ranitidine	O
+and	O
+cimetidine	O
+in	O
+inhibiting	O
+acid	O
+secretion	O
+in	O
+patients	O
+with	O
+gastric	O
+hypersecretory	O
+states	O
+.	O
+
+The	O
+H2	O
+-	O
+histamine	O
+receptor	O
+antagonists	O
+ranitidine	O
+and	O
+cimetidine	O
+were	O
+compared	O
+for	O
+their	O
+abilities	O
+to	O
+control	O
+gastric	O
+acid	O
+hypersecretion	O
+on	O
+a	O
+short	O
+-	O
+and	O
+long	O
+-	O
+term	O
+basis	O
+in	O
+22	O
+patients	O
+with	O
+gastric	O
+acid	O
+hypersecretory	O
+states	O
+.	O
+
+Nineteen	O
+patients	O
+had	O
+Zollinger	B
+-	I
+Ellison	I
+syndrome	I
+,	O
+one	O
+patient	O
+had	O
+systemic	B
+mastocytosis	I
+,	O
+and	O
+two	O
+patients	O
+had	O
+idiopathic	O
+hypersecretion	O
+.	O
+
+The	O
+rates	O
+of	O
+onset	O
+of	O
+the	O
+action	O
+of	O
+cimetidine	O
+and	O
+ranitidine	O
+were	O
+the	O
+same	O
+.	O
+
+The	O
+actions	O
+of	O
+both	O
+drugs	O
+were	O
+increased	O
+by	O
+anticholinergic	O
+agents	O
+,	O
+and	O
+there	O
+was	O
+a	O
+close	O
+correlation	O
+between	O
+the	O
+daily	O
+maintenance	O
+dose	O
+of	O
+each	O
+drug	O
+needed	O
+to	O
+control	O
+acid	O
+secretion	O
+.	O
+
+However	O
+,	O
+ranitidine	O
+was	O
+threefold	O
+more	O
+potent	O
+than	O
+cimetidine	O
+both	O
+in	O
+acute	O
+inhibition	O
+studies	O
+and	O
+in	O
+the	O
+median	O
+maintenance	O
+dose	O
+needed	O
+(	O
+1	O
+.	O
+2	O
+g	O
+per	O
+day	O
+for	O
+ranitidine	O
+and	O
+3	O
+.	O
+6	O
+g	O
+per	O
+day	O
+for	O
+cimetidine	O
+)	O
+.	O
+
+Sixty	O
+percent	O
+of	O
+the	O
+males	O
+developed	O
+breast	O
+changes	O
+or	O
+impotence	B
+while	O
+taking	O
+cimetidine	O
+and	O
+in	O
+all	O
+cases	O
+these	O
+changes	O
+disappeared	O
+when	O
+cimetidine	O
+was	O
+replaced	O
+by	O
+ranitidine	O
+.	O
+
+Treatment	O
+with	O
+high	O
+doses	O
+of	O
+cimetidine	O
+(	O
+one	O
+to	O
+60	O
+months	O
+;	O
+median	O
+,	O
+11	O
+months	O
+)	O
+or	O
+ranitidine	O
+(	O
+two	O
+to	O
+31	O
+months	O
+;	O
+median	O
+,	O
+14	O
+months	O
+)	O
+was	O
+not	O
+associated	O
+with	O
+hepatic	B
+or	I
+hematologic	I
+toxicity	I
+or	O
+alterations	O
+of	O
+serum	O
+gastrin	O
+concentrations	O
+,	O
+but	O
+ranitidine	O
+therapy	O
+was	O
+associated	O
+with	O
+a	O
+significantly	O
+lower	O
+serum	O
+creatinine	O
+level	O
+than	O
+seen	O
+with	O
+cimetidine	O
+therapy	O
+.	O
+
+The	O
+results	O
+show	O
+that	O
+both	O
+drugs	O
+can	O
+adequately	O
+inhibit	O
+acid	O
+secretion	O
+in	O
+patients	O
+with	O
+gastric	O
+hypersecretory	O
+states	O
+.	O
+
+Both	O
+are	O
+safe	O
+at	O
+high	O
+doses	O
+,	O
+but	O
+ranitidine	O
+is	O
+threefold	O
+more	O
+potent	O
+and	O
+does	O
+not	O
+cause	O
+the	O
+antiandrogen	O
+side	O
+effects	O
+frequently	O
+seen	O
+with	O
+high	O
+doses	O
+of	O
+cimetidine	O
+.	O
+
+Epileptogenic	O
+properties	O
+of	O
+enflurane	O
+and	O
+their	O
+clinical	O
+interpretation	O
+.	O
+
+Three	O
+cases	O
+of	O
+EEG	O
+changes	O
+induced	O
+by	O
+single	O
+exposure	O
+to	O
+enflurane	O
+anesthesia	O
+are	O
+reported	O
+.	O
+
+In	O
+one	O
+patient	O
+,	O
+enflurane	O
+administered	O
+during	O
+a	O
+donor	O
+nephrectomy	O
+resulted	O
+in	O
+unexpected	O
+partial	O
+motor	O
+seizures	B
+.	O
+
+Until	O
+the	O
+cause	O
+of	O
+the	O
+seizures	B
+was	O
+correctly	O
+identified	O
+,	O
+the	O
+patient	O
+was	O
+inappropriately	O
+treated	O
+with	O
+anticonvulsants	O
+.	O
+
+Two	O
+other	O
+patients	O
+suffered	O
+from	O
+partial	O
+,	O
+complex	O
+and	O
+generalized	O
+seizures	B
+uncontrolled	O
+by	O
+medication	O
+.	O
+
+Epileptic	B
+foci	O
+delineated	O
+and	O
+activated	O
+by	O
+enflurane	O
+were	O
+surgically	O
+ablated	O
+and	O
+the	O
+patients	O
+are	O
+now	O
+seizure	B
+-	O
+free	O
+.	O
+
+Previous	O
+exposures	O
+to	O
+enflurane	O
+have	O
+to	O
+be	O
+disclosed	O
+to	O
+avoid	O
+mistakes	O
+in	O
+clinical	O
+interpretation	O
+of	O
+the	O
+EEG	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+enflurane	O
+may	O
+prove	O
+to	O
+be	O
+a	O
+safe	O
+fast	O
+acting	O
+activator	O
+of	O
+epileptic	B
+foci	O
+during	O
+corticography	O
+or	O
+depth	O
+electrode	O
+intraoperative	O
+recordings	O
+.	O
+
+Development	O
+of	O
+isoproterenol	O
+-	O
+induced	O
+cardiac	B
+hypertrophy	I
+.	O
+
+The	O
+development	O
+of	O
+cardiac	B
+hypertrophy	I
+was	O
+studied	O
+in	O
+adult	O
+female	O
+Wistar	O
+rats	O
+following	O
+daily	O
+subcutaneous	O
+injections	O
+of	O
+isoproterenol	O
+(	O
+ISO	O
+)	O
+(	O
+0	O
+.	O
+3	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+)	O
+.	O
+
+A	O
+time	O
+course	O
+was	O
+established	O
+for	O
+the	O
+change	O
+in	O
+tissue	O
+mass	O
+,	O
+RNA	O
+and	O
+DNA	O
+content	O
+,	O
+as	O
+well	O
+as	O
+hydroxyproline	O
+content	O
+.	O
+
+Heart	O
+weight	O
+increased	O
+44	O
+%	O
+after	O
+8	O
+days	O
+of	O
+treatment	O
+with	O
+a	O
+half	O
+time	O
+of	O
+3	O
+.	O
+4	O
+days	O
+.	O
+
+Ventricular	O
+RNA	O
+content	O
+was	O
+elevated	O
+26	O
+%	O
+after	O
+24	O
+h	O
+of	O
+a	O
+single	O
+injection	O
+and	O
+reached	O
+a	O
+maximal	O
+level	O
+following	O
+8	O
+days	O
+of	O
+therapy	O
+.	O
+
+The	O
+half	O
+time	O
+for	O
+RNA	O
+accumulation	O
+was	O
+2	O
+.	O
+0	O
+days	O
+.	O
+
+The	O
+total	O
+content	O
+of	O
+hydroxyproline	O
+remained	O
+stable	O
+during	O
+the	O
+first	O
+2	O
+days	O
+of	O
+treatment	O
+but	O
+increased	O
+46	O
+%	O
+after	O
+4	O
+days	O
+of	O
+therapy	O
+.	O
+
+Ventricular	O
+DNA	O
+content	O
+was	O
+unchanged	O
+during	O
+the	O
+early	O
+stage	O
+(	O
+1	O
+-	O
+4	O
+days	O
+)	O
+of	O
+hypertrophic	B
+growth	O
+but	O
+increased	O
+to	O
+a	O
+new	O
+steady	O
+-	O
+state	O
+level	O
+19	O
+%	O
+above	O
+the	O
+controls	O
+after	O
+8	O
+days	O
+of	O
+treatment	O
+.	O
+
+Intraventricular	O
+pressures	O
+and	O
+coronary	O
+flow	O
+measures	O
+were	O
+similar	O
+for	O
+control	O
+and	O
+experimental	O
+animals	O
+following	O
+4	O
+days	O
+of	O
+developed	O
+hypertrophy	B
+.	O
+
+However	O
+,	O
+dP	O
+/	O
+dt	O
+in	O
+the	O
+ISO	O
+-	O
+treated	O
+hearts	O
+was	O
+slightly	O
+but	O
+significantly	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+elevated	O
+.	O
+
+These	O
+data	O
+indicate	O
+that	O
+the	O
+adaptive	O
+response	O
+to	O
+ISO	O
+shows	O
+an	O
+early	O
+hypertrophic	B
+phase	O
+(	O
+1	O
+-	O
+4	O
+days	O
+)	O
+characterized	O
+by	O
+a	O
+substantial	O
+increase	O
+in	O
+RNA	O
+content	O
+and	O
+cardiac	O
+mass	O
+in	O
+the	O
+absence	O
+of	O
+changes	O
+in	O
+DNA	O
+.	O
+
+However	O
+,	O
+prolonged	O
+stimulation	O
+(	O
+8	O
+-	O
+12	O
+days	O
+)	O
+appears	O
+to	O
+represent	O
+a	O
+complex	O
+integration	O
+of	O
+both	O
+cellular	O
+hypertrophy	B
+and	O
+hyperplasia	B
+within	O
+the	O
+heart	O
+.	O
+
+Multiple	O
+side	O
+effects	O
+of	O
+penicillamine	O
+therapy	O
+in	O
+one	O
+patient	O
+with	O
+rheumatoid	B
+arthritis	I
+.	O
+
+Skin	B
+rashes	I
+,	O
+proteinuria	B
+,	O
+systemic	B
+lupus	I
+erythematosus	I
+,	O
+polymyositis	B
+and	O
+myasthenia	B
+gravis	I
+have	O
+all	O
+been	O
+recorded	O
+as	O
+complications	O
+of	O
+penicillamine	O
+therapy	O
+in	O
+patients	O
+with	O
+rheumatoid	B
+arthritis	I
+.	O
+
+A	O
+patient	O
+who	O
+had	O
+developed	O
+all	O
+5	O
+is	O
+now	O
+described	O
+.	O
+
+The	O
+skin	B
+lesion	I
+resembled	O
+elastosis	B
+perforans	I
+serpiginosa	I
+,	O
+which	O
+has	O
+been	O
+reported	O
+as	O
+a	O
+rare	O
+side	O
+effect	O
+in	O
+patients	O
+with	O
+Wilson	B
+'	I
+s	I
+disease	I
+but	O
+not	O
+in	O
+patients	O
+with	O
+rheumatoid	B
+arthritis	I
+treated	O
+with	O
+penicillamine	O
+.	O
+
+Obsolete	O
+but	O
+dangerous	O
+antacid	O
+preparations	O
+.	O
+
+One	O
+case	O
+of	O
+acute	O
+hypercalcaemia	B
+and	O
+two	O
+of	O
+recurrent	O
+nephrolithiasis	B
+are	O
+reported	O
+in	O
+patients	O
+who	O
+had	O
+regularly	O
+consumed	O
+large	O
+amounts	O
+of	O
+calcium	O
+carbon	O
+-	O
+ate	O
+-	O
+sodium	O
+bicarbonate	O
+powders	O
+for	O
+more	O
+than	O
+20	O
+years	O
+.	O
+
+The	O
+powders	O
+had	O
+been	O
+obtained	O
+from	O
+pharmacists	O
+unknown	O
+to	O
+the	O
+patients	O
+'	O
+medical	O
+practitioners	O
+.	O
+
+It	O
+is	O
+suggested	O
+that	O
+these	O
+preparations	O
+were	O
+responsible	O
+for	O
+the	O
+patient	O
+'	O
+s	O
+problems	O
+,	O
+and	O
+that	O
+such	O
+powders	O
+should	O
+no	O
+longer	O
+be	O
+freely	O
+obtainable	O
+.	O
+
+Doxorubicin	O
+cardiomyopathy	B
+in	O
+children	O
+with	O
+left	O
+-	O
+sided	O
+Wilms	B
+tumor	I
+.	O
+
+Two	O
+children	O
+with	O
+Wilms	B
+tumor	I
+of	O
+the	O
+left	O
+kidney	O
+experienced	O
+severe	O
+anthracycline	O
+cardiomyopathy	B
+after	O
+irradiation	O
+to	O
+the	O
+tumor	B
+bed	O
+and	O
+conventional	O
+dosage	O
+of	O
+doxorubicin	O
+.	O
+
+The	O
+cardiomyopathy	B
+is	O
+attributed	O
+1	O
+)	O
+to	O
+the	O
+fact	O
+that	O
+radiation	O
+fields	O
+for	O
+left	O
+Wilms	B
+tumor	I
+include	O
+the	O
+lower	O
+portion	O
+of	O
+the	O
+heart	O
+and	O
+2	O
+)	O
+to	O
+the	O
+interaction	O
+of	O
+doxorubicin	O
+and	O
+irradiation	O
+on	O
+cardiac	O
+muscle	O
+.	O
+
+It	O
+is	O
+recommended	O
+that	O
+doxorubicin	O
+dosage	O
+be	O
+sharply	O
+restricted	O
+in	O
+children	O
+with	O
+Wilms	B
+tumor	I
+of	O
+the	O
+left	O
+kidney	O
+who	O
+receive	O
+postoperative	O
+irradiation	O
+.	O
+
+Effects	O
+of	O
+calcitonin	O
+on	O
+rat	O
+extrapyramidal	O
+motor	O
+system	O
+:	O
+behavioral	O
+and	O
+biochemical	O
+data	O
+.	O
+
+The	O
+effects	O
+of	O
+i	O
+.	O
+v	O
+.	O
+c	O
+.	O
+injection	O
+of	O
+human	O
+and	O
+salmon	O
+calcitonin	O
+on	O
+biochemical	O
+and	O
+behavioral	O
+parameters	O
+related	O
+to	O
+the	O
+extrapyramidal	O
+motor	O
+system	O
+,	O
+were	O
+investigated	O
+in	O
+male	O
+rats	O
+.	O
+
+Calcitonin	O
+injection	O
+resulted	O
+in	O
+a	O
+potentiation	O
+of	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+and	O
+a	O
+partial	O
+prevention	O
+of	O
+apomorphine	O
+-	O
+induced	O
+hyperactivity	B
+.	O
+
+Moreover	O
+calcitonin	O
+induced	O
+a	O
+significant	O
+decrease	O
+in	O
+nigral	O
+GAD	O
+activity	O
+but	O
+no	O
+change	O
+in	O
+striatal	O
+DA	O
+and	O
+DOPAC	O
+concentration	O
+or	O
+GAD	O
+activity	O
+.	O
+
+The	O
+results	O
+are	O
+discussed	O
+in	O
+view	O
+of	O
+a	O
+primary	O
+action	O
+of	O
+calcitonin	O
+on	O
+the	O
+striatonigral	O
+GABAergic	O
+pathway	O
+mediating	O
+the	O
+DA	O
+-	O
+related	O
+behavioral	O
+messages	O
+of	O
+striatal	O
+origin	O
+.	O
+
+Naloxazone	O
+pretreatment	O
+modifies	O
+cardiorespiratory	O
+,	O
+temperature	O
+,	O
+and	O
+behavioral	O
+effects	O
+of	O
+morphine	O
+.	O
+
+Behavioral	O
+and	O
+cardiorespiratory	O
+responses	O
+to	O
+a	O
+lethal	O
+dose	O
+of	O
+morphine	O
+were	O
+evaluated	O
+in	O
+rats	O
+pretreated	O
+with	O
+saline	O
+or	O
+naloxazone	O
+,	O
+an	O
+antagonist	O
+of	O
+high	O
+-	O
+affinity	O
+mu	O
+1	O
+opioid	O
+receptors	O
+.	O
+
+Pretreatment	O
+with	O
+naloxazone	O
+significantly	O
+blocked	O
+morphine	O
+analgesia	B
+,	O
+catalepsy	B
+and	O
+hypothermia	B
+at	O
+a	O
+dose	O
+which	O
+completely	O
+eliminated	O
+high	O
+-	O
+affinity	O
+binding	O
+in	O
+brain	O
+membranes	O
+.	O
+
+Moreover	O
+,	O
+naloxazone	O
+significantly	O
+attenuated	O
+the	O
+morphine	O
+-	O
+induced	O
+hypotension	B
+and	O
+respiratory	B
+depression	I
+,	O
+whereas	O
+morphine	O
+-	O
+induced	O
+bradycardia	B
+was	O
+less	O
+affected	O
+.	O
+
+Results	O
+indicate	O
+that	O
+subpopulations	O
+of	O
+mu	O
+receptors	O
+may	O
+mediate	O
+selective	O
+behavioral	O
+and	O
+cardiorespiratory	O
+responses	O
+to	O
+morphine	O
+.	O
+
+Modification	O
+of	O
+drug	O
+action	O
+by	O
+hyperammonemia	B
+.	O
+
+Pretreatment	O
+with	O
+ammonium	O
+acetate	O
+(	O
+NH4Ac	O
+)	O
+(	O
+6	O
+mmol	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+approximately	O
+doubled	O
+the	O
+time	O
+morphine	O
+-	O
+treated	O
+mice	O
+remained	O
+on	O
+a	O
+hot	O
+surface	O
+and	O
+similarly	O
+increased	O
+muscular	O
+incoordination	B
+by	O
+diazepam	O
+,	O
+but	O
+NH4Ac	O
+treatment	O
+alone	O
+had	O
+no	O
+effect	O
+.	O
+
+Thus	O
+,	O
+hyperammonemia	B
+is	O
+capable	O
+of	O
+altering	O
+drug	O
+action	O
+and	O
+must	O
+be	O
+considered	O
+along	O
+with	O
+impaired	O
+drug	O
+metabolism	O
+in	O
+enhanced	O
+drug	O
+responses	O
+associated	O
+with	O
+liver	B
+disease	I
+.	O
+
+Experiments	O
+in	O
+vitro	O
+showed	O
+that	O
+acetylcholine	O
+-	O
+induced	O
+catecholamine	O
+release	O
+from	O
+bovine	O
+adrenal	O
+medulla	O
+is	O
+depressed	O
+as	O
+much	O
+as	O
+50	O
+%	O
+by	O
+0	O
+.	O
+3	O
+mM	O
+NH4Ac	O
+and	O
+KCl	O
+-	O
+induced	O
+contractions	O
+of	O
+guinea	O
+-	O
+pig	O
+ileum	O
+were	O
+inhibited	O
+20	O
+%	O
+by	O
+5	O
+mM	O
+NH4Ac	O
+.	O
+
+Addition	O
+of	O
+excess	O
+calcium	O
+reversed	O
+the	O
+depression	B
+in	O
+both	O
+tissues	O
+,	O
+but	O
+calcium	O
+-	O
+independent	O
+catecholamine	O
+release	O
+by	O
+acetaldehyde	O
+was	O
+not	O
+blocked	O
+by	O
+NH4Ac	O
+.	O
+
+These	O
+results	O
+suggested	O
+that	O
+ammonia	O
+blocks	O
+calcium	O
+channels	O
+.	O
+
+Parallels	O
+in	O
+the	O
+actions	O
+of	O
+NH4Ac	O
+and	O
+the	O
+calcium	O
+channel	O
+blocker	O
+verapamil	O
+support	O
+this	O
+concept	O
+.	O
+
+Both	O
+verapamil	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+and	O
+NH4Ac	O
+pretreatment	O
+enhanced	O
+morphine	O
+analgesia	B
+-	O
+and	O
+diazepam	O
+-	O
+induced	O
+muscular	O
+incoordination	B
+and	O
+antagonized	O
+amphetamine	O
+-	O
+induced	O
+motor	O
+activity	O
+,	O
+and	O
+neither	O
+verapamil	O
+nor	O
+NH4Ac	O
+affected	O
+the	O
+convulsant	O
+action	O
+of	O
+metrazol	O
+.	O
+
+The	O
+data	O
+suggest	O
+that	O
+hyperammonemia	B
+exerts	O
+a	O
+calcium	O
+channel	O
+blocking	O
+action	O
+which	O
+enhances	O
+the	O
+effects	O
+of	O
+central	O
+nervous	O
+system	O
+depressants	O
+and	O
+certain	O
+opioid	O
+analgesics	O
+.	O
+
+Levodopa	O
+-	O
+induced	O
+dyskinesia	B
+and	O
+thalamotomy	O
+.	O
+
+Levodopa	O
+-	O
+induced	O
+dyskinesia	B
+of	O
+the	O
+limbs	O
+in	O
+thirteen	O
+cases	O
+of	O
+Parkinsonism	B
+,	O
+which	O
+was	O
+choreic	O
+,	O
+ballistic	O
+or	O
+dystonic	B
+in	O
+type	O
+,	O
+was	O
+alleviated	O
+almost	O
+completely	O
+by	O
+stereotaxic	O
+surgery	O
+using	O
+a	O
+microelectrode	O
+technique	O
+for	O
+the	O
+ventralis	O
+oralis	O
+anterior	O
+and	O
+posterior	O
+nuclei	O
+of	O
+the	O
+thalamus	O
+,	O
+but	O
+much	O
+less	O
+by	O
+the	O
+ventralis	O
+intermedius	O
+nucleus	O
+.	O
+
+Control	O
+of	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+by	O
+thalamic	B
+lesions	I
+in	O
+the	O
+course	O
+of	O
+routine	O
+treatment	O
+of	O
+Parkinsonism	B
+is	O
+discussed	O
+.	O
+
+Treatment	O
+of	O
+ifosfamide	O
+-	O
+induced	O
+urothelial	B
+toxicity	I
+by	O
+oral	O
+administration	O
+of	O
+sodium	O
+2	O
+-	O
+mercaptoethane	O
+sulphonate	O
+(	O
+MESNA	O
+)	O
+to	O
+patients	O
+with	O
+inoperable	O
+lung	B
+cancer	I
+.	O
+
+The	O
+protective	O
+effect	O
+of	O
+oral	O
+administration	O
+of	O
+the	O
+thiol	O
+compound	O
+sodium	O
+2	O
+-	O
+mercaptoethane	O
+sulphonate	O
+(	O
+MESNA	O
+)	O
+against	O
+urothelial	B
+toxicity	I
+induced	O
+by	O
+ifosfamide	O
+(	O
+IF	O
+)	O
+was	O
+tested	O
+in	O
+a	O
+group	O
+of	O
+45	O
+patients	O
+with	O
+inoperable	O
+lung	B
+cancer	I
+under	O
+treatment	O
+with	O
+IF	O
+(	O
+2250	O
+mg	O
+/	O
+m2	O
+on	O
+days	O
+2	O
+-	O
+5	O
+)	O
+as	O
+part	O
+of	O
+a	O
+polychemotherapy	O
+regimen	O
+repeated	O
+in	O
+a	O
+4	O
+-	O
+week	O
+cycle	O
+.	O
+
+MESNA	O
+was	O
+given	O
+orally	O
+on	O
+the	O
+days	O
+of	O
+treatment	O
+with	O
+IF	O
+in	O
+3	O
+doses	O
+of	O
+840	O
+mg	O
+/	O
+m2	O
+,	O
+each	O
+administered	O
+at	O
+0	O
+hr	O
+(	O
+=	O
+injection	O
+of	O
+IF	O
+)	O
+,	O
+4	O
+hr	O
+and	O
+8	O
+hr	O
+p	O
+.	O
+i	O
+.	O
+
+Out	O
+of	O
+a	O
+total	O
+of	O
+88	O
+courses	O
+of	O
+this	O
+treatment	O
+we	O
+observed	O
+10	O
+episodes	O
+of	O
+asymptomatic	O
+microscopic	O
+haematuria	B
+and	O
+no	O
+episodes	O
+of	O
+gross	O
+haematuria	B
+.	O
+
+In	O
+this	O
+group	O
+of	O
+45	O
+patients	O
+under	O
+protection	O
+with	O
+MESNA	O
+there	O
+were	O
+5	O
+complete	O
+remissions	O
+and	O
+9	O
+partial	O
+remissions	O
+(	O
+total	O
+31	O
+%	O
+)	O
+.	O
+
+A	O
+further	O
+group	O
+of	O
+25	O
+patients	O
+under	O
+polychemotherapy	O
+with	O
+IF	O
+were	O
+treated	O
+by	O
+conventional	O
+prophylactic	O
+measures	O
+(	O
+raised	O
+fluid	O
+intake	O
+and	O
+forced	O
+diuresis	O
+)	O
+.	O
+
+In	O
+this	O
+group	O
+there	O
+were	O
+1	O
+complete	O
+and	O
+5	O
+partial	O
+remissions	O
+(	O
+total	O
+24	O
+%	O
+)	O
+,	O
+but	O
+nearly	O
+all	O
+patients	O
+developed	O
+either	O
+gross	O
+haematuria	B
+and	O
+/	O
+or	O
+symptoms	O
+of	O
+bladder	B
+irritation	I
+(	O
+cystitis	B
+and	O
+pollakisuria	B
+)	O
+.	O
+
+There	O
+were	O
+no	O
+appreciable	O
+differences	O
+between	O
+the	O
+MESNA	O
+series	O
+and	O
+the	O
+conventional	O
+prophylaxis	O
+series	O
+with	O
+respect	O
+to	O
+either	O
+haematological	O
+or	O
+systemic	O
+toxicity	B
+of	O
+the	O
+cytostatic	O
+treatment	O
+.	O
+
+Our	O
+results	O
+support	O
+the	O
+view	O
+that	O
+MESNA	O
+,	O
+given	O
+orally	O
+in	O
+conjunction	O
+with	O
+combined	O
+cytostatic	O
+regimens	O
+which	O
+include	O
+IF	O
+,	O
+simplifies	O
+the	O
+treatment	O
+and	O
+provides	O
+optimum	O
+protection	O
+for	O
+the	O
+urinary	O
+epithelium	O
+.	O
+
+Protection	O
+with	O
+oral	O
+MESNA	O
+is	O
+particularly	O
+suitable	O
+for	O
+outpatients	O
+.	O
+
+Myoclonic	B
+,	I
+atonic	I
+,	I
+and	I
+absence	I
+seizures	I
+following	O
+institution	O
+of	O
+carbamazepine	O
+therapy	O
+in	O
+children	O
+.	O
+
+Five	O
+children	O
+,	O
+aged	O
+3	O
+to	O
+11	O
+years	O
+,	O
+treated	O
+with	O
+carbamazepine	O
+for	O
+epilepsy	B
+,	O
+had	O
+an	O
+acute	O
+aberrant	O
+reaction	O
+characterized	O
+by	O
+the	O
+onset	O
+of	O
+myoclonic	B
+,	I
+atypical	I
+absence	I
+and	I
+/	I
+or	I
+atonic	I
+(	I
+minor	I
+motor	I
+)	I
+seizures	I
+within	O
+a	O
+few	O
+days	O
+.	O
+
+When	O
+the	O
+carbamazepine	O
+was	O
+discontinued	O
+,	O
+two	O
+of	O
+the	O
+children	O
+returned	O
+to	O
+their	O
+former	O
+state	O
+very	O
+quickly	O
+,	O
+two	O
+had	O
+the	O
+minor	O
+motor	O
+seizures	B
+resolve	O
+in	O
+3	O
+and	O
+6	O
+months	O
+,	O
+and	O
+one	O
+had	O
+the	O
+seizures	B
+persist	O
+.	O
+
+The	O
+child	O
+in	O
+whom	O
+the	O
+seizures	B
+persisted	O
+was	O
+later	O
+found	O
+to	O
+have	O
+ceroid	B
+lipofuscinosis	I
+.	O
+
+The	O
+other	O
+children	O
+are	O
+doing	O
+well	O
+on	O
+other	O
+anticonvulsants	O
+.	O
+
+Effect	O
+of	O
+prostaglandin	O
+synthetase	O
+inhibitors	O
+on	O
+experimentally	O
+induced	O
+convulsions	B
+in	O
+rats	O
+.	O
+
+To	O
+investigate	O
+the	O
+relationship	O
+of	O
+prostaglandins	O
+(	O
+PGs	O
+)	O
+to	O
+seizure	B
+induction	O
+,	O
+the	O
+effects	O
+of	O
+six	O
+PG	O
+synthetase	O
+inhibitors	O
+on	O
+convulsions	B
+induced	O
+by	O
+flurothyl	O
+,	O
+picrotoxin	O
+,	O
+pentetrazol	O
+(	O
+PTZ	O
+)	O
+,	O
+electroshock	O
+or	O
+bicuculline	O
+were	O
+evaluated	O
+.	O
+
+Ibuprofen	O
+,	O
+sulindac	O
+,	O
+mefenamic	O
+acid	O
+,	O
+and	O
+low	O
+dose	O
+meclofenamic	O
+acid	O
+increased	O
+the	O
+latency	O
+-	O
+to	O
+-	O
+onset	O
+in	O
+the	O
+flurothyl	O
+and	O
+/	O
+or	O
+PTZ	O
+models	O
+;	O
+the	O
+electroshock	O
+,	O
+picrotoxin	O
+and	O
+bicuculline	O
+models	O
+were	O
+not	O
+significantly	O
+affected	O
+by	O
+any	O
+of	O
+the	O
+pretreatment	O
+agents	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+PGs	O
+are	O
+involved	O
+in	O
+the	O
+mechanism	O
+(	O
+s	O
+)	O
+underlying	O
+fluorthyl	O
+-	O
+and	O
+PTZ	O
+-	O
+induced	O
+convulsions	B
+,	O
+but	O
+not	O
+picrotoxin	O
+-	O
+,	O
+electroshock	O
+-	O
+,	O
+or	O
+bicuculline	O
+-	O
+induced	O
+convulsions	B
+.	O
+
+Acute	O
+changes	O
+of	O
+blood	O
+ammonia	O
+may	O
+predict	O
+short	O
+-	O
+term	O
+adverse	O
+effects	O
+of	O
+valproic	O
+acid	O
+.	O
+
+Valproic	O
+acid	O
+(	O
+VPA	O
+)	O
+was	O
+given	O
+to	O
+24	O
+epileptic	B
+patients	O
+who	O
+were	O
+already	O
+being	O
+treated	O
+with	O
+other	O
+antiepileptic	O
+drugs	O
+.	O
+
+A	O
+standardized	O
+loading	O
+dose	O
+of	O
+VPA	O
+was	O
+administered	O
+,	O
+and	O
+venous	O
+blood	O
+was	O
+sampled	O
+at	O
+0	O
+,	O
+1	O
+,	O
+2	O
+,	O
+3	O
+,	O
+and	O
+4	O
+hours	O
+.	O
+
+Ammonia	O
+(	O
+NH3	O
+)	O
+was	O
+higher	O
+in	O
+patients	O
+who	O
+,	O
+during	O
+continuous	O
+therapy	O
+,	O
+complained	O
+of	O
+drowsiness	B
+(	O
+7	O
+patients	O
+)	O
+than	O
+in	O
+those	O
+who	O
+were	O
+symptom	O
+-	O
+free	O
+(	O
+17	O
+patients	O
+)	O
+,	O
+although	O
+VPA	O
+plasma	O
+levels	O
+were	O
+similar	O
+in	O
+both	O
+groups	O
+.	O
+
+By	O
+measuring	O
+VPA	O
+-	O
+induced	O
+changes	O
+of	O
+blood	O
+NH3	O
+content	O
+,	O
+it	O
+may	O
+be	O
+possible	O
+to	O
+identify	O
+patients	O
+at	O
+higher	O
+risk	O
+of	O
+obtundation	O
+when	O
+VPA	O
+is	O
+given	O
+chronically	O
+.	O
+
+Effect	O
+of	O
+captopril	O
+on	O
+pre	O
+-	O
+existing	O
+and	O
+aminonucleoside	O
+-	O
+induced	O
+proteinuria	B
+in	O
+spontaneously	O
+hypertensive	B
+rats	O
+.	O
+
+Proteinuria	B
+is	O
+a	O
+side	O
+effect	O
+of	O
+captopril	O
+treatment	O
+in	O
+hypertensive	B
+patients	O
+.	O
+
+The	O
+possibility	O
+of	O
+reproducing	O
+the	O
+same	O
+renal	B
+abnormality	I
+with	O
+captopril	O
+was	O
+examined	O
+in	O
+SHR	O
+.	O
+
+Oral	O
+administration	O
+of	O
+captopril	O
+at	O
+100	O
+mg	O
+/	O
+kg	O
+for	O
+14	O
+days	O
+failed	O
+to	O
+aggravate	O
+proteinuria	B
+pre	O
+-	O
+existing	O
+in	O
+SHR	O
+.	O
+
+Also	O
+,	O
+captopril	O
+treatment	O
+failed	O
+to	O
+potentiate	O
+or	O
+facilitate	O
+development	O
+of	O
+massive	O
+proteinuria	B
+invoked	O
+by	O
+puromycin	O
+aminonucleoside	O
+in	O
+SHR	O
+.	O
+
+Captopril	O
+had	O
+little	O
+or	O
+no	O
+demonstrable	O
+effects	O
+on	O
+serum	O
+electrolyte	O
+concentrations	O
+,	O
+excretion	O
+of	O
+urine	O
+,	O
+sodium	O
+and	O
+potassium	O
+,	O
+endogenous	O
+creatinine	O
+clearance	O
+,	O
+body	O
+weight	O
+,	O
+and	O
+food	O
+and	O
+water	O
+consumption	O
+.	O
+
+However	O
+,	O
+ketone	O
+bodies	O
+were	O
+consistently	O
+present	O
+in	O
+urine	O
+and	O
+several	O
+lethalities	O
+occurred	O
+during	O
+multiple	O
+dosing	O
+of	O
+captopril	O
+in	O
+SHR	O
+.	O
+
+Complete	O
+heart	B
+block	I
+following	O
+a	O
+single	O
+dose	O
+of	O
+trazodone	O
+.	O
+
+Forty	O
+minutes	O
+after	O
+receiving	O
+a	O
+single	O
+starting	O
+dose	O
+of	O
+trazodone	O
+,	O
+a	O
+patient	O
+developed	O
+complete	O
+heart	B
+block	I
+.	O
+
+The	O
+case	O
+illustrates	O
+that	O
+,	O
+despite	O
+the	O
+results	O
+of	O
+earlier	O
+studies	O
+,	O
+trazodone	O
+'	O
+s	O
+effect	O
+on	O
+cardiac	O
+conduction	O
+may	O
+be	O
+severe	O
+in	O
+individuals	O
+at	O
+risk	O
+for	O
+conduction	O
+delay	O
+.	O
+
+Phenobarbital	O
+-	O
+induced	O
+dyskinesia	B
+in	O
+a	O
+neurologically	B
+-	I
+impaired	I
+child	O
+.	O
+
+A	O
+2	O
+-	O
+year	O
+-	O
+old	O
+child	O
+with	O
+known	O
+neurologic	B
+impairment	I
+developed	O
+a	O
+dyskinesia	B
+soon	O
+after	O
+starting	O
+phenobarbital	O
+therapy	O
+for	O
+seizures	B
+.	O
+
+Known	O
+causes	O
+of	O
+movement	B
+disorders	I
+were	O
+eliminated	O
+after	O
+evaluation	O
+.	O
+
+On	O
+repeat	O
+challenge	O
+with	O
+phenobarbital	O
+,	O
+the	O
+dyskinesia	B
+recurred	O
+.	O
+
+Phenobarbital	O
+should	O
+be	O
+added	O
+to	O
+the	O
+list	O
+of	O
+anticonvulsant	O
+drugs	O
+that	O
+can	O
+cause	O
+movement	B
+disorders	I
+.	O
+
+Effects	O
+of	O
+amine	O
+pretreatment	O
+on	O
+ketamine	O
+catatonia	B
+in	O
+pinealectomized	O
+or	O
+hypophysectomized	O
+animals	O
+.	O
+
+The	O
+present	O
+studies	O
+were	O
+designed	O
+to	O
+clarify	O
+the	O
+role	O
+of	O
+catecholamines	O
+and	O
+pineal	O
+idolamines	O
+on	O
+ketamine	O
+-	O
+induced	O
+catatonia	B
+in	O
+the	O
+intact	O
+,	O
+pinealectomized	O
+or	O
+hypophysectomized	O
+chick	O
+and	O
+rat	O
+.	O
+
+In	O
+the	O
+pinealectomized	O
+chick	O
+,	O
+pretreatment	O
+with	O
+dopamine	O
+increased	O
+the	O
+duration	O
+of	O
+catatonia	B
+(	O
+DOC	O
+)	O
+after	O
+ketamine	O
+,	O
+but	O
+pretreatment	O
+with	O
+norepinephrine	O
+did	O
+not	O
+.	O
+
+The	O
+pineal	O
+indolamines	O
+exhibited	O
+mixed	O
+actions	O
+.	O
+
+Serotonin	O
+and	O
+N	O
+-	O
+acetyl	O
+serotonin	O
+which	O
+augmented	O
+ketamine	O
+DOC	O
+,	O
+did	O
+not	O
+do	O
+so	O
+in	O
+the	O
+absence	O
+of	O
+the	O
+pineal	O
+gland	O
+,	O
+whereas	O
+melatonin	O
+potentiated	O
+the	O
+ketamine	O
+DOC	O
+in	O
+both	O
+the	O
+intact	O
+and	O
+pinealectomized	O
+chick	O
+.	O
+
+Ketamine	O
+was	O
+more	O
+potent	O
+in	O
+the	O
+hypophysectomized	O
+chick	O
+and	O
+the	O
+circadian	O
+rhythm	O
+noted	O
+in	O
+the	O
+intact	O
+chick	O
+was	O
+absent	O
+;	O
+furthermore	O
+,	O
+melatonin	O
+did	O
+not	O
+augment	O
+the	O
+ketamine	O
+DOC	O
+whereas	O
+dopamine	O
+continued	O
+to	O
+do	O
+so	O
+.	O
+
+This	O
+study	O
+did	O
+not	O
+demonstrate	O
+a	O
+species	O
+difference	O
+regarding	O
+the	O
+role	O
+of	O
+the	O
+amines	O
+on	O
+the	O
+pineal	O
+in	O
+spite	O
+of	O
+the	O
+immature	O
+blood	O
+-	O
+brain	O
+barrier	O
+in	O
+the	O
+young	O
+chick	O
+and	O
+the	O
+intact	O
+barrier	O
+in	O
+the	O
+rat	O
+.	O
+
+In	O
+addition	O
+,	O
+these	O
+data	O
+indicate	O
+a	O
+direct	O
+role	O
+of	O
+the	O
+pituitary	O
+in	O
+the	O
+augmentation	O
+of	O
+ketamine	O
+DOC	O
+induced	O
+by	O
+melatonin	O
+.	O
+
+Furthermore	O
+,	O
+dopamine	O
+appeared	O
+to	O
+act	O
+on	O
+systems	O
+more	O
+closely	O
+involved	O
+with	O
+the	O
+induction	O
+of	O
+ketamine	O
+catatonia	B
+rather	O
+than	O
+directly	O
+on	O
+the	O
+pituitary	O
+.	O
+
+Heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+,	O
+thrombosis	B
+,	O
+and	O
+hemorrhage	B
+.	O
+
+Sixty	O
+-	O
+two	O
+patients	O
+with	O
+a	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B
+are	O
+reported	O
+.	O
+
+Clinical	O
+manifestations	O
+of	O
+this	O
+disorder	O
+include	O
+hemorrhage	B
+or	O
+,	O
+more	O
+frequently	O
+,	O
+thromboembolic	B
+events	O
+in	O
+patients	O
+receiving	O
+heparin	O
+.	O
+
+Laboratory	O
+testing	O
+has	O
+revealed	O
+a	B
+falling	I
+platelet	I
+count	I
+,	O
+increased	O
+resistance	O
+to	O
+heparin	O
+,	O
+and	O
+aggregation	O
+of	O
+platelets	O
+by	O
+the	O
+patient	O
+'	O
+s	O
+plasma	O
+when	O
+heparin	O
+is	O
+added	O
+.	O
+
+Immunologic	O
+testing	O
+has	O
+demonstrated	O
+the	O
+presence	O
+of	O
+a	O
+heparin	O
+-	O
+dependent	O
+platelet	O
+membrane	O
+antibody	O
+.	O
+
+The	O
+20	O
+deaths	O
+,	O
+52	O
+hemorrhagic	B
+and	I
+thromboembolic	I
+complications	I
+,	O
+and	O
+21	O
+surgical	O
+procedures	O
+to	O
+manage	O
+the	O
+complications	O
+confirm	O
+the	O
+seriousness	O
+of	O
+the	O
+disorder	O
+.	O
+
+Specific	O
+risk	O
+factors	O
+have	O
+not	O
+been	O
+identified	O
+;	O
+therefore	O
+,	O
+all	O
+patients	O
+receiving	O
+heparin	O
+should	O
+be	O
+monitored	O
+.	O
+
+If	O
+the	O
+platelet	O
+count	O
+falls	O
+to	O
+less	O
+than	O
+100	O
+,	O
+000	O
+/	O
+mm3	O
+,	O
+while	O
+the	O
+patient	O
+is	O
+receiving	O
+heparin	O
+,	O
+platelet	B
+aggregation	I
+testing	O
+,	O
+using	O
+the	O
+patient	O
+'	O
+s	O
+plasma	O
+,	O
+is	O
+indicated	O
+.	O
+
+Management	O
+consists	O
+of	O
+cessation	O
+of	O
+heparin	O
+,	O
+platelet	O
+anti	O
+-	O
+aggregating	O
+agents	O
+,	O
+and	O
+alternate	O
+forms	O
+of	O
+anticoagulation	O
+when	O
+indicated	O
+.	O
+
+Ventricular	B
+fibrillation	I
+from	O
+diatrizoate	O
+with	O
+and	O
+without	O
+chelating	O
+agents	O
+.	O
+
+The	O
+toxicity	B
+of	O
+Renografin	O
+76	O
+%	O
+was	O
+compared	O
+with	O
+that	O
+of	O
+Hypaque	O
+76	O
+%	O
+by	O
+selective	O
+injection	O
+of	O
+each	O
+into	O
+the	O
+right	O
+coronary	O
+artery	O
+of	O
+dogs	O
+.	O
+
+Renografin	O
+contains	O
+the	O
+chelating	O
+agents	O
+sodium	O
+citrate	O
+and	O
+disodium	O
+edetate	O
+,	O
+while	O
+Hypaque	O
+contains	O
+calcium	O
+disodium	O
+edetate	O
+and	O
+no	O
+sodium	O
+citrate	O
+.	O
+
+Ventricular	B
+fibrillation	I
+occurred	O
+significantly	O
+more	O
+often	O
+with	O
+Renografin	O
+,	O
+suggesting	O
+that	O
+chelating	O
+agents	O
+contribute	O
+to	O
+toxicity	B
+in	O
+coronary	O
+angiography	O
+.	O
+
+Long	O
+-	O
+term	O
+efficacy	O
+and	O
+toxicity	B
+of	O
+high	O
+-	O
+dose	O
+amiodarone	O
+therapy	O
+for	O
+ventricular	B
+tachycardia	I
+or	O
+ventricular	B
+fibrillation	I
+.	O
+
+Amiodarone	O
+was	O
+administered	O
+to	O
+154	O
+patients	O
+who	O
+had	O
+sustained	O
+,	O
+symptomatic	O
+ventricular	B
+tachycardia	I
+(	O
+VT	B
+)	O
+(	O
+n	O
+=	O
+118	O
+)	O
+or	O
+a	O
+cardiac	B
+arrest	I
+(	O
+n	O
+=	O
+36	O
+)	O
+and	O
+who	O
+were	O
+refractory	O
+to	O
+conventional	O
+antiarrhythmic	O
+drugs	O
+.	O
+
+The	O
+loading	O
+dose	O
+was	O
+800	O
+mg	O
+/	O
+day	O
+for	O
+6	O
+weeks	O
+and	O
+the	O
+maintenance	O
+dose	O
+was	O
+600	O
+mg	O
+/	O
+day	O
+.	O
+
+Sixty	O
+-	O
+nine	O
+percent	O
+of	O
+patients	O
+continued	O
+treatment	O
+with	O
+amiodarone	O
+and	O
+had	O
+no	O
+recurrence	O
+of	O
+symptomatic	O
+VT	B
+or	O
+ventricular	B
+fibrillation	I
+(	O
+VF	B
+)	O
+over	O
+a	O
+follow	O
+-	O
+up	O
+of	O
+6	O
+to	O
+52	O
+months	O
+(	O
+mean	O
++	O
+/	O
+-	O
+standard	O
+deviation	O
+14	O
+.	O
+2	O
++	O
+/	O
+-	O
+8	O
+.	O
+2	O
+)	O
+.	O
+
+Six	O
+percent	O
+of	O
+the	O
+patients	O
+had	O
+a	O
+nonfatal	O
+recurrence	O
+of	O
+VT	B
+and	O
+were	O
+successfully	O
+managed	O
+by	O
+continuing	O
+amiodarone	O
+at	O
+a	O
+higher	O
+dose	O
+or	O
+by	O
+the	O
+addition	O
+of	O
+a	O
+conventional	O
+antiarrhythmic	O
+drug	O
+.	O
+
+One	O
+or	O
+more	O
+adverse	O
+drug	O
+reactions	O
+occurred	O
+in	O
+51	O
+%	O
+of	O
+patients	O
+.	O
+
+Adverse	O
+effects	O
+forced	O
+a	O
+reduction	O
+in	O
+the	O
+dose	O
+of	O
+amiodarone	O
+in	O
+41	O
+%	O
+and	O
+discontinuation	O
+of	O
+amiodarone	O
+in	O
+10	O
+%	O
+of	O
+patients	O
+.	O
+
+The	O
+most	O
+common	O
+symptomatic	O
+adverse	O
+reactions	O
+were	O
+tremor	B
+or	O
+ataxia	B
+(	O
+35	O
+%	O
+)	O
+,	O
+nausea	B
+and	O
+anorexia	B
+(	O
+8	O
+%	O
+)	O
+,	O
+visual	B
+halos	I
+or	I
+blurring	I
+(	O
+6	O
+%	O
+)	O
+,	O
+thyroid	B
+function	I
+abnormalities	I
+(	O
+6	O
+%	O
+)	O
+and	O
+pulmonary	B
+interstitial	I
+infiltrates	I
+(	O
+5	O
+%	O
+)	O
+.	O
+
+Although	O
+large	O
+-	O
+dose	O
+amiodarone	O
+is	O
+highly	O
+effective	O
+in	O
+the	O
+long	O
+-	O
+term	O
+treatment	O
+of	O
+VT	B
+or	O
+VF	B
+refractory	O
+to	O
+conventional	O
+antiarrhythmic	O
+drugs	O
+,	O
+it	O
+causes	O
+significant	O
+toxicity	B
+in	O
+approximately	O
+50	O
+%	O
+of	O
+patients	O
+.	O
+
+However	O
+,	O
+when	O
+the	O
+dose	O
+is	O
+adjusted	O
+based	O
+on	O
+clinical	O
+response	O
+or	O
+the	O
+development	O
+of	O
+adverse	O
+effects	O
+,	O
+75	O
+%	O
+of	O
+patients	O
+with	O
+VT	B
+or	O
+VF	B
+can	O
+be	O
+successfully	O
+managed	O
+with	O
+amiodarone	O
+.	O
+
+Why	O
+may	O
+epsilon	O
+-	O
+aminocaproic	O
+acid	O
+(	O
+EACA	O
+)	O
+induce	O
+myopathy	B
+in	O
+man	O
+?	O
+
+Report	O
+of	O
+a	O
+case	O
+and	O
+literature	O
+review	O
+.	O
+
+A	O
+case	O
+of	O
+necrotizing	B
+myopathy	I
+due	O
+to	O
+a	O
+short	O
+epsilon	O
+-	O
+aminocaproic	O
+acid	O
+(	O
+EACA	O
+)	O
+treatment	O
+in	O
+a	O
+72	O
+year	O
+-	O
+old	O
+patient	O
+with	O
+subarachnoid	B
+haemorrhage	I
+(	O
+SAH	B
+)	O
+is	O
+described	O
+.	O
+
+Pathogenetic	O
+hypotheses	O
+are	O
+discussed	O
+.	O
+
+Cerebral	B
+hemorrhage	I
+associated	O
+with	O
+phenylpropanolamine	O
+in	O
+combination	O
+with	O
+caffeine	O
+.	O
+
+Phenylpropanolamine	O
+(	O
+PPA	O
+)	O
+is	O
+a	O
+drug	O
+that	O
+has	O
+been	O
+associated	O
+with	O
+serious	O
+side	O
+effects	O
+including	O
+stroke	B
+.	O
+
+It	O
+is	O
+often	O
+combined	O
+with	O
+caffeine	O
+in	O
+diet	O
+preparations	O
+and	O
+"	O
+look	O
+-	O
+alike	O
+"	O
+pills	O
+.	O
+
+In	O
+order	O
+to	O
+determine	O
+if	O
+PPA	O
+/	O
+caffeine	O
+can	O
+lead	O
+to	O
+stroke	B
+in	O
+normotensive	O
+and	O
+/	O
+or	O
+hypertensive	B
+rats	O
+,	O
+we	O
+administered	O
+the	O
+combination	O
+in	O
+six	O
+times	O
+the	O
+allowed	O
+human	O
+dose	O
+calculated	O
+on	O
+a	O
+per	O
+weight	O
+basis	O
+for	O
+the	O
+rats	O
+two	O
+times	O
+per	O
+day	O
+for	O
+five	O
+days	O
+.	O
+
+Subarachnoid	B
+and	I
+cerebral	I
+hemorrhage	I
+was	O
+noted	O
+in	O
+18	O
+%	O
+of	O
+the	O
+hypertensive	B
+rats	O
+.	O
+
+A	O
+single	O
+PPA	O
+/	O
+caffeine	O
+administration	O
+(	O
+same	O
+dose	O
+)	O
+lead	O
+to	O
+acute	O
+hypertension	B
+in	O
+both	O
+the	O
+normotensive	O
+and	O
+hypertensive	B
+animals	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+PPA	O
+/	O
+caffeine	O
+can	O
+lead	O
+to	O
+cerebral	B
+hemorrhage	I
+in	O
+previously	O
+hypertensive	B
+animals	O
+when	O
+administered	O
+in	O
+greater	O
+than	O
+the	O
+allowed	O
+dosage	O
+.	O
+
+An	O
+acute	O
+elevation	O
+in	O
+blood	O
+pressure	O
+may	O
+be	O
+a	O
+contributing	O
+factor	O
+.	O
+
+Renal	B
+papillary	I
+necrosis	I
+due	O
+to	O
+naproxen	O
+.	O
+
+A	O
+31	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+rheumatoid	B
+arthritis	I
+,	O
+who	O
+had	O
+previously	O
+been	O
+treated	O
+with	O
+sulindac	O
+,	O
+fenoprofen	O
+calcium	O
+,	O
+high	O
+dose	O
+salicylates	O
+and	O
+gold	O
+salts	O
+,	O
+developed	O
+renal	B
+papillary	I
+necrosis	I
+(	O
+RPN	B
+)	O
+4	O
+months	O
+after	O
+institution	O
+of	O
+naproxen	O
+therapy	O
+.	O
+
+No	O
+other	O
+factor	O
+predisposing	O
+to	O
+RPN	B
+could	O
+be	O
+discovered	O
+.	O
+
+Sulindac	O
+was	O
+substituted	O
+for	O
+naproxen	O
+and	O
+no	O
+further	O
+adverse	O
+renal	O
+effects	O
+occurred	O
+over	O
+the	O
+next	O
+12	O
+months	O
+.	O
+
+We	O
+review	O
+previous	O
+reports	O
+linking	O
+RPN	B
+to	O
+antiinflammatory	O
+drug	O
+use	O
+and	O
+discuss	O
+possible	O
+advantages	O
+of	O
+sulindac	O
+in	O
+patients	O
+who	O
+have	O
+experienced	O
+renal	B
+toxicity	I
+from	O
+other	O
+antiinflammatory	O
+agents	O
+.	O
+
+Nephrotoxic	B
+effects	O
+of	O
+aminoglycoside	O
+treatment	O
+on	O
+renal	O
+protein	O
+reabsorption	O
+and	O
+accumulation	O
+.	O
+
+To	O
+quantify	O
+the	O
+effects	O
+of	O
+gentamicin	O
+,	O
+kanamycin	O
+and	O
+netilmicin	O
+on	O
+renal	O
+protein	O
+reabsorption	O
+and	O
+accumulation	O
+,	O
+these	O
+drugs	O
+were	O
+administered	O
+to	O
+rats	O
+intraperitoneally	O
+(	O
+30	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+)	O
+for	O
+7	O
+,	O
+14	O
+or	O
+21	O
+days	O
+.	O
+
+Scanning	O
+electron	O
+microscopy	O
+of	O
+the	O
+glomerular	O
+endothelia	O
+,	O
+urinary	O
+measurements	O
+of	O
+sodium	O
+,	O
+potassium	O
+,	O
+endogenous	O
+lysozyme	O
+,	O
+N	O
+-	O
+acetyl	O
+-	O
+beta	O
+-	O
+D	O
+-	O
+glucosaminidase	O
+(	O
+NAG	O
+)	O
+as	O
+well	O
+as	O
+clearance	O
+and	O
+accumulation	O
+experiments	O
+after	O
+i	O
+.	O
+v	O
+.	O
+administration	O
+of	O
+egg	O
+-	O
+white	O
+lysozyme	O
+and	O
+measurements	O
+of	O
+inulin	O
+clearance	O
+(	O
+GFR	O
+)	O
+were	O
+done	O
+in	O
+each	O
+treatment	O
+group	O
+.	O
+
+Gentamicin	O
+administration	O
+decreased	O
+diameter	O
+,	O
+density	O
+and	O
+shape	O
+of	O
+endothelial	O
+fenestrae	O
+.	O
+
+Kanamycin	O
+and	O
+netilmicin	O
+appeared	O
+to	O
+have	O
+no	O
+effect	O
+at	O
+the	O
+dose	O
+used	O
+.	O
+
+All	O
+three	O
+aminoglycosides	O
+decreased	O
+GFR	O
+and	O
+increased	O
+urinary	O
+excretion	O
+of	O
+sodium	O
+and	O
+potassium	O
+.	O
+
+While	O
+gentamicin	O
+and	O
+kanamycin	O
+decreased	O
+the	O
+percentage	O
+reabsorption	O
+and	O
+accumulation	O
+of	O
+lysozyme	O
+after	O
+i	O
+.	O
+v	O
+.	O
+administration	O
+of	O
+egg	O
+-	O
+white	O
+lysozyme	O
+netilmicin	O
+had	O
+no	O
+effect	O
+.	O
+
+Daily	O
+excretion	O
+of	O
+total	O
+protein	O
+,	O
+endogenous	O
+lysozyme	O
+and	O
+NAG	O
+increased	O
+only	O
+after	O
+treatment	O
+with	O
+kanamycin	O
+and	O
+gentamicin	O
+.	O
+
+Thus	O
+,	O
+aminoglycosides	O
+may	O
+act	O
+as	O
+nephrotoxicants	O
+at	O
+glomerular	O
+and	O
+/	O
+or	O
+tubular	O
+level	O
+inducing	O
+impairment	B
+of	I
+renal	I
+reabsorption	I
+and	O
+accumulation	O
+of	O
+proteins	O
+.	O
+
+Induction	O
+of	O
+the	O
+obstructive	B
+sleep	I
+apnea	I
+syndrome	I
+in	O
+a	O
+woman	O
+by	O
+exogenous	O
+androgen	O
+administration	O
+.	O
+
+We	O
+documented	O
+airway	O
+occlusion	O
+during	O
+sleep	O
+and	O
+an	O
+abnormally	O
+high	O
+supraglottic	O
+resistance	O
+while	O
+awake	O
+in	O
+a	O
+54	O
+-	O
+yr	O
+-	O
+old	O
+woman	O
+who	O
+had	O
+developed	O
+physical	O
+changes	O
+and	O
+the	O
+syndrome	B
+of	I
+obstructive	I
+sleep	I
+apnea	I
+while	O
+being	O
+administered	O
+exogenous	O
+androgens	O
+.	O
+
+When	O
+the	O
+androgens	O
+were	O
+withdrawn	O
+,	O
+the	O
+patient	O
+'	O
+s	O
+physical	O
+changes	O
+,	O
+symptoms	O
+,	O
+sleep	O
+study	O
+,	O
+and	O
+supraglottic	O
+resistance	O
+all	O
+returned	O
+to	O
+normal	O
+.	O
+
+A	O
+rechallenge	O
+with	O
+androgen	O
+produced	O
+symptoms	O
+of	O
+obstructive	B
+sleep	I
+apnea	I
+that	O
+abated	O
+upon	O
+withdrawal	O
+of	O
+the	O
+hormone	O
+.	O
+
+Previous	O
+reports	O
+have	O
+favored	O
+a	O
+role	O
+of	O
+androgens	O
+in	O
+the	O
+pathogenesis	O
+of	O
+sleep	B
+apnea	I
+.	O
+
+Our	O
+report	O
+provides	O
+direct	O
+evidence	O
+for	O
+this	O
+role	O
+.	O
+
+Structural	O
+and	O
+functional	O
+measurements	O
+indicate	O
+that	O
+androgens	O
+exert	O
+a	O
+permissive	O
+or	O
+necessary	O
+action	O
+on	O
+the	O
+structural	O
+configuration	O
+of	O
+the	O
+oropharynx	O
+that	O
+predisposes	O
+to	O
+obstruction	O
+during	O
+sleep	O
+.	O
+
+Development	O
+of	O
+the	O
+obstructive	B
+sleep	I
+apnea	I
+syndrome	I
+must	O
+be	O
+considered	O
+a	O
+possible	O
+side	O
+effect	O
+of	O
+androgen	O
+therapy	O
+.	O
+
+Cardiotoxic	B
+and	O
+possible	O
+leukemogenic	O
+effects	O
+of	O
+adriamycin	O
+in	O
+nonhuman	O
+primates	O
+.	O
+
+10	O
+monkeys	O
+(	O
+macaques	O
+)	O
+received	O
+adriamycin	O
+by	O
+monthly	O
+intravenous	O
+injections	O
+at	O
+12	O
+mg	O
+/	O
+m2	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+8	O
+of	O
+the	O
+10	O
+monkeys	O
+developed	O
+congestive	B
+heart	I
+failure	I
+at	O
+an	O
+average	O
+cumulative	O
+adriamycin	O
+dose	O
+(	O
+310	O
+mg	O
+/	O
+m2	O
+)	O
+well	O
+below	O
+that	O
+considered	O
+the	O
+safe	O
+upper	O
+limit	O
+(	O
+550	O
+mg	O
+/	O
+m2	O
+)	O
+in	O
+man	O
+.	O
+
+Histologically	O
+,	O
+the	O
+myocardial	B
+lesions	I
+resembled	O
+those	O
+found	O
+in	O
+human	O
+anthracycline	O
+-	O
+induced	O
+cardiomyopathy	B
+.	O
+
+1	O
+of	O
+the	O
+10	O
+monkeys	O
+developed	O
+acute	B
+myeloblastic	I
+leukemia	I
+after	O
+receiving	O
+324	O
+mg	O
+/	O
+m2	O
+of	O
+adriamycin	O
+;	O
+the	O
+10th	O
+monkey	O
+is	O
+alive	O
+and	O
+well	O
+26	O
+months	O
+after	O
+the	O
+last	O
+dose	O
+of	O
+drug	O
+.	O
+
+Our	O
+results	O
+suggest	O
+that	O
+adriamycin	O
+is	O
+a	O
+more	O
+potent	O
+cardiotoxin	O
+in	O
+monkeys	O
+than	O
+in	O
+man	O
+,	O
+and	O
+that	O
+leukemia	B
+may	O
+be	O
+a	O
+consequence	O
+of	O
+prolonged	O
+treatment	O
+with	O
+this	O
+drug	O
+.	O
+
+Tricuspid	B
+valve	I
+regurgitation	I
+and	O
+lithium	O
+carbonate	O
+toxicity	B
+in	O
+a	O
+newborn	O
+infant	O
+.	O
+
+A	O
+newborn	O
+with	O
+massive	O
+tricuspid	B
+regurgitation	I
+,	O
+atrial	B
+flutter	I
+,	O
+congestive	B
+heart	I
+failure	I
+,	O
+and	O
+a	O
+high	O
+serum	O
+lithium	O
+level	O
+is	O
+described	O
+.	O
+
+This	O
+is	O
+the	O
+first	O
+patient	O
+to	O
+initially	O
+manifest	O
+tricuspid	B
+regurgitation	I
+and	O
+atrial	B
+flutter	I
+,	O
+and	O
+the	O
+11th	O
+described	O
+patient	O
+with	O
+cardiac	B
+disease	I
+among	O
+infants	O
+exposed	O
+to	O
+lithium	O
+compounds	O
+in	O
+the	O
+first	O
+trimester	O
+of	O
+pregnancy	O
+.	O
+
+Sixty	O
+-	O
+three	O
+percent	O
+of	O
+these	O
+infants	O
+had	O
+tricuspid	O
+valve	O
+involvement	O
+.	O
+
+Lithium	O
+carbonate	O
+may	O
+be	O
+a	O
+factor	O
+in	O
+the	O
+increasing	O
+incidence	O
+of	O
+congenital	B
+heart	I
+disease	I
+when	O
+taken	O
+during	O
+early	O
+pregnancy	O
+.	O
+
+It	O
+also	O
+causes	O
+neurologic	B
+depression	I
+,	O
+cyanosis	B
+,	O
+and	O
+cardiac	B
+arrhythmia	I
+when	O
+consumed	O
+prior	O
+to	O
+delivery	O
+.	O
+
+Effects	O
+of	O
+the	O
+novel	O
+compound	O
+aniracetam	O
+(	O
+Ro	O
+13	O
+-	O
+5057	O
+)	O
+upon	O
+impaired	B
+learning	I
+and	I
+memory	I
+in	O
+rodents	O
+.	O
+
+The	O
+effect	O
+of	O
+aniracetam	O
+(	O
+Ro	O
+13	O
+-	O
+5057	O
+,	O
+1	O
+-	O
+anisoyl	O
+-	O
+2	O
+-	O
+pyrrolidinone	O
+)	O
+was	O
+studied	O
+on	O
+various	O
+forms	O
+of	O
+experimentally	O
+impaired	B
+cognitive	I
+functions	I
+(	O
+learning	O
+and	O
+memory	O
+)	O
+in	O
+rodents	O
+and	O
+produced	O
+the	O
+following	O
+effects	O
+:	O
+(	O
+1	O
+)	O
+almost	O
+complete	O
+prevention	O
+of	O
+the	O
+incapacity	O
+to	O
+learn	O
+a	O
+discrete	O
+escape	O
+response	O
+in	O
+rats	O
+exposed	O
+to	O
+sublethal	O
+hypercapnia	B
+immediately	O
+before	O
+the	O
+acquisition	O
+session	O
+;	O
+(	O
+2	O
+)	O
+partial	O
+(	O
+rats	O
+)	O
+or	O
+complete	O
+(	O
+mice	O
+)	O
+prevention	O
+of	O
+the	O
+scopolamine	O
+-	O
+induced	O
+short	O
+-	O
+term	O
+amnesia	B
+for	O
+a	O
+passive	O
+avoidance	O
+task	O
+;	O
+(	O
+3	O
+)	O
+complete	O
+protection	O
+against	O
+amnesia	B
+for	O
+a	O
+passive	O
+avoidance	O
+task	O
+in	O
+rats	O
+submitted	O
+to	O
+electroconvulsive	O
+shock	O
+immediately	O
+after	O
+avoidance	O
+acquisition	O
+;	O
+(	O
+4	O
+)	O
+prevention	O
+of	O
+the	O
+long	O
+-	O
+term	O
+retention	O
+-	O
+or	O
+retrieval	O
+-	O
+deficit	O
+for	O
+a	O
+passive	O
+avoidance	O
+task	O
+induced	O
+in	O
+rats	O
+and	O
+mice	O
+by	O
+chloramphenicol	O
+or	O
+cycloheximide	O
+administered	O
+immediately	O
+after	O
+acquisition	O
+;	O
+(	O
+5	O
+)	O
+reversal	O
+,	O
+when	O
+administered	O
+as	O
+late	O
+as	O
+1	O
+h	O
+before	O
+the	O
+retention	O
+test	O
+,	O
+of	O
+the	O
+deficit	O
+in	O
+retention	O
+or	O
+retrieval	O
+of	O
+a	O
+passive	O
+avoidance	O
+task	O
+induced	O
+by	O
+cycloheximide	O
+injected	O
+2	O
+days	O
+previously	O
+;	O
+(	O
+6	O
+)	O
+prevention	O
+of	O
+the	O
+deficit	O
+in	O
+the	O
+retrieval	O
+of	O
+an	O
+active	O
+avoidance	O
+task	O
+induced	O
+in	O
+mice	O
+by	O
+subconvulsant	O
+electroshock	O
+or	O
+hypercapnia	B
+applied	O
+immediately	O
+before	O
+retrieval	O
+testing	O
+(	O
+24	O
+h	O
+after	O
+acquisition	O
+)	O
+.	O
+
+These	O
+improvements	O
+or	O
+normalizations	O
+of	O
+impaired	B
+cognitive	I
+functions	I
+were	O
+seen	O
+at	O
+oral	O
+aniracetam	O
+doses	O
+of	O
+10	O
+-	O
+100	O
+mg	O
+/	O
+kg	O
+.	O
+
+Generally	O
+,	O
+the	O
+dose	O
+-	O
+response	O
+curves	O
+were	O
+bell	O
+-	O
+shaped	O
+.	O
+
+The	O
+mechanisms	O
+underlying	O
+the	O
+activity	O
+of	O
+aniracetam	O
+and	O
+its	O
+'	O
+therapeutic	O
+window	O
+'	O
+are	O
+unknown	O
+.	O
+
+Piracetam	O
+,	O
+another	O
+pyrrolidinone	O
+derivative	O
+was	O
+used	O
+for	O
+comparison	O
+.	O
+
+It	O
+was	O
+active	O
+only	O
+in	O
+six	O
+of	O
+nine	O
+tests	O
+and	O
+had	O
+about	O
+one	O
+-	O
+tenth	O
+the	O
+potency	O
+of	O
+aniracetam	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+aniracetam	O
+improves	O
+cognitive	O
+functions	O
+which	O
+are	O
+impaired	O
+by	O
+different	O
+procedure	O
+and	O
+in	O
+different	O
+phases	O
+of	O
+the	O
+learning	O
+and	O
+memory	O
+process	O
+.	O
+
+Effect	O
+of	O
+calcium	O
+chloride	O
+on	O
+gross	O
+behavioural	O
+changes	O
+produced	O
+by	O
+carbachol	O
+and	O
+eserine	O
+in	O
+cats	O
+.	O
+
+The	O
+effect	O
+of	O
+calcium	O
+chloride	O
+injected	O
+into	O
+the	O
+cerebral	O
+ventricles	O
+of	O
+group	O
+-	O
+housed	O
+unanaesthetized	O
+cats	O
+upon	O
+vocalization	O
+(	O
+rage	O
+,	O
+hissing	O
+and	O
+snarling	O
+)	O
+,	O
+fighting	O
+(	O
+attack	O
+with	O
+paws	O
+and	O
+claws	O
+,	O
+defense	O
+with	O
+paws	O
+and	O
+claws	O
+and	O
+biting	O
+)	O
+,	O
+mydriasis	B
+,	O
+tremor	B
+and	O
+clonic	B
+-	I
+tonic	I
+convulsions	I
+produced	O
+by	O
+carbachol	O
+and	O
+eserine	O
+injected	O
+similarly	O
+was	O
+investigated	O
+.	O
+
+Calcium	O
+chloride	O
+depressed	O
+or	O
+almost	O
+completely	O
+abolished	O
+the	O
+vocalization	O
+and	O
+fighting	O
+due	O
+to	O
+carbachol	O
+and	O
+eserine	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+mydriasis	B
+,	O
+tremor	B
+and	O
+clonic	B
+-	I
+tonic	I
+convulsions	I
+evoked	O
+by	O
+carbachol	O
+and	O
+eserine	O
+were	O
+not	O
+significantly	O
+changed	O
+by	O
+calcium	O
+chloride	O
+.	O
+
+It	O
+is	O
+apparent	O
+that	O
+calcium	O
+chloride	O
+can	O
+"	O
+dissociate	O
+"	O
+vocalization	O
+and	O
+fighting	O
+from	O
+autonomic	O
+and	O
+motor	O
+phenomena	O
+such	O
+as	O
+mydriasis	B
+,	O
+tremor	B
+and	O
+clonic	B
+-	I
+tonic	I
+convulsions	I
+caused	O
+by	O
+carbachol	O
+and	O
+eserine	O
+.	O
+
+Calcium	O
+chloride	O
+inhibited	O
+the	O
+vocalization	O
+and	O
+fighting	O
+produced	O
+by	O
+carbachol	O
+and	O
+eserine	O
+most	O
+probably	O
+by	O
+a	O
+nonspecific	O
+stabilizing	O
+action	O
+on	O
+central	O
+muscarinic	O
+cholinoceptive	O
+sites	O
+.	O
+
+These	O
+results	O
+further	O
+support	O
+the	O
+view	O
+that	O
+calcium	O
+ions	O
+in	O
+excess	O
+have	O
+an	O
+atropine	O
+-	O
+like	O
+action	O
+also	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+.	O
+
+Thiazide	O
+diuretics	O
+,	O
+hypokalemia	B
+and	O
+cardiac	B
+arrhythmias	I
+.	O
+
+Thiazide	O
+diuretics	O
+are	O
+widely	O
+accepted	O
+as	O
+the	O
+cornerstone	O
+of	O
+antihypertensive	O
+treatment	O
+programs	O
+.	O
+
+Hypokalemia	B
+is	O
+a	O
+commonly	O
+encountered	O
+metabolic	O
+consequence	O
+of	O
+chronic	O
+thiazide	O
+therapy	O
+.	O
+
+We	O
+treated	O
+38	O
+patients	O
+(	O
+22	O
+low	O
+renin	O
+,	O
+16	O
+normal	O
+renin	O
+)	O
+with	O
+moderate	O
+diastolic	B
+hypertension	I
+with	O
+hydrochlorothiazide	O
+(	O
+HCTC	O
+)	O
+administered	O
+on	O
+a	O
+twice	O
+daily	O
+schedule	O
+.	O
+
+Initial	O
+dose	O
+was	O
+50	O
+mg	O
+and	O
+the	O
+dose	O
+was	O
+increased	O
+at	O
+monthly	O
+intervals	O
+to	O
+100	O
+mg	O
+,	O
+150	O
+mg	O
+and	O
+200	O
+mg	O
+daily	O
+until	O
+blood	O
+pressure	O
+normalized	O
+.	O
+
+The	O
+serum	O
+K	O
+during	O
+the	O
+control	O
+period	O
+was	O
+4	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+mEq	O
+/	O
+l	O
+an	O
+on	O
+50	O
+,	O
+100	O
+,	O
+150	O
+and	O
+200	O
+mg	O
+HCTZ	O
+daily	O
+3	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+,	O
+3	O
+.	O
+4	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+,	O
+2	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+,	O
+and	O
+2	O
+.	O
+4	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+mEq	O
+/	O
+l	O
+,	O
+respectively	O
+.	O
+
+Corresponding	O
+figures	O
+for	O
+whole	O
+body	O
+K	O
+were	O
+4107	O
++	O
+/	O
+-	O
+208	O
+,	O
+3722	O
++	O
+/	O
+-	O
+319	O
+,	O
+3628	O
++	O
+/	O
+-	O
+257	O
+,	O
+3551	O
++	O
+/	O
+-	O
+336	O
+,	O
+and	O
+3269	O
++	O
+/	O
+-	O
+380	O
+mEq	O
+,	O
+respectively	O
+.	O
+
+In	O
+13	O
+patients	O
+we	O
+observed	O
+the	O
+effects	O
+of	O
+HCTZ	O
+therapy	O
+(	O
+100	O
+mg	O
+daily	O
+)	O
+on	O
+the	O
+occurrence	O
+of	O
+PVC	O
+'	O
+s	O
+during	O
+rest	O
+as	O
+well	O
+as	O
+during	O
+static	O
+and	O
+dynamic	O
+exercise	O
+.	O
+
+During	O
+rest	O
+we	O
+observed	O
+0	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+08	O
+PVC	O
+beats	O
+/	O
+min	O
++	O
+/	O
+-	O
+SEM	O
+and	O
+during	O
+static	O
+and	O
+dynamic	O
+exercise	O
+0	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+06	O
+and	O
+0	O
+.	O
+8	O
++	O
+/	O
+-	O
+0	O
+.	O
+15	O
+,	O
+respectively	O
+.	O
+
+Corresponding	O
+figures	O
+during	O
+HCTZ	O
+therapy	O
+100	O
+mg	O
+daily	O
+were	O
+1	O
+.	O
+4	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+,	O
+3	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+and	O
+5	O
+.	O
+7	O
+4	O
+/	O
+-	O
+0	O
+.	O
+8	O
+,	O
+respectively	O
+.	O
+
+The	O
+occurrence	O
+of	O
+PVC	O
+'	O
+s	O
+correlated	O
+significantly	O
+with	O
+the	O
+fall	O
+in	O
+serum	O
+K	O
++	O
+observed	O
+r	O
+=	O
+0	O
+.	O
+72	O
+,	O
+p	O
+less	O
+than	O
+0	O
+.	O
+001	O
+.	O
+
+In	O
+conclusion	O
+we	O
+found	O
+that	O
+thiazide	O
+diuretics	O
+cause	O
+hypokalemia	B
+and	O
+depletion	O
+of	O
+body	O
+potassium	O
+.	O
+
+The	O
+more	O
+profound	O
+hypokalemia	B
+,	O
+the	O
+greater	O
+the	O
+propensity	O
+for	O
+the	O
+occurrence	O
+of	O
+PVC	O
+'	O
+s	O
+.	O
+
+Circulating	O
+lysosomal	O
+enzymes	O
+and	O
+acute	B
+hepatic	I
+necrosis	I
+.	O
+
+The	O
+activities	O
+of	O
+the	O
+lysosomal	O
+enzymes	O
+acid	O
+and	O
+neutral	O
+protease	O
+,	O
+N	O
+-	O
+acetylglucosaminidase	O
+,	O
+and	O
+acid	O
+phosphatase	O
+were	O
+measured	O
+in	O
+the	O
+serum	O
+of	O
+patients	O
+with	O
+fulminant	B
+hepatic	I
+failure	I
+.	O
+
+Acid	O
+protease	O
+(	O
+cathepsin	O
+D	O
+)	O
+activity	O
+was	O
+increased	O
+about	O
+tenfold	O
+in	O
+patients	O
+who	O
+died	O
+and	O
+nearly	O
+fourfold	O
+in	O
+those	O
+who	O
+survived	O
+fulminant	B
+hepatic	I
+failure	I
+after	O
+paracetamol	O
+overdose	B
+,	O
+whereas	O
+activities	O
+were	O
+increased	O
+equally	O
+in	O
+patients	O
+with	O
+fulminant	B
+hepatic	I
+failure	I
+due	O
+to	O
+viral	B
+hepatitis	I
+whether	O
+or	O
+not	O
+they	O
+survived	O
+.	O
+
+A	O
+correlation	O
+was	O
+found	O
+between	O
+serum	O
+acid	O
+protease	O
+activity	O
+and	O
+prothrombin	O
+time	O
+,	O
+and	O
+the	O
+increase	O
+in	O
+cathepsin	O
+D	O
+activity	O
+was	O
+sustained	O
+over	O
+several	O
+days	O
+compared	O
+with	O
+aspartate	O
+aminotransferase	O
+,	O
+which	O
+showed	O
+a	O
+sharp	O
+early	O
+peak	O
+and	O
+then	O
+a	O
+fall	O
+.	O
+
+Circulating	O
+lysosomal	O
+proteases	O
+can	O
+damage	O
+other	O
+organs	O
+,	O
+and	O
+measurement	O
+of	O
+their	O
+activity	O
+may	O
+therefore	O
+be	O
+of	O
+added	O
+value	O
+in	O
+assessing	O
+prognosis	O
+in	O
+this	O
+condition	O
+.	O
+
+Hepatic	B
+veno	I
+-	I
+occlusive	I
+disease	I
+caused	O
+by	O
+6	O
+-	O
+thioguanine	O
+.	O
+
+Clinically	O
+reversible	O
+veno	B
+-	I
+occlusive	I
+disease	I
+of	I
+the	I
+liver	I
+developed	O
+in	O
+a	O
+23	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+acute	B
+lymphocytic	I
+leukemia	I
+after	O
+10	O
+months	O
+of	O
+maintenance	O
+therapy	O
+with	O
+6	O
+-	O
+thioguanine	O
+.	O
+
+Serial	O
+liver	O
+biopsies	O
+showed	O
+the	O
+development	O
+and	O
+resolution	O
+of	O
+intense	O
+sinusoidal	O
+engorgement	O
+.	O
+
+Although	O
+this	O
+disease	O
+was	O
+clinically	O
+reversible	O
+,	O
+some	O
+subintimal	O
+fibrosis	B
+about	O
+the	O
+terminal	O
+hepatic	O
+veins	O
+persisted	O
+.	O
+
+This	O
+case	O
+presented	O
+a	O
+unique	O
+opportunity	O
+to	O
+observe	O
+the	O
+histologic	O
+features	O
+of	O
+clinically	O
+reversible	O
+hepatic	B
+veno	I
+-	I
+occlusive	I
+disease	I
+over	O
+time	O
+,	O
+and	O
+may	O
+be	O
+the	O
+first	O
+case	O
+of	O
+veno	O
+-	O
+occlusive	O
+related	O
+solely	O
+to	O
+6	O
+-	O
+thioguanine	O
+.	O
+
+Chlorpropamide	O
+-	O
+induced	O
+optic	B
+neuropathy	I
+.	O
+
+A	O
+65	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+adult	B
+-	I
+onset	I
+diabetes	I
+treated	O
+with	O
+chlorpropamide	O
+(	O
+Diabenese	O
+)	O
+had	O
+a	O
+toxic	B
+optic	I
+neuropathy	I
+that	O
+resolved	O
+with	O
+discontinuation	O
+of	O
+chlorpropamide	O
+therapy	O
+.	O
+
+Visual	B
+loss	I
+occurs	O
+in	O
+diabetics	B
+for	O
+a	O
+variety	O
+of	O
+reasons	O
+,	O
+and	O
+accurate	O
+diagnosis	O
+is	O
+necessary	O
+to	O
+institute	O
+appropriate	O
+therapy	O
+.	O
+
+The	O
+possibility	O
+of	O
+a	O
+drug	O
+-	O
+induced	O
+optic	B
+neuropathy	I
+should	O
+be	O
+considered	O
+in	O
+the	O
+differential	O
+diagnosis	O
+of	O
+visual	B
+loss	I
+in	O
+diabetics	B
+.	O
+
+Plasma	O
+and	O
+urinary	O
+lipids	O
+and	O
+lipoproteins	O
+during	O
+the	O
+development	O
+of	O
+nephrotic	B
+syndrome	I
+induced	O
+in	O
+the	O
+rat	O
+by	O
+puromycin	O
+aminonucleoside	O
+.	O
+
+This	O
+study	O
+was	O
+undertaken	O
+to	O
+ascertain	O
+whether	O
+the	O
+alterations	O
+of	O
+plasma	O
+lipoproteins	O
+found	O
+in	O
+nephrotic	B
+syndrome	I
+induced	O
+by	O
+puromycin	O
+aminonucleoside	O
+were	O
+due	O
+to	O
+nephrotic	B
+syndrome	I
+per	O
+se	O
+,	O
+or	O
+,	O
+at	O
+least	O
+in	O
+part	O
+,	O
+to	O
+the	O
+aminonucleoside	O
+.	O
+
+The	O
+purpose	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+changes	O
+in	O
+plasma	O
+and	O
+urinary	O
+lipoproteins	O
+during	O
+the	O
+administration	O
+of	O
+puromycin	O
+aminonucleoside	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+for	O
+7	O
+days	O
+)	O
+and	O
+the	O
+subsequent	O
+development	O
+of	O
+nephrotic	B
+syndrome	I
+.	O
+
+Since	O
+massive	O
+albuminuria	B
+occurred	O
+after	O
+6	O
+days	O
+of	O
+treatment	O
+,	O
+the	O
+time	O
+-	O
+course	O
+study	O
+was	O
+divided	O
+into	O
+two	O
+stages	O
+:	O
+pre	O
+-	O
+nephrotic	B
+stage	O
+(	O
+day	O
+1	O
+-	O
+5	O
+)	O
+and	O
+nephrotic	B
+stage	O
+(	O
+day	O
+6	O
+-	O
+11	O
+)	O
+.	O
+
+In	O
+pre	O
+-	O
+nephrotic	B
+stage	O
+the	O
+plasma	O
+level	O
+of	O
+fatty	O
+acids	O
+,	O
+triacylglycerol	O
+and	O
+VLDL	O
+decreased	O
+while	O
+that	O
+of	O
+phospholipid	O
+,	O
+cholesteryl	O
+esters	O
+and	O
+HDL	O
+remained	O
+constant	O
+.	O
+
+Plasma	O
+apolipoprotein	O
+A	O
+-	O
+I	O
+tended	O
+to	O
+increase	O
+(	O
+40	O
+%	O
+increase	O
+at	O
+day	O
+5	O
+)	O
+.	O
+
+At	O
+the	O
+beginning	O
+of	O
+nephrotic	B
+stage	O
+(	O
+day	O
+6	O
+)	O
+the	O
+concentration	O
+of	O
+plasma	O
+albumin	O
+dropped	O
+to	O
+a	O
+very	O
+low	O
+level	O
+,	O
+while	O
+that	O
+of	O
+apolipoprotein	O
+A	O
+-	O
+I	O
+increased	O
+abruptly	O
+(	O
+4	O
+-	O
+fold	O
+increase	O
+)	O
+and	O
+continued	O
+to	O
+rise	O
+,	O
+although	O
+less	O
+steeply	O
+,	O
+in	O
+the	O
+following	O
+days	O
+.	O
+
+The	O
+plasma	O
+concentration	O
+of	O
+HDL	O
+followed	O
+the	O
+same	O
+pattern	O
+.	O
+
+Plasma	O
+VLDL	O
+and	O
+LDL	O
+increased	O
+at	O
+a	O
+later	O
+stage	O
+(	O
+day	O
+9	O
+)	O
+.	O
+
+Plasma	O
+apolipoprotein	O
+A	O
+-	O
+I	O
+was	O
+found	O
+not	O
+only	O
+in	O
+HDL	O
+(	O
+1	O
+.	O
+063	O
+-	O
+1	O
+.	O
+210	O
+g	O
+/	O
+ml	O
+)	O
+but	O
+also	O
+in	O
+the	O
+LDL	O
+density	O
+class	O
+(	O
+1	O
+.	O
+025	O
+-	O
+1	O
+.	O
+050	O
+g	O
+/	O
+ml	O
+)	O
+.	O
+
+In	O
+the	O
+pre	O
+-	O
+nephrotic	B
+stage	O
+lipoproteinuria	O
+was	O
+negligible	O
+,	O
+while	O
+in	O
+the	O
+early	O
+nephrotic	B
+stage	O
+the	O
+urinary	O
+loss	O
+of	O
+plasma	O
+lipoproteins	O
+consisted	O
+mainly	O
+of	O
+HDL	O
+.	O
+
+These	O
+observations	O
+indicate	O
+that	O
+puromycin	O
+aminonucleoside	O
+alters	O
+plasma	O
+lipoproteins	O
+by	O
+lowering	O
+VLDL	O
+and	O
+increasing	O
+HDL	O
+.	O
+
+It	O
+is	O
+likely	O
+that	O
+the	O
+early	O
+and	O
+striking	O
+increase	O
+of	O
+plasma	O
+HDL	O
+found	O
+in	O
+nephrotic	B
+rats	O
+is	O
+related	O
+to	O
+a	O
+direct	O
+effect	O
+of	O
+the	O
+drug	O
+on	O
+HDL	O
+metabolism	O
+.	O
+
+Fatal	O
+aplastic	B
+anemia	I
+following	O
+topical	O
+administration	O
+of	O
+ophthalmic	O
+chloramphenicol	O
+.	O
+
+A	O
+73	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+died	O
+of	O
+aplastic	B
+anemia	I
+less	O
+than	O
+two	O
+months	O
+after	O
+undergoing	O
+cataract	B
+extraction	O
+and	O
+beginning	O
+topical	O
+therapy	O
+with	O
+chloramphenicol	O
+.	O
+
+The	O
+first	O
+signs	O
+of	O
+pancytopenia	B
+began	O
+within	O
+one	O
+month	O
+of	O
+the	O
+surgery	O
+.	O
+
+The	O
+pattern	O
+of	O
+the	O
+aplastic	B
+anemia	I
+was	O
+associated	O
+with	O
+an	O
+idiosyncratic	O
+response	O
+to	O
+chloramphenicol	O
+.	O
+
+This	O
+was	O
+the	O
+second	O
+report	O
+of	O
+fatal	O
+aplastic	B
+anemia	I
+after	O
+topical	O
+treatment	O
+with	O
+chloramphenicol	O
+for	O
+ocular	O
+conditions	O
+,	O
+although	O
+two	O
+cases	O
+of	O
+reversible	O
+bone	B
+marrow	I
+hypoplasia	I
+have	O
+also	O
+been	O
+reported	O
+.	O
+
+Any	O
+other	O
+suspected	O
+cases	O
+of	O
+ocular	B
+toxicity	I
+associated	O
+with	O
+topically	O
+applied	O
+chloramphenicol	O
+should	O
+be	O
+reported	O
+to	O
+the	O
+National	O
+Registry	O
+of	O
+Drug	O
+-	O
+Induced	O
+Ocular	O
+Side	O
+Effects	O
+,	O
+Oregon	O
+Health	O
+Sciences	O
+University	O
+,	O
+Portland	O
+,	O
+OR	O
+97201	O
+.	O
+
+Midazolam	O
+compared	O
+with	O
+thiopentone	O
+as	O
+an	O
+induction	O
+agent	O
+.	O
+
+In	O
+patients	O
+premedicated	O
+with	O
+scopolamine	O
++	O
+morphine	O
+(	O
++	O
+5	O
+mg	O
+nitrazepam	O
+the	O
+evening	O
+before	O
+surgery	O
+)	O
+,	O
+the	O
+sleep	O
+-	O
+inducing	O
+effect	O
+of	O
+midazolam	O
+0	O
+.	O
+15	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+was	O
+clearly	O
+slower	O
+in	O
+onset	O
+than	O
+that	O
+of	O
+thiopentone	O
+4	O
+.	O
+67	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+Somewhat	O
+fewer	O
+cardiovascular	O
+and	O
+local	O
+sequelae	O
+were	O
+found	O
+in	O
+the	O
+midazolam	O
+group	O
+,	O
+but	O
+,	O
+although	O
+apnoea	B
+occurred	O
+less	O
+often	O
+in	O
+the	O
+midazolam	O
+group	O
+it	O
+lasted	O
+longer	O
+.	O
+
+On	O
+the	O
+whole	O
+,	O
+the	O
+differences	O
+between	O
+midazolam	O
+and	O
+thiopentone	O
+had	O
+no	O
+apparent	O
+clinical	O
+consequences	O
+.	O
+
+Midazolam	O
+is	O
+a	O
+new	O
+alternative	O
+agent	O
+for	O
+induction	O
+in	O
+combination	O
+anaesthesia	O
+.	O
+
+Extrapyramidal	O
+side	O
+effects	O
+and	O
+oral	O
+haloperidol	O
+:	O
+an	O
+analysis	O
+of	O
+explanatory	O
+patient	O
+and	O
+treatment	O
+characteristics	O
+.	O
+
+The	O
+incidence	O
+of	O
+extrapyramidal	O
+side	O
+effects	O
+(	O
+EPS	O
+)	O
+was	O
+evaluated	O
+in	O
+98	O
+patients	O
+treated	O
+with	O
+haloperidol	O
+.	O
+
+The	O
+incidence	O
+of	O
+parkinsonism	B
+was	O
+higher	O
+at	O
+higher	O
+doses	O
+of	O
+haloperidol	O
+and	O
+in	O
+younger	O
+patients	O
+.	O
+
+Prophylactic	O
+antiparkinsonian	O
+medication	O
+was	O
+effective	O
+in	O
+younger	O
+but	O
+not	O
+in	O
+older	O
+patients	O
+.	O
+
+However	O
+,	O
+these	O
+medications	O
+were	O
+more	O
+effective	O
+in	O
+both	O
+young	O
+and	O
+old	O
+patients	O
+when	O
+given	O
+after	O
+parkinsonism	B
+developed	O
+.	O
+
+Akathisia	B
+was	O
+controlled	O
+by	O
+the	O
+benzodiazepine	O
+lorazepam	O
+in	O
+14	O
+out	O
+of	O
+16	O
+patients	O
+,	O
+while	O
+prophylactic	O
+antiparkinsonians	O
+were	O
+ineffective	O
+.	O
+
+The	O
+present	O
+study	O
+points	O
+to	O
+patient	O
+characteristics	O
+that	O
+may	O
+be	O
+of	O
+significance	O
+in	O
+the	O
+development	O
+of	O
+EPS	O
+due	O
+to	O
+haloperidol	O
+.	O
+
+Deaths	O
+from	O
+local	O
+anesthetic	O
+-	O
+induced	O
+convulsions	B
+in	O
+mice	O
+.	O
+
+Median	O
+convulsant	O
+(	O
+CD50	O
+)	O
+and	O
+median	O
+lethal	O
+(	O
+LD50	O
+)	O
+doses	O
+of	O
+three	O
+representative	O
+local	O
+anesthetics	O
+were	O
+determined	O
+in	O
+adult	O
+mice	O
+to	O
+evaluate	O
+the	O
+threat	O
+to	O
+life	O
+of	O
+local	O
+anesthetic	O
+-	O
+induced	O
+convulsions	B
+.	O
+
+The	O
+CD50	O
+and	O
+LD50	O
+,	O
+respectively	O
+,	O
+were	O
+57	O
+.	O
+7	O
+and	O
+58	O
+.	O
+7	O
+mg	O
+/	O
+kg	O
+for	O
+bupivacaine	O
+,	O
+111	O
+.	O
+0	O
+and	O
+133	O
+.	O
+1	O
+mg	O
+/	O
+kg	O
+for	O
+lidocaine	O
+,	O
+and	O
+243	O
+.	O
+4	O
+and	O
+266	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+for	O
+chloroprocaine	O
+.	O
+
+When	O
+given	O
+intraperitoneally	O
+,	O
+bupivacaine	O
+thus	O
+was	O
+only	O
+about	O
+twice	O
+as	O
+toxic	O
+as	O
+lidocaine	O
+and	O
+four	O
+times	O
+as	O
+toxic	O
+as	O
+chloroprocaine	O
+.	O
+
+Convulsions	B
+always	O
+preceded	O
+death	O
+,	O
+except	O
+after	O
+precipitous	O
+cardiopulmonary	B
+arrest	I
+from	O
+extreme	O
+doses	O
+.	O
+
+A	O
+CD50	O
+dose	O
+of	O
+local	O
+anesthetic	O
+(	O
+causing	O
+convulsions	B
+in	O
+50	O
+%	O
+of	O
+mice	O
+)	O
+was	O
+fatal	O
+in	O
+90	O
+%	O
+of	O
+bupivacaine	O
+-	O
+induced	O
+seizures	B
+,	O
+in	O
+57	O
+%	O
+of	O
+the	O
+chloroprocaine	O
+group	O
+,	O
+and	O
+in	O
+6	O
+%	O
+of	O
+the	O
+lidocaine	O
+group	O
+.	O
+
+The	O
+narrow	O
+gap	O
+between	O
+convulsant	O
+and	O
+lethal	O
+doses	O
+of	O
+local	O
+anesthetics	O
+indicates	O
+that	O
+untreated	O
+convulsions	B
+present	O
+much	O
+more	O
+of	O
+a	O
+threat	O
+to	O
+life	O
+than	O
+heretofore	O
+appreciated	O
+.	O
+
+REM	B
+sleep	I
+deprivation	I
+changes	O
+behavioral	O
+response	O
+to	O
+catecholaminergic	O
+and	O
+serotonergic	O
+receptor	O
+activation	O
+in	O
+rats	O
+.	O
+
+The	O
+effects	O
+of	O
+REM	B
+sleep	I
+deprivation	I
+(	O
+REMD	B
+)	O
+on	O
+apomorphine	O
+-	O
+induced	O
+aggressiveness	B
+and	O
+quipazine	O
+-	O
+induced	O
+head	B
+twitches	I
+in	O
+rats	O
+were	O
+determined	O
+.	O
+
+Forty	O
+-	O
+eight	O
+hr	O
+of	O
+REMD	B
+increased	O
+apomorphine	O
+-	O
+induced	O
+aggressiveness	B
+,	O
+and	O
+reduced	O
+(	O
+immediately	O
+after	O
+completing	O
+of	O
+REMD	B
+)	O
+or	O
+increased	O
+(	O
+96	O
+hr	O
+after	O
+completing	O
+of	O
+REMD	B
+)	O
+quipazine	O
+-	O
+induced	O
+head	B
+twitches	I
+.	O
+
+Results	O
+are	O
+discussed	O
+in	O
+terms	O
+of	O
+similarity	O
+to	O
+pharmacological	O
+effects	O
+of	O
+other	O
+antidepressive	O
+treatments	O
+.	O
+
+Fatal	O
+aplastic	B
+anemia	I
+due	O
+to	O
+indomethacin	O
+-	O
+-	O
+lymphocyte	O
+transformation	O
+tests	O
+in	O
+vitro	O
+.	O
+
+Although	O
+indomethacin	O
+has	O
+been	O
+implicated	O
+as	O
+a	O
+possible	O
+cause	O
+of	O
+aplastic	B
+anemia	I
+on	O
+the	O
+basis	O
+of	O
+a	O
+few	O
+clinical	O
+observations	O
+,	O
+its	O
+role	O
+has	O
+not	O
+been	O
+definitely	O
+established	O
+.	O
+
+A	O
+case	O
+of	O
+fatal	O
+aplastic	B
+anemia	I
+is	O
+described	O
+in	O
+which	O
+no	O
+drugs	O
+other	O
+than	O
+allopurinol	O
+and	O
+indomethacin	O
+were	O
+given	O
+.	O
+
+Indomethacin	O
+was	O
+first	O
+given	O
+four	O
+weeks	O
+prior	O
+to	O
+the	O
+onset	O
+of	O
+symptoms	O
+.	O
+
+A	O
+positive	O
+lymphocyte	O
+transformation	O
+test	O
+with	O
+indomethacin	O
+in	O
+vitro	O
+further	O
+substantiates	O
+the	O
+potential	O
+role	O
+of	O
+this	O
+drug	O
+in	O
+causing	O
+aplastic	B
+anemia	I
+in	O
+a	O
+susceptible	O
+patient	O
+.	O
+
+Fortunately	O
+,	O
+this	O
+seems	O
+to	O
+be	O
+a	O
+very	O
+rare	O
+complication	O
+.	O
+
+Dose	O
+-	O
+effect	O
+and	O
+structure	O
+-	O
+function	O
+relationships	O
+in	O
+doxorubicin	O
+cardiomyopathy	B
+.	O
+
+The	O
+cardiomyopathy	B
+(	O
+CM	B
+)	O
+produced	O
+by	O
+the	O
+anticancer	O
+drug	O
+doxorubicin	O
+(	O
+DXR	O
+)	O
+(	O
+Adriamycin	O
+)	O
+provides	O
+a	O
+unique	O
+opportunity	O
+to	O
+analyze	O
+dose	O
+-	O
+effect	O
+and	O
+structure	O
+-	O
+function	O
+relationships	O
+during	O
+development	O
+of	O
+myocardial	B
+disease	I
+.	O
+
+We	O
+measured	O
+the	O
+degree	O
+of	O
+morphologic	O
+damage	O
+by	O
+ultrastructural	O
+examination	O
+of	O
+endomyocardial	O
+biopsy	O
+and	O
+the	O
+degree	O
+of	O
+performance	O
+abnormally	O
+by	O
+right	O
+heart	O
+catheterization	O
+in	O
+patients	O
+receiving	O
+DXR	O
+.	O
+
+Morphologic	O
+damage	O
+was	O
+variable	O
+but	O
+was	O
+proportional	O
+to	O
+the	O
+total	O
+cumulative	O
+DXR	O
+dose	O
+between	O
+100	O
+and	O
+600	O
+mg	O
+/	O
+m2	O
+.	O
+
+Performance	O
+abnormalities	O
+correlated	O
+weakly	O
+with	O
+dose	O
+,	O
+exhibited	O
+a	O
+curvilinear	O
+relationship	O
+,	O
+and	O
+had	O
+a	O
+"	O
+threshold	O
+"	O
+for	O
+expression	O
+.	O
+
+Catheterization	O
+abnormalities	O
+correlated	O
+well	O
+with	O
+morphologic	O
+damage	O
+(	O
+r	O
+=	O
+0	O
+.	O
+57	O
+to	O
+0	O
+.	O
+78	O
+)	O
+in	O
+a	O
+subgroup	O
+of	O
+patients	O
+in	O
+whom	O
+exercise	O
+hemodynamics	O
+were	O
+measured	O
+,	O
+and	O
+this	O
+relationship	O
+also	O
+exhibited	O
+a	O
+curvilinear	O
+,	O
+threshold	O
+configuration	O
+.	O
+
+In	O
+DXR	O
+-	O
+CM	B
+myocardial	B
+damage	I
+is	O
+proportional	O
+to	O
+the	O
+degree	O
+of	O
+cytotoxic	O
+insult	O
+(	O
+DXR	O
+dose	O
+)	O
+while	O
+myocardial	O
+function	O
+is	O
+preserved	O
+until	O
+a	O
+critical	O
+dose	O
+or	O
+degree	O
+of	O
+damage	O
+is	O
+reached	O
+,	O
+after	O
+which	O
+myocardial	O
+performance	O
+deteriorates	O
+rapidly	O
+.	O
+
+Massive	O
+cerebral	B
+edema	I
+associated	O
+with	O
+fulminant	O
+hepatic	B
+failure	I
+in	O
+acetaminophen	O
+overdose	B
+:	O
+possible	O
+role	O
+of	O
+cranial	O
+decompression	O
+.	O
+
+Cerebral	B
+edema	I
+may	O
+complicate	O
+the	O
+course	O
+of	O
+fulminant	B
+hepatic	I
+failure	I
+.	O
+
+Response	O
+to	O
+conventional	O
+therapy	O
+has	O
+been	O
+disappointing	O
+.	O
+
+We	O
+present	O
+a	O
+patient	O
+with	O
+fatal	O
+acetaminophen	O
+-	O
+induced	O
+fulminant	B
+hepatic	I
+failure	I
+,	O
+with	O
+signs	O
+and	O
+symptoms	O
+of	O
+cerebral	B
+edema	I
+,	O
+unresponsive	O
+to	O
+conventional	O
+medical	O
+therapy	O
+.	O
+
+Cranial	O
+decompression	O
+was	O
+carried	O
+out	O
+.	O
+
+A	O
+justification	O
+of	O
+the	O
+need	O
+for	O
+further	O
+evaluation	O
+of	O
+cranial	O
+decompression	O
+in	O
+such	O
+patients	O
+is	O
+presented	O
+.	O
+
+Subjective	O
+assessment	O
+of	O
+sexual	B
+dysfunction	I
+of	O
+patients	O
+on	O
+long	O
+-	O
+term	O
+administration	O
+of	O
+digoxin	O
+.	O
+
+Various	O
+data	O
+suggest	O
+that	O
+male	O
+patients	O
+who	O
+have	O
+received	O
+digoxin	O
+on	O
+a	O
+longterm	O
+basis	O
+have	O
+increased	O
+levels	O
+of	O
+serum	O
+estrogen	O
+and	O
+decreased	O
+levels	O
+of	O
+plasma	O
+testosterone	O
+and	O
+luteinizing	O
+hormone	O
+(	O
+LH	O
+)	O
+.	O
+
+This	O
+study	O
+was	O
+undertaken	O
+to	O
+investigate	O
+the	O
+links	O
+between	O
+the	O
+long	O
+-	O
+term	O
+administration	O
+of	O
+digoxin	O
+therapy	O
+and	O
+sexual	O
+behavior	O
+,	O
+and	O
+the	O
+effect	O
+of	O
+digoxin	O
+on	O
+plasma	O
+levels	O
+of	O
+estradiol	O
+,	O
+testosterone	O
+,	O
+and	O
+LH	O
+.	O
+
+The	O
+patients	O
+of	O
+the	O
+study	O
+and	O
+control	O
+group	O
+(	O
+without	O
+digoxin	O
+)	O
+were	O
+of	O
+similar	O
+cardiac	O
+functional	O
+capacity	O
+and	O
+age	O
+(	O
+25	O
+-	O
+40	O
+years	O
+)	O
+and	O
+were	O
+randomly	O
+selected	O
+from	O
+the	O
+rheumatic	B
+heart	I
+disease	I
+patients	O
+.	O
+
+A	O
+subjective	O
+assessment	O
+of	O
+sexual	O
+behavior	O
+in	O
+the	O
+study	O
+and	O
+control	O
+groups	O
+was	O
+carried	O
+out	O
+,	O
+using	O
+parameters	O
+such	O
+as	O
+sexual	O
+desire	O
+,	O
+sexual	O
+excitement	O
+,	O
+and	O
+frequency	O
+of	O
+sexual	O
+relations	O
+.	O
+
+Personal	O
+interviews	O
+and	O
+a	O
+questionnaire	O
+were	O
+also	O
+used	O
+for	O
+the	O
+evaluation	O
+of	O
+sexual	O
+behavior	O
+.	O
+
+The	O
+findings	O
+support	O
+the	O
+reports	O
+concerning	O
+digoxin	O
+effect	O
+on	O
+plasma	O
+estradiol	O
+,	O
+testosterone	O
+,	O
+and	O
+LH	O
+.	O
+
+The	O
+differences	O
+in	O
+the	O
+means	O
+were	O
+significant	O
+.	O
+
+Tests	O
+used	O
+to	O
+evaluate	O
+the	O
+changes	O
+in	O
+sexual	O
+behavior	O
+showed	O
+a	O
+significant	O
+decrease	B
+in	I
+sexual	I
+desire	I
+,	O
+sexual	O
+excitement	O
+phase	O
+(	O
+erection	O
+)	O
+,	O
+and	O
+frequency	O
+of	O
+sexual	O
+relations	O
+in	O
+the	O
+study	O
+group	O
+.	O
+
+Endometrial	B
+carcinoma	I
+after	O
+Hodgkin	B
+disease	I
+in	O
+childhood	O
+.	O
+
+A	O
+34	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+developed	O
+metastic	O
+endometrial	B
+carcinoma	I
+after	O
+Hodgkin	B
+disease	I
+in	O
+childhood	O
+.	O
+
+She	O
+had	O
+ovarian	B
+failure	I
+after	O
+abdominal	O
+irradiation	O
+and	O
+chemotherapy	O
+for	O
+Hodgkin	B
+disease	I
+,	O
+and	O
+received	O
+exogenous	O
+estrogens	O
+,	O
+a	O
+treatment	O
+implicated	O
+in	O
+the	O
+development	O
+of	O
+endometrial	B
+cancer	I
+in	O
+menopausal	O
+women	O
+.	O
+
+Young	O
+women	O
+on	O
+replacement	O
+estrogens	O
+for	O
+ovarian	B
+failure	I
+after	O
+cancer	B
+therapy	O
+may	O
+also	O
+have	O
+increased	O
+risk	O
+of	O
+endometrial	B
+carcinoma	I
+and	O
+should	O
+be	O
+examined	O
+periodically	O
+.	O
+
+Long	O
+-	O
+term	O
+lithium	O
+treatment	O
+and	O
+the	O
+kidney	O
+.	O
+
+Interim	O
+report	O
+on	O
+fifty	O
+patients	O
+.	O
+
+This	O
+is	O
+a	O
+report	O
+on	O
+the	O
+first	O
+part	O
+of	O
+our	O
+study	O
+of	O
+the	O
+effects	O
+of	O
+long	O
+-	O
+term	O
+lithium	O
+treatment	O
+on	O
+the	O
+kidney	O
+.	O
+
+Creatinine	O
+clearance	O
+,	O
+maximum	O
+urinary	O
+osmolality	O
+and	O
+24	O
+hour	O
+urine	O
+volume	O
+have	O
+been	O
+tested	O
+in	O
+50	O
+affectively	O
+ill	O
+patients	O
+who	O
+have	O
+been	O
+on	O
+long	O
+-	O
+term	O
+lithium	O
+for	O
+more	O
+than	O
+one	O
+year	O
+.	O
+
+These	O
+findings	O
+have	O
+been	O
+compared	O
+with	O
+norms	O
+and	O
+with	O
+values	O
+of	O
+the	O
+same	O
+tests	O
+from	O
+screening	O
+prior	O
+to	O
+lithium	O
+,	O
+available	O
+for	O
+most	O
+of	O
+our	O
+patients	O
+.	O
+
+No	O
+evidence	O
+was	O
+found	O
+for	O
+any	O
+reduction	O
+of	O
+glomerular	O
+filtration	O
+during	O
+lithium	O
+treatment	O
+.	O
+
+Low	O
+clearance	O
+values	O
+found	O
+in	O
+several	O
+patients	O
+could	O
+be	O
+accounted	O
+for	O
+by	O
+their	O
+age	O
+and	O
+their	O
+pre	O
+-	O
+lithium	O
+values	O
+.	O
+
+Urinary	O
+concentration	O
+defect	O
+appeared	O
+frequent	O
+but	O
+the	O
+extent	O
+of	O
+the	O
+impairment	O
+is	O
+difficult	O
+to	O
+assess	O
+because	O
+of	O
+the	O
+uncertainty	O
+about	O
+the	O
+norms	O
+applicable	O
+to	O
+this	O
+group	O
+of	O
+patients	O
+.	O
+
+The	O
+concentration	O
+defect	O
+appeared	O
+reversible	O
+,	O
+at	O
+least	O
+in	O
+part	O
+.	O
+
+Polyuria	B
+above	O
+3	O
+litres	O
+/	O
+24	O
+hours	O
+was	O
+found	O
+in	O
+10	O
+%	O
+of	O
+patients	O
+.	O
+
+An	O
+attempt	O
+is	O
+made	O
+to	O
+draw	O
+practical	O
+conclusions	O
+from	O
+the	O
+preliminary	O
+findings	O
+.	O
+
+Nephrotoxicity	B
+of	O
+cyclosporin	O
+A	O
+and	O
+FK506	O
+:	O
+inhibition	O
+of	O
+calcineurin	O
+phosphatase	O
+.	O
+
+Cyclosporin	O
+A	O
+(	O
+CsA	O
+;	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+Fujimycine	O
+(	O
+FK506	O
+;	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+but	O
+not	O
+the	O
+related	O
+macrolide	O
+immunosuppressant	O
+rapamycin	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+,	O
+caused	O
+a	O
+reduction	O
+of	O
+glomerular	O
+filtration	O
+rate	O
+,	O
+degenerative	O
+changes	O
+of	O
+proximal	O
+tubular	O
+epithelium	O
+,	O
+and	O
+hypertrophy	B
+of	O
+the	O
+juxtaglomerular	O
+apparatus	O
+in	O
+male	O
+Wistar	O
+rats	O
+when	O
+given	O
+for	O
+10	O
+days	O
+.	O
+
+The	O
+molecular	O
+mechanisms	O
+of	O
+CsA	O
+and	O
+FK506	O
+toxicity	B
+were	O
+investigated	O
+.	O
+
+Cyclophilin	O
+A	O
+and	O
+FK506	O
+-	O
+binding	O
+protein	O
+,	O
+the	O
+main	O
+intracytoplasmic	O
+receptors	O
+for	O
+CsA	O
+and	O
+FK506	O
+,	O
+respectively	O
+,	O
+were	O
+each	O
+detected	O
+in	O
+renal	O
+tissue	O
+extract	O
+.	O
+
+In	O
+the	O
+kidney	O
+,	O
+high	O
+levels	O
+of	O
+immunoreactive	O
+and	O
+enzymatically	O
+active	O
+calcineurin	O
+were	O
+found	O
+which	O
+were	O
+inhibited	O
+by	O
+the	O
+immunosuppressants	O
+CsA	O
+and	O
+FK506	O
+,	O
+but	O
+not	O
+by	O
+rapamycin	O
+.	O
+
+Finally	O
+,	O
+specific	O
+immunophilin	O
+-	O
+drug	O
+-	O
+calcineurin	O
+complexes	O
+formed	O
+only	O
+in	O
+the	O
+presence	O
+of	O
+CsA	O
+and	O
+FK506	O
+,	O
+but	O
+not	O
+rapamycin	O
+.	O
+
+These	O
+results	O
+suggest	O
+that	O
+the	O
+nephrotoxic	B
+effects	O
+of	O
+CsA	O
+and	O
+FK506	O
+is	O
+likely	O
+mediated	O
+through	O
+binding	O
+to	O
+renal	O
+immunophilin	O
+and	O
+inhibiting	O
+calcineurin	O
+phosphatase	O
+.	O
+
+Acute	B
+renal	I
+failure	I
+in	O
+high	O
+dose	O
+carboplatin	O
+chemotherapy	O
+.	O
+
+Carboplatin	O
+has	O
+been	O
+reported	O
+to	O
+cause	O
+acute	B
+renal	I
+failure	I
+when	O
+administered	O
+in	O
+high	O
+doses	O
+to	O
+adult	O
+patients	O
+.	O
+
+We	O
+report	O
+a	O
+4	O
+1	O
+/	O
+2	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+who	O
+was	O
+treated	O
+with	O
+high	O
+-	O
+dose	O
+carboplatin	O
+for	O
+metastatic	O
+parameningeal	O
+embryonal	B
+rhabdomyosarcoma	I
+.	O
+
+Acute	B
+renal	I
+failure	I
+developed	O
+followed	O
+by	O
+a	O
+slow	O
+partial	O
+recovery	O
+of	O
+renal	O
+function	O
+.	O
+
+Possible	O
+contributing	O
+factors	O
+are	O
+discussed	O
+.	O
+
+Clinical	O
+evaluation	O
+on	O
+combined	O
+administration	O
+of	O
+oral	O
+prostacyclin	O
+analogue	O
+beraprost	O
+and	O
+phosphodiesterase	O
+inhibitor	O
+cilostazol	O
+.	O
+
+Among	O
+various	O
+oral	O
+antiplatelets	O
+,	O
+a	O
+combination	O
+of	O
+a	O
+novel	O
+prostacyclin	O
+analogue	O
+beraprost	O
+(	O
+BPT	O
+)	O
+and	O
+a	O
+potent	O
+phosphodiesterase	O
+inhibitor	O
+cilostazol	O
+(	O
+CLZ	O
+)	O
+may	O
+result	O
+in	O
+untoward	O
+clinical	O
+effects	O
+due	O
+to	O
+possible	O
+synergistic	O
+elevation	O
+of	O
+intracellular	O
+cAMP	O
+(	O
+cyclic	O
+adenosine	O
+3	O
+'	O
+,	O
+5	O
+'	O
+-	O
+monophosphate	O
+)	O
+.	O
+
+Thereby	O
+,	O
+a	O
+clinical	O
+study	O
+of	O
+the	O
+combined	O
+administration	O
+of	O
+the	O
+two	O
+agents	O
+was	O
+attempted	O
+.	O
+
+Twelve	O
+healthy	O
+volunteers	O
+were	O
+assigned	O
+to	O
+take	O
+BPT	O
+/	O
+CLZ	O
+in	O
+the	O
+following	O
+schedule	O
+;	O
+BPT	O
+:	O
+40	O
+micrograms	O
+at	O
+day	O
+1	O
+and	O
+120	O
+micrograms	O
+t	O
+.	O
+i	O
+.	O
+d	O
+.	O
+from	O
+day	O
+7	O
+to	O
+14	O
+,	O
+CLZ	O
+:	O
+200	O
+mg	O
+t	O
+.	O
+i	O
+.	O
+d	O
+.	O
+from	O
+day	O
+3	O
+to	O
+14	O
+.	O
+
+At	O
+various	O
+time	O
+intervals	O
+,	O
+physical	O
+examination	O
+and	O
+blood	O
+collection	O
+for	O
+ex	O
+vivo	O
+platelet	B
+aggregation	I
+and	O
+determination	O
+of	O
+intraplatelet	O
+cAMP	O
+were	O
+performed	O
+.	O
+
+Throughout	O
+the	O
+observation	O
+period	O
+,	O
+no	O
+significant	O
+alteration	O
+in	O
+vital	O
+signs	O
+was	O
+observed	O
+.	O
+
+Seven	O
+out	O
+of	O
+12	O
+subjects	O
+experienced	O
+headache	B
+of	O
+a	O
+short	O
+duration	O
+accompanying	O
+facial	B
+flush	I
+in	O
+one	O
+and	O
+nausea	B
+in	O
+one	O
+,	O
+especially	O
+after	O
+ingestion	O
+of	O
+CLZ	O
+.	O
+
+All	O
+of	O
+these	O
+symptoms	O
+,	O
+probably	O
+caused	O
+by	O
+the	O
+vasodilating	O
+effect	O
+of	O
+the	O
+two	O
+agents	O
+,	O
+were	O
+of	O
+mild	O
+degree	O
+and	O
+no	O
+special	O
+treatment	O
+was	O
+required	O
+.	O
+
+Intraplatelet	O
+cAMP	O
+content	O
+was	O
+gradually	O
+but	O
+significantly	O
+increased	O
+to	O
+9	O
+.	O
+84	O
++	O
+/	O
+-	O
+4	O
+.	O
+59	O
+pmol	O
+per	O
+10	O
+(	O
+9	O
+)	O
+platelets	O
+at	O
+day	O
+14	O
+in	O
+comparison	O
+with	O
+the	O
+initial	O
+value	O
+(	O
+6	O
+.	O
+87	O
++	O
+/	O
+-	O
+2	O
+.	O
+25	O
+pmol	O
+)	O
+.	O
+
+The	O
+platelet	O
+aggregability	O
+was	O
+significantly	O
+suppressed	O
+at	O
+various	O
+time	O
+intervals	O
+but	O
+no	O
+additive	O
+or	O
+synergistic	O
+inhibitory	O
+effect	O
+by	O
+the	O
+combined	O
+administration	O
+was	O
+noted	O
+.	O
+
+In	O
+conclusion	O
+,	O
+the	O
+combined	O
+administration	O
+of	O
+BPT	O
+/	O
+CLZ	O
+is	O
+safe	O
+at	O
+doses	O
+used	O
+in	O
+the	O
+study	O
+,	O
+though	O
+the	O
+beneficial	O
+clinical	O
+effect	O
+of	O
+the	O
+combined	O
+administration	O
+has	O
+yet	O
+to	O
+be	O
+elucidated	O
+.	O
+
+Pravastatin	O
+-	O
+associated	O
+myopathy	B
+.	O
+
+Report	O
+of	O
+a	O
+case	O
+.	O
+
+A	O
+case	O
+of	O
+acute	O
+inflammatory	B
+myopathy	I
+associated	O
+with	O
+the	O
+use	O
+of	O
+pravastatin	O
+,	O
+a	O
+new	O
+hydrophilic	O
+3	O
+-	O
+hydroxy	O
+-	O
+3	O
+methylglutaril	O
+coenzyme	O
+A	O
+reductase	O
+inhibitor	O
+,	O
+is	O
+reported	O
+.	O
+
+The	O
+patient	O
+,	O
+a	O
+69	O
+-	O
+year	O
+-	O
+old	O
+man	O
+was	O
+affected	O
+by	O
+non	B
+-	I
+insulin	I
+-	I
+dependent	I
+diabetes	I
+mellitus	I
+and	O
+hypertension	B
+.	O
+
+He	O
+assumed	O
+pravastatin	O
+(	O
+20	O
+mg	O
+/	O
+day	O
+)	O
+because	O
+of	O
+hypercholesterolemia	B
+.	O
+
+He	O
+was	O
+admitted	O
+with	O
+acute	O
+myopathy	B
+of	O
+the	O
+lower	O
+limbs	O
+which	O
+resolved	O
+in	O
+a	O
+few	O
+days	O
+after	O
+pravastatin	O
+discontinuation	O
+.	O
+
+A	O
+previously	O
+unknown	O
+hypothyroidism	B
+,	O
+probably	O
+due	O
+to	O
+chronic	O
+autoimmune	B
+thyroiditis	I
+,	O
+was	O
+evidenced	O
+.	O
+
+Muscle	O
+biopsy	O
+(	O
+left	O
+gastrocnemius	O
+)	O
+revealed	O
+a	O
+perimysial	O
+and	O
+endomysial	O
+inflammatory	O
+infiltrate	O
+with	O
+a	O
+prevalence	O
+of	O
+CD4	O
++	O
+lymphocytes	O
+.	O
+
+While	O
+lovastatin	O
+and	O
+simvastatin	O
+have	O
+been	O
+associated	O
+with	O
+toxic	O
+myopathy	B
+,	O
+pravastatin	O
+-	O
+associated	O
+myopathy	B
+could	O
+represent	O
+a	O
+distinct	O
+,	O
+inflammatory	O
+entity	O
+.	O
+
+Reversal	O
+of	O
+ammonia	O
+coma	B
+in	O
+rats	O
+by	O
+L	O
+-	O
+dopa	O
+:	O
+a	O
+peripheral	O
+effect	O
+.	O
+
+Ammonia	O
+coma	B
+was	O
+produced	O
+in	O
+rats	O
+within	O
+10	O
+to	O
+15	O
+minutes	O
+of	O
+an	O
+intraperitonealinjection	O
+of	O
+1	O
+.	O
+7	O
+mmol	O
+NH4CL	O
+.	O
+
+This	O
+coma	B
+was	O
+prevented	O
+with	O
+1	O
+.	O
+68	O
+mmol	O
+L	O
+-	O
+dopa	O
+given	O
+by	O
+gastric	O
+intubation	O
+15	O
+minutes	O
+before	O
+the	O
+ammonium	O
+salt	O
+injection	O
+.	O
+
+The	O
+effect	O
+of	O
+L	O
+-	O
+dopa	O
+was	O
+correlated	O
+with	O
+a	O
+decrease	O
+in	O
+blood	O
+and	O
+brain	O
+ammonia	O
+,	O
+an	O
+increase	O
+in	O
+brain	O
+dopamine	O
+,	O
+and	O
+an	O
+increase	O
+in	O
+renal	O
+excretion	O
+of	O
+ammonia	O
+and	O
+urea	O
+.	O
+
+Intraventricular	O
+infusion	O
+of	O
+dopamine	O
+sufficient	O
+to	O
+raise	O
+the	O
+brain	O
+dopamine	O
+to	O
+the	O
+same	O
+extent	O
+did	O
+not	O
+prevent	O
+the	O
+ammonia	O
+coma	B
+nor	O
+affect	O
+the	O
+blood	O
+and	O
+brain	O
+ammonia	O
+concentrations	O
+.	O
+
+Bilateral	O
+nephrectomy	O
+eliminated	O
+the	O
+beneficial	O
+effect	O
+of	O
+L	O
+-	O
+dopa	O
+on	O
+blood	O
+and	O
+brain	O
+ammonia	O
+and	O
+the	O
+ammonia	O
+coma	B
+was	O
+not	O
+prevented	O
+.	O
+
+Thus	O
+,	O
+the	O
+reduction	O
+in	O
+blood	O
+and	O
+brain	O
+ammonia	O
+and	O
+the	O
+prevention	O
+of	O
+ammonia	O
+coma	B
+after	O
+L	O
+-	O
+dopa	O
+,	O
+can	O
+be	O
+accounted	O
+for	O
+by	O
+the	O
+peripheral	O
+effect	O
+of	O
+dopamine	O
+on	O
+renal	O
+function	O
+rather	O
+than	O
+its	O
+central	O
+action	O
+.	O
+
+These	O
+results	O
+provide	O
+a	O
+reasonable	O
+explanation	O
+for	O
+the	O
+beneficial	O
+effects	O
+observed	O
+in	O
+some	O
+encephalopathic	B
+patients	O
+receiving	O
+L	O
+-	O
+dopa	O
+.	O
+
+Etoposide	O
+-	O
+related	O
+myocardial	B
+infarction	I
+.	O
+
+The	O
+occurrence	O
+of	O
+a	O
+myocardial	B
+infarction	I
+is	O
+reported	O
+after	O
+chemotherapy	O
+containing	O
+etoposide	O
+,	O
+in	O
+a	O
+man	O
+with	O
+no	O
+risk	O
+factors	O
+for	O
+coronary	B
+heart	I
+disease	I
+.	O
+
+Possible	O
+causal	O
+mechanisms	O
+are	O
+discussed	O
+.	O
+
+Halogenated	O
+anesthetics	O
+form	O
+liver	O
+adducts	O
+and	O
+antigens	O
+that	O
+cross	O
+-	O
+react	O
+with	O
+halothane	O
+-	O
+induced	O
+antibodies	O
+.	O
+
+Two	O
+halogenated	O
+anesthetics	O
+,	O
+enflurane	O
+and	O
+isoflurane	O
+,	O
+have	O
+been	O
+associated	O
+with	O
+an	O
+allergic	O
+-	O
+type	O
+hepatic	B
+injury	I
+both	O
+alone	O
+and	O
+following	O
+previous	O
+exposure	O
+to	O
+halothane	O
+.	O
+
+Halothane	O
+hepatitis	B
+appears	O
+to	O
+involve	O
+an	O
+aberrant	O
+immune	O
+response	O
+.	O
+
+An	O
+antibody	O
+response	O
+to	O
+a	O
+protein	O
+-	O
+bound	O
+biotransformation	O
+product	O
+(	O
+trifluoroacetyl	O
+adduct	O
+)	O
+has	O
+been	O
+detected	O
+on	O
+halothane	O
+hepatitis	B
+patients	O
+.	O
+
+This	O
+study	O
+was	O
+performed	O
+to	O
+determine	O
+cross	O
+-	O
+reactivity	O
+between	O
+enflurane	O
+and	O
+isoflurane	O
+with	O
+the	O
+hypersensitivity	B
+induced	O
+by	O
+halothane	O
+.	O
+
+The	O
+subcellular	O
+and	O
+lobular	O
+production	O
+of	O
+hepatic	O
+neoantigens	O
+recognized	O
+by	O
+halothane	O
+-	O
+induced	O
+antibodies	O
+following	O
+enflurane	O
+and	O
+isoflurane	O
+,	O
+and	O
+the	O
+biochemical	O
+nature	O
+of	O
+these	O
+neoantigens	O
+was	O
+investigated	O
+in	O
+two	O
+animal	O
+models	O
+.	O
+
+Enflurane	O
+administration	O
+resulted	O
+in	O
+neoantigens	O
+detected	O
+in	O
+both	O
+the	O
+microsomal	O
+and	O
+cytosolic	O
+fraction	O
+of	O
+liver	O
+homogenates	O
+and	O
+in	O
+the	O
+centrilobular	O
+region	O
+of	O
+the	O
+liver	O
+.	O
+
+In	O
+the	O
+same	O
+liver	O
+,	O
+biochemical	O
+analysis	O
+detected	O
+fluorinated	O
+liver	O
+adducts	O
+that	O
+were	O
+up	O
+to	O
+20	O
+-	O
+fold	O
+greater	O
+in	O
+guinea	O
+pigs	O
+than	O
+in	O
+rats	O
+.	O
+
+This	O
+supports	O
+and	O
+extends	O
+previous	O
+evidence	O
+for	O
+a	O
+mechanism	O
+by	O
+which	O
+enflurane	O
+and	O
+/	O
+or	O
+isoflurane	O
+could	O
+produce	O
+a	O
+hypersensitivity	B
+condition	O
+similar	O
+to	O
+that	O
+of	O
+halothane	O
+hepatitis	B
+either	O
+alone	O
+or	O
+subsequent	O
+to	O
+halothane	O
+administration	O
+.	O
+
+The	O
+guinea	O
+pig	O
+would	O
+appear	O
+to	O
+be	O
+a	O
+useful	O
+model	O
+for	O
+further	O
+investigations	O
+of	O
+the	O
+immunological	O
+response	O
+to	O
+these	O
+antigens	O
+.	O
+
+Cholinergic	O
+toxicity	B
+resulting	O
+from	O
+ocular	O
+instillation	O
+of	O
+echothiophate	O
+iodide	O
+eye	O
+drops	O
+.	O
+
+A	O
+patient	O
+developed	O
+a	O
+severe	O
+cholinergic	O
+syndrome	O
+from	O
+the	O
+use	O
+of	O
+echothiophate	O
+iodide	O
+ophthalmic	O
+drops	O
+,	O
+presented	O
+with	O
+profound	O
+muscle	B
+weakness	I
+and	O
+was	O
+initially	O
+given	O
+the	O
+diagnosis	O
+of	O
+myasthenia	B
+gravis	I
+.	O
+
+Red	O
+blood	O
+cell	O
+and	O
+serum	O
+cholinesterase	O
+levels	O
+were	O
+severely	O
+depressed	O
+and	O
+symptoms	O
+resolved	O
+spontaneously	O
+following	O
+discontinuation	O
+of	O
+the	O
+eye	O
+drops	O
+.	O
+
+Seizure	B
+after	O
+flumazenil	O
+administration	O
+in	O
+a	O
+pediatric	O
+patient	O
+.	O
+
+Flumazenil	O
+is	O
+a	O
+benzodiazepine	O
+receptor	O
+antagonist	O
+used	O
+to	O
+reverse	O
+sedation	O
+and	O
+respiratory	B
+depression	I
+induced	O
+by	O
+benzodiazepines	O
+.	O
+
+Seizures	B
+and	O
+cardiac	B
+arrhythmias	I
+have	O
+complicated	O
+its	O
+use	O
+in	O
+adult	O
+patients	O
+.	O
+
+Overdose	B
+patients	O
+who	O
+have	O
+coingested	O
+tricyclic	O
+antidepressants	O
+have	O
+a	O
+higher	O
+risk	O
+of	O
+these	O
+complications	O
+.	O
+
+Little	O
+information	O
+exists	O
+concerning	O
+adverse	O
+effects	O
+of	O
+flumazenil	O
+in	O
+children	O
+.	O
+
+We	O
+report	O
+the	O
+occurrence	O
+of	O
+a	O
+generalized	O
+tonic	B
+-	I
+clonic	I
+seizure	I
+in	O
+a	O
+pediatric	O
+patient	O
+following	O
+the	O
+administration	O
+of	O
+flumazenil	O
+.	O
+
+Phase	O
+I	O
+trial	O
+of	O
+13	O
+-	O
+cis	O
+-	O
+retinoic	O
+acid	O
+in	O
+children	O
+with	O
+neuroblastoma	B
+following	O
+bone	O
+marrow	O
+transplantation	O
+.	O
+
+PURPOSE	O
+:	O
+Treatment	O
+of	O
+neuroblastoma	B
+cell	O
+lines	O
+with	O
+13	O
+-	O
+cis	O
+-	O
+retinoic	O
+acid	O
+(	O
+cis	O
+-	O
+RA	O
+)	O
+can	O
+cause	O
+sustained	O
+inhibition	O
+of	O
+proliferation	O
+.	O
+
+Since	O
+cis	O
+-	O
+RA	O
+has	O
+demonstrated	O
+clinical	O
+responses	O
+in	O
+neuroblastoma	B
+patients	O
+,	O
+it	O
+may	O
+be	O
+effective	O
+in	O
+preventing	O
+relapse	O
+after	O
+cytotoxic	O
+therapy	O
+.	O
+
+This	O
+phase	O
+I	O
+trial	O
+was	O
+designed	O
+to	O
+determine	O
+the	O
+maximal	O
+-	O
+tolerated	O
+dosage	O
+(	O
+MTD	O
+)	O
+,	O
+toxicities	B
+,	O
+and	O
+pharmacokinetics	O
+of	O
+cis	O
+-	O
+RA	O
+administered	O
+on	O
+an	O
+intermittent	O
+schedule	O
+in	O
+children	O
+with	O
+neuroblastoma	B
+following	O
+bone	O
+marrow	O
+transplantation	O
+(	O
+BMT	O
+)	O
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+Fifty	O
+-	O
+one	O
+assessable	O
+patients	O
+,	O
+2	O
+to	O
+12	O
+years	O
+of	O
+age	O
+,	O
+were	O
+treated	O
+with	O
+oral	O
+cis	O
+-	O
+RA	O
+administered	O
+in	O
+two	O
+equally	O
+divided	O
+doses	O
+daily	O
+for	O
+2	O
+weeks	O
+,	O
+followed	O
+by	O
+a	O
+2	O
+-	O
+week	O
+rest	O
+period	O
+,	O
+for	O
+up	O
+to	O
+12	O
+courses	O
+.	O
+
+The	O
+dose	O
+was	O
+escalated	O
+from	O
+100	O
+to	O
+200	O
+mg	O
+/	O
+m2	O
+/	O
+d	O
+until	O
+dose	O
+-	O
+limiting	O
+toxicity	B
+(	O
+DLT	O
+)	O
+was	O
+observed	O
+.	O
+
+A	O
+single	O
+intrapatient	O
+dose	O
+escalation	O
+was	O
+permitted	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+MTD	O
+of	O
+cis	O
+-	O
+RA	O
+was	O
+160	O
+mg	O
+/	O
+m2	O
+/	O
+d	O
+.	O
+
+Dose	O
+-	O
+limiting	O
+toxicities	B
+in	O
+six	O
+of	O
+nine	O
+patients	O
+at	O
+200	O
+mg	O
+/	O
+m2	O
+/	O
+d	O
+included	O
+hypercalcemia	B
+(	O
+n	O
+=	O
+3	O
+)	O
+,	O
+rash	B
+(	O
+n	O
+=	O
+2	O
+)	O
+,	O
+and	O
+anemia	B
+/	O
+thrombocytopenia	B
+/	O
+emesis	B
+/	O
+rash	B
+(	O
+n	O
+=	O
+1	O
+)	O
+.	O
+
+All	O
+toxicities	B
+resolved	O
+after	O
+cis	O
+-	O
+RA	O
+was	O
+discontinued	O
+.	O
+
+Three	O
+complete	O
+responses	O
+were	O
+observed	O
+in	O
+marrow	O
+metastases	B
+.	O
+
+Serum	O
+levels	O
+of	O
+7	O
+.	O
+4	O
++	O
+/	O
+-	O
+3	O
+.	O
+0	O
+mumol	O
+/	O
+L	O
+(	O
+peak	O
+)	O
+and	O
+4	O
+.	O
+0	O
++	O
+/	O
+-	O
+2	O
+.	O
+8	O
+mumol	O
+/	O
+L	O
+(	O
+trough	O
+)	O
+at	O
+the	O
+MTD	O
+were	O
+maintained	O
+during	O
+14	O
+days	O
+of	O
+therapy	O
+.	O
+
+The	O
+DLT	O
+correlated	O
+with	O
+serum	O
+levels	O
+>	O
+or	O
+=	O
+10	O
+mumol	O
+/	O
+L	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+MTD	O
+of	O
+cis	O
+-	O
+RA	O
+given	O
+on	O
+this	O
+intermittent	O
+schedule	O
+was	O
+160	O
+mg	O
+/	O
+m2	O
+/	O
+d	O
+.	O
+
+Serum	O
+levels	O
+known	O
+to	O
+be	O
+effective	O
+against	O
+neuroblastoma	B
+in	O
+vitro	O
+were	O
+achieved	O
+at	O
+this	O
+dose	O
+.	O
+
+The	O
+DLT	O
+included	O
+hypercalcemia	B
+,	O
+and	O
+may	O
+be	O
+predicted	O
+by	O
+serum	O
+cis	O
+-	O
+RA	O
+levels	O
+.	O
+
+Monitoring	O
+of	O
+serum	O
+calcium	O
+and	O
+cis	O
+-	O
+RA	O
+levels	O
+is	O
+indicated	O
+in	O
+future	O
+trials	O
+.	O
+
+Time	O
+dependence	O
+of	O
+plasma	O
+malondialdehyde	O
+,	O
+oxypurines	O
+,	O
+and	O
+nucleosides	O
+during	O
+incomplete	O
+cerebral	B
+ischemia	I
+in	O
+the	O
+rat	O
+.	O
+
+Incomplete	O
+cerebral	B
+ischemia	I
+(	O
+30	O
+min	O
+)	O
+was	O
+induced	O
+in	O
+the	O
+rat	O
+by	O
+bilaterally	O
+clamping	O
+the	O
+common	O
+carotid	O
+arteries	O
+.	O
+
+Peripheral	O
+venous	O
+blood	O
+samples	O
+were	O
+withdrawn	O
+from	O
+the	O
+femoral	O
+vein	O
+four	O
+times	O
+(	O
+once	O
+every	O
+5	O
+min	O
+)	O
+before	O
+ischemia	B
+(	O
+0	O
+time	O
+)	O
+and	O
+5	O
+,	O
+15	O
+,	O
+and	O
+30	O
+min	O
+after	O
+ischemia	B
+.	O
+
+Plasma	O
+extracts	O
+were	O
+analyzed	O
+by	O
+a	O
+highly	O
+sensitive	O
+high	O
+-	O
+performance	O
+liquid	O
+chromatographic	O
+method	O
+for	O
+the	O
+direct	O
+determination	O
+of	O
+malondialdehyde	O
+,	O
+oxypurines	O
+,	O
+and	O
+nucleosides	O
+.	O
+
+During	O
+ischemia	B
+,	O
+a	O
+time	O
+-	O
+dependent	O
+increase	O
+of	O
+plasma	O
+oxypurines	O
+and	O
+nucleosides	O
+was	O
+observed	O
+.	O
+
+Plasma	O
+malondialdehyde	O
+,	O
+which	O
+was	O
+present	O
+in	O
+minimal	O
+amount	O
+at	O
+zero	O
+time	O
+(	O
+0	O
+.	O
+058	O
+mumol	O
+/	O
+liter	O
+plasma	O
+;	O
+SD	O
+0	O
+.	O
+015	O
+)	O
+,	O
+increased	O
+after	O
+5	O
+min	O
+of	O
+ischemia	B
+,	O
+resulting	O
+in	O
+a	O
+fivefold	O
+increase	O
+after	O
+30	O
+min	O
+of	O
+carotid	O
+occlusion	O
+(	O
+0	O
+.	O
+298	O
+mumol	O
+/	O
+liter	O
+plasma	O
+;	O
+SD	O
+0	O
+.	O
+078	O
+)	O
+.	O
+
+Increased	O
+plasma	O
+malondialdehyde	O
+was	O
+also	O
+recorded	O
+in	O
+two	O
+other	O
+groups	O
+of	O
+animals	O
+subjected	O
+to	O
+the	O
+same	O
+experimental	O
+model	O
+,	O
+one	O
+receiving	O
+20	O
+mg	O
+/	O
+kg	O
+b	O
+.	O
+w	O
+.	O
+of	O
+the	O
+cyclooxygenase	O
+inhibitor	O
+acetylsalicylate	O
+intravenously	O
+immediately	O
+before	O
+ischemia	B
+,	O
+the	O
+other	O
+receiving	O
+650	O
+micrograms	O
+/	O
+kg	O
+b	O
+.	O
+w	O
+.	O
+of	O
+the	O
+hypotensive	B
+drug	O
+nitroprusside	O
+at	O
+a	O
+flow	O
+rate	O
+of	O
+103	O
+microliters	O
+/	O
+min	O
+intravenously	O
+during	O
+ischemia	B
+,	O
+although	O
+in	O
+this	O
+latter	O
+group	O
+malondialdehyde	O
+was	O
+significantly	O
+higher	O
+.	O
+
+The	O
+present	O
+data	O
+indicate	O
+that	O
+the	O
+determination	O
+of	O
+malondialdehyde	O
+,	O
+oxypurines	O
+,	O
+and	O
+nucleosides	O
+in	O
+peripheral	O
+blood	O
+,	O
+may	O
+be	O
+used	O
+to	O
+monitor	O
+the	O
+metabolic	O
+alterations	O
+of	O
+tissues	O
+occurring	O
+during	O
+ischemic	B
+phenomena	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Acute	O
+renal	B
+toxicity	I
+of	O
+doxorubicin	O
+(	O
+adriamycin	O
+)	O
+-	O
+loaded	O
+cyanoacrylate	O
+nanoparticles	O
+.	O
+
+Acute	O
+doxorubicin	O
+-	O
+loaded	O
+nanoparticle	O
+(	O
+DXNP	O
+)	O
+renal	B
+toxicity	I
+was	O
+explored	O
+in	O
+both	O
+normal	O
+rats	O
+and	O
+rats	O
+with	O
+experimental	O
+glomerulonephritis	B
+.	O
+
+In	O
+normal	O
+rats	O
+,	O
+2	O
+/	O
+6	O
+rats	O
+given	O
+free	O
+doxorubicin	O
+(	O
+DX	O
+)	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+died	O
+within	O
+one	O
+week	O
+,	O
+whereas	O
+all	O
+control	O
+animals	O
+and	O
+all	O
+rats	O
+having	O
+received	O
+free	O
+NP	O
+or	O
+DXNP	O
+survived	O
+.	O
+
+A	O
+3	O
+times	O
+higher	O
+proteinuria	B
+appeared	O
+in	O
+animals	O
+treated	O
+with	O
+DXNP	O
+than	O
+in	O
+those	O
+treated	O
+with	O
+DX	O
+.	O
+
+Free	O
+NP	O
+did	O
+not	O
+provoke	O
+any	O
+proteinuria	B
+.	O
+
+Two	O
+hr	O
+post	O
+-	O
+injection	O
+,	O
+DXNP	O
+was	O
+2	O
+.	O
+7	O
+times	O
+more	O
+concentrated	O
+in	O
+kidneys	O
+than	O
+free	O
+DX	O
+(	O
+p	O
+<	O
+0	O
+.	O
+025	O
+)	O
+.	O
+
+In	O
+rats	O
+with	O
+immune	O
+experimental	O
+glomerulonephritis	B
+,	O
+5	O
+/	O
+6	O
+rats	O
+given	O
+DX	O
+died	O
+within	O
+7	O
+days	O
+,	O
+in	O
+contrast	O
+to	O
+animals	O
+treated	O
+by	O
+DXNP	O
+,	O
+NP	O
+,	O
+or	O
+untreated	O
+,	O
+which	O
+all	O
+survived	O
+.	O
+
+Proteinuria	B
+appeared	O
+in	O
+all	O
+series	O
+,	O
+but	O
+was	O
+2	O
+-	O
+5	O
+times	O
+more	O
+intense	O
+(	O
+p	O
+>	O
+0	O
+.	O
+001	O
+)	O
+and	O
+prolonged	O
+after	O
+doxorubicin	O
+treatment	O
+(	O
+400	O
+-	O
+700	O
+mg	O
+/	O
+day	O
+)	O
+,	O
+without	O
+significant	O
+difference	O
+between	O
+DXNP	O
+and	O
+DX	O
+.	O
+
+Rats	O
+treated	O
+by	O
+unloaded	O
+NP	O
+behaved	O
+as	O
+controls	O
+.	O
+
+These	O
+results	O
+demonstrate	O
+that	O
+,	O
+in	O
+these	O
+experimental	O
+conditions	O
+,	O
+DXNP	O
+killed	O
+less	O
+animals	O
+than	O
+free	O
+DX	O
+,	O
+despite	O
+of	O
+an	O
+enhanced	O
+renal	B
+toxicity	I
+of	O
+the	O
+former	O
+.	O
+
+Both	O
+effects	O
+(	O
+better	O
+survival	O
+and	O
+nephrosis	B
+)	O
+are	O
+most	O
+probably	O
+related	O
+to	O
+an	O
+enhanced	O
+capture	O
+of	O
+DXNP	O
+by	O
+cells	O
+of	O
+the	O
+mononuclear	O
+phagocyte	O
+system	O
+,	O
+including	O
+mesangial	O
+cells	O
+.	O
+
+Prostaglandin	O
+E2	O
+-	O
+induced	O
+bladder	B
+hyperactivity	I
+in	O
+normal	O
+,	O
+conscious	O
+rats	O
+:	O
+involvement	O
+of	O
+tachykinins	O
+?	O
+
+In	O
+normal	O
+conscious	O
+rats	O
+investigated	O
+by	O
+continuous	O
+cystometry	O
+,	O
+intravesically	O
+instilled	O
+prostaglandin	O
+(	O
+PG	O
+)	O
+E2	O
+facilitated	O
+micturition	O
+and	O
+increased	O
+basal	O
+intravesical	O
+pressure	O
+.	O
+
+The	O
+effect	O
+was	O
+attenuated	O
+by	O
+both	O
+the	O
+NK1	O
+receptor	O
+selective	O
+antagonist	O
+RP	O
+67	O
+,	O
+580	O
+and	O
+the	O
+NK2	O
+receptor	O
+selective	O
+antagonist	O
+SR	O
+48	O
+,	O
+968	O
+,	O
+given	O
+intra	O
+-	O
+arterially	O
+,	O
+suggesting	O
+that	O
+it	O
+was	O
+mediated	O
+by	O
+stimulation	O
+of	O
+both	O
+NK1	O
+and	O
+NK2	O
+receptors	O
+.	O
+
+Intra	O
+-	O
+arterially	O
+given	O
+PGE2	O
+produced	O
+a	O
+distinct	O
+increase	O
+in	O
+bladder	O
+pressure	O
+before	O
+initiating	O
+a	O
+micturition	O
+reflex	O
+,	O
+indicating	O
+that	O
+the	O
+PG	O
+had	O
+a	O
+direct	O
+contractant	O
+effect	O
+on	O
+the	O
+detrusor	O
+smooth	O
+muscle	O
+.	O
+
+The	O
+effect	O
+of	O
+intra	O
+-	O
+arterial	O
+PGE2	O
+could	O
+not	O
+be	O
+blocked	O
+by	O
+intra	O
+-	O
+arterial	O
+RP	O
+67	O
+,	O
+580	O
+or	O
+SR	O
+48	O
+,	O
+968	O
+,	O
+which	O
+opens	O
+the	O
+possibility	O
+that	O
+the	O
+micturition	O
+reflex	O
+elicited	O
+by	O
+intra	O
+-	O
+arterial	O
+PGE2	O
+was	O
+mediated	O
+by	O
+pathways	O
+other	O
+than	O
+the	O
+reflex	O
+initiated	O
+when	O
+the	O
+PG	O
+was	O
+given	O
+intravesically	O
+.	O
+
+The	O
+present	O
+results	O
+thus	O
+suggest	O
+that	O
+intra	O
+-	O
+arterial	O
+PGE2	O
+,	O
+given	O
+near	O
+the	O
+bladder	O
+,	O
+may	O
+initiate	O
+micturition	O
+in	O
+the	O
+normal	O
+rat	O
+chiefly	O
+by	O
+directly	O
+contracting	O
+the	O
+smooth	O
+muscle	O
+of	O
+the	O
+detrusor	O
+.	O
+
+However	O
+,	O
+when	O
+given	O
+intravesically	O
+,	O
+PGE2	O
+may	O
+stimulate	O
+micturition	O
+by	O
+releasing	O
+tachykinins	O
+from	O
+nerves	O
+in	O
+and	O
+/	O
+or	O
+immediately	O
+below	O
+the	O
+urothelium	O
+.	O
+
+These	O
+tachykinins	O
+,	O
+in	O
+turn	O
+,	O
+initiate	O
+a	O
+micturition	O
+reflex	O
+by	O
+stimulating	O
+NK1	O
+and	O
+NK2	O
+receptors	O
+.	O
+
+Prostanoids	O
+may	O
+,	O
+via	O
+release	O
+of	O
+tachykinins	O
+,	O
+contribute	O
+to	O
+both	O
+urge	O
+and	O
+bladder	B
+hyperactivity	I
+seen	O
+in	O
+inflammatory	O
+conditions	O
+of	O
+the	O
+lower	O
+urinary	O
+tract	O
+.	O
+
+Refractory	O
+cardiogenic	B
+shock	I
+and	O
+complete	O
+heart	B
+block	I
+after	O
+verapamil	O
+SR	O
+and	O
+metoprolol	O
+treatment	O
+.	O
+
+A	O
+case	O
+report	O
+.	O
+
+A	O
+seventy	O
+-	O
+eight	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+presented	O
+with	O
+complete	O
+heart	B
+block	I
+and	O
+refractory	O
+hypotension	B
+two	O
+days	O
+after	O
+a	O
+therapeutic	O
+dose	O
+of	O
+sustained	O
+-	O
+release	O
+verapamil	O
+with	O
+concomitant	O
+use	O
+of	O
+metoprolol	O
+.	O
+
+The	O
+patient	O
+continued	O
+to	O
+remain	O
+hypotensive	B
+with	O
+complete	O
+heart	B
+block	I
+,	O
+even	O
+with	O
+multiple	O
+uses	O
+of	O
+intravenous	O
+atropine	O
+as	O
+well	O
+as	O
+high	O
+doses	O
+of	O
+pressor	O
+agents	O
+such	O
+as	O
+dopamine	O
+and	O
+dobutamine	O
+.	O
+
+However	O
+,	O
+shortly	O
+after	O
+the	O
+use	O
+of	O
+intravenous	O
+calcium	O
+chloride	O
+,	O
+the	O
+refractory	O
+hypotension	B
+and	O
+complete	O
+heart	B
+block	I
+resolved	O
+.	O
+
+Protective	O
+effect	O
+of	O
+misoprostol	O
+on	O
+indomethacin	O
+induced	O
+renal	B
+dysfunction	I
+in	O
+elderly	O
+patients	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+evaluate	O
+the	O
+possible	O
+protective	O
+effects	O
+of	O
+misoprostol	O
+on	O
+renal	O
+function	O
+in	O
+hospitalized	O
+elderly	O
+patients	O
+treated	O
+with	O
+indomethacin	O
+.	O
+
+METHODS	O
+:	O
+Forty	O
+-	O
+five	O
+hospitalized	O
+elderly	O
+patients	O
+(	O
+>	O
+65	O
+years	O
+old	O
+)	O
+who	O
+required	O
+therapy	O
+with	O
+nonsteroidal	O
+antiinflammatory	O
+drugs	O
+(	O
+NSAID	O
+)	O
+were	O
+randomly	O
+assigned	O
+to	O
+receive	O
+either	O
+indomethacin	O
+,	O
+150	O
+mg	O
+/	O
+day	O
+(	O
+Group	O
+A	O
+)	O
+,	O
+or	O
+indomethacin	O
+150	O
+mg	O
+/	O
+day	O
+plus	O
+misoprostol	O
+at	O
+0	O
+.	O
+6	O
+mg	O
+/	O
+day	O
+(	O
+Group	O
+B	O
+)	O
+.	O
+
+Laboratory	O
+variables	O
+of	O
+renal	O
+function	O
+[	O
+serum	O
+creatinine	O
+,	O
+blood	O
+urea	O
+nitrogen	O
+(	O
+BUN	O
+)	O
+and	O
+electrolytes	O
+]	O
+were	O
+evaluated	O
+before	O
+initiation	O
+of	O
+therapy	O
+and	O
+every	O
+2	O
+days	O
+,	O
+until	O
+termination	O
+of	O
+the	O
+study	O
+(	O
+a	O
+period	O
+of	O
+at	O
+least	O
+6	O
+days	O
+)	O
+.	O
+
+Response	O
+to	O
+treatment	O
+was	O
+estimated	O
+by	O
+the	O
+visual	O
+analog	O
+scale	O
+for	O
+severity	O
+of	O
+pain	B
+.	O
+
+RESULTS	O
+:	O
+Forty	O
+-	O
+two	O
+patients	O
+completed	O
+the	O
+study	O
+,	O
+22	O
+in	O
+Group	O
+A	O
+and	O
+20	O
+in	O
+Group	O
+B	O
+.	O
+
+BUN	O
+and	O
+creatinine	O
+increased	O
+by	O
+>	O
+50	O
+%	O
+of	O
+baseline	O
+levels	O
+in	O
+54	O
+and	O
+45	O
+%	O
+of	O
+Group	O
+A	O
+patients	O
+,	O
+respectively	O
+,	O
+compared	O
+to	O
+only	O
+20	O
+and	O
+10	O
+%	O
+of	O
+Group	O
+B	O
+patients	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Potassium	O
+(	O
+K	O
+)	O
+increment	O
+of	O
+0	O
+.	O
+6	O
+mEq	O
+/	O
+l	O
+or	O
+more	O
+was	O
+observed	O
+in	O
+50	O
+%	O
+of	O
+Group	O
+A	O
+,	O
+but	O
+in	O
+only	O
+15	O
+%	O
+of	O
+Group	O
+B	O
+patients	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+The	O
+mean	O
+increments	O
+in	O
+BUN	O
+,	O
+creatinine	O
+,	O
+and	O
+K	O
+were	O
+reduced	O
+by	O
+63	O
+,	O
+80	O
+,	O
+and	O
+42	O
+%	O
+,	O
+respectively	O
+,	O
+in	O
+Group	O
+B	O
+patients	O
+compared	O
+to	O
+Group	O
+A	O
+.	O
+Response	O
+to	O
+treatment	O
+did	O
+not	O
+differ	O
+significantly	O
+between	O
+the	O
+2	O
+groups	O
+.	O
+
+CONCLUSION	O
+:	O
+Hospitalized	O
+elderly	O
+patients	O
+are	O
+at	O
+risk	O
+for	O
+developing	O
+indomethacin	O
+related	O
+renal	B
+dysfunction	I
+.	O
+
+Addition	O
+of	O
+misoprostol	O
+can	O
+minimize	O
+this	O
+renal	B
+impairment	I
+without	O
+affecting	O
+pain	B
+control	O
+.	O
+
+Cognitive	B
+deterioration	I
+from	O
+long	O
+-	O
+term	O
+abuse	O
+of	O
+dextromethorphan	O
+:	O
+a	O
+case	O
+report	O
+.	O
+
+Dextromethorphan	O
+(	O
+DM	O
+)	O
+,	O
+the	O
+dextrorotatory	O
+isomer	O
+of	O
+3	O
+-	O
+hydroxy	O
+-	O
+N	O
+-	O
+methylmorphinan	O
+,	O
+is	O
+the	O
+main	O
+ingredient	O
+in	O
+a	O
+number	O
+of	O
+widely	O
+available	O
+,	O
+over	O
+-	O
+the	O
+-	O
+counter	O
+antitussives	O
+.	O
+
+Initial	O
+studies	O
+(	O
+Bornstein	O
+1968	O
+)	O
+showed	O
+that	O
+it	O
+possessed	O
+no	O
+respiratory	O
+suppressant	O
+effects	O
+and	O
+no	O
+addiction	O
+liability	O
+.	O
+
+Subsequently	O
+,	O
+however	O
+,	O
+several	O
+articles	O
+reporting	O
+abuse	O
+of	O
+this	O
+drug	O
+have	O
+appeared	O
+in	O
+the	O
+literature	O
+.	O
+
+The	O
+drug	O
+is	O
+known	O
+to	O
+cause	O
+a	O
+variety	O
+of	O
+acute	O
+toxic	O
+effects	O
+,	O
+ranging	O
+from	O
+nausea	B
+,	O
+restlessness	B
+,	O
+insomnia	B
+,	O
+ataxia	B
+,	O
+slurred	O
+speech	O
+and	O
+nystagmus	B
+to	O
+mood	O
+changes	O
+,	O
+perceptual	O
+alterations	O
+,	O
+inattention	O
+,	O
+disorientation	O
+and	O
+aggressive	B
+behavior	I
+(	O
+Rammer	O
+et	O
+al	O
+1988	O
+;	O
+Katona	O
+and	O
+Watson	O
+1986	O
+;	O
+Isbell	O
+and	O
+Fraser	O
+1953	O
+;	O
+Devlin	O
+et	O
+al	O
+1985	O
+;	O
+McCarthy	O
+1971	O
+;	O
+Dodds	O
+and	O
+Revai	O
+1967	O
+;	O
+Degkwitz	O
+1964	O
+;	O
+Hildebrand	O
+et	O
+al	O
+1989	O
+)	O
+.	O
+
+There	O
+have	O
+also	O
+been	O
+two	O
+reported	O
+fatalities	O
+from	O
+DM	O
+overdoses	O
+(	O
+Fleming	O
+1986	O
+)	O
+.	O
+
+However	O
+,	O
+there	O
+are	O
+no	O
+reports	O
+describing	O
+the	O
+effects	O
+of	O
+chronic	O
+abuse	O
+.	O
+
+This	O
+report	O
+describes	O
+a	O
+case	O
+of	O
+cognitive	B
+deterioration	I
+resulting	O
+from	O
+prolonged	O
+use	O
+of	O
+DM	O
+.	O
+
+Effects	O
+of	O
+ouabain	O
+on	O
+myocardial	O
+oxygen	O
+supply	O
+and	O
+demand	O
+in	O
+patients	O
+with	O
+chronic	O
+coronary	B
+artery	I
+disease	I
+.	O
+
+A	O
+hemodynamic	O
+,	O
+volumetric	O
+,	O
+and	O
+metabolic	O
+study	O
+in	O
+patients	O
+without	O
+heart	B
+failure	I
+.	O
+
+The	O
+effects	O
+of	O
+digitalis	O
+glycosides	O
+on	O
+myocardial	O
+oxygen	O
+supply	O
+and	O
+demand	O
+are	O
+of	O
+particular	O
+interest	O
+in	O
+the	O
+presence	O
+of	O
+obstructive	O
+coronary	B
+artery	I
+disease	I
+,	O
+but	O
+have	O
+not	O
+been	O
+measured	O
+previously	O
+in	O
+man	O
+.	O
+
+We	O
+assessed	O
+the	O
+effects	O
+of	O
+ouabain	O
+(	O
+0	O
+.	O
+015	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+)	O
+on	O
+hemodynamic	O
+,	O
+volumetric	O
+,	O
+and	O
+metabolic	O
+parameters	O
+in	O
+11	O
+patients	O
+with	O
+severe	O
+chronic	O
+coronary	B
+artery	I
+disease	I
+without	O
+clinical	O
+congestive	B
+heart	I
+failure	I
+.	O
+
+Because	O
+the	O
+protocol	O
+was	O
+long	O
+and	O
+involved	O
+interventions	O
+which	O
+might	O
+affect	O
+the	O
+determinations	O
+,	O
+we	O
+also	O
+studied	O
+in	O
+nine	O
+patients	O
+using	O
+an	O
+identical	O
+protocol	O
+except	O
+that	O
+ouabain	O
+administration	O
+was	O
+omitted	O
+.	O
+
+Left	O
+ventricular	O
+end	O
+-	O
+diastolic	O
+pressure	O
+and	O
+left	O
+ventricular	O
+end	O
+-	O
+diastolic	O
+volume	O
+fell	O
+in	O
+each	O
+patient	O
+given	O
+ouabain	O
+,	O
+even	O
+though	O
+they	O
+were	O
+initially	O
+elevated	O
+in	O
+only	O
+two	O
+patients	O
+.	O
+
+Left	O
+ventricular	O
+end	O
+-	O
+diastolic	O
+pressure	O
+fell	O
+from	O
+11	O
+.	O
+5	O
++	O
+/	O
+-	O
+1	O
+.	O
+4	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SE	O
+)	O
+to	O
+5	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+9	O
+mm	O
+Hg	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+001	O
+)	O
+and	O
+left	O
+ventricular	O
+end	O
+-	O
+diastolic	O
+volume	O
+fell	O
+from	O
+100	O
++	O
+/	O
+-	O
+17	O
+to	O
+82	O
++	O
+/	O
+-	O
+12	O
+ml	O
+/	O
+m2	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+1	O
+h	O
+after	O
+ouabain	O
+infusion	O
+was	O
+completed	O
+.	O
+
+The	O
+maximum	O
+velocity	O
+of	O
+contractile	O
+element	O
+shortening	O
+increased	O
+from	O
+1	O
+.	O
+68	O
++	O
+/	O
+-	O
+0	O
+.	O
+11	O
+ml	O
+/	O
+s	O
+to	O
+2	O
+.	O
+18	O
++	O
+/	O
+-	O
+0	O
+.	O
+21	O
+muscle	O
+-	O
+lengths	O
+/	O
+s	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+05	O
+)	O
+and	O
+is	O
+consistent	O
+with	O
+an	O
+increase	O
+in	O
+contractility	O
+.	O
+
+No	O
+significant	O
+change	O
+in	O
+these	O
+parameters	O
+occurred	O
+in	O
+the	O
+control	O
+patients	O
+.	O
+
+No	O
+significant	O
+change	O
+in	O
+myocardial	O
+oxygen	O
+consumption	O
+occurred	O
+after	O
+ouabain	O
+administration	O
+but	O
+this	O
+may	O
+be	O
+related	O
+to	O
+a	O
+greater	O
+decrease	O
+in	O
+mean	O
+arterial	O
+pressure	O
+in	O
+the	O
+ouabain	O
+patients	O
+than	O
+in	O
+the	O
+control	O
+patients	O
+.	O
+
+We	O
+conclude	O
+that	O
+in	O
+patients	O
+with	O
+chronic	O
+coronary	B
+artery	I
+disease	I
+who	O
+are	O
+not	O
+in	O
+clinical	O
+congestive	B
+heart	I
+failure	I
+left	B
+ventricular	I
+end	I
+-	I
+diastolic	I
+volume	I
+falls	I
+after	O
+ouabain	O
+administration	O
+even	O
+when	O
+it	O
+is	O
+initially	O
+normal	O
+.	O
+
+Though	O
+this	O
+fall	O
+would	O
+be	O
+associated	O
+with	O
+a	O
+decrease	O
+in	O
+wall	O
+tension	O
+,	O
+and	O
+,	O
+therefore	O
+,	O
+of	O
+myocardial	O
+oxygen	O
+consumption	O
+,	O
+it	O
+may	O
+not	O
+be	O
+of	O
+sufficient	O
+magnitude	O
+to	O
+prevent	O
+a	O
+net	O
+increase	O
+in	O
+myocardial	O
+oxygen	O
+consumption	O
+.	O
+
+Nevertheless	O
+,	O
+compensatory	O
+mechanisms	O
+prevent	O
+a	O
+deterioration	O
+of	O
+resting	O
+myocardial	O
+metabolism	O
+.	O
+
+Dexamethasone	O
+-	O
+induced	O
+ocular	B
+hypertension	I
+in	O
+perfusion	O
+-	O
+cultured	O
+human	O
+eyes	O
+.	O
+
+PURPOSE	O
+:	O
+Glucocorticoid	O
+administration	O
+can	O
+lead	O
+to	O
+the	O
+development	O
+of	O
+ocular	B
+hypertension	I
+and	O
+corticosteroid	B
+glaucoma	I
+in	O
+a	O
+subset	O
+of	O
+the	O
+population	O
+through	O
+a	O
+decrease	O
+in	O
+the	O
+aqueous	O
+humor	O
+outflow	O
+facility	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+whether	O
+glucocorticoid	O
+treatment	O
+can	O
+directly	O
+affect	O
+the	O
+outflow	O
+facility	O
+of	O
+isolated	O
+,	O
+perfusion	O
+-	O
+cultured	O
+human	O
+eyes	O
+.	O
+
+METHODS	O
+:	O
+The	O
+anterior	O
+segments	O
+of	O
+human	O
+donor	O
+eyes	O
+from	O
+regional	O
+eye	O
+banks	O
+were	O
+placed	O
+in	O
+a	O
+constant	O
+flow	O
+,	O
+variable	O
+pressure	O
+perfusion	O
+culture	O
+system	O
+.	O
+
+Paired	O
+eyes	O
+were	O
+perfused	O
+in	O
+serum	O
+-	O
+free	O
+media	O
+with	O
+or	O
+without	O
+10	O
+(	O
+-	O
+7	O
+)	O
+M	O
+dexamethasone	O
+for	O
+12	O
+days	O
+.	O
+
+Intraocular	O
+pressure	O
+was	O
+monitored	O
+daily	O
+.	O
+
+After	O
+incubation	O
+,	O
+the	O
+eyes	O
+were	O
+morphologically	O
+characterized	O
+by	O
+light	O
+microscopy	O
+,	O
+transmission	O
+and	O
+scanning	O
+electron	O
+microscopy	O
+,	O
+and	O
+scanning	O
+laser	O
+confocal	O
+microscopy	O
+.	O
+
+RESULTS	O
+:	O
+A	O
+significant	O
+increase	O
+in	O
+intraocular	O
+pressure	O
+developed	O
+in	O
+13	O
+of	O
+the	O
+44	O
+pairs	O
+of	O
+eyes	O
+perfused	O
+with	O
+dexamethasone	O
+with	O
+an	O
+average	O
+pressure	O
+rise	O
+of	O
+17	O
+.	O
+5	O
++	O
+/	O
+-	O
+3	O
+.	O
+8	O
+mm	O
+Hg	O
+after	O
+12	O
+days	O
+of	O
+dexamethasone	O
+exposure	O
+.	O
+
+The	O
+contralateral	O
+control	O
+eyes	O
+,	O
+which	O
+did	O
+not	O
+receive	O
+dexamethasone	O
+,	O
+maintained	O
+a	O
+stable	O
+intraocular	O
+pressure	O
+during	O
+the	O
+same	O
+period	O
+.	O
+
+The	O
+outflow	O
+pathway	O
+of	O
+the	O
+untreated	O
+eyes	O
+appeared	O
+morphologically	O
+normal	O
+.	O
+
+In	O
+contrast	O
+,	O
+the	O
+dexamethasone	O
+-	O
+treated	O
+hypertensive	B
+eyes	I
+had	O
+thickened	O
+trabecular	O
+beams	O
+,	O
+decreased	O
+intertrabecular	O
+spaces	O
+,	O
+thickened	O
+juxtacanalicular	O
+tissue	O
+,	O
+activated	O
+trabecular	O
+meshwork	O
+cells	O
+,	O
+and	O
+increased	O
+amounts	O
+of	O
+amorphogranular	O
+extracellular	O
+material	O
+,	O
+especially	O
+in	O
+the	O
+juxtacanalicular	O
+tissue	O
+and	O
+beneath	O
+the	O
+endothelial	O
+lining	O
+of	O
+the	O
+canal	O
+of	O
+Schlemm	O
+.	O
+
+The	O
+dexamethasone	O
+-	O
+treated	O
+nonresponder	O
+eyes	O
+appeared	O
+to	O
+be	O
+morphologically	O
+similar	O
+to	O
+the	O
+untreated	O
+eyes	O
+,	O
+although	O
+several	O
+subtle	O
+dexamethasone	O
+-	O
+induced	O
+morphologic	O
+changes	O
+were	O
+evident	O
+.	O
+
+CONCLUSION	O
+:	O
+Dexamethasone	O
+treatment	O
+of	O
+isolated	O
+,	O
+perfusion	O
+-	O
+cultured	O
+human	O
+eyes	O
+led	O
+to	O
+the	O
+generation	O
+of	O
+ocular	B
+hypertension	I
+in	O
+approximately	O
+30	O
+%	O
+of	O
+the	O
+dexamethasone	O
+-	O
+treated	O
+eyes	O
+.	O
+
+Steroid	O
+treatment	O
+resulted	O
+in	O
+morphologic	O
+changes	O
+in	O
+the	O
+trabecular	O
+meshwork	O
+similar	O
+to	O
+those	O
+reported	O
+for	O
+corticosteroid	B
+glaucoma	I
+and	O
+open	B
+angle	I
+glaucoma	I
+.	O
+
+This	O
+system	O
+may	O
+provide	O
+an	O
+acute	O
+model	O
+in	O
+which	O
+to	O
+study	O
+the	O
+pathogenic	O
+mechanisms	O
+involved	O
+in	O
+steroid	B
+glaucoma	I
+and	O
+primary	B
+open	I
+angle	I
+glaucoma	I
+.	O
+
+Auditory	O
+disturbance	O
+associated	O
+with	O
+interscalene	O
+brachial	O
+plexus	O
+block	O
+.	O
+
+We	O
+performed	O
+an	O
+audiometric	O
+study	O
+in	O
+20	O
+patients	O
+who	O
+underwent	O
+surgery	O
+of	O
+the	O
+shoulder	O
+region	O
+under	O
+an	O
+interscalene	O
+brachial	O
+plexus	O
+block	O
+(	O
+IBPB	O
+)	O
+.	O
+
+Bupivacaine	O
+0	O
+.	O
+75	O
+%	O
+with	O
+adrenaline	O
+was	O
+given	O
+followed	O
+by	O
+a	O
+24	O
+-	O
+hr	O
+continuous	O
+infusion	O
+of	O
+0	O
+.	O
+25	O
+%	O
+bupivacaine	O
+.	O
+
+Three	O
+audiometric	O
+threshold	O
+measurements	O
+(	O
+0	O
+.	O
+25	O
+-	O
+18	O
+kHz	O
+)	O
+were	O
+made	O
+:	O
+the	O
+first	O
+before	O
+IBPB	O
+,	O
+the	O
+second	O
+2	O
+-	O
+6	O
+h	O
+after	O
+surgery	O
+and	O
+the	O
+third	O
+on	O
+the	O
+first	O
+day	O
+after	O
+operation	O
+.	O
+
+In	O
+four	O
+patients	O
+hearing	B
+impairment	I
+on	O
+the	O
+side	O
+of	O
+the	O
+block	O
+was	O
+demonstrated	O
+after	O
+operation	O
+,	O
+in	O
+three	O
+measurements	O
+on	O
+the	O
+day	O
+of	O
+surgery	O
+and	O
+in	O
+one	O
+on	O
+the	O
+following	O
+day	O
+.	O
+
+The	O
+frequencies	O
+at	O
+which	O
+the	O
+impairment	O
+occurred	O
+varied	O
+between	O
+patients	O
+;	O
+in	O
+one	O
+only	O
+low	O
+frequencies	O
+(	O
+0	O
+.	O
+25	O
+-	O
+0	O
+.	O
+5	O
+kHz	O
+)	O
+were	O
+involved	O
+.	O
+
+The	O
+maximum	O
+change	O
+in	O
+threshold	O
+was	O
+35	O
+dB	O
+at	O
+6	O
+kHz	O
+measured	O
+at	O
+the	O
+end	O
+of	O
+the	O
+continuous	O
+infusion	O
+of	O
+bupivacaine	O
+.	O
+
+This	O
+patient	O
+had	O
+hearing	O
+threshold	O
+changes	O
+(	O
+15	O
+-	O
+20	O
+dB	O
+)	O
+at	O
+6	O
+-	O
+10	O
+kHz	O
+on	O
+the	O
+opposite	O
+side	O
+also	O
+.	O
+
+IBPB	O
+may	O
+cause	O
+transient	O
+auditory	B
+dysfunction	I
+in	O
+the	O
+ipsilateral	O
+ear	O
+,	O
+possibly	O
+via	O
+an	O
+effect	O
+on	O
+sympathetic	O
+innervation	O
+.	O
+
+The	O
+safety	O
+and	O
+efficacy	O
+of	O
+combination	O
+N	O
+-	O
+butyl	O
+-	O
+deoxynojirimycin	O
+(	O
+SC	O
+-	O
+48334	O
+)	O
+and	O
+zidovudine	O
+in	O
+patients	O
+with	O
+HIV	B
+-	I
+1	I
+infection	I
+and	O
+200	O
+-	O
+500	O
+CD4	O
+cells	O
+/	O
+mm3	O
+.	O
+
+We	O
+conducted	O
+a	O
+double	O
+-	O
+blind	O
+,	O
+randomized	O
+phase	O
+II	O
+study	O
+to	O
+evaluate	O
+the	O
+safety	O
+and	O
+activity	O
+of	O
+combination	O
+therapy	O
+with	O
+N	O
+-	O
+butyl	O
+-	O
+deoxynojirimycin	O
+(	O
+SC	O
+-	O
+48334	O
+)	O
+(	O
+an	O
+alpha	O
+-	O
+glucosidase	O
+I	O
+inhibitor	O
+)	O
+and	O
+zidovudine	O
+versus	O
+zidovudine	O
+alone	O
+.	O
+
+Patients	O
+with	O
+200	O
+to	O
+500	O
+CD4	O
+cells	O
+/	O
+mm3	O
+who	O
+tolerated	O
+<	O
+or	O
+=	O
+12	O
+weeks	O
+of	O
+prior	O
+zidovudine	O
+therapy	O
+received	O
+SC	O
+-	O
+48334	O
+(	O
+1000	O
+mg	O
+every	O
+8	O
+h	O
+)	O
+and	O
+zidovudine	O
+(	O
+100	O
+mg	O
+every	O
+8	O
+h	O
+)	O
+or	O
+zidovudine	O
+and	O
+placebo	O
+.	O
+
+Sixty	O
+patients	O
+received	O
+combination	O
+therapy	O
+and	O
+58	O
+,	O
+zidovudine	O
+and	O
+placebo	O
+.	O
+
+Twenty	O
+-	O
+three	O
+patients	O
+(	O
+38	O
+%	O
+)	O
+and	O
+15	O
+(	O
+26	O
+%	O
+)	O
+,	O
+in	O
+the	O
+combination	O
+and	O
+zidovudine	O
+groups	O
+,	O
+respectively	O
+,	O
+discontinued	O
+therapy	O
+(	O
+p	O
+=	O
+0	O
+.	O
+15	O
+)	O
+.	O
+
+The	O
+mean	O
+SC	O
+-	O
+48334	O
+steady	O
+-	O
+state	O
+trough	O
+level	O
+(	O
+4	O
+.	O
+04	O
++	O
+/	O
+-	O
+0	O
+.	O
+99	O
+micrograms	O
+/	O
+ml	O
+)	O
+was	O
+below	O
+the	O
+in	O
+vitro	O
+inhibitory	O
+concentration	O
+for	O
+human	O
+immunodeficiency	B
+virus	O
+(	O
+HIV	O
+)	O
+.	O
+
+The	O
+mean	O
+increase	O
+in	O
+CD4	O
+cells	O
+at	O
+week	O
+4	O
+was	O
+73	O
+.	O
+8	O
+cells	O
+/	O
+mm3	O
+and	O
+52	O
+.	O
+4	O
+cells	O
+/	O
+mm3	O
+for	O
+the	O
+combination	O
+and	O
+zidovudine	O
+groups	O
+,	O
+respectively	O
+(	O
+p	O
+>	O
+0	O
+.	O
+36	O
+)	O
+.	O
+
+For	O
+patients	O
+with	O
+prior	O
+zidovudine	O
+therapy	O
+,	O
+the	O
+mean	O
+change	O
+in	O
+CD4	O
+cells	O
+in	O
+the	O
+combination	O
+and	O
+zidovudine	O
+groups	O
+was	O
+63	O
+.	O
+7	O
+cells	O
+/	O
+mm3	O
+and	O
+4	O
+.	O
+9	O
+cells	O
+/	O
+mm3	O
+at	O
+week	O
+8	O
+and	O
+6	O
+.	O
+8	O
+cells	O
+/	O
+mm3	O
+and	O
+-	O
+45	O
+.	O
+1	O
+cells	O
+/	O
+mm3	O
+at	O
+week	O
+16	O
+,	O
+respectively	O
+.	O
+
+The	O
+number	O
+of	O
+patients	O
+with	O
+suppression	O
+of	O
+HIV	O
+p24	O
+antigenemia	O
+in	O
+the	O
+combination	O
+and	O
+zidovudine	O
+groups	O
+was	O
+six	O
+(	O
+40	O
+%	O
+)	O
+and	O
+two	O
+(	O
+11	O
+%	O
+)	O
+at	O
+week	O
+4	O
+(	O
+p	O
+=	O
+0	O
+.	O
+10	O
+)	O
+and	O
+five	O
+(	O
+45	O
+%	O
+)	O
+and	O
+two	O
+(	O
+14	O
+%	O
+)	O
+at	O
+week	O
+24	O
+(	O
+p	O
+=	O
+0	O
+.	O
+08	O
+)	O
+,	O
+respectively	O
+.	O
+
+Diarrhea	B
+,	O
+flatulence	B
+,	O
+abdominal	B
+pain	I
+,	O
+and	O
+weight	B
+loss	I
+were	O
+common	O
+for	O
+combination	O
+recipients	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Prolonged	O
+paralysis	B
+due	O
+to	O
+nondepolarizing	O
+neuromuscular	O
+blocking	O
+agents	O
+and	O
+corticosteroids	O
+.	O
+
+The	O
+long	O
+-	O
+term	O
+use	O
+of	O
+nondepolarizing	O
+neuromuscular	O
+blocking	O
+agents	O
+(	O
+ND	O
+-	O
+NMBA	O
+)	O
+has	O
+recently	O
+been	O
+implicated	O
+as	O
+a	O
+cause	O
+of	O
+prolonged	O
+muscle	B
+weakness	I
+,	O
+although	O
+the	O
+site	O
+of	O
+the	O
+lesion	O
+and	O
+the	O
+predisposing	O
+factors	O
+have	O
+been	O
+unclear	O
+.	O
+
+We	O
+report	O
+3	O
+patients	O
+(	O
+age	O
+37	O
+-	O
+52	O
+years	O
+)	O
+with	O
+acute	O
+respiratory	B
+insufficiency	I
+who	O
+developed	O
+prolonged	O
+weakness	B
+following	O
+the	O
+discontinuation	O
+of	O
+ND	O
+-	O
+NMBAs	O
+.	O
+
+Two	O
+patients	O
+also	O
+received	O
+intravenous	O
+corticosteroids	O
+.	O
+
+Renal	O
+function	O
+was	O
+normal	O
+but	O
+hepatic	O
+function	O
+was	O
+impaired	O
+in	O
+all	O
+patients	O
+,	O
+and	O
+all	O
+had	O
+acidosis	B
+.	O
+
+Electrophysiologic	O
+studies	O
+revealed	O
+low	O
+amplitude	O
+compound	O
+motor	O
+action	O
+potentials	O
+,	O
+normal	O
+sensory	O
+studies	O
+,	O
+and	O
+fibrillations	O
+.	O
+
+Repetitive	O
+stimulation	O
+at	O
+2	O
+Hz	O
+showed	O
+a	O
+decremental	O
+response	O
+in	O
+2	O
+patients	O
+.	O
+
+The	O
+serum	O
+vecuronium	O
+level	O
+measured	O
+in	O
+1	O
+patient	O
+14	O
+days	O
+after	O
+the	O
+drug	O
+had	O
+been	O
+discontinued	O
+was	O
+172	O
+ng	O
+/	O
+mL	O
+.	O
+
+A	O
+muscle	O
+biopsy	O
+in	O
+this	O
+patient	O
+showed	O
+loss	B
+of	I
+thick	I
+,	I
+myosin	I
+filaments	I
+.	O
+
+The	O
+weakness	B
+in	O
+these	O
+patients	O
+is	O
+due	O
+to	O
+pathology	B
+at	I
+both	I
+the	I
+neuromuscular	I
+junction	I
+(	O
+most	O
+likely	O
+due	O
+to	O
+ND	O
+-	O
+NMBA	O
+)	O
+and	O
+muscle	O
+(	O
+most	O
+likely	O
+due	O
+to	O
+corticosteroids	O
+)	O
+.	O
+
+Hepatic	B
+dysfunction	I
+and	O
+acidosis	B
+are	O
+contributing	O
+risk	O
+factors	O
+.	O
+
+Failure	O
+of	O
+ancrod	O
+in	O
+the	O
+treatment	O
+of	O
+heparin	O
+-	O
+induced	O
+arterial	O
+thrombosis	B
+.	O
+
+The	O
+morbidity	O
+and	O
+mortality	O
+associated	O
+with	O
+heparin	O
+-	O
+induced	O
+thrombosis	B
+remain	O
+high	O
+despite	O
+numerous	O
+empirical	O
+therapies	O
+.	O
+
+Ancrod	O
+has	O
+been	O
+used	O
+successfully	O
+for	O
+prophylaxis	O
+against	O
+development	O
+of	O
+thrombosis	B
+in	O
+patients	O
+with	O
+heparin	O
+induced	O
+platelet	B
+aggregation	I
+who	O
+require	O
+brief	O
+reexposure	O
+to	O
+heparin	O
+,	O
+but	O
+its	O
+success	O
+in	O
+patients	O
+who	O
+have	O
+developed	O
+the	O
+thrombosis	B
+syndrome	O
+is	O
+not	O
+well	O
+defined	O
+.	O
+
+The	O
+authors	O
+present	O
+a	O
+case	O
+of	O
+failure	O
+of	O
+ancrod	O
+treatment	O
+in	O
+a	O
+patient	O
+with	O
+heparin	O
+-	O
+induced	O
+thrombosis	B
+.	O
+
+Water	B
+intoxication	I
+associated	O
+with	O
+oxytocin	O
+administration	O
+during	O
+saline	O
+-	O
+induced	O
+abortion	B
+.	O
+
+Four	O
+cases	O
+of	O
+water	B
+intoxication	I
+in	O
+connection	O
+with	O
+oxytocin	O
+administration	O
+during	O
+saline	O
+-	O
+induced	O
+abortions	B
+are	O
+described	O
+.	O
+
+The	O
+mechanism	O
+of	O
+water	B
+intoxication	I
+is	O
+discussed	O
+in	O
+regard	O
+to	O
+these	O
+cases	O
+.	O
+
+Oxytocin	O
+administration	O
+during	O
+midtrimester	O
+-	O
+induced	O
+abortions	B
+is	O
+advocated	O
+only	O
+if	O
+it	O
+can	O
+be	O
+carried	O
+out	O
+under	O
+careful	O
+observations	O
+of	O
+an	O
+alert	O
+nursing	O
+staff	O
+,	O
+aware	O
+of	O
+the	O
+symptoms	O
+of	O
+water	B
+intoxication	I
+and	O
+instructed	O
+to	O
+watch	O
+the	O
+diuresis	O
+and	O
+report	O
+such	O
+early	O
+signs	O
+of	O
+the	O
+syndrome	O
+as	O
+asthenia	B
+,	O
+muscular	O
+irritability	B
+,	O
+or	O
+headaches	B
+.	O
+
+The	O
+oxytocin	O
+should	O
+be	O
+given	O
+only	O
+in	O
+Ringers	O
+lactate	O
+or	O
+,	O
+alternately	O
+,	O
+in	O
+Ringers	O
+lactate	O
+and	O
+a	O
+5	O
+per	O
+cent	O
+dextrose	O
+and	O
+water	O
+solutions	O
+.	O
+
+The	O
+urinary	O
+output	O
+should	O
+be	O
+monitored	O
+and	O
+the	O
+oxytocin	O
+administration	O
+discontinued	O
+and	O
+the	O
+serum	O
+electrolytes	O
+checked	O
+if	O
+the	O
+urinary	O
+output	O
+decreases	O
+.	O
+
+The	O
+oxytocin	O
+should	O
+not	O
+be	O
+administered	O
+in	O
+excess	O
+of	O
+36	O
+hours	O
+.	O
+
+If	O
+the	O
+patient	O
+has	O
+not	O
+aborted	O
+by	O
+then	O
+the	O
+oxytocin	O
+should	O
+be	O
+discontinued	O
+for	O
+10	O
+to	O
+12	O
+hours	O
+in	O
+order	O
+to	O
+perform	O
+electrolyte	O
+determinations	O
+and	O
+correct	O
+any	O
+electrolyte	O
+imbalance	O
+.	O
+
+Light	O
+chain	O
+proteinuria	B
+and	O
+cellular	O
+mediated	O
+immunity	O
+in	O
+rifampin	O
+treated	O
+patients	O
+with	O
+tuberculosis	B
+.	O
+
+Light	O
+chain	O
+proteinuria	B
+was	O
+found	O
+in	O
+9	O
+of	O
+17	O
+tuberculosis	B
+patients	O
+treated	O
+with	O
+rifampin	O
+.	O
+
+Concomitant	O
+assay	O
+of	O
+cellular	O
+mediated	O
+immunity	O
+in	O
+these	O
+patients	O
+using	O
+skin	O
+test	O
+antigen	O
+and	O
+a	O
+lymphokine	O
+in	O
+vitro	O
+test	O
+provided	O
+results	O
+that	O
+were	O
+different	O
+.	O
+
+Response	O
+to	O
+Varidase	O
+skin	O
+test	O
+antigen	O
+was	O
+negative	O
+for	O
+all	O
+eight	O
+tuberculosis	B
+patients	O
+tested	O
+,	O
+but	O
+there	O
+occurred	O
+a	O
+hyper	O
+-	O
+responsiveness	O
+of	O
+the	O
+lymphocytes	O
+of	O
+these	O
+eight	O
+patients	O
+to	O
+phytomitogen	O
+(	O
+PHA	O
+-	O
+P	O
+)	O
+.	O
+as	O
+well	O
+as	O
+of	O
+those	O
+of	O
+seven	O
+other	O
+tuberculous	B
+patients	O
+.	O
+
+This	O
+last	O
+finding	O
+may	O
+be	O
+related	O
+to	O
+time	O
+of	O
+testing	O
+and	O
+/	O
+or	O
+endogenous	O
+serum	O
+binding	O
+of	O
+rifampin	O
+which	O
+could	O
+have	O
+inhibited	O
+mitogen	O
+activity	O
+for	O
+the	O
+lymphocyte	O
+.	O
+
+KF17837	O
+:	O
+a	O
+novel	O
+selective	O
+adenosine	O
+A2A	O
+receptor	O
+antagonist	O
+with	O
+anticataleptic	O
+activity	O
+.	O
+
+KF17837	O
+is	O
+a	O
+novel	O
+selective	O
+adenosine	O
+A2A	O
+receptor	O
+antagonist	O
+.	O
+
+Oral	O
+administration	O
+of	O
+KF17837	O
+(	O
+2	O
+.	O
+5	O
+,	O
+10	O
+.	O
+0	O
+and	O
+30	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+)	O
+significantly	O
+ameliorated	O
+the	O
+cataleptic	B
+responses	O
+induced	O
+by	O
+intracerebroventricular	O
+administration	O
+of	O
+an	O
+adenosine	O
+A2A	O
+receptor	O
+agonist	O
+,	O
+CGS	O
+21680	O
+(	O
+10	O
+micrograms	O
+)	O
+,	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+.	O
+
+KF17837	O
+also	O
+reduced	O
+the	O
+catalepsy	B
+induced	O
+by	O
+haloperidol	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+and	O
+by	O
+reserpine	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+These	O
+anticataleptic	O
+effects	O
+were	O
+exhibited	O
+dose	O
+dependently	O
+at	O
+doses	O
+from	O
+0	O
+.	O
+625	O
+and	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+,	O
+respectively	O
+.	O
+
+Moreover	O
+,	O
+KF17837	O
+(	O
+0	O
+.	O
+625	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+)	O
+potentiated	O
+the	O
+anticataleptic	O
+effects	O
+of	O
+a	O
+subthreshold	O
+dose	O
+of	O
+L	O
+-	O
+3	O
+,	O
+4	O
+-	O
+dihydroxyphenylalanine	O
+(	O
+L	O
+-	O
+DOPA	O
+;	O
+25	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+plus	O
+benserazide	O
+(	O
+6	O
+.	O
+25	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+These	O
+results	O
+suggested	O
+that	O
+KF17837	O
+is	O
+a	O
+centrally	O
+active	O
+adenosine	O
+A2A	O
+receptor	O
+antagonist	O
+and	O
+that	O
+the	O
+dopaminergic	O
+function	O
+of	O
+the	O
+nigrostriatal	O
+pathway	O
+is	O
+potentiated	O
+by	O
+adenosine	O
+A2A	O
+receptor	O
+antagonists	O
+.	O
+
+Furthermore	O
+,	O
+KF17837	O
+may	O
+be	O
+a	O
+useful	O
+drug	O
+in	O
+the	O
+treatment	O
+of	O
+parkinsonism	B
+.	O
+
+Effect	O
+of	O
+nondopaminergic	O
+drugs	O
+on	O
+L	O
+-	O
+dopa	O
+-	O
+induced	O
+dyskinesias	B
+in	O
+MPTP	O
+-	O
+treated	O
+monkeys	O
+.	O
+
+A	O
+group	O
+of	O
+four	O
+monkeys	O
+was	O
+rendered	O
+parkinsonian	B
+with	O
+the	O
+toxin	O
+MPTP	O
+.	O
+
+They	O
+were	O
+then	O
+treated	O
+chronically	O
+with	O
+L	O
+-	O
+DOPA	O
+/	O
+benserazide	O
+50	O
+/	O
+12	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+given	O
+orally	O
+daily	O
+for	O
+2	O
+months	O
+.	O
+
+This	O
+dose	O
+produced	O
+a	O
+striking	O
+antiparkinsonian	O
+effect	O
+,	O
+but	O
+all	O
+animals	O
+manifested	O
+dyskinesia	B
+.	O
+
+A	O
+series	O
+of	O
+agents	O
+acting	O
+primarily	O
+on	O
+neurotransmitters	O
+other	O
+than	O
+dopamine	O
+were	O
+then	O
+tested	O
+in	O
+combination	O
+with	O
+L	O
+-	O
+DOPA	O
+to	O
+see	O
+if	O
+the	O
+dyskinetic	B
+movements	O
+would	O
+be	O
+modified	O
+.	O
+
+Several	O
+drugs	O
+,	O
+including	O
+clonidine	O
+,	O
+physostigmine	O
+,	O
+methysergide	O
+,	O
+5	O
+-	O
+MDOT	O
+,	O
+propranolol	O
+,	O
+and	O
+MK	O
+-	O
+801	O
+,	O
+markedly	O
+reduced	O
+the	O
+dyskinetic	B
+movements	O
+but	O
+at	O
+the	O
+cost	O
+of	O
+a	O
+return	O
+of	O
+parkinsonian	B
+symptomatology	O
+.	O
+
+However	O
+,	O
+yohimbine	O
+and	O
+meperidine	O
+reduced	O
+predominantly	O
+the	O
+dyskinetic	B
+movements	O
+.	O
+
+Baclofen	O
+was	O
+also	O
+useful	O
+in	O
+one	O
+monkey	O
+against	O
+a	O
+more	O
+dystonic	B
+form	O
+of	O
+dyskinesia	B
+.	O
+
+Atropine	O
+converted	O
+the	O
+dystonic	B
+movements	O
+into	O
+chorea	B
+.	O
+
+Hallucinations	B
+and	O
+ifosfamide	O
+-	O
+induced	O
+neurotoxicity	B
+.	O
+
+BACKGROUND	O
+:	O
+Hallucinations	B
+as	O
+a	O
+symptom	O
+of	O
+central	O
+neurotoxicity	B
+are	O
+a	O
+known	O
+but	O
+poorly	O
+described	O
+side	O
+effect	O
+of	O
+ifosfamide	O
+.	O
+
+Most	O
+cases	O
+of	O
+ifosfamide	O
+-	O
+induced	O
+hallucinations	B
+have	O
+been	O
+reported	O
+with	O
+other	O
+mental	O
+status	O
+changes	O
+.	O
+
+METHODS	O
+:	O
+The	O
+authors	O
+interviewed	O
+six	O
+persons	O
+with	O
+ifosfamide	O
+-	O
+induced	O
+hallucinations	B
+in	O
+the	O
+presence	O
+of	O
+a	O
+clear	O
+sensorium	O
+.	O
+
+All	O
+patients	O
+were	O
+receiving	O
+high	O
+-	O
+dose	O
+ifosfamide	O
+as	O
+part	O
+of	O
+their	O
+bone	O
+marrow	O
+transplant	O
+procedure	O
+.	O
+
+RESULTS	O
+:	O
+Hallucinations	B
+occurred	O
+only	O
+when	O
+the	O
+patient	O
+'	O
+s	O
+eyes	O
+were	O
+closed	O
+and	O
+,	O
+in	O
+all	O
+but	O
+one	O
+case	O
+,	O
+were	O
+reported	O
+as	O
+disturbing	O
+or	O
+frightening	O
+.	O
+
+Underreporting	O
+of	O
+these	O
+hallucinations	B
+by	O
+patients	O
+is	O
+likely	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Hallucinations	B
+may	O
+be	O
+the	O
+sole	O
+or	O
+first	O
+manifestation	O
+of	O
+neurotoxicity	B
+.	O
+
+The	O
+incidence	O
+may	O
+be	O
+dose	O
+and	O
+infusion	O
+-	O
+time	O
+related	O
+.	O
+
+The	O
+clinician	O
+should	O
+be	O
+alerted	O
+for	O
+possible	O
+ifosfamide	O
+-	O
+induced	O
+hallucinations	B
+,	O
+which	O
+may	O
+occur	O
+without	O
+other	O
+signs	O
+of	O
+neurotoxicity	B
+.	O
+
+"	O
+Eyes	O
+-	O
+closed	O
+"	O
+hallucinatory	B
+experiences	O
+appear	O
+to	O
+be	O
+an	O
+unusual	O
+feature	O
+of	O
+this	O
+presentation	O
+.	O
+
+Patients	O
+anxious	O
+about	O
+this	O
+experience	O
+respond	O
+well	O
+to	O
+support	O
+and	O
+education	O
+about	O
+this	O
+occurrence	O
+.	O
+
+Optimal	O
+pharmacologic	O
+management	O
+of	O
+disturbed	O
+patients	O
+is	O
+unclear	O
+.	O
+
+If	O
+agitation	B
+becomes	O
+marked	O
+,	O
+high	O
+-	O
+potency	O
+neuroleptics	O
+(	O
+i	O
+.	O
+e	O
+.	O
+,	O
+haloperidol	O
+)	O
+may	O
+be	O
+effective	O
+.	O
+
+Photodistributed	O
+nifedipine	O
+-	O
+induced	O
+facial	O
+telangiectasia	B
+.	O
+
+Five	O
+months	O
+after	O
+starting	O
+nifedipine	O
+(	O
+Adalat	O
+)	O
+,	O
+two	O
+patients	O
+developed	O
+photodistributed	O
+facial	O
+telangiectasia	B
+,	O
+which	O
+became	O
+more	O
+noticeable	O
+with	O
+time	O
+.	O
+
+Neither	O
+patient	O
+complained	O
+of	O
+photosensitivity	O
+or	O
+flushing	B
+.	O
+
+Both	O
+patients	O
+reported	O
+a	O
+significant	O
+cosmetic	O
+improvement	O
+after	O
+discontinuing	O
+the	O
+drug	O
+.	O
+
+One	O
+commenced	O
+the	O
+closely	O
+related	O
+drug	O
+amlodipine	O
+3	O
+years	O
+later	O
+,	O
+with	O
+recurrence	O
+of	O
+telangiectasia	B
+.	O
+
+The	O
+photodistribution	O
+of	O
+the	O
+telangiectasia	B
+suggests	O
+a	O
+significant	O
+drug	O
+/	O
+light	O
+interaction	O
+.	O
+
+Penicillamine	O
+-	O
+induced	O
+rapidly	O
+progressive	O
+glomerulonephritis	B
+in	O
+a	O
+patient	O
+with	O
+rheumatoid	B
+arthritis	I
+.	O
+
+A	O
+67	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+rheumatoid	B
+arthritis	I
+presented	O
+rapidly	O
+progressive	O
+glomerulonephritis	B
+(	O
+RPGN	B
+)	O
+after	O
+5	O
+months	O
+of	O
+D	O
+-	O
+penicillamine	O
+(	O
+250	O
+mg	O
+/	O
+day	O
+)	O
+treatment	O
+.	O
+
+Light	O
+microscopy	O
+study	O
+showed	O
+severe	O
+glomerulonephritis	B
+with	O
+crescent	O
+formation	O
+in	O
+60	O
+%	O
+of	O
+the	O
+glomeruli	O
+and	O
+infiltration	O
+of	O
+inflammatory	O
+cells	O
+in	O
+the	O
+wall	O
+of	O
+an	O
+arteriole	O
+.	O
+
+Immunofluorescence	O
+revealed	O
+scanty	O
+granular	O
+IgG	O
+,	O
+IgA	O
+and	O
+C3	O
+deposits	O
+along	O
+the	O
+capillary	O
+walls	O
+and	O
+mesangium	O
+.	O
+
+The	O
+patient	O
+was	O
+treated	O
+with	O
+steroid	O
+pulse	O
+,	O
+plasmapheresis	O
+,	O
+cyclophosphamide	O
+and	O
+antiplatelet	O
+agents	O
+.	O
+
+A	O
+complete	O
+recovery	O
+of	O
+renal	O
+function	O
+was	O
+achieved	O
+in	O
+a	O
+few	O
+weeks	O
+.	O
+
+This	O
+new	O
+case	O
+of	O
+RPGN	B
+in	O
+the	O
+course	O
+of	O
+D	O
+-	O
+penicillamine	O
+treatment	O
+emphasizes	O
+the	O
+need	O
+for	O
+frequent	O
+monitoring	O
+of	O
+renal	O
+function	O
+and	O
+evaluation	O
+of	O
+urinary	O
+sediment	O
+and	O
+proteinuria	B
+in	O
+these	O
+patients	O
+.	O
+
+The	O
+prompt	O
+discontinuation	O
+of	O
+D	O
+-	O
+penicillamine	O
+and	O
+vigorous	O
+treatment	O
+measures	O
+could	O
+allow	O
+for	O
+a	O
+good	O
+prognosis	O
+as	O
+in	O
+this	O
+case	O
+.	O
+
+A	O
+case	O
+of	O
+polymyositis	B
+in	O
+a	O
+patient	O
+with	O
+primary	B
+biliary	I
+cirrhosis	I
+treated	O
+with	O
+D	O
+-	O
+penicillamine	O
+.	O
+
+Although	O
+D	O
+-	O
+penicillamine	O
+has	O
+been	O
+used	O
+for	O
+many	O
+rheumatologic	B
+diseases	I
+,	O
+toxicity	B
+limits	O
+its	O
+usefulness	O
+in	O
+many	O
+patients	O
+.	O
+
+Polymyositis	B
+/	O
+dermatomyositis	B
+can	O
+develop	O
+as	O
+one	O
+of	O
+the	O
+autoimmune	O
+complications	O
+of	O
+D	O
+-	O
+penicillamine	O
+treatment	O
+,	O
+but	O
+its	O
+exact	O
+pathogenesis	O
+remains	O
+unclear	O
+.	O
+
+We	O
+report	O
+a	O
+patient	O
+with	O
+primary	B
+biliary	I
+cirrhosis	I
+,	O
+who	O
+developed	O
+polymyositis	B
+while	O
+receiving	O
+D	O
+-	O
+penicillamine	O
+therapy	O
+.	O
+
+We	O
+described	O
+the	O
+special	O
+clinical	O
+course	O
+of	O
+the	O
+patient	O
+.	O
+
+Patients	O
+receiving	O
+D	O
+-	O
+penicillamine	O
+therapy	O
+should	O
+be	O
+followed	O
+carefully	O
+for	O
+the	O
+development	O
+of	O
+autoimmune	O
+complications	O
+like	O
+polymyositis	B
+/	O
+dermatomyositis	B
+.	O
+
+Hyperalgesia	B
+and	O
+myoclonus	B
+in	O
+terminal	O
+cancer	B
+patients	O
+treated	O
+with	O
+continuous	O
+intravenous	O
+morphine	O
+.	O
+
+Eight	O
+cancer	B
+patients	O
+in	O
+the	O
+terminal	O
+stages	O
+of	O
+the	O
+disease	O
+treated	O
+with	O
+high	O
+doses	O
+of	O
+intravenous	O
+morphine	O
+developed	O
+hyperalgesia	B
+.	O
+
+All	O
+cases	O
+were	O
+retrospectively	O
+sampled	O
+from	O
+three	O
+different	O
+hospitals	O
+in	O
+Copenhagen	O
+.	O
+
+Five	O
+patients	O
+developed	O
+universal	O
+hyperalgesia	B
+and	O
+hyperesthesia	B
+which	O
+in	O
+2	O
+cases	O
+were	O
+accompanied	O
+by	O
+myoclonus	B
+.	O
+
+In	O
+3	O
+patients	O
+a	O
+pre	O
+-	O
+existing	O
+neuralgia	B
+increased	O
+to	O
+excruciating	O
+intensity	O
+and	O
+in	O
+2	O
+of	O
+these	O
+cases	O
+myoclonus	B
+occurred	O
+simultaneously	O
+.	O
+
+Although	O
+only	O
+few	O
+clinical	O
+descriptions	O
+of	O
+the	O
+relationship	O
+between	O
+hyperalgesia	B
+/	O
+myoclonus	B
+and	O
+high	O
+doses	O
+of	O
+morphine	O
+are	O
+available	O
+,	O
+experimental	O
+support	O
+from	O
+animal	O
+studies	O
+indicates	O
+that	O
+morphine	O
+,	O
+or	O
+its	O
+metabolites	O
+,	O
+plays	O
+a	O
+causative	O
+role	O
+for	O
+the	O
+observed	O
+behavioural	O
+syndrome	O
+.	O
+
+The	O
+possible	O
+mechanisms	O
+are	O
+discussed	O
+and	O
+treatment	O
+proposals	O
+given	O
+suggesting	O
+the	O
+use	O
+of	O
+more	O
+efficacious	O
+opioids	O
+with	O
+less	O
+excitatory	O
+potency	O
+in	O
+these	O
+situations	O
+.	O
+
+Liposomal	O
+daunorubicin	O
+in	O
+advanced	O
+Kaposi	B
+'	I
+s	I
+sarcoma	I
+:	O
+a	O
+phase	O
+II	O
+study	O
+.	O
+
+We	O
+report	O
+a	O
+non	O
+-	O
+randomized	O
+Phase	O
+II	O
+clinical	O
+trial	O
+to	O
+assess	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+liposomal	O
+daunorubicin	O
+(	O
+DaunoXome	O
+)	O
+in	O
+the	O
+treatment	O
+of	O
+AIDS	B
+related	O
+Kaposi	B
+'	I
+s	I
+sarcoma	I
+.	O
+
+Eleven	O
+homosexual	O
+men	O
+with	O
+advanced	O
+Kaposi	B
+'	I
+s	I
+sarcoma	I
+were	O
+entered	O
+in	O
+the	O
+trial	O
+.	O
+
+Changes	O
+in	O
+size	O
+,	O
+colour	O
+and	O
+associated	O
+oedema	B
+of	O
+selected	O
+'	O
+target	O
+'	O
+lesions	O
+were	O
+measured	O
+.	O
+
+Clinical	O
+,	O
+biochemical	O
+and	O
+haematological	O
+toxicities	B
+were	O
+assessed	O
+.	O
+
+Ten	O
+subjects	O
+were	O
+evaluated	O
+.	O
+
+A	O
+partial	O
+response	O
+was	O
+achieved	O
+in	O
+four	O
+,	O
+of	O
+whom	O
+two	O
+subsequently	O
+relapsed	O
+.	O
+
+Stabilization	O
+of	O
+Kaposi	B
+'	I
+s	I
+sarcoma	I
+occurred	O
+in	O
+the	O
+remaining	O
+six	O
+,	O
+maintained	O
+until	O
+the	O
+end	O
+of	O
+the	O
+trial	O
+period	O
+in	O
+four	O
+.	O
+
+The	O
+drug	O
+was	O
+generally	O
+well	O
+tolerated	O
+,	O
+with	O
+few	O
+mild	O
+symptoms	O
+of	O
+toxicity	B
+.	O
+
+The	O
+main	O
+problem	O
+encountered	O
+was	O
+haematological	O
+toxicity	B
+,	O
+with	O
+three	O
+subjects	O
+experiencing	O
+severe	O
+neutropenia	B
+(	O
+neutrophil	O
+count	O
+<	O
+0	O
+.	O
+5	O
+x	O
+10	O
+(	O
+9	O
+)	O
+/	O
+l	O
+)	O
+.	O
+
+There	O
+was	O
+no	O
+evidence	O
+of	O
+cardiotoxicity	B
+.	O
+
+In	O
+this	O
+small	O
+patient	O
+sample	O
+,	O
+liposomal	O
+daunorubicin	O
+was	O
+an	O
+effective	O
+and	O
+well	O
+tolerated	O
+agent	O
+in	O
+the	O
+treatment	O
+of	O
+Kaposi	B
+'	I
+s	I
+sarcoma	I
+.	O
+
+Long	O
+-	O
+term	O
+effects	O
+of	O
+vincristine	O
+on	O
+the	O
+peripheral	O
+nervous	O
+system	O
+.	O
+
+Forty	O
+patients	O
+with	O
+Non	B
+-	I
+Hodgkin	I
+'	I
+s	I
+Lymphoma	I
+treated	O
+with	O
+vincristine	O
+between	O
+1984	O
+and	O
+1990	O
+(	O
+cumulative	O
+dose	O
+12	O
+mg	O
+in	O
+18	O
+-	O
+24	O
+weeks	O
+)	O
+were	O
+investigated	O
+in	O
+order	O
+to	O
+evaluate	O
+the	O
+long	O
+term	O
+effects	O
+of	O
+vincristine	O
+on	O
+the	O
+peripheral	O
+nervous	O
+system	O
+.	O
+
+The	O
+patients	O
+were	O
+interviewed	O
+with	O
+emphasis	O
+on	O
+neuropathic	B
+symptoms	I
+.	O
+
+Physical	O
+and	O
+quantitative	O
+sensory	O
+examination	O
+with	O
+determination	O
+of	O
+vibratory	O
+perception	O
+and	O
+thermal	O
+discrimination	O
+thresholds	O
+were	O
+performed	O
+,	O
+four	O
+to	O
+77	O
+months	O
+(	O
+median	O
+34	O
+months	O
+)	O
+after	O
+vincristine	O
+treatment	O
+.	O
+
+Twenty	O
+-	O
+seven	O
+patients	O
+reported	O
+neuropathic	B
+symptoms	I
+.	O
+
+In	O
+13	O
+of	O
+these	O
+27	O
+patients	O
+symptoms	O
+were	O
+still	O
+present	O
+at	O
+the	O
+time	O
+of	O
+examination	O
+.	O
+
+In	O
+these	O
+patients	O
+sensory	O
+signs	O
+and	O
+symptoms	O
+predominated	O
+.	O
+
+In	O
+the	O
+other	O
+14	O
+patients	O
+symptoms	O
+had	O
+been	O
+present	O
+in	O
+the	O
+past	O
+.	O
+
+Symptoms	O
+persisted	O
+maximally	O
+40	O
+months	O
+since	O
+cessation	O
+of	O
+therapy	O
+.	O
+
+There	O
+was	O
+no	O
+age	O
+difference	O
+between	O
+patients	O
+with	O
+and	O
+without	O
+complaints	O
+at	O
+the	O
+time	O
+of	O
+examination	O
+.	O
+
+Normal	O
+reflexes	O
+were	O
+found	O
+in	O
+two	O
+third	O
+of	O
+patients	O
+.	O
+
+Neuropathic	O
+complaints	O
+were	O
+not	O
+very	O
+troublesome	O
+on	O
+the	O
+long	O
+term	O
+.	O
+
+It	O
+is	O
+concluded	O
+that	O
+with	O
+the	O
+above	O
+mentioned	O
+vincristine	O
+dose	O
+schedule	O
+signs	O
+and	O
+symptoms	O
+of	O
+vincristine	O
+neuropathy	B
+are	O
+reversible	O
+for	O
+a	O
+great	O
+deal	O
+and	O
+prognosis	O
+is	O
+fairly	O
+good	O
+.	O
+
+Hepatic	O
+adenomas	B
+and	O
+focal	B
+nodular	I
+hyperplasia	I
+of	O
+the	O
+liver	O
+in	O
+young	O
+women	O
+on	O
+oral	O
+contraceptives	O
+:	O
+case	O
+reports	O
+.	O
+
+Two	O
+cases	O
+of	O
+hepatic	O
+adenoma	B
+and	O
+one	O
+of	O
+focal	B
+nodular	I
+hyperplasia	I
+presumably	O
+associated	O
+with	O
+the	O
+use	O
+of	O
+oral	O
+contraceptives	O
+,	O
+are	O
+reported	O
+.	O
+
+Special	O
+reference	O
+is	O
+made	O
+to	O
+their	O
+clinical	O
+presentation	O
+,	O
+which	O
+may	O
+be	O
+totally	O
+asymptomatic	O
+.	O
+
+Liver	O
+-	O
+function	O
+tests	O
+are	O
+of	O
+little	O
+diagnostic	O
+value	O
+,	O
+but	O
+valuable	O
+information	O
+may	O
+be	O
+obtained	O
+from	O
+both	O
+liver	O
+scanning	O
+and	O
+hepatic	O
+angiography	O
+.	O
+
+Histologic	O
+differences	O
+and	O
+clinical	O
+similarities	O
+between	O
+hepatic	O
+adenoma	B
+and	O
+focal	B
+nodular	I
+hyperplasia	I
+of	O
+the	O
+liver	O
+are	O
+discussed	O
+.	O
+
+Loss	O
+of	O
+glutamate	O
+decarboxylase	O
+mRNA	O
+-	O
+containing	O
+neurons	O
+in	O
+the	O
+rat	O
+dentate	O
+gyrus	O
+following	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+.	O
+
+In	O
+situ	O
+hybridization	O
+methods	O
+were	O
+used	O
+to	O
+determine	O
+if	O
+glutamic	O
+acid	O
+decarboxylase	O
+(	O
+GAD	O
+)	O
+mRNA	O
+-	O
+containing	O
+neurons	O
+within	O
+the	O
+hilus	O
+of	O
+the	O
+dentate	O
+gyrus	O
+are	O
+vulnerable	O
+to	O
+seizure	B
+-	O
+induced	O
+damage	O
+in	O
+a	O
+model	O
+of	O
+chronic	O
+seizures	B
+.	O
+
+Sprague	O
+-	O
+Dawley	O
+rats	O
+were	O
+injected	O
+intraperitoneally	O
+with	O
+pilocarpine	O
+,	O
+and	O
+the	O
+hippocampal	O
+formation	O
+was	O
+studied	O
+histologically	O
+at	O
+1	O
+,	O
+2	O
+,	O
+4	O
+,	O
+and	O
+8	O
+week	O
+intervals	O
+after	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B
+.	O
+
+In	O
+situ	O
+hybridization	O
+histochemistry	O
+,	O
+using	O
+a	O
+digoxigenin	O
+-	O
+labeled	O
+GAD	O
+cRNA	O
+probe	O
+,	O
+demonstrated	O
+a	O
+substantial	O
+decrease	O
+in	O
+the	O
+number	O
+of	O
+GAD	O
+mRNA	O
+-	O
+containing	O
+neurons	O
+in	O
+the	O
+hilus	O
+of	O
+the	O
+dentate	O
+gyrus	O
+in	O
+the	O
+pilocarpine	O
+-	O
+treated	O
+rats	O
+as	O
+compared	O
+to	O
+controls	O
+at	O
+all	O
+time	O
+intervals	O
+.	O
+
+Additional	O
+neuronanatomical	O
+studies	O
+,	O
+including	O
+cresyl	O
+violet	O
+staining	O
+,	O
+neuronal	B
+degeneration	I
+methods	O
+,	O
+and	O
+histochemical	O
+localization	O
+of	O
+glial	O
+fibrillary	O
+acidic	O
+protein	O
+,	O
+suggested	O
+that	O
+the	O
+decrease	O
+in	O
+the	O
+number	O
+of	O
+GAD	O
+mRNA	O
+-	O
+containing	O
+neurons	O
+was	O
+related	O
+to	O
+neuronal	B
+loss	I
+rather	O
+than	O
+to	O
+a	O
+decrease	O
+in	O
+GAD	O
+mRNA	O
+levels	O
+.	O
+
+The	O
+loss	O
+of	O
+GAD	O
+mRNA	O
+-	O
+containing	O
+neurons	O
+in	O
+the	O
+hilus	O
+contrasted	O
+with	O
+the	O
+relative	O
+preservation	O
+of	O
+labeled	O
+putative	O
+basket	O
+cells	O
+along	O
+the	O
+inner	O
+margin	O
+of	O
+the	O
+granule	O
+cell	O
+layer	O
+.	O
+
+Quantitative	O
+analyses	O
+of	O
+labeled	O
+neurons	O
+in	O
+three	O
+regions	O
+of	O
+the	O
+dentate	O
+gyrus	O
+in	O
+the	O
+1	O
+and	O
+2	O
+week	O
+groups	O
+showed	O
+statistically	O
+significant	O
+decreases	O
+in	O
+the	O
+mean	O
+number	O
+of	O
+GAD	O
+mRNA	O
+-	O
+containing	O
+neurons	O
+in	O
+the	O
+hilus	O
+of	O
+both	O
+groups	O
+of	O
+experimental	O
+animals	O
+.	O
+
+No	O
+significant	O
+differences	O
+were	O
+found	O
+in	O
+the	O
+molecular	O
+layer	O
+or	O
+the	O
+granule	O
+cell	O
+layer	O
+,	O
+which	O
+included	O
+labeled	O
+neurons	O
+along	O
+the	O
+lower	O
+margin	O
+of	O
+the	O
+granule	O
+cell	O
+layer	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+,	O
+in	O
+this	O
+model	O
+,	O
+a	O
+subpopulation	O
+of	O
+GAD	O
+mRNA	O
+-	O
+containing	O
+neurons	O
+within	O
+the	O
+dentate	O
+gyrus	O
+is	O
+selectively	O
+vulnerable	O
+to	O
+seizure	B
+-	O
+induced	O
+damage	O
+.	O
+
+Such	O
+differential	O
+vulnerability	O
+appears	O
+to	O
+be	O
+another	O
+indication	O
+of	O
+the	O
+heterogeneity	O
+of	O
+GABA	O
+neurons	O
+.	O
+
+Effects	O
+of	O
+deliberate	O
+hypotension	B
+induced	O
+by	O
+labetalol	O
+with	O
+isoflurane	O
+on	O
+neuropsychological	O
+function	O
+.	O
+
+The	O
+effect	O
+of	O
+deliberate	O
+hypotension	B
+on	O
+brain	O
+function	O
+measured	O
+by	O
+neuropsychological	O
+tests	O
+was	O
+studied	O
+in	O
+41	O
+adult	O
+patients	O
+.	O
+
+Twenty	O
+-	O
+four	O
+patients	O
+were	O
+anaesthetized	O
+for	O
+middle	O
+-	O
+ear	O
+surgery	O
+with	O
+deliberate	O
+hypotension	B
+induced	O
+by	O
+labetalol	O
+with	O
+isoflurane	O
+(	O
+hypotensive	B
+group	O
+)	O
+.	O
+
+Seventeen	O
+patients	O
+without	O
+hypotension	B
+served	O
+as	O
+a	O
+control	O
+group	O
+.	O
+
+The	O
+mean	O
+arterial	O
+pressure	O
+was	O
+77	O
++	O
+/	O
+-	O
+2	O
+mmHg	O
+(	O
+10	O
+.	O
+3	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+kPa	O
+)	O
+before	O
+hypotension	B
+and	O
+50	O
++	O
+/	O
+-	O
+0	O
+mmHg	O
+(	O
+6	O
+.	O
+7	O
++	O
+/	O
+-	O
+0	O
+.	O
+0	O
+kPa	O
+)	O
+during	O
+hypotension	B
+in	O
+the	O
+hypotensive	B
+group	O
+,	O
+and	O
+86	O
++	O
+/	O
+-	O
+2	O
+mmHg	O
+(	O
+11	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+kPa	O
+)	O
+during	O
+anaesthesia	O
+in	O
+the	O
+control	O
+group	O
+.	O
+
+The	O
+following	O
+psychological	O
+tests	O
+were	O
+performed	O
+:	O
+four	O
+subtests	O
+of	O
+the	O
+Wechsler	O
+Adult	O
+Intelligence	O
+Scale	O
+(	O
+similarities	O
+,	O
+digit	O
+span	O
+,	O
+vocabulary	O
+and	O
+digit	O
+symbol	O
+)	O
+,	O
+Trail	O
+-	O
+Making	O
+tests	O
+A	O
+and	O
+B	O
+,	O
+Zung	O
+tests	O
+(	O
+self	O
+-	O
+rating	O
+anxiety	B
+scale	O
+and	O
+self	O
+-	O
+rating	O
+depression	B
+scale	O
+)	O
+and	O
+two	O
+-	O
+part	O
+memory	O
+test	O
+battery	O
+with	O
+immediate	O
+and	O
+delayed	O
+recall	O
+.	O
+
+The	O
+tests	O
+were	O
+performed	O
+preoperatively	O
+and	O
+2	O
+days	O
+postoperatively	O
+.	O
+
+There	O
+were	O
+no	O
+statistically	O
+significant	O
+differences	O
+between	O
+the	O
+groups	O
+in	O
+any	O
+of	O
+the	O
+tests	O
+in	O
+the	O
+changes	O
+from	O
+preoperative	O
+value	O
+to	O
+postoperative	O
+value	O
+.	O
+
+The	O
+results	O
+indicate	O
+that	O
+hypotension	B
+induced	O
+by	O
+labetalol	O
+with	O
+isoflurane	O
+has	O
+no	O
+significant	O
+harmful	O
+effects	O
+on	O
+mental	O
+functions	O
+compared	O
+to	O
+normotensive	O
+anaesthesia	O
+.	O
+
+Apparent	O
+cure	O
+of	O
+rheumatoid	B
+arthritis	I
+by	O
+bone	O
+marrow	O
+transplantation	O
+.	O
+
+We	O
+describe	O
+the	O
+induction	O
+of	O
+sustained	O
+remissions	O
+and	O
+possible	O
+cure	O
+of	O
+severe	O
+erosive	O
+rheumatoid	B
+arthritis	I
+(	O
+RA	B
+)	O
+by	O
+bone	O
+marrow	O
+transplantation	O
+(	O
+BMT	O
+)	O
+in	O
+2	O
+patients	O
+.	O
+
+BMT	O
+was	O
+used	O
+to	O
+treat	O
+severe	O
+aplastic	B
+anemia	I
+which	O
+was	O
+caused	O
+by	O
+gold	O
+in	O
+one	O
+case	O
+and	O
+D	O
+-	O
+penicillamine	O
+in	O
+the	O
+other	O
+.	O
+
+In	O
+the	O
+8	O
+and	O
+6	O
+years	O
+since	O
+the	O
+transplants	O
+(	O
+representing	O
+8	O
+and	O
+4	O
+years	O
+since	O
+cessation	O
+of	O
+all	O
+immunosuppressive	O
+therapy	O
+,	O
+respectively	O
+)	O
+,	O
+the	O
+RA	B
+in	O
+each	O
+case	O
+has	O
+been	O
+completely	O
+quiescent	O
+.	O
+
+Although	O
+short	O
+term	O
+remission	O
+of	O
+severe	O
+RA	B
+following	O
+BMT	O
+has	O
+been	O
+reported	O
+,	O
+these	O
+are	O
+the	O
+first	O
+cases	O
+for	O
+which	O
+prolonged	O
+followup	O
+has	O
+been	O
+available	O
+.	O
+
+This	O
+experience	O
+raises	O
+the	O
+question	O
+of	O
+the	O
+role	O
+of	O
+BMT	O
+itself	O
+as	O
+a	O
+therapeutic	O
+option	O
+for	O
+patients	O
+with	O
+uncontrolled	O
+destructive	O
+synovitis	B
+.	O
+
+Seizures	B
+induced	O
+by	O
+combined	O
+levomepromazine	O
+-	O
+fluvoxamine	O
+treatment	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+combined	O
+levomepromazine	O
+-	O
+fluvoxamine	O
+treatment	O
+-	O
+induced	O
+seizures	B
+.	O
+
+It	O
+seems	O
+that	O
+combined	O
+treatment	O
+of	O
+fluvoxamine	O
+with	O
+phenothiazines	O
+may	O
+possess	O
+proconvulsive	O
+activity	O
+.	O
+
+Case	O
+report	O
+:	O
+pentamidine	O
+and	O
+polymorphic	O
+ventricular	B
+tachycardia	I
+revisited	O
+.	O
+
+Pentamidine	O
+isethionate	O
+has	O
+been	O
+associated	O
+with	O
+ventricular	B
+tachyarrhythmias	I
+,	O
+including	O
+torsade	B
+de	I
+pointes	I
+.	O
+
+This	O
+article	O
+reports	O
+two	O
+cases	O
+of	O
+this	O
+complication	O
+and	O
+reviews	O
+all	O
+reported	O
+cases	O
+to	O
+date	O
+.	O
+
+Pentamidine	O
+-	O
+induced	O
+torsade	B
+de	I
+pointes	I
+may	O
+be	O
+related	O
+to	O
+serum	O
+magnesium	O
+levels	O
+and	O
+hypomagnesemia	B
+may	O
+synergistically	O
+induce	O
+torsade	O
+.	O
+
+Torsade	B
+de	I
+pointes	I
+occurred	O
+after	O
+an	O
+average	O
+of	O
+10	O
+days	O
+of	O
+treatment	O
+with	O
+pentamidine	O
+.	O
+
+In	O
+these	O
+patients	O
+,	O
+no	O
+other	O
+acute	O
+side	O
+effects	O
+of	O
+pentamidine	O
+were	O
+observed	O
+.	O
+
+Torsade	B
+de	I
+pointes	I
+can	O
+be	O
+treated	O
+when	O
+recognized	O
+early	O
+,	O
+possibly	O
+without	O
+discontinuation	O
+of	O
+pentamidine	O
+.	O
+
+When	O
+QTc	B
+interval	I
+prolongation	I
+is	O
+observed	O
+,	O
+early	O
+magnesium	O
+supplementation	O
+is	O
+advocated	O
+.	O
+
+Efficacy	O
+and	O
+tolerability	O
+of	O
+lovastatin	O
+in	O
+3390	O
+women	O
+with	O
+moderate	O
+hypercholesterolemia	B
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+evaluate	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+lovastatin	O
+in	O
+women	O
+with	O
+moderate	O
+hypercholesterolemia	B
+.	O
+
+DESIGN	O
+:	O
+The	O
+Expanded	O
+Clinical	O
+Evaluation	O
+of	O
+Lovastatin	O
+(	O
+EXCEL	O
+)	O
+Study	O
+,	O
+a	O
+multicenter	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+diet	O
+-	O
+and	O
+placebo	O
+-	O
+controlled	O
+trial	O
+,	O
+in	O
+which	O
+participants	O
+were	O
+randomly	O
+assigned	O
+to	O
+receive	O
+placebo	O
+or	O
+lovastatin	O
+at	O
+doses	O
+of	O
+20	O
+or	O
+40	O
+mg	O
+once	O
+daily	O
+,	O
+or	O
+20	O
+or	O
+40	O
+mg	O
+twice	O
+daily	O
+for	O
+48	O
+weeks	O
+.	O
+
+SETTING	O
+:	O
+Ambulatory	O
+patients	O
+recruited	O
+by	O
+362	O
+participating	O
+centers	O
+throughout	O
+the	O
+United	O
+States	O
+.	O
+
+PATIENTS	O
+:	O
+Women	O
+(	O
+n	O
+=	O
+3390	O
+)	O
+from	O
+the	O
+total	O
+cohort	O
+of	O
+8245	O
+volunteers	O
+.	O
+
+MEASUREMENTS	O
+:	O
+Plasma	O
+total	O
+,	O
+low	O
+-	O
+density	O
+lipoprotein	O
+(	O
+LDL	O
+)	O
+,	O
+and	O
+high	O
+-	O
+density	O
+lipoprotein	O
+(	O
+HDL	O
+)	O
+cholesterol	O
+,	O
+and	O
+triglycerides	O
+;	O
+and	O
+laboratory	O
+and	O
+clinical	O
+evidence	O
+of	O
+adverse	O
+events	O
+monitored	O
+periodically	O
+throughout	O
+the	O
+study	O
+.	O
+
+RESULTS	O
+:	O
+Among	O
+women	O
+,	O
+lovastatin	O
+(	O
+20	O
+to	O
+80	O
+mg	O
+/	O
+d	O
+)	O
+produced	O
+sustained	O
+(	O
+12	O
+-	O
+to	O
+48	O
+-	O
+week	O
+)	O
+,	O
+dose	O
+-	O
+related	O
+changes	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+:	O
+decreases	O
+in	O
+LDL	O
+cholesterol	O
+(	O
+24	O
+%	O
+to	O
+40	O
+%	O
+)	O
+and	O
+triglycerides	O
+(	O
+9	O
+%	O
+to	O
+18	O
+%	O
+)	O
+,	O
+and	O
+increases	O
+in	O
+HDL	O
+cholesterol	O
+(	O
+6	O
+.	O
+7	O
+%	O
+to	O
+8	O
+.	O
+6	O
+%	O
+)	O
+.	O
+
+Depending	O
+on	O
+the	O
+dose	O
+,	O
+from	O
+82	O
+%	O
+to	O
+95	O
+%	O
+of	O
+lovastatin	O
+-	O
+treated	O
+women	O
+achieved	O
+the	O
+National	O
+Cholesterol	O
+Education	O
+Program	O
+goal	O
+of	O
+LDL	O
+cholesterol	O
+levels	O
+less	O
+than	O
+4	O
+.	O
+14	O
+mmol	O
+/	O
+L	O
+(	O
+160	O
+mg	O
+/	O
+dL	O
+)	O
+,	O
+and	O
+40	O
+%	O
+to	O
+87	O
+%	O
+achieved	O
+the	O
+goal	O
+of	O
+3	O
+.	O
+36	O
+mmol	O
+/	O
+L	O
+(	O
+130	O
+mg	O
+/	O
+dL	O
+)	O
+.	O
+
+Successive	O
+transaminase	O
+elevations	O
+greater	O
+than	O
+three	O
+times	O
+the	O
+upper	O
+limit	O
+of	O
+normal	O
+occurred	O
+in	O
+0	O
+.	O
+1	O
+%	O
+of	O
+women	O
+and	O
+were	O
+dose	O
+dependent	O
+above	O
+the	O
+20	O
+-	O
+mg	O
+dose	O
+.	O
+
+Myopathy	B
+,	O
+defined	O
+as	O
+muscle	O
+symptoms	O
+with	O
+creatine	O
+kinase	O
+elevations	O
+greater	O
+than	O
+10	O
+times	O
+the	O
+upper	O
+limit	O
+of	O
+normal	O
+,	O
+was	O
+rare	O
+and	O
+associated	O
+with	O
+the	O
+highest	O
+recommended	O
+daily	O
+dose	O
+of	O
+lovastatin	O
+(	O
+80	O
+mg	O
+)	O
+.	O
+
+Estrogen	O
+-	O
+replacement	O
+therapy	O
+appeared	O
+to	O
+have	O
+no	O
+effect	O
+on	O
+either	O
+the	O
+efficacy	O
+or	O
+safety	O
+profile	O
+of	O
+lovastatin	O
+.	O
+
+CONCLUSION	O
+:	O
+Lovastatin	O
+is	O
+highly	O
+effective	O
+and	O
+generally	O
+well	O
+tolerated	O
+as	O
+therapy	O
+for	O
+primary	O
+hypercholesterolemia	B
+in	O
+women	O
+.	O
+
+Tetany	B
+and	O
+rhabdomyolysis	B
+due	O
+to	O
+surreptitious	O
+furosemide	O
+-	O
+-	O
+importance	O
+of	O
+magnesium	O
+supplementation	O
+.	O
+
+Diuretics	O
+may	O
+induce	O
+hypokalemia	B
+,	O
+hypocalcemia	B
+and	O
+hypomagnesemia	B
+.	O
+
+While	O
+severe	O
+hypokalemia	B
+may	O
+cause	O
+muscle	B
+weakness	I
+,	O
+severe	O
+hypomagnesemia	B
+is	O
+associated	O
+with	O
+muscle	B
+spasms	I
+and	O
+tetany	B
+which	O
+cannot	O
+be	O
+corrected	O
+by	O
+potassium	O
+and	O
+calcium	O
+supplementation	O
+alone	O
+(	O
+1	O
+,	O
+2	O
+)	O
+.	O
+
+Surreptitious	O
+diuretic	O
+ingestion	O
+has	O
+been	O
+described	O
+,	O
+mainly	O
+in	O
+women	O
+who	O
+are	O
+concerned	O
+that	O
+they	O
+are	O
+obese	B
+or	O
+edematous	B
+.	O
+
+Symptomatic	O
+hypokalemia	B
+has	O
+been	O
+reported	O
+in	O
+such	O
+patients	O
+(	O
+3	O
+-	O
+7	O
+)	O
+and	O
+in	O
+one	O
+case	O
+hypocalcemia	B
+was	O
+observed	O
+(	O
+8	O
+)	O
+,	O
+but	O
+the	O
+effects	O
+of	O
+magnesium	O
+depletion	O
+were	O
+not	O
+noted	O
+in	O
+these	O
+patients	O
+.	O
+
+Ciprofloxacin	O
+-	O
+induced	O
+nephrotoxicity	B
+in	O
+patients	O
+with	O
+cancer	B
+.	O
+
+Nephrotoxicity	B
+associated	O
+with	O
+ciprofloxacin	O
+is	O
+uncommon	O
+.	O
+
+Five	O
+patients	O
+with	O
+cancer	B
+who	O
+developed	O
+acute	B
+renal	I
+failure	I
+that	O
+followed	O
+treatment	O
+with	O
+ciprofloxacin	O
+are	O
+described	O
+and	O
+an	O
+additional	O
+15	O
+cases	O
+reported	O
+in	O
+the	O
+literature	O
+are	O
+reviewed	O
+.	O
+
+Other	O
+than	O
+elevation	O
+of	O
+serum	O
+creatinine	O
+levels	O
+,	O
+characteristic	O
+clinical	O
+manifestations	O
+and	O
+abnormal	O
+laboratory	O
+findings	O
+are	O
+not	O
+frequently	O
+present	O
+.	O
+
+Allergic	O
+interstitial	B
+nephritis	I
+is	O
+believed	O
+to	O
+be	O
+the	O
+underlying	O
+pathological	O
+-	O
+process	O
+.	O
+
+Definitive	O
+diagnosis	O
+requires	O
+performance	O
+of	O
+renal	O
+biopsy	O
+,	O
+although	O
+this	O
+is	O
+not	O
+always	O
+feasible	O
+.	O
+
+An	O
+improvement	O
+in	O
+renal	O
+function	O
+that	O
+followed	O
+the	O
+discontinuation	O
+of	O
+the	O
+offending	O
+antibiotic	O
+supports	O
+the	O
+presumptive	O
+diagnosis	O
+of	O
+ciprofloxacin	O
+-	O
+induced	O
+acute	B
+renal	I
+failure	I
+.	O
+
+Venous	B
+complications	I
+of	O
+midazolam	O
+versus	O
+diazepam	O
+.	O
+
+Although	O
+some	O
+studies	O
+have	O
+suggested	O
+fewer	O
+venous	B
+complications	I
+are	O
+associated	O
+with	O
+midazolam	O
+than	O
+with	O
+diazepam	O
+for	O
+endoscopic	O
+procedures	O
+,	O
+this	O
+variable	O
+has	O
+not	O
+been	O
+well	O
+documented	O
+.	O
+
+We	O
+prospectively	O
+evaluated	O
+the	O
+incidence	O
+of	O
+venous	B
+complications	I
+after	O
+intravenous	O
+injection	O
+of	O
+diazepam	O
+or	O
+midazolam	O
+in	O
+122	O
+consecutive	O
+patients	O
+undergoing	O
+colonoscopy	O
+and	O
+esophagogastroduodenoscopy	O
+.	O
+
+Overall	O
+,	O
+venous	B
+complications	I
+were	O
+more	O
+frequent	O
+with	O
+diazepam	O
+(	O
+22	O
+of	O
+62	O
+patients	O
+)	O
+than	O
+with	O
+midazolam	O
+(	O
+4	O
+of	O
+60	O
+patients	O
+)	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+A	O
+palpable	O
+venous	O
+cord	O
+was	O
+present	O
+in	O
+23	O
+%	O
+(	O
+14	O
+of	O
+62	O
+)	O
+of	O
+patients	O
+in	O
+the	O
+diazepam	O
+group	O
+,	O
+compared	O
+with	O
+2	O
+%	O
+(	O
+1	O
+of	O
+60	O
+patients	O
+)	O
+in	O
+the	O
+midazolam	O
+group	O
+(	O
+p	O
+<	O
+0	O
+.	O
+002	O
+)	O
+.	O
+
+Pain	B
+at	O
+the	O
+injection	O
+site	O
+occurred	O
+in	O
+35	O
+%	O
+(	O
+22	O
+of	O
+62	O
+)	O
+of	O
+patients	O
+in	O
+the	O
+diazepam	O
+group	O
+compared	O
+with	O
+7	O
+%	O
+(	O
+4	O
+of	O
+60	O
+patients	O
+)	O
+in	O
+the	O
+midazolam	O
+group	O
+(	O
+p	O
+<	O
+0	O
+.	O
+001	O
+)	O
+.	O
+
+Swelling	B
+and	O
+warmth	O
+at	O
+the	O
+injection	O
+site	O
+were	O
+not	O
+significantly	O
+different	O
+between	O
+the	O
+two	O
+groups	O
+.	O
+
+Smoking	O
+,	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drug	O
+use	O
+,	O
+intravenous	O
+catheter	O
+site	O
+,	O
+dwell	O
+time	O
+of	O
+the	O
+needle	O
+,	O
+alcohol	O
+use	O
+,	O
+and	O
+pain	B
+during	O
+the	O
+injection	O
+had	O
+no	O
+effect	O
+on	O
+the	O
+incidence	O
+of	O
+venous	B
+complications	I
+.	O
+
+Clarithromycin	O
+-	O
+associated	O
+visual	B
+hallucinations	I
+in	O
+a	O
+patient	O
+with	O
+chronic	B
+renal	I
+failure	I
+on	O
+continuous	O
+ambulatory	O
+peritoneal	O
+dialysis	O
+.	O
+
+Visual	B
+hallucinations	I
+are	O
+a	O
+rare	O
+event	O
+in	O
+chronic	B
+renal	I
+failure	I
+and	O
+not	O
+related	O
+to	O
+uremia	B
+per	O
+se	O
+.	O
+
+Unreported	O
+in	O
+the	O
+literature	O
+is	O
+visual	B
+hallucinations	I
+occurring	O
+in	O
+association	O
+with	O
+the	O
+new	O
+macrolide	O
+antibiotic	O
+,	O
+clarithromycin	O
+.	O
+
+We	O
+describe	O
+such	O
+a	O
+case	O
+in	O
+a	O
+patient	O
+with	O
+end	B
+-	I
+stage	I
+renal	I
+disease	I
+(	O
+ESRD	B
+)	O
+maintained	O
+on	O
+continuous	O
+ambulatory	O
+peritoneal	O
+dialysis	O
+(	O
+CAPD	O
+)	O
+.	O
+
+The	O
+combination	O
+of	O
+a	O
+relatively	O
+high	O
+dose	O
+of	O
+clarithromycin	O
+in	O
+face	O
+of	O
+chronic	B
+renal	I
+failure	I
+in	O
+a	O
+functionally	O
+anephric	O
+patient	O
+,	O
+with	O
+underlying	O
+aluminum	O
+intoxication	O
+,	O
+may	O
+have	O
+facilitated	O
+the	O
+appearance	O
+of	O
+this	O
+neurotoxic	B
+side	O
+effect	O
+.	O
+
+It	O
+is	O
+important	O
+to	O
+understand	O
+the	O
+pharmacokinetics	O
+of	O
+medications	O
+in	O
+face	O
+of	O
+chronic	B
+renal	I
+failure	I
+,	O
+the	O
+possibility	O
+of	O
+drug	O
+interactions	O
+,	O
+and	O
+how	O
+these	O
+factors	O
+should	O
+help	O
+guide	O
+medication	O
+therapy	O
+in	O
+the	O
+ESRD	B
+patient	O
+.	O
+
+Changes	O
+in	O
+peroxisomes	O
+in	O
+preneoplastic	O
+liver	O
+and	O
+hepatoma	B
+of	O
+mice	O
+induced	O
+by	O
+alpha	O
+-	O
+benzene	O
+hexachloride	O
+.	O
+
+Peroxisomes	O
+in	O
+hepatomas	B
+and	O
+hyperplastic	O
+preneoplastic	O
+liver	B
+lesions	I
+induced	O
+in	O
+mice	O
+by	O
+500	O
+ppm	O
+alpha	O
+-	O
+benzene	O
+hexachloride	O
+were	O
+examined	O
+histochemically	O
+and	O
+electron	O
+microscopically	O
+.	O
+
+Although	O
+most	O
+of	O
+the	O
+hepatomas	B
+were	O
+well	O
+-	O
+differentiated	O
+tumors	B
+and	O
+contained	O
+a	O
+considerable	O
+number	O
+of	O
+peroxisomes	O
+,	O
+the	O
+tumor	B
+cells	O
+did	O
+not	O
+respond	O
+to	O
+ethyl	O
+-	O
+alpha	O
+-	O
+p	O
+-	O
+chlorophenoxyisobutyrate	O
+with	O
+proliferation	O
+of	O
+peroxisomes	O
+.	O
+
+At	O
+the	O
+16th	O
+week	O
+of	O
+carcinogen	O
+feeding	O
+,	O
+hyperplastic	O
+nodules	O
+appeared	O
+and	O
+advanced	O
+to	O
+further	O
+stages	O
+.	O
+
+A	O
+majority	O
+of	O
+the	O
+nodules	O
+showed	O
+a	O
+considerable	O
+number	O
+of	O
+peroxisomes	O
+and	O
+the	O
+inductive	O
+proliferation	O
+of	O
+peroxisomes	O
+.	O
+
+Within	O
+the	O
+nodules	O
+,	O
+foci	O
+of	O
+proliferation	O
+of	O
+the	O
+cells	O
+that	O
+showed	O
+no	O
+inducibility	O
+of	O
+proliferation	O
+of	O
+peroxisomes	O
+appeared	O
+.	O
+
+These	O
+cells	O
+proliferated	O
+further	O
+,	O
+replacing	O
+the	O
+most	O
+part	O
+of	O
+the	O
+nodules	O
+,	O
+and	O
+with	O
+this	O
+process	O
+hepatomas	B
+appeared	O
+to	O
+have	O
+been	O
+formed	O
+.	O
+
+No	O
+abnormal	O
+matrical	O
+inclusions	O
+of	O
+peroxisomes	O
+were	O
+formed	O
+in	O
+the	O
+cells	O
+of	O
+hyperplastic	O
+nodules	O
+by	O
+ethyl	O
+-	O
+alpha	O
+-	O
+p	O
+-	O
+chlorophenoxyisobutyrate	O
+unlike	O
+in	O
+the	O
+case	O
+of	O
+rats	O
+.	O
+
+Contribution	O
+of	O
+the	O
+sympathetic	O
+nervous	O
+system	O
+to	O
+salt	O
+-	O
+sensitivity	O
+in	O
+lifetime	O
+captopril	O
+-	O
+treated	O
+spontaneously	O
+hypertensive	B
+rats	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+test	O
+the	O
+hypothesis	O
+that	O
+,	O
+in	O
+lifetime	O
+captopril	O
+-	O
+treated	O
+spontaneously	O
+hypertensive	B
+rats	O
+(	O
+SHR	O
+)	O
+,	O
+the	O
+sympathetic	O
+nervous	O
+system	O
+contributes	O
+importantly	O
+to	O
+the	O
+hypertensive	B
+effect	O
+of	O
+dietary	O
+sodium	O
+chloride	O
+supplementation	O
+.	O
+
+METHODS	O
+:	O
+Male	O
+SHR	O
+(	O
+aged	O
+6	O
+weeks	O
+)	O
+that	O
+had	O
+been	O
+treated	O
+from	O
+conception	O
+onward	O
+with	O
+either	O
+captopril	O
+or	O
+vehicle	O
+remained	O
+on	O
+a	O
+basal	O
+sodium	O
+chloride	O
+diet	O
+or	O
+were	O
+fed	O
+a	O
+high	O
+sodium	O
+chloride	O
+diet	O
+.	O
+
+After	O
+2	O
+weeks	O
+,	O
+the	O
+rats	O
+were	O
+subjected	O
+to	O
+ganglionic	O
+blockade	O
+and	O
+2	O
+days	O
+later	O
+,	O
+an	O
+infusion	O
+of	O
+clonidine	O
+.	O
+
+RESULTS	O
+:	O
+Lifetime	O
+captopril	O
+treatment	O
+significantly	O
+lowered	O
+mean	O
+arterial	O
+pressure	O
+in	O
+both	O
+groups	O
+.	O
+
+Intravenous	O
+infusion	O
+of	O
+the	O
+ganglionic	O
+blocker	O
+hexamethonium	O
+resulted	O
+in	O
+a	O
+rapid	O
+decline	O
+in	O
+MAP	O
+that	O
+eliminated	O
+the	O
+dietary	O
+sodium	O
+chloride	O
+-	O
+induced	O
+increase	B
+in	I
+MAP	I
+in	O
+both	O
+groups	O
+.	O
+
+Infusion	O
+of	O
+the	O
+central	O
+nervous	O
+system	O
+alpha2	O
+-	O
+adrenergic	O
+receptor	O
+agonist	O
+clonidine	O
+also	O
+resulted	O
+in	O
+a	O
+greater	O
+reduction	O
+in	O
+MAP	O
+in	O
+both	O
+groups	O
+of	O
+SHR	O
+that	O
+were	O
+fed	O
+the	O
+high	O
+(	O
+compared	O
+with	O
+the	O
+basal	O
+)	O
+sodium	O
+chloride	O
+diet	O
+.	O
+
+CONCLUSIONS	O
+:	O
+In	O
+both	O
+lifetime	O
+captopril	O
+-	O
+treated	O
+and	O
+control	O
+SHR	O
+,	O
+the	O
+sympathetic	O
+nervous	O
+system	O
+contributes	O
+to	O
+the	O
+pressor	O
+effects	O
+of	O
+a	O
+high	O
+sodium	O
+chloride	O
+diet	O
+.	O
+
+Angioedema	B
+associated	O
+with	O
+droperidol	O
+administration	O
+.	O
+
+Angioedema	B
+,	O
+also	O
+known	O
+as	O
+angioneurotic	B
+edema	I
+or	O
+Quincke	B
+'	I
+s	I
+disease	I
+,	O
+is	O
+a	O
+well	O
+-	O
+demarcated	O
+,	O
+localized	O
+edema	B
+involving	O
+the	O
+subcutaneous	O
+tissues	O
+that	O
+may	O
+cause	O
+upper	B
+-	I
+airway	I
+obstruction	I
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+previously	O
+healthy	O
+19	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+no	O
+known	O
+drug	B
+allergies	I
+in	O
+whom	O
+angioedema	B
+with	O
+significant	O
+tongue	B
+swelling	I
+and	O
+protrusion	O
+developed	O
+within	O
+10	O
+minutes	O
+of	O
+the	O
+administration	O
+of	O
+a	O
+single	O
+IV	O
+dose	O
+of	O
+droperidol	O
+.	O
+
+Late	O
+cardiotoxicity	B
+after	O
+treatment	O
+for	O
+a	O
+malignant	O
+bone	B
+tumor	I
+.	O
+
+Cardiac	O
+function	O
+was	O
+assessed	O
+in	O
+long	O
+-	O
+term	O
+survivors	O
+of	O
+malignant	O
+bone	B
+tumors	I
+who	O
+were	O
+treated	O
+according	O
+to	O
+Rosen	O
+'	O
+s	O
+T5	O
+or	O
+T10	O
+protocol	O
+,	O
+both	O
+including	O
+doxorubicin	O
+.	O
+
+Thirty	O
+-	O
+one	O
+patients	O
+,	O
+age	O
+10	O
+-	O
+45	O
+years	O
+(	O
+median	O
+age	O
+17	O
+.	O
+8	O
+years	O
+)	O
+were	O
+evaluated	O
+2	O
+.	O
+3	O
+-	O
+14	O
+.	O
+1	O
+years	O
+(	O
+median	O
+8	O
+.	O
+9	O
+years	O
+)	O
+following	O
+completion	O
+of	O
+treatment	O
+.	O
+
+Cumulative	O
+doses	O
+of	O
+doxorubicin	O
+were	O
+225	O
+-	O
+550	O
+mg	O
+/	O
+m2	O
+(	O
+median	O
+dose	O
+360	O
+)	O
+.	O
+
+The	O
+evaluation	O
+consisted	O
+of	O
+a	O
+history	O
+,	O
+physical	O
+examination	O
+,	O
+electrocardiogram	O
+(	O
+ECG	O
+)	O
+,	O
+signal	O
+averaged	O
+ECG	O
+,	O
+24	O
+-	O
+hour	O
+ambulatory	O
+ECG	O
+,	O
+echocardiography	O
+and	O
+radionuclide	O
+angiography	O
+.	O
+
+Eighteen	O
+of	O
+31	O
+(	O
+58	O
+%	O
+)	O
+patients	O
+showed	O
+cardiac	B
+toxicity	I
+,	O
+defined	O
+as	O
+having	O
+one	O
+or	O
+more	O
+of	O
+the	O
+following	O
+abnormalities	O
+:	O
+late	O
+potentials	O
+,	O
+complex	O
+ventricular	B
+arrhythmias	I
+,	O
+left	O
+ventricular	B
+dilation	I
+,	O
+decreased	O
+shortening	O
+fraction	O
+,	O
+or	O
+decreased	O
+ejection	O
+fraction	O
+.	O
+
+The	O
+incidence	O
+of	O
+cardiac	B
+abnormalities	I
+increased	O
+with	O
+length	O
+of	O
+follow	O
+-	O
+up	O
+(	O
+P	O
+<	O
+or	O
+=	O
+.	O
+05	O
+)	O
+.	O
+
+No	O
+correlation	O
+could	O
+be	O
+demonstrated	O
+between	O
+cumulative	O
+dose	O
+of	O
+doxorubicin	O
+and	O
+cardiac	O
+status	O
+,	O
+except	O
+for	O
+heart	O
+rate	O
+variability	O
+.	O
+
+When	O
+adjusted	O
+to	O
+body	O
+surface	O
+area	O
+,	O
+the	O
+left	O
+ventricular	O
+posterior	O
+wall	O
+thickness	O
+(	O
+LVPW	O
+index	O
+)	O
+was	O
+decreased	O
+in	O
+all	O
+patients	O
+.	O
+
+The	O
+incidence	O
+of	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B
+is	O
+high	O
+and	O
+increases	O
+with	O
+follow	O
+-	O
+up	O
+,	O
+irrespective	O
+of	O
+cumulative	O
+dose	O
+.	O
+
+Life	O
+-	O
+long	O
+cardiac	O
+follow	O
+-	O
+up	O
+in	O
+these	O
+patients	O
+is	O
+warranted	O
+.	O
+
+The	O
+results	O
+of	O
+our	O
+study	O
+suggest	O
+that	O
+heart	O
+rate	O
+variability	O
+and	O
+LVPW	O
+index	O
+could	O
+be	O
+sensitive	O
+indicators	O
+for	O
+cardiotoxicity	B
+.	O
+
+Acute	O
+blood	O
+pressure	O
+elevations	O
+with	O
+caffeine	O
+in	O
+men	O
+with	O
+borderline	O
+systemic	O
+hypertension	B
+.	O
+
+Whether	O
+the	O
+vasoconstrictive	O
+actions	O
+of	O
+caffeine	O
+are	O
+enhanced	O
+in	O
+hypertensive	B
+persons	O
+has	O
+not	O
+been	O
+demonstrated	O
+.	O
+
+Thus	O
+,	O
+caffeine	O
+(	O
+3	O
+.	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+versus	O
+placebo	O
+was	O
+tested	O
+in	O
+48	O
+healthy	O
+men	O
+(	O
+aged	O
+20	O
+to	O
+35	O
+years	O
+)	O
+selected	O
+after	O
+screening	O
+on	O
+2	O
+separate	O
+occasions	O
+.	O
+
+Borderline	O
+hypertensive	B
+men	O
+(	O
+n	O
+=	O
+24	O
+)	O
+were	O
+selected	O
+with	O
+screening	O
+systolic	O
+blood	O
+pressure	O
+(	O
+BP	O
+)	O
+of	O
+140	O
+to	O
+160	O
+mm	O
+Hg	O
+and	O
+/	O
+or	O
+diastolic	O
+BP	O
+90	O
+to	O
+99	O
+mm	O
+Hg	O
+.	O
+
+Low	O
+-	O
+risk	O
+controls	O
+(	O
+n	O
+=	O
+24	O
+)	O
+reported	O
+no	O
+parental	O
+history	O
+of	O
+hypertension	B
+and	O
+had	O
+screening	O
+BP	O
+<	O
+130	O
+/	O
+85	O
+mm	O
+Hg	O
+.	O
+
+Participants	O
+were	O
+then	O
+tested	O
+on	O
+2	O
+occasions	O
+after	O
+12	O
+-	O
+hour	O
+abstinence	O
+from	O
+caffeine	O
+in	O
+each	O
+of	O
+2	O
+protocols	O
+;	O
+this	O
+required	O
+a	O
+total	O
+of	O
+4	O
+laboratory	O
+visits	O
+.	O
+
+Caffeine	O
+-	O
+induced	O
+changes	O
+in	O
+diastolic	O
+BP	O
+were	O
+2	O
+to	O
+3	O
+times	O
+larger	O
+in	O
+borderline	O
+subjects	O
+than	O
+in	O
+controls	O
+(	O
++	O
+8	O
+.	O
+4	O
+vs	O
++	O
+3	O
+.	O
+8	O
+mm	O
+Hg	O
+,	O
+p	O
+<	O
+0	O
+.	O
+0001	O
+)	O
+,	O
+and	O
+were	O
+attributable	O
+to	O
+larger	O
+changes	O
+in	O
+impedance	O
+-	O
+derived	O
+measures	O
+of	O
+systemic	O
+vascular	O
+resistance	O
+(	O
++	O
+135	O
+vs	O
++	O
+45	O
+dynes	O
+.	O
+s	O
+.	O
+cm	O
+-	O
+5	O
+,	O
+p	O
+<	O
+0	O
+.	O
+004	O
+)	O
+.	O
+
+These	O
+findings	O
+were	O
+consistent	O
+and	O
+reached	O
+significance	O
+in	O
+both	O
+protocols	O
+.	O
+
+The	O
+percentage	O
+of	O
+borderline	O
+subjects	O
+in	O
+whom	O
+diastolic	O
+BP	O
+changes	O
+exceeded	O
+the	O
+median	O
+control	O
+response	O
+was	O
+96	O
+%	O
+.	O
+
+Consequently	O
+,	O
+whereas	O
+all	O
+participants	O
+exhibited	O
+normotensive	O
+levels	O
+during	O
+the	O
+resting	O
+predrug	O
+baseline	O
+,	O
+33	O
+%	O
+of	O
+borderline	O
+subjects	O
+achieved	O
+hypertensive	B
+BP	O
+levels	O
+after	O
+caffeine	O
+ingestion	O
+.	O
+
+Thus	O
+,	O
+in	O
+borderline	O
+hypertensive	B
+men	O
+,	O
+exaggerated	O
+responses	O
+to	O
+caffeine	O
+were	O
+:	O
+selective	O
+for	O
+diastolic	O
+BP	O
+,	O
+consistent	O
+with	O
+greater	O
+vasoconstriction	O
+,	O
+replicated	O
+in	O
+2	O
+protocols	O
+,	O
+and	O
+representative	O
+of	O
+nearly	O
+all	O
+borderline	O
+hypertensives	B
+.	O
+
+We	O
+suspect	O
+that	O
+the	O
+potential	O
+for	O
+caffeine	O
+to	O
+stabilize	O
+high	O
+resistance	O
+states	O
+in	O
+susceptible	O
+persons	O
+suggests	O
+that	O
+its	O
+use	O
+may	O
+facilitate	O
+their	O
+disease	O
+progression	O
+,	O
+as	O
+well	O
+as	O
+hinder	O
+accurate	O
+diagnosis	O
+and	O
+treatment	O
+.	O
+
+Absence	O
+of	O
+effect	O
+of	O
+sertraline	O
+on	O
+time	O
+-	O
+based	O
+sensitization	O
+of	O
+cognitive	B
+impairment	I
+with	O
+haloperidol	O
+.	O
+
+This	O
+double	O
+-	O
+blind	O
+,	O
+randomized	O
+,	O
+placebo	O
+-	O
+controlled	O
+study	O
+evaluated	O
+the	O
+effects	O
+of	O
+haloperidol	O
+alone	O
+and	O
+haloperidol	O
+plus	O
+sertraline	O
+on	O
+cognitive	O
+and	O
+psychomotor	O
+function	O
+in	O
+24	O
+healthy	O
+male	O
+subjects	O
+.	O
+
+METHOD	O
+:	O
+All	O
+subjects	O
+received	O
+placebo	O
+on	O
+Day	O
+1	O
+and	O
+haloperidol	O
+2	O
+mg	O
+on	O
+Days	O
+2	O
+and	O
+25	O
+.	O
+
+From	O
+Days	O
+9	O
+to	O
+25	O
+,	O
+subjects	O
+were	O
+randomly	O
+assigned	O
+to	O
+either	O
+sertraline	O
+(	O
+12	O
+subjects	O
+)	O
+or	O
+placebo	O
+(	O
+12	O
+subjects	O
+)	O
+;	O
+the	O
+sertraline	O
+dose	O
+was	O
+titrated	O
+from	O
+50	O
+to	O
+200	O
+mg	O
+/	O
+day	O
+from	O
+Days	O
+9	O
+to	O
+16	O
+,	O
+and	O
+remained	O
+at	O
+200	O
+mg	O
+/	O
+day	O
+for	O
+the	O
+final	O
+10	O
+days	O
+of	O
+the	O
+drug	O
+administration	O
+period	O
+.	O
+
+Cognitive	O
+function	O
+testing	O
+was	O
+performed	O
+before	O
+dosing	O
+and	O
+over	O
+a	O
+24	O
+-	O
+hour	O
+period	O
+after	O
+dosing	O
+on	O
+Days	O
+1	O
+,	O
+2	O
+,	O
+and	O
+25	O
+.	O
+
+RESULTS	O
+:	O
+Impairment	B
+of	I
+cognitive	I
+function	I
+was	O
+observed	O
+6	O
+to	O
+8	O
+hours	O
+after	O
+administration	O
+of	O
+haloperidol	O
+on	O
+Day	O
+2	O
+but	O
+was	O
+not	O
+evident	O
+23	O
+hours	O
+after	O
+dosing	O
+.	O
+
+When	O
+single	O
+-	O
+dose	O
+haloperidol	O
+was	O
+given	O
+again	O
+25	O
+days	O
+later	O
+,	O
+greater	O
+impairment	O
+with	O
+earlier	O
+onset	O
+was	O
+noted	O
+in	O
+several	O
+tests	O
+in	O
+both	O
+treatment	O
+groups	O
+,	O
+suggesting	O
+enhancement	O
+of	O
+this	O
+effect	O
+.	O
+
+There	O
+was	O
+no	O
+indication	O
+that	O
+sertraline	O
+exacerbated	O
+the	O
+impairment	O
+produced	O
+by	O
+haloperidol	O
+since	O
+an	O
+equivalent	O
+effect	O
+also	O
+occurred	O
+in	O
+the	O
+placebo	O
+group	O
+.	O
+
+Three	O
+subjects	O
+(	O
+2	O
+on	O
+sertraline	O
+and	O
+1	O
+on	O
+placebo	O
+)	O
+withdrew	O
+from	O
+the	O
+study	O
+because	O
+of	O
+side	O
+effects	O
+.	O
+
+Ten	O
+subjects	O
+in	O
+each	O
+group	O
+reported	O
+side	O
+effects	O
+related	O
+to	O
+treatment	O
+.	O
+
+The	O
+side	O
+effect	O
+profiles	O
+of	O
+sertraline	O
+and	O
+of	O
+placebo	O
+were	O
+similar	O
+.	O
+
+CONCLUSION	O
+:	O
+Haloperidol	O
+produced	O
+a	O
+clear	O
+profile	O
+of	O
+cognitive	B
+impairment	I
+that	O
+was	O
+not	O
+worsened	O
+by	O
+concomitant	O
+sertraline	O
+administration	O
+.	O
+
+Coexistence	O
+of	O
+cerebral	B
+venous	I
+sinus	I
+and	I
+internal	I
+carotid	I
+artery	I
+thrombosis	I
+associated	O
+with	O
+exogenous	O
+sex	O
+hormones	O
+.	O
+
+A	O
+case	O
+report	O
+.	O
+
+A	O
+forty	O
+-	O
+six	O
+year	O
+-	O
+old	O
+premenopausal	O
+woman	O
+developed	O
+headache	B
+,	O
+nausea	B
+and	O
+vomiting	B
+,	O
+left	O
+hemiparesis	B
+and	O
+seizure	B
+two	O
+days	O
+after	O
+parenteral	O
+use	O
+of	O
+progesterone	O
+and	O
+estradiol	O
+.	O
+
+Diabetes	B
+mellitus	I
+(	O
+DM	B
+)	O
+was	O
+found	O
+during	O
+admission	O
+.	O
+
+Computed	O
+tomography	O
+showed	O
+a	O
+hemorrhagic	B
+infarct	I
+in	O
+the	O
+right	O
+frontal	O
+lobe	O
+and	O
+increased	O
+density	O
+in	O
+the	O
+superior	O
+sagittal	O
+sinus	O
+(	O
+SSS	O
+)	O
+.	O
+
+Left	O
+carotid	O
+angiography	O
+found	O
+occlusion	B
+of	I
+the	I
+left	I
+internal	I
+carotid	I
+artery	I
+(	O
+ICA	O
+)	O
+.	O
+
+Right	O
+carotid	O
+angiograms	O
+failed	O
+to	O
+show	O
+the	O
+SSS	O
+and	O
+inferior	O
+sagittal	O
+sinus	O
+,	O
+suggestive	O
+of	O
+venous	B
+sinus	I
+thrombosis	I
+.	O
+
+Coexistence	O
+of	O
+the	O
+cerebral	B
+artery	I
+and	I
+the	I
+venous	I
+sinus	I
+occlusion	I
+has	O
+been	O
+described	O
+infrequently	O
+.	O
+
+In	O
+this	O
+case	O
+,	O
+the	O
+authors	O
+postulate	O
+that	O
+the	O
+use	O
+of	O
+estradiol	O
+and	O
+progesterone	O
+and	O
+the	O
+underlying	O
+DM	B
+increased	O
+vascular	O
+thrombogenicity	O
+,	O
+which	O
+provided	O
+a	O
+common	O
+denominator	O
+for	O
+thrombosis	B
+of	I
+both	I
+the	I
+ICA	I
+and	I
+the	I
+venous	I
+sinus	I
+.	O
+
+Chemotherapy	O
+of	O
+advanced	O
+inoperable	O
+non	B
+-	I
+small	I
+cell	I
+lung	I
+cancer	I
+with	O
+paclitaxel	O
+:	O
+a	O
+phase	O
+II	O
+trial	O
+.	O
+
+Paclitaxel	O
+(	O
+Taxol	O
+;	O
+Bristol	O
+-	O
+Myers	O
+Squibb	O
+Company	O
+,	O
+Princeton	O
+,	O
+NJ	O
+)	O
+has	O
+demonstrated	O
+significant	O
+antineoplastic	O
+activity	O
+against	O
+different	O
+tumor	B
+types	O
+,	O
+notably	O
+ovarian	B
+and	I
+breast	I
+carcinoma	I
+.	O
+
+Two	O
+phase	O
+II	O
+trials	O
+of	O
+24	O
+-	O
+hour	O
+paclitaxel	O
+infusions	O
+in	O
+chemotherapy	O
+-	O
+naive	O
+patients	O
+with	O
+stage	O
+IIIB	O
+or	O
+IV	O
+non	B
+-	I
+small	I
+cell	I
+lung	I
+cancer	I
+(	O
+NSCLC	B
+)	O
+reported	O
+response	O
+rates	O
+of	O
+21	O
+%	O
+and	O
+24	O
+%	O
+.	O
+
+Leukopenia	B
+was	O
+dose	O
+limiting	O
+:	O
+as	O
+many	O
+as	O
+62	O
+.	O
+5	O
+%	O
+of	O
+patients	O
+experienced	O
+grade	O
+4	O
+leukopenia	B
+.	O
+
+We	O
+investigated	O
+the	O
+efficacy	O
+and	O
+toxicity	B
+of	O
+a	O
+3	O
+-	O
+hour	O
+paclitaxel	O
+infusion	O
+in	O
+a	O
+phase	O
+II	O
+trial	O
+in	O
+patients	O
+with	O
+inoperable	O
+stage	O
+IIIB	O
+or	O
+IV	O
+NSCLC	B
+.	O
+
+The	O
+58	O
+patients	O
+treated	O
+(	O
+41	O
+men	O
+and	O
+17	O
+women	O
+)	O
+had	O
+a	O
+median	O
+age	O
+of	O
+59	O
+years	O
+(	O
+age	O
+range	O
+,	O
+25	O
+to	O
+75	O
+)	O
+and	O
+a	O
+performance	O
+status	O
+of	O
+0	O
+through	O
+2	O
+.	O
+
+Most	O
+patients	O
+(	O
+72	O
+.	O
+4	O
+%	O
+)	O
+had	O
+stage	O
+IV	O
+NSCLC	B
+.	O
+
+Paclitaxel	O
+225	O
+mg	O
+/	O
+m2	O
+was	O
+infused	O
+over	O
+3	O
+hours	O
+every	O
+3	O
+weeks	O
+with	O
+standard	O
+prophylactic	O
+premedication	O
+.	O
+
+Of	O
+50	O
+patients	O
+evaluable	O
+for	O
+response	O
+,	O
+12	O
+(	O
+24	O
+%	O
+)	O
+had	O
+partial	O
+remission	O
+,	O
+26	O
+(	O
+52	O
+%	O
+)	O
+had	O
+no	O
+change	O
+,	O
+and	O
+12	O
+had	O
+disease	O
+progression	O
+(	O
+24	O
+%	O
+)	O
+.	O
+
+Hematologic	O
+toxicities	B
+were	O
+mild	O
+:	O
+only	O
+one	O
+patient	O
+(	O
+2	O
+%	O
+)	O
+developed	O
+grade	O
+3	O
+or	O
+4	O
+neutropenia	B
+,	O
+while	O
+29	O
+%	O
+had	O
+grade	O
+1	O
+or	O
+2	O
+.	O
+
+Grade	O
+1	O
+or	O
+2	O
+polyneuropathy	B
+affected	O
+56	O
+%	O
+of	O
+patients	O
+while	O
+only	O
+one	O
+(	O
+2	O
+%	O
+)	O
+experienced	O
+severe	O
+polyneuropathy	B
+.	O
+
+Similarly	O
+,	O
+grade	O
+1	O
+or	O
+2	O
+myalgia	B
+/	O
+arthralgia	B
+was	O
+observed	O
+in	O
+63	O
+.	O
+2	O
+%	O
+of	O
+patients	O
+,	O
+but	O
+only	O
+14	O
+.	O
+3	O
+%	O
+experienced	O
+grade	O
+3	O
+or	O
+4	O
+.	O
+
+Nausea	B
+and	O
+vomiting	B
+were	O
+infrequent	O
+,	O
+with	O
+14	O
+%	O
+of	O
+patients	O
+experiencing	O
+grade	O
+1	O
+or	O
+2	O
+and	O
+only	O
+2	O
+%	O
+experiencing	O
+grade	O
+3	O
+or	O
+4	O
+.	O
+
+Paclitaxel	O
+is	O
+thus	O
+an	O
+active	O
+single	O
+agent	O
+in	O
+this	O
+patient	O
+population	O
+,	O
+with	O
+a	O
+3	O
+-	O
+hour	O
+infusion	O
+proving	O
+comparably	O
+effective	O
+to	O
+a	O
+24	O
+-	O
+hour	O
+infusion	O
+and	O
+superior	O
+in	O
+terms	O
+of	O
+the	O
+incidence	O
+of	O
+hematologic	O
+and	O
+nonhematologic	O
+toxicity	B
+.	O
+
+Further	O
+phase	O
+II	O
+studies	O
+with	O
+paclitaxel	O
+combined	O
+with	O
+other	O
+drugs	O
+active	O
+against	O
+NSCLC	B
+are	O
+indicated	O
+,	O
+and	O
+phase	O
+III	O
+studies	O
+comparing	O
+paclitaxel	O
+with	O
+standard	O
+chemotherapy	O
+remain	O
+to	O
+be	O
+completed	O
+.	O
+
+Paclitaxel	O
+combined	O
+with	O
+carboplatin	O
+in	O
+the	O
+first	O
+-	O
+line	O
+treatment	O
+of	O
+advanced	O
+ovarian	B
+cancer	I
+.	O
+
+In	O
+a	O
+phase	O
+I	O
+study	O
+to	O
+determine	O
+the	O
+maximum	O
+tolerated	O
+dose	O
+of	O
+paclitaxel	O
+(	O
+Taxol	O
+;	O
+Bristol	O
+-	O
+Myers	O
+Squibb	O
+Company	O
+,	O
+Princeton	O
+,	O
+NJ	O
+)	O
+given	O
+as	O
+a	O
+3	O
+-	O
+hour	O
+infusion	O
+in	O
+combination	O
+with	O
+carboplatin	O
+administered	O
+every	O
+21	O
+days	O
+to	O
+women	O
+with	O
+advanced	O
+ovarian	B
+cancer	I
+,	O
+paclitaxel	O
+doses	O
+were	O
+escalated	O
+as	O
+follows	O
+:	O
+level	O
+1	O
+,	O
+135	O
+mg	O
+/	O
+m2	O
+;	O
+level	O
+2	O
+,	O
+160	O
+mg	O
+/	O
+m2	O
+;	O
+level	O
+3	O
+,	O
+185	O
+mg	O
+/	O
+m2	O
+;	O
+and	O
+level	O
+4	O
+,	O
+210	O
+mg	O
+/	O
+m2	O
+.	O
+
+The	O
+fixed	O
+dose	O
+of	O
+carboplatin	O
+at	O
+levels	O
+1	O
+through	O
+4	O
+was	O
+given	O
+to	O
+achieve	O
+an	O
+area	O
+under	O
+the	O
+concentration	O
+-	O
+time	O
+curve	O
+(	O
+AUC	O
+)	O
+of	O
+5	O
+using	O
+the	O
+Calvert	O
+formula	O
+.	O
+
+In	O
+levels	O
+5	O
+and	O
+6	O
+the	O
+carboplatin	O
+dose	O
+was	O
+targeted	O
+at	O
+AUCs	O
+of	O
+6	O
+and	O
+7	O
+.	O
+5	O
+,	O
+respectively	O
+,	O
+combined	O
+with	O
+a	O
+fixed	O
+paclitaxel	O
+dose	O
+of	O
+185	O
+mg	O
+/	O
+m2	O
+.	O
+
+To	O
+date	O
+,	O
+30	O
+previously	O
+untreated	O
+patients	O
+,	O
+all	O
+with	O
+a	O
+good	O
+performance	O
+status	O
+(	O
+Eastern	O
+Cooperative	O
+Oncology	O
+Group	O
+0	O
+to	O
+2	O
+)	O
+have	O
+been	O
+entered	O
+into	O
+this	O
+ongoing	O
+study	O
+.	O
+
+The	O
+dose	O
+-	O
+limiting	O
+toxicity	B
+of	O
+the	O
+combination	O
+was	O
+myelosuppression	B
+(	O
+leukopenia	B
+,	O
+granulocytopenia	B
+,	O
+and	O
+thrombocytopenia	B
+)	O
+.	O
+
+Neurotoxicity	B
+was	O
+largely	O
+moderate	O
+.	O
+
+So	O
+far	O
+,	O
+14	O
+patients	O
+are	O
+evaluable	O
+for	O
+response	O
+;	O
+of	O
+these	O
+,	O
+eight	O
+(	O
+57	O
+%	O
+)	O
+showed	O
+objective	O
+(	O
+complete	O
+or	O
+partial	O
+)	O
+response	O
+and	O
+disease	O
+stabilized	O
+in	O
+six	O
+patients	O
+.	O
+
+No	O
+patient	O
+had	O
+disease	O
+progression	O
+.	O
+
+We	O
+conclude	O
+that	O
+the	O
+combination	O
+of	O
+paclitaxel	O
+185	O
+mg	O
+/	O
+m2	O
+administered	O
+as	O
+a	O
+3	O
+-	O
+hour	O
+infusion	O
+followed	O
+immediately	O
+by	O
+a	O
+1	O
+-	O
+hour	O
+infusion	O
+of	O
+carboplatin	O
+at	O
+an	O
+AUC	O
+of	O
+6	O
+can	O
+be	O
+administered	O
+safely	O
+in	O
+a	O
+21	O
+-	O
+day	O
+schedule	O
+in	O
+the	O
+outpatient	O
+setting	O
+.	O
+
+The	O
+recommended	O
+dose	O
+for	O
+phase	O
+III	O
+studies	O
+is	O
+paclitaxel	O
+185	O
+mg	O
+/	O
+m2	O
+and	O
+carboplatin	O
+AUC	O
+6	O
+.	O
+
+Effects	O
+of	O
+acute	O
+steroid	O
+administration	O
+on	O
+ventilatory	O
+and	O
+peripheral	O
+muscles	O
+in	O
+rats	O
+.	O
+
+Occasional	O
+case	O
+reports	O
+have	O
+shown	O
+that	O
+acute	O
+myopathy	B
+may	O
+occur	O
+in	O
+patients	O
+treated	O
+with	O
+massive	O
+doses	O
+of	O
+corticosteroids	O
+.	O
+
+The	O
+mechanism	O
+of	O
+this	O
+myopathy	B
+is	O
+poorly	O
+understood	O
+.	O
+
+Therefore	O
+,	O
+60	O
+male	O
+rats	O
+were	O
+randomly	O
+assigned	O
+to	O
+receive	O
+daily	O
+injection	O
+of	O
+saline	O
+(	O
+C	O
+)	O
+,	O
+methylprednisolone	O
+(	O
+M	O
+)	O
+,	O
+or	O
+triamcinolone	O
+(	O
+T	O
+)	O
+80	O
+mg	O
+/	O
+kg	O
+/	O
+d	O
+for	O
+5	O
+d	O
+.	O
+
+Nutritional	O
+intake	O
+,	O
+measured	O
+daily	O
+in	O
+15	O
+animals	O
+,	O
+showed	O
+a	O
+significant	O
+reduction	B
+of	I
+food	I
+intake	I
+in	O
+the	O
+steroid	O
+-	O
+treated	O
+groups	O
+(	O
+-	O
+50	O
+and	O
+-	O
+79	O
+%	O
+in	O
+M	O
+and	O
+T	O
+,	O
+respectively	O
+)	O
+.	O
+
+This	O
+was	O
+associated	O
+with	O
+a	O
+similar	O
+loss	B
+in	I
+body	I
+weight	I
+.	O
+
+In	O
+the	O
+45	O
+remaining	O
+animals	O
+,	O
+diaphragm	O
+contractility	O
+and	O
+histopathologic	O
+features	O
+of	O
+several	O
+muscles	O
+were	O
+studied	O
+.	O
+
+Weights	O
+of	O
+respiratory	O
+and	O
+peripheral	O
+muscles	O
+were	O
+similarly	O
+decreased	O
+after	O
+steroid	O
+treatment	O
+.	O
+
+Maximal	O
+twitches	O
+of	O
+the	O
+diaphragm	O
+were	O
+lower	O
+in	O
+the	O
+C	O
+group	O
+(	O
+653	O
++	O
+/	O
+-	O
+174	O
+g	O
+/	O
+cm	O
+(	O
+2	O
+)	O
+)	O
+than	O
+in	O
+the	O
+M	O
+group	O
+(	O
+837	O
++	O
+/	O
+-	O
+171	O
+g	O
+/	O
+cm	O
+(	O
+2	O
+)	O
+;	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+and	O
+the	O
+T	O
+group	O
+(	O
+765	O
++	O
+/	O
+-	O
+145	O
+g	O
+/	O
+cm	O
+(	O
+2	O
+)	O
+,	O
+NS	O
+)	O
+.	O
+
+Half	O
+-	O
+relaxation	O
+time	O
+was	O
+prolonged	O
+in	O
+both	O
+steroid	O
+groups	O
+,	O
+and	O
+time	O
+to	O
+peak	O
+tension	O
+was	O
+longer	O
+with	O
+M	O
+,	O
+whereas	O
+tetanic	B
+tensions	O
+were	O
+similar	O
+.	O
+
+Steroid	O
+treatment	O
+also	O
+induced	O
+a	O
+leftward	O
+shift	O
+of	O
+the	O
+force	O
+-	O
+frequency	O
+curve	O
+at	O
+25	O
+and	O
+50	O
+Hz	O
+when	O
+compared	O
+with	O
+saline	O
+treatment	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+ATPase	O
+staining	O
+of	O
+the	O
+diaphragm	O
+,	O
+scalenus	O
+medius	O
+,	O
+and	O
+gastrocnemius	O
+showed	O
+type	O
+IIb	O
+fiber	O
+atrophy	B
+in	O
+the	O
+steroid	O
+groups	O
+and	O
+also	O
+diaphragmatic	O
+type	O
+IIa	O
+atrophy	B
+with	O
+T	O
+,	O
+whereas	O
+histologic	O
+examinations	O
+revealed	O
+a	O
+normal	O
+muscular	O
+pattern	O
+with	O
+absence	O
+of	O
+necrosis	B
+.	O
+
+Finally	O
+,	O
+a	O
+pair	O
+-	O
+fed	O
+(	O
+PF	O
+)	O
+study	O
+,	O
+performed	O
+in	O
+18	O
+rats	O
+(	O
+C	O
+,	O
+T	O
+,	O
+and	O
+PF	O
+)	O
+,	O
+showed	O
+that	O
+muscle	B
+atrophy	I
+was	O
+considerably	O
+less	O
+pronounced	O
+in	O
+PF	O
+animals	O
+than	O
+in	O
+T	O
+-	O
+treated	O
+animals	O
+.	O
+
+We	O
+conclude	O
+that	O
+(	O
+1	O
+)	O
+short	O
+-	O
+term	O
+treatment	O
+with	O
+massive	O
+doses	O
+of	O
+steroids	O
+induced	O
+severe	O
+respiratory	O
+and	O
+limb	O
+muscle	O
+wasting	O
+;	O
+(	O
+2	O
+)	O
+both	O
+types	O
+of	O
+steroids	O
+induced	O
+predominantly	O
+type	O
+IIb	O
+atrophy	B
+,	O
+resulting	O
+in	O
+the	O
+expected	O
+alterations	O
+in	O
+diaphragm	O
+contractile	O
+properties	O
+;	O
+(	O
+3	O
+)	O
+neither	O
+steroid	O
+caused	O
+muscle	O
+necrosis	B
+;	O
+(	O
+4	O
+)	O
+type	O
+IIb	O
+atrophy	B
+was	O
+not	O
+caused	O
+by	O
+acute	O
+nutritional	O
+deprivation	O
+alone	O
+.	O
+
+Continuous	O
+subcutaneous	O
+administration	O
+of	O
+mesna	O
+to	O
+prevent	O
+ifosfamide	O
+-	O
+induced	O
+hemorrhagic	B
+cystitis	I
+.	O
+
+Hemorrhagic	B
+cystitis	I
+is	O
+a	O
+major	O
+potential	O
+toxicity	B
+of	O
+ifosfamide	O
+that	O
+can	O
+be	O
+prevented	O
+by	O
+administering	O
+mesna	O
+along	O
+with	O
+the	O
+cytotoxic	O
+agent	O
+.	O
+
+Mesna	O
+is	O
+generally	O
+administered	O
+by	O
+the	O
+intravenous	O
+route	O
+,	O
+although	O
+experience	O
+with	O
+oral	O
+delivery	O
+of	O
+the	O
+drug	O
+has	O
+increased	O
+.	O
+
+The	O
+continuous	O
+subcutaneous	O
+administration	O
+of	O
+mesna	O
+has	O
+the	O
+advantage	O
+of	O
+not	O
+requiring	O
+intravenous	O
+access	O
+.	O
+
+In	O
+addition	O
+,	O
+subcutaneous	O
+delivery	O
+of	O
+the	O
+neutralizing	O
+agent	O
+will	O
+not	O
+be	O
+associated	O
+with	O
+the	O
+risk	O
+of	O
+inadequate	O
+urinary	O
+mesna	O
+concentrations	O
+,	O
+such	O
+as	O
+in	O
+a	O
+patient	O
+taking	O
+oral	O
+mesna	O
+who	O
+experiences	O
+severe	O
+ifosfamide	O
+-	O
+induced	O
+emesis	B
+and	O
+is	O
+unable	O
+to	O
+absorb	O
+the	O
+drug	O
+.	O
+
+Limited	O
+clinical	O
+experience	O
+with	O
+continuous	O
+subcutaneous	O
+mesna	O
+administration	O
+suggests	O
+it	O
+is	O
+a	O
+safe	O
+,	O
+practical	O
+,	O
+and	O
+economic	O
+method	O
+of	O
+drug	O
+delivery	O
+that	O
+permits	O
+ifosfamide	O
+to	O
+be	O
+administered	O
+successfully	O
+in	O
+the	O
+outpatient	O
+setting	O
+.	O
+
+Leg	B
+and	I
+back	I
+pain	I
+after	O
+spinal	O
+anaesthesia	O
+involving	O
+hyperbaric	O
+5	O
+%	O
+lignocaine	O
+.	O
+
+Fifty	O
+-	O
+four	O
+patients	O
+,	O
+aged	O
+27	O
+-	O
+90	O
+years	O
+,	O
+who	O
+were	O
+given	O
+lignocaine	O
+5	O
+%	O
+in	O
+6	O
+.	O
+8	O
+%	O
+glucose	O
+solution	O
+for	O
+spinal	O
+anaesthesia	O
+were	O
+studied	O
+.	O
+
+Thirteen	O
+of	O
+these	O
+patients	O
+experienced	O
+pain	B
+in	I
+the	I
+legs	I
+and	I
+/	I
+or	I
+back	I
+after	O
+recovery	O
+from	O
+anaesthesia	O
+.	O
+
+The	O
+patients	O
+affected	O
+were	O
+younger	O
+(	O
+p	O
+<	O
+0	O
+.	O
+05	O
+)	O
+and	O
+the	O
+site	O
+of	O
+the	O
+dural	O
+puncture	O
+was	O
+higher	O
+(	O
+p	O
+<	O
+0	O
+.	O
+01	O
+)	O
+than	O
+those	O
+individuals	O
+without	O
+pain	B
+.	O
+
+Five	O
+of	O
+the	O
+13	O
+patients	O
+(	O
+38	O
+%	O
+)	O
+with	O
+pain	B
+and	O
+seven	O
+of	O
+the	O
+41	O
+patients	O
+(	O
+17	O
+%	O
+)	O
+without	O
+pain	B
+admitted	O
+to	O
+a	O
+high	O
+alcohol	O
+intake	O
+,	O
+which	O
+might	O
+be	O
+a	O
+contributing	O
+factor	O
+.	O
+
+Leg	B
+and	I
+/	I
+or	I
+back	I
+pain	I
+is	O
+associated	O
+with	O
+the	O
+intrathecal	O
+use	O
+of	O
+hyperbaric	O
+5	O
+%	O
+lignocaine	O
+.	O
+
+The	O
+use	O
+of	O
+serum	O
+cholinesterase	O
+in	O
+succinylcholine	O
+apnoea	B
+.	O
+
+Fifteen	O
+patients	O
+demonstrating	O
+unexpected	O
+prolonged	O
+apnoea	B
+lasting	O
+several	O
+hours	O
+after	O
+succinylcholine	O
+have	O
+been	O
+treated	O
+by	O
+a	O
+new	O
+preparation	O
+of	O
+human	O
+serum	O
+cholinesterase	O
+.	O
+
+Adequate	O
+spontaneous	O
+respiration	O
+was	O
+re	O
+-	O
+established	O
+in	O
+an	O
+average	O
+period	O
+of	O
+ten	O
+minutes	O
+after	O
+the	O
+injection	O
+.	O
+
+In	O
+12	O
+patients	O
+biochemical	O
+genetic	O
+examinations	O
+confirmed	O
+the	O
+presence	O
+of	O
+an	O
+atypical	O
+serum	O
+cholinesterase	O
+.	O
+
+In	O
+three	O
+patients	O
+none	O
+of	O
+the	O
+usual	O
+variants	O
+were	O
+found	O
+.	O
+
+It	O
+is	O
+therefore	O
+supposed	O
+that	O
+other	O
+unknown	O
+variants	O
+of	O
+serum	O
+cholinesterase	O
+exist	O
+which	O
+cannot	O
+hydrolyze	O
+succinylcholine	O
+.	O
+
+The	O
+use	O
+of	O
+serum	O
+cholinesterase	O
+in	O
+succinylcholine	O
+apnoea	B
+provided	O
+considerable	O
+relief	O
+to	O
+both	O
+patient	O
+and	O
+anaesthetist	O
+.	O
+
+Increased	O
+sulfation	O
+and	O
+decreased	O
+7alpha	O
+-	O
+hydroxylation	O
+of	O
+deoxycholic	O
+acid	O
+in	O
+ethinyl	O
+estradiol	O
+-	O
+induced	O
+cholestasis	B
+in	O
+rats	O
+.	O
+
+Deoxycholic	O
+acid	O
+conjugation	O
+,	O
+transport	O
+capacity	O
+,	O
+and	O
+metabolism	O
+were	O
+compared	O
+in	O
+control	O
+and	O
+ethinyl	O
+estradiol	O
+-	O
+treated	O
+rats	O
+.	O
+
+Control	O
+rats	O
+were	O
+found	O
+to	O
+have	O
+a	O
+lower	O
+capacity	O
+to	O
+transport	O
+deoxycholic	O
+acid	O
+than	O
+taurodeoxycholic	O
+acid	O
+,	O
+and	O
+both	O
+were	O
+decreased	O
+by	O
+ethinyl	O
+estradiol	O
+treatment	O
+.	O
+
+During	O
+[	O
+24	O
+-	O
+14C	O
+]	O
+sodium	O
+deoxycholate	O
+infusion	O
+,	O
+[	O
+14C	O
+]	O
+biliary	O
+bile	O
+acid	O
+secretion	O
+increased	O
+,	O
+but	O
+bile	O
+flow	O
+did	O
+not	O
+change	O
+significantly	O
+in	O
+either	O
+control	O
+or	O
+ethinyl	O
+estradiol	O
+-	O
+treated	O
+rats	O
+.	O
+
+Ethinyl	O
+estradiol	O
+-	O
+treated	O
+animals	O
+excreted	O
+significantly	O
+less	O
+14C	O
+as	O
+taurocholic	O
+acid	O
+than	O
+did	O
+control	O
+animals	O
+,	O
+consistent	O
+with	O
+an	O
+impairment	O
+of	O
+7alpha	O
+-	O
+hydroxylation	O
+of	O
+taurodeoxycholic	O
+acid	O
+.	O
+
+Ethinyl	O
+estradiol	O
+treatment	O
+did	O
+not	O
+impair	O
+conjugation	O
+of	O
+deoxycholic	O
+acid	O
+,	O
+but	O
+did	O
+result	O
+in	O
+an	O
+increase	O
+in	O
+sulfation	O
+of	O
+taurodeoxycholic	O
+acid	O
+from	O
+1	O
+.	O
+5	O
+%	O
+in	O
+controls	O
+to	O
+nearly	O
+4	O
+.	O
+0	O
+%	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+These	O
+results	O
+are	O
+consistent	O
+with	O
+the	O
+hypothesis	O
+that	O
+the	O
+rat	O
+has	O
+a	O
+poorer	O
+tolerance	O
+for	O
+deoxycholic	O
+acid	O
+than	O
+do	O
+certain	O
+other	O
+species	O
+.	O
+
+Furthermore	O
+,	O
+the	O
+rat	O
+converts	O
+deoxycholic	O
+acid	O
+,	O
+a	O
+poor	O
+choleretic	O
+,	O
+to	O
+taurocholic	O
+acid	O
+,	O
+a	O
+good	O
+choleretic	O
+.	O
+
+When	O
+this	O
+conversion	O
+is	O
+impaired	O
+with	O
+ethinyl	O
+estradiol	O
+treatment	O
+,	O
+sulfation	O
+may	O
+be	O
+an	O
+important	O
+alternate	O
+pathway	O
+for	O
+excretion	O
+of	O
+this	O
+potentially	O
+harmful	O
+bile	O
+acid	O
+.	O
+
+Influence	O
+of	O
+diet	O
+free	O
+of	O
+NAD	O
+-	O
+precursors	O
+on	O
+acetaminophen	O
+hepatotoxicity	B
+in	O
+mice	O
+.	O
+
+Recently	O
+,	O
+we	O
+demonstrated	O
+the	O
+hepatoprotective	O
+effects	O
+of	O
+nicotinic	O
+acid	O
+amide	O
+,	O
+a	O
+selective	O
+inhibitor	O
+of	O
+poly	O
+(	O
+ADP	O
+-	O
+ribose	O
+)	O
+polymerase	O
+(	O
+PARP	O
+;	O
+EC	O
+2	O
+.	O
+4	O
+.	O
+2	O
+.	O
+30	O
+)	O
+on	O
+mice	O
+suffering	O
+from	O
+acetaminophen	O
+(	O
+AAP	O
+)	O
+-	O
+hepatitis	B
+,	O
+suggesting	O
+that	O
+the	O
+AAP	O
+-	O
+induced	O
+liver	B
+injury	I
+involves	O
+a	O
+step	O
+which	O
+depends	O
+on	O
+adenoribosylation	O
+.	O
+
+The	O
+present	O
+study	O
+investigates	O
+the	O
+effects	O
+of	O
+a	O
+diet	O
+free	O
+of	O
+precursors	O
+of	O
+NAD	O
+,	O
+the	O
+substrate	O
+on	O
+which	O
+PARP	O
+acts	O
+,	O
+in	O
+female	O
+NMRI	O
+mice	O
+with	O
+AAP	O
+hepatitis	B
+and	O
+evaluates	O
+the	O
+influence	O
+of	O
+simultaneous	O
+ethanol	O
+consumption	O
+in	O
+these	O
+animals	O
+.	O
+
+Liver	B
+injuries	I
+were	O
+quantified	O
+as	O
+serum	O
+activities	O
+of	O
+glutamate	O
+-	O
+oxaloacetate	O
+transaminase	O
+(	O
+GOT	O
+)	O
+and	O
+glutamate	O
+-	O
+pyruvate	O
+transaminase	O
+(	O
+GPT	O
+)	O
+.	O
+
+While	O
+AAP	O
+caused	O
+a	O
+117	O
+-	O
+fold	O
+elevation	O
+of	O
+serum	O
+transaminase	O
+activities	O
+in	O
+mice	O
+kept	O
+on	O
+a	O
+standard	O
+laboratory	O
+diet	O
+,	O
+which	O
+was	O
+significantly	O
+exacerbated	O
+by	O
+ethanol	O
+and	O
+inhibited	O
+by	O
+nicotinic	O
+acid	O
+amide	O
+(	O
+NAA	O
+)	O
+,	O
+adverse	O
+effects	O
+were	O
+noted	O
+in	O
+animals	O
+fed	O
+a	O
+diet	O
+free	O
+of	O
+precursors	O
+of	O
+NAD	O
+.	O
+
+In	O
+these	O
+animals	O
+,	O
+only	O
+minor	O
+increases	O
+of	O
+serum	O
+transaminase	O
+activities	O
+were	O
+measured	O
+in	O
+the	O
+presence	O
+of	O
+AAP	O
+,	O
+and	O
+unlike	O
+the	O
+exacerbation	O
+caused	O
+by	O
+ethanol	O
+in	O
+mice	O
+on	O
+a	O
+standard	O
+diet	O
+,	O
+the	O
+liver	B
+damage	I
+was	O
+inhibited	O
+by	O
+50	O
+%	O
+by	O
+ethanol	O
+.	O
+
+A	O
+further	O
+64	O
+%	O
+reduction	O
+of	O
+hepatitis	B
+was	O
+observed	O
+,	O
+when	O
+NAA	O
+was	O
+given	O
+to	O
+ethanol	O
+/	O
+AAP	O
+-	O
+mice	O
+.	O
+
+Our	O
+results	O
+provide	O
+evidence	O
+that	O
+the	O
+AAP	O
+-	O
+induced	O
+hepatitis	B
+and	O
+its	O
+exacerbation	O
+by	O
+ethanol	O
+can	O
+either	O
+be	O
+reduced	O
+by	O
+end	O
+-	O
+product	O
+inhibition	O
+of	O
+PARP	O
+by	O
+NAA	O
+or	O
+by	O
+dietary	O
+depletion	O
+of	O
+the	O
+enzyme	O
+'	O
+s	O
+substrate	O
+NAD	O
+.	O
+
+We	O
+see	O
+the	O
+main	O
+application	O
+of	O
+NAA	O
+as	O
+for	O
+the	O
+combinational	O
+use	O
+in	O
+pharmaceutical	O
+preparations	O
+of	O
+acetaminophen	O
+in	O
+order	O
+to	O
+avoid	O
+hepatic	B
+damage	I
+in	O
+patients	O
+treated	O
+with	O
+this	O
+widely	O
+used	O
+analgesic	O
+.	O
+
+Nightmares	O
+and	O
+hallucinations	B
+after	O
+long	O
+-	O
+term	O
+intake	O
+of	O
+tramadol	O
+combined	O
+with	O
+antidepressants	O
+.	O
+
+Tramadol	O
+is	O
+a	O
+weak	O
+opioid	O
+with	O
+effects	O
+on	O
+adrenergic	O
+and	O
+serotonergic	O
+neurotransmission	O
+that	O
+is	O
+used	O
+to	O
+treat	O
+cancer	B
+pain	B
+and	O
+chronic	O
+non	O
+malignant	O
+pain	B
+.	O
+
+This	O
+drug	O
+was	O
+initiated	O
+in	O
+association	O
+with	O
+paroxetine	O
+and	O
+dosulepine	O
+hydrochloride	O
+in	O
+a	O
+tetraparetic	B
+patient	O
+with	O
+chronic	B
+pain	I
+.	O
+
+Fifty	O
+-	O
+six	O
+days	O
+after	O
+initiation	O
+of	O
+the	O
+treatment	O
+the	O
+patient	O
+presented	O
+hallucinations	B
+that	O
+only	O
+stopped	O
+after	O
+the	O
+withdrawal	O
+of	O
+psycho	O
+-	O
+active	O
+drugs	O
+and	O
+tramadol	O
+.	O
+
+The	O
+case	O
+report	O
+questions	O
+the	O
+long	O
+term	O
+use	O
+of	O
+pain	B
+killers	O
+combined	O
+with	O
+psycho	O
+-	O
+active	O
+drugs	O
+in	O
+chronic	O
+non	O
+malignant	O
+pain	B
+,	O
+especially	O
+if	O
+pain	B
+is	O
+under	O
+control	O
+.	O
+
+Effect	O
+of	O
+calcium	O
+chloride	O
+and	O
+4	O
+-	O
+aminopyridine	O
+therapy	O
+on	O
+desipramine	O
+toxicity	B
+in	O
+rats	O
+.	O
+
+BACKGROUND	O
+:	O
+Hypotension	B
+is	O
+a	O
+major	O
+contributor	O
+to	O
+mortality	O
+in	O
+tricyclic	O
+antidepressant	O
+overdose	B
+.	O
+
+Recent	O
+data	O
+suggest	O
+that	O
+tricyclic	O
+antidepressants	O
+inhibit	O
+calcium	O
+influx	O
+in	O
+some	O
+tissues	O
+.	O
+
+This	O
+study	O
+addressed	O
+the	O
+potential	O
+role	O
+of	O
+calcium	O
+channel	O
+blockade	O
+in	O
+tricyclic	O
+antidepressant	O
+-	O
+induced	O
+hypotension	B
+.	O
+
+METHODS	O
+:	O
+Two	O
+interventions	O
+were	O
+studied	O
+that	O
+have	O
+been	O
+shown	O
+previously	O
+to	O
+improve	O
+blood	O
+pressure	O
+with	O
+calcium	O
+channel	O
+blocker	O
+overdose	B
+.	O
+
+CaCl2	O
+and	O
+4	O
+-	O
+aminopyridine	O
+.	O
+
+Anesthetized	O
+rats	O
+received	O
+the	O
+tricyclic	O
+antidepressant	O
+desipramine	O
+IP	O
+to	O
+produce	O
+hypotension	B
+,	O
+QRS	O
+prolongation	O
+,	O
+and	O
+bradycardia	B
+.	O
+
+Fifteen	O
+min	O
+later	O
+,	O
+animals	O
+received	O
+CaCl2	O
+,	O
+NaHCO3	O
+,	O
+or	O
+saline	O
+.	O
+
+In	O
+a	O
+second	O
+experiment	O
+,	O
+rats	O
+received	O
+tricyclic	O
+antidepressant	O
+desipramine	O
+IP	O
+followed	O
+in	O
+15	O
+min	O
+by	O
+4	O
+-	O
+aminopyridine	O
+or	O
+saline	O
+.	O
+
+RESULTS	O
+:	O
+NaHCO3	O
+briefly	O
+(	O
+5	O
+min	O
+)	O
+reversed	O
+hypotension	B
+and	O
+QRS	O
+prolongation	O
+.	O
+
+CaCl2	O
+and	O
+4	O
+-	O
+aminopyridine	O
+failed	O
+to	O
+improve	O
+blood	O
+pressure	O
+.	O
+
+The	O
+incidence	O
+of	O
+ventricular	B
+arrhythmias	I
+(	O
+p	O
+=	O
+0	O
+.	O
+004	O
+)	O
+and	O
+seizures	B
+(	O
+p	O
+=	O
+0	O
+.	O
+03	O
+)	O
+in	O
+the	O
+CaCl2	O
+group	O
+was	O
+higher	O
+than	O
+the	O
+other	O
+groups	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+administration	O
+of	O
+CaCl2	O
+or	O
+4	O
+-	O
+aminopyridine	O
+did	O
+not	O
+reverse	O
+tricyclic	O
+antidepressant	O
+-	O
+induced	O
+hypotension	B
+in	O
+rats	O
+.	O
+
+CaCl2	O
+therapy	O
+may	O
+possibly	O
+worsen	O
+both	O
+cardiovascular	B
+and	I
+central	I
+nervous	I
+system	I
+toxicity	I
+.	O
+
+These	O
+findings	O
+do	O
+not	O
+support	O
+a	O
+role	O
+for	O
+calcium	O
+channel	O
+inhibition	O
+in	O
+the	O
+pathogenesis	O
+of	O
+tricyclic	O
+antidepressant	O
+-	O
+induced	O
+hypotension	B
+.	O
+
+Valsartan	O
+,	O
+a	O
+new	O
+angiotensin	O
+II	O
+antagonist	O
+for	O
+the	O
+treatment	O
+of	O
+essential	O
+hypertension	B
+:	O
+a	O
+comparative	O
+study	O
+of	O
+the	O
+efficacy	O
+and	O
+safety	O
+against	O
+amlodipine	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+compare	O
+the	O
+antihypertensive	O
+efficacy	O
+of	O
+a	O
+new	O
+angiotensin	O
+II	O
+antagonist	O
+,	O
+valsartan	O
+,	O
+with	O
+a	O
+reference	O
+therapy	O
+,	O
+amlodipine	O
+.	O
+
+METHODS	O
+:	O
+One	O
+hundred	O
+sixty	O
+-	O
+eight	O
+adult	O
+outpatients	O
+with	O
+mild	O
+to	O
+moderate	O
+hypertension	B
+were	O
+randomly	O
+allocated	O
+in	O
+double	O
+-	O
+blind	O
+fashion	O
+and	O
+equal	O
+number	O
+to	O
+receive	O
+80	O
+mg	O
+valsartan	O
+or	O
+5	O
+mg	O
+amlodipine	O
+for	O
+12	O
+weeks	O
+.	O
+
+After	O
+8	O
+weeks	O
+of	O
+therapy	O
+,	O
+in	O
+patients	O
+whose	O
+blood	O
+pressure	O
+remained	O
+uncontrolled	O
+,	O
+5	O
+mg	O
+amlodipine	O
+was	O
+added	O
+to	O
+the	O
+initial	O
+therapy	O
+.	O
+
+Patients	O
+were	O
+assessed	O
+at	O
+4	O
+,	O
+8	O
+,	O
+and	O
+12	O
+weeks	O
+.	O
+
+The	O
+primary	O
+efficacy	O
+variable	O
+was	O
+change	O
+from	O
+baseline	O
+in	O
+mean	O
+sitting	O
+diastolic	O
+blood	O
+pressure	O
+at	O
+8	O
+weeks	O
+.	O
+
+Secondary	O
+variables	O
+included	O
+change	O
+in	O
+sitting	O
+systolic	O
+blood	O
+pressure	O
+and	O
+responder	O
+rates	O
+.	O
+
+RESULTS	O
+:	O
+Both	O
+valsartan	O
+and	O
+amlodipine	O
+were	O
+effective	O
+at	O
+lowering	O
+blood	O
+pressure	O
+at	O
+4	O
+,	O
+8	O
+,	O
+and	O
+12	O
+weeks	O
+.	O
+
+Similar	O
+decreases	O
+were	O
+observed	O
+in	O
+both	O
+groups	O
+,	O
+with	O
+no	O
+statistically	O
+significant	O
+differences	O
+between	O
+the	O
+groups	O
+for	O
+any	O
+variable	O
+analyzed	O
+.	O
+
+For	O
+the	O
+primary	O
+variable	O
+the	O
+difference	O
+was	O
+0	O
+.	O
+5	O
+mm	O
+Hg	O
+in	O
+favor	O
+of	O
+valsartan	O
+(	O
+p	O
+=	O
+0	O
+.	O
+68	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+-	O
+2	O
+.	O
+7	O
+to	O
+1	O
+.	O
+7	O
+)	O
+.	O
+
+Responder	O
+rates	O
+at	O
+8	O
+weeks	O
+were	O
+66	O
+.	O
+7	O
+%	O
+for	O
+valsartan	O
+and	O
+60	O
+.	O
+2	O
+%	O
+for	O
+amlodipine	O
+(	O
+p	O
+=	O
+0	O
+.	O
+39	O
+)	O
+.	O
+
+Both	O
+treatments	O
+were	O
+well	O
+tolerated	O
+.	O
+
+The	O
+incidence	O
+of	O
+drug	O
+-	O
+related	O
+dependent	O
+edema	B
+was	O
+somewhat	O
+higher	O
+in	O
+the	O
+amlodipine	O
+group	O
+,	O
+particularly	O
+at	O
+a	O
+dose	O
+of	O
+10	O
+mg	O
+per	O
+day	O
+(	O
+2	O
+.	O
+4	O
+%	O
+for	O
+80	O
+mg	O
+valsartan	O
+;	O
+3	O
+.	O
+6	O
+%	O
+for	O
+5	O
+mg	O
+amlodipine	O
+;	O
+0	O
+%	O
+for	O
+valsartan	O
+plus	O
+5	O
+mg	O
+amlodipine	O
+;	O
+14	O
+.	O
+3	O
+%	O
+for	O
+10	O
+mg	O
+amlodipine	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+data	O
+show	O
+that	O
+valsartan	O
+is	O
+at	O
+least	O
+as	O
+effective	O
+as	O
+amlodipine	O
+in	O
+the	O
+treatment	O
+of	O
+mild	O
+to	O
+moderate	O
+hypertension	B
+.	O
+
+The	O
+results	O
+also	O
+show	O
+valsartan	O
+to	O
+be	O
+well	O
+tolerated	O
+and	O
+suggest	O
+that	O
+it	O
+is	O
+not	O
+associated	O
+with	O
+side	O
+effects	O
+characteristic	O
+of	O
+this	O
+comparator	O
+class	O
+,	O
+dihydropyridine	O
+calcium	O
+antagonists	O
+.	O
+
+A	O
+measure	O
+of	O
+pupillary	B
+oscillation	I
+as	O
+a	O
+marker	O
+of	O
+cocaine	O
+-	O
+induced	O
+paranoia	B
+.	O
+
+Cocaine	O
+-	O
+induced	O
+paranoia	B
+(	O
+CIP	B
+)	O
+remains	O
+an	O
+important	O
+drug	O
+-	O
+induced	O
+model	O
+of	O
+idiopathic	O
+paranoia	B
+for	O
+which	O
+no	O
+psychophysiologic	O
+marker	O
+has	O
+yet	O
+emerged	O
+.	O
+
+Measures	O
+of	O
+pupillary	B
+oscillation	I
+were	O
+able	O
+to	O
+significantly	O
+distinguish	O
+a	O
+group	O
+of	O
+abstinent	O
+crack	O
+cocaine	O
+abusers	O
+endorsing	O
+past	O
+CIP	B
+(	O
+n	O
+=	O
+32	O
+)	O
+from	O
+another	O
+group	O
+of	O
+crack	O
+addicts	O
+who	O
+denied	O
+past	O
+CIP	B
+(	O
+n	O
+=	O
+29	O
+)	O
+.	O
+
+Serotonin	B
+syndrome	I
+from	O
+venlafaxine	O
+-	O
+tranylcypromine	O
+interaction	O
+.	O
+
+Excessive	O
+stimulation	O
+of	O
+serotonin	O
+5HT1A	O
+receptors	O
+causes	O
+a	O
+syndrome	O
+of	O
+serotonin	O
+excess	O
+that	O
+consists	O
+of	O
+shivering	O
+,	O
+muscle	B
+rigidity	I
+,	O
+salivation	B
+,	O
+confusion	B
+,	O
+agitation	B
+and	O
+hyperthermia	B
+.	O
+
+The	O
+most	O
+common	O
+cause	O
+of	O
+this	O
+syndrome	O
+is	O
+an	O
+interaction	O
+between	O
+a	O
+monoamine	O
+oxidase	O
+inhibitor	O
+(	O
+MAOI	O
+)	O
+and	O
+a	O
+specific	O
+serotonin	O
+reuptake	O
+inhibitor	O
+.	O
+
+Venlafaxine	O
+is	O
+a	O
+new	O
+antidepressant	O
+agent	O
+that	O
+inhibits	O
+the	O
+reuptake	O
+of	O
+serotonin	O
+and	O
+norepinephrine	O
+.	O
+
+We	O
+report	O
+a	O
+venlafaxine	O
+-	O
+MAOI	O
+interaction	O
+that	O
+resulted	O
+in	O
+the	O
+serotonin	B
+syndrome	I
+in	O
+a	O
+23	O
+-	O
+y	O
+-	O
+old	O
+male	O
+who	O
+was	O
+taking	O
+tranylcypromine	O
+for	O
+depression	B
+.	O
+
+He	O
+had	O
+been	O
+well	O
+until	O
+the	O
+morning	O
+of	O
+presentation	O
+when	O
+he	O
+took	O
+1	O
+/	O
+2	O
+tab	O
+of	O
+venlafaxine	O
+.	O
+
+Within	O
+2	O
+h	O
+he	O
+became	O
+confused	O
+with	O
+jerking	O
+movements	O
+of	O
+his	O
+extremities	O
+,	O
+tremors	B
+and	O
+rigidity	B
+.	O
+
+He	O
+was	O
+brought	O
+directly	O
+to	O
+a	O
+hospital	O
+where	O
+he	O
+was	O
+found	O
+to	O
+be	O
+agitated	O
+and	O
+confused	O
+with	O
+shivering	O
+,	O
+myoclonic	B
+jerks	I
+,	O
+rigidity	B
+,	O
+salivation	B
+and	O
+diaphoresis	O
+.	O
+
+His	O
+pupils	O
+were	O
+7	O
+mm	O
+and	O
+sluggishly	O
+reactive	O
+to	O
+light	O
+.	O
+
+Vital	O
+signs	O
+were	O
+:	O
+blood	O
+pressure	O
+120	O
+/	O
+67	O
+mm	O
+Hg	O
+,	O
+heart	O
+rate	O
+127	O
+/	O
+min	O
+,	O
+respiratory	O
+rate	O
+28	O
+/	O
+min	O
+,	O
+and	O
+temperature	O
+97	O
+F	O
+.	O
+
+After	O
+180	O
+mg	O
+of	O
+diazepam	O
+i	O
+.	O
+v	O
+.	O
+he	O
+remained	O
+tremulous	O
+with	O
+muscle	B
+rigidity	I
+and	O
+clenched	O
+jaws	O
+.	O
+
+He	O
+was	O
+intubated	O
+for	O
+airway	O
+protection	O
+and	O
+because	O
+of	O
+hypoventilation	B
+,	O
+and	O
+was	O
+paralyzed	B
+to	O
+control	O
+muscle	B
+rigidity	I
+.	O
+
+His	O
+subsequent	O
+course	O
+was	O
+remarkable	O
+for	O
+non	O
+-	O
+immune	O
+thrombocytopenia	B
+which	O
+resolved	O
+.	O
+
+The	O
+patient	O
+'	O
+s	O
+maximal	O
+temperature	O
+was	O
+101	O
+.	O
+2	O
+F	O
+and	O
+his	O
+CPK	O
+remained	O
+<	O
+500	O
+units	O
+/	O
+L	O
+with	O
+no	O
+other	O
+evidence	O
+of	O
+rhabdomyolysis	B
+.	O
+
+His	O
+mental	O
+status	O
+normalized	O
+and	O
+he	O
+was	O
+transferred	O
+to	O
+a	O
+psychiatry	O
+ward	O
+.	O
+
+This	O
+patient	O
+survived	O
+without	O
+sequelae	O
+due	O
+to	O
+the	O
+aggressive	O
+sedation	O
+and	O
+neuromuscular	O
+paralysis	B
+.	O
+
+Cyclophosphamide	O
+associated	O
+bladder	B
+cancer	I
+-	O
+-	O
+a	O
+highly	O
+aggressive	O
+disease	O
+:	O
+analysis	O
+of	O
+12	O
+cases	O
+.	O
+
+PURPOSE	O
+:	O
+We	O
+gained	O
+knowledge	O
+of	O
+the	O
+etiology	O
+,	O
+treatment	O
+and	O
+prevention	O
+of	O
+cyclophosphamide	O
+associated	O
+urothelial	B
+cancer	I
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+The	O
+medical	O
+records	O
+of	O
+6	O
+men	O
+and	O
+6	O
+women	O
+(	O
+mean	O
+age	O
+55	O
+years	O
+)	O
+with	O
+cyclophosphamide	O
+associated	O
+bladder	B
+cancer	I
+were	O
+reviewed	O
+.	O
+
+RESULTS	O
+:	O
+All	O
+tumors	B
+were	O
+grade	O
+3	O
+or	O
+4	O
+transitional	O
+cell	O
+carcinoma	B
+.	O
+
+Of	O
+the	O
+5	O
+patients	O
+initially	O
+treated	O
+with	O
+endoscopic	O
+resection	O
+alone	O
+only	O
+1	O
+is	O
+alive	O
+without	O
+disease	O
+.	O
+
+Of	O
+the	O
+6	O
+patients	O
+who	O
+underwent	O
+early	O
+cystectomy	O
+4	O
+were	O
+alive	O
+at	O
+24	O
+to	O
+111	O
+months	O
+.	O
+
+The	O
+remaining	O
+patient	O
+with	O
+extensive	O
+cancer	B
+underwent	O
+partial	O
+cystectomy	O
+for	O
+palliation	O
+and	O
+died	O
+3	O
+months	O
+later	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Cyclophosphamide	O
+associated	O
+bladder	B
+tumor	I
+is	O
+an	O
+aggressive	O
+disease	O
+.	O
+
+However	O
+,	O
+long	O
+-	O
+term	O
+survival	O
+is	O
+possible	O
+when	O
+radical	O
+cystectomy	O
+is	O
+performed	O
+for	O
+bladder	B
+tumors	I
+with	O
+any	O
+sign	O
+of	O
+invasion	O
+and	O
+for	O
+recurrent	O
+high	O
+grade	O
+disease	O
+,	O
+even	O
+when	O
+noninvasive	O
+.	O
+
+A	O
+phase	O
+I	O
+clinical	O
+study	O
+of	O
+the	O
+antipurine	O
+antifolate	O
+lometrexol	O
+(	O
+DDATHF	O
+)	O
+given	O
+with	O
+oral	O
+folic	O
+acid	O
+.	O
+
+Lometrexol	O
+is	O
+an	O
+antifolate	O
+which	O
+inhibits	O
+glycinamide	O
+ribonucleotide	O
+formyltransferase	O
+(	O
+GARFT	O
+)	O
+,	O
+an	O
+enzyme	O
+essential	O
+for	O
+de	O
+novo	O
+purine	O
+synthesis	O
+.	O
+
+Extensive	O
+experimental	O
+and	O
+limited	O
+clinical	O
+data	O
+have	O
+shown	O
+that	O
+lometrexol	O
+has	O
+activity	O
+against	O
+tumours	B
+which	O
+are	O
+refractory	O
+to	O
+other	O
+drugs	O
+,	O
+notably	O
+methotrexate	O
+.	O
+
+However	O
+,	O
+the	O
+initial	O
+clinical	O
+development	O
+of	O
+lometrexol	O
+was	O
+curtailed	O
+because	O
+of	O
+severe	O
+and	O
+cumulative	O
+antiproliferative	O
+toxicities	B
+.	O
+
+Preclinical	O
+murine	O
+studies	O
+demonstrated	O
+that	O
+the	O
+toxicity	B
+of	O
+lometrexol	O
+can	O
+be	O
+prevented	O
+by	O
+low	O
+dose	O
+folic	O
+acid	O
+administration	O
+,	O
+i	O
+.	O
+e	O
+.	O
+for	O
+7	O
+days	O
+prior	O
+to	O
+and	O
+7	O
+days	O
+following	O
+a	O
+single	O
+bolus	O
+dose	O
+.	O
+
+This	O
+observation	O
+prompted	O
+a	O
+Phase	O
+I	O
+clinical	O
+study	O
+of	O
+lometrexol	O
+given	O
+with	O
+folic	O
+acid	O
+supplementation	O
+which	O
+has	O
+confirmed	O
+that	O
+the	O
+toxicity	B
+of	O
+lometrexol	O
+can	O
+be	O
+markedly	O
+reduced	O
+by	O
+folic	O
+acid	O
+supplementation	O
+.	O
+
+Thrombocytopenia	B
+and	O
+mucositis	B
+were	O
+the	O
+major	O
+toxicities	B
+.	O
+
+There	O
+was	O
+no	O
+clear	O
+relationship	O
+between	O
+clinical	O
+toxicity	B
+and	O
+the	O
+extent	O
+of	O
+plasma	O
+folate	O
+elevation	O
+.	O
+
+Associated	O
+studies	O
+demonstrated	O
+that	O
+lometrexol	O
+plasma	O
+pharmacokinetics	O
+were	O
+not	O
+altered	O
+by	O
+folic	O
+acid	O
+administration	O
+indicating	O
+that	O
+supplementation	O
+is	O
+unlikely	O
+to	O
+reduce	O
+toxicity	B
+by	O
+enhancing	O
+lometrexol	O
+plasma	O
+clearance	O
+.	O
+
+The	O
+work	O
+described	O
+in	O
+this	O
+report	O
+has	O
+identified	O
+for	O
+the	O
+first	O
+time	O
+a	O
+clinically	O
+acceptable	O
+schedule	O
+for	O
+the	O
+administration	O
+of	O
+a	O
+GARFT	O
+inhibitor	O
+.	O
+
+This	O
+information	O
+will	O
+facilitate	O
+the	O
+future	O
+evaluation	O
+of	O
+this	O
+class	O
+of	O
+compounds	O
+in	O
+cancer	B
+therapy	O
+.	O
+
+Fatal	O
+excited	O
+delirium	B
+following	O
+cocaine	O
+use	O
+:	O
+epidemiologic	O
+findings	O
+provide	O
+new	O
+evidence	O
+for	O
+mechanisms	O
+of	O
+cocaine	O
+toxicity	B
+.	O
+
+We	O
+describe	O
+an	O
+outbreak	O
+of	O
+deaths	O
+from	O
+cocaine	O
+-	O
+induced	O
+excited	O
+delirium	B
+(	O
+EDDs	B
+)	O
+in	O
+Dade	O
+County	O
+,	O
+Florida	O
+between	O
+1979	O
+and	O
+1990	O
+.	O
+
+From	O
+a	O
+registry	O
+of	O
+all	O
+cocaine	O
+-	O
+related	O
+deaths	O
+in	O
+Dade	O
+County	O
+,	O
+Florida	O
+,	O
+from	O
+1969	O
+-	O
+1990	O
+,	O
+58	O
+EDDs	B
+were	O
+compared	O
+with	O
+125	O
+victims	O
+of	O
+accidental	O
+cocaine	O
+overdose	B
+without	O
+excited	O
+delirium	B
+.	O
+
+Compared	O
+with	O
+controls	O
+,	O
+EDDs	B
+were	O
+more	O
+frequently	O
+black	O
+,	O
+male	O
+,	O
+and	O
+younger	O
+.	O
+
+They	O
+were	O
+less	O
+likely	O
+to	O
+have	O
+a	O
+low	O
+body	O
+mass	O
+index	O
+,	O
+and	O
+more	O
+likely	O
+to	O
+have	O
+died	O
+in	O
+police	O
+custody	O
+,	O
+to	O
+have	O
+received	O
+medical	O
+treatment	O
+immediately	O
+before	O
+death	O
+,	O
+to	O
+have	O
+survived	O
+for	O
+a	O
+longer	O
+period	O
+,	O
+to	O
+have	O
+developed	O
+hyperthermia	B
+,	O
+and	O
+to	O
+have	O
+died	O
+in	O
+summer	O
+months	O
+.	O
+
+EDDs	B
+had	O
+concentrations	O
+of	O
+cocaine	O
+and	O
+benzoylecgonine	O
+in	O
+autopsy	O
+blood	O
+that	O
+were	O
+similar	O
+to	O
+those	O
+for	O
+controls	O
+.	O
+
+The	O
+epidemiologic	O
+findings	O
+are	O
+most	O
+consistent	O
+with	O
+the	O
+hypothesis	O
+that	O
+chronic	O
+cocaine	O
+use	O
+disrupts	O
+dopaminergic	O
+function	O
+and	O
+,	O
+when	O
+coupled	O
+with	O
+recent	O
+cocaine	O
+use	O
+,	O
+may	O
+precipitate	O
+agitation	B
+,	O
+delirium	B
+,	O
+aberrant	O
+thermoregulation	O
+,	O
+rhabdomyolysis	B
+,	O
+and	O
+sudden	B
+death	I
+.	O
+
+Pemoline	O
+induced	O
+acute	O
+choreoathetosis	B
+:	O
+case	O
+report	O
+and	O
+review	O
+of	O
+the	O
+literature	O
+.	O
+
+BACKGROUND	O
+:	O
+Pemoline	O
+is	O
+an	O
+oxazolidine	O
+derivative	O
+that	O
+is	O
+structurally	O
+different	O
+from	O
+amphetamines	O
+and	O
+used	O
+in	O
+the	O
+treatment	O
+of	O
+attention	B
+deficit	I
+disorder	I
+.	O
+
+Pemoline	O
+has	O
+not	O
+been	O
+commonly	O
+associated	O
+in	O
+the	O
+literature	O
+as	O
+a	O
+cause	O
+of	O
+acute	O
+movement	B
+disorders	I
+.	O
+
+The	O
+following	O
+case	O
+describes	O
+two	O
+children	O
+acutely	O
+poisoned	O
+with	O
+pemoline	O
+who	O
+experienced	O
+profound	O
+choreoathetosis	B
+.	O
+
+CASE	O
+REPORT	O
+:	O
+Two	O
+,	O
+3	O
+-	O
+year	O
+-	O
+old	O
+male	O
+,	O
+identical	O
+twin	O
+siblings	O
+presented	O
+to	O
+the	O
+emergency	O
+department	O
+after	O
+found	O
+playing	O
+with	O
+a	O
+an	O
+empty	O
+bottle	O
+of	O
+pemoline	O
+originally	O
+containing	O
+59	O
+tablets	O
+.	O
+
+The	O
+children	O
+had	O
+a	O
+medical	O
+history	O
+significant	O
+for	O
+attention	B
+deficit	I
+disorder	I
+previously	O
+treated	O
+with	O
+methylphenidate	O
+without	O
+success	O
+.	O
+
+This	O
+was	O
+their	O
+first	O
+day	O
+of	O
+pemoline	O
+therapy	O
+.	O
+
+The	O
+choreoathetoid	B
+movements	O
+began	O
+45	O
+min	O
+to	O
+1	O
+h	O
+after	O
+ingestion	O
+.	O
+
+The	O
+children	O
+gave	O
+no	O
+history	O
+of	O
+prior	O
+movement	B
+disorders	I
+and	O
+there	O
+was	O
+no	O
+family	O
+history	O
+of	O
+movement	B
+disorders	I
+.	O
+
+The	O
+children	O
+received	O
+gastrointestinal	O
+decontamination	O
+and	O
+high	O
+doses	O
+of	O
+intravenous	O
+benzodiazepines	O
+in	O
+an	O
+attempt	O
+to	O
+control	O
+the	O
+choreoathetoid	B
+movements	O
+.	O
+
+Despite	O
+treatment	O
+,	O
+the	O
+children	O
+continued	O
+to	O
+have	O
+choreoathetosis	B
+for	O
+approximately	O
+24	O
+hours	O
+.	O
+
+Forty	O
+-	O
+eight	O
+hours	O
+after	O
+admission	O
+,	O
+the	O
+children	O
+appeared	O
+to	O
+be	O
+at	O
+their	O
+baseline	O
+and	O
+were	O
+discharged	O
+home	O
+.	O
+
+CONCLUSION	O
+:	O
+Pemoline	O
+associated	O
+movement	B
+disorder	I
+has	O
+been	O
+rarely	O
+reported	O
+in	O
+the	O
+acute	O
+toxicology	O
+literature	O
+.	O
+
+The	O
+possibility	O
+of	O
+choreoathetoid	B
+movements	O
+should	O
+be	O
+considered	O
+in	O
+patients	O
+presenting	O
+after	O
+pemoline	O
+overdose	B
+.	O
+
+Effect	O
+of	O
+myopic	O
+excimer	O
+laser	O
+photorefractive	O
+keratectomy	O
+on	O
+the	O
+electrophysiologic	O
+function	O
+of	O
+the	O
+retina	O
+and	O
+optic	O
+nerve	O
+.	O
+
+PURPOSE	O
+:	O
+To	O
+assess	O
+by	O
+electrophysiologic	O
+testing	O
+the	O
+effect	O
+of	O
+photorefractive	O
+keratectomy	O
+(	O
+PRK	O
+)	O
+on	O
+the	O
+retina	O
+and	O
+optic	O
+nerve	O
+.	O
+
+SETTING	O
+:	O
+Eye	O
+Clinic	O
+,	O
+S	O
+.	O
+
+Salvatore	O
+Hospital	O
+,	O
+L	O
+'	O
+Aquila	O
+University	O
+,	O
+Italy	O
+.	O
+
+METHODS	O
+:	O
+Standard	O
+pattern	O
+electroretinograms	O
+(	O
+P	O
+-	O
+ERGs	O
+)	O
+and	O
+standard	O
+pattern	O
+visual	O
+evoked	O
+potentials	O
+(	O
+P	O
+-	O
+VEPs	O
+)	O
+were	O
+done	O
+in	O
+25	O
+eyes	O
+of	O
+25	O
+patients	O
+who	O
+had	O
+myopic	O
+PRK	O
+for	O
+an	O
+attempted	O
+correction	O
+between	O
+5	O
+.	O
+00	O
+and	O
+15	O
+.	O
+00	O
+diopters	O
+(	O
+D	O
+)	O
+(	O
+mean	O
+8	O
+.	O
+00	O
+D	O
+)	O
+.	O
+
+Testing	O
+was	O
+done	O
+preoperatively	O
+and	O
+3	O
+,	O
+6	O
+,	O
+12	O
+,	O
+and	O
+18	O
+months	O
+postoperatively	O
+.	O
+
+The	O
+contralateral	O
+eyes	O
+served	O
+as	O
+controls	O
+.	O
+
+During	O
+the	O
+follow	O
+-	O
+up	O
+,	O
+3	O
+patients	O
+(	O
+12	O
+%	O
+)	O
+developed	O
+steroid	O
+-	O
+induced	O
+elevated	B
+intraocular	I
+pressure	I
+(	O
+IOP	O
+)	O
+that	O
+resolved	O
+after	O
+corticosteroid	O
+therapy	O
+was	O
+discontinued	O
+.	O
+
+RESULTS	O
+:	O
+No	O
+statistically	O
+significant	O
+differences	O
+were	O
+seen	O
+between	O
+treated	O
+and	O
+control	O
+eyes	O
+nor	O
+between	O
+treated	O
+eyes	O
+preoperatively	O
+and	O
+postoperatively	O
+.	O
+
+CONCLUSION	O
+:	O
+Myopic	O
+excimer	O
+laser	O
+PRK	O
+did	O
+not	O
+seem	O
+to	O
+affect	O
+the	O
+posterior	O
+segment	O
+.	O
+
+The	O
+transient	O
+steroid	O
+-	O
+induced	O
+IOP	B
+rise	I
+did	O
+not	O
+seem	O
+to	O
+cause	O
+functional	O
+impairment	O
+.	O
+
+Neutrophil	O
+superoxide	O
+and	O
+hydrogen	O
+peroxide	O
+production	O
+in	O
+patients	O
+with	O
+acute	B
+liver	I
+failure	I
+.	O
+
+Defects	O
+in	O
+superoxide	O
+and	O
+hydrogen	O
+peroxide	O
+production	O
+may	O
+be	O
+implicated	O
+in	O
+the	O
+high	O
+incidence	O
+of	O
+bacterial	B
+infections	I
+in	O
+patients	O
+with	O
+acute	B
+liver	I
+failure	I
+(	O
+ALF	B
+)	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+oxygen	O
+radical	O
+production	O
+in	O
+patients	O
+with	O
+ALF	B
+due	O
+to	O
+paracetamol	O
+overdose	B
+was	O
+compared	O
+with	O
+that	O
+of	O
+healthy	O
+volunteers	O
+.	O
+
+Neutrophils	O
+from	O
+14	O
+ALF	B
+patients	O
+were	O
+stimulated	O
+via	O
+the	O
+complement	O
+receptors	O
+using	O
+zymosan	O
+opsonized	O
+with	O
+ALF	B
+or	O
+control	O
+serum	O
+.	O
+
+Superoxide	O
+and	O
+hydrogen	O
+peroxide	O
+production	O
+by	O
+ALF	B
+neutrophils	O
+stimulated	O
+with	O
+zymosan	O
+opsonized	O
+with	O
+ALF	B
+serum	O
+was	O
+significantly	O
+reduced	O
+compared	O
+with	O
+the	O
+control	O
+subjects	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+This	O
+defect	O
+persisted	O
+when	O
+zymosan	O
+opsonized	O
+by	O
+control	O
+serum	O
+was	O
+used	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+.	O
+
+Superoxide	O
+and	O
+hydrogen	O
+peroxide	O
+production	O
+in	O
+neutrophils	O
+stimulated	O
+with	O
+formyl	O
+-	O
+methionyl	O
+-	O
+leucyl	O
+-	O
+phenylalanine	O
+(	O
+fMLP	O
+)	O
+from	O
+a	O
+further	O
+18	O
+ALF	B
+patients	O
+was	O
+unaffected	O
+compared	O
+with	O
+control	O
+neutrophils	O
+.	O
+
+Serum	O
+C3	O
+complement	O
+levels	O
+were	O
+significantly	O
+reduced	O
+in	O
+ALF	B
+patients	O
+compared	O
+with	O
+control	O
+subjects	O
+(	O
+P	O
+<	O
+0	O
+.	O
+0005	O
+)	O
+.	O
+
+These	O
+results	O
+demonstrate	O
+a	O
+neutrophil	O
+defect	O
+in	O
+ALF	B
+due	O
+to	O
+paracetamol	O
+overdose	B
+,	O
+that	O
+is	O
+complement	O
+dependent	O
+but	O
+independent	O
+of	O
+serum	O
+complement	O
+,	O
+possibly	O
+connected	O
+to	O
+the	O
+complement	O
+receptor	O
+.	O
+
+Cholesteryl	O
+hemisuccinate	O
+treatment	O
+protects	O
+rodents	O
+from	O
+the	O
+toxic	O
+effects	O
+of	O
+acetaminophen	O
+,	O
+adriamycin	O
+,	O
+carbon	O
+tetrachloride	O
+,	O
+chloroform	O
+and	O
+galactosamine	O
+.	O
+
+In	O
+addition	O
+to	O
+its	O
+use	O
+as	O
+a	O
+stabilizer	O
+/	O
+rigidifier	O
+of	O
+membranes	O
+,	O
+cholesteryl	O
+hemisuccinate	O
+,	O
+tris	O
+salt	O
+(	O
+CS	O
+)	O
+administration	O
+has	O
+also	O
+been	O
+shown	O
+to	O
+protect	O
+rats	O
+from	O
+the	O
+hepatotoxic	B
+effects	O
+of	O
+carbon	O
+tetrachloride	O
+(	O
+CCl4	O
+)	O
+.	O
+
+To	O
+further	O
+our	O
+understanding	O
+of	O
+the	O
+mechanism	O
+of	O
+CS	O
+cytoprotection	O
+,	O
+we	O
+examined	O
+in	O
+rats	O
+and	O
+mice	O
+the	O
+protective	O
+abilities	O
+of	O
+CS	O
+and	O
+the	O
+non	O
+-	O
+hydrolyzable	O
+ether	O
+form	O
+of	O
+CS	O
+,	O
+gamma	O
+-	O
+cholesteryloxybutyric	O
+acid	O
+,	O
+tris	O
+salt	O
+(	O
+CSE	O
+)	O
+against	O
+acetaminophen	O
+-	O
+,	O
+adriamycin	O
+-	O
+,	O
+carbon	O
+tetrachloride	O
+-	O
+,	O
+chloroform	O
+-	O
+and	O
+galactosamine	O
+-	O
+induced	O
+toxicity	B
+.	O
+
+The	O
+results	O
+of	O
+these	O
+studies	O
+demonstrated	O
+that	O
+CS	O
+-	O
+mediated	O
+protection	O
+is	O
+not	O
+selective	O
+for	O
+a	O
+particular	O
+species	O
+,	O
+organ	O
+system	O
+or	O
+toxic	O
+chemical	O
+.	O
+
+A	O
+24	O
+-	O
+h	O
+pretreatment	O
+of	O
+both	O
+rats	O
+and	O
+mice	O
+with	O
+a	O
+single	O
+dose	O
+of	O
+CS	O
+(	O
+100mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+,	O
+resulted	O
+in	O
+significant	O
+protection	O
+against	O
+the	O
+hepatotoxic	B
+effects	O
+of	O
+CCl4	O
+,	O
+CHCl3	O
+,	O
+acetaminophen	O
+and	O
+galactosamine	O
+and	O
+against	O
+the	O
+lethal	O
+(	O
+and	O
+presumably	O
+cardiotoxic	B
+)	O
+effect	O
+of	O
+adriamycin	O
+administration	O
+.	O
+
+Maximal	O
+CS	O
+-	O
+mediated	O
+protection	O
+was	O
+observed	O
+in	O
+experimental	O
+animals	O
+pretreated	O
+24	O
+h	O
+prior	O
+to	O
+the	O
+toxic	O
+insult	O
+.	O
+
+These	O
+data	O
+suggest	O
+that	O
+CS	O
+intervenes	O
+in	O
+a	O
+critical	O
+cellular	O
+event	O
+that	O
+is	O
+an	O
+important	O
+common	O
+pathway	O
+to	O
+toxic	O
+cell	O
+death	O
+.	O
+
+The	O
+mechanism	O
+of	O
+CS	O
+protection	O
+does	O
+not	O
+appear	O
+to	O
+be	O
+dependent	O
+on	O
+the	O
+inhibition	O
+of	O
+chemical	O
+bioactivation	O
+to	O
+a	O
+toxic	O
+reactive	O
+intermediate	O
+(	O
+in	O
+light	O
+of	O
+the	O
+protection	O
+observed	O
+against	O
+galactosamine	O
+hepatotoxicity	B
+)	O
+.	O
+
+However	O
+,	O
+based	O
+on	O
+the	O
+data	O
+presented	O
+,	O
+we	O
+can	O
+not	O
+exclude	O
+the	O
+possibility	O
+that	O
+CS	O
+administration	O
+inhibits	O
+chemical	O
+bioactivation	O
+.	O
+
+Our	O
+findings	O
+do	O
+suggest	O
+that	O
+CS	O
+-	O
+mediated	O
+protection	O
+is	O
+dependent	O
+on	O
+the	O
+action	O
+of	O
+the	O
+intact	O
+anionic	O
+CS	O
+molecule	O
+(	O
+non	O
+-	O
+hydrolyzable	O
+CSE	O
+was	O
+as	O
+protective	O
+as	O
+CS	O
+)	O
+,	O
+whose	O
+mechanism	O
+has	O
+yet	O
+to	O
+be	O
+defined	O
+.	O
+
+A	O
+murine	O
+model	O
+of	O
+adenomyosis	B
+:	O
+the	O
+effects	O
+of	O
+hyperprolactinemia	B
+induced	O
+by	O
+fluoxetine	O
+hydrochloride	O
+,	O
+a	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitor	O
+,	O
+on	O
+adenomyosis	B
+induction	O
+in	O
+Wistar	O
+albino	O
+rats	O
+.	O
+
+OBJECTIVE	O
+:	O
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+investigate	O
+whether	O
+fluoxetine	O
+given	O
+to	O
+castrated	O
+and	O
+noncastrated	O
+rats	O
+caused	O
+hyperprolactinemia	B
+and	O
+its	O
+effects	O
+with	O
+respect	O
+to	O
+adenomyosis	B
+.	O
+
+DESIGN	O
+:	O
+Fluoxetine	O
+,	O
+a	O
+serotonin	O
+reuptake	O
+inhibitor	O
+,	O
+was	O
+given	O
+to	O
+Wistar	O
+Albino	O
+rats	O
+for	O
+98	O
+days	O
+to	O
+produce	O
+hyperprolactinemia	B
+.	O
+
+The	O
+drug	O
+was	O
+given	O
+to	O
+two	O
+groups	O
+consisting	O
+of	O
+castrated	O
+and	O
+noncastrated	O
+rats	O
+and	O
+compared	O
+to	O
+two	O
+groups	O
+of	O
+castrated	O
+and	O
+noncastrated	O
+controls	O
+.	O
+
+Prolactin	O
+levels	O
+were	O
+measured	O
+and	O
+the	O
+uteri	O
+of	O
+the	O
+rats	O
+were	O
+removed	O
+for	O
+histopathological	O
+analysis	O
+at	O
+the	O
+end	O
+of	O
+98	O
+days	O
+.	O
+
+SETTING	O
+:	O
+Marmara	O
+University	O
+School	O
+of	O
+Medicine	O
+,	O
+Department	O
+of	O
+Histology	O
+and	O
+Embryology	O
+,	O
+Zeynep	O
+Kamil	O
+Women	O
+and	O
+Children	O
+'	O
+s	O
+Hospital	O
+.	O
+
+MAIN	O
+OUTCOME	O
+MEASURES	O
+:	O
+Serum	O
+prolactin	O
+levels	O
+,	O
+uterine	O
+histopathology	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+prolactin	O
+levels	O
+of	O
+castrated	O
+and	O
+noncastrated	O
+groups	O
+treated	O
+with	O
+fluoxetine	O
+were	O
+statistically	O
+significantly	O
+higher	O
+when	O
+compared	O
+to	O
+their	O
+respective	O
+control	O
+groups	O
+.	O
+
+Histological	O
+studies	O
+revealed	O
+11	O
+cases	O
+of	O
+adenomyosis	B
+,	O
+all	O
+within	O
+the	O
+noncastrated	O
+group	O
+receiving	O
+fluoxetine	O
+.	O
+
+CONCLUSION	O
+:	O
+It	O
+was	O
+suggested	O
+that	O
+high	O
+serum	O
+prolactin	O
+levels	O
+cause	O
+degeneration	O
+of	O
+myometrial	O
+cells	O
+in	O
+the	O
+presence	O
+of	O
+ovarian	O
+steroids	O
+that	O
+results	O
+in	O
+a	O
+myometrial	O
+invasion	O
+by	O
+endometrial	O
+stroma	O
+.	O
+
+This	O
+invasion	O
+eventually	O
+progresses	O
+to	O
+adenomyosis	B
+.	O
+
+Postinfarction	O
+ventricular	B
+septal	I
+defect	I
+associated	O
+with	O
+long	O
+-	O
+term	O
+steroid	O
+therapy	O
+.	O
+
+Two	O
+cases	O
+of	O
+postinfarction	O
+ventricular	B
+septal	I
+rupture	I
+in	O
+patients	O
+on	O
+long	O
+-	O
+term	O
+steroid	O
+therapy	O
+are	O
+presented	O
+and	O
+the	O
+favourable	O
+outcome	O
+in	O
+both	O
+cases	O
+described	O
+.	O
+
+A	O
+possible	O
+association	O
+between	O
+steroid	O
+therapy	O
+and	O
+subsequent	O
+postinfarction	O
+septal	B
+rupture	I
+is	O
+discussed	O
+.	O
+
+Neuroactive	O
+steroids	O
+protect	O
+against	O
+pilocarpine	O
+-	O
+and	O
+kainic	O
+acid	O
+-	O
+induced	O
+limbic	O
+seizures	B
+and	O
+status	B
+epilepticus	I
+in	O
+mice	O
+.	O
+
+Several	O
+structurally	O
+related	O
+metabolites	O
+of	O
+progesterone	O
+(	O
+3	O
+alpha	O
+-	O
+hydroxy	O
+pregnane	O
+-	O
+20	O
+-	O
+ones	O
+)	O
+and	O
+deoxycorticosterone	O
+(	O
+3	O
+alpha	O
+-	O
+hydroxy	O
+pregnane	O
+-	O
+21	O
+-	O
+diol	O
+-	O
+20	O
+-	O
+ones	O
+)	O
+and	O
+their	O
+3	O
+beta	O
+-	O
+epimers	O
+were	O
+evaluated	O
+for	O
+protective	O
+activity	O
+against	O
+pilocarpine	O
+-	O
+,	O
+kainic	O
+acid	O
+-	O
+and	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+-	O
+induced	O
+seizures	B
+in	O
+mice	O
+.	O
+
+Steroids	O
+with	O
+the	O
+3	O
+-	O
+hydroxy	O
+group	O
+in	O
+the	O
+alpha	O
+-	O
+position	O
+and	O
+5	O
+-	O
+H	O
+in	O
+the	O
+alpha	O
+-	O
+or	O
+beta	O
+-	O
+configurations	O
+were	O
+highly	O
+effective	O
+in	O
+protecting	O
+against	O
+pilocarpine	O
+(	O
+416	O
+mg	O
+/	O
+kg	O
+,	O
+s	O
+.	O
+c	O
+.	O
+)	O
+-	O
+induced	O
+limbic	O
+motor	O
+seizures	B
+and	O
+status	B
+epilepticus	I
+(	O
+ED50	O
+values	O
+,	O
+7	O
+.	O
+0	O
+-	O
+18	O
+.	O
+7	O
+mg	O
+/	O
+kg	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+The	O
+corresponding	O
+epimers	O
+with	O
+the	O
+3	O
+-	O
+hydroxy	O
+group	O
+in	O
+the	O
+beta	O
+-	O
+position	O
+were	O
+also	O
+effective	O
+but	O
+less	O
+potent	O
+(	O
+ED50	O
+values	O
+,	O
+33	O
+.	O
+8	O
+-	O
+63	O
+.	O
+5	O
+,	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+Although	O
+the	O
+neuroactive	O
+steroids	O
+were	O
+considerably	O
+less	O
+potent	O
+than	O
+the	O
+benzodiazepine	O
+clonazepam	O
+in	O
+protecting	O
+against	O
+pilocarpine	O
+seizures	B
+,	O
+steroids	O
+with	O
+the	O
+5	O
+alpha	O
+,	O
+3	O
+alpha	O
+-	O
+configuration	O
+had	O
+comparable	O
+or	O
+higher	O
+protective	O
+index	O
+values	O
+(	O
+TD50	O
+for	O
+motor	O
+impairment	O
+divided	O
+by	O
+ED50	O
+for	O
+seizure	B
+protection	O
+)	O
+than	O
+clonazepam	O
+,	O
+indicating	O
+that	O
+some	O
+neuroactive	O
+steroids	O
+may	O
+have	O
+lower	O
+relative	O
+toxicity	B
+.	O
+
+Steroids	O
+with	O
+the	O
+5	O
+alpha	O
+,	O
+3	O
+alpha	O
+-	O
+or	O
+5	O
+beta	O
+,	O
+3	O
+alpha	O
+-	O
+configurations	O
+also	O
+produced	O
+a	O
+dose	O
+-	O
+dependent	O
+delay	O
+in	O
+the	O
+onset	O
+of	O
+limbic	O
+seizures	B
+induced	O
+by	O
+kainic	O
+acid	O
+(	O
+32	O
+mg	O
+/	O
+kg	O
+,	O
+s	O
+.	O
+c	O
+.	O
+)	O
+,	O
+but	O
+did	O
+not	O
+completely	O
+protect	O
+against	O
+the	O
+seizures	B
+.	O
+
+However	O
+,	O
+when	O
+a	O
+second	O
+dose	O
+of	O
+the	O
+steroid	O
+was	O
+administered	O
+1	O
+hr	O
+after	O
+the	O
+first	O
+dose	O
+,	O
+complete	O
+protection	O
+from	O
+the	O
+kainic	O
+acid	O
+-	O
+induced	O
+limbic	O
+seizures	B
+and	O
+status	B
+epilepticus	I
+was	O
+obtained	O
+.	O
+
+The	O
+steroids	O
+also	O
+caused	O
+a	O
+dose	O
+-	O
+dependent	O
+delay	O
+in	O
+NMDA	O
+(	O
+257	O
+mg	O
+/	O
+kg	O
+,	O
+s	O
+.	O
+c	O
+.	O
+)	O
+-	O
+induced	O
+lethality	O
+,	O
+but	O
+did	O
+not	O
+completely	O
+protect	O
+against	O
+NMDA	O
+seizures	B
+or	O
+lethality	O
+.	O
+
+We	O
+conclude	O
+that	O
+neuroactive	O
+steroids	O
+are	O
+highly	O
+effective	O
+in	O
+protecting	O
+against	O
+pilocarpine	O
+-	O
+and	O
+kainic	O
+acid	O
+-	O
+induced	O
+seizures	B
+and	O
+status	B
+epilepticus	I
+in	O
+mice	O
+,	O
+and	O
+may	O
+be	O
+of	O
+utility	O
+in	O
+the	O
+treatment	O
+of	O
+some	O
+forms	O
+of	O
+status	B
+epilepticus	I
+in	O
+humans	O
+.	O
+
+Hepatic	O
+and	O
+extrahepatic	O
+angiotensinogen	O
+gene	O
+expression	O
+in	O
+rats	O
+with	O
+acute	O
+nephrotic	B
+syndrome	I
+.	O
+
+Plasma	O
+concentration	O
+and	O
+urine	O
+excretion	O
+of	O
+the	O
+renin	O
+-	O
+angiotensin	O
+system	O
+proteins	O
+are	O
+altered	O
+in	O
+rats	O
+with	O
+nephrotic	B
+syndrome	I
+(	O
+NS	B
+)	O
+.	O
+
+In	O
+this	O
+work	O
+the	O
+messenger	O
+ribonucleic	O
+acid	O
+(	O
+mRNA	O
+)	O
+levels	O
+of	O
+angiotensinogen	O
+(	O
+Ao	O
+)	O
+were	O
+analyzed	O
+with	O
+the	O
+slot	O
+-	O
+blot	O
+hybridization	O
+technique	O
+in	O
+liver	O
+and	O
+other	O
+extrahepatic	O
+tissues	O
+:	O
+kidney	O
+,	O
+heart	O
+,	O
+brain	O
+,	O
+and	O
+adrenal	O
+gland	O
+from	O
+control	O
+,	O
+nephrotic	B
+,	O
+and	O
+pair	O
+-	O
+fed	O
+(	O
+PF	O
+)	O
+rats	O
+.	O
+
+NS	B
+was	O
+induced	O
+by	O
+a	O
+single	O
+injection	O
+of	O
+puromycin	O
+amino	O
+-	O
+nucleoside	O
+(	O
+PAN	O
+)	O
+.	O
+
+Although	O
+a	O
+great	O
+urinary	O
+excretion	O
+and	O
+half	O
+-	O
+normal	O
+plasma	O
+levels	O
+of	O
+Ao	O
+were	O
+observed	O
+on	O
+day	O
+6	O
+after	O
+PAN	O
+injection	O
+,	O
+when	O
+NS	B
+was	O
+clearly	O
+established	O
+,	O
+hepatic	O
+Ao	O
+mRNA	O
+levels	O
+did	O
+not	O
+change	O
+.	O
+
+Furthermore	O
+,	O
+the	O
+Ao	O
+mRNA	O
+levels	O
+did	O
+not	O
+change	O
+in	O
+any	O
+of	O
+the	O
+extrahepatic	O
+tissues	O
+studied	O
+on	O
+day	O
+6	O
+,	O
+nor	O
+did	O
+its	O
+hepatic	O
+levels	O
+at	O
+days	O
+1	O
+,	O
+3	O
+,	O
+5	O
+,	O
+or	O
+7	O
+after	O
+PAN	O
+injection	O
+.	O
+
+These	O
+data	O
+suggest	O
+that	O
+the	O
+hepatic	O
+and	O
+extrahepatic	O
+Ao	O
+mRNA	O
+levels	O
+are	O
+unaltered	O
+during	O
+the	O
+development	O
+of	O
+the	O
+acute	O
+NS	B
+induced	O
+by	O
+PAN	O
+.	O
+
+Neuroleptic	B
+malignant	I
+syndrome	I
+with	O
+risperidone	O
+.	O
+
+Neuroleptic	B
+malignant	I
+syndrome	I
+is	O
+thought	O
+to	O
+be	O
+a	O
+result	O
+of	O
+dopamine	O
+D2	O
+receptor	O
+blockade	O
+in	O
+the	O
+striatum	O
+of	O
+the	O
+basal	O
+ganglia	O
+.	O
+
+Risperidone	O
+,	O
+a	O
+benzisoxazole	O
+derivative	O
+antipsychotic	O
+,	O
+has	O
+high	O
+serotonin	O
+5	O
+-	O
+HT2	O
+receptor	O
+blockade	O
+and	O
+dose	O
+-	O
+related	O
+D2	O
+receptor	O
+blockade	O
+.	O
+
+The	O
+high	O
+ratio	O
+is	O
+believed	O
+to	O
+impart	O
+the	O
+low	O
+frequency	O
+of	O
+extrapyramidal	B
+symptoms	I
+with	O
+risperidone	O
+at	O
+low	O
+dosages	O
+.	O
+
+With	O
+this	O
+low	O
+frequency	O
+of	O
+extrapyramidal	B
+symptoms	I
+,	O
+it	O
+was	O
+thought	O
+the	O
+frequency	O
+of	O
+neuroleptic	B
+malignant	I
+syndrome	I
+might	O
+also	O
+be	O
+lowered	O
+.	O
+
+A	O
+73	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+developed	O
+neuroleptic	B
+malignant	I
+syndrome	I
+after	O
+monotherapy	O
+with	O
+risperidone	O
+.	O
+
+The	O
+syndrome	O
+reversed	O
+after	O
+discontinuing	O
+risperidone	O
+and	O
+starting	O
+treatment	O
+with	O
+dantrolene	O
+and	O
+bromocriptine	O
+.	O
+
+It	O
+appears	O
+that	O
+the	O
+protection	O
+from	O
+extrapyramidal	O
+side	O
+effects	O
+observed	O
+with	O
+risperidone	O
+does	O
+not	O
+ensure	O
+protection	O
+from	O
+neuroleptic	B
+malignant	I
+syndrome	I
+.	O
+
+The	O
+attenuating	O
+effect	O
+of	O
+carteolol	O
+hydrochloride	O
+,	O
+a	O
+beta	O
+-	O
+adrenoceptor	O
+antagonist	O
+,	O
+on	O
+neuroleptic	O
+-	O
+induced	O
+catalepsy	B
+in	O
+rats	O
+.	O
+
+It	O
+is	O
+known	O
+that	O
+beta	O
+-	O
+adrenoceptor	O
+antagonists	O
+are	O
+effective	O
+in	O
+the	O
+treatment	O
+of	O
+akathisia	B
+,	O
+one	O
+of	O
+the	O
+extrapyramidal	O
+side	O
+effects	O
+that	O
+occur	O
+during	O
+neuroleptic	O
+treatment	O
+.	O
+
+Neuroleptic	O
+-	O
+induced	O
+catalepsy	B
+,	O
+a	O
+model	O
+of	O
+neuroleptic	O
+-	O
+induced	O
+extrapyramidal	O
+side	O
+effects	O
+,	O
+was	O
+considered	O
+suitable	O
+as	O
+a	O
+model	O
+for	O
+predicting	O
+neuroleptic	O
+-	O
+induced	O
+akathisia	B
+in	O
+humans	O
+,	O
+although	O
+neuroleptic	O
+-	O
+induced	O
+catalepsy	B
+was	O
+not	O
+considered	O
+a	O
+specific	O
+test	O
+for	O
+neuroleptic	O
+-	O
+induced	O
+akathisia	B
+.	O
+
+Therefore	O
+,	O
+the	O
+effects	O
+of	O
+carteolol	O
+,	O
+a	O
+beta	O
+-	O
+adrenoceptor	O
+antagonist	O
+,	O
+on	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+in	O
+rats	O
+were	O
+behaviorally	O
+studied	O
+and	O
+compared	O
+with	O
+those	O
+of	O
+propranolol	O
+and	O
+biperiden	O
+,	O
+a	O
+muscarinic	O
+receptor	O
+antagonist	O
+.	O
+
+Carteolol	O
+,	O
+as	O
+well	O
+as	O
+propranolol	O
+and	O
+biperiden	O
+,	O
+inhibited	O
+the	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+.	O
+
+The	O
+inhibitory	O
+effect	O
+of	O
+carteolol	O
+was	O
+almost	O
+comparable	O
+to	O
+that	O
+of	O
+propranolol	O
+,	O
+but	O
+was	O
+weaker	O
+than	O
+that	O
+of	O
+biperiden	O
+.	O
+
+Carteolol	O
+did	O
+not	O
+evoke	O
+postsynaptic	O
+dopamine	O
+receptor	O
+-	O
+stimulating	O
+behavioral	O
+signs	O
+such	O
+as	O
+stereotypy	O
+and	O
+hyperlocomotion	B
+in	O
+rats	O
+.	O
+
+Carteolol	O
+did	O
+not	O
+antagonize	O
+the	O
+inhibitory	O
+effects	O
+of	O
+haloperidol	O
+on	O
+apomorphine	O
+-	O
+induced	O
+stereotypy	O
+and	O
+locomotor	O
+activity	O
+in	O
+rats	O
+.	O
+
+In	O
+addition	O
+,	O
+carteolol	O
+did	O
+not	O
+evoke	O
+5	O
+-	O
+HT1A	O
+receptor	O
+-	O
+stimulating	O
+behavioral	O
+signs	O
+such	O
+as	O
+flat	O
+body	O
+posture	O
+and	O
+forepaw	O
+treading	O
+and	O
+did	O
+not	O
+inhibit	O
+5	O
+-	O
+hydroxytryptophan	O
+-	O
+induced	O
+head	O
+twitch	O
+in	O
+rats	O
+.	O
+
+Finally	O
+,	O
+carteolol	O
+did	O
+not	O
+inhibit	O
+physostigmine	O
+-	O
+induced	O
+lethality	O
+in	O
+rats	O
+.	O
+
+These	O
+results	O
+strongly	O
+suggest	O
+that	O
+carteolol	O
+improves	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B
+via	O
+its	O
+beta	O
+-	O
+adrenoceptor	O
+antagonistic	O
+activity	O
+and	O
+is	O
+expected	O
+to	O
+be	O
+effective	O
+in	O
+the	O
+treatment	O
+of	O
+akathisia	B
+without	O
+attenuating	O
+neuroleptic	O
+-	O
+induced	O
+antipsychotic	O
+effects	O
+due	O
+to	O
+its	O
+postsynaptic	O
+dopamine	O
+receptor	O
+antagonistic	O
+activity	O
+.	O
+
+Granulosa	B
+cell	I
+tumor	I
+of	I
+the	I
+ovary	I
+associated	O
+with	O
+antecedent	O
+tamoxifen	O
+use	O
+.	O
+
+BACKGROUND	O
+:	O
+Increased	O
+attention	O
+has	O
+been	O
+focused	O
+recently	O
+on	O
+the	O
+estrogenic	O
+effects	O
+of	O
+tamoxifen	O
+.	O
+
+Review	O
+of	O
+the	O
+literature	O
+reveals	O
+an	O
+association	O
+between	O
+tamoxifen	O
+use	O
+and	O
+gynecologic	O
+tumors	B
+.	O
+
+CASE	O
+:	O
+A	O
+52	O
+-	O
+year	O
+-	O
+old	O
+postmenopausal	O
+woman	O
+was	O
+treated	O
+with	O
+tamoxifen	O
+for	O
+stage	O
+II	O
+estrogen	O
+receptor	O
+-	O
+positive	O
+breast	B
+carcinoma	I
+.	O
+
+Her	O
+aspartate	O
+transaminase	O
+and	O
+alanine	O
+transaminase	O
+levels	O
+increase	O
+markedly	O
+after	O
+6	O
+months	O
+of	O
+tamoxifen	O
+use	O
+.	O
+
+After	O
+an	O
+additional	O
+17	O
+months	O
+of	O
+elevated	O
+serum	O
+transaminases	O
+,	O
+the	O
+patient	O
+was	O
+found	O
+to	O
+have	O
+a	O
+stage	O
+Ic	O
+granulosa	B
+cell	I
+tumor	I
+of	I
+the	I
+ovary	I
+.	O
+
+CONCLUSION	O
+:	O
+Patients	O
+with	O
+tamoxifen	O
+-	O
+induced	O
+liver	B
+dysfunction	I
+may	O
+be	O
+at	O
+increased	O
+risk	O
+for	O
+granulosa	B
+cell	I
+tumors	I
+because	O
+of	O
+alterations	O
+in	O
+tamoxifen	O
+metabolism	O
+.	O
+
+Lifetime	O
+treatment	O
+of	O
+mice	O
+with	O
+azidothymidine	O
+(	O
+AZT	O
+)	O
+produces	O
+myelodysplasia	B
+.	O
+
+AZT	O
+has	O
+induced	O
+a	O
+macrocytic	B
+anemia	I
+in	O
+AIDS	B
+patients	O
+on	O
+long	O
+term	O
+AZT	O
+therapy	O
+.	O
+
+It	O
+is	O
+generally	O
+assumed	O
+that	O
+DNA	O
+elongation	O
+is	O
+stopped	O
+by	O
+the	O
+insertion	O
+of	O
+AZT	O
+into	O
+the	O
+chain	O
+in	O
+place	O
+of	O
+thymidine	O
+thus	O
+preventing	O
+the	O
+phosphate	O
+hydroxyl	O
+linkages	O
+and	O
+therefore	O
+suppresses	O
+hemopoietic	O
+progenitor	O
+cell	O
+proliferation	O
+in	O
+an	O
+early	O
+stage	O
+of	O
+differentiation	O
+.	O
+
+CBA	O
+/	O
+Ca	O
+male	O
+mice	O
+started	O
+on	O
+AZT	O
+0	O
+.	O
+75	O
+mg	O
+/	O
+ml	O
+H2O	O
+at	O
+84	O
+days	O
+of	O
+age	O
+and	O
+kept	O
+on	O
+it	O
+for	O
+687	O
+days	O
+when	O
+dosage	O
+reduced	O
+to	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+ml	O
+H2O	O
+for	O
+a	O
+group	O
+,	O
+another	O
+group	O
+removed	O
+from	O
+AZT	O
+to	O
+see	O
+recovery	O
+,	O
+and	O
+third	O
+group	O
+remained	O
+on	O
+0	O
+.	O
+75	O
+mg	O
+.	O
+
+At	O
+687	O
+days	O
+mice	O
+that	O
+had	O
+been	O
+on	O
+0	O
+.	O
+75	O
+mg	O
+had	O
+average	O
+platelet	O
+counts	O
+of	O
+2	O
+.	O
+5	O
+x	O
+10	O
+(	O
+6	O
+)	O
+.	O
+
+Histological	O
+examination	O
+on	O
+9	O
+of	O
+10	O
+mice	O
+with	O
+such	O
+thrombocytopenia	B
+showed	O
+changes	O
+compatible	O
+with	O
+myelodysplastic	B
+syndrome	I
+(	O
+MDS	B
+)	O
+.	O
+
+A	O
+variety	O
+of	O
+histological	O
+patterns	O
+was	O
+observed	O
+.	O
+
+There	O
+were	O
+two	O
+cases	O
+of	O
+hypocellular	O
+myelodysplasia	B
+,	O
+two	O
+cases	O
+of	O
+hypersegmented	O
+myelodysplastic	B
+granulocytosis	O
+,	O
+two	O
+cases	O
+of	O
+hypercellular	O
+marrow	O
+with	O
+abnormal	O
+megakaryocytes	O
+with	O
+bizarre	O
+nuclei	O
+,	O
+one	O
+case	O
+of	O
+megakaryocytic	O
+myelosis	O
+associated	O
+with	O
+a	O
+hyperplastic	B
+marrow	I
+,	O
+dysmyelopoiesis	B
+and	O
+a	O
+hypocellular	B
+marrow	I
+and	O
+two	O
+cases	O
+of	O
+myelodysplasia	B
+with	O
+dyserythropoiesis	B
+,	O
+hemosiderosis	B
+and	O
+a	O
+hypocellular	B
+marrow	I
+.	O
+
+Above	O
+mentioned	O
+AZT	O
+incorporation	O
+may	O
+have	O
+induced	O
+an	O
+ineffective	O
+hemopoiesis	O
+in	O
+the	O
+primitive	O
+hemopoietic	O
+progenitor	O
+cells	O
+,	O
+which	O
+is	O
+known	O
+to	O
+be	O
+seen	O
+commonly	O
+in	O
+the	O
+myelodysplastic	B
+syndrome	I
+.	O
+
+Biphasic	O
+response	O
+of	O
+the	O
+SA	O
+node	O
+of	O
+the	O
+dog	O
+heart	O
+in	O
+vivo	O
+to	O
+selective	O
+administration	O
+of	O
+ketamine	O
+.	O
+
+Effect	O
+of	O
+ketamine	O
+on	O
+the	O
+SA	O
+node	O
+of	O
+the	O
+dog	O
+heart	O
+was	O
+studied	O
+in	O
+vivo	O
+using	O
+a	O
+selective	O
+perfusion	O
+technique	O
+of	O
+the	O
+SA	O
+node	O
+artery	O
+.	O
+
+Injections	O
+of	O
+ketamine	O
+in	O
+doses	O
+from	O
+100	O
+microgram	O
+to	O
+3	O
+mg	O
+into	O
+the	O
+artery	O
+produced	O
+a	O
+depression	B
+of	O
+the	O
+SA	O
+nodal	O
+activity	O
+by	O
+a	O
+direct	O
+action	O
+.	O
+
+This	O
+depression	B
+was	O
+followed	O
+by	O
+the	O
+sudden	O
+appearance	O
+of	O
+a	O
+stimulatory	O
+phase	O
+.	O
+
+Bilateral	O
+vagotomy	O
+and	O
+sympathectomy	O
+or	O
+prior	O
+administration	O
+of	O
+a	O
+ganglion	O
+blocker	O
+failed	O
+to	O
+inhibit	O
+the	O
+occurrence	O
+of	O
+the	O
+ketamine	O
+-	O
+induced	O
+tachycardia	B
+,	O
+while	O
+it	O
+was	O
+completely	O
+abolished	O
+in	O
+the	O
+reserpinized	O
+dogs	O
+or	O
+by	O
+a	O
+prior	O
+injection	O
+of	O
+a	O
+beta	O
+-	O
+blocking	O
+agent	O
+into	O
+the	O
+SA	O
+node	O
+artery	O
+.	O
+
+This	O
+may	O
+indicate	O
+that	O
+an	O
+activation	O
+of	O
+the	O
+peripheral	O
+adrenergic	O
+mechanism	O
+plays	O
+an	O
+important	O
+role	O
+in	O
+the	O
+induction	O
+of	O
+the	O
+excitatory	O
+effect	O
+of	O
+ketamine	O
+injected	O
+in	O
+the	O
+SA	O
+node	O
+artery	O
+.	O
+
+Over	O
+expression	O
+of	O
+vascular	O
+endothelial	O
+growth	O
+factor	O
+and	O
+its	O
+receptor	O
+during	O
+the	O
+development	O
+of	O
+estrogen	O
+-	O
+induced	O
+rat	O
+pituitary	B
+tumors	I
+may	O
+mediate	O
+estrogen	O
+-	O
+initiated	O
+tumor	B
+angiogenesis	O
+.	O
+
+Estrogens	O
+,	O
+which	O
+have	O
+been	O
+associated	O
+with	O
+several	O
+types	O
+of	O
+human	O
+and	O
+animal	O
+cancers	B
+,	O
+can	O
+induce	O
+tumor	B
+angiogenesis	O
+in	O
+the	O
+pituitary	O
+of	O
+Fischer	O
+344	O
+rats	O
+.	O
+
+The	O
+mechanistic	O
+details	O
+of	O
+tumor	B
+angiogenesis	O
+induction	O
+,	O
+during	O
+estrogen	O
+carcinogenesis	B
+,	O
+are	O
+still	O
+unknown	O
+.	O
+
+To	O
+elucidate	O
+the	O
+role	O
+of	O
+estrogen	O
+in	O
+the	O
+regulation	O
+of	O
+tumor	B
+angiogenesis	O
+in	O
+the	O
+pituitary	O
+of	O
+female	O
+rats	O
+,	O
+the	O
+density	O
+of	O
+blood	O
+vessels	O
+was	O
+analysed	O
+using	O
+factor	O
+VIII	O
+related	O
+antigen	O
+(	O
+FVIIIRAg	O
+)	O
+immunohistochemistry	O
+and	O
+the	O
+expression	O
+of	O
+vascular	O
+endothelial	O
+growth	O
+factor	O
+/	O
+vascular	O
+permeability	O
+factor	O
+(	O
+VEGF	O
+/	O
+VPF	O
+)	O
+was	O
+examined	O
+by	O
+Western	O
+blot	O
+and	O
+immunohistochemical	O
+analysis	O
+.	O
+
+The	O
+expression	O
+of	O
+VEGF	O
+receptor	O
+(	O
+VEGFR	O
+-	O
+2	O
+/	O
+Flk	O
+-	O
+1	O
+/	O
+KDR	O
+)	O
+was	O
+also	O
+examined	O
+by	O
+immunohistochemistry	O
+.	O
+
+The	O
+results	O
+demonstrated	O
+that	O
+17beta	O
+-	O
+estradiol	O
+(	O
+E2	O
+)	O
+induces	O
+neovascularization	O
+,	O
+as	O
+well	O
+as	O
+the	O
+growth	O
+and	O
+enlargement	O
+of	O
+blood	O
+vessels	O
+after	O
+7	O
+days	O
+of	O
+exposure	O
+.	O
+
+The	O
+high	O
+tumor	B
+angiogenic	O
+potential	O
+was	O
+associated	O
+with	O
+an	O
+elevated	O
+VEGF	O
+/	O
+VPF	O
+protein	O
+expression	O
+in	O
+the	O
+E2	O
+exposed	O
+pituitary	O
+of	O
+ovariectomized	O
+(	O
+OVEX	O
+)	O
+rats	O
+.	O
+
+VEGF	O
+/	O
+VPF	O
+and	O
+FVIIIRAg	O
+immunohistochemistry	O
+and	O
+endothelial	O
+specific	O
+lectin	O
+(	O
+UEA1	O
+)	O
+binding	O
+studies	O
+,	O
+indicate	O
+that	O
+the	O
+elevation	O
+of	O
+VEGF	O
+protein	O
+expression	O
+initially	O
+occurred	O
+in	O
+both	O
+blood	O
+vessels	O
+and	O
+non	O
+-	O
+endothelial	O
+cells	O
+.	O
+
+After	O
+15	O
+days	O
+of	O
+E2	O
+exposure	O
+,	O
+VEGF	O
+/	O
+VPF	O
+protein	O
+expression	O
+,	O
+in	O
+the	O
+non	O
+-	O
+endothelial	O
+cell	O
+population	O
+,	O
+sharply	O
+declined	O
+and	O
+was	O
+restricted	O
+to	O
+the	O
+blood	O
+vessels	O
+.	O
+
+The	O
+function	O
+of	O
+non	O
+-	O
+endothelial	O
+-	O
+derived	O
+VEGF	O
+is	O
+not	O
+clear	O
+.	O
+
+Furthermore	O
+,	O
+immunohistochemical	O
+studies	O
+demonstrated	O
+that	O
+VEGFR	O
+-	O
+2	O
+(	O
+flk	O
+-	O
+1	O
+/	O
+KDR	O
+)	O
+,	O
+expression	O
+was	O
+elevated	O
+significantly	O
+in	O
+the	O
+endothelial	O
+cells	O
+of	O
+microblood	O
+vessels	O
+after	O
+7	O
+days	O
+of	O
+E2	O
+exposure	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+over	O
+expression	O
+of	O
+VEGF	O
+and	O
+its	O
+receptor	O
+(	O
+VEGFR	O
+-	O
+2	O
+)	O
+may	O
+play	O
+an	O
+important	O
+role	O
+in	O
+the	O
+initial	O
+step	O
+of	O
+the	O
+regulation	O
+of	O
+estrogen	O
+induced	O
+tumor	B
+angiogenesis	O
+in	O
+the	O
+rat	O
+pituitary	O
+.	O
+
+Persistent	O
+nephrogenic	B
+diabetes	I
+insipidus	I
+following	O
+lithium	O
+therapy	O
+.	O
+
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+patient	O
+who	O
+developed	O
+severe	O
+hypernatraemic	O
+dehydration	B
+following	O
+a	O
+head	B
+injury	I
+.	O
+
+Ten	O
+years	O
+previously	O
+he	O
+had	O
+been	O
+diagnosed	O
+to	O
+have	O
+lithium	O
+-	O
+induced	O
+nephrogenic	B
+diabetes	I
+insipidus	I
+,	O
+and	O
+lithium	O
+therapy	O
+had	O
+been	O
+discontinued	O
+.	O
+
+He	O
+remained	O
+thirsty	O
+and	O
+polyuric	B
+despite	O
+cessation	O
+of	O
+lithium	O
+and	O
+investigations	O
+on	O
+admission	O
+showed	O
+him	O
+to	O
+have	O
+normal	O
+osmoregulated	O
+thirst	O
+and	O
+vasopressin	O
+secretion	O
+,	O
+with	O
+clear	O
+evidence	O
+of	O
+nephrogenic	B
+diabetes	I
+insipidus	I
+.	O
+
+Lithium	O
+induced	O
+nephrogenic	B
+diabetes	I
+insipidus	I
+is	O
+considered	O
+to	O
+be	O
+reversible	O
+on	O
+cessation	O
+of	O
+therapy	O
+but	O
+polyuria	B
+persisted	O
+in	O
+this	O
+patient	O
+for	O
+ten	O
+years	O
+after	O
+lithium	O
+was	O
+stopped	O
+.	O
+
+We	O
+discuss	O
+the	O
+possible	O
+renal	O
+mechanisms	O
+and	O
+the	O
+implications	O
+for	O
+management	O
+of	O
+patients	O
+with	O
+lithium	O
+-	O
+induced	O
+nephrogenic	B
+diabetes	I
+insipidus	I
+.	O
+
+Effects	O
+of	O
+NIK	O
+-	O
+247	O
+on	O
+cholinesterase	O
+and	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+.	O
+
+The	O
+effects	O
+of	O
+NIK	O
+-	O
+247	O
+on	O
+cholinesterase	O
+,	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+and	O
+spontaneous	O
+movement	O
+were	O
+examined	O
+and	O
+compared	O
+with	O
+those	O
+of	O
+the	O
+well	O
+-	O
+known	O
+cholinesterase	O
+inhibitors	O
+tacrine	O
+and	O
+E	O
+-	O
+2020	O
+.	O
+
+NIK	O
+-	O
+247	O
+,	O
+tacrine	O
+and	O
+E	O
+-	O
+2020	O
+all	O
+strongly	O
+inhibited	O
+acetylcholinesterase	O
+(	O
+AChE	O
+)	O
+in	O
+human	O
+red	O
+blood	O
+cells	O
+(	O
+IC50s	O
+=	O
+1	O
+.	O
+0	O
+x	O
+10	O
+(	O
+-	O
+6	O
+)	O
+,	O
+2	O
+.	O
+9	O
+x	O
+10	O
+(	O
+-	O
+7	O
+)	O
+and	O
+3	O
+.	O
+7	O
+x	O
+10	O
+(	O
+-	O
+8	O
+)	O
+M	O
+,	O
+respectively	O
+)	O
+.	O
+
+In	O
+addition	O
+,	O
+NIK	O
+-	O
+247	O
+and	O
+tacrine	O
+,	O
+but	O
+not	O
+E	O
+-	O
+2020	O
+,	O
+strongly	O
+inhibited	O
+butyrylcholinestrase	O
+(	O
+BuChE	O
+)	O
+in	O
+human	O
+serum	O
+.	O
+
+All	O
+three	O
+drugs	O
+produced	O
+mixed	O
+inhibition	O
+of	O
+AChE	O
+activity	O
+.	O
+
+Moreover	O
+,	O
+the	O
+inhibitory	O
+effect	O
+of	O
+NIK	O
+-	O
+247	O
+on	O
+AChE	O
+was	O
+reversible	O
+.	O
+
+All	O
+compounds	O
+at	O
+0	O
+.	O
+1	O
+-	O
+1	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+significantly	O
+improved	O
+the	O
+amnesia	B
+induced	O
+by	O
+scopolamine	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+in	O
+rats	O
+performing	O
+a	O
+passive	O
+avoidance	O
+task	O
+.	O
+
+The	O
+three	O
+compounds	O
+at	O
+1	O
+and	O
+3	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+did	O
+not	O
+significantly	O
+decrease	O
+spontaneous	O
+movement	O
+by	O
+rats	O
+.	O
+
+These	O
+findings	O
+suggest	O
+that	O
+NIK	O
+-	O
+247	O
+at	O
+a	O
+low	O
+dose	O
+(	O
+0	O
+.	O
+1	O
+-	O
+1	O
+mg	O
+/	O
+kg	O
+p	O
+.	O
+o	O
+.	O
+)	O
+improves	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B
+but	O
+does	O
+not	O
+affect	O
+spontaneous	O
+movement	O
+.	O
+
+The	O
+findings	O
+suggest	O
+that	O
+NIK	O
+-	O
+247	O
+may	O
+be	O
+a	O
+useful	O
+drug	O
+for	O
+the	O
+treatment	O
+of	O
+Alzheimer	B
+'	I
+s	I
+disease	I
+.	O
+
+Potential	O
+therapeutic	O
+use	O
+of	O
+the	O
+selective	O
+dopamine	O
+D1	O
+receptor	O
+agonist	O
+,	O
+A	O
+-	O
+86929	O
+:	O
+an	O
+acute	O
+study	O
+in	O
+parkinsonian	B
+levodopa	O
+-	O
+primed	O
+monkeys	O
+.	O
+
+The	O
+clinical	O
+utility	O
+of	O
+dopamine	O
+(	O
+DA	O
+)	O
+D1	O
+receptor	O
+agonists	O
+in	O
+the	O
+treatment	O
+of	O
+Parkinson	B
+'	I
+s	I
+disease	I
+(	O
+PD	B
+)	O
+is	O
+still	O
+unclear	O
+.	O
+
+The	O
+therapeutic	O
+use	O
+of	O
+selective	O
+DA	O
+D1	O
+receptor	O
+agonists	O
+such	O
+as	O
+SKF	O
+-	O
+82958	O
+(	O
+6	O
+-	O
+chloro	O
+-	O
+7	O
+,	O
+8	O
+-	O
+dihydroxy	O
+-	O
+3	O
+-	O
+allyl	O
+-	O
+1	O
+-	O
+phenyl	O
+-	O
+2	O
+,	O
+3	O
+,	O
+4	O
+,	O
+5	O
+-	O
+tetrahydro	O
+-	O
+1H	O
+-	O
+3	O
+-	O
+benzaze	O
+pine	O
+hydrobromide	O
+)	O
+and	O
+A	O
+-	O
+77636	O
+(	O
+[	O
+1R	O
+,	O
+3S	O
+]	O
+3	O
+-	O
+[	O
+1	O
+'	O
+-	O
+admantyl	O
+]	O
+-	O
+1	O
+-	O
+aminomethyl	O
+-	O
+3	O
+,	O
+4	O
+-	O
+dihydro	O
+-	O
+5	O
+,	O
+6	O
+-	O
+dihydroxy	O
+-	O
+1H	O
+-	O
+2	O
+-	O
+benzo	O
+pyran	O
+hydrochloride	O
+)	O
+seems	O
+limited	O
+because	O
+of	O
+their	O
+duration	O
+of	O
+action	O
+,	O
+which	O
+is	O
+too	O
+short	O
+for	O
+SKF	O
+-	O
+82958	O
+(	O
+<	O
+1	O
+hr	O
+)	O
+and	O
+too	O
+long	O
+for	O
+A	O
+-	O
+77636	O
+(	O
+>	O
+20	O
+hr	O
+,	O
+leading	O
+to	O
+behavioral	O
+tolerance	O
+)	O
+.	O
+
+We	O
+therefore	O
+conducted	O
+the	O
+present	O
+acute	O
+dose	O
+-	O
+response	O
+study	O
+in	O
+four	O
+1	O
+-	O
+methyl	O
+-	O
+4	O
+-	O
+phenyl	O
+-	O
+1	O
+,	O
+2	O
+,	O
+3	O
+,	O
+6	O
+-	O
+tetrahydropyridine	O
+(	O
+MPTP	O
+)	O
+-	O
+exposed	O
+cynomolgus	O
+monkeys	O
+primed	O
+to	O
+exhibit	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+to	O
+evaluate	O
+the	O
+locomotor	O
+and	O
+dyskinetic	B
+effects	O
+on	O
+challenge	O
+with	O
+four	O
+doses	O
+(	O
+from	O
+0	O
+.	O
+03	O
+to	O
+1	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+)	O
+of	O
+A	O
+-	O
+86929	O
+(	O
+[	O
+-	O
+]	O
+-	O
+[	O
+5aR	O
+,	O
+11bS	O
+]	O
+-	O
+4	O
+,	O
+5	O
+,	O
+5a	O
+,	O
+6	O
+,	O
+7	O
+,	O
+11b	O
+-	O
+hexahydro	O
+-	O
+2	O
+-	O
+propyl	O
+-	O
+3	O
+-	O
+thia	O
+-	O
+5	O
+-	O
++	O
++	O
++	O
+azacyclopent	O
+-	O
+1	O
+-	O
+ena	O
+[	O
+c	O
+]	O
+phenathrene	O
+-	O
+9	O
+-	O
+10	O
+-	O
+diol	O
+)	O
+,	O
+a	O
+selective	O
+and	O
+full	O
+DA	O
+D1	O
+-	O
+like	O
+receptor	O
+agonist	O
+with	O
+an	O
+intermediate	O
+duration	O
+of	O
+action	O
+.	O
+
+Levodopa	O
+and	O
+the	O
+DA	O
+D2	O
+-	O
+like	O
+receptor	O
+agonist	O
+,	O
+LY	O
+-	O
+171555	O
+(	O
+[	O
+4aR	O
+-	O
+trans	O
+]	O
+-	O
+4	O
+,	O
+4a	O
+,	O
+5	O
+,	O
+6	O
+,	O
+7	O
+,	O
+8	O
+,	O
+8a	O
+,	O
+9	O
+-	O
+o	O
+-	O
+dihydro	O
+-	O
+5n	O
+-	O
+propyl	O
+-	O
+2H	O
+-	O
+pyrazo	O
+lo	O
+-	O
+3	O
+-	O
+4	O
+-	O
+quinoline	O
+hydrochloride	O
+)	O
+were	O
+also	O
+used	O
+for	O
+comparison	O
+.	O
+
+Acute	O
+administration	O
+of	O
+A	O
+-	O
+86929	O
+was	O
+as	O
+efficacious	O
+in	O
+alleviating	O
+MPTP	O
+-	O
+induced	O
+parkinsonism	B
+as	O
+levodopa	O
+and	O
+LY	O
+-	O
+171555	O
+,	O
+but	O
+was	O
+less	O
+likely	O
+to	O
+reproduce	O
+the	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+in	O
+these	O
+animals	O
+than	O
+with	O
+either	O
+LY	O
+-	O
+171555	O
+or	O
+subsequent	O
+challenge	O
+of	O
+levodopa	O
+.	O
+
+Selective	O
+stimulation	O
+of	O
+the	O
+DA	O
+D1	O
+receptor	O
+may	O
+provide	O
+better	O
+integration	O
+of	O
+neural	O
+inputs	O
+transmitted	O
+to	O
+the	O
+internal	O
+segment	O
+of	O
+the	O
+globus	O
+pallidus	O
+(	O
+referred	O
+to	O
+as	O
+the	O
+basal	O
+ganglia	O
+output	O
+)	O
+compared	O
+with	O
+levodopa	O
+and	O
+selective	O
+DA	O
+D2	O
+receptor	O
+agonist	O
+.	O
+
+Potent	O
+DA	O
+D1	O
+receptor	O
+agents	O
+with	O
+an	O
+intermediate	O
+duration	O
+of	O
+efficacy	O
+such	O
+as	O
+A	O
+-	O
+86929	O
+(	O
+approximately	O
+4	O
+hr	O
+at	O
+higher	O
+doses	O
+tested	O
+)	O
+are	O
+potential	O
+therapeutic	O
+tools	O
+in	O
+PD	B
+and	O
+merit	O
+further	O
+attention	O
+.	O
+
+Neuropeptide	O
+-	O
+Y	O
+immunoreactivity	O
+in	O
+the	O
+pilocarpine	O
+model	O
+of	O
+temporal	B
+lobe	I
+epilepsy	I
+.	O
+
+Neuropeptide	O
+-	O
+Y	O
+(	O
+NPY	O
+)	O
+is	O
+expressed	O
+by	O
+granule	O
+cells	O
+and	O
+mossy	O
+fibres	O
+of	O
+the	O
+hippocampal	O
+dentate	O
+gyrus	O
+during	O
+experimental	O
+temporal	B
+lobe	I
+epilepsy	I
+(	O
+TLE	B
+)	O
+.	O
+
+This	O
+expression	O
+may	O
+represent	O
+an	O
+endogenous	O
+damping	O
+mechanism	O
+since	O
+NPY	O
+has	O
+been	O
+shown	O
+to	O
+block	O
+seizure	B
+-	O
+like	O
+events	O
+following	O
+high	O
+-	O
+frequency	O
+stimulation	O
+in	O
+hippocampal	O
+slices	O
+.	O
+
+The	O
+pilocarpine	O
+(	O
+PILO	O
+)	O
+model	O
+of	O
+epilepsy	B
+is	O
+characterized	O
+by	O
+an	O
+acute	O
+period	O
+of	O
+status	B
+epilepticus	I
+followed	O
+by	O
+spontaneous	O
+recurrent	O
+seizures	B
+and	O
+related	O
+brain	B
+damage	I
+.	O
+
+We	O
+report	O
+peroxidase	O
+-	O
+antiperoxidase	O
+immunostaining	O
+for	O
+NPY	O
+in	O
+several	O
+brain	O
+regions	O
+in	O
+this	O
+model	O
+.	O
+
+PILO	O
+-	O
+injected	O
+animals	O
+exhibited	O
+NPY	O
+immunoreactivity	O
+in	O
+the	O
+region	O
+of	O
+the	O
+mossy	O
+fibre	O
+terminals	O
+,	O
+in	O
+the	O
+dentate	O
+gyrus	O
+inner	O
+molecular	O
+layer	O
+and	O
+,	O
+in	O
+a	O
+few	O
+cases	O
+,	O
+within	O
+presumed	O
+granule	O
+cells	O
+.	O
+
+NPY	O
+immunoreactivity	O
+was	O
+also	O
+dramatically	O
+changed	O
+in	O
+the	O
+entorhinal	O
+cortex	O
+,	O
+amygdala	O
+and	O
+sensorimotor	O
+areas	O
+.	O
+
+In	O
+addition	O
+,	O
+PILO	O
+injected	O
+animals	O
+exhibited	O
+a	O
+reduction	O
+in	O
+the	O
+number	O
+of	O
+NPY	O
+-	O
+immunoreactive	O
+interneurons	O
+compared	O
+with	O
+controls	O
+.	O
+
+The	O
+results	O
+demonstrate	O
+that	O
+changes	O
+in	O
+NPY	O
+expression	O
+,	O
+including	O
+expression	O
+in	O
+the	O
+granule	O
+cells	O
+and	O
+mossy	O
+fibres	O
+and	O
+the	O
+loss	O
+of	O
+vulnerable	O
+NPY	O
+neurons	O
+,	O
+are	O
+present	O
+in	O
+the	O
+PILO	O
+model	O
+of	O
+TLE	B
+.	O
+
+However	O
+,	O
+the	O
+significance	O
+of	O
+this	O
+changed	O
+synthesis	O
+of	O
+NPY	O
+remains	O
+to	O
+be	O
+determined	O
+.	O
+
+Posteroventral	O
+medial	O
+pallidotomy	O
+in	O
+advanced	O
+Parkinson	B
+'	I
+s	I
+disease	I
+.	O
+
+BACKGROUND	O
+:	O
+Posteroventral	O
+medial	O
+pallidotomy	O
+sometimes	O
+produces	O
+striking	O
+improvement	O
+in	O
+patients	O
+with	O
+advanced	O
+Parkinson	B
+'	I
+s	I
+disease	I
+,	O
+but	O
+the	O
+studies	O
+to	O
+date	O
+have	O
+involved	O
+small	O
+numbers	O
+of	O
+patients	O
+and	O
+short	O
+-	O
+term	O
+follow	O
+-	O
+up	O
+.	O
+
+METHODS	O
+:	O
+Forty	O
+patients	O
+with	O
+Parkinson	B
+'	I
+s	I
+disease	I
+underwent	O
+serial	O
+,	O
+detailed	O
+assessments	O
+both	O
+after	O
+drug	O
+withdrawal	O
+(	O
+"	O
+off	O
+"	O
+period	O
+)	O
+and	O
+while	O
+taking	O
+their	O
+optimal	O
+medical	O
+regimens	O
+(	O
+"	O
+on	O
+"	O
+period	O
+)	O
+.	O
+
+All	O
+patients	O
+were	O
+examined	O
+preoperatively	O
+and	O
+39	O
+were	O
+examined	O
+at	O
+six	O
+months	O
+;	O
+27	O
+of	O
+the	O
+patients	O
+were	O
+also	O
+examined	O
+at	O
+one	O
+year	O
+,	O
+and	O
+11	O
+at	O
+two	O
+years	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+percent	O
+improvements	O
+at	O
+six	O
+months	O
+were	O
+as	O
+follows	O
+:	O
+off	O
+-	O
+period	O
+score	O
+for	O
+overall	O
+motor	O
+function	O
+,	O
+28	O
+percent	O
+(	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+19	O
+to	O
+38	O
+percent	O
+)	O
+,	O
+with	O
+most	O
+of	O
+the	O
+improvement	O
+in	O
+the	O
+contralateral	O
+limbs	O
+;	O
+off	O
+-	O
+period	O
+score	O
+for	O
+activities	O
+of	O
+daily	O
+living	O
+,	O
+29	O
+percent	O
+(	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+19	O
+to	O
+39	O
+percent	O
+)	O
+;	O
+on	O
+-	O
+period	O
+score	O
+for	O
+contralateral	O
+dyskinesias	B
+,	O
+82	O
+percent	O
+(	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+72	O
+to	O
+91	O
+percent	O
+)	O
+;	O
+and	O
+on	O
+-	O
+period	O
+score	O
+for	O
+ipsilateral	O
+dyskinesias	B
+,	O
+44	O
+percent	O
+(	O
+95	O
+percent	O
+confidence	O
+interval	O
+,	O
+29	O
+to	O
+59	O
+percent	O
+)	O
+.	O
+
+The	O
+improvements	O
+in	O
+dyskinesias	B
+and	O
+the	O
+total	O
+scores	O
+for	O
+off	O
+-	O
+period	O
+parkinsonism	B
+,	O
+contralateral	O
+bradykinesia	B
+,	O
+and	O
+rigidity	B
+were	O
+sustained	O
+in	O
+the	O
+11	O
+patients	O
+examined	O
+at	O
+two	O
+years	O
+.	O
+
+The	O
+improvement	O
+in	O
+ipsilateral	O
+dyskinesias	B
+was	O
+lost	O
+after	O
+one	O
+year	O
+,	O
+and	O
+the	O
+improvements	O
+in	O
+postural	O
+stability	O
+and	O
+gait	O
+lasted	O
+only	O
+three	O
+to	O
+six	O
+months	O
+.	O
+
+Approximately	O
+half	O
+the	O
+patients	O
+who	O
+had	O
+been	O
+dependent	O
+on	O
+assistance	O
+in	O
+activities	O
+of	O
+daily	O
+living	O
+in	O
+the	O
+off	O
+period	O
+before	O
+surgery	O
+became	O
+independent	O
+after	O
+surgery	O
+.	O
+
+The	O
+complications	O
+of	O
+surgery	O
+were	O
+generally	O
+well	O
+tolerated	O
+,	O
+and	O
+there	O
+were	O
+no	O
+significant	O
+changes	O
+in	O
+the	O
+use	O
+of	O
+medication	O
+.	O
+
+CONCLUSIONS	O
+:	O
+In	O
+late	O
+-	O
+stage	O
+Parkinson	B
+'	I
+s	I
+disease	I
+,	O
+pallidotomy	O
+significantly	O
+reduces	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B
+and	O
+off	O
+-	O
+period	O
+disability	O
+.	O
+
+Much	O
+of	O
+the	O
+benefit	O
+is	O
+sustained	O
+at	O
+two	O
+years	O
+,	O
+although	O
+some	O
+improvements	O
+,	O
+such	O
+as	O
+those	O
+on	O
+the	O
+ipsilateral	O
+side	O
+and	O
+in	O
+axial	O
+symptoms	O
+,	O
+wane	O
+within	O
+the	O
+first	O
+year	O
+.	O
+
+The	O
+on	O
+-	O
+period	O
+symptoms	O
+that	O
+are	O
+resistant	O
+to	O
+dopaminergic	O
+therapy	O
+do	O
+not	O
+respond	O
+to	O
+pallidotomy	O
+.	O
+
+Clarithromycin	O
+-	O
+induced	O
+ventricular	B
+tachycardia	I
+.	O
+
+Clarithromycin	O
+is	O
+a	O
+relatively	O
+new	O
+macrolide	O
+antibiotic	O
+that	O
+offers	O
+twice	O
+-	O
+daily	O
+dosing	O
+.	O
+
+It	O
+differs	O
+from	O
+erythromycin	O
+only	O
+in	O
+the	O
+methylation	O
+of	O
+the	O
+hydroxyl	O
+group	O
+at	O
+position	O
+6	O
+.	O
+
+Although	O
+the	O
+side	O
+-	O
+effect	O
+profile	O
+of	O
+erythromycin	O
+is	O
+established	O
+,	O
+including	O
+gastroenteritis	B
+and	O
+interactions	O
+with	O
+other	O
+drugs	O
+subject	O
+to	O
+hepatic	O
+mixed	O
+-	O
+function	O
+oxidase	O
+metabolism	O
+,	O
+experience	O
+with	O
+the	O
+newer	O
+macrolides	O
+is	O
+still	O
+being	O
+recorded	O
+.	O
+
+Cardiotoxicity	B
+has	O
+been	O
+demonstrated	O
+after	O
+both	O
+intravenous	O
+and	O
+oral	O
+administration	O
+of	O
+erythromycin	O
+but	O
+has	O
+never	O
+been	O
+reported	O
+with	O
+the	O
+newer	O
+macrolides	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+ventricular	B
+dysrhythmias	I
+that	O
+occurred	O
+after	O
+six	O
+therapeutic	O
+doses	O
+of	O
+clarithromycin	O
+.	O
+
+The	O
+dysrhythmias	B
+resolved	O
+after	O
+discontinuation	O
+of	O
+the	O
+drug	O
+.	O
+
+Effect	O
+of	O
+glyceryl	O
+trinitrate	O
+on	O
+the	O
+sphincter	B
+of	I
+Oddi	I
+spasm	I
+evoked	O
+by	O
+prostigmine	O
+-	O
+morphine	O
+administration	O
+.	O
+
+OBJECTIVE	O
+:	O
+In	O
+this	O
+study	O
+the	O
+effect	O
+of	O
+glyceryl	O
+trinitrate	O
+on	O
+the	O
+prostigmine	O
+-	O
+morphine	O
+-	O
+induced	O
+sphincter	B
+of	I
+Oddi	I
+spasm	I
+was	O
+evaluated	O
+in	O
+nine	O
+female	O
+patients	O
+with	O
+sphincter	B
+of	I
+Oddi	I
+dyskinesia	I
+.	O
+
+METHOD	O
+:	O
+Sphincter	B
+of	I
+Oddi	I
+spasm	I
+was	O
+induced	O
+by	O
+prostigmine	O
+-	O
+morphine	O
+administration	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+prostigmine	O
+intramuscularly	O
+and	O
+10	O
+mg	O
+morphine	O
+subcutaneously	O
+)	O
+and	O
+visualized	O
+by	O
+quantitative	O
+hepatobiliary	O
+scintigraphy	O
+.	O
+
+The	O
+entire	O
+procedure	O
+was	O
+repeated	O
+during	O
+glyceryl	O
+trinitrate	O
+infusion	O
+(	O
+Nitrolingual	O
+1	O
+microg	O
+/	O
+kg	O
+/	O
+min	O
+for	O
+120	O
+min	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+Prostigmine	O
+-	O
+morphine	O
+provocation	O
+caused	O
+significant	O
+increases	O
+in	O
+the	O
+time	O
+to	O
+peak	O
+activity	O
+(	O
+Tmax	O
+)	O
+over	O
+the	O
+hepatic	O
+hilum	O
+(	O
+HH	O
+:	O
+34	O
+.	O
+33	O
++	O
+/	O
+-	O
+5	O
+.	O
+05	O
+vs	O
+.	O
+22	O
+.	O
+77	O
++	O
+/	O
+-	O
+3	O
+.	O
+26	O
+)	O
+and	O
+the	O
+common	O
+bile	O
+duct	O
+(	O
+CBD	O
+:	O
+60	O
+.	O
+44	O
++	O
+/	O
+-	O
+5	O
+.	O
+99	O
+vs	O
+.	O
+40	O
+.	O
+0	O
++	O
+/	O
+-	O
+2	O
+.	O
+88	O
+)	O
+and	O
+in	O
+the	O
+half	O
+-	O
+time	O
+of	O
+excretion	O
+(	O
+T1	O
+/	O
+2	O
+)	O
+over	O
+the	O
+liver	O
+parenchyma	O
+(	O
+LP	O
+:	O
+120	O
+.	O
+04	O
++	O
+/	O
+-	O
+16	O
+.	O
+01	O
+vs	O
+.	O
+27	O
+.	O
+37	O
++	O
+/	O
+-	O
+2	O
+.	O
+19	O
+)	O
+,	O
+HH	O
+(	O
+117	O
+.	O
+61	O
++	O
+/	O
+-	O
+14	O
+.	O
+71	O
+vs	O
+.	O
+31	O
+.	O
+85	O
++	O
+/	O
+-	O
+3	O
+.	O
+99	O
+)	O
+and	O
+CBD	O
+(	O
+158	O
+.	O
+11	O
++	O
+/	O
+-	O
+9	O
+.	O
+18	O
+vs	O
+.	O
+40	O
+.	O
+1	O
++	O
+/	O
+-	O
+6	O
+.	O
+24	O
+)	O
+,	O
+indicating	O
+a	O
+complete	O
+spasm	B
+at	O
+the	O
+level	O
+of	O
+the	O
+sphincter	O
+of	O
+Oddi	O
+.	O
+
+Glyceryl	O
+trinitrate	O
+infusion	O
+completely	O
+normalized	O
+the	O
+prostigmine	O
+-	O
+morphine	O
+-	O
+induced	O
+alterations	O
+in	O
+these	O
+quantitative	O
+parameters	O
+(	O
+TmaX	O
+over	O
+the	O
+LP	O
+:	O
+11	O
+.	O
+33	O
++	O
+/	O
+-	O
+1	O
+.	O
+13	O
+;	O
+over	O
+the	O
+HH	O
+:	O
+18	O
+.	O
+88	O
++	O
+/	O
+-	O
+1	O
+.	O
+48	O
+;	O
+and	O
+over	O
+the	O
+CBD	O
+:	O
+36	O
+.	O
+22	O
++	O
+/	O
+-	O
+1	O
+.	O
+92	O
+;	O
+and	O
+T1	O
+/	O
+2	O
+over	O
+the	O
+LP	O
+:	O
+28	O
+.	O
+21	O
++	O
+/	O
+-	O
+1	O
+.	O
+83	O
+;	O
+over	O
+the	O
+HH	O
+:	O
+33	O
+.	O
+42	O
++	O
+/	O
+-	O
+3	O
+.	O
+10	O
+;	O
+and	O
+over	O
+the	O
+CBD	O
+:	O
+41	O
+.	O
+66	O
++	O
+/	O
+-	O
+6	O
+.	O
+33	O
+)	O
+,	O
+suggesting	O
+an	O
+effective	O
+sphincter	O
+-	O
+relaxing	O
+effect	O
+of	O
+glyceryl	O
+trinitrate	O
+.	O
+
+CONCLUSION	O
+:	O
+These	O
+results	O
+provide	O
+the	O
+first	O
+evidence	O
+of	O
+the	O
+effectiveness	O
+of	O
+glyceryl	O
+trinitrate	O
+on	O
+the	O
+morphine	O
+-	O
+induced	O
+sphincter	B
+of	I
+Oddi	I
+spasm	I
+in	O
+humans	O
+.	O
+
+Since	O
+glyceryl	O
+trinitrate	O
+is	O
+able	O
+to	O
+overcome	O
+even	O
+the	O
+drastic	O
+effect	O
+of	O
+morphine	O
+,	O
+it	O
+might	O
+be	O
+of	O
+relevance	O
+in	O
+the	O
+treatment	O
+of	O
+sphincter	B
+of	I
+Oddi	I
+dyskinesia	I
+.	O
+
+Immunopathology	O
+of	O
+penicillamine	O
+-	O
+induced	O
+glomerular	B
+disease	I
+.	O
+
+Four	O
+patients	O
+with	O
+rheumatoid	B
+arthritis	I
+developed	O
+heavy	O
+proteinuria	B
+after	O
+five	O
+to	O
+12	O
+months	O
+of	O
+treatment	O
+with	O
+D	O
+-	O
+penicillamine	O
+.	O
+
+Light	O
+microscopy	O
+of	O
+renal	O
+biopsy	O
+samples	O
+showed	O
+minimal	O
+glomerular	O
+capillary	O
+wall	O
+thickening	O
+and	O
+mesangial	O
+matrix	O
+increase	O
+,	O
+or	O
+no	O
+departure	O
+from	O
+normal	O
+.	O
+
+Electron	O
+microscopy	O
+,	O
+however	O
+,	O
+revealed	O
+subepithelial	O
+electron	O
+-	O
+dense	O
+deposits	O
+,	O
+fusion	O
+of	O
+epithelial	O
+cell	O
+foot	O
+processes	O
+,	O
+and	O
+evidence	O
+of	O
+mesangial	O
+cell	O
+hyperactivity	O
+.	O
+
+Immunofluorescence	O
+microscopy	O
+demonstrated	O
+granular	O
+capillary	O
+wall	O
+deposits	O
+of	O
+IgG	O
+and	O
+C3	O
+.	O
+
+The	O
+findings	O
+were	O
+similar	O
+to	O
+those	O
+in	O
+early	O
+membranous	B
+glomerulonephritis	I
+,	O
+differences	O
+being	O
+observed	O
+however	O
+in	O
+the	O
+results	O
+of	O
+staining	O
+for	O
+the	O
+early	O
+-	O
+acting	O
+complement	O
+components	O
+C1q	O
+and	O
+C4	O
+.	O
+
+It	O
+is	O
+tentatively	O
+concluded	O
+that	O
+complement	O
+was	O
+activated	O
+by	O
+the	O
+classical	O
+pathway	O
+.	O
+
+Experimental	O
+cranial	O
+pain	B
+elicited	O
+by	O
+capsaicin	O
+:	O
+a	O
+PET	O
+study	O
+.	O
+
+Using	O
+a	O
+positron	O
+emission	O
+tomography	O
+(	O
+PET	O
+)	O
+study	O
+it	O
+was	O
+shown	O
+recently	O
+that	O
+in	O
+migraine	B
+without	O
+aura	O
+certain	O
+areas	O
+in	O
+the	O
+brain	O
+stem	O
+were	O
+activated	O
+during	O
+the	O
+headache	B
+state	O
+,	O
+but	O
+not	O
+in	O
+the	O
+headache	B
+free	O
+interval	O
+.	O
+
+It	O
+was	O
+suggested	O
+that	O
+this	O
+brain	O
+stem	O
+activation	O
+is	O
+inherent	O
+to	O
+the	O
+migraine	B
+attack	O
+itself	O
+and	O
+represents	O
+the	O
+so	O
+called	O
+'	O
+migraine	B
+generator	O
+'	O
+.	O
+
+To	O
+test	O
+this	O
+hypothesis	O
+we	O
+performed	O
+an	O
+experimental	O
+pain	B
+study	O
+in	O
+seven	O
+healthy	O
+volunteers	O
+,	O
+using	O
+the	O
+same	O
+positioning	O
+in	O
+the	O
+PET	O
+scanner	O
+as	O
+in	O
+the	O
+migraine	B
+patients	O
+.	O
+
+A	O
+small	O
+amount	O
+of	O
+capsaicin	O
+was	O
+administered	O
+subcutaneously	O
+in	O
+the	O
+right	O
+forehead	O
+to	O
+evoke	O
+a	O
+burning	O
+painful	B
+sensation	O
+in	O
+the	O
+first	O
+division	O
+of	O
+the	O
+trigeminal	O
+nerve	O
+.	O
+
+Increases	O
+of	O
+regional	O
+cerebral	O
+blood	O
+flow	O
+(	O
+rCBF	O
+)	O
+were	O
+found	O
+bilaterally	O
+in	O
+the	O
+insula	O
+,	O
+in	O
+the	O
+anterior	O
+cingulate	O
+cortex	O
+,	O
+the	O
+cavernous	O
+sinus	O
+and	O
+the	O
+cerebellum	O
+.	O
+
+Using	O
+the	O
+same	O
+stereotactic	O
+space	O
+limits	O
+as	O
+in	O
+the	O
+above	O
+mentioned	O
+migraine	B
+study	O
+no	O
+brain	O
+stem	O
+activation	O
+was	O
+found	O
+in	O
+the	O
+acute	O
+pain	B
+state	O
+compared	O
+to	O
+the	O
+pain	B
+free	O
+state	O
+.	O
+
+The	O
+increase	O
+of	O
+activation	O
+in	O
+the	O
+region	O
+of	O
+the	O
+cavernous	O
+sinus	O
+however	O
+,	O
+suggests	O
+that	O
+this	O
+structure	O
+is	O
+more	O
+likely	O
+to	O
+be	O
+involved	O
+in	O
+trigeminal	O
+transmitted	O
+pain	B
+as	O
+such	O
+,	O
+rather	O
+than	O
+in	O
+a	O
+specific	O
+type	O
+of	O
+headache	B
+as	O
+was	O
+suggested	O
+for	O
+cluster	B
+headache	I
+.	O
+
+Value	O
+of	O
+methylprednisolone	O
+in	O
+prevention	O
+of	O
+the	O
+arthralgia	B
+-	O
+myalgia	B
+syndrome	O
+associated	O
+with	O
+the	O
+total	O
+dose	O
+infusion	O
+of	O
+iron	O
+dextran	O
+:	O
+a	O
+double	O
+blind	O
+randomized	O
+trial	O
+.	O
+
+The	O
+safety	O
+and	O
+efficacy	O
+of	O
+total	O
+dose	O
+infusion	O
+(	O
+TDI	O
+)	O
+of	O
+iron	O
+dextran	O
+has	O
+been	O
+well	O
+documented	O
+.	O
+
+In	O
+40	O
+%	O
+of	O
+treated	O
+patients	O
+,	O
+an	O
+arthralgia	B
+-	O
+myalgia	B
+syndrome	O
+develops	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+randomized	O
+,	O
+double	O
+-	O
+blind	O
+,	O
+prospective	O
+study	O
+was	O
+to	O
+investigate	O
+whether	O
+intravenous	O
+(	O
+i	O
+.	O
+v	O
+.	O
+)	O
+administration	O
+of	O
+methylprednisolone	O
+(	O
+MP	O
+)	O
+prevents	O
+this	O
+complication	O
+.	O
+
+Sixty	O
+-	O
+five	O
+patients	O
+,	O
+34	O
+women	O
+and	O
+31	O
+men	O
+,	O
+ages	O
+36	O
+to	O
+80	O
+years	O
+,	O
+received	O
+either	O
+normal	O
+saline	O
+before	O
+and	O
+after	O
+TDI	O
+(	O
+group	O
+1	O
+)	O
+,	O
+125	O
+mg	O
+i	O
+.	O
+v	O
+.	O
+MP	O
+before	O
+and	O
+saline	O
+after	O
+TDI	O
+(	O
+group	O
+2	O
+)	O
+,	O
+or	O
+125	O
+mg	O
+i	O
+.	O
+v	O
+.	O
+MP	O
+before	O
+and	O
+after	O
+TDI	O
+(	O
+group	O
+3	O
+)	O
+.	O
+
+Patients	O
+were	O
+observed	O
+for	O
+72	O
+hours	O
+and	O
+reactions	O
+were	O
+recorded	O
+and	O
+graded	O
+according	O
+to	O
+severity	O
+.	O
+
+Fifty	O
+-	O
+eight	O
+percent	O
+of	O
+group	O
+1	O
+patients	O
+,	O
+33	O
+%	O
+of	O
+group	O
+2	O
+,	O
+and	O
+26	O
+%	O
+of	O
+group	O
+3	O
+had	O
+reactions	O
+to	O
+TDI	O
+.	O
+
+The	O
+severity	O
+of	O
+reactions	O
+(	O
+minimal	O
+,	O
+mild	O
+,	O
+and	O
+moderate	O
+,	O
+respectively	O
+)	O
+was	O
+as	O
+follows	O
+:	O
+group	O
+1	O
+-	O
+-	O
+6	O
+,	O
+6	O
+,	O
+and	O
+2	O
+;	O
+group	O
+2	O
+-	O
+-	O
+1	O
+,	O
+5	O
+,	O
+and	O
+0	O
+;	O
+group	O
+3	O
+-	O
+-	O
+5	O
+,	O
+1	O
+,	O
+and	O
+0	O
+.	O
+
+Data	O
+were	O
+analyzed	O
+by	O
+the	O
+two	O
+-	O
+sided	O
+Fisher	O
+'	O
+s	O
+exact	O
+test	O
+using	O
+95	O
+%	O
+confidence	O
+intervals	O
+with	O
+the	O
+approximation	O
+of	O
+Woolf	O
+.	O
+
+These	O
+data	O
+demonstrate	O
+that	O
+administration	O
+of	O
+MP	O
+before	O
+and	O
+after	O
+TDI	O
+reduces	O
+the	O
+frequency	O
+and	O
+severity	O
+of	O
+the	O
+arthralgia	B
+-	O
+myalgia	B
+syndrome	O
+.	O
+
+We	O
+conclude	O
+that	O
+125	O
+mg	O
+i	O
+.	O
+v	O
+.	O
+MP	O
+should	O
+be	O
+given	O
+routinely	O
+before	O
+and	O
+after	O
+TDI	O
+of	O
+iron	O
+dextran	O
+.	O
+
+Prolongation	B
+of	I
+the	I
+QT	I
+interval	I
+related	O
+to	O
+cisapride	O
+-	O
+diltiazem	O
+interaction	O
+.	O
+
+Cisapride	O
+,	O
+a	O
+cytochrome	O
+P450	O
+3A4	O
+(	O
+CYP3A4	O
+)	O
+substrate	O
+,	O
+is	O
+widely	O
+prescribed	O
+for	O
+the	O
+treatment	O
+of	O
+gastrointestinal	B
+motility	I
+disorders	I
+.	O
+
+Prolongation	B
+of	I
+QT	I
+interval	I
+,	O
+torsades	B
+de	I
+pointes	I
+,	O
+and	O
+sudden	B
+cardiac	I
+death	I
+have	O
+been	O
+reported	O
+after	O
+concomitant	O
+administration	O
+with	O
+erythromycin	O
+or	O
+azole	O
+antifungal	O
+agents	O
+,	O
+but	O
+not	O
+with	O
+other	O
+CYP3A4	O
+inhibitors	O
+.	O
+
+A	O
+possible	O
+drug	O
+interaction	O
+occurred	O
+in	O
+a	O
+45	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+who	O
+was	O
+taking	O
+cisapride	O
+for	O
+gastroesophageal	B
+reflux	I
+disorder	I
+and	O
+diltiazem	O
+,	O
+an	O
+agent	O
+that	O
+has	O
+inhibitory	O
+effect	O
+on	O
+CYP3A4	O
+,	O
+for	O
+hypertension	B
+.	O
+
+The	O
+patient	O
+was	O
+in	O
+near	O
+syncope	B
+and	O
+had	O
+QT	B
+-	I
+interval	I
+prolongation	I
+.	O
+
+After	O
+discontinuing	O
+cisapride	O
+,	O
+the	O
+QT	O
+interval	O
+returned	O
+to	O
+normal	O
+and	O
+symptoms	O
+did	O
+not	O
+recur	O
+.	O
+
+We	O
+suggest	O
+that	O
+caution	O
+be	O
+taken	O
+when	O
+cisapride	O
+is	O
+prescribed	O
+with	O
+any	O
+potent	O
+inhibitor	O
+of	O
+CYP3A4	O
+,	O
+including	O
+diltiazem	O
+.	O
+
+Cortical	O
+motor	O
+overactivation	O
+in	O
+parkinsonian	B
+patients	O
+with	O
+L	O
+-	O
+dopa	O
+-	O
+induced	O
+peak	O
+-	O
+dose	O
+dyskinesia	B
+.	O
+
+We	O
+have	O
+studied	O
+the	O
+regional	O
+cerebral	O
+blood	O
+flow	O
+(	O
+rCBF	O
+)	O
+changes	O
+induced	O
+by	O
+the	O
+execution	O
+of	O
+a	O
+finger	O
+-	O
+to	O
+-	O
+thumb	O
+opposition	O
+motor	O
+task	O
+in	O
+the	O
+supplementary	O
+and	O
+primary	O
+motor	O
+cortex	O
+of	O
+two	O
+groups	O
+of	O
+parkinsonian	B
+patients	O
+on	O
+L	O
+-	O
+dopa	O
+medication	O
+,	O
+the	O
+first	O
+one	O
+without	O
+L	O
+-	O
+dopa	O
+induced	O
+dyskinesia	B
+(	O
+n	O
+=	O
+23	O
+)	O
+and	O
+the	O
+other	O
+with	O
+moderate	O
+peak	O
+-	O
+dose	O
+dyskinesia	B
+(	O
+n	O
+=	O
+15	O
+)	O
+,	O
+and	O
+of	O
+a	O
+group	O
+of	O
+14	O
+normal	O
+subjects	O
+.	O
+
+Single	O
+photon	O
+emission	O
+tomography	O
+with	O
+i	O
+.	O
+v	O
+.	O
+133Xe	O
+was	O
+used	O
+to	O
+measure	O
+the	O
+rCBF	O
+changes	O
+.	O
+
+The	O
+dyskinetic	B
+parkinsonian	B
+patients	O
+exhibited	O
+a	O
+pattern	O
+of	O
+response	O
+which	O
+was	O
+markedly	O
+different	O
+from	O
+those	O
+of	O
+the	O
+normal	O
+subjects	O
+and	O
+non	O
+-	O
+dyskinetic	B
+parkinsonian	B
+patients	O
+,	O
+with	O
+a	O
+significant	O
+overactivation	O
+in	O
+the	O
+supplementary	O
+motor	O
+area	O
+and	O
+the	O
+ipsi	O
+-	O
+and	O
+contralateral	O
+primary	O
+motor	O
+areas	O
+.	O
+
+These	O
+results	O
+are	O
+compatible	O
+with	O
+the	O
+hypothesis	O
+that	O
+an	O
+hyperkinetic	B
+abnormal	B
+involuntary	I
+movement	I
+,	O
+like	O
+L	O
+-	O
+dopa	O
+-	O
+induced	O
+peak	O
+dose	O
+dyskinesia	B
+,	O
+is	O
+due	O
+to	O
+a	O
+disinhibition	O
+of	O
+the	O
+primary	O
+and	O
+associated	O
+motor	O
+cortex	O
+secondary	O
+to	O
+an	O
+excessive	O
+outflow	O
+of	O
+the	O
+pallidothalamocortical	O
+motor	O
+loop	O
+.	O
+
+Open	O
+-	O
+label	O
+assessment	O
+of	O
+levofloxacin	O
+for	O
+the	O
+treatment	O
+of	O
+acute	O
+bacterial	O
+sinusitis	B
+in	O
+adults	O
+.	O
+
+PURPOSE	O
+:	O
+To	O
+evaluate	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+levofloxacin	O
+(	O
+500	O
+mg	O
+orally	O
+once	O
+daily	O
+for	O
+10	O
+to	O
+14	O
+days	O
+)	O
+in	O
+treating	O
+adult	O
+outpatients	O
+with	O
+acute	O
+bacterial	O
+sinusitis	B
+.	O
+
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+A	O
+total	O
+of	O
+329	O
+patients	O
+enrolled	O
+in	O
+the	O
+study	O
+at	O
+24	O
+centers	O
+.	O
+
+All	O
+patients	O
+had	O
+a	O
+pre	O
+-	O
+therapy	O
+Gram	O
+'	O
+s	O
+stain	O
+and	O
+culture	O
+of	O
+sinus	O
+exudate	O
+obtained	O
+by	O
+antral	O
+puncture	O
+or	O
+nasal	O
+endoscopy	O
+.	O
+
+Clinical	O
+response	O
+was	O
+assessed	O
+on	O
+the	O
+basis	O
+of	O
+signs	O
+and	O
+symptoms	O
+and	O
+sinus	O
+radiograph	O
+or	O
+computed	O
+tomography	O
+results	O
+.	O
+
+Microbiologic	O
+cure	O
+rates	O
+were	O
+determined	O
+on	O
+the	O
+basis	O
+of	O
+presumed	O
+plus	O
+documented	O
+eradication	O
+of	O
+the	O
+pre	O
+-	O
+therapy	O
+pathogen	O
+(	O
+s	O
+)	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+most	O
+common	O
+pathogens	O
+were	O
+Haemophilus	O
+influenzae	O
+,	O
+Streptococcus	O
+pneumoniae	O
+,	O
+Staphylococcus	O
+aureus	O
+,	O
+and	O
+Moraxella	O
+catarrhalis	O
+.	O
+
+Of	O
+300	O
+clinically	O
+evaluable	O
+patients	O
+,	O
+175	O
+(	O
+58	O
+%	O
+)	O
+were	O
+cured	O
+and	O
+90	O
+(	O
+30	O
+%	O
+)	O
+were	O
+improved	O
+at	O
+the	O
+post	O
+-	O
+therapy	O
+evaluation	O
+,	O
+resulting	O
+in	O
+a	O
+clinical	O
+success	O
+rate	O
+of	O
+88	O
+%	O
+.	O
+
+Thirty	O
+-	O
+five	O
+patients	O
+(	O
+12	O
+%	O
+)	O
+clinically	O
+failed	O
+treatment	O
+.	O
+
+The	O
+microbiologic	O
+eradication	O
+rate	O
+(	O
+presumed	O
+plus	O
+documented	O
+)	O
+among	O
+138	O
+microbiologically	O
+evaluable	O
+patients	O
+was	O
+92	O
+%	O
+.	O
+
+Microbiologic	O
+eradication	O
+rates	O
+(	O
+presumed	O
+plus	O
+documented	O
+)	O
+of	O
+the	O
+most	O
+common	O
+pathogens	O
+ranged	O
+from	O
+93	O
+%	O
+(	O
+M	O
+.	O
+catarrhalis	O
+)	O
+to	O
+100	O
+%	O
+(	O
+S	O
+.	O
+pneumoniae	O
+)	O
+at	O
+the	O
+post	O
+-	O
+therapy	O
+visit	O
+.	O
+
+All	O
+but	O
+one	O
+of	O
+the	O
+265	O
+patients	O
+who	O
+were	O
+cured	O
+or	O
+improved	O
+at	O
+post	O
+-	O
+therapy	O
+returned	O
+for	O
+a	O
+long	O
+-	O
+term	O
+follow	O
+-	O
+up	O
+visit	O
+;	O
+243	O
+(	O
+92	O
+%	O
+)	O
+remained	O
+well	O
+4	O
+to	O
+6	O
+weeks	O
+after	O
+therapy	O
+;	O
+and	O
+21	O
+(	O
+8	O
+%	O
+)	O
+had	O
+a	O
+relapse	O
+of	O
+symptoms	O
+.	O
+
+Adverse	O
+events	O
+considered	O
+to	O
+be	O
+related	O
+to	O
+levofloxacin	O
+administration	O
+were	O
+reported	O
+by	O
+29	O
+patients	O
+(	O
+9	O
+%	O
+)	O
+.	O
+
+The	O
+most	O
+common	O
+drug	O
+-	O
+related	O
+adverse	O
+events	O
+were	O
+diarrhea	B
+,	O
+flatulence	B
+,	O
+and	O
+nausea	B
+;	O
+most	O
+adverse	O
+events	O
+were	O
+mild	O
+to	O
+moderate	O
+in	O
+severity	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+results	O
+of	O
+this	O
+study	O
+indicate	O
+that	O
+levofloxacin	O
+500	O
+mg	O
+once	O
+daily	O
+is	O
+an	O
+effective	O
+and	O
+safe	O
+treatment	O
+for	O
+acute	O
+bacterial	O
+sinusitis	B
+.	O
+
+Iatrogenic	O
+risks	O
+of	O
+endometrial	B
+carcinoma	I
+after	O
+treatment	O
+for	O
+breast	B
+cancer	I
+in	O
+a	O
+large	O
+French	O
+case	O
+-	O
+control	O
+study	O
+.	O
+
+F	O
+d	O
+ration	O
+Nationale	O
+des	O
+Centres	O
+de	O
+Lutte	O
+Contre	O
+le	O
+Cancer	O
+(	O
+FNCLCC	O
+)	O
+.	O
+
+Since	O
+tamoxifen	O
+is	O
+widely	O
+used	O
+in	O
+breast	B
+cancer	I
+treatment	O
+and	O
+has	O
+been	O
+proposed	O
+for	O
+the	O
+prevention	O
+of	O
+breast	B
+cancer	I
+,	O
+its	O
+endometrial	O
+iatrogenic	O
+effects	O
+must	O
+be	O
+carefully	O
+examined	O
+.	O
+
+We	O
+have	O
+investigated	O
+the	O
+association	O
+between	O
+endometrial	B
+cancer	I
+and	O
+tamoxifen	O
+use	O
+or	O
+other	O
+treatments	O
+in	O
+women	O
+treated	O
+for	O
+breast	B
+cancer	I
+in	O
+a	O
+case	O
+-	O
+control	O
+study	O
+.	O
+
+Cases	O
+of	O
+endometrial	B
+cancer	I
+diagnosed	O
+after	O
+breast	B
+cancer	I
+(	O
+n	O
+=	O
+135	O
+)	O
+and	O
+467	O
+controls	O
+matched	O
+for	O
+age	O
+,	O
+year	O
+of	O
+diagnosis	O
+of	O
+breast	B
+cancer	I
+and	O
+hospital	O
+and	O
+survival	O
+time	O
+with	O
+an	O
+intact	O
+uterus	O
+were	O
+included	O
+.	O
+
+Women	O
+who	O
+had	O
+received	O
+tamoxifen	O
+were	O
+significantly	O
+more	O
+likely	O
+to	O
+have	O
+endometrial	B
+cancer	I
+diagnosed	O
+than	O
+those	O
+who	O
+had	O
+not	O
+(	O
+crude	O
+relative	O
+risk	O
+=	O
+4	O
+.	O
+9	O
+,	O
+p	O
+=	O
+0	O
+.	O
+0001	O
+)	O
+.	O
+
+Univariate	O
+and	O
+adjusted	O
+analyses	O
+showed	O
+that	O
+the	O
+risk	O
+increased	O
+with	O
+the	O
+length	O
+of	O
+treatment	O
+(	O
+p	O
+=	O
+0	O
+.	O
+0001	O
+)	O
+or	O
+the	O
+cumulative	O
+dose	O
+of	O
+tamoxifen	O
+received	O
+(	O
+p	O
+=	O
+0	O
+.	O
+0001	O
+)	O
+,	O
+irrespective	O
+of	O
+the	O
+daily	O
+dose	O
+.	O
+
+Women	O
+who	O
+had	O
+undergone	O
+pelvic	O
+radiotherapy	O
+also	O
+had	O
+a	O
+higher	O
+risk	O
+(	O
+crude	O
+relative	O
+risk	O
+=	O
+7	O
+.	O
+8	O
+,	O
+p	O
+=	O
+0	O
+.	O
+0001	O
+)	O
+.	O
+
+After	O
+adjusting	O
+for	O
+confounding	O
+factors	O
+,	O
+the	O
+risk	O
+was	O
+higher	O
+for	O
+tamoxifen	O
+users	O
+(	O
+p	O
+=	O
+0	O
+.	O
+0012	O
+)	O
+,	O
+treatment	O
+for	O
+more	O
+than	O
+3	O
+years	O
+(	O
+all	O
+p	O
+<	O
+0	O
+.	O
+03	O
+)	O
+and	O
+pelvic	O
+radiotherapy	O
+(	O
+p	O
+=	O
+0	O
+.	O
+012	O
+)	O
+.	O
+
+Women	O
+who	O
+had	O
+endometrial	B
+cancer	I
+and	O
+had	O
+received	O
+tamoxifen	O
+had	O
+more	O
+advanced	B
+disease	I
+and	O
+poorer	O
+prognosis	O
+than	O
+those	O
+with	O
+endometrial	B
+cancer	I
+who	O
+had	O
+not	O
+received	O
+this	O
+treatment	O
+.	O
+
+Our	O
+results	O
+suggest	O
+a	O
+causal	O
+role	O
+of	O
+tamoxifen	O
+in	O
+endometrial	B
+cancer	I
+,	O
+particularly	O
+when	O
+used	O
+as	O
+currently	O
+proposed	O
+for	O
+breast	B
+cancer	I
+prevention	O
+.	O
+
+Pelvic	O
+radiotherapy	O
+may	O
+be	O
+an	O
+additional	O
+iatrogenic	O
+factor	O
+for	O
+women	O
+with	O
+breast	B
+cancer	I
+.	O
+
+Endometrial	B
+cancers	I
+diagnosed	O
+in	O
+women	O
+treated	O
+with	O
+tamoxifen	O
+have	O
+poorer	O
+prognosis	O
+.	O
+
+Women	O
+who	O
+receive	O
+tamoxifen	O
+for	O
+breast	B
+cancer	I
+should	O
+be	O
+offered	O
+gynaecological	O
+surveillance	O
+during	O
+and	O
+after	O
+treatment	O
+.	O
+
+A	O
+long	O
+-	O
+term	O
+evaluation	O
+of	O
+the	O
+risk	O
+-	O
+benefit	O
+ratio	O
+of	O
+tamoxifen	O
+as	O
+a	O
+preventive	O
+treatment	O
+for	O
+breast	B
+cancer	I
+is	O
+clearly	O
+warranted	O
+.	O
+
+Contribution	O
+of	O
+the	O
+glycine	O
+site	O
+of	O
+NMDA	O
+receptors	O
+in	O
+rostral	O
+and	O
+intermediate	O
+-	O
+caudal	O
+parts	O
+of	O
+the	O
+striatum	O
+to	O
+the	O
+regulation	O
+of	O
+muscle	O
+tone	O
+in	O
+rats	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+assess	O
+the	O
+contribution	O
+of	O
+the	O
+glycine	O
+site	O
+of	O
+NMDA	O
+receptors	O
+in	O
+the	O
+striatum	O
+to	O
+the	O
+regulation	O
+of	O
+muscle	O
+tone	O
+.	O
+
+Muscle	O
+tone	O
+was	O
+examined	O
+using	O
+a	O
+combined	O
+mechanoand	O
+electromyographic	O
+method	O
+,	O
+which	O
+measured	O
+simultaneously	O
+the	O
+muscle	O
+resistance	O
+(	O
+MMG	O
+)	O
+of	O
+the	O
+rat	O
+'	O
+s	O
+hind	O
+foot	O
+to	O
+passive	O
+extension	O
+and	O
+flexion	O
+in	O
+the	O
+ankle	O
+joint	O
+and	O
+the	O
+electromyographic	O
+activity	O
+(	O
+EMG	O
+)	O
+of	O
+the	O
+antagonistic	O
+muscles	O
+of	O
+that	O
+joint	O
+:	O
+gastrocnemius	O
+and	O
+tibialis	O
+anterior	O
+.	O
+
+Muscle	B
+rigidity	I
+was	O
+induced	O
+by	O
+haloperidol	O
+(	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+
+5	O
+,	O
+7	O
+-	O
+dichlorokynurenic	O
+acid	O
+(	O
+5	O
+,	O
+7	O
+-	O
+DCKA	O
+)	O
+,	O
+a	O
+selective	O
+glycine	O
+site	O
+antagonist	O
+,	O
+injected	O
+in	O
+doses	O
+of	O
+2	O
+.	O
+5	O
+and	O
+4	O
+.	O
+5	O
+microg	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+bilaterally	O
+,	O
+into	O
+the	O
+rostral	O
+region	O
+of	O
+the	O
+striatum	O
+,	O
+decreased	O
+both	O
+the	O
+haloperidol	O
+-	O
+induced	O
+muscle	B
+rigidity	I
+(	O
+MMG	O
+)	O
+and	O
+the	O
+enhanced	O
+electromyographic	O
+activity	O
+(	O
+EMG	O
+)	O
+.	O
+
+5	O
+,	O
+7	O
+-	O
+DCKA	O
+injected	O
+bilaterally	O
+in	O
+a	O
+dose	O
+of	O
+4	O
+.	O
+5	O
+microg	O
+/	O
+0	O
+.	O
+5	O
+microl	O
+into	O
+the	O
+intermediate	O
+-	O
+caudal	O
+region	O
+of	O
+the	O
+striatum	O
+of	O
+rats	O
+not	O
+pretreated	O
+with	O
+haloperidol	O
+had	O
+no	O
+effect	O
+on	O
+the	O
+muscle	O
+tone	O
+.	O
+
+The	O
+present	O
+results	O
+suggest	O
+that	O
+blockade	O
+of	O
+the	O
+glycine	O
+site	O
+of	O
+NMDA	O
+receptors	O
+in	O
+the	O
+rostral	O
+part	O
+of	O
+the	O
+striatum	O
+may	O
+be	O
+mainly	O
+responsible	O
+for	O
+the	O
+antiparkinsonian	O
+action	O
+of	O
+this	O
+drug	O
+.	O
+
+Carboplatin	O
+toxic	O
+effects	O
+on	O
+the	O
+peripheral	O
+nervous	O
+system	O
+of	O
+the	O
+rat	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+most	O
+striking	O
+of	O
+carboplatin	O
+'	O
+s	O
+advantages	O
+(	O
+CBDCA	O
+)	O
+over	O
+cisplatin	O
+(	O
+CDDP	O
+)	O
+is	O
+its	O
+markedly	O
+reduced	O
+rate	O
+of	O
+neurotoxic	B
+effects	O
+.	O
+
+However	O
+,	O
+the	O
+use	O
+of	O
+CBDCA	O
+higher	O
+-	O
+intensity	O
+schedules	O
+and	O
+the	O
+association	O
+with	O
+other	O
+neurotoxic	B
+drugs	O
+in	O
+polychemotherapy	O
+may	O
+cause	O
+some	O
+concern	O
+about	O
+its	O
+safety	O
+with	O
+respect	O
+to	O
+peripheral	B
+nervous	I
+system	I
+damage	I
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+Two	O
+different	O
+schedules	O
+of	O
+CBDCA	O
+administration	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+and	O
+15	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+twice	O
+a	O
+week	O
+for	O
+nine	O
+times	O
+)	O
+were	O
+evaluated	O
+in	O
+Wistar	O
+rats	O
+.	O
+
+Neurotoxicity	B
+was	O
+assessed	O
+for	O
+behavioral	O
+(	O
+tail	O
+-	O
+flick	O
+test	O
+)	O
+,	O
+neurophysiological	O
+(	O
+nerve	O
+conduction	O
+velocity	O
+in	O
+the	O
+tail	O
+nerve	O
+)	O
+,	O
+morphological	O
+,	O
+morphometrical	O
+and	O
+analytical	O
+effects	O
+.	O
+
+RESULTS	O
+:	O
+CBDCA	O
+administration	O
+induced	O
+dose	O
+-	O
+dependent	O
+peripheral	B
+neurotoxicity	I
+.	O
+
+Pain	B
+perception	O
+and	O
+nerve	O
+conduction	O
+velocity	O
+in	O
+the	O
+tail	O
+were	O
+significantly	O
+impaired	O
+,	O
+particularly	O
+after	O
+the	O
+high	O
+-	O
+dose	O
+treatment	O
+.	O
+
+The	O
+dorsal	O
+root	O
+ganglia	O
+sensory	O
+neurons	O
+and	O
+,	O
+to	O
+a	O
+lesser	O
+extent	O
+,	O
+satellite	O
+cells	O
+showed	O
+the	O
+same	O
+changes	O
+as	O
+those	O
+induced	O
+by	O
+CDDP	O
+,	O
+mainly	O
+affecting	O
+the	O
+nucleus	O
+and	O
+nucleolus	O
+of	O
+ganglionic	O
+sensory	O
+neurons	O
+.	O
+
+Moreover	O
+,	O
+significant	O
+amounts	O
+of	O
+platinum	O
+were	O
+detected	O
+in	O
+the	O
+dorsal	O
+root	O
+ganglia	O
+and	O
+kidney	O
+after	O
+CBDCA	O
+treatment	O
+.	O
+
+CONCLUSIONS	O
+:	O
+CBDCA	O
+is	O
+neurotoxic	B
+in	O
+our	O
+model	O
+,	O
+and	O
+the	O
+type	O
+of	O
+pathological	O
+changes	O
+it	O
+induces	O
+are	O
+so	O
+closely	O
+similar	O
+to	O
+those	O
+caused	O
+by	O
+CDDP	O
+that	O
+it	O
+is	O
+probable	O
+that	O
+neurotoxicity	B
+is	O
+induced	O
+in	O
+the	O
+two	O
+drugs	O
+by	O
+the	O
+same	O
+mechanism	O
+.	O
+
+This	O
+model	O
+can	O
+be	O
+used	O
+alone	O
+or	O
+in	O
+combination	O
+with	O
+other	O
+drugs	O
+to	O
+explore	O
+the	O
+effect	O
+of	O
+CBDCA	O
+on	O
+the	O
+peripheral	O
+nervous	O
+system	O
+.	O
+
+Effects	O
+of	O
+cisapride	O
+on	O
+symptoms	O
+and	O
+postcibal	O
+small	O
+-	O
+bowel	O
+motor	O
+function	O
+in	O
+patients	O
+with	O
+irritable	B
+bowel	I
+syndrome	I
+.	O
+
+BACKGROUND	O
+:	O
+Irritable	B
+bowel	I
+syndrome	I
+is	O
+a	O
+common	O
+cause	O
+of	O
+abdominal	B
+pain	I
+and	O
+discomfort	O
+and	O
+may	O
+be	O
+related	O
+to	O
+disordered	B
+gastrointestinal	I
+motility	I
+.	O
+
+Our	O
+aim	O
+was	O
+to	O
+assess	O
+the	O
+effects	O
+of	O
+long	O
+-	O
+term	O
+treatment	O
+with	O
+a	O
+prokinetic	O
+agent	O
+,	O
+cisapride	O
+,	O
+on	O
+postprandial	O
+jejunal	O
+motility	O
+and	O
+symptoms	O
+in	O
+the	O
+irritable	B
+bowel	I
+syndrome	I
+(	O
+IBS	B
+)	O
+.	O
+
+METHODS	O
+:	O
+Thirty	O
+-	O
+eight	O
+patients	O
+with	O
+IBS	B
+(	O
+constipation	B
+-	O
+predominant	O
+,	O
+n	O
+=	O
+17	O
+;	O
+diarrhoea	B
+-	O
+predominant	O
+,	O
+n	O
+=	O
+21	O
+)	O
+underwent	O
+24	O
+-	O
+h	O
+ambulatory	O
+jejunal	O
+manometry	O
+before	O
+and	O
+after	O
+12	O
+week	O
+'	O
+s	O
+treatment	O
+[	O
+cisapride	O
+,	O
+5	O
+mg	O
+three	O
+times	O
+daily	O
+(	O
+n	O
+=	O
+19	O
+)	O
+or	O
+placebo	O
+(	O
+n	O
+=	O
+19	O
+)	O
+]	O
+.	O
+
+RESULTS	O
+:	O
+In	O
+diarrhoea	B
+-	O
+predominant	O
+patients	O
+significant	O
+differences	O
+in	O
+contraction	O
+characteristics	O
+were	O
+observed	O
+between	O
+the	O
+cisapride	O
+and	O
+placebo	O
+groups	O
+.	O
+
+In	O
+cisapride	O
+-	O
+treated	O
+diarrhoea	B
+-	O
+predominant	O
+patients	O
+the	O
+mean	O
+contraction	O
+amplitude	O
+was	O
+higher	O
+(	O
+29	O
+.	O
+3	O
++	O
+/	O
+-	O
+3	O
+.	O
+2	O
+versus	O
+24	O
+.	O
+9	O
++	O
+/	O
+-	O
+2	O
+.	O
+6	O
+mm	O
+Hg	O
+,	O
+cisapride	O
+versus	O
+placebo	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+;	O
+pretreatment	O
+,	O
+25	O
+.	O
+7	O
++	O
+/	O
+-	O
+6	O
+.	O
+0	O
+mm	O
+Hg	O
+)	O
+,	O
+the	O
+mean	O
+contraction	O
+duration	O
+longer	O
+(	O
+3	O
+.	O
+4	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+versus	O
+3	O
+.	O
+0	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+sec	O
+,	O
+cisapride	O
+versus	O
+placebo	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+;	O
+pretreatment	O
+,	O
+3	O
+.	O
+1	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+sec	O
+)	O
+,	O
+and	O
+the	O
+mean	O
+contraction	O
+frequency	O
+lower	O
+(	O
+2	O
+.	O
+0	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+versus	O
+2	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+4	O
+cont	O
+.	O
+/	O
+min	O
+,	O
+cisapride	O
+versus	O
+placebo	O
+(	O
+P	O
+<	O
+0	O
+.	O
+001	O
+)	O
+;	O
+pretreatment	O
+,	O
+2	O
+.	O
+5	O
++	O
+/	O
+-	O
+1	O
+.	O
+1	O
+cont	O
+.	O
+/	O
+min	O
+]	O
+than	O
+patients	O
+treated	O
+with	O
+placebo	O
+.	O
+
+No	O
+significant	O
+differences	O
+in	O
+jejunal	O
+motility	O
+were	O
+found	O
+in	O
+the	O
+constipation	B
+-	O
+predominant	O
+IBS	B
+group	O
+.	O
+
+Symptoms	O
+were	O
+assessed	O
+by	O
+using	O
+a	O
+visual	O
+analogue	O
+scale	O
+before	O
+and	O
+after	O
+treatment	O
+.	O
+
+Symptom	O
+scores	O
+relating	O
+to	O
+the	O
+severity	O
+of	O
+constipation	B
+were	O
+lower	O
+in	O
+cisapride	O
+-	O
+treated	O
+constipation	B
+-	O
+predominant	O
+IBS	B
+patients	O
+[	O
+score	O
+,	O
+54	O
++	O
+/	O
+-	O
+5	O
+versus	O
+67	O
++	O
+/	O
+-	O
+14	O
+mm	O
+,	O
+cisapride	O
+versus	O
+placebo	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+;	O
+pretreatment	O
+,	O
+62	O
++	O
+/	O
+-	O
+19	O
+mm	O
+]	O
+.	O
+
+Diarrhoea	B
+-	O
+predominant	O
+IBS	B
+patients	O
+had	O
+a	O
+higher	O
+pain	B
+score	O
+after	O
+cisapride	O
+therapy	O
+[	O
+score	O
+,	O
+55	O
++	O
+/	O
+-	O
+15	O
+versus	O
+34	O
++	O
+/	O
+-	O
+12	O
+mm	O
+,	O
+cisapride	O
+versus	O
+placebo	O
+(	O
+P	O
+<	O
+0	O
+.	O
+05	O
+)	O
+;	O
+pretreatment	O
+,	O
+67	O
++	O
+/	O
+-	O
+19	O
+mm	O
+]	O
+.	O
+
+CONCLUSION	O
+:	O
+Cisapride	O
+affects	O
+jejunal	O
+contraction	O
+characteristics	O
+and	O
+some	O
+symptoms	O
+in	O
+IBS	B
+.	O
+
+Prevention	O
+of	O
+breast	B
+cancer	I
+with	O
+tamoxifen	O
+:	O
+preliminary	O
+findings	O
+from	O
+the	O
+Italian	O
+randomised	O
+trial	O
+among	O
+hysterectomised	O
+women	O
+.	O
+
+Italian	O
+Tamoxifen	O
+Prevention	O
+Study	O
+.	O
+
+BACKGROUND	O
+:	O
+Tamoxifen	O
+is	O
+a	O
+candidate	O
+chemopreventive	O
+agent	O
+in	O
+breast	B
+cancer	I
+,	O
+although	O
+the	O
+drug	O
+may	O
+be	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+endometrial	B
+cancer	I
+.	O
+
+Therefore	O
+we	O
+did	O
+a	O
+trial	O
+in	O
+hysterectomised	O
+women	O
+of	O
+tamoxifen	O
+as	O
+a	O
+chemopreventive	O
+.	O
+
+METHODS	O
+:	O
+In	O
+October	O
+,	O
+1992	O
+,	O
+we	O
+started	O
+a	O
+double	O
+-	O
+blind	O
+placebo	O
+-	O
+controlled	O
+,	O
+randomised	O
+trial	O
+of	O
+tamoxifen	O
+in	O
+women	O
+(	O
+mainly	O
+in	O
+Italy	O
+)	O
+who	O
+did	O
+not	O
+have	O
+breast	B
+cancer	I
+and	O
+who	O
+had	O
+had	O
+a	O
+hysterectomy	O
+.	O
+
+Women	O
+were	O
+randomised	O
+to	O
+receive	O
+tamoxifen	O
+20	O
+mg	O
+per	O
+day	O
+or	O
+placebo	O
+,	O
+both	O
+orally	O
+for	O
+5	O
+years	O
+.	O
+
+The	O
+original	O
+plan	O
+was	O
+to	O
+follow	O
+the	O
+intervention	O
+phase	O
+by	O
+5	O
+years	O
+'	O
+follow	O
+-	O
+up	O
+.	O
+
+In	O
+June	O
+,	O
+1997	O
+,	O
+the	O
+trialists	O
+and	O
+the	O
+data	O
+-	O
+monitoring	O
+committee	O
+decided	O
+to	O
+end	O
+recruitment	O
+primarily	O
+because	O
+of	O
+the	O
+number	O
+of	O
+women	O
+dropping	O
+out	O
+of	O
+the	O
+study	O
+.	O
+
+Recruitment	O
+ended	O
+on	O
+July	O
+11	O
+,	O
+1997	O
+,	O
+and	O
+the	O
+study	O
+will	O
+continue	O
+as	O
+planned	O
+.	O
+
+The	O
+primary	O
+endpoints	O
+are	O
+the	O
+occurrence	O
+of	O
+and	O
+deaths	O
+from	O
+breast	B
+cancer	I
+.	O
+
+This	O
+preliminary	O
+interim	O
+analysis	O
+is	O
+based	O
+on	O
+intention	O
+-	O
+to	O
+-	O
+treat	O
+.	O
+
+FINDINGS	O
+:	O
+5408	O
+women	O
+were	O
+randomised	O
+;	O
+participating	O
+women	O
+have	O
+a	O
+median	O
+follow	O
+-	O
+up	O
+of	O
+46	O
+months	O
+for	O
+major	O
+endpoints	O
+.	O
+
+41	O
+cases	O
+of	O
+breast	B
+cancer	I
+occurred	O
+so	O
+far	O
+;	O
+there	O
+have	O
+been	O
+no	O
+deaths	O
+from	O
+breast	B
+cancer	I
+.	O
+
+There	O
+is	O
+no	O
+difference	O
+in	O
+breast	B
+-	I
+cancer	I
+frequency	O
+between	O
+the	O
+placebo	O
+(	O
+22	O
+cases	O
+)	O
+and	O
+tamoxifen	O
+(	O
+19	O
+)	O
+arms	O
+.	O
+
+There	O
+is	O
+a	O
+statistically	O
+significant	O
+reduction	O
+of	O
+breast	B
+cancer	I
+among	O
+women	O
+receiving	O
+tamoxifen	O
+who	O
+also	O
+used	O
+hormone	O
+-	O
+replacement	O
+therapy	O
+during	O
+the	O
+trial	O
+:	O
+among	O
+390	O
+women	O
+on	O
+such	O
+therapy	O
+and	O
+allocated	O
+to	O
+placebo	O
+,	O
+we	O
+found	O
+eight	O
+cases	O
+of	O
+breast	B
+cancer	I
+compared	O
+with	O
+one	O
+case	O
+among	O
+362	O
+women	O
+allocated	O
+to	O
+tamoxifen	O
+.	O
+
+Compared	O
+with	O
+the	O
+placebo	O
+group	O
+,	O
+there	O
+was	O
+a	O
+significantly	O
+increased	O
+risk	O
+of	O
+vascular	B
+events	I
+and	O
+hypertriglyceridaemia	B
+among	O
+women	O
+on	O
+tamoxifen	O
+.	O
+
+INTERPRETATION	O
+:	O
+Although	O
+this	O
+preliminary	O
+analysis	O
+has	O
+low	O
+power	O
+,	O
+in	O
+this	O
+cohort	O
+of	O
+women	O
+at	O
+low	O
+-	O
+to	O
+-	O
+normal	O
+risk	O
+of	O
+breast	B
+cancer	I
+,	O
+the	O
+postulated	O
+protective	O
+effects	O
+of	O
+tamoxifen	O
+are	O
+not	O
+yet	O
+apparent	O
+.	O
+
+Women	O
+using	O
+hormone	O
+-	O
+replacement	O
+therapy	O
+appear	O
+to	O
+have	O
+benefited	O
+from	O
+use	O
+of	O
+tamoxifen	O
+.	O
+
+There	O
+were	O
+no	O
+deaths	O
+from	O
+breast	B
+cancer	I
+recorded	O
+in	O
+women	O
+in	O
+the	O
+study	O
+.	O
+
+It	O
+is	O
+essential	O
+to	O
+continue	O
+follow	O
+-	O
+up	O
+to	O
+quantify	O
+the	O
+long	O
+-	O
+term	O
+risks	O
+and	O
+benefits	O
+of	O
+tamoxifen	O
+therapy	O
+.	O
+
+Epileptogenic	O
+activity	O
+of	O
+folic	O
+acid	O
+after	O
+drug	O
+induces	O
+SLE	B
+(	O
+folic	O
+acid	O
+and	O
+epilepsy	B
+)	O
+
+OBJECTIVE	O
+:	O
+To	O
+study	O
+the	O
+effect	O
+of	O
+folic	O
+acid	O
+-	O
+containing	O
+multivitamin	O
+supplementation	O
+in	O
+epileptic	B
+women	O
+before	O
+and	O
+during	O
+pregnancy	O
+in	O
+order	O
+to	O
+determine	O
+the	O
+rate	O
+of	O
+structural	O
+birth	B
+defects	I
+and	O
+epilepsy	B
+-	O
+related	O
+side	O
+effects	O
+.	O
+
+STUDY	O
+DESIGN	O
+:	O
+First	O
+a	O
+randomised	O
+trial	O
+,	O
+later	O
+periconception	O
+care	O
+including	O
+in	O
+total	O
+12225	O
+females	O
+.	O
+
+RESULTS	O
+:	O
+Of	O
+60	O
+epileptic	B
+women	O
+with	O
+periconceptional	O
+folic	O
+acid	O
+(	O
+0	O
+.	O
+8	O
+mg	O
+)	O
+-	O
+containing	O
+multivitamin	O
+supplementation	O
+,	O
+no	O
+one	O
+developed	O
+epilepsy	B
+-	O
+related	O
+side	O
+effects	O
+during	O
+the	O
+periconception	O
+period	O
+.	O
+
+One	O
+epileptic	B
+woman	O
+delivered	O
+a	O
+newborn	O
+with	O
+cleft	B
+lip	I
+and	I
+palate	I
+.	O
+
+Another	O
+patient	O
+exhibited	O
+with	O
+a	O
+cluster	O
+of	O
+seizures	B
+after	O
+the	O
+periconception	O
+period	O
+using	O
+another	O
+multivitamin	O
+.	O
+
+This	O
+22	O
+-	O
+year	O
+-	O
+old	O
+epileptic	B
+woman	O
+was	O
+treated	O
+continuously	O
+by	O
+carbamazepine	O
+and	O
+a	O
+folic	O
+acid	O
+(	O
+1	O
+mg	O
+)	O
+-	O
+containing	O
+multivitamin	O
+from	O
+the	O
+20th	O
+week	O
+of	O
+gestation	O
+.	O
+
+She	O
+developed	O
+status	B
+epilepticus	I
+and	O
+later	O
+symptoms	O
+of	O
+systemic	B
+lupus	I
+erythematodes	I
+.	O
+
+Her	O
+pregnancy	O
+ended	O
+with	O
+stillbirth	B
+.	O
+
+CONCLUSIONS	O
+:	O
+The	O
+epileptic	B
+pregnant	O
+patient	O
+'	O
+s	O
+autoimmune	B
+disease	I
+(	O
+probably	O
+drug	O
+-	O
+induced	O
+lupus	B
+)	O
+could	O
+damage	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+,	O
+therefore	O
+the	O
+therapeutic	O
+dose	O
+(	O
+>	O
+or	O
+=	O
+1	O
+mg	O
+)	O
+of	O
+folic	O
+acid	O
+triggered	O
+a	O
+cluster	O
+of	O
+seizures	B
+.	O
+
+Physiological	O
+dose	O
+(	O
+<	O
+1	O
+mg	O
+)	O
+of	O
+folic	O
+acid	O
+both	O
+in	O
+healthy	O
+and	O
+60	O
+epileptic	B
+women	O
+,	O
+all	O
+without	O
+any	O
+autoimmune	B
+disease	I
+,	O
+did	O
+not	O
+increase	O
+the	O
+risk	O
+for	O
+epileptic	B
+seizures	I
+.	O
+
+Stroke	B
+and	O
+cocaine	O
+or	O
+amphetamine	O
+use	O
+.	O
+
+The	O
+association	O
+of	O
+cocaine	O
+and	O
+amphetamine	O
+use	O
+with	O
+hemorrhagic	O
+and	O
+ischemic	B
+stroke	B
+is	O
+based	O
+almost	O
+solely	O
+on	O
+data	O
+from	O
+case	O
+series	O
+.	O
+
+The	O
+limited	O
+number	O
+of	O
+epidemiologic	O
+studies	O
+of	O
+stroke	B
+and	O
+use	O
+of	O
+cocaine	O
+and	O
+/	O
+or	O
+amphetamine	O
+have	O
+been	O
+done	O
+in	O
+settings	O
+that	O
+serve	O
+mostly	O
+the	O
+poor	O
+and	O
+/	O
+or	O
+minorities	O
+.	O
+
+This	O
+case	O
+-	O
+control	O
+study	O
+was	O
+conducted	O
+in	O
+the	O
+defined	O
+population	O
+comprising	O
+members	O
+of	O
+Kaiser	O
+Permanente	O
+of	O
+Northern	O
+and	O
+Southern	O
+California	O
+.	O
+
+We	O
+attempted	O
+to	O
+identify	O
+all	O
+incident	O
+strokes	B
+in	O
+women	O
+ages	O
+15	O
+-	O
+44	O
+years	O
+during	O
+a	O
+3	O
+-	O
+year	O
+period	O
+using	O
+hospital	O
+admission	O
+and	O
+discharge	O
+records	O
+,	O
+emergency	O
+department	O
+logs	O
+,	O
+and	O
+payment	O
+requests	O
+for	O
+out	O
+-	O
+of	O
+-	O
+plan	O
+hospitalizations	O
+.	O
+
+We	O
+selected	O
+controls	O
+,	O
+matched	O
+on	O
+age	O
+and	O
+facility	O
+of	O
+usual	O
+care	O
+,	O
+at	O
+random	O
+from	O
+healthy	O
+members	O
+of	O
+the	O
+health	O
+plan	O
+.	O
+
+We	O
+obtained	O
+information	O
+in	O
+face	O
+-	O
+to	O
+-	O
+face	O
+interviews	O
+.	O
+
+There	O
+were	O
+347	O
+confirmed	O
+stroke	B
+cases	O
+and	O
+1	O
+,	O
+021	O
+controls	O
+.	O
+
+The	O
+univariate	O
+matched	O
+odds	O
+ratio	O
+for	O
+stroke	B
+in	O
+women	O
+who	O
+admitted	O
+to	O
+using	O
+cocaine	O
+and	O
+/	O
+or	O
+amphetamine	O
+was	O
+8	O
+.	O
+5	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+=	O
+3	O
+.	O
+6	O
+-	O
+20	O
+.	O
+0	O
+)	O
+.	O
+
+After	O
+further	O
+adjustment	O
+for	O
+potential	O
+confounders	O
+,	O
+the	O
+odds	O
+ratio	O
+in	O
+women	O
+who	O
+reported	O
+using	O
+cocaine	O
+and	O
+/	O
+or	O
+amphetamine	O
+was	O
+7	O
+.	O
+0	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+=	O
+2	O
+.	O
+8	O
+-	O
+17	O
+.	O
+9	O
+)	O
+.	O
+
+The	O
+use	O
+of	O
+cocaine	O
+and	O
+/	O
+or	O
+amphetamine	O
+is	O
+a	O
+strong	O
+risk	O
+factor	O
+for	O
+stroke	B
+in	O
+this	O
+socioeconomically	O
+heterogeneous	O
+,	O
+insured	O
+urban	O
+population	O
+.	O
+
+Acute	B
+renal	I
+failure	I
+subsequent	O
+to	O
+the	O
+administration	O
+of	O
+rifampicin	O
+.	O
+
+A	O
+follow	O
+-	O
+up	O
+study	O
+of	O
+cases	O
+reported	O
+earlier	O
+.	O
+
+A	O
+clinical	O
+presentation	O
+is	O
+made	O
+of	O
+a	O
+2	O
+-	O
+3	O
+year	O
+follow	O
+-	O
+up	O
+of	O
+six	O
+cases	O
+of	O
+acute	B
+renal	I
+failure	I
+that	O
+have	O
+been	O
+reported	O
+earlier	O
+.	O
+
+The	O
+patients	O
+had	O
+developed	O
+transient	O
+renal	B
+failure	I
+after	O
+the	O
+intermittent	O
+administration	O
+of	O
+rifampicin	O
+.	O
+
+The	O
+stage	O
+of	O
+olig	O
+-	O
+anuria	B
+lasted	O
+for	O
+1	O
+-	O
+3	O
+weeks	O
+,	O
+and	O
+five	O
+of	O
+the	O
+patients	O
+were	O
+treated	O
+by	O
+hemodialysis	O
+.	O
+
+Two	O
+of	O
+the	O
+patients	O
+died	O
+due	O
+to	O
+unrelated	O
+causes	O
+during	O
+the	O
+follow	O
+-	O
+up	O
+period	O
+.	O
+
+The	O
+four	O
+patients	O
+re	O
+-	O
+examined	O
+were	O
+clinically	O
+cured	O
+.	O
+
+Pathologic	O
+findings	O
+by	O
+light	O
+microscopy	O
+and	O
+immunofluorescence	O
+at	O
+biopsy	O
+were	O
+scarce	O
+.	O
+
+Nothing	O
+abnormal	O
+was	O
+seen	O
+by	O
+electron	O
+microscopy	O
+in	O
+two	O
+of	O
+the	O
+cases	O
+studied	O
+.	O
+
+Renal	O
+function	O
+was	O
+normal	O
+.	O
+
+In	O
+three	O
+cases	O
+the	O
+excretion	O
+at	O
+131I	O
+-	O
+hippuran	O
+renography	O
+was	O
+slightly	O
+slowed	O
+.	O
+
+Although	O
+in	O
+the	O
+acute	O
+stage	O
+the	O
+renal	B
+lesions	I
+histologically	O
+appeared	O
+toxic	O
+,	O
+evidence	O
+suggestive	O
+of	O
+an	O
+immunological	O
+mechanism	O
+cannot	O
+be	O
+excluded	O
+.	O
+
+Chronic	O
+effects	O
+of	O
+a	O
+novel	O
+synthetic	O
+anthracycline	O
+derivative	O
+(	O
+SM	O
+-	O
+5887	O
+)	O
+on	O
+normal	O
+heart	O
+and	O
+doxorubicin	O
+-	O
+induced	O
+cardiomyopathy	B
+in	O
+beagle	O
+dogs	O
+.	O
+
+This	O
+study	O
+was	O
+designed	O
+to	O
+investigate	O
+the	O
+chronic	O
+cardiotoxic	B
+potential	O
+of	O
+SM	O
+-	O
+5887	O
+and	O
+a	O
+possible	O
+deteriorating	O
+effect	O
+of	O
+SM	O
+-	O
+5887	O
+on	O
+low	O
+-	O
+grade	O
+cardiotoxicity	B
+pre	O
+-	O
+induced	O
+by	O
+doxorubicin	O
+in	O
+beagle	O
+dogs	O
+.	O
+
+In	O
+the	O
+chronic	O
+treatment	O
+,	O
+beagle	O
+dogs	O
+of	O
+each	O
+sex	O
+were	O
+given	O
+intravenously	O
+once	O
+every	O
+3	O
+weeks	O
+,	O
+either	O
+a	O
+sublethal	O
+dose	O
+of	O
+doxorubicin	O
+(	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+or	O
+SM	O
+-	O
+5887	O
+(	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+The	O
+experiment	O
+was	O
+terminated	O
+3	O
+weeks	O
+after	O
+the	O
+ninth	O
+dosing	O
+.	O
+
+Animals	O
+which	O
+received	O
+over	O
+six	O
+courses	O
+of	O
+doxorubicin	O
+demonstrated	O
+the	O
+electrocardiogram	O
+(	O
+ECG	O
+)	O
+changes	O
+,	O
+decrease	O
+of	O
+blood	O
+pressure	O
+and	O
+high	O
+-	O
+grade	O
+histopathological	O
+cardiomyopathy	B
+,	O
+while	O
+animals	O
+which	O
+were	O
+terminally	O
+sacrificed	O
+after	O
+the	O
+SM	O
+-	O
+5887	O
+administration	O
+did	O
+not	O
+show	O
+any	O
+changes	O
+in	O
+ECG	O
+,	O
+blood	O
+pressure	O
+and	O
+histopathological	O
+examinations	O
+.	O
+
+To	O
+examine	O
+a	O
+possibly	O
+deteriorating	O
+cardiotoxic	B
+effect	O
+of	O
+SM	O
+-	O
+5887	O
+,	O
+low	O
+-	O
+grade	O
+cardiomyopathy	B
+was	O
+induced	O
+in	O
+dogs	O
+by	O
+four	O
+courses	O
+of	O
+doxorubicin	O
+(	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+
+Nine	O
+weeks	O
+after	O
+pre	O
+-	O
+treatment	O
+,	O
+dogs	O
+were	O
+given	O
+four	O
+courses	O
+of	O
+either	O
+doxorubicin	O
+(	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+or	O
+SM	O
+-	O
+5887	O
+(	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+once	O
+every	O
+3	O
+weeks	O
+.	O
+
+The	O
+low	O
+-	O
+grade	O
+cardiotoxic	B
+changes	O
+were	O
+enhanced	O
+by	O
+the	O
+additional	O
+doxorubicin	O
+treatment	O
+.	O
+
+On	O
+the	O
+contrary	O
+,	O
+the	O
+SM	O
+-	O
+5887	O
+treatment	O
+did	O
+not	O
+progress	O
+the	O
+grade	O
+of	O
+cardiomyopathy	B
+.	O
+
+In	O
+conclusion	O
+,	O
+SM	O
+-	O
+5887	O
+does	O
+not	O
+have	O
+any	O
+potential	O
+of	O
+chronic	O
+cardiotoxicity	B
+and	O
+deteriorating	O
+effect	O
+on	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B
+in	O
+dogs	O
+.	O
+
+Risk	O
+for	O
+valvular	B
+heart	I
+disease	I
+among	O
+users	O
+of	O
+fenfluramine	O
+and	O
+dexfenfluramine	O
+who	O
+underwent	O
+echocardiography	O
+before	O
+use	O
+of	O
+medication	O
+.	O
+
+BACKGROUND	O
+:	O
+Because	O
+uncontrolled	O
+echocardiographic	O
+surveys	O
+suggested	O
+that	O
+up	O
+to	O
+30	O
+%	O
+to	O
+38	O
+%	O
+of	O
+users	O
+of	O
+fenfluramine	O
+and	O
+dexfenfluramine	O
+had	O
+valvular	B
+disease	I
+,	O
+these	O
+drugs	O
+were	O
+withdrawn	O
+from	O
+the	O
+market	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+determine	O
+the	O
+risk	O
+for	O
+new	O
+or	O
+worsening	O
+valvular	B
+abnormalities	I
+among	O
+users	O
+of	O
+fenfluramine	O
+or	O
+dexfenfluramine	O
+who	O
+underwent	O
+echocardiography	O
+before	O
+they	O
+began	O
+to	O
+take	O
+these	O
+medications	O
+.	O
+
+DESIGN	O
+:	O
+Cohort	O
+study	O
+.	O
+
+SETTING	O
+:	O
+Academic	O
+primary	O
+care	O
+practices	O
+.	O
+
+PATIENTS	O
+:	O
+46	O
+patients	O
+who	O
+used	O
+fenfluramine	O
+or	O
+dexfenfluramine	O
+for	O
+14	O
+days	O
+or	O
+more	O
+and	O
+had	O
+echocardiograms	O
+obtained	O
+before	O
+therapy	O
+.	O
+
+MEASUREMENTS	O
+:	O
+Follow	O
+-	O
+up	O
+echocardiography	O
+.	O
+
+The	O
+primary	O
+outcome	O
+was	O
+new	O
+or	O
+worsening	O
+valvulopathy	B
+,	O
+defined	O
+as	O
+progression	O
+of	O
+either	O
+aortic	B
+or	I
+mitral	I
+regurgitation	I
+by	O
+at	O
+least	O
+one	O
+degree	O
+of	O
+severity	O
+and	O
+disease	O
+that	O
+met	O
+U	O
+.	O
+S	O
+.	O
+
+Food	O
+and	O
+Drug	O
+Administration	O
+criteria	O
+(	O
+at	O
+least	O
+mild	O
+aortic	B
+regurgitation	I
+or	O
+moderate	O
+mitral	B
+regurgitation	I
+)	O
+.	O
+
+RESULTS	O
+:	O
+Two	O
+patients	O
+(	O
+4	O
+.	O
+3	O
+%	O
+[	O
+95	O
+%	O
+CI	O
+,	O
+0	O
+.	O
+6	O
+%	O
+to	O
+14	O
+.	O
+8	O
+%	O
+]	O
+)	O
+receiving	O
+fenfluramine	O
+-	O
+phentermine	O
+developed	O
+valvular	B
+heart	I
+disease	I
+.	O
+
+One	O
+had	O
+baseline	O
+bicuspid	B
+aortic	I
+valve	I
+and	O
+mild	O
+aortic	B
+regurgitation	I
+that	O
+progressed	O
+to	O
+moderate	O
+regurgitation	O
+.	O
+
+The	O
+second	O
+patient	O
+developed	O
+new	O
+moderate	O
+aortic	B
+insufficiency	I
+.	O
+
+CONCLUSION	O
+:	O
+Users	O
+of	O
+diet	O
+medications	O
+are	O
+at	O
+risk	O
+for	O
+valvular	B
+heart	I
+disease	I
+.	O
+
+However	O
+,	O
+the	O
+incidence	O
+may	O
+be	O
+lower	O
+than	O
+that	O
+reported	O
+previously	O
+.	O
+
+Therapeutic	O
+drug	O
+monitoring	O
+of	O
+tobramycin	O
+:	O
+once	O
+-	O
+daily	O
+versus	O
+twice	O
+-	O
+daily	O
+dosage	O
+schedules	O
+.	O
+
+OBJECTIVE	O
+:	O
+To	O
+evaluate	O
+the	O
+effect	O
+of	O
+dosage	O
+regimen	O
+(	O
+once	O
+-	O
+daily	O
+vs	O
+.	O
+twice	O
+-	O
+daily	O
+)	O
+of	O
+tobramicyn	O
+on	O
+steady	O
+-	O
+state	O
+serum	O
+concentrations	O
+and	O
+toxicity	B
+.	O
+
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+Patients	O
+undergoing	O
+treatment	O
+with	O
+i	O
+.	O
+v	O
+.	O
+tobramycin	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+)	O
+were	O
+randomised	O
+to	O
+two	O
+groups	O
+.	O
+
+Group	O
+OD	O
+(	O
+n	O
+=	O
+22	O
+)	O
+received	O
+a	O
+once	O
+-	O
+daily	O
+dose	O
+of	O
+tobramycin	O
+and	O
+group	O
+TD	O
+(	O
+n	O
+=	O
+21	O
+)	O
+received	O
+the	O
+same	O
+dose	O
+divided	O
+into	O
+two	O
+doses	O
+daily	O
+.	O
+
+Tobramycin	O
+serum	O
+concentrations	O
+(	O
+peak	O
+and	O
+trough	O
+)	O
+were	O
+measured	O
+by	O
+enzyme	O
+multiplied	O
+immunoassay	O
+.	O
+
+The	O
+renal	O
+and	O
+auditory	O
+functions	O
+of	O
+the	O
+patients	O
+were	O
+monitored	O
+before	O
+,	O
+during	O
+and	O
+immediately	O
+after	O
+treatment	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+two	O
+groups	O
+were	O
+comparable	O
+with	O
+respect	O
+to	O
+sex	O
+,	O
+age	O
+,	O
+body	O
+weight	O
+and	O
+renal	O
+function	O
+.	O
+
+No	O
+statistically	O
+significant	O
+differences	O
+were	O
+found	O
+in	O
+mean	O
+daily	O
+dose	O
+,	O
+duration	O
+of	O
+treatment	O
+,	O
+or	O
+cumulative	O
+dose	O
+.	O
+
+Trough	O
+concentrations	O
+were	O
+<	O
+2	O
+g	O
+/	O
+ml	O
+in	O
+the	O
+two	O
+groups	O
+(	O
+100	O
+%	O
+)	O
+.	O
+
+Peak	O
+concentrations	O
+were	O
+>	O
+6	O
+microg	O
+/	O
+ml	O
+in	O
+100	O
+%	O
+of	O
+the	O
+OD	O
+group	O
+and	O
+in	O
+67	O
+%	O
+of	O
+the	O
+TD	O
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+Mean	O
+peak	O
+concentrations	O
+were	O
+markedly	O
+different	O
+:	O
+11	O
+.	O
+00	O
++	O
+/	O
+-	O
+2	O
+.	O
+89	O
+microg	O
+/	O
+ml	O
+in	O
+OD	O
+vs	O
+.	O
+6	O
+.	O
+53	O
++	O
+/	O
+-	O
+1	O
+.	O
+45	O
+microg	O
+/	O
+ml	O
+in	O
+TD	O
+(	O
+P	O
+<	O
+0	O
+.	O
+01	O
+)	O
+.	O
+
+The	O
+pharmacokinetics	O
+parameters	O
+were	O
+:	O
+Ke	O
+,	O
+(	O
+0	O
+.	O
+15	O
++	O
+/	O
+-	O
+0	O
+.	O
+03	O
+/	O
+h	O
+in	O
+OD	O
+vs	O
+.	O
+0	O
+.	O
+24	O
++	O
+/	O
+-	O
+0	O
+.	O
+06	O
+/	O
+h	O
+in	O
+TD	O
+)	O
+,	O
+t1	O
+/	O
+2	O
+,	O
+(	O
+4	O
+.	O
+95	O
++	O
+/	O
+-	O
+1	O
+.	O
+41	O
+h	O
+in	O
+OD	O
+vs	O
+.	O
+3	O
+.	O
+07	O
++	O
+/	O
+-	O
+0	O
+.	O
+71	O
+h	O
+in	O
+TD	O
+)	O
+,	O
+Vd	O
+(	O
+0	O
+.	O
+35	O
++	O
+/	O
+-	O
+0	O
+.	O
+11	O
+l	O
+/	O
+kg	O
+in	O
+OD	O
+vs	O
+.	O
+0	O
+.	O
+33	O
++	O
+/	O
+-	O
+0	O
+.	O
+09	O
+l	O
+/	O
+kg	O
+in	O
+TD	O
+)	O
+,	O
+Cl	O
+(	O
+0	O
+.	O
+86	O
++	O
+/	O
+-	O
+0	O
+.	O
+29	O
+ml	O
+/	O
+min	O
+/	O
+kg	O
+in	O
+OD	O
+vs	O
+.	O
+1	O
+.	O
+28	O
++	O
+/	O
+-	O
+0	O
+.	O
+33	O
+ml	O
+/	O
+min	O
+/	O
+kg	O
+in	O
+TD	O
+)	O
+.	O
+
+Increased	O
+serum	O
+creatinine	O
+was	O
+observed	O
+in	O
+73	O
+%	O
+of	O
+patients	O
+in	O
+OD	O
+versus	O
+57	O
+%	O
+of	O
+patients	O
+in	O
+TD	O
+,	O
+without	O
+evidence	O
+of	O
+nephrotoxicity	B
+.	O
+
+In	O
+TD	O
+group	O
+,	O
+three	O
+patients	O
+developed	O
+decreased	B
+auditory	I
+function	I
+,	O
+of	O
+which	O
+one	O
+presented	O
+with	O
+an	O
+auditory	B
+loss	I
+of	O
+-	O
+30	O
+dB	O
+,	O
+whereas	O
+in	O
+the	O
+OD	O
+group	O
+only	O
+one	O
+patient	O
+presented	O
+decreased	B
+auditory	I
+function	I
+.	O
+
+CONCLUSION	O
+:	O
+This	O
+small	O
+study	O
+suggests	O
+that	O
+a	O
+once	O
+-	O
+daily	O
+dosing	O
+regimen	O
+of	O
+tobramycin	O
+is	O
+at	O
+least	O
+as	O
+effective	O
+as	O
+and	O
+is	O
+no	O
+more	O
+and	O
+possibly	O
+less	O
+toxic	O
+than	O
+the	O
+twice	O
+-	O
+daily	O
+regimen	O
+.	O
+
+Using	O
+a	O
+single	O
+-	O
+dose	O
+therapy	O
+,	O
+peak	O
+concentration	O
+determination	O
+is	O
+not	O
+necessary	O
+,	O
+only	O
+trough	O
+samples	O
+should	O
+be	O
+monitored	O
+to	O
+ensure	O
+levels	O
+below	O
+2	O
+microg	O
+/	O
+ml	O
+.	O
+
+Enhanced	O
+bradycardia	B
+induced	O
+by	O
+beta	O
+-	O
+adrenoceptor	O
+antagonists	O
+in	O
+rats	O
+pretreated	O
+with	O
+isoniazid	O
+.	O
+
+High	O
+doses	O
+of	O
+isoniazid	O
+increase	O
+hypotension	B
+induced	O
+by	O
+vasodilators	O
+and	O
+change	O
+the	O
+accompanying	O
+reflex	O
+tachycardia	B
+to	O
+bradycardia	B
+,	O
+an	O
+interaction	O
+attributed	O
+to	O
+decreased	O
+synthesis	O
+of	O
+brain	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+(	O
+GABA	O
+)	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+the	O
+possible	O
+enhancement	O
+by	O
+isoniazid	O
+of	O
+bradycardia	B
+induced	O
+by	O
+beta	O
+-	O
+adrenoceptor	O
+antagonists	O
+was	O
+determined	O
+in	O
+rats	O
+anaesthetised	O
+with	O
+chloralose	O
+-	O
+urethane	O
+.	O
+
+Isoniazid	O
+significantly	O
+increased	O
+bradycardia	B
+after	O
+propranolol	O
+,	O
+pindolol	O
+,	O
+labetalol	O
+and	O
+atenolol	O
+,	O
+as	O
+well	O
+as	O
+after	O
+clonidine	O
+,	O
+but	O
+not	O
+after	O
+hexamethonium	O
+or	O
+carbachol	O
+.	O
+
+Enhancement	O
+was	O
+not	O
+observed	O
+in	O
+rats	O
+pretreated	O
+with	O
+methylatropine	O
+or	O
+previously	O
+vagotomised	O
+.	O
+
+These	O
+results	O
+are	O
+compatible	O
+with	O
+interference	O
+by	O
+isoniazid	O
+with	O
+GABAergic	O
+inhibition	O
+of	O
+cardiac	O
+parasympathetic	O
+tone	O
+.	O
+
+Such	O
+interference	O
+could	O
+be	O
+exerted	O
+centrally	O
+,	O
+possibly	O
+at	O
+the	O
+nucleus	O
+ambiguus	O
+,	O
+or	O
+peripherally	O
+at	O
+the	O
+sinus	O
+node	O
+.	O
+
+Structural	B
+and	I
+functional	I
+impairment	I
+of	I
+mitochondria	I
+in	O
+adriamycin	O
+-	O
+induced	O
+cardiomyopathy	B
+in	O
+mice	O
+:	O
+suppression	O
+of	O
+cytochrome	O
+c	O
+oxidase	O
+II	O
+gene	O
+expression	O
+.	O
+
+The	O
+use	O
+of	O
+adriamycin	O
+(	O
+ADR	O
+)	O
+in	O
+cancer	B
+chemotherapy	O
+has	O
+been	O
+limited	O
+due	O
+to	O
+its	O
+cumulative	O
+cardiovascular	B
+toxicity	I
+.	O
+
+Earlier	O
+observations	O
+that	O
+ADR	O
+interacts	O
+with	O
+mitochondrial	O
+cytochrome	O
+c	O
+oxidase	O
+(	O
+COX	O
+)	O
+and	O
+suppresses	O
+its	O
+enzyme	O
+activity	O
+led	O
+us	O
+to	O
+investigate	O
+ADR	O
+'	O
+s	O
+action	O
+on	O
+the	O
+cardiovascular	O
+functions	O
+and	O
+heart	O
+mitochondrial	O
+morphology	O
+in	O
+Balb	O
+-	O
+c	O
+mice	O
+i	O
+.	O
+p	O
+.	O
+treated	O
+with	O
+ADR	O
+for	O
+several	O
+weeks	O
+.	O
+
+At	O
+various	O
+times	O
+during	O
+treatment	O
+,	O
+the	O
+animals	O
+were	O
+assessed	O
+for	O
+cardiovascular	O
+functions	O
+by	O
+electrocardiography	O
+and	O
+for	O
+heart	O
+tissue	O
+damage	O
+by	O
+electron	O
+microscopy	O
+.	O
+
+In	O
+parallel	O
+,	O
+total	O
+RNA	O
+was	O
+extracted	O
+from	O
+samples	O
+of	O
+dissected	O
+heart	O
+and	O
+analyzed	O
+by	O
+Northern	O
+blot	O
+hybridization	O
+to	O
+determine	O
+the	O
+steady	O
+-	O
+state	O
+level	O
+of	O
+three	O
+RNA	O
+transcripts	O
+encoded	O
+by	O
+the	O
+COXII	O
+,	O
+COXIII	O
+,	O
+and	O
+COXIV	O
+genes	O
+.	O
+
+Similarly	O
+,	O
+samples	O
+obtained	O
+from	O
+the	O
+liver	O
+of	O
+the	O
+same	O
+animals	O
+were	O
+analyzed	O
+for	O
+comparative	O
+studies	O
+.	O
+
+Our	O
+results	O
+indicated	O
+that	O
+1	O
+)	O
+treatment	O
+of	O
+mice	O
+with	O
+ADR	O
+caused	O
+cardiovascular	B
+arrhythmias	I
+characterized	O
+by	O
+bradycardia	B
+,	O
+extension	O
+of	O
+ventricular	O
+depolarization	O
+time	O
+(	O
+tQRS	O
+)	O
+,	O
+and	O
+failure	O
+of	O
+QRS	O
+at	O
+high	O
+concentrations	O
+(	O
+10	O
+-	O
+14	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+cumulative	O
+dose	O
+)	O
+;	O
+2	O
+)	O
+the	O
+heart	O
+mitochondria	O
+underwent	O
+swelling	B
+,	O
+fusion	O
+,	O
+dissolution	O
+,	O
+and	O
+/	O
+or	O
+disruption	O
+of	O
+mitochondrial	O
+cristae	O
+after	O
+several	O
+weeks	O
+of	O
+treatment	O
+.	O
+
+Such	O
+abnormalities	O
+were	O
+not	O
+observed	O
+in	O
+the	O
+mitochondria	O
+of	O
+liver	O
+tissue	O
+;	O
+and	O
+3	O
+)	O
+among	O
+the	O
+three	O
+genes	O
+of	O
+COX	O
+enzyme	O
+examined	O
+,	O
+only	O
+COXII	O
+gene	O
+expression	O
+was	O
+suppressed	O
+by	O
+ADR	O
+treatment	O
+,	O
+mainly	O
+after	O
+8	O
+weeks	O
+in	O
+both	O
+heart	O
+and	O
+liver	O
+.	O
+
+Knowing	O
+that	O
+heart	O
+mitochondria	O
+represent	O
+almost	O
+40	O
+%	O
+of	O
+heart	O
+muscle	O
+by	O
+weight	O
+,	O
+we	O
+conclude	O
+that	O
+the	O
+deteriorating	O
+effects	O
+of	O
+ADR	O
+on	O
+cardiovascular	O
+function	O
+involve	O
+mitochondrial	B
+structural	I
+and	I
+functional	I
+impairment	I
+.	O
+
diff --git a/data/disease_all/.DS_Store b/data/disease_all/.DS_Store
new file mode 100644
index 0000000..1f8d7d9
Binary files /dev/null and b/data/disease_all/.DS_Store differ
diff --git a/data/disease_all/OUTPUT.CONLL b/data/disease_all/OUTPUT.CONLL
new file mode 100644
index 0000000..b7c82bd
--- /dev/null
+++ b/data/disease_all/OUTPUT.CONLL
@@ -0,0 +1,124751 @@
+Torsade	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+ventricular	POS	I-NP
+tachycardia	POS	I-NP
+during	POS	O
+low	POS	O
+dose	POS	O
+intermittent	POS	O
+dobutamine	POS	O
+treatment	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+dilated	POS	B-NP
+cardiomyopathy	POS	I-NP
+and	POS	O
+congestive	POS	B-NP
+heart	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+The	POS	O
+authors	POS	O
+describe	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+56	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+with	POS	O
+chronic	POS	O
+,	POS	O
+severe	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+secondary	POS	O
+to	POS	O
+dilated	POS	B-NP
+cardiomyopathy	POS	I-NP
+and	POS	O
+absence	POS	O
+of	POS	O
+significant	POS	O
+ventricular	POS	B-NP
+arrhythmias	POS	I-NP
+who	POS	O
+developed	POS	O
+QT	POS	B-NP
+prolongation	POS	I-NP
+and	POS	O
+torsade	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+ventricular	POS	I-NP
+tachycardia	POS	I-NP
+during	POS	O
+one	POS	O
+cycle	POS	O
+of	POS	O
+intermittent	POS	O
+low	POS	O
+dose	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mcg	POS	O
+/	POS	O
+kg	POS	O
+per	POS	O
+min	POS	O
+)	POS	O
+dobutamine	POS	O
+.	POS	O
+This	POS	O
+report	POS	O
+of	POS	O
+torsade	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+ventricular	POS	I-NP
+tachycardia	POS	I-NP
+during	POS	O
+intermittent	POS	O
+dobutamine	POS	O
+supports	POS	O
+the	POS	O
+hypothesis	POS	O
+that	POS	O
+unpredictable	POS	O
+fatal	POS	O
+arrhythmias	POS	B-NP
+may	POS	O
+occur	POS	O
+even	POS	O
+with	POS	O
+low	POS	O
+doses	POS	O
+and	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+no	POS	O
+history	POS	O
+of	POS	O
+significant	POS	O
+rhythm	POS	B-NP
+disturbances	POS	I-NP
+.	POS	O
+The	POS	O
+mechanisms	POS	O
+of	POS	O
+proarrhythmic	POS	O
+effects	POS	O
+of	POS	O
+Dubutamine	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+Positive	POS	O
+skin	POS	O
+tests	POS	O
+in	POS	O
+late	POS	O
+reactions	POS	O
+to	POS	O
+radiographic	POS	O
+contrast	POS	O
+media	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+last	POS	O
+few	POS	O
+years	POS	O
+delayed	POS	O
+reactions	POS	O
+several	POS	O
+hours	POS	O
+after	POS	O
+the	POS	O
+injection	POS	O
+of	POS	O
+radiographic	POS	O
+and	POS	O
+contrast	POS	O
+materials	POS	O
+(	POS	O
+PRC	POS	O
+)	POS	O
+have	POS	O
+been	POS	O
+described	POS	O
+with	POS	O
+increasing	POS	O
+frequency	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+report	POS	O
+two	POS	O
+observations	POS	O
+on	POS	O
+patients	POS	O
+with	POS	O
+delayed	POS	O
+reactions	POS	O
+in	POS	O
+whom	POS	O
+intradermoreactions	POS	O
+(	POS	O
+IDR	POS	O
+)	POS	O
+and	POS	O
+patch	POS	O
+tests	POS	O
+to	POS	O
+a	POS	O
+series	POS	O
+of	POS	O
+ionic	POS	O
+and	POS	O
+non	POS	O
+ionic	POS	O
+PRC	POS	O
+were	POS	O
+studied	POS	O
+.	POS	O
+After	POS	O
+angiography	POS	O
+by	POS	O
+the	POS	O
+venous	POS	O
+route	POS	O
+in	POS	O
+patient	POS	O
+n	POS	O
+degree	POS	O
+1	POS	O
+a	POS	O
+biphasic	POS	O
+reaction	POS	O
+with	POS	O
+an	POS	O
+immediate	POS	O
+reaction	POS	O
+(	POS	O
+dyspnea	POS	B-NP
+,	POS	O
+loss	POS	B-NP
+of	POS	I-NP
+consciousness	POS	I-NP
+)	POS	O
+and	POS	O
+delayed	POS	O
+macro	POS	O
+-	POS	O
+papular	POS	B-NP
+rash	POS	I-NP
+appeared	POS	O
+,	POS	O
+whilst	POS	O
+patient	POS	O
+n	POS	O
+degree	POS	O
+2	POS	O
+developed	POS	O
+a	POS	O
+generalised	POS	B-NP
+sensation	POS	I-NP
+of	POS	I-NP
+heat	POS	I-NP
+,	POS	O
+persistent	POS	O
+pain	POS	B-NP
+at	POS	O
+the	POS	O
+site	POS	O
+of	POS	O
+injection	POS	O
+immediately	POS	O
+and	POS	O
+a	POS	O
+generalised	POS	O
+macro	POS	O
+-	POS	O
+papular	POS	B-NP
+reaction	POS	I-NP
+after	POS	O
+24	POS	O
+hours	POS	O
+.	POS	O
+The	POS	O
+skin	POS	O
+tests	POS	O
+revealed	POS	O
+positive	POS	O
+delayed	POS	O
+reactions	POS	O
+of	POS	O
+24	POS	O
+hours	POS	O
+and	POS	O
+48	POS	O
+hours	POS	O
+by	POS	O
+IDR	POS	O
+and	POS	O
+patch	POS	O
+tests	POS	O
+to	POS	O
+only	POS	O
+some	POS	O
+PRC	POS	O
+with	POS	O
+common	POS	O
+chains	POS	O
+in	POS	O
+their	POS	O
+structures	POS	O
+.	POS	O
+The	POS	O
+positive	POS	O
+skin	POS	O
+tests	POS	O
+are	POS	O
+in	POS	O
+favour	POS	O
+of	POS	O
+immunological	POS	O
+reactions	POS	O
+and	POS	O
+may	POS	O
+help	POS	O
+in	POS	O
+diagnosis	POS	O
+of	POS	O
+allergy	POS	B-NP
+in	POS	O
+the	POS	O
+patients	POS	O
+.	POS	O
+Risk	POS	O
+of	POS	O
+transient	POS	O
+hyperammonemic	POS	B-NP
+encephalopathy	POS	I-NP
+in	POS	O
+cancer	POS	B-NP
+patients	POS	O
+who	POS	O
+received	POS	O
+continuous	POS	O
+infusion	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+with	POS	O
+the	POS	O
+complication	POS	O
+of	POS	O
+dehydration	POS	B-NP
+and	POS	O
+infection	POS	O
+.	POS	O
+From	POS	O
+1986	POS	O
+to	POS	O
+1998	POS	O
+,	POS	O
+29	POS	O
+cancer	POS	B-NP
+patients	POS	O
+who	POS	O
+had	POS	O
+32	POS	O
+episodes	POS	O
+of	POS	O
+transient	POS	O
+hyperammonemic	POS	B-NP
+encephalopathy	POS	I-NP
+related	POS	O
+to	POS	O
+continuous	POS	O
+infusion	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+(	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+)	POS	O
+were	POS	O
+identified	POS	O
+.	POS	O
+None	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+had	POS	O
+decompensated	POS	B-NP
+liver	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+Onset	POS	O
+of	POS	O
+hyperammonemic	POS	B-NP
+encephalopathy	POS	I-NP
+varied	POS	O
+from	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+to	POS	O
+5	POS	O
+days	POS	O
+(	POS	O
+mean	POS	O
+:	POS	O
+2	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+days	POS	O
+)	POS	O
+after	POS	O
+the	POS	O
+initiation	POS	O
+of	POS	O
+chemotherapy	POS	O
+.	POS	O
+Plasma	POS	O
+ammonium	POS	O
+level	POS	O
+ranged	POS	O
+from	POS	O
+248	POS	O
+to	POS	O
+2387	POS	O
+microg	POS	O
+%	POS	O
+(	POS	O
+mean	POS	O
+:	POS	O
+626	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+431	POS	O
+microg	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Among	POS	O
+the	POS	O
+32	POS	O
+episodes	POS	O
+,	POS	O
+26	POS	O
+(	POS	O
+81	POS	O
+%	POS	O
+)	POS	O
+had	POS	O
+various	POS	O
+degrees	POS	O
+of	POS	O
+azotemia	POS	B-NP
+,	POS	O
+18	POS	O
+(	POS	O
+56	POS	O
+%	POS	O
+)	POS	O
+occurred	POS	O
+during	POS	O
+bacterial	POS	B-NP
+infections	POS	I-NP
+and	POS	O
+14	POS	O
+(	POS	O
+44	POS	O
+%	POS	O
+)	POS	O
+without	POS	O
+infection	POS	O
+occurred	POS	O
+during	POS	O
+periods	POS	O
+of	POS	O
+dehydration	POS	B-NP
+.	POS	O
+Higher	POS	O
+plasma	POS	O
+ammonium	POS	O
+levels	POS	O
+and	POS	O
+more	POS	O
+rapid	POS	O
+onset	POS	O
+of	POS	O
+hyperammonemia	POS	B-NP
+were	POS	O
+seen	POS	O
+in	POS	O
+18	POS	O
+patients	POS	O
+with	POS	O
+bacterial	POS	B-NP
+infections	POS	I-NP
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+003	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+0006	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+and	POS	O
+in	POS	O
+nine	POS	O
+patients	POS	O
+receiving	POS	O
+high	POS	O
+daily	POS	O
+doses	POS	O
+(	POS	O
+2600	POS	O
+or	POS	O
+1800	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+)	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+0001	POS	O
+and	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+0001	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+25	POS	O
+out	POS	O
+of	POS	O
+32	POS	O
+episodes	POS	O
+(	POS	O
+78	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+plasma	POS	O
+ammonium	POS	O
+levels	POS	O
+and	POS	O
+mental	POS	O
+status	POS	O
+returned	POS	O
+to	POS	O
+normal	POS	O
+within	POS	O
+2	POS	O
+days	POS	O
+after	POS	O
+adequate	POS	O
+management	POS	O
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+hyperammonemic	POS	B-NP
+encephalopathy	POS	I-NP
+can	POS	O
+occur	POS	O
+in	POS	O
+patients	POS	O
+receiving	POS	O
+continuous	POS	O
+infusion	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+.	POS	O
+Azotemia	POS	B-NP
+,	POS	O
+body	POS	B-NP
+fluid	POS	I-NP
+insufficiency	POS	I-NP
+and	POS	O
+bacterial	POS	B-NP
+infections	POS	I-NP
+were	POS	O
+frequently	POS	O
+found	POS	O
+in	POS	O
+these	POS	O
+patients	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+therefore	POS	O
+important	POS	O
+to	POS	O
+recognize	POS	O
+this	POS	O
+condition	POS	O
+in	POS	O
+patients	POS	O
+receiving	POS	O
+continuous	POS	O
+infusion	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+quinine	POS	O
+and	POS	O
+4	POS	O
+-	POS	O
+aminopyridine	POS	O
+on	POS	O
+conditioned	POS	O
+place	POS	O
+preference	POS	O
+and	POS	O
+changes	POS	O
+in	POS	O
+motor	POS	O
+activity	POS	O
+induced	POS	O
+by	POS	O
+morphine	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+1	POS	O
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+two	POS	O
+unselective	POS	O
+potassium	POS	O
+(	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+)	POS	O
+channel	POS	O
+blockers	POS	O
+,	POS	O
+quinine	POS	O
+(	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+,	POS	O
+25	POS	O
+and	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+and	POS	O
+4	POS	O
+-	POS	O
+aminopyridine	POS	O
+(	POS	O
+1	POS	O
+and	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+,	POS	O
+on	POS	O
+conditioned	POS	O
+place	POS	O
+preference	POS	O
+and	POS	O
+biphasic	POS	O
+changes	POS	O
+in	POS	O
+motor	POS	O
+activity	POS	O
+induced	POS	O
+by	POS	O
+morphine	POS	O
+(	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+were	POS	O
+tested	POS	O
+in	POS	O
+Wistar	POS	O
+rats	POS	O
+.	POS	O
+Quinine	POS	O
+is	POS	O
+known	POS	O
+to	POS	O
+block	POS	O
+voltage	POS	O
+-	POS	O
+,	POS	O
+calcium	POS	O
+-	POS	O
+and	POS	O
+ATP	POS	O
+-	POS	O
+sensitive	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+channels	POS	O
+while	POS	O
+4	POS	O
+-	POS	O
+aminopyridine	POS	O
+is	POS	O
+known	POS	O
+to	POS	O
+block	POS	O
+voltage	POS	O
+-	POS	O
+sensitive	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+channels	POS	O
+.	POS	O
+2	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+counterbalanced	POS	O
+method	POS	O
+,	POS	O
+quinine	POS	O
+attenuated	POS	O
+morphine	POS	O
+-	POS	O
+induced	POS	O
+place	POS	O
+preference	POS	O
+,	POS	O
+whereas	POS	O
+4	POS	O
+-	POS	O
+aminopyridine	POS	O
+was	POS	O
+ineffective	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+motor	POS	O
+activity	POS	O
+test	POS	O
+measured	POS	O
+with	POS	O
+an	POS	O
+Animex	POS	O
+-	POS	O
+activity	POS	O
+meter	POS	O
+neither	POS	O
+of	POS	O
+the	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+channel	POS	O
+blockers	POS	O
+affected	POS	O
+morphine	POS	O
+-	POS	O
+induced	POS	O
+hypoactivity	POS	O
+,	POS	O
+but	POS	O
+both	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+channel	POS	O
+blockers	POS	O
+prevented	POS	O
+morphine	POS	O
+-	POS	O
+induced	POS	O
+secondary	POS	O
+hyperactivity	POS	B-NP
+.	POS	O
+3	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+the	POS	O
+involvement	POS	O
+of	POS	O
+quinine	POS	O
+-	POS	O
+sensitive	POS	O
+but	POS	O
+not	POS	O
+4	POS	O
+-	POS	O
+aminopyridine	POS	O
+-	POS	O
+sensitive	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+channels	POS	O
+in	POS	O
+morphine	POS	O
+reward	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+also	POS	O
+suggested	POS	O
+that	POS	O
+the	POS	O
+blockade	POS	O
+of	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+channels	POS	O
+sensitive	POS	O
+to	POS	O
+these	POS	O
+blockers	POS	O
+is	POS	O
+not	POS	O
+sufficient	POS	O
+to	POS	O
+prevent	POS	O
+morphine	POS	O
+-	POS	O
+induced	POS	O
+hypoactivity	POS	O
+whereas	POS	O
+morphine	POS	O
+-	POS	O
+induced	POS	O
+hyperactivity	POS	B-NP
+seems	POS	O
+to	POS	O
+be	POS	O
+connected	POS	O
+to	POS	O
+both	POS	O
+quinine	POS	O
+-	POS	O
+and	POS	O
+4	POS	O
+-	POS	O
+aminopyridine	POS	O
+-	POS	O
+sensitive	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+channels	POS	O
+.	POS	O
+Nociceptin	POS	O
+/	POS	O
+orphanin	POS	O
+FQ	POS	O
+and	POS	O
+nocistatin	POS	O
+on	POS	O
+learning	POS	O
+and	POS	O
+memory	POS	B-NP
+impairment	POS	I-NP
+induced	POS	O
+by	POS	O
+scopolamine	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+1	POS	O
+.	POS	O
+Nociceptin	POS	O
+,	POS	O
+also	POS	O
+known	POS	O
+as	POS	O
+orphanin	POS	O
+FQ	POS	O
+,	POS	O
+is	POS	O
+an	POS	O
+endogenous	POS	O
+ligand	POS	O
+for	POS	O
+the	POS	O
+orphan	POS	O
+opioid	POS	O
+receptor	POS	O
+-	POS	O
+like	POS	O
+receptor	POS	O
+1	POS	O
+(	POS	O
+ORL1	POS	O
+)	POS	O
+and	POS	O
+involves	POS	O
+in	POS	O
+various	POS	O
+functions	POS	O
+in	POS	O
+the	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+(	POS	O
+CNS	POS	O
+)	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+other	POS	O
+hand	POS	O
+,	POS	O
+nocistatin	POS	O
+is	POS	O
+recently	POS	O
+isolated	POS	O
+from	POS	O
+the	POS	O
+same	POS	O
+precursor	POS	O
+as	POS	O
+nociceptin	POS	O
+and	POS	O
+blocks	POS	O
+nociceptin	POS	O
+-	POS	O
+induced	POS	O
+allodynia	POS	B-NP
+and	POS	O
+hyperalgesia	POS	B-NP
+.	POS	O
+2	POS	O
+.	POS	O
+Although	POS	O
+ORL1	POS	O
+receptors	POS	O
+which	POS	O
+display	POS	O
+a	POS	O
+high	POS	O
+degree	POS	O
+of	POS	O
+sequence	POS	O
+homology	POS	O
+with	POS	O
+classical	POS	O
+opioid	POS	O
+receptors	POS	O
+are	POS	O
+abundant	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+,	POS	O
+little	POS	O
+is	POS	O
+known	POS	O
+regarding	POS	O
+their	POS	O
+role	POS	O
+in	POS	O
+learning	POS	O
+and	POS	O
+memory	POS	O
+.	POS	O
+3	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+designed	POS	O
+to	POS	O
+investigate	POS	O
+whether	POS	O
+nociceptin	POS	O
+/	POS	O
+orphanin	POS	O
+FQ	POS	O
+and	POS	O
+nocistatin	POS	O
+could	POS	O
+modulate	POS	O
+impairment	POS	O
+of	POS	O
+learning	POS	O
+and	POS	O
+memory	POS	O
+induced	POS	O
+by	POS	O
+scopolamine	POS	O
+,	POS	O
+a	POS	O
+muscarinic	POS	O
+cholinergic	POS	O
+receptor	POS	O
+antagonist	POS	O
+,	POS	O
+using	POS	O
+spontaneous	POS	O
+alternation	POS	O
+of	POS	O
+Y	POS	O
+-	POS	O
+maze	POS	O
+and	POS	O
+step	POS	O
+-	POS	O
+down	POS	O
+type	POS	O
+passive	POS	O
+avoidance	POS	O
+tasks	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+4	POS	O
+.	POS	O
+While	POS	O
+nocistatin	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+5	POS	O
+.	POS	O
+0	POS	O
+nmol	POS	O
+mouse	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+)	POS	O
+administered	POS	O
+30	POS	O
+min	POS	O
+before	POS	O
+spontaneous	POS	O
+alternation	POS	O
+performance	POS	O
+or	POS	O
+the	POS	O
+training	POS	O
+session	POS	O
+of	POS	O
+the	POS	O
+passive	POS	O
+avoidance	POS	O
+task	POS	O
+,	POS	O
+had	POS	O
+no	POS	O
+effect	POS	O
+on	POS	O
+spontaneous	POS	O
+alternation	POS	O
+or	POS	O
+passive	POS	O
+avoidance	POS	O
+behaviours	POS	O
+,	POS	O
+a	POS	O
+lower	POS	O
+per	POS	O
+cent	POS	O
+alternation	POS	O
+and	POS	O
+shorter	POS	O
+median	POS	O
+step	POS	O
+-	POS	O
+down	POS	O
+latency	POS	O
+in	POS	O
+the	POS	O
+retention	POS	O
+test	POS	O
+were	POS	O
+obtained	POS	O
+in	POS	O
+nociceptin	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+and	POS	O
+/	POS	O
+or	POS	O
+5	POS	O
+.	POS	O
+0	POS	O
+nmol	POS	O
+mouse	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+)	POS	O
+-	POS	O
+treated	POS	O
+normal	POS	O
+mice	POS	O
+.	POS	O
+5	POS	O
+.	POS	O
+Administration	POS	O
+of	POS	O
+nocistatin	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+and	POS	O
+/	POS	O
+or	POS	O
+5	POS	O
+.	POS	O
+0	POS	O
+nmol	POS	O
+mouse	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+)	POS	O
+30	POS	O
+min	POS	O
+before	POS	O
+spontaneous	POS	O
+alternation	POS	O
+performance	POS	O
+or	POS	O
+the	POS	O
+training	POS	O
+session	POS	O
+of	POS	O
+the	POS	O
+passive	POS	O
+avoidance	POS	O
+task	POS	O
+,	POS	O
+attenuated	POS	O
+the	POS	O
+scopolamine	POS	O
+-	POS	O
+induced	POS	O
+impairment	POS	O
+of	POS	O
+spontaneous	POS	O
+alternation	POS	O
+and	POS	O
+passive	POS	O
+avoidance	POS	O
+behaviours	POS	O
+.	POS	O
+6	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+indicated	POS	O
+that	POS	O
+nocistatin	POS	O
+,	POS	O
+a	POS	O
+new	POS	O
+biologically	POS	O
+active	POS	O
+peptide	POS	O
+,	POS	O
+ameliorates	POS	O
+impairments	POS	O
+of	POS	O
+spontaneous	POS	O
+alternation	POS	O
+and	POS	O
+passive	POS	O
+avoidance	POS	O
+induced	POS	O
+by	POS	O
+scopolamine	POS	O
+,	POS	O
+and	POS	O
+suggested	POS	O
+that	POS	O
+these	POS	O
+peptides	POS	O
+play	POS	O
+opposite	POS	O
+roles	POS	O
+in	POS	O
+learning	POS	O
+and	POS	O
+memory	POS	O
+.	POS	O
+Meloxicam	POS	O
+-	POS	O
+induced	POS	O
+liver	POS	B-NP
+toxicity	POS	I-NP
+.	POS	O
+We	POS	O
+report	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+female	POS	O
+patient	POS	O
+with	POS	O
+rheumatoid	POS	B-NP
+arthritis	POS	I-NP
+who	POS	O
+developed	POS	O
+acute	POS	B-NP
+cytolytic	POS	I-NP
+hepatitis	POS	I-NP
+due	POS	O
+to	POS	O
+meloxicam	POS	O
+.	POS	O
+Recently	POS	O
+introduced	POS	O
+in	POS	O
+Belgium	POS	O
+,	POS	O
+meloxicam	POS	O
+is	POS	O
+the	POS	O
+first	POS	O
+nonsteroidal	POS	O
+antiinflammatory	POS	O
+drug	POS	O
+with	POS	O
+selective	POS	O
+action	POS	O
+on	POS	O
+the	POS	O
+inducible	POS	O
+form	POS	O
+of	POS	O
+cyclooxygenase	POS	O
+2	POS	O
+.	POS	O
+The	POS	O
+acute	POS	O
+cytolytic	POS	B-NP
+hepatitis	POS	I-NP
+occurred	POS	O
+rapidly	POS	O
+after	POS	O
+meloxicam	POS	O
+administration	POS	O
+and	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+antinuclear	POS	O
+antibodies	POS	O
+suggesting	POS	O
+a	POS	O
+hypersensitivity	POS	B-NP
+mechanism	POS	O
+.	POS	O
+This	POS	O
+first	POS	O
+case	POS	O
+of	POS	O
+meloxicam	POS	O
+related	POS	O
+liver	POS	B-NP
+toxicity	POS	I-NP
+demonstrates	POS	O
+the	POS	O
+potential	POS	O
+of	POS	O
+this	POS	O
+drug	POS	O
+to	POS	O
+induce	POS	O
+hepatic	POS	B-NP
+damage	POS	I-NP
+.	POS	O
+Induction	POS	O
+of	POS	O
+apoptosis	POS	O
+by	POS	O
+remoxipride	POS	O
+metabolites	POS	O
+in	POS	O
+HL60	POS	O
+and	POS	O
+CD34	POS	O
++	POS	O
+/	POS	O
+CD19	POS	O
+-	POS	O
+human	POS	O
+bone	POS	O
+marrow	POS	O
+progenitor	POS	O
+cells	POS	O
+:	POS	O
+potential	POS	O
+relevance	POS	O
+to	POS	O
+remoxipride	POS	O
+-	POS	O
+induced	POS	O
+aplastic	POS	B-NP
+anemia	POS	I-NP
+.	POS	O
+The	POS	O
+antipsychotic	POS	O
+agent	POS	O
+,	POS	O
+remoxipride	POS	O
+[	POS	O
+(	POS	O
+S	POS	O
+)	POS	O
+-	POS	O
+(	POS	O
+-	POS	O
+)	POS	O
+-	POS	O
+3	POS	O
+-	POS	O
+bromo	POS	O
+-	POS	O
+N	POS	O
+-	POS	O
+[	POS	O
+(	POS	O
+1	POS	O
+-	POS	O
+ethyl	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+pyrrolidinyl	POS	O
+)	POS	O
+methyl	POS	O
+]	POS	O
+-	POS	O
+2	POS	O
+,	POS	O
+6	POS	O
+-	POS	O
+dimethoxybenz	POS	O
+amide	POS	O
+]	POS	O
+has	POS	O
+been	POS	O
+associated	POS	O
+with	POS	O
+acquired	POS	O
+aplastic	POS	B-NP
+anemia	POS	I-NP
+.	POS	O
+We	POS	O
+have	POS	O
+examined	POS	O
+the	POS	O
+ability	POS	O
+of	POS	O
+remoxipride	POS	O
+,	POS	O
+three	POS	O
+pyrrolidine	POS	O
+ring	POS	O
+metabolites	POS	O
+and	POS	O
+five	POS	O
+aromatic	POS	O
+ring	POS	O
+metabolites	POS	O
+of	POS	O
+the	POS	O
+parent	POS	O
+compound	POS	O
+to	POS	O
+induce	POS	O
+apoptosis	POS	O
+in	POS	O
+HL60	POS	O
+cells	POS	O
+and	POS	O
+human	POS	O
+bone	POS	O
+marrow	POS	O
+progenitor	POS	O
+(	POS	O
+HBMP	POS	O
+)	POS	O
+cells	POS	O
+.	POS	O
+Cells	POS	O
+were	POS	O
+treated	POS	O
+for	POS	O
+0	POS	O
+-	POS	O
+24	POS	O
+h	POS	O
+with	POS	O
+each	POS	O
+compound	POS	O
+(	POS	O
+0	POS	O
+-	POS	O
+200	POS	O
+microM	POS	O
+)	POS	O
+.	POS	O
+Apoptosis	POS	O
+was	POS	O
+assessed	POS	O
+by	POS	O
+fluorescence	POS	O
+microscopy	POS	O
+in	POS	O
+Hoechst	POS	O
+33342	POS	O
+-	POS	O
+and	POS	O
+propidium	POS	O
+iodide	POS	O
+stained	POS	O
+cell	POS	O
+samples	POS	O
+.	POS	O
+Results	POS	O
+were	POS	O
+confirmed	POS	O
+by	POS	O
+determination	POS	O
+of	POS	O
+internucleosomal	POS	O
+DNA	POS	O
+fragmentation	POS	O
+using	POS	O
+gel	POS	O
+electrophoresis	POS	O
+for	POS	O
+HL60	POS	O
+cell	POS	O
+samples	POS	O
+and	POS	O
+terminal	POS	O
+deoxynucleotidyl	POS	O
+transferase	POS	O
+assay	POS	O
+in	POS	O
+HBMP	POS	O
+cells	POS	O
+.	POS	O
+The	POS	O
+catechol	POS	O
+and	POS	O
+hydroquinone	POS	O
+metabolites	POS	O
+,	POS	O
+NCQ436	POS	O
+and	POS	O
+NCQ344	POS	O
+,	POS	O
+induced	POS	O
+apoptosis	POS	O
+in	POS	O
+HL60	POS	O
+and	POS	O
+HBMP	POS	O
+cells	POS	O
+in	POS	O
+a	POS	O
+time	POS	O
+-	POS	O
+and	POS	O
+concentration	POS	O
+dependent	POS	O
+manner	POS	O
+,	POS	O
+while	POS	O
+the	POS	O
+phenols	POS	O
+,	POS	O
+NCR181	POS	O
+,	POS	O
+FLA873	POS	O
+,	POS	O
+and	POS	O
+FLA797	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+derivatives	POS	O
+formed	POS	O
+by	POS	O
+oxidation	POS	O
+of	POS	O
+the	POS	O
+pyrrolidine	POS	O
+ring	POS	O
+,	POS	O
+FLA838	POS	O
+,	POS	O
+NCM001	POS	O
+,	POS	O
+and	POS	O
+NCL118	POS	O
+,	POS	O
+had	POS	O
+no	POS	O
+effect	POS	O
+.	POS	O
+No	POS	O
+necrosis	POS	B-NP
+was	POS	O
+observed	POS	O
+in	POS	O
+cells	POS	O
+treated	POS	O
+with	POS	O
+NCQ436	POS	O
+but	POS	O
+NCQ344	POS	O
+had	POS	O
+a	POS	O
+biphasic	POS	O
+effect	POS	O
+in	POS	O
+both	POS	O
+cell	POS	O
+types	POS	O
+,	POS	O
+inducing	POS	O
+apoptosis	POS	O
+at	POS	O
+lower	POS	O
+concentrations	POS	O
+and	POS	O
+necrosis	POS	B-NP
+at	POS	O
+higher	POS	O
+concentrations	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+show	POS	O
+that	POS	O
+the	POS	O
+catechol	POS	O
+and	POS	O
+hydroquinone	POS	O
+metabolites	POS	O
+of	POS	O
+remoxipride	POS	O
+have	POS	O
+direct	POS	O
+toxic	POS	O
+effects	POS	O
+in	POS	O
+HL60	POS	O
+and	POS	O
+HBMP	POS	O
+cells	POS	O
+,	POS	O
+leading	POS	O
+to	POS	O
+apoptosis	POS	O
+,	POS	O
+while	POS	O
+the	POS	O
+phenol	POS	O
+metabolites	POS	O
+were	POS	O
+inactive	POS	O
+.	POS	O
+Similarly	POS	O
+,	POS	O
+benzene	POS	O
+-	POS	O
+derived	POS	O
+catechol	POS	O
+and	POS	O
+hydroquinone	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+phenol	POS	O
+,	POS	O
+induce	POS	O
+apoptosis	POS	O
+in	POS	O
+HBMP	POS	O
+cells	POS	O
+[	POS	O
+Moran	POS	O
+et	POS	O
+al	POS	O
+.	POS	O
+,	POS	O
+Mol	POS	O
+.	POS	O
+Pharmacol	POS	O
+.	POS	O
+,	POS	O
+50	POS	O
+(	POS	O
+1996	POS	O
+)	POS	O
+610	POS	O
+-	POS	O
+615	POS	O
+]	POS	O
+.	POS	O
+We	POS	O
+propose	POS	O
+that	POS	O
+remoxipride	POS	O
+and	POS	O
+benzene	POS	O
+may	POS	O
+induce	POS	O
+aplastic	POS	B-NP
+anemia	POS	I-NP
+via	POS	O
+production	POS	O
+of	POS	O
+similar	POS	O
+reactive	POS	O
+metabolites	POS	O
+and	POS	O
+that	POS	O
+the	POS	O
+ability	POS	O
+of	POS	O
+NCQ436	POS	O
+and	POS	O
+NCQ344	POS	O
+to	POS	O
+induce	POS	O
+apoptosis	POS	O
+in	POS	O
+HBMP	POS	O
+cells	POS	O
+may	POS	O
+contribute	POS	O
+to	POS	O
+the	POS	O
+mechanism	POS	O
+underlying	POS	O
+acquired	POS	O
+aplastic	POS	B-NP
+anemia	POS	I-NP
+that	POS	O
+has	POS	O
+been	POS	O
+associated	POS	O
+with	POS	O
+remoxipride	POS	O
+.	POS	O
+Synthesis	POS	O
+and	POS	O
+preliminary	POS	O
+pharmacological	POS	O
+investigations	POS	O
+of	POS	O
+1	POS	O
+-	POS	O
+(	POS	O
+1	POS	O
+,	POS	O
+2	POS	O
+-	POS	O
+dihydro	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+acenaphthylenyl	POS	O
+)	POS	O
+piperazine	POS	O
+derivatives	POS	O
+as	POS	O
+potential	POS	O
+atypical	POS	O
+antipsychotic	POS	O
+agents	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+In	POS	O
+research	POS	O
+towards	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+new	POS	O
+atypical	POS	O
+antipsychotic	POS	O
+agents	POS	O
+,	POS	O
+one	POS	O
+strategy	POS	O
+is	POS	O
+that	POS	O
+the	POS	O
+dopaminergic	POS	O
+system	POS	O
+can	POS	O
+be	POS	O
+modulated	POS	O
+through	POS	O
+manipulation	POS	O
+of	POS	O
+the	POS	O
+serotonergic	POS	O
+system	POS	O
+.	POS	O
+The	POS	O
+synthesis	POS	O
+and	POS	O
+preliminary	POS	O
+pharmacological	POS	O
+evaluation	POS	O
+of	POS	O
+a	POS	O
+series	POS	O
+of	POS	O
+potential	POS	O
+atypical	POS	O
+antipsychotic	POS	O
+agents	POS	O
+based	POS	O
+on	POS	O
+the	POS	O
+structure	POS	O
+of	POS	O
+1	POS	O
+-	POS	O
+(	POS	O
+1	POS	O
+,	POS	O
+2	POS	O
+-	POS	O
+dihydro	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+acenaphthylenyl	POS	O
+)	POS	O
+piperazine	POS	O
+(	POS	O
+7	POS	O
+)	POS	O
+is	POS	O
+described	POS	O
+.	POS	O
+Compound	POS	O
+7e	POS	O
+,	POS	O
+5	POS	O
+-	POS	O
+{	POS	O
+2	POS	O
+-	POS	O
+[	POS	O
+4	POS	O
+-	POS	O
+(	POS	O
+1	POS	O
+,	POS	O
+2	POS	O
+-	POS	O
+dihydro	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+acenaphthylenyl	POS	O
+)	POS	O
+piperazinyl	POS	O
+]	POS	O
+ethyl	POS	O
+}	POS	O
+-	POS	O
+2	POS	O
+,	POS	O
+3	POS	O
+-	POS	O
+dihy	POS	O
+dro	POS	O
+-	POS	O
+1H	POS	O
+-	POS	O
+indol	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+one	POS	O
+,	POS	O
+from	POS	O
+this	POS	O
+series	POS	O
+showed	POS	O
+significant	POS	O
+affinities	POS	O
+at	POS	O
+the	POS	O
+5	POS	O
+-	POS	O
+HT1A	POS	O
+and	POS	O
+5	POS	O
+-	POS	O
+HT2A	POS	O
+receptors	POS	O
+and	POS	O
+moderate	POS	O
+affinity	POS	O
+at	POS	O
+the	POS	O
+D2	POS	O
+receptor	POS	O
+.	POS	O
+7e	POS	O
+exhibits	POS	O
+a	POS	O
+high	POS	O
+reversal	POS	O
+of	POS	O
+catalepsy	POS	B-NP
+induced	POS	O
+by	POS	O
+haloperidol	POS	O
+indicating	POS	O
+its	POS	O
+atypical	POS	O
+antipsychotic	POS	O
+nature	POS	O
+.	POS	O
+Sub	POS	O
+-	POS	O
+chronic	POS	O
+inhibition	POS	O
+of	POS	O
+nitric	POS	O
+-	POS	O
+oxide	POS	O
+synthesis	POS	O
+modifies	POS	O
+haloperidol	POS	O
+-	POS	O
+induced	POS	O
+catalepsy	POS	B-NP
+and	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+NADPH	POS	O
+-	POS	O
+diaphorase	POS	O
+neurons	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+RATIONALE	POS	O
+:	POS	O
+NG	POS	O
+-	POS	O
+nitro	POS	O
+-	POS	O
+L	POS	O
+-	POS	O
+arginine	POS	O
+(	POS	O
+L	POS	O
+-	POS	O
+NOARG	POS	O
+)	POS	O
+,	POS	O
+an	POS	O
+inhibitor	POS	O
+of	POS	O
+nitric	POS	O
+-	POS	O
+oxide	POS	O
+synthase	POS	O
+(	POS	O
+NOS	POS	O
+)	POS	O
+,	POS	O
+induces	POS	O
+catalepsy	POS	B-NP
+in	POS	O
+mice	POS	O
+.	POS	O
+This	POS	O
+effect	POS	O
+undergoes	POS	O
+rapid	POS	O
+tolerance	POS	O
+,	POS	O
+showing	POS	O
+a	POS	O
+significant	POS	O
+decrease	POS	O
+after	POS	O
+2	POS	O
+days	POS	O
+of	POS	O
+sub	POS	O
+-	POS	O
+chronic	POS	O
+L	POS	O
+-	POS	O
+NOARG	POS	O
+treatment	POS	O
+.	POS	O
+Nitric	POS	O
+oxide	POS	O
+(	POS	O
+NO	POS	O
+)	POS	O
+has	POS	O
+been	POS	O
+shown	POS	O
+to	POS	O
+influence	POS	O
+dopaminergic	POS	O
+neurotransmission	POS	O
+in	POS	O
+the	POS	O
+striatum	POS	O
+.	POS	O
+Neuroleptic	POS	B-NP
+drugs	POS	O
+such	POS	O
+as	POS	O
+haloperidol	POS	O
+,	POS	O
+which	POS	O
+block	POS	O
+dopamine	POS	O
+receptors	POS	O
+,	POS	O
+also	POS	O
+cause	POS	O
+catalepsy	POS	B-NP
+in	POS	O
+rodents	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+To	POS	O
+investigate	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+subchronic	POS	O
+L	POS	O
+-	POS	O
+NOARG	POS	O
+treatment	POS	O
+in	POS	O
+haloperidol	POS	O
+-	POS	O
+induced	POS	O
+catalepsy	POS	B-NP
+and	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+NOS	POS	O
+neurons	POS	O
+in	POS	O
+areas	POS	O
+related	POS	O
+to	POS	O
+motor	POS	O
+control	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Male	POS	O
+albino	POS	O
+Swiss	POS	O
+mice	POS	O
+were	POS	O
+treated	POS	O
+sub	POS	O
+-	POS	O
+chronically	POS	O
+(	POS	O
+twice	POS	O
+a	POS	O
+day	POS	O
+for	POS	O
+4	POS	O
+days	POS	O
+)	POS	O
+with	POS	O
+L	POS	O
+-	POS	O
+NOARG	POS	O
+(	POS	O
+40	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+or	POS	O
+haloperidol	POS	O
+(	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+.	POS	O
+Catalepsy	POS	B-NP
+was	POS	O
+evaluated	POS	O
+at	POS	O
+the	POS	O
+beginning	POS	O
+and	POS	O
+the	POS	O
+end	POS	O
+of	POS	O
+the	POS	O
+treatments	POS	O
+.	POS	O
+Reduced	POS	O
+nicotinamide	POS	O
+adenine	POS	O
+dinucleotide	POS	O
+phosphate	POS	O
+-	POS	O
+diaphorase	POS	O
+(	POS	O
+NADPH	POS	O
+-	POS	O
+d	POS	O
+)	POS	O
+histochemistry	POS	O
+was	POS	O
+also	POS	O
+employed	POS	O
+to	POS	O
+visualize	POS	O
+NOS	POS	O
+as	POS	O
+an	POS	O
+index	POS	O
+of	POS	O
+enzyme	POS	O
+expression	POS	O
+in	POS	O
+mice	POS	O
+brain	POS	O
+regions	POS	O
+related	POS	O
+to	POS	O
+motor	POS	O
+control	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+L	POS	O
+-	POS	O
+NOARG	POS	O
+sub	POS	O
+-	POS	O
+chronic	POS	O
+administration	POS	O
+produced	POS	O
+tolerance	POS	O
+of	POS	O
+L	POS	O
+-	POS	O
+NOARG	POS	O
+and	POS	O
+of	POS	O
+haloperidol	POS	O
+-	POS	O
+induced	POS	O
+catalepsy	POS	B-NP
+.	POS	O
+It	POS	O
+also	POS	O
+induced	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+NADPH	POS	O
+-	POS	O
+d	POS	O
+-	POS	O
+positive	POS	O
+cells	POS	O
+in	POS	O
+the	POS	O
+dorsal	POS	O
+part	POS	O
+of	POS	O
+the	POS	O
+caudate	POS	O
+and	POS	O
+accumbens	POS	O
+nuclei	POS	O
+compared	POS	O
+with	POS	O
+haloperidol	POS	O
+and	POS	O
+in	POS	O
+the	POS	O
+pedunculopontine	POS	O
+tegmental	POS	O
+nucleus	POS	O
+compared	POS	O
+with	POS	O
+saline	POS	O
+.	POS	O
+In	POS	O
+contrast	POS	O
+,	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+NADPH	POS	O
+-	POS	O
+d	POS	O
+neuron	POS	O
+number	POS	O
+in	POS	O
+the	POS	O
+substantia	POS	O
+nigra	POS	O
+,	POS	O
+pars	POS	O
+compacta	POS	O
+in	POS	O
+both	POS	O
+haloperidol	POS	O
+-	POS	O
+treated	POS	O
+and	POS	O
+L	POS	O
+-	POS	O
+NOARG	POS	O
+-	POS	O
+treated	POS	O
+animals	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+results	POS	O
+give	POS	O
+further	POS	O
+support	POS	O
+to	POS	O
+the	POS	O
+hypothesis	POS	O
+that	POS	O
+NO	POS	O
+plays	POS	O
+a	POS	O
+role	POS	O
+in	POS	O
+motor	POS	O
+behavior	POS	O
+control	POS	O
+and	POS	O
+suggest	POS	O
+that	POS	O
+it	POS	O
+may	POS	O
+take	POS	O
+part	POS	O
+in	POS	O
+the	POS	O
+synaptic	POS	O
+changes	POS	O
+produced	POS	O
+by	POS	O
+antipsychotic	POS	O
+treatment	POS	O
+.	POS	O
+Prolonged	POS	O
+left	POS	O
+ventricular	POS	B-NP
+dysfunction	POS	I-NP
+occurs	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+after	POS	O
+both	POS	O
+dobutamine	POS	O
+and	POS	O
+exercise	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+ischaemia	POS	I-NP
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+determine	POS	O
+whether	POS	O
+pharmacological	POS	O
+stress	POS	O
+leads	POS	O
+to	POS	O
+prolonged	POS	O
+but	POS	O
+reversible	POS	O
+left	POS	O
+ventricular	POS	B-NP
+dysfunction	POS	I-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+,	POS	O
+similar	POS	O
+to	POS	O
+that	POS	O
+seen	POS	O
+after	POS	O
+exercise	POS	O
+.	POS	O
+DESIGN	POS	O
+:	POS	O
+A	POS	O
+randomised	POS	O
+crossover	POS	O
+study	POS	O
+of	POS	O
+recovery	POS	O
+time	POS	O
+of	POS	O
+systolic	POS	O
+and	POS	O
+diastolic	POS	O
+left	POS	O
+ventricular	POS	O
+function	POS	O
+after	POS	O
+exercise	POS	O
+and	POS	O
+dobutamine	POS	O
+induced	POS	O
+ischaemia	POS	B-NP
+.	POS	O
+SUBJECTS	POS	O
+:	POS	O
+10	POS	O
+patients	POS	O
+with	POS	O
+stable	POS	O
+angina	POS	B-NP
+,	POS	O
+angiographically	POS	B-NP
+proven	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+,	POS	O
+and	POS	O
+normal	POS	B-NP
+left	POS	I-NP
+ventricular	POS	I-NP
+function	POS	I-NP
+.	POS	O
+INTERVENTIONS	POS	O
+:	POS	O
+Treadmill	POS	O
+exercise	POS	O
+and	POS	O
+dobutamine	POS	O
+stress	POS	O
+were	POS	O
+performed	POS	O
+on	POS	O
+different	POS	O
+days	POS	O
+.	POS	O
+Quantitative	POS	O
+assessment	POS	O
+of	POS	O
+systolic	POS	O
+and	POS	O
+diastolic	POS	O
+left	POS	O
+ventricular	POS	O
+function	POS	O
+was	POS	O
+performed	POS	O
+using	POS	O
+transthoracic	POS	O
+echocardiography	POS	O
+at	POS	O
+baseline	POS	O
+and	POS	O
+at	POS	O
+regular	POS	O
+intervals	POS	O
+after	POS	O
+each	POS	O
+test	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Both	POS	O
+forms	POS	O
+of	POS	O
+stress	POS	O
+led	POS	O
+to	POS	O
+prolonged	POS	O
+but	POS	O
+reversible	POS	O
+systolic	POS	O
+and	POS	O
+diastolic	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+difference	POS	O
+in	POS	O
+the	POS	O
+maximum	POS	O
+double	POS	O
+product	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+53	POS	O
+)	POS	O
+or	POS	O
+ST	POS	B-NP
+depression	POS	I-NP
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+63	POS	O
+)	POS	O
+with	POS	O
+either	POS	O
+form	POS	O
+of	POS	O
+stress	POS	O
+.	POS	O
+After	POS	O
+exercise	POS	O
+,	POS	O
+ejection	POS	O
+fraction	POS	O
+was	POS	O
+reduced	POS	O
+at	POS	O
+15	POS	O
+and	POS	O
+30	POS	O
+minutes	POS	O
+compared	POS	O
+with	POS	O
+baseline	POS	O
+(	POS	O
+mean	POS	O
+(	POS	O
+SEM	POS	O
+)	POS	O
+,	POS	O
+-	POS	O
+5	POS	O
+.	POS	O
+6	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+)	POS	O
+%	POS	O
+,	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+;	POS	O
+and	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+1	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+2	POS	O
+)	POS	O
+%	POS	O
+,	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+at	POS	O
+30	POS	O
+and	POS	O
+45	POS	O
+minutes	POS	O
+after	POS	O
+dobutamine	POS	O
+(	POS	O
+-	POS	O
+10	POS	O
+.	POS	O
+8	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+8	POS	O
+)	POS	O
+%	POS	O
+and	POS	O
+-	POS	O
+5	POS	O
+.	POS	O
+5	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+8	POS	O
+)	POS	O
+%	POS	O
+,	POS	O
+both	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+Regional	POS	O
+analysis	POS	O
+showed	POS	O
+a	POS	O
+reduction	POS	O
+in	POS	O
+the	POS	O
+worst	POS	O
+affected	POS	O
+segment	POS	O
+15	POS	O
+and	POS	O
+30	POS	O
+minutes	POS	O
+after	POS	O
+exercise	POS	O
+(	POS	O
+-	POS	O
+27	POS	O
+.	POS	O
+9	POS	O
+(	POS	O
+7	POS	O
+.	POS	O
+2	POS	O
+)	POS	O
+%	POS	O
+and	POS	O
+-	POS	O
+28	POS	O
+.	POS	O
+6	POS	O
+(	POS	O
+5	POS	O
+.	POS	O
+7	POS	O
+)	POS	O
+%	POS	O
+,	POS	O
+both	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+at	POS	O
+30	POS	O
+minutes	POS	O
+after	POS	O
+dobutamine	POS	O
+(	POS	O
+-	POS	O
+32	POS	O
+(	POS	O
+5	POS	O
+.	POS	O
+3	POS	O
+)	POS	O
+%	POS	O
+,	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+isovolumic	POS	O
+relaxation	POS	O
+period	POS	O
+was	POS	O
+prolonged	POS	O
+45	POS	O
+minutes	POS	O
+after	POS	O
+each	POS	O
+form	POS	O
+of	POS	O
+stress	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+In	POS	O
+patients	POS	O
+with	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+,	POS	O
+dobutamine	POS	O
+induced	POS	O
+ischaemia	POS	B-NP
+results	POS	O
+in	POS	O
+prolonged	POS	O
+reversible	POS	O
+left	POS	O
+ventricular	POS	B-NP
+dysfunction	POS	I-NP
+,	POS	O
+presumed	POS	O
+to	POS	O
+be	POS	O
+myocardial	POS	B-NP
+stunning	POS	I-NP
+,	POS	O
+similar	POS	O
+to	POS	O
+that	POS	O
+seen	POS	O
+after	POS	O
+exercise	POS	O
+.	POS	O
+Dobutamine	POS	O
+induced	POS	O
+ischaemia	POS	B-NP
+could	POS	O
+therefore	POS	O
+be	POS	O
+used	POS	O
+to	POS	O
+study	POS	O
+the	POS	O
+pathophysiology	POS	O
+of	POS	O
+this	POS	O
+phenomenon	POS	O
+further	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+Anorexigens	POS	O
+and	POS	O
+pulmonary	POS	B-NP
+hypertension	POS	I-NP
+in	POS	O
+the	POS	O
+United	POS	O
+States	POS	O
+:	POS	O
+results	POS	O
+from	POS	O
+the	POS	O
+surveillance	POS	O
+of	POS	O
+North	POS	O
+American	POS	O
+pulmonary	POS	B-NP
+hypertension	POS	I-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+The	POS	O
+use	POS	O
+of	POS	O
+appetite	POS	O
+suppressants	POS	O
+in	POS	O
+Europe	POS	O
+has	POS	O
+been	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+primary	POS	O
+pulmonary	POS	B-NP
+hypertension	POS	I-NP
+(	POS	O
+PPH	POS	B-NP
+)	POS	O
+.	POS	O
+Recently	POS	O
+,	POS	O
+fenfluramine	POS	O
+appetite	POS	O
+suppressants	POS	O
+became	POS	O
+widely	POS	O
+used	POS	O
+in	POS	O
+the	POS	O
+United	POS	O
+States	POS	O
+but	POS	O
+were	POS	O
+withdrawn	POS	O
+in	POS	O
+September	POS	O
+1997	POS	O
+because	POS	O
+of	POS	O
+concerns	POS	O
+over	POS	O
+adverse	POS	O
+effects	POS	O
+.	POS	O
+MATERIALS	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+conducted	POS	O
+a	POS	O
+prospective	POS	O
+surveillance	POS	O
+study	POS	O
+on	POS	O
+patients	POS	O
+diagnosed	POS	O
+with	POS	O
+pulmonary	POS	B-NP
+hypertension	POS	I-NP
+at	POS	O
+12	POS	O
+large	POS	O
+referral	POS	O
+centers	POS	O
+in	POS	O
+North	POS	O
+America	POS	O
+.	POS	O
+Data	POS	O
+collected	POS	O
+on	POS	O
+patients	POS	O
+seen	POS	O
+from	POS	O
+September	POS	O
+1	POS	O
+,	POS	O
+1996	POS	O
+,	POS	O
+to	POS	O
+December	POS	O
+31	POS	O
+,	POS	O
+1997	POS	O
+,	POS	O
+included	POS	O
+the	POS	O
+cause	POS	O
+of	POS	O
+the	POS	O
+pulmonary	POS	B-NP
+hypertension	POS	I-NP
+and	POS	O
+its	POS	O
+severity	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+no	POS	O
+identifiable	POS	O
+cause	POS	O
+of	POS	O
+pulmonary	POS	B-NP
+hypertension	POS	I-NP
+were	POS	O
+classed	POS	O
+as	POS	O
+PPH	POS	B-NP
+.	POS	O
+A	POS	O
+history	POS	O
+of	POS	O
+drug	POS	O
+exposure	POS	O
+also	POS	O
+was	POS	O
+taken	POS	O
+with	POS	O
+special	POS	O
+attention	POS	O
+on	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+antidepressants	POS	O
+,	POS	O
+anorexigens	POS	O
+,	POS	O
+and	POS	O
+amphetamines	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Five	POS	O
+hundred	POS	O
+seventy	POS	O
+-	POS	O
+nine	POS	O
+patients	POS	O
+were	POS	O
+studied	POS	O
+,	POS	O
+205	POS	O
+with	POS	O
+PPH	POS	B-NP
+and	POS	O
+374	POS	O
+with	POS	O
+pulmonary	POS	B-NP
+hypertension	POS	I-NP
+from	POS	O
+other	POS	O
+causes	POS	O
+(	POS	O
+secondary	POS	O
+pulmonary	POS	B-NP
+hypertension	POS	I-NP
+[	POS	O
+SPH	POS	O
+]	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+use	POS	O
+of	POS	O
+anorexigens	POS	O
+was	POS	O
+common	POS	O
+in	POS	O
+both	POS	O
+groups	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+of	POS	O
+the	POS	O
+medications	POS	O
+surveyed	POS	O
+,	POS	O
+only	POS	O
+the	POS	O
+fenfluramines	POS	O
+had	POS	O
+a	POS	O
+significant	POS	O
+preferential	POS	O
+association	POS	O
+with	POS	O
+PPH	POS	B-NP
+as	POS	O
+compared	POS	O
+with	POS	O
+SPH	POS	B-NP
+(	POS	O
+adjusted	POS	O
+odds	POS	O
+ratio	POS	O
+for	POS	O
+use	POS	O
+>	POS	O
+6	POS	O
+months	POS	O
+,	POS	O
+7	POS	O
+.	POS	O
+5	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+7	POS	O
+to	POS	O
+32	POS	O
+.	POS	O
+4	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+association	POS	O
+was	POS	O
+stronger	POS	O
+with	POS	O
+longer	POS	O
+duration	POS	O
+of	POS	O
+use	POS	O
+when	POS	O
+compared	POS	O
+to	POS	O
+shorter	POS	O
+duration	POS	O
+of	POS	O
+use	POS	O
+and	POS	O
+was	POS	O
+more	POS	O
+pronounced	POS	O
+in	POS	O
+recent	POS	O
+users	POS	O
+than	POS	O
+in	POS	O
+remote	POS	O
+users	POS	O
+.	POS	O
+An	POS	O
+unexpectedly	POS	O
+high	POS	O
+(	POS	O
+11	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+number	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+SPH	POS	B-NP
+had	POS	O
+used	POS	O
+anorexigens	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+The	POS	O
+magnitude	POS	O
+of	POS	O
+the	POS	O
+association	POS	O
+with	POS	O
+PPH	POS	B-NP
+,	POS	O
+the	POS	O
+increase	POS	O
+of	POS	O
+association	POS	O
+with	POS	O
+increasing	POS	O
+duration	POS	O
+of	POS	O
+use	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+specificity	POS	O
+for	POS	O
+fenfluramines	POS	O
+are	POS	O
+consistent	POS	O
+with	POS	O
+previous	POS	O
+studies	POS	O
+indicating	POS	O
+that	POS	O
+fenfluramines	POS	O
+are	POS	O
+causally	POS	O
+related	POS	O
+to	POS	O
+PPH	POS	B-NP
+.	POS	O
+The	POS	O
+high	POS	O
+prevalence	POS	O
+of	POS	O
+anorexigen	POS	O
+use	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+SPH	POS	B-NP
+also	POS	O
+raises	POS	O
+the	POS	O
+possibility	POS	O
+that	POS	O
+these	POS	O
+drugs	POS	O
+precipitate	POS	O
+pulmonary	POS	B-NP
+hypertension	POS	I-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+underlying	POS	O
+conditions	POS	O
+associated	POS	O
+with	POS	O
+SPH	POS	B-NP
+.	POS	O
+Clinical	POS	O
+aspects	POS	O
+of	POS	O
+heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+and	POS	O
+thrombosis	POS	B-NP
+and	POS	O
+other	POS	O
+side	POS	O
+effects	POS	O
+of	POS	O
+heparin	POS	O
+therapy	POS	O
+.	POS	O
+Heparin	POS	O
+,	POS	O
+first	POS	O
+used	POS	O
+to	POS	O
+prevent	POS	O
+the	POS	O
+clotting	POS	O
+of	POS	O
+blood	POS	O
+in	POS	O
+vitro	POS	O
+,	POS	O
+has	POS	O
+been	POS	O
+clinically	POS	O
+used	POS	O
+to	POS	O
+treat	POS	O
+thrombosis	POS	B-NP
+for	POS	O
+more	POS	O
+than	POS	O
+50	POS	O
+years	POS	O
+.	POS	O
+Although	POS	O
+several	POS	O
+new	POS	O
+anticoagulant	POS	O
+drugs	POS	O
+are	POS	O
+in	POS	O
+development	POS	O
+,	POS	O
+heparin	POS	O
+remains	POS	O
+the	POS	O
+anticoagulant	POS	O
+of	POS	O
+choice	POS	O
+to	POS	O
+treat	POS	O
+acute	POS	O
+thrombotic	POS	B-NP
+episodes	POS	O
+.	POS	O
+The	POS	O
+clinical	POS	O
+effects	POS	O
+of	POS	O
+heparin	POS	O
+are	POS	O
+meritorious	POS	O
+,	POS	O
+but	POS	O
+side	POS	O
+effects	POS	O
+do	POS	O
+exist	POS	O
+.	POS	O
+Bleeding	POS	O
+is	POS	O
+the	POS	O
+primary	POS	O
+untoward	POS	O
+effect	POS	O
+of	POS	O
+heparin	POS	O
+.	POS	O
+Major	POS	O
+bleeding	POS	B-NP
+is	POS	O
+of	POS	O
+primary	POS	O
+concern	POS	O
+in	POS	O
+patients	POS	O
+receiving	POS	O
+heparin	POS	O
+therapy	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+additional	POS	O
+important	POS	O
+untoward	POS	O
+effects	POS	O
+of	POS	O
+heparin	POS	O
+therapy	POS	O
+include	POS	O
+heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+,	POS	O
+heparin	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+osteoporosis	POS	I-NP
+,	POS	O
+eosinophilia	POS	B-NP
+,	POS	O
+skin	POS	B-NP
+reactions	POS	I-NP
+,	POS	O
+allergic	POS	B-NP
+reactions	POS	I-NP
+other	POS	O
+than	POS	O
+thrombocytopenia	POS	B-NP
+,	POS	O
+alopecia	POS	B-NP
+,	POS	O
+transaminasemia	POS	B-NP
+,	POS	O
+hyperkalemia	POS	B-NP
+,	POS	O
+hypoaldosteronism	POS	B-NP
+,	POS	O
+and	POS	O
+priapism	POS	B-NP
+.	POS	O
+These	POS	O
+side	POS	O
+effects	POS	O
+are	POS	O
+relatively	POS	O
+rare	POS	O
+in	POS	O
+a	POS	O
+given	POS	O
+individual	POS	O
+,	POS	O
+but	POS	O
+given	POS	O
+the	POS	O
+extremely	POS	O
+widespread	POS	O
+use	POS	O
+of	POS	O
+heparin	POS	O
+,	POS	O
+some	POS	O
+are	POS	O
+quite	POS	O
+common	POS	O
+,	POS	O
+particularly	POS	O
+HITT	POS	B-NP
+and	POS	O
+osteoporosis	POS	B-NP
+.	POS	O
+Although	POS	O
+reasonable	POS	O
+incidences	POS	O
+of	POS	O
+many	POS	O
+of	POS	O
+these	POS	O
+side	POS	O
+effects	POS	O
+can	POS	O
+be	POS	O
+"	POS	O
+softly	POS	O
+"	POS	O
+deduced	POS	O
+from	POS	O
+current	POS	O
+reports	POS	O
+dealing	POS	O
+with	POS	O
+unfractionated	POS	O
+heparin	POS	O
+,	POS	O
+at	POS	O
+present	POS	O
+the	POS	O
+incidences	POS	O
+of	POS	O
+these	POS	O
+side	POS	O
+effects	POS	O
+with	POS	O
+newer	POS	O
+low	POS	O
+molecular	POS	O
+weight	POS	O
+heparins	POS	O
+appear	POS	O
+to	POS	O
+be	POS	O
+much	POS	O
+less	POS	O
+common	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+only	POS	O
+longer	POS	O
+experience	POS	O
+will	POS	O
+more	POS	O
+clearly	POS	O
+define	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+each	POS	O
+side	POS	O
+effect	POS	O
+with	POS	O
+low	POS	O
+molecular	POS	O
+weight	POS	O
+preparations	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+bilateral	POS	O
+optic	POS	B-NP
+neuropathy	POS	I-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+on	POS	O
+tacrolimus	POS	O
+(	POS	O
+FK506	POS	O
+)	POS	O
+therapy	POS	O
+after	POS	O
+liver	POS	O
+transplantation	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+To	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+bilateral	POS	O
+optic	POS	B-NP
+neuropathy	POS	I-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+receiving	POS	O
+tacrolimus	POS	O
+(	POS	O
+FK	POS	O
+506	POS	O
+,	POS	O
+Prograf	POS	O
+;	POS	O
+Fujisawa	POS	O
+USA	POS	O
+,	POS	O
+Inc	POS	O
+,	POS	O
+Deerfield	POS	O
+,	POS	O
+Illinois	POS	O
+)	POS	O
+for	POS	O
+immunosuppression	POS	O
+after	POS	O
+orthotropic	POS	O
+liver	POS	O
+transplantation	POS	O
+.	POS	O
+METHOD	POS	O
+:	POS	O
+Case	POS	O
+report	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+58	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+receiving	POS	O
+tacrolimus	POS	O
+after	POS	O
+orthotropic	POS	O
+liver	POS	O
+transplantation	POS	O
+,	POS	O
+serial	POS	O
+neuro	POS	O
+-	POS	O
+ophthalmologic	POS	O
+examinations	POS	O
+and	POS	O
+laboratory	POS	O
+studies	POS	O
+were	POS	O
+performed	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+patient	POS	O
+had	POS	O
+episodic	POS	B-NP
+deterioration	POS	I-NP
+of	POS	I-NP
+vision	POS	I-NP
+in	POS	I-NP
+both	POS	I-NP
+eyes	POS	I-NP
+,	POS	O
+with	POS	O
+clinical	POS	O
+features	POS	O
+resembling	POS	O
+ischemic	POS	B-NP
+optic	POS	I-NP
+neuropathies	POS	I-NP
+.	POS	O
+Deterioration	POS	B-NP
+of	POS	I-NP
+vision	POS	I-NP
+occurred	POS	O
+despite	POS	O
+discontinuation	POS	O
+of	POS	O
+the	POS	O
+tacrolimus	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Tacrolimus	POS	O
+and	POS	O
+other	POS	O
+immunosuppressive	POS	O
+agents	POS	O
+may	POS	O
+be	POS	O
+associated	POS	O
+with	POS	O
+optic	POS	B-NP
+nerve	POS	I-NP
+toxicity	POS	I-NP
+.	POS	O
+Hypercalcemia	POS	B-NP
+,	POS	O
+arrhythmia	POS	B-NP
+,	POS	O
+and	POS	O
+mood	POS	O
+stabilizers	POS	O
+.	POS	O
+Recent	POS	O
+findings	POS	O
+in	POS	O
+a	POS	O
+bipolar	POS	B-NP
+patient	POS	O
+receiving	POS	O
+maintenance	POS	O
+lithium	POS	O
+therapy	POS	O
+who	POS	O
+developed	POS	O
+hypercalcemia	POS	B-NP
+and	POS	O
+severe	POS	O
+bradyarrhythmia	POS	B-NP
+prompted	POS	O
+the	POS	O
+authors	POS	O
+to	POS	O
+conduct	POS	O
+a	POS	O
+retrospective	POS	O
+study	POS	O
+of	POS	O
+bipolar	POS	B-NP
+patients	POS	O
+with	POS	O
+lithium	POS	O
+-	POS	O
+associated	POS	O
+hypercalcemia	POS	B-NP
+.	POS	O
+A	POS	O
+printout	POS	O
+of	POS	O
+all	POS	O
+cases	POS	O
+of	POS	O
+hypercalcemia	POS	B-NP
+that	POS	O
+presented	POS	O
+during	POS	O
+a	POS	O
+1	POS	O
+-	POS	O
+year	POS	O
+period	POS	O
+was	POS	O
+generated	POS	O
+.	POS	O
+After	POS	O
+eliminating	POS	O
+spurious	POS	O
+hypercalcemias	POS	B-NP
+or	POS	O
+those	POS	O
+associated	POS	O
+with	POS	O
+intravenous	POS	O
+fluids	POS	O
+,	POS	O
+the	POS	O
+authors	POS	O
+identified	POS	O
+18	POS	O
+non	POS	O
+-	POS	O
+lithium	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+with	POS	O
+hypercalcemias	POS	B-NP
+related	POS	O
+to	POS	O
+malignancies	POS	B-NP
+and	POS	O
+other	POS	O
+medical	POS	O
+conditions	POS	O
+(	POS	O
+group	POS	O
+A	POS	O
+)	POS	O
+and	POS	O
+12	POS	O
+patients	POS	O
+with	POS	O
+lithium	POS	O
+-	POS	O
+associated	POS	O
+hypercalcemia	POS	B-NP
+(	POS	O
+group	POS	O
+B	POS	O
+)	POS	O
+.	POS	O
+Patients	POS	O
+in	POS	O
+group	POS	O
+B	POS	O
+were	POS	O
+not	POS	O
+comparable	POS	O
+to	POS	O
+those	POS	O
+in	POS	O
+group	POS	O
+A	POS	O
+,	POS	O
+as	POS	O
+the	POS	O
+latter	POS	O
+were	POS	O
+medically	POS	O
+compromised	POS	O
+and	POS	O
+were	POS	O
+receiving	POS	O
+multiple	POS	O
+pharmacotherapies	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+two	POS	O
+control	POS	O
+groups	POS	O
+were	POS	O
+generated	POS	O
+:	POS	O
+group	POS	O
+C1	POS	O
+,	POS	O
+which	POS	O
+included	POS	O
+age	POS	O
+-	POS	O
+and	POS	O
+sex	POS	O
+-	POS	O
+comparable	POS	O
+lithium	POS	O
+-	POS	O
+treated	POS	O
+bipolar	POS	O
+normocalcemic	POS	O
+patients	POS	O
+,	POS	O
+and	POS	O
+group	POS	O
+C2	POS	O
+,	POS	O
+which	POS	O
+included	POS	O
+bipolar	POS	B-NP
+normocalcemic	POS	I-NP
+patients	POS	O
+treated	POS	O
+with	POS	O
+anticonvulsant	POS	O
+mood	POS	O
+stabilizers	POS	O
+.	POS	O
+The	POS	O
+electrocardiographic	POS	O
+(	POS	O
+ECG	POS	O
+)	POS	O
+findings	POS	O
+for	POS	O
+patients	POS	O
+in	POS	O
+group	POS	O
+B	POS	O
+were	POS	O
+compared	POS	O
+with	POS	O
+those	POS	O
+of	POS	O
+patients	POS	O
+in	POS	O
+groups	POS	O
+C1	POS	O
+and	POS	O
+C2	POS	O
+.	POS	O
+It	POS	O
+was	POS	O
+found	POS	O
+that	POS	O
+these	POS	O
+groups	POS	O
+did	POS	O
+not	POS	O
+differ	POS	O
+in	POS	O
+their	POS	O
+overall	POS	O
+frequency	POS	O
+of	POS	O
+ECG	POS	B-NP
+abnormalities	POS	I-NP
+;	POS	O
+however	POS	O
+,	POS	O
+there	POS	O
+were	POS	O
+significant	POS	O
+differences	POS	O
+in	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+conduction	POS	B-NP
+defects	POS	I-NP
+.	POS	O
+Patients	POS	O
+with	POS	O
+hypercalcemia	POS	B-NP
+resulting	POS	O
+from	POS	O
+medical	POS	O
+diseases	POS	O
+and	POS	O
+bipolar	POS	B-NP
+patients	POS	O
+with	POS	O
+lithium	POS	O
+-	POS	O
+associated	POS	O
+hypercalcemia	POS	B-NP
+had	POS	O
+significantly	POS	O
+higher	POS	O
+frequencies	POS	O
+of	POS	O
+conduction	POS	B-NP
+defects	POS	I-NP
+.	POS	O
+Patients	POS	O
+in	POS	O
+group	POS	O
+A	POS	O
+had	POS	O
+significant	POS	O
+mortality	POS	O
+at	POS	O
+2	POS	O
+-	POS	O
+year	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+(	POS	O
+28	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+in	POS	O
+contrast	POS	O
+to	POS	O
+zero	POS	O
+mortality	POS	O
+in	POS	O
+the	POS	O
+other	POS	O
+three	POS	O
+groups	POS	O
+.	POS	O
+The	POS	O
+clinical	POS	O
+implications	POS	O
+of	POS	O
+these	POS	O
+findings	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+Attenuation	POS	O
+of	POS	O
+nephrotoxicity	POS	B-NP
+by	POS	O
+a	POS	O
+novel	POS	O
+lipid	POS	O
+nanosphere	POS	O
+(	POS	O
+NS	POS	O
+-	POS	O
+718	POS	O
+)	POS	O
+incorporating	POS	O
+amphotericin	POS	O
+B	POS	O
+.	POS	O
+NS	POS	O
+-	POS	O
+718	POS	O
+,	POS	O
+a	POS	O
+lipid	POS	O
+nanosphere	POS	O
+incorporating	POS	O
+amphotericin	POS	O
+B	POS	O
+,	POS	O
+is	POS	O
+effective	POS	O
+against	POS	O
+pathogenic	POS	O
+fungi	POS	O
+and	POS	O
+has	POS	O
+low	POS	B-NP
+toxicity	POS	I-NP
+.	POS	O
+We	POS	O
+compared	POS	O
+the	POS	O
+toxicity	POS	B-NP
+of	POS	O
+NS	POS	O
+-	POS	O
+718	POS	O
+with	POS	O
+that	POS	O
+of	POS	O
+Fungizone	POS	O
+(	POS	O
+amphotericin	POS	O
+B	POS	O
+-	POS	O
+sodium	POS	O
+deoxycholate	POS	O
+;	POS	O
+D	POS	O
+-	POS	O
+AmB	POS	O
+)	POS	O
+in	POS	O
+vitro	POS	O
+using	POS	O
+renal	POS	O
+cell	POS	O
+cultures	POS	O
+and	POS	O
+in	POS	O
+vivo	POS	O
+by	POS	O
+biochemical	POS	O
+analysis	POS	O
+,	POS	O
+histopathological	POS	O
+study	POS	O
+of	POS	O
+the	POS	O
+kidney	POS	O
+and	POS	O
+pharmacokinetic	POS	O
+study	POS	O
+of	POS	O
+amphotericin	POS	O
+B	POS	O
+following	POS	O
+intravenous	POS	O
+infusion	POS	O
+of	POS	O
+the	POS	O
+formulation	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+Incubation	POS	O
+with	POS	O
+NS	POS	O
+-	POS	O
+718	POS	O
+resulted	POS	O
+in	POS	O
+significantly	POS	O
+less	POS	O
+damage	POS	O
+of	POS	O
+cultured	POS	O
+human	POS	O
+renal	POS	O
+proximal	POS	O
+tubular	POS	O
+epithelial	POS	O
+cells	POS	O
+compared	POS	O
+with	POS	O
+D	POS	O
+-	POS	O
+AmB	POS	O
+.	POS	O
+Serum	POS	O
+blood	POS	O
+urea	POS	O
+and	POS	O
+creatinine	POS	O
+concentrations	POS	O
+increased	POS	O
+significantly	POS	O
+in	POS	O
+rats	POS	O
+given	POS	O
+an	POS	O
+iv	POS	O
+infusion	POS	O
+of	POS	O
+D	POS	O
+-	POS	O
+AmB	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+but	POS	O
+not	POS	O
+in	POS	O
+those	POS	O
+given	POS	O
+the	POS	O
+same	POS	O
+dose	POS	O
+of	POS	O
+NS	POS	O
+-	POS	O
+718	POS	O
+.	POS	O
+Histopathological	POS	O
+examination	POS	O
+of	POS	O
+the	POS	O
+kidney	POS	O
+showed	POS	O
+tubular	POS	O
+necrosis	POS	B-NP
+in	POS	O
+D	POS	O
+-	POS	O
+AmB	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+but	POS	O
+no	POS	O
+change	POS	O
+in	POS	O
+NS	POS	O
+-	POS	O
+718	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+.	POS	O
+Amphotericin	POS	O
+B	POS	O
+concentrations	POS	O
+in	POS	O
+the	POS	O
+kidney	POS	O
+in	POS	O
+NS	POS	O
+-	POS	O
+718	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+were	POS	O
+higher	POS	O
+than	POS	O
+those	POS	O
+in	POS	O
+D	POS	O
+-	POS	O
+AmB	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+.	POS	O
+Our	POS	O
+in	POS	O
+vitro	POS	O
+and	POS	O
+in	POS	O
+vivo	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+incorporation	POS	O
+of	POS	O
+amphotericin	POS	O
+B	POS	O
+into	POS	O
+lipid	POS	O
+nanospheres	POS	O
+of	POS	O
+NS	POS	O
+-	POS	O
+718	POS	O
+attenuates	POS	O
+the	POS	O
+nephrotoxicity	POS	B-NP
+of	POS	O
+amphotericin	POS	O
+B	POS	O
+.	POS	O
+Patterns	POS	O
+of	POS	O
+sulfadiazine	POS	O
+acute	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+Sulfadiazine	POS	O
+acute	POS	O
+nephrotoxicity	POS	B-NP
+is	POS	O
+reviving	POS	O
+specially	POS	O
+because	POS	O
+of	POS	O
+its	POS	O
+use	POS	O
+in	POS	O
+toxoplasmosis	POS	B-NP
+in	POS	O
+HIV	POS	B-NP
+-	POS	I-NP
+positive	POS	I-NP
+patients	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+4	POS	O
+cases	POS	O
+,	POS	O
+one	POS	O
+of	POS	O
+them	POS	O
+in	POS	O
+a	POS	O
+previously	POS	O
+healthy	POS	O
+person	POS	O
+.	POS	O
+Under	POS	O
+treatment	POS	O
+with	POS	O
+sulfadiazine	POS	O
+they	POS	O
+developed	POS	O
+oliguria	POS	B-NP
+,	POS	O
+abdominal	POS	B-NP
+pain	POS	I-NP
+,	POS	O
+renal	POS	B-NP
+failure	POS	I-NP
+and	POS	O
+showed	POS	O
+multiple	POS	B-NP
+radiolucent	POS	I-NP
+renal	POS	I-NP
+calculi	POS	I-NP
+in	POS	O
+echography	POS	O
+.	POS	O
+All	POS	O
+patients	POS	O
+recovered	POS	O
+their	POS	O
+previous	POS	O
+normal	POS	O
+renal	POS	O
+function	POS	O
+after	POS	O
+adequate	POS	O
+hydration	POS	O
+and	POS	O
+alcalinization	POS	O
+.	POS	O
+A	POS	O
+nephrostomy	POS	O
+tube	POS	O
+had	POS	O
+to	POS	O
+be	POS	O
+placed	POS	O
+in	POS	O
+one	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+for	POS	O
+ureteral	POS	B-NP
+lithiasis	POS	I-NP
+in	POS	O
+a	POS	O
+single	POS	O
+functional	POS	O
+kidney	POS	O
+.	POS	O
+None	POS	O
+of	POS	O
+them	POS	O
+needed	POS	O
+dialysis	POS	O
+or	POS	O
+a	POS	O
+renal	POS	O
+biopsy	POS	O
+because	POS	O
+of	POS	O
+a	POS	O
+typical	POS	O
+benign	POS	O
+course	POS	O
+.	POS	O
+Treatment	POS	O
+with	POS	O
+sulfadiazine	POS	O
+requires	POS	O
+exquisite	POS	O
+control	POS	O
+of	POS	O
+renal	POS	O
+function	POS	O
+,	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+water	POS	O
+ingestion	POS	O
+and	POS	O
+possibly	POS	O
+the	POS	O
+alcalinization	POS	O
+of	POS	O
+the	POS	O
+urine	POS	O
+.	POS	O
+We	POS	O
+communicate	POS	O
+a	POS	O
+case	POS	O
+in	POS	O
+a	POS	O
+previously	POS	O
+healthy	POS	O
+person	POS	O
+,	POS	O
+a	POS	O
+fact	POS	O
+not	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+recent	POS	O
+literature	POS	O
+.	POS	O
+Probably	POS	O
+many	POS	O
+more	POS	O
+cases	POS	O
+are	POS	O
+not	POS	O
+detected	POS	O
+.	POS	O
+We	POS	O
+think	POS	O
+that	POS	O
+a	POS	O
+prospective	POS	O
+study	POS	O
+would	POS	O
+be	POS	O
+useful	POS	O
+.	POS	O
+Downbeat	POS	B-NP
+nystagmus	POS	I-NP
+associated	POS	O
+with	POS	O
+intravenous	POS	O
+patient	POS	O
+-	POS	O
+controlled	POS	O
+administration	POS	O
+of	POS	O
+morphine	POS	O
+.	POS	O
+IMPLICATIONS	POS	O
+:	POS	O
+This	POS	O
+case	POS	O
+documents	POS	O
+a	POS	O
+patient	POS	O
+who	POS	O
+developed	POS	O
+dizziness	POS	B-NP
+with	POS	O
+downbeating	POS	B-NP
+nystagmus	POS	I-NP
+while	POS	O
+receiving	POS	O
+a	POS	O
+relatively	POS	O
+large	POS	O
+dose	POS	O
+of	POS	O
+IV	POS	O
+patient	POS	O
+-	POS	O
+controlled	POS	O
+analgesia	POS	O
+morphine	POS	O
+.	POS	O
+Although	POS	O
+there	POS	O
+have	POS	O
+been	POS	O
+case	POS	O
+reports	POS	O
+of	POS	O
+epidural	POS	O
+morphine	POS	O
+with	POS	O
+these	POS	O
+symptoms	POS	O
+and	POS	O
+signs	POS	O
+,	POS	O
+this	POS	O
+has	POS	O
+not	POS	O
+been	POS	O
+previously	POS	O
+documented	POS	O
+with	POS	O
+IV	POS	O
+or	POS	O
+patient	POS	O
+-	POS	O
+controlled	POS	O
+analgesia	POS	O
+morphine	POS	O
+.	POS	O
+Hemodynamic	POS	O
+and	POS	O
+antiadrenergic	POS	O
+effects	POS	O
+of	POS	O
+dronedarone	POS	O
+and	POS	O
+amiodarone	POS	O
+in	POS	O
+animals	POS	O
+with	POS	O
+a	POS	O
+healed	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+The	POS	O
+hemodynamic	POS	O
+and	POS	O
+antiadrenergic	POS	O
+effects	POS	O
+of	POS	O
+dronedarone	POS	O
+,	POS	O
+a	POS	O
+noniodinated	POS	O
+compound	POS	O
+structurally	POS	O
+related	POS	O
+to	POS	O
+amiodarone	POS	O
+,	POS	O
+were	POS	O
+compared	POS	O
+with	POS	O
+those	POS	O
+of	POS	O
+amiodarone	POS	O
+after	POS	O
+prolonged	POS	O
+oral	POS	O
+administration	POS	O
+,	POS	O
+both	POS	O
+at	POS	O
+rest	POS	O
+and	POS	O
+during	POS	O
+sympathetic	POS	O
+stimulation	POS	O
+in	POS	O
+conscious	POS	O
+dogs	POS	O
+with	POS	O
+a	POS	O
+healed	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+All	POS	O
+dogs	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+6	POS	O
+)	POS	O
+randomly	POS	O
+received	POS	O
+orally	POS	O
+dronedarone	POS	O
+(	POS	O
+10	POS	O
+and	POS	O
+30	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+,	POS	O
+amiodarone	POS	O
+(	POS	O
+10	POS	O
+and	POS	O
+30	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+placebo	POS	O
+twice	POS	O
+daily	POS	O
+for	POS	O
+7	POS	O
+days	POS	O
+,	POS	O
+with	POS	O
+a	POS	O
+3	POS	O
+-	POS	O
+week	POS	O
+washout	POS	O
+between	POS	O
+consecutive	POS	O
+treatments	POS	O
+.	POS	O
+Heart	POS	O
+rate	POS	O
+(	POS	O
+HR	POS	O
+)	POS	O
+,	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+(	POS	O
+MBP	POS	O
+)	POS	O
+,	POS	O
+positive	POS	O
+rate	POS	O
+of	POS	O
+increase	POS	O
+of	POS	O
+left	POS	O
+ventricular	POS	O
+pressure	POS	O
+(	POS	O
++	POS	O
+LVdP	POS	O
+/	POS	O
+dt	POS	O
+)	POS	O
+,	POS	O
+echocardiographically	POS	O
+assessed	POS	O
+left	POS	O
+ventricular	POS	O
+ejection	POS	O
+fraction	POS	O
+(	POS	O
+LVEF	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+fractional	POS	O
+shortening	POS	O
+(	POS	O
+FS	POS	O
+)	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+chronotropic	POS	O
+response	POS	O
+to	POS	O
+isoproterenol	POS	O
+and	POS	O
+exercise	POS	O
+-	POS	O
+induced	POS	O
+sympathetic	POS	O
+stimulation	POS	O
+were	POS	O
+evaluated	POS	O
+under	POS	O
+baseline	POS	O
+and	POS	O
+posttreatment	POS	O
+conditions	POS	O
+.	POS	O
+Resting	POS	O
+values	POS	O
+of	POS	O
+LVEF	POS	O
+,	POS	O
+FS	POS	O
+,	POS	O
++	POS	O
+LVdP	POS	O
+/	POS	O
+dt	POS	O
+,	POS	O
+and	POS	O
+MBP	POS	O
+remained	POS	O
+unchanged	POS	O
+whatever	POS	O
+the	POS	O
+drug	POS	O
+and	POS	O
+the	POS	O
+dosing	POS	O
+regimen	POS	O
+,	POS	O
+whereas	POS	O
+resting	POS	O
+HR	POS	O
+was	POS	O
+significantly	POS	O
+and	POS	O
+dose	POS	O
+-	POS	O
+dependently	POS	O
+lowered	POS	O
+after	POS	O
+dronedarone	POS	O
+and	POS	O
+to	POS	O
+a	POS	O
+lesser	POS	O
+extent	POS	O
+after	POS	O
+amiodarone	POS	O
+.	POS	O
+Both	POS	O
+dronedarone	POS	O
+and	POS	O
+amiodarone	POS	O
+significantly	POS	O
+reduced	POS	O
+the	POS	O
+exercise	POS	O
+-	POS	O
+induced	POS	O
+tachycardia	POS	B-NP
+and	POS	O
+,	POS	O
+at	POS	O
+the	POS	O
+highest	POS	O
+dose	POS	O
+,	POS	O
+decreased	POS	O
+the	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+tachycardia	POS	B-NP
+.	POS	O
+Thus	POS	O
+,	POS	O
+dronedarone	POS	O
+and	POS	O
+amiodarone	POS	O
+displayed	POS	O
+a	POS	O
+similar	POS	O
+level	POS	O
+of	POS	O
+antiadrenergic	POS	O
+effect	POS	O
+and	POS	O
+did	POS	O
+not	POS	O
+impair	POS	O
+the	POS	O
+resting	POS	O
+left	POS	O
+ventricular	POS	O
+function	POS	O
+.	POS	O
+Consequently	POS	O
+,	POS	O
+dronedarone	POS	O
+might	POS	O
+be	POS	O
+particularly	POS	O
+suitable	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+and	POS	O
+prevention	POS	O
+of	POS	O
+various	POS	O
+clinical	POS	O
+arrhythmias	POS	B-NP
+,	POS	O
+without	POS	O
+compromising	POS	O
+the	POS	O
+left	POS	O
+ventricular	POS	O
+function	POS	O
+.	POS	O
+Phase	POS	O
+2	POS	O
+trial	POS	O
+of	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+(	POS	O
+40	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+)	POS	O
+in	POS	O
+platinum	POS	O
+/	POS	O
+paclitaxel	POS	O
+-	POS	O
+refractory	POS	O
+ovarian	POS	O
+and	POS	O
+fallopian	POS	B-NP
+tube	POS	I-NP
+cancers	POS	I-NP
+and	POS	O
+primary	POS	O
+carcinoma	POS	B-NP
+of	POS	O
+the	POS	O
+peritoneum	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Several	POS	O
+studies	POS	O
+have	POS	O
+demonstrated	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+(	POS	O
+Doxil	POS	O
+)	POS	O
+to	POS	O
+be	POS	O
+an	POS	O
+active	POS	O
+antineoplastic	POS	O
+agent	POS	O
+in	POS	O
+platinum	POS	O
+-	POS	O
+resistant	POS	O
+ovarian	POS	B-NP
+cancer	POS	I-NP
+,	POS	O
+with	POS	O
+dose	POS	O
+limiting	POS	O
+toxicity	POS	B-NP
+of	POS	O
+the	POS	O
+standard	POS	O
+dosing	POS	O
+regimen	POS	O
+(	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+q	POS	O
+4	POS	O
+weeks	POS	O
+)	POS	O
+being	POS	O
+severe	POS	O
+erythrodysesthesia	POS	B-NP
+(	POS	O
+"	POS	B-NP
+hand	POS	I-NP
+-	POS	I-NP
+foot	POS	I-NP
+syndrome	POS	I-NP
+"	POS	O
+)	POS	O
+and	POS	O
+stomatitis	POS	B-NP
+.	POS	O
+We	POS	O
+wished	POS	O
+to	POS	O
+develop	POS	O
+a	POS	O
+more	POS	O
+tolerable	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+treatment	POS	O
+regimen	POS	O
+and	POS	O
+document	POS	O
+its	POS	O
+level	POS	O
+of	POS	O
+activity	POS	O
+in	POS	O
+a	POS	O
+well	POS	O
+-	POS	O
+defined	POS	O
+patient	POS	O
+population	POS	O
+with	POS	O
+platinum	POS	O
+/	POS	O
+paclitaxel	POS	O
+-	POS	O
+refractory	POS	O
+disease	POS	O
+.	POS	O
+METHODS	POS	O
+AND	POS	O
+MATERIALS	POS	O
+:	POS	O
+Patients	POS	O
+with	POS	O
+ovarian	POS	B-NP
+or	POS	I-NP
+fallopian	POS	I-NP
+tube	POS	I-NP
+cancers	POS	I-NP
+or	POS	O
+primary	POS	B-NP
+peritoneal	POS	I-NP
+carcinoma	POS	I-NP
+with	POS	O
+platinum	POS	O
+/	POS	O
+paclitaxel	POS	O
+-	POS	O
+refractory	POS	O
+disease	POS	O
+(	POS	O
+stable	POS	O
+or	POS	O
+progressive	POS	O
+disease	POS	O
+following	POS	O
+treatment	POS	O
+with	POS	O
+these	POS	O
+agents	POS	O
+or	POS	O
+previous	POS	O
+objective	POS	O
+response	POS	O
+<	POS	O
+3	POS	O
+months	POS	O
+in	POS	O
+duration	POS	O
+)	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+40	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+q	POS	O
+4	POS	O
+weeks	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+49	POS	O
+patients	POS	O
+(	POS	O
+median	POS	O
+age	POS	O
+:	POS	O
+60	POS	O
+;	POS	O
+range	POS	O
+41	POS	O
+-	POS	O
+81	POS	O
+)	POS	O
+entered	POS	O
+this	POS	O
+phase	POS	O
+2	POS	O
+trial	POS	O
+.	POS	O
+The	POS	O
+median	POS	O
+number	POS	O
+of	POS	O
+prior	POS	O
+regimens	POS	O
+was	POS	O
+2	POS	O
+(	POS	O
+range	POS	O
+:	POS	O
+1	POS	O
+-	POS	O
+6	POS	O
+)	POS	O
+.	POS	O
+Six	POS	O
+(	POS	O
+12	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+4	POS	O
+(	POS	O
+8	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+experienced	POS	O
+grade	POS	B-NP
+2	POS	I-NP
+hand	POS	I-NP
+-	POS	I-NP
+foot	POS	I-NP
+syndrome	POS	I-NP
+and	POS	O
+stomatitis	POS	B-NP
+,	POS	O
+respectively	POS	O
+(	POS	O
+no	POS	O
+episodes	POS	O
+of	POS	O
+grade	POS	O
+3	POS	O
+)	POS	O
+.	POS	O
+One	POS	O
+patient	POS	O
+developed	POS	O
+grade	POS	O
+3	POS	O
+diarrhea	POS	B-NP
+requiring	POS	O
+hospitalization	POS	O
+for	POS	O
+hydration	POS	O
+.	POS	O
+Six	POS	O
+(	POS	O
+12	POS	O
+%	POS	O
+)	POS	O
+individuals	POS	O
+required	POS	O
+dose	POS	O
+reductions	POS	O
+.	POS	O
+The	POS	O
+median	POS	O
+number	POS	O
+of	POS	O
+courses	POS	O
+of	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+administered	POS	O
+on	POS	O
+this	POS	O
+protocol	POS	O
+was	POS	O
+2	POS	O
+(	POS	O
+range	POS	O
+:	POS	O
+1	POS	O
+-	POS	O
+12	POS	O
+)	POS	O
+.	POS	O
+Four	POS	O
+of	POS	O
+44	POS	O
+patients	POS	O
+(	POS	O
+9	POS	O
+%	POS	O
+)	POS	O
+evaluable	POS	O
+for	POS	O
+response	POS	O
+exhibited	POS	O
+objective	POS	O
+and	POS	O
+subjective	POS	O
+evidence	POS	O
+of	POS	O
+an	POS	O
+antineoplastic	POS	O
+effect	POS	O
+of	POS	O
+therapy	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+This	POS	O
+modified	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+regimen	POS	O
+results	POS	O
+in	POS	O
+less	POS	O
+toxicity	POS	B-NP
+(	POS	O
+stomatitis	POS	B-NP
+,	POS	O
+hand	POS	B-NP
+-	POS	I-NP
+foot	POS	I-NP
+syndrome	POS	I-NP
+)	POS	O
+than	POS	O
+the	POS	O
+standard	POS	O
+FDA	POS	O
+-	POS	O
+approved	POS	O
+dose	POS	O
+schedule	POS	O
+.	POS	O
+Definite	POS	O
+,	POS	O
+although	POS	O
+limited	POS	O
+,	POS	O
+antineoplastic	POS	O
+activity	POS	O
+is	POS	O
+observed	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+well	POS	O
+-	POS	O
+defined	POS	O
+platinum	POS	O
+-	POS	O
+and	POS	O
+paclitaxel	POS	O
+-	POS	O
+refractory	POS	O
+ovarian	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+Efficacy	POS	O
+of	POS	O
+olanzapine	POS	O
+in	POS	O
+acute	POS	B-NP
+bipolar	POS	I-NP
+mania	POS	I-NP
+:	POS	O
+a	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+study	POS	O
+.	POS	O
+The	POS	O
+Olanzipine	POS	O
+HGGW	POS	O
+Study	POS	O
+Group	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+We	POS	O
+compared	POS	O
+the	POS	O
+efficacy	POS	O
+and	POS	O
+safety	POS	O
+of	POS	O
+olanzapine	POS	O
+vs	POS	O
+placebo	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+acute	POS	B-NP
+bipolar	POS	I-NP
+mania	POS	I-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Four	POS	O
+-	POS	O
+week	POS	O
+,	POS	O
+randomized	POS	O
+,	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+parallel	POS	O
+study	POS	O
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+115	POS	O
+patients	POS	O
+with	POS	O
+a	POS	O
+DSM	POS	O
+-	POS	O
+IV	POS	O
+diagnosis	POS	O
+of	POS	O
+bipolar	POS	B-NP
+disorder	POS	I-NP
+,	POS	O
+manic	POS	B-NP
+or	POS	O
+mixed	POS	O
+,	POS	O
+were	POS	O
+randomized	POS	O
+to	POS	O
+olanzapine	POS	O
+,	POS	O
+5	POS	O
+to	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+d	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+55	POS	O
+)	POS	O
+,	POS	O
+or	POS	O
+placebo	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+60	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+primary	POS	O
+efficacy	POS	O
+measure	POS	O
+was	POS	O
+the	POS	O
+Young	POS	O
+-	POS	O
+Mania	POS	O
+Rating	POS	O
+Scale	POS	O
+(	POS	O
+Y	POS	O
+-	POS	O
+MRS	POS	O
+)	POS	O
+total	POS	O
+score	POS	O
+.	POS	O
+Response	POS	O
+and	POS	O
+euthymia	POS	B-NP
+were	POS	O
+defined	POS	O
+,	POS	O
+a	POS	O
+priori	POS	O
+,	POS	O
+as	POS	O
+at	POS	O
+least	POS	O
+a	POS	O
+50	POS	O
+%	POS	O
+improvement	POS	O
+from	POS	O
+baseline	POS	O
+to	POS	O
+end	POS	O
+point	POS	O
+and	POS	O
+as	POS	O
+a	POS	O
+score	POS	O
+of	POS	O
+no	POS	O
+less	POS	O
+than	POS	O
+12	POS	O
+at	POS	O
+end	POS	O
+point	POS	O
+in	POS	O
+the	POS	O
+Y	POS	O
+-	POS	O
+MRS	POS	O
+total	POS	O
+score	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Safety	POS	O
+was	POS	O
+assessed	POS	O
+using	POS	O
+adverse	POS	O
+events	POS	O
+,	POS	O
+Extrapyramidal	POS	B-NP
+Symptom	POS	I-NP
+(	POS	O
+EPS	POS	B-NP
+)	POS	O
+rating	POS	O
+scales	POS	O
+,	POS	O
+laboratory	POS	O
+values	POS	O
+,	POS	O
+electrocardiograms	POS	O
+,	POS	O
+vital	POS	O
+signs	POS	O
+,	POS	O
+and	POS	O
+weight	POS	O
+change	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Olanzapine	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+demonstrated	POS	O
+a	POS	O
+statistically	POS	O
+significant	POS	O
+greater	POS	O
+mean	POS	O
+(	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+SD	POS	O
+)	POS	O
+improvement	POS	O
+in	POS	O
+Y	POS	O
+-	POS	O
+MRS	POS	O
+total	POS	O
+score	POS	O
+than	POS	O
+placebo	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+(	POS	O
+-	POS	O
+14	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+and	POS	O
+-	POS	O
+8	POS	O
+.	POS	O
+1	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+12	POS	O
+.	POS	O
+7	POS	O
+,	POS	O
+respectively	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+which	POS	O
+was	POS	O
+evident	POS	O
+at	POS	O
+the	POS	O
+first	POS	O
+postbaseline	POS	O
+observation	POS	O
+1	POS	O
+week	POS	O
+after	POS	O
+randomization	POS	O
+and	POS	O
+was	POS	O
+maintained	POS	O
+throughout	POS	O
+the	POS	O
+study	POS	O
+(	POS	O
+last	POS	O
+observation	POS	O
+carried	POS	O
+forward	POS	O
+)	POS	O
+.	POS	O
+Olanzapine	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+demonstrated	POS	O
+a	POS	O
+higher	POS	O
+rate	POS	O
+of	POS	O
+response	POS	O
+(	POS	O
+65	POS	O
+%	POS	O
+vs	POS	O
+43	POS	O
+%	POS	O
+,	POS	O
+respectively	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+and	POS	O
+euthymia	POS	B-NP
+(	POS	O
+61	POS	O
+%	POS	O
+vs	POS	O
+36	POS	O
+%	POS	O
+,	POS	O
+respectively	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+than	POS	O
+placebo	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+no	POS	O
+statistically	POS	O
+significant	POS	O
+differences	POS	O
+in	POS	O
+EPSs	POS	O
+between	POS	O
+groups	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+olanzapine	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+had	POS	O
+a	POS	O
+statistically	POS	O
+significant	POS	O
+greater	POS	O
+mean	POS	O
+(	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+SD	POS	O
+)	POS	O
+weight	POS	O
+gain	POS	O
+than	POS	O
+placebo	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+1	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+8	POS	O
+vs	POS	O
+0	POS	O
+.	POS	O
+45	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
+kg	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+and	POS	O
+also	POS	O
+experienced	POS	O
+more	POS	O
+treatment	POS	O
+-	POS	O
+emergent	POS	O
+somnolence	POS	B-NP
+(	POS	O
+21	POS	O
+patients	POS	O
+[	POS	O
+38	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+]	POS	O
+vs	POS	O
+5	POS	O
+[	POS	O
+8	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+]	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Olanzapine	POS	O
+demonstrated	POS	O
+greater	POS	O
+efficacy	POS	O
+than	POS	O
+placebo	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+acute	POS	O
+bipolar	POS	B-NP
+mania	POS	I-NP
+and	POS	O
+was	POS	O
+generally	POS	O
+well	POS	O
+tolerated	POS	O
+.	POS	O
+The	POS	O
+effect	POS	O
+of	POS	O
+pupil	POS	O
+dilation	POS	O
+with	POS	O
+tropicamide	POS	O
+on	POS	O
+vision	POS	O
+and	POS	O
+driving	POS	O
+simulator	POS	O
+performance	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+To	POS	O
+assess	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+pupil	POS	O
+dilation	POS	O
+on	POS	O
+vision	POS	O
+and	POS	O
+driving	POS	O
+ability	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+A	POS	O
+series	POS	O
+of	POS	O
+tests	POS	O
+on	POS	O
+various	POS	O
+parameters	POS	O
+of	POS	O
+visual	POS	O
+function	POS	O
+and	POS	O
+driving	POS	O
+simulator	POS	O
+performance	POS	O
+were	POS	O
+performed	POS	O
+on	POS	O
+12	POS	O
+healthy	POS	O
+drivers	POS	O
+,	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+pupil	POS	O
+dilation	POS	O
+using	POS	O
+guttae	POS	O
+tropicamide	POS	O
+1	POS	O
+%	POS	O
+.	POS	O
+A	POS	O
+driving	POS	O
+simulator	POS	O
+(	POS	O
+Transport	POS	O
+Research	POS	O
+Laboratory	POS	O
+)	POS	O
+was	POS	O
+used	POS	O
+to	POS	O
+measure	POS	O
+reaction	POS	O
+time	POS	O
+(	POS	O
+RT	POS	O
+)	POS	O
+,	POS	O
+speed	POS	O
+maintenance	POS	O
+and	POS	O
+steering	POS	O
+accuracy	POS	O
+.	POS	O
+Tests	POS	O
+of	POS	O
+basic	POS	O
+visual	POS	O
+function	POS	O
+included	POS	O
+high	POS	O
+-	POS	O
+and	POS	O
+low	POS	O
+-	POS	O
+contrast	POS	O
+visual	POS	O
+acuity	POS	O
+(	POS	O
+HCVA	POS	O
+and	POS	O
+LCVA	POS	O
+)	POS	O
+,	POS	O
+Pelli	POS	O
+-	POS	O
+Robson	POS	O
+contrast	POS	O
+threshold	POS	O
+(	POS	O
+CT	POS	O
+)	POS	O
+and	POS	O
+Goldmann	POS	O
+perimetry	POS	O
+(	POS	O
+FIELDS	POS	O
+)	POS	O
+.	POS	O
+Useful	POS	O
+Field	POS	O
+of	POS	O
+View	POS	O
+(	POS	O
+UFOV	POS	O
+-	POS	O
+-	POS	O
+a	POS	O
+test	POS	O
+of	POS	O
+visual	POS	O
+attention	POS	O
+)	POS	O
+was	POS	O
+also	POS	O
+undertaken	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+differences	POS	O
+in	POS	O
+the	POS	O
+pre	POS	O
+-	POS	O
+and	POS	O
+post	POS	O
+-	POS	O
+dilatation	POS	O
+measurements	POS	O
+were	POS	O
+tested	POS	O
+for	POS	O
+statistical	POS	O
+significance	POS	O
+at	POS	O
+the	POS	O
+95	POS	O
+%	POS	O
+level	POS	O
+using	POS	O
+one	POS	O
+-	POS	O
+tail	POS	O
+paired	POS	O
+t	POS	O
+-	POS	O
+tests	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Pupillary	POS	O
+dilation	POS	O
+resulted	POS	O
+in	POS	O
+a	POS	O
+statistically	POS	O
+significant	POS	O
+deterioration	POS	O
+in	POS	O
+CT	POS	O
+and	POS	O
+HCVA	POS	O
+only	POS	O
+.	POS	O
+Five	POS	O
+of	POS	O
+12	POS	O
+drivers	POS	O
+also	POS	O
+exhibited	POS	O
+deterioration	POS	O
+in	POS	O
+LCVA	POS	O
+,	POS	O
+CT	POS	O
+and	POS	O
+RT	POS	O
+.	POS	O
+Little	POS	O
+evidence	POS	O
+emerged	POS	O
+for	POS	O
+deterioration	POS	O
+in	POS	O
+FIELDS	POS	O
+and	POS	O
+UFOV	POS	O
+.	POS	O
+Also	POS	O
+,	POS	O
+7	POS	O
+of	POS	O
+12	POS	O
+drivers	POS	O
+appeared	POS	O
+to	POS	O
+adjust	POS	O
+their	POS	O
+driving	POS	O
+behaviour	POS	O
+by	POS	O
+reducing	POS	O
+their	POS	O
+speed	POS	O
+on	POS	O
+the	POS	O
+driving	POS	O
+simulator	POS	O
+,	POS	O
+leading	POS	O
+to	POS	O
+improved	POS	O
+steering	POS	O
+accuracy	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Pupillary	POS	O
+dilation	POS	O
+may	POS	O
+lead	POS	O
+to	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+vision	POS	O
+and	POS	O
+daylight	POS	O
+driving	POS	O
+performance	POS	O
+in	POS	O
+young	POS	O
+people	POS	O
+.	POS	O
+A	POS	O
+larger	POS	O
+study	POS	O
+,	POS	O
+including	POS	O
+a	POS	O
+broader	POS	O
+spectrum	POS	O
+of	POS	O
+subjects	POS	O
+,	POS	O
+is	POS	O
+warranted	POS	O
+before	POS	O
+guidelines	POS	O
+can	POS	O
+be	POS	O
+recommended	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+isotretinoin	POS	O
+embryopathy	POS	B-NP
+with	POS	O
+bilateral	POS	B-NP
+anotia	POS	I-NP
+and	POS	O
+Taussig	POS	B-NP
+-	POS	I-NP
+Bing	POS	I-NP
+malformation	POS	I-NP
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+newborn	POS	O
+infant	POS	O
+with	POS	O
+multiple	POS	B-NP
+congenital	POS	I-NP
+anomalies	POS	I-NP
+(	POS	O
+anotia	POS	B-NP
+and	POS	O
+Taussig	POS	B-NP
+-	POS	I-NP
+Bing	POS	I-NP
+malformation	POS	I-NP
+)	POS	O
+due	POS	O
+to	POS	O
+exposure	POS	O
+to	POS	O
+isotretinoin	POS	O
+within	POS	O
+the	POS	O
+first	POS	O
+trimester	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+paper	POS	O
+we	POS	O
+aim	POS	O
+to	POS	O
+draw	POS	O
+to	POS	O
+the	POS	O
+fact	POS	O
+that	POS	O
+caution	POS	O
+is	POS	O
+needed	POS	O
+when	POS	O
+prescribing	POS	O
+vitamin	POS	O
+A	POS	O
+-	POS	O
+containing	POS	O
+drugs	POS	O
+to	POS	O
+women	POS	O
+of	POS	O
+childbearing	POS	O
+years	POS	O
+.	POS	O
+Effect	POS	O
+of	POS	O
+methoxamine	POS	O
+on	POS	O
+maximum	POS	O
+urethral	POS	O
+pressure	POS	O
+in	POS	O
+women	POS	O
+with	POS	O
+genuine	POS	O
+stress	POS	B-NP
+incontinence	POS	I-NP
+:	POS	O
+a	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+,	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+crossover	POS	O
+study	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+the	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+potential	POS	O
+role	POS	O
+for	POS	O
+a	POS	O
+selective	POS	O
+alpha1	POS	O
+-	POS	O
+adrenoceptor	POS	O
+agonist	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+urinary	POS	B-NP
+stress	POS	I-NP
+incontinence	POS	I-NP
+.	POS	O
+A	POS	O
+randomised	POS	O
+,	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+,	POS	O
+crossover	POS	O
+study	POS	O
+design	POS	O
+was	POS	O
+employed	POS	O
+.	POS	O
+Half	POS	O
+log	POS	O
+incremental	POS	O
+doses	POS	O
+of	POS	O
+intravenous	POS	O
+methoxamine	POS	O
+or	POS	O
+placebo	POS	O
+(	POS	O
+saline	POS	O
+)	POS	O
+were	POS	O
+administered	POS	O
+to	POS	O
+a	POS	O
+group	POS	O
+of	POS	O
+women	POS	O
+with	POS	O
+genuine	POS	O
+stress	POS	B-NP
+incontinence	POS	I-NP
+while	POS	O
+measuring	POS	O
+maximum	POS	O
+urethral	POS	O
+pressure	POS	O
+(	POS	O
+MUP	POS	O
+)	POS	O
+,	POS	O
+blood	POS	O
+pressure	POS	O
+,	POS	O
+heart	POS	O
+rate	POS	O
+,	POS	O
+and	POS	O
+symptomatic	POS	O
+side	POS	O
+effects	POS	O
+.	POS	O
+Methoxamine	POS	O
+evoked	POS	O
+non	POS	O
+-	POS	O
+significant	POS	O
+increases	POS	O
+in	POS	O
+MUP	POS	O
+and	POS	O
+diastolic	POS	O
+blood	POS	O
+pressure	POS	O
+but	POS	O
+caused	POS	O
+a	POS	O
+significant	POS	O
+rise	POS	O
+in	POS	O
+systolic	POS	O
+blood	POS	O
+pressure	POS	O
+and	POS	O
+significant	POS	O
+fall	POS	O
+in	POS	O
+heart	POS	O
+rate	POS	O
+at	POS	O
+maximum	POS	O
+dosage	POS	O
+.	POS	O
+Systemic	POS	O
+side	POS	O
+effects	POS	O
+including	POS	O
+piloerection	POS	B-NP
+,	POS	O
+headache	POS	B-NP
+,	POS	O
+and	POS	O
+cold	POS	B-NP
+extremities	POS	I-NP
+were	POS	O
+experienced	POS	O
+in	POS	O
+all	POS	O
+subjects	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+the	POS	O
+clinical	POS	O
+usefulness	POS	O
+of	POS	O
+direct	POS	O
+,	POS	O
+peripherally	POS	O
+acting	POS	O
+sub	POS	O
+-	POS	O
+type	POS	O
+-	POS	O
+selective	POS	O
+alpha1	POS	O
+-	POS	O
+adrenoceptor	POS	O
+agonists	POS	O
+in	POS	O
+the	POS	O
+medical	POS	O
+treatment	POS	O
+of	POS	O
+stress	POS	B-NP
+incontinence	POS	I-NP
+may	POS	O
+be	POS	O
+limited	POS	O
+by	POS	O
+associated	POS	O
+piloerection	POS	O
+and	POS	O
+cardiovascular	POS	B-NP
+side	POS	I-NP
+effects	POS	I-NP
+.	POS	O
+Hyperglycemic	POS	B-NP
+effect	POS	O
+of	POS	O
+amino	POS	O
+compounds	POS	O
+structurally	POS	O
+related	POS	O
+to	POS	O
+caproate	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+chronic	POS	O
+feeding	POS	O
+of	POS	O
+small	POS	O
+amounts	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+-	POS	O
+3	POS	O
+%	POS	O
+of	POS	O
+diet	POS	O
+weight	POS	O
+)	POS	O
+of	POS	O
+certain	POS	O
+amino	POS	O
+derivatives	POS	O
+of	POS	O
+caproate	POS	O
+resulted	POS	O
+in	POS	O
+hyperglycemia	POS	B-NP
+,	POS	O
+an	POS	O
+elevated	POS	O
+glucose	POS	O
+tolerance	POS	O
+curve	POS	O
+and	POS	O
+,	POS	O
+occasionally	POS	O
+,	POS	O
+glucosuria	POS	B-NP
+.	POS	O
+Effective	POS	O
+compounds	POS	O
+included	POS	O
+norleucine	POS	O
+,	POS	O
+norvaline	POS	O
+,	POS	O
+glutamate	POS	O
+,	POS	O
+epsilon	POS	O
+-	POS	O
+aminocaproate	POS	O
+,	POS	O
+methionine	POS	O
+,	POS	O
+and	POS	O
+leucine	POS	O
+.	POS	O
+Toleration	POS	O
+of	POS	O
+high	POS	O
+doses	POS	O
+of	POS	O
+angiotensin	POS	O
+-	POS	O
+converting	POS	O
+enzyme	POS	O
+inhibitors	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+chronic	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+:	POS	O
+results	POS	O
+from	POS	O
+the	POS	O
+ATLAS	POS	O
+trial	POS	O
+.	POS	O
+The	POS	O
+Assessment	POS	O
+of	POS	O
+Treatment	POS	O
+with	POS	O
+Lisinopril	POS	O
+and	POS	O
+Survival	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Treatment	POS	O
+with	POS	O
+angiotensin	POS	O
+-	POS	O
+converting	POS	O
+enzyme	POS	O
+(	POS	O
+ACE	POS	O
+)	POS	O
+inhibitors	POS	O
+reduces	POS	O
+mortality	POS	O
+and	POS	O
+morbidity	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+chronic	POS	B-NP
+heart	POS	I-NP
+failure	POS	I-NP
+(	POS	O
+CHF	POS	B-NP
+)	POS	O
+,	POS	O
+but	POS	O
+most	POS	O
+affected	POS	O
+patients	POS	O
+are	POS	O
+not	POS	O
+receiving	POS	O
+these	POS	O
+agents	POS	O
+or	POS	O
+are	POS	O
+being	POS	O
+treated	POS	O
+with	POS	O
+doses	POS	O
+lower	POS	O
+than	POS	O
+those	POS	O
+found	POS	O
+to	POS	O
+be	POS	O
+efficacious	POS	O
+in	POS	O
+trials	POS	O
+,	POS	O
+primarily	POS	O
+because	POS	O
+of	POS	O
+concerns	POS	O
+about	POS	O
+the	POS	O
+safety	POS	O
+and	POS	O
+tolerability	POS	O
+of	POS	O
+these	POS	O
+agents	POS	O
+,	POS	O
+especially	POS	O
+at	POS	O
+the	POS	O
+recommended	POS	O
+doses	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+examines	POS	O
+the	POS	O
+safety	POS	O
+and	POS	O
+tolerability	POS	O
+of	POS	O
+high	POS	O
+-	POS	O
+compared	POS	O
+with	POS	O
+low	POS	O
+-	POS	O
+dose	POS	O
+lisinopril	POS	O
+in	POS	O
+CHF	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+The	POS	O
+Assessment	POS	O
+of	POS	O
+Lisinopril	POS	O
+and	POS	O
+Survival	POS	O
+study	POS	O
+was	POS	O
+a	POS	O
+multicenter	POS	O
+,	POS	O
+randomized	POS	O
+,	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+trial	POS	O
+in	POS	O
+which	POS	O
+patients	POS	O
+with	POS	O
+or	POS	O
+without	POS	O
+previous	POS	O
+ACE	POS	O
+inhibitor	POS	O
+treatment	POS	O
+were	POS	O
+stabilized	POS	O
+receiving	POS	O
+medium	POS	O
+-	POS	O
+dose	POS	O
+lisinopril	POS	O
+(	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+or	POS	O
+15	POS	O
+.	POS	O
+0	POS	O
+mg	POS	O
+once	POS	O
+daily	POS	O
+[	POS	O
+OD	POS	O
+]	POS	O
+)	POS	O
+for	POS	O
+2	POS	O
+to	POS	O
+4	POS	O
+weeks	POS	O
+and	POS	O
+then	POS	O
+randomized	POS	O
+to	POS	O
+high	POS	O
+-	POS	O
+(	POS	O
+35	POS	O
+.	POS	O
+0	POS	O
+or	POS	O
+32	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+OD	POS	O
+)	POS	O
+or	POS	O
+low	POS	O
+-	POS	O
+dose	POS	O
+(	POS	O
+5	POS	O
+.	POS	O
+0	POS	O
+or	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+OD	POS	O
+)	POS	O
+groups	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+New	POS	O
+York	POS	O
+Heart	POS	O
+Association	POS	O
+classes	POS	O
+II	POS	O
+to	POS	O
+IV	POS	O
+CHF	POS	B-NP
+and	POS	O
+left	POS	O
+ventricular	POS	O
+ejection	POS	O
+fractions	POS	O
+of	POS	O
+no	POS	O
+greater	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+30	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+3164	POS	O
+)	POS	O
+were	POS	O
+randomized	POS	O
+and	POS	O
+followed	POS	O
+up	POS	O
+for	POS	O
+a	POS	O
+median	POS	O
+of	POS	O
+46	POS	O
+months	POS	O
+.	POS	O
+We	POS	O
+examined	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+adverse	POS	O
+events	POS	O
+and	POS	O
+the	POS	O
+need	POS	O
+for	POS	O
+discontinuation	POS	O
+and	POS	O
+dose	POS	O
+reduction	POS	O
+during	POS	O
+treatment	POS	O
+,	POS	O
+with	POS	O
+a	POS	O
+focus	POS	O
+on	POS	O
+hypotension	POS	B-NP
+and	POS	O
+renal	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Of	POS	O
+405	POS	O
+patients	POS	O
+not	POS	O
+previously	POS	O
+receiving	POS	O
+an	POS	O
+ACE	POS	O
+inhibitor	POS	O
+,	POS	O
+doses	POS	O
+in	POS	O
+only	POS	O
+4	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+could	POS	O
+not	POS	O
+be	POS	O
+titrated	POS	O
+to	POS	O
+the	POS	O
+medium	POS	O
+doses	POS	O
+required	POS	O
+for	POS	O
+randomization	POS	O
+because	POS	O
+of	POS	O
+symptoms	POS	O
+possibly	POS	O
+related	POS	O
+to	POS	O
+hypotension	POS	B-NP
+(	POS	O
+2	POS	O
+.	POS	O
+0	POS	O
+%	POS	O
+)	POS	O
+or	POS	O
+because	POS	O
+of	POS	O
+renal	POS	B-NP
+dysfunction	POS	I-NP
+or	POS	O
+hyperkalemia	POS	B-NP
+(	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Doses	POS	O
+in	POS	O
+more	POS	O
+than	POS	O
+90	POS	O
+%	POS	O
+of	POS	O
+randomized	POS	O
+patients	POS	O
+in	POS	O
+the	POS	O
+high	POS	O
+-	POS	O
+and	POS	O
+low	POS	O
+-	POS	O
+dose	POS	O
+groups	POS	O
+were	POS	O
+titrated	POS	O
+to	POS	O
+their	POS	O
+assigned	POS	O
+target	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+mean	POS	O
+doses	POS	O
+of	POS	O
+blinded	POS	O
+medication	POS	O
+in	POS	O
+both	POS	O
+groups	POS	O
+remained	POS	O
+similar	POS	O
+throughout	POS	O
+the	POS	O
+study	POS	O
+.	POS	O
+Withdrawals	POS	B-NP
+occurred	POS	O
+in	POS	O
+27	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+high	POS	O
+-	POS	O
+and	POS	O
+30	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+low	POS	O
+-	POS	O
+dose	POS	O
+groups	POS	O
+.	POS	O
+Subgroups	POS	O
+presumed	POS	O
+to	POS	O
+be	POS	O
+at	POS	O
+higher	POS	O
+risk	POS	O
+for	POS	O
+ACE	POS	O
+inhibitor	POS	O
+intolerance	POS	O
+(	POS	O
+blood	POS	O
+pressure	POS	O
+,	POS	O
+<	POS	O
+120	POS	O
+mm	POS	O
+Hg	POS	O
+;	POS	O
+creatinine	POS	O
+,	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+132	POS	O
+.	POS	O
+6	POS	O
+micromol	POS	O
+/	POS	O
+L	POS	O
+[	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+]	POS	O
+;	POS	O
+age	POS	O
+,	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+70	POS	O
+years	POS	O
+;	POS	O
+and	POS	O
+patients	POS	O
+with	POS	O
+diabetes	POS	B-NP
+)	POS	O
+generally	POS	O
+tolerated	POS	O
+the	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+strategy	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+These	POS	O
+findings	POS	O
+demonstrate	POS	O
+that	POS	O
+ACE	POS	O
+inhibitor	POS	O
+therapy	POS	O
+in	POS	O
+most	POS	O
+patients	POS	O
+with	POS	O
+CHF	POS	B-NP
+can	POS	O
+be	POS	O
+successfully	POS	O
+titrated	POS	O
+to	POS	O
+and	POS	O
+maintained	POS	O
+at	POS	O
+high	POS	O
+doses	POS	O
+,	POS	O
+and	POS	O
+that	POS	O
+more	POS	O
+aggressive	POS	O
+use	POS	O
+of	POS	O
+these	POS	O
+agents	POS	O
+is	POS	O
+warranted	POS	O
+.	POS	O
+Cocaine	POS	O
+,	POS	O
+ethanol	POS	O
+,	POS	O
+and	POS	O
+cocaethylene	POS	O
+cardiotoxity	POS	O
+in	POS	O
+an	POS	O
+animal	POS	O
+model	POS	O
+of	POS	O
+cocaine	POS	O
+and	POS	O
+ethanol	POS	O
+abuse	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+Simultaneous	POS	O
+abuse	POS	O
+of	POS	O
+cocaine	POS	O
+and	POS	O
+ethanol	POS	O
+affects	POS	O
+12	POS	O
+million	POS	O
+Americans	POS	O
+annually	POS	O
+.	POS	O
+In	POS	O
+combination	POS	O
+,	POS	O
+these	POS	O
+substances	POS	O
+are	POS	O
+substantially	POS	O
+more	POS	O
+toxic	POS	O
+than	POS	O
+either	POS	O
+drug	POS	O
+alone	POS	O
+.	POS	O
+Their	POS	O
+combined	POS	O
+cardiac	POS	B-NP
+toxicity	POS	I-NP
+may	POS	O
+be	POS	O
+due	POS	O
+to	POS	O
+independent	POS	O
+effects	POS	O
+of	POS	O
+each	POS	O
+drug	POS	O
+;	POS	O
+however	POS	O
+,	POS	O
+they	POS	O
+may	POS	O
+also	POS	O
+be	POS	O
+due	POS	O
+to	POS	O
+cocaethylene	POS	O
+(	POS	O
+CE	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+cocaine	POS	O
+metabolite	POS	O
+formed	POS	O
+only	POS	O
+in	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+ethanol	POS	O
+.	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+delineate	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+CE	POS	O
+in	POS	O
+the	POS	O
+combined	POS	O
+cardiotoxicity	POS	B-NP
+of	POS	O
+cocaine	POS	O
+and	POS	O
+ethanol	POS	O
+in	POS	O
+a	POS	O
+model	POS	O
+simulating	POS	O
+their	POS	O
+abuse	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Twenty	POS	O
+-	POS	O
+three	POS	O
+dogs	POS	O
+were	POS	O
+randomized	POS	O
+to	POS	O
+receive	POS	O
+either	POS	O
+1	POS	O
+)	POS	O
+three	POS	O
+intravenous	POS	O
+(	POS	O
+IV	POS	O
+)	POS	O
+boluses	POS	O
+of	POS	O
+cocaine	POS	O
+7	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+with	POS	O
+ethanol	POS	O
+(	POS	O
+1	POS	O
+g	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+as	POS	O
+an	POS	O
+IV	POS	O
+infusion	POS	O
+(	POS	O
+C	POS	O
++	POS	O
+E	POS	O
+,	POS	O
+n	POS	O
+=	POS	O
+8	POS	O
+)	POS	O
+,	POS	O
+2	POS	O
+)	POS	O
+three	POS	O
+cocaine	POS	O
+boluses	POS	O
+only	POS	O
+(	POS	O
+C	POS	O
+,	POS	O
+n	POS	O
+=	POS	O
+6	POS	O
+)	POS	O
+,	POS	O
+3	POS	O
+)	POS	O
+ethanol	POS	O
+infusion	POS	O
+only	POS	O
+(	POS	O
+E	POS	O
+,	POS	O
+n	POS	O
+=	POS	O
+5	POS	O
+)	POS	O
+,	POS	O
+or	POS	O
+4	POS	O
+)	POS	O
+placebo	POS	O
+boluses	POS	O
+and	POS	O
+infusion	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+4	POS	O
+)	POS	O
+.	POS	O
+Hemodynamic	POS	O
+measurements	POS	O
+,	POS	O
+electrocardiograms	POS	O
+,	POS	O
+and	POS	O
+serum	POS	O
+drug	POS	O
+concentrations	POS	O
+were	POS	O
+obtained	POS	O
+at	POS	O
+baseline	POS	O
+,	POS	O
+and	POS	O
+then	POS	O
+at	POS	O
+fixed	POS	O
+time	POS	O
+intervals	POS	O
+after	POS	O
+each	POS	O
+drug	POS	O
+was	POS	O
+administered	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Two	POS	O
+of	POS	O
+eight	POS	O
+dogs	POS	O
+in	POS	O
+the	POS	O
+C	POS	O
++	POS	O
+E	POS	O
+group	POS	O
+experienced	POS	O
+cardiovascular	POS	B-NP
+collapse	POS	I-NP
+.	POS	O
+The	POS	O
+most	POS	O
+dramatic	POS	O
+hemodynamic	POS	O
+changes	POS	O
+occurred	POS	O
+after	POS	O
+each	POS	O
+cocaine	POS	O
+bolus	POS	O
+in	POS	O
+the	POS	O
+C	POS	O
++	POS	O
+E	POS	O
+and	POS	O
+C	POS	O
+only	POS	O
+groups	POS	O
+;	POS	O
+however	POS	O
+,	POS	O
+persistent	POS	O
+hemodynamic	POS	O
+changes	POS	O
+occurred	POS	O
+in	POS	O
+the	POS	O
+C	POS	O
++	POS	O
+E	POS	O
+group	POS	O
+.	POS	O
+Peak	POS	O
+CE	POS	O
+levels	POS	O
+were	POS	O
+associated	POS	O
+with	POS	O
+a	POS	O
+45	POS	O
+%	POS	O
+(	POS	O
+SD	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+22	POS	O
+%	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+22	POS	O
+%	POS	O
+to	POS	O
+69	POS	O
+%	POS	O
+)	POS	O
+decrease	POS	O
+in	POS	O
+cardiac	POS	O
+output	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+56	POS	O
+%	POS	O
+(	POS	O
+SD	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+23	POS	O
+%	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+32	POS	O
+%	POS	O
+to	POS	O
+80	POS	O
+%	POS	O
+)	POS	O
+decrease	POS	O
+in	POS	O
+dP	POS	O
+/	POS	O
+dt	POS	O
+(	POS	O
+max	POS	O
+)	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+.	POS	O
+006	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+23	POS	O
+%	POS	O
+(	POS	O
+SD	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+15	POS	O
+%	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+7	POS	O
+%	POS	O
+to	POS	O
+49	POS	O
+%	POS	O
+)	POS	O
+decrease	POS	O
+in	POS	O
+SVO	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+025	POS	O
+)	POS	O
+.	POS	O
+Ventricular	POS	B-NP
+arrhythmias	POS	I-NP
+were	POS	O
+primarily	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+C	POS	O
++	POS	O
+E	POS	O
+group	POS	O
+,	POS	O
+in	POS	O
+which	POS	O
+four	POS	O
+of	POS	O
+eight	POS	O
+dogs	POS	O
+experienced	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Cocaine	POS	O
+and	POS	O
+ethanol	POS	O
+in	POS	O
+combination	POS	O
+were	POS	O
+more	POS	O
+toxic	POS	O
+than	POS	O
+either	POS	O
+substance	POS	O
+alone	POS	O
+.	POS	O
+Co	POS	O
+-	POS	O
+administration	POS	O
+resulted	POS	O
+in	POS	O
+prolonged	POS	O
+cardiac	POS	B-NP
+toxicity	POS	I-NP
+and	POS	O
+was	POS	O
+dysrhythmogenic	POS	O
+.	POS	O
+Peak	POS	O
+serum	POS	O
+cocaethylene	POS	O
+concentrations	POS	O
+were	POS	O
+associated	POS	O
+with	POS	O
+prolonged	POS	O
+myocardial	POS	B-NP
+depression	POS	I-NP
+.	POS	O
+Worsening	POS	O
+of	POS	O
+Parkinsonism	POS	B-NP
+after	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+veralipride	POS	O
+for	POS	O
+treatment	POS	O
+of	POS	O
+menopause	POS	O
+:	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+We	POS	O
+describe	POS	O
+a	POS	O
+female	POS	O
+patient	POS	O
+with	POS	O
+stable	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+who	POS	O
+has	POS	O
+shown	POS	O
+a	POS	O
+marked	POS	O
+worsening	POS	O
+of	POS	O
+her	POS	O
+motor	POS	O
+functions	POS	O
+following	POS	O
+therapy	POS	O
+of	POS	O
+menopause	POS	O
+related	POS	O
+symptoms	POS	O
+with	POS	O
+veralipride	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+the	POS	O
+improvement	POS	O
+of	POS	O
+her	POS	O
+symptoms	POS	O
+back	POS	O
+to	POS	O
+baseline	POS	O
+after	POS	O
+discontinuation	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+.	POS	O
+We	POS	O
+emphasize	POS	O
+the	POS	O
+anti	POS	O
+-	POS	O
+dopaminergic	POS	O
+effect	POS	O
+of	POS	O
+veralipride	POS	O
+.	POS	O
+Viracept	POS	O
+and	POS	O
+irregular	POS	O
+heartbeat	POS	O
+warning	POS	O
+.	POS	O
+A	POS	O
+group	POS	O
+of	POS	O
+doctors	POS	O
+in	POS	O
+Boston	POS	O
+warn	POS	O
+that	POS	O
+the	POS	O
+protease	POS	O
+inhibitor	POS	O
+Viracept	POS	O
+may	POS	O
+cause	POS	O
+an	POS	O
+irregular	POS	O
+heart	POS	O
+beat	POS	O
+,	POS	O
+known	POS	O
+as	POS	O
+bradycardia	POS	B-NP
+,	POS	O
+in	POS	O
+people	POS	O
+with	POS	O
+HIV	POS	B-NP
+.	POS	O
+Bradycardia	POS	B-NP
+occurred	POS	O
+in	POS	O
+a	POS	O
+45	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+male	POS	O
+patient	POS	O
+who	POS	O
+was	POS	O
+Viracept	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+other	POS	O
+anti	POS	O
+-	POS	O
+HIV	POS	O
+drugs	POS	O
+.	POS	O
+The	POS	O
+symptoms	POS	O
+ceased	POS	O
+after	POS	O
+switching	POS	O
+to	POS	O
+another	POS	O
+drug	POS	O
+combination	POS	O
+.	POS	O
+Frequency	POS	O
+of	POS	O
+appearance	POS	O
+of	POS	O
+myeloperoxidase	POS	O
+-	POS	O
+antineutrophil	POS	O
+cytoplasmic	POS	O
+antibody	POS	O
+(	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	O
+)	POS	O
+in	POS	O
+Graves	POS	B-NP
+'	POS	I-NP
+disease	POS	I-NP
+patients	POS	O
+treated	POS	O
+with	POS	O
+propylthiouracil	POS	O
+and	POS	O
+the	POS	O
+relationship	POS	O
+between	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	B-NP
+and	POS	O
+clinical	POS	O
+manifestations	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+Myeloperoxidase	POS	O
+antineutrophil	POS	O
+cytoplasmic	POS	O
+antibody	POS	O
+(	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	O
+)	POS	O
+-	POS	O
+positive	POS	O
+vasculitis	POS	B-NP
+has	POS	O
+been	POS	O
+reported	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+Graves	POS	B-NP
+'	POS	I-NP
+disease	POS	I-NP
+who	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+propylthiouracil	POS	O
+(	POS	O
+PTU	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+appearance	POS	O
+of	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	B-NP
+in	POS	O
+these	POS	O
+cases	POS	O
+was	POS	O
+suspected	POS	O
+of	POS	O
+being	POS	O
+related	POS	O
+to	POS	O
+PTU	POS	B-NP
+because	POS	O
+the	POS	O
+titres	POS	O
+of	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	O
+decreased	POS	O
+when	POS	O
+PTU	POS	B-NP
+was	POS	O
+stopped	POS	O
+.	POS	O
+Nevertheless	POS	O
+,	POS	O
+there	POS	O
+have	POS	O
+been	POS	O
+no	POS	O
+studies	POS	O
+on	POS	O
+the	POS	O
+temporal	POS	O
+relationship	POS	O
+between	POS	O
+the	POS	O
+appearance	POS	O
+of	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	B-NP
+and	POS	O
+vasculitis	POS	B-NP
+during	POS	O
+PTU	POS	O
+therapy	POS	O
+,	POS	O
+or	POS	O
+on	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	B-NP
+in	POS	O
+untreated	POS	O
+Graves	POS	B-NP
+'	POS	I-NP
+disease	POS	I-NP
+patients	POS	O
+.	POS	O
+Therefore	POS	O
+,	POS	O
+we	POS	O
+sought	POS	O
+to	POS	O
+address	POS	O
+these	POS	O
+parameters	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+Graves	POS	B-NP
+'	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+PATIENTS	POS	O
+:	POS	O
+We	POS	O
+investigated	POS	O
+102	POS	O
+untreated	POS	O
+patients	POS	O
+with	POS	O
+hyperthyroidism	POS	B-NP
+due	POS	O
+to	POS	O
+Graves	POS	B-NP
+'	POS	I-NP
+disease	POS	I-NP
+for	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	B-NP
+,	POS	O
+and	POS	O
+for	POS	O
+the	POS	O
+development	POS	O
+vasculitis	POS	B-NP
+after	POS	O
+starting	POS	O
+PTU	POS	O
+therapy	POS	O
+.	POS	O
+Twenty	POS	O
+-	POS	O
+nine	POS	O
+of	POS	O
+them	POS	O
+were	POS	O
+later	POS	O
+excluded	POS	O
+because	POS	O
+of	POS	O
+adverse	POS	O
+effects	POS	O
+of	POS	O
+PTU	POS	B-NP
+or	POS	O
+because	POS	O
+the	POS	O
+observation	POS	O
+period	POS	O
+was	POS	O
+less	POS	O
+than	POS	O
+3	POS	O
+months	POS	O
+.	POS	O
+The	POS	O
+remaining	POS	O
+73	POS	O
+patients	POS	O
+(	POS	O
+55	POS	O
+women	POS	O
+and	POS	O
+18	POS	O
+men	POS	O
+)	POS	O
+,	POS	O
+all	POS	O
+of	POS	O
+whom	POS	O
+were	POS	O
+examined	POS	O
+for	POS	O
+more	POS	O
+than	POS	O
+3	POS	O
+months	POS	O
+,	POS	O
+were	POS	O
+adopted	POS	O
+as	POS	O
+the	POS	O
+subjects	POS	O
+of	POS	O
+the	POS	O
+investigation	POS	O
+.	POS	O
+The	POS	O
+median	POS	O
+observation	POS	O
+period	POS	O
+was	POS	O
+23	POS	O
+.	POS	O
+6	POS	O
+months	POS	O
+(	POS	O
+range	POS	O
+:	POS	O
+3	POS	O
+-	POS	O
+37	POS	O
+months	POS	O
+)	POS	O
+.	POS	O
+MEASUREMENTS	POS	O
+:	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	B-NP
+was	POS	O
+measured	POS	O
+at	POS	O
+intervals	POS	O
+of	POS	O
+2	POS	O
+-	POS	O
+6	POS	O
+months	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Before	POS	O
+treatment	POS	O
+,	POS	O
+the	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	O
+titres	POS	O
+of	POS	O
+all	POS	O
+102	POS	O
+untreated	POS	O
+Graves	POS	B-NP
+'	POS	I-NP
+disease	POS	I-NP
+patients	POS	O
+were	POS	O
+within	POS	O
+the	POS	O
+reference	POS	O
+range	POS	O
+(	POS	O
+below	POS	O
+10	POS	O
+U	POS	O
+/	POS	O
+ml	POS	O
+)	POS	O
+.	POS	O
+Three	POS	O
+(	POS	O
+4	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+)	POS	O
+of	POS	O
+the	POS	O
+73	POS	O
+patients	POS	O
+were	POS	O
+positive	POS	O
+for	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	B-NP
+at	POS	O
+13	POS	O
+,	POS	O
+16	POS	O
+and	POS	O
+17	POS	O
+months	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+after	POS	O
+the	POS	O
+start	POS	O
+of	POS	O
+PTU	POS	O
+therapy	POS	O
+.	POS	O
+In	POS	O
+two	POS	O
+of	POS	O
+them	POS	O
+,	POS	O
+the	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	O
+titres	POS	O
+transiently	POS	O
+increased	POS	O
+to	POS	O
+12	POS	O
+.	POS	O
+8	POS	O
+and	POS	O
+15	POS	O
+.	POS	O
+0	POS	O
+U	POS	O
+/	POS	O
+ml	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+despite	POS	O
+continued	POS	O
+PTU	POS	O
+therapy	POS	O
+,	POS	O
+but	POS	O
+no	POS	O
+vasculitic	POS	B-NP
+disorders	POS	I-NP
+developed	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+third	POS	O
+patient	POS	O
+,	POS	O
+the	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	O
+titre	POS	O
+increased	POS	O
+to	POS	O
+204	POS	O
+U	POS	O
+/	POS	O
+ml	POS	O
+and	POS	O
+she	POS	O
+developed	POS	O
+a	POS	O
+higher	POS	O
+fever	POS	B-NP
+,	POS	O
+oral	POS	B-NP
+ulcers	POS	I-NP
+and	POS	O
+polyarthralgia	POS	B-NP
+,	POS	O
+but	POS	O
+the	POS	O
+symptoms	POS	O
+resolved	POS	O
+2	POS	O
+weeks	POS	O
+after	POS	O
+stopping	POS	O
+PTU	POS	O
+therapy	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	O
+titre	POS	O
+decreased	POS	O
+to	POS	O
+20	POS	O
+.	POS	O
+7	POS	O
+U	POS	O
+/	POS	O
+ml	POS	O
+by	POS	O
+4	POS	O
+months	POS	O
+after	POS	O
+discontinuing	POS	O
+PTU	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+PTU	POS	O
+therapy	POS	O
+may	POS	O
+be	POS	O
+related	POS	O
+to	POS	O
+the	POS	O
+appearance	POS	O
+of	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	B-NP
+,	POS	O
+but	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	O
+does	POS	O
+not	POS	O
+appear	POS	O
+to	POS	O
+be	POS	O
+closely	POS	O
+related	POS	O
+to	POS	O
+vasculitis	POS	B-NP
+.	POS	O
+Prevalence	POS	O
+of	POS	O
+heart	POS	B-NP
+disease	POS	I-NP
+in	POS	O
+asymptomatic	POS	O
+chronic	POS	O
+cocaine	POS	O
+users	POS	O
+.	POS	O
+To	POS	O
+determine	POS	O
+the	POS	O
+prevalence	POS	O
+of	POS	O
+heart	POS	B-NP
+disease	POS	I-NP
+in	POS	O
+outpatient	POS	O
+young	POS	O
+asymptomatic	POS	O
+chronic	POS	O
+cocaine	POS	O
+users	POS	O
+,	POS	O
+35	POS	O
+cocaine	POS	O
+users	POS	O
+and	POS	O
+32	POS	O
+age	POS	O
+-	POS	O
+matched	POS	O
+controls	POS	O
+underwent	POS	O
+resting	POS	O
+and	POS	O
+exercise	POS	O
+electrocardiography	POS	O
+(	POS	O
+ECG	POS	O
+)	POS	O
+and	POS	O
+Doppler	POS	O
+echocardiography	POS	O
+.	POS	O
+Findings	POS	O
+consistent	POS	O
+with	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+were	POS	O
+detected	POS	O
+in	POS	O
+12	POS	O
+(	POS	O
+34	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+and	POS	O
+3	POS	O
+(	POS	O
+9	POS	O
+%	POS	O
+)	POS	O
+controls	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+Decreased	POS	O
+left	POS	O
+ventricular	POS	O
+systolic	POS	O
+function	POS	O
+was	POS	O
+demonstrated	POS	O
+in	POS	O
+5	POS	O
+(	POS	O
+14	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+,	POS	O
+but	POS	O
+in	POS	O
+none	POS	O
+of	POS	O
+the	POS	O
+controls	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+055	POS	O
+)	POS	O
+.	POS	O
+Finally	POS	O
+,	POS	O
+resting	POS	O
+and	POS	O
+peak	POS	O
+exercise	POS	O
+abnormal	POS	O
+left	POS	O
+ventricular	POS	O
+filling	POS	O
+was	POS	O
+detected	POS	O
+in	POS	O
+38	POS	O
+and	POS	O
+35	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+as	POS	O
+compared	POS	O
+to	POS	O
+19	POS	O
+and	POS	O
+9	POS	O
+%	POS	O
+of	POS	O
+controls	POS	O
+,	POS	O
+respectively	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+11	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+coronary	POS	O
+artery	POS	O
+or	POS	O
+myocardial	POS	B-NP
+disease	POS	I-NP
+is	POS	O
+common	POS	O
+(	POS	O
+38	POS	O
+%	POS	O
+)	POS	O
+in	POS	O
+young	POS	O
+asymptomatic	POS	O
+chronic	POS	O
+cocaine	POS	O
+users	POS	O
+.	POS	O
+Therefore	POS	O
+,	POS	O
+screening	POS	O
+ECG	POS	O
+and	POS	O
+echocardiography	POS	O
+may	POS	O
+be	POS	O
+warranted	POS	O
+in	POS	O
+these	POS	O
+patients	POS	O
+.	POS	O
+Cardioprotective	POS	O
+effects	POS	O
+of	POS	O
+Picrorrhiza	POS	O
+kurroa	POS	O
+against	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+myocardial	POS	O
+stress	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+cardioprotective	POS	O
+effect	POS	O
+of	POS	O
+the	POS	O
+ethanol	POS	O
+extract	POS	O
+of	POS	O
+Picrorrhiza	POS	O
+kurroa	POS	O
+rhizomes	POS	O
+and	POS	O
+roots	POS	O
+(	POS	O
+PK	POS	O
+)	POS	O
+on	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+in	POS	O
+rats	POS	O
+with	POS	O
+respect	POS	O
+to	POS	O
+lipid	POS	O
+metabolism	POS	O
+in	POS	O
+serum	POS	O
+and	POS	O
+heart	POS	O
+tissue	POS	O
+has	POS	O
+been	POS	O
+investigated	POS	O
+.	POS	O
+Oral	POS	O
+pre	POS	O
+-	POS	O
+treatment	POS	O
+with	POS	O
+PK	POS	O
+(	POS	O
+80	POS	O
+mg	POS	O
+kg	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+day	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+for	POS	O
+15	POS	O
+days	POS	O
+)	POS	O
+significantly	POS	O
+prevented	POS	O
+the	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+and	POS	O
+maintained	POS	O
+the	POS	O
+rats	POS	O
+at	POS	O
+near	POS	O
+normal	POS	O
+status	POS	O
+.	POS	O
+Phase	POS	O
+2	POS	O
+early	POS	O
+afterdepolarization	POS	B-NP
+as	POS	O
+a	POS	O
+trigger	POS	O
+of	POS	O
+polymorphic	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+in	POS	O
+acquired	POS	B-NP
+long	POS	I-NP
+-	POS	I-NP
+QT	POS	I-NP
+syndrome	POS	I-NP
+:	POS	O
+direct	POS	O
+evidence	POS	O
+from	POS	O
+intracellular	POS	O
+recordings	POS	O
+in	POS	O
+the	POS	O
+intact	POS	O
+left	POS	O
+ventricular	POS	O
+wall	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+This	POS	O
+study	POS	O
+examined	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+phase	POS	O
+2	POS	O
+early	POS	O
+afterdepolarization	POS	B-NP
+(	POS	O
+EAD	POS	B-NP
+)	POS	O
+in	POS	O
+producing	POS	O
+a	POS	O
+trigger	POS	O
+to	POS	O
+initiate	POS	O
+torsade	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+(	POS	O
+TdP	POS	B-NP
+)	POS	O
+with	POS	O
+QT	POS	B-NP
+prolongation	POS	I-NP
+induced	POS	O
+by	POS	O
+dl	POS	O
+-	POS	O
+sotalol	POS	O
+and	POS	O
+azimilide	POS	O
+.	POS	O
+The	POS	O
+contribution	POS	O
+of	POS	O
+transmural	POS	O
+dispersion	POS	O
+of	POS	O
+repolarization	POS	O
+(	POS	O
+TDR	POS	O
+)	POS	O
+to	POS	O
+transmural	POS	O
+propagation	POS	O
+of	POS	O
+EAD	POS	B-NP
+and	POS	O
+the	POS	O
+maintenance	POS	O
+of	POS	O
+TdP	POS	B-NP
+was	POS	O
+also	POS	O
+evaluated	POS	O
+.	POS	O
+METHODS	POS	O
+AND	POS	O
+RESULTS	POS	O
+:	POS	O
+Transmembrane	POS	O
+action	POS	O
+potentials	POS	O
+from	POS	O
+epicardium	POS	O
+,	POS	O
+midmyocardium	POS	O
+,	POS	O
+and	POS	O
+endocardium	POS	O
+were	POS	O
+recorded	POS	O
+simultaneously	POS	O
+,	POS	O
+together	POS	O
+with	POS	O
+a	POS	O
+transmural	POS	O
+ECG	POS	O
+,	POS	O
+in	POS	O
+arterially	POS	O
+perfused	POS	O
+canine	POS	O
+and	POS	O
+rabbit	POS	O
+left	POS	O
+ventricular	POS	O
+preparations	POS	O
+.	POS	O
+dl	POS	O
+-	POS	O
+Sotalol	POS	O
+preferentially	POS	O
+prolonged	POS	O
+action	POS	O
+potential	POS	O
+duration	POS	O
+(	POS	O
+APD	POS	O
+)	POS	O
+in	POS	O
+M	POS	O
+cells	POS	O
+dose	POS	O
+-	POS	O
+dependently	POS	O
+(	POS	O
+1	POS	O
+to	POS	O
+100	POS	O
+micromol	POS	O
+/	POS	O
+L	POS	O
+)	POS	O
+,	POS	O
+leading	POS	O
+to	POS	O
+QT	POS	O
+prolongation	POS	O
+and	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+TDR	POS	O
+.	POS	O
+Azimilide	POS	O
+,	POS	O
+however	POS	O
+,	POS	O
+significantly	POS	O
+prolonged	POS	O
+APD	POS	O
+and	POS	O
+QT	POS	O
+interval	POS	O
+at	POS	O
+concentrations	POS	O
+from	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+to	POS	O
+10	POS	O
+micromol	POS	O
+/	POS	O
+L	POS	O
+but	POS	O
+shortened	POS	O
+them	POS	O
+at	POS	O
+30	POS	O
+micromol	POS	O
+/	POS	O
+L	POS	O
+.	POS	O
+Unlike	POS	O
+dl	POS	O
+-	POS	O
+sotalol	POS	O
+,	POS	O
+azimilide	POS	O
+(	POS	O
+>	POS	O
+3	POS	O
+micromol	POS	O
+/	POS	O
+L	POS	O
+)	POS	O
+increased	POS	O
+epicardial	POS	O
+APD	POS	O
+markedly	POS	O
+,	POS	O
+causing	POS	O
+a	POS	O
+diminished	POS	O
+TDR	POS	O
+.	POS	O
+Although	POS	O
+both	POS	O
+dl	POS	O
+-	POS	O
+sotalol	POS	O
+and	POS	O
+azimilide	POS	O
+rarely	POS	O
+induced	POS	O
+EADs	POS	B-NP
+in	POS	O
+canine	POS	O
+left	POS	O
+ventricles	POS	O
+,	POS	O
+they	POS	O
+produced	POS	O
+frequent	POS	O
+EADs	POS	B-NP
+in	POS	O
+rabbits	POS	O
+,	POS	O
+in	POS	O
+which	POS	O
+more	POS	O
+pronounced	POS	O
+QT	POS	B-NP
+prolongation	POS	I-NP
+was	POS	O
+seen	POS	O
+.	POS	O
+An	POS	O
+increase	POS	O
+in	POS	O
+TDR	POS	O
+by	POS	O
+dl	POS	O
+-	POS	O
+sotalol	POS	O
+facilitated	POS	O
+transmural	POS	O
+propagation	POS	O
+of	POS	O
+EADs	POS	B-NP
+that	POS	O
+initiated	POS	O
+multiple	POS	O
+episodes	POS	O
+of	POS	O
+spontaneous	POS	O
+TdP	POS	B-NP
+in	POS	O
+3	POS	O
+of	POS	O
+6	POS	O
+rabbit	POS	O
+left	POS	O
+ventricles	POS	O
+.	POS	O
+Of	POS	O
+note	POS	O
+,	POS	O
+although	POS	O
+azimilide	POS	O
+(	POS	O
+3	POS	O
+to	POS	O
+10	POS	O
+micromol	POS	O
+/	POS	O
+L	POS	O
+)	POS	O
+increased	POS	O
+APD	POS	O
+more	POS	O
+than	POS	O
+dl	POS	O
+-	POS	O
+sotalol	POS	O
+,	POS	O
+its	POS	O
+EADs	POS	B-NP
+often	POS	O
+failed	POS	O
+to	POS	O
+propagate	POS	O
+transmurally	POS	O
+,	POS	O
+probably	POS	O
+because	POS	O
+of	POS	O
+a	POS	O
+diminished	POS	O
+TDR	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+This	POS	O
+study	POS	O
+provides	POS	O
+the	POS	O
+first	POS	O
+direct	POS	O
+evidence	POS	O
+from	POS	O
+intracellular	POS	O
+action	POS	O
+potential	POS	O
+recordings	POS	O
+that	POS	O
+phase	POS	O
+2	POS	O
+EAD	POS	B-NP
+can	POS	O
+be	POS	O
+generated	POS	O
+from	POS	O
+intact	POS	O
+ventricular	POS	O
+wall	POS	O
+and	POS	O
+produce	POS	O
+a	POS	O
+trigger	POS	O
+to	POS	O
+initiate	POS	O
+the	POS	O
+onset	POS	O
+of	POS	O
+TdP	POS	B-NP
+under	POS	O
+QT	POS	O
+prolongation	POS	O
+.	POS	O
+A	POS	O
+pilot	POS	O
+study	POS	O
+to	POS	O
+assess	POS	O
+the	POS	O
+safety	POS	O
+of	POS	O
+dobutamine	POS	O
+stress	POS	O
+echocardiography	POS	O
+in	POS	O
+the	POS	O
+emergency	POS	O
+department	POS	O
+evaluation	POS	O
+of	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+.	POS	O
+STUDY	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+Chest	POS	B-NP
+pain	POS	I-NP
+in	POS	O
+the	POS	O
+setting	POS	O
+of	POS	O
+cocaine	POS	O
+use	POS	O
+poses	POS	O
+a	POS	O
+diagnostic	POS	O
+dilemma	POS	O
+.	POS	O
+Dobutamine	POS	O
+stress	POS	O
+echocardiography	POS	O
+(	POS	O
+DSE	POS	O
+)	POS	O
+is	POS	O
+a	POS	O
+widely	POS	O
+available	POS	O
+and	POS	O
+sensitive	POS	O
+test	POS	O
+for	POS	O
+evaluating	POS	O
+cardiac	POS	B-NP
+ischemia	POS	I-NP
+.	POS	O
+Because	POS	O
+of	POS	O
+the	POS	O
+theoretical	POS	O
+concern	POS	O
+regarding	POS	O
+administration	POS	O
+of	POS	O
+dobutamine	POS	O
+in	POS	O
+the	POS	O
+setting	POS	O
+of	POS	O
+cocaine	POS	O
+use	POS	O
+,	POS	O
+we	POS	O
+conducted	POS	O
+a	POS	O
+pilot	POS	O
+study	POS	O
+to	POS	O
+assess	POS	O
+the	POS	O
+safety	POS	O
+of	POS	O
+DSE	POS	O
+in	POS	O
+emergency	POS	O
+department	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+A	POS	O
+prospective	POS	O
+case	POS	O
+series	POS	O
+was	POS	O
+conducted	POS	O
+in	POS	O
+the	POS	O
+intensive	POS	O
+diagnostic	POS	O
+and	POS	O
+treatment	POS	O
+unit	POS	O
+in	POS	O
+the	POS	O
+ED	POS	O
+of	POS	O
+an	POS	O
+urban	POS	O
+tertiary	POS	O
+-	POS	O
+care	POS	O
+teaching	POS	O
+hospital	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+eligible	POS	O
+for	POS	O
+DSE	POS	B-NP
+if	POS	O
+they	POS	O
+had	POS	O
+used	POS	O
+cocaine	POS	O
+within	POS	O
+24	POS	O
+hours	POS	O
+preceding	POS	O
+the	POS	O
+onset	POS	O
+of	POS	O
+chest	POS	B-NP
+pain	POS	I-NP
+and	POS	O
+had	POS	O
+a	POS	O
+normal	POS	O
+ECG	POS	O
+and	POS	O
+tropinin	POS	O
+I	POS	O
+level	POS	O
+.	POS	O
+Patients	POS	O
+exhibiting	POS	O
+signs	POS	O
+of	POS	O
+continuing	POS	O
+cocaine	POS	B-NP
+toxicity	POS	I-NP
+were	POS	O
+excluded	POS	O
+from	POS	O
+the	POS	O
+study	POS	O
+.	POS	O
+All	POS	O
+patients	POS	O
+were	POS	O
+admitted	POS	O
+to	POS	O
+the	POS	O
+hospital	POS	O
+for	POS	O
+serial	POS	O
+testing	POS	O
+after	POS	O
+the	POS	O
+DSE	POS	O
+testing	POS	O
+in	POS	O
+the	POS	O
+intensive	POS	O
+diagnostic	POS	O
+and	POS	O
+treatment	POS	O
+unit	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Twenty	POS	O
+-	POS	O
+four	POS	O
+patients	POS	O
+were	POS	O
+enrolled	POS	O
+.	POS	O
+Two	POS	O
+patients	POS	O
+had	POS	O
+inadequate	POS	O
+resting	POS	O
+images	POS	O
+,	POS	O
+one	POS	O
+DSE	POS	O
+was	POS	O
+terminated	POS	O
+because	POS	O
+of	POS	O
+inferior	POS	B-NP
+hypokinesis	POS	I-NP
+,	POS	O
+another	POS	O
+DSE	POS	O
+was	POS	O
+terminated	POS	O
+because	POS	O
+of	POS	O
+a	POS	O
+rate	POS	O
+-	POS	O
+related	POS	O
+atrial	POS	B-NP
+conduction	POS	I-NP
+deficit	POS	I-NP
+,	POS	O
+and	POS	O
+1	POS	O
+patient	POS	O
+did	POS	O
+not	POS	O
+reach	POS	O
+the	POS	O
+target	POS	O
+heart	POS	O
+rate	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+19	POS	O
+patients	POS	O
+completed	POS	O
+a	POS	O
+DSE	POS	O
+and	POS	O
+reached	POS	O
+their	POS	O
+target	POS	O
+heart	POS	O
+rates	POS	O
+.	POS	O
+None	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+experienced	POS	O
+signs	POS	O
+of	POS	O
+exaggerated	POS	O
+adrenergic	POS	O
+response	POS	O
+,	POS	O
+which	POS	O
+was	POS	O
+defined	POS	O
+as	POS	O
+a	POS	O
+systolic	POS	O
+blood	POS	O
+pressure	POS	O
+of	POS	O
+greater	POS	O
+than	POS	O
+200	POS	O
+mm	POS	O
+Hg	POS	O
+or	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+tachydysrhythmias	POS	B-NP
+(	POS	O
+excluding	POS	O
+sinus	POS	B-NP
+tachycardia	POS	I-NP
+)	POS	O
+.	POS	O
+Further	POS	O
+suggesting	POS	O
+lack	POS	O
+of	POS	O
+exaggerated	POS	O
+adrenergic	POS	O
+response	POS	O
+,	POS	O
+13	POS	O
+(	POS	O
+65	POS	O
+%	POS	O
+)	POS	O
+of	POS	O
+20	POS	O
+patients	POS	O
+required	POS	O
+supplemental	POS	O
+atropine	POS	O
+to	POS	O
+reach	POS	O
+their	POS	O
+target	POS	O
+heart	POS	O
+rates	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+No	POS	O
+exaggerated	POS	O
+adrenergic	POS	O
+response	POS	O
+was	POS	O
+detected	POS	O
+when	POS	O
+dobutamine	POS	O
+was	POS	O
+administered	POS	O
+to	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+related	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+.	POS	O
+Prenatal	POS	O
+cocaine	POS	O
+exposure	POS	O
+and	POS	O
+cranial	POS	O
+sonographic	POS	O
+findings	POS	O
+in	POS	O
+preterm	POS	B-NP
+infants	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+Prenatal	POS	O
+cocaine	POS	O
+exposure	POS	O
+has	POS	O
+been	POS	O
+linked	POS	O
+with	POS	O
+subependymal	POS	B-NP
+hemorrhage	POS	I-NP
+and	POS	O
+the	POS	O
+formation	POS	O
+of	POS	O
+cysts	POS	B-NP
+that	POS	O
+are	POS	O
+detectable	POS	O
+on	POS	O
+cranial	POS	O
+sonography	POS	O
+in	POS	O
+neonates	POS	O
+born	POS	O
+at	POS	O
+term	POS	O
+.	POS	O
+We	POS	O
+sought	POS	O
+to	POS	O
+determine	POS	O
+if	POS	O
+prenatal	POS	O
+cocaine	POS	O
+exposure	POS	O
+increases	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+subependymal	POS	B-NP
+cysts	POS	I-NP
+in	POS	O
+preterm	POS	B-NP
+infants	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+retrospectively	POS	O
+reviewed	POS	O
+the	POS	O
+medical	POS	O
+records	POS	O
+and	POS	O
+cranial	POS	O
+sonograms	POS	O
+obtained	POS	O
+during	POS	O
+a	POS	O
+1	POS	O
+-	POS	O
+year	POS	O
+period	POS	O
+on	POS	O
+122	POS	O
+premature	POS	O
+(	POS	O
+<	POS	O
+36	POS	O
+weeks	POS	O
+of	POS	O
+gestation	POS	O
+)	POS	O
+infants	POS	O
+.	POS	O
+Infants	POS	O
+were	POS	O
+categorized	POS	O
+into	POS	O
+1	POS	O
+of	POS	O
+2	POS	O
+groups	POS	O
+:	POS	O
+those	POS	O
+exposed	POS	O
+to	POS	O
+cocaine	POS	O
+and	POS	O
+those	POS	O
+not	POS	O
+exposed	POS	O
+to	POS	O
+cocaine	POS	O
+.	POS	O
+Infants	POS	O
+were	POS	O
+assigned	POS	O
+to	POS	O
+the	POS	O
+cocaine	POS	O
+-	POS	O
+exposed	POS	O
+group	POS	O
+if	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+maternal	POS	O
+history	POS	O
+of	POS	O
+cocaine	POS	B-NP
+abuse	POS	I-NP
+during	POS	O
+pregnancy	POS	O
+or	POS	O
+if	POS	O
+maternal	POS	O
+or	POS	O
+neonatal	POS	O
+urine	POS	O
+toxicology	POS	O
+results	POS	O
+were	POS	O
+positive	POS	O
+at	POS	O
+the	POS	O
+time	POS	O
+of	POS	O
+delivery	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Five	POS	O
+of	POS	O
+the	POS	O
+122	POS	O
+infants	POS	O
+were	POS	O
+excluded	POS	O
+from	POS	O
+the	POS	O
+study	POS	O
+because	POS	O
+of	POS	O
+insufficient	POS	O
+medical	POS	O
+and	POS	O
+drug	POS	O
+histories	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+subependymal	POS	B-NP
+cysts	POS	I-NP
+in	POS	O
+the	POS	O
+117	POS	O
+remaining	POS	O
+infants	POS	O
+was	POS	O
+14	POS	O
+%	POS	O
+(	POS	O
+16	POS	O
+of	POS	O
+117	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+subependymal	POS	B-NP
+cysts	POS	I-NP
+in	POS	O
+infants	POS	O
+exposed	POS	O
+to	POS	O
+cocaine	POS	O
+prenatally	POS	O
+was	POS	O
+44	POS	O
+%	POS	O
+(	POS	O
+8	POS	O
+of	POS	O
+18	POS	O
+)	POS	O
+compared	POS	O
+with	POS	O
+8	POS	O
+%	POS	O
+(	POS	O
+8	POS	O
+of	POS	O
+99	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+unexposed	POS	O
+group	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+We	POS	O
+found	POS	O
+an	POS	O
+increased	POS	O
+incidence	POS	O
+of	POS	O
+subependymal	POS	B-NP
+cyst	POS	I-NP
+formation	POS	O
+in	POS	O
+preterm	POS	B-NP
+infants	POS	O
+who	POS	O
+were	POS	O
+exposed	POS	O
+to	POS	O
+cocaine	POS	O
+prenatally	POS	O
+.	POS	O
+This	POS	O
+result	POS	O
+is	POS	O
+consistent	POS	O
+with	POS	O
+results	POS	O
+of	POS	O
+similar	POS	O
+studies	POS	O
+in	POS	O
+term	POS	O
+infants	POS	O
+.	POS	O
+Thalidomide	POS	B-NP
+neuropathy	POS	I-NP
+in	POS	O
+patients	POS	O
+treated	POS	O
+for	POS	O
+metastatic	POS	B-NP
+prostate	POS	I-NP
+cancer	POS	I-NP
+.	POS	O
+We	POS	O
+prospectively	POS	O
+evaluated	POS	O
+thalidomide	POS	O
+-	POS	O
+induced	POS	O
+neuropathy	POS	B-NP
+using	POS	O
+electrodiagnostic	POS	O
+studies	POS	O
+.	POS	O
+Sixty	POS	O
+-	POS	O
+seven	POS	O
+men	POS	O
+with	POS	O
+metastatic	POS	B-NP
+androgen	POS	I-NP
+-	POS	I-NP
+independent	POS	I-NP
+prostate	POS	I-NP
+cancer	POS	I-NP
+in	POS	O
+an	POS	O
+open	POS	O
+-	POS	O
+label	POS	O
+trial	POS	O
+of	POS	O
+oral	POS	O
+thalidomide	POS	O
+underwent	POS	O
+neurologic	POS	O
+examinations	POS	O
+and	POS	O
+nerve	POS	O
+conduction	POS	O
+studies	POS	O
+(	POS	O
+NCS	POS	O
+)	POS	O
+prior	POS	O
+to	POS	O
+and	POS	O
+at	POS	O
+3	POS	O
+-	POS	O
+month	POS	O
+intervals	POS	O
+during	POS	O
+treatment	POS	O
+.	POS	O
+NCS	POS	O
+included	POS	O
+recording	POS	O
+of	POS	O
+sensory	POS	O
+nerve	POS	O
+action	POS	O
+potentials	POS	O
+(	POS	O
+SNAPs	POS	O
+)	POS	O
+from	POS	O
+median	POS	O
+,	POS	O
+radial	POS	O
+,	POS	O
+ulnar	POS	O
+,	POS	O
+and	POS	O
+sural	POS	O
+nerves	POS	O
+.	POS	O
+SNAP	POS	O
+amplitudes	POS	O
+for	POS	O
+each	POS	O
+nerve	POS	O
+were	POS	O
+expressed	POS	O
+as	POS	O
+the	POS	O
+percentage	POS	O
+of	POS	O
+its	POS	O
+baseline	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+mean	POS	O
+of	POS	O
+the	POS	O
+four	POS	O
+was	POS	O
+termed	POS	O
+the	POS	O
+SNAP	POS	O
+index	POS	O
+.	POS	O
+A	POS	O
+40	POS	O
+%	POS	O
+decline	POS	O
+in	POS	O
+the	POS	O
+SNAP	POS	O
+index	POS	O
+was	POS	O
+considered	POS	O
+clinically	POS	O
+significant	POS	O
+.	POS	O
+Thalidomide	POS	B-NP
+was	POS	O
+discontinued	POS	O
+in	POS	O
+55	POS	O
+patients	POS	O
+for	POS	O
+lack	POS	O
+of	POS	O
+therapeutic	POS	O
+response	POS	O
+.	POS	O
+Of	POS	O
+67	POS	O
+patients	POS	O
+initially	POS	O
+enrolled	POS	O
+,	POS	O
+24	POS	O
+remained	POS	O
+on	POS	O
+thalidomide	POS	O
+for	POS	O
+3	POS	O
+months	POS	O
+,	POS	O
+8	POS	O
+remained	POS	O
+at	POS	O
+6	POS	O
+months	POS	O
+,	POS	O
+and	POS	O
+3	POS	O
+remained	POS	O
+at	POS	O
+9	POS	O
+months	POS	O
+.	POS	O
+Six	POS	O
+patients	POS	O
+developed	POS	O
+neuropathy	POS	B-NP
+.	POS	O
+Clinical	POS	O
+symptoms	POS	O
+and	POS	O
+a	POS	O
+decline	POS	O
+in	POS	O
+the	POS	O
+SNAP	POS	O
+index	POS	O
+occurred	POS	O
+concurrently	POS	O
+.	POS	O
+Older	POS	O
+age	POS	O
+and	POS	O
+cumulative	POS	O
+dose	POS	O
+were	POS	O
+possible	POS	O
+contributing	POS	O
+factors	POS	O
+.	POS	O
+Neuropathy	POS	B-NP
+may	POS	O
+thus	POS	O
+be	POS	O
+a	POS	O
+common	POS	O
+complication	POS	O
+of	POS	O
+thalidomide	POS	O
+in	POS	O
+older	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+SNAP	POS	O
+index	POS	O
+can	POS	O
+be	POS	O
+used	POS	O
+to	POS	O
+monitor	POS	O
+peripheral	POS	B-NP
+neuropathy	POS	I-NP
+,	POS	O
+but	POS	O
+not	POS	O
+for	POS	O
+early	POS	O
+detection	POS	O
+.	POS	O
+Overexpression	POS	O
+of	POS	O
+copper	POS	O
+/	POS	O
+zinc	POS	O
+-	POS	O
+superoxide	POS	O
+dismutase	POS	O
+protects	POS	O
+from	POS	O
+kanamycin	POS	O
+-	POS	O
+induced	POS	O
+hearing	POS	B-NP
+loss	POS	I-NP
+.	POS	O
+The	POS	O
+participation	POS	O
+of	POS	O
+reactive	POS	O
+oxygen	POS	O
+species	POS	O
+in	POS	O
+aminoglycoside	POS	O
+-	POS	O
+induced	POS	O
+ototoxicity	POS	B-NP
+has	POS	O
+been	POS	O
+deduced	POS	O
+from	POS	O
+observations	POS	O
+that	POS	O
+aminoglycoside	POS	O
+-	POS	O
+iron	POS	O
+complexes	POS	O
+catalyze	POS	O
+the	POS	O
+formation	POS	O
+of	POS	O
+superoxide	POS	O
+radicals	POS	O
+in	POS	O
+vitro	POS	O
+and	POS	O
+that	POS	O
+antioxidants	POS	O
+attenuate	POS	O
+ototoxicity	POS	B-NP
+in	POS	O
+vivo	POS	O
+.	POS	O
+We	POS	O
+therefore	POS	O
+hypothesized	POS	O
+that	POS	O
+overexpression	POS	O
+of	POS	O
+Cu	POS	O
+/	POS	O
+Zn	POS	O
+-	POS	O
+superoxide	POS	O
+dismutase	POS	O
+(	POS	O
+h	POS	O
+-	POS	O
+SOD1	POS	O
+)	POS	O
+should	POS	O
+protect	POS	O
+transgenic	POS	O
+mice	POS	O
+from	POS	O
+ototoxicity	POS	B-NP
+.	POS	O
+Immunocytochemistry	POS	O
+confirmed	POS	O
+expression	POS	O
+of	POS	O
+h	POS	O
+-	POS	O
+SOD1	POS	O
+in	POS	O
+inner	POS	O
+ear	POS	O
+tissues	POS	O
+of	POS	O
+transgenic	POS	O
+C57BL	POS	O
+/	POS	O
+6	POS	O
+-	POS	O
+TgN	POS	O
+[	POS	O
+SOD1	POS	O
+]	POS	O
+3Cje	POS	O
+mice	POS	O
+.	POS	O
+Transgenic	POS	O
+and	POS	O
+nontransgenic	POS	O
+littermates	POS	O
+received	POS	O
+kanamycin	POS	O
+(	POS	O
+400	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+body	POS	O
+weight	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+for	POS	O
+10	POS	O
+days	POS	O
+beginning	POS	O
+on	POS	O
+day	POS	O
+10	POS	O
+after	POS	O
+birth	POS	O
+.	POS	O
+Auditory	POS	O
+thresholds	POS	O
+were	POS	O
+tested	POS	O
+by	POS	O
+evoked	POS	O
+auditory	POS	O
+brain	POS	O
+stem	POS	O
+responses	POS	O
+at	POS	O
+1	POS	O
+month	POS	O
+after	POS	O
+birth	POS	O
+.	POS	O
+In	POS	O
+nontransgenic	POS	O
+animals	POS	O
+,	POS	O
+the	POS	O
+threshold	POS	O
+in	POS	O
+the	POS	O
+kanamycin	POS	O
+-	POS	O
+treated	POS	O
+group	POS	O
+was	POS	O
+45	POS	O
+-	POS	O
+50	POS	O
+dB	POS	O
+higher	POS	O
+than	POS	O
+in	POS	O
+saline	POS	O
+-	POS	O
+injected	POS	O
+controls	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+transgenic	POS	O
+group	POS	O
+,	POS	O
+kanamycin	POS	O
+increased	POS	O
+the	POS	O
+threshold	POS	O
+by	POS	O
+only	POS	O
+15	POS	O
+dB	POS	O
+over	POS	O
+the	POS	O
+respective	POS	O
+controls	POS	O
+.	POS	O
+The	POS	O
+effects	POS	O
+were	POS	O
+similar	POS	O
+at	POS	O
+12	POS	O
+and	POS	O
+24	POS	O
+kHz	POS	O
+.	POS	O
+The	POS	O
+protection	POS	O
+by	POS	O
+overexpression	POS	O
+of	POS	O
+superoxide	POS	O
+dismutase	POS	O
+supports	POS	O
+the	POS	O
+hypothesis	POS	O
+that	POS	O
+oxidant	POS	O
+stress	POS	O
+plays	POS	O
+a	POS	O
+significant	POS	O
+role	POS	O
+in	POS	O
+aminoglycoside	POS	O
+-	POS	O
+induced	POS	O
+ototoxicity	POS	B-NP
+.	POS	O
+The	POS	O
+results	POS	O
+also	POS	O
+suggest	POS	O
+transgenic	POS	O
+animals	POS	O
+as	POS	O
+suitable	POS	O
+models	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+underlying	POS	O
+mechanisms	POS	O
+and	POS	O
+possible	POS	O
+strategies	POS	O
+for	POS	O
+prevention	POS	O
+.	POS	O
+Fatty	POS	O
+liver	POS	O
+induced	POS	O
+by	POS	O
+tetracycline	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+.	POS	O
+Dose	POS	O
+-	POS	O
+response	POS	O
+relationships	POS	O
+and	POS	O
+effect	POS	O
+of	POS	O
+sex	POS	O
+.	POS	O
+Dose	POS	O
+-	POS	O
+response	POS	O
+relationships	POS	O
+,	POS	O
+biochemical	POS	O
+mechanisms	POS	O
+,	POS	O
+and	POS	O
+sex	POS	O
+differences	POS	O
+in	POS	O
+the	POS	O
+experimental	POS	O
+fatty	POS	O
+liver	POS	O
+induced	POS	O
+by	POS	O
+tetracycline	POS	O
+were	POS	O
+studied	POS	O
+in	POS	O
+the	POS	O
+intact	POS	O
+rat	POS	O
+and	POS	O
+with	POS	O
+the	POS	O
+isolated	POS	O
+perfused	POS	O
+rat	POS	O
+liver	POS	O
+in	POS	O
+vitro	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+intact	POS	O
+male	POS	O
+and	POS	O
+female	POS	O
+rat	POS	O
+,	POS	O
+no	POS	O
+direct	POS	O
+relationship	POS	O
+was	POS	O
+observed	POS	O
+between	POS	O
+dose	POS	O
+of	POS	O
+tetracycline	POS	O
+and	POS	O
+hepatic	POS	O
+accumulation	POS	O
+of	POS	O
+triglyceride	POS	O
+.	POS	O
+With	POS	O
+provision	POS	O
+of	POS	O
+adequate	POS	O
+oleic	POS	O
+acid	POS	O
+as	POS	O
+a	POS	O
+substrate	POS	O
+for	POS	O
+the	POS	O
+isolated	POS	O
+perfused	POS	O
+liver	POS	O
+,	POS	O
+a	POS	O
+direct	POS	O
+relationship	POS	O
+was	POS	O
+observed	POS	O
+between	POS	O
+dose	POS	O
+of	POS	O
+tetracycline	POS	O
+and	POS	O
+both	POS	O
+accumulation	POS	O
+of	POS	O
+triglyceride	POS	O
+in	POS	O
+the	POS	O
+liver	POS	O
+and	POS	O
+depression	POS	B-NP
+of	POS	O
+output	POS	O
+of	POS	O
+triglyceride	POS	O
+by	POS	O
+livers	POS	O
+from	POS	O
+male	POS	O
+and	POS	O
+female	POS	O
+rats	POS	O
+.	POS	O
+Marked	POS	O
+differences	POS	O
+were	POS	O
+observed	POS	O
+between	POS	O
+female	POS	O
+and	POS	O
+male	POS	O
+rats	POS	O
+with	POS	O
+regard	POS	O
+to	POS	O
+base	POS	O
+line	POS	O
+(	POS	O
+control	POS	O
+)	POS	O
+hepatic	POS	O
+concentration	POS	O
+of	POS	O
+triglyceride	POS	O
+and	POS	O
+output	POS	O
+of	POS	O
+triglyceride	POS	O
+.	POS	O
+Accumulation	POS	O
+of	POS	O
+hepatic	POS	O
+triglyceride	POS	O
+,	POS	O
+as	POS	O
+a	POS	O
+per	POS	O
+cent	POS	O
+of	POS	O
+control	POS	O
+values	POS	O
+,	POS	O
+in	POS	O
+response	POS	O
+to	POS	O
+graded	POS	O
+doses	POS	O
+of	POS	O
+tetracycline	POS	O
+,	POS	O
+did	POS	O
+not	POS	O
+differ	POS	O
+significantly	POS	O
+between	POS	O
+male	POS	O
+,	POS	O
+female	POS	O
+and	POS	O
+pregnant	POS	O
+rat	POS	O
+livers	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+livers	POS	O
+from	POS	O
+female	POS	O
+,	POS	O
+and	POS	O
+especially	POS	O
+pregnant	POS	O
+female	POS	O
+rats	POS	O
+,	POS	O
+were	POS	O
+strikingly	POS	O
+resistant	POS	O
+to	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+tetracycline	POS	O
+on	POS	O
+depression	POS	B-NP
+of	POS	O
+output	POS	O
+of	POS	O
+triglyceride	POS	O
+under	POS	O
+these	POS	O
+experimental	POS	O
+conditions	POS	O
+.	POS	O
+These	POS	O
+differences	POS	O
+between	POS	O
+the	POS	O
+sexes	POS	O
+could	POS	O
+not	POS	O
+be	POS	O
+related	POS	O
+to	POS	O
+altered	POS	O
+disposition	POS	O
+of	POS	O
+tetracycline	POS	O
+or	POS	O
+altered	POS	O
+uptake	POS	O
+of	POS	O
+oleic	POS	O
+acid	POS	O
+.	POS	O
+Depressed	POS	O
+hepatic	POS	O
+secretion	POS	O
+of	POS	O
+triglyceride	POS	O
+accounted	POS	O
+only	POS	O
+for	POS	O
+30	POS	O
+to	POS	O
+50	POS	O
+%	POS	O
+of	POS	O
+accumulated	POS	O
+hepatic	POS	O
+triglyceride	POS	O
+,	POS	O
+indicating	POS	O
+that	POS	O
+additional	POS	O
+mechanisms	POS	O
+must	POS	O
+be	POS	O
+involved	POS	O
+in	POS	O
+the	POS	O
+production	POS	O
+of	POS	O
+the	POS	O
+triglyceride	POS	O
+-	POS	O
+rich	POS	O
+fatty	POS	O
+liver	POS	O
+in	POS	O
+response	POS	O
+to	POS	O
+tetracycline	POS	O
+.	POS	O
+Prednisone	POS	O
+induces	POS	O
+anxiety	POS	B-NP
+and	POS	O
+glial	POS	O
+cerebral	POS	O
+changes	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+assess	POS	O
+whether	POS	O
+prednisone	POS	O
+(	POS	O
+PDN	POS	O
+)	POS	O
+produces	POS	O
+anxiety	POS	B-NP
+and	POS	O
+/	POS	O
+or	POS	O
+cerebral	POS	O
+glial	POS	O
+changes	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Male	POS	O
+Wistar	POS	O
+rats	POS	O
+were	POS	O
+studied	POS	O
+and	POS	O
+3	POS	O
+groups	POS	O
+were	POS	O
+formed	POS	O
+(	POS	O
+8	POS	O
+rats	POS	O
+per	POS	O
+group	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+moderate	POS	O
+-	POS	O
+dose	POS	O
+group	POS	O
+received	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+PDN	POS	O
+released	POS	O
+from	POS	O
+a	POS	O
+subcutaneous	POS	O
+implant	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+group	POS	O
+,	POS	O
+implants	POS	O
+containing	POS	O
+PDN	POS	O
+equivalent	POS	O
+to	POS	O
+60	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+were	POS	O
+applied	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+implants	POS	O
+contained	POS	O
+no	POS	O
+PDN	POS	O
+.	POS	O
+Anxiety	POS	O
+was	POS	O
+assessed	POS	O
+using	POS	O
+an	POS	O
+open	POS	O
+field	POS	O
+and	POS	O
+elevated	POS	O
+plus	POS	O
+-	POS	O
+maze	POS	O
+devices	POS	O
+.	POS	O
+The	POS	O
+number	POS	O
+of	POS	O
+cells	POS	O
+and	POS	O
+cytoplasmic	POS	O
+transformation	POS	O
+of	POS	O
+astrocytes	POS	O
+and	POS	O
+microglia	POS	O
+cells	POS	O
+were	POS	O
+assessed	POS	O
+by	POS	O
+immunohistochemical	POS	O
+analyses	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Anxiety	POS	B-NP
+was	POS	O
+documented	POS	O
+in	POS	O
+both	POS	O
+groups	POS	O
+of	POS	O
+PDN	POS	O
+treated	POS	O
+rats	POS	O
+compared	POS	O
+with	POS	O
+controls	POS	O
+.	POS	O
+The	POS	O
+magnitude	POS	O
+of	POS	O
+transformation	POS	O
+of	POS	O
+the	POS	O
+microglia	POS	O
+assessed	POS	O
+by	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+intersections	POS	O
+was	POS	O
+significantly	POS	O
+higher	POS	O
+in	POS	O
+the	POS	O
+PDN	POS	O
+groups	POS	O
+than	POS	O
+in	POS	O
+controls	POS	O
+in	POS	O
+the	POS	O
+prefrontal	POS	O
+cortex	POS	O
+(	POS	O
+moderate	POS	O
+-	POS	O
+dose	POS	O
+,	POS	O
+24	POS	O
+.	POS	O
+1	POS	O
+;	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+,	POS	O
+23	POS	O
+.	POS	O
+6	POS	O
+;	POS	O
+controls	POS	O
+18	POS	O
+.	POS	O
+7	POS	O
+;	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+and	POS	O
+striatum	POS	O
+(	POS	O
+moderate	POS	O
+-	POS	O
+dose	POS	O
+25	POS	O
+.	POS	O
+6	POS	O
+;	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+26	POS	O
+.	POS	O
+3	POS	O
+;	POS	O
+controls	POS	O
+18	POS	O
+.	POS	O
+9	POS	O
+;	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+in	POS	O
+hippocampus	POS	O
+.	POS	O
+The	POS	O
+number	POS	O
+of	POS	O
+stained	POS	O
+microglia	POS	O
+cells	POS	O
+was	POS	O
+significantly	POS	O
+higher	POS	O
+in	POS	O
+the	POS	O
+PDN	POS	O
+treated	POS	O
+groups	POS	O
+in	POS	O
+the	POS	O
+prefrontal	POS	O
+cortex	POS	O
+than	POS	O
+in	POS	O
+controls	POS	O
+(	POS	O
+moderate	POS	O
+-	POS	O
+dose	POS	O
+,	POS	O
+29	POS	O
+.	POS	O
+1	POS	O
+;	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+,	POS	O
+28	POS	O
+.	POS	O
+4	POS	O
+;	POS	O
+control	POS	O
+,	POS	O
+17	POS	O
+.	POS	O
+7	POS	O
+cells	POS	O
+per	POS	O
+field	POS	O
+;	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+Stained	POS	O
+microglia	POS	O
+cells	POS	O
+were	POS	O
+significantly	POS	O
+more	POS	O
+numerous	POS	O
+striatum	POS	O
+and	POS	O
+hippocampus	POS	O
+in	POS	O
+the	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+group	POS	O
+compared	POS	O
+to	POS	O
+controls	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Subacute	POS	O
+exposure	POS	O
+to	POS	O
+PDN	POS	O
+induced	POS	O
+anxiety	POS	B-NP
+and	POS	O
+reactivity	POS	O
+of	POS	O
+microglia	POS	O
+.	POS	O
+The	POS	O
+relevance	POS	O
+of	POS	O
+these	POS	O
+features	POS	O
+for	POS	O
+patients	POS	O
+using	POS	O
+PDN	POS	B-NP
+remains	POS	O
+to	POS	O
+be	POS	O
+elucidated	POS	O
+.	POS	O
+Phase	POS	O
+II	POS	O
+study	POS	O
+of	POS	O
+carboplatin	POS	O
+and	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+recurrent	POS	O
+squamous	POS	B-NP
+cell	POS	I-NP
+carcinoma	POS	I-NP
+of	POS	I-NP
+the	POS	I-NP
+cervix	POS	I-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+The	POS	O
+activity	POS	O
+of	POS	O
+the	POS	O
+combination	POS	O
+of	POS	O
+carboplatin	POS	O
+and	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+was	POS	O
+tested	POS	O
+in	POS	O
+a	POS	O
+Phase	POS	O
+II	POS	O
+study	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+recurrent	POS	O
+cervical	POS	B-NP
+carcinoma	POS	I-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+The	POS	O
+combination	POS	O
+of	POS	O
+carboplatin	POS	O
+(	POS	O
+area	POS	O
+under	POS	O
+the	POS	O
+concentration	POS	O
+curve	POS	O
+[	POS	O
+AUC	POS	O
+]	POS	O
+,	POS	O
+5	POS	O
+)	POS	O
+and	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+(	POS	O
+Doxil	POS	O
+;	POS	O
+starting	POS	O
+dose	POS	O
+,	POS	O
+40	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+)	POS	O
+was	POS	O
+administered	POS	O
+intravenously	POS	O
+every	POS	O
+28	POS	O
+days	POS	O
+to	POS	O
+37	POS	O
+patients	POS	O
+with	POS	O
+recurrent	POS	O
+squamous	POS	B-NP
+cell	POS	I-NP
+cervical	POS	I-NP
+carcinoma	POS	I-NP
+to	POS	O
+determine	POS	O
+antitumor	POS	O
+activity	POS	O
+and	POS	O
+toxicity	POS	B-NP
+profile	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Twenty	POS	O
+-	POS	O
+nine	POS	O
+patients	POS	O
+were	POS	O
+assessable	POS	O
+for	POS	O
+response	POS	O
+,	POS	O
+and	POS	O
+35	POS	O
+patients	POS	O
+were	POS	O
+assessable	POS	O
+for	POS	O
+toxicity	POS	B-NP
+.	POS	O
+The	POS	O
+overall	POS	O
+response	POS	O
+rate	POS	O
+was	POS	O
+38	POS	O
+%	POS	O
+,	POS	O
+the	POS	O
+median	POS	O
+time	POS	O
+to	POS	O
+response	POS	O
+was	POS	O
+10	POS	O
+weeks	POS	O
+,	POS	O
+the	POS	O
+median	POS	O
+duration	POS	O
+of	POS	O
+response	POS	O
+was	POS	O
+26	POS	O
+weeks	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+median	POS	O
+survival	POS	O
+was	POS	O
+37	POS	O
+weeks	POS	O
+.	POS	O
+The	POS	O
+main	POS	O
+toxic	POS	O
+effect	POS	O
+was	POS	O
+myelosuppression	POS	B-NP
+,	POS	O
+with	POS	O
+Grade	POS	O
+3	POS	O
+and	POS	O
+4	POS	O
+neutropenia	POS	B-NP
+in	POS	O
+16	POS	O
+patients	POS	O
+,	POS	O
+anemia	POS	B-NP
+in	POS	O
+12	POS	O
+patients	POS	O
+,	POS	O
+thrombocytopenia	POS	B-NP
+in	POS	O
+11	POS	O
+patients	POS	O
+,	POS	O
+and	POS	O
+neutropenic	POS	B-NP
+fever	POS	I-NP
+in	POS	O
+3	POS	O
+patients	POS	O
+.	POS	O
+Four	POS	O
+patients	POS	O
+had	POS	O
+five	POS	O
+infusion	POS	O
+-	POS	O
+related	POS	O
+reactions	POS	O
+during	POS	O
+the	POS	O
+infusion	POS	O
+of	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+,	POS	O
+leading	POS	O
+to	POS	O
+treatment	POS	O
+discontinuation	POS	O
+in	POS	O
+three	POS	O
+patients	POS	O
+.	POS	O
+Grade	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+2	POS	O
+nonhematologic	POS	O
+toxicity	POS	B-NP
+included	POS	O
+nausea	POS	B-NP
+in	POS	O
+17	POS	O
+patients	POS	O
+,	POS	O
+emesis	POS	B-NP
+in	POS	O
+14	POS	O
+patients	POS	O
+,	POS	O
+fatigue	POS	B-NP
+in	POS	O
+9	POS	O
+patients	POS	O
+,	POS	O
+mucositis	POS	B-NP
+and	POS	O
+/	POS	O
+or	POS	O
+stomatitis	POS	B-NP
+in	POS	O
+8	POS	O
+patients	POS	O
+,	POS	O
+constipation	POS	B-NP
+in	POS	O
+6	POS	O
+patients	POS	O
+,	POS	O
+weight	POS	B-NP
+loss	POS	I-NP
+in	POS	O
+5	POS	O
+patients	POS	O
+,	POS	O
+hand	POS	B-NP
+-	POS	I-NP
+foot	POS	I-NP
+syndrome	POS	I-NP
+in	POS	O
+2	POS	O
+patients	POS	O
+,	POS	O
+and	POS	O
+skin	POS	B-NP
+reactions	POS	I-NP
+in	POS	O
+3	POS	O
+patients	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+combination	POS	O
+of	POS	O
+carboplatin	POS	O
+and	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+has	POS	O
+modest	POS	O
+activity	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+recurrent	POS	O
+cervical	POS	B-NP
+carcinoma	POS	I-NP
+.	POS	O
+Antimicrobial	POS	O
+-	POS	O
+induced	POS	O
+mania	POS	B-NP
+(	POS	O
+antibiomania	POS	B-NP
+)	POS	O
+:	POS	O
+a	POS	O
+review	POS	O
+of	POS	O
+spontaneous	POS	O
+reports	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+reviewed	POS	O
+reported	POS	O
+cases	POS	O
+of	POS	O
+antibiotic	POS	O
+-	POS	O
+induced	POS	O
+manic	POS	B-NP
+episodes	POS	O
+by	POS	O
+means	POS	O
+of	POS	O
+a	POS	O
+MEDLINE	POS	O
+and	POS	O
+PsychLit	POS	O
+search	POS	O
+for	POS	O
+reports	POS	O
+of	POS	O
+antibiotic	POS	O
+-	POS	O
+induced	POS	O
+mania	POS	B-NP
+.	POS	O
+Unpublished	POS	O
+reports	POS	O
+were	POS	O
+requested	POS	O
+from	POS	O
+the	POS	O
+World	POS	O
+Health	POS	O
+Organization	POS	O
+(	POS	O
+WHO	POS	O
+)	POS	O
+and	POS	O
+the	POS	O
+Food	POS	O
+and	POS	O
+Drug	POS	O
+Administration	POS	O
+(	POS	O
+FDA	POS	O
+)	POS	O
+.	POS	O
+Twenty	POS	O
+-	POS	O
+one	POS	O
+reports	POS	O
+of	POS	O
+antimicrobial	POS	O
+-	POS	O
+induced	POS	O
+mania	POS	B-NP
+were	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+literature	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+6	POS	O
+cases	POS	O
+implicating	POS	O
+clarithromycin	POS	O
+,	POS	O
+13	POS	O
+implicating	POS	O
+isoniazid	POS	O
+,	POS	O
+and	POS	O
+1	POS	O
+case	POS	O
+each	POS	O
+implicating	POS	O
+erythromycin	POS	O
+and	POS	O
+amoxicillin	POS	O
+.	POS	O
+The	POS	O
+WHO	POS	O
+reported	POS	O
+82	POS	O
+cases	POS	O
+.	POS	O
+Of	POS	O
+these	POS	O
+,	POS	O
+clarithromycin	POS	O
+was	POS	O
+implicated	POS	O
+in	POS	O
+23	POS	O
+(	POS	O
+27	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+)	POS	O
+cases	POS	O
+,	POS	O
+ciprofloxacin	POS	O
+in	POS	O
+12	POS	O
+(	POS	O
+14	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+cases	POS	O
+,	POS	O
+and	POS	O
+ofloxacin	POS	O
+in	POS	O
+10	POS	O
+(	POS	O
+12	POS	O
+%	POS	O
+)	POS	O
+cases	POS	O
+.	POS	O
+Cotrimoxazole	POS	O
+,	POS	O
+metronidazole	POS	O
+,	POS	O
+and	POS	O
+erythromycin	POS	O
+were	POS	O
+involved	POS	O
+in	POS	O
+15	POS	O
+reported	POS	O
+manic	POS	B-NP
+episodes	POS	O
+.	POS	O
+Cases	POS	O
+reported	POS	O
+by	POS	O
+the	POS	O
+FDA	POS	O
+showed	POS	O
+clarithromycin	POS	O
+and	POS	O
+ciprofloxacin	POS	O
+to	POS	O
+be	POS	O
+the	POS	O
+most	POS	O
+frequently	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+mania	POS	B-NP
+.	POS	O
+Statistical	POS	O
+analysis	POS	O
+of	POS	O
+the	POS	O
+data	POS	O
+would	POS	O
+not	POS	O
+have	POS	O
+demonstrated	POS	O
+a	POS	O
+significant	POS	O
+statistical	POS	O
+correlative	POS	O
+risk	POS	O
+and	POS	O
+was	POS	O
+therefore	POS	O
+not	POS	O
+undertaken	POS	O
+.	POS	O
+Patients	POS	O
+have	POS	O
+an	POS	O
+increased	POS	O
+risk	POS	O
+of	POS	O
+developing	POS	O
+mania	POS	B-NP
+while	POS	O
+being	POS	O
+treated	POS	O
+with	POS	O
+antimicrobials	POS	O
+.	POS	O
+Although	POS	O
+this	POS	O
+is	POS	O
+not	POS	O
+a	POS	O
+statistically	POS	O
+significant	POS	O
+risk	POS	O
+,	POS	O
+physicians	POS	O
+must	POS	O
+be	POS	O
+aware	POS	O
+of	POS	O
+the	POS	O
+effect	POS	O
+and	POS	O
+reversibility	POS	O
+.	POS	O
+Further	POS	O
+research	POS	O
+clearly	POS	O
+is	POS	O
+required	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+antimicrobial	POS	O
+-	POS	O
+induced	POS	O
+mania	POS	B-NP
+,	POS	O
+the	POS	O
+relative	POS	O
+risk	POS	O
+factors	POS	O
+of	POS	O
+developing	POS	O
+an	POS	O
+antimicrobial	POS	O
+-	POS	O
+induced	POS	O
+manic	POS	B-NP
+episode	POS	O
+among	POS	O
+various	POS	O
+demographic	POS	O
+populations	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+patients	POS	O
+who	POS	O
+continue	POS	O
+to	POS	O
+have	POS	O
+persistent	POS	O
+affective	POS	B-NP
+disorders	POS	I-NP
+once	POS	O
+the	POS	O
+initial	POS	O
+episode	POS	O
+,	POS	O
+which	POS	O
+occurs	POS	O
+while	POS	O
+the	POS	O
+patient	POS	O
+is	POS	O
+taking	POS	O
+antibiotics	POS	O
+,	POS	O
+subsides	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+elected	POS	O
+to	POS	O
+name	POS	O
+this	POS	O
+syndrome	POS	O
+"	POS	O
+antibiomania	POS	B-NP
+.	POS	O
+"	POS	O
+Levodopa	POS	O
+-	POS	O
+induced	POS	O
+ocular	POS	B-NP
+dyskinesias	POS	I-NP
+in	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+Levodopa	POS	O
+-	POS	O
+induced	POS	O
+ocular	POS	B-NP
+dyskinesias	POS	I-NP
+are	POS	O
+very	POS	O
+uncommon	POS	O
+.	POS	O
+Usually	POS	O
+they	POS	O
+occur	POS	O
+simultaneously	POS	O
+with	POS	O
+limb	POS	O
+peak	POS	O
+-	POS	O
+dose	POS	O
+choreatic	POS	B-NP
+dyskinesias	POS	I-NP
+.	POS	O
+We	POS	O
+report	POS	O
+on	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+leftward	POS	O
+and	POS	O
+upward	POS	O
+deviations	POS	O
+of	POS	O
+gaze	POS	O
+during	POS	O
+the	POS	O
+peak	POS	O
+effect	POS	O
+of	POS	O
+levodopa	POS	O
+,	POS	O
+and	POS	O
+hypothesize	POS	O
+that	POS	O
+a	POS	O
+severe	POS	O
+dopaminergic	POS	O
+denervation	POS	O
+in	POS	O
+the	POS	O
+caudate	POS	O
+nucleus	POS	O
+is	POS	O
+needed	POS	O
+for	POS	O
+the	POS	O
+appearance	POS	O
+of	POS	O
+these	POS	O
+levodopa	POS	O
+-	POS	O
+induce	POS	O
+ocular	POS	O
+dyskinesias	POS	B-NP
+.	POS	O
+A	POS	O
+comparison	POS	O
+of	POS	O
+glyceryl	POS	O
+trinitrate	POS	O
+with	POS	O
+diclofenac	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+primary	POS	O
+dysmenorrhea	POS	B-NP
+:	POS	O
+an	POS	O
+open	POS	O
+,	POS	O
+randomized	POS	O
+,	POS	O
+cross	POS	O
+-	POS	O
+over	POS	O
+trial	POS	O
+.	POS	O
+Primary	POS	B-NP
+dysmenorrhea	POS	I-NP
+is	POS	O
+a	POS	O
+syndrome	POS	O
+characterized	POS	O
+by	POS	O
+painful	POS	B-NP
+uterine	POS	I-NP
+contractility	POS	I-NP
+caused	POS	O
+by	POS	O
+a	POS	O
+hypersecretion	POS	O
+of	POS	O
+endometrial	POS	O
+prostaglandins	POS	O
+;	POS	O
+non	POS	O
+-	POS	O
+steroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+are	POS	O
+the	POS	O
+first	POS	O
+choice	POS	O
+for	POS	O
+its	POS	O
+treatment	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+in	POS	O
+vivo	POS	O
+and	POS	O
+in	POS	O
+vitro	POS	O
+studies	POS	O
+have	POS	O
+demonstrated	POS	O
+that	POS	O
+myometrial	POS	O
+cells	POS	O
+are	POS	O
+also	POS	O
+targets	POS	O
+of	POS	O
+the	POS	O
+relaxant	POS	O
+effects	POS	O
+of	POS	O
+nitric	POS	O
+oxide	POS	O
+(	POS	O
+NO	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+efficacy	POS	O
+of	POS	O
+glyceryl	POS	O
+trinitrate	POS	O
+(	POS	O
+GTN	POS	O
+)	POS	O
+,	POS	O
+an	POS	O
+NO	POS	O
+donor	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+resolution	POS	O
+of	POS	O
+primary	POS	O
+dysmenorrhea	POS	B-NP
+in	POS	O
+comparison	POS	O
+with	POS	O
+diclofenac	POS	O
+(	POS	O
+DCF	POS	O
+)	POS	O
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+24	POS	O
+patients	POS	O
+with	POS	O
+the	POS	O
+diagnosis	POS	O
+of	POS	O
+severe	POS	O
+primary	POS	O
+dysmenorrhea	POS	B-NP
+were	POS	O
+studied	POS	O
+during	POS	O
+two	POS	O
+consecutive	POS	O
+menstrual	POS	O
+cycles	POS	O
+.	POS	O
+In	POS	O
+an	POS	O
+open	POS	O
+,	POS	O
+cross	POS	O
+-	POS	O
+over	POS	O
+,	POS	O
+controlled	POS	O
+design	POS	O
+,	POS	O
+patients	POS	O
+were	POS	O
+randomized	POS	O
+to	POS	O
+receive	POS	O
+either	POS	O
+DCF	POS	O
+per	POS	O
+os	POS	O
+or	POS	O
+GTN	POS	O
+patches	POS	O
+the	POS	O
+first	POS	O
+days	POS	O
+of	POS	O
+menses	POS	O
+,	POS	O
+when	POS	O
+menstrual	POS	B-NP
+cramps	POS	I-NP
+became	POS	O
+unendurable	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+subsequent	POS	O
+cycle	POS	O
+the	POS	O
+other	POS	O
+treatment	POS	O
+was	POS	O
+used	POS	O
+.	POS	O
+Patients	POS	O
+received	POS	O
+up	POS	O
+to	POS	O
+3	POS	O
+doses	POS	O
+/	POS	O
+day	POS	O
+of	POS	O
+50	POS	O
+mg	POS	O
+DCF	POS	O
+or	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+24	POS	O
+h	POS	O
+transdermal	POS	O
+GTN	POS	O
+for	POS	O
+the	POS	O
+first	POS	O
+3	POS	O
+days	POS	O
+of	POS	O
+the	POS	O
+cycle	POS	O
+,	POS	O
+according	POS	O
+to	POS	O
+their	POS	O
+needs	POS	O
+.	POS	O
+The	POS	O
+participants	POS	O
+recorded	POS	O
+menstrual	POS	O
+symptoms	POS	O
+and	POS	O
+possible	POS	O
+side	POS	O
+-	POS	O
+effects	POS	O
+at	POS	O
+different	POS	O
+times	POS	O
+(	POS	O
+0	POS	O
+,	POS	O
+30	POS	O
+,	POS	O
+60	POS	O
+,	POS	O
+120	POS	O
+minutes	POS	O
+)	POS	O
+after	POS	O
+the	POS	O
+first	POS	O
+dose	POS	O
+of	POS	O
+medication	POS	O
+on	POS	O
+the	POS	O
+first	POS	O
+day	POS	O
+of	POS	O
+the	POS	O
+cycle	POS	O
+,	POS	O
+with	POS	O
+both	POS	O
+drugs	POS	O
+.	POS	O
+The	POS	O
+difference	POS	O
+in	POS	O
+pain	POS	B-NP
+intensity	POS	O
+score	POS	O
+(	POS	O
+DPI	POS	O
+)	POS	O
+was	POS	O
+the	POS	O
+main	POS	O
+outcome	POS	O
+variable	POS	O
+.	POS	O
+Both	POS	O
+treatments	POS	O
+significantly	POS	O
+reduced	POS	O
+DPI	POS	O
+by	POS	O
+the	POS	O
+30th	POS	O
+minute	POS	O
+(	POS	O
+GTN	POS	O
+,	POS	O
+-	POS	O
+12	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+17	POS	O
+.	POS	O
+9	POS	O
+;	POS	O
+DCF	POS	O
+,	POS	O
+-	POS	O
+18	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+16	POS	O
+.	POS	O
+6	POS	O
+)	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+DCF	POS	O
+continued	POS	O
+to	POS	O
+be	POS	O
+effective	POS	O
+in	POS	O
+reducing	POS	O
+pelvic	POS	B-NP
+pain	POS	I-NP
+for	POS	O
+two	POS	O
+hours	POS	O
+,	POS	O
+whereas	POS	O
+GTN	POS	O
+scores	POS	O
+remained	POS	O
+more	POS	O
+or	POS	O
+less	POS	O
+stable	POS	O
+after	POS	O
+30	POS	O
+min	POS	O
+and	POS	O
+significantly	POS	O
+higher	POS	O
+than	POS	O
+those	POS	O
+for	POS	O
+DFC	POS	B-NP
+(	POS	O
+after	POS	O
+one	POS	O
+hour	POS	O
+:	POS	O
+GTN	POS	O
+,	POS	O
+-	POS	O
+12	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+17	POS	O
+.	POS	O
+9	POS	O
+;	POS	O
+DFC	POS	O
+,	POS	O
+-	POS	O
+18	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+16	POS	O
+.	POS	O
+6	POS	O
+and	POS	O
+after	POS	O
+two	POS	O
+hours	POS	O
+:	POS	O
+GTN	POS	O
+,	POS	O
+-	POS	O
+23	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+20	POS	O
+.	POS	O
+5	POS	O
+;	POS	O
+DFC	POS	O
+,	POS	O
+-	POS	O
+59	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+17	POS	O
+.	POS	O
+9	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+0001	POS	O
+)	POS	O
+.	POS	O
+Low	POS	B-NP
+back	POS	I-NP
+pain	POS	I-NP
+was	POS	O
+also	POS	O
+relieved	POS	O
+by	POS	O
+both	POS	O
+drugs	POS	O
+.	POS	O
+Headache	POS	B-NP
+was	POS	O
+significantly	POS	O
+increased	POS	O
+by	POS	O
+GTN	POS	O
+but	POS	O
+not	POS	O
+by	POS	O
+DCF	POS	O
+.	POS	O
+Eight	POS	O
+patients	POS	O
+stopped	POS	O
+using	POS	O
+GTN	POS	O
+because	POS	O
+headache	POS	B-NP
+-	POS	O
+-	POS	O
+attributed	POS	O
+to	POS	O
+its	POS	O
+use	POS	O
+-	POS	O
+-	POS	O
+became	POS	O
+intolerable	POS	O
+.	POS	O
+These	POS	O
+findings	POS	O
+indicate	POS	O
+that	POS	O
+GTN	POS	O
+has	POS	O
+a	POS	O
+reduced	POS	O
+efficacy	POS	O
+and	POS	O
+tolerability	POS	O
+by	POS	O
+comparison	POS	O
+with	POS	O
+DCF	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+primary	POS	O
+dysmenorrhea	POS	B-NP
+.	POS	O
+Temocapril	POS	O
+,	POS	O
+a	POS	O
+long	POS	O
+-	POS	O
+acting	POS	O
+non	POS	O
+-	POS	O
+SH	POS	O
+group	POS	O
+angiotensin	POS	O
+converting	POS	O
+enzyme	POS	O
+inhibitor	POS	O
+,	POS	O
+modulates	POS	O
+glomerular	POS	B-NP
+injury	POS	I-NP
+in	POS	O
+chronic	POS	O
+puromycin	POS	O
+aminonucleoside	POS	O
+nephrosis	POS	B-NP
+.	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+determine	POS	O
+whether	POS	O
+chronic	POS	O
+administration	POS	O
+of	POS	O
+temocapril	POS	O
+,	POS	O
+a	POS	O
+long	POS	O
+-	POS	O
+acting	POS	O
+non	POS	O
+-	POS	O
+SH	POS	O
+group	POS	O
+angiotensin	POS	O
+converting	POS	O
+enzyme	POS	O
+(	POS	O
+ACE	POS	O
+)	POS	O
+inhibitor	POS	O
+,	POS	O
+reduced	POS	O
+proteinuria	POS	B-NP
+,	POS	O
+inhibited	POS	O
+glomerular	POS	B-NP
+hypertrophy	POS	I-NP
+and	POS	O
+prevented	POS	O
+glomerulosclerosis	POS	B-NP
+in	POS	O
+chronic	POS	O
+puromycin	POS	O
+aminonucleoside	POS	O
+(	POS	O
+PAN	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+nephrotic	POS	B-NP
+rats	POS	O
+.	POS	O
+Nephrosis	POS	B-NP
+was	POS	O
+induced	POS	O
+by	POS	O
+injection	POS	O
+of	POS	O
+PAN	POS	O
+(	POS	O
+15mg	POS	O
+/	POS	O
+100g	POS	O
+body	POS	O
+weight	POS	O
+)	POS	O
+in	POS	O
+male	POS	O
+Sprague	POS	O
+-	POS	O
+Dawley	POS	O
+(	POS	O
+SD	POS	O
+)	POS	O
+rats	POS	O
+.	POS	O
+Four	POS	O
+groups	POS	O
+were	POS	O
+used	POS	O
+,	POS	O
+i	POS	O
+)	POS	O
+the	POS	O
+PAN	POS	O
+group	POS	O
+(	POS	O
+14	POS	O
+)	POS	O
+,	POS	O
+ii	POS	O
+)	POS	O
+PAN	POS	O
+/	POS	O
+temocapril	POS	O
+(	POS	O
+13	POS	O
+)	POS	O
+,	POS	O
+iii	POS	O
+)	POS	O
+temocapril	POS	O
+(	POS	O
+14	POS	O
+)	POS	O
+and	POS	O
+iv	POS	O
+)	POS	O
+untreated	POS	O
+controls	POS	O
+(	POS	O
+15	POS	O
+)	POS	O
+.	POS	O
+Temocapril	POS	O
+(	POS	O
+8	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+was	POS	O
+administered	POS	O
+to	POS	O
+the	POS	O
+rats	POS	O
+which	POS	O
+were	POS	O
+killed	POS	O
+at	POS	O
+weeks	POS	O
+4	POS	O
+,	POS	O
+14	POS	O
+or	POS	O
+20	POS	O
+.	POS	O
+At	POS	O
+each	POS	O
+time	POS	O
+point	POS	O
+,	POS	O
+systolic	POS	O
+blood	POS	O
+pressure	POS	O
+(	POS	O
+BP	POS	O
+)	POS	O
+,	POS	O
+urinary	POS	O
+protein	POS	O
+excretion	POS	O
+and	POS	O
+renal	POS	O
+histopathological	POS	O
+findings	POS	O
+were	POS	O
+evaluated	POS	O
+,	POS	O
+and	POS	O
+morphometric	POS	O
+image	POS	O
+analysis	POS	O
+was	POS	O
+done	POS	O
+.	POS	O
+Systolic	POS	O
+BP	POS	O
+in	POS	O
+the	POS	O
+PAN	POS	O
+group	POS	O
+was	POS	O
+significantly	POS	O
+high	POS	O
+at	POS	O
+4	POS	O
+,	POS	O
+14	POS	O
+and	POS	O
+20	POS	O
+weeks	POS	O
+,	POS	O
+but	POS	O
+was	POS	O
+normal	POS	O
+in	POS	O
+the	POS	O
+PAN	POS	O
+/	POS	O
+temocapril	POS	O
+group	POS	O
+.	POS	O
+Urinary	POS	O
+protein	POS	O
+excretion	POS	O
+in	POS	O
+the	POS	O
+PAN	POS	O
+group	POS	O
+increased	POS	O
+significantly	POS	O
+,	POS	O
+peaking	POS	O
+at	POS	O
+8	POS	O
+days	POS	O
+,	POS	O
+then	POS	O
+decreased	POS	O
+at	POS	O
+4	POS	O
+weeks	POS	O
+,	POS	O
+but	POS	O
+rose	POS	O
+again	POS	O
+significantly	POS	O
+at	POS	O
+14	POS	O
+and	POS	O
+20	POS	O
+weeks	POS	O
+.	POS	O
+Temocapril	POS	O
+did	POS	O
+not	POS	O
+attenuate	POS	O
+proteinuria	POS	B-NP
+at	POS	O
+8	POS	O
+days	POS	O
+,	POS	O
+but	POS	O
+it	POS	O
+did	POS	O
+markedly	POS	O
+lower	POS	O
+it	POS	O
+from	POS	O
+weeks	POS	O
+4	POS	O
+to	POS	O
+20	POS	O
+.	POS	O
+The	POS	O
+glomerulosclerosis	POS	B-NP
+index	POS	O
+(	POS	O
+GSI	POS	O
+)	POS	O
+was	POS	O
+6	POS	O
+.	POS	O
+21	POS	O
+%	POS	O
+at	POS	O
+4	POS	O
+weeks	POS	O
+and	POS	O
+respectively	POS	O
+25	POS	O
+.	POS	O
+35	POS	O
+%	POS	O
+and	POS	O
+30	POS	O
+.	POS	O
+49	POS	O
+%	POS	O
+at	POS	O
+14	POS	O
+and	POS	O
+20	POS	O
+weeks	POS	O
+in	POS	O
+the	POS	O
+PAN	POS	O
+group	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+correlation	POS	O
+between	POS	O
+urinary	POS	O
+protein	POS	O
+excretion	POS	O
+and	POS	O
+GSI	POS	O
+(	POS	O
+r	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+808	POS	O
+,	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+0001	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+ratio	POS	O
+of	POS	O
+glomerular	POS	O
+tuft	POS	O
+area	POS	O
+to	POS	O
+the	POS	O
+area	POS	O
+of	POS	O
+Bowman	POS	O
+'	POS	O
+s	POS	O
+capsules	POS	O
+(	POS	O
+GT	POS	O
+/	POS	O
+BC	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+PAN	POS	O
+group	POS	O
+was	POS	O
+significantly	POS	O
+increased	POS	O
+,	POS	O
+but	POS	O
+it	POS	O
+was	POS	O
+significantly	POS	O
+lower	POS	O
+in	POS	O
+the	POS	O
+PAN	POS	O
+/	POS	O
+temocapril	POS	O
+group	POS	O
+.	POS	O
+It	POS	O
+appears	POS	O
+that	POS	O
+temocapril	POS	O
+was	POS	O
+effective	POS	O
+in	POS	O
+retarding	POS	O
+renal	POS	O
+progression	POS	O
+and	POS	O
+protected	POS	O
+renal	POS	O
+function	POS	O
+in	POS	O
+PAN	POS	O
+neprotic	POS	O
+rats	POS	O
+.	POS	O
+Pulmonary	POS	B-NP
+hypertension	POS	I-NP
+after	POS	O
+ibuprofen	POS	O
+prophylaxis	POS	B-NP
+in	POS	O
+very	POS	O
+preterm	POS	B-NP
+infants	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+three	POS	O
+cases	POS	O
+of	POS	O
+severe	POS	O
+hypoxaemia	POS	B-NP
+after	POS	O
+ibuprofen	POS	O
+administration	POS	O
+during	POS	O
+a	POS	O
+randomised	POS	O
+controlled	POS	O
+trial	POS	O
+of	POS	O
+prophylactic	POS	O
+treatment	POS	O
+of	POS	O
+patent	POS	O
+ductus	POS	B-NP
+arteriosus	POS	I-NP
+with	POS	O
+ibuprofen	POS	O
+in	POS	O
+premature	POS	O
+infants	POS	O
+born	POS	O
+at	POS	O
+less	POS	O
+than	POS	O
+28	POS	O
+weeks	POS	O
+of	POS	O
+gestation	POS	O
+.	POS	O
+Echocardiography	POS	O
+showed	POS	O
+severely	POS	O
+decreased	POS	O
+pulmonary	POS	O
+blood	POS	O
+flow	POS	O
+.	POS	O
+Hypoxaemia	POS	B-NP
+resolved	POS	O
+quickly	POS	O
+on	POS	O
+inhaled	POS	O
+nitric	POS	O
+oxide	POS	O
+therapy	POS	O
+.	POS	O
+We	POS	O
+suggest	POS	O
+that	POS	O
+investigators	POS	O
+involved	POS	O
+in	POS	O
+similar	POS	O
+trials	POS	O
+pay	POS	O
+close	POS	O
+attention	POS	O
+to	POS	O
+pulmonary	POS	O
+pressure	POS	O
+if	POS	O
+hypoxaemia	POS	B-NP
+occurs	POS	O
+after	POS	O
+prophylactic	POS	O
+administration	POS	O
+of	POS	O
+ibuprofen	POS	O
+.	POS	O
+Hyponatremia	POS	B-NP
+and	POS	O
+syndrome	POS	O
+of	POS	O
+inappropriate	POS	O
+anti	POS	O
+-	POS	O
+diuretic	POS	O
+hormone	POS	O
+reported	POS	O
+with	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+Vincristine	POS	O
+:	POS	O
+an	POS	O
+over	POS	O
+-	POS	O
+representation	POS	O
+of	POS	O
+Asians	POS	O
+?	POS	O
+PURPOSE	POS	O
+:	POS	O
+This	POS	O
+retrospective	POS	O
+study	POS	O
+used	POS	O
+a	POS	O
+pharmaceutical	POS	O
+company	POS	O
+'	POS	O
+s	POS	O
+global	POS	O
+safety	POS	O
+database	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+reporting	POS	O
+rate	POS	O
+of	POS	O
+hyponatremia	POS	B-NP
+and	POS	O
+/	POS	O
+or	POS	O
+syndrome	POS	O
+of	POS	O
+inappropriate	POS	O
+secretion	POS	O
+of	POS	O
+anti	POS	O
+-	POS	O
+diuretic	POS	O
+hormone	POS	O
+(	POS	O
+SIADH	POS	B-NP
+)	POS	O
+among	POS	O
+vincristine	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+and	POS	O
+to	POS	O
+explore	POS	O
+the	POS	O
+possibility	POS	O
+of	POS	O
+at	POS	O
+-	POS	O
+risk	POS	O
+population	POS	O
+subgroups	POS	O
+.	POS	O
+METHOD	POS	O
+:	POS	O
+We	POS	O
+searched	POS	O
+the	POS	O
+Eli	POS	O
+Lilly	POS	O
+and	POS	O
+Company	POS	O
+'	POS	O
+s	POS	O
+computerized	POS	O
+adverse	POS	O
+event	POS	O
+database	POS	O
+for	POS	O
+all	POS	O
+reported	POS	O
+cases	POS	O
+of	POS	O
+hyponatremia	POS	B-NP
+and	POS	O
+/	POS	O
+or	POS	O
+SIADH	POS	B-NP
+as	POS	O
+of	POS	O
+1	POS	O
+November	POS	O
+1999	POS	O
+that	POS	O
+had	POS	O
+been	POS	O
+reported	POS	O
+during	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+vincristine	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+76	POS	O
+cases	POS	O
+of	POS	O
+hyponatremia	POS	B-NP
+and	POS	O
+/	POS	O
+or	POS	O
+SIADH	POS	B-NP
+associated	POS	O
+with	POS	O
+vincristine	POS	O
+use	POS	O
+were	POS	O
+identified	POS	O
+.	POS	O
+The	POS	O
+overall	POS	O
+reporting	POS	O
+rate	POS	O
+was	POS	O
+estimated	POS	O
+to	POS	O
+be	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+/	POS	O
+100	POS	O
+,	POS	O
+000	POS	O
+treated	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+average	POS	O
+age	POS	O
+of	POS	O
+patients	POS	O
+was	POS	O
+35	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+28	POS	O
+.	POS	O
+3	POS	O
+years	POS	O
+,	POS	O
+and	POS	O
+62	POS	O
+%	POS	O
+were	POS	O
+males	POS	O
+.	POS	O
+Approximately	POS	O
+75	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+were	POS	O
+receiving	POS	O
+treatment	POS	O
+for	POS	O
+leukemia	POS	B-NP
+or	POS	O
+lymphoma	POS	B-NP
+.	POS	O
+Among	POS	O
+the	POS	O
+39	POS	O
+reports	POS	O
+that	POS	O
+included	POS	O
+information	POS	O
+on	POS	O
+race	POS	O
+,	POS	O
+the	POS	O
+racial	POS	O
+distribution	POS	O
+was	POS	O
+:	POS	O
+1	POS	O
+Black	POS	O
+,	POS	O
+3	POS	O
+Caucasian	POS	O
+,	POS	O
+and	POS	O
+35	POS	O
+Asian	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Our	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+Asian	POS	O
+patients	POS	O
+may	POS	O
+be	POS	O
+at	POS	O
+increased	POS	O
+risk	POS	O
+of	POS	O
+hyponatremia	POS	B-NP
+and	POS	O
+/	POS	O
+or	POS	O
+SIADH	POS	B-NP
+associated	POS	O
+with	POS	O
+vincristine	POS	O
+use	POS	O
+.	POS	O
+Although	POS	O
+the	POS	O
+overall	POS	O
+reported	POS	O
+rate	POS	O
+of	POS	O
+SIADH	POS	B-NP
+associated	POS	O
+with	POS	O
+vincristine	POS	O
+is	POS	O
+very	POS	O
+low	POS	O
+,	POS	O
+physicians	POS	O
+caring	POS	O
+for	POS	O
+Asian	POS	O
+oncology	POS	O
+patients	POS	O
+should	POS	O
+be	POS	O
+aware	POS	O
+of	POS	O
+this	POS	O
+potential	POS	O
+serious	POS	O
+but	POS	O
+reversible	POS	O
+adverse	POS	O
+event	POS	O
+.	POS	O
+Delayed	POS	B-NP
+toxicity	POS	I-NP
+of	POS	O
+cyclophosphamide	POS	O
+on	POS	O
+the	POS	O
+bladder	POS	O
+of	POS	O
+DBA	POS	O
+/	POS	O
+2	POS	O
+and	POS	O
+C57BL	POS	O
+/	POS	O
+6	POS	O
+female	POS	O
+mouse	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+describes	POS	O
+the	POS	O
+delayed	POS	O
+development	POS	O
+of	POS	O
+a	POS	O
+severe	POS	O
+bladder	POS	B-NP
+pathology	POS	I-NP
+in	POS	O
+a	POS	O
+susceptible	POS	O
+strain	POS	O
+of	POS	O
+mice	POS	O
+(	POS	O
+DBA	POS	O
+/	POS	O
+2	POS	O
+)	POS	O
+but	POS	O
+not	POS	O
+in	POS	O
+a	POS	O
+resistant	POS	O
+strain	POS	O
+(	POS	O
+C57BL	POS	O
+/	POS	O
+6	POS	O
+)	POS	O
+when	POS	O
+both	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+a	POS	O
+single	POS	O
+300	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+dose	POS	O
+of	POS	O
+cyclophosphamide	POS	O
+(	POS	O
+CY	POS	O
+)	POS	O
+.	POS	O
+Inbred	POS	O
+DBA	POS	O
+/	POS	O
+2	POS	O
+and	POS	O
+C57BL	POS	O
+/	POS	O
+6	POS	O
+female	POS	O
+mice	POS	O
+were	POS	O
+injected	POS	O
+with	POS	O
+CY	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+on	POS	O
+the	POS	O
+bladder	POS	O
+was	POS	O
+assessed	POS	O
+during	POS	O
+100	POS	O
+days	POS	O
+by	POS	O
+light	POS	O
+microscopy	POS	O
+using	POS	O
+different	POS	O
+staining	POS	O
+procedures	POS	O
+,	POS	O
+and	POS	O
+after	POS	O
+30	POS	O
+days	POS	O
+by	POS	O
+conventional	POS	O
+electron	POS	O
+microscopy	POS	O
+.	POS	O
+Early	POS	O
+CY	POS	O
+toxicity	POS	B-NP
+caused	POS	O
+a	POS	O
+typical	POS	O
+haemorrhagic	POS	B-NP
+cystitis	POS	I-NP
+in	POS	O
+both	POS	O
+strains	POS	O
+that	POS	O
+was	POS	O
+completely	POS	O
+repaired	POS	O
+in	POS	O
+about	POS	O
+7	POS	O
+-	POS	O
+10	POS	O
+days	POS	O
+.	POS	O
+After	POS	O
+30	POS	O
+days	POS	O
+of	POS	O
+CY	POS	O
+injection	POS	O
+ulcerous	POS	B-NP
+and	POS	O
+non	POS	O
+-	POS	O
+ulcerous	POS	O
+forms	POS	O
+of	POS	O
+chronic	POS	B-NP
+cystitis	POS	I-NP
+appeared	POS	O
+in	POS	O
+86	POS	O
+%	POS	O
+of	POS	O
+DBA	POS	O
+/	POS	O
+2	POS	O
+mice	POS	O
+but	POS	O
+only	POS	O
+in	POS	O
+4	POS	O
+%	POS	O
+of	POS	O
+C57BL	POS	O
+/	POS	O
+6	POS	O
+mice	POS	O
+.	POS	O
+Delayed	POS	O
+cystitis	POS	B-NP
+was	POS	O
+characterized	POS	O
+by	POS	O
+infiltration	POS	O
+and	POS	O
+transepithelial	POS	O
+passage	POS	O
+into	POS	O
+the	POS	O
+lumen	POS	O
+of	POS	O
+inflammatory	POS	O
+cells	POS	O
+and	POS	O
+by	POS	O
+frequent	POS	O
+exfoliation	POS	O
+of	POS	O
+the	POS	O
+urothelium	POS	O
+.	POS	O
+Mast	POS	O
+cells	POS	O
+appeared	POS	O
+in	POS	O
+the	POS	O
+connective	POS	O
+and	POS	O
+muscular	POS	O
+layers	POS	O
+of	POS	O
+the	POS	O
+bladder	POS	O
+at	POS	O
+a	POS	O
+much	POS	O
+higher	POS	O
+number	POS	O
+in	POS	O
+DBA	POS	O
+/	POS	O
+2	POS	O
+mice	POS	O
+than	POS	O
+in	POS	O
+C57BL	POS	O
+/	POS	O
+6	POS	O
+mice	POS	O
+or	POS	O
+untreated	POS	O
+controls	POS	O
+.	POS	O
+Electron	POS	O
+microscopy	POS	O
+disclosed	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+the	POS	O
+typical	POS	O
+discoidal	POS	O
+vesicles	POS	O
+normally	POS	O
+present	POS	O
+in	POS	O
+the	POS	O
+cytoplasm	POS	O
+of	POS	O
+surface	POS	O
+cells	POS	O
+.	POS	O
+Instead	POS	O
+,	POS	O
+numerous	POS	O
+abnormal	POS	O
+vesicles	POS	O
+containing	POS	O
+one	POS	O
+or	POS	O
+several	POS	O
+dark	POS	O
+granules	POS	O
+were	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+cytoplasm	POS	O
+of	POS	O
+cells	POS	O
+from	POS	O
+all	POS	O
+the	POS	O
+epithelial	POS	O
+layers	POS	O
+.	POS	O
+Delayed	POS	O
+cystitis	POS	B-NP
+still	POS	O
+persisted	POS	O
+in	POS	O
+DBA	POS	O
+/	POS	O
+2	POS	O
+mice	POS	O
+100	POS	O
+days	POS	O
+after	POS	O
+treatment	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+delayed	POS	O
+toxicity	POS	B-NP
+of	POS	O
+CY	POS	O
+in	POS	O
+female	POS	O
+DBA	POS	O
+/	POS	O
+2	POS	O
+mice	POS	O
+causes	POS	O
+a	POS	O
+bladder	POS	O
+pathology	POS	O
+that	POS	O
+is	POS	O
+not	POS	O
+observed	POS	O
+in	POS	O
+C57BL	POS	O
+/	POS	O
+6	POS	O
+mice	POS	O
+.	POS	O
+This	POS	O
+pathology	POS	O
+resembles	POS	O
+interstitial	POS	B-NP
+cystitis	POS	I-NP
+in	POS	O
+humans	POS	O
+and	POS	O
+could	POS	O
+perhaps	POS	O
+be	POS	O
+used	POS	O
+as	POS	O
+an	POS	O
+animal	POS	O
+model	POS	O
+for	POS	O
+studies	POS	O
+on	POS	O
+the	POS	O
+disease	POS	O
+.	POS	O
+High	POS	O
+-	POS	O
+dose	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+/	POS	O
+folinic	POS	O
+acid	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+three	POS	O
+-	POS	O
+weekly	POS	O
+mitomycin	POS	O
+C	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+advanced	POS	O
+gastric	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+A	POS	O
+phase	POS	O
+II	POS	O
+study	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+The	POS	O
+24	POS	O
+-	POS	O
+hour	POS	O
+continuous	POS	O
+infusion	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+(	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+)	POS	O
+and	POS	O
+folinic	POS	O
+acid	POS	O
+(	POS	O
+FA	POS	O
+)	POS	O
+as	POS	O
+part	POS	O
+of	POS	O
+several	POS	O
+new	POS	O
+multidrug	POS	O
+chemotherapy	POS	O
+regimens	POS	O
+in	POS	O
+advanced	POS	O
+gastric	POS	B-NP
+cancer	POS	I-NP
+(	POS	O
+AGC	POS	O
+)	POS	O
+has	POS	O
+shown	POS	O
+to	POS	O
+be	POS	O
+effective	POS	O
+,	POS	O
+with	POS	O
+low	POS	B-NP
+toxicity	POS	I-NP
+.	POS	O
+In	POS	O
+a	POS	O
+previous	POS	O
+phase	POS	O
+II	POS	O
+study	POS	O
+with	POS	O
+3	POS	O
+-	POS	O
+weekly	POS	O
+bolus	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+,	POS	O
+FA	POS	O
+and	POS	O
+mitomycin	POS	O
+C	POS	O
+(	POS	O
+MMC	POS	O
+)	POS	O
+we	POS	O
+found	POS	O
+a	POS	O
+low	POS	O
+toxicity	POS	B-NP
+rate	POS	O
+and	POS	O
+response	POS	O
+rates	POS	O
+comparable	POS	O
+to	POS	O
+those	POS	O
+of	POS	O
+regimens	POS	O
+such	POS	O
+as	POS	O
+ELF	POS	O
+,	POS	O
+FAM	POS	O
+or	POS	O
+FAMTX	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+promising	POS	O
+median	POS	O
+overall	POS	O
+survival	POS	O
+.	POS	O
+In	POS	O
+order	POS	O
+to	POS	O
+improve	POS	O
+this	POS	O
+MMC	POS	O
+-	POS	O
+dependent	POS	O
+schedule	POS	O
+we	POS	O
+initiated	POS	O
+a	POS	O
+phase	POS	O
+II	POS	O
+study	POS	O
+with	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+/	POS	O
+FA	POS	O
+and	POS	O
+3	POS	O
+-	POS	O
+weekly	POS	O
+bolus	POS	O
+MMC	POS	O
+.	POS	O
+PATIENTS	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+From	POS	O
+February	POS	O
+,	POS	O
+1998	POS	O
+to	POS	O
+September	POS	O
+,	POS	O
+2000	POS	O
+we	POS	O
+recruited	POS	O
+33	POS	O
+patients	POS	O
+with	POS	O
+AGC	POS	O
+to	POS	O
+receive	POS	O
+weekly	POS	O
+24	POS	O
+-	POS	O
+hour	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+2	POS	O
+,	POS	O
+600	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+preceded	POS	O
+by	POS	O
+2	POS	O
+-	POS	O
+hour	POS	O
+FA	POS	O
+500	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+for	POS	O
+6	POS	O
+weeks	POS	O
+,	POS	O
+followed	POS	O
+by	POS	O
+a	POS	O
+2	POS	O
+-	POS	O
+week	POS	O
+rest	POS	O
+period	POS	O
+.	POS	O
+Bolus	POS	O
+MMC	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+was	POS	O
+added	POS	O
+in	POS	O
+3	POS	O
+-	POS	O
+weekly	POS	O
+intervals	POS	O
+.	POS	O
+Treatment	POS	O
+given	POS	O
+on	POS	O
+an	POS	O
+outpatient	POS	O
+basis	POS	O
+,	POS	O
+using	POS	O
+portable	POS	O
+pump	POS	O
+systems	POS	O
+,	POS	O
+was	POS	O
+repeated	POS	O
+on	POS	O
+day	POS	O
+57	POS	O
+.	POS	O
+Patients	POS	O
+'	POS	O
+characteristics	POS	O
+were	POS	O
+:	POS	O
+male	POS	O
+/	POS	O
+female	POS	O
+ratio	POS	O
+20	POS	O
+/	POS	O
+13	POS	O
+;	POS	O
+median	POS	O
+age	POS	O
+57	POS	O
+(	POS	O
+27	POS	O
+-	POS	O
+75	POS	O
+)	POS	O
+years	POS	O
+;	POS	O
+median	POS	O
+WHO	POS	O
+status	POS	O
+1	POS	O
+(	POS	O
+0	POS	O
+-	POS	O
+2	POS	O
+)	POS	O
+.	POS	O
+18	POS	O
+patients	POS	O
+had	POS	O
+a	POS	O
+primary	POS	O
+AGC	POS	O
+,	POS	O
+and	POS	O
+15	POS	O
+showed	POS	O
+a	POS	O
+relapsed	POS	O
+AGC	POS	O
+.	POS	O
+Median	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+was	POS	O
+11	POS	O
+.	POS	O
+8	POS	O
+months	POS	O
+(	POS	O
+range	POS	O
+of	POS	O
+those	POS	O
+surviving	POS	O
+:	POS	O
+2	POS	O
+.	POS	O
+7	POS	O
+-	POS	O
+11	POS	O
+.	POS	O
+8	POS	O
+months	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+32	POS	O
+patients	POS	O
+were	POS	O
+evaluable	POS	O
+for	POS	O
+response	POS	O
+-	POS	O
+complete	POS	O
+remission	POS	O
+9	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+3	POS	O
+)	POS	O
+,	POS	O
+partial	POS	O
+remission	POS	O
+45	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+15	POS	O
+)	POS	O
+,	POS	O
+no	POS	O
+change	POS	O
+27	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+9	POS	O
+)	POS	O
+,	POS	O
+progressive	POS	O
+disease	POS	O
+15	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+5	POS	O
+)	POS	O
+.	POS	O
+Median	POS	O
+overall	POS	O
+survival	POS	O
+time	POS	O
+was	POS	O
+10	POS	O
+.	POS	O
+2	POS	O
+months	POS	O
+[	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+(	POS	O
+CI	POS	O
+)	POS	O
+:	POS	O
+8	POS	O
+.	POS	O
+7	POS	O
+-	POS	O
+11	POS	O
+.	POS	O
+6	POS	O
+]	POS	O
+,	POS	O
+and	POS	O
+median	POS	O
+progression	POS	O
+-	POS	O
+free	POS	O
+survival	POS	O
+time	POS	O
+was	POS	O
+7	POS	O
+.	POS	O
+6	POS	O
+months	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+:	POS	O
+4	POS	O
+.	POS	O
+4	POS	O
+-	POS	O
+10	POS	O
+.	POS	O
+9	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+worst	POS	O
+toxicities	POS	B-NP
+(	POS	O
+%	POS	O
+)	POS	O
+observed	POS	O
+were	POS	O
+(	POS	O
+CTC	POS	O
+-	POS	O
+NCI	POS	O
+1	POS	O
+/	POS	O
+2	POS	O
+/	POS	O
+3	POS	O
+)	POS	O
+:	POS	O
+leukopenia	POS	B-NP
+45	POS	O
+.	POS	O
+5	POS	O
+/	POS	O
+18	POS	O
+.	POS	O
+2	POS	O
+/	POS	O
+6	POS	O
+.	POS	O
+1	POS	O
+,	POS	O
+thrombocytopenia	POS	B-NP
+33	POS	O
+.	POS	O
+3	POS	O
+/	POS	O
+9	POS	O
+.	POS	O
+1	POS	O
+/	POS	O
+6	POS	O
+.	POS	O
+1	POS	O
+,	POS	O
+vomitus	POS	O
+24	POS	O
+.	POS	O
+2	POS	O
+/	POS	O
+9	POS	O
+.	POS	O
+1	POS	O
+/	POS	O
+0	POS	O
+,	POS	O
+diarrhea	POS	B-NP
+36	POS	O
+.	POS	O
+4	POS	O
+/	POS	O
+6	POS	O
+.	POS	O
+1	POS	O
+/	POS	O
+3	POS	O
+.	POS	O
+0	POS	O
+,	POS	O
+stomatitis	POS	B-NP
+18	POS	O
+.	POS	O
+2	POS	O
+/	POS	O
+9	POS	O
+.	POS	O
+1	POS	O
+/	POS	O
+0	POS	O
+,	POS	O
+hand	POS	O
+-	POS	O
+foot	POS	B-NP
+syndrome	POS	I-NP
+12	POS	O
+.	POS	O
+1	POS	O
+/	POS	O
+0	POS	O
+/	POS	O
+0	POS	O
+.	POS	O
+Two	POS	O
+patients	POS	O
+developed	POS	O
+hemolytic	POS	B-NP
+-	POS	I-NP
+uremic	POS	I-NP
+syndrome	POS	I-NP
+(	POS	O
+HUS	POS	B-NP
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+High	POS	O
+-	POS	O
+dose	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+/	POS	O
+FA	POS	O
+/	POS	O
+MMC	POS	O
+is	POS	O
+an	POS	O
+effective	POS	O
+and	POS	O
+well	POS	O
+-	POS	O
+tolerated	POS	O
+outpatient	POS	O
+regimen	POS	O
+for	POS	O
+AGC	POS	O
+(	POS	O
+objective	POS	O
+response	POS	O
+rate	POS	O
+54	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+It	POS	O
+may	POS	O
+serve	POS	O
+as	POS	O
+an	POS	O
+alternative	POS	O
+to	POS	O
+cisplatin	POS	O
+-	POS	O
+containing	POS	O
+regimens	POS	O
+;	POS	O
+however	POS	O
+,	POS	O
+it	POS	O
+has	POS	O
+to	POS	O
+be	POS	O
+considered	POS	O
+that	POS	O
+possibly	POS	O
+HUS	POS	B-NP
+may	POS	O
+occur	POS	O
+.	POS	O
+Persistent	POS	O
+sterile	POS	O
+leukocyturia	POS	B-NP
+is	POS	O
+associated	POS	O
+with	POS	O
+impaired	POS	B-NP
+renal	POS	I-NP
+function	POS	I-NP
+in	POS	I-NP
+human	POS	I-NP
+immunodeficiency	POS	I-NP
+virus	POS	I-NP
+type	POS	I-NP
+1	POS	I-NP
+-	POS	I-NP
+infected	POS	I-NP
+children	POS	O
+treated	POS	O
+with	POS	O
+indinavir	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Prolonged	POS	O
+administration	POS	O
+of	POS	O
+indinavir	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+a	POS	O
+variety	POS	O
+of	POS	O
+renal	POS	B-NP
+complications	POS	I-NP
+in	POS	O
+adults	POS	O
+.	POS	O
+These	POS	O
+well	POS	O
+-	POS	O
+documented	POS	O
+side	POS	O
+effects	POS	O
+have	POS	O
+restricted	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+this	POS	O
+potent	POS	O
+protease	POS	O
+inhibitor	POS	O
+in	POS	O
+children	POS	O
+.	POS	O
+DESIGN	POS	O
+:	POS	O
+A	POS	O
+prospective	POS	O
+study	POS	O
+to	POS	O
+monitor	POS	O
+indinavir	POS	O
+-	POS	O
+related	POS	O
+nephrotoxicity	POS	B-NP
+in	POS	O
+a	POS	O
+cohort	POS	O
+of	POS	O
+30	POS	O
+human	POS	O
+immunodeficiency	POS	B-NP
+virus	POS	I-NP
+type	POS	I-NP
+1	POS	I-NP
+-	POS	I-NP
+infected	POS	I-NP
+children	POS	O
+treated	POS	O
+with	POS	O
+indinavir	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Urinary	POS	O
+pH	POS	O
+,	POS	O
+albumin	POS	O
+,	POS	O
+creatinine	POS	O
+,	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+erythrocytes	POS	O
+,	POS	O
+leukocytes	POS	O
+,	POS	O
+bacteria	POS	O
+and	POS	O
+crystals	POS	O
+,	POS	O
+and	POS	O
+culture	POS	O
+were	POS	O
+analyzed	POS	O
+every	POS	O
+3	POS	O
+months	POS	O
+for	POS	O
+96	POS	O
+weeks	POS	O
+.	POS	O
+Serum	POS	O
+creatinine	POS	O
+levels	POS	O
+were	POS	O
+routinely	POS	O
+determined	POS	O
+at	POS	O
+the	POS	O
+same	POS	O
+time	POS	O
+points	POS	O
+.	POS	O
+Steady	POS	O
+-	POS	O
+state	POS	O
+pharmacokinetics	POS	O
+of	POS	O
+indinavir	POS	O
+were	POS	O
+done	POS	O
+at	POS	O
+week	POS	O
+4	POS	O
+after	POS	O
+the	POS	O
+initiation	POS	O
+of	POS	O
+indinavir	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+cumulative	POS	O
+incidence	POS	O
+of	POS	O
+persistent	POS	O
+sterile	POS	O
+leukocyturia	POS	B-NP
+(	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+75	POS	O
+cells	POS	O
+/	POS	O
+micro	POS	O
+L	POS	O
+in	POS	O
+at	POS	O
+least	POS	O
+2	POS	O
+consecutive	POS	O
+visits	POS	O
+)	POS	O
+after	POS	O
+96	POS	O
+weeks	POS	O
+was	POS	O
+53	POS	O
+%	POS	O
+.	POS	O
+Persistent	POS	O
+sterile	POS	O
+leukocyturia	POS	B-NP
+was	POS	O
+frequently	POS	O
+associated	POS	O
+with	POS	O
+a	POS	O
+mild	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+urine	POS	O
+albumin	POS	O
+/	POS	O
+creatinine	POS	O
+ratio	POS	O
+and	POS	O
+by	POS	O
+microscopic	POS	O
+hematuria	POS	B-NP
+.	POS	O
+The	POS	O
+cumulative	POS	O
+incidence	POS	O
+of	POS	O
+serum	POS	O
+creatinine	POS	O
+levels	POS	O
+>	POS	O
+50	POS	O
+%	POS	O
+above	POS	O
+normal	POS	B-NP
+was	POS	O
+33	POS	O
+%	POS	O
+after	POS	O
+96	POS	O
+weeks	POS	O
+.	POS	O
+Children	POS	O
+with	POS	O
+persistent	POS	O
+sterile	POS	O
+leukocyturia	POS	B-NP
+more	POS	O
+frequently	POS	O
+had	POS	O
+serum	POS	O
+creatinine	POS	O
+levels	POS	O
+of	POS	O
+50	POS	O
+%	POS	O
+above	POS	O
+normal	POS	B-NP
+than	POS	O
+those	POS	O
+children	POS	O
+without	POS	O
+persistent	POS	O
+sterile	POS	O
+leukocyturia	POS	B-NP
+.	POS	O
+In	POS	O
+children	POS	O
+younger	POS	O
+than	POS	O
+5	POS	O
+.	POS	O
+6	POS	O
+years	POS	O
+,	POS	O
+persistent	POS	O
+sterile	POS	O
+leukocyturia	POS	B-NP
+was	POS	O
+significantly	POS	O
+more	POS	O
+frequent	POS	O
+than	POS	O
+in	POS	O
+older	POS	O
+children	POS	O
+.	POS	O
+A	POS	O
+higher	POS	O
+cumulative	POS	O
+incidence	POS	O
+of	POS	O
+persistent	POS	O
+leukocyturia	POS	B-NP
+was	POS	O
+found	POS	O
+in	POS	O
+children	POS	O
+with	POS	O
+an	POS	O
+area	POS	O
+under	POS	O
+the	POS	O
+curve	POS	O
+>	POS	O
+19	POS	O
+mg	POS	O
+/	POS	O
+L	POS	O
+x	POS	O
+h	POS	O
+or	POS	O
+a	POS	O
+peak	POS	O
+serum	POS	O
+level	POS	O
+of	POS	O
+indinavir	POS	O
+>	POS	O
+12	POS	O
+mg	POS	O
+/	POS	O
+L	POS	O
+.	POS	O
+In	POS	O
+4	POS	O
+children	POS	O
+,	POS	O
+indinavir	POS	O
+was	POS	O
+discontinued	POS	O
+because	POS	O
+of	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+Subsequently	POS	O
+,	POS	O
+the	POS	O
+serum	POS	O
+creatinine	POS	O
+levels	POS	O
+decreased	POS	O
+,	POS	O
+the	POS	O
+urine	POS	O
+albumin	POS	O
+/	POS	O
+creatinine	POS	O
+ratios	POS	O
+returned	POS	O
+to	POS	O
+zero	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+leukocyturia	POS	B-NP
+disappeared	POS	O
+within	POS	O
+3	POS	O
+months	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Children	POS	O
+treated	POS	O
+with	POS	O
+indinavir	POS	O
+have	POS	O
+a	POS	O
+high	POS	O
+cumulative	POS	O
+incidence	POS	O
+of	POS	O
+persistent	POS	O
+sterile	POS	O
+leukocyturia	POS	B-NP
+.	POS	O
+Children	POS	O
+with	POS	O
+persistent	POS	O
+sterile	POS	O
+leukocyturia	POS	B-NP
+more	POS	O
+frequently	POS	O
+had	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+serum	POS	O
+creatinine	POS	O
+levels	POS	O
+of	POS	O
+>	POS	O
+50	POS	O
+%	POS	O
+above	POS	O
+normal	POS	B-NP
+.	POS	O
+Younger	POS	O
+children	POS	O
+have	POS	O
+an	POS	O
+additional	POS	O
+risk	POS	O
+for	POS	O
+renal	POS	B-NP
+complications	POS	I-NP
+.	POS	O
+The	POS	O
+impairment	POS	B-NP
+of	POS	I-NP
+the	POS	I-NP
+renal	POS	I-NP
+function	POS	I-NP
+in	POS	O
+these	POS	O
+children	POS	O
+occurred	POS	O
+in	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+clinical	POS	O
+symptoms	POS	O
+of	POS	O
+nephrolithiasis	POS	B-NP
+.	POS	O
+Indinavir	POS	O
+-	POS	O
+associated	POS	O
+nephrotoxicity	POS	B-NP
+must	POS	O
+be	POS	O
+monitored	POS	O
+closely	POS	O
+,	POS	O
+especially	POS	O
+in	POS	O
+children	POS	O
+with	POS	O
+risk	POS	O
+factors	POS	O
+such	POS	O
+as	POS	O
+persistent	POS	O
+sterile	POS	O
+leukocyturia	POS	B-NP
+,	POS	O
+age	POS	O
+<	POS	O
+5	POS	O
+.	POS	O
+6	POS	O
+years	POS	O
+,	POS	O
+an	POS	O
+area	POS	O
+under	POS	O
+the	POS	O
+curve	POS	O
+of	POS	O
+indinavir	POS	O
+>	POS	O
+19	POS	O
+mg	POS	O
+/	POS	O
+L	POS	O
+x	POS	O
+h	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+C	POS	O
+(	POS	O
+max	POS	O
+)	POS	O
+>	POS	O
+12	POS	O
+mg	POS	O
+/	POS	O
+L	POS	O
+.	POS	O
+Utility	POS	O
+of	POS	O
+troponin	POS	O
+I	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+.	POS	O
+Baseline	POS	B-NP
+electrocardiogram	POS	I-NP
+abnormalities	POS	I-NP
+and	POS	O
+market	POS	O
+elevations	POS	O
+not	POS	O
+associated	POS	O
+with	POS	O
+myocardial	POS	B-NP
+necrosis	POS	I-NP
+make	POS	O
+accurate	POS	O
+diagnosis	POS	O
+of	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+(	POS	O
+MI	POS	B-NP
+)	POS	O
+difficult	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+.	POS	O
+Troponin	POS	O
+sampling	POS	O
+may	POS	O
+offer	POS	O
+greater	POS	O
+diagnostic	POS	O
+utility	POS	O
+in	POS	O
+these	POS	O
+patients	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+assess	POS	O
+outcomes	POS	O
+based	POS	O
+on	POS	O
+troponin	POS	O
+positivity	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	B-NP
+chest	POS	I-NP
+pain	POS	I-NP
+admitted	POS	O
+for	POS	O
+exclusion	POS	O
+of	POS	O
+MI	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Outcomes	POS	O
+were	POS	O
+examined	POS	O
+in	POS	O
+patients	POS	O
+admitted	POS	O
+for	POS	O
+possible	POS	O
+MI	POS	B-NP
+after	POS	O
+cocaine	POS	O
+use	POS	O
+.	POS	O
+All	POS	O
+patients	POS	O
+underwent	POS	O
+a	POS	O
+rapid	POS	O
+rule	POS	O
+-	POS	O
+in	POS	O
+protocol	POS	O
+that	POS	O
+included	POS	O
+serial	POS	O
+sampling	POS	O
+of	POS	O
+creatine	POS	O
+kinase	POS	O
+(	POS	O
+CK	POS	O
+)	POS	O
+,	POS	O
+CK	POS	O
+-	POS	O
+MB	POS	O
+,	POS	O
+and	POS	O
+cardiac	POS	B-NP
+troponin	POS	I-NP
+I	POS	I-NP
+(	POS	O
+cTnI	POS	O
+)	POS	O
+over	POS	O
+eight	POS	O
+hours	POS	O
+.	POS	O
+Outcomes	POS	O
+included	POS	O
+CK	POS	O
+-	POS	O
+MB	POS	B-NP
+MI	POS	I-NP
+(	POS	O
+CK	POS	O
+-	POS	O
+MB	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+8	POS	O
+ng	POS	O
+/	POS	O
+mL	POS	O
+with	POS	O
+a	POS	O
+relative	POS	O
+index	POS	O
+[	POS	O
+(	POS	O
+CK	POS	O
+-	POS	O
+MB	POS	O
+x	POS	O
+100	POS	O
+)	POS	O
+/	POS	O
+total	POS	O
+CK	POS	O
+]	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+4	POS	O
+,	POS	O
+cardiac	POS	B-NP
+death	POS	I-NP
+,	POS	O
+and	POS	O
+significant	POS	O
+coronary	POS	B-NP
+disease	POS	I-NP
+(	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+50	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Of	POS	O
+the	POS	O
+246	POS	O
+admitted	POS	O
+patients	POS	O
+,	POS	O
+34	POS	O
+(	POS	O
+14	POS	O
+%	POS	O
+)	POS	O
+met	POS	O
+CK	POS	O
+-	POS	O
+MB	POS	O
+criteria	POS	O
+for	POS	O
+MI	POS	B-NP
+and	POS	O
+38	POS	O
+(	POS	O
+16	POS	O
+%	POS	O
+)	POS	O
+had	POS	O
+cTnI	POS	O
+elevations	POS	O
+.	POS	O
+Angiography	POS	O
+was	POS	O
+performed	POS	O
+in	POS	O
+29	POS	O
+of	POS	O
+38	POS	O
+patients	POS	O
+who	POS	O
+were	POS	O
+cTnI	POS	O
+-	POS	O
+positive	POS	O
+,	POS	O
+with	POS	O
+significant	POS	O
+disease	POS	O
+present	POS	O
+in	POS	O
+25	POS	O
+(	POS	O
+86	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Three	POS	O
+of	POS	O
+the	POS	O
+four	POS	O
+patients	POS	O
+without	POS	O
+significant	POS	O
+disease	POS	O
+who	POS	O
+had	POS	O
+cTnI	POS	O
+elevations	POS	O
+met	POS	O
+CK	POS	O
+-	POS	O
+MB	POS	O
+criteria	POS	O
+for	POS	O
+MI	POS	B-NP
+,	POS	O
+and	POS	O
+the	POS	O
+other	POS	O
+had	POS	O
+a	POS	O
+peak	POS	O
+CK	POS	O
+-	POS	O
+MB	POS	O
+level	POS	O
+of	POS	O
+13	POS	O
+ng	POS	O
+/	POS	O
+mL	POS	O
+.	POS	O
+Sensitivities	POS	O
+,	POS	O
+specificities	POS	O
+,	POS	O
+and	POS	O
+positive	POS	O
+and	POS	O
+negative	POS	O
+likelihood	POS	O
+ratios	POS	O
+for	POS	O
+predicting	POS	O
+cardiac	POS	B-NP
+death	POS	I-NP
+or	POS	O
+significant	POS	O
+disease	POS	O
+were	POS	O
+high	POS	O
+for	POS	O
+both	POS	O
+CK	POS	O
+-	POS	O
+MB	POS	B-NP
+MI	POS	I-NP
+and	POS	O
+cTnI	POS	O
+and	POS	O
+were	POS	O
+not	POS	O
+significantly	POS	O
+different	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Most	POS	O
+patients	POS	O
+with	POS	O
+cTnI	POS	O
+elevations	POS	O
+meet	POS	O
+CK	POS	O
+-	POS	O
+MB	POS	O
+criteria	POS	O
+for	POS	O
+MI	POS	B-NP
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+have	POS	O
+a	POS	O
+high	POS	O
+incidence	POS	O
+of	POS	O
+underlying	POS	O
+significant	POS	O
+disease	POS	O
+.	POS	O
+Troponin	POS	O
+appears	POS	O
+to	POS	O
+have	POS	O
+an	POS	O
+equivalent	POS	O
+diagnostic	POS	O
+accuracy	POS	O
+compared	POS	O
+with	POS	O
+CK	POS	O
+-	POS	O
+MB	POS	O
+for	POS	O
+diagnosing	POS	O
+necrosis	POS	B-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+and	POS	O
+suspected	POS	O
+MI	POS	B-NP
+.	POS	O
+Acute	POS	B-NP
+interstitial	POS	I-NP
+nephritis	POS	I-NP
+due	POS	O
+to	POS	O
+nicergoline	POS	O
+(	POS	O
+Sermion	POS	O
+)	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+acute	POS	O
+interstitial	POS	B-NP
+nephritis	POS	I-NP
+(	POS	O
+AIN	POS	B-NP
+)	POS	O
+due	POS	O
+to	POS	O
+nicergoline	POS	O
+(	POS	O
+Sermion	POS	O
+)	POS	O
+.	POS	O
+A	POS	O
+50	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+patient	POS	O
+admitted	POS	O
+to	POS	O
+our	POS	O
+hospital	POS	O
+for	POS	O
+fever	POS	B-NP
+and	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+Before	POS	O
+admission	POS	O
+,	POS	O
+he	POS	O
+had	POS	O
+been	POS	O
+taking	POS	O
+nicergoline	POS	O
+and	POS	O
+bendazac	POS	O
+lysine	POS	O
+due	POS	O
+to	POS	O
+retinal	POS	B-NP
+vein	POS	I-NP
+occlusion	POS	I-NP
+at	POS	O
+ophthalmologic	POS	O
+department	POS	O
+.	POS	O
+Thereafter	POS	O
+,	POS	O
+he	POS	O
+experienced	POS	O
+intermittent	POS	B-NP
+fever	POS	I-NP
+and	POS	O
+skin	POS	B-NP
+rash	POS	I-NP
+.	POS	O
+On	POS	O
+admission	POS	O
+,	POS	O
+clinical	POS	O
+symptoms	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+e	POS	O
+.	POS	O
+arthralgia	POS	B-NP
+and	POS	O
+fever	POS	B-NP
+)	POS	O
+and	POS	O
+laboratory	POS	O
+findings	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+e	POS	O
+.	POS	O
+eosinophilia	POS	B-NP
+and	POS	O
+renal	POS	B-NP
+failure	POS	I-NP
+)	POS	O
+suggested	POS	O
+AIN	POS	B-NP
+,	POS	O
+and	POS	O
+which	POS	O
+was	POS	O
+confirmed	POS	O
+by	POS	O
+pathologic	POS	O
+findings	POS	O
+on	POS	O
+renal	POS	O
+biopsy	POS	O
+.	POS	O
+A	POS	O
+lymphocyte	POS	O
+transformation	POS	O
+test	POS	O
+demonstrated	POS	O
+a	POS	O
+positive	POS	O
+result	POS	O
+against	POS	O
+nicergoline	POS	O
+.	POS	O
+Treatment	POS	O
+was	POS	O
+consisted	POS	O
+of	POS	O
+withdrawal	POS	O
+of	POS	O
+nicergoline	POS	O
+and	POS	O
+intravenous	POS	O
+methylprednisolone	POS	O
+,	POS	O
+and	POS	O
+his	POS	O
+renal	POS	O
+function	POS	O
+was	POS	O
+completely	POS	O
+recovered	POS	O
+.	POS	O
+To	POS	O
+our	POS	O
+knowledge	POS	O
+,	POS	O
+this	POS	O
+is	POS	O
+the	POS	O
+first	POS	O
+report	POS	O
+of	POS	O
+nicergoline	POS	O
+-	POS	O
+associated	POS	O
+AIN	POS	B-NP
+.	POS	O
+Neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+complicated	POS	O
+by	POS	O
+massive	POS	O
+intestinal	POS	B-NP
+bleeding	POS	I-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+chronic	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+A	POS	O
+patient	POS	O
+with	POS	O
+chronic	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+(	POS	O
+CRF	POS	B-NP
+)	POS	O
+developed	POS	O
+neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+(	POS	O
+NMS	POS	B-NP
+)	POS	O
+after	POS	O
+administration	POS	O
+of	POS	O
+risperidone	POS	O
+and	POS	O
+levomepromazine	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+to	POS	O
+the	POS	O
+typical	POS	O
+symptoms	POS	O
+of	POS	O
+NMS	POS	B-NP
+,	POS	O
+massive	POS	O
+intestinal	POS	B-NP
+bleeding	POS	I-NP
+was	POS	O
+observed	POS	O
+during	POS	O
+the	POS	O
+episode	POS	O
+.	POS	O
+This	POS	O
+report	POS	O
+suggests	POS	O
+that	POS	O
+NMS	POS	B-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+CRF	POS	B-NP
+may	POS	O
+be	POS	O
+complicated	POS	O
+by	POS	O
+intestinal	POS	B-NP
+bleeding	POS	I-NP
+and	POS	O
+needs	POS	O
+special	POS	O
+caution	POS	O
+for	POS	O
+this	POS	O
+complication	POS	O
+.	POS	O
+Blood	POS	O
+brain	POS	O
+barrier	POS	O
+in	POS	O
+right	POS	O
+-	POS	O
+and	POS	O
+left	POS	O
+-	POS	O
+pawed	POS	O
+female	POS	O
+rats	POS	O
+assessed	POS	O
+by	POS	O
+a	POS	O
+new	POS	O
+staining	POS	O
+method	POS	O
+.	POS	O
+The	POS	O
+asymmetrical	POS	O
+breakdown	POS	O
+of	POS	O
+the	POS	O
+blood	POS	O
+-	POS	O
+brain	POS	O
+barrier	POS	O
+(	POS	O
+BBB	POS	O
+)	POS	O
+was	POS	O
+studied	POS	O
+in	POS	O
+female	POS	O
+rats	POS	O
+.	POS	O
+Paw	POS	O
+preference	POS	O
+was	POS	O
+assessed	POS	O
+by	POS	O
+a	POS	O
+food	POS	O
+reaching	POS	O
+test	POS	O
+.	POS	O
+Adrenaline	POS	O
+-	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+was	POS	O
+used	POS	O
+to	POS	O
+destroy	POS	O
+the	POS	O
+BBB	POS	O
+,	POS	O
+which	POS	O
+was	POS	O
+evaluated	POS	O
+using	POS	O
+triphenyltetrazolium	POS	O
+(	POS	O
+TTC	POS	O
+)	POS	O
+staining	POS	O
+of	POS	O
+the	POS	O
+brain	POS	O
+slices	POS	O
+just	POS	O
+after	POS	O
+giving	POS	O
+adrenaline	POS	O
+for	POS	O
+30	POS	O
+s	POS	O
+.	POS	O
+In	POS	O
+normal	POS	O
+rats	POS	O
+,	POS	O
+the	POS	O
+whole	POS	O
+brain	POS	O
+sections	POS	O
+exhibited	POS	O
+complete	POS	O
+staining	POS	O
+with	POS	O
+TTC	POS	O
+.	POS	O
+After	POS	O
+adrenaline	POS	O
+infusion	POS	O
+for	POS	O
+30	POS	O
+s	POS	O
+,	POS	O
+there	POS	O
+were	POS	O
+large	POS	O
+unstained	POS	O
+areas	POS	O
+in	POS	O
+the	POS	O
+left	POS	O
+brain	POS	O
+in	POS	O
+right	POS	O
+-	POS	O
+pawed	POS	O
+animals	POS	O
+,	POS	O
+and	POS	O
+vice	POS	O
+versa	POS	O
+in	POS	O
+left	POS	O
+-	POS	O
+pawed	POS	O
+animals	POS	O
+.	POS	O
+Similar	POS	O
+results	POS	O
+were	POS	O
+obtained	POS	O
+in	POS	O
+seizure	POS	B-NP
+-	POS	O
+induced	POS	O
+breakdown	POS	O
+of	POS	O
+BBB	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+were	POS	O
+explained	POS	O
+by	POS	O
+an	POS	O
+asymmetric	POS	O
+cerebral	POS	O
+blood	POS	O
+flow	POS	O
+depending	POS	O
+upon	POS	O
+the	POS	O
+paw	POS	O
+preference	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+It	POS	O
+was	POS	O
+suggested	POS	O
+that	POS	O
+this	POS	O
+new	POS	O
+method	POS	O
+and	POS	O
+the	POS	O
+results	POS	O
+are	POS	O
+consistent	POS	O
+with	POS	O
+contralateral	POS	O
+motor	POS	O
+control	POS	O
+that	POS	O
+may	POS	O
+be	POS	O
+important	POS	O
+in	POS	O
+determining	POS	O
+the	POS	O
+dominant	POS	O
+cerebral	POS	O
+hemisphere	POS	O
+in	POS	O
+animals	POS	O
+.	POS	O
+Carvedilol	POS	O
+protects	POS	O
+against	POS	O
+doxorubicin	POS	O
+-	POS	O
+induced	POS	O
+mitochondrial	POS	B-NP
+cardiomyopathy	POS	I-NP
+.	POS	O
+Several	POS	O
+cytopathic	POS	B-NP
+mechanisms	POS	O
+have	POS	O
+been	POS	O
+suggested	POS	O
+to	POS	O
+mediate	POS	O
+the	POS	O
+dose	POS	O
+-	POS	O
+limiting	POS	O
+cumulative	POS	O
+and	POS	O
+irreversible	POS	O
+cardiomyopathy	POS	B-NP
+caused	POS	O
+by	POS	O
+doxorubicin	POS	O
+.	POS	O
+Recent	POS	O
+evidence	POS	O
+indicates	POS	O
+that	POS	O
+oxidative	POS	O
+stress	POS	O
+and	POS	O
+mitochondrial	POS	B-NP
+dysfunction	POS	I-NP
+are	POS	O
+key	POS	O
+factors	POS	O
+in	POS	O
+the	POS	O
+pathogenic	POS	O
+process	POS	O
+.	POS	O
+The	POS	O
+objective	POS	O
+of	POS	O
+this	POS	O
+investigation	POS	O
+was	POS	O
+to	POS	O
+test	POS	O
+the	POS	O
+hypothesis	POS	O
+that	POS	O
+carvedilol	POS	O
+,	POS	O
+a	POS	O
+nonselective	POS	O
+beta	POS	O
+-	POS	O
+adrenergic	POS	O
+receptor	POS	O
+antagonist	POS	O
+with	POS	O
+potent	POS	O
+antioxidant	POS	O
+properties	POS	O
+,	POS	O
+protects	POS	O
+against	POS	O
+the	POS	O
+cardiac	POS	O
+and	POS	O
+hepatic	POS	O
+mitochondrial	POS	O
+bioenergetic	POS	O
+dysfunction	POS	O
+associated	POS	O
+with	POS	O
+subchronic	POS	O
+doxorubicin	POS	O
+toxicity	POS	B-NP
+.	POS	O
+Heart	POS	O
+and	POS	O
+liver	POS	O
+mitochondria	POS	O
+were	POS	O
+isolated	POS	O
+from	POS	O
+rats	POS	O
+treated	POS	O
+for	POS	O
+7	POS	O
+weeks	POS	O
+with	POS	O
+doxorubicin	POS	O
+(	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+sc	POS	O
+/	POS	O
+week	POS	O
+)	POS	O
+,	POS	O
+carvedilol	POS	O
+(	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+ip	POS	O
+/	POS	O
+week	POS	O
+)	POS	O
+,	POS	O
+or	POS	O
+the	POS	O
+combination	POS	O
+of	POS	O
+the	POS	O
+two	POS	O
+drugs	POS	O
+.	POS	O
+Heart	POS	O
+mitochondria	POS	O
+isolated	POS	O
+from	POS	O
+doxorubicin	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+exhibited	POS	O
+depressed	POS	O
+rates	POS	O
+for	POS	O
+state	POS	O
+3	POS	O
+respiration	POS	O
+(	POS	O
+336	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+26	POS	O
+versus	POS	O
+425	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+53	POS	O
+natom	POS	O
+O	POS	O
+/	POS	O
+min	POS	O
+/	POS	O
+mg	POS	O
+protein	POS	O
+)	POS	O
+and	POS	O
+a	POS	O
+lower	POS	O
+respiratory	POS	O
+control	POS	O
+ratio	POS	O
+(	POS	O
+RCR	POS	O
+)	POS	O
+(	POS	O
+4	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+6	POS	O
+versus	POS	O
+5	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+4	POS	O
+)	POS	O
+compared	POS	O
+with	POS	O
+cardiac	POS	O
+mitochondria	POS	O
+isolated	POS	O
+from	POS	O
+saline	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+.	POS	O
+Mitochondrial	POS	O
+calcium	POS	O
+-	POS	O
+loading	POS	O
+capacity	POS	O
+and	POS	O
+the	POS	O
+activity	POS	O
+of	POS	O
+NADH	POS	O
+-	POS	O
+dehydrogenase	POS	O
+were	POS	O
+also	POS	O
+suppressed	POS	O
+in	POS	O
+cardiac	POS	O
+mitochondria	POS	O
+from	POS	O
+doxorubicin	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+.	POS	O
+Doxorubicin	POS	O
+treatment	POS	O
+also	POS	O
+caused	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+RCR	POS	O
+for	POS	O
+liver	POS	O
+mitochondria	POS	O
+(	POS	O
+3	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+versus	POS	O
+5	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+for	POS	O
+control	POS	O
+rats	POS	O
+)	POS	O
+and	POS	O
+inhibition	POS	O
+of	POS	O
+hepatic	POS	O
+cytochrome	POS	O
+oxidase	POS	O
+activity	POS	O
+.	POS	O
+Coadministration	POS	O
+of	POS	O
+carvedilol	POS	O
+decreased	POS	O
+the	POS	O
+extent	POS	O
+of	POS	O
+cellular	POS	O
+vacuolization	POS	O
+in	POS	O
+cardiac	POS	O
+myocytes	POS	O
+and	POS	O
+prevented	POS	O
+the	POS	O
+inhibitory	POS	O
+effect	POS	O
+of	POS	O
+doxorubicin	POS	O
+on	POS	O
+mitochondrial	POS	O
+respiration	POS	O
+in	POS	O
+both	POS	O
+heart	POS	O
+and	POS	O
+liver	POS	O
+.	POS	O
+Carvedilol	POS	O
+also	POS	O
+prevented	POS	O
+the	POS	O
+decrease	POS	O
+in	POS	O
+mitochondrial	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+loading	POS	O
+capacity	POS	O
+and	POS	O
+the	POS	O
+inhibition	POS	O
+of	POS	O
+the	POS	O
+respiratory	POS	O
+complexes	POS	O
+of	POS	O
+heart	POS	O
+mitochondria	POS	O
+caused	POS	O
+by	POS	O
+doxorubicin	POS	O
+.	POS	O
+Carvedilol	POS	O
+by	POS	O
+itself	POS	O
+did	POS	O
+not	POS	O
+affect	POS	O
+any	POS	O
+of	POS	O
+the	POS	O
+parameters	POS	O
+measured	POS	O
+for	POS	O
+heart	POS	O
+or	POS	O
+liver	POS	O
+mitochondria	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+concluded	POS	O
+that	POS	O
+this	POS	O
+protection	POS	O
+by	POS	O
+carvedilol	POS	O
+against	POS	O
+both	POS	O
+the	POS	O
+structural	POS	O
+and	POS	O
+functional	POS	O
+cardiac	POS	O
+tissue	POS	O
+damage	POS	O
+may	POS	O
+afford	POS	O
+significant	POS	O
+clinical	POS	O
+advantage	POS	O
+in	POS	O
+minimizing	POS	O
+the	POS	O
+dose	POS	O
+-	POS	O
+limiting	POS	O
+mitochondrial	POS	B-NP
+dysfunction	POS	I-NP
+and	POS	O
+cardiomyopathy	POS	B-NP
+that	POS	O
+accompanies	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+doxorubicin	POS	O
+therapy	POS	O
+in	POS	O
+cancer	POS	B-NP
+patients	POS	O
+.	POS	O
+Cocaine	POS	O
+-	POS	O
+induced	POS	O
+hyperactivity	POS	B-NP
+is	POS	O
+more	POS	O
+influenced	POS	O
+by	POS	O
+adenosine	POS	O
+receptor	POS	O
+agonists	POS	O
+than	POS	O
+amphetamine	POS	O
+-	POS	O
+induced	POS	O
+hyperactivity	POS	B-NP
+.	POS	O
+The	POS	O
+influence	POS	O
+of	POS	O
+adenosine	POS	O
+receptor	POS	O
+agonists	POS	O
+and	POS	O
+antagonists	POS	O
+on	POS	O
+cocaine	POS	O
+-	POS	O
+and	POS	O
+amphetamine	POS	O
+-	POS	O
+induced	POS	O
+hyperactivity	POS	B-NP
+was	POS	O
+examined	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+All	POS	O
+adenosine	POS	O
+receptor	POS	O
+agonists	POS	O
+significantly	POS	O
+decreased	POS	O
+the	POS	O
+locomotor	POS	O
+activity	POS	O
+in	POS	O
+mice	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+effects	POS	O
+were	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+.	POS	O
+It	POS	O
+seems	POS	O
+that	POS	O
+adenosine	POS	O
+A1	POS	O
+and	POS	O
+A2	POS	O
+receptors	POS	O
+might	POS	O
+be	POS	O
+involved	POS	O
+in	POS	O
+this	POS	O
+reaction	POS	O
+.	POS	O
+Moreover	POS	O
+,	POS	O
+all	POS	O
+adenosine	POS	O
+receptor	POS	O
+agonists	POS	O
+:	POS	O
+2	POS	O
+-	POS	O
+p	POS	O
+-	POS	O
+(	POS	O
+2	POS	O
+-	POS	O
+carboxyethyl	POS	O
+)	POS	O
+phenethylamino	POS	O
+-	POS	O
+5	POS	O
+'	POS	O
+-	POS	O
+N	POS	O
+-	POS	O
+ethylcarboxamidoadenosine	POS	O
+(	POS	O
+CGS	POS	O
+21680	POS	O
+)	POS	O
+,	POS	O
+A2A	POS	O
+receptor	POS	O
+agonist	POS	O
+,	POS	O
+N6	POS	O
+-	POS	O
+cyclopentyladenosine	POS	O
+(	POS	O
+CPA	POS	O
+)	POS	O
+,	POS	O
+A1	POS	O
+receptor	POS	O
+agonist	POS	O
+,	POS	O
+and	POS	O
+5	POS	O
+'	POS	O
+-	POS	O
+N	POS	O
+-	POS	O
+ethylcarboxamidoadenosine	POS	O
+(	POS	O
+NECA	POS	O
+)	POS	O
+,	POS	O
+A2	POS	O
+/	POS	O
+A1	POS	O
+receptor	POS	O
+agonist	POS	O
+significantly	POS	O
+and	POS	O
+dose	POS	O
+-	POS	O
+dependently	POS	O
+decreased	POS	O
+cocaine	POS	O
+-	POS	O
+induced	POS	O
+locomotor	POS	O
+activity	POS	O
+.	POS	O
+CPA	POS	O
+reduced	POS	O
+cocaine	POS	O
+action	POS	O
+at	POS	O
+the	POS	O
+doses	POS	O
+which	POS	O
+,	POS	O
+given	POS	O
+alone	POS	O
+,	POS	O
+did	POS	O
+not	POS	O
+influence	POS	O
+motility	POS	O
+,	POS	O
+while	POS	O
+CGS	POS	O
+21680	POS	O
+and	POS	O
+NECA	POS	O
+decreased	POS	O
+the	POS	O
+action	POS	O
+of	POS	O
+cocaine	POS	O
+at	POS	O
+the	POS	O
+doses	POS	O
+which	POS	O
+,	POS	O
+given	POS	O
+alone	POS	O
+,	POS	O
+decreased	POS	O
+locomotor	POS	O
+activity	POS	O
+in	POS	O
+animals	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+the	POS	O
+involvement	POS	O
+of	POS	O
+both	POS	O
+adenosine	POS	O
+receptors	POS	O
+in	POS	O
+the	POS	O
+action	POS	O
+of	POS	O
+cocaine	POS	O
+although	POS	O
+agonists	POS	O
+of	POS	O
+A1	POS	O
+receptors	POS	O
+seem	POS	O
+to	POS	O
+have	POS	O
+stronger	POS	O
+influence	POS	O
+on	POS	O
+it	POS	O
+.	POS	O
+The	POS	O
+selective	POS	O
+blockade	POS	O
+of	POS	O
+A2	POS	O
+adenosine	POS	O
+receptor	POS	O
+by	POS	O
+DMPX	POS	O
+(	POS	O
+3	POS	O
+,	POS	O
+7	POS	O
+-	POS	O
+dimethyl	POS	O
+-	POS	O
+1	POS	O
+-	POS	O
+propargylxanthine	POS	O
+)	POS	O
+significantly	POS	O
+enhanced	POS	O
+cocaine	POS	O
+-	POS	O
+induced	POS	O
+locomotor	POS	O
+activity	POS	O
+of	POS	O
+animals	POS	O
+.	POS	O
+Caffeine	POS	O
+had	POS	O
+similar	POS	O
+action	POS	O
+but	POS	O
+the	POS	O
+effect	POS	O
+was	POS	O
+not	POS	O
+significant	POS	O
+.	POS	O
+CPT	POS	O
+(	POS	O
+8	POS	O
+-	POS	O
+cyclopentyltheophylline	POS	O
+)	POS	O
+-	POS	O
+-	POS	O
+A1	POS	O
+receptor	POS	O
+antagonist	POS	O
+,	POS	O
+did	POS	O
+not	POS	O
+show	POS	O
+any	POS	O
+influence	POS	O
+in	POS	O
+this	POS	O
+test	POS	O
+.	POS	O
+Similarly	POS	O
+,	POS	O
+all	POS	O
+adenosine	POS	O
+receptor	POS	O
+agonists	POS	O
+decreased	POS	O
+amphetamine	POS	O
+-	POS	O
+induced	POS	O
+hyperactivity	POS	B-NP
+,	POS	O
+but	POS	O
+at	POS	O
+the	POS	O
+higher	POS	O
+doses	POS	O
+than	POS	O
+those	POS	O
+which	POS	O
+were	POS	O
+active	POS	O
+in	POS	O
+cocaine	POS	O
+-	POS	O
+induced	POS	O
+hyperactivity	POS	B-NP
+.	POS	O
+The	POS	O
+selective	POS	O
+blockade	POS	O
+of	POS	O
+A2	POS	O
+adenosine	POS	O
+receptors	POS	O
+(	POS	O
+DMPX	POS	O
+)	POS	O
+and	POS	O
+non	POS	O
+-	POS	O
+selective	POS	O
+blockade	POS	O
+of	POS	O
+adenosine	POS	O
+receptors	POS	O
+(	POS	O
+caffeine	POS	O
+)	POS	O
+significantly	POS	O
+increased	POS	O
+the	POS	O
+action	POS	O
+of	POS	O
+amphetamine	POS	O
+in	POS	O
+the	POS	O
+locomotor	POS	O
+activity	POS	O
+test	POS	O
+.	POS	O
+Our	POS	O
+results	POS	O
+have	POS	O
+shown	POS	O
+that	POS	O
+all	POS	O
+adenosine	POS	O
+receptor	POS	O
+agonists	POS	O
+(	POS	O
+A1	POS	O
+and	POS	O
+A2	POS	O
+)	POS	O
+reduce	POS	O
+cocaine	POS	O
+-	POS	O
+and	POS	O
+amphetamine	POS	O
+-	POS	O
+induced	POS	O
+locomotor	POS	O
+activity	POS	O
+and	POS	O
+indicate	POS	O
+that	POS	O
+cocaine	POS	O
+-	POS	O
+induced	POS	O
+hyperactivity	POS	B-NP
+is	POS	O
+more	POS	O
+influenced	POS	O
+by	POS	O
+adenosine	POS	O
+receptor	POS	O
+agonists	POS	O
+(	POS	O
+particularly	POS	O
+A1	POS	O
+receptors	POS	O
+)	POS	O
+than	POS	O
+amphetamine	POS	O
+-	POS	O
+induced	POS	O
+hyperactivity	POS	B-NP
+.	POS	O
+Amiodarone	POS	O
+and	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+bradyarrhythmia	POS	B-NP
+requiring	POS	O
+permanent	POS	O
+pacemaker	POS	O
+in	POS	O
+elderly	POS	O
+patients	POS	O
+with	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+and	POS	O
+prior	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+determine	POS	O
+whether	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+amiodarone	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+(	POS	O
+AF	POS	B-NP
+)	POS	O
+increases	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+bradyarrhythmia	POS	B-NP
+requiring	POS	O
+a	POS	O
+permanent	POS	O
+pacemaker	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Reports	POS	O
+of	POS	O
+severe	POS	O
+bradyarrhythmia	POS	B-NP
+during	POS	O
+amiodarone	POS	O
+therapy	POS	O
+are	POS	O
+infrequent	POS	O
+and	POS	O
+limited	POS	O
+to	POS	O
+studies	POS	O
+assessing	POS	O
+the	POS	O
+therapy	POS	O
+'	POS	O
+s	POS	O
+use	POS	O
+in	POS	O
+the	POS	O
+management	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+ventricular	POS	B-NP
+arrhythmias	POS	I-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+A	POS	O
+study	POS	O
+cohort	POS	O
+of	POS	O
+8	POS	O
+,	POS	O
+770	POS	O
+patients	POS	O
+age	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+65	POS	O
+years	POS	O
+with	POS	O
+a	POS	O
+new	POS	O
+diagnosis	POS	O
+of	POS	O
+AF	POS	B-NP
+was	POS	O
+identified	POS	O
+from	POS	O
+a	POS	O
+provincewide	POS	O
+database	POS	O
+of	POS	O
+Quebec	POS	O
+residents	POS	O
+with	POS	O
+a	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+(	POS	O
+MI	POS	B-NP
+)	POS	O
+between	POS	O
+1991	POS	O
+and	POS	O
+1999	POS	O
+.	POS	O
+Using	POS	O
+a	POS	O
+nested	POS	O
+case	POS	O
+-	POS	O
+control	POS	O
+design	POS	O
+,	POS	O
+477	POS	O
+cases	POS	O
+of	POS	O
+bradyarrhythmia	POS	B-NP
+requiring	POS	O
+a	POS	O
+permanent	POS	O
+pacemaker	POS	O
+were	POS	O
+matched	POS	O
+(	POS	O
+1	POS	O
+:	POS	O
+4	POS	O
+)	POS	O
+to	POS	O
+1	POS	O
+,	POS	O
+908	POS	O
+controls	POS	O
+.	POS	O
+Multivariable	POS	O
+logistic	POS	O
+regression	POS	O
+was	POS	O
+used	POS	O
+to	POS	O
+estimate	POS	O
+the	POS	O
+odds	POS	O
+ratio	POS	O
+(	POS	O
+OR	POS	O
+)	POS	O
+of	POS	O
+pacemaker	POS	O
+insertion	POS	O
+associated	POS	O
+with	POS	O
+amiodarone	POS	O
+use	POS	O
+,	POS	O
+controlling	POS	O
+for	POS	O
+baseline	POS	O
+risk	POS	O
+factors	POS	O
+and	POS	O
+exposure	POS	O
+to	POS	O
+sotalol	POS	O
+,	POS	O
+Class	POS	O
+I	POS	O
+antiarrhythmic	POS	O
+agents	POS	O
+,	POS	O
+beta	POS	O
+-	POS	O
+blockers	POS	O
+,	POS	O
+calcium	POS	O
+channel	POS	O
+blockers	POS	O
+,	POS	O
+and	POS	O
+digoxin	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+amiodarone	POS	O
+use	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+increased	POS	O
+risk	POS	O
+of	POS	O
+pacemaker	POS	O
+insertion	POS	O
+(	POS	O
+OR	POS	O
+:	POS	O
+2	POS	O
+.	POS	O
+14	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+[	POS	O
+CI	POS	O
+]	POS	O
+:	POS	O
+1	POS	O
+.	POS	O
+30	POS	O
+to	POS	O
+3	POS	O
+.	POS	O
+54	POS	O
+)	POS	O
+.	POS	O
+This	POS	O
+effect	POS	O
+was	POS	O
+modified	POS	O
+by	POS	O
+gender	POS	O
+,	POS	O
+with	POS	O
+a	POS	O
+greater	POS	O
+risk	POS	O
+in	POS	O
+women	POS	O
+versus	POS	O
+men	POS	O
+(	POS	O
+OR	POS	O
+:	POS	O
+3	POS	O
+.	POS	O
+86	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+:	POS	O
+1	POS	O
+.	POS	O
+70	POS	O
+to	POS	O
+8	POS	O
+.	POS	O
+75	POS	O
+vs	POS	O
+.	POS	O
+OR	POS	O
+:	POS	O
+1	POS	O
+.	POS	O
+52	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+:	POS	O
+0	POS	O
+.	POS	O
+80	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+89	POS	O
+)	POS	O
+.	POS	O
+Digoxin	POS	O
+was	POS	O
+the	POS	O
+only	POS	O
+other	POS	O
+medication	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+increased	POS	O
+risk	POS	O
+of	POS	O
+pacemaker	POS	O
+insertion	POS	O
+(	POS	O
+OR	POS	O
+:	POS	O
+1	POS	O
+.	POS	O
+78	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+:	POS	O
+1	POS	O
+.	POS	O
+37	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+31	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+This	POS	O
+study	POS	O
+suggests	POS	O
+that	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+amiodarone	POS	O
+in	POS	O
+elderly	POS	O
+patients	POS	O
+with	POS	O
+AF	POS	B-NP
+and	POS	O
+a	POS	O
+previous	POS	O
+MI	POS	B-NP
+increases	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+bradyarrhythmia	POS	B-NP
+requiring	POS	O
+a	POS	O
+permanent	POS	O
+pacemaker	POS	O
+.	POS	O
+The	POS	O
+finding	POS	O
+of	POS	O
+an	POS	O
+augmented	POS	O
+risk	POS	O
+of	POS	O
+pacemaker	POS	O
+insertion	POS	O
+in	POS	O
+elderly	POS	O
+women	POS	O
+receiving	POS	O
+amiodarone	POS	O
+requires	POS	O
+further	POS	O
+investigation	POS	O
+.	POS	O
+Indomethacin	POS	O
+-	POS	O
+induced	POS	O
+morphologic	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+urinary	POS	O
+bladder	POS	O
+epithelium	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+To	POS	O
+evaluate	POS	O
+the	POS	O
+morphologic	POS	O
+changes	POS	O
+in	POS	O
+rat	POS	O
+urothelium	POS	O
+induced	POS	O
+by	POS	O
+indomethacin	POS	O
+.	POS	O
+Nonsteroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+cystitis	POS	B-NP
+is	POS	O
+a	POS	O
+poorly	POS	O
+recognized	POS	O
+and	POS	O
+under	POS	O
+-	POS	O
+reported	POS	O
+condition	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+to	POS	O
+tiaprofenic	POS	O
+acid	POS	O
+,	POS	O
+indomethacin	POS	O
+has	POS	O
+been	POS	O
+reported	POS	O
+to	POS	O
+be	POS	O
+associated	POS	O
+with	POS	O
+this	POS	O
+condition	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Three	POS	O
+groups	POS	O
+were	POS	O
+established	POS	O
+:	POS	O
+a	POS	O
+control	POS	O
+group	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+10	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+group	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+10	POS	O
+)	POS	O
+,	POS	O
+treated	POS	O
+with	POS	O
+one	POS	O
+intraperitoneal	POS	O
+injection	POS	O
+of	POS	O
+indomethacin	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+therapeutic	POS	O
+dose	POS	O
+group	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+10	POS	O
+)	POS	O
+in	POS	O
+which	POS	O
+oral	POS	O
+indomethacin	POS	O
+was	POS	O
+administered	POS	O
+3	POS	O
+.	POS	O
+25	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+body	POS	O
+weight	POS	O
+daily	POS	O
+for	POS	O
+3	POS	O
+weeks	POS	O
+.	POS	O
+The	POS	O
+animals	POS	O
+were	POS	O
+then	POS	O
+killed	POS	O
+and	POS	O
+the	POS	O
+bladders	POS	O
+removed	POS	O
+for	POS	O
+light	POS	O
+and	POS	O
+electron	POS	O
+microscopic	POS	O
+studies	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+light	POS	O
+microscopic	POS	O
+findings	POS	O
+showed	POS	O
+some	POS	O
+focal	POS	O
+epithelial	POS	O
+degeneration	POS	O
+that	POS	O
+was	POS	O
+more	POS	O
+prominent	POS	O
+in	POS	O
+the	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+group	POS	O
+.	POS	O
+When	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+,	POS	O
+both	POS	O
+indomethacin	POS	O
+groups	POS	O
+revealed	POS	O
+statistically	POS	O
+increased	POS	O
+numbers	POS	O
+of	POS	O
+mast	POS	O
+cells	POS	O
+in	POS	O
+the	POS	O
+mucosa	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+0001	POS	O
+)	POS	O
+and	POS	O
+penetration	POS	O
+of	POS	O
+lanthanum	POS	O
+nitrate	POS	O
+through	POS	O
+intercellular	POS	O
+areas	POS	O
+of	POS	O
+the	POS	O
+epithelium	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+the	POS	O
+difference	POS	O
+in	POS	O
+mast	POS	O
+cell	POS	O
+counts	POS	O
+between	POS	O
+the	POS	O
+high	POS	O
+and	POS	O
+therapeutic	POS	O
+dose	POS	O
+groups	POS	O
+was	POS	O
+also	POS	O
+statistically	POS	O
+significant	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+0001	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Indomethacin	POS	O
+resulted	POS	O
+in	POS	O
+histopathologic	POS	O
+findings	POS	O
+typical	POS	O
+of	POS	O
+interstitial	POS	B-NP
+cystitis	POS	I-NP
+,	POS	O
+such	POS	O
+as	POS	O
+leaky	POS	B-NP
+bladder	POS	I-NP
+epithelium	POS	I-NP
+and	POS	O
+mucosal	POS	B-NP
+mastocytosis	POS	I-NP
+.	POS	O
+The	POS	O
+true	POS	O
+incidence	POS	O
+of	POS	O
+nonsteroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+cystitis	POS	B-NP
+in	POS	O
+humans	POS	O
+must	POS	O
+be	POS	O
+clarified	POS	O
+by	POS	O
+prospective	POS	O
+clinical	POS	O
+trials	POS	O
+.	POS	O
+An	POS	O
+open	POS	O
+-	POS	O
+label	POS	O
+phase	POS	O
+II	POS	O
+study	POS	O
+of	POS	O
+low	POS	O
+-	POS	O
+dose	POS	O
+thalidomide	POS	O
+in	POS	O
+androgen	POS	O
+-	POS	O
+independent	POS	O
+prostate	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+The	POS	O
+antiangiogenic	POS	O
+effects	POS	O
+of	POS	O
+thalidomide	POS	O
+have	POS	O
+been	POS	O
+assessed	POS	O
+in	POS	O
+clinical	POS	O
+trials	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+various	POS	O
+solid	POS	O
+and	POS	O
+haematological	POS	O
+malignancies	POS	O
+.	POS	O
+Thalidomide	POS	O
+blocks	POS	O
+the	POS	O
+activity	POS	O
+of	POS	O
+angiogenic	POS	O
+agents	POS	O
+including	POS	O
+bFGF	POS	O
+,	POS	O
+VEGF	POS	O
+and	POS	O
+IL	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+We	POS	O
+undertook	POS	O
+an	POS	O
+open	POS	O
+-	POS	O
+label	POS	O
+study	POS	O
+using	POS	O
+thalidomide	POS	O
+100	POS	O
+mg	POS	O
+once	POS	O
+daily	POS	O
+for	POS	O
+up	POS	O
+to	POS	O
+6	POS	O
+months	POS	O
+in	POS	O
+20	POS	O
+men	POS	O
+with	POS	O
+androgen	POS	O
+-	POS	O
+independent	POS	O
+prostate	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+The	POS	O
+mean	POS	O
+time	POS	O
+of	POS	O
+study	POS	O
+was	POS	O
+109	POS	O
+days	POS	O
+(	POS	O
+median	POS	O
+107	POS	O
+,	POS	O
+range	POS	O
+4	POS	O
+-	POS	O
+184	POS	O
+days	POS	O
+)	POS	O
+.	POS	O
+Patients	POS	O
+underwent	POS	O
+regular	POS	O
+measurement	POS	O
+of	POS	O
+prostate	POS	O
+-	POS	O
+specific	POS	O
+antigen	POS	O
+(	POS	O
+PSA	POS	O
+)	POS	O
+,	POS	O
+urea	POS	O
+and	POS	O
+electrolytes	POS	O
+,	POS	O
+serum	POS	O
+bFGF	POS	O
+and	POS	O
+VEGF	POS	O
+.	POS	O
+Three	POS	O
+men	POS	O
+(	POS	O
+15	POS	O
+%	POS	O
+)	POS	O
+showed	POS	O
+a	POS	O
+decline	POS	O
+in	POS	O
+serum	POS	O
+PSA	POS	O
+of	POS	O
+at	POS	O
+least	POS	O
+50	POS	O
+%	POS	O
+,	POS	O
+sustained	POS	O
+throughout	POS	O
+treatment	POS	O
+.	POS	O
+Of	POS	O
+16	POS	O
+men	POS	O
+treated	POS	O
+for	POS	O
+at	POS	O
+least	POS	O
+2	POS	O
+months	POS	O
+,	POS	O
+six	POS	O
+(	POS	O
+37	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+showed	POS	O
+a	POS	O
+fall	POS	O
+in	POS	O
+absolute	POS	O
+PSA	POS	O
+by	POS	O
+a	POS	O
+median	POS	O
+of	POS	O
+48	POS	O
+%	POS	O
+.	POS	O
+Increasing	POS	O
+levels	POS	O
+of	POS	O
+serum	POS	O
+bFGF	POS	O
+and	POS	O
+VEGF	POS	O
+were	POS	O
+associated	POS	O
+with	POS	O
+progressive	POS	O
+disease	POS	O
+;	POS	O
+five	POS	O
+of	POS	O
+six	POS	O
+men	POS	O
+who	POS	O
+demonstrated	POS	O
+a	POS	O
+fall	POS	O
+in	POS	O
+PSA	POS	O
+also	POS	O
+showed	POS	O
+a	POS	O
+decline	POS	O
+in	POS	O
+bFGF	POS	O
+and	POS	O
+VEGF	POS	O
+levels	POS	O
+,	POS	O
+and	POS	O
+three	POS	O
+of	POS	O
+four	POS	O
+men	POS	O
+with	POS	O
+a	POS	O
+rising	POS	O
+PSA	POS	O
+showed	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+both	POS	O
+growth	POS	O
+factors	POS	O
+.	POS	O
+Adverse	POS	O
+effects	POS	O
+included	POS	O
+constipation	POS	B-NP
+,	POS	O
+morning	POS	B-NP
+drowsiness	POS	I-NP
+,	POS	O
+dizziness	POS	B-NP
+and	POS	O
+rash	POS	B-NP
+,	POS	O
+and	POS	O
+resulted	POS	O
+in	POS	O
+withdrawal	POS	O
+from	POS	O
+the	POS	O
+study	POS	O
+by	POS	O
+three	POS	O
+men	POS	O
+.	POS	O
+Evidence	POS	O
+of	POS	O
+peripheral	POS	B-NP
+sensory	POS	I-NP
+neuropathy	POS	I-NP
+was	POS	O
+found	POS	O
+in	POS	O
+nine	POS	O
+of	POS	O
+13	POS	O
+men	POS	O
+before	POS	O
+treatment	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+seven	POS	O
+men	POS	O
+who	POS	O
+completed	POS	O
+six	POS	O
+months	POS	O
+on	POS	O
+thalidomide	POS	O
+,	POS	O
+subclinical	POS	O
+evidence	POS	O
+of	POS	O
+peripheral	POS	B-NP
+neuropathy	POS	I-NP
+was	POS	O
+found	POS	O
+in	POS	O
+four	POS	O
+before	POS	O
+treatment	POS	O
+,	POS	O
+but	POS	O
+in	POS	O
+all	POS	O
+seven	POS	O
+at	POS	O
+repeat	POS	O
+testing	POS	O
+.	POS	O
+The	POS	O
+findings	POS	O
+indicate	POS	O
+that	POS	O
+thalidomide	POS	O
+may	POS	O
+be	POS	O
+an	POS	O
+option	POS	O
+for	POS	O
+patients	POS	O
+who	POS	O
+have	POS	O
+failed	POS	O
+other	POS	O
+forms	POS	O
+of	POS	O
+therapy	POS	O
+,	POS	O
+provided	POS	O
+close	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+is	POS	O
+maintained	POS	O
+for	POS	O
+development	POS	O
+of	POS	O
+peripheral	POS	B-NP
+neuropathy	POS	I-NP
+.	POS	O
+Central	POS	B-NP
+nervous	POS	I-NP
+system	POS	I-NP
+toxicity	POS	I-NP
+following	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+levobupivacaine	POS	O
+for	POS	O
+lumbar	POS	B-NP
+plexus	POS	I-NP
+block	POS	I-NP
+:	POS	O
+A	POS	O
+report	POS	O
+of	POS	O
+two	POS	O
+cases	POS	O
+.	POS	O
+BACKGROUND	POS	O
+AND	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+Central	POS	O
+nervous	POS	O
+system	POS	O
+and	POS	O
+cardiac	POS	B-NP
+toxicity	POS	I-NP
+following	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+local	POS	O
+anesthetics	POS	O
+is	POS	O
+a	POS	O
+recognized	POS	O
+complication	POS	O
+of	POS	O
+regional	POS	O
+anesthesia	POS	O
+.	POS	O
+Levobupivacaine	POS	O
+,	POS	O
+the	POS	O
+pure	POS	O
+S	POS	O
+(	POS	O
+-	POS	O
+)	POS	O
+enantiomer	POS	O
+of	POS	O
+bupivacaine	POS	O
+,	POS	O
+was	POS	O
+developed	POS	O
+to	POS	O
+improve	POS	O
+the	POS	O
+cardiac	POS	O
+safety	POS	O
+profile	POS	O
+of	POS	O
+bupivacaine	POS	O
+.	POS	O
+We	POS	O
+describe	POS	O
+2	POS	O
+cases	POS	O
+of	POS	O
+grand	POS	O
+mal	POS	O
+seizures	POS	B-NP
+following	POS	O
+accidental	POS	O
+intravascular	POS	O
+injection	POS	O
+of	POS	O
+levobupivacaine	POS	O
+.	POS	O
+CASE	POS	O
+REPORT	POS	O
+:	POS	O
+Two	POS	O
+patients	POS	O
+presenting	POS	O
+for	POS	O
+elective	POS	O
+orthopedic	POS	O
+surgery	POS	O
+of	POS	O
+the	POS	O
+lower	POS	O
+limb	POS	O
+underwent	POS	O
+blockade	POS	O
+of	POS	O
+the	POS	O
+lumbar	POS	O
+plexus	POS	O
+via	POS	O
+the	POS	O
+posterior	POS	O
+approach	POS	O
+.	POS	O
+Immediately	POS	O
+after	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+levobupivacaine	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+with	POS	O
+epinephrine	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+microgram	POS	O
+/	POS	O
+mL	POS	O
+,	POS	O
+the	POS	O
+patients	POS	O
+developed	POS	O
+grand	POS	O
+mal	POS	O
+seizures	POS	B-NP
+,	POS	O
+despite	POS	O
+negative	POS	O
+aspiration	POS	O
+for	POS	O
+blood	POS	O
+and	POS	O
+no	POS	O
+clinical	POS	O
+signs	POS	O
+of	POS	O
+intravenous	POS	O
+epinephrine	POS	O
+administration	POS	O
+.	POS	O
+The	POS	O
+seizures	POS	B-NP
+were	POS	O
+successfully	POS	O
+treated	POS	O
+with	POS	O
+sodium	POS	O
+thiopental	POS	O
+in	POS	O
+addition	POS	O
+to	POS	O
+succinylcholine	POS	O
+in	POS	O
+1	POS	O
+patient	POS	O
+.	POS	O
+Neither	POS	O
+patient	POS	O
+developed	POS	O
+signs	POS	O
+of	POS	O
+cardiovascular	POS	B-NP
+toxicity	POS	I-NP
+.	POS	O
+Both	POS	O
+patients	POS	O
+were	POS	O
+treated	POS	O
+preoperatively	POS	O
+with	POS	O
+beta	POS	O
+-	POS	O
+adrenergic	POS	O
+antagonist	POS	O
+medications	POS	O
+,	POS	O
+which	POS	O
+may	POS	O
+have	POS	O
+masked	POS	O
+the	POS	O
+cardiovascular	POS	O
+signs	POS	O
+of	POS	O
+the	POS	O
+unintentional	POS	O
+intravascular	POS	O
+administration	POS	O
+of	POS	O
+levobupivacaine	POS	O
+with	POS	O
+epinephrine	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Although	POS	O
+levobupivacaine	POS	O
+may	POS	O
+have	POS	O
+a	POS	O
+safer	POS	O
+cardiac	POS	B-NP
+toxicity	POS	I-NP
+profile	POS	O
+than	POS	O
+racemic	POS	O
+bupivacaine	POS	O
+,	POS	O
+if	POS	O
+adequate	POS	O
+amounts	POS	O
+of	POS	O
+levobupivacaine	POS	O
+reach	POS	O
+the	POS	O
+circulation	POS	O
+,	POS	O
+it	POS	O
+will	POS	O
+result	POS	O
+in	POS	O
+convulsions	POS	B-NP
+.	POS	O
+Plasma	POS	O
+concentrations	POS	O
+sufficient	POS	O
+to	POS	O
+result	POS	O
+in	POS	O
+central	POS	B-NP
+nervous	POS	I-NP
+system	POS	I-NP
+toxicity	POS	I-NP
+did	POS	O
+not	POS	O
+produce	POS	O
+manifestations	POS	O
+of	POS	O
+cardiac	POS	B-NP
+toxicity	POS	I-NP
+in	POS	O
+these	POS	O
+2	POS	O
+patients	POS	O
+.	POS	O
+Amiodarone	POS	O
+-	POS	O
+induced	POS	O
+torsade	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+during	POS	O
+bladder	POS	O
+irrigation	POS	O
+:	POS	O
+an	POS	O
+unusual	POS	O
+presentation	POS	O
+-	POS	O
+-	POS	O
+a	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+present	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+early	POS	O
+(	POS	O
+within	POS	O
+4	POS	O
+days	POS	O
+)	POS	O
+development	POS	O
+of	POS	O
+torsade	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+(	POS	O
+TdP	POS	B-NP
+)	POS	O
+associated	POS	O
+with	POS	O
+oral	POS	O
+amiodarone	POS	O
+therapy	POS	O
+.	POS	O
+Consistent	POS	O
+with	POS	O
+other	POS	O
+reports	POS	O
+this	POS	O
+case	POS	O
+of	POS	O
+TdP	POS	B-NP
+occurred	POS	O
+in	POS	O
+the	POS	O
+context	POS	O
+of	POS	O
+multiple	POS	O
+exacerbating	POS	O
+factors	POS	O
+including	POS	O
+hypokalemia	POS	B-NP
+and	POS	O
+digoxin	POS	O
+excess	POS	O
+.	POS	O
+Transient	POS	O
+prolongation	POS	O
+of	POS	O
+the	POS	O
+QT	POS	O
+during	POS	O
+bladder	POS	O
+irrigation	POS	O
+prompted	POS	O
+the	POS	O
+episode	POS	O
+of	POS	O
+TdP	POS	B-NP
+.	POS	O
+It	POS	O
+is	POS	O
+well	POS	O
+known	POS	O
+that	POS	O
+bradycardia	POS	B-NP
+exacerbates	POS	O
+acquired	POS	O
+TdP	POS	B-NP
+.	POS	O
+The	POS	O
+authors	POS	O
+speculate	POS	O
+that	POS	O
+the	POS	O
+increased	POS	O
+vagal	POS	O
+tone	POS	O
+during	POS	O
+bladder	POS	O
+irrigation	POS	O
+,	POS	O
+a	POS	O
+vagal	POS	O
+maneuver	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+context	POS	O
+of	POS	O
+amiodarone	POS	O
+therapy	POS	O
+resulted	POS	O
+in	POS	O
+amiodarone	POS	O
+-	POS	O
+induced	POS	O
+proarrhythmia	POS	B-NP
+.	POS	O
+In	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+amiodarone	POS	O
+therapy	POS	O
+,	POS	O
+a	POS	O
+second	POS	O
+bladder	POS	O
+irrigation	POS	O
+did	POS	O
+not	POS	O
+induce	POS	O
+TdP	POS	B-NP
+despite	POS	O
+hypokalemia	POS	B-NP
+and	POS	O
+hypomagnesemia	POS	B-NP
+.	POS	O
+Anaesthetic	POS	B-NP
+complications	POS	I-NP
+associated	POS	O
+with	POS	O
+myotonia	POS	B-NP
+congenita	POS	I-NP
+:	POS	O
+case	POS	O
+study	POS	O
+and	POS	O
+comparison	POS	O
+with	POS	O
+other	POS	O
+myotonic	POS	B-NP
+disorders	POS	I-NP
+.	POS	O
+Myotonia	POS	B-NP
+congenita	POS	I-NP
+(	POS	O
+MC	POS	B-NP
+)	POS	O
+is	POS	O
+caused	POS	O
+by	POS	O
+a	POS	O
+defect	POS	O
+in	POS	O
+the	POS	O
+skeletal	POS	O
+muscle	POS	O
+chloride	POS	O
+channel	POS	O
+function	POS	O
+,	POS	O
+which	POS	O
+may	POS	O
+cause	POS	O
+sustained	POS	O
+membrane	POS	O
+depolarisation	POS	O
+.	POS	O
+We	POS	O
+describe	POS	O
+a	POS	O
+previously	POS	O
+healthy	POS	O
+32	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+who	POS	O
+developed	POS	O
+a	POS	O
+life	POS	O
+-	POS	O
+threatening	POS	O
+muscle	POS	B-NP
+spasm	POS	I-NP
+and	POS	O
+secondary	POS	O
+ventilation	POS	O
+difficulties	POS	O
+following	POS	O
+a	POS	O
+preoperative	POS	O
+injection	POS	O
+of	POS	O
+suxamethonium	POS	O
+.	POS	O
+The	POS	O
+muscle	POS	B-NP
+spasms	POS	I-NP
+disappeared	POS	O
+spontaneously	POS	O
+and	POS	O
+the	POS	O
+surgery	POS	O
+proceeded	POS	O
+without	POS	O
+further	POS	O
+problems	POS	O
+.	POS	O
+When	POS	O
+subsequently	POS	O
+questioned	POS	O
+,	POS	O
+she	POS	O
+reported	POS	O
+minor	POS	O
+symptoms	POS	O
+suggesting	POS	O
+a	POS	O
+myotonic	POS	B-NP
+condition	POS	O
+.	POS	O
+Myotonia	POS	B-NP
+was	POS	O
+found	POS	O
+on	POS	O
+clinical	POS	O
+examination	POS	O
+and	POS	O
+EMG	POS	O
+.	POS	O
+The	POS	O
+diagnosis	POS	O
+MC	POS	O
+was	POS	O
+confirmed	POS	O
+genetically	POS	O
+.	POS	O
+Neither	POS	O
+the	POS	O
+patient	POS	O
+nor	POS	O
+the	POS	O
+anaesthetist	POS	O
+were	POS	O
+aware	POS	O
+of	POS	O
+the	POS	O
+diagnosis	POS	O
+before	POS	O
+this	POS	O
+potentially	POS	O
+lethal	POS	O
+complication	POS	O
+occurred	POS	O
+.	POS	O
+We	POS	O
+give	POS	O
+a	POS	O
+brief	POS	O
+overview	POS	O
+of	POS	O
+ion	POS	O
+channel	POS	O
+disorders	POS	O
+including	POS	O
+malignant	POS	B-NP
+hyperthermia	POS	I-NP
+and	POS	O
+their	POS	O
+anaesthetic	POS	O
+considerations	POS	O
+.	POS	O
+Respiratory	POS	O
+pattern	POS	O
+in	POS	O
+a	POS	O
+rat	POS	O
+model	POS	O
+of	POS	O
+epilepsy	POS	B-NP
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+Apnea	POS	B-NP
+is	POS	O
+known	POS	O
+to	POS	O
+occur	POS	O
+during	POS	O
+seizures	POS	B-NP
+,	POS	O
+but	POS	O
+systematic	POS	O
+studies	POS	O
+of	POS	O
+ictal	POS	O
+respiratory	POS	O
+changes	POS	O
+in	POS	O
+adults	POS	O
+are	POS	O
+few	POS	O
+.	POS	O
+Data	POS	O
+regarding	POS	O
+respiratory	POS	B-NP
+pattern	POS	I-NP
+defects	POS	I-NP
+during	POS	O
+interictal	POS	O
+periods	POS	O
+also	POS	O
+are	POS	O
+scarce	POS	O
+.	POS	O
+Here	POS	O
+we	POS	O
+sought	POS	O
+to	POS	O
+generate	POS	O
+information	POS	O
+with	POS	O
+regard	POS	O
+to	POS	O
+the	POS	O
+interictal	POS	O
+period	POS	O
+in	POS	O
+animals	POS	O
+with	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+epilepsy	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Twelve	POS	O
+rats	POS	O
+(	POS	O
+six	POS	O
+chronically	POS	O
+epileptic	POS	B-NP
+animals	POS	O
+and	POS	O
+six	POS	O
+controls	POS	O
+)	POS	O
+were	POS	O
+anesthetized	POS	O
+,	POS	O
+given	POS	O
+tracheotomies	POS	O
+,	POS	O
+and	POS	O
+subjected	POS	O
+to	POS	O
+hyperventilation	POS	B-NP
+or	POS	O
+hypoventilation	POS	B-NP
+conditions	POS	O
+.	POS	O
+Breathing	POS	O
+movements	POS	O
+caused	POS	O
+changes	POS	O
+in	POS	O
+thoracic	POS	O
+volume	POS	O
+and	POS	O
+forced	POS	O
+air	POS	O
+to	POS	O
+flow	POS	O
+tidally	POS	O
+through	POS	O
+a	POS	O
+pneumotachograph	POS	O
+.	POS	O
+This	POS	O
+flow	POS	O
+was	POS	O
+measured	POS	O
+by	POS	O
+using	POS	O
+a	POS	O
+differential	POS	O
+pressure	POS	O
+transducer	POS	O
+,	POS	O
+passed	POS	O
+through	POS	O
+a	POS	O
+polygraph	POS	O
+,	POS	O
+and	POS	O
+from	POS	O
+this	POS	O
+to	POS	O
+a	POS	O
+computer	POS	O
+with	POS	O
+custom	POS	O
+software	POS	O
+that	POS	O
+derived	POS	O
+ventilation	POS	O
+(	POS	O
+VE	POS	O
+)	POS	O
+,	POS	O
+tidal	POS	O
+volume	POS	O
+(	POS	O
+VT	POS	O
+)	POS	O
+,	POS	O
+inspiratory	POS	O
+time	POS	O
+(	POS	O
+TI	POS	O
+)	POS	O
+,	POS	O
+expiratory	POS	O
+time	POS	O
+(	POS	O
+TE	POS	O
+)	POS	O
+,	POS	O
+breathing	POS	O
+frequency	POS	O
+(	POS	O
+f	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+mean	POS	O
+inspiratory	POS	O
+flow	POS	O
+(	POS	O
+VT	POS	O
+/	POS	O
+TI	POS	O
+)	POS	O
+on	POS	O
+a	POS	O
+breath	POS	O
+-	POS	O
+by	POS	O
+-	POS	O
+breath	POS	O
+basis	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+hyperventilation	POS	O
+maneuver	POS	O
+caused	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+spontaneous	POS	O
+ventilation	POS	O
+in	POS	O
+pilocarpine	POS	O
+-	POS	O
+treated	POS	O
+and	POS	O
+control	POS	O
+rats	POS	O
+.	POS	O
+Although	POS	O
+VE	POS	O
+had	POS	O
+a	POS	O
+similar	POS	O
+decrease	POS	O
+in	POS	O
+both	POS	O
+groups	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+epileptic	POS	B-NP
+group	POS	O
+,	POS	O
+the	POS	O
+decrease	POS	O
+in	POS	O
+VE	POS	O
+was	POS	O
+due	POS	O
+to	POS	O
+a	POS	O
+significant	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+increase	POS	O
+in	POS	O
+TE	POS	O
+peak	POS	O
+in	POS	O
+relation	POS	O
+to	POS	O
+that	POS	O
+of	POS	O
+the	POS	O
+control	POS	O
+animals	POS	O
+.	POS	O
+The	POS	O
+hypoventilation	POS	B-NP
+maneuver	POS	O
+led	POS	O
+to	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+arterial	POS	O
+Paco2	POS	O
+,	POS	O
+followed	POS	O
+by	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+VE	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+epileptic	POS	B-NP
+group	POS	O
+,	POS	O
+the	POS	O
+increase	POS	O
+in	POS	O
+VE	POS	O
+was	POS	O
+mediated	POS	O
+by	POS	O
+a	POS	O
+significant	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+decrease	POS	O
+in	POS	O
+TE	POS	O
+peak	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+.	POS	O
+Systemic	POS	O
+application	POS	O
+of	POS	O
+KCN	POS	O
+,	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+peripheral	POS	O
+chemoreception	POS	O
+activation	POS	O
+on	POS	O
+ventilation	POS	O
+,	POS	O
+led	POS	O
+to	POS	O
+a	POS	O
+similar	POS	O
+increase	POS	O
+in	POS	O
+VE	POS	O
+for	POS	O
+both	POS	O
+groups	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+data	POS	O
+indicate	POS	O
+that	POS	O
+pilocarpine	POS	O
+-	POS	O
+treated	POS	O
+animals	POS	O
+have	POS	O
+an	POS	O
+altered	POS	O
+ability	POS	O
+to	POS	O
+react	POS	O
+to	POS	O
+(	POS	O
+or	POS	O
+compensate	POS	O
+for	POS	O
+)	POS	O
+blood	POS	O
+gas	POS	O
+changes	POS	O
+with	POS	O
+changes	POS	O
+in	POS	O
+ventilation	POS	O
+and	POS	O
+suggest	POS	O
+that	POS	O
+it	POS	O
+is	POS	O
+centrally	POS	O
+determined	POS	O
+.	POS	O
+We	POS	O
+speculate	POS	O
+on	POS	O
+the	POS	O
+possible	POS	O
+relation	POS	O
+of	POS	O
+the	POS	O
+current	POS	O
+findings	POS	O
+on	POS	O
+treating	POS	O
+different	POS	O
+epilepsy	POS	B-NP
+-	POS	O
+associated	POS	O
+conditions	POS	O
+.	POS	O
+Fatal	POS	O
+myeloencephalopathy	POS	B-NP
+due	POS	O
+to	POS	O
+intrathecal	POS	O
+vincristine	POS	O
+administration	POS	O
+.	POS	O
+Vincristine	POS	O
+was	POS	O
+accidentally	POS	O
+given	POS	O
+intrathecally	POS	O
+to	POS	O
+a	POS	O
+child	POS	O
+with	POS	O
+leukaemia	POS	B-NP
+,	POS	O
+producing	POS	O
+sensory	POS	O
+and	POS	O
+motor	POS	O
+dysfunction	POS	O
+followed	POS	O
+by	POS	O
+encephalopathy	POS	B-NP
+and	POS	O
+death	POS	B-NP
+.	POS	O
+Separate	POS	O
+times	POS	O
+for	POS	O
+administering	POS	O
+vincristine	POS	O
+and	POS	O
+intrathecal	POS	O
+therapy	POS	O
+is	POS	O
+recommended	POS	O
+.	POS	O
+Progesterone	POS	O
+potentiation	POS	O
+of	POS	O
+bupivacaine	POS	O
+arrhythmogenicity	POS	O
+in	POS	O
+pentobarbital	POS	O
+-	POS	O
+anesthetized	POS	O
+rats	POS	O
+and	POS	O
+beating	POS	O
+rat	POS	O
+heart	POS	O
+cell	POS	O
+cultures	POS	O
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+progesterone	POS	O
+treatment	POS	O
+on	POS	O
+bupivacaine	POS	O
+arrhythmogenicity	POS	O
+in	POS	O
+beating	POS	O
+rat	POS	O
+heart	POS	O
+myocyte	POS	O
+cultures	POS	O
+and	POS	O
+on	POS	O
+anesthetized	POS	O
+rats	POS	O
+were	POS	O
+determined	POS	O
+.	POS	O
+After	POS	O
+determining	POS	O
+the	POS	O
+bupivacaine	POS	O
+AD50	POS	O
+(	POS	O
+the	POS	O
+concentration	POS	O
+of	POS	O
+bupivacaine	POS	O
+that	POS	O
+caused	POS	O
+50	POS	O
+%	POS	O
+of	POS	O
+all	POS	O
+beating	POS	O
+rat	POS	O
+heart	POS	O
+myocyte	POS	O
+cultures	POS	O
+to	POS	O
+become	POS	O
+arrhythmic	POS	O
+)	POS	O
+,	POS	O
+we	POS	O
+determined	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+1	POS	O
+-	POS	O
+hour	POS	O
+progesterone	POS	O
+HCl	POS	O
+exposure	POS	O
+on	POS	O
+myocyte	POS	O
+contractile	POS	O
+rhythm	POS	O
+.	POS	O
+Each	POS	O
+concentration	POS	O
+of	POS	O
+progesterone	POS	O
+(	POS	O
+6	POS	O
+.	POS	O
+25	POS	O
+,	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+,	POS	O
+25	POS	O
+,	POS	O
+and	POS	O
+50	POS	O
+micrograms	POS	O
+/	POS	O
+ml	POS	O
+)	POS	O
+caused	POS	O
+a	POS	O
+significant	POS	O
+and	POS	O
+concentration	POS	O
+-	POS	O
+dependent	POS	O
+reduction	POS	O
+in	POS	O
+the	POS	O
+AD50	POS	O
+for	POS	O
+bupivacaine	POS	O
+.	POS	O
+Estradiol	POS	O
+treatment	POS	O
+also	POS	O
+increased	POS	O
+the	POS	O
+arrhythmogenicity	POS	O
+of	POS	O
+bupivacaine	POS	O
+in	POS	O
+myocyte	POS	O
+cultures	POS	O
+,	POS	O
+but	POS	O
+was	POS	O
+only	POS	O
+one	POS	O
+fourth	POS	O
+as	POS	O
+potent	POS	O
+as	POS	O
+progesterone	POS	O
+.	POS	O
+Neither	POS	O
+progesterone	POS	O
+nor	POS	O
+estradiol	POS	O
+effects	POS	O
+on	POS	O
+bupivacaine	POS	O
+arrhythmogenicity	POS	O
+were	POS	O
+potentiated	POS	O
+by	POS	O
+epinephrine	POS	O
+.	POS	O
+Chronic	POS	O
+progesterone	POS	O
+pretreatment	POS	O
+(	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+for	POS	O
+21	POS	O
+days	POS	O
+)	POS	O
+caused	POS	O
+a	POS	O
+significant	POS	O
+increase	POS	O
+in	POS	O
+bupivacaine	POS	O
+arrhythmogenicity	POS	O
+in	POS	O
+intact	POS	O
+pentobarbital	POS	O
+-	POS	O
+anesthetized	POS	O
+rats	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+decrease	POS	O
+in	POS	O
+the	POS	O
+time	POS	O
+to	POS	O
+onset	POS	O
+of	POS	O
+arrhythmia	POS	B-NP
+as	POS	O
+compared	POS	O
+with	POS	O
+control	POS	O
+nonprogesterone	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+(	POS	O
+6	POS	O
+.	POS	O
+2	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+vs	POS	O
+.	POS	O
+30	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+min	POS	O
+,	POS	O
+mean	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+SE	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+indicate	POS	O
+that	POS	O
+progesterone	POS	O
+can	POS	O
+potentiate	POS	O
+bupivacaine	POS	O
+arrhythmogenicity	POS	O
+both	POS	O
+in	POS	O
+vivo	POS	O
+and	POS	O
+in	POS	O
+vitro	POS	O
+.	POS	O
+Potentiation	POS	O
+of	POS	O
+bupivacaine	POS	O
+arrhythmia	POS	B-NP
+in	POS	O
+myocyte	POS	O
+cultures	POS	O
+suggests	POS	O
+that	POS	O
+this	POS	O
+effect	POS	O
+is	POS	O
+at	POS	O
+least	POS	O
+partly	POS	O
+mediated	POS	O
+at	POS	O
+the	POS	O
+myocyte	POS	O
+level	POS	O
+.	POS	O
+Increased	POS	O
+serum	POS	O
+soluble	POS	O
+Fas	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+due	POS	O
+to	POS	O
+paracetamol	POS	O
+overdose	POS	B-NP
+.	POS	O
+BACKGROUND	POS	O
+/	POS	O
+AIMS	POS	O
+:	POS	O
+Experimental	POS	O
+studies	POS	O
+have	POS	O
+suggested	POS	O
+that	POS	O
+apoptosis	POS	O
+via	POS	O
+the	POS	O
+Fas	POS	O
+/	POS	O
+Fas	POS	O
+Ligand	POS	O
+signaling	POS	O
+system	POS	O
+may	POS	O
+play	POS	O
+an	POS	O
+important	POS	O
+role	POS	O
+in	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+the	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+soluble	POS	O
+form	POS	O
+of	POS	O
+Fas	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+METHODOLOGY	POS	O
+:	POS	O
+Serum	POS	O
+levels	POS	O
+of	POS	O
+sFas	POS	O
+(	POS	O
+soluble	POS	O
+Fas	POS	O
+)	POS	O
+were	POS	O
+measured	POS	O
+by	POS	O
+ELISA	POS	O
+in	POS	O
+24	POS	O
+patients	POS	O
+with	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+and	POS	O
+10	POS	O
+normal	POS	B-NP
+control	POS	O
+subjects	POS	O
+.	POS	O
+Serum	POS	O
+levels	POS	O
+of	POS	O
+tumor	POS	B-NP
+necrosis	POS	O
+factor	POS	O
+-	POS	O
+alpha	POS	O
+and	POS	O
+interferon	POS	O
+-	POS	O
+gamma	POS	O
+were	POS	O
+also	POS	O
+determined	POS	O
+by	POS	O
+ELISA	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Serum	POS	O
+sFas	POS	O
+was	POS	O
+significantly	POS	O
+increased	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+(	POS	O
+median	POS	O
+,	POS	O
+26	POS	O
+.	POS	O
+8	POS	O
+U	POS	O
+/	POS	O
+mL	POS	O
+;	POS	O
+range	POS	O
+,	POS	O
+6	POS	O
+.	POS	O
+9	POS	O
+-	POS	O
+52	POS	O
+.	POS	O
+7	POS	O
+U	POS	O
+/	POS	O
+mL	POS	O
+)	POS	O
+compared	POS	O
+to	POS	O
+the	POS	O
+normal	POS	O
+controls	POS	O
+(	POS	O
+median	POS	O
+,	POS	O
+8	POS	O
+.	POS	O
+6	POS	O
+U	POS	O
+/	POS	O
+mL	POS	O
+;	POS	O
+range	POS	O
+,	POS	O
+6	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+12	POS	O
+.	POS	O
+0	POS	O
+U	POS	O
+/	POS	O
+mL	POS	O
+,	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+0001	POS	O
+)	POS	O
+.	POS	O
+Levels	POS	O
+were	POS	O
+significantly	POS	O
+greater	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+due	POS	O
+to	POS	O
+paracetamol	POS	O
+overdose	POS	B-NP
+(	POS	O
+median	POS	O
+,	POS	O
+28	POS	O
+.	POS	O
+7	POS	O
+U	POS	O
+/	POS	O
+mL	POS	O
+;	POS	O
+range	POS	O
+,	POS	O
+12	POS	O
+.	POS	O
+8	POS	O
+-	POS	O
+52	POS	O
+.	POS	O
+7	POS	O
+U	POS	O
+/	POS	O
+mL	POS	O
+,	POS	O
+n	POS	O
+=	POS	O
+17	POS	O
+)	POS	O
+than	POS	O
+those	POS	O
+due	POS	O
+to	POS	O
+non	POS	O
+-	POS	O
+A	POS	O
+to	POS	O
+E	POS	O
+hepatitis	POS	B-NP
+(	POS	O
+median	POS	O
+,	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+U	POS	O
+/	POS	O
+mL	POS	O
+;	POS	O
+range	POS	O
+,	POS	O
+6	POS	O
+.	POS	O
+9	POS	O
+-	POS	O
+46	POS	O
+.	POS	O
+0	POS	O
+U	POS	O
+/	POS	O
+mL	POS	O
+,	POS	O
+n	POS	O
+=	POS	O
+7	POS	O
+,	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+relationship	POS	O
+of	POS	O
+sFas	POS	O
+to	POS	O
+eventual	POS	O
+outcome	POS	O
+in	POS	O
+the	POS	O
+patients	POS	O
+.	POS	O
+A	POS	O
+significant	POS	O
+correlation	POS	O
+was	POS	O
+observed	POS	O
+between	POS	O
+serum	POS	O
+sFas	POS	O
+levels	POS	O
+and	POS	O
+aspartate	POS	O
+aminotransferase	POS	O
+(	POS	O
+r	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+613	POS	O
+,	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+increased	POS	O
+concentration	POS	O
+of	POS	O
+sFas	POS	O
+in	POS	O
+serum	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+may	POS	O
+reflect	POS	O
+activation	POS	O
+of	POS	O
+Fas	POS	O
+-	POS	O
+mediated	POS	O
+apoptosis	POS	O
+in	POS	O
+the	POS	O
+liver	POS	O
+and	POS	O
+this	POS	O
+together	POS	O
+with	POS	O
+increased	POS	O
+tumor	POS	B-NP
+necrosis	POS	O
+factor	POS	O
+-	POS	O
+alpha	POS	O
+may	POS	O
+be	POS	O
+an	POS	O
+important	POS	O
+factor	POS	O
+in	POS	O
+liver	POS	B-NP
+cell	POS	I-NP
+loss	POS	I-NP
+.	POS	O
+Bilateral	POS	O
+subthalamic	POS	O
+nucleus	POS	O
+stimulation	POS	O
+for	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+High	POS	O
+frequency	POS	O
+stimulation	POS	O
+of	POS	O
+the	POS	O
+subthalamic	POS	O
+nucleus	POS	O
+(	POS	O
+STN	POS	O
+)	POS	O
+is	POS	O
+known	POS	O
+to	POS	O
+ameliorate	POS	O
+the	POS	O
+signs	POS	O
+and	POS	O
+symptoms	POS	O
+of	POS	O
+advanced	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+AIM	POS	O
+:	POS	O
+We	POS	O
+studied	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+high	POS	O
+frequency	POS	O
+STN	POS	O
+stimulation	POS	O
+in	POS	O
+23	POS	O
+patients	POS	O
+.	POS	O
+METHOD	POS	O
+:	POS	O
+Twenty	POS	O
+-	POS	O
+three	POS	O
+patients	POS	O
+suffering	POS	O
+from	POS	O
+severe	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+Stages	POS	O
+III	POS	O
+-	POS	O
+V	POS	O
+on	POS	O
+Hoehn	POS	O
+and	POS	O
+Yahr	POS	O
+scale	POS	O
+)	POS	O
+and	POS	O
+,	POS	O
+particularly	POS	O
+bradykinesia	POS	B-NP
+,	POS	O
+rigidity	POS	B-NP
+,	POS	O
+and	POS	O
+levodopa	POS	O
+-	POS	O
+induced	POS	O
+dyskinesias	POS	B-NP
+underwent	POS	O
+bilateral	POS	O
+implantation	POS	O
+of	POS	O
+electrodes	POS	O
+in	POS	O
+the	POS	O
+STN	POS	O
+.	POS	O
+Preoperative	POS	O
+and	POS	O
+postoperative	POS	O
+assessments	POS	O
+of	POS	O
+these	POS	O
+patients	POS	O
+at	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+,	POS	O
+6	POS	O
+and	POS	O
+12	POS	O
+months	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+,	POS	O
+in	POS	O
+"	POS	O
+on	POS	O
+"	POS	O
+and	POS	O
+"	POS	O
+off	POS	O
+"	POS	O
+drug	POS	O
+conditions	POS	O
+,	POS	O
+was	POS	O
+carried	POS	O
+out	POS	O
+using	POS	O
+Unified	POS	O
+Parkinson	POS	O
+'	POS	O
+s	POS	O
+Disease	POS	O
+Rating	POS	O
+Scale	POS	O
+,	POS	O
+Hoehn	POS	B-NP
+and	POS	O
+Yahr	POS	O
+staging	POS	O
+,	POS	O
+England	POS	O
+activities	POS	O
+of	POS	O
+daily	POS	O
+living	POS	O
+score	POS	O
+and	POS	O
+video	POS	O
+recordings	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+After	POS	O
+one	POS	O
+year	POS	O
+of	POS	O
+electrical	POS	O
+stimulation	POS	O
+of	POS	O
+the	POS	O
+STN	POS	O
+,	POS	O
+the	POS	O
+patients	POS	O
+'	POS	O
+scores	POS	O
+for	POS	O
+activities	POS	O
+of	POS	O
+daily	POS	O
+living	POS	O
+and	POS	O
+motor	POS	O
+examination	POS	O
+scores	POS	O
+(	POS	O
+Unified	POS	O
+Parkinson	POS	O
+'	POS	O
+s	POS	O
+Disease	POS	O
+Rating	POS	O
+Scale	POS	O
+parts	POS	O
+II	POS	O
+and	POS	O
+III	POS	O
+)	POS	O
+off	POS	O
+medication	POS	O
+improved	POS	O
+by	POS	O
+62	POS	O
+%	POS	O
+and	POS	O
+61	POS	O
+%	POS	O
+respectively	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+0005	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+subscores	POS	O
+for	POS	O
+the	POS	O
+akinesia	POS	B-NP
+,	POS	O
+rigidity	POS	B-NP
+,	POS	O
+tremor	POS	B-NP
+and	POS	O
+gait	POS	O
+also	POS	O
+improved	POS	O
+.	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+0005	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+average	POS	O
+levodopa	POS	O
+dose	POS	O
+decreased	POS	O
+from	POS	O
+813	POS	O
+mg	POS	O
+to	POS	O
+359	POS	O
+mg	POS	O
+.	POS	O
+The	POS	O
+cognitive	POS	O
+functions	POS	O
+remained	POS	O
+unchanged	POS	O
+.	POS	O
+Two	POS	O
+patients	POS	O
+developed	POS	O
+device	POS	O
+-	POS	O
+related	POS	O
+complications	POS	O
+and	POS	O
+two	POS	O
+patients	POS	O
+experienced	POS	O
+abnormal	POS	B-NP
+weight	POS	I-NP
+gain	POS	I-NP
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Bilateral	POS	O
+subthalamic	POS	O
+nucleus	POS	O
+stimulation	POS	O
+is	POS	O
+an	POS	O
+effective	POS	O
+treatment	POS	O
+for	POS	O
+advanced	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+It	POS	O
+reduces	POS	O
+the	POS	O
+severity	POS	O
+of	POS	O
+"	POS	O
+off	POS	O
+"	POS	O
+phase	POS	O
+symptoms	POS	O
+,	POS	O
+improves	POS	O
+the	POS	O
+axial	POS	O
+symptoms	POS	O
+and	POS	O
+reduces	POS	O
+levodopa	POS	O
+requirements	POS	O
+.	POS	O
+The	POS	O
+reduction	POS	O
+in	POS	O
+the	POS	O
+levodopa	POS	O
+dose	POS	O
+is	POS	O
+useful	POS	O
+in	POS	O
+controlling	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+dyskinesias	POS	B-NP
+.	POS	O
+Acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+occurring	POS	O
+during	POS	O
+intravenous	POS	O
+desferrioxamine	POS	O
+therapy	POS	O
+:	POS	O
+recovery	POS	O
+after	POS	O
+haemodialysis	POS	O
+.	POS	O
+A	POS	O
+patient	POS	O
+with	POS	O
+transfusion	POS	B-NP
+-	POS	I-NP
+dependent	POS	I-NP
+thalassemia	POS	I-NP
+was	POS	O
+undergoing	POS	O
+home	POS	O
+intravenous	POS	O
+desferrioxamine	POS	O
+(	POS	O
+DFX	POS	O
+)	POS	O
+treatment	POS	O
+by	POS	O
+means	POS	O
+of	POS	O
+a	POS	O
+totally	POS	O
+implanted	POS	O
+system	POS	O
+because	POS	O
+of	POS	O
+his	POS	O
+poor	POS	O
+compliance	POS	O
+with	POS	O
+the	POS	O
+nightly	POS	O
+subcutaneous	POS	O
+therapy	POS	O
+.	POS	O
+Due	POS	O
+to	POS	O
+an	POS	O
+accidental	POS	O
+malfunctioning	POS	O
+of	POS	O
+the	POS	O
+infusion	POS	O
+pump	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+inadvertently	POS	O
+administered	POS	O
+a	POS	O
+toxic	POS	O
+dosage	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+which	POS	O
+caused	POS	O
+renal	POS	B-NP
+insufficiency	POS	I-NP
+.	POS	O
+Given	POS	O
+the	POS	O
+progressive	POS	O
+deterioration	POS	O
+of	POS	O
+the	POS	O
+symptoms	POS	O
+and	POS	O
+of	POS	O
+the	POS	O
+laboratory	POS	O
+values	POS	O
+,	POS	O
+despite	POS	O
+adequate	POS	O
+medical	POS	O
+treatment	POS	O
+,	POS	O
+a	POS	O
+decision	POS	O
+was	POS	O
+made	POS	O
+to	POS	O
+introduce	POS	O
+haemodialytical	POS	O
+therapy	POS	O
+in	POS	O
+order	POS	O
+to	POS	O
+remove	POS	O
+the	POS	O
+drug	POS	O
+and	POS	O
+therapy	POS	O
+reduce	POS	O
+the	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+From	POS	O
+the	POS	O
+results	POS	O
+obtained	POS	O
+,	POS	O
+haemodialysis	POS	O
+can	POS	O
+therefore	POS	O
+be	POS	O
+suggested	POS	O
+as	POS	O
+a	POS	O
+useful	POS	O
+therapy	POS	O
+in	POS	O
+rare	POS	O
+cases	POS	O
+of	POS	O
+progressive	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+caused	POS	O
+by	POS	O
+desferrioxamine	POS	O
+.	POS	O
+Ocular	POS	B-NP
+motility	POS	I-NP
+changes	POS	O
+after	POS	O
+subtenon	POS	O
+carboplatin	POS	O
+chemotherapy	POS	O
+for	POS	O
+retinoblastoma	POS	B-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Focal	POS	O
+subtenon	POS	O
+carboplatin	POS	O
+injections	POS	O
+have	POS	O
+recently	POS	O
+been	POS	O
+used	POS	O
+as	POS	O
+a	POS	O
+presumably	POS	O
+toxicity	POS	O
+-	POS	O
+free	POS	O
+adjunct	POS	O
+to	POS	O
+systemic	POS	O
+chemotherapy	POS	O
+for	POS	O
+intraocular	POS	B-NP
+retinoblastoma	POS	I-NP
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+report	POS	O
+our	POS	O
+clinical	POS	O
+experience	POS	O
+with	POS	O
+abnormal	POS	B-NP
+ocular	POS	I-NP
+motility	POS	I-NP
+in	POS	O
+patients	POS	O
+treated	POS	O
+with	POS	O
+subtenon	POS	O
+carboplatin	POS	O
+chemotherapy	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+noted	POS	O
+abnormal	POS	B-NP
+ocular	POS	I-NP
+motility	POS	I-NP
+in	POS	O
+10	POS	O
+consecutive	POS	O
+patients	POS	O
+with	POS	O
+retinoblastoma	POS	B-NP
+who	POS	O
+had	POS	O
+received	POS	O
+subtenon	POS	O
+carboplatin	POS	O
+.	POS	O
+During	POS	O
+ocular	POS	O
+manipulation	POS	O
+under	POS	O
+general	POS	O
+anesthesia	POS	O
+,	POS	O
+we	POS	O
+assessed	POS	O
+their	POS	O
+eyes	POS	O
+by	POS	O
+forced	POS	O
+duction	POS	O
+testing	POS	O
+,	POS	O
+comparing	POS	O
+ocular	POS	O
+motility	POS	O
+after	POS	O
+tumor	POS	B-NP
+control	POS	O
+with	POS	O
+ocular	POS	B-NP
+motility	POS	I-NP
+at	POS	O
+diagnosis	POS	O
+.	POS	O
+Eyes	POS	O
+subsequently	POS	O
+enucleated	POS	O
+because	POS	O
+of	POS	O
+treatment	POS	O
+failure	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+4	POS	O
+)	POS	O
+were	POS	O
+examined	POS	O
+histologically	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Limitation	POS	O
+of	POS	O
+ocular	POS	B-NP
+motility	POS	I-NP
+was	POS	O
+detected	POS	O
+in	POS	O
+all	POS	O
+12	POS	O
+eyes	POS	O
+of	POS	O
+10	POS	O
+patients	POS	O
+treated	POS	O
+for	POS	O
+intraocular	POS	B-NP
+retinoblastoma	POS	I-NP
+with	POS	O
+1	POS	O
+to	POS	O
+6	POS	O
+injections	POS	O
+of	POS	O
+subtenon	POS	O
+carboplatin	POS	O
+as	POS	O
+part	POS	O
+of	POS	O
+multimodality	POS	O
+therapy	POS	O
+.	POS	O
+Histopathological	POS	O
+examination	POS	O
+revealed	POS	O
+many	POS	O
+lipophages	POS	O
+in	POS	O
+the	POS	O
+periorbital	POS	O
+fat	POS	O
+surrounding	POS	O
+the	POS	O
+optic	POS	O
+nerve	POS	O
+in	POS	O
+1	POS	O
+eye	POS	O
+,	POS	O
+indicative	POS	O
+of	POS	O
+phagocytosis	POS	O
+of	POS	O
+previously	POS	O
+existing	POS	O
+fat	POS	O
+cells	POS	O
+and	POS	O
+suggesting	POS	O
+prior	POS	O
+fat	POS	O
+necrosis	POS	B-NP
+.	POS	O
+The	POS	O
+enucleations	POS	O
+were	POS	O
+technically	POS	O
+difficult	POS	O
+and	POS	O
+hazardous	POS	O
+for	POS	O
+globe	POS	O
+rupture	POS	O
+because	POS	O
+of	POS	O
+extensive	POS	O
+orbital	POS	O
+soft	POS	O
+tissue	POS	O
+adhesions	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Subtenon	POS	O
+carboplatin	POS	O
+chemotherapy	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+significant	POS	O
+fibrosis	POS	B-NP
+of	POS	O
+orbital	POS	O
+soft	POS	O
+tissues	POS	O
+,	POS	O
+leading	POS	O
+to	POS	O
+mechanical	POS	O
+restriction	POS	O
+of	POS	O
+eye	POS	O
+movements	POS	O
+and	POS	O
+making	POS	O
+subsequent	POS	O
+enucleation	POS	O
+difficult	POS	O
+.	POS	O
+Subtenon	POS	O
+carboplatin	POS	O
+is	POS	O
+not	POS	O
+free	POS	O
+of	POS	O
+toxicity	POS	B-NP
+,	POS	O
+and	POS	O
+its	POS	O
+use	POS	O
+is	POS	O
+best	POS	O
+restricted	POS	O
+to	POS	O
+specific	POS	O
+indications	POS	O
+.	POS	O
+Ethambutol	POS	O
+and	POS	O
+optic	POS	B-NP
+neuropathy	POS	I-NP
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+To	POS	O
+demonstrate	POS	O
+the	POS	O
+association	POS	O
+between	POS	O
+ethambutol	POS	O
+and	POS	O
+optic	POS	B-NP
+neuropathy	POS	I-NP
+.	POS	O
+METHOD	POS	O
+:	POS	O
+Thirteen	POS	O
+patients	POS	O
+who	POS	O
+developed	POS	O
+optic	POS	B-NP
+neuropathy	POS	I-NP
+after	POS	O
+being	POS	O
+treated	POS	O
+with	POS	O
+ethambutol	POS	O
+for	POS	O
+tuberculosis	POS	B-NP
+of	POS	O
+the	POS	O
+lung	POS	O
+or	POS	O
+lymph	POS	O
+node	POS	O
+at	POS	O
+Siriraj	POS	O
+Hospital	POS	O
+between	POS	O
+1997	POS	O
+and	POS	O
+2001	POS	O
+were	POS	O
+retrospectively	POS	O
+reviewed	POS	O
+.	POS	O
+The	POS	O
+clinical	POS	O
+characteristics	POS	O
+and	POS	O
+initial	POS	O
+and	POS	O
+final	POS	O
+visual	POS	O
+acuity	POS	O
+were	POS	O
+analyzed	POS	O
+to	POS	O
+determine	POS	O
+visual	POS	O
+outcome	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+All	POS	O
+patients	POS	O
+had	POS	O
+optic	POS	B-NP
+neuropathy	POS	I-NP
+between	POS	O
+1	POS	O
+to	POS	O
+6	POS	O
+months	POS	O
+(	POS	O
+mean	POS	O
+=	POS	O
+2	POS	O
+.	POS	O
+9	POS	O
+months	POS	O
+)	POS	O
+after	POS	O
+starting	POS	O
+ethambutol	POS	O
+therapy	POS	O
+at	POS	O
+a	POS	O
+dosage	POS	O
+ranging	POS	O
+from	POS	O
+13	POS	O
+to	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+(	POS	O
+mean	POS	O
+=	POS	O
+17	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+.	POS	O
+Seven	POS	O
+(	POS	O
+54	POS	O
+%	POS	O
+)	POS	O
+of	POS	O
+the	POS	O
+13	POS	O
+patients	POS	O
+experienced	POS	O
+visual	POS	O
+recovery	POS	O
+after	POS	O
+stopping	POS	O
+the	POS	O
+drug	POS	O
+.	POS	O
+Of	POS	O
+6	POS	O
+patients	POS	O
+with	POS	O
+irreversible	POS	O
+visual	POS	B-NP
+impairment	POS	I-NP
+,	POS	O
+4	POS	O
+patients	POS	O
+had	POS	O
+diabetes	POS	B-NP
+mellitus	POS	I-NP
+,	POS	O
+glaucoma	POS	B-NP
+and	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+heavy	POS	O
+smoking	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Early	POS	O
+recognition	POS	O
+of	POS	O
+optic	POS	B-NP
+neuropathy	POS	I-NP
+should	POS	O
+be	POS	O
+considered	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+ethambutol	POS	O
+therapy	POS	O
+.	POS	O
+A	POS	O
+low	POS	O
+dose	POS	O
+and	POS	O
+prompt	POS	O
+discontinuation	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+is	POS	O
+recommended	POS	O
+particularly	POS	O
+in	POS	O
+individuals	POS	O
+with	POS	O
+diabetes	POS	B-NP
+mellitus	POS	I-NP
+,	POS	O
+glaucoma	POS	B-NP
+or	POS	O
+who	POS	O
+are	POS	O
+heavy	POS	O
+smokers	POS	O
+.	POS	O
+Treatment	POS	O
+of	POS	O
+compensatory	POS	O
+gustatory	POS	B-NP
+hyperhidrosis	POS	I-NP
+with	POS	O
+topical	POS	O
+glycopyrrolate	POS	O
+.	POS	O
+Gustatory	POS	B-NP
+hyperhidrosis	POS	I-NP
+is	POS	O
+facial	POS	B-NP
+sweating	POS	I-NP
+usually	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+eating	POS	O
+of	POS	O
+hot	POS	O
+spicy	POS	O
+food	POS	O
+or	POS	O
+even	POS	O
+smelling	POS	O
+this	POS	O
+food	POS	O
+.	POS	O
+Current	POS	O
+options	POS	O
+of	POS	O
+treatment	POS	O
+include	POS	O
+oral	POS	O
+anticholinergic	POS	O
+drugs	POS	O
+,	POS	O
+the	POS	O
+topical	POS	O
+application	POS	O
+of	POS	O
+anticholinergics	POS	O
+or	POS	O
+aluminum	POS	O
+chloride	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+injection	POS	O
+of	POS	O
+botulinum	POS	O
+toxin	POS	O
+.	POS	O
+Thirteen	POS	O
+patients	POS	O
+have	POS	O
+been	POS	O
+treated	POS	O
+to	POS	O
+date	POS	O
+with	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+or	POS	O
+2	POS	O
+%	POS	O
+topical	POS	O
+glycopyrrolate	POS	O
+.	POS	O
+All	POS	O
+patients	POS	O
+had	POS	O
+gustatory	POS	B-NP
+hyperhidrosis	POS	I-NP
+,	POS	O
+which	POS	O
+interfered	POS	O
+with	POS	O
+their	POS	O
+social	POS	O
+activities	POS	O
+,	POS	O
+after	POS	O
+transthroacic	POS	O
+endoscopic	POS	O
+sympathectomy	POS	O
+,	POS	O
+and	POS	O
+which	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+compensatory	POS	O
+focal	POS	O
+hyperhidrosis	POS	B-NP
+.	POS	O
+After	POS	O
+applying	POS	O
+topical	POS	O
+glycopyrrolate	POS	O
+,	POS	O
+the	POS	O
+subjective	POS	O
+effect	POS	O
+was	POS	O
+excellent	POS	O
+(	POS	O
+no	POS	O
+sweating	POS	O
+after	POS	O
+eating	POS	O
+hot	POS	O
+spicy	POS	O
+food	POS	O
+)	POS	O
+in	POS	O
+10	POS	O
+patients	POS	O
+(	POS	O
+77	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+fair	POS	O
+(	POS	O
+clearly	POS	O
+reduced	POS	O
+sweating	POS	O
+)	POS	O
+in	POS	O
+3	POS	O
+patients	POS	O
+(	POS	O
+23	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+All	POS	O
+had	POS	O
+reported	POS	O
+incidents	POS	O
+of	POS	O
+being	POS	O
+very	POS	O
+embarrassed	POS	O
+whilst	POS	O
+eating	POS	O
+hot	POS	O
+spicy	POS	O
+foods	POS	O
+.	POS	O
+Adverse	POS	O
+effects	POS	O
+included	POS	O
+a	POS	O
+mildly	POS	O
+dry	POS	B-NP
+mouth	POS	I-NP
+and	POS	O
+a	POS	O
+sore	POS	B-NP
+throat	POS	I-NP
+in	POS	O
+2	POS	O
+patients	POS	O
+(	POS	O
+2	POS	O
+%	POS	O
+glycopyrrolate	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+light	POS	O
+headache	POS	B-NP
+in	POS	O
+1	POS	O
+patient	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+glycopyrrolate	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+topical	POS	O
+application	POS	O
+of	POS	O
+a	POS	O
+glycopyrrolate	POS	O
+pad	POS	O
+appeared	POS	O
+to	POS	O
+be	POS	O
+safe	POS	O
+,	POS	O
+efficacious	POS	O
+,	POS	O
+well	POS	O
+tolerated	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+convenient	POS	O
+method	POS	O
+of	POS	O
+treatment	POS	O
+for	POS	O
+moderate	POS	O
+to	POS	O
+severe	POS	O
+symptoms	POS	O
+of	POS	O
+gustatory	POS	B-NP
+hyperhidrosis	POS	I-NP
+in	POS	O
+post	POS	O
+transthoracic	POS	O
+endoscopic	POS	O
+sympathectomy	POS	O
+or	POS	O
+sympathicotomy	POS	O
+patients	POS	O
+,	POS	O
+with	POS	O
+few	POS	O
+side	POS	O
+effects	POS	O
+.	POS	O
+Neuroleptic	POS	B-NP
+-	POS	O
+associated	POS	O
+hyperprolactinemia	POS	B-NP
+.	POS	O
+Can	POS	O
+it	POS	O
+be	POS	O
+treated	POS	O
+with	POS	O
+bromocriptine	POS	O
+?	POS	O
+Six	POS	O
+stable	POS	O
+psychiatric	POS	O
+outpatients	POS	O
+with	POS	O
+hyperprolactinemia	POS	B-NP
+and	POS	O
+amenorrhea	POS	B-NP
+/	POS	O
+oligomenorrhea	POS	B-NP
+associated	POS	O
+with	POS	O
+their	POS	O
+neuroleptic	POS	O
+medications	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+bromocriptine	POS	O
+.	POS	O
+Daily	POS	O
+dosages	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+10	POS	O
+mg	POS	O
+corrected	POS	O
+the	POS	O
+hyperprolactinemia	POS	B-NP
+and	POS	O
+restored	POS	O
+menstruation	POS	O
+in	POS	O
+four	POS	O
+of	POS	O
+the	POS	O
+six	POS	O
+patients	POS	O
+.	POS	O
+One	POS	O
+woman	POS	O
+,	POS	O
+however	POS	O
+,	POS	O
+developed	POS	O
+worsened	POS	O
+psychiatric	POS	B-NP
+symptoms	POS	I-NP
+while	POS	O
+taking	POS	O
+bromocriptine	POS	O
+,	POS	O
+and	POS	O
+it	POS	O
+was	POS	O
+discontinued	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+three	POS	O
+of	POS	O
+six	POS	O
+patients	POS	O
+had	POS	O
+their	POS	O
+menstrual	POS	O
+irregularity	POS	O
+successfully	POS	O
+corrected	POS	O
+with	POS	O
+bromocriptine	POS	O
+.	POS	O
+This	POS	O
+suggests	POS	O
+that	POS	O
+bromocriptine	POS	O
+should	POS	O
+be	POS	O
+further	POS	O
+evaluated	POS	O
+as	POS	O
+potential	POS	O
+therapy	POS	O
+for	POS	O
+neuroleptic	POS	O
+-	POS	O
+associated	POS	O
+hyperprolactinemia	POS	B-NP
+and	POS	O
+amenorrhea	POS	B-NP
+/	POS	O
+galactorrhea	POS	B-NP
+.	POS	O
+Ethacrynic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+convulsions	POS	B-NP
+and	POS	O
+brain	POS	O
+neurotransmitters	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+Intracerebroventricular	POS	O
+injection	POS	O
+of	POS	O
+ethacrynic	POS	O
+acid	POS	O
+(	POS	O
+50	POS	O
+%	POS	O
+convulsive	POS	B-NP
+dose	POS	O
+;	POS	O
+50	POS	O
+micrograms	POS	O
+/	POS	O
+mouse	POS	O
+)	POS	O
+accelerated	POS	O
+the	POS	O
+synthesis	POS	O
+/	POS	O
+turnover	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+hydroxytryptamine	POS	O
+(	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+)	POS	O
+but	POS	O
+suppressed	POS	O
+the	POS	O
+synthesis	POS	O
+of	POS	O
+gamma	POS	O
+-	POS	O
+aminobutyric	POS	O
+acid	POS	O
+and	POS	O
+acetylcholine	POS	O
+in	POS	O
+mouse	POS	O
+brain	POS	O
+.	POS	O
+These	POS	O
+effects	POS	O
+were	POS	O
+completely	POS	O
+antagonized	POS	O
+by	POS	O
+pretreatment	POS	O
+with	POS	O
+a	POS	O
+glutamate	POS	O
+/	POS	O
+N	POS	O
+-	POS	O
+methyl	POS	O
+-	POS	O
+D	POS	O
+-	POS	O
+aspartate	POS	O
+antagonist	POS	O
+,	POS	O
+aminophosphonovaleric	POS	O
+acid	POS	O
+.	POS	O
+In	POS	O
+ethacrynic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+convulsions	POS	B-NP
+,	POS	O
+these	POS	O
+neurotransmitter	POS	O
+systems	POS	O
+may	POS	O
+be	POS	O
+differentially	POS	O
+modulated	POS	O
+,	POS	O
+probably	POS	O
+through	POS	O
+activation	POS	O
+of	POS	O
+glutaminergic	POS	O
+neurons	POS	O
+in	POS	O
+the	POS	O
+brain	POS	O
+.	POS	O
+Pharmacology	POS	O
+of	POS	O
+gamma	POS	O
+-	POS	O
+aminobutyric	POS	O
+acidA	POS	O
+receptor	POS	O
+complex	POS	O
+after	POS	O
+the	POS	O
+in	POS	O
+vivo	POS	O
+administration	POS	O
+of	POS	O
+the	POS	O
+anxioselective	POS	O
+and	POS	O
+anticonvulsant	POS	O
+beta	POS	O
+-	POS	O
+carboline	POS	O
+derivative	POS	O
+abecarnil	POS	O
+.	POS	O
+In	POS	O
+rodents	POS	O
+,	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+the	POS	O
+beta	POS	O
+-	POS	O
+carboline	POS	O
+derivative	POS	O
+isopropyl	POS	O
+-	POS	O
+6	POS	O
+-	POS	O
+benzyloxy	POS	O
+-	POS	O
+4	POS	O
+-	POS	O
+methoxymethyl	POS	O
+-	POS	O
+beta	POS	O
+-	POS	O
+carboline	POS	O
+-	POS	O
+3	POS	O
+-	POS	O
+carboxylate	POS	O
+(	POS	O
+abecarrnil	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+new	POS	O
+ligand	POS	O
+for	POS	O
+benzodiazepine	POS	O
+receptors	POS	O
+possessing	POS	O
+anxiolytic	POS	O
+and	POS	O
+anticonvulsant	POS	O
+properties	POS	O
+,	POS	O
+was	POS	O
+evaluated	POS	O
+on	POS	O
+the	POS	O
+function	POS	O
+of	POS	O
+central	POS	O
+gamma	POS	O
+-	POS	O
+aminobutyric	POS	O
+acid	POS	O
+(	POS	O
+GABA	POS	O
+)	POS	O
+A	POS	O
+receptor	POS	O
+complex	POS	O
+,	POS	O
+both	POS	O
+in	POS	O
+vitro	POS	O
+and	POS	O
+in	POS	O
+vivo	POS	O
+.	POS	O
+Added	POS	O
+in	POS	O
+vitro	POS	O
+to	POS	O
+rat	POS	O
+cortical	POS	O
+membrane	POS	O
+preparation	POS	O
+,	POS	O
+abecarnil	POS	O
+increased	POS	O
+[	POS	O
+3H	POS	O
+]	POS	O
+GABA	POS	O
+binding	POS	O
+,	POS	O
+enhanced	POS	O
+muscimol	POS	O
+-	POS	O
+stimulated	POS	O
+36Cl	POS	O
+-	POS	O
+uptake	POS	O
+and	POS	O
+reduced	POS	O
+the	POS	O
+binding	POS	O
+of	POS	O
+t	POS	O
+-	POS	O
+[	POS	O
+35S	POS	O
+]	POS	O
+butylbicyclophosphorothionate	POS	O
+(	POS	O
+[	POS	O
+35S	POS	O
+]	POS	O
+TBPS	POS	O
+)	POS	O
+.	POS	O
+These	POS	O
+effects	POS	O
+were	POS	O
+similar	POS	O
+to	POS	O
+those	POS	O
+induced	POS	O
+by	POS	O
+diazepam	POS	O
+,	POS	O
+whereas	POS	O
+the	POS	O
+partial	POS	O
+agonist	POS	O
+Ro	POS	O
+16	POS	O
+-	POS	O
+6028	POS	O
+(	POS	O
+tert	POS	O
+-	POS	O
+butyl	POS	O
+-	POS	O
+(	POS	O
+S	POS	O
+)	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+bromo	POS	O
+-	POS	O
+11	POS	O
+,	POS	O
+12	POS	O
+,	POS	O
+13	POS	O
+,	POS	O
+13a	POS	O
+-	POS	O
+tetrahydro	POS	O
+-	POS	O
+9	POS	O
+-	POS	O
+oxo	POS	O
+-	POS	O
+9H	POS	O
+-	POS	O
+imidazo	POS	O
+[	POS	O
+1	POS	O
+,	POS	O
+5	POS	O
+-	POS	O
+a	POS	O
+]	POS	O
+-	POS	O
+pyrrolo	POS	O
+-	POS	O
+[	POS	O
+2	POS	O
+,	POS	O
+1	POS	O
+-	POS	O
+c	POS	O
+]	POS	O
+[	POS	O
+1	POS	O
+,	POS	O
+4	POS	O
+]	POS	O
+benzodiazepine	POS	O
+-	POS	O
+1	POS	O
+-	POS	O
+carboxylate	POS	O
+)	POS	O
+showed	POS	O
+very	POS	O
+weak	POS	O
+efficacy	POS	O
+in	POS	O
+these	POS	O
+biochemical	POS	O
+tests	POS	O
+.	POS	O
+After	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+injection	POS	O
+to	POS	O
+rats	POS	O
+,	POS	O
+abecarnil	POS	O
+and	POS	O
+diazepam	POS	O
+decreased	POS	O
+in	POS	O
+a	POS	O
+time	POS	O
+-	POS	O
+dependent	POS	O
+and	POS	O
+dose	POS	O
+-	POS	O
+related	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+25	POS	O
+-	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+manner	POS	O
+[	POS	O
+35S	POS	O
+]	POS	O
+TBPS	POS	O
+binding	POS	O
+measured	POS	O
+ex	POS	O
+vivo	POS	O
+in	POS	O
+the	POS	O
+cerebral	POS	O
+cortex	POS	O
+.	POS	O
+Moreover	POS	O
+,	POS	O
+both	POS	O
+drugs	POS	O
+at	POS	O
+the	POS	O
+dose	POS	O
+of	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+antagonized	POS	O
+completely	POS	O
+the	POS	O
+convulsant	POS	O
+activity	POS	O
+and	POS	O
+the	POS	O
+increase	POS	O
+of	POS	O
+[	POS	O
+35S	POS	O
+]	POS	O
+TBPS	POS	O
+binding	POS	O
+induced	POS	O
+by	POS	O
+isoniazide	POS	O
+(	POS	O
+350	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+s	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+)	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+the	POS	O
+increase	POS	O
+of	POS	O
+[	POS	O
+35S	POS	O
+]	POS	O
+TBPS	POS	O
+binding	POS	O
+induced	POS	O
+by	POS	O
+foot	POS	O
+-	POS	O
+shock	POS	O
+stress	POS	O
+.	POS	O
+To	POS	O
+better	POS	O
+correlate	POS	O
+the	POS	O
+biochemical	POS	O
+and	POS	O
+the	POS	O
+pharmacological	POS	O
+effects	POS	O
+,	POS	O
+we	POS	O
+studied	POS	O
+the	POS	O
+action	POS	O
+of	POS	O
+abecarnil	POS	O
+on	POS	O
+[	POS	O
+35S	POS	O
+]	POS	O
+TBPS	POS	O
+binding	POS	O
+,	POS	O
+exploratory	POS	O
+motility	POS	O
+and	POS	O
+on	POS	O
+isoniazid	POS	O
+-	POS	O
+induced	POS	O
+biochemical	POS	O
+and	POS	O
+pharmacological	POS	O
+effects	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+In	POS	O
+these	POS	O
+animals	POS	O
+,	POS	O
+abecarnil	POS	O
+produced	POS	O
+a	POS	O
+paralleled	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+-	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+reduction	POS	O
+of	POS	O
+both	POS	O
+motor	POS	O
+behavior	POS	O
+and	POS	O
+cortical	POS	O
+[	POS	O
+35S	POS	O
+]	POS	O
+TBPS	POS	O
+binding	POS	O
+.	POS	O
+Moreover	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+of	POS	O
+this	POS	O
+beta	POS	O
+-	POS	O
+carboline	POS	O
+reduced	POS	O
+markedly	POS	O
+the	POS	O
+increase	POS	O
+of	POS	O
+[	POS	O
+35S	POS	O
+]	POS	O
+TBPS	POS	O
+binding	POS	O
+and	POS	O
+the	POS	O
+convulsions	POS	B-NP
+induced	POS	O
+by	POS	O
+isoniazid	POS	O
+(	POS	O
+200	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+s	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+)	POS	O
+.	POS	O
+(	POS	O
+ABSTRACT	POS	O
+TRUNCATED	POS	O
+AT	POS	O
+250	POS	O
+WORDS	POS	O
+)	POS	O
+Recurrent	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+in	POS	O
+a	POS	O
+postpartum	POS	O
+patient	POS	O
+receiving	POS	O
+bromocriptine	POS	O
+.	POS	O
+Myocardial	POS	B-NP
+infarction	POS	I-NP
+in	POS	O
+puerperium	POS	B-NP
+is	POS	O
+infrequently	POS	O
+reported	POS	O
+.	POS	O
+Spasm	POS	B-NP
+,	POS	O
+coronary	POS	B-NP
+dissection	POS	I-NP
+,	POS	O
+or	POS	O
+atheromatous	POS	B-NP
+etiology	POS	O
+has	POS	O
+been	POS	O
+described	POS	O
+.	POS	O
+Bromocriptine	POS	O
+has	POS	O
+been	POS	O
+implicated	POS	O
+in	POS	O
+several	POS	O
+previous	POS	O
+case	POS	O
+reports	POS	O
+of	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+in	POS	O
+the	POS	O
+puerperium	POS	O
+.	POS	O
+Our	POS	O
+case	POS	O
+(	POS	O
+including	POS	O
+an	POS	O
+inadvertent	POS	O
+rechallenge	POS	O
+)	POS	O
+suggests	POS	O
+such	POS	O
+a	POS	O
+relationship	POS	O
+.	POS	O
+Although	POS	O
+generally	POS	O
+regarded	POS	O
+as	POS	O
+"	POS	O
+safe	POS	O
+,	POS	O
+"	POS	O
+possible	POS	O
+serious	POS	O
+cardiac	POS	O
+effects	POS	O
+of	POS	O
+bromocriptine	POS	O
+should	POS	O
+be	POS	O
+acknowledged	POS	O
+.	POS	O
+Asterixis	POS	B-NP
+induced	POS	O
+by	POS	O
+carbamazepine	POS	O
+therapy	POS	O
+.	POS	O
+There	POS	O
+are	POS	O
+very	POS	O
+few	POS	O
+reports	POS	O
+about	POS	O
+asterixis	POS	B-NP
+as	POS	O
+a	POS	O
+side	POS	O
+effect	POS	O
+of	POS	O
+treatment	POS	O
+with	POS	O
+psychopharmacologic	POS	O
+agents	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+report	POS	O
+we	POS	O
+present	POS	O
+four	POS	O
+patients	POS	O
+treated	POS	O
+with	POS	O
+a	POS	O
+combination	POS	O
+of	POS	O
+different	POS	O
+psychotropic	POS	O
+drugs	POS	O
+,	POS	O
+in	POS	O
+whom	POS	O
+asterixis	POS	B-NP
+was	POS	O
+triggered	POS	O
+either	POS	O
+by	POS	O
+adding	POS	O
+carbamazepine	POS	O
+(	POS	O
+CBZ	POS	O
+)	POS	O
+to	POS	O
+a	POS	O
+treatment	POS	O
+regimen	POS	O
+,	POS	O
+or	POS	O
+by	POS	O
+increasing	POS	O
+its	POS	O
+dosage	POS	O
+.	POS	O
+Neither	POS	O
+dosage	POS	O
+nor	POS	O
+serum	POS	O
+levels	POS	O
+of	POS	O
+CBZ	POS	O
+were	POS	O
+in	POS	O
+a	POS	O
+higher	POS	O
+range	POS	O
+.	POS	O
+We	POS	O
+consider	POS	O
+asterixis	POS	B-NP
+to	POS	O
+be	POS	O
+an	POS	O
+easily	POS	O
+overlooked	POS	O
+sign	POS	O
+of	POS	O
+neurotoxicity	POS	B-NP
+,	POS	O
+which	POS	O
+may	POS	O
+occur	POS	O
+even	POS	O
+at	POS	O
+low	POS	O
+or	POS	O
+moderate	POS	O
+dosage	POS	O
+levels	POS	O
+,	POS	O
+if	POS	O
+certain	POS	O
+drugs	POS	O
+as	POS	O
+lithium	POS	O
+or	POS	O
+clozapine	POS	O
+are	POS	O
+used	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+CBZ	POS	O
+.	POS	O
+Pharmacodynamics	POS	O
+of	POS	O
+the	POS	O
+hypotensive	POS	B-NP
+effect	POS	O
+of	POS	O
+levodopa	POS	O
+in	POS	O
+parkinsonian	POS	B-NP
+patients	POS	O
+.	POS	O
+Blood	POS	O
+pressure	POS	O
+effects	POS	O
+of	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+levodopa	POS	O
+were	POS	O
+examined	POS	O
+in	POS	O
+parkinsonian	POS	B-NP
+patients	POS	O
+with	POS	O
+stable	POS	O
+and	POS	O
+fluctuating	POS	O
+responses	POS	O
+to	POS	O
+levodopa	POS	O
+.	POS	O
+The	POS	O
+magnitude	POS	O
+of	POS	O
+the	POS	O
+hypotensive	POS	B-NP
+effect	POS	O
+of	POS	O
+levodopa	POS	O
+was	POS	O
+concentration	POS	O
+dependent	POS	O
+and	POS	O
+was	POS	O
+fit	POS	O
+to	POS	O
+an	POS	O
+Emax	POS	O
+model	POS	O
+in	POS	O
+fluctuating	POS	O
+responders	POS	O
+.	POS	O
+Stable	POS	O
+responders	POS	O
+demonstrated	POS	O
+a	POS	O
+small	POS	O
+hypotensive	POS	B-NP
+response	POS	O
+.	POS	O
+Baseline	POS	O
+blood	POS	O
+pressures	POS	O
+were	POS	O
+higher	POS	O
+in	POS	O
+fluctuating	POS	O
+patients	POS	O
+;	POS	O
+a	POS	O
+higher	POS	O
+baseline	POS	O
+blood	POS	O
+pressure	POS	O
+correlated	POS	O
+with	POS	O
+greater	POS	O
+hypotensive	POS	B-NP
+effects	POS	O
+.	POS	O
+Antiparkinsonian	POS	O
+effects	POS	O
+of	POS	O
+levodopa	POS	O
+temporally	POS	O
+correlated	POS	O
+with	POS	O
+blood	POS	O
+pressure	POS	O
+changes	POS	O
+.	POS	O
+Phenylalanine	POS	O
+,	POS	O
+a	POS	O
+large	POS	O
+neutral	POS	O
+amino	POS	O
+acid	POS	O
+(	POS	O
+LNAA	POS	O
+)	POS	O
+competing	POS	O
+with	POS	O
+levodopa	POS	O
+for	POS	O
+transport	POS	O
+across	POS	O
+the	POS	O
+blood	POS	O
+-	POS	O
+brain	POS	O
+barrier	POS	O
+,	POS	O
+reduced	POS	O
+the	POS	O
+hypotensive	POS	B-NP
+and	POS	O
+antiparkinsonian	POS	O
+effects	POS	O
+of	POS	O
+levodopa	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+levodopa	POS	O
+has	POS	O
+a	POS	O
+central	POS	O
+hypotensive	POS	B-NP
+action	POS	O
+that	POS	O
+parallels	POS	O
+the	POS	O
+motor	POS	O
+effects	POS	O
+in	POS	O
+fluctuating	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+hypotensive	POS	B-NP
+effect	POS	O
+appears	POS	O
+to	POS	O
+be	POS	O
+related	POS	O
+to	POS	O
+the	POS	O
+higher	POS	O
+baseline	POS	O
+blood	POS	O
+pressure	POS	O
+we	POS	O
+observed	POS	O
+in	POS	O
+fluctuating	POS	O
+patients	POS	O
+relative	POS	O
+to	POS	O
+stable	POS	O
+patients	POS	O
+.	POS	O
+Syndrome	POS	B-NP
+of	POS	I-NP
+inappropriate	POS	I-NP
+secretion	POS	I-NP
+of	POS	I-NP
+antidiuretic	POS	I-NP
+hormone	POS	I-NP
+after	POS	O
+infusional	POS	O
+vincristine	POS	O
+.	POS	O
+A	POS	O
+77	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+with	POS	O
+refractory	POS	O
+multiple	POS	B-NP
+myeloma	POS	I-NP
+was	POS	O
+treated	POS	O
+with	POS	O
+a	POS	O
+4	POS	O
+-	POS	O
+day	POS	O
+continuous	POS	O
+intravenous	POS	O
+infusion	POS	O
+of	POS	O
+vincristine	POS	O
+and	POS	O
+doxorubicin	POS	O
+and	POS	O
+4	POS	O
+days	POS	O
+of	POS	O
+oral	POS	O
+dexamethasone	POS	O
+.	POS	O
+Nine	POS	O
+days	POS	O
+after	POS	O
+her	POS	O
+second	POS	O
+cycle	POS	O
+she	POS	O
+presented	POS	O
+with	POS	O
+lethargy	POS	B-NP
+and	POS	O
+weakness	POS	B-NP
+associated	POS	O
+with	POS	O
+hyponatremia	POS	B-NP
+.	POS	O
+Evaluation	POS	O
+revealed	POS	O
+the	POS	O
+syndrome	POS	O
+of	POS	O
+inappropriate	POS	O
+secretion	POS	O
+of	POS	O
+antidiuretic	POS	O
+hormone	POS	O
+,	POS	O
+which	POS	O
+was	POS	O
+attributed	POS	O
+to	POS	O
+the	POS	O
+vincristine	POS	O
+infusion	POS	O
+.	POS	O
+After	POS	O
+normal	POS	O
+serum	POS	O
+sodium	POS	O
+levels	POS	O
+returned	POS	O
+,	POS	O
+further	POS	O
+doxorubicin	POS	O
+and	POS	O
+dexamethasone	POS	O
+chemotherapy	POS	O
+without	POS	O
+vincristine	POS	O
+did	POS	O
+not	POS	O
+produce	POS	O
+this	POS	O
+complication	POS	O
+.	POS	O
+Heart	POS	B-NP
+failure	POS	I-NP
+:	POS	O
+to	POS	O
+digitalise	POS	O
+or	POS	O
+not	POS	O
+?	POS	O
+The	POS	O
+view	POS	O
+against	POS	O
+.	POS	O
+Despite	POS	O
+extensive	POS	O
+clinical	POS	O
+experience	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+digoxin	POS	O
+is	POS	O
+still	POS	O
+not	POS	O
+well	POS	O
+defined	POS	O
+.	POS	O
+In	POS	O
+patients	POS	O
+with	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+digoxin	POS	O
+is	POS	O
+beneficial	POS	O
+for	POS	O
+ventricular	POS	O
+rate	POS	O
+control	POS	O
+.	POS	O
+For	POS	O
+patients	POS	O
+in	POS	O
+sinus	POS	O
+rhythm	POS	O
+and	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+the	POS	O
+situation	POS	O
+is	POS	O
+less	POS	O
+clear	POS	O
+.	POS	O
+Digoxin	POS	O
+has	POS	O
+a	POS	O
+narrow	POS	O
+therapeutic	POS	O
+:	POS	O
+toxic	POS	O
+ratio	POS	O
+and	POS	O
+concentrations	POS	O
+are	POS	O
+affected	POS	O
+by	POS	O
+a	POS	O
+number	POS	O
+of	POS	O
+drugs	POS	O
+.	POS	O
+Also	POS	O
+,	POS	O
+digoxin	POS	O
+has	POS	O
+undesirable	POS	O
+effects	POS	O
+such	POS	O
+as	POS	O
+increasing	POS	O
+peripheral	POS	O
+resistance	POS	O
+and	POS	O
+myocardial	POS	O
+demands	POS	O
+,	POS	O
+and	POS	O
+causing	POS	O
+arrhythmias	POS	B-NP
+.	POS	O
+There	POS	O
+is	POS	O
+a	POS	O
+paucity	POS	O
+of	POS	O
+data	POS	O
+from	POS	O
+well	POS	O
+-	POS	O
+designed	POS	O
+trials	POS	O
+.	POS	O
+The	POS	O
+trials	POS	O
+that	POS	O
+are	POS	O
+available	POS	O
+are	POS	O
+generally	POS	O
+small	POS	O
+with	POS	O
+limitations	POS	O
+in	POS	O
+design	POS	O
+and	POS	O
+these	POS	O
+show	POS	O
+variation	POS	O
+in	POS	O
+patient	POS	O
+benefit	POS	O
+.	POS	O
+More	POS	O
+convincing	POS	O
+evidence	POS	O
+is	POS	O
+required	POS	O
+showing	POS	O
+that	POS	O
+digoxin	POS	O
+improves	POS	O
+symptoms	POS	O
+or	POS	O
+exercise	POS	O
+capacity	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+no	POS	O
+trial	POS	O
+has	POS	O
+had	POS	O
+sufficient	POS	O
+power	POS	O
+to	POS	O
+evaluate	POS	O
+mortality	POS	O
+.	POS	O
+Pooled	POS	O
+analysis	POS	O
+of	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+other	POS	O
+inotropic	POS	O
+drugs	POS	O
+shows	POS	O
+an	POS	O
+excess	POS	O
+mortality	POS	O
+and	POS	O
+there	POS	O
+is	POS	O
+a	POS	O
+possibility	POS	O
+that	POS	O
+digoxin	POS	O
+may	POS	O
+increase	POS	O
+mortality	POS	O
+after	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+(	POS	O
+MI	POS	B-NP
+)	POS	O
+.	POS	O
+Angiotensin	POS	O
+-	POS	O
+converting	POS	O
+enzyme	POS	O
+(	POS	O
+ACE	POS	O
+)	POS	O
+inhibitors	POS	O
+should	POS	O
+be	POS	O
+used	POS	O
+first	POS	O
+as	POS	O
+they	POS	O
+are	POS	O
+safer	POS	O
+,	POS	O
+do	POS	O
+not	POS	O
+require	POS	O
+blood	POS	O
+level	POS	O
+monitoring	POS	O
+,	POS	O
+modify	POS	O
+progression	POS	O
+of	POS	O
+disease	POS	O
+,	POS	O
+relieve	POS	O
+symptoms	POS	O
+,	POS	O
+improve	POS	O
+exercise	POS	B-NP
+tolerance	POS	I-NP
+and	POS	O
+reduce	POS	O
+mortality	POS	O
+.	POS	O
+Caution	POS	O
+should	POS	O
+be	POS	O
+exercised	POS	O
+in	POS	O
+using	POS	O
+digoxin	POS	O
+until	POS	O
+large	POS	O
+mortality	POS	O
+trials	POS	O
+are	POS	O
+completed	POS	O
+showing	POS	O
+either	POS	O
+benefit	POS	O
+or	POS	O
+harm	POS	O
+.	POS	O
+Until	POS	O
+then	POS	O
+digoxin	POS	O
+should	POS	O
+be	POS	O
+considered	POS	O
+a	POS	O
+third	POS	O
+-	POS	O
+line	POS	O
+therapy	POS	O
+.	POS	O
+Isradipine	POS	O
+treatment	POS	O
+for	POS	O
+hypertension	POS	B-NP
+in	POS	O
+general	POS	O
+practice	POS	O
+in	POS	O
+Hong	POS	O
+Kong	POS	O
+.	POS	O
+A	POS	O
+6	POS	O
+-	POS	O
+week	POS	O
+open	POS	O
+study	POS	O
+of	POS	O
+the	POS	O
+introduction	POS	O
+of	POS	O
+isradipine	POS	O
+treatment	POS	O
+was	POS	O
+conducted	POS	O
+in	POS	O
+general	POS	O
+practice	POS	O
+in	POS	O
+Hong	POS	O
+Kong	POS	O
+.	POS	O
+303	POS	O
+Chinese	POS	O
+patients	POS	O
+with	POS	O
+mild	POS	O
+to	POS	O
+moderate	POS	O
+hypertension	POS	B-NP
+entered	POS	O
+the	POS	O
+study	POS	O
+.	POS	O
+Side	POS	O
+effects	POS	O
+were	POS	O
+reported	POS	O
+in	POS	O
+21	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+and	POS	O
+caused	POS	O
+withdrawal	POS	O
+from	POS	O
+the	POS	O
+study	POS	O
+in	POS	O
+3	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+main	POS	O
+side	POS	O
+-	POS	O
+effects	POS	O
+were	POS	O
+headache	POS	B-NP
+,	POS	O
+dizziness	POS	B-NP
+,	POS	O
+palpitation	POS	B-NP
+and	POS	O
+flushing	POS	B-NP
+and	POS	O
+these	POS	O
+were	POS	O
+not	POS	O
+more	POS	O
+frequent	POS	O
+than	POS	O
+reported	POS	O
+in	POS	O
+other	POS	O
+studies	POS	O
+with	POS	O
+isradipine	POS	O
+or	POS	O
+with	POS	O
+placebo	POS	O
+.	POS	O
+Supine	POS	O
+blood	POS	O
+pressure	POS	O
+was	POS	O
+reduced	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+from	POS	O
+170	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+20	POS	O
+/	POS	O
+102	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+mmHg	POS	O
+to	POS	O
+153	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+19	POS	O
+/	POS	O
+92	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+8	POS	O
+,	POS	O
+147	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+18	POS	O
+/	POS	O
+88	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+7	POS	O
+and	POS	O
+144	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+14	POS	O
+/	POS	O
+87	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+mmHg	POS	O
+at	POS	O
+2	POS	O
+,	POS	O
+4	POS	O
+and	POS	O
+6	POS	O
+weeks	POS	O
+respectively	POS	O
+in	POS	O
+evaluable	POS	O
+patients	POS	O
+.	POS	O
+Similar	POS	O
+reductions	POS	O
+occurred	POS	O
+in	POS	O
+standing	POS	O
+blood	POS	O
+pressure	POS	O
+and	POS	O
+there	POS	O
+was	POS	O
+no	POS	O
+evidence	POS	O
+of	POS	O
+postural	POS	B-NP
+hypotension	POS	I-NP
+.	POS	O
+Normalization	POS	O
+and	POS	O
+responder	POS	O
+rates	POS	O
+at	POS	O
+6	POS	O
+weeks	POS	O
+were	POS	O
+86	POS	O
+%	POS	O
+and	POS	O
+69	POS	O
+%	POS	O
+respectively	POS	O
+.	POS	O
+Dosage	POS	O
+was	POS	O
+increased	POS	O
+from	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+b	POS	O
+.	POS	O
+d	POS	O
+.	POS	O
+to	POS	O
+5	POS	O
+mg	POS	O
+b	POS	O
+.	POS	O
+d	POS	O
+.	POS	O
+at	POS	O
+4	POS	O
+weeks	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+diastolic	POS	O
+blood	POS	O
+pressure	POS	O
+greater	POS	O
+than	POS	O
+90	POS	O
+mmHg	POS	O
+and	POS	O
+their	POS	O
+further	POS	O
+response	POS	O
+was	POS	O
+greater	POS	O
+than	POS	O
+those	POS	O
+remaining	POS	O
+on	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+b	POS	O
+.	POS	O
+d	POS	O
+.	POS	O
+Pharmacological	POS	O
+characteristics	POS	O
+and	POS	O
+side	POS	O
+effects	POS	O
+of	POS	O
+a	POS	O
+new	POS	O
+galenic	POS	O
+formulation	POS	O
+of	POS	O
+propofol	POS	O
+without	POS	O
+soyabean	POS	O
+oil	POS	O
+.	POS	O
+We	POS	O
+compared	POS	O
+the	POS	O
+pharmacokinetics	POS	O
+,	POS	O
+pharmacodynamics	POS	O
+and	POS	O
+safety	POS	O
+profile	POS	O
+of	POS	O
+a	POS	O
+new	POS	O
+galenic	POS	O
+formulation	POS	O
+of	POS	O
+propofol	POS	O
+(	POS	O
+AM149	POS	O
+1	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+which	POS	O
+does	POS	O
+not	POS	O
+contain	POS	O
+soyabean	POS	O
+oil	POS	O
+,	POS	O
+with	POS	O
+a	POS	O
+standard	POS	O
+formulation	POS	O
+of	POS	O
+propofol	POS	O
+(	POS	O
+Disoprivan	POS	O
+1	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+randomised	POS	O
+,	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+cross	POS	O
+-	POS	O
+over	POS	O
+study	POS	O
+,	POS	O
+30	POS	O
+healthy	POS	O
+volunteers	POS	O
+received	POS	O
+a	POS	O
+single	POS	O
+intravenous	POS	O
+bolus	POS	O
+injection	POS	O
+of	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+.	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+propofol	POS	O
+.	POS	O
+Plasma	POS	O
+propofol	POS	O
+levels	POS	O
+were	POS	O
+measured	POS	O
+for	POS	O
+48	POS	O
+h	POS	O
+following	POS	O
+drug	POS	O
+administration	POS	O
+and	POS	O
+evaluated	POS	O
+according	POS	O
+to	POS	O
+a	POS	O
+three	POS	O
+-	POS	O
+compartment	POS	O
+model	POS	O
+.	POS	O
+The	POS	O
+pharmacodynamic	POS	O
+parameters	POS	O
+assessed	POS	O
+included	POS	O
+induction	POS	O
+and	POS	O
+emergence	POS	O
+times	POS	O
+,	POS	O
+respiratory	POS	O
+and	POS	O
+cardiovascular	POS	O
+effects	POS	O
+,	POS	O
+and	POS	O
+pain	POS	B-NP
+on	POS	O
+injection	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+monitored	POS	O
+for	POS	O
+side	POS	O
+effects	POS	O
+over	POS	O
+48	POS	O
+h	POS	O
+.	POS	O
+Owing	POS	O
+to	POS	O
+a	POS	O
+high	POS	O
+incidence	POS	O
+of	POS	O
+thrombophlebitis	POS	B-NP
+,	POS	O
+the	POS	O
+study	POS	O
+was	POS	O
+terminated	POS	O
+prematurely	POS	O
+and	POS	O
+only	POS	O
+the	POS	O
+data	POS	O
+of	POS	O
+the	POS	O
+two	POS	O
+parallel	POS	O
+treatment	POS	O
+groups	POS	O
+(	POS	O
+15	POS	O
+patients	POS	O
+in	POS	O
+each	POS	O
+group	POS	O
+)	POS	O
+were	POS	O
+analysed	POS	O
+.	POS	O
+Plasma	POS	O
+concentrations	POS	O
+did	POS	O
+not	POS	O
+differ	POS	O
+significantly	POS	O
+between	POS	O
+the	POS	O
+two	POS	O
+formulations	POS	O
+.	POS	O
+Anaesthesia	POS	B-NP
+induction	POS	O
+and	POS	O
+emergence	POS	O
+times	POS	O
+,	POS	O
+respiratory	POS	O
+and	POS	O
+cardiovascular	POS	O
+variables	POS	O
+showed	POS	O
+no	POS	O
+significant	POS	O
+differences	POS	O
+between	POS	O
+the	POS	O
+two	POS	O
+treatment	POS	O
+groups	POS	O
+.	POS	O
+Pain	POS	B-NP
+on	POS	O
+injection	POS	O
+(	POS	O
+80	POS	O
+vs	POS	O
+.	POS	O
+20	POS	O
+%	POS	O
+,	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+and	POS	O
+thrombophlebitis	POS	B-NP
+(	POS	O
+93	POS	O
+.	POS	O
+3	POS	O
+vs	POS	O
+.	POS	O
+6	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+,	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+occurred	POS	O
+more	POS	O
+frequently	POS	O
+with	POS	O
+AM149	POS	O
+than	POS	O
+with	POS	O
+Disoprivan	POS	O
+.	POS	O
+Although	POS	O
+both	POS	O
+formulations	POS	O
+had	POS	O
+similar	POS	O
+pharmacokinetic	POS	O
+and	POS	O
+pharmacodynamic	POS	O
+profiles	POS	O
+the	POS	O
+new	POS	O
+formulation	POS	O
+is	POS	O
+not	POS	O
+suitable	POS	O
+for	POS	O
+clinical	POS	O
+use	POS	O
+due	POS	O
+to	POS	O
+the	POS	O
+high	POS	O
+incidence	POS	O
+of	POS	O
+thrombophlebitis	POS	B-NP
+produced	POS	O
+.	POS	O
+Pure	POS	B-NP
+red	POS	I-NP
+cell	POS	I-NP
+aplasia	POS	I-NP
+,	POS	O
+toxic	POS	B-NP
+dermatitis	POS	I-NP
+and	POS	O
+lymphadenopathy	POS	B-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+taking	POS	O
+diphenylhydantoin	POS	O
+.	POS	O
+A	POS	O
+patient	POS	O
+taking	POS	O
+diphenylhydantoin	POS	O
+for	POS	O
+3	POS	O
+weeks	POS	O
+developed	POS	O
+a	POS	O
+generalized	POS	O
+skin	POS	B-NP
+rash	POS	I-NP
+,	POS	O
+lymphadenopathy	POS	B-NP
+and	POS	O
+pure	POS	B-NP
+red	POS	I-NP
+cell	POS	I-NP
+aplasia	POS	I-NP
+.	POS	O
+After	POS	O
+withdrawal	POS	O
+of	POS	O
+the	POS	O
+pharmacon	POS	O
+all	POS	O
+symptoms	POS	O
+disappeared	POS	O
+spontaneously	POS	O
+.	POS	O
+Skin	POS	B-NP
+rash	POS	I-NP
+is	POS	O
+a	POS	O
+well	POS	O
+-	POS	O
+known	POS	O
+complication	POS	O
+of	POS	O
+diphenylhydantoin	POS	O
+treatment	POS	O
+as	POS	O
+is	POS	O
+benign	POS	O
+and	POS	O
+malignant	POS	B-NP
+lymphadenopathy	POS	I-NP
+.	POS	O
+Pure	POS	B-NP
+red	POS	I-NP
+cell	POS	I-NP
+aplasia	POS	I-NP
+associated	POS	O
+with	POS	O
+diphenylhydantoin	POS	O
+medication	POS	O
+has	POS	O
+been	POS	O
+reported	POS	O
+in	POS	O
+3	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+exact	POS	O
+mechanism	POS	O
+by	POS	O
+which	POS	O
+diphenylhydantoin	POS	O
+exerts	POS	O
+its	POS	O
+toxic	POS	O
+effects	POS	O
+is	POS	O
+not	POS	O
+known	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+patient	POS	O
+the	POS	O
+time	POS	O
+relation	POS	O
+between	POS	O
+the	POS	O
+ingestion	POS	O
+of	POS	O
+diphenylhydantoin	POS	O
+and	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+the	POS	O
+skin	POS	B-NP
+rash	POS	I-NP
+,	POS	O
+lymphadenopathy	POS	B-NP
+and	POS	O
+pure	POS	B-NP
+red	POS	I-NP
+cell	POS	I-NP
+aplasia	POS	I-NP
+is	POS	O
+very	POS	O
+suggestive	POS	O
+of	POS	O
+a	POS	O
+direct	POS	O
+connection	POS	O
+.	POS	O
+Vinorelbine	POS	O
+-	POS	O
+related	POS	O
+cardiac	POS	O
+events	POS	O
+:	POS	O
+a	POS	O
+meta	POS	O
+-	POS	O
+analysis	POS	O
+of	POS	O
+randomized	POS	O
+clinical	POS	O
+trials	POS	O
+.	POS	O
+Several	POS	O
+cases	POS	O
+of	POS	O
+cardiac	POS	B-NP
+adverse	POS	I-NP
+reactions	POS	I-NP
+related	POS	O
+to	POS	O
+vinorelbine	POS	O
+(	POS	O
+VNR	POS	O
+)	POS	O
+have	POS	O
+been	POS	O
+reported	POS	O
+in	POS	O
+the	POS	O
+literature	POS	O
+.	POS	O
+In	POS	O
+order	POS	O
+to	POS	O
+quantify	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+these	POS	O
+cardiac	POS	O
+events	POS	O
+,	POS	O
+we	POS	O
+performed	POS	O
+a	POS	O
+meta	POS	O
+-	POS	O
+analysis	POS	O
+of	POS	O
+clinical	POS	O
+trials	POS	O
+comparing	POS	O
+VNR	POS	O
+with	POS	O
+other	POS	O
+chemotherapeutic	POS	O
+agents	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+various	POS	O
+malignancies	POS	B-NP
+.	POS	O
+Randomized	POS	O
+clinical	POS	O
+trials	POS	O
+comparing	POS	O
+VNR	POS	O
+with	POS	O
+other	POS	O
+drugs	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+cancer	POS	B-NP
+were	POS	O
+searched	POS	O
+in	POS	O
+Medline	POS	O
+,	POS	O
+Embase	POS	O
+,	POS	O
+Evidence	POS	O
+-	POS	O
+based	POS	O
+Medicine	POS	O
+Reviews	POS	O
+databases	POS	O
+and	POS	O
+the	POS	O
+Cochrane	POS	O
+library	POS	O
+from	POS	O
+1987	POS	O
+to	POS	O
+2002	POS	O
+.	POS	O
+Outcomes	POS	O
+of	POS	O
+interest	POS	O
+were	POS	O
+severe	POS	O
+cardiac	POS	B-NP
+events	POS	I-NP
+,	POS	O
+toxic	POS	B-NP
+deaths	POS	I-NP
+and	POS	O
+cardiac	POS	B-NP
+event	POS	I-NP
+-	POS	I-NP
+related	POS	I-NP
+deaths	POS	I-NP
+reported	POS	O
+in	POS	O
+each	POS	O
+publication	POS	O
+.	POS	O
+We	POS	O
+found	POS	O
+19	POS	O
+trials	POS	O
+,	POS	O
+involving	POS	O
+2441	POS	O
+patients	POS	O
+treated	POS	O
+by	POS	O
+VNR	POS	O
+and	POS	O
+2050	POS	O
+control	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+cardiac	POS	B-NP
+events	POS	I-NP
+with	POS	O
+VNR	POS	O
+was	POS	O
+1	POS	O
+.	POS	O
+19	POS	O
+%	POS	O
+[	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+(	POS	O
+CI	POS	O
+)	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+75	POS	O
+;	POS	O
+1	POS	O
+.	POS	O
+67	POS	O
+)	POS	O
+]	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+difference	POS	O
+in	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+cardiac	POS	O
+events	POS	O
+between	POS	O
+VNR	POS	O
+and	POS	O
+other	POS	O
+drugs	POS	O
+[	POS	O
+odds	POS	O
+ratio	POS	O
+:	POS	O
+0	POS	O
+.	POS	O
+92	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+54	POS	O
+;	POS	O
+1	POS	O
+.	POS	O
+55	POS	O
+)	POS	O
+]	POS	O
+.	POS	O
+The	POS	O
+risk	POS	O
+of	POS	O
+VNR	POS	O
+cardiac	POS	O
+events	POS	O
+was	POS	O
+similar	POS	O
+to	POS	O
+vindesine	POS	O
+(	POS	O
+VDS	POS	O
+)	POS	O
+and	POS	O
+other	POS	O
+cardiotoxic	POS	B-NP
+drugs	POS	O
+[	POS	O
+fluorouracil	POS	O
+,	POS	O
+anthracyclines	POS	O
+,	POS	O
+gemcitabine	POS	O
+(	POS	O
+GEM	POS	O
+)	POS	O
+em	POS	O
+leader	POS	O
+]	POS	O
+.	POS	O
+Even	POS	O
+if	POS	O
+it	POS	O
+did	POS	O
+not	POS	O
+reach	POS	O
+statistical	POS	O
+significance	POS	O
+because	POS	O
+of	POS	O
+a	POS	O
+few	POS	O
+number	POS	O
+of	POS	O
+cases	POS	O
+,	POS	O
+the	POS	O
+risk	POS	O
+was	POS	O
+lower	POS	O
+in	POS	O
+trials	POS	O
+excluding	POS	O
+patients	POS	O
+with	POS	O
+cardiac	POS	B-NP
+history	POS	I-NP
+,	POS	O
+and	POS	O
+seemed	POS	O
+to	POS	O
+be	POS	O
+higher	POS	O
+in	POS	O
+trials	POS	O
+including	POS	O
+patients	POS	O
+with	POS	O
+pre	POS	O
+-	POS	O
+existing	POS	O
+cardiac	POS	B-NP
+diseases	POS	I-NP
+.	POS	O
+Vinorelbine	POS	O
+-	POS	O
+related	POS	O
+cardiac	POS	O
+events	POS	O
+concern	POS	O
+about	POS	O
+1	POS	O
+%	POS	O
+of	POS	O
+treated	POS	O
+patients	POS	O
+in	POS	O
+clinical	POS	O
+trials	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+risk	POS	O
+associated	POS	O
+with	POS	O
+VNR	POS	O
+seems	POS	O
+to	POS	O
+be	POS	O
+similar	POS	O
+to	POS	O
+that	POS	O
+of	POS	O
+other	POS	O
+chemotherapeutic	POS	O
+agents	POS	O
+in	POS	O
+the	POS	O
+same	POS	O
+indications	POS	O
+.	POS	O
+MRI	POS	O
+findings	POS	O
+of	POS	O
+hypoxic	POS	O
+cortical	POS	O
+laminar	POS	O
+necrosis	POS	B-NP
+in	POS	O
+a	POS	O
+child	POS	O
+with	POS	O
+hemolytic	POS	B-NP
+anemia	POS	I-NP
+crisis	POS	O
+.	POS	O
+We	POS	O
+present	POS	O
+magnetic	POS	O
+resonance	POS	O
+imaging	POS	O
+findings	POS	O
+of	POS	O
+a	POS	O
+5	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+girl	POS	O
+who	POS	O
+had	POS	O
+a	POS	O
+rapidly	POS	O
+installing	POS	O
+hemolytic	POS	B-NP
+anemia	POS	I-NP
+crisis	POS	O
+induced	POS	O
+by	POS	O
+trimethoprim	POS	O
+-	POS	O
+sulfomethoxazole	POS	O
+,	POS	O
+resulting	POS	O
+in	POS	O
+cerebral	POS	B-NP
+anoxia	POS	I-NP
+leading	POS	O
+to	POS	O
+permanent	POS	O
+damage	POS	O
+.	POS	O
+Magnetic	POS	O
+Resonance	POS	O
+imaging	POS	O
+revealed	POS	O
+cortical	POS	O
+laminar	POS	O
+necrosis	POS	B-NP
+in	POS	O
+arterial	POS	O
+border	POS	O
+zones	POS	O
+in	POS	O
+both	POS	O
+cerebral	POS	O
+hemispheres	POS	O
+,	POS	O
+ischemic	POS	O
+changes	POS	O
+in	POS	O
+subcortical	POS	O
+white	POS	O
+matter	POS	O
+of	POS	O
+left	POS	O
+cerebral	POS	O
+hemisphere	POS	O
+,	POS	O
+and	POS	O
+in	POS	O
+the	POS	O
+left	POS	O
+putamen	POS	O
+.	POS	O
+Although	POS	O
+cortical	POS	O
+laminar	POS	O
+necrosis	POS	B-NP
+is	POS	O
+a	POS	O
+classic	POS	O
+entity	POS	O
+in	POS	O
+adulthood	POS	O
+related	POS	O
+to	POS	O
+conditions	POS	O
+of	POS	O
+energy	POS	O
+depletions	POS	O
+,	POS	O
+there	POS	O
+are	POS	O
+few	POS	O
+reports	POS	O
+available	POS	O
+in	POS	O
+children	POS	O
+.	POS	O
+A	POS	O
+wide	POS	O
+review	POS	O
+of	POS	O
+the	POS	O
+literature	POS	O
+is	POS	O
+also	POS	O
+presented	POS	O
+.	POS	O
+The	POS	O
+natural	POS	O
+history	POS	O
+of	POS	O
+Vigabatrin	POS	B-NP
+associated	POS	I-NP
+visual	POS	I-NP
+field	POS	I-NP
+defects	POS	I-NP
+in	POS	O
+patients	POS	O
+electing	POS	O
+to	POS	O
+continue	POS	O
+their	POS	O
+medication	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+To	POS	O
+determine	POS	O
+the	POS	O
+natural	POS	O
+history	POS	O
+of	POS	O
+visual	POS	B-NP
+field	POS	I-NP
+defects	POS	I-NP
+in	POS	O
+a	POS	O
+group	POS	O
+of	POS	O
+patients	POS	O
+known	POS	O
+to	POS	O
+have	POS	O
+Vigabatrin	POS	O
+-	POS	O
+associated	POS	O
+changes	POS	O
+who	POS	O
+elected	POS	O
+to	POS	O
+continue	POS	O
+the	POS	O
+medication	POS	O
+because	POS	O
+of	POS	O
+good	POS	O
+seizure	POS	B-NP
+control	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+All	POS	O
+patients	POS	O
+taking	POS	O
+Vigabatrin	POS	O
+alone	POS	O
+or	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+other	POS	O
+antiepileptic	POS	O
+drugs	POS	O
+for	POS	O
+at	POS	O
+least	POS	O
+5	POS	O
+years	POS	O
+(	POS	O
+range	POS	O
+5	POS	O
+-	POS	O
+12	POS	O
+years	POS	O
+)	POS	O
+were	POS	O
+entered	POS	O
+into	POS	O
+a	POS	O
+visual	POS	O
+surveillance	POS	O
+programme	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+followed	POS	O
+up	POS	O
+at	POS	O
+6	POS	O
+-	POS	O
+monthly	POS	O
+intervals	POS	O
+for	POS	O
+not	POS	O
+less	POS	O
+than	POS	O
+18	POS	O
+months	POS	O
+(	POS	O
+range	POS	O
+18	POS	O
+-	POS	O
+43	POS	O
+months	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+all	POS	O
+,	POS	O
+16	POS	O
+patients	POS	O
+with	POS	O
+unequivocal	POS	O
+defects	POS	O
+continued	POS	O
+the	POS	O
+medication	POS	O
+.	POS	O
+Following	POS	O
+already	POS	O
+published	POS	O
+methodology	POS	O
+(	POS	O
+Eye	POS	O
+2002	POS	O
+;	POS	O
+16	POS	O
+;	POS	O
+567	POS	O
+-	POS	O
+571	POS	O
+)	POS	O
+monocular	POS	O
+mean	POS	O
+radial	POS	O
+degrees	POS	O
+(	POS	O
+MRDs	POS	O
+)	POS	O
+to	POS	O
+the	POS	O
+I	POS	O
+/	POS	O
+4e	POS	O
+isopter	POS	O
+on	POS	O
+Goldmann	POS	O
+perimetry	POS	O
+was	POS	O
+calculated	POS	O
+for	POS	O
+the	POS	O
+right	POS	O
+eye	POS	O
+at	POS	O
+the	POS	O
+time	POS	O
+of	POS	O
+discovery	POS	O
+of	POS	O
+a	POS	O
+visual	POS	B-NP
+field	POS	I-NP
+defect	POS	I-NP
+and	POS	O
+again	POS	O
+after	POS	O
+not	POS	O
+less	POS	O
+than	POS	O
+18	POS	O
+months	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Mean	POS	O
+right	POS	O
+eye	POS	O
+MRD	POS	O
+at	POS	O
+presentation	POS	O
+was	POS	O
+36	POS	O
+.	POS	O
+98	POS	O
+degrees	POS	O
+(	POS	O
+range	POS	O
+22	POS	O
+.	POS	O
+25	POS	O
+-	POS	O
+51	POS	O
+.	POS	O
+0	POS	O
+)	POS	O
+,	POS	O
+compared	POS	O
+to	POS	O
+38	POS	O
+.	POS	O
+40	POS	O
+degrees	POS	O
+(	POS	O
+range	POS	O
+22	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+49	POS	O
+.	POS	O
+75	POS	O
+)	POS	O
+after	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+338	POS	O
+unpaired	POS	O
+t	POS	O
+-	POS	O
+test	POS	O
+.	POS	O
+Only	POS	O
+one	POS	O
+patient	POS	O
+demonstrated	POS	O
+a	POS	O
+deterioration	POS	O
+in	POS	O
+visual	POS	O
+field	POS	O
+during	POS	O
+the	POS	O
+study	POS	O
+period	POS	O
+and	POS	O
+discontinued	POS	O
+treatment	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Established	POS	O
+visual	POS	B-NP
+field	POS	I-NP
+defects	POS	I-NP
+presumed	POS	O
+to	POS	O
+be	POS	O
+due	POS	O
+to	POS	O
+Vigabatrin	POS	O
+therapy	POS	O
+did	POS	O
+not	POS	O
+usually	POS	O
+progress	POS	O
+in	POS	O
+spite	POS	O
+of	POS	O
+continuing	POS	O
+use	POS	O
+of	POS	O
+the	POS	O
+medication	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+give	POS	O
+support	POS	O
+to	POS	O
+the	POS	O
+hypothesis	POS	O
+that	POS	O
+the	POS	O
+pathogenesis	POS	O
+of	POS	O
+Vigabatrin	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+visual	POS	I-NP
+field	POS	I-NP
+defects	POS	I-NP
+may	POS	O
+be	POS	O
+an	POS	O
+idiosyncratic	POS	O
+adverse	POS	O
+drug	POS	O
+reaction	POS	O
+rather	POS	O
+than	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+toxicity	POS	B-NP
+.	POS	O
+Induction	POS	O
+of	POS	O
+rosaceiform	POS	B-NP
+dermatitis	POS	I-NP
+during	POS	O
+treatment	POS	O
+of	POS	O
+facial	POS	B-NP
+inflammatory	POS	I-NP
+dermatoses	POS	I-NP
+with	POS	O
+tacrolimus	POS	O
+ointment	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Tacrolimus	POS	O
+ointment	POS	O
+is	POS	O
+increasingly	POS	O
+used	POS	O
+for	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+treatment	POS	O
+of	POS	O
+sensitive	POS	O
+areas	POS	O
+such	POS	O
+as	POS	O
+the	POS	O
+face	POS	O
+,	POS	O
+and	POS	O
+recent	POS	O
+observations	POS	O
+indicate	POS	O
+that	POS	O
+the	POS	O
+treatment	POS	O
+is	POS	O
+effective	POS	O
+in	POS	O
+steroid	POS	O
+-	POS	O
+aggravated	POS	O
+rosacea	POS	B-NP
+and	POS	O
+perioral	POS	B-NP
+dermatitis	POS	I-NP
+.	POS	O
+We	POS	O
+report	POS	O
+on	POS	O
+rosaceiform	POS	B-NP
+dermatitis	POS	I-NP
+as	POS	O
+a	POS	O
+complication	POS	O
+of	POS	O
+treatment	POS	O
+with	POS	O
+tacrolimus	POS	O
+ointment	POS	O
+.	POS	O
+OBSERVATIONS	POS	O
+:	POS	O
+Six	POS	O
+adult	POS	O
+patients	POS	O
+with	POS	O
+inflammatory	POS	B-NP
+facial	POS	I-NP
+dermatoses	POS	I-NP
+were	POS	O
+treated	POS	O
+with	POS	O
+tacrolimus	POS	O
+ointment	POS	O
+because	POS	O
+of	POS	O
+the	POS	O
+ineffectiveness	POS	O
+of	POS	O
+standard	POS	O
+treatments	POS	O
+.	POS	O
+Within	POS	O
+2	POS	O
+to	POS	O
+3	POS	O
+weeks	POS	O
+of	POS	O
+initially	POS	O
+effective	POS	O
+and	POS	O
+well	POS	O
+-	POS	O
+tolerated	POS	O
+treatment	POS	O
+,	POS	O
+3	POS	O
+patients	POS	O
+with	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+rosacea	POS	B-NP
+and	POS	O
+1	POS	O
+with	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+acne	POS	B-NP
+experienced	POS	O
+sudden	POS	B-NP
+worsening	POS	I-NP
+with	POS	O
+pustular	POS	B-NP
+rosaceiform	POS	I-NP
+lesions	POS	I-NP
+.	POS	O
+Biopsy	POS	B-NP
+revealed	POS	O
+an	POS	O
+abundance	POS	O
+of	POS	O
+Demodex	POS	O
+mites	POS	O
+in	POS	O
+2	POS	O
+of	POS	O
+these	POS	O
+patients	POS	O
+.	POS	O
+In	POS	O
+1	POS	O
+patient	POS	O
+with	POS	O
+eyelid	POS	B-NP
+eczema	POS	I-NP
+,	POS	O
+rosaceiform	POS	B-NP
+periocular	POS	I-NP
+dermatitis	POS	I-NP
+gradually	POS	O
+appeared	POS	O
+after	POS	O
+3	POS	O
+weeks	POS	O
+of	POS	O
+treatment	POS	O
+.	POS	O
+In	POS	O
+1	POS	O
+patient	POS	O
+with	POS	O
+atopic	POS	B-NP
+dermatitis	POS	I-NP
+,	POS	O
+telangiectatic	POS	B-NP
+and	POS	O
+papular	POS	B-NP
+rosacea	POS	I-NP
+insidiously	POS	I-NP
+appeared	POS	O
+after	POS	O
+5	POS	O
+months	POS	O
+of	POS	O
+treatment	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Our	POS	O
+observations	POS	O
+suggest	POS	O
+that	POS	O
+the	POS	O
+spectrum	POS	O
+of	POS	O
+rosaceiform	POS	B-NP
+dermatitis	POS	I-NP
+as	POS	O
+a	POS	O
+complication	POS	O
+of	POS	O
+treatment	POS	O
+with	POS	O
+tacrolimus	POS	O
+ointment	POS	O
+is	POS	O
+heterogeneous	POS	O
+.	POS	O
+A	POS	O
+variety	POS	O
+of	POS	O
+factors	POS	O
+,	POS	O
+such	POS	O
+as	POS	O
+vasoactive	POS	O
+properties	POS	O
+of	POS	O
+tacrolimus	POS	O
+,	POS	O
+proliferation	POS	O
+of	POS	O
+Demodex	POS	O
+due	POS	O
+to	POS	O
+local	POS	O
+immunosuppression	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+occlusive	POS	O
+properties	POS	O
+of	POS	O
+the	POS	O
+ointment	POS	O
+,	POS	O
+may	POS	O
+be	POS	O
+involved	POS	O
+in	POS	O
+the	POS	O
+observed	POS	O
+phenomena	POS	O
+.	POS	O
+Future	POS	O
+studies	POS	O
+are	POS	O
+needed	POS	O
+to	POS	O
+identify	POS	O
+individual	POS	O
+risk	POS	O
+factors	POS	O
+.	POS	O
+Intravascular	POS	B-NP
+hemolysis	POS	I-NP
+and	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+following	POS	O
+intermittent	POS	O
+rifampin	POS	O
+therapy	POS	O
+.	POS	O
+Renal	POS	B-NP
+failure	POS	I-NP
+is	POS	O
+a	POS	O
+rare	POS	O
+complication	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+rifampin	POS	O
+.	POS	O
+Intravascular	POS	B-NP
+hemolysis	POS	I-NP
+leading	POS	O
+to	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+following	POS	O
+rifampin	POS	O
+therapy	POS	O
+is	POS	O
+extremely	POS	O
+rare	POS	O
+.	POS	O
+Two	POS	O
+patients	POS	O
+with	POS	O
+leprosy	POS	B-NP
+who	POS	O
+developed	POS	O
+hemolysis	POS	B-NP
+and	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+following	POS	O
+rifampin	POS	O
+are	POS	O
+reported	POS	O
+.	POS	O
+Structural	POS	B-NP
+abnormalities	POS	I-NP
+in	POS	O
+the	POS	O
+brains	POS	O
+of	POS	O
+human	POS	O
+subjects	POS	O
+who	POS	O
+use	POS	O
+methamphetamine	POS	O
+.	POS	O
+We	POS	O
+visualize	POS	O
+,	POS	O
+for	POS	O
+the	POS	O
+first	POS	O
+time	POS	O
+,	POS	O
+the	POS	O
+profile	POS	O
+of	POS	O
+structural	POS	O
+deficits	POS	O
+in	POS	O
+the	POS	O
+human	POS	O
+brain	POS	O
+associated	POS	O
+with	POS	O
+chronic	POS	O
+methamphetamine	POS	O
+(	POS	O
+MA	POS	O
+)	POS	O
+abuse	POS	O
+.	POS	O
+Studies	POS	O
+of	POS	O
+human	POS	O
+subjects	POS	O
+who	POS	O
+have	POS	O
+used	POS	O
+MA	POS	O
+chronically	POS	O
+have	POS	O
+revealed	POS	O
+deficits	POS	O
+in	POS	O
+dopaminergic	POS	O
+and	POS	O
+serotonergic	POS	O
+systems	POS	O
+and	POS	O
+cerebral	POS	O
+metabolic	POS	O
+abnormalities	POS	O
+.	POS	O
+Using	POS	O
+magnetic	POS	O
+resonance	POS	O
+imaging	POS	O
+(	POS	O
+MRI	POS	O
+)	POS	O
+and	POS	O
+new	POS	O
+computational	POS	O
+brain	POS	O
+-	POS	O
+mapping	POS	O
+techniques	POS	O
+,	POS	O
+we	POS	O
+determined	POS	O
+the	POS	O
+pattern	POS	O
+of	POS	O
+structural	POS	O
+brain	POS	O
+alterations	POS	O
+associated	POS	O
+with	POS	O
+chronic	POS	O
+MA	POS	O
+abuse	POS	O
+in	POS	O
+human	POS	O
+subjects	POS	O
+and	POS	O
+related	POS	O
+these	POS	O
+deficits	POS	O
+to	POS	O
+cognitive	POS	B-NP
+impairment	POS	I-NP
+.	POS	O
+We	POS	O
+used	POS	O
+high	POS	O
+-	POS	O
+resolution	POS	O
+MRI	POS	O
+and	POS	O
+surface	POS	O
+-	POS	O
+based	POS	O
+computational	POS	O
+image	POS	O
+analyses	POS	O
+to	POS	O
+map	POS	O
+regional	POS	O
+abnormalities	POS	O
+in	POS	O
+the	POS	O
+cortex	POS	O
+,	POS	O
+hippocampus	POS	O
+,	POS	O
+white	POS	O
+matter	POS	O
+,	POS	O
+and	POS	O
+ventricles	POS	O
+in	POS	O
+22	POS	O
+human	POS	O
+subjects	POS	O
+who	POS	O
+used	POS	O
+MA	POS	O
+and	POS	O
+21	POS	O
+age	POS	O
+-	POS	O
+matched	POS	O
+,	POS	O
+healthy	POS	O
+controls	POS	O
+.	POS	O
+Cortical	POS	O
+maps	POS	O
+revealed	POS	O
+severe	POS	O
+gray	POS	B-NP
+-	POS	I-NP
+matter	POS	I-NP
+deficits	POS	I-NP
+in	POS	O
+the	POS	O
+cingulate	POS	O
+,	POS	O
+limbic	POS	O
+,	POS	O
+and	POS	O
+paralimbic	POS	O
+cortices	POS	O
+of	POS	O
+MA	POS	O
+abusers	POS	O
+(	POS	O
+averaging	POS	O
+11	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+below	POS	O
+control	POS	O
+;	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+On	POS	O
+average	POS	O
+,	POS	O
+MA	POS	O
+abusers	POS	O
+had	POS	O
+7	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+smaller	POS	O
+hippocampal	POS	O
+volumes	POS	O
+than	POS	O
+control	POS	O
+subjects	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+;	POS	O
+left	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+;	POS	O
+right	POS	O
+,	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+and	POS	O
+significant	POS	O
+white	POS	B-NP
+-	POS	I-NP
+matter	POS	I-NP
+hypertrophy	POS	I-NP
+(	POS	O
+7	POS	O
+.	POS	O
+0	POS	O
+%	POS	O
+;	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+Hippocampal	POS	B-NP
+deficits	POS	I-NP
+were	POS	O
+mapped	POS	O
+and	POS	O
+correlated	POS	O
+with	POS	O
+memory	POS	O
+performance	POS	O
+on	POS	O
+a	POS	O
+word	POS	O
+-	POS	O
+recall	POS	O
+test	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+MRI	POS	O
+-	POS	O
+based	POS	O
+maps	POS	O
+suggest	POS	O
+that	POS	O
+chronic	POS	O
+methamphetamine	POS	O
+abuse	POS	O
+causes	POS	O
+a	POS	O
+selective	POS	O
+pattern	POS	O
+of	POS	O
+cerebral	POS	B-NP
+deterioration	POS	I-NP
+that	POS	O
+contributes	POS	O
+to	POS	O
+impaired	POS	O
+memory	POS	O
+performance	POS	O
+.	POS	O
+MA	POS	O
+may	POS	O
+selectively	POS	O
+damage	POS	O
+the	POS	O
+medial	POS	O
+temporal	POS	O
+lobe	POS	O
+and	POS	O
+,	POS	O
+consistent	POS	O
+with	POS	O
+metabolic	POS	O
+studies	POS	O
+,	POS	O
+the	POS	O
+cingulate	POS	O
+-	POS	O
+limbic	POS	O
+cortex	POS	O
+,	POS	O
+inducing	POS	O
+neuroadaptation	POS	O
+,	POS	O
+neuropil	POS	O
+reduction	POS	O
+,	POS	O
+or	POS	O
+cell	POS	O
+death	POS	O
+.	POS	O
+Prominent	POS	O
+white	POS	O
+-	POS	O
+matter	POS	O
+hypertrophy	POS	B-NP
+may	POS	O
+result	POS	O
+from	POS	O
+altered	POS	O
+myelination	POS	O
+and	POS	O
+adaptive	POS	O
+glial	POS	O
+changes	POS	O
+,	POS	O
+including	POS	O
+gliosis	POS	B-NP
+secondary	POS	O
+to	POS	O
+neuronal	POS	B-NP
+damage	POS	I-NP
+.	POS	O
+These	POS	O
+brain	POS	O
+substrates	POS	O
+may	POS	O
+help	POS	O
+account	POS	O
+for	POS	O
+the	POS	O
+symptoms	POS	O
+of	POS	O
+MA	POS	O
+abuse	POS	O
+,	POS	O
+providing	POS	O
+therapeutic	POS	O
+targets	POS	O
+for	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+brain	POS	B-NP
+injury	POS	I-NP
+.	POS	O
+Disruption	POS	O
+of	POS	O
+hepatic	POS	O
+lipid	POS	O
+homeostasis	POS	O
+in	POS	O
+mice	POS	O
+after	POS	O
+amiodarone	POS	O
+treatment	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+peroxisome	POS	O
+proliferator	POS	O
+-	POS	O
+activated	POS	O
+receptor	POS	O
+-	POS	O
+alpha	POS	O
+target	POS	O
+gene	POS	O
+activation	POS	O
+.	POS	O
+Amiodarone	POS	O
+,	POS	O
+an	POS	O
+efficacious	POS	O
+and	POS	O
+widely	POS	O
+used	POS	O
+antiarrhythmic	POS	O
+agent	POS	O
+,	POS	O
+has	POS	O
+been	POS	O
+reported	POS	O
+to	POS	O
+cause	POS	O
+hepatotoxicity	POS	B-NP
+in	POS	O
+some	POS	O
+patients	POS	O
+.	POS	O
+To	POS	O
+gain	POS	O
+insight	POS	O
+into	POS	O
+the	POS	O
+mechanism	POS	O
+of	POS	O
+this	POS	O
+unwanted	POS	O
+effect	POS	O
+,	POS	O
+mice	POS	O
+were	POS	O
+administered	POS	O
+various	POS	O
+doses	POS	O
+of	POS	O
+amiodarone	POS	O
+and	POS	O
+examined	POS	O
+for	POS	O
+changes	POS	O
+in	POS	O
+hepatic	POS	O
+histology	POS	O
+and	POS	O
+gene	POS	O
+regulation	POS	O
+.	POS	O
+Amiodarone	POS	O
+induced	POS	O
+hepatomegaly	POS	B-NP
+,	POS	O
+hepatocyte	POS	O
+microvesicular	POS	O
+lipid	POS	O
+accumulation	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+significant	POS	O
+decrease	POS	O
+in	POS	O
+serum	POS	O
+triglycerides	POS	O
+and	POS	O
+glucose	POS	O
+.	POS	O
+Northern	POS	O
+blot	POS	O
+analysis	POS	O
+of	POS	O
+hepatic	POS	O
+RNA	POS	O
+revealed	POS	O
+a	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+expression	POS	O
+of	POS	O
+a	POS	O
+number	POS	O
+of	POS	O
+genes	POS	O
+critical	POS	O
+for	POS	O
+fatty	POS	O
+acid	POS	O
+oxidation	POS	O
+,	POS	O
+lipoprotein	POS	O
+assembly	POS	O
+,	POS	O
+and	POS	O
+lipid	POS	O
+transport	POS	O
+.	POS	O
+Many	POS	O
+of	POS	O
+these	POS	O
+genes	POS	O
+are	POS	O
+regulated	POS	O
+by	POS	O
+the	POS	O
+peroxisome	POS	O
+proliferator	POS	O
+-	POS	O
+activated	POS	O
+receptor	POS	O
+-	POS	O
+alpha	POS	O
+(	POS	O
+PPARalpha	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+ligand	POS	O
+-	POS	O
+activated	POS	O
+nuclear	POS	O
+hormone	POS	O
+receptor	POS	O
+transcription	POS	O
+factor	POS	O
+.	POS	O
+The	POS	O
+absence	POS	O
+of	POS	O
+induction	POS	O
+of	POS	O
+these	POS	O
+genes	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+hepatomegaly	POS	B-NP
+in	POS	O
+PPARalpha	POS	O
+knockout	POS	O
+[	POS	O
+PPARalpha	POS	O
+-	POS	O
+/	POS	O
+-	POS	O
+]	POS	O
+mice	POS	O
+indicated	POS	O
+that	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+amiodarone	POS	O
+were	POS	O
+dependent	POS	O
+upon	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+a	POS	O
+functional	POS	O
+PPARalpha	POS	O
+gene	POS	O
+.	POS	O
+Compared	POS	O
+to	POS	O
+wild	POS	O
+-	POS	O
+type	POS	O
+mice	POS	O
+,	POS	O
+treatment	POS	O
+of	POS	O
+PPARalpha	POS	O
+-	POS	O
+/	POS	O
+-	POS	O
+mice	POS	O
+with	POS	O
+amiodarone	POS	O
+resulted	POS	O
+in	POS	O
+an	POS	O
+increased	POS	O
+rate	POS	O
+and	POS	O
+extent	POS	O
+of	POS	O
+total	POS	O
+body	POS	O
+weight	POS	O
+loss	POS	O
+.	POS	O
+The	POS	O
+inability	POS	O
+of	POS	O
+amiodarone	POS	O
+to	POS	O
+directly	POS	O
+activate	POS	O
+either	POS	O
+human	POS	O
+or	POS	O
+mouse	POS	O
+PPARalpha	POS	O
+transiently	POS	O
+expressed	POS	O
+in	POS	O
+human	POS	O
+HepG2	POS	O
+hepatoma	POS	O
+cells	POS	O
+indicates	POS	O
+that	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+amiodarone	POS	O
+on	POS	O
+the	POS	O
+function	POS	O
+of	POS	O
+this	POS	O
+receptor	POS	O
+were	POS	O
+indirect	POS	O
+.	POS	O
+Based	POS	O
+upon	POS	O
+these	POS	O
+results	POS	O
+,	POS	O
+we	POS	O
+conclude	POS	O
+that	POS	O
+amiodarone	POS	O
+disrupts	POS	O
+hepatic	POS	O
+lipid	POS	O
+homeostasis	POS	O
+and	POS	O
+that	POS	O
+the	POS	O
+increased	POS	O
+expression	POS	O
+of	POS	O
+PPARalpha	POS	O
+target	POS	O
+genes	POS	O
+is	POS	O
+secondary	POS	O
+to	POS	O
+this	POS	O
+toxic	POS	O
+effect	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+provide	POS	O
+important	POS	O
+new	POS	O
+mechanistic	POS	O
+information	POS	O
+regarding	POS	O
+the	POS	O
+hepatotoxic	POS	B-NP
+effects	POS	O
+of	POS	O
+amiodarone	POS	O
+and	POS	O
+indicate	POS	O
+that	POS	O
+PPARalpha	POS	O
+protects	POS	O
+against	POS	O
+amiodarone	POS	O
+-	POS	O
+induced	POS	O
+hepatotoxicity	POS	B-NP
+.	POS	O
+Safety	POS	O
+and	POS	O
+compliance	POS	O
+with	POS	O
+once	POS	O
+-	POS	O
+daily	POS	O
+niacin	POS	O
+extended	POS	O
+-	POS	O
+release	POS	O
+/	POS	O
+lovastatin	POS	O
+as	POS	O
+initial	POS	O
+therapy	POS	O
+in	POS	O
+the	POS	O
+Impact	POS	O
+of	POS	O
+Medical	POS	O
+Subspecialty	POS	O
+on	POS	O
+Patient	POS	O
+Compliance	POS	O
+to	POS	O
+Treatment	POS	O
+(	POS	O
+IMPACT	POS	O
+)	POS	O
+study	POS	O
+.	POS	O
+Niacin	POS	O
+extended	POS	O
+-	POS	O
+release	POS	O
+/	POS	O
+lovastatin	POS	O
+is	POS	O
+a	POS	O
+new	POS	O
+combination	POS	O
+product	POS	O
+approved	POS	O
+for	POS	O
+treatment	POS	O
+of	POS	O
+primary	POS	O
+hypercholesterolemia	POS	B-NP
+and	POS	O
+mixed	POS	O
+dyslipidemia	POS	B-NP
+.	POS	O
+This	POS	O
+open	POS	O
+-	POS	O
+labeled	POS	O
+,	POS	O
+multicenter	POS	O
+study	POS	O
+evaluated	POS	O
+the	POS	O
+safety	POS	O
+of	POS	O
+bedtime	POS	O
+niacin	POS	O
+extended	POS	O
+-	POS	O
+release	POS	O
+/	POS	O
+lovastatin	POS	O
+when	POS	O
+dosed	POS	O
+as	POS	O
+initial	POS	O
+therapy	POS	O
+and	POS	O
+patient	POS	O
+compliance	POS	O
+to	POS	O
+treatment	POS	O
+in	POS	O
+various	POS	O
+clinical	POS	O
+practice	POS	O
+settings	POS	O
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+4	POS	O
+,	POS	O
+499	POS	O
+patients	POS	O
+with	POS	O
+dyslipidemia	POS	B-NP
+requiring	POS	O
+drug	POS	O
+intervention	POS	O
+was	POS	O
+enrolled	POS	O
+at	POS	O
+1	POS	O
+,	POS	O
+081	POS	O
+sites	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+1	POS	O
+tablet	POS	O
+(	POS	O
+500	POS	O
+mg	POS	O
+of	POS	O
+niacin	POS	O
+extended	POS	O
+-	POS	O
+release	POS	O
+/	POS	O
+20	POS	O
+mg	POS	O
+of	POS	O
+lovastatin	POS	O
+)	POS	O
+once	POS	O
+nightly	POS	O
+for	POS	O
+4	POS	O
+weeks	POS	O
+and	POS	O
+then	POS	O
+2	POS	O
+tablets	POS	O
+for	POS	O
+8	POS	O
+weeks	POS	O
+.	POS	O
+Patients	POS	O
+also	POS	O
+received	POS	O
+dietary	POS	O
+counseling	POS	O
+,	POS	O
+educational	POS	O
+materials	POS	O
+,	POS	O
+and	POS	O
+reminders	POS	O
+to	POS	O
+call	POS	O
+a	POS	O
+toll	POS	O
+-	POS	O
+free	POS	O
+number	POS	O
+that	POS	O
+provided	POS	O
+further	POS	O
+education	POS	O
+about	POS	O
+dyslipidemia	POS	B-NP
+and	POS	O
+niacin	POS	O
+extended	POS	O
+-	POS	O
+release	POS	O
+/	POS	O
+lovastatin	POS	O
+.	POS	O
+Primary	POS	O
+end	POS	O
+points	POS	O
+were	POS	O
+study	POS	O
+compliance	POS	O
+,	POS	O
+increases	POS	O
+in	POS	O
+liver	POS	O
+transaminases	POS	O
+to	POS	O
+>	POS	O
+3	POS	O
+times	POS	O
+the	POS	O
+upper	POS	O
+limit	POS	O
+of	POS	O
+normal	POS	O
+,	POS	O
+and	POS	O
+clinical	POS	O
+myopathy	POS	B-NP
+.	POS	O
+Final	POS	O
+study	POS	O
+status	POS	O
+was	POS	O
+available	POS	O
+for	POS	O
+4	POS	O
+,	POS	O
+217	POS	O
+patients	POS	O
+(	POS	O
+94	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Compliance	POS	O
+to	POS	O
+niacin	POS	O
+extended	POS	O
+-	POS	O
+release	POS	O
+/	POS	O
+lovastatin	POS	O
+was	POS	O
+77	POS	O
+%	POS	O
+,	POS	O
+with	POS	O
+3	POS	O
+,	POS	O
+245	POS	O
+patients	POS	O
+completing	POS	O
+the	POS	O
+study	POS	O
+.	POS	O
+Patients	POS	O
+in	POS	O
+the	POS	O
+southeast	POS	O
+and	POS	O
+those	POS	O
+enrolled	POS	O
+by	POS	O
+endocrinologists	POS	O
+had	POS	O
+the	POS	O
+lowest	POS	O
+compliance	POS	O
+and	POS	O
+highest	POS	O
+adverse	POS	O
+event	POS	O
+rates	POS	O
+.	POS	O
+Flushing	POS	O
+was	POS	O
+the	POS	O
+most	POS	O
+common	POS	O
+adverse	POS	O
+event	POS	O
+,	POS	O
+reported	POS	O
+by	POS	O
+18	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+and	POS	O
+leading	POS	O
+to	POS	O
+discontinuation	POS	O
+by	POS	O
+6	POS	O
+%	POS	O
+.	POS	O
+Incidence	POS	O
+of	POS	O
+increased	POS	O
+aspartate	POS	O
+aminotransferase	POS	O
+and	POS	O
+/	POS	O
+or	POS	O
+alanine	POS	O
+aminotransferase	POS	O
+>	POS	O
+3	POS	O
+times	POS	O
+the	POS	O
+upper	POS	O
+limit	POS	O
+of	POS	O
+normal	POS	O
+was	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+.	POS	O
+An	POS	O
+increase	POS	O
+of	POS	O
+creatine	POS	O
+phosphokinase	POS	O
+to	POS	O
+>	POS	O
+5	POS	O
+times	POS	O
+the	POS	O
+upper	POS	O
+limit	POS	O
+of	POS	O
+normal	POS	O
+occurred	POS	O
+in	POS	O
+0	POS	O
+.	POS	O
+24	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+,	POS	O
+and	POS	O
+no	POS	O
+cases	POS	O
+of	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+myopathy	POS	B-NP
+were	POS	O
+observed	POS	O
+.	POS	O
+Niacin	POS	O
+extended	POS	O
+-	POS	O
+release	POS	O
+/	POS	O
+lovastatin	POS	O
+1	POS	O
+,	POS	O
+000	POS	O
+/	POS	O
+40	POS	O
+mg	POS	O
+,	POS	O
+dosed	POS	O
+as	POS	O
+initial	POS	O
+therapy	POS	O
+,	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+good	POS	O
+compliance	POS	O
+and	POS	O
+safety	POS	O
+and	POS	O
+had	POS	O
+very	POS	O
+low	POS	O
+incidences	POS	O
+of	POS	O
+increased	POS	O
+liver	POS	O
+and	POS	O
+muscle	POS	O
+enzymes	POS	O
+.	POS	O
+Protective	POS	O
+effect	POS	O
+of	POS	O
+Terminalia	POS	O
+chebula	POS	O
+against	POS	O
+experimental	POS	O
+myocardial	POS	B-NP
+injury	POS	I-NP
+induced	POS	O
+by	POS	O
+isoproterenol	POS	O
+.	POS	O
+Cardioprotective	POS	O
+effect	POS	O
+of	POS	O
+ethanolic	POS	O
+extract	POS	O
+of	POS	O
+Terminalia	POS	O
+chebula	POS	O
+fruits	POS	O
+(	POS	O
+500	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+body	POS	O
+wt	POS	O
+)	POS	O
+was	POS	O
+examined	POS	O
+in	POS	O
+isoproterenol	POS	O
+(	POS	O
+200	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+body	POS	O
+wt	POS	O
+)	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+damage	POS	I-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+In	POS	O
+isoproterenol	POS	O
+administered	POS	O
+rats	POS	O
+,	POS	O
+the	POS	O
+level	POS	O
+of	POS	O
+lipid	POS	O
+peroxides	POS	O
+increased	POS	O
+significantly	POS	O
+in	POS	O
+the	POS	O
+serum	POS	O
+and	POS	O
+heart	POS	O
+.	POS	O
+A	POS	O
+significant	POS	O
+decrease	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+activity	POS	O
+of	POS	O
+the	POS	O
+myocardial	POS	O
+marker	POS	O
+enzymes	POS	O
+with	POS	O
+a	POS	O
+concomitant	POS	O
+increase	POS	O
+in	POS	O
+their	POS	O
+activity	POS	O
+in	POS	O
+serum	POS	O
+.	POS	O
+Histopathological	POS	O
+examination	POS	O
+was	POS	O
+carried	POS	O
+out	POS	O
+to	POS	O
+confirm	POS	O
+the	POS	O
+myocardial	POS	B-NP
+necrosis	POS	I-NP
+.	POS	O
+T	POS	O
+.	POS	O
+chebula	POS	O
+extract	POS	O
+pretreatment	POS	O
+was	POS	O
+found	POS	O
+to	POS	O
+ameliorate	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+isoproterenol	POS	O
+on	POS	O
+lipid	POS	O
+peroxide	POS	O
+formation	POS	O
+and	POS	O
+retained	POS	O
+the	POS	O
+activities	POS	O
+of	POS	O
+the	POS	O
+diagnostic	POS	O
+marker	POS	O
+enzymes	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+postoperative	POS	B-NP
+anxiety	POS	I-NP
+due	POS	O
+to	POS	O
+low	POS	O
+dose	POS	O
+droperidol	POS	O
+used	POS	O
+with	POS	O
+patient	POS	O
+-	POS	O
+controlled	POS	O
+analgesia	POS	B-NP
+.	POS	O
+A	POS	O
+multiparous	POS	O
+woman	POS	O
+in	POS	O
+good	POS	O
+psychological	POS	O
+health	POS	O
+underwent	POS	O
+urgent	POS	O
+caesarean	POS	O
+section	POS	O
+in	POS	O
+labour	POS	O
+.	POS	O
+Postoperatively	POS	O
+,	POS	O
+she	POS	O
+was	POS	O
+given	POS	O
+a	POS	O
+patient	POS	O
+-	POS	O
+controlled	POS	O
+analgesia	POS	O
+device	POS	O
+delivering	POS	O
+boluses	POS	O
+of	POS	O
+diamorphine	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+and	POS	O
+droperidol	POS	O
+0	POS	O
+.	POS	O
+025	POS	O
+mg	POS	O
+.	POS	O
+Whilst	POS	O
+using	POS	O
+the	POS	O
+device	POS	O
+she	POS	O
+gradually	POS	O
+became	POS	O
+anxious	POS	B-NP
+,	POS	O
+the	POS	O
+feeling	POS	O
+worsening	POS	O
+after	POS	O
+each	POS	O
+bolus	POS	O
+.	POS	O
+The	POS	O
+diagnosis	POS	O
+of	POS	O
+droperidol	POS	O
+-	POS	O
+induced	POS	O
+psychological	POS	O
+disturbance	POS	O
+was	POS	O
+not	POS	O
+made	POS	O
+straight	POS	O
+away	POS	O
+although	POS	O
+on	POS	O
+subsequent	POS	O
+close	POS	O
+questioning	POS	O
+the	POS	O
+patient	POS	O
+gave	POS	O
+a	POS	O
+very	POS	O
+clear	POS	O
+history	POS	O
+.	POS	O
+After	POS	O
+she	POS	O
+had	POS	O
+received	POS	O
+a	POS	O
+total	POS	O
+of	POS	O
+only	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+mg	POS	O
+droperidol	POS	O
+,	POS	O
+a	POS	O
+syringe	POS	O
+containing	POS	O
+diamorphine	POS	O
+only	POS	O
+was	POS	O
+substituted	POS	O
+and	POS	O
+her	POS	O
+unease	POS	O
+resolved	POS	O
+completely	POS	O
+.	POS	O
+We	POS	O
+feel	POS	O
+that	POS	O
+,	POS	O
+although	POS	O
+the	POS	O
+dramatic	POS	O
+extrapyramidal	POS	O
+side	POS	O
+effects	POS	O
+of	POS	O
+dopaminergic	POS	O
+antiemetics	POS	O
+are	POS	O
+well	POS	O
+known	POS	O
+,	POS	O
+more	POS	O
+subtle	POS	O
+manifestations	POS	O
+may	POS	O
+easily	POS	O
+be	POS	O
+overlooked	POS	O
+.	POS	O
+Accurate	POS	O
+patient	POS	O
+history	POS	O
+contributes	POS	O
+to	POS	O
+differentiating	POS	O
+diabetes	POS	B-NP
+insipidus	POS	I-NP
+:	POS	O
+a	POS	O
+case	POS	O
+study	POS	O
+.	POS	O
+This	POS	O
+case	POS	O
+study	POS	O
+highlights	POS	O
+the	POS	O
+important	POS	O
+contribution	POS	O
+of	POS	O
+nursing	POS	O
+in	POS	O
+obtaining	POS	O
+an	POS	O
+accurate	POS	O
+health	POS	O
+history	POS	O
+.	POS	O
+The	POS	O
+case	POS	O
+discussed	POS	O
+herein	POS	O
+initially	POS	O
+appeared	POS	O
+to	POS	O
+be	POS	O
+neurogenic	POS	B-NP
+diabetes	POS	I-NP
+insipidus	POS	I-NP
+(	POS	O
+DI	POS	B-NP
+)	POS	O
+secondary	POS	O
+to	POS	O
+a	POS	O
+traumatic	POS	B-NP
+brain	POS	I-NP
+injury	POS	I-NP
+.	POS	O
+The	POS	O
+nursing	POS	O
+staff	POS	O
+,	POS	O
+by	POS	O
+reviewing	POS	O
+the	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+health	POS	O
+history	POS	O
+with	POS	O
+his	POS	O
+family	POS	O
+,	POS	O
+discovered	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+polydipsia	POS	B-NP
+and	POS	O
+long	POS	O
+-	POS	O
+standing	POS	O
+lithium	POS	O
+use	POS	O
+.	POS	O
+Lithium	POS	O
+is	POS	O
+implicated	POS	O
+in	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+nephrogenic	POS	B-NP
+DI	POS	I-NP
+,	POS	O
+and	POS	O
+because	POS	O
+the	POS	O
+patient	POS	O
+had	POS	O
+not	POS	O
+received	POS	O
+lithium	POS	O
+since	POS	O
+being	POS	O
+admitted	POS	O
+to	POS	O
+the	POS	O
+hospital	POS	O
+,	POS	O
+his	POS	O
+treatment	POS	O
+changed	POS	O
+to	POS	O
+focus	POS	O
+on	POS	O
+nephrogenic	POS	B-NP
+DI	POS	I-NP
+.	POS	O
+By	POS	O
+combining	POS	O
+information	POS	O
+from	POS	O
+the	POS	O
+patient	POS	O
+history	POS	O
+,	POS	O
+the	POS	O
+physical	POS	O
+examination	POS	O
+,	POS	O
+and	POS	O
+radiologic	POS	O
+and	POS	O
+laboratory	POS	O
+studies	POS	O
+,	POS	O
+the	POS	O
+critical	POS	O
+care	POS	O
+team	POS	O
+demonstrated	POS	O
+that	POS	O
+the	POS	O
+patient	POS	O
+had	POS	O
+been	POS	O
+self	POS	O
+-	POS	O
+treating	POS	O
+his	POS	O
+lithium	POS	O
+-	POS	O
+induced	POS	O
+nephrogenic	POS	B-NP
+DI	POS	I-NP
+and	POS	O
+developed	POS	O
+neurogenic	POS	O
+DI	POS	O
+secondary	POS	O
+to	POS	O
+brain	POS	B-NP
+trauma	POS	I-NP
+.	POS	O
+Thus	POS	O
+successful	POS	O
+treatment	POS	O
+required	POS	O
+that	POS	O
+nephrogenic	POS	B-NP
+and	POS	O
+neurogenic	POS	B-NP
+DI	POS	I-NP
+be	POS	O
+treated	POS	O
+concomitantly	POS	O
+.	POS	O
+Factors	POS	O
+contributing	POS	O
+to	POS	O
+ribavirin	POS	O
+-	POS	O
+induced	POS	O
+anemia	POS	B-NP
+.	POS	O
+BACKGROUND	POS	O
+AND	POS	O
+AIM	POS	O
+:	POS	O
+Interferon	POS	O
+and	POS	O
+ribavirin	POS	O
+combination	POS	O
+therapy	POS	O
+for	POS	O
+chronic	POS	O
+hepatitis	POS	O
+C	POS	O
+produces	POS	O
+hemolytic	POS	B-NP
+anemia	POS	I-NP
+.	POS	O
+This	POS	O
+study	POS	O
+was	POS	O
+conducted	POS	O
+to	POS	O
+identify	POS	O
+the	POS	O
+factors	POS	O
+contributing	POS	O
+to	POS	O
+ribavirin	POS	O
+-	POS	O
+induced	POS	O
+anemia	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Eighty	POS	O
+-	POS	O
+eight	POS	O
+patients	POS	O
+with	POS	O
+chronic	POS	B-NP
+hepatitis	POS	I-NP
+C	POS	I-NP
+who	POS	O
+received	POS	O
+interferon	POS	O
+-	POS	O
+alpha	POS	O
+-	POS	O
+2b	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+6	POS	O
+MU	POS	O
+administered	POS	O
+intramuscularly	POS	O
+for	POS	O
+24	POS	O
+weeks	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+ribavirin	POS	O
+administered	POS	O
+orally	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+600	POS	O
+mg	POS	O
+or	POS	O
+800	POS	O
+mg	POS	O
+participated	POS	O
+in	POS	O
+the	POS	O
+study	POS	O
+.	POS	O
+A	POS	O
+hemoglobin	POS	O
+concentration	POS	O
+of	POS	O
+<	POS	O
+10	POS	O
+g	POS	O
+/	POS	O
+dL	POS	O
+was	POS	O
+defined	POS	O
+as	POS	O
+ribavirin	POS	O
+-	POS	O
+induced	POS	O
+anemia	POS	B-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Ribavirin	POS	O
+-	POS	O
+induced	POS	O
+anemia	POS	B-NP
+occurred	POS	O
+in	POS	O
+18	POS	O
+(	POS	O
+20	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+during	POS	O
+treatment	POS	O
+.	POS	O
+A	POS	O
+2	POS	O
+g	POS	O
+/	POS	O
+dL	POS	O
+decrease	POS	O
+in	POS	O
+hemoglobin	POS	O
+concentrations	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+anemia	POS	B-NP
+was	POS	O
+observed	POS	O
+at	POS	O
+week	POS	O
+2	POS	O
+after	POS	O
+the	POS	O
+start	POS	O
+of	POS	O
+treatment	POS	O
+.	POS	O
+The	POS	O
+hemoglobin	POS	O
+concentration	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+2	POS	O
+g	POS	O
+/	POS	O
+dL	POS	O
+decrease	POS	O
+at	POS	O
+week	POS	O
+2	POS	O
+was	POS	O
+observed	POS	O
+to	POS	O
+be	POS	O
+significantly	POS	O
+lower	POS	O
+even	POS	O
+after	POS	O
+week	POS	O
+2	POS	O
+than	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+<	POS	O
+2	POS	O
+g	POS	O
+/	POS	O
+dL	POS	O
+decrease	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+A	POS	O
+significant	POS	O
+relationship	POS	O
+was	POS	O
+observed	POS	O
+between	POS	O
+the	POS	O
+rate	POS	O
+of	POS	O
+reduction	POS	O
+of	POS	O
+hemoglobin	POS	O
+concentrations	POS	O
+at	POS	O
+week	POS	O
+2	POS	O
+and	POS	O
+the	POS	O
+severity	POS	O
+of	POS	O
+anemia	POS	B-NP
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+Such	POS	O
+factors	POS	O
+as	POS	O
+sex	POS	O
+(	POS	O
+female	POS	O
+)	POS	O
+,	POS	O
+age	POS	O
+(	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+60	POS	O
+years	POS	O
+old	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+ribavirin	POS	O
+dose	POS	O
+by	POS	O
+body	POS	O
+weight	POS	O
+(	POS	O
+12	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+or	POS	O
+more	POS	O
+)	POS	O
+were	POS	O
+significant	POS	O
+by	POS	O
+univariate	POS	O
+analysis	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Careful	POS	O
+administration	POS	O
+is	POS	O
+necessary	POS	O
+in	POS	O
+patients	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+60	POS	O
+years	POS	O
+old	POS	O
+,	POS	O
+in	POS	O
+female	POS	O
+patients	POS	O
+,	POS	O
+and	POS	O
+in	POS	O
+patients	POS	O
+receiving	POS	O
+a	POS	O
+ribavirin	POS	O
+dose	POS	O
+of	POS	O
+12	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+or	POS	O
+more	POS	O
+.	POS	O
+Patients	POS	O
+who	POS	O
+experience	POS	O
+a	POS	O
+fall	POS	O
+in	POS	O
+hemoglobin	POS	O
+concentrations	POS	O
+of	POS	O
+2	POS	O
+g	POS	O
+/	POS	O
+dL	POS	O
+or	POS	O
+more	POS	O
+at	POS	O
+week	POS	O
+2	POS	O
+after	POS	O
+the	POS	O
+start	POS	O
+of	POS	O
+treatment	POS	O
+should	POS	O
+be	POS	O
+monitored	POS	O
+with	POS	O
+particular	POS	O
+care	POS	O
+.	POS	O
+Zidovudine	POS	O
+-	POS	O
+induced	POS	O
+hepatitis	POS	B-NP
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+acute	POS	B-NP
+hepatitis	POS	I-NP
+induced	POS	O
+by	POS	O
+zidovudine	POS	O
+in	POS	O
+a	POS	O
+38	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+patient	POS	O
+with	POS	O
+AIDS	POS	B-NP
+is	POS	O
+presented	POS	O
+.	POS	O
+The	POS	O
+mechanism	POS	O
+whereby	POS	O
+the	POS	O
+hepatitis	POS	B-NP
+was	POS	O
+induced	POS	O
+is	POS	O
+not	POS	O
+known	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+tolerated	POS	O
+well	POS	O
+an	POS	O
+alternative	POS	O
+reverse	POS	O
+transcriptase	POS	O
+inhibitor	POS	O
+,	POS	O
+2	POS	O
+'	POS	O
+3	POS	O
+'	POS	O
+dideoxyinosine	POS	O
+.	POS	O
+Physicians	POS	O
+caring	POS	O
+for	POS	O
+patients	POS	O
+with	POS	O
+AIDS	POS	B-NP
+should	POS	O
+be	POS	O
+aware	POS	O
+of	POS	O
+this	POS	O
+hitherto	POS	O
+rarely	POS	O
+reported	POS	O
+complication	POS	O
+.	POS	O
+Oxidative	POS	O
+damage	POS	O
+precedes	POS	O
+nitrative	POS	O
+damage	POS	O
+in	POS	O
+adriamycin	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+mitochondrial	POS	I-NP
+injury	POS	I-NP
+.	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+determine	POS	O
+if	POS	O
+elevated	POS	O
+reactive	POS	O
+oxygen	POS	O
+(	POS	O
+ROS	POS	O
+)	POS	O
+/	POS	O
+nitrogen	POS	O
+species	POS	O
+(	POS	O
+RNS	POS	O
+)	POS	O
+reported	POS	O
+to	POS	O
+be	POS	O
+present	POS	O
+in	POS	O
+adriamycin	POS	O
+(	POS	O
+ADR	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+actually	POS	O
+resulted	POS	O
+in	POS	O
+cardiomyocyte	POS	O
+oxidative	POS	O
+/	POS	O
+nitrative	POS	O
+damage	POS	O
+,	POS	O
+and	POS	O
+to	POS	O
+quantitatively	POS	O
+determine	POS	O
+the	POS	O
+time	POS	O
+course	POS	O
+and	POS	O
+subcellular	POS	O
+localization	POS	O
+of	POS	O
+these	POS	O
+postulated	POS	O
+damage	POS	O
+products	POS	O
+using	POS	O
+an	POS	O
+in	POS	O
+vivo	POS	O
+approach	POS	O
+.	POS	O
+B6C3	POS	O
+mice	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+a	POS	O
+single	POS	O
+dose	POS	O
+of	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+ADR	POS	O
+.	POS	O
+Ultrastructural	POS	O
+damage	POS	O
+and	POS	O
+levels	POS	O
+of	POS	O
+4	POS	O
+-	POS	O
+hydroxy	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+nonenal	POS	O
+(	POS	O
+4HNE	POS	O
+)	POS	O
+-	POS	O
+protein	POS	O
+adducts	POS	O
+and	POS	O
+3	POS	O
+-	POS	O
+nitrotyrosine	POS	O
+(	POS	O
+3NT	POS	O
+)	POS	O
+were	POS	O
+analyzed	POS	O
+.	POS	O
+Quantitative	POS	O
+ultrastructural	POS	O
+damage	POS	O
+using	POS	O
+computerized	POS	O
+image	POS	O
+techniques	POS	O
+showed	POS	O
+cardiomyocyte	POS	B-NP
+injury	POS	I-NP
+as	POS	O
+early	POS	O
+as	POS	O
+3	POS	O
+hours	POS	O
+,	POS	O
+with	POS	O
+mitochondria	POS	O
+being	POS	O
+the	POS	O
+most	POS	O
+extensively	POS	O
+and	POS	O
+progressively	POS	O
+injured	POS	O
+subcellular	POS	O
+organelle	POS	O
+.	POS	O
+Analysis	POS	O
+of	POS	O
+4HNE	POS	O
+protein	POS	O
+adducts	POS	O
+by	POS	O
+immunogold	POS	O
+electron	POS	O
+microscopy	POS	O
+showed	POS	O
+appearance	POS	O
+of	POS	O
+4HNE	POS	O
+protein	POS	O
+adducts	POS	O
+in	POS	O
+mitochondria	POS	O
+as	POS	O
+early	POS	O
+as	POS	O
+3	POS	O
+hours	POS	O
+,	POS	O
+with	POS	O
+a	POS	O
+peak	POS	O
+at	POS	O
+6	POS	O
+hours	POS	O
+and	POS	O
+subsequent	POS	O
+decline	POS	O
+at	POS	O
+24	POS	O
+hours	POS	O
+.	POS	O
+3NT	POS	O
+levels	POS	O
+were	POS	O
+significantly	POS	O
+increased	POS	O
+in	POS	O
+all	POS	O
+subcellular	POS	O
+compartments	POS	O
+at	POS	O
+6	POS	O
+hours	POS	O
+and	POS	O
+subsequently	POS	O
+declined	POS	O
+at	POS	O
+24	POS	O
+hours	POS	O
+.	POS	O
+Our	POS	O
+data	POS	O
+showed	POS	O
+ADR	POS	O
+induced	POS	O
+4HNE	POS	O
+-	POS	O
+protein	POS	O
+adducts	POS	O
+in	POS	O
+mitochondria	POS	O
+at	POS	O
+the	POS	O
+same	POS	O
+time	POS	O
+point	POS	O
+as	POS	O
+when	POS	O
+mitochondrial	POS	B-NP
+injury	POS	I-NP
+initially	POS	O
+appeared	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+document	POS	O
+for	POS	O
+the	POS	O
+first	POS	O
+time	POS	O
+in	POS	O
+vivo	POS	O
+that	POS	O
+mitochondrial	POS	O
+oxidative	POS	O
+damage	POS	O
+precedes	POS	O
+nitrative	POS	O
+damage	POS	O
+.	POS	O
+The	POS	O
+progressive	POS	O
+nature	POS	O
+of	POS	O
+mitochondrial	POS	B-NP
+injury	POS	I-NP
+suggests	POS	O
+that	POS	O
+mitochondria	POS	O
+,	POS	O
+not	POS	O
+other	POS	O
+subcellular	POS	O
+organelles	POS	O
+,	POS	O
+are	POS	O
+the	POS	O
+major	POS	O
+site	POS	O
+of	POS	O
+intracellular	POS	O
+injury	POS	O
+.	POS	O
+Sotalol	POS	O
+-	POS	O
+induced	POS	O
+coronary	POS	B-NP
+spasm	POS	I-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+dilated	POS	B-NP
+cardiomyopathy	POS	I-NP
+associated	POS	O
+with	POS	O
+sustained	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+.	POS	O
+A	POS	O
+54	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+with	POS	O
+severe	POS	O
+left	POS	B-NP
+ventricular	POS	I-NP
+dysfunction	POS	I-NP
+due	POS	O
+to	POS	O
+dilated	POS	B-NP
+cardiomyopathy	POS	I-NP
+was	POS	O
+referred	POS	O
+to	POS	O
+our	POS	O
+hospital	POS	O
+for	POS	O
+symptomatic	POS	O
+incessant	POS	O
+sustained	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+(	POS	O
+VT	POS	B-NP
+)	POS	O
+.	POS	O
+After	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+nifekalant	POS	O
+hydrochloride	POS	O
+,	POS	O
+sustained	POS	O
+VT	POS	B-NP
+was	POS	O
+terminated	POS	O
+.	POS	O
+An	POS	O
+alternate	POS	O
+class	POS	O
+III	POS	O
+agent	POS	O
+,	POS	O
+sotalol	POS	O
+,	POS	O
+was	POS	O
+also	POS	O
+effective	POS	O
+for	POS	O
+the	POS	O
+prevention	POS	O
+of	POS	O
+VT	POS	B-NP
+.	POS	O
+However	POS	O
+,	POS	O
+one	POS	O
+month	POS	O
+after	POS	O
+switching	POS	O
+over	POS	O
+nifekalant	POS	O
+to	POS	O
+sotalol	POS	O
+,	POS	O
+a	POS	O
+short	POS	O
+duration	POS	O
+of	POS	O
+ST	POS	O
+elevation	POS	O
+was	POS	O
+documented	POS	O
+in	POS	O
+ECG	POS	O
+monitoring	POS	O
+at	POS	O
+almost	POS	O
+the	POS	O
+same	POS	O
+time	POS	O
+for	POS	O
+three	POS	O
+consecutive	POS	O
+days	POS	O
+.	POS	O
+ST	POS	O
+elevation	POS	O
+with	POS	O
+chest	POS	B-NP
+discomfort	POS	I-NP
+disappeared	POS	O
+since	POS	O
+he	POS	O
+began	POS	O
+taking	POS	O
+long	POS	O
+-	POS	O
+acting	POS	O
+diltiazem	POS	O
+.	POS	O
+Coronary	POS	B-NP
+vasospasm	POS	I-NP
+may	POS	O
+be	POS	O
+induced	POS	O
+by	POS	O
+the	POS	O
+non	POS	O
+-	POS	O
+selective	POS	O
+beta	POS	O
+-	POS	O
+blocking	POS	O
+properties	POS	O
+of	POS	O
+sotalol	POS	O
+.	POS	O
+Effects	POS	O
+of	POS	O
+the	POS	O
+antidepressant	POS	O
+trazodone	POS	O
+,	POS	O
+a	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+2A	POS	O
+/	POS	O
+2C	POS	O
+receptor	POS	O
+antagonist	POS	O
+,	POS	O
+on	POS	O
+dopamine	POS	O
+-	POS	O
+dependent	POS	O
+behaviors	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+RATIONALE	POS	O
+:	POS	O
+5	POS	O
+-	POS	O
+Hydroxytryptamine	POS	O
+,	POS	O
+via	POS	O
+stimulation	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+2C	POS	O
+receptors	POS	O
+,	POS	O
+exerts	POS	O
+a	POS	O
+tonic	POS	O
+inhibitory	POS	O
+influence	POS	O
+on	POS	O
+dopaminergic	POS	O
+neurotransmission	POS	O
+,	POS	O
+whereas	POS	O
+activation	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+2A	POS	O
+receptors	POS	O
+enhances	POS	O
+stimulated	POS	O
+DAergic	POS	O
+neurotransmission	POS	O
+.	POS	O
+The	POS	O
+antidepressant	POS	O
+trazodone	POS	O
+is	POS	O
+a	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+2A	POS	O
+/	POS	O
+2C	POS	O
+receptor	POS	O
+antagonist	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+To	POS	O
+evaluate	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+trazodone	POS	O
+treatment	POS	O
+on	POS	O
+behaviors	POS	O
+dependent	POS	O
+on	POS	O
+the	POS	O
+functional	POS	O
+status	POS	O
+of	POS	O
+the	POS	O
+nigrostriatal	POS	O
+DAergic	POS	O
+system	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+The	POS	O
+effect	POS	O
+of	POS	O
+pretreatment	POS	O
+with	POS	O
+trazodone	POS	O
+on	POS	O
+dexamphetamine	POS	O
+-	POS	O
+and	POS	O
+apomorphine	POS	O
+-	POS	O
+induced	POS	O
+oral	POS	O
+stereotypies	POS	B-NP
+,	POS	O
+on	POS	O
+catalepsy	POS	B-NP
+induced	POS	O
+by	POS	O
+haloperidol	POS	O
+and	POS	O
+apomorphine	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+,	POS	O
+on	POS	O
+ergometrine	POS	O
+-	POS	O
+induced	POS	O
+wet	POS	O
+dog	POS	O
+shake	POS	O
+(	POS	O
+WDS	POS	O
+)	POS	O
+behavior	POS	O
+and	POS	O
+fluoxetine	POS	O
+-	POS	O
+induced	POS	O
+penile	POS	O
+erections	POS	O
+was	POS	O
+studied	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+We	POS	O
+also	POS	O
+investigated	POS	O
+whether	POS	O
+trazodone	POS	O
+induces	POS	O
+catalepsy	POS	B-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Trazodone	POS	O
+at	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+did	POS	O
+not	POS	O
+induce	POS	O
+catalepsy	POS	B-NP
+,	POS	O
+and	POS	O
+did	POS	O
+not	POS	O
+antagonize	POS	O
+apomorphine	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+and	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+stereotypy	POS	O
+and	POS	O
+apomorphine	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+catalepsy	POS	B-NP
+.	POS	O
+However	POS	O
+,	POS	O
+pretreatment	POS	O
+with	POS	O
+5	POS	O
+,	POS	O
+10	POS	O
+and	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+trazodone	POS	O
+enhanced	POS	O
+dexamphetamine	POS	O
+stereotypy	POS	B-NP
+,	POS	O
+and	POS	O
+antagonized	POS	O
+haloperidol	POS	O
+catalepsy	POS	B-NP
+,	POS	O
+ergometrine	POS	O
+-	POS	O
+induced	POS	O
+WDS	POS	O
+behavior	POS	O
+and	POS	O
+fluoxetine	POS	O
+-	POS	O
+induced	POS	O
+penile	POS	O
+erections	POS	O
+.	POS	O
+Trazodone	POS	O
+at	POS	O
+30	POS	O
+,	POS	O
+40	POS	O
+and	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+induced	POS	O
+catalepsy	POS	B-NP
+and	POS	O
+antagonized	POS	O
+apomorphine	POS	O
+and	POS	O
+dexamphetamine	POS	O
+stereotypies	POS	B-NP
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Our	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+trazodone	POS	O
+at	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+does	POS	O
+not	POS	O
+block	POS	O
+pre	POS	O
+-	POS	O
+and	POS	O
+postsynaptic	POS	O
+striatal	POS	O
+D2	POS	O
+DA	POS	O
+receptors	POS	O
+,	POS	O
+while	POS	O
+at	POS	O
+30	POS	O
+,	POS	O
+40	POS	O
+and	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+it	POS	O
+blocks	POS	O
+postsynaptic	POS	O
+striatal	POS	O
+D2	POS	O
+DA	POS	O
+receptors	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+at	POS	O
+5	POS	O
+,	POS	O
+10	POS	O
+and	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+trazodone	POS	O
+blocks	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+2A	POS	O
+and	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+2C	POS	O
+receptors	POS	O
+.	POS	O
+We	POS	O
+suggest	POS	O
+that	POS	O
+trazodone	POS	O
+(	POS	O
+5	POS	O
+,	POS	O
+10	POS	O
+and	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+,	POS	O
+by	POS	O
+blocking	POS	O
+the	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+2C	POS	O
+receptors	POS	O
+,	POS	O
+releases	POS	O
+the	POS	O
+nigrostriatal	POS	O
+DAergic	POS	O
+neurons	POS	O
+from	POS	O
+tonic	POS	O
+inhibition	POS	O
+caused	POS	O
+by	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+,	POS	O
+and	POS	O
+thereby	POS	O
+potentiates	POS	O
+dexamphetamine	POS	O
+stereotypy	POS	O
+and	POS	O
+antagonizes	POS	O
+haloperidol	POS	O
+catalepsy	POS	B-NP
+.	POS	O
+Swallowing	POS	B-NP
+abnormalities	POS	I-NP
+and	POS	O
+dyskinesia	POS	B-NP
+in	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+Gastrointestinal	POS	B-NP
+abnormalities	POS	I-NP
+in	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+PD	POS	B-NP
+)	POS	O
+have	POS	O
+been	POS	O
+known	POS	O
+for	POS	O
+almost	POS	O
+two	POS	O
+centuries	POS	O
+,	POS	O
+but	POS	O
+many	POS	O
+aspects	POS	O
+concerning	POS	O
+their	POS	O
+pathophysiology	POS	O
+have	POS	O
+not	POS	O
+been	POS	O
+completely	POS	O
+clarified	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+characterize	POS	O
+the	POS	O
+oropharyngeal	POS	O
+dynamics	POS	O
+in	POS	O
+PD	POS	B-NP
+patients	POS	O
+with	POS	O
+and	POS	O
+without	POS	O
+levodopa	POS	O
+-	POS	O
+induced	POS	O
+dyskinesia	POS	B-NP
+.	POS	O
+Fifteen	POS	O
+dyskinetic	POS	B-NP
+,	POS	O
+12	POS	O
+nondyskinetic	POS	B-NP
+patients	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+control	POS	O
+group	POS	O
+were	POS	O
+included	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+asked	POS	O
+about	POS	O
+dysphagia	POS	B-NP
+and	POS	O
+evaluated	POS	O
+with	POS	O
+the	POS	O
+Unified	POS	O
+Parkinson	POS	O
+'	POS	O
+s	POS	O
+Disease	POS	O
+Rating	POS	O
+Scale	POS	O
+Parts	POS	O
+II	POS	O
+and	POS	O
+III	POS	O
+and	POS	O
+the	POS	O
+Hoehn	POS	B-NP
+and	POS	O
+Yahr	POS	O
+scale	POS	O
+.	POS	O
+Deglutition	POS	B-NP
+was	POS	O
+assessed	POS	O
+using	POS	O
+modified	POS	O
+barium	POS	O
+swallow	POS	O
+with	POS	O
+videofluoroscopy	POS	O
+.	POS	O
+Nondyskinetic	POS	B-NP
+patients	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+the	POS	O
+dyskinetic	POS	B-NP
+ones	POS	O
+,	POS	O
+showed	POS	O
+less	POS	O
+oropharyngeal	POS	O
+swallowing	POS	O
+efficiency	POS	O
+(	POS	O
+OPSE	POS	O
+)	POS	O
+for	POS	O
+liquid	POS	O
+food	POS	O
+than	POS	O
+controls	POS	O
+(	POS	O
+Dunnett	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+.	POS	O
+Dyskinetic	POS	B-NP
+patients	POS	O
+tended	POS	O
+to	POS	O
+have	POS	O
+a	POS	O
+greater	POS	O
+OPSE	POS	O
+than	POS	O
+nondyskinetic	POS	O
+(	POS	O
+Dunnett	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+06	POS	O
+)	POS	O
+.	POS	O
+Patients	POS	O
+who	POS	O
+were	POS	O
+using	POS	O
+a	POS	O
+higher	POS	O
+dose	POS	O
+of	POS	O
+levodopa	POS	O
+had	POS	O
+a	POS	O
+greater	POS	O
+OPSE	POS	O
+and	POS	O
+a	POS	O
+trend	POS	O
+toward	POS	O
+a	POS	O
+smaller	POS	O
+oral	POS	O
+transit	POS	O
+time	POS	O
+(	POS	O
+Pearson	POS	O
+'	POS	O
+s	POS	O
+correlation	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+08	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+.	POS	O
+Neither	POS	O
+the	POS	O
+report	POS	O
+of	POS	O
+dysphagia	POS	B-NP
+nor	POS	O
+any	POS	O
+of	POS	O
+the	POS	O
+PD	POS	B-NP
+severity	POS	O
+parameters	POS	O
+correlated	POS	O
+to	POS	O
+the	POS	O
+videofluoroscopic	POS	O
+variables	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+current	POS	O
+study	POS	O
+,	POS	O
+dyskinetic	POS	B-NP
+patients	POS	O
+performed	POS	O
+better	POS	O
+in	POS	O
+swallowing	POS	O
+function	POS	O
+,	POS	O
+which	POS	O
+could	POS	O
+be	POS	O
+explained	POS	O
+on	POS	O
+the	POS	O
+basis	POS	O
+of	POS	O
+a	POS	O
+greater	POS	O
+levodopa	POS	O
+dose	POS	O
+.	POS	O
+Our	POS	O
+results	POS	O
+suggest	POS	O
+a	POS	O
+role	POS	O
+for	POS	O
+levodopa	POS	O
+in	POS	O
+the	POS	O
+oral	POS	O
+phase	POS	O
+of	POS	O
+deglutition	POS	O
+and	POS	O
+confirm	POS	O
+that	POS	O
+dysphagia	POS	B-NP
+is	POS	O
+not	POS	O
+a	POS	O
+good	POS	O
+predictor	POS	O
+of	POS	O
+deglutition	POS	O
+alterations	POS	O
+in	POS	O
+PD	POS	B-NP
+.	POS	O
+Inhibition	POS	O
+of	POS	O
+nuclear	POS	O
+factor	POS	O
+-	POS	O
+kappaB	POS	O
+activation	POS	O
+attenuates	POS	O
+tubulointerstitial	POS	B-NP
+nephritis	POS	I-NP
+induced	POS	O
+by	POS	O
+gentamicin	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Animals	POS	O
+treated	POS	O
+with	POS	O
+gentamicin	POS	O
+can	POS	O
+show	POS	O
+residual	POS	O
+areas	POS	O
+of	POS	O
+interstitial	POS	B-NP
+fibrosis	POS	I-NP
+in	POS	O
+the	POS	O
+renal	POS	O
+cortex	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+investigated	POS	O
+the	POS	O
+expression	POS	O
+of	POS	O
+nuclear	POS	O
+factor	POS	O
+-	POS	O
+kappaB	POS	O
+(	POS	O
+NF	POS	O
+-	POS	O
+kappaB	POS	O
+)	POS	O
+,	POS	O
+mitogen	POS	O
+-	POS	O
+activated	POS	O
+protein	POS	O
+(	POS	O
+MAP	POS	O
+)	POS	O
+kinases	POS	O
+and	POS	O
+macrophages	POS	O
+in	POS	O
+the	POS	O
+renal	POS	O
+cortex	POS	O
+and	POS	O
+structural	POS	O
+and	POS	O
+functional	POS	O
+renal	POS	O
+changes	POS	O
+of	POS	O
+rats	POS	O
+treated	POS	O
+with	POS	O
+gentamicin	POS	O
+or	POS	O
+gentamicin	POS	O
++	POS	O
+pyrrolidine	POS	O
+dithiocarbamate	POS	O
+(	POS	O
+PDTC	POS	O
+)	POS	O
+,	POS	O
+an	POS	O
+NF	POS	O
+-	POS	O
+kappaB	POS	O
+inhibitor	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+38	POS	O
+female	POS	O
+Wistar	POS	O
+rats	POS	O
+were	POS	O
+injected	POS	O
+with	POS	O
+gentamicin	POS	O
+,	POS	O
+40	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+twice	POS	O
+a	POS	O
+day	POS	O
+for	POS	O
+9	POS	O
+days	POS	O
+,	POS	O
+38	POS	O
+with	POS	O
+gentamicin	POS	O
++	POS	O
+PDTC	POS	O
+,	POS	O
+and	POS	O
+28	POS	O
+with	POS	O
+0	POS	O
+.	POS	O
+15	POS	O
+M	POS	O
+NaCl	POS	O
+solution	POS	O
+.	POS	O
+The	POS	O
+animals	POS	O
+were	POS	O
+killed	POS	O
+5	POS	O
+and	POS	O
+30	POS	O
+days	POS	O
+after	POS	O
+these	POS	O
+injections	POS	O
+and	POS	O
+the	POS	O
+kidneys	POS	O
+were	POS	O
+removed	POS	O
+for	POS	O
+histological	POS	O
+and	POS	O
+immunohistochemical	POS	O
+studies	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+of	POS	O
+the	POS	O
+immunohistochemical	POS	O
+studies	POS	O
+were	POS	O
+scored	POS	O
+according	POS	O
+to	POS	O
+the	POS	O
+extent	POS	O
+of	POS	O
+staining	POS	O
+.	POS	O
+The	POS	O
+fractional	POS	O
+interstitial	POS	O
+area	POS	O
+was	POS	O
+determined	POS	O
+by	POS	O
+morphometry	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Gentamicin	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+presented	POS	O
+a	POS	O
+transitory	POS	O
+increase	POS	O
+in	POS	O
+plasma	POS	O
+creatinine	POS	O
+levels	POS	O
+.	POS	O
+Increased	POS	O
+ED	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+MAP	POS	O
+kinases	POS	O
+and	POS	O
+NF	POS	O
+-	POS	O
+kappaB	POS	O
+staining	POS	O
+were	POS	O
+also	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+renal	POS	O
+cortex	POS	O
+from	POS	O
+all	POS	O
+gentamicin	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+compared	POS	O
+to	POS	O
+control	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+animals	POS	O
+killed	POS	O
+on	POS	O
+day	POS	O
+30	POS	O
+also	POS	O
+presented	POS	O
+fibrosis	POS	B-NP
+in	POS	O
+the	POS	O
+renal	POS	O
+cortex	POS	O
+despite	POS	O
+the	POS	O
+recovery	POS	O
+of	POS	O
+renal	POS	O
+function	POS	O
+.	POS	O
+Treatment	POS	O
+with	POS	O
+PDTC	POS	O
+reduced	POS	O
+the	POS	O
+functional	POS	O
+and	POS	O
+structural	POS	O
+changes	POS	O
+induced	POS	O
+by	POS	O
+gentamicin	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+These	POS	O
+data	POS	O
+show	POS	O
+that	POS	O
+inhibition	POS	O
+of	POS	O
+NF	POS	O
+-	POS	O
+kappaB	POS	O
+activation	POS	O
+attenuates	POS	O
+tubulointerstitial	POS	B-NP
+nephritis	POS	I-NP
+induced	POS	O
+by	POS	O
+gentamicin	POS	O
+.	POS	O
+Glucose	POS	O
+metabolism	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+schizophrenia	POS	B-NP
+treated	POS	O
+with	POS	O
+atypical	POS	O
+antipsychotic	POS	O
+agents	POS	O
+:	POS	O
+a	POS	O
+frequently	POS	O
+sampled	POS	O
+intravenous	POS	O
+glucose	POS	O
+tolerance	POS	O
+test	POS	O
+and	POS	O
+minimal	POS	O
+model	POS	O
+analysis	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+While	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+new	POS	O
+-	POS	O
+onset	POS	O
+diabetes	POS	B-NP
+mellitus	POS	I-NP
+may	POS	O
+be	POS	O
+increasing	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+schizophrenia	POS	B-NP
+treated	POS	O
+with	POS	O
+certain	POS	O
+atypical	POS	O
+antipsychotic	POS	O
+agents	POS	O
+,	POS	O
+it	POS	O
+remains	POS	O
+unclear	POS	O
+whether	POS	O
+atypical	POS	O
+agents	POS	O
+are	POS	O
+directly	POS	O
+affecting	POS	O
+glucose	POS	O
+metabolism	POS	O
+or	POS	O
+simply	POS	O
+increasing	POS	O
+known	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+diabetes	POS	B-NP
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+study	POS	O
+the	POS	O
+2	POS	O
+drugs	POS	O
+most	POS	O
+clearly	POS	O
+implicated	POS	O
+(	POS	O
+clozapine	POS	O
+and	POS	O
+olanzapine	POS	O
+)	POS	O
+and	POS	O
+risperidone	POS	O
+using	POS	O
+a	POS	O
+frequently	POS	O
+sampled	POS	O
+intravenous	POS	O
+glucose	POS	O
+tolerance	POS	O
+test	POS	O
+.	POS	O
+DESIGN	POS	O
+:	POS	O
+A	POS	O
+cross	POS	O
+-	POS	O
+sectional	POS	O
+design	POS	O
+in	POS	O
+stable	POS	O
+,	POS	O
+treated	POS	O
+patients	POS	O
+with	POS	O
+schizophrenia	POS	B-NP
+evaluated	POS	O
+using	POS	O
+a	POS	O
+frequently	POS	O
+sampled	POS	O
+intravenous	POS	O
+glucose	POS	O
+tolerance	POS	O
+test	POS	O
+and	POS	O
+the	POS	O
+Bergman	POS	O
+minimal	POS	O
+model	POS	O
+analysis	POS	O
+.	POS	O
+SETTING	POS	O
+:	POS	O
+Subjects	POS	O
+were	POS	O
+recruited	POS	O
+from	POS	O
+an	POS	O
+urban	POS	O
+community	POS	O
+mental	POS	O
+health	POS	O
+clinic	POS	O
+and	POS	O
+were	POS	O
+studied	POS	O
+at	POS	O
+a	POS	O
+general	POS	O
+clinical	POS	O
+research	POS	O
+center	POS	O
+.	POS	O
+Patients	POS	O
+Fifty	POS	O
+subjects	POS	O
+signed	POS	O
+informed	POS	O
+consent	POS	O
+and	POS	O
+41	POS	O
+underwent	POS	O
+the	POS	O
+frequently	POS	O
+sampled	POS	O
+intravenous	POS	O
+glucose	POS	O
+tolerance	POS	O
+test	POS	O
+.	POS	O
+Thirty	POS	O
+-	POS	O
+six	POS	O
+nonobese	POS	O
+subjects	POS	O
+with	POS	O
+schizophrenia	POS	B-NP
+or	POS	O
+schizoaffective	POS	B-NP
+disorder	POS	I-NP
+,	POS	O
+matched	POS	O
+by	POS	O
+body	POS	O
+mass	POS	O
+index	POS	O
+and	POS	O
+treated	POS	O
+with	POS	O
+either	POS	O
+clozapine	POS	O
+,	POS	O
+olanzapine	POS	O
+,	POS	O
+or	POS	O
+risperidone	POS	O
+,	POS	O
+were	POS	O
+included	POS	O
+in	POS	O
+the	POS	O
+analysis	POS	O
+.	POS	O
+MAIN	POS	O
+OUTCOME	POS	O
+MEASURES	POS	O
+:	POS	O
+Fasting	POS	O
+plasma	POS	O
+glucose	POS	O
+and	POS	O
+fasting	POS	O
+serum	POS	O
+insulin	POS	O
+levels	POS	O
+,	POS	O
+insulin	POS	O
+sensitivity	POS	O
+index	POS	O
+,	POS	O
+homeostasis	POS	O
+model	POS	O
+assessment	POS	O
+of	POS	O
+insulin	POS	B-NP
+resistance	POS	I-NP
+,	POS	O
+and	POS	O
+glucose	POS	O
+effectiveness	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+mean	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+SD	POS	O
+duration	POS	O
+of	POS	O
+treatment	POS	O
+with	POS	O
+the	POS	O
+identified	POS	O
+atypical	POS	O
+antipsychotic	POS	O
+agent	POS	O
+was	POS	O
+68	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+28	POS	O
+.	POS	O
+9	POS	O
+months	POS	O
+(	POS	O
+clozapine	POS	O
+)	POS	O
+,	POS	O
+29	POS	O
+.	POS	O
+5	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+17	POS	O
+.	POS	O
+5	POS	O
+months	POS	O
+(	POS	O
+olanzapine	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+40	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+33	POS	O
+.	POS	O
+7	POS	O
+(	POS	O
+risperidone	POS	O
+)	POS	O
+.	POS	O
+Fasting	POS	O
+serum	POS	O
+insulin	POS	O
+concentrations	POS	O
+differed	POS	O
+among	POS	O
+groups	POS	O
+(	POS	O
+F	POS	O
+(	POS	O
+33	POS	O
+)	POS	O
+=	POS	O
+3	POS	O
+.	POS	O
+35	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+047	POS	O
+)	POS	O
+(	POS	O
+clozapine	POS	O
+>	POS	O
+olanzapine	POS	O
+>	POS	O
+risperidone	POS	O
+)	POS	O
+with	POS	O
+significant	POS	O
+differences	POS	O
+between	POS	O
+clozapine	POS	O
+and	POS	O
+risperidone	POS	O
+(	POS	O
+t	POS	O
+(	POS	O
+33	POS	O
+)	POS	O
+=	POS	O
+2	POS	O
+.	POS	O
+32	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+03	POS	O
+)	POS	O
+and	POS	O
+olanzapine	POS	O
+and	POS	O
+risperidone	POS	O
+(	POS	O
+t	POS	O
+(	POS	O
+33	POS	O
+)	POS	O
+=	POS	O
+2	POS	O
+.	POS	O
+15	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+04	POS	O
+)	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+difference	POS	O
+in	POS	O
+insulin	POS	O
+sensitivity	POS	O
+index	POS	O
+among	POS	O
+groups	POS	O
+(	POS	O
+F	POS	O
+(	POS	O
+33	POS	O
+)	POS	O
+=	POS	O
+10	POS	O
+.	POS	O
+66	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+(	POS	O
+clozapine	POS	O
+<	POS	O
+olanzapine	POS	O
+<	POS	O
+risperidone	POS	O
+)	POS	O
+,	POS	O
+with	POS	O
+subjects	POS	O
+who	POS	O
+received	POS	O
+clozapine	POS	O
+and	POS	O
+olanzapine	POS	O
+exhibiting	POS	O
+significant	POS	O
+insulin	POS	B-NP
+resistance	POS	I-NP
+compared	POS	O
+with	POS	O
+subjects	POS	O
+who	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+risperidone	POS	O
+(	POS	O
+clozapine	POS	O
+vs	POS	O
+risperidone	POS	O
+,	POS	O
+t	POS	O
+(	POS	O
+33	POS	O
+)	POS	O
+=	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+29	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+001	POS	O
+;	POS	O
+olanzapine	POS	O
+vs	POS	O
+risperidone	POS	O
+,	POS	O
+t	POS	O
+(	POS	O
+33	POS	O
+)	POS	O
+=	POS	O
+-	POS	O
+3	POS	O
+.	POS	O
+62	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+001	POS	O
+[	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+001	POS	O
+]	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+homeostasis	POS	O
+model	POS	O
+assessment	POS	O
+of	POS	O
+insulin	POS	O
+resistance	POS	O
+also	POS	O
+differed	POS	O
+significantly	POS	O
+among	POS	O
+groups	POS	O
+(	POS	O
+F	POS	O
+(	POS	O
+33	POS	O
+)	POS	O
+=	POS	O
+4	POS	O
+.	POS	O
+92	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+(	POS	O
+clozapine	POS	O
+>	POS	O
+olanzapine	POS	O
+>	POS	O
+risperidone	POS	O
+)	POS	O
+(	POS	O
+clozapine	POS	O
+vs	POS	O
+risperidone	POS	O
+,	POS	O
+t	POS	O
+(	POS	O
+33	POS	O
+)	POS	O
+=	POS	O
+2	POS	O
+.	POS	O
+94	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+006	POS	O
+;	POS	O
+olanzapine	POS	O
+vs	POS	O
+risperidone	POS	O
+,	POS	O
+t	POS	O
+(	POS	O
+33	POS	O
+)	POS	O
+=	POS	O
+2	POS	O
+.	POS	O
+42	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+difference	POS	O
+among	POS	O
+groups	POS	O
+in	POS	O
+glucose	POS	O
+effectiveness	POS	O
+(	POS	O
+F	POS	O
+(	POS	O
+30	POS	O
+)	POS	O
+=	POS	O
+4	POS	O
+.	POS	O
+18	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+(	POS	O
+clozapine	POS	O
+<	POS	O
+olanzapine	POS	O
+<	POS	O
+risperidone	POS	O
+)	POS	O
+with	POS	O
+significant	POS	O
+differences	POS	O
+between	POS	O
+clozapine	POS	O
+and	POS	O
+risperidone	POS	O
+(	POS	O
+t	POS	O
+(	POS	O
+30	POS	O
+)	POS	O
+=	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+59	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+and	POS	O
+olanzapine	POS	O
+and	POS	O
+risperidone	POS	O
+(	POS	O
+t	POS	O
+(	POS	O
+30	POS	O
+)	POS	O
+=	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+34	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+03	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Both	POS	O
+nonobese	POS	O
+clozapine	POS	O
+-	POS	O
+and	POS	O
+olanzapine	POS	O
+-	POS	O
+treated	POS	O
+groups	POS	O
+displayed	POS	O
+significant	POS	O
+insulin	POS	B-NP
+resistance	POS	I-NP
+and	POS	O
+impairment	POS	O
+of	POS	O
+glucose	POS	O
+effectiveness	POS	O
+compared	POS	O
+with	POS	O
+risperidone	POS	O
+-	POS	O
+treated	POS	O
+subjects	POS	O
+.	POS	O
+Patients	POS	O
+taking	POS	O
+clozapine	POS	O
+and	POS	O
+olanzapine	POS	O
+must	POS	O
+be	POS	O
+examined	POS	O
+for	POS	O
+insulin	POS	B-NP
+resistance	POS	I-NP
+and	POS	O
+its	POS	O
+consequences	POS	O
+.	POS	O
+Thoracic	POS	B-NP
+hematomyelia	POS	I-NP
+secondary	POS	O
+to	POS	O
+coumadin	POS	O
+anticoagulant	POS	O
+therapy	POS	O
+:	POS	O
+a	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+thoracic	POS	B-NP
+hematomyelia	POS	I-NP
+secondary	POS	O
+to	POS	O
+anticoagulant	POS	O
+therapy	POS	O
+is	POS	O
+presented	POS	O
+.	POS	O
+Clinical	POS	O
+features	POS	O
+,	POS	O
+similar	POS	O
+to	POS	O
+2	POS	O
+other	POS	O
+previously	POS	O
+reported	POS	O
+cases	POS	O
+,	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+A	POS	O
+high	POS	O
+index	POS	O
+of	POS	O
+suspicion	POS	O
+may	POS	O
+lead	POS	O
+to	POS	O
+a	POS	O
+quick	POS	O
+diagnostic	POS	O
+procedure	POS	O
+and	POS	O
+successful	POS	O
+decompressive	POS	O
+surgery	POS	O
+.	POS	O
+Mania	POS	B-NP
+associated	POS	O
+with	POS	O
+fluoxetine	POS	O
+treatment	POS	O
+in	POS	O
+adolescents	POS	O
+.	POS	O
+Fluoxetine	POS	O
+,	POS	O
+a	POS	O
+selective	POS	O
+serotonin	POS	O
+reuptake	POS	O
+inhibitor	POS	O
+,	POS	O
+is	POS	O
+gaining	POS	O
+increased	POS	O
+acceptance	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+adolescent	POS	B-NP
+depression	POS	I-NP
+.	POS	O
+Generally	POS	O
+safe	POS	O
+and	POS	O
+well	POS	O
+tolerated	POS	O
+by	POS	O
+adults	POS	O
+,	POS	O
+fluoxetine	POS	O
+has	POS	O
+been	POS	O
+reported	POS	O
+to	POS	O
+induce	POS	O
+mania	POS	B-NP
+.	POS	O
+The	POS	O
+cases	POS	O
+of	POS	O
+five	POS	O
+depressed	POS	B-NP
+adolescents	POS	O
+,	POS	O
+14	POS	O
+-	POS	O
+16	POS	O
+years	POS	O
+of	POS	O
+age	POS	O
+,	POS	O
+who	POS	O
+developed	POS	O
+mania	POS	B-NP
+during	POS	O
+pharmacotherapy	POS	O
+with	POS	O
+fluoxetine	POS	O
+,	POS	O
+are	POS	O
+reported	POS	O
+here	POS	O
+.	POS	O
+Apparent	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+mania	POS	B-NP
+or	POS	O
+hypomania	POS	B-NP
+during	POS	O
+fluoxetine	POS	O
+pharmacotherapy	POS	O
+in	POS	O
+this	POS	O
+population	POS	O
+were	POS	O
+the	POS	O
+combination	POS	O
+of	POS	O
+attention	POS	B-NP
+-	POS	I-NP
+deficit	POS	I-NP
+hyperactivity	POS	I-NP
+disorder	POS	I-NP
+and	POS	O
+affective	POS	B-NP
+instability	POS	I-NP
+;	POS	O
+major	POS	B-NP
+depression	POS	I-NP
+with	POS	O
+psychotic	POS	B-NP
+features	POS	O
+;	POS	O
+a	POS	O
+family	POS	O
+history	POS	O
+of	POS	O
+affective	POS	B-NP
+disorder	POS	I-NP
+,	POS	O
+especially	POS	O
+bipolar	POS	B-NP
+disorder	POS	I-NP
+;	POS	O
+and	POS	O
+a	POS	O
+diagnosis	POS	O
+of	POS	O
+bipolar	POS	B-NP
+disorder	POS	I-NP
+.	POS	O
+Further	POS	O
+study	POS	O
+is	POS	O
+needed	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+optimal	POS	O
+dosage	POS	O
+and	POS	O
+to	POS	O
+identify	POS	O
+risk	POS	O
+factors	POS	O
+that	POS	O
+increase	POS	O
+individual	POS	O
+vulnerability	POS	O
+to	POS	O
+fluoxetine	POS	O
+induced	POS	O
+mania	POS	B-NP
+in	POS	O
+adolescents	POS	O
+.	POS	O
+Acute	POS	B-NP
+renal	POS	I-NP
+insufficiency	POS	I-NP
+after	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+melphalan	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+primary	POS	O
+systemic	POS	B-NP
+amyloidosis	POS	I-NP
+during	POS	O
+stem	POS	O
+cell	POS	O
+transplantation	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Patients	POS	O
+with	POS	O
+primary	POS	O
+systemic	POS	B-NP
+amyloidosis	POS	I-NP
+(	POS	O
+AL	POS	O
+)	POS	O
+have	POS	O
+a	POS	O
+poor	POS	O
+prognosis	POS	O
+.	POS	O
+Median	POS	O
+survival	POS	O
+time	POS	O
+from	POS	O
+standard	POS	O
+treatments	POS	O
+is	POS	O
+only	POS	O
+17	POS	O
+months	POS	O
+.	POS	O
+High	POS	O
+-	POS	O
+dose	POS	O
+intravenous	POS	O
+melphalan	POS	O
+followed	POS	O
+by	POS	O
+peripheral	POS	O
+blood	POS	O
+stem	POS	O
+cell	POS	O
+transplant	POS	O
+(	POS	O
+PBSCT	POS	O
+)	POS	O
+appears	POS	O
+to	POS	O
+be	POS	O
+the	POS	O
+most	POS	O
+promising	POS	O
+therapy	POS	O
+,	POS	O
+but	POS	O
+treatment	POS	O
+mortality	POS	O
+can	POS	O
+be	POS	O
+high	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+have	POS	O
+noted	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+insufficiency	POS	I-NP
+immediately	POS	O
+after	POS	O
+melphalan	POS	O
+conditioning	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+was	POS	O
+undertaken	POS	O
+to	POS	O
+further	POS	O
+examine	POS	O
+its	POS	O
+risk	POS	O
+factors	POS	O
+and	POS	O
+impact	POS	O
+on	POS	O
+posttransplant	POS	O
+mortality	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Consecutive	POS	O
+AL	POS	O
+patients	POS	O
+who	POS	O
+underwent	POS	O
+PBSCT	POS	O
+were	POS	O
+studied	POS	O
+retrospectively	POS	O
+.	POS	O
+Acute	POS	B-NP
+renal	POS	I-NP
+insufficiency	POS	I-NP
+(	POS	O
+ARI	POS	B-NP
+)	POS	O
+after	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+melphalan	POS	O
+was	POS	O
+defined	POS	O
+by	POS	O
+a	POS	O
+minimum	POS	O
+increase	POS	O
+of	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+(	POS	O
+44	POS	O
+micromol	POS	O
+/	POS	O
+L	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+serum	POS	O
+creatinine	POS	O
+level	POS	O
+that	POS	O
+is	POS	O
+greater	POS	O
+than	POS	O
+50	POS	O
+%	POS	O
+of	POS	O
+baseline	POS	O
+immediately	POS	O
+after	POS	O
+conditioning	POS	O
+.	POS	O
+Urine	POS	O
+sediment	POS	O
+score	POS	O
+was	POS	O
+the	POS	O
+sum	POS	O
+of	POS	O
+the	POS	O
+individual	POS	O
+types	POS	O
+of	POS	O
+sediment	POS	O
+identified	POS	O
+on	POS	O
+urine	POS	O
+microscopy	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Of	POS	O
+the	POS	O
+80	POS	O
+patients	POS	O
+studied	POS	O
+,	POS	O
+ARI	POS	B-NP
+developed	POS	O
+in	POS	O
+18	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+after	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+melphalan	POS	O
+.	POS	O
+Univariate	POS	O
+analysis	POS	O
+identified	POS	O
+age	POS	O
+,	POS	O
+hypoalbuminemia	POS	B-NP
+,	POS	O
+heavy	POS	O
+proteinuria	POS	B-NP
+,	POS	O
+diuretic	POS	O
+use	POS	O
+,	POS	O
+and	POS	O
+urine	POS	O
+sediment	POS	O
+score	POS	O
+(	POS	O
+>	POS	O
+3	POS	O
+)	POS	O
+as	POS	O
+risk	POS	O
+factors	POS	O
+.	POS	O
+Age	POS	O
+and	POS	O
+urine	POS	O
+sediment	POS	O
+score	POS	O
+remained	POS	O
+independently	POS	O
+significant	POS	O
+risk	POS	O
+factors	POS	O
+in	POS	O
+the	POS	O
+multivariate	POS	O
+analysis	POS	O
+.	POS	O
+Patients	POS	O
+who	POS	O
+had	POS	O
+ARI	POS	B-NP
+after	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+melphalan	POS	O
+underwent	POS	O
+dialysis	POS	O
+more	POS	O
+often	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+007	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+had	POS	O
+a	POS	O
+worse	POS	O
+1	POS	O
+-	POS	O
+year	POS	O
+survival	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+03	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+The	POS	O
+timing	POS	O
+of	POS	O
+renal	POS	B-NP
+injury	POS	I-NP
+strongly	POS	O
+suggests	POS	O
+melphalan	POS	O
+as	POS	O
+the	POS	O
+causative	POS	O
+agent	POS	O
+.	POS	O
+Ongoing	POS	O
+tubular	POS	B-NP
+injury	POS	I-NP
+may	POS	O
+be	POS	O
+a	POS	O
+prerequisite	POS	O
+for	POS	O
+renal	POS	B-NP
+injury	POS	I-NP
+by	POS	O
+melphalan	POS	O
+as	POS	O
+evidenced	POS	O
+by	POS	O
+the	POS	O
+active	POS	O
+urinary	POS	O
+sediment	POS	O
+.	POS	O
+Development	POS	O
+of	POS	O
+ARI	POS	O
+adversely	POS	O
+affected	POS	O
+the	POS	O
+outcome	POS	O
+after	POS	O
+PBSCT	POS	O
+.	POS	O
+Effective	POS	O
+preventive	POS	O
+measures	POS	O
+may	POS	O
+help	POS	O
+decrease	POS	O
+the	POS	O
+treatment	POS	O
+mortality	POS	O
+of	POS	O
+PBSCT	POS	O
+in	POS	O
+AL	POS	O
+patients	POS	O
+.	POS	O
+Focal	POS	B-NP
+cerebral	POS	I-NP
+ischemia	POS	I-NP
+in	POS	O
+rats	POS	O
+:	POS	O
+effect	POS	O
+of	POS	O
+phenylephrine	POS	O
+-	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+during	POS	O
+reperfusion	POS	O
+.	POS	O
+After	POS	O
+180	POS	O
+min	POS	O
+of	POS	O
+temporary	POS	O
+middle	POS	O
+cerebral	POS	B-NP
+artery	POS	I-NP
+occlusion	POS	I-NP
+in	POS	O
+spontaneously	POS	O
+hypertensive	POS	B-NP
+rats	POS	O
+,	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+phenylephrine	POS	O
+-	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+on	POS	O
+ischemic	POS	B-NP
+brain	POS	I-NP
+injury	POS	I-NP
+and	POS	O
+blood	POS	O
+-	POS	O
+brain	POS	O
+barrier	POS	O
+permeability	POS	O
+was	POS	O
+determined	POS	O
+.	POS	O
+Blood	POS	O
+pressure	POS	O
+was	POS	O
+manipulated	POS	O
+by	POS	O
+one	POS	O
+of	POS	O
+the	POS	O
+following	POS	O
+schedules	POS	O
+during	POS	O
+120	POS	O
+min	POS	O
+of	POS	O
+reperfusion	POS	O
+:	POS	O
+Control	POS	O
+,	POS	O
+normotensive	POS	O
+reperfusion	POS	O
+;	POS	O
+90	POS	O
+/	POS	O
+hypertension	POS	B-NP
+(	POS	O
+90	POS	O
+/	POS	O
+HTN	POS	O
+)	POS	O
+,	POS	O
+blood	POS	O
+pressure	POS	O
+was	POS	O
+increased	POS	O
+by	POS	O
+35	POS	O
+mm	POS	O
+Hg	POS	O
+during	POS	O
+the	POS	O
+initial	POS	O
+90	POS	O
+min	POS	O
+of	POS	O
+reperfusion	POS	O
+only	POS	O
+;	POS	O
+15	POS	O
+/	POS	O
+hypertension	POS	B-NP
+(	POS	O
+15	POS	O
+/	POS	O
+HTN	POS	O
+)	POS	O
+,	POS	O
+normotensive	POS	O
+reperfusion	POS	O
+for	POS	O
+30	POS	O
+min	POS	O
+followed	POS	O
+by	POS	O
+15	POS	O
+min	POS	O
+of	POS	O
+hypertension	POS	B-NP
+and	POS	O
+75	POS	O
+min	POS	O
+of	POS	O
+normotension	POS	O
+.	POS	O
+Part	POS	O
+A	POS	O
+,	POS	O
+for	POS	O
+eight	POS	O
+rats	POS	O
+in	POS	O
+each	POS	O
+group	POS	O
+brain	POS	B-NP
+injury	POS	I-NP
+was	POS	O
+evaluated	POS	O
+by	POS	O
+staining	POS	O
+tissue	POS	O
+using	POS	O
+2	POS	O
+,	POS	O
+3	POS	O
+,	POS	O
+5	POS	O
+-	POS	O
+triphenyltetrazolium	POS	O
+chloride	POS	O
+and	POS	O
+edema	POS	B-NP
+was	POS	O
+evaluated	POS	O
+by	POS	O
+microgravimetry	POS	O
+.	POS	O
+Part	POS	O
+B	POS	O
+,	POS	O
+for	POS	O
+eight	POS	O
+different	POS	O
+rats	POS	O
+in	POS	O
+each	POS	O
+group	POS	O
+blood	POS	O
+-	POS	O
+brain	POS	O
+barrier	POS	O
+permeability	POS	O
+was	POS	O
+evaluated	POS	O
+by	POS	O
+measuring	POS	O
+the	POS	O
+amount	POS	O
+and	POS	O
+extent	POS	O
+of	POS	O
+extravasation	POS	O
+of	POS	O
+Evans	POS	O
+Blue	POS	O
+dye	POS	O
+.	POS	O
+Brain	POS	O
+injury	POS	O
+(	POS	O
+percentage	POS	O
+of	POS	O
+the	POS	O
+ischemic	POS	O
+hemisphere	POS	O
+)	POS	O
+was	POS	O
+less	POS	O
+in	POS	O
+the	POS	O
+15	POS	O
+/	POS	O
+HTN	POS	O
+group	POS	O
+(	POS	O
+16	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+,	POS	O
+mean	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+SD	POS	O
+)	POS	O
+versus	POS	O
+the	POS	O
+90	POS	O
+/	POS	O
+HTN	POS	O
+group	POS	O
+(	POS	O
+30	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+)	POS	O
+,	POS	O
+which	POS	O
+was	POS	O
+in	POS	O
+turn	POS	O
+less	POS	O
+than	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+(	POS	O
+42	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+5	POS	O
+)	POS	O
+.	POS	O
+Specific	POS	O
+gravity	POS	O
+was	POS	O
+greater	POS	O
+in	POS	O
+the	POS	O
+15	POS	O
+/	POS	O
+HTN	POS	O
+group	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+043	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+002	POS	O
+)	POS	O
+versus	POS	O
+the	POS	O
+90	POS	O
+/	POS	O
+HTN	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+036	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+003	POS	O
+)	POS	O
+and	POS	O
+control	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+037	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+003	POS	O
+)	POS	O
+groups	POS	O
+.	POS	O
+Evans	POS	O
+Blue	POS	O
+(	POS	O
+mug	POS	O
+g	POS	O
+-	POS	O
+1	POS	O
+of	POS	O
+brain	POS	O
+tissue	POS	O
+)	POS	O
+was	POS	O
+greater	POS	O
+in	POS	O
+the	POS	O
+90	POS	O
+/	POS	O
+HTN	POS	O
+group	POS	O
+(	POS	O
+24	POS	O
+.	POS	O
+4	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+0	POS	O
+)	POS	O
+versus	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+(	POS	O
+12	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+1	POS	O
+)	POS	O
+,	POS	O
+which	POS	O
+was	POS	O
+in	POS	O
+turn	POS	O
+greater	POS	O
+than	POS	O
+the	POS	O
+15	POS	O
+/	POS	O
+HTN	POS	O
+group	POS	O
+(	POS	O
+7	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+3	POS	O
+.	POS	O
+2	POS	O
+)	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+supports	POS	O
+a	POS	O
+hypothesis	POS	O
+that	POS	O
+during	POS	O
+reperfusion	POS	O
+,	POS	O
+a	POS	O
+short	POS	O
+interval	POS	O
+of	POS	O
+hypertension	POS	B-NP
+decreases	POS	O
+brain	POS	B-NP
+injury	POS	I-NP
+and	POS	O
+edema	POS	B-NP
+;	POS	O
+and	POS	O
+that	POS	O
+sustained	POS	O
+hypertension	POS	B-NP
+increases	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+vasogenic	POS	B-NP
+edema	POS	I-NP
+.	POS	O
+People	POS	O
+aged	POS	O
+over	POS	O
+75	POS	O
+in	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+on	POS	O
+warfarin	POS	O
+:	POS	O
+the	POS	O
+rate	POS	O
+of	POS	O
+major	POS	O
+hemorrhage	POS	B-NP
+and	POS	O
+stroke	POS	B-NP
+in	POS	O
+more	POS	O
+than	POS	O
+500	POS	O
+patient	POS	O
+-	POS	O
+years	POS	O
+of	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+To	POS	O
+determine	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+major	POS	O
+hemorrhage	POS	B-NP
+and	POS	O
+stroke	POS	B-NP
+in	POS	O
+people	POS	O
+aged	POS	O
+76	POS	O
+and	POS	O
+older	POS	O
+with	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+on	POS	O
+adjusted	POS	O
+-	POS	O
+dose	POS	O
+warfarin	POS	O
+who	POS	O
+had	POS	O
+been	POS	O
+recently	POS	O
+been	POS	O
+admitted	POS	O
+to	POS	O
+hospital	POS	O
+.	POS	O
+DESIGN	POS	O
+:	POS	O
+A	POS	O
+retrospective	POS	O
+observational	POS	O
+cohort	POS	O
+study	POS	O
+.	POS	O
+SETTING	POS	O
+:	POS	O
+A	POS	O
+major	POS	O
+healthcare	POS	O
+network	POS	O
+involving	POS	O
+four	POS	O
+tertiary	POS	O
+hospitals	POS	O
+.	POS	O
+PARTICIPANTS	POS	O
+:	POS	O
+Two	POS	O
+hundred	POS	O
+thirty	POS	O
+-	POS	O
+five	POS	O
+patients	POS	O
+aged	POS	O
+76	POS	O
+and	POS	O
+older	POS	O
+admitted	POS	O
+to	POS	O
+a	POS	O
+major	POS	O
+healthcare	POS	O
+network	POS	O
+between	POS	O
+July	POS	O
+1	POS	O
+,	POS	O
+2001	POS	O
+,	POS	O
+and	POS	O
+June	POS	O
+30	POS	O
+,	POS	O
+2002	POS	O
+,	POS	O
+with	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+on	POS	O
+warfarin	POS	O
+were	POS	O
+enrolled	POS	O
+.	POS	O
+MEASUREMENTS	POS	O
+:	POS	O
+Information	POS	O
+regarding	POS	O
+major	POS	O
+bleeding	POS	B-NP
+episodes	POS	O
+,	POS	O
+strokes	POS	B-NP
+,	POS	O
+and	POS	O
+warfarin	POS	O
+use	POS	O
+was	POS	O
+obtained	POS	O
+from	POS	O
+patients	POS	O
+,	POS	O
+relatives	POS	O
+,	POS	O
+primary	POS	O
+physicians	POS	O
+,	POS	O
+and	POS	O
+medical	POS	O
+records	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Two	POS	O
+hundred	POS	O
+twenty	POS	O
+-	POS	O
+eight	POS	O
+patients	POS	O
+(	POS	O
+42	POS	O
+%	POS	O
+men	POS	O
+)	POS	O
+with	POS	O
+a	POS	O
+mean	POS	O
+age	POS	O
+of	POS	O
+81	POS	O
+.	POS	O
+1	POS	O
+(	POS	O
+range	POS	O
+76	POS	O
+-	POS	O
+94	POS	O
+)	POS	O
+were	POS	O
+included	POS	O
+in	POS	O
+the	POS	O
+analysis	POS	O
+.	POS	O
+Total	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+on	POS	O
+warfarin	POS	O
+was	POS	O
+530	POS	O
+years	POS	O
+(	POS	O
+mean	POS	O
+28	POS	O
+months	POS	O
+)	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+53	POS	O
+major	POS	O
+hemorrhages	POS	B-NP
+,	POS	O
+for	POS	O
+an	POS	O
+annual	POS	O
+rate	POS	O
+of	POS	O
+10	POS	O
+.	POS	O
+0	POS	O
+%	POS	O
+,	POS	O
+including	POS	O
+24	POS	O
+(	POS	O
+45	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+)	POS	O
+life	POS	O
+-	POS	O
+threatening	POS	O
+and	POS	O
+five	POS	O
+(	POS	O
+9	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+fatal	POS	O
+bleeds	POS	B-NP
+.	POS	O
+The	POS	O
+annual	POS	O
+stroke	POS	B-NP
+rate	POS	O
+after	POS	O
+initiation	POS	O
+of	POS	O
+warfarin	POS	O
+was	POS	O
+2	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+The	POS	O
+rate	POS	O
+of	POS	O
+major	POS	O
+hemorrhage	POS	B-NP
+was	POS	O
+high	POS	O
+in	POS	O
+this	POS	O
+old	POS	O
+,	POS	O
+frail	POS	O
+group	POS	O
+,	POS	O
+but	POS	O
+excluding	POS	O
+fatalities	POS	B-NP
+,	POS	O
+resulted	POS	O
+in	POS	O
+no	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+sequelae	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+stroke	POS	B-NP
+rate	POS	O
+on	POS	O
+warfarin	POS	O
+was	POS	O
+low	POS	O
+,	POS	O
+demonstrating	POS	O
+how	POS	O
+effective	POS	O
+warfarin	POS	O
+treatment	POS	O
+is	POS	O
+.	POS	O
+Safety	POS	O
+of	POS	O
+celecoxib	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+adverse	POS	O
+skin	POS	O
+reactions	POS	O
+to	POS	O
+acetaminophen	POS	O
+(	POS	O
+paracetamol	POS	O
+)	POS	O
+and	POS	O
+nimesulide	POS	O
+associated	POS	O
+or	POS	O
+not	POS	O
+with	POS	O
+common	POS	O
+non	POS	O
+-	POS	O
+steroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Acetaminophen	POS	O
+(	POS	O
+paracetamol	POS	O
+-	POS	O
+-	POS	O
+P	POS	O
+)	POS	O
+and	POS	O
+Nimesulide	POS	O
+(	POS	O
+N	POS	O
+)	POS	O
+are	POS	O
+widely	POS	O
+used	POS	O
+analgesic	POS	O
+-	POS	O
+antipyretic	POS	O
+/	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+.	POS	O
+The	POS	O
+rate	POS	O
+of	POS	O
+adverse	POS	O
+hypersensitivity	POS	B-NP
+reactions	POS	O
+to	POS	O
+these	POS	O
+agents	POS	O
+is	POS	O
+generally	POS	O
+low	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+contrary	POS	O
+non	POS	O
+-	POS	O
+steroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+(	POS	O
+NSAIDs	POS	O
+)	POS	O
+are	POS	O
+commonly	POS	O
+involved	POS	O
+in	POS	O
+such	POS	O
+reactions	POS	O
+.	POS	O
+Celecoxib	POS	O
+(	POS	O
+CE	POS	O
+)	POS	O
+is	POS	O
+a	POS	O
+novel	POS	O
+drug	POS	O
+,	POS	O
+with	POS	O
+high	POS	O
+selectivity	POS	O
+and	POS	O
+affinity	POS	O
+for	POS	O
+COX	POS	O
+-	POS	O
+2	POS	O
+enzyme	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+We	POS	O
+evaluated	POS	O
+the	POS	O
+tolerability	POS	O
+of	POS	O
+CE	POS	O
+in	POS	O
+a	POS	O
+group	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+documented	POS	O
+history	POS	O
+of	POS	O
+adverse	POS	O
+cutaneous	POS	O
+reactions	POS	O
+to	POS	O
+P	POS	O
+and	POS	O
+N	POS	O
+associated	POS	O
+or	POS	O
+not	POS	O
+to	POS	O
+classic	POS	O
+NSAIDs	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+studied	POS	O
+9	POS	O
+patients	POS	O
+with	POS	O
+hypersensitivity	POS	B-NP
+to	POS	O
+P	POS	O
+and	POS	O
+N	POS	O
+with	POS	O
+or	POS	O
+without	POS	O
+associated	POS	O
+reactions	POS	O
+to	POS	O
+classic	POS	O
+NSAIDs	POS	O
+.	POS	O
+The	POS	O
+diagnosis	POS	O
+of	POS	O
+P	POS	O
+and	POS	O
+N	POS	O
+-	POS	O
+induced	POS	O
+skin	POS	O
+reactions	POS	O
+was	POS	O
+based	POS	O
+in	POS	O
+vivo	POS	O
+challenge	POS	O
+.	POS	O
+The	POS	O
+placebo	POS	O
+was	POS	O
+blindly	POS	O
+administered	POS	O
+at	POS	O
+the	POS	O
+beginning	POS	O
+of	POS	O
+each	POS	O
+challenge	POS	O
+.	POS	O
+After	POS	O
+three	POS	O
+days	POS	O
+,	POS	O
+a	POS	O
+cumulative	POS	O
+dosage	POS	O
+of	POS	O
+200	POS	O
+mg	POS	O
+of	POS	O
+CE	POS	O
+in	POS	O
+refracted	POS	O
+doses	POS	O
+were	POS	O
+given	POS	O
+.	POS	O
+After	POS	O
+2	POS	O
+-	POS	O
+3	POS	O
+days	POS	O
+,	POS	O
+a	POS	O
+single	POS	O
+dose	POS	O
+of	POS	O
+200	POS	O
+mg	POS	O
+was	POS	O
+administered	POS	O
+.	POS	O
+All	POS	O
+patients	POS	O
+were	POS	O
+observed	POS	O
+for	POS	O
+6	POS	O
+hours	POS	O
+after	POS	O
+each	POS	O
+challenge	POS	O
+,	POS	O
+and	POS	O
+controlled	POS	O
+again	POS	O
+after	POS	O
+24	POS	O
+hours	POS	O
+to	POS	O
+exclude	POS	O
+delayed	POS	O
+reactions	POS	O
+.	POS	O
+The	POS	O
+challenge	POS	O
+was	POS	O
+considered	POS	O
+positive	POS	O
+if	POS	O
+one	POS	O
+or	POS	O
+more	POS	O
+of	POS	O
+the	POS	O
+following	POS	O
+appeared	POS	O
+:	POS	O
+erythema	POS	B-NP
+,	POS	O
+rush	POS	B-NP
+or	POS	O
+urticaria	POS	B-NP
+-	POS	O
+angioedema	POS	B-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+No	POS	O
+reaction	POS	O
+was	POS	O
+observed	POS	O
+with	POS	O
+placebo	POS	O
+and	POS	O
+eight	POS	O
+patients	POS	O
+(	POS	O
+88	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+)	POS	O
+tolerated	POS	O
+CE	POS	O
+.	POS	O
+Only	POS	O
+one	POS	O
+patient	POS	O
+developed	POS	O
+a	POS	O
+moderate	POS	O
+angioedema	POS	B-NP
+of	POS	I-NP
+the	POS	I-NP
+lips	POS	I-NP
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Only	POS	O
+one	POS	O
+hypersensitivity	POS	B-NP
+reaction	POS	O
+to	POS	O
+CE	POS	O
+was	POS	O
+documented	POS	O
+among	POS	O
+9	POS	O
+P	POS	O
+and	POS	O
+N	POS	O
+-	POS	O
+highly	POS	O
+NSAIDs	POS	O
+intolerant	POS	O
+patients	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+we	POS	O
+conclude	POS	O
+that	POS	O
+CE	POS	O
+is	POS	O
+a	POS	O
+reasonably	POS	O
+safe	POS	O
+alternative	POS	O
+to	POS	O
+be	POS	O
+used	POS	O
+in	POS	O
+subjects	POS	O
+who	POS	O
+do	POS	O
+not	POS	O
+tolerate	POS	O
+P	POS	O
+and	POS	O
+N	POS	O
+.	POS	O
+Case	POS	O
+-	POS	O
+control	POS	O
+study	POS	O
+of	POS	O
+regular	POS	O
+analgesic	POS	O
+and	POS	O
+nonsteroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+use	POS	O
+and	POS	O
+end	POS	O
+-	POS	O
+stage	POS	O
+renal	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Studies	POS	O
+on	POS	O
+the	POS	O
+association	POS	O
+between	POS	O
+the	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+use	POS	O
+of	POS	O
+aspirin	POS	O
+and	POS	O
+other	POS	O
+analgesic	POS	O
+and	POS	O
+nonsteroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+(	POS	O
+NSAIDs	POS	O
+)	POS	O
+and	POS	O
+end	POS	O
+-	POS	O
+stage	POS	O
+renal	POS	B-NP
+disease	POS	I-NP
+(	POS	O
+ESRD	POS	B-NP
+)	POS	O
+have	POS	O
+given	POS	O
+conflicting	POS	O
+results	POS	O
+.	POS	O
+In	POS	O
+order	POS	O
+to	POS	O
+examine	POS	O
+this	POS	O
+association	POS	O
+,	POS	O
+a	POS	O
+case	POS	O
+-	POS	O
+control	POS	O
+study	POS	O
+with	POS	O
+incident	POS	O
+cases	POS	O
+of	POS	O
+ESRD	POS	B-NP
+was	POS	O
+carried	POS	O
+out	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+The	POS	O
+cases	POS	O
+were	POS	O
+all	POS	O
+patients	POS	O
+entering	POS	O
+the	POS	O
+local	POS	O
+dialysis	POS	O
+program	POS	O
+because	POS	O
+of	POS	O
+ESRD	POS	B-NP
+in	POS	O
+the	POS	O
+study	POS	O
+area	POS	O
+between	POS	O
+June	POS	O
+1	POS	O
+,	POS	O
+1995	POS	O
+and	POS	O
+November	POS	O
+30	POS	O
+,	POS	O
+1997	POS	O
+.	POS	O
+They	POS	O
+were	POS	O
+classified	POS	O
+according	POS	O
+to	POS	O
+the	POS	O
+underlying	POS	O
+disease	POS	O
+,	POS	O
+which	POS	O
+had	POS	O
+presumably	POS	O
+led	POS	O
+them	POS	O
+to	POS	O
+ESRD	POS	B-NP
+.	POS	O
+Controls	POS	O
+were	POS	O
+patients	POS	O
+admitted	POS	O
+to	POS	O
+the	POS	O
+same	POS	O
+hospitals	POS	O
+from	POS	O
+where	POS	O
+the	POS	O
+cases	POS	O
+arose	POS	O
+,	POS	O
+also	POS	O
+matched	POS	O
+by	POS	O
+age	POS	O
+and	POS	O
+sex	POS	O
+.	POS	O
+Odds	POS	O
+ratios	POS	O
+were	POS	O
+calculated	POS	O
+using	POS	O
+a	POS	O
+conditional	POS	O
+logistic	POS	O
+model	POS	O
+,	POS	O
+including	POS	O
+potential	POS	O
+confounding	POS	O
+factors	POS	O
+,	POS	O
+both	POS	O
+for	POS	O
+the	POS	O
+whole	POS	O
+study	POS	O
+population	POS	O
+and	POS	O
+for	POS	O
+the	POS	O
+various	POS	O
+underlying	POS	O
+diseases	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Five	POS	O
+hundred	POS	O
+and	POS	O
+eighty	POS	O
+-	POS	O
+three	POS	O
+cases	POS	O
+and	POS	O
+1190	POS	O
+controls	POS	O
+were	POS	O
+included	POS	O
+in	POS	O
+the	POS	O
+analysis	POS	O
+.	POS	O
+Long	POS	O
+-	POS	O
+term	POS	O
+use	POS	O
+of	POS	O
+any	POS	O
+analgesic	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+overall	POS	O
+odds	POS	O
+ratio	POS	O
+of	POS	O
+1	POS	O
+.	POS	O
+22	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+89	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+66	POS	O
+)	POS	O
+.	POS	O
+For	POS	O
+specific	POS	O
+groups	POS	O
+of	POS	O
+drugs	POS	O
+,	POS	O
+the	POS	O
+risks	POS	O
+were	POS	O
+1	POS	O
+.	POS	O
+56	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+05	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+30	POS	O
+)	POS	O
+for	POS	O
+aspirin	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+03	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+60	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+76	POS	O
+)	POS	O
+for	POS	O
+pyrazolones	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+80	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+39	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+63	POS	O
+)	POS	O
+for	POS	O
+paracetamol	POS	O
+,	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+94	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+57	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+56	POS	O
+)	POS	O
+for	POS	O
+nonaspirin	POS	O
+NSAIDs	POS	O
+.	POS	O
+The	POS	O
+risk	POS	O
+of	POS	O
+ESRD	POS	B-NP
+associated	POS	O
+with	POS	O
+aspirin	POS	O
+was	POS	O
+related	POS	O
+to	POS	O
+the	POS	O
+cumulated	POS	O
+dose	POS	O
+and	POS	O
+duration	POS	O
+of	POS	O
+use	POS	O
+,	POS	O
+and	POS	O
+it	POS	O
+was	POS	O
+particularly	POS	O
+high	POS	O
+among	POS	O
+the	POS	O
+subset	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+vascular	POS	B-NP
+nephropathy	POS	I-NP
+as	POS	O
+underlying	POS	O
+disease	POS	O
+[	POS	O
+2	POS	O
+.	POS	O
+35	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+17	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+72	POS	O
+)	POS	O
+]	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Our	POS	O
+data	POS	O
+indicate	POS	O
+that	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+use	POS	O
+of	POS	O
+nonaspirin	POS	O
+analgesic	POS	O
+drugs	POS	O
+and	POS	O
+NSAIDs	POS	O
+is	POS	O
+not	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+increased	POS	O
+risk	POS	O
+of	POS	O
+ESRD	POS	B-NP
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+chronic	POS	O
+use	POS	O
+of	POS	O
+aspirin	POS	O
+may	POS	O
+increase	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+ESRD	POS	B-NP
+.	POS	O
+Two	POS	O
+cases	POS	O
+of	POS	O
+amisulpride	POS	O
+overdose	POS	B-NP
+:	POS	O
+a	POS	O
+cause	POS	O
+for	POS	O
+prolonged	POS	O
+QT	POS	B-NP
+syndrome	POS	I-NP
+.	POS	O
+Two	POS	O
+cases	POS	O
+of	POS	O
+deliberate	POS	B-NP
+self	POS	I-NP
+-	POS	I-NP
+poisoning	POS	I-NP
+with	POS	O
+5	POS	O
+g	POS	O
+and	POS	O
+3	POS	O
+.	POS	O
+6	POS	O
+g	POS	O
+of	POS	O
+amisulpride	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+are	POS	O
+reported	POS	O
+.	POS	O
+In	POS	O
+both	POS	O
+cases	POS	O
+,	POS	O
+QT	POS	B-NP
+prolongation	POS	I-NP
+and	POS	O
+hypocalcaemia	POS	B-NP
+were	POS	O
+noted	POS	O
+.	POS	O
+The	POS	O
+QT	POS	O
+prolongation	POS	O
+appeared	POS	O
+to	POS	O
+respond	POS	O
+to	POS	O
+administration	POS	O
+of	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+calcium	POS	O
+gluconate	POS	O
+.	POS	O
+Growth	POS	O
+-	POS	O
+associated	POS	O
+protein	POS	O
+43	POS	O
+expression	POS	O
+in	POS	O
+hippocampal	POS	O
+molecular	POS	O
+layer	POS	O
+of	POS	O
+chronic	POS	O
+epileptic	POS	B-NP
+rats	POS	O
+treated	POS	O
+with	POS	O
+cycloheximide	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+GAP43	POS	O
+has	POS	O
+been	POS	O
+thought	POS	O
+to	POS	O
+be	POS	O
+linked	POS	O
+with	POS	O
+mossy	POS	O
+fiber	POS	O
+sprouting	POS	O
+(	POS	O
+MFS	POS	B-NP
+)	POS	O
+in	POS	O
+various	POS	O
+experimental	POS	O
+models	POS	O
+of	POS	O
+epilepsy	POS	B-NP
+.	POS	O
+To	POS	O
+investigate	POS	O
+how	POS	O
+GAP43	POS	O
+expression	POS	O
+(	POS	O
+GAP43	POS	O
+-	POS	O
+ir	POS	O
+)	POS	O
+correlates	POS	O
+with	POS	O
+MFS	POS	B-NP
+,	POS	O
+we	POS	O
+assessed	POS	O
+the	POS	O
+intensity	POS	O
+(	POS	O
+densitometry	POS	O
+)	POS	O
+and	POS	O
+extension	POS	O
+(	POS	O
+width	POS	O
+)	POS	O
+of	POS	O
+GAP43	POS	O
+-	POS	O
+ir	POS	O
+in	POS	O
+the	POS	O
+inner	POS	O
+molecular	POS	O
+layer	POS	O
+of	POS	O
+the	POS	O
+dentate	POS	O
+gyrus	POS	O
+(	POS	O
+IML	POS	O
+)	POS	O
+of	POS	O
+rats	POS	O
+subject	POS	O
+to	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+induced	POS	O
+by	POS	O
+pilocarpine	POS	O
+(	POS	O
+Pilo	POS	O
+)	POS	O
+,	POS	O
+previously	POS	O
+injected	POS	O
+or	POS	O
+not	POS	O
+with	POS	O
+cycloheximide	POS	O
+(	POS	O
+CHX	POS	O
+)	POS	O
+,	POS	O
+which	POS	O
+has	POS	O
+been	POS	O
+shown	POS	O
+to	POS	O
+inhibit	POS	O
+MFS	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+CHX	POS	O
+was	POS	O
+injected	POS	O
+before	POS	O
+the	POS	O
+Pilo	POS	O
+injection	POS	O
+in	POS	O
+adult	POS	O
+Wistar	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+Pilo	POS	O
+group	POS	O
+was	POS	O
+injected	POS	O
+with	POS	O
+the	POS	O
+same	POS	O
+drugs	POS	O
+,	POS	O
+except	POS	O
+for	POS	O
+CHX	POS	O
+.	POS	O
+Animals	POS	O
+were	POS	O
+killed	POS	O
+between	POS	O
+30	POS	O
+and	POS	O
+60	POS	O
+days	POS	O
+later	POS	O
+,	POS	O
+and	POS	O
+brain	POS	O
+sections	POS	O
+were	POS	O
+processed	POS	O
+for	POS	O
+GAP43	POS	O
+immunohistochemistry	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Densitometry	POS	O
+showed	POS	O
+no	POS	O
+significant	POS	O
+difference	POS	O
+regarding	POS	O
+GAP43	POS	O
+-	POS	O
+ir	POS	O
+in	POS	O
+the	POS	O
+IML	POS	O
+between	POS	O
+Pilo	POS	O
+,	POS	O
+CHX	POS	O
++	POS	O
+Pilo	POS	O
+,	POS	O
+and	POS	O
+control	POS	O
+groups	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+results	POS	O
+of	POS	O
+the	POS	O
+width	POS	O
+of	POS	O
+the	POS	O
+GAP43	POS	O
+-	POS	O
+ir	POS	O
+band	POS	O
+in	POS	O
+the	POS	O
+IML	POS	O
+showed	POS	O
+that	POS	O
+CHX	POS	O
++	POS	O
+Pilo	POS	O
+and	POS	O
+control	POS	O
+animals	POS	O
+had	POS	O
+a	POS	O
+significantly	POS	O
+larger	POS	O
+band	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+03	POS	O
+)	POS	O
+as	POS	O
+compared	POS	O
+with	POS	O
+that	POS	O
+in	POS	O
+the	POS	O
+Pilo	POS	O
+group	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Our	POS	O
+current	POS	O
+finding	POS	O
+that	POS	O
+animals	POS	O
+in	POS	O
+the	POS	O
+CHX	POS	O
++	POS	O
+Pilo	POS	O
+group	POS	O
+have	POS	O
+a	POS	O
+GAP43	POS	O
+-	POS	O
+ir	POS	O
+band	POS	O
+in	POS	O
+the	POS	O
+IML	POS	O
+,	POS	O
+similar	POS	O
+to	POS	O
+that	POS	O
+of	POS	O
+controls	POS	O
+,	POS	O
+reinforces	POS	O
+prior	POS	O
+data	POS	O
+on	POS	O
+the	POS	O
+blockade	POS	O
+of	POS	O
+MFS	POS	B-NP
+in	POS	O
+these	POS	O
+animals	POS	O
+.	POS	O
+The	POS	O
+change	POS	O
+in	POS	O
+GAP43	POS	O
+-	POS	O
+ir	POS	O
+present	POS	O
+in	POS	O
+Pilo	POS	O
+-	POS	O
+treated	POS	O
+animals	POS	O
+was	POS	O
+a	POS	O
+thinning	POS	O
+of	POS	O
+the	POS	O
+band	POS	O
+to	POS	O
+a	POS	O
+very	POS	O
+narrow	POS	O
+layer	POS	O
+just	POS	O
+above	POS	O
+the	POS	O
+granule	POS	O
+cell	POS	O
+layer	POS	O
+that	POS	O
+is	POS	O
+likely	POS	O
+to	POS	O
+be	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+loss	POS	O
+of	POS	O
+hilar	POS	O
+cell	POS	O
+projections	POS	O
+that	POS	O
+express	POS	O
+GAP	POS	O
+-	POS	O
+43	POS	O
+.	POS	O
+Nicotine	POS	O
+antagonizes	POS	O
+caffeine	POS	O
+-	POS	O
+but	POS	O
+not	POS	O
+pentylenetetrazole	POS	O
+-	POS	O
+induced	POS	O
+anxiogenic	POS	O
+effect	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+RATIONALE	POS	O
+:	POS	O
+Nicotine	POS	O
+and	POS	O
+caffeine	POS	O
+are	POS	O
+widely	POS	O
+consumed	POS	O
+licit	POS	O
+psychoactive	POS	O
+drugs	POS	O
+worldwide	POS	O
+.	POS	O
+Epidemiological	POS	O
+studies	POS	O
+showed	POS	O
+that	POS	O
+they	POS	O
+were	POS	O
+generally	POS	O
+used	POS	O
+concurrently	POS	O
+.	POS	O
+Although	POS	O
+some	POS	O
+studies	POS	O
+in	POS	O
+experimental	POS	O
+animals	POS	O
+indicate	POS	O
+clear	POS	O
+pharmacological	POS	O
+interactions	POS	O
+between	POS	O
+them	POS	O
+,	POS	O
+no	POS	O
+studies	POS	O
+have	POS	O
+shown	POS	O
+a	POS	O
+specific	POS	O
+interaction	POS	O
+on	POS	O
+anxiety	POS	B-NP
+responses	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+investigates	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+nicotine	POS	O
+on	POS	O
+anxiety	POS	B-NP
+induced	POS	O
+by	POS	O
+caffeine	POS	O
+and	POS	O
+another	POS	O
+anxiogenic	POS	O
+drug	POS	O
+,	POS	O
+pentylenetetrazole	POS	O
+,	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+The	POS	O
+elevated	POS	O
+plus	POS	O
+-	POS	O
+maze	POS	O
+(	POS	O
+EPM	POS	O
+)	POS	O
+test	POS	O
+was	POS	O
+used	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+drugs	POS	O
+on	POS	O
+anxiety	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Adult	POS	O
+male	POS	O
+Swiss	POS	O
+Webster	POS	O
+mice	POS	O
+(	POS	O
+25	POS	O
+-	POS	O
+32	POS	O
+g	POS	O
+)	POS	O
+were	POS	O
+given	POS	O
+nicotine	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+25	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+s	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+)	POS	O
+or	POS	O
+saline	POS	O
+10	POS	O
+min	POS	O
+before	POS	O
+caffeine	POS	O
+(	POS	O
+70	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+or	POS	O
+pentylenetetrazole	POS	O
+(	POS	O
+15	POS	O
+and	POS	O
+30	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+injections	POS	O
+.	POS	O
+After	POS	O
+15	POS	O
+min	POS	O
+,	POS	O
+mice	POS	O
+were	POS	O
+evaluated	POS	O
+for	POS	O
+their	POS	O
+open	POS	O
+-	POS	O
+and	POS	O
+closed	POS	O
+-	POS	O
+arm	POS	O
+time	POS	O
+and	POS	O
+entries	POS	O
+on	POS	O
+the	POS	O
+EPM	POS	O
+for	POS	O
+a	POS	O
+10	POS	O
+-	POS	O
+min	POS	O
+session	POS	O
+.	POS	O
+Locomotor	POS	O
+activity	POS	O
+was	POS	O
+recorded	POS	O
+for	POS	O
+individual	POS	O
+groups	POS	O
+by	POS	O
+using	POS	O
+the	POS	O
+same	POS	O
+treatment	POS	O
+protocol	POS	O
+with	POS	O
+the	POS	O
+EPM	POS	O
+test	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Nicotine	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+25	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+itself	POS	O
+did	POS	O
+not	POS	O
+produce	POS	O
+any	POS	O
+significant	POS	O
+effect	POS	O
+in	POS	O
+the	POS	O
+EPM	POS	O
+test	POS	O
+,	POS	O
+whereas	POS	O
+caffeine	POS	O
+(	POS	O
+70	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+and	POS	O
+pentylenetetrazole	POS	O
+(	POS	O
+30	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+produced	POS	O
+an	POS	O
+anxiogenic	POS	O
+effect	POS	O
+,	POS	O
+apparent	POS	O
+with	POS	O
+decreases	POS	O
+in	POS	O
+open	POS	O
+-	POS	O
+arm	POS	O
+time	POS	O
+and	POS	O
+entry	POS	O
+.	POS	O
+Nicotine	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+25	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+pretreatment	POS	O
+blocked	POS	O
+the	POS	O
+caffeine	POS	O
+-	POS	O
+but	POS	O
+not	POS	O
+pentylenetetrazole	POS	O
+-	POS	O
+induced	POS	O
+anxiety	POS	B-NP
+.	POS	O
+Administration	POS	O
+of	POS	O
+each	POS	O
+drug	POS	O
+and	POS	O
+their	POS	O
+combinations	POS	O
+did	POS	O
+not	POS	O
+produce	POS	O
+any	POS	O
+effect	POS	O
+on	POS	O
+locomotor	POS	O
+activity	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Our	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+the	POS	O
+antagonistic	POS	O
+effect	POS	O
+of	POS	O
+nicotine	POS	O
+on	POS	O
+caffeine	POS	O
+-	POS	O
+induced	POS	O
+anxiety	POS	B-NP
+is	POS	O
+specific	POS	O
+to	POS	O
+caffeine	POS	O
+,	POS	O
+instead	POS	O
+of	POS	O
+a	POS	O
+non	POS	O
+-	POS	O
+specific	POS	O
+anxiolytic	POS	O
+effect	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+it	POS	O
+may	POS	O
+extend	POS	O
+the	POS	O
+current	POS	O
+findings	POS	O
+on	POS	O
+the	POS	O
+interaction	POS	O
+between	POS	O
+nicotine	POS	O
+and	POS	O
+caffeine	POS	O
+.	POS	O
+Long	POS	O
+term	POS	O
+hormone	POS	O
+therapy	POS	O
+for	POS	O
+perimenopausal	POS	O
+and	POS	O
+postmenopausal	POS	O
+women	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Hormone	POS	O
+therapy	POS	O
+(	POS	O
+HT	POS	O
+)	POS	O
+is	POS	O
+widely	POS	O
+used	POS	O
+for	POS	O
+controlling	POS	O
+menopausal	POS	O
+symptoms	POS	O
+.	POS	O
+It	POS	O
+has	POS	O
+also	POS	O
+been	POS	O
+used	POS	O
+for	POS	O
+the	POS	O
+management	POS	O
+and	POS	O
+prevention	POS	O
+of	POS	O
+cardiovascular	POS	B-NP
+disease	POS	I-NP
+,	POS	O
+osteoporosis	POS	B-NP
+and	POS	O
+dementia	POS	B-NP
+in	POS	O
+older	POS	O
+women	POS	O
+but	POS	O
+the	POS	O
+evidence	POS	O
+supporting	POS	O
+its	POS	O
+use	POS	O
+for	POS	O
+these	POS	O
+indications	POS	O
+is	POS	O
+largely	POS	O
+observational	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+To	POS	O
+assess	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+HT	POS	O
+on	POS	O
+mortality	POS	O
+,	POS	O
+heart	POS	B-NP
+disease	POS	I-NP
+,	POS	O
+venous	POS	B-NP
+thromboembolism	POS	I-NP
+,	POS	O
+stroke	POS	B-NP
+,	POS	O
+transient	POS	B-NP
+ischaemic	POS	I-NP
+attacks	POS	I-NP
+,	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+,	POS	O
+colorectal	POS	B-NP
+cancer	POS	I-NP
+,	POS	O
+ovarian	POS	B-NP
+cancer	POS	I-NP
+,	POS	O
+endometrial	POS	B-NP
+cancer	POS	I-NP
+,	POS	O
+gallbladder	POS	B-NP
+disease	POS	I-NP
+,	POS	O
+cognitive	POS	B-NP
+function	POS	I-NP
+,	POS	O
+dementia	POS	B-NP
+,	POS	O
+fractures	POS	B-NP
+and	POS	O
+quality	POS	O
+of	POS	O
+life	POS	O
+.	POS	O
+SEARCH	POS	O
+STRATEGY	POS	O
+:	POS	O
+We	POS	O
+searched	POS	O
+the	POS	O
+following	POS	O
+databases	POS	O
+up	POS	O
+to	POS	O
+November	POS	O
+2004	POS	O
+:	POS	O
+the	POS	O
+Cochrane	POS	O
+Menstrual	POS	O
+Disorders	POS	O
+and	POS	O
+Subfertility	POS	O
+Group	POS	O
+Trials	POS	O
+Register	POS	O
+,	POS	O
+Cochrane	POS	O
+Central	POS	O
+Register	POS	O
+of	POS	O
+Controlled	POS	O
+Trials	POS	O
+(	POS	O
+CENTRAL	POS	O
+)	POS	O
+,	POS	O
+MEDLINE	POS	O
+,	POS	O
+EMBASE	POS	O
+,	POS	O
+Biological	POS	O
+Abstracts	POS	O
+.	POS	O
+Relevant	POS	O
+non	POS	O
+-	POS	O
+indexed	POS	O
+journals	POS	O
+and	POS	O
+conference	POS	O
+abstracts	POS	O
+were	POS	O
+also	POS	O
+searched	POS	O
+.	POS	O
+SELECTION	POS	O
+CRITERIA	POS	O
+:	POS	O
+Randomised	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+trials	POS	O
+of	POS	O
+HT	POS	O
+(	POS	O
+oestrogens	POS	O
+with	POS	O
+or	POS	O
+without	POS	O
+progestogens	POS	O
+)	POS	O
+versus	POS	O
+placebo	POS	O
+,	POS	O
+taken	POS	O
+for	POS	O
+at	POS	O
+least	POS	O
+one	POS	O
+year	POS	O
+by	POS	O
+perimenopausal	POS	O
+or	POS	O
+postmenopausal	POS	O
+women	POS	O
+.	POS	O
+DATA	POS	O
+COLLECTION	POS	O
+AND	POS	O
+ANALYSIS	POS	O
+:	POS	O
+Fifteen	POS	O
+RCTs	POS	O
+were	POS	O
+included	POS	O
+.	POS	O
+Trials	POS	O
+were	POS	O
+assessed	POS	O
+for	POS	O
+quality	POS	O
+and	POS	O
+two	POS	O
+review	POS	O
+authors	POS	O
+extracted	POS	O
+data	POS	O
+independently	POS	O
+.	POS	O
+They	POS	O
+calculated	POS	O
+risk	POS	O
+ratios	POS	O
+for	POS	O
+dichotomous	POS	O
+outcomes	POS	O
+and	POS	O
+weighted	POS	O
+mean	POS	O
+differences	POS	O
+for	POS	O
+continuous	POS	O
+outcomes	POS	O
+.	POS	O
+Clinical	POS	O
+heterogeneity	POS	O
+precluded	POS	O
+meta	POS	O
+-	POS	O
+analysis	POS	O
+for	POS	O
+most	POS	O
+outcomes	POS	O
+.	POS	O
+MAIN	POS	O
+RESULTS	POS	O
+:	POS	O
+All	POS	O
+the	POS	O
+statistically	POS	O
+significant	POS	O
+results	POS	O
+were	POS	O
+derived	POS	O
+from	POS	O
+the	POS	O
+two	POS	O
+biggest	POS	O
+trials	POS	O
+.	POS	O
+In	POS	O
+relatively	POS	O
+healthy	POS	O
+women	POS	O
+,	POS	O
+combined	POS	O
+continuous	POS	O
+HT	POS	O
+significantly	POS	O
+increased	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+venous	POS	B-NP
+thromboembolism	POS	I-NP
+or	POS	O
+coronary	POS	B-NP
+event	POS	I-NP
+(	POS	O
+after	POS	O
+one	POS	O
+year	POS	O
+'	POS	O
+s	POS	O
+use	POS	O
+)	POS	O
+,	POS	O
+stroke	POS	B-NP
+(	POS	O
+after	POS	O
+3	POS	O
+years	POS	O
+)	POS	O
+,	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+(	POS	O
+after	POS	O
+5	POS	O
+years	POS	O
+)	POS	O
+and	POS	O
+gallbladder	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+Long	POS	O
+-	POS	O
+term	POS	O
+oestrogen	POS	O
+-	POS	O
+only	POS	O
+HT	POS	O
+also	POS	O
+significantly	POS	O
+increased	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+stroke	POS	B-NP
+and	POS	O
+gallbladder	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+Overall	POS	O
+,	POS	O
+the	POS	O
+only	POS	O
+statistically	POS	O
+significant	POS	O
+benefits	POS	O
+of	POS	O
+HT	POS	O
+were	POS	O
+a	POS	O
+decreased	POS	O
+incidence	POS	O
+of	POS	O
+fractures	POS	B-NP
+and	POS	O
+colon	POS	B-NP
+cancer	POS	I-NP
+with	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+use	POS	O
+.	POS	O
+Among	POS	O
+relatively	POS	O
+healthy	POS	O
+women	POS	O
+over	POS	O
+65	POS	O
+years	POS	O
+taking	POS	O
+continuous	POS	O
+combined	POS	O
+HT	POS	O
+,	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+statistically	POS	O
+significant	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+dementia	POS	B-NP
+.	POS	O
+Among	POS	O
+women	POS	O
+with	POS	O
+cardiovascular	POS	B-NP
+disease	POS	I-NP
+,	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+use	POS	O
+of	POS	O
+combined	POS	O
+continuous	POS	O
+HT	POS	O
+significantly	POS	O
+increased	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+venous	POS	B-NP
+thromboembolism	POS	I-NP
+.	POS	O
+No	POS	O
+trials	POS	O
+focussed	POS	O
+specifically	POS	O
+on	POS	O
+younger	POS	O
+women	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+one	POS	O
+trial	POS	O
+analysed	POS	O
+subgroups	POS	O
+of	POS	O
+2839	POS	O
+relatively	POS	O
+healthy	POS	O
+50	POS	O
+to	POS	O
+59	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+women	POS	O
+taking	POS	O
+combined	POS	O
+continuous	POS	O
+HT	POS	O
+and	POS	O
+1637	POS	O
+taking	POS	O
+oestrogen	POS	O
+-	POS	O
+only	POS	O
+HT	POS	O
+,	POS	O
+versus	POS	O
+similar	POS	O
+-	POS	O
+sized	POS	O
+placebo	POS	O
+groups	POS	O
+.	POS	O
+The	POS	O
+only	POS	O
+significantly	POS	O
+increased	POS	O
+risk	POS	O
+reported	POS	O
+was	POS	O
+for	POS	O
+venous	POS	B-NP
+thromboembolism	POS	I-NP
+in	POS	O
+women	POS	O
+taking	POS	O
+combined	POS	O
+continuous	POS	O
+HT	POS	O
+;	POS	O
+their	POS	O
+absolute	POS	O
+risk	POS	O
+remained	POS	O
+very	POS	O
+low	POS	O
+.	POS	O
+AUTHORS	POS	O
+'	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+HT	POS	O
+is	POS	O
+not	POS	O
+indicated	POS	O
+for	POS	O
+the	POS	O
+routine	POS	O
+management	POS	O
+of	POS	O
+chronic	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+We	POS	O
+need	POS	O
+more	POS	O
+evidence	POS	O
+on	POS	O
+the	POS	O
+safety	POS	O
+of	POS	O
+HT	POS	O
+for	POS	O
+menopausal	POS	O
+symptom	POS	O
+control	POS	O
+,	POS	O
+though	POS	O
+short	POS	O
+-	POS	O
+term	POS	O
+use	POS	O
+appears	POS	O
+to	POS	O
+be	POS	O
+relatively	POS	O
+safe	POS	O
+for	POS	O
+healthy	POS	O
+younger	POS	O
+women	POS	O
+.	POS	O
+Drug	POS	O
+-	POS	O
+induced	POS	O
+liver	POS	B-NP
+injury	POS	I-NP
+:	POS	O
+an	POS	O
+analysis	POS	O
+of	POS	O
+461	POS	O
+incidences	POS	O
+submitted	POS	O
+to	POS	O
+the	POS	O
+Spanish	POS	O
+registry	POS	O
+over	POS	O
+a	POS	O
+10	POS	O
+-	POS	O
+year	POS	O
+period	POS	O
+.	POS	O
+BACKGROUND	POS	O
+&	POS	O
+AIMS	POS	O
+:	POS	O
+Progress	POS	O
+in	POS	O
+the	POS	O
+understanding	POS	O
+of	POS	O
+susceptibility	POS	O
+factors	POS	O
+to	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+liver	POS	B-NP
+injury	POS	I-NP
+(	POS	O
+DILI	POS	B-NP
+)	POS	O
+and	POS	O
+outcome	POS	O
+predictability	POS	O
+are	POS	O
+hampered	POS	O
+by	POS	O
+the	POS	O
+lack	POS	O
+of	POS	O
+systematic	POS	O
+programs	POS	O
+to	POS	O
+detect	POS	O
+bona	POS	O
+fide	POS	O
+cases	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+A	POS	O
+cooperative	POS	O
+network	POS	O
+was	POS	O
+created	POS	O
+in	POS	O
+1994	POS	O
+in	POS	O
+Spain	POS	O
+to	POS	O
+identify	POS	O
+all	POS	O
+suspicions	POS	O
+of	POS	O
+DILI	POS	B-NP
+following	POS	O
+a	POS	O
+prospective	POS	O
+structured	POS	O
+report	POS	O
+form	POS	O
+.	POS	O
+The	POS	O
+liver	POS	B-NP
+damage	POS	I-NP
+was	POS	O
+characterized	POS	O
+according	POS	O
+to	POS	O
+hepatocellular	POS	B-NP
+,	POS	O
+cholestatic	POS	B-NP
+,	POS	O
+and	POS	O
+mixed	POS	O
+laboratory	POS	O
+criteria	POS	O
+and	POS	O
+to	POS	O
+histologic	POS	O
+criteria	POS	O
+when	POS	O
+available	POS	O
+.	POS	O
+Further	POS	O
+evaluation	POS	O
+of	POS	O
+causality	POS	O
+assessment	POS	O
+was	POS	O
+centrally	POS	O
+performed	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Since	POS	O
+April	POS	O
+1994	POS	O
+to	POS	O
+August	POS	O
+2004	POS	O
+,	POS	O
+461	POS	O
+out	POS	O
+of	POS	O
+570	POS	O
+submitted	POS	O
+cases	POS	O
+,	POS	O
+involving	POS	O
+505	POS	O
+drugs	POS	O
+,	POS	O
+were	POS	O
+deemed	POS	O
+to	POS	O
+be	POS	O
+related	POS	O
+to	POS	O
+DILI	POS	B-NP
+.	POS	O
+The	POS	O
+antiinfective	POS	O
+group	POS	O
+of	POS	O
+drugs	POS	O
+was	POS	O
+the	POS	O
+more	POS	O
+frequently	POS	O
+incriminated	POS	O
+,	POS	O
+amoxicillin	POS	O
+-	POS	O
+clavulanate	POS	O
+accounting	POS	O
+for	POS	O
+the	POS	O
+12	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+whole	POS	O
+series	POS	O
+.	POS	O
+The	POS	O
+hepatocellular	POS	O
+pattern	POS	O
+of	POS	O
+damage	POS	O
+was	POS	O
+the	POS	O
+most	POS	O
+common	POS	O
+(	POS	O
+58	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+was	POS	O
+inversely	POS	O
+correlated	POS	O
+with	POS	O
+age	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+0001	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+had	POS	O
+the	POS	O
+worst	POS	O
+outcome	POS	O
+(	POS	O
+Cox	POS	O
+regression	POS	O
+,	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+034	POS	O
+)	POS	O
+.	POS	O
+Indeed	POS	O
+,	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+liver	POS	O
+transplantation	POS	O
+and	POS	O
+death	POS	O
+in	POS	O
+this	POS	O
+group	POS	O
+was	POS	O
+11	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+if	POS	O
+patients	POS	O
+had	POS	O
+jaundice	POS	B-NP
+at	POS	O
+presentation	POS	O
+,	POS	O
+whereas	POS	O
+the	POS	O
+corresponding	POS	O
+figure	POS	O
+was	POS	O
+3	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+in	POS	O
+nonjaundiced	POS	O
+patients	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+04	POS	O
+)	POS	O
+.	POS	O
+Factors	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+fulminant	POS	B-NP
+hepatic	POS	I-NP
+failure	POS	I-NP
+were	POS	O
+female	POS	O
+sex	POS	O
+(	POS	O
+OR	POS	O
+=	POS	O
+25	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+:	POS	O
+4	POS	O
+.	POS	O
+1	POS	O
+-	POS	O
+151	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+0001	POS	O
+)	POS	O
+,	POS	O
+hepatocellular	POS	B-NP
+damage	POS	I-NP
+(	POS	O
+OR	POS	O
+=	POS	O
+7	POS	O
+.	POS	O
+9	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+:	POS	O
+1	POS	O
+.	POS	O
+6	POS	O
+-	POS	O
+37	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+009	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+higher	POS	O
+baseline	POS	O
+plasma	POS	O
+bilirubin	POS	O
+value	POS	O
+(	POS	O
+OR	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+15	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+:	POS	O
+1	POS	O
+.	POS	O
+09	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+22	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+0001	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Patients	POS	O
+with	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+hepatocellular	POS	B-NP
+jaundice	POS	I-NP
+have	POS	O
+11	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+chance	POS	O
+of	POS	O
+progressing	POS	O
+to	POS	O
+death	POS	O
+or	POS	O
+transplantation	POS	O
+.	POS	O
+Amoxicillin	POS	O
+-	POS	O
+clavulanate	POS	O
+stands	POS	O
+out	POS	O
+as	POS	O
+the	POS	O
+most	POS	O
+common	POS	O
+drug	POS	O
+related	POS	O
+to	POS	O
+DILI	POS	B-NP
+.	POS	O
+Morphological	POS	O
+evaluation	POS	O
+of	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+d	POS	O
+-	POS	O
+ribose	POS	O
+on	POS	O
+adriamycin	POS	O
+-	POS	O
+evoked	POS	O
+cardiotoxicity	POS	B-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+influence	POS	O
+of	POS	O
+d	POS	O
+-	POS	O
+ribose	POS	O
+on	POS	O
+adriamycin	POS	O
+-	POS	O
+induced	POS	O
+myocardiopathy	POS	B-NP
+in	POS	O
+rats	POS	O
+was	POS	O
+studied	POS	O
+.	POS	O
+Adriamycin	POS	O
+in	POS	O
+the	POS	O
+cumulative	POS	O
+dose	POS	O
+of	POS	O
+25	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+evoked	POS	O
+fully	POS	O
+developed	POS	O
+cardiac	POS	B-NP
+toxicity	POS	I-NP
+.	POS	O
+D	POS	O
+-	POS	O
+ribose	POS	O
+in	POS	O
+the	POS	O
+multiple	POS	O
+doses	POS	O
+of	POS	O
+200	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+did	POS	O
+not	POS	O
+influence	POS	O
+ADR	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+In	POS	O
+vivo	POS	O
+evidences	POS	O
+suggesting	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+oxidative	POS	O
+stress	POS	O
+in	POS	O
+pathogenesis	POS	O
+of	POS	O
+vancomycin	POS	O
+-	POS	O
+induced	POS	O
+nephrotoxicity	POS	B-NP
+:	POS	O
+protection	POS	O
+by	POS	O
+erdosteine	POS	O
+.	POS	O
+The	POS	O
+aims	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+were	POS	O
+to	POS	O
+examine	POS	O
+vancomycin	POS	O
+(	POS	O
+VCM	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+oxidative	POS	O
+stress	POS	O
+that	POS	O
+promotes	POS	O
+production	POS	O
+of	POS	O
+reactive	POS	O
+oxygen	POS	O
+species	POS	O
+(	POS	O
+ROS	POS	O
+)	POS	O
+and	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+erdosteine	POS	O
+,	POS	O
+an	POS	O
+expectorant	POS	O
+agent	POS	O
+,	POS	O
+which	POS	O
+has	POS	O
+also	POS	O
+antioxidant	POS	O
+properties	POS	O
+,	POS	O
+on	POS	O
+kidney	POS	O
+tissue	POS	O
+against	POS	O
+the	POS	O
+possible	POS	O
+VCM	POS	O
+-	POS	O
+induced	POS	O
+renal	POS	B-NP
+impairment	POS	I-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+Rats	POS	O
+were	POS	O
+divided	POS	O
+into	POS	O
+three	POS	O
+groups	POS	O
+:	POS	O
+sham	POS	O
+,	POS	O
+VCM	POS	O
+and	POS	O
+VCM	POS	O
+plus	POS	O
+erdosteine	POS	O
+.	POS	O
+VCM	POS	O
+was	POS	O
+administrated	POS	O
+intraperitoneally	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+with	POS	O
+200mgkg	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+twice	POS	O
+daily	POS	O
+for	POS	O
+7	POS	O
+days	POS	O
+.	POS	O
+Erdosteine	POS	O
+was	POS	O
+administered	POS	O
+orally	POS	O
+.	POS	O
+VCM	POS	O
+administration	POS	O
+to	POS	O
+control	POS	O
+rats	POS	O
+significantly	POS	O
+increased	POS	O
+renal	POS	O
+malondialdehyde	POS	O
+(	POS	O
+MDA	POS	O
+)	POS	O
+and	POS	O
+urinary	POS	O
+N	POS	O
+-	POS	O
+acetyl	POS	O
+-	POS	O
+beta	POS	O
+-	POS	O
+d	POS	O
+-	POS	O
+glucosaminidase	POS	O
+(	POS	O
+NAG	POS	O
+,	POS	O
+a	POS	O
+marker	POS	O
+of	POS	O
+renal	POS	B-NP
+tubular	POS	I-NP
+injury	POS	I-NP
+)	POS	O
+excretion	POS	O
+but	POS	O
+decreased	POS	O
+superoxide	POS	O
+dismutase	POS	O
+(	POS	O
+SOD	POS	O
+)	POS	O
+and	POS	O
+catalase	POS	O
+(	POS	O
+CAT	POS	O
+)	POS	O
+activities	POS	O
+.	POS	O
+Erdosteine	POS	O
+administration	POS	O
+with	POS	O
+VCM	POS	O
+injections	POS	O
+caused	POS	O
+significantly	POS	O
+decreased	POS	O
+renal	POS	O
+MDA	POS	O
+and	POS	O
+urinary	POS	O
+NAG	POS	O
+excretion	POS	O
+,	POS	O
+and	POS	O
+increased	POS	O
+SOD	POS	O
+activity	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+CAT	POS	O
+activity	POS	O
+in	POS	O
+renal	POS	O
+tissue	POS	O
+when	POS	O
+compared	POS	O
+with	POS	O
+VCM	POS	O
+alone	POS	O
+.	POS	O
+Erdosteine	POS	O
+showed	POS	O
+histopathological	POS	O
+protection	POS	O
+against	POS	O
+VCM	POS	O
+-	POS	O
+induced	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+There	POS	O
+were	POS	O
+a	POS	O
+significant	POS	O
+dilatation	POS	B-NP
+of	POS	I-NP
+tubular	POS	I-NP
+lumens	POS	I-NP
+,	POS	O
+extensive	POS	O
+epithelial	POS	O
+cell	POS	O
+vacuolization	POS	O
+,	POS	O
+atrophy	POS	B-NP
+,	POS	O
+desquamation	POS	B-NP
+,	POS	O
+and	POS	O
+necrosis	POS	B-NP
+in	POS	O
+VCM	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+more	POS	O
+than	POS	O
+those	POS	O
+of	POS	O
+the	POS	O
+control	POS	O
+and	POS	O
+the	POS	O
+erdosteine	POS	O
+groups	POS	O
+.	POS	O
+Erdosteine	POS	O
+caused	POS	O
+a	POS	O
+marked	POS	O
+reduction	POS	O
+in	POS	O
+the	POS	O
+extent	POS	O
+of	POS	O
+tubular	POS	B-NP
+damage	POS	I-NP
+.	POS	O
+It	POS	O
+is	POS	O
+concluded	POS	O
+that	POS	O
+oxidative	POS	O
+tubular	POS	O
+damage	POS	O
+plays	POS	O
+an	POS	O
+important	POS	O
+role	POS	O
+in	POS	O
+the	POS	O
+VCM	POS	O
+-	POS	O
+induced	POS	O
+nephrotoxicity	POS	B-NP
+and	POS	O
+the	POS	O
+modulation	POS	O
+of	POS	O
+oxidative	POS	O
+stress	POS	O
+with	POS	O
+erdosteine	POS	O
+reduces	POS	O
+the	POS	O
+VCM	POS	O
+-	POS	O
+induced	POS	O
+kidney	POS	O
+damage	POS	O
+both	POS	O
+at	POS	O
+the	POS	O
+biochemical	POS	O
+and	POS	O
+histological	POS	O
+levels	POS	O
+.	POS	O
+Gemfibrozil	POS	O
+-	POS	O
+lovastatin	POS	O
+therapy	POS	O
+for	POS	O
+primary	POS	O
+hyperlipoproteinemias	POS	B-NP
+.	POS	O
+The	POS	O
+specific	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+retrospective	POS	O
+,	POS	O
+observational	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+assess	POS	O
+safety	POS	O
+and	POS	O
+efficacy	POS	O
+of	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+(	POS	O
+21	POS	O
+months	POS	O
+/	POS	O
+patient	POS	O
+)	POS	O
+,	POS	O
+open	POS	O
+-	POS	O
+label	POS	O
+,	POS	O
+gemfibrozil	POS	O
+-	POS	O
+lovastatin	POS	O
+treatment	POS	O
+in	POS	O
+80	POS	O
+patients	POS	O
+with	POS	O
+primary	POS	O
+mixed	POS	O
+hyperlipidemia	POS	B-NP
+(	POS	O
+68	POS	O
+%	POS	O
+of	POS	O
+whom	POS	O
+had	POS	O
+atherosclerotic	POS	B-NP
+vascular	POS	I-NP
+disease	POS	I-NP
+)	POS	O
+.	POS	O
+Because	POS	O
+ideal	POS	O
+lipid	POS	O
+targets	POS	O
+were	POS	O
+not	POS	O
+reached	POS	O
+(	POS	O
+low	POS	O
+-	POS	O
+density	POS	O
+lipoprotein	POS	O
+(	POS	O
+LDL	POS	O
+)	POS	O
+cholesterol	POS	O
+less	POS	O
+than	POS	O
+130	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+,	POS	O
+high	POS	O
+-	POS	O
+density	POS	O
+lipoprotein	POS	O
+(	POS	O
+HDL	POS	O
+)	POS	O
+cholesterol	POS	O
+greater	POS	O
+than	POS	O
+35	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+,	POS	O
+or	POS	O
+total	POS	O
+cholesterol	POS	O
+/	POS	O
+HDL	POS	O
+cholesterol	POS	O
+less	POS	O
+than	POS	O
+4	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+)	POS	O
+with	POS	O
+diet	POS	O
+plus	POS	O
+a	POS	O
+single	POS	O
+drug	POS	O
+,	POS	O
+gemfibrozil	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+g	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+-	POS	O
+lovastatin	POS	O
+(	POS	O
+primarily	POS	O
+20	POS	O
+or	POS	O
+40	POS	O
+mg	POS	O
+)	POS	O
+treatment	POS	O
+was	POS	O
+given	POS	O
+.	POS	O
+Follow	POS	O
+-	POS	O
+up	POS	O
+visits	POS	O
+were	POS	O
+scheduled	POS	O
+with	POS	O
+2	POS	O
+-	POS	O
+drug	POS	O
+therapy	POS	O
+every	POS	O
+6	POS	O
+to	POS	O
+8	POS	O
+weeks	POS	O
+,	POS	O
+an	POS	O
+average	POS	O
+of	POS	O
+10	POS	O
+.	POS	O
+3	POS	O
+visits	POS	O
+per	POS	O
+patient	POS	O
+,	POS	O
+with	POS	O
+741	POS	O
+batteries	POS	O
+of	POS	O
+6	POS	O
+liver	POS	O
+function	POS	O
+tests	POS	O
+and	POS	O
+714	POS	O
+creatine	POS	O
+phosphokinase	POS	O
+levels	POS	O
+measured	POS	O
+.	POS	O
+Only	POS	O
+1	POS	O
+of	POS	O
+the	POS	O
+4	POS	O
+,	POS	O
+446	POS	O
+liver	POS	O
+function	POS	O
+tests	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+gamma	POS	O
+glutamyl	POS	O
+transferase	POS	O
+,	POS	O
+was	POS	O
+greater	POS	O
+than	POS	O
+or	POS	O
+equal	POS	O
+to	POS	O
+3	POS	O
+times	POS	O
+the	POS	O
+upper	POS	O
+normal	POS	O
+limit	POS	O
+.	POS	O
+Of	POS	O
+the	POS	O
+714	POS	O
+creatine	POS	O
+phosphokinase	POS	O
+levels	POS	O
+,	POS	O
+9	POS	O
+%	POS	O
+were	POS	O
+high	POS	O
+;	POS	O
+only	POS	O
+1	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+)	POS	O
+was	POS	O
+greater	POS	O
+than	POS	O
+or	POS	O
+equal	POS	O
+to	POS	O
+3	POS	O
+times	POS	O
+the	POS	O
+upper	POS	O
+normal	POS	O
+limit	POS	O
+.	POS	O
+With	POS	O
+2	POS	O
+-	POS	O
+drug	POS	O
+therapy	POS	O
+,	POS	O
+mean	POS	O
+total	POS	O
+cholesterol	POS	O
+decreased	POS	O
+22	POS	O
+%	POS	O
+from	POS	O
+255	POS	O
+to	POS	O
+200	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+,	POS	O
+triglyceride	POS	O
+levels	POS	O
+decreased	POS	O
+35	POS	O
+%	POS	O
+from	POS	O
+236	POS	O
+to	POS	O
+154	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+,	POS	O
+LDL	POS	O
+cholesterol	POS	O
+decreased	POS	O
+26	POS	O
+%	POS	O
+from	POS	O
+176	POS	O
+to	POS	O
+131	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+total	POS	O
+cholesterol	POS	O
+/	POS	O
+HDL	POS	O
+cholesterol	POS	O
+ratio	POS	O
+decreased	POS	O
+24	POS	O
+%	POS	O
+from	POS	O
+7	POS	O
+.	POS	O
+1	POS	O
+to	POS	O
+5	POS	O
+.	POS	O
+4	POS	O
+,	POS	O
+all	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+or	POS	O
+equal	POS	O
+to	POS	O
+0	POS	O
+.	POS	O
+0001	POS	O
+.	POS	O
+Myositis	POS	B-NP
+,	POS	O
+attributable	POS	O
+to	POS	O
+the	POS	O
+drug	POS	O
+combination	POS	O
+and	POS	O
+symptomatic	POS	O
+enough	POS	O
+to	POS	O
+discontinue	POS	O
+it	POS	O
+,	POS	O
+occurred	POS	O
+in	POS	O
+3	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+,	POS	O
+and	POS	O
+in	POS	O
+1	POS	O
+%	POS	O
+with	POS	O
+concurrent	POS	O
+high	POS	O
+creatine	POS	O
+phosphokinase	POS	O
+(	POS	O
+769	POS	O
+U	POS	O
+/	POS	O
+liter	POS	O
+)	POS	O
+;	POS	O
+no	POS	O
+patients	POS	O
+had	POS	O
+rhabdomyolysis	POS	B-NP
+or	POS	O
+myoglobinuria	POS	B-NP
+.	POS	O
+(	POS	O
+ABSTRACT	POS	O
+TRUNCATED	POS	O
+AT	POS	O
+250	POS	O
+WORDS	POS	O
+)	POS	O
+Does	POS	O
+domperidone	POS	O
+potentiate	POS	O
+mirtazapine	POS	O
+-	POS	O
+associated	POS	O
+restless	POS	B-NP
+legs	POS	I-NP
+syndrome	POS	I-NP
+?	POS	O
+There	POS	O
+is	POS	O
+now	POS	O
+evidence	POS	O
+to	POS	O
+suggest	POS	O
+a	POS	O
+central	POS	O
+role	POS	O
+for	POS	O
+the	POS	O
+dopaminergic	POS	O
+system	POS	O
+in	POS	O
+restless	POS	B-NP
+legs	POS	I-NP
+syndrome	POS	I-NP
+(	POS	O
+RLS	POS	B-NP
+)	POS	O
+.	POS	O
+For	POS	O
+example	POS	O
+,	POS	O
+the	POS	O
+symptoms	POS	O
+of	POS	O
+RLS	POS	B-NP
+can	POS	O
+be	POS	O
+dramatically	POS	O
+improved	POS	O
+by	POS	O
+levodopa	POS	O
+and	POS	O
+dopamine	POS	O
+agonists	POS	O
+,	POS	O
+whereas	POS	O
+central	POS	O
+dopamine	POS	O
+D2	POS	O
+receptor	POS	O
+antagonists	POS	O
+can	POS	O
+induce	POS	O
+or	POS	O
+aggravate	POS	O
+RLS	POS	B-NP
+symptoms	POS	O
+.	POS	O
+To	POS	O
+our	POS	O
+knowledge	POS	O
+,	POS	O
+there	POS	O
+is	POS	O
+no	POS	O
+previous	POS	O
+report	POS	O
+regarding	POS	O
+whether	POS	O
+domperidone	POS	O
+,	POS	O
+a	POS	O
+peripheral	POS	O
+dopamine	POS	O
+D2	POS	O
+receptor	POS	O
+antagonist	POS	O
+,	POS	O
+can	POS	O
+also	POS	O
+induce	POS	O
+or	POS	O
+aggravate	POS	O
+symptoms	POS	O
+of	POS	O
+RLS	POS	B-NP
+.	POS	O
+Mirtazapine	POS	O
+,	POS	O
+the	POS	O
+first	POS	O
+noradrenergic	POS	O
+and	POS	O
+specific	POS	O
+serotonergic	POS	O
+antidepressant	POS	O
+(	POS	O
+NaSSA	POS	O
+)	POS	O
+,	POS	O
+has	POS	O
+been	POS	O
+associated	POS	O
+with	POS	O
+RLS	POS	B-NP
+in	POS	O
+several	POS	O
+recent	POS	O
+publications	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+report	POS	O
+here	POS	O
+a	POS	O
+depressed	POS	B-NP
+patient	POS	O
+comorbid	POS	O
+with	POS	O
+postprandial	POS	B-NP
+dyspepsia	POS	I-NP
+who	POS	O
+developed	POS	O
+RLS	POS	B-NP
+after	POS	O
+mirtazapine	POS	O
+had	POS	O
+been	POS	O
+added	POS	O
+to	POS	O
+his	POS	O
+domperidone	POS	O
+therapy	POS	O
+.	POS	O
+Our	POS	O
+patient	POS	O
+started	POS	O
+to	POS	O
+have	POS	O
+symptoms	POS	O
+of	POS	O
+RLS	POS	B-NP
+only	POS	O
+after	POS	O
+he	POS	O
+had	POS	O
+been	POS	O
+treated	POS	O
+with	POS	O
+mirtazapine	POS	O
+,	POS	O
+and	POS	O
+his	POS	O
+RLS	POS	B-NP
+symptoms	POS	O
+resolved	POS	O
+completely	POS	O
+upon	POS	O
+discontinuation	POS	O
+of	POS	O
+his	POS	O
+mirtazapine	POS	O
+.	POS	O
+Such	POS	O
+a	POS	O
+temporal	POS	O
+relationship	POS	O
+between	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+mirtazapine	POS	O
+and	POS	O
+the	POS	O
+symptoms	POS	O
+of	POS	O
+RLS	POS	B-NP
+in	POS	O
+our	POS	O
+patient	POS	O
+did	POS	O
+not	POS	O
+support	POS	O
+a	POS	O
+potentiating	POS	O
+effect	POS	O
+of	POS	O
+domperione	POS	O
+on	POS	O
+mirtazapine	POS	O
+-	POS	O
+associated	POS	O
+RLS	POS	B-NP
+.	POS	O
+However	POS	O
+,	POS	O
+physicians	POS	O
+should	POS	O
+be	POS	O
+aware	POS	O
+of	POS	O
+the	POS	O
+possibility	POS	O
+that	POS	O
+mirtazapine	POS	O
+can	POS	O
+be	POS	O
+associated	POS	O
+with	POS	O
+RLS	POS	B-NP
+in	POS	O
+some	POS	O
+individuals	POS	O
+,	POS	O
+especially	POS	O
+those	POS	O
+receiving	POS	O
+concomitant	POS	O
+dopamine	POS	O
+D2	POS	O
+receptor	POS	O
+antagonists	POS	O
+.	POS	O
+Antiandrogenic	POS	O
+therapy	POS	O
+can	POS	O
+cause	POS	O
+coronary	POS	B-NP
+arterial	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+AIM	POS	O
+:	POS	O
+To	POS	O
+study	POS	O
+the	POS	O
+change	POS	O
+of	POS	O
+lipid	POS	O
+metabolism	POS	O
+by	POS	O
+antiandrogen	POS	O
+therapy	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+prostate	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+MATERIALS	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+studied	POS	O
+with	POS	O
+a	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+years	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+the	POS	O
+changes	POS	O
+in	POS	O
+plasma	POS	O
+cholesterols	POS	O
+(	POS	O
+C	POS	O
+)	POS	O
+,	POS	O
+triglycerides	POS	O
+(	POS	O
+TG	POS	O
+)	POS	O
+,	POS	O
+lipoproteins	POS	O
+(	POS	O
+LP	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+apolipoproteins	POS	O
+(	POS	O
+Apo	POS	O
+)	POS	O
+B	POS	O
+-	POS	O
+100	POS	O
+,	POS	O
+A	POS	O
+-	POS	O
+I	POS	O
+,	POS	O
+and	POS	O
+A	POS	O
+-	POS	O
+II	POS	O
+pro	POS	O
+fi	POS	O
+les	POS	O
+in	POS	O
+24	POS	O
+patients	POS	O
+of	POS	O
+mean	POS	O
+age	POS	O
+60	POS	O
+years	POS	O
+with	POS	O
+low	POS	O
+risk	POS	O
+prostate	POS	B-NP
+cancer	POS	I-NP
+(	POS	O
+stage	POS	O
+:	POS	O
+T1cN0M0	POS	O
+,	POS	O
+Gleason	POS	O
+score	POS	O
+:	POS	O
+2	POS	O
+-	POS	O
+5	POS	O
+)	POS	O
+during	POS	O
+treatment	POS	O
+with	POS	O
+cyproterone	POS	O
+acetate	POS	O
+(	POS	O
+CPA	POS	O
+)	POS	O
+without	POS	O
+surgical	POS	O
+management	POS	O
+or	POS	O
+radiation	POS	O
+therapy	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Significant	POS	O
+decreases	POS	O
+of	POS	O
+HDL	POS	O
+-	POS	O
+C	POS	O
+,	POS	O
+Apo	POS	O
+A	POS	O
+-	POS	O
+I	POS	O
+and	POS	O
+Apo	POS	O
+A	POS	O
+-	POS	O
+II	POS	O
+and	POS	O
+an	POS	O
+increase	POS	O
+of	POS	O
+triglyceride	POS	O
+levels	POS	O
+in	POS	O
+VLDL	POS	O
+were	POS	O
+induced	POS	O
+by	POS	O
+CPA	POS	O
+.	POS	O
+After	POS	O
+a	POS	O
+period	POS	O
+of	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+years	POS	O
+on	POS	O
+CPA	POS	O
+treatment	POS	O
+,	POS	O
+four	POS	O
+patients	POS	O
+out	POS	O
+of	POS	O
+twenty	POS	O
+-	POS	O
+four	POS	O
+were	POS	O
+found	POS	O
+to	POS	O
+be	POS	O
+affected	POS	O
+by	POS	O
+coronary	POS	B-NP
+heart	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Ischaemic	POS	B-NP
+coronary	POS	I-NP
+arteriosclerosis	POS	I-NP
+with	POS	O
+an	POS	O
+incidence	POS	O
+rate	POS	O
+of	POS	O
+16	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+as	POS	O
+caused	POS	O
+by	POS	O
+prolonged	POS	O
+CPA	POS	O
+therapy	POS	O
+is	POS	O
+mediated	POS	O
+through	POS	O
+changes	POS	O
+in	POS	O
+HDL	POS	O
+cholesterol	POS	O
+,	POS	O
+Apo	POS	O
+A	POS	O
+-	POS	O
+I	POS	O
+and	POS	O
+Apo	POS	O
+A	POS	O
+-	POS	O
+II	POS	O
+pro	POS	O
+fi	POS	O
+les	POS	O
+,	POS	O
+other	POS	O
+than	POS	O
+the	POS	O
+well	POS	O
+-	POS	O
+known	POS	O
+hyperglyceridemic	POS	O
+effect	POS	O
+caused	POS	O
+by	POS	O
+estrogen	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+Fluorouracil	POS	O
+cardiotoxicity	POS	B-NP
+induced	POS	O
+by	POS	O
+alpha	POS	O
+-	POS	O
+fluoro	POS	O
+-	POS	O
+beta	POS	O
+-	POS	O
+alanine	POS	O
+.	POS	O
+Cardiotoxicity	POS	B-NP
+is	POS	O
+a	POS	O
+rare	POS	O
+complication	POS	O
+occurring	POS	O
+during	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+(	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+)	POS	O
+treatment	POS	O
+for	POS	O
+malignancies	POS	B-NP
+.	POS	O
+We	POS	O
+herein	POS	O
+report	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+70	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+with	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+,	POS	O
+in	POS	O
+whom	POS	O
+a	POS	O
+high	POS	O
+serum	POS	O
+level	POS	O
+of	POS	O
+alpha	POS	O
+-	POS	O
+fluoro	POS	O
+-	POS	O
+beta	POS	O
+-	POS	O
+alanine	POS	O
+(	POS	O
+FBAL	POS	O
+)	POS	O
+was	POS	O
+observed	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+,	POS	O
+who	POS	O
+had	POS	O
+unresectable	POS	O
+colon	POS	B-NP
+cancer	POS	I-NP
+metastases	POS	O
+to	POS	O
+the	POS	O
+liver	POS	O
+and	POS	O
+lung	POS	O
+,	POS	O
+was	POS	O
+referred	POS	O
+to	POS	O
+us	POS	O
+for	POS	O
+chemotherapy	POS	O
+from	POS	O
+an	POS	O
+affiliated	POS	O
+hospital	POS	O
+;	POS	O
+he	POS	O
+had	POS	O
+no	POS	O
+cardiac	POS	B-NP
+history	POS	I-NP
+.	POS	O
+After	POS	O
+admission	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+received	POS	O
+a	POS	O
+continuous	POS	O
+intravenous	POS	O
+infusion	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+(	POS	O
+1000	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+,	POS	O
+during	POS	O
+which	POS	O
+precordial	POS	B-NP
+pain	POS	I-NP
+with	POS	O
+right	POS	B-NP
+bundle	POS	I-NP
+branch	POS	I-NP
+block	POS	I-NP
+occurred	POS	O
+concomitantly	POS	O
+with	POS	O
+a	POS	O
+high	POS	O
+serum	POS	O
+FBAL	POS	O
+concentration	POS	O
+of	POS	O
+1955	POS	O
+ng	POS	O
+/	POS	O
+ml	POS	O
+.	POS	O
+Both	POS	O
+the	POS	O
+precordial	POS	B-NP
+pain	POS	I-NP
+and	POS	O
+the	POS	O
+electrocardiographic	POS	O
+changes	POS	O
+disappeared	POS	O
+spontaneously	POS	O
+after	POS	O
+the	POS	O
+discontinuation	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+.	POS	O
+As	POS	O
+the	POS	O
+precordial	POS	B-NP
+pain	POS	I-NP
+in	POS	O
+this	POS	O
+patient	POS	O
+was	POS	O
+considered	POS	O
+to	POS	O
+have	POS	O
+been	POS	O
+due	POS	O
+to	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+,	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+was	POS	O
+abandoned	POS	O
+.	POS	O
+Instead	POS	O
+,	POS	O
+oral	POS	O
+administration	POS	O
+of	POS	O
+S	POS	O
+-	POS	O
+1	POS	O
+(	POS	O
+a	POS	O
+derivative	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+)	POS	O
+,	POS	O
+at	POS	O
+200	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+twice	POS	O
+a	POS	O
+week	POS	O
+,	POS	O
+was	POS	O
+instituted	POS	O
+,	POS	O
+because	POS	O
+S	POS	O
+-	POS	O
+1	POS	O
+has	POS	O
+a	POS	O
+strong	POS	O
+inhibitory	POS	O
+effect	POS	O
+on	POS	O
+dihydropyrimidine	POS	O
+dehydrogenase	POS	O
+,	POS	O
+which	POS	O
+catalyzes	POS	O
+the	POS	O
+degradative	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+into	POS	O
+FBAL	POS	O
+.	POS	O
+The	POS	O
+serum	POS	O
+FBAL	POS	O
+concentration	POS	O
+subsequently	POS	O
+decreased	POS	O
+to	POS	O
+352	POS	O
+ng	POS	O
+/	POS	O
+ml	POS	O
+,	POS	O
+the	POS	O
+same	POS	O
+as	POS	O
+the	POS	O
+value	POS	O
+measured	POS	O
+on	POS	O
+the	POS	O
+first	POS	O
+day	POS	O
+of	POS	O
+S	POS	O
+-	POS	O
+1	POS	O
+administration	POS	O
+.	POS	O
+Thereafter	POS	O
+,	POS	O
+no	POS	O
+cardiac	POS	O
+symptoms	POS	O
+were	POS	O
+observed	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+achieved	POS	O
+a	POS	O
+partial	POS	O
+response	POS	O
+6	POS	O
+months	POS	O
+after	POS	O
+the	POS	O
+initiation	POS	O
+of	POS	O
+the	POS	O
+S	POS	O
+-	POS	O
+1	POS	O
+treatment	POS	O
+.	POS	O
+The	POS	O
+experience	POS	O
+of	POS	O
+this	POS	O
+case	POS	O
+,	POS	O
+together	POS	O
+with	POS	O
+a	POS	O
+review	POS	O
+of	POS	O
+the	POS	O
+literature	POS	O
+,	POS	O
+suggests	POS	O
+that	POS	O
+FBAL	POS	O
+is	POS	O
+related	POS	O
+to	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+S	POS	O
+-	POS	O
+1	POS	O
+may	POS	O
+be	POS	O
+administered	POS	O
+safely	POS	O
+to	POS	O
+patients	POS	O
+with	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+Hepatocellular	POS	B-NP
+carcinoma	POS	I-NP
+in	POS	O
+Fanconi	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+anemia	POS	I-NP
+treated	POS	O
+with	POS	O
+androgen	POS	O
+and	POS	O
+corticosteroid	POS	O
+.	POS	O
+The	POS	O
+case	POS	O
+of	POS	O
+an	POS	O
+11	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+boy	POS	O
+is	POS	O
+reported	POS	O
+who	POS	O
+was	POS	O
+known	POS	O
+to	POS	O
+have	POS	O
+Fanconi	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+anemia	POS	I-NP
+for	POS	O
+3	POS	O
+years	POS	O
+and	POS	O
+was	POS	O
+treated	POS	O
+with	POS	O
+androgens	POS	O
+,	POS	O
+corticosteroids	POS	O
+and	POS	O
+transfusions	POS	O
+.	POS	O
+Two	POS	O
+weeks	POS	O
+before	POS	O
+his	POS	O
+death	POS	O
+he	POS	O
+was	POS	O
+readmitted	POS	O
+because	POS	O
+of	POS	O
+aplastic	POS	B-NP
+crisis	POS	I-NP
+with	POS	O
+septicemia	POS	B-NP
+and	POS	O
+marked	POS	O
+abnormalities	POS	O
+in	POS	O
+liver	POS	O
+function	POS	O
+and	POS	O
+died	POS	O
+of	POS	O
+hemorrhagic	POS	B-NP
+bronchopneumonia	POS	I-NP
+.	POS	O
+At	POS	O
+autopsy	POS	O
+peliosis	POS	B-NP
+and	POS	O
+multiple	POS	B-NP
+hepatic	POS	I-NP
+tumors	POS	I-NP
+were	POS	O
+found	POS	O
+which	POS	O
+histologically	POS	O
+proved	POS	O
+to	POS	O
+be	POS	O
+well	POS	O
+-	POS	O
+differentiated	POS	O
+hepatocellular	POS	O
+carcinoma	POS	B-NP
+.	POS	O
+This	POS	O
+case	POS	O
+contributes	POS	O
+to	POS	O
+the	POS	O
+previous	POS	O
+observations	POS	O
+that	POS	O
+non	POS	B-NP
+-	POS	I-NP
+metastasizing	POS	I-NP
+hepatic	POS	I-NP
+neoplasms	POS	I-NP
+and	POS	O
+peliosis	POS	B-NP
+can	POS	O
+develop	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+androgen	POS	O
+-	POS	O
+and	POS	O
+corticosteroid	POS	O
+-	POS	O
+treated	POS	O
+Fanconi	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+anemia	POS	I-NP
+.	POS	O
+The	POS	O
+influence	POS	O
+of	POS	O
+the	POS	O
+time	POS	O
+interval	POS	O
+between	POS	O
+monoHER	POS	O
+and	POS	O
+doxorubicin	POS	O
+administration	POS	O
+on	POS	O
+the	POS	O
+protection	POS	O
+against	POS	O
+doxorubicin	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+in	POS	O
+mice	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+Despite	POS	O
+its	POS	O
+well	POS	O
+-	POS	O
+known	POS	O
+cardiotoxicity	POS	B-NP
+,	POS	O
+the	POS	O
+anthracyclin	POS	O
+doxorubicin	POS	O
+(	POS	O
+DOX	POS	O
+)	POS	O
+continues	POS	O
+to	POS	O
+be	POS	O
+an	POS	O
+effective	POS	O
+and	POS	O
+widely	POS	O
+used	POS	O
+chemotherapeutic	POS	O
+agent	POS	O
+.	POS	O
+DOX	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+damage	POS	I-NP
+presumably	POS	O
+results	POS	O
+from	POS	O
+the	POS	O
+formation	POS	O
+of	POS	O
+free	POS	O
+radicals	POS	O
+by	POS	O
+DOX	POS	O
+.	POS	O
+Reactive	POS	O
+oxygen	POS	O
+species	POS	O
+particularly	POS	O
+affect	POS	O
+the	POS	O
+cardiac	POS	O
+myocytes	POS	O
+because	POS	O
+these	POS	O
+cells	POS	O
+seem	POS	O
+to	POS	O
+have	POS	O
+a	POS	O
+relatively	POS	O
+poor	POS	O
+antioxidant	POS	O
+defense	POS	O
+system	POS	O
+.	POS	O
+The	POS	O
+semisynthetic	POS	O
+flavonoid	POS	O
+monohydroxyethylrutoside	POS	O
+(	POS	O
+monoHER	POS	O
+)	POS	O
+showed	POS	O
+cardioprotection	POS	O
+against	POS	O
+DOX	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+through	POS	O
+its	POS	O
+radical	POS	O
+scavenging	POS	O
+and	POS	O
+iron	POS	O
+chelating	POS	O
+properties	POS	O
+.	POS	O
+Because	POS	O
+of	POS	O
+the	POS	O
+relatively	POS	O
+short	POS	O
+final	POS	O
+half	POS	O
+-	POS	O
+life	POS	O
+of	POS	O
+monoHER	POS	O
+(	POS	O
+about	POS	O
+30	POS	O
+min	POS	O
+)	POS	O
+,	POS	O
+it	POS	O
+is	POS	O
+expected	POS	O
+that	POS	O
+the	POS	O
+time	POS	O
+interval	POS	O
+between	POS	O
+monoHER	POS	O
+and	POS	O
+DOX	POS	O
+might	POS	O
+be	POS	O
+of	POS	O
+influence	POS	O
+on	POS	O
+the	POS	O
+cardioprotective	POS	O
+effect	POS	O
+of	POS	O
+monoHER	POS	O
+.	POS	O
+Therefore	POS	O
+,	POS	O
+the	POS	O
+aim	POS	O
+of	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+investigate	POS	O
+this	POS	O
+possible	POS	O
+effect	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Six	POS	O
+groups	POS	O
+of	POS	O
+6	POS	O
+BALB	POS	O
+/	POS	O
+c	POS	O
+mice	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+saline	POS	O
+,	POS	O
+DOX	POS	O
+alone	POS	O
+or	POS	O
+DOX	POS	O
+(	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+)	POS	O
+preceded	POS	O
+by	POS	O
+monoHER	POS	O
+(	POS	O
+500	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+with	POS	O
+an	POS	O
+interval	POS	O
+of	POS	O
+10	POS	O
+,	POS	O
+30	POS	O
+,	POS	O
+60	POS	O
+or	POS	O
+120	POS	O
+min	POS	O
+.	POS	O
+After	POS	O
+a	POS	O
+6	POS	O
+-	POS	O
+week	POS	O
+treatment	POS	O
+period	POS	O
+and	POS	O
+additional	POS	O
+observation	POS	O
+for	POS	O
+2	POS	O
+weeks	POS	O
+,	POS	O
+the	POS	O
+mice	POS	O
+were	POS	O
+sacrificed	POS	O
+.	POS	O
+Their	POS	O
+cardiac	POS	O
+tissues	POS	O
+were	POS	O
+processed	POS	O
+for	POS	O
+light	POS	O
+microscopy	POS	O
+,	POS	O
+after	POS	O
+which	POS	O
+cardiomyocyte	POS	O
+damage	POS	O
+was	POS	O
+evaluated	POS	O
+according	POS	O
+to	POS	O
+Billingham	POS	O
+(	POS	O
+in	POS	O
+Cancer	POS	O
+Treat	POS	O
+Rep	POS	O
+62	POS	O
+(	POS	O
+6	POS	O
+)	POS	O
+:	POS	O
+865	POS	O
+-	POS	O
+872	POS	O
+,	POS	O
+1978	POS	O
+)	POS	O
+.	POS	O
+Microscopic	POS	O
+evaluation	POS	O
+revealed	POS	O
+that	POS	O
+treatment	POS	O
+with	POS	O
+DOX	POS	O
+alone	POS	O
+induced	POS	O
+significant	POS	O
+cardiac	POS	B-NP
+damage	POS	I-NP
+in	POS	O
+comparison	POS	O
+to	POS	O
+the	POS	O
+saline	POS	O
+control	POS	O
+group	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+number	POS	O
+of	POS	O
+damaged	POS	O
+cardiomyocytes	POS	O
+was	POS	O
+9	POS	O
+.	POS	O
+6	POS	O
+-	POS	O
+fold	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+4	POS	O
+.	POS	O
+4	POS	O
+-	POS	O
+21	POS	O
+.	POS	O
+0	POS	O
+)	POS	O
+higher	POS	O
+in	POS	O
+mice	POS	O
+treated	POS	O
+with	POS	O
+DOX	POS	O
+alone	POS	O
+than	POS	O
+that	POS	O
+in	POS	O
+animals	POS	O
+of	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+.	POS	O
+The	POS	O
+ratio	POS	O
+of	POS	O
+aberrant	POS	O
+cardiomyocytes	POS	O
+in	POS	O
+mice	POS	O
+treated	POS	O
+with	POS	O
+DOX	POS	O
+preceded	POS	O
+by	POS	O
+monoHER	POS	O
+and	POS	O
+those	POS	O
+in	POS	O
+mice	POS	O
+treated	POS	O
+with	POS	O
+saline	POS	O
+ranged	POS	O
+from	POS	O
+1	POS	O
+.	POS	O
+6	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+8	POS	O
+(	POS	O
+mean	POS	O
+2	POS	O
+.	POS	O
+2	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+1	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+019	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+protective	POS	O
+effect	POS	O
+by	POS	O
+adding	POS	O
+monoHER	POS	O
+before	POS	O
+DOX	POS	O
+led	POS	O
+to	POS	O
+a	POS	O
+significant	POS	O
+4	POS	O
+.	POS	O
+4	POS	O
+-	POS	O
+fold	POS	O
+reduction	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
+-	POS	O
+8	POS	O
+.	POS	O
+2	POS	O
+)	POS	O
+of	POS	O
+abnormal	POS	O
+cardiomyocytes	POS	O
+.	POS	O
+This	POS	O
+protective	POS	O
+effect	POS	O
+did	POS	O
+not	POS	O
+depend	POS	O
+on	POS	O
+the	POS	O
+time	POS	O
+interval	POS	O
+between	POS	O
+monoHER	POS	O
+and	POS	O
+DOX	POS	O
+administration	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+345	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+The	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+in	POS	O
+an	POS	O
+outpatient	POS	O
+clinical	POS	O
+setting	POS	O
+monoHER	POS	O
+may	POS	O
+be	POS	O
+administered	POS	O
+shortly	POS	O
+before	POS	O
+DOX	POS	O
+.	POS	O
+Clinical	POS	O
+evaluation	POS	O
+of	POS	O
+adverse	POS	O
+effects	POS	O
+during	POS	O
+bepridil	POS	O
+administration	POS	O
+for	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+and	POS	O
+flutter	POS	B-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Bepridil	POS	O
+hydrochloride	POS	O
+(	POS	O
+Bpd	POS	O
+)	POS	O
+has	POS	O
+attracted	POS	O
+attention	POS	O
+as	POS	O
+an	POS	O
+effective	POS	O
+drug	POS	O
+for	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+(	POS	O
+AF	POS	B-NP
+)	POS	O
+and	POS	O
+atrial	POS	B-NP
+flutter	POS	I-NP
+(	POS	O
+AFL	POS	B-NP
+)	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+serious	POS	O
+adverse	POS	O
+effects	POS	O
+,	POS	O
+including	POS	O
+torsade	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+(	POS	O
+Tdp	POS	B-NP
+)	POS	O
+,	POS	O
+have	POS	O
+been	POS	O
+reported	POS	O
+.	POS	O
+METHODS	POS	O
+AND	POS	O
+RESULTS	POS	O
+:	POS	O
+Adverse	POS	O
+effects	POS	O
+of	POS	O
+Bpd	POS	O
+requiring	POS	O
+discontinuation	POS	O
+of	POS	O
+treatment	POS	O
+were	POS	O
+evaluated	POS	O
+.	POS	O
+Bpd	POS	O
+was	POS	O
+administered	POS	O
+to	POS	O
+459	POS	O
+patients	POS	O
+(	POS	O
+361	POS	O
+males	POS	O
+,	POS	O
+63	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+12	POS	O
+years	POS	O
+old	POS	O
+)	POS	O
+comprising	POS	O
+378	POS	O
+AF	POS	B-NP
+and	POS	O
+81	POS	O
+AFL	POS	B-NP
+cases	POS	O
+.	POS	O
+Mean	POS	O
+left	POS	O
+ventricular	POS	O
+ejection	POS	O
+fraction	POS	O
+and	POS	O
+atrial	POS	O
+dimension	POS	O
+(	POS	O
+LAD	POS	O
+)	POS	O
+were	POS	O
+66	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+11	POS	O
+%	POS	O
+and	POS	O
+40	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+mm	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Adverse	POS	O
+effects	POS	O
+were	POS	O
+observed	POS	O
+in	POS	O
+19	POS	O
+patients	POS	O
+(	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+during	POS	O
+an	POS	O
+average	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+of	POS	O
+20	POS	O
+months	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+marked	POS	O
+QT	POS	O
+prolongation	POS	O
+greater	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+55	POS	O
+s	POS	O
+in	POS	O
+13	POS	O
+patients	POS	O
+,	POS	O
+bradycardia	POS	B-NP
+less	POS	O
+than	POS	O
+40	POS	O
+beats	POS	O
+/	POS	O
+min	POS	O
+in	POS	O
+6	POS	O
+patients	POS	O
+,	POS	O
+dizziness	POS	B-NP
+and	POS	O
+general	POS	B-NP
+fatigue	POS	I-NP
+in	POS	O
+1	POS	O
+patient	POS	O
+each	POS	O
+.	POS	O
+In	POS	O
+4	POS	O
+of	POS	O
+13	POS	O
+patients	POS	O
+with	POS	O
+QT	POS	B-NP
+prolongation	POS	I-NP
+,	POS	O
+Tdp	POS	B-NP
+occurred	POS	O
+.	POS	O
+The	POS	O
+major	POS	O
+triggering	POS	O
+factors	POS	O
+of	POS	O
+Tdp	POS	O
+were	POS	O
+hypokalemia	POS	B-NP
+and	POS	O
+sudden	POS	O
+decrease	POS	O
+in	POS	O
+heart	POS	O
+rate	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+no	POS	O
+differences	POS	O
+in	POS	O
+the	POS	O
+clinical	POS	O
+backgrounds	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+with	POS	O
+and	POS	O
+without	POS	O
+Tdp	POS	O
+other	POS	O
+than	POS	O
+LAD	POS	O
+and	POS	O
+age	POS	O
+,	POS	O
+which	POS	O
+were	POS	O
+larger	POS	O
+and	POS	O
+older	POS	O
+in	POS	O
+the	POS	O
+patients	POS	O
+with	POS	O
+Tdp	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Careful	POS	O
+observation	POS	O
+of	POS	O
+serum	POS	O
+potassium	POS	O
+concentration	POS	O
+and	POS	O
+the	POS	O
+ECG	POS	O
+should	POS	O
+always	POS	O
+be	POS	O
+done	POS	O
+during	POS	O
+Bpd	POS	O
+administration	POS	O
+,	POS	O
+particularly	POS	O
+in	POS	O
+elderly	POS	O
+patients	POS	O
+.	POS	O
+Enhanced	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+hypertrophy	POS	I-NP
+in	POS	O
+transgenic	POS	O
+rats	POS	O
+with	POS	O
+low	POS	O
+brain	POS	O
+angiotensinogen	POS	O
+.	POS	O
+We	POS	O
+have	POS	O
+previously	POS	O
+shown	POS	O
+that	POS	O
+a	POS	O
+permanent	POS	B-NP
+deficiency	POS	I-NP
+in	POS	I-NP
+the	POS	I-NP
+brain	POS	I-NP
+renin	POS	I-NP
+-	POS	I-NP
+angiotensin	POS	I-NP
+system	POS	I-NP
+(	POS	O
+RAS	POS	O
+)	POS	O
+may	POS	O
+increase	POS	O
+the	POS	O
+sensitivity	POS	O
+of	POS	O
+the	POS	O
+baroreflex	POS	O
+control	POS	O
+of	POS	O
+heart	POS	O
+rate	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+we	POS	O
+aimed	POS	O
+at	POS	O
+studying	POS	O
+the	POS	O
+involvement	POS	O
+of	POS	O
+the	POS	O
+brain	POS	O
+RAS	POS	O
+in	POS	O
+the	POS	O
+cardiac	POS	O
+reactivity	POS	O
+to	POS	O
+the	POS	O
+beta	POS	O
+-	POS	O
+adrenoceptor	POS	O
+(	POS	O
+beta	POS	O
+-	POS	O
+AR	POS	O
+)	POS	O
+agonist	POS	O
+isoproterenol	POS	O
+(	POS	O
+Iso	POS	O
+)	POS	O
+.	POS	O
+Transgenic	POS	O
+rats	POS	O
+with	POS	O
+low	POS	O
+brain	POS	O
+angiotensinogen	POS	O
+(	POS	O
+TGR	POS	O
+)	POS	O
+were	POS	O
+used	POS	O
+.	POS	O
+In	POS	O
+isolated	POS	O
+hearts	POS	O
+,	POS	O
+Iso	POS	O
+induced	POS	O
+a	POS	O
+significantly	POS	O
+greater	POS	O
+increase	POS	O
+in	POS	O
+left	POS	O
+ventricular	POS	O
+(	POS	O
+LV	POS	O
+)	POS	O
+pressure	POS	O
+and	POS	O
+maximal	POS	O
+contraction	POS	O
+(	POS	O
++	POS	O
+dP	POS	O
+/	POS	O
+dt	POS	O
+(	POS	O
+max	POS	O
+)	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+TGR	POS	O
+than	POS	O
+in	POS	O
+the	POS	O
+Sprague	POS	O
+-	POS	O
+Dawley	POS	O
+(	POS	O
+SD	POS	O
+)	POS	O
+rats	POS	O
+.	POS	O
+LV	POS	B-NP
+hypertrophy	POS	I-NP
+induced	POS	O
+by	POS	O
+Iso	POS	O
+treatment	POS	O
+was	POS	O
+significantly	POS	O
+higher	POS	O
+in	POS	O
+TGR	POS	O
+than	POS	O
+in	POS	O
+SD	POS	O
+rats	POS	O
+(	POS	O
+in	POS	O
+g	POS	O
+LV	POS	O
+wt	POS	O
+/	POS	O
+100	POS	O
+g	POS	O
+body	POS	O
+wt	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+28	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+004	POS	O
+vs	POS	O
+.	POS	O
+0	POS	O
+.	POS	O
+24	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+004	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+greater	POS	O
+LV	POS	B-NP
+hypertrophy	POS	I-NP
+in	POS	O
+TGR	POS	O
+rats	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+more	POS	O
+pronounced	POS	O
+downregulation	POS	O
+of	POS	O
+beta	POS	O
+-	POS	O
+AR	POS	O
+and	POS	O
+upregulation	POS	O
+of	POS	O
+LV	POS	O
+beta	POS	O
+-	POS	O
+AR	POS	O
+kinase	POS	O
+-	POS	O
+1	POS	O
+mRNA	POS	O
+levels	POS	O
+compared	POS	O
+with	POS	O
+those	POS	O
+in	POS	O
+SD	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+decrease	POS	O
+in	POS	O
+the	POS	O
+heart	POS	O
+rate	POS	O
+(	POS	O
+HR	POS	O
+)	POS	O
+induced	POS	O
+by	POS	O
+the	POS	O
+beta	POS	O
+-	POS	O
+AR	POS	O
+antagonist	POS	O
+metoprolol	POS	O
+in	POS	O
+conscious	POS	O
+rats	POS	O
+was	POS	O
+significantly	POS	O
+attenuated	POS	O
+in	POS	O
+TGR	POS	O
+compared	POS	O
+with	POS	O
+SD	POS	O
+rats	POS	O
+(	POS	O
+-	POS	O
+9	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+vs	POS	O
+.	POS	O
+-	POS	O
+18	POS	O
+.	POS	O
+1	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+whereas	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+parasympathetic	POS	O
+blockade	POS	O
+by	POS	O
+atropine	POS	O
+on	POS	O
+HR	POS	O
+was	POS	O
+similar	POS	O
+in	POS	O
+both	POS	O
+strains	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+TGR	POS	O
+are	POS	O
+more	POS	O
+sensitive	POS	O
+to	POS	O
+beta	POS	O
+-	POS	O
+AR	POS	O
+agonist	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	O
+inotropic	POS	O
+response	POS	O
+and	POS	O
+hypertrophy	POS	B-NP
+,	POS	O
+possibly	POS	O
+due	POS	O
+to	POS	O
+chronically	POS	O
+low	POS	O
+sympathetic	POS	O
+outflow	POS	O
+directed	POS	O
+to	POS	O
+the	POS	O
+heart	POS	O
+.	POS	O
+Drug	POS	O
+-	POS	O
+induced	POS	O
+long	POS	O
+QT	POS	B-NP
+syndrome	POS	I-NP
+in	POS	O
+injection	POS	O
+drug	POS	O
+users	POS	O
+receiving	POS	O
+methadone	POS	O
+:	POS	O
+high	POS	O
+frequency	POS	O
+in	POS	O
+hospitalized	POS	O
+patients	POS	O
+and	POS	O
+risk	POS	O
+factors	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Drug	POS	O
+-	POS	O
+induced	POS	O
+long	POS	O
+QT	POS	B-NP
+syndrome	POS	I-NP
+is	POS	O
+a	POS	O
+serious	POS	O
+adverse	POS	O
+drug	POS	O
+reaction	POS	O
+.	POS	O
+Methadone	POS	O
+prolongs	POS	O
+the	POS	O
+QT	POS	O
+interval	POS	O
+in	POS	O
+vitro	POS	O
+in	POS	O
+a	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+manner	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+inpatient	POS	O
+setting	POS	O
+,	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+QT	POS	O
+interval	POS	O
+prolongation	POS	O
+with	POS	O
+methadone	POS	O
+treatment	POS	O
+,	POS	O
+its	POS	O
+dose	POS	O
+dependence	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+importance	POS	O
+of	POS	O
+cofactors	POS	O
+such	POS	O
+as	POS	O
+drug	POS	O
+-	POS	O
+drug	POS	O
+interactions	POS	O
+remain	POS	O
+unknown	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+performed	POS	O
+a	POS	O
+systematic	POS	O
+,	POS	O
+retrospective	POS	O
+study	POS	O
+comparing	POS	O
+active	POS	O
+or	POS	O
+former	POS	O
+intravenous	POS	O
+drug	POS	O
+users	POS	O
+receiving	POS	O
+methadone	POS	O
+and	POS	O
+those	POS	O
+not	POS	O
+receiving	POS	O
+methadone	POS	O
+among	POS	O
+all	POS	O
+patients	POS	O
+hospitalized	POS	O
+over	POS	O
+a	POS	O
+5	POS	O
+-	POS	O
+year	POS	O
+period	POS	O
+in	POS	O
+a	POS	O
+tertiary	POS	O
+care	POS	O
+hospital	POS	O
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+167	POS	O
+patients	POS	O
+receiving	POS	O
+methadone	POS	O
+fulfilled	POS	O
+the	POS	O
+inclusion	POS	O
+criteria	POS	O
+and	POS	O
+were	POS	O
+compared	POS	O
+with	POS	O
+a	POS	O
+control	POS	O
+group	POS	O
+of	POS	O
+80	POS	O
+injection	POS	O
+drug	POS	O
+users	POS	O
+not	POS	O
+receiving	POS	O
+methadone	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+to	POS	O
+methadone	POS	O
+dose	POS	O
+,	POS	O
+15	POS	O
+demographic	POS	O
+,	POS	O
+biological	POS	O
+,	POS	O
+and	POS	O
+pharmacological	POS	O
+variables	POS	O
+were	POS	O
+considered	POS	O
+as	POS	O
+potential	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+QT	POS	B-NP
+prolongation	POS	I-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Among	POS	O
+167	POS	O
+methadone	POS	O
+maintenance	POS	O
+patients	POS	O
+,	POS	O
+the	POS	O
+prevalence	POS	O
+of	POS	O
+QTc	POS	O
+prolongation	POS	O
+to	POS	O
+0	POS	O
+.	POS	O
+50	POS	O
+second	POS	O
+(	POS	O
+(	POS	O
+1	POS	O
+/	POS	O
+2	POS	O
+)	POS	O
+)	POS	O
+or	POS	O
+longer	POS	O
+was	POS	O
+16	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+compared	POS	O
+with	POS	O
+0	POS	O
+%	POS	O
+in	POS	O
+80	POS	O
+control	POS	O
+subjects	POS	O
+.	POS	O
+Six	POS	O
+patients	POS	O
+(	POS	O
+3	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+methadone	POS	O
+group	POS	O
+presented	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+.	POS	O
+QTc	POS	O
+length	POS	O
+was	POS	O
+weakly	POS	O
+but	POS	O
+significantly	POS	O
+associated	POS	O
+with	POS	O
+methadone	POS	O
+daily	POS	O
+dose	POS	O
+(	POS	O
+Spearman	POS	O
+rank	POS	O
+correlation	POS	O
+coefficient	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+20	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+Multivariate	POS	O
+regression	POS	O
+analysis	POS	O
+allowed	POS	O
+attribution	POS	O
+of	POS	O
+31	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+of	POS	O
+QTc	POS	O
+variability	POS	O
+to	POS	O
+methadone	POS	O
+dose	POS	O
+,	POS	O
+cytochrome	POS	O
+P	POS	O
+-	POS	O
+450	POS	O
+3A4	POS	O
+drug	POS	O
+-	POS	O
+drug	POS	O
+interactions	POS	O
+,	POS	O
+hypokalemia	POS	B-NP
+,	POS	O
+and	POS	O
+altered	POS	B-NP
+liver	POS	I-NP
+function	POS	I-NP
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+QT	POS	O
+interval	POS	O
+prolongation	POS	O
+in	POS	O
+methadone	POS	O
+maintenance	POS	O
+patients	POS	O
+hospitalized	POS	O
+in	POS	O
+a	POS	O
+tertiary	POS	O
+care	POS	O
+center	POS	O
+is	POS	O
+a	POS	O
+frequent	POS	O
+finding	POS	O
+.	POS	O
+Methadone	POS	O
+dose	POS	O
+,	POS	O
+presence	POS	O
+of	POS	O
+cytochrome	POS	O
+P	POS	O
+-	POS	O
+450	POS	O
+3A4	POS	O
+inhibitors	POS	O
+,	POS	O
+potassium	POS	O
+level	POS	O
+,	POS	O
+and	POS	O
+liver	POS	O
+function	POS	O
+contribute	POS	O
+to	POS	O
+QT	POS	B-NP
+prolongation	POS	I-NP
+.	POS	O
+Long	POS	B-NP
+QT	POS	I-NP
+syndrome	POS	I-NP
+can	POS	O
+occur	POS	O
+with	POS	O
+low	POS	O
+doses	POS	O
+of	POS	O
+methadone	POS	O
+.	POS	O
+Mechanisms	POS	O
+of	POS	O
+hypertension	POS	B-NP
+induced	POS	O
+by	POS	O
+nitric	POS	O
+oxide	POS	O
+(	POS	O
+NO	POS	O
+)	POS	O
+deficiency	POS	O
+:	POS	O
+focus	POS	O
+on	POS	O
+venous	POS	O
+function	POS	O
+.	POS	O
+Loss	POS	O
+of	POS	O
+endothelial	POS	O
+cell	POS	O
+-	POS	O
+derived	POS	O
+nitric	POS	O
+oxide	POS	O
+(	POS	O
+NO	POS	O
+)	POS	O
+in	POS	O
+hypertension	POS	B-NP
+is	POS	O
+a	POS	O
+hallmark	POS	O
+of	POS	O
+arterial	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+Experimental	POS	O
+hypertension	POS	B-NP
+created	POS	O
+by	POS	O
+the	POS	O
+removal	POS	O
+of	POS	O
+NO	POS	O
+,	POS	O
+however	POS	O
+,	POS	O
+involves	POS	O
+mechanisms	POS	O
+in	POS	O
+addition	POS	O
+to	POS	O
+decreased	POS	O
+arterial	POS	O
+vasodilator	POS	O
+activity	POS	O
+.	POS	O
+These	POS	O
+include	POS	O
+augmented	POS	O
+endothelin	POS	O
+-	POS	O
+1	POS	O
+(	POS	O
+ET	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+release	POS	O
+,	POS	O
+increased	POS	O
+sympathetic	POS	O
+nervous	POS	O
+system	POS	O
+activity	POS	O
+,	POS	O
+and	POS	O
+elevated	POS	O
+tissue	POS	O
+oxidative	POS	O
+stress	POS	O
+.	POS	O
+We	POS	O
+hypothesized	POS	O
+that	POS	O
+increased	POS	O
+venous	POS	O
+smooth	POS	O
+muscle	POS	O
+(	POS	O
+venomotor	POS	O
+)	POS	O
+tone	POS	O
+plays	POS	O
+a	POS	O
+role	POS	O
+in	POS	O
+Nomega	POS	O
+-	POS	O
+nitro	POS	O
+-	POS	O
+L	POS	O
+-	POS	O
+arginine	POS	O
+(	POS	O
+LNNA	POS	O
+)	POS	O
+hypertension	POS	B-NP
+through	POS	O
+these	POS	O
+mechanisms	POS	O
+.	POS	O
+Rats	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+the	POS	O
+NO	POS	O
+synthase	POS	O
+inhibitor	POS	O
+LNNA	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+g	POS	O
+/	POS	O
+L	POS	O
+in	POS	O
+drinking	POS	O
+water	POS	O
+)	POS	O
+for	POS	O
+2	POS	O
+weeks	POS	O
+.	POS	O
+Mean	POS	O
+arterial	POS	O
+pressure	POS	O
+of	POS	O
+conscious	POS	O
+rats	POS	O
+was	POS	O
+119	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+2	POS	O
+mm	POS	O
+Hg	POS	O
+in	POS	O
+control	POS	O
+and	POS	O
+194	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+5	POS	O
+mm	POS	O
+Hg	POS	O
+in	POS	O
+LNNA	POS	O
+rats	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+Carotid	POS	O
+arteries	POS	O
+and	POS	O
+vena	POS	O
+cava	POS	O
+were	POS	O
+removed	POS	O
+for	POS	O
+measurement	POS	O
+of	POS	O
+isometric	POS	O
+contraction	POS	O
+.	POS	O
+Maximal	POS	O
+contraction	POS	O
+to	POS	O
+norepinephrine	POS	O
+was	POS	O
+modestly	POS	O
+reduced	POS	O
+in	POS	O
+arteries	POS	O
+from	POS	O
+LNNA	POS	O
+compared	POS	O
+with	POS	O
+control	POS	O
+rats	POS	O
+whereas	POS	O
+the	POS	O
+maximum	POS	O
+contraction	POS	O
+to	POS	O
+ET	POS	O
+-	POS	O
+1	POS	O
+was	POS	O
+significantly	POS	O
+reduced	POS	O
+(	POS	O
+54	POS	O
+%	POS	O
+control	POS	O
+)	POS	O
+.	POS	O
+Maximum	POS	O
+contraction	POS	O
+of	POS	O
+vena	POS	O
+cava	POS	O
+to	POS	O
+norepinephrine	POS	O
+(	POS	O
+37	POS	O
+%	POS	O
+control	POS	O
+)	POS	O
+also	POS	O
+was	POS	O
+reduced	POS	O
+but	POS	O
+no	POS	O
+change	POS	O
+in	POS	O
+response	POS	O
+to	POS	O
+ET	POS	O
+-	POS	O
+1	POS	O
+was	POS	O
+observed	POS	O
+.	POS	O
+Mean	POS	O
+circulatory	POS	O
+filling	POS	O
+pressure	POS	O
+,	POS	O
+an	POS	O
+in	POS	O
+vivo	POS	O
+measure	POS	O
+of	POS	O
+venomotor	POS	O
+tone	POS	O
+,	POS	O
+was	POS	O
+not	POS	O
+elevated	POS	O
+in	POS	O
+LNNA	POS	O
+hypertension	POS	B-NP
+at	POS	O
+1	POS	O
+or	POS	O
+2	POS	O
+weeks	POS	O
+after	POS	O
+LNNA	POS	O
+.	POS	O
+The	POS	O
+superoxide	POS	O
+scavenger	POS	O
+tempol	POS	O
+(	POS	O
+30	POS	O
+,	POS	O
+100	POS	O
+,	POS	O
+and	POS	O
+300	POS	O
+micromol	POS	O
+kg	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+,	POS	O
+IV	POS	O
+)	POS	O
+did	POS	O
+not	POS	O
+change	POS	O
+arterial	POS	O
+pressure	POS	O
+in	POS	O
+control	POS	O
+rats	POS	O
+but	POS	O
+caused	POS	O
+a	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+decrease	POS	O
+in	POS	O
+LNNA	POS	O
+rats	POS	O
+(	POS	O
+-	POS	O
+18	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+8	POS	O
+,	POS	O
+-	POS	O
+26	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+15	POS	O
+,	POS	O
+and	POS	O
+-	POS	O
+54	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+11	POS	O
+mm	POS	O
+Hg	POS	O
+)	POS	O
+.	POS	O
+Similarly	POS	O
+,	POS	O
+ganglionic	POS	O
+blockade	POS	O
+with	POS	O
+hexamethonium	POS	O
+caused	POS	O
+a	POS	O
+significantly	POS	O
+greater	POS	O
+fall	POS	O
+in	POS	O
+LNNA	POS	O
+hypertensive	POS	B-NP
+rats	POS	O
+(	POS	O
+76	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+9	POS	O
+mm	POS	O
+Hg	POS	O
+)	POS	O
+compared	POS	O
+with	POS	O
+control	POS	O
+rats	POS	O
+(	POS	O
+35	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+10	POS	O
+mm	POS	O
+Hg	POS	O
+)	POS	O
+.	POS	O
+Carotid	POS	O
+arteries	POS	O
+,	POS	O
+vena	POS	O
+cava	POS	O
+,	POS	O
+and	POS	O
+sympathetic	POS	O
+ganglia	POS	O
+from	POS	O
+LNNA	POS	O
+rats	POS	O
+had	POS	O
+higher	POS	O
+basal	POS	O
+levels	POS	O
+of	POS	O
+superoxide	POS	O
+compared	POS	O
+with	POS	O
+those	POS	O
+from	POS	O
+control	POS	O
+rats	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+while	POS	O
+NO	POS	O
+deficiency	POS	O
+increases	POS	O
+oxidative	POS	O
+stress	POS	O
+and	POS	O
+sympathetic	POS	O
+activity	POS	O
+in	POS	O
+both	POS	O
+arterial	POS	O
+and	POS	O
+venous	POS	O
+vessels	POS	O
+,	POS	O
+the	POS	O
+impact	POS	O
+on	POS	O
+veins	POS	O
+does	POS	O
+not	POS	O
+make	POS	O
+a	POS	O
+major	POS	O
+contribution	POS	O
+to	POS	O
+this	POS	O
+form	POS	O
+of	POS	O
+hypertension	POS	B-NP
+.	POS	O
+Association	POS	O
+of	POS	O
+DRD2	POS	O
+polymorphisms	POS	O
+and	POS	O
+chlorpromazine	POS	O
+-	POS	O
+induced	POS	O
+extrapyramidal	POS	B-NP
+syndrome	POS	I-NP
+in	POS	O
+Chinese	POS	O
+schizophrenic	POS	B-NP
+patients	POS	O
+.	POS	O
+AIM	POS	B-NP
+:	POS	O
+Extrapyramidal	POS	B-NP
+syndrome	POS	I-NP
+(	POS	O
+EPS	POS	B-NP
+)	POS	O
+is	POS	O
+most	POS	O
+commonly	POS	O
+affected	POS	O
+by	POS	O
+typical	POS	O
+antipsychotic	POS	O
+drugs	POS	O
+that	POS	O
+have	POS	O
+a	POS	O
+high	POS	O
+affinity	POS	O
+with	POS	O
+the	POS	O
+D2	POS	O
+receptor	POS	O
+.	POS	O
+Recently	POS	O
+,	POS	O
+many	POS	O
+research	POS	O
+groups	POS	O
+have	POS	O
+reported	POS	O
+on	POS	O
+the	POS	O
+positive	POS	O
+relationship	POS	O
+between	POS	O
+the	POS	O
+genetic	POS	O
+variations	POS	O
+in	POS	O
+the	POS	O
+DRD2	POS	O
+gene	POS	O
+and	POS	O
+the	POS	O
+therapeutic	POS	O
+response	POS	O
+in	POS	O
+schizophrenia	POS	B-NP
+patients	POS	O
+as	POS	O
+a	POS	O
+result	POS	O
+of	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+variations	POS	O
+in	POS	O
+the	POS	O
+receptor	POS	O
+in	POS	O
+modulating	POS	O
+receptor	POS	O
+expression	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+,	POS	O
+we	POS	O
+evaluate	POS	O
+the	POS	O
+role	POS	O
+DRD2	POS	O
+plays	POS	O
+in	POS	O
+chlorpromazine	POS	O
+-	POS	O
+induced	POS	O
+EPS	POS	B-NP
+in	POS	O
+schizophrenic	POS	B-NP
+patients	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+identified	POS	O
+seven	POS	O
+SNP	POS	O
+(	POS	O
+single	POS	O
+nucleotide	POS	O
+polymorphism	POS	O
+)	POS	O
+(	POS	O
+-	POS	O
+141Cins	POS	O
+>	POS	O
+del	POS	O
+,	POS	O
+TaqIB	POS	O
+,	POS	O
+TaqID	POS	O
+,	POS	O
+Ser311Cys	POS	O
+,	POS	O
+rs6275	POS	O
+,	POS	O
+rs6277	POS	O
+and	POS	O
+TaqIA	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+DRD2	POS	O
+gene	POS	O
+in	POS	O
+146	POS	O
+schizophrenic	POS	B-NP
+inpatients	POS	O
+(	POS	O
+59	POS	O
+with	POS	O
+EPS	POS	B-NP
+and	POS	O
+87	POS	O
+without	POS	O
+EPS	POS	B-NP
+according	POS	O
+to	POS	O
+the	POS	O
+Simpson	POS	O
+-	POS	O
+Angus	POS	O
+Scale	POS	O
+)	POS	O
+treated	POS	O
+with	POS	O
+chlorpromazine	POS	O
+after	POS	O
+8	POS	O
+weeks	POS	O
+.	POS	O
+The	POS	O
+alleles	POS	O
+of	POS	O
+all	POS	O
+loci	POS	O
+were	POS	O
+determined	POS	O
+by	POS	O
+PCR	POS	O
+(	POS	O
+polymerase	POS	O
+chain	POS	O
+reaction	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Polymorphisms	POS	O
+TaqID	POS	O
+,	POS	O
+Ser311Cys	POS	O
+and	POS	O
+rs6277	POS	O
+were	POS	O
+not	POS	O
+polymorphic	POS	O
+in	POS	O
+the	POS	O
+population	POS	O
+recruited	POS	O
+in	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+.	POS	O
+No	POS	O
+statistical	POS	O
+significance	POS	O
+was	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+allele	POS	O
+distribution	POS	O
+of	POS	O
+-	POS	O
+141Cins	POS	O
+>	POS	O
+del	POS	O
+,	POS	O
+TaqIB	POS	O
+,	POS	O
+rs6275	POS	O
+and	POS	O
+TaqIA	POS	O
+or	POS	O
+in	POS	O
+the	POS	O
+estimated	POS	O
+haplotypes	POS	O
+(	POS	O
+constituted	POS	O
+by	POS	O
+TaqIB	POS	O
+,	POS	O
+rs6275	POS	O
+and	POS	O
+TaqIA	POS	O
+)	POS	O
+in	POS	O
+linkage	POS	O
+disequilibrium	POS	O
+between	POS	O
+the	POS	O
+two	POS	O
+groups	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Our	POS	O
+results	POS	O
+did	POS	O
+not	POS	O
+lend	POS	O
+strong	POS	O
+support	POS	O
+to	POS	O
+the	POS	O
+view	POS	O
+that	POS	O
+the	POS	O
+genetic	POS	O
+variation	POS	O
+of	POS	O
+the	POS	O
+DRD2	POS	O
+gene	POS	O
+plays	POS	O
+a	POS	O
+major	POS	O
+role	POS	O
+in	POS	O
+the	POS	O
+individually	POS	O
+variable	POS	O
+adverse	POS	O
+effect	POS	O
+induced	POS	O
+by	POS	O
+chlorpromazine	POS	O
+,	POS	O
+at	POS	O
+least	POS	O
+in	POS	O
+Chinese	POS	O
+patients	POS	O
+with	POS	O
+schizophrenia	POS	B-NP
+.	POS	O
+Our	POS	O
+results	POS	O
+confirmed	POS	O
+a	POS	O
+previous	POS	O
+study	POS	O
+on	POS	O
+the	POS	O
+relationship	POS	O
+between	POS	O
+DRD2	POS	O
+and	POS	O
+EPS	POS	B-NP
+in	POS	O
+Caucasians	POS	O
+.	POS	O
+Physical	POS	O
+training	POS	O
+decreases	POS	O
+susceptibility	POS	O
+to	POS	O
+subsequent	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+in	POS	O
+the	POS	O
+rat	POS	O
+.	POS	O
+Regular	POS	O
+motor	POS	O
+activity	POS	O
+has	POS	O
+many	POS	O
+benefits	POS	O
+for	POS	O
+mental	POS	O
+and	POS	O
+physical	POS	O
+condition	POS	O
+but	POS	O
+its	POS	O
+implications	POS	O
+for	POS	O
+epilepsy	POS	B-NP
+are	POS	O
+still	POS	O
+controversial	POS	O
+.	POS	O
+In	POS	O
+order	POS	O
+to	POS	O
+elucidate	POS	O
+this	POS	O
+problem	POS	O
+,	POS	O
+we	POS	O
+have	POS	O
+studied	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+physical	POS	O
+activity	POS	O
+on	POS	O
+susceptibility	POS	O
+to	POS	O
+subsequent	POS	O
+seizures	POS	B-NP
+.	POS	O
+Male	POS	O
+Wistar	POS	O
+rats	POS	O
+were	POS	O
+subjected	POS	O
+to	POS	O
+repeated	POS	O
+training	POS	O
+sessions	POS	O
+in	POS	O
+a	POS	O
+treadmill	POS	O
+and	POS	O
+swimming	POS	O
+pool	POS	O
+.	POS	O
+Thereafter	POS	O
+,	POS	O
+seizures	POS	B-NP
+were	POS	O
+induced	POS	O
+by	POS	O
+pilocarpine	POS	O
+injections	POS	O
+in	POS	O
+trained	POS	O
+and	POS	O
+non	POS	O
+-	POS	O
+trained	POS	O
+control	POS	O
+groups	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+acute	POS	O
+period	POS	O
+of	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+,	POS	O
+we	POS	O
+measured	POS	O
+:	POS	O
+(	POS	O
+1	POS	O
+)	POS	O
+the	POS	O
+latency	POS	O
+of	POS	O
+the	POS	O
+first	POS	O
+motor	POS	O
+sign	POS	O
+,	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+the	POS	O
+intensity	POS	O
+of	POS	O
+seizures	POS	B-NP
+,	POS	O
+(	POS	O
+3	POS	O
+)	POS	O
+the	POS	O
+time	POS	O
+when	POS	O
+it	POS	O
+occurred	POS	O
+within	POS	O
+the	POS	O
+6	POS	O
+-	POS	O
+h	POS	O
+observation	POS	O
+period	POS	O
+,	POS	O
+and	POS	O
+(	POS	O
+4	POS	O
+)	POS	O
+the	POS	O
+time	POS	O
+when	POS	O
+the	POS	O
+acute	POS	O
+period	POS	O
+ended	POS	O
+.	POS	O
+All	POS	O
+these	POS	O
+behavioral	POS	O
+parameters	POS	O
+showed	POS	O
+statistically	POS	O
+significant	POS	O
+changes	POS	O
+suggesting	POS	O
+that	POS	O
+regular	POS	O
+physical	POS	O
+exercises	POS	O
+decrease	POS	O
+susceptibility	POS	O
+to	POS	O
+subsequently	POS	O
+induced	POS	O
+seizures	POS	B-NP
+and	POS	O
+ameliorate	POS	O
+the	POS	O
+course	POS	O
+of	POS	O
+experimentally	POS	O
+induced	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+.	POS	O
+Tonic	POS	O
+dopaminergic	POS	O
+stimulation	POS	O
+impairs	POS	O
+associative	POS	O
+learning	POS	O
+in	POS	O
+healthy	POS	O
+subjects	POS	O
+.	POS	O
+Endogenous	POS	O
+dopamine	POS	O
+plays	POS	O
+a	POS	O
+central	POS	O
+role	POS	O
+in	POS	O
+salience	POS	O
+coding	POS	O
+during	POS	O
+associative	POS	O
+learning	POS	O
+.	POS	O
+Administration	POS	O
+of	POS	O
+the	POS	O
+dopamine	POS	O
+precursor	POS	O
+levodopa	POS	O
+enhances	POS	O
+learning	POS	O
+in	POS	O
+healthy	POS	O
+subjects	POS	O
+and	POS	O
+stroke	POS	B-NP
+patients	POS	O
+.	POS	O
+Because	POS	O
+levodopa	POS	O
+increases	POS	O
+both	POS	O
+phasic	POS	O
+and	POS	O
+tonic	POS	O
+dopaminergic	POS	O
+neurotransmission	POS	O
+,	POS	O
+the	POS	O
+critical	POS	O
+mechanism	POS	O
+mediating	POS	O
+the	POS	O
+enhancement	POS	O
+of	POS	O
+learning	POS	O
+is	POS	O
+unresolved	POS	O
+.	POS	O
+We	POS	O
+here	POS	O
+probed	POS	O
+how	POS	O
+selective	POS	O
+tonic	POS	O
+dopaminergic	POS	O
+stimulation	POS	O
+affects	POS	O
+associative	POS	O
+learning	POS	O
+.	POS	O
+Forty	POS	O
+healthy	POS	O
+subjects	POS	O
+were	POS	O
+trained	POS	O
+in	POS	O
+a	POS	O
+novel	POS	O
+vocabulary	POS	O
+of	POS	O
+45	POS	O
+concrete	POS	O
+nouns	POS	O
+over	POS	O
+the	POS	O
+course	POS	O
+of	POS	O
+5	POS	O
+consecutive	POS	O
+training	POS	O
+days	POS	O
+in	POS	O
+a	POS	O
+prospective	POS	O
+,	POS	O
+randomized	POS	O
+,	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+design	POS	O
+.	POS	O
+Subjects	POS	O
+received	POS	O
+the	POS	O
+tonically	POS	O
+stimulating	POS	O
+dopamine	POS	O
+-	POS	O
+receptor	POS	O
+agonist	POS	O
+pergolide	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+mg	POS	O
+)	POS	O
+vs	POS	O
+placebo	POS	O
+120	POS	O
+min	POS	O
+before	POS	O
+training	POS	O
+on	POS	O
+each	POS	O
+training	POS	O
+day	POS	O
+.	POS	O
+The	POS	O
+dopamine	POS	O
+agonist	POS	O
+significantly	POS	O
+impaired	POS	O
+novel	POS	O
+word	POS	O
+learning	POS	O
+compared	POS	O
+to	POS	O
+placebo	POS	O
+.	POS	O
+This	POS	O
+learning	POS	O
+decrement	POS	O
+persisted	POS	O
+up	POS	O
+to	POS	O
+the	POS	O
+last	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+4	POS	O
+weeks	POS	O
+post	POS	O
+-	POS	O
+training	POS	O
+.	POS	O
+Subjects	POS	O
+treated	POS	O
+with	POS	O
+pergolide	POS	O
+also	POS	O
+showed	POS	O
+restricted	POS	O
+emotional	POS	O
+responses	POS	O
+compared	POS	O
+to	POS	O
+the	POS	O
+PLACEBO	POS	O
+group	POS	O
+.	POS	O
+The	POS	O
+extent	POS	O
+of	POS	O
+'	POS	O
+flattened	POS	O
+'	POS	O
+affect	POS	O
+with	POS	O
+pergolide	POS	O
+was	POS	O
+related	POS	O
+to	POS	O
+the	POS	O
+degree	POS	O
+of	POS	O
+learning	POS	O
+inhibition	POS	O
+.	POS	O
+These	POS	O
+findings	POS	O
+suggest	POS	O
+that	POS	O
+tonic	POS	O
+occupation	POS	O
+of	POS	O
+dopamine	POS	O
+receptors	POS	O
+impairs	POS	O
+learning	POS	O
+by	POS	O
+competition	POS	O
+with	POS	O
+phasic	POS	O
+dopamine	POS	O
+signals	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+phasic	POS	O
+signaling	POS	O
+seems	POS	O
+to	POS	O
+be	POS	O
+the	POS	O
+critical	POS	O
+mechanism	POS	O
+by	POS	O
+which	POS	O
+dopamine	POS	O
+enhances	POS	O
+associative	POS	O
+learning	POS	O
+in	POS	O
+healthy	POS	O
+subjects	POS	O
+and	POS	O
+stroke	POS	B-NP
+patients	POS	O
+.	POS	O
+Minocycline	POS	O
+-	POS	O
+induced	POS	O
+vasculitis	POS	B-NP
+fulfilling	POS	O
+the	POS	O
+criteria	POS	O
+of	POS	O
+polyarteritis	POS	B-NP
+nodosa	POS	I-NP
+.	POS	O
+A	POS	O
+47	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+who	POS	O
+had	POS	O
+been	POS	O
+taking	POS	O
+minocycline	POS	O
+for	POS	O
+palmoplantar	POS	B-NP
+pustulosis	POS	I-NP
+developed	POS	O
+fever	POS	B-NP
+,	POS	O
+myalgias	POS	B-NP
+,	POS	O
+polyneuropathy	POS	B-NP
+,	POS	O
+and	POS	O
+testicular	POS	B-NP
+pain	POS	I-NP
+,	POS	O
+with	POS	O
+elevated	POS	B-NP
+C	POS	I-NP
+-	POS	I-NP
+reactive	POS	I-NP
+protein	POS	I-NP
+(	POS	O
+CRP	POS	O
+)	POS	O
+.	POS	O
+Neither	POS	O
+myeloperoxidase	POS	O
+-	POS	O
+nor	POS	O
+proteinase	POS	O
+-	POS	O
+3	POS	O
+-	POS	O
+antineutrophil	POS	O
+cytoplasmic	POS	O
+antibody	POS	O
+was	POS	O
+positive	POS	O
+.	POS	O
+These	POS	O
+manifestations	POS	O
+met	POS	O
+the	POS	O
+American	POS	O
+College	POS	O
+of	POS	O
+Rheumatology	POS	O
+1990	POS	O
+criteria	POS	O
+for	POS	O
+the	POS	O
+classification	POS	O
+of	POS	O
+polyarteritis	POS	B-NP
+nodosa	POS	I-NP
+.	POS	O
+Stopping	POS	O
+minocycline	POS	O
+led	POS	O
+to	POS	O
+amelioration	POS	O
+of	POS	O
+symptoms	POS	O
+and	POS	O
+normalization	POS	O
+of	POS	O
+CRP	POS	O
+level	POS	O
+.	POS	O
+To	POS	O
+our	POS	O
+knowledge	POS	O
+,	POS	O
+this	POS	O
+is	POS	O
+the	POS	O
+second	POS	O
+case	POS	O
+of	POS	O
+minocycline	POS	O
+-	POS	O
+induced	POS	O
+vasculitis	POS	B-NP
+satisfying	POS	O
+the	POS	O
+criteria	POS	O
+.	POS	O
+Differential	POS	O
+diagnosis	POS	O
+for	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+disease	POS	O
+is	POS	O
+invaluable	POS	O
+even	POS	O
+for	POS	O
+patients	POS	O
+with	POS	O
+classical	POS	O
+polyarteritis	POS	B-NP
+nodosa	POS	I-NP
+.	POS	O
+Intramuscular	POS	B-NP
+hepatitis	POS	I-NP
+B	POS	I-NP
+immune	POS	O
+globulin	POS	O
+combined	POS	O
+with	POS	O
+lamivudine	POS	O
+in	POS	O
+prevention	POS	O
+of	POS	O
+hepatitis	POS	B-NP
+B	POS	I-NP
+recurrence	POS	O
+after	POS	O
+liver	POS	O
+transplantation	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Combined	POS	O
+hepatitis	POS	B-NP
+B	POS	I-NP
+immune	POS	O
+globulin	POS	O
+(	POS	O
+HBIg	POS	O
+)	POS	O
+and	POS	O
+lamivudine	POS	O
+in	POS	O
+prophylaxis	POS	O
+of	POS	O
+the	POS	O
+recurrence	POS	O
+of	POS	O
+hepatitis	POS	B-NP
+B	POS	I-NP
+after	POS	O
+liver	POS	O
+transplantation	POS	O
+has	POS	O
+significantly	POS	O
+improved	POS	O
+the	POS	O
+survival	POS	O
+of	POS	O
+HBsAg	POS	O
+positive	POS	O
+patients	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+was	POS	O
+undertaken	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+outcomes	POS	O
+of	POS	O
+liver	POS	O
+transplantation	POS	O
+for	POS	O
+patients	POS	O
+with	POS	O
+hepatitis	POS	B-NP
+B	POS	I-NP
+virus	POS	O
+(	POS	O
+HBV	POS	O
+)	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+A	POS	O
+retrospective	POS	O
+chart	POS	O
+analysis	POS	O
+and	POS	O
+a	POS	O
+review	POS	O
+of	POS	O
+the	POS	O
+organ	POS	O
+transplant	POS	O
+database	POS	O
+identified	POS	O
+51	POS	O
+patients	POS	O
+(	POS	O
+43	POS	O
+men	POS	O
+and	POS	O
+8	POS	O
+women	POS	O
+)	POS	O
+transplanted	POS	O
+for	POS	O
+benign	POS	O
+HBV	POS	O
+-	POS	O
+related	POS	O
+cirrhotic	POS	B-NP
+diseases	POS	I-NP
+between	POS	O
+June	POS	O
+2002	POS	O
+and	POS	O
+December	POS	O
+2004	POS	O
+who	POS	O
+had	POS	O
+survived	POS	O
+more	POS	O
+than	POS	O
+3	POS	O
+months	POS	O
+.	POS	O
+HBIg	POS	O
+was	POS	O
+administered	POS	O
+intravenously	POS	O
+during	POS	O
+the	POS	O
+first	POS	O
+week	POS	O
+and	POS	O
+intramuscularly	POS	O
+thereafter	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+At	POS	O
+a	POS	O
+median	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+of	POS	O
+14	POS	O
+.	POS	O
+1	POS	O
+months	POS	O
+,	POS	O
+the	POS	O
+overall	POS	O
+recurrence	POS	O
+rate	POS	O
+in	POS	O
+the	POS	O
+51	POS	O
+patients	POS	O
+was	POS	O
+3	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+(	POS	O
+2	POS	O
+/	POS	O
+51	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+overall	POS	O
+patient	POS	O
+survival	POS	O
+was	POS	O
+88	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+,	POS	O
+and	POS	O
+82	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+after	POS	O
+1	POS	O
+and	POS	O
+2	POS	O
+years	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+A	POS	O
+daily	POS	O
+oral	POS	O
+dose	POS	O
+of	POS	O
+100	POS	O
+mg	POS	O
+lamivudine	POS	O
+for	POS	O
+2	POS	O
+weeks	POS	O
+before	POS	O
+transplantation	POS	O
+for	POS	O
+10	POS	O
+patients	POS	O
+enabled	POS	O
+57	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+(	POS	O
+4	POS	O
+/	POS	O
+7	POS	O
+)	POS	O
+and	POS	O
+62	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+(	POS	O
+5	POS	O
+/	POS	O
+8	POS	O
+)	POS	O
+of	POS	O
+HBV	POS	O
+-	POS	O
+DNA	POS	O
+and	POS	O
+HBeAg	POS	O
+positive	POS	O
+patients	POS	O
+respectively	POS	O
+to	POS	O
+convert	POS	O
+to	POS	O
+be	POS	O
+negative	POS	O
+.	POS	O
+Intramuscular	POS	O
+HBIg	POS	O
+was	POS	O
+well	POS	O
+tolerated	POS	O
+in	POS	O
+all	POS	O
+patients	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Lamivudine	POS	O
+combined	POS	O
+with	POS	O
+intramuscular	POS	O
+HBIg	POS	O
+can	POS	O
+effectively	POS	O
+prevent	POS	O
+allograft	POS	O
+from	POS	O
+the	POS	O
+recurrence	POS	O
+of	POS	O
+HBV	POS	O
+after	POS	O
+liver	POS	O
+transplantation	POS	O
+.	POS	O
+Anticonvulsant	POS	O
+effect	POS	O
+of	POS	O
+eslicarbazepine	POS	O
+acetate	POS	O
+(	POS	O
+BIA	POS	O
+2	POS	O
+-	POS	O
+093	POS	O
+)	POS	O
+on	POS	O
+seizures	POS	B-NP
+induced	POS	O
+by	POS	O
+microperfusion	POS	O
+of	POS	O
+picrotoxin	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+of	POS	O
+freely	POS	O
+moving	POS	O
+rats	POS	O
+.	POS	O
+Eslicarbazepine	POS	O
+acetate	POS	O
+(	POS	O
+BIA	POS	O
+2	POS	O
+-	POS	O
+093	POS	O
+,	POS	O
+S	POS	O
+-	POS	O
+(	POS	O
+-	POS	O
+)	POS	O
+-	POS	O
+10	POS	O
+-	POS	O
+acetoxy	POS	O
+-	POS	O
+10	POS	O
+,	POS	O
+11	POS	O
+-	POS	O
+dihydro	POS	O
+-	POS	O
+5H	POS	O
+-	POS	O
+dibenzo	POS	O
+/	POS	O
+b	POS	O
+,	POS	O
+f	POS	O
+/	POS	O
+azepine	POS	O
+-	POS	O
+5	POS	O
+-	POS	O
+carboxamide	POS	O
+)	POS	O
+is	POS	O
+a	POS	O
+novel	POS	O
+antiepileptic	POS	O
+drug	POS	O
+,	POS	O
+now	POS	O
+in	POS	O
+Phase	POS	O
+III	POS	O
+clinical	POS	O
+trials	POS	O
+,	POS	O
+designed	POS	O
+with	POS	O
+the	POS	O
+aim	POS	O
+of	POS	O
+improving	POS	O
+efficacy	POS	O
+and	POS	O
+safety	POS	O
+in	POS	O
+comparison	POS	O
+with	POS	O
+the	POS	O
+structurally	POS	O
+related	POS	O
+drugs	POS	O
+carbamazepine	POS	O
+(	POS	O
+CBZ	POS	O
+)	POS	O
+and	POS	O
+oxcarbazepine	POS	O
+(	POS	O
+OXC	POS	O
+)	POS	O
+.	POS	O
+We	POS	O
+have	POS	O
+studied	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+oral	POS	O
+treatment	POS	O
+with	POS	O
+eslicarbazepine	POS	O
+acetate	POS	O
+on	POS	O
+a	POS	O
+whole	POS	O
+-	POS	O
+animal	POS	O
+model	POS	O
+in	POS	O
+which	POS	O
+partial	POS	O
+seizures	POS	B-NP
+can	POS	O
+be	POS	O
+elicited	POS	O
+repeatedly	POS	O
+on	POS	O
+different	POS	O
+days	POS	O
+without	POS	O
+changes	POS	O
+in	POS	O
+threshold	POS	O
+or	POS	O
+seizure	POS	B-NP
+patterns	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+animals	POS	O
+treated	POS	O
+with	POS	O
+threshold	POS	O
+doses	POS	O
+of	POS	O
+picrotoxin	POS	O
+,	POS	O
+the	POS	O
+average	POS	O
+number	POS	O
+of	POS	O
+seizures	POS	B-NP
+was	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+,	POS	O
+and	POS	O
+average	POS	O
+seizure	POS	B-NP
+duration	POS	O
+was	POS	O
+39	POS	O
+.	POS	O
+5	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+8	POS	O
+.	POS	O
+4s	POS	O
+.	POS	O
+Pre	POS	O
+-	POS	O
+treatment	POS	O
+with	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+30	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+2h	POS	O
+before	POS	O
+picrotoxin	POS	O
+microperfusion	POS	O
+prevented	POS	O
+seizures	POS	B-NP
+in	POS	O
+the	POS	O
+75	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+rats	POS	O
+.	POS	O
+Lower	POS	O
+doses	POS	O
+(	POS	O
+3	POS	O
+and	POS	O
+10mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+did	POS	O
+not	POS	O
+suppress	POS	O
+seizures	POS	B-NP
+,	POS	O
+however	POS	O
+,	POS	O
+after	POS	O
+administration	POS	O
+of	POS	O
+10mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+significant	POS	O
+reductions	POS	O
+in	POS	O
+seizures	POS	B-NP
+duration	POS	O
+(	POS	O
+24	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+8s	POS	O
+)	POS	O
+and	POS	O
+seizure	POS	B-NP
+number	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+34	POS	O
+)	POS	O
+were	POS	O
+found	POS	O
+.	POS	O
+No	POS	O
+adverse	POS	O
+effects	POS	O
+of	POS	O
+eslicarbazepine	POS	O
+acetate	POS	O
+were	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+behavioral	POS	O
+/	POS	O
+EEG	POS	O
+patterns	POS	O
+studied	POS	O
+,	POS	O
+including	POS	O
+sleep	POS	O
+/	POS	O
+wakefulness	POS	O
+cycle	POS	O
+,	POS	O
+at	POS	O
+the	POS	O
+doses	POS	O
+studied	POS	O
+.	POS	O
+Acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+associated	POS	O
+with	POS	O
+prolonged	POS	O
+intake	POS	O
+of	POS	O
+slimming	POS	O
+pills	POS	O
+containing	POS	O
+anthraquinones	POS	O
+.	POS	O
+Chinese	POS	O
+herbal	POS	O
+medicine	POS	O
+preparations	POS	O
+are	POS	O
+widely	POS	O
+available	POS	O
+and	POS	O
+often	POS	O
+regarded	POS	O
+by	POS	O
+the	POS	O
+public	POS	O
+as	POS	O
+natural	POS	O
+and	POS	O
+safe	POS	O
+remedies	POS	O
+for	POS	O
+a	POS	O
+variety	POS	O
+of	POS	O
+medical	POS	O
+conditions	POS	O
+.	POS	O
+Nephropathy	POS	B-NP
+caused	POS	O
+by	POS	O
+Chinese	POS	O
+herbs	POS	O
+has	POS	O
+previously	POS	O
+been	POS	O
+reported	POS	O
+,	POS	O
+usually	POS	O
+involving	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+aristolochic	POS	O
+acids	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+23	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+who	POS	O
+developed	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+following	POS	O
+prolonged	POS	O
+use	POS	O
+of	POS	O
+a	POS	O
+proprietary	POS	O
+Chinese	POS	O
+herbal	POS	O
+slimming	POS	O
+pill	POS	O
+that	POS	O
+contained	POS	O
+anthraquinone	POS	O
+derivatives	POS	O
+,	POS	O
+extracted	POS	O
+from	POS	O
+Rhizoma	POS	O
+Rhei	POS	O
+(	POS	O
+rhubarb	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+renal	POS	B-NP
+injury	POS	I-NP
+was	POS	O
+probably	POS	O
+aggravated	POS	O
+by	POS	O
+the	POS	O
+concomitant	POS	O
+intake	POS	O
+of	POS	O
+a	POS	O
+non	POS	O
+-	POS	O
+steroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drug	POS	O
+,	POS	O
+diclofenac	POS	O
+.	POS	O
+Renal	POS	O
+pathology	POS	O
+was	POS	O
+that	POS	O
+of	POS	O
+hypocellular	POS	B-NP
+interstitial	POS	I-NP
+fibrosis	POS	I-NP
+.	POS	O
+Spontaneous	POS	B-NP
+renal	POS	I-NP
+recovery	POS	I-NP
+occurred	POS	O
+upon	POS	O
+cessation	POS	O
+of	POS	O
+the	POS	O
+slimming	POS	O
+pills	POS	O
+,	POS	O
+but	POS	O
+mild	POS	O
+interstitial	POS	B-NP
+fibrosis	POS	I-NP
+and	POS	O
+tubular	POS	B-NP
+atrophy	POS	I-NP
+was	POS	O
+still	POS	O
+evident	POS	O
+histologically	POS	O
+4	POS	O
+months	POS	O
+later	POS	O
+.	POS	O
+Although	POS	O
+a	POS	O
+causal	POS	O
+relationship	POS	O
+between	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+an	POS	O
+anthraquinone	POS	O
+-	POS	O
+containing	POS	O
+herbal	POS	O
+agent	POS	O
+and	POS	O
+renal	POS	B-NP
+injury	POS	I-NP
+remains	POS	O
+to	POS	O
+be	POS	O
+proven	POS	O
+,	POS	O
+phytotherapy	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+interstitial	POS	I-NP
+nephropathy	POS	I-NP
+should	POS	O
+be	POS	O
+considered	POS	O
+in	POS	O
+patients	POS	O
+who	POS	O
+present	POS	O
+with	POS	O
+unexplained	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+Chloroacetaldehyde	POS	O
+as	POS	O
+a	POS	O
+sulfhydryl	POS	O
+reagent	POS	O
+:	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+critical	POS	O
+thiol	POS	O
+groups	POS	O
+in	POS	O
+ifosfamide	POS	O
+nephropathy	POS	B-NP
+.	POS	O
+Chloroacetaldehyde	POS	O
+(	POS	O
+CAA	POS	O
+)	POS	O
+is	POS	O
+a	POS	O
+metabolite	POS	O
+of	POS	O
+the	POS	O
+alkylating	POS	O
+agent	POS	O
+ifosfamide	POS	O
+(	POS	O
+IFO	POS	O
+)	POS	O
+and	POS	O
+putatively	POS	O
+responsible	POS	O
+for	POS	O
+renal	POS	O
+damage	POS	O
+following	POS	O
+anti	POS	O
+-	POS	O
+tumor	POS	O
+therapy	POS	O
+with	POS	O
+IFO	POS	O
+.	POS	O
+Depletion	POS	O
+of	POS	O
+sulfhydryl	POS	O
+(	POS	O
+SH	POS	O
+)	POS	O
+groups	POS	O
+has	POS	O
+been	POS	O
+reported	POS	O
+from	POS	O
+cell	POS	O
+culture	POS	O
+,	POS	O
+animal	POS	O
+and	POS	O
+clinical	POS	O
+studies	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+work	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+CAA	POS	O
+on	POS	O
+human	POS	O
+proximal	POS	O
+tubule	POS	O
+cells	POS	O
+in	POS	O
+primary	POS	O
+culture	POS	O
+(	POS	O
+hRPTEC	POS	O
+)	POS	O
+was	POS	O
+investigated	POS	O
+.	POS	O
+Toxicity	POS	O
+of	POS	O
+CAA	POS	O
+was	POS	O
+determined	POS	O
+by	POS	O
+protein	POS	O
+content	POS	O
+,	POS	O
+cell	POS	O
+number	POS	O
+,	POS	O
+LDH	POS	O
+release	POS	O
+,	POS	O
+trypan	POS	O
+blue	POS	O
+exclusion	POS	O
+assay	POS	O
+and	POS	O
+caspase	POS	O
+-	POS	O
+3	POS	O
+activity	POS	O
+.	POS	O
+Free	POS	O
+thiols	POS	O
+were	POS	O
+measured	POS	O
+by	POS	O
+the	POS	O
+method	POS	O
+of	POS	O
+Ellman	POS	O
+.	POS	O
+CAA	POS	O
+reduced	POS	O
+hRPTEC	POS	O
+cell	POS	O
+number	POS	O
+and	POS	O
+protein	POS	O
+,	POS	O
+induced	POS	O
+a	POS	O
+loss	POS	O
+in	POS	O
+free	POS	O
+intracellular	POS	O
+thiols	POS	O
+and	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+necrosis	POS	B-NP
+markers	POS	O
+.	POS	O
+CAA	POS	O
+but	POS	O
+not	POS	O
+acrolein	POS	O
+inhibited	POS	O
+the	POS	O
+cysteine	POS	O
+proteases	POS	O
+caspase	POS	O
+-	POS	O
+3	POS	O
+,	POS	O
+caspase	POS	O
+-	POS	O
+8	POS	O
+and	POS	O
+cathepsin	POS	O
+B	POS	O
+.	POS	O
+Caspase	POS	O
+activation	POS	O
+by	POS	O
+cisplatin	POS	O
+was	POS	O
+inhibited	POS	O
+by	POS	O
+CAA	POS	O
+.	POS	O
+In	POS	O
+cells	POS	O
+stained	POS	O
+with	POS	O
+fluorescent	POS	O
+dyes	POS	O
+targeting	POS	O
+lysosomes	POS	O
+,	POS	O
+CAA	POS	O
+induced	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+lysosomal	POS	O
+size	POS	O
+and	POS	O
+lysosomal	POS	O
+leakage	POS	O
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+CAA	POS	O
+on	POS	O
+cysteine	POS	O
+protease	POS	O
+activities	POS	O
+and	POS	O
+thiols	POS	O
+could	POS	O
+be	POS	O
+reproduced	POS	O
+in	POS	O
+cell	POS	O
+lysate	POS	O
+.	POS	O
+Acidification	POS	O
+,	POS	O
+which	POS	O
+slowed	POS	O
+the	POS	O
+reaction	POS	O
+of	POS	O
+CAA	POS	O
+with	POS	O
+thiol	POS	O
+donors	POS	O
+,	POS	O
+could	POS	O
+also	POS	O
+attenuate	POS	O
+effects	POS	O
+of	POS	O
+CAA	POS	O
+on	POS	O
+necrosis	POS	O
+markers	POS	O
+,	POS	O
+thiol	POS	O
+depletion	POS	O
+and	POS	O
+cysteine	POS	O
+protease	POS	O
+inhibition	POS	O
+in	POS	O
+living	POS	O
+cells	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+CAA	POS	O
+directly	POS	O
+reacts	POS	O
+with	POS	O
+cellular	POS	O
+protein	POS	O
+and	POS	O
+non	POS	O
+-	POS	O
+protein	POS	O
+thiols	POS	O
+,	POS	O
+mediating	POS	O
+its	POS	O
+toxicity	POS	O
+on	POS	O
+hRPTEC	POS	O
+.	POS	O
+This	POS	O
+effect	POS	O
+can	POS	O
+be	POS	O
+reduced	POS	O
+by	POS	O
+acidification	POS	O
+.	POS	O
+Therefore	POS	O
+,	POS	O
+urinary	POS	O
+acidification	POS	O
+could	POS	O
+be	POS	O
+an	POS	O
+option	POS	O
+to	POS	O
+prevent	POS	O
+IFO	POS	O
+nephropathy	POS	B-NP
+in	POS	O
+patients	POS	O
+.	POS	O
+Stereological	POS	O
+methods	POS	O
+reveal	POS	O
+the	POS	O
+robust	POS	O
+size	POS	O
+and	POS	O
+stability	POS	O
+of	POS	O
+ectopic	POS	O
+hilar	POS	O
+granule	POS	O
+cells	POS	O
+after	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+in	POS	O
+the	POS	O
+adult	POS	O
+rat	POS	O
+.	POS	O
+Following	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+in	POS	O
+the	POS	O
+rat	POS	O
+,	POS	O
+dentate	POS	O
+granule	POS	O
+cell	POS	O
+neurogenesis	POS	O
+increases	POS	O
+greatly	POS	O
+,	POS	O
+and	POS	O
+many	POS	O
+of	POS	O
+the	POS	O
+new	POS	O
+neurons	POS	O
+appear	POS	O
+to	POS	O
+develop	POS	O
+ectopically	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+hilar	POS	O
+region	POS	O
+of	POS	O
+the	POS	O
+hippocampal	POS	O
+formation	POS	O
+.	POS	O
+It	POS	O
+has	POS	O
+been	POS	O
+suggested	POS	O
+that	POS	O
+the	POS	O
+ectopic	POS	O
+hilar	POS	O
+granule	POS	O
+cells	POS	O
+could	POS	O
+contribute	POS	O
+to	POS	O
+the	POS	O
+spontaneous	POS	O
+seizures	POS	B-NP
+that	POS	O
+ultimately	POS	O
+develop	POS	O
+after	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+population	POS	O
+has	POS	O
+never	POS	O
+been	POS	O
+quantified	POS	O
+,	POS	O
+so	POS	O
+it	POS	O
+is	POS	O
+unclear	POS	O
+whether	POS	O
+it	POS	O
+is	POS	O
+substantial	POS	O
+enough	POS	O
+to	POS	O
+have	POS	O
+a	POS	O
+strong	POS	O
+influence	POS	O
+on	POS	O
+epileptogenesis	POS	B-NP
+.	POS	O
+To	POS	O
+quantify	POS	O
+this	POS	O
+population	POS	O
+,	POS	O
+the	POS	O
+total	POS	O
+number	POS	O
+of	POS	O
+ectopic	POS	O
+hilar	POS	O
+granule	POS	O
+cells	POS	O
+was	POS	O
+estimated	POS	O
+using	POS	O
+unbiased	POS	O
+stereology	POS	O
+at	POS	O
+different	POS	O
+times	POS	O
+after	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+.	POS	O
+The	POS	O
+number	POS	O
+of	POS	O
+hilar	POS	O
+neurons	POS	O
+immunoreactive	POS	O
+for	POS	O
+Prox	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+a	POS	O
+granule	POS	O
+-	POS	O
+cell	POS	O
+-	POS	O
+specific	POS	O
+marker	POS	O
+,	POS	O
+was	POS	O
+estimated	POS	O
+using	POS	O
+the	POS	O
+optical	POS	O
+fractionator	POS	O
+method	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+the	POS	O
+size	POS	O
+of	POS	O
+the	POS	O
+hilar	POS	O
+ectopic	POS	O
+granule	POS	O
+cell	POS	O
+population	POS	O
+after	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+is	POS	O
+substantial	POS	O
+,	POS	O
+and	POS	O
+stable	POS	O
+over	POS	O
+time	POS	O
+.	POS	O
+Interestingly	POS	O
+,	POS	O
+the	POS	O
+size	POS	O
+of	POS	O
+the	POS	O
+population	POS	O
+appears	POS	O
+to	POS	O
+be	POS	O
+correlated	POS	O
+with	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+behavioral	POS	O
+seizures	POS	B-NP
+,	POS	O
+because	POS	O
+animals	POS	O
+with	POS	O
+more	POS	O
+ectopic	POS	O
+granule	POS	O
+cells	POS	O
+in	POS	O
+the	POS	O
+hilus	POS	O
+have	POS	O
+more	POS	O
+frequent	POS	O
+behavioral	POS	O
+seizures	POS	B-NP
+.	POS	O
+The	POS	O
+hilar	POS	O
+ectopic	POS	O
+granule	POS	O
+cell	POS	O
+population	POS	O
+does	POS	O
+not	POS	O
+appear	POS	O
+to	POS	O
+vary	POS	O
+systematically	POS	O
+across	POS	O
+the	POS	O
+septotemporal	POS	O
+axis	POS	O
+,	POS	O
+although	POS	O
+it	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+volume	POS	O
+of	POS	O
+the	POS	O
+hilus	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+provide	POS	O
+new	POS	O
+insight	POS	O
+into	POS	O
+the	POS	O
+potential	POS	O
+role	POS	O
+of	POS	O
+ectopic	POS	O
+hilar	POS	O
+granule	POS	O
+cells	POS	O
+in	POS	O
+the	POS	O
+pilocarpine	POS	O
+model	POS	O
+of	POS	O
+temporal	POS	B-NP
+lobe	POS	I-NP
+epilepsy	POS	I-NP
+.	POS	O
+A	POS	O
+prospective	POS	O
+,	POS	O
+open	POS	O
+-	POS	O
+label	POS	O
+trial	POS	O
+of	POS	O
+galantamine	POS	O
+in	POS	O
+autistic	POS	B-NP
+disorder	POS	I-NP
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+Post	POS	O
+-	POS	O
+mortem	POS	O
+studies	POS	O
+have	POS	O
+reported	POS	O
+abnormalities	POS	O
+of	POS	O
+the	POS	O
+cholinergic	POS	O
+system	POS	O
+in	POS	O
+autism	POS	B-NP
+.	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+assess	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+galantamine	POS	O
+,	POS	O
+an	POS	O
+acetylcholinesterase	POS	O
+inhibitor	POS	O
+and	POS	O
+nicotinic	POS	O
+receptor	POS	O
+modulator	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+interfering	POS	O
+behaviors	POS	O
+in	POS	O
+children	POS	O
+with	POS	O
+autism	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Thirteen	POS	O
+medication	POS	O
+-	POS	O
+free	POS	O
+children	POS	O
+with	POS	O
+autism	POS	B-NP
+(	POS	O
+mean	POS	O
+age	POS	O
+,	POS	O
+8	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+3	POS	O
+.	POS	O
+5	POS	O
+years	POS	O
+)	POS	O
+participated	POS	O
+in	POS	O
+a	POS	O
+12	POS	O
+-	POS	O
+week	POS	O
+,	POS	O
+open	POS	O
+-	POS	O
+label	POS	O
+trial	POS	O
+of	POS	O
+galantamine	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+rated	POS	O
+monthly	POS	O
+by	POS	O
+parents	POS	O
+on	POS	O
+the	POS	O
+Aberrant	POS	O
+Behavior	POS	O
+Checklist	POS	O
+(	POS	O
+ABC	POS	O
+)	POS	O
+and	POS	O
+the	POS	O
+Conners	POS	O
+'	POS	O
+Parent	POS	O
+Rating	POS	O
+Scale	POS	O
+-	POS	O
+Revised	POS	O
+,	POS	O
+and	POS	O
+by	POS	O
+a	POS	O
+physician	POS	O
+using	POS	O
+the	POS	O
+Children	POS	O
+'	POS	O
+s	POS	O
+Psychiatric	POS	O
+Rating	POS	O
+Scale	POS	O
+and	POS	O
+the	POS	O
+Clinical	POS	O
+Global	POS	O
+Impressions	POS	O
+scale	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Patients	POS	O
+showed	POS	O
+a	POS	O
+significant	POS	O
+reduction	POS	O
+in	POS	O
+parent	POS	O
+-	POS	O
+rated	POS	O
+irritability	POS	B-NP
+and	POS	O
+social	POS	O
+withdrawal	POS	O
+on	POS	O
+the	POS	O
+ABC	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+significant	POS	O
+improvements	POS	O
+in	POS	O
+emotional	POS	O
+lability	POS	O
+and	POS	O
+inattention	POS	B-NP
+on	POS	O
+the	POS	O
+Conners	POS	O
+'	POS	O
+Parent	POS	O
+Rating	POS	O
+Scale	POS	O
+-	POS	O
+-	POS	O
+Revised	POS	O
+.	POS	O
+Similarly	POS	O
+,	POS	O
+clinician	POS	O
+ratings	POS	O
+showed	POS	O
+reductions	POS	O
+in	POS	O
+the	POS	O
+anger	POS	O
+subscale	POS	O
+of	POS	O
+the	POS	O
+Children	POS	O
+'	POS	O
+s	POS	O
+Psychiatric	POS	O
+Rating	POS	O
+Scale	POS	O
+.	POS	O
+Eight	POS	O
+of	POS	O
+13	POS	O
+participants	POS	O
+were	POS	O
+rated	POS	O
+as	POS	O
+responders	POS	O
+on	POS	O
+the	POS	O
+basis	POS	O
+of	POS	O
+their	POS	O
+improvement	POS	O
+scores	POS	O
+on	POS	O
+the	POS	O
+Clinical	POS	O
+Global	POS	O
+Impressions	POS	O
+scale	POS	O
+.	POS	O
+Overall	POS	O
+,	POS	O
+galantamine	POS	O
+was	POS	O
+well	POS	O
+-	POS	O
+tolerated	POS	O
+,	POS	O
+with	POS	O
+no	POS	O
+significant	POS	O
+adverse	POS	O
+effects	POS	O
+apart	POS	O
+from	POS	O
+headaches	POS	B-NP
+in	POS	O
+one	POS	O
+patient	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+In	POS	O
+this	POS	O
+open	POS	O
+trial	POS	O
+,	POS	O
+galantamine	POS	O
+was	POS	O
+well	POS	O
+-	POS	O
+tolerated	POS	O
+and	POS	O
+appeared	POS	O
+to	POS	O
+be	POS	O
+beneficial	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+interfering	POS	O
+behaviors	POS	O
+in	POS	O
+children	POS	O
+with	POS	O
+autism	POS	B-NP
+,	POS	O
+particularly	POS	O
+aggression	POS	B-NP
+,	POS	O
+behavioral	POS	B-NP
+dyscontrol	POS	I-NP
+,	POS	O
+and	POS	O
+inattention	POS	B-NP
+.	POS	O
+Further	POS	O
+controlled	POS	O
+trials	POS	O
+are	POS	O
+warranted	POS	O
+.	POS	O
+Randomized	POS	O
+comparison	POS	O
+of	POS	O
+olanzapine	POS	O
+versus	POS	O
+risperidone	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+first	POS	O
+-	POS	O
+episode	POS	O
+schizophrenia	POS	B-NP
+:	POS	O
+4	POS	O
+-	POS	O
+month	POS	O
+outcomes	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+The	POS	O
+authors	POS	O
+compared	POS	O
+4	POS	O
+-	POS	O
+month	POS	O
+treatment	POS	O
+outcomes	POS	O
+for	POS	O
+olanzapine	POS	O
+versus	POS	O
+risperidone	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+first	POS	O
+-	POS	O
+episode	POS	O
+schizophrenia	POS	B-NP
+spectrum	POS	O
+disorders	POS	O
+.	POS	O
+METHOD	POS	O
+:	POS	O
+One	POS	O
+hundred	POS	O
+twelve	POS	O
+subjects	POS	O
+(	POS	O
+70	POS	O
+%	POS	O
+male	POS	O
+;	POS	O
+mean	POS	O
+age	POS	O
+=	POS	O
+23	POS	O
+.	POS	O
+3	POS	O
+years	POS	O
+[	POS	O
+SD	POS	O
+=	POS	O
+5	POS	O
+.	POS	O
+1	POS	O
+]	POS	O
+)	POS	O
+with	POS	O
+first	POS	O
+-	POS	O
+episode	POS	O
+schizophrenia	POS	B-NP
+(	POS	O
+75	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+schizophreniform	POS	B-NP
+disorder	POS	I-NP
+(	POS	O
+17	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+or	POS	O
+schizoaffective	POS	B-NP
+disorder	POS	I-NP
+(	POS	O
+8	POS	O
+%	POS	O
+)	POS	O
+were	POS	O
+randomly	POS	O
+assigned	POS	O
+to	POS	O
+treatment	POS	O
+with	POS	O
+olanzapine	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+or	POS	O
+risperidone	POS	O
+(	POS	O
+1	POS	O
+-	POS	O
+6	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Response	POS	O
+rates	POS	O
+did	POS	O
+not	POS	O
+significantly	POS	O
+differ	POS	O
+between	POS	O
+olanzapine	POS	O
+(	POS	O
+43	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+28	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+-	POS	O
+58	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+risperidone	POS	O
+(	POS	O
+54	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+39	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+-	POS	O
+68	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Among	POS	O
+those	POS	O
+responding	POS	O
+to	POS	O
+treatment	POS	O
+,	POS	O
+more	POS	O
+subjects	POS	O
+in	POS	O
+the	POS	O
+olanzapine	POS	O
+group	POS	O
+(	POS	O
+40	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+16	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+-	POS	O
+65	POS	O
+.	POS	O
+0	POS	O
+%	POS	O
+)	POS	O
+than	POS	O
+in	POS	O
+the	POS	O
+risperidone	POS	O
+group	POS	O
+(	POS	O
+18	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+0	POS	O
+%	POS	O
+-	POS	O
+39	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+)	POS	O
+had	POS	O
+subsequent	POS	O
+ratings	POS	O
+not	POS	O
+meeting	POS	O
+response	POS	O
+criteria	POS	O
+.	POS	O
+Negative	POS	O
+symptom	POS	O
+outcomes	POS	O
+and	POS	O
+measures	POS	O
+of	POS	O
+parkinsonism	POS	B-NP
+and	POS	O
+akathisia	POS	B-NP
+did	POS	O
+not	POS	O
+differ	POS	O
+between	POS	O
+medications	POS	O
+.	POS	O
+Extrapyramidal	POS	B-NP
+symptom	POS	I-NP
+severity	POS	O
+scores	POS	O
+were	POS	O
+1	POS	O
+.	POS	O
+4	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+6	POS	O
+)	POS	O
+with	POS	O
+risperidone	POS	O
+and	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+0	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+4	POS	O
+)	POS	O
+with	POS	O
+olanzapine	POS	O
+.	POS	O
+Significantly	POS	O
+more	POS	O
+weight	POS	O
+gain	POS	O
+occurred	POS	O
+with	POS	O
+olanzapine	POS	O
+than	POS	O
+with	POS	O
+risperidone	POS	O
+:	POS	O
+the	POS	O
+increase	POS	O
+in	POS	O
+weight	POS	O
+at	POS	O
+4	POS	O
+months	POS	O
+relative	POS	O
+to	POS	O
+baseline	POS	O
+weight	POS	O
+was	POS	O
+17	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+14	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+-	POS	O
+20	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+with	POS	O
+olanzapine	POS	O
+and	POS	O
+11	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+8	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+-	POS	O
+14	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+)	POS	O
+with	POS	O
+risperidone	POS	O
+.	POS	O
+Body	POS	O
+mass	POS	O
+index	POS	O
+at	POS	O
+baseline	POS	O
+and	POS	O
+at	POS	O
+4	POS	O
+months	POS	O
+was	POS	O
+24	POS	O
+.	POS	O
+3	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+22	POS	O
+.	POS	O
+8	POS	O
+-	POS	O
+25	POS	O
+.	POS	O
+7	POS	O
+)	POS	O
+versus	POS	O
+28	POS	O
+.	POS	O
+2	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+26	POS	O
+.	POS	O
+7	POS	O
+-	POS	O
+29	POS	O
+.	POS	O
+7	POS	O
+)	POS	O
+with	POS	O
+olanzapine	POS	O
+and	POS	O
+23	POS	O
+.	POS	O
+9	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+22	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+25	POS	O
+.	POS	O
+3	POS	O
+)	POS	O
+versus	POS	O
+26	POS	O
+.	POS	O
+7	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+25	POS	O
+.	POS	O
+2	POS	O
+-	POS	O
+28	POS	O
+.	POS	O
+2	POS	O
+)	POS	O
+with	POS	O
+risperidone	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Clinical	POS	O
+outcomes	POS	O
+with	POS	O
+risperidone	POS	O
+were	POS	O
+equal	POS	O
+to	POS	O
+those	POS	O
+with	POS	O
+olanzapine	POS	O
+,	POS	O
+and	POS	O
+response	POS	O
+may	POS	O
+be	POS	O
+more	POS	O
+stable	POS	O
+.	POS	O
+Olanzapine	POS	O
+may	POS	O
+have	POS	O
+an	POS	O
+advantage	POS	O
+for	POS	O
+motor	POS	O
+side	POS	O
+effects	POS	O
+.	POS	O
+Both	POS	O
+medications	POS	O
+caused	POS	O
+substantial	POS	O
+rapid	POS	O
+weight	POS	O
+gain	POS	O
+,	POS	O
+but	POS	O
+weight	POS	B-NP
+gain	POS	I-NP
+was	POS	O
+greater	POS	O
+with	POS	O
+olanzapine	POS	O
+.	POS	O
+Early	POS	B-NP
+paracentral	POS	I-NP
+visual	POS	I-NP
+field	POS	I-NP
+loss	POS	I-NP
+in	POS	O
+patients	POS	O
+taking	POS	O
+hydroxychloroquine	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+review	POS	O
+the	POS	O
+natural	POS	O
+history	POS	O
+and	POS	O
+ocular	POS	O
+and	POS	O
+systemic	POS	O
+adverse	POS	O
+effects	POS	O
+of	POS	O
+patients	POS	O
+taking	POS	O
+hydroxychloroquine	POS	O
+sulfate	POS	O
+who	POS	O
+attended	POS	O
+an	POS	O
+ophthalmic	POS	O
+screening	POS	O
+program	POS	O
+.	POS	O
+DESIGN	POS	O
+:	POS	O
+Retrospective	POS	O
+study	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Records	POS	O
+of	POS	O
+262	POS	O
+patients	POS	O
+who	POS	O
+were	POS	O
+taking	POS	O
+hydroxychloroquine	POS	O
+and	POS	O
+screened	POS	O
+in	POS	O
+the	POS	O
+Department	POS	O
+of	POS	O
+Ophthalmology	POS	O
+were	POS	O
+reviewed	POS	O
+.	POS	O
+Of	POS	O
+the	POS	O
+262	POS	O
+patients	POS	O
+,	POS	O
+14	POS	O
+(	POS	O
+18	POS	O
+%	POS	O
+)	POS	O
+of	POS	O
+76	POS	O
+who	POS	O
+had	POS	O
+stopped	POS	O
+treatment	POS	O
+at	POS	O
+the	POS	O
+time	POS	O
+of	POS	O
+the	POS	O
+study	POS	O
+experienced	POS	O
+documented	POS	O
+adverse	POS	O
+effects	POS	O
+.	POS	O
+Systemic	POS	O
+adverse	POS	O
+effects	POS	O
+occurred	POS	O
+in	POS	O
+8	POS	O
+patients	POS	O
+(	POS	O
+10	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+ocular	POS	O
+adverse	POS	O
+effects	POS	O
+,	POS	O
+in	POS	O
+5	POS	O
+(	POS	O
+6	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Thirty	POS	O
+-	POS	O
+five	POS	O
+patients	POS	O
+(	POS	O
+13	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+had	POS	O
+visual	POS	B-NP
+field	POS	I-NP
+abnormalities	POS	I-NP
+,	POS	O
+which	POS	O
+were	POS	O
+attributed	POS	O
+to	POS	O
+hydroxychloroquine	POS	O
+treatment	POS	O
+in	POS	O
+4	POS	O
+patients	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Three	POS	O
+of	POS	O
+the	POS	O
+4	POS	O
+patients	POS	O
+were	POS	O
+taking	POS	O
+less	POS	O
+than	POS	O
+6	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+per	POS	O
+day	POS	O
+and	POS	O
+all	POS	O
+patients	POS	O
+had	POS	O
+normal	POS	O
+renal	POS	O
+and	POS	O
+liver	POS	O
+function	POS	O
+test	POS	O
+results	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+current	POS	O
+study	POS	O
+used	POS	O
+a	POS	O
+protocol	POS	O
+of	POS	O
+visual	POS	O
+acuity	POS	O
+and	POS	O
+color	POS	O
+vision	POS	O
+assessment	POS	O
+,	POS	O
+funduscopy	POS	O
+,	POS	O
+and	POS	O
+Humphrey	POS	O
+10	POS	O
+-	POS	O
+2	POS	O
+visual	POS	O
+field	POS	O
+testing	POS	O
+and	POS	O
+shows	POS	O
+that	POS	O
+visual	POS	B-NP
+field	POS	I-NP
+defects	POS	I-NP
+appeared	POS	O
+before	POS	O
+any	POS	O
+corresponding	POS	O
+changes	POS	O
+in	POS	O
+any	POS	O
+other	POS	O
+tested	POS	O
+clinical	POS	O
+parameters	POS	O
+;	POS	O
+the	POS	O
+defects	POS	O
+were	POS	O
+reproducible	POS	O
+and	POS	O
+the	POS	O
+test	POS	O
+parameters	POS	O
+were	POS	O
+reliable	POS	O
+.	POS	O
+Patients	POS	O
+taking	POS	O
+hydroxychloroquine	POS	O
+can	POS	O
+demonstrate	POS	O
+a	POS	O
+toxic	POS	O
+reaction	POS	O
+in	POS	O
+the	POS	O
+retina	POS	O
+despite	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+known	POS	O
+risk	POS	O
+factors	POS	O
+.	POS	O
+Screening	POS	O
+,	POS	O
+including	POS	O
+Humphrey	POS	O
+10	POS	O
+-	POS	O
+2	POS	O
+visual	POS	O
+field	POS	O
+assessment	POS	O
+,	POS	O
+is	POS	O
+recommended	POS	O
+2	POS	O
+years	POS	O
+after	POS	O
+the	POS	O
+initial	POS	O
+baseline	POS	O
+and	POS	O
+yearly	POS	O
+thereafter	POS	O
+.	POS	O
+Peri	POS	O
+-	POS	O
+operative	POS	O
+atrioventricular	POS	B-NP
+block	POS	I-NP
+as	POS	O
+a	POS	O
+result	POS	O
+of	POS	O
+chemotherapy	POS	O
+with	POS	O
+epirubicin	POS	O
+and	POS	O
+paclitaxel	POS	O
+.	POS	O
+A	POS	O
+47	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+presented	POS	O
+for	POS	O
+mastectomy	POS	O
+and	POS	O
+immediate	POS	O
+latissimus	POS	O
+dorsi	POS	O
+flap	POS	O
+reconstruction	POS	O
+having	POS	O
+been	POS	O
+diagnosed	POS	O
+with	POS	O
+carcinoma	POS	B-NP
+of	POS	O
+the	POS	O
+breast	POS	O
+6	POS	O
+months	POS	O
+previously	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+preceding	POS	O
+months	POS	O
+she	POS	O
+had	POS	O
+received	POS	O
+neo	POS	O
+-	POS	O
+adjuvant	POS	O
+chemotherapy	POS	O
+with	POS	O
+epirubicin	POS	O
+,	POS	O
+paclitaxel	POS	O
+(	POS	O
+Taxol	POS	O
+)	POS	O
+and	POS	O
+cyclophosphamide	POS	O
+.	POS	O
+This	POS	O
+had	POS	O
+been	POS	O
+apparently	POS	O
+uncomplicated	POS	O
+and	POS	O
+she	POS	O
+had	POS	O
+maintained	POS	O
+a	POS	O
+remarkably	POS	O
+high	POS	O
+level	POS	O
+of	POS	O
+physical	POS	O
+activity	POS	O
+.	POS	O
+She	POS	O
+was	POS	O
+found	POS	O
+to	POS	O
+be	POS	O
+bradycardic	POS	O
+at	POS	O
+pre	POS	O
+-	POS	O
+operative	POS	O
+assessment	POS	O
+but	POS	O
+had	POS	O
+no	POS	O
+cardiac	POS	B-NP
+symptoms	POS	I-NP
+.	POS	O
+Second	POS	O
+degree	POS	O
+Mobitz	POS	B-NP
+type	POS	I-NP
+II	POS	I-NP
+atrioventricular	POS	I-NP
+block	POS	I-NP
+was	POS	O
+diagnosed	POS	O
+on	POS	O
+electrocardiogram	POS	O
+,	POS	O
+and	POS	O
+temporary	POS	O
+transvenous	POS	O
+ventricular	POS	O
+pacing	POS	O
+instituted	POS	O
+in	POS	O
+the	POS	O
+peri	POS	O
+-	POS	O
+operative	POS	O
+period	POS	O
+.	POS	O
+We	POS	O
+discuss	POS	O
+how	POS	O
+evidence	POS	O
+-	POS	O
+based	POS	O
+guidelines	POS	O
+would	POS	O
+not	POS	O
+have	POS	O
+been	POS	O
+helpful	POS	O
+in	POS	O
+this	POS	O
+case	POS	O
+,	POS	O
+and	POS	O
+how	POS	O
+chemotherapy	POS	O
+can	POS	O
+exhibit	POS	O
+substantial	POS	O
+cardiotoxicity	POS	B-NP
+that	POS	O
+may	POS	O
+develop	POS	O
+over	POS	O
+many	POS	O
+years	POS	O
+.	POS	O
+We	POS	O
+suggest	POS	O
+that	POS	O
+patients	POS	O
+who	POS	O
+have	POS	O
+received	POS	O
+chemotherapy	POS	O
+at	POS	O
+any	POS	O
+time	POS	O
+should	POS	O
+have	POS	O
+a	POS	O
+pre	POS	O
+-	POS	O
+operative	POS	O
+electrocardiogram	POS	O
+even	POS	O
+if	POS	O
+they	POS	O
+are	POS	O
+asymptomatic	POS	O
+.	POS	O
+Risks	POS	O
+and	POS	O
+benefits	POS	O
+of	POS	O
+COX	POS	O
+-	POS	O
+2	POS	O
+inhibitors	POS	O
+vs	POS	O
+non	POS	O
+-	POS	O
+selective	POS	O
+NSAIDs	POS	O
+:	POS	O
+does	POS	O
+their	POS	O
+cardiovascular	POS	O
+risk	POS	O
+exceed	POS	O
+their	POS	O
+gastrointestinal	POS	O
+benefit	POS	O
+?	POS	O
+A	POS	O
+retrospective	POS	O
+cohort	POS	O
+study	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+The	POS	O
+risk	POS	O
+of	POS	O
+acute	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+(	POS	O
+AMI	POS	B-NP
+)	POS	O
+with	POS	O
+COX	POS	O
+-	POS	O
+2	POS	O
+inhibitors	POS	O
+may	POS	O
+offset	POS	O
+their	POS	O
+gastrointestinal	POS	O
+(	POS	O
+GI	POS	O
+)	POS	O
+benefit	POS	O
+compared	POS	O
+with	POS	O
+non	POS	O
+-	POS	O
+selective	POS	O
+(	POS	O
+NS	POS	O
+)	POS	O
+non	POS	O
+-	POS	O
+steroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+(	POS	O
+NSAIDs	POS	O
+)	POS	O
+.	POS	O
+We	POS	O
+aimed	POS	O
+to	POS	O
+compare	POS	O
+the	POS	O
+risks	POS	O
+of	POS	O
+hospitalization	POS	O
+for	POS	O
+AMI	POS	B-NP
+and	POS	O
+GI	POS	B-NP
+bleeding	POS	I-NP
+among	POS	O
+elderly	POS	O
+patients	POS	O
+using	POS	O
+COX	POS	O
+-	POS	O
+2	POS	O
+inhibitors	POS	O
+,	POS	O
+NS	POS	O
+-	POS	O
+NSAIDs	POS	O
+and	POS	O
+acetaminophen	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+conducted	POS	O
+a	POS	O
+retrospective	POS	O
+cohort	POS	O
+study	POS	O
+using	POS	O
+administrative	POS	O
+data	POS	O
+of	POS	O
+patients	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+65	POS	O
+years	POS	O
+of	POS	O
+age	POS	O
+who	POS	O
+filled	POS	O
+a	POS	O
+prescription	POS	O
+for	POS	O
+NSAID	POS	O
+or	POS	O
+acetaminophen	POS	O
+during	POS	O
+1999	POS	O
+-	POS	O
+2002	POS	O
+.	POS	O
+Outcomes	POS	O
+were	POS	O
+compared	POS	O
+using	POS	O
+Cox	POS	O
+regression	POS	O
+models	POS	O
+with	POS	O
+time	POS	O
+-	POS	O
+dependent	POS	O
+exposures	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Person	POS	O
+-	POS	O
+years	POS	O
+of	POS	O
+exposure	POS	O
+among	POS	O
+non	POS	O
+-	POS	O
+users	POS	O
+of	POS	O
+aspirin	POS	O
+were	POS	O
+:	POS	O
+75	POS	O
+,	POS	O
+761	POS	O
+to	POS	O
+acetaminophen	POS	O
+,	POS	O
+42	POS	O
+,	POS	O
+671	POS	O
+to	POS	O
+rofecoxib	POS	O
+65	POS	O
+,	POS	O
+860	POS	O
+to	POS	O
+celecoxib	POS	O
+,	POS	O
+and	POS	O
+37	POS	O
+,	POS	O
+495	POS	O
+to	POS	O
+NS	POS	O
+-	POS	O
+NSAIDs	POS	O
+.	POS	O
+Among	POS	O
+users	POS	O
+of	POS	O
+aspirin	POS	O
+,	POS	O
+they	POS	O
+were	POS	O
+:	POS	O
+14	POS	O
+,	POS	O
+671	POS	O
+to	POS	O
+rofecoxib	POS	O
+,	POS	O
+22	POS	O
+,	POS	O
+875	POS	O
+to	POS	O
+celecoxib	POS	O
+,	POS	O
+9	POS	O
+,	POS	O
+832	POS	O
+to	POS	O
+NS	POS	O
+-	POS	O
+NSAIDs	POS	O
+and	POS	O
+38	POS	O
+,	POS	O
+048	POS	O
+to	POS	O
+acetaminophen	POS	O
+.	POS	O
+Among	POS	O
+non	POS	O
+-	POS	O
+users	POS	O
+of	POS	O
+aspirin	POS	O
+,	POS	O
+the	POS	O
+adjusted	POS	O
+hazard	POS	O
+ratios	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+)	POS	O
+of	POS	O
+hospitalization	POS	O
+for	POS	O
+AMI	POS	B-NP
+/	POS	O
+GI	POS	O
+vs	POS	O
+the	POS	O
+acetaminophen	POS	O
+(	POS	O
+with	POS	O
+no	POS	O
+aspirin	POS	O
+)	POS	O
+group	POS	O
+were	POS	O
+:	POS	O
+rofecoxib	POS	O
+1	POS	O
+.	POS	O
+27	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+13	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+42	POS	O
+)	POS	O
+,	POS	O
+celecoxib	POS	O
+0	POS	O
+.	POS	O
+93	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+83	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+03	POS	O
+)	POS	O
+,	POS	O
+naproxen	POS	O
+1	POS	O
+.	POS	O
+59	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+31	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+93	POS	O
+)	POS	O
+,	POS	O
+diclofenac	POS	O
+1	POS	O
+.	POS	O
+17	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+99	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+38	POS	O
+)	POS	O
+and	POS	O
+ibuprofen	POS	O
+1	POS	O
+.	POS	O
+05	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+74	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+51	POS	O
+)	POS	O
+.	POS	O
+Among	POS	O
+users	POS	O
+of	POS	O
+aspirin	POS	O
+,	POS	O
+they	POS	O
+were	POS	O
+:	POS	O
+rofecoxib	POS	O
+1	POS	O
+.	POS	O
+73	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+52	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+98	POS	O
+)	POS	O
+,	POS	O
+celecoxib	POS	O
+1	POS	O
+.	POS	O
+34	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+19	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+52	POS	O
+)	POS	O
+,	POS	O
+ibuprofen	POS	O
+1	POS	O
+.	POS	O
+51	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+95	POS	O
+,	POS	O
+2	POS	O
+.	POS	O
+41	POS	O
+)	POS	O
+,	POS	O
+diclofenac	POS	O
+1	POS	O
+.	POS	O
+69	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+35	POS	O
+,	POS	O
+2	POS	O
+.	POS	O
+10	POS	O
+)	POS	O
+,	POS	O
+naproxen	POS	O
+1	POS	O
+.	POS	O
+35	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+97	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+88	POS	O
+)	POS	O
+and	POS	O
+acetaminophen	POS	O
+1	POS	O
+.	POS	O
+29	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+17	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+42	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Among	POS	O
+non	POS	O
+-	POS	O
+users	POS	O
+of	POS	O
+aspirin	POS	O
+,	POS	O
+naproxen	POS	O
+seemed	POS	O
+to	POS	O
+carry	POS	O
+the	POS	O
+highest	POS	O
+risk	POS	O
+for	POS	O
+AMI	POS	B-NP
+/	POS	O
+GI	POS	B-NP
+bleeding	POS	I-NP
+.	POS	O
+The	POS	O
+AMI	POS	O
+/	POS	O
+GI	POS	B-NP
+toxicity	POS	I-NP
+of	POS	O
+celecoxib	POS	O
+was	POS	O
+similar	POS	O
+to	POS	O
+that	POS	O
+of	POS	O
+acetaminophen	POS	O
+and	POS	O
+seemed	POS	O
+to	POS	O
+be	POS	O
+better	POS	O
+than	POS	O
+those	POS	O
+of	POS	O
+rofecoxib	POS	O
+and	POS	O
+NS	POS	O
+-	POS	O
+NSAIDs	POS	O
+.	POS	O
+Among	POS	O
+users	POS	O
+of	POS	O
+aspirin	POS	O
+,	POS	O
+both	POS	O
+celecoxib	POS	O
+and	POS	O
+naproxen	POS	O
+seemed	POS	O
+to	POS	O
+be	POS	O
+the	POS	O
+least	POS	O
+toxic	POS	O
+.	POS	O
+Quinine	POS	O
+-	POS	O
+induced	POS	O
+arrhythmia	POS	B-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+severe	POS	O
+malaria	POS	B-NP
+.	POS	O
+It	POS	O
+was	POS	O
+reported	POS	O
+that	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+severe	POS	O
+malaria	POS	B-NP
+patient	POS	O
+with	POS	O
+jaundice	POS	B-NP
+who	POS	O
+presented	POS	O
+with	POS	O
+arrhythmia	POS	B-NP
+(	POS	O
+premature	POS	B-NP
+ventricular	POS	I-NP
+contraction	POS	I-NP
+)	POS	O
+while	POS	O
+getting	POS	O
+quinine	POS	O
+infusion	POS	O
+was	POS	O
+reported	POS	O
+.	POS	O
+A	POS	O
+man	POS	O
+,	POS	O
+25	POS	O
+years	POS	O
+old	POS	O
+,	POS	O
+was	POS	O
+admitted	POS	O
+to	POS	O
+hospital	POS	O
+with	POS	O
+high	POS	B-NP
+fever	POS	I-NP
+,	POS	O
+chill	POS	B-NP
+,	POS	O
+vomiting	POS	B-NP
+,	POS	O
+jaundice	POS	B-NP
+.	POS	O
+The	POS	O
+patient	POS	O
+was	POS	O
+fully	POS	O
+conscious	POS	O
+,	POS	O
+blood	POS	O
+pressure	POS	O
+120	POS	O
+/	POS	O
+80	POS	O
+mmHg	POS	O
+,	POS	O
+pulse	POS	O
+rate	POS	O
+100	POS	O
+x	POS	O
+/	POS	O
+minute	POS	O
+,	POS	O
+regular	POS	O
+.	POS	O
+On	POS	O
+admission	POS	O
+,	POS	O
+laboratory	POS	O
+examination	POS	O
+showed	POS	O
+Plasmodium	POS	O
+falciparum	POS	O
+(	POS	O
++	POS	O
++	POS	O
++	POS	O
++	POS	O
+)	POS	O
+,	POS	O
+total	POS	O
+bilirubin	POS	O
+8	POS	O
+.	POS	O
+25	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+,	POS	O
+conjugated	POS	O
+bilirubin	POS	O
+4	POS	O
+.	POS	O
+36	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+,	POS	O
+unconjugated	POS	O
+bilirubin	POS	O
+3	POS	O
+.	POS	O
+89	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+,	POS	O
+potassium	POS	O
+3	POS	O
+.	POS	O
+52	POS	O
+meq	POS	O
+/	POS	O
+L	POS	O
+Patient	POS	O
+was	POS	O
+diagnosed	POS	O
+as	POS	O
+severe	POS	O
+malaria	POS	B-NP
+with	POS	O
+jaundice	POS	B-NP
+and	POS	O
+got	POS	O
+quinine	POS	O
+infusion	POS	O
+in	POS	O
+dextrose	POS	O
+5	POS	O
+%	POS	O
+500	POS	O
+mg	POS	O
+/	POS	O
+8	POS	O
+hour	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+second	POS	O
+day	POS	O
+the	POS	O
+patient	POS	O
+had	POS	O
+vomitus	POS	B-NP
+,	POS	O
+diarrhea	POS	B-NP
+,	POS	O
+tinnitus	POS	B-NP
+,	POS	O
+loss	POS	B-NP
+of	POS	I-NP
+hearing	POS	I-NP
+.	POS	O
+After	POS	O
+30	POS	O
+hours	POS	O
+of	POS	O
+quinine	POS	O
+infusion	POS	O
+the	POS	O
+patient	POS	O
+felt	POS	O
+palpitation	POS	B-NP
+and	POS	O
+electrocardiography	POS	O
+(	POS	O
+ECG	POS	O
+)	POS	O
+recording	POS	O
+showed	POS	O
+premature	POS	B-NP
+ventricular	POS	I-NP
+contraction	POS	I-NP
+(	POS	O
+PVC	POS	O
+)	POS	O
+>	POS	O
+5	POS	O
+x	POS	O
+/	POS	O
+minute	POS	O
+,	POS	O
+trigemini	POS	O
+,	POS	O
+constant	POS	O
+type	POS	O
+-	POS	O
+-	POS	O
+sinoatrial	POS	O
+block	POS	O
+,	POS	O
+positive	POS	O
+U	POS	O
+wave	POS	O
+.	POS	O
+He	POS	O
+was	POS	O
+treated	POS	O
+with	POS	O
+lidocaine	POS	O
+50	POS	O
+mg	POS	O
+intravenously	POS	O
+followed	POS	O
+by	POS	O
+infusion	POS	O
+1500	POS	O
+mg	POS	O
+in	POS	O
+dextrose	POS	O
+5	POS	O
+%	POS	O
+/	POS	O
+24	POS	O
+hour	POS	O
+and	POS	O
+potassium	POS	O
+aspartate	POS	O
+tablet	POS	O
+.	POS	O
+Quinine	POS	O
+infusion	POS	O
+was	POS	O
+discontinued	POS	O
+and	POS	O
+changed	POS	O
+with	POS	O
+sulfate	POS	O
+quinine	POS	O
+tablets	POS	O
+.	POS	O
+Three	POS	O
+hours	POS	O
+later	POS	O
+the	POS	O
+patient	POS	O
+felt	POS	O
+better	POS	O
+,	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+PVC	POS	O
+reduced	POS	O
+to	POS	O
+4	POS	O
+-	POS	O
+5	POS	O
+x	POS	O
+/	POS	O
+minute	POS	O
+and	POS	O
+on	POS	O
+the	POS	O
+third	POS	O
+day	POS	O
+ECG	POS	O
+was	POS	O
+normal	POS	O
+,	POS	O
+potassium	POS	O
+level	POS	O
+was	POS	O
+3	POS	O
+.	POS	O
+34	POS	O
+meq	POS	O
+/	POS	O
+L	POS	O
+.	POS	O
+He	POS	O
+was	POS	O
+discharged	POS	O
+on	POS	O
+7th	POS	O
+day	POS	O
+in	POS	O
+good	POS	O
+condition	POS	O
+.	POS	O
+Quinine	POS	O
+,	POS	O
+like	POS	O
+quinidine	POS	O
+,	POS	O
+is	POS	O
+a	POS	O
+chincona	POS	O
+alkaloid	POS	O
+that	POS	O
+has	POS	O
+anti	POS	O
+-	POS	O
+arrhythmic	POS	O
+property	POS	O
+,	POS	O
+although	POS	O
+it	POS	O
+also	POS	O
+pro	POS	O
+-	POS	O
+arrhythmic	POS	O
+that	POS	O
+can	POS	O
+cause	POS	O
+various	POS	O
+arrhythmias	POS	B-NP
+,	POS	O
+including	POS	O
+severe	POS	O
+arrhythmia	POS	B-NP
+such	POS	O
+as	POS	O
+multiple	POS	O
+PVC	POS	O
+.	POS	O
+Administration	POS	O
+of	POS	O
+parenteral	POS	O
+quinine	POS	O
+must	POS	O
+be	POS	O
+done	POS	O
+carefully	POS	O
+and	POS	O
+with	POS	O
+good	POS	O
+observation	POS	O
+because	POS	O
+of	POS	O
+its	POS	O
+pro	POS	O
+-	POS	O
+arrhythmic	POS	O
+effect	POS	O
+,	POS	O
+especially	POS	O
+in	POS	O
+older	POS	O
+patients	POS	O
+who	POS	O
+have	POS	O
+heart	POS	B-NP
+diseases	POS	I-NP
+or	POS	O
+patients	POS	O
+with	POS	O
+electrolyte	POS	B-NP
+disorder	POS	I-NP
+(	POS	O
+hypokalemia	POS	B-NP
+)	POS	O
+which	POS	O
+frequently	POS	O
+occurs	POS	O
+due	POS	O
+to	POS	O
+vomiting	POS	B-NP
+and	POS	O
+or	POS	O
+diarrhea	POS	B-NP
+in	POS	O
+malaria	POS	B-NP
+cases	POS	O
+.	POS	O
+Penicillamine	POS	B-NP
+-	POS	I-NP
+related	POS	I-NP
+lichenoid	POS	I-NP
+dermatitis	POS	I-NP
+and	POS	O
+utility	POS	O
+of	POS	O
+zinc	POS	O
+acetate	POS	O
+in	POS	O
+a	POS	O
+Wilson	POS	B-NP
+disease	POS	I-NP
+patient	POS	O
+with	POS	O
+hepatic	POS	B-NP
+presentation	POS	I-NP
+,	POS	O
+anxiety	POS	B-NP
+and	POS	O
+SPECT	POS	B-NP
+abnormalities	POS	I-NP
+.	POS	O
+Wilson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+is	POS	O
+an	POS	O
+autosomal	POS	B-NP
+recessive	POS	I-NP
+disorder	POS	I-NP
+of	POS	I-NP
+hepatic	POS	I-NP
+copper	POS	I-NP
+metabolism	POS	I-NP
+with	POS	O
+consequent	POS	O
+copper	POS	O
+accumulation	POS	O
+and	POS	O
+toxicity	POS	B-NP
+in	POS	O
+many	POS	O
+tissues	POS	O
+and	POS	O
+consequent	POS	O
+hepatic	POS	O
+,	POS	O
+neurologic	POS	O
+and	POS	O
+psychiatric	POS	B-NP
+disorders	POS	I-NP
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+Wilson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+with	POS	O
+chronic	POS	B-NP
+liver	POS	I-NP
+disease	POS	I-NP
+;	POS	O
+moreover	POS	O
+,	POS	O
+in	POS	O
+our	POS	O
+patient	POS	O
+,	POS	O
+presenting	POS	O
+also	POS	O
+with	POS	O
+high	POS	O
+levels	POS	O
+of	POS	O
+state	POS	O
+anxiety	POS	B-NP
+without	POS	O
+depression	POS	B-NP
+,	POS	O
+99mTc	POS	O
+-	POS	O
+ECD	POS	O
+-	POS	O
+SPECT	POS	O
+showed	POS	O
+cortical	POS	O
+hypoperfusion	POS	O
+in	POS	O
+frontal	POS	O
+lobes	POS	O
+,	POS	O
+more	POS	O
+marked	POS	O
+on	POS	O
+the	POS	O
+left	POS	O
+frontal	POS	O
+lobe	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+of	POS	O
+our	POS	O
+patient	POS	O
+,	POS	O
+penicillamine	POS	O
+was	POS	O
+interrupted	POS	O
+after	POS	O
+the	POS	O
+appearance	POS	O
+of	POS	O
+a	POS	O
+lichenoid	POS	B-NP
+dermatitis	POS	I-NP
+,	POS	O
+and	POS	O
+zinc	POS	O
+acetate	POS	O
+permitted	POS	O
+to	POS	O
+continue	POS	O
+the	POS	O
+successful	POS	O
+treatment	POS	O
+of	POS	O
+the	POS	O
+patient	POS	O
+without	POS	O
+side	POS	O
+-	POS	O
+effects	POS	O
+.	POS	O
+In	POS	O
+our	POS	O
+case	POS	O
+the	POS	O
+therapy	POS	O
+with	POS	O
+zinc	POS	O
+acetate	POS	O
+represented	POS	O
+an	POS	O
+effective	POS	O
+treatment	POS	O
+for	POS	O
+a	POS	O
+Wilson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+patient	POS	O
+in	POS	O
+which	POS	O
+penicillamine	POS	O
+-	POS	O
+related	POS	O
+side	POS	O
+effects	POS	O
+appeared	POS	O
+.	POS	O
+The	POS	O
+safety	POS	O
+of	POS	O
+the	POS	O
+zinc	POS	O
+acetate	POS	O
+allowed	POS	O
+us	POS	O
+to	POS	O
+avoid	POS	O
+other	POS	O
+potentially	POS	O
+toxic	POS	O
+chelating	POS	O
+drugs	POS	O
+;	POS	O
+this	POS	O
+observation	POS	O
+is	POS	O
+in	POS	O
+line	POS	O
+with	POS	O
+the	POS	O
+growing	POS	O
+evidence	POS	O
+on	POS	O
+the	POS	O
+efficacy	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+Wilson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+Since	POS	O
+most	POS	O
+of	POS	O
+Wilson	POS	O
+'	POS	O
+s	POS	O
+disease	POS	O
+penicillamine	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+do	POS	O
+not	POS	O
+seem	POS	O
+to	POS	O
+develop	POS	O
+this	POS	O
+skin	POS	B-NP
+lesion	POS	I-NP
+,	POS	O
+it	POS	O
+could	POS	O
+be	POS	O
+conceivable	POS	O
+that	POS	O
+a	POS	O
+specific	POS	O
+genetic	POS	O
+factor	POS	O
+is	POS	O
+involved	POS	O
+in	POS	O
+drug	POS	O
+response	POS	O
+.	POS	O
+Further	POS	O
+studies	POS	O
+are	POS	O
+needed	POS	O
+for	POS	O
+a	POS	O
+better	POS	O
+clarification	POS	O
+of	POS	O
+Wilson	POS	O
+'	POS	O
+s	POS	O
+disease	POS	O
+therapy	POS	O
+,	POS	O
+and	POS	O
+in	POS	O
+particular	POS	O
+to	POS	O
+differentiate	POS	O
+specific	POS	O
+therapies	POS	O
+for	POS	O
+different	POS	O
+Wilson	POS	O
+'	POS	O
+s	POS	O
+disease	POS	O
+phenotypes	POS	O
+.	POS	O
+A	POS	O
+dramatic	POS	O
+drop	POS	O
+in	POS	O
+blood	POS	O
+pressure	POS	O
+following	POS	O
+prehospital	POS	O
+GTN	POS	O
+administration	POS	O
+.	POS	O
+A	POS	O
+male	POS	O
+in	POS	O
+his	POS	O
+sixties	POS	O
+with	POS	O
+no	POS	O
+history	POS	O
+of	POS	O
+cardiac	POS	B-NP
+chest	POS	I-NP
+pain	POS	I-NP
+awoke	POS	O
+with	POS	O
+chest	POS	B-NP
+pain	POS	I-NP
+following	POS	O
+an	POS	O
+afternoon	POS	O
+sleep	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+did	POS	O
+not	POS	O
+self	POS	O
+medicate	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+observations	POS	O
+were	POS	O
+within	POS	O
+normal	POS	O
+limits	POS	O
+,	POS	O
+he	POS	O
+was	POS	O
+administered	POS	O
+oxygen	POS	O
+via	POS	O
+a	POS	O
+face	POS	O
+mask	POS	O
+and	POS	O
+glyceryl	POS	O
+trinitrate	POS	O
+(	POS	O
+GTN	POS	O
+)	POS	O
+.	POS	O
+Several	POS	O
+minutes	POS	O
+after	POS	O
+the	POS	O
+GTN	POS	O
+the	POS	O
+patient	POS	O
+experienced	POS	O
+a	POS	O
+sudden	POS	O
+drop	POS	O
+in	POS	O
+blood	POS	O
+pressure	POS	O
+and	POS	O
+heart	POS	O
+rate	POS	O
+,	POS	O
+this	POS	O
+was	POS	O
+rectified	POS	O
+by	POS	O
+atropine	POS	O
+sulphate	POS	O
+and	POS	O
+a	POS	O
+fluid	POS	O
+challenge	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+further	POS	O
+deterioration	POS	O
+in	POS	O
+the	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+condition	POS	O
+during	POS	O
+transport	POS	O
+to	POS	O
+hospital	POS	O
+.	POS	O
+There	POS	O
+are	POS	O
+very	POS	O
+few	POS	O
+documented	POS	O
+case	POS	O
+like	POS	O
+this	POS	O
+in	POS	O
+the	POS	O
+prehospital	POS	O
+scientific	POS	O
+literature	POS	O
+.	POS	O
+The	POS	O
+cause	POS	O
+appears	POS	O
+to	POS	O
+be	POS	O
+the	POS	O
+Bezold	POS	O
+-	POS	O
+Jarish	POS	O
+reflex	POS	O
+,	POS	O
+stimulation	POS	O
+of	POS	O
+the	POS	O
+ventricular	POS	O
+walls	POS	O
+which	POS	O
+in	POS	O
+turn	POS	O
+decreases	POS	O
+sympathetic	POS	O
+outflow	POS	O
+from	POS	O
+the	POS	O
+vasomotor	POS	O
+centre	POS	O
+.	POS	O
+Prehospital	POS	O
+care	POS	O
+providers	POS	O
+who	POS	O
+are	POS	O
+managing	POS	O
+any	POS	O
+patient	POS	O
+with	POS	O
+a	POS	O
+syncopal	POS	B-NP
+episode	POS	O
+that	POS	O
+fails	POS	O
+to	POS	O
+recover	POS	O
+within	POS	O
+a	POS	O
+reasonable	POS	O
+time	POS	O
+frame	POS	O
+should	POS	O
+consider	POS	O
+the	POS	O
+Bezold	POS	O
+-	POS	O
+Jarisch	POS	O
+reflex	POS	O
+as	POS	O
+the	POS	O
+cause	POS	O
+and	POS	O
+manage	POS	O
+the	POS	O
+patient	POS	O
+accordingly	POS	O
+.	POS	O
+Chronic	POS	O
+lesion	POS	O
+of	POS	O
+rostral	POS	O
+ventrolateral	POS	O
+medulla	POS	O
+in	POS	O
+spontaneously	POS	O
+hypertensive	POS	B-NP
+rats	POS	O
+.	POS	O
+We	POS	O
+studied	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+chronic	POS	O
+selective	POS	O
+neuronal	POS	O
+lesion	POS	O
+of	POS	O
+rostral	POS	O
+ventrolateral	POS	O
+medulla	POS	O
+on	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+,	POS	O
+heart	POS	O
+rate	POS	O
+,	POS	O
+and	POS	O
+neurogenic	POS	O
+tone	POS	O
+in	POS	O
+conscious	POS	O
+,	POS	O
+unrestrained	POS	O
+spontaneously	POS	O
+hypertensive	POS	B-NP
+rats	POS	O
+.	POS	O
+The	POS	O
+lesions	POS	O
+were	POS	O
+placed	POS	O
+via	POS	O
+bilateral	POS	O
+microinjections	POS	O
+of	POS	O
+30	POS	O
+nmol	POS	O
+/	POS	O
+200	POS	O
+nl	POS	O
+N	POS	O
+-	POS	O
+methyl	POS	O
+-	POS	O
+D	POS	O
+-	POS	O
+aspartic	POS	O
+acid	POS	O
+.	POS	O
+The	POS	O
+restimulation	POS	O
+of	POS	O
+this	POS	O
+area	POS	O
+with	POS	O
+N	POS	O
+-	POS	O
+methyl	POS	O
+-	POS	O
+D	POS	O
+-	POS	O
+aspartic	POS	O
+acid	POS	O
+15	POS	O
+days	POS	O
+postlesion	POS	O
+failed	POS	O
+to	POS	O
+produce	POS	O
+a	POS	O
+pressor	POS	O
+response	POS	O
+.	POS	O
+One	POS	O
+day	POS	O
+postlesion	POS	O
+,	POS	O
+the	POS	O
+resting	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+was	POS	O
+significantly	POS	O
+decreased	POS	O
+in	POS	O
+lesioned	POS	O
+rats	POS	O
+when	POS	O
+compared	POS	O
+with	POS	O
+sham	POS	O
+rats	POS	O
+(	POS	O
+100	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+7	POS	O
+versus	POS	O
+173	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+mm	POS	O
+Hg	POS	O
+,	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+Fifteen	POS	O
+days	POS	O
+later	POS	O
+,	POS	O
+the	POS	O
+lesioned	POS	O
+group	POS	O
+still	POS	O
+showed	POS	O
+values	POS	O
+significantly	POS	O
+lower	POS	O
+than	POS	O
+the	POS	O
+sham	POS	O
+group	POS	O
+(	POS	O
+150	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+versus	POS	O
+167	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+5	POS	O
+mm	POS	O
+Hg	POS	O
+,	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+No	POS	O
+significant	POS	O
+heart	POS	O
+rate	POS	O
+differences	POS	O
+were	POS	O
+observed	POS	O
+between	POS	O
+the	POS	O
+sham	POS	O
+and	POS	O
+lesioned	POS	O
+groups	POS	O
+.	POS	O
+The	POS	O
+ganglionic	POS	O
+blocker	POS	O
+trimethaphan	POS	O
+(	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+)	POS	O
+caused	POS	O
+similar	POS	O
+reductions	POS	O
+in	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+in	POS	O
+both	POS	O
+lesioned	POS	O
+and	POS	O
+sham	POS	O
+groups	POS	O
+.	POS	O
+The	POS	O
+trimethaphan	POS	O
+-	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+was	POS	O
+accompanied	POS	O
+by	POS	O
+a	POS	O
+significant	POS	O
+bradycardia	POS	B-NP
+in	POS	O
+lesioned	POS	O
+rats	POS	O
+(	POS	O
+-	POS	O
+32	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+13	POS	O
+beats	POS	O
+per	POS	O
+minute	POS	O
+)	POS	O
+but	POS	O
+a	POS	O
+tachycardia	POS	B-NP
+in	POS	O
+sham	POS	O
+rats	POS	O
+(	POS	O
++	POS	O
+33	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+12	POS	O
+beats	POS	O
+per	POS	O
+minute	POS	O
+)	POS	O
+1	POS	O
+day	POS	O
+postlesion	POS	O
+.	POS	O
+Therefore	POS	O
+,	POS	O
+rostral	POS	O
+ventrolateral	POS	O
+medulla	POS	O
+neurons	POS	O
+appear	POS	O
+to	POS	O
+play	POS	O
+a	POS	O
+significant	POS	O
+role	POS	O
+in	POS	O
+maintaining	POS	O
+hypertension	POS	B-NP
+in	POS	O
+conscious	POS	O
+spontaneously	POS	O
+hypertensive	POS	B-NP
+rats	POS	O
+.	POS	O
+Spinal	POS	O
+or	POS	O
+suprabulbar	POS	O
+structures	POS	O
+could	POS	O
+be	POS	O
+responsible	POS	O
+for	POS	O
+the	POS	O
+gradual	POS	O
+recovery	POS	O
+of	POS	O
+the	POS	O
+hypertension	POS	B-NP
+in	POS	O
+the	POS	O
+lesioned	POS	O
+rats	POS	O
+.	POS	O
+Acute	POS	O
+encephalopathy	POS	B-NP
+and	POS	O
+cerebral	POS	B-NP
+vasospasm	POS	I-NP
+after	POS	O
+multiagent	POS	O
+chemotherapy	POS	O
+including	POS	O
+PEG	POS	O
+-	POS	O
+asparaginase	POS	O
+and	POS	O
+intrathecal	POS	O
+cytarabine	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+acute	POS	B-NP
+lymphoblastic	POS	I-NP
+leukemia	POS	I-NP
+.	POS	O
+A	POS	O
+7	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+girl	POS	O
+with	POS	O
+an	POS	O
+unusual	POS	O
+reaction	POS	O
+to	POS	O
+induction	POS	O
+chemotherapy	POS	O
+for	POS	O
+precursor	POS	B-NP
+B	POS	I-NP
+-	POS	I-NP
+cell	POS	I-NP
+acute	POS	I-NP
+lymphoblastic	POS	I-NP
+leukemia	POS	I-NP
+(	POS	O
+ALL	POS	B-NP
+)	POS	O
+is	POS	O
+described	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+developed	POS	O
+acute	POS	O
+encephalopathy	POS	B-NP
+evidenced	POS	O
+by	POS	O
+behavioral	POS	O
+changes	POS	O
+,	POS	O
+aphasia	POS	B-NP
+,	POS	O
+incontinence	POS	B-NP
+,	POS	O
+visual	POS	B-NP
+hallucinations	POS	I-NP
+,	POS	O
+and	POS	O
+right	POS	B-NP
+-	POS	I-NP
+sided	POS	I-NP
+weakness	POS	I-NP
+with	POS	O
+diffuse	POS	B-NP
+cerebral	POS	I-NP
+vasospasm	POS	I-NP
+on	POS	O
+magnetic	POS	O
+resonance	POS	O
+angiography	POS	O
+after	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+intrathecal	POS	O
+cytarabine	POS	O
+.	POS	O
+Vincristine	POS	O
+,	POS	O
+dexamethasone	POS	O
+,	POS	O
+and	POS	O
+polyethylene	POS	O
+glycol	POS	O
+-	POS	O
+asparaginase	POS	O
+were	POS	O
+also	POS	O
+administered	POS	O
+before	POS	O
+the	POS	O
+episode	POS	O
+as	POS	O
+part	POS	O
+of	POS	O
+induction	POS	O
+therapy	POS	O
+.	POS	O
+Neurologic	POS	O
+status	POS	O
+returned	POS	O
+to	POS	O
+baseline	POS	O
+within	POS	O
+10	POS	O
+days	POS	O
+of	POS	O
+the	POS	O
+acute	POS	O
+event	POS	O
+,	POS	O
+and	POS	O
+magnetic	POS	O
+resonance	POS	O
+angiography	POS	O
+findings	POS	O
+returned	POS	O
+to	POS	O
+normal	POS	O
+4	POS	O
+months	POS	O
+later	POS	O
+.	POS	O
+Comparison	POS	O
+of	POS	O
+valsartan	POS	O
+/	POS	O
+hydrochlorothiazide	POS	O
+combination	POS	O
+therapy	POS	O
+at	POS	O
+doses	POS	O
+up	POS	O
+to	POS	O
+320	POS	O
+/	POS	O
+25	POS	O
+mg	POS	O
+versus	POS	O
+monotherapy	POS	O
+:	POS	O
+a	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+study	POS	O
+followed	POS	O
+by	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+combination	POS	O
+therapy	POS	O
+in	POS	O
+hypertensive	POS	B-NP
+adults	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+One	POS	O
+third	POS	O
+of	POS	O
+patients	POS	O
+treated	POS	O
+for	POS	O
+hypertension	POS	B-NP
+attain	POS	O
+adequate	POS	O
+blood	POS	O
+pressure	POS	O
+(	POS	O
+BP	POS	O
+)	POS	O
+control	POS	O
+,	POS	O
+and	POS	O
+multidrug	POS	O
+regimens	POS	O
+are	POS	O
+often	POS	O
+required	POS	O
+.	POS	O
+Given	POS	O
+the	POS	O
+lifelong	POS	O
+nature	POS	O
+of	POS	O
+hypertension	POS	B-NP
+,	POS	O
+there	POS	O
+is	POS	O
+a	POS	O
+need	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+efficacy	POS	O
+and	POS	O
+tolerability	POS	O
+of	POS	O
+higher	POS	O
+doses	POS	O
+of	POS	O
+combination	POS	O
+anti	POS	O
+-	POS	O
+hypertensive	POS	O
+therapies	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+This	POS	O
+study	POS	O
+investigated	POS	O
+the	POS	O
+efficacy	POS	O
+and	POS	O
+tolerability	POS	O
+of	POS	O
+valsartan	POS	O
+(	POS	O
+VAL	POS	O
+)	POS	O
+or	POS	O
+hydrochlorothiazide	POS	O
+(	POS	O
+HCTZ	POS	O
+)	POS	O
+-	POS	O
+monotherapy	POS	O
+and	POS	O
+higher	POS	O
+-	POS	O
+dose	POS	O
+combinations	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+essential	POS	O
+hypertension	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+The	POS	O
+first	POS	O
+part	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+an	POS	O
+8	POS	O
+-	POS	O
+week	POS	O
+,	POS	O
+multicenter	POS	O
+,	POS	O
+randomized	POS	O
+,	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+placebo	POS	O
+controlled	POS	O
+,	POS	O
+parallel	POS	O
+-	POS	O
+group	POS	O
+trial	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+essential	POS	O
+hypertension	POS	B-NP
+(	POS	O
+mean	POS	O
+sitting	POS	O
+diastolic	POS	O
+BP	POS	O
+[	POS	O
+MSDBP	POS	O
+]	POS	O
+,	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+95	POS	O
+mm	POS	O
+Hg	POS	O
+and	POS	O
+<	POS	O
+110	POS	O
+mm	POS	O
+Hg	POS	O
+)	POS	O
+were	POS	O
+randomized	POS	O
+to	POS	O
+1	POS	O
+of	POS	O
+8	POS	O
+treatment	POS	O
+groups	POS	O
+:	POS	O
+VAL	POS	O
+160	POS	O
+or	POS	O
+320	POS	O
+mg	POS	O
+;	POS	O
+HCTZ	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+or	POS	O
+25	POS	O
+mg	POS	O
+;	POS	O
+VAL	POS	O
+/	POS	O
+HCTZ	POS	O
+160	POS	O
+/	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+,	POS	O
+320	POS	O
+/	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+,	POS	O
+or	POS	O
+320	POS	O
+/	POS	O
+25	POS	O
+mg	POS	O
+;	POS	O
+or	POS	O
+placebo	POS	O
+.	POS	O
+Mean	POS	O
+changes	POS	O
+in	POS	O
+MSDBP	POS	O
+and	POS	O
+mean	POS	O
+sitting	POS	O
+systolic	POS	O
+BP	POS	O
+(	POS	O
+MSSBP	POS	O
+)	POS	O
+were	POS	O
+analyzed	POS	O
+at	POS	O
+the	POS	O
+8	POS	O
+-	POS	O
+week	POS	O
+core	POS	O
+study	POS	O
+end	POS	O
+point	POS	O
+.	POS	O
+VAL	POS	O
+/	POS	O
+HCTZ	POS	O
+320	POS	O
+/	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+and	POS	O
+320	POS	O
+/	POS	O
+25	POS	O
+mg	POS	O
+were	POS	O
+further	POS	O
+investigated	POS	O
+in	POS	O
+a	POS	O
+54	POS	O
+-	POS	O
+week	POS	O
+,	POS	O
+open	POS	O
+-	POS	O
+label	POS	O
+extension	POS	O
+.	POS	O
+Response	POS	O
+was	POS	O
+defined	POS	O
+as	POS	O
+MSDBP	POS	O
+<	POS	O
+90	POS	O
+mm	POS	O
+Hg	POS	O
+or	POS	O
+a	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+10	POS	O
+mm	POS	O
+Hg	POS	O
+decrease	POS	O
+compared	POS	O
+to	POS	O
+baseline	POS	O
+.	POS	O
+Control	POS	O
+was	POS	O
+defined	POS	O
+as	POS	O
+MSDBP	POS	O
+<	POS	O
+90	POS	O
+mm	POS	O
+Hg	POS	O
+compared	POS	O
+with	POS	O
+baseline	POS	O
+.	POS	O
+Tolerability	POS	O
+was	POS	O
+assessed	POS	O
+by	POS	O
+monitoring	POS	O
+adverse	POS	O
+events	POS	O
+at	POS	O
+randomization	POS	O
+and	POS	O
+all	POS	O
+subsequent	POS	O
+study	POS	O
+visits	POS	O
+and	POS	O
+regular	POS	O
+evaluation	POS	O
+of	POS	O
+hematology	POS	O
+and	POS	O
+blood	POS	O
+chemistry	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+1346	POS	O
+patients	POS	O
+were	POS	O
+randomized	POS	O
+into	POS	O
+the	POS	O
+8	POS	O
+-	POS	O
+week	POS	O
+core	POS	O
+study	POS	O
+(	POS	O
+734	POS	O
+men	POS	O
+,	POS	O
+612	POS	O
+women	POS	O
+;	POS	O
+924	POS	O
+white	POS	O
+,	POS	O
+291	POS	O
+black	POS	O
+,	POS	O
+23	POS	O
+Asian	POS	O
+,	POS	O
+108	POS	O
+other	POS	O
+;	POS	O
+mean	POS	O
+age	POS	O
+,	POS	O
+52	POS	O
+.	POS	O
+7	POS	O
+years	POS	O
+;	POS	O
+mean	POS	O
+weight	POS	O
+,	POS	O
+92	POS	O
+.	POS	O
+6	POS	O
+kg	POS	O
+)	POS	O
+.	POS	O
+All	POS	O
+active	POS	O
+treatments	POS	O
+were	POS	O
+associated	POS	O
+with	POS	O
+significantly	POS	O
+reduced	POS	O
+MSSBP	POS	O
+and	POS	O
+MSDBP	POS	O
+during	POS	O
+the	POS	O
+core	POS	O
+8	POS	O
+-	POS	O
+week	POS	O
+study	POS	O
+,	POS	O
+with	POS	O
+each	POS	O
+monotherapy	POS	O
+significantly	POS	O
+contributing	POS	O
+to	POS	O
+the	POS	O
+overall	POS	O
+effect	POS	O
+of	POS	O
+combination	POS	O
+therapy	POS	O
+(	POS	O
+VAL	POS	O
+and	POS	O
+HCTZ	POS	O
+,	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+Each	POS	O
+combination	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+significantly	POS	O
+greater	POS	O
+reductions	POS	O
+in	POS	O
+MSSBP	POS	O
+and	POS	O
+MSDBP	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+monotherapies	POS	O
+and	POS	O
+placebo	POS	O
+(	POS	O
+all	POS	O
+,	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+reduction	POS	O
+in	POS	O
+MSSBP	POS	O
+/	POS	O
+MSDBP	POS	O
+with	POS	O
+VAL	POS	O
+/	POS	O
+HCTZ	POS	O
+320	POS	O
+/	POS	O
+25	POS	O
+mg	POS	O
+was	POS	O
+24	POS	O
+.	POS	O
+7	POS	O
+/	POS	O
+16	POS	O
+.	POS	O
+6	POS	O
+mm	POS	O
+Hg	POS	O
+,	POS	O
+compared	POS	O
+with	POS	O
+5	POS	O
+.	POS	O
+9	POS	O
+/	POS	O
+7	POS	O
+.	POS	O
+0	POS	O
+mm	POS	O
+Hg	POS	O
+with	POS	O
+placebo	POS	O
+.	POS	O
+The	POS	O
+reduction	POS	O
+in	POS	O
+MSSBP	POS	O
+was	POS	O
+significantly	POS	O
+greater	POS	O
+with	POS	O
+VAL	POS	O
+/	POS	O
+HCTZ	POS	O
+320	POS	O
+/	POS	O
+25	POS	O
+mg	POS	O
+compared	POS	O
+with	POS	O
+VAL	POS	O
+/	POS	O
+HCTZ	POS	O
+160	POS	O
+/	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+002	POS	O
+)	POS	O
+.	POS	O
+Rates	POS	O
+of	POS	O
+response	POS	O
+and	POS	O
+BP	POS	O
+control	POS	O
+were	POS	O
+significantly	POS	O
+higher	POS	O
+in	POS	O
+the	POS	O
+groups	POS	O
+that	POS	O
+received	POS	O
+combination	POS	O
+treatment	POS	O
+compared	POS	O
+with	POS	O
+those	POS	O
+that	POS	O
+received	POS	O
+monotherapy	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+hypokalemia	POS	B-NP
+was	POS	O
+lower	POS	O
+with	POS	O
+VAL	POS	O
+/	POS	O
+HCTZ	POS	O
+combinations	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+)	POS	O
+than	POS	O
+with	POS	O
+HCTZ	POS	O
+monotherapies	POS	O
+(	POS	O
+7	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+-	POS	O
+13	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+majority	POS	O
+of	POS	O
+adverse	POS	O
+events	POS	O
+in	POS	O
+the	POS	O
+core	POS	O
+study	POS	O
+were	POS	O
+of	POS	O
+mild	POS	O
+to	POS	O
+moderate	POS	O
+severity	POS	O
+.	POS	O
+The	POS	O
+efficacy	POS	O
+and	POS	O
+tolerability	POS	O
+of	POS	O
+VAL	POS	O
+/	POS	O
+HCTZ	POS	O
+combinations	POS	O
+were	POS	O
+maintained	POS	O
+during	POS	O
+the	POS	O
+extension	POS	O
+(	POS	O
+797	POS	O
+patients	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+population	POS	O
+,	POS	O
+combination	POS	O
+therapies	POS	O
+with	POS	O
+VAL	POS	O
+/	POS	O
+HCTZ	POS	O
+were	POS	O
+associated	POS	O
+with	POS	O
+significantly	POS	O
+greater	POS	O
+BP	POS	O
+reductions	POS	O
+compared	POS	O
+with	POS	O
+either	POS	O
+monotherapy	POS	O
+,	POS	O
+were	POS	O
+well	POS	O
+tolerated	POS	O
+,	POS	O
+and	POS	O
+were	POS	O
+associated	POS	O
+with	POS	O
+less	POS	O
+hypokalemia	POS	B-NP
+than	POS	O
+HCTZ	POS	O
+alone	POS	O
+.	POS	O
+Succimer	POS	O
+chelation	POS	O
+improves	POS	O
+learning	POS	O
+,	POS	O
+attention	POS	O
+,	POS	O
+and	POS	O
+arousal	POS	O
+regulation	POS	O
+in	POS	O
+lead	POS	O
+-	POS	O
+exposed	POS	O
+rats	POS	O
+but	POS	O
+produces	POS	O
+lasting	POS	O
+cognitive	POS	B-NP
+impairment	POS	I-NP
+in	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+lead	POS	O
+exposure	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+There	POS	O
+is	POS	O
+growing	POS	O
+pressure	POS	O
+for	POS	O
+clinicians	POS	O
+to	POS	O
+prescribe	POS	O
+chelation	POS	O
+therapy	POS	O
+at	POS	O
+only	POS	O
+slightly	POS	O
+elevated	POS	O
+blood	POS	O
+lead	POS	O
+levels	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+very	POS	O
+few	POS	O
+studies	POS	O
+have	POS	O
+evaluated	POS	O
+whether	POS	O
+chelation	POS	O
+improves	POS	O
+cognitive	POS	O
+outcomes	POS	O
+in	POS	O
+Pb	POS	O
+-	POS	O
+exposed	POS	O
+children	POS	O
+,	POS	O
+or	POS	O
+whether	POS	O
+these	POS	O
+agents	POS	O
+have	POS	O
+adverse	POS	O
+effects	POS	O
+that	POS	O
+may	POS	O
+affect	POS	O
+brain	POS	O
+development	POS	O
+in	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+Pb	POS	O
+exposure	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+designed	POS	O
+to	POS	O
+answer	POS	O
+these	POS	O
+questions	POS	O
+,	POS	O
+using	POS	O
+a	POS	O
+rodent	POS	O
+model	POS	O
+of	POS	O
+early	POS	O
+childhood	POS	O
+Pb	POS	O
+exposure	POS	O
+and	POS	O
+treatment	POS	O
+with	POS	O
+succimer	POS	O
+,	POS	O
+a	POS	O
+widely	POS	O
+used	POS	O
+chelating	POS	O
+agent	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+Pb	POS	B-NP
+poisoning	POS	I-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Pb	POS	O
+exposure	POS	O
+produced	POS	O
+lasting	POS	O
+impairments	POS	O
+in	POS	O
+learning	POS	O
+,	POS	O
+attention	POS	O
+,	POS	O
+inhibitory	POS	O
+control	POS	O
+,	POS	O
+and	POS	O
+arousal	POS	O
+regulation	POS	O
+,	POS	O
+paralleling	POS	O
+the	POS	O
+areas	POS	O
+of	POS	O
+dysfunction	POS	O
+seen	POS	O
+in	POS	O
+Pb	POS	O
+-	POS	O
+exposed	POS	O
+children	POS	O
+.	POS	O
+Succimer	POS	O
+treatment	POS	O
+of	POS	O
+the	POS	O
+Pb	POS	O
+-	POS	O
+exposed	POS	O
+rats	POS	O
+significantly	POS	O
+improved	POS	O
+learning	POS	O
+,	POS	O
+attention	POS	O
+,	POS	O
+and	POS	O
+arousal	POS	O
+regulation	POS	O
+,	POS	O
+although	POS	O
+the	POS	O
+efficacy	POS	O
+of	POS	O
+the	POS	O
+treatment	POS	O
+varied	POS	O
+as	POS	O
+a	POS	O
+function	POS	O
+of	POS	O
+the	POS	O
+Pb	POS	O
+exposure	POS	O
+level	POS	O
+and	POS	O
+the	POS	O
+specific	POS	O
+functional	POS	O
+deficit	POS	O
+.	POS	O
+In	POS	O
+contrast	POS	O
+,	POS	O
+succimer	POS	O
+treatment	POS	O
+of	POS	O
+rats	POS	O
+not	POS	O
+previously	POS	O
+exposed	POS	O
+to	POS	O
+Pb	POS	O
+produced	POS	O
+lasting	POS	O
+and	POS	O
+pervasive	POS	O
+cognitive	POS	O
+and	POS	O
+affective	POS	B-NP
+dysfunction	POS	I-NP
+comparable	POS	O
+in	POS	O
+magnitude	POS	O
+to	POS	O
+that	POS	O
+produced	POS	O
+by	POS	O
+the	POS	O
+higher	POS	O
+Pb	POS	O
+exposure	POS	O
+regimen	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+These	POS	O
+are	POS	O
+the	POS	O
+first	POS	O
+data	POS	O
+,	POS	O
+to	POS	O
+our	POS	O
+knowledge	POS	O
+,	POS	O
+to	POS	O
+show	POS	O
+that	POS	O
+treatment	POS	O
+with	POS	O
+any	POS	O
+chelating	POS	O
+agent	POS	O
+can	POS	O
+alleviate	POS	O
+cognitive	POS	B-NP
+deficits	POS	I-NP
+due	POS	O
+to	POS	O
+Pb	POS	O
+exposure	POS	O
+.	POS	O
+These	POS	O
+findings	POS	O
+suggest	POS	O
+that	POS	O
+it	POS	O
+may	POS	O
+be	POS	O
+possible	POS	O
+to	POS	O
+identify	POS	O
+a	POS	O
+succimer	POS	O
+treatment	POS	O
+protocol	POS	O
+that	POS	O
+improves	POS	O
+cognitive	POS	O
+outcomes	POS	O
+in	POS	O
+Pb	POS	O
+-	POS	O
+exposed	POS	O
+children	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+they	POS	O
+also	POS	O
+suggest	POS	O
+that	POS	O
+succimer	POS	O
+treatment	POS	O
+should	POS	O
+be	POS	O
+strongly	POS	O
+discouraged	POS	O
+for	POS	O
+children	POS	O
+who	POS	O
+do	POS	O
+not	POS	O
+have	POS	O
+elevated	POS	O
+tissue	POS	O
+levels	POS	O
+of	POS	O
+Pb	POS	O
+or	POS	O
+other	POS	O
+heavy	POS	O
+metals	POS	O
+.	POS	O
+Caffeine	POS	O
+challenge	POS	O
+test	POS	O
+in	POS	O
+panic	POS	B-NP
+disorder	POS	I-NP
+and	POS	O
+depression	POS	B-NP
+with	POS	O
+panic	POS	B-NP
+attacks	POS	I-NP
+.	POS	O
+Our	POS	O
+aim	POS	O
+was	POS	O
+to	POS	O
+observe	POS	O
+if	POS	O
+patients	POS	O
+with	POS	O
+panic	POS	B-NP
+disorder	POS	I-NP
+(	POS	O
+PD	POS	B-NP
+)	POS	O
+and	POS	O
+patients	POS	O
+with	POS	O
+major	POS	O
+depression	POS	B-NP
+with	POS	O
+panic	POS	B-NP
+attacks	POS	I-NP
+(	POS	O
+MDP	POS	O
+)	POS	O
+(	POS	O
+Diagnostic	POS	O
+and	POS	O
+Statistical	POS	O
+Manual	POS	O
+of	POS	O
+Mental	POS	O
+Disorders	POS	O
+,	POS	O
+Fourth	POS	O
+Edition	POS	O
+criteria	POS	O
+)	POS	O
+respond	POS	O
+in	POS	O
+a	POS	O
+similar	POS	O
+way	POS	O
+to	POS	O
+the	POS	O
+induction	POS	O
+of	POS	O
+panic	POS	B-NP
+attacks	POS	I-NP
+by	POS	O
+an	POS	O
+oral	POS	O
+caffeine	POS	O
+challenge	POS	O
+test	POS	O
+.	POS	O
+We	POS	O
+randomly	POS	O
+selected	POS	O
+29	POS	O
+patients	POS	O
+with	POS	O
+PD	POS	B-NP
+,	POS	O
+27	POS	O
+with	POS	O
+MDP	POS	O
+,	POS	O
+25	POS	O
+with	POS	O
+major	POS	O
+depression	POS	B-NP
+without	POS	O
+panic	POS	B-NP
+attacks	POS	I-NP
+(	POS	O
+MD	POS	B-NP
+)	POS	O
+,	POS	O
+and	POS	O
+28	POS	O
+healthy	POS	O
+volunteers	POS	O
+.	POS	O
+The	POS	O
+patients	POS	O
+had	POS	O
+no	POS	O
+psychotropic	POS	O
+drug	POS	O
+for	POS	O
+at	POS	O
+least	POS	O
+a	POS	O
+4	POS	O
+-	POS	O
+week	POS	O
+period	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+randomized	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+experiment	POS	O
+performed	POS	O
+in	POS	O
+2	POS	O
+occasions	POS	O
+7	POS	O
+days	POS	O
+apart	POS	O
+,	POS	O
+480	POS	O
+mg	POS	O
+caffeine	POS	O
+and	POS	O
+a	POS	O
+caffeine	POS	O
+-	POS	O
+free	POS	O
+(	POS	O
+placebo	POS	O
+)	POS	O
+solution	POS	O
+were	POS	O
+administered	POS	O
+in	POS	O
+a	POS	O
+coffee	POS	O
+form	POS	O
+and	POS	O
+anxiety	POS	B-NP
+scales	POS	O
+were	POS	O
+applied	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+each	POS	O
+test	POS	O
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+58	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+17	POS	O
+)	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+PD	POS	B-NP
+,	POS	O
+44	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+12	POS	O
+)	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+MDP	POS	O
+,	POS	O
+12	POS	O
+.	POS	O
+0	POS	O
+%	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+3	POS	O
+)	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+MD	POS	B-NP
+,	POS	O
+and	POS	O
+7	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+2	POS	O
+)	POS	O
+of	POS	O
+control	POS	O
+subjects	POS	O
+had	POS	O
+a	POS	O
+panic	POS	B-NP
+attack	POS	O
+after	POS	O
+the	POS	O
+480	POS	O
+-	POS	O
+mg	POS	O
+caffeine	POS	O
+challenge	POS	O
+test	POS	O
+(	POS	O
+chi	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+(	POS	O
+3	POS	O
+)	POS	O
+=	POS	O
+16	POS	O
+.	POS	O
+22	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+patients	POS	O
+with	POS	O
+PD	POS	B-NP
+and	POS	O
+MDP	POS	O
+were	POS	O
+more	POS	O
+sensitive	POS	O
+to	POS	O
+caffeine	POS	O
+than	POS	O
+were	POS	O
+patients	POS	O
+with	POS	O
+MD	POS	B-NP
+and	POS	O
+healthy	POS	O
+volunteers	POS	O
+.	POS	O
+No	POS	O
+panic	POS	B-NP
+attack	POS	O
+was	POS	O
+observed	POS	O
+after	POS	O
+the	POS	O
+caffeine	POS	O
+-	POS	O
+free	POS	O
+solution	POS	O
+intake	POS	O
+.	POS	O
+The	POS	O
+patients	POS	O
+with	POS	O
+MD	POS	B-NP
+had	POS	O
+a	POS	O
+lower	POS	O
+heart	POS	O
+rate	POS	O
+response	POS	O
+to	POS	O
+the	POS	O
+test	POS	O
+than	POS	O
+all	POS	O
+the	POS	O
+other	POS	O
+groups	POS	O
+(	POS	O
+2	POS	O
+-	POS	O
+way	POS	O
+analysis	POS	O
+of	POS	O
+variance	POS	O
+,	POS	O
+group	POS	O
+by	POS	O
+time	POS	O
+interaction	POS	O
+with	POS	O
+Greenhouse	POS	O
+-	POS	O
+Geisser	POS	O
+correction	POS	O
+:	POS	O
+F	POS	O
+(	POS	O
+3	POS	O
+,	POS	O
+762	POS	O
+)	POS	O
+=	POS	O
+2	POS	O
+.	POS	O
+85	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+026	POS	O
+)	POS	O
+.	POS	O
+Our	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+there	POS	O
+is	POS	O
+an	POS	O
+association	POS	O
+between	POS	O
+panic	POS	B-NP
+attacks	POS	I-NP
+,	POS	O
+no	POS	O
+matter	POS	O
+if	POS	O
+associated	POS	O
+with	POS	O
+PD	POS	B-NP
+or	POS	O
+MDP	POS	O
+,	POS	O
+and	POS	O
+hyperreactivity	POS	B-NP
+to	POS	O
+an	POS	O
+oral	POS	O
+caffeine	POS	O
+challenge	POS	O
+test	POS	O
+.	POS	O
+Mitral	POS	O
+annuloplasty	POS	O
+as	POS	O
+a	POS	O
+ventricular	POS	O
+restoration	POS	O
+method	POS	O
+for	POS	O
+the	POS	O
+failing	POS	O
+left	POS	O
+ventricle	POS	O
+:	POS	O
+a	POS	O
+pilot	POS	O
+study	POS	O
+.	POS	O
+BACKGROUND	POS	O
+AND	POS	O
+AIM	POS	O
+OF	POS	O
+THE	POS	O
+STUDY	POS	O
+:	POS	O
+Undersized	POS	O
+mitral	POS	O
+annuloplasty	POS	O
+(	POS	O
+MAP	POS	O
+)	POS	O
+is	POS	O
+effective	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+dilated	POS	B-NP
+cardiomyopathy	POS	I-NP
+and	POS	O
+functional	POS	B-NP
+mitral	POS	I-NP
+regurgitation	POS	I-NP
+(	POS	O
+MR	POS	O
+)	POS	O
+since	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+addressing	POS	O
+the	POS	O
+MR	POS	O
+,	POS	O
+the	POS	O
+MAP	POS	O
+may	POS	O
+also	POS	O
+reshape	POS	O
+the	POS	O
+dilated	POS	O
+left	POS	O
+ventricular	POS	O
+(	POS	O
+LV	POS	O
+)	POS	O
+base	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+direct	POS	O
+benefits	POS	O
+of	POS	O
+this	POS	O
+possible	POS	O
+reshaping	POS	O
+on	POS	O
+LV	POS	O
+function	POS	O
+in	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+underlying	POS	O
+MR	POS	O
+remain	POS	O
+incompletely	POS	O
+understood	POS	O
+.	POS	O
+The	POS	O
+study	POS	O
+aim	POS	O
+was	POS	O
+to	POS	O
+identify	POS	O
+these	POS	O
+benefits	POS	O
+in	POS	O
+a	POS	O
+canine	POS	O
+model	POS	O
+of	POS	O
+acute	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Six	POS	O
+dogs	POS	O
+underwent	POS	O
+MAP	POS	O
+with	POS	O
+a	POS	O
+prosthetic	POS	O
+band	POS	O
+on	POS	O
+the	POS	O
+posterior	POS	O
+mitral	POS	O
+annulus	POS	O
+,	POS	O
+using	POS	O
+four	POS	O
+mattress	POS	O
+sutures	POS	O
+.	POS	O
+The	POS	O
+sutures	POS	O
+were	POS	O
+passed	POS	O
+individually	POS	O
+through	POS	O
+four	POS	O
+tourniquets	POS	O
+and	POS	O
+exteriorized	POS	O
+untied	POS	O
+via	POS	O
+the	POS	O
+left	POS	O
+atriotomy	POS	O
+.	POS	O
+Sonomicrometry	POS	O
+crystals	POS	O
+were	POS	O
+implanted	POS	O
+around	POS	O
+the	POS	O
+mitral	POS	O
+annulus	POS	O
+and	POS	O
+left	POS	O
+ventricle	POS	O
+to	POS	O
+measure	POS	O
+geometry	POS	O
+and	POS	O
+regional	POS	O
+function	POS	O
+.	POS	O
+Acute	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+was	POS	O
+induced	POS	O
+by	POS	O
+propranolol	POS	O
+and	POS	O
+volume	POS	O
+loading	POS	O
+after	POS	O
+weaning	POS	O
+from	POS	O
+cardiopulmonary	POS	O
+bypass	POS	O
+;	POS	O
+an	POS	O
+absence	POS	O
+of	POS	O
+MR	POS	O
+was	POS	O
+confirmed	POS	O
+by	POS	O
+echocardiography	POS	O
+.	POS	O
+MAP	POS	O
+was	POS	O
+accomplished	POS	O
+by	POS	O
+cinching	POS	O
+the	POS	O
+tourniquets	POS	O
+.	POS	O
+Data	POS	O
+were	POS	O
+acquired	POS	O
+at	POS	O
+baseline	POS	O
+,	POS	O
+after	POS	O
+induction	POS	O
+of	POS	O
+acute	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+,	POS	O
+and	POS	O
+after	POS	O
+MAP	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+MAP	POS	O
+decreased	POS	O
+mitral	POS	O
+annular	POS	O
+dimensions	POS	O
+in	POS	O
+both	POS	O
+commissure	POS	O
+-	POS	O
+commissure	POS	O
+and	POS	O
+septal	POS	O
+-	POS	O
+lateral	POS	O
+directions	POS	O
+.	POS	O
+Concomitantly	POS	O
+,	POS	O
+the	POS	O
+diastolic	POS	O
+diameter	POS	O
+of	POS	O
+the	POS	O
+LV	POS	O
+base	POS	O
+and	POS	O
+LV	POS	O
+sphericity	POS	O
+decreased	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+e	POS	O
+.	POS	O
+,	POS	O
+improved	POS	O
+)	POS	O
+from	POS	O
+37	POS	O
+.	POS	O
+4	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+9	POS	O
+.	POS	O
+3	POS	O
+to	POS	O
+35	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+10	POS	O
+mm	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+063	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+from	POS	O
+67	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+18	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+to	POS	O
+65	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+18	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+016	POS	O
+)	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Decreases	POS	O
+were	POS	O
+evident	POS	O
+in	POS	O
+both	POS	O
+LV	POS	O
+end	POS	O
+-	POS	O
+diastolic	POS	O
+pressure	POS	O
+(	POS	O
+from	POS	O
+17	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+7	POS	O
+to	POS	O
+15	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+mmHg	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+0480	POS	O
+and	POS	O
+Tau	POS	O
+(	POS	O
+from	POS	O
+48	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+8	POS	O
+to	POS	O
+45	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+8	POS	O
+ms	POS	O
+,	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+,	POS	O
+while	POS	O
+fractional	POS	O
+shortening	POS	O
+at	POS	O
+the	POS	O
+LV	POS	O
+base	POS	O
+increased	POS	O
+from	POS	O
+7	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+to	POS	O
+9	POS	O
+.	POS	O
+4	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+045	POS	O
+)	POS	O
+.	POS	O
+After	POS	O
+MAP	POS	O
+,	POS	O
+increases	POS	O
+were	POS	O
+identified	POS	O
+in	POS	O
+both	POS	O
+cardiac	POS	O
+output	POS	O
+(	POS	O
+from	POS	O
+1	POS	O
+.	POS	O
+54	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+57	POS	O
+to	POS	O
+1	POS	O
+.	POS	O
+65	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+57	POS	O
+1	POS	O
+/	POS	O
+min	POS	O
+)	POS	O
+and	POS	O
+Emax	POS	O
+(	POS	O
+from	POS	O
+1	POS	O
+.	POS	O
+86	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+41	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+31	POS	O
+mmHg	POS	O
+/	POS	O
+ml	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+The	POS	O
+data	POS	O
+acquired	POS	O
+suggest	POS	O
+that	POS	O
+isolated	POS	O
+MAP	POS	O
+may	POS	O
+have	POS	O
+certain	POS	O
+benefits	POS	O
+on	POS	O
+LV	POS	O
+dimension	POS	O
+/	POS	O
+function	POS	O
+in	POS	O
+acute	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+,	POS	O
+even	POS	O
+in	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+MR	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+further	POS	O
+investigations	POS	O
+are	POS	O
+warranted	POS	O
+in	POS	O
+a	POS	O
+model	POS	O
+of	POS	O
+chronic	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+.	POS	O
+Piperacillin	POS	O
+/	POS	O
+tazobactam	POS	O
+-	POS	O
+induced	POS	O
+seizure	POS	B-NP
+rapidly	POS	O
+reversed	POS	O
+by	POS	O
+high	POS	O
+flux	POS	O
+hemodialysis	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+on	POS	O
+peritoneal	POS	O
+dialysis	POS	O
+.	POS	O
+Despite	POS	O
+popular	POS	O
+use	POS	O
+of	POS	O
+piperacillin	POS	O
+,	POS	O
+the	POS	O
+dire	POS	O
+neurotoxicity	POS	B-NP
+associated	POS	O
+with	POS	O
+piperacillin	POS	O
+still	POS	O
+goes	POS	O
+unrecognized	POS	O
+,	POS	O
+leading	POS	O
+to	POS	O
+a	POS	O
+delay	POS	O
+in	POS	O
+appropriate	POS	O
+management	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+57	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+with	POS	O
+end	POS	O
+-	POS	O
+stage	POS	O
+renal	POS	B-NP
+disease	POS	I-NP
+receiving	POS	O
+continuous	POS	O
+ambulatory	POS	O
+peritoneal	POS	O
+dialysis	POS	O
+(	POS	O
+CAPD	POS	O
+)	POS	O
+,	POS	O
+who	POS	O
+developed	POS	O
+slurred	POS	B-NP
+speech	POS	I-NP
+,	POS	O
+tremor	POS	B-NP
+,	POS	O
+bizarre	POS	B-NP
+behavior	POS	I-NP
+,	POS	O
+progressive	POS	B-NP
+mental	POS	I-NP
+confusion	POS	I-NP
+,	POS	O
+and	POS	O
+2	POS	O
+episodes	POS	O
+of	POS	O
+generalized	POS	O
+tonic	POS	O
+-	POS	O
+clonic	POS	B-NP
+seizure	POS	I-NP
+(	POS	O
+GTCS	POS	B-NP
+)	POS	O
+after	POS	O
+5	POS	O
+doses	POS	O
+of	POS	O
+piperacillin	POS	O
+/	POS	O
+tazobactam	POS	O
+(	POS	O
+2	POS	O
+g	POS	O
+/	POS	O
+250	POS	O
+mg	POS	O
+)	POS	O
+were	POS	O
+given	POS	O
+for	POS	O
+bronchiectasis	POS	B-NP
+with	POS	O
+secondary	POS	B-NP
+infection	POS	I-NP
+.	POS	O
+The	POS	O
+laboratory	POS	O
+data	POS	O
+revealed	POS	O
+normal	POS	O
+plasma	POS	O
+electrolyte	POS	O
+and	POS	O
+ammonia	POS	O
+levels	POS	O
+but	POS	O
+leukocytosis	POS	B-NP
+.	POS	O
+Neurologic	POS	O
+examinations	POS	O
+showed	POS	O
+dysarthria	POS	B-NP
+and	POS	O
+bilateral	POS	B-NP
+Babinski	POS	I-NP
+sign	POS	O
+.	POS	O
+Computed	POS	O
+tomography	POS	O
+of	POS	O
+brain	POS	O
+and	POS	O
+electroencephalogram	POS	O
+were	POS	O
+unremarkable	POS	O
+.	POS	O
+Despite	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+antiepileptic	POS	O
+agents	POS	O
+,	POS	O
+another	POS	O
+GTCS	POS	B-NP
+episode	POS	O
+recurred	POS	O
+after	POS	O
+the	POS	O
+sixth	POS	O
+dose	POS	O
+of	POS	O
+piperacillin	POS	O
+/	POS	O
+tazobactam	POS	O
+.	POS	O
+Brain	POS	O
+magnetic	POS	O
+resonance	POS	O
+imaging	POS	O
+did	POS	O
+not	POS	O
+demonstrate	POS	O
+acute	POS	B-NP
+infarction	POS	I-NP
+and	POS	O
+organic	POS	B-NP
+brain	POS	I-NP
+lesions	POS	I-NP
+.	POS	O
+Initiation	POS	O
+of	POS	O
+high	POS	O
+-	POS	O
+flux	POS	O
+hemodialysis	POS	O
+rapidly	POS	O
+reversed	POS	O
+the	POS	O
+neurologic	POS	O
+symptoms	POS	O
+within	POS	O
+4	POS	O
+hours	POS	O
+.	POS	O
+Piperacillin	POS	O
+-	POS	O
+induced	POS	O
+encephalopathy	POS	B-NP
+should	POS	O
+be	POS	O
+considered	POS	O
+in	POS	O
+any	POS	O
+uremic	POS	B-NP
+patients	POS	O
+with	POS	O
+unexplained	POS	O
+neurological	POS	B-NP
+manifestations	POS	I-NP
+.	POS	O
+CAPD	POS	B-NP
+is	POS	O
+inefficient	POS	O
+in	POS	O
+removing	POS	O
+piperacillin	POS	O
+,	POS	O
+whereas	POS	O
+hemodialysis	POS	O
+can	POS	O
+rapidly	POS	O
+terminate	POS	O
+the	POS	O
+piperacillin	POS	O
+-	POS	O
+induced	POS	O
+encephalopathy	POS	B-NP
+.	POS	O
+Frequency	POS	O
+of	POS	O
+transient	POS	O
+ipsilateral	POS	O
+vocal	POS	B-NP
+cord	POS	I-NP
+paralysis	POS	I-NP
+in	POS	O
+patients	POS	O
+undergoing	POS	O
+carotid	POS	O
+endarterectomy	POS	O
+under	POS	O
+local	POS	O
+anesthesia	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Especially	POS	O
+because	POS	O
+of	POS	O
+improvements	POS	O
+in	POS	O
+clinical	POS	O
+neurologic	POS	O
+monitoring	POS	O
+,	POS	O
+carotid	POS	O
+endarterectomy	POS	O
+done	POS	O
+under	POS	O
+local	POS	O
+anesthesia	POS	O
+has	POS	O
+become	POS	O
+the	POS	O
+technique	POS	O
+of	POS	O
+choice	POS	O
+in	POS	O
+several	POS	O
+centers	POS	O
+.	POS	O
+Temporary	POS	O
+ipsilateral	POS	O
+vocal	POS	B-NP
+nerve	POS	I-NP
+palsies	POS	I-NP
+due	POS	O
+to	POS	O
+local	POS	O
+anesthetics	POS	O
+have	POS	O
+been	POS	O
+described	POS	O
+,	POS	O
+however	POS	O
+.	POS	O
+Such	POS	O
+complications	POS	O
+are	POS	O
+most	POS	O
+important	POS	O
+in	POS	O
+situations	POS	O
+where	POS	O
+there	POS	O
+is	POS	O
+a	POS	O
+pre	POS	O
+-	POS	O
+existing	POS	O
+contralateral	POS	O
+paralysis	POS	B-NP
+.	POS	O
+We	POS	O
+therefore	POS	O
+examined	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+local	POS	O
+anesthesia	POS	O
+on	POS	O
+vocal	POS	O
+cord	POS	O
+function	POS	O
+to	POS	O
+better	POS	O
+understand	POS	O
+its	POS	O
+possible	POS	O
+consequences	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+This	POS	O
+prospective	POS	O
+study	POS	O
+included	POS	O
+28	POS	O
+patients	POS	O
+undergoing	POS	O
+carotid	POS	O
+endarterectomy	POS	O
+under	POS	O
+local	POS	O
+anesthesia	POS	O
+.	POS	O
+Vocal	POS	O
+cord	POS	O
+function	POS	O
+was	POS	O
+evaluated	POS	O
+before	POS	O
+,	POS	O
+during	POS	O
+,	POS	O
+and	POS	O
+after	POS	O
+surgery	POS	O
+(	POS	O
+postoperative	POS	O
+day	POS	O
+1	POS	O
+)	POS	O
+using	POS	O
+flexible	POS	O
+laryngoscopy	POS	O
+.	POS	O
+Anesthesia	POS	O
+was	POS	O
+performed	POS	O
+by	POS	O
+injecting	POS	O
+20	POS	O
+to	POS	O
+40	POS	O
+mL	POS	O
+of	POS	O
+a	POS	O
+mixture	POS	O
+of	POS	O
+long	POS	O
+-	POS	O
+acting	POS	O
+(	POS	O
+ropivacaine	POS	O
+)	POS	O
+and	POS	O
+short	POS	O
+-	POS	O
+acting	POS	O
+(	POS	O
+prilocaine	POS	O
+)	POS	O
+anesthetic	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+All	POS	O
+patients	POS	O
+had	POS	O
+normal	POS	O
+vocal	POS	O
+cord	POS	O
+function	POS	O
+preoperatively	POS	O
+.	POS	O
+Twelve	POS	O
+patients	POS	O
+(	POS	O
+43	POS	O
+%	POS	O
+)	POS	O
+were	POS	O
+found	POS	O
+to	POS	O
+have	POS	O
+intraoperative	POS	O
+ipsilateral	POS	O
+vocal	POS	B-NP
+cord	POS	I-NP
+paralysis	POS	I-NP
+.	POS	O
+It	POS	O
+resolved	POS	O
+in	POS	O
+all	POS	O
+cases	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+24	POS	O
+hours	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+no	POS	O
+significant	POS	O
+differences	POS	O
+in	POS	O
+operating	POS	O
+time	POS	O
+or	POS	O
+volume	POS	O
+or	POS	O
+frequency	POS	O
+of	POS	O
+anesthetic	POS	O
+administration	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+temporary	POS	O
+vocal	POS	B-NP
+cord	POS	I-NP
+paralysis	POS	I-NP
+compared	POS	O
+with	POS	O
+those	POS	O
+without	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Local	POS	O
+anesthesia	POS	O
+led	POS	O
+to	POS	O
+temporary	POS	O
+ipsilateral	POS	O
+vocal	POS	B-NP
+cord	POS	I-NP
+paralysis	POS	I-NP
+in	POS	O
+almost	POS	O
+half	POS	O
+of	POS	O
+these	POS	O
+patients	POS	O
+.	POS	O
+Because	POS	O
+pre	POS	O
+-	POS	O
+existing	POS	O
+paralysis	POS	B-NP
+is	POS	O
+of	POS	O
+a	POS	O
+relevant	POS	O
+frequency	POS	O
+(	POS	O
+up	POS	O
+to	POS	O
+3	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+preoperative	POS	O
+evaluation	POS	O
+of	POS	O
+vocal	POS	O
+cord	POS	O
+function	POS	O
+before	POS	O
+carotid	POS	O
+endarterectomy	POS	O
+under	POS	O
+local	POS	O
+anesthesia	POS	O
+is	POS	O
+recommended	POS	O
+to	POS	O
+avoid	POS	O
+intraoperative	POS	B-NP
+bilateral	POS	I-NP
+paralysis	POS	I-NP
+.	POS	O
+In	POS	O
+patients	POS	O
+with	POS	O
+preoperative	POS	B-NP
+contralateral	POS	I-NP
+vocal	POS	I-NP
+cord	POS	I-NP
+paralysis	POS	I-NP
+,	POS	O
+surgery	POS	O
+under	POS	O
+general	POS	O
+anesthesia	POS	O
+should	POS	O
+be	POS	O
+considered	POS	O
+.	POS	O
+Impaired	POS	O
+fear	POS	O
+recognition	POS	O
+in	POS	O
+regular	POS	O
+recreational	POS	O
+cocaine	POS	O
+users	POS	O
+.	POS	O
+INTRODUCTION	POS	O
+:	POS	O
+The	POS	O
+ability	POS	O
+to	POS	O
+read	POS	O
+facial	POS	O
+expressions	POS	O
+is	POS	O
+essential	POS	O
+for	POS	O
+normal	POS	O
+human	POS	O
+social	POS	O
+interaction	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+conduct	POS	O
+the	POS	O
+first	POS	O
+investigation	POS	O
+of	POS	O
+facial	POS	O
+expression	POS	O
+recognition	POS	O
+performance	POS	O
+in	POS	O
+recreational	POS	O
+cocaine	POS	O
+users	POS	O
+.	POS	O
+MATERIALS	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+Three	POS	O
+groups	POS	O
+,	POS	O
+comprised	POS	O
+of	POS	O
+21	POS	O
+cocaine	POS	O
+naive	POS	O
+participants	POS	O
+(	POS	O
+CN	POS	O
+)	POS	O
+,	POS	O
+30	POS	O
+occasional	POS	O
+cocaine	POS	O
+(	POS	O
+OC	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+48	POS	O
+regular	POS	O
+recreational	POS	O
+cocaine	POS	O
+(	POS	O
+RC	POS	O
+)	POS	O
+users	POS	O
+,	POS	O
+were	POS	O
+compared	POS	O
+.	POS	O
+An	POS	O
+emotional	POS	O
+facial	POS	O
+expression	POS	O
+(	POS	O
+EFE	POS	O
+)	POS	O
+task	POS	O
+consisting	POS	O
+of	POS	O
+a	POS	O
+male	POS	O
+and	POS	O
+female	POS	O
+face	POS	O
+expressing	POS	O
+six	POS	O
+basic	POS	O
+emotions	POS	O
+(	POS	O
+happiness	POS	O
+,	POS	O
+surprise	POS	O
+,	POS	O
+sadness	POS	O
+,	POS	O
+anger	POS	O
+,	POS	O
+fear	POS	O
+,	POS	O
+and	POS	O
+disgust	POS	O
+)	POS	O
+was	POS	O
+administered	POS	O
+.	POS	O
+Mean	POS	O
+percent	POS	O
+accuracy	POS	O
+and	POS	O
+latencies	POS	O
+for	POS	O
+correct	POS	O
+responses	POS	O
+across	POS	O
+eight	POS	O
+presentations	POS	O
+of	POS	O
+each	POS	O
+basic	POS	O
+emotion	POS	O
+were	POS	O
+derived	POS	O
+.	POS	O
+Participants	POS	O
+were	POS	O
+also	POS	O
+assessed	POS	O
+with	POS	O
+the	POS	O
+"	POS	O
+Eyes	POS	O
+task	POS	O
+"	POS	O
+to	POS	O
+investigate	POS	O
+their	POS	O
+ability	POS	O
+to	POS	O
+recognize	POS	O
+more	POS	O
+complex	POS	O
+emotional	POS	O
+states	POS	O
+and	POS	O
+the	POS	O
+Symptom	POS	O
+CheckList	POS	O
+-	POS	O
+90	POS	O
+-	POS	O
+Revised	POS	O
+to	POS	O
+measure	POS	O
+psychopathology	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+There	POS	O
+were	POS	O
+no	POS	O
+group	POS	O
+differences	POS	O
+in	POS	O
+psychopathology	POS	O
+or	POS	O
+"	POS	O
+eyes	POS	O
+task	POS	O
+"	POS	O
+performance	POS	O
+,	POS	O
+but	POS	O
+the	POS	O
+RC	POS	O
+group	POS	O
+,	POS	O
+who	POS	O
+otherwise	POS	O
+had	POS	O
+similar	POS	O
+illicit	POS	O
+substance	POS	O
+use	POS	O
+histories	POS	O
+to	POS	O
+the	POS	O
+OC	POS	O
+group	POS	O
+,	POS	O
+exhibited	POS	O
+impaired	POS	O
+fear	POS	O
+recognition	POS	O
+accuracy	POS	O
+compared	POS	O
+to	POS	O
+the	POS	O
+OC	POS	O
+and	POS	O
+CN	POS	O
+groups	POS	O
+.	POS	O
+The	POS	O
+RC	POS	O
+group	POS	O
+also	POS	O
+correctly	POS	O
+identified	POS	O
+anger	POS	O
+,	POS	O
+fear	POS	O
+,	POS	O
+happiness	POS	O
+,	POS	O
+and	POS	O
+surprise	POS	O
+,	POS	O
+more	POS	O
+slowly	POS	O
+than	POS	O
+CN	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+OC	POS	O
+participants	POS	O
+.	POS	O
+The	POS	O
+OC	POS	O
+group	POS	O
+was	POS	O
+slower	POS	O
+than	POS	O
+CN	POS	O
+when	POS	O
+correctly	POS	O
+identifying	POS	O
+disgust	POS	O
+.	POS	O
+The	POS	O
+selective	POS	O
+deficit	POS	O
+in	POS	O
+fear	POS	O
+recognition	POS	O
+accuracy	POS	O
+manifested	POS	O
+by	POS	O
+the	POS	O
+RC	POS	O
+group	POS	O
+cannot	POS	O
+be	POS	O
+explained	POS	O
+by	POS	O
+the	POS	O
+subacute	POS	O
+effects	POS	O
+of	POS	O
+cocaine	POS	O
+,	POS	O
+or	POS	O
+ecstasy	POS	O
+,	POS	O
+because	POS	O
+recent	POS	O
+and	POS	O
+less	POS	O
+recent	POS	O
+users	POS	O
+of	POS	O
+these	POS	O
+drugs	POS	O
+within	POS	O
+this	POS	O
+group	POS	O
+were	POS	O
+similarly	POS	O
+impaired	POS	O
+.	POS	O
+Possible	POS	O
+parallels	POS	O
+between	POS	O
+RC	POS	O
+users	POS	O
+and	POS	O
+psychopaths	POS	O
+with	POS	O
+respect	POS	O
+to	POS	O
+impaired	POS	O
+fear	POS	O
+recognition	POS	O
+,	POS	O
+amygdala	POS	B-NP
+dysfunction	POS	I-NP
+,	POS	O
+and	POS	O
+etiology	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+Damage	POS	O
+of	POS	O
+substantia	POS	O
+nigra	POS	O
+pars	POS	O
+reticulata	POS	O
+during	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+in	POS	O
+the	POS	O
+rat	POS	O
+:	POS	O
+immunohistochemical	POS	O
+study	POS	O
+of	POS	O
+neurons	POS	O
+,	POS	O
+astrocytes	POS	O
+and	POS	O
+serum	POS	O
+-	POS	O
+protein	POS	O
+extravasation	POS	O
+.	POS	O
+The	POS	O
+substantia	POS	O
+nigra	POS	O
+has	POS	O
+a	POS	O
+gating	POS	O
+function	POS	O
+controlling	POS	O
+the	POS	O
+spread	POS	O
+of	POS	O
+epileptic	POS	B-NP
+seizure	POS	I-NP
+activity	POS	O
+.	POS	O
+Additionally	POS	O
+,	POS	O
+in	POS	O
+models	POS	O
+of	POS	O
+prolonged	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+the	POS	O
+pars	POS	O
+reticulata	POS	O
+of	POS	O
+substantia	POS	O
+nigra	POS	O
+(	POS	O
+SNR	POS	O
+)	POS	O
+suffers	POS	O
+from	POS	O
+a	POS	O
+massive	POS	O
+lesion	POS	O
+which	POS	O
+may	POS	O
+arise	POS	O
+from	POS	O
+a	POS	O
+massive	POS	O
+metabolic	POS	O
+derangement	POS	O
+and	POS	O
+hyperexcitation	POS	B-NP
+developing	POS	O
+in	POS	O
+the	POS	O
+activated	POS	O
+SNR	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+,	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+was	POS	O
+induced	POS	O
+by	POS	O
+systemic	POS	O
+injection	POS	O
+of	POS	O
+pilocarpine	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+neuropathology	POS	O
+of	POS	O
+SNR	POS	O
+was	POS	O
+investigated	POS	O
+using	POS	O
+immunohistochemical	POS	O
+techniques	POS	O
+with	POS	O
+the	POS	O
+major	POS	O
+emphasis	POS	O
+on	POS	O
+the	POS	O
+time	POS	O
+-	POS	O
+course	POS	O
+of	POS	O
+changes	POS	O
+in	POS	O
+neurons	POS	O
+and	POS	O
+astrocytes	POS	O
+.	POS	O
+Animals	POS	O
+surviving	POS	O
+20	POS	O
+,	POS	O
+30	POS	O
+,	POS	O
+40	POS	O
+,	POS	O
+60	POS	O
+min	POS	O
+,	POS	O
+2	POS	O
+,	POS	O
+3	POS	O
+,	POS	O
+6	POS	O
+hours	POS	O
+,	POS	O
+1	POS	O
+,	POS	O
+2	POS	O
+,	POS	O
+and	POS	O
+3	POS	O
+days	POS	O
+after	POS	O
+induction	POS	O
+of	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+were	POS	O
+perfusion	POS	O
+-	POS	O
+fixed	POS	O
+,	POS	O
+and	POS	O
+brains	POS	O
+processed	POS	O
+for	POS	O
+immunohistochemical	POS	O
+staining	POS	O
+of	POS	O
+SNR	POS	O
+.	POS	O
+Nissl	POS	O
+-	POS	O
+staining	POS	O
+and	POS	O
+antibodies	POS	O
+against	POS	O
+the	POS	O
+neuron	POS	O
+-	POS	O
+specific	POS	O
+calcium	POS	O
+-	POS	O
+binding	POS	O
+protein	POS	O
+,	POS	O
+parvalbumin	POS	O
+,	POS	O
+served	POS	O
+to	POS	O
+detect	POS	O
+neuronal	POS	O
+damage	POS	O
+in	POS	O
+SNR	POS	O
+.	POS	O
+Antibodies	POS	O
+against	POS	O
+the	POS	O
+astroglia	POS	O
+-	POS	O
+specific	POS	O
+cytoskeletal	POS	O
+protein	POS	O
+,	POS	O
+glial	POS	O
+fibrillary	POS	O
+acidic	POS	O
+protein	POS	O
+(	POS	O
+GFAP	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+against	POS	O
+the	POS	O
+glial	POS	O
+calcium	POS	O
+-	POS	O
+binding	POS	O
+protein	POS	O
+,	POS	O
+S	POS	O
+-	POS	O
+100	POS	O
+protein	POS	O
+,	POS	O
+were	POS	O
+used	POS	O
+to	POS	O
+assess	POS	O
+the	POS	O
+status	POS	O
+of	POS	O
+astrocytes	POS	O
+.	POS	O
+Immunohistochemical	POS	O
+staining	POS	O
+for	POS	O
+serum	POS	O
+-	POS	O
+albumin	POS	O
+and	POS	O
+immunoglobulins	POS	O
+in	POS	O
+brain	POS	O
+tissue	POS	O
+was	POS	O
+taken	POS	O
+as	POS	O
+indicator	POS	O
+of	POS	O
+blood	POS	O
+-	POS	O
+brain	POS	O
+barrier	POS	O
+disturbances	POS	O
+and	POS	O
+vasogenic	POS	B-NP
+edema	POS	I-NP
+formation	POS	O
+.	POS	O
+Immunohistochemical	POS	O
+staining	POS	O
+indicated	POS	O
+loss	POS	O
+of	POS	O
+GFAP	POS	O
+-	POS	O
+staining	POS	O
+already	POS	O
+at	POS	O
+30	POS	O
+min	POS	O
+after	POS	O
+induction	POS	O
+of	POS	O
+seizures	POS	B-NP
+in	POS	O
+an	POS	O
+oval	POS	O
+focus	POS	O
+situated	POS	O
+in	POS	O
+the	POS	O
+center	POS	O
+of	POS	O
+SNR	POS	O
+while	POS	O
+sparing	POS	O
+medial	POS	O
+and	POS	O
+lateral	POS	O
+aspects	POS	O
+.	POS	O
+At	POS	O
+1	POS	O
+h	POS	O
+there	POS	O
+was	POS	O
+additional	POS	O
+vacuolation	POS	O
+in	POS	O
+S	POS	O
+-	POS	O
+100	POS	O
+protein	POS	O
+staining	POS	O
+.	POS	O
+By	POS	O
+2	POS	O
+hours	POS	O
+,	POS	O
+parvalbumin	POS	O
+-	POS	O
+staining	POS	O
+changed	POS	O
+in	POS	O
+the	POS	O
+central	POS	O
+SNR	POS	O
+indicating	POS	O
+neuronal	POS	O
+damage	POS	O
+,	POS	O
+and	POS	O
+Nissl	POS	O
+-	POS	O
+staining	POS	O
+visualized	POS	O
+some	POS	O
+neuronal	POS	O
+distortion	POS	O
+.	POS	O
+Staining	POS	O
+for	POS	O
+serum	POS	O
+-	POS	O
+proteins	POS	O
+occurred	POS	O
+in	POS	O
+a	POS	O
+patchy	POS	O
+manner	POS	O
+throughout	POS	O
+the	POS	O
+forebrain	POS	O
+during	POS	O
+the	POS	O
+first	POS	O
+hours	POS	O
+.	POS	O
+By	POS	O
+6	POS	O
+h	POS	O
+,	POS	O
+vasogenic	POS	O
+edema	POS	B-NP
+covered	POS	O
+the	POS	O
+lesioned	POS	O
+SNR	POS	O
+.	POS	O
+By	POS	O
+24	POS	O
+h	POS	O
+,	POS	O
+glial	POS	O
+and	POS	O
+neuronal	POS	O
+markers	POS	O
+indicated	POS	O
+a	POS	O
+massive	POS	O
+lesion	POS	O
+in	POS	O
+the	POS	O
+center	POS	O
+of	POS	O
+SNR	POS	O
+.	POS	O
+By	POS	O
+48	POS	O
+-	POS	O
+72	POS	O
+h	POS	O
+,	POS	O
+astrocytes	POS	O
+surrounding	POS	O
+the	POS	O
+lesion	POS	O
+increased	POS	O
+in	POS	O
+size	POS	O
+,	POS	O
+and	POS	O
+polymorphic	POS	O
+phagocytotic	POS	O
+cells	POS	O
+invaded	POS	O
+the	POS	O
+damaged	POS	O
+area	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+further	POS	O
+group	POS	O
+of	POS	O
+animals	POS	O
+surviving	POS	O
+1	POS	O
+to	POS	O
+5	POS	O
+days	POS	O
+,	POS	O
+conventional	POS	O
+paraffin	POS	O
+-	POS	O
+sections	POS	O
+confirmed	POS	O
+the	POS	O
+neuronal	POS	O
+and	POS	O
+glial	POS	O
+damage	POS	O
+of	POS	O
+SNR	POS	O
+.	POS	O
+Additional	POS	O
+pathology	POS	O
+of	POS	O
+similar	POS	O
+quality	POS	O
+was	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+globus	POS	O
+pallidus	POS	O
+.	POS	O
+Since	POS	O
+astrocytes	POS	O
+were	POS	O
+always	POS	O
+damaged	POS	O
+in	POS	O
+parallel	POS	O
+with	POS	O
+neurons	POS	O
+in	POS	O
+SNR	POS	O
+it	POS	O
+is	POS	O
+proposed	POS	O
+that	POS	O
+the	POS	O
+anatomical	POS	O
+and	POS	O
+functional	POS	O
+interrelationship	POS	O
+between	POS	O
+neurons	POS	O
+and	POS	O
+astrocytes	POS	O
+is	POS	O
+particularly	POS	O
+tight	POS	O
+in	POS	O
+SNR	POS	O
+.	POS	O
+Both	POS	O
+cell	POS	O
+elements	POS	O
+may	POS	O
+suffer	POS	O
+in	POS	O
+common	POS	O
+from	POS	O
+metabolic	POS	O
+disturbance	POS	O
+and	POS	O
+neurotransmitter	POS	B-NP
+dysfunction	POS	I-NP
+as	POS	O
+occur	POS	O
+during	POS	O
+massive	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+.	POS	O
+Neuroprotective	POS	O
+effects	POS	O
+of	POS	O
+melatonin	POS	O
+upon	POS	O
+the	POS	O
+offspring	POS	O
+cerebellar	POS	O
+cortex	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+model	POS	O
+of	POS	O
+BCNU	POS	O
+-	POS	O
+induced	POS	O
+cortical	POS	B-NP
+dysplasia	POS	I-NP
+.	POS	O
+Cortical	POS	B-NP
+dysplasia	POS	I-NP
+is	POS	O
+a	POS	O
+malformation	POS	B-NP
+characterized	POS	O
+by	POS	O
+defects	POS	O
+in	POS	O
+proliferation	POS	O
+,	POS	O
+migration	POS	O
+and	POS	O
+maturation	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+was	POS	O
+designed	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+alterations	POS	O
+in	POS	O
+offspring	POS	O
+rat	POS	O
+cerebellum	POS	O
+induced	POS	O
+by	POS	O
+maternal	POS	O
+exposure	POS	O
+to	POS	O
+carmustine	POS	O
+-	POS	O
+[	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+-	POS	O
+bis	POS	O
+(	POS	O
+2	POS	O
+-	POS	O
+chloroethyl	POS	O
+)	POS	O
+-	POS	O
+1	POS	O
+-	POS	O
+nitrosoure	POS	O
+]	POS	O
+(	POS	O
+BCNU	POS	O
+)	POS	O
+and	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+exogenous	POS	O
+melatonin	POS	O
+upon	POS	O
+cerebellar	POS	O
+BCNU	POS	O
+-	POS	O
+induced	POS	O
+cortical	POS	B-NP
+dysplasia	POS	I-NP
+,	POS	O
+using	POS	O
+histological	POS	O
+and	POS	O
+biochemical	POS	O
+analyses	POS	O
+.	POS	O
+Pregnant	POS	O
+Wistar	POS	O
+rats	POS	O
+were	POS	O
+assigned	POS	O
+to	POS	O
+five	POS	O
+groups	POS	O
+:	POS	O
+intact	POS	O
+-	POS	O
+control	POS	O
+,	POS	O
+saline	POS	O
+-	POS	O
+control	POS	O
+,	POS	O
+melatonin	POS	O
+-	POS	O
+treated	POS	O
+,	POS	O
+BCNU	POS	O
+-	POS	O
+exposed	POS	O
+and	POS	O
+BCNU	POS	O
+-	POS	O
+exposed	POS	O
+plus	POS	O
+melatonin	POS	O
+.	POS	O
+Rats	POS	O
+were	POS	O
+exposed	POS	O
+to	POS	O
+BCNU	POS	O
+on	POS	O
+embryonic	POS	O
+day	POS	O
+15	POS	O
+and	POS	O
+melatonin	POS	O
+was	POS	O
+given	POS	O
+until	POS	O
+delivery	POS	O
+.	POS	O
+Immuno	POS	O
+/	POS	O
+histochemistry	POS	O
+and	POS	O
+electron	POS	O
+microscopy	POS	O
+were	POS	O
+carried	POS	O
+out	POS	O
+on	POS	O
+the	POS	O
+offspring	POS	O
+cerebellum	POS	O
+,	POS	O
+and	POS	O
+levels	POS	O
+of	POS	O
+malondialdehyde	POS	O
+and	POS	O
+superoxide	POS	O
+dismutase	POS	O
+were	POS	O
+determined	POS	O
+.	POS	O
+Histopathologically	POS	O
+,	POS	O
+typical	POS	O
+findings	POS	O
+were	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+cerebella	POS	O
+from	POS	O
+the	POS	O
+control	POS	O
+groups	POS	O
+,	POS	O
+but	POS	O
+the	POS	O
+findings	POS	O
+consistent	POS	O
+with	POS	O
+early	POS	O
+embryonic	POS	O
+development	POS	O
+were	POS	O
+noted	POS	O
+in	POS	O
+BCNU	POS	O
+-	POS	O
+exposed	POS	O
+cortical	POS	B-NP
+dysplasia	POS	I-NP
+group	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+a	POS	O
+marked	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+TUNEL	POS	O
+positive	POS	O
+cells	POS	O
+and	POS	O
+nestin	POS	O
+positive	POS	O
+cells	POS	O
+in	POS	O
+BCNU	POS	O
+-	POS	O
+exposed	POS	O
+group	POS	O
+,	POS	O
+but	POS	O
+a	POS	O
+decreased	POS	O
+immunoreactivity	POS	O
+to	POS	O
+glial	POS	O
+fibrillary	POS	O
+acidic	POS	O
+protein	POS	O
+,	POS	O
+synaptophysin	POS	O
+and	POS	O
+transforming	POS	O
+growth	POS	O
+factor	POS	O
+beta1	POS	O
+was	POS	O
+observed	POS	O
+,	POS	O
+indicating	POS	O
+a	POS	O
+delayed	POS	O
+maturation	POS	O
+,	POS	O
+and	POS	O
+melatonin	POS	O
+significantly	POS	O
+reversed	POS	O
+these	POS	O
+changes	POS	O
+.	POS	O
+Malondialdehyde	POS	O
+level	POS	O
+in	POS	O
+BCNU	POS	O
+-	POS	O
+exposed	POS	O
+group	POS	O
+was	POS	O
+higher	POS	O
+than	POS	O
+those	POS	O
+in	POS	O
+control	POS	O
+groups	POS	O
+and	POS	O
+melatonin	POS	O
+decreased	POS	O
+malondialdehyde	POS	O
+levels	POS	O
+in	POS	O
+BCNU	POS	O
+group	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+,	POS	O
+while	POS	O
+there	POS	O
+were	POS	O
+no	POS	O
+significant	POS	O
+differences	POS	O
+in	POS	O
+the	POS	O
+superoxide	POS	O
+dismutase	POS	O
+levels	POS	O
+between	POS	O
+these	POS	O
+groups	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+exposure	POS	O
+of	POS	O
+animals	POS	O
+to	POS	O
+BCNU	POS	O
+during	POS	O
+pregnancy	POS	O
+leads	POS	O
+to	POS	O
+delayed	POS	O
+maturation	POS	O
+of	POS	O
+offspring	POS	O
+cerebellum	POS	O
+and	POS	O
+melatonin	POS	O
+protects	POS	O
+the	POS	O
+cerebellum	POS	O
+against	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+BCNU	POS	O
+.	POS	O
+Reduced	POS	O
+cardiotoxicity	POS	B-NP
+of	POS	O
+doxorubicin	POS	O
+given	POS	O
+in	POS	O
+the	POS	O
+form	POS	O
+of	POS	O
+N	POS	O
+-	POS	O
+(	POS	O
+2	POS	O
+-	POS	O
+hydroxypropyl	POS	O
+)	POS	O
+methacrylamide	POS	O
+conjugates	POS	O
+:	POS	O
+and	POS	O
+experimental	POS	O
+study	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+.	POS	O
+A	POS	O
+rat	POS	O
+model	POS	O
+was	POS	O
+used	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+general	POS	O
+acute	POS	B-NP
+toxicity	POS	I-NP
+and	POS	O
+the	POS	O
+late	POS	O
+cardiotoxicity	POS	B-NP
+of	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+doxorubicin	POS	O
+(	POS	O
+DOX	POS	O
+)	POS	O
+given	POS	O
+either	POS	O
+as	POS	O
+free	POS	O
+drug	POS	O
+or	POS	O
+in	POS	O
+the	POS	O
+form	POS	O
+of	POS	O
+three	POS	O
+N	POS	O
+-	POS	O
+(	POS	O
+2	POS	O
+-	POS	O
+hydroxypropyl	POS	O
+)	POS	O
+methacrylamide	POS	O
+(	POS	O
+HPMA	POS	O
+)	POS	O
+copolymer	POS	O
+conjugates	POS	O
+.	POS	O
+In	POS	O
+these	POS	O
+HPMA	POS	O
+copolymers	POS	O
+,	POS	O
+DOX	POS	O
+was	POS	O
+covalently	POS	O
+bound	POS	O
+via	POS	O
+peptide	POS	O
+linkages	POS	O
+that	POS	O
+were	POS	O
+either	POS	O
+non	POS	O
+-	POS	O
+biodegradable	POS	O
+(	POS	O
+Gly	POS	O
+-	POS	O
+Gly	POS	O
+)	POS	O
+or	POS	O
+degradable	POS	O
+by	POS	O
+lysosomal	POS	O
+proteinases	POS	O
+(	POS	O
+Gly	POS	O
+-	POS	O
+Phe	POS	O
+-	POS	O
+Leu	POS	O
+-	POS	O
+Gly	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+one	POS	O
+biodegradable	POS	O
+conjugate	POS	O
+containing	POS	O
+galactosamine	POS	O
+was	POS	O
+used	POS	O
+;	POS	O
+this	POS	O
+residue	POS	O
+was	POS	O
+targeted	POS	O
+to	POS	O
+the	POS	O
+liver	POS	O
+.	POS	O
+Over	POS	O
+the	POS	O
+first	POS	O
+3	POS	O
+weeks	POS	O
+after	POS	O
+the	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+administration	POS	O
+of	POS	O
+free	POS	O
+and	POS	O
+polymer	POS	O
+-	POS	O
+bound	POS	O
+DOX	POS	O
+,	POS	O
+all	POS	O
+animals	POS	O
+showed	POS	O
+a	POS	O
+transient	POS	O
+reduction	POS	O
+in	POS	O
+body	POS	O
+weight	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+maximal	POS	O
+reduction	POS	O
+in	POS	O
+body	POS	O
+weight	POS	O
+seen	POS	O
+in	POS	O
+animals	POS	O
+that	POS	O
+received	POS	O
+polymer	POS	O
+-	POS	O
+bound	POS	O
+DOX	POS	O
+(	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+was	POS	O
+significantly	POS	O
+lower	POS	O
+than	POS	O
+that	POS	O
+observed	POS	O
+in	POS	O
+those	POS	O
+that	POS	O
+received	POS	O
+free	POS	O
+DOX	POS	O
+(	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+or	POS	O
+a	POS	O
+mixture	POS	O
+of	POS	O
+the	POS	O
+unmodified	POS	O
+parent	POS	O
+HPMA	POS	O
+copolymer	POS	O
+and	POS	O
+free	POS	O
+DOX	POS	O
+(	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+;	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+Throughout	POS	O
+the	POS	O
+study	POS	O
+(	POS	O
+20	POS	O
+weeks	POS	O
+)	POS	O
+,	POS	O
+deaths	POS	O
+related	POS	O
+to	POS	O
+cardiotoxicity	POS	B-NP
+were	POS	O
+observed	POS	O
+only	POS	O
+in	POS	O
+animals	POS	O
+that	POS	O
+received	POS	O
+either	POS	O
+free	POS	O
+DOX	POS	O
+or	POS	O
+the	POS	O
+mixture	POS	O
+of	POS	O
+HPMA	POS	O
+copolymer	POS	O
+and	POS	O
+free	POS	O
+DOX	POS	O
+;	POS	O
+in	POS	O
+these	POS	O
+cases	POS	O
+,	POS	O
+histological	POS	O
+investigations	POS	O
+revealed	POS	O
+marked	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+heart	POS	O
+that	POS	O
+were	POS	O
+consistent	POS	O
+with	POS	O
+DOX	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+Sequential	POS	O
+measurements	POS	O
+of	POS	O
+cardiac	POS	O
+output	POS	O
+in	POS	O
+surviving	POS	O
+animals	POS	O
+that	POS	O
+received	POS	O
+either	POS	O
+free	POS	O
+DOX	POS	O
+or	POS	O
+the	POS	O
+mixture	POS	O
+of	POS	O
+HPMA	POS	O
+copolymer	POS	O
+and	POS	O
+free	POS	O
+DOX	POS	O
+showed	POS	O
+a	POS	O
+reduction	POS	O
+of	POS	O
+approximately	POS	O
+30	POS	O
+%	POS	O
+in	POS	O
+function	POS	O
+beginning	POS	O
+at	POS	O
+the	POS	O
+4th	POS	O
+week	POS	O
+after	POS	O
+drug	POS	O
+administration	POS	O
+.	POS	O
+The	POS	O
+heart	POS	O
+rate	POS	O
+in	POS	O
+these	POS	O
+animals	POS	O
+was	POS	O
+approximately	POS	O
+12	POS	O
+%	POS	O
+lower	POS	O
+than	POS	O
+that	POS	O
+measured	POS	O
+in	POS	O
+age	POS	O
+-	POS	O
+matched	POS	O
+control	POS	O
+rats	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+Animals	POS	O
+that	POS	O
+were	POS	O
+given	POS	O
+the	POS	O
+HPMA	POS	O
+copolymer	POS	O
+conjugates	POS	O
+containing	POS	O
+DOX	POS	O
+exhibited	POS	O
+no	POS	O
+significant	POS	O
+change	POS	O
+in	POS	O
+cardiac	POS	O
+output	POS	O
+throughout	POS	O
+the	POS	O
+study	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+no	POS	O
+significant	POS	O
+histological	POS	O
+change	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+heart	POS	O
+of	POS	O
+animals	POS	O
+that	POS	O
+received	POS	O
+DOX	POS	O
+in	POS	O
+the	POS	O
+form	POS	O
+of	POS	O
+HPMA	POS	O
+copolymer	POS	O
+conjugates	POS	O
+and	POS	O
+were	POS	O
+killed	POS	O
+at	POS	O
+the	POS	O
+end	POS	O
+of	POS	O
+the	POS	O
+study	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+these	POS	O
+animals	POS	O
+had	POS	O
+shown	POS	O
+a	POS	O
+significant	POS	O
+increase	POS	O
+in	POS	O
+heart	POS	O
+rate	POS	O
+beginning	POS	O
+at	POS	O
+8	POS	O
+weeks	POS	O
+after	POS	O
+drug	POS	O
+administration	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+(	POS	O
+ABSTRACT	POS	O
+TRUNCATED	POS	O
+AT	POS	O
+400	POS	O
+WORDS	POS	O
+)	POS	O
+Corneal	POS	B-NP
+ulcers	POS	I-NP
+associated	POS	O
+with	POS	O
+aerosolized	POS	O
+crack	POS	O
+cocaine	POS	O
+use	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+We	POS	O
+report	POS	O
+4	POS	O
+cases	POS	O
+of	POS	O
+corneal	POS	B-NP
+ulcers	POS	I-NP
+associated	POS	O
+with	POS	O
+drug	POS	B-NP
+abuse	POS	I-NP
+.	POS	O
+The	POS	O
+pathogenesis	POS	O
+of	POS	O
+these	POS	O
+ulcers	POS	B-NP
+and	POS	O
+management	POS	O
+of	POS	O
+these	POS	O
+patients	POS	O
+are	POS	O
+also	POS	O
+reviewed	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Review	POS	O
+of	POS	O
+all	POS	O
+cases	POS	O
+of	POS	O
+corneal	POS	B-NP
+ulcers	POS	I-NP
+associated	POS	O
+with	POS	O
+drug	POS	B-NP
+abuse	POS	I-NP
+seen	POS	O
+at	POS	O
+our	POS	O
+institution	POS	O
+from	POS	O
+July	POS	O
+2006	POS	O
+to	POS	O
+December	POS	O
+2006	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Four	POS	O
+patients	POS	O
+with	POS	O
+corneal	POS	B-NP
+ulcers	POS	I-NP
+associated	POS	O
+with	POS	O
+crack	POS	O
+cocaine	POS	O
+use	POS	O
+were	POS	O
+reviewed	POS	O
+.	POS	O
+All	POS	O
+corneal	POS	B-NP
+ulcers	POS	I-NP
+were	POS	O
+cultured	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+patients	POS	O
+were	POS	O
+admitted	POS	O
+to	POS	O
+the	POS	O
+hospital	POS	O
+for	POS	O
+intensive	POS	O
+topical	POS	O
+antibiotic	POS	O
+treatment	POS	O
+.	POS	O
+Each	POS	O
+patient	POS	O
+received	POS	O
+comprehensive	POS	O
+health	POS	O
+care	POS	O
+,	POS	O
+including	POS	O
+medical	POS	O
+and	POS	O
+substance	POS	O
+abuse	POS	O
+consultations	POS	O
+.	POS	O
+Streptococcal	POS	O
+organisms	POS	O
+were	POS	O
+found	POS	O
+in	POS	O
+3	POS	O
+cases	POS	O
+and	POS	O
+Capnocytophaga	POS	O
+and	POS	O
+Brevibacterium	POS	O
+casei	POS	O
+in	POS	O
+1	POS	O
+patient	POS	O
+.	POS	O
+The	POS	O
+infections	POS	O
+responded	POS	O
+to	POS	O
+antibiotic	POS	O
+treatment	POS	O
+.	POS	O
+Two	POS	O
+patients	POS	O
+needed	POS	O
+a	POS	O
+lateral	POS	O
+tarsorrhaphy	POS	O
+for	POS	O
+persistent	POS	O
+epithelial	POS	B-NP
+defects	POS	I-NP
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Aerosolized	POS	O
+crack	POS	O
+cocaine	POS	O
+use	POS	O
+can	POS	O
+be	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+corneal	POS	B-NP
+ulcers	POS	I-NP
+.	POS	O
+Drug	POS	O
+abuse	POS	O
+provides	POS	O
+additional	POS	O
+challenges	POS	O
+for	POS	O
+management	POS	O
+.	POS	O
+Not	POS	O
+only	POS	O
+treatment	POS	O
+of	POS	O
+their	POS	O
+infections	POS	O
+but	POS	O
+also	POS	O
+the	POS	O
+overall	POS	O
+poor	POS	O
+health	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+and	POS	O
+increased	POS	O
+risk	POS	O
+of	POS	O
+noncompliance	POS	O
+need	POS	O
+to	POS	O
+be	POS	O
+addressed	POS	O
+.	POS	O
+Comprehensive	POS	O
+care	POS	O
+may	POS	O
+provide	POS	O
+the	POS	O
+patient	POS	O
+the	POS	O
+opportunity	POS	O
+to	POS	O
+discontinue	POS	O
+their	POS	O
+substance	POS	B-NP
+abuse	POS	I-NP
+,	POS	O
+improve	POS	O
+their	POS	O
+overall	POS	O
+health	POS	O
+,	POS	O
+and	POS	O
+prevent	POS	O
+future	POS	O
+corneal	POS	B-NP
+complications	POS	I-NP
+.	POS	O
+Topical	POS	O
+0	POS	O
+.	POS	O
+025	POS	O
+%	POS	O
+capsaicin	POS	O
+in	POS	O
+chronic	POS	O
+post	POS	O
+-	POS	O
+herpetic	POS	B-NP
+neuralgia	POS	I-NP
+:	POS	O
+efficacy	POS	O
+,	POS	O
+predictors	POS	O
+of	POS	O
+response	POS	O
+and	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+course	POS	O
+.	POS	O
+In	POS	O
+order	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+efficacy	POS	O
+,	POS	O
+time	POS	O
+-	POS	O
+course	POS	O
+of	POS	O
+action	POS	O
+and	POS	O
+predictors	POS	O
+of	POS	O
+response	POS	O
+to	POS	O
+topical	POS	O
+capsaicin	POS	O
+,	POS	O
+39	POS	O
+patients	POS	O
+with	POS	O
+chronic	POS	B-NP
+post	POS	I-NP
+-	POS	I-NP
+herpetic	POS	I-NP
+neuralgia	POS	I-NP
+(	POS	O
+PHN	POS	B-NP
+)	POS	O
+,	POS	O
+median	POS	O
+duration	POS	O
+24	POS	O
+months	POS	O
+,	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+0	POS	O
+.	POS	O
+025	POS	O
+%	POS	O
+capsaicin	POS	O
+cream	POS	O
+for	POS	O
+8	POS	O
+weeks	POS	O
+.	POS	O
+During	POS	O
+therapy	POS	O
+the	POS	O
+patients	POS	O
+rated	POS	O
+their	POS	O
+pain	POS	B-NP
+on	POS	O
+a	POS	O
+visual	POS	O
+analogue	POS	O
+scale	POS	O
+(	POS	O
+VAS	POS	O
+)	POS	O
+and	POS	O
+a	POS	O
+verbal	POS	O
+outcome	POS	O
+scale	POS	O
+.	POS	O
+A	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+investigation	POS	O
+was	POS	O
+performed	POS	O
+10	POS	O
+-	POS	O
+12	POS	O
+months	POS	O
+after	POS	O
+study	POS	O
+onset	POS	O
+on	POS	O
+the	POS	O
+patients	POS	O
+who	POS	O
+had	POS	O
+improved	POS	O
+.	POS	O
+Nineteen	POS	O
+patients	POS	O
+(	POS	O
+48	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+)	POS	O
+substantially	POS	O
+improved	POS	O
+after	POS	O
+the	POS	O
+8	POS	O
+-	POS	O
+week	POS	O
+trial	POS	O
+;	POS	O
+5	POS	O
+(	POS	O
+12	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+)	POS	O
+discontinued	POS	O
+therapy	POS	O
+due	POS	O
+to	POS	O
+side	POS	O
+-	POS	O
+effects	POS	O
+such	POS	O
+as	POS	O
+intolerable	POS	O
+capsaicin	POS	O
+-	POS	O
+induced	POS	O
+burning	POS	O
+sensations	POS	O
+(	POS	O
+4	POS	O
+)	POS	O
+or	POS	O
+mastitis	POS	B-NP
+(	POS	O
+1	POS	O
+)	POS	O
+;	POS	O
+15	POS	O
+(	POS	O
+38	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+reported	POS	O
+no	POS	O
+benefit	POS	O
+.	POS	O
+The	POS	O
+decrease	POS	O
+in	POS	O
+VAS	POS	O
+ratings	POS	O
+was	POS	O
+significant	POS	O
+after	POS	O
+2	POS	O
+weeks	POS	O
+of	POS	O
+continuous	POS	O
+application	POS	O
+.	POS	O
+Of	POS	O
+the	POS	O
+responders	POS	O
+72	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+were	POS	O
+still	POS	O
+improved	POS	O
+at	POS	O
+the	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+;	POS	O
+only	POS	O
+one	POS	O
+-	POS	O
+third	POS	O
+of	POS	O
+them	POS	O
+had	POS	O
+continued	POS	O
+application	POS	O
+irregularly	POS	O
+.	POS	O
+Treatment	POS	O
+effect	POS	O
+was	POS	O
+not	POS	O
+dependent	POS	O
+on	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+age	POS	O
+,	POS	O
+duration	POS	O
+or	POS	O
+localization	POS	O
+of	POS	O
+PHN	POS	B-NP
+(	POS	O
+trigeminal	POS	O
+involvement	POS	O
+was	POS	O
+excluded	POS	O
+)	POS	O
+,	POS	O
+sensory	POS	B-NP
+disturbance	POS	I-NP
+or	POS	O
+pain	POS	B-NP
+character	POS	O
+.	POS	O
+Treatment	POS	O
+response	POS	O
+was	POS	O
+not	POS	O
+correlated	POS	O
+with	POS	O
+the	POS	O
+incidence	POS	O
+,	POS	O
+time	POS	O
+-	POS	O
+course	POS	O
+or	POS	O
+severity	POS	O
+of	POS	O
+capsaicin	POS	O
+-	POS	O
+induced	POS	O
+burning	POS	O
+.	POS	O
+If	POS	O
+confirmed	POS	O
+in	POS	O
+controlled	POS	O
+trials	POS	O
+,	POS	O
+the	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+results	POS	O
+of	POS	O
+this	POS	O
+open	POS	O
+,	POS	O
+non	POS	O
+-	POS	O
+randomized	POS	O
+study	POS	O
+might	POS	O
+indicate	POS	O
+that	POS	O
+the	POS	O
+analgesic	POS	O
+effect	POS	O
+of	POS	O
+capsaicin	POS	O
+in	POS	O
+PHN	POS	B-NP
+is	POS	O
+mediated	POS	O
+by	POS	O
+both	POS	O
+interference	POS	O
+with	POS	O
+neuropeptide	POS	O
+metabolism	POS	O
+and	POS	O
+morphological	POS	O
+changes	POS	O
+(	POS	O
+perhaps	POS	O
+degeneration	POS	O
+)	POS	O
+of	POS	O
+nociceptive	POS	O
+afferents	POS	O
+.	POS	O
+Myo	POS	O
+-	POS	O
+inositol	POS	O
+-	POS	O
+1	POS	O
+-	POS	O
+phosphate	POS	O
+(	POS	O
+MIP	POS	O
+)	POS	O
+synthase	POS	O
+inhibition	POS	O
+:	POS	O
+in	POS	O
+-	POS	O
+vivo	POS	O
+study	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+Lithium	POS	O
+and	POS	O
+valproate	POS	O
+are	POS	O
+the	POS	O
+prototypic	POS	O
+mood	POS	O
+stabilizers	POS	O
+and	POS	O
+have	POS	O
+diverse	POS	O
+structures	POS	O
+and	POS	O
+targets	POS	O
+.	POS	O
+Both	POS	O
+drugs	POS	O
+influence	POS	O
+inositol	POS	O
+metabolism	POS	O
+.	POS	O
+Lithium	POS	O
+inhibits	POS	O
+IMPase	POS	O
+and	POS	O
+valproate	POS	O
+inhibits	POS	O
+MIP	POS	O
+synthase	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+shows	POS	O
+that	POS	O
+MIP	POS	O
+synthase	POS	O
+inhibition	POS	O
+does	POS	O
+not	POS	O
+replicate	POS	O
+or	POS	O
+augment	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+lithium	POS	O
+in	POS	O
+the	POS	O
+inositol	POS	O
+sensitive	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+model	POS	O
+.	POS	O
+This	POS	O
+lack	POS	O
+of	POS	O
+effects	POS	O
+may	POS	O
+stem	POS	O
+from	POS	O
+the	POS	O
+low	POS	O
+contribution	POS	O
+of	POS	O
+de	POS	O
+-	POS	O
+novo	POS	O
+synthesis	POS	O
+to	POS	O
+cellular	POS	O
+inositol	POS	O
+supply	POS	O
+or	POS	O
+to	POS	O
+the	POS	O
+inhibition	POS	O
+of	POS	O
+the	POS	O
+de	POS	O
+-	POS	O
+novo	POS	O
+synthesis	POS	O
+by	POS	O
+lithium	POS	O
+itself	POS	O
+.	POS	O
+Non	POS	O
+-	POS	O
+steroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+-	POS	O
+associated	POS	O
+acute	POS	O
+interstitial	POS	B-NP
+nephritis	POS	I-NP
+with	POS	O
+granular	POS	B-NP
+tubular	POS	I-NP
+basement	POS	I-NP
+membrane	POS	I-NP
+deposits	POS	I-NP
+.	POS	O
+Acute	POS	O
+tubulo	POS	O
+-	POS	O
+interstitial	POS	B-NP
+nephritis	POS	I-NP
+(	POS	O
+ATIN	POS	B-NP
+)	POS	O
+is	POS	O
+an	POS	O
+important	POS	O
+cause	POS	O
+of	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+resulting	POS	O
+from	POS	O
+a	POS	O
+variety	POS	O
+of	POS	O
+insults	POS	O
+,	POS	O
+including	POS	O
+immune	POS	O
+complex	POS	O
+-	POS	O
+mediated	POS	O
+tubulo	POS	O
+-	POS	O
+interstitial	POS	B-NP
+injury	POS	I-NP
+,	POS	O
+but	POS	O
+drugs	POS	O
+such	POS	O
+as	POS	O
+non	POS	O
+-	POS	O
+steroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+(	POS	O
+NSAIDs	POS	O
+)	POS	O
+are	POS	O
+a	POS	O
+far	POS	O
+more	POS	O
+frequent	POS	O
+cause	POS	O
+.	POS	O
+Overall	POS	O
+,	POS	O
+as	POS	O
+an	POS	O
+entity	POS	O
+,	POS	O
+ATIN	POS	B-NP
+remains	POS	O
+under	POS	O
+-	POS	O
+diagnosed	POS	O
+,	POS	O
+as	POS	O
+symptoms	POS	O
+resolve	POS	O
+spontaneously	POS	O
+if	POS	O
+the	POS	O
+medication	POS	O
+is	POS	O
+stopped	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+on	POS	O
+a	POS	O
+14	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+boy	POS	O
+who	POS	O
+developed	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+2	POS	O
+weeks	POS	O
+after	POS	O
+aortic	POS	O
+valve	POS	O
+surgery	POS	O
+.	POS	O
+He	POS	O
+was	POS	O
+put	POS	O
+on	POS	O
+aspirin	POS	O
+following	POS	O
+surgery	POS	O
+and	POS	O
+took	POS	O
+ibuprofen	POS	O
+for	POS	O
+fever	POS	B-NP
+for	POS	O
+nearly	POS	O
+a	POS	O
+week	POS	O
+prior	POS	O
+to	POS	O
+presentation	POS	O
+.	POS	O
+He	POS	O
+then	POS	O
+presented	POS	O
+to	POS	O
+the	POS	O
+emergency	POS	O
+department	POS	O
+feeling	POS	O
+quite	POS	O
+ill	POS	O
+and	POS	O
+was	POS	O
+found	POS	O
+to	POS	O
+have	POS	O
+a	POS	O
+blood	POS	O
+urea	POS	O
+nitrogen	POS	O
+(	POS	O
+BUN	POS	O
+)	POS	O
+concentration	POS	O
+of	POS	O
+of	POS	O
+147	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+,	POS	O
+creatinine	POS	O
+of	POS	O
+15	POS	O
+.	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+and	POS	O
+serum	POS	O
+potassium	POS	O
+of	POS	O
+8	POS	O
+.	POS	O
+7	POS	O
+mEq	POS	O
+/	POS	O
+l	POS	O
+.	POS	O
+Dialysis	POS	O
+was	POS	O
+immediately	POS	O
+initiated	POS	O
+.	POS	O
+A	POS	O
+kidney	POS	O
+biopsy	POS	O
+showed	POS	O
+inflammatory	POS	O
+infiltrate	POS	O
+consistent	POS	O
+with	POS	O
+ATIN	POS	B-NP
+.	POS	O
+However	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+tubular	POS	O
+basement	POS	O
+membrane	POS	O
+(	POS	O
+TBM	POS	O
+)	POS	O
+,	POS	O
+very	POS	O
+intense	POS	O
+granular	POS	O
+deposits	POS	O
+of	POS	O
+polyclonal	POS	O
+IgG	POS	O
+and	POS	O
+C3	POS	O
+were	POS	O
+noted	POS	O
+.	POS	O
+He	POS	O
+needed	POS	O
+dialysis	POS	O
+for	POS	O
+2	POS	O
+weeks	POS	O
+and	POS	O
+was	POS	O
+treated	POS	O
+successfully	POS	O
+with	POS	O
+steroids	POS	O
+for	POS	O
+6	POS	O
+months	POS	O
+.	POS	O
+His	POS	O
+renal	POS	O
+recovery	POS	O
+and	POS	O
+disappearance	POS	O
+of	POS	O
+proteinuria	POS	B-NP
+took	POS	O
+a	POS	O
+year	POS	O
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+this	POS	O
+is	POS	O
+a	POS	O
+first	POS	O
+report	POS	O
+of	POS	O
+NSAIDs	POS	O
+-	POS	O
+associated	POS	O
+ATIN	POS	B-NP
+,	POS	O
+showing	POS	O
+deposits	POS	O
+of	POS	O
+granular	POS	O
+immune	POS	O
+complex	POS	O
+present	POS	O
+only	POS	O
+in	POS	O
+the	POS	O
+TBM	POS	B-NP
+and	POS	O
+not	POS	O
+in	POS	O
+the	POS	O
+glomeruli	POS	O
+.	POS	O
+Rifampicin	POS	O
+-	POS	O
+associated	POS	O
+segmental	POS	O
+necrotizing	POS	B-NP
+glomerulonephritis	POS	I-NP
+in	POS	O
+staphylococcal	POS	B-NP
+endocarditis	POS	I-NP
+.	POS	O
+Segmental	POS	B-NP
+necrotising	POS	I-NP
+glomerulonephritis	POS	I-NP
+has	POS	O
+been	POS	O
+reported	POS	O
+as	POS	O
+complication	POS	O
+of	POS	O
+rifampicin	POS	O
+therapy	POS	O
+in	POS	O
+patients	POS	O
+receiving	POS	O
+treatment	POS	O
+for	POS	O
+tuberculosis	POS	B-NP
+.	POS	O
+Changing	POS	O
+epidemiology	POS	O
+of	POS	O
+infections	POS	O
+such	POS	O
+as	POS	O
+infective	POS	B-NP
+endocarditis	POS	I-NP
+(	POS	O
+IE	POS	B-NP
+)	POS	O
+has	POS	O
+led	POS	O
+to	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+rifampicin	POS	O
+for	POS	O
+Staphylococcal	POS	B-NP
+infections	POS	I-NP
+.	POS	O
+We	POS	O
+describe	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+Staphylococcal	POS	B-NP
+IE	POS	I-NP
+who	POS	O
+developed	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+secondary	POS	O
+to	POS	O
+a	POS	O
+segmental	POS	O
+necrotising	POS	B-NP
+glomerulonephritis	POS	I-NP
+while	POS	O
+being	POS	O
+treated	POS	O
+with	POS	O
+rifampicin	POS	O
+,	POS	O
+and	POS	O
+review	POS	O
+the	POS	O
+literature	POS	O
+regarding	POS	O
+this	POS	O
+complication	POS	O
+of	POS	O
+rifampicin	POS	O
+therapy	POS	O
+.	POS	O
+Rate	POS	O
+of	POS	O
+YMDD	POS	O
+motif	POS	O
+mutants	POS	O
+in	POS	O
+lamivudine	POS	O
+-	POS	O
+untreated	POS	O
+Iranian	POS	O
+patients	POS	O
+with	POS	O
+chronic	POS	B-NP
+hepatitis	POS	I-NP
+B	POS	I-NP
+virus	POS	I-NP
+infection	POS	I-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Lamivudine	POS	O
+is	POS	O
+used	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+chronic	POS	B-NP
+hepatitis	POS	I-NP
+B	POS	I-NP
+patients	POS	O
+.	POS	O
+Recent	POS	O
+studies	POS	O
+show	POS	O
+that	POS	O
+the	POS	O
+YMDD	POS	O
+motif	POS	O
+mutants	POS	O
+(	POS	O
+resistant	POS	O
+hepatitis	POS	O
+B	POS	O
+virus	POS	O
+)	POS	O
+occur	POS	O
+as	POS	O
+natural	POS	O
+genome	POS	O
+variability	POS	O
+in	POS	O
+lamivudine	POS	O
+-	POS	O
+untreated	POS	O
+chronic	POS	O
+hepatitis	POS	B-NP
+B	POS	I-NP
+patients	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+we	POS	O
+aimed	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+rate	POS	O
+of	POS	O
+YMDD	POS	O
+motif	POS	O
+mutants	POS	O
+in	POS	O
+lamivudine	POS	O
+-	POS	O
+untreated	POS	O
+chronic	POS	O
+hepatitis	POS	B-NP
+B	POS	I-NP
+patients	POS	O
+in	POS	O
+Iran	POS	O
+.	POS	O
+PATIENTS	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+77	POS	O
+chronic	POS	O
+hepatitis	POS	B-NP
+B	POS	I-NP
+patients	POS	O
+who	POS	O
+had	POS	O
+not	POS	O
+been	POS	O
+treated	POS	O
+with	POS	O
+lamivudine	POS	O
+were	POS	O
+included	POS	O
+in	POS	O
+the	POS	O
+study	POS	O
+.	POS	O
+Serum	POS	O
+samples	POS	O
+from	POS	O
+patients	POS	O
+were	POS	O
+tested	POS	O
+by	POS	O
+polymerase	POS	O
+chain	POS	O
+reaction	POS	O
+-	POS	O
+restriction	POS	O
+fragment	POS	O
+length	POS	O
+polymorphism	POS	O
+(	POS	O
+PCR	POS	O
+-	POS	O
+RFLP	POS	O
+)	POS	O
+for	POS	O
+detection	POS	O
+of	POS	O
+YMDD	POS	O
+motif	POS	O
+mutants	POS	O
+.	POS	O
+All	POS	O
+patients	POS	O
+were	POS	O
+also	POS	O
+tested	POS	O
+for	POS	O
+liver	POS	O
+enzymes	POS	O
+,	POS	O
+anti	POS	O
+-	POS	O
+HCV	POS	O
+,	POS	O
+HBeAg	POS	O
+,	POS	O
+and	POS	O
+anti	POS	O
+-	POS	O
+HBe	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Of	POS	O
+the	POS	O
+77	POS	O
+patients	POS	O
+enrolled	POS	O
+in	POS	O
+the	POS	O
+study	POS	O
+,	POS	O
+73	POS	O
+%	POS	O
+were	POS	O
+male	POS	O
+and	POS	O
+27	POS	O
+%	POS	O
+were	POS	O
+female	POS	O
+.	POS	O
+Mean	POS	O
+ALT	POS	O
+and	POS	O
+AST	POS	O
+levels	POS	O
+were	POS	O
+124	POS	O
+.	POS	O
+4	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+73	POS	O
+.	POS	O
+4	POS	O
+and	POS	O
+103	POS	O
+.	POS	O
+1	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+81	POS	O
+IU	POS	O
+/	POS	O
+l	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+HBeAg	POS	O
+was	POS	O
+positive	POS	O
+in	POS	O
+40	POS	O
+%	POS	O
+and	POS	O
+anti	POS	O
+-	POS	O
+HBe	POS	O
+in	POS	O
+60	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+.	POS	O
+Anti	POS	O
+-	POS	O
+HCV	POS	O
+was	POS	O
+negative	POS	O
+in	POS	O
+all	POS	O
+of	POS	O
+them	POS	O
+.	POS	O
+YMDD	POS	O
+motif	POS	O
+mutants	POS	O
+were	POS	O
+not	POS	O
+detected	POS	O
+in	POS	O
+any	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+despite	POS	O
+the	POS	O
+liver	POS	O
+enzyme	POS	O
+levels	POS	O
+and	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+HBeAg	POS	O
+or	POS	O
+anti	POS	O
+-	POS	O
+HBe	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Although	POS	O
+the	POS	O
+natural	POS	O
+occurrence	POS	O
+of	POS	O
+YMDD	POS	O
+motif	POS	O
+mutants	POS	O
+in	POS	O
+lamivudine	POS	O
+-	POS	O
+untreated	POS	O
+patients	POS	O
+with	POS	O
+chronic	POS	B-NP
+hepatitis	POS	I-NP
+B	POS	I-NP
+has	POS	O
+been	POS	O
+reported	POS	O
+,	POS	O
+these	POS	O
+mutants	POS	O
+were	POS	O
+not	POS	O
+detected	POS	O
+in	POS	O
+Iranian	POS	O
+lamivudine	POS	O
+-	POS	O
+untreated	POS	O
+chronic	POS	O
+hepatitis	POS	B-NP
+B	POS	I-NP
+patients	POS	O
+.	POS	O
+Branch	POS	B-NP
+retinal	POS	I-NP
+vein	POS	I-NP
+occlusion	POS	I-NP
+and	POS	O
+fluoxetine	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+branch	POS	O
+retinal	POS	B-NP
+vein	POS	I-NP
+occlusion	POS	I-NP
+associated	POS	O
+with	POS	O
+fluoxetine	POS	O
+-	POS	O
+induced	POS	O
+secondary	POS	O
+hypertension	POS	B-NP
+is	POS	O
+described	POS	O
+.	POS	O
+Although	POS	O
+an	POS	O
+infrequent	POS	O
+complication	POS	O
+of	POS	O
+selective	POS	O
+serotonin	POS	O
+reuptake	POS	O
+inhibitor	POS	O
+therapy	POS	O
+,	POS	O
+it	POS	O
+is	POS	O
+important	POS	O
+that	POS	O
+ophthalmologists	POS	O
+are	POS	O
+aware	POS	O
+that	POS	O
+these	POS	O
+agents	POS	O
+can	POS	O
+cause	POS	O
+hypertension	POS	B-NP
+because	POS	O
+this	POS	O
+class	POS	O
+of	POS	O
+drugs	POS	O
+is	POS	O
+widely	POS	O
+prescribed	POS	O
+.	POS	O
+The	POS	O
+differential	POS	O
+effects	POS	O
+of	POS	O
+bupivacaine	POS	O
+and	POS	O
+lidocaine	POS	O
+on	POS	O
+prostaglandin	POS	O
+E2	POS	O
+release	POS	O
+,	POS	O
+cyclooxygenase	POS	O
+gene	POS	O
+expression	POS	O
+and	POS	O
+pain	POS	B-NP
+in	POS	O
+a	POS	O
+clinical	POS	O
+pain	POS	B-NP
+model	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+In	POS	O
+addition	POS	O
+to	POS	O
+blocking	POS	O
+nociceptive	POS	O
+input	POS	O
+from	POS	O
+surgical	POS	O
+sites	POS	O
+,	POS	O
+long	POS	O
+-	POS	O
+acting	POS	O
+local	POS	O
+anesthetics	POS	O
+might	POS	O
+directly	POS	O
+modulate	POS	O
+inflammation	POS	B-NP
+.	POS	O
+In	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+,	POS	O
+we	POS	O
+describe	POS	O
+the	POS	O
+proinflammatory	POS	O
+effects	POS	O
+of	POS	O
+bupivacaine	POS	O
+on	POS	O
+local	POS	O
+prostaglandin	POS	O
+E2	POS	O
+(	POS	O
+PGE2	POS	O
+)	POS	O
+production	POS	O
+and	POS	O
+cyclooxygenase	POS	O
+(	POS	O
+COX	POS	O
+)	POS	O
+gene	POS	O
+expression	POS	O
+that	POS	O
+increases	POS	O
+postoperative	POS	B-NP
+pain	POS	I-NP
+in	POS	O
+human	POS	O
+subjects	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Subjects	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+114	POS	O
+)	POS	O
+undergoing	POS	O
+extraction	POS	O
+of	POS	O
+impacted	POS	O
+third	POS	O
+molars	POS	O
+received	POS	O
+either	POS	O
+2	POS	O
+%	POS	O
+lidocaine	POS	O
+or	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+bupivacaine	POS	O
+before	POS	O
+surgery	POS	O
+and	POS	O
+either	POS	O
+rofecoxib	POS	O
+50	POS	O
+mg	POS	O
+or	POS	O
+placebo	POS	O
+orally	POS	O
+90	POS	O
+min	POS	O
+before	POS	O
+surgery	POS	O
+and	POS	O
+for	POS	O
+the	POS	O
+following	POS	O
+48	POS	O
+h	POS	O
+.	POS	O
+Oral	POS	O
+mucosal	POS	O
+biopsies	POS	O
+were	POS	O
+taken	POS	O
+before	POS	O
+surgery	POS	O
+and	POS	O
+48	POS	O
+h	POS	O
+after	POS	O
+surgery	POS	O
+.	POS	O
+After	POS	O
+extraction	POS	O
+,	POS	O
+a	POS	O
+microdialysis	POS	O
+probe	POS	O
+was	POS	O
+placed	POS	O
+at	POS	O
+the	POS	O
+surgical	POS	O
+site	POS	O
+for	POS	O
+PGE2	POS	O
+and	POS	O
+thromboxane	POS	O
+B2	POS	O
+(	POS	O
+TXB2	POS	O
+)	POS	O
+measurements	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+bupivacaine	POS	O
+/	POS	O
+rofecoxib	POS	O
+group	POS	O
+reported	POS	O
+significantly	POS	O
+less	POS	O
+pain	POS	B-NP
+,	POS	O
+as	POS	O
+assessed	POS	O
+by	POS	O
+a	POS	O
+visual	POS	O
+analog	POS	O
+scale	POS	O
+,	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+other	POS	O
+three	POS	O
+treatment	POS	O
+groups	POS	O
+over	POS	O
+the	POS	O
+first	POS	O
+4	POS	O
+h	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+bupivacaine	POS	O
+/	POS	O
+placebo	POS	O
+group	POS	O
+reported	POS	O
+significantly	POS	O
+more	POS	O
+pain	POS	B-NP
+at	POS	O
+24	POS	O
+h	POS	O
+and	POS	O
+PGE2	POS	O
+levels	POS	O
+during	POS	O
+the	POS	O
+first	POS	O
+4	POS	O
+h	POS	O
+were	POS	O
+significantly	POS	O
+higher	POS	O
+than	POS	O
+the	POS	O
+other	POS	O
+three	POS	O
+treatment	POS	O
+groups	POS	O
+.	POS	O
+Moreover	POS	O
+,	POS	O
+bupivacaine	POS	O
+significantly	POS	O
+increased	POS	O
+COX	POS	O
+-	POS	O
+2	POS	O
+gene	POS	O
+expression	POS	O
+at	POS	O
+48	POS	O
+h	POS	O
+as	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+lidocaine	POS	O
+/	POS	O
+placebo	POS	O
+group	POS	O
+.	POS	O
+Thromboxane	POS	O
+levels	POS	O
+were	POS	O
+not	POS	O
+significantly	POS	O
+affected	POS	O
+by	POS	O
+any	POS	O
+of	POS	O
+the	POS	O
+treatments	POS	O
+,	POS	O
+indicating	POS	O
+that	POS	O
+the	POS	O
+effects	POS	O
+seen	POS	O
+were	POS	O
+attributable	POS	O
+to	POS	O
+inhibition	POS	O
+of	POS	O
+COX	POS	O
+-	POS	O
+2	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+COX	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+bupivacaine	POS	O
+stimulates	POS	O
+COX	POS	O
+-	POS	O
+2	POS	O
+gene	POS	O
+expression	POS	O
+after	POS	O
+tissue	POS	O
+injury	POS	O
+,	POS	O
+which	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+higher	POS	O
+PGE2	POS	O
+production	POS	O
+and	POS	O
+pain	POS	B-NP
+after	POS	O
+the	POS	O
+local	POS	O
+anesthetic	POS	O
+effect	POS	O
+dissipates	POS	O
+.	POS	O
+p75NTR	POS	O
+expression	POS	O
+in	POS	O
+rat	POS	O
+urinary	POS	O
+bladder	POS	O
+sensory	POS	O
+neurons	POS	O
+and	POS	O
+spinal	POS	O
+cord	POS	O
+with	POS	O
+cyclophosphamide	POS	O
+-	POS	O
+induced	POS	O
+cystitis	POS	B-NP
+.	POS	O
+A	POS	O
+role	POS	O
+for	POS	O
+nerve	POS	O
+growth	POS	O
+factor	POS	O
+(	POS	O
+NGF	POS	O
+)	POS	O
+in	POS	O
+contributing	POS	O
+to	POS	O
+increased	POS	O
+voiding	POS	O
+frequency	POS	O
+and	POS	O
+altered	POS	O
+sensation	POS	O
+from	POS	O
+the	POS	O
+urinary	POS	O
+bladder	POS	O
+has	POS	O
+been	POS	O
+suggested	POS	O
+.	POS	O
+Previous	POS	O
+studies	POS	O
+have	POS	O
+examined	POS	O
+the	POS	O
+expression	POS	O
+and	POS	O
+regulation	POS	O
+of	POS	O
+tyrosine	POS	O
+kinase	POS	O
+receptors	POS	O
+(	POS	O
+Trks	POS	O
+)	POS	O
+in	POS	O
+micturition	POS	O
+reflexes	POS	O
+with	POS	O
+urinary	POS	B-NP
+bladder	POS	I-NP
+inflammation	POS	I-NP
+.	POS	O
+The	POS	O
+present	POS	O
+studies	POS	O
+examine	POS	O
+the	POS	O
+expression	POS	O
+and	POS	O
+regulation	POS	O
+of	POS	O
+another	POS	O
+receptor	POS	O
+known	POS	O
+to	POS	O
+bind	POS	O
+NGF	POS	O
+,	POS	O
+p75	POS	O
+(	POS	O
+NTR	POS	O
+)	POS	O
+,	POS	O
+after	POS	O
+various	POS	O
+durations	POS	O
+of	POS	O
+bladder	POS	B-NP
+inflammation	POS	I-NP
+induced	POS	O
+by	POS	O
+cyclophosphamide	POS	O
+(	POS	O
+CYP	POS	O
+)	POS	O
+.	POS	O
+CYP	POS	O
+-	POS	O
+induced	POS	O
+cystitis	POS	B-NP
+increased	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+p75	POS	O
+(	POS	O
+NTR	POS	O
+)	POS	O
+expression	POS	O
+in	POS	O
+the	POS	O
+superficial	POS	O
+lateral	POS	O
+and	POS	O
+medial	POS	O
+dorsal	POS	O
+horn	POS	O
+in	POS	O
+L1	POS	O
+-	POS	O
+L2	POS	O
+and	POS	O
+L6	POS	O
+-	POS	O
+S1	POS	O
+spinal	POS	O
+segments	POS	O
+.	POS	O
+The	POS	O
+number	POS	O
+of	POS	O
+p75	POS	O
+(	POS	O
+NTR	POS	O
+)	POS	O
+-	POS	O
+immunoreactive	POS	O
+(	POS	O
+-	POS	O
+IR	POS	O
+)	POS	O
+cells	POS	O
+in	POS	O
+the	POS	O
+lumbosacral	POS	O
+dorsal	POS	O
+root	POS	O
+ganglia	POS	O
+(	POS	O
+DRG	POS	O
+)	POS	O
+also	POS	O
+increased	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+with	POS	O
+CYP	POS	O
+-	POS	O
+induced	POS	O
+cystitis	POS	B-NP
+(	POS	O
+acute	POS	O
+,	POS	O
+intermediate	POS	O
+,	POS	O
+and	POS	O
+chronic	POS	O
+)	POS	O
+.	POS	O
+Quantitative	POS	O
+,	POS	O
+real	POS	O
+-	POS	O
+time	POS	O
+polymerase	POS	O
+chain	POS	O
+reaction	POS	O
+also	POS	O
+demonstrated	POS	O
+significant	POS	O
+increases	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+in	POS	O
+p75	POS	O
+(	POS	O
+NTR	POS	O
+)	POS	O
+mRNA	POS	O
+in	POS	O
+DRG	POS	O
+with	POS	O
+intermediate	POS	O
+and	POS	O
+chronic	POS	O
+CYP	POS	O
+-	POS	O
+induced	POS	O
+cystitis	POS	B-NP
+.	POS	O
+Retrograde	POS	O
+dye	POS	O
+-	POS	O
+tracing	POS	O
+techniques	POS	O
+with	POS	O
+Fastblue	POS	O
+were	POS	O
+used	POS	O
+to	POS	O
+identify	POS	O
+presumptive	POS	O
+bladder	POS	O
+afferent	POS	O
+cells	POS	O
+in	POS	O
+the	POS	O
+lumbosacral	POS	O
+DRG	POS	O
+.	POS	O
+In	POS	O
+bladder	POS	O
+afferent	POS	O
+cells	POS	O
+in	POS	O
+DRG	POS	O
+,	POS	O
+p75	POS	O
+(	POS	O
+NTR	POS	O
+)	POS	O
+-	POS	O
+IR	POS	O
+was	POS	O
+also	POS	O
+increased	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+with	POS	O
+cystitis	POS	B-NP
+.	POS	O
+In	POS	O
+addition	POS	O
+to	POS	O
+increases	POS	O
+in	POS	O
+p75	POS	O
+(	POS	O
+NTR	POS	O
+)	POS	O
+-	POS	O
+IR	POS	O
+in	POS	O
+DRG	POS	O
+cell	POS	O
+bodies	POS	O
+,	POS	O
+increases	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+in	POS	O
+pericellular	POS	O
+(	POS	O
+encircling	POS	O
+DRG	POS	O
+cells	POS	O
+)	POS	O
+p75	POS	O
+(	POS	O
+NTR	POS	O
+)	POS	O
+-	POS	O
+IR	POS	O
+in	POS	O
+DRG	POS	O
+also	POS	O
+increased	POS	O
+.	POS	O
+Confocal	POS	O
+analyses	POS	O
+demonstrated	POS	O
+that	POS	O
+pericellular	POS	O
+p75	POS	O
+(	POS	O
+NTR	POS	O
+)	POS	O
+-	POS	O
+IR	POS	O
+was	POS	O
+not	POS	O
+colocalized	POS	O
+with	POS	O
+the	POS	O
+glial	POS	O
+marker	POS	O
+,	POS	O
+glial	POS	O
+fibrillary	POS	O
+acidic	POS	O
+protein	POS	O
+(	POS	O
+GFAP	POS	O
+)	POS	O
+.	POS	O
+These	POS	O
+studies	POS	O
+demonstrate	POS	O
+that	POS	O
+p75	POS	O
+(	POS	O
+NTR	POS	O
+)	POS	O
+expression	POS	O
+in	POS	O
+micturition	POS	O
+reflexes	POS	O
+is	POS	O
+present	POS	O
+constitutively	POS	O
+and	POS	O
+modified	POS	O
+by	POS	O
+bladder	POS	B-NP
+inflammation	POS	I-NP
+.	POS	O
+The	POS	O
+functional	POS	O
+significance	POS	O
+of	POS	O
+p75	POS	O
+(	POS	O
+NTR	POS	O
+)	POS	O
+expression	POS	O
+in	POS	O
+micturition	POS	B-NP
+reflexes	POS	I-NP
+remains	POS	O
+to	POS	O
+be	POS	O
+determined	POS	O
+.	POS	O
+Azathioprine	POS	O
+-	POS	O
+induced	POS	O
+suicidal	POS	B-NP
+erythrocyte	POS	I-NP
+death	POS	I-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Azathioprine	POS	O
+is	POS	O
+widely	POS	O
+used	POS	O
+as	POS	O
+an	POS	O
+immunosuppressive	POS	O
+drug	POS	O
+.	POS	O
+The	POS	O
+side	POS	O
+effects	POS	O
+of	POS	O
+azathioprine	POS	O
+include	POS	O
+anemia	POS	B-NP
+,	POS	O
+which	POS	O
+has	POS	O
+been	POS	O
+attributed	POS	O
+to	POS	O
+bone	POS	O
+marrow	POS	O
+suppression	POS	O
+.	POS	O
+Alternatively	POS	O
+,	POS	O
+anemia	POS	B-NP
+could	POS	O
+result	POS	O
+from	POS	O
+accelerated	POS	O
+suicidal	POS	O
+erythrocyte	POS	O
+death	POS	O
+or	POS	O
+eryptosis	POS	O
+,	POS	O
+which	POS	O
+is	POS	O
+characterized	POS	O
+by	POS	O
+exposure	POS	O
+of	POS	O
+phosphatidylserine	POS	O
+(	POS	O
+PS	POS	O
+)	POS	O
+at	POS	O
+the	POS	O
+erythrocyte	POS	O
+surface	POS	O
+and	POS	O
+by	POS	O
+cell	POS	O
+shrinkage	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+The	POS	O
+present	POS	O
+experiments	POS	O
+explored	POS	O
+whether	POS	O
+azathioprine	POS	O
+influences	POS	O
+eryptosis	POS	O
+.	POS	O
+According	POS	O
+to	POS	O
+annexin	POS	O
+V	POS	O
+binding	POS	O
+,	POS	O
+erythrocytes	POS	O
+from	POS	O
+patients	POS	O
+indeed	POS	O
+showed	POS	O
+a	POS	O
+significant	POS	O
+increase	POS	O
+of	POS	O
+PS	POS	O
+exposure	POS	O
+within	POS	O
+1	POS	O
+week	POS	O
+of	POS	O
+treatment	POS	O
+with	POS	O
+azathioprine	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+second	POS	O
+series	POS	O
+,	POS	O
+cytosolic	POS	O
+Ca2	POS	O
++	POS	O
+activity	POS	O
+(	POS	O
+Fluo3	POS	O
+fluorescence	POS	O
+)	POS	O
+,	POS	O
+cell	POS	O
+volume	POS	O
+(	POS	O
+forward	POS	O
+scatter	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+PS	POS	O
+-	POS	O
+exposure	POS	O
+(	POS	O
+annexin	POS	O
+V	POS	O
+binding	POS	O
+)	POS	O
+were	POS	O
+determined	POS	O
+by	POS	O
+FACS	POS	O
+analysis	POS	O
+in	POS	O
+erythrocytes	POS	O
+from	POS	O
+healthy	POS	O
+volunteers	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Exposure	POS	O
+to	POS	O
+azathioprine	POS	O
+(	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+2	POS	O
+microg	POS	O
+/	POS	O
+mL	POS	O
+)	POS	O
+for	POS	O
+48	POS	O
+hours	POS	O
+increased	POS	O
+cytosolic	POS	O
+Ca2	POS	O
++	POS	O
+activity	POS	O
+and	POS	O
+annexin	POS	O
+V	POS	O
+binding	POS	O
+and	POS	O
+decreased	POS	O
+forward	POS	O
+scatter	POS	O
+.	POS	O
+The	POS	O
+effect	POS	O
+of	POS	O
+azathioprine	POS	O
+on	POS	O
+both	POS	O
+annexin	POS	O
+V	POS	O
+binding	POS	O
+and	POS	O
+forward	POS	O
+scatter	POS	O
+was	POS	O
+significantly	POS	O
+blunted	POS	O
+in	POS	O
+the	POS	O
+nominal	POS	O
+absence	POS	O
+of	POS	O
+extracellular	POS	O
+Ca2	POS	O
++	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Azathioprine	POS	O
+triggers	POS	O
+suicidal	POS	O
+erythrocyte	POS	O
+death	POS	O
+,	POS	O
+an	POS	O
+effect	POS	O
+presumably	POS	O
+contributing	POS	O
+to	POS	O
+azathioprine	POS	O
+-	POS	O
+induced	POS	O
+anemia	POS	B-NP
+.	POS	O
+Levetiracetam	POS	O
+as	POS	O
+an	POS	O
+adjunct	POS	O
+to	POS	O
+phenobarbital	POS	O
+treatment	POS	O
+in	POS	O
+cats	POS	O
+with	POS	O
+suspected	POS	O
+idiopathic	POS	B-NP
+epilepsy	POS	I-NP
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+assess	POS	O
+pharmacokinetics	POS	O
+,	POS	O
+efficacy	POS	O
+,	POS	O
+and	POS	O
+tolerability	POS	O
+of	POS	O
+oral	POS	O
+levetiracetam	POS	O
+administered	POS	O
+as	POS	O
+an	POS	O
+adjunct	POS	O
+to	POS	O
+phenobarbital	POS	O
+treatment	POS	O
+in	POS	O
+cats	POS	O
+with	POS	O
+poorly	POS	O
+controlled	POS	O
+suspected	POS	O
+idiopathic	POS	B-NP
+epilepsy	POS	I-NP
+.	POS	O
+DESIGN	POS	O
+-	POS	O
+Open	POS	O
+-	POS	O
+label	POS	O
+,	POS	O
+noncomparative	POS	O
+clinical	POS	O
+trial	POS	O
+.	POS	O
+ANIMALS	POS	O
+:	POS	O
+12	POS	O
+cats	POS	O
+suspected	POS	O
+to	POS	O
+have	POS	O
+idiopathic	POS	B-NP
+epilepsy	POS	I-NP
+that	POS	O
+was	POS	O
+poorly	POS	O
+controlled	POS	O
+with	POS	O
+phenobarbital	POS	O
+or	POS	O
+that	POS	O
+had	POS	O
+unacceptable	POS	O
+adverse	POS	O
+effects	POS	O
+when	POS	O
+treated	POS	O
+with	POS	O
+phenobarbital	POS	O
+.	POS	O
+PROCEDURES	POS	O
+:	POS	O
+Cats	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+levetiracetam	POS	O
+(	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+[	POS	O
+9	POS	O
+.	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+lb	POS	O
+]	POS	O
+,	POS	O
+PO	POS	O
+,	POS	O
+q	POS	O
+8	POS	O
+h	POS	O
+)	POS	O
+.	POS	O
+After	POS	O
+a	POS	O
+minimum	POS	O
+of	POS	O
+1	POS	O
+week	POS	O
+of	POS	O
+treatment	POS	O
+,	POS	O
+serum	POS	O
+levetiracetam	POS	O
+concentrations	POS	O
+were	POS	O
+measured	POS	O
+before	POS	O
+and	POS	O
+2	POS	O
+,	POS	O
+4	POS	O
+,	POS	O
+and	POS	O
+6	POS	O
+hours	POS	O
+after	POS	O
+drug	POS	O
+administration	POS	O
+,	POS	O
+and	POS	O
+maximum	POS	O
+and	POS	O
+minimum	POS	O
+serum	POS	O
+concentrations	POS	O
+and	POS	O
+elimination	POS	O
+half	POS	O
+-	POS	O
+life	POS	O
+were	POS	O
+calculated	POS	O
+.	POS	O
+Seizure	POS	B-NP
+frequencies	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+initiation	POS	O
+of	POS	O
+levetiracetam	POS	O
+treatment	POS	O
+were	POS	O
+compared	POS	O
+,	POS	O
+and	POS	O
+adverse	POS	O
+effects	POS	O
+were	POS	O
+recorded	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Median	POS	O
+maximum	POS	O
+serum	POS	O
+levetiracetam	POS	O
+concentration	POS	O
+was	POS	O
+25	POS	O
+.	POS	O
+5	POS	O
+microg	POS	O
+/	POS	O
+mL	POS	O
+,	POS	O
+median	POS	O
+minimum	POS	O
+serum	POS	O
+levetiracetam	POS	O
+concentration	POS	O
+was	POS	O
+8	POS	O
+.	POS	O
+3	POS	O
+microg	POS	O
+/	POS	O
+mL	POS	O
+,	POS	O
+and	POS	O
+median	POS	O
+elimination	POS	O
+half	POS	O
+-	POS	O
+life	POS	O
+was	POS	O
+2	POS	O
+.	POS	O
+9	POS	O
+hours	POS	O
+.	POS	O
+Median	POS	O
+seizure	POS	B-NP
+frequency	POS	O
+prior	POS	O
+to	POS	O
+treatment	POS	O
+with	POS	O
+levetiracetam	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+1	POS	O
+seizures	POS	B-NP
+/	POS	O
+mo	POS	O
+)	POS	O
+was	POS	O
+significantly	POS	O
+higher	POS	O
+than	POS	O
+median	POS	O
+seizure	POS	B-NP
+frequency	POS	O
+after	POS	O
+initiation	POS	O
+of	POS	O
+levetiracetam	POS	O
+treatment	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+42	POS	O
+seizures	POS	B-NP
+/	POS	O
+mo	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+7	POS	O
+of	POS	O
+10	POS	O
+cats	POS	O
+were	POS	O
+classified	POS	O
+as	POS	O
+having	POS	O
+responded	POS	O
+to	POS	O
+levetiracetam	POS	O
+treatment	POS	O
+(	POS	O
+ie	POS	O
+,	POS	O
+reduction	POS	O
+in	POS	O
+seizure	POS	B-NP
+frequency	POS	O
+of	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+50	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Two	POS	O
+cats	POS	O
+had	POS	O
+transient	POS	O
+lethargy	POS	B-NP
+and	POS	O
+inappetence	POS	B-NP
+.	POS	O
+CONCLUSIONS	POS	O
+AND	POS	O
+CLINICAL	POS	O
+RELEVANCE	POS	O
+:	POS	O
+Results	POS	O
+suggested	POS	O
+that	POS	O
+levetiracetam	POS	O
+is	POS	O
+well	POS	O
+tolerated	POS	O
+in	POS	O
+cats	POS	O
+and	POS	O
+may	POS	O
+be	POS	O
+useful	POS	O
+as	POS	O
+an	POS	O
+adjunct	POS	O
+to	POS	O
+phenobarbital	POS	O
+treatment	POS	O
+in	POS	O
+cats	POS	O
+with	POS	O
+idiopathic	POS	B-NP
+epilepsy	POS	I-NP
+.	POS	O
+Serotonin	POS	O
+reuptake	POS	O
+inhibitors	POS	O
+,	POS	O
+paranoia	POS	B-NP
+,	POS	O
+and	POS	O
+the	POS	O
+ventral	POS	O
+basal	POS	O
+ganglia	POS	O
+.	POS	O
+Antidepressants	POS	O
+have	POS	O
+previously	POS	O
+been	POS	O
+associated	POS	O
+with	POS	O
+paranoid	POS	O
+reactions	POS	O
+in	POS	O
+psychiatric	POS	B-NP
+patients	POS	O
+.	POS	O
+Five	POS	O
+cases	POS	O
+of	POS	O
+paranoid	POS	B-NP
+exacerbation	POS	I-NP
+with	POS	O
+the	POS	O
+serotonin	POS	O
+reuptake	POS	O
+inhibitors	POS	O
+fluoxetine	POS	O
+and	POS	O
+amitriptyline	POS	O
+are	POS	O
+reported	POS	O
+here	POS	O
+.	POS	O
+Elements	POS	O
+common	POS	O
+to	POS	O
+these	POS	O
+cases	POS	O
+included	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+paranoid	POS	O
+symptomatology	POS	O
+and	POS	O
+the	POS	O
+concomitant	POS	O
+occurrence	POS	O
+of	POS	O
+depressive	POS	B-NP
+and	POS	O
+psychotic	POS	B-NP
+symptoms	POS	I-NP
+.	POS	O
+Complicated	POS	B-NP
+depressive	POS	I-NP
+disorders	POS	I-NP
+(	POS	O
+including	POS	O
+atypicality	POS	O
+of	POS	O
+course	POS	O
+and	POS	O
+symptomatology	POS	O
+,	POS	O
+chronicity	POS	B-NP
+,	POS	O
+psychosis	POS	B-NP
+,	POS	O
+bipolarity	POS	B-NP
+,	POS	O
+and	POS	O
+secondary	POS	O
+onset	POS	O
+in	POS	O
+the	POS	O
+course	POS	O
+of	POS	O
+a	POS	O
+primary	POS	O
+psychosis	POS	B-NP
+)	POS	O
+may	POS	O
+present	POS	O
+particular	POS	O
+vulnerability	POS	O
+to	POS	O
+paranoid	POS	B-NP
+exacerbations	POS	I-NP
+associated	POS	O
+with	POS	O
+serotonin	POS	O
+reuptake	POS	O
+inhibitors	POS	O
+.	POS	O
+Although	POS	O
+the	POS	O
+pharmacology	POS	O
+and	POS	O
+neurobiology	POS	O
+of	POS	O
+paranoia	POS	B-NP
+remain	POS	O
+cryptic	POS	O
+,	POS	O
+several	POS	O
+mechanisms	POS	O
+,	POS	O
+including	POS	O
+5HT3	POS	O
+receptor	POS	O
+-	POS	O
+mediated	POS	O
+dopamine	POS	O
+release	POS	O
+,	POS	O
+beta	POS	O
+-	POS	O
+noradrenergic	POS	O
+receptor	POS	O
+downregulation	POS	O
+,	POS	O
+or	POS	O
+GABAB	POS	O
+receptor	POS	O
+upregulation	POS	O
+acting	POS	O
+in	POS	O
+the	POS	O
+vicinity	POS	O
+of	POS	O
+the	POS	O
+ventral	POS	O
+basal	POS	O
+ganglia	POS	O
+(	POS	O
+possibly	POS	O
+in	POS	O
+lateral	POS	O
+orbitofrontal	POS	O
+or	POS	O
+anterior	POS	O
+cingulate	POS	O
+circuits	POS	O
+)	POS	O
+,	POS	O
+might	POS	O
+apply	POS	O
+to	POS	O
+this	POS	O
+phenomenon	POS	O
+.	POS	O
+These	POS	O
+cases	POS	O
+call	POS	O
+attention	POS	O
+to	POS	O
+possible	POS	O
+paranoid	POS	B-NP
+exacerbations	POS	I-NP
+with	POS	O
+serotonin	POS	O
+reuptake	POS	O
+blockers	POS	O
+in	POS	O
+select	POS	O
+patients	POS	O
+and	POS	O
+raise	POS	O
+neurobiological	POS	O
+considerations	POS	O
+regarding	POS	O
+paranoia	POS	B-NP
+.	POS	O
+Clinical	POS	O
+comparison	POS	O
+of	POS	O
+cardiorespiratory	POS	B-NP
+effects	POS	I-NP
+during	POS	O
+unilateral	POS	O
+and	POS	O
+conventional	POS	O
+spinal	POS	O
+anaesthesia	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Spinal	POS	O
+anaesthesia	POS	O
+is	POS	O
+widely	POS	O
+employed	POS	O
+in	POS	O
+clinical	POS	O
+practice	POS	O
+but	POS	O
+has	POS	O
+the	POS	O
+main	POS	O
+drawback	POS	O
+of	POS	O
+post	POS	O
+-	POS	O
+spinal	POS	O
+block	POS	O
+hypotension	POS	B-NP
+.	POS	O
+Efforts	POS	O
+must	POS	O
+therefore	POS	O
+continue	POS	O
+to	POS	O
+be	POS	O
+made	POS	O
+to	POS	O
+obviate	POS	O
+this	POS	O
+setback	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+evaluate	POS	O
+the	POS	O
+cardiovascular	POS	O
+and	POS	O
+respiratory	POS	O
+changes	POS	O
+during	POS	O
+unilateral	POS	O
+and	POS	O
+conventional	POS	O
+spinal	POS	O
+anaesthesia	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+With	POS	O
+ethical	POS	O
+approval	POS	O
+,	POS	O
+we	POS	O
+studied	POS	O
+74	POS	O
+American	POS	O
+Society	POS	O
+of	POS	O
+Anesthesiologists	POS	O
+(	POS	O
+ASA	POS	O
+)	POS	O
+,	POS	O
+physical	POS	O
+status	POS	O
+class	POS	O
+1	POS	O
+and	POS	O
+2	POS	O
+patients	POS	O
+scheduled	POS	O
+for	POS	O
+elective	POS	O
+unilateral	POS	O
+lower	POS	O
+limb	POS	O
+surgery	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+randomly	POS	O
+allocated	POS	O
+into	POS	O
+one	POS	O
+of	POS	O
+two	POS	O
+groups	POS	O
+:	POS	O
+lateral	POS	O
+and	POS	O
+conventional	POS	O
+spinal	POS	O
+anaesthesia	POS	O
+groups	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+lateral	POS	O
+position	POS	O
+with	POS	O
+operative	POS	O
+side	POS	O
+down	POS	O
+,	POS	O
+patients	POS	O
+recived	POS	O
+10	POS	O
+mg	POS	O
+(	POS	O
+2mls	POS	O
+)	POS	O
+of	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+hyperbaric	POS	O
+bupivacaine	POS	O
+through	POS	O
+a	POS	O
+25	POS	O
+-	POS	O
+gauge	POS	O
+spinal	POS	O
+needle	POS	O
+.	POS	O
+Patients	POS	O
+in	POS	O
+the	POS	O
+unilateral	POS	O
+group	POS	O
+were	POS	O
+maintained	POS	O
+in	POS	O
+the	POS	O
+lateral	POS	O
+position	POS	O
+for	POS	O
+15	POS	O
+minutes	POS	O
+following	POS	O
+spinal	POS	O
+injection	POS	O
+while	POS	O
+those	POS	O
+in	POS	O
+the	POS	O
+conventional	POS	O
+group	POS	O
+were	POS	O
+turned	POS	O
+supine	POS	O
+immediately	POS	O
+after	POS	O
+injection	POS	O
+.	POS	O
+Blood	POS	O
+pressure	POS	O
+,	POS	O
+heart	POS	O
+rate	POS	O
+,	POS	O
+respiratory	POS	O
+rate	POS	O
+and	POS	O
+oxygen	POS	O
+saturation	POS	O
+were	POS	O
+monitored	POS	O
+over	POS	O
+1	POS	O
+hour	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Three	POS	O
+patients	POS	O
+(	POS	O
+8	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+unilateral	POS	O
+group	POS	O
+and	POS	O
+5	POS	O
+(	POS	O
+13	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+conventional	POS	O
+group	POS	O
+developed	POS	O
+hypotension	POS	B-NP
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+71	POS	O
+.	POS	O
+Four	POS	O
+(	POS	O
+10	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+in	POS	O
+the	POS	O
+conventional	POS	O
+group	POS	O
+and	POS	O
+1	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+unilateral	POS	O
+group	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+17	POS	O
+required	POS	O
+epinephrine	POS	O
+infusion	POS	O
+to	POS	O
+treat	POS	O
+hypotension	POS	B-NP
+.	POS	O
+Patients	POS	O
+in	POS	O
+the	POS	O
+conventional	POS	O
+group	POS	O
+had	POS	O
+statistically	POS	O
+significant	POS	O
+greater	POS	O
+fall	POS	O
+in	POS	O
+the	POS	O
+systolic	POS	O
+blood	POS	O
+pressures	POS	O
+at	POS	O
+15	POS	O
+,	POS	O
+30	POS	O
+and	POS	O
+45	POS	O
+minutes	POS	O
+when	POS	O
+compared	POS	O
+to	POS	O
+the	POS	O
+baseline	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+003	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+004	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+respiratory	POS	O
+rate	POS	O
+and	POS	O
+oxygen	POS	O
+saturations	POS	O
+in	POS	O
+the	POS	O
+two	POS	O
+groups	POS	O
+were	POS	O
+similar	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Compared	POS	O
+to	POS	O
+conventional	POS	O
+spinal	POS	O
+anaesthesia	POS	O
+,	POS	O
+unilateral	POS	O
+spinal	POS	O
+anaesthesia	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+fewer	POS	O
+cardiovascular	POS	B-NP
+perturbations	POS	I-NP
+.	POS	O
+Also	POS	O
+,	POS	O
+the	POS	O
+type	POS	O
+of	POS	O
+spinal	POS	O
+block	POS	O
+instituted	POS	O
+affected	POS	O
+neither	POS	O
+the	POS	O
+respiratory	POS	O
+rate	POS	O
+nor	POS	O
+the	POS	O
+arterial	POS	O
+oxygen	POS	O
+saturation	POS	O
+.	POS	O
+Spectrum	POS	O
+of	POS	O
+adverse	POS	O
+events	POS	O
+after	POS	O
+generic	POS	O
+HAART	POS	O
+in	POS	O
+southern	POS	O
+Indian	POS	O
+HIV	POS	O
+-	POS	O
+infected	POS	O
+patients	POS	O
+.	POS	O
+To	POS	O
+determine	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+clinically	POS	O
+significant	POS	O
+adverse	POS	O
+events	POS	O
+after	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+,	POS	O
+fixed	POS	O
+-	POS	O
+dose	POS	O
+,	POS	O
+generic	POS	O
+highly	POS	O
+active	POS	O
+antiretroviral	POS	O
+therapy	POS	O
+(	POS	O
+HAART	POS	O
+)	POS	O
+use	POS	O
+among	POS	O
+HIV	POS	O
+-	POS	O
+infected	POS	O
+individuals	POS	O
+in	POS	O
+South	POS	O
+India	POS	O
+,	POS	O
+we	POS	O
+examined	POS	O
+the	POS	O
+experiences	POS	O
+of	POS	O
+3154	POS	O
+HIV	POS	O
+-	POS	O
+infected	POS	O
+individuals	POS	O
+who	POS	O
+received	POS	O
+a	POS	O
+minimum	POS	O
+of	POS	O
+3	POS	O
+months	POS	O
+of	POS	O
+generic	POS	O
+HAART	POS	O
+between	POS	O
+February	POS	O
+1996	POS	O
+and	POS	O
+December	POS	O
+2006	POS	O
+at	POS	O
+a	POS	O
+tertiary	POS	O
+HIV	POS	O
+care	POS	O
+referral	POS	O
+center	POS	O
+in	POS	O
+South	POS	O
+India	POS	O
+.	POS	O
+The	POS	O
+most	POS	O
+common	POS	O
+regimens	POS	O
+were	POS	O
+3TC	POS	O
++	POS	O
+d4T	POS	O
++	POS	O
+nevirapine	POS	O
+(	POS	O
+NVP	POS	O
+)	POS	O
+(	POS	O
+54	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+zidovudine	POS	O
+(	POS	O
+AZT	POS	O
+)	POS	O
++	POS	O
+3TC	POS	O
++	POS	O
+NVP	POS	O
+(	POS	O
+14	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+3TC	POS	O
++	POS	O
+d4T	POS	O
++	POS	O
+efavirenz	POS	O
+(	POS	O
+EFV	POS	O
+)	POS	O
+(	POS	O
+20	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+AZT	POS	O
++	POS	O
+3TC	POS	O
++	POS	O
+EFV	POS	O
+(	POS	O
+5	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+most	POS	O
+common	POS	O
+adverse	POS	O
+events	POS	O
+and	POS	O
+median	POS	O
+CD4	POS	O
+at	POS	O
+time	POS	O
+of	POS	O
+event	POS	O
+were	POS	O
+rash	POS	B-NP
+(	POS	O
+15	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+;	POS	O
+CD4	POS	O
+,	POS	O
+285	POS	O
+cells	POS	O
+/	POS	O
+microL	POS	O
+)	POS	O
+and	POS	O
+peripheral	POS	B-NP
+neuropathy	POS	I-NP
+(	POS	O
+9	POS	O
+.	POS	O
+0	POS	O
+%	POS	O
+and	POS	O
+348	POS	O
+cells	POS	O
+/	POS	O
+microL	POS	O
+)	POS	O
+.	POS	O
+Clinically	POS	O
+significant	POS	O
+anemia	POS	B-NP
+(	POS	O
+hemoglobin	POS	O
+<	POS	O
+7	POS	O
+g	POS	O
+/	POS	O
+dL	POS	O
+)	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+5	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+(	POS	O
+CD4	POS	O
+,	POS	O
+165	POS	O
+cells	POS	O
+/	POS	O
+microL	POS	O
+)	POS	O
+and	POS	O
+hepatitis	POS	B-NP
+(	POS	O
+clinical	POS	O
+jaundice	POS	B-NP
+with	POS	O
+alanine	POS	O
+aminotransferase	POS	O
+>	POS	O
+5	POS	O
+times	POS	O
+upper	POS	O
+limits	POS	O
+of	POS	O
+normal	POS	O
+)	POS	O
+in	POS	O
+3	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+(	POS	O
+CD4	POS	O
+,	POS	O
+260	POS	O
+cells	POS	O
+/	POS	O
+microL	POS	O
+)	POS	O
+.	POS	O
+Women	POS	O
+were	POS	O
+significantly	POS	O
+more	POS	O
+likely	POS	O
+to	POS	O
+experience	POS	O
+lactic	POS	B-NP
+acidosis	POS	I-NP
+,	POS	O
+while	POS	O
+men	POS	O
+were	POS	O
+significantly	POS	O
+more	POS	O
+likely	POS	O
+to	POS	O
+experience	POS	O
+immune	POS	B-NP
+reconstitution	POS	I-NP
+syndrome	POS	I-NP
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+Among	POS	O
+the	POS	O
+patients	POS	O
+with	POS	O
+1	POS	O
+year	POS	O
+of	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+,	POS	O
+NVP	POS	O
+therapy	POS	O
+was	POS	O
+significantly	POS	O
+associated	POS	O
+with	POS	O
+developing	POS	O
+rash	POS	B-NP
+and	POS	O
+d4T	POS	O
+therapy	POS	O
+with	POS	O
+developing	POS	O
+peripheral	POS	B-NP
+neuropathy	POS	I-NP
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+Anemia	POS	B-NP
+and	POS	O
+hepatitis	POS	B-NP
+often	POS	O
+occur	POS	O
+within	POS	O
+12	POS	O
+weeks	POS	O
+of	POS	O
+initiating	POS	O
+generic	POS	O
+HAART	POS	O
+.	POS	O
+Frequent	POS	O
+and	POS	O
+early	POS	O
+monitoring	POS	O
+for	POS	O
+these	POS	O
+toxicities	POS	B-NP
+is	POS	O
+warranted	POS	O
+in	POS	O
+developing	POS	O
+countries	POS	O
+where	POS	O
+generic	POS	O
+HAART	POS	O
+is	POS	O
+increasingly	POS	O
+available	POS	O
+.	POS	O
+Thalidomide	POS	O
+and	POS	O
+sensory	POS	B-NP
+neurotoxicity	POS	I-NP
+:	POS	O
+a	POS	O
+neurophysiological	POS	O
+study	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Recent	POS	O
+studies	POS	O
+confirmed	POS	O
+a	POS	O
+high	POS	O
+incidence	POS	O
+of	POS	O
+sensory	POS	B-NP
+axonal	POS	I-NP
+neuropathy	POS	I-NP
+in	POS	O
+patients	POS	O
+treated	POS	O
+with	POS	O
+different	POS	O
+doses	POS	O
+of	POS	O
+thalidomide	POS	O
+.	POS	O
+The	POS	O
+study	POS	O
+'	POS	O
+s	POS	O
+aims	POS	O
+were	POS	O
+to	POS	O
+measure	POS	O
+variations	POS	O
+in	POS	O
+sural	POS	O
+nerve	POS	O
+sensory	POS	O
+action	POS	O
+potential	POS	O
+(	POS	O
+SAP	POS	O
+)	POS	O
+amplitude	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+refractory	POS	O
+cutaneous	POS	B-NP
+lupus	POS	I-NP
+erythematosus	POS	I-NP
+(	POS	O
+CLE	POS	B-NP
+)	POS	O
+treated	POS	O
+with	POS	O
+thalidomide	POS	O
+and	POS	O
+use	POS	O
+these	POS	O
+findings	POS	O
+to	POS	O
+identify	POS	O
+the	POS	O
+neurotoxic	POS	B-NP
+potential	POS	O
+of	POS	O
+thalidomide	POS	O
+and	POS	O
+the	POS	O
+recovery	POS	O
+capacity	POS	O
+of	POS	O
+sensory	POS	O
+fibres	POS	O
+after	POS	O
+discontinuation	POS	O
+of	POS	O
+treatment	POS	O
+.	POS	O
+PATIENTS	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+Clinical	POS	O
+and	POS	O
+electrophysiological	POS	O
+data	POS	O
+in	POS	O
+12	POS	O
+female	POS	O
+patients	POS	O
+with	POS	O
+CLE	POS	B-NP
+during	POS	O
+treatment	POS	O
+with	POS	O
+thalidomide	POS	O
+and	POS	O
+up	POS	O
+to	POS	O
+47	POS	O
+months	POS	O
+after	POS	O
+discontinuation	POS	O
+of	POS	O
+treatment	POS	O
+were	POS	O
+analysed	POS	O
+.	POS	O
+Sural	POS	O
+nerve	POS	O
+SAP	POS	O
+amplitude	POS	O
+reduction	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+40	POS	O
+%	POS	O
+was	POS	O
+the	POS	O
+criteria	POS	O
+for	POS	O
+discontinuing	POS	O
+therapy	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+During	POS	O
+treatment	POS	O
+,	POS	O
+11	POS	O
+patients	POS	O
+showed	POS	O
+a	POS	O
+reduction	POS	O
+in	POS	O
+sural	POS	O
+nerve	POS	O
+SAP	POS	O
+amplitude	POS	O
+compared	POS	O
+to	POS	O
+baseline	POS	O
+values	POS	O
+(	POS	O
+9	POS	O
+with	POS	O
+a	POS	O
+reduction	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+50	POS	O
+%	POS	O
+and	POS	O
+2	POS	O
+<	POS	O
+50	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+One	POS	O
+patient	POS	O
+showed	POS	O
+no	POS	O
+changes	POS	O
+in	POS	O
+SAP	POS	O
+amplitude	POS	O
+.	POS	O
+Five	POS	O
+patients	POS	O
+complained	POS	O
+of	POS	O
+paresthesias	POS	B-NP
+and	POS	O
+leg	POS	B-NP
+cramps	POS	I-NP
+.	POS	O
+After	POS	O
+thalidomide	POS	O
+treatment	POS	O
+,	POS	O
+sural	POS	O
+SAP	POS	O
+amplitude	POS	O
+recovered	POS	O
+in	POS	O
+3	POS	O
+patients	POS	O
+.	POS	O
+At	POS	O
+detection	POS	O
+of	POS	O
+reduction	POS	O
+in	POS	O
+sural	POS	O
+nerve	POS	O
+SAP	POS	O
+amplitude	POS	O
+,	POS	O
+the	POS	O
+median	POS	O
+thalidomide	POS	O
+cumulative	POS	O
+dose	POS	O
+was	POS	O
+21	POS	O
+.	POS	O
+4	POS	O
+g	POS	O
+.	POS	O
+The	POS	O
+threshold	POS	O
+neurotoxic	POS	B-NP
+dosage	POS	O
+is	POS	O
+lower	POS	O
+than	POS	O
+previously	POS	O
+reported	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Sural	POS	O
+nerve	POS	O
+SAP	POS	O
+amplitude	POS	O
+reduction	POS	O
+is	POS	O
+a	POS	O
+reliable	POS	O
+and	POS	O
+sensitive	POS	O
+marker	POS	O
+of	POS	O
+degeneration	POS	O
+and	POS	O
+recovery	POS	O
+of	POS	O
+sensory	POS	O
+fibres	POS	O
+.	POS	O
+This	POS	O
+electrophysiological	POS	O
+parameter	POS	O
+provides	POS	O
+information	POS	O
+about	POS	O
+subclinical	POS	O
+neurotoxic	POS	B-NP
+potential	POS	O
+of	POS	O
+thalidomide	POS	O
+but	POS	O
+is	POS	O
+not	POS	O
+helpful	POS	O
+in	POS	O
+predicting	POS	O
+the	POS	O
+appearance	POS	O
+of	POS	O
+sensory	POS	B-NP
+symptoms	POS	I-NP
+.	POS	O
+Five	POS	O
+cases	POS	O
+of	POS	O
+encephalitis	POS	B-NP
+during	POS	O
+treatment	POS	O
+of	POS	O
+loiasis	POS	B-NP
+with	POS	O
+diethylcarbamazine	POS	O
+.	POS	O
+Five	POS	O
+cases	POS	O
+of	POS	O
+encephalitis	POS	B-NP
+following	POS	O
+treatment	POS	O
+with	POS	O
+diethylcarbamazine	POS	O
+(	POS	O
+DEC	POS	O
+)	POS	O
+were	POS	O
+observed	POS	O
+in	POS	O
+Congolese	POS	O
+patients	POS	O
+with	POS	O
+Loa	POS	B-NP
+loa	POS	I-NP
+filariasis	POS	I-NP
+.	POS	O
+Two	POS	O
+cases	POS	O
+had	POS	O
+a	POS	O
+fatal	POS	O
+outcome	POS	O
+and	POS	O
+one	POS	O
+resulted	POS	O
+in	POS	O
+severe	POS	O
+sequelae	POS	O
+.	POS	O
+The	POS	O
+notable	POS	O
+fact	POS	O
+was	POS	O
+that	POS	O
+this	POS	O
+complication	POS	O
+occurred	POS	O
+in	POS	O
+three	POS	O
+patients	POS	O
+hospitalized	POS	O
+before	POS	O
+treatment	POS	O
+began	POS	O
+,	POS	O
+with	POS	O
+whom	POS	O
+particularly	POS	O
+strict	POS	O
+therapeutic	POS	O
+precautions	POS	O
+were	POS	O
+taken	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+e	POS	O
+.	POS	O
+,	POS	O
+initial	POS	O
+dose	POS	O
+less	POS	O
+than	POS	O
+10	POS	O
+mg	POS	O
+of	POS	O
+DEC	POS	O
+,	POS	O
+very	POS	O
+gradual	POS	O
+dose	POS	O
+increases	POS	O
+,	POS	O
+and	POS	O
+associated	POS	O
+anti	POS	O
+-	POS	O
+allergic	POS	O
+treatment	POS	O
+.	POS	O
+This	POS	O
+type	POS	O
+of	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+complication	POS	O
+may	POS	O
+not	POS	O
+be	POS	O
+that	POS	O
+uncommon	POS	O
+in	POS	O
+highly	POS	O
+endemic	POS	O
+regions	POS	O
+.	POS	O
+It	POS	O
+occurs	POS	O
+primarily	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+exclusively	POS	O
+,	POS	O
+in	POS	O
+subjects	POS	O
+presenting	POS	O
+with	POS	O
+a	POS	O
+high	POS	O
+microfilarial	POS	O
+load	POS	O
+.	POS	O
+The	POS	O
+relationship	POS	O
+between	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+encephalitis	POS	B-NP
+and	POS	O
+the	POS	O
+decrease	POS	O
+in	POS	O
+microfilaremia	POS	B-NP
+is	POS	O
+evident	POS	O
+.	POS	O
+The	POS	O
+pathophysiological	POS	O
+mechanisms	POS	O
+are	POS	O
+discussed	POS	O
+in	POS	O
+the	POS	O
+light	POS	O
+of	POS	O
+these	POS	O
+observations	POS	O
+and	POS	O
+the	POS	O
+few	POS	O
+other	POS	O
+comments	POS	O
+on	POS	O
+this	POS	O
+subject	POS	O
+published	POS	O
+in	POS	O
+the	POS	O
+literature	POS	O
+.	POS	O
+Amiodarone	POS	O
+-	POS	O
+related	POS	O
+pulmonary	POS	O
+mass	POS	O
+and	POS	O
+unique	POS	O
+membranous	POS	B-NP
+glomerulonephritis	POS	I-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+valvular	POS	B-NP
+heart	POS	I-NP
+disease	POS	I-NP
+:	POS	O
+Diagnostic	POS	O
+pitfall	POS	O
+and	POS	O
+new	POS	O
+findings	POS	O
+.	POS	O
+Amiodarone	POS	O
+is	POS	O
+an	POS	O
+anti	POS	O
+-	POS	O
+arrhythmic	POS	O
+drug	POS	O
+for	POS	O
+life	POS	O
+-	POS	O
+threatening	POS	O
+tachycardia	POS	B-NP
+,	POS	O
+but	POS	O
+various	POS	O
+adverse	POS	O
+effects	POS	O
+have	POS	O
+been	POS	O
+reported	POS	O
+.	POS	O
+Reported	POS	O
+herein	POS	O
+is	POS	O
+an	POS	O
+autopsy	POS	O
+case	POS	O
+of	POS	O
+valvular	POS	B-NP
+heart	POS	I-NP
+disease	POS	I-NP
+,	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+who	POS	O
+developed	POS	O
+a	POS	O
+lung	POS	O
+mass	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+cm	POS	O
+in	POS	O
+diameter	POS	O
+)	POS	O
+and	POS	O
+proteinuria	POS	B-NP
+(	POS	O
+2	POS	O
+.	POS	O
+76	POS	O
+g	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+after	POS	O
+treatment	POS	O
+with	POS	O
+amiodarone	POS	O
+for	POS	O
+a	POS	O
+long	POS	O
+time	POS	O
+.	POS	O
+The	POS	O
+lung	POS	O
+mass	POS	O
+was	POS	O
+highly	POS	O
+suspected	POS	O
+to	POS	O
+be	POS	O
+lung	POS	B-NP
+cancer	POS	I-NP
+on	POS	O
+CT	POS	O
+and	POS	O
+positron	POS	O
+emission	POS	O
+tomography	POS	O
+,	POS	O
+but	POS	O
+histologically	POS	O
+the	POS	O
+lesion	POS	O
+was	POS	O
+composed	POS	O
+of	POS	O
+lymphoplasmacytic	POS	O
+infiltrates	POS	O
+in	POS	O
+alveolar	POS	O
+walls	POS	O
+and	POS	O
+intra	POS	O
+-	POS	O
+alveolar	POS	O
+accumulation	POS	O
+of	POS	O
+foamy	POS	O
+macrophages	POS	O
+containing	POS	O
+characteristic	POS	O
+myelinoid	POS	O
+bodies	POS	O
+,	POS	O
+indicating	POS	O
+that	POS	O
+it	POS	O
+was	POS	O
+an	POS	O
+amiodarone	POS	O
+-	POS	O
+related	POS	O
+lesion	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+the	POS	O
+lung	POS	O
+tissue	POS	O
+had	POS	O
+unevenly	POS	O
+distributed	POS	O
+hemosiderin	POS	O
+deposition	POS	O
+,	POS	O
+and	POS	O
+abnormally	POS	O
+tortuous	POS	O
+capillaries	POS	O
+were	POS	O
+seen	POS	O
+in	POS	O
+the	POS	O
+mass	POS	O
+and	POS	O
+in	POS	O
+heavily	POS	O
+hemosiderotic	POS	O
+lung	POS	O
+portions	POS	O
+outside	POS	O
+the	POS	O
+mass	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+kidneys	POS	O
+,	POS	O
+glomeruli	POS	O
+had	POS	O
+membrane	POS	O
+spikes	POS	O
+,	POS	O
+prominent	POS	O
+swelling	POS	O
+of	POS	O
+podocytes	POS	O
+and	POS	O
+subepithelial	POS	O
+deposits	POS	O
+,	POS	O
+which	POS	O
+were	POS	O
+sometimes	POS	O
+large	POS	O
+and	POS	O
+hump	POS	O
+-	POS	O
+like	POS	O
+.	POS	O
+Autoimmune	POS	B-NP
+diseases	POS	I-NP
+,	POS	O
+viral	POS	B-NP
+hepatitis	POS	I-NP
+,	POS	O
+malignant	POS	B-NP
+neoplasms	POS	I-NP
+or	POS	O
+other	POS	O
+diseases	POS	O
+with	POS	O
+a	POS	O
+known	POS	O
+relationship	POS	O
+to	POS	O
+membranous	POS	O
+glomerulonephritis	POS	B-NP
+were	POS	O
+not	POS	O
+found	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+case	POS	O
+highlights	POS	O
+the	POS	O
+possibility	POS	O
+that	POS	O
+differential	POS	O
+diagnosis	POS	O
+between	POS	O
+an	POS	O
+amiodarone	POS	O
+-	POS	O
+related	POS	O
+pulmonary	POS	B-NP
+lesion	POS	I-NP
+and	POS	O
+a	POS	O
+neoplasm	POS	B-NP
+can	POS	O
+be	POS	O
+very	POS	O
+difficult	POS	O
+radiologically	POS	O
+,	POS	O
+and	POS	O
+suggests	POS	O
+that	POS	O
+membranous	POS	O
+glomerulonephritis	POS	B-NP
+might	POS	O
+be	POS	O
+another	POS	O
+possible	POS	O
+complication	POS	O
+of	POS	O
+amiodarone	POS	O
+treatment	POS	O
+.	POS	O
+Risk	POS	O
+of	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+associated	POS	O
+with	POS	O
+initial	POS	O
+sulphonylurea	POS	O
+treatment	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+type	POS	B-NP
+2	POS	I-NP
+diabetes	POS	I-NP
+:	POS	O
+a	POS	O
+matched	POS	O
+case	POS	O
+-	POS	O
+control	POS	O
+study	POS	O
+.	POS	O
+AIMS	POS	O
+:	POS	O
+This	POS	O
+study	POS	O
+sought	POS	O
+to	POS	O
+assess	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+developing	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+CAD	POS	B-NP
+)	POS	O
+associated	POS	O
+with	POS	O
+initial	POS	O
+treatment	POS	O
+of	POS	O
+type	POS	B-NP
+2	POS	I-NP
+diabetes	POS	I-NP
+with	POS	O
+different	POS	O
+sulphonylureas	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+In	POS	O
+type	POS	B-NP
+2	POS	I-NP
+diabetic	POS	I-NP
+patients	POS	O
+,	POS	O
+cases	POS	O
+who	POS	O
+developed	POS	O
+CAD	POS	B-NP
+were	POS	O
+compared	POS	O
+retrospectively	POS	O
+with	POS	O
+controls	POS	O
+that	POS	O
+did	POS	O
+not	POS	O
+.	POS	O
+The	POS	O
+20	POS	O
+-	POS	O
+year	POS	O
+risk	POS	O
+of	POS	O
+CAD	POS	B-NP
+at	POS	O
+diagnosis	POS	O
+of	POS	O
+diabetes	POS	B-NP
+,	POS	O
+using	POS	O
+the	POS	O
+UKPDS	POS	B-NP
+risk	POS	O
+engine	POS	O
+,	POS	O
+was	POS	O
+used	POS	O
+to	POS	O
+match	POS	O
+cases	POS	O
+with	POS	O
+controls	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+76	POS	O
+cases	POS	O
+of	POS	O
+CAD	POS	B-NP
+were	POS	O
+compared	POS	O
+with	POS	O
+152	POS	O
+controls	POS	O
+.	POS	O
+The	POS	O
+hazard	POS	O
+of	POS	O
+developing	POS	O
+CAD	POS	B-NP
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+)	POS	O
+associated	POS	O
+with	POS	O
+initial	POS	O
+treatment	POS	O
+increased	POS	O
+by	POS	O
+2	POS	O
+.	POS	O
+4	POS	O
+-	POS	O
+fold	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+3	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+004	POS	O
+)	POS	O
+with	POS	O
+glibenclamide	POS	O
+;	POS	O
+2	POS	O
+-	POS	O
+fold	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+6	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+099	POS	O
+)	POS	O
+with	POS	O
+glipizide	POS	O
+;	POS	O
+2	POS	O
+.	POS	O
+9	POS	O
+-	POS	O
+fold	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+6	POS	O
+-	POS	O
+5	POS	O
+.	POS	O
+1	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+000	POS	O
+)	POS	O
+with	POS	O
+either	POS	O
+,	POS	O
+and	POS	O
+was	POS	O
+unchanged	POS	O
+with	POS	O
+metformin	POS	O
+.	POS	O
+The	POS	O
+hazard	POS	O
+decreased	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+-	POS	O
+fold	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+7	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+385	POS	O
+)	POS	O
+with	POS	O
+glimepiride	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+4	POS	O
+-	POS	O
+fold	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+192	POS	O
+)	POS	O
+with	POS	O
+gliclazide	POS	O
+,	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+4	POS	O
+-	POS	O
+fold	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+1	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+09	POS	O
+)	POS	O
+with	POS	O
+either	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Initiating	POS	O
+treatment	POS	O
+of	POS	O
+type	POS	B-NP
+2	POS	I-NP
+diabetes	POS	I-NP
+with	POS	O
+glibenclamide	POS	O
+or	POS	O
+glipizide	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+increased	POS	O
+risk	POS	O
+of	POS	O
+CAD	POS	B-NP
+in	POS	O
+comparison	POS	O
+to	POS	O
+gliclazide	POS	O
+or	POS	O
+glimepiride	POS	O
+.	POS	O
+If	POS	O
+confirmed	POS	O
+,	POS	O
+this	POS	O
+may	POS	O
+be	POS	O
+important	POS	O
+because	POS	O
+most	POS	O
+Indian	POS	O
+patients	POS	O
+receive	POS	O
+the	POS	O
+cheaper	POS	O
+older	POS	O
+sulphonylureas	POS	O
+,	POS	O
+and	POS	O
+present	POS	O
+guidelines	POS	O
+do	POS	O
+not	POS	O
+distinguish	POS	O
+between	POS	O
+individual	POS	O
+agents	POS	O
+.	POS	O
+Reduced	POS	O
+progression	POS	O
+of	POS	O
+adriamycin	POS	O
+nephropathy	POS	B-NP
+in	POS	O
+spontaneously	POS	O
+hypertensive	POS	B-NP
+rats	POS	O
+treated	POS	O
+by	POS	O
+losartan	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+the	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+antihypertensive	POS	O
+effects	POS	O
+of	POS	O
+angiotensin	POS	O
+II	POS	O
+type	POS	O
+-	POS	O
+1	POS	O
+receptor	POS	O
+blocker	POS	O
+,	POS	O
+losartan	POS	O
+,	POS	O
+and	POS	O
+its	POS	O
+potential	POS	O
+in	POS	O
+slowing	POS	O
+down	POS	O
+renal	POS	O
+disease	POS	O
+progression	POS	O
+in	POS	O
+spontaneously	POS	O
+hypertensive	POS	B-NP
+rats	POS	O
+(	POS	O
+SHR	POS	O
+)	POS	O
+with	POS	O
+adriamycin	POS	O
+(	POS	O
+ADR	POS	O
+)	POS	O
+nephropathy	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Six	POS	O
+-	POS	O
+month	POS	O
+-	POS	O
+old	POS	O
+female	POS	O
+SHR	POS	O
+were	POS	O
+randomly	POS	O
+selected	POS	O
+in	POS	O
+six	POS	O
+groups	POS	O
+.	POS	O
+Two	POS	O
+control	POS	O
+groups	POS	O
+(	POS	O
+SH	POS	O
+(	POS	O
+6	POS	O
+)	POS	O
+,	POS	O
+SH	POS	O
+(	POS	O
+12	POS	O
+)	POS	O
+)	POS	O
+received	POS	O
+vehicle	POS	O
+.	POS	O
+Groups	POS	O
+ADR	POS	O
+(	POS	O
+6	POS	O
+)	POS	O
+,	POS	O
+ADR	POS	O
++	POS	O
+LOS	POS	O
+(	POS	O
+6	POS	O
+)	POS	O
+and	POS	O
+ADR	POS	O
+(	POS	O
+12	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+ADR	POS	O
++	POS	O
+LOS	POS	O
+(	POS	O
+12	POS	O
+)	POS	O
+received	POS	O
+ADR	POS	O
+(	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+b	POS	O
+.	POS	O
+w	POS	O
+.	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+)	POS	O
+twice	POS	O
+in	POS	O
+a	POS	O
+3	POS	O
+-	POS	O
+week	POS	O
+interval	POS	O
+.	POS	O
+Group	POS	O
+ADR	POS	O
++	POS	O
+LOS	POS	O
+(	POS	O
+6	POS	O
+)	POS	O
+received	POS	O
+losartan	POS	O
+(	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+b	POS	O
+.	POS	O
+w	POS	O
+.	POS	O
+/	POS	O
+day	POS	O
+by	POS	O
+gavages	POS	O
+)	POS	O
+for	POS	O
+6	POS	O
+weeks	POS	O
+and	POS	O
+group	POS	O
+ADR	POS	O
++	POS	O
+LOS	POS	O
+(	POS	O
+12	POS	O
+)	POS	O
+for	POS	O
+12	POS	O
+weeks	POS	O
+after	POS	O
+second	POS	O
+injection	POS	O
+of	POS	O
+ADR	POS	O
+.	POS	O
+Animals	POS	O
+were	POS	O
+killed	POS	O
+after	POS	O
+6	POS	O
+or	POS	O
+12	POS	O
+weeks	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Haemodynamic	POS	O
+measurements	POS	O
+were	POS	O
+performed	POS	O
+on	POS	O
+anaesthetized	POS	O
+animals	POS	O
+,	POS	O
+blood	POS	O
+and	POS	O
+urine	POS	O
+samples	POS	O
+were	POS	O
+taken	POS	O
+for	POS	O
+biochemical	POS	O
+analysis	POS	O
+and	POS	O
+the	POS	O
+left	POS	O
+kidney	POS	O
+was	POS	O
+processed	POS	O
+for	POS	O
+morphological	POS	O
+studies	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Short	POS	O
+-	POS	O
+term	POS	O
+losartan	POS	O
+treatment	POS	O
+,	POS	O
+besides	POS	O
+antihypertensive	POS	O
+effect	POS	O
+,	POS	O
+improved	POS	O
+glomerular	POS	O
+filtration	POS	O
+rate	POS	O
+and	POS	O
+ameliorated	POS	O
+glomerulosclerosis	POS	B-NP
+resulting	POS	O
+in	POS	O
+decreased	POS	O
+proteinuria	POS	B-NP
+.	POS	O
+Prolonged	POS	O
+treatment	POS	O
+with	POS	O
+losartan	POS	O
+showed	POS	O
+further	POS	O
+reduction	POS	O
+of	POS	O
+glomerulosclerosis	POS	B-NP
+associated	POS	O
+with	POS	O
+reduced	POS	O
+progression	POS	O
+of	POS	O
+tubular	POS	B-NP
+atrophy	POS	I-NP
+and	POS	O
+interstitial	POS	B-NP
+fibrosis	POS	I-NP
+,	POS	O
+thus	POS	O
+preventing	POS	O
+heavy	POS	O
+proteinuria	POS	B-NP
+and	POS	O
+chronic	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+Losartan	POS	O
+reduced	POS	O
+uraemia	POS	B-NP
+and	POS	O
+increased	POS	O
+urea	POS	O
+clearance	POS	O
+in	POS	O
+advanced	POS	O
+ADR	POS	O
+nephropathy	POS	B-NP
+in	POS	O
+SHR	POS	O
+.	POS	O
+Histological	POS	O
+examination	POS	O
+showed	POS	O
+that	POS	O
+losartan	POS	O
+could	POS	O
+prevent	POS	O
+tubular	POS	B-NP
+atrophy	POS	I-NP
+,	POS	O
+interstitial	POS	B-NP
+infiltration	POS	I-NP
+and	POS	O
+fibrosis	POS	B-NP
+in	POS	O
+ADR	POS	B-NP
+nephropathy	POS	I-NP
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Losartan	POS	O
+reduces	POS	O
+the	POS	O
+rate	POS	O
+of	POS	O
+progression	POS	O
+of	POS	O
+ADR	POS	O
+-	POS	O
+induced	POS	O
+focal	POS	O
+segmental	POS	O
+glomerulosclerosis	POS	B-NP
+to	POS	O
+end	POS	O
+-	POS	O
+stage	POS	O
+renal	POS	B-NP
+disease	POS	I-NP
+in	POS	O
+SHR	POS	O
+.	POS	O
+The	POS	O
+risks	POS	O
+of	POS	O
+aprotinin	POS	O
+and	POS	O
+tranexamic	POS	O
+acid	POS	O
+in	POS	O
+cardiac	POS	O
+surgery	POS	O
+:	POS	O
+a	POS	O
+one	POS	O
+-	POS	O
+year	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+of	POS	O
+1188	POS	O
+consecutive	POS	O
+patients	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Our	POS	O
+aim	POS	O
+was	POS	O
+to	POS	O
+investigate	POS	O
+postoperative	POS	B-NP
+complications	POS	I-NP
+and	POS	O
+mortality	POS	O
+after	POS	O
+administration	POS	O
+of	POS	O
+aprotinin	POS	O
+compared	POS	O
+to	POS	O
+tranexamic	POS	O
+acid	POS	O
+in	POS	O
+an	POS	O
+unselected	POS	O
+,	POS	O
+consecutive	POS	O
+cohort	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Perioperative	POS	O
+data	POS	O
+from	POS	O
+consecutive	POS	O
+cardiac	POS	O
+surgery	POS	O
+patients	POS	O
+were	POS	O
+prospectively	POS	O
+collected	POS	O
+between	POS	O
+September	POS	O
+2005	POS	O
+and	POS	O
+June	POS	O
+2006	POS	O
+in	POS	O
+a	POS	O
+university	POS	O
+-	POS	O
+affiliated	POS	O
+clinic	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+1188	POS	O
+)	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+first	POS	O
+5	POS	O
+mo	POS	O
+,	POS	O
+596	POS	O
+patients	POS	O
+received	POS	O
+aprotinin	POS	O
+(	POS	O
+Group	POS	O
+A	POS	O
+)	POS	O
+;	POS	O
+in	POS	O
+the	POS	O
+next	POS	O
+5	POS	O
+mo	POS	O
+,	POS	O
+592	POS	O
+patients	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+tranexamic	POS	O
+acid	POS	O
+(	POS	O
+Group	POS	O
+T	POS	O
+)	POS	O
+.	POS	O
+Except	POS	O
+for	POS	O
+antifibrinolytic	POS	O
+therapy	POS	O
+,	POS	O
+the	POS	O
+anesthetic	POS	O
+and	POS	O
+surgical	POS	O
+protocols	POS	O
+remained	POS	O
+unchanged	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+pre	POS	O
+-	POS	O
+and	POS	O
+intraoperative	POS	O
+variables	POS	O
+were	POS	O
+comparable	POS	O
+between	POS	O
+the	POS	O
+treatment	POS	O
+groups	POS	O
+.	POS	O
+Postoperatively	POS	O
+,	POS	O
+a	POS	O
+significantly	POS	O
+higher	POS	O
+incidence	POS	O
+of	POS	O
+seizures	POS	B-NP
+was	POS	O
+found	POS	O
+in	POS	O
+Group	POS	O
+T	POS	O
+(	POS	O
+4	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+vs	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+,	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+This	POS	O
+difference	POS	O
+was	POS	O
+also	POS	O
+significant	POS	O
+in	POS	O
+the	POS	O
+primary	POS	O
+valve	POS	O
+surgery	POS	O
+and	POS	O
+the	POS	O
+high	POS	O
+risk	POS	O
+surgery	POS	O
+subgroups	POS	O
+(	POS	O
+7	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+vs	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+003	POS	O
+;	POS	O
+7	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+vs	POS	O
+2	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+035	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+.	POS	O
+Persistent	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+(	POS	O
+7	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+vs	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+020	POS	O
+)	POS	O
+and	POS	O
+renal	POS	B-NP
+failure	POS	I-NP
+(	POS	O
+9	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+vs	POS	O
+1	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+002	POS	O
+)	POS	O
+were	POS	O
+also	POS	O
+more	POS	O
+common	POS	O
+in	POS	O
+Group	POS	O
+T	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+primary	POS	O
+valve	POS	O
+surgery	POS	O
+subgroup	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+contrary	POS	O
+,	POS	O
+among	POS	O
+primary	POS	O
+coronary	POS	O
+artery	POS	O
+bypass	POS	O
+surgery	POS	O
+patients	POS	O
+,	POS	O
+there	POS	O
+were	POS	O
+more	POS	O
+acute	POS	O
+myocardial	POS	B-NP
+infarctions	POS	I-NP
+and	POS	O
+renal	POS	B-NP
+dysfunction	POS	I-NP
+in	POS	O
+Group	POS	O
+A	POS	O
+(	POS	O
+5	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+vs	POS	O
+2	POS	O
+.	POS	O
+0	POS	O
+%	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+027	POS	O
+;	POS	O
+22	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+vs	POS	O
+15	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+036	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+1	POS	O
+-	POS	O
+yr	POS	O
+mortality	POS	O
+was	POS	O
+significantly	POS	O
+higher	POS	O
+after	POS	O
+aprotinin	POS	O
+treatment	POS	O
+in	POS	O
+the	POS	O
+high	POS	O
+risk	POS	O
+surgery	POS	O
+group	POS	O
+(	POS	O
+17	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+vs	POS	O
+9	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+034	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Both	POS	O
+antifibrinolytic	POS	O
+drugs	POS	O
+bear	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+adverse	POS	O
+outcome	POS	O
+depending	POS	O
+on	POS	O
+the	POS	O
+type	POS	O
+of	POS	O
+cardiac	POS	O
+surgery	POS	O
+.	POS	O
+Administration	POS	O
+of	POS	O
+aprotinin	POS	O
+should	POS	O
+be	POS	O
+avoided	POS	O
+in	POS	O
+coronary	POS	O
+artery	POS	O
+bypass	POS	O
+graft	POS	O
+and	POS	O
+high	POS	O
+risk	POS	O
+patients	POS	O
+,	POS	O
+whereas	POS	O
+administration	POS	O
+of	POS	O
+tranexamic	POS	O
+acid	POS	O
+is	POS	O
+not	POS	O
+recommended	POS	O
+in	POS	O
+valve	POS	O
+surgery	POS	O
+.	POS	O
+Delirium	POS	B-NP
+in	POS	O
+an	POS	O
+elderly	POS	O
+woman	POS	O
+possibly	POS	O
+associated	POS	O
+with	POS	O
+administration	POS	O
+of	POS	O
+misoprostol	POS	O
+.	POS	O
+Misoprostol	POS	O
+has	POS	O
+been	POS	O
+associated	POS	O
+with	POS	O
+adverse	POS	O
+reactions	POS	O
+,	POS	O
+including	POS	O
+gastrointestinal	POS	B-NP
+symptoms	POS	I-NP
+,	POS	O
+gynecologic	POS	B-NP
+problems	POS	I-NP
+,	POS	O
+and	POS	O
+headache	POS	B-NP
+.	POS	O
+Changes	POS	B-NP
+in	POS	I-NP
+mental	POS	I-NP
+status	POS	I-NP
+,	POS	O
+however	POS	O
+,	POS	O
+have	POS	O
+not	POS	O
+been	POS	O
+reported	POS	O
+.	POS	O
+We	POS	O
+present	POS	O
+a	POS	O
+case	POS	O
+in	POS	O
+which	POS	O
+an	POS	O
+89	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+in	POS	O
+a	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+care	POS	O
+facility	POS	O
+became	POS	O
+confused	POS	O
+after	POS	O
+the	POS	O
+initiation	POS	O
+of	POS	O
+misoprostol	POS	O
+therapy	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+change	POS	O
+in	POS	O
+mental	POS	O
+status	POS	O
+was	POS	O
+first	POS	O
+reported	POS	O
+nine	POS	O
+days	POS	O
+after	POS	O
+the	POS	O
+initiation	POS	O
+of	POS	O
+therapy	POS	O
+.	POS	O
+Her	POS	O
+delirium	POS	B-NP
+significantly	POS	O
+improved	POS	O
+after	POS	O
+misoprostol	POS	O
+was	POS	O
+discontinued	POS	O
+and	POS	O
+her	POS	O
+mental	POS	O
+status	POS	O
+returned	POS	O
+to	POS	O
+normal	POS	O
+within	POS	O
+a	POS	O
+week	POS	O
+.	POS	O
+Because	POS	O
+no	POS	O
+other	POS	O
+factors	POS	O
+related	POS	O
+to	POS	O
+this	POS	O
+patient	POS	O
+changed	POS	O
+significantly	POS	O
+,	POS	O
+the	POS	O
+delirium	POS	B-NP
+experienced	POS	O
+by	POS	O
+this	POS	O
+patient	POS	O
+possibly	POS	O
+resulted	POS	O
+from	POS	O
+misoprostol	POS	O
+therapy	POS	O
+.	POS	O
+The	POS	O
+biological	POS	O
+properties	POS	O
+of	POS	O
+the	POS	O
+optical	POS	O
+isomers	POS	O
+of	POS	O
+propranolol	POS	O
+and	POS	O
+their	POS	O
+effects	POS	O
+on	POS	O
+cardiac	POS	B-NP
+arrhythmias	POS	I-NP
+.	POS	O
+1	POS	O
+.	POS	O
+The	POS	O
+optical	POS	O
+isomers	POS	O
+of	POS	O
+propranolol	POS	O
+have	POS	O
+been	POS	O
+compared	POS	O
+for	POS	O
+their	POS	O
+beta	POS	O
+-	POS	O
+blocking	POS	O
+and	POS	O
+antiarrhythmic	POS	O
+activities	POS	O
+.	POS	O
+2	POS	O
+.	POS	O
+In	POS	O
+blocking	POS	O
+the	POS	O
+positive	POS	O
+inotropic	POS	O
+and	POS	O
+chronotropic	POS	O
+responses	POS	O
+to	POS	O
+isoprenaline	POS	O
+,	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+propranolol	POS	O
+had	POS	O
+less	POS	O
+than	POS	O
+one	POS	O
+hundredth	POS	O
+the	POS	O
+potency	POS	O
+of	POS	O
+(	POS	O
+-	POS	O
+)	POS	O
+-	POS	O
+propranolol	POS	O
+.	POS	O
+At	POS	O
+dose	POS	O
+levels	POS	O
+of	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+propranolol	POS	O
+which	POS	O
+attenuated	POS	O
+the	POS	O
+responses	POS	O
+to	POS	O
+isoprenaline	POS	O
+,	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+prolongation	POS	O
+of	POS	O
+the	POS	O
+PR	POS	O
+interval	POS	O
+of	POS	O
+the	POS	O
+electrocardiogram	POS	O
+.	POS	O
+3	POS	O
+.	POS	O
+The	POS	O
+metabolic	POS	O
+responses	POS	O
+to	POS	O
+isoprenaline	POS	O
+in	POS	O
+dogs	POS	O
+(	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+circulating	POS	O
+glucose	POS	O
+,	POS	O
+lactate	POS	O
+and	POS	O
+free	POS	O
+fatty	POS	O
+acids	POS	O
+)	POS	O
+were	POS	O
+all	POS	O
+blocked	POS	O
+by	POS	O
+(	POS	O
+-	POS	O
+)	POS	O
+-	POS	O
+propranolol	POS	O
+.	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+Propranolol	POS	O
+had	POS	O
+no	POS	O
+effect	POS	O
+on	POS	O
+fatty	POS	O
+acid	POS	O
+mobilization	POS	O
+but	POS	O
+significantly	POS	O
+reduced	POS	O
+the	POS	O
+increments	POS	O
+in	POS	O
+both	POS	O
+lactate	POS	O
+and	POS	O
+glucose	POS	O
+.	POS	O
+4	POS	O
+.	POS	O
+Both	POS	O
+isomers	POS	O
+of	POS	O
+propranolol	POS	O
+possessed	POS	O
+similar	POS	O
+depressant	POS	O
+potency	POS	O
+on	POS	O
+isolated	POS	O
+atrial	POS	O
+muscle	POS	O
+taken	POS	O
+from	POS	O
+guinea	POS	O
+-	POS	O
+pigs	POS	O
+.	POS	O
+5	POS	O
+.	POS	O
+The	POS	O
+isomers	POS	O
+of	POS	O
+propranolol	POS	O
+exhibited	POS	O
+similar	POS	O
+local	POS	O
+anaesthetic	POS	O
+potencies	POS	O
+on	POS	O
+an	POS	O
+isolated	POS	O
+frog	POS	O
+nerve	POS	O
+preparation	POS	O
+at	POS	O
+a	POS	O
+level	POS	O
+approximately	POS	O
+three	POS	O
+times	POS	O
+that	POS	O
+of	POS	O
+procaine	POS	O
+.	POS	O
+The	POS	O
+racemic	POS	O
+compound	POS	O
+was	POS	O
+significantly	POS	O
+less	POS	O
+potent	POS	O
+than	POS	O
+either	POS	O
+isomer	POS	O
+.	POS	O
+6	POS	O
+.	POS	O
+Both	POS	O
+isomers	POS	O
+of	POS	O
+propranolol	POS	O
+were	POS	O
+capable	POS	O
+of	POS	O
+preventing	POS	O
+adrenaline	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+arrhythmias	POS	I-NP
+in	POS	O
+cats	POS	O
+anaesthetized	POS	O
+with	POS	O
+halothane	POS	O
+,	POS	O
+but	POS	O
+the	POS	O
+mean	POS	O
+dose	POS	O
+of	POS	O
+(	POS	O
+-	POS	O
+)	POS	O
+-	POS	O
+propranolol	POS	O
+was	POS	O
+0	POS	O
+.	POS	O
+09	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+whereas	POS	O
+that	POS	O
+of	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+propranolol	POS	O
+was	POS	O
+4	POS	O
+.	POS	O
+2	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+At	POS	O
+the	POS	O
+effective	POS	O
+dose	POS	O
+level	POS	O
+of	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+propranolol	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+prolongation	POS	O
+of	POS	O
+the	POS	O
+PR	POS	O
+interval	POS	O
+of	POS	O
+the	POS	O
+electrocardiogram	POS	O
+.	POS	O
+Blockade	POS	O
+of	POS	O
+arrhythmias	POS	B-NP
+with	POS	O
+both	POS	O
+isomers	POS	O
+was	POS	O
+surmountable	POS	O
+by	POS	O
+increasing	POS	O
+the	POS	O
+dose	POS	O
+of	POS	O
+adrenaline	POS	O
+.	POS	O
+7	POS	O
+.	POS	O
+Both	POS	O
+isomers	POS	O
+of	POS	O
+propranolol	POS	O
+were	POS	O
+also	POS	O
+capable	POS	O
+of	POS	O
+reversing	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+caused	POS	O
+by	POS	O
+ouabain	POS	O
+in	POS	O
+anaesthetized	POS	O
+cats	POS	O
+and	POS	O
+dogs	POS	O
+.	POS	O
+The	POS	O
+dose	POS	O
+of	POS	O
+(	POS	O
+-	POS	O
+)	POS	O
+-	POS	O
+propranolol	POS	O
+was	POS	O
+significantly	POS	O
+smaller	POS	O
+than	POS	O
+that	POS	O
+of	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+propranolol	POS	O
+in	POS	O
+both	POS	O
+species	POS	O
+but	POS	O
+much	POS	O
+higher	POS	O
+than	POS	O
+that	POS	O
+required	POS	O
+to	POS	O
+produce	POS	O
+evidence	POS	O
+of	POS	O
+beta	POS	O
+-	POS	O
+blockade	POS	O
+.	POS	O
+8	POS	O
+.	POS	O
+The	POS	O
+implications	POS	O
+of	POS	O
+these	POS	O
+results	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+Topotecan	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+radiotherapy	POS	O
+in	POS	O
+unresectable	POS	O
+glioblastoma	POS	B-NP
+:	POS	O
+a	POS	O
+phase	POS	O
+2	POS	O
+study	POS	O
+.	POS	O
+Improving	POS	O
+glioblastoma	POS	B-NP
+multiforme	POS	I-NP
+(	POS	O
+GBM	POS	B-NP
+)	POS	O
+treatment	POS	O
+with	POS	O
+radio	POS	O
+-	POS	O
+chemotherapy	POS	O
+remains	POS	O
+a	POS	O
+challenge	POS	O
+.	POS	O
+Topotecan	POS	O
+is	POS	O
+an	POS	O
+attractive	POS	O
+option	POS	O
+as	POS	O
+it	POS	O
+exhibits	POS	O
+growth	POS	O
+inhibition	POS	O
+of	POS	O
+human	POS	O
+glioma	POS	B-NP
+as	POS	O
+well	POS	O
+as	POS	O
+brain	POS	O
+penetration	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+assessed	POS	O
+the	POS	O
+combination	POS	O
+of	POS	O
+radiotherapy	POS	O
+(	POS	O
+60	POS	O
+Gy	POS	O
+/	POS	O
+30	POS	O
+fractions	POS	O
+/	POS	O
+40	POS	O
+days	POS	O
+)	POS	O
+and	POS	O
+topotecan	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+/	POS	O
+day	POS	O
+on	POS	O
+days	POS	O
+1	POS	O
+-	POS	O
+5	POS	O
+on	POS	O
+weeks	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+and	POS	O
+5	POS	O
+)	POS	O
+in	POS	O
+50	POS	O
+adults	POS	O
+with	POS	O
+histologically	POS	O
+proven	POS	O
+and	POS	O
+untreated	POS	O
+GBM	POS	B-NP
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+non	POS	B-NP
+-	POS	I-NP
+hematological	POS	I-NP
+toxicities	POS	I-NP
+was	POS	O
+low	POS	O
+and	POS	O
+grade	POS	O
+3	POS	O
+-	POS	O
+4	POS	O
+hematological	POS	B-NP
+toxicities	POS	I-NP
+were	POS	O
+reported	POS	O
+in	POS	O
+20	POS	O
+patients	POS	O
+(	POS	O
+mainly	POS	O
+lymphopenia	POS	B-NP
+and	POS	O
+neutropenia	POS	B-NP
+)	POS	O
+.	POS	O
+Partial	POS	O
+response	POS	O
+and	POS	O
+stabilization	POS	O
+rates	POS	O
+were	POS	O
+2	POS	O
+%	POS	O
+and	POS	O
+32	POS	O
+%	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+with	POS	O
+an	POS	O
+overall	POS	O
+time	POS	O
+to	POS	O
+progression	POS	O
+of	POS	O
+12	POS	O
+weeks	POS	O
+.	POS	O
+One	POS	O
+-	POS	O
+year	POS	O
+overall	POS	O
+survival	POS	O
+(	POS	O
+OS	POS	O
+)	POS	O
+rate	POS	O
+was	POS	O
+42	POS	O
+%	POS	O
+,	POS	O
+with	POS	O
+a	POS	O
+median	POS	O
+OS	POS	O
+of	POS	O
+40	POS	O
+weeks	POS	O
+.	POS	O
+Topotecan	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+radiotherapy	POS	O
+was	POS	O
+well	POS	O
+tolerated	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+while	POS	O
+response	POS	O
+and	POS	O
+stabilization	POS	O
+concerned	POS	O
+one	POS	O
+-	POS	O
+third	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+,	POS	O
+the	POS	O
+study	POS	O
+did	POS	O
+not	POS	O
+show	POS	O
+increased	POS	O
+benefits	POS	O
+in	POS	O
+terms	POS	O
+of	POS	O
+survival	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+unresectable	POS	O
+GBM	POS	B-NP
+.	POS	O
+Long	POS	O
+-	POS	O
+term	POS	O
+lithium	POS	O
+therapy	POS	O
+leading	POS	O
+to	POS	O
+hyperparathyroidism	POS	B-NP
+:	POS	O
+a	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+This	POS	O
+paper	POS	O
+reviews	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+chronic	POS	O
+lithium	POS	O
+therapy	POS	O
+on	POS	O
+serum	POS	O
+calcium	POS	O
+level	POS	O
+and	POS	O
+parathyroid	POS	O
+glands	POS	O
+,	POS	O
+its	POS	O
+pathogenesis	POS	O
+,	POS	O
+and	POS	O
+treatment	POS	O
+options	POS	O
+.	POS	O
+We	POS	O
+examined	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+lithium	POS	O
+-	POS	O
+treated	POS	O
+patient	POS	O
+who	POS	O
+had	POS	O
+recurrent	POS	O
+hypercalcemia	POS	B-NP
+to	POS	O
+better	POS	O
+understand	POS	O
+the	POS	O
+disease	POS	O
+process	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Primary	POS	B-NP
+hyperparathyroidism	POS	I-NP
+is	POS	O
+a	POS	O
+rare	POS	O
+but	POS	O
+potentially	POS	O
+life	POS	O
+-	POS	O
+threatening	POS	O
+side	POS	O
+effect	POS	O
+of	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+lithium	POS	O
+therapy	POS	O
+.	POS	O
+Careful	POS	O
+patient	POS	O
+selection	POS	O
+and	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+can	POS	O
+reduce	POS	O
+morbidity	POS	O
+.	POS	O
+PRACTICAL	POS	O
+IMPLICATIONS	POS	O
+:	POS	O
+As	POS	O
+much	POS	O
+as	POS	O
+15	POS	O
+%	POS	O
+of	POS	O
+lithium	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+become	POS	O
+hypercalcemic	POS	B-NP
+.	POS	O
+By	POS	O
+routinely	POS	O
+monitoring	POS	O
+serum	POS	O
+calcium	POS	O
+levels	POS	O
+,	POS	O
+healthcare	POS	O
+providers	POS	O
+can	POS	O
+improve	POS	O
+the	POS	O
+quality	POS	O
+of	POS	O
+life	POS	O
+of	POS	O
+this	POS	O
+patient	POS	O
+group	POS	O
+.	POS	O
+Comparison	POS	O
+of	POS	O
+laryngeal	POS	O
+mask	POS	O
+with	POS	O
+endotracheal	POS	O
+tube	POS	O
+for	POS	O
+anesthesia	POS	O
+in	POS	O
+endoscopic	POS	O
+sinus	POS	O
+surgery	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+compare	POS	O
+surgical	POS	O
+conditions	POS	O
+,	POS	O
+including	POS	O
+the	POS	O
+amount	POS	O
+of	POS	O
+intraoperative	POS	O
+bleeding	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+intraoperative	POS	O
+blood	POS	O
+pressure	POS	O
+,	POS	O
+during	POS	O
+functional	POS	O
+endoscopic	POS	O
+sinus	POS	O
+surgery	POS	O
+(	POS	O
+FESS	POS	O
+)	POS	O
+using	POS	O
+flexible	POS	O
+reinforced	POS	O
+laryngeal	POS	O
+mask	POS	O
+airway	POS	O
+(	POS	O
+FRLMA	POS	O
+)	POS	O
+versus	POS	O
+endotracheal	POS	O
+tube	POS	O
+(	POS	O
+ETT	POS	O
+)	POS	O
+in	POS	O
+maintaining	POS	O
+controlled	POS	O
+hypotension	POS	B-NP
+anesthesia	POS	O
+induced	POS	O
+by	POS	O
+propofol	POS	O
+-	POS	O
+remifentanil	POS	O
+total	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+anesthesia	POS	O
+(	POS	O
+TIVA	POS	O
+)	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Sixty	POS	O
+normotensive	POS	O
+American	POS	O
+Society	POS	O
+of	POS	O
+Anesthesiologists	POS	O
+I	POS	O
+-	POS	O
+II	POS	O
+adult	POS	O
+patients	POS	O
+undergoing	POS	O
+FESS	POS	B-NP
+under	POS	O
+controlled	POS	O
+hypotension	POS	B-NP
+anesthesia	POS	O
+caused	POS	O
+by	POS	O
+propofol	POS	O
+-	POS	O
+remifentanil	POS	O
+-	POS	O
+TIVA	POS	O
+were	POS	O
+randomly	POS	O
+assigned	POS	O
+into	POS	O
+two	POS	O
+groups	POS	O
+:	POS	O
+group	POS	O
+I	POS	O
+,	POS	O
+FRLMA	POS	O
+;	POS	O
+group	POS	O
+II	POS	O
+,	POS	O
+ETT	POS	O
+.	POS	O
+Hemorrhage	POS	O
+was	POS	O
+measured	POS	O
+and	POS	O
+the	POS	O
+visibility	POS	O
+of	POS	O
+the	POS	O
+operative	POS	O
+field	POS	O
+was	POS	O
+evaluated	POS	O
+according	POS	O
+to	POS	O
+a	POS	O
+six	POS	O
+-	POS	O
+point	POS	O
+scale	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Controlled	POS	O
+hypotension	POS	B-NP
+was	POS	O
+achieved	POS	O
+within	POS	O
+a	POS	O
+shorter	POS	O
+period	POS	O
+using	POS	O
+laryngeal	POS	O
+mask	POS	O
+using	POS	O
+lower	POS	O
+rates	POS	O
+of	POS	O
+remifentanil	POS	O
+infusion	POS	O
+and	POS	O
+lower	POS	O
+total	POS	O
+dose	POS	O
+of	POS	O
+remifentanil	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+In	POS	O
+summary	POS	O
+,	POS	O
+our	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+airway	POS	O
+management	POS	O
+using	POS	O
+FRLMA	POS	O
+during	POS	O
+controlled	POS	O
+hypotension	POS	B-NP
+anesthesia	POS	O
+provided	POS	O
+better	POS	O
+surgical	POS	O
+conditions	POS	O
+in	POS	O
+terms	POS	O
+of	POS	O
+quality	POS	O
+of	POS	O
+operative	POS	O
+field	POS	O
+and	POS	O
+blood	POS	O
+loss	POS	O
+and	POS	O
+allowed	POS	O
+for	POS	O
+convenient	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+with	POS	O
+low	POS	O
+doses	POS	O
+of	POS	O
+remifentanil	POS	O
+during	POS	O
+TIVA	POS	O
+in	POS	O
+patients	POS	O
+undergoing	POS	O
+FESS	POS	B-NP
+.	POS	O
+Nonalcoholic	POS	B-NP
+fatty	POS	I-NP
+liver	POS	I-NP
+disease	POS	I-NP
+during	POS	O
+valproate	POS	O
+therapy	POS	O
+.	POS	O
+Valproic	POS	O
+acid	POS	O
+(	POS	O
+VPA	POS	O
+)	POS	O
+is	POS	O
+effective	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+many	POS	O
+types	POS	O
+of	POS	O
+epilepsy	POS	B-NP
+,	POS	O
+but	POS	O
+its	POS	O
+use	POS	O
+can	POS	O
+be	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+body	POS	O
+weight	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+nonalcoholic	POS	B-NP
+fatty	POS	I-NP
+liver	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+NAFLD	POS	B-NP
+)	POS	O
+arising	POS	O
+in	POS	O
+a	POS	O
+child	POS	O
+who	POS	O
+developed	POS	O
+obesity	POS	B-NP
+during	POS	O
+VPA	POS	O
+treatment	POS	O
+.	POS	O
+Laboratory	POS	O
+data	POS	O
+revealed	POS	O
+hyperinsulinemia	POS	B-NP
+with	POS	O
+insulin	POS	B-NP
+resistance	POS	I-NP
+.	POS	O
+After	POS	O
+the	POS	O
+withdrawal	POS	O
+of	POS	O
+VPA	POS	O
+therapy	POS	O
+,	POS	O
+our	POS	O
+patient	POS	O
+showed	POS	O
+a	POS	O
+significant	POS	O
+weight	POS	B-NP
+loss	POS	I-NP
+,	POS	O
+a	POS	O
+decrease	POS	O
+of	POS	O
+body	POS	O
+mass	POS	O
+index	POS	O
+,	POS	O
+and	POS	O
+normalization	POS	O
+of	POS	O
+metabolic	POS	O
+and	POS	O
+endocrine	POS	O
+parameters	POS	O
+;	POS	O
+moreover	POS	O
+,	POS	O
+ultrasound	POS	O
+measurements	POS	O
+showed	POS	O
+a	POS	O
+complete	POS	O
+normalization	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+case	POS	O
+suggests	POS	O
+that	POS	O
+obesity	POS	B-NP
+,	POS	O
+hyperinsulinemia	POS	B-NP
+,	POS	O
+insulin	POS	B-NP
+resistance	POS	I-NP
+,	POS	O
+and	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+treatment	POS	O
+with	POS	O
+VPA	POS	O
+may	POS	O
+be	POS	O
+all	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+NAFLD	POS	B-NP
+;	POS	O
+this	POS	O
+side	POS	O
+effect	POS	O
+is	POS	O
+reversible	POS	O
+after	POS	O
+VPA	POS	O
+withdrawal	POS	O
+.	POS	O
+Carbimazole	POS	O
+induced	POS	O
+ANCA	POS	B-NP
+positive	POS	O
+vasculitis	POS	B-NP
+.	POS	O
+Anti	POS	O
+-	POS	O
+thyroid	POS	O
+drugs	POS	O
+,	POS	O
+like	POS	O
+carbimazole	POS	O
+and	POS	O
+propylthiouracil	POS	O
+(	POS	O
+PTU	POS	B-NP
+)	POS	O
+are	POS	O
+commonly	POS	O
+prescribed	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+hyperthyroidism	POS	B-NP
+.	POS	O
+One	POS	O
+should	POS	O
+be	POS	O
+aware	POS	O
+of	POS	O
+the	POS	O
+side	POS	O
+effects	POS	O
+of	POS	O
+antithyroid	POS	O
+medications	POS	O
+.	POS	O
+Antineutrophil	POS	O
+cytoplasmic	POS	O
+antibody	POS	O
+(	POS	O
+ANCA	POS	B-NP
+)	POS	I-NP
+-	POS	I-NP
+-	POS	I-NP
+associated	POS	I-NP
+vasculitis	POS	I-NP
+is	POS	O
+a	POS	O
+potentially	POS	O
+life	POS	O
+-	POS	O
+threatening	POS	O
+adverse	POS	O
+effect	POS	O
+of	POS	O
+antithyroidmedications	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+Graves	POS	B-NP
+'	POS	I-NP
+disease	POS	I-NP
+who	POS	O
+developed	POS	O
+ANCA	POS	B-NP
+positive	POS	O
+carbimazole	POS	O
+induced	POS	O
+vasculitis	POS	B-NP
+.	POS	O
+The	POS	O
+episode	POS	O
+was	POS	O
+characterized	POS	O
+by	POS	O
+a	POS	O
+vasculitic	POS	B-NP
+skin	POS	I-NP
+rash	POS	I-NP
+associated	POS	O
+with	POS	O
+large	POS	O
+joint	POS	B-NP
+arthritis	POS	I-NP
+,	POS	O
+pyrexia	POS	B-NP
+and	POS	O
+parotiditis	POS	B-NP
+but	POS	O
+no	POS	O
+renal	POS	O
+or	POS	O
+pulmonary	POS	B-NP
+involvement	POS	I-NP
+.	POS	O
+He	POS	O
+was	POS	O
+referred	POS	O
+to	POS	O
+us	POS	O
+for	POS	O
+neurological	POS	O
+evaluation	POS	O
+because	POS	O
+he	POS	O
+had	POS	O
+difficulty	POS	O
+in	POS	O
+getting	POS	O
+up	POS	O
+from	POS	O
+squatting	POS	O
+position	POS	O
+and	POS	O
+was	POS	O
+suspected	POS	O
+to	POS	O
+have	POS	O
+myositis	POS	B-NP
+.	POS	O
+Carbimazole	POS	O
+and	POS	O
+methimazole	POS	O
+have	POS	O
+a	POS	O
+lower	POS	O
+incidence	POS	O
+of	POS	O
+reported	POS	O
+ANCA	POS	B-NP
+positive	POS	O
+side	POS	O
+effects	POS	O
+than	POS	O
+PUT	POS	O
+.	POS	O
+To	POS	O
+the	POS	O
+best	POS	O
+of	POS	O
+our	POS	O
+knowledge	POS	O
+this	POS	O
+is	POS	O
+the	POS	O
+first	POS	O
+ANCA	POS	B-NP
+positive	POS	O
+carbimazole	POS	O
+induced	POS	O
+vasculitis	POS	B-NP
+case	POS	O
+reported	POS	O
+from	POS	O
+India	POS	O
+.	POS	O
+Aspirin	POS	O
+for	POS	O
+the	POS	O
+primary	POS	O
+prevention	POS	O
+of	POS	O
+cardiovascular	POS	O
+events	POS	O
+:	POS	O
+an	POS	O
+update	POS	O
+of	POS	O
+the	POS	O
+evidence	POS	O
+for	POS	O
+the	POS	O
+U	POS	O
+.	POS	O
+S	POS	O
+.	POS	O
+Preventive	POS	O
+Services	POS	O
+Task	POS	O
+Force	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Coronary	POS	B-NP
+heart	POS	I-NP
+disease	POS	I-NP
+and	POS	O
+cerebrovascular	POS	B-NP
+disease	POS	I-NP
+are	POS	O
+leading	POS	O
+causes	POS	O
+of	POS	O
+death	POS	O
+in	POS	O
+the	POS	O
+United	POS	O
+States	POS	O
+.	POS	O
+In	POS	O
+2002	POS	O
+,	POS	O
+the	POS	O
+U	POS	O
+.	POS	O
+S	POS	O
+.	POS	O
+Preventive	POS	O
+Services	POS	O
+Task	POS	O
+Force	POS	O
+(	POS	O
+USPSTF	POS	O
+)	POS	O
+strongly	POS	O
+recommended	POS	O
+that	POS	O
+clinicians	POS	O
+discuss	POS	O
+aspirin	POS	O
+with	POS	O
+adults	POS	O
+who	POS	O
+are	POS	O
+at	POS	O
+increased	POS	O
+risk	POS	O
+for	POS	O
+coronary	POS	B-NP
+heart	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+To	POS	O
+determine	POS	O
+the	POS	O
+benefits	POS	O
+and	POS	O
+harms	POS	O
+of	POS	O
+taking	POS	O
+aspirin	POS	O
+for	POS	O
+the	POS	O
+primary	POS	O
+prevention	POS	O
+of	POS	O
+myocardial	POS	B-NP
+infarctions	POS	I-NP
+,	POS	O
+strokes	POS	B-NP
+,	POS	O
+and	POS	O
+death	POS	O
+.	POS	O
+DATA	POS	O
+SOURCES	POS	O
+:	POS	O
+MEDLINE	POS	O
+and	POS	O
+Cochrane	POS	O
+Library	POS	O
+(	POS	O
+search	POS	O
+dates	POS	O
+,	POS	O
+1	POS	O
+January	POS	O
+2001	POS	O
+to	POS	O
+28	POS	O
+August	POS	O
+2008	POS	O
+)	POS	O
+,	POS	O
+recent	POS	O
+systematic	POS	O
+reviews	POS	O
+,	POS	O
+reference	POS	O
+lists	POS	O
+of	POS	O
+retrieved	POS	O
+articles	POS	O
+,	POS	O
+and	POS	O
+suggestions	POS	O
+from	POS	O
+experts	POS	O
+.	POS	O
+STUDY	POS	O
+SELECTION	POS	O
+:	POS	O
+English	POS	O
+-	POS	O
+language	POS	O
+randomized	POS	O
+,	POS	O
+controlled	POS	O
+trials	POS	O
+(	POS	O
+RCTs	POS	O
+)	POS	O
+;	POS	O
+case	POS	O
+-	POS	O
+control	POS	O
+studies	POS	O
+;	POS	O
+meta	POS	O
+-	POS	O
+analyses	POS	O
+;	POS	O
+and	POS	O
+systematic	POS	O
+reviews	POS	O
+of	POS	O
+aspirin	POS	O
+versus	POS	O
+control	POS	O
+for	POS	O
+the	POS	O
+primary	POS	O
+prevention	POS	O
+of	POS	O
+cardiovascular	POS	B-NP
+disease	POS	I-NP
+(	POS	O
+CVD	POS	B-NP
+)	POS	O
+were	POS	O
+selected	POS	O
+to	POS	O
+answer	POS	O
+the	POS	O
+following	POS	O
+questions	POS	O
+:	POS	O
+Does	POS	O
+aspirin	POS	O
+decrease	POS	O
+coronary	POS	B-NP
+heart	POS	I-NP
+events	POS	I-NP
+,	POS	O
+strokes	POS	B-NP
+,	POS	O
+death	POS	B-NP
+from	POS	O
+coronary	POS	B-NP
+heart	POS	I-NP
+events	POS	I-NP
+or	POS	O
+stroke	POS	B-NP
+,	POS	O
+or	POS	O
+all	POS	O
+-	POS	O
+cause	POS	O
+mortality	POS	O
+in	POS	O
+adults	POS	O
+without	POS	O
+known	POS	O
+CVD	POS	B-NP
+?	POS	O
+Does	POS	O
+aspirin	POS	O
+increase	POS	O
+gastrointestinal	POS	B-NP
+bleeding	POS	I-NP
+or	POS	O
+hemorrhagic	POS	B-NP
+strokes	POS	I-NP
+?	POS	O
+DATA	POS	O
+EXTRACTION	POS	O
+:	POS	O
+All	POS	O
+studies	POS	O
+were	POS	O
+reviewed	POS	O
+,	POS	O
+abstracted	POS	O
+,	POS	O
+and	POS	O
+rated	POS	O
+for	POS	O
+quality	POS	O
+by	POS	O
+using	POS	O
+predefined	POS	O
+USPSTF	POS	O
+criteria	POS	O
+.	POS	O
+DATA	POS	O
+SYNTHESIS	POS	O
+:	POS	O
+New	POS	O
+evidence	POS	O
+from	POS	O
+1	POS	O
+good	POS	O
+-	POS	O
+quality	POS	O
+RCT	POS	O
+,	POS	O
+1	POS	O
+good	POS	O
+-	POS	O
+quality	POS	O
+meta	POS	O
+-	POS	O
+analysis	POS	O
+,	POS	O
+and	POS	O
+2	POS	O
+fair	POS	O
+-	POS	O
+quality	POS	O
+subanalyses	POS	O
+of	POS	O
+RCTs	POS	O
+demonstrates	POS	O
+that	POS	O
+aspirin	POS	O
+use	POS	O
+reduces	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+CVD	POS	B-NP
+events	POS	O
+in	POS	O
+patients	POS	O
+without	POS	O
+known	POS	O
+CVD	POS	B-NP
+.	POS	O
+Men	POS	O
+in	POS	O
+these	POS	O
+studies	POS	O
+experienced	POS	O
+fewer	POS	O
+myocardial	POS	B-NP
+infarctions	POS	I-NP
+and	POS	O
+women	POS	O
+experienced	POS	O
+fewer	POS	O
+ischemic	POS	B-NP
+strokes	POS	I-NP
+.	POS	O
+Aspirin	POS	B-NP
+does	POS	O
+not	POS	O
+seem	POS	O
+to	POS	O
+affect	POS	O
+CVD	POS	B-NP
+mortality	POS	O
+or	POS	O
+all	POS	O
+-	POS	O
+cause	POS	O
+mortality	POS	O
+in	POS	O
+either	POS	O
+men	POS	O
+or	POS	O
+women	POS	O
+.	POS	O
+The	POS	O
+use	POS	O
+of	POS	O
+aspirin	POS	O
+for	POS	O
+primary	POS	O
+prevention	POS	O
+increases	POS	O
+the	POS	O
+risk	POS	O
+for	POS	O
+major	POS	O
+bleeding	POS	O
+events	POS	O
+,	POS	O
+primarily	POS	O
+gastrointestinal	POS	B-NP
+bleeding	POS	I-NP
+events	POS	O
+,	POS	O
+in	POS	O
+both	POS	O
+men	POS	O
+and	POS	O
+women	POS	O
+.	POS	O
+Men	POS	O
+have	POS	O
+an	POS	O
+increased	POS	O
+risk	POS	O
+for	POS	O
+hemorrhagic	POS	B-NP
+strokes	POS	I-NP
+with	POS	O
+aspirin	POS	O
+use	POS	O
+.	POS	O
+A	POS	O
+new	POS	O
+RCT	POS	O
+and	POS	O
+meta	POS	O
+-	POS	O
+analysis	POS	O
+suggest	POS	O
+that	POS	O
+the	POS	O
+risk	POS	O
+for	POS	O
+hemorrhagic	POS	B-NP
+strokes	POS	I-NP
+in	POS	O
+women	POS	O
+is	POS	O
+not	POS	O
+statistically	POS	O
+significantly	POS	O
+increased	POS	O
+.	POS	O
+LIMITATIONS	POS	O
+:	POS	O
+New	POS	O
+evidence	POS	O
+on	POS	O
+aspirin	POS	O
+for	POS	O
+the	POS	O
+primary	POS	O
+prevention	POS	O
+of	POS	O
+CVD	POS	B-NP
+is	POS	O
+limited	POS	O
+.	POS	O
+The	POS	O
+dose	POS	O
+of	POS	O
+aspirin	POS	O
+used	POS	O
+in	POS	O
+the	POS	O
+RCTs	POS	O
+varied	POS	O
+,	POS	O
+which	POS	O
+prevented	POS	O
+the	POS	O
+estimation	POS	O
+of	POS	O
+the	POS	O
+most	POS	O
+appropriate	POS	O
+dose	POS	O
+for	POS	O
+primary	POS	O
+prevention	POS	O
+.	POS	O
+Several	POS	O
+of	POS	O
+the	POS	O
+RCTs	POS	O
+were	POS	O
+conducted	POS	O
+within	POS	O
+populations	POS	O
+of	POS	O
+health	POS	O
+professionals	POS	O
+,	POS	O
+which	POS	O
+potentially	POS	O
+limits	POS	O
+generalizability	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Aspirin	POS	O
+reduces	POS	O
+the	POS	O
+risk	POS	O
+for	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+in	POS	O
+men	POS	O
+and	POS	O
+strokes	POS	B-NP
+in	POS	O
+women	POS	O
+.	POS	O
+Aspirin	POS	O
+use	POS	O
+increases	POS	O
+the	POS	O
+risk	POS	O
+for	POS	O
+serious	POS	O
+bleeding	POS	B-NP
+events	POS	O
+.	POS	O
+Reducing	POS	O
+harm	POS	O
+associated	POS	O
+with	POS	O
+anticoagulation	POS	O
+:	POS	O
+practical	POS	O
+considerations	POS	O
+of	POS	O
+argatroban	POS	O
+therapy	POS	O
+in	POS	O
+heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+.	POS	O
+Argatroban	POS	O
+is	POS	O
+a	POS	O
+hepatically	POS	O
+metabolized	POS	O
+,	POS	O
+direct	POS	O
+thrombin	POS	O
+inhibitor	POS	O
+used	POS	O
+for	POS	O
+prophylaxis	POS	O
+or	POS	O
+treatment	POS	O
+of	POS	O
+thrombosis	POS	B-NP
+in	POS	O
+heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+(	POS	O
+HIT	POS	B-NP
+)	POS	O
+and	POS	O
+for	POS	O
+patients	POS	O
+with	POS	O
+or	POS	O
+at	POS	O
+risk	POS	O
+of	POS	O
+HIT	POS	B-NP
+undergoing	POS	O
+percutaneous	POS	O
+coronary	POS	O
+intervention	POS	O
+(	POS	O
+PCI	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+objective	POS	O
+of	POS	O
+this	POS	O
+review	POS	O
+is	POS	O
+to	POS	O
+summarize	POS	O
+practical	POS	O
+considerations	POS	O
+of	POS	O
+argatroban	POS	O
+therapy	POS	O
+in	POS	O
+HIT	POS	B-NP
+.	POS	O
+The	POS	O
+US	POS	O
+FDA	POS	O
+-	POS	O
+recommended	POS	O
+argatroban	POS	O
+dose	POS	O
+in	POS	O
+HIT	POS	B-NP
+is	POS	O
+2	POS	O
+microg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+(	POS	O
+reduced	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+hepatic	POS	B-NP
+impairment	POS	I-NP
+and	POS	O
+in	POS	O
+paediatric	POS	O
+patients	POS	O
+)	POS	O
+,	POS	O
+adjusted	POS	O
+to	POS	O
+achieve	POS	O
+activated	POS	O
+partial	POS	O
+thromboplastin	POS	O
+times	POS	O
+(	POS	O
+aPTTs	POS	O
+)	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+3	POS	O
+times	POS	O
+baseline	POS	O
+(	POS	O
+not	POS	O
+>	POS	O
+100	POS	O
+seconds	POS	O
+)	POS	O
+.	POS	O
+Contemporary	POS	O
+experiences	POS	O
+indicate	POS	O
+that	POS	O
+reduced	POS	O
+doses	POS	O
+are	POS	O
+also	POS	O
+needed	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+conditions	POS	O
+associated	POS	O
+with	POS	O
+hepatic	POS	B-NP
+hypoperfusion	POS	I-NP
+,	POS	O
+e	POS	O
+.	POS	O
+g	POS	O
+.	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+,	POS	O
+yet	POS	O
+are	POS	O
+unnecessary	POS	O
+for	POS	O
+renal	POS	B-NP
+dysfunction	POS	I-NP
+,	POS	O
+adult	POS	O
+age	POS	O
+,	POS	O
+sex	POS	O
+,	POS	O
+race	POS	O
+/	POS	O
+ethnicity	POS	O
+or	POS	O
+obesity	POS	B-NP
+.	POS	O
+Argatroban	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+microg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+typically	POS	O
+supports	POS	O
+therapeutic	POS	O
+aPTTs	POS	O
+.	POS	O
+The	POS	O
+FDA	POS	O
+-	POS	O
+recommended	POS	O
+dose	POS	O
+during	POS	O
+PCI	POS	O
+is	POS	O
+25	POS	O
+microg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+(	POS	O
+350	POS	O
+microg	POS	O
+/	POS	O
+kg	POS	O
+initial	POS	O
+bolus	POS	O
+)	POS	O
+,	POS	O
+adjusted	POS	O
+to	POS	O
+achieve	POS	O
+activated	POS	O
+clotting	POS	O
+times	POS	O
+(	POS	O
+ACTs	POS	O
+)	POS	O
+of	POS	O
+300	POS	O
+-	POS	O
+450	POS	O
+sec	POS	O
+.	POS	O
+For	POS	O
+PCI	POS	O
+,	POS	O
+argatroban	POS	O
+has	POS	O
+not	POS	O
+been	POS	O
+investigated	POS	O
+in	POS	O
+hepatically	POS	O
+impaired	POS	O
+patients	POS	O
+;	POS	O
+dose	POS	O
+adjustment	POS	O
+is	POS	O
+unnecessary	POS	O
+for	POS	O
+adult	POS	O
+age	POS	O
+,	POS	O
+sex	POS	O
+,	POS	O
+race	POS	O
+/	POS	O
+ethnicity	POS	O
+or	POS	O
+obesity	POS	B-NP
+,	POS	O
+and	POS	O
+lesser	POS	O
+doses	POS	O
+may	POS	O
+be	POS	O
+adequate	POS	O
+with	POS	O
+concurrent	POS	O
+glycoprotein	POS	O
+IIb	POS	O
+/	POS	O
+IIIa	POS	O
+inhibition	POS	O
+.	POS	O
+Argatroban	POS	O
+prolongs	POS	O
+the	POS	O
+International	POS	O
+Normalized	POS	O
+Ratio	POS	O
+,	POS	O
+and	POS	O
+published	POS	O
+approaches	POS	O
+for	POS	O
+monitoring	POS	O
+the	POS	O
+argatroban	POS	O
+-	POS	O
+to	POS	O
+-	POS	O
+warfarin	POS	O
+transition	POS	O
+should	POS	O
+be	POS	O
+followed	POS	O
+.	POS	O
+Major	POS	O
+bleeding	POS	O
+with	POS	O
+argatroban	POS	O
+is	POS	O
+0	POS	O
+-	POS	O
+10	POS	O
+%	POS	O
+in	POS	O
+the	POS	O
+non	POS	O
+-	POS	O
+interventional	POS	O
+setting	POS	O
+and	POS	O
+0	POS	O
+-	POS	O
+5	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+periprocedurally	POS	O
+.	POS	O
+Argatroban	POS	O
+has	POS	O
+no	POS	O
+specific	POS	O
+antidote	POS	O
+,	POS	O
+and	POS	O
+if	POS	O
+excessive	POS	O
+anticoagulation	POS	O
+occurs	POS	O
+,	POS	O
+argatroban	POS	O
+infusion	POS	O
+should	POS	O
+be	POS	O
+stopped	POS	O
+or	POS	O
+reduced	POS	O
+.	POS	O
+Improved	POS	O
+familiarity	POS	O
+of	POS	O
+healthcare	POS	O
+professionals	POS	O
+with	POS	O
+argatroban	POS	O
+therapy	POS	O
+in	POS	O
+HIT	POS	B-NP
+,	POS	O
+including	POS	O
+in	POS	O
+special	POS	O
+populations	POS	O
+and	POS	O
+during	POS	O
+PCI	POS	O
+,	POS	O
+may	POS	O
+facilitate	POS	O
+reduction	POS	O
+of	POS	O
+harm	POS	O
+associated	POS	O
+with	POS	O
+HIT	POS	B-NP
+(	POS	O
+e	POS	O
+.	POS	O
+g	POS	O
+.	POS	O
+fewer	POS	O
+thromboses	POS	B-NP
+)	POS	O
+or	POS	O
+its	POS	O
+treatment	POS	O
+(	POS	O
+e	POS	O
+.	POS	O
+g	POS	O
+.	POS	O
+fewer	POS	O
+argatroban	POS	O
+medication	POS	O
+errors	POS	O
+)	POS	O
+.	POS	O
+Rhabdomyolysis	POS	B-NP
+and	POS	O
+brain	POS	B-NP
+ischemic	POS	I-NP
+stroke	POS	I-NP
+in	POS	O
+a	POS	O
+heroin	POS	O
+-	POS	O
+dependent	POS	O
+male	POS	O
+under	POS	O
+methadone	POS	O
+maintenance	POS	O
+therapy	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+There	POS	O
+are	POS	O
+several	POS	O
+complications	POS	O
+associated	POS	O
+with	POS	O
+heroin	POS	B-NP
+abuse	POS	I-NP
+,	POS	O
+some	POS	O
+of	POS	O
+which	POS	O
+are	POS	O
+life	POS	O
+-	POS	O
+threatening	POS	O
+.	POS	O
+Methadone	POS	O
+may	POS	O
+aggravate	POS	O
+this	POS	O
+problem	POS	O
+.	POS	O
+METHOD	POS	O
+:	POS	O
+A	POS	O
+clinical	POS	O
+case	POS	O
+description	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+A	POS	O
+33	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+presented	POS	O
+with	POS	O
+rhabdomyolysis	POS	B-NP
+and	POS	O
+cerebral	POS	B-NP
+ischemic	POS	I-NP
+stroke	POS	I-NP
+after	POS	O
+intravenous	POS	O
+heroin	POS	O
+.	POS	O
+He	POS	O
+had	POS	O
+used	POS	O
+heroin	POS	O
+since	POS	O
+age	POS	O
+20	POS	O
+,	POS	O
+and	POS	O
+had	POS	O
+used	POS	O
+150	POS	O
+mg	POS	O
+methadone	POS	O
+daily	POS	O
+for	POS	O
+6	POS	O
+months	POS	O
+.	POS	O
+He	POS	O
+was	POS	O
+found	POS	O
+unconsciousness	POS	B-NP
+at	POS	O
+home	POS	O
+and	POS	O
+was	POS	O
+sent	POS	O
+to	POS	O
+our	POS	O
+hospital	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+ER	POS	O
+,	POS	O
+his	POS	O
+opiate	POS	O
+level	POS	O
+was	POS	O
+4497	POS	O
+ng	POS	O
+/	POS	O
+ml	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+ICU	POS	O
+,	POS	O
+we	POS	O
+found	POS	O
+rhabdomyolysis	POS	B-NP
+,	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+and	POS	O
+acute	POS	B-NP
+respiratory	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+After	POS	O
+transfer	POS	O
+to	POS	O
+an	POS	O
+internal	POS	O
+ward	POS	O
+,	POS	O
+we	POS	O
+noted	POS	O
+aphasia	POS	B-NP
+and	POS	O
+weakness	POS	B-NP
+of	POS	I-NP
+his	POS	I-NP
+left	POS	I-NP
+limbs	POS	I-NP
+.	POS	O
+After	POS	O
+MRI	POS	O
+,	POS	O
+we	POS	O
+found	POS	O
+cerebral	POS	B-NP
+ischemic	POS	I-NP
+infarction	POS	I-NP
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Those	POS	O
+using	POS	O
+methadone	POS	O
+and	POS	O
+heroin	POS	O
+simultaneously	POS	O
+may	POS	O
+increase	POS	O
+risk	POS	O
+of	POS	O
+rhabdomyolysis	POS	B-NP
+and	POS	O
+ischemic	POS	B-NP
+stroke	POS	I-NP
+.	POS	O
+Patients	POS	O
+under	POS	O
+methadone	POS	O
+maintenance	POS	O
+therapy	POS	O
+should	POS	O
+be	POS	O
+warned	POS	O
+regarding	POS	O
+these	POS	O
+serious	POS	O
+adverse	POS	O
+events	POS	O
+.	POS	O
+Hypotheses	POS	O
+of	POS	O
+heroin	POS	O
+-	POS	O
+related	POS	O
+rhabdomyolysis	POS	B-NP
+and	POS	O
+stroke	POS	B-NP
+in	POS	O
+heroin	POS	O
+abusers	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+Increased	POS	O
+vulnerability	POS	O
+to	POS	O
+6	POS	O
+-	POS	O
+hydroxydopamine	POS	O
+lesion	POS	O
+and	POS	O
+reduced	POS	O
+development	POS	O
+of	POS	O
+dyskinesias	POS	B-NP
+in	POS	O
+mice	POS	O
+lacking	POS	O
+CB1	POS	O
+cannabinoid	POS	O
+receptors	POS	O
+.	POS	O
+Motor	POS	B-NP
+impairment	POS	I-NP
+,	POS	O
+dopamine	POS	O
+(	POS	O
+DA	POS	O
+)	POS	O
+neuronal	POS	O
+activity	POS	O
+and	POS	O
+proenkephalin	POS	O
+(	POS	O
+PENK	POS	O
+)	POS	O
+gene	POS	O
+expression	POS	O
+in	POS	O
+the	POS	O
+caudate	POS	O
+-	POS	O
+putamen	POS	O
+(	POS	O
+CPu	POS	O
+)	POS	O
+were	POS	O
+measured	POS	O
+in	POS	O
+6	POS	O
+-	POS	O
+OHDA	POS	O
+-	POS	O
+lesioned	POS	O
+and	POS	O
+treated	POS	O
+(	POS	O
+L	POS	O
+-	POS	O
+DOPA	POS	O
++	POS	O
+benserazide	POS	O
+)	POS	O
+CB1	POS	O
+KO	POS	O
+and	POS	O
+WT	POS	O
+mice	POS	O
+.	POS	O
+A	POS	O
+lesion	POS	O
+induced	POS	O
+by	POS	O
+6	POS	O
+-	POS	O
+OHDA	POS	O
+produced	POS	O
+more	POS	O
+severe	POS	O
+motor	POS	O
+deterioration	POS	O
+in	POS	O
+CB1	POS	O
+KO	POS	O
+mice	POS	O
+accompanied	POS	O
+by	POS	O
+more	POS	O
+loss	POS	O
+of	POS	O
+DA	POS	O
+neurons	POS	O
+and	POS	O
+increased	POS	O
+PENK	POS	O
+gene	POS	O
+expression	POS	O
+in	POS	O
+the	POS	O
+CPu	POS	O
+.	POS	O
+Oxidative	POS	O
+/	POS	O
+nitrosative	POS	O
+and	POS	O
+neuroinflammatory	POS	O
+parameters	POS	O
+were	POS	O
+estimated	POS	O
+in	POS	O
+the	POS	O
+CPu	POS	O
+and	POS	O
+cingulate	POS	O
+cortex	POS	O
+(	POS	O
+Cg	POS	O
+)	POS	O
+.	POS	O
+CB1	POS	O
+KO	POS	O
+mice	POS	O
+exhibited	POS	O
+higher	POS	O
+MDA	POS	O
+levels	POS	O
+and	POS	O
+iNOS	POS	O
+protein	POS	O
+expression	POS	O
+in	POS	O
+the	POS	O
+CPu	POS	O
+and	POS	O
+Cg	POS	O
+compared	POS	O
+to	POS	O
+WT	POS	O
+mice	POS	O
+.	POS	O
+Treatment	POS	O
+with	POS	O
+L	POS	O
+-	POS	O
+DOPA	POS	O
++	POS	O
+benserazide	POS	O
+(	POS	O
+12	POS	O
+weeks	POS	O
+)	POS	O
+resulted	POS	O
+in	POS	O
+less	POS	O
+severe	POS	O
+dyskinesias	POS	B-NP
+in	POS	O
+CB1	POS	O
+KO	POS	O
+than	POS	O
+in	POS	O
+WT	POS	O
+mice	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+revealed	POS	O
+that	POS	O
+the	POS	O
+lack	POS	O
+of	POS	O
+cannabinoid	POS	O
+CB1	POS	O
+receptors	POS	O
+increased	POS	O
+the	POS	O
+severity	POS	O
+of	POS	O
+motor	POS	O
+impairment	POS	O
+and	POS	O
+DA	POS	O
+lesion	POS	O
+,	POS	O
+and	POS	O
+reduced	POS	O
+L	POS	O
+-	POS	O
+DOPA	POS	O
+-	POS	O
+induced	POS	O
+dyskinesias	POS	B-NP
+.	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+activation	POS	O
+of	POS	O
+CB1	POS	O
+receptors	POS	O
+offers	POS	O
+neuroprotection	POS	O
+against	POS	O
+dopaminergic	POS	O
+lesion	POS	O
+and	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+L	POS	O
+-	POS	O
+DOPA	POS	O
+-	POS	O
+induced	POS	O
+dyskinesias	POS	B-NP
+.	POS	O
+Hepatocellular	POS	O
+oxidant	POS	O
+stress	POS	O
+following	POS	O
+intestinal	POS	B-NP
+ischemia	POS	I-NP
+-	POS	O
+reperfusion	POS	B-NP
+injury	POS	I-NP
+.	POS	O
+Reperfusion	POS	O
+of	POS	O
+ischemic	POS	O
+intestine	POS	O
+results	POS	O
+in	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+dysfunction	POS	I-NP
+characterized	POS	O
+by	POS	O
+hepatocellular	POS	O
+enzyme	POS	O
+release	POS	O
+into	POS	O
+plasma	POS	O
+,	POS	O
+reduction	POS	O
+in	POS	O
+bile	POS	O
+flow	POS	O
+rate	POS	O
+,	POS	O
+and	POS	O
+neutrophil	POS	O
+sequestration	POS	O
+within	POS	O
+the	POS	O
+liver	POS	O
+.	POS	O
+The	POS	O
+pathophysiology	POS	O
+underlying	POS	O
+this	POS	O
+acute	POS	O
+hepatic	POS	B-NP
+injury	POS	I-NP
+is	POS	O
+unknown	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+was	POS	O
+undertaken	POS	O
+to	POS	O
+determine	POS	O
+whether	POS	O
+oxidants	POS	O
+are	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+hepatic	POS	B-NP
+injury	POS	I-NP
+and	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+relative	POS	O
+value	POS	O
+of	POS	O
+several	POS	O
+indirect	POS	O
+methods	POS	O
+of	POS	O
+assessing	POS	O
+oxidant	POS	O
+exposure	POS	O
+in	POS	O
+vivo	POS	O
+.	POS	O
+Rats	POS	O
+were	POS	O
+subjected	POS	O
+to	POS	O
+a	POS	O
+standardized	POS	O
+intestinal	POS	O
+ischemia	POS	B-NP
+-	POS	O
+reperfusion	POS	B-NP
+injury	POS	I-NP
+.	POS	O
+Hepatic	POS	O
+tissue	POS	O
+was	POS	O
+assayed	POS	O
+for	POS	O
+lipid	POS	O
+peroxidation	POS	O
+products	POS	O
+and	POS	O
+oxidized	POS	O
+and	POS	O
+reduced	POS	O
+glutathione	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+change	POS	O
+in	POS	O
+hepatic	POS	O
+tissue	POS	O
+total	POS	O
+glutathione	POS	O
+following	POS	O
+intestinal	POS	O
+ischemia	POS	B-NP
+-	POS	O
+reperfusion	POS	B-NP
+injury	POS	I-NP
+.	POS	O
+Oxidized	POS	O
+glutathione	POS	O
+(	POS	O
+GSSG	POS	O
+)	POS	O
+increased	POS	O
+significantly	POS	O
+following	POS	O
+30	POS	O
+and	POS	O
+60	POS	O
+min	POS	O
+of	POS	O
+reperfusion	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+increase	POS	O
+in	POS	O
+any	POS	O
+of	POS	O
+the	POS	O
+products	POS	O
+of	POS	O
+lipid	POS	O
+peroxidation	POS	O
+associated	POS	O
+with	POS	O
+this	POS	O
+injury	POS	O
+.	POS	O
+An	POS	O
+increase	POS	O
+in	POS	O
+GSSG	POS	O
+within	POS	O
+hepatic	POS	O
+tissue	POS	O
+during	POS	O
+intestinal	POS	O
+reperfusion	POS	O
+suggests	POS	O
+exposure	POS	O
+of	POS	O
+hepatocytes	POS	O
+to	POS	O
+an	POS	O
+oxidant	POS	O
+stress	POS	O
+.	POS	O
+The	POS	O
+lack	POS	O
+of	POS	O
+a	POS	O
+significant	POS	O
+increase	POS	O
+in	POS	O
+products	POS	O
+of	POS	O
+lipid	POS	O
+peroxidation	POS	O
+suggests	POS	O
+that	POS	O
+the	POS	O
+oxidant	POS	O
+stress	POS	O
+is	POS	O
+of	POS	O
+insufficient	POS	O
+magnitude	POS	O
+to	POS	O
+result	POS	O
+in	POS	O
+irreversible	POS	O
+injury	POS	O
+to	POS	O
+hepatocyte	POS	O
+cell	POS	O
+membranes	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+also	POS	O
+suggest	POS	O
+that	POS	O
+the	POS	O
+measurement	POS	O
+of	POS	O
+tissue	POS	O
+GSSG	POS	O
+may	POS	O
+be	POS	O
+a	POS	O
+more	POS	O
+sensitive	POS	O
+indicator	POS	O
+of	POS	O
+oxidant	POS	O
+stress	POS	O
+than	POS	O
+measurement	POS	O
+of	POS	O
+products	POS	O
+of	POS	O
+lipid	POS	O
+peroxidation	POS	O
+.	POS	O
+Animal	POS	O
+model	POS	O
+of	POS	O
+mania	POS	B-NP
+induced	POS	O
+by	POS	O
+ouabain	POS	O
+:	POS	O
+Evidence	POS	O
+of	POS	O
+oxidative	POS	O
+stress	POS	O
+in	POS	O
+submitochondrial	POS	O
+particles	POS	O
+of	POS	O
+the	POS	O
+rat	POS	O
+brain	POS	O
+.	POS	O
+The	POS	O
+intracerebroventricular	POS	O
+(	POS	O
+ICV	POS	O
+)	POS	O
+administration	POS	O
+of	POS	O
+ouabain	POS	O
+(	POS	O
+a	POS	O
+Na	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+/	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+ATPase	POS	O
+inhibitor	POS	O
+)	POS	O
+in	POS	O
+rats	POS	O
+has	POS	O
+been	POS	O
+suggested	POS	O
+to	POS	O
+mimic	POS	O
+some	POS	O
+symptoms	POS	O
+of	POS	O
+human	POS	O
+bipolar	POS	B-NP
+mania	POS	I-NP
+.	POS	O
+Clinical	POS	O
+studies	POS	O
+have	POS	O
+shown	POS	O
+that	POS	O
+bipolar	POS	B-NP
+disorder	POS	I-NP
+may	POS	O
+be	POS	O
+related	POS	O
+to	POS	O
+mitochondrial	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+Herein	POS	O
+,	POS	O
+we	POS	O
+investigated	POS	O
+the	POS	O
+behavioral	POS	O
+and	POS	O
+biochemical	POS	O
+effects	POS	O
+induced	POS	O
+by	POS	O
+the	POS	O
+ICV	POS	O
+administration	POS	O
+of	POS	O
+ouabain	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+To	POS	O
+achieve	POS	O
+this	POS	O
+aim	POS	O
+,	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+ouabain	POS	O
+injection	POS	O
+immediately	POS	O
+after	POS	O
+and	POS	O
+7	POS	O
+days	POS	O
+following	POS	O
+a	POS	O
+single	POS	O
+ICV	POS	O
+administration	POS	O
+(	POS	O
+at	POS	O
+concentrations	POS	O
+of	POS	O
+10	POS	O
+(	POS	O
+-	POS	O
+2	POS	O
+)	POS	O
+and	POS	O
+10	POS	O
+(	POS	O
+-	POS	O
+3	POS	O
+)	POS	O
+M	POS	O
+)	POS	O
+on	POS	O
+locomotion	POS	O
+was	POS	O
+measured	POS	O
+using	POS	O
+the	POS	O
+open	POS	O
+-	POS	O
+field	POS	O
+test	POS	O
+.	POS	O
+Additionally	POS	O
+,	POS	O
+thiobarbituric	POS	O
+acid	POS	O
+reactive	POS	O
+substances	POS	O
+(	POS	O
+TBARSs	POS	O
+)	POS	O
+and	POS	O
+superoxide	POS	O
+production	POS	O
+were	POS	O
+measured	POS	O
+in	POS	O
+submitochondrial	POS	O
+particles	POS	O
+of	POS	O
+the	POS	O
+prefrontal	POS	O
+cortex	POS	O
+,	POS	O
+hippocampus	POS	O
+,	POS	O
+striatum	POS	O
+and	POS	O
+amygdala	POS	O
+.	POS	O
+Our	POS	O
+findings	POS	O
+demonstrated	POS	O
+that	POS	O
+ouabain	POS	O
+at	POS	O
+10	POS	O
+(	POS	O
+-	POS	O
+2	POS	O
+)	POS	O
+and	POS	O
+10	POS	O
+(	POS	O
+-	POS	O
+3	POS	O
+)	POS	O
+M	POS	O
+induced	POS	O
+hyperlocomotion	POS	B-NP
+in	POS	O
+rats	POS	O
+,	POS	O
+and	POS	O
+this	POS	O
+response	POS	O
+remained	POS	O
+up	POS	O
+to	POS	O
+7	POS	O
+days	POS	O
+following	POS	O
+a	POS	O
+single	POS	O
+ICV	POS	O
+injection	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+we	POS	O
+observed	POS	O
+that	POS	O
+the	POS	O
+persistent	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+spontaneous	POS	O
+locomotion	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+increased	POS	O
+TBARS	POS	O
+levels	POS	O
+and	POS	O
+superoxide	POS	O
+generation	POS	O
+in	POS	O
+submitochondrial	POS	O
+particles	POS	O
+in	POS	O
+the	POS	O
+prefrontal	POS	O
+cortex	POS	O
+,	POS	O
+striatum	POS	O
+and	POS	O
+amygdala	POS	O
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+ouabain	POS	O
+-	POS	O
+induced	POS	O
+mania	POS	B-NP
+-	POS	O
+like	POS	O
+behavior	POS	O
+may	POS	O
+provide	POS	O
+a	POS	O
+useful	POS	O
+animal	POS	O
+model	POS	O
+to	POS	O
+test	POS	O
+the	POS	O
+hypothesis	POS	O
+of	POS	O
+the	POS	O
+involvement	POS	O
+of	POS	O
+oxidative	POS	O
+stress	POS	O
+in	POS	O
+bipolar	POS	B-NP
+disorder	POS	I-NP
+.	POS	O
+Intraoperative	POS	O
+dialysis	POS	O
+during	POS	O
+liver	POS	O
+transplantation	POS	O
+with	POS	O
+citrate	POS	O
+dialysate	POS	O
+.	POS	O
+Liver	POS	O
+transplantation	POS	O
+for	POS	O
+acutely	POS	O
+ill	POS	O
+patients	POS	O
+with	POS	O
+fulminant	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+carries	POS	O
+high	POS	O
+intraoperative	POS	O
+and	POS	O
+immediate	POS	O
+postoperative	POS	O
+risks	POS	O
+.	POS	O
+These	POS	O
+are	POS	O
+increased	POS	O
+with	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+concomitant	POS	O
+acute	POS	B-NP
+kidney	POS	I-NP
+injury	POS	I-NP
+(	POS	O
+AKI	POS	B-NP
+)	POS	O
+and	POS	O
+intraoperative	POS	O
+dialysis	POS	O
+is	POS	O
+sometimes	POS	O
+required	POS	O
+to	POS	O
+allow	POS	O
+the	POS	O
+transplant	POS	O
+to	POS	O
+proceed	POS	O
+.	POS	O
+The	POS	O
+derangements	POS	O
+in	POS	O
+the	POS	O
+procoagulant	POS	O
+and	POS	O
+anticoagulant	POS	O
+pathways	POS	O
+during	POS	O
+fulminant	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+can	POS	O
+lead	POS	O
+to	POS	O
+difficulties	POS	O
+with	POS	O
+anticoagulation	POS	O
+during	POS	O
+dialysis	POS	O
+,	POS	O
+especially	POS	O
+when	POS	O
+continued	POS	O
+in	POS	O
+the	POS	O
+operating	POS	O
+room	POS	O
+.	POS	O
+Systemic	POS	O
+anticoagulation	POS	O
+is	POS	O
+unsafe	POS	O
+and	POS	O
+regional	POS	O
+citrate	POS	O
+anticoagulation	POS	O
+in	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+a	POS	O
+functional	POS	O
+liver	POS	O
+carries	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+citrate	POS	O
+toxicity	POS	O
+.	POS	O
+Citrate	POS	O
+dialysate	POS	O
+,	POS	O
+a	POS	O
+new	POS	O
+dialysate	POS	O
+with	POS	O
+citric	POS	O
+acid	POS	O
+can	POS	O
+be	POS	O
+used	POS	O
+for	POS	O
+anticoagulation	POS	O
+in	POS	O
+patients	POS	O
+who	POS	O
+cannot	POS	O
+tolerate	POS	O
+heparin	POS	O
+or	POS	O
+regional	POS	O
+citrate	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+40	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+female	POS	O
+with	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+fulminant	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+with	POS	O
+associated	POS	O
+AKI	POS	B-NP
+who	POS	O
+underwent	POS	O
+intraoperative	POS	O
+dialytic	POS	O
+support	POS	O
+during	POS	O
+liver	POS	O
+transplantation	POS	O
+anticoagulated	POS	O
+with	POS	O
+citrate	POS	O
+dialysate	POS	O
+during	POS	O
+the	POS	O
+entire	POS	O
+procedure	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+tolerated	POS	O
+the	POS	O
+procedure	POS	O
+well	POS	O
+without	POS	O
+any	POS	O
+signs	POS	O
+of	POS	O
+citrate	POS	O
+toxicity	POS	B-NP
+and	POS	O
+maintained	POS	O
+adequate	POS	O
+anticoagulation	POS	O
+for	POS	O
+patency	POS	O
+of	POS	O
+the	POS	O
+dialysis	POS	O
+circuit	POS	O
+.	POS	O
+Citrate	POS	O
+dialysate	POS	O
+is	POS	O
+a	POS	O
+safe	POS	O
+alternative	POS	O
+for	POS	O
+intradialytic	POS	O
+support	POS	O
+of	POS	O
+liver	POS	O
+transplantation	POS	O
+in	POS	O
+fulminant	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+Delirium	POS	B-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+toxic	POS	O
+flecainide	POS	O
+plasma	POS	O
+concentrations	POS	O
+:	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+a	POS	O
+pharmacokinetic	POS	O
+drug	POS	O
+interaction	POS	O
+with	POS	O
+paroxetine	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+describe	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+flecainide	POS	O
+-	POS	O
+induced	POS	O
+delirium	POS	B-NP
+associated	POS	O
+with	POS	O
+a	POS	O
+pharmacokinetic	POS	O
+drug	POS	O
+interaction	POS	O
+with	POS	O
+paroxetine	POS	O
+.	POS	O
+CASE	POS	O
+SUMMARY	POS	O
+:	POS	O
+A	POS	O
+69	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+white	POS	O
+female	POS	O
+presented	POS	O
+to	POS	O
+the	POS	O
+emergency	POS	O
+department	POS	O
+with	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+confusion	POS	B-NP
+and	POS	O
+paranoia	POS	B-NP
+over	POS	O
+the	POS	O
+past	POS	O
+several	POS	O
+days	POS	O
+.	POS	O
+On	POS	O
+admission	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+taking	POS	O
+carvedilol	POS	O
+12	POS	O
+mg	POS	O
+twice	POS	O
+daily	POS	O
+,	POS	O
+warfarin	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+,	POS	O
+folic	POS	O
+acid	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+,	POS	O
+levothyroxine	POS	O
+100	POS	O
+microg	POS	O
+/	POS	O
+day	POS	O
+,	POS	O
+pantoprazole	POS	O
+40	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+,	POS	O
+paroxetine	POS	O
+40	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+,	POS	O
+and	POS	O
+flecainide	POS	O
+100	POS	O
+mg	POS	O
+twice	POS	O
+daily	POS	O
+.	POS	O
+Flecainide	POS	O
+had	POS	O
+been	POS	O
+started	POS	O
+2	POS	O
+weeks	POS	O
+prior	POS	O
+for	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+.	POS	O
+Laboratory	POS	O
+test	POS	O
+findings	POS	O
+on	POS	O
+admission	POS	O
+were	POS	O
+notable	POS	O
+only	POS	O
+for	POS	O
+a	POS	O
+flecainide	POS	O
+plasma	POS	O
+concentration	POS	O
+of	POS	O
+1360	POS	O
+microg	POS	O
+/	POS	O
+L	POS	O
+(	POS	O
+reference	POS	O
+range	POS	O
+200	POS	O
+-	POS	O
+1000	POS	O
+)	POS	O
+.	POS	O
+A	POS	O
+metabolic	POS	O
+drug	POS	O
+interaction	POS	O
+between	POS	O
+flecainide	POS	O
+and	POS	O
+paroxetine	POS	O
+,	POS	O
+which	POS	O
+the	POS	O
+patient	POS	O
+had	POS	O
+been	POS	O
+taking	POS	O
+for	POS	O
+more	POS	O
+than	POS	O
+5	POS	O
+years	POS	O
+,	POS	O
+was	POS	O
+considered	POS	O
+.	POS	O
+Paroxetine	POS	O
+was	POS	O
+discontinued	POS	O
+and	POS	O
+the	POS	O
+dose	POS	O
+of	POS	O
+flecainide	POS	O
+was	POS	O
+reduced	POS	O
+to	POS	O
+50	POS	O
+mg	POS	O
+twice	POS	O
+daily	POS	O
+.	POS	O
+Her	POS	O
+delirium	POS	B-NP
+resolved	POS	O
+3	POS	O
+days	POS	O
+later	POS	O
+.	POS	O
+DISCUSSION	POS	O
+:	POS	O
+Flecainide	POS	O
+and	POS	O
+pharmacologically	POS	O
+similar	POS	O
+agents	POS	O
+that	POS	O
+interact	POS	O
+with	POS	O
+sodium	POS	O
+channels	POS	O
+may	POS	O
+cause	POS	O
+delirium	POS	B-NP
+in	POS	O
+susceptible	POS	O
+patients	POS	O
+.	POS	O
+A	POS	O
+MEDLINE	POS	O
+search	POS	O
+(	POS	O
+1966	POS	O
+-	POS	O
+January	POS	O
+2009	POS	O
+)	POS	O
+revealed	POS	O
+one	POS	O
+in	POS	O
+vivo	POS	O
+pharmacokinetic	POS	O
+study	POS	O
+on	POS	O
+the	POS	O
+interaction	POS	O
+between	POS	O
+flecainide	POS	O
+,	POS	O
+a	POS	O
+CYP2D6	POS	O
+substrate	POS	O
+,	POS	O
+and	POS	O
+paroxetine	POS	O
+,	POS	O
+a	POS	O
+CYP2D6	POS	O
+inhibitor	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+3	POS	O
+case	POS	O
+reports	POS	O
+of	POS	O
+flecainide	POS	O
+-	POS	O
+induced	POS	O
+delirium	POS	B-NP
+.	POS	O
+According	POS	O
+to	POS	O
+the	POS	O
+Naranjo	POS	O
+probability	POS	O
+scale	POS	O
+,	POS	O
+flecainide	POS	O
+was	POS	O
+the	POS	O
+probable	POS	O
+cause	POS	O
+of	POS	O
+the	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+delirium	POS	B-NP
+;	POS	O
+the	POS	O
+Horn	POS	O
+Drug	POS	O
+Interaction	POS	O
+Probability	POS	O
+Scale	POS	O
+indicates	POS	O
+a	POS	O
+possible	POS	O
+pharmacokinetic	POS	O
+drug	POS	O
+interaction	POS	O
+between	POS	O
+flecainide	POS	O
+and	POS	O
+paroxetine	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Supratherapeutic	POS	O
+flecainide	POS	O
+plasma	POS	O
+concentrations	POS	O
+may	POS	O
+cause	POS	O
+delirium	POS	B-NP
+.	POS	O
+Because	POS	O
+toxicity	POS	B-NP
+may	POS	O
+occur	POS	O
+when	POS	O
+flecainide	POS	O
+is	POS	O
+prescribed	POS	O
+with	POS	O
+paroxetine	POS	O
+and	POS	O
+other	POS	O
+potent	POS	O
+CYP2D6	POS	O
+inhibitors	POS	O
+,	POS	O
+flecainide	POS	O
+plasma	POS	O
+concentrations	POS	O
+should	POS	O
+be	POS	O
+monitored	POS	O
+closely	POS	O
+with	POS	O
+commencement	POS	O
+of	POS	O
+CYP2D6	POS	O
+inhibitors	POS	O
+.	POS	O
+Efficacy	POS	O
+of	POS	O
+everolimus	POS	O
+(	POS	O
+RAD001	POS	O
+)	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+advanced	POS	O
+NSCLC	POS	B-NP
+previously	POS	O
+treated	POS	O
+with	POS	O
+chemotherapy	POS	O
+alone	POS	O
+or	POS	O
+with	POS	O
+chemotherapy	POS	O
+and	POS	O
+EGFR	POS	O
+inhibitors	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Treatment	POS	O
+options	POS	O
+are	POS	O
+scarce	POS	O
+in	POS	O
+pretreated	POS	O
+advanced	POS	O
+non	POS	B-NP
+-	POS	I-NP
+small	POS	I-NP
+-	POS	I-NP
+cell	POS	I-NP
+lung	POS	I-NP
+cancer	POS	I-NP
+(	POS	O
+NSCLC	POS	B-NP
+)	POS	O
+patients	POS	O
+.	POS	O
+RAD001	POS	O
+,	POS	O
+an	POS	O
+oral	POS	O
+inhibitor	POS	O
+of	POS	O
+the	POS	O
+mammalian	POS	O
+target	POS	O
+of	POS	O
+rapamycin	POS	O
+(	POS	O
+mTOR	POS	O
+)	POS	O
+,	POS	O
+has	POS	O
+shown	POS	O
+phase	POS	O
+I	POS	O
+efficacy	POS	O
+in	POS	O
+NSCLC	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Stage	POS	O
+IIIb	POS	O
+or	POS	O
+IV	POS	O
+NSCLC	POS	B-NP
+patients	POS	O
+,	POS	O
+with	POS	O
+two	POS	O
+or	POS	O
+fewer	POS	O
+prior	POS	O
+chemotherapy	POS	O
+regimens	POS	O
+,	POS	O
+one	POS	O
+platinum	POS	O
+based	POS	O
+(	POS	O
+stratum	POS	O
+1	POS	O
+)	POS	O
+or	POS	O
+both	POS	O
+chemotherapy	POS	O
+and	POS	O
+epidermal	POS	O
+growth	POS	O
+factor	POS	O
+receptor	POS	O
+tyrosine	POS	O
+kinase	POS	O
+inhibitors	POS	O
+(	POS	O
+stratum	POS	O
+2	POS	O
+)	POS	O
+,	POS	O
+received	POS	O
+RAD001	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+until	POS	O
+progression	POS	O
+or	POS	O
+unacceptable	POS	O
+toxicity	POS	B-NP
+.	POS	O
+Primary	POS	O
+objective	POS	O
+was	POS	O
+overall	POS	O
+response	POS	O
+rate	POS	O
+(	POS	O
+ORR	POS	O
+)	POS	O
+.	POS	O
+Analyses	POS	O
+of	POS	O
+markers	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+mTOR	POS	O
+pathway	POS	O
+were	POS	O
+carried	POS	O
+out	POS	O
+on	POS	O
+archival	POS	O
+tumor	POS	B-NP
+from	POS	O
+a	POS	O
+subgroup	POS	O
+using	POS	O
+immunohistochemistry	POS	O
+(	POS	O
+IHC	POS	O
+)	POS	O
+and	POS	O
+direct	POS	O
+mutation	POS	O
+sequencing	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Eighty	POS	O
+-	POS	O
+five	POS	O
+patients	POS	O
+were	POS	O
+enrolled	POS	O
+,	POS	O
+42	POS	O
+in	POS	O
+stratum	POS	O
+1	POS	O
+and	POS	O
+43	POS	O
+in	POS	O
+stratum	POS	O
+.	POS	O
+ORR	POS	O
+was	POS	O
+4	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+(	POS	O
+7	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+stratum	POS	O
+1	POS	O
+;	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+stratum	POS	O
+2	POS	O
+)	POS	O
+.	POS	O
+Overall	POS	O
+disease	POS	O
+control	POS	O
+rate	POS	O
+was	POS	O
+47	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+.	POS	O
+Median	POS	O
+progression	POS	O
+-	POS	O
+free	POS	O
+survivals	POS	O
+(	POS	O
+PFSs	POS	O
+)	POS	O
+were	POS	O
+2	POS	O
+.	POS	O
+6	POS	O
+(	POS	O
+stratum	POS	O
+1	POS	O
+)	POS	O
+and	POS	O
+2	POS	O
+.	POS	O
+7	POS	O
+months	POS	O
+(	POS	O
+stratum	POS	O
+2	POS	O
+)	POS	O
+.	POS	O
+Common	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+grade	POS	O
+3	POS	O
+events	POS	O
+were	POS	O
+fatigue	POS	B-NP
+,	POS	O
+dyspnea	POS	B-NP
+,	POS	O
+stomatitis	POS	B-NP
+,	POS	O
+anemia	POS	B-NP
+,	POS	O
+and	POS	O
+thrombocytopenia	POS	B-NP
+.	POS	O
+Pneumonitis	POS	B-NP
+,	POS	O
+probably	POS	O
+or	POS	O
+possibly	POS	O
+related	POS	O
+,	POS	O
+mainly	POS	O
+grade	POS	O
+1	POS	O
+/	POS	O
+2	POS	O
+,	POS	O
+occurred	POS	O
+in	POS	O
+25	POS	O
+%	POS	O
+.	POS	O
+Cox	POS	O
+regression	POS	O
+analysis	POS	O
+of	POS	O
+IHC	POS	O
+scores	POS	O
+found	POS	O
+that	POS	O
+only	POS	O
+phospho	POS	O
+AKT	POS	O
+(	POS	O
+pAKT	POS	O
+)	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+independent	POS	O
+predictor	POS	O
+of	POS	O
+worse	POS	O
+PFS	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+RAD001	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+was	POS	O
+well	POS	O
+tolerated	POS	O
+,	POS	O
+showing	POS	O
+modest	POS	O
+clinical	POS	O
+activity	POS	O
+in	POS	O
+pretreated	POS	O
+NSCLC	POS	B-NP
+.	POS	O
+Evaluation	POS	O
+of	POS	O
+RAD001	POS	O
+plus	POS	O
+standard	POS	O
+therapy	POS	O
+for	POS	O
+metastatic	POS	O
+NSCLC	POS	B-NP
+continues	POS	O
+.	POS	O
+Posttransplant	POS	B-NP
+anemia	POS	I-NP
+:	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+sirolimus	POS	O
+.	POS	O
+Posttransplant	POS	B-NP
+anemia	POS	I-NP
+is	POS	O
+a	POS	O
+common	POS	O
+problem	POS	O
+that	POS	O
+may	POS	O
+hinder	POS	O
+patients	POS	O
+'	POS	O
+quality	POS	O
+of	POS	O
+life	POS	O
+.	POS	O
+It	POS	O
+occurs	POS	O
+in	POS	O
+12	POS	O
+to	POS	O
+76	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+,	POS	O
+and	POS	O
+is	POS	O
+most	POS	O
+common	POS	O
+in	POS	O
+the	POS	O
+immediate	POS	O
+posttransplant	POS	O
+period	POS	O
+.	POS	O
+A	POS	O
+variety	POS	O
+of	POS	O
+factors	POS	O
+have	POS	O
+been	POS	O
+identified	POS	O
+that	POS	O
+increase	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+posttransplant	POS	O
+anemia	POS	B-NP
+,	POS	O
+of	POS	O
+which	POS	O
+the	POS	O
+level	POS	O
+of	POS	O
+renal	POS	O
+function	POS	O
+is	POS	O
+most	POS	O
+important	POS	O
+.	POS	O
+Sirolimus	POS	O
+,	POS	O
+a	POS	O
+mammalian	POS	O
+target	POS	O
+of	POS	O
+rapamycin	POS	O
+inhibitor	POS	O
+,	POS	O
+has	POS	O
+been	POS	O
+implicated	POS	O
+as	POS	O
+playing	POS	O
+a	POS	O
+special	POS	O
+role	POS	O
+in	POS	O
+posttransplant	POS	O
+anemia	POS	B-NP
+.	POS	O
+This	POS	O
+review	POS	O
+considers	POS	O
+anemia	POS	B-NP
+associated	POS	O
+with	POS	O
+sirolimus	POS	O
+,	POS	O
+including	POS	O
+its	POS	O
+presentation	POS	O
+,	POS	O
+mechanisms	POS	O
+,	POS	O
+and	POS	O
+management	POS	O
+.	POS	O
+Coronary	POS	O
+computerized	POS	O
+tomography	POS	O
+angiography	POS	O
+for	POS	O
+rapid	POS	O
+discharge	POS	O
+of	POS	O
+low	POS	O
+-	POS	O
+risk	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Most	POS	O
+patients	POS	O
+presenting	POS	O
+to	POS	O
+emergency	POS	O
+departments	POS	O
+(	POS	O
+EDs	POS	O
+)	POS	O
+with	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+are	POS	O
+admitted	POS	O
+for	POS	O
+at	POS	O
+least	POS	O
+12	POS	O
+hours	POS	O
+and	POS	O
+receive	POS	O
+a	POS	O
+"	POS	O
+rule	POS	O
+out	POS	O
+acute	POS	O
+coronary	POS	B-NP
+syndrome	POS	I-NP
+"	POS	O
+protocol	POS	O
+,	POS	O
+often	POS	O
+with	POS	O
+noninvasive	POS	O
+testing	POS	O
+prior	POS	O
+to	POS	O
+discharge	POS	O
+.	POS	O
+In	POS	O
+patients	POS	O
+without	POS	O
+cocaine	POS	O
+use	POS	O
+,	POS	O
+coronary	POS	O
+computerized	POS	O
+tomography	POS	O
+angiography	POS	O
+(	POS	O
+CTA	POS	O
+)	POS	O
+has	POS	O
+been	POS	O
+shown	POS	O
+to	POS	O
+be	POS	O
+useful	POS	O
+for	POS	O
+identifying	POS	O
+a	POS	O
+group	POS	O
+of	POS	O
+patients	POS	O
+at	POS	O
+low	POS	O
+risk	POS	O
+for	POS	O
+cardiac	POS	B-NP
+events	POS	I-NP
+who	POS	O
+can	POS	O
+be	POS	O
+safely	POS	O
+discharged	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+unclear	POS	O
+whether	POS	O
+a	POS	O
+coronary	POS	O
+CTA	POS	O
+strategy	POS	O
+would	POS	O
+be	POS	O
+efficacious	POS	O
+in	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+,	POS	O
+as	POS	O
+coronary	POS	B-NP
+vasospasm	POS	I-NP
+may	POS	O
+account	POS	O
+for	POS	O
+some	POS	O
+of	POS	O
+the	POS	O
+ischemia	POS	B-NP
+.	POS	O
+We	POS	O
+studied	POS	O
+whether	POS	O
+a	POS	O
+negative	POS	O
+coronary	POS	O
+CTA	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+could	POS	O
+identify	POS	O
+a	POS	O
+subset	POS	O
+safe	POS	O
+for	POS	O
+discharge	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+prospectively	POS	O
+evaluated	POS	O
+the	POS	O
+safety	POS	O
+of	POS	O
+coronary	POS	O
+CTA	POS	O
+for	POS	O
+low	POS	O
+-	POS	O
+risk	POS	O
+patients	POS	O
+who	POS	O
+presented	POS	O
+to	POS	O
+the	POS	O
+ED	POS	O
+with	POS	O
+cocaineassociated	POS	B-NP
+chest	POS	I-NP
+pain	POS	I-NP
+(	POS	O
+self	POS	O
+-	POS	O
+reported	POS	O
+or	POS	O
+positive	POS	O
+urine	POS	O
+test	POS	O
+)	POS	O
+.	POS	O
+Consecutive	POS	O
+patients	POS	O
+received	POS	O
+either	POS	O
+immediate	POS	O
+coronary	POS	O
+CTA	POS	O
+in	POS	O
+the	POS	O
+ED	POS	O
+(	POS	O
+without	POS	O
+serial	POS	O
+markers	POS	O
+)	POS	O
+or	POS	O
+underwent	POS	O
+coronary	POS	O
+CTA	POS	O
+after	POS	O
+a	POS	O
+brief	POS	O
+observation	POS	O
+period	POS	O
+with	POS	O
+serial	POS	O
+cardiac	POS	O
+marker	POS	O
+measurements	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+negative	POS	O
+coronary	POS	O
+CTA	POS	O
+(	POS	O
+maximal	POS	O
+stenosis	POS	B-NP
+less	POS	O
+than	POS	O
+50	POS	O
+%	POS	O
+)	POS	O
+were	POS	O
+discharged	POS	O
+.	POS	O
+The	POS	O
+main	POS	O
+outcome	POS	O
+was	POS	O
+30	POS	O
+-	POS	O
+day	POS	O
+cardiovascular	POS	O
+death	POS	O
+or	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+59	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+were	POS	O
+evaluated	POS	O
+.	POS	O
+Patients	POS	O
+had	POS	O
+a	POS	O
+mean	POS	O
+age	POS	O
+of	POS	O
+45	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+6	POS	O
+yrs	POS	O
+and	POS	O
+were	POS	O
+86	POS	O
+%	POS	O
+black	POS	O
+,	POS	O
+66	POS	O
+%	POS	O
+male	POS	O
+.	POS	O
+Seventy	POS	O
+-	POS	O
+nine	POS	O
+percent	POS	O
+had	POS	O
+a	POS	O
+normal	POS	O
+or	POS	O
+nonspecific	POS	O
+ECG	POS	O
+and	POS	O
+85	POS	O
+%	POS	O
+had	POS	O
+a	POS	O
+TIMI	POS	B-NP
+score	POS	O
+<	POS	O
+2	POS	O
+.	POS	O
+Twenty	POS	O
+patients	POS	O
+received	POS	O
+coronary	POS	O
+CTA	POS	O
+immediately	POS	O
+in	POS	O
+the	POS	O
+ED	POS	O
+,	POS	O
+18	POS	O
+of	POS	O
+whom	POS	O
+were	POS	O
+discharged	POS	O
+following	POS	O
+CTA	POS	O
+(	POS	O
+90	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Thirty	POS	O
+-	POS	O
+nine	POS	O
+received	POS	O
+coronary	POS	O
+CTA	POS	O
+after	POS	O
+a	POS	O
+brief	POS	O
+observation	POS	O
+period	POS	O
+,	POS	O
+with	POS	O
+37	POS	O
+discharged	POS	O
+home	POS	O
+following	POS	O
+CTA	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Six	POS	O
+patients	POS	O
+had	POS	O
+coronary	POS	B-NP
+stenosis	POS	I-NP
+>	POS	O
+or	POS	O
+=	POS	O
+50	POS	O
+%	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+30	POS	O
+-	POS	O
+day	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+period	POS	O
+,	POS	O
+no	POS	O
+patients	POS	O
+died	POS	O
+of	POS	O
+a	POS	O
+cardiovascular	POS	B-NP
+event	POS	I-NP
+(	POS	O
+0	POS	O
+%	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+,	POS	O
+0	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+no	POS	O
+patient	POS	O
+sustained	POS	O
+a	POS	O
+nonfatal	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+(	POS	O
+0	POS	O
+%	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+,	POS	O
+0	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Although	POS	O
+cocaine	POS	O
+-	POS	O
+associated	POS	O
+myocardial	POS	B-NP
+ischemia	POS	I-NP
+can	POS	O
+result	POS	O
+from	POS	O
+coronary	POS	B-NP
+vasoconstriction	POS	I-NP
+,	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	O
+associated	POS	O
+chest	POS	B-NP
+pain	POS	I-NP
+,	POS	O
+a	POS	O
+non	POS	B-NP
+-	POS	I-NP
+ischemic	POS	I-NP
+ECG	POS	I-NP
+,	POS	O
+and	POS	O
+a	POS	O
+TIMI	POS	B-NP
+risk	POS	O
+score	POS	O
+<	POS	O
+2	POS	O
+may	POS	O
+be	POS	O
+safely	POS	O
+discharged	POS	O
+from	POS	O
+the	POS	O
+ED	POS	O
+after	POS	O
+a	POS	O
+negative	POS	O
+coronary	POS	O
+CTA	POS	O
+with	POS	O
+a	POS	O
+low	POS	O
+risk	POS	O
+of	POS	O
+30	POS	O
+-	POS	O
+day	POS	O
+adverse	POS	O
+events	POS	O
+.	POS	O
+Bilateral	POS	O
+haemorrhagic	POS	B-NP
+infarction	POS	I-NP
+of	POS	O
+the	POS	O
+globus	POS	O
+pallidus	POS	O
+after	POS	O
+cocaine	POS	O
+and	POS	O
+alcohol	POS	B-NP
+intoxication	POS	I-NP
+.	POS	O
+Cocaine	POS	O
+is	POS	O
+a	POS	O
+risk	POS	O
+factor	POS	O
+for	POS	O
+both	POS	O
+ischemic	POS	B-NP
+and	POS	O
+haemorrhagic	POS	B-NP
+stroke	POS	I-NP
+.	POS	O
+We	POS	O
+present	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+31	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+with	POS	O
+bilateral	POS	B-NP
+ischemia	POS	I-NP
+of	POS	O
+the	POS	O
+globus	POS	O
+pallidus	POS	O
+after	POS	O
+excessive	POS	O
+alcohol	POS	O
+and	POS	O
+intranasal	POS	O
+cocaine	POS	O
+use	POS	O
+.	POS	O
+Drug	POS	O
+-	POS	O
+related	POS	O
+globus	POS	O
+pallidus	POS	O
+infarctions	POS	O
+are	POS	O
+most	POS	O
+often	POS	O
+associated	POS	O
+with	POS	O
+heroin	POS	O
+.	POS	O
+Bilateral	POS	O
+basal	POS	O
+ganglia	POS	O
+infarcts	POS	B-NP
+after	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+cocaine	POS	O
+,	POS	O
+without	POS	O
+concurrent	POS	O
+heroin	POS	O
+use	POS	O
+,	POS	O
+have	POS	O
+never	POS	O
+been	POS	O
+reported	POS	O
+.	POS	O
+In	POS	O
+our	POS	O
+patient	POS	O
+,	POS	O
+transient	POS	O
+cardiac	POS	B-NP
+arrhythmia	POS	I-NP
+or	POS	O
+respiratory	POS	B-NP
+dysfunction	POS	I-NP
+related	POS	O
+to	POS	O
+cocaine	POS	O
+and	POS	O
+/	POS	O
+or	POS	O
+ethanol	POS	O
+use	POS	O
+were	POS	O
+the	POS	O
+most	POS	O
+likely	POS	O
+causes	POS	O
+of	POS	O
+cerebral	POS	B-NP
+hypoperfusion	POS	I-NP
+.	POS	O
+Late	POS	O
+fulminant	POS	O
+posterior	POS	O
+reversible	POS	O
+encephalopathy	POS	B-NP
+syndrome	POS	I-NP
+after	POS	O
+liver	POS	O
+transplant	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+Posterior	POS	B-NP
+leukoencephalopathy	POS	I-NP
+due	POS	O
+to	POS	O
+calcineurin	POS	O
+-	POS	O
+inhibitor	POS	O
+-	POS	O
+related	POS	O
+neurotoxicity	POS	B-NP
+is	POS	O
+a	POS	O
+rare	POS	O
+but	POS	O
+severe	POS	O
+complication	POS	O
+that	POS	O
+results	POS	O
+from	POS	O
+treatment	POS	O
+with	POS	O
+immunosuppressive	POS	O
+agents	POS	O
+(	POS	O
+primarily	POS	O
+those	POS	O
+administered	POS	O
+after	POS	O
+a	POS	O
+liver	POS	O
+or	POS	O
+kidney	POS	O
+transplant	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+pathophysiologic	POS	O
+mechanisms	POS	O
+of	POS	O
+that	POS	O
+disorder	POS	O
+remain	POS	O
+unknown	POS	O
+.	POS	O
+CASE	POS	O
+:	POS	O
+We	POS	O
+report	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+46	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+who	POS	O
+received	POS	O
+a	POS	O
+liver	POS	O
+transplant	POS	O
+in	POS	O
+our	POS	O
+center	POS	O
+as	POS	O
+treatment	POS	O
+for	POS	O
+alcoholic	POS	O
+cirrhosis	POS	B-NP
+and	POS	O
+in	POS	O
+whom	POS	O
+either	POS	O
+a	POS	O
+fulminant	POS	B-NP
+course	POS	O
+of	POS	O
+posterior	POS	B-NP
+leukoencephalopathy	POS	I-NP
+or	POS	O
+posterior	POS	O
+reversible	POS	O
+encephalopathy	POS	B-NP
+syndrome	POS	I-NP
+developed	POS	O
+110	POS	O
+days	POS	O
+after	POS	O
+transplant	POS	O
+.	POS	O
+After	POS	O
+an	POS	O
+initially	POS	O
+uneventful	POS	O
+course	POS	O
+after	POS	O
+the	POS	O
+transplant	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+rapidly	POS	O
+fell	POS	O
+into	POS	O
+deep	POS	O
+coma	POS	B-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Cerebral	POS	O
+MRI	POS	O
+scan	POS	O
+showed	POS	O
+typical	POS	O
+signs	POS	O
+of	POS	O
+enhancement	POS	O
+in	POS	O
+the	POS	O
+pontine	POS	O
+and	POS	O
+posterior	POS	O
+regions	POS	O
+.	POS	O
+Switching	POS	O
+the	POS	O
+immunosuppressive	POS	O
+regimen	POS	O
+from	POS	O
+tacrolimus	POS	O
+to	POS	O
+cyclosporine	POS	O
+did	POS	O
+not	POS	O
+improve	POS	O
+the	POS	O
+clinical	POS	O
+situation	POS	O
+.	POS	O
+The	POS	O
+termination	POS	O
+of	POS	O
+treatment	POS	O
+with	POS	O
+any	POS	O
+calcineurin	POS	O
+inhibitor	POS	O
+resulted	POS	O
+in	POS	O
+a	POS	O
+complete	POS	O
+resolution	POS	O
+of	POS	O
+that	POS	O
+complication	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Posterior	POS	O
+reversible	POS	O
+encephalopathy	POS	B-NP
+syndrome	POS	I-NP
+after	POS	O
+liver	POS	O
+transplant	POS	O
+is	POS	O
+rare	POS	O
+.	POS	O
+We	POS	O
+recommend	POS	O
+a	POS	O
+complete	POS	O
+cessation	POS	O
+of	POS	O
+any	POS	O
+calcineurin	POS	O
+inhibitor	POS	O
+rather	POS	O
+than	POS	O
+a	POS	O
+dose	POS	O
+reduction	POS	O
+.	POS	O
+Prolonged	POS	O
+hypothermia	POS	B-NP
+as	POS	O
+a	POS	O
+bridge	POS	O
+to	POS	O
+recovery	POS	O
+for	POS	O
+cerebral	POS	B-NP
+edema	POS	I-NP
+and	POS	O
+intracranial	POS	B-NP
+hypertension	POS	I-NP
+associated	POS	O
+with	POS	O
+fulminant	POS	B-NP
+hepatic	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+To	POS	O
+review	POS	O
+evidence	POS	O
+-	POS	O
+based	POS	O
+treatment	POS	O
+options	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+cerebral	POS	B-NP
+edema	POS	I-NP
+complicating	POS	O
+fulminant	POS	B-NP
+hepatic	POS	I-NP
+failure	POS	I-NP
+(	POS	O
+FHF	POS	B-NP
+)	POS	O
+and	POS	O
+discuss	POS	O
+the	POS	O
+potential	POS	O
+applications	POS	O
+of	POS	O
+hypothermia	POS	B-NP
+.	POS	O
+METHOD	POS	O
+:	POS	O
+Case	POS	O
+-	POS	O
+based	POS	O
+observations	POS	O
+from	POS	O
+a	POS	O
+medical	POS	O
+intensive	POS	O
+care	POS	O
+unit	POS	O
+(	POS	O
+MICU	POS	O
+)	POS	O
+in	POS	O
+a	POS	O
+tertiary	POS	O
+care	POS	O
+facility	POS	O
+in	POS	O
+a	POS	O
+27	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+female	POS	O
+with	POS	O
+FHF	POS	B-NP
+from	POS	O
+acetaminophen	POS	O
+and	POS	O
+resultant	POS	O
+cerebral	POS	B-NP
+edema	POS	I-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Our	POS	O
+patient	POS	O
+was	POS	O
+admitted	POS	O
+to	POS	O
+the	POS	O
+MICU	POS	O
+after	POS	O
+being	POS	O
+found	POS	O
+unresponsive	POS	O
+with	POS	O
+presumed	POS	O
+toxicity	POS	B-NP
+from	POS	O
+acetaminophen	POS	O
+which	POS	O
+was	POS	O
+ingested	POS	O
+over	POS	O
+a	POS	O
+2	POS	O
+-	POS	O
+day	POS	O
+period	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+had	POS	O
+depressed	POS	O
+of	POS	O
+mental	POS	O
+status	POS	O
+lasting	POS	O
+at	POS	O
+least	POS	O
+24	POS	O
+h	POS	O
+prior	POS	O
+to	POS	O
+admission	POS	O
+.	POS	O
+Initial	POS	O
+evaluation	POS	O
+confirmed	POS	O
+FHF	POS	B-NP
+from	POS	O
+acetaminophen	POS	O
+and	POS	O
+cerebral	POS	B-NP
+edema	POS	I-NP
+.	POS	O
+The	POS	O
+patient	POS	O
+was	POS	O
+treated	POS	O
+with	POS	O
+hyperosmolar	POS	O
+therapy	POS	O
+,	POS	O
+hyperventilation	POS	B-NP
+,	POS	O
+sedation	POS	O
+,	POS	O
+and	POS	O
+chemical	POS	O
+paralysis	POS	B-NP
+.	POS	O
+Her	POS	O
+intracranial	POS	O
+pressure	POS	O
+remained	POS	O
+elevated	POS	O
+despite	POS	O
+maximal	POS	O
+medical	POS	O
+therapy	POS	O
+.	POS	O
+We	POS	O
+then	POS	O
+initiated	POS	O
+therapeutic	POS	O
+hypothermia	POS	B-NP
+which	POS	O
+was	POS	O
+continued	POS	O
+for	POS	O
+5	POS	O
+days	POS	O
+.	POS	O
+At	POS	O
+re	POS	O
+-	POS	O
+warming	POS	O
+,	POS	O
+patient	POS	O
+had	POS	O
+resolution	POS	O
+of	POS	O
+her	POS	O
+cerebral	POS	B-NP
+edema	POS	I-NP
+and	POS	O
+intracranial	POS	B-NP
+hypertension	POS	I-NP
+.	POS	O
+At	POS	O
+discharge	POS	O
+,	POS	O
+she	POS	O
+had	POS	O
+complete	POS	O
+recovery	POS	O
+of	POS	O
+neurological	POS	O
+and	POS	O
+hepatic	POS	O
+functions	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+In	POS	O
+patients	POS	O
+with	POS	O
+FHF	POS	B-NP
+and	POS	O
+cerebral	POS	B-NP
+edema	POS	I-NP
+from	POS	O
+acetaminophen	POS	O
+overdose	POS	B-NP
+,	POS	O
+prolonged	POS	O
+therapeutic	POS	O
+hypothermia	POS	B-NP
+could	POS	O
+potentially	POS	O
+be	POS	O
+used	POS	O
+as	POS	O
+a	POS	O
+life	POS	O
+saving	POS	O
+therapy	POS	O
+and	POS	O
+a	POS	O
+bridge	POS	O
+to	POS	O
+hepatic	POS	O
+and	POS	O
+neurological	POS	O
+recovery	POS	O
+.	POS	O
+A	POS	O
+clinical	POS	O
+trial	POS	O
+of	POS	O
+hypothermia	POS	B-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+this	POS	O
+condition	POS	O
+is	POS	O
+warranted	POS	O
+.	POS	O
+Binasal	POS	B-NP
+visual	POS	I-NP
+field	POS	I-NP
+defects	POS	I-NP
+are	POS	O
+not	POS	O
+specific	POS	O
+to	POS	O
+vigabatrin	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+investigated	POS	O
+the	POS	O
+visual	POS	B-NP
+defects	POS	I-NP
+associated	POS	O
+with	POS	O
+the	POS	O
+antiepileptic	POS	O
+drug	POS	O
+vigabatrin	POS	O
+(	POS	O
+VGB	POS	O
+)	POS	O
+.	POS	O
+Two	POS	O
+hundred	POS	O
+four	POS	O
+people	POS	O
+with	POS	O
+epilepsy	POS	B-NP
+were	POS	O
+grouped	POS	O
+on	POS	O
+the	POS	O
+basis	POS	O
+of	POS	O
+antiepileptic	POS	O
+drug	POS	O
+therapy	POS	O
+(	POS	O
+current	POS	O
+,	POS	O
+previous	POS	O
+,	POS	O
+or	POS	O
+no	POS	O
+exposure	POS	O
+to	POS	O
+VGB	POS	O
+)	POS	O
+.	POS	O
+Groups	POS	O
+were	POS	O
+matched	POS	O
+with	POS	O
+respect	POS	O
+to	POS	O
+age	POS	O
+,	POS	O
+gender	POS	O
+,	POS	O
+and	POS	O
+seizure	POS	B-NP
+frequency	POS	O
+.	POS	O
+All	POS	O
+patients	POS	O
+underwent	POS	O
+objective	POS	O
+assessment	POS	O
+of	POS	O
+electrophysiological	POS	O
+function	POS	O
+(	POS	O
+wide	POS	O
+-	POS	O
+field	POS	O
+multifocal	POS	O
+electroretinography	POS	O
+)	POS	O
+and	POS	O
+conventional	POS	O
+visual	POS	O
+field	POS	O
+testing	POS	O
+(	POS	O
+static	POS	O
+perimetry	POS	O
+)	POS	O
+.	POS	O
+Bilateral	POS	B-NP
+visual	POS	I-NP
+field	POS	I-NP
+constriction	POS	I-NP
+was	POS	O
+observed	POS	O
+in	POS	O
+59	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+currently	POS	O
+taking	POS	O
+VGB	POS	O
+,	POS	O
+43	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+who	POS	O
+previously	POS	O
+took	POS	O
+VGB	POS	O
+,	POS	O
+and	POS	O
+24	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+no	POS	O
+exposure	POS	O
+to	POS	O
+VGB	POS	O
+.	POS	O
+Assessment	POS	O
+of	POS	O
+retinal	POS	O
+function	POS	O
+revealed	POS	O
+abnormal	POS	O
+responses	POS	O
+in	POS	O
+48	POS	O
+%	POS	O
+of	POS	O
+current	POS	O
+VGB	POS	O
+users	POS	O
+and	POS	O
+22	POS	O
+%	POS	O
+of	POS	O
+prior	POS	O
+VGB	POS	O
+users	POS	O
+,	POS	O
+but	POS	O
+in	POS	O
+none	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+without	POS	O
+previous	POS	O
+exposure	POS	O
+to	POS	O
+VGB	POS	B-NP
+.	POS	O
+Bilateral	POS	B-NP
+visual	POS	I-NP
+field	POS	I-NP
+abnormalities	POS	I-NP
+are	POS	O
+common	POS	O
+in	POS	O
+the	POS	O
+treated	POS	O
+epilepsy	POS	B-NP
+population	POS	O
+,	POS	O
+irrespective	POS	O
+of	POS	O
+drug	POS	O
+history	POS	O
+.	POS	O
+Assessment	POS	O
+by	POS	O
+conventional	POS	O
+static	POS	O
+perimetry	POS	O
+may	POS	O
+neither	POS	O
+be	POS	O
+sufficiently	POS	O
+sensitive	POS	O
+nor	POS	O
+specific	POS	O
+to	POS	O
+reliably	POS	O
+identify	POS	O
+retinal	POS	B-NP
+toxicity	POS	I-NP
+associated	POS	O
+with	POS	O
+VGB	POS	B-NP
+.	POS	O
+Smoking	POS	O
+of	POS	O
+crack	POS	O
+cocaine	POS	O
+as	POS	O
+a	POS	O
+risk	POS	O
+factor	POS	O
+for	POS	O
+HIV	POS	B-NP
+infection	POS	I-NP
+among	POS	O
+people	POS	O
+who	POS	O
+use	POS	O
+injection	POS	O
+drugs	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Little	POS	O
+is	POS	O
+known	POS	O
+about	POS	O
+the	POS	O
+possible	POS	O
+role	POS	O
+that	POS	O
+smoking	POS	O
+crack	POS	O
+cocaine	POS	O
+has	POS	O
+on	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+HIV	POS	B-NP
+infection	POS	I-NP
+.	POS	O
+Given	POS	O
+the	POS	O
+increasing	POS	O
+use	POS	O
+of	POS	O
+crack	POS	O
+cocaine	POS	O
+,	POS	O
+we	POS	O
+sought	POS	O
+to	POS	O
+examine	POS	O
+whether	POS	O
+use	POS	O
+of	POS	O
+this	POS	O
+illicit	POS	O
+drug	POS	O
+has	POS	O
+become	POS	O
+a	POS	O
+risk	POS	O
+factor	POS	O
+for	POS	O
+HIV	POS	B-NP
+infection	POS	I-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+included	POS	O
+data	POS	O
+from	POS	O
+people	POS	O
+participating	POS	O
+in	POS	O
+the	POS	O
+Vancouver	POS	O
+Injection	POS	O
+Drug	POS	O
+Users	POS	O
+Study	POS	O
+who	POS	O
+reported	POS	O
+injecting	POS	O
+illicit	POS	O
+drugs	POS	O
+at	POS	O
+least	POS	O
+once	POS	O
+in	POS	O
+the	POS	O
+month	POS	O
+before	POS	O
+enrolment	POS	O
+,	POS	O
+lived	POS	O
+in	POS	O
+the	POS	O
+greater	POS	O
+Vancouver	POS	O
+area	POS	O
+,	POS	O
+were	POS	O
+HIV	POS	O
+-	POS	O
+negative	POS	O
+at	POS	O
+enrolment	POS	O
+and	POS	O
+completed	POS	O
+at	POS	O
+least	POS	O
+1	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+study	POS	O
+visit	POS	O
+.	POS	O
+To	POS	O
+determine	POS	O
+whether	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+HIV	POS	B-NP
+seroconversion	POS	I-NP
+among	POS	O
+daily	POS	O
+smokers	POS	O
+of	POS	O
+crack	POS	O
+cocaine	POS	O
+changed	POS	O
+over	POS	O
+time	POS	O
+,	POS	O
+we	POS	O
+used	POS	O
+Cox	POS	O
+proportional	POS	O
+hazards	POS	O
+regression	POS	O
+and	POS	O
+divided	POS	O
+the	POS	O
+study	POS	O
+into	POS	O
+3	POS	O
+periods	POS	O
+:	POS	O
+May	POS	O
+1	POS	O
+,	POS	O
+1996	POS	O
+-	POS	O
+Nov	POS	O
+.	POS	O
+30	POS	O
+,	POS	O
+1999	POS	O
+(	POS	O
+period	POS	O
+1	POS	O
+)	POS	O
+,	POS	O
+Dec	POS	O
+.	POS	O
+1	POS	O
+,	POS	O
+1999	POS	O
+-	POS	O
+Nov	POS	O
+.	POS	O
+30	POS	O
+,	POS	O
+2002	POS	O
+(	POS	O
+period	POS	O
+2	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+Dec	POS	O
+.	POS	O
+1	POS	O
+,	POS	O
+2002	POS	O
+-	POS	O
+Dec	POS	O
+.	POS	O
+30	POS	O
+,	POS	O
+2005	POS	O
+(	POS	O
+period	POS	O
+3	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Overall	POS	O
+,	POS	O
+1048	POS	O
+eligible	POS	O
+injection	POS	O
+drug	POS	O
+users	POS	O
+were	POS	O
+included	POS	O
+in	POS	O
+our	POS	O
+study	POS	O
+.	POS	O
+Of	POS	O
+these	POS	O
+,	POS	O
+137	POS	O
+acquired	POS	O
+HIV	POS	B-NP
+infection	POS	I-NP
+during	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+proportion	POS	O
+of	POS	O
+participants	POS	O
+who	POS	O
+reported	POS	O
+daily	POS	O
+smoking	POS	O
+of	POS	O
+crack	POS	O
+cocaine	POS	O
+increased	POS	O
+from	POS	O
+11	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+in	POS	O
+period	POS	O
+1	POS	O
+to	POS	O
+39	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+in	POS	O
+period	POS	O
+3	POS	O
+.	POS	O
+After	POS	O
+adjusting	POS	O
+for	POS	O
+potential	POS	O
+confounders	POS	O
+,	POS	O
+we	POS	O
+found	POS	O
+that	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+HIV	POS	B-NP
+seroconversion	POS	I-NP
+among	POS	O
+participants	POS	O
+who	POS	O
+were	POS	O
+daily	POS	O
+smokers	POS	O
+of	POS	O
+crack	POS	O
+cocaine	POS	O
+increased	POS	O
+over	POS	O
+time	POS	O
+(	POS	O
+period	POS	O
+1	POS	O
+:	POS	O
+hazard	POS	O
+ratio	POS	O
+[	POS	O
+HR	POS	O
+]	POS	O
+1	POS	O
+.	POS	O
+03	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+[	POS	O
+CI	POS	O
+]	POS	O
+0	POS	O
+.	POS	O
+57	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+85	POS	O
+;	POS	O
+period	POS	O
+2	POS	O
+:	POS	O
+HR	POS	O
+1	POS	O
+.	POS	O
+68	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+1	POS	O
+.	POS	O
+01	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+80	POS	O
+;	POS	O
+and	POS	O
+period	POS	O
+3	POS	O
+:	POS	O
+HR	POS	O
+2	POS	O
+.	POS	O
+74	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+1	POS	O
+.	POS	O
+06	POS	O
+-	POS	O
+7	POS	O
+.	POS	O
+11	POS	O
+)	POS	O
+.	POS	O
+INTERPRETATION	POS	O
+:	POS	O
+Smoking	POS	O
+of	POS	O
+crack	POS	O
+cocaine	POS	O
+was	POS	O
+found	POS	O
+to	POS	O
+be	POS	O
+an	POS	O
+independent	POS	O
+risk	POS	O
+factor	POS	O
+for	POS	O
+HIV	POS	B-NP
+seroconversion	POS	I-NP
+among	POS	O
+people	POS	O
+who	POS	O
+were	POS	O
+injection	POS	O
+drug	POS	O
+users	POS	O
+.	POS	O
+This	POS	O
+finding	POS	O
+points	POS	O
+to	POS	O
+the	POS	O
+urgent	POS	O
+need	POS	O
+for	POS	O
+evidence	POS	O
+-	POS	O
+based	POS	O
+public	POS	O
+health	POS	O
+initiatives	POS	O
+targeted	POS	O
+at	POS	O
+people	POS	O
+who	POS	O
+smoke	POS	O
+crack	POS	O
+cocaine	POS	O
+.	POS	O
+Fluoxetine	POS	O
+improves	POS	O
+the	POS	O
+memory	POS	B-NP
+deficits	POS	I-NP
+caused	POS	O
+by	POS	O
+the	POS	O
+chemotherapy	POS	O
+agent	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+.	POS	O
+Cancer	POS	B-NP
+patients	POS	O
+who	POS	O
+have	POS	O
+been	POS	O
+treated	POS	O
+with	POS	O
+systemic	POS	O
+adjuvant	POS	O
+chemotherapy	POS	O
+have	POS	O
+described	POS	O
+experiencing	POS	O
+deteriorations	POS	O
+in	POS	O
+cognition	POS	O
+.	POS	O
+A	POS	O
+widely	POS	O
+used	POS	O
+chemotherapeutic	POS	O
+agent	POS	O
+,	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+(	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+)	POS	O
+,	POS	O
+readily	POS	O
+crosses	POS	O
+the	POS	O
+blood	POS	O
+-	POS	O
+brain	POS	O
+barrier	POS	O
+and	POS	O
+so	POS	O
+could	POS	O
+have	POS	O
+a	POS	O
+direct	POS	O
+effect	POS	O
+on	POS	O
+brain	POS	O
+function	POS	O
+.	POS	O
+In	POS	O
+particular	POS	O
+this	POS	O
+anti	POS	O
+mitotic	POS	O
+drug	POS	O
+could	POS	O
+reduce	POS	O
+cell	POS	O
+proliferation	POS	O
+in	POS	O
+the	POS	O
+neurogenic	POS	O
+regions	POS	O
+of	POS	O
+the	POS	O
+adult	POS	O
+brain	POS	O
+.	POS	O
+In	POS	O
+contrast	POS	O
+reports	POS	O
+indicate	POS	O
+that	POS	O
+hippocampal	POS	O
+dependent	POS	O
+neurogenesis	POS	O
+and	POS	O
+cognition	POS	O
+are	POS	O
+enhanced	POS	O
+by	POS	O
+the	POS	O
+SSRI	POS	O
+antidepressant	POS	O
+Fluoxetine	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+investigation	POS	O
+the	POS	O
+behavioural	POS	O
+effects	POS	O
+of	POS	O
+chronic	POS	O
+(	POS	O
+two	POS	O
+week	POS	O
+)	POS	O
+treatment	POS	O
+with	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+and	POS	O
+(	POS	O
+three	POS	O
+weeks	POS	O
+)	POS	O
+with	POS	O
+Fluoxetine	POS	O
+either	POS	O
+separately	POS	O
+or	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+were	POS	O
+tested	POS	O
+on	POS	O
+adult	POS	O
+Lister	POS	O
+hooded	POS	O
+rats	POS	O
+.	POS	O
+Behavioural	POS	O
+effects	POS	O
+were	POS	O
+tested	POS	O
+using	POS	O
+a	POS	O
+context	POS	O
+dependent	POS	O
+conditioned	POS	O
+emotional	POS	O
+response	POS	O
+test	POS	O
+(	POS	O
+CER	POS	O
+)	POS	O
+which	POS	O
+showed	POS	O
+that	POS	O
+animals	POS	O
+treated	POS	O
+with	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+had	POS	O
+a	POS	O
+significant	POS	O
+reduction	POS	O
+in	POS	O
+freezing	POS	O
+time	POS	O
+compared	POS	O
+to	POS	O
+controls	POS	O
+.	POS	O
+A	POS	O
+separate	POS	O
+group	POS	O
+of	POS	O
+animals	POS	O
+was	POS	O
+tested	POS	O
+using	POS	O
+a	POS	O
+hippocampal	POS	O
+dependent	POS	O
+spatial	POS	O
+working	POS	O
+memory	POS	O
+test	POS	O
+,	POS	O
+the	POS	O
+object	POS	O
+location	POS	O
+recognition	POS	O
+test	POS	O
+(	POS	O
+OLR	POS	O
+)	POS	O
+.	POS	O
+Animals	POS	O
+treated	POS	O
+only	POS	O
+with	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+showed	POS	O
+significant	POS	O
+deficits	POS	O
+in	POS	O
+their	POS	O
+ability	POS	O
+to	POS	O
+carry	POS	O
+out	POS	O
+the	POS	O
+OLR	POS	O
+task	POS	O
+but	POS	O
+co	POS	O
+administration	POS	O
+of	POS	O
+Fluoxetine	POS	O
+improved	POS	O
+their	POS	O
+performance	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+chemotherapy	POS	O
+caused	POS	O
+a	POS	O
+significant	POS	O
+reduction	POS	O
+in	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+proliferating	POS	O
+cells	POS	O
+in	POS	O
+the	POS	O
+sub	POS	O
+granular	POS	O
+zone	POS	O
+of	POS	O
+the	POS	O
+dentate	POS	O
+gyrus	POS	O
+compared	POS	O
+to	POS	O
+controls	POS	O
+.	POS	O
+This	POS	O
+reduction	POS	O
+was	POS	O
+eliminated	POS	O
+when	POS	O
+Fluoxetine	POS	O
+was	POS	O
+co	POS	O
+administered	POS	O
+with	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+.	POS	O
+Fluoxetine	POS	O
+on	POS	O
+its	POS	O
+own	POS	O
+had	POS	O
+no	POS	O
+effect	POS	O
+on	POS	O
+proliferating	POS	O
+cell	POS	O
+number	POS	O
+or	POS	O
+behaviour	POS	O
+.	POS	O
+These	POS	O
+findings	POS	O
+suggest	POS	O
+that	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+can	POS	O
+negatively	POS	O
+affect	POS	O
+both	POS	O
+cell	POS	O
+proliferation	POS	O
+and	POS	O
+hippocampal	POS	O
+dependent	POS	O
+working	POS	O
+memory	POS	O
+and	POS	O
+that	POS	O
+these	POS	O
+deficits	POS	O
+can	POS	O
+be	POS	O
+reversed	POS	O
+by	POS	O
+the	POS	O
+simultaneous	POS	O
+administration	POS	O
+of	POS	O
+the	POS	O
+antidepressant	POS	O
+Fluoxetine	POS	O
+.	POS	O
+Liver	POS	O
+-	POS	O
+specific	POS	O
+ablation	POS	O
+of	POS	O
+integrin	POS	O
+-	POS	O
+linked	POS	O
+kinase	POS	O
+in	POS	O
+mice	POS	O
+results	POS	O
+in	POS	O
+enhanced	POS	O
+and	POS	O
+prolonged	POS	O
+cell	POS	O
+proliferation	POS	O
+and	POS	O
+hepatomegaly	POS	B-NP
+after	POS	O
+phenobarbital	POS	O
+administration	POS	O
+.	POS	O
+We	POS	O
+have	POS	O
+recently	POS	O
+demonstrated	POS	O
+that	POS	O
+disruption	POS	O
+of	POS	O
+extracellular	POS	O
+matrix	POS	O
+(	POS	O
+ECM	POS	O
+)	POS	O
+/	POS	O
+integrin	POS	O
+signaling	POS	O
+via	POS	O
+elimination	POS	O
+of	POS	O
+integrin	POS	O
+-	POS	O
+linked	POS	O
+kinase	POS	O
+(	POS	O
+ILK	POS	O
+)	POS	O
+in	POS	O
+hepatocytes	POS	O
+interferes	POS	O
+with	POS	O
+signals	POS	O
+leading	POS	O
+to	POS	O
+termination	POS	O
+of	POS	O
+liver	POS	O
+regeneration	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+investigates	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+ILK	POS	O
+in	POS	O
+liver	POS	B-NP
+enlargement	POS	I-NP
+induced	POS	O
+by	POS	O
+phenobarbital	POS	O
+(	POS	O
+PB	POS	O
+)	POS	O
+.	POS	O
+Wild	POS	O
+-	POS	O
+type	POS	O
+(	POS	O
+WT	POS	O
+)	POS	O
+and	POS	O
+ILK	POS	O
+:	POS	O
+liver	POS	O
+-	POS	O
+/	POS	O
+-	POS	O
+mice	POS	O
+were	POS	O
+given	POS	O
+PB	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+in	POS	O
+drinking	POS	O
+water	POS	O
+)	POS	O
+for	POS	O
+10	POS	O
+days	POS	O
+.	POS	O
+Livers	POS	O
+were	POS	O
+harvested	POS	O
+on	POS	O
+2	POS	O
+,	POS	O
+5	POS	O
+,	POS	O
+and	POS	O
+10	POS	O
+days	POS	O
+during	POS	O
+PB	POS	O
+administration	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+hepatocyte	POS	O
+-	POS	O
+specific	POS	O
+ILK	POS	O
+/	POS	O
+liver	POS	O
+-	POS	O
+/	POS	O
+-	POS	O
+mice	POS	O
+,	POS	O
+the	POS	O
+liver	POS	O
+:	POS	O
+body	POS	O
+weight	POS	O
+ratio	POS	O
+was	POS	O
+more	POS	O
+than	POS	O
+double	POS	O
+as	POS	O
+compared	POS	O
+to	POS	O
+0	POS	O
+h	POS	O
+at	POS	O
+day	POS	O
+2	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+times	POS	O
+)	POS	O
+,	POS	O
+while	POS	O
+at	POS	O
+days	POS	O
+5	POS	O
+and	POS	O
+10	POS	O
+,	POS	O
+it	POS	O
+was	POS	O
+enlarged	POS	O
+three	POS	O
+times	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+WT	POS	O
+mice	POS	O
+,	POS	O
+the	POS	O
+increase	POS	O
+was	POS	O
+as	POS	O
+expected	POS	O
+from	POS	O
+previous	POS	O
+literature	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+8	POS	O
+times	POS	O
+)	POS	O
+and	POS	O
+seems	POS	O
+to	POS	O
+have	POS	O
+leveled	POS	O
+off	POS	O
+after	POS	O
+day	POS	O
+2	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+slightly	POS	O
+increased	POS	O
+proliferating	POS	O
+cell	POS	O
+nuclear	POS	O
+antigen	POS	O
+-	POS	O
+positive	POS	O
+cells	POS	O
+in	POS	O
+the	POS	O
+ILK	POS	O
+/	POS	O
+liver	POS	O
+-	POS	O
+/	POS	O
+-	POS	O
+animals	POS	O
+at	POS	O
+day	POS	O
+2	POS	O
+as	POS	O
+compared	POS	O
+to	POS	O
+WT	POS	O
+after	POS	O
+PB	POS	O
+administration	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+WT	POS	O
+animals	POS	O
+,	POS	O
+the	POS	O
+proliferative	POS	O
+response	POS	O
+had	POS	O
+come	POS	O
+back	POS	O
+to	POS	O
+normal	POS	O
+by	POS	O
+days	POS	O
+5	POS	O
+and	POS	O
+10	POS	O
+.	POS	O
+Hepatocytes	POS	O
+of	POS	O
+the	POS	O
+ILK	POS	O
+/	POS	O
+liver	POS	O
+-	POS	O
+/	POS	O
+-	POS	O
+mice	POS	O
+continued	POS	O
+to	POS	O
+proliferate	POS	O
+up	POS	O
+until	POS	O
+day	POS	O
+10	POS	O
+.	POS	O
+ILK	POS	O
+/	POS	O
+liver	POS	O
+-	POS	O
+/	POS	O
+-	POS	O
+mice	POS	O
+also	POS	O
+showed	POS	O
+increased	POS	O
+expression	POS	O
+of	POS	O
+key	POS	O
+genes	POS	O
+involved	POS	O
+in	POS	O
+hepatocyte	POS	O
+proliferation	POS	O
+at	POS	O
+different	POS	O
+time	POS	O
+points	POS	O
+during	POS	O
+PB	POS	O
+administration	POS	O
+.	POS	O
+In	POS	O
+summary	POS	O
+,	POS	O
+ECM	POS	O
+proteins	POS	O
+communicate	POS	O
+with	POS	O
+the	POS	O
+signaling	POS	O
+machinery	POS	O
+of	POS	O
+dividing	POS	O
+cells	POS	O
+via	POS	O
+ILK	POS	O
+to	POS	O
+regulate	POS	O
+hepatocyte	POS	O
+proliferation	POS	O
+and	POS	O
+termination	POS	O
+of	POS	O
+the	POS	O
+proliferative	POS	O
+response	POS	O
+.	POS	O
+Lack	POS	O
+of	POS	O
+ILK	POS	O
+in	POS	O
+the	POS	O
+hepatocytes	POS	O
+imparts	POS	O
+prolonged	POS	O
+proliferative	POS	O
+response	POS	O
+not	POS	O
+only	POS	O
+to	POS	O
+stimuli	POS	O
+related	POS	O
+to	POS	O
+liver	POS	O
+regeneration	POS	O
+but	POS	O
+also	POS	O
+to	POS	O
+xenobiotic	POS	O
+chemical	POS	O
+mitogens	POS	O
+,	POS	O
+such	POS	O
+as	POS	O
+PB	POS	O
+.	POS	O
+Decreased	POS	O
+Expression	POS	O
+of	POS	O
+Na	POS	O
+/	POS	O
+K	POS	O
+-	POS	O
+ATPase	POS	O
+,	POS	O
+NHE3	POS	O
+,	POS	O
+NBC1	POS	O
+,	POS	O
+AQP1	POS	O
+and	POS	O
+OAT	POS	O
+in	POS	O
+Gentamicin	POS	O
+-	POS	O
+induced	POS	O
+Nephropathy	POS	B-NP
+.	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+aimed	POS	O
+to	POS	O
+determine	POS	O
+whether	POS	O
+there	POS	O
+is	POS	O
+an	POS	O
+altered	POS	O
+regulation	POS	O
+of	POS	O
+tubular	POS	O
+transporters	POS	O
+in	POS	O
+gentamicin	POS	O
+-	POS	O
+induced	POS	O
+nephropathy	POS	B-NP
+.	POS	O
+Sprague	POS	O
+-	POS	O
+Dawley	POS	O
+male	POS	O
+rats	POS	O
+(	POS	O
+200	POS	O
+~	POS	O
+250	POS	O
+g	POS	O
+)	POS	O
+were	POS	O
+subcutaneously	POS	O
+injected	POS	O
+with	POS	O
+gentamicin	POS	O
+(	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+per	POS	O
+day	POS	O
+)	POS	O
+for	POS	O
+7	POS	O
+days	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+expression	POS	O
+of	POS	O
+tubular	POS	O
+transporters	POS	O
+was	POS	O
+determined	POS	O
+by	POS	O
+immunoblotting	POS	O
+and	POS	O
+immunohistochemistry	POS	O
+.	POS	O
+The	POS	O
+mRNA	POS	O
+and	POS	O
+protein	POS	O
+expression	POS	O
+of	POS	O
+OAT	POS	O
+was	POS	O
+also	POS	O
+determined	POS	O
+.	POS	O
+Gentamicin	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+exhibited	POS	O
+significantly	POS	O
+decreased	POS	O
+creatinine	POS	O
+clearance	POS	O
+along	POS	O
+with	POS	O
+increased	POS	O
+plasma	POS	O
+creatinine	POS	O
+levels	POS	O
+.	POS	O
+Accordingly	POS	O
+,	POS	O
+the	POS	O
+fractional	POS	O
+excretion	POS	O
+of	POS	O
+sodium	POS	O
+increased	POS	O
+.	POS	O
+Urine	POS	O
+volume	POS	O
+was	POS	O
+increased	POS	O
+,	POS	O
+while	POS	O
+urine	POS	O
+osmolality	POS	O
+and	POS	O
+free	POS	O
+water	POS	O
+reabsorption	POS	O
+were	POS	O
+decreased	POS	O
+.	POS	O
+Immunoblotting	POS	O
+and	POS	O
+immunohistochemistry	POS	O
+revealed	POS	O
+decreased	POS	O
+expression	POS	O
+of	POS	O
+Na	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+/	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+ATPase	POS	O
+,	POS	O
+NHE3	POS	O
+,	POS	O
+NBC1	POS	O
+,	POS	O
+and	POS	O
+AQP1	POS	O
+in	POS	O
+the	POS	O
+kidney	POS	O
+of	POS	O
+gentamicin	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+expression	POS	O
+of	POS	O
+OAT1	POS	O
+and	POS	O
+OAT3	POS	O
+was	POS	O
+also	POS	O
+decreased	POS	O
+.	POS	O
+Gentamicin	POS	O
+-	POS	O
+induced	POS	O
+nephropathy	POS	B-NP
+may	POS	O
+at	POS	O
+least	POS	O
+in	POS	O
+part	POS	O
+be	POS	O
+causally	POS	O
+related	POS	O
+with	POS	O
+a	POS	O
+decreased	POS	O
+expression	POS	O
+of	POS	O
+Na	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+/	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+ATPase	POS	O
+,	POS	O
+NHE3	POS	O
+,	POS	O
+NBC1	POS	O
+,	POS	O
+AQP1	POS	O
+and	POS	O
+OAT	POS	O
+.	POS	O
+Acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+after	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+methotrexate	POS	O
+therapy	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+ileostomy	POS	O
+.	POS	O
+High	POS	O
+-	POS	O
+dose	POS	O
+methotrexate	POS	O
+(	POS	O
+HD	POS	B-NP
+-	POS	O
+MTX	POS	O
+)	POS	O
+is	POS	O
+an	POS	O
+important	POS	O
+treatment	POS	O
+for	POS	O
+Burkitt	POS	B-NP
+lymphoma	POS	I-NP
+,	POS	O
+but	POS	O
+can	POS	O
+cause	POS	O
+hepatic	POS	B-NP
+and	POS	I-NP
+renal	POS	I-NP
+toxicity	POS	I-NP
+when	POS	O
+its	POS	O
+clearance	POS	O
+is	POS	O
+delayed	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+after	POS	O
+HD	POS	B-NP
+-	POS	O
+MTX	POS	O
+therapy	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+ileostomy	POS	O
+,	POS	O
+The	POS	O
+patient	POS	O
+was	POS	O
+a	POS	O
+3	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+boy	POS	O
+who	POS	O
+had	POS	O
+received	POS	O
+a	POS	O
+living	POS	O
+-	POS	O
+related	POS	O
+liver	POS	O
+transplantation	POS	O
+for	POS	O
+congenital	POS	B-NP
+biliary	POS	I-NP
+atresia	POS	I-NP
+.	POS	O
+At	POS	O
+day	POS	O
+833	POS	O
+after	POS	O
+the	POS	O
+transplantation	POS	O
+,	POS	O
+he	POS	O
+was	POS	O
+diagnosed	POS	O
+with	POS	O
+PTLD	POS	B-NP
+(	POS	O
+post	POS	B-NP
+-	POS	I-NP
+transplantation	POS	I-NP
+lymphoproliferative	POS	I-NP
+disorder	POS	I-NP
+,	POS	O
+Burkitt	POS	B-NP
+-	POS	I-NP
+type	POS	I-NP
+malignant	POS	I-NP
+lymphoma	POS	I-NP
+)	POS	O
+.	POS	O
+During	POS	O
+induction	POS	O
+therapy	POS	O
+,	POS	O
+he	POS	O
+suffered	POS	O
+ileal	POS	B-NP
+perforation	POS	I-NP
+and	POS	O
+ileostomy	POS	B-NP
+was	POS	O
+performed	POS	O
+.	POS	O
+Subsequent	POS	O
+HD	POS	B-NP
+-	POS	O
+MTX	POS	O
+therapy	POS	O
+caused	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+that	POS	O
+required	POS	O
+continuous	POS	O
+hemodialysis	POS	O
+.	POS	O
+We	POS	O
+supposed	POS	O
+that	POS	O
+intravascular	POS	B-NP
+hypovolemia	POS	I-NP
+due	POS	O
+to	POS	O
+substantial	POS	O
+drainage	POS	O
+from	POS	O
+the	POS	O
+ileostoma	POS	B-NP
+caused	POS	O
+acute	POS	B-NP
+prerenal	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+After	POS	O
+recovery	POS	O
+of	POS	O
+his	POS	O
+renal	POS	O
+function	POS	O
+,	POS	O
+we	POS	O
+could	POS	O
+safely	POS	O
+treat	POS	O
+the	POS	O
+patient	POS	O
+with	POS	O
+HD	POS	B-NP
+-	POS	O
+MTX	POS	O
+therapy	POS	O
+by	POS	O
+controlling	POS	O
+drainage	POS	O
+from	POS	O
+ileostoma	POS	B-NP
+with	POS	O
+total	POS	O
+parenteral	POS	O
+nutrition	POS	O
+.	POS	O
+Longitudinal	POS	O
+association	POS	O
+of	POS	O
+alcohol	POS	O
+use	POS	O
+with	POS	O
+HIV	POS	B-NP
+disease	POS	I-NP
+progression	POS	O
+and	POS	O
+psychological	POS	O
+health	POS	O
+of	POS	O
+women	POS	O
+with	POS	O
+HIV	POS	B-NP
+.	POS	O
+We	POS	O
+evaluated	POS	O
+the	POS	O
+association	POS	O
+of	POS	O
+alcohol	POS	O
+consumption	POS	O
+and	POS	O
+depression	POS	B-NP
+,	POS	O
+and	POS	O
+their	POS	O
+effects	POS	O
+on	POS	O
+HIV	POS	B-NP
+disease	POS	I-NP
+progression	POS	O
+among	POS	O
+women	POS	O
+with	POS	O
+HIV	POS	B-NP
+.	POS	O
+The	POS	O
+study	POS	O
+included	POS	O
+871	POS	O
+women	POS	O
+with	POS	O
+HIV	POS	B-NP
+who	POS	O
+were	POS	O
+recruited	POS	O
+from	POS	O
+1993	POS	O
+-	POS	O
+1995	POS	O
+in	POS	O
+four	POS	O
+US	POS	O
+cities	POS	O
+.	POS	O
+The	POS	O
+participants	POS	O
+had	POS	O
+physical	POS	O
+examination	POS	O
+,	POS	O
+medical	POS	O
+record	POS	O
+extraction	POS	O
+,	POS	O
+and	POS	O
+venipuncture	POS	O
+,	POS	O
+CD4	POS	O
++	POS	O
+T	POS	O
+-	POS	O
+cell	POS	O
+counts	POS	O
+determination	POS	O
+,	POS	O
+measurement	POS	O
+of	POS	O
+depression	POS	B-NP
+symptoms	POS	O
+(	POS	O
+using	POS	O
+the	POS	O
+self	POS	O
+-	POS	O
+report	POS	O
+Center	POS	O
+for	POS	O
+Epidemiological	POS	O
+Studies	POS	O
+-	POS	O
+Depression	POS	O
+Scale	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+alcohol	POS	O
+use	POS	O
+assessment	POS	O
+at	POS	O
+enrollment	POS	O
+,	POS	O
+and	POS	O
+semiannually	POS	O
+until	POS	O
+March	POS	O
+2000	POS	O
+.	POS	O
+Multilevel	POS	O
+random	POS	O
+coefficient	POS	O
+ordinal	POS	O
+models	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+multilevel	POS	O
+models	POS	O
+with	POS	O
+joint	POS	O
+responses	POS	O
+were	POS	O
+used	POS	O
+in	POS	O
+the	POS	O
+analysis	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+significant	POS	O
+association	POS	O
+between	POS	O
+level	POS	O
+of	POS	O
+alcohol	POS	O
+use	POS	O
+and	POS	O
+CD4	POS	O
++	POS	O
+T	POS	O
+-	POS	O
+cell	POS	O
+counts	POS	O
+.	POS	O
+When	POS	O
+participants	POS	O
+were	POS	O
+stratified	POS	O
+by	POS	O
+antiretroviral	POS	O
+therapy	POS	O
+(	POS	O
+ART	POS	O
+)	POS	O
+use	POS	O
+,	POS	O
+the	POS	O
+association	POS	O
+between	POS	O
+alcohol	POS	O
+and	POS	O
+CD4	POS	O
++	POS	O
+T	POS	O
+-	POS	O
+cell	POS	O
+did	POS	O
+not	POS	O
+reach	POS	O
+statistical	POS	O
+significance	POS	O
+.	POS	O
+The	POS	O
+association	POS	O
+between	POS	O
+alcohol	POS	O
+consumption	POS	O
+and	POS	O
+depression	POS	B-NP
+was	POS	O
+significant	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+Depression	POS	B-NP
+had	POS	O
+a	POS	O
+significant	POS	O
+negative	POS	O
+effect	POS	O
+on	POS	O
+CD4	POS	O
++	POS	O
+T	POS	O
+-	POS	O
+cell	POS	O
+counts	POS	O
+over	POS	O
+time	POS	O
+regardless	POS	O
+of	POS	O
+ART	POS	O
+use	POS	O
+.	POS	O
+Our	POS	O
+findings	POS	O
+suggest	POS	O
+that	POS	O
+alcohol	POS	O
+consumption	POS	O
+has	POS	O
+a	POS	O
+direct	POS	O
+association	POS	O
+with	POS	O
+depression	POS	B-NP
+.	POS	O
+Moreover	POS	O
+,	POS	O
+depression	POS	B-NP
+is	POS	O
+associated	POS	O
+with	POS	O
+HIV	POS	B-NP
+disease	POS	I-NP
+progression	POS	O
+.	POS	O
+Our	POS	O
+findings	POS	O
+have	POS	O
+implications	POS	O
+for	POS	O
+the	POS	O
+provision	POS	O
+of	POS	O
+alcohol	POS	O
+use	POS	O
+interventions	POS	O
+and	POS	O
+psychological	POS	O
+resources	POS	O
+to	POS	O
+improve	POS	O
+the	POS	O
+health	POS	O
+of	POS	O
+women	POS	O
+with	POS	O
+HIV	POS	O
+.	POS	O
+Chemokine	POS	O
+CCL2	POS	O
+and	POS	O
+its	POS	O
+receptor	POS	O
+CCR2	POS	O
+are	POS	O
+increased	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+following	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Neuroinflammation	POS	O
+occurs	POS	O
+after	POS	O
+seizures	POS	B-NP
+and	POS	O
+is	POS	O
+implicated	POS	O
+in	POS	O
+epileptogenesis	POS	B-NP
+.	POS	O
+CCR2	POS	O
+is	POS	O
+a	POS	O
+chemokine	POS	O
+receptor	POS	O
+for	POS	O
+CCL2	POS	O
+and	POS	O
+their	POS	O
+interaction	POS	O
+mediates	POS	O
+monocyte	POS	O
+infiltration	POS	O
+in	POS	O
+the	POS	O
+neuroinflammatory	POS	O
+cascade	POS	O
+triggered	POS	O
+in	POS	O
+different	POS	O
+brain	POS	B-NP
+pathologies	POS	I-NP
+.	POS	O
+In	POS	O
+this	POS	O
+work	POS	O
+CCR2	POS	O
+and	POS	O
+CCL2	POS	O
+expression	POS	O
+were	POS	O
+examined	POS	O
+following	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+(	POS	O
+SE	POS	B-NP
+)	POS	O
+induced	POS	O
+by	POS	O
+pilocarpine	POS	O
+injection	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+SE	POS	B-NP
+was	POS	O
+induced	POS	O
+by	POS	O
+pilocarpine	POS	O
+injection	POS	O
+.	POS	O
+Control	POS	O
+rats	POS	O
+were	POS	O
+injected	POS	O
+with	POS	O
+saline	POS	O
+instead	POS	O
+of	POS	O
+pilocarpine	POS	O
+.	POS	O
+Five	POS	O
+days	POS	O
+after	POS	O
+SE	POS	O
+,	POS	O
+CCR2	POS	O
+staining	POS	O
+in	POS	O
+neurons	POS	O
+and	POS	O
+glial	POS	O
+cells	POS	O
+was	POS	O
+examined	POS	O
+using	POS	O
+imunohistochemical	POS	O
+analyses	POS	O
+.	POS	O
+The	POS	O
+number	POS	O
+of	POS	O
+CCR2	POS	O
+positive	POS	O
+cells	POS	O
+was	POS	O
+determined	POS	O
+using	POS	O
+stereology	POS	O
+probes	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+.	POS	O
+CCL2	POS	O
+expression	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+was	POS	O
+examined	POS	O
+by	POS	O
+molecular	POS	O
+assay	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Increased	POS	O
+CCR2	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+after	POS	O
+SE	POS	B-NP
+.	POS	O
+Seizures	POS	B-NP
+also	POS	O
+resulted	POS	O
+in	POS	O
+alterations	POS	O
+to	POS	O
+the	POS	O
+cell	POS	O
+types	POS	O
+expressing	POS	O
+CCR2	POS	O
+.	POS	O
+Increased	POS	O
+numbers	POS	O
+of	POS	O
+neurons	POS	O
+that	POS	O
+expressed	POS	O
+CCR2	POS	O
+was	POS	O
+observed	POS	O
+following	POS	O
+SE	POS	B-NP
+.	POS	O
+Microglial	POS	O
+cells	POS	O
+were	POS	O
+more	POS	O
+closely	POS	O
+apposed	POS	O
+to	POS	O
+the	POS	O
+CCR2	POS	O
+-	POS	O
+labeled	POS	O
+cells	POS	O
+in	POS	O
+SE	POS	O
+rats	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+rats	POS	O
+that	POS	O
+experienced	POS	O
+SE	POS	O
+exhibited	POS	O
+CCR2	POS	O
+-	POS	O
+labeling	POS	O
+in	POS	O
+populations	POS	O
+of	POS	O
+hypertrophied	POS	O
+astrocytes	POS	O
+,	POS	O
+especially	POS	O
+in	POS	O
+CA1	POS	O
+and	POS	O
+dentate	POS	O
+gyrus	POS	O
+.	POS	O
+These	POS	O
+CCR2	POS	O
++	POS	O
+astroctytes	POS	O
+were	POS	O
+not	POS	O
+observed	POS	O
+in	POS	O
+control	POS	O
+rats	POS	O
+.	POS	O
+Examination	POS	O
+of	POS	O
+CCL2	POS	O
+expression	POS	O
+showed	POS	O
+that	POS	O
+it	POS	O
+was	POS	O
+elevated	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+following	POS	O
+SE	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+The	POS	O
+data	POS	O
+show	POS	O
+that	POS	O
+CCR2	POS	O
+and	POS	O
+CCL2	POS	O
+are	POS	O
+up	POS	O
+-	POS	O
+regulated	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+after	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+SE	POS	B-NP
+.	POS	O
+Seizures	POS	B-NP
+also	POS	O
+result	POS	O
+in	POS	O
+changes	POS	O
+to	POS	O
+CCR2	POS	O
+receptor	POS	O
+expression	POS	O
+in	POS	O
+neurons	POS	O
+and	POS	O
+astrocytes	POS	O
+.	POS	O
+These	POS	O
+changes	POS	O
+might	POS	O
+be	POS	O
+involved	POS	O
+in	POS	O
+detrimental	POS	O
+neuroplasticity	POS	O
+and	POS	O
+neuroinflammatory	POS	O
+changes	POS	O
+that	POS	O
+occur	POS	O
+following	POS	O
+seizures	POS	B-NP
+.	POS	O
+Metallothionein	POS	O
+induction	POS	O
+reduces	POS	O
+caspase	POS	O
+-	POS	O
+3	POS	O
+activity	POS	O
+and	POS	O
+TNFalpha	POS	O
+levels	POS	O
+with	POS	O
+preservation	POS	O
+of	POS	O
+cognitive	POS	O
+function	POS	O
+and	POS	O
+intact	POS	O
+hippocampal	POS	O
+neurons	POS	O
+in	POS	O
+carmustine	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+.	POS	O
+Hippocampal	POS	O
+integrity	POS	O
+is	POS	O
+essential	POS	O
+for	POS	O
+cognitive	POS	O
+functions	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+other	POS	O
+hand	POS	O
+,	POS	O
+induction	POS	O
+of	POS	O
+metallothionein	POS	O
+(	POS	O
+MT	POS	O
+)	POS	O
+by	POS	O
+ZnSO	POS	O
+(	POS	O
+4	POS	O
+)	POS	O
+and	POS	O
+its	POS	O
+role	POS	O
+in	POS	O
+neuroprotection	POS	O
+has	POS	O
+been	POS	O
+documented	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+aimed	POS	O
+to	POS	O
+explore	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+MT	POS	O
+induction	POS	O
+on	POS	O
+carmustine	POS	O
+(	POS	O
+BCNU	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+hippocampal	POS	B-NP
+cognitive	POS	I-NP
+dysfunction	POS	I-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+60	POS	O
+male	POS	O
+Wistar	POS	O
+albino	POS	O
+rats	POS	O
+were	POS	O
+randomly	POS	O
+divided	POS	O
+into	POS	O
+four	POS	O
+groups	POS	O
+(	POS	O
+15	POS	O
+/	POS	O
+group	POS	O
+)	POS	O
+:	POS	O
+The	POS	O
+control	POS	O
+group	POS	O
+injected	POS	O
+with	POS	O
+single	POS	O
+doses	POS	O
+of	POS	O
+normal	POS	O
+saline	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+)	POS	O
+followed	POS	O
+24	POS	O
+h	POS	O
+later	POS	O
+by	POS	O
+BCNU	POS	O
+solvent	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+second	POS	O
+group	POS	O
+administered	POS	O
+ZnSO	POS	O
+(	POS	O
+4	POS	O
+)	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+micromol	POS	O
+/	POS	O
+10	POS	O
+microl	POS	O
+normal	POS	O
+saline	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+,	POS	O
+once	POS	O
+)	POS	O
+then	POS	O
+BCNU	POS	O
+solvent	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+)	POS	O
+after	POS	O
+24	POS	O
+h	POS	O
+.	POS	O
+Third	POS	O
+group	POS	O
+received	POS	O
+BCNU	POS	O
+(	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+,	POS	O
+once	POS	O
+)	POS	O
+24	POS	O
+h	POS	O
+after	POS	O
+injection	POS	O
+with	POS	O
+normal	POS	O
+saline	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+)	POS	O
+.	POS	O
+Fourth	POS	O
+group	POS	O
+received	POS	O
+a	POS	O
+single	POS	O
+dose	POS	O
+of	POS	O
+ZnSO	POS	O
+(	POS	O
+4	POS	O
+)	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+micromol	POS	O
+/	POS	O
+10	POS	O
+microl	POS	O
+normal	POS	O
+saline	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+)	POS	O
+then	POS	O
+BCNU	POS	O
+(	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+,	POS	O
+once	POS	O
+)	POS	O
+after	POS	O
+24	POS	O
+h	POS	O
+.	POS	O
+The	POS	O
+obtained	POS	O
+data	POS	O
+revealed	POS	O
+that	POS	O
+BCNU	POS	O
+administration	POS	O
+resulted	POS	O
+in	POS	O
+deterioration	POS	O
+of	POS	O
+learning	POS	O
+and	POS	O
+short	POS	O
+-	POS	O
+term	POS	O
+memory	POS	O
+(	POS	O
+STM	POS	O
+)	POS	O
+,	POS	O
+as	POS	O
+measured	POS	O
+by	POS	O
+using	POS	O
+radial	POS	O
+arm	POS	O
+water	POS	O
+maze	POS	O
+,	POS	O
+accompanied	POS	O
+with	POS	O
+decreased	POS	O
+hippocampal	POS	O
+glutathione	POS	O
+reductase	POS	O
+(	POS	O
+GR	POS	O
+)	POS	O
+activity	POS	O
+and	POS	O
+reduced	POS	O
+glutathione	POS	O
+(	POS	O
+GSH	POS	O
+)	POS	O
+content	POS	O
+.	POS	O
+Also	POS	O
+,	POS	O
+BCNU	POS	O
+administration	POS	O
+increased	POS	O
+serum	POS	O
+tumor	POS	O
+necrosis	POS	O
+factor	POS	O
+-	POS	O
+alpha	POS	O
+(	POS	O
+TNFalpha	POS	O
+)	POS	O
+,	POS	O
+hippocampal	POS	O
+MT	POS	O
+and	POS	O
+malondialdehyde	POS	O
+(	POS	O
+MDA	POS	O
+)	POS	O
+contents	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+caspase	POS	O
+-	POS	O
+3	POS	O
+activity	POS	O
+in	POS	O
+addition	POS	O
+to	POS	O
+histological	POS	O
+alterations	POS	O
+.	POS	O
+ZnSO	POS	O
+(	POS	O
+4	POS	O
+)	POS	O
+pretreatment	POS	O
+counteracted	POS	O
+BCNU	POS	O
+-	POS	O
+induced	POS	O
+inhibition	POS	O
+of	POS	O
+GR	POS	O
+and	POS	O
+depletion	POS	O
+of	POS	O
+GSH	POS	O
+and	POS	O
+resulted	POS	O
+in	POS	O
+significant	POS	O
+reduction	POS	O
+in	POS	O
+the	POS	O
+levels	POS	O
+of	POS	O
+MDA	POS	O
+and	POS	O
+TNFalpha	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+the	POS	O
+activity	POS	O
+of	POS	O
+caspase	POS	O
+-	POS	O
+3	POS	O
+.	POS	O
+The	POS	O
+histological	POS	O
+features	POS	O
+were	POS	O
+improved	POS	O
+in	POS	O
+hippocampus	POS	O
+of	POS	O
+rats	POS	O
+treated	POS	O
+with	POS	O
+ZnSO	POS	O
+(	POS	O
+4	POS	O
+)	POS	O
++	POS	O
+BCNU	POS	O
+compared	POS	O
+to	POS	O
+only	POS	O
+BCNU	POS	O
+-	POS	O
+treated	POS	O
+animals	POS	O
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+MT	POS	O
+induction	POS	O
+halts	POS	O
+BCNU	POS	O
+-	POS	O
+induced	POS	O
+hippocampal	POS	B-NP
+toxicity	POS	I-NP
+as	POS	O
+it	POS	O
+prevented	POS	O
+GR	POS	O
+inhibition	POS	O
+and	POS	O
+GSH	POS	O
+depletion	POS	O
+and	POS	O
+counteracted	POS	O
+the	POS	O
+increased	POS	O
+levels	POS	O
+of	POS	O
+TNFalpha	POS	O
+,	POS	O
+MDA	POS	O
+and	POS	O
+caspase	POS	O
+-	POS	O
+3	POS	O
+activity	POS	O
+with	POS	O
+subsequent	POS	O
+preservation	POS	O
+of	POS	O
+cognition	POS	O
+.	POS	O
+Fatal	POS	O
+carbamazepine	POS	O
+induced	POS	O
+fulminant	POS	B-NP
+eosinophilic	POS	I-NP
+(	POS	O
+hypersensitivity	POS	B-NP
+)	POS	O
+myocarditis	POS	B-NP
+:	POS	O
+emphasis	POS	O
+on	POS	O
+anatomical	POS	O
+and	POS	O
+histological	POS	O
+characteristics	POS	O
+,	POS	O
+mechanisms	POS	O
+and	POS	O
+genetics	POS	O
+of	POS	O
+drug	POS	O
+hypersensitivity	POS	B-NP
+and	POS	O
+differential	POS	O
+diagnosis	POS	O
+.	POS	O
+The	POS	O
+most	POS	O
+severe	POS	O
+adverse	POS	O
+reactions	POS	O
+to	POS	O
+carbamazepine	POS	O
+have	POS	O
+been	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+haemopoietic	POS	O
+system	POS	O
+,	POS	O
+the	POS	O
+liver	POS	O
+and	POS	O
+the	POS	O
+cardiovascular	POS	O
+system	POS	O
+.	POS	O
+A	POS	O
+frequently	POS	O
+fatal	POS	O
+,	POS	O
+although	POS	O
+exceptionally	POS	O
+rare	POS	O
+side	POS	O
+effect	POS	O
+of	POS	O
+carbamazepine	POS	O
+is	POS	O
+necrotizing	POS	B-NP
+eosinophilic	POS	I-NP
+(	POS	O
+hypersensitivity	POS	B-NP
+)	POS	O
+myocarditis	POS	B-NP
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+hypersensitivity	POS	B-NP
+myocarditis	POS	I-NP
+secondary	POS	O
+to	POS	O
+administration	POS	O
+of	POS	O
+carbamazepine	POS	O
+.	POS	O
+Acute	POS	O
+hypersensitivity	POS	B-NP
+myocarditis	POS	I-NP
+was	POS	O
+not	POS	O
+suspected	POS	O
+clinically	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+diagnosis	POS	O
+was	POS	O
+made	POS	O
+post	POS	O
+-	POS	O
+mortem	POS	O
+.	POS	O
+Histology	POS	O
+revealed	POS	O
+diffuse	POS	O
+infiltration	POS	O
+of	POS	O
+the	POS	O
+myocardium	POS	O
+by	POS	O
+eosinophils	POS	O
+and	POS	O
+lymphocytes	POS	O
+with	POS	O
+myocyte	POS	B-NP
+damage	POS	I-NP
+.	POS	O
+Clinically	POS	O
+,	POS	O
+death	POS	B-NP
+was	POS	O
+due	POS	O
+to	POS	O
+cardiogenic	POS	B-NP
+shock	POS	I-NP
+.	POS	O
+To	POS	O
+best	POS	O
+of	POS	O
+our	POS	O
+knowledge	POS	O
+this	POS	O
+is	POS	O
+the	POS	O
+second	POS	O
+case	POS	O
+of	POS	O
+fatal	POS	O
+carbamazepine	POS	O
+induced	POS	O
+myocarditis	POS	B-NP
+reported	POS	O
+in	POS	O
+English	POS	O
+literature	POS	O
+.	POS	O
+Neuropsychiatric	POS	O
+behaviors	POS	O
+in	POS	O
+the	POS	O
+MPTP	POS	O
+marmoset	POS	O
+model	POS	O
+of	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+Neuropsychiatric	POS	B-NP
+symptoms	POS	I-NP
+are	POS	O
+increasingly	POS	O
+recognised	POS	O
+as	POS	O
+a	POS	O
+significant	POS	O
+problem	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+PD	POS	B-NP
+)	POS	O
+.	POS	O
+These	POS	O
+symptoms	POS	O
+may	POS	O
+be	POS	O
+due	POS	O
+to	POS	O
+'	POS	O
+sensitisation	POS	O
+'	POS	O
+following	POS	O
+repeated	POS	O
+levodopa	POS	O
+treatment	POS	O
+or	POS	O
+a	POS	O
+direct	POS	O
+effect	POS	O
+of	POS	O
+dopamine	POS	O
+on	POS	O
+the	POS	O
+disease	POS	O
+state	POS	O
+.	POS	O
+The	POS	O
+levodopa	POS	O
+-	POS	O
+treated	POS	O
+MPTP	POS	O
+-	POS	O
+lesioned	POS	O
+marmoset	POS	O
+was	POS	O
+used	POS	O
+as	POS	O
+a	POS	O
+model	POS	O
+of	POS	O
+neuropsychiatric	POS	B-NP
+symptoms	POS	I-NP
+in	POS	O
+PD	POS	B-NP
+patients	POS	O
+.	POS	O
+Here	POS	O
+we	POS	O
+compare	POS	O
+the	POS	O
+time	POS	O
+course	POS	O
+of	POS	O
+levodopa	POS	O
+-	POS	O
+induced	POS	O
+motor	POS	O
+fluctuations	POS	O
+and	POS	O
+neuropsychiatric	POS	O
+-	POS	O
+like	POS	O
+behaviors	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+relationship	POS	O
+between	POS	O
+duration	POS	O
+of	POS	O
+treatment	POS	O
+and	POS	O
+onset	POS	O
+of	POS	O
+symptoms	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Marmosets	POS	O
+were	POS	O
+administered	POS	O
+1	POS	O
+-	POS	O
+methyl	POS	O
+-	POS	O
+4	POS	O
+-	POS	O
+phenyl	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+2	POS	O
+,	POS	O
+3	POS	O
+,	POS	O
+6	POS	O
+-	POS	O
+tetrahydropyridine	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+0	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+s	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+)	POS	O
+for	POS	O
+five	POS	O
+days	POS	O
+,	POS	O
+resulting	POS	O
+in	POS	O
+stable	POS	O
+parkinsonism	POS	B-NP
+.	POS	O
+Levodopa	POS	O
+(	POS	O
+15	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+and	POS	O
+benserazide	POS	O
+,	POS	O
+3	POS	O
+.	POS	O
+75	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+p	POS	O
+.	POS	O
+o	POS	O
+.	POS	O
+b	POS	O
+.	POS	O
+i	POS	O
+.	POS	O
+d	POS	O
+,	POS	O
+was	POS	O
+administered	POS	O
+for	POS	O
+30	POS	O
+days	POS	O
+.	POS	O
+Animals	POS	O
+were	POS	O
+evaluated	POS	O
+for	POS	O
+parkinsonian	POS	B-NP
+disability	POS	I-NP
+,	POS	O
+dyskinesia	POS	B-NP
+and	POS	O
+on	POS	O
+-	POS	O
+time	POS	O
+(	POS	O
+motor	POS	O
+fluctuations	POS	O
+)	POS	O
+and	POS	O
+neuropsychiatric	POS	O
+-	POS	O
+like	POS	O
+behaviors	POS	O
+on	POS	O
+Day	POS	O
+0	POS	O
+(	POS	O
+prior	POS	O
+to	POS	O
+levodopa	POS	O
+)	POS	O
+and	POS	O
+on	POS	O
+Days	POS	O
+1	POS	O
+,	POS	O
+7	POS	O
+,	POS	O
+13	POS	O
+,	POS	O
+27	POS	O
+and	POS	O
+30	POS	O
+of	POS	O
+treatment	POS	O
+using	POS	O
+post	POS	O
+hoc	POS	O
+DVD	POS	O
+analysis	POS	O
+by	POS	O
+a	POS	O
+trained	POS	O
+rater	POS	O
+,	POS	O
+blind	POS	O
+to	POS	O
+the	POS	O
+treatment	POS	O
+day	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+neuropsychiatric	POS	O
+-	POS	O
+like	POS	O
+behavior	POS	O
+rating	POS	O
+scale	POS	O
+demonstrated	POS	O
+high	POS	O
+interrater	POS	O
+reliability	POS	O
+between	POS	O
+three	POS	O
+trained	POS	O
+raters	POS	O
+of	POS	O
+differing	POS	O
+professional	POS	O
+backgrounds	POS	O
+.	POS	O
+As	POS	O
+anticipated	POS	O
+,	POS	O
+animals	POS	O
+exhibited	POS	O
+a	POS	O
+progressive	POS	O
+increase	POS	O
+in	POS	O
+levodopa	POS	O
+-	POS	O
+induced	POS	O
+motor	POS	O
+fluctuations	POS	O
+,	POS	O
+dyskinesia	POS	B-NP
+and	POS	O
+wearing	POS	O
+-	POS	O
+off	POS	O
+,	POS	O
+that	POS	O
+correlated	POS	O
+with	POS	O
+the	POS	O
+duration	POS	O
+of	POS	O
+levodopa	POS	O
+therapy	POS	O
+.	POS	O
+In	POS	O
+contrast	POS	O
+,	POS	O
+levodopa	POS	O
+-	POS	O
+induced	POS	O
+neuropsychiatric	POS	B-NP
+-	POS	I-NP
+like	POS	I-NP
+behaviors	POS	I-NP
+were	POS	O
+present	POS	O
+on	POS	O
+Day	POS	O
+1	POS	O
+of	POS	O
+levodopa	POS	O
+treatment	POS	O
+and	POS	O
+their	POS	O
+severity	POS	O
+did	POS	O
+not	POS	O
+correlate	POS	O
+with	POS	O
+duration	POS	O
+of	POS	O
+treatment	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+neuropsychiatric	POS	B-NP
+disorders	POS	I-NP
+in	POS	O
+PD	POS	B-NP
+are	POS	O
+more	POS	O
+likely	POS	O
+an	POS	O
+interaction	POS	O
+between	POS	O
+levodopa	POS	O
+and	POS	O
+the	POS	O
+disease	POS	O
+state	POS	O
+than	POS	O
+a	POS	O
+consequence	POS	O
+of	POS	O
+sensitisation	POS	O
+to	POS	O
+repeated	POS	O
+dopaminergic	POS	O
+therapy	POS	O
+.	POS	O
+Contrast	POS	O
+medium	POS	O
+nephrotoxicity	POS	B-NP
+after	POS	O
+renal	POS	O
+artery	POS	O
+and	POS	O
+coronary	POS	B-NP
+angioplasty	POS	I-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Renal	POS	B-NP
+dysfunction	POS	I-NP
+induced	POS	O
+by	POS	O
+iodinated	POS	O
+contrast	POS	O
+medium	POS	O
+(	POS	O
+CM	POS	O
+)	POS	O
+administration	POS	O
+can	POS	O
+minimize	POS	O
+the	POS	O
+benefit	POS	O
+of	POS	O
+the	POS	O
+interventional	POS	O
+procedure	POS	O
+in	POS	O
+patients	POS	O
+undergoing	POS	O
+renal	POS	O
+angioplasty	POS	O
+(	POS	O
+PTRA	POS	O
+)	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+To	POS	O
+compare	POS	O
+the	POS	O
+susceptibility	POS	O
+to	POS	O
+nephrotoxic	POS	B-NP
+effect	POS	O
+of	POS	O
+CM	POS	B-NP
+in	POS	O
+patients	POS	O
+undergoing	POS	O
+PTRA	POS	O
+with	POS	O
+that	POS	O
+of	POS	O
+patients	POS	O
+submitted	POS	O
+to	POS	O
+percutaneous	POS	O
+coronary	POS	O
+intervention	POS	O
+(	POS	O
+PCI	POS	O
+)	POS	O
+.	POS	O
+MATERIAL	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+33	POS	O
+patients	POS	O
+successfully	POS	O
+treated	POS	O
+with	POS	O
+PTRA	POS	O
+(	POS	O
+PTRA	POS	O
+group	POS	O
+,	POS	O
+mean	POS	O
+age	POS	O
+70	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+12	POS	O
+years	POS	O
+,	POS	O
+23	POS	O
+female	POS	O
+,	POS	O
+basal	POS	O
+creatinine	POS	O
+1	POS	O
+.	POS	O
+46	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+79	POS	O
+,	POS	O
+range	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+9	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+)	POS	O
+were	POS	O
+compared	POS	O
+with	POS	O
+33	POS	O
+patients	POS	O
+undergoing	POS	O
+successful	POS	O
+PCI	POS	O
+(	POS	O
+PCI	POS	O
+group	POS	O
+)	POS	O
+,	POS	O
+matched	POS	O
+for	POS	O
+basal	POS	O
+creatinine	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+44	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+6	POS	O
+,	POS	O
+range	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+-	POS	O
+3	POS	O
+.	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+)	POS	O
+,	POS	O
+gender	POS	O
+,	POS	O
+and	POS	O
+age	POS	O
+.	POS	O
+In	POS	O
+both	POS	O
+groups	POS	O
+postprocedural	POS	O
+(	POS	O
+48	POS	O
+h	POS	O
+)	POS	O
+serum	POS	O
+creatinine	POS	O
+was	POS	O
+measured	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Postprocedural	POS	O
+creatinine	POS	O
+level	POS	O
+decreased	POS	O
+nonsignificantly	POS	O
+in	POS	O
+the	POS	O
+PTRA	POS	O
+group	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+46	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+8	POS	O
+vs	POS	O
+.	POS	O
+1	POS	O
+.	POS	O
+34	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+NS	POS	O
+)	POS	O
+and	POS	O
+increased	POS	O
+significantly	POS	O
+in	POS	O
+the	POS	O
+PCI	POS	O
+group	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+44	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+6	POS	O
+vs	POS	O
+.	POS	O
+1	POS	O
+.	POS	O
+57	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+,	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+.	POS	O
+Changes	POS	O
+in	POS	O
+serum	POS	O
+creatinine	POS	O
+after	POS	O
+intervention	POS	O
+(	POS	O
+after	POS	O
+-	POS	O
+before	POS	O
+)	POS	O
+were	POS	O
+significantly	POS	O
+different	POS	O
+between	POS	O
+the	POS	O
+PTRA	POS	O
+and	POS	O
+PCI	POS	O
+groups	POS	O
+(	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+12	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+vs	POS	O
+.	POS	O
+0	POS	O
+.	POS	O
+13	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+014	POS	O
+)	POS	O
+.	POS	O
+This	POS	O
+difference	POS	O
+was	POS	O
+not	POS	O
+related	POS	O
+to	POS	O
+either	POS	O
+a	POS	O
+different	POS	O
+clinical	POS	O
+risk	POS	O
+profile	POS	O
+or	POS	O
+to	POS	O
+the	POS	O
+volume	POS	O
+of	POS	O
+CM	POS	O
+administered	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+In	POS	O
+this	POS	O
+preliminary	POS	O
+study	POS	O
+patients	POS	O
+submitted	POS	O
+to	POS	O
+PTRA	POS	O
+showed	POS	O
+a	POS	O
+lower	POS	O
+susceptibility	POS	O
+to	POS	O
+renal	POS	B-NP
+damage	POS	I-NP
+induced	POS	O
+by	POS	O
+CM	POS	O
+administration	POS	O
+than	POS	O
+PCI	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+effectiveness	POS	O
+of	POS	O
+PTRA	POS	O
+on	POS	O
+renal	POS	O
+function	POS	O
+seems	POS	O
+to	POS	O
+be	POS	O
+barely	POS	O
+influenced	POS	O
+by	POS	O
+CM	POS	B-NP
+toxicity	POS	I-NP
+.	POS	O
+Diphenhydramine	POS	O
+prevents	POS	O
+the	POS	O
+haemodynamic	POS	O
+changes	POS	O
+of	POS	O
+cimetidine	POS	O
+in	POS	O
+ICU	POS	O
+patients	POS	O
+.	POS	O
+Cimetidine	POS	O
+,	POS	O
+a	POS	O
+histamine	POS	O
+2	POS	O
+(	POS	O
+H2	POS	O
+)	POS	O
+antagonist	POS	O
+,	POS	O
+produces	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+arterial	POS	O
+pressure	POS	O
+due	POS	O
+to	POS	O
+vasodilatation	POS	O
+,	POS	O
+especially	POS	O
+in	POS	O
+critically	POS	O
+ill	POS	O
+patients	POS	O
+.	POS	O
+This	POS	O
+may	POS	O
+be	POS	O
+because	POS	O
+cimetidine	POS	O
+acts	POS	O
+as	POS	O
+a	POS	O
+histamine	POS	O
+agonist	POS	O
+.	POS	O
+We	POS	O
+,	POS	O
+therefore	POS	O
+,	POS	O
+investigated	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+the	POS	O
+histamine	POS	O
+1	POS	O
+(	POS	O
+H1	POS	O
+)	POS	O
+receptor	POS	O
+antagonist	POS	O
+,	POS	O
+diphenhydramine	POS	O
+,	POS	O
+on	POS	O
+the	POS	O
+haemodynamic	POS	O
+changes	POS	O
+observed	POS	O
+after	POS	O
+cimetidine	POS	O
+in	POS	O
+ICU	POS	O
+patients	POS	O
+.	POS	O
+Each	POS	O
+patient	POS	O
+was	POS	O
+studied	POS	O
+on	POS	O
+two	POS	O
+separate	POS	O
+days	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+random	POS	O
+fashion	POS	O
+,	POS	O
+they	POS	O
+received	POS	O
+cimetidine	POS	O
+200	POS	O
+mg	POS	O
+iv	POS	O
+on	POS	O
+one	POS	O
+day	POS	O
+,	POS	O
+and	POS	O
+on	POS	O
+the	POS	O
+other	POS	O
+,	POS	O
+a	POS	O
+pretreatment	POS	O
+of	POS	O
+diphenhydramine	POS	O
+40	POS	O
+mg	POS	O
+iv	POS	O
+with	POS	O
+cimetidine	POS	O
+200	POS	O
+mg	POS	O
+iv	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+non	POS	O
+-	POS	O
+pretreatment	POS	O
+group	POS	O
+,	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+(	POS	O
+MAP	POS	O
+)	POS	O
+decreased	POS	O
+from	POS	O
+107	POS	O
+.	POS	O
+4	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+8	POS	O
+.	POS	O
+4	POS	O
+mmHg	POS	O
+to	POS	O
+86	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+11	POS	O
+.	POS	O
+4	POS	O
+mmHg	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+two	POS	O
+minutes	POS	O
+after	POS	O
+cimetidine	POS	O
+.	POS	O
+Also	POS	O
+,	POS	O
+systemic	POS	O
+vascular	POS	O
+resistance	POS	O
+(	POS	O
+SVR	POS	O
+)	POS	O
+decreased	POS	O
+during	POS	O
+the	POS	O
+eight	POS	O
+-	POS	O
+minute	POS	O
+observation	POS	O
+period	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+contrast	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+pretreatment	POS	O
+group	POS	O
+,	POS	O
+little	POS	O
+haemodynamic	POS	O
+change	POS	O
+was	POS	O
+seen	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+an	POS	O
+H1	POS	O
+antagonist	POS	O
+may	POS	O
+be	POS	O
+useful	POS	O
+in	POS	O
+preventing	POS	O
+hypotension	POS	B-NP
+caused	POS	O
+by	POS	O
+iv	POS	O
+cimetidine	POS	O
+,	POS	O
+since	POS	O
+the	POS	O
+vasodilating	POS	O
+activity	POS	O
+of	POS	O
+cimetidine	POS	O
+is	POS	O
+mediated	POS	O
+,	POS	O
+in	POS	O
+part	POS	O
+,	POS	O
+through	POS	O
+the	POS	O
+H1	POS	O
+receptor	POS	O
+.	POS	O
+Medical	POS	O
+and	POS	O
+psychiatric	POS	O
+outcomes	POS	O
+for	POS	O
+patients	POS	O
+transplanted	POS	O
+for	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+:	POS	O
+a	POS	O
+case	POS	O
+-	POS	O
+control	POS	O
+study	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+hepatotoxicity	POS	B-NP
+is	POS	O
+the	POS	O
+most	POS	O
+common	POS	O
+cause	POS	O
+of	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+(	POS	O
+ALF	POS	B-NP
+)	POS	O
+in	POS	O
+the	POS	O
+UK	POS	O
+.	POS	O
+Patients	POS	O
+often	POS	O
+consume	POS	O
+the	POS	O
+drug	POS	O
+with	POS	O
+suicidal	POS	O
+intent	POS	O
+or	POS	O
+with	POS	O
+a	POS	O
+background	POS	O
+of	POS	O
+substance	POS	O
+dependence	POS	O
+.	POS	O
+AIMS	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+compared	POS	O
+the	POS	O
+severity	POS	O
+of	POS	O
+pretransplant	POS	B-NP
+illness	POS	I-NP
+,	POS	O
+psychiatric	POS	O
+co	POS	O
+-	POS	O
+morbidity	POS	O
+,	POS	O
+medical	POS	O
+and	POS	O
+psychosocial	POS	O
+outcomes	POS	O
+of	POS	O
+all	POS	O
+patients	POS	O
+who	POS	O
+had	POS	O
+undergone	POS	O
+liver	POS	O
+transplantation	POS	O
+(	POS	O
+LT	POS	O
+)	POS	O
+emergently	POS	O
+between	POS	O
+1999	POS	O
+-	POS	O
+2004	POS	O
+for	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+ALF	POS	B-NP
+(	POS	O
+n	POS	O
+=	POS	O
+36	POS	O
+)	POS	O
+with	POS	O
+age	POS	O
+-	POS	O
+and	POS	O
+sex	POS	O
+-	POS	O
+matched	POS	O
+patients	POS	O
+undergoing	POS	O
+emergent	POS	O
+LT	POS	O
+for	POS	O
+non	POS	O
+-	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+ALF	POS	B-NP
+(	POS	O
+n	POS	O
+=	POS	O
+35	POS	O
+)	POS	O
+and	POS	O
+elective	POS	O
+LT	POS	O
+for	POS	O
+chronic	POS	B-NP
+liver	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+CLD	POS	B-NP
+,	POS	O
+n	POS	O
+=	POS	O
+34	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+ALF	POS	B-NP
+patients	POS	O
+undergoing	POS	O
+LT	POS	O
+had	POS	O
+a	POS	O
+greater	POS	O
+severity	POS	O
+of	POS	O
+pre	POS	O
+-	POS	O
+LT	POS	O
+illness	POS	O
+reflected	POS	O
+by	POS	O
+higher	POS	O
+Acute	POS	O
+Physiology	POS	O
+and	POS	O
+Chronic	POS	O
+Health	POS	O
+Evaluation	POS	O
+II	POS	O
+scores	POS	O
+and	POS	O
+requirement	POS	O
+for	POS	O
+organ	POS	O
+support	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+other	POS	O
+two	POS	O
+groups	POS	O
+.	POS	O
+Twenty	POS	O
+(	POS	O
+56	POS	O
+%	POS	O
+)	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+ALF	POS	B-NP
+patients	POS	O
+had	POS	O
+a	POS	O
+formal	POS	O
+psychiatric	POS	O
+diagnosis	POS	O
+before	POS	O
+LT	POS	O
+(	POS	O
+non	POS	O
+-	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+ALF	POS	B-NP
+=	POS	O
+0	POS	O
+/	POS	O
+35	POS	O
+,	POS	O
+CLD	POS	B-NP
+=	POS	O
+2	POS	O
+/	POS	O
+34	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+for	POS	O
+all	POS	O
+)	POS	O
+and	POS	O
+nine	POS	O
+(	POS	O
+25	POS	O
+%	POS	O
+)	POS	O
+had	POS	O
+a	POS	O
+previous	POS	O
+suicide	POS	O
+attempt	POS	O
+.	POS	O
+During	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+(	POS	O
+median	POS	O
+5	POS	O
+years	POS	O
+)	POS	O
+,	POS	O
+there	POS	O
+were	POS	O
+no	POS	O
+significant	POS	O
+differences	POS	O
+in	POS	O
+rejection	POS	O
+(	POS	O
+acute	POS	O
+and	POS	O
+chronic	POS	O
+)	POS	O
+,	POS	O
+graft	POS	B-NP
+failure	POS	I-NP
+or	POS	O
+survival	POS	O
+between	POS	O
+the	POS	O
+groups	POS	O
+(	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+ALF	POS	B-NP
+1	POS	O
+year	POS	O
+87	POS	O
+%	POS	O
+,	POS	O
+5	POS	O
+years	POS	O
+75	POS	O
+%	POS	O
+;	POS	O
+non	POS	O
+-	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+ALF	POS	B-NP
+88	POS	O
+%	POS	O
+,	POS	O
+78	POS	O
+%	POS	O
+;	POS	O
+CLD	POS	B-NP
+93	POS	O
+%	POS	O
+,	POS	O
+82	POS	O
+%	POS	O
+:	POS	O
+P	POS	O
+>	POS	O
+0	POS	O
+.	POS	O
+6	POS	O
+log	POS	O
+rank	POS	O
+)	POS	O
+.	POS	O
+Two	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+ALF	POS	B-NP
+patients	POS	O
+reattempted	POS	O
+suicide	POS	O
+post	POS	O
+-	POS	O
+LT	POS	O
+(	POS	O
+one	POS	O
+died	POS	O
+8	POS	O
+years	POS	O
+post	POS	O
+-	POS	O
+LT	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Despite	POS	O
+a	POS	O
+high	POS	O
+prevalence	POS	O
+of	POS	O
+psychiatric	POS	B-NP
+disturbance	POS	I-NP
+,	POS	O
+outcomes	POS	O
+for	POS	O
+patients	POS	O
+transplanted	POS	O
+emergently	POS	O
+for	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+ALF	POS	B-NP
+were	POS	O
+comparable	POS	O
+to	POS	O
+those	POS	O
+transplanted	POS	O
+for	POS	O
+non	POS	O
+-	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+ALF	POS	B-NP
+and	POS	O
+electively	POS	O
+for	POS	O
+CLD	POS	B-NP
+.	POS	O
+Multidisciplinary	POS	O
+approaches	POS	O
+with	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+psychiatric	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+may	POS	O
+contribute	POS	O
+to	POS	O
+low	POS	O
+post	POS	O
+-	POS	O
+transplant	POS	O
+suicide	POS	O
+rates	POS	O
+seen	POS	O
+and	POS	O
+low	POS	O
+rates	POS	O
+of	POS	O
+graft	POS	B-NP
+loss	POS	I-NP
+because	POS	O
+of	POS	O
+non	POS	O
+-	POS	O
+compliance	POS	O
+.	POS	O
+Antithrombotic	POS	O
+drug	POS	O
+use	POS	O
+,	POS	O
+cerebral	POS	B-NP
+microbleeds	POS	I-NP
+,	POS	O
+and	POS	O
+intracerebral	POS	B-NP
+hemorrhage	POS	I-NP
+:	POS	O
+a	POS	O
+systematic	POS	O
+review	POS	O
+of	POS	O
+published	POS	O
+and	POS	O
+unpublished	POS	O
+studies	POS	O
+.	POS	O
+BACKGROUND	POS	O
+AND	POS	O
+PURPOSE	POS	O
+:	POS	O
+Cerebral	POS	B-NP
+microbleeds	POS	I-NP
+(	POS	O
+MB	POS	B-NP
+)	POS	O
+are	POS	O
+potential	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+intracerebral	POS	B-NP
+hemorrhage	POS	I-NP
+(	POS	O
+ICH	POS	B-NP
+)	POS	O
+,	POS	O
+but	POS	O
+it	POS	O
+is	POS	O
+unclear	POS	O
+if	POS	O
+they	POS	O
+are	POS	O
+a	POS	O
+contraindication	POS	O
+to	POS	O
+using	POS	O
+antithrombotic	POS	O
+drugs	POS	O
+.	POS	O
+Insights	POS	O
+could	POS	O
+be	POS	O
+gained	POS	O
+by	POS	O
+pooling	POS	O
+data	POS	O
+on	POS	O
+MB	POS	B-NP
+frequency	POS	O
+stratified	POS	O
+by	POS	O
+antithrombotic	POS	O
+use	POS	O
+in	POS	O
+cohorts	POS	O
+with	POS	O
+ICH	POS	B-NP
+and	POS	O
+ischemic	POS	B-NP
+stroke	POS	I-NP
+(	POS	O
+IS	POS	O
+)	POS	O
+/	POS	O
+transient	POS	O
+ischemic	POS	B-NP
+attack	POS	I-NP
+(	POS	O
+TIA	POS	B-NP
+)	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+performed	POS	O
+a	POS	O
+systematic	POS	O
+review	POS	O
+of	POS	O
+published	POS	O
+and	POS	O
+unpublished	POS	O
+data	POS	O
+from	POS	O
+cohorts	POS	O
+with	POS	O
+stroke	POS	B-NP
+or	POS	O
+TIA	POS	B-NP
+to	POS	O
+compare	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+MB	POS	B-NP
+in	POS	O
+:	POS	O
+(	POS	O
+1	POS	O
+)	POS	O
+antithrombotic	POS	O
+users	POS	O
+vs	POS	O
+nonantithrombotic	POS	O
+users	POS	O
+with	POS	O
+ICH	POS	B-NP
+;	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+antithrombotic	POS	O
+users	POS	O
+vs	POS	O
+nonusers	POS	O
+with	POS	O
+IS	POS	O
+/	POS	O
+TIA	POS	B-NP
+;	POS	O
+and	POS	O
+(	POS	O
+3	POS	O
+)	POS	O
+ICH	POS	B-NP
+vs	POS	O
+ischemic	POS	B-NP
+events	POS	O
+stratified	POS	O
+by	POS	O
+antithrombotic	POS	O
+use	POS	O
+.	POS	O
+We	POS	O
+also	POS	O
+analyzed	POS	O
+published	POS	O
+and	POS	O
+unpublished	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+data	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+ICH	POS	B-NP
+in	POS	O
+antithrombotic	POS	O
+users	POS	O
+with	POS	O
+MB	POS	B-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+In	POS	O
+a	POS	O
+pooled	POS	O
+analysis	POS	O
+of	POS	O
+1460	POS	O
+ICH	POS	B-NP
+and	POS	O
+3817	POS	O
+IS	POS	O
+/	POS	O
+TIA	POS	B-NP
+,	POS	O
+MB	POS	B-NP
+were	POS	O
+more	POS	O
+frequent	POS	O
+in	POS	O
+ICH	POS	B-NP
+vs	POS	O
+IS	POS	O
+/	POS	O
+TIA	POS	B-NP
+in	POS	O
+all	POS	O
+treatment	POS	O
+groups	POS	O
+,	POS	O
+but	POS	O
+the	POS	O
+excess	POS	O
+increased	POS	O
+from	POS	O
+2	POS	O
+.	POS	O
+8	POS	O
+(	POS	O
+odds	POS	O
+ratio	POS	O
+;	POS	O
+range	POS	O
+,	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
+-	POS	O
+3	POS	O
+.	POS	O
+5	POS	O
+)	POS	O
+in	POS	O
+nonantithrombotic	POS	O
+users	POS	O
+to	POS	O
+5	POS	O
+.	POS	O
+7	POS	O
+(	POS	O
+range	POS	O
+,	POS	O
+3	POS	O
+.	POS	O
+4	POS	O
+-	POS	O
+9	POS	O
+.	POS	O
+7	POS	O
+)	POS	O
+in	POS	O
+antiplatelet	POS	O
+users	POS	O
+and	POS	O
+8	POS	O
+.	POS	O
+0	POS	O
+(	POS	O
+range	POS	O
+,	POS	O
+3	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+17	POS	O
+.	POS	O
+8	POS	O
+)	POS	O
+in	POS	O
+warfarin	POS	O
+users	POS	O
+(	POS	O
+P	POS	O
+difference	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+also	POS	O
+an	POS	O
+excess	POS	O
+of	POS	O
+MB	POS	B-NP
+in	POS	O
+warfarin	POS	O
+users	POS	O
+vs	POS	O
+nonusers	POS	O
+with	POS	O
+ICH	POS	B-NP
+(	POS	O
+OR	POS	O
+,	POS	O
+2	POS	O
+.	POS	O
+7	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+6	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+4	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+but	POS	O
+none	POS	O
+in	POS	O
+warfarin	POS	O
+users	POS	O
+with	POS	O
+IS	POS	O
+/	POS	O
+TIA	POS	B-NP
+(	POS	O
+OR	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+7	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+33	POS	O
+;	POS	O
+P	POS	O
+difference	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+a	POS	O
+smaller	POS	O
+excess	POS	O
+of	POS	O
+MB	POS	B-NP
+in	POS	O
+antiplatelet	POS	O
+users	POS	O
+vs	POS	O
+nonusers	POS	O
+with	POS	O
+ICH	POS	B-NP
+(	POS	O
+OR	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+7	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+but	POS	O
+findings	POS	O
+were	POS	O
+similar	POS	O
+for	POS	O
+antiplatelet	POS	O
+users	POS	O
+with	POS	O
+IS	POS	O
+/	POS	O
+TIA	POS	B-NP
+(	POS	O
+OR	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+4	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+7	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+;	POS	O
+P	POS	O
+difference	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+25	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+pooled	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+data	POS	O
+for	POS	O
+768	POS	O
+antithrombotic	POS	O
+users	POS	O
+,	POS	O
+presence	POS	O
+of	POS	O
+MB	POS	B-NP
+at	POS	O
+baseline	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+a	POS	O
+substantially	POS	O
+increased	POS	O
+risk	POS	O
+of	POS	O
+subsequent	POS	O
+ICH	POS	B-NP
+(	POS	O
+OR	POS	O
+,	POS	O
+12	POS	O
+.	POS	O
+1	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+,	POS	O
+3	POS	O
+.	POS	O
+4	POS	O
+-	POS	O
+42	POS	O
+.	POS	O
+5	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+excess	POS	O
+of	POS	O
+MB	POS	B-NP
+in	POS	O
+warfarin	POS	O
+users	POS	O
+with	POS	O
+ICH	POS	B-NP
+compared	POS	O
+to	POS	O
+other	POS	O
+groups	POS	O
+suggests	POS	O
+that	POS	O
+MB	POS	B-NP
+increase	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+warfarin	POS	O
+-	POS	O
+associated	POS	O
+ICH	POS	B-NP
+.	POS	O
+Limited	POS	O
+prospective	POS	O
+data	POS	O
+corroborate	POS	O
+these	POS	O
+findings	POS	O
+,	POS	O
+but	POS	O
+larger	POS	O
+prospective	POS	O
+studies	POS	O
+are	POS	O
+urgently	POS	O
+required	POS	O
+.	POS	O
+Studies	POS	O
+of	POS	O
+synergy	POS	O
+between	POS	O
+morphine	POS	O
+and	POS	O
+a	POS	O
+novel	POS	O
+sodium	POS	O
+channel	POS	O
+blocker	POS	O
+,	POS	O
+CNSB002	POS	O
+,	POS	O
+in	POS	O
+rat	POS	O
+models	POS	O
+of	POS	O
+inflammatory	POS	O
+and	POS	O
+neuropathic	POS	B-NP
+pain	POS	I-NP
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+This	POS	O
+study	POS	O
+determined	POS	O
+the	POS	O
+antihyperalgesic	POS	O
+effect	POS	O
+of	POS	O
+CNSB002	POS	O
+,	POS	O
+a	POS	O
+sodium	POS	O
+channel	POS	O
+blocker	POS	O
+with	POS	O
+antioxidant	POS	O
+properties	POS	O
+given	POS	O
+alone	POS	O
+and	POS	O
+in	POS	O
+combinations	POS	O
+with	POS	O
+morphine	POS	O
+in	POS	O
+rat	POS	O
+models	POS	O
+of	POS	O
+inflammatory	POS	O
+and	POS	O
+neuropathic	POS	B-NP
+pain	POS	I-NP
+.	POS	O
+DESIGN	POS	O
+:	POS	O
+Dose	POS	O
+response	POS	O
+curves	POS	O
+for	POS	O
+nonsedating	POS	O
+doses	POS	O
+of	POS	O
+morphine	POS	O
+and	POS	O
+CNSB002	POS	O
+given	POS	O
+intraperitoneally	POS	O
+alone	POS	O
+and	POS	O
+together	POS	O
+in	POS	O
+combinations	POS	O
+were	POS	O
+constructed	POS	O
+for	POS	O
+antihyperalgesic	POS	O
+effect	POS	O
+using	POS	O
+paw	POS	O
+withdrawal	POS	O
+from	POS	O
+noxious	POS	O
+heat	POS	O
+in	POS	O
+two	POS	O
+rat	POS	O
+pain	POS	B-NP
+models	POS	O
+:	POS	O
+carrageenan	POS	O
+-	POS	O
+induced	POS	O
+paw	POS	O
+inflammation	POS	B-NP
+and	POS	O
+streptozotocin	POS	O
+(	POS	O
+STZ	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+diabetic	POS	B-NP
+neuropathy	POS	I-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+maximum	POS	O
+nonsedating	POS	O
+doses	POS	O
+were	POS	O
+:	POS	O
+morphine	POS	O
+,	POS	O
+3	POS	O
+.	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+;	POS	O
+CNSB002	POS	O
+10	POS	O
+.	POS	O
+0	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+;	POS	O
+5	POS	O
+.	POS	O
+0	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+CNSB002	POS	O
+with	POS	O
+morphine	POS	O
+3	POS	O
+.	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+in	POS	O
+combination	POS	O
+.	POS	O
+The	POS	O
+doses	POS	O
+calculated	POS	O
+to	POS	O
+cause	POS	O
+50	POS	O
+%	POS	O
+reversal	POS	O
+of	POS	O
+hyperalgesia	POS	B-NP
+(	POS	O
+ED50	POS	O
+)	POS	O
+were	POS	O
+7	POS	O
+.	POS	O
+54	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+81	POS	O
+)	POS	O
+and	POS	O
+4	POS	O
+.	POS	O
+83	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+54	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+carrageenan	POS	O
+model	POS	O
+and	POS	O
+44	POS	O
+.	POS	O
+18	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+37	POS	O
+)	POS	O
+and	POS	O
+9	POS	O
+.	POS	O
+14	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+24	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+STZ	POS	O
+-	POS	O
+induced	POS	O
+neuropathy	POS	B-NP
+model	POS	O
+for	POS	O
+CNSB002	POS	O
+and	POS	O
+morphine	POS	O
+,	POS	O
+respectively	POS	O
+(	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+;	POS	O
+mean	POS	O
+,	POS	O
+SEM	POS	O
+)	POS	O
+.	POS	O
+These	POS	O
+values	POS	O
+were	POS	O
+greater	POS	O
+than	POS	O
+the	POS	O
+maximum	POS	O
+nonsedating	POS	O
+doses	POS	O
+.	POS	O
+The	POS	O
+ED50	POS	O
+values	POS	O
+for	POS	O
+morphine	POS	O
+when	POS	O
+given	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+CNSB002	POS	O
+(	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+were	POS	O
+less	POS	O
+than	POS	O
+the	POS	O
+maximum	POS	O
+nonsedating	POS	O
+dose	POS	O
+:	POS	O
+0	POS	O
+.	POS	O
+56	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+55	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+carrageenan	POS	O
+model	POS	O
+and	POS	O
+1	POS	O
+.	POS	O
+37	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+23	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+neuropathy	POS	B-NP
+model	POS	O
+(	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+;	POS	O
+mean	POS	O
+,	POS	O
+SEM	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+antinociception	POS	O
+after	POS	O
+morphine	POS	O
+(	POS	O
+3	POS	O
+.	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+was	POS	O
+increased	POS	O
+by	POS	O
+co	POS	O
+-	POS	O
+administration	POS	O
+with	POS	O
+CNSB002	POS	O
+from	POS	O
+28	POS	O
+.	POS	O
+0	POS	O
+and	POS	O
+31	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+to	POS	O
+114	POS	O
+.	POS	O
+6	POS	O
+and	POS	O
+56	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+reversal	POS	O
+of	POS	O
+hyperalgesia	POS	B-NP
+in	POS	O
+the	POS	O
+inflammatory	POS	O
+and	POS	O
+neuropathic	POS	B-NP
+models	POS	O
+,	POS	O
+respectively	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+;	POS	O
+one	POS	O
+-	POS	O
+way	POS	O
+analysis	POS	O
+of	POS	O
+variance	POS	O
+-	POS	O
+significantly	POS	O
+greater	POS	O
+than	POS	O
+either	POS	O
+drug	POS	O
+given	POS	O
+alone	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+maximum	POS	O
+antihyperalgesic	POS	O
+effect	POS	O
+achievable	POS	O
+with	POS	O
+nonsedating	POS	O
+doses	POS	O
+of	POS	O
+morphine	POS	O
+may	POS	O
+be	POS	O
+increased	POS	O
+significantly	POS	O
+when	POS	O
+the	POS	O
+drug	POS	O
+is	POS	O
+used	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+CNSB002	POS	O
+.	POS	O
+Heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+:	POS	O
+a	POS	O
+practical	POS	O
+review	POS	O
+.	POS	O
+Heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+(	POS	O
+HIT	POS	B-NP
+)	POS	O
+remains	POS	O
+under	POS	O
+-	POS	O
+recognized	POS	O
+despite	POS	O
+its	POS	O
+potentially	POS	O
+devastating	POS	O
+outcomes	POS	O
+.	POS	O
+It	POS	O
+begins	POS	O
+when	POS	O
+heparin	POS	O
+exposure	POS	O
+stimulates	POS	O
+the	POS	O
+formation	POS	O
+of	POS	O
+heparin	POS	O
+-	POS	O
+platelet	POS	O
+factor	POS	O
+4	POS	O
+antibodies	POS	O
+,	POS	O
+which	POS	O
+in	POS	O
+turn	POS	O
+triggers	POS	O
+the	POS	O
+release	POS	O
+of	POS	O
+procoagulant	POS	O
+platelet	POS	O
+particles	POS	O
+.	POS	O
+Thrombosis	POS	B-NP
+and	POS	O
+thrombocytopenia	POS	B-NP
+that	POS	O
+follow	POS	O
+comprise	POS	O
+the	POS	O
+2	POS	O
+hallmark	POS	O
+traits	POS	O
+of	POS	O
+HIT	POS	B-NP
+,	POS	O
+with	POS	O
+the	POS	O
+former	POS	O
+largely	POS	O
+responsible	POS	O
+for	POS	O
+significant	POS	O
+vascular	POS	B-NP
+complications	POS	I-NP
+.	POS	O
+The	POS	O
+prevalence	POS	O
+of	POS	O
+HIT	POS	B-NP
+varies	POS	O
+among	POS	O
+several	POS	O
+subgroups	POS	O
+,	POS	O
+with	POS	O
+greater	POS	O
+incidence	POS	O
+in	POS	O
+surgical	POS	O
+as	POS	O
+compared	POS	O
+with	POS	O
+medical	POS	O
+populations	POS	O
+.	POS	O
+HIT	POS	B-NP
+must	POS	O
+be	POS	O
+acknowledged	POS	O
+for	POS	O
+its	POS	O
+intense	POS	O
+predilection	POS	O
+for	POS	O
+thrombosis	POS	B-NP
+and	POS	O
+suspected	POS	O
+whenever	POS	O
+thrombosis	POS	B-NP
+occurs	POS	O
+after	POS	O
+heparin	POS	O
+exposure	POS	O
+.	POS	O
+Early	POS	O
+recognition	POS	O
+that	POS	O
+incorporates	POS	O
+the	POS	O
+clinical	POS	O
+and	POS	O
+serologic	POS	O
+clues	POS	O
+is	POS	O
+paramount	POS	O
+to	POS	O
+timely	POS	O
+institution	POS	O
+of	POS	O
+treatment	POS	O
+,	POS	O
+as	POS	O
+its	POS	O
+delay	POS	O
+may	POS	O
+result	POS	O
+in	POS	O
+catastrophic	POS	O
+outcomes	POS	O
+.	POS	O
+The	POS	O
+treatment	POS	O
+of	POS	O
+HIT	POS	B-NP
+mandates	POS	O
+an	POS	O
+immediate	POS	O
+cessation	POS	O
+of	POS	O
+all	POS	O
+heparin	POS	O
+exposure	POS	O
+and	POS	O
+the	POS	O
+institution	POS	O
+of	POS	O
+an	POS	O
+antithrombotic	POS	O
+therapy	POS	O
+,	POS	O
+most	POS	O
+commonly	POS	O
+using	POS	O
+a	POS	O
+direct	POS	O
+thrombin	POS	O
+inhibitor	POS	O
+.	POS	O
+Current	POS	O
+"	POS	O
+diagnostic	POS	O
+"	POS	O
+tests	POS	O
+,	POS	O
+which	POS	O
+primarily	POS	O
+include	POS	O
+functional	POS	O
+and	POS	O
+antigenic	POS	O
+assays	POS	O
+,	POS	O
+have	POS	O
+more	POS	O
+of	POS	O
+a	POS	O
+confirmatory	POS	O
+than	POS	O
+diagnostic	POS	O
+role	POS	O
+in	POS	O
+the	POS	O
+management	POS	O
+of	POS	O
+HIT	POS	B-NP
+.	POS	O
+Special	POS	O
+attention	POS	O
+must	POS	O
+be	POS	O
+paid	POS	O
+to	POS	O
+cardiac	POS	O
+patients	POS	O
+who	POS	O
+are	POS	O
+often	POS	O
+exposed	POS	O
+to	POS	O
+heparin	POS	O
+multiple	POS	O
+times	POS	O
+during	POS	O
+their	POS	O
+course	POS	O
+of	POS	O
+treatment	POS	O
+.	POS	O
+Direct	POS	O
+thrombin	POS	O
+inhibitors	POS	O
+are	POS	O
+appropriate	POS	O
+,	POS	O
+evidence	POS	O
+-	POS	O
+based	POS	O
+alternatives	POS	O
+to	POS	O
+heparin	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+HIT	POS	B-NP
+,	POS	O
+who	POS	O
+need	POS	O
+to	POS	O
+undergo	POS	O
+percutaneous	POS	O
+coronary	POS	O
+intervention	POS	O
+.	POS	O
+As	POS	O
+heparin	POS	O
+remains	POS	O
+one	POS	O
+of	POS	O
+the	POS	O
+most	POS	O
+frequently	POS	O
+used	POS	O
+medications	POS	O
+today	POS	O
+with	POS	O
+potential	POS	O
+for	POS	O
+HIT	POS	B-NP
+with	POS	O
+every	POS	O
+heparin	POS	O
+exposure	POS	O
+,	POS	O
+a	POS	O
+close	POS	O
+vigilance	POS	O
+of	POS	O
+platelet	POS	O
+counts	POS	O
+must	POS	O
+be	POS	O
+practiced	POS	O
+whenever	POS	O
+heparin	POS	O
+is	POS	O
+initiated	POS	O
+.	POS	O
+Abductor	POS	B-NP
+paralysis	POS	I-NP
+after	POS	O
+botox	POS	O
+injection	POS	O
+for	POS	O
+adductor	POS	B-NP
+spasmodic	POS	I-NP
+dysphonia	POS	I-NP
+.	POS	O
+OBJECTIVES	POS	O
+/	POS	O
+HYPOTHESIS	POS	O
+:	POS	O
+Botulinum	POS	O
+toxin	POS	O
+(	POS	O
+Botox	POS	O
+)	POS	O
+injections	POS	O
+into	POS	O
+the	POS	O
+thyroarytenoid	POS	O
+muscles	POS	O
+are	POS	O
+the	POS	O
+current	POS	O
+standard	POS	O
+of	POS	O
+care	POS	O
+for	POS	O
+adductor	POS	B-NP
+spasmodic	POS	I-NP
+dysphonia	POS	I-NP
+(	POS	O
+ADSD	POS	B-NP
+)	POS	O
+.	POS	O
+Reported	POS	O
+adverse	POS	O
+effects	POS	O
+include	POS	O
+a	POS	O
+period	POS	O
+of	POS	O
+breathiness	POS	B-NP
+,	POS	O
+throat	POS	B-NP
+pain	POS	I-NP
+,	POS	O
+and	POS	O
+difficulty	POS	O
+with	POS	O
+swallowing	POS	O
+liquids	POS	O
+.	POS	O
+Here	POS	O
+we	POS	O
+report	POS	O
+multiple	POS	O
+cases	POS	O
+of	POS	O
+bilateral	POS	B-NP
+abductor	POS	I-NP
+paralysis	POS	I-NP
+following	POS	O
+Botox	POS	O
+injections	POS	O
+for	POS	O
+ADSD	POS	B-NP
+,	POS	O
+a	POS	O
+complication	POS	O
+previously	POS	O
+unreported	POS	O
+.	POS	O
+STUDY	POS	O
+DESIGN	POS	O
+:	POS	O
+Retrospective	POS	O
+case	POS	O
+series	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Patients	POS	O
+that	POS	O
+received	POS	O
+Botox	POS	O
+injections	POS	O
+for	POS	O
+spasmodic	POS	B-NP
+dysphonia	POS	I-NP
+between	POS	O
+January	POS	O
+2000	POS	O
+and	POS	O
+October	POS	O
+2009	POS	O
+were	POS	O
+evaluated	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+ADSD	POS	B-NP
+were	POS	O
+identified	POS	O
+.	POS	O
+The	POS	O
+number	POS	O
+of	POS	O
+treatments	POS	O
+received	POS	O
+and	POS	O
+adverse	POS	O
+effects	POS	O
+were	POS	O
+noted	POS	O
+.	POS	O
+For	POS	O
+patients	POS	O
+with	POS	O
+bilateral	POS	B-NP
+abductor	POS	I-NP
+paralysis	POS	I-NP
+,	POS	O
+age	POS	O
+,	POS	O
+sex	POS	O
+,	POS	O
+paralytic	POS	B-NP
+Botox	POS	I-NP
+dose	POS	O
+,	POS	O
+prior	POS	O
+Botox	POS	O
+dose	POS	O
+,	POS	O
+and	POS	O
+course	POS	O
+following	POS	O
+paralysis	POS	B-NP
+were	POS	O
+noted	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+From	POS	O
+a	POS	O
+database	POS	O
+of	POS	O
+452	POS	O
+patients	POS	O
+receiving	POS	O
+Botox	POS	O
+,	POS	O
+352	POS	O
+patients	POS	O
+had	POS	O
+been	POS	O
+diagnosed	POS	O
+with	POS	O
+ADSD	POS	B-NP
+.	POS	O
+Of	POS	O
+these	POS	O
+352	POS	O
+patients	POS	O
+,	POS	O
+eight	POS	O
+patients	POS	O
+suffered	POS	O
+bilateral	POS	B-NP
+abductor	POS	I-NP
+paralysis	POS	I-NP
+,	POS	O
+and	POS	O
+two	POS	O
+suffered	POS	O
+this	POS	O
+complication	POS	O
+twice	POS	O
+.	POS	O
+All	POS	O
+affected	POS	B-NP
+patients	POS	O
+were	POS	O
+females	POS	O
+over	POS	O
+the	POS	O
+age	POS	O
+of	POS	O
+50	POS	O
+years	POS	O
+.	POS	O
+Most	POS	O
+patients	POS	O
+had	POS	O
+received	POS	O
+treatments	POS	O
+prior	POS	O
+to	POS	O
+abductor	POS	B-NP
+paralysis	POS	I-NP
+and	POS	O
+continued	POS	O
+receiving	POS	O
+after	POS	O
+paralysis	POS	B-NP
+.	POS	O
+Seven	POS	O
+patients	POS	O
+recovered	POS	O
+after	POS	O
+a	POS	O
+brief	POS	O
+period	POS	O
+of	POS	O
+activity	POS	O
+restrictions	POS	O
+,	POS	O
+and	POS	O
+one	POS	O
+underwent	POS	O
+a	POS	O
+tracheotomy	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+abductor	POS	B-NP
+paralysis	POS	I-NP
+after	POS	O
+Botox	POS	O
+injection	POS	O
+for	POS	O
+ADSD	POS	B-NP
+was	POS	O
+0	POS	O
+.	POS	O
+34	POS	O
+%	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Bilateral	POS	O
+abductor	POS	B-NP
+paralysis	POS	I-NP
+is	POS	O
+a	POS	O
+rare	POS	O
+complication	POS	O
+of	POS	O
+Botox	POS	O
+injections	POS	O
+for	POS	O
+ADSD	POS	B-NP
+,	POS	O
+causing	POS	O
+difficulty	POS	O
+with	POS	O
+breathing	POS	B-NP
+upon	POS	I-NP
+exertion	POS	I-NP
+.	POS	O
+The	POS	O
+likely	POS	O
+mechanism	POS	O
+of	POS	O
+paralysis	POS	B-NP
+is	POS	O
+diffusion	POS	O
+of	POS	O
+Botox	POS	O
+around	POS	O
+the	POS	O
+muscular	POS	O
+process	POS	O
+of	POS	O
+the	POS	O
+arytenoid	POS	O
+to	POS	O
+the	POS	O
+posterior	POS	O
+cricoarytenoid	POS	O
+muscles	POS	O
+.	POS	O
+The	POS	O
+paralysis	POS	B-NP
+is	POS	O
+temporary	POS	O
+,	POS	O
+and	POS	O
+watchful	POS	O
+waiting	POS	O
+with	POS	O
+restriction	POS	O
+of	POS	O
+activity	POS	O
+is	POS	O
+the	POS	O
+recommended	POS	O
+management	POS	O
+.	POS	O
+Mitochondrial	POS	B-NP
+impairment	POS	I-NP
+contributes	POS	O
+to	POS	O
+cocaine	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+dysfunction	POS	I-NP
+:	POS	O
+Prevention	POS	O
+by	POS	O
+the	POS	O
+targeted	POS	O
+antioxidant	POS	O
+MitoQ	POS	O
+.	POS	O
+The	POS	O
+goal	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+assess	POS	O
+mitochondrial	POS	O
+function	POS	O
+and	POS	O
+ROS	POS	O
+production	POS	O
+in	POS	O
+an	POS	O
+experimental	POS	O
+model	POS	O
+of	POS	O
+cocaine	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+We	POS	O
+hypothesized	POS	O
+that	POS	O
+cocaine	POS	B-NP
+abuse	POS	I-NP
+may	POS	O
+lead	POS	O
+to	POS	O
+altered	POS	O
+mitochondrial	POS	O
+function	POS	O
+that	POS	O
+in	POS	O
+turn	POS	O
+may	POS	O
+cause	POS	O
+left	POS	O
+ventricular	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+Seven	POS	O
+days	POS	O
+of	POS	O
+cocaine	POS	O
+administration	POS	O
+to	POS	O
+rats	POS	O
+led	POS	O
+to	POS	O
+an	POS	O
+increased	POS	O
+oxygen	POS	O
+consumption	POS	O
+detected	POS	O
+in	POS	O
+cardiac	POS	O
+fibers	POS	O
+,	POS	O
+specifically	POS	O
+through	POS	O
+complex	POS	O
+I	POS	O
+and	POS	O
+complex	POS	O
+III	POS	O
+.	POS	O
+ROS	POS	O
+levels	POS	O
+were	POS	O
+increased	POS	O
+,	POS	O
+specifically	POS	O
+in	POS	O
+interfibrillar	POS	O
+mitochondria	POS	O
+.	POS	O
+In	POS	O
+parallel	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+ATP	POS	O
+synthesis	POS	O
+,	POS	O
+whereas	POS	O
+no	POS	O
+difference	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+subsarcolemmal	POS	O
+mitochondria	POS	O
+.	POS	O
+This	POS	O
+uncoupling	POS	O
+effect	POS	O
+on	POS	O
+oxidative	POS	O
+phosphorylation	POS	O
+was	POS	O
+not	POS	O
+detectable	POS	O
+after	POS	O
+short	POS	O
+-	POS	O
+term	POS	O
+exposure	POS	O
+to	POS	O
+cocaine	POS	O
+,	POS	O
+suggesting	POS	O
+that	POS	O
+these	POS	O
+mitochondrial	POS	B-NP
+abnormalities	POS	I-NP
+were	POS	O
+a	POS	O
+late	POS	O
+rather	POS	O
+than	POS	O
+a	POS	O
+primary	POS	O
+event	POS	O
+in	POS	O
+the	POS	O
+pathological	POS	O
+response	POS	O
+to	POS	O
+cocaine	POS	O
+.	POS	O
+MitoQ	POS	O
+,	POS	O
+a	POS	O
+mitochondrial	POS	O
+-	POS	O
+targeted	POS	O
+antioxidant	POS	O
+,	POS	O
+was	POS	O
+shown	POS	O
+to	POS	O
+completely	POS	O
+prevent	POS	O
+these	POS	O
+mitochondrial	POS	O
+abnormalities	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+cardiac	POS	B-NP
+dysfunction	POS	I-NP
+characterized	POS	O
+here	POS	O
+by	POS	O
+a	POS	O
+diastolic	POS	B-NP
+dysfunction	POS	I-NP
+studied	POS	O
+with	POS	O
+a	POS	O
+conductance	POS	O
+catheter	POS	O
+to	POS	O
+obtain	POS	O
+pressure	POS	O
+-	POS	O
+volume	POS	O
+data	POS	O
+.	POS	O
+Taken	POS	O
+together	POS	O
+,	POS	O
+these	POS	O
+results	POS	O
+extend	POS	O
+previous	POS	O
+studies	POS	O
+and	POS	O
+demonstrate	POS	O
+that	POS	O
+cocaine	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+dysfunction	POS	I-NP
+may	POS	O
+be	POS	O
+due	POS	O
+to	POS	O
+a	POS	O
+mitochondrial	POS	B-NP
+defect	POS	I-NP
+.	POS	O
+Trimethoprim	POS	O
+-	POS	O
+induced	POS	O
+immune	POS	O
+hemolytic	POS	B-NP
+anemia	POS	I-NP
+in	POS	O
+a	POS	O
+pediatric	POS	O
+oncology	POS	O
+patient	POS	O
+presenting	POS	O
+as	POS	O
+an	POS	O
+acute	POS	B-NP
+hemolytic	POS	I-NP
+transfusion	POS	I-NP
+reaction	POS	I-NP
+.	POS	O
+A	POS	O
+10	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+male	POS	O
+with	POS	O
+acute	POS	B-NP
+leukemia	POS	I-NP
+presented	POS	O
+with	POS	O
+post	POS	O
+-	POS	O
+chemotherapy	POS	O
+anemia	POS	B-NP
+.	POS	O
+During	POS	O
+red	POS	O
+cell	POS	O
+transfusion	POS	O
+,	POS	O
+he	POS	O
+developed	POS	O
+hemoglobinuria	POS	B-NP
+.	POS	O
+Transfusion	POS	O
+reaction	POS	O
+workup	POS	O
+was	POS	O
+negative	POS	O
+.	POS	O
+Drug	POS	O
+-	POS	O
+induced	POS	O
+immune	POS	O
+hemolytic	POS	B-NP
+anemia	POS	I-NP
+was	POS	O
+suspected	POS	O
+because	POS	O
+of	POS	O
+positive	POS	O
+direct	POS	O
+antiglobulin	POS	O
+test	POS	O
+,	POS	O
+negative	POS	O
+eluate	POS	O
+,	POS	O
+and	POS	O
+microspherocytes	POS	O
+on	POS	O
+smear	POS	O
+pre	POS	O
+-	POS	O
+and	POS	O
+post	POS	O
+-	POS	O
+transfusion	POS	O
+.	POS	O
+Drug	POS	O
+studies	POS	O
+using	POS	O
+the	POS	O
+indirect	POS	O
+antiglobulin	POS	O
+test	POS	O
+were	POS	O
+strongly	POS	O
+positive	POS	O
+with	POS	O
+trimethoprim	POS	O
+and	POS	O
+trimethoprim	POS	O
+-	POS	O
+sulfamethoxazole	POS	O
+but	POS	O
+negative	POS	O
+with	POS	O
+sulfamethoxazole	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+recovered	POS	O
+after	POS	O
+discontinuing	POS	O
+the	POS	O
+drug	POS	O
+,	POS	O
+with	POS	O
+no	POS	O
+recurrence	POS	O
+in	POS	O
+2	POS	O
+years	POS	O
+.	POS	O
+Other	POS	O
+causes	POS	O
+of	POS	O
+anemia	POS	B-NP
+should	POS	O
+be	POS	O
+considered	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+worse	POS	O
+-	POS	O
+than	POS	O
+-	POS	O
+expected	POS	O
+anemia	POS	B-NP
+after	POS	O
+chemotherapy	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+hemolysis	POS	B-NP
+during	POS	O
+transfusion	POS	O
+is	POS	O
+not	POS	O
+always	POS	O
+a	POS	O
+transfusion	POS	O
+reaction	POS	O
+.	POS	O
+Verapamil	POS	O
+stimulation	POS	O
+test	POS	O
+in	POS	O
+hyperprolactinemia	POS	B-NP
+:	POS	O
+loss	POS	O
+of	POS	O
+prolactin	POS	O
+response	POS	O
+in	POS	O
+anatomic	POS	O
+or	POS	O
+functional	POS	O
+stalk	POS	O
+effect	POS	O
+.	POS	O
+AIM	POS	O
+:	POS	O
+Verapamil	POS	O
+stimulation	POS	O
+test	POS	O
+was	POS	O
+previously	POS	O
+investigated	POS	O
+as	POS	O
+a	POS	O
+tool	POS	O
+for	POS	O
+differential	POS	O
+diagnosis	POS	O
+of	POS	O
+hyperprolactinemia	POS	B-NP
+,	POS	O
+but	POS	O
+with	POS	O
+conflicting	POS	O
+results	POS	O
+.	POS	O
+Macroprolactinemia	POS	B-NP
+was	POS	O
+never	POS	O
+considered	POS	O
+in	POS	O
+those	POS	O
+previous	POS	O
+studies	POS	O
+.	POS	O
+Here	POS	O
+,	POS	O
+we	POS	O
+aimed	POS	O
+to	POS	O
+re	POS	O
+-	POS	O
+investigate	POS	O
+the	POS	O
+diagnostic	POS	O
+value	POS	O
+of	POS	O
+verapamil	POS	O
+in	POS	O
+a	POS	O
+population	POS	O
+who	POS	O
+were	POS	O
+all	POS	O
+screened	POS	O
+for	POS	O
+macroprolactinemia	POS	B-NP
+.	POS	O
+Prolactin	POS	O
+responses	POS	O
+to	POS	O
+verapamil	POS	O
+in	POS	O
+65	POS	O
+female	POS	O
+patients	POS	O
+(	POS	O
+age	POS	O
+:	POS	O
+29	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+8	POS	O
+.	POS	O
+1	POS	O
+years	POS	O
+)	POS	O
+with	POS	O
+hyperprolactinemia	POS	B-NP
+were	POS	O
+tested	POS	O
+in	POS	O
+a	POS	O
+descriptive	POS	O
+,	POS	O
+matched	POS	O
+case	POS	O
+-	POS	O
+control	POS	O
+study	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Verapamil	POS	O
+80	POS	O
+mg	POS	O
+,	POS	O
+p	POS	O
+.	POS	O
+o	POS	O
+.	POS	O
+was	POS	O
+administered	POS	O
+,	POS	O
+and	POS	O
+then	POS	O
+PRL	POS	O
+levels	POS	O
+were	POS	O
+measured	POS	O
+at	POS	O
+8th	POS	O
+and	POS	O
+16th	POS	O
+hours	POS	O
+,	POS	O
+by	POS	O
+immunometric	POS	O
+chemiluminescence	POS	O
+.	POS	O
+Verapamil	POS	O
+responsiveness	POS	O
+was	POS	O
+determined	POS	O
+by	POS	O
+peak	POS	O
+percent	POS	O
+change	POS	O
+in	POS	O
+basal	POS	O
+prolactin	POS	O
+levels	POS	O
+(	POS	O
+PRL	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Verapamil	POS	O
+significantly	POS	O
+increased	POS	O
+PRL	POS	O
+levels	POS	O
+in	POS	O
+healthy	POS	O
+controls	POS	O
+(	POS	O
+N	POS	O
+.	POS	O
+8	POS	O
+,	POS	O
+PRL	POS	O
+:	POS	O
+183	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+macroprolactinoma	POS	B-NP
+(	POS	O
+N	POS	O
+.	POS	O
+8	POS	O
+,	POS	O
+PRL	POS	O
+:	POS	O
+7	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+microprolactinoma	POS	B-NP
+(	POS	O
+N	POS	O
+.	POS	O
+19	POS	O
+,	POS	O
+PRL	POS	O
+:	POS	O
+21	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+macroprolactinemia	POS	B-NP
+(	POS	O
+N	POS	O
+.	POS	O
+23	POS	O
+,	POS	O
+PRL	POS	O
+:	POS	O
+126	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+in	POS	O
+pseudoprolactinoma	POS	B-NP
+(	POS	O
+N	POS	O
+.	POS	O
+8	POS	O
+,	POS	O
+PRL	POS	O
+:	POS	O
+0	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+risperidone	POS	O
+-	POS	O
+induced	POS	O
+hyperprolactinemia	POS	B-NP
+(	POS	O
+N	POS	O
+.	POS	O
+7	POS	O
+,	POS	O
+PRL	POS	O
+:	POS	O
+3	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+ROC	POS	O
+curve	POS	O
+analysis	POS	O
+revealed	POS	O
+that	POS	O
+unresponsiveness	POS	O
+to	POS	O
+verapamil	POS	O
+defined	POS	O
+as	POS	O
+PRL	POS	O
+<	POS	O
+7	POS	O
+%	POS	O
+,	POS	O
+discriminated	POS	O
+anatomical	POS	O
+or	POS	O
+functional	POS	O
+stalk	POS	O
+effect	POS	O
+(	POS	O
+sensitivity	POS	O
+:	POS	O
+74	POS	O
+%	POS	O
+,	POS	O
+specificity	POS	O
+:	POS	O
+73	POS	O
+%	POS	O
+,	POS	O
+AUC	POS	O
+:	POS	O
+0	POS	O
+.	POS	O
+855	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+04	POS	O
+,	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+,	POS	O
+CI	POS	O
+:	POS	O
+0	POS	O
+.	POS	O
+768	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+942	POS	O
+)	POS	O
+associated	POS	O
+with	POS	O
+pseudoprolactinoma	POS	O
+or	POS	O
+risperidone	POS	O
+-	POS	O
+induced	POS	O
+hyperprolactinemia	POS	B-NP
+,	POS	O
+respectively	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Verapamil	POS	O
+responsiveness	POS	O
+is	POS	O
+not	POS	O
+a	POS	O
+reliable	POS	O
+finding	POS	O
+for	POS	O
+the	POS	O
+differential	POS	O
+diagnosis	POS	O
+of	POS	O
+hyperprolactinemia	POS	B-NP
+.	POS	O
+However	POS	O
+,	POS	O
+verapamil	POS	O
+unresponsiveness	POS	O
+discriminates	POS	O
+stalk	POS	O
+effect	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+e	POS	O
+.	POS	O
+,	POS	O
+anatomically	POS	O
+or	POS	O
+functionally	POS	O
+inhibited	POS	O
+dopaminergic	POS	O
+tonus	POS	O
+)	POS	O
+from	POS	O
+other	POS	O
+causes	POS	O
+of	POS	O
+hyperprolactinemia	POS	B-NP
+with	POS	O
+varying	POS	O
+degrees	POS	O
+of	POS	O
+responsiveness	POS	O
+.	POS	O
+Blockade	POS	O
+of	POS	O
+endothelial	POS	O
+-	POS	O
+mesenchymal	POS	O
+transition	POS	O
+by	POS	O
+a	POS	O
+Smad3	POS	O
+inhibitor	POS	O
+delays	POS	O
+the	POS	O
+early	POS	O
+development	POS	O
+of	POS	O
+streptozotocin	POS	O
+-	POS	O
+induced	POS	O
+diabetic	POS	B-NP
+nephropathy	POS	I-NP
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+A	POS	O
+multicenter	POS	O
+,	POS	O
+controlled	POS	O
+trial	POS	O
+showed	POS	O
+that	POS	O
+early	POS	O
+blockade	POS	O
+of	POS	O
+the	POS	O
+renin	POS	O
+-	POS	O
+angiotensin	POS	O
+system	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+type	POS	B-NP
+1	POS	I-NP
+diabetes	POS	I-NP
+and	POS	O
+normoalbuminuria	POS	B-NP
+did	POS	O
+not	POS	O
+retard	POS	O
+the	POS	O
+progression	POS	O
+of	POS	O
+nephropathy	POS	B-NP
+,	POS	O
+suggesting	POS	O
+that	POS	O
+other	POS	O
+mechanism	POS	O
+(	POS	O
+s	POS	O
+)	POS	O
+are	POS	O
+involved	POS	O
+in	POS	O
+the	POS	O
+pathogenesis	POS	O
+of	POS	O
+early	POS	O
+diabetic	POS	B-NP
+nephropathy	POS	I-NP
+(	POS	O
+diabetic	POS	B-NP
+nephropathy	POS	I-NP
+)	POS	O
+.	POS	O
+We	POS	O
+have	POS	O
+previously	POS	O
+demonstrated	POS	O
+that	POS	O
+endothelial	POS	O
+-	POS	O
+mesenchymal	POS	O
+-	POS	O
+transition	POS	O
+(	POS	O
+EndoMT	POS	O
+)	POS	O
+contributes	POS	O
+to	POS	O
+the	POS	O
+early	POS	O
+development	POS	O
+of	POS	O
+renal	POS	B-NP
+interstitial	POS	I-NP
+fibrosis	POS	I-NP
+independently	POS	O
+of	POS	O
+microalbuminuria	POS	B-NP
+in	POS	O
+mice	POS	O
+with	POS	O
+streptozotocin	POS	O
+(	POS	O
+STZ	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+diabetes	POS	B-NP
+.	POS	O
+In	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+,	POS	O
+we	POS	O
+hypothesized	POS	O
+that	POS	O
+blocking	POS	O
+EndoMT	POS	O
+reduces	POS	O
+the	POS	O
+early	POS	O
+development	POS	O
+of	POS	O
+diabetic	POS	B-NP
+nephropathy	POS	I-NP
+.	POS	O
+RESEARCH	POS	O
+DESIGN	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+EndoMT	POS	O
+was	POS	O
+induced	POS	O
+in	POS	O
+a	POS	O
+mouse	POS	O
+pancreatic	POS	O
+microvascular	POS	O
+endothelial	POS	O
+cell	POS	O
+line	POS	O
+(	POS	O
+MMEC	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+advanced	POS	O
+glycation	POS	O
+end	POS	O
+products	POS	O
+(	POS	O
+AGEs	POS	O
+)	POS	O
+and	POS	O
+in	POS	O
+the	POS	O
+endothelial	POS	O
+lineage	POS	O
+-	POS	O
+traceble	POS	O
+mouse	POS	O
+line	POS	O
+Tie2	POS	O
+-	POS	O
+Cre	POS	O
+;	POS	O
+Loxp	POS	O
+-	POS	O
+EGFP	POS	O
+by	POS	O
+administration	POS	O
+of	POS	O
+AGEs	POS	O
+,	POS	O
+with	POS	O
+nonglycated	POS	O
+mouse	POS	O
+albumin	POS	O
+serving	POS	O
+as	POS	O
+a	POS	O
+control	POS	O
+.	POS	O
+Phosphorylated	POS	O
+Smad3	POS	O
+was	POS	O
+detected	POS	O
+by	POS	O
+immunoprecipitation	POS	O
+/	POS	O
+Western	POS	O
+blotting	POS	O
+and	POS	O
+confocal	POS	O
+microscopy	POS	O
+.	POS	O
+Blocking	POS	O
+studies	POS	O
+using	POS	O
+receptor	POS	O
+for	POS	O
+AGE	POS	O
+siRNA	POS	O
+and	POS	O
+a	POS	O
+specific	POS	O
+inhibitor	POS	O
+of	POS	O
+Smad3	POS	O
+(	POS	O
+SIS3	POS	O
+)	POS	O
+were	POS	O
+performed	POS	O
+in	POS	O
+MMECs	POS	O
+and	POS	O
+in	POS	O
+STZ	POS	O
+-	POS	O
+induced	POS	O
+diabetic	POS	B-NP
+nephropathy	POS	I-NP
+in	POS	O
+Tie2	POS	O
+-	POS	O
+Cre	POS	O
+;	POS	O
+Loxp	POS	O
+-	POS	O
+EGFP	POS	O
+mice	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Confocal	POS	O
+microscopy	POS	O
+and	POS	O
+real	POS	O
+-	POS	O
+time	POS	O
+PCR	POS	O
+demonstrated	POS	O
+that	POS	O
+AGEs	POS	O
+induced	POS	O
+EndoMT	POS	O
+in	POS	O
+MMECs	POS	O
+and	POS	O
+in	POS	O
+Tie2	POS	O
+-	POS	O
+Cre	POS	O
+;	POS	O
+Loxp	POS	O
+-	POS	O
+EGFP	POS	O
+mice	POS	O
+.	POS	O
+Immunoprecipitation	POS	O
+/	POS	O
+Western	POS	O
+blotting	POS	O
+showed	POS	O
+that	POS	O
+Smad3	POS	O
+was	POS	O
+activated	POS	O
+by	POS	O
+AGEs	POS	O
+but	POS	O
+was	POS	O
+inhibited	POS	O
+by	POS	O
+SIS3	POS	O
+in	POS	O
+MMECs	POS	O
+and	POS	O
+in	POS	O
+STZ	POS	O
+-	POS	O
+induced	POS	O
+diabetic	POS	B-NP
+nephropathy	POS	I-NP
+.	POS	O
+Confocal	POS	O
+microscopy	POS	O
+and	POS	O
+real	POS	O
+-	POS	O
+time	POS	O
+PCR	POS	O
+further	POS	O
+demonstrated	POS	O
+that	POS	O
+SIS3	POS	O
+abrogated	POS	O
+EndoMT	POS	O
+,	POS	O
+reduced	POS	O
+renal	POS	B-NP
+fibrosis	POS	I-NP
+,	POS	O
+and	POS	O
+retarded	POS	O
+progression	POS	O
+of	POS	O
+nephropathy	POS	B-NP
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+EndoMT	POS	O
+is	POS	O
+a	POS	O
+novel	POS	O
+pathway	POS	O
+leading	POS	O
+to	POS	O
+early	POS	O
+development	POS	O
+of	POS	O
+diabetic	POS	B-NP
+nephropathy	POS	I-NP
+.	POS	O
+Blockade	POS	O
+of	POS	O
+EndoMT	POS	O
+by	POS	O
+SIS3	POS	O
+may	POS	O
+provide	POS	O
+a	POS	O
+new	POS	O
+strategy	POS	O
+to	POS	O
+retard	POS	O
+the	POS	O
+progression	POS	O
+of	POS	O
+diabetic	POS	B-NP
+nephropathy	POS	I-NP
+and	POS	O
+other	POS	O
+diabetes	POS	B-NP
+complications	POS	O
+.	POS	O
+Cytostatic	POS	O
+and	POS	O
+anti	POS	O
+-	POS	O
+angiogenic	POS	O
+effects	POS	O
+of	POS	O
+temsirolimus	POS	O
+in	POS	O
+refractory	POS	O
+mantle	POS	B-NP
+cell	POS	I-NP
+lymphoma	POS	I-NP
+.	POS	O
+Mantle	POS	B-NP
+cell	POS	I-NP
+lymphoma	POS	I-NP
+(	POS	O
+MCL	POS	B-NP
+)	POS	O
+is	POS	O
+a	POS	O
+rare	POS	O
+and	POS	O
+aggressive	POS	B-NP
+type	POS	I-NP
+of	POS	I-NP
+B	POS	I-NP
+-	POS	I-NP
+cell	POS	I-NP
+non	POS	I-NP
+-	POS	I-NP
+Hodgkin	POS	I-NP
+'	POS	I-NP
+s	POS	I-NP
+lymphoma	POS	I-NP
+.	POS	O
+Patients	POS	O
+become	POS	O
+progressively	POS	O
+refractory	POS	O
+to	POS	O
+conventional	POS	O
+chemotherapy	POS	O
+,	POS	O
+and	POS	O
+their	POS	O
+prognosis	POS	O
+is	POS	O
+poor	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+a	POS	O
+38	POS	O
+%	POS	O
+remission	POS	O
+rate	POS	O
+has	POS	O
+been	POS	O
+recently	POS	O
+reported	POS	O
+in	POS	O
+refractory	POS	O
+MCL	POS	O
+treated	POS	O
+with	POS	O
+temsirolimus	POS	O
+,	POS	O
+a	POS	O
+mTOR	POS	O
+inhibitor	POS	O
+.	POS	O
+Here	POS	O
+we	POS	O
+had	POS	O
+the	POS	O
+opportunity	POS	O
+to	POS	O
+study	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+refractory	POS	O
+MCL	POS	B-NP
+who	POS	O
+had	POS	O
+tumor	POS	B-NP
+regression	POS	O
+two	POS	O
+months	POS	O
+after	POS	O
+temsirolimus	POS	O
+treatment	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+progression	POS	O
+-	POS	O
+free	POS	O
+survival	POS	O
+of	POS	O
+10	POS	O
+months	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+case	POS	O
+,	POS	O
+lymph	POS	O
+node	POS	O
+biopsies	POS	O
+were	POS	O
+performed	POS	O
+before	POS	O
+and	POS	O
+six	POS	O
+months	POS	O
+after	POS	O
+temsirolimus	POS	O
+therapy	POS	O
+.	POS	O
+Comparison	POS	O
+of	POS	O
+the	POS	O
+two	POS	O
+biopsies	POS	O
+showed	POS	O
+that	POS	O
+temsirolimus	POS	O
+inhibited	POS	O
+tumor	POS	B-NP
+cell	POS	I-NP
+proliferation	POS	I-NP
+through	POS	I-NP
+cell	POS	I-NP
+cycle	POS	I-NP
+arrest	POS	I-NP
+,	POS	O
+but	POS	O
+did	POS	O
+not	POS	O
+induce	POS	O
+any	POS	O
+change	POS	O
+in	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+apoptotic	POS	O
+tumor	POS	B-NP
+cells	POS	O
+.	POS	O
+Apart	POS	O
+from	POS	O
+this	POS	O
+cytostatic	POS	O
+effect	POS	O
+,	POS	O
+temsirolimus	POS	O
+had	POS	O
+an	POS	O
+antiangiogenic	POS	O
+effect	POS	O
+with	POS	O
+decrease	POS	O
+of	POS	O
+tumor	POS	B-NP
+microvessel	POS	O
+density	POS	O
+and	POS	O
+of	POS	O
+VEGF	POS	O
+expression	POS	O
+.	POS	O
+Moreover	POS	O
+,	POS	O
+numerous	POS	O
+patchy	POS	O
+,	POS	O
+well	POS	O
+-	POS	O
+limited	POS	O
+fibrotic	POS	O
+areas	POS	O
+,	POS	O
+compatible	POS	O
+with	POS	O
+post	POS	O
+-	POS	O
+necrotic	POS	O
+tissue	POS	O
+repair	POS	O
+,	POS	O
+were	POS	O
+found	POS	O
+after	POS	O
+6	POS	O
+-	POS	O
+month	POS	O
+temsirolimus	POS	O
+therapy	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+temsirolimus	POS	O
+reduced	POS	O
+tumor	POS	B-NP
+burden	POS	O
+through	POS	O
+associated	POS	O
+cytostatic	POS	O
+and	POS	O
+anti	POS	O
+-	POS	O
+angiogenic	POS	O
+effects	POS	O
+.	POS	O
+This	POS	O
+dual	POS	O
+effect	POS	O
+of	POS	O
+temsirolimus	POS	O
+on	POS	O
+tumor	POS	B-NP
+tissue	POS	O
+could	POS	O
+contribute	POS	O
+to	POS	O
+its	POS	O
+recently	POS	O
+reported	POS	O
+efficiency	POS	O
+in	POS	O
+refractory	POS	O
+MCL	POS	B-NP
+resistant	POS	O
+to	POS	O
+conventional	POS	O
+chemotherapy	POS	O
+.	POS	O
+Acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+due	POS	O
+to	POS	O
+rifampicin	POS	O
+.	POS	O
+A	POS	O
+23	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+male	POS	O
+patient	POS	O
+with	POS	O
+bacteriologically	POS	O
+proven	POS	O
+pulmonary	POS	B-NP
+tuberculosis	POS	I-NP
+was	POS	O
+treated	POS	O
+with	POS	O
+the	POS	O
+various	POS	O
+regimens	POS	O
+of	POS	O
+antituberculosis	POS	O
+drugs	POS	O
+for	POS	O
+nearly	POS	O
+15	POS	O
+months	POS	O
+.	POS	O
+Rifampicin	POS	O
+was	POS	O
+administered	POS	O
+thrice	POS	O
+as	POS	O
+one	POS	O
+of	POS	O
+the	POS	O
+3	POS	O
+-	POS	O
+4	POS	O
+drug	POS	O
+regimen	POS	O
+and	POS	O
+each	POS	O
+time	POS	O
+he	POS	O
+developed	POS	O
+untoward	POS	O
+side	POS	O
+effects	POS	O
+like	POS	O
+nausea	POS	B-NP
+,	POS	O
+vomiting	POS	B-NP
+and	POS	O
+fever	POS	B-NP
+with	POS	O
+chills	POS	B-NP
+and	POS	O
+rigors	POS	B-NP
+.	POS	O
+The	POS	O
+last	POS	O
+such	POS	O
+episode	POS	O
+was	POS	O
+of	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+at	POS	O
+which	POS	O
+stage	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+seen	POS	O
+by	POS	O
+the	POS	O
+authors	POS	O
+of	POS	O
+this	POS	O
+report	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+,	POS	O
+however	POS	O
+,	POS	O
+made	POS	O
+a	POS	O
+full	POS	O
+recovery	POS	O
+.	POS	O
+Syncope	POS	B-NP
+caused	POS	O
+by	POS	O
+hyperkalemia	POS	B-NP
+during	POS	O
+use	POS	O
+of	POS	O
+a	POS	O
+combined	POS	O
+therapy	POS	O
+with	POS	O
+the	POS	O
+angiotensin	POS	O
+-	POS	O
+converting	POS	O
+enzyme	POS	O
+inhibitor	POS	O
+and	POS	O
+spironolactone	POS	O
+.	POS	O
+A	POS	O
+76	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+with	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+coronary	POS	O
+artery	POS	O
+bypass	POS	O
+grafting	POS	O
+and	POS	O
+prior	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+was	POS	O
+transferred	POS	O
+to	POS	O
+the	POS	O
+emergency	POS	O
+room	POS	O
+with	POS	O
+loss	POS	O
+of	POS	O
+consciousness	POS	O
+due	POS	O
+to	POS	O
+marked	POS	O
+bradycardia	POS	B-NP
+caused	POS	O
+by	POS	O
+hyperkalemia	POS	B-NP
+.	POS	O
+The	POS	O
+concentration	POS	O
+of	POS	O
+serum	POS	O
+potassium	POS	O
+was	POS	O
+high	POS	O
+,	POS	O
+and	POS	O
+normal	POS	O
+sinus	POS	O
+rhythm	POS	O
+was	POS	O
+restored	POS	O
+after	POS	O
+correction	POS	O
+of	POS	O
+the	POS	O
+serum	POS	O
+potassium	POS	O
+level	POS	O
+.	POS	O
+The	POS	O
+cause	POS	O
+of	POS	O
+hyperkalemia	POS	B-NP
+was	POS	O
+considered	POS	O
+to	POS	O
+be	POS	O
+several	POS	O
+doses	POS	O
+of	POS	O
+spiranolactone	POS	O
+,	POS	O
+an	POS	O
+aldosterone	POS	O
+antagonist	POS	O
+,	POS	O
+in	POS	O
+addition	POS	O
+to	POS	O
+the	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+intake	POS	O
+of	POS	O
+ramipril	POS	O
+,	POS	O
+an	POS	O
+ACE	POS	O
+inhibitor	POS	O
+.	POS	O
+This	POS	O
+case	POS	O
+is	POS	O
+a	POS	O
+good	POS	O
+example	POS	O
+of	POS	O
+electrolyte	POS	O
+imbalance	POS	O
+causing	POS	O
+acute	POS	O
+life	POS	O
+-	POS	O
+threatening	POS	O
+cardiac	POS	O
+events	POS	O
+.	POS	O
+Clinicians	POS	O
+should	POS	O
+be	POS	O
+alert	POS	O
+to	POS	O
+the	POS	O
+possibility	POS	O
+of	POS	O
+hyperkalemia	POS	B-NP
+,	POS	O
+especially	POS	O
+in	POS	O
+elderly	POS	O
+patients	POS	O
+using	POS	O
+ACE	POS	O
+/	POS	O
+ARB	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+potassium	POS	O
+sparing	POS	O
+agents	POS	O
+and	POS	O
+who	POS	O
+have	POS	O
+mild	POS	O
+renal	POS	B-NP
+disturbance	POS	I-NP
+.	POS	O
+Diffuse	POS	B-NP
+skeletal	POS	I-NP
+pain	POS	I-NP
+after	POS	O
+administration	POS	O
+of	POS	O
+alendronate	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Osteoporosis	POS	B-NP
+is	POS	O
+caused	POS	O
+by	POS	O
+bone	POS	O
+resorption	POS	O
+in	POS	O
+excess	POS	O
+of	POS	O
+bone	POS	O
+formation	POS	O
+,	POS	O
+and	POS	O
+bisphosphonates	POS	O
+,	POS	O
+are	POS	O
+used	POS	O
+to	POS	O
+inhibit	POS	O
+bone	POS	O
+resorption	POS	O
+.	POS	O
+Alendronate	POS	O
+,	POS	O
+a	POS	O
+biphosphonate	POS	O
+,	POS	O
+is	POS	O
+effective	POS	O
+for	POS	O
+both	POS	O
+the	POS	O
+treatment	POS	O
+and	POS	O
+prevention	POS	O
+of	POS	O
+osteoporosis	POS	B-NP
+in	POS	O
+postmenopausal	POS	O
+women	POS	O
+.	POS	O
+Side	POS	O
+effects	POS	O
+are	POS	O
+relatively	POS	O
+few	POS	O
+and	POS	O
+prominently	POS	O
+gastrointestinal	POS	O
+.	POS	O
+Musculoskeletal	POS	B-NP
+pain	POS	I-NP
+may	POS	O
+be	POS	O
+an	POS	O
+important	POS	O
+side	POS	O
+effect	POS	O
+in	POS	O
+these	POS	O
+patients	POS	O
+.	POS	O
+We	POS	O
+presented	POS	O
+a	POS	O
+patient	POS	O
+admitted	POS	O
+to	POS	O
+our	POS	O
+out	POS	O
+-	POS	O
+patient	POS	O
+clinic	POS	O
+with	POS	O
+diffuse	POS	O
+skeletal	POS	B-NP
+pain	POS	I-NP
+after	POS	O
+three	POS	O
+consecutive	POS	O
+administration	POS	O
+of	POS	O
+alendronate	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+patients	POS	O
+with	POS	O
+osteoporosis	POS	B-NP
+can	POS	O
+report	POS	O
+pain	POS	B-NP
+,	POS	O
+and	POS	O
+bisphosphonate	POS	B-NP
+-	POS	I-NP
+related	POS	I-NP
+pain	POS	I-NP
+should	POS	O
+also	POS	O
+be	POS	O
+considered	POS	O
+before	POS	O
+ascribing	POS	O
+this	POS	O
+complaint	POS	O
+to	POS	O
+osteoporosis	POS	B-NP
+.	POS	O
+Cerebrospinal	POS	O
+fluid	POS	O
+penetration	POS	O
+of	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+daptomycin	POS	O
+in	POS	O
+suspected	POS	O
+Staphylococcus	POS	O
+aureus	POS	O
+meningitis	POS	B-NP
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+methicillin	POS	O
+-	POS	O
+sensitive	POS	O
+Staphylococcus	POS	O
+aureus	POS	O
+(	POS	O
+MSSA	POS	O
+)	POS	O
+bacteremia	POS	B-NP
+with	POS	O
+suspected	POS	O
+MSSA	POS	B-NP
+meningitis	POS	I-NP
+treated	POS	O
+with	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+daptomycin	POS	O
+assessed	POS	O
+with	POS	O
+concurrent	POS	O
+serum	POS	O
+and	POS	O
+cerebrospinal	POS	O
+fluid	POS	O
+(	POS	O
+CSF	POS	O
+)	POS	O
+concentrations	POS	O
+.	POS	O
+CASE	POS	O
+SUMMARY	POS	O
+:	POS	O
+A	POS	O
+54	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+male	POS	O
+presented	POS	O
+to	POS	O
+the	POS	O
+emergency	POS	O
+department	POS	O
+with	POS	O
+generalized	POS	B-NP
+weakness	POS	I-NP
+and	POS	O
+presumed	POS	O
+health	POS	O
+-	POS	O
+care	POS	O
+-	POS	O
+associated	POS	O
+pneumonia	POS	B-NP
+shown	POS	O
+on	POS	O
+chest	POS	O
+radiograph	POS	O
+.	POS	O
+Treatment	POS	O
+was	POS	O
+empirically	POS	O
+initiated	POS	O
+with	POS	O
+vancomycin	POS	O
+,	POS	O
+levofloxacin	POS	O
+,	POS	O
+and	POS	O
+piperacillin	POS	O
+/	POS	O
+tazobactam	POS	O
+.	POS	O
+Blood	POS	O
+cultures	POS	O
+revealed	POS	O
+S	POS	O
+.	POS	O
+aureus	POS	O
+susceptible	POS	O
+to	POS	O
+oxacillin	POS	O
+.	POS	O
+Empiric	POS	O
+antibiotic	POS	O
+treatment	POS	O
+was	POS	O
+narrowed	POS	O
+to	POS	O
+nafcillin	POS	O
+on	POS	O
+day	POS	O
+4	POS	O
+.	POS	O
+On	POS	O
+day	POS	O
+8	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+developed	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+(	POS	O
+serum	POS	O
+creatinine	POS	O
+1	POS	O
+.	POS	O
+9	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+,	POS	O
+increased	POS	O
+from	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+the	POS	O
+previous	POS	O
+day	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+8	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+on	POS	O
+admission	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+Glasgow	POS	O
+Coma	POS	B-NP
+Score	POS	O
+was	POS	O
+3	POS	O
+,	POS	O
+with	POS	O
+normal	POS	O
+findings	POS	O
+shown	POS	O
+on	POS	O
+computed	POS	O
+tomography	POS	O
+scan	POS	O
+of	POS	O
+the	POS	O
+head	POS	O
+72	POS	O
+hours	POS	O
+following	POS	O
+an	POS	O
+episode	POS	O
+of	POS	O
+cardiac	POS	B-NP
+arrest	POS	I-NP
+on	POS	O
+day	POS	O
+10	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+experienced	POS	O
+relapsing	POS	O
+MSSA	POS	B-NP
+bacteremia	POS	B-NP
+on	POS	O
+day	POS	O
+9	POS	O
+,	POS	O
+increasing	POS	O
+the	POS	O
+suspicion	POS	O
+for	POS	O
+a	POS	O
+central	POS	B-NP
+nervous	POS	I-NP
+system	POS	I-NP
+(	POS	I-NP
+CNS	POS	I-NP
+)	POS	I-NP
+infection	POS	I-NP
+.	POS	O
+Nafcillin	POS	O
+was	POS	O
+discontinued	POS	O
+and	POS	O
+daptomycin	POS	O
+9	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+daily	POS	O
+was	POS	O
+initiated	POS	O
+for	POS	O
+suspected	POS	O
+meningitis	POS	B-NP
+and	POS	O
+was	POS	O
+continued	POS	O
+until	POS	O
+the	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+death	POS	O
+on	POS	O
+day	POS	O
+16	POS	O
+.	POS	O
+Daptomycin	POS	O
+serum	POS	O
+and	POS	O
+CSF	POS	O
+trough	POS	O
+concentrations	POS	O
+were	POS	O
+11	POS	O
+.	POS	O
+21	POS	O
+ug	POS	O
+/	POS	O
+mL	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+52	POS	O
+ug	POS	O
+/	POS	O
+mL	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+prior	POS	O
+to	POS	O
+the	POS	O
+third	POS	O
+dose	POS	O
+.	POS	O
+Lumbar	POS	O
+puncture	POS	O
+results	POS	O
+were	POS	O
+inconclusive	POS	O
+and	POS	O
+no	POS	O
+further	POS	O
+blood	POS	O
+cultures	POS	O
+were	POS	O
+positive	POS	O
+for	POS	O
+MSSA	POS	O
+.	POS	O
+Creatine	POS	O
+kinase	POS	O
+levels	POS	O
+were	POS	O
+normal	POS	O
+prior	POS	O
+to	POS	O
+daptomycin	POS	O
+therapy	POS	O
+and	POS	O
+were	POS	O
+not	POS	O
+reassessed	POS	O
+.	POS	O
+DISCUSSION	POS	O
+:	POS	O
+Daptomycin	POS	O
+was	POS	O
+initiated	POS	O
+in	POS	O
+our	POS	O
+patient	POS	O
+secondary	POS	O
+to	POS	O
+possible	POS	O
+nafcillin	POS	O
+-	POS	O
+induced	POS	O
+acute	POS	O
+interstitial	POS	B-NP
+nephritis	POS	I-NP
+and	POS	O
+relapsing	POS	B-NP
+bacteremia	POS	I-NP
+.	POS	O
+At	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+9	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+resultant	POS	O
+penetration	POS	O
+of	POS	O
+5	POS	O
+%	POS	O
+was	POS	O
+higher	POS	O
+than	POS	O
+in	POS	O
+previous	POS	O
+reports	POS	O
+,	POS	O
+more	POS	O
+consistent	POS	O
+with	POS	O
+inflamed	POS	O
+meninges	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+High	POS	O
+-	POS	O
+dose	POS	O
+daptomycin	POS	O
+may	POS	O
+be	POS	O
+an	POS	O
+alternative	POS	O
+option	POS	O
+for	POS	O
+MSSA	POS	O
+bacteremia	POS	B-NP
+with	POS	O
+or	POS	O
+without	POS	O
+a	POS	O
+CNS	POS	O
+source	POS	O
+in	POS	O
+patients	POS	O
+who	POS	O
+have	POS	O
+failed	POS	O
+or	POS	O
+cannot	POS	O
+tolerate	POS	O
+standard	POS	O
+therapy	POS	O
+.	POS	O
+Further	POS	O
+clinical	POS	O
+evaluation	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+confirmed	POS	O
+meningitis	POS	B-NP
+is	POS	O
+warranted	POS	O
+.	POS	O
+The	POS	O
+role	POS	O
+of	POS	O
+nitric	POS	O
+oxide	POS	O
+in	POS	O
+convulsions	POS	B-NP
+induced	POS	O
+by	POS	O
+lindane	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+Lindane	POS	O
+is	POS	O
+an	POS	O
+organochloride	POS	O
+pesticide	POS	O
+and	POS	O
+scabicide	POS	O
+.	POS	O
+It	POS	O
+evokes	POS	O
+convulsions	POS	B-NP
+mainly	POS	O
+trough	POS	O
+the	POS	O
+blockage	POS	O
+of	POS	O
+GABA	POS	O
+(	POS	O
+A	POS	O
+)	POS	O
+receptors	POS	O
+.	POS	O
+Nitric	POS	O
+oxide	POS	O
+(	POS	O
+NO	POS	O
+)	POS	O
+,	POS	O
+gaseous	POS	O
+neurotransmitter	POS	O
+,	POS	O
+has	POS	O
+contradictor	POS	O
+role	POS	O
+in	POS	O
+epileptogenesis	POS	B-NP
+due	POS	O
+to	POS	O
+opposite	POS	O
+effects	POS	O
+of	POS	O
+L	POS	O
+-	POS	O
+arginine	POS	O
+,	POS	O
+precursor	POS	O
+of	POS	O
+NO	POS	O
+syntheses	POS	O
+(	POS	O
+NOS	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+L	POS	O
+-	POS	O
+NAME	POS	O
+(	POS	O
+NOS	POS	O
+inhibitor	POS	O
+)	POS	O
+observed	POS	O
+in	POS	O
+different	POS	O
+epilepsy	POS	B-NP
+models	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+the	POS	O
+current	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+NO	POS	O
+on	POS	O
+the	POS	O
+behavioral	POS	O
+and	POS	O
+EEG	POS	O
+characteristics	POS	O
+of	POS	O
+lindane	POS	O
+-	POS	O
+induced	POS	O
+epilepsy	POS	B-NP
+in	POS	O
+male	POS	O
+Wistar	POS	O
+albino	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+administration	POS	O
+of	POS	O
+L	POS	O
+-	POS	O
+arginine	POS	O
+(	POS	O
+600	POS	O
+,	POS	O
+800	POS	O
+and	POS	O
+1000	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+in	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+manner	POS	O
+significantly	POS	O
+increased	POS	O
+convulsion	POS	B-NP
+incidence	POS	O
+and	POS	O
+severity	POS	O
+and	POS	O
+shortened	POS	O
+latency	POS	O
+time	POS	O
+to	POS	O
+first	POS	O
+convulsion	POS	B-NP
+elicited	POS	O
+by	POS	O
+lower	POS	O
+lindane	POS	O
+dose	POS	O
+(	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+contrary	POS	O
+,	POS	O
+pretreatment	POS	O
+with	POS	O
+L	POS	O
+-	POS	O
+NAME	POS	O
+(	POS	O
+500	POS	O
+,	POS	O
+700	POS	O
+and	POS	O
+900	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+decreased	POS	O
+convulsion	POS	B-NP
+incidence	POS	O
+and	POS	O
+severity	POS	O
+and	POS	O
+prolonged	POS	O
+latency	POS	O
+time	POS	O
+to	POS	O
+convulsion	POS	B-NP
+following	POS	O
+injection	POS	O
+with	POS	O
+a	POS	O
+convulsive	POS	B-NP
+dose	POS	O
+of	POS	O
+lindane	POS	O
+(	POS	O
+8	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+.	POS	O
+EEG	POS	O
+analyses	POS	O
+showed	POS	O
+increase	POS	O
+of	POS	O
+number	POS	O
+and	POS	O
+duration	POS	O
+of	POS	O
+ictal	POS	O
+periods	POS	O
+in	POS	O
+EEG	POS	O
+of	POS	O
+rats	POS	O
+receiving	POS	O
+l	POS	O
+-	POS	O
+arginine	POS	O
+prior	POS	O
+to	POS	O
+lindane	POS	O
+and	POS	O
+decrease	POS	O
+of	POS	O
+this	POS	O
+number	POS	O
+in	POS	O
+rats	POS	O
+pretreated	POS	O
+with	POS	O
+L	POS	O
+-	POS	O
+NAME	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+support	POS	O
+the	POS	O
+conclusion	POS	O
+that	POS	O
+NO	POS	O
+plays	POS	O
+a	POS	O
+role	POS	O
+of	POS	O
+endogenous	POS	O
+convulsant	POS	O
+in	POS	O
+rat	POS	O
+model	POS	O
+of	POS	O
+lindane	POS	O
+seizures	POS	B-NP
+.	POS	O
+Severe	POS	B-NP
+polyneuropathy	POS	I-NP
+and	POS	O
+motor	POS	B-NP
+loss	POS	I-NP
+after	POS	O
+intrathecal	POS	O
+thiotepa	POS	O
+combination	POS	O
+chemotherapy	POS	O
+:	POS	O
+description	POS	O
+of	POS	O
+two	POS	O
+cases	POS	O
+.	POS	O
+Two	POS	O
+cases	POS	O
+of	POS	O
+severe	POS	O
+delayed	POS	O
+neurologic	POS	B-NP
+toxicity	POS	I-NP
+related	POS	O
+to	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+intrathecal	POS	O
+(	POS	O
+IT	POS	O
+)	POS	O
+combination	POS	O
+chemotherapy	POS	O
+including	POS	O
+thiotepa	POS	O
+(	POS	O
+TSPA	POS	O
+)	POS	O
+are	POS	O
+presented	POS	O
+.	POS	O
+Both	POS	O
+cases	POS	O
+developed	POS	O
+axonal	POS	B-NP
+neuropathy	POS	I-NP
+with	POS	O
+motor	POS	O
+predominance	POS	O
+in	POS	O
+the	POS	O
+lower	POS	O
+extremities	POS	O
+1	POS	O
+and	POS	O
+6	POS	O
+months	POS	O
+after	POS	O
+IT	POS	O
+chemotherapy	POS	O
+was	POS	O
+administered	POS	O
+.	POS	O
+Neurologic	POS	B-NP
+toxicities	POS	I-NP
+have	POS	O
+been	POS	O
+described	POS	O
+with	POS	O
+IT	POS	O
+-	POS	O
+methotrexate	POS	O
+,	POS	O
+IT	POS	O
+-	POS	O
+cytosine	POS	O
+arabinoside	POS	O
+and	POS	O
+IT	POS	O
+-	POS	O
+TSPA	POS	O
+.	POS	O
+To	POS	O
+our	POS	O
+knowledge	POS	O
+,	POS	O
+however	POS	O
+,	POS	O
+axonal	POS	B-NP
+neuropathy	POS	I-NP
+following	POS	O
+administration	POS	O
+of	POS	O
+these	POS	O
+three	POS	O
+agents	POS	O
+has	POS	O
+not	POS	O
+been	POS	O
+previously	POS	O
+described	POS	O
+.	POS	O
+In	POS	O
+spite	POS	O
+of	POS	O
+the	POS	O
+fact	POS	O
+that	POS	O
+TSPA	POS	O
+is	POS	O
+a	POS	O
+useful	POS	O
+IT	POS	O
+agent	POS	O
+,	POS	O
+its	POS	O
+combination	POS	O
+with	POS	O
+MTX	POS	O
+,	POS	O
+ara	POS	O
+-	POS	O
+C	POS	O
+and	POS	O
+radiotherapy	POS	O
+could	POS	O
+cause	POS	O
+severe	POS	O
+neurotoxicity	POS	B-NP
+.	POS	O
+This	POS	O
+unexpected	POS	O
+complication	POS	O
+indicates	POS	O
+the	POS	O
+need	POS	O
+for	POS	O
+further	POS	O
+toxicology	POS	O
+research	POS	O
+on	POS	O
+IT	POS	O
+-	POS	O
+TSPA	POS	O
+.	POS	O
+Effects	POS	O
+of	POS	O
+cromakalim	POS	O
+and	POS	O
+pinacidil	POS	O
+on	POS	O
+large	POS	O
+epicardial	POS	O
+and	POS	O
+small	POS	O
+coronary	POS	O
+arteries	POS	O
+in	POS	O
+conscious	POS	O
+dogs	POS	O
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+bolus	POS	O
+administration	POS	O
+of	POS	O
+cromakalim	POS	O
+(	POS	O
+1	POS	O
+-	POS	O
+10	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+and	POS	O
+pinacidil	POS	O
+(	POS	O
+3	POS	O
+-	POS	O
+100	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+on	POS	O
+large	POS	O
+(	POS	O
+circumflex	POS	O
+artery	POS	O
+)	POS	O
+and	POS	O
+small	POS	O
+coronary	POS	O
+arteries	POS	O
+and	POS	O
+on	POS	O
+systemic	POS	O
+hemodynamics	POS	O
+were	POS	O
+investigated	POS	O
+in	POS	O
+chronically	POS	O
+instrumented	POS	O
+conscious	POS	O
+dogs	POS	O
+and	POS	O
+compared	POS	O
+to	POS	O
+those	POS	O
+of	POS	O
+nitroglycerin	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+03	POS	O
+-	POS	O
+10	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+.	POS	O
+Nitroglycerin	POS	O
+,	POS	O
+up	POS	O
+to	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+selectively	POS	O
+increased	POS	O
+circumflex	POS	O
+artery	POS	O
+diameter	POS	O
+(	POS	O
+CxAD	POS	O
+)	POS	O
+without	POS	O
+simultaneously	POS	O
+affecting	POS	O
+any	POS	O
+other	POS	O
+cardiac	POS	O
+or	POS	O
+systemic	POS	O
+hemodynamic	POS	O
+parameter	POS	O
+.	POS	O
+In	POS	O
+contrast	POS	O
+,	POS	O
+cromakalim	POS	O
+and	POS	O
+pinacidil	POS	O
+at	POS	O
+all	POS	O
+doses	POS	O
+and	POS	O
+nitroglycerin	POS	O
+at	POS	O
+doses	POS	O
+higher	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+simultaneously	POS	O
+and	POS	O
+dose	POS	O
+-	POS	O
+dependently	POS	O
+increased	POS	O
+CxAD	POS	O
+,	POS	O
+coronary	POS	O
+blood	POS	O
+flow	POS	O
+and	POS	O
+heart	POS	O
+rate	POS	O
+and	POS	O
+decreased	POS	O
+coronary	POS	O
+vascular	POS	O
+resistance	POS	O
+and	POS	O
+aortic	POS	O
+pressure	POS	O
+.	POS	O
+Cromakalim	POS	O
+was	POS	O
+approximately	POS	O
+8	POS	O
+-	POS	O
+to	POS	O
+9	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+fold	POS	O
+more	POS	O
+potent	POS	O
+than	POS	O
+pinacidil	POS	O
+in	POS	O
+increasing	POS	O
+CxAD	POS	O
+.	POS	O
+Vasodilation	POS	O
+of	POS	O
+large	POS	O
+and	POS	O
+small	POS	O
+coronary	POS	O
+vessels	POS	O
+and	POS	O
+hypotension	POS	B-NP
+induced	POS	O
+by	POS	O
+cromakalim	POS	O
+and	POS	O
+pinacidil	POS	O
+were	POS	O
+not	POS	O
+affected	POS	O
+by	POS	O
+prior	POS	O
+combined	POS	O
+beta	POS	O
+adrenergic	POS	O
+and	POS	O
+muscarinic	POS	O
+receptors	POS	O
+blockade	POS	O
+but	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+tachycardia	POS	B-NP
+was	POS	O
+abolished	POS	O
+.	POS	O
+When	POS	O
+circumflex	POS	O
+artery	POS	O
+blood	POS	O
+flow	POS	O
+was	POS	O
+maintained	POS	O
+constant	POS	O
+,	POS	O
+the	POS	O
+increases	POS	O
+in	POS	O
+CxAD	POS	O
+induced	POS	O
+by	POS	O
+cromakalim	POS	O
+(	POS	O
+10	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+,	POS	O
+pinacidil	POS	O
+(	POS	O
+30	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+and	POS	O
+nitroglycerin	POS	O
+(	POS	O
+10	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+were	POS	O
+reduced	POS	O
+by	POS	O
+68	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+7	POS	O
+,	POS	O
+54	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+9	POS	O
+and	POS	O
+1	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+%	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+whereas	POS	O
+nitroglycerin	POS	O
+preferentially	POS	O
+and	POS	O
+flow	POS	O
+-	POS	O
+independently	POS	O
+dilates	POS	O
+large	POS	O
+coronary	POS	O
+arteries	POS	O
+,	POS	O
+cromakalim	POS	O
+and	POS	O
+pinacidil	POS	O
+dilate	POS	O
+both	POS	O
+large	POS	O
+and	POS	O
+small	POS	O
+coronary	POS	O
+arteries	POS	O
+and	POS	O
+this	POS	O
+effect	POS	O
+is	POS	O
+not	POS	O
+dependent	POS	O
+upon	POS	O
+the	POS	O
+simultaneous	POS	O
+beta	POS	O
+adrenoceptors	POS	O
+-	POS	O
+mediated	POS	O
+rise	POS	O
+in	POS	O
+myocardial	POS	O
+metabolic	POS	O
+demand	POS	O
+.	POS	O
+Finally	POS	O
+,	POS	O
+two	POS	O
+mechanisms	POS	O
+at	POS	O
+least	POS	O
+,	POS	O
+direct	POS	O
+vasodilation	POS	O
+and	POS	O
+flow	POS	O
+dependency	POS	O
+,	POS	O
+are	POS	O
+involved	POS	O
+in	POS	O
+the	POS	O
+cromakalim	POS	O
+-	POS	O
+and	POS	O
+pinacidil	POS	O
+-	POS	O
+induced	POS	O
+increase	POS	O
+in	POS	O
+CxAD	POS	O
+.	POS	O
+Mefenamic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+neutropenia	POS	B-NP
+and	POS	O
+renal	POS	B-NP
+failure	POS	I-NP
+in	POS	O
+elderly	POS	O
+females	POS	O
+with	POS	O
+hypothyroidism	POS	B-NP
+.	POS	O
+We	POS	O
+report	POS	O
+mefenamic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+non	POS	B-NP
+-	POS	I-NP
+oliguric	POS	I-NP
+renal	POS	I-NP
+failure	POS	I-NP
+and	POS	O
+severe	POS	O
+neutropenia	POS	B-NP
+occurring	POS	O
+simultaneously	POS	O
+in	POS	O
+two	POS	O
+elderly	POS	O
+females	POS	O
+.	POS	O
+The	POS	O
+neutropenia	POS	B-NP
+was	POS	O
+due	POS	O
+to	POS	O
+maturation	POS	O
+arrest	POS	O
+of	POS	O
+the	POS	O
+myeloid	POS	O
+series	POS	O
+in	POS	O
+one	POS	O
+patient	POS	O
+.	POS	O
+Both	POS	O
+patients	POS	O
+were	POS	O
+also	POS	O
+hypothyroid	POS	B-NP
+,	POS	O
+but	POS	O
+it	POS	O
+is	POS	O
+not	POS	O
+clear	POS	O
+whether	POS	O
+this	POS	O
+was	POS	O
+a	POS	O
+predisposing	POS	O
+factor	POS	O
+to	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+these	POS	O
+adverse	POS	O
+reactions	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+it	POS	O
+would	POS	O
+seem	POS	O
+prudent	POS	O
+not	POS	O
+to	POS	O
+use	POS	O
+mefenamic	POS	O
+acid	POS	O
+in	POS	O
+hypothyroid	POS	B-NP
+patients	POS	O
+until	POS	O
+the	POS	O
+hypothyroidism	POS	B-NP
+has	POS	O
+been	POS	O
+corrected	POS	O
+.	POS	O
+Etiology	POS	O
+of	POS	O
+hypercalcemia	POS	B-NP
+in	POS	O
+hemodialysis	POS	B-NP
+patients	POS	O
+on	POS	O
+calcium	POS	O
+carbonate	POS	O
+therapy	POS	O
+.	POS	O
+Fourteen	POS	O
+of	POS	O
+39	POS	O
+dialysis	POS	O
+patients	POS	O
+(	POS	O
+36	POS	O
+%	POS	O
+)	POS	O
+became	POS	O
+hypercalcemic	POS	B-NP
+after	POS	O
+switching	POS	O
+to	POS	O
+calcium	POS	O
+carbonate	POS	O
+as	POS	O
+their	POS	O
+principal	POS	O
+phosphate	POS	O
+binder	POS	O
+.	POS	O
+In	POS	O
+order	POS	O
+to	POS	O
+identify	POS	O
+risk	POS	O
+factors	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+hypercalcemia	POS	B-NP
+,	POS	O
+indirect	POS	O
+parameters	POS	O
+of	POS	O
+intestinal	POS	O
+calcium	POS	O
+reabsorption	POS	O
+and	POS	O
+bone	POS	O
+turnover	POS	O
+rate	POS	O
+in	POS	O
+these	POS	O
+14	POS	O
+patients	POS	O
+were	POS	O
+compared	POS	O
+with	POS	O
+results	POS	O
+in	POS	O
+14	POS	O
+eucalcemic	POS	O
+patients	POS	O
+matched	POS	O
+for	POS	O
+age	POS	O
+,	POS	O
+sex	POS	O
+,	POS	O
+length	POS	O
+of	POS	O
+time	POS	O
+on	POS	O
+dialysis	POS	O
+,	POS	O
+and	POS	O
+etiology	POS	O
+of	POS	O
+renal	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+In	POS	O
+addition	POS	O
+to	POS	O
+experiencing	POS	O
+hypercalcemic	POS	B-NP
+episodes	POS	O
+with	POS	O
+peak	POS	O
+calcium	POS	O
+values	POS	O
+of	POS	O
+2	POS	O
+.	POS	O
+7	POS	O
+to	POS	O
+3	POS	O
+.	POS	O
+8	POS	O
+mmol	POS	O
+/	POS	O
+L	POS	O
+(	POS	O
+10	POS	O
+.	POS	O
+7	POS	O
+to	POS	O
+15	POS	O
+.	POS	O
+0	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+)	POS	O
+,	POS	O
+patients	POS	O
+in	POS	O
+the	POS	O
+hypercalcemic	POS	B-NP
+group	POS	O
+exhibited	POS	O
+a	POS	O
+significant	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+mean	POS	O
+calcium	POS	O
+concentration	POS	O
+obtained	POS	O
+during	POS	O
+6	POS	O
+months	POS	O
+before	POS	O
+the	POS	O
+switch	POS	O
+,	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+mean	POS	O
+value	POS	O
+obtained	POS	O
+during	POS	O
+the	POS	O
+7	POS	O
+months	POS	O
+of	POS	O
+observation	POS	O
+after	POS	O
+the	POS	O
+switch	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+4	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+03	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+03	POS	O
+mmol	POS	O
+/	POS	O
+L	POS	O
+[	POS	O
+9	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+2	POS	O
+to	POS	O
+10	POS	O
+.	POS	O
+2	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+]	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+006	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+contrast	POS	O
+,	POS	O
+eucalcemic	POS	O
+patients	POS	O
+exhibited	POS	O
+no	POS	O
+change	POS	O
+in	POS	O
+mean	POS	O
+calcium	POS	O
+values	POS	O
+over	POS	O
+the	POS	O
+same	POS	O
+time	POS	O
+period	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+mmol	POS	O
+/	POS	O
+L	POS	O
+[	POS	O
+9	POS	O
+.	POS	O
+2	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+2	POS	O
+to	POS	O
+9	POS	O
+.	POS	O
+2	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+]	POS	O
+)	POS	O
+.	POS	O
+CaCO3	POS	O
+dosage	POS	O
+,	POS	O
+calculated	POS	O
+dietary	POS	O
+calcium	POS	O
+intake	POS	O
+,	POS	O
+and	POS	O
+circulating	POS	O
+levels	POS	O
+of	POS	O
+vitamin	POS	O
+D	POS	O
+metabolites	POS	O
+were	POS	O
+similar	POS	O
+in	POS	O
+both	POS	O
+groups	POS	O
+.	POS	O
+Physical	POS	O
+activity	POS	O
+index	POS	O
+and	POS	O
+predialysis	POS	O
+serum	POS	O
+bicarbonate	POS	O
+levels	POS	O
+also	POS	O
+were	POS	O
+similar	POS	O
+in	POS	O
+both	POS	O
+groups	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+difference	POS	O
+in	POS	O
+parameters	POS	O
+reflecting	POS	O
+bone	POS	O
+turnover	POS	O
+rates	POS	O
+between	POS	O
+groups	POS	O
+.	POS	O
+(	POS	O
+ABSTRACT	POS	O
+TRUNCATED	POS	O
+AT	POS	O
+250	POS	O
+WORDS	POS	O
+)	POS	O
+Late	POS	O
+-	POS	O
+onset	POS	O
+scleroderma	POS	B-NP
+renal	POS	I-NP
+crisis	POS	I-NP
+induced	POS	O
+by	POS	O
+tacrolimus	POS	O
+and	POS	O
+prednisolone	POS	O
+:	POS	O
+a	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+Scleroderma	POS	B-NP
+renal	POS	I-NP
+crisis	POS	I-NP
+(	POS	O
+SRC	POS	B-NP
+)	POS	O
+is	POS	O
+a	POS	O
+rare	POS	O
+complication	POS	O
+of	POS	O
+systemic	POS	B-NP
+sclerosis	POS	I-NP
+(	POS	O
+SSc	POS	B-NP
+)	POS	O
+but	POS	O
+can	POS	O
+be	POS	O
+severe	POS	O
+enough	POS	O
+to	POS	O
+require	POS	O
+temporary	POS	O
+or	POS	O
+permanent	POS	O
+renal	POS	O
+replacement	POS	O
+therapy	POS	O
+.	POS	O
+Moderate	POS	O
+to	POS	O
+high	POS	O
+dose	POS	O
+corticosteroid	POS	O
+use	POS	O
+is	POS	O
+recognized	POS	O
+as	POS	O
+a	POS	O
+major	POS	O
+risk	POS	O
+factor	POS	O
+for	POS	O
+SRC	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+there	POS	O
+have	POS	O
+been	POS	O
+reports	POS	O
+of	POS	O
+thrombotic	POS	B-NP
+microangiopathy	POS	I-NP
+precipitated	POS	O
+by	POS	O
+cyclosporine	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+SSc	POS	B-NP
+.	POS	O
+In	POS	O
+this	POS	O
+article	POS	O
+,	POS	O
+we	POS	O
+report	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+SRC	POS	B-NP
+induced	POS	O
+by	POS	O
+tacrolimus	POS	O
+and	POS	O
+corticosteroids	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+work	POS	O
+is	POS	O
+to	POS	O
+call	POS	O
+attention	POS	O
+to	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+tacrolimus	POS	O
+use	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+SSc	POS	B-NP
+.	POS	O
+Methyldopa	POS	O
+-	POS	O
+induced	POS	O
+hemolytic	POS	B-NP
+anemia	POS	I-NP
+in	POS	O
+a	POS	O
+15	POS	O
+year	POS	O
+old	POS	O
+presenting	POS	O
+as	POS	O
+near	POS	B-NP
+-	POS	I-NP
+syncope	POS	I-NP
+.	POS	O
+Methyldopa	POS	B-NP
+is	POS	O
+an	POS	O
+antihypertensive	POS	O
+medication	POS	O
+which	POS	O
+is	POS	O
+available	POS	O
+generically	POS	O
+and	POS	O
+under	POS	O
+the	POS	O
+trade	POS	O
+name	POS	O
+Aldomet	POS	O
+that	POS	O
+is	POS	O
+widely	POS	O
+prescribed	POS	O
+in	POS	O
+the	POS	O
+adult	POS	O
+population	POS	O
+and	POS	O
+infrequently	POS	O
+used	POS	O
+in	POS	O
+children	POS	O
+.	POS	O
+Methyldopa	POS	B-NP
+causes	POS	O
+an	POS	O
+autoimmune	POS	B-NP
+hemolytic	POS	I-NP
+anemia	POS	I-NP
+in	POS	O
+a	POS	O
+small	POS	O
+percentage	POS	O
+of	POS	O
+patients	POS	O
+who	POS	O
+take	POS	O
+the	POS	O
+drug	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+methyldopa	POS	O
+-	POS	O
+induced	POS	O
+hemolytic	POS	B-NP
+anemia	POS	I-NP
+in	POS	O
+a	POS	O
+15	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+boy	POS	O
+who	POS	O
+presented	POS	O
+to	POS	O
+the	POS	O
+emergency	POS	O
+department	POS	O
+with	POS	O
+near	POS	O
+-	POS	O
+syncope	POS	B-NP
+.	POS	O
+The	POS	O
+boy	POS	O
+had	POS	O
+been	POS	O
+treated	POS	O
+with	POS	O
+intravenous	POS	O
+methyldopa	POS	O
+during	POS	O
+a	POS	O
+trauma	POS	B-NP
+admission	POS	O
+seven	POS	O
+weeks	POS	O
+prior	POS	O
+to	POS	O
+presentation	POS	O
+.	POS	O
+Evaluation	POS	O
+revealed	POS	O
+a	POS	O
+hemoglobin	POS	O
+of	POS	O
+three	POS	O
+grams	POS	O
+,	POS	O
+3	POS	O
++	POS	O
+Coombs	POS	O
+'	POS	O
+test	POS	O
+with	POS	O
+polyspecific	POS	O
+anti	POS	O
+-	POS	O
+human	POS	O
+globulin	POS	O
+and	POS	O
+monospecific	POS	O
+IgG	POS	O
+reagents	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+warm	POS	O
+reacting	POS	O
+autoantibody	POS	O
+.	POS	O
+Transfusion	POS	O
+and	POS	O
+corticosteroid	POS	O
+therapy	POS	O
+resulted	POS	O
+in	POS	O
+a	POS	O
+complete	POS	O
+recovery	POS	O
+of	POS	O
+the	POS	O
+patient	POS	O
+.	POS	O
+Emergency	POS	O
+physicians	POS	O
+treating	POS	O
+children	POS	O
+must	POS	O
+be	POS	O
+aware	POS	O
+of	POS	O
+this	POS	O
+syndrome	POS	O
+in	POS	O
+order	POS	O
+to	POS	O
+diagnose	POS	O
+and	POS	O
+treat	POS	O
+it	POS	O
+correctly	POS	O
+.	POS	O
+A	POS	O
+brief	POS	O
+review	POS	O
+of	POS	O
+autoimmune	POS	O
+and	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+hemolytic	POS	B-NP
+anemias	POS	I-NP
+is	POS	O
+provided	POS	O
+.	POS	O
+The	POS	O
+risk	POS	O
+and	POS	O
+associated	POS	O
+factors	POS	O
+of	POS	O
+methamphetamine	POS	O
+psychosis	POS	B-NP
+in	POS	O
+methamphetamine	POS	O
+-	POS	O
+dependent	POS	O
+patients	POS	O
+in	POS	O
+Malaysia	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+The	POS	O
+objective	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+lifetime	POS	O
+and	POS	O
+current	POS	O
+methamphetamine	POS	O
+-	POS	O
+induced	POS	O
+psychosis	POS	B-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+methamphetamine	POS	O
+dependence	POS	O
+.	POS	O
+The	POS	O
+association	POS	O
+between	POS	O
+psychiatric	POS	O
+co	POS	O
+-	POS	O
+morbidity	POS	O
+and	POS	O
+methamphetamine	POS	O
+-	POS	O
+induced	POS	O
+psychosis	POS	B-NP
+was	POS	O
+also	POS	O
+studied	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+This	POS	O
+was	POS	O
+a	POS	O
+cross	POS	O
+-	POS	O
+sectional	POS	O
+study	POS	O
+conducted	POS	O
+concurrently	POS	O
+at	POS	O
+a	POS	O
+teaching	POS	O
+hospital	POS	O
+and	POS	O
+a	POS	O
+drug	POS	O
+rehabilitation	POS	O
+center	POS	O
+in	POS	O
+Malaysia	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+the	POS	O
+diagnosis	POS	O
+of	POS	O
+methamphetamine	POS	O
+based	POS	O
+on	POS	O
+DSM	POS	O
+-	POS	O
+IV	POS	O
+were	POS	O
+interviewed	POS	O
+using	POS	O
+the	POS	O
+Mini	POS	O
+International	POS	O
+Neuropsychiatric	POS	O
+Interview	POS	O
+(	POS	O
+M	POS	O
+.	POS	O
+I	POS	O
+.	POS	O
+N	POS	O
+.	POS	O
+I	POS	O
+.	POS	O
+)	POS	O
+for	POS	O
+methamphetamine	POS	O
+-	POS	O
+induced	POS	O
+psychosis	POS	B-NP
+and	POS	O
+other	POS	O
+Axis	POS	B-NP
+I	POS	I-NP
+psychiatric	POS	I-NP
+disorders	POS	I-NP
+.	POS	O
+The	POS	O
+information	POS	O
+on	POS	O
+sociodemographic	POS	O
+background	POS	O
+and	POS	O
+drug	POS	O
+use	POS	O
+history	POS	O
+was	POS	O
+obtained	POS	O
+from	POS	O
+interview	POS	O
+or	POS	O
+medical	POS	O
+records	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Of	POS	O
+292	POS	O
+subjects	POS	O
+,	POS	O
+47	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+subjects	POS	O
+had	POS	O
+a	POS	O
+past	POS	O
+history	POS	O
+of	POS	O
+psychotic	POS	B-NP
+symptoms	POS	I-NP
+and	POS	O
+13	POS	O
+.	POS	O
+0	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+were	POS	O
+having	POS	O
+current	POS	O
+psychotic	POS	B-NP
+symptoms	POS	I-NP
+.	POS	O
+Co	POS	O
+-	POS	O
+morbid	POS	O
+major	POS	O
+depressive	POS	B-NP
+disorder	POS	I-NP
+(	POS	O
+OR	POS	O
+=	POS	O
+7	POS	O
+.	POS	O
+18	POS	O
+,	POS	O
+95	POS	O
+CI	POS	O
+=	POS	O
+2	POS	O
+.	POS	O
+612	POS	O
+-	POS	O
+19	POS	O
+.	POS	O
+708	POS	O
+)	POS	O
+,	POS	O
+bipolar	POS	B-NP
+disorder	POS	I-NP
+(	POS	O
+OR	POS	O
+=	POS	O
+13	POS	O
+.	POS	O
+807	POS	O
+,	POS	O
+95	POS	O
+CI	POS	O
+=	POS	O
+5	POS	O
+.	POS	O
+194	POS	O
+-	POS	O
+36	POS	O
+.	POS	O
+706	POS	O
+)	POS	O
+,	POS	O
+antisocial	POS	B-NP
+personality	POS	I-NP
+disorder	POS	I-NP
+(	POS	O
+OR	POS	O
+=	POS	O
+12	POS	O
+.	POS	O
+619	POS	O
+,	POS	O
+95	POS	O
+CI	POS	O
+=	POS	O
+6	POS	O
+.	POS	O
+702	POS	O
+-	POS	O
+23	POS	O
+.	POS	O
+759	POS	O
+)	POS	O
+and	POS	O
+heavy	POS	O
+methamphetamine	POS	O
+uses	POS	O
+were	POS	O
+significantly	POS	O
+associated	POS	O
+with	POS	O
+lifetime	POS	O
+methamphetamine	POS	O
+-	POS	O
+induced	POS	O
+psychosis	POS	B-NP
+after	POS	O
+adjusted	POS	O
+for	POS	O
+other	POS	O
+factors	POS	O
+.	POS	O
+Major	POS	O
+depressive	POS	B-NP
+disorder	POS	I-NP
+(	POS	O
+OR	POS	O
+=	POS	O
+2	POS	O
+.	POS	O
+870	POS	O
+,	POS	O
+CI	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+154	POS	O
+-	POS	O
+7	POS	O
+.	POS	O
+142	POS	O
+)	POS	O
+and	POS	O
+antisocial	POS	B-NP
+personality	POS	I-NP
+disorder	POS	I-NP
+(	POS	O
+OR	POS	O
+=	POS	O
+3	POS	O
+.	POS	O
+299	POS	O
+,	POS	O
+95	POS	O
+CI	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+375	POS	O
+-	POS	O
+7	POS	O
+.	POS	O
+914	POS	O
+)	POS	O
+were	POS	O
+the	POS	O
+only	POS	O
+factors	POS	O
+associated	POS	O
+with	POS	O
+current	POS	O
+psychosis	POS	B-NP
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+There	POS	O
+was	POS	O
+a	POS	O
+high	POS	O
+risk	POS	O
+of	POS	O
+psychosis	POS	B-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+methamphetamine	POS	B-NP
+dependence	POS	I-NP
+.	POS	O
+It	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+co	POS	B-NP
+-	POS	I-NP
+morbid	POS	I-NP
+affective	POS	I-NP
+disorder	POS	I-NP
+,	POS	O
+antisocial	POS	B-NP
+personality	POS	I-NP
+,	POS	O
+and	POS	O
+heavy	POS	O
+methamphetamine	POS	O
+use	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+recommended	POS	O
+that	POS	O
+all	POS	O
+cases	POS	O
+of	POS	O
+methamphetamine	POS	O
+dependence	POS	O
+should	POS	O
+be	POS	O
+screened	POS	O
+for	POS	O
+psychotic	POS	B-NP
+symptoms	POS	I-NP
+.	POS	O
+Cerebellar	POS	O
+sensory	POS	O
+processing	POS	O
+alterations	POS	O
+impact	POS	O
+motor	POS	O
+cortical	POS	O
+plasticity	POS	O
+in	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+:	POS	O
+clues	POS	O
+from	POS	O
+dyskinetic	POS	B-NP
+patients	POS	O
+.	POS	O
+The	POS	O
+plasticity	POS	O
+of	POS	O
+primary	POS	O
+motor	POS	O
+cortex	POS	O
+(	POS	O
+M1	POS	O
+)	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+PD	POS	B-NP
+)	POS	O
+and	POS	O
+levodopa	POS	O
+-	POS	O
+induced	POS	O
+dyskinesias	POS	B-NP
+(	POS	O
+LIDs	POS	B-NP
+)	POS	O
+is	POS	O
+severely	POS	O
+impaired	POS	O
+.	POS	O
+We	POS	O
+recently	POS	O
+reported	POS	O
+in	POS	O
+young	POS	O
+healthy	POS	O
+subjects	POS	O
+that	POS	O
+inhibitory	POS	O
+cerebellar	POS	O
+stimulation	POS	O
+enhanced	POS	O
+the	POS	O
+sensorimotor	POS	O
+plasticity	POS	O
+of	POS	O
+M1	POS	O
+that	POS	O
+was	POS	O
+induced	POS	O
+by	POS	O
+paired	POS	O
+associative	POS	O
+stimulation	POS	O
+(	POS	O
+PAS	POS	O
+)	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+demonstrates	POS	O
+that	POS	O
+the	POS	O
+deficient	POS	O
+sensorimotor	POS	O
+M1	POS	O
+plasticity	POS	O
+in	POS	O
+16	POS	O
+patients	POS	O
+with	POS	O
+LIDs	POS	B-NP
+could	POS	O
+be	POS	O
+reinstated	POS	O
+by	POS	O
+a	POS	O
+single	POS	O
+session	POS	O
+of	POS	O
+real	POS	O
+inhibitory	POS	O
+cerebellar	POS	O
+stimulation	POS	O
+but	POS	O
+not	POS	O
+sham	POS	O
+stimulation	POS	O
+.	POS	O
+This	POS	O
+was	POS	O
+evident	POS	O
+only	POS	O
+when	POS	O
+a	POS	O
+sensory	POS	O
+component	POS	O
+was	POS	O
+involved	POS	O
+in	POS	O
+the	POS	O
+induction	POS	O
+of	POS	O
+plasticity	POS	O
+,	POS	O
+indicating	POS	O
+that	POS	O
+cerebellar	POS	O
+sensory	POS	O
+processing	POS	O
+function	POS	O
+is	POS	O
+involved	POS	O
+in	POS	O
+the	POS	O
+resurgence	POS	O
+of	POS	O
+M1	POS	O
+plasticity	POS	O
+.	POS	O
+The	POS	O
+benefit	POS	O
+of	POS	O
+inhibitory	POS	O
+cerebellar	POS	O
+stimulation	POS	O
+on	POS	O
+LIDs	POS	B-NP
+is	POS	O
+known	POS	O
+.	POS	O
+To	POS	O
+explore	POS	O
+whether	POS	O
+this	POS	O
+benefit	POS	O
+is	POS	O
+linked	POS	O
+to	POS	O
+the	POS	O
+restoration	POS	O
+of	POS	O
+sensorimotor	POS	O
+plasticity	POS	O
+of	POS	O
+M1	POS	O
+,	POS	O
+we	POS	O
+conducted	POS	O
+an	POS	O
+additional	POS	O
+study	POS	O
+looking	POS	O
+at	POS	O
+changes	POS	O
+in	POS	O
+LIDs	POS	B-NP
+and	POS	O
+PAS	POS	O
+-	POS	O
+induced	POS	O
+plasticity	POS	O
+after	POS	O
+10	POS	O
+sessions	POS	O
+of	POS	O
+either	POS	O
+bilateral	POS	O
+,	POS	O
+real	POS	O
+inhibitory	POS	O
+cerebellar	POS	O
+stimulation	POS	O
+or	POS	O
+sham	POS	O
+stimulation	POS	O
+.	POS	O
+Only	POS	O
+real	POS	O
+and	POS	O
+not	POS	O
+sham	POS	O
+stimulation	POS	O
+had	POS	O
+an	POS	O
+antidyskinetic	POS	O
+effect	POS	O
+and	POS	O
+it	POS	O
+was	POS	O
+paralleled	POS	O
+by	POS	O
+a	POS	O
+resurgence	POS	O
+in	POS	O
+the	POS	O
+sensorimotor	POS	O
+plasticity	POS	O
+of	POS	O
+M1	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+alterations	POS	O
+in	POS	O
+cerebellar	POS	O
+sensory	POS	O
+processing	POS	O
+function	POS	O
+,	POS	O
+occurring	POS	O
+secondary	POS	O
+to	POS	O
+abnormal	POS	O
+basal	POS	O
+ganglia	POS	O
+signals	POS	O
+reaching	POS	O
+it	POS	O
+,	POS	O
+may	POS	O
+be	POS	O
+an	POS	O
+important	POS	O
+element	POS	O
+contributing	POS	O
+to	POS	O
+the	POS	O
+maladaptive	POS	O
+sensorimotor	POS	O
+plasticity	POS	O
+of	POS	O
+M1	POS	O
+and	POS	O
+the	POS	O
+emergence	POS	O
+of	POS	O
+abnormal	POS	B-NP
+involuntary	POS	I-NP
+movements	POS	I-NP
+.	POS	O
+The	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+safety	POS	O
+of	POS	O
+danazol	POS	O
+in	POS	O
+women	POS	O
+with	POS	O
+hereditary	POS	B-NP
+angioedema	POS	I-NP
+.	POS	O
+Although	POS	O
+the	POS	O
+short	POS	O
+-	POS	O
+term	POS	O
+safety	POS	O
+(	POS	O
+less	POS	O
+than	POS	O
+or	POS	O
+equal	POS	O
+to	POS	O
+6	POS	O
+months	POS	O
+)	POS	O
+of	POS	O
+danazol	POS	O
+has	POS	O
+been	POS	O
+established	POS	O
+in	POS	O
+a	POS	O
+variety	POS	O
+of	POS	O
+settings	POS	O
+,	POS	O
+no	POS	O
+information	POS	O
+exists	POS	O
+as	POS	O
+to	POS	O
+its	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+safety	POS	O
+.	POS	O
+We	POS	O
+therefore	POS	O
+investigated	POS	O
+the	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+safety	POS	O
+of	POS	O
+danazol	POS	O
+by	POS	O
+performing	POS	O
+a	POS	O
+retrospective	POS	O
+chart	POS	O
+review	POS	O
+of	POS	O
+60	POS	O
+female	POS	O
+patients	POS	O
+with	POS	O
+hereditary	POS	B-NP
+angioedema	POS	I-NP
+treated	POS	O
+with	POS	O
+danazol	POS	O
+for	POS	O
+a	POS	O
+continuous	POS	O
+period	POS	O
+of	POS	O
+6	POS	O
+months	POS	O
+or	POS	O
+longer	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+age	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+was	POS	O
+35	POS	O
+.	POS	O
+2	POS	O
+years	POS	O
+and	POS	O
+the	POS	O
+mean	POS	O
+duration	POS	O
+of	POS	O
+therapy	POS	O
+was	POS	O
+59	POS	O
+.	POS	O
+7	POS	O
+months	POS	O
+.	POS	O
+Virtually	POS	O
+all	POS	O
+patients	POS	O
+experienced	POS	O
+one	POS	O
+or	POS	O
+more	POS	O
+adverse	POS	O
+reactions	POS	O
+.	POS	O
+Menstrual	POS	B-NP
+abnormalities	POS	I-NP
+(	POS	O
+79	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+weight	POS	B-NP
+gain	POS	I-NP
+(	POS	O
+60	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+muscle	POS	B-NP
+cramps	POS	I-NP
+/	POS	O
+myalgias	POS	B-NP
+(	POS	O
+40	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+transaminase	POS	O
+elevations	POS	O
+(	POS	O
+40	POS	O
+%	POS	O
+)	POS	O
+were	POS	O
+the	POS	O
+most	POS	O
+common	POS	O
+adverse	POS	O
+reactions	POS	O
+.	POS	O
+The	POS	O
+drug	POS	O
+was	POS	O
+discontinued	POS	O
+due	POS	O
+to	POS	O
+adverse	POS	O
+reactions	POS	O
+in	POS	O
+8	POS	O
+patients	POS	O
+.	POS	O
+No	POS	O
+patient	POS	O
+has	POS	O
+died	POS	O
+or	POS	O
+suffered	POS	O
+any	POS	O
+apparent	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+sequelae	POS	O
+that	POS	O
+were	POS	O
+directly	POS	O
+attributable	POS	O
+to	POS	O
+the	POS	O
+drug	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+,	POS	O
+despite	POS	O
+a	POS	O
+relatively	POS	O
+high	POS	O
+incidence	POS	O
+of	POS	O
+adverse	POS	O
+reactions	POS	O
+,	POS	O
+danazol	POS	O
+has	POS	O
+proven	POS	O
+to	POS	O
+be	POS	O
+remarkably	POS	O
+safe	POS	O
+over	POS	O
+the	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+in	POS	O
+this	POS	O
+group	POS	O
+of	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+function	POS	O
+of	POS	O
+P2X3	POS	O
+receptor	POS	O
+and	POS	O
+NK1	POS	O
+receptor	POS	O
+antagonists	POS	O
+on	POS	O
+cyclophosphamide	POS	O
+-	POS	O
+induced	POS	O
+cystitis	POS	B-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+the	POS	O
+study	POS	O
+is	POS	O
+to	POS	O
+explore	POS	O
+the	POS	O
+function	POS	O
+of	POS	O
+P2X3	POS	O
+and	POS	O
+NK1	POS	O
+receptors	POS	O
+antagonists	POS	O
+on	POS	O
+cyclophosphamide	POS	O
+(	POS	O
+CYP	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+cystitis	POS	B-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Sixty	POS	O
+female	POS	O
+Sprague	POS	O
+-	POS	O
+Dawley	POS	O
+(	POS	O
+SD	POS	O
+)	POS	O
+rats	POS	O
+were	POS	O
+randomly	POS	O
+divided	POS	O
+into	POS	O
+three	POS	O
+groups	POS	O
+.	POS	O
+The	POS	O
+rats	POS	O
+in	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+were	POS	O
+intraperitoneally	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+injected	POS	O
+with	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+saline	POS	O
+(	POS	O
+4	POS	O
+ml	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+;	POS	O
+the	POS	O
+rats	POS	O
+in	POS	O
+the	POS	O
+model	POS	O
+group	POS	O
+were	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+injected	POS	O
+with	POS	O
+CYP	POS	O
+(	POS	O
+150	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+;	POS	O
+and	POS	O
+the	POS	O
+rats	POS	O
+in	POS	O
+the	POS	O
+intervention	POS	O
+group	POS	O
+were	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+injected	POS	O
+with	POS	O
+CYP	POS	O
+with	POS	O
+subsequently	POS	O
+perfusion	POS	O
+of	POS	O
+bladder	POS	O
+with	POS	O
+P2X3	POS	O
+and	POS	O
+NK1	POS	O
+receptors	POS	O
+'	POS	O
+antagonists	POS	O
+,	POS	O
+Suramin	POS	O
+and	POS	O
+GR	POS	O
+82334	POS	O
+.	POS	O
+Spontaneous	POS	O
+pain	POS	O
+behaviors	POS	O
+following	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+CYP	POS	O
+were	POS	O
+observed	POS	O
+.	POS	O
+Urodynamic	POS	O
+parameters	POS	O
+,	POS	O
+bladder	POS	O
+pressure	POS	O
+-	POS	O
+volume	POS	O
+curve	POS	O
+,	POS	O
+maximum	POS	O
+voiding	POS	O
+pressure	POS	O
+(	POS	O
+MVP	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+maximum	POS	O
+cystometric	POS	O
+capacity	POS	O
+(	POS	O
+MCC	POS	O
+)	POS	O
+,	POS	O
+were	POS	O
+recorded	POS	O
+.	POS	O
+Pathological	POS	O
+changes	POS	O
+in	POS	O
+bladder	POS	O
+tissue	POS	O
+were	POS	O
+observed	POS	O
+.	POS	O
+Immunofluorescence	POS	O
+was	POS	O
+used	POS	O
+to	POS	O
+detect	POS	O
+the	POS	O
+expression	POS	O
+of	POS	O
+P2X3	POS	O
+and	POS	O
+NK1	POS	O
+receptors	POS	O
+in	POS	O
+bladder	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Cyclophosphamide	POS	O
+treatment	POS	O
+increased	POS	O
+the	POS	O
+spontaneous	POS	O
+pain	POS	B-NP
+behaviors	POS	O
+scores	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+bladder	POS	B-NP
+instability	POS	I-NP
+during	POS	O
+urine	POS	O
+storage	POS	O
+period	POS	O
+of	POS	O
+model	POS	O
+group	POS	O
+was	POS	O
+significantly	POS	O
+higher	POS	O
+than	POS	O
+intervention	POS	O
+group	POS	O
+(	POS	O
+X	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+=	POS	O
+7	POS	O
+.	POS	O
+619	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+007	POS	O
+)	POS	O
+and	POS	O
+control	POS	O
+group	POS	O
+(	POS	O
+X	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+=	POS	O
+13	POS	O
+.	POS	O
+755	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+000	POS	O
+)	POS	O
+.	POS	O
+MCC	POS	O
+in	POS	O
+the	POS	O
+model	POS	O
+group	POS	O
+was	POS	O
+lower	POS	O
+than	POS	O
+the	POS	O
+control	POS	O
+and	POS	O
+intervention	POS	O
+groups	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+Histological	POS	O
+changes	POS	O
+evident	POS	O
+in	POS	O
+model	POS	O
+and	POS	O
+intervention	POS	O
+groups	POS	O
+rats	POS	O
+'	POS	O
+bladder	POS	O
+included	POS	O
+edema	POS	B-NP
+,	POS	O
+vasodilation	POS	B-NP
+,	POS	O
+and	POS	O
+infiltration	POS	O
+of	POS	O
+inflammatory	POS	O
+cells	POS	O
+.	POS	O
+In	POS	O
+model	POS	O
+group	POS	O
+,	POS	O
+the	POS	O
+expression	POS	O
+of	POS	O
+P2X3	POS	O
+receptor	POS	O
+increased	POS	O
+in	POS	O
+urothelium	POS	O
+and	POS	O
+suburothelium	POS	O
+,	POS	O
+and	POS	O
+NK1	POS	O
+receptor	POS	O
+increased	POS	O
+in	POS	O
+suburothelium	POS	O
+,	POS	O
+while	POS	O
+the	POS	O
+expression	POS	O
+of	POS	O
+them	POS	O
+in	POS	O
+intervention	POS	O
+group	POS	O
+was	POS	O
+lower	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+In	POS	O
+CYP	POS	O
+-	POS	O
+induced	POS	O
+cystitis	POS	B-NP
+,	POS	O
+the	POS	O
+expression	POS	O
+of	POS	O
+P2X3	POS	O
+and	POS	O
+NK1	POS	O
+receptors	POS	O
+increased	POS	O
+in	POS	O
+urothelium	POS	O
+and	POS	O
+/	POS	O
+or	POS	O
+suburothelium	POS	O
+.	POS	O
+Perfusion	POS	O
+of	POS	O
+bladder	POS	O
+with	POS	O
+P2X3	POS	O
+and	POS	O
+NK1	POS	O
+receptors	POS	O
+antagonists	POS	O
+ameliorated	POS	O
+the	POS	O
+bladder	POS	O
+function	POS	O
+.	POS	O
+Patient	POS	O
+tolerance	POS	O
+study	POS	O
+of	POS	O
+topical	POS	O
+chlorhexidine	POS	O
+diphosphanilate	POS	O
+:	POS	O
+a	POS	O
+new	POS	O
+topical	POS	O
+agent	POS	O
+for	POS	O
+burns	POS	O
+.	POS	O
+Effective	POS	O
+topical	POS	O
+antimicrobial	POS	O
+agents	POS	O
+decrease	POS	O
+infection	POS	O
+and	POS	O
+mortality	POS	O
+in	POS	O
+burn	POS	O
+patients	POS	O
+.	POS	O
+Chlorhexidine	POS	O
+phosphanilate	POS	O
+(	POS	O
+CHP	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+new	POS	O
+broad	POS	O
+-	POS	O
+spectrum	POS	O
+antimicrobial	POS	O
+agent	POS	O
+,	POS	O
+has	POS	O
+been	POS	O
+evaluated	POS	O
+as	POS	O
+a	POS	O
+topical	POS	O
+burn	POS	O
+wound	POS	O
+dressing	POS	O
+in	POS	O
+cream	POS	O
+form	POS	O
+,	POS	O
+but	POS	O
+preliminary	POS	O
+clinical	POS	O
+trials	POS	O
+reported	POS	O
+that	POS	O
+it	POS	O
+was	POS	O
+painful	POS	O
+upon	POS	O
+application	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+compared	POS	O
+various	POS	O
+concentrations	POS	O
+of	POS	O
+CHP	POS	O
+to	POS	O
+determine	POS	O
+if	POS	O
+a	POS	O
+tolerable	POS	O
+concentration	POS	O
+could	POS	O
+be	POS	O
+identified	POS	O
+with	POS	O
+retention	POS	O
+of	POS	O
+antimicrobial	POS	O
+efficacy	POS	O
+.	POS	O
+Twenty	POS	O
+-	POS	O
+nine	POS	O
+burn	POS	B-NP
+patients	POS	O
+,	POS	O
+each	POS	O
+with	POS	O
+two	POS	O
+similar	POS	O
+burns	POS	B-NP
+which	POS	O
+could	POS	O
+be	POS	O
+separately	POS	O
+treated	POS	O
+,	POS	O
+were	POS	O
+given	POS	O
+pairs	POS	O
+of	POS	O
+treatments	POS	O
+at	POS	O
+successive	POS	O
+12	POS	O
+-	POS	O
+h	POS	O
+intervals	POS	O
+over	POS	O
+a	POS	O
+3	POS	O
+-	POS	O
+day	POS	O
+period	POS	O
+.	POS	O
+One	POS	O
+burn	POS	O
+site	POS	O
+was	POS	O
+treated	POS	O
+with	POS	O
+each	POS	O
+of	POS	O
+four	POS	O
+different	POS	O
+CHP	POS	O
+concentrations	POS	O
+,	POS	O
+from	POS	O
+0	POS	O
+.	POS	O
+25	POS	O
+per	POS	O
+cent	POS	O
+to	POS	O
+2	POS	O
+per	POS	O
+cent	POS	O
+,	POS	O
+their	POS	O
+vehicle	POS	O
+,	POS	O
+and	POS	O
+1	POS	O
+per	POS	O
+cent	POS	O
+silver	POS	O
+sulphadiazine	POS	O
+(	POS	O
+AgSD	POS	O
+)	POS	O
+cream	POS	O
+,	POS	O
+an	POS	O
+antimicrobial	POS	O
+agent	POS	O
+frequently	POS	O
+used	POS	O
+for	POS	O
+topical	POS	O
+treatment	POS	O
+of	POS	O
+burn	POS	B-NP
+wounds	POS	I-NP
+.	POS	O
+The	POS	O
+other	POS	O
+site	POS	O
+was	POS	O
+always	POS	O
+treated	POS	O
+with	POS	O
+AgSD	POS	O
+cream	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+a	POS	O
+direct	POS	O
+relationship	POS	O
+between	POS	O
+CHP	POS	O
+concentration	POS	O
+and	POS	O
+patients	POS	O
+'	POS	O
+ratings	POS	O
+of	POS	O
+pain	POS	B-NP
+on	POS	O
+an	POS	O
+analogue	POS	O
+scale	POS	O
+.	POS	O
+The	POS	O
+0	POS	O
+.	POS	O
+25	POS	O
+per	POS	O
+cent	POS	O
+CHP	POS	O
+cream	POS	O
+was	POS	O
+closest	POS	O
+to	POS	O
+AgSD	POS	O
+in	POS	O
+pain	POS	B-NP
+tolerance	POS	I-NP
+;	POS	O
+however	POS	O
+,	POS	O
+none	POS	O
+of	POS	O
+the	POS	O
+treatments	POS	O
+differed	POS	O
+statistically	POS	O
+from	POS	O
+AgSD	POS	B-NP
+or	POS	O
+from	POS	O
+each	POS	O
+other	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+ease	POS	O
+of	POS	O
+application	POS	O
+of	POS	O
+CHP	POS	O
+creams	POS	O
+was	POS	O
+less	POS	O
+satisfactory	POS	O
+than	POS	O
+that	POS	O
+of	POS	O
+AgSD	POS	B-NP
+.	POS	O
+It	POS	O
+was	POS	O
+concluded	POS	O
+that	POS	O
+formulations	POS	O
+at	POS	O
+or	POS	O
+below	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+per	POS	O
+cent	POS	O
+CHP	POS	O
+may	POS	O
+prove	POS	O
+acceptable	POS	O
+for	POS	O
+wound	POS	O
+care	POS	O
+,	POS	O
+but	POS	O
+the	POS	O
+vehicle	POS	O
+system	POS	O
+needs	POS	O
+pharmaceutical	POS	O
+improvement	POS	O
+to	POS	O
+render	POS	O
+it	POS	O
+more	POS	O
+tolerable	POS	O
+and	POS	O
+easier	POS	O
+to	POS	O
+use	POS	O
+.	POS	O
+Acute	POS	O
+hepatitis	POS	B-NP
+associated	POS	O
+with	POS	O
+clopidogrel	POS	O
+:	POS	O
+a	POS	O
+case	POS	O
+report	POS	O
+and	POS	O
+review	POS	O
+of	POS	O
+the	POS	O
+literature	POS	O
+.	POS	O
+Drug	POS	O
+-	POS	O
+induced	POS	O
+hepatotoxicity	POS	B-NP
+is	POS	O
+a	POS	O
+common	POS	O
+cause	POS	O
+of	POS	O
+acute	POS	B-NP
+hepatitis	POS	I-NP
+,	POS	O
+and	POS	O
+the	POS	O
+recognition	POS	O
+of	POS	O
+the	POS	O
+responsible	POS	O
+drug	POS	O
+may	POS	O
+be	POS	O
+difficult	POS	O
+.	POS	O
+We	POS	O
+describe	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+clopidogrel	POS	O
+-	POS	O
+related	POS	O
+acute	POS	O
+hepatitis	POS	B-NP
+.	POS	O
+The	POS	O
+diagnosis	POS	O
+is	POS	O
+strongly	POS	O
+suggested	POS	O
+by	POS	O
+an	POS	O
+accurate	POS	O
+medical	POS	O
+history	POS	O
+and	POS	O
+liver	POS	O
+biopsy	POS	O
+.	POS	O
+Reports	POS	O
+about	POS	O
+cases	POS	O
+of	POS	O
+hepatotoxicity	POS	B-NP
+due	POS	O
+to	POS	O
+clopidogrel	POS	O
+are	POS	O
+increasing	POS	O
+in	POS	O
+the	POS	O
+last	POS	O
+few	POS	O
+years	POS	O
+,	POS	O
+after	POS	O
+the	POS	O
+increased	POS	O
+use	POS	O
+of	POS	O
+this	POS	O
+drug	POS	O
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+we	POS	O
+believe	POS	O
+that	POS	O
+physicians	POS	O
+should	POS	O
+carefully	POS	O
+consider	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+hepatic	POS	B-NP
+injury	POS	I-NP
+when	POS	O
+clopidogrel	POS	O
+is	POS	O
+prescribed	POS	O
+.	POS	O
+Bortezomib	POS	O
+and	POS	O
+dexamethasone	POS	O
+as	POS	O
+salvage	POS	O
+therapy	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+relapsed	POS	B-NP
+/	POS	I-NP
+refractory	POS	I-NP
+multiple	POS	I-NP
+myeloma	POS	I-NP
+:	POS	O
+analysis	POS	O
+of	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+clinical	POS	O
+outcomes	POS	O
+.	POS	O
+Bortezomib	POS	O
+(	POS	O
+bort	POS	O
+)	POS	O
+-	POS	O
+dexamethasone	POS	O
+(	POS	O
+dex	POS	O
+)	POS	O
+is	POS	O
+an	POS	O
+effective	POS	O
+therapy	POS	O
+for	POS	O
+relapsed	POS	B-NP
+/	POS	I-NP
+refractory	POS	I-NP
+(	POS	I-NP
+R	POS	I-NP
+/	POS	I-NP
+R	POS	I-NP
+)	POS	I-NP
+multiple	POS	I-NP
+myeloma	POS	I-NP
+(	POS	O
+MM	POS	B-NP
+)	POS	O
+.	POS	O
+This	POS	O
+retrospective	POS	O
+study	POS	O
+investigated	POS	O
+the	POS	O
+combination	POS	O
+of	POS	O
+bort	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+on	POS	O
+days	POS	O
+1	POS	O
+,	POS	O
+4	POS	O
+,	POS	O
+8	POS	O
+,	POS	O
+and	POS	O
+11	POS	O
+every	POS	O
+3	POS	O
+weeks	POS	O
+)	POS	O
+and	POS	O
+dex	POS	O
+(	POS	O
+20	POS	O
+mg	POS	O
+on	POS	O
+the	POS	O
+day	POS	O
+of	POS	O
+and	POS	O
+the	POS	O
+day	POS	O
+after	POS	O
+bort	POS	O
+)	POS	O
+as	POS	O
+salvage	POS	O
+treatment	POS	O
+in	POS	O
+85	POS	O
+patients	POS	O
+with	POS	O
+R	POS	O
+/	POS	O
+R	POS	O
+MM	POS	O
+after	POS	O
+prior	POS	O
+autologous	POS	O
+stem	POS	O
+cell	POS	O
+transplantation	POS	O
+or	POS	O
+conventional	POS	O
+chemotherapy	POS	O
+.	POS	O
+The	POS	O
+median	POS	O
+number	POS	O
+of	POS	O
+prior	POS	O
+lines	POS	O
+of	POS	O
+therapy	POS	O
+was	POS	O
+2	POS	O
+.	POS	O
+Eighty	POS	O
+-	POS	O
+seven	POS	O
+percent	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+had	POS	O
+received	POS	O
+immunomodulatory	POS	O
+drugs	POS	O
+included	POS	O
+in	POS	O
+some	POS	O
+line	POS	O
+of	POS	O
+therapy	POS	O
+before	POS	O
+bort	POS	O
+-	POS	O
+dex	POS	O
+.	POS	O
+The	POS	O
+median	POS	O
+number	POS	O
+of	POS	O
+bort	POS	O
+-	POS	O
+dex	POS	O
+cycles	POS	O
+was	POS	O
+6	POS	O
+,	POS	O
+up	POS	O
+to	POS	O
+a	POS	O
+maximum	POS	O
+of	POS	O
+12	POS	O
+cycles	POS	O
+.	POS	O
+On	POS	O
+an	POS	O
+intention	POS	O
+-	POS	O
+to	POS	O
+-	POS	O
+treat	POS	O
+basis	POS	O
+,	POS	O
+55	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+achieved	POS	O
+at	POS	O
+least	POS	O
+partial	POS	O
+response	POS	O
+,	POS	O
+including	POS	O
+19	POS	O
+%	POS	O
+CR	POS	O
+and	POS	O
+35	POS	O
+%	POS	O
+achieved	POS	O
+at	POS	O
+least	POS	O
+very	POS	O
+good	POS	O
+partial	POS	O
+response	POS	O
+.	POS	O
+Median	POS	O
+durations	POS	O
+of	POS	O
+response	POS	O
+,	POS	O
+time	POS	O
+to	POS	O
+next	POS	O
+therapy	POS	O
+and	POS	O
+treatment	POS	O
+-	POS	O
+free	POS	O
+interval	POS	O
+were	POS	O
+8	POS	O
+,	POS	O
+11	POS	O
+.	POS	O
+2	POS	O
+,	POS	O
+and	POS	O
+5	POS	O
+.	POS	O
+1	POS	O
+months	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+The	POS	O
+most	POS	O
+relevant	POS	O
+adverse	POS	O
+event	POS	O
+was	POS	O
+peripheral	POS	B-NP
+neuropathy	POS	I-NP
+,	POS	O
+which	POS	O
+occurred	POS	O
+in	POS	O
+78	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+(	POS	O
+grade	POS	O
+II	POS	O
+,	POS	O
+38	POS	O
+%	POS	O
+;	POS	O
+grade	POS	O
+III	POS	O
+,	POS	O
+21	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+led	POS	O
+to	POS	O
+treatment	POS	O
+discontinuation	POS	O
+in	POS	O
+6	POS	O
+%	POS	O
+.	POS	O
+With	POS	O
+a	POS	O
+median	POS	O
+follow	POS	O
+up	POS	O
+of	POS	O
+22	POS	O
+months	POS	O
+,	POS	O
+median	POS	O
+time	POS	O
+to	POS	O
+progression	POS	O
+,	POS	O
+progression	POS	O
+-	POS	O
+free	POS	O
+survival	POS	O
+(	POS	O
+PFS	POS	O
+)	POS	O
+and	POS	O
+overall	POS	O
+survival	POS	O
+(	POS	O
+OS	POS	O
+)	POS	O
+were	POS	O
+8	POS	O
+.	POS	O
+9	POS	O
+,	POS	O
+8	POS	O
+.	POS	O
+7	POS	O
+,	POS	O
+and	POS	O
+22	POS	O
+months	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Prolonged	POS	O
+PFS	POS	O
+and	POS	O
+OS	POS	O
+were	POS	O
+observed	POS	O
+in	POS	O
+patients	POS	O
+achieving	POS	O
+CR	POS	O
+and	POS	O
+receiving	POS	O
+bort	POS	O
+-	POS	O
+dex	POS	O
+a	POS	O
+single	POS	O
+line	POS	O
+of	POS	O
+prior	POS	O
+therapy	POS	O
+.	POS	O
+Bort	POS	O
+-	POS	O
+dex	POS	O
+was	POS	O
+an	POS	O
+effective	POS	O
+salvage	POS	O
+treatment	POS	O
+for	POS	O
+MM	POS	B-NP
+patients	POS	O
+,	POS	O
+particularly	POS	O
+for	POS	O
+those	POS	O
+in	POS	O
+first	POS	O
+relapse	POS	O
+.	POS	O
+Pubertal	POS	O
+exposure	POS	O
+to	POS	O
+Bisphenol	POS	O
+A	POS	O
+increases	POS	O
+anxiety	POS	B-NP
+-	POS	O
+like	POS	O
+behavior	POS	O
+and	POS	O
+decreases	POS	O
+acetylcholinesterase	POS	O
+activity	POS	O
+of	POS	O
+hippocampus	POS	O
+in	POS	O
+adult	POS	O
+male	POS	O
+mice	POS	O
+.	POS	O
+The	POS	O
+negative	POS	O
+effects	POS	O
+of	POS	O
+Bisphenol	POS	O
+A	POS	O
+(	POS	O
+BPA	POS	O
+)	POS	O
+on	POS	O
+neurodevelopment	POS	O
+and	POS	O
+behaviors	POS	O
+have	POS	O
+been	POS	O
+well	POS	O
+established	POS	O
+.	POS	O
+Acetylcholinesterase	POS	O
+(	POS	O
+AChE	POS	O
+)	POS	O
+is	POS	O
+a	POS	O
+regulatory	POS	O
+enzyme	POS	O
+which	POS	O
+is	POS	O
+involved	POS	O
+in	POS	O
+anxiety	POS	B-NP
+-	POS	O
+like	POS	O
+behavior	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+investigated	POS	O
+behavioral	POS	O
+phenotypes	POS	O
+and	POS	O
+AChE	POS	O
+activity	POS	O
+in	POS	O
+male	POS	O
+mice	POS	O
+following	POS	O
+BPA	POS	O
+exposure	POS	O
+during	POS	O
+puberty	POS	B-NP
+.	POS	O
+On	POS	O
+postnatal	POS	O
+day	POS	O
+(	POS	O
+PND	POS	O
+)	POS	O
+35	POS	O
+,	POS	O
+male	POS	O
+mice	POS	O
+were	POS	O
+exposed	POS	O
+to	POS	O
+50mg	POS	O
+BPA	POS	O
+/	POS	O
+kg	POS	O
+diet	POS	O
+per	POS	O
+day	POS	O
+for	POS	O
+a	POS	O
+period	POS	O
+of	POS	O
+35	POS	O
+days	POS	O
+.	POS	O
+On	POS	O
+PND71	POS	O
+,	POS	O
+a	POS	O
+behavioral	POS	O
+assay	POS	O
+was	POS	O
+performed	POS	O
+using	POS	O
+the	POS	O
+elevated	POS	O
+plus	POS	O
+maze	POS	O
+(	POS	O
+EPM	POS	O
+)	POS	O
+and	POS	O
+the	POS	O
+light	POS	O
+/	POS	O
+dark	POS	O
+test	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+AChE	POS	O
+activity	POS	O
+was	POS	O
+measured	POS	O
+in	POS	O
+the	POS	O
+prefrontal	POS	O
+cortex	POS	O
+,	POS	O
+hypothalamus	POS	O
+,	POS	O
+cerebellum	POS	O
+and	POS	O
+hippocampus	POS	O
+.	POS	O
+Results	POS	O
+from	POS	O
+our	POS	O
+behavioral	POS	O
+phenotyping	POS	O
+indicated	POS	O
+that	POS	O
+anxiety	POS	B-NP
+-	POS	O
+like	POS	O
+behavior	POS	O
+was	POS	O
+increased	POS	O
+in	POS	O
+mice	POS	O
+exposed	POS	O
+to	POS	O
+BPA	POS	O
+.	POS	O
+AChE	POS	O
+activity	POS	O
+was	POS	O
+significantly	POS	O
+decreased	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+of	POS	O
+mice	POS	O
+with	POS	O
+BPA	POS	O
+compared	POS	O
+to	POS	O
+control	POS	O
+mice	POS	O
+,	POS	O
+whereas	POS	O
+no	POS	O
+difference	POS	O
+was	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+prefrontal	POS	O
+cortex	POS	O
+,	POS	O
+hypothalamus	POS	O
+and	POS	O
+cerebellum	POS	O
+.	POS	O
+Our	POS	O
+findings	POS	O
+showed	POS	O
+that	POS	O
+pubertal	POS	O
+BPA	POS	O
+exposure	POS	O
+increased	POS	O
+anxiety	POS	B-NP
+-	POS	O
+like	POS	O
+behavior	POS	O
+,	POS	O
+which	POS	O
+may	POS	O
+be	POS	O
+associated	POS	O
+with	POS	O
+decreased	POS	O
+AChE	POS	O
+activity	POS	O
+of	POS	O
+the	POS	O
+hippocampus	POS	O
+in	POS	O
+adult	POS	O
+male	POS	O
+mice	POS	O
+.	POS	O
+Further	POS	O
+studies	POS	O
+are	POS	O
+necessary	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+cholinergic	POS	O
+signaling	POS	O
+of	POS	O
+the	POS	O
+hippocampus	POS	O
+in	POS	O
+PBE	POS	O
+induced	POS	O
+anxiety	POS	B-NP
+-	POS	O
+like	POS	O
+behaviors	POS	O
+.	POS	O
+Biochemical	POS	O
+effects	POS	O
+of	POS	O
+Solidago	POS	O
+virgaurea	POS	O
+extract	POS	O
+on	POS	O
+experimental	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+Cardiovascular	POS	B-NP
+diseases	POS	I-NP
+(	POS	O
+CVDs	POS	B-NP
+)	POS	O
+are	POS	O
+the	POS	O
+major	POS	O
+health	POS	O
+problem	POS	O
+of	POS	O
+advanced	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+developing	POS	O
+countries	POS	O
+of	POS	O
+the	POS	O
+world	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+protective	POS	O
+effect	POS	O
+of	POS	O
+the	POS	O
+Solidago	POS	O
+virgaurea	POS	O
+extract	POS	O
+on	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+subcutaneous	POS	O
+injection	POS	O
+of	POS	O
+isoproterenol	POS	O
+(	POS	O
+30	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+into	POS	O
+rats	POS	O
+twice	POS	O
+at	POS	O
+an	POS	O
+interval	POS	O
+of	POS	O
+24	POS	O
+h	POS	O
+,	POS	O
+for	POS	O
+two	POS	O
+consecutive	POS	O
+days	POS	O
+,	POS	O
+led	POS	O
+to	POS	O
+a	POS	O
+significant	POS	O
+increase	POS	O
+in	POS	O
+serum	POS	O
+lactate	POS	O
+dehydrogenase	POS	O
+,	POS	O
+creatine	POS	O
+phosphokinase	POS	O
+,	POS	O
+alanine	POS	O
+transaminase	POS	O
+,	POS	O
+aspartate	POS	O
+transaminase	POS	O
+,	POS	O
+and	POS	O
+angiotensin	POS	O
+-	POS	O
+converting	POS	O
+enzyme	POS	O
+activities	POS	O
+,	POS	O
+total	POS	O
+cholesterol	POS	O
+,	POS	O
+triglycerides	POS	O
+,	POS	O
+free	POS	O
+serum	POS	O
+fatty	POS	O
+acid	POS	O
+,	POS	O
+cardiac	POS	O
+tissue	POS	O
+malondialdehyde	POS	O
+(	POS	O
+MDA	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+nitric	POS	O
+oxide	POS	O
+levels	POS	O
+and	POS	O
+a	POS	O
+significant	POS	O
+decrease	POS	O
+in	POS	O
+levels	POS	O
+of	POS	O
+glutathione	POS	O
+and	POS	O
+superoxide	POS	O
+dismutase	POS	O
+in	POS	O
+cardiac	POS	O
+tissue	POS	O
+as	POS	O
+compared	POS	O
+to	POS	O
+the	POS	O
+normal	POS	O
+control	POS	O
+group	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+Pretreatment	POS	O
+with	POS	O
+S	POS	O
+.	POS	O
+virgaurea	POS	O
+extract	POS	O
+for	POS	O
+5	POS	O
+weeks	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+250	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+followed	POS	O
+by	POS	O
+isoproterenol	POS	O
+injection	POS	O
+significantly	POS	O
+prevented	POS	O
+the	POS	O
+observed	POS	O
+alterations	POS	O
+.	POS	O
+Captopril	POS	O
+(	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+,	POS	O
+given	POS	O
+orally	POS	O
+)	POS	O
+,	POS	O
+an	POS	O
+inhibitor	POS	O
+of	POS	O
+angiotensin	POS	O
+-	POS	O
+converting	POS	O
+enzyme	POS	O
+used	POS	O
+as	POS	O
+a	POS	O
+standard	POS	O
+cardioprotective	POS	O
+drug	POS	O
+,	POS	O
+was	POS	O
+used	POS	O
+as	POS	O
+a	POS	O
+positive	POS	O
+control	POS	O
+in	POS	O
+this	POS	O
+study	POS	O
+.	POS	O
+The	POS	O
+data	POS	O
+of	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+suggest	POS	O
+that	POS	O
+S	POS	O
+.	POS	O
+virgaurea	POS	O
+extract	POS	O
+exerts	POS	O
+its	POS	O
+protective	POS	O
+effect	POS	O
+by	POS	O
+decreasing	POS	O
+MDA	POS	O
+level	POS	O
+and	POS	O
+increasing	POS	O
+the	POS	O
+antioxidant	POS	O
+status	POS	O
+in	POS	O
+isoproterenol	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+study	POS	O
+emphasizes	POS	O
+the	POS	O
+beneficial	POS	O
+action	POS	O
+of	POS	O
+S	POS	O
+.	POS	O
+virgaurea	POS	O
+extract	POS	O
+as	POS	O
+a	POS	O
+cardioprotective	POS	O
+agent	POS	O
+.	POS	O
+"	POS	O
+Real	POS	O
+-	POS	O
+world	POS	O
+"	POS	O
+data	POS	O
+on	POS	O
+the	POS	O
+efficacy	POS	O
+and	POS	O
+safety	POS	O
+of	POS	O
+lenalidomide	POS	O
+and	POS	O
+dexamethasone	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+relapsed	POS	B-NP
+/	POS	I-NP
+refractory	POS	I-NP
+multiple	POS	I-NP
+myeloma	POS	I-NP
+who	POS	O
+were	POS	O
+treated	POS	O
+according	POS	O
+to	POS	O
+the	POS	O
+standard	POS	O
+clinical	POS	O
+practice	POS	O
+:	POS	O
+a	POS	O
+study	POS	O
+of	POS	O
+the	POS	O
+Greek	POS	O
+Myeloma	POS	B-NP
+Study	POS	O
+Group	POS	O
+.	POS	O
+Lenalidomide	POS	O
+and	POS	O
+dexamethasone	POS	O
+(	POS	O
+RD	POS	O
+)	POS	O
+is	POS	O
+a	POS	O
+standard	POS	O
+of	POS	O
+care	POS	O
+for	POS	O
+relapsed	POS	B-NP
+/	POS	I-NP
+refractory	POS	I-NP
+multiple	POS	I-NP
+myeloma	POS	I-NP
+(	POS	O
+RRMM	POS	O
+)	POS	O
+,	POS	O
+but	POS	O
+there	POS	O
+is	POS	O
+limited	POS	O
+published	POS	O
+data	POS	O
+on	POS	O
+its	POS	O
+efficacy	POS	O
+and	POS	O
+safety	POS	O
+in	POS	O
+the	POS	O
+"	POS	O
+real	POS	O
+world	POS	O
+"	POS	O
+(	POS	O
+RW	POS	O
+)	POS	O
+,	POS	O
+according	POS	O
+to	POS	O
+the	POS	O
+International	POS	O
+Society	POS	O
+of	POS	O
+Pharmacoeconomics	POS	O
+and	POS	O
+Outcomes	POS	O
+Research	POS	O
+definition	POS	O
+.	POS	O
+We	POS	O
+studied	POS	O
+212	POS	O
+RRMM	POS	O
+patients	POS	O
+who	POS	O
+received	POS	O
+RD	POS	O
+in	POS	O
+RW	POS	O
+.	POS	O
+Objective	POS	O
+response	POS	O
+(	POS	O
+>	POS	O
+PR	POS	O
+(	POS	O
+partial	POS	O
+response	POS	O
+)	POS	O
+)	POS	O
+rate	POS	O
+was	POS	O
+77	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+(	POS	O
+complete	POS	O
+response	POS	O
+(	POS	O
+CR	POS	O
+)	POS	O
+,	POS	O
+20	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Median	POS	O
+time	POS	O
+to	POS	O
+first	POS	O
+and	POS	O
+best	POS	O
+response	POS	O
+was	POS	O
+2	POS	O
+and	POS	O
+5	POS	O
+months	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Median	POS	O
+time	POS	O
+to	POS	O
+CR	POS	O
+when	POS	O
+RD	POS	O
+was	POS	O
+given	POS	O
+as	POS	O
+2nd	POS	O
+or	POS	O
+>	POS	O
+2	POS	O
+(	POS	O
+nd	POS	O
+)	POS	O
+-	POS	O
+line	POS	O
+treatment	POS	O
+at	POS	O
+4	POS	O
+and	POS	O
+11	POS	O
+months	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Quality	POS	O
+of	POS	O
+response	POS	O
+was	POS	O
+independent	POS	O
+of	POS	O
+previous	POS	O
+lines	POS	O
+of	POS	O
+therapies	POS	O
+or	POS	O
+previous	POS	O
+exposure	POS	O
+to	POS	O
+thalidomide	POS	O
+or	POS	O
+bortezomib	POS	O
+.	POS	O
+Median	POS	O
+duration	POS	O
+of	POS	O
+response	POS	O
+was	POS	O
+34	POS	O
+.	POS	O
+4	POS	O
+months	POS	O
+,	POS	O
+and	POS	O
+it	POS	O
+was	POS	O
+higher	POS	O
+in	POS	O
+patients	POS	O
+who	POS	O
+received	POS	O
+RD	POS	B-NP
+until	POS	O
+progression	POS	O
+(	POS	O
+not	POS	O
+reached	POS	O
+versus	POS	O
+19	POS	O
+months	POS	O
+,	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+Improvement	POS	O
+of	POS	O
+humoral	POS	O
+immunity	POS	O
+occurred	POS	O
+in	POS	O
+60	POS	O
+%	POS	O
+of	POS	O
+responders	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+and	POS	O
+in	POS	O
+the	POS	O
+majority	POS	O
+of	POS	O
+patients	POS	O
+who	POS	O
+achieved	POS	O
+stable	POS	O
+disease	POS	O
+.	POS	O
+Adverse	POS	O
+events	POS	O
+were	POS	O
+reported	POS	O
+in	POS	O
+68	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+(	POS	O
+myelosuppression	POS	B-NP
+in	POS	O
+49	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+12	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+needed	POS	O
+hospitalization	POS	O
+.	POS	O
+Peripheral	POS	B-NP
+neuropathy	POS	I-NP
+was	POS	O
+observed	POS	O
+only	POS	O
+in	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+and	POS	O
+deep	POS	O
+vein	POS	B-NP
+thrombosis	POS	I-NP
+in	POS	O
+5	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+.	POS	O
+Dose	POS	O
+reductions	POS	O
+were	POS	O
+needed	POS	O
+in	POS	O
+31	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+and	POS	O
+permanent	POS	O
+discontinuation	POS	O
+in	POS	O
+38	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+.	POS	O
+Median	POS	O
+time	POS	O
+to	POS	O
+treatment	POS	O
+discontinuation	POS	O
+was	POS	O
+16	POS	O
+.	POS	O
+8	POS	O
+months	POS	O
+.	POS	O
+Performance	POS	O
+status	POS	O
+(	POS	O
+PS	POS	O
+)	POS	O
+and	POS	O
+initial	POS	O
+lenalidomide	POS	O
+dose	POS	O
+predicted	POS	O
+for	POS	O
+treatment	POS	O
+discontinuation	POS	O
+.	POS	O
+Extra	POS	B-NP
+-	POS	I-NP
+medullary	POS	I-NP
+relapses	POS	I-NP
+occurred	POS	O
+in	POS	O
+3	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+.	POS	O
+Our	POS	O
+study	POS	O
+confirms	POS	O
+that	POS	O
+RD	POS	O
+is	POS	O
+effective	POS	O
+and	POS	O
+safe	POS	O
+in	POS	O
+RRMM	POS	O
+in	POS	O
+the	POS	O
+RW	POS	O
+;	POS	O
+it	POS	O
+produces	POS	O
+durable	POS	O
+responses	POS	O
+especially	POS	O
+in	POS	O
+patients	POS	O
+who	POS	O
+continue	POS	O
+on	POS	O
+treatment	POS	O
+till	POS	O
+progression	POS	O
+and	POS	O
+improves	POS	O
+humoral	POS	O
+immunity	POS	O
+even	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+stable	POS	O
+disease	POS	O
+.	POS	O
+The	POS	O
+cytogenetic	POS	O
+action	POS	O
+of	POS	O
+ifosfamide	POS	O
+,	POS	O
+mesna	POS	O
+,	POS	O
+and	POS	O
+their	POS	O
+combination	POS	O
+on	POS	O
+peripheral	POS	O
+rabbit	POS	O
+lymphocytes	POS	O
+:	POS	O
+an	POS	O
+in	POS	O
+vivo	POS	O
+/	POS	O
+in	POS	O
+vitro	POS	O
+cytogenetic	POS	O
+study	POS	O
+.	POS	O
+Ifosfamide	POS	O
+(	POS	O
+IFO	POS	O
+)	POS	O
+is	POS	O
+an	POS	O
+alkylating	POS	O
+nitrogen	POS	O
+mustard	POS	O
+,	POS	O
+administrated	POS	O
+as	POS	O
+an	POS	O
+antineoplasmic	POS	O
+agent	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+characterized	POS	O
+by	POS	O
+its	POS	O
+intense	POS	O
+urotoxic	POS	O
+action	POS	O
+,	POS	O
+leading	POS	O
+to	POS	O
+hemorrhagic	POS	B-NP
+cystitis	POS	I-NP
+.	POS	O
+This	POS	O
+side	POS	O
+effect	POS	O
+of	POS	O
+IFO	POS	O
+raises	POS	O
+the	POS	O
+requirement	POS	O
+for	POS	O
+the	POS	O
+co	POS	O
+-	POS	O
+administration	POS	O
+with	POS	O
+sodium	POS	O
+2	POS	O
+-	POS	O
+sulfanylethanesulfonate	POS	O
+(	POS	O
+Mesna	POS	O
+)	POS	O
+aiming	POS	O
+to	POS	O
+avoid	POS	O
+or	POS	O
+minimize	POS	O
+this	POS	O
+effect	POS	O
+.	POS	O
+IFO	POS	O
+and	POS	O
+Mesna	POS	O
+were	POS	O
+administrated	POS	O
+separately	POS	O
+on	POS	O
+rabbit	POS	O
+'	POS	O
+s	POS	O
+lymphocytes	POS	O
+in	POS	O
+vivo	POS	O
+,	POS	O
+which	POS	O
+were	POS	O
+later	POS	O
+developed	POS	O
+in	POS	O
+vitro	POS	O
+.	POS	O
+Cytogenetic	POS	O
+markers	POS	O
+for	POS	O
+sister	POS	O
+chromatid	POS	O
+exchanges	POS	O
+(	POS	O
+SCEs	POS	O
+)	POS	O
+,	POS	O
+proliferation	POS	O
+rate	POS	O
+index	POS	O
+(	POS	O
+PRI	POS	O
+)	POS	O
+and	POS	O
+Mitotic	POS	O
+Index	POS	O
+were	POS	O
+recorded	POS	O
+.	POS	O
+Mesna	POS	O
+'	POS	O
+s	POS	O
+action	POS	O
+,	POS	O
+in	POS	O
+conjunction	POS	O
+with	POS	O
+IFO	POS	O
+reduces	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+SCEs	POS	O
+,	POS	O
+in	POS	O
+comparison	POS	O
+with	POS	O
+the	POS	O
+SCEs	POS	O
+recordings	POS	O
+obtained	POS	O
+when	POS	O
+IFO	POS	O
+is	POS	O
+administered	POS	O
+alone	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+to	POS	O
+this	POS	O
+,	POS	O
+when	POS	O
+high	POS	O
+concentrations	POS	O
+of	POS	O
+Mesna	POS	O
+were	POS	O
+administered	POS	O
+alone	POS	O
+significant	POS	O
+reductions	POS	O
+of	POS	O
+the	POS	O
+PRI	POS	O
+were	POS	O
+noted	POS	O
+,	POS	O
+than	POS	O
+with	POS	O
+IFO	POS	O
+acting	POS	O
+at	POS	O
+the	POS	O
+same	POS	O
+concentration	POS	O
+on	POS	O
+the	POS	O
+lymphocytes	POS	O
+.	POS	O
+Mesna	POS	O
+significantly	POS	O
+reduces	POS	O
+IFO	POS	O
+'	POS	O
+s	POS	O
+genotoxicity	POS	B-NP
+,	POS	O
+while	POS	O
+when	POS	O
+administered	POS	O
+in	POS	O
+high	POS	O
+concentrations	POS	O
+it	POS	O
+acts	POS	O
+in	POS	O
+an	POS	O
+inhibitory	POS	O
+fashion	POS	O
+on	POS	O
+the	POS	O
+cytostatic	POS	O
+action	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+.	POS	O
+Risk	POS	O
+factors	POS	O
+and	POS	O
+predictors	POS	O
+of	POS	O
+levodopa	POS	O
+-	POS	O
+induced	POS	O
+dyskinesia	POS	B-NP
+among	POS	O
+multiethnic	POS	O
+Malaysians	POS	O
+with	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+Chronic	POS	O
+pulsatile	POS	O
+levodopa	POS	O
+therapy	POS	O
+for	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+PD	POS	B-NP
+)	POS	O
+leads	POS	O
+to	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+motor	POS	O
+fluctuations	POS	O
+and	POS	O
+dyskinesia	POS	B-NP
+.	POS	O
+We	POS	O
+studied	POS	O
+the	POS	O
+prevalence	POS	O
+and	POS	O
+predictors	POS	O
+of	POS	O
+levodopa	POS	O
+-	POS	O
+induced	POS	O
+dyskinesia	POS	B-NP
+among	POS	O
+multiethnic	POS	O
+Malaysian	POS	O
+patients	POS	O
+with	POS	O
+PD	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+This	POS	O
+is	POS	O
+a	POS	O
+cross	POS	O
+-	POS	O
+sectional	POS	O
+study	POS	O
+involving	POS	O
+95	POS	O
+patients	POS	O
+with	POS	O
+PD	POS	B-NP
+on	POS	O
+uninterrupted	POS	O
+levodopa	POS	O
+therapy	POS	O
+for	POS	O
+at	POS	O
+least	POS	O
+6	POS	O
+months	POS	O
+.	POS	O
+The	POS	O
+instrument	POS	O
+used	POS	O
+was	POS	O
+the	POS	O
+UPDRS	POS	O
+questionnaires	POS	O
+.	POS	O
+The	POS	O
+predictors	POS	O
+of	POS	O
+dyskinesia	POS	B-NP
+were	POS	O
+determined	POS	O
+using	POS	O
+multivariate	POS	O
+logistic	POS	O
+regression	POS	O
+analysis	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+mean	POS	O
+age	POS	O
+was	POS	O
+65	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+8	POS	O
+.	POS	O
+5	POS	O
+years	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+onset	POS	O
+age	POS	O
+was	POS	O
+58	POS	O
+.	POS	O
+5	POS	O
++	POS	O
+9	POS	O
+.	POS	O
+8	POS	O
+years	POS	O
+.	POS	O
+The	POS	O
+median	POS	O
+disease	POS	O
+duration	POS	O
+was	POS	O
+6	POS	O
+(	POS	O
+7	POS	O
+)	POS	O
+years	POS	O
+.	POS	O
+Dyskinesia	POS	B-NP
+was	POS	O
+present	POS	O
+in	POS	O
+44	POS	O
+%	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+42	POS	O
+)	POS	O
+with	POS	O
+median	POS	O
+levodopa	POS	O
+therapy	POS	O
+of	POS	O
+3	POS	O
+years	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+64	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+Chinese	POS	O
+,	POS	O
+31	POS	O
+%	POS	O
+Malays	POS	O
+,	POS	O
+and	POS	O
+3	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+Indians	POS	O
+and	POS	O
+other	POS	O
+ethnic	POS	O
+groups	POS	O
+.	POS	O
+Eighty	POS	O
+-	POS	O
+one	POS	O
+percent	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+dyskinesia	POS	B-NP
+had	POS	O
+clinical	POS	O
+fluctuations	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+dyskinesia	POS	B-NP
+had	POS	O
+lower	POS	O
+onset	POS	O
+age	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+longer	POS	O
+duration	POS	O
+of	POS	O
+levodopa	POS	O
+therapy	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+longer	POS	O
+disease	POS	O
+duration	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+higher	POS	O
+total	POS	O
+daily	POS	O
+levodopa	POS	O
+dose	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+higher	POS	O
+total	POS	O
+UPDRS	POS	O
+scores	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+005	POS	O
+)	POS	O
+than	POS	O
+patients	POS	O
+without	POS	O
+dyskinesia	POS	B-NP
+.	POS	O
+The	POS	O
+three	POS	O
+significant	POS	O
+predictors	POS	O
+of	POS	O
+dyskinesia	POS	B-NP
+were	POS	O
+duration	POS	O
+of	POS	O
+levodopa	POS	O
+therapy	POS	O
+,	POS	O
+onset	POS	O
+age	POS	O
+,	POS	O
+and	POS	O
+total	POS	O
+daily	POS	O
+levodopa	POS	O
+dose	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+prevalence	POS	O
+of	POS	O
+levodopa	POS	O
+-	POS	O
+induced	POS	O
+dyskinesia	POS	B-NP
+in	POS	O
+our	POS	O
+patients	POS	O
+was	POS	O
+44	POS	O
+%	POS	O
+.	POS	O
+The	POS	O
+most	POS	O
+significant	POS	O
+predictors	POS	O
+were	POS	O
+duration	POS	O
+of	POS	O
+levodopa	POS	O
+therapy	POS	O
+,	POS	O
+total	POS	O
+daily	POS	O
+levodopa	POS	O
+dose	POS	O
+,	POS	O
+and	POS	O
+onset	POS	O
+age	POS	O
+.	POS	O
+Dose	POS	O
+-	POS	O
+dependent	POS	O
+neurotoxicity	POS	B-NP
+of	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+busulfan	POS	O
+in	POS	O
+children	POS	O
+:	POS	O
+a	POS	O
+clinical	POS	O
+and	POS	O
+pharmacological	POS	O
+study	POS	O
+.	POS	O
+Busulfan	POS	O
+is	POS	O
+known	POS	O
+to	POS	O
+be	POS	O
+neurotoxic	POS	B-NP
+in	POS	O
+animals	POS	O
+and	POS	O
+humans	POS	O
+,	POS	O
+but	POS	O
+its	POS	O
+acute	POS	O
+neurotoxicity	POS	B-NP
+remains	POS	O
+poorly	POS	O
+characterized	POS	O
+in	POS	O
+children	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+here	POS	O
+a	POS	O
+retrospective	POS	O
+study	POS	O
+of	POS	O
+123	POS	O
+children	POS	O
+(	POS	O
+median	POS	O
+age	POS	O
+,	POS	O
+6	POS	O
+.	POS	O
+5	POS	O
+years	POS	O
+)	POS	O
+receiving	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+busulfan	POS	O
+in	POS	O
+combined	POS	O
+chemotherapy	POS	O
+before	POS	O
+bone	POS	O
+marrow	POS	O
+transplantation	POS	O
+for	POS	O
+malignant	POS	B-NP
+solid	POS	I-NP
+tumors	POS	I-NP
+,	POS	O
+brain	POS	B-NP
+tumors	POS	I-NP
+excluded	POS	O
+.	POS	O
+Busulfan	POS	O
+was	POS	O
+given	POS	O
+p	POS	O
+.	POS	O
+o	POS	O
+.	POS	O
+,	POS	O
+every	POS	O
+6	POS	O
+hours	POS	O
+for	POS	O
+16	POS	O
+doses	POS	O
+over	POS	O
+4	POS	O
+days	POS	O
+.	POS	O
+Two	POS	O
+total	POS	O
+doses	POS	O
+were	POS	O
+consecutively	POS	O
+used	POS	O
+:	POS	O
+16	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+then	POS	O
+600	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+.	POS	O
+The	POS	O
+dose	POS	O
+calculation	POS	O
+on	POS	O
+the	POS	O
+basis	POS	O
+of	POS	O
+body	POS	O
+surface	POS	O
+area	POS	O
+results	POS	O
+in	POS	O
+higher	POS	O
+doses	POS	O
+in	POS	O
+young	POS	O
+children	POS	O
+than	POS	O
+in	POS	O
+older	POS	O
+patients	POS	O
+(	POS	O
+16	POS	O
+to	POS	O
+28	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+.	POS	O
+Ninety	POS	O
+-	POS	O
+six	POS	O
+patients	POS	O
+were	POS	O
+not	POS	O
+given	POS	O
+anticonvulsive	POS	O
+prophylaxis	POS	B-NP
+;	POS	O
+7	POS	O
+(	POS	O
+7	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+developed	POS	O
+seizures	POS	B-NP
+during	POS	O
+the	POS	O
+4	POS	O
+days	POS	O
+of	POS	O
+the	POS	O
+busulfan	POS	O
+course	POS	O
+or	POS	O
+within	POS	O
+24	POS	O
+h	POS	O
+after	POS	O
+the	POS	O
+last	POS	O
+dosing	POS	O
+.	POS	O
+When	POS	O
+the	POS	O
+total	POS	O
+busulfan	POS	O
+dose	POS	O
+was	POS	O
+taken	POS	O
+into	POS	O
+account	POS	O
+,	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+difference	POS	O
+in	POS	O
+terms	POS	O
+of	POS	O
+neurotoxicity	POS	B-NP
+incidence	POS	O
+among	POS	O
+patients	POS	O
+under	POS	O
+16	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+1	POS	O
+of	POS	O
+57	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+patients	POS	O
+under	POS	O
+600	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+(	POS	O
+6	POS	O
+of	POS	O
+39	POS	O
+,	POS	O
+15	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+.	POS	O
+Twenty	POS	O
+-	POS	O
+seven	POS	O
+patients	POS	O
+were	POS	O
+given	POS	O
+a	POS	O
+600	POS	O
+-	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+busulfan	POS	O
+total	POS	O
+dose	POS	O
+with	POS	O
+continuous	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+infusion	POS	O
+of	POS	O
+clonazepam	POS	O
+;	POS	O
+none	POS	O
+had	POS	O
+any	POS	O
+neurological	POS	O
+symptoms	POS	O
+.	POS	O
+Busulfan	POS	O
+levels	POS	O
+were	POS	O
+measured	POS	O
+by	POS	O
+a	POS	O
+gas	POS	O
+chromatographic	POS	O
+-	POS	O
+mass	POS	O
+spectrometry	POS	O
+assay	POS	O
+in	POS	O
+the	POS	O
+plasma	POS	O
+and	POS	O
+cerebrospinal	POS	O
+fluid	POS	O
+of	POS	O
+9	POS	O
+children	POS	O
+without	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+disease	POS	O
+under	POS	O
+600	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+busulfan	POS	O
+with	POS	O
+clonazepam	POS	O
+:	POS	O
+busulfan	POS	O
+cerebrospinal	POS	O
+fluid	POS	O
+:	POS	O
+plasma	POS	O
+ratio	POS	O
+was	POS	O
+1	POS	O
+.	POS	O
+39	POS	O
+.	POS	O
+This	POS	O
+was	POS	O
+significantly	POS	O
+different	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+from	POS	O
+the	POS	O
+cerebrospinal	POS	O
+fluid	POS	O
+:	POS	O
+plasma	POS	O
+ratio	POS	O
+previously	POS	O
+defined	POS	O
+in	POS	O
+children	POS	O
+receiving	POS	O
+a	POS	O
+16	POS	O
+-	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+total	POS	O
+dose	POS	O
+of	POS	O
+busulfan	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+shows	POS	O
+that	POS	O
+busulfan	POS	O
+neurotoxicity	POS	B-NP
+is	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+in	POS	O
+children	POS	O
+and	POS	O
+efficiently	POS	O
+prevented	POS	O
+by	POS	O
+clonazepam	POS	O
+.	POS	O
+A	POS	O
+busulfan	POS	O
+dose	POS	O
+calculated	POS	O
+on	POS	O
+the	POS	O
+basis	POS	O
+of	POS	O
+body	POS	O
+surface	POS	O
+area	POS	O
+,	POS	O
+resulting	POS	O
+in	POS	O
+higher	POS	O
+doses	POS	O
+in	POS	O
+young	POS	O
+children	POS	O
+,	POS	O
+was	POS	O
+followed	POS	O
+by	POS	O
+increased	POS	O
+neurotoxicity	POS	B-NP
+,	POS	O
+close	POS	O
+to	POS	O
+neurotoxicity	POS	B-NP
+incidence	POS	O
+observed	POS	O
+in	POS	O
+adults	POS	O
+.	POS	O
+Since	POS	O
+plasma	POS	O
+pharmacokinetic	POS	O
+studies	POS	O
+showed	POS	O
+a	POS	O
+faster	POS	O
+busulfan	POS	O
+clearance	POS	O
+in	POS	O
+children	POS	O
+than	POS	O
+in	POS	O
+adults	POS	O
+,	POS	O
+this	POS	O
+new	POS	O
+dose	POS	O
+may	POS	O
+approximate	POS	O
+more	POS	O
+closely	POS	O
+the	POS	O
+adult	POS	O
+systemic	POS	O
+exposure	POS	O
+obtained	POS	O
+after	POS	O
+the	POS	O
+usual	POS	O
+16	POS	O
+-	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+total	POS	O
+dose	POS	O
+,	POS	O
+with	POS	O
+potential	POS	O
+inferences	POS	O
+in	POS	O
+terms	POS	O
+of	POS	O
+anticancer	POS	O
+or	POS	O
+myeloablative	POS	O
+effects	POS	O
+.	POS	O
+The	POS	O
+busulfan	POS	O
+dose	POS	O
+in	POS	O
+children	POS	O
+and	POS	O
+infants	POS	O
+undergoing	POS	O
+bone	POS	O
+marrow	POS	O
+transplantation	POS	O
+should	POS	O
+be	POS	O
+reconsidered	POS	O
+on	POS	O
+the	POS	O
+basis	POS	O
+of	POS	O
+pharmacokinetic	POS	O
+studies	POS	O
+.	POS	O
+An	POS	O
+unexpected	POS	O
+diagnosis	POS	O
+in	POS	O
+a	POS	O
+renal	POS	O
+-	POS	O
+transplant	POS	O
+patient	POS	O
+with	POS	O
+proteinuria	POS	B-NP
+treated	POS	O
+with	POS	O
+everolimus	POS	O
+:	POS	O
+AL	POS	O
+amyloidosis	POS	B-NP
+.	POS	O
+Proteinuria	POS	B-NP
+is	POS	O
+an	POS	O
+expected	POS	O
+complication	POS	O
+in	POS	O
+transplant	POS	O
+patients	POS	O
+treated	POS	O
+with	POS	O
+mammalian	POS	O
+target	POS	O
+of	POS	O
+rapamycin	POS	O
+inhibitors	POS	O
+(	POS	O
+mTOR	POS	O
+-	POS	O
+i	POS	O
+)	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+clinical	POS	O
+suspicion	POS	O
+should	POS	O
+always	POS	O
+be	POS	O
+supported	POS	O
+by	POS	O
+histological	POS	O
+evidence	POS	O
+in	POS	O
+order	POS	O
+to	POS	O
+investigate	POS	O
+potential	POS	O
+alternate	POS	O
+diagnoses	POS	O
+such	POS	O
+as	POS	O
+acute	POS	O
+or	POS	O
+chronic	POS	B-NP
+rejection	POS	I-NP
+,	POS	O
+interstitial	POS	B-NP
+fibrosis	POS	I-NP
+and	POS	O
+tubular	POS	B-NP
+atrophy	POS	I-NP
+,	POS	O
+or	POS	O
+recurrent	POS	O
+or	POS	O
+de	POS	O
+novo	POS	O
+glomerulopathy	POS	B-NP
+.	POS	O
+In	POS	O
+this	POS	O
+case	POS	O
+we	POS	O
+report	POS	O
+the	POS	O
+unexpected	POS	O
+diagnosis	POS	O
+of	POS	O
+amyloidosis	POS	B-NP
+in	POS	O
+a	POS	O
+renal	POS	O
+-	POS	O
+transplant	POS	O
+patient	POS	O
+with	POS	O
+pre	POS	O
+-	POS	O
+transplant	POS	O
+monoclonal	POS	O
+gammapathy	POS	O
+of	POS	O
+undetermined	POS	O
+significance	POS	O
+who	POS	O
+developed	POS	O
+proteinuria	POS	B-NP
+after	POS	O
+conversion	POS	O
+from	POS	O
+tacrolimus	POS	O
+to	POS	O
+everolimus	POS	O
+.	POS	O
+Long	POS	O
+-	POS	O
+term	POS	O
+oral	POS	O
+galactose	POS	O
+treatment	POS	O
+prevents	POS	O
+cognitive	POS	B-NP
+deficits	POS	I-NP
+in	POS	O
+male	POS	O
+Wistar	POS	O
+rats	POS	O
+treated	POS	O
+intracerebroventricularly	POS	O
+with	POS	O
+streptozotocin	POS	O
+.	POS	O
+Basic	POS	O
+and	POS	O
+clinical	POS	O
+research	POS	O
+has	POS	O
+demonstrated	POS	O
+that	POS	O
+dementia	POS	B-NP
+of	POS	O
+sporadic	POS	O
+Alzheimer	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+sAD	POS	B-NP
+)	POS	O
+type	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+dysfunction	POS	O
+of	POS	O
+the	POS	O
+insulin	POS	O
+-	POS	O
+receptor	POS	O
+(	POS	O
+IR	POS	O
+)	POS	O
+system	POS	O
+followed	POS	O
+by	POS	O
+decreased	POS	O
+glucose	POS	O
+transport	POS	O
+via	POS	O
+glucose	POS	O
+transporter	POS	O
+GLUT4	POS	O
+and	POS	O
+decreased	POS	O
+glucose	POS	O
+metabolism	POS	O
+in	POS	O
+brain	POS	O
+cells	POS	O
+.	POS	O
+An	POS	O
+alternative	POS	O
+source	POS	O
+of	POS	O
+energy	POS	O
+is	POS	O
+d	POS	O
+-	POS	O
+galactose	POS	O
+(	POS	O
+the	POS	O
+C	POS	O
+-	POS	O
+4	POS	O
+-	POS	O
+epimer	POS	O
+of	POS	O
+d	POS	O
+-	POS	O
+glucose	POS	O
+)	POS	O
+which	POS	O
+is	POS	O
+transported	POS	O
+into	POS	O
+the	POS	O
+brain	POS	O
+by	POS	O
+insulin	POS	O
+-	POS	O
+independent	POS	O
+GLUT3	POS	O
+transporter	POS	O
+where	POS	O
+it	POS	O
+might	POS	O
+be	POS	O
+metabolized	POS	O
+to	POS	O
+glucose	POS	O
+via	POS	O
+the	POS	O
+Leloir	POS	O
+pathway	POS	O
+.	POS	O
+Exclusively	POS	O
+parenteral	POS	O
+daily	POS	O
+injections	POS	O
+of	POS	O
+galactose	POS	O
+induce	POS	O
+memory	POS	O
+deterioration	POS	O
+in	POS	O
+rodents	POS	O
+and	POS	O
+are	POS	O
+used	POS	O
+to	POS	O
+generate	POS	O
+animal	POS	O
+aging	POS	O
+model	POS	O
+,	POS	O
+but	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+oral	POS	O
+galactose	POS	O
+treatment	POS	O
+on	POS	O
+cognitive	POS	O
+functions	POS	O
+have	POS	O
+never	POS	O
+been	POS	O
+tested	POS	O
+.	POS	O
+We	POS	O
+have	POS	O
+investigated	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+continuous	POS	O
+daily	POS	O
+oral	POS	O
+galactose	POS	O
+(	POS	O
+200	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+treatment	POS	O
+on	POS	O
+cognitive	POS	B-NP
+deficits	POS	I-NP
+in	POS	O
+streptozotocin	POS	O
+-	POS	O
+induced	POS	O
+(	POS	O
+STZ	POS	O
+-	POS	O
+icv	POS	O
+)	POS	O
+rat	POS	O
+model	POS	O
+of	POS	O
+sAD	POS	O
+,	POS	O
+tested	POS	O
+by	POS	O
+Morris	POS	O
+Water	POS	O
+Maze	POS	O
+and	POS	O
+Passive	POS	O
+Avoidance	POS	O
+test	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+One	POS	O
+month	POS	O
+of	POS	O
+oral	POS	O
+galactose	POS	O
+treatment	POS	O
+initiated	POS	O
+immediately	POS	O
+after	POS	O
+the	POS	O
+STZ	POS	O
+-	POS	O
+icv	POS	O
+administration	POS	O
+,	POS	O
+successfully	POS	O
+prevented	POS	O
+development	POS	O
+of	POS	O
+the	POS	O
+STZ	POS	O
+-	POS	O
+icv	POS	O
+-	POS	O
+induced	POS	O
+cognitive	POS	B-NP
+deficits	POS	I-NP
+.	POS	O
+Beneficial	POS	O
+effect	POS	O
+of	POS	O
+oral	POS	O
+galactose	POS	O
+was	POS	O
+independent	POS	O
+of	POS	O
+the	POS	O
+rat	POS	O
+age	POS	O
+and	POS	O
+of	POS	O
+the	POS	O
+galactose	POS	O
+dose	POS	O
+ranging	POS	O
+from	POS	O
+100	POS	O
+to	POS	O
+300	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+.	POS	O
+Additionally	POS	O
+,	POS	O
+oral	POS	O
+galactose	POS	O
+administration	POS	O
+led	POS	O
+to	POS	O
+the	POS	O
+appearance	POS	O
+of	POS	O
+galactose	POS	O
+in	POS	O
+the	POS	O
+blood	POS	O
+.	POS	O
+The	POS	O
+increase	POS	O
+of	POS	O
+galactose	POS	O
+concentration	POS	O
+in	POS	O
+the	POS	O
+cerebrospinal	POS	O
+fluid	POS	O
+was	POS	O
+several	POS	O
+times	POS	O
+lower	POS	O
+after	POS	O
+oral	POS	O
+than	POS	O
+after	POS	O
+parenteral	POS	O
+administration	POS	O
+of	POS	O
+the	POS	O
+same	POS	O
+galactose	POS	O
+dose	POS	O
+.	POS	O
+Oral	POS	O
+galactose	POS	O
+exposure	POS	O
+might	POS	O
+have	POS	O
+beneficial	POS	O
+effects	POS	O
+on	POS	O
+learning	POS	O
+and	POS	O
+memory	POS	O
+ability	POS	O
+and	POS	O
+could	POS	O
+be	POS	O
+worth	POS	O
+investigating	POS	O
+for	POS	O
+improvement	POS	O
+of	POS	O
+cognitive	POS	B-NP
+deficits	POS	I-NP
+associated	POS	O
+with	POS	O
+glucose	POS	B-NP
+hypometabolism	POS	I-NP
+in	POS	O
+AD	POS	B-NP
+.	POS	O
+An	POS	O
+investigation	POS	O
+of	POS	O
+the	POS	O
+pattern	POS	O
+of	POS	O
+kidney	POS	B-NP
+injury	POS	I-NP
+in	POS	O
+HIV	POS	O
+-	POS	O
+positive	POS	O
+persons	POS	O
+exposed	POS	O
+to	POS	O
+tenofovir	POS	O
+disoproxil	POS	O
+fumarate	POS	O
+:	POS	O
+an	POS	O
+examination	POS	O
+of	POS	O
+a	POS	O
+large	POS	O
+population	POS	O
+database	POS	O
+(	POS	O
+MHRA	POS	O
+database	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+potential	POS	O
+for	POS	O
+tenofovir	POS	O
+to	POS	O
+cause	POS	O
+a	POS	O
+range	POS	O
+of	POS	O
+kidney	POS	B-NP
+syndromes	POS	I-NP
+has	POS	O
+been	POS	O
+established	POS	O
+from	POS	O
+mechanistic	POS	O
+and	POS	O
+randomised	POS	O
+clinical	POS	O
+trials	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+exact	POS	O
+pattern	POS	O
+of	POS	O
+kidney	POS	O
+involvement	POS	O
+is	POS	O
+still	POS	O
+uncertain	POS	O
+.	POS	O
+We	POS	O
+undertook	POS	O
+a	POS	O
+descriptive	POS	O
+analysis	POS	O
+of	POS	O
+Yellow	POS	O
+Card	POS	O
+records	POS	O
+of	POS	O
+407	POS	O
+HIV	POS	O
+-	POS	O
+positive	POS	O
+persons	POS	O
+taking	POS	O
+tenofovir	POS	O
+disoproxil	POS	O
+fumarate	POS	O
+(	POS	O
+TDF	POS	O
+)	POS	O
+as	POS	O
+part	POS	O
+of	POS	O
+their	POS	O
+antiretroviral	POS	O
+therapy	POS	O
+regimen	POS	O
+and	POS	O
+submitted	POS	O
+to	POS	O
+the	POS	O
+Medicines	POS	O
+and	POS	O
+Healthcare	POS	O
+Products	POS	O
+Regulatory	POS	O
+Agency	POS	O
+(	POS	O
+MHRA	POS	O
+)	POS	O
+with	POS	O
+suspected	POS	O
+kidney	POS	O
+adverse	POS	O
+effects	POS	O
+.	POS	O
+Reports	POS	O
+that	POS	O
+satisfy	POS	O
+defined	POS	O
+criteria	POS	O
+were	POS	O
+classified	POS	O
+as	POS	O
+acute	POS	B-NP
+kidney	POS	I-NP
+injury	POS	I-NP
+,	POS	O
+kidney	POS	B-NP
+tubular	POS	I-NP
+dysfunction	POS	I-NP
+and	POS	O
+Fanconi	POS	B-NP
+syndrome	POS	I-NP
+.	POS	O
+Of	POS	O
+the	POS	O
+407	POS	O
+Yellow	POS	O
+Card	POS	O
+records	POS	O
+analysed	POS	O
+,	POS	O
+106	POS	O
+satisfied	POS	O
+criteria	POS	O
+for	POS	O
+TDF	POS	O
+-	POS	O
+related	POS	O
+kidney	POS	B-NP
+disease	POS	I-NP
+,	POS	O
+of	POS	O
+which	POS	O
+53	POS	O
+(	POS	O
+50	POS	O
+%	POS	O
+)	POS	O
+had	POS	O
+features	POS	O
+of	POS	O
+kidney	POS	B-NP
+tubular	POS	I-NP
+dysfunction	POS	I-NP
+,	POS	O
+35	POS	O
+(	POS	O
+33	POS	O
+%	POS	O
+)	POS	O
+were	POS	O
+found	POS	O
+to	POS	O
+have	POS	O
+features	POS	O
+of	POS	O
+glomerular	POS	B-NP
+dysfunction	POS	I-NP
+and	POS	O
+18	POS	O
+(	POS	O
+17	POS	O
+%	POS	O
+)	POS	O
+had	POS	O
+Fanconi	POS	B-NP
+syndrome	POS	I-NP
+.	POS	O
+The	POS	O
+median	POS	O
+TDF	POS	O
+exposure	POS	O
+was	POS	O
+316	POS	O
+days	POS	O
+(	POS	O
+interquartile	POS	O
+range	POS	O
+120	POS	O
+-	POS	O
+740	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+hospitalisation	POS	O
+for	POS	O
+TDF	POS	O
+kidney	POS	O
+adverse	POS	O
+effects	POS	O
+was	POS	O
+high	POS	O
+,	POS	O
+particularly	POS	O
+amongst	POS	O
+patients	POS	O
+with	POS	O
+features	POS	O
+of	POS	O
+Fanconi	POS	B-NP
+syndrome	POS	I-NP
+.	POS	O
+The	POS	O
+pattern	POS	O
+of	POS	O
+kidney	POS	B-NP
+syndromes	POS	I-NP
+in	POS	O
+this	POS	O
+population	POS	O
+series	POS	O
+mirrors	POS	O
+that	POS	O
+reported	POS	O
+in	POS	O
+randomised	POS	O
+clinical	POS	O
+trials	POS	O
+.	POS	O
+Cessation	POS	O
+of	POS	O
+TDF	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+complete	POS	O
+restoration	POS	O
+of	POS	O
+kidney	POS	O
+function	POS	O
+in	POS	O
+up	POS	O
+half	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+in	POS	O
+this	POS	O
+report	POS	O
+.	POS	O
+Incidence	POS	O
+of	POS	O
+postoperative	POS	B-NP
+delirium	POS	I-NP
+is	POS	O
+high	POS	O
+even	POS	O
+in	POS	O
+a	POS	O
+population	POS	O
+without	POS	O
+known	POS	O
+risk	POS	O
+factors	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+Postoperative	POS	O
+delirium	POS	B-NP
+is	POS	O
+a	POS	O
+recognized	POS	O
+complication	POS	O
+in	POS	O
+populations	POS	O
+at	POS	O
+risk	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+is	POS	O
+to	POS	O
+assess	POS	O
+the	POS	O
+prevalence	POS	O
+of	POS	O
+early	POS	O
+postoperative	POS	B-NP
+delirium	POS	I-NP
+in	POS	O
+a	POS	O
+population	POS	O
+without	POS	O
+known	POS	O
+risk	POS	O
+factors	POS	O
+admitted	POS	O
+to	POS	O
+the	POS	O
+ICU	POS	O
+for	POS	O
+postoperative	POS	O
+monitoring	POS	O
+after	POS	O
+elective	POS	O
+major	POS	O
+surgery	POS	O
+.	POS	O
+The	POS	O
+secondary	POS	O
+outcome	POS	O
+investigated	POS	O
+is	POS	O
+to	POS	O
+identify	POS	O
+eventual	POS	O
+independent	POS	O
+risk	POS	O
+factors	POS	O
+among	POS	O
+demographic	POS	O
+data	POS	O
+and	POS	O
+anesthetic	POS	O
+drugs	POS	O
+used	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+An	POS	O
+observational	POS	O
+,	POS	O
+prospective	POS	O
+study	POS	O
+was	POS	O
+conducted	POS	O
+on	POS	O
+a	POS	O
+consecutive	POS	O
+cohort	POS	O
+of	POS	O
+patients	POS	O
+admitted	POS	O
+to	POS	O
+our	POS	O
+ICU	POS	O
+within	POS	O
+and	POS	O
+for	POS	O
+at	POS	O
+least	POS	O
+24	POS	O
+h	POS	O
+after	POS	O
+major	POS	O
+surgical	POS	O
+procedures	POS	O
+.	POS	O
+Exclusion	POS	O
+criteria	POS	O
+were	POS	O
+any	POS	O
+preexisting	POS	O
+predisposing	POS	O
+factor	POS	O
+for	POS	O
+delirium	POS	B-NP
+or	POS	O
+other	POS	O
+potentially	POS	O
+confounding	POS	O
+neurological	POS	B-NP
+dysfunctions	POS	I-NP
+.	POS	O
+Patients	POS	O
+were	POS	O
+assessed	POS	O
+daily	POS	O
+using	POS	O
+the	POS	O
+confusion	POS	B-NP
+assessment	POS	O
+method	POS	O
+for	POS	O
+the	POS	O
+ICU	POS	O
+scale	POS	O
+for	POS	O
+3	POS	O
+days	POS	O
+after	POS	O
+the	POS	O
+surgical	POS	O
+procedure	POS	O
+.	POS	O
+Early	POS	O
+postoperative	POS	B-NP
+delirium	POS	I-NP
+incidence	POS	O
+risk	POS	O
+factors	POS	O
+were	POS	O
+then	POS	O
+assessed	POS	O
+through	POS	O
+three	POS	O
+different	POS	O
+multiple	POS	O
+regression	POS	O
+models	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+According	POS	O
+to	POS	O
+the	POS	O
+confusion	POS	B-NP
+assessment	POS	O
+method	POS	O
+for	POS	O
+the	POS	O
+ICU	POS	O
+scale	POS	O
+,	POS	O
+28	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+were	POS	O
+diagnosed	POS	O
+with	POS	O
+early	POS	O
+postoperative	POS	B-NP
+delirium	POS	I-NP
+.	POS	O
+The	POS	O
+use	POS	O
+of	POS	O
+thiopentone	POS	O
+was	POS	O
+significantly	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+eight	POS	O
+-	POS	O
+fold	POS	O
+-	POS	O
+higher	POS	O
+risk	POS	O
+for	POS	O
+delirium	POS	B-NP
+compared	POS	O
+to	POS	O
+propofol	POS	O
+(	POS	O
+57	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+vs	POS	O
+.	POS	O
+7	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+,	POS	O
+RR	POS	O
+=	POS	O
+8	POS	O
+.	POS	O
+0	POS	O
+,	POS	O
+X2	POS	O
+=	POS	O
+4	POS	O
+.	POS	O
+256	POS	O
+;	POS	O
+df	POS	O
+=	POS	O
+1	POS	O
+;	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+<	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+early	POS	O
+postoperative	POS	B-NP
+delirium	POS	I-NP
+was	POS	O
+found	POS	O
+to	POS	O
+be	POS	O
+a	POS	O
+very	POS	O
+common	POS	O
+complication	POS	O
+after	POS	O
+major	POS	O
+surgery	POS	O
+,	POS	O
+even	POS	O
+in	POS	O
+a	POS	O
+population	POS	O
+without	POS	O
+known	POS	O
+risk	POS	O
+factors	POS	O
+.	POS	O
+Thiopentone	POS	O
+was	POS	O
+independently	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+its	POS	O
+relative	POS	O
+risk	POS	O
+.	POS	O
+A	POS	O
+single	POS	O
+neurotoxic	POS	B-NP
+dose	POS	O
+of	POS	O
+methamphetamine	POS	O
+induces	POS	O
+a	POS	O
+long	POS	O
+-	POS	O
+lasting	POS	O
+depressive	POS	O
+-	POS	O
+like	POS	O
+behaviour	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+Methamphetamine	POS	O
+(	POS	O
+METH	POS	O
+)	POS	O
+triggers	POS	O
+a	POS	O
+disruption	POS	O
+of	POS	O
+the	POS	O
+monoaminergic	POS	O
+system	POS	O
+and	POS	O
+METH	POS	O
+abuse	POS	O
+leads	POS	O
+to	POS	O
+negative	POS	O
+emotional	POS	O
+states	POS	O
+including	POS	O
+depressive	POS	B-NP
+symptoms	POS	I-NP
+during	POS	O
+drug	POS	O
+withdrawal	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+it	POS	O
+is	POS	O
+currently	POS	O
+unknown	POS	O
+if	POS	O
+the	POS	O
+acute	POS	O
+toxic	POS	O
+dosage	POS	O
+of	POS	O
+METH	POS	O
+also	POS	O
+causes	POS	O
+a	POS	O
+long	POS	O
+-	POS	O
+lasting	POS	O
+depressive	POS	B-NP
+phenotype	POS	O
+and	POS	O
+persistent	POS	O
+monoaminergic	POS	B-NP
+deficits	POS	I-NP
+.	POS	O
+Thus	POS	O
+,	POS	O
+we	POS	O
+now	POS	O
+assessed	POS	O
+the	POS	O
+depressive	POS	O
+-	POS	O
+like	POS	O
+behaviour	POS	O
+in	POS	O
+mice	POS	O
+at	POS	O
+early	POS	O
+and	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+periods	POS	O
+following	POS	O
+a	POS	O
+single	POS	O
+high	POS	O
+METH	POS	O
+dose	POS	O
+(	POS	O
+30	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+.	POS	O
+METH	POS	O
+did	POS	O
+not	POS	O
+alter	POS	O
+the	POS	O
+motor	POS	O
+function	POS	O
+and	POS	O
+procedural	POS	O
+memory	POS	O
+of	POS	O
+mice	POS	O
+as	POS	O
+assessed	POS	O
+by	POS	O
+swimming	POS	O
+speed	POS	O
+and	POS	O
+escape	POS	O
+latency	POS	O
+to	POS	O
+find	POS	O
+the	POS	O
+platform	POS	O
+in	POS	O
+a	POS	O
+cued	POS	O
+version	POS	O
+of	POS	O
+the	POS	O
+water	POS	O
+maze	POS	O
+task	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+METH	POS	O
+significantly	POS	O
+increased	POS	O
+the	POS	O
+immobility	POS	O
+time	POS	O
+in	POS	O
+the	POS	O
+tail	POS	O
+suspension	POS	O
+test	POS	O
+at	POS	O
+3	POS	O
+and	POS	O
+49	POS	O
+days	POS	O
+post	POS	O
+-	POS	O
+administration	POS	O
+.	POS	O
+This	POS	O
+depressive	POS	O
+-	POS	O
+like	POS	O
+profile	POS	O
+induced	POS	O
+by	POS	O
+METH	POS	O
+was	POS	O
+accompanied	POS	O
+by	POS	O
+a	POS	O
+marked	POS	O
+depletion	POS	O
+of	POS	O
+frontostriatal	POS	O
+dopaminergic	POS	O
+and	POS	O
+serotonergic	POS	O
+neurotransmission	POS	O
+,	POS	O
+indicated	POS	O
+by	POS	O
+a	POS	O
+reduction	POS	O
+in	POS	O
+the	POS	O
+levels	POS	O
+of	POS	O
+dopamine	POS	O
+,	POS	O
+DOPAC	POS	O
+and	POS	O
+HVA	POS	O
+,	POS	O
+tyrosine	POS	O
+hydroxylase	POS	O
+and	POS	O
+serotonin	POS	O
+,	POS	O
+observed	POS	O
+at	POS	O
+both	POS	O
+3	POS	O
+and	POS	O
+49	POS	O
+days	POS	O
+post	POS	O
+-	POS	O
+administration	POS	O
+.	POS	O
+In	POS	O
+parallel	POS	O
+,	POS	O
+another	POS	O
+neurochemical	POS	O
+feature	POS	O
+of	POS	O
+depression	POS	B-NP
+-	POS	O
+-	POS	O
+astroglial	POS	O
+dysfunction	POS	O
+-	POS	O
+-	POS	O
+was	POS	O
+unaffected	POS	O
+in	POS	O
+the	POS	O
+cortex	POS	O
+and	POS	O
+the	POS	O
+striatal	POS	O
+levels	POS	O
+of	POS	O
+the	POS	O
+astrocytic	POS	O
+protein	POS	O
+marker	POS	O
+,	POS	O
+glial	POS	O
+fibrillary	POS	O
+acidic	POS	O
+protein	POS	O
+,	POS	O
+were	POS	O
+only	POS	O
+transiently	POS	O
+increased	POS	O
+at	POS	O
+3	POS	O
+days	POS	O
+.	POS	O
+These	POS	O
+findings	POS	O
+demonstrate	POS	O
+for	POS	O
+the	POS	O
+first	POS	O
+time	POS	O
+that	POS	O
+a	POS	O
+single	POS	O
+high	POS	O
+dose	POS	O
+of	POS	O
+METH	POS	O
+induces	POS	O
+long	POS	O
+-	POS	O
+lasting	POS	O
+depressive	POS	O
+-	POS	O
+like	POS	O
+behaviour	POS	O
+in	POS	O
+mice	POS	O
+associated	POS	O
+with	POS	O
+a	POS	O
+persistent	POS	O
+disruption	POS	O
+of	POS	O
+frontostriatal	POS	O
+dopaminergic	POS	O
+and	POS	O
+serotonergic	POS	O
+homoeostasis	POS	O
+.	POS	O
+Linezolid	POS	O
+-	POS	O
+induced	POS	O
+optic	POS	B-NP
+neuropathy	POS	I-NP
+.	POS	O
+Many	POS	O
+systemic	POS	O
+antimicrobials	POS	O
+have	POS	O
+been	POS	O
+implicated	POS	O
+to	POS	O
+cause	POS	O
+ocular	POS	O
+adverse	POS	O
+effects	POS	O
+.	POS	O
+This	POS	O
+is	POS	O
+especially	POS	O
+relevant	POS	O
+in	POS	O
+multidrug	POS	O
+therapy	POS	O
+where	POS	O
+more	POS	O
+than	POS	O
+one	POS	O
+drug	POS	O
+can	POS	O
+cause	POS	O
+a	POS	O
+similar	POS	O
+ocular	POS	O
+adverse	POS	O
+effect	POS	O
+.	POS	O
+We	POS	O
+describe	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+progressive	POS	O
+loss	POS	O
+of	POS	O
+vision	POS	O
+associated	POS	O
+with	POS	O
+linezolid	POS	O
+therapy	POS	O
+.	POS	O
+A	POS	O
+45	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+male	POS	O
+patient	POS	O
+who	POS	O
+was	POS	O
+on	POS	O
+treatment	POS	O
+with	POS	O
+multiple	POS	O
+second	POS	O
+-	POS	O
+line	POS	O
+anti	POS	O
+-	POS	O
+tuberculous	POS	O
+drugs	POS	O
+including	POS	O
+linezolid	POS	O
+and	POS	O
+ethambutol	POS	O
+for	POS	O
+extensively	POS	O
+drug	POS	O
+-	POS	O
+resistant	POS	O
+tuberculosis	POS	B-NP
+(	POS	O
+XDR	POS	O
+-	POS	O
+TB	POS	O
+)	POS	O
+presented	POS	O
+to	POS	O
+us	POS	O
+with	POS	O
+painless	POS	O
+progressive	POS	O
+loss	POS	O
+of	POS	O
+vision	POS	O
+in	POS	O
+both	POS	O
+eyes	POS	O
+.	POS	O
+Color	POS	B-NP
+vision	POS	I-NP
+was	POS	O
+defective	POS	O
+and	POS	O
+fundus	POS	O
+examination	POS	O
+revealed	POS	O
+optic	POS	B-NP
+disc	POS	I-NP
+edema	POS	I-NP
+in	POS	O
+both	POS	O
+eyes	POS	O
+.	POS	O
+Ethambutol	POS	O
+-	POS	O
+induced	POS	O
+toxic	POS	O
+optic	POS	B-NP
+neuropathy	POS	I-NP
+was	POS	O
+suspected	POS	O
+and	POS	O
+tablet	POS	O
+ethambutol	POS	O
+was	POS	O
+withdrawn	POS	O
+.	POS	O
+Deterioration	POS	B-NP
+of	POS	I-NP
+vision	POS	I-NP
+occurred	POS	O
+despite	POS	O
+withdrawal	POS	O
+of	POS	O
+ethambutol	POS	O
+.	POS	O
+Discontinuation	POS	O
+of	POS	O
+linezolid	POS	O
+resulted	POS	O
+in	POS	O
+marked	POS	O
+improvement	POS	O
+of	POS	O
+vision	POS	O
+.	POS	O
+Our	POS	O
+report	POS	O
+emphasizes	POS	O
+the	POS	O
+need	POS	O
+for	POS	O
+monitoring	POS	O
+of	POS	O
+visual	POS	O
+function	POS	O
+in	POS	O
+patients	POS	O
+on	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+linezolid	POS	O
+treatment	POS	O
+.	POS	O
+Resuscitation	POS	O
+with	POS	O
+lipid	POS	O
+,	POS	O
+epinephrine	POS	O
+,	POS	O
+or	POS	O
+both	POS	O
+in	POS	O
+levobupivacaine	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+toxicity	POS	I-NP
+in	POS	O
+newborn	POS	O
+piglets	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+The	POS	O
+optimal	POS	O
+dosing	POS	O
+regimens	POS	O
+of	POS	O
+lipid	POS	O
+emulsion	POS	O
+,	POS	O
+epinephrine	POS	O
+,	POS	O
+or	POS	O
+both	POS	O
+are	POS	O
+not	POS	O
+yet	POS	O
+determined	POS	O
+in	POS	O
+neonates	POS	O
+in	POS	O
+cases	POS	O
+of	POS	O
+local	POS	O
+anaesthetic	POS	O
+systemic	POS	B-NP
+toxicity	POS	I-NP
+(	POS	O
+LAST	POS	O
+)	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Newborn	POS	O
+piglets	POS	O
+received	POS	O
+levobupivacaine	POS	O
+until	POS	O
+cardiovascular	POS	B-NP
+collapse	POS	I-NP
+occurred	POS	O
+.	POS	O
+Standard	POS	O
+cardiopulmonary	POS	O
+resuscitation	POS	O
+was	POS	O
+started	POS	O
+and	POS	O
+electrocardiogram	POS	O
+(	POS	O
+ECG	POS	O
+)	POS	O
+was	POS	O
+monitored	POS	O
+for	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+,	POS	O
+fibrillation	POS	B-NP
+,	POS	O
+or	POS	O
+QRS	POS	B-NP
+prolongation	POS	I-NP
+.	POS	O
+Piglets	POS	O
+were	POS	O
+then	POS	O
+randomly	POS	O
+allocated	POS	O
+to	POS	O
+four	POS	O
+groups	POS	O
+:	POS	O
+control	POS	O
+(	POS	O
+saline	POS	O
+)	POS	O
+,	POS	O
+Intralipid	POS	O
+(	POS	O
+)	POS	O
+alone	POS	O
+,	POS	O
+epinephrine	POS	O
+alone	POS	O
+,	POS	O
+or	POS	O
+a	POS	O
+combination	POS	O
+of	POS	O
+Intralipd	POS	O
+plus	POS	O
+epinephrine	POS	O
+.	POS	O
+Resuscitation	POS	O
+continued	POS	O
+for	POS	O
+30	POS	O
+min	POS	O
+or	POS	O
+until	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+return	POS	O
+of	POS	O
+spontaneous	POS	O
+circulation	POS	O
+(	POS	O
+ROSC	POS	O
+)	POS	O
+accompanied	POS	O
+by	POS	O
+a	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+at	POS	O
+or	POS	O
+superior	POS	O
+to	POS	O
+the	POS	O
+baseline	POS	O
+pressure	POS	O
+and	POS	O
+normal	POS	O
+sinus	POS	O
+rhythm	POS	O
+for	POS	O
+a	POS	O
+period	POS	O
+of	POS	O
+30	POS	O
+min	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+ROSC	POS	O
+was	POS	O
+achieved	POS	O
+in	POS	O
+only	POS	O
+one	POS	O
+of	POS	O
+the	POS	O
+control	POS	O
+piglets	POS	O
+compared	POS	O
+with	POS	O
+most	POS	O
+of	POS	O
+the	POS	O
+treated	POS	O
+piglets	POS	O
+.	POS	O
+Mortality	POS	O
+was	POS	O
+not	POS	O
+significantly	POS	O
+different	POS	O
+between	POS	O
+the	POS	O
+three	POS	O
+treatment	POS	O
+groups	POS	O
+,	POS	O
+but	POS	O
+was	POS	O
+significantly	POS	O
+lower	POS	O
+in	POS	O
+all	POS	O
+the	POS	O
+treatment	POS	O
+groups	POS	O
+compared	POS	O
+with	POS	O
+control	POS	O
+.	POS	O
+The	POS	O
+number	POS	O
+of	POS	O
+ECG	POS	B-NP
+abnormalities	POS	I-NP
+was	POS	O
+zero	POS	O
+in	POS	O
+the	POS	O
+Intralipid	POS	O
+only	POS	O
+group	POS	O
+,	POS	O
+but	POS	O
+14	POS	O
+and	POS	O
+17	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+epinephrine	POS	O
+and	POS	O
+epinephrine	POS	O
+plus	POS	O
+lipid	POS	O
+groups	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Lipid	POS	O
+emulsion	POS	O
+with	POS	O
+or	POS	O
+without	POS	O
+epinephrine	POS	O
+,	POS	O
+or	POS	O
+epinephrine	POS	O
+alone	POS	O
+were	POS	O
+equally	POS	O
+effective	POS	O
+in	POS	O
+achieving	POS	O
+a	POS	O
+return	POS	O
+to	POS	O
+spontaneous	POS	O
+circulation	POS	O
+in	POS	O
+this	POS	O
+model	POS	O
+of	POS	O
+LAST	POS	O
+.	POS	O
+Epinephrine	POS	O
+alone	POS	O
+or	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+lipid	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+increased	POS	O
+number	POS	O
+of	POS	O
+ECG	POS	B-NP
+abnormalities	POS	I-NP
+compared	POS	O
+with	POS	O
+lipid	POS	O
+emulsion	POS	O
+alone	POS	O
+.	POS	O
+Incidence	POS	O
+of	POS	O
+heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+type	POS	O
+II	POS	O
+and	POS	O
+postoperative	POS	O
+recovery	POS	O
+of	POS	O
+platelet	POS	O
+count	POS	O
+in	POS	O
+liver	POS	O
+graft	POS	O
+recipients	POS	O
+:	POS	O
+a	POS	O
+retrospective	POS	O
+cohort	POS	O
+analysis	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Thrombocytopenia	POS	B-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+end	POS	O
+-	POS	O
+stage	POS	O
+liver	POS	B-NP
+disease	POS	I-NP
+is	POS	O
+a	POS	O
+common	POS	O
+disorder	POS	O
+caused	POS	O
+mainly	POS	O
+by	POS	O
+portal	POS	O
+hypertension	POS	B-NP
+,	POS	O
+low	POS	O
+levels	POS	O
+of	POS	O
+thrombopoetin	POS	O
+,	POS	O
+and	POS	O
+endotoxemia	POS	B-NP
+.	POS	O
+The	POS	O
+impact	POS	O
+of	POS	O
+immune	POS	O
+-	POS	O
+mediated	POS	O
+heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+type	POS	O
+II	POS	O
+(	POS	O
+HIT	POS	B-NP
+type	POS	O
+II	POS	O
+)	POS	O
+as	POS	O
+a	POS	O
+cause	POS	O
+of	POS	O
+thrombocytopenia	POS	B-NP
+after	POS	O
+liver	POS	O
+transplantation	POS	O
+is	POS	O
+not	POS	O
+yet	POS	O
+understood	POS	O
+,	POS	O
+with	POS	O
+few	POS	O
+literature	POS	O
+citations	POS	O
+reporting	POS	O
+contradictory	POS	O
+results	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+our	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+demonstrate	POS	O
+the	POS	O
+perioperative	POS	O
+course	POS	O
+of	POS	O
+thrombocytopenia	POS	B-NP
+after	POS	O
+liver	POS	O
+transplantation	POS	O
+and	POS	O
+determine	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+clinical	POS	O
+HIT	POS	B-NP
+type	POS	O
+II	POS	O
+.	POS	O
+METHOD	POS	O
+:	POS	O
+We	POS	O
+retrospectively	POS	O
+evaluated	POS	O
+the	POS	O
+medical	POS	O
+records	POS	O
+of	POS	O
+205	POS	O
+consecutive	POS	O
+adult	POS	O
+patients	POS	O
+who	POS	O
+underwent	POS	O
+full	POS	O
+-	POS	O
+size	POS	O
+liver	POS	O
+transplantation	POS	O
+between	POS	O
+January	POS	O
+2006	POS	O
+and	POS	O
+December	POS	O
+2010	POS	O
+due	POS	O
+to	POS	O
+end	POS	O
+-	POS	O
+stage	POS	O
+or	POS	O
+malignant	POS	B-NP
+liver	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+Preoperative	POS	O
+platelet	POS	O
+count	POS	O
+,	POS	O
+postoperative	POS	O
+course	POS	O
+of	POS	O
+platelets	POS	O
+,	POS	O
+and	POS	O
+clinical	POS	O
+signs	POS	O
+of	POS	O
+HIT	POS	B-NP
+type	POS	O
+II	POS	O
+were	POS	O
+analyzed	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+155	POS	O
+(	POS	O
+75	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+)	POS	O
+of	POS	O
+205	POS	O
+patients	POS	O
+had	POS	O
+thrombocytopenia	POS	B-NP
+before	POS	O
+transplantation	POS	O
+,	POS	O
+significantly	POS	O
+influenced	POS	O
+by	POS	O
+Model	POS	O
+of	POS	O
+End	POS	O
+-	POS	O
+Stage	POS	O
+Liver	POS	O
+Disease	POS	O
+score	POS	O
+and	POS	O
+liver	POS	B-NP
+cirrhosis	POS	I-NP
+.	POS	O
+The	POS	O
+platelet	POS	O
+count	POS	O
+exceeded	POS	O
+100	POS	O
+,	POS	O
+000	POS	O
+/	POS	O
+uL	POS	O
+in	POS	O
+most	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+193	POS	O
+)	POS	O
+at	POS	O
+a	POS	O
+medium	POS	O
+of	POS	O
+7	POS	O
+d	POS	O
+.	POS	O
+Regarding	POS	O
+HIT	POS	B-NP
+II	POS	O
+,	POS	O
+there	POS	O
+were	POS	O
+four	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+95	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+with	POS	O
+a	POS	O
+background	POS	O
+of	POS	O
+HIT	POS	B-NP
+type	POS	O
+II	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+HIT	POS	B-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+end	POS	O
+-	POS	O
+stage	POS	O
+hepatic	POS	B-NP
+failure	POS	I-NP
+is	POS	O
+,	POS	O
+with	POS	O
+about	POS	O
+1	POS	O
+.	POS	O
+95	POS	O
+%	POS	O
+,	POS	O
+rare	POS	O
+.	POS	O
+For	POS	O
+further	POS	O
+reduction	POS	O
+of	POS	O
+HIT	POS	B-NP
+type	POS	O
+II	POS	O
+,	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+intravenous	POS	O
+heparin	POS	O
+should	POS	O
+be	POS	O
+avoided	POS	O
+and	POS	O
+the	POS	O
+prophylactic	POS	O
+anticoagulation	POS	O
+should	POS	O
+be	POS	O
+performed	POS	O
+with	POS	O
+low	POS	O
+-	POS	O
+molecular	POS	O
+-	POS	O
+weight	POS	O
+heparin	POS	O
+after	POS	O
+normalization	POS	O
+of	POS	O
+platelet	POS	O
+count	POS	O
+.	POS	O
+Takotsubo	POS	B-NP
+syndrome	POS	I-NP
+(	POS	O
+or	POS	O
+apical	POS	B-NP
+ballooning	POS	I-NP
+syndrome	POS	I-NP
+)	POS	O
+secondary	POS	O
+to	POS	O
+Zolmitriptan	POS	O
+.	POS	O
+Takotsubo	POS	B-NP
+syndrome	POS	I-NP
+(	POS	O
+TS	POS	B-NP
+)	POS	O
+,	POS	O
+also	POS	O
+known	POS	O
+as	POS	O
+broken	POS	O
+heart	POS	B-NP
+syndrome	POS	I-NP
+,	POS	O
+is	POS	O
+characterized	POS	O
+by	POS	O
+left	POS	B-NP
+ventricle	POS	I-NP
+apical	POS	I-NP
+ballooning	POS	I-NP
+with	POS	O
+elevated	POS	O
+cardiac	POS	O
+biomarkers	POS	O
+and	POS	O
+electrocardiographic	POS	O
+changes	POS	O
+suggestive	POS	O
+of	POS	O
+an	POS	O
+acute	POS	O
+coronary	POS	B-NP
+syndrome	POS	I-NP
+(	POS	O
+ie	POS	O
+,	POS	O
+ST	POS	B-NP
+-	POS	I-NP
+segment	POS	I-NP
+elevation	POS	I-NP
+,	POS	O
+T	POS	O
+wave	POS	O
+inversions	POS	O
+,	POS	O
+and	POS	O
+pathologic	POS	O
+Q	POS	O
+waves	POS	O
+)	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+54	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+with	POS	O
+medical	POS	O
+history	POS	O
+of	POS	O
+mitral	POS	B-NP
+valve	POS	I-NP
+prolapse	POS	I-NP
+and	POS	O
+migraines	POS	B-NP
+,	POS	O
+who	POS	O
+was	POS	O
+admitted	POS	O
+to	POS	O
+the	POS	O
+hospital	POS	O
+for	POS	O
+substernal	POS	B-NP
+chest	POS	I-NP
+pain	POS	I-NP
+and	POS	O
+electrocardiogram	POS	O
+demonstrated	POS	O
+1	POS	O
+/	POS	O
+2	POS	O
+mm	POS	O
+ST	POS	O
+-	POS	O
+segment	POS	O
+elevation	POS	O
+in	POS	O
+leads	POS	O
+II	POS	O
+,	POS	O
+III	POS	O
+,	POS	O
+aVF	POS	O
+,	POS	O
+V5	POS	O
+,	POS	O
+and	POS	O
+V6	POS	O
+and	POS	O
+positive	POS	O
+troponin	POS	O
+I	POS	O
+.	POS	O
+Emergent	POS	O
+coronary	POS	O
+angiogram	POS	O
+revealed	POS	O
+normal	POS	O
+coronary	POS	O
+arteries	POS	O
+with	POS	O
+moderately	POS	O
+reduced	POS	O
+left	POS	O
+ventricular	POS	O
+ejection	POS	O
+fraction	POS	O
+with	POS	O
+wall	POS	O
+motion	POS	O
+abnormalities	POS	O
+consistent	POS	O
+with	POS	O
+TS	POS	B-NP
+.	POS	O
+Detailed	POS	O
+history	POS	O
+obtained	POS	O
+retrospectively	POS	O
+revealed	POS	O
+that	POS	O
+the	POS	O
+patient	POS	O
+took	POS	O
+zolmitriptan	POS	O
+sparingly	POS	O
+only	POS	O
+when	POS	O
+she	POS	O
+had	POS	O
+migraines	POS	B-NP
+.	POS	O
+But	POS	O
+before	POS	O
+this	POS	O
+event	POS	O
+,	POS	O
+she	POS	O
+was	POS	O
+taking	POS	O
+zolmitriptan	POS	O
+2	POS	O
+-	POS	O
+3	POS	O
+times	POS	O
+daily	POS	O
+for	POS	O
+several	POS	O
+days	POS	O
+because	POS	O
+of	POS	O
+a	POS	O
+persistent	POS	O
+migraine	POS	B-NP
+headache	POS	I-NP
+.	POS	O
+She	POS	O
+otherwise	POS	O
+reported	POS	O
+that	POS	O
+she	POS	O
+is	POS	O
+quite	POS	O
+active	POS	O
+,	POS	O
+rides	POS	O
+horses	POS	O
+,	POS	O
+and	POS	O
+does	POS	O
+show	POS	O
+jumping	POS	O
+without	POS	O
+any	POS	O
+limitations	POS	O
+in	POS	O
+her	POS	O
+physical	POS	O
+activity	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+evidence	POS	O
+of	POS	O
+any	POS	O
+recent	POS	O
+stress	POS	O
+or	POS	O
+status	POS	B-NP
+migrainosus	POS	I-NP
+.	POS	O
+Extensive	POS	O
+literature	POS	O
+search	POS	O
+revealed	POS	O
+multiple	POS	O
+cases	POS	O
+of	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+vasospasm	POS	I-NP
+secondary	POS	O
+to	POS	O
+zolmitriptan	POS	O
+,	POS	O
+but	POS	O
+none	POS	O
+of	POS	O
+the	POS	O
+cases	POS	O
+were	POS	O
+associated	POS	O
+with	POS	O
+TS	POS	B-NP
+.	POS	O
+Depression	POS	B-NP
+,	POS	O
+impulsiveness	POS	B-NP
+,	POS	O
+sleep	POS	O
+,	POS	O
+and	POS	O
+memory	POS	O
+in	POS	O
+past	POS	O
+and	POS	O
+present	POS	O
+polydrug	POS	O
+users	POS	O
+of	POS	O
+3	POS	O
+,	POS	O
+4	POS	O
+-	POS	O
+methylenedioxymethamphetamine	POS	O
+(	POS	O
+MDMA	POS	O
+,	POS	O
+ecstasy	POS	O
+)	POS	O
+.	POS	O
+RATIONALE	POS	O
+:	POS	O
+Ecstasy	POS	O
+(	POS	O
+3	POS	O
+,	POS	O
+4	POS	O
+-	POS	O
+methylenedioxymethamphetamine	POS	O
+,	POS	O
+MDMA	POS	O
+)	POS	O
+is	POS	O
+a	POS	O
+worldwide	POS	O
+recreational	POS	O
+drug	POS	O
+of	POS	O
+abuse	POS	O
+.	POS	O
+Unfortunately	POS	O
+,	POS	O
+the	POS	O
+results	POS	O
+from	POS	O
+human	POS	O
+research	POS	O
+investigating	POS	O
+its	POS	O
+psychological	POS	O
+effects	POS	O
+have	POS	O
+been	POS	O
+inconsistent	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+aimed	POS	O
+to	POS	O
+be	POS	O
+the	POS	O
+largest	POS	O
+to	POS	O
+date	POS	O
+in	POS	O
+sample	POS	O
+size	POS	O
+and	POS	O
+5HT	POS	O
+-	POS	O
+related	POS	O
+behaviors	POS	O
+;	POS	O
+the	POS	O
+first	POS	O
+to	POS	O
+compare	POS	O
+present	POS	O
+ecstasy	POS	O
+users	POS	O
+with	POS	O
+past	POS	O
+users	POS	O
+after	POS	O
+an	POS	O
+abstinence	POS	O
+of	POS	O
+4	POS	O
+or	POS	O
+more	POS	O
+years	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+first	POS	O
+to	POS	O
+include	POS	O
+robust	POS	O
+controls	POS	O
+for	POS	O
+other	POS	O
+recreational	POS	O
+substances	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+A	POS	O
+sample	POS	O
+of	POS	O
+997	POS	O
+participants	POS	O
+(	POS	O
+52	POS	O
+%	POS	O
+male	POS	O
+)	POS	O
+was	POS	O
+recruited	POS	O
+to	POS	O
+four	POS	O
+control	POS	O
+groups	POS	O
+(	POS	O
+non	POS	O
+-	POS	O
+drug	POS	O
+(	POS	O
+ND	POS	O
+)	POS	O
+,	POS	O
+alcohol	POS	O
+/	POS	O
+nicotine	POS	O
+(	POS	O
+AN	POS	O
+)	POS	O
+,	POS	O
+cannabis	POS	O
+/	POS	O
+alcohol	POS	O
+/	POS	O
+nicotine	POS	O
+(	POS	O
+CAN	POS	O
+)	POS	O
+,	POS	O
+non	POS	B-NP
+-	POS	I-NP
+ecstasy	POS	I-NP
+polydrug	POS	I-NP
+(	POS	O
+PD	POS	B-NP
+)	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+two	POS	O
+ecstasy	POS	O
+polydrug	POS	O
+groups	POS	O
+(	POS	O
+present	POS	O
+(	POS	O
+MDMA	POS	O
+)	POS	O
+and	POS	O
+past	POS	O
+users	POS	O
+(	POS	O
+EX	POS	O
+-	POS	O
+MDMA	POS	O
+)	POS	O
+.	POS	O
+Participants	POS	O
+completed	POS	O
+a	POS	O
+drug	POS	O
+history	POS	O
+questionnaire	POS	O
+,	POS	O
+Beck	POS	O
+Depression	POS	O
+Inventory	POS	O
+,	POS	O
+Barratt	POS	O
+Impulsiveness	POS	O
+Scale	POS	O
+,	POS	O
+Pittsburgh	POS	O
+Sleep	POS	O
+Quality	POS	O
+Index	POS	O
+,	POS	O
+and	POS	O
+Wechsler	POS	O
+Memory	POS	O
+Scale	POS	O
+-	POS	O
+Revised	POS	O
+which	POS	O
+,	POS	O
+in	POS	O
+total	POS	O
+,	POS	O
+provided	POS	O
+13	POS	O
+psychometric	POS	O
+measures	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+While	POS	O
+the	POS	O
+CAN	POS	O
+and	POS	O
+PD	POS	B-NP
+groups	POS	O
+tended	POS	O
+to	POS	O
+record	POS	O
+greater	POS	O
+deficits	POS	O
+than	POS	O
+the	POS	O
+non	POS	O
+-	POS	O
+drug	POS	O
+controls	POS	O
+,	POS	O
+the	POS	O
+MDMA	POS	O
+and	POS	O
+EX	POS	O
+-	POS	O
+MDMA	POS	O
+groups	POS	O
+recorded	POS	O
+greater	POS	O
+deficits	POS	O
+than	POS	O
+all	POS	O
+the	POS	O
+control	POS	O
+groups	POS	O
+on	POS	O
+ten	POS	O
+of	POS	O
+the	POS	O
+13	POS	O
+psychometric	POS	O
+measures	POS	O
+.	POS	O
+Strikingly	POS	O
+,	POS	O
+despite	POS	O
+prolonged	POS	O
+abstinence	POS	O
+(	POS	O
+mean	POS	O
+,	POS	O
+4	POS	O
+.	POS	O
+98	POS	O
+;	POS	O
+range	POS	O
+,	POS	O
+4	POS	O
+-	POS	O
+9	POS	O
+years	POS	O
+)	POS	O
+,	POS	O
+past	POS	O
+ecstasy	POS	O
+users	POS	O
+showed	POS	O
+few	POS	O
+signs	POS	O
+of	POS	O
+recovery	POS	O
+.	POS	O
+Compared	POS	O
+with	POS	O
+present	POS	O
+ecstasy	POS	O
+users	POS	O
+,	POS	O
+the	POS	O
+past	POS	O
+users	POS	O
+showed	POS	O
+no	POS	O
+change	POS	O
+for	POS	O
+ten	POS	O
+measures	POS	O
+,	POS	O
+increased	POS	O
+impairment	POS	O
+for	POS	O
+two	POS	O
+measures	POS	O
+,	POS	O
+and	POS	O
+improvement	POS	O
+on	POS	O
+just	POS	O
+one	POS	O
+measure	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Given	POS	O
+this	POS	O
+record	POS	O
+of	POS	O
+impaired	POS	B-NP
+memory	POS	I-NP
+and	POS	O
+clinically	POS	O
+significant	POS	O
+levels	POS	O
+of	POS	O
+depression	POS	B-NP
+,	POS	O
+impulsiveness	POS	B-NP
+,	POS	O
+and	POS	O
+sleep	POS	B-NP
+disturbance	POS	I-NP
+,	POS	O
+the	POS	O
+prognosis	POS	O
+for	POS	O
+the	POS	O
+current	POS	O
+generation	POS	O
+of	POS	O
+ecstasy	POS	O
+users	POS	O
+is	POS	O
+a	POS	O
+major	POS	O
+cause	POS	O
+for	POS	O
+concern	POS	O
+.	POS	O
+Association	POS	O
+of	POS	O
+common	POS	O
+genetic	POS	O
+variants	POS	O
+of	POS	O
+HOMER1	POS	O
+gene	POS	O
+with	POS	O
+levodopa	POS	O
+adverse	POS	O
+effects	POS	O
+in	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+patients	POS	O
+.	POS	O
+Levodopa	POS	B-NP
+is	POS	O
+the	POS	O
+most	POS	O
+effective	POS	O
+symptomatic	POS	O
+therapy	POS	O
+for	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+,	POS	O
+but	POS	O
+its	POS	O
+chronic	POS	O
+use	POS	O
+could	POS	O
+lead	POS	O
+to	POS	O
+chronic	POS	O
+adverse	POS	O
+outcomes	POS	O
+,	POS	O
+such	POS	O
+as	POS	O
+motor	POS	O
+fluctuations	POS	O
+,	POS	O
+dyskinesia	POS	B-NP
+and	POS	O
+visual	POS	B-NP
+hallucinations	POS	I-NP
+.	POS	O
+HOMER1	POS	O
+is	POS	O
+a	POS	O
+protein	POS	O
+with	POS	O
+pivotal	POS	O
+function	POS	O
+in	POS	O
+glutamate	POS	O
+transmission	POS	O
+,	POS	O
+which	POS	O
+has	POS	O
+been	POS	O
+related	POS	O
+to	POS	O
+the	POS	O
+pathogenesis	POS	O
+of	POS	O
+these	POS	O
+complications	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+investigates	POS	O
+whether	POS	O
+polymorphisms	POS	O
+in	POS	O
+the	POS	O
+HOMER1	POS	O
+gene	POS	O
+promoter	POS	O
+region	POS	O
+are	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+the	POS	O
+chronic	POS	O
+complications	POS	O
+of	POS	O
+levodopa	POS	O
+therapy	POS	O
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+205	POS	O
+patients	POS	O
+with	POS	O
+idiopathic	POS	B-NP
+Parkinson	POS	I-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+were	POS	O
+investigated	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+genotyped	POS	O
+for	POS	O
+rs4704559	POS	O
+,	POS	O
+rs10942891	POS	O
+and	POS	O
+rs4704560	POS	O
+by	POS	O
+allelic	POS	O
+discrimination	POS	O
+with	POS	O
+Taqman	POS	O
+assays	POS	O
+.	POS	O
+The	POS	O
+rs4704559	POS	O
+G	POS	O
+allele	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+a	POS	O
+lower	POS	O
+prevalence	POS	O
+of	POS	O
+dyskinesia	POS	B-NP
+(	POS	O
+prevalence	POS	O
+ratio	POS	O
+(	POS	O
+PR	POS	O
+)	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+615	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+(	POS	O
+CI	POS	O
+)	POS	O
+0	POS	O
+.	POS	O
+426	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+887	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+009	POS	O
+)	POS	O
+and	POS	O
+visual	POS	B-NP
+hallucinations	POS	I-NP
+(	POS	O
+PR	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+515	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+0	POS	O
+.	POS	O
+295	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+899	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+020	POS	O
+)	POS	O
+.	POS	O
+Our	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+HOMER1	POS	O
+rs4704559	POS	O
+G	POS	O
+allele	POS	O
+has	POS	O
+a	POS	O
+protective	POS	O
+role	POS	O
+for	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+levodopa	POS	O
+adverse	POS	O
+effects	POS	O
+.	POS	O
+Crocin	POS	O
+improves	POS	O
+lipid	POS	O
+dysregulation	POS	O
+in	POS	O
+subacute	POS	O
+diazinon	POS	O
+exposure	POS	O
+through	POS	O
+ERK1	POS	O
+/	POS	O
+2	POS	O
+pathway	POS	O
+in	POS	O
+rat	POS	O
+liver	POS	O
+.	POS	O
+INTRODUCTION	POS	O
+:	POS	O
+Diazinon	POS	O
+Yis	POS	O
+one	POS	O
+of	POS	O
+the	POS	O
+most	POS	O
+broadly	POS	O
+used	POS	O
+organophosphorus	POS	O
+insecticides	POS	O
+in	POS	O
+agriculture	POS	O
+.	POS	O
+It	POS	O
+has	POS	O
+been	POS	O
+shown	POS	O
+that	POS	O
+exposure	POS	O
+to	POS	O
+diazinon	POS	O
+may	POS	O
+interfere	POS	O
+with	POS	O
+lipid	POS	O
+metabolism	POS	O
+.	POS	O
+Moreover	POS	O
+,	POS	O
+the	POS	O
+hypolipidemic	POS	O
+effect	POS	O
+of	POS	O
+crocin	POS	O
+has	POS	O
+been	POS	O
+established	POS	O
+.	POS	O
+Earlier	POS	O
+studies	POS	O
+revealed	POS	O
+the	POS	O
+major	POS	O
+role	POS	O
+of	POS	O
+Extracellular	POS	O
+signal	POS	O
+-	POS	O
+regulated	POS	O
+kinase	POS	O
+(	POS	O
+ERK	POS	O
+)	POS	O
+pathways	POS	O
+in	POS	O
+low	POS	O
+-	POS	O
+density	POS	O
+lipoprotein	POS	O
+receptor	POS	O
+(	POS	O
+LDLr	POS	O
+)	POS	O
+expression	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+evaluate	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+regulation	POS	O
+of	POS	O
+lipid	POS	O
+metabolism	POS	O
+,	POS	O
+ERK	POS	O
+and	POS	O
+LDLr	POS	O
+expression	POS	O
+in	POS	O
+the	POS	O
+liver	POS	O
+of	POS	O
+rats	POS	O
+exposed	POS	O
+to	POS	O
+subacute	POS	O
+diazinon	POS	O
+.	POS	O
+Furthermore	POS	O
+ameliorating	POS	O
+effect	POS	O
+of	POS	O
+crocin	POS	O
+on	POS	O
+diazinon	POS	O
+induced	POS	O
+disturbed	POS	O
+cholesterol	POS	O
+homeostasis	POS	O
+was	POS	O
+studied	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+24	POS	O
+Rats	POS	O
+were	POS	O
+divided	POS	O
+into	POS	O
+4	POS	O
+groups	POS	O
+and	POS	O
+received	POS	O
+following	POS	O
+treatments	POS	O
+for	POS	O
+4	POS	O
+weeks	POS	O
+;	POS	O
+Corn	POS	O
+oil	POS	O
+(	POS	O
+control	POS	O
+)	POS	O
+,	POS	O
+diazinon	POS	O
+(	POS	O
+15mg	POS	O
+/	POS	O
+kg	POS	O
+per	POS	O
+day	POS	O
+,	POS	O
+orally	POS	O
+)	POS	O
+and	POS	O
+crocin	POS	O
+(	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+and	POS	O
+25mg	POS	O
+/	POS	O
+kg	POS	O
+per	POS	O
+day	POS	O
+,	POS	O
+intraperitoneally	POS	O
+)	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+diazinon	POS	O
+(	POS	O
+15	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+levels	POS	O
+of	POS	O
+cholesterol	POS	O
+,	POS	O
+triglyceride	POS	O
+and	POS	O
+LDL	POS	O
+in	POS	O
+blood	POS	O
+of	POS	O
+rats	POS	O
+were	POS	O
+analyzed	POS	O
+.	POS	O
+Moreover	POS	O
+mRNA	POS	O
+levels	POS	O
+of	POS	O
+LDLr	POS	O
+and	POS	O
+ERK1	POS	O
+/	POS	O
+2	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+protein	POS	O
+levels	POS	O
+of	POS	O
+total	POS	O
+and	POS	O
+activated	POS	O
+forms	POS	O
+of	POS	O
+ERK1	POS	O
+/	POS	O
+2	POS	O
+in	POS	O
+rat	POS	O
+liver	POS	O
+were	POS	O
+evaluated	POS	O
+by	POS	O
+Western	POS	O
+blotting	POS	O
+and	POS	O
+quantitative	POS	O
+real	POS	O
+time	POS	O
+polymerase	POS	O
+chain	POS	O
+reaction	POS	O
+analysis	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Our	POS	O
+data	POS	O
+showed	POS	O
+that	POS	O
+subacute	POS	O
+exposure	POS	O
+to	POS	O
+diazinon	POS	O
+significantly	POS	O
+increased	POS	O
+concentrations	POS	O
+of	POS	O
+cholesterol	POS	O
+,	POS	O
+triglyceride	POS	O
+and	POS	O
+LDL	POS	O
+.	POS	O
+Moreover	POS	O
+diazinon	POS	O
+decreased	POS	O
+ERK1	POS	O
+/	POS	O
+2	POS	O
+protein	POS	O
+phosphorylation	POS	O
+and	POS	O
+LDLr	POS	O
+transcript	POS	O
+.	POS	O
+Crocin	POS	O
+reduced	POS	O
+inhibition	POS	O
+of	POS	O
+ERK	POS	O
+activation	POS	O
+and	POS	O
+diazinon	POS	O
+-	POS	O
+induced	POS	O
+hyperlipemia	POS	B-NP
+and	POS	O
+increased	POS	O
+levels	POS	O
+of	POS	O
+LDLr	POS	O
+transcript	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Crocin	POS	O
+may	POS	O
+be	POS	O
+considered	POS	O
+as	POS	O
+a	POS	O
+novel	POS	O
+protective	POS	O
+agent	POS	O
+in	POS	O
+diazinon	POS	O
+-	POS	O
+induced	POS	O
+hyperlipemia	POS	B-NP
+through	POS	O
+modulating	POS	O
+of	POS	O
+ERK	POS	O
+pathway	POS	O
+and	POS	O
+increase	POS	O
+of	POS	O
+LDLr	POS	O
+expression	POS	O
+.	POS	O
+GEM	POS	O
+-	POS	O
+P	POS	O
+chemotherapy	POS	O
+is	POS	O
+active	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+relapsed	POS	B-NP
+Hodgkin	POS	I-NP
+lymphoma	POS	I-NP
+.	POS	O
+Hodgkin	POS	B-NP
+lymphoma	POS	I-NP
+(	POS	O
+HL	POS	B-NP
+)	POS	O
+is	POS	O
+a	POS	O
+relatively	POS	O
+chemosensitive	POS	B-NP
+malignancy	POS	I-NP
+.	POS	O
+However	POS	O
+,	POS	O
+for	POS	O
+those	POS	O
+who	POS	O
+relapse	POS	O
+,	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+chemotherapy	POS	O
+with	POS	O
+autologous	POS	O
+stem	POS	O
+cell	POS	O
+transplant	POS	O
+is	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+choice	POS	O
+which	POS	O
+relies	POS	O
+on	POS	O
+adequate	POS	O
+disease	POS	O
+control	POS	O
+with	POS	O
+salvage	POS	O
+chemotherapy	POS	O
+.	POS	O
+Regimens	POS	O
+commonly	POS	O
+used	POS	O
+often	POS	O
+require	POS	O
+inpatient	POS	O
+administration	POS	O
+and	POS	O
+can	POS	O
+be	POS	O
+difficult	POS	O
+to	POS	O
+deliver	POS	O
+due	POS	O
+to	POS	O
+toxicity	POS	B-NP
+.	POS	O
+Gemcitabine	POS	O
+and	POS	O
+cisplatin	POS	O
+have	POS	O
+activity	POS	O
+in	POS	O
+HL	POS	B-NP
+,	POS	O
+non	POS	B-NP
+-	POS	I-NP
+overlapping	POS	I-NP
+toxicity	POS	I-NP
+with	POS	O
+first	POS	O
+-	POS	O
+line	POS	O
+chemotherapeutics	POS	O
+,	POS	O
+and	POS	O
+may	POS	O
+be	POS	O
+delivered	POS	O
+in	POS	O
+an	POS	O
+outpatient	POS	O
+setting	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+retrospective	POS	O
+single	POS	O
+-	POS	O
+centre	POS	O
+analysis	POS	O
+,	POS	O
+patients	POS	O
+with	POS	O
+relapsed	POS	O
+or	POS	O
+refractory	POS	O
+HL	POS	B-NP
+treated	POS	O
+with	POS	O
+gemcitabine	POS	O
+1	POS	O
+,	POS	O
+000	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+day	POS	O
+(	POS	O
+D	POS	O
+)	POS	O
+1	POS	O
+,	POS	O
+D8	POS	O
+and	POS	O
+D15	POS	O
+;	POS	O
+methylprednisolone	POS	O
+1	POS	O
+,	POS	O
+000	POS	O
+mg	POS	O
+D1	POS	O
+-	POS	O
+5	POS	O
+;	POS	O
+and	POS	O
+cisplatin	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+D15	POS	O
+,	POS	O
+every	POS	O
+28	POS	O
+days	POS	O
+(	POS	O
+GEM	POS	O
+-	POS	O
+P	POS	O
+)	POS	O
+were	POS	O
+included	POS	O
+.	POS	O
+Demographic	POS	O
+,	POS	O
+survival	POS	O
+,	POS	O
+response	POS	O
+and	POS	O
+toxicity	POS	B-NP
+data	POS	O
+were	POS	O
+recorded	POS	O
+.	POS	O
+Forty	POS	O
+-	POS	O
+one	POS	O
+eligible	POS	O
+patients	POS	O
+were	POS	O
+identified	POS	O
+:	POS	O
+median	POS	O
+age	POS	O
+27	POS	O
+.	POS	O
+One	POS	O
+hundred	POS	O
+and	POS	O
+twenty	POS	O
+-	POS	O
+two	POS	O
+cycles	POS	O
+of	POS	O
+GEM	POS	O
+-	POS	O
+P	POS	O
+were	POS	O
+administered	POS	O
+in	POS	O
+total	POS	O
+(	POS	O
+median	POS	O
+3	POS	O
+cycles	POS	O
+;	POS	O
+range	POS	O
+1	POS	O
+-	POS	O
+6	POS	O
+)	POS	O
+.	POS	O
+Twenty	POS	O
+of	POS	O
+41	POS	O
+(	POS	O
+48	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+received	POS	O
+GEM	POS	O
+-	POS	O
+P	POS	O
+as	POS	O
+second	POS	O
+-	POS	O
+line	POS	O
+treatment	POS	O
+and	POS	O
+11	POS	O
+/	POS	O
+41	POS	O
+(	POS	O
+27	POS	O
+%	POS	O
+)	POS	O
+as	POS	O
+third	POS	O
+-	POS	O
+line	POS	O
+therapy	POS	O
+.	POS	O
+Overall	POS	O
+response	POS	O
+rate	POS	O
+(	POS	O
+ORR	POS	O
+)	POS	O
+to	POS	O
+GEM	POS	O
+-	POS	O
+P	POS	O
+in	POS	O
+the	POS	O
+entire	POS	O
+cohort	POS	O
+was	POS	O
+80	POS	O
+%	POS	O
+(	POS	O
+complete	POS	O
+response	POS	O
+(	POS	O
+CR	POS	O
+)	POS	O
+37	POS	O
+%	POS	O
+,	POS	O
+partial	POS	O
+response	POS	O
+44	POS	O
+%	POS	O
+)	POS	O
+with	POS	O
+14	POS	O
+/	POS	O
+15	POS	O
+CR	POS	O
+confirmed	POS	O
+as	POS	O
+a	POS	O
+metabolic	POS	O
+CR	POS	O
+on	POS	O
+PET	POS	O
+and	POS	O
+ORR	POS	O
+of	POS	O
+85	POS	O
+%	POS	O
+in	POS	O
+the	POS	O
+20	POS	O
+second	POS	O
+-	POS	O
+line	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+most	POS	O
+common	POS	O
+grade	POS	O
+3	POS	O
+/	POS	O
+4	POS	O
+toxicities	POS	B-NP
+were	POS	O
+haematological	POS	B-NP
+:	POS	O
+neutropenia	POS	B-NP
+54	POS	O
+%	POS	O
+and	POS	O
+thrombocytopenia	POS	B-NP
+51	POS	O
+%	POS	O
+.	POS	O
+Median	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+from	POS	O
+the	POS	O
+start	POS	O
+of	POS	O
+GEM	POS	O
+-	POS	O
+P	POS	O
+was	POS	O
+4	POS	O
+.	POS	O
+5	POS	O
+years	POS	O
+.	POS	O
+Following	POS	O
+GEM	POS	O
+-	POS	O
+P	POS	O
+,	POS	O
+5	POS	O
+-	POS	O
+year	POS	O
+progression	POS	O
+-	POS	O
+free	POS	O
+survival	POS	O
+was	POS	O
+46	POS	O
+%	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+(	POS	O
+CI	POS	O
+)	POS	O
+,	POS	O
+30	POS	O
+-	POS	O
+62	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+5	POS	O
+-	POS	O
+year	POS	O
+overall	POS	O
+survival	POS	O
+was	POS	O
+59	POS	O
+%	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+,	POS	O
+43	POS	O
+-	POS	O
+74	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Fourteen	POS	O
+of	POS	O
+41	POS	O
+patients	POS	O
+proceeded	POS	O
+directly	POS	O
+to	POS	O
+autologous	POS	O
+transplant	POS	O
+.	POS	O
+GEM	POS	O
+-	POS	O
+P	POS	O
+is	POS	O
+a	POS	O
+salvage	POS	O
+chemotherapy	POS	O
+with	POS	O
+relatively	POS	O
+high	POS	O
+response	POS	O
+rates	POS	O
+,	POS	O
+leading	POS	O
+to	POS	O
+successful	POS	O
+transplantation	POS	O
+in	POS	O
+appropriate	POS	O
+patients	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+relapsed	POS	O
+or	POS	O
+refractory	POS	O
+HL	POS	B-NP
+.	POS	O
+Basal	POS	B-NP
+functioning	POS	I-NP
+of	POS	I-NP
+the	POS	I-NP
+hypothalamic	POS	I-NP
+-	POS	I-NP
+pituitary	POS	I-NP
+-	POS	I-NP
+adrenal	POS	I-NP
+(	POS	I-NP
+HPA	POS	I-NP
+)	POS	I-NP
+axis	POS	I-NP
+and	POS	I-NP
+psychological	POS	I-NP
+distress	POS	I-NP
+in	POS	O
+recreational	POS	O
+ecstasy	POS	O
+polydrug	POS	O
+users	POS	O
+.	POS	O
+RATIONALE	POS	O
+:	POS	O
+Ecstasy	POS	O
+(	POS	O
+MDMA	POS	O
+)	POS	O
+is	POS	O
+a	POS	O
+psychostimulant	POS	O
+drug	POS	O
+which	POS	O
+is	POS	O
+increasingly	POS	O
+associated	POS	O
+with	POS	O
+psychobiological	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+While	POS	O
+some	POS	O
+recent	POS	O
+studies	POS	O
+suggest	POS	O
+acute	POS	O
+changes	POS	O
+in	POS	O
+neuroendocrine	POS	O
+function	POS	O
+,	POS	O
+less	POS	O
+is	POS	O
+known	POS	O
+about	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+changes	POS	O
+in	POS	O
+HPA	POS	O
+functionality	POS	O
+in	POS	O
+recreational	POS	O
+users	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+The	POS	O
+current	POS	O
+study	POS	O
+is	POS	O
+the	POS	O
+first	POS	O
+to	POS	O
+explore	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+ecstasy	POS	O
+-	POS	O
+polydrug	POS	O
+use	POS	O
+on	POS	O
+psychological	POS	O
+distress	POS	O
+and	POS	O
+basal	POS	O
+functioning	POS	O
+of	POS	O
+the	POS	O
+HPA	POS	O
+axis	POS	O
+through	POS	O
+assessing	POS	O
+the	POS	O
+secretion	POS	O
+of	POS	O
+cortisol	POS	O
+across	POS	O
+the	POS	O
+diurnal	POS	O
+period	POS	O
+.	POS	O
+METHOD	POS	O
+:	POS	O
+Seventy	POS	O
+-	POS	O
+six	POS	O
+participants	POS	O
+(	POS	O
+21	POS	O
+nonusers	POS	O
+,	POS	O
+29	POS	O
+light	POS	O
+ecstasy	POS	O
+-	POS	O
+polydrug	POS	O
+users	POS	O
+,	POS	O
+26	POS	O
+heavy	POS	O
+ecstasy	POS	O
+-	POS	O
+polydrug	POS	O
+users	POS	O
+)	POS	O
+completed	POS	O
+a	POS	O
+substance	POS	O
+use	POS	O
+inventory	POS	O
+and	POS	O
+measures	POS	O
+of	POS	O
+psychological	POS	O
+distress	POS	O
+at	POS	O
+baseline	POS	O
+,	POS	O
+then	POS	O
+two	POS	O
+consecutive	POS	O
+days	POS	O
+of	POS	O
+cortisol	POS	O
+sampling	POS	O
+(	POS	O
+on	POS	O
+awakening	POS	O
+,	POS	O
+30	POS	O
+min	POS	O
+post	POS	O
+awakening	POS	O
+,	POS	O
+between	POS	O
+1400	POS	O
+and	POS	O
+1600	POS	O
+hours	POS	O
+and	POS	O
+pre	POS	O
+bedtime	POS	O
+)	POS	O
+.	POS	O
+On	POS	O
+day	POS	O
+2	POS	O
+,	POS	O
+participants	POS	O
+also	POS	O
+attended	POS	O
+the	POS	O
+laboratory	POS	O
+to	POS	O
+complete	POS	O
+a	POS	O
+20	POS	O
+-	POS	O
+min	POS	O
+multitasking	POS	O
+stressor	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Both	POS	O
+user	POS	O
+groups	POS	O
+exhibited	POS	O
+significantly	POS	O
+greater	POS	O
+levels	POS	O
+of	POS	O
+anxiety	POS	B-NP
+and	POS	O
+depression	POS	B-NP
+than	POS	O
+nonusers	POS	O
+.	POS	O
+On	POS	O
+day	POS	O
+1	POS	O
+,	POS	O
+all	POS	O
+participants	POS	O
+exhibited	POS	O
+a	POS	O
+typical	POS	O
+cortisol	POS	O
+profile	POS	O
+,	POS	O
+though	POS	O
+light	POS	O
+users	POS	O
+had	POS	O
+significantly	POS	O
+elevated	POS	O
+levels	POS	O
+pre	POS	O
+-	POS	O
+bed	POS	O
+.	POS	O
+On	POS	O
+day	POS	O
+2	POS	O
+,	POS	O
+heavy	POS	O
+users	POS	O
+demonstrated	POS	O
+elevated	POS	O
+levels	POS	O
+upon	POS	O
+awakening	POS	O
+and	POS	O
+all	POS	O
+ecstasy	POS	O
+-	POS	O
+polydrug	POS	O
+users	POS	O
+demonstrated	POS	O
+elevated	POS	O
+pre	POS	O
+-	POS	O
+bed	POS	O
+levels	POS	O
+compared	POS	O
+to	POS	O
+non	POS	O
+-	POS	O
+users	POS	O
+.	POS	O
+Significant	POS	O
+between	POS	O
+group	POS	O
+differences	POS	O
+were	POS	O
+also	POS	O
+observed	POS	O
+in	POS	O
+afternoon	POS	O
+cortisol	POS	O
+levels	POS	O
+and	POS	O
+in	POS	O
+overall	POS	O
+cortisol	POS	O
+secretion	POS	O
+across	POS	O
+the	POS	O
+day	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+increases	POS	O
+in	POS	O
+anxiety	POS	B-NP
+and	POS	O
+depression	POS	B-NP
+are	POS	O
+in	POS	O
+line	POS	O
+with	POS	O
+previous	POS	O
+observations	POS	O
+in	POS	O
+recreational	POS	O
+ecstasy	POS	O
+-	POS	O
+polydrug	POS	O
+users	POS	O
+.	POS	O
+Dysregulated	POS	O
+diurnal	POS	O
+cortisol	POS	O
+may	POS	O
+be	POS	O
+indicative	POS	O
+of	POS	O
+inappropriate	POS	O
+anticipation	POS	O
+of	POS	O
+forthcoming	POS	O
+demands	POS	O
+and	POS	O
+hypersecretion	POS	B-NP
+may	POS	O
+lead	POS	O
+to	POS	O
+the	POS	O
+increased	POS	O
+psychological	POS	O
+and	POS	O
+physical	POS	O
+morbidity	POS	O
+associated	POS	O
+with	POS	O
+heavy	POS	O
+recreational	POS	O
+use	POS	O
+of	POS	O
+ecstasy	POS	O
+.	POS	O
+Ifosfamide	POS	O
+related	POS	O
+encephalopathy	POS	B-NP
+:	POS	O
+the	POS	O
+need	POS	O
+for	POS	O
+a	POS	O
+timely	POS	O
+EEG	POS	O
+evaluation	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Ifosfamide	POS	O
+is	POS	O
+an	POS	O
+alkylating	POS	O
+agent	POS	O
+useful	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+a	POS	O
+wide	POS	O
+range	POS	O
+of	POS	O
+cancers	POS	B-NP
+including	POS	O
+sarcomas	POS	B-NP
+,	POS	O
+lymphoma	POS	B-NP
+,	POS	O
+gynecologic	POS	B-NP
+and	POS	O
+testicular	POS	B-NP
+cancers	POS	I-NP
+.	POS	O
+Encephalopathy	POS	B-NP
+has	POS	O
+been	POS	O
+reported	POS	O
+in	POS	O
+10	POS	O
+-	POS	O
+40	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+receiving	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+IV	POS	O
+ifosfamide	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+highlight	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+electroencephalogram	POS	O
+(	POS	O
+EEG	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+early	POS	O
+detection	POS	O
+and	POS	O
+management	POS	O
+of	POS	O
+ifosfamide	POS	O
+related	POS	O
+encephalopathy	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Retrospective	POS	O
+chart	POS	O
+review	POS	O
+including	POS	O
+clinical	POS	O
+data	POS	O
+and	POS	O
+EEG	POS	O
+recordings	POS	O
+was	POS	O
+done	POS	O
+on	POS	O
+five	POS	O
+patients	POS	O
+,	POS	O
+admitted	POS	O
+to	POS	O
+MD	POS	O
+Anderson	POS	O
+Cancer	POS	O
+Center	POS	O
+between	POS	O
+years	POS	O
+2009	POS	O
+and	POS	O
+2012	POS	O
+,	POS	O
+who	POS	O
+developed	POS	O
+ifosfamide	POS	O
+related	POS	O
+acute	POS	B-NP
+encephalopathy	POS	I-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+All	POS	O
+five	POS	O
+patients	POS	O
+experienced	POS	O
+symptoms	POS	O
+of	POS	O
+encephalopathy	POS	B-NP
+soon	POS	O
+after	POS	O
+(	POS	O
+within	POS	O
+12	POS	O
+h	POS	O
+-	POS	O
+2	POS	O
+days	POS	O
+)	POS	O
+receiving	POS	O
+ifosfamide	POS	O
+.	POS	O
+Two	POS	O
+patients	POS	O
+developed	POS	O
+generalized	POS	O
+convulsions	POS	B-NP
+while	POS	O
+one	POS	O
+patient	POS	O
+developed	POS	O
+continuous	POS	O
+non	POS	O
+-	POS	O
+convulsive	POS	B-NP
+status	POS	I-NP
+epilepticus	POS	I-NP
+(	POS	O
+NCSE	POS	B-NP
+)	POS	O
+that	POS	O
+required	POS	O
+ICU	POS	O
+admission	POS	O
+and	POS	O
+intubation	POS	O
+.	POS	O
+Initial	POS	O
+EEG	POS	O
+showed	POS	O
+epileptiform	POS	O
+discharges	POS	O
+in	POS	O
+three	POS	O
+patients	POS	O
+;	POS	O
+run	POS	O
+of	POS	O
+triphasic	POS	O
+waves	POS	O
+in	POS	O
+one	POS	O
+patient	POS	O
+and	POS	O
+moderate	POS	O
+degree	POS	O
+diffuse	POS	O
+generalized	POS	O
+slowing	POS	O
+.	POS	O
+Mixed	POS	O
+pattern	POS	O
+with	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+both	POS	O
+sharps	POS	O
+and	POS	O
+triphasic	POS	O
+waves	POS	O
+were	POS	O
+also	POS	O
+noted	POS	O
+.	POS	O
+Repeat	POS	O
+EEGs	POS	O
+within	POS	O
+24	POS	O
+_	POS	O
+h	POS	O
+of	POS	O
+symptom	POS	O
+onset	POS	O
+showed	POS	O
+marked	POS	O
+improvement	POS	O
+that	POS	O
+was	POS	O
+correlated	POS	O
+with	POS	O
+clinical	POS	O
+improvement	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Severity	POS	O
+of	POS	O
+ifosfamide	POS	O
+related	POS	O
+encephalopathy	POS	B-NP
+correlates	POS	O
+with	POS	O
+EEG	POS	O
+changes	POS	O
+.	POS	O
+We	POS	O
+suggest	POS	O
+a	POS	O
+timely	POS	O
+EEG	POS	O
+evaluation	POS	O
+for	POS	O
+patients	POS	O
+receiving	POS	O
+ifosfamide	POS	O
+who	POS	O
+develop	POS	O
+features	POS	O
+of	POS	O
+encephalopathy	POS	B-NP
+.	POS	O
+Incidence	POS	O
+of	POS	O
+contrast	POS	O
+-	POS	O
+induced	POS	O
+nephropathy	POS	B-NP
+in	POS	O
+hospitalised	POS	O
+patients	POS	O
+with	POS	O
+cancer	POS	B-NP
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+To	POS	O
+determine	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+and	POS	O
+possible	POS	O
+factors	POS	O
+related	POS	O
+to	POS	O
+contrast	POS	O
+-	POS	O
+induced	POS	O
+nephropathy	POS	B-NP
+(	POS	O
+CIN	POS	B-NP
+)	POS	O
+in	POS	O
+hospitalised	POS	O
+patients	POS	O
+with	POS	O
+cancer	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Ninety	POS	O
+adult	POS	O
+patients	POS	O
+were	POS	O
+enrolled	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+were	POS	O
+excluded	POS	O
+.	POS	O
+Blood	POS	O
+samples	POS	O
+were	POS	O
+examined	POS	O
+the	POS	O
+day	POS	O
+before	POS	O
+contrast	POS	O
+-	POS	O
+enhanced	POS	O
+computed	POS	O
+tomography	POS	O
+(	POS	O
+CT	POS	O
+)	POS	O
+and	POS	O
+serially	POS	O
+for	POS	O
+3	POS	O
+days	POS	O
+thereafter	POS	O
+.	POS	O
+CIN	POS	B-NP
+was	POS	O
+defined	POS	O
+as	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+serum	POS	O
+creatinine	POS	O
+(	POS	O
+Cr	POS	O
+)	POS	O
+of	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+or	POS	O
+more	POS	O
+,	POS	O
+or	POS	O
+elevation	POS	O
+of	POS	O
+Cr	POS	O
+to	POS	O
+25	POS	O
+%	POS	O
+over	POS	O
+baseline	POS	O
+.	POS	O
+Relationships	POS	O
+between	POS	O
+CIN	POS	B-NP
+and	POS	O
+possible	POS	O
+risk	POS	O
+factors	POS	O
+were	POS	O
+investigated	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+CIN	POS	B-NP
+was	POS	O
+detected	POS	O
+in	POS	O
+18	POS	O
+/	POS	O
+90	POS	O
+(	POS	O
+20	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+.	POS	O
+CIN	POS	B-NP
+developed	POS	O
+in	POS	O
+25	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+patients	POS	O
+who	POS	O
+underwent	POS	O
+chemotherapy	POS	O
+and	POS	O
+in	POS	O
+11	POS	O
+%	POS	O
+patients	POS	O
+who	POS	O
+did	POS	O
+not	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+)	POS	O
+.	POS	O
+CIN	POS	B-NP
+more	POS	O
+frequently	POS	O
+developed	POS	O
+in	POS	O
+patients	POS	O
+who	POS	O
+had	POS	O
+undergone	POS	O
+CT	POS	O
+within	POS	O
+45	POS	O
+days	POS	O
+after	POS	O
+the	POS	O
+last	POS	O
+chemotherapy	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+005	POS	O
+)	POS	O
+;	POS	O
+it	POS	O
+was	POS	O
+also	POS	O
+an	POS	O
+independent	POS	O
+risk	POS	O
+factor	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+017	POS	O
+)	POS	O
+.	POS	O
+CIN	POS	B-NP
+was	POS	O
+significantly	POS	O
+more	POS	O
+after	POS	O
+treatment	POS	O
+with	POS	O
+bevacizumab	POS	O
+/	POS	O
+irinotecan	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+021	POS	O
+)	POS	O
+and	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+hypertension	POS	B-NP
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+044	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+CIN	POS	B-NP
+after	POS	O
+CT	POS	O
+in	POS	O
+hospitalised	POS	O
+oncological	POS	O
+patients	POS	O
+was	POS	O
+20	POS	O
+%	POS	O
+.	POS	O
+CIN	POS	B-NP
+developed	POS	O
+4	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+times	POS	O
+more	POS	O
+frequently	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+cancer	POS	B-NP
+who	POS	O
+had	POS	O
+undergone	POS	O
+recent	POS	O
+chemotherapy	POS	O
+.	POS	O
+Hypertension	POS	B-NP
+and	POS	O
+the	POS	O
+combination	POS	O
+of	POS	O
+bevacizumab	POS	O
+/	POS	O
+irinotecan	POS	O
+may	POS	O
+be	POS	O
+additional	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+CIN	POS	B-NP
+development	POS	O
+.	POS	O
+KEY	POS	O
+POINTS	POS	O
+:	POS	O
+.	POS	O
+Contrast	POS	O
+-	POS	O
+induced	POS	O
+nephropathy	POS	B-NP
+(	POS	O
+CIN	POS	B-NP
+)	POS	O
+is	POS	O
+a	POS	O
+concern	POS	O
+for	POS	O
+oncological	POS	O
+patients	POS	O
+undergoing	POS	O
+CT	POS	O
+.	POS	O
+.	POS	O
+CIN	POS	B-NP
+occurs	POS	O
+more	POS	O
+often	POS	O
+when	POS	O
+CT	POS	O
+is	POS	O
+performed	POS	O
+<	POS	O
+45	POS	O
+days	POS	O
+after	POS	O
+chemotherapy	POS	O
+.	POS	O
+.	POS	O
+Hypertension	POS	B-NP
+and	POS	O
+treatment	POS	O
+with	POS	O
+bevacizumab	POS	O
+appear	POS	O
+to	POS	O
+be	POS	O
+additional	POS	O
+risk	POS	O
+factors	POS	O
+.	POS	O
+Syndrome	POS	B-NP
+of	POS	I-NP
+inappropriate	POS	I-NP
+antidiuretic	POS	I-NP
+hormone	POS	I-NP
+secretion	POS	I-NP
+associated	POS	O
+with	POS	O
+desvenlafaxine	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+syndrome	POS	O
+of	POS	O
+inappropriate	POS	O
+anti	POS	O
+-	POS	O
+diuretic	POS	O
+hormone	POS	O
+(	POS	O
+SIADH	POS	B-NP
+)	POS	O
+secretion	POS	O
+associated	POS	O
+with	POS	O
+desvenlafaxine	POS	O
+.	POS	O
+CASE	POS	O
+SUMMARY	POS	O
+:	POS	O
+A	POS	O
+57	POS	O
+-	POS	O
+year	POS	O
+old	POS	O
+female	POS	O
+with	POS	O
+hyponatraemia	POS	B-NP
+.	POS	O
+Her	POS	O
+medications	POS	O
+included	POS	O
+desvenlafaxine	POS	O
+,	POS	O
+and	POS	O
+symptoms	POS	O
+included	POS	O
+nausea	POS	B-NP
+,	POS	O
+anxiety	POS	B-NP
+and	POS	O
+confusion	POS	B-NP
+.	POS	O
+The	POS	O
+serum	POS	O
+sodium	POS	O
+at	POS	O
+this	POS	O
+time	POS	O
+was	POS	O
+120	POS	O
+mmol	POS	O
+/	POS	O
+L	POS	O
+,	POS	O
+serum	POS	O
+osmolality	POS	O
+was	POS	O
+263	POS	O
+mosmol	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+urine	POS	O
+osmolality	POS	O
+410	POS	O
+mosmol	POS	O
+/	POS	O
+kg	POS	O
+and	POS	O
+urine	POS	O
+sodium	POS	O
+63	POS	O
+mmol	POS	O
+/	POS	O
+L	POS	O
+,	POS	O
+consistent	POS	O
+with	POS	O
+a	POS	O
+diagnosis	POS	O
+of	POS	O
+SIADH	POS	B-NP
+.	POS	O
+Desvenlafaxine	POS	O
+was	POS	O
+ceased	POS	O
+and	POS	O
+fluid	POS	O
+restriction	POS	O
+implemented	POS	O
+.	POS	O
+After	POS	O
+4	POS	O
+days	POS	O
+the	POS	O
+sodium	POS	O
+increased	POS	O
+to	POS	O
+128	POS	O
+mmol	POS	O
+/	POS	O
+L	POS	O
+and	POS	O
+fluid	POS	O
+restriction	POS	O
+was	POS	O
+relaxed	POS	O
+.	POS	O
+During	POS	O
+her	POS	O
+further	POS	O
+3	POS	O
+weeks	POS	O
+inpatient	POS	O
+admission	POS	O
+the	POS	O
+serum	POS	O
+sodium	POS	O
+ranged	POS	O
+from	POS	O
+134	POS	O
+to	POS	O
+137	POS	O
+mmol	POS	O
+/	POS	O
+L	POS	O
+during	POS	O
+treatment	POS	O
+with	POS	O
+mirtazapine	POS	O
+.	POS	O
+DISCUSSION	POS	O
+:	POS	O
+SIADH	POS	B-NP
+has	POS	O
+been	POS	O
+widely	POS	O
+reported	POS	O
+with	POS	O
+a	POS	O
+range	POS	O
+of	POS	O
+antidepressants	POS	O
+.	POS	O
+This	POS	O
+case	POS	O
+report	POS	O
+suggests	POS	O
+that	POS	O
+desvenlafaxine	POS	O
+might	POS	O
+cause	POS	O
+clinically	POS	O
+significant	POS	O
+hyponatremia	POS	B-NP
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Clinicians	POS	O
+should	POS	O
+be	POS	O
+aware	POS	O
+of	POS	O
+the	POS	O
+potential	POS	O
+for	POS	O
+antidepressants	POS	O
+to	POS	O
+cause	POS	O
+hyponatremia	POS	B-NP
+,	POS	O
+and	POS	O
+take	POS	O
+appropriate	POS	O
+corrective	POS	O
+action	POS	O
+where	POS	O
+necessary	POS	O
+.	POS	O
+Oxidative	POS	O
+stress	POS	O
+on	POS	O
+cardiotoxicity	POS	B-NP
+after	POS	O
+treatment	POS	O
+with	POS	O
+single	POS	O
+and	POS	O
+multiple	POS	O
+doses	POS	O
+of	POS	O
+doxorubicin	POS	O
+.	POS	O
+The	POS	O
+mechanism	POS	O
+of	POS	O
+doxorubicin	POS	O
+(	POS	O
+DOX	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+remains	POS	O
+controversial	POS	O
+.	POS	O
+Wistar	POS	O
+rats	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+66	POS	O
+)	POS	O
+received	POS	O
+DOX	POS	O
+injections	POS	O
+intraperitoneally	POS	O
+and	POS	O
+were	POS	O
+randomly	POS	O
+assigned	POS	O
+to	POS	O
+2	POS	O
+experimental	POS	O
+protocols	POS	O
+:	POS	O
+(	POS	O
+1	POS	O
+)	POS	O
+rats	POS	O
+were	POS	O
+killed	POS	O
+before	POS	O
+(	POS	O
+-	POS	O
+24	POS	O
+h	POS	O
+,	POS	O
+n	POS	O
+=	POS	O
+8	POS	O
+)	POS	O
+and	POS	O
+24	POS	O
+h	POS	O
+after	POS	O
+(	POS	O
++	POS	O
+24	POS	O
+h	POS	O
+,	POS	O
+n	POS	O
+=	POS	O
+8	POS	O
+)	POS	O
+a	POS	O
+single	POS	O
+dose	POS	O
+of	POS	O
+DOX	POS	O
+(	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+body	POS	O
+weight	POS	O
+)	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+DOX	POS	O
+acute	POS	O
+effect	POS	O
+and	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+rats	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+58	POS	O
+)	POS	O
+received	POS	O
+4	POS	O
+injections	POS	O
+of	POS	O
+DOX	POS	O
+(	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+body	POS	O
+weight	POS	O
+/	POS	O
+week	POS	O
+)	POS	O
+and	POS	O
+were	POS	O
+killed	POS	O
+before	POS	O
+the	POS	O
+first	POS	O
+injection	POS	O
+(	POS	O
+M0	POS	O
+)	POS	O
+and	POS	O
+1	POS	O
+week	POS	O
+after	POS	O
+each	POS	O
+injection	POS	O
+(	POS	O
+M1	POS	O
+,	POS	O
+M2	POS	O
+,	POS	O
+M3	POS	O
+,	POS	O
+and	POS	O
+M4	POS	O
+)	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+chronological	POS	O
+effects	POS	O
+.	POS	O
+Animals	POS	O
+used	POS	O
+at	POS	O
+M0	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+8	POS	O
+)	POS	O
+were	POS	O
+also	POS	O
+used	POS	O
+at	POS	O
+moment	POS	O
+-	POS	O
+24	POS	O
+h	POS	O
+of	POS	O
+acute	POS	O
+study	POS	O
+.	POS	O
+Cardiac	POS	O
+total	POS	O
+antioxidant	POS	O
+performance	POS	O
+(	POS	O
+TAP	POS	O
+)	POS	O
+,	POS	O
+DNA	POS	O
+damage	POS	O
+,	POS	O
+and	POS	O
+morphology	POS	O
+analyses	POS	O
+were	POS	O
+carried	POS	O
+out	POS	O
+at	POS	O
+each	POS	O
+time	POS	O
+point	POS	O
+.	POS	O
+Single	POS	O
+dose	POS	O
+of	POS	O
+DOX	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+increased	POS	O
+cardiac	POS	B-NP
+disarrangement	POS	I-NP
+,	POS	O
+necrosis	POS	B-NP
+,	POS	O
+and	POS	O
+DNA	POS	O
+damage	POS	O
+(	POS	O
+strand	POS	O
+breaks	POS	O
+(	POS	O
+SBs	POS	O
+)	POS	O
+and	POS	O
+oxidized	POS	O
+pyrimidines	POS	O
+)	POS	O
+and	POS	O
+decreased	POS	O
+TAP	POS	O
+.	POS	O
+The	POS	O
+chronological	POS	O
+study	POS	O
+showed	POS	O
+an	POS	O
+effect	POS	O
+of	POS	O
+a	POS	O
+cumulative	POS	O
+dose	POS	O
+on	POS	O
+body	POS	O
+weight	POS	O
+(	POS	O
+R	POS	O
+=	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+99	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+011	POS	O
+)	POS	O
+,	POS	O
+necrosis	POS	B-NP
+(	POS	O
+R	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+00	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+004	POS	O
+)	POS	O
+,	POS	O
+TAP	POS	O
+(	POS	O
+R	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+95	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+049	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+DNA	POS	O
+SBs	POS	O
+(	POS	O
+R	POS	O
+=	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+95	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+049	POS	O
+)	POS	O
+.	POS	O
+DNA	POS	O
+SBs	POS	O
+damage	POS	O
+was	POS	O
+negatively	POS	O
+associated	POS	O
+with	POS	O
+TAP	POS	O
+(	POS	O
+R	POS	O
+=	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+98	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+018	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+necrosis	POS	B-NP
+(	POS	O
+R	POS	O
+=	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+97	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+027	POS	O
+)	POS	O
+.	POS	O
+Our	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+oxidative	POS	O
+damage	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+acute	POS	O
+cardiotoxicity	POS	B-NP
+induced	POS	O
+by	POS	O
+a	POS	O
+single	POS	O
+dose	POS	O
+of	POS	O
+DOX	POS	O
+only	POS	O
+.	POS	O
+Increased	POS	O
+resistance	POS	O
+to	POS	O
+the	POS	O
+oxidative	POS	O
+stress	POS	O
+is	POS	O
+plausible	POS	O
+for	POS	O
+the	POS	O
+multiple	POS	O
+dose	POS	O
+of	POS	O
+DOX	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+different	POS	O
+mechanisms	POS	O
+may	POS	O
+be	POS	O
+involved	POS	O
+in	POS	O
+acute	POS	B-NP
+toxicity	POS	I-NP
+versus	POS	O
+chronic	POS	B-NP
+toxicity	POS	I-NP
+.	POS	O
+Tacrolimus	POS	O
+-	POS	O
+related	POS	O
+seizure	POS	B-NP
+after	POS	O
+pediatric	POS	O
+liver	POS	O
+transplantation	POS	O
+-	POS	O
+-	POS	O
+a	POS	O
+single	POS	O
+-	POS	O
+center	POS	O
+experience	POS	O
+.	POS	O
+To	POS	O
+identify	POS	O
+the	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+new	POS	O
+-	POS	O
+onset	POS	O
+seizures	POS	B-NP
+after	POS	O
+pediatric	POS	O
+LT	POS	O
+and	POS	O
+to	POS	O
+assess	POS	O
+their	POS	O
+clinical	POS	O
+implications	POS	O
+and	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+prognosis	POS	O
+.	POS	O
+The	POS	O
+clinical	POS	O
+and	POS	O
+laboratory	POS	O
+data	POS	O
+of	POS	O
+27	POS	O
+consecutive	POS	O
+children	POS	O
+who	POS	O
+underwent	POS	O
+LT	POS	O
+from	POS	O
+January	POS	O
+2007	POS	O
+to	POS	O
+December	POS	O
+2010	POS	O
+in	POS	O
+our	POS	O
+center	POS	O
+were	POS	O
+analyzed	POS	O
+retrospectively	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+divided	POS	O
+into	POS	O
+seizures	POS	B-NP
+group	POS	O
+and	POS	O
+a	POS	O
+non	POS	O
+-	POS	O
+seizures	POS	B-NP
+group	POS	O
+.	POS	O
+Pre	POS	O
+-	POS	O
+operative	POS	O
+,	POS	O
+intra	POS	O
+-	POS	O
+operative	POS	O
+,	POS	O
+and	POS	O
+post	POS	O
+-	POS	O
+operative	POS	O
+data	POS	O
+were	POS	O
+collected	POS	O
+.	POS	O
+Seizures	POS	B-NP
+occurred	POS	O
+in	POS	O
+four	POS	O
+children	POS	O
+,	POS	O
+an	POS	O
+incidence	POS	O
+of	POS	O
+14	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+.	POS	O
+All	POS	O
+exhibited	POS	O
+generalized	POS	O
+tonic	POS	O
+-	POS	O
+clonic	POS	B-NP
+seizures	POS	B-NP
+within	POS	O
+the	POS	O
+first	POS	O
+two	POS	O
+wk	POS	O
+after	POS	O
+LT	POS	O
+.	POS	O
+Univariate	POS	O
+analysis	POS	O
+showed	POS	O
+that	POS	O
+the	POS	O
+risk	POS	O
+factors	POS	O
+associated	POS	O
+with	POS	O
+seizures	POS	B-NP
+after	POS	O
+pediatric	POS	O
+LT	POS	O
+included	POS	O
+gender	POS	O
+,	POS	O
+pediatric	POS	B-NP
+end	POS	I-NP
+-	POS	I-NP
+stage	POS	I-NP
+liver	POS	I-NP
+disease	POS	I-NP
+score	POS	O
+before	POS	O
+surgery	POS	O
+,	POS	O
+Child	POS	O
+-	POS	O
+Pugh	POS	O
+score	POS	O
+before	POS	O
+surgery	POS	O
+,	POS	O
+serum	POS	O
+total	POS	O
+bilirubin	POS	O
+after	POS	O
+surgery	POS	O
+,	POS	O
+and	POS	O
+trough	POS	O
+TAC	POS	O
+level	POS	O
+.	POS	O
+Multivariate	POS	O
+analysis	POS	O
+showed	POS	O
+that	POS	O
+trough	POS	O
+TAC	POS	O
+level	POS	O
+was	POS	O
+the	POS	O
+only	POS	O
+independent	POS	O
+risk	POS	O
+factor	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+seizures	POS	B-NP
+.	POS	O
+All	POS	O
+children	POS	O
+who	POS	O
+experienced	POS	O
+seizures	POS	B-NP
+survived	POS	O
+with	POS	O
+good	POS	O
+graft	POS	O
+function	POS	O
+and	POS	O
+remained	POS	O
+seizure	POS	B-NP
+-	POS	O
+free	POS	O
+without	POS	O
+anti	POS	O
+-	POS	O
+epileptic	POS	B-NP
+drugs	POS	O
+over	POS	O
+a	POS	O
+mean	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+period	POS	O
+of	POS	O
+33	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+14	POS	O
+.	POS	O
+6	POS	O
+months	POS	O
+.	POS	O
+High	POS	O
+trough	POS	O
+TAC	POS	O
+level	POS	O
+was	POS	O
+the	POS	O
+predominant	POS	O
+factor	POS	O
+that	POS	O
+contributed	POS	O
+to	POS	O
+seizures	POS	B-NP
+in	POS	O
+the	POS	O
+early	POS	O
+post	POS	O
+-	POS	O
+operative	POS	O
+period	POS	O
+after	POS	O
+pediatric	POS	O
+LT	POS	O
+.	POS	O
+High	POS	O
+PELD	POS	O
+and	POS	O
+Child	POS	O
+-	POS	O
+Pugh	POS	O
+scores	POS	O
+before	POS	O
+LT	POS	O
+and	POS	O
+high	POS	O
+post	POS	O
+-	POS	O
+operative	POS	O
+serum	POS	O
+Tbil	POS	O
+may	POS	O
+be	POS	O
+contributory	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+TAC	POS	O
+-	POS	O
+related	POS	O
+seizures	POS	B-NP
+.	POS	O
+The	POS	O
+flavonoid	POS	O
+apigenin	POS	O
+delays	POS	O
+forgetting	POS	O
+of	POS	O
+passive	POS	O
+avoidance	POS	O
+conditioning	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+experiments	POS	O
+were	POS	O
+performed	POS	O
+to	POS	O
+study	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+the	POS	O
+flavonoid	POS	O
+apigenin	POS	O
+(	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+intraperitoneally	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+,	POS	O
+1	POS	O
+h	POS	O
+before	POS	O
+acquisition	POS	O
+)	POS	O
+,	POS	O
+on	POS	O
+24	POS	O
+h	POS	O
+retention	POS	O
+performance	POS	O
+and	POS	O
+forgetting	POS	O
+of	POS	O
+a	POS	O
+step	POS	O
+-	POS	O
+through	POS	O
+passive	POS	O
+avoidance	POS	O
+task	POS	O
+,	POS	O
+in	POS	O
+young	POS	O
+male	POS	O
+Wistar	POS	O
+rats	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+no	POS	O
+differences	POS	O
+between	POS	O
+saline	POS	O
+-	POS	O
+and	POS	O
+apigenin	POS	O
+-	POS	O
+treated	POS	O
+groups	POS	O
+in	POS	O
+the	POS	O
+24	POS	O
+h	POS	O
+retention	POS	O
+trial	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+apigenin	POS	O
+did	POS	O
+not	POS	O
+prevent	POS	O
+the	POS	O
+amnesia	POS	B-NP
+induced	POS	O
+by	POS	O
+scopolamine	POS	O
+(	POS	O
+1mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+,	POS	O
+30	POS	O
+min	POS	O
+before	POS	O
+the	POS	O
+acquisition	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+saline	POS	O
+-	POS	O
+and	POS	O
+apigenin	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+that	POS	O
+did	POS	O
+not	POS	O
+step	POS	O
+through	POS	O
+into	POS	O
+the	POS	O
+dark	POS	O
+compartment	POS	O
+during	POS	O
+the	POS	O
+cut	POS	O
+-	POS	O
+off	POS	O
+time	POS	O
+(	POS	O
+540	POS	O
+s	POS	O
+)	POS	O
+were	POS	O
+retested	POS	O
+weekly	POS	O
+for	POS	O
+up	POS	O
+to	POS	O
+eight	POS	O
+weeks	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+saline	POS	O
+treated	POS	O
+group	POS	O
+,	POS	O
+the	POS	O
+first	POS	O
+significant	POS	O
+decline	POS	O
+in	POS	O
+passive	POS	O
+avoidance	POS	O
+response	POS	O
+was	POS	O
+observed	POS	O
+at	POS	O
+four	POS	O
+weeks	POS	O
+,	POS	O
+and	POS	O
+complete	POS	O
+memory	POS	B-NP
+loss	POS	I-NP
+was	POS	O
+found	POS	O
+five	POS	O
+weeks	POS	O
+after	POS	O
+the	POS	O
+acquisition	POS	O
+of	POS	O
+the	POS	O
+passive	POS	O
+avoidance	POS	O
+task	POS	O
+.	POS	O
+At	POS	O
+the	POS	O
+end	POS	O
+of	POS	O
+the	POS	O
+experimental	POS	O
+period	POS	O
+,	POS	O
+60	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+animals	POS	O
+treated	POS	O
+with	POS	O
+apigenin	POS	O
+still	POS	O
+did	POS	O
+not	POS	O
+step	POS	O
+through	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+1	POS	O
+)	POS	O
+apigenin	POS	O
+delays	POS	O
+the	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+forgetting	POS	O
+but	POS	O
+did	POS	O
+not	POS	O
+modulate	POS	O
+the	POS	O
+24	POS	O
+h	POS	O
+retention	POS	O
+of	POS	O
+fear	POS	O
+memory	POS	O
+and	POS	O
+2	POS	O
+)	POS	O
+the	POS	O
+obtained	POS	O
+beneficial	POS	O
+effect	POS	O
+of	POS	O
+apigenin	POS	O
+on	POS	O
+the	POS	O
+passive	POS	O
+avoidance	POS	O
+conditioning	POS	O
+is	POS	O
+mediated	POS	O
+by	POS	O
+mechanisms	POS	O
+that	POS	O
+do	POS	O
+not	POS	O
+implicate	POS	O
+its	POS	O
+action	POS	O
+on	POS	O
+the	POS	O
+muscarinic	POS	O
+cholinergic	POS	O
+system	POS	O
+.	POS	O
+Histamine	POS	O
+antagonists	POS	O
+and	POS	O
+d	POS	O
+-	POS	O
+tubocurarine	POS	O
+-	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+in	POS	O
+cardiac	POS	O
+surgical	POS	O
+patients	POS	O
+.	POS	O
+Hemodynamic	POS	O
+effects	POS	O
+and	POS	O
+histamine	POS	O
+release	POS	O
+by	POS	O
+bolus	POS	O
+injection	POS	O
+of	POS	O
+0	POS	O
+.	POS	O
+35	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+of	POS	O
+d	POS	O
+-	POS	O
+tubocurarine	POS	O
+were	POS	O
+studied	POS	O
+in	POS	O
+24	POS	O
+patients	POS	O
+.	POS	O
+H1	POS	O
+-	POS	O
+and	POS	O
+H2	POS	O
+-	POS	O
+histamine	POS	O
+antagonists	POS	O
+or	POS	O
+placebo	POS	O
+were	POS	O
+given	POS	O
+before	POS	O
+dosing	POS	O
+with	POS	O
+d	POS	O
+-	POS	O
+tubocurarine	POS	O
+in	POS	O
+a	POS	O
+randomized	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+fashion	POS	O
+to	POS	O
+four	POS	O
+groups	POS	O
+:	POS	O
+group	POS	O
+1	POS	O
+-	POS	O
+-	POS	O
+placebo	POS	O
+;	POS	O
+group	POS	O
+2	POS	O
+-	POS	O
+-	POS	O
+cimetidine	POS	O
+,	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+plus	POS	O
+placebo	POS	O
+;	POS	O
+group	POS	O
+3	POS	O
+-	POS	O
+-	POS	O
+chlorpheniramine	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+plus	POS	O
+placebo	POS	O
+;	POS	O
+and	POS	O
+group	POS	O
+4	POS	O
+-	POS	O
+-	POS	O
+cimetidine	POS	O
+plus	POS	O
+chlorpheniramine	POS	O
+.	POS	O
+Histamine	POS	O
+release	POS	O
+occurred	POS	O
+in	POS	O
+most	POS	O
+patients	POS	O
+,	POS	O
+the	POS	O
+highest	POS	O
+level	POS	O
+2	POS	O
+minutes	POS	O
+after	POS	O
+d	POS	O
+-	POS	O
+tubocurarine	POS	O
+dosing	POS	O
+.	POS	O
+Group	POS	O
+1	POS	O
+had	POS	O
+a	POS	O
+moderate	POS	O
+negative	POS	O
+correlation	POS	O
+between	POS	O
+plasma	POS	O
+histamine	POS	O
+change	POS	O
+and	POS	O
+systemic	POS	O
+vascular	POS	O
+resistance	POS	O
+(	POS	O
+r	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+58	POS	O
+;	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+not	POS	O
+present	POS	O
+in	POS	O
+group	POS	O
+4	POS	O
+.	POS	O
+Prior	POS	O
+dosing	POS	O
+with	POS	O
+antagonists	POS	O
+partially	POS	O
+prevented	POS	O
+the	POS	O
+fall	POS	O
+in	POS	O
+systemic	POS	O
+vascular	POS	O
+resistance	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+demonstrate	POS	O
+that	POS	O
+the	POS	O
+hemodynamic	POS	O
+changes	POS	O
+associated	POS	O
+with	POS	O
+d	POS	O
+-	POS	O
+tubocurarine	POS	O
+dosing	POS	O
+are	POS	O
+only	POS	O
+partially	POS	O
+explained	POS	O
+by	POS	O
+histamine	POS	O
+release	POS	O
+.	POS	O
+Thus	POS	O
+prior	POS	O
+dosing	POS	O
+with	POS	O
+H1	POS	O
+-	POS	O
+and	POS	O
+H2	POS	O
+-	POS	O
+antagonists	POS	O
+provides	POS	O
+only	POS	O
+partial	POS	O
+protection	POS	O
+.	POS	O
+Cholecystokinin	POS	O
+-	POS	O
+octapeptide	POS	O
+restored	POS	O
+morphine	POS	O
+-	POS	O
+induced	POS	O
+hippocampal	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+potentiation	POS	O
+impairment	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+Cholecystokinin	POS	O
+-	POS	O
+octapeptide	POS	O
+(	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+)	POS	O
+,	POS	O
+which	POS	O
+is	POS	O
+a	POS	O
+typical	POS	O
+brain	POS	O
+-	POS	O
+gut	POS	O
+peptide	POS	O
+,	POS	O
+exerts	POS	O
+a	POS	O
+wide	POS	O
+range	POS	O
+of	POS	O
+biological	POS	O
+activities	POS	O
+on	POS	O
+the	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+.	POS	O
+We	POS	O
+have	POS	O
+previously	POS	O
+reported	POS	O
+that	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+significantly	POS	O
+alleviated	POS	O
+morphine	POS	O
+-	POS	O
+induced	POS	O
+amnesia	POS	B-NP
+and	POS	O
+reversed	POS	O
+spine	POS	O
+density	POS	O
+decreases	POS	O
+in	POS	O
+the	POS	O
+CA1	POS	O
+region	POS	O
+of	POS	O
+the	POS	O
+hippocampus	POS	O
+in	POS	O
+morphine	POS	O
+-	POS	O
+treated	POS	O
+animals	POS	O
+.	POS	O
+Here	POS	O
+,	POS	O
+we	POS	O
+investigated	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+on	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+potentiation	POS	O
+(	POS	O
+LTP	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+lateral	POS	O
+perforant	POS	O
+path	POS	O
+(	POS	O
+LPP	POS	O
+)	POS	O
+-	POS	O
+granule	POS	O
+cell	POS	O
+synapse	POS	O
+of	POS	O
+rat	POS	O
+dentate	POS	O
+gyrus	POS	O
+(	POS	O
+DG	POS	O
+)	POS	O
+in	POS	O
+acute	POS	O
+saline	POS	O
+or	POS	O
+morphine	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+.	POS	O
+Population	POS	O
+spikes	POS	O
+(	POS	O
+PS	POS	O
+)	POS	O
+,	POS	O
+which	POS	O
+were	POS	O
+evoked	POS	O
+by	POS	O
+stimulation	POS	O
+of	POS	O
+the	POS	O
+LPP	POS	O
+,	POS	O
+were	POS	O
+recorded	POS	O
+in	POS	O
+the	POS	O
+DG	POS	O
+region	POS	O
+.	POS	O
+Acute	POS	O
+morphine	POS	O
+(	POS	O
+30mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+s	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+)	POS	O
+treatment	POS	O
+significantly	POS	O
+attenuated	POS	O
+hippocampal	POS	O
+LTP	POS	O
+and	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+(	POS	O
+1ug	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+)	POS	O
+restored	POS	O
+the	POS	O
+amplitude	POS	O
+of	POS	O
+PS	POS	O
+that	POS	O
+was	POS	O
+attenuated	POS	O
+by	POS	O
+morphine	POS	O
+injection	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+microinjection	POS	O
+of	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+and	POS	O
+1ug	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+)	POS	O
+also	POS	O
+significantly	POS	O
+augmented	POS	O
+hippocampal	POS	O
+LTP	POS	O
+in	POS	O
+saline	POS	O
+-	POS	O
+treated	POS	O
+(	POS	O
+1ml	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+s	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+)	POS	O
+rats	POS	O
+.	POS	O
+Pre	POS	O
+-	POS	O
+treatment	POS	O
+of	POS	O
+the	POS	O
+CCK2	POS	O
+receptor	POS	O
+antagonist	POS	O
+L	POS	O
+-	POS	O
+365	POS	O
+,	POS	O
+260	POS	O
+(	POS	O
+10ug	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+)	POS	O
+reversed	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+,	POS	O
+but	POS	O
+the	POS	O
+CCK1	POS	O
+receptor	POS	O
+antagonist	POS	O
+L	POS	O
+-	POS	O
+364	POS	O
+,	POS	O
+718	POS	O
+(	POS	O
+10ug	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+)	POS	O
+did	POS	O
+not	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+results	POS	O
+demonstrate	POS	O
+that	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+attenuates	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+morphine	POS	O
+on	POS	O
+hippocampal	POS	O
+LTP	POS	O
+through	POS	O
+CCK2	POS	O
+receptors	POS	O
+and	POS	O
+suggest	POS	O
+an	POS	O
+ameliorative	POS	O
+function	POS	O
+of	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+on	POS	O
+morphine	POS	O
+-	POS	O
+induced	POS	O
+memory	POS	B-NP
+impairment	POS	I-NP
+.	POS	O
+Glial	POS	O
+activation	POS	O
+and	POS	O
+post	POS	O
+-	POS	O
+synaptic	POS	O
+neurotoxicity	POS	B-NP
+:	POS	O
+the	POS	O
+key	POS	O
+events	POS	O
+in	POS	O
+Streptozotocin	POS	O
+(	POS	O
+ICV	POS	O
+)	POS	O
+induced	POS	O
+memory	POS	B-NP
+impairment	POS	I-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+glial	POS	O
+activation	POS	O
+and	POS	O
+post	POS	O
+synaptic	POS	B-NP
+toxicity	POS	I-NP
+in	POS	O
+ICV	POS	O
+Streptozotocin	POS	O
+(	POS	O
+STZ	POS	O
+)	POS	O
+induced	POS	O
+memory	POS	O
+impaired	POS	O
+rats	POS	O
+was	POS	O
+explored	POS	O
+.	POS	O
+In	POS	O
+experiment	POS	O
+set	POS	O
+up	POS	O
+1	POS	O
+:	POS	O
+Memory	POS	B-NP
+deficit	POS	I-NP
+was	POS	O
+found	POS	O
+in	POS	O
+Morris	POS	O
+water	POS	O
+maze	POS	O
+test	POS	O
+on	POS	O
+14	POS	O
+-	POS	O
+16	POS	O
+days	POS	O
+after	POS	O
+STZ	POS	O
+(	POS	O
+ICV	POS	O
+;	POS	O
+3mg	POS	O
+/	POS	O
+Kg	POS	O
+)	POS	O
+administration	POS	O
+.	POS	O
+STZ	POS	O
+causes	POS	O
+increased	POS	O
+expression	POS	O
+of	POS	O
+GFAP	POS	O
+,	POS	O
+CD11b	POS	O
+and	POS	O
+TNF	POS	O
+-	POS	O
+a	POS	O
+indicating	POS	O
+glial	POS	O
+activation	POS	O
+and	POS	O
+neuroinflammation	POS	O
+.	POS	O
+STZ	POS	O
+also	POS	O
+significantly	POS	O
+increased	POS	O
+the	POS	O
+level	POS	O
+of	POS	O
+ROS	POS	O
+,	POS	O
+nitrite	POS	O
+,	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+and	POS	O
+reduced	POS	O
+the	POS	O
+mitochondrial	POS	O
+activity	POS	O
+in	POS	O
+synaptosomal	POS	O
+preparation	POS	O
+illustrating	POS	O
+free	POS	O
+radical	POS	O
+generation	POS	O
+and	POS	O
+excitotoxicity	POS	O
+.	POS	O
+Increased	POS	O
+expression	POS	O
+and	POS	O
+activity	POS	O
+of	POS	O
+Caspase	POS	O
+-	POS	O
+3	POS	O
+was	POS	O
+also	POS	O
+observed	POS	O
+in	POS	O
+STZ	POS	O
+treated	POS	O
+rat	POS	O
+which	POS	O
+specify	POS	O
+apoptotic	POS	O
+cell	POS	O
+death	POS	O
+in	POS	O
+hippocampus	POS	O
+and	POS	O
+cortex	POS	O
+.	POS	O
+STZ	POS	O
+treatment	POS	O
+showed	POS	O
+decrease	POS	O
+expression	POS	O
+of	POS	O
+post	POS	O
+synaptic	POS	O
+markers	POS	O
+CaMKIIa	POS	O
+and	POS	O
+PSD	POS	O
+-	POS	O
+95	POS	O
+,	POS	O
+while	POS	O
+,	POS	O
+expression	POS	O
+of	POS	O
+pre	POS	O
+synaptic	POS	O
+markers	POS	O
+(	POS	O
+synaptophysin	POS	O
+and	POS	O
+SNAP	POS	O
+-	POS	O
+25	POS	O
+)	POS	O
+remains	POS	O
+unaltered	POS	O
+indicating	POS	O
+selective	POS	O
+post	POS	O
+synaptic	POS	O
+neurotoxicity	POS	B-NP
+.	POS	O
+Oral	POS	O
+treatment	POS	O
+with	POS	O
+Memantine	POS	O
+(	POS	O
+10mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+and	POS	O
+Ibuprofen	POS	O
+(	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+daily	POS	O
+for	POS	O
+13	POS	O
+days	POS	O
+attenuated	POS	O
+STZ	POS	O
+induced	POS	O
+glial	POS	O
+activation	POS	O
+,	POS	O
+apoptotic	POS	O
+cell	POS	O
+death	POS	O
+and	POS	O
+post	POS	O
+synaptic	POS	O
+neurotoxicity	POS	B-NP
+in	POS	O
+rat	POS	O
+brain	POS	O
+.	POS	O
+Further	POS	O
+,	POS	O
+in	POS	O
+experiment	POS	O
+set	POS	O
+up	POS	O
+2	POS	O
+:	POS	O
+where	POS	O
+memory	POS	O
+function	POS	O
+was	POS	O
+not	POS	O
+affected	POS	O
+i	POS	O
+.	POS	O
+e	POS	O
+.	POS	O
+7	POS	O
+-	POS	O
+9	POS	O
+days	POS	O
+after	POS	O
+STZ	POS	O
+treatment	POS	O
+.	POS	O
+The	POS	O
+level	POS	O
+of	POS	O
+GFAP	POS	O
+,	POS	O
+CD11b	POS	O
+,	POS	O
+TNF	POS	O
+-	POS	O
+a	POS	O
+,	POS	O
+ROS	POS	O
+and	POS	O
+nitrite	POS	O
+levels	POS	O
+were	POS	O
+increased	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+other	POS	O
+hand	POS	O
+,	POS	O
+apoptotic	POS	O
+marker	POS	O
+,	POS	O
+synaptic	POS	O
+markers	POS	O
+,	POS	O
+mitochondrial	POS	O
+activity	POS	O
+and	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+levels	POS	O
+remained	POS	O
+unaffected	POS	B-NP
+.	POS	O
+Collective	POS	O
+data	POS	O
+indicates	POS	O
+that	POS	O
+neuroinflammatory	POS	O
+process	POS	O
+and	POS	O
+oxidative	POS	O
+stress	POS	O
+occurs	POS	O
+earlier	POS	O
+to	POS	O
+apoptosis	POS	O
+and	POS	O
+does	POS	O
+not	POS	O
+affect	POS	O
+memory	POS	O
+function	POS	O
+.	POS	O
+Present	POS	O
+study	POS	O
+clearly	POS	O
+suggests	POS	O
+that	POS	O
+glial	POS	O
+activation	POS	O
+and	POS	O
+post	POS	O
+synaptic	POS	O
+neurotoxicity	POS	B-NP
+are	POS	O
+the	POS	O
+key	POS	O
+factors	POS	O
+in	POS	O
+STZ	POS	O
+induced	POS	O
+memory	POS	B-NP
+impairment	POS	I-NP
+and	POS	O
+neuronal	POS	B-NP
+cell	POS	I-NP
+death	POS	I-NP
+.	POS	O
+Comparison	POS	O
+of	POS	O
+effects	POS	O
+of	POS	O
+isotonic	POS	O
+sodium	POS	O
+chloride	POS	O
+with	POS	O
+diltiazem	POS	O
+in	POS	O
+prevention	POS	O
+of	POS	O
+contrast	POS	O
+-	POS	O
+induced	POS	O
+nephropathy	POS	B-NP
+.	POS	O
+INTRODUCTION	POS	O
+AND	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+Contrast	POS	O
+-	POS	O
+induced	POS	O
+nephropathy	POS	B-NP
+(	POS	O
+CIN	POS	B-NP
+)	POS	O
+significantly	POS	O
+increases	POS	O
+the	POS	O
+morbidity	POS	O
+and	POS	O
+mortality	POS	O
+of	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+is	POS	O
+to	POS	O
+investigate	POS	O
+and	POS	O
+compare	POS	O
+the	POS	O
+protective	POS	O
+effects	POS	O
+of	POS	O
+isotonic	POS	O
+sodium	POS	O
+chloride	POS	O
+with	POS	O
+sodium	POS	O
+bicarbonate	POS	O
+infusion	POS	O
+and	POS	O
+isotonic	POS	O
+sodium	POS	O
+chloride	POS	O
+infusion	POS	O
+with	POS	O
+diltiazem	POS	O
+,	POS	O
+a	POS	O
+calcium	POS	O
+channel	POS	O
+blocker	POS	O
+,	POS	O
+in	POS	O
+preventing	POS	O
+CIN	POS	O
+.	POS	O
+MATERIALS	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+Our	POS	O
+study	POS	O
+included	POS	O
+patients	POS	O
+who	POS	O
+were	POS	O
+administered	POS	O
+30	POS	O
+-	POS	O
+60	POS	O
+mL	POS	O
+of	POS	O
+iodinated	POS	O
+contrast	POS	O
+agent	POS	O
+for	POS	O
+percutaneous	POS	O
+coronary	POS	O
+angiography	POS	O
+(	POS	O
+PCAG	POS	O
+)	POS	O
+,	POS	O
+all	POS	O
+with	POS	O
+creatinine	POS	O
+values	POS	O
+between	POS	O
+1	POS	O
+.	POS	O
+1	POS	O
+and	POS	O
+3	POS	O
+.	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+divided	POS	O
+into	POS	O
+three	POS	O
+groups	POS	O
+and	POS	O
+each	POS	O
+group	POS	O
+had	POS	O
+20	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+first	POS	O
+group	POS	O
+of	POS	O
+patients	POS	O
+was	POS	O
+administered	POS	O
+isotonic	POS	O
+sodium	POS	O
+chloride	POS	O
+;	POS	O
+the	POS	O
+second	POS	O
+group	POS	O
+was	POS	O
+administered	POS	O
+a	POS	O
+solution	POS	O
+that	POS	O
+of	POS	O
+5	POS	O
+%	POS	O
+dextrose	POS	O
+and	POS	O
+sodium	POS	O
+bicarbonate	POS	O
+,	POS	O
+while	POS	O
+the	POS	O
+third	POS	O
+group	POS	O
+was	POS	O
+administered	POS	O
+isotonic	POS	O
+sodium	POS	O
+chloride	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+the	POS	O
+contrast	POS	O
+injection	POS	O
+.	POS	O
+The	POS	O
+third	POS	O
+group	POS	O
+received	POS	O
+an	POS	O
+additional	POS	O
+injection	POS	O
+of	POS	O
+diltiazem	POS	O
+the	POS	O
+day	POS	O
+before	POS	O
+and	POS	O
+first	POS	O
+2	POS	O
+days	POS	O
+after	POS	O
+the	POS	O
+contrast	POS	O
+injection	POS	O
+.	POS	O
+All	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+'	POS	O
+plasma	POS	O
+blood	POS	O
+urea	POS	O
+nitrogen	POS	O
+(	POS	O
+BUN	POS	O
+)	POS	O
+and	POS	O
+creatinine	POS	O
+levels	POS	O
+were	POS	O
+measured	POS	O
+on	POS	O
+the	POS	O
+second	POS	O
+and	POS	O
+seventh	POS	O
+day	POS	O
+after	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+intravenous	POS	O
+contrast	POS	O
+material	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+basal	POS	O
+creatinine	POS	O
+levels	POS	O
+were	POS	O
+similar	POS	O
+for	POS	O
+all	POS	O
+three	POS	O
+groups	POS	O
+(	POS	O
+p	POS	O
+>	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+Among	POS	O
+a	POS	O
+total	POS	O
+of	POS	O
+60	POS	O
+patients	POS	O
+included	POS	O
+in	POS	O
+the	POS	O
+study	POS	O
+,	POS	O
+16	POS	O
+patients	POS	O
+developed	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+(	POS	O
+ARF	POS	B-NP
+)	POS	O
+on	POS	O
+the	POS	O
+second	POS	O
+day	POS	O
+after	POS	O
+contrast	POS	O
+material	POS	O
+was	POS	O
+injected	POS	O
+(	POS	O
+26	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+number	POS	O
+of	POS	O
+patients	POS	O
+who	POS	O
+developed	POS	O
+ARF	POS	B-NP
+on	POS	O
+the	POS	O
+second	POS	O
+day	POS	O
+after	POS	O
+the	POS	O
+injection	POS	O
+in	POS	O
+the	POS	O
+first	POS	O
+group	POS	O
+was	POS	O
+five	POS	O
+(	POS	O
+25	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+second	POS	O
+group	POS	O
+was	POS	O
+six	POS	O
+(	POS	O
+30	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+the	POS	O
+third	POS	O
+group	POS	O
+was	POS	O
+five	POS	O
+(	POS	O
+25	POS	O
+%	POS	O
+)	POS	O
+(	POS	O
+p	POS	O
+>	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+significant	POS	O
+difference	POS	O
+between	POS	O
+isotonic	POS	O
+sodium	POS	O
+chloride	POS	O
+,	POS	O
+sodium	POS	O
+bicarbonate	POS	O
+and	POS	O
+isotonic	POS	O
+sodium	POS	O
+chloride	POS	O
+with	POS	O
+diltiazem	POS	O
+application	POS	O
+in	POS	O
+prevention	POS	O
+of	POS	O
+CIN	POS	B-NP
+.	POS	O
+Neurocognitive	POS	O
+and	POS	O
+neuroradiologic	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+late	POS	O
+effects	POS	O
+in	POS	O
+children	POS	O
+treated	POS	O
+on	POS	O
+Pediatric	POS	O
+Oncology	POS	O
+Group	POS	O
+(	POS	O
+POG	POS	O
+)	POS	O
+P9605	POS	O
+(	POS	O
+standard	POS	O
+risk	POS	O
+)	POS	O
+and	POS	O
+P9201	POS	O
+(	POS	O
+lesser	POS	O
+risk	POS	O
+)	POS	O
+acute	POS	B-NP
+lymphoblastic	POS	I-NP
+leukemia	POS	I-NP
+protocols	POS	O
+(	POS	O
+ACCL0131	POS	O
+)	POS	O
+:	POS	O
+a	POS	O
+methotrexate	POS	O
+consequence	POS	O
+?	POS	O
+A	POS	O
+report	POS	O
+from	POS	O
+the	POS	O
+Children	POS	O
+'	POS	O
+s	POS	O
+Oncology	POS	O
+Group	POS	O
+.	POS	O
+Concerns	POS	O
+about	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+methotrexate	POS	O
+(	POS	O
+MTX	POS	O
+)	POS	O
+neurotoxicity	POS	B-NP
+in	POS	O
+the	POS	O
+1990s	POS	O
+led	POS	O
+to	POS	O
+modifications	POS	O
+in	POS	O
+intrathecal	POS	O
+(	POS	O
+IT	POS	O
+)	POS	O
+therapy	POS	O
+,	POS	O
+leucovorin	POS	O
+rescue	POS	O
+,	POS	O
+and	POS	O
+frequency	POS	O
+of	POS	O
+systemic	POS	O
+MTX	POS	O
+administration	POS	O
+in	POS	O
+children	POS	O
+with	POS	O
+acute	POS	B-NP
+lymphoblastic	POS	I-NP
+leukemia	POS	I-NP
+.	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+,	POS	O
+neurocognitive	POS	O
+outcomes	POS	O
+and	POS	O
+neuroradiologic	POS	O
+evidence	POS	O
+of	POS	O
+leukoencephalopathy	POS	B-NP
+were	POS	O
+compared	POS	O
+in	POS	O
+children	POS	O
+treated	POS	O
+with	POS	O
+intense	POS	B-NP
+central	POS	I-NP
+nervous	POS	I-NP
+system	POS	I-NP
+(	POS	O
+CNS	POS	O
+)	POS	O
+-	POS	O
+directed	POS	O
+therapy	POS	O
+(	POS	O
+P9605	POS	O
+)	POS	O
+versus	POS	O
+those	POS	O
+receiving	POS	O
+fewer	POS	O
+CNS	POS	O
+-	POS	O
+directed	POS	O
+treatment	POS	O
+days	POS	O
+during	POS	O
+intensive	POS	O
+consolidation	POS	O
+(	POS	O
+P9201	POS	O
+)	POS	O
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+66	POS	O
+children	POS	O
+from	POS	O
+16	POS	O
+Pediatric	POS	O
+Oncology	POS	O
+Group	POS	O
+institutions	POS	O
+with	POS	O
+"	POS	O
+standard	POS	O
+-	POS	O
+risk	POS	O
+"	POS	O
+acute	POS	B-NP
+lymphoblastic	POS	I-NP
+leukemia	POS	I-NP
+,	POS	O
+1	POS	O
+.	POS	O
+00	POS	O
+to	POS	O
+9	POS	O
+.	POS	O
+99	POS	O
+years	POS	O
+at	POS	O
+diagnosis	POS	O
+,	POS	O
+without	POS	O
+evidence	POS	O
+of	POS	O
+CNS	POS	B-NP
+leukemia	POS	I-NP
+at	POS	O
+diagnosis	POS	O
+were	POS	O
+enrolled	POS	O
+on	POS	O
+ACCL0131	POS	O
+:	POS	O
+28	POS	O
+from	POS	O
+P9201	POS	O
+and	POS	O
+38	POS	O
+from	POS	O
+P9605	POS	O
+.	POS	O
+Magnetic	POS	O
+resonance	POS	O
+imaging	POS	O
+scans	POS	O
+and	POS	O
+standard	POS	O
+neuropsychological	POS	O
+tests	POS	O
+were	POS	O
+performed	POS	O
+>	POS	O
+2	POS	O
+.	POS	O
+6	POS	O
+years	POS	O
+after	POS	O
+the	POS	O
+end	POS	O
+of	POS	O
+treatment	POS	O
+.	POS	O
+Significantly	POS	O
+more	POS	O
+P9605	POS	O
+patients	POS	O
+developed	POS	O
+leukoencephalopathy	POS	B-NP
+compared	POS	O
+with	POS	O
+P9201	POS	O
+patients	POS	O
+(	POS	O
+68	POS	O
+%	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+49	POS	O
+%	POS	O
+-	POS	O
+83	POS	O
+%	POS	O
+vs	POS	O
+.	POS	O
+22	POS	O
+%	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+5	POS	O
+%	POS	O
+-	POS	O
+44	POS	O
+%	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+identified	POS	O
+as	POS	O
+late	POS	O
+as	POS	O
+7	POS	O
+.	POS	O
+7	POS	O
+years	POS	O
+after	POS	O
+the	POS	O
+end	POS	O
+of	POS	O
+treatment	POS	O
+.	POS	O
+Overall	POS	O
+,	POS	O
+40	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+scored	POS	O
+<	POS	O
+85	POS	O
+on	POS	O
+either	POS	O
+Verbal	POS	O
+or	POS	O
+Performance	POS	O
+IQ	POS	O
+.	POS	O
+Children	POS	O
+on	POS	O
+both	POS	O
+studies	POS	O
+had	POS	O
+significant	POS	O
+attention	POS	B-NP
+problems	POS	I-NP
+,	POS	O
+but	POS	O
+P9605	POS	O
+children	POS	O
+scored	POS	O
+below	POS	O
+average	POS	O
+on	POS	O
+more	POS	O
+neurocognitive	POS	O
+measures	POS	O
+than	POS	O
+those	POS	O
+treated	POS	O
+on	POS	O
+P9201	POS	O
+(	POS	O
+82	POS	O
+%	POS	O
+,	POS	O
+14	POS	O
+/	POS	O
+17	POS	O
+measures	POS	O
+vs	POS	O
+.	POS	O
+24	POS	O
+%	POS	O
+,	POS	O
+4	POS	O
+/	POS	O
+17	POS	O
+measures	POS	O
+)	POS	O
+.	POS	O
+This	POS	O
+supports	POS	O
+ongoing	POS	O
+concerns	POS	O
+about	POS	O
+intensive	POS	O
+MTX	POS	O
+exposure	POS	O
+as	POS	O
+a	POS	O
+major	POS	O
+contributor	POS	O
+to	POS	O
+CNS	POS	O
+late	POS	O
+effects	POS	O
+.	POS	O
+Tranexamic	POS	O
+acid	POS	O
+overdosage	POS	O
+-	POS	O
+induced	POS	O
+generalized	POS	O
+seizure	POS	B-NP
+in	POS	O
+renal	POS	B-NP
+failure	POS	I-NP
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+45	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+lady	POS	O
+with	POS	O
+chronic	POS	B-NP
+kidney	POS	I-NP
+disease	POS	I-NP
+stage	POS	O
+4	POS	O
+due	POS	O
+to	POS	O
+chronic	POS	O
+tubulointerstial	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+She	POS	O
+was	POS	O
+admitted	POS	O
+to	POS	O
+our	POS	O
+center	POS	O
+for	POS	O
+severe	POS	O
+anemia	POS	B-NP
+due	POS	O
+to	POS	O
+menorrhagia	POS	B-NP
+and	POS	O
+deterioration	POS	B-NP
+of	POS	I-NP
+renal	POS	I-NP
+function	POS	I-NP
+.	POS	O
+She	POS	O
+was	POS	O
+infused	POS	O
+three	POS	O
+units	POS	O
+of	POS	O
+packed	POS	O
+cells	POS	O
+during	POS	O
+a	POS	O
+session	POS	O
+of	POS	O
+hemodialysis	POS	O
+.	POS	O
+Tranexamic	POS	O
+acid	POS	O
+(	POS	O
+TNA	POS	O
+)	POS	O
+1	POS	O
+g	POS	O
+8	POS	O
+-	POS	O
+hourly	POS	O
+was	POS	O
+administered	POS	O
+to	POS	O
+her	POS	O
+to	POS	O
+control	POS	O
+bleeding	POS	O
+per	POS	O
+vaginum	POS	O
+.	POS	O
+Two	POS	O
+hours	POS	O
+after	POS	O
+the	POS	O
+sixth	POS	O
+dose	POS	O
+of	POS	O
+TNA	POS	O
+,	POS	O
+she	POS	O
+had	POS	O
+an	POS	O
+episode	POS	O
+of	POS	O
+generalized	POS	O
+tonic	POS	O
+clonic	POS	B-NP
+convulsions	POS	B-NP
+.	POS	O
+TNA	POS	O
+was	POS	O
+discontinued	POS	O
+.	POS	O
+Investigations	POS	O
+of	POS	O
+the	POS	O
+patient	POS	O
+revealed	POS	O
+no	POS	O
+biochemical	POS	O
+or	POS	O
+structural	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+abnormalities	POS	O
+that	POS	O
+could	POS	O
+have	POS	O
+provoked	POS	O
+the	POS	O
+convulsions	POS	B-NP
+.	POS	O
+She	POS	O
+did	POS	O
+not	POS	O
+require	POS	O
+any	POS	O
+further	POS	O
+dialytic	POS	O
+support	POS	O
+.	POS	O
+She	POS	O
+had	POS	O
+no	POS	O
+further	POS	O
+episodes	POS	O
+of	POS	O
+convulsion	POS	B-NP
+till	POS	O
+dis	POS	O
+-	POS	O
+charge	POS	O
+and	POS	O
+during	POS	O
+the	POS	O
+two	POS	O
+months	POS	O
+of	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+the	POS	O
+precipitating	POS	O
+cause	POS	O
+of	POS	O
+convulsions	POS	B-NP
+was	POS	O
+believed	POS	O
+to	POS	O
+be	POS	O
+an	POS	O
+overdose	POS	B-NP
+of	POS	O
+TNA	POS	O
+.	POS	O
+Pre	POS	O
+-	POS	O
+treatment	POS	O
+of	POS	O
+bupivacaine	POS	O
+-	POS	O
+induced	POS	O
+cardiovascular	POS	B-NP
+depression	POS	I-NP
+using	POS	O
+different	POS	O
+lipid	POS	O
+formulations	POS	O
+of	POS	O
+propofol	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Pre	POS	O
+-	POS	O
+treatment	POS	O
+with	POS	O
+lipid	POS	O
+emulsions	POS	O
+has	POS	O
+been	POS	O
+shown	POS	O
+to	POS	O
+increase	POS	O
+lethal	POS	O
+doses	POS	O
+of	POS	O
+bupivacaine	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+lipid	POS	O
+content	POS	O
+of	POS	O
+propofol	POS	O
+may	POS	O
+alleviate	POS	O
+bupivacaine	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+is	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+propofol	POS	O
+in	POS	O
+intralipid	POS	O
+or	POS	O
+medialipid	POS	O
+emulsions	POS	O
+on	POS	O
+bupivacaine	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Rats	POS	O
+were	POS	O
+anaesthetised	POS	O
+with	POS	O
+ketamine	POS	O
+and	POS	O
+were	POS	O
+given	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+propofol	POS	O
+in	POS	O
+intralipid	POS	O
+(	POS	O
+Group	POS	O
+P	POS	O
+)	POS	O
+,	POS	O
+propofol	POS	O
+in	POS	O
+medialipid	POS	O
+(	POS	O
+Group	POS	O
+L	POS	O
+)	POS	O
+,	POS	O
+or	POS	O
+saline	POS	O
+(	POS	O
+Group	POS	O
+C	POS	O
+)	POS	O
+over	POS	O
+20	POS	O
+min	POS	O
+.	POS	O
+Thereafter	POS	O
+,	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+bupivacaine	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+was	POS	O
+infused	POS	O
+.	POS	O
+We	POS	O
+recorded	POS	O
+time	POS	O
+to	POS	O
+first	POS	O
+dysrhythmia	POS	B-NP
+occurrence	POS	O
+,	POS	O
+respective	POS	O
+times	POS	O
+to	POS	O
+25	POS	O
+%	POS	O
+and	POS	O
+50	POS	O
+%	POS	O
+reduction	POS	O
+of	POS	O
+the	POS	O
+heart	POS	O
+rate	POS	O
+(	POS	O
+HR	POS	O
+)	POS	O
+and	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+,	POS	O
+and	POS	O
+time	POS	O
+to	POS	O
+asystole	POS	B-NP
+and	POS	O
+total	POS	O
+amount	POS	O
+of	POS	O
+bupivacaine	POS	O
+consumption	POS	O
+.	POS	O
+Blood	POS	O
+and	POS	O
+tissue	POS	O
+samples	POS	O
+were	POS	O
+collected	POS	O
+following	POS	O
+asystole	POS	B-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+time	POS	O
+to	POS	O
+first	POS	O
+dysrhythmia	POS	B-NP
+occurrence	POS	O
+,	POS	O
+time	POS	O
+to	POS	O
+25	POS	O
+%	POS	O
+and	POS	O
+50	POS	O
+%	POS	O
+reductions	POS	O
+in	POS	O
+HR	POS	O
+,	POS	O
+and	POS	O
+time	POS	O
+to	POS	O
+asystole	POS	B-NP
+were	POS	O
+longer	POS	O
+in	POS	O
+Group	POS	O
+P	POS	O
+than	POS	O
+the	POS	O
+other	POS	O
+groups	POS	O
+.	POS	O
+The	POS	O
+cumulative	POS	O
+bupivacaine	POS	O
+dose	POS	O
+given	POS	O
+at	POS	O
+those	POS	O
+time	POS	O
+points	POS	O
+was	POS	O
+higher	POS	O
+in	POS	O
+Group	POS	O
+P	POS	O
+.	POS	O
+Plasma	POS	O
+bupivacaine	POS	O
+levels	POS	O
+were	POS	O
+significantly	POS	O
+lower	POS	O
+in	POS	O
+Group	POS	O
+P	POS	O
+than	POS	O
+in	POS	O
+Group	POS	O
+C	POS	O
+.	POS	O
+Bupivacaine	POS	O
+levels	POS	O
+in	POS	O
+the	POS	O
+brain	POS	O
+and	POS	O
+heart	POS	O
+were	POS	O
+significantly	POS	O
+lower	POS	O
+in	POS	O
+Group	POS	O
+P	POS	O
+and	POS	O
+Group	POS	O
+L	POS	O
+than	POS	O
+in	POS	O
+Group	POS	O
+C	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+pre	POS	O
+-	POS	O
+treatment	POS	O
+with	POS	O
+propofol	POS	O
+in	POS	O
+intralipid	POS	O
+,	POS	O
+compared	POS	O
+with	POS	O
+propofol	POS	O
+in	POS	O
+medialipid	POS	O
+or	POS	O
+saline	POS	O
+,	POS	O
+delayed	POS	O
+the	POS	O
+onset	POS	O
+of	POS	O
+bupivacaine	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxic	POS	B-NP
+effects	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+reduced	POS	O
+plasma	POS	O
+bupivacaine	POS	O
+levels	POS	O
+.	POS	O
+Further	POS	O
+studies	POS	O
+are	POS	O
+needed	POS	O
+to	POS	O
+explore	POS	O
+tissue	POS	O
+bupivacaine	POS	O
+levels	POS	O
+of	POS	O
+propofol	POS	O
+in	POS	O
+medialipid	POS	O
+and	POS	O
+adapt	POS	O
+these	POS	O
+results	POS	O
+to	POS	O
+clinical	POS	O
+practice	POS	O
+.	POS	O
+Drug	POS	O
+-	POS	O
+Induced	POS	O
+Acute	POS	O
+Liver	POS	B-NP
+Injury	POS	I-NP
+Within	POS	O
+12	POS	O
+Hours	POS	O
+After	POS	O
+Fluvastatin	POS	O
+Therapy	POS	O
+.	POS	O
+Although	POS	O
+statins	POS	O
+are	POS	O
+generally	POS	O
+well	POS	O
+-	POS	O
+tolerated	POS	O
+drugs	POS	O
+,	POS	O
+recent	POS	O
+cases	POS	O
+of	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+liver	POS	B-NP
+injury	POS	I-NP
+associated	POS	O
+with	POS	O
+their	POS	O
+use	POS	O
+have	POS	O
+been	POS	O
+reported	POS	O
+.	POS	O
+A	POS	O
+52	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+Chinese	POS	O
+man	POS	O
+reported	POS	O
+with	POS	O
+liver	POS	B-NP
+damage	POS	I-NP
+,	POS	O
+which	POS	O
+appeared	POS	O
+12	POS	O
+hours	POS	O
+after	POS	O
+beginning	POS	O
+treatment	POS	O
+with	POS	O
+fluvastatin	POS	O
+.	POS	O
+Patient	POS	O
+presented	POS	O
+with	POS	O
+complaints	POS	O
+of	POS	O
+increasing	POS	O
+nausea	POS	B-NP
+,	POS	O
+anorexia	POS	B-NP
+,	POS	O
+and	POS	O
+upper	POS	B-NP
+abdominal	POS	I-NP
+pain	POS	I-NP
+.	POS	O
+His	POS	O
+laboratory	POS	O
+values	POS	O
+showed	POS	O
+elevated	POS	O
+creatine	POS	O
+kinase	POS	O
+and	POS	O
+transaminases	POS	O
+.	POS	O
+Testing	POS	O
+for	POS	O
+autoantibodies	POS	O
+was	POS	O
+also	POS	O
+negative	POS	O
+.	POS	O
+The	POS	O
+liver	POS	O
+biochemistries	POS	O
+eventually	POS	O
+normalized	POS	O
+within	POS	O
+3	POS	O
+weeks	POS	O
+of	POS	O
+stopping	POS	O
+the	POS	O
+fluvastatin	POS	O
+.	POS	O
+Therefore	POS	O
+,	POS	O
+when	POS	O
+prescribing	POS	O
+statins	POS	O
+,	POS	O
+the	POS	O
+possibility	POS	O
+of	POS	O
+hepatic	POS	B-NP
+damage	POS	I-NP
+should	POS	O
+be	POS	O
+taken	POS	O
+into	POS	O
+account	POS	O
+.	POS	O
+Fluconazole	POS	O
+associated	POS	O
+agranulocytosis	POS	B-NP
+and	POS	O
+thrombocytopenia	POS	B-NP
+.	POS	O
+CASE	POS	O
+:	POS	O
+We	POS	O
+describe	POS	O
+a	POS	O
+second	POS	O
+case	POS	O
+of	POS	O
+fluconazole	POS	O
+associated	POS	O
+agranulocytosis	POS	B-NP
+with	POS	O
+thrombocytopenia	POS	B-NP
+and	POS	O
+recovery	POS	O
+upon	POS	O
+discontinuation	POS	O
+of	POS	O
+therapy	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+began	POS	O
+to	POS	O
+have	POS	O
+changes	POS	O
+in	POS	O
+white	POS	O
+blood	POS	O
+cells	POS	O
+and	POS	O
+platelets	POS	O
+within	POS	O
+48	POS	O
+h	POS	O
+of	POS	O
+administration	POS	O
+of	POS	O
+fluconazole	POS	O
+and	POS	O
+began	POS	O
+to	POS	O
+recover	POS	O
+with	POS	O
+48	POS	O
+h	POS	O
+of	POS	O
+discontinuation	POS	O
+.	POS	O
+This	POS	O
+case	POS	O
+highlights	POS	O
+that	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+blood	POS	B-NP
+dyscrasias	POS	I-NP
+can	POS	O
+occur	POS	O
+unexpectedly	POS	O
+as	POS	O
+a	POS	O
+result	POS	O
+of	POS	O
+treatment	POS	O
+with	POS	O
+a	POS	O
+commonly	POS	O
+used	POS	O
+drug	POS	O
+thought	POS	O
+to	POS	O
+be	POS	O
+"	POS	O
+safe	POS	O
+"	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+According	POS	O
+to	POS	O
+Naranjo	POS	O
+'	POS	O
+s	POS	O
+algorithm	POS	O
+the	POS	O
+likelihood	POS	O
+that	POS	O
+our	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+agranulocytosis	POS	B-NP
+and	POS	O
+thrombocytopenia	POS	B-NP
+occurred	POS	O
+as	POS	O
+a	POS	O
+result	POS	O
+of	POS	O
+therapy	POS	O
+with	POS	O
+fluconazole	POS	O
+is	POS	O
+probable	POS	O
+,	POS	O
+with	POS	O
+a	POS	O
+total	POS	O
+of	POS	O
+six	POS	O
+points	POS	O
+.	POS	O
+We	POS	O
+feel	POS	O
+that	POS	O
+the	POS	O
+weight	POS	O
+of	POS	O
+the	POS	O
+overall	POS	O
+evidence	POS	O
+of	POS	O
+this	POS	O
+evidence	POS	O
+is	POS	O
+strong	POS	O
+.	POS	O
+In	POS	O
+particular	POS	O
+the	POS	O
+temporal	POS	O
+relationship	POS	O
+of	POS	O
+bone	POS	O
+marrow	POS	O
+suppression	POS	O
+to	POS	O
+the	POS	O
+initiation	POS	O
+of	POS	O
+fluconazole	POS	O
+and	POS	O
+the	POS	O
+abatement	POS	O
+of	POS	O
+symptoms	POS	O
+that	POS	O
+rapidly	POS	O
+reversed	POS	O
+immediately	POS	O
+following	POS	O
+discontinuation	POS	O
+.	POS	O
+Two	POS	O
+-	POS	O
+dimensional	POS	O
+speckle	POS	O
+tracking	POS	O
+echocardiography	POS	O
+combined	POS	O
+with	POS	O
+high	POS	O
+-	POS	O
+sensitive	POS	O
+cardiac	POS	O
+troponin	POS	O
+T	POS	O
+in	POS	O
+early	POS	O
+detection	POS	O
+and	POS	O
+prediction	POS	O
+of	POS	O
+cardiotoxicity	POS	B-NP
+during	POS	O
+epirubicine	POS	O
+-	POS	O
+based	POS	O
+chemotherapy	POS	O
+.	POS	O
+AIMS	POS	O
+:	POS	O
+To	POS	O
+investigate	POS	O
+whether	POS	O
+alterations	POS	O
+of	POS	O
+myocardial	POS	O
+strain	POS	O
+and	POS	O
+high	POS	O
+-	POS	O
+sensitive	POS	O
+cardiac	POS	O
+troponin	POS	O
+T	POS	O
+(	POS	O
+cTnT	POS	O
+)	POS	O
+could	POS	O
+predict	POS	O
+future	POS	O
+cardiac	POS	B-NP
+dysfunction	POS	I-NP
+in	POS	O
+patients	POS	O
+after	POS	O
+epirubicin	POS	O
+exposure	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Seventy	POS	O
+-	POS	O
+five	POS	O
+patients	POS	O
+with	POS	O
+non	POS	B-NP
+-	POS	I-NP
+Hodgkin	POS	I-NP
+lymphoma	POS	I-NP
+treated	POS	O
+with	POS	O
+epirubicin	POS	O
+were	POS	O
+studied	POS	O
+.	POS	O
+Blood	POS	O
+collection	POS	O
+and	POS	O
+echocardiography	POS	O
+were	POS	O
+performed	POS	O
+at	POS	O
+baseline	POS	O
+,	POS	O
+1	POS	O
+day	POS	O
+after	POS	O
+the	POS	O
+third	POS	O
+cycle	POS	O
+,	POS	O
+and	POS	O
+1	POS	O
+day	POS	O
+after	POS	O
+completion	POS	O
+of	POS	O
+chemotherapy	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+studied	POS	O
+using	POS	O
+echocardiography	POS	O
+during	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+.	POS	O
+Global	POS	O
+longitudinal	POS	O
+(	POS	O
+GLS	POS	O
+)	POS	O
+,	POS	O
+circumferential	POS	O
+(	POS	O
+GCS	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+radial	POS	O
+strain	POS	O
+(	POS	O
+GRS	POS	O
+)	POS	O
+were	POS	O
+calculated	POS	O
+using	POS	O
+speckle	POS	O
+tracking	POS	O
+echocardiography	POS	O
+.	POS	O
+Left	POS	O
+ventricular	POS	O
+ejection	POS	O
+fraction	POS	O
+was	POS	O
+analysed	POS	O
+by	POS	O
+real	POS	O
+-	POS	O
+time	POS	O
+3D	POS	O
+echocardiography	POS	O
+.	POS	O
+Cardiotoxicity	POS	B-NP
+was	POS	O
+defined	POS	O
+as	POS	O
+a	POS	O
+reduction	POS	O
+of	POS	O
+the	POS	O
+LVEF	POS	O
+of	POS	O
+>	POS	O
+5	POS	O
+%	POS	O
+to	POS	O
+<	POS	O
+55	POS	O
+%	POS	O
+with	POS	O
+symptoms	POS	O
+of	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+or	POS	O
+an	POS	O
+asymptomatic	POS	O
+reduction	POS	O
+of	POS	O
+the	POS	O
+LVEF	POS	O
+of	POS	O
+>	POS	O
+10	POS	O
+%	POS	O
+to	POS	O
+<	POS	O
+55	POS	O
+%	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Fourteen	POS	O
+patients	POS	O
+(	POS	O
+18	POS	O
+.	POS	O
+67	POS	O
+%	POS	O
+)	POS	O
+developed	POS	O
+cardiotoxicity	POS	B-NP
+after	POS	O
+treatment	POS	O
+.	POS	O
+GLS	POS	O
+(	POS	O
+-	POS	O
+18	POS	O
+.	POS	O
+48	POS	O
++	POS	O
+1	POS	O
+.	POS	O
+72	POS	O
+%	POS	O
+vs	POS	O
+.	POS	O
+-	POS	O
+15	POS	O
+.	POS	O
+96	POS	O
++	POS	O
+1	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+GCS	POS	B-NP
+(	POS	O
+-	POS	O
+20	POS	O
+.	POS	O
+93	POS	O
++	POS	O
+2	POS	O
+.	POS	O
+86	POS	O
+%	POS	O
+vs	POS	O
+.	POS	O
+-	POS	O
+19	POS	O
+.	POS	O
+20	POS	O
++	POS	O
+3	POS	O
+.	POS	O
+21	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+GRS	POS	O
+(	POS	O
+39	POS	O
+.	POS	O
+23	POS	O
++	POS	O
+6	POS	O
+.	POS	O
+44	POS	O
+%	POS	O
+vs	POS	O
+.	POS	O
+34	POS	O
+.	POS	O
+98	POS	O
++	POS	O
+6	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+)	POS	O
+were	POS	O
+markedly	POS	O
+reduced	POS	O
+and	POS	O
+cTnT	POS	O
+was	POS	O
+elevated	POS	O
+from	POS	O
+0	POS	O
+.	POS	O
+0010	POS	O
++	POS	O
+0	POS	O
+.	POS	O
+0020	POS	O
+to	POS	O
+0	POS	O
+.	POS	O
+0073	POS	O
++	POS	O
+0	POS	O
+.	POS	O
+0038	POS	O
+ng	POS	O
+/	POS	O
+mL	POS	O
+(	POS	O
+P	POS	O
+all	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+at	POS	O
+the	POS	O
+completion	POS	O
+of	POS	O
+chemotherapy	POS	O
+compared	POS	O
+with	POS	O
+baseline	POS	O
+values	POS	O
+.	POS	O
+A	POS	O
+>	POS	O
+15	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+decrease	POS	O
+in	POS	O
+GLS	POS	O
+[	POS	O
+sensitivity	POS	O
+,	POS	O
+86	POS	O
+%	POS	O
+;	POS	O
+specificity	POS	O
+,	POS	O
+75	POS	O
+%	POS	O
+;	POS	O
+area	POS	O
+under	POS	O
+the	POS	O
+curve	POS	O
+(	POS	O
+AUC	POS	O
+)	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+815	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+]	POS	O
+and	POS	O
+a	POS	O
+>	POS	O
+0	POS	O
+.	POS	O
+004	POS	O
+ng	POS	O
+/	POS	O
+mL	POS	O
+elevation	POS	O
+in	POS	O
+cTnT	POS	O
+(	POS	O
+sensitivity	POS	O
+,	POS	O
+79	POS	O
+%	POS	O
+;	POS	O
+specificity	POS	O
+,	POS	O
+64	POS	O
+%	POS	O
+;	POS	O
+AUC	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+757	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+005	POS	O
+)	POS	O
+from	POS	O
+baseline	POS	O
+to	POS	O
+the	POS	O
+third	POS	O
+cycle	POS	O
+of	POS	O
+chemotherapy	POS	O
+predicted	POS	O
+later	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+The	POS	O
+decrease	POS	O
+in	POS	O
+GLS	POS	O
+remained	POS	O
+the	POS	O
+only	POS	O
+independent	POS	O
+predictor	POS	O
+of	POS	O
+cardiotoxicity	POS	B-NP
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+000	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+GLS	POS	O
+combined	POS	O
+with	POS	O
+cTnT	POS	O
+may	POS	O
+provide	POS	O
+a	POS	O
+reliable	POS	O
+and	POS	O
+non	POS	O
+-	POS	O
+invasive	POS	O
+method	POS	O
+to	POS	O
+predict	POS	O
+cardiac	POS	B-NP
+dysfunction	POS	I-NP
+in	POS	O
+patients	POS	O
+receiving	POS	O
+anthracycline	POS	O
+-	POS	O
+based	POS	O
+chemotherapy	POS	O
+.	POS	O
+Prevention	POS	O
+of	POS	O
+etomidate	POS	O
+-	POS	O
+induced	POS	O
+myoclonus	POS	B-NP
+:	POS	O
+which	POS	O
+is	POS	O
+superior	POS	O
+:	POS	O
+Fentanyl	POS	O
+,	POS	O
+midazolam	POS	O
+,	POS	O
+or	POS	O
+a	POS	O
+combination	POS	O
+?	POS	O
+A	POS	O
+Retrospective	POS	O
+comparative	POS	O
+study	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+In	POS	O
+this	POS	O
+retrospective	POS	O
+comparative	POS	O
+study	POS	O
+,	POS	O
+we	POS	O
+aimed	POS	O
+to	POS	O
+compare	POS	O
+the	POS	O
+effectiveness	POS	O
+of	POS	O
+fentanyl	POS	O
+,	POS	O
+midazolam	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+combination	POS	O
+of	POS	O
+fentanyl	POS	O
+and	POS	O
+midazolam	POS	O
+to	POS	O
+prevent	POS	O
+etomidate	POS	O
+-	POS	O
+induced	POS	O
+myoclonus	POS	B-NP
+.	POS	O
+MATERIAL	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+This	POS	O
+study	POS	O
+was	POS	O
+performed	POS	O
+based	POS	O
+on	POS	O
+anesthesia	POS	O
+records	POS	O
+.	POS	O
+Depending	POS	O
+on	POS	O
+the	POS	O
+drugs	POS	O
+that	POS	O
+would	POS	O
+be	POS	O
+given	POS	O
+before	POS	O
+the	POS	O
+induction	POS	O
+of	POS	O
+anesthesia	POS	O
+with	POS	O
+etomidate	POS	O
+,	POS	O
+the	POS	O
+patients	POS	O
+were	POS	O
+separated	POS	O
+into	POS	O
+4	POS	O
+groups	POS	O
+:	POS	O
+no	POS	O
+pretreatment	POS	O
+(	POS	O
+Group	POS	O
+NP	POS	O
+)	POS	O
+,	POS	O
+fentanyl	POS	O
+1	POS	O
+ug	POS	O
+.	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+(	POS	O
+Group	POS	O
+F	POS	O
+)	POS	O
+,	POS	O
+midazolam	POS	O
+0	POS	O
+.	POS	O
+03	POS	O
+mg	POS	O
+.	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+(	POS	O
+Group	POS	O
+M	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+midazolam	POS	O
+0	POS	O
+.	POS	O
+015	POS	O
+mg	POS	O
+.	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
++	POS	O
+fentanyl	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+ug	POS	O
+.	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+(	POS	O
+Group	POS	O
+FM	POS	O
+)	POS	O
+.	POS	O
+Patients	POS	O
+who	POS	O
+received	POS	O
+the	POS	O
+same	POS	O
+anesthetic	POS	O
+procedure	POS	O
+were	POS	O
+selected	POS	O
+:	POS	O
+2	POS	O
+minutes	POS	O
+after	POS	O
+intravenous	POS	O
+injections	POS	O
+of	POS	O
+the	POS	O
+pretreatment	POS	O
+drugs	POS	O
+,	POS	O
+anesthesia	POS	O
+is	POS	O
+induced	POS	O
+with	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+mg	POS	O
+.	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+etomidate	POS	O
+injected	POS	O
+intravenously	POS	O
+over	POS	O
+a	POS	O
+period	POS	O
+of	POS	O
+20	POS	O
+-	POS	O
+30	POS	O
+seconds	POS	O
+.	POS	O
+Myoclonic	POS	B-NP
+movements	POS	I-NP
+are	POS	O
+evaluated	POS	O
+,	POS	O
+which	POS	O
+were	POS	O
+observed	POS	O
+and	POS	O
+graded	POS	O
+according	POS	O
+to	POS	O
+clinical	POS	O
+severity	POS	O
+during	POS	O
+the	POS	O
+2	POS	O
+minutes	POS	O
+after	POS	O
+etomidate	POS	O
+injection	POS	O
+.	POS	O
+The	POS	O
+severity	POS	O
+of	POS	O
+pain	POS	B-NP
+due	POS	O
+to	POS	O
+etomidate	POS	O
+injection	POS	O
+,	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+,	POS	O
+heart	POS	O
+rate	POS	O
+,	POS	O
+and	POS	O
+adverse	POS	O
+effects	POS	O
+were	POS	O
+also	POS	O
+evaluated	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Study	POS	O
+results	POS	O
+showed	POS	O
+that	POS	O
+myoclonus	POS	B-NP
+incidence	POS	O
+was	POS	O
+85	POS	O
+%	POS	O
+,	POS	O
+40	POS	O
+%	POS	O
+,	POS	O
+70	POS	O
+%	POS	O
+,	POS	O
+and	POS	O
+25	POS	O
+%	POS	O
+in	POS	O
+Group	POS	O
+NP	POS	O
+,	POS	O
+Group	POS	O
+F	POS	O
+,	POS	O
+Group	POS	O
+M	POS	O
+,	POS	O
+and	POS	O
+Group	POS	O
+FM	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+and	POS	O
+were	POS	O
+significantly	POS	O
+lower	POS	O
+in	POS	O
+Group	POS	O
+F	POS	O
+and	POS	O
+Group	POS	O
+FM	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+pretreatment	POS	O
+with	POS	O
+fentanyl	POS	O
+or	POS	O
+combination	POS	O
+of	POS	O
+fentanyl	POS	O
+and	POS	O
+midazolam	POS	O
+was	POS	O
+effective	POS	O
+in	POS	O
+preventing	POS	O
+etomidate	POS	O
+-	POS	O
+induced	POS	O
+myoclonus	POS	B-NP
+.	POS	O
+Convulsant	POS	O
+effect	POS	O
+of	POS	O
+lindane	POS	O
+and	POS	O
+regional	POS	O
+brain	POS	O
+concentration	POS	O
+of	POS	O
+GABA	POS	O
+and	POS	O
+dopamine	POS	O
+.	POS	O
+Lindane	POS	O
+(	POS	O
+gamma	POS	O
+-	POS	O
+hexachlorocyclohexane	POS	O
+)	POS	O
+is	POS	O
+an	POS	O
+organochlorine	POS	O
+insecticide	POS	O
+with	POS	O
+known	POS	O
+neurotoxic	POS	B-NP
+effects	POS	O
+.	POS	O
+Its	POS	O
+mechanism	POS	O
+of	POS	O
+action	POS	O
+is	POS	O
+not	POS	O
+well	POS	O
+understood	POS	O
+although	POS	O
+it	POS	O
+has	POS	O
+been	POS	O
+proposed	POS	O
+that	POS	O
+lindane	POS	O
+acts	POS	O
+as	POS	O
+a	POS	O
+non	POS	O
+-	POS	O
+competitive	POS	O
+antagonist	POS	O
+at	POS	O
+the	POS	O
+gamma	POS	O
+-	POS	O
+aminobutyric	POS	O
+acid	POS	O
+(	POS	O
+GABA	POS	O
+)	POS	O
+-	POS	O
+A	POS	O
+receptor	POS	O
+.	POS	O
+We	POS	O
+studied	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+lindane	POS	O
+(	POS	O
+150	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+on	POS	O
+the	POS	O
+GABAergic	POS	O
+and	POS	O
+dopaminergic	POS	O
+systems	POS	O
+by	POS	O
+measuring	POS	O
+the	POS	O
+concentration	POS	O
+of	POS	O
+GABA	POS	O
+,	POS	O
+dopamine	POS	O
+and	POS	O
+its	POS	O
+metabolites	POS	O
+in	POS	O
+7	POS	O
+brain	POS	O
+areas	POS	O
+at	POS	O
+the	POS	O
+onset	POS	O
+of	POS	O
+seizures	POS	B-NP
+.	POS	O
+All	POS	O
+animals	POS	O
+suffered	POS	O
+tonic	POS	O
+convulsions	POS	B-NP
+at	POS	O
+18	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+4	POS	O
+min	POS	O
+after	POS	O
+lindane	POS	O
+administration	POS	O
+.	POS	O
+The	POS	O
+concentration	POS	O
+of	POS	O
+GABA	POS	O
+was	POS	O
+only	POS	O
+slightly	POS	O
+but	POS	O
+significantly	POS	O
+decreased	POS	O
+in	POS	O
+the	POS	O
+colliculi	POS	O
+without	POS	O
+modifications	POS	O
+in	POS	O
+the	POS	O
+other	POS	O
+areas	POS	O
+.	POS	O
+The	POS	O
+concentration	POS	O
+of	POS	O
+dopamine	POS	O
+was	POS	O
+increased	POS	O
+in	POS	O
+the	POS	O
+mesencephalon	POS	O
+and	POS	O
+that	POS	O
+of	POS	O
+its	POS	O
+metabolite	POS	O
+DOPAC	POS	O
+was	POS	O
+also	POS	O
+increased	POS	O
+in	POS	O
+the	POS	O
+mesencephalon	POS	O
+and	POS	O
+the	POS	O
+striatum	POS	O
+.	POS	O
+Cholestatic	POS	O
+presentation	POS	O
+of	POS	O
+yellow	POS	O
+phosphorus	POS	O
+poisoning	POS	O
+.	POS	O
+Yellow	POS	O
+phosphorus	POS	O
+,	POS	O
+a	POS	O
+component	POS	O
+of	POS	O
+certain	POS	O
+pesticide	POS	O
+pastes	POS	O
+and	POS	O
+fireworks	POS	O
+,	POS	O
+is	POS	O
+well	POS	O
+known	POS	O
+to	POS	O
+cause	POS	O
+hepatotoxicity	POS	B-NP
+.	POS	O
+Poisoning	POS	O
+with	POS	O
+yellow	POS	O
+phosphorus	POS	O
+classically	POS	O
+manifests	POS	O
+with	POS	O
+acute	POS	B-NP
+hepatitis	POS	I-NP
+leading	POS	O
+to	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+which	POS	O
+may	POS	O
+need	POS	O
+liver	POS	O
+transplantation	POS	O
+.	POS	O
+We	POS	O
+present	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+yellow	POS	O
+phosphorus	POS	O
+poisoning	POS	B-NP
+in	POS	O
+which	POS	O
+a	POS	O
+patient	POS	O
+presented	POS	O
+with	POS	O
+florid	POS	O
+clinical	POS	O
+features	POS	O
+of	POS	O
+cholestasis	POS	B-NP
+highlighting	POS	O
+the	POS	O
+fact	POS	O
+that	POS	O
+cholestasis	POS	B-NP
+can	POS	O
+rarely	POS	O
+be	POS	O
+a	POS	O
+presenting	POS	O
+feature	POS	O
+of	POS	O
+yellow	POS	O
+phosphorus	POS	O
+hepatotoxicity	POS	B-NP
+.	POS	O
+Vasovagal	POS	B-NP
+syncope	POS	I-NP
+and	POS	O
+severe	POS	O
+bradycardia	POS	B-NP
+following	POS	O
+intranasal	POS	O
+dexmedetomidine	POS	O
+for	POS	O
+pediatric	POS	O
+procedural	POS	O
+sedation	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+syncope	POS	B-NP
+and	POS	O
+bradycardia	POS	B-NP
+in	POS	O
+an	POS	O
+11	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+girl	POS	O
+following	POS	O
+administration	POS	O
+of	POS	O
+intranasal	POS	O
+dexmedetomidine	POS	O
+for	POS	O
+sedation	POS	O
+for	POS	O
+a	POS	O
+voiding	POS	O
+cystourethrogram	POS	O
+.	POS	O
+Following	POS	O
+successful	POS	O
+completion	POS	O
+of	POS	O
+VCUG	POS	O
+and	POS	O
+a	POS	O
+60	POS	O
+-	POS	O
+min	POS	O
+recovery	POS	O
+period	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+level	POS	O
+of	POS	O
+consciousness	POS	O
+and	POS	O
+vital	POS	O
+signs	POS	O
+returned	POS	O
+to	POS	O
+presedation	POS	O
+levels	POS	O
+.	POS	O
+Upon	POS	O
+leaving	POS	O
+the	POS	O
+sedation	POS	O
+area	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+collapsed	POS	O
+,	POS	O
+with	POS	O
+no	POS	O
+apparent	POS	O
+inciting	POS	O
+event	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+quickly	POS	O
+regained	POS	O
+consciousness	POS	O
+and	POS	O
+no	POS	O
+injury	POS	O
+occurred	POS	O
+.	POS	O
+The	POS	O
+primary	POS	O
+abnormality	POS	O
+found	POS	O
+was	POS	O
+persistent	POS	O
+bradycardia	POS	B-NP
+,	POS	O
+and	POS	O
+she	POS	O
+was	POS	O
+admitted	POS	O
+to	POS	O
+the	POS	O
+hospital	POS	O
+for	POS	O
+telemetric	POS	O
+observation	POS	O
+.	POS	O
+The	POS	O
+bradycardia	POS	B-NP
+lasted	POS	O
+~	POS	O
+2	POS	O
+h	POS	O
+,	POS	O
+and	POS	O
+further	POS	O
+cardiac	POS	O
+workup	POS	O
+revealed	POS	O
+no	POS	O
+underlying	POS	O
+abnormality	POS	O
+.	POS	O
+Unanticipated	POS	O
+and	POS	O
+previously	POS	O
+unreported	POS	O
+outcomes	POS	O
+may	POS	O
+be	POS	O
+witnessed	POS	O
+as	POS	O
+we	POS	O
+expand	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+certain	POS	O
+sedatives	POS	O
+to	POS	O
+alternative	POS	O
+routes	POS	O
+of	POS	O
+administration	POS	O
+.	POS	O
+Paradoxical	POS	O
+severe	POS	O
+agitation	POS	B-NP
+induced	POS	O
+by	POS	O
+add	POS	O
+-	POS	O
+on	POS	O
+high	POS	O
+-	POS	O
+doses	POS	O
+quetiapine	POS	O
+in	POS	O
+schizo	POS	B-NP
+-	POS	I-NP
+affective	POS	I-NP
+disorder	POS	I-NP
+.	POS	O
+We	POS	O
+report	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+35	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+patient	POS	O
+suffering	POS	O
+from	POS	O
+schizo	POS	B-NP
+-	POS	I-NP
+affective	POS	I-NP
+disorder	POS	I-NP
+since	POS	O
+the	POS	O
+age	POS	O
+of	POS	O
+19	POS	O
+years	POS	O
+,	POS	O
+treated	POS	O
+by	POS	O
+a	POS	O
+combination	POS	O
+of	POS	O
+first	POS	O
+-	POS	O
+generation	POS	O
+antipsychotics	POS	O
+,	POS	O
+zuclopenthixol	POS	O
+(	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+and	POS	O
+lithium	POS	O
+(	POS	O
+1200	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+(	POS	O
+serum	POS	O
+lithium	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+85	POS	O
+mEq	POS	O
+/	POS	O
+l	POS	O
+)	POS	O
+.	POS	O
+This	POS	O
+patient	POS	O
+had	POS	O
+no	POS	O
+associated	POS	O
+personality	POS	B-NP
+disorder	POS	I-NP
+(	POS	O
+particularly	POS	O
+no	POS	O
+antisocial	POS	B-NP
+disorder	POS	I-NP
+)	POS	O
+and	POS	O
+no	POS	O
+substance	POS	B-NP
+abuse	POS	I-NP
+disorder	POS	I-NP
+.	POS	O
+Within	POS	O
+the	POS	O
+48	POS	O
+h	POS	O
+following	POS	O
+the	POS	O
+gradual	POS	O
+introduction	POS	O
+of	POS	O
+quetiapine	POS	O
+(	POS	O
+up	POS	O
+to	POS	O
+600	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+presented	POS	O
+severe	POS	O
+agitation	POS	B-NP
+without	POS	O
+an	POS	O
+environmental	POS	O
+explanation	POS	O
+,	POS	O
+contrasting	POS	O
+with	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+aggressiveness	POS	B-NP
+or	POS	O
+personality	POS	B-NP
+disorder	POS	I-NP
+.	POS	O
+The	POS	O
+diagnoses	POS	O
+of	POS	O
+manic	POS	B-NP
+shift	POS	O
+and	POS	O
+akathisia	POS	B-NP
+were	POS	O
+dismissed	POS	O
+.	POS	O
+The	POS	O
+withdrawal	POS	O
+and	POS	O
+the	POS	O
+gradual	POS	O
+reintroduction	POS	O
+of	POS	O
+quetiapine	POS	O
+2	POS	O
+weeks	POS	O
+later	POS	O
+,	POS	O
+which	POS	O
+led	POS	O
+to	POS	O
+another	POS	O
+severe	POS	O
+agitation	POS	B-NP
+,	POS	O
+enabled	POS	O
+us	POS	O
+to	POS	O
+attribute	POS	O
+the	POS	O
+agitation	POS	B-NP
+specifically	POS	O
+to	POS	O
+quetiapine	POS	O
+.	POS	O
+Antioxidant	POS	O
+effects	POS	O
+of	POS	O
+bovine	POS	O
+lactoferrin	POS	O
+on	POS	O
+dexamethasone	POS	O
+-	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+in	POS	O
+rat	POS	O
+.	POS	O
+Dexamethasone	POS	O
+-	POS	O
+(	POS	O
+Dex	POS	O
+-	POS	O
+)	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+is	POS	O
+associated	POS	O
+with	POS	O
+enhanced	POS	O
+oxidative	POS	O
+stress	POS	O
+.	POS	O
+Lactoferrin	POS	O
+(	POS	O
+LF	POS	O
+)	POS	O
+is	POS	O
+an	POS	O
+iron	POS	O
+-	POS	O
+binding	POS	O
+glycoprotein	POS	O
+with	POS	O
+antihypertensive	POS	O
+properties	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+,	POS	O
+we	POS	O
+investigated	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+chronic	POS	O
+administration	POS	O
+of	POS	O
+LF	POS	O
+on	POS	O
+oxidative	POS	O
+stress	POS	O
+and	POS	O
+hypertension	POS	B-NP
+upon	POS	O
+Dex	POS	O
+administration	POS	O
+.	POS	O
+Male	POS	O
+Wistar	POS	O
+rats	POS	O
+were	POS	O
+treated	POS	O
+by	POS	O
+Dex	POS	O
+(	POS	O
+30	POS	O
+u	POS	O
+g	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+subcutaneously	POS	O
+)	POS	O
+or	POS	O
+saline	POS	O
+for	POS	O
+14	POS	O
+days	POS	O
+.	POS	O
+Oral	POS	O
+bovine	POS	O
+LF	POS	O
+(	POS	O
+30	POS	O
+,	POS	O
+100	POS	O
+,	POS	O
+300	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+was	POS	O
+given	POS	O
+from	POS	O
+day	POS	O
+8	POS	O
+to	POS	O
+14	POS	O
+in	POS	O
+a	POS	O
+reversal	POS	O
+study	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+prevention	POS	O
+study	POS	O
+,	POS	O
+rats	POS	O
+received	POS	O
+4	POS	O
+days	POS	O
+of	POS	O
+LF	POS	O
+treatment	POS	O
+followed	POS	O
+by	POS	O
+Dex	POS	O
+and	POS	O
+continued	POS	O
+during	POS	O
+the	POS	O
+test	POS	O
+period	POS	O
+.	POS	O
+Systolic	POS	O
+blood	POS	O
+pressure	POS	O
+(	POS	O
+SBP	POS	O
+)	POS	O
+was	POS	O
+measured	POS	O
+using	POS	O
+tail	POS	O
+-	POS	O
+cuff	POS	O
+method	POS	O
+.	POS	O
+Thymus	POS	O
+weight	POS	O
+was	POS	O
+used	POS	O
+as	POS	O
+a	POS	O
+marker	POS	O
+of	POS	O
+glucocorticoid	POS	O
+activity	POS	O
+.	POS	O
+Plasma	POS	O
+hydrogen	POS	O
+peroxide	POS	O
+(	POS	O
+H2O2	POS	O
+)	POS	O
+concentration	POS	O
+and	POS	O
+ferric	POS	O
+reducing	POS	O
+antioxidant	POS	O
+power	POS	O
+(	POS	O
+FRAP	POS	O
+)	POS	O
+value	POS	O
+were	POS	O
+determined	POS	O
+.	POS	O
+Dexamethasone	POS	O
+significantly	POS	O
+increased	POS	O
+SBP	POS	O
+and	POS	O
+plasma	POS	O
+H2O2	POS	O
+level	POS	O
+and	POS	O
+decreased	POS	O
+thymus	POS	O
+and	POS	O
+body	POS	O
+weights	POS	O
+.	POS	O
+LF	POS	O
+lowered	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+and	POS	O
+dose	POS	O
+dependently	POS	O
+prevented	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+Dex	POS	O
+-	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+.	POS	O
+LF	POS	O
+prevented	POS	O
+body	POS	O
+weight	POS	O
+loss	POS	O
+and	POS	O
+significantly	POS	O
+reduced	POS	O
+the	POS	O
+elevated	POS	O
+plasma	POS	O
+H2O2	POS	O
+and	POS	O
+increased	POS	O
+FRAP	POS	O
+values	POS	O
+.	POS	O
+Chronic	POS	O
+administration	POS	O
+of	POS	O
+LF	POS	O
+strongly	POS	O
+reduced	POS	O
+the	POS	O
+blood	POS	O
+pressure	POS	O
+and	POS	O
+production	POS	O
+of	POS	O
+ROS	POS	O
+and	POS	O
+improved	POS	O
+antioxidant	POS	O
+capacity	POS	O
+in	POS	O
+Dex	POS	O
+-	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+,	POS	O
+suggesting	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+inhibition	POS	O
+of	POS	O
+oxidative	POS	O
+stress	POS	O
+as	POS	O
+another	POS	O
+mechanism	POS	O
+of	POS	O
+antihypertensive	POS	O
+action	POS	O
+of	POS	O
+LF	POS	O
+.	POS	O
+The	POS	O
+association	POS	O
+between	POS	O
+tranexamic	POS	O
+acid	POS	O
+and	POS	O
+convulsive	POS	B-NP
+seizures	POS	I-NP
+after	POS	O
+cardiac	POS	O
+surgery	POS	O
+:	POS	O
+a	POS	O
+multivariate	POS	O
+analysis	POS	O
+in	POS	O
+11	POS	O
+529	POS	O
+patients	POS	O
+.	POS	O
+Because	POS	O
+of	POS	O
+a	POS	O
+lack	POS	O
+of	POS	O
+contemporary	POS	O
+data	POS	O
+regarding	POS	O
+seizures	POS	B-NP
+after	POS	O
+cardiac	POS	O
+surgery	POS	O
+,	POS	O
+we	POS	O
+undertook	POS	O
+a	POS	O
+retrospective	POS	O
+analysis	POS	O
+of	POS	O
+prospectively	POS	O
+collected	POS	O
+data	POS	O
+from	POS	O
+11	POS	O
+529	POS	O
+patients	POS	O
+in	POS	O
+whom	POS	O
+cardiopulmonary	POS	O
+bypass	POS	O
+was	POS	O
+used	POS	O
+from	POS	O
+January	POS	O
+2004	POS	O
+to	POS	O
+December	POS	O
+2010	POS	O
+.	POS	O
+A	POS	O
+convulsive	POS	O
+seizure	POS	B-NP
+was	POS	O
+defined	POS	O
+as	POS	O
+a	POS	O
+transient	POS	O
+episode	POS	O
+of	POS	O
+disturbed	POS	O
+brain	POS	O
+function	POS	O
+characterised	POS	O
+by	POS	O
+abnormal	POS	B-NP
+involuntary	POS	I-NP
+motor	POS	I-NP
+movements	POS	I-NP
+.	POS	O
+Multivariate	POS	O
+regression	POS	O
+analysis	POS	O
+was	POS	O
+performed	POS	O
+to	POS	O
+identify	POS	O
+independent	POS	O
+predictors	POS	O
+of	POS	O
+postoperative	POS	B-NP
+seizures	POS	I-NP
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+100	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+developed	POS	O
+postoperative	POS	B-NP
+convulsive	POS	I-NP
+seizures	POS	I-NP
+.	POS	O
+Generalised	POS	O
+and	POS	O
+focal	POS	O
+seizures	POS	B-NP
+were	POS	O
+identified	POS	O
+in	POS	O
+68	POS	O
+and	POS	O
+32	POS	O
+patients	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+The	POS	O
+median	POS	O
+(	POS	O
+IQR	POS	O
+[	POS	O
+range	POS	O
+]	POS	O
+)	POS	O
+time	POS	O
+after	POS	O
+surgery	POS	O
+when	POS	O
+the	POS	O
+seizure	POS	B-NP
+occurred	POS	O
+was	POS	O
+7	POS	O
+(	POS	O
+6	POS	O
+-	POS	O
+12	POS	O
+[	POS	O
+1	POS	O
+-	POS	O
+216	POS	O
+]	POS	O
+)	POS	O
+h	POS	O
+and	POS	O
+8	POS	O
+(	POS	O
+6	POS	O
+-	POS	O
+11	POS	O
+[	POS	O
+4	POS	O
+-	POS	O
+18	POS	O
+]	POS	O
+)	POS	O
+h	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Epileptiform	POS	O
+findings	POS	O
+on	POS	O
+electroencephalography	POS	O
+were	POS	O
+seen	POS	O
+in	POS	O
+19	POS	O
+patients	POS	O
+.	POS	O
+Independent	POS	O
+predictors	POS	O
+of	POS	O
+postoperative	POS	O
+seizures	POS	B-NP
+included	POS	O
+age	POS	O
+,	POS	O
+female	POS	O
+sex	POS	O
+,	POS	O
+redo	POS	O
+cardiac	POS	O
+surgery	POS	O
+,	POS	O
+calcification	POS	B-NP
+of	POS	I-NP
+ascending	POS	I-NP
+aorta	POS	I-NP
+,	POS	O
+congestive	POS	B-NP
+heart	POS	I-NP
+failure	POS	I-NP
+,	POS	O
+deep	POS	O
+hypothermic	POS	B-NP
+circulatory	POS	I-NP
+arrest	POS	I-NP
+,	POS	O
+duration	POS	O
+of	POS	O
+aortic	POS	O
+cross	POS	O
+-	POS	O
+clamp	POS	O
+and	POS	O
+tranexamic	POS	O
+acid	POS	O
+.	POS	O
+When	POS	O
+tested	POS	O
+in	POS	O
+a	POS	O
+multivariate	POS	O
+regression	POS	O
+analysis	POS	O
+,	POS	O
+tranexamic	POS	O
+acid	POS	O
+was	POS	O
+a	POS	O
+strong	POS	O
+independent	POS	O
+predictor	POS	O
+of	POS	O
+seizures	POS	B-NP
+(	POS	O
+OR	POS	O
+14	POS	O
+.	POS	O
+3	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+5	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+36	POS	O
+.	POS	O
+7	POS	O
+;	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+convulsive	POS	B-NP
+seizures	POS	I-NP
+had	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+times	POS	O
+higher	POS	O
+in	POS	O
+-	POS	O
+hospital	POS	O
+mortality	POS	O
+rates	POS	O
+and	POS	O
+twice	POS	O
+the	POS	O
+length	POS	O
+of	POS	O
+hospital	POS	O
+stay	POS	O
+compared	POS	O
+with	POS	O
+patients	POS	O
+without	POS	O
+convulsive	POS	B-NP
+seizures	POS	I-NP
+.	POS	O
+Mean	POS	O
+(	POS	O
+IQR	POS	O
+[	POS	O
+range	POS	O
+]	POS	O
+)	POS	O
+length	POS	O
+of	POS	O
+stay	POS	O
+in	POS	O
+the	POS	O
+intensive	POS	O
+care	POS	O
+unit	POS	O
+was	POS	O
+115	POS	O
+(	POS	O
+49	POS	O
+-	POS	O
+228	POS	O
+[	POS	O
+32	POS	O
+-	POS	O
+481	POS	O
+]	POS	O
+)	POS	O
+h	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+convulsive	POS	B-NP
+seizures	POS	I-NP
+compared	POS	O
+with	POS	O
+26	POS	O
+(	POS	O
+22	POS	O
+-	POS	O
+69	POS	O
+[	POS	O
+14	POS	O
+-	POS	O
+1080	POS	O
+]	POS	O
+)	POS	O
+h	POS	O
+in	POS	O
+patients	POS	O
+without	POS	O
+seizures	POS	B-NP
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+Convulsive	POS	B-NP
+seizures	POS	I-NP
+are	POS	O
+a	POS	O
+serious	POS	O
+postoperative	POS	O
+complication	POS	O
+after	POS	O
+cardiac	POS	O
+surgery	POS	O
+.	POS	O
+As	POS	O
+tranexamic	POS	O
+acid	POS	O
+is	POS	O
+the	POS	O
+only	POS	O
+modifiable	POS	O
+factor	POS	O
+,	POS	O
+its	POS	O
+administration	POS	O
+,	POS	O
+particularly	POS	O
+in	POS	O
+doses	POS	O
+exceeding	POS	O
+80	POS	O
+mg	POS	O
+.	POS	O
+kg	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+,	POS	O
+should	POS	O
+be	POS	O
+weighed	POS	O
+against	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+postoperative	POS	B-NP
+seizures	POS	I-NP
+.	POS	O
+Dysfunctional	POS	O
+overnight	POS	O
+memory	POS	O
+consolidation	POS	O
+in	POS	O
+ecstasy	POS	O
+users	POS	O
+.	POS	O
+Sleep	POS	O
+plays	POS	O
+an	POS	O
+important	POS	O
+role	POS	O
+in	POS	O
+the	POS	O
+consolidation	POS	O
+and	POS	O
+integration	POS	O
+of	POS	O
+memory	POS	O
+in	POS	O
+a	POS	O
+process	POS	O
+called	POS	O
+overnight	POS	O
+memory	POS	O
+consolidation	POS	O
+.	POS	O
+Previous	POS	O
+studies	POS	O
+indicate	POS	O
+that	POS	O
+ecstasy	POS	O
+users	POS	O
+have	POS	O
+marked	POS	O
+and	POS	O
+persistent	POS	O
+neurocognitive	POS	O
+and	POS	O
+sleep	POS	B-NP
+-	POS	I-NP
+related	POS	I-NP
+impairments	POS	I-NP
+.	POS	O
+We	POS	O
+extend	POS	O
+past	POS	O
+research	POS	O
+by	POS	O
+examining	POS	O
+overnight	POS	O
+memory	POS	O
+consolidation	POS	O
+among	POS	O
+regular	POS	O
+ecstasy	POS	O
+users	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+12	POS	O
+)	POS	O
+and	POS	O
+drug	POS	O
+naive	POS	O
+healthy	POS	O
+controls	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+26	POS	O
+)	POS	O
+.	POS	O
+Memory	POS	O
+recall	POS	O
+of	POS	O
+word	POS	O
+pairs	POS	O
+was	POS	O
+evaluated	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+a	POS	O
+period	POS	O
+of	POS	O
+sleep	POS	O
+,	POS	O
+with	POS	O
+and	POS	O
+without	POS	O
+interference	POS	O
+prior	POS	O
+to	POS	O
+testing	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+we	POS	O
+assessed	POS	O
+neurocognitive	POS	O
+performances	POS	O
+across	POS	O
+tasks	POS	O
+of	POS	O
+learning	POS	O
+,	POS	O
+memory	POS	O
+and	POS	O
+executive	POS	O
+functioning	POS	O
+.	POS	O
+Ecstasy	POS	O
+users	POS	O
+demonstrated	POS	O
+impaired	POS	O
+overnight	POS	O
+memory	POS	O
+consolidation	POS	O
+,	POS	O
+a	POS	O
+finding	POS	O
+that	POS	O
+was	POS	O
+more	POS	O
+pronounced	POS	O
+following	POS	O
+associative	POS	O
+interference	POS	O
+.	POS	O
+Additionally	POS	O
+,	POS	O
+ecstasy	POS	O
+users	POS	O
+demonstrated	POS	O
+impairments	POS	O
+on	POS	O
+tasks	POS	O
+recruiting	POS	O
+frontostriatal	POS	O
+and	POS	O
+hippocampal	POS	O
+neural	POS	O
+circuitry	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+domains	POS	O
+of	POS	O
+proactive	POS	O
+interference	POS	O
+memory	POS	O
+,	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+memory	POS	O
+,	POS	O
+encoding	POS	O
+,	POS	O
+working	POS	O
+memory	POS	O
+and	POS	O
+complex	POS	O
+planning	POS	O
+.	POS	O
+We	POS	O
+suggest	POS	O
+that	POS	O
+ecstasy	POS	O
+-	POS	O
+associated	POS	O
+dysfunction	POS	O
+in	POS	O
+fronto	POS	O
+-	POS	O
+temporal	POS	O
+circuitry	POS	O
+may	POS	O
+underlie	POS	O
+overnight	POS	O
+consolidation	POS	O
+memory	POS	B-NP
+impairments	POS	I-NP
+in	POS	O
+regular	POS	O
+ecstasy	POS	O
+users	POS	O
+.	POS	O
+Normoammonemic	POS	B-NP
+encephalopathy	POS	I-NP
+:	POS	O
+solely	POS	O
+valproate	POS	O
+induced	POS	O
+or	POS	O
+multiple	POS	O
+mechanisms	POS	O
+?	POS	O
+A	POS	O
+77	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+presented	POS	O
+with	POS	O
+subacute	POS	O
+onset	POS	O
+progressive	POS	O
+confusion	POS	B-NP
+,	POS	O
+aggression	POS	B-NP
+,	POS	O
+auditory	POS	B-NP
+hallucinations	POS	I-NP
+and	POS	O
+delusions	POS	B-NP
+.	POS	O
+In	POS	O
+the	POS	O
+preceding	POS	O
+months	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+had	POS	O
+a	POS	O
+number	POS	O
+of	POS	O
+admissions	POS	O
+with	POS	O
+transient	POS	O
+unilateral	POS	B-NP
+hemiparesis	POS	I-NP
+with	POS	O
+facial	POS	B-NP
+droop	POS	I-NP
+,	POS	O
+and	POS	O
+had	POS	O
+been	POS	O
+started	POS	O
+on	POS	O
+valproate	POS	O
+for	POS	O
+presumed	POS	O
+hemiplegic	POS	B-NP
+migraine	POS	I-NP
+.	POS	O
+Valproate	POS	B-NP
+was	POS	O
+withdrawn	POS	O
+soon	POS	O
+after	POS	O
+admission	POS	O
+and	POS	O
+her	POS	O
+cognitive	POS	O
+abilities	POS	O
+have	POS	O
+gradually	POS	O
+improved	POS	O
+over	POS	O
+3	POS	O
+months	POS	O
+of	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+.	POS	O
+Valproate	POS	O
+levels	POS	O
+taken	POS	O
+prior	POS	O
+to	POS	O
+withdrawal	POS	O
+were	POS	O
+subtherapeutic	POS	O
+and	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+normoammonaemic	POS	O
+.	POS	O
+EEG	POS	O
+undertaken	POS	O
+during	POS	O
+inpatient	POS	O
+stay	POS	O
+showed	POS	O
+changes	POS	O
+consistent	POS	O
+with	POS	O
+encephalopathy	POS	B-NP
+,	POS	O
+and	POS	O
+low	POS	O
+titre	POS	O
+N	POS	O
+-	POS	O
+methyl	POS	O
+-	POS	O
+D	POS	O
+-	POS	O
+aspartate	POS	O
+(	POS	O
+NMDA	POS	O
+)	POS	O
+receptor	POS	O
+antibodies	POS	O
+were	POS	O
+present	POS	O
+in	POS	O
+this	POS	O
+patient	POS	O
+.	POS	O
+The	POS	O
+possible	POS	O
+aetiologies	POS	O
+of	POS	O
+valproate	POS	O
+-	POS	O
+induced	POS	O
+encephalopathy	POS	B-NP
+and	POS	O
+NMDA	POS	O
+receptor	POS	O
+-	POS	O
+associated	POS	O
+encephalitis	POS	B-NP
+present	POS	O
+a	POS	O
+diagnostic	POS	O
+dilemma	POS	O
+.	POS	O
+We	POS	O
+present	POS	O
+a	POS	O
+putative	POS	O
+combinatorial	POS	O
+hypothesis	POS	O
+to	POS	O
+explain	POS	O
+this	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+symptoms	POS	O
+.	POS	O
+Cerebellar	POS	O
+and	POS	O
+oculomotor	POS	B-NP
+dysfunction	POS	I-NP
+induced	POS	O
+by	POS	O
+rapid	POS	O
+infusion	POS	O
+of	POS	O
+pethidine	POS	O
+.	POS	O
+Pethidine	POS	O
+is	POS	O
+an	POS	O
+opioid	POS	O
+that	POS	O
+gains	POS	O
+its	POS	O
+popularity	POS	O
+for	POS	O
+the	POS	O
+effective	POS	O
+pain	POS	B-NP
+control	POS	O
+through	POS	O
+acting	POS	O
+on	POS	O
+the	POS	O
+opioid	POS	O
+-	POS	O
+receptors	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+rapid	POS	O
+pain	POS	B-NP
+relief	POS	O
+sometimes	POS	O
+brings	POS	O
+about	POS	O
+unfavourable	POS	O
+side	POS	O
+effects	POS	O
+that	POS	O
+largely	POS	O
+limit	POS	O
+its	POS	O
+clinical	POS	O
+utility	POS	O
+.	POS	O
+Common	POS	O
+side	POS	O
+effects	POS	O
+include	POS	O
+nausea	POS	B-NP
+,	POS	O
+vomiting	POS	B-NP
+and	POS	O
+hypotension	POS	B-NP
+.	POS	O
+In	POS	O
+patients	POS	O
+with	POS	O
+impaired	POS	B-NP
+renal	POS	I-NP
+and	POS	I-NP
+liver	POS	I-NP
+function	POS	I-NP
+,	POS	O
+and	POS	O
+those	POS	O
+who	POS	O
+need	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+pain	POS	B-NP
+control	POS	O
+,	POS	O
+pethidine	POS	O
+may	POS	O
+cause	POS	O
+excitatory	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+(	POS	O
+CNS	POS	O
+)	POS	O
+effects	POS	O
+through	POS	O
+its	POS	O
+neurotoxic	POS	O
+metabolite	POS	O
+,	POS	O
+norpethidine	POS	O
+,	POS	O
+resulting	POS	O
+in	POS	O
+irritability	POS	B-NP
+and	POS	O
+seizure	POS	B-NP
+attack	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+contrary	POS	O
+,	POS	O
+though	POS	O
+not	POS	O
+clinically	POS	O
+apparent	POS	O
+,	POS	O
+pethidine	POS	O
+potentially	POS	O
+causes	POS	O
+inhibitory	POS	O
+impacts	POS	O
+on	POS	O
+the	POS	O
+CNS	POS	O
+and	POS	O
+impairs	POS	O
+normal	POS	O
+cerebellar	POS	O
+and	POS	O
+oculomotor	POS	O
+function	POS	O
+in	POS	O
+the	POS	O
+short	POS	O
+term	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+case	POS	O
+report	POS	O
+,	POS	O
+we	POS	O
+highlight	POS	O
+opioid	POS	O
+'	POS	O
+s	POS	O
+inhibitory	POS	O
+side	POS	O
+effects	POS	O
+on	POS	O
+the	POS	O
+cerebellar	POS	O
+structure	POS	O
+that	POS	O
+causes	POS	O
+dysmetria	POS	B-NP
+,	POS	O
+dysarthria	POS	B-NP
+,	POS	O
+reduced	POS	O
+smooth	POS	O
+pursuit	POS	O
+gain	POS	O
+and	POS	O
+decreased	POS	O
+saccadic	POS	O
+velocity	POS	O
+.	POS	O
+Baboon	POS	B-NP
+syndrome	POS	I-NP
+induced	POS	O
+by	POS	O
+ketoconazole	POS	O
+.	POS	O
+A	POS	O
+27	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+male	POS	O
+patient	POS	O
+presented	POS	O
+with	POS	O
+a	POS	O
+maculopapular	POS	B-NP
+eruption	POS	I-NP
+on	POS	O
+the	POS	O
+flexural	POS	O
+areas	POS	O
+and	POS	O
+buttocks	POS	O
+after	POS	O
+using	POS	O
+oral	POS	O
+ketoconazole	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+was	POS	O
+diagnosed	POS	O
+with	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+baboon	POS	B-NP
+syndrome	POS	I-NP
+based	POS	O
+on	POS	O
+his	POS	O
+history	POS	O
+,	POS	O
+which	POS	O
+included	POS	O
+prior	POS	O
+sensitivity	POS	O
+to	POS	O
+topical	POS	O
+ketoconazole	POS	O
+,	POS	O
+a	POS	O
+physical	POS	O
+examination	POS	O
+,	POS	O
+and	POS	O
+histopathological	POS	O
+findings	POS	O
+.	POS	O
+Baboon	POS	B-NP
+syndrome	POS	I-NP
+is	POS	O
+a	POS	O
+drug	POS	O
+-	POS	O
+or	POS	O
+contact	POS	O
+allergen	POS	O
+-	POS	O
+related	POS	O
+maculopapular	POS	B-NP
+eruption	POS	I-NP
+that	POS	O
+typically	POS	O
+involves	POS	O
+the	POS	O
+flexural	POS	O
+and	POS	O
+gluteal	POS	O
+areas	POS	O
+.	POS	O
+To	POS	O
+the	POS	O
+best	POS	O
+of	POS	O
+our	POS	O
+knowledge	POS	O
+,	POS	O
+this	POS	O
+is	POS	O
+the	POS	O
+first	POS	O
+reported	POS	O
+case	POS	O
+of	POS	O
+ketoconazole	POS	O
+-	POS	O
+induced	POS	O
+baboon	POS	B-NP
+syndrome	POS	I-NP
+in	POS	O
+the	POS	O
+English	POS	O
+literature	POS	O
+.	POS	O
+A	POS	O
+Case	POS	O
+of	POS	O
+Sudden	POS	B-NP
+Cardiac	POS	I-NP
+Death	POS	I-NP
+due	POS	O
+to	POS	O
+Pilsicainide	POS	O
+-	POS	O
+Induced	POS	O
+Torsades	POS	O
+de	POS	O
+Pointes	POS	B-NP
+.	POS	O
+An	POS	O
+84	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+male	POS	O
+received	POS	O
+oral	POS	O
+pilsicainide	POS	O
+,	POS	O
+a	POS	O
+pure	POS	O
+sodium	POS	O
+channel	POS	O
+blocker	POS	O
+with	POS	O
+slow	POS	O
+recovery	POS	O
+kinetics	POS	O
+,	POS	O
+to	POS	O
+convert	POS	O
+his	POS	O
+paroxysmal	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+to	POS	O
+a	POS	O
+sinus	POS	O
+rhythm	POS	O
+;	POS	O
+the	POS	O
+patient	POS	O
+developed	POS	O
+sudden	POS	O
+cardiac	POS	B-NP
+death	POS	I-NP
+two	POS	O
+days	POS	O
+later	POS	O
+.	POS	O
+The	POS	O
+Holter	POS	O
+electrocardiogram	POS	O
+,	POS	O
+which	POS	O
+was	POS	O
+worn	POS	O
+by	POS	O
+chance	POS	O
+,	POS	O
+revealed	POS	O
+torsade	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+with	POS	O
+gradually	POS	O
+prolonged	POS	O
+QT	POS	O
+intervals	POS	O
+.	POS	O
+This	POS	O
+drug	POS	O
+is	POS	O
+rapidly	POS	O
+absorbed	POS	O
+from	POS	O
+the	POS	O
+gastrointestinal	POS	O
+tract	POS	O
+,	POS	O
+and	POS	O
+most	POS	O
+of	POS	O
+it	POS	O
+is	POS	O
+excreted	POS	O
+from	POS	O
+the	POS	O
+kidney	POS	O
+.	POS	O
+Although	POS	O
+the	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+renal	POS	O
+function	POS	O
+was	POS	O
+not	POS	O
+highly	POS	O
+impaired	POS	O
+and	POS	O
+the	POS	O
+dose	POS	O
+of	POS	O
+pilsicainide	POS	O
+was	POS	O
+low	POS	O
+,	POS	O
+the	POS	O
+plasma	POS	O
+concentration	POS	O
+of	POS	O
+pilsicainide	POS	O
+may	POS	O
+have	POS	O
+been	POS	O
+high	POS	O
+,	POS	O
+which	POS	O
+can	POS	O
+produce	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+in	POS	O
+the	POS	O
+octogenarian	POS	O
+.	POS	O
+Although	POS	O
+the	POS	O
+oral	POS	O
+administration	POS	O
+of	POS	O
+class	POS	O
+IC	POS	O
+drugs	POS	O
+,	POS	O
+including	POS	O
+pilsicainide	POS	O
+,	POS	O
+is	POS	O
+effective	POS	O
+to	POS	O
+terminate	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+,	POS	O
+careful	POS	O
+consideration	POS	O
+must	POS	O
+be	POS	O
+taken	POS	O
+before	POS	O
+giving	POS	O
+these	POS	O
+drugs	POS	O
+to	POS	O
+octogenarians	POS	O
+.	POS	O
+All	POS	O
+-	POS	O
+trans	POS	O
+retinoic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+inflammatory	POS	B-NP
+myositis	POS	I-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+acute	POS	B-NP
+promyelocytic	POS	I-NP
+leukemia	POS	I-NP
+.	POS	O
+All	POS	O
+-	POS	O
+trans	POS	O
+retinoic	POS	O
+acid	POS	O
+(	POS	O
+ATRA	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+component	POS	O
+of	POS	O
+standard	POS	O
+therapy	POS	O
+for	POS	O
+acute	POS	B-NP
+promyelocytic	POS	I-NP
+leukemia	POS	I-NP
+(	POS	O
+APL	POS	B-NP
+)	POS	O
+,	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+potentially	POS	O
+serious	POS	O
+but	POS	O
+treatable	POS	O
+adverse	POS	O
+effects	POS	O
+involving	POS	O
+numerous	POS	O
+organ	POS	O
+systems	POS	O
+,	POS	O
+including	POS	O
+rare	POS	O
+skeletal	POS	O
+muscle	POS	O
+involvement	POS	O
+.	POS	O
+Only	POS	O
+a	POS	O
+handful	POS	O
+of	POS	O
+cases	POS	O
+of	POS	O
+ATRA	POS	O
+-	POS	O
+induced	POS	O
+myositis	POS	B-NP
+in	POS	O
+children	POS	O
+have	POS	O
+been	POS	O
+reported	POS	O
+,	POS	O
+and	POS	O
+none	POS	O
+in	POS	O
+the	POS	O
+radiology	POS	O
+literature	POS	O
+.	POS	O
+We	POS	O
+present	POS	O
+such	POS	O
+a	POS	O
+case	POS	O
+in	POS	O
+a	POS	O
+15	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+boy	POS	O
+with	POS	O
+APL	POS	B-NP
+,	POS	O
+where	POS	O
+recognition	POS	O
+of	POS	O
+imaging	POS	O
+findings	POS	O
+played	POS	O
+a	POS	O
+crucial	POS	O
+role	POS	O
+in	POS	O
+making	POS	O
+the	POS	O
+diagnosis	POS	O
+and	POS	O
+facilitated	POS	O
+prompt	POS	O
+,	POS	O
+effective	POS	O
+treatment	POS	O
+.	POS	O
+Tolerability	POS	O
+of	POS	O
+lomustine	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+cyclophosphamide	POS	O
+in	POS	O
+dogs	POS	O
+with	POS	O
+lymphoma	POS	B-NP
+.	POS	O
+This	POS	O
+retrospective	POS	O
+study	POS	O
+describes	POS	O
+toxicity	POS	B-NP
+associated	POS	O
+with	POS	O
+a	POS	O
+protocol	POS	O
+of	POS	O
+lomustine	POS	O
+(	POS	O
+CCNU	POS	O
+)	POS	O
+and	POS	O
+cyclophosphamide	POS	O
+(	POS	O
+CTX	POS	O
+)	POS	O
+in	POS	O
+dogs	POS	O
+with	POS	O
+lymphoma	POS	B-NP
+.	POS	O
+CCNU	POS	O
+was	POS	O
+administered	POS	O
+per	POS	O
+os	POS	O
+(	POS	O
+PO	POS	O
+)	POS	O
+at	POS	O
+a	POS	O
+targeted	POS	O
+dosage	POS	O
+of	POS	O
+60	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+body	POS	O
+surface	POS	O
+area	POS	O
+on	POS	O
+day	POS	O
+0	POS	O
+,	POS	O
+CTX	POS	O
+was	POS	O
+administered	POS	O
+PO	POS	O
+at	POS	O
+a	POS	O
+targeted	POS	O
+dosage	POS	O
+of	POS	O
+250	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+divided	POS	O
+over	POS	O
+days	POS	O
+0	POS	O
+through	POS	O
+4	POS	O
+,	POS	O
+and	POS	O
+all	POS	O
+dogs	POS	O
+received	POS	O
+prophylactic	POS	O
+antibiotics	POS	O
+.	POS	O
+Ninety	POS	O
+treatments	POS	O
+were	POS	O
+given	POS	O
+to	POS	O
+the	POS	O
+57	POS	O
+dogs	POS	O
+included	POS	O
+in	POS	O
+the	POS	O
+study	POS	O
+.	POS	O
+Neutropenia	POS	B-NP
+was	POS	O
+the	POS	O
+principal	POS	O
+toxic	POS	O
+effect	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+overall	POS	O
+frequency	POS	O
+of	POS	O
+grade	POS	O
+4	POS	O
+neutropenia	POS	B-NP
+after	POS	O
+the	POS	O
+first	POS	O
+treatment	POS	O
+of	POS	O
+CCNU	POS	O
+/	POS	O
+CTX	POS	B-NP
+was	POS	O
+30	POS	O
+%	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+,	POS	O
+19	POS	O
+-	POS	O
+43	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+body	POS	O
+weight	POS	O
+of	POS	O
+dogs	POS	O
+with	POS	O
+grade	POS	O
+4	POS	O
+neutropenia	POS	B-NP
+(	POS	O
+19	POS	O
+.	POS	O
+7	POS	O
+kg	POS	O
++	POS	O
+13	POS	O
+.	POS	O
+4	POS	O
+kg	POS	O
+)	POS	O
+was	POS	O
+significantly	POS	O
+less	POS	O
+than	POS	O
+the	POS	O
+mean	POS	O
+body	POS	O
+weight	POS	O
+of	POS	O
+dogs	POS	O
+that	POS	O
+did	POS	O
+not	POS	O
+develop	POS	O
+grade	POS	O
+4	POS	O
+neutropenia	POS	B-NP
+(	POS	O
+31	POS	O
+.	POS	O
+7	POS	O
+kg	POS	O
++	POS	O
+12	POS	O
+.	POS	O
+4	POS	O
+kg	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+005	POS	O
+)	POS	O
+.	POS	O
+One	POS	O
+dog	POS	O
+(	POS	O
+3	POS	O
+%	POS	O
+)	POS	O
+developed	POS	O
+hematologic	POS	O
+changes	POS	O
+suggestive	POS	O
+of	POS	O
+hepatotoxicity	POS	B-NP
+.	POS	O
+No	POS	O
+dogs	POS	O
+had	POS	O
+evidence	POS	O
+of	POS	O
+either	POS	O
+renal	POS	B-NP
+toxicity	POS	I-NP
+or	POS	O
+hemorrhagic	POS	B-NP
+cystitis	POS	I-NP
+.	POS	O
+Adverse	POS	O
+gastrointestinal	POS	O
+effects	POS	O
+were	POS	O
+uncommon	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+basis	POS	O
+of	POS	O
+the	POS	O
+findings	POS	O
+reported	POS	O
+herein	POS	O
+,	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+60	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+of	POS	O
+CCNU	POS	O
+combined	POS	O
+with	POS	O
+250	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+of	POS	O
+CTX	POS	B-NP
+(	POS	O
+divided	POS	O
+over	POS	O
+5	POS	O
+days	POS	O
+)	POS	O
+q	POS	O
+4	POS	O
+wk	POS	O
+is	POS	O
+tolerable	POS	O
+in	POS	O
+tumor	POS	B-NP
+-	POS	O
+bearing	POS	O
+dogs	POS	O
+.	POS	O
+Nelarabine	POS	O
+neurotoxicity	POS	B-NP
+with	POS	O
+concurrent	POS	O
+intrathecal	POS	O
+chemotherapy	POS	O
+:	POS	O
+Case	POS	O
+report	POS	O
+and	POS	O
+review	POS	O
+of	POS	O
+literature	POS	O
+.	POS	O
+Severe	POS	O
+nelarabine	POS	O
+neurotoxicity	POS	B-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+who	POS	O
+received	POS	O
+concurrent	POS	O
+intrathecal	POS	O
+(	POS	O
+IT	POS	O
+)	POS	O
+chemotherapy	POS	O
+is	POS	O
+reported	POS	O
+.	POS	O
+A	POS	O
+37	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+Caucasian	POS	O
+woman	POS	O
+with	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+T	POS	B-NP
+-	POS	I-NP
+cell	POS	I-NP
+lymphoblastic	POS	I-NP
+lymphoma	POS	I-NP
+was	POS	O
+admitted	POS	O
+for	POS	O
+relapsed	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+She	POS	O
+was	POS	O
+originally	POS	O
+treated	POS	O
+with	POS	O
+induction	POS	O
+chemotherapy	POS	O
+followed	POS	O
+by	POS	O
+an	POS	O
+autologous	POS	O
+transplant	POS	O
+.	POS	O
+She	POS	O
+developed	POS	O
+relapsed	POS	B-NP
+disease	POS	I-NP
+10	POS	O
+months	POS	O
+later	POS	O
+with	POS	O
+leukemic	POS	B-NP
+involvement	POS	I-NP
+.	POS	O
+She	POS	O
+was	POS	O
+re	POS	O
+-	POS	O
+induced	POS	O
+with	POS	O
+nelarabine	POS	O
+1500	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+on	POS	O
+days	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+,	POS	O
+and	POS	O
+5	POS	O
+with	POS	O
+1	POS	O
+dose	POS	O
+of	POS	O
+IT	POS	O
+cytarabine	POS	O
+100	POS	O
+mg	POS	O
+on	POS	O
+day	POS	O
+2	POS	O
+as	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+(	POS	O
+CNS	POS	O
+)	POS	O
+prophylaxis	POS	O
+.	POS	O
+At	POS	O
+the	POS	O
+time	POS	O
+of	POS	O
+treatment	POS	O
+,	POS	O
+she	POS	O
+was	POS	O
+on	POS	O
+continuous	POS	O
+renal	POS	O
+replacement	POS	O
+therapy	POS	O
+due	POS	O
+to	POS	O
+sequelae	POS	O
+of	POS	O
+tumor	POS	B-NP
+lysis	POS	I-NP
+syndrome	POS	I-NP
+(	POS	O
+TLS	POS	O
+)	POS	O
+.	POS	O
+She	POS	O
+tolerated	POS	O
+therapy	POS	O
+well	POS	O
+,	POS	O
+entered	POS	O
+a	POS	O
+complete	POS	O
+remission	POS	O
+,	POS	O
+and	POS	O
+recovered	POS	O
+her	POS	O
+renal	POS	O
+function	POS	O
+.	POS	O
+She	POS	O
+received	POS	O
+a	POS	O
+second	POS	O
+cycle	POS	O
+of	POS	O
+nelarabine	POS	O
+without	POS	O
+additional	POS	O
+IT	POS	O
+prophylaxis	POS	O
+one	POS	O
+month	POS	O
+later	POS	O
+.	POS	O
+A	POS	O
+week	POS	O
+after	POS	O
+this	POS	O
+second	POS	O
+cycle	POS	O
+,	POS	O
+she	POS	O
+noted	POS	O
+numbness	POS	B-NP
+in	POS	O
+her	POS	O
+lower	POS	O
+extremities	POS	O
+.	POS	O
+Predominantly	POS	O
+sensory	POS	O
+,	POS	O
+though	POS	O
+also	POS	O
+motor	POS	O
+and	POS	O
+autonomic	POS	O
+,	POS	O
+peripheral	POS	B-NP
+neuropathy	POS	I-NP
+started	POS	O
+in	POS	O
+her	POS	O
+feet	POS	O
+,	POS	O
+ascended	POS	O
+proximally	POS	O
+to	POS	O
+the	POS	O
+mid	POS	O
+-	POS	O
+thoracic	POS	O
+region	POS	O
+,	POS	O
+and	POS	O
+eventually	POS	O
+included	POS	O
+her	POS	O
+distal	POS	O
+upper	POS	O
+extremities	POS	O
+.	POS	O
+A	POS	O
+magnetic	POS	O
+resonance	POS	O
+imaging	POS	O
+(	POS	O
+MRI	POS	O
+)	POS	O
+of	POS	O
+her	POS	O
+spine	POS	O
+demonstrated	POS	O
+changes	POS	O
+from	POS	O
+C2	POS	O
+to	POS	O
+C6	POS	O
+consistent	POS	O
+with	POS	O
+subacute	POS	O
+combined	POS	O
+degeneration	POS	O
+.	POS	O
+Nelarabine	POS	O
+was	POS	O
+felt	POS	O
+to	POS	O
+be	POS	O
+the	POS	O
+cause	POS	O
+of	POS	O
+her	POS	O
+symptoms	POS	O
+.	POS	O
+Her	POS	B-NP
+neuropathy	POS	I-NP
+stabilized	POS	O
+and	POS	O
+showed	POS	O
+slight	POS	O
+improvement	POS	O
+and	POS	O
+ultimately	POS	O
+received	POS	O
+an	POS	O
+unrelated	POS	O
+,	POS	O
+reduced	POS	O
+-	POS	O
+intensity	POS	O
+allogeneic	POS	O
+transplant	POS	O
+while	POS	O
+in	POS	O
+complete	POS	O
+remission	POS	O
+,	POS	O
+but	POS	O
+relapsed	POS	B-NP
+disease	POS	I-NP
+10	POS	O
+weeks	POS	O
+later	POS	O
+.	POS	O
+She	POS	O
+is	POS	O
+currently	POS	O
+being	POS	O
+treated	POS	O
+with	POS	O
+best	POS	O
+supportive	POS	O
+care	POS	O
+.	POS	O
+To	POS	O
+our	POS	O
+knowledge	POS	O
+,	POS	O
+this	POS	O
+is	POS	O
+the	POS	O
+first	POS	O
+published	POS	O
+case	POS	O
+report	POS	O
+of	POS	O
+severe	POS	O
+neurotoxicity	POS	B-NP
+caused	POS	O
+by	POS	O
+nelarabine	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+who	POS	O
+received	POS	O
+concurrent	POS	O
+IT	POS	O
+chemotherapy	POS	O
+.	POS	O
+Valproate	POS	O
+-	POS	O
+induced	POS	O
+hyperammonemic	POS	B-NP
+encephalopathy	POS	I-NP
+in	POS	O
+a	POS	O
+renal	POS	O
+transplanted	POS	O
+patient	POS	O
+.	POS	O
+Neurological	POS	B-NP
+complications	POS	I-NP
+after	POS	O
+renal	POS	O
+transplantation	POS	O
+constitute	POS	O
+an	POS	O
+important	POS	O
+cause	POS	O
+of	POS	O
+morbidity	POS	O
+and	POS	O
+mortality	POS	O
+.	POS	O
+Their	POS	O
+differential	POS	O
+diagnosis	POS	O
+is	POS	O
+difficult	POS	O
+and	POS	O
+essential	POS	O
+for	POS	O
+subsequent	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+management	POS	O
+.	POS	O
+Valproate	POS	O
+-	POS	O
+induced	POS	O
+hyperammonemic	POS	B-NP
+encephalopathy	POS	I-NP
+is	POS	O
+an	POS	O
+uncommon	POS	O
+but	POS	O
+serious	POS	O
+effect	POS	O
+of	POS	O
+valproate	POS	O
+treatment	POS	O
+.	POS	O
+Here	POS	O
+,	POS	O
+we	POS	O
+describe	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+15	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+girl	POS	O
+who	POS	O
+was	POS	O
+on	POS	O
+a	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+therapy	POS	O
+with	POS	O
+valproate	POS	O
+due	POS	O
+to	POS	O
+epilepsy	POS	B-NP
+and	POS	O
+revealed	POS	O
+impaired	POS	B-NP
+consciousness	POS	I-NP
+with	POS	O
+hyperammonemia	POS	B-NP
+12	POS	O
+days	POS	O
+after	POS	O
+renal	POS	O
+transplantation	POS	O
+.	POS	O
+After	POS	O
+withdraw	POS	O
+of	POS	O
+valproate	POS	O
+,	POS	O
+patients	POS	O
+'	POS	O
+symptoms	POS	O
+resolved	POS	O
+within	POS	O
+24	POS	O
+h	POS	O
+.	POS	O
+Clinicians	POS	O
+should	POS	O
+increase	POS	O
+their	POS	O
+awareness	POS	O
+for	POS	O
+potential	POS	O
+complication	POS	O
+of	POS	O
+valproate	POS	O
+,	POS	O
+especially	POS	O
+in	POS	O
+transplanted	POS	O
+patients	POS	O
+.	POS	O
+Necrotising	POS	B-NP
+fasciitis	POS	I-NP
+after	POS	O
+bortezomib	POS	O
+and	POS	O
+dexamethasone	POS	O
+-	POS	O
+containing	POS	O
+regimen	POS	O
+in	POS	O
+an	POS	O
+elderly	POS	O
+patient	POS	O
+of	POS	O
+Waldenstrom	POS	B-NP
+macroglobulinaemia	POS	I-NP
+.	POS	O
+Bortezomib	POS	O
+and	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+dexamethasone	POS	O
+-	POS	O
+containing	POS	O
+regimens	POS	O
+are	POS	O
+considered	POS	O
+to	POS	O
+be	POS	O
+generally	POS	O
+tolerable	POS	O
+with	POS	O
+few	POS	O
+severe	POS	O
+bacterial	POS	B-NP
+infections	POS	I-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+B	POS	B-NP
+-	POS	I-NP
+cell	POS	I-NP
+malignancies	POS	I-NP
+.	POS	O
+However	POS	O
+,	POS	O
+information	POS	O
+is	POS	O
+limited	POS	O
+concerning	POS	O
+the	POS	O
+safety	POS	O
+of	POS	O
+the	POS	O
+regimen	POS	O
+in	POS	O
+elderly	POS	O
+patients	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+76	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+with	POS	O
+Waldenstrom	POS	B-NP
+macroglobulinaemia	POS	I-NP
+who	POS	O
+suffered	POS	O
+necrotising	POS	B-NP
+fasciitis	POS	I-NP
+without	POS	O
+neutropenia	POS	B-NP
+after	POS	O
+the	POS	O
+combination	POS	O
+treatment	POS	O
+with	POS	O
+bortezomib	POS	O
+,	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+dexamethasone	POS	O
+and	POS	O
+rituximab	POS	O
+.	POS	O
+Despite	POS	O
+immediate	POS	O
+intravenous	POS	O
+antimicrobial	POS	O
+therapy	POS	O
+,	POS	O
+he	POS	O
+succumbed	POS	O
+23	POS	O
+h	POS	O
+after	POS	O
+the	POS	O
+onset	POS	O
+.	POS	O
+Physicians	POS	O
+should	POS	O
+recognise	POS	O
+the	POS	O
+possibility	POS	O
+of	POS	O
+fatal	POS	O
+bacterial	POS	B-NP
+infections	POS	I-NP
+related	POS	O
+to	POS	O
+bortezomib	POS	O
+plus	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+dexamethasone	POS	O
+in	POS	O
+elderly	POS	O
+patients	POS	O
+,	POS	O
+and	POS	O
+we	POS	O
+believe	POS	O
+this	POS	O
+case	POS	O
+warrants	POS	O
+further	POS	O
+investigation	POS	O
+.	POS	O
+An	POS	O
+integrated	POS	O
+characterization	POS	O
+of	POS	O
+serological	POS	O
+,	POS	O
+pathological	POS	O
+,	POS	O
+and	POS	O
+functional	POS	O
+events	POS	O
+in	POS	O
+doxorubicin	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+Many	POS	O
+efficacious	POS	O
+cancer	POS	B-NP
+treatments	POS	O
+cause	POS	O
+significant	POS	O
+cardiac	POS	B-NP
+morbidity	POS	I-NP
+,	POS	O
+yet	POS	O
+biomarkers	POS	O
+or	POS	O
+functional	POS	O
+indices	POS	O
+of	POS	O
+early	POS	O
+damage	POS	O
+,	POS	O
+which	POS	O
+would	POS	O
+allow	POS	O
+monitoring	POS	O
+and	POS	O
+intervention	POS	O
+,	POS	O
+are	POS	O
+lacking	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+,	POS	O
+we	POS	O
+have	POS	O
+utilized	POS	O
+a	POS	O
+rat	POS	O
+model	POS	O
+of	POS	O
+progressive	POS	O
+doxorubicin	POS	O
+(	POS	O
+DOX	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+cardiomyopathy	POS	B-NP
+,	POS	O
+applying	POS	O
+multiple	POS	O
+approaches	POS	O
+,	POS	O
+including	POS	O
+cardiac	POS	O
+magnetic	POS	O
+resonance	POS	O
+imaging	POS	O
+(	POS	O
+MRI	POS	O
+)	POS	O
+,	POS	O
+to	POS	O
+provide	POS	O
+the	POS	O
+most	POS	O
+comprehensive	POS	O
+characterization	POS	O
+to	POS	O
+date	POS	O
+of	POS	O
+the	POS	O
+timecourse	POS	O
+of	POS	O
+serological	POS	O
+,	POS	O
+pathological	POS	O
+,	POS	O
+and	POS	O
+functional	POS	O
+events	POS	O
+underlying	POS	O
+this	POS	O
+toxicity	POS	B-NP
+.	POS	O
+Hannover	POS	O
+Wistar	POS	O
+rats	POS	O
+were	POS	O
+dosed	POS	O
+with	POS	O
+1	POS	O
+.	POS	O
+25	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+DOX	POS	O
+weekly	POS	O
+for	POS	O
+8	POS	O
+weeks	POS	O
+followed	POS	O
+by	POS	O
+a	POS	O
+4	POS	O
+week	POS	O
+off	POS	O
+-	POS	O
+dosing	POS	O
+"	POS	O
+recovery	POS	O
+"	POS	O
+period	POS	O
+.	POS	O
+Electron	POS	O
+microscopy	POS	O
+of	POS	O
+the	POS	O
+myocardium	POS	O
+revealed	POS	O
+subcellular	POS	O
+degeneration	POS	O
+and	POS	O
+marked	POS	O
+mitochondrial	POS	O
+changes	POS	O
+after	POS	O
+a	POS	O
+single	POS	O
+dose	POS	O
+.	POS	O
+Histopathological	POS	O
+analysis	POS	O
+revealed	POS	O
+progressive	POS	O
+cardiomyocyte	POS	B-NP
+degeneration	POS	I-NP
+,	POS	O
+hypertrophy	POS	B-NP
+/	POS	I-NP
+cytomegaly	POS	I-NP
+,	POS	O
+and	POS	O
+extensive	POS	O
+vacuolation	POS	O
+after	POS	O
+two	POS	O
+doses	POS	O
+.	POS	O
+Extensive	POS	O
+replacement	POS	O
+fibrosis	POS	B-NP
+(	POS	O
+quantified	POS	O
+by	POS	O
+Sirius	POS	O
+red	POS	O
+staining	POS	O
+)	POS	O
+developed	POS	O
+during	POS	O
+the	POS	O
+off	POS	O
+-	POS	O
+dosing	POS	O
+period	POS	O
+.	POS	O
+Functional	POS	O
+indices	POS	O
+assessed	POS	O
+by	POS	O
+cardiac	POS	O
+MRI	POS	O
+(	POS	O
+including	POS	O
+left	POS	O
+ventricular	POS	O
+ejection	POS	O
+fraction	POS	O
+(	POS	O
+LVEF	POS	O
+)	POS	O
+,	POS	O
+cardiac	POS	O
+output	POS	O
+,	POS	O
+and	POS	O
+E	POS	O
+/	POS	O
+A	POS	O
+ratio	POS	O
+)	POS	O
+declined	POS	O
+progressively	POS	O
+,	POS	O
+reaching	POS	O
+statistical	POS	O
+significance	POS	O
+after	POS	O
+two	POS	O
+doses	POS	O
+and	POS	O
+culminating	POS	O
+in	POS	O
+"	POS	O
+clinical	POS	O
+"	POS	O
+LV	POS	B-NP
+dysfunction	POS	I-NP
+by	POS	O
+12	POS	O
+weeks	POS	O
+.	POS	O
+Significant	POS	O
+increases	POS	O
+in	POS	O
+peak	POS	O
+myocardial	POS	O
+contrast	POS	O
+enhancement	POS	O
+and	POS	O
+serological	POS	O
+cardiac	POS	O
+troponin	POS	O
+I	POS	O
+(	POS	O
+cTnI	POS	O
+)	POS	O
+emerged	POS	O
+after	POS	O
+eight	POS	O
+doses	POS	O
+,	POS	O
+importantly	POS	O
+preceding	POS	O
+the	POS	O
+LVEF	POS	O
+decline	POS	O
+to	POS	O
+<	POS	O
+50	POS	O
+%	POS	O
+.	POS	O
+Troponin	POS	O
+I	POS	O
+levels	POS	O
+positively	POS	O
+correlated	POS	O
+with	POS	O
+delayed	POS	O
+and	POS	O
+peak	POS	O
+gadolinium	POS	O
+contrast	POS	O
+enhancement	POS	O
+,	POS	O
+histopathological	POS	O
+grading	POS	O
+,	POS	O
+and	POS	O
+diastolic	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+In	POS	O
+summary	POS	O
+,	POS	O
+subcellular	POS	O
+cardiomyocyte	POS	B-NP
+degeneration	POS	I-NP
+was	POS	O
+the	POS	O
+earliest	POS	O
+marker	POS	O
+,	POS	O
+followed	POS	O
+by	POS	O
+progressive	POS	O
+functional	POS	O
+decline	POS	O
+and	POS	O
+histopathological	POS	O
+manifestations	POS	O
+.	POS	O
+Myocardial	POS	O
+contrast	POS	O
+enhancement	POS	O
+and	POS	O
+elevations	POS	O
+in	POS	O
+cTnI	POS	O
+occurred	POS	O
+later	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+all	POS	O
+indices	POS	O
+predated	POS	O
+"	POS	O
+clinical	POS	O
+"	POS	O
+LV	POS	B-NP
+dysfunction	POS	I-NP
+and	POS	O
+thus	POS	O
+warrant	POS	O
+further	POS	O
+evaluation	POS	O
+as	POS	O
+predictive	POS	O
+biomarkers	POS	O
+.	POS	O
+Intradermal	POS	O
+glutamate	POS	O
+and	POS	O
+capsaicin	POS	O
+injections	POS	O
+:	POS	O
+intra	POS	O
+-	POS	O
+and	POS	O
+interindividual	POS	O
+variability	POS	O
+of	POS	O
+provoked	POS	O
+hyperalgesia	POS	B-NP
+and	POS	O
+allodynia	POS	B-NP
+.	POS	O
+Intradermal	POS	O
+injections	POS	O
+of	POS	O
+glutamate	POS	O
+and	POS	O
+capsaicin	POS	O
+are	POS	O
+attractive	POS	O
+to	POS	O
+use	POS	O
+in	POS	O
+human	POS	O
+experimental	POS	O
+pain	POS	B-NP
+models	POS	O
+because	POS	O
+hyperalgesia	POS	B-NP
+and	POS	O
+allodynia	POS	B-NP
+mimic	POS	O
+isolated	POS	O
+aspects	POS	O
+of	POS	O
+clinical	POS	O
+pain	POS	B-NP
+disorders	POS	I-NP
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+reproducibility	POS	O
+of	POS	O
+these	POS	O
+models	POS	O
+.	POS	O
+Twenty	POS	O
+healthy	POS	O
+male	POS	O
+volunteers	POS	O
+(	POS	O
+mean	POS	O
+age	POS	O
+24	POS	O
+years	POS	O
+;	POS	O
+range	POS	O
+18	POS	O
+-	POS	O
+38	POS	O
+years	POS	O
+)	POS	O
+received	POS	O
+intradermal	POS	O
+injections	POS	O
+of	POS	O
+glutamate	POS	O
+and	POS	O
+capsaicin	POS	O
+in	POS	O
+the	POS	O
+volar	POS	O
+forearm	POS	O
+.	POS	O
+Magnitudes	POS	O
+of	POS	O
+secondary	POS	O
+pinprick	POS	O
+hyperalgesia	POS	B-NP
+and	POS	O
+brush	POS	O
+-	POS	O
+evoked	POS	O
+allodynia	POS	B-NP
+were	POS	O
+investigated	POS	O
+using	POS	O
+von	POS	O
+Frey	POS	O
+filaments	POS	O
+(	POS	O
+gauges	POS	O
+10	POS	O
+,	POS	O
+15	POS	O
+,	POS	O
+60	POS	O
+and	POS	O
+100	POS	O
+g	POS	O
+)	POS	O
+and	POS	O
+brush	POS	O
+strokes	POS	B-NP
+.	POS	O
+Areas	POS	O
+of	POS	O
+secondary	POS	O
+hyperalgesia	POS	B-NP
+and	POS	O
+allodynia	POS	B-NP
+were	POS	O
+quantified	POS	O
+immediately	POS	O
+after	POS	O
+injection	POS	O
+and	POS	O
+after	POS	O
+15	POS	O
+,	POS	O
+30	POS	O
+and	POS	O
+60	POS	O
+min	POS	O
+.	POS	O
+Two	POS	O
+identical	POS	O
+experiments	POS	O
+separated	POS	O
+by	POS	O
+at	POS	O
+least	POS	O
+7	POS	O
+days	POS	O
+were	POS	O
+performed	POS	O
+.	POS	O
+Reproducibility	POS	O
+across	POS	O
+and	POS	O
+within	POS	O
+volunteers	POS	O
+(	POS	O
+inter	POS	O
+-	POS	O
+and	POS	O
+intra	POS	O
+-	POS	O
+individual	POS	O
+variation	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+was	POS	O
+assessed	POS	O
+using	POS	O
+intraclass	POS	O
+correlation	POS	O
+coefficient	POS	O
+(	POS	O
+ICC	POS	O
+)	POS	O
+and	POS	O
+coefficient	POS	O
+of	POS	O
+variation	POS	O
+(	POS	O
+CV	POS	O
+)	POS	O
+.	POS	O
+Secondary	POS	B-NP
+pinprick	POS	I-NP
+hyperalgesia	POS	I-NP
+was	POS	O
+observed	POS	O
+as	POS	O
+a	POS	O
+marked	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+visual	POS	O
+analogue	POS	O
+scale	POS	O
+(	POS	O
+VAS	POS	O
+)	POS	O
+response	POS	O
+to	POS	O
+von	POS	O
+Frey	POS	O
+gauges	POS	O
+60	POS	O
+and	POS	O
+100	POS	O
+g	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+after	POS	O
+glutamate	POS	O
+injection	POS	O
+.	POS	O
+For	POS	O
+capsaicin	POS	O
+,	POS	O
+secondary	POS	O
+pinprick	POS	O
+hyperalgesia	POS	B-NP
+was	POS	O
+detected	POS	O
+with	POS	O
+all	POS	O
+von	POS	O
+Frey	POS	O
+gauges	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+Glutamate	POS	O
+evoked	POS	O
+reproducible	POS	O
+VAS	POS	O
+response	POS	O
+to	POS	O
+all	POS	O
+von	POS	O
+Frey	POS	O
+gauges	POS	O
+(	POS	O
+ICC	POS	O
+>	POS	O
+0	POS	O
+.	POS	O
+60	POS	O
+)	POS	O
+and	POS	O
+brush	POS	O
+strokes	POS	B-NP
+(	POS	O
+ICC	POS	O
+>	POS	O
+0	POS	O
+.	POS	O
+83	POS	O
+)	POS	O
+.	POS	O
+Capsaicin	POS	O
+injection	POS	O
+was	POS	O
+reproducible	POS	O
+for	POS	O
+secondary	POS	O
+hyperalgesia	POS	B-NP
+(	POS	O
+ICC	POS	O
+>	POS	O
+0	POS	O
+.	POS	O
+70	POS	O
+)	POS	O
+and	POS	O
+allodynia	POS	B-NP
+(	POS	O
+ICC	POS	O
+>	POS	O
+0	POS	O
+.	POS	O
+71	POS	O
+)	POS	O
+.	POS	O
+Intra	POS	O
+-	POS	O
+individual	POS	O
+variability	POS	O
+was	POS	O
+generally	POS	O
+lower	POS	O
+for	POS	O
+the	POS	O
+VAS	POS	O
+response	POS	O
+to	POS	O
+von	POS	O
+Frey	POS	O
+and	POS	O
+brush	POS	O
+compared	POS	O
+with	POS	O
+areas	POS	O
+of	POS	O
+secondary	POS	O
+hyperalgesia	POS	B-NP
+and	POS	O
+allodynia	POS	B-NP
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+glutamate	POS	O
+and	POS	O
+capsaicin	POS	O
+yield	POS	O
+reproducible	POS	O
+hyperalgesic	POS	B-NP
+and	POS	O
+allodynic	POS	O
+responses	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+present	POS	O
+model	POS	O
+is	POS	O
+well	POS	O
+suited	POS	O
+for	POS	O
+basic	POS	O
+research	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+for	POS	O
+assessing	POS	O
+the	POS	O
+modulation	POS	O
+of	POS	O
+central	POS	O
+phenomena	POS	O
+.	POS	O
+Ocular	POS	O
+-	POS	O
+specific	POS	O
+ER	POS	O
+stress	POS	O
+reduction	POS	O
+rescues	POS	O
+glaucoma	POS	B-NP
+in	POS	O
+murine	POS	O
+glucocorticoid	POS	O
+-	POS	O
+induced	POS	O
+glaucoma	POS	B-NP
+.	POS	O
+Administration	POS	O
+of	POS	O
+glucocorticoids	POS	O
+induces	POS	O
+ocular	POS	O
+hypertension	POS	B-NP
+in	POS	O
+some	POS	O
+patients	POS	O
+.	POS	O
+If	POS	O
+untreated	POS	O
+,	POS	O
+these	POS	O
+patients	POS	O
+can	POS	O
+develop	POS	O
+a	POS	O
+secondary	POS	O
+glaucoma	POS	B-NP
+that	POS	O
+resembles	POS	O
+primary	POS	O
+open	POS	O
+-	POS	O
+angle	POS	O
+glaucoma	POS	B-NP
+(	POS	O
+POAG	POS	B-NP
+)	POS	O
+.	POS	O
+The	POS	O
+underlying	POS	O
+pathology	POS	O
+of	POS	O
+glucocorticoid	POS	O
+-	POS	O
+induced	POS	O
+glaucoma	POS	B-NP
+is	POS	O
+not	POS	O
+fully	POS	O
+understood	POS	O
+,	POS	O
+due	POS	O
+in	POS	O
+part	POS	O
+to	POS	O
+lack	POS	O
+of	POS	O
+an	POS	O
+appropriate	POS	O
+animal	POS	O
+model	POS	O
+.	POS	O
+Here	POS	O
+,	POS	O
+we	POS	O
+developed	POS	O
+a	POS	O
+murine	POS	O
+model	POS	O
+of	POS	O
+glucocorticoid	POS	O
+-	POS	O
+induced	POS	O
+glaucoma	POS	B-NP
+that	POS	O
+exhibits	POS	O
+glaucoma	POS	B-NP
+features	POS	O
+that	POS	O
+are	POS	O
+observed	POS	O
+in	POS	O
+patients	POS	O
+.	POS	O
+Treatment	POS	O
+of	POS	O
+WT	POS	O
+mice	POS	O
+with	POS	O
+topical	POS	O
+ocular	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+dexamethasone	POS	O
+led	POS	O
+to	POS	O
+elevation	POS	O
+of	POS	O
+intraocular	POS	O
+pressure	POS	O
+(	POS	O
+IOP	POS	O
+)	POS	O
+,	POS	O
+functional	POS	O
+and	POS	O
+structural	POS	O
+loss	POS	O
+of	POS	O
+retinal	POS	O
+ganglion	POS	O
+cells	POS	O
+,	POS	O
+and	POS	O
+axonal	POS	B-NP
+degeneration	POS	I-NP
+,	POS	O
+resembling	POS	O
+glucocorticoid	POS	O
+-	POS	O
+induced	POS	O
+glaucoma	POS	B-NP
+in	POS	O
+human	POS	O
+patients	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+dexamethasone	POS	O
+-	POS	O
+induced	POS	O
+ocular	POS	O
+hypertension	POS	B-NP
+was	POS	O
+associated	POS	O
+with	POS	O
+chronic	POS	O
+ER	POS	O
+stress	POS	O
+of	POS	O
+the	POS	O
+trabecular	POS	O
+meshwork	POS	O
+(	POS	O
+TM	POS	O
+)	POS	O
+.	POS	O
+Similar	POS	O
+to	POS	O
+patients	POS	O
+,	POS	O
+withdrawal	POS	O
+of	POS	O
+dexamethasone	POS	O
+treatment	POS	O
+reduced	POS	O
+elevated	POS	O
+IOP	POS	O
+and	POS	O
+ER	POS	O
+stress	POS	O
+in	POS	O
+this	POS	O
+animal	POS	O
+model	POS	O
+.	POS	O
+Dexamethasone	POS	O
+induced	POS	O
+the	POS	O
+transcriptional	POS	O
+factor	POS	O
+CHOP	POS	O
+,	POS	O
+a	POS	O
+marker	POS	O
+for	POS	O
+chronic	POS	O
+ER	POS	O
+stress	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+anterior	POS	O
+segment	POS	O
+tissues	POS	O
+,	POS	O
+and	POS	O
+Chop	POS	O
+deletion	POS	O
+reduced	POS	O
+ER	POS	O
+stress	POS	O
+in	POS	O
+these	POS	O
+tissues	POS	O
+and	POS	O
+prevented	POS	O
+dexamethasone	POS	O
+-	POS	O
+induced	POS	O
+ocular	POS	O
+hypertension	POS	B-NP
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+reduction	POS	B-NP
+of	POS	I-NP
+ER	POS	I-NP
+stress	POS	I-NP
+in	POS	O
+the	POS	O
+TM	POS	O
+with	POS	O
+sodium	POS	O
+4	POS	O
+-	POS	O
+phenylbutyrate	POS	O
+prevented	POS	O
+dexamethasone	POS	O
+-	POS	O
+induced	POS	O
+ocular	POS	O
+hypertension	POS	B-NP
+in	POS	O
+WT	POS	O
+mice	POS	O
+.	POS	O
+Our	POS	O
+data	POS	O
+indicate	POS	O
+that	POS	O
+ER	POS	O
+stress	POS	O
+contributes	POS	O
+to	POS	O
+glucocorticoid	POS	O
+-	POS	O
+induced	POS	O
+ocular	POS	O
+hypertension	POS	B-NP
+and	POS	O
+suggest	POS	O
+that	POS	O
+reducing	POS	O
+ER	POS	O
+stress	POS	O
+has	POS	O
+potential	POS	O
+as	POS	O
+a	POS	O
+therapeutic	POS	O
+strategy	POS	O
+for	POS	O
+treating	POS	O
+glucocorticoid	POS	O
+-	POS	O
+induced	POS	O
+glaucoma	POS	B-NP
+.	POS	O
+Effects	POS	O
+of	POS	O
+ginsenosides	POS	O
+on	POS	O
+opioid	POS	O
+-	POS	O
+induced	POS	O
+hyperalgesia	POS	B-NP
+in	POS	O
+mice	POS	O
+.	POS	O
+Opioid	POS	O
+-	POS	O
+induced	POS	O
+hyperalgesia	POS	B-NP
+(	POS	O
+OIH	POS	O
+)	POS	O
+is	POS	O
+characterized	POS	O
+by	POS	O
+nociceptive	POS	O
+sensitization	POS	O
+caused	POS	O
+by	POS	O
+the	POS	O
+cessation	POS	O
+of	POS	O
+chronic	POS	O
+opioid	POS	O
+use	POS	O
+.	POS	O
+OIH	POS	O
+can	POS	O
+limit	POS	O
+the	POS	O
+clinical	POS	O
+use	POS	O
+of	POS	O
+opioid	POS	O
+analgesics	POS	O
+and	POS	O
+complicate	POS	O
+withdrawal	POS	O
+from	POS	O
+opioid	POS	O
+addiction	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+,	POS	O
+we	POS	O
+investigated	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+Re	POS	O
+,	POS	O
+Rg1	POS	O
+,	POS	O
+and	POS	O
+Rb1	POS	O
+ginsenosides	POS	O
+,	POS	O
+the	POS	O
+bioactive	POS	O
+components	POS	O
+of	POS	O
+ginseng	POS	O
+,	POS	O
+on	POS	O
+OIH	POS	O
+.	POS	O
+OIH	POS	O
+was	POS	O
+achieved	POS	O
+in	POS	O
+mice	POS	O
+after	POS	O
+subcutaneous	POS	O
+administration	POS	O
+of	POS	O
+morphine	POS	O
+for	POS	O
+7	POS	O
+consecutive	POS	O
+days	POS	O
+three	POS	O
+times	POS	O
+per	POS	O
+day	POS	O
+.	POS	O
+During	POS	O
+withdrawal	POS	O
+(	POS	O
+days	POS	O
+8	POS	O
+and	POS	O
+9	POS	O
+)	POS	O
+,	POS	O
+these	POS	O
+mice	POS	O
+were	POS	O
+administered	POS	O
+Re	POS	O
+,	POS	O
+Rg1	POS	O
+,	POS	O
+or	POS	O
+Rb1	POS	O
+intragastrically	POS	O
+two	POS	O
+times	POS	O
+per	POS	O
+day	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+test	POS	O
+day	POS	O
+(	POS	O
+day	POS	O
+10	POS	O
+)	POS	O
+,	POS	O
+mice	POS	O
+were	POS	O
+subjected	POS	O
+to	POS	O
+the	POS	O
+thermal	POS	O
+sensitivity	POS	O
+test	POS	O
+and	POS	O
+the	POS	O
+acetic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+writhing	POS	O
+test	POS	O
+.	POS	O
+Re	POS	O
+(	POS	O
+300	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+inhibited	POS	O
+OIH	POS	O
+in	POS	O
+both	POS	O
+the	POS	O
+thermal	POS	O
+sensitivity	POS	O
+test	POS	O
+and	POS	O
+the	POS	O
+acetic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+writhing	POS	O
+test	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+Rg1	POS	O
+and	POS	O
+Rb1	POS	O
+ginsenosides	POS	O
+failed	POS	O
+to	POS	O
+prevent	POS	O
+OIH	POS	O
+in	POS	O
+either	POS	O
+test	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+Rg1	POS	O
+showed	POS	O
+a	POS	O
+tendency	POS	O
+to	POS	O
+aggravate	POS	O
+OIH	POS	O
+in	POS	O
+the	POS	O
+acetic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+writhing	POS	O
+test	POS	O
+.	POS	O
+Our	POS	O
+data	POS	O
+suggested	POS	O
+that	POS	O
+the	POS	O
+ginsenoside	POS	O
+Re	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+Rg1	POS	O
+or	POS	O
+Rb1	POS	O
+,	POS	O
+may	POS	O
+contribute	POS	O
+toward	POS	O
+reversal	POS	O
+of	POS	O
+OIH	POS	O
+.	POS	O
+A	POS	O
+comparison	POS	O
+of	POS	O
+severe	POS	O
+hemodynamic	POS	B-NP
+disturbances	POS	I-NP
+between	POS	O
+dexmedetomidine	POS	O
+and	POS	O
+propofol	POS	O
+for	POS	O
+sedation	POS	O
+in	POS	O
+neurocritical	POS	O
+care	POS	O
+patients	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+Dexmedetomidine	POS	O
+and	POS	O
+propofol	POS	O
+are	POS	O
+commonly	POS	O
+used	POS	O
+sedatives	POS	O
+in	POS	O
+neurocritical	POS	O
+care	POS	O
+as	POS	O
+they	POS	O
+allow	POS	O
+for	POS	O
+frequent	POS	O
+neurologic	POS	O
+examinations	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+both	POS	O
+agents	POS	O
+are	POS	O
+associated	POS	O
+with	POS	O
+significant	POS	O
+hemodynamic	POS	O
+side	POS	O
+effects	POS	O
+.	POS	O
+The	POS	O
+primary	POS	O
+objective	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+is	POS	O
+to	POS	O
+compare	POS	O
+the	POS	O
+prevalence	POS	O
+of	POS	O
+severe	POS	O
+hemodynamic	POS	O
+effects	POS	O
+in	POS	O
+neurocritical	POS	O
+care	POS	O
+patients	POS	O
+receiving	POS	O
+dexmedetomidine	POS	O
+and	POS	O
+propofol	POS	O
+.	POS	O
+DESIGN	POS	O
+:	POS	O
+Multicenter	POS	O
+,	POS	O
+retrospective	POS	O
+,	POS	O
+propensity	POS	O
+-	POS	O
+matched	POS	O
+cohort	POS	O
+study	POS	O
+.	POS	O
+SETTING	POS	O
+:	POS	O
+Neurocritical	POS	O
+care	POS	O
+units	POS	O
+at	POS	O
+two	POS	O
+academic	POS	O
+medical	POS	O
+centers	POS	O
+with	POS	O
+dedicated	POS	O
+neurocritical	POS	O
+care	POS	O
+teams	POS	O
+and	POS	O
+board	POS	O
+-	POS	O
+certified	POS	O
+neurointensivists	POS	O
+.	POS	O
+PATIENTS	POS	O
+:	POS	O
+Neurocritical	POS	O
+care	POS	O
+patients	POS	O
+admitted	POS	O
+between	POS	O
+July	POS	O
+2009	POS	O
+and	POS	O
+September	POS	O
+2012	POS	O
+were	POS	O
+evaluated	POS	O
+and	POS	O
+then	POS	O
+matched	POS	O
+1	POS	O
+:	POS	O
+1	POS	O
+based	POS	O
+on	POS	O
+propensity	POS	O
+scoring	POS	O
+of	POS	O
+baseline	POS	O
+characteristics	POS	O
+.	POS	O
+INTERVENTIONS	POS	O
+:	POS	O
+Continuous	POS	O
+sedation	POS	O
+with	POS	O
+dexmedetomidine	POS	O
+or	POS	O
+propofol	POS	O
+.	POS	O
+MEASUREMENTS	POS	O
+AND	POS	O
+MAIN	POS	O
+RESULTS	POS	O
+:	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+342	POS	O
+patients	POS	O
+(	POS	O
+105	POS	O
+dexmedetomidine	POS	O
+and	POS	O
+237	POS	O
+propofol	POS	O
+)	POS	O
+were	POS	O
+included	POS	O
+in	POS	O
+the	POS	O
+analysis	POS	O
+,	POS	O
+with	POS	O
+190	POS	O
+matched	POS	O
+(	POS	O
+95	POS	O
+in	POS	O
+each	POS	O
+group	POS	O
+)	POS	O
+by	POS	O
+propensity	POS	O
+score	POS	O
+.	POS	O
+The	POS	O
+primary	POS	O
+outcome	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+a	POS	O
+composite	POS	O
+of	POS	O
+severe	POS	O
+hypotension	POS	B-NP
+(	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+<	POS	O
+60	POS	O
+mm	POS	O
+Hg	POS	O
+)	POS	O
+and	POS	O
+bradycardia	POS	B-NP
+(	POS	O
+heart	POS	O
+rate	POS	O
+<	POS	O
+50	POS	O
+beats	POS	O
+/	POS	O
+min	POS	O
+)	POS	O
+during	POS	O
+sedative	POS	O
+infusion	POS	O
+.	POS	O
+No	POS	O
+difference	POS	O
+in	POS	O
+the	POS	O
+primary	POS	O
+composite	POS	O
+outcome	POS	O
+in	POS	O
+both	POS	O
+the	POS	O
+unmatched	POS	O
+(	POS	O
+30	POS	O
+%	POS	O
+vs	POS	O
+30	POS	O
+%	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+94	POS	O
+)	POS	O
+or	POS	O
+matched	POS	O
+cohorts	POS	O
+(	POS	O
+28	POS	O
+%	POS	O
+vs	POS	O
+34	POS	O
+%	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+35	POS	O
+)	POS	O
+could	POS	O
+be	POS	O
+found	POS	O
+.	POS	O
+When	POS	O
+analyzed	POS	O
+separately	POS	O
+,	POS	O
+no	POS	O
+differences	POS	O
+could	POS	O
+be	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+prevalence	POS	O
+of	POS	O
+severe	POS	O
+hypotension	POS	B-NP
+or	POS	O
+bradycardia	POS	B-NP
+in	POS	O
+either	POS	O
+the	POS	O
+unmatched	POS	O
+or	POS	O
+matched	POS	O
+cohorts	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Severe	POS	O
+hypotension	POS	B-NP
+and	POS	O
+bradycardia	POS	B-NP
+occur	POS	O
+at	POS	O
+similar	POS	O
+prevalence	POS	O
+in	POS	O
+neurocritical	POS	O
+care	POS	O
+patients	POS	O
+who	POS	O
+receive	POS	O
+dexmedetomidine	POS	O
+or	POS	O
+propofol	POS	O
+.	POS	O
+Providers	POS	O
+should	POS	O
+similarly	POS	O
+consider	POS	O
+the	POS	O
+likelihood	POS	O
+of	POS	O
+hypotension	POS	B-NP
+or	POS	O
+bradycardia	POS	B-NP
+before	POS	O
+starting	POS	O
+either	POS	O
+sedative	POS	O
+.	POS	O
+Hydroxytyrosol	POS	O
+ameliorates	POS	O
+oxidative	POS	O
+stress	POS	O
+and	POS	O
+mitochondrial	POS	B-NP
+dysfunction	POS	I-NP
+in	POS	O
+doxorubicin	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+in	POS	O
+rats	POS	O
+with	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+Oxidative	POS	O
+stress	POS	O
+is	POS	O
+involved	POS	O
+in	POS	O
+several	POS	O
+processes	POS	O
+including	POS	O
+cancer	POS	B-NP
+,	POS	O
+aging	POS	O
+and	POS	O
+cardiovascular	POS	B-NP
+disease	POS	I-NP
+,	POS	O
+and	POS	O
+has	POS	O
+been	POS	O
+shown	POS	O
+to	POS	O
+potentiate	POS	O
+the	POS	O
+therapeutic	POS	O
+effect	POS	O
+of	POS	O
+drugs	POS	O
+such	POS	O
+as	POS	O
+doxorubicin	POS	O
+.	POS	O
+Doxorubicin	POS	O
+causes	POS	O
+significant	POS	O
+cardiotoxicity	POS	B-NP
+characterized	POS	O
+by	POS	O
+marked	POS	O
+increases	POS	O
+in	POS	O
+oxidative	POS	O
+stress	POS	O
+and	POS	O
+mitochondrial	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+Herein	POS	O
+,	POS	O
+we	POS	O
+investigate	POS	O
+whether	POS	O
+doxorubicin	POS	O
+-	POS	O
+associated	POS	O
+chronic	POS	O
+cardiac	POS	B-NP
+toxicity	POS	I-NP
+can	POS	O
+be	POS	O
+ameliorated	POS	O
+with	POS	O
+the	POS	O
+antioxidant	POS	O
+hydroxytyrosol	POS	O
+in	POS	O
+rats	POS	O
+with	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+Thirty	POS	O
+-	POS	O
+six	POS	O
+rats	POS	O
+bearing	POS	O
+breast	POS	B-NP
+tumors	POS	I-NP
+induced	POS	O
+chemically	POS	O
+were	POS	O
+divided	POS	O
+into	POS	O
+4	POS	O
+groups	POS	O
+:	POS	O
+control	POS	O
+,	POS	O
+hydroxytyrosol	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+5mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+5days	POS	O
+/	POS	O
+week	POS	O
+)	POS	O
+,	POS	O
+doxorubicin	POS	O
+(	POS	O
+1mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+week	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+doxorubicin	POS	O
+plus	POS	O
+hydroxytyrosol	POS	O
+.	POS	O
+Cardiac	POS	O
+disturbances	POS	O
+at	POS	O
+the	POS	O
+cellular	POS	O
+and	POS	O
+mitochondrial	POS	O
+level	POS	O
+,	POS	O
+mitochondrial	POS	O
+electron	POS	O
+transport	POS	O
+chain	POS	O
+complexes	POS	O
+I	POS	O
+-	POS	O
+IV	POS	O
+and	POS	O
+apoptosis	POS	O
+-	POS	O
+inducing	POS	O
+factor	POS	O
+,	POS	O
+and	POS	O
+oxidative	POS	O
+stress	POS	O
+markers	POS	O
+have	POS	O
+been	POS	O
+analyzed	POS	O
+.	POS	O
+Hydroxytyrosol	POS	O
+improved	POS	O
+the	POS	O
+cardiac	POS	B-NP
+disturbances	POS	I-NP
+enhanced	POS	O
+by	POS	O
+doxorubicin	POS	O
+by	POS	O
+significantly	POS	O
+reducing	POS	O
+the	POS	O
+percentage	POS	O
+of	POS	O
+altered	POS	O
+mitochondria	POS	O
+and	POS	O
+oxidative	POS	O
+damage	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+hydroxytyrosol	POS	O
+improve	POS	O
+the	POS	O
+mitochondrial	POS	O
+electron	POS	O
+transport	POS	O
+chain	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+demonstrates	POS	O
+that	POS	O
+hydroxytyrosol	POS	O
+protect	POS	O
+rat	POS	O
+heart	POS	O
+damage	POS	O
+provoked	POS	O
+by	POS	O
+doxorubicin	POS	O
+decreasing	POS	O
+oxidative	POS	O
+damage	POS	O
+and	POS	O
+mitochondrial	POS	O
+alterations	POS	O
+.	POS	O
+Amiodarone	POS	O
+-	POS	O
+induced	POS	O
+myxoedema	POS	B-NP
+coma	POS	I-NP
+.	POS	O
+A	POS	O
+62	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+was	POS	O
+found	POS	O
+to	POS	O
+have	POS	O
+bradycardia	POS	B-NP
+,	POS	O
+hypothermia	POS	B-NP
+and	POS	O
+respiratory	POS	B-NP
+failure	POS	I-NP
+3	POS	O
+weeks	POS	O
+after	POS	O
+initiation	POS	O
+of	POS	O
+amiodarone	POS	O
+therapy	POS	O
+for	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+.	POS	O
+Thyroid	POS	O
+-	POS	O
+stimulating	POS	O
+hormone	POS	O
+was	POS	O
+found	POS	O
+to	POS	O
+be	POS	O
+168	POS	O
+uIU	POS	O
+/	POS	O
+mL	POS	O
+(	POS	O
+nl	POS	O
+.	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+-	POS	O
+5	POS	O
+uIU	POS	O
+/	POS	O
+mL	POS	O
+)	POS	O
+and	POS	O
+free	POS	O
+thyroxine	POS	O
+(	POS	O
+FT4	POS	O
+)	POS	O
+was	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+2	POS	O
+ng	POS	O
+/	POS	O
+dL	POS	O
+(	POS	O
+nl	POS	O
+.	POS	O
+0	POS	O
+.	POS	O
+8	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+8	POS	O
+ng	POS	O
+/	POS	O
+dL	POS	O
+)	POS	O
+.	POS	O
+He	POS	O
+received	POS	O
+intravenous	POS	O
+fluids	POS	O
+,	POS	O
+vasopressor	POS	O
+therapy	POS	O
+and	POS	O
+stress	POS	O
+dose	POS	O
+steroids	POS	O
+;	POS	O
+he	POS	O
+was	POS	O
+intubated	POS	O
+and	POS	O
+admitted	POS	O
+to	POS	O
+the	POS	O
+intensive	POS	O
+care	POS	O
+unit	POS	O
+.	POS	O
+He	POS	O
+received	POS	O
+500	POS	O
+ug	POS	O
+of	POS	O
+intravenous	POS	O
+levothyroxine	POS	O
+in	POS	O
+the	POS	O
+first	POS	O
+18	POS	O
+h	POS	O
+of	POS	O
+therapy	POS	O
+,	POS	O
+and	POS	O
+150	POS	O
+ug	POS	O
+intravenous	POS	O
+daily	POS	O
+thereafter	POS	O
+.	POS	O
+Haemodynamic	POS	O
+improvement	POS	O
+,	POS	O
+along	POS	O
+with	POS	O
+complete	POS	O
+recovery	POS	O
+of	POS	O
+mental	POS	O
+status	POS	O
+,	POS	O
+occurred	POS	O
+after	POS	O
+48	POS	O
+h	POS	O
+.	POS	O
+Twelve	POS	O
+hours	POS	O
+after	POS	O
+the	POS	O
+initiation	POS	O
+of	POS	O
+therapy	POS	O
+,	POS	O
+FT4	POS	O
+was	POS	O
+0	POS	O
+.	POS	O
+96	POS	O
+ng	POS	O
+/	POS	O
+dL	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+was	POS	O
+maintained	POS	O
+on	POS	O
+levothyroxine	POS	O
+175	POS	O
+(	POS	O
+g	POS	O
+POorally	POS	O
+daily	POS	O
+.	POS	O
+A	POS	O
+thyroid	POS	O
+ultrasound	POS	O
+showed	POS	O
+diffuse	POS	O
+heterogeneity	POS	O
+.	POS	O
+The	POS	O
+24	POS	O
+hour	POS	O
+excretion	POS	O
+of	POS	O
+iodine	POS	O
+was	POS	O
+3657	POS	O
+(	POS	O
+mcg	POS	O
+(	POS	O
+25	POS	O
+-	POS	O
+756	POS	O
+(	POS	O
+mcg	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+only	POS	O
+two	POS	O
+cases	POS	O
+of	POS	O
+amiodarone	POS	O
+-	POS	O
+induced	POS	O
+myxoedema	POS	B-NP
+coma	POS	I-NP
+in	POS	O
+the	POS	O
+literature	POS	O
+report	POS	O
+patient	POS	O
+death	POS	B-NP
+despite	POS	O
+supportive	POS	O
+therapy	POS	O
+and	POS	O
+thyroid	POS	O
+hormone	POS	O
+replacement	POS	O
+.	POS	O
+This	POS	O
+case	POS	O
+represents	POS	O
+the	POS	O
+most	POS	O
+thoroughly	POS	O
+investigated	POS	O
+case	POS	O
+of	POS	O
+amiodarone	POS	O
+-	POS	O
+induced	POS	O
+myxoedema	POS	B-NP
+coma	POS	I-NP
+with	POS	O
+a	POS	O
+history	POS	O
+significant	POS	O
+for	POS	O
+subclinical	POS	B-NP
+thyroid	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+Use	POS	O
+of	POS	O
+argatroban	POS	O
+and	POS	O
+catheter	POS	O
+-	POS	O
+directed	POS	O
+thrombolysis	POS	B-NP
+with	POS	O
+alteplase	POS	O
+in	POS	O
+an	POS	O
+oncology	POS	O
+patient	POS	O
+with	POS	O
+heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+with	POS	O
+thrombosis	POS	B-NP
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+The	POS	O
+case	POS	O
+of	POS	O
+an	POS	O
+oncology	POS	O
+patient	POS	O
+who	POS	O
+developed	POS	O
+heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+with	POS	O
+thrombosis	POS	B-NP
+(	POS	O
+HITT	POS	B-NP
+)	POS	O
+and	POS	O
+was	POS	O
+treated	POS	O
+with	POS	O
+argatroban	POS	O
+plus	POS	O
+catheter	POS	O
+-	POS	O
+directed	POS	O
+thrombolysis	POS	B-NP
+(	POS	O
+CDT	POS	O
+)	POS	O
+with	POS	O
+alteplase	POS	O
+is	POS	O
+presented	POS	O
+.	POS	O
+SUMMARY	POS	O
+:	POS	O
+A	POS	O
+63	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+Caucasian	POS	O
+man	POS	O
+with	POS	O
+renal	POS	B-NP
+amyloidosis	POS	I-NP
+undergoing	POS	O
+peripheral	POS	O
+blood	POS	O
+stem	POS	O
+cell	POS	O
+collection	POS	O
+for	POS	O
+an	POS	O
+autologous	POS	O
+stem	POS	O
+cell	POS	O
+transplant	POS	O
+developed	POS	O
+extensive	POS	O
+bilateral	POS	B-NP
+upper	POS	I-NP
+-	POS	I-NP
+extremity	POS	I-NP
+deep	POS	I-NP
+venous	POS	I-NP
+thrombosis	POS	I-NP
+(	POS	O
+DVT	POS	B-NP
+)	POS	O
+and	POS	O
+pulmonary	POS	B-NP
+embolism	POS	I-NP
+secondary	POS	O
+to	POS	O
+heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+.	POS	O
+A	POS	O
+continuous	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+infusion	POS	O
+of	POS	O
+argatroban	POS	O
+was	POS	O
+initiated	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+managed	POS	O
+on	POS	O
+the	POS	O
+general	POS	O
+medical	POS	O
+floor	POS	O
+.	POS	O
+After	POS	O
+one	POS	O
+week	POS	O
+of	POS	O
+therapy	POS	O
+,	POS	O
+he	POS	O
+was	POS	O
+transferred	POS	O
+to	POS	O
+the	POS	O
+intensive	POS	O
+care	POS	O
+unit	POS	O
+with	POS	O
+cardiopulmonary	POS	O
+compromise	POS	O
+related	POS	O
+to	POS	O
+superior	POS	B-NP
+vena	POS	I-NP
+cava	POS	I-NP
+(	POS	I-NP
+SVC	POS	I-NP
+)	POS	I-NP
+syndrome	POS	I-NP
+.	POS	O
+A	POS	O
+percutaneous	POS	O
+mechanical	POS	O
+thrombectomy	POS	O
+and	POS	O
+CDT	POS	O
+with	POS	O
+alteplase	POS	O
+were	POS	O
+attempted	POS	O
+,	POS	O
+but	POS	O
+the	POS	O
+procedure	POS	O
+was	POS	O
+aborted	POS	O
+due	POS	O
+to	POS	O
+epistaxis	POS	B-NP
+.	POS	O
+The	POS	O
+epistaxis	POS	B-NP
+resolved	POS	O
+the	POS	O
+next	POS	O
+day	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+restarted	POS	O
+on	POS	O
+argatroban	POS	O
+.	POS	O
+A	POS	O
+second	POS	O
+percutaneous	POS	O
+mechanical	POS	O
+thrombectomy	POS	O
+was	POS	O
+performed	POS	O
+six	POS	O
+days	POS	O
+later	POS	O
+and	POS	O
+resulted	POS	O
+in	POS	O
+partial	POS	O
+revascularization	POS	O
+of	POS	O
+the	POS	O
+SVC	POS	O
+and	POS	O
+central	POS	O
+veins	POS	O
+.	POS	O
+Postthrombectomy	POS	O
+continuous	POS	O
+CDT	POS	O
+with	POS	O
+alteplase	POS	O
+was	POS	O
+commenced	POS	O
+while	POS	O
+argatroban	POS	O
+was	POS	O
+withheld	POS	O
+,	POS	O
+and	POS	O
+complete	POS	O
+patency	POS	O
+of	POS	O
+the	POS	O
+SVC	POS	O
+and	POS	O
+central	POS	O
+veins	POS	O
+was	POS	O
+achieved	POS	O
+after	POS	O
+three	POS	O
+days	POS	O
+of	POS	O
+therapy	POS	O
+.	POS	O
+Alteplase	POS	O
+was	POS	O
+discontinued	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+reinitiated	POS	O
+on	POS	O
+argatroban	POS	O
+;	POS	O
+ultimately	POS	O
+,	POS	O
+he	POS	O
+was	POS	O
+transitioned	POS	O
+to	POS	O
+warfarin	POS	O
+for	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+anticoagulation	POS	O
+.	POS	O
+Although	POS	O
+the	POS	O
+patient	POS	O
+recovered	POS	O
+,	POS	O
+he	POS	O
+experienced	POS	O
+permanent	POS	O
+vision	POS	O
+and	POS	O
+hearing	POS	B-NP
+loss	POS	I-NP
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+end	POS	O
+-	POS	O
+stage	POS	O
+renal	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+A	POS	O
+63	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+with	POS	O
+renal	POS	B-NP
+amyloidosis	POS	I-NP
+and	POS	O
+SVC	POS	B-NP
+syndrome	POS	I-NP
+secondary	POS	O
+to	POS	O
+HITT	POS	B-NP
+was	POS	O
+successfully	POS	O
+treated	POS	O
+with	POS	O
+argatroban	POS	O
+and	POS	O
+CDT	POS	O
+with	POS	O
+alteplase	POS	O
+.	POS	O
+Effects	POS	O
+of	POS	O
+dehydroepiandrosterone	POS	O
+in	POS	O
+amphetamine	POS	O
+-	POS	O
+induced	POS	O
+schizophrenia	POS	B-NP
+models	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+examine	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+dehydroepiandrosterone	POS	O
+(	POS	O
+DHEA	POS	O
+)	POS	O
+on	POS	O
+animal	POS	O
+models	POS	O
+of	POS	O
+schizophrenia	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Seventy	POS	O
+Swiss	POS	O
+albino	POS	O
+female	POS	O
+mice	POS	O
+(	POS	O
+25	POS	O
+-	POS	O
+35	POS	O
+g	POS	O
+)	POS	O
+were	POS	O
+divided	POS	O
+into	POS	O
+4	POS	O
+groups	POS	O
+:	POS	O
+amphetamine	POS	O
+-	POS	O
+free	POS	O
+(	POS	O
+control	POS	O
+)	POS	O
+,	POS	O
+amphetamine	POS	O
+,	POS	O
+50	POS	O
+,	POS	O
+and	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+DHEA	POS	O
+.	POS	O
+The	POS	O
+DHEA	POS	O
+was	POS	O
+administered	POS	O
+intraperitoneally	POS	O
+(	POS	O
+ip	POS	O
+)	POS	O
+for	POS	O
+5	POS	O
+days	POS	O
+.	POS	O
+Amphetamine	POS	O
+(	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+ip	POS	O
+)	POS	O
+induced	POS	O
+hyper	POS	O
+locomotion	POS	O
+,	POS	O
+apomorphine	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+subcutaneously	POS	O
+[	POS	O
+sc	POS	O
+]	POS	O
+)	POS	O
+induced	POS	O
+climbing	POS	O
+,	POS	O
+and	POS	O
+haloperidol	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+sc	POS	O
+)	POS	O
+induced	POS	O
+catalepsy	POS	B-NP
+tests	POS	O
+were	POS	O
+used	POS	O
+as	POS	O
+animal	POS	O
+models	POS	O
+of	POS	O
+schizophrenia	POS	B-NP
+.	POS	O
+The	POS	O
+study	POS	O
+was	POS	O
+conducted	POS	O
+at	POS	O
+the	POS	O
+Animal	POS	O
+Experiment	POS	O
+Laboratories	POS	O
+,	POS	O
+Department	POS	O
+of	POS	O
+Pharmacology	POS	O
+,	POS	O
+Medical	POS	O
+School	POS	O
+,	POS	O
+Eskisehir	POS	O
+Osmangazi	POS	O
+University	POS	O
+,	POS	O
+Eskisehir	POS	O
+,	POS	O
+Turkey	POS	O
+between	POS	O
+March	POS	O
+and	POS	O
+May	POS	O
+2012	POS	O
+.	POS	O
+Statistical	POS	O
+analysis	POS	O
+was	POS	O
+carried	POS	O
+out	POS	O
+using	POS	O
+Kruskal	POS	O
+-	POS	O
+Wallis	POS	O
+test	POS	O
+for	POS	O
+hyper	POS	O
+locomotion	POS	O
+,	POS	O
+and	POS	O
+one	POS	O
+-	POS	O
+way	POS	O
+ANOVA	POS	O
+for	POS	O
+climbing	POS	O
+and	POS	O
+catalepsy	POS	B-NP
+tests	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+In	POS	O
+the	POS	O
+amphetamine	POS	O
+-	POS	O
+induced	POS	O
+locomotion	POS	O
+test	POS	O
+,	POS	O
+there	POS	O
+were	POS	O
+significant	POS	O
+increases	POS	O
+in	POS	O
+all	POS	O
+movements	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+amphetamine	POS	O
+-	POS	O
+free	POS	O
+group	POS	O
+.	POS	O
+Both	POS	O
+DHEA	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+significantly	POS	O
+decreased	POS	O
+all	POS	O
+movements	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+amphetamine	POS	O
+-	POS	O
+induced	POS	O
+locomotion	POS	O
+group	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+difference	POS	O
+between	POS	O
+groups	POS	O
+in	POS	O
+the	POS	O
+haloperidol	POS	O
+-	POS	O
+induced	POS	O
+catalepsy	POS	B-NP
+test	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+significant	POS	O
+difference	POS	O
+between	POS	O
+groups	POS	O
+in	POS	O
+terms	POS	O
+of	POS	O
+total	POS	O
+climbing	POS	O
+time	POS	O
+in	POS	O
+the	POS	O
+apomorphine	POS	O
+-	POS	O
+induced	POS	O
+climbing	POS	O
+test	POS	O
+(	POS	O
+p	POS	O
+>	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+We	POS	O
+observed	POS	O
+that	POS	O
+DHEA	POS	O
+reduced	POS	O
+locomotor	POS	O
+activity	POS	O
+and	POS	O
+increased	POS	O
+catalepsy	POS	B-NP
+at	POS	O
+both	POS	O
+doses	POS	O
+,	POS	O
+while	POS	O
+it	POS	O
+had	POS	O
+no	POS	O
+effect	POS	O
+on	POS	O
+climbing	POS	O
+behavior	POS	O
+.	POS	O
+We	POS	O
+suggest	POS	O
+that	POS	O
+DHEA	POS	O
+displays	POS	O
+typical	POS	O
+neuroleptic	POS	O
+-	POS	O
+like	POS	O
+effects	POS	O
+,	POS	O
+and	POS	O
+may	POS	O
+be	POS	O
+used	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+schizophrenia	POS	B-NP
+.	POS	O
+Availability	POS	O
+of	POS	O
+human	POS	O
+induced	POS	O
+pluripotent	POS	O
+stem	POS	O
+cell	POS	O
+-	POS	O
+derived	POS	O
+cardiomyocytes	POS	O
+in	POS	O
+assessment	POS	O
+of	POS	O
+drug	POS	O
+potential	POS	O
+for	POS	O
+QT	POS	O
+prolongation	POS	O
+.	POS	O
+Field	POS	O
+potential	POS	O
+duration	POS	O
+(	POS	O
+FPD	POS	O
+)	POS	O
+in	POS	O
+human	POS	O
+-	POS	O
+induced	POS	O
+pluripotent	POS	O
+stem	POS	O
+cell	POS	O
+-	POS	O
+derived	POS	O
+cardiomyocytes	POS	O
+(	POS	O
+hiPS	POS	O
+-	POS	O
+CMs	POS	O
+)	POS	O
+,	POS	O
+which	POS	O
+can	POS	O
+express	POS	O
+QT	POS	O
+interval	POS	O
+in	POS	O
+an	POS	O
+electrocardiogram	POS	O
+,	POS	O
+is	POS	O
+reported	POS	O
+to	POS	O
+be	POS	O
+a	POS	O
+useful	POS	O
+tool	POS	O
+to	POS	O
+predict	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+channel	POS	O
+and	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+channel	POS	O
+blocker	POS	O
+effects	POS	O
+on	POS	O
+QT	POS	O
+interval	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+there	POS	O
+is	POS	O
+no	POS	O
+report	POS	O
+showing	POS	O
+that	POS	O
+this	POS	O
+technique	POS	O
+can	POS	O
+be	POS	O
+used	POS	O
+to	POS	O
+predict	POS	O
+multichannel	POS	O
+blocker	POS	O
+potential	POS	O
+for	POS	O
+QT	POS	O
+prolongation	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+is	POS	O
+to	POS	O
+show	POS	O
+that	POS	O
+FPD	POS	O
+from	POS	O
+MEA	POS	O
+(	POS	O
+Multielectrode	POS	O
+array	POS	O
+)	POS	O
+of	POS	O
+hiPS	POS	O
+-	POS	O
+CMs	POS	O
+can	POS	O
+detect	POS	O
+QT	POS	O
+prolongation	POS	O
+induced	POS	O
+by	POS	O
+multichannel	POS	O
+blockers	POS	O
+.	POS	O
+hiPS	POS	O
+-	POS	O
+CMs	POS	O
+were	POS	O
+seeded	POS	O
+onto	POS	O
+MEA	POS	O
+and	POS	O
+FPD	POS	O
+was	POS	O
+measured	POS	O
+for	POS	O
+2min	POS	O
+every	POS	O
+10min	POS	O
+for	POS	O
+30min	POS	O
+after	POS	O
+drug	POS	O
+exposure	POS	O
+for	POS	O
+the	POS	O
+vehicle	POS	O
+and	POS	O
+each	POS	O
+drug	POS	O
+concentration	POS	O
+.	POS	O
+IKr	POS	O
+and	POS	O
+IKs	POS	O
+blockers	POS	O
+concentration	POS	O
+-	POS	O
+dependently	POS	O
+prolonged	POS	O
+corrected	POS	O
+FPD	POS	O
+(	POS	O
+FPDc	POS	O
+)	POS	O
+,	POS	O
+whereas	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+channel	POS	O
+blockers	POS	O
+concentration	POS	O
+-	POS	O
+dependently	POS	O
+shortened	POS	O
+FPDc	POS	O
+.	POS	O
+Also	POS	O
+,	POS	O
+the	POS	O
+multichannel	POS	O
+blockers	POS	O
+Amiodarone	POS	O
+,	POS	O
+Paroxetine	POS	O
+,	POS	O
+Terfenadine	POS	O
+and	POS	O
+Citalopram	POS	O
+prolonged	POS	O
+FPDc	POS	O
+in	POS	O
+a	POS	O
+concentration	POS	O
+dependent	POS	O
+manner	POS	O
+.	POS	O
+Finally	POS	O
+,	POS	O
+the	POS	O
+IKr	POS	O
+blockers	POS	O
+,	POS	O
+Terfenadine	POS	O
+and	POS	O
+Citalopram	POS	O
+,	POS	O
+which	POS	O
+are	POS	O
+reported	POS	O
+to	POS	O
+cause	POS	O
+Torsade	POS	B-NP
+de	POS	I-NP
+Pointes	POS	I-NP
+(	POS	O
+TdP	POS	B-NP
+)	POS	O
+in	POS	O
+clinical	POS	O
+practice	POS	O
+,	POS	O
+produced	POS	O
+early	POS	O
+afterdepolarization	POS	B-NP
+(	POS	O
+EAD	POS	B-NP
+)	POS	O
+.	POS	O
+hiPS	POS	O
+-	POS	O
+CMs	POS	O
+using	POS	O
+MEA	POS	O
+system	POS	O
+and	POS	O
+FPDc	POS	O
+can	POS	O
+predict	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+drug	POS	O
+candidates	POS	O
+on	POS	O
+QT	POS	O
+interval	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+also	POS	O
+shows	POS	O
+that	POS	O
+this	POS	O
+assay	POS	O
+can	POS	O
+help	POS	O
+detect	POS	O
+EAD	POS	B-NP
+for	POS	O
+drugs	POS	O
+with	POS	O
+TdP	POS	B-NP
+potential	POS	O
+.	POS	O
+Dermal	POS	B-NP
+developmental	POS	I-NP
+toxicity	POS	I-NP
+of	POS	O
+N	POS	O
+-	POS	O
+phenylimide	POS	O
+herbicides	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+S	POS	O
+-	POS	O
+53482	POS	O
+and	POS	O
+S	POS	O
+-	POS	O
+23121	POS	O
+are	POS	O
+N	POS	O
+-	POS	O
+phenylimide	POS	O
+herbicides	POS	O
+and	POS	O
+produced	POS	O
+embryolethality	POS	B-NP
+,	POS	O
+teratogenicity	POS	B-NP
+(	POS	O
+mainly	POS	O
+ventricular	POS	B-NP
+septal	POS	I-NP
+defects	POS	I-NP
+and	POS	O
+wavy	POS	O
+ribs	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+growth	POS	B-NP
+retardation	POS	I-NP
+in	POS	O
+rats	POS	O
+in	POS	O
+conventional	POS	O
+oral	POS	O
+developmental	POS	O
+toxicity	POS	B-NP
+studies	POS	O
+.	POS	O
+Our	POS	O
+objective	POS	O
+in	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+investigate	POS	O
+whether	POS	O
+the	POS	O
+compounds	POS	O
+induce	POS	O
+developmental	POS	O
+toxicity	POS	O
+via	POS	O
+the	POS	O
+dermal	POS	O
+route	POS	O
+,	POS	O
+which	POS	O
+is	POS	O
+more	POS	O
+relevant	POS	O
+to	POS	O
+occupational	POS	O
+exposure	POS	O
+,	POS	O
+hence	POS	O
+better	POS	O
+addressing	POS	O
+human	POS	O
+health	POS	O
+risks	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+S	POS	O
+-	POS	O
+53482	POS	O
+was	POS	O
+administered	POS	O
+dermally	POS	O
+to	POS	O
+rats	POS	O
+at	POS	O
+30	POS	O
+,	POS	O
+100	POS	O
+,	POS	O
+and	POS	O
+300	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+during	POS	O
+organogenesis	POS	O
+,	POS	O
+and	POS	O
+S	POS	O
+-	POS	O
+23121	POS	O
+was	POS	O
+administered	POS	O
+at	POS	O
+200	POS	O
+,	POS	O
+400	POS	O
+,	POS	O
+and	POS	O
+800	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+the	POS	O
+maximum	POS	O
+applicable	POS	O
+dose	POS	O
+level	POS	O
+)	POS	O
+.	POS	O
+Fetuses	POS	O
+were	POS	O
+obtained	POS	O
+by	POS	O
+a	POS	O
+Cesarean	POS	O
+section	POS	O
+and	POS	O
+examined	POS	O
+for	POS	O
+external	POS	O
+,	POS	O
+visceral	POS	O
+,	POS	O
+and	POS	O
+skeletal	POS	O
+alterations	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Dermal	POS	O
+exposure	POS	O
+of	POS	O
+rats	POS	O
+to	POS	O
+S	POS	O
+-	POS	O
+53482	POS	O
+at	POS	O
+300	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+produced	POS	O
+patterns	POS	O
+of	POS	O
+developmental	POS	O
+toxicity	POS	B-NP
+similar	POS	O
+to	POS	O
+those	POS	O
+resulting	POS	O
+from	POS	O
+oral	POS	O
+exposure	POS	O
+.	POS	O
+Toxicity	POS	O
+included	POS	O
+embryolethality	POS	B-NP
+,	POS	O
+teratogenicity	POS	B-NP
+,	POS	O
+and	POS	O
+growth	POS	B-NP
+retardation	POS	I-NP
+.	POS	O
+Dermal	POS	O
+administration	POS	O
+of	POS	O
+S	POS	O
+-	POS	O
+23121	POS	O
+at	POS	O
+800	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+resulted	POS	O
+in	POS	O
+an	POS	O
+increased	POS	O
+incidence	POS	O
+of	POS	O
+embryonic	POS	B-NP
+death	POS	I-NP
+and	POS	O
+ventricular	POS	B-NP
+septal	POS	I-NP
+defect	POS	I-NP
+,	POS	O
+but	POS	O
+retarded	POS	O
+fetal	POS	O
+growth	POS	O
+was	POS	O
+not	POS	O
+observed	POS	O
+as	POS	O
+it	POS	O
+was	POS	O
+following	POS	O
+oral	POS	O
+exposure	POS	O
+to	POS	O
+S	POS	O
+-	POS	O
+23121	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Based	POS	O
+on	POS	O
+the	POS	O
+results	POS	O
+,	POS	O
+S	POS	O
+-	POS	O
+53482	POS	O
+and	POS	O
+S	POS	O
+-	POS	O
+23121	POS	O
+were	POS	O
+teratogenic	POS	O
+when	POS	O
+administered	POS	O
+dermally	POS	O
+to	POS	O
+pregnant	POS	O
+rats	POS	O
+as	POS	O
+were	POS	O
+the	POS	O
+compounds	POS	O
+administered	POS	O
+orally	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+investigation	POS	O
+of	POS	O
+the	POS	O
+mechanism	POS	O
+and	POS	O
+its	POS	O
+human	POS	O
+relevancy	POS	O
+become	POS	O
+more	POS	O
+important	POS	O
+.	POS	O
+Rates	POS	O
+of	POS	O
+Renal	POS	O
+Toxicity	POS	O
+in	POS	O
+Cancer	POS	O
+Patients	POS	O
+Receiving	POS	O
+Cisplatin	POS	O
+With	POS	O
+and	POS	O
+Without	POS	O
+Mannitol	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Cisplatin	POS	O
+is	POS	O
+a	POS	O
+widely	POS	O
+used	POS	O
+antineoplastic	POS	O
+.	POS	O
+One	POS	O
+of	POS	O
+the	POS	O
+major	POS	O
+complications	POS	O
+of	POS	O
+cisplatin	POS	O
+use	POS	O
+is	POS	O
+dose	POS	O
+-	POS	O
+limiting	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+There	POS	O
+are	POS	O
+many	POS	O
+strategies	POS	O
+to	POS	O
+prevent	POS	O
+this	POS	O
+toxicity	POS	B-NP
+,	POS	O
+including	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+mannitol	POS	O
+as	POS	O
+a	POS	O
+nephroprotectant	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+hydration	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+We	POS	O
+aimed	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+rates	POS	O
+of	POS	O
+cisplatin	POS	O
+-	POS	O
+induced	POS	O
+nephrotoxicity	POS	B-NP
+in	POS	O
+cancer	POS	B-NP
+patients	POS	O
+receiving	POS	O
+single	POS	O
+-	POS	O
+agent	POS	O
+cisplatin	POS	O
+with	POS	O
+and	POS	O
+without	POS	O
+mannitol	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+This	POS	O
+single	POS	O
+-	POS	O
+center	POS	O
+retrospective	POS	O
+analysis	POS	O
+was	POS	O
+a	POS	O
+quasi	POS	O
+experiment	POS	O
+created	POS	O
+by	POS	O
+the	POS	O
+national	POS	O
+mannitol	POS	O
+shortage	POS	O
+.	POS	O
+Data	POS	O
+were	POS	O
+collected	POS	O
+on	POS	O
+adult	POS	O
+cancer	POS	B-NP
+patients	POS	O
+receiving	POS	O
+single	POS	O
+-	POS	O
+agent	POS	O
+cisplatin	POS	O
+as	POS	O
+an	POS	O
+outpatient	POS	O
+from	POS	O
+January	POS	O
+2011	POS	O
+to	POS	O
+September	POS	O
+2012	POS	O
+.	POS	O
+The	POS	O
+primary	POS	O
+outcome	POS	O
+was	POS	O
+acute	POS	B-NP
+kidney	POS	I-NP
+injury	POS	I-NP
+(	POS	O
+AKI	POS	B-NP
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+We	POS	O
+evaluated	POS	O
+143	POS	O
+patients	POS	O
+who	POS	O
+received	POS	O
+single	POS	O
+-	POS	O
+agent	POS	O
+cisplatin	POS	O
+;	POS	O
+97	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+had	POS	O
+head	POS	B-NP
+and	POS	I-NP
+neck	POS	I-NP
+cancer	POS	I-NP
+as	POS	O
+their	POS	O
+primary	POS	B-NP
+malignancy	POS	I-NP
+.	POS	O
+Patients	POS	O
+who	POS	O
+did	POS	O
+not	POS	O
+receive	POS	O
+mannitol	POS	O
+were	POS	O
+more	POS	O
+likely	POS	O
+to	POS	O
+develop	POS	O
+nephrotoxicity	POS	B-NP
+:	POS	O
+odds	POS	O
+ratio	POS	O
+[	POS	O
+OR	POS	O
+]	POS	O
+=	POS	O
+2	POS	O
+.	POS	O
+646	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+008	POS	O
+,	POS	O
+6	POS	O
+.	POS	O
+944	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+048	POS	O
+)	POS	O
+.	POS	O
+Patients	POS	O
+who	POS	O
+received	POS	O
+the	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+dosing	POS	O
+and	POS	O
+patients	POS	O
+who	POS	O
+had	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+hypertension	POS	B-NP
+also	POS	O
+had	POS	O
+a	POS	O
+higher	POS	O
+likelihood	POS	O
+of	POS	O
+developing	POS	O
+nephrotoxicity	POS	B-NP
+:	POS	O
+OR	POS	O
+=	POS	O
+11	POS	O
+.	POS	O
+494	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+4	POS	O
+.	POS	O
+149	POS	O
+,	POS	O
+32	POS	O
+.	POS	O
+258	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+0001	POS	O
+)	POS	O
+and	POS	O
+OR	POS	O
+=	POS	O
+3	POS	O
+.	POS	O
+219	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+228	POS	O
+,	POS	O
+8	POS	O
+.	POS	O
+439	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+017	POS	O
+)	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+When	POS	O
+limited	POS	O
+quantities	POS	O
+of	POS	O
+mannitol	POS	O
+are	POS	O
+available	POS	O
+,	POS	O
+it	POS	O
+should	POS	O
+preferentially	POS	O
+be	POS	O
+given	POS	O
+to	POS	O
+patients	POS	O
+at	POS	O
+particularly	POS	O
+high	POS	O
+risk	POS	O
+of	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+Our	POS	O
+analysis	POS	O
+suggests	POS	O
+that	POS	O
+those	POS	O
+patients	POS	O
+receiving	POS	O
+the	POS	O
+dosing	POS	O
+schedule	POS	O
+of	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+cisplatin	POS	O
+every	POS	O
+3	POS	O
+weeks	POS	O
+and	POS	O
+those	POS	O
+with	POS	O
+hypertension	POS	B-NP
+are	POS	O
+at	POS	O
+the	POS	O
+greatest	POS	O
+risk	POS	O
+of	POS	O
+nephrotoxicity	POS	B-NP
+and	POS	O
+would	POS	O
+benefit	POS	O
+from	POS	O
+the	POS	O
+addition	POS	O
+of	POS	O
+mannitol	POS	O
+.	POS	O
+Metformin	POS	O
+protects	POS	O
+against	POS	O
+seizures	POS	B-NP
+,	POS	O
+learning	POS	B-NP
+and	POS	I-NP
+memory	POS	I-NP
+impairments	POS	I-NP
+and	POS	O
+oxidative	POS	O
+damage	POS	O
+induced	POS	O
+by	POS	O
+pentylenetetrazole	POS	O
+-	POS	O
+induced	POS	O
+kindling	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+Cognitive	POS	B-NP
+impairment	POS	I-NP
+,	POS	O
+the	POS	O
+most	POS	O
+common	POS	O
+and	POS	O
+severe	POS	O
+comorbidity	POS	O
+of	POS	O
+epilepsy	POS	B-NP
+,	POS	O
+greatly	POS	O
+diminishes	POS	O
+the	POS	O
+quality	POS	O
+of	POS	O
+life	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+current	POS	O
+therapeutic	POS	O
+interventions	POS	O
+for	POS	O
+epilepsy	POS	B-NP
+can	POS	O
+also	POS	O
+cause	POS	O
+untoward	POS	O
+cognitive	POS	O
+effects	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+there	POS	O
+is	POS	O
+an	POS	O
+urgent	POS	O
+need	POS	O
+for	POS	O
+new	POS	O
+kinds	POS	O
+of	POS	O
+agents	POS	O
+targeting	POS	O
+both	POS	O
+seizures	POS	B-NP
+and	POS	O
+cognition	POS	B-NP
+deficits	POS	I-NP
+.	POS	O
+Oxidative	POS	O
+stress	POS	O
+is	POS	O
+considered	POS	O
+to	POS	O
+play	POS	O
+an	POS	O
+important	POS	O
+role	POS	O
+in	POS	O
+epileptogenesis	POS	B-NP
+and	POS	O
+cognitive	POS	B-NP
+deficits	POS	I-NP
+,	POS	O
+and	POS	O
+antioxidants	POS	O
+have	POS	O
+a	POS	O
+putative	POS	O
+antiepileptic	POS	O
+potential	POS	O
+.	POS	O
+Metformin	POS	O
+,	POS	O
+the	POS	O
+most	POS	O
+commonly	POS	O
+prescribed	POS	O
+antidiabetic	POS	O
+oral	POS	O
+drug	POS	O
+,	POS	O
+has	POS	O
+antioxidant	POS	O
+properties	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+was	POS	O
+designed	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+ameliorative	POS	O
+effects	POS	O
+of	POS	O
+metformin	POS	O
+on	POS	O
+seizures	POS	B-NP
+,	POS	O
+cognitive	POS	B-NP
+impairment	POS	I-NP
+and	POS	O
+brain	POS	O
+oxidative	POS	O
+stress	POS	O
+markers	POS	O
+observed	POS	O
+in	POS	O
+pentylenetetrazole	POS	O
+-	POS	O
+induced	POS	O
+kindling	POS	O
+animals	POS	O
+.	POS	O
+Male	POS	O
+C57BL	POS	O
+/	POS	O
+6	POS	O
+mice	POS	O
+were	POS	O
+administered	POS	O
+with	POS	O
+subconvulsive	POS	O
+dose	POS	O
+of	POS	O
+pentylenetetrazole	POS	O
+(	POS	O
+37	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+every	POS	O
+other	POS	O
+day	POS	O
+for	POS	O
+14	POS	O
+injections	POS	O
+.	POS	O
+Metformin	POS	O
+was	POS	O
+injected	POS	O
+intraperitoneally	POS	O
+in	POS	O
+dose	POS	O
+of	POS	O
+200mg	POS	O
+/	POS	O
+kg	POS	O
+along	POS	O
+with	POS	O
+alternate	POS	O
+-	POS	O
+day	POS	O
+PTZ	POS	O
+.	POS	O
+We	POS	O
+found	POS	O
+that	POS	O
+metformin	POS	O
+suppressed	POS	O
+the	POS	O
+progression	POS	O
+of	POS	O
+kindling	POS	O
+,	POS	O
+ameliorated	POS	O
+the	POS	O
+cognitive	POS	B-NP
+impairment	POS	I-NP
+and	POS	O
+decreased	POS	O
+brain	POS	O
+oxidative	POS	O
+stress	POS	O
+.	POS	O
+Thus	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+concluded	POS	O
+that	POS	O
+metformin	POS	O
+may	POS	O
+be	POS	O
+a	POS	O
+potential	POS	O
+agent	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+epilepsy	POS	B-NP
+as	POS	O
+well	POS	O
+as	POS	O
+a	POS	O
+protective	POS	O
+medicine	POS	O
+against	POS	O
+cognitive	POS	B-NP
+impairment	POS	I-NP
+induced	POS	O
+by	POS	O
+seizures	POS	B-NP
+.	POS	O
+P53	POS	O
+inhibition	POS	O
+exacerbates	POS	O
+late	POS	O
+-	POS	O
+stage	POS	O
+anthracycline	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+AIMS	POS	O
+:	POS	O
+Doxorubicin	POS	O
+(	POS	O
+DOX	POS	O
+)	POS	O
+is	POS	O
+an	POS	O
+effective	POS	O
+anti	POS	O
+-	POS	O
+cancer	POS	O
+therapeutic	POS	O
+,	POS	O
+but	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+both	POS	O
+acute	POS	O
+and	POS	O
+late	POS	O
+-	POS	O
+stage	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+Children	POS	O
+are	POS	O
+particularly	POS	O
+sensitive	POS	O
+to	POS	O
+DOX	POS	O
+-	POS	O
+induced	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+.	POS	O
+Here	POS	O
+,	POS	O
+the	POS	O
+impact	POS	O
+of	POS	O
+p53	POS	O
+inhibition	POS	O
+on	POS	O
+acute	POS	O
+vs	POS	O
+.	POS	O
+late	POS	O
+-	POS	O
+stage	POS	O
+DOX	POS	O
+cardiotoxicity	POS	B-NP
+was	POS	O
+examined	POS	O
+in	POS	O
+a	POS	O
+juvenile	POS	O
+model	POS	O
+.	POS	O
+METHODS	POS	O
+AND	POS	O
+RESULTS	POS	O
+:	POS	O
+Two	POS	O
+-	POS	O
+week	POS	O
+-	POS	O
+old	POS	O
+MHC	POS	O
+-	POS	O
+CB7	POS	O
+mice	POS	O
+(	POS	O
+which	POS	O
+express	POS	O
+dominant	POS	O
+-	POS	O
+interfering	POS	O
+p53	POS	O
+in	POS	O
+cardiomyocytes	POS	O
+)	POS	O
+and	POS	O
+their	POS	O
+non	POS	O
+-	POS	O
+transgenic	POS	O
+(	POS	O
+NON	POS	O
+-	POS	O
+TXG	POS	O
+)	POS	O
+littermates	POS	O
+received	POS	O
+weekly	POS	O
+DOX	POS	O
+injections	POS	O
+for	POS	O
+5	POS	O
+weeks	POS	O
+(	POS	O
+25	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+cumulative	POS	O
+dose	POS	O
+)	POS	O
+.	POS	O
+One	POS	O
+week	POS	O
+after	POS	O
+the	POS	O
+last	POS	O
+DOX	POS	O
+treatment	POS	O
+(	POS	O
+acute	POS	O
+stage	POS	O
+)	POS	O
+,	POS	O
+MHC	POS	O
+-	POS	O
+CB7	POS	O
+mice	POS	O
+exhibited	POS	O
+improved	POS	O
+cardiac	POS	O
+function	POS	O
+and	POS	O
+lower	POS	O
+levels	POS	O
+of	POS	O
+cardiomyocyte	POS	O
+apoptosis	POS	O
+when	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+NON	POS	O
+-	POS	O
+TXG	POS	O
+mice	POS	O
+.	POS	O
+Surprisingly	POS	O
+,	POS	O
+by	POS	O
+13	POS	O
+weeks	POS	O
+following	POS	O
+the	POS	O
+last	POS	O
+DOX	POS	O
+treatment	POS	O
+(	POS	O
+late	POS	O
+stage	POS	O
+)	POS	O
+,	POS	O
+MHC	POS	O
+-	POS	O
+CB7	POS	O
+exhibited	POS	O
+a	POS	O
+progressive	POS	O
+decrease	POS	O
+in	POS	O
+cardiac	POS	O
+function	POS	O
+and	POS	O
+higher	POS	O
+rates	POS	O
+of	POS	O
+cardiomyocyte	POS	O
+apoptosis	POS	O
+when	POS	O
+compared	POS	O
+with	POS	O
+NON	POS	O
+-	POS	O
+TXG	POS	O
+mice	POS	O
+.	POS	O
+p53	POS	O
+inhibition	POS	O
+blocked	POS	O
+transient	POS	O
+DOX	POS	O
+-	POS	O
+induced	POS	O
+STAT3	POS	O
+activation	POS	O
+in	POS	O
+MHC	POS	O
+-	POS	O
+CB7	POS	O
+mice	POS	O
+,	POS	O
+which	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+enhanced	POS	O
+induction	POS	O
+of	POS	O
+the	POS	O
+DNA	POS	O
+repair	POS	O
+proteins	POS	O
+Ku70	POS	O
+and	POS	O
+Ku80	POS	O
+.	POS	O
+Mice	POS	O
+with	POS	O
+cardiomyocyte	POS	O
+-	POS	O
+restricted	POS	O
+deletion	POS	O
+of	POS	O
+STAT3	POS	O
+exhibited	POS	O
+worse	POS	O
+cardiac	POS	O
+function	POS	O
+,	POS	O
+higher	POS	O
+levels	POS	O
+of	POS	O
+cardiomyocyte	POS	O
+apoptosis	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+greater	POS	O
+induction	POS	O
+of	POS	O
+Ku70	POS	O
+and	POS	O
+Ku80	POS	O
+in	POS	O
+response	POS	O
+to	POS	O
+DOX	POS	O
+treatment	POS	O
+during	POS	O
+the	POS	O
+acute	POS	O
+stage	POS	O
+when	POS	O
+compared	POS	O
+with	POS	O
+control	POS	O
+animals	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+These	POS	O
+data	POS	O
+support	POS	O
+a	POS	O
+model	POS	O
+wherein	POS	O
+a	POS	O
+p53	POS	O
+-	POS	O
+dependent	POS	O
+cardioprotective	POS	O
+pathway	POS	O
+,	POS	O
+mediated	POS	O
+via	POS	O
+STAT3	POS	O
+activation	POS	O
+,	POS	O
+mitigates	POS	O
+DOX	POS	O
+-	POS	O
+induced	POS	O
+myocardial	POS	O
+stress	POS	O
+during	POS	O
+drug	POS	O
+delivery	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+these	POS	O
+data	POS	O
+suggest	POS	O
+an	POS	O
+explanation	POS	O
+as	POS	O
+to	POS	O
+how	POS	O
+p53	POS	O
+inhibition	POS	O
+can	POS	O
+result	POS	O
+in	POS	O
+cardioprotection	POS	O
+during	POS	O
+drug	POS	O
+treatment	POS	O
+and	POS	O
+,	POS	O
+paradoxically	POS	O
+,	POS	O
+enhanced	POS	O
+cardiotoxicity	POS	B-NP
+long	POS	O
+after	POS	O
+the	POS	O
+cessation	POS	O
+of	POS	O
+drug	POS	O
+treatment	POS	O
+.	POS	O
+Metronidazole	POS	O
+-	POS	O
+induced	POS	O
+encephalopathy	POS	B-NP
+:	POS	O
+an	POS	O
+uncommon	POS	O
+scenario	POS	O
+.	POS	O
+Metronidazole	POS	O
+can	POS	O
+produce	POS	O
+neurological	POS	B-NP
+complications	POS	I-NP
+although	POS	O
+it	POS	O
+is	POS	O
+not	POS	O
+a	POS	O
+common	POS	O
+scenario	POS	O
+.	POS	O
+We	POS	O
+present	POS	O
+a	POS	O
+case	POS	O
+where	POS	O
+a	POS	O
+patient	POS	O
+developed	POS	O
+features	POS	O
+of	POS	O
+encephalopathy	POS	B-NP
+following	POS	O
+prolonged	POS	O
+metronidazole	POS	O
+intake	POS	O
+.	POS	O
+Magnetic	POS	O
+resonance	POS	O
+imaging	POS	O
+(	POS	O
+MRI	POS	O
+)	POS	O
+brain	POS	O
+showed	POS	O
+abnormal	POS	O
+signal	POS	O
+intensity	POS	O
+involving	POS	O
+both	POS	O
+dentate	POS	O
+nuclei	POS	O
+of	POS	O
+cerebellum	POS	O
+and	POS	O
+splenium	POS	O
+of	POS	O
+corpus	POS	O
+callosum	POS	O
+.	POS	O
+The	POS	O
+diagnosis	POS	O
+of	POS	O
+metronidazole	POS	O
+toxicity	POS	B-NP
+was	POS	O
+made	POS	O
+by	POS	O
+the	POS	O
+MRI	POS	O
+findings	POS	O
+and	POS	O
+supported	POS	O
+clinically	POS	O
+.	POS	O
+Aconitine	POS	O
+-	POS	O
+induced	POS	O
+Ca2	POS	O
++	POS	O
+overload	POS	O
+causes	POS	O
+arrhythmia	POS	B-NP
+and	POS	O
+triggers	POS	O
+apoptosis	POS	O
+through	POS	O
+p38	POS	O
+MAPK	POS	O
+signaling	POS	O
+pathway	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+Aconitine	POS	O
+is	POS	O
+a	POS	O
+major	POS	O
+bioactive	POS	O
+diterpenoid	POS	O
+alkaloid	POS	O
+with	POS	O
+high	POS	O
+content	POS	O
+derived	POS	O
+from	POS	O
+herbal	POS	O
+aconitum	POS	O
+plants	POS	O
+.	POS	O
+Emerging	POS	O
+evidence	POS	O
+indicates	POS	O
+that	POS	O
+voltage	POS	O
+-	POS	O
+dependent	POS	O
+Na	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+channels	POS	O
+have	POS	O
+pivotal	POS	O
+roles	POS	O
+in	POS	O
+the	POS	O
+cardiotoxicity	POS	B-NP
+of	POS	O
+aconitine	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+no	POS	O
+reports	POS	O
+are	POS	O
+available	POS	O
+on	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+in	POS	O
+aconitine	POS	B-NP
+poisoning	POS	I-NP
+.	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+,	POS	O
+we	POS	O
+explored	POS	O
+the	POS	O
+importance	POS	O
+of	POS	O
+pathological	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+signaling	POS	O
+in	POS	O
+aconitine	POS	O
+poisoning	POS	B-NP
+in	POS	O
+vitro	POS	O
+and	POS	O
+in	POS	O
+vivo	POS	O
+.	POS	O
+We	POS	O
+found	POS	O
+that	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+overload	POS	O
+lead	POS	O
+to	POS	O
+accelerated	POS	O
+beating	POS	O
+rhythm	POS	O
+in	POS	O
+adult	POS	O
+rat	POS	O
+ventricular	POS	O
+myocytes	POS	O
+and	POS	O
+caused	POS	O
+arrhythmia	POS	B-NP
+in	POS	O
+conscious	POS	O
+freely	POS	O
+moving	POS	O
+rats	POS	O
+.	POS	O
+To	POS	O
+investigate	POS	O
+effects	POS	O
+of	POS	O
+aconitine	POS	O
+on	POS	O
+myocardial	POS	B-NP
+injury	POS	I-NP
+,	POS	O
+we	POS	O
+performed	POS	O
+cytotoxicity	POS	B-NP
+assay	POS	O
+in	POS	O
+neonatal	POS	O
+rat	POS	O
+ventricular	POS	O
+myocytes	POS	O
+(	POS	O
+NRVMs	POS	O
+)	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+measured	POS	O
+lactate	POS	O
+dehydrogenase	POS	O
+level	POS	O
+in	POS	O
+the	POS	O
+culture	POS	O
+medium	POS	O
+of	POS	O
+NRVMs	POS	O
+and	POS	O
+activities	POS	O
+of	POS	O
+serum	POS	O
+cardiac	POS	O
+enzymes	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+showed	POS	O
+that	POS	O
+aconitine	POS	O
+resulted	POS	O
+in	POS	O
+myocardial	POS	B-NP
+injury	POS	I-NP
+and	POS	O
+reduced	POS	O
+NRVMs	POS	O
+viability	POS	O
+dose	POS	O
+-	POS	O
+dependently	POS	O
+.	POS	O
+To	POS	O
+confirm	POS	O
+the	POS	O
+pro	POS	O
+-	POS	O
+apoptotic	POS	O
+effects	POS	O
+,	POS	O
+we	POS	O
+performed	POS	O
+flow	POS	O
+cytometric	POS	O
+detection	POS	O
+,	POS	O
+cardiac	POS	O
+histology	POS	O
+,	POS	O
+transmission	POS	O
+electron	POS	O
+microscopy	POS	O
+and	POS	O
+terminal	POS	O
+deoxynucleotidyl	POS	O
+transferase	POS	O
+-	POS	O
+mediated	POS	O
+dUTP	POS	O
+-	POS	O
+biotin	POS	O
+nick	POS	O
+end	POS	O
+labeling	POS	O
+assay	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+showed	POS	O
+that	POS	O
+aconitine	POS	O
+stimulated	POS	O
+apoptosis	POS	O
+time	POS	O
+-	POS	O
+dependently	POS	O
+.	POS	O
+The	POS	O
+expression	POS	O
+analysis	POS	O
+of	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+handling	POS	O
+proteins	POS	O
+demonstrated	POS	O
+that	POS	O
+aconitine	POS	O
+promoted	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+overload	POS	O
+through	POS	O
+the	POS	O
+expression	POS	O
+regulation	POS	O
+of	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+handling	POS	O
+proteins	POS	O
+.	POS	O
+The	POS	O
+expression	POS	O
+analysis	POS	O
+of	POS	O
+apoptosis	POS	O
+-	POS	O
+related	POS	O
+proteins	POS	O
+revealed	POS	O
+that	POS	O
+pro	POS	O
+-	POS	O
+apoptotic	POS	O
+protein	POS	O
+expression	POS	O
+was	POS	O
+upregulated	POS	O
+,	POS	O
+and	POS	O
+anti	POS	O
+-	POS	O
+apoptotic	POS	O
+protein	POS	O
+BCL	POS	O
+-	POS	O
+2	POS	O
+expression	POS	O
+was	POS	O
+downregulated	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+increased	POS	O
+phosphorylation	POS	O
+of	POS	O
+MAPK	POS	O
+family	POS	O
+members	POS	O
+,	POS	O
+especially	POS	O
+the	POS	O
+P	POS	O
+-	POS	O
+P38	POS	O
+/	POS	O
+P38	POS	O
+ratio	POS	O
+was	POS	O
+found	POS	O
+in	POS	O
+cardiac	POS	O
+tissues	POS	O
+.	POS	O
+Hence	POS	O
+,	POS	O
+our	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+aconitine	POS	O
+significantly	POS	O
+aggravates	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+overload	POS	O
+and	POS	O
+causes	POS	O
+arrhythmia	POS	B-NP
+and	POS	O
+finally	POS	O
+promotes	POS	O
+apoptotic	POS	O
+development	POS	O
+via	POS	O
+phosphorylation	POS	O
+of	POS	O
+P38	POS	O
+mitogen	POS	O
+-	POS	O
+activated	POS	O
+protein	POS	O
+kinase	POS	O
+.	POS	O
+Chronic	POS	O
+treatment	POS	O
+with	POS	O
+metformin	POS	O
+suppresses	POS	O
+toll	POS	O
+-	POS	O
+like	POS	O
+receptor	POS	O
+4	POS	O
+signaling	POS	O
+and	POS	O
+attenuates	POS	O
+left	POS	O
+ventricular	POS	B-NP
+dysfunction	POS	I-NP
+following	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+Acute	POS	O
+treatment	POS	O
+with	POS	O
+metformin	POS	O
+has	POS	O
+a	POS	O
+protective	POS	O
+effect	POS	O
+in	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+by	POS	O
+suppression	POS	O
+of	POS	O
+inflammatory	POS	O
+responses	POS	O
+due	POS	O
+to	POS	O
+activation	POS	O
+of	POS	O
+AMP	POS	O
+-	POS	O
+activated	POS	O
+protein	POS	O
+kinase	POS	O
+(	POS	O
+AMPK	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+,	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+chronic	POS	O
+pre	POS	O
+-	POS	O
+treatment	POS	O
+with	POS	O
+metformin	POS	O
+on	POS	O
+cardiac	POS	B-NP
+dysfunction	POS	I-NP
+and	POS	O
+toll	POS	O
+-	POS	O
+like	POS	O
+receptor	POS	O
+4	POS	O
+(	POS	O
+TLR4	POS	O
+)	POS	O
+activities	POS	O
+following	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+and	POS	O
+their	POS	O
+relation	POS	O
+with	POS	O
+AMPK	POS	O
+were	POS	O
+assessed	POS	O
+.	POS	O
+Male	POS	O
+Wistar	POS	O
+rats	POS	O
+were	POS	O
+randomly	POS	O
+assigned	POS	O
+to	POS	O
+one	POS	O
+of	POS	O
+5	POS	O
+groups	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+6	POS	O
+)	POS	O
+:	POS	O
+normal	POS	O
+control	POS	O
+and	POS	O
+groups	POS	O
+were	POS	O
+injected	POS	O
+isoproterenol	POS	O
+after	POS	O
+chronic	POS	O
+pre	POS	O
+-	POS	O
+treatment	POS	O
+with	POS	O
+0	POS	O
+,	POS	O
+25	POS	O
+,	POS	O
+50	POS	O
+,	POS	O
+or	POS	O
+100mg	POS	O
+/	POS	O
+kg	POS	O
+of	POS	O
+metformin	POS	O
+twice	POS	O
+daily	POS	O
+for	POS	O
+14	POS	O
+days	POS	O
+.	POS	O
+Isoproterenol	POS	O
+(	POS	O
+100mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+was	POS	O
+injected	POS	O
+subcutaneously	POS	O
+on	POS	O
+the	POS	O
+13th	POS	O
+and	POS	O
+14th	POS	O
+days	POS	O
+to	POS	O
+induce	POS	O
+acute	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+Isoproterenol	POS	O
+alone	POS	O
+decreased	POS	O
+left	POS	O
+ventricular	POS	O
+systolic	POS	O
+pressure	POS	O
+and	POS	O
+myocardial	POS	O
+contractility	POS	O
+indexed	POS	O
+as	POS	O
+LVdp	POS	O
+/	POS	O
+dtmax	POS	O
+and	POS	O
+LVdp	POS	O
+/	POS	O
+dtmin	POS	O
+.	POS	O
+The	POS	O
+left	POS	O
+ventricular	POS	B-NP
+dysfunction	POS	I-NP
+was	POS	O
+significantly	POS	O
+lower	POS	O
+in	POS	O
+the	POS	O
+groups	POS	O
+treated	POS	O
+with	POS	O
+25	POS	O
+and	POS	O
+50mg	POS	O
+/	POS	O
+kg	POS	O
+of	POS	O
+metformin	POS	O
+.	POS	O
+Metfromin	POS	O
+markedly	POS	O
+lowered	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+elevation	POS	O
+in	POS	O
+the	POS	O
+levels	POS	O
+of	POS	O
+TLR4	POS	O
+mRNA	POS	O
+,	POS	O
+myeloid	POS	O
+differentiation	POS	O
+protein	POS	O
+88	POS	O
+(	POS	O
+MyD88	POS	O
+)	POS	O
+,	POS	O
+tumor	POS	B-NP
+necrosis	POS	I-NP
+factor	POS	O
+-	POS	O
+alpha	POS	O
+(	POS	O
+TNF	POS	O
+-	POS	O
+a	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+interleukin	POS	O
+6	POS	O
+(	POS	O
+IL	POS	O
+-	POS	O
+6	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+heart	POS	O
+tissues	POS	O
+.	POS	O
+Similar	POS	O
+changes	POS	O
+were	POS	O
+also	POS	O
+seen	POS	O
+in	POS	O
+the	POS	O
+serum	POS	O
+levels	POS	O
+of	POS	O
+TNF	POS	O
+-	POS	O
+a	POS	O
+and	POS	O
+IL	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+lower	POS	O
+doses	POS	O
+of	POS	O
+25	POS	O
+and	POS	O
+50mg	POS	O
+/	POS	O
+kg	POS	O
+were	POS	O
+more	POS	O
+effective	POS	O
+than	POS	O
+100mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+Phosphorylated	POS	O
+AMPKa	POS	O
+(	POS	O
+p	POS	O
+-	POS	O
+AMPK	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+myocardium	POS	O
+was	POS	O
+significantly	POS	O
+elevated	POS	O
+by	POS	O
+25mg	POS	O
+/	POS	O
+kg	POS	O
+of	POS	O
+metformin	POS	O
+,	POS	O
+slightly	POS	O
+by	POS	O
+50mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+by	POS	O
+100mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+Chronic	POS	O
+pre	POS	O
+-	POS	O
+treatment	POS	O
+with	POS	O
+metformin	POS	O
+reduces	POS	O
+post	POS	O
+-	POS	O
+myocardial	POS	O
+infarction	POS	O
+cardiac	POS	O
+dysfunction	POS	O
+and	POS	O
+suppresses	POS	O
+inflammatory	POS	O
+responses	POS	O
+,	POS	O
+possibly	POS	O
+through	POS	O
+inhibition	POS	O
+of	POS	O
+TLR4	POS	O
+activities	POS	O
+.	POS	O
+This	POS	O
+mechanism	POS	O
+can	POS	O
+be	POS	O
+considered	POS	O
+as	POS	O
+a	POS	O
+target	POS	O
+to	POS	O
+protect	POS	O
+infarcted	POS	O
+myocardium	POS	O
+.	POS	O
+Unusual	POS	O
+complications	POS	O
+of	POS	O
+antithyroid	POS	O
+drug	POS	O
+therapy	POS	O
+:	POS	O
+four	POS	O
+case	POS	O
+reports	POS	O
+and	POS	O
+review	POS	O
+of	POS	O
+literature	POS	O
+.	POS	O
+Two	POS	O
+cases	POS	O
+of	POS	O
+propylthiouracil	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+acute	POS	I-NP
+hepatitis	POS	I-NP
+,	POS	O
+one	POS	O
+case	POS	O
+of	POS	O
+fatal	POS	O
+methimazole	POS	O
+-	POS	O
+associated	POS	O
+hepatocellular	POS	B-NP
+necrosis	POS	I-NP
+and	POS	O
+one	POS	O
+case	POS	O
+of	POS	O
+propylthiouracil	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+lupus	POS	I-NP
+-	POS	I-NP
+like	POS	I-NP
+syndrome	POS	I-NP
+are	POS	O
+described	POS	O
+.	POS	O
+The	POS	O
+literature	POS	O
+related	POS	O
+to	POS	O
+antithyroid	POS	O
+drug	POS	O
+side	POS	O
+effects	POS	O
+and	POS	O
+the	POS	O
+mechanisms	POS	O
+for	POS	O
+their	POS	O
+occurrence	POS	O
+are	POS	O
+reviewed	POS	O
+and	POS	O
+the	POS	O
+efficacy	POS	O
+and	POS	O
+complications	POS	O
+of	POS	O
+thyroidectomy	POS	O
+and	POS	O
+radioiodine	POS	O
+compared	POS	O
+to	POS	O
+those	POS	O
+of	POS	O
+antithyroid	POS	O
+drugs	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+concluded	POS	O
+that	POS	O
+in	POS	O
+most	POS	O
+circumstances	POS	O
+131I	POS	O
+is	POS	O
+the	POS	O
+therapy	POS	O
+of	POS	O
+choice	POS	O
+for	POS	O
+hyperthyroidism	POS	B-NP
+.	POS	O
+Neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+induced	POS	O
+by	POS	O
+combination	POS	O
+therapy	POS	O
+with	POS	O
+tetrabenazine	POS	O
+and	POS	O
+tiapride	POS	O
+in	POS	O
+a	POS	O
+Japanese	POS	O
+patient	POS	O
+with	POS	O
+Huntington	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+at	POS	O
+the	POS	O
+terminal	POS	O
+stage	POS	O
+of	POS	O
+recurrent	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+We	POS	O
+herein	POS	O
+describe	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+an	POS	O
+81	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+Japanese	POS	O
+woman	POS	O
+with	POS	O
+neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+that	POS	O
+occurred	POS	O
+36	POS	O
+days	POS	O
+after	POS	O
+the	POS	O
+initiation	POS	O
+of	POS	O
+combination	POS	O
+therapy	POS	O
+with	POS	O
+tiapride	POS	O
+(	POS	O
+75	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+and	POS	O
+tetrabenazine	POS	O
+(	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+for	POS	O
+Huntington	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+The	POS	O
+patient	POS	O
+had	POS	O
+been	POS	O
+treated	POS	O
+with	POS	O
+tiapride	POS	O
+or	POS	O
+tetrabenazine	POS	O
+alone	POS	O
+without	POS	O
+any	POS	O
+adverse	POS	O
+effects	POS	O
+before	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+the	POS	O
+combination	POS	O
+therapy	POS	O
+.	POS	O
+She	POS	O
+also	POS	O
+had	POS	O
+advanced	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+when	POS	O
+the	POS	O
+combination	POS	O
+therapy	POS	O
+was	POS	O
+initiated	POS	O
+.	POS	O
+To	POS	O
+the	POS	O
+best	POS	O
+of	POS	O
+our	POS	O
+knowledge	POS	O
+,	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+due	POS	O
+to	POS	O
+combination	POS	O
+therapy	POS	O
+with	POS	O
+tetrabenazine	POS	O
+and	POS	O
+tiapride	POS	O
+has	POS	O
+not	POS	O
+been	POS	O
+previously	POS	O
+reported	POS	O
+.	POS	O
+Tetrabenazine	POS	O
+should	POS	O
+be	POS	O
+administered	POS	O
+very	POS	O
+carefully	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+other	POS	O
+neuroleptic	POS	O
+drugs	POS	O
+,	POS	O
+particularly	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+a	POS	O
+worsening	POS	O
+general	POS	O
+condition	POS	O
+.	POS	O
+A	POS	O
+metoprolol	POS	O
+-	POS	O
+terbinafine	POS	O
+combination	POS	O
+induced	POS	O
+bradycardia	POS	B-NP
+.	POS	O
+To	POS	O
+report	POS	O
+a	POS	O
+sinus	POS	B-NP
+bradycardia	POS	I-NP
+induced	POS	O
+by	POS	O
+metoprolol	POS	O
+and	POS	O
+terbinafine	POS	O
+drug	POS	O
+-	POS	O
+drug	POS	O
+interaction	POS	O
+and	POS	O
+its	POS	O
+management	POS	O
+.	POS	O
+A	POS	O
+63	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+Caucasian	POS	O
+man	POS	O
+on	POS	O
+metoprolol	POS	O
+200	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+for	POS	O
+stable	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+was	POS	O
+prescribed	POS	O
+a	POS	O
+90	POS	O
+-	POS	O
+day	POS	O
+course	POS	O
+of	POS	O
+oral	POS	O
+terbinafine	POS	O
+250	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+for	POS	O
+onychomycosis	POS	B-NP
+.	POS	O
+On	POS	O
+the	POS	O
+49th	POS	O
+day	POS	O
+of	POS	O
+terbinafine	POS	O
+therapy	POS	O
+,	POS	O
+he	POS	O
+was	POS	O
+brought	POS	O
+to	POS	O
+the	POS	O
+emergency	POS	O
+room	POS	O
+for	POS	O
+a	POS	O
+decrease	POS	O
+of	POS	O
+his	POS	O
+global	POS	O
+health	POS	O
+status	POS	O
+,	POS	O
+confusion	POS	B-NP
+and	POS	O
+falls	POS	O
+.	POS	O
+The	POS	O
+electrocardiogram	POS	O
+revealed	POS	O
+a	POS	O
+37	POS	O
+beats	POS	O
+/	POS	O
+min	POS	O
+sinus	POS	O
+bradycardia	POS	B-NP
+.	POS	O
+A	POS	O
+score	POS	O
+of	POS	O
+7	POS	O
+on	POS	O
+the	POS	O
+Naranjo	POS	O
+adverse	POS	O
+drug	POS	O
+reaction	POS	O
+probability	POS	O
+scale	POS	O
+indicates	POS	O
+a	POS	O
+probable	POS	O
+relationship	POS	O
+between	POS	O
+the	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+sinus	POS	O
+bradycardia	POS	B-NP
+and	POS	O
+the	POS	O
+drug	POS	O
+interaction	POS	O
+between	POS	O
+metoprolol	POS	O
+and	POS	O
+terbinafine	POS	O
+.	POS	O
+The	POS	O
+heart	POS	O
+rate	POS	O
+ameliorated	POS	O
+first	POS	O
+with	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+the	POS	O
+dose	POS	O
+of	POS	O
+metoprolol	POS	O
+.	POS	O
+It	POS	O
+was	POS	O
+subsequently	POS	O
+changed	POS	O
+to	POS	O
+bisoprolol	POS	O
+and	POS	O
+the	POS	O
+heart	POS	O
+rate	POS	O
+remained	POS	O
+normal	POS	O
+.	POS	O
+By	POS	O
+inhibiting	POS	O
+the	POS	O
+cytochrome	POS	O
+P450	POS	O
+2D6	POS	O
+,	POS	O
+terbinafine	POS	O
+had	POS	O
+decreased	POS	O
+metoprolol	POS	O
+'	POS	O
+s	POS	O
+clearance	POS	O
+,	POS	O
+leading	POS	O
+in	POS	O
+metoprolol	POS	O
+accumulation	POS	O
+which	POS	O
+has	POS	O
+resulted	POS	O
+in	POS	O
+clinically	POS	O
+significant	POS	O
+sinus	POS	B-NP
+bradycardia	POS	I-NP
+.	POS	O
+Optochiasmatic	POS	B-NP
+and	POS	O
+peripheral	POS	B-NP
+neuropathy	POS	I-NP
+due	POS	O
+to	POS	O
+ethambutol	POS	O
+overtreatment	POS	O
+.	POS	O
+Ethambutol	POS	O
+is	POS	O
+known	POS	O
+to	POS	O
+cause	POS	O
+optic	POS	B-NP
+neuropathy	POS	I-NP
+and	POS	O
+,	POS	O
+more	POS	O
+rarely	POS	O
+,	POS	O
+axonal	POS	B-NP
+polyneuropathy	POS	I-NP
+.	POS	O
+We	POS	O
+characterize	POS	O
+the	POS	O
+clinical	POS	O
+,	POS	O
+neurophysiological	POS	O
+,	POS	O
+and	POS	O
+neuroimaging	POS	O
+findings	POS	O
+in	POS	O
+a	POS	O
+72	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+who	POS	O
+developed	POS	O
+visual	POS	B-NP
+loss	POS	I-NP
+and	POS	O
+paresthesias	POS	B-NP
+after	POS	O
+11	POS	O
+weeks	POS	O
+of	POS	O
+exposure	POS	O
+to	POS	O
+a	POS	O
+supratherapeutic	POS	O
+dose	POS	O
+of	POS	O
+ethambutol	POS	O
+.	POS	O
+This	POS	O
+case	POS	O
+demonstrates	POS	O
+the	POS	O
+selective	POS	O
+vulnerability	POS	O
+of	POS	O
+the	POS	O
+anterior	POS	O
+visual	POS	O
+pathways	POS	O
+and	POS	O
+peripheral	POS	O
+nerves	POS	O
+to	POS	O
+ethambutol	POS	O
+toxicity	POS	B-NP
+.	POS	O
+Testosterone	POS	O
+ameliorates	POS	O
+streptozotocin	POS	O
+-	POS	O
+induced	POS	O
+memory	POS	B-NP
+impairment	POS	I-NP
+in	POS	O
+male	POS	O
+rats	POS	O
+.	POS	O
+AIM	POS	O
+:	POS	O
+To	POS	O
+study	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+testosterone	POS	O
+on	POS	O
+streptozotocin	POS	O
+(	POS	O
+STZ	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+memory	POS	B-NP
+impairment	POS	I-NP
+in	POS	O
+male	POS	O
+rats	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Adult	POS	O
+male	POS	O
+Wistar	POS	O
+rats	POS	O
+were	POS	O
+intracerebroventricularly	POS	O
+(	POS	O
+icv	POS	O
+)	POS	O
+infused	POS	O
+with	POS	O
+STZ	POS	O
+(	POS	O
+750	POS	O
+ug	POS	O
+)	POS	O
+on	POS	O
+d	POS	O
+1	POS	O
+and	POS	O
+d	POS	O
+3	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+passive	POS	O
+avoidance	POS	O
+task	POS	O
+was	POS	O
+assessed	POS	O
+2	POS	O
+weeks	POS	O
+after	POS	O
+the	POS	O
+first	POS	O
+injection	POS	O
+of	POS	O
+STZ	POS	O
+.	POS	O
+Castration	POS	O
+surgery	POS	O
+was	POS	O
+performed	POS	O
+in	POS	O
+another	POS	O
+group	POS	O
+of	POS	O
+rats	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+passive	POS	O
+avoidance	POS	O
+task	POS	O
+was	POS	O
+assessed	POS	O
+4	POS	O
+weeks	POS	O
+after	POS	O
+the	POS	O
+operation	POS	O
+.	POS	O
+Testosterone	POS	O
+(	POS	O
+1	POS	O
+mg	POS	O
+.	POS	O
+kg	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+.	POS	O
+d	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+,	POS	O
+sc	POS	O
+)	POS	O
+,	POS	O
+the	POS	O
+androgen	POS	O
+receptor	POS	O
+antagonist	POS	O
+flutamide	POS	O
+(	POS	O
+10	POS	O
+mg	POS	O
+.	POS	O
+kg	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+.	POS	O
+d	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+,	POS	O
+ip	POS	O
+)	POS	O
+,	POS	O
+the	POS	O
+estrogen	POS	O
+receptor	POS	O
+antagonist	POS	O
+tamoxifen	POS	O
+(	POS	O
+1	POS	O
+mg	POS	O
+.	POS	O
+kg	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+.	POS	O
+d	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+,	POS	O
+ip	POS	O
+)	POS	O
+or	POS	O
+the	POS	O
+aromatase	POS	O
+inhibitor	POS	O
+letrozole	POS	O
+(	POS	O
+4	POS	O
+mg	POS	O
+.	POS	O
+kg	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+.	POS	O
+d	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+,	POS	O
+ip	POS	O
+)	POS	O
+were	POS	O
+administered	POS	O
+for	POS	O
+6	POS	O
+d	POS	O
+after	POS	O
+the	POS	O
+first	POS	O
+injection	POS	O
+of	POS	O
+STZ	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+STZ	POS	O
+administration	POS	O
+and	POS	O
+castration	POS	O
+markedly	POS	O
+decreased	POS	O
+both	POS	O
+STL1	POS	O
+(	POS	O
+the	POS	O
+short	POS	O
+memory	POS	O
+)	POS	O
+and	POS	O
+STL2	POS	O
+(	POS	O
+the	POS	O
+long	POS	O
+memory	POS	O
+)	POS	O
+in	POS	O
+passive	POS	O
+avoidance	POS	O
+tests	POS	O
+.	POS	O
+Testosterone	POS	O
+replacement	POS	O
+almost	POS	O
+restored	POS	O
+the	POS	O
+STL1	POS	O
+and	POS	O
+STL2	POS	O
+in	POS	O
+castrated	POS	O
+rats	POS	O
+,	POS	O
+and	POS	O
+significantly	POS	O
+prolonged	POS	O
+the	POS	O
+STL1	POS	O
+and	POS	O
+STL2	POS	O
+in	POS	O
+STZ	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+.	POS	O
+Administration	POS	O
+of	POS	O
+flutamide	POS	O
+,	POS	O
+letrozole	POS	O
+or	POS	O
+tamoxifen	POS	O
+significantly	POS	O
+impaired	POS	O
+the	POS	O
+memory	POS	O
+in	POS	O
+intact	POS	O
+rats	POS	O
+,	POS	O
+and	POS	O
+significantly	POS	O
+attenuated	POS	O
+the	POS	O
+testosterone	POS	O
+replacement	POS	O
+in	POS	O
+improving	POS	O
+STZ	POS	O
+-	POS	O
+and	POS	O
+castration	POS	O
+-	POS	O
+induced	POS	O
+memory	POS	B-NP
+impairment	POS	I-NP
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Testosterone	POS	O
+administration	POS	O
+ameliorates	POS	O
+STZ	POS	O
+-	POS	O
+and	POS	O
+castration	POS	O
+-	POS	O
+induced	POS	O
+memory	POS	B-NP
+impairment	POS	I-NP
+in	POS	O
+male	POS	O
+Wistar	POS	O
+rats	POS	O
+.	POS	O
+Behavioral	POS	O
+and	POS	O
+neurochemical	POS	O
+studies	POS	O
+in	POS	O
+mice	POS	O
+pretreated	POS	O
+with	POS	O
+garcinielliptone	POS	O
+FC	POS	O
+in	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+.	POS	O
+Garcinielliptone	POS	O
+FC	POS	O
+(	POS	O
+GFC	POS	O
+)	POS	O
+isolated	POS	O
+from	POS	O
+hexanic	POS	O
+fraction	POS	O
+seed	POS	O
+extract	POS	O
+of	POS	O
+species	POS	O
+Platonia	POS	O
+insignis	POS	O
+Mart	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+widely	POS	O
+used	POS	O
+in	POS	O
+folk	POS	O
+medicine	POS	O
+to	POS	O
+treat	POS	O
+skin	POS	B-NP
+diseases	POS	I-NP
+in	POS	O
+both	POS	O
+humans	POS	O
+and	POS	O
+animals	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+the	POS	O
+seed	POS	O
+decoction	POS	O
+has	POS	O
+been	POS	O
+used	POS	O
+to	POS	O
+treat	POS	O
+diarrheas	POS	B-NP
+and	POS	O
+inflammatory	POS	B-NP
+diseases	POS	I-NP
+.	POS	O
+However	POS	O
+,	POS	O
+there	POS	O
+is	POS	O
+no	POS	O
+research	POS	O
+on	POS	O
+GFC	POS	O
+effects	POS	O
+in	POS	O
+the	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+of	POS	O
+rodents	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+aimed	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+GFC	POS	O
+effects	POS	O
+at	POS	O
+doses	POS	O
+of	POS	O
+25	POS	O
+,	POS	O
+50	POS	O
+or	POS	O
+75	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+on	POS	O
+seizure	POS	B-NP
+parameters	POS	O
+to	POS	O
+determine	POS	O
+their	POS	O
+anticonvulsant	POS	O
+activity	POS	O
+and	POS	O
+its	POS	O
+effects	POS	O
+on	POS	O
+amino	POS	O
+acid	POS	O
+(	POS	O
+r	POS	O
+-	POS	O
+aminobutyric	POS	O
+acid	POS	O
+(	POS	O
+GABA	POS	O
+)	POS	O
+,	POS	O
+glutamine	POS	O
+,	POS	O
+aspartate	POS	O
+and	POS	O
+glutathione	POS	O
+)	POS	O
+levels	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+on	POS	O
+acetylcholinesterase	POS	O
+(	POS	O
+AChE	POS	O
+)	POS	O
+activity	POS	O
+in	POS	O
+mice	POS	O
+hippocampus	POS	O
+after	POS	O
+seizures	POS	B-NP
+.	POS	O
+GFC	POS	O
+produced	POS	O
+an	POS	O
+increased	POS	O
+latency	POS	O
+to	POS	O
+first	POS	O
+seizure	POS	B-NP
+,	POS	O
+at	POS	O
+doses	POS	O
+25mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+20	POS	O
+.	POS	O
+12	POS	O
++	POS	O
+2	POS	O
+.	POS	O
+20	POS	O
+min	POS	O
+)	POS	O
+,	POS	O
+50mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+20	POS	O
+.	POS	O
+95	POS	O
++	POS	O
+2	POS	O
+.	POS	O
+21	POS	O
+min	POS	O
+)	POS	O
+or	POS	O
+75	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+23	POS	O
+.	POS	O
+43	POS	O
++	POS	O
+1	POS	O
+.	POS	O
+99	POS	O
+min	POS	O
+)	POS	O
+when	POS	O
+compared	POS	O
+with	POS	O
+seized	POS	O
+mice	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+GABA	POS	O
+content	POS	O
+of	POS	O
+mice	POS	O
+hippocampus	POS	O
+treated	POS	O
+with	POS	O
+GFC75	POS	O
+plus	POS	O
+P400	POS	O
+showed	POS	O
+an	POS	O
+increase	POS	O
+of	POS	O
+46	POS	O
+.	POS	O
+90	POS	O
+%	POS	O
+when	POS	O
+compared	POS	O
+with	POS	O
+seized	POS	O
+mice	POS	O
+.	POS	O
+In	POS	O
+aspartate	POS	O
+,	POS	O
+glutamine	POS	O
+and	POS	O
+glutamate	POS	O
+levels	POS	O
+detected	POS	O
+a	POS	O
+decrease	POS	O
+of	POS	O
+5	POS	O
+.	POS	O
+21	POS	O
+%	POS	O
+,	POS	O
+13	POS	O
+.	POS	O
+55	POS	O
+%	POS	O
+and	POS	O
+21	POS	O
+.	POS	O
+80	POS	O
+%	POS	O
+,	POS	O
+respectively	POS	O
+in	POS	O
+mice	POS	O
+hippocampus	POS	O
+treated	POS	O
+with	POS	O
+GFC75	POS	O
+plus	POS	O
+P400	POS	O
+when	POS	O
+compared	POS	O
+with	POS	O
+seized	POS	O
+mice	POS	O
+.	POS	O
+Hippocampus	POS	O
+mice	POS	O
+treated	POS	O
+with	POS	O
+GFC75	POS	O
+plus	POS	O
+P400	POS	O
+showed	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+AChE	POS	O
+activity	POS	O
+(	POS	O
+63	POS	O
+.	POS	O
+30	POS	O
+%	POS	O
+)	POS	O
+when	POS	O
+compared	POS	O
+with	POS	O
+seized	POS	O
+mice	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+GFC	POS	O
+can	POS	O
+exert	POS	O
+anticonvulsant	POS	O
+activity	POS	O
+and	POS	O
+reduce	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+installation	POS	O
+of	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+,	POS	O
+as	POS	O
+demonstrated	POS	O
+by	POS	O
+increase	POS	O
+in	POS	O
+latency	POS	O
+to	POS	O
+first	POS	O
+seizure	POS	B-NP
+and	POS	O
+decrease	POS	O
+in	POS	O
+mortality	POS	O
+rate	POS	O
+of	POS	O
+animals	POS	O
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+our	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+GFC	POS	O
+may	POS	O
+influence	POS	O
+in	POS	O
+epileptogenesis	POS	B-NP
+and	POS	O
+promote	POS	O
+anticonvulsant	POS	O
+actions	POS	O
+in	POS	O
+pilocarpine	POS	O
+model	POS	O
+by	POS	O
+modulating	POS	O
+the	POS	O
+GABA	POS	O
+and	POS	O
+glutamate	POS	O
+contents	POS	O
+and	POS	O
+of	POS	O
+AChE	POS	O
+activity	POS	O
+in	POS	O
+seized	POS	O
+mice	POS	O
+hippocampus	POS	O
+.	POS	O
+This	POS	O
+compound	POS	O
+may	POS	O
+be	POS	O
+useful	POS	O
+to	POS	O
+produce	POS	O
+neuronal	POS	O
+protection	POS	O
+and	POS	O
+it	POS	O
+can	POS	O
+be	POS	O
+considered	POS	O
+as	POS	O
+an	POS	O
+anticonvulsant	POS	O
+agent	POS	O
+.	POS	O
+Standard	POS	O
+operating	POS	O
+procedures	POS	O
+for	POS	O
+antibiotic	POS	O
+therapy	POS	O
+and	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+acute	POS	B-NP
+kidney	POS	I-NP
+injury	POS	I-NP
+:	POS	O
+a	POS	O
+prospective	POS	O
+,	POS	O
+clinical	POS	O
+,	POS	O
+non	POS	O
+-	POS	O
+interventional	POS	O
+,	POS	O
+observational	POS	O
+study	POS	O
+.	POS	O
+INTRODUCTION	POS	O
+:	POS	O
+Acute	POS	B-NP
+kidney	POS	I-NP
+injury	POS	I-NP
+(	POS	O
+AKI	POS	B-NP
+)	POS	O
+occurs	POS	O
+in	POS	O
+7	POS	O
+%	POS	O
+of	POS	O
+hospitalized	POS	O
+and	POS	O
+66	POS	O
+%	POS	O
+of	POS	O
+Intensive	POS	O
+Care	POS	O
+Unit	POS	O
+(	POS	O
+ICU	POS	O
+)	POS	O
+patients	POS	O
+.	POS	O
+It	POS	O
+increases	POS	O
+mortality	POS	O
+,	POS	O
+hospital	POS	O
+length	POS	O
+of	POS	O
+stay	POS	O
+,	POS	O
+and	POS	O
+costs	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+investigate	POS	O
+,	POS	O
+whether	POS	O
+there	POS	O
+is	POS	O
+an	POS	O
+association	POS	O
+between	POS	O
+adherence	POS	O
+to	POS	O
+guidelines	POS	O
+(	POS	O
+standard	POS	O
+operating	POS	O
+procedures	POS	O
+(	POS	O
+SOP	POS	O
+)	POS	O
+)	POS	O
+for	POS	O
+potentially	POS	O
+nephrotoxic	POS	B-NP
+antibiotics	POS	O
+and	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+AKI	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+This	POS	O
+study	POS	O
+was	POS	O
+carried	POS	O
+out	POS	O
+as	POS	O
+a	POS	O
+prospective	POS	O
+,	POS	O
+clinical	POS	O
+,	POS	O
+non	POS	O
+-	POS	O
+interventional	POS	O
+,	POS	O
+observational	POS	O
+study	POS	O
+.	POS	O
+Data	POS	O
+collection	POS	O
+was	POS	O
+performed	POS	O
+over	POS	O
+a	POS	O
+total	POS	O
+of	POS	O
+170	POS	O
+days	POS	O
+in	POS	O
+three	POS	O
+ICUs	POS	O
+at	POS	O
+Charite	POS	O
+-	POS	O
+Universitaetsmedizin	POS	O
+Berlin	POS	O
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+675	POS	O
+patients	POS	O
+were	POS	O
+included	POS	O
+;	POS	O
+163	POS	O
+of	POS	O
+these	POS	O
+had	POS	O
+therapy	POS	O
+with	POS	O
+vancomycin	POS	O
+,	POS	O
+gentamicin	POS	O
+,	POS	O
+or	POS	O
+tobramycin	POS	O
+;	POS	O
+were	POS	O
+>	POS	O
+18	POS	O
+years	POS	O
+;	POS	O
+and	POS	O
+treated	POS	O
+in	POS	O
+the	POS	O
+ICU	POS	O
+for	POS	O
+>	POS	O
+24	POS	O
+hours	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+an	POS	O
+adherence	POS	O
+to	POS	O
+SOP	POS	O
+>	POS	O
+70	POS	O
+%	POS	O
+were	POS	O
+classified	POS	O
+into	POS	O
+the	POS	O
+high	POS	O
+adherence	POS	O
+group	POS	O
+(	POS	O
+HAG	POS	O
+)	POS	O
+and	POS	O
+patients	POS	O
+with	POS	O
+an	POS	O
+adherence	POS	O
+of	POS	O
+<	POS	O
+70	POS	O
+%	POS	O
+into	POS	O
+the	POS	O
+low	POS	O
+adherence	POS	O
+group	POS	O
+(	POS	O
+LAG	POS	O
+)	POS	O
+.	POS	O
+AKI	POS	B-NP
+was	POS	O
+defined	POS	O
+according	POS	O
+to	POS	O
+RIFLE	POS	O
+criteria	POS	O
+.	POS	O
+Adherence	POS	O
+to	POS	O
+SOPs	POS	O
+was	POS	O
+evaluated	POS	O
+by	POS	O
+retrospective	POS	O
+expert	POS	O
+audit	POS	O
+.	POS	O
+Development	POS	O
+of	POS	O
+AKI	POS	B-NP
+was	POS	O
+compared	POS	O
+between	POS	O
+groups	POS	O
+with	POS	O
+exact	POS	O
+Chi2	POS	O
+-	POS	O
+test	POS	O
+and	POS	O
+multivariate	POS	O
+logistic	POS	O
+regression	POS	O
+analysis	POS	O
+(	POS	O
+two	POS	O
+-	POS	O
+sided	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+LAG	POS	O
+consisted	POS	O
+of	POS	O
+75	POS	O
+patients	POS	O
+(	POS	O
+46	POS	O
+%	POS	O
+)	POS	O
+versus	POS	O
+88	POS	O
+HAG	POS	O
+patients	POS	O
+(	POS	O
+54	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+AKI	POS	B-NP
+occurred	POS	O
+significantly	POS	O
+more	POS	O
+often	POS	O
+in	POS	O
+LAG	POS	O
+with	POS	O
+36	POS	O
+%	POS	O
+versus	POS	O
+21	POS	O
+%	POS	O
+in	POS	O
+HAG	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+035	POS	O
+)	POS	O
+.	POS	O
+Basic	POS	O
+characteristics	POS	O
+were	POS	O
+comparable	POS	O
+,	POS	O
+except	POS	O
+an	POS	O
+increased	POS	O
+rate	POS	O
+of	POS	O
+soft	POS	B-NP
+tissue	POS	I-NP
+infections	POS	I-NP
+in	POS	O
+LAG	POS	O
+.	POS	O
+Multivariate	POS	O
+analysis	POS	O
+revealed	POS	O
+an	POS	O
+odds	POS	O
+ratio	POS	O
+of	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+fold	POS	O
+for	POS	O
+LAG	POS	O
+to	POS	O
+develop	POS	O
+AKI	POS	B-NP
+compared	POS	O
+with	POS	O
+HAG	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+1	POS	O
+.	POS	O
+195	POS	O
+to	POS	O
+5	POS	O
+.	POS	O
+124	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+039	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Low	POS	O
+adherence	POS	O
+to	POS	O
+SOPs	POS	O
+for	POS	O
+potentially	POS	O
+nephrotoxic	POS	B-NP
+antibiotics	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+a	POS	O
+higher	POS	O
+occurrence	POS	O
+of	POS	O
+AKI	POS	B-NP
+.	POS	O
+TRIAL	POS	O
+REGISTRATION	POS	O
+:	POS	O
+Current	POS	O
+Controlled	POS	O
+Trials	POS	O
+ISRCTN54598675	POS	O
+.	POS	O
+Registered	POS	O
+17	POS	O
+August	POS	O
+2007	POS	O
+.	POS	O
+Rhabdomyolysis	POS	B-NP
+in	POS	O
+a	POS	O
+hepatitis	POS	B-NP
+C	POS	I-NP
+virus	POS	I-NP
+infected	POS	I-NP
+patient	POS	O
+treated	POS	O
+with	POS	O
+telaprevir	POS	O
+and	POS	O
+simvastatin	POS	O
+.	POS	O
+A	POS	O
+46	POS	O
+-	POS	O
+year	POS	O
+old	POS	O
+man	POS	O
+with	POS	O
+a	POS	O
+chronic	POS	B-NP
+hepatitis	POS	I-NP
+C	POS	I-NP
+virus	POS	I-NP
+infection	POS	I-NP
+received	POS	O
+triple	POS	O
+therapy	POS	O
+with	POS	O
+ribavirin	POS	O
+,	POS	O
+pegylated	POS	O
+interferon	POS	O
+and	POS	O
+telaprevir	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+also	POS	O
+received	POS	O
+simvastatin	POS	O
+.	POS	O
+One	POS	O
+month	POS	O
+after	POS	O
+starting	POS	O
+the	POS	O
+antiviral	POS	O
+therapy	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+admitted	POS	O
+to	POS	O
+the	POS	O
+hospital	POS	O
+because	POS	O
+he	POS	O
+developed	POS	O
+rhabdomyolysis	POS	B-NP
+.	POS	O
+At	POS	O
+admission	POS	O
+simvastatin	POS	O
+and	POS	O
+all	POS	O
+antiviral	POS	O
+drugs	POS	O
+were	POS	O
+discontinued	POS	O
+because	POS	O
+toxicity	POS	B-NP
+due	POS	O
+to	POS	O
+a	POS	O
+drug	POS	O
+-	POS	O
+drug	POS	O
+interaction	POS	O
+was	POS	O
+suspected	POS	O
+.	POS	O
+The	POS	O
+creatine	POS	O
+kinase	POS	O
+peaked	POS	O
+at	POS	O
+62	POS	O
+,	POS	O
+246	POS	O
+IU	POS	O
+/	POS	O
+L	POS	O
+and	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+treated	POS	O
+with	POS	O
+intravenous	POS	O
+normal	POS	O
+saline	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+renal	POS	O
+function	POS	O
+remained	POS	O
+unaffected	POS	B-NP
+.	POS	O
+Fourteen	POS	O
+days	POS	O
+after	POS	O
+hospitalization	POS	O
+,	POS	O
+creatine	POS	O
+kinase	POS	O
+level	POS	O
+had	POS	O
+returned	POS	O
+to	POS	O
+230	POS	O
+IU	POS	O
+/	POS	O
+L	POS	O
+and	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+discharged	POS	O
+.	POS	O
+Telaprevir	POS	O
+was	POS	O
+considered	POS	O
+the	POS	O
+probable	POS	O
+causative	POS	O
+agent	POS	O
+of	POS	O
+an	POS	O
+interaction	POS	O
+with	POS	O
+simvastatin	POS	O
+according	POS	O
+to	POS	O
+the	POS	O
+Drug	POS	O
+Interaction	POS	O
+Probability	POS	O
+Scale	POS	O
+.	POS	O
+The	POS	O
+interaction	POS	O
+is	POS	O
+due	POS	O
+to	POS	O
+inhibition	POS	O
+of	POS	O
+CYP3A4	POS	O
+-	POS	O
+mediated	POS	O
+simvastatin	POS	O
+clearance	POS	O
+.	POS	O
+Simvastatin	POS	O
+plasma	POS	O
+concentration	POS	O
+increased	POS	O
+30	POS	O
+times	POS	O
+in	POS	O
+this	POS	O
+patient	POS	O
+and	POS	O
+statin	POS	O
+induced	POS	O
+muscle	POS	B-NP
+toxicity	POS	I-NP
+is	POS	O
+related	POS	O
+to	POS	O
+the	POS	O
+concentration	POS	O
+of	POS	O
+the	POS	O
+statin	POS	O
+in	POS	O
+blood	POS	O
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+with	POS	O
+this	POS	O
+case	POS	O
+we	POS	O
+illustrate	POS	O
+that	POS	O
+telaprevir	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+statins	POS	O
+are	POS	O
+susceptible	POS	O
+to	POS	O
+clinical	POS	O
+relevant	POS	O
+drug	POS	O
+-	POS	O
+drug	POS	O
+interactions	POS	O
+.	POS	O
+Combination	POS	O
+of	POS	O
+bortezomib	POS	O
+,	POS	O
+thalidomide	POS	O
+,	POS	O
+and	POS	O
+dexamethasone	POS	O
+(	POS	O
+VTD	POS	O
+)	POS	O
+as	POS	O
+a	POS	O
+consolidation	POS	O
+therapy	POS	O
+after	POS	O
+autologous	POS	O
+stem	POS	O
+cell	POS	O
+transplantation	POS	O
+for	POS	O
+symptomatic	POS	O
+multiple	POS	O
+myeloma	POS	B-NP
+in	POS	O
+Japanese	POS	O
+patients	POS	O
+.	POS	O
+Consolidation	POS	O
+therapy	POS	O
+for	POS	O
+patients	POS	O
+with	POS	O
+multiple	POS	B-NP
+myeloma	POS	I-NP
+(	POS	O
+MM	POS	B-NP
+)	POS	O
+has	POS	O
+been	POS	O
+widely	POS	O
+adopted	POS	O
+to	POS	O
+improve	POS	O
+treatment	POS	O
+response	POS	O
+following	POS	O
+autologous	POS	O
+stem	POS	O
+cell	POS	O
+transplantation	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+,	POS	O
+we	POS	O
+retrospectively	POS	O
+analyzed	POS	O
+the	POS	O
+safety	POS	O
+and	POS	O
+efficacy	POS	O
+of	POS	O
+combination	POS	O
+regimen	POS	O
+of	POS	O
+bortezomib	POS	O
+,	POS	O
+thalidomide	POS	O
+,	POS	O
+and	POS	O
+dexamethasone	POS	O
+(	POS	O
+VTD	POS	O
+)	POS	O
+as	POS	O
+consolidation	POS	O
+therapy	POS	O
+in	POS	O
+24	POS	O
+Japanese	POS	O
+patients	POS	O
+with	POS	O
+newly	POS	O
+diagnosed	POS	O
+MM	POS	B-NP
+.	POS	O
+VTD	POS	B-NP
+consisted	POS	O
+of	POS	O
+bortezomib	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+and	POS	O
+dexamethasone	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+40	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+on	POS	O
+days	POS	O
+1	POS	O
+,	POS	O
+8	POS	O
+,	POS	O
+15	POS	O
+,	POS	O
+and	POS	O
+22	POS	O
+of	POS	O
+a	POS	O
+35	POS	O
+-	POS	O
+day	POS	O
+cycle	POS	O
+,	POS	O
+with	POS	O
+daily	POS	O
+oral	POS	O
+thalidomide	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+.	POS	O
+Grade	POS	O
+3	POS	O
+-	POS	O
+4	POS	O
+neutropenia	POS	B-NP
+and	POS	O
+thrombocytopenia	POS	B-NP
+were	POS	O
+documented	POS	O
+in	POS	O
+four	POS	O
+and	POS	O
+three	POS	O
+patients	POS	O
+(	POS	O
+17	POS	O
+and	POS	O
+13	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+but	POS	O
+drug	POS	O
+dose	POS	O
+reduction	POS	O
+due	POS	O
+to	POS	O
+cytopenia	POS	B-NP
+was	POS	O
+not	POS	O
+required	POS	O
+in	POS	O
+any	POS	O
+case	POS	O
+.	POS	O
+Peripheral	POS	B-NP
+neuropathy	POS	I-NP
+was	POS	O
+common	POS	O
+(	POS	O
+63	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+but	POS	O
+severe	POS	O
+grade	POS	O
+3	POS	O
+-	POS	O
+4	POS	O
+peripheral	POS	B-NP
+neuropathy	POS	I-NP
+was	POS	O
+not	POS	O
+observed	POS	O
+.	POS	O
+Very	POS	O
+good	POS	O
+partial	POS	O
+response	POS	O
+or	POS	O
+better	POS	O
+response	POS	O
+(	POS	O
+>	POS	O
+VGPR	POS	O
+)	POS	O
+rates	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+consolidation	POS	O
+therapy	POS	O
+were	POS	O
+54	POS	O
+and	POS	O
+79	POS	O
+%	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Patients	POS	O
+had	POS	O
+a	POS	O
+significant	POS	O
+probability	POS	O
+of	POS	O
+improving	POS	O
+from	POS	O
+<	POS	O
+VGPR	POS	O
+before	POS	O
+consolidation	POS	O
+therapy	POS	O
+to	POS	O
+>	POS	O
+VGPR	POS	O
+after	POS	O
+consolidation	POS	O
+therapy	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+041	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+VTD	POS	O
+regimen	POS	O
+may	POS	O
+be	POS	O
+safe	POS	O
+and	POS	O
+effective	POS	O
+as	POS	O
+a	POS	O
+consolidation	POS	O
+therapy	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+MM	POS	B-NP
+in	POS	O
+Japanese	POS	O
+population	POS	O
+.	POS	O
+Conversion	POS	O
+to	POS	O
+sirolimus	POS	O
+ameliorates	POS	O
+cyclosporine	POS	O
+-	POS	O
+induced	POS	O
+nephropathy	POS	B-NP
+in	POS	O
+the	POS	O
+rat	POS	O
+:	POS	O
+focus	POS	O
+on	POS	O
+serum	POS	O
+,	POS	O
+urine	POS	O
+,	POS	O
+gene	POS	O
+,	POS	O
+and	POS	O
+protein	POS	O
+renal	POS	O
+expression	POS	O
+biomarkers	POS	O
+.	POS	O
+Protocols	POS	O
+of	POS	O
+conversion	POS	O
+from	POS	O
+cyclosporin	POS	O
+A	POS	O
+(	POS	O
+CsA	POS	O
+)	POS	O
+to	POS	O
+sirolimus	POS	O
+(	POS	O
+SRL	POS	O
+)	POS	O
+have	POS	O
+been	POS	O
+widely	POS	O
+used	POS	O
+in	POS	O
+immunotherapy	POS	O
+after	POS	O
+transplantation	POS	O
+to	POS	O
+prevent	POS	O
+CsA	POS	O
+-	POS	O
+induced	POS	O
+nephropathy	POS	B-NP
+,	POS	O
+but	POS	O
+the	POS	O
+molecular	POS	O
+mechanisms	POS	O
+underlying	POS	O
+these	POS	O
+protocols	POS	O
+remain	POS	O
+nuclear	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+aimed	POS	O
+to	POS	O
+identify	POS	O
+the	POS	O
+molecular	POS	O
+pathways	POS	O
+and	POS	O
+putative	POS	O
+biomarkers	POS	O
+of	POS	O
+CsA	POS	O
+-	POS	O
+to	POS	O
+-	POS	O
+SRL	POS	O
+conversion	POS	O
+in	POS	O
+a	POS	O
+rat	POS	O
+model	POS	O
+.	POS	O
+Four	POS	O
+animal	POS	O
+groups	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+6	POS	O
+)	POS	O
+were	POS	O
+tested	POS	O
+during	POS	O
+9	POS	O
+weeks	POS	O
+:	POS	O
+control	POS	O
+,	POS	O
+CsA	POS	O
+,	POS	O
+SRL	POS	O
+,	POS	O
+and	POS	O
+conversion	POS	O
+(	POS	O
+CsA	POS	O
+for	POS	O
+3	POS	O
+weeks	POS	O
+followed	POS	O
+by	POS	O
+SRL	POS	O
+for	POS	O
+6	POS	O
+weeks	POS	O
+)	POS	O
+.	POS	O
+Classical	POS	O
+and	POS	O
+emergent	POS	O
+serum	POS	O
+,	POS	O
+urinary	POS	O
+,	POS	O
+and	POS	O
+kidney	POS	O
+tissue	POS	O
+(	POS	O
+gene	POS	O
+and	POS	O
+protein	POS	O
+expression	POS	O
+)	POS	O
+markers	POS	O
+were	POS	O
+assessed	POS	O
+.	POS	O
+Renal	POS	B-NP
+lesions	POS	I-NP
+were	POS	O
+analyzed	POS	O
+in	POS	O
+hematoxylin	POS	O
+and	POS	O
+eosin	POS	O
+,	POS	O
+periodic	POS	O
+acid	POS	O
+-	POS	O
+Schiff	POS	O
+,	POS	O
+and	POS	O
+Masson	POS	O
+'	POS	O
+s	POS	O
+trichrome	POS	O
+stains	POS	O
+.	POS	O
+SRL	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+presented	POS	O
+proteinuria	POS	B-NP
+and	POS	O
+NGAL	POS	O
+(	POS	O
+serum	POS	O
+and	POS	O
+urinary	POS	O
+)	POS	O
+as	POS	O
+the	POS	O
+best	POS	O
+markers	POS	O
+of	POS	O
+renal	POS	B-NP
+impairment	POS	I-NP
+.	POS	O
+Short	POS	O
+CsA	POS	O
+treatment	POS	O
+presented	POS	O
+slight	POS	O
+or	POS	O
+even	POS	O
+absent	POS	O
+kidney	POS	O
+lesions	POS	O
+and	POS	O
+TGF	POS	O
+-	POS	O
+b	POS	O
+,	POS	O
+NF	POS	O
+-	POS	O
+kb	POS	O
+,	POS	O
+mTOR	POS	O
+,	POS	O
+PCNA	POS	O
+,	POS	O
+TP53	POS	O
+,	POS	O
+KIM	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+and	POS	O
+CTGF	POS	O
+as	POS	O
+relevant	POS	O
+gene	POS	O
+and	POS	O
+protein	POS	O
+changes	POS	O
+.	POS	O
+Prolonged	POS	O
+CsA	POS	O
+exposure	POS	O
+aggravated	POS	O
+renal	POS	B-NP
+damage	POS	I-NP
+,	POS	O
+without	POS	O
+clear	POS	O
+changes	POS	O
+on	POS	O
+the	POS	O
+traditional	POS	O
+markers	POS	O
+,	POS	O
+but	POS	O
+with	POS	O
+changes	POS	O
+in	POS	O
+serums	POS	O
+TGF	POS	O
+-	POS	O
+b	POS	O
+and	POS	O
+IL	POS	O
+-	POS	O
+7	POS	O
+,	POS	O
+TBARs	POS	O
+clearance	POS	O
+,	POS	O
+and	POS	O
+kidney	POS	O
+TGF	POS	O
+-	POS	O
+b	POS	O
+and	POS	O
+mTOR	POS	O
+.	POS	O
+Conversion	POS	O
+to	POS	O
+SRL	POS	O
+prevented	POS	O
+CsA	POS	O
+-	POS	O
+induced	POS	O
+renal	POS	O
+damage	POS	O
+evolution	POS	O
+(	POS	O
+absent	POS	O
+/	POS	O
+mild	POS	O
+grade	POS	O
+lesions	POS	B-NP
+)	POS	O
+,	POS	O
+while	POS	O
+NGAL	POS	O
+(	POS	O
+serum	POS	O
+versus	POS	O
+urine	POS	O
+)	POS	O
+seems	POS	O
+to	POS	O
+be	POS	O
+a	POS	O
+feasible	POS	O
+biomarker	POS	O
+of	POS	O
+CsA	POS	O
+replacement	POS	O
+to	POS	O
+SRL	POS	O
+.	POS	O
+Kinin	POS	O
+B2	POS	O
+receptor	POS	O
+deletion	POS	O
+and	POS	O
+blockage	POS	O
+ameliorates	POS	O
+cisplatin	POS	O
+-	POS	O
+induced	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+injury	POS	I-NP
+.	POS	O
+Cisplatin	POS	O
+treatment	POS	O
+has	POS	O
+been	POS	O
+adopted	POS	O
+in	POS	O
+some	POS	O
+chemotherapies	POS	O
+;	POS	O
+however	POS	O
+,	POS	O
+this	POS	O
+drug	POS	O
+can	POS	O
+induce	POS	O
+acute	POS	B-NP
+kidney	POS	I-NP
+injury	POS	I-NP
+due	POS	O
+its	POS	O
+ability	POS	O
+to	POS	O
+negatively	POS	O
+affect	POS	O
+renal	POS	O
+function	POS	O
+,	POS	O
+augment	POS	O
+serum	POS	O
+levels	POS	O
+of	POS	O
+creatinine	POS	O
+and	POS	O
+urea	POS	O
+,	POS	O
+increase	POS	O
+the	POS	O
+acute	POS	O
+tubular	POS	O
+necrosis	POS	O
+score	POS	O
+and	POS	O
+up	POS	O
+-	POS	O
+regulate	POS	O
+cytokines	POS	O
+(	POS	O
+e	POS	O
+.	POS	O
+g	POS	O
+.	POS	O
+,	POS	O
+IL	POS	O
+-	POS	O
+1b	POS	O
+and	POS	O
+TNF	POS	O
+-	POS	O
+a	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+kinin	POS	O
+B2	POS	O
+receptor	POS	O
+has	POS	O
+been	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+inflammation	POS	O
+process	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+the	POS	O
+regulation	POS	O
+of	POS	O
+cytokine	POS	O
+expression	POS	O
+,	POS	O
+and	POS	O
+its	POS	O
+deletion	POS	O
+resulted	POS	O
+in	POS	O
+an	POS	O
+improvement	POS	O
+in	POS	O
+the	POS	O
+diabetic	POS	B-NP
+nephropathy	POS	I-NP
+status	POS	O
+.	POS	O
+To	POS	O
+examine	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+the	POS	O
+kinin	POS	O
+B2	POS	O
+receptor	POS	O
+in	POS	O
+cisplatin	POS	O
+-	POS	O
+induced	POS	O
+acute	POS	B-NP
+kidney	POS	I-NP
+injury	POS	I-NP
+,	POS	O
+kinin	POS	O
+B2	POS	O
+receptor	POS	O
+knockout	POS	O
+mice	POS	O
+were	POS	O
+challenged	POS	O
+with	POS	O
+cisplatin	POS	O
+.	POS	O
+Additionally	POS	O
+,	POS	O
+WT	POS	O
+mice	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+a	POS	O
+B2	POS	O
+receptor	POS	O
+antagonist	POS	O
+after	POS	O
+cisplatin	POS	O
+administration	POS	O
+.	POS	O
+B2	POS	O
+receptor	POS	O
+-	POS	O
+deficient	POS	O
+mice	POS	O
+were	POS	O
+less	POS	O
+sensitive	POS	O
+to	POS	O
+this	POS	O
+drug	POS	O
+than	POS	O
+the	POS	O
+WT	POS	O
+mice	POS	O
+,	POS	O
+as	POS	O
+shown	POS	O
+by	POS	O
+reduced	POS	O
+weight	POS	O
+loss	POS	O
+,	POS	O
+better	POS	O
+preservation	POS	O
+of	POS	O
+kidney	POS	O
+function	POS	O
+,	POS	O
+down	POS	O
+regulation	POS	O
+of	POS	O
+inflammatory	POS	O
+cytokines	POS	O
+and	POS	O
+less	POS	O
+acute	POS	O
+tubular	POS	O
+necrosis	POS	B-NP
+.	POS	O
+Moreover	POS	O
+,	POS	O
+treatment	POS	O
+with	POS	O
+the	POS	O
+kinin	POS	O
+B2	POS	O
+receptor	POS	O
+antagonist	POS	O
+effectively	POS	O
+reduced	POS	O
+the	POS	O
+levels	POS	O
+of	POS	O
+serum	POS	O
+creatinine	POS	O
+and	POS	O
+blood	POS	O
+urea	POS	O
+after	POS	O
+cisplatin	POS	O
+administration	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+our	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+the	POS	O
+kinin	POS	O
+B2	POS	O
+receptor	POS	O
+is	POS	O
+involved	POS	O
+in	POS	O
+cisplatin	POS	O
+-	POS	O
+induced	POS	O
+acute	POS	B-NP
+kidney	POS	I-NP
+injury	POS	I-NP
+by	POS	O
+mediating	POS	O
+the	POS	O
+necrotic	POS	O
+process	POS	O
+and	POS	O
+the	POS	O
+expression	POS	O
+of	POS	O
+inflammatory	POS	O
+cytokines	POS	O
+,	POS	O
+thus	POS	O
+resulting	POS	O
+in	POS	O
+declined	POS	O
+renal	POS	O
+function	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+highlight	POS	O
+the	POS	O
+kinin	POS	O
+B2	POS	O
+receptor	POS	O
+antagonist	POS	O
+treatment	POS	O
+in	POS	O
+amelioration	POS	O
+of	POS	O
+nephrotoxicity	POS	B-NP
+induced	POS	O
+by	POS	O
+cisplatin	POS	O
+therapy	POS	O
+.	POS	O
+Safety	POS	O
+and	POS	O
+efficacy	POS	O
+of	POS	O
+fluocinolone	POS	O
+acetonide	POS	O
+intravitreal	POS	O
+implant	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+59	POS	O
+mg	POS	O
+)	POS	O
+in	POS	O
+birdshot	POS	B-NP
+retinochoroidopathy	POS	I-NP
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+To	POS	O
+report	POS	O
+the	POS	O
+treatment	POS	O
+outcomes	POS	O
+of	POS	O
+the	POS	O
+fluocinolone	POS	O
+acetonide	POS	O
+intravitreal	POS	O
+implant	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+59	POS	O
+mg	POS	O
+)	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+birdshot	POS	B-NP
+retinochoroidopathy	POS	I-NP
+whose	POS	I-NP
+disease	POS	I-NP
+is	POS	O
+refractory	POS	O
+or	POS	O
+intolerant	POS	O
+to	POS	O
+conventional	POS	O
+immunomodulatory	POS	O
+therapy	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+A	POS	O
+retrospective	POS	O
+case	POS	O
+series	POS	O
+involving	POS	O
+11	POS	O
+birdshot	POS	O
+retinochoroidopathy	POS	B-NP
+patients	POS	O
+(	POS	O
+11	POS	O
+eyes	POS	O
+)	POS	O
+.	POS	O
+Eleven	POS	O
+patients	POS	O
+(	POS	O
+11	POS	O
+eyes	POS	O
+)	POS	O
+underwent	POS	O
+surgery	POS	O
+for	POS	O
+fluocinolone	POS	O
+acetonide	POS	O
+implant	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+59	POS	O
+mg	POS	O
+)	POS	O
+.	POS	O
+Treatment	POS	O
+outcomes	POS	O
+of	POS	O
+interest	POS	O
+were	POS	O
+noted	POS	O
+at	POS	O
+baseline	POS	O
+,	POS	O
+before	POS	O
+fluocinolone	POS	O
+acetonide	POS	O
+implant	POS	O
+,	POS	O
+and	POS	O
+then	POS	O
+at	POS	O
+6	POS	O
+months	POS	O
+,	POS	O
+1	POS	O
+year	POS	O
+,	POS	O
+2	POS	O
+years	POS	O
+,	POS	O
+3	POS	O
+years	POS	O
+,	POS	O
+and	POS	O
+beyond	POS	O
+3	POS	O
+years	POS	O
+.	POS	O
+Disease	POS	O
+activity	POS	O
+markers	POS	O
+,	POS	O
+including	POS	O
+signs	POS	O
+of	POS	O
+ocular	POS	B-NP
+inflammation	POS	I-NP
+,	POS	O
+evidence	POS	O
+of	POS	O
+retinal	POS	B-NP
+vasculitis	POS	I-NP
+,	POS	O
+Swedish	POS	O
+interactive	POS	O
+threshold	POS	O
+algorithm	POS	O
+-	POS	O
+short	POS	O
+wavelength	POS	O
+automated	POS	O
+perimetry	POS	O
+Humphrey	POS	O
+visual	POS	O
+field	POS	O
+analysis	POS	O
+,	POS	O
+electroretinographic	POS	O
+parameters	POS	O
+,	POS	O
+and	POS	O
+optical	POS	O
+coherence	POS	O
+tomography	POS	O
+were	POS	O
+recorded	POS	O
+.	POS	O
+Data	POS	O
+on	POS	O
+occurrence	POS	O
+of	POS	O
+cataract	POS	B-NP
+and	POS	O
+raised	POS	O
+intraocular	POS	O
+pressure	POS	O
+were	POS	O
+collected	POS	O
+in	POS	O
+all	POS	O
+eyes	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Intraocular	POS	B-NP
+inflammation	POS	I-NP
+was	POS	O
+present	POS	O
+in	POS	O
+54	POS	O
+.	POS	O
+5	POS	O
+,	POS	O
+9	POS	O
+.	POS	O
+9	POS	O
+,	POS	O
+11	POS	O
+.	POS	O
+1	POS	O
+,	POS	O
+and	POS	O
+0	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+at	POS	O
+baseline	POS	O
+,	POS	O
+6	POS	O
+months	POS	O
+,	POS	O
+1	POS	O
+year	POS	O
+,	POS	O
+2	POS	O
+years	POS	O
+,	POS	O
+3	POS	O
+years	POS	O
+,	POS	O
+and	POS	O
+beyond	POS	O
+3	POS	O
+years	POS	O
+after	POS	O
+receiving	POS	O
+the	POS	O
+implant	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Active	POS	O
+vasculitis	POS	B-NP
+was	POS	O
+noted	POS	O
+in	POS	O
+36	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+patients	POS	O
+at	POS	O
+baseline	POS	O
+and	POS	O
+0	POS	O
+%	POS	O
+at	POS	O
+3	POS	O
+years	POS	O
+of	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+.	POS	O
+More	POS	O
+than	POS	O
+20	POS	O
+%	POS	O
+(	POS	O
+47	POS	O
+.	POS	O
+61	POS	O
+-	POS	O
+67	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+)	POS	O
+reduction	POS	O
+in	POS	O
+central	POS	O
+retinal	POS	O
+thickness	POS	O
+was	POS	O
+noted	POS	O
+in	POS	O
+all	POS	O
+patients	POS	O
+with	POS	O
+cystoid	POS	B-NP
+macular	POS	I-NP
+edema	POS	I-NP
+at	POS	O
+6	POS	O
+months	POS	O
+,	POS	O
+1	POS	O
+year	POS	O
+,	POS	O
+2	POS	O
+years	POS	O
+,	POS	O
+and	POS	O
+3	POS	O
+years	POS	O
+postimplant	POS	O
+.	POS	O
+At	POS	O
+baseline	POS	O
+,	POS	O
+54	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+patients	POS	O
+were	POS	O
+on	POS	O
+immunomodulatory	POS	O
+agents	POS	O
+.	POS	O
+This	POS	O
+percentage	POS	O
+decreased	POS	O
+to	POS	O
+45	POS	O
+.	POS	O
+45	POS	O
+,	POS	O
+44	POS	O
+.	POS	O
+4	POS	O
+,	POS	O
+and	POS	O
+14	POS	O
+.	POS	O
+28	POS	O
+%	POS	O
+at	POS	O
+1	POS	O
+year	POS	O
+,	POS	O
+2	POS	O
+years	POS	O
+,	POS	O
+and	POS	O
+3	POS	O
+years	POS	O
+postimplant	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Adverse	POS	O
+events	POS	O
+included	POS	O
+increased	POS	O
+intraocular	POS	O
+pressure	POS	O
+(	POS	O
+54	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+cataract	POS	B-NP
+formation	POS	O
+(	POS	O
+100	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+The	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+fluocinolone	POS	O
+acetonide	POS	O
+implant	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+59	POS	O
+mg	POS	O
+)	POS	O
+helps	POS	O
+to	POS	O
+control	POS	O
+inflammation	POS	B-NP
+in	POS	O
+otherwise	POS	O
+treatment	POS	O
+-	POS	O
+refractory	POS	O
+cases	POS	O
+of	POS	O
+birdshot	POS	B-NP
+retinochoroidopathy	POS	I-NP
+.	POS	O
+It	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+significant	POS	O
+side	POS	O
+effects	POS	O
+of	POS	O
+cataract	POS	B-NP
+and	POS	O
+ocular	POS	B-NP
+hypertension	POS	I-NP
+requiring	POS	O
+treatment	POS	O
+.	POS	O
+Optimal	POS	O
+precurarizing	POS	O
+dose	POS	O
+of	POS	O
+rocuronium	POS	O
+to	POS	O
+decrease	POS	O
+fasciculation	POS	B-NP
+and	POS	O
+myalgia	POS	B-NP
+following	POS	O
+succinylcholine	POS	O
+administration	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Succinylcholine	POS	O
+commonly	POS	O
+produces	POS	O
+frequent	POS	O
+adverse	POS	O
+effects	POS	O
+,	POS	O
+including	POS	O
+muscle	POS	B-NP
+fasciculation	POS	I-NP
+and	POS	O
+myalgia	POS	B-NP
+.	POS	O
+The	POS	O
+current	POS	O
+study	POS	O
+identified	POS	O
+the	POS	O
+optimal	POS	O
+dose	POS	O
+of	POS	O
+rocuronium	POS	O
+to	POS	O
+prevent	POS	O
+succinylcholine	POS	O
+-	POS	O
+induced	POS	O
+fasciculation	POS	B-NP
+and	POS	O
+myalgia	POS	B-NP
+and	POS	O
+evaluated	POS	O
+the	POS	O
+influence	POS	O
+of	POS	O
+rocuronium	POS	O
+on	POS	O
+the	POS	O
+speed	POS	O
+of	POS	O
+onset	POS	O
+produced	POS	O
+by	POS	O
+succinylcholine	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+This	POS	O
+randomized	POS	O
+,	POS	O
+double	POS	O
+-	POS	O
+blinded	POS	O
+study	POS	O
+was	POS	O
+conducted	POS	O
+in	POS	O
+100	POS	O
+patients	POS	O
+randomly	POS	O
+allocated	POS	O
+into	POS	O
+five	POS	O
+groups	POS	O
+of	POS	O
+20	POS	O
+patients	POS	O
+each	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+randomized	POS	O
+to	POS	O
+receive	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+03	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+04	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+06	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+rocuronium	POS	O
+as	POS	O
+a	POS	O
+precurarizing	POS	O
+dose	POS	O
+.	POS	O
+Neuromuscular	POS	O
+monitoring	POS	O
+after	POS	O
+each	POS	O
+precurarizing	POS	O
+dose	POS	O
+was	POS	O
+recorded	POS	O
+from	POS	O
+the	POS	O
+adductor	POS	O
+pollicis	POS	O
+muscle	POS	O
+using	POS	O
+acceleromyography	POS	O
+with	POS	O
+train	POS	O
+-	POS	O
+of	POS	O
+-	POS	O
+four	POS	O
+stimulation	POS	O
+of	POS	O
+the	POS	O
+ulnar	POS	O
+nerve	POS	O
+.	POS	O
+All	POS	O
+patients	POS	O
+received	POS	O
+succinylcholine	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+at	POS	O
+2	POS	O
+minutes	POS	O
+after	POS	O
+the	POS	O
+precurarization	POS	O
+,	POS	O
+and	POS	O
+were	POS	O
+assessed	POS	O
+the	POS	O
+incidence	POS	O
+and	POS	O
+severity	POS	O
+of	POS	O
+fasciculations	POS	B-NP
+,	POS	O
+while	POS	O
+myalgia	POS	B-NP
+was	POS	O
+assessed	POS	O
+at	POS	O
+24	POS	O
+hours	POS	O
+after	POS	O
+surgery	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+incidence	POS	O
+and	POS	O
+severity	POS	O
+of	POS	O
+visible	POS	O
+muscle	POS	B-NP
+fasciculation	POS	I-NP
+was	POS	O
+significantly	POS	O
+less	POS	O
+with	POS	O
+increasing	POS	O
+the	POS	O
+amount	POS	O
+of	POS	O
+precurarizing	POS	O
+dose	POS	O
+of	POS	O
+rocuronium	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+Those	POS	O
+of	POS	O
+myalgia	POS	B-NP
+tend	POS	O
+to	POS	O
+decrease	POS	O
+according	POS	O
+to	POS	O
+increasing	POS	O
+the	POS	O
+amount	POS	O
+of	POS	O
+precurarizing	POS	O
+dose	POS	O
+of	POS	O
+rocuronium	POS	O
+,	POS	O
+but	POS	O
+there	POS	O
+was	POS	O
+no	POS	O
+significance	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+072	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+onset	POS	O
+time	POS	O
+of	POS	O
+succinylcholine	POS	O
+was	POS	O
+significantly	POS	O
+longer	POS	O
+with	POS	O
+increasing	POS	O
+the	POS	O
+amount	POS	O
+of	POS	O
+precurarizing	POS	O
+dose	POS	O
+of	POS	O
+rocuronium	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Precurarization	POS	O
+with	POS	O
+0	POS	O
+.	POS	O
+04	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+rocuronium	POS	O
+was	POS	O
+the	POS	O
+optimal	POS	O
+dose	POS	O
+considering	POS	O
+the	POS	O
+reduction	POS	O
+in	POS	O
+the	POS	O
+incidence	POS	O
+and	POS	O
+severity	POS	O
+of	POS	O
+fasciculation	POS	B-NP
+and	POS	O
+myalgia	POS	B-NP
+with	POS	O
+acceptable	POS	O
+onset	POS	O
+time	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+safe	POS	O
+and	POS	O
+effective	POS	O
+precurarization	POS	O
+.	POS	O
+Absence	POS	O
+of	POS	O
+PKC	POS	O
+-	POS	O
+alpha	POS	O
+attenuates	POS	O
+lithium	POS	O
+-	POS	O
+induced	POS	O
+nephrogenic	POS	B-NP
+diabetes	POS	I-NP
+insipidus	POS	I-NP
+.	POS	O
+Lithium	POS	B-NP
+,	POS	O
+an	POS	O
+effective	POS	O
+antipsychotic	POS	O
+,	POS	O
+induces	POS	O
+nephrogenic	POS	B-NP
+diabetes	POS	I-NP
+insipidus	POS	I-NP
+(	POS	O
+NDI	POS	B-NP
+)	POS	O
+in	POS	O
+40	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+decreased	POS	O
+capacity	POS	O
+to	POS	O
+concentrate	POS	O
+urine	POS	O
+is	POS	O
+likely	POS	O
+due	POS	O
+to	POS	O
+lithium	POS	O
+acutely	POS	O
+disrupting	POS	O
+the	POS	O
+cAMP	POS	O
+pathway	POS	O
+and	POS	O
+chronically	POS	O
+reducing	POS	O
+urea	POS	O
+transporter	POS	O
+(	POS	O
+UT	POS	O
+-	POS	O
+A1	POS	O
+)	POS	O
+and	POS	O
+water	POS	O
+channel	POS	O
+(	POS	O
+AQP2	POS	O
+)	POS	O
+expression	POS	O
+in	POS	O
+the	POS	O
+inner	POS	O
+medulla	POS	O
+.	POS	O
+Targeting	POS	O
+an	POS	O
+alternative	POS	O
+signaling	POS	O
+pathway	POS	O
+,	POS	O
+such	POS	O
+as	POS	O
+PKC	POS	O
+-	POS	O
+mediated	POS	O
+signaling	POS	O
+,	POS	O
+may	POS	O
+be	POS	O
+an	POS	O
+effective	POS	O
+method	POS	O
+of	POS	O
+treating	POS	O
+lithium	POS	O
+-	POS	O
+induced	POS	O
+polyuria	POS	B-NP
+.	POS	O
+PKC	POS	O
+-	POS	O
+alpha	POS	O
+null	POS	O
+mice	POS	O
+(	POS	O
+PKCa	POS	O
+KO	POS	O
+)	POS	O
+and	POS	O
+strain	POS	O
+-	POS	O
+matched	POS	O
+wild	POS	O
+type	POS	O
+(	POS	O
+WT	POS	O
+)	POS	O
+controls	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+lithium	POS	O
+for	POS	O
+0	POS	O
+,	POS	O
+3	POS	O
+or	POS	O
+5	POS	O
+days	POS	O
+.	POS	O
+WT	POS	O
+mice	POS	O
+had	POS	O
+increased	POS	O
+urine	POS	O
+output	POS	O
+and	POS	O
+lowered	POS	O
+urine	POS	O
+osmolality	POS	O
+after	POS	O
+3	POS	O
+and	POS	O
+5	POS	O
+days	POS	O
+of	POS	O
+treatment	POS	O
+whereas	POS	O
+PKCa	POS	O
+KO	POS	O
+mice	POS	O
+had	POS	O
+no	POS	O
+change	POS	O
+in	POS	O
+urine	POS	O
+output	POS	O
+or	POS	O
+concentration	POS	O
+.	POS	O
+Western	POS	O
+blot	POS	O
+analysis	POS	O
+revealed	POS	O
+that	POS	O
+AQP2	POS	O
+expression	POS	O
+in	POS	O
+medullary	POS	O
+tissues	POS	O
+was	POS	O
+lowered	POS	O
+after	POS	O
+3	POS	O
+and	POS	O
+5	POS	O
+days	POS	O
+in	POS	O
+WT	POS	O
+mice	POS	O
+;	POS	O
+however	POS	O
+,	POS	O
+AQP2	POS	O
+was	POS	O
+unchanged	POS	O
+in	POS	O
+PKCa	POS	O
+KO	POS	O
+.	POS	O
+Similar	POS	O
+results	POS	O
+were	POS	O
+observed	POS	O
+with	POS	O
+UT	POS	O
+-	POS	O
+A1	POS	O
+expression	POS	O
+.	POS	O
+Animals	POS	O
+were	POS	O
+also	POS	O
+treated	POS	O
+with	POS	O
+lithium	POS	O
+for	POS	O
+6	POS	O
+weeks	POS	O
+.	POS	O
+Lithium	POS	O
+-	POS	O
+treated	POS	O
+WT	POS	O
+mice	POS	O
+had	POS	O
+19	POS	O
+-	POS	O
+fold	POS	O
+increased	POS	O
+urine	POS	O
+output	POS	O
+whereas	POS	O
+treated	POS	O
+PKCa	POS	O
+KO	POS	O
+animals	POS	O
+had	POS	O
+a	POS	O
+4	POS	O
+-	POS	O
+fold	POS	O
+increase	POS	O
+in	POS	O
+output	POS	O
+.	POS	O
+AQP2	POS	O
+and	POS	O
+UT	POS	O
+-	POS	O
+A1	POS	O
+expression	POS	O
+was	POS	O
+lowered	POS	O
+in	POS	O
+6	POS	O
+week	POS	O
+lithium	POS	O
+-	POS	O
+treated	POS	O
+WT	POS	O
+animals	POS	O
+whereas	POS	O
+in	POS	O
+treated	POS	O
+PKCa	POS	O
+KO	POS	O
+mice	POS	O
+,	POS	O
+AQP2	POS	O
+was	POS	O
+only	POS	O
+reduced	POS	O
+by	POS	O
+2	POS	O
+-	POS	O
+fold	POS	O
+and	POS	O
+UT	POS	O
+-	POS	O
+A1	POS	O
+expression	POS	O
+was	POS	O
+unaffected	POS	O
+.	POS	O
+Urinary	POS	O
+sodium	POS	O
+,	POS	O
+potassium	POS	O
+and	POS	O
+calcium	POS	O
+were	POS	O
+elevated	POS	O
+in	POS	O
+lithium	POS	O
+-	POS	O
+fed	POS	O
+WT	POS	O
+but	POS	O
+not	POS	O
+in	POS	O
+lithium	POS	O
+-	POS	O
+fed	POS	O
+PKCa	POS	O
+KO	POS	O
+mice	POS	O
+.	POS	O
+Our	POS	O
+data	POS	O
+show	POS	O
+that	POS	O
+ablation	POS	O
+of	POS	O
+PKCa	POS	O
+preserves	POS	O
+AQP2	POS	O
+and	POS	O
+UT	POS	O
+-	POS	O
+A1	POS	O
+protein	POS	O
+expression	POS	O
+and	POS	O
+localization	POS	O
+in	POS	O
+lithium	POS	O
+-	POS	O
+induced	POS	O
+NDI	POS	O
+,	POS	O
+and	POS	O
+prevents	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+the	POS	O
+severe	POS	O
+polyuria	POS	B-NP
+associated	POS	O
+with	POS	O
+lithium	POS	O
+therapy	POS	O
+.	POS	O
+Is	POS	O
+Dysguesia	POS	B-NP
+Going	POS	O
+to	POS	O
+be	POS	O
+a	POS	O
+Rare	POS	O
+or	POS	O
+a	POS	O
+Common	POS	O
+Side	POS	O
+-	POS	O
+effect	POS	O
+of	POS	O
+Amlodipine	POS	O
+?	POS	O
+A	POS	O
+very	POS	O
+rare	POS	O
+side	POS	O
+-	POS	O
+effect	POS	O
+of	POS	O
+amlodipine	POS	O
+is	POS	O
+dysguesia	POS	B-NP
+.	POS	O
+A	POS	O
+review	POS	O
+of	POS	O
+the	POS	O
+literature	POS	O
+produced	POS	O
+only	POS	O
+one	POS	O
+case	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+about	POS	O
+a	POS	O
+female	POS	O
+with	POS	O
+essential	POS	O
+hypertension	POS	B-NP
+on	POS	O
+drug	POS	O
+treatment	POS	O
+with	POS	O
+amlodipine	POS	O
+developed	POS	O
+loss	POS	B-NP
+of	POS	I-NP
+taste	POS	I-NP
+sensation	POS	I-NP
+.	POS	O
+Condition	POS	O
+moderately	POS	O
+improved	POS	O
+on	POS	O
+stoppage	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+for	POS	O
+25	POS	O
+days	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+amlodipine	POS	O
+can	POS	O
+cause	POS	O
+dysguesia	POS	B-NP
+.	POS	O
+Here	POS	O
+,	POS	O
+we	POS	O
+describe	POS	O
+the	POS	O
+clinical	POS	O
+presentation	POS	O
+and	POS	O
+review	POS	O
+the	POS	O
+relevant	POS	O
+literature	POS	O
+on	POS	O
+amlodipine	POS	O
+and	POS	O
+dysguesia	POS	B-NP
+.	POS	O
+Rhabdomyolysis	POS	B-NP
+in	POS	O
+association	POS	O
+with	POS	O
+simvastatin	POS	O
+and	POS	O
+dosage	POS	O
+increment	POS	O
+in	POS	O
+clarithromycin	POS	O
+.	POS	O
+Clarithromycin	POS	O
+is	POS	O
+the	POS	O
+most	POS	O
+documented	POS	O
+cytochrome	POS	O
+P450	POS	O
+3A4	POS	O
+(	POS	O
+CYP3A4	POS	O
+)	POS	O
+inhibitor	POS	O
+to	POS	O
+cause	POS	O
+an	POS	O
+adverse	POS	O
+interaction	POS	O
+with	POS	O
+simvastatin	POS	O
+.	POS	O
+This	POS	O
+particular	POS	O
+case	POS	O
+is	POS	O
+of	POS	O
+interest	POS	O
+as	POS	O
+rhabdomyolysis	POS	B-NP
+only	POS	O
+occurred	POS	O
+after	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+dose	POS	O
+of	POS	O
+clarithromycin	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+developed	POS	O
+raised	POS	O
+cardiac	POS	O
+biomarkers	POS	O
+without	POS	O
+any	POS	O
+obvious	POS	O
+cardiac	POS	O
+issues	POS	O
+,	POS	O
+a	POS	O
+phenomenon	POS	O
+that	POS	O
+has	POS	O
+been	POS	O
+linked	POS	O
+to	POS	O
+rhabdomyolysis	POS	B-NP
+previously	POS	O
+.	POS	O
+To	POS	O
+date	POS	O
+,	POS	O
+there	POS	O
+has	POS	O
+been	POS	O
+no	POS	O
+reported	POS	O
+effect	POS	O
+of	POS	O
+rhabdomyolysis	POS	B-NP
+on	POS	O
+the	POS	O
+structure	POS	O
+and	POS	O
+function	POS	O
+of	POS	O
+cardiac	POS	O
+muscle	POS	O
+.	POS	O
+Clinicians	POS	O
+need	POS	O
+to	POS	O
+be	POS	O
+aware	POS	O
+of	POS	O
+prescribing	POS	O
+concomitant	POS	O
+medications	POS	O
+that	POS	O
+increase	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+myopathy	POS	B-NP
+or	POS	O
+inhibit	POS	O
+the	POS	O
+CYP3A4	POS	O
+enzyme	POS	O
+.	POS	O
+Our	POS	O
+case	POS	O
+suggests	POS	O
+that	POS	O
+troponin	POS	O
+elevation	POS	O
+could	POS	O
+be	POS	O
+associated	POS	O
+with	POS	O
+statin	POS	O
+induced	POS	O
+rhabdomyolysis	POS	B-NP
+,	POS	O
+which	POS	O
+may	POS	O
+warrant	POS	O
+further	POS	O
+studies	POS	O
+.	POS	O
+Characterization	POS	O
+of	POS	O
+a	POS	O
+novel	POS	O
+BCHE	POS	O
+"	POS	O
+silent	POS	O
+"	POS	O
+allele	POS	O
+:	POS	O
+point	POS	O
+mutation	POS	O
+(	POS	O
+p	POS	O
+.	POS	O
+Val204Asp	POS	O
+)	POS	O
+causes	POS	O
+loss	POS	O
+of	POS	O
+activity	POS	O
+and	POS	O
+prolonged	POS	O
+apnea	POS	B-NP
+with	POS	O
+suxamethonium	POS	O
+.	POS	O
+Butyrylcholinesterase	POS	B-NP
+deficiency	POS	I-NP
+is	POS	O
+characterized	POS	O
+by	POS	O
+prolonged	POS	O
+apnea	POS	B-NP
+after	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+muscle	POS	O
+relaxants	POS	O
+(	POS	O
+suxamethonium	POS	O
+or	POS	O
+mivacurium	POS	O
+)	POS	O
+in	POS	O
+patients	POS	O
+who	POS	O
+have	POS	O
+mutations	POS	O
+in	POS	O
+the	POS	O
+BCHE	POS	O
+gene	POS	O
+.	POS	O
+Here	POS	O
+,	POS	O
+we	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+prolonged	POS	O
+neuromuscular	POS	B-NP
+block	POS	I-NP
+after	POS	O
+administration	POS	O
+of	POS	O
+suxamethonium	POS	O
+leading	POS	O
+to	POS	O
+the	POS	O
+discovery	POS	O
+of	POS	O
+a	POS	O
+novel	POS	O
+BCHE	POS	O
+variant	POS	O
+(	POS	O
+c	POS	O
+.	POS	O
+695T	POS	O
+>	POS	O
+A	POS	O
+,	POS	O
+p	POS	O
+.	POS	O
+Val204Asp	POS	O
+)	POS	O
+.	POS	O
+Inhibition	POS	O
+studies	POS	O
+,	POS	O
+kinetic	POS	O
+analysis	POS	O
+and	POS	O
+molecular	POS	O
+dynamics	POS	O
+were	POS	O
+undertaken	POS	O
+to	POS	O
+understand	POS	O
+how	POS	O
+this	POS	O
+mutation	POS	O
+disrupts	POS	O
+the	POS	O
+catalytic	POS	O
+triad	POS	O
+and	POS	O
+determines	POS	O
+a	POS	O
+"	POS	O
+silent	POS	O
+"	POS	O
+phenotype	POS	O
+.	POS	O
+Low	POS	O
+activity	POS	O
+of	POS	O
+patient	POS	O
+plasma	POS	O
+butyrylcholinesterase	POS	O
+with	POS	O
+butyrylthiocholine	POS	O
+(	POS	O
+BTC	POS	O
+)	POS	O
+and	POS	O
+benzoylcholine	POS	O
+,	POS	O
+and	POS	O
+values	POS	O
+of	POS	O
+dibucaine	POS	O
+and	POS	O
+fluoride	POS	O
+numbers	POS	O
+fit	POS	O
+with	POS	O
+heterozygous	POS	O
+atypical	POS	O
+silent	POS	O
+genotype	POS	O
+.	POS	O
+Electrophoretic	POS	O
+analysis	POS	O
+of	POS	O
+plasma	POS	O
+BChE	POS	O
+of	POS	O
+the	POS	O
+proband	POS	O
+and	POS	O
+his	POS	O
+mother	POS	O
+showed	POS	O
+that	POS	O
+patient	POS	O
+has	POS	O
+a	POS	O
+reduced	POS	O
+amount	POS	O
+of	POS	O
+tetrameric	POS	O
+enzyme	POS	O
+in	POS	O
+plasma	POS	O
+and	POS	O
+that	POS	O
+minor	POS	O
+fast	POS	O
+-	POS	O
+moving	POS	O
+BChE	POS	O
+components	POS	O
+:	POS	O
+monomer	POS	O
+,	POS	O
+dimer	POS	O
+,	POS	O
+and	POS	O
+monomer	POS	O
+-	POS	O
+albumin	POS	O
+conjugate	POS	O
+are	POS	O
+missing	POS	O
+.	POS	O
+Kinetic	POS	O
+analysis	POS	O
+showed	POS	O
+that	POS	O
+the	POS	O
+p	POS	O
+.	POS	O
+Val204Asp	POS	O
+/	POS	O
+p	POS	O
+.	POS	O
+Asp70Gly	POS	O
+-	POS	O
+p	POS	O
+.	POS	O
+Ala539Thr	POS	O
+BChE	POS	O
+displays	POS	O
+a	POS	O
+pure	POS	O
+Michaelian	POS	O
+behavior	POS	O
+with	POS	O
+BTC	POS	O
+as	POS	O
+the	POS	O
+substrate	POS	O
+.	POS	O
+Both	POS	O
+catalytic	POS	O
+parameters	POS	O
+Km	POS	O
+=	POS	O
+265	POS	O
+uM	POS	O
+for	POS	O
+BTC	POS	O
+,	POS	O
+two	POS	O
+times	POS	O
+higher	POS	O
+than	POS	O
+that	POS	O
+of	POS	O
+the	POS	O
+atypical	POS	O
+enzyme	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+low	POS	O
+Vmax	POS	O
+are	POS	O
+consistent	POS	O
+with	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+activity	POS	O
+against	POS	O
+suxamethonium	POS	O
+.	POS	O
+Molecular	POS	O
+dynamic	POS	O
+(	POS	O
+MD	POS	O
+)	POS	O
+simulations	POS	O
+showed	POS	O
+that	POS	O
+the	POS	O
+overall	POS	O
+effect	POS	O
+of	POS	O
+the	POS	O
+mutation	POS	O
+p	POS	O
+.	POS	O
+Val204Asp	POS	O
+is	POS	O
+disruption	POS	O
+of	POS	O
+hydrogen	POS	O
+bonding	POS	O
+between	POS	O
+Gln223	POS	O
+and	POS	O
+Glu441	POS	O
+,	POS	O
+leading	POS	O
+Ser198	POS	O
+and	POS	O
+His438	POS	O
+to	POS	O
+move	POS	O
+away	POS	O
+from	POS	O
+each	POS	O
+other	POS	O
+with	POS	O
+subsequent	POS	O
+disruption	POS	O
+of	POS	O
+the	POS	O
+catalytic	POS	O
+triad	POS	O
+functionality	POS	O
+regardless	POS	O
+of	POS	O
+the	POS	O
+type	POS	O
+of	POS	O
+substrate	POS	O
+.	POS	O
+MD	POS	O
+also	POS	O
+showed	POS	O
+that	POS	O
+the	POS	O
+enzyme	POS	O
+volume	POS	O
+is	POS	O
+increased	POS	O
+,	POS	O
+suggesting	POS	O
+a	POS	O
+pre	POS	O
+-	POS	O
+denaturation	POS	O
+state	POS	O
+.	POS	O
+This	POS	O
+fits	POS	O
+with	POS	O
+the	POS	O
+reduced	POS	O
+concentration	POS	O
+of	POS	O
+p	POS	O
+.	POS	O
+Ala204Asp	POS	O
+/	POS	O
+p	POS	O
+.	POS	O
+Asp70Gly	POS	O
+-	POS	O
+p	POS	O
+.	POS	O
+Ala539Thr	POS	O
+tetrameric	POS	O
+enzyme	POS	O
+in	POS	O
+the	POS	O
+plasma	POS	O
+and	POS	O
+non	POS	O
+-	POS	O
+detectable	POS	O
+fast	POS	O
+moving	POS	O
+-	POS	O
+bands	POS	O
+on	POS	O
+electrophoresis	POS	O
+gels	POS	O
+.	POS	O
+Delayed	POS	O
+anemia	POS	B-NP
+after	POS	O
+treatment	POS	O
+with	POS	O
+injectable	POS	O
+artesunate	POS	O
+in	POS	O
+the	POS	O
+Democratic	POS	O
+Republic	POS	O
+of	POS	O
+the	POS	O
+Congo	POS	O
+:	POS	O
+a	POS	O
+manageable	POS	O
+issue	POS	O
+.	POS	O
+Cases	POS	O
+of	POS	O
+delayed	POS	O
+hemolytic	POS	B-NP
+anemia	POS	I-NP
+have	POS	O
+been	POS	O
+described	POS	O
+after	POS	O
+treatment	POS	O
+with	POS	O
+injectable	POS	O
+artesunate	POS	O
+,	POS	O
+the	POS	O
+current	POS	O
+World	POS	O
+Health	POS	O
+Organization	POS	O
+(	POS	O
+WHO	POS	O
+)	POS	O
+-	POS	O
+recommended	POS	O
+first	POS	O
+-	POS	O
+line	POS	O
+drug	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+severe	POS	O
+malaria	POS	B-NP
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+350	POS	O
+patients	POS	O
+(	POS	O
+215	POS	O
+[	POS	O
+61	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+]	POS	O
+<	POS	O
+5	POS	O
+years	POS	O
+of	POS	O
+age	POS	O
+and	POS	O
+135	POS	O
+[	POS	O
+38	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+]	POS	O
+>	POS	O
+5	POS	O
+years	POS	O
+of	POS	O
+age	POS	O
+)	POS	O
+were	POS	O
+followed	POS	O
+-	POS	O
+up	POS	O
+after	POS	O
+treatment	POS	O
+with	POS	O
+injectable	POS	O
+artesunate	POS	O
+for	POS	O
+severe	POS	O
+malaria	POS	B-NP
+in	POS	O
+hospitals	POS	O
+and	POS	O
+health	POS	O
+centers	POS	O
+of	POS	O
+the	POS	O
+Democratic	POS	O
+Republic	POS	O
+of	POS	O
+the	POS	O
+Congo	POS	O
+.	POS	O
+Complete	POS	O
+series	POS	O
+of	POS	O
+hemoglobin	POS	O
+(	POS	O
+Hb	POS	O
+)	POS	O
+measurements	POS	O
+were	POS	O
+available	POS	O
+for	POS	O
+201	POS	O
+patients	POS	O
+.	POS	O
+A	POS	O
+decrease	POS	O
+in	POS	O
+Hb	POS	O
+levels	POS	O
+between	POS	O
+2	POS	O
+and	POS	O
+5	POS	O
+g	POS	O
+/	POS	O
+dL	POS	O
+was	POS	O
+detected	POS	O
+in	POS	O
+23	POS	O
+(	POS	O
+11	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+during	POS	O
+the	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+period	POS	O
+.	POS	O
+For	POS	O
+five	POS	O
+patients	POS	O
+,	POS	O
+Hb	POS	O
+levels	POS	O
+decreased	POS	O
+below	POS	O
+5	POS	O
+g	POS	O
+/	POS	O
+dL	POS	O
+during	POS	O
+at	POS	O
+least	POS	O
+one	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+visit	POS	O
+.	POS	O
+All	POS	O
+cases	POS	O
+of	POS	O
+delayed	POS	O
+anemia	POS	B-NP
+were	POS	O
+clinically	POS	O
+manageable	POS	O
+and	POS	O
+resolved	POS	O
+within	POS	O
+one	POS	O
+month	POS	O
+.	POS	O
+Regulation	POS	O
+of	POS	O
+signal	POS	O
+transducer	POS	O
+and	POS	O
+activator	POS	O
+of	POS	O
+transcription	POS	O
+3	POS	O
+and	POS	O
+apoptotic	POS	O
+pathways	POS	O
+by	POS	O
+betaine	POS	O
+attenuates	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+acute	POS	O
+myocardial	POS	B-NP
+injury	POS	I-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+designed	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+cardioprotective	POS	O
+effects	POS	O
+of	POS	O
+betaine	POS	O
+on	POS	O
+acute	POS	O
+myocardial	POS	B-NP
+ischemia	POS	I-NP
+induced	POS	O
+experimentally	POS	O
+in	POS	O
+rats	POS	O
+focusing	POS	O
+on	POS	O
+regulation	POS	O
+of	POS	O
+signal	POS	O
+transducer	POS	O
+and	POS	O
+activator	POS	O
+of	POS	O
+transcription	POS	O
+3	POS	O
+(	POS	O
+STAT3	POS	O
+)	POS	O
+and	POS	O
+apoptotic	POS	O
+pathways	POS	O
+as	POS	O
+the	POS	O
+potential	POS	O
+mechanism	POS	O
+underlying	POS	O
+the	POS	O
+drug	POS	O
+effect	POS	O
+.	POS	O
+Male	POS	O
+Sprague	POS	O
+Dawley	POS	O
+rats	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+betaine	POS	O
+(	POS	O
+100	POS	O
+,	POS	O
+200	POS	O
+,	POS	O
+and	POS	O
+400	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+orally	POS	O
+for	POS	O
+40	POS	O
+days	POS	O
+.	POS	O
+Acute	POS	O
+myocardial	POS	B-NP
+ischemic	POS	I-NP
+injury	POS	I-NP
+was	POS	O
+induced	POS	O
+in	POS	O
+rats	POS	O
+by	POS	O
+subcutaneous	POS	O
+injection	POS	O
+of	POS	O
+isoproterenol	POS	O
+(	POS	O
+85	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+,	POS	O
+for	POS	O
+two	POS	O
+consecutive	POS	O
+days	POS	O
+.	POS	O
+Serum	POS	O
+cardiac	POS	O
+marker	POS	O
+enzyme	POS	O
+,	POS	O
+histopathological	POS	O
+variables	POS	O
+and	POS	O
+expression	POS	O
+of	POS	O
+protein	POS	O
+levels	POS	O
+were	POS	O
+analyzed	POS	O
+.	POS	O
+Oral	POS	O
+administration	POS	O
+of	POS	O
+betaine	POS	O
+(	POS	O
+200	POS	O
+and	POS	O
+400	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+significantly	POS	O
+reduced	POS	O
+the	POS	O
+level	POS	O
+of	POS	O
+cardiac	POS	O
+marker	POS	O
+enzyme	POS	O
+in	POS	O
+the	POS	O
+serum	POS	O
+and	POS	O
+prevented	POS	O
+left	POS	O
+ventricular	POS	O
+remodeling	POS	O
+.	POS	O
+Western	POS	O
+blot	POS	O
+analysis	POS	O
+showed	POS	O
+that	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+phosphorylation	POS	O
+of	POS	O
+STAT3	POS	O
+was	POS	O
+maintained	POS	O
+or	POS	O
+further	POS	O
+enhanced	POS	O
+by	POS	O
+betaine	POS	O
+treatment	POS	O
+in	POS	O
+myocardium	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+betaine	POS	O
+(	POS	O
+200	POS	O
+and	POS	O
+400	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+treatment	POS	O
+increased	POS	O
+the	POS	O
+ventricular	POS	O
+expression	POS	O
+of	POS	O
+Bcl	POS	O
+-	POS	O
+2	POS	O
+and	POS	O
+reduced	POS	O
+the	POS	O
+level	POS	O
+of	POS	O
+Bax	POS	O
+,	POS	O
+therefore	POS	O
+causing	POS	O
+a	POS	O
+significant	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+ratio	POS	O
+of	POS	O
+Bcl	POS	O
+-	POS	O
+2	POS	O
+/	POS	O
+Bax	POS	O
+.	POS	O
+The	POS	O
+protective	POS	O
+role	POS	O
+of	POS	O
+betaine	POS	O
+on	POS	O
+myocardial	POS	B-NP
+damage	POS	I-NP
+was	POS	O
+further	POS	O
+confirmed	POS	O
+by	POS	O
+histopathological	POS	O
+examination	POS	O
+.	POS	O
+In	POS	O
+summary	POS	O
+,	POS	O
+our	POS	O
+results	POS	O
+showed	POS	O
+that	POS	O
+betaine	POS	O
+pretreatment	POS	O
+attenuated	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+acute	POS	O
+myocardial	POS	B-NP
+ischemia	POS	I-NP
+via	POS	O
+the	POS	O
+regulation	POS	O
+of	POS	O
+STAT3	POS	O
+and	POS	O
+apoptotic	POS	O
+pathways	POS	O
+.	POS	O
+Quetiapine	POS	O
+-	POS	O
+induced	POS	O
+neutropenia	POS	B-NP
+in	POS	O
+a	POS	O
+bipolar	POS	O
+patient	POS	O
+with	POS	O
+hepatocellular	POS	B-NP
+carcinoma	POS	I-NP
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+Quetiapine	POS	O
+is	POS	O
+a	POS	O
+dibenzothiazepine	POS	O
+derivative	POS	O
+,	POS	O
+similar	POS	O
+to	POS	O
+clozapine	POS	O
+,	POS	O
+which	POS	O
+has	POS	O
+the	POS	O
+highest	POS	O
+risk	POS	O
+of	POS	O
+causing	POS	O
+blood	POS	B-NP
+dyscrasias	POS	I-NP
+,	POS	O
+especially	POS	O
+neutropenia	POS	B-NP
+.	POS	O
+There	POS	O
+are	POS	O
+some	POS	O
+case	POS	O
+reports	POS	O
+about	POS	O
+this	POS	O
+side	POS	O
+effect	POS	O
+of	POS	O
+quetiapine	POS	O
+,	POS	O
+but	POS	O
+possible	POS	O
+risk	POS	O
+factors	POS	O
+are	POS	O
+seldom	POS	O
+discussed	POS	O
+and	POS	O
+identified	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+hepatocellular	POS	B-NP
+carcinoma	POS	I-NP
+that	POS	O
+developed	POS	O
+neutropenia	POS	B-NP
+after	POS	O
+treatment	POS	O
+with	POS	O
+quetiapine	POS	O
+is	POS	O
+described	POS	O
+here	POS	O
+.	POS	O
+CASE	POS	O
+REPORT	POS	O
+:	POS	O
+A	POS	O
+62	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+Taiwanese	POS	O
+widow	POS	O
+with	POS	O
+bipolar	POS	B-NP
+disorder	POS	I-NP
+was	POS	O
+diagnosed	POS	O
+with	POS	O
+hepatocellular	POS	B-NP
+carcinoma	POS	I-NP
+at	POS	O
+age	POS	O
+60	POS	O
+.	POS	O
+She	POS	O
+developed	POS	O
+leucopenia	POS	B-NP
+after	POS	O
+being	POS	O
+treated	POS	O
+with	POS	O
+quetiapine	POS	O
+.	POS	O
+After	POS	O
+quetiapine	POS	O
+was	POS	O
+discontinued	POS	O
+,	POS	O
+her	POS	O
+white	POS	O
+blood	POS	O
+cell	POS	O
+count	POS	O
+returned	POS	O
+to	POS	O
+normal	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Although	POS	O
+neutropenia	POS	B-NP
+is	POS	O
+not	POS	O
+a	POS	O
+common	POS	O
+side	POS	O
+effect	POS	O
+of	POS	O
+quetiapine	POS	O
+,	POS	O
+physicians	POS	O
+should	POS	O
+be	POS	O
+cautious	POS	O
+about	POS	O
+its	POS	O
+presentation	POS	O
+and	POS	O
+associated	POS	O
+risk	POS	O
+factors	POS	O
+.	POS	O
+Hepatic	POS	B-NP
+dysfunction	POS	I-NP
+may	POS	O
+be	POS	O
+one	POS	O
+of	POS	O
+the	POS	O
+possible	POS	O
+risk	POS	O
+factors	POS	O
+,	POS	O
+and	POS	O
+concomitant	POS	O
+fever	POS	B-NP
+may	POS	O
+be	POS	O
+a	POS	O
+diagnostic	POS	O
+marker	POS	O
+for	POS	O
+adverse	POS	O
+reaction	POS	O
+to	POS	O
+quetiapine	POS	O
+.	POS	O
+Lateral	POS	B-NP
+antebrachial	POS	I-NP
+cutaneous	POS	I-NP
+neuropathy	POS	I-NP
+after	POS	O
+steroid	POS	O
+injection	POS	O
+at	POS	O
+lateral	POS	O
+epicondyle	POS	O
+.	POS	O
+BACKGROUND	POS	O
+AND	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+This	POS	O
+report	POS	O
+aimed	POS	O
+to	POS	O
+present	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+lateral	POS	B-NP
+antebrachial	POS	I-NP
+cutaneous	POS	I-NP
+neuropathy	POS	I-NP
+(	POS	O
+LACNP	POS	B-NP
+)	POS	O
+that	POS	O
+occurred	POS	O
+after	POS	O
+a	POS	O
+steroid	POS	O
+injection	POS	O
+in	POS	O
+the	POS	O
+lateral	POS	O
+epicondyle	POS	O
+to	POS	O
+treat	POS	O
+lateral	POS	B-NP
+epicondylitis	POS	I-NP
+in	POS	O
+a	POS	O
+40	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+.	POS	O
+MATERIAL	POS	O
+AND	POS	O
+METHOD	POS	O
+:	POS	O
+A	POS	O
+40	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+presented	POS	O
+with	POS	O
+decreased	POS	B-NP
+sensation	POS	I-NP
+and	POS	O
+paresthesia	POS	B-NP
+over	POS	O
+her	POS	O
+right	POS	O
+lateral	POS	O
+forearm	POS	O
+;	POS	O
+the	POS	O
+paresthesia	POS	B-NP
+had	POS	O
+occurred	POS	O
+after	POS	O
+a	POS	O
+steroid	POS	O
+injection	POS	O
+in	POS	O
+the	POS	O
+right	POS	O
+lateral	POS	O
+epicondyle	POS	O
+3	POS	O
+months	POS	O
+before	POS	O
+.	POS	O
+Her	POS	O
+sensation	POS	O
+of	POS	O
+light	POS	O
+touch	POS	O
+and	POS	O
+pain	POS	B-NP
+was	POS	O
+diminished	POS	O
+over	POS	O
+the	POS	O
+lateral	POS	O
+side	POS	O
+of	POS	O
+the	POS	O
+right	POS	O
+forearm	POS	O
+and	POS	O
+wrist	POS	O
+area	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+sensory	POS	O
+action	POS	O
+potential	POS	O
+amplitude	POS	O
+of	POS	O
+the	POS	O
+right	POS	O
+lateral	POS	O
+antebrachial	POS	O
+cutaneous	POS	O
+nerve	POS	O
+(	POS	O
+LACN	POS	O
+)	POS	O
+(	POS	O
+6	POS	O
+.	POS	O
+2	POS	O
+uV	POS	O
+)	POS	O
+was	POS	O
+lower	POS	O
+than	POS	O
+that	POS	O
+of	POS	O
+the	POS	O
+left	POS	O
+(	POS	O
+13	POS	O
+.	POS	O
+1	POS	O
+uV	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+difference	POS	O
+of	POS	O
+amplitude	POS	O
+between	POS	O
+both	POS	O
+sides	POS	O
+was	POS	O
+significant	POS	O
+because	POS	O
+there	POS	O
+was	POS	O
+more	POS	O
+than	POS	O
+a	POS	O
+50	POS	O
+%	POS	O
+reduction	POS	O
+.	POS	O
+She	POS	O
+was	POS	O
+diagnosed	POS	O
+with	POS	O
+right	POS	O
+LACNP	POS	O
+(	POS	O
+mainly	POS	O
+axonal	POS	O
+involvement	POS	O
+)	POS	O
+on	POS	O
+the	POS	O
+basis	POS	O
+of	POS	O
+the	POS	O
+clinical	POS	O
+manifestation	POS	O
+and	POS	O
+the	POS	O
+electrodiagnostic	POS	O
+findings	POS	O
+.	POS	O
+Her	POS	O
+symptoms	POS	O
+improved	POS	O
+through	POS	O
+physical	POS	O
+therapy	POS	O
+but	POS	O
+persisted	POS	O
+to	POS	O
+some	POS	O
+degree	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+This	POS	O
+report	POS	O
+describes	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+woman	POS	O
+with	POS	O
+LACNP	POS	B-NP
+that	POS	O
+developed	POS	O
+after	POS	O
+a	POS	O
+steroid	POS	O
+injection	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+lateral	POS	B-NP
+epicondylitis	POS	I-NP
+.	POS	O
+An	POS	O
+electrodiagnostic	POS	O
+study	POS	O
+,	POS	O
+including	POS	O
+a	POS	O
+nerve	POS	O
+conduction	POS	O
+study	POS	O
+of	POS	O
+the	POS	O
+LACN	POS	O
+,	POS	O
+was	POS	O
+helpful	POS	O
+to	POS	O
+diagnose	POS	O
+right	POS	O
+LACNP	POS	O
+and	POS	O
+to	POS	O
+find	POS	O
+the	POS	O
+passage	POS	O
+of	POS	O
+the	POS	O
+LACN	POS	O
+on	POS	O
+the	POS	O
+lateral	POS	O
+epicondyle	POS	O
+.	POS	O
+Curcumin	POS	O
+prevents	POS	O
+maleate	POS	O
+-	POS	O
+induced	POS	O
+nephrotoxicity	POS	B-NP
+:	POS	O
+relation	POS	O
+to	POS	O
+hemodynamic	POS	O
+alterations	POS	O
+,	POS	O
+oxidative	POS	O
+stress	POS	O
+,	POS	O
+mitochondrial	POS	O
+oxygen	POS	O
+consumption	POS	O
+and	POS	O
+activity	POS	O
+of	POS	O
+respiratory	POS	O
+complex	POS	O
+I	POS	O
+.	POS	O
+The	POS	O
+potential	POS	O
+protective	POS	O
+effect	POS	O
+of	POS	O
+the	POS	O
+dietary	POS	O
+antioxidant	POS	O
+curcumin	POS	O
+(	POS	O
+120	POS	O
+mg	POS	O
+/	POS	O
+Kg	POS	O
+/	POS	O
+day	POS	O
+for	POS	O
+6	POS	O
+days	POS	O
+)	POS	O
+against	POS	O
+the	POS	O
+renal	POS	B-NP
+injury	POS	I-NP
+induced	POS	O
+by	POS	O
+maleate	POS	O
+was	POS	O
+evaluated	POS	O
+.	POS	O
+Tubular	POS	O
+proteinuria	POS	B-NP
+and	POS	O
+oxidative	POS	O
+stress	POS	O
+were	POS	O
+induced	POS	O
+by	POS	O
+a	POS	O
+single	POS	O
+injection	POS	O
+of	POS	O
+maleate	POS	O
+(	POS	O
+400	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+Maleate	POS	O
+-	POS	O
+induced	POS	O
+renal	POS	B-NP
+injury	POS	I-NP
+included	POS	O
+increase	POS	B-NP
+in	POS	I-NP
+renal	POS	I-NP
+vascular	POS	I-NP
+resistance	POS	I-NP
+and	POS	O
+in	POS	O
+the	POS	O
+urinary	POS	O
+excretion	POS	O
+of	POS	O
+total	POS	O
+protein	POS	O
+,	POS	O
+glucose	POS	O
+,	POS	O
+sodium	POS	O
+,	POS	O
+neutrophil	POS	O
+gelatinase	POS	O
+-	POS	O
+associated	POS	O
+lipocalin	POS	O
+(	POS	O
+NGAL	POS	O
+)	POS	O
+and	POS	O
+N	POS	O
+-	POS	O
+acetyl	POS	O
+b	POS	O
+-	POS	O
+D	POS	O
+-	POS	O
+glucosaminidase	POS	O
+(	POS	O
+NAG	POS	O
+)	POS	O
+,	POS	O
+upregulation	POS	O
+of	POS	O
+kidney	POS	O
+injury	POS	O
+molecule	POS	O
+(	POS	O
+KIM	POS	O
+)	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+decrease	POS	O
+in	POS	O
+renal	POS	O
+blood	POS	O
+flow	POS	O
+and	POS	O
+claudin	POS	O
+-	POS	O
+2	POS	O
+expression	POS	O
+besides	POS	O
+of	POS	O
+necrosis	POS	B-NP
+and	POS	O
+apoptosis	POS	O
+of	POS	O
+tubular	POS	O
+cells	POS	O
+on	POS	O
+24	POS	O
+h	POS	O
+.	POS	O
+Oxidative	POS	O
+stress	POS	O
+was	POS	O
+determined	POS	O
+by	POS	O
+measuring	POS	O
+the	POS	O
+oxidation	POS	O
+of	POS	O
+lipids	POS	O
+and	POS	O
+proteins	POS	O
+and	POS	O
+diminution	POS	O
+in	POS	O
+renal	POS	O
+Nrf2	POS	O
+levels	POS	O
+.	POS	O
+Studies	POS	O
+were	POS	O
+also	POS	O
+conducted	POS	O
+in	POS	O
+renal	POS	O
+epithelial	POS	O
+LLC	POS	O
+-	POS	O
+PK1	POS	O
+cells	POS	O
+and	POS	O
+in	POS	O
+mitochondria	POS	O
+isolated	POS	O
+from	POS	O
+kidneys	POS	O
+of	POS	O
+all	POS	O
+the	POS	O
+experimental	POS	O
+groups	POS	O
+.	POS	O
+Maleate	POS	O
+induced	POS	O
+cell	POS	O
+damage	POS	O
+and	POS	O
+reactive	POS	O
+oxygen	POS	O
+species	POS	O
+(	POS	O
+ROS	POS	O
+)	POS	O
+production	POS	O
+in	POS	O
+LLC	POS	O
+-	POS	O
+PK1	POS	O
+cells	POS	O
+in	POS	O
+culture	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+maleate	POS	O
+treatment	POS	O
+reduced	POS	O
+oxygen	POS	O
+consumption	POS	O
+in	POS	O
+ADP	POS	O
+-	POS	O
+stimulated	POS	O
+mitochondria	POS	O
+and	POS	O
+diminished	POS	O
+respiratory	POS	O
+control	POS	O
+index	POS	O
+when	POS	O
+using	POS	O
+malate	POS	O
+/	POS	O
+glutamate	POS	O
+as	POS	O
+substrate	POS	O
+.	POS	O
+The	POS	O
+activities	POS	O
+of	POS	O
+both	POS	O
+complex	POS	O
+I	POS	O
+and	POS	O
+aconitase	POS	O
+were	POS	O
+also	POS	O
+diminished	POS	O
+.	POS	O
+All	POS	O
+the	POS	O
+above	POS	O
+-	POS	O
+described	POS	O
+alterations	POS	O
+were	POS	O
+prevented	POS	O
+by	POS	O
+curcumin	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+concluded	POS	O
+that	POS	O
+curcumin	POS	O
+is	POS	O
+able	POS	O
+to	POS	O
+attenuate	POS	O
+in	POS	O
+vivo	POS	O
+maleate	POS	O
+-	POS	O
+induced	POS	O
+nephropathy	POS	B-NP
+and	POS	O
+in	POS	O
+vitro	POS	O
+cell	POS	O
+damage	POS	O
+.	POS	O
+The	POS	O
+in	POS	O
+vivo	POS	O
+protection	POS	O
+was	POS	O
+associated	POS	O
+to	POS	O
+the	POS	O
+prevention	POS	O
+of	POS	O
+oxidative	POS	O
+stress	POS	O
+and	POS	O
+preservation	POS	O
+of	POS	O
+mitochondrial	POS	O
+oxygen	POS	O
+consumption	POS	O
+and	POS	O
+activity	POS	O
+of	POS	O
+respiratory	POS	O
+complex	POS	O
+I	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+in	POS	O
+vitro	POS	O
+protection	POS	O
+was	POS	O
+associated	POS	O
+to	POS	O
+the	POS	O
+prevention	POS	O
+of	POS	O
+ROS	POS	O
+production	POS	O
+.	POS	O
+Anticonvulsant	POS	O
+actions	POS	O
+of	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+on	POS	O
+the	POS	O
+lithium	POS	O
+-	POS	O
+pilocarpine	POS	O
+model	POS	O
+of	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+,	POS	O
+a	POS	O
+noncompetitive	POS	O
+N	POS	O
+-	POS	O
+methyl	POS	O
+-	POS	O
+D	POS	O
+-	POS	O
+aspartate	POS	O
+(	POS	O
+NMDA	POS	O
+)	POS	O
+receptor	POS	O
+antagonist	POS	O
+,	POS	O
+was	POS	O
+tested	POS	O
+for	POS	O
+anticonvulsant	POS	O
+effects	POS	O
+in	POS	O
+rats	POS	O
+using	POS	O
+two	POS	O
+seizure	POS	B-NP
+models	POS	O
+,	POS	O
+coadministration	POS	O
+of	POS	O
+lithium	POS	O
+and	POS	O
+pilocarpine	POS	O
+and	POS	O
+administration	POS	O
+of	POS	O
+a	POS	O
+high	POS	O
+dose	POS	O
+of	POS	O
+pilocarpine	POS	O
+alone	POS	O
+.	POS	O
+Three	POS	O
+major	POS	O
+results	POS	O
+are	POS	O
+reported	POS	O
+.	POS	O
+First	POS	O
+,	POS	O
+pretreatment	POS	O
+with	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+produced	POS	O
+an	POS	O
+effective	POS	O
+and	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+anticonvulsant	POS	O
+action	POS	O
+with	POS	O
+the	POS	O
+lithium	POS	O
+-	POS	O
+pilocarpine	POS	O
+model	POS	O
+but	POS	O
+not	POS	O
+with	POS	O
+rats	POS	O
+treated	POS	O
+with	POS	O
+pilocarpine	POS	O
+alone	POS	O
+,	POS	O
+suggesting	POS	O
+that	POS	O
+different	POS	O
+biochemical	POS	O
+mechanisms	POS	O
+control	POS	O
+seizures	POS	B-NP
+in	POS	O
+these	POS	O
+two	POS	O
+models	POS	O
+.	POS	O
+Second	POS	O
+,	POS	O
+the	POS	O
+anticonvulsant	POS	O
+effect	POS	O
+of	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+in	POS	O
+the	POS	O
+lithium	POS	O
+-	POS	O
+pilocarpine	POS	O
+model	POS	O
+only	POS	O
+occurred	POS	O
+after	POS	O
+initial	POS	O
+periods	POS	O
+of	POS	O
+seizure	POS	B-NP
+activity	POS	O
+.	POS	O
+This	POS	O
+observation	POS	O
+is	POS	O
+suggested	POS	O
+to	POS	O
+be	POS	O
+an	POS	O
+in	POS	O
+vivo	POS	O
+demonstration	POS	O
+of	POS	O
+the	POS	O
+conclusion	POS	O
+derived	POS	O
+from	POS	O
+in	POS	O
+vitro	POS	O
+experiments	POS	O
+that	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+binding	POS	O
+requires	POS	O
+agonist	POS	O
+-	POS	O
+induced	POS	O
+opening	POS	O
+of	POS	O
+the	POS	O
+channel	POS	O
+sites	POS	O
+of	POS	O
+the	POS	O
+NMDA	POS	O
+receptor	POS	O
+.	POS	O
+Third	POS	O
+,	POS	O
+although	POS	O
+it	POS	O
+is	POS	O
+relatively	POS	O
+easy	POS	O
+to	POS	O
+block	POS	O
+seizures	POS	B-NP
+induced	POS	O
+by	POS	O
+lithium	POS	O
+and	POS	O
+pilocarpine	POS	O
+by	POS	O
+administration	POS	O
+of	POS	O
+anticonvulsants	POS	O
+prior	POS	O
+to	POS	O
+pilocarpine	POS	O
+,	POS	O
+it	POS	O
+is	POS	O
+more	POS	O
+difficult	POS	O
+to	POS	O
+terminate	POS	O
+ongoing	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+and	POS	O
+block	POS	O
+the	POS	O
+lethality	POS	O
+of	POS	O
+the	POS	O
+seizures	POS	B-NP
+.	POS	O
+Administration	POS	O
+of	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+30	POS	O
+or	POS	O
+60	POS	O
+min	POS	O
+after	POS	O
+pilocarpine	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+e	POS	O
+.	POS	O
+,	POS	O
+during	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+,	POS	O
+gradually	POS	O
+reduced	POS	O
+electrical	POS	O
+and	POS	O
+behavioral	POS	O
+seizure	POS	B-NP
+activity	POS	O
+and	POS	O
+greatly	POS	O
+enhanced	POS	O
+the	POS	O
+survival	POS	O
+rate	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+activation	POS	O
+of	POS	O
+NMDA	POS	O
+receptors	POS	O
+plays	POS	O
+an	POS	O
+important	POS	O
+role	POS	O
+in	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+and	POS	O
+brain	POS	B-NP
+damage	POS	I-NP
+in	POS	O
+the	POS	O
+lithium	POS	O
+-	POS	O
+pilocarpine	POS	O
+model	POS	O
+.	POS	O
+This	POS	O
+was	POS	O
+further	POS	O
+supported	POS	O
+by	POS	O
+results	POS	O
+showing	POS	O
+that	POS	O
+nonconvulsive	POS	B-NP
+doses	POS	O
+of	POS	O
+NMDA	POS	O
+and	POS	O
+pilocarpine	POS	O
+were	POS	O
+synergistic	POS	O
+,	POS	O
+resulting	POS	O
+in	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+and	POS	O
+subsequent	POS	O
+mortality	POS	O
+.	POS	O
+Continuous	POS	O
+infusion	POS	O
+tobramycin	POS	O
+combined	POS	O
+with	POS	O
+carbenicillin	POS	O
+for	POS	O
+infections	POS	O
+in	POS	O
+cancer	POS	B-NP
+patients	POS	O
+.	POS	O
+The	POS	O
+cure	POS	O
+rate	POS	O
+of	POS	O
+infections	POS	B-NP
+in	POS	O
+cancer	POS	B-NP
+patients	POS	O
+is	POS	O
+adversely	POS	O
+affected	POS	O
+by	POS	O
+neutropenia	POS	B-NP
+(	POS	O
+less	POS	O
+than	POS	O
+1	POS	O
+,	POS	O
+000	POS	O
+/	POS	O
+mm3	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+particular	POS	O
+,	POS	O
+patients	POS	O
+with	POS	O
+severe	POS	O
+neutropenia	POS	B-NP
+(	POS	O
+less	POS	O
+than	POS	O
+100	POS	O
+/	POS	O
+mm3	POS	O
+)	POS	O
+have	POS	O
+shown	POS	O
+a	POS	O
+poor	POS	O
+response	POS	O
+to	POS	O
+antibiotics	POS	O
+.	POS	O
+To	POS	O
+overcome	POS	O
+the	POS	O
+adverse	POS	O
+effects	POS	O
+of	POS	O
+neutropenia	POS	B-NP
+,	POS	O
+tobramycin	POS	O
+was	POS	O
+given	POS	O
+by	POS	O
+continuous	POS	O
+infusion	POS	O
+and	POS	O
+combined	POS	O
+with	POS	O
+intermittent	POS	O
+carbenicillin	POS	O
+.	POS	O
+Tobramycin	POS	O
+was	POS	O
+given	POS	O
+to	POS	O
+a	POS	O
+total	POS	O
+daily	POS	O
+dose	POS	O
+of	POS	O
+300	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+and	POS	O
+carbenicillin	POS	O
+was	POS	O
+given	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+5	POS	O
+gm	POS	O
+every	POS	O
+four	POS	O
+hours	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+125	POS	O
+infectious	POS	O
+episodes	POS	O
+in	POS	O
+116	POS	O
+cancer	POS	B-NP
+patients	POS	O
+receiving	POS	O
+myelosuppressive	POS	O
+chemotherapy	POS	O
+.	POS	O
+The	POS	O
+overall	POS	O
+cure	POS	O
+rate	POS	O
+was	POS	O
+70	POS	O
+%	POS	O
+.	POS	O
+Pneumonia	POS	B-NP
+was	POS	O
+the	POS	O
+most	POS	O
+common	POS	O
+infection	POS	O
+and	POS	O
+61	POS	O
+%	POS	O
+of	POS	O
+59	POS	O
+episodes	POS	O
+were	POS	O
+cured	POS	O
+.	POS	O
+Gram	POS	O
+-	POS	O
+negative	POS	O
+bacilli	POS	O
+were	POS	O
+the	POS	O
+most	POS	O
+common	POS	O
+causative	POS	O
+organisms	POS	O
+and	POS	O
+69	POS	O
+%	POS	O
+of	POS	O
+these	POS	O
+infections	POS	B-NP
+were	POS	O
+cured	POS	O
+.	POS	O
+The	POS	O
+most	POS	O
+common	POS	O
+pathogen	POS	O
+was	POS	O
+Klebsiella	POS	O
+pneumoniae	POS	O
+and	POS	O
+this	POS	O
+,	POS	O
+together	POS	O
+with	POS	O
+Escherichia	POS	O
+coli	POS	O
+and	POS	O
+Pseudomonas	POS	O
+aeruginosa	POS	O
+,	POS	O
+accounted	POS	O
+for	POS	O
+74	POS	O
+%	POS	O
+of	POS	O
+all	POS	O
+gram	POS	O
+-	POS	O
+negative	POS	O
+bacillary	POS	B-NP
+infections	POS	I-NP
+.	POS	O
+Response	POS	O
+was	POS	O
+not	POS	O
+influenced	POS	O
+by	POS	O
+the	POS	O
+initial	POS	O
+neutrophil	POS	O
+count	POS	O
+,	POS	O
+with	POS	O
+a	POS	O
+62	POS	O
+%	POS	O
+cure	POS	O
+rate	POS	O
+for	POS	O
+39	POS	O
+episodes	POS	O
+associated	POS	O
+with	POS	O
+severe	POS	O
+neutropenia	POS	B-NP
+.	POS	O
+However	POS	O
+,	POS	O
+failure	POS	O
+of	POS	O
+the	POS	O
+neutrophil	POS	O
+count	POS	O
+to	POS	O
+increase	POS	O
+during	POS	O
+therapy	POS	O
+adversely	POS	O
+affected	POS	O
+response	POS	O
+.	POS	O
+Azotemia	POS	B-NP
+was	POS	O
+the	POS	O
+major	POS	O
+side	POS	O
+effect	POS	O
+recognized	POS	O
+,	POS	O
+and	POS	O
+it	POS	O
+occurred	POS	O
+in	POS	O
+11	POS	O
+%	POS	O
+of	POS	O
+episodes	POS	O
+.	POS	O
+Major	POS	O
+azotemia	POS	B-NP
+(	POS	O
+serum	POS	O
+creatinine	POS	O
+greater	POS	O
+than	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+or	POS	O
+BUN	POS	O
+greater	POS	O
+than	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+)	POS	O
+occurred	POS	O
+in	POS	O
+only	POS	O
+2	POS	O
+%	POS	O
+.	POS	O
+Azotemia	POS	B-NP
+was	POS	O
+not	POS	O
+related	POS	O
+to	POS	O
+duration	POS	O
+of	POS	O
+therapy	POS	O
+or	POS	O
+serum	POS	O
+tobramycin	POS	O
+concentration	POS	O
+.	POS	O
+This	POS	O
+antibiotic	POS	O
+regimen	POS	O
+showed	POS	O
+both	POS	O
+therapeutic	POS	O
+efficacy	POS	O
+and	POS	O
+acceptable	POS	O
+renal	POS	B-NP
+toxicity	POS	I-NP
+for	POS	O
+these	POS	O
+patients	POS	O
+.	POS	O
+Incidence	POS	O
+of	POS	O
+solid	POS	O
+tumours	POS	B-NP
+among	POS	O
+pesticide	POS	O
+applicators	POS	O
+exposed	POS	O
+to	POS	O
+the	POS	O
+organophosphate	POS	O
+insecticide	POS	O
+diazinon	POS	O
+in	POS	O
+the	POS	O
+Agricultural	POS	O
+Health	POS	O
+Study	POS	O
+:	POS	O
+an	POS	O
+updated	POS	O
+analysis	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+Diazinon	POS	O
+,	POS	O
+a	POS	O
+common	POS	O
+organophosphate	POS	O
+insecticide	POS	O
+with	POS	O
+genotoxic	POS	O
+properties	POS	O
+,	POS	O
+was	POS	O
+previously	POS	O
+associated	POS	O
+with	POS	O
+lung	POS	B-NP
+cancer	POS	I-NP
+in	POS	O
+the	POS	O
+Agricultural	POS	O
+Health	POS	O
+Study	POS	O
+(	POS	O
+AHS	POS	O
+)	POS	O
+cohort	POS	O
+,	POS	O
+but	POS	O
+few	POS	O
+other	POS	O
+epidemiological	POS	O
+studies	POS	O
+have	POS	O
+examined	POS	O
+diazinon	POS	O
+-	POS	O
+associated	POS	O
+cancer	POS	B-NP
+risk	POS	O
+.	POS	O
+We	POS	O
+used	POS	O
+updated	POS	O
+diazinon	POS	O
+exposure	POS	O
+and	POS	O
+cancer	POS	B-NP
+incidence	POS	O
+information	POS	O
+to	POS	O
+evaluate	POS	O
+solid	POS	O
+tumour	POS	B-NP
+risk	POS	O
+in	POS	O
+the	POS	O
+AHS	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Male	POS	O
+pesticide	POS	O
+applicators	POS	O
+in	POS	O
+Iowa	POS	O
+and	POS	O
+North	POS	O
+Carolina	POS	O
+reported	POS	O
+lifetime	POS	O
+diazinon	POS	O
+use	POS	O
+at	POS	O
+enrolment	POS	O
+(	POS	O
+1993	POS	O
+-	POS	O
+1997	POS	O
+)	POS	O
+and	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+(	POS	O
+1998	POS	O
+-	POS	O
+2005	POS	O
+)	POS	O
+;	POS	O
+cancer	POS	B-NP
+incidence	POS	O
+was	POS	O
+assessed	POS	O
+through	POS	O
+2010	POS	O
+(	POS	O
+North	POS	O
+Carolina	POS	O
+)	POS	O
+/	POS	O
+2011	POS	O
+(	POS	O
+Iowa	POS	O
+)	POS	O
+.	POS	O
+Among	POS	O
+applicators	POS	O
+with	POS	O
+usage	POS	O
+information	POS	O
+sufficient	POS	O
+to	POS	O
+evaluate	POS	O
+exposure	POS	O
+-	POS	O
+response	POS	O
+patterns	POS	O
+,	POS	O
+we	POS	O
+used	POS	O
+Poisson	POS	O
+regression	POS	O
+to	POS	O
+estimate	POS	O
+adjusted	POS	O
+rate	POS	O
+ratios	POS	O
+(	POS	O
+RRs	POS	O
+)	POS	O
+and	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+for	POS	O
+cancer	POS	B-NP
+sites	POS	O
+with	POS	O
+>	POS	O
+10	POS	O
+exposed	POS	O
+cases	POS	O
+for	POS	O
+both	POS	O
+lifetime	POS	O
+(	POS	O
+LT	POS	O
+)	POS	O
+exposure	POS	O
+days	POS	O
+and	POS	O
+intensity	POS	O
+-	POS	O
+weighted	POS	O
+(	POS	O
+IW	POS	O
+)	POS	O
+lifetime	POS	O
+exposure	POS	O
+days	POS	O
+(	POS	O
+accounting	POS	O
+for	POS	O
+factors	POS	O
+impacting	POS	O
+exposure	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+We	POS	O
+observed	POS	O
+elevated	POS	O
+lung	POS	B-NP
+cancer	POS	I-NP
+risks	POS	O
+(	POS	O
+N	POS	O
+=	POS	O
+283	POS	O
+)	POS	O
+among	POS	O
+applicators	POS	O
+with	POS	O
+the	POS	O
+greatest	POS	O
+number	POS	O
+of	POS	O
+LT	POS	O
+(	POS	O
+RR	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+60	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+1	POS	O
+.	POS	O
+11	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+31	POS	O
+;	POS	O
+Ptrend	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+and	POS	O
+IW	POS	O
+days	POS	O
+of	POS	O
+diazinon	POS	O
+use	POS	O
+(	POS	O
+RR	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+41	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+0	POS	O
+.	POS	O
+98	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+04	POS	O
+;	POS	O
+Ptrend	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+08	POS	O
+)	POS	O
+.	POS	O
+Kidney	POS	B-NP
+cancer	POS	I-NP
+(	POS	O
+N	POS	O
+=	POS	O
+94	POS	O
+)	POS	O
+risks	POS	O
+were	POS	O
+non	POS	O
+-	POS	O
+significantly	POS	O
+elevated	POS	O
+(	POS	O
+RRLT	POS	O
+days	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+77	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+0	POS	O
+.	POS	O
+90	POS	O
+to	POS	O
+3	POS	O
+.	POS	O
+51	POS	O
+;	POS	O
+Ptrend	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+09	POS	O
+;	POS	O
+RRIW	POS	O
+days	POS	O
+1	POS	O
+.	POS	O
+37	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+0	POS	O
+.	POS	O
+64	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+92	POS	O
+;	POS	O
+Ptrend	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+50	POS	O
+)	POS	O
+,	POS	O
+as	POS	O
+were	POS	O
+risks	POS	O
+for	POS	O
+aggressive	POS	O
+prostate	POS	B-NP
+cancer	POS	I-NP
+(	POS	O
+N	POS	O
+=	POS	O
+656	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Our	POS	O
+updated	POS	O
+evaluation	POS	O
+of	POS	O
+diazinon	POS	O
+provides	POS	O
+additional	POS	O
+evidence	POS	O
+of	POS	O
+an	POS	O
+association	POS	O
+with	POS	O
+lung	POS	B-NP
+cancer	POS	I-NP
+risk	POS	O
+.	POS	O
+Newly	POS	O
+identified	POS	O
+links	POS	O
+to	POS	O
+kidney	POS	B-NP
+cancer	POS	I-NP
+and	POS	O
+associations	POS	O
+with	POS	O
+aggressive	POS	O
+prostate	POS	B-NP
+cancer	POS	I-NP
+require	POS	O
+further	POS	O
+evaluation	POS	O
+.	POS	O
+Associations	POS	O
+of	POS	O
+Ozone	POS	O
+and	POS	O
+PM2	POS	O
+.	POS	O
+5	POS	O
+Concentrations	POS	O
+With	POS	O
+Parkinson	POS	O
+'	POS	O
+s	POS	O
+Disease	POS	O
+Among	POS	O
+Participants	POS	O
+in	POS	O
+the	POS	O
+Agricultural	POS	O
+Health	POS	O
+Study	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+This	POS	O
+study	POS	O
+describes	POS	O
+associations	POS	O
+of	POS	O
+ozone	POS	O
+and	POS	O
+fine	POS	O
+particulate	POS	O
+matter	POS	O
+with	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+observed	POS	O
+among	POS	O
+farmers	POS	O
+in	POS	O
+North	POS	O
+Carolina	POS	O
+and	POS	O
+Iowa	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+used	POS	O
+logistic	POS	O
+regression	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+associations	POS	O
+of	POS	O
+these	POS	O
+pollutants	POS	O
+with	POS	O
+self	POS	O
+-	POS	O
+reported	POS	O
+,	POS	O
+doctor	POS	O
+-	POS	O
+diagnosed	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+Daily	POS	O
+predicted	POS	O
+pollutant	POS	O
+concentrations	POS	O
+were	POS	O
+used	POS	O
+to	POS	O
+derive	POS	O
+surrogates	POS	O
+of	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+exposure	POS	O
+and	POS	O
+link	POS	O
+them	POS	O
+to	POS	O
+study	POS	O
+participants	POS	O
+'	POS	O
+geocoded	POS	O
+addresses	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+We	POS	O
+observed	POS	O
+positive	POS	O
+associations	POS	O
+of	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+with	POS	O
+ozone	POS	O
+(	POS	O
+odds	POS	O
+ratio	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+39	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+:	POS	O
+0	POS	O
+.	POS	O
+98	POS	O
+to	POS	O
+1	POS	O
+.	POS	O
+98	POS	O
+)	POS	O
+and	POS	O
+fine	POS	O
+particulate	POS	O
+matter	POS	O
+(	POS	O
+odds	POS	O
+ratio	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+34	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+:	POS	O
+0	POS	O
+.	POS	O
+93	POS	O
+to	POS	O
+1	POS	O
+.	POS	O
+93	POS	O
+)	POS	O
+in	POS	O
+North	POS	O
+Carolina	POS	O
+but	POS	O
+not	POS	O
+in	POS	O
+Iowa	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+plausibility	POS	O
+of	POS	O
+an	POS	O
+effect	POS	O
+of	POS	O
+ambient	POS	O
+concentrations	POS	O
+of	POS	O
+these	POS	O
+pollutants	POS	O
+on	POS	O
+Parkinson	POS	O
+'	POS	O
+s	POS	O
+disease	POS	O
+risk	POS	O
+is	POS	O
+supported	POS	O
+by	POS	O
+experimental	POS	O
+data	POS	O
+demonstrating	POS	O
+damage	POS	O
+to	POS	O
+dopaminergic	POS	O
+neurons	POS	O
+at	POS	O
+relevant	POS	O
+concentrations	POS	O
+.	POS	O
+Additional	POS	O
+studies	POS	O
+are	POS	O
+needed	POS	O
+to	POS	O
+address	POS	O
+uncertainties	POS	O
+related	POS	O
+to	POS	O
+confounding	POS	O
+and	POS	O
+to	POS	O
+examine	POS	O
+temporal	POS	O
+aspects	POS	O
+of	POS	O
+the	POS	O
+associations	POS	O
+we	POS	O
+observed	POS	O
+.	POS	O
+Low	POS	O
+functional	POS	O
+programming	POS	O
+of	POS	O
+renal	POS	O
+AT2R	POS	O
+mediates	POS	O
+the	POS	O
+developmental	POS	O
+origin	POS	O
+of	POS	O
+glomerulosclerosis	POS	B-NP
+in	POS	O
+adult	POS	O
+offspring	POS	O
+induced	POS	O
+by	POS	O
+prenatal	POS	O
+caffeine	POS	O
+exposure	POS	O
+.	POS	O
+UNASSIGNED	POS	O
+:	POS	O
+Our	POS	O
+previous	POS	O
+study	POS	O
+has	POS	O
+indicated	POS	O
+that	POS	O
+prenatal	POS	O
+caffeine	POS	O
+exposure	POS	O
+(	POS	O
+PCE	POS	O
+)	POS	O
+could	POS	O
+induce	POS	O
+intrauterine	POS	B-NP
+growth	POS	I-NP
+retardation	POS	I-NP
+(	POS	O
+IUGR	POS	B-NP
+)	POS	O
+of	POS	O
+offspring	POS	O
+.	POS	O
+Recent	POS	O
+research	POS	O
+suggested	POS	O
+that	POS	O
+IUGR	POS	B-NP
+is	POS	O
+a	POS	O
+risk	POS	O
+factor	POS	O
+for	POS	O
+glomerulosclerosis	POS	B-NP
+.	POS	O
+However	POS	O
+,	POS	O
+whether	POS	O
+PCE	POS	O
+could	POS	O
+induce	POS	O
+glomerulosclerosis	POS	B-NP
+and	POS	O
+its	POS	O
+underlying	POS	O
+mechanisms	POS	O
+remain	POS	O
+unknown	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+aimed	POS	O
+to	POS	O
+demonstrate	POS	O
+the	POS	O
+induction	POS	O
+to	POS	O
+glomerulosclerosis	POS	B-NP
+in	POS	O
+adult	POS	O
+offspring	POS	O
+by	POS	O
+PCE	POS	O
+and	POS	O
+its	POS	O
+intrauterine	POS	O
+programming	POS	O
+mechanisms	POS	O
+.	POS	O
+A	POS	O
+rat	POS	O
+model	POS	O
+of	POS	O
+IUGR	POS	B-NP
+was	POS	O
+established	POS	O
+by	POS	O
+PCE	POS	O
+,	POS	O
+male	POS	O
+fetuses	POS	O
+and	POS	O
+adult	POS	O
+offspring	POS	O
+at	POS	O
+the	POS	O
+age	POS	O
+of	POS	O
+postnatal	POS	O
+week	POS	O
+24	POS	O
+were	POS	O
+euthanized	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+revealed	POS	O
+that	POS	O
+the	POS	O
+adult	POS	O
+offspring	POS	O
+kidneys	POS	O
+in	POS	O
+the	POS	O
+PCE	POS	O
+group	POS	O
+exhibited	POS	O
+glomerulosclerosis	POS	B-NP
+as	POS	O
+well	POS	O
+as	POS	O
+interstitial	POS	B-NP
+fibrosis	POS	I-NP
+,	POS	O
+accompanied	POS	O
+by	POS	O
+elevated	POS	O
+levels	POS	O
+of	POS	O
+serum	POS	O
+creatinine	POS	O
+and	POS	O
+urine	POS	O
+protein	POS	O
+.	POS	O
+Renal	POS	O
+angiotensin	POS	O
+II	POS	O
+receptor	POS	O
+type	POS	O
+2	POS	O
+(	POS	O
+AT2R	POS	O
+)	POS	O
+gene	POS	O
+expression	POS	O
+in	POS	O
+adult	POS	O
+offspring	POS	O
+was	POS	O
+reduced	POS	O
+by	POS	O
+PCE	POS	O
+,	POS	O
+whereas	POS	O
+the	POS	O
+renal	POS	O
+angiotensin	POS	O
+II	POS	O
+receptor	POS	O
+type	POS	O
+1a	POS	O
+(	POS	O
+AT1aR	POS	O
+)	POS	O
+/	POS	O
+AT2R	POS	O
+expression	POS	O
+ratio	POS	O
+was	POS	O
+increased	POS	O
+.	POS	O
+The	POS	O
+fetal	POS	O
+kidneys	POS	O
+in	POS	O
+the	POS	O
+PCE	POS	O
+group	POS	O
+displayed	POS	O
+an	POS	O
+enlarged	POS	O
+Bowman	POS	O
+'	POS	O
+s	POS	O
+space	POS	O
+and	POS	O
+a	POS	O
+shrunken	POS	O
+glomerular	POS	O
+tuft	POS	O
+,	POS	O
+accompanied	POS	O
+by	POS	O
+a	POS	O
+reduced	POS	O
+cortex	POS	O
+width	POS	O
+and	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+nephrogenic	POS	O
+zone	POS	O
+/	POS	O
+cortical	POS	O
+zone	POS	O
+ratio	POS	O
+.	POS	O
+Observation	POS	O
+by	POS	O
+electronic	POS	O
+microscope	POS	O
+revealed	POS	O
+structural	POS	O
+damage	POS	O
+of	POS	O
+podocytes	POS	O
+;	POS	O
+the	POS	O
+reduced	POS	O
+expression	POS	O
+level	POS	O
+of	POS	O
+podocyte	POS	O
+marker	POS	O
+genes	POS	O
+,	POS	O
+nephrin	POS	O
+and	POS	O
+podocin	POS	O
+,	POS	O
+was	POS	O
+also	POS	O
+detected	POS	O
+by	POS	O
+q	POS	O
+-	POS	O
+PCR	POS	O
+.	POS	O
+Moreover	POS	O
+,	POS	O
+AT2R	POS	O
+gene	POS	O
+and	POS	O
+protein	POS	O
+expressions	POS	O
+in	POS	O
+fetal	POS	O
+kidneys	POS	O
+were	POS	O
+inhibited	POS	O
+by	POS	O
+PCE	POS	O
+,	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+repression	POS	O
+of	POS	O
+the	POS	O
+gene	POS	O
+expression	POS	O
+of	POS	O
+glial	POS	O
+-	POS	O
+cell	POS	O
+-	POS	O
+line	POS	O
+-	POS	O
+derived	POS	O
+neurotrophic	POS	O
+factor	POS	O
+(	POS	O
+GDNF	POS	O
+)	POS	O
+/	POS	O
+tyrosine	POS	O
+kinase	POS	O
+receptor	POS	O
+(	POS	O
+c	POS	O
+-	POS	O
+Ret	POS	O
+)	POS	O
+signaling	POS	O
+pathway	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+demonstrated	POS	O
+that	POS	O
+PCE	POS	O
+could	POS	O
+induce	POS	O
+dysplasia	POS	B-NP
+of	POS	O
+fetal	POS	O
+kidneys	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+glomerulosclerosis	POS	B-NP
+of	POS	O
+adult	POS	O
+offspring	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+low	POS	O
+functional	POS	O
+programming	POS	O
+of	POS	O
+renal	POS	O
+AT2R	POS	O
+might	POS	O
+mediate	POS	O
+the	POS	O
+developmental	POS	O
+origin	POS	O
+of	POS	O
+adult	POS	O
+glomerulosclerosis	POS	B-NP
+.	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+-	POS	O
+Butadiene	POS	O
+,	POS	O
+CML	POS	B-NP
+and	POS	O
+the	POS	O
+t	POS	O
+(	POS	O
+9	POS	O
+:	POS	O
+22	POS	O
+)	POS	O
+translocation	POS	O
+:	POS	O
+A	POS	O
+reality	POS	O
+check	POS	O
+.	POS	O
+UNASSIGNED	POS	O
+:	POS	O
+Epidemiological	POS	O
+studies	POS	O
+of	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+-	POS	O
+butadiene	POS	O
+have	POS	O
+suggest	POS	O
+that	POS	O
+exposures	POS	O
+to	POS	O
+humans	POS	O
+are	POS	O
+associated	POS	O
+with	POS	O
+chronic	POS	B-NP
+myeloid	POS	I-NP
+leukemia	POS	I-NP
+(	POS	O
+CML	POS	B-NP
+)	POS	O
+.	POS	O
+CML	POS	B-NP
+has	POS	O
+a	POS	O
+well	POS	O
+-	POS	O
+documented	POS	O
+association	POS	O
+with	POS	O
+ionizing	POS	O
+radiation	POS	O
+,	POS	O
+but	POS	O
+reports	POS	O
+of	POS	O
+associations	POS	O
+with	POS	O
+chemical	POS	O
+exposures	POS	O
+have	POS	O
+been	POS	O
+questioned	POS	O
+.	POS	O
+Ionizing	POS	O
+radiation	POS	O
+is	POS	O
+capable	POS	O
+of	POS	O
+inducing	POS	O
+the	POS	O
+requisite	POS	O
+CML	POS	O
+-	POS	O
+associated	POS	O
+t	POS	O
+(	POS	O
+9	POS	O
+:	POS	O
+22	POS	O
+)	POS	O
+translocation	POS	O
+(	POS	O
+Philadelphia	POS	O
+chromosome	POS	O
+)	POS	O
+in	POS	O
+appropriate	POS	O
+cells	POS	O
+in	POS	O
+vitro	POS	O
+but	POS	O
+,	POS	O
+thus	POS	O
+far	POS	O
+,	POS	O
+chemicals	POS	O
+have	POS	O
+not	POS	O
+shown	POS	O
+this	POS	O
+capacity	POS	O
+.	POS	O
+We	POS	O
+have	POS	O
+proposed	POS	O
+that	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+-	POS	O
+butadiene	POS	O
+metabolites	POS	O
+be	POS	O
+so	POS	O
+tested	POS	O
+as	POS	O
+a	POS	O
+reality	POS	O
+check	POS	O
+on	POS	O
+the	POS	O
+epidemiological	POS	O
+reports	POS	O
+.	POS	O
+In	POS	O
+order	POS	O
+to	POS	O
+conduct	POS	O
+reliable	POS	O
+testing	POS	O
+in	POS	O
+this	POS	O
+regard	POS	O
+,	POS	O
+it	POS	O
+is	POS	O
+essential	POS	O
+that	POS	O
+a	POS	O
+positive	POS	O
+control	POS	O
+for	POS	O
+induction	POS	O
+be	POS	O
+available	POS	O
+.	POS	O
+We	POS	O
+have	POS	O
+used	POS	O
+ionizing	POS	O
+radiation	POS	O
+to	POS	O
+develop	POS	O
+such	POS	O
+a	POS	O
+control	POS	O
+.	POS	O
+Results	POS	O
+described	POS	O
+here	POS	O
+demonstrate	POS	O
+that	POS	O
+this	POS	O
+agent	POS	O
+does	POS	O
+in	POS	O
+fact	POS	O
+induce	POS	O
+pathogenic	POS	O
+t	POS	O
+(	POS	O
+9	POS	O
+:	POS	O
+22	POS	O
+)	POS	O
+translocations	POS	O
+in	POS	O
+a	POS	O
+human	POS	O
+myeloid	POS	O
+cell	POS	O
+line	POS	O
+in	POS	O
+vitro	POS	O
+,	POS	O
+but	POS	O
+does	POS	O
+so	POS	O
+at	POS	O
+low	POS	O
+frequencies	POS	O
+.	POS	O
+Conditions	POS	O
+that	POS	O
+will	POS	O
+be	POS	O
+required	POS	O
+for	POS	O
+studies	POS	O
+of	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+-	POS	O
+butadiene	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+Cancer	POS	O
+incidence	POS	O
+and	POS	O
+metolachlor	POS	O
+use	POS	O
+in	POS	O
+the	POS	O
+Agricultural	POS	O
+Health	POS	O
+Study	POS	O
+:	POS	O
+An	POS	O
+update	POS	O
+.	POS	O
+UNASSIGNED	POS	O
+:	POS	O
+Metolachlor	POS	O
+,	POS	O
+a	POS	O
+widely	POS	O
+used	POS	O
+herbicide	POS	O
+,	POS	O
+is	POS	O
+classified	POS	O
+as	POS	O
+a	POS	O
+Group	POS	O
+C	POS	O
+carcinogen	POS	O
+by	POS	O
+the	POS	O
+U	POS	O
+.	POS	O
+S	POS	O
+.	POS	O
+Environmental	POS	O
+Protection	POS	O
+Agency	POS	O
+based	POS	O
+on	POS	O
+increased	POS	O
+liver	POS	B-NP
+neoplasms	POS	I-NP
+in	POS	O
+female	POS	O
+rats	POS	O
+.	POS	O
+Epidemiologic	POS	O
+studies	POS	O
+of	POS	O
+the	POS	O
+health	POS	O
+effects	POS	O
+of	POS	O
+metolachlor	POS	O
+have	POS	O
+been	POS	O
+limited	POS	O
+.	POS	O
+The	POS	O
+Agricultural	POS	O
+Health	POS	O
+Study	POS	O
+(	POS	O
+AHS	POS	O
+)	POS	O
+is	POS	O
+a	POS	O
+prospective	POS	O
+cohort	POS	O
+study	POS	O
+including	POS	O
+licensed	POS	O
+private	POS	O
+and	POS	O
+commercial	POS	O
+pesticide	POS	O
+applicators	POS	O
+in	POS	O
+Iowa	POS	O
+and	POS	O
+North	POS	O
+Carolina	POS	O
+enrolled	POS	O
+1993	POS	O
+-	POS	O
+1997	POS	O
+.	POS	O
+We	POS	O
+evaluated	POS	O
+cancer	POS	B-NP
+incidence	POS	O
+through	POS	O
+2010	POS	O
+/	POS	O
+2011	POS	O
+(	POS	O
+NC	POS	O
+/	POS	O
+IA	POS	O
+)	POS	O
+for	POS	O
+49	POS	O
+,	POS	O
+616	POS	O
+applicators	POS	O
+,	POS	O
+53	POS	O
+%	POS	O
+of	POS	O
+whom	POS	O
+reported	POS	O
+ever	POS	O
+using	POS	O
+metolachlor	POS	O
+.	POS	O
+We	POS	O
+used	POS	O
+Poisson	POS	O
+regression	POS	O
+to	POS	O
+evaluate	POS	O
+relations	POS	O
+between	POS	O
+two	POS	O
+metrics	POS	O
+of	POS	O
+metolachlor	POS	O
+use	POS	O
+(	POS	O
+lifetime	POS	O
+days	POS	O
+,	POS	O
+intensity	POS	O
+-	POS	O
+weighted	POS	O
+lifetime	POS	O
+days	POS	O
+)	POS	O
+and	POS	O
+cancer	POS	B-NP
+incidence	POS	O
+.	POS	O
+We	POS	O
+saw	POS	O
+no	POS	O
+association	POS	O
+between	POS	O
+metolachlor	POS	O
+use	POS	O
+and	POS	O
+incidence	POS	O
+of	POS	O
+all	POS	O
+cancers	POS	B-NP
+combined	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+5	POS	O
+,	POS	O
+701	POS	O
+with	POS	O
+a	POS	O
+5	POS	O
+-	POS	O
+year	POS	O
+lag	POS	O
+)	POS	O
+or	POS	O
+most	POS	O
+site	POS	O
+-	POS	O
+specific	POS	O
+cancers	POS	B-NP
+.	POS	O
+For	POS	O
+liver	POS	B-NP
+cancer	POS	I-NP
+,	POS	O
+in	POS	O
+analyses	POS	O
+restricted	POS	O
+to	POS	O
+exposed	POS	O
+workers	POS	O
+,	POS	O
+elevations	POS	O
+observed	POS	O
+at	POS	O
+higher	POS	O
+categories	POS	O
+of	POS	O
+use	POS	O
+were	POS	O
+not	POS	O
+statistically	POS	O
+significant	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+trends	POS	O
+for	POS	O
+both	POS	O
+lifetime	POS	O
+and	POS	O
+intensity	POS	O
+-	POS	O
+weighted	POS	O
+lifetime	POS	O
+days	POS	O
+of	POS	O
+metolachor	POS	O
+use	POS	O
+were	POS	O
+positive	POS	O
+and	POS	O
+statistically	POS	O
+significant	POS	O
+with	POS	O
+an	POS	O
+unexposed	POS	O
+reference	POS	O
+group	POS	O
+.	POS	O
+A	POS	O
+similar	POS	O
+pattern	POS	O
+was	POS	O
+observed	POS	O
+for	POS	O
+follicular	POS	B-NP
+cell	POS	I-NP
+lymphoma	POS	I-NP
+,	POS	O
+but	POS	O
+no	POS	O
+other	POS	O
+lymphoma	POS	B-NP
+subtypes	POS	O
+.	POS	O
+An	POS	O
+earlier	POS	O
+suggestion	POS	O
+of	POS	O
+increased	POS	O
+lung	POS	B-NP
+cancer	POS	I-NP
+risk	POS	O
+at	POS	O
+high	POS	O
+levels	POS	O
+of	POS	O
+metolachlor	POS	O
+use	POS	O
+in	POS	O
+this	POS	O
+cohort	POS	O
+was	POS	O
+not	POS	O
+confirmed	POS	O
+in	POS	O
+this	POS	O
+update	POS	O
+.	POS	O
+This	POS	O
+suggestion	POS	O
+of	POS	O
+an	POS	O
+association	POS	O
+between	POS	O
+metolachlor	POS	O
+and	POS	O
+liver	POS	B-NP
+cancer	POS	I-NP
+among	POS	O
+pesticide	POS	O
+applicators	POS	O
+is	POS	O
+a	POS	O
+novel	POS	O
+finding	POS	O
+and	POS	O
+echoes	POS	O
+observation	POS	O
+of	POS	O
+increased	POS	O
+liver	POS	B-NP
+neoplasms	POS	I-NP
+in	POS	O
+some	POS	O
+animal	POS	O
+studies	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+our	POS	O
+findings	POS	O
+for	POS	O
+both	POS	O
+liver	POS	B-NP
+cancer	POS	I-NP
+and	POS	O
+follicular	POS	B-NP
+cell	POS	I-NP
+lymphoma	POS	I-NP
+warrant	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+to	POS	O
+better	POS	O
+differentiate	POS	O
+effects	POS	O
+of	POS	O
+metolachlor	POS	O
+use	POS	O
+from	POS	O
+other	POS	O
+factors	POS	O
+.	POS	O
+Mechanisms	POS	O
+Underlying	POS	O
+Latent	POS	O
+Disease	POS	O
+Risk	POS	O
+Associated	POS	O
+with	POS	O
+Early	POS	O
+-	POS	O
+Life	POS	O
+Arsenic	POS	O
+Exposure	POS	O
+:	POS	O
+Current	POS	O
+Research	POS	O
+Trends	POS	O
+and	POS	O
+Scientific	POS	O
+Gaps	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Millions	POS	O
+of	POS	O
+individuals	POS	O
+worldwide	POS	O
+,	POS	O
+particularly	POS	O
+those	POS	O
+living	POS	O
+in	POS	O
+rural	POS	O
+and	POS	O
+developing	POS	O
+areas	POS	O
+,	POS	O
+are	POS	O
+exposed	POS	O
+to	POS	O
+harmful	POS	O
+levels	POS	O
+of	POS	O
+inorganic	POS	O
+arsenic	POS	O
+(	POS	O
+iAs	POS	O
+)	POS	O
+in	POS	O
+their	POS	O
+drinking	POS	O
+water	POS	O
+.	POS	O
+Inorganic	POS	O
+As	POS	O
+exposure	POS	O
+during	POS	O
+key	POS	O
+developmental	POS	O
+periods	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+a	POS	O
+variety	POS	O
+of	POS	O
+adverse	POS	O
+health	POS	O
+effects	POS	O
+including	POS	O
+those	POS	O
+that	POS	O
+are	POS	O
+evident	POS	O
+in	POS	O
+adulthood	POS	O
+.	POS	O
+There	POS	O
+is	POS	O
+considerable	POS	O
+interest	POS	O
+in	POS	O
+identifying	POS	O
+the	POS	O
+molecular	POS	O
+mechanisms	POS	O
+that	POS	O
+relate	POS	O
+early	POS	O
+-	POS	O
+life	POS	O
+iAs	POS	O
+exposure	POS	O
+to	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+these	POS	O
+latent	POS	B-NP
+diseases	POS	I-NP
+,	POS	O
+particularly	POS	O
+in	POS	O
+relationship	POS	O
+to	POS	O
+cancer	POS	B-NP
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+This	POS	O
+work	POS	O
+summarizes	POS	O
+research	POS	O
+on	POS	O
+the	POS	O
+molecular	POS	O
+mechanisms	POS	O
+that	POS	O
+underlie	POS	O
+the	POS	O
+increased	POS	O
+risk	POS	O
+of	POS	O
+cancer	POS	B-NP
+development	POS	O
+in	POS	O
+adulthood	POS	O
+that	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+early	POS	O
+-	POS	O
+life	POS	O
+iAs	POS	O
+exposure	POS	O
+.	POS	O
+DISCUSSION	POS	O
+:	POS	O
+Epigenetic	POS	O
+reprogramming	POS	O
+that	POS	O
+imparts	POS	O
+functional	POS	O
+changes	POS	O
+in	POS	O
+gene	POS	O
+expression	POS	O
+,	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+cancer	POS	B-NP
+stem	POS	O
+cells	POS	O
+,	POS	O
+and	POS	O
+immunomodulation	POS	O
+are	POS	O
+plausible	POS	O
+underlying	POS	O
+mechanisms	POS	O
+by	POS	O
+which	POS	O
+early	POS	O
+-	POS	O
+life	POS	O
+iAs	POS	O
+exposure	POS	O
+elicits	POS	O
+latent	POS	O
+carcinogenic	POS	O
+effects	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Evidence	POS	O
+is	POS	O
+mounting	POS	O
+that	POS	O
+relates	POS	O
+early	POS	O
+-	POS	O
+life	POS	O
+iAs	POS	O
+exposure	POS	O
+and	POS	O
+cancer	POS	B-NP
+development	POS	O
+later	POS	O
+in	POS	O
+life	POS	O
+.	POS	O
+Future	POS	O
+research	POS	O
+should	POS	O
+include	POS	O
+animal	POS	O
+studies	POS	O
+that	POS	O
+address	POS	O
+mechanistic	POS	O
+hypotheses	POS	O
+and	POS	O
+studies	POS	O
+of	POS	O
+human	POS	O
+populations	POS	O
+that	POS	O
+integrate	POS	O
+early	POS	O
+-	POS	O
+life	POS	O
+exposure	POS	O
+,	POS	O
+molecular	POS	O
+alterations	POS	O
+,	POS	O
+and	POS	O
+latent	POS	O
+disease	POS	O
+outcomes	POS	O
+.	POS	O
+Nifedipine	POS	O
+induced	POS	O
+bradycardia	POS	B-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+autonomic	POS	B-NP
+neuropathy	POS	I-NP
+.	POS	O
+An	POS	O
+80	POS	O
+year	POS	O
+old	POS	O
+diabetic	POS	O
+male	POS	O
+with	POS	O
+evidence	POS	O
+of	POS	O
+peripheral	POS	O
+and	POS	O
+autonomic	POS	B-NP
+neuropathy	POS	I-NP
+was	POS	O
+admitted	POS	O
+with	POS	O
+chest	POS	B-NP
+pain	POS	I-NP
+.	POS	O
+He	POS	O
+was	POS	O
+found	POS	O
+to	POS	O
+have	POS	O
+atrial	POS	B-NP
+flutter	POS	I-NP
+at	POS	O
+a	POS	O
+ventricular	POS	O
+rate	POS	O
+of	POS	O
+70	POS	O
+/	POS	O
+min	POS	O
+which	POS	O
+slowed	POS	O
+down	POS	O
+to	POS	O
+30	POS	O
+-	POS	O
+40	POS	O
+/	POS	O
+min	POS	O
+when	POS	O
+nifedipine	POS	O
+(	POS	O
+60	POS	O
+mg	POS	O
+)	POS	O
+in	POS	O
+3	POS	O
+divided	POS	O
+doses	POS	O
+,	POS	O
+during	POS	O
+which	POS	O
+he	POS	O
+was	POS	O
+paced	POS	O
+at	POS	O
+a	POS	O
+rate	POS	O
+of	POS	O
+70	POS	O
+/	POS	O
+min	POS	O
+.	POS	O
+This	POS	O
+is	POS	O
+inconsistent	POS	O
+with	POS	O
+the	POS	O
+well	POS	O
+-	POS	O
+established	POS	O
+finding	POS	O
+that	POS	O
+nifedipine	POS	O
+induces	POS	O
+tachycardia	POS	B-NP
+in	POS	O
+normally	POS	O
+innervated	POS	O
+hearts	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+in	POS	O
+hearts	POS	O
+deprived	POS	O
+of	POS	O
+compensatory	POS	O
+sympathetic	POS	O
+drive	POS	O
+,	POS	O
+it	POS	O
+may	POS	O
+lead	POS	O
+to	POS	O
+bradycardia	POS	B-NP
+.	POS	O
+The	POS	O
+effect	POS	O
+of	POS	O
+haloperidol	POS	O
+in	POS	O
+cocaine	POS	O
+and	POS	O
+amphetamine	POS	O
+intoxication	POS	O
+.	POS	O
+The	POS	O
+effectiveness	POS	O
+of	POS	O
+haloperidol	POS	O
+pretreatment	POS	O
+in	POS	O
+preventing	POS	O
+the	POS	O
+toxic	POS	O
+effects	POS	O
+of	POS	O
+high	POS	O
+doses	POS	O
+of	POS	O
+amphetamine	POS	O
+and	POS	O
+cocaine	POS	O
+was	POS	O
+studied	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+model	POS	O
+,	POS	O
+toxic	POS	O
+effects	POS	O
+were	POS	O
+induced	POS	O
+by	POS	O
+intraperitoneal	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+injection	POS	O
+of	POS	O
+amphetamine	POS	O
+75	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+100	POS	O
+%	POS	O
+death	POS	O
+rate	POS	O
+)	POS	O
+or	POS	O
+cocaine	POS	O
+70	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+82	POS	O
+%	POS	O
+death	POS	O
+rate	POS	O
+)	POS	O
+.	POS	O
+Haloperidol	POS	O
+failed	POS	O
+to	POS	O
+prevent	POS	O
+amphetamine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+,	POS	O
+but	POS	O
+did	POS	O
+lower	POS	O
+the	POS	O
+mortality	POS	O
+rate	POS	O
+at	POS	O
+most	POS	O
+doses	POS	O
+tested	POS	O
+.	POS	O
+Haloperidol	POS	O
+decreased	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+cocaine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+at	POS	O
+the	POS	O
+two	POS	O
+highest	POS	O
+doses	POS	O
+,	POS	O
+but	POS	O
+the	POS	O
+lowering	POS	O
+of	POS	O
+the	POS	O
+mortality	POS	O
+rate	POS	O
+did	POS	O
+not	POS	O
+reach	POS	O
+statistical	POS	O
+significance	POS	O
+at	POS	O
+any	POS	O
+dose	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+suggest	POS	O
+a	POS	O
+protective	POS	O
+role	POS	O
+for	POS	O
+the	POS	O
+central	POS	O
+dopamine	POS	O
+blocker	POS	O
+haloperidol	POS	O
+against	POS	O
+death	POS	O
+from	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+amphetamine	POS	O
+exposure	POS	O
+without	POS	O
+reducing	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+seizures	POS	B-NP
+.	POS	O
+In	POS	O
+contrast	POS	O
+,	POS	O
+haloperidol	POS	O
+demonstrated	POS	O
+an	POS	O
+ability	POS	O
+to	POS	O
+reduce	POS	O
+cocaine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+without	POS	O
+significantly	POS	O
+reducing	POS	O
+mortality	POS	O
+.	POS	O
+Autoradiographic	POS	O
+evidence	POS	O
+of	POS	O
+estrogen	POS	O
+binding	POS	O
+sites	POS	O
+in	POS	O
+nuclei	POS	O
+of	POS	O
+diethylstilbesterol	POS	O
+induced	POS	O
+hamster	POS	B-NP
+renal	POS	I-NP
+carcinomas	POS	I-NP
+.	POS	O
+Estrogen	POS	O
+binding	POS	O
+sites	POS	O
+were	POS	O
+demonstrated	POS	O
+by	POS	O
+autoradiography	POS	O
+in	POS	O
+one	POS	O
+transplantable	POS	O
+and	POS	O
+five	POS	O
+primary	POS	O
+diethylstilbesterol	POS	O
+induced	POS	O
+renal	POS	B-NP
+carcinomas	POS	I-NP
+in	POS	O
+three	POS	O
+hamsters	POS	O
+.	POS	O
+Radiolabelling	POS	O
+,	POS	O
+following	POS	O
+the	POS	O
+in	POS	O
+vivo	POS	O
+injection	POS	O
+of	POS	O
+3H	POS	O
+-	POS	O
+17	POS	O
+beta	POS	O
+estradiol	POS	O
+,	POS	O
+was	POS	O
+increased	POS	O
+only	POS	O
+over	POS	O
+the	POS	O
+nuclei	POS	O
+of	POS	O
+tumor	POS	B-NP
+cells	POS	O
+;	POS	O
+stereologic	POS	O
+analysis	POS	O
+revealed	POS	O
+a	POS	O
+4	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+to	POS	O
+6	POS	O
+.	POS	O
+7	POS	O
+-	POS	O
+times	POS	O
+higher	POS	O
+concentration	POS	O
+of	POS	O
+reduced	POS	O
+silver	POS	O
+grains	POS	O
+over	POS	O
+nuclei	POS	O
+than	POS	O
+cytoplasm	POS	O
+of	POS	O
+these	POS	O
+cells	POS	O
+.	POS	O
+Despite	POS	O
+rapid	POS	O
+tubular	POS	O
+excretion	POS	O
+of	POS	O
+estradiol	POS	O
+which	POS	O
+peaked	POS	O
+in	POS	O
+less	POS	O
+than	POS	O
+1	POS	O
+h	POS	O
+,	POS	O
+the	POS	O
+normal	POS	O
+cells	POS	O
+did	POS	O
+not	POS	O
+appear	POS	O
+to	POS	O
+bind	POS	O
+the	POS	O
+ligand	POS	O
+.	POS	O
+This	POS	O
+is	POS	O
+the	POS	O
+first	POS	O
+published	POS	O
+report	POS	O
+documenting	POS	O
+the	POS	O
+preferential	POS	O
+in	POS	O
+vivo	POS	O
+binding	POS	O
+of	POS	O
+estrogen	POS	O
+to	POS	O
+nuclei	POS	O
+of	POS	O
+cells	POS	O
+in	POS	O
+estrogen	POS	O
+induced	POS	O
+hamster	POS	O
+renal	POS	O
+carcinomas	POS	B-NP
+.	POS	O
+Bradycardia	POS	B-NP
+due	POS	O
+to	POS	O
+biperiden	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+38	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+male	POS	O
+patient	POS	O
+suffering	POS	O
+from	POS	O
+a	POS	O
+severe	POS	O
+postzosteric	POS	O
+trigeminal	POS	B-NP
+neuralgia	POS	I-NP
+,	POS	O
+intravenous	POS	O
+application	POS	O
+of	POS	O
+10	POS	O
+mg	POS	O
+biperiden	POS	O
+lactate	POS	O
+led	POS	O
+to	POS	O
+a	POS	O
+long	POS	O
+-	POS	O
+lasting	POS	O
+paradoxical	POS	O
+reaction	POS	O
+characterized	POS	O
+by	POS	O
+considerable	POS	O
+bradycardia	POS	B-NP
+,	POS	O
+dysarthria	POS	B-NP
+,	POS	O
+and	POS	O
+dysphagia	POS	B-NP
+.	POS	O
+The	POS	O
+heart	POS	O
+rate	POS	O
+was	POS	O
+back	POS	O
+to	POS	O
+normal	POS	O
+within	POS	O
+12	POS	O
+hours	POS	O
+upon	POS	O
+administration	POS	O
+of	POS	O
+orciprenaline	POS	O
+under	POS	O
+cardiac	POS	O
+monitoring	POS	O
+in	POS	O
+an	POS	O
+intensive	POS	O
+care	POS	O
+unit	POS	O
+.	POS	O
+Bradycardia	POS	B-NP
+induced	POS	O
+by	POS	O
+biperiden	POS	O
+is	POS	O
+attributed	POS	O
+to	POS	O
+the	POS	O
+speed	POS	O
+of	POS	O
+injection	POS	O
+and	POS	O
+to	POS	O
+a	POS	O
+dose	POS	O
+-	POS	O
+related	POS	O
+dual	POS	O
+effect	POS	O
+of	POS	O
+atropine	POS	O
+-	POS	O
+like	POS	O
+drugs	POS	O
+on	POS	O
+muscarine	POS	O
+receptors	POS	O
+.	POS	O
+Deliberate	POS	O
+hypotension	POS	B-NP
+induced	POS	O
+by	POS	O
+labetalol	POS	O
+with	POS	O
+halothane	POS	O
+,	POS	O
+enflurane	POS	O
+or	POS	O
+isoflurane	POS	O
+for	POS	O
+middle	POS	O
+-	POS	O
+ear	POS	O
+surgery	POS	O
+.	POS	O
+The	POS	O
+feasibility	POS	O
+of	POS	O
+using	POS	O
+labetalol	POS	O
+,	POS	O
+an	POS	O
+alpha	POS	O
+-	POS	O
+and	POS	O
+beta	POS	O
+-	POS	O
+adrenergic	POS	O
+blocking	POS	O
+agent	POS	O
+,	POS	O
+as	POS	O
+a	POS	O
+hypotensive	POS	B-NP
+agent	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+inhalation	POS	O
+anaesthetics	POS	O
+(	POS	O
+halothane	POS	O
+,	POS	O
+enflurane	POS	O
+or	POS	O
+isoflurane	POS	O
+)	POS	O
+was	POS	O
+studied	POS	O
+in	POS	O
+23	POS	O
+adult	POS	O
+patients	POS	O
+undergoing	POS	O
+middle	POS	O
+-	POS	O
+ear	POS	O
+surgery	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+was	POS	O
+decreased	POS	O
+from	POS	O
+86	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+5	POS	O
+(	POS	O
+s	POS	O
+.	POS	O
+e	POS	O
+.	POS	O
+mean	POS	O
+)	POS	O
+mmHg	POS	O
+to	POS	O
+52	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+mmHg	POS	O
+(	POS	O
+11	POS	O
+.	POS	O
+5	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+to	POS	O
+6	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+kPa	POS	O
+)	POS	O
+for	POS	O
+98	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+10	POS	O
+min	POS	O
+in	POS	O
+the	POS	O
+halothane	POS	O
+(	POS	O
+H	POS	O
+)	POS	O
+group	POS	O
+,	POS	O
+from	POS	O
+79	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+5	POS	O
+to	POS	O
+53	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+mmHg	POS	O
+(	POS	O
+10	POS	O
+.	POS	O
+5	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+to	POS	O
+7	POS	O
+.	POS	O
+1	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+kPa	POS	O
+)	POS	O
+for	POS	O
+129	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+11	POS	O
+min	POS	O
+in	POS	O
+the	POS	O
+enflurane	POS	O
+(	POS	O
+E	POS	O
+)	POS	O
+group	POS	O
+,	POS	O
+and	POS	O
+from	POS	O
+80	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+to	POS	O
+49	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+mmHg	POS	O
+(	POS	O
+10	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+to	POS	O
+6	POS	O
+.	POS	O
+5	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+kPa	POS	O
+)	POS	O
+for	POS	O
+135	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+15	POS	O
+min	POS	O
+in	POS	O
+the	POS	O
+isoflurane	POS	O
+(	POS	O
+I	POS	O
+)	POS	O
+group	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+H	POS	O
+concentration	POS	O
+during	POS	O
+hypotension	POS	B-NP
+in	POS	O
+the	POS	O
+inspiratory	POS	O
+gas	POS	O
+was	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+vol	POS	O
+%	POS	O
+,	POS	O
+the	POS	O
+mean	POS	O
+E	POS	O
+concentration	POS	O
+1	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+2	POS	O
+vol	POS	O
+%	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+mean	POS	O
+I	POS	O
+concentration	POS	O
+1	POS	O
+.	POS	O
+0	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+vol	POS	O
+%	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+the	POS	O
+patients	POS	O
+received	POS	O
+fentanyl	POS	O
+and	POS	O
+d	POS	O
+-	POS	O
+tubocurarine	POS	O
+.	POS	O
+The	POS	O
+initial	POS	O
+dose	POS	O
+of	POS	O
+labetalol	POS	O
+for	POS	O
+lowering	POS	O
+blood	POS	O
+pressure	POS	O
+was	POS	O
+similar	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+52	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+59	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+in	POS	O
+all	POS	O
+the	POS	O
+groups	POS	O
+.	POS	O
+During	POS	O
+hypotension	POS	B-NP
+,	POS	O
+the	POS	O
+heart	POS	O
+rate	POS	O
+was	POS	O
+stable	POS	O
+without	POS	O
+tachy	POS	O
+-	POS	O
+or	POS	O
+bradycardia	POS	B-NP
+.	POS	O
+The	POS	O
+operating	POS	O
+conditions	POS	O
+regarding	POS	O
+bleeding	POS	B-NP
+were	POS	O
+estimated	POS	O
+in	POS	O
+a	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+manner	POS	O
+,	POS	O
+and	POS	O
+did	POS	O
+not	POS	O
+differ	POS	O
+significantly	POS	O
+between	POS	O
+the	POS	O
+groups	POS	O
+.	POS	O
+During	POS	O
+hypotension	POS	B-NP
+,	POS	O
+the	POS	O
+serum	POS	O
+creatinine	POS	O
+concentration	POS	O
+rose	POS	O
+significantly	POS	O
+in	POS	O
+all	POS	O
+groups	POS	O
+from	POS	O
+the	POS	O
+values	POS	O
+before	POS	O
+hypotension	POS	B-NP
+and	POS	O
+returned	POS	O
+postoperatively	POS	O
+to	POS	O
+the	POS	O
+initial	POS	O
+level	POS	O
+in	POS	O
+the	POS	O
+other	POS	O
+groups	POS	O
+,	POS	O
+except	POS	O
+the	POS	O
+isoflurane	POS	O
+group	POS	O
+.	POS	O
+After	POS	O
+hypotension	POS	B-NP
+there	POS	O
+was	POS	O
+no	POS	O
+rebound	POS	O
+phenomenon	POS	O
+in	POS	O
+either	POS	O
+blood	POS	O
+pressure	POS	O
+or	POS	O
+heart	POS	O
+rate	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+labetalol	POS	O
+induces	POS	O
+easily	POS	O
+adjustable	POS	O
+hypotension	POS	B-NP
+without	POS	O
+compensatory	POS	O
+tachycardia	POS	B-NP
+and	POS	O
+rebound	POS	O
+hypertension	POS	B-NP
+.	POS	O
+Convulsion	POS	B-NP
+following	POS	O
+intravenous	POS	O
+fluorescein	POS	O
+angiography	POS	O
+.	POS	O
+Tonic	POS	O
+-	POS	O
+clonic	POS	O
+seizures	POS	B-NP
+followed	POS	O
+intravenous	POS	O
+fluorescein	POS	O
+injection	POS	O
+for	POS	O
+fundus	POS	O
+angiography	POS	O
+in	POS	O
+a	POS	O
+47	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+male	POS	O
+.	POS	O
+Despite	POS	O
+precautions	POS	O
+this	POS	O
+adverse	POS	O
+reaction	POS	O
+recurred	POS	O
+on	POS	O
+re	POS	O
+-	POS	O
+exposure	POS	O
+to	POS	O
+intravenous	POS	O
+fluorescein	POS	O
+.	POS	O
+Pharmacology	POS	O
+of	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+(	POS	O
+phenytoin	POS	O
+prodrug	POS	O
+)	POS	O
+.	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+,	POS	O
+the	POS	O
+disodium	POS	O
+phosphate	POS	O
+ester	POS	O
+of	POS	O
+3	POS	O
+-	POS	O
+hydroxymethyl	POS	O
+-	POS	O
+5	POS	O
+,	POS	O
+5	POS	O
+-	POS	O
+diphenylhydantoin	POS	O
+,	POS	O
+is	POS	O
+a	POS	O
+prodrug	POS	O
+of	POS	O
+phenytoin	POS	O
+with	POS	O
+advantageous	POS	O
+physicochemical	POS	O
+properties	POS	O
+.	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+is	POS	O
+rapidly	POS	O
+converted	POS	O
+enzymatically	POS	O
+to	POS	O
+phenytoin	POS	O
+in	POS	O
+vivo	POS	O
+.	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+and	POS	O
+phenytoin	POS	O
+sodium	POS	O
+have	POS	O
+equivalent	POS	O
+anticonvulsant	POS	O
+activity	POS	O
+against	POS	O
+seizures	POS	B-NP
+induced	POS	O
+by	POS	O
+maximal	POS	O
+electroshock	POS	O
+(	POS	O
+MES	POS	O
+)	POS	O
+in	POS	O
+mice	POS	O
+following	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+,	POS	O
+oral	POS	O
+,	POS	O
+or	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+administration	POS	O
+.	POS	O
+The	POS	O
+ED50	POS	O
+doses	POS	O
+were	POS	O
+16	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+for	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+and	POS	O
+8	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+for	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+phenytoin	POS	O
+sodium	POS	O
+.	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+and	POS	O
+phenytoin	POS	O
+sodium	POS	O
+have	POS	O
+similar	POS	O
+antiarrhythmic	POS	O
+activity	POS	O
+against	POS	O
+ouabain	POS	O
+-	POS	O
+induced	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+in	POS	O
+anesthetized	POS	O
+dogs	POS	O
+.	POS	O
+The	POS	O
+total	POS	O
+doses	POS	O
+of	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+or	POS	O
+phenytoin	POS	O
+sodium	POS	O
+necessary	POS	O
+to	POS	O
+convert	POS	O
+the	POS	O
+arrhythmia	POS	B-NP
+to	POS	O
+a	POS	O
+normal	POS	O
+sinus	POS	O
+rhythm	POS	O
+were	POS	O
+24	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+and	POS	O
+14	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Only	POS	O
+phenytoin	POS	O
+sodium	POS	O
+displayed	POS	O
+in	POS	O
+vitro	POS	O
+antiarrhythmic	POS	O
+activity	POS	O
+against	POS	O
+strophanthidin	POS	O
+-	POS	O
+induced	POS	O
+arrhythmias	POS	B-NP
+in	POS	O
+guinea	POS	O
+pig	POS	O
+right	POS	O
+atria	POS	O
+.	POS	O
+In	POS	O
+anesthetized	POS	O
+dogs	POS	O
+,	POS	O
+a	POS	O
+high	POS	O
+dose	POS	O
+of	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+(	POS	O
+31	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+was	POS	O
+infused	POS	O
+over	POS	O
+15	POS	O
+,	POS	O
+20	POS	O
+,	POS	O
+and	POS	O
+30	POS	O
+min	POS	O
+and	POS	O
+the	POS	O
+responses	POS	O
+were	POS	O
+compared	POS	O
+to	POS	O
+an	POS	O
+equimolar	POS	O
+dose	POS	O
+of	POS	O
+phenytoin	POS	O
+sodium	POS	O
+(	POS	O
+21	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+and	POS	O
+phenytoin	POS	O
+sodium	POS	O
+treatments	POS	O
+produced	POS	O
+similar	POS	O
+marked	POS	O
+reductions	POS	O
+in	POS	O
+diastolic	POS	O
+blood	POS	O
+pressure	POS	O
+and	POS	O
+contractile	POS	O
+force	POS	O
+(	POS	O
+LVdP	POS	O
+/	POS	O
+dt	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+maximum	POS	O
+effects	POS	O
+of	POS	O
+each	POS	O
+treatment	POS	O
+occurred	POS	O
+at	POS	O
+the	POS	O
+time	POS	O
+of	POS	O
+maximum	POS	O
+phenytoin	POS	O
+sodium	POS	O
+levels	POS	O
+.	POS	O
+Acute	POS	B-NP
+toxicity	POS	I-NP
+studies	POS	O
+of	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+and	POS	O
+phenytoin	POS	O
+sodium	POS	O
+were	POS	O
+carried	POS	O
+out	POS	O
+in	POS	O
+mice	POS	O
+,	POS	O
+rats	POS	O
+,	POS	O
+rabbits	POS	O
+,	POS	O
+and	POS	O
+dogs	POS	O
+by	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+m	POS	O
+.	POS	O
+,	POS	O
+and	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+routes	POS	O
+of	POS	O
+administration	POS	O
+.	POS	O
+The	POS	O
+systemic	POS	O
+toxic	POS	O
+signs	POS	O
+of	POS	O
+both	POS	O
+agents	POS	O
+were	POS	O
+similar	POS	O
+and	POS	O
+occurred	POS	O
+at	POS	O
+approximately	POS	O
+equivalent	POS	O
+doses	POS	O
+.	POS	O
+Importantly	POS	O
+,	POS	O
+the	POS	O
+local	POS	O
+irritation	POS	O
+of	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+was	POS	O
+markedly	POS	O
+less	POS	O
+than	POS	O
+phenytoin	POS	O
+sodium	POS	O
+following	POS	O
+i	POS	O
+.	POS	O
+m	POS	O
+.	POS	O
+administration	POS	O
+.	POS	O
+(	POS	O
+ABSTRACT	POS	O
+TRUNCATED	POS	O
+AT	POS	O
+250	POS	O
+WORDS	POS	O
+)	POS	O
+Tachyphylaxis	POS	O
+to	POS	O
+systemic	POS	O
+but	POS	O
+not	POS	O
+to	POS	O
+airway	POS	O
+responses	POS	O
+during	POS	O
+prolonged	POS	O
+therapy	POS	O
+with	POS	O
+high	POS	O
+dose	POS	O
+inhaled	POS	O
+salbutamol	POS	O
+in	POS	O
+asthmatics	POS	O
+.	POS	O
+High	POS	O
+doses	POS	O
+of	POS	O
+inhaled	POS	O
+salbutamol	POS	O
+produce	POS	O
+substantial	POS	O
+improvements	POS	O
+in	POS	O
+airway	POS	O
+response	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+asthma	POS	B-NP
+,	POS	O
+and	POS	O
+are	POS	O
+associated	POS	O
+with	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+systemic	POS	O
+beta	POS	O
+-	POS	O
+adrenoceptor	POS	O
+responses	POS	O
+.	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+investigate	POS	O
+whether	POS	O
+tachyphylaxis	POS	B-NP
+occurs	POS	O
+during	POS	O
+prolonged	POS	O
+treatment	POS	O
+with	POS	O
+high	POS	O
+dose	POS	O
+inhaled	POS	O
+salbutamol	POS	O
+.	POS	O
+Twelve	POS	O
+asthmatic	POS	B-NP
+patients	POS	O
+(	POS	O
+FEV1	POS	O
+,	POS	O
+81	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+%	POS	O
+predicted	POS	O
+)	POS	O
+,	POS	O
+requiring	POS	O
+only	POS	O
+occasional	POS	O
+inhaled	POS	O
+beta	POS	O
+-	POS	O
+agonists	POS	O
+as	POS	O
+their	POS	O
+sole	POS	O
+therapy	POS	O
+,	POS	O
+were	POS	O
+given	POS	O
+a	POS	O
+14	POS	O
+-	POS	O
+day	POS	O
+treatment	POS	O
+with	POS	O
+high	POS	O
+dose	POS	O
+inhaled	POS	O
+salbutamol	POS	O
+(	POS	O
+HDS	POS	O
+)	POS	O
+,	POS	O
+4	POS	O
+,	POS	O
+000	POS	O
+micrograms	POS	O
+daily	POS	O
+,	POS	O
+low	POS	O
+dose	POS	O
+inhaled	POS	O
+salbutamol	POS	O
+(	POS	O
+LDS	POS	O
+)	POS	O
+,	POS	O
+800	POS	O
+micrograms	POS	O
+daily	POS	O
+,	POS	O
+or	POS	O
+placebo	POS	O
+(	POS	O
+PI	POS	O
+)	POS	O
+by	POS	O
+metered	POS	O
+-	POS	O
+dose	POS	O
+inhaler	POS	O
+in	POS	O
+a	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+randomized	POS	O
+crossover	POS	O
+design	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+14	POS	O
+-	POS	O
+day	POS	O
+run	POS	O
+-	POS	O
+in	POS	O
+and	POS	O
+during	POS	O
+washout	POS	O
+periods	POS	O
+,	POS	O
+inhaled	POS	O
+beta	POS	O
+-	POS	O
+agonists	POS	O
+were	POS	O
+withheld	POS	O
+and	POS	O
+ipratropium	POS	O
+bromide	POS	O
+was	POS	O
+substituted	POS	O
+for	POS	O
+rescue	POS	O
+purposes	POS	O
+.	POS	O
+At	POS	O
+the	POS	O
+end	POS	O
+of	POS	O
+each	POS	O
+14	POS	O
+-	POS	O
+day	POS	O
+treatment	POS	O
+,	POS	O
+a	POS	O
+dose	POS	O
+-	POS	O
+response	POS	O
+curve	POS	O
+(	POS	O
+DRC	POS	O
+)	POS	O
+was	POS	O
+performed	POS	O
+,	POS	O
+and	POS	O
+airway	POS	O
+(	POS	O
+FEV1	POS	O
+,	POS	O
+FEF25	POS	O
+-	POS	O
+75	POS	O
+)	POS	O
+chronotropic	POS	O
+(	POS	O
+HR	POS	O
+)	POS	O
+,	POS	O
+tremor	POS	B-NP
+,	POS	O
+and	POS	O
+metabolic	POS	O
+(	POS	O
+K	POS	O
+,	POS	O
+Glu	POS	O
+)	POS	O
+responses	POS	O
+were	POS	O
+measured	POS	O
+at	POS	O
+each	POS	O
+step	POS	O
+(	POS	O
+from	POS	O
+100	POS	O
+to	POS	O
+4	POS	O
+,	POS	O
+000	POS	O
+micrograms	POS	O
+)	POS	O
+.	POS	O
+Treatment	POS	O
+had	POS	O
+no	POS	O
+significant	POS	O
+effect	POS	O
+on	POS	O
+baseline	POS	O
+values	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+increases	POS	O
+in	POS	O
+FEV1	POS	O
+and	POS	O
+FEF25	POS	O
+-	POS	O
+75	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+pretreatment	POS	O
+with	POS	O
+HDS	POS	O
+did	POS	O
+not	POS	O
+displace	POS	O
+the	POS	O
+DRC	POS	O
+to	POS	O
+the	POS	O
+right	POS	O
+.	POS	O
+DRC	POS	O
+for	POS	O
+HR	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+K	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+Glu	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+005	POS	O
+)	POS	O
+were	POS	O
+attenuated	POS	O
+after	POS	O
+treatment	POS	O
+with	POS	O
+HDS	POS	B-NP
+compared	POS	O
+with	POS	O
+PI	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+also	POS	O
+differences	POS	O
+between	POS	O
+HDS	POS	O
+and	POS	O
+LDS	POS	O
+for	POS	O
+HR	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+and	POS	O
+Glu	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+responses	POS	O
+.	POS	O
+Frequency	POS	O
+and	POS	O
+severity	POS	O
+of	POS	O
+subjective	POS	O
+adverse	POS	O
+effects	POS	O
+were	POS	O
+also	POS	O
+reduced	POS	O
+after	POS	O
+HDS	POS	B-NP
+:	POS	O
+tremor	POS	B-NP
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+palpitations	POS	B-NP
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+(	POS	O
+ABSTRACT	POS	O
+TRUNCATED	POS	O
+AT	POS	O
+250	POS	O
+WORDS	POS	O
+)	POS	O
+Phenytoin	POS	O
+induced	POS	O
+fatal	POS	O
+hepatic	POS	B-NP
+injury	POS	I-NP
+.	POS	O
+A	POS	O
+61	POS	O
+year	POS	O
+old	POS	O
+female	POS	O
+developed	POS	O
+fatal	POS	O
+hepatic	POS	B-NP
+failure	POS	I-NP
+after	POS	O
+phenytoin	POS	O
+administration	POS	O
+.	POS	O
+A	POS	O
+typical	POS	O
+multisystem	POS	O
+clinical	POS	O
+pattern	POS	O
+precedes	POS	O
+the	POS	O
+manifestations	POS	O
+of	POS	O
+hepatic	POS	B-NP
+injury	POS	I-NP
+.	POS	O
+The	POS	O
+hematologic	POS	O
+,	POS	O
+biochemical	POS	O
+and	POS	O
+pathologic	POS	O
+features	POS	O
+indicate	POS	O
+a	POS	O
+mixed	POS	O
+hepatocellular	POS	B-NP
+damage	POS	I-NP
+due	POS	O
+to	POS	O
+drug	POS	O
+hypersensitivity	POS	B-NP
+.	POS	O
+In	POS	O
+a	POS	O
+patient	POS	O
+receiving	POS	O
+phenytoin	POS	O
+who	POS	O
+presents	POS	O
+a	POS	O
+viral	POS	B-NP
+-	POS	I-NP
+like	POS	I-NP
+illness	POS	I-NP
+,	POS	O
+early	POS	O
+recognition	POS	O
+and	POS	O
+discontinuation	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+are	POS	O
+mandatory	POS	O
+.	POS	O
+Treatment	POS	O
+of	POS	O
+lethal	POS	O
+pertussis	POS	O
+vaccine	POS	O
+reaction	POS	O
+with	POS	O
+histamine	POS	O
+H1	POS	O
+antagonists	POS	O
+.	POS	O
+We	POS	O
+studied	POS	O
+mortality	POS	O
+after	POS	O
+pertussis	POS	O
+immunization	POS	O
+in	POS	O
+the	POS	O
+mouse	POS	O
+.	POS	O
+Without	POS	O
+treatment	POS	O
+,	POS	O
+73	POS	O
+of	POS	O
+92	POS	O
+animals	POS	O
+(	POS	O
+80	POS	O
+%	POS	O
+)	POS	O
+died	POS	O
+after	POS	O
+injection	POS	O
+of	POS	O
+bovine	POS	O
+serum	POS	O
+albumin	POS	O
+(	POS	O
+BSA	POS	O
+)	POS	O
+on	POS	O
+day	POS	O
++	POS	O
+7	POS	O
+of	POS	O
+pertussis	POS	O
+immunization	POS	O
+.	POS	O
+After	POS	O
+pretreatment	POS	O
+with	POS	O
+3	POS	O
+mg	POS	O
+of	POS	O
+cyproheptadine	POS	O
+,	POS	O
+2	POS	O
+mg	POS	O
+mianserin	POS	O
+,	POS	O
+or	POS	O
+2	POS	O
+mg	POS	O
+chlorpheniramine	POS	O
+,	POS	O
+only	POS	O
+5	POS	O
+of	POS	O
+105	POS	O
+animals	POS	O
+(	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+died	POS	O
+after	POS	O
+receiving	POS	O
+BSA	POS	O
+on	POS	O
+day	POS	O
++	POS	O
+7	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+Blockade	POS	O
+of	POS	O
+histamine	POS	O
+H1	POS	O
+receptors	POS	O
+may	POS	O
+reduce	POS	O
+mortality	POS	O
+in	POS	O
+pertussis	POS	O
+immunization	POS	O
+-	POS	O
+induced	POS	O
+encephalopathy	POS	B-NP
+in	POS	O
+mice	POS	O
+.	POS	O
+Support	POS	O
+for	POS	O
+adrenaline	POS	O
+-	POS	O
+hypertension	POS	B-NP
+hypothesis	POS	O
+:	POS	O
+18	POS	O
+hour	POS	O
+pressor	POS	O
+effect	POS	O
+after	POS	O
+6	POS	O
+hours	POS	O
+adrenaline	POS	O
+infusion	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+double	POS	O
+blind	POS	O
+,	POS	O
+crossover	POS	O
+study	POS	O
+6	POS	O
+h	POS	O
+infusions	POS	O
+of	POS	O
+adrenaline	POS	O
+(	POS	O
+15	POS	O
+ng	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+;	POS	O
+1	POS	O
+ng	POS	O
+=	POS	O
+5	POS	O
+.	POS	O
+458	POS	O
+pmol	POS	O
+)	POS	O
+,	POS	O
+noradrenaline	POS	O
+(	POS	O
+30	POS	O
+ng	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+;	POS	O
+1	POS	O
+ng	POS	O
+=	POS	O
+5	POS	O
+.	POS	O
+911	POS	O
+pmol	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+5	POS	O
+%	POS	O
+dextrose	POS	O
+solution	POS	O
+(	POS	O
+5	POS	O
+.	POS	O
+4	POS	O
+ml	POS	O
+/	POS	O
+h	POS	O
+)	POS	O
+,	POS	O
+were	POS	O
+given	POS	O
+to	POS	O
+ten	POS	O
+healthy	POS	O
+volunteers	POS	O
+in	POS	O
+random	POS	O
+order	POS	O
+2	POS	O
+weeks	POS	O
+apart	POS	O
+.	POS	O
+By	POS	O
+means	POS	O
+of	POS	O
+intra	POS	O
+-	POS	O
+arterial	POS	O
+ambulatory	POS	O
+monitoring	POS	O
+the	POS	O
+haemodynamic	POS	O
+effects	POS	O
+were	POS	O
+followed	POS	O
+for	POS	O
+18	POS	O
+h	POS	O
+after	POS	O
+the	POS	O
+infusions	POS	O
+were	POS	O
+stopped	POS	O
+.	POS	O
+Adrenaline	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+noradrenaline	POS	O
+,	POS	O
+caused	POS	O
+a	POS	O
+delayed	POS	O
+and	POS	O
+protracted	POS	O
+pressor	POS	O
+effect	POS	O
+.	POS	O
+Over	POS	O
+the	POS	O
+total	POS	O
+postinfusion	POS	O
+period	POS	O
+systolic	POS	O
+and	POS	O
+diastolic	POS	O
+arterial	POS	O
+pressure	POS	O
+were	POS	O
+6	POS	O
+(	POS	O
+SEM	POS	O
+2	POS	O
+)	POS	O
+%	POS	O
+and	POS	O
+7	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+%	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+higher	POS	O
+than	POS	O
+after	POS	O
+dextrose	POS	O
+infusion	POS	O
+(	POS	O
+ANOVA	POS	O
+,	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+"	POS	O
+stress	POS	O
+"	POS	O
+levels	POS	O
+of	POS	O
+adrenaline	POS	O
+(	POS	O
+230	POS	O
+pg	POS	O
+/	POS	O
+ml	POS	O
+)	POS	O
+for	POS	O
+6	POS	O
+h	POS	O
+cause	POS	O
+a	POS	O
+delayed	POS	O
+and	POS	O
+protracted	POS	O
+pressor	POS	O
+effect	POS	O
+.	POS	O
+These	POS	O
+findings	POS	O
+are	POS	O
+strong	POS	O
+support	POS	O
+for	POS	O
+the	POS	O
+adrenaline	POS	O
+-	POS	O
+hypertension	POS	B-NP
+hypothesis	POS	O
+in	POS	O
+man	POS	O
+.	POS	O
+Effect	POS	O
+of	POS	O
+alkylxanthines	POS	O
+on	POS	O
+gentamicin	POS	O
+-	POS	O
+induced	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+in	POS	O
+the	POS	O
+rat	POS	O
+.	POS	O
+Adenosine	POS	O
+antagonists	POS	O
+have	POS	O
+been	POS	O
+previously	POS	O
+shown	POS	O
+to	POS	O
+be	POS	O
+of	POS	O
+benefit	POS	O
+in	POS	O
+some	POS	O
+ischaemic	POS	B-NP
+and	POS	O
+nephrotoxic	POS	B-NP
+models	POS	O
+of	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+(	POS	O
+ARF	POS	B-NP
+)	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+,	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+three	POS	O
+alkylxanthines	POS	O
+with	POS	O
+different	POS	O
+potencies	POS	O
+as	POS	O
+adenosine	POS	O
+antagonists	POS	O
+8	POS	O
+-	POS	O
+phenyltheophylline	POS	O
+,	POS	O
+theophylline	POS	O
+and	POS	O
+enprofylline	POS	O
+,	POS	O
+were	POS	O
+examined	POS	O
+in	POS	O
+rats	POS	O
+developing	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+after	POS	O
+4	POS	O
+daily	POS	O
+injections	POS	O
+of	POS	O
+gentamicin	POS	O
+(	POS	O
+200	POS	O
+mg	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+.	POS	O
+Renal	POS	O
+function	POS	O
+was	POS	O
+assessed	POS	O
+by	POS	O
+biochemical	POS	O
+(	POS	O
+plasma	POS	O
+urea	POS	O
+and	POS	O
+creatinine	POS	O
+)	POS	O
+,	POS	O
+functional	POS	O
+(	POS	O
+urine	POS	O
+analysis	POS	O
+and	POS	O
+[	POS	O
+3H	POS	O
+]	POS	O
+inulin	POS	O
+and	POS	O
+[	POS	O
+14C	POS	O
+]	POS	O
+p	POS	O
+-	POS	O
+aminohippuric	POS	O
+acid	POS	O
+clearances	POS	O
+)	POS	O
+and	POS	O
+morphological	POS	O
+(	POS	O
+degree	POS	O
+of	POS	O
+necrosis	POS	B-NP
+)	POS	O
+indices	POS	O
+.	POS	O
+The	POS	O
+various	POS	O
+drug	POS	O
+treatments	POS	O
+produced	POS	O
+improvements	POS	O
+in	POS	O
+some	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+all	POS	O
+,	POS	O
+measurements	POS	O
+of	POS	O
+renal	POS	O
+function	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+any	POS	O
+improvement	POS	O
+produced	POS	O
+by	POS	O
+drug	POS	O
+treatment	POS	O
+was	POS	O
+largely	POS	O
+a	POS	O
+result	POS	O
+of	POS	O
+a	POS	O
+beneficial	POS	O
+effect	POS	O
+exerted	POS	O
+by	POS	O
+its	POS	O
+vehicle	POS	O
+(	POS	O
+polyethylene	POS	O
+glycol	POS	O
+and	POS	O
+NaOH	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+lack	POS	O
+of	POS	O
+any	POS	O
+consistent	POS	O
+protective	POS	O
+effect	POS	O
+noted	POS	O
+with	POS	O
+the	POS	O
+alkylxanthines	POS	O
+tested	POS	O
+in	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+indicates	POS	O
+that	POS	O
+adenosine	POS	O
+plays	POS	O
+little	POS	O
+,	POS	O
+if	POS	O
+any	POS	O
+,	POS	O
+pathophysiological	POS	O
+role	POS	O
+in	POS	O
+gentamicin	POS	O
+-	POS	O
+induced	POS	O
+ARF	POS	B-NP
+.	POS	O
+Adverse	POS	O
+ocular	POS	O
+reactions	POS	O
+possibly	POS	O
+associated	POS	O
+with	POS	O
+isotretinoin	POS	O
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+261	POS	O
+adverse	POS	O
+ocular	POS	B-NP
+reactions	POS	I-NP
+occurred	POS	O
+in	POS	O
+237	POS	O
+patients	POS	O
+who	POS	O
+received	POS	O
+isotretinoin	POS	O
+,	POS	O
+a	POS	O
+commonly	POS	O
+used	POS	O
+drug	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+severe	POS	O
+cystic	POS	B-NP
+acne	POS	I-NP
+.	POS	O
+Blepharoconjunctivitis	POS	B-NP
+,	POS	O
+subjective	POS	O
+complaints	POS	O
+of	POS	O
+dry	POS	B-NP
+eyes	POS	I-NP
+,	POS	O
+blurred	POS	B-NP
+vision	POS	I-NP
+,	POS	O
+contact	POS	B-NP
+lens	POS	I-NP
+intolerance	POS	I-NP
+,	POS	O
+and	POS	O
+photodermatitis	POS	B-NP
+are	POS	O
+reversible	POS	O
+side	POS	O
+effects	POS	O
+.	POS	O
+More	POS	O
+serious	POS	O
+ocular	POS	O
+adverse	POS	O
+reactions	POS	O
+include	POS	O
+papilledema	POS	B-NP
+,	POS	O
+pseudotumor	POS	B-NP
+cerebri	POS	I-NP
+,	POS	O
+and	POS	O
+white	POS	O
+or	POS	O
+gray	POS	O
+subepithelial	POS	O
+corneal	POS	O
+opacities	POS	O
+;	POS	O
+all	POS	O
+of	POS	O
+these	POS	O
+are	POS	O
+reversible	POS	O
+if	POS	O
+the	POS	O
+drug	POS	O
+is	POS	O
+discontinued	POS	O
+.	POS	O
+Reported	POS	O
+cases	POS	O
+of	POS	O
+decreased	POS	O
+dark	POS	O
+adaptation	POS	O
+are	POS	O
+under	POS	O
+investigation	POS	O
+.	POS	O
+Isotretinoin	POS	O
+is	POS	O
+contraindicated	POS	O
+in	POS	O
+pregnancy	POS	O
+because	POS	O
+of	POS	O
+the	POS	O
+many	POS	O
+reported	POS	O
+congenital	POS	B-NP
+abnormalities	POS	I-NP
+after	POS	O
+maternal	POS	O
+use	POS	O
+(	POS	O
+including	POS	O
+microphthalmos	POS	B-NP
+,	POS	O
+orbital	POS	B-NP
+hypertelorism	POS	I-NP
+,	POS	O
+and	POS	O
+optic	POS	B-NP
+nerve	POS	I-NP
+hypoplasia	POS	I-NP
+)	POS	O
+.	POS	O
+Procaterol	POS	O
+and	POS	O
+terbutaline	POS	O
+in	POS	O
+bronchial	POS	B-NP
+asthma	POS	I-NP
+.	POS	O
+A	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+,	POS	O
+cross	POS	O
+-	POS	O
+over	POS	O
+study	POS	O
+.	POS	O
+Procaterol	POS	O
+,	POS	O
+a	POS	O
+new	POS	O
+beta	POS	O
+-	POS	O
+2	POS	O
+adrenoceptor	POS	O
+stimulant	POS	O
+,	POS	O
+was	POS	O
+studied	POS	O
+in	POS	O
+a	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+,	POS	O
+cross	POS	O
+-	POS	O
+over	POS	O
+trial	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+bronchial	POS	B-NP
+asthma	POS	I-NP
+.	POS	O
+Oral	POS	O
+procaterol	POS	O
+50	POS	O
+micrograms	POS	O
+b	POS	O
+.	POS	O
+d	POS	O
+.	POS	O
+,	POS	O
+procaterol	POS	O
+100	POS	O
+micrograms	POS	O
+b	POS	O
+.	POS	O
+d	POS	O
+.	POS	O
+,	POS	O
+and	POS	O
+terbutaline	POS	O
+5	POS	O
+mg	POS	O
+t	POS	O
+.	POS	O
+i	POS	O
+.	POS	O
+d	POS	O
+.	POS	O
+,	POS	O
+were	POS	O
+compared	POS	O
+when	POS	O
+given	POS	O
+randomly	POS	O
+in	POS	O
+1	POS	O
+-	POS	O
+week	POS	O
+treatment	POS	O
+periods	POS	O
+.	POS	O
+The	POS	O
+best	POS	O
+clinical	POS	O
+effect	POS	O
+was	POS	O
+found	POS	O
+with	POS	O
+terbutaline	POS	O
+.	POS	O
+Both	POS	O
+anti	POS	O
+-	POS	O
+asthmatic	POS	O
+and	POS	O
+tremorgenic	POS	O
+effects	POS	O
+of	POS	O
+procaterol	POS	O
+were	POS	O
+dose	POS	O
+-	POS	O
+related	POS	O
+.	POS	O
+Procaterol	POS	O
+appeared	POS	O
+effective	POS	O
+in	POS	O
+the	POS	O
+doses	POS	O
+tested	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+twice	POS	O
+daily	POS	O
+regimen	POS	O
+would	POS	O
+appear	POS	O
+to	POS	O
+be	POS	O
+suitable	POS	O
+with	POS	O
+this	POS	O
+drug	POS	O
+.	POS	O
+Subacute	POS	O
+effects	POS	O
+of	POS	O
+propranolol	POS	O
+and	POS	O
+B	POS	O
+24	POS	O
+/	POS	O
+76	POS	O
+on	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+rat	POS	O
+heart	POS	B-NP
+hypertrophy	POS	I-NP
+in	POS	O
+correlation	POS	O
+with	POS	O
+blood	POS	O
+pressure	POS	O
+.	POS	O
+We	POS	O
+compared	POS	O
+the	POS	O
+potential	POS	O
+beta	POS	O
+-	POS	O
+receptor	POS	O
+blocker	POS	O
+,	POS	O
+B	POS	O
+24	POS	O
+/	POS	O
+76	POS	O
+i	POS	O
+.	POS	O
+e	POS	O
+.	POS	O
+1	POS	O
+-	POS	O
+(	POS	O
+2	POS	O
+,	POS	O
+4	POS	O
+-	POS	O
+dichlorophenoxy	POS	O
+)	POS	O
+-	POS	O
+3	POS	O
+[	POS	O
+2	POS	O
+-	POS	O
+3	POS	O
+,	POS	O
+4	POS	O
+-	POS	O
+dimethoxyphenyl	POS	O
+)	POS	O
+ethanolamino	POS	O
+]	POS	O
+-	POS	O
+prop	POS	O
+an	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+ol	POS	O
+,	POS	O
+which	POS	O
+is	POS	O
+characterized	POS	O
+by	POS	O
+beta	POS	O
+1	POS	O
+-	POS	O
+adrenoceptor	POS	O
+blocking	POS	O
+and	POS	O
+beta	POS	O
+2	POS	O
+-	POS	O
+adrenoceptor	POS	O
+stimulating	POS	O
+properties	POS	O
+with	POS	O
+propranolol	POS	O
+.	POS	O
+The	POS	O
+studies	POS	O
+were	POS	O
+performed	POS	O
+using	POS	O
+an	POS	O
+experimental	POS	O
+model	POS	O
+of	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+heart	POS	B-NP
+hypertrophy	POS	I-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+A	POS	O
+correlation	POS	O
+of	POS	O
+the	POS	O
+blood	POS	O
+pressure	POS	O
+was	POS	O
+neither	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+development	POS	O
+nor	POS	O
+in	POS	O
+the	POS	O
+attempt	POS	O
+to	POS	O
+suppress	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+heart	POS	B-NP
+hypertrophy	POS	I-NP
+with	POS	O
+the	POS	O
+two	POS	O
+beta	POS	O
+-	POS	O
+receptor	POS	O
+blockers	POS	O
+.	POS	O
+Both	POS	O
+beta	POS	O
+-	POS	O
+blockers	POS	O
+influenced	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+hypertrophy	POS	B-NP
+to	POS	O
+a	POS	O
+different	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+reproducible	POS	O
+extent	POS	O
+.	POS	O
+It	POS	O
+was	POS	O
+possible	POS	O
+to	POS	O
+suppress	POS	O
+the	POS	O
+increased	POS	O
+ornithine	POS	O
+decarboxylase	POS	O
+activity	POS	O
+with	POS	O
+both	POS	O
+beta	POS	O
+-	POS	O
+blockers	POS	O
+in	POS	O
+hypertrophied	POS	O
+hearts	POS	O
+,	POS	O
+but	POS	O
+there	POS	O
+was	POS	O
+no	POS	O
+effect	POS	O
+on	POS	O
+the	POS	O
+heart	POS	O
+mass	POS	O
+.	POS	O
+Neither	POS	O
+propranolol	POS	O
+nor	POS	O
+B	POS	O
+24	POS	O
+/	POS	O
+76	POS	O
+could	POS	O
+stop	POS	O
+the	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+characteristic	POS	O
+myosin	POS	O
+isoenzyme	POS	O
+pattern	POS	O
+of	POS	O
+the	POS	O
+hypertrophied	POS	O
+rat	POS	O
+heart	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+the	POS	O
+investigations	POS	O
+did	POS	O
+not	POS	O
+provide	POS	O
+any	POS	O
+evidence	POS	O
+that	POS	O
+the	POS	O
+beta	POS	O
+-	POS	O
+receptor	POS	O
+blockers	POS	O
+propranolol	POS	O
+and	POS	O
+B	POS	O
+24	POS	O
+/	POS	O
+76	POS	O
+have	POS	O
+the	POS	O
+potency	POS	O
+to	POS	O
+prevent	POS	O
+isoproterenol	POS	O
+from	POS	O
+producing	POS	O
+heart	POS	B-NP
+hypertrophy	POS	I-NP
+.	POS	O
+Increased	POS	O
+anxiogenic	POS	O
+effects	POS	O
+of	POS	O
+caffeine	POS	O
+in	POS	O
+panic	POS	B-NP
+disorders	POS	I-NP
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+oral	POS	O
+administration	POS	O
+of	POS	O
+caffeine	POS	O
+(	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+on	POS	O
+behavioral	POS	O
+ratings	POS	O
+,	POS	O
+somatic	POS	O
+symptoms	POS	O
+,	POS	O
+blood	POS	O
+pressure	POS	O
+and	POS	O
+plasma	POS	O
+levels	POS	O
+of	POS	O
+3	POS	O
+-	POS	O
+methoxy	POS	O
+-	POS	O
+4	POS	O
+-	POS	O
+hydroxyphenethyleneglycol	POS	O
+(	POS	O
+MHPG	POS	O
+)	POS	O
+and	POS	O
+cortisol	POS	O
+were	POS	O
+determined	POS	O
+in	POS	O
+17	POS	O
+healthy	POS	O
+subjects	POS	O
+and	POS	O
+21	POS	O
+patients	POS	O
+meeting	POS	O
+DSM	POS	O
+-	POS	O
+III	POS	O
+criteria	POS	O
+for	POS	O
+agoraphobia	POS	B-NP
+with	POS	O
+panic	POS	B-NP
+attacks	POS	I-NP
+or	POS	O
+panic	POS	B-NP
+disorder	POS	I-NP
+.	POS	O
+Caffeine	POS	O
+produced	POS	O
+significantly	POS	O
+greater	POS	O
+increases	POS	O
+in	POS	O
+subject	POS	O
+-	POS	O
+rated	POS	O
+anxiety	POS	B-NP
+,	POS	O
+nervousness	POS	B-NP
+,	POS	O
+fear	POS	B-NP
+,	POS	O
+nausea	POS	B-NP
+,	POS	O
+palpitations	POS	B-NP
+,	POS	O
+restlessness	POS	B-NP
+,	POS	O
+and	POS	O
+tremors	POS	B-NP
+in	POS	O
+the	POS	O
+patients	POS	O
+compared	POS	O
+with	POS	O
+healthy	POS	O
+subjects	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+patients	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+the	POS	O
+healthy	POS	O
+subjects	POS	O
+,	POS	O
+these	POS	O
+symptoms	POS	O
+were	POS	O
+significantly	POS	O
+correlated	POS	O
+with	POS	O
+plasma	POS	O
+caffeine	POS	O
+levels	POS	O
+.	POS	O
+Seventy	POS	O
+-	POS	O
+one	POS	O
+percent	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+reported	POS	O
+that	POS	O
+the	POS	O
+behavioral	POS	O
+effects	POS	O
+of	POS	O
+caffeine	POS	O
+were	POS	O
+similar	POS	O
+to	POS	O
+those	POS	O
+experienced	POS	O
+during	POS	O
+panic	POS	B-NP
+attacks	POS	I-NP
+.	POS	O
+Caffeine	POS	O
+did	POS	O
+not	POS	O
+alter	POS	O
+plasma	POS	O
+MHPG	POS	O
+levels	POS	O
+in	POS	O
+either	POS	O
+the	POS	O
+healthy	POS	O
+subjects	POS	O
+or	POS	O
+patients	POS	O
+.	POS	O
+Caffeine	POS	O
+increased	POS	O
+plasma	POS	O
+cortisol	POS	O
+levels	POS	O
+equally	POS	O
+in	POS	O
+the	POS	O
+patient	POS	O
+and	POS	O
+healthy	POS	O
+groups	POS	O
+.	POS	O
+Because	POS	O
+caffeine	POS	O
+is	POS	O
+an	POS	O
+adenosine	POS	O
+receptor	POS	O
+antagonist	POS	O
+,	POS	O
+these	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+some	POS	O
+panic	POS	B-NP
+disorder	POS	I-NP
+patients	POS	O
+may	POS	O
+have	POS	O
+abnormalities	POS	O
+in	POS	O
+neuronal	POS	O
+systems	POS	O
+involving	POS	O
+adenosine	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+anxiety	POS	B-NP
+disorders	POS	I-NP
+may	POS	O
+benefit	POS	O
+by	POS	O
+avoiding	POS	O
+caffeine	POS	O
+-	POS	O
+containing	POS	O
+foods	POS	O
+and	POS	O
+beverages	POS	O
+.	POS	O
+Comparison	POS	O
+of	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+oxitropium	POS	O
+bromide	POS	O
+and	POS	O
+of	POS	O
+slow	POS	O
+-	POS	O
+release	POS	O
+theophylline	POS	O
+on	POS	O
+nocturnal	POS	O
+asthma	POS	B-NP
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+a	POS	O
+new	POS	O
+inhaled	POS	O
+antimuscarinic	POS	O
+drug	POS	O
+,	POS	O
+oxitropium	POS	O
+bromide	POS	O
+,	POS	O
+and	POS	O
+of	POS	O
+a	POS	O
+slow	POS	O
+-	POS	O
+release	POS	O
+theophylline	POS	O
+preparation	POS	O
+upon	POS	O
+nocturnal	POS	O
+asthma	POS	B-NP
+were	POS	O
+compared	POS	O
+in	POS	O
+a	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+study	POS	O
+.	POS	O
+Two	POS	O
+samples	POS	O
+were	POS	O
+studied	POS	O
+:	POS	O
+12	POS	O
+patients	POS	O
+received	POS	O
+oxitropium	POS	O
+at	POS	O
+600	POS	O
+micrograms	POS	O
+(	POS	O
+6	POS	O
+subjects	POS	O
+)	POS	O
+or	POS	O
+at	POS	O
+400	POS	O
+micrograms	POS	O
+t	POS	O
+.	POS	O
+i	POS	O
+.	POS	O
+d	POS	O
+.	POS	O
+(	POS	O
+6	POS	O
+subjects	POS	O
+)	POS	O
+whereas	POS	O
+11	POS	O
+received	POS	O
+theophylline	POS	O
+at	POS	O
+300	POS	O
+mg	POS	O
+b	POS	O
+.	POS	O
+i	POS	O
+.	POS	O
+d	POS	O
+.	POS	O
+Morning	POS	O
+dipping	POS	O
+,	POS	O
+assessed	POS	O
+by	POS	O
+the	POS	O
+fall	POS	O
+in	POS	O
+peak	POS	O
+flow	POS	O
+overnight	POS	O
+,	POS	O
+was	POS	O
+significantly	POS	O
+reduced	POS	O
+in	POS	O
+the	POS	O
+periods	POS	O
+when	POS	O
+either	POS	O
+active	POS	O
+drug	POS	O
+was	POS	O
+taken	POS	O
+,	POS	O
+whereas	POS	O
+no	POS	O
+difference	POS	O
+was	POS	O
+noticed	POS	O
+during	POS	O
+the	POS	O
+placebo	POS	O
+administration	POS	O
+.	POS	O
+No	POS	O
+significant	POS	O
+difference	POS	O
+was	POS	O
+noticed	POS	O
+between	POS	O
+results	POS	O
+obtained	POS	O
+with	POS	O
+either	POS	O
+active	POS	O
+drug	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+with	POS	O
+either	POS	O
+dosage	POS	O
+of	POS	O
+oxitropium	POS	O
+.	POS	O
+No	POS	O
+subject	POS	O
+reported	POS	O
+side	POS	O
+effects	POS	O
+of	POS	O
+oxitropium	POS	O
+,	POS	O
+as	POS	O
+compared	POS	O
+to	POS	O
+three	POS	O
+subjects	POS	O
+reporting	POS	O
+nausea	POS	B-NP
+,	POS	O
+vomiting	POS	B-NP
+and	POS	O
+tremors	POS	B-NP
+after	POS	O
+theophylline	POS	O
+.	POS	O
+Oxitropium	POS	O
+proves	POS	O
+to	POS	O
+be	POS	O
+a	POS	O
+valuable	POS	O
+alternative	POS	O
+to	POS	O
+theophylline	POS	O
+in	POS	O
+nocturnal	POS	B-NP
+asthma	POS	I-NP
+,	POS	O
+since	POS	O
+it	POS	O
+is	POS	O
+equally	POS	O
+potent	POS	O
+,	POS	O
+safer	POS	O
+and	POS	O
+does	POS	O
+not	POS	O
+require	POS	O
+the	POS	O
+titration	POS	O
+of	POS	O
+dosage	POS	O
+.	POS	O
+Penicillin	POS	O
+anaphylaxis	POS	B-NP
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+oral	POS	O
+penicillin	POS	O
+anaphylaxis	POS	B-NP
+is	POS	O
+described	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+terminology	POS	O
+,	POS	O
+occurrence	POS	O
+,	POS	O
+clinical	POS	O
+manifestations	POS	O
+,	POS	O
+pathogenesis	POS	O
+,	POS	O
+prevention	POS	O
+,	POS	O
+and	POS	O
+treatment	POS	O
+of	POS	O
+anaphylaxis	POS	B-NP
+are	POS	O
+reviewed	POS	O
+.	POS	O
+Emergency	POS	O
+physicians	POS	O
+should	POS	O
+be	POS	O
+aware	POS	O
+of	POS	O
+oral	POS	O
+penicillin	POS	O
+anaphylaxis	POS	B-NP
+in	POS	O
+order	POS	O
+to	POS	O
+prevent	POS	O
+its	POS	O
+occurrence	POS	O
+by	POS	O
+prescribing	POS	O
+the	POS	O
+antibiotic	POS	O
+judiciously	POS	O
+and	POS	O
+knowledgeably	POS	O
+and	POS	O
+to	POS	O
+offer	POS	O
+optimal	POS	O
+medical	POS	O
+therapy	POS	O
+once	POS	O
+this	POS	O
+life	POS	O
+-	POS	O
+threatening	POS	O
+reaction	POS	O
+has	POS	O
+begun	POS	O
+.	POS	O
+Reversible	POS	O
+valproic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+dementia	POS	B-NP
+:	POS	O
+a	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+Reversible	POS	O
+valproic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+dementia	POS	B-NP
+was	POS	O
+documented	POS	O
+in	POS	O
+a	POS	O
+21	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+with	POS	O
+epilepsy	POS	B-NP
+who	POS	O
+had	POS	O
+a	POS	O
+3	POS	O
+-	POS	O
+year	POS	O
+history	POS	O
+of	POS	O
+insidious	POS	O
+progressive	POS	O
+decline	POS	O
+in	POS	O
+global	POS	O
+cognitive	POS	O
+abilities	POS	O
+documented	POS	O
+by	POS	O
+serial	POS	O
+neuropsychological	POS	O
+studies	POS	O
+.	POS	O
+Repeat	POS	O
+neuropsychological	POS	O
+testing	POS	O
+7	POS	O
+weeks	POS	O
+after	POS	O
+discontinuation	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+revealed	POS	O
+dramatic	POS	O
+improvement	POS	O
+in	POS	O
+IQ	POS	O
+,	POS	O
+memory	POS	O
+,	POS	O
+naming	POS	O
+,	POS	O
+and	POS	O
+other	POS	O
+tasks	POS	O
+commensurate	POS	O
+with	POS	O
+clinical	POS	O
+recovery	POS	O
+in	POS	O
+his	POS	O
+intellectual	POS	O
+capacity	POS	O
+.	POS	O
+Possible	POS	O
+pathophysiological	POS	O
+mechanisms	POS	O
+which	POS	O
+may	POS	O
+have	POS	O
+been	POS	O
+operative	POS	O
+in	POS	O
+this	POS	O
+case	POS	O
+include	POS	O
+:	POS	O
+a	POS	O
+direct	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+(	POS	O
+CNS	POS	O
+)	POS	O
+toxic	POS	O
+effect	POS	O
+of	POS	O
+valproic	POS	O
+acid	POS	O
+;	POS	O
+a	POS	O
+paradoxical	POS	O
+epileptogenic	POS	O
+effect	POS	O
+secondary	POS	O
+to	POS	O
+the	POS	O
+drug	POS	O
+;	POS	O
+and	POS	O
+an	POS	O
+indirect	POS	O
+CNS	POS	O
+toxic	POS	O
+effect	POS	O
+mediated	POS	O
+through	POS	O
+valproic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+hyperammonemia	POS	B-NP
+.	POS	O
+Reversal	POS	O
+of	POS	O
+scopolamine	POS	O
+-	POS	O
+induced	POS	O
+amnesia	POS	B-NP
+of	POS	O
+passive	POS	O
+avoidance	POS	O
+by	POS	O
+pre	POS	O
+-	POS	O
+and	POS	O
+post	POS	O
+-	POS	O
+training	POS	O
+naloxone	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+series	POS	O
+of	POS	O
+five	POS	O
+experiments	POS	O
+,	POS	O
+the	POS	O
+modulating	POS	O
+role	POS	O
+of	POS	O
+naloxone	POS	O
+on	POS	O
+a	POS	O
+scopolamine	POS	O
+-	POS	O
+induced	POS	O
+retention	POS	O
+deficit	POS	O
+in	POS	O
+a	POS	O
+passive	POS	O
+avoidance	POS	O
+paradigm	POS	O
+was	POS	O
+investigated	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+Scopolamine	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+methyl	POS	O
+scopolamine	POS	O
+(	POS	O
+1	POS	O
+and	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+,	POS	O
+induced	POS	O
+an	POS	O
+amnesia	POS	B-NP
+as	POS	O
+measured	POS	O
+by	POS	O
+latency	POS	O
+and	POS	O
+duration	POS	O
+parameters	POS	O
+.	POS	O
+Naloxone	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+,	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+,	POS	O
+and	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+injected	POS	O
+prior	POS	O
+to	POS	O
+training	POS	O
+attenuated	POS	O
+the	POS	O
+retention	POS	O
+deficit	POS	O
+with	POS	O
+a	POS	O
+peak	POS	O
+of	POS	O
+activity	POS	O
+at	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+The	POS	O
+effect	POS	O
+of	POS	O
+naloxone	POS	O
+could	POS	O
+be	POS	O
+antagonized	POS	O
+with	POS	O
+morphine	POS	O
+(	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+,	POS	O
+and	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+,	POS	O
+demonstrating	POS	O
+the	POS	O
+opioid	POS	O
+specificity	POS	O
+of	POS	O
+the	POS	O
+naloxone	POS	O
+effect	POS	O
+.	POS	O
+Post	POS	O
+-	POS	O
+training	POS	O
+administration	POS	O
+of	POS	O
+naloxone	POS	O
+(	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+as	POS	O
+a	POS	O
+single	POS	O
+or	POS	O
+as	POS	O
+a	POS	O
+split	POS	O
+dose	POS	O
+also	POS	O
+attenuated	POS	O
+the	POS	O
+scopolamine	POS	O
+-	POS	O
+induced	POS	O
+amnesia	POS	B-NP
+.	POS	O
+Control	POS	O
+experiments	POS	O
+indicated	POS	O
+that	POS	O
+neither	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+pain	POS	B-NP
+sensitivity	POS	O
+(	POS	O
+pre	POS	O
+-	POS	O
+training	POS	O
+naloxone	POS	O
+)	POS	O
+nor	POS	O
+an	POS	O
+induced	POS	O
+aversive	POS	O
+state	POS	O
+(	POS	O
+post	POS	O
+-	POS	O
+training	POS	O
+naloxone	POS	O
+)	POS	O
+appear	POS	O
+to	POS	O
+be	POS	O
+responsible	POS	O
+for	POS	O
+the	POS	O
+influence	POS	O
+of	POS	O
+naloxone	POS	O
+on	POS	O
+the	POS	O
+scopolamine	POS	O
+-	POS	O
+induced	POS	O
+retention	POS	B-NP
+deficit	POS	I-NP
+.	POS	O
+These	POS	O
+results	POS	O
+extend	POS	O
+previous	POS	O
+findings	POS	O
+implicating	POS	O
+a	POS	O
+cholinergic	POS	O
+-	POS	O
+opioid	POS	O
+interaction	POS	O
+in	POS	O
+memory	POS	O
+processes	POS	O
+.	POS	O
+A	POS	O
+possible	POS	O
+mechanism	POS	O
+for	POS	O
+this	POS	O
+interaction	POS	O
+involving	POS	O
+the	POS	O
+septo	POS	O
+-	POS	O
+hippocampal	POS	O
+cholinergic	POS	O
+pathway	POS	O
+is	POS	O
+discussed	POS	O
+.	POS	O
+Electron	POS	O
+microscopic	POS	O
+investigations	POS	O
+of	POS	O
+the	POS	O
+cyclophosphamide	POS	O
+-	POS	O
+induced	POS	O
+lesions	POS	O
+of	POS	O
+the	POS	O
+urinary	POS	O
+bladder	POS	O
+of	POS	O
+the	POS	O
+rat	POS	O
+and	POS	O
+their	POS	O
+prevention	POS	O
+by	POS	O
+mesna	POS	O
+.	POS	O
+Fully	POS	O
+developed	POS	O
+cyclophosphamide	POS	O
+-	POS	O
+induced	POS	O
+cystitis	POS	B-NP
+is	POS	O
+characterized	POS	O
+by	POS	O
+nearly	POS	O
+complete	POS	O
+detachment	POS	B-NP
+of	POS	I-NP
+the	POS	I-NP
+urothelium	POS	I-NP
+,	POS	O
+severe	POS	O
+submucosal	POS	B-NP
+edema	POS	I-NP
+owing	POS	O
+to	POS	O
+damage	POS	O
+to	POS	O
+the	POS	O
+microvascular	POS	O
+bed	POS	O
+and	POS	O
+focal	POS	O
+muscle	POS	B-NP
+necroses	POS	I-NP
+.	POS	O
+The	POS	O
+initial	POS	O
+response	POS	O
+to	POS	O
+the	POS	O
+primary	POS	O
+attack	POS	O
+by	POS	O
+the	POS	O
+cyclophosphamide	POS	O
+metabolites	POS	O
+seems	POS	O
+to	POS	O
+be	POS	O
+fragmentation	POS	O
+of	POS	O
+the	POS	O
+luminal	POS	O
+membrane	POS	O
+.	POS	O
+This	POS	O
+damages	POS	O
+the	POS	O
+cellular	POS	O
+barrier	POS	O
+against	POS	O
+the	POS	O
+hypertonic	POS	O
+urine	POS	O
+.	POS	O
+Subsequent	POS	O
+breaks	POS	O
+in	POS	O
+the	POS	O
+lateral	POS	O
+cell	POS	O
+membranes	POS	O
+of	POS	O
+the	POS	O
+superficial	POS	O
+cells	POS	O
+and	POS	O
+in	POS	O
+all	POS	O
+the	POS	O
+plasma	POS	O
+membranes	POS	O
+of	POS	O
+the	POS	O
+intermediate	POS	O
+and	POS	O
+basal	POS	O
+cells	POS	O
+,	POS	O
+intercellular	POS	O
+and	POS	O
+intracellular	POS	O
+edema	POS	B-NP
+and	POS	O
+disintegration	POS	O
+of	POS	O
+the	POS	O
+desmosomes	POS	O
+and	POS	O
+hemidesmosomes	POS	O
+lead	POS	O
+to	POS	O
+progressive	POS	O
+degeneration	POS	O
+and	POS	O
+detachment	POS	O
+of	POS	O
+the	POS	O
+epithelial	POS	O
+cells	POS	O
+with	POS	O
+exposure	POS	O
+and	POS	O
+splitting	POS	O
+of	POS	O
+the	POS	O
+basal	POS	O
+membrane	POS	O
+.	POS	O
+The	POS	O
+morphological	POS	O
+changes	POS	O
+of	POS	O
+the	POS	O
+endothelial	POS	O
+cells	POS	O
+,	POS	O
+which	POS	O
+become	POS	O
+more	POS	O
+pronounced	POS	O
+in	POS	O
+the	POS	O
+later	POS	O
+stages	POS	O
+of	POS	O
+the	POS	O
+experiment	POS	O
+,	POS	O
+the	POS	O
+involvement	POS	O
+of	POS	O
+blood	POS	O
+vessels	POS	O
+regardless	POS	O
+of	POS	O
+their	POS	O
+diameter	POS	O
+and	POS	O
+the	POS	O
+location	POS	O
+-	POS	O
+dependent	POS	O
+extent	POS	O
+of	POS	O
+the	POS	O
+damage	POS	O
+indicate	POS	O
+a	POS	O
+direct	POS	O
+type	POS	O
+of	POS	O
+damage	POS	O
+which	POS	O
+is	POS	O
+preceded	POS	O
+by	POS	O
+a	POS	O
+mediator	POS	O
+-	POS	O
+induced	POS	O
+increase	POS	O
+in	POS	O
+permeability	POS	O
+,	POS	O
+the	POS	O
+morphological	POS	O
+correlate	POS	O
+of	POS	O
+which	POS	O
+is	POS	O
+the	POS	O
+formation	POS	O
+of	POS	O
+gaps	POS	O
+in	POS	O
+the	POS	O
+interendothelial	POS	O
+cell	POS	O
+connections	POS	O
+on	POS	O
+the	POS	O
+venules	POS	O
+.	POS	O
+These	POS	O
+changes	POS	O
+can	POS	O
+be	POS	O
+effectively	POS	O
+prevented	POS	O
+by	POS	O
+mesna	POS	O
+.	POS	O
+The	POS	O
+only	POS	O
+sign	POS	O
+of	POS	O
+a	POS	O
+possible	POS	O
+involvement	POS	O
+is	POS	O
+the	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+specific	POS	O
+granules	POS	O
+with	POS	O
+a	POS	O
+presumed	POS	O
+lysosomal	POS	O
+function	POS	O
+in	POS	O
+the	POS	O
+superficial	POS	O
+cells	POS	O
+.	POS	O
+Increase	POS	O
+in	POS	O
+intragastric	POS	O
+pressure	POS	O
+during	POS	O
+suxamethonium	POS	O
+-	POS	O
+induced	POS	O
+muscle	POS	B-NP
+fasciculations	POS	I-NP
+in	POS	O
+children	POS	O
+:	POS	O
+inhibition	POS	O
+by	POS	O
+alfentanil	POS	O
+.	POS	O
+Changes	POS	O
+in	POS	O
+intragastric	POS	O
+pressure	POS	O
+after	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+suxamethonium	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+were	POS	O
+studied	POS	O
+in	POS	O
+32	POS	O
+children	POS	O
+(	POS	O
+mean	POS	O
+age	POS	O
+6	POS	O
+.	POS	O
+9	POS	O
+yr	POS	O
+)	POS	O
+pretreated	POS	O
+with	POS	O
+either	POS	O
+physiological	POS	O
+saline	POS	O
+or	POS	O
+alfentanil	POS	O
+50	POS	O
+micrograms	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+Anaesthesia	POS	B-NP
+was	POS	O
+induced	POS	O
+with	POS	O
+thiopentone	POS	O
+5	POS	O
+mg	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+and	POS	O
+intensity	POS	O
+of	POS	O
+muscle	POS	B-NP
+fasciculations	POS	I-NP
+caused	POS	O
+by	POS	O
+suxamethonium	POS	O
+were	POS	O
+significantly	POS	O
+greater	POS	O
+in	POS	O
+the	POS	O
+control	POS	O
+than	POS	O
+in	POS	O
+the	POS	O
+alfentanil	POS	O
+group	POS	O
+.	POS	O
+The	POS	O
+intragastric	POS	O
+pressure	POS	O
+during	POS	O
+muscle	POS	B-NP
+fasciculations	POS	I-NP
+was	POS	O
+significantly	POS	O
+higher	POS	O
+in	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+(	POS	O
+16	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+(	POS	O
+SEM	POS	O
+)	POS	O
+cm	POS	O
+H2O	POS	O
+)	POS	O
+than	POS	O
+in	POS	O
+the	POS	O
+alfentanil	POS	O
+group	POS	O
+(	POS	O
+7	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+(	POS	O
+SEM	POS	O
+)	POS	O
+cm	POS	O
+H2O	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+increase	POS	O
+in	POS	O
+intragastric	POS	O
+pressure	POS	O
+was	POS	O
+directly	POS	O
+related	POS	O
+to	POS	O
+the	POS	O
+intensity	POS	O
+of	POS	O
+muscle	POS	B-NP
+fasciculations	POS	I-NP
+(	POS	O
+regression	POS	O
+line	POS	O
+:	POS	O
+y	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
++	POS	O
+4	POS	O
+.	POS	O
+78x	POS	O
+with	POS	O
+r	POS	O
+of	POS	O
+0	POS	O
+.	POS	O
+78	POS	O
+)	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+concluded	POS	O
+that	POS	O
+intragastric	POS	O
+pressure	POS	O
+increases	POS	O
+significantly	POS	O
+during	POS	O
+muscle	POS	B-NP
+fasciculations	POS	I-NP
+caused	POS	O
+by	POS	O
+suxamethonium	POS	O
+in	POS	O
+healthy	POS	O
+children	POS	O
+.	POS	O
+Alfentanil	POS	O
+50	POS	O
+micrograms	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+effectively	POS	O
+inhibits	POS	O
+the	POS	O
+incidence	POS	O
+and	POS	O
+intensity	POS	O
+of	POS	O
+suxamethonium	POS	O
+-	POS	O
+induced	POS	O
+muscle	POS	B-NP
+fasciculations	POS	I-NP
+;	POS	O
+moreover	POS	O
+,	POS	O
+intragastric	POS	O
+pressure	POS	O
+remains	POS	O
+at	POS	O
+its	POS	O
+control	POS	O
+value	POS	O
+.	POS	O
+Acute	POS	O
+insulin	POS	O
+treatment	POS	O
+normalizes	POS	O
+the	POS	O
+resistance	POS	O
+to	POS	O
+the	POS	O
+cardiotoxic	POS	B-NP
+effect	POS	O
+of	POS	O
+isoproterenol	POS	O
+in	POS	O
+streptozotocin	POS	O
+diabetic	POS	O
+rats	POS	O
+.	POS	O
+A	POS	O
+morphometric	POS	O
+study	POS	O
+of	POS	O
+isoproterenol	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+fibrosis	POS	I-NP
+.	POS	O
+The	POS	O
+acute	POS	O
+effect	POS	O
+of	POS	O
+insulin	POS	O
+treatment	POS	O
+on	POS	O
+the	POS	O
+earlier	POS	O
+reported	POS	O
+protective	POS	O
+effect	POS	O
+of	POS	O
+streptozotocin	POS	O
+diabetes	POS	B-NP
+against	POS	O
+the	POS	O
+cardiotoxic	POS	B-NP
+effect	POS	O
+of	POS	O
+high	POS	O
+doses	POS	O
+of	POS	O
+isoproterenol	POS	O
+(	POS	O
+ISO	POS	O
+)	POS	O
+was	POS	O
+investigated	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+Thirty	POS	O
+to	POS	O
+135	POS	O
+min	POS	O
+after	POS	O
+the	POS	O
+injection	POS	O
+of	POS	O
+crystalline	POS	O
+insulin	POS	O
+,	POS	O
+ISO	POS	O
+was	POS	O
+given	POS	O
+subcutaneously	POS	O
+and	POS	O
+when	POS	O
+ISO	POS	O
+induced	POS	O
+fibrosis	POS	B-NP
+in	POS	O
+the	POS	O
+myocardium	POS	O
+was	POS	O
+morphometrically	POS	O
+analyzed	POS	O
+7	POS	O
+days	POS	O
+later	POS	O
+,	POS	O
+a	POS	O
+highly	POS	O
+significant	POS	O
+correlation	POS	O
+(	POS	O
+r	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+83	POS	O
+,	POS	O
+2	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+006	POS	O
+)	POS	O
+to	POS	O
+the	POS	O
+slope	POS	O
+of	POS	O
+the	POS	O
+fall	POS	O
+in	POS	O
+blood	POS	O
+glucose	POS	O
+after	POS	O
+insulin	POS	O
+treatment	POS	O
+appeared	POS	O
+.	POS	O
+The	POS	O
+myocardial	POS	O
+content	POS	O
+of	POS	O
+catecholamines	POS	O
+was	POS	O
+estimated	POS	O
+in	POS	O
+these	POS	O
+8	POS	O
+day	POS	O
+diabetic	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+norepinephrine	POS	O
+content	POS	O
+was	POS	O
+significantly	POS	O
+increased	POS	O
+while	POS	O
+epinephrine	POS	O
+remained	POS	O
+unchanged	POS	O
+.	POS	O
+An	POS	O
+enhanced	POS	O
+sympathetic	POS	O
+nervous	POS	O
+system	POS	O
+activity	POS	O
+with	POS	O
+a	POS	O
+consequent	POS	O
+down	POS	O
+regulation	POS	O
+of	POS	O
+the	POS	O
+myocardial	POS	O
+beta	POS	O
+-	POS	O
+adrenergic	POS	O
+receptors	POS	O
+could	POS	O
+,	POS	O
+therefore	POS	O
+,	POS	O
+explain	POS	O
+this	POS	O
+catecholamine	POS	O
+resistance	POS	O
+.	POS	O
+The	POS	O
+rapid	POS	O
+reversion	POS	O
+after	POS	O
+insulin	POS	O
+treatment	POS	O
+excludes	POS	O
+the	POS	O
+possibility	POS	O
+that	POS	O
+streptozotocin	POS	O
+in	POS	O
+itself	POS	O
+causes	POS	O
+the	POS	O
+ISO	POS	O
+resistance	POS	O
+and	POS	O
+points	POS	O
+towards	POS	O
+a	POS	O
+direct	POS	O
+insulin	POS	O
+effect	POS	O
+on	POS	O
+myocardial	POS	O
+catecholamine	POS	O
+sensitivity	POS	O
+in	POS	O
+diabetic	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+phenomenon	POS	O
+described	POS	O
+might	POS	O
+elucidate	POS	O
+pathogenetic	POS	O
+mechanisms	POS	O
+behind	POS	O
+toxic	POS	O
+myocardial	POS	B-NP
+cell	POS	I-NP
+degeneration	POS	I-NP
+and	POS	O
+may	POS	O
+possibly	POS	O
+have	POS	O
+relevance	POS	O
+for	POS	O
+acute	POS	O
+cardiovascular	POS	O
+complications	POS	O
+in	POS	O
+diabetic	POS	B-NP
+patients	POS	O
+.	POS	O
+Differential	POS	O
+effects	POS	O
+of	POS	O
+non	POS	O
+-	POS	O
+steroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+on	POS	O
+seizures	POS	B-NP
+produced	POS	O
+by	POS	O
+pilocarpine	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+muscarinic	POS	O
+cholinergic	POS	O
+agonist	POS	O
+pilocarpine	POS	O
+induces	POS	O
+in	POS	O
+rats	POS	O
+seizures	POS	B-NP
+and	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+followed	POS	O
+by	POS	O
+widespread	POS	O
+damage	POS	O
+to	POS	O
+the	POS	O
+forebrain	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+designed	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+5	POS	O
+non	POS	O
+-	POS	O
+steroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+,	POS	O
+sodium	POS	O
+salicylate	POS	O
+,	POS	O
+phenylbutazone	POS	O
+,	POS	O
+indomethacin	POS	O
+,	POS	O
+ibuprofen	POS	O
+and	POS	O
+mefenamic	POS	O
+acid	POS	O
+,	POS	O
+on	POS	O
+seizures	POS	B-NP
+produced	POS	O
+by	POS	O
+pilocarpine	POS	O
+.	POS	O
+Pretreatment	POS	O
+of	POS	O
+rats	POS	O
+with	POS	O
+sodium	POS	O
+salicylate	POS	O
+,	POS	O
+ED50	POS	O
+103	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+60	POS	O
+-	POS	O
+174	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+phenylbutazone	POS	O
+,	POS	O
+59	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+50	POS	O
+-	POS	O
+70	POS	O
+)	POS	O
+converted	POS	O
+the	POS	O
+non	POS	O
+-	POS	O
+convulsant	POS	O
+dose	POS	O
+of	POS	O
+pilocarpine	POS	O
+,	POS	O
+200	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+to	POS	O
+a	POS	O
+convulsant	POS	O
+one	POS	O
+.	POS	O
+Indomethacin	POS	O
+,	POS	O
+1	POS	O
+-	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+and	POS	O
+ibuprofen	POS	O
+,	POS	O
+10	POS	O
+-	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+failed	POS	O
+to	POS	O
+modulate	POS	O
+seizures	POS	B-NP
+produced	POS	O
+by	POS	O
+pilocarpine	POS	O
+.	POS	O
+Mefenamic	POS	O
+acid	POS	O
+,	POS	O
+26	POS	O
+(	POS	O
+22	POS	O
+-	POS	O
+30	POS	O
+)	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+prevented	POS	O
+seizures	POS	B-NP
+and	POS	O
+protected	POS	O
+rats	POS	O
+from	POS	O
+seizure	POS	B-NP
+-	POS	O
+related	POS	O
+brain	POS	B-NP
+damage	POS	I-NP
+induced	POS	O
+by	POS	O
+pilocarpine	POS	O
+,	POS	O
+380	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+non	POS	O
+-	POS	O
+steroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+differentially	POS	O
+modulate	POS	O
+the	POS	O
+threshold	POS	O
+for	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+.	POS	O
+Acute	POS	B-NP
+neurologic	POS	I-NP
+dysfunction	POS	I-NP
+after	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+etoposide	POS	O
+therapy	POS	O
+for	POS	O
+malignant	POS	B-NP
+glioma	POS	I-NP
+.	POS	O
+Etoposide	POS	O
+(	POS	O
+VP	POS	O
+-	POS	O
+16	POS	O
+-	POS	O
+213	POS	O
+)	POS	O
+has	POS	O
+been	POS	O
+used	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+many	POS	O
+solid	POS	O
+tumors	POS	B-NP
+and	POS	O
+hematologic	POS	B-NP
+malignancies	POS	I-NP
+.	POS	O
+When	POS	O
+used	POS	O
+in	POS	O
+high	POS	O
+doses	POS	O
+and	POS	O
+in	POS	O
+conjunction	POS	O
+with	POS	O
+autologous	POS	O
+bone	POS	O
+marrow	POS	O
+transplantation	POS	O
+,	POS	O
+this	POS	O
+agent	POS	O
+has	POS	O
+activity	POS	O
+against	POS	O
+several	POS	O
+treatment	POS	O
+-	POS	O
+resistant	POS	O
+cancers	POS	B-NP
+including	POS	O
+malignant	POS	B-NP
+glioma	POS	I-NP
+.	POS	O
+In	POS	O
+six	POS	O
+of	POS	O
+eight	POS	O
+patients	POS	O
+(	POS	O
+75	POS	O
+%	POS	O
+)	POS	O
+who	POS	O
+we	POS	O
+treated	POS	O
+for	POS	O
+recurrent	POS	O
+or	POS	O
+resistant	POS	O
+glioma	POS	B-NP
+,	POS	O
+sudden	POS	O
+severe	POS	O
+neurologic	POS	B-NP
+deterioration	POS	I-NP
+occurred	POS	O
+.	POS	O
+This	POS	O
+developed	POS	O
+a	POS	O
+median	POS	O
+of	POS	O
+9	POS	O
+days	POS	O
+after	POS	O
+initiation	POS	O
+of	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+etoposide	POS	O
+therapy	POS	O
+.	POS	O
+Significant	POS	O
+clinical	POS	O
+manifestations	POS	O
+have	POS	O
+included	POS	O
+confusion	POS	B-NP
+,	POS	O
+papilledema	POS	B-NP
+,	POS	O
+somnolence	POS	B-NP
+,	POS	O
+exacerbation	POS	B-NP
+of	POS	I-NP
+motor	POS	I-NP
+deficits	POS	I-NP
+,	POS	O
+and	POS	O
+sharp	POS	O
+increase	POS	O
+in	POS	O
+seizure	POS	B-NP
+activity	POS	O
+.	POS	O
+These	POS	O
+abnormalities	POS	O
+resolved	POS	O
+rapidly	POS	O
+after	POS	O
+initiation	POS	O
+of	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+intravenous	POS	O
+dexamethasone	POS	O
+therapy	POS	O
+.	POS	O
+In	POS	O
+all	POS	O
+patients	POS	O
+,	POS	O
+computerized	POS	O
+tomographic	POS	O
+(	POS	O
+CT	POS	O
+)	POS	O
+brain	POS	O
+scans	POS	O
+demonstrated	POS	O
+stability	POS	O
+in	POS	O
+tumor	POS	B-NP
+size	POS	O
+and	POS	O
+peritumor	POS	B-NP
+edema	POS	I-NP
+when	POS	O
+compared	POS	O
+with	POS	O
+pretransplant	POS	O
+scans	POS	O
+.	POS	O
+This	POS	O
+complication	POS	O
+appears	POS	O
+to	POS	O
+represent	POS	O
+a	POS	O
+significant	POS	O
+new	POS	O
+toxicity	POS	B-NP
+of	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+etoposide	POS	O
+therapy	POS	O
+for	POS	O
+malignant	POS	B-NP
+glioma	POS	I-NP
+.	POS	O
+Progressive	POS	B-NP
+bile	POS	I-NP
+duct	POS	I-NP
+injury	POS	I-NP
+after	POS	O
+thiabendazole	POS	O
+administration	POS	O
+.	POS	O
+A	POS	O
+27	POS	O
+-	POS	O
+yr	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+developed	POS	O
+jaundice	POS	B-NP
+2	POS	O
+wk	POS	O
+after	POS	O
+exposure	POS	O
+to	POS	O
+thiabendazole	POS	O
+.	POS	O
+Cholestasis	POS	B-NP
+persisted	POS	O
+for	POS	O
+3	POS	O
+yr	POS	O
+,	POS	O
+at	POS	O
+which	POS	O
+time	POS	O
+a	POS	O
+liver	POS	O
+transplant	POS	O
+was	POS	O
+performed	POS	O
+.	POS	O
+Two	POS	O
+liver	POS	O
+biopsy	POS	O
+specimens	POS	O
+and	POS	O
+the	POS	O
+hepatectomy	POS	O
+specimen	POS	O
+were	POS	O
+remarkable	POS	O
+for	POS	O
+almost	POS	O
+complete	POS	O
+disappearance	POS	O
+of	POS	O
+interlobular	POS	O
+bile	POS	O
+ducts	POS	O
+.	POS	O
+Prominent	POS	O
+fibrosis	POS	B-NP
+and	POS	O
+hepatocellular	POS	B-NP
+regeneration	POS	I-NP
+were	POS	O
+also	POS	O
+present	POS	O
+;	POS	O
+however	POS	O
+,	POS	O
+the	POS	O
+lobular	POS	O
+architecture	POS	O
+was	POS	O
+preserved	POS	O
+.	POS	O
+This	POS	O
+case	POS	O
+represents	POS	O
+an	POS	O
+example	POS	O
+of	POS	O
+"	POS	O
+idiosyncratic	POS	O
+"	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+liver	POS	B-NP
+damage	POS	I-NP
+in	POS	O
+which	POS	O
+the	POS	O
+primary	POS	O
+target	POS	O
+of	POS	O
+injury	POS	O
+is	POS	O
+the	POS	O
+bile	POS	O
+duct	POS	O
+.	POS	O
+An	POS	O
+autoimmune	POS	O
+pathogenesis	POS	O
+of	POS	O
+the	POS	O
+bile	POS	O
+duct	POS	O
+destruction	POS	O
+is	POS	O
+suggested	POS	O
+.	POS	O
+Differential	POS	O
+effects	POS	O
+of	POS	O
+1	POS	O
+,	POS	O
+4	POS	O
+-	POS	O
+dihydropyridine	POS	O
+calcium	POS	O
+channel	POS	O
+blockers	POS	O
+:	POS	O
+therapeutic	POS	O
+implications	POS	O
+.	POS	O
+Increasing	POS	O
+recognition	POS	O
+of	POS	O
+the	POS	O
+importance	POS	O
+of	POS	O
+calcium	POS	O
+in	POS	O
+the	POS	O
+pathogenesis	POS	O
+of	POS	O
+cardiovascular	POS	B-NP
+disease	POS	I-NP
+has	POS	O
+stimulated	POS	O
+research	POS	O
+into	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+calcium	POS	O
+channel	POS	O
+blocking	POS	O
+agents	POS	O
+for	POS	O
+treatment	POS	O
+of	POS	O
+a	POS	O
+variety	POS	O
+of	POS	O
+cardiovascular	POS	B-NP
+diseases	POS	I-NP
+.	POS	O
+The	POS	O
+favorable	POS	O
+efficacy	POS	O
+and	POS	O
+tolerability	POS	O
+profiles	POS	O
+of	POS	O
+these	POS	O
+agents	POS	O
+make	POS	O
+them	POS	O
+attractive	POS	O
+therapeutic	POS	O
+modalities	POS	O
+.	POS	O
+Clinical	POS	O
+applications	POS	O
+of	POS	O
+calcium	POS	O
+channel	POS	O
+blockers	POS	O
+parallel	POS	O
+their	POS	O
+tissue	POS	O
+selectivity	POS	O
+.	POS	O
+In	POS	O
+contrast	POS	O
+to	POS	O
+verapamil	POS	O
+and	POS	O
+diltiazem	POS	O
+,	POS	O
+which	POS	O
+are	POS	O
+roughly	POS	O
+equipotent	POS	O
+in	POS	O
+their	POS	O
+actions	POS	O
+on	POS	O
+the	POS	O
+heart	POS	O
+and	POS	O
+vascular	POS	O
+smooth	POS	O
+muscle	POS	O
+,	POS	O
+the	POS	O
+dihydropyridine	POS	O
+calcium	POS	O
+channel	POS	O
+blockers	POS	O
+are	POS	O
+a	POS	O
+group	POS	O
+of	POS	O
+potent	POS	O
+peripheral	POS	O
+vasodilator	POS	O
+agents	POS	O
+that	POS	O
+exert	POS	O
+minimal	POS	O
+electrophysiologic	POS	O
+effects	POS	O
+on	POS	O
+cardiac	POS	O
+nodal	POS	O
+or	POS	O
+conduction	POS	O
+tissue	POS	O
+.	POS	O
+As	POS	O
+the	POS	O
+first	POS	O
+dihydropyridine	POS	O
+available	POS	O
+for	POS	O
+use	POS	O
+in	POS	O
+the	POS	O
+United	POS	O
+States	POS	O
+,	POS	O
+nifedipine	POS	O
+controls	POS	O
+angina	POS	B-NP
+and	POS	O
+hypertension	POS	B-NP
+with	POS	O
+minimal	POS	O
+depression	POS	B-NP
+of	POS	O
+cardiac	POS	B-NP
+function	POS	I-NP
+.	POS	O
+Additional	POS	O
+members	POS	O
+of	POS	O
+this	POS	O
+group	POS	O
+of	POS	O
+calcium	POS	O
+channel	POS	O
+blockers	POS	O
+have	POS	O
+been	POS	O
+studied	POS	O
+for	POS	O
+a	POS	O
+variety	POS	O
+of	POS	O
+indications	POS	O
+for	POS	O
+which	POS	O
+they	POS	O
+may	POS	O
+offer	POS	O
+advantages	POS	O
+over	POS	O
+current	POS	O
+therapy	POS	O
+.	POS	O
+Once	POS	O
+or	POS	O
+twice	POS	O
+daily	POS	O
+dosage	POS	O
+possible	POS	O
+with	POS	O
+nitrendipine	POS	O
+and	POS	O
+nisoldipine	POS	O
+offers	POS	O
+a	POS	O
+convenient	POS	O
+administration	POS	O
+schedule	POS	O
+,	POS	O
+which	POS	O
+encourages	POS	O
+patient	POS	O
+compliance	POS	O
+in	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+therapy	POS	O
+of	POS	O
+hypertension	POS	B-NP
+.	POS	O
+The	POS	O
+coronary	POS	O
+vasodilating	POS	O
+properties	POS	O
+of	POS	O
+nisoldipine	POS	O
+have	POS	O
+led	POS	O
+to	POS	O
+the	POS	O
+investigation	POS	O
+of	POS	O
+this	POS	O
+agent	POS	O
+for	POS	O
+use	POS	O
+in	POS	O
+angina	POS	B-NP
+.	POS	O
+Selectivity	POS	O
+for	POS	O
+the	POS	O
+cerebrovascular	POS	O
+bed	POS	O
+makes	POS	O
+nimodipine	POS	O
+potentially	POS	O
+useful	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+subarachnoid	POS	B-NP
+hemorrhage	POS	I-NP
+,	POS	O
+migraine	POS	B-NP
+headache	POS	I-NP
+,	POS	O
+dementia	POS	B-NP
+,	POS	O
+and	POS	O
+stroke	POS	B-NP
+.	POS	O
+In	POS	O
+general	POS	O
+,	POS	O
+the	POS	O
+dihydropyridine	POS	O
+calcium	POS	O
+channel	POS	O
+blockers	POS	O
+are	POS	O
+usually	POS	O
+well	POS	O
+tolerated	POS	O
+,	POS	O
+with	POS	O
+headache	POS	B-NP
+,	POS	O
+facial	POS	B-NP
+flushing	POS	I-NP
+,	POS	O
+palpitations	POS	B-NP
+,	POS	O
+edema	POS	B-NP
+,	POS	O
+nausea	POS	B-NP
+,	POS	O
+anorexia	POS	B-NP
+,	POS	O
+and	POS	O
+dizziness	POS	B-NP
+being	POS	O
+the	POS	O
+more	POS	O
+common	POS	O
+adverse	POS	O
+effects	POS	O
+.	POS	O
+The	POS	O
+enhancement	POS	O
+of	POS	O
+aminonucleoside	POS	O
+nephrosis	POS	B-NP
+by	POS	O
+the	POS	O
+co	POS	O
+-	POS	O
+administration	POS	O
+of	POS	O
+protamine	POS	O
+.	POS	O
+An	POS	O
+experimental	POS	O
+model	POS	O
+of	POS	O
+focal	POS	O
+segmental	POS	O
+glomerular	POS	B-NP
+sclerosis	POS	I-NP
+(	POS	O
+FSGS	POS	B-NP
+)	POS	O
+was	POS	O
+developed	POS	O
+in	POS	O
+rats	POS	O
+by	POS	O
+the	POS	O
+combined	POS	O
+administration	POS	O
+of	POS	O
+puromycin	POS	O
+-	POS	O
+aminonucleoside	POS	O
+(	POS	O
+AMNS	POS	O
+)	POS	O
+and	POS	O
+protamine	POS	O
+sulfate	POS	O
+(	POS	O
+PS	POS	O
+)	POS	O
+.	POS	O
+Male	POS	O
+Sprague	POS	O
+-	POS	O
+Dawley	POS	O
+rats	POS	O
+,	POS	O
+uninephrectomized	POS	O
+three	POS	O
+weeks	POS	O
+before	POS	O
+,	POS	O
+received	POS	O
+daily	POS	O
+injections	POS	O
+of	POS	O
+subcutaneous	POS	O
+AMNS	POS	O
+(	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+100	POS	O
+g	POS	O
+body	POS	O
+wt	POS	O
+)	POS	O
+and	POS	O
+intravenous	POS	O
+PS	POS	O
+(	POS	O
+2	POS	O
+separated	POS	O
+doses	POS	O
+of	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+100	POS	O
+g	POS	O
+body	POS	O
+wt	POS	O
+)	POS	O
+for	POS	O
+four	POS	O
+days	POS	O
+.	POS	O
+The	POS	O
+series	POS	O
+of	POS	O
+injections	POS	O
+were	POS	O
+repeated	POS	O
+another	POS	O
+three	POS	O
+times	POS	O
+at	POS	O
+10	POS	O
+day	POS	O
+intervals	POS	O
+.	POS	O
+The	POS	O
+animals	POS	O
+were	POS	O
+sacrificed	POS	O
+on	POS	O
+days	POS	O
+24	POS	O
+,	POS	O
+52	POS	O
+,	POS	O
+and	POS	O
+80	POS	O
+.	POS	O
+They	POS	O
+developed	POS	O
+nephrotic	POS	B-NP
+syndrome	POS	I-NP
+and	POS	O
+finally	POS	O
+renal	POS	B-NP
+failure	POS	I-NP
+.	POS	O
+The	POS	O
+time	POS	O
+-	POS	O
+course	POS	O
+curve	POS	O
+of	POS	O
+creatinine	POS	O
+clearance	POS	O
+dropped	POS	O
+and	POS	O
+showed	POS	O
+significant	POS	O
+difference	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+from	POS	O
+that	POS	O
+of	POS	O
+each	POS	O
+control	POS	O
+group	POS	O
+,	POS	O
+such	POS	O
+as	POS	O
+,	POS	O
+AMNS	POS	O
+alone	POS	O
+,	POS	O
+PS	POS	O
+alone	POS	O
+or	POS	O
+saline	POS	O
+injected	POS	O
+.	POS	O
+Their	POS	O
+glomeruli	POS	O
+showed	POS	O
+changes	POS	O
+of	POS	O
+progressive	POS	O
+FSGS	POS	B-NP
+.	POS	O
+The	POS	O
+ultrastructural	POS	O
+studies	POS	O
+in	POS	O
+the	POS	O
+initial	POS	O
+stage	POS	O
+revealed	POS	O
+significant	POS	O
+lack	POS	O
+of	POS	O
+particles	POS	O
+of	POS	O
+perfused	POS	O
+ruthenium	POS	O
+red	POS	O
+on	POS	O
+the	POS	O
+lamina	POS	O
+rara	POS	O
+externa	POS	O
+and	POS	O
+marked	POS	O
+changes	POS	O
+in	POS	O
+epithelial	POS	O
+cell	POS	O
+cytoplasm	POS	O
+.	POS	O
+Therefore	POS	O
+,	POS	O
+it	POS	O
+is	POS	O
+suggested	POS	O
+that	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+PS	POS	O
+enhances	POS	O
+the	POS	O
+toxicity	POS	O
+of	POS	O
+AMNS	POS	O
+on	POS	O
+the	POS	O
+glomerulus	POS	O
+and	POS	O
+readily	POS	O
+produces	POS	O
+progressive	POS	O
+FSGS	POS	B-NP
+in	POS	O
+rats	POS	O
+resulting	POS	O
+in	POS	O
+the	POS	O
+end	POS	O
+-	POS	O
+stage	POS	O
+renal	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+Theophylline	POS	O
+neurotoxicity	POS	B-NP
+in	POS	O
+pregnant	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+this	POS	O
+investigation	POS	O
+was	POS	O
+to	POS	O
+determine	POS	O
+whether	POS	O
+the	POS	O
+neurotoxicity	POS	B-NP
+of	POS	O
+theophylline	POS	O
+is	POS	O
+altered	POS	O
+in	POS	O
+advanced	POS	O
+pregnancy	POS	O
+.	POS	O
+Sprague	POS	O
+-	POS	O
+Dawley	POS	O
+rats	POS	O
+that	POS	O
+were	POS	O
+20	POS	O
+days	POS	O
+pregnant	POS	O
+and	POS	O
+nonpregnant	POS	O
+rats	POS	O
+of	POS	O
+the	POS	O
+same	POS	O
+age	POS	O
+and	POS	O
+strain	POS	O
+received	POS	O
+infusions	POS	O
+of	POS	O
+aminophylline	POS	O
+until	POS	O
+onset	POS	O
+of	POS	O
+maximal	POS	O
+seizures	POS	B-NP
+which	POS	O
+occurred	POS	O
+after	POS	O
+28	POS	O
+and	POS	O
+30	POS	O
+minutes	POS	O
+respectively	POS	O
+.	POS	O
+Theophylline	POS	O
+concentrations	POS	O
+at	POS	O
+this	POS	O
+endpoint	POS	O
+in	POS	O
+serum	POS	O
+(	POS	O
+total	POS	O
+)	POS	O
+and	POS	O
+CSF	POS	O
+were	POS	O
+similar	POS	O
+but	POS	O
+serum	POS	O
+(	POS	O
+free	POS	O
+)	POS	O
+and	POS	O
+brain	POS	O
+concentrations	POS	O
+were	POS	O
+slightly	POS	O
+different	POS	O
+in	POS	O
+pregnant	POS	O
+rats	POS	O
+.	POS	O
+Theophylline	POS	O
+serum	POS	O
+protein	POS	O
+binding	POS	O
+determined	POS	O
+by	POS	O
+equilibrium	POS	O
+dialysis	POS	O
+was	POS	O
+lower	POS	O
+in	POS	O
+pregnant	POS	O
+rats	POS	O
+.	POS	O
+Fetal	POS	O
+serum	POS	O
+concentrations	POS	O
+at	POS	O
+onset	POS	O
+of	POS	O
+seizures	POS	B-NP
+in	POS	O
+the	POS	O
+mother	POS	O
+were	POS	O
+similar	POS	O
+to	POS	O
+maternal	POS	O
+brain	POS	O
+and	POS	O
+CSF	POS	O
+concentrations	POS	O
+and	POS	O
+correlated	POS	O
+significantly	POS	O
+with	POS	O
+the	POS	O
+former	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+concluded	POS	O
+that	POS	O
+advanced	POS	O
+pregnancy	POS	O
+has	POS	O
+a	POS	O
+negligible	POS	O
+effect	POS	O
+on	POS	O
+the	POS	O
+neurotoxic	POS	B-NP
+response	POS	O
+to	POS	O
+theophylline	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+Hyperkalemia	POS	B-NP
+induced	POS	O
+by	POS	O
+indomethacin	POS	O
+and	POS	O
+naproxen	POS	O
+and	POS	O
+reversed	POS	O
+by	POS	O
+fludrocortisone	POS	O
+.	POS	O
+We	POS	O
+have	POS	O
+described	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+severe	POS	O
+rheumatoid	POS	B-NP
+arthritis	POS	I-NP
+and	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+mefenamic	POS	O
+acid	POS	O
+nephropathy	POS	B-NP
+in	POS	O
+whom	POS	O
+hyperkalemia	POS	B-NP
+and	POS	O
+inappropriate	POS	O
+hypoaldosteronism	POS	B-NP
+were	POS	O
+caused	POS	O
+by	POS	O
+both	POS	O
+indomethacin	POS	O
+and	POS	O
+naproxen	POS	O
+,	POS	O
+without	POS	O
+major	POS	O
+decline	POS	O
+in	POS	O
+renal	POS	O
+function	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+likely	POS	O
+that	POS	O
+preexisting	POS	O
+renal	POS	B-NP
+disease	POS	I-NP
+predisposed	POS	O
+this	POS	O
+patient	POS	O
+to	POS	O
+type	POS	B-NP
+IV	POS	I-NP
+renal	POS	I-NP
+tubular	POS	I-NP
+acidosis	POS	I-NP
+with	POS	O
+prostaglandin	POS	O
+synthetase	POS	O
+inhibitors	POS	O
+.	POS	O
+Because	POS	O
+he	POS	O
+was	POS	O
+unable	POS	O
+to	POS	O
+discontinue	POS	O
+nonsteroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drug	POS	O
+therapy	POS	O
+,	POS	O
+fludrocortisone	POS	O
+was	POS	O
+added	POS	O
+,	POS	O
+correcting	POS	O
+the	POS	O
+hyperkalemia	POS	B-NP
+and	POS	O
+allowing	POS	O
+indomethacin	POS	O
+therapy	POS	O
+to	POS	O
+be	POS	O
+continued	POS	O
+safely	POS	O
+.	POS	O
+Hypotension	POS	B-NP
+as	POS	O
+a	POS	O
+manifestation	POS	O
+of	POS	O
+cardiotoxicity	POS	B-NP
+in	POS	O
+three	POS	O
+patients	POS	O
+receiving	POS	O
+cisplatin	POS	O
+and	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+.	POS	O
+Cardiac	POS	B-NP
+symptoms	POS	I-NP
+,	POS	O
+including	POS	O
+hypotension	POS	B-NP
+,	POS	O
+developed	POS	O
+in	POS	O
+three	POS	O
+patients	POS	O
+with	POS	O
+advanced	POS	O
+colorectal	POS	B-NP
+carcinoma	POS	B-NP
+while	POS	O
+being	POS	O
+treated	POS	O
+with	POS	O
+cisplatin	POS	O
+(	POS	O
+CDDP	POS	O
+)	POS	O
+and	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+(	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+two	POS	O
+patients	POS	O
+,	POS	O
+hypotension	POS	B-NP
+was	POS	O
+associated	POS	O
+with	POS	O
+severe	POS	O
+left	POS	O
+ventricular	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+All	POS	O
+three	POS	O
+patients	POS	O
+required	POS	O
+therapy	POS	O
+discontinuation	POS	O
+.	POS	O
+Cardiac	POS	O
+enzymes	POS	O
+remained	POS	O
+normal	POS	O
+despite	POS	O
+transient	POS	O
+electrocardiographic	POS	O
+(	POS	O
+EKG	POS	O
+)	POS	O
+changes	POS	O
+.	POS	O
+The	POS	O
+presentation	POS	O
+and	POS	O
+cardiac	POS	O
+evaluation	POS	O
+(	POS	O
+hemodynamic	POS	O
+,	POS	O
+echocardiographic	POS	O
+,	POS	O
+and	POS	O
+scintigraphic	POS	O
+)	POS	O
+of	POS	O
+these	POS	O
+patients	POS	O
+suggest	POS	O
+new	POS	O
+manifestations	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+cardiotoxicity	POS	B-NP
+that	POS	O
+may	POS	O
+be	POS	O
+influenced	POS	O
+by	POS	O
+CDDP	POS	O
+.	POS	O
+The	POS	O
+possible	POS	O
+pathophysiologic	POS	O
+mechanisms	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+Fatal	POS	O
+aplastic	POS	B-NP
+anemia	POS	I-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+treated	POS	O
+with	POS	O
+carbamazepine	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+fatal	POS	O
+aplastic	POS	B-NP
+anemia	POS	I-NP
+due	POS	O
+to	POS	O
+carbamazepine	POS	O
+treatment	POS	O
+in	POS	O
+an	POS	O
+epileptic	POS	B-NP
+woman	POS	O
+is	POS	O
+reported	POS	O
+.	POS	O
+Despite	POS	O
+concerns	POS	O
+of	POS	O
+fatal	POS	O
+bone	POS	B-NP
+marrow	POS	I-NP
+toxicity	POS	I-NP
+due	POS	O
+to	POS	O
+carbamazepine	POS	O
+,	POS	O
+this	POS	O
+is	POS	O
+only	POS	O
+the	POS	O
+fourth	POS	O
+documented	POS	O
+and	POS	O
+published	POS	O
+report	POS	O
+.	POS	O
+Carbamazepine	POS	O
+is	POS	O
+a	POS	O
+safe	POS	O
+drug	POS	O
+,	POS	O
+but	POS	O
+physicians	POS	O
+and	POS	O
+patients	POS	O
+should	POS	O
+be	POS	O
+aware	POS	O
+of	POS	O
+the	POS	O
+exceedingly	POS	O
+rare	POS	O
+but	POS	O
+potentially	POS	O
+fatal	POS	O
+side	POS	O
+effects	POS	O
+,	POS	O
+better	POS	O
+prevented	POS	O
+by	POS	O
+clinical	POS	O
+than	POS	O
+by	POS	O
+laboratory	POS	O
+monitoring	POS	O
+.	POS	O
+Participation	POS	O
+of	POS	O
+a	POS	O
+bulbospinal	POS	O
+serotonergic	POS	O
+pathway	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+brain	POS	O
+in	POS	O
+clonidine	POS	O
+-	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+and	POS	O
+bradycardia	POS	B-NP
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+microinjection	POS	O
+of	POS	O
+clonidine	POS	O
+(	POS	O
+1	POS	O
+-	POS	O
+10	POS	O
+micrograms	POS	O
+in	POS	O
+1	POS	O
+microliter	POS	O
+)	POS	O
+into	POS	O
+a	POS	O
+region	POS	O
+adjacent	POS	O
+to	POS	O
+the	POS	O
+ventrolateral	POS	O
+surface	POS	O
+of	POS	O
+the	POS	O
+medulla	POS	O
+oblongata	POS	O
+on	POS	O
+cardiovascular	POS	O
+function	POS	O
+were	POS	O
+assessed	POS	O
+in	POS	O
+urethane	POS	O
+-	POS	O
+anesthetized	POS	O
+rats	POS	O
+.	POS	O
+Intramedullary	POS	O
+administration	POS	O
+of	POS	O
+clonidine	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+saline	POS	O
+vehicle	POS	O
+,	POS	O
+caused	POS	O
+a	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+decrease	POS	O
+in	POS	O
+both	POS	O
+the	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+and	POS	O
+the	POS	O
+heart	POS	O
+rate	POS	O
+.	POS	O
+The	POS	O
+clonidine	POS	O
+-	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+was	POS	O
+antagonized	POS	O
+by	POS	O
+prior	POS	O
+spinal	POS	O
+transection	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+bilateral	POS	O
+vagotomy	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+other	POS	O
+hand	POS	O
+,	POS	O
+the	POS	O
+clonidine	POS	O
+-	POS	O
+induced	POS	O
+bradycardia	POS	B-NP
+was	POS	O
+antagonized	POS	O
+by	POS	O
+prior	POS	O
+bilateral	POS	O
+vagotomy	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+spinal	POS	O
+transection	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+selective	POS	O
+destruction	POS	O
+of	POS	O
+the	POS	O
+spinal	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+nerves	POS	O
+,	POS	O
+produced	POS	O
+by	POS	O
+bilateral	POS	O
+spinal	POS	O
+injection	POS	O
+of	POS	O
+5	POS	O
+,	POS	O
+7	POS	O
+-	POS	O
+dihydroxytryptamine	POS	O
+,	POS	O
+reduced	POS	O
+the	POS	O
+magnitude	POS	O
+of	POS	O
+the	POS	O
+vasodepressor	POS	O
+or	POS	O
+the	POS	O
+bradycardiac	POS	O
+responses	POS	O
+to	POS	O
+clonidine	POS	O
+microinjected	POS	O
+into	POS	O
+the	POS	O
+area	POS	O
+near	POS	O
+the	POS	O
+ventrolateral	POS	O
+surface	POS	O
+of	POS	O
+the	POS	O
+medulla	POS	O
+oblongata	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+data	POS	O
+indicate	POS	O
+that	POS	O
+a	POS	O
+bulbospinal	POS	O
+serotonergic	POS	O
+pathway	POS	O
+is	POS	O
+involved	POS	O
+in	POS	O
+development	POS	O
+of	POS	O
+clonidine	POS	O
+-	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+and	POS	O
+bradycardia	POS	B-NP
+.	POS	O
+The	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+is	POS	O
+brought	POS	O
+about	POS	O
+by	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+sympathetic	POS	O
+efferent	POS	O
+activity	POS	O
+,	POS	O
+whereas	POS	O
+the	POS	O
+induced	POS	O
+bradycardia	POS	B-NP
+was	POS	O
+due	POS	O
+to	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+vagal	POS	O
+efferent	POS	O
+activity	POS	O
+.	POS	O
+Hypertension	POS	B-NP
+in	POS	O
+neuroblastoma	POS	B-NP
+induced	POS	O
+by	POS	O
+imipramine	POS	O
+.	POS	O
+Hypertension	POS	B-NP
+is	POS	O
+a	POS	O
+well	POS	O
+-	POS	O
+known	POS	O
+finding	POS	O
+in	POS	O
+some	POS	O
+patients	POS	O
+with	POS	O
+neuroblastoma	POS	B-NP
+.	POS	O
+However	POS	O
+,	POS	O
+it	POS	O
+has	POS	O
+not	POS	O
+previously	POS	O
+been	POS	O
+described	POS	O
+in	POS	O
+association	POS	O
+with	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+Imipramine	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+severe	POS	O
+hypertension	POS	B-NP
+(	POS	O
+blood	POS	O
+pressure	POS	O
+190	POS	O
+/	POS	O
+160	POS	O
+)	POS	O
+in	POS	O
+a	POS	O
+4	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+girl	POS	O
+with	POS	O
+neuroblastoma	POS	B-NP
+who	POS	O
+was	POS	O
+given	POS	O
+Imipramine	POS	O
+to	POS	O
+control	POS	O
+a	POS	O
+behavior	POS	B-NP
+disorder	POS	I-NP
+.	POS	O
+It	POS	O
+was	POS	O
+determined	POS	O
+later	POS	O
+that	POS	O
+this	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+tumor	POS	B-NP
+was	POS	O
+recurring	POS	O
+at	POS	O
+the	POS	O
+time	POS	O
+of	POS	O
+her	POS	O
+hypertensive	POS	B-NP
+episode	POS	O
+.	POS	O
+Since	POS	O
+she	POS	O
+had	POS	O
+no	POS	O
+blood	POS	O
+pressure	POS	O
+elevation	POS	O
+at	POS	O
+initial	POS	O
+diagnosis	POS	O
+and	POS	O
+none	POS	O
+following	POS	O
+discontinuation	POS	O
+of	POS	O
+the	POS	O
+Imipramine	POS	O
+(	POS	O
+when	POS	O
+she	POS	O
+was	POS	O
+in	POS	O
+florid	POS	O
+relapse	POS	O
+)	POS	O
+,	POS	O
+we	POS	O
+believe	POS	O
+that	POS	O
+this	POS	O
+drug	POS	O
+rather	POS	O
+than	POS	O
+her	POS	O
+underlying	POS	O
+disease	POS	O
+alone	POS	O
+caused	POS	O
+her	POS	O
+hypertension	POS	B-NP
+.	POS	O
+The	POS	O
+mechanism	POS	O
+for	POS	O
+this	POS	O
+reaction	POS	O
+is	POS	O
+believed	POS	O
+to	POS	O
+be	POS	O
+increased	POS	O
+levels	POS	O
+of	POS	O
+vasoactive	POS	O
+catecholamines	POS	O
+due	POS	O
+to	POS	O
+interference	POS	O
+of	POS	O
+their	POS	O
+physiologic	POS	O
+inactivation	POS	O
+by	POS	O
+Imipramine	POS	O
+.	POS	O
+From	POS	O
+this	POS	O
+experience	POS	O
+,	POS	O
+we	POS	O
+urge	POS	O
+extreme	POS	O
+caution	POS	O
+in	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+tricyclic	POS	O
+antidepressants	POS	O
+in	POS	O
+children	POS	O
+with	POS	O
+active	POS	O
+neuroblastoma	POS	B-NP
+.	POS	O
+Rechallenge	POS	O
+of	POS	O
+patients	POS	O
+who	POS	O
+developed	POS	O
+oral	POS	O
+candidiasis	POS	B-NP
+or	POS	O
+hoarseness	POS	B-NP
+with	POS	O
+beclomethasone	POS	O
+dipropionate	POS	O
+.	POS	O
+Of	POS	O
+158	POS	O
+asthmatic	POS	B-NP
+patients	POS	O
+who	POS	O
+were	POS	O
+placed	POS	O
+on	POS	O
+inhaled	POS	O
+beclomethasone	POS	O
+,	POS	O
+15	POS	O
+(	POS	O
+9	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+developed	POS	O
+either	POS	O
+hoarseness	POS	B-NP
+(	POS	O
+8	POS	O
+)	POS	O
+,	POS	O
+oral	POS	O
+thrush	POS	B-NP
+(	POS	O
+6	POS	O
+)	POS	O
+,	POS	O
+or	POS	O
+both	POS	O
+(	POS	O
+1	POS	O
+)	POS	O
+.	POS	O
+When	POS	O
+their	POS	O
+adverse	POS	O
+reactions	POS	O
+subsided	POS	O
+,	POS	O
+seven	POS	O
+of	POS	O
+these	POS	O
+15	POS	O
+patients	POS	O
+were	POS	O
+rechallenged	POS	O
+with	POS	O
+inhaled	POS	O
+beclomethasone	POS	O
+.	POS	O
+These	POS	O
+included	POS	O
+five	POS	O
+cases	POS	O
+who	POS	O
+developed	POS	O
+hoarseness	POS	B-NP
+and	POS	O
+three	POS	O
+who	POS	O
+developed	POS	O
+Candidiasis	POS	B-NP
+.	POS	O
+One	POS	O
+patient	POS	O
+had	POS	O
+both	POS	O
+.	POS	O
+Oral	POS	O
+thrush	POS	B-NP
+did	POS	O
+not	POS	O
+recur	POS	O
+,	POS	O
+but	POS	O
+60	POS	O
+%	POS	O
+(	POS	O
+3	POS	O
+/	POS	O
+5	POS	O
+)	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+hoarseness	POS	B-NP
+had	POS	O
+recurrence	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+patients	POS	O
+may	POS	O
+be	POS	O
+restarted	POS	O
+on	POS	O
+inhaled	POS	O
+beclomethasone	POS	O
+when	POS	O
+clinically	POS	O
+indicated	POS	O
+;	POS	O
+however	POS	O
+,	POS	O
+because	POS	O
+of	POS	O
+the	POS	O
+high	POS	O
+recurrence	POS	O
+rate	POS	O
+,	POS	O
+patients	POS	O
+who	POS	O
+develop	POS	O
+hoarseness	POS	B-NP
+should	POS	O
+not	POS	O
+be	POS	O
+re	POS	O
+-	POS	O
+challenged	POS	O
+.	POS	O
+Concomitant	POS	O
+use	POS	O
+of	POS	O
+oral	POS	O
+prednisone	POS	O
+and	POS	O
+topical	POS	O
+beclomethasone	POS	O
+may	POS	O
+increase	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+developing	POS	O
+hoarseness	POS	B-NP
+or	POS	O
+candidiasis	POS	B-NP
+.	POS	O
+Cyclophosphamide	POS	B-NP
+cardiotoxicity	POS	I-NP
+:	POS	O
+an	POS	O
+analysis	POS	O
+of	POS	O
+dosing	POS	O
+as	POS	O
+a	POS	O
+risk	POS	O
+factor	POS	O
+.	POS	O
+Patients	POS	O
+who	POS	O
+undergo	POS	O
+bone	POS	O
+marrow	POS	O
+transplantation	POS	O
+are	POS	O
+generally	POS	O
+immunosuppressed	POS	O
+with	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+cyclophosphamide	POS	O
+(	POS	O
+CYA	POS	O
+)	POS	O
+which	POS	O
+is	POS	O
+usually	POS	O
+calculated	POS	O
+based	POS	O
+on	POS	O
+the	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+weight	POS	O
+.	POS	O
+At	POS	O
+these	POS	O
+high	POS	O
+doses	POS	O
+of	POS	O
+CYA	POS	O
+,	POS	O
+serious	POS	O
+cardiotoxicity	POS	B-NP
+may	POS	O
+occur	POS	O
+,	POS	O
+but	POS	O
+definitive	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+such	POS	O
+cardiotoxicity	POS	B-NP
+have	POS	O
+not	POS	O
+been	POS	O
+described	POS	O
+.	POS	O
+Since	POS	O
+chemotherapeutic	POS	O
+agent	POS	O
+toxicity	POS	B-NP
+generally	POS	O
+correlates	POS	O
+with	POS	O
+dose	POS	O
+per	POS	O
+body	POS	O
+surface	POS	O
+area	POS	O
+,	POS	O
+we	POS	O
+retrospectively	POS	O
+calculated	POS	O
+the	POS	O
+dose	POS	O
+of	POS	O
+CYA	POS	O
+in	POS	O
+patients	POS	O
+transplanted	POS	O
+at	POS	O
+our	POS	O
+institution	POS	O
+to	POS	O
+determine	POS	O
+whether	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+CYA	POS	O
+cardiotoxicity	POS	B-NP
+correlated	POS	O
+with	POS	O
+the	POS	O
+dose	POS	O
+per	POS	O
+body	POS	O
+surface	POS	O
+area	POS	O
+.	POS	O
+Eighty	POS	O
+patients	POS	O
+who	POS	O
+were	POS	O
+to	POS	O
+receive	POS	O
+CYA	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+d	POS	O
+for	POS	O
+four	POS	O
+days	POS	O
+as	POS	O
+preparation	POS	O
+for	POS	O
+marrow	POS	O
+grafting	POS	O
+underwent	POS	O
+a	POS	O
+total	POS	O
+of	POS	O
+84	POS	O
+transplants	POS	O
+for	POS	O
+aplastic	POS	B-NP
+anemia	POS	I-NP
+,	POS	O
+Wiskott	POS	B-NP
+-	POS	I-NP
+Aldrich	POS	I-NP
+syndrome	POS	I-NP
+,	POS	O
+or	POS	O
+severe	POS	O
+combined	POS	O
+immunodeficiency	POS	B-NP
+syndrome	POS	I-NP
+.	POS	O
+Fourteen	POS	O
+of	POS	O
+84	POS	O
+(	POS	O
+17	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+had	POS	O
+symptoms	POS	O
+and	POS	O
+signs	POS	O
+consistent	POS	O
+with	POS	O
+CYA	POS	O
+cardiotoxicity	POS	B-NP
+within	POS	O
+ten	POS	O
+days	POS	O
+of	POS	O
+receiving	POS	O
+1	POS	O
+to	POS	O
+4	POS	O
+doses	POS	O
+of	POS	O
+CYA	POS	O
+.	POS	O
+Six	POS	O
+of	POS	O
+the	POS	O
+14	POS	O
+patients	POS	O
+died	POS	O
+with	POS	O
+congestive	POS	B-NP
+heart	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+The	POS	O
+dose	POS	O
+of	POS	O
+CYA	POS	O
+per	POS	O
+body	POS	O
+surface	POS	O
+area	POS	O
+was	POS	O
+calculated	POS	O
+for	POS	O
+all	POS	O
+patients	POS	O
+and	POS	O
+the	POS	O
+patients	POS	O
+were	POS	O
+divided	POS	O
+into	POS	O
+two	POS	O
+groups	POS	O
+based	POS	O
+on	POS	O
+daily	POS	O
+CYA	POS	O
+dose	POS	O
+:	POS	O
+Group	POS	O
+1	POS	O
+,	POS	O
+CYA	POS	O
+less	POS	O
+than	POS	O
+or	POS	O
+equal	POS	O
+to	POS	O
+1	POS	O
+.	POS	O
+55	POS	O
+g	POS	O
+/	POS	O
+m2	POS	O
+/	POS	O
+d	POS	O
+;	POS	O
+Group	POS	O
+2	POS	O
+,	POS	O
+CYA	POS	O
+greater	POS	O
+than	POS	O
+1	POS	O
+.	POS	O
+55	POS	O
+g	POS	O
+/	POS	O
+m2	POS	O
+/	POS	O
+d	POS	O
+.	POS	O
+Cardiotoxicity	POS	B-NP
+that	POS	O
+was	POS	O
+thought	POS	O
+to	POS	O
+be	POS	O
+related	POS	O
+to	POS	O
+CYA	POS	O
+occurred	POS	O
+in	POS	O
+1	POS	O
+/	POS	O
+32	POS	O
+(	POS	O
+3	POS	O
+%	POS	O
+)	POS	O
+of	POS	O
+patients	POS	O
+in	POS	O
+Group	POS	O
+1	POS	O
+and	POS	O
+in	POS	O
+13	POS	O
+/	POS	O
+52	POS	O
+(	POS	O
+25	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+in	POS	O
+Group	POS	O
+2	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+025	POS	O
+)	POS	O
+.	POS	O
+Congestive	POS	B-NP
+heart	POS	I-NP
+failure	POS	I-NP
+caused	POS	O
+or	POS	O
+contributed	POS	O
+to	POS	O
+death	POS	O
+in	POS	O
+0	POS	O
+/	POS	O
+32	POS	O
+patients	POS	O
+in	POS	O
+Group	POS	O
+1	POS	O
+v	POS	O
+6	POS	O
+/	POS	O
+52	POS	O
+(	POS	O
+12	POS	O
+%	POS	O
+)	POS	O
+of	POS	O
+patients	POS	O
+in	POS	O
+Group	POS	O
+2	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+25	POS	O
+)	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+difference	POS	O
+in	POS	O
+the	POS	O
+rate	POS	O
+of	POS	O
+engraftment	POS	O
+of	POS	O
+evaluable	POS	O
+patients	POS	O
+in	POS	O
+the	POS	O
+two	POS	O
+groups	POS	O
+(	POS	O
+P	POS	O
+greater	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+)	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+the	POS	O
+CYA	POS	O
+cardiotoxicity	POS	B-NP
+correlates	POS	O
+with	POS	O
+CYA	POS	O
+dosage	POS	O
+as	POS	O
+calculated	POS	O
+by	POS	O
+body	POS	O
+surface	POS	O
+area	POS	O
+,	POS	O
+and	POS	O
+that	POS	O
+patients	POS	O
+with	POS	O
+aplastic	POS	B-NP
+anemia	POS	I-NP
+and	POS	O
+immunodeficiencies	POS	B-NP
+can	POS	O
+be	POS	O
+effectively	POS	O
+prepared	POS	O
+for	POS	O
+bone	POS	O
+marrow	POS	O
+grafting	POS	O
+at	POS	O
+a	POS	O
+CYA	POS	O
+dose	POS	O
+of	POS	O
+1	POS	O
+.	POS	O
+55	POS	O
+g	POS	O
+/	POS	O
+m2	POS	O
+/	POS	O
+d	POS	O
+for	POS	O
+four	POS	O
+days	POS	O
+with	POS	O
+a	POS	O
+lower	POS	O
+incidence	POS	O
+of	POS	O
+cardiotoxicity	POS	B-NP
+than	POS	O
+patients	POS	O
+whose	POS	O
+CYA	POS	O
+dosage	POS	O
+is	POS	O
+calculated	POS	O
+based	POS	O
+on	POS	O
+weight	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+reaffirms	POS	O
+the	POS	O
+principle	POS	O
+that	POS	O
+drug	POS	O
+toxicity	POS	B-NP
+correlates	POS	O
+with	POS	O
+dose	POS	O
+per	POS	O
+body	POS	O
+surface	POS	O
+area	POS	O
+.	POS	O
+Studies	POS	O
+of	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+aminoglycoside	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+The	POS	O
+epidemiology	POS	O
+of	POS	O
+aminoglycoside	POS	O
+-	POS	O
+induced	POS	O
+nephrotoxicity	POS	B-NP
+is	POS	O
+not	POS	O
+fully	POS	O
+understood	POS	O
+.	POS	O
+Experimental	POS	O
+studies	POS	O
+in	POS	O
+healthy	POS	O
+human	POS	O
+volunteers	POS	O
+indicate	POS	O
+aminoglycosides	POS	O
+cause	POS	O
+proximal	POS	O
+tubular	POS	B-NP
+damage	POS	I-NP
+in	POS	O
+most	POS	O
+patients	POS	O
+,	POS	O
+but	POS	O
+rarely	POS	O
+,	POS	O
+if	POS	O
+ever	POS	O
+,	POS	O
+cause	POS	O
+glomerular	POS	B-NP
+or	POS	I-NP
+tubular	POS	I-NP
+dysfunction	POS	I-NP
+.	POS	O
+Clinical	POS	O
+trials	POS	O
+of	POS	O
+aminoglycosides	POS	O
+in	POS	O
+seriously	POS	O
+ill	POS	O
+patients	POS	O
+indicate	POS	O
+that	POS	O
+the	POS	O
+relative	POS	O
+risk	POS	O
+for	POS	O
+developing	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+during	POS	O
+therapy	POS	O
+ranges	POS	O
+from	POS	O
+8	POS	O
+to	POS	O
+10	POS	O
+and	POS	O
+that	POS	O
+the	POS	O
+attributable	POS	O
+risk	POS	O
+is	POS	O
+70	POS	O
+%	POS	O
+to	POS	O
+80	POS	O
+%	POS	O
+.	POS	O
+Further	POS	O
+analysis	POS	O
+of	POS	O
+these	POS	O
+data	POS	O
+suggests	POS	O
+that	POS	O
+the	POS	O
+duration	POS	O
+of	POS	O
+therapy	POS	O
+,	POS	O
+plasma	POS	O
+aminoglycoside	POS	O
+levels	POS	O
+,	POS	O
+liver	POS	B-NP
+disease	POS	I-NP
+,	POS	O
+advanced	POS	O
+age	POS	O
+,	POS	O
+high	POS	O
+initial	POS	O
+estimated	POS	O
+creatinine	POS	O
+clearance	POS	O
+and	POS	O
+,	POS	O
+possibly	POS	O
+,	POS	O
+female	POS	O
+gender	POS	O
+all	POS	O
+increase	POS	O
+the	POS	O
+risk	POS	O
+for	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+Other	POS	O
+causes	POS	O
+of	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+,	POS	O
+such	POS	O
+as	POS	O
+shock	POS	B-NP
+,	POS	O
+appear	POS	O
+to	POS	O
+have	POS	O
+an	POS	O
+additive	POS	O
+effect	POS	O
+.	POS	O
+Predictive	POS	O
+models	POS	O
+have	POS	O
+been	POS	O
+developed	POS	O
+from	POS	O
+these	POS	O
+analyses	POS	O
+that	POS	O
+should	POS	O
+be	POS	O
+useful	POS	O
+for	POS	O
+identifying	POS	O
+patients	POS	O
+at	POS	O
+high	POS	O
+risk	POS	O
+.	POS	O
+These	POS	O
+models	POS	O
+may	POS	O
+also	POS	O
+be	POS	O
+useful	POS	O
+in	POS	O
+developing	POS	O
+insights	POS	O
+into	POS	O
+the	POS	O
+pathophysiology	POS	O
+of	POS	O
+aminoglycoside	POS	O
+-	POS	O
+induced	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+Central	POS	O
+action	POS	O
+of	POS	O
+narcotic	POS	O
+analgesics	POS	O
+.	POS	O
+Part	POS	O
+IV	POS	O
+.	POS	O
+Noradrenergic	POS	O
+influences	POS	O
+on	POS	O
+the	POS	O
+activity	POS	O
+of	POS	O
+analgesics	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+effect	POS	O
+of	POS	O
+clonidine	POS	O
+,	POS	O
+naphazoline	POS	O
+and	POS	O
+xylometazoline	POS	O
+on	POS	O
+analgesia	POS	O
+induced	POS	O
+by	POS	O
+morphine	POS	O
+,	POS	O
+codeine	POS	O
+,	POS	O
+fentanyl	POS	O
+and	POS	O
+pentazocine	POS	O
+,	POS	O
+and	POS	O
+on	POS	O
+cataleptic	POS	O
+effect	POS	O
+of	POS	O
+morphine	POS	O
+,	POS	O
+codine	POS	O
+and	POS	O
+fentanyl	POS	O
+was	POS	O
+studied	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+biochemical	POS	O
+assays	POS	O
+on	POS	O
+the	POS	O
+influence	POS	O
+of	POS	O
+four	POS	O
+analgesics	POS	O
+on	POS	O
+the	POS	O
+brain	POS	O
+concentration	POS	O
+and	POS	O
+turnover	POS	O
+of	POS	O
+noradrenaline	POS	O
+(	POS	O
+NA	POS	O
+)	POS	O
+were	POS	O
+also	POS	O
+performed	POS	O
+.	POS	O
+It	POS	O
+was	POS	O
+found	POS	O
+that	POS	O
+three	POS	O
+drugs	POS	O
+stimulating	POS	O
+central	POS	O
+NA	POS	O
+receptors	POS	O
+failed	POS	O
+to	POS	O
+affect	POS	O
+the	POS	O
+analgesic	POS	O
+ED50	POS	O
+of	POS	O
+all	POS	O
+antinociceptive	POS	O
+agents	POS	O
+and	POS	O
+they	POS	O
+enhanced	POS	O
+catalepsy	POS	B-NP
+induced	POS	O
+by	POS	O
+morphine	POS	O
+and	POS	O
+fentanyl	POS	O
+.	POS	O
+Codeine	POS	O
+catalepsy	POS	B-NP
+was	POS	O
+increased	POS	O
+by	POS	O
+clonidine	POS	O
+and	POS	O
+decreased	POS	O
+by	POS	O
+naphazoline	POS	O
+and	POS	O
+xylometazoline	POS	O
+.	POS	O
+The	POS	O
+brain	POS	O
+concentration	POS	O
+of	POS	O
+NA	POS	O
+was	POS	O
+not	POS	O
+changed	POS	O
+by	POS	O
+morphine	POS	O
+and	POS	O
+fentanyl	POS	O
+,	POS	O
+but	POS	O
+one	POS	O
+of	POS	O
+the	POS	O
+doses	POS	O
+of	POS	O
+codeine	POS	O
+(	POS	O
+45	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+slightly	POS	O
+enhanced	POS	O
+it	POS	O
+.	POS	O
+Pentazocine	POS	O
+dose	POS	O
+-	POS	O
+dependently	POS	O
+decreased	POS	O
+the	POS	O
+brain	POS	O
+level	POS	O
+of	POS	O
+NA	POS	O
+.	POS	O
+The	POS	O
+rate	POS	O
+of	POS	O
+NA	POS	O
+turnover	POS	O
+was	POS	O
+not	POS	O
+altered	POS	O
+by	POS	O
+analgesics	POS	O
+except	POS	O
+for	POS	O
+the	POS	O
+higher	POS	O
+dose	POS	O
+of	POS	O
+fentanyl	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+following	POS	O
+which	POS	O
+the	POS	O
+disappearance	POS	O
+of	POS	O
+NA	POS	O
+from	POS	O
+the	POS	O
+brain	POS	O
+was	POS	O
+diminished	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+are	POS	O
+discussed	POS	O
+in	POS	O
+the	POS	O
+light	POS	O
+of	POS	O
+various	POS	O
+and	POS	O
+non	POS	O
+-	POS	O
+uniform	POS	O
+data	POS	O
+from	POS	O
+the	POS	O
+literature	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+suggested	POS	O
+that	POS	O
+in	POS	O
+rats	POS	O
+the	POS	O
+brain	POS	O
+NA	POS	O
+plays	POS	O
+a	POS	O
+less	POS	O
+important	POS	O
+function	POS	O
+than	POS	O
+the	POS	O
+other	POS	O
+monoamines	POS	O
+in	POS	O
+the	POS	O
+behavioural	POS	O
+activity	POS	O
+of	POS	O
+potent	POS	O
+analgesics	POS	O
+.	POS	O
+Flurothyl	POS	O
+seizure	POS	B-NP
+thresholds	POS	O
+in	POS	O
+mice	POS	O
+treated	POS	O
+neonatally	POS	O
+with	POS	O
+a	POS	O
+single	POS	O
+injection	POS	O
+of	POS	O
+monosodium	POS	O
+glutamate	POS	O
+(	POS	O
+MSG	POS	O
+)	POS	O
+:	POS	O
+evaluation	POS	O
+of	POS	O
+experimental	POS	O
+parameters	POS	O
+in	POS	O
+flurothyl	POS	O
+seizure	POS	B-NP
+testing	POS	O
+.	POS	O
+Monosodium	POS	O
+glutamate	POS	O
+(	POS	O
+MSG	POS	O
+)	POS	O
+administration	POS	O
+to	POS	O
+neonatal	POS	O
+rodents	POS	O
+produces	POS	O
+convulsions	POS	B-NP
+and	POS	O
+results	POS	O
+in	POS	O
+numerous	POS	O
+biochemical	POS	O
+and	POS	O
+behavioral	POS	B-NP
+deficits	POS	I-NP
+.	POS	O
+These	POS	O
+studies	POS	O
+were	POS	O
+undertaken	POS	O
+to	POS	O
+determine	POS	O
+if	POS	O
+neonatal	POS	O
+administration	POS	O
+of	POS	O
+MSG	POS	O
+produced	POS	O
+permanent	POS	O
+alterations	POS	O
+in	POS	O
+seizure	POS	B-NP
+susceptibility	POS	O
+,	POS	O
+since	POS	O
+previous	POS	O
+investigations	POS	O
+were	POS	O
+inconclusive	POS	O
+.	POS	O
+A	POS	O
+flurothyl	POS	O
+ether	POS	O
+seizure	POS	B-NP
+screening	POS	O
+technique	POS	O
+was	POS	O
+used	POS	O
+to	POS	O
+evaluate	POS	O
+seizure	POS	B-NP
+susceptibility	POS	O
+in	POS	O
+adult	POS	O
+mice	POS	O
+that	POS	O
+received	POS	O
+neonatal	POS	O
+injections	POS	O
+of	POS	O
+MSG	POS	O
+(	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+g	POS	O
+and	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+g	POS	O
+)	POS	O
+.	POS	O
+MSG	POS	O
+treatment	POS	O
+resulted	POS	O
+in	POS	O
+significant	POS	O
+reductions	POS	O
+in	POS	O
+whole	POS	O
+brain	POS	O
+weight	POS	O
+but	POS	O
+did	POS	O
+not	POS	O
+alter	POS	O
+seizure	POS	B-NP
+threshold	POS	O
+.	POS	O
+A	POS	O
+naloxone	POS	O
+(	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+challenge	POS	O
+was	POS	O
+also	POS	O
+ineffective	POS	O
+in	POS	O
+altering	POS	O
+the	POS	O
+seizure	POS	B-NP
+thresholds	POS	O
+of	POS	O
+either	POS	O
+control	POS	O
+of	POS	O
+MSG	POS	O
+-	POS	O
+treated	POS	O
+mice	POS	O
+.	POS	O
+Flurothyl	POS	O
+ether	POS	O
+produced	POS	O
+hypothermia	POS	B-NP
+which	POS	O
+was	POS	O
+correlated	POS	O
+with	POS	O
+the	POS	O
+duration	POS	O
+of	POS	O
+flurothyl	POS	O
+exposure	POS	O
+;	POS	O
+however	POS	O
+,	POS	O
+the	POS	O
+relationship	POS	O
+of	POS	O
+hypothermia	POS	B-NP
+to	POS	O
+seizure	POS	B-NP
+induction	POS	O
+was	POS	O
+unclear	POS	O
+.	POS	O
+Flurothyl	POS	O
+seizure	POS	B-NP
+testing	POS	O
+proved	POS	O
+to	POS	O
+be	POS	O
+a	POS	O
+rapid	POS	O
+and	POS	O
+reliable	POS	O
+technique	POS	O
+with	POS	O
+which	POS	O
+to	POS	O
+evaluate	POS	O
+seizure	POS	B-NP
+susceptibility	POS	O
+.	POS	O
+Susceptibility	POS	O
+to	POS	O
+seizures	POS	B-NP
+produced	POS	O
+by	POS	O
+pilocarpine	POS	O
+in	POS	O
+rats	POS	O
+after	POS	O
+microinjection	POS	O
+of	POS	O
+isoniazid	POS	O
+or	POS	O
+gamma	POS	O
+-	POS	O
+vinyl	POS	O
+-	POS	O
+GABA	POS	O
+into	POS	O
+the	POS	O
+substantia	POS	O
+nigra	POS	O
+.	POS	O
+Pilocarpine	POS	O
+,	POS	O
+given	POS	O
+intraperitoneally	POS	O
+to	POS	O
+rats	POS	O
+,	POS	O
+reproduces	POS	O
+the	POS	O
+neuropathological	POS	O
+sequelae	POS	O
+of	POS	O
+temporal	POS	B-NP
+lobe	POS	I-NP
+epilepsy	POS	I-NP
+and	POS	O
+provides	POS	O
+a	POS	O
+relevant	POS	O
+animal	POS	O
+model	POS	O
+for	POS	O
+studying	POS	O
+mechanisms	POS	O
+of	POS	O
+buildup	POS	O
+of	POS	O
+convulsive	POS	B-NP
+activity	POS	O
+and	POS	O
+pathways	POS	O
+operative	POS	O
+in	POS	O
+the	POS	O
+generalization	POS	O
+and	POS	O
+propagation	POS	O
+of	POS	O
+seizures	POS	B-NP
+within	POS	O
+the	POS	O
+forebrain	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+,	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+manipulating	POS	O
+the	POS	O
+activity	POS	O
+of	POS	O
+the	POS	O
+gamma	POS	O
+-	POS	O
+aminobutyric	POS	O
+acid	POS	O
+(	POS	O
+GABA	POS	O
+)	POS	O
+-	POS	O
+mediated	POS	O
+synaptic	POS	O
+inhibition	POS	O
+within	POS	O
+the	POS	O
+substantia	POS	O
+nigra	POS	O
+on	POS	O
+seizures	POS	B-NP
+produced	POS	O
+by	POS	O
+pilocarpine	POS	O
+in	POS	O
+rats	POS	O
+,	POS	O
+were	POS	O
+investigated	POS	O
+.	POS	O
+In	POS	O
+animals	POS	O
+pretreated	POS	O
+with	POS	O
+microinjections	POS	O
+of	POS	O
+isoniazid	POS	O
+,	POS	O
+150	POS	O
+micrograms	POS	O
+,	POS	O
+an	POS	O
+inhibitor	POS	O
+of	POS	O
+activity	POS	O
+of	POS	O
+the	POS	O
+GABA	POS	O
+-	POS	O
+synthesizing	POS	O
+enzyme	POS	O
+,	POS	O
+L	POS	O
+-	POS	O
+glutamic	POS	O
+acid	POS	O
+decarboxylase	POS	O
+,	POS	O
+into	POS	O
+the	POS	O
+substantia	POS	O
+nigra	POS	O
+pars	POS	O
+reticulata	POS	O
+(	POS	O
+SNR	POS	O
+)	POS	O
+,	POS	O
+bilaterally	POS	O
+,	POS	O
+non	POS	O
+-	POS	O
+convulsant	POS	O
+doses	POS	O
+of	POS	O
+pilocarpine	POS	O
+,	POS	O
+100	POS	O
+and	POS	O
+200	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+resulted	POS	O
+in	POS	O
+severe	POS	O
+motor	POS	B-NP
+limbic	POS	I-NP
+seizures	POS	I-NP
+and	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+.	POS	O
+Electroencephalographic	POS	O
+and	POS	O
+behavioral	POS	O
+monitoring	POS	O
+revealed	POS	O
+a	POS	O
+profound	POS	O
+reduction	POS	O
+of	POS	O
+the	POS	O
+threshold	POS	O
+for	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+convulsions	POS	B-NP
+.	POS	O
+Morphological	POS	O
+analysis	POS	O
+of	POS	O
+frontal	POS	O
+forebrain	POS	O
+sections	POS	O
+with	POS	O
+light	POS	O
+microscopy	POS	O
+revealed	POS	O
+seizure	POS	B-NP
+-	POS	O
+related	POS	O
+damage	POS	O
+to	POS	O
+the	POS	O
+hippocampal	POS	O
+formation	POS	O
+,	POS	O
+thalamus	POS	O
+,	POS	O
+amygdala	POS	O
+,	POS	O
+olfactory	POS	O
+cortex	POS	O
+,	POS	O
+substantia	POS	O
+nigra	POS	O
+and	POS	O
+neocortex	POS	O
+,	POS	O
+which	POS	O
+is	POS	O
+typically	POS	O
+observed	POS	O
+with	POS	O
+pilocarpine	POS	O
+in	POS	O
+doses	POS	O
+exceeding	POS	O
+350	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+Bilateral	POS	O
+intrastriatal	POS	O
+injections	POS	O
+of	POS	O
+isoniazid	POS	O
+did	POS	O
+not	POS	O
+augment	POS	O
+seizures	POS	B-NP
+produced	POS	O
+by	POS	O
+pilocarpine	POS	O
+,	POS	O
+200	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+Application	POS	O
+of	POS	O
+an	POS	O
+irreversible	POS	O
+inhibitor	POS	O
+of	POS	O
+GABA	POS	O
+transaminase	POS	O
+,	POS	O
+gamma	POS	O
+-	POS	O
+vinyl	POS	O
+-	POS	O
+GABA	POS	O
+(	POS	O
+D	POS	O
+,	POS	O
+L	POS	O
+-	POS	O
+4	POS	O
+-	POS	O
+amino	POS	O
+-	POS	O
+hex	POS	O
+-	POS	O
+5	POS	O
+-	POS	O
+enoic	POS	O
+acid	POS	O
+)	POS	O
+,	POS	O
+5	POS	O
+micrograms	POS	O
+,	POS	O
+into	POS	O
+the	POS	O
+SNR	POS	O
+,	POS	O
+bilaterally	POS	O
+,	POS	O
+suppressed	POS	O
+the	POS	O
+appearance	POS	O
+of	POS	O
+electrographic	POS	O
+and	POS	O
+behavioral	POS	O
+seizures	POS	B-NP
+produced	POS	O
+by	POS	O
+pilocarpine	POS	O
+,	POS	O
+380	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+This	POS	O
+treatment	POS	O
+was	POS	O
+also	POS	O
+sufficient	POS	O
+to	POS	O
+protect	POS	O
+animals	POS	O
+from	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+brain	POS	O
+damage	POS	O
+.	POS	O
+Microinjections	POS	O
+of	POS	O
+gamma	POS	O
+-	POS	O
+vinyl	POS	O
+-	POS	O
+GABA	POS	O
+,	POS	O
+5	POS	O
+micrograms	POS	O
+,	POS	O
+into	POS	O
+the	POS	O
+dorsal	POS	O
+striatum	POS	O
+,	POS	O
+bilaterally	POS	O
+,	POS	O
+failed	POS	O
+to	POS	O
+prevent	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+convulsions	POS	B-NP
+produced	POS	O
+by	POS	O
+pilocarpine	POS	O
+,	POS	O
+380	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+demonstrate	POS	O
+that	POS	O
+the	POS	O
+threshold	POS	O
+for	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+in	POS	O
+rats	POS	O
+is	POS	O
+subjected	POS	O
+to	POS	O
+the	POS	O
+regulation	POS	O
+of	POS	O
+the	POS	O
+GABA	POS	O
+-	POS	O
+mediated	POS	O
+synaptic	POS	O
+inhibition	POS	O
+within	POS	O
+the	POS	O
+substantia	POS	O
+nigra	POS	O
+.	POS	O
+Human	POS	O
+and	POS	O
+canine	POS	O
+ventricular	POS	O
+vasoactive	POS	O
+intestinal	POS	O
+polypeptide	POS	O
+:	POS	O
+decrease	POS	O
+with	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+.	POS	O
+Vasoactive	POS	O
+intestinal	POS	O
+polypeptide	POS	O
+(	POS	O
+VIP	POS	O
+)	POS	O
+is	POS	O
+a	POS	O
+systemic	POS	O
+and	POS	O
+coronary	POS	O
+vasodilator	POS	O
+that	POS	O
+may	POS	O
+have	POS	O
+positive	POS	O
+inotropic	POS	O
+properties	POS	O
+.	POS	O
+Myocardial	POS	O
+levels	POS	O
+of	POS	O
+VIP	POS	O
+were	POS	O
+assayed	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+in	POS	O
+two	POS	O
+canine	POS	O
+models	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+first	POS	O
+,	POS	O
+cobalt	POS	O
+cardiomyopathy	POS	B-NP
+was	POS	O
+induced	POS	O
+in	POS	O
+eight	POS	O
+dogs	POS	O
+;	POS	O
+VIP	POS	O
+(	POS	O
+by	POS	O
+radioimmunoassay	POS	O
+)	POS	O
+decreased	POS	O
+from	POS	O
+35	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+11	POS	O
+pg	POS	O
+/	POS	O
+mg	POS	O
+protein	POS	O
+(	POS	O
+mean	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+SD	POS	O
+)	POS	O
+to	POS	O
+5	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+pg	POS	O
+/	POS	O
+mg	POS	O
+protein	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+six	POS	O
+dogs	POS	O
+with	POS	O
+doxorubicin	POS	O
+-	POS	O
+induced	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+,	POS	O
+VIP	POS	O
+decreased	POS	O
+from	POS	O
+31	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+7	POS	O
+to	POS	O
+11	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+pg	POS	O
+/	POS	O
+mg	POS	O
+protein	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+VIP	POS	O
+content	POS	O
+of	POS	O
+left	POS	O
+ventricular	POS	O
+muscle	POS	O
+of	POS	O
+resected	POS	O
+failing	POS	O
+hearts	POS	O
+in	POS	O
+10	POS	O
+patients	POS	O
+receiving	POS	O
+a	POS	O
+heart	POS	O
+transplant	POS	O
+was	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+papillary	POS	O
+muscles	POS	O
+in	POS	O
+14	POS	O
+patients	POS	O
+(	POS	O
+five	POS	O
+with	POS	O
+rheumatic	POS	B-NP
+disease	POS	I-NP
+,	POS	O
+nine	POS	O
+with	POS	O
+myxomatous	POS	B-NP
+degeneration	POS	I-NP
+)	POS	O
+receiving	POS	O
+mitral	POS	B-NP
+valve	POS	I-NP
+prostheses	POS	I-NP
+.	POS	O
+The	POS	O
+lowest	POS	O
+myocardial	POS	O
+VIP	POS	O
+concentration	POS	O
+was	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+hearts	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+coronary	POS	B-NP
+disease	POS	I-NP
+(	POS	O
+one	POS	O
+patient	POS	O
+receiving	POS	O
+a	POS	O
+transplant	POS	O
+and	POS	O
+three	POS	O
+receiving	POS	O
+mitral	POS	O
+prostheses	POS	O
+)	POS	O
+(	POS	O
+6	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+9	POS	O
+pg	POS	O
+/	POS	O
+mg	POS	O
+protein	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+other	POS	O
+patients	POS	O
+undergoing	POS	O
+transplantation	POS	O
+had	POS	O
+an	POS	O
+average	POS	O
+ejection	POS	O
+fraction	POS	O
+of	POS	O
+17	POS	O
+%	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+%	POS	O
+and	POS	O
+a	POS	O
+VIP	POS	O
+level	POS	O
+of	POS	O
+8	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+3	POS	O
+.	POS	O
+9	POS	O
+pg	POS	O
+/	POS	O
+mg	POS	O
+protein	POS	O
+.	POS	O
+The	POS	O
+hearts	POS	O
+without	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+average	POS	O
+ejection	POS	O
+fraction	POS	O
+of	POS	O
+this	POS	O
+group	POS	O
+62	POS	O
+%	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+10	POS	O
+%	POS	O
+)	POS	O
+had	POS	O
+a	POS	O
+VIP	POS	O
+concentration	POS	O
+of	POS	O
+14	POS	O
+.	POS	O
+1	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+7	POS	O
+.	POS	O
+9	POS	O
+pg	POS	O
+/	POS	O
+mg	POS	O
+protein	POS	O
+,	POS	O
+and	POS	O
+this	POS	O
+was	POS	O
+greater	POS	O
+than	POS	O
+in	POS	O
+hearts	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+with	POS	O
+coronary	POS	B-NP
+disease	POS	I-NP
+and	POS	O
+the	POS	O
+hearts	POS	O
+of	POS	O
+patients	POS	O
+receiving	POS	O
+a	POS	O
+transplant	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+Myocardial	POS	O
+catecholamines	POS	O
+were	POS	O
+also	POS	O
+determined	POS	O
+in	POS	O
+14	POS	O
+subjects	POS	O
+;	POS	O
+a	POS	O
+weak	POS	O
+correlation	POS	O
+(	POS	O
+r	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+57	POS	O
+,	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+between	POS	O
+the	POS	O
+tissue	POS	O
+concentrations	POS	O
+of	POS	O
+VIP	POS	O
+and	POS	O
+norepinephrine	POS	O
+was	POS	O
+noted	POS	O
+.	POS	O
+(	POS	O
+ABSTRACT	POS	O
+TRUNCATED	POS	O
+AT	POS	O
+250	POS	O
+WORDS	POS	O
+)	POS	O
+Non	POS	O
+-	POS	O
+invasive	POS	O
+detection	POS	O
+of	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+by	POS	O
+body	POS	O
+surface	POS	O
+electrocardiographic	POS	O
+mapping	POS	O
+after	POS	O
+dipyridamole	POS	O
+infusion	POS	O
+.	POS	O
+Electrocardiographic	POS	O
+changes	POS	O
+after	POS	O
+dipyridamole	POS	O
+infusion	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+568	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+4	POS	O
+min	POS	O
+)	POS	O
+were	POS	O
+studied	POS	O
+in	POS	O
+41	POS	O
+patients	POS	O
+with	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+and	POS	O
+compared	POS	O
+with	POS	O
+those	POS	O
+after	POS	O
+submaximal	POS	O
+treadmill	POS	O
+exercise	POS	O
+by	POS	O
+use	POS	O
+of	POS	O
+the	POS	O
+body	POS	O
+surface	POS	O
+mapping	POS	O
+technique	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+divided	POS	O
+into	POS	O
+three	POS	O
+groups	POS	O
+;	POS	O
+19	POS	O
+patients	POS	O
+without	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+(	POS	O
+non	POS	B-NP
+-	POS	I-NP
+MI	POS	I-NP
+group	POS	O
+)	POS	O
+,	POS	O
+14	POS	O
+with	POS	O
+anterior	POS	B-NP
+infarction	POS	I-NP
+(	POS	O
+ANT	POS	B-NP
+-	POS	I-NP
+MI	POS	I-NP
+)	POS	O
+and	POS	O
+eight	POS	O
+with	POS	O
+inferior	POS	B-NP
+infarction	POS	I-NP
+(	POS	O
+INF	POS	B-NP
+-	POS	I-NP
+MI	POS	I-NP
+)	POS	O
+.	POS	O
+Eighty	POS	O
+-	POS	O
+seven	POS	O
+unipolar	POS	O
+electrocardiograms	POS	O
+(	POS	O
+ECGs	POS	O
+)	POS	O
+distributed	POS	O
+over	POS	O
+the	POS	O
+entire	POS	O
+thoracic	POS	O
+surface	POS	O
+were	POS	O
+simultaneously	POS	O
+recorded	POS	O
+.	POS	O
+After	POS	O
+dipyridamole	POS	O
+,	POS	O
+ischemic	POS	B-NP
+ST	POS	I-NP
+-	POS	I-NP
+segment	POS	I-NP
+depression	POS	I-NP
+(	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+mV	POS	O
+or	POS	O
+more	POS	O
+)	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+84	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+non	POS	O
+-	POS	O
+MI	POS	B-NP
+group	POS	O
+,	POS	O
+29	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+ANT	POS	O
+-	POS	O
+MI	POS	B-NP
+group	POS	O
+,	POS	O
+63	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+INF	POS	O
+-	POS	O
+MI	POS	B-NP
+group	POS	O
+and	POS	O
+61	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+total	POS	O
+population	POS	O
+.	POS	O
+Exercise	POS	O
+-	POS	O
+induced	POS	O
+ST	POS	B-NP
+depression	POS	I-NP
+was	POS	O
+observed	POS	O
+in	POS	O
+84	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+non	POS	O
+-	POS	O
+MI	POS	B-NP
+group	POS	O
+,	POS	O
+43	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+ANT	POS	O
+-	POS	O
+MI	POS	B-NP
+group	POS	O
+,	POS	O
+38	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+INF	POS	O
+-	POS	O
+MI	POS	B-NP
+group	POS	O
+and	POS	O
+61	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+total	POS	O
+.	POS	O
+For	POS	O
+individual	POS	O
+patients	POS	O
+,	POS	O
+there	POS	O
+were	POS	O
+no	POS	O
+obvious	POS	O
+differences	POS	O
+between	POS	O
+the	POS	O
+body	POS	O
+surface	POS	O
+distribution	POS	O
+of	POS	O
+ST	POS	O
+depression	POS	B-NP
+in	POS	O
+both	POS	O
+tests	POS	O
+.	POS	O
+The	POS	O
+increase	POS	O
+in	POS	O
+pressure	POS	O
+rate	POS	O
+product	POS	O
+after	POS	O
+dipyridamole	POS	O
+was	POS	O
+significantly	POS	O
+less	POS	O
+than	POS	O
+that	POS	O
+during	POS	O
+the	POS	O
+treadmill	POS	O
+exercise	POS	O
+.	POS	O
+The	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+the	POS	O
+dipyridamole	POS	O
+-	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+ischemia	POS	I-NP
+is	POS	O
+caused	POS	O
+by	POS	O
+the	POS	O
+inhomogenous	POS	O
+distribution	POS	O
+of	POS	O
+myocardial	POS	O
+blood	POS	O
+flow	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+the	POS	O
+dipyridamole	POS	O
+ECG	POS	O
+test	POS	O
+is	POS	O
+as	POS	O
+useful	POS	O
+as	POS	O
+the	POS	O
+exercise	POS	O
+ECG	POS	O
+test	POS	O
+for	POS	O
+the	POS	O
+assessment	POS	O
+of	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+Bradycardia	POS	B-NP
+after	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+intravenous	POS	O
+methylprednisolone	POS	O
+therapy	POS	O
+.	POS	O
+In	POS	O
+5	POS	O
+consecutive	POS	O
+patients	POS	O
+with	POS	O
+rheumatoid	POS	B-NP
+arthritis	POS	I-NP
+who	POS	O
+received	POS	O
+intravenous	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+methylprednisolone	POS	O
+(	POS	O
+MP	POS	O
+)	POS	O
+therapy	POS	O
+(	POS	O
+1	POS	O
+g	POS	O
+daily	POS	O
+for	POS	O
+2	POS	O
+or	POS	O
+3	POS	O
+consecutive	POS	O
+days	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+decline	POS	O
+in	POS	O
+pulse	POS	O
+rate	POS	O
+was	POS	O
+observed	POS	O
+,	POS	O
+most	POS	O
+pronounced	POS	O
+on	POS	O
+day	POS	O
+4	POS	O
+.	POS	O
+In	POS	O
+one	POS	O
+of	POS	O
+the	POS	O
+5	POS	O
+patients	POS	O
+the	POS	O
+bradycardia	POS	B-NP
+was	POS	O
+associated	POS	O
+with	POS	O
+complaints	POS	O
+of	POS	O
+substernal	POS	O
+pressure	POS	O
+.	POS	O
+Reversal	POS	O
+to	POS	O
+normal	POS	O
+heart	POS	O
+rate	POS	O
+was	POS	O
+found	POS	O
+on	POS	O
+day	POS	O
+7	POS	O
+.	POS	O
+Electrocardiographic	POS	O
+registrations	POS	O
+showed	POS	O
+sinus	POS	B-NP
+bradycardia	POS	I-NP
+in	POS	O
+all	POS	O
+cases	POS	O
+.	POS	O
+No	POS	O
+significant	POS	O
+changes	POS	O
+in	POS	O
+plasma	POS	O
+concentrations	POS	O
+of	POS	O
+electrolytes	POS	O
+were	POS	O
+found	POS	O
+.	POS	O
+Careful	POS	O
+observation	POS	O
+of	POS	O
+patients	POS	O
+receiving	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+MP	POS	O
+is	POS	O
+recommended	POS	O
+.	POS	O
+High	POS	O
+-	POS	O
+dose	POS	O
+MP	POS	O
+may	POS	O
+be	POS	O
+contraindicated	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+known	POS	O
+heart	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+Two	POS	O
+cases	POS	O
+of	POS	O
+downbeat	POS	B-NP
+nystagmus	POS	I-NP
+and	POS	O
+oscillopsia	POS	B-NP
+associated	POS	O
+with	POS	O
+carbamazepine	POS	O
+.	POS	O
+Downbeat	POS	B-NP
+nystagmus	POS	I-NP
+is	POS	O
+often	POS	O
+associated	POS	O
+with	POS	O
+structural	POS	O
+lesions	POS	O
+at	POS	O
+the	POS	O
+craniocervical	POS	O
+junction	POS	O
+,	POS	O
+but	POS	O
+has	POS	O
+occasionally	POS	O
+been	POS	O
+reported	POS	O
+as	POS	O
+a	POS	O
+manifestation	POS	O
+of	POS	O
+metabolic	POS	O
+imbalance	POS	O
+or	POS	O
+drug	POS	O
+intoxication	POS	O
+.	POS	O
+We	POS	O
+recorded	POS	O
+the	POS	O
+eye	POS	O
+movements	POS	O
+of	POS	O
+two	POS	O
+patients	POS	O
+with	POS	O
+reversible	POS	O
+downbeat	POS	B-NP
+nystagmus	POS	I-NP
+related	POS	O
+to	POS	O
+carbamazepine	POS	O
+therapy	POS	O
+.	POS	O
+The	POS	O
+nystagmus	POS	B-NP
+of	POS	O
+both	POS	O
+patients	POS	O
+resolved	POS	O
+after	POS	O
+reduction	POS	O
+of	POS	O
+the	POS	O
+serum	POS	O
+carbamazepine	POS	O
+levels	POS	O
+.	POS	O
+Neuroradiologic	POS	O
+investigations	POS	O
+including	POS	O
+magnetic	POS	O
+resonance	POS	O
+imaging	POS	O
+scans	POS	O
+in	POS	O
+both	POS	O
+patients	POS	O
+showed	POS	O
+no	POS	O
+evidence	POS	O
+of	POS	O
+intracranial	POS	B-NP
+abnormality	POS	I-NP
+.	POS	O
+In	POS	O
+patients	POS	O
+with	POS	O
+downbeat	POS	B-NP
+nystagmus	POS	I-NP
+who	POS	O
+are	POS	O
+taking	POS	O
+anticonvulsant	POS	O
+medications	POS	O
+,	POS	O
+consideration	POS	O
+should	POS	O
+be	POS	O
+given	POS	O
+to	POS	O
+reduction	POS	O
+in	POS	O
+dose	POS	O
+before	POS	O
+further	POS	O
+investigation	POS	O
+is	POS	O
+undertaken	POS	O
+.	POS	O
+Improvement	POS	O
+by	POS	O
+denopamine	POS	O
+(	POS	O
+TA	POS	O
+-	POS	O
+064	POS	O
+)	POS	O
+of	POS	O
+pentobarbital	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+failure	POS	I-NP
+in	POS	O
+the	POS	O
+dog	POS	O
+heart	POS	O
+-	POS	O
+lung	POS	O
+preparation	POS	O
+.	POS	O
+The	POS	O
+efficacy	POS	O
+of	POS	O
+denopamine	POS	O
+,	POS	O
+an	POS	O
+orally	POS	O
+active	POS	O
+beta	POS	O
+1	POS	O
+-	POS	O
+adrenoceptor	POS	O
+agonist	POS	O
+,	POS	O
+in	POS	O
+improving	POS	O
+cardiac	POS	B-NP
+failure	POS	I-NP
+was	POS	O
+assessed	POS	O
+in	POS	O
+dog	POS	O
+heart	POS	O
+-	POS	O
+lung	POS	O
+preparations	POS	O
+.	POS	O
+Cardiac	POS	O
+functions	POS	O
+depressed	POS	O
+by	POS	O
+pentobarbital	POS	O
+(	POS	O
+118	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+28	POS	O
+mg	POS	O
+;	POS	O
+mean	POS	O
+value	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+SD	POS	O
+)	POS	O
+such	POS	O
+that	POS	O
+cardiac	POS	O
+output	POS	O
+and	POS	O
+maximum	POS	O
+rate	POS	O
+of	POS	O
+rise	POS	O
+of	POS	O
+left	POS	O
+ventricular	POS	O
+pressure	POS	O
+(	POS	O
+LV	POS	O
+dP	POS	O
+/	POS	O
+dt	POS	O
+max	POS	O
+)	POS	O
+had	POS	O
+been	POS	O
+reduced	POS	O
+by	POS	O
+about	POS	O
+35	POS	O
+%	POS	O
+and	POS	O
+26	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+respective	POS	O
+controls	POS	O
+were	POS	O
+improved	POS	O
+by	POS	O
+denopamine	POS	O
+(	POS	O
+10	POS	O
+-	POS	O
+300	POS	O
+micrograms	POS	O
+)	POS	O
+in	POS	O
+a	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+manner	POS	O
+.	POS	O
+With	POS	O
+100	POS	O
+micrograms	POS	O
+denopamine	POS	O
+,	POS	O
+almost	POS	O
+complete	POS	O
+restoration	POS	O
+of	POS	O
+cardiac	POS	O
+performance	POS	O
+was	POS	O
+attained	POS	O
+,	POS	O
+associated	POS	O
+with	POS	O
+a	POS	O
+slight	POS	O
+increase	POS	O
+in	POS	O
+heart	POS	O
+rate	POS	O
+.	POS	O
+No	POS	O
+arrhythmias	POS	B-NP
+were	POS	O
+induced	POS	O
+by	POS	O
+these	POS	O
+doses	POS	O
+of	POS	O
+denopamine	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+warrant	POS	O
+clinical	POS	O
+trials	POS	O
+of	POS	O
+denopamine	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+cardiac	POS	B-NP
+failure	POS	I-NP
+.	POS	O
+Clonazepam	POS	O
+monotherapy	POS	O
+for	POS	O
+epilepsy	POS	B-NP
+in	POS	O
+childhood	POS	O
+.	POS	O
+Sixty	POS	O
+patients	POS	O
+(	POS	O
+age	POS	O
+-	POS	O
+range	POS	O
+one	POS	O
+month	POS	O
+to	POS	O
+14	POS	O
+years	POS	O
+)	POS	O
+with	POS	O
+other	POS	O
+types	POS	O
+of	POS	O
+epilepsy	POS	B-NP
+than	POS	O
+infantile	POS	B-NP
+spasms	POS	I-NP
+were	POS	O
+treated	POS	O
+with	POS	O
+clonazepam	POS	O
+.	POS	O
+Disappearance	POS	O
+of	POS	O
+seizures	POS	B-NP
+and	POS	O
+normalization	POS	O
+of	POS	O
+abnormal	POS	O
+EEG	POS	O
+with	POS	O
+disappearance	POS	O
+of	POS	O
+seizures	POS	B-NP
+were	POS	O
+recognized	POS	O
+in	POS	O
+77	POS	O
+%	POS	O
+and	POS	O
+50	POS	O
+%	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Seizures	POS	B-NP
+disappeared	POS	O
+in	POS	O
+71	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+with	POS	O
+generalized	POS	O
+seizures	POS	B-NP
+and	POS	O
+89	POS	O
+%	POS	O
+of	POS	O
+partial	POS	O
+seizures	POS	B-NP
+.	POS	O
+Improvement	POS	O
+of	POS	O
+abnormal	POS	O
+EEG	POS	O
+was	POS	O
+noticed	POS	O
+in	POS	O
+76	POS	O
+%	POS	O
+of	POS	O
+diffuse	POS	O
+paroxysms	POS	B-NP
+and	POS	O
+in	POS	O
+67	POS	O
+%	POS	O
+of	POS	O
+focal	POS	O
+paroxysms	POS	B-NP
+.	POS	O
+In	POS	O
+excellent	POS	O
+cases	POS	O
+,	POS	O
+mean	POS	O
+effective	POS	O
+dosages	POS	O
+were	POS	O
+0	POS	O
+.	POS	O
+086	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+021	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+in	POS	O
+infants	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+057	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+022	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+in	POS	O
+schoolchildren	POS	O
+,	POS	O
+this	POS	O
+difference	POS	O
+was	POS	O
+statistically	POS	O
+significant	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+005	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+side	POS	O
+effects	POS	O
+such	POS	O
+as	POS	O
+drowsiness	POS	B-NP
+and	POS	O
+ataxia	POS	B-NP
+was	POS	O
+only	POS	O
+5	POS	O
+%	POS	O
+.	POS	O
+Postmarketing	POS	O
+study	POS	O
+of	POS	O
+timolol	POS	O
+-	POS	O
+hydrochlorothiazide	POS	O
+antihypertensive	POS	O
+therapy	POS	O
+.	POS	O
+A	POS	O
+postmarketing	POS	O
+surveillance	POS	O
+study	POS	O
+was	POS	O
+conducted	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+safety	POS	O
+and	POS	O
+efficacy	POS	O
+of	POS	O
+a	POS	O
+fixed	POS	O
+-	POS	O
+ratio	POS	O
+combination	POS	O
+containing	POS	O
+10	POS	O
+mg	POS	O
+of	POS	O
+timolol	POS	O
+maleate	POS	O
+and	POS	O
+25	POS	O
+mg	POS	O
+of	POS	O
+hydrochlorothiazide	POS	O
+,	POS	O
+administered	POS	O
+twice	POS	O
+daily	POS	O
+for	POS	O
+one	POS	O
+month	POS	O
+to	POS	O
+hypertensive	POS	B-NP
+patients	POS	O
+.	POS	O
+Data	POS	O
+on	POS	O
+9	POS	O
+,	POS	O
+037	POS	O
+patients	POS	O
+were	POS	O
+collected	POS	O
+by	POS	O
+1	POS	O
+,	POS	O
+455	POS	O
+participating	POS	O
+physicians	POS	O
+.	POS	O
+Mean	POS	O
+systolic	POS	O
+blood	POS	O
+pressure	POS	O
+decreased	POS	O
+25	POS	O
+mmHg	POS	O
+and	POS	O
+mean	POS	O
+diastolic	POS	O
+blood	POS	O
+pressure	POS	O
+declined	POS	O
+15	POS	O
+mmHg	POS	O
+after	POS	O
+one	POS	O
+month	POS	O
+of	POS	O
+timolol	POS	O
+-	POS	O
+hydrochlorothiazide	POS	O
+therapy	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+,	POS	O
+both	POS	O
+comparisons	POS	O
+)	POS	O
+.	POS	O
+Age	POS	O
+,	POS	O
+race	POS	O
+,	POS	O
+and	POS	O
+sex	POS	O
+appeared	POS	O
+to	POS	O
+have	POS	O
+no	POS	O
+influence	POS	O
+on	POS	O
+the	POS	O
+decrease	POS	O
+in	POS	O
+blood	POS	O
+pressure	POS	O
+.	POS	O
+The	POS	O
+antihypertensive	POS	O
+effect	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+was	POS	O
+greater	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+more	POS	O
+severe	POS	O
+hypertension	POS	B-NP
+.	POS	O
+Overall	POS	O
+,	POS	O
+1	POS	O
+,	POS	O
+453	POS	O
+patients	POS	O
+experienced	POS	O
+a	POS	O
+total	POS	O
+of	POS	O
+2	POS	O
+,	POS	O
+658	POS	O
+adverse	POS	O
+events	POS	O
+,	POS	O
+the	POS	O
+most	POS	O
+common	POS	O
+being	POS	O
+fatigue	POS	B-NP
+,	POS	O
+dizziness	POS	B-NP
+,	POS	O
+and	POS	O
+weakness	POS	B-NP
+.	POS	O
+Treatment	POS	O
+in	POS	O
+590	POS	O
+patients	POS	O
+was	POS	O
+discontinued	POS	O
+because	POS	O
+of	POS	O
+adverse	POS	O
+events	POS	O
+.	POS	O
+Salicylate	POS	O
+nephropathy	POS	B-NP
+in	POS	O
+the	POS	O
+Gunn	POS	O
+rat	POS	O
+:	POS	O
+potential	POS	O
+role	POS	O
+of	POS	O
+prostaglandins	POS	O
+.	POS	O
+We	POS	O
+examined	POS	O
+the	POS	O
+potential	POS	O
+role	POS	O
+of	POS	O
+prostaglandins	POS	O
+in	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+analgesic	POS	O
+nephropathy	POS	B-NP
+in	POS	O
+the	POS	O
+Gunn	POS	O
+strain	POS	O
+of	POS	O
+rat	POS	O
+.	POS	O
+The	POS	O
+homozygous	POS	O
+Gunn	POS	O
+rats	POS	O
+have	POS	O
+unconjugated	POS	O
+hyperbilirubinemia	POS	B-NP
+due	POS	O
+to	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+glucuronyl	POS	O
+transferase	POS	O
+,	POS	O
+leading	POS	O
+to	POS	O
+marked	POS	O
+bilirubin	POS	O
+deposition	POS	O
+in	POS	O
+renal	POS	O
+medulla	POS	O
+and	POS	O
+papilla	POS	O
+.	POS	O
+These	POS	O
+rats	POS	O
+are	POS	O
+also	POS	O
+highly	POS	O
+susceptible	POS	O
+to	POS	O
+develop	POS	O
+papillary	POS	B-NP
+necrosis	POS	I-NP
+with	POS	O
+analgesic	POS	O
+administration	POS	O
+.	POS	O
+We	POS	O
+used	POS	O
+homozygous	POS	O
+(	POS	O
+jj	POS	O
+)	POS	O
+and	POS	O
+phenotypically	POS	O
+normal	POS	B-NP
+heterozygous	POS	O
+(	POS	O
+jJ	POS	O
+)	POS	O
+animals	POS	O
+.	POS	O
+Four	POS	O
+groups	POS	O
+of	POS	O
+rats	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+7	POS	O
+)	POS	O
+were	POS	O
+studied	POS	O
+:	POS	O
+jj	POS	O
+and	POS	O
+jJ	POS	O
+rats	POS	O
+treated	POS	O
+either	POS	O
+with	POS	O
+aspirin	POS	O
+300	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+every	POS	O
+other	POS	O
+day	POS	O
+or	POS	O
+sham	POS	O
+-	POS	O
+treated	POS	O
+.	POS	O
+After	POS	O
+one	POS	O
+week	POS	O
+,	POS	O
+slices	POS	O
+of	POS	O
+cortex	POS	O
+,	POS	O
+outer	POS	O
+and	POS	O
+inner	POS	O
+medulla	POS	O
+from	POS	O
+one	POS	O
+kidney	POS	O
+were	POS	O
+incubated	POS	O
+in	POS	O
+buffer	POS	O
+and	POS	O
+prostaglandin	POS	O
+synthesis	POS	O
+was	POS	O
+determined	POS	O
+by	POS	O
+radioimmunoassay	POS	O
+.	POS	O
+The	POS	O
+other	POS	O
+kidney	POS	O
+was	POS	O
+examined	POS	O
+histologically	POS	O
+.	POS	O
+A	POS	O
+marked	POS	O
+corticomedullary	POS	O
+gradient	POS	O
+of	POS	O
+prostaglandin	POS	O
+synthesis	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+all	POS	O
+groups	POS	O
+.	POS	O
+PGE2	POS	O
+synthesis	POS	O
+was	POS	O
+significantly	POS	O
+higher	POS	O
+in	POS	O
+outer	POS	O
+medulla	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+cortex	POS	O
+or	POS	O
+inner	POS	O
+medulla	POS	O
+,	POS	O
+of	POS	O
+jj	POS	O
+(	POS	O
+38	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+ng	POS	O
+/	POS	O
+mg	POS	O
+prot	POS	O
+)	POS	O
+than	POS	O
+jJ	POS	O
+rats	POS	O
+(	POS	O
+15	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+3	POS	O
+)	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+Aspirin	POS	O
+treatment	POS	O
+reduced	POS	O
+PGE2	POS	O
+synthesis	POS	O
+in	POS	O
+all	POS	O
+regions	POS	O
+,	POS	O
+but	POS	O
+outer	POS	O
+medullary	POS	O
+PGE2	POS	O
+remained	POS	O
+higher	POS	O
+in	POS	O
+jj	POS	O
+(	POS	O
+18	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+3	POS	O
+)	POS	O
+than	POS	O
+jJ	POS	O
+rats	POS	O
+(	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+2	POS	O
+)	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+PGF2	POS	O
+alpha	POS	O
+was	POS	O
+also	POS	O
+significantly	POS	O
+higher	POS	O
+in	POS	O
+the	POS	O
+outer	POS	O
+medulla	POS	O
+of	POS	O
+jj	POS	O
+rats	POS	O
+with	POS	O
+and	POS	O
+without	POS	O
+aspirin	POS	O
+administration	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+changes	POS	O
+in	POS	O
+renal	POS	O
+prostaglandin	POS	O
+synthesis	POS	O
+were	POS	O
+accompanied	POS	O
+by	POS	O
+evidence	POS	O
+of	POS	O
+renal	POS	B-NP
+damage	POS	I-NP
+in	POS	O
+aspirin	POS	O
+-	POS	O
+treated	POS	O
+jj	POS	O
+but	POS	O
+not	POS	O
+jJ	POS	O
+rats	POS	O
+as	POS	O
+evidenced	POS	O
+by	POS	O
+:	POS	O
+increased	POS	O
+incidence	POS	O
+and	POS	O
+severity	POS	O
+of	POS	O
+hematuria	POS	B-NP
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+;	POS	O
+increased	POS	O
+serum	POS	O
+creatinine	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+;	POS	O
+and	POS	O
+increase	POS	O
+in	POS	O
+outer	POS	O
+medullary	POS	O
+histopathologic	POS	O
+lesions	POS	B-NP
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+005	POS	O
+compared	POS	O
+to	POS	O
+either	POS	O
+sham	POS	O
+-	POS	O
+treated	POS	O
+jj	POS	O
+or	POS	O
+aspirin	POS	O
+-	POS	O
+treated	POS	O
+jJ	POS	O
+)	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+enhanced	POS	O
+prostaglandin	POS	O
+synthesis	POS	O
+contributes	POS	O
+to	POS	O
+maintenance	POS	O
+of	POS	O
+renal	POS	O
+function	POS	O
+and	POS	O
+morphological	POS	O
+integrity	POS	O
+,	POS	O
+and	POS	O
+that	POS	O
+inhibition	POS	O
+of	POS	O
+prostaglandin	POS	O
+synthesis	POS	O
+may	POS	O
+lead	POS	O
+to	POS	O
+pathological	POS	O
+renal	POS	B-NP
+medullary	POS	I-NP
+lesions	POS	I-NP
+and	POS	O
+deterioration	POS	B-NP
+of	POS	I-NP
+renal	POS	I-NP
+function	POS	I-NP
+.	POS	O
+Prophylactic	POS	O
+lidocaine	POS	O
+in	POS	O
+the	POS	O
+early	POS	O
+phase	POS	O
+of	POS	O
+suspected	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+Four	POS	O
+hundred	POS	O
+two	POS	O
+patients	POS	O
+with	POS	O
+suspected	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+seen	POS	O
+within	POS	O
+6	POS	O
+hours	POS	O
+of	POS	O
+the	POS	O
+onset	POS	O
+of	POS	O
+symptoms	POS	O
+entered	POS	O
+a	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+randomized	POS	O
+trial	POS	O
+of	POS	O
+lidocaine	POS	O
+vs	POS	O
+placebo	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+1	POS	O
+hour	POS	O
+after	POS	O
+administration	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+ventricular	POS	B-NP
+fibrillation	POS	I-NP
+or	POS	O
+sustained	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+among	POS	O
+the	POS	O
+204	POS	O
+patients	POS	O
+with	POS	O
+acute	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+was	POS	O
+low	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+.	POS	O
+Lidocaine	POS	O
+,	POS	O
+given	POS	O
+in	POS	O
+a	POS	O
+300	POS	O
+mg	POS	O
+dose	POS	O
+intramuscularly	POS	O
+followed	POS	O
+by	POS	O
+100	POS	O
+mg	POS	O
+intravenously	POS	O
+,	POS	O
+did	POS	O
+not	POS	O
+prevent	POS	O
+sustained	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+,	POS	O
+although	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+reduction	POS	O
+in	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+warning	POS	O
+arrhythmias	POS	B-NP
+between	POS	O
+15	POS	O
+and	POS	O
+45	POS	O
+minutes	POS	O
+after	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+lidocaine	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+average	POS	O
+plasma	POS	O
+lidocaine	POS	O
+level	POS	O
+10	POS	O
+minutes	POS	O
+after	POS	O
+administration	POS	O
+for	POS	O
+patients	POS	O
+without	POS	O
+a	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+was	POS	O
+significantly	POS	O
+higher	POS	O
+than	POS	O
+that	POS	O
+for	POS	O
+patients	POS	O
+with	POS	O
+an	POS	O
+acute	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+The	POS	O
+mean	POS	O
+plasma	POS	O
+lidocaine	POS	O
+level	POS	O
+of	POS	O
+patients	POS	O
+on	POS	O
+beta	POS	O
+-	POS	O
+blocking	POS	O
+agents	POS	O
+was	POS	O
+no	POS	O
+different	POS	O
+from	POS	O
+that	POS	O
+in	POS	O
+patients	POS	O
+not	POS	O
+on	POS	O
+beta	POS	O
+blocking	POS	O
+agents	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+1	POS	O
+-	POS	O
+hour	POS	O
+study	POS	O
+period	POS	O
+,	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+side	POS	O
+effects	POS	O
+was	POS	O
+significantly	POS	O
+greater	POS	O
+in	POS	O
+the	POS	O
+lidocaine	POS	O
+group	POS	O
+,	POS	O
+hypotension	POS	B-NP
+occurred	POS	O
+in	POS	O
+11	POS	O
+patients	POS	O
+,	POS	O
+nine	POS	O
+of	POS	O
+whom	POS	O
+had	POS	O
+received	POS	O
+lidocaine	POS	O
+,	POS	O
+and	POS	O
+four	POS	O
+patients	POS	O
+died	POS	O
+from	POS	O
+asystole	POS	B-NP
+,	POS	O
+three	POS	O
+of	POS	O
+whom	POS	O
+had	POS	O
+had	POS	O
+lidocaine	POS	O
+.	POS	O
+We	POS	O
+cannot	POS	O
+advocate	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+lidocaine	POS	O
+prophylactically	POS	O
+in	POS	O
+the	POS	O
+early	POS	O
+hours	POS	O
+of	POS	O
+suspected	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+Evidence	POS	O
+for	POS	O
+a	POS	O
+cholinergic	POS	O
+role	POS	O
+in	POS	O
+haloperidol	POS	O
+-	POS	O
+induced	POS	O
+catalepsy	POS	B-NP
+.	POS	O
+Experiments	POS	O
+in	POS	O
+mice	POS	O
+tested	POS	O
+previous	POS	O
+evidence	POS	O
+that	POS	O
+activation	POS	O
+of	POS	O
+cholinergic	POS	O
+systems	POS	O
+promotes	POS	O
+catalepsy	POS	B-NP
+and	POS	O
+that	POS	O
+cholinergic	POS	O
+mechanisms	POS	O
+need	POS	O
+to	POS	O
+be	POS	O
+intact	POS	O
+for	POS	O
+full	POS	O
+expression	POS	O
+of	POS	O
+neuroleptic	POS	O
+-	POS	O
+induced	POS	O
+catalepsy	POS	B-NP
+.	POS	O
+Large	POS	O
+doses	POS	O
+of	POS	O
+the	POS	O
+cholinomimetic	POS	O
+,	POS	O
+pilocarpine	POS	O
+,	POS	O
+could	POS	O
+induce	POS	O
+catalepsy	POS	B-NP
+when	POS	O
+peripheral	POS	O
+cholinergic	POS	O
+receptors	POS	O
+were	POS	O
+blocked	POS	O
+.	POS	O
+Low	POS	O
+doses	POS	O
+of	POS	O
+pilocarpine	POS	O
+caused	POS	O
+a	POS	O
+pronounced	POS	O
+enhancement	POS	O
+of	POS	O
+the	POS	O
+catalepsy	POS	B-NP
+that	POS	O
+was	POS	O
+induced	POS	O
+by	POS	O
+the	POS	O
+dopaminergic	POS	O
+blocker	POS	O
+,	POS	O
+haloperidol	POS	O
+.	POS	O
+A	POS	O
+muscarinic	POS	O
+receptor	POS	O
+blocker	POS	O
+,	POS	O
+atropine	POS	O
+,	POS	O
+disrupted	POS	O
+haloperidol	POS	O
+-	POS	O
+induced	POS	O
+catalepsy	POS	B-NP
+.	POS	O
+Intracranial	POS	O
+injection	POS	O
+of	POS	O
+an	POS	O
+acetylcholine	POS	O
+-	POS	O
+synthesis	POS	O
+inhibitor	POS	O
+,	POS	O
+hemicholinium	POS	O
+,	POS	O
+prevented	POS	O
+the	POS	O
+catalepsy	POS	B-NP
+that	POS	O
+is	POS	O
+usually	POS	O
+induced	POS	O
+by	POS	O
+haloperidol	POS	O
+.	POS	O
+These	POS	O
+findings	POS	O
+suggest	POS	O
+the	POS	O
+hypothesis	POS	O
+that	POS	O
+the	POS	O
+catalepsy	POS	B-NP
+that	POS	O
+is	POS	O
+produced	POS	O
+by	POS	O
+neuroleptics	POS	O
+such	POS	O
+as	POS	O
+haloperidol	POS	O
+is	POS	O
+actually	POS	O
+mediated	POS	O
+by	POS	O
+intrinsic	POS	O
+central	POS	O
+cholinergic	POS	O
+systems	POS	O
+.	POS	O
+Alternatively	POS	O
+,	POS	O
+activation	POS	O
+of	POS	O
+central	POS	O
+cholinergic	POS	O
+systems	POS	O
+could	POS	O
+promote	POS	O
+catalepsy	POS	B-NP
+by	POS	O
+suppression	POS	O
+of	POS	O
+dopaminergic	POS	O
+systems	POS	O
+.	POS	O
+Cardiovascular	POS	B-NP
+dysfunction	POS	I-NP
+and	POS	O
+hypersensitivity	POS	B-NP
+to	POS	O
+sodium	POS	O
+pentobarbital	POS	O
+induced	POS	O
+by	POS	O
+chronic	POS	O
+barium	POS	O
+chloride	POS	O
+ingestion	POS	O
+.	POS	O
+Barium	POS	O
+-	POS	O
+supplemented	POS	O
+Long	POS	O
+-	POS	O
+Evans	POS	O
+hooded	POS	O
+rats	POS	O
+were	POS	O
+characterized	POS	O
+by	POS	O
+a	POS	O
+persistent	POS	O
+hypertension	POS	B-NP
+that	POS	O
+was	POS	O
+evident	POS	O
+after	POS	O
+1	POS	O
+month	POS	O
+of	POS	O
+barium	POS	O
+(	POS	O
+100	POS	O
+micrograms	POS	O
+/	POS	O
+ml	POS	O
+mineral	POS	O
+fortified	POS	O
+water	POS	O
+)	POS	O
+treatment	POS	O
+.	POS	O
+Analysis	POS	O
+of	POS	O
+in	POS	O
+vivo	POS	O
+myocardial	POS	O
+excitability	POS	O
+,	POS	O
+contractility	POS	O
+,	POS	O
+and	POS	O
+metabolic	POS	O
+characteristics	POS	O
+at	POS	O
+16	POS	O
+months	POS	O
+revealed	POS	O
+other	POS	O
+significant	POS	O
+barium	POS	O
+-	POS	O
+induced	POS	O
+disturbances	POS	O
+within	POS	O
+the	POS	O
+cardiovascular	POS	O
+system	POS	O
+.	POS	O
+The	POS	O
+most	POS	O
+distinctive	POS	O
+aspect	POS	O
+of	POS	O
+the	POS	O
+barium	POS	O
+effect	POS	O
+was	POS	O
+a	POS	O
+demonstrated	POS	O
+hypersensitivity	POS	B-NP
+of	POS	I-NP
+the	POS	I-NP
+cardiovascular	POS	I-NP
+system	POS	I-NP
+to	POS	O
+sodium	POS	O
+pentobarbital	POS	O
+.	POS	O
+Under	POS	O
+barbiturate	POS	O
+anesthesia	POS	O
+,	POS	O
+virtually	POS	O
+all	POS	O
+of	POS	O
+the	POS	O
+myocardial	POS	O
+contractile	POS	O
+indices	POS	O
+were	POS	O
+depressed	POS	O
+significantly	POS	O
+in	POS	O
+barium	POS	O
+-	POS	O
+exposed	POS	O
+rats	POS	O
+relative	POS	O
+to	POS	O
+the	POS	O
+corresponding	POS	O
+control	POS	O
+-	POS	O
+fed	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+lack	POS	O
+of	POS	O
+a	POS	O
+similar	POS	O
+response	POS	O
+to	POS	O
+ketamine	POS	O
+and	POS	O
+xylazine	POS	O
+anesthesia	POS	O
+revealed	POS	O
+that	POS	O
+the	POS	O
+cardiovascular	POS	O
+actions	POS	O
+of	POS	O
+sodium	POS	O
+pentobarbital	POS	O
+in	POS	O
+barium	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+were	POS	O
+linked	POS	O
+specifically	POS	O
+to	POS	O
+this	POS	O
+anesthetic	POS	O
+,	POS	O
+and	POS	O
+were	POS	O
+not	POS	O
+representative	POS	O
+of	POS	O
+a	POS	O
+generalized	POS	O
+anesthetic	POS	O
+response	POS	O
+.	POS	O
+Other	POS	O
+myocardial	POS	O
+pathophysiologic	POS	O
+and	POS	O
+metabolic	POS	O
+changes	POS	O
+induced	POS	O
+by	POS	O
+barium	POS	O
+were	POS	O
+manifest	POS	O
+,	POS	O
+irrespective	POS	O
+of	POS	O
+the	POS	O
+anesthetic	POS	O
+employed	POS	O
+.	POS	O
+The	POS	O
+contractile	POS	O
+element	POS	O
+shortening	POS	O
+velocity	POS	O
+of	POS	O
+the	POS	O
+cardiac	POS	O
+muscle	POS	O
+fibers	POS	O
+was	POS	O
+significantly	POS	O
+slower	POS	O
+in	POS	O
+both	POS	O
+groups	POS	O
+of	POS	O
+barium	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+relative	POS	O
+to	POS	O
+the	POS	O
+control	POS	O
+groups	POS	O
+,	POS	O
+irrespective	POS	O
+of	POS	O
+the	POS	O
+anesthetic	POS	O
+regimen	POS	O
+.	POS	O
+Similarly	POS	O
+,	POS	O
+significant	POS	O
+disturbances	POS	O
+in	POS	O
+myocardial	POS	O
+energy	POS	O
+metabolism	POS	O
+were	POS	O
+detected	POS	O
+in	POS	O
+the	POS	O
+barium	POS	O
+-	POS	O
+exposed	POS	O
+rats	POS	O
+which	POS	O
+were	POS	O
+consistent	POS	O
+with	POS	O
+the	POS	O
+reduced	POS	O
+contractile	POS	O
+element	POS	O
+shortening	POS	O
+velocity	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+the	POS	O
+excitability	POS	O
+of	POS	O
+the	POS	O
+cardiac	POS	O
+conduction	POS	O
+system	POS	O
+was	POS	O
+depressed	POS	O
+preferentially	POS	O
+in	POS	O
+the	POS	O
+atrioventricular	POS	O
+nodal	POS	O
+region	POS	O
+of	POS	O
+hearts	POS	O
+from	POS	O
+barium	POS	O
+-	POS	O
+exposed	POS	O
+rats	POS	O
+.	POS	O
+Overall	POS	O
+,	POS	O
+the	POS	O
+altered	POS	O
+cardiac	POS	O
+contractility	POS	O
+and	POS	O
+excitability	POS	O
+characteristics	POS	O
+,	POS	O
+the	POS	O
+myocardial	POS	B-NP
+metabolic	POS	I-NP
+disturbances	POS	I-NP
+,	POS	O
+and	POS	O
+the	POS	O
+hypersensitivity	POS	B-NP
+of	POS	O
+the	POS	O
+cardiovascular	POS	O
+system	POS	O
+to	POS	O
+sodium	POS	O
+pentobarbital	POS	O
+suggest	POS	O
+the	POS	O
+existence	POS	O
+of	POS	O
+a	POS	O
+heretofore	POS	O
+undescribed	POS	O
+cardiomyopathic	POS	B-NP
+disorder	POS	I-NP
+induced	POS	O
+by	POS	O
+chronic	POS	O
+barium	POS	O
+exposure	POS	O
+.	POS	O
+These	POS	O
+experimental	POS	O
+findings	POS	O
+represent	POS	O
+the	POS	O
+first	POS	O
+indication	POS	O
+that	POS	O
+life	POS	O
+-	POS	O
+long	POS	O
+barium	POS	O
+ingestion	POS	O
+may	POS	O
+have	POS	O
+significant	POS	O
+adverse	POS	O
+effects	POS	O
+on	POS	O
+the	POS	O
+mammalian	POS	O
+cardiovascular	POS	O
+system	POS	O
+.	POS	O
+Propranolol	POS	O
+antagonism	POS	O
+of	POS	O
+phenylpropanolamine	POS	O
+-	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+.	POS	O
+Phenylpropanolamine	POS	B-NP
+(	POS	O
+PPA	POS	O
+)	POS	O
+overdose	POS	B-NP
+can	POS	O
+cause	POS	O
+severe	POS	O
+hypertension	POS	B-NP
+,	POS	O
+intracerebral	POS	B-NP
+hemorrhage	POS	I-NP
+,	POS	O
+and	POS	O
+death	POS	B-NP
+.	POS	O
+We	POS	O
+studied	POS	O
+the	POS	O
+efficacy	POS	O
+and	POS	O
+safety	POS	O
+of	POS	O
+propranolol	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+PPA	POS	O
+-	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+.	POS	O
+Subjects	POS	O
+received	POS	O
+propranolol	POS	O
+either	POS	O
+by	POS	O
+mouth	POS	O
+for	POS	O
+48	POS	O
+hours	POS	O
+before	POS	O
+PPA	POS	O
+or	POS	O
+as	POS	O
+a	POS	O
+rapid	POS	O
+intravenous	POS	O
+infusion	POS	O
+after	POS	O
+PPA	POS	O
+.	POS	O
+PPA	POS	O
+,	POS	O
+75	POS	O
+mg	POS	O
+alone	POS	O
+,	POS	O
+increased	POS	O
+blood	POS	O
+pressure	POS	O
+(	POS	O
+31	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+14	POS	O
+mm	POS	O
+Hg	POS	O
+systolic	POS	O
+,	POS	O
+20	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+5	POS	O
+mm	POS	O
+Hg	POS	O
+diastolic	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+propranolol	POS	O
+pretreatment	POS	O
+antagonized	POS	O
+this	POS	O
+increase	POS	O
+(	POS	O
+12	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+10	POS	O
+mm	POS	O
+Hg	POS	O
+systolic	POS	O
+,	POS	O
+10	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+7	POS	O
+mm	POS	O
+Hg	POS	O
+diastolic	POS	O
+)	POS	O
+.	POS	O
+Intravenous	POS	O
+propranolol	POS	O
+after	POS	O
+PPA	POS	O
+also	POS	O
+decreased	POS	O
+blood	POS	O
+pressure	POS	O
+.	POS	O
+Left	POS	O
+ventricular	POS	O
+function	POS	O
+(	POS	O
+assessed	POS	O
+by	POS	O
+echocardiography	POS	O
+)	POS	O
+showed	POS	O
+that	POS	O
+PPA	POS	O
+increased	POS	O
+the	POS	O
+stroke	POS	B-NP
+volume	POS	O
+30	POS	O
+%	POS	O
+(	POS	O
+from	POS	O
+62	POS	O
+.	POS	O
+5	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+20	POS	O
+.	POS	O
+9	POS	O
+to	POS	O
+80	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+22	POS	O
+.	POS	O
+4	POS	O
+ml	POS	O
+)	POS	O
+,	POS	O
+the	POS	O
+ejection	POS	O
+fraction	POS	O
+9	POS	O
+%	POS	O
+(	POS	O
+from	POS	O
+64	POS	O
+%	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+10	POS	O
+%	POS	O
+to	POS	O
+70	POS	O
+%	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+7	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+cardiac	POS	O
+output	POS	O
+14	POS	O
+%	POS	O
+(	POS	O
+from	POS	O
+3	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+6	POS	O
+to	POS	O
+4	POS	O
+.	POS	O
+1	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+0	POS	O
+L	POS	O
+/	POS	O
+min	POS	O
+)	POS	O
+.	POS	O
+Intravenous	POS	O
+propranolol	POS	O
+reversed	POS	O
+these	POS	O
+effects	POS	O
+.	POS	O
+Systemic	POS	O
+vascular	POS	O
+resistance	POS	O
+was	POS	O
+increased	POS	O
+by	POS	O
+PPA	POS	O
+28	POS	O
+%	POS	O
+(	POS	O
+from	POS	O
+1710	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+200	POS	O
+to	POS	O
+2190	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+700	POS	O
+dyne	POS	O
+X	POS	O
+sec	POS	O
+/	POS	O
+cm5	POS	O
+)	POS	O
+and	POS	O
+was	POS	O
+further	POS	O
+increased	POS	O
+by	POS	O
+propranolol	POS	O
+22	POS	O
+%	POS	O
+(	POS	O
+to	POS	O
+2660	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1200	POS	O
+dyne	POS	O
+X	POS	O
+sec	POS	O
+/	POS	O
+cm5	POS	O
+)	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+PPA	POS	O
+increases	POS	O
+blood	POS	O
+pressure	POS	O
+by	POS	O
+increasing	POS	O
+systemic	POS	O
+vascular	POS	O
+resistance	POS	O
+and	POS	O
+cardiac	POS	O
+output	POS	O
+,	POS	O
+and	POS	O
+that	POS	O
+propranolol	POS	O
+antagonizes	POS	O
+this	POS	O
+increase	POS	O
+by	POS	O
+reversing	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+PPA	POS	O
+on	POS	O
+cardiac	POS	O
+output	POS	O
+.	POS	O
+That	POS	O
+propranolol	POS	O
+antagonizes	POS	O
+the	POS	O
+pressor	POS	O
+effect	POS	O
+of	POS	O
+PPA	POS	O
+is	POS	O
+in	POS	O
+contrast	POS	O
+to	POS	O
+the	POS	O
+interaction	POS	O
+in	POS	O
+which	POS	O
+propranolol	POS	O
+enhances	POS	O
+the	POS	O
+pressor	POS	O
+effect	POS	O
+of	POS	O
+norepinephrine	POS	O
+.	POS	O
+This	POS	O
+is	POS	O
+probably	POS	O
+because	POS	O
+PPA	POS	O
+has	POS	O
+less	POS	O
+beta	POS	O
+2	POS	O
+activity	POS	O
+than	POS	O
+does	POS	O
+norepinephrine	POS	O
+.	POS	O
+Mesangial	POS	O
+function	POS	O
+and	POS	O
+glomerular	POS	B-NP
+sclerosis	POS	I-NP
+in	POS	O
+rats	POS	O
+with	POS	O
+aminonucleoside	POS	O
+nephrosis	POS	B-NP
+.	POS	O
+The	POS	O
+possible	POS	O
+relationship	POS	O
+between	POS	O
+mesangial	POS	B-NP
+dysfunction	POS	I-NP
+and	POS	O
+development	POS	O
+of	POS	O
+glomerular	POS	B-NP
+sclerosis	POS	I-NP
+was	POS	O
+studied	POS	O
+in	POS	O
+the	POS	O
+puromycin	POS	O
+aminonucleoside	POS	O
+(	POS	O
+PAN	POS	O
+)	POS	O
+model	POS	O
+.	POS	O
+Five	POS	O
+male	POS	O
+Wistar	POS	O
+rats	POS	O
+received	POS	O
+repeated	POS	O
+subcutaneous	POS	O
+PAN	POS	O
+injections	POS	O
+;	POS	O
+five	POS	O
+controls	POS	O
+received	POS	O
+saline	POS	O
+only	POS	O
+.	POS	O
+After	POS	O
+4	POS	O
+weeks	POS	O
+the	POS	O
+PAN	POS	O
+rats	POS	O
+were	POS	O
+severely	POS	O
+proteinuric	POS	O
+(	POS	O
+190	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+80	POS	O
+mg	POS	O
+/	POS	O
+24	POS	O
+hr	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+all	POS	O
+rats	POS	O
+were	POS	O
+given	POS	O
+colloidal	POS	O
+carbon	POS	O
+(	POS	O
+CC	POS	O
+)	POS	O
+intravenously	POS	O
+.	POS	O
+At	POS	O
+5	POS	O
+months	POS	O
+glomerular	POS	B-NP
+sclerosis	POS	I-NP
+was	POS	O
+found	POS	O
+in	POS	O
+7	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+3	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+glomeruli	POS	O
+of	POS	O
+PAN	POS	O
+rats	POS	O
+;	POS	O
+glomeruli	POS	O
+of	POS	O
+the	POS	O
+controls	POS	O
+were	POS	O
+normal	POS	O
+.	POS	O
+Glomeruli	POS	O
+of	POS	O
+PAN	POS	O
+rats	POS	O
+contained	POS	O
+significantly	POS	O
+more	POS	O
+CC	POS	O
+than	POS	O
+glomeruli	POS	O
+of	POS	O
+controls	POS	O
+.	POS	O
+Glomeruli	POS	O
+with	POS	O
+sclerosis	POS	B-NP
+contained	POS	O
+significantly	POS	O
+more	POS	O
+CC	POS	O
+than	POS	O
+non	POS	O
+-	POS	O
+sclerotic	POS	O
+glomeruli	POS	O
+in	POS	O
+the	POS	O
+same	POS	O
+kidneys	POS	O
+.	POS	O
+CC	POS	O
+was	POS	O
+preferentially	POS	O
+localized	POS	O
+within	POS	O
+the	POS	O
+sclerotic	POS	O
+areas	POS	O
+of	POS	O
+the	POS	O
+affected	POS	O
+glomeruli	POS	O
+.	POS	O
+Since	POS	O
+mesangial	POS	O
+CC	POS	O
+clearance	POS	O
+from	POS	O
+the	POS	O
+mesangium	POS	O
+did	POS	O
+not	POS	O
+change	POS	O
+during	POS	O
+chronic	POS	O
+PAN	POS	O
+treatment	POS	O
+,	POS	O
+we	POS	O
+conclude	POS	O
+that	POS	O
+this	POS	O
+preferential	POS	O
+CC	POS	O
+localization	POS	O
+within	POS	O
+the	POS	O
+lesions	POS	B-NP
+is	POS	O
+caused	POS	O
+by	POS	O
+an	POS	O
+increased	POS	O
+CC	POS	O
+uptake	POS	O
+shortly	POS	O
+after	POS	O
+injection	POS	O
+in	POS	O
+apparent	POS	O
+vulnerable	POS	O
+areas	POS	O
+where	POS	O
+sclerosis	POS	B-NP
+will	POS	O
+develop	POS	O
+subsequently	POS	O
+.	POS	O
+Cluster	POS	O
+analysis	POS	O
+showed	POS	O
+a	POS	O
+random	POS	O
+distribution	POS	O
+of	POS	O
+lesions	POS	B-NP
+in	POS	O
+the	POS	O
+PAN	POS	O
+glomeruli	POS	O
+in	POS	O
+concordance	POS	O
+with	POS	O
+the	POS	O
+random	POS	O
+localization	POS	O
+of	POS	O
+mesangial	POS	O
+areas	POS	O
+with	POS	O
+dysfunction	POS	O
+in	POS	O
+this	POS	O
+model	POS	O
+.	POS	O
+Similar	POS	O
+to	POS	O
+the	POS	O
+remnant	POS	O
+kidney	POS	O
+model	POS	O
+in	POS	O
+PAN	POS	O
+nephrosis	POS	B-NP
+the	POS	O
+development	POS	O
+of	POS	O
+glomerular	POS	B-NP
+sclerosis	POS	I-NP
+may	POS	O
+be	POS	O
+related	POS	O
+to	POS	O
+"	POS	O
+mesangial	POS	O
+overloading	POS	O
+.	POS	O
+"	POS	O
+Relationship	POS	O
+between	POS	O
+nicotine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+and	POS	O
+hippocampal	POS	O
+nicotinic	POS	O
+receptors	POS	O
+.	POS	O
+A	POS	O
+controversy	POS	O
+has	POS	O
+existed	POS	O
+for	POS	O
+several	POS	O
+years	POS	O
+concerning	POS	O
+the	POS	O
+physiological	POS	O
+relevance	POS	O
+of	POS	O
+the	POS	O
+nicotinic	POS	O
+receptor	POS	O
+measured	POS	O
+by	POS	O
+alpha	POS	O
+-	POS	O
+bungarotoxin	POS	O
+binding	POS	O
+.	POS	O
+Using	POS	O
+mice	POS	O
+derived	POS	O
+from	POS	O
+a	POS	O
+classical	POS	O
+F2	POS	O
+and	POS	O
+backcross	POS	O
+genetic	POS	O
+design	POS	O
+,	POS	O
+a	POS	O
+relationship	POS	O
+between	POS	O
+nicotine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+and	POS	O
+alpha	POS	O
+-	POS	O
+bungarotoxin	POS	O
+nicotinic	POS	O
+receptor	POS	O
+concentration	POS	O
+was	POS	O
+found	POS	O
+.	POS	O
+Mice	POS	O
+sensitive	POS	O
+to	POS	O
+the	POS	O
+convulsant	POS	O
+effects	POS	O
+of	POS	O
+nicotine	POS	O
+had	POS	O
+greater	POS	O
+alpha	POS	O
+-	POS	O
+bungarotoxin	POS	O
+binding	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+than	POS	O
+seizure	POS	B-NP
+insensitive	POS	O
+mice	POS	O
+.	POS	O
+The	POS	O
+binding	POS	O
+sites	POS	O
+from	POS	O
+seizure	POS	B-NP
+sensitive	POS	O
+and	POS	O
+resistant	POS	O
+mice	POS	O
+were	POS	O
+equally	POS	O
+affected	POS	O
+by	POS	O
+treatment	POS	O
+with	POS	O
+dithiothreitol	POS	O
+,	POS	O
+trypsin	POS	O
+or	POS	O
+heat	POS	O
+.	POS	O
+Thus	POS	O
+it	POS	O
+appears	POS	O
+that	POS	O
+the	POS	O
+difference	POS	O
+between	POS	O
+seizure	POS	B-NP
+sensitive	POS	O
+and	POS	O
+insensitive	POS	O
+animals	POS	O
+may	POS	O
+be	POS	O
+due	POS	O
+to	POS	O
+a	POS	O
+difference	POS	O
+in	POS	O
+hippocampal	POS	O
+nicotinic	POS	O
+receptor	POS	O
+concentration	POS	O
+as	POS	O
+measured	POS	O
+with	POS	O
+alpha	POS	O
+-	POS	O
+bungarotoxin	POS	O
+binding	POS	O
+.	POS	O
+The	POS	O
+role	POS	O
+of	POS	O
+p	POS	O
+-	POS	O
+aminophenol	POS	O
+in	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+nephrotoxicity	POS	B-NP
+:	POS	O
+effect	POS	O
+of	POS	O
+bis	POS	O
+(	POS	O
+p	POS	O
+-	POS	O
+nitrophenyl	POS	O
+)	POS	O
+phosphate	POS	O
+on	POS	O
+acetaminophen	POS	O
+and	POS	O
+p	POS	O
+-	POS	O
+aminophenol	POS	O
+nephrotoxicity	POS	B-NP
+and	POS	O
+metabolism	POS	O
+in	POS	O
+Fischer	POS	O
+344	POS	O
+rats	POS	O
+.	POS	O
+Acetaminophen	POS	O
+(	POS	O
+APAP	POS	O
+)	POS	O
+produces	POS	O
+proximal	POS	O
+tubular	POS	O
+necrosis	POS	B-NP
+in	POS	O
+Fischer	POS	O
+344	POS	O
+(	POS	O
+F344	POS	O
+)	POS	O
+rats	POS	O
+.	POS	O
+Recently	POS	O
+,	POS	O
+p	POS	O
+-	POS	O
+aminophenol	POS	O
+(	POS	O
+PAP	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+known	POS	O
+potent	POS	O
+nephrotoxicant	POS	O
+,	POS	O
+was	POS	O
+identified	POS	O
+as	POS	O
+a	POS	O
+metabolite	POS	O
+of	POS	O
+APAP	POS	O
+in	POS	O
+F344	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+determine	POS	O
+if	POS	O
+PAP	POS	O
+formation	POS	O
+is	POS	O
+a	POS	O
+requisite	POS	O
+step	POS	O
+in	POS	O
+APAP	POS	O
+-	POS	O
+induced	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+Therefore	POS	O
+,	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+bis	POS	O
+(	POS	O
+p	POS	O
+-	POS	O
+nitrophenyl	POS	O
+)	POS	O
+phosphate	POS	O
+(	POS	O
+BNPP	POS	O
+)	POS	O
+,	POS	O
+an	POS	O
+acylamidase	POS	O
+inhibitor	POS	O
+,	POS	O
+on	POS	O
+APAP	POS	O
+and	POS	O
+PAP	POS	O
+nephrotoxicity	POS	B-NP
+and	POS	O
+metabolism	POS	O
+was	POS	O
+determined	POS	O
+.	POS	O
+BNPP	POS	O
+(	POS	O
+1	POS	O
+to	POS	O
+8	POS	O
+mM	POS	O
+)	POS	O
+reduced	POS	O
+APAP	POS	O
+deacetylation	POS	O
+and	POS	O
+covalent	POS	O
+binding	POS	O
+in	POS	O
+F344	POS	O
+renal	POS	O
+cortical	POS	O
+homogenates	POS	O
+in	POS	O
+a	POS	O
+concentration	POS	O
+-	POS	O
+dependent	POS	O
+manner	POS	O
+.	POS	O
+Pretreatment	POS	O
+of	POS	O
+animals	POS	O
+with	POS	O
+BNPP	POS	O
+prior	POS	O
+to	POS	O
+APAP	POS	O
+or	POS	O
+PAP	POS	O
+administration	POS	O
+resulted	POS	O
+in	POS	O
+marked	POS	O
+reduction	POS	O
+of	POS	O
+APAP	POS	O
+(	POS	O
+900	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+nephrotoxicity	POS	B-NP
+but	POS	O
+not	POS	O
+PAP	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+This	POS	O
+result	POS	O
+was	POS	O
+not	POS	O
+due	POS	O
+to	POS	O
+altered	POS	O
+disposition	POS	O
+of	POS	O
+either	POS	O
+APAP	POS	O
+or	POS	O
+acetylated	POS	O
+metabolites	POS	O
+in	POS	O
+plasma	POS	O
+or	POS	O
+renal	POS	O
+cortical	POS	O
+and	POS	O
+hepatic	POS	O
+tissue	POS	O
+.	POS	O
+Rather	POS	O
+,	POS	O
+BNPP	POS	O
+pretreatment	POS	O
+reduced	POS	O
+the	POS	O
+fraction	POS	O
+of	POS	O
+APAP	POS	O
+excreted	POS	O
+as	POS	O
+PAP	POS	O
+by	POS	O
+64	POS	O
+and	POS	O
+75	POS	O
+%	POS	O
+after	POS	O
+APAP	POS	O
+doses	POS	O
+of	POS	O
+750	POS	O
+and	POS	O
+900	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+BNPP	POS	O
+did	POS	O
+not	POS	O
+alter	POS	O
+the	POS	O
+excretion	POS	O
+of	POS	O
+APAP	POS	O
+or	POS	O
+any	POS	O
+of	POS	O
+its	POS	O
+non	POS	O
+-	POS	O
+deacetylated	POS	O
+metabolites	POS	O
+nor	POS	O
+did	POS	O
+BNPP	POS	O
+alter	POS	O
+excretion	POS	O
+of	POS	O
+PAP	POS	O
+or	POS	O
+its	POS	O
+metabolites	POS	O
+after	POS	O
+PAP	POS	O
+doses	POS	O
+of	POS	O
+150	POS	O
+and	POS	O
+300	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+Therefore	POS	O
+,	POS	O
+the	POS	O
+BNPP	POS	O
+-	POS	O
+induced	POS	O
+reduction	POS	O
+in	POS	O
+APAP	POS	O
+-	POS	O
+induced	POS	O
+nephrotoxicity	POS	B-NP
+appears	POS	O
+to	POS	O
+be	POS	O
+due	POS	O
+to	POS	O
+inhibition	POS	O
+of	POS	O
+APAP	POS	O
+deacetylation	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+concluded	POS	O
+that	POS	O
+PAP	POS	O
+formation	POS	O
+,	POS	O
+in	POS	O
+vivo	POS	O
+,	POS	O
+accounts	POS	O
+,	POS	O
+at	POS	O
+least	POS	O
+in	POS	O
+part	POS	O
+,	POS	O
+for	POS	O
+APAP	POS	O
+-	POS	O
+induced	POS	O
+renal	POS	B-NP
+tubular	POS	I-NP
+necrosis	POS	I-NP
+.	POS	O
+Morphine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+in	POS	O
+newborn	POS	O
+infants	POS	O
+.	POS	O
+Two	POS	O
+neonates	POS	O
+suffered	POS	O
+from	POS	O
+generalized	POS	O
+seizures	POS	B-NP
+during	POS	O
+the	POS	O
+course	POS	O
+of	POS	O
+intravenous	POS	O
+morphine	POS	O
+sulfate	POS	O
+for	POS	O
+post	POS	O
+-	POS	O
+operative	POS	O
+analgesia	POS	O
+.	POS	O
+They	POS	O
+received	POS	O
+morphine	POS	O
+in	POS	O
+doses	POS	O
+of	POS	O
+32	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+hr	POS	O
+and	POS	O
+40	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+hr	POS	O
+larger	POS	O
+than	POS	O
+a	POS	O
+group	POS	O
+of	POS	O
+10	POS	O
+neonates	POS	O
+who	POS	O
+received	POS	O
+6	POS	O
+-	POS	O
+24	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+hr	POS	O
+and	POS	O
+had	POS	O
+no	POS	O
+seizures	POS	B-NP
+.	POS	O
+Plasma	POS	O
+concentrations	POS	O
+of	POS	O
+morphine	POS	O
+in	POS	O
+these	POS	O
+neonates	POS	O
+was	POS	O
+excessive	POS	O
+(	POS	O
+60	POS	O
+and	POS	O
+90	POS	O
+mg	POS	O
+/	POS	O
+ml	POS	O
+)	POS	O
+.	POS	O
+Other	POS	O
+known	POS	O
+reasons	POS	O
+for	POS	O
+seizures	POS	B-NP
+were	POS	O
+ruled	POS	O
+out	POS	O
+and	POS	O
+the	POS	O
+convulsions	POS	B-NP
+stopped	POS	O
+a	POS	O
+few	POS	O
+hours	POS	O
+after	POS	O
+cessation	POS	O
+of	POS	O
+morphine	POS	O
+and	POS	O
+did	POS	O
+not	POS	O
+reoccur	POS	O
+in	POS	O
+the	POS	O
+subsequent	POS	O
+8	POS	O
+months	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+suggested	POS	O
+that	POS	O
+post	POS	O
+-	POS	O
+operative	POS	O
+intravenous	POS	O
+morphine	POS	O
+should	POS	O
+not	POS	O
+exceed	POS	O
+20	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+ml	POS	O
+in	POS	O
+neonates	POS	O
+.	POS	O
+Indomethacin	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+in	POS	O
+sodium	POS	O
+and	POS	O
+volume	POS	O
+depleted	POS	O
+rats	POS	O
+.	POS	O
+After	POS	O
+a	POS	O
+single	POS	O
+oral	POS	O
+dose	POS	O
+of	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+indomethacin	POS	O
+(	POS	O
+IDM	POS	O
+)	POS	O
+to	POS	O
+sodium	POS	O
+and	POS	O
+volume	POS	O
+depleted	POS	O
+rats	POS	O
+plasma	POS	O
+renin	POS	O
+activity	POS	O
+(	POS	O
+PRA	POS	O
+)	POS	O
+and	POS	O
+systolic	POS	O
+blood	POS	O
+pressure	POS	O
+fell	POS	O
+significantly	POS	O
+within	POS	O
+four	POS	O
+hours	POS	O
+.	POS	O
+In	POS	O
+sodium	POS	O
+repleted	POS	O
+animals	POS	O
+indomethacin	POS	O
+did	POS	O
+not	POS	O
+change	POS	O
+systolic	POS	O
+blood	POS	O
+pressure	POS	O
+(	POS	O
+BP	POS	O
+)	POS	O
+although	POS	O
+plasma	POS	O
+renin	POS	O
+activity	POS	O
+was	POS	O
+decreased	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+indomethacin	POS	O
+by	POS	O
+inhibition	POS	O
+of	POS	O
+prostaglandin	POS	O
+synthesis	POS	O
+may	POS	O
+diminish	POS	O
+the	POS	O
+blood	POS	O
+pressure	POS	O
+maintaining	POS	O
+effect	POS	O
+of	POS	O
+the	POS	O
+stimulated	POS	O
+renin	POS	O
+-	POS	O
+angiotensin	POS	O
+system	POS	O
+in	POS	O
+sodium	POS	O
+and	POS	O
+volume	POS	O
+depletion	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+antiarrhythmic	POS	O
+activity	POS	O
+of	POS	O
+one	POS	O
+N	POS	O
+-	POS	O
+substituted	POS	O
+piperazine	POS	O
+derivative	POS	O
+of	POS	O
+trans	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+amino	POS	O
+-	POS	O
+3	POS	O
+-	POS	O
+hydroxy	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+2	POS	O
+,	POS	O
+3	POS	O
+,	POS	O
+4	POS	O
+-	POS	O
+tetrahydroanaphthalene	POS	O
+.	POS	O
+The	POS	O
+antiarrhythmic	POS	O
+activity	POS	O
+of	POS	O
+the	POS	O
+compound	POS	O
+N	POS	O
+-	POS	O
+(	POS	O
+trans	POS	O
+-	POS	O
+3	POS	O
+-	POS	O
+hydroxy	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+2	POS	O
+,	POS	O
+3	POS	O
+,	POS	O
+4	POS	O
+-	POS	O
+tetrahydro	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+naphthyl	POS	O
+)	POS	O
+-	POS	O
+N	POS	O
+-	POS	O
+(	POS	O
+3	POS	O
+-	POS	O
+oxo	POS	O
+-	POS	O
+3	POS	O
+-	POS	O
+phenyl	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+methylpropyl	POS	O
+)	POS	O
+-	POS	O
+piperazine	POS	O
+hydrochloride	POS	O
+,	POS	O
+referred	POS	O
+to	POS	O
+as	POS	O
+P11	POS	O
+,	POS	O
+is	POS	O
+studied	POS	O
+on	POS	O
+anaesthesized	POS	O
+cats	POS	O
+and	POS	O
+Wistar	POS	O
+albino	POS	O
+rats	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+on	POS	O
+non	POS	O
+-	POS	O
+anaesthesized	POS	O
+rabbits	POS	O
+.	POS	O
+Four	POS	O
+types	POS	O
+of	POS	O
+experimental	POS	O
+arrhythmia	POS	B-NP
+are	POS	O
+used	POS	O
+-	POS	O
+-	POS	O
+with	POS	O
+BaCl2	POS	O
+,	POS	O
+with	POS	O
+chloroform	POS	O
+-	POS	O
+adrenaline	POS	O
+,	POS	O
+with	POS	O
+strophantine	POS	O
+G	POS	O
+and	POS	O
+with	POS	O
+aconitine	POS	O
+.	POS	O
+The	POS	O
+compound	POS	O
+P11	POS	O
+is	POS	O
+introduced	POS	O
+in	POS	O
+doses	POS	O
+of	POS	O
+0	POS	O
+.	POS	O
+25	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+intravenously	POS	O
+and	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+orally	POS	O
+.	POS	O
+The	POS	O
+compound	POS	O
+manifests	POS	O
+antiarrhythmic	POS	O
+activity	POS	O
+in	POS	O
+all	POS	O
+models	POS	O
+of	POS	O
+experimental	POS	O
+arrhythmia	POS	B-NP
+used	POS	O
+,	POS	O
+causing	POS	O
+greatest	POS	O
+inhibition	POS	O
+on	POS	O
+the	POS	O
+arrhythmia	POS	B-NP
+induced	POS	O
+by	POS	O
+chloroform	POS	O
+-	POS	O
+adrenaline	POS	O
+(	POS	O
+in	POS	O
+90	POS	O
+per	POS	O
+cent	POS	O
+)	POS	O
+and	POS	O
+with	POS	O
+BaCl2	POS	O
+(	POS	O
+in	POS	O
+84	POS	O
+per	POS	O
+cent	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+obtained	POS	O
+are	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+beta	POS	O
+-	POS	O
+adrenoblocking	POS	O
+and	POS	O
+with	POS	O
+the	POS	O
+membrane	POS	O
+-	POS	O
+stabilizing	POS	O
+action	POS	O
+of	POS	O
+the	POS	O
+compound	POS	O
+.	POS	O
+Recurrent	POS	O
+subarachnoid	POS	B-NP
+hemorrhage	POS	I-NP
+associated	POS	O
+with	POS	O
+aminocaproic	POS	O
+acid	POS	O
+therapy	POS	O
+and	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+artery	POS	I-NP
+thrombosis	POS	I-NP
+.	POS	O
+Case	POS	O
+report	POS	O
+.	POS	O
+Epsilon	POS	O
+aminocaproic	POS	O
+acid	POS	O
+(	POS	O
+EACA	POS	O
+)	POS	O
+has	POS	O
+been	POS	O
+used	POS	O
+to	POS	O
+prevent	POS	O
+rebleeding	POS	B-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+subarachnoid	POS	B-NP
+hemorrhage	POS	I-NP
+(	POS	O
+SAH	POS	B-NP
+)	POS	O
+.	POS	O
+Although	POS	O
+this	POS	O
+agent	POS	O
+does	POS	O
+decrease	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+rebleeding	POS	B-NP
+,	POS	O
+several	POS	O
+reports	POS	O
+have	POS	O
+described	POS	O
+thrombotic	POS	B-NP
+complications	POS	O
+of	POS	O
+EACA	POS	O
+therapy	POS	O
+.	POS	O
+These	POS	O
+complications	POS	O
+have	POS	O
+included	POS	O
+clinical	POS	O
+deterioration	POS	O
+and	POS	O
+intracranial	POS	B-NP
+vascular	POS	I-NP
+thrombosis	POS	I-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+SAH	POS	B-NP
+,	POS	O
+arteriolar	POS	O
+and	POS	O
+capillary	POS	O
+fibrin	POS	O
+thrombi	POS	B-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+fibrinolytic	POS	B-NP
+syndromes	POS	I-NP
+treated	POS	O
+with	POS	O
+EACA	POS	O
+,	POS	O
+or	POS	O
+other	POS	O
+thromboembolic	POS	B-NP
+phenomena	POS	I-NP
+.	POS	O
+Since	POS	O
+intravascular	POS	O
+fibrin	POS	O
+thrombi	POS	B-NP
+are	POS	O
+often	POS	O
+observed	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+fibrinolytic	POS	B-NP
+disorders	POS	I-NP
+,	POS	O
+EACA	POS	O
+should	POS	O
+not	POS	O
+be	POS	O
+implicated	POS	O
+in	POS	O
+the	POS	O
+pathogenesis	POS	O
+of	POS	O
+fibrin	POS	O
+thrombi	POS	B-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+disseminated	POS	B-NP
+intravascular	POS	I-NP
+coagulation	POS	I-NP
+or	POS	O
+other	POS	O
+"	POS	O
+consumption	POS	O
+coagulopathies	POS	B-NP
+.	POS	O
+"	POS	O
+This	POS	O
+report	POS	O
+describes	POS	O
+subtotal	POS	O
+infarction	POS	O
+of	POS	O
+the	POS	O
+kidney	POS	O
+due	POS	O
+to	POS	O
+thrombosis	POS	B-NP
+of	POS	O
+a	POS	O
+normal	POS	B-NP
+renal	POS	I-NP
+artery	POS	I-NP
+.	POS	O
+This	POS	O
+occlusion	POS	O
+occurred	POS	O
+after	POS	O
+EACA	POS	O
+therapy	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+SAH	POS	B-NP
+and	POS	O
+histopathological	POS	O
+documentation	POS	O
+of	POS	O
+recurrent	POS	O
+SAH	POS	B-NP
+.	POS	O
+The	POS	O
+corresponding	POS	O
+clinical	POS	O
+event	POS	O
+was	POS	O
+characterized	POS	O
+by	POS	O
+marked	POS	O
+hypertension	POS	B-NP
+and	POS	O
+abrupt	POS	O
+neurological	POS	B-NP
+deterioration	POS	I-NP
+.	POS	O
+Effect	POS	O
+of	POS	O
+vincristine	POS	O
+sulfate	POS	O
+on	POS	O
+Pseudomonas	POS	O
+infections	POS	O
+in	POS	O
+monkeys	POS	O
+.	POS	O
+In	POS	O
+rhesus	POS	O
+monkeys	POS	O
+,	POS	O
+intravenous	POS	O
+challenge	POS	O
+with	POS	O
+0	POS	O
+.	POS	O
+6	POS	O
+x	POS	O
+10	POS	O
+(	POS	O
+10	POS	O
+)	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+2	POS	O
+x	POS	O
+10	POS	O
+(	POS	O
+10	POS	O
+)	POS	O
+Pseudomonas	POS	O
+aeruginosa	POS	O
+organisms	POS	O
+caused	POS	O
+acute	POS	B-NP
+illness	POS	I-NP
+of	POS	O
+4	POS	O
+to	POS	O
+5	POS	O
+days	POS	O
+'	POS	O
+duration	POS	O
+with	POS	O
+spontaneous	POS	O
+recovery	POS	O
+in	POS	O
+13	POS	O
+of	POS	O
+15	POS	O
+monkeys	POS	O
+;	POS	O
+blood	POS	O
+cultures	POS	O
+became	POS	O
+negative	POS	O
+3	POS	O
+to	POS	O
+17	POS	O
+days	POS	O
+after	POS	O
+challenge	POS	O
+.	POS	O
+Leukocytosis	POS	B-NP
+was	POS	O
+observed	POS	O
+in	POS	O
+all	POS	O
+monkeys	POS	O
+.	POS	O
+Intravenous	POS	O
+or	POS	O
+intratracheal	POS	O
+inoculation	POS	O
+of	POS	O
+2	POS	O
+.	POS	O
+0	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+of	POS	O
+vincristine	POS	O
+sulfate	POS	O
+was	POS	O
+followed	POS	O
+by	POS	O
+leukopenia	POS	B-NP
+in	POS	O
+4	POS	O
+to	POS	O
+5	POS	O
+days	POS	O
+.	POS	O
+Intravenous	POS	O
+inoculation	POS	O
+of	POS	O
+4	POS	O
+.	POS	O
+2	POS	O
+x	POS	O
+10	POS	O
+(	POS	O
+10	POS	O
+)	POS	O
+to	POS	O
+7	POS	O
+.	POS	O
+8	POS	O
+x	POS	O
+10	POS	O
+(	POS	O
+10	POS	O
+)	POS	O
+pyocin	POS	O
+type	POS	O
+6	POS	O
+Pseudomonas	POS	O
+organisms	POS	O
+in	POS	O
+monkeys	POS	O
+given	POS	O
+vincristine	POS	O
+sulfate	POS	O
+4	POS	O
+days	POS	O
+previously	POS	O
+resulted	POS	O
+in	POS	O
+fatal	POS	O
+infection	POS	B-NP
+in	POS	O
+11	POS	O
+of	POS	O
+14	POS	O
+monkeys	POS	O
+,	POS	O
+whereas	POS	O
+none	POS	O
+of	POS	O
+four	POS	O
+receiving	POS	O
+Pseudomonas	POS	O
+alone	POS	O
+died	POS	O
+.	POS	O
+These	POS	O
+studies	POS	O
+suggest	POS	O
+that	POS	O
+an	POS	O
+antimetabolite	POS	O
+-	POS	O
+induced	POS	O
+leukopenia	POS	B-NP
+predisposes	POS	O
+to	POS	O
+severe	POS	O
+Pseudomonas	POS	B-NP
+sepsis	POS	I-NP
+and	POS	O
+that	POS	O
+such	POS	O
+monkeys	POS	O
+may	POS	O
+serve	POS	O
+as	POS	O
+a	POS	O
+biological	POS	O
+model	POS	O
+for	POS	O
+study	POS	O
+of	POS	O
+comparative	POS	O
+efficacy	POS	O
+of	POS	O
+antimicrobial	POS	O
+agents	POS	O
+.	POS	O
+Modification	POS	O
+by	POS	O
+propranolol	POS	O
+of	POS	O
+cardiovascular	POS	O
+effects	POS	O
+of	POS	O
+induced	POS	O
+hypoglycaemia	POS	B-NP
+.	POS	O
+The	POS	O
+cardiovascular	POS	O
+effects	POS	O
+of	POS	O
+hypoglycaemia	POS	B-NP
+,	POS	O
+with	POS	O
+and	POS	O
+without	POS	O
+beta	POS	O
+-	POS	O
+blockade	POS	O
+,	POS	O
+were	POS	O
+compared	POS	O
+in	POS	O
+fourteen	POS	O
+healthy	POS	O
+men	POS	O
+.	POS	O
+Eight	POS	O
+received	POS	O
+insulin	POS	O
+alone	POS	O
+,	POS	O
+and	POS	O
+eight	POS	O
+,	POS	O
+including	POS	O
+two	POS	O
+of	POS	O
+the	POS	O
+original	POS	O
+insulin	POS	O
+-	POS	O
+only	POS	O
+group	POS	O
+,	POS	O
+were	POS	O
+given	POS	O
+propranolol	POS	O
+and	POS	O
+insulin	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+insulin	POS	O
+-	POS	O
+group	POS	O
+the	POS	O
+period	POS	O
+of	POS	O
+hypoglycaemia	POS	B-NP
+was	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+heart	POS	O
+-	POS	O
+rate	POS	O
+and	POS	O
+a	POS	O
+fall	POS	O
+in	POS	O
+diastolic	POS	O
+blood	POS	O
+-	POS	O
+pressure	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+propranolol	POS	O
+-	POS	O
+insulin	POS	O
+group	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+fall	POS	O
+in	POS	O
+heart	POS	O
+-	POS	O
+rate	POS	O
+in	POS	O
+most	POS	O
+subjects	POS	O
+and	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+diastolic	POS	O
+pressure	POS	O
+.	POS	O
+Typical	POS	O
+S	POS	O
+-	POS	O
+T	POS	O
+/	POS	O
+T	POS	O
+changes	POS	O
+occurred	POS	O
+in	POS	O
+the	POS	O
+insulin	POS	O
+-	POS	O
+group	POS	O
+but	POS	O
+in	POS	O
+none	POS	O
+of	POS	O
+the	POS	O
+propranolol	POS	O
+-	POS	O
+insulin	POS	O
+group	POS	O
+.	POS	O
+Hypertension	POS	B-NP
+in	POS	O
+diabetics	POS	O
+prone	POS	O
+to	POS	O
+hypoglycaemia	POS	B-NP
+attacks	POS	O
+should	POS	O
+not	POS	O
+be	POS	O
+treated	POS	O
+with	POS	O
+beta	POS	O
+-	POS	O
+blockers	POS	O
+because	POS	O
+these	POS	O
+drugs	POS	O
+may	POS	O
+cause	POS	O
+a	POS	O
+sharp	POS	O
+rise	POS	O
+in	POS	O
+blood	POS	O
+-	POS	O
+pressure	POS	O
+in	POS	O
+such	POS	O
+patients	POS	O
+.	POS	O
+Long	POS	O
+-	POS	O
+term	POS	O
+propranolol	POS	O
+therapy	POS	O
+in	POS	O
+pregnancy	POS	O
+:	POS	O
+maternal	POS	O
+and	POS	O
+fetal	POS	O
+outcome	POS	O
+.	POS	O
+Propranolol	POS	O
+,	POS	O
+a	POS	O
+beta	POS	O
+-	POS	O
+adrenergic	POS	O
+blocking	POS	O
+agent	POS	O
+,	POS	O
+has	POS	O
+found	POS	O
+an	POS	O
+important	POS	O
+position	POS	O
+in	POS	O
+the	POS	O
+practice	POS	O
+of	POS	O
+medicine	POS	O
+.	POS	O
+Its	POS	O
+use	POS	O
+in	POS	O
+pregnancy	POS	O
+,	POS	O
+however	POS	O
+,	POS	O
+is	POS	O
+an	POS	O
+open	POS	O
+question	POS	O
+as	POS	O
+a	POS	O
+number	POS	O
+of	POS	O
+detrimental	POS	O
+side	POS	O
+effects	POS	O
+have	POS	O
+been	POS	O
+reported	POS	O
+in	POS	O
+the	POS	O
+fetus	POS	O
+and	POS	O
+neonate	POS	O
+.	POS	O
+Ten	POS	O
+patients	POS	O
+and	POS	O
+12	POS	O
+pregnancies	POS	O
+are	POS	O
+reported	POS	O
+where	POS	O
+chronic	POS	O
+propranolol	POS	O
+has	POS	O
+been	POS	O
+administered	POS	O
+.	POS	O
+Five	POS	O
+patients	POS	O
+with	POS	O
+serial	POS	O
+pregnancies	POS	O
+with	POS	O
+and	POS	O
+without	POS	O
+propranolol	POS	O
+therapy	POS	O
+are	POS	O
+also	POS	O
+examined	POS	O
+.	POS	O
+Maternal	POS	O
+,	POS	O
+fetal	POS	O
+,	POS	O
+and	POS	O
+neonatal	POS	B-NP
+complications	POS	I-NP
+are	POS	O
+examined	POS	O
+.	POS	O
+An	POS	O
+attempt	POS	O
+is	POS	O
+made	POS	O
+to	POS	O
+differentiate	POS	O
+drug	POS	O
+-	POS	O
+related	POS	O
+complications	POS	O
+from	POS	O
+maternal	POS	O
+disease	POS	O
+-	POS	O
+-	POS	O
+related	POS	O
+complications	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+previously	POS	O
+reported	POS	O
+hypoglycemia	POS	B-NP
+,	POS	O
+hyperbilirubinemia	POS	B-NP
+,	POS	O
+polycythemia	POS	B-NP
+,	POS	O
+neonatal	POS	B-NP
+apnea	POS	I-NP
+,	POS	O
+and	POS	O
+bradycardia	POS	B-NP
+are	POS	O
+not	POS	O
+invariable	POS	O
+and	POS	O
+cannot	POS	O
+be	POS	O
+statistically	POS	O
+correlated	POS	O
+with	POS	O
+chronic	POS	O
+propranolol	POS	O
+therapy	POS	O
+.	POS	O
+Growth	POS	B-NP
+retardation	POS	I-NP
+,	POS	O
+however	POS	O
+,	POS	O
+appears	POS	O
+to	POS	O
+be	POS	O
+significant	POS	O
+in	POS	O
+both	POS	O
+of	POS	O
+our	POS	O
+series	POS	O
+.	POS	O
+Central	POS	O
+excitatory	POS	O
+actions	POS	O
+of	POS	O
+flurazepam	POS	O
+.	POS	O
+Toxic	POS	O
+actions	POS	O
+of	POS	O
+flurazepam	POS	O
+(	POS	O
+FZP	POS	O
+)	POS	O
+were	POS	O
+studied	POS	O
+in	POS	O
+cats	POS	O
+,	POS	O
+mice	POS	O
+and	POS	O
+rats	POS	O
+.	POS	O
+High	POS	O
+doses	POS	O
+caused	POS	O
+an	POS	O
+apparent	POS	O
+central	POS	O
+excitation	POS	O
+,	POS	O
+most	POS	O
+clearly	POS	O
+seen	POS	O
+as	POS	O
+clonic	POS	B-NP
+convulsions	POS	B-NP
+,	POS	O
+superimposed	POS	O
+on	POS	O
+general	POS	O
+depression	POS	B-NP
+.	POS	O
+Following	POS	O
+a	POS	O
+lethal	POS	O
+dose	POS	O
+,	POS	O
+death	POS	B-NP
+was	POS	O
+always	POS	O
+associated	POS	O
+with	POS	O
+convulsions	POS	B-NP
+.	POS	O
+Comparing	POS	O
+the	POS	O
+relative	POS	O
+sensitivity	POS	O
+to	POS	O
+central	POS	O
+depression	POS	B-NP
+and	POS	O
+excitation	POS	O
+revealed	POS	O
+that	POS	O
+rats	POS	O
+were	POS	O
+least	POS	O
+likely	POS	O
+to	POS	O
+have	POS	O
+convulsions	POS	B-NP
+at	POS	O
+doses	POS	O
+that	POS	O
+did	POS	O
+not	POS	O
+first	POS	O
+cause	POS	O
+loss	POS	B-NP
+of	POS	I-NP
+consciousness	POS	I-NP
+,	POS	O
+while	POS	O
+cats	POS	O
+most	POS	O
+clearly	POS	O
+showed	POS	O
+marked	POS	O
+central	POS	O
+excitatory	POS	O
+actions	POS	O
+.	POS	O
+Signs	POS	O
+of	POS	O
+FZP	POS	O
+toxocity	POS	O
+in	POS	O
+cats	POS	O
+included	POS	O
+excessive	POS	O
+salivation	POS	B-NP
+,	POS	O
+extreme	POS	O
+apprehensive	POS	O
+behavior	POS	O
+,	POS	O
+retching	POS	B-NP
+,	POS	O
+muscle	POS	B-NP
+tremors	POS	I-NP
+and	POS	O
+convulsions	POS	B-NP
+.	POS	O
+An	POS	O
+interaction	POS	O
+between	POS	O
+FZP	POS	O
+and	POS	O
+pentylenetetrazol	POS	O
+(	POS	O
+PTZ	POS	O
+)	POS	O
+was	POS	O
+shown	POS	O
+by	POS	O
+pretreating	POS	O
+mice	POS	O
+with	POS	O
+FZP	POS	O
+before	POS	O
+PTZ	POS	O
+challenge	POS	O
+.	POS	O
+As	POS	O
+a	POS	O
+function	POS	O
+of	POS	O
+dose	POS	O
+,	POS	O
+FZP	POS	O
+first	POS	O
+protected	POS	O
+against	POS	O
+convulsions	POS	B-NP
+and	POS	O
+death	POS	B-NP
+.	POS	O
+At	POS	O
+higher	POS	O
+doses	POS	O
+,	POS	O
+however	POS	O
+,	POS	O
+convulsions	POS	B-NP
+again	POS	O
+emerged	POS	O
+.	POS	O
+These	POS	O
+doses	POS	O
+of	POS	O
+FZP	POS	O
+were	POS	O
+lower	POS	O
+than	POS	O
+those	POS	O
+that	POS	O
+would	POS	O
+alone	POS	O
+cause	POS	O
+convulsions	POS	B-NP
+.	POS	O
+These	POS	O
+results	POS	O
+may	POS	O
+be	POS	O
+relevant	POS	O
+to	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+FZP	POS	O
+in	POS	O
+clinical	POS	O
+situations	POS	O
+in	POS	O
+which	POS	O
+there	POS	O
+is	POS	O
+increased	POS	O
+neural	POS	O
+excitability	POS	O
+,	POS	O
+such	POS	O
+as	POS	O
+epilepsy	POS	B-NP
+or	POS	O
+sedative	POS	O
+-	POS	O
+hypnotic	POS	O
+drug	POS	O
+withdrawal	POS	O
+.	POS	O
+Use	POS	O
+of	POS	O
+propranolol	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+idiopathic	POS	B-NP
+orthostatic	POS	I-NP
+hypotension	POS	I-NP
+.	POS	O
+Five	POS	O
+patients	POS	O
+with	POS	O
+idiopathic	POS	B-NP
+orthostatic	POS	I-NP
+hypotension	POS	I-NP
+who	POS	O
+had	POS	O
+physiologic	POS	O
+and	POS	O
+biochemical	POS	O
+evidence	POS	O
+of	POS	O
+severe	POS	O
+autonomic	POS	B-NP
+dysfunction	POS	I-NP
+were	POS	O
+included	POS	O
+in	POS	O
+the	POS	O
+study	POS	O
+.	POS	O
+They	POS	O
+all	POS	O
+exhibited	POS	O
+markedly	POS	O
+reduced	POS	O
+plasma	POS	O
+catecholamines	POS	O
+and	POS	O
+plasma	POS	O
+renin	POS	O
+activity	POS	O
+in	POS	O
+both	POS	O
+recumbent	POS	O
+and	POS	O
+upright	POS	O
+positions	POS	O
+and	POS	O
+had	POS	O
+marked	POS	O
+hypersensitivity	POS	B-NP
+to	POS	O
+the	POS	O
+pressor	POS	O
+effects	POS	O
+of	POS	O
+infused	POS	O
+norepinephrine	POS	O
+.	POS	O
+Treatment	POS	O
+with	POS	O
+propanolol	POS	O
+administered	POS	O
+intravenously	POS	O
+(	POS	O
+1	POS	O
+-	POS	O
+5	POS	O
+mg	POS	O
+)	POS	O
+produced	POS	O
+increases	POS	O
+in	POS	O
+supine	POS	O
+and	POS	O
+upright	POS	O
+blood	POS	O
+pressure	POS	O
+in	POS	O
+4	POS	O
+of	POS	O
+the	POS	O
+5	POS	O
+individuals	POS	O
+with	POS	O
+rises	POS	O
+ranging	POS	O
+from	POS	O
+11	POS	O
+/	POS	O
+6	POS	O
+to	POS	O
+22	POS	O
+/	POS	O
+11	POS	O
+mmHg	POS	O
+.	POS	O
+Chronic	POS	O
+oral	POS	O
+administration	POS	O
+of	POS	O
+propranolol	POS	O
+(	POS	O
+40	POS	O
+-	POS	O
+160	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+also	POS	O
+elevated	POS	O
+the	POS	O
+blood	POS	O
+pressures	POS	O
+of	POS	O
+these	POS	O
+individuals	POS	O
+with	POS	O
+increases	POS	O
+in	POS	O
+the	POS	O
+order	POS	O
+of	POS	O
+20	POS	O
+-	POS	O
+35	POS	O
+/	POS	O
+15	POS	O
+-	POS	O
+25	POS	O
+mmg	POS	O
+being	POS	O
+observed	POS	O
+.	POS	O
+In	POS	O
+1	POS	O
+patient	POS	O
+,	POS	O
+marked	POS	O
+hypertension	POS	B-NP
+was	POS	O
+induced	POS	O
+by	POS	O
+propranolol	POS	O
+and	POS	O
+the	POS	O
+drug	POS	O
+had	POS	O
+to	POS	O
+be	POS	O
+withdrawn	POS	O
+.	POS	O
+It	POS	O
+otherwise	POS	O
+was	POS	O
+well	POS	O
+tolerated	POS	O
+and	POS	O
+no	POS	O
+important	POS	O
+side	POS	O
+effects	POS	O
+were	POS	O
+observed	POS	O
+.	POS	O
+Treatment	POS	O
+has	POS	O
+been	POS	O
+continued	POS	O
+in	POS	O
+3	POS	O
+individuals	POS	O
+for	POS	O
+6	POS	O
+-	POS	O
+13	POS	O
+months	POS	O
+with	POS	O
+persistence	POS	O
+of	POS	O
+the	POS	O
+pressor	POS	O
+effect	POS	O
+,	POS	O
+although	POS	O
+there	POS	O
+appears	POS	O
+to	POS	O
+have	POS	O
+been	POS	O
+some	POS	O
+decrease	POS	O
+in	POS	O
+the	POS	O
+degree	POS	O
+of	POS	O
+response	POS	O
+with	POS	O
+time	POS	O
+.	POS	O
+Hemodynamic	POS	O
+measurements	POS	O
+in	POS	O
+1	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+demonstrated	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+total	POS	O
+peripheral	POS	O
+resistance	POS	O
+and	POS	O
+essentially	POS	O
+no	POS	O
+change	POS	O
+in	POS	O
+cardiac	POS	O
+output	POS	O
+following	POS	O
+propranolol	POS	O
+therapy	POS	O
+.	POS	O
+The	POS	O
+studies	POS	O
+suggest	POS	O
+that	POS	O
+propranolol	POS	O
+is	POS	O
+a	POS	O
+useful	POS	O
+drug	POS	O
+in	POS	O
+selected	POS	O
+patients	POS	O
+with	POS	O
+severe	POS	O
+idiopathic	POS	B-NP
+orthostatic	POS	I-NP
+hypotension	POS	I-NP
+.	POS	O
+Total	POS	O
+intravenous	POS	O
+anesthesia	POS	O
+with	POS	O
+etomidate	POS	O
+.	POS	O
+III	POS	O
+.	POS	O
+Some	POS	O
+observations	POS	O
+in	POS	O
+adults	POS	O
+.	POS	O
+An	POS	O
+investigation	POS	O
+was	POS	O
+undertaken	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+dosage	POS	O
+of	POS	O
+etomidate	POS	O
+required	POS	O
+to	POS	O
+maintain	POS	O
+sleep	POS	O
+in	POS	O
+adults	POS	O
+undergoing	POS	O
+surgery	POS	O
+under	POS	O
+regional	POS	O
+local	POS	O
+anesthesia	POS	O
+.	POS	O
+Premedication	POS	O
+of	POS	O
+diazepam	POS	O
+10	POS	O
+mg	POS	O
+and	POS	O
+atropine	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+was	POS	O
+given	POS	O
+,	POS	O
+and	POS	O
+sleep	POS	O
+was	POS	O
+induced	POS	O
+and	POS	O
+maintained	POS	O
+by	POS	O
+intermittent	POS	O
+intravenous	POS	O
+injections	POS	O
+of	POS	O
+etomidate	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+/	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+given	POS	O
+whenever	POS	O
+the	POS	O
+patient	POS	O
+would	POS	O
+open	POS	O
+his	POS	O
+eyes	POS	O
+on	POS	O
+request	POS	O
+.	POS	O
+A	POS	O
+mean	POS	O
+overall	POS	O
+dose	POS	O
+of	POS	O
+etomidate	POS	O
+17	POS	O
+.	POS	O
+4	POS	O
+microgram	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+.	POS	O
+was	POS	O
+required	POS	O
+to	POS	O
+maintain	POS	O
+sleep	POS	O
+,	POS	O
+but	POS	O
+great	POS	O
+individual	POS	O
+variation	POS	O
+occurred	POS	O
+,	POS	O
+with	POS	O
+older	POS	O
+patients	POS	O
+requiring	POS	O
+less	POS	O
+drug	POS	O
+.	POS	O
+The	POS	O
+investigation	POS	O
+was	POS	O
+discontinued	POS	O
+after	POS	O
+18	POS	O
+patients	POS	O
+because	POS	O
+of	POS	O
+the	POS	O
+frequency	POS	O
+and	POS	O
+intensity	POS	O
+of	POS	O
+side	POS	O
+-	POS	O
+effects	POS	O
+,	POS	O
+particularly	POS	O
+pain	POS	B-NP
+and	POS	O
+myoclonia	POS	B-NP
+,	POS	O
+which	POS	O
+caused	POS	O
+the	POS	O
+technique	POS	O
+to	POS	O
+be	POS	O
+abandoned	POS	O
+in	POS	O
+two	POS	O
+cases	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+considered	POS	O
+unlikely	POS	O
+that	POS	O
+etomidate	POS	O
+will	POS	O
+prove	POS	O
+to	POS	O
+be	POS	O
+the	POS	O
+hypnotic	POS	O
+of	POS	O
+choice	POS	O
+for	POS	O
+a	POS	O
+totally	POS	O
+intravenous	POS	O
+anesthetic	POS	O
+technique	POS	O
+in	POS	O
+adults	POS	O
+because	POS	O
+of	POS	O
+the	POS	O
+high	POS	O
+incidence	POS	O
+of	POS	O
+myoclonia	POS	B-NP
+after	POS	O
+prolonged	POS	O
+administration	POS	O
+.	POS	O
+In	POS	O
+several	POS	O
+patients	POS	O
+uncontrollable	POS	O
+muscle	POS	B-NP
+movements	POS	I-NP
+persisted	POS	O
+for	POS	O
+many	POS	O
+minutes	POS	O
+after	POS	O
+complete	POS	O
+recovery	POS	O
+of	POS	O
+consciousness	POS	O
+.	POS	O
+Evidence	POS	O
+for	POS	O
+cardiac	POS	O
+beta	POS	O
+2	POS	O
+-	POS	O
+adrenoceptors	POS	O
+in	POS	O
+man	POS	O
+.	POS	O
+We	POS	O
+compared	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+single	POS	O
+doses	POS	O
+of	POS	O
+50	POS	O
+mg	POS	O
+atenolol	POS	O
+(	POS	O
+cardioselective	POS	O
+)	POS	O
+,	POS	O
+40	POS	O
+mg	POS	O
+propranolol	POS	O
+(	POS	O
+nonselective	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+placebo	POS	O
+on	POS	O
+both	POS	O
+exercise	POS	O
+-	POS	O
+and	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+tachycardia	POS	B-NP
+in	POS	O
+two	POS	O
+experiments	POS	O
+involving	POS	O
+nine	POS	O
+normal	POS	O
+subjects	POS	O
+.	POS	O
+Maximal	POS	O
+exercise	POS	O
+heart	POS	O
+rate	POS	O
+was	POS	O
+reduced	POS	O
+from	POS	O
+187	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+(	POS	O
+SEM	POS	O
+)	POS	O
+after	POS	O
+placebo	POS	O
+to	POS	O
+146	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+7	POS	O
+bpm	POS	O
+after	POS	O
+atenolol	POS	O
+and	POS	O
+138	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+bpm	POS	O
+after	POS	O
+propranolol	POS	O
+,	POS	O
+but	POS	O
+there	POS	O
+were	POS	O
+no	POS	O
+differences	POS	O
+between	POS	O
+the	POS	O
+drugs	POS	O
+.	POS	O
+The	POS	O
+effects	POS	O
+on	POS	O
+isoproterenol	POS	O
+tachycardia	POS	B-NP
+were	POS	O
+determined	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+atropine	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+04	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+IV	POS	O
+)	POS	O
+.	POS	O
+Isoproterenol	POS	O
+sensitivity	POS	O
+was	POS	O
+determined	POS	O
+as	POS	O
+the	POS	O
+intravenous	POS	O
+dose	POS	O
+that	POS	O
+increased	POS	O
+heart	POS	O
+rate	POS	O
+by	POS	O
+25	POS	O
+bpm	POS	O
+(	POS	O
+CD25	POS	O
+)	POS	O
+and	POS	O
+this	POS	O
+was	POS	O
+increased	POS	O
+from	POS	O
+1	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+micrograms	POS	O
+after	POS	O
+placebo	POS	O
+to	POS	O
+38	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+8	POS	O
+.	POS	O
+3	POS	O
+micrograms	POS	O
+after	POS	O
+propranolol	POS	O
+and	POS	O
+8	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+7	POS	O
+micrograms	POS	O
+after	POS	O
+atenolol	POS	O
+.	POS	O
+The	POS	O
+difference	POS	O
+in	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+the	POS	O
+two	POS	O
+was	POS	O
+significant	POS	O
+.	POS	O
+After	POS	O
+atropine	POS	O
+the	POS	O
+CD25	POS	O
+was	POS	O
+unchanged	POS	O
+after	POS	O
+placebo	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+micrograms	POS	O
+)	POS	O
+and	POS	O
+atenolol	POS	O
+(	POS	O
+7	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+micrograms	POS	O
+)	POS	O
+;	POS	O
+it	POS	O
+was	POS	O
+reduced	POS	O
+after	POS	O
+propranolol	POS	O
+(	POS	O
+24	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+5	POS	O
+.	POS	O
+0	POS	O
+micrograms	POS	O
+)	POS	O
+,	POS	O
+but	POS	O
+remained	POS	O
+different	POS	O
+from	POS	O
+atenolol	POS	O
+.	POS	O
+This	POS	O
+change	POS	O
+with	POS	O
+propranolol	POS	O
+sensitivity	POS	O
+was	POS	O
+calculated	POS	O
+as	POS	O
+the	POS	O
+apparent	POS	O
+Ka	POS	O
+,	POS	O
+this	POS	O
+was	POS	O
+unchanged	POS	O
+by	POS	O
+atropine	POS	O
+(	POS	O
+11	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+1	POS	O
+and	POS	O
+10	POS	O
+.	POS	O
+1	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+ml	POS	O
+/	POS	O
+ng	POS	O
+)	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+are	POS	O
+consistent	POS	O
+with	POS	O
+the	POS	O
+hypothesis	POS	O
+that	POS	O
+exercise	POS	O
+-	POS	O
+induced	POS	O
+tachycardia	POS	B-NP
+results	POS	O
+largely	POS	O
+from	POS	O
+beta	POS	O
+1	POS	O
+-	POS	O
+receptor	POS	O
+activation	POS	O
+that	POS	O
+is	POS	O
+blocked	POS	O
+by	POS	O
+both	POS	O
+cardioselective	POS	O
+and	POS	O
+nonselective	POS	O
+drugs	POS	O
+,	POS	O
+whereas	POS	O
+isoproterenol	POS	O
+activates	POS	O
+both	POS	O
+beta	POS	O
+1	POS	O
+-	POS	O
+and	POS	O
+beta	POS	O
+2	POS	O
+-	POS	O
+receptors	POS	O
+so	POS	O
+that	POS	O
+after	POS	O
+cardioselective	POS	O
+blockade	POS	O
+there	POS	O
+remains	POS	O
+a	POS	O
+beta	POS	O
+2	POS	O
+-	POS	O
+component	POS	O
+that	POS	O
+can	POS	O
+be	POS	O
+blocked	POS	O
+with	POS	O
+a	POS	O
+nonselective	POS	O
+drug	POS	O
+.	POS	O
+While	POS	O
+there	POS	O
+appear	POS	O
+to	POS	O
+be	POS	O
+beta	POS	O
+2	POS	O
+-	POS	O
+receptors	POS	O
+in	POS	O
+the	POS	O
+human	POS	O
+heart	POS	O
+,	POS	O
+their	POS	O
+physiologic	POS	O
+or	POS	O
+pathologic	POS	O
+roles	POS	O
+remain	POS	O
+to	POS	O
+be	POS	O
+defined	POS	O
+.	POS	O
+Hormones	POS	O
+and	POS	O
+risk	POS	O
+of	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+This	POS	O
+paper	POS	O
+reports	POS	O
+the	POS	O
+results	POS	O
+of	POS	O
+a	POS	O
+study	POS	O
+of	POS	O
+50	POS	O
+menopausal	POS	O
+women	POS	O
+receiving	POS	O
+hormonal	POS	O
+replacement	POS	O
+therapy	POS	O
+.	POS	O
+The	POS	O
+majority	POS	O
+(	POS	O
+29	POS	O
+)	POS	O
+had	POS	O
+surgical	POS	O
+menopause	POS	O
+;	POS	O
+their	POS	O
+mean	POS	O
+age	POS	O
+was	POS	O
+45	POS	O
+.	POS	O
+7	POS	O
+years	POS	O
+.	POS	O
+It	POS	O
+was	POS	O
+hypothesized	POS	O
+that	POS	O
+progestins	POS	O
+could	POS	O
+equilibrate	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+the	POS	O
+estrogenic	POS	O
+stimulation	POS	O
+on	POS	O
+the	POS	O
+mammary	POS	O
+and	POS	O
+endometrial	POS	O
+target	POS	O
+tissues	POS	O
+of	POS	O
+women	POS	O
+on	POS	O
+hormonal	POS	O
+replacement	POS	O
+therapy	POS	O
+.	POS	O
+The	POS	O
+treatment	POS	O
+schedule	POS	O
+consisted	POS	O
+of	POS	O
+conjugated	POS	O
+estrogens	POS	O
+(	POS	O
+Premarin	POS	O
+)	POS	O
+1	POS	O
+.	POS	O
+25	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+for	POS	O
+21	POS	O
+days	POS	O
+and	POS	O
+Medroxyprogesterone	POS	O
+acetate	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+for	POS	O
+10	POS	O
+days	POS	O
+in	POS	O
+each	POS	O
+month	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+treatment	POS	O
+period	POS	O
+was	POS	O
+18	POS	O
+months	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+period	POS	O
+,	POS	O
+attention	POS	O
+was	POS	O
+paid	POS	O
+to	POS	O
+breast	POS	O
+modifications	POS	O
+as	POS	O
+evidenced	POS	O
+by	POS	O
+symptomatology	POS	O
+,	POS	O
+physical	POS	O
+examination	POS	O
+,	POS	O
+and	POS	O
+plate	POS	O
+thermography	POS	O
+.	POS	O
+Mastodynia	POS	B-NP
+was	POS	O
+reported	POS	O
+by	POS	O
+21	POS	O
+patients	POS	O
+,	POS	O
+and	POS	O
+physical	POS	O
+examination	POS	O
+revealed	POS	O
+a	POS	O
+light	POS	O
+increase	POS	O
+in	POS	O
+breast	POS	O
+firmness	POS	O
+in	POS	O
+12	POS	O
+women	POS	O
+and	POS	O
+a	POS	O
+moderate	POS	O
+increase	POS	O
+in	POS	O
+breast	POS	B-NP
+nodularity	POS	I-NP
+in	POS	O
+2	POS	O
+women	POS	O
+.	POS	O
+Themography	POS	B-NP
+confirmed	POS	O
+the	POS	O
+existence	POS	O
+of	POS	O
+an	POS	O
+excessive	POS	O
+breast	POS	O
+stimulation	POS	O
+in	POS	O
+1	POS	O
+women	POS	O
+who	POS	O
+complained	POS	O
+of	POS	O
+moderate	POS	O
+mastodynia	POS	B-NP
+and	POS	O
+in	POS	O
+5	POS	O
+of	POS	O
+the	POS	O
+7	POS	O
+women	POS	O
+who	POS	O
+complained	POS	O
+of	POS	O
+severe	POS	O
+mastodynia	POS	B-NP
+.	POS	O
+Normalization	POS	O
+was	POS	O
+obtained	POS	O
+by	POS	O
+halving	POS	O
+the	POS	O
+estrogen	POS	O
+dose	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+hormonal	POS	O
+replacement	POS	O
+therapy	POS	O
+can	POS	O
+be	POS	O
+safely	POS	O
+prescribed	POS	O
+if	POS	O
+the	POS	O
+following	POS	O
+criteria	POS	O
+are	POS	O
+satisfied	POS	O
+:	POS	O
+1	POS	O
+)	POS	O
+preliminary	POS	O
+evaluation	POS	O
+of	POS	O
+patients	POS	O
+from	POS	O
+a	POS	O
+clinical	POS	O
+,	POS	O
+metabolic	POS	O
+,	POS	O
+cytologic	POS	O
+,	POS	O
+and	POS	O
+mammographic	POS	O
+perspective	POS	O
+;	POS	O
+2	POS	O
+)	POS	O
+cyclic	POS	O
+treatment	POS	O
+schedule	POS	O
+,	POS	O
+with	POS	O
+a	POS	O
+progestative	POS	O
+phase	POS	O
+of	POS	O
+10	POS	O
+days	POS	O
+;	POS	O
+and	POS	O
+3	POS	O
+)	POS	O
+periodic	POS	O
+complete	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+,	POS	O
+with	POS	O
+accurate	POS	O
+thermographic	POS	O
+evaluation	POS	O
+of	POS	O
+the	POS	O
+breast	POS	O
+target	POS	O
+tissues	POS	O
+.	POS	O
+Early	POS	O
+infections	POS	O
+in	POS	O
+kidney	POS	O
+,	POS	O
+heart	POS	O
+,	POS	O
+and	POS	O
+liver	POS	O
+transplant	POS	O
+recipients	POS	O
+on	POS	O
+cyclosporine	POS	O
+.	POS	O
+Eighty	POS	O
+-	POS	O
+one	POS	O
+renal	POS	O
+,	POS	O
+seventeen	POS	O
+heart	POS	O
+,	POS	O
+and	POS	O
+twenty	POS	O
+-	POS	O
+four	POS	O
+liver	POS	O
+transplant	POS	O
+patients	POS	O
+were	POS	O
+followed	POS	O
+for	POS	O
+infection	POS	O
+.	POS	O
+Seventeen	POS	O
+renal	POS	O
+patients	POS	O
+received	POS	O
+azathioprine	POS	O
+(	POS	O
+Aza	POS	O
+)	POS	O
+and	POS	O
+prednisone	POS	O
+as	POS	O
+part	POS	O
+of	POS	O
+a	POS	O
+randomized	POS	O
+trial	POS	O
+of	POS	O
+immunosuppression	POS	O
+with	POS	O
+21	POS	O
+cyclosporine	POS	O
+-	POS	O
+and	POS	O
+-	POS	O
+prednisone	POS	O
+-	POS	O
+treated	POS	O
+renal	POS	O
+transplant	POS	O
+patients	POS	O
+.	POS	O
+All	POS	O
+others	POS	O
+received	POS	O
+cyclosporine	POS	O
+and	POS	O
+prednisone	POS	O
+.	POS	O
+The	POS	O
+randomized	POS	O
+Aza	POS	O
+patients	POS	O
+had	POS	O
+more	POS	O
+overall	POS	O
+infections	POS	B-NP
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+and	POS	O
+more	POS	O
+nonviral	POS	B-NP
+infections	POS	I-NP
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+than	POS	O
+the	POS	O
+randomized	POS	O
+cyclosporine	POS	O
+patients	POS	O
+.	POS	O
+Heart	POS	O
+and	POS	O
+liver	POS	O
+patients	POS	O
+had	POS	O
+more	POS	O
+infections	POS	O
+than	POS	O
+cyclosporine	POS	O
+renal	POS	O
+patients	POS	O
+but	POS	O
+fewer	POS	O
+infections	POS	B-NP
+than	POS	O
+the	POS	O
+Aza	POS	O
+renal	POS	O
+patients	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+no	POS	O
+infectious	POS	B-NP
+deaths	POS	I-NP
+in	POS	O
+renal	POS	O
+transplant	POS	O
+patients	POS	O
+on	POS	O
+cyclosporine	POS	O
+or	POS	O
+Aza	POS	O
+,	POS	O
+but	POS	O
+infection	POS	O
+played	POS	O
+a	POS	O
+major	POS	O
+role	POS	O
+in	POS	O
+3	POS	O
+out	POS	O
+of	POS	O
+6	POS	O
+cardiac	POS	O
+transplant	POS	O
+deaths	POS	O
+and	POS	O
+in	POS	O
+8	POS	O
+out	POS	O
+of	POS	O
+9	POS	O
+liver	POS	B-NP
+transplant	POS	I-NP
+deaths	POS	I-NP
+.	POS	O
+Renal	POS	O
+patients	POS	O
+on	POS	O
+cyclosporine	POS	O
+had	POS	O
+the	POS	O
+fewest	POS	O
+bacteremias	POS	B-NP
+.	POS	O
+Analysis	POS	O
+of	POS	O
+site	POS	O
+of	POS	O
+infection	POS	O
+showed	POS	O
+a	POS	O
+preponderance	POS	O
+of	POS	O
+abdominal	POS	B-NP
+infections	POS	I-NP
+in	POS	O
+liver	POS	O
+patients	POS	O
+,	POS	O
+intrathoracic	POS	B-NP
+infections	POS	I-NP
+in	POS	O
+heart	POS	O
+patients	POS	O
+,	POS	O
+and	POS	O
+urinary	POS	B-NP
+tract	POS	I-NP
+infections	POS	I-NP
+in	POS	O
+renal	POS	O
+patients	POS	O
+.	POS	O
+Pulmonary	POS	B-NP
+infections	POS	I-NP
+were	POS	O
+less	POS	O
+common	POS	O
+in	POS	O
+cyclosporine	POS	O
+-	POS	O
+treated	POS	O
+renal	POS	O
+patients	POS	O
+than	POS	O
+in	POS	O
+Aza	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+Aza	POS	O
+patients	POS	O
+had	POS	O
+significantly	POS	O
+more	POS	O
+staphylococcal	POS	B-NP
+infections	POS	I-NP
+than	POS	O
+all	POS	O
+other	POS	O
+transplant	POS	O
+groups	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+005	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+systemic	POS	B-NP
+fungal	POS	I-NP
+infections	POS	I-NP
+occurred	POS	O
+only	POS	O
+in	POS	O
+the	POS	O
+liver	POS	O
+transplant	POS	O
+group	POS	O
+.	POS	O
+Cytomegalovirus	POS	O
+(	POS	O
+CMV	POS	O
+)	POS	O
+shedding	POS	O
+or	POS	O
+serological	POS	O
+rises	POS	O
+in	POS	O
+antibody	POS	O
+titer	POS	O
+,	POS	O
+or	POS	O
+both	POS	O
+occurred	POS	O
+in	POS	O
+78	POS	O
+%	POS	O
+of	POS	O
+cyclosporine	POS	O
+patients	POS	O
+and	POS	O
+76	POS	O
+%	POS	O
+of	POS	O
+Aza	POS	O
+patients	POS	O
+.	POS	O
+Of	POS	O
+the	POS	O
+cyclosporine	POS	O
+patients	POS	O
+,	POS	O
+15	POS	O
+%	POS	O
+had	POS	O
+symptoms	POS	O
+related	POS	O
+to	POS	O
+CMV	POS	B-NP
+infection	POS	I-NP
+.	POS	O
+Serological	POS	O
+evidence	POS	O
+for	POS	O
+Epstein	POS	B-NP
+Barr	POS	I-NP
+Virus	POS	I-NP
+infection	POS	I-NP
+was	POS	O
+found	POS	O
+in	POS	O
+20	POS	O
+%	POS	O
+of	POS	O
+65	POS	O
+cyclosporine	POS	O
+patients	POS	O
+studied	POS	O
+.	POS	O
+Three	POS	O
+had	POS	O
+associated	POS	O
+symptoms	POS	O
+,	POS	O
+and	POS	O
+one	POS	O
+developed	POS	O
+a	POS	O
+lymphoma	POS	B-NP
+.	POS	O
+Structure	POS	O
+-	POS	O
+activity	POS	O
+and	POS	O
+dose	POS	O
+-	POS	O
+effect	POS	O
+relationships	POS	O
+of	POS	O
+the	POS	O
+antagonism	POS	O
+of	POS	O
+picrotoxin	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+by	POS	O
+cholecystokinin	POS	O
+,	POS	O
+fragments	POS	O
+and	POS	O
+analogues	POS	O
+of	POS	O
+cholecystokinin	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+Intraperitoneal	POS	O
+administration	POS	O
+of	POS	O
+cholecystokinin	POS	O
+octapeptide	POS	O
+sulphate	POS	O
+ester	POS	O
+(	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+SE	POS	O
+)	POS	O
+and	POS	O
+nonsulphated	POS	O
+cholecystokinin	POS	O
+octapeptide	POS	O
+(	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+NS	POS	O
+)	POS	O
+enhanced	POS	O
+the	POS	O
+latency	POS	O
+of	POS	O
+seizures	POS	B-NP
+induced	POS	O
+by	POS	O
+picrotoxin	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+Experiments	POS	O
+with	POS	O
+N	POS	O
+-	POS	O
+and	POS	O
+C	POS	O
+-	POS	O
+terminal	POS	O
+fragments	POS	O
+revealed	POS	O
+that	POS	O
+the	POS	O
+C	POS	O
+-	POS	O
+terminal	POS	O
+tetrapeptide	POS	O
+(	POS	O
+CCK	POS	O
+-	POS	O
+5	POS	O
+-	POS	O
+8	POS	O
+)	POS	O
+was	POS	O
+the	POS	O
+active	POS	O
+centre	POS	O
+of	POS	O
+the	POS	O
+CCK	POS	O
+octapeptide	POS	O
+molecule	POS	O
+.	POS	O
+The	POS	O
+analogues	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+SE	POS	O
+and	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+NS	POS	O
+(	POS	O
+dose	POS	O
+range	POS	O
+0	POS	O
+.	POS	O
+2	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+4	POS	O
+mumol	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+and	POS	O
+caerulein	POS	O
+dose	POS	O
+range	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+8	POS	O
+mumol	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+showed	POS	O
+bell	POS	O
+-	POS	O
+shaped	POS	O
+dose	POS	O
+-	POS	O
+effect	POS	O
+curves	POS	O
+,	POS	O
+with	POS	O
+the	POS	O
+greatest	POS	O
+maximum	POS	O
+inhibition	POS	O
+for	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+NS	POS	O
+.	POS	O
+The	POS	O
+peptide	POS	O
+CCK	POS	O
+-	POS	O
+5	POS	O
+-	POS	O
+8	POS	O
+had	POS	O
+weak	POS	O
+anticonvulsant	POS	O
+activity	POS	O
+in	POS	O
+comparison	POS	O
+to	POS	O
+the	POS	O
+octapeptides	POS	O
+,	POS	O
+3	POS	O
+.	POS	O
+2	POS	O
+mumol	POS	O
+/	POS	O
+kg	POS	O
+and	POS	O
+larger	POS	O
+doses	POS	O
+of	POS	O
+the	POS	O
+reference	POS	O
+drug	POS	O
+,	POS	O
+diazepam	POS	O
+,	POS	O
+totally	POS	O
+prevented	POS	O
+picrotoxin	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+and	POS	O
+mortality	POS	O
+.	POS	O
+The	POS	O
+maximum	POS	O
+effect	POS	O
+of	POS	O
+the	POS	O
+peptides	POS	O
+tested	POS	O
+was	POS	O
+less	POS	O
+than	POS	O
+that	POS	O
+of	POS	O
+diazepam	POS	O
+.	POS	O
+Experiments	POS	O
+with	POS	O
+analogues	POS	O
+and	POS	O
+derivatives	POS	O
+of	POS	O
+CCK	POS	O
+-	POS	O
+5	POS	O
+-	POS	O
+8	POS	O
+demonstrated	POS	O
+that	POS	O
+the	POS	O
+effectiveness	POS	O
+of	POS	O
+the	POS	O
+beta	POS	O
+-	POS	O
+alanyl	POS	O
+derivatives	POS	O
+of	POS	O
+CCK	POS	O
+-	POS	O
+5	POS	O
+-	POS	O
+8	POS	O
+were	POS	O
+enhanced	POS	O
+and	POS	O
+that	POS	O
+they	POS	O
+were	POS	O
+equipotent	POS	O
+with	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+SE	POS	O
+.	POS	O
+Of	POS	O
+the	POS	O
+CCK	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+8	POS	O
+analogues	POS	O
+,	POS	O
+Ser	POS	O
+(	POS	O
+SO3H	POS	O
+)	POS	O
+7	POS	O
+-	POS	O
+Ac	POS	O
+-	POS	O
+CCK	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+SE	POS	O
+and	POS	O
+Thr	POS	O
+(	POS	O
+SO3H	POS	O
+)	POS	O
+7	POS	O
+-	POS	O
+Ac	POS	O
+-	POS	O
+CCK	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+SE	POS	O
+and	POS	O
+Hyp	POS	O
+(	POS	O
+SO3H	POS	O
+)	POS	O
+-	POS	O
+Ac	POS	O
+-	POS	O
+CCK	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+SE	POS	O
+were	POS	O
+slightly	POS	O
+more	POS	O
+active	POS	O
+than	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+SE	POS	O
+.	POS	O
+Vasopressin	POS	O
+as	POS	O
+a	POS	O
+possible	POS	O
+contributor	POS	O
+to	POS	O
+hypertension	POS	B-NP
+.	POS	O
+The	POS	O
+role	POS	O
+of	POS	O
+vasopressin	POS	O
+as	POS	O
+a	POS	O
+pressor	POS	O
+agent	POS	O
+to	POS	O
+the	POS	O
+hypertensive	POS	B-NP
+process	POS	O
+was	POS	O
+examined	POS	O
+.	POS	O
+Vasopressin	POS	O
+plays	POS	O
+a	POS	O
+major	POS	O
+role	POS	O
+in	POS	O
+the	POS	O
+pathogenesis	POS	O
+of	POS	O
+DOCA	POS	O
+-	POS	O
+salt	POS	O
+hypertension	POS	B-NP
+,	POS	O
+since	POS	O
+the	POS	O
+elevation	POS	O
+of	POS	O
+blood	POS	O
+pressure	POS	O
+was	POS	O
+not	POS	O
+substantial	POS	O
+in	POS	O
+the	POS	O
+rats	POS	O
+with	POS	O
+lithium	POS	O
+-	POS	O
+treated	POS	O
+diabetes	POS	B-NP
+insipidus	POS	I-NP
+after	POS	O
+DOCA	POS	O
+-	POS	O
+salt	POS	O
+treatment	POS	O
+.	POS	O
+Administration	POS	O
+of	POS	O
+DDAVP	POS	O
+which	POS	O
+has	POS	O
+antidiuretic	POS	O
+action	POS	O
+but	POS	O
+minimal	POS	O
+vasopressor	POS	O
+effect	POS	O
+failed	POS	O
+to	POS	O
+increase	POS	O
+blood	POS	O
+pressure	POS	O
+to	POS	O
+the	POS	O
+levels	POS	O
+observed	POS	O
+after	POS	O
+administration	POS	O
+of	POS	O
+AVP	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+the	POS	O
+pressor	POS	O
+action	POS	O
+of	POS	O
+vasopressin	POS	O
+appears	POS	O
+to	POS	O
+be	POS	O
+important	POS	O
+in	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+this	POS	O
+model	POS	O
+of	POS	O
+hypertension	POS	B-NP
+,	POS	O
+since	POS	O
+the	POS	O
+enhanced	POS	O
+pressor	POS	O
+responsiveness	POS	O
+to	POS	O
+the	POS	O
+hormone	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+initial	POS	O
+stage	POS	O
+of	POS	O
+hypertension	POS	B-NP
+.	POS	O
+Increased	POS	O
+secretion	POS	O
+of	POS	O
+vasopressin	POS	O
+from	POS	O
+neurohypophysis	POS	O
+also	POS	O
+promotes	POS	O
+the	POS	O
+function	POS	O
+of	POS	O
+the	POS	O
+hormone	POS	O
+as	POS	O
+a	POS	O
+pathogenetic	POS	O
+factor	POS	O
+in	POS	O
+hypertension	POS	B-NP
+.	POS	O
+An	POS	O
+unproportional	POS	O
+release	POS	O
+of	POS	O
+vasopressin	POS	O
+compared	POS	O
+to	POS	O
+plasma	POS	O
+osmolality	POS	O
+may	POS	O
+be	POS	O
+induced	POS	O
+by	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+an	POS	O
+adjusting	POS	O
+control	POS	O
+of	POS	O
+angiotensin	POS	O
+II	POS	O
+forming	POS	O
+and	POS	O
+receptor	POS	O
+binding	POS	O
+capacity	POS	O
+for	POS	O
+sodium	POS	O
+balance	POS	O
+in	POS	O
+the	POS	O
+brain	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+vasopressin	POS	O
+remains	POS	O
+to	POS	O
+be	POS	O
+determined	POS	O
+in	POS	O
+human	POS	O
+essential	POS	O
+hypertension	POS	B-NP
+.	POS	O
+Toxic	POS	B-NP
+hepatitis	POS	I-NP
+induced	POS	O
+by	POS	O
+disulfiram	POS	O
+in	POS	O
+a	POS	O
+non	POS	O
+-	POS	O
+alcoholic	POS	O
+.	POS	O
+A	POS	O
+reversible	POS	O
+toxic	POS	B-NP
+liver	POS	I-NP
+damage	POS	I-NP
+was	POS	O
+observed	POS	O
+in	POS	O
+a	POS	O
+non	POS	O
+-	POS	O
+alcoholic	POS	O
+woman	POS	O
+treated	POS	O
+with	POS	O
+disulfiram	POS	O
+.	POS	O
+The	POS	O
+causative	POS	O
+relationship	POS	O
+was	POS	O
+proven	POS	O
+by	POS	O
+challenge	POS	O
+.	POS	O
+Atrial	POS	B-NP
+thrombosis	POS	I-NP
+involving	POS	O
+the	POS	O
+heart	POS	O
+of	POS	O
+F	POS	O
+-	POS	O
+344	POS	O
+rats	POS	O
+ingesting	POS	O
+quinacrine	POS	O
+hydrochloride	POS	O
+.	POS	O
+Quinacrine	POS	O
+hydrochloride	POS	O
+is	POS	O
+toxic	POS	O
+for	POS	O
+the	POS	O
+heart	POS	O
+of	POS	O
+F	POS	O
+-	POS	O
+344	POS	O
+rats	POS	O
+.	POS	O
+Rats	POS	O
+treated	POS	O
+with	POS	O
+500	POS	O
+ppm	POS	O
+quinacrine	POS	O
+hydrochloride	POS	O
+in	POS	O
+the	POS	O
+diet	POS	O
+all	POS	O
+developed	POS	O
+a	POS	O
+high	POS	O
+incidence	POS	O
+of	POS	O
+left	POS	O
+atrial	POS	B-NP
+thrombosis	POS	I-NP
+.	POS	O
+The	POS	O
+lesion	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+cardiac	POS	B-NP
+hypertrophy	POS	I-NP
+and	POS	O
+dilatation	POS	O
+and	POS	O
+focal	POS	O
+myocardial	POS	B-NP
+degeneration	POS	I-NP
+.	POS	O
+Rats	POS	O
+died	POS	O
+from	POS	O
+cardiac	POS	B-NP
+hypertrophy	POS	I-NP
+with	POS	O
+severe	POS	O
+acute	POS	O
+and	POS	O
+chronic	POS	O
+congestion	POS	O
+of	POS	O
+the	POS	O
+lungs	POS	O
+,	POS	O
+liver	POS	O
+,	POS	O
+and	POS	O
+other	POS	O
+organs	POS	O
+.	POS	O
+Seventy	POS	O
+percent	POS	O
+of	POS	O
+rats	POS	O
+given	POS	O
+250	POS	O
+ppm	POS	O
+quinacrine	POS	O
+hydrochloride	POS	O
+and	POS	O
+1	POS	O
+,	POS	O
+000	POS	O
+ppm	POS	O
+sodium	POS	O
+nitrite	POS	O
+simultaneously	POS	O
+in	POS	O
+the	POS	O
+diet	POS	O
+had	POS	O
+thrombosis	POS	B-NP
+of	POS	O
+the	POS	O
+atria	POS	O
+of	POS	O
+the	POS	O
+heart	POS	O
+,	POS	O
+while	POS	O
+untreated	POS	O
+control	POS	O
+rats	POS	O
+in	POS	O
+this	POS	O
+laboratory	POS	O
+did	POS	O
+not	POS	O
+have	POS	O
+atrial	POS	B-NP
+thrombosis	POS	I-NP
+.	POS	O
+Sodium	POS	O
+nitrite	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+quinacrine	POS	O
+hydrochloride	POS	O
+appeared	POS	O
+to	POS	O
+have	POS	O
+no	POS	O
+additional	POS	O
+effect	POS	O
+.	POS	O
+Alternating	POS	O
+sinus	POS	O
+rhythm	POS	O
+and	POS	O
+intermittent	POS	O
+sinoatrial	POS	B-NP
+block	POS	I-NP
+induced	POS	O
+by	POS	O
+propranolol	POS	O
+.	POS	O
+Alternating	POS	O
+sinus	POS	O
+rhythm	POS	O
+and	POS	O
+intermittent	POS	O
+sinoatrial	POS	O
+(	POS	O
+S	POS	O
+-	POS	O
+A	POS	O
+)	POS	O
+block	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+a	POS	O
+57	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+,	POS	O
+under	POS	O
+treatment	POS	O
+for	POS	O
+angina	POS	B-NP
+with	POS	O
+80	POS	O
+mg	POS	O
+propranolol	POS	O
+daily	POS	O
+.	POS	O
+The	POS	O
+electrocardiogram	POS	O
+showed	POS	O
+alternation	POS	O
+of	POS	O
+long	POS	O
+and	POS	O
+short	POS	O
+P	POS	O
+-	POS	O
+P	POS	O
+intervals	POS	O
+and	POS	O
+occasional	POS	O
+pauses	POS	O
+.	POS	O
+These	POS	O
+pauses	POS	O
+were	POS	O
+always	POS	O
+preceded	POS	O
+by	POS	O
+the	POS	O
+short	POS	O
+P	POS	O
+-	POS	O
+P	POS	O
+intervals	POS	O
+and	POS	O
+were	POS	O
+usually	POS	O
+followed	POS	O
+by	POS	O
+one	POS	O
+or	POS	O
+two	POS	O
+P	POS	O
+-	POS	O
+P	POS	O
+intervals	POS	O
+of	POS	O
+0	POS	O
+.	POS	O
+92	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+95	POS	O
+s	POS	O
+representing	POS	O
+the	POS	O
+basic	POS	O
+sinus	POS	O
+cycle	POS	O
+.	POS	O
+Following	POS	O
+these	POS	O
+basic	POS	O
+sinus	POS	O
+cycles	POS	O
+,	POS	O
+alternating	POS	O
+rhythm	POS	O
+started	POS	O
+with	POS	O
+the	POS	O
+longer	POS	O
+P	POS	O
+-	POS	O
+P	POS	O
+interval	POS	O
+.	POS	O
+The	POS	O
+long	POS	O
+P	POS	O
+-	POS	O
+P	POS	O
+intervals	POS	O
+ranged	POS	O
+between	POS	O
+1	POS	O
+.	POS	O
+04	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+12	POS	O
+s	POS	O
+and	POS	O
+the	POS	O
+short	POS	O
+P	POS	O
+-	POS	O
+P	POS	O
+intervals	POS	O
+between	POS	O
+0	POS	O
+.	POS	O
+80	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+84	POS	O
+s	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+The	POS	O
+duration	POS	O
+of	POS	O
+the	POS	O
+pauses	POS	O
+were	POS	O
+equal	POS	O
+or	POS	O
+almost	POS	O
+equal	POS	O
+to	POS	O
+one	POS	O
+short	POS	O
+plus	POS	O
+one	POS	O
+long	POS	O
+P	POS	O
+-	POS	O
+P	POS	O
+interval	POS	O
+or	POS	O
+to	POS	O
+twice	POS	O
+the	POS	O
+basic	POS	O
+sinus	POS	O
+cycle	POS	O
+.	POS	O
+In	POS	O
+one	POS	O
+recording	POS	O
+a	POS	O
+short	POS	O
+period	POS	O
+of	POS	O
+regular	POS	O
+sinus	POS	O
+rhythm	POS	O
+with	POS	O
+intermittent	POS	O
+2	POS	O
+/	POS	O
+1	POS	O
+S	POS	O
+-	POS	O
+A	POS	O
+block	POS	O
+was	POS	O
+observed	POS	O
+.	POS	O
+This	POS	O
+short	POS	O
+period	POS	O
+of	POS	O
+sinus	POS	O
+rhythm	POS	O
+was	POS	O
+interrupted	POS	O
+by	POS	O
+sudden	POS	O
+prolongation	POS	O
+of	POS	O
+the	POS	O
+P	POS	O
+-	POS	O
+P	POS	O
+interval	POS	O
+starting	POS	O
+the	POS	O
+alternative	POS	O
+rhythm	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+small	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+shape	POS	O
+of	POS	O
+the	POS	O
+P	POS	O
+waves	POS	O
+and	POS	O
+P	POS	O
+-	POS	O
+R	POS	O
+intervals	POS	O
+.	POS	O
+S	POS	O
+-	POS	O
+A	POS	O
+conduction	POS	O
+through	POS	O
+two	POS	O
+pathways	POS	O
+,	POS	O
+the	POS	O
+first	POS	O
+with	POS	O
+2	POS	O
+/	POS	O
+1	POS	O
+block	POS	O
+the	POS	O
+second	POS	O
+having	POS	O
+0	POS	O
+.	POS	O
+12	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+14	POS	O
+s	POS	O
+longer	POS	O
+conduction	POS	O
+time	POS	O
+and	POS	O
+with	POS	O
+occasional	POS	O
+2	POS	O
+/	POS	O
+1	POS	O
+block	POS	O
+was	POS	O
+proposed	POS	O
+for	POS	O
+the	POS	O
+explanation	POS	O
+of	POS	O
+the	POS	O
+alternating	POS	O
+P	POS	O
+-	POS	O
+P	POS	O
+interval	POS	O
+and	POS	O
+other	POS	O
+electrocardiographic	POS	O
+features	POS	O
+seen	POS	O
+.	POS	O
+Atropine	POS	O
+1	POS	O
+mg	POS	O
+given	POS	O
+intravenously	POS	O
+resulted	POS	O
+in	POS	O
+shortening	POS	O
+of	POS	O
+all	POS	O
+P	POS	O
+-	POS	O
+P	POS	O
+intervals	POS	O
+without	POS	O
+changing	POS	O
+the	POS	O
+rhythm	POS	O
+.	POS	O
+The	POS	O
+abnormal	POS	O
+rhythm	POS	O
+disappeared	POS	O
+with	POS	O
+the	POS	O
+withdrawal	POS	O
+of	POS	O
+propranolol	POS	O
+and	POS	O
+when	POS	O
+the	POS	O
+drug	POS	O
+was	POS	O
+restarted	POS	O
+a	POS	O
+2	POS	O
+/	POS	O
+1	POS	O
+S	POS	O
+-	POS	O
+A	POS	O
+block	POS	O
+was	POS	O
+seen	POS	O
+.	POS	O
+This	POS	O
+was	POS	O
+accepted	POS	O
+as	POS	O
+evidence	POS	O
+for	POS	O
+propranolol	POS	O
+being	POS	O
+the	POS	O
+cause	POS	O
+of	POS	O
+this	POS	O
+conduction	POS	O
+disorder	POS	O
+.	POS	O
+Antitumor	POS	B-NP
+effect	POS	I-NP
+,	POS	O
+cardiotoxicity	POS	B-NP
+,	POS	O
+and	POS	O
+nephrotoxicity	POS	B-NP
+of	POS	O
+doxorubicin	POS	O
+in	POS	O
+the	POS	O
+IgM	POS	O
+solid	POS	O
+immunocytoma	POS	O
+-	POS	O
+bearing	POS	O
+LOU	POS	O
+/	POS	O
+M	POS	O
+/	POS	O
+WSL	POS	O
+rat	POS	O
+.	POS	O
+Antitumor	POS	O
+activity	POS	O
+,	POS	O
+cardiotoxicity	POS	B-NP
+,	POS	O
+and	POS	O
+nephrotoxicity	POS	B-NP
+induced	POS	O
+by	POS	O
+doxorubicin	POS	O
+were	POS	O
+studied	POS	O
+in	POS	O
+LOU	POS	O
+/	POS	O
+M	POS	O
+/	POS	O
+WSL	POS	O
+inbred	POS	O
+rats	POS	O
+each	POS	O
+bearing	POS	O
+a	POS	O
+transplantable	POS	O
+solid	POS	O
+IgM	POS	O
+immunocytoma	POS	B-NP
+.	POS	O
+Animals	POS	O
+with	POS	O
+a	POS	O
+tumor	POS	B-NP
+(	POS	O
+diameter	POS	O
+,	POS	O
+15	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+3	POS	O
+.	POS	O
+3	POS	O
+mm	POS	O
+)	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+iv	POS	O
+injections	POS	O
+of	POS	O
+doxorubicin	POS	O
+on	POS	O
+5	POS	O
+consecutive	POS	O
+days	POS	O
+,	POS	O
+followed	POS	O
+by	POS	O
+1	POS	O
+weekly	POS	O
+injection	POS	O
+for	POS	O
+7	POS	O
+weeks	POS	O
+(	POS	O
+dose	POS	O
+range	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+015	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+0	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+body	POS	O
+wt	POS	O
+)	POS	O
+.	POS	O
+Tumor	POS	B-NP
+regression	POS	O
+was	POS	O
+observed	POS	O
+with	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+doxorubicin	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+Complete	POS	O
+disappearance	POS	O
+of	POS	O
+the	POS	O
+tumor	POS	B-NP
+was	POS	O
+induced	POS	O
+with	POS	O
+1	POS	O
+.	POS	O
+0	POS	O
+mg	POS	O
+doxorubicin	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+Histologic	POS	O
+evidence	POS	O
+of	POS	O
+cardiotoxicity	POS	B-NP
+scored	POS	O
+as	POS	O
+grade	POS	O
+III	POS	O
+was	POS	O
+only	POS	O
+observed	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+1	POS	O
+.	POS	O
+0	POS	O
+mg	POS	O
+doxorubicin	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+Light	POS	O
+microscopic	POS	O
+evidence	POS	O
+of	POS	O
+renal	POS	B-NP
+damage	POS	I-NP
+was	POS	O
+seen	POS	O
+above	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+doxorubicin	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+which	POS	O
+resulted	POS	O
+in	POS	O
+albuminuria	POS	B-NP
+and	POS	O
+very	POS	O
+low	POS	O
+serum	POS	O
+albumin	POS	O
+levels	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+group	POS	O
+that	POS	O
+received	POS	O
+1	POS	O
+.	POS	O
+0	POS	O
+mg	POS	O
+doxorubicin	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+the	POS	O
+serum	POS	O
+albumin	POS	O
+level	POS	O
+decreased	POS	O
+from	POS	O
+33	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+1	POS	O
+to	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+g	POS	O
+/	POS	O
+liter	POS	O
+.	POS	O
+Ascites	POS	O
+and	POS	O
+hydrothorax	POS	B-NP
+were	POS	O
+observed	POS	O
+simultaneously	POS	O
+.	POS	O
+The	POS	O
+same	POS	O
+experiments	POS	O
+were	POS	O
+performed	POS	O
+with	POS	O
+non	POS	O
+-	POS	O
+tumor	POS	O
+-	POS	O
+bearing	POS	O
+rats	POS	O
+,	POS	O
+in	POS	O
+which	POS	O
+no	POS	O
+major	POS	O
+differences	POS	O
+were	POS	O
+observed	POS	O
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+antitumor	POS	O
+activity	POS	O
+,	POS	O
+cardiotoxicity	POS	B-NP
+,	POS	O
+and	POS	O
+nephrotoxicity	POS	B-NP
+were	POS	O
+studied	POS	O
+simultaneously	POS	O
+in	POS	O
+the	POS	O
+same	POS	O
+LOU	POS	O
+/	POS	O
+M	POS	O
+/	POS	O
+WSL	POS	O
+rat	POS	O
+.	POS	O
+Albuminuria	POS	B-NP
+due	POS	O
+to	POS	O
+renal	POS	B-NP
+damage	POS	I-NP
+led	POS	O
+to	POS	O
+extremely	POS	O
+low	POS	O
+serum	POS	O
+albumin	POS	O
+levels	POS	O
+,	POS	O
+so	POS	O
+ascites	POS	B-NP
+and	POS	O
+hydrothorax	POS	B-NP
+were	POS	O
+not	POS	O
+necessarily	POS	O
+a	POS	O
+consequence	POS	O
+of	POS	O
+the	POS	O
+observed	POS	O
+cardiomyopathy	POS	B-NP
+.	POS	O
+Intraoperative	POS	B-NP
+bradycardia	POS	I-NP
+and	POS	O
+hypotension	POS	B-NP
+associated	POS	O
+with	POS	O
+timolol	POS	O
+and	POS	O
+pilocarpine	POS	O
+eye	POS	O
+drops	POS	O
+.	POS	O
+A	POS	O
+69	POS	O
+-	POS	O
+yr	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+,	POS	O
+who	POS	O
+was	POS	O
+concurrently	POS	O
+being	POS	O
+treated	POS	O
+with	POS	O
+pilocarpine	POS	O
+nitrate	POS	O
+and	POS	O
+timolol	POS	O
+maleate	POS	O
+eye	POS	O
+drops	POS	O
+,	POS	O
+developed	POS	O
+a	POS	O
+bradycardia	POS	B-NP
+and	POS	O
+became	POS	O
+hypotensive	POS	B-NP
+during	POS	O
+halothane	POS	O
+anaesthesia	POS	O
+.	POS	O
+Both	POS	O
+timolol	POS	O
+and	POS	O
+pilocarpine	POS	O
+were	POS	O
+subsequently	POS	O
+identified	POS	O
+in	POS	O
+a	POS	O
+24	POS	O
+-	POS	O
+h	POS	O
+collection	POS	O
+of	POS	O
+urine	POS	O
+.	POS	O
+Timolol	POS	O
+(	POS	O
+but	POS	O
+not	POS	O
+pilocarpine	POS	O
+)	POS	O
+was	POS	O
+detected	POS	O
+in	POS	O
+a	POS	O
+sample	POS	O
+of	POS	O
+plasma	POS	O
+removed	POS	O
+during	POS	O
+surgery	POS	O
+;	POS	O
+the	POS	O
+plasma	POS	O
+concentration	POS	O
+of	POS	O
+timolol	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+6	POS	O
+ng	POS	O
+ml	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+was	POS	O
+consistent	POS	O
+with	POS	O
+partial	POS	O
+beta	POS	O
+-	POS	O
+adrenoceptor	POS	O
+blockade	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+postulated	POS	O
+that	POS	O
+this	POS	O
+action	POS	O
+may	POS	O
+have	POS	O
+been	POS	O
+enhanced	POS	O
+during	POS	O
+halothane	POS	O
+anaesthesia	POS	O
+with	POS	O
+resultant	POS	O
+bradycardia	POS	B-NP
+and	POS	O
+hypotension	POS	B-NP
+.	POS	O
+Pilocarpine	POS	O
+may	POS	O
+have	POS	O
+had	POS	O
+a	POS	O
+contributory	POS	O
+effect	POS	O
+.	POS	O
+Succinylcholine	POS	O
+apnoea	POS	B-NP
+:	POS	O
+attempted	POS	O
+reversal	POS	O
+with	POS	O
+anticholinesterases	POS	O
+.	POS	O
+Anticholinesterases	POS	O
+were	POS	O
+administered	POS	O
+in	POS	O
+an	POS	O
+attempt	POS	O
+to	POS	O
+antagonize	POS	O
+prolonged	POS	O
+neuromuscular	POS	O
+blockade	POS	O
+following	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+succinylcholine	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+later	POS	O
+found	POS	O
+to	POS	O
+be	POS	O
+homozygous	POS	O
+for	POS	O
+atypical	POS	O
+plasma	POS	O
+cholinesterase	POS	O
+.	POS	O
+Edrophonium	POS	O
+10	POS	O
+mg	POS	O
+,	POS	O
+given	POS	O
+74	POS	O
+min	POS	O
+after	POS	O
+succinylcholine	POS	O
+,	POS	O
+when	POS	O
+train	POS	O
+-	POS	O
+of	POS	O
+-	POS	O
+four	POS	O
+stimulation	POS	O
+was	POS	O
+characteristic	POS	O
+of	POS	O
+phase	POS	O
+II	POS	O
+block	POS	O
+,	POS	O
+produced	POS	O
+partial	POS	O
+antagonism	POS	O
+which	POS	O
+was	POS	O
+not	POS	O
+sustained	POS	O
+.	POS	O
+Repeated	POS	O
+doses	POS	O
+of	POS	O
+edrophonium	POS	O
+to	POS	O
+70	POS	O
+mg	POS	O
+and	POS	O
+neostigmine	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+did	POS	O
+not	POS	O
+antagonize	POS	O
+or	POS	O
+augment	POS	O
+the	POS	O
+block	POS	O
+.	POS	O
+Spontaneous	POS	O
+respiration	POS	O
+recommenced	POS	O
+200	POS	O
+min	POS	O
+after	POS	O
+succinylcholine	POS	O
+administration	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+concluded	POS	O
+that	POS	O
+anticholinesterases	POS	O
+are	POS	O
+only	POS	O
+partially	POS	O
+effective	POS	O
+in	POS	O
+restoring	POS	O
+neuromuscular	POS	O
+function	POS	O
+in	POS	O
+succinylcholine	POS	O
+apnoea	POS	B-NP
+despite	POS	O
+muscle	POS	O
+twitch	POS	O
+activity	POS	O
+typical	POS	O
+of	POS	O
+phase	POS	O
+II	POS	O
+block	POS	O
+.	POS	O
+Effect	POS	O
+of	POS	O
+doxorubicin	POS	O
+on	POS	O
+[	POS	O
+omega	POS	O
+-	POS	O
+I	POS	O
+-	POS	O
+131	POS	O
+]	POS	O
+heptadecanoic	POS	O
+acid	POS	O
+myocardial	POS	O
+scintigraphy	POS	O
+and	POS	O
+echocardiography	POS	O
+in	POS	O
+dogs	POS	O
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+serial	POS	O
+treatment	POS	O
+with	POS	O
+doxorubicin	POS	O
+on	POS	O
+dynamic	POS	O
+myocardial	POS	O
+scintigraphy	POS	O
+with	POS	O
+[	POS	O
+omega	POS	O
+-	POS	O
+I	POS	O
+-	POS	O
+131	POS	O
+]	POS	O
+heptadecanoic	POS	O
+acid	POS	O
+(	POS	O
+I	POS	O
+-	POS	O
+131	POS	O
+HA	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+on	POS	O
+global	POS	O
+left	POS	O
+-	POS	O
+ventricular	POS	O
+function	POS	O
+determined	POS	O
+echocardiographically	POS	O
+,	POS	O
+were	POS	O
+studied	POS	O
+in	POS	O
+a	POS	O
+group	POS	O
+of	POS	O
+nine	POS	O
+mongrel	POS	O
+dogs	POS	O
+.	POS	O
+Total	POS	O
+extractable	POS	O
+myocardial	POS	O
+lipid	POS	O
+was	POS	O
+compared	POS	O
+postmortem	POS	O
+between	POS	O
+a	POS	O
+group	POS	O
+of	POS	O
+control	POS	O
+dogs	POS	O
+and	POS	O
+doxorubicin	POS	O
+-	POS	O
+treated	POS	O
+dogs	POS	O
+.	POS	O
+A	POS	O
+significant	POS	O
+and	POS	O
+then	POS	O
+progressive	POS	O
+fall	POS	O
+in	POS	O
+global	POS	O
+LV	POS	O
+function	POS	O
+was	POS	O
+observed	POS	O
+at	POS	O
+a	POS	O
+cumulative	POS	O
+doxorubicin	POS	O
+dose	POS	O
+of	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+A	POS	O
+significant	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+myocardial	POS	O
+t1	POS	O
+/	POS	O
+2	POS	O
+of	POS	O
+the	POS	O
+I	POS	O
+-	POS	O
+131	POS	O
+HA	POS	O
+was	POS	O
+observed	POS	O
+only	POS	O
+at	POS	O
+a	POS	O
+higher	POS	O
+cumulative	POS	O
+dose	POS	O
+,	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+No	POS	O
+significant	POS	O
+alteration	POS	O
+in	POS	O
+total	POS	O
+extractable	POS	O
+myocardial	POS	O
+lipids	POS	O
+was	POS	O
+observed	POS	O
+between	POS	O
+control	POS	O
+dogs	POS	O
+and	POS	O
+those	POS	O
+treated	POS	O
+with	POS	O
+doxorubicin	POS	O
+.	POS	O
+Our	POS	O
+findings	POS	O
+suggest	POS	O
+that	POS	O
+the	POS	O
+changes	POS	O
+leading	POS	O
+to	POS	O
+an	POS	O
+alteration	POS	O
+of	POS	O
+myocardial	POS	O
+dynamic	POS	O
+imaging	POS	O
+with	POS	O
+I	POS	O
+-	POS	O
+131	POS	O
+HA	POS	O
+are	POS	O
+not	POS	O
+the	POS	O
+initiating	POS	O
+factor	POS	O
+in	POS	O
+doxorubicin	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+Hemodynamics	POS	O
+and	POS	O
+myocardial	POS	O
+metabolism	POS	O
+under	POS	O
+deliberate	POS	O
+hypotension	POS	B-NP
+.	POS	O
+An	POS	O
+experimental	POS	O
+study	POS	O
+in	POS	O
+dogs	POS	O
+.	POS	O
+Coronary	POS	O
+blood	POS	O
+flow	POS	O
+,	POS	O
+cardiac	POS	O
+work	POS	O
+and	POS	O
+metabolism	POS	O
+were	POS	O
+studied	POS	O
+in	POS	O
+dogs	POS	O
+under	POS	O
+sodium	POS	O
+nitroprusside	POS	O
+(	POS	O
+SNP	POS	O
+)	POS	O
+and	POS	O
+trimetaphan	POS	O
+(	POS	O
+TMP	POS	O
+)	POS	O
+deliberate	POS	O
+hypotension	POS	B-NP
+(	POS	O
+20	POS	O
+%	POS	O
+and	POS	O
+40	POS	O
+%	POS	O
+mean	POS	O
+pressure	POS	O
+decrease	POS	O
+from	POS	O
+baseline	POS	O
+)	POS	O
+.	POS	O
+Regarding	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+on	POS	O
+coronary	POS	O
+blood	POS	O
+flow	POS	O
+,	POS	O
+aortic	POS	O
+and	POS	O
+coronary	POS	O
+sinus	POS	O
+metabolic	POS	O
+data	POS	O
+(	POS	O
+pH	POS	O
+,	POS	O
+pO2	POS	O
+,	POS	O
+pCO2	POS	O
+)	POS	O
+we	POS	O
+could	POS	O
+confirm	POS	O
+that	POS	O
+nitroprusside	POS	O
+hypotension	POS	B-NP
+could	POS	O
+be	POS	O
+safely	POS	O
+used	POS	O
+to	POS	O
+30	POS	O
+%	POS	O
+mean	POS	O
+blood	POS	O
+pressure	POS	O
+decrease	POS	O
+from	POS	O
+control	POS	O
+,	POS	O
+trimetaphan	POS	O
+hypotension	POS	B-NP
+to	POS	O
+20	POS	O
+%	POS	O
+mean	POS	O
+blood	POS	O
+pressure	POS	O
+decrease	POS	O
+.	POS	O
+Cardiac	POS	O
+work	POS	O
+was	POS	O
+significantly	POS	O
+reduced	POS	O
+during	POS	O
+SNP	POS	O
+hypotension	POS	B-NP
+.	POS	O
+Myocardial	POS	O
+O2	POS	O
+consumption	POS	O
+and	POS	O
+O2	POS	O
+availability	POS	O
+were	POS	O
+directly	POS	O
+dependent	POS	O
+on	POS	O
+the	POS	O
+coronary	POS	O
+perfusion	POS	O
+.	POS	O
+Careful	POS	O
+invasive	POS	O
+monitoring	POS	O
+of	POS	O
+the	POS	O
+blood	POS	O
+pressure	POS	O
+,	POS	O
+blood	POS	O
+gases	POS	O
+and	POS	O
+of	POS	O
+the	POS	O
+ECG	POS	O
+ST	POS	O
+-	POS	O
+T	POS	O
+segment	POS	O
+is	POS	O
+mandatory	POS	O
+.	POS	O
+Evidence	POS	O
+for	POS	O
+a	POS	O
+selective	POS	O
+brain	POS	O
+noradrenergic	POS	O
+involvement	POS	O
+in	POS	O
+the	POS	O
+locomotor	POS	O
+stimulant	POS	O
+effects	POS	O
+of	POS	O
+amphetamine	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+.	POS	O
+Male	POS	O
+rats	POS	O
+received	POS	O
+the	POS	O
+noradrenaline	POS	O
+neurotoxin	POS	O
+DSP4	POS	O
+(	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+7	POS	O
+days	POS	O
+prior	POS	O
+to	POS	O
+injection	POS	O
+of	POS	O
+D	POS	O
+-	POS	O
+amphetamine	POS	O
+(	POS	O
+10	POS	O
+or	POS	O
+40	POS	O
+mumol	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+hyperactivity	POS	B-NP
+induced	POS	O
+by	POS	O
+D	POS	O
+-	POS	O
+amphetamine	POS	O
+(	POS	O
+10	POS	O
+mumol	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+was	POS	O
+significantly	POS	O
+reduced	POS	O
+by	POS	O
+DSP4	POS	O
+pretreatment	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+increased	POS	O
+rearings	POS	O
+and	POS	O
+the	POS	O
+amphetamine	POS	O
+-	POS	O
+induced	POS	O
+stereotypies	POS	B-NP
+were	POS	O
+not	POS	O
+blocked	POS	O
+by	POS	O
+pretreatment	POS	O
+with	POS	O
+DSP4	POS	O
+.	POS	O
+The	POS	O
+reduction	POS	O
+of	POS	O
+amphetamine	POS	O
+hyperactivity	POS	B-NP
+induced	POS	O
+by	POS	O
+DSP4	POS	O
+was	POS	O
+blocked	POS	O
+by	POS	O
+pretreatment	POS	O
+with	POS	O
+the	POS	O
+noradrenaline	POS	O
+-	POS	O
+uptake	POS	O
+blocking	POS	O
+agent	POS	O
+,	POS	O
+desipramine	POS	O
+,	POS	O
+which	POS	O
+prevents	POS	O
+the	POS	O
+neurotoxic	POS	B-NP
+action	POS	O
+of	POS	O
+DSP4	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+results	POS	O
+suggest	POS	O
+a	POS	O
+selective	POS	O
+involvement	POS	O
+of	POS	O
+central	POS	O
+noradrenergic	POS	O
+neurones	POS	O
+in	POS	O
+the	POS	O
+locomotor	POS	O
+stimulant	POS	O
+effect	POS	O
+of	POS	O
+amphetamine	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+.	POS	O
+Accelerated	POS	O
+junctional	POS	O
+rhythms	POS	O
+during	POS	O
+oral	POS	O
+verapamil	POS	O
+therapy	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+examined	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+atrioventricular	POS	O
+(	POS	O
+AV	POS	O
+)	POS	O
+dissociation	POS	O
+and	POS	O
+accelerated	POS	O
+junctional	POS	O
+rhythms	POS	O
+in	POS	O
+59	POS	O
+patients	POS	O
+receiving	POS	O
+oral	POS	O
+verapamil	POS	O
+.	POS	O
+Accelerated	POS	O
+junctional	POS	O
+rhythms	POS	O
+and	POS	O
+AV	POS	O
+dissociation	POS	O
+were	POS	O
+frequent	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+supraventricular	POS	B-NP
+tachyarrhythmias	POS	I-NP
+,	POS	O
+particularly	POS	O
+AV	POS	B-NP
+nodal	POS	I-NP
+reentry	POS	I-NP
+.	POS	O
+Verapamil	POS	O
+administration	POS	O
+to	POS	O
+these	POS	O
+patients	POS	O
+led	POS	O
+to	POS	O
+an	POS	O
+asymptomatic	POS	O
+increase	POS	O
+in	POS	O
+activity	POS	O
+of	POS	O
+these	POS	O
+junctional	POS	O
+pacemakers	POS	O
+.	POS	O
+In	POS	O
+patients	POS	O
+with	POS	O
+various	POS	O
+chest	POS	B-NP
+pain	POS	I-NP
+syndromes	POS	I-NP
+,	POS	O
+verapamil	POS	O
+neither	POS	O
+increased	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+junctional	POS	O
+rhythms	POS	O
+nor	POS	O
+suppressed	POS	O
+their	POS	O
+role	POS	O
+as	POS	O
+escape	POS	O
+rhythms	POS	O
+under	POS	O
+physiologically	POS	O
+appropriate	POS	O
+circumstances	POS	O
+.	POS	O
+Interstrain	POS	O
+variation	POS	O
+in	POS	O
+acute	POS	O
+toxic	POS	O
+response	POS	O
+to	POS	O
+caffeine	POS	O
+among	POS	O
+inbred	POS	O
+mice	POS	O
+.	POS	O
+Acute	POS	O
+toxic	POS	O
+dosage	POS	O
+-	POS	O
+dependent	POS	O
+behavioral	POS	O
+effects	POS	O
+of	POS	O
+caffeine	POS	O
+were	POS	O
+compared	POS	O
+in	POS	O
+adult	POS	O
+males	POS	O
+from	POS	O
+seven	POS	O
+inbred	POS	O
+mouse	POS	O
+strains	POS	O
+(	POS	O
+A	POS	O
+/	POS	O
+J	POS	O
+,	POS	O
+BALB	POS	O
+/	POS	O
+cJ	POS	O
+,	POS	O
+CBA	POS	O
+/	POS	O
+J	POS	O
+,	POS	O
+C3H	POS	O
+/	POS	O
+HeJ	POS	O
+,	POS	O
+C57BL	POS	O
+/	POS	O
+6J	POS	O
+,	POS	O
+DBA	POS	O
+/	POS	O
+2J	POS	O
+,	POS	O
+SWR	POS	O
+/	POS	O
+J	POS	O
+)	POS	O
+.	POS	O
+C57BL	POS	O
+/	POS	O
+6J	POS	O
+,	POS	O
+chosen	POS	O
+as	POS	O
+a	POS	O
+"	POS	O
+prototypic	POS	O
+"	POS	O
+mouse	POS	O
+strain	POS	O
+,	POS	O
+was	POS	O
+used	POS	O
+to	POS	O
+determine	POS	O
+behavioral	POS	O
+responses	POS	O
+to	POS	O
+a	POS	O
+broad	POS	O
+range	POS	O
+(	POS	O
+5	POS	O
+-	POS	O
+500	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+of	POS	O
+caffeine	POS	O
+doses	POS	O
+.	POS	O
+Five	POS	O
+phenotypic	POS	O
+characteristics	POS	O
+-	POS	O
+-	POS	O
+locomotor	POS	O
+activity	POS	O
+,	POS	O
+righting	POS	O
+ability	POS	O
+,	POS	O
+clonic	POS	O
+seizure	POS	B-NP
+induction	POS	O
+,	POS	O
+stress	POS	B-NP
+-	POS	I-NP
+induced	POS	I-NP
+lethality	POS	I-NP
+,	POS	O
+death	POS	B-NP
+without	POS	O
+external	POS	O
+stress	POS	O
+-	POS	O
+-	POS	O
+were	POS	O
+scored	POS	O
+at	POS	O
+various	POS	O
+caffeine	POS	O
+doses	POS	O
+in	POS	O
+drug	POS	O
+-	POS	O
+naive	POS	O
+animals	POS	O
+under	POS	O
+empirically	POS	O
+optimized	POS	O
+,	POS	O
+rigidly	POS	O
+constant	POS	O
+experimental	POS	O
+conditions	POS	O
+.	POS	O
+Mice	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+12	POS	O
+for	POS	O
+each	POS	O
+point	POS	O
+)	POS	O
+received	POS	O
+single	POS	O
+IP	POS	O
+injections	POS	O
+of	POS	O
+a	POS	O
+fixed	POS	O
+volume	POS	O
+/	POS	O
+g	POS	O
+body	POS	O
+weight	POS	O
+of	POS	O
+physiological	POS	O
+saline	POS	O
+carrier	POS	O
+with	POS	O
+or	POS	O
+without	POS	O
+caffeine	POS	O
+in	POS	O
+doses	POS	O
+ranging	POS	O
+from	POS	O
+125	POS	O
+-	POS	O
+500	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+Loss	POS	O
+of	POS	O
+righting	POS	O
+ability	POS	O
+was	POS	O
+scored	POS	O
+at	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+,	POS	O
+5	POS	O
+min	POS	O
+post	POS	O
+dosing	POS	O
+and	POS	O
+at	POS	O
+5	POS	O
+min	POS	O
+intervals	POS	O
+thereafter	POS	O
+for	POS	O
+20	POS	O
+min	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+same	POS	O
+animals	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+clonic	POS	B-NP
+seizures	POS	B-NP
+was	POS	O
+scored	POS	O
+as	POS	O
+to	POS	O
+time	POS	O
+of	POS	O
+onset	POS	O
+and	POS	O
+severity	POS	O
+for	POS	O
+20	POS	O
+min	POS	O
+after	POS	O
+drug	POS	O
+administration	POS	O
+.	POS	O
+When	POS	O
+these	POS	O
+proceeded	POS	O
+to	POS	O
+tonic	POS	O
+seizures	POS	B-NP
+,	POS	O
+death	POS	B-NP
+occurred	POS	O
+in	POS	O
+less	POS	O
+than	POS	O
+20	POS	O
+min	POS	O
+.	POS	O
+Animals	POS	O
+surviving	POS	O
+for	POS	O
+20	POS	O
+min	POS	O
+were	POS	O
+immediately	POS	O
+stressed	POS	O
+by	POS	O
+a	POS	O
+swim	POS	O
+test	POS	O
+in	POS	O
+25	POS	O
+degrees	POS	O
+C	POS	O
+water	POS	O
+,	POS	O
+and	POS	O
+death	POS	O
+-	POS	O
+producing	POS	O
+tonic	POS	O
+seizures	POS	B-NP
+were	POS	O
+scored	POS	O
+for	POS	O
+2	POS	O
+min	POS	O
+.	POS	O
+In	POS	O
+other	POS	O
+animals	POS	O
+locomotor	POS	O
+activity	POS	O
+was	POS	O
+measured	POS	O
+15	POS	O
+or	POS	O
+60	POS	O
+min	POS	O
+after	POS	O
+caffeine	POS	O
+administration	POS	O
+.	POS	O
+By	POS	O
+any	POS	O
+single	POS	O
+behavioral	POS	O
+criterion	POS	O
+or	POS	O
+a	POS	O
+combination	POS	O
+of	POS	O
+these	POS	O
+criteria	POS	O
+,	POS	O
+marked	POS	O
+differences	POS	O
+in	POS	O
+response	POS	O
+to	POS	O
+toxic	POS	O
+caffeine	POS	O
+doses	POS	O
+were	POS	O
+observed	POS	O
+between	POS	O
+strains	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+behavioral	POS	B-NP
+toxicity	POS	I-NP
+testing	POS	O
+of	POS	O
+alkylxanthines	POS	O
+in	POS	O
+a	POS	O
+single	POS	O
+mouse	POS	O
+strain	POS	O
+may	POS	O
+be	POS	O
+misleading	POS	O
+and	POS	O
+suggest	POS	O
+that	POS	O
+toxic	POS	O
+responses	POS	O
+of	POS	O
+the	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+to	POS	O
+this	POS	O
+class	POS	O
+of	POS	O
+compounds	POS	O
+are	POS	O
+genetically	POS	O
+influenced	POS	O
+in	POS	O
+mammals	POS	O
+.	POS	O
+Treatment	POS	O
+of	POS	O
+ovarian	POS	B-NP
+cancer	POS	I-NP
+with	POS	O
+a	POS	O
+combination	POS	O
+of	POS	O
+cis	POS	O
+-	POS	O
+platinum	POS	O
+,	POS	O
+adriamycin	POS	O
+,	POS	O
+cyclophosphamide	POS	O
+and	POS	O
+hexamethylmelamine	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+last	POS	O
+2	POS	O
+1	POS	O
+/	POS	O
+2	POS	O
+years	POS	O
+,	POS	O
+38	POS	O
+patients	POS	O
+with	POS	O
+ovarian	POS	B-NP
+cancer	POS	I-NP
+were	POS	O
+treated	POS	O
+with	POS	O
+a	POS	O
+combination	POS	O
+of	POS	O
+cisplatinum	POS	O
+(	POS	O
+CPDD	POS	O
+)	POS	O
+,	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+,	POS	O
+adriamycin	POS	O
+,	POS	O
+30	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+,	POS	O
+cyclophosphamide	POS	O
+,	POS	O
+300	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+,	POS	O
+on	POS	O
+day	POS	O
+1	POS	O
+;	POS	O
+and	POS	O
+hexamethylmelamine	POS	O
+(	POS	O
+HMM	POS	O
+)	POS	O
+,	POS	O
+6	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+daily	POS	O
+,	POS	O
+for	POS	O
+14	POS	O
+days	POS	O
+.	POS	O
+Each	POS	O
+course	POS	O
+was	POS	O
+repeated	POS	O
+monthly	POS	O
+.	POS	O
+2	POS	O
+patients	POS	O
+had	POS	O
+stage	POS	O
+II	POS	O
+,	POS	O
+14	POS	O
+stage	POS	O
+III	POS	O
+and	POS	O
+22	POS	O
+stage	POS	O
+IV	POS	O
+disease	POS	O
+.	POS	O
+14	POS	O
+of	POS	O
+the	POS	O
+38	POS	O
+patients	POS	O
+were	POS	O
+previously	POS	O
+treated	POS	O
+with	POS	O
+chemotherapy	POS	O
+,	POS	O
+1	POS	O
+with	POS	O
+radiation	POS	O
+,	POS	O
+6	POS	O
+with	POS	O
+both	POS	O
+chemotherapy	POS	O
+and	POS	O
+radiation	POS	O
+,	POS	O
+and	POS	O
+17	POS	O
+did	POS	O
+not	POS	O
+have	POS	O
+any	POS	O
+treatment	POS	O
+before	POS	O
+CPDD	POS	B-NP
+combination	POS	O
+.	POS	O
+31	POS	O
+of	POS	O
+the	POS	O
+38	POS	O
+cases	POS	O
+(	POS	O
+81	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+demonstrated	POS	O
+objective	POS	O
+responses	POS	O
+lasting	POS	O
+for	POS	O
+2	POS	O
+months	POS	O
+or	POS	O
+more	POS	O
+.	POS	O
+These	POS	O
+responses	POS	O
+were	POS	O
+partial	POS	O
+in	POS	O
+19	POS	O
+and	POS	O
+complete	POS	O
+in	POS	O
+12	POS	O
+cases	POS	O
+.	POS	O
+Hematologic	POS	B-NP
+toxicity	POS	I-NP
+was	POS	O
+moderate	POS	O
+and	POS	O
+with	POS	O
+reversible	POS	O
+anemia	POS	B-NP
+developing	POS	O
+in	POS	O
+71	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+.	POS	O
+Gastrointestinal	POS	B-NP
+side	POS	I-NP
+effects	POS	I-NP
+from	POS	O
+CPDD	POS	B-NP
+were	POS	O
+universal	POS	O
+.	POS	O
+HMM	POS	O
+gastrointestinal	POS	B-NP
+toxicity	POS	I-NP
+necessitated	POS	O
+discontinuation	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+in	POS	O
+5	POS	O
+patients	POS	O
+.	POS	O
+Severe	POS	O
+nephrotoxicity	POS	B-NP
+was	POS	O
+observed	POS	O
+in	POS	O
+2	POS	O
+patients	POS	O
+but	POS	O
+was	POS	O
+reversible	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+no	POS	O
+drug	POS	O
+-	POS	O
+related	POS	O
+deaths	POS	O
+.	POS	O
+Nontraumatic	POS	B-NP
+dissecting	POS	I-NP
+aneurysm	POS	I-NP
+of	POS	I-NP
+the	POS	I-NP
+basilar	POS	I-NP
+artery	POS	I-NP
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+nontraumatic	POS	O
+dissecting	POS	O
+aneurysm	POS	B-NP
+of	POS	O
+the	POS	O
+basilar	POS	O
+artery	POS	O
+in	POS	O
+association	POS	O
+with	POS	O
+hypertension	POS	B-NP
+,	POS	O
+smoke	POS	O
+,	POS	O
+and	POS	O
+oral	POS	O
+contraceptives	POS	O
+is	POS	O
+reported	POS	O
+in	POS	O
+a	POS	O
+young	POS	O
+female	POS	O
+patient	POS	O
+with	POS	O
+a	POS	O
+locked	POS	O
+-	POS	O
+in	POS	O
+syndrome	POS	O
+.	POS	O
+A	POS	O
+method	POS	O
+for	POS	O
+the	POS	O
+measurement	POS	O
+of	POS	O
+tremor	POS	B-NP
+,	POS	O
+and	POS	O
+a	POS	O
+comparison	POS	O
+of	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+tocolytic	POS	O
+beta	POS	O
+-	POS	O
+mimetics	POS	O
+.	POS	O
+A	POS	O
+method	POS	O
+permitting	POS	O
+measurement	POS	O
+of	POS	O
+finger	POS	O
+tremor	POS	O
+as	POS	O
+a	POS	O
+displacement	POS	O
+-	POS	O
+time	POS	O
+curve	POS	O
+is	POS	O
+described	POS	O
+,	POS	O
+using	POS	O
+a	POS	O
+test	POS	O
+system	POS	O
+with	POS	O
+simple	POS	O
+amplitude	POS	O
+calibration	POS	O
+.	POS	O
+The	POS	O
+coordinates	POS	O
+of	POS	O
+the	POS	O
+inversion	POS	O
+points	POS	O
+of	POS	O
+the	POS	O
+displacement	POS	O
+-	POS	O
+time	POS	O
+curves	POS	O
+were	POS	O
+transferred	POS	O
+through	POS	O
+graphical	POS	O
+input	POS	O
+equipment	POS	O
+to	POS	O
+punched	POS	O
+tape	POS	O
+.	POS	O
+By	POS	O
+means	POS	O
+of	POS	O
+a	POS	O
+computer	POS	O
+program	POS	O
+,	POS	O
+periods	POS	O
+and	POS	O
+amplitudes	POS	O
+of	POS	O
+tremor	POS	B-NP
+oscillations	POS	O
+were	POS	O
+calculated	POS	O
+and	POS	O
+classified	POS	O
+.	POS	O
+The	POS	O
+event	POS	O
+frequency	POS	O
+for	POS	O
+each	POS	O
+class	POS	O
+of	POS	O
+periods	POS	O
+and	POS	O
+amplitudes	POS	O
+was	POS	O
+determined	POS	O
+.	POS	O
+The	POS	O
+actions	POS	O
+of	POS	O
+fenoterol	POS	O
+-	POS	O
+hydrobromide	POS	O
+,	POS	O
+ritodrin	POS	O
+-	POS	O
+HCl	POS	O
+and	POS	O
+placebo	POS	O
+given	POS	O
+to	POS	O
+10	POS	O
+healthy	POS	O
+subjects	POS	O
+by	POS	O
+intravenous	POS	O
+infusion	POS	O
+in	POS	O
+a	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+crossover	POS	O
+study	POS	O
+were	POS	O
+tested	POS	O
+by	POS	O
+this	POS	O
+method	POS	O
+.	POS	O
+At	POS	O
+therapeutic	POS	O
+doses	POS	O
+both	POS	O
+substances	POS	O
+raised	POS	O
+the	POS	O
+mean	POS	O
+tremor	POS	B-NP
+amplitude	POS	O
+to	POS	O
+about	POS	O
+three	POS	O
+times	POS	O
+the	POS	O
+control	POS	O
+level	POS	O
+.	POS	O
+At	POS	O
+the	POS	O
+same	POS	O
+time	POS	O
+,	POS	O
+the	POS	O
+mean	POS	O
+period	POS	O
+within	POS	O
+each	POS	O
+class	POS	O
+of	POS	O
+amplitudes	POS	O
+shortened	POS	O
+by	POS	O
+10	POS	O
+-	POS	O
+-	POS	O
+20	POS	O
+ms	POS	O
+,	POS	O
+whereas	POS	O
+the	POS	O
+mean	POS	O
+periods	POS	O
+calculated	POS	O
+from	POS	O
+all	POS	O
+oscillations	POS	O
+together	POS	O
+did	POS	O
+not	POS	O
+change	POS	O
+significantly	POS	O
+.	POS	O
+After	POS	O
+the	POS	O
+end	POS	O
+of	POS	O
+fenoterol	POS	O
+-	POS	O
+hydrobromide	POS	O
+infusion	POS	O
+,	POS	O
+tremor	POS	B-NP
+amplitudes	POS	O
+decreased	POS	O
+significantly	POS	O
+faster	POS	O
+than	POS	O
+those	POS	O
+following	POS	O
+ritodrin	POS	O
+-	POS	O
+HCl	POS	O
+infusion	POS	O
+.	POS	O
+Propylthiouracil	POS	O
+-	POS	O
+induced	POS	O
+hepatic	POS	B-NP
+damage	POS	I-NP
+.	POS	O
+Two	POS	O
+cases	POS	O
+of	POS	O
+propylthiouracil	POS	O
+-	POS	O
+induced	POS	O
+liver	POS	B-NP
+damage	POS	I-NP
+have	POS	O
+been	POS	O
+observed	POS	O
+.	POS	O
+The	POS	O
+first	POS	O
+case	POS	O
+is	POS	O
+of	POS	O
+an	POS	O
+acute	POS	O
+type	POS	O
+of	POS	O
+damage	POS	O
+,	POS	O
+proven	POS	O
+by	POS	O
+rechallenge	POS	O
+;	POS	O
+the	POS	O
+second	POS	O
+presents	POS	O
+a	POS	O
+clinical	POS	O
+and	POS	O
+histologic	POS	O
+picture	POS	O
+resembling	POS	O
+chronic	POS	O
+active	POS	O
+hepatitis	POS	B-NP
+,	POS	O
+with	POS	O
+spontaneous	POS	O
+remission	POS	O
+.	POS	O
+Studies	POS	O
+on	POS	O
+the	POS	O
+bradycardia	POS	B-NP
+induced	POS	O
+by	POS	O
+bepridil	POS	O
+.	POS	O
+Bepridil	POS	O
+,	POS	O
+a	POS	O
+novel	POS	O
+active	POS	O
+compound	POS	O
+for	POS	O
+prophylactic	POS	O
+treatment	POS	O
+of	POS	O
+anginal	POS	B-NP
+attacks	POS	I-NP
+,	POS	O
+induced	POS	O
+persistent	POS	O
+bradycardia	POS	B-NP
+and	POS	O
+a	POS	O
+non	POS	O
+-	POS	O
+specific	POS	O
+anti	POS	O
+-	POS	O
+tachycardial	POS	O
+effect	POS	O
+,	POS	O
+the	POS	O
+mechanisms	POS	O
+of	POS	O
+which	POS	O
+were	POS	O
+investigated	POS	O
+in	POS	O
+vitro	POS	O
+and	POS	O
+in	POS	O
+vivo	POS	O
+.	POS	O
+In	POS	O
+vitro	POS	O
+perfusion	POS	O
+of	POS	O
+bepridil	POS	O
+in	POS	O
+the	POS	O
+life	POS	O
+-	POS	O
+support	POS	O
+medium	POS	O
+for	POS	O
+isolated	POS	O
+sino	POS	O
+-	POS	O
+atrial	POS	O
+tissue	POS	O
+from	POS	O
+rabbit	POS	O
+heart	POS	O
+,	POS	O
+caused	POS	O
+a	POS	O
+reduction	POS	O
+in	POS	O
+action	POS	O
+potential	POS	O
+(	POS	O
+AP	POS	O
+)	POS	O
+spike	POS	O
+frequency	POS	O
+(	POS	O
+recorded	POS	O
+by	POS	O
+KCl	POS	O
+microelectrodes	POS	O
+)	POS	O
+starting	POS	O
+at	POS	O
+doses	POS	O
+of	POS	O
+5	POS	O
+X	POS	O
+10	POS	O
+(	POS	O
+-	POS	O
+6	POS	O
+)	POS	O
+M	POS	O
+.	POS	O
+This	POS	O
+effect	POS	O
+was	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+up	POS	O
+to	POS	O
+concentrations	POS	O
+of	POS	O
+5	POS	O
+X	POS	O
+10	POS	O
+(	POS	O
+-	POS	O
+5	POS	O
+)	POS	O
+M	POS	O
+,	POS	O
+whereupon	POS	O
+blockade	POS	O
+of	POS	O
+sinus	POS	O
+activity	POS	O
+set	POS	O
+in	POS	O
+.	POS	O
+Bepridil	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+5	POS	O
+X	POS	O
+10	POS	O
+(	POS	O
+-	POS	O
+6	POS	O
+)	POS	O
+M	POS	O
+,	POS	O
+induced	POS	O
+a	POS	O
+concomitant	POS	O
+reduction	POS	O
+in	POS	O
+AP	POS	O
+amplitude	POS	O
+(	POS	O
+falling	POS	O
+from	POS	O
+71	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+8	POS	O
+mV	POS	O
+to	POS	O
+47	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+mV	POS	O
+)	POS	O
+,	POS	O
+maximum	POS	O
+systolic	POS	O
+depolarization	POS	O
+velocity	POS	O
+(	POS	O
+phase	POS	O
+0	POS	O
+)	POS	O
+which	POS	O
+fell	POS	O
+from	POS	O
+1	POS	O
+.	POS	O
+85	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+35	POS	O
+V	POS	O
+/	POS	O
+s	POS	O
+to	POS	O
+0	POS	O
+.	POS	O
+84	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+28	POS	O
+V	POS	O
+/	POS	O
+s	POS	O
+,	POS	O
+together	POS	O
+with	POS	O
+maximum	POS	O
+diastolic	POS	O
+depolarization	POS	O
+velocity	POS	O
+(	POS	O
+phase	POS	O
+4	POS	O
+)	POS	O
+which	POS	O
+fell	POS	O
+from	POS	O
+38	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+3	POS	O
+mV	POS	O
+/	POS	O
+s	POS	O
+to	POS	O
+24	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+5	POS	O
+mV	POS	O
+/	POS	O
+s	POS	O
+.	POS	O
+In	POS	O
+vivo	POS	O
+injection	POS	O
+of	POS	O
+bepridil	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+)	POS	O
+into	POS	O
+6	POS	O
+anaesthetized	POS	O
+dogs	POS	O
+which	POS	O
+had	POS	O
+undergone	POS	O
+ablation	POS	O
+of	POS	O
+all	POS	O
+the	POS	O
+extrinsic	POS	O
+cardiac	POS	O
+afferent	POS	O
+nerve	POS	O
+supply	POS	O
+,	POS	O
+together	POS	O
+with	POS	O
+a	POS	O
+bilateral	POS	O
+medullo	POS	O
+-	POS	O
+adrenalectomy	POS	O
+,	POS	O
+caused	POS	O
+a	POS	O
+marked	POS	O
+reduction	POS	O
+in	POS	O
+heart	POS	O
+rate	POS	O
+which	POS	O
+fell	POS	O
+from	POS	O
+98	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+2	POS	O
+beats	POS	O
+/	POS	O
+min	POS	O
+to	POS	O
+76	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+5	POS	O
+.	POS	O
+3	POS	O
+beats	POS	O
+/	POS	O
+min	POS	O
+sustained	POS	O
+for	POS	O
+more	POS	O
+than	POS	O
+45	POS	O
+min	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+concluded	POS	O
+that	POS	O
+bepridil	POS	O
+reduces	POS	O
+heart	POS	O
+rate	POS	O
+by	POS	O
+acting	POS	O
+directly	POS	O
+on	POS	O
+the	POS	O
+sinus	POS	O
+node	POS	O
+.	POS	O
+This	POS	O
+effect	POS	O
+,	POS	O
+which	POS	O
+results	POS	O
+in	POS	O
+a	POS	O
+flattening	POS	O
+of	POS	O
+the	POS	O
+phase	POS	O
+0	POS	O
+and	POS	O
+phase	POS	O
+4	POS	O
+slope	POS	O
+,	POS	O
+together	POS	O
+with	POS	O
+a	POS	O
+longer	POS	O
+AP	POS	O
+duration	POS	O
+,	POS	O
+may	POS	O
+be	POS	O
+due	POS	O
+to	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+time	POS	O
+constants	POS	O
+of	POS	O
+slow	POS	O
+inward	POS	O
+ionic	POS	O
+currents	POS	O
+(	POS	O
+already	POS	O
+demonstrated	POS	O
+elsewhere	POS	O
+)	POS	O
+,	POS	O
+but	POS	O
+also	POS	O
+to	POS	O
+an	POS	O
+increased	POS	O
+time	POS	O
+constant	POS	O
+for	POS	O
+deactivation	POS	O
+of	POS	O
+the	POS	O
+outward	POS	O
+potassium	POS	O
+current	POS	O
+(	POS	O
+Ip	POS	O
+)	POS	O
+.	POS	O
+Hepatitis	POS	B-NP
+and	POS	I-NP
+renal	POS	I-NP
+tubular	POS	I-NP
+acidosis	POS	I-NP
+after	POS	O
+anesthesia	POS	O
+with	POS	O
+methoxyflurane	POS	O
+.	POS	O
+A	POS	O
+69	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+operated	POS	O
+for	POS	O
+acute	POS	B-NP
+cholecystitis	POS	I-NP
+under	POS	O
+methoxyflurane	POS	O
+anesthesia	POS	O
+developed	POS	O
+postoperatively	POS	O
+a	POS	O
+hepatic	POS	B-NP
+insufficiency	POS	I-NP
+syndrome	POS	I-NP
+and	POS	O
+renal	POS	B-NP
+tubular	POS	I-NP
+acidosis	POS	I-NP
+.	POS	O
+Massive	POS	B-NP
+bleeding	POS	I-NP
+appeared	POS	O
+during	POS	O
+surgery	POS	O
+which	POS	O
+lasted	POS	O
+for	POS	O
+six	POS	O
+hours	POS	O
+.	POS	O
+Postoperative	POS	O
+evolution	POS	O
+under	POS	O
+supportive	POS	O
+therapy	POS	O
+was	POS	O
+favourable	POS	O
+.	POS	O
+Complete	POS	O
+recovery	POS	O
+was	POS	O
+confirmed	POS	O
+by	POS	O
+repeated	POS	O
+controls	POS	O
+performed	POS	O
+over	POS	O
+a	POS	O
+period	POS	O
+of	POS	O
+one	POS	O
+year	POS	O
+after	POS	O
+surgery	POS	O
+.	POS	O
+Pituitary	POS	O
+response	POS	O
+to	POS	O
+luteinizing	POS	O
+hormone	POS	O
+-	POS	O
+releasing	POS	O
+hormone	POS	O
+during	POS	O
+haloperidol	POS	O
+-	POS	O
+induced	POS	O
+hyperprolactinemia	POS	B-NP
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+a	POS	O
+6	POS	O
+-	POS	O
+hour	POS	O
+infusion	POS	O
+with	POS	O
+haloperidol	POS	O
+on	POS	O
+serum	POS	O
+prolactin	POS	O
+and	POS	O
+luteinizing	POS	O
+hormone	POS	O
+(	POS	O
+LH	POS	O
+)	POS	O
+levels	POS	O
+was	POS	O
+studied	POS	O
+in	POS	O
+a	POS	O
+group	POS	O
+of	POS	O
+male	POS	O
+subjects	POS	O
+.	POS	O
+Five	POS	O
+hours	POS	O
+after	POS	O
+starting	POS	O
+the	POS	O
+infusions	POS	O
+,	POS	O
+a	POS	O
+study	POS	O
+of	POS	O
+the	POS	O
+pituitary	POS	O
+responses	POS	O
+to	POS	O
+LH	POS	O
+-	POS	O
+releasing	POS	O
+hormone	POS	O
+(	POS	O
+LH	POS	O
+-	POS	O
+RH	POS	O
+)	POS	O
+was	POS	O
+carried	POS	O
+out	POS	O
+.	POS	O
+Control	POS	O
+patients	POS	O
+received	POS	O
+infusions	POS	O
+of	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+NaCl	POS	O
+solution	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+course	POS	O
+of	POS	O
+haloperidol	POS	O
+infusions	POS	O
+,	POS	O
+significant	POS	O
+hyperprolactinemia	POS	B-NP
+was	POS	O
+found	POS	O
+,	POS	O
+together	POS	O
+with	POS	O
+an	POS	O
+abolished	POS	O
+pituitary	POS	O
+response	POS	O
+to	POS	O
+LH	POS	O
+-	POS	O
+RH	POS	O
+,	POS	O
+as	POS	O
+compared	POS	O
+with	POS	O
+responses	POS	O
+of	POS	O
+control	POS	O
+subjects	POS	O
+.	POS	O
+Antirifampicin	POS	O
+antibodies	POS	O
+in	POS	O
+acute	POS	O
+rifampicin	POS	O
+-	POS	O
+associated	POS	O
+renal	POS	B-NP
+failure	POS	I-NP
+.	POS	O
+5	POS	O
+patients	POS	O
+with	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+(	POS	O
+3	POS	O
+with	POS	O
+thrombopenia	POS	B-NP
+and	POS	O
+hemolysis	POS	B-NP
+)	POS	O
+induced	POS	O
+by	POS	O
+the	POS	O
+reintroduction	POS	O
+of	POS	O
+rifampicin	POS	O
+are	POS	O
+described	POS	O
+.	POS	O
+No	POS	O
+correlation	POS	O
+was	POS	O
+found	POS	O
+between	POS	O
+the	POS	O
+severity	POS	O
+of	POS	O
+clinical	POS	O
+manifestations	POS	O
+and	POS	O
+the	POS	O
+total	POS	O
+dose	POS	O
+taken	POS	O
+by	POS	O
+the	POS	O
+patients	POS	O
+.	POS	O
+In	POS	O
+all	POS	O
+but	POS	O
+1	POS	O
+patient	POS	O
+,	POS	O
+antirifampicin	POS	O
+antibodies	POS	O
+were	POS	O
+detected	POS	O
+.	POS	O
+Antibodies	POS	O
+suggested	POS	O
+to	POS	O
+be	POS	O
+of	POS	O
+the	POS	O
+IgM	POS	O
+class	POS	O
+were	POS	O
+detected	POS	O
+in	POS	O
+all	POS	O
+3	POS	O
+patients	POS	O
+with	POS	O
+hematological	POS	B-NP
+disorders	POS	I-NP
+.	POS	O
+The	POS	O
+pattern	POS	O
+of	POS	O
+non	POS	O
+-	POS	O
+specific	POS	O
+acute	POS	O
+tubular	POS	O
+necrosis	POS	B-NP
+found	POS	O
+in	POS	O
+the	POS	O
+2	POS	O
+biopsied	POS	O
+patients	POS	O
+,	POS	O
+indistinguishable	POS	O
+from	POS	O
+that	POS	O
+of	POS	O
+ischemic	POS	O
+origin	POS	O
+,	POS	O
+raised	POS	O
+the	POS	O
+possibility	POS	O
+of	POS	O
+a	POS	O
+vascular	POS	B-NP
+-	POS	I-NP
+mediated	POS	I-NP
+damage	POS	I-NP
+.	POS	O
+In	POS	O
+3	POS	O
+patients	POS	O
+,	POS	O
+the	POS	O
+possibility	POS	O
+of	POS	O
+a	POS	O
+triggering	POS	O
+immunoallergic	POS	O
+mechanism	POS	O
+is	POS	O
+discussed	POS	O
+.	POS	O
+Cardiovascular	POS	O
+effects	POS	O
+of	POS	O
+hypotension	POS	B-NP
+induced	POS	O
+by	POS	O
+adenosine	POS	O
+triphosphate	POS	O
+and	POS	O
+sodium	POS	O
+nitroprusside	POS	O
+on	POS	O
+dogs	POS	O
+with	POS	O
+denervated	POS	O
+hearts	POS	O
+.	POS	O
+Adenosine	POS	O
+triphosphate	POS	O
+(	POS	O
+ATP	POS	O
+)	POS	O
+and	POS	O
+sodium	POS	O
+nitroprusside	POS	O
+(	POS	O
+SNP	POS	O
+)	POS	O
+are	POS	O
+administered	POS	O
+to	POS	O
+patients	POS	O
+to	POS	O
+induce	POS	O
+and	POS	O
+control	POS	O
+hypotension	POS	B-NP
+during	POS	O
+anesthesia	POS	O
+.	POS	O
+SNP	POS	O
+is	POS	O
+authorized	POS	O
+for	POS	O
+clinical	POS	O
+use	POS	O
+in	POS	O
+USA	POS	O
+and	POS	O
+UK	POS	O
+,	POS	O
+and	POS	O
+ATP	POS	O
+is	POS	O
+clinically	POS	O
+used	POS	O
+in	POS	O
+other	POS	O
+countries	POS	O
+such	POS	O
+as	POS	O
+Japan	POS	O
+.	POS	O
+We	POS	O
+investigated	POS	O
+how	POS	O
+these	POS	O
+two	POS	O
+drugs	POS	O
+act	POS	O
+on	POS	O
+the	POS	O
+cardiovascular	POS	O
+systems	POS	O
+of	POS	O
+20	POS	O
+dogs	POS	O
+whose	POS	O
+hearts	POS	O
+had	POS	O
+been	POS	O
+denervated	POS	O
+by	POS	O
+a	POS	O
+procedure	POS	O
+we	POS	O
+had	POS	O
+devised	POS	O
+.	POS	O
+ATP	POS	O
+(	POS	O
+10	POS	O
+dogs	POS	O
+)	POS	O
+or	POS	O
+SNP	POS	O
+(	POS	O
+10	POS	O
+dogs	POS	O
+)	POS	O
+was	POS	O
+administered	POS	O
+to	POS	O
+reduce	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+by	POS	O
+30	POS	O
+%	POS	O
+to	POS	O
+70	POS	O
+%	POS	O
+of	POS	O
+control	POS	O
+.	POS	O
+Before	POS	O
+,	POS	O
+during	POS	O
+and	POS	O
+after	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+,	POS	O
+we	POS	O
+measured	POS	O
+major	POS	O
+cardiovascular	POS	O
+parameters	POS	O
+.	POS	O
+Hypotension	POS	B-NP
+induced	POS	O
+by	POS	O
+ATP	POS	O
+was	POS	O
+accompanied	POS	O
+by	POS	O
+significant	POS	O
+decreases	POS	O
+in	POS	O
+mean	POS	O
+pulmonary	POS	O
+arterial	POS	O
+pressure	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+central	POS	O
+venous	POS	O
+pressure	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+left	POS	O
+ventricular	POS	O
+end	POS	O
+-	POS	O
+diastolic	POS	O
+pressure	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+total	POS	O
+peripheral	POS	O
+resistance	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+rate	POS	O
+pressure	POS	O
+product	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+total	POS	O
+body	POS	O
+oxygen	POS	O
+consumption	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+heart	POS	O
+rate	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+;	POS	O
+all	POS	O
+these	POS	O
+variables	POS	O
+returned	POS	O
+normal	POS	O
+within	POS	O
+30	POS	O
+min	POS	O
+after	POS	O
+ATP	POS	O
+was	POS	O
+stopped	POS	O
+.	POS	O
+Cardiac	POS	O
+output	POS	O
+did	POS	O
+not	POS	O
+change	POS	O
+.	POS	O
+During	POS	O
+hypotension	POS	B-NP
+produced	POS	O
+by	POS	O
+SNP	POS	O
+similar	POS	O
+decreases	POS	O
+were	POS	O
+observed	POS	O
+in	POS	O
+mean	POS	O
+pulmonary	POS	O
+arterial	POS	O
+pressure	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+,	POS	O
+central	POS	O
+venous	POS	O
+pressure	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+left	POS	O
+ventricular	POS	O
+end	POS	O
+-	POS	O
+diastolic	POS	O
+pressure	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+,	POS	O
+total	POS	O
+peripheral	POS	O
+resistance	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+rate	POS	O
+pressure	POS	O
+product	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+oxygen	POS	O
+content	POS	O
+difference	POS	O
+between	POS	O
+arterial	POS	O
+and	POS	O
+mixed	POS	O
+venous	POS	O
+blood	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+,	POS	O
+while	POS	O
+heart	POS	O
+rate	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+and	POS	O
+cardiac	POS	O
+output	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+were	POS	O
+increased	POS	O
+.	POS	O
+Recoveries	POS	O
+of	POS	O
+heart	POS	O
+rate	POS	O
+and	POS	O
+left	POS	O
+ventricular	POS	O
+end	POS	O
+-	POS	O
+diastolic	POS	O
+pressure	POS	O
+were	POS	O
+not	POS	O
+shown	POS	O
+within	POS	O
+60	POS	O
+min	POS	O
+after	POS	O
+SNP	POS	O
+had	POS	O
+been	POS	O
+stopped	POS	O
+.	POS	O
+Both	POS	O
+ATP	POS	O
+and	POS	O
+SNP	POS	O
+should	POS	O
+act	POS	O
+on	POS	O
+the	POS	O
+pacemaker	POS	O
+tissue	POS	O
+of	POS	O
+the	POS	O
+heart	POS	O
+.	POS	O
+Comparative	POS	O
+study	POS	O
+:	POS	O
+Endografine	POS	O
+(	POS	O
+diatrizoate	POS	O
+)	POS	O
+,	POS	O
+Vasurix	POS	O
+polyvidone	POS	O
+(	POS	O
+acetrizoate	POS	O
+)	POS	O
+,	POS	O
+Dimer	POS	O
+-	POS	O
+X	POS	O
+(	POS	O
+iocarmate	POS	O
+)	POS	O
+and	POS	O
+Hexabrix	POS	O
+(	POS	O
+ioxaglate	POS	O
+)	POS	O
+in	POS	O
+hysterosalpingography	POS	O
+.	POS	O
+Side	POS	O
+effects	POS	O
+of	POS	O
+hysterosalpingography	POS	O
+with	POS	O
+Dimer	POS	O
+-	POS	O
+X	POS	O
+,	POS	O
+Hexabrix	POS	O
+,	POS	O
+Vasurix	POS	O
+polyvidone	POS	O
+and	POS	O
+Endografine	POS	O
+in	POS	O
+142	POS	O
+consecutive	POS	O
+patients	POS	O
+,	POS	O
+receiving	POS	O
+one	POS	O
+of	POS	O
+the	POS	O
+four	POS	O
+tested	POS	O
+media	POS	O
+were	POS	O
+evaluated	POS	O
+from	POS	O
+replies	POS	O
+to	POS	O
+postal	POS	O
+questionnaires	POS	O
+.	POS	O
+The	POS	O
+Dimer	POS	O
+-	POS	O
+X	POS	O
+group	POS	O
+had	POS	O
+a	POS	O
+higher	POS	O
+incidence	POS	O
+of	POS	O
+nausea	POS	B-NP
+and	POS	O
+dizziness	POS	B-NP
+.	POS	O
+The	POS	O
+Endografine	POS	O
+group	POS	O
+had	POS	O
+a	POS	O
+higher	POS	O
+incidence	POS	O
+of	POS	O
+abdominal	POS	B-NP
+pain	POS	I-NP
+.	POS	O
+These	POS	O
+differences	POS	O
+occur	POS	O
+especially	POS	O
+in	POS	O
+the	POS	O
+age	POS	O
+groups	POS	O
+under	POS	O
+30	POS	O
+years	POS	O
+.	POS	O
+Hexabrix	POS	O
+and	POS	O
+Vasurix	POS	O
+polyvidone	POS	O
+are	POS	O
+considered	POS	O
+the	POS	O
+best	POS	O
+contrast	POS	O
+media	POS	O
+for	POS	O
+hysterosalpingography	POS	O
+and	POS	O
+perhaps	POS	O
+because	POS	O
+of	POS	O
+its	POS	O
+low	POS	O
+toxicity	POS	O
+Hexabrix	POS	O
+should	POS	O
+be	POS	O
+preferred	POS	O
+.	POS	O
+Post	POS	O
+-	POS	O
+suxamethonium	POS	O
+pains	POS	O
+in	POS	O
+Nigerian	POS	O
+surgical	POS	O
+patients	POS	O
+.	POS	O
+Contrary	POS	O
+to	POS	O
+an	POS	O
+earlier	POS	O
+report	POS	O
+by	POS	O
+Coxon	POS	O
+,	POS	O
+scoline	POS	O
+pain	POS	B-NP
+occurs	POS	O
+in	POS	O
+African	POS	O
+negroes	POS	O
+.	POS	O
+Its	POS	O
+incidence	POS	O
+was	POS	O
+determined	POS	O
+in	POS	O
+a	POS	O
+prospective	POS	O
+study	POS	O
+involving	POS	O
+a	POS	O
+total	POS	O
+of	POS	O
+100	POS	O
+Nigerian	POS	O
+patients	POS	O
+(	POS	O
+50	POS	O
+out	POS	O
+-	POS	O
+patients	POS	O
+and	POS	O
+50	POS	O
+in	POS	O
+-	POS	O
+patients	POS	O
+)	POS	O
+.	POS	O
+About	POS	O
+62	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+out	POS	O
+-	POS	O
+patients	POS	O
+developed	POS	O
+scoline	POS	B-NP
+pain	POS	I-NP
+as	POS	O
+compared	POS	O
+with	POS	O
+about	POS	O
+26	POS	O
+%	POS	O
+among	POS	O
+the	POS	O
+in	POS	O
+-	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+abolition	POS	O
+of	POS	O
+muscle	POS	B-NP
+fasciculations	POS	I-NP
+(	POS	O
+by	POS	O
+0	POS	O
+.	POS	O
+075mg	POS	O
+/	POS	O
+kg	POS	O
+dose	POS	O
+of	POS	O
+Fazadinium	POS	O
+)	POS	O
+did	POS	O
+not	POS	O
+influence	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+scoline	POS	O
+pain	POS	B-NP
+.	POS	O
+Neither	POS	O
+the	POS	O
+type	POS	O
+of	POS	O
+induction	POS	O
+agent	POS	O
+(	POS	O
+Althesin	POS	O
+or	POS	O
+Thiopentone	POS	O
+)	POS	O
+nor	POS	O
+the	POS	O
+salt	POS	O
+preparation	POS	O
+of	POS	O
+suxamethonium	POS	O
+used	POS	O
+(	POS	O
+chloride	POS	O
+or	POS	O
+bromide	POS	O
+)	POS	O
+,	POS	O
+affected	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+scoline	POS	B-NP
+pain	POS	I-NP
+.	POS	O
+Invasive	POS	B-NP
+carcinoma	POS	I-NP
+of	POS	I-NP
+the	POS	I-NP
+renal	POS	I-NP
+pelvis	POS	I-NP
+following	POS	O
+cyclophosphamide	POS	O
+therapy	POS	O
+for	POS	O
+nonmalignant	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+A	POS	O
+47	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+with	POS	O
+right	POS	O
+hydroureteronephrosis	POS	B-NP
+due	POS	O
+to	POS	O
+ureterovesical	POS	B-NP
+junction	POS	I-NP
+obstruction	POS	I-NP
+had	POS	O
+gross	POS	O
+hematuria	POS	B-NP
+after	POS	O
+being	POS	O
+treated	POS	O
+for	POS	O
+five	POS	O
+years	POS	O
+wtih	POS	O
+cyclophosphamide	POS	O
+for	POS	O
+cerebral	POS	B-NP
+vasculitis	POS	I-NP
+.	POS	O
+A	POS	O
+right	POS	O
+nephroureterectomy	POS	O
+was	POS	O
+required	POS	O
+for	POS	O
+control	POS	O
+of	POS	O
+bleeding	POS	B-NP
+.	POS	O
+The	POS	O
+pathology	POS	O
+specimen	POS	O
+contained	POS	O
+clinically	POS	O
+occult	POS	O
+invasive	POS	O
+carcinoma	POS	B-NP
+of	POS	I-NP
+the	POS	I-NP
+renal	POS	I-NP
+pelvis	POS	I-NP
+.	POS	O
+Although	POS	O
+the	POS	O
+ability	POS	O
+of	POS	O
+cyclophosphamide	POS	O
+to	POS	O
+cause	POS	O
+hemorrhagic	POS	B-NP
+cystitis	POS	I-NP
+and	POS	O
+urine	POS	O
+cytologic	POS	O
+abnormalities	POS	O
+indistinguishable	POS	O
+from	POS	O
+high	POS	O
+grade	POS	O
+carcinoma	POS	B-NP
+is	POS	O
+well	POS	O
+known	POS	O
+,	POS	O
+it	POS	O
+is	POS	O
+less	POS	O
+widely	POS	O
+appreciated	POS	O
+that	POS	O
+it	POS	O
+is	POS	O
+also	POS	O
+associated	POS	O
+with	POS	O
+carcinoma	POS	B-NP
+of	POS	I-NP
+the	POS	I-NP
+urinary	POS	I-NP
+tract	POS	I-NP
+.	POS	O
+Twenty	POS	O
+carcinomas	POS	B-NP
+of	POS	O
+the	POS	O
+urinary	POS	O
+bladder	POS	O
+and	POS	O
+one	POS	O
+carcinoma	POS	B-NP
+of	POS	O
+the	POS	O
+prostate	POS	O
+have	POS	O
+been	POS	O
+reported	POS	O
+in	POS	O
+association	POS	O
+with	POS	O
+its	POS	O
+use	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+case	POS	O
+is	POS	O
+the	POS	O
+first	POS	O
+carcinoma	POS	B-NP
+of	POS	I-NP
+the	POS	I-NP
+renal	POS	I-NP
+pelvis	POS	I-NP
+reported	POS	O
+in	POS	O
+association	POS	O
+with	POS	O
+cyclophosphamide	POS	O
+treatment	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+the	POS	O
+third	POS	O
+urinary	POS	B-NP
+tract	POS	I-NP
+cancer	POS	I-NP
+reported	POS	O
+in	POS	O
+association	POS	O
+with	POS	O
+cyclophosphamide	POS	O
+treatment	POS	O
+for	POS	O
+nonmalignant	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+The	POS	O
+association	POS	O
+of	POS	O
+the	POS	O
+tumor	POS	B-NP
+with	POS	O
+preexisting	POS	O
+hydroureteronephrosis	POS	B-NP
+suggests	POS	O
+that	POS	O
+stasis	POS	O
+prolonged	POS	O
+and	POS	O
+intensified	POS	O
+exposure	POS	O
+of	POS	O
+upper	POS	O
+urinary	POS	O
+tract	POS	O
+epithelium	POS	O
+to	POS	O
+cyclophosphamide	POS	O
+.	POS	O
+Patients	POS	O
+who	POS	O
+are	POS	O
+candidates	POS	O
+for	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+cyclophosphamide	POS	O
+treatment	POS	O
+should	POS	O
+be	POS	O
+routinely	POS	O
+evaluated	POS	O
+for	POS	O
+obstructive	POS	B-NP
+uropathy	POS	I-NP
+.	POS	O
+Medial	POS	O
+changes	POS	O
+in	POS	O
+arterial	POS	B-NP
+spasm	POS	I-NP
+induced	POS	O
+by	POS	O
+L	POS	O
+-	POS	O
+norepinephrine	POS	O
+.	POS	O
+In	POS	O
+normal	POS	O
+rats	POS	O
+,	POS	O
+the	POS	O
+media	POS	O
+of	POS	O
+small	POS	O
+arteries	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+4	POS	O
+-	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+2	POS	O
+mm	POS	O
+in	POS	O
+diameter	POS	O
+)	POS	O
+previously	POS	O
+was	POS	O
+shown	POS	O
+to	POS	O
+contain	POS	O
+intracellular	POS	O
+vacuoles	POS	O
+,	POS	O
+identified	POS	O
+ultrastructurally	POS	O
+as	POS	O
+herniations	POS	O
+of	POS	O
+one	POS	O
+smooth	POS	O
+muscle	POS	O
+cell	POS	O
+into	POS	O
+another	POS	O
+.	POS	O
+The	POS	O
+hypothesis	POS	O
+that	POS	O
+intense	POS	O
+vasoconstriction	POS	O
+would	POS	O
+increase	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+such	POS	O
+vacuoles	POS	O
+has	POS	O
+been	POS	O
+tested	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+media	POS	O
+of	POS	O
+the	POS	O
+saphenous	POS	O
+artery	POS	O
+and	POS	O
+its	POS	O
+distal	POS	O
+branch	POS	O
+,	POS	O
+vasoconstriction	POS	O
+induced	POS	O
+by	POS	O
+L	POS	O
+-	POS	O
+norepinephrine	POS	O
+produced	POS	O
+many	POS	O
+cell	POS	O
+-	POS	O
+to	POS	O
+-	POS	O
+cell	POS	O
+hernias	POS	O
+within	POS	O
+15	POS	O
+minutes	POS	O
+.	POS	O
+At	POS	O
+1	POS	O
+day	POS	O
+their	POS	O
+number	POS	O
+was	POS	O
+reduced	POS	O
+to	POS	O
+about	POS	O
+1	POS	O
+/	POS	O
+10	POS	O
+of	POS	O
+the	POS	O
+original	POS	O
+number	POS	O
+.	POS	O
+By	POS	O
+7	POS	O
+days	POS	O
+the	POS	O
+vessel	POS	O
+was	POS	O
+almost	POS	O
+restored	POS	O
+to	POS	O
+normal	POS	O
+.	POS	O
+Triple	POS	O
+stimulation	POS	O
+over	POS	O
+1	POS	O
+day	POS	O
+induced	POS	O
+more	POS	O
+severe	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+media	POS	O
+.	POS	O
+These	POS	O
+findings	POS	O
+suggest	POS	O
+that	POS	O
+smooth	POS	O
+muscle	POS	O
+cells	POS	O
+are	POS	O
+susceptible	POS	O
+to	POS	O
+damage	POS	O
+in	POS	O
+the	POS	O
+course	POS	O
+of	POS	O
+their	POS	O
+specific	POS	O
+function	POS	O
+.	POS	O
+The	POS	O
+experimental	POS	O
+data	POS	O
+are	POS	O
+discussed	POS	O
+in	POS	O
+relation	POS	O
+to	POS	O
+medial	POS	O
+changes	POS	O
+observed	POS	O
+in	POS	O
+other	POS	O
+instances	POS	O
+of	POS	O
+arterial	POS	B-NP
+spasm	POS	I-NP
+.	POS	O
+Endothelial	POS	O
+changes	POS	O
+that	POS	O
+developed	POS	O
+in	POS	O
+the	POS	O
+same	POS	O
+experimental	POS	O
+model	POS	O
+were	POS	O
+described	POS	O
+in	POS	O
+a	POS	O
+previous	POS	O
+paper	POS	O
+.	POS	O
+Bilateral	POS	O
+retinal	POS	O
+artery	POS	O
+and	POS	O
+choriocapillaris	POS	B-NP
+occlusion	POS	I-NP
+following	POS	O
+the	POS	O
+injection	POS	O
+of	POS	O
+long	POS	O
+-	POS	O
+acting	POS	O
+corticosteroid	POS	O
+suspensions	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+other	POS	O
+drugs	POS	O
+:	POS	O
+I	POS	O
+.	POS	O
+Clinical	POS	O
+studies	POS	O
+.	POS	O
+Two	POS	O
+well	POS	O
+-	POS	O
+documented	POS	O
+cases	POS	O
+of	POS	O
+bilateral	POS	O
+retinal	POS	O
+artery	POS	O
+and	POS	O
+choriocapillaris	POS	B-NP
+occlusions	POS	I-NP
+with	POS	O
+blindness	POS	B-NP
+following	POS	O
+head	POS	O
+and	POS	O
+neck	POS	O
+soft	POS	O
+-	POS	O
+tissue	POS	O
+injection	POS	O
+with	POS	O
+methylprednisolone	POS	O
+acetate	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+lidocaine	POS	O
+,	POS	O
+epinephrine	POS	O
+,	POS	O
+or	POS	O
+penicillin	POS	O
+are	POS	O
+reported	POS	O
+.	POS	O
+One	POS	O
+case	POS	O
+had	POS	O
+only	POS	O
+a	POS	O
+unilateral	POS	O
+injection	POS	O
+.	POS	O
+The	POS	O
+acute	POS	O
+observations	POS	O
+included	POS	O
+hazy	POS	B-NP
+sensorium	POS	I-NP
+,	POS	O
+superior	POS	B-NP
+gaze	POS	I-NP
+palsy	POS	I-NP
+,	POS	O
+pupillary	POS	B-NP
+abnormalities	POS	I-NP
+,	POS	O
+and	POS	O
+conjunctival	POS	B-NP
+hemorrhages	POS	I-NP
+with	POS	O
+edema	POS	B-NP
+.	POS	O
+Follow	POS	O
+-	POS	O
+up	POS	O
+changes	POS	O
+showed	POS	O
+marked	POS	O
+visual	POS	B-NP
+loss	POS	I-NP
+,	POS	O
+constricted	POS	O
+visual	POS	O
+fields	POS	O
+,	POS	O
+optic	POS	B-NP
+nerve	POS	I-NP
+pallor	POS	I-NP
+,	POS	O
+vascular	POS	B-NP
+attenuation	POS	I-NP
+,	POS	O
+and	POS	O
+chorioretinal	POS	B-NP
+atrophy	POS	I-NP
+.	POS	O
+The	POS	O
+literature	POS	O
+is	POS	O
+reviewed	POS	O
+,	POS	O
+and	POS	O
+possible	POS	O
+causes	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+Abnormalities	POS	O
+of	POS	O
+the	POS	O
+pupil	POS	O
+and	POS	O
+visual	POS	O
+-	POS	O
+evoked	POS	O
+potential	POS	O
+in	POS	O
+quinine	POS	O
+amblyopia	POS	B-NP
+.	POS	O
+Total	POS	B-NP
+blindness	POS	I-NP
+with	POS	O
+a	POS	O
+transient	POS	O
+tonic	POS	O
+pupillary	POS	O
+response	POS	O
+,	POS	O
+denervation	POS	O
+supersensitivity	POS	O
+,	POS	O
+and	POS	O
+abnormal	POS	O
+visual	POS	O
+-	POS	O
+evoked	POS	O
+potentials	POS	O
+developed	POS	O
+in	POS	O
+a	POS	O
+54	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+after	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+quinine	POS	O
+sulfate	POS	O
+for	POS	O
+leg	POS	B-NP
+cramps	POS	I-NP
+.	POS	O
+He	POS	O
+later	POS	O
+recovered	POS	O
+normal	POS	O
+visual	POS	O
+acuity	POS	O
+.	POS	O
+A	POS	O
+transient	POS	O
+tonic	POS	O
+pupillary	POS	O
+response	POS	O
+,	POS	O
+denervation	POS	O
+supersensitivity	POS	O
+,	POS	O
+and	POS	O
+abnormal	POS	O
+visual	POS	O
+-	POS	O
+evoked	POS	O
+potentials	POS	O
+in	POS	O
+quinine	POS	O
+toxicity	POS	B-NP
+,	POS	O
+to	POS	O
+our	POS	O
+knowledge	POS	O
+,	POS	O
+have	POS	O
+not	POS	O
+been	POS	O
+previously	POS	O
+reported	POS	O
+.	POS	O
+Suxamethonium	POS	B-NP
+-	POS	I-NP
+induced	POS	I-NP
+jaw	POS	I-NP
+stiffness	POS	I-NP
+and	POS	O
+myalgia	POS	B-NP
+associated	POS	O
+with	POS	O
+atypical	POS	O
+cholinesterase	POS	O
+:	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+An	POS	O
+11	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+boy	POS	O
+was	POS	O
+given	POS	O
+halothane	POS	O
+,	POS	O
+nitrous	POS	O
+oxide	POS	O
+and	POS	O
+oxygen	POS	O
+,	POS	O
+pancuronium	POS	O
+0	POS	O
+.	POS	O
+4	POS	O
+mg	POS	O
+and	POS	O
+suxamethonium	POS	O
+100	POS	O
+mg	POS	O
+for	POS	O
+induction	POS	O
+of	POS	O
+anaesthesia	POS	O
+.	POS	O
+In	POS	O
+response	POS	O
+to	POS	O
+this	POS	O
+a	POS	O
+marked	POS	O
+jaw	POS	B-NP
+stiffness	POS	I-NP
+occurred	POS	O
+which	POS	O
+lasted	POS	O
+for	POS	O
+two	POS	O
+minutes	POS	O
+and	POS	O
+the	POS	O
+anaesthesia	POS	O
+were	POS	O
+terminated	POS	O
+.	POS	O
+Four	POS	O
+hours	POS	O
+of	POS	O
+apnoea	POS	B-NP
+ensued	POS	O
+and	POS	O
+he	POS	O
+suffered	POS	O
+generalized	POS	O
+severe	POS	O
+myalgia	POS	B-NP
+lasting	POS	O
+for	POS	O
+one	POS	O
+week	POS	O
+.	POS	O
+He	POS	O
+was	POS	O
+found	POS	O
+to	POS	O
+have	POS	O
+atypical	POS	O
+plasma	POS	O
+cholinesterase	POS	O
+with	POS	O
+a	POS	O
+dibucaine	POS	O
+number	POS	O
+of	POS	O
+12	POS	O
+,	POS	O
+indicating	POS	O
+homozygocity	POS	O
+.	POS	O
+This	POS	O
+was	POS	O
+verified	POS	O
+by	POS	O
+study	POS	O
+of	POS	O
+the	POS	O
+family	POS	O
+.	POS	O
+The	POS	O
+case	POS	O
+shows	POS	O
+that	POS	O
+prolonged	POS	O
+jaw	POS	B-NP
+rigidity	POS	I-NP
+and	POS	O
+myalgia	POS	B-NP
+may	POS	O
+occur	POS	O
+after	POS	O
+suxamethonium	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+atypical	POS	O
+cholinesterase	POS	O
+despite	POS	O
+pretreatment	POS	O
+with	POS	O
+pancuronium	POS	O
+.	POS	O
+Indomethacin	POS	O
+-	POS	O
+induced	POS	O
+hyperkalemia	POS	B-NP
+in	POS	O
+three	POS	O
+patients	POS	O
+with	POS	O
+gouty	POS	B-NP
+arthritis	POS	I-NP
+.	POS	O
+We	POS	O
+describe	POS	O
+three	POS	O
+patients	POS	O
+in	POS	O
+whom	POS	O
+severe	POS	O
+,	POS	O
+life	POS	O
+-	POS	O
+threatening	POS	O
+hyperkalemia	POS	B-NP
+and	POS	O
+renal	POS	B-NP
+insufficiency	POS	I-NP
+developed	POS	O
+after	POS	O
+treatment	POS	O
+of	POS	O
+acute	POS	O
+gouty	POS	B-NP
+arthritis	POS	I-NP
+with	POS	O
+indomethacin	POS	O
+.	POS	O
+This	POS	O
+complication	POS	O
+may	POS	O
+result	POS	O
+from	POS	O
+an	POS	O
+inhibition	POS	O
+of	POS	O
+prostaglandin	POS	O
+synthesis	POS	O
+and	POS	O
+consequent	POS	O
+hyporeninemic	POS	B-NP
+hypoaidosteronism	POS	I-NP
+.	POS	O
+Careful	POS	O
+attention	POS	O
+to	POS	O
+renal	POS	O
+function	POS	O
+and	POS	O
+potassium	POS	O
+balance	POS	O
+in	POS	O
+patients	POS	O
+receiving	POS	O
+indomethacin	POS	O
+or	POS	O
+other	POS	O
+nonsteroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+agents	POS	O
+,	POS	O
+particularly	POS	O
+in	POS	O
+those	POS	O
+patients	POS	O
+with	POS	O
+diabetes	POS	B-NP
+mellitus	POS	I-NP
+or	POS	O
+preexisting	POS	B-NP
+renal	POS	I-NP
+disease	POS	I-NP
+,	POS	O
+will	POS	O
+help	POS	O
+prevent	POS	O
+this	POS	O
+potentially	POS	O
+serious	POS	O
+complication	POS	O
+.	POS	O
+Etomidate	POS	O
+:	POS	O
+a	POS	O
+foreshortened	POS	O
+clinical	POS	O
+trial	POS	O
+.	POS	O
+A	POS	O
+clinical	POS	O
+evaluation	POS	O
+of	POS	O
+etomidate	POS	O
+for	POS	O
+outpatient	POS	O
+cystoscopy	POS	O
+was	POS	O
+embarked	POS	O
+upon	POS	O
+.	POS	O
+Unpremedicated	POS	O
+patients	POS	O
+were	POS	O
+given	POS	O
+fentanyl	POS	O
+1	POS	O
+microgram	POS	O
+/	POS	O
+kg	POS	O
+followed	POS	O
+by	POS	O
+etomidate	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+Anaesthesia	POS	O
+was	POS	O
+maintained	POS	O
+with	POS	O
+intermittent	POS	O
+etomidate	POS	O
+in	POS	O
+2	POS	O
+-	POS	O
+4	POS	O
+mg	POS	O
+doses	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+interviewed	POS	O
+personally	POS	O
+later	POS	O
+the	POS	O
+same	POS	O
+day	POS	O
+,	POS	O
+and	POS	O
+by	POS	O
+questionnaire	POS	O
+three	POS	O
+to	POS	O
+four	POS	O
+weeks	POS	O
+later	POS	O
+.	POS	O
+The	POS	O
+trial	POS	O
+was	POS	O
+discontinued	POS	O
+after	POS	O
+20	POS	O
+cases	POS	O
+because	POS	O
+of	POS	O
+an	POS	O
+unacceptable	POS	O
+incidence	POS	O
+of	POS	O
+side	POS	O
+effects	POS	O
+.	POS	O
+Venous	POS	B-NP
+pain	POS	I-NP
+occurred	POS	O
+in	POS	O
+68	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+and	POS	O
+50	POS	O
+%	POS	O
+had	POS	O
+redness	POS	B-NP
+,	POS	O
+pain	POS	B-NP
+or	POS	O
+swelling	POS	B-NP
+related	POS	O
+to	POS	O
+the	POS	O
+injection	POS	O
+site	POS	O
+,	POS	O
+in	POS	O
+some	POS	O
+cases	POS	O
+lasting	POS	O
+up	POS	O
+to	POS	O
+three	POS	O
+weeks	POS	O
+after	POS	O
+anaesthesia	POS	O
+.	POS	O
+Skeletal	POS	B-NP
+movements	POS	I-NP
+occurred	POS	O
+in	POS	O
+50	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+;	POS	O
+30	POS	O
+%	POS	O
+experienced	POS	O
+respiratory	POS	B-NP
+upset	POS	I-NP
+,	POS	O
+one	POS	O
+sufficiently	POS	O
+severe	POS	O
+to	POS	O
+necessitate	POS	O
+abandoning	POS	O
+the	POS	O
+technique	POS	O
+.	POS	O
+Nausea	POS	B-NP
+and	POS	O
+vomiting	POS	B-NP
+occurred	POS	O
+in	POS	O
+40	POS	O
+%	POS	O
+and	POS	O
+25	POS	O
+%	POS	O
+had	POS	O
+disturbing	POS	O
+emergence	POS	O
+psychoses	POS	B-NP
+.	POS	O
+Levodopa	POS	O
+-	POS	O
+induced	POS	O
+dyskinesias	POS	B-NP
+are	POS	O
+improved	POS	O
+by	POS	O
+fluoxetine	POS	O
+.	POS	O
+We	POS	O
+evaluated	POS	O
+the	POS	O
+severity	POS	O
+of	POS	O
+motor	POS	B-NP
+disability	POS	I-NP
+and	POS	O
+dyskinesias	POS	B-NP
+in	POS	O
+seven	POS	O
+levodopa	POS	O
+-	POS	O
+responsive	POS	O
+patients	POS	O
+with	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+after	POS	O
+an	POS	O
+acute	POS	O
+challenge	POS	O
+with	POS	O
+the	POS	O
+mixed	POS	O
+dopamine	POS	O
+agonist	POS	O
+,	POS	O
+apomorphine	POS	O
+,	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+fluoxetine	POS	O
+(	POS	O
+20	POS	O
+mg	POS	O
+twice	POS	O
+per	POS	O
+day	POS	O
+)	POS	O
+for	POS	O
+11	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+days	POS	O
+.	POS	O
+After	POS	O
+fluoxetine	POS	O
+treatment	POS	O
+,	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+47	POS	O
+%	POS	O
+improvement	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+of	POS	O
+apomorphine	POS	O
+-	POS	O
+induced	POS	O
+dyskinesias	POS	B-NP
+without	POS	O
+modification	POS	O
+of	POS	O
+parkinsonian	POS	B-NP
+motor	POS	I-NP
+disability	POS	I-NP
+.	POS	O
+The	POS	O
+dyskinesias	POS	B-NP
+were	POS	O
+reduced	POS	O
+predominantly	POS	O
+in	POS	O
+the	POS	O
+lower	POS	O
+limbs	POS	O
+during	POS	O
+the	POS	O
+onset	POS	O
+and	POS	O
+disappearance	POS	O
+of	POS	O
+dystonic	POS	B-NP
+dyskinesias	POS	I-NP
+(	POS	O
+onset	POS	O
+-	POS	O
+and	POS	O
+end	POS	O
+-	POS	O
+of	POS	O
+-	POS	O
+dose	POS	O
+dyskinesias	POS	B-NP
+)	POS	O
+and	POS	O
+in	POS	O
+the	POS	O
+upper	POS	O
+limbs	POS	O
+during	POS	O
+choreic	POS	B-NP
+mid	POS	O
+-	POS	O
+dose	POS	O
+dyskinesias	POS	B-NP
+.	POS	O
+The	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+increased	POS	O
+brain	POS	O
+serotoninergic	POS	O
+transmission	POS	O
+with	POS	O
+fluoxetine	POS	O
+may	POS	O
+reduce	POS	O
+levodopa	POS	O
+-	POS	O
+or	POS	O
+dopamine	POS	O
+agonist	POS	O
+-	POS	O
+induced	POS	O
+dyskinesias	POS	B-NP
+without	POS	O
+aggravating	POS	O
+parkinsonian	POS	B-NP
+motor	POS	I-NP
+disability	POS	I-NP
+.	POS	O
+A	POS	O
+large	POS	O
+population	POS	O
+-	POS	O
+based	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+study	POS	O
+of	POS	O
+trimethoprim	POS	O
+-	POS	O
+sulfamethoxazole	POS	O
+,	POS	O
+trimethoprim	POS	O
+,	POS	O
+and	POS	O
+cephalexin	POS	O
+for	POS	O
+uncommon	POS	O
+serious	POS	O
+drug	POS	B-NP
+toxicity	POS	I-NP
+.	POS	O
+We	POS	O
+conducted	POS	O
+a	POS	O
+population	POS	O
+-	POS	O
+based	POS	O
+45	POS	O
+-	POS	O
+day	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+study	POS	O
+of	POS	O
+232	POS	O
+,	POS	O
+390	POS	O
+people	POS	O
+who	POS	O
+were	POS	O
+prescribed	POS	O
+trimethoprim	POS	O
+-	POS	O
+sulfamethoxazole	POS	O
+(	POS	O
+TMP	POS	O
+-	POS	O
+SMZ	POS	O
+)	POS	O
+,	POS	O
+266	POS	O
+,	POS	O
+951	POS	O
+prescribed	POS	O
+trimethoprim	POS	O
+alone	POS	O
+,	POS	O
+and	POS	O
+196	POS	O
+,	POS	O
+397	POS	O
+prescribed	POS	O
+cephalexin	POS	O
+,	POS	O
+to	POS	O
+estimate	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+serious	POS	O
+liver	POS	O
+,	POS	O
+blood	POS	O
+,	POS	O
+skin	POS	O
+,	POS	O
+and	POS	O
+renal	POS	B-NP
+disorders	POS	I-NP
+resulting	POS	O
+in	POS	O
+referral	POS	O
+or	POS	O
+hospitalization	POS	O
+associated	POS	O
+with	POS	O
+these	POS	O
+drugs	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+were	POS	O
+based	POS	O
+on	POS	O
+information	POS	O
+recorded	POS	O
+on	POS	O
+office	POS	O
+computers	POS	O
+by	POS	O
+selected	POS	O
+general	POS	O
+practitioners	POS	O
+in	POS	O
+the	POS	O
+United	POS	O
+Kingdom	POS	O
+,	POS	O
+together	POS	O
+with	POS	O
+a	POS	O
+review	POS	O
+of	POS	O
+clinical	POS	O
+records	POS	O
+.	POS	O
+The	POS	O
+risk	POS	O
+of	POS	O
+clinically	POS	O
+important	POS	O
+idiopathic	POS	B-NP
+liver	POS	I-NP
+disease	POS	I-NP
+was	POS	O
+similar	POS	O
+for	POS	O
+persons	POS	O
+prescribed	POS	O
+TMP	POS	O
+-	POS	O
+SMZ	POS	O
+(	POS	O
+5	POS	O
+.	POS	O
+2	POS	O
+/	POS	O
+100	POS	O
+,	POS	O
+000	POS	O
+)	POS	O
+and	POS	O
+those	POS	O
+prescribed	POS	O
+trimethoprim	POS	O
+alone	POS	O
+(	POS	O
+3	POS	O
+.	POS	O
+8	POS	O
+/	POS	O
+100	POS	O
+,	POS	O
+000	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+risk	POS	O
+for	POS	O
+those	POS	O
+prescribed	POS	O
+cephalexin	POS	O
+was	POS	O
+somewhat	POS	O
+lower	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+0	POS	O
+/	POS	O
+100	POS	O
+,	POS	O
+000	POS	O
+)	POS	O
+.	POS	O
+Only	POS	O
+five	POS	O
+patients	POS	O
+experienced	POS	O
+blood	POS	B-NP
+disorders	POS	I-NP
+,	POS	O
+one	POS	O
+of	POS	O
+whom	POS	O
+was	POS	O
+exposed	POS	O
+to	POS	O
+TMP	POS	O
+-	POS	O
+SMZ	POS	O
+;	POS	O
+of	POS	O
+seven	POS	O
+with	POS	O
+erythema	POS	B-NP
+multiforme	POS	I-NP
+and	POS	O
+Stevens	POS	B-NP
+-	POS	I-NP
+Johnson	POS	I-NP
+syndrome	POS	I-NP
+,	POS	O
+four	POS	O
+were	POS	O
+exposed	POS	O
+to	POS	O
+TMP	POS	O
+-	POS	O
+SMZ	POS	O
+.	POS	O
+The	POS	O
+one	POS	O
+case	POS	O
+of	POS	O
+toxic	POS	O
+epidermal	POS	B-NP
+necrolysis	POS	I-NP
+occurred	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+who	POS	O
+took	POS	O
+cephalexin	POS	O
+.	POS	O
+Finally	POS	O
+,	POS	O
+only	POS	O
+five	POS	O
+cases	POS	O
+of	POS	O
+acute	POS	O
+parenchymal	POS	B-NP
+renal	POS	I-NP
+disease	POS	I-NP
+occurred	POS	O
+,	POS	O
+none	POS	O
+likely	POS	O
+to	POS	O
+be	POS	O
+caused	POS	O
+by	POS	O
+a	POS	O
+study	POS	O
+drug	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+the	POS	O
+serious	POS	O
+diseases	POS	O
+studied	POS	O
+is	POS	O
+small	POS	O
+for	POS	O
+the	POS	O
+three	POS	O
+agents	POS	O
+,	POS	O
+and	POS	O
+compares	POS	O
+reasonably	POS	O
+with	POS	O
+the	POS	O
+risk	POS	O
+for	POS	O
+many	POS	O
+other	POS	O
+antibiotics	POS	O
+.	POS	O
+Clinical	POS	O
+safety	POS	O
+of	POS	O
+lidocaine	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	O
+-	POS	O
+associated	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+STUDY	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+evaluate	POS	O
+the	POS	O
+safety	POS	O
+of	POS	O
+lidocaine	POS	O
+in	POS	O
+the	POS	O
+setting	POS	O
+of	POS	O
+cocaine	POS	O
+-	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+(	POS	O
+MI	POS	B-NP
+)	POS	O
+.	POS	O
+DESIGN	POS	O
+:	POS	O
+A	POS	O
+retrospective	POS	O
+,	POS	O
+multicenter	POS	O
+study	POS	O
+.	POS	O
+SETTING	POS	O
+:	POS	O
+Twenty	POS	O
+-	POS	O
+nine	POS	O
+university	POS	O
+,	POS	O
+university	POS	O
+-	POS	O
+affiliated	POS	O
+,	POS	O
+or	POS	O
+community	POS	O
+hospitals	POS	O
+during	POS	O
+a	POS	O
+6	POS	O
+-	POS	O
+year	POS	O
+period	POS	O
+(	POS	O
+total	POS	O
+of	POS	O
+117	POS	O
+cumulative	POS	O
+hospital	POS	O
+-	POS	O
+years	POS	O
+)	POS	O
+.	POS	O
+PARTICIPANTS	POS	O
+:	POS	O
+Patients	POS	O
+with	POS	O
+cocaine	POS	O
+-	POS	O
+associated	POS	O
+MI	POS	B-NP
+who	POS	O
+received	POS	O
+lidocaine	POS	O
+in	POS	O
+the	POS	O
+emergency	POS	O
+department	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Of	POS	O
+29	POS	O
+patients	POS	O
+who	POS	O
+received	POS	O
+lidocaine	POS	O
+in	POS	O
+the	POS	O
+setting	POS	O
+of	POS	O
+cocaine	POS	O
+-	POS	O
+associated	POS	O
+MI	POS	B-NP
+,	POS	O
+no	POS	O
+patient	POS	O
+died	POS	O
+;	POS	O
+exhibited	POS	O
+bradydysrhythmias	POS	B-NP
+,	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+,	POS	O
+or	POS	O
+ventricular	POS	B-NP
+fibrillation	POS	I-NP
+;	POS	O
+or	POS	O
+experienced	POS	O
+seizures	POS	B-NP
+after	POS	O
+administration	POS	O
+of	POS	O
+lidocaine	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+,	POS	O
+0	POS	O
+%	POS	O
+to	POS	O
+11	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Despite	POS	O
+theoretical	POS	O
+concerns	POS	O
+that	POS	O
+lidocaine	POS	O
+may	POS	O
+enhance	POS	O
+cocaine	POS	B-NP
+toxicity	POS	I-NP
+,	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+lidocaine	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	O
+-	POS	O
+associated	POS	O
+MI	POS	B-NP
+was	POS	O
+not	POS	O
+associated	POS	O
+with	POS	O
+significant	POS	O
+cardiovascular	POS	B-NP
+or	POS	I-NP
+central	POS	I-NP
+nervous	POS	I-NP
+system	POS	I-NP
+toxicity	POS	I-NP
+.	POS	O
+Experimental	POS	O
+progressive	POS	O
+muscular	POS	B-NP
+dystrophy	POS	I-NP
+and	POS	O
+its	POS	O
+treatment	POS	O
+with	POS	O
+high	POS	O
+doses	POS	O
+anabolizing	POS	O
+agents	POS	O
+.	POS	O
+We	POS	O
+are	POS	O
+still	POS	O
+a	POS	O
+long	POS	O
+way	POS	O
+from	POS	O
+discovering	POS	O
+an	POS	O
+unequivocal	POS	O
+pathogenetic	POS	O
+interpretation	POS	O
+of	POS	O
+progressive	POS	O
+muscular	POS	B-NP
+dystrophy	POS	I-NP
+in	POS	O
+man	POS	O
+.	POS	O
+Noteworthy	POS	O
+efforts	POS	O
+have	POS	O
+been	POS	O
+made	POS	O
+in	POS	O
+the	POS	O
+experimental	POS	O
+field	POS	O
+;	POS	O
+a	POS	O
+recessive	POS	B-NP
+autosomic	POS	I-NP
+form	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+mouse	POS	O
+seems	POS	O
+to	POS	O
+bear	POS	O
+the	POS	O
+closest	POS	O
+resemblance	POS	O
+to	POS	O
+the	POS	O
+human	POS	O
+form	POS	O
+from	POS	O
+the	POS	O
+genetic	POS	O
+point	POS	O
+of	POS	O
+view	POS	O
+.	POS	O
+Myopathy	POS	B-NP
+due	POS	O
+to	POS	O
+lack	POS	O
+of	POS	O
+vitamin	POS	O
+E	POS	O
+and	POS	O
+myopathy	POS	B-NP
+induced	POS	O
+by	POS	O
+certain	POS	O
+viruses	POS	O
+have	POS	O
+much	POS	O
+in	POS	O
+common	POS	O
+anatomically	POS	O
+and	POS	O
+pathologically	POS	O
+with	POS	O
+the	POS	O
+human	POS	O
+form	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+induced	POS	O
+myodystrophy	POS	B-NP
+in	POS	O
+the	POS	O
+rat	POS	O
+by	POS	O
+giving	POS	O
+it	POS	O
+a	POS	O
+diet	POS	O
+lacking	POS	O
+in	POS	O
+vitamin	POS	O
+E	POS	O
+.	POS	O
+The	POS	O
+pharmacological	POS	O
+characteristics	POS	O
+of	POS	O
+vitamin	POS	O
+E	POS	O
+and	POS	O
+the	POS	O
+degenerative	POS	O
+changes	POS	O
+brought	POS	O
+about	POS	O
+by	POS	O
+its	POS	O
+deficiency	POS	O
+,	POS	O
+especially	POS	O
+in	POS	O
+the	POS	O
+muscles	POS	O
+,	POS	O
+are	POS	O
+illustrated	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+thus	POS	O
+confirmed	POS	O
+that	POS	O
+the	POS	O
+histological	POS	O
+characteristics	POS	O
+of	POS	O
+myopathic	POS	O
+rat	POS	O
+muscle	POS	O
+induced	POS	O
+experimentally	POS	O
+are	POS	O
+extraordinarily	POS	O
+similar	POS	O
+to	POS	O
+those	POS	O
+of	POS	O
+human	POS	O
+myopathy	POS	B-NP
+as	POS	O
+confirmed	POS	O
+during	POS	O
+biopsies	POS	O
+performed	POS	O
+at	POS	O
+the	POS	O
+Orthopaedic	POS	O
+Traumatological	POS	O
+Centre	POS	O
+,	POS	O
+Florence	POS	O
+.	POS	O
+The	POS	O
+encouraging	POS	O
+results	POS	O
+obtained	POS	O
+in	POS	O
+various	POS	O
+authoratative	POS	O
+departments	POS	O
+in	POS	O
+myopathic	POS	B-NP
+patients	POS	O
+by	POS	O
+using	POS	O
+anabolizing	POS	O
+steroids	POS	O
+have	POS	O
+encouraged	POS	O
+the	POS	O
+authors	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+beneficial	POS	O
+effects	POS	O
+of	POS	O
+one	POS	O
+anabolizing	POS	O
+agent	POS	O
+(	POS	O
+Dianabol	POS	O
+,	POS	O
+CIBA	POS	O
+)	POS	O
+at	POS	O
+high	POS	O
+doses	POS	O
+in	POS	O
+rats	POS	O
+rendered	POS	O
+myopathic	POS	B-NP
+by	POS	O
+a	POS	O
+diet	POS	O
+deficient	POS	O
+in	POS	O
+vitamin	POS	O
+E	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+way	POS	O
+they	POS	O
+obtained	POS	O
+appreciable	POS	O
+changes	POS	O
+in	POS	O
+body	POS	O
+weight	POS	O
+(	POS	O
+increased	POS	O
+from	POS	O
+50	POS	O
+to	POS	O
+70	POS	O
+g	POS	O
+after	POS	O
+forty	POS	O
+days	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+5	POS	O
+mg	POS	O
+per	POS	O
+day	POS	O
+of	POS	O
+anabolizing	POS	O
+agent	POS	O
+)	POS	O
+,	POS	O
+but	POS	O
+most	POS	O
+of	POS	O
+all	POS	O
+they	POS	O
+found	POS	O
+histological	POS	O
+changes	POS	O
+due	POS	O
+to	POS	O
+"	POS	O
+regenerative	POS	O
+"	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+muscle	POS	O
+tissue	POS	O
+,	POS	O
+which	POS	O
+however	POS	O
+maintained	POS	O
+its	POS	O
+myopathic	POS	B-NP
+characteristics	POS	O
+in	POS	O
+the	POS	O
+control	POS	O
+animals	POS	O
+that	POS	O
+were	POS	O
+not	POS	O
+treated	POS	O
+with	POS	O
+the	POS	O
+anabolizing	POS	O
+agent	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+conclude	POS	O
+by	POS	O
+affirming	POS	O
+the	POS	O
+undoubted	POS	O
+efficacy	POS	O
+of	POS	O
+the	POS	O
+anabolizing	POS	O
+steroids	POS	O
+in	POS	O
+experimental	POS	O
+myopathic	POS	B-NP
+disease	POS	I-NP
+,	POS	O
+but	POS	O
+they	POS	O
+have	POS	O
+reservations	POS	O
+as	POS	O
+to	POS	O
+the	POS	O
+transfer	POS	O
+of	POS	O
+the	POS	O
+results	POS	O
+into	POS	O
+the	POS	O
+human	POS	O
+field	POS	O
+,	POS	O
+where	POS	O
+high	POS	O
+dosage	POS	O
+cannot	POS	O
+be	POS	O
+carried	POS	O
+out	POS	O
+continuously	POS	O
+because	POS	O
+of	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+on	POS	O
+virility	POS	O
+;	POS	O
+because	POS	O
+the	POS	O
+tissue	POS	O
+injury	POS	O
+too	POS	O
+often	POS	O
+occurs	POS	O
+at	POS	O
+an	POS	O
+irreversible	POS	O
+stage	POS	O
+vis	POS	O
+-	POS	O
+a	POS	O
+-	POS	O
+vis	POS	O
+the	POS	O
+"	POS	O
+regeneration	POS	O
+"	POS	O
+of	POS	O
+the	POS	O
+muscle	POS	O
+tissue	POS	O
+;	POS	O
+and	POS	O
+finally	POS	O
+because	POS	O
+the	POS	O
+dystrophic	POS	O
+injurious	POS	O
+agent	POS	O
+is	POS	O
+certainly	POS	O
+not	POS	O
+the	POS	O
+lack	POS	O
+of	POS	O
+vitamin	POS	O
+E	POS	O
+but	POS	O
+something	POS	O
+as	POS	O
+yet	POS	O
+unknown	POS	O
+.	POS	O
+Paclitaxel	POS	O
+3	POS	O
+-	POS	O
+hour	POS	O
+infusion	POS	O
+given	POS	O
+alone	POS	O
+and	POS	O
+combined	POS	O
+with	POS	O
+carboplatin	POS	O
+:	POS	O
+preliminary	POS	O
+results	POS	O
+of	POS	O
+dose	POS	O
+-	POS	O
+escalation	POS	O
+trials	POS	O
+.	POS	O
+Paclitaxel	POS	O
+(	POS	O
+Taxol	POS	O
+;	POS	O
+Bristol	POS	O
+-	POS	O
+Myers	POS	O
+Squibb	POS	O
+Company	POS	O
+,	POS	O
+Princeton	POS	O
+,	POS	O
+NJ	POS	O
+)	POS	O
+by	POS	O
+3	POS	O
+-	POS	O
+hour	POS	O
+infusion	POS	O
+was	POS	O
+combined	POS	O
+with	POS	O
+carboplatin	POS	O
+in	POS	O
+a	POS	O
+phase	POS	O
+I	POS	O
+/	POS	O
+II	POS	O
+study	POS	O
+directed	POS	O
+to	POS	O
+patients	POS	O
+with	POS	O
+non	POS	B-NP
+-	POS	I-NP
+small	POS	I-NP
+cell	POS	I-NP
+lung	POS	I-NP
+cancer	POS	I-NP
+.	POS	O
+Carboplatin	POS	O
+was	POS	O
+given	POS	O
+at	POS	O
+a	POS	O
+fixed	POS	O
+target	POS	O
+area	POS	O
+under	POS	O
+the	POS	O
+concentration	POS	O
+-	POS	O
+time	POS	O
+curve	POS	O
+of	POS	O
+6	POS	O
+.	POS	O
+0	POS	O
+by	POS	O
+the	POS	O
+Calvert	POS	O
+formula	POS	O
+,	POS	O
+whereas	POS	O
+paclitaxel	POS	O
+was	POS	O
+escalated	POS	O
+in	POS	O
+patient	POS	O
+cohorts	POS	O
+from	POS	O
+150	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+(	POS	O
+dose	POS	O
+level	POS	O
+I	POS	O
+)	POS	O
+to	POS	O
+175	POS	O
+,	POS	O
+200	POS	O
+,	POS	O
+225	POS	O
+,	POS	O
+and	POS	O
+250	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+.	POS	O
+The	POS	O
+225	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+level	POS	O
+was	POS	O
+expanded	POS	O
+for	POS	O
+the	POS	O
+phase	POS	O
+II	POS	O
+study	POS	O
+since	POS	O
+the	POS	O
+highest	POS	O
+level	POS	O
+achieved	POS	O
+(	POS	O
+250	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+)	POS	O
+required	POS	O
+modification	POS	O
+because	POS	O
+of	POS	O
+nonhematologic	POS	O
+toxicities	POS	B-NP
+(	POS	O
+arthralgia	POS	B-NP
+and	POS	O
+sensory	POS	B-NP
+neuropathy	POS	I-NP
+)	POS	O
+.	POS	O
+Therapeutic	POS	O
+effects	POS	O
+were	POS	O
+noted	POS	O
+at	POS	O
+all	POS	O
+dose	POS	O
+levels	POS	O
+,	POS	O
+with	POS	O
+objective	POS	O
+responses	POS	O
+in	POS	O
+17	POS	O
+(	POS	O
+two	POS	O
+complete	POS	O
+and	POS	O
+15	POS	O
+partial	POS	O
+regressions	POS	O
+)	POS	O
+of	POS	O
+41	POS	O
+previously	POS	O
+untreated	POS	O
+patients	POS	O
+.	POS	O
+Toxicities	POS	B-NP
+were	POS	O
+compared	POS	O
+with	POS	O
+a	POS	O
+cohort	POS	O
+of	POS	O
+patients	POS	O
+in	POS	O
+a	POS	O
+phase	POS	O
+I	POS	O
+trial	POS	O
+of	POS	O
+paclitaxel	POS	O
+alone	POS	O
+at	POS	O
+identical	POS	O
+dose	POS	O
+levels	POS	O
+.	POS	O
+Carboplatin	POS	O
+did	POS	O
+not	POS	O
+appear	POS	O
+to	POS	O
+add	POS	O
+to	POS	O
+the	POS	O
+hematologic	POS	O
+toxicities	POS	B-NP
+observed	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+paclitaxel	POS	O
+/	POS	O
+carboplatin	POS	O
+combination	POS	O
+could	POS	O
+be	POS	O
+dosed	POS	O
+every	POS	O
+3	POS	O
+weeks	POS	O
+.	POS	O
+The	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+effect	POS	O
+of	POS	O
+misoprostol	POS	O
+on	POS	O
+indomethacin	POS	O
+-	POS	O
+induced	POS	O
+renal	POS	B-NP
+dysfunction	POS	I-NP
+in	POS	O
+well	POS	O
+compensated	POS	O
+cirrhosis	POS	B-NP
+.	POS	O
+Misoprostol	POS	O
+(	POS	O
+200	POS	O
+micrograms	POS	O
+)	POS	O
+has	POS	O
+been	POS	O
+shown	POS	O
+to	POS	O
+acutely	POS	O
+counteract	POS	O
+the	POS	O
+indomethacin	POS	O
+-	POS	O
+induced	POS	O
+renal	POS	B-NP
+dysfunction	POS	I-NP
+in	POS	O
+well	POS	O
+compensated	POS	O
+cirrhotic	POS	B-NP
+patients	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+determine	POS	O
+if	POS	O
+the	POS	O
+prophylactic	POS	O
+value	POS	O
+of	POS	O
+misoprostol	POS	O
+was	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+.	POS	O
+Parameters	POS	O
+of	POS	O
+renal	POS	O
+hemodynamics	POS	O
+and	POS	O
+tubular	POS	O
+sodium	POS	O
+and	POS	O
+water	POS	O
+handling	POS	O
+were	POS	O
+assessed	POS	O
+by	POS	O
+clearance	POS	O
+techniques	POS	O
+in	POS	O
+26	POS	O
+well	POS	O
+compensated	POS	O
+cirrhotic	POS	B-NP
+patients	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+an	POS	O
+oral	POS	O
+combination	POS	O
+of	POS	O
+50	POS	O
+mg	POS	O
+of	POS	O
+indomethacin	POS	O
+and	POS	O
+various	POS	O
+doses	POS	O
+of	POS	O
+misoprostol	POS	O
+.	POS	O
+The	POS	O
+200	POS	O
+-	POS	O
+micrograms	POS	O
+dose	POS	O
+was	POS	O
+able	POS	O
+to	POS	O
+totally	POS	O
+abolish	POS	O
+the	POS	O
+deleterious	POS	O
+renal	POS	O
+effects	POS	O
+of	POS	O
+indomethacin	POS	O
+,	POS	O
+whereas	POS	O
+the	POS	O
+800	POS	O
+-	POS	O
+micrograms	POS	O
+dose	POS	O
+resulted	POS	O
+in	POS	O
+significant	POS	O
+worsening	POS	O
+of	POS	O
+renal	POS	O
+hemodynamics	POS	O
+and	POS	O
+sodium	POS	O
+retention	POS	O
+.	POS	O
+These	POS	O
+changes	POS	O
+were	POS	O
+maximal	POS	O
+in	POS	O
+the	POS	O
+hour	POS	O
+immediately	POS	O
+after	POS	O
+medications	POS	O
+and	POS	O
+slowly	POS	O
+returned	POS	O
+toward	POS	O
+base	POS	O
+-	POS	O
+line	POS	O
+levels	POS	O
+thereafter	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+the	POS	O
+renal	POS	O
+protective	POS	O
+effects	POS	O
+of	POS	O
+misoprostol	POS	O
+is	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+until	POS	O
+this	POS	O
+apparent	POS	O
+ability	POS	O
+of	POS	O
+200	POS	O
+micrograms	POS	O
+of	POS	O
+misoprostol	POS	O
+to	POS	O
+prevent	POS	O
+the	POS	O
+adverse	POS	O
+effects	POS	O
+of	POS	O
+indomethacin	POS	O
+on	POS	O
+renal	POS	O
+function	POS	O
+is	POS	O
+confirmed	POS	O
+with	POS	O
+chronic	POS	O
+frequent	POS	O
+dosing	POS	O
+,	POS	O
+it	POS	O
+would	POS	O
+be	POS	O
+prudent	POS	O
+to	POS	O
+avoid	POS	O
+nonsteroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+therapy	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+cirrhosis	POS	B-NP
+.	POS	O
+Increased	POS	O
+frequency	POS	O
+and	POS	O
+severity	POS	O
+of	POS	O
+angio	POS	B-NP
+-	POS	I-NP
+oedema	POS	I-NP
+related	POS	O
+to	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+therapy	POS	O
+with	POS	O
+angiotensin	POS	O
+-	POS	O
+converting	POS	O
+enzyme	POS	O
+inhibitor	POS	O
+in	POS	O
+two	POS	O
+patients	POS	O
+.	POS	O
+Adverse	POS	O
+reactions	POS	O
+to	POS	O
+drugs	POS	O
+are	POS	O
+well	POS	O
+recognized	POS	O
+as	POS	O
+a	POS	O
+cause	POS	O
+of	POS	O
+acute	POS	O
+or	POS	O
+chronic	POS	O
+urticaria	POS	B-NP
+,	POS	O
+and	POS	O
+angio	POS	B-NP
+-	POS	I-NP
+oedema	POS	I-NP
+.	POS	O
+Angiotensin	POS	O
+-	POS	O
+converting	POS	O
+enzyme	POS	O
+(	POS	O
+ACE	POS	O
+)	POS	O
+inhibitors	POS	O
+,	POS	O
+used	POS	O
+to	POS	O
+treat	POS	O
+hypertension	POS	B-NP
+and	POS	O
+congestive	POS	B-NP
+heart	POS	I-NP
+failure	POS	I-NP
+,	POS	O
+were	POS	O
+introduced	POS	O
+in	POS	O
+Europe	POS	O
+in	POS	O
+the	POS	O
+middle	POS	O
+of	POS	O
+the	POS	O
+eighties	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+these	POS	O
+drugs	POS	O
+has	POS	O
+increased	POS	O
+progressively	POS	O
+.	POS	O
+Soon	POS	O
+after	POS	O
+the	POS	O
+introduction	POS	O
+of	POS	O
+ACE	POS	O
+inhibitors	POS	O
+,	POS	O
+acute	POS	O
+bouts	POS	O
+of	POS	O
+angio	POS	B-NP
+-	POS	I-NP
+oedema	POS	I-NP
+were	POS	O
+reported	POS	O
+in	POS	O
+association	POS	O
+with	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+these	POS	O
+drugs	POS	O
+.	POS	O
+We	POS	O
+wish	POS	O
+to	POS	O
+draw	POS	O
+attention	POS	O
+to	POS	O
+the	POS	O
+possibility	POS	O
+of	POS	O
+adverse	POS	O
+reactions	POS	O
+to	POS	O
+ACE	POS	O
+inhibitors	POS	O
+after	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+use	POS	O
+and	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+pre	POS	O
+-	POS	O
+existing	POS	O
+angio	POS	O
+-	POS	O
+oedema	POS	B-NP
+.	POS	O
+Myoclonus	POS	B-NP
+associated	POS	O
+with	POS	O
+lorazepam	POS	O
+therapy	POS	O
+in	POS	O
+very	POS	O
+-	POS	O
+low	POS	O
+-	POS	O
+birth	POS	O
+-	POS	O
+weight	POS	O
+infants	POS	O
+.	POS	O
+Lorazepam	POS	O
+is	POS	O
+being	POS	O
+used	POS	O
+with	POS	O
+increasing	POS	O
+frequency	POS	O
+as	POS	O
+a	POS	O
+sedative	POS	O
+in	POS	O
+the	POS	O
+newborn	POS	O
+and	POS	O
+the	POS	O
+young	POS	O
+infant	POS	O
+.	POS	O
+Concern	POS	O
+has	POS	O
+been	POS	O
+raised	POS	O
+with	POS	O
+regard	POS	O
+to	POS	O
+the	POS	O
+safety	POS	O
+of	POS	O
+lorazepam	POS	O
+in	POS	O
+this	POS	O
+age	POS	O
+group	POS	O
+,	POS	O
+especially	POS	O
+in	POS	O
+very	POS	O
+-	POS	O
+low	POS	O
+-	POS	O
+birth	POS	O
+-	POS	O
+weight	POS	O
+(	POS	O
+VLBW	POS	O
+;	POS	O
+<	POS	O
+1	POS	O
+,	POS	O
+500	POS	O
+g	POS	O
+)	POS	O
+infants	POS	O
+.	POS	O
+Three	POS	O
+young	POS	O
+infants	POS	O
+,	POS	O
+all	POS	O
+of	POS	O
+birth	POS	O
+weight	POS	O
+<	POS	O
+1	POS	O
+,	POS	O
+500	POS	O
+g	POS	O
+,	POS	O
+experienced	POS	O
+myoclonus	POS	B-NP
+following	POS	O
+the	POS	O
+intravenous	POS	O
+administration	POS	O
+of	POS	O
+lorazepam	POS	O
+.	POS	O
+The	POS	O
+potential	POS	O
+neurotoxic	POS	B-NP
+effects	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+(	POS	O
+and	POS	O
+its	POS	O
+vehicle	POS	O
+)	POS	O
+in	POS	O
+this	POS	O
+population	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+Injectable	POS	O
+lorazepam	POS	O
+should	POS	O
+be	POS	O
+used	POS	O
+with	POS	O
+caution	POS	O
+in	POS	O
+VLBW	POS	O
+infants	POS	O
+.	POS	O
+Transvenous	POS	O
+right	POS	O
+ventricular	POS	O
+pacing	POS	O
+during	POS	O
+cardiopulmonary	POS	O
+resuscitation	POS	O
+of	POS	O
+pediatric	POS	O
+patients	POS	O
+with	POS	O
+acute	POS	B-NP
+cardiomyopathy	POS	I-NP
+.	POS	O
+We	POS	O
+describe	POS	O
+the	POS	O
+cardiopulmonary	POS	O
+resuscitation	POS	O
+efforts	POS	O
+on	POS	O
+five	POS	O
+patients	POS	O
+who	POS	O
+presented	POS	O
+in	POS	O
+acute	POS	B-NP
+circulatory	POS	I-NP
+failure	POS	I-NP
+from	POS	O
+myocardial	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+Three	POS	O
+patients	POS	O
+had	POS	O
+acute	POS	O
+viral	POS	O
+myocarditis	POS	B-NP
+,	POS	O
+one	POS	O
+had	POS	O
+a	POS	O
+carbamazepine	POS	O
+-	POS	O
+induced	POS	O
+acute	POS	O
+eosinophilic	POS	B-NP
+myocarditis	POS	I-NP
+,	POS	O
+and	POS	O
+one	POS	O
+had	POS	O
+cardiac	POS	B-NP
+hemosiderosis	POS	I-NP
+resulting	POS	O
+in	POS	O
+acute	POS	B-NP
+cardiogenic	POS	I-NP
+shock	POS	I-NP
+.	POS	O
+All	POS	O
+patients	POS	O
+were	POS	O
+continuously	POS	O
+monitored	POS	O
+with	POS	O
+central	POS	O
+venous	POS	O
+and	POS	O
+arterial	POS	O
+catheters	POS	O
+in	POS	O
+addition	POS	O
+to	POS	O
+routine	POS	O
+noninvasive	POS	O
+monitoring	POS	O
+.	POS	O
+An	POS	O
+introducer	POS	O
+sheath	POS	O
+,	POS	O
+a	POS	O
+pacemaker	POS	O
+,	POS	O
+and	POS	O
+sterile	POS	O
+pacing	POS	O
+wires	POS	O
+were	POS	O
+made	POS	O
+readily	POS	O
+available	POS	O
+for	POS	O
+the	POS	O
+patients	POS	O
+,	POS	O
+should	POS	O
+the	POS	O
+need	POS	O
+arise	POS	O
+to	POS	O
+terminate	POS	O
+resistant	POS	O
+cardiac	POS	B-NP
+dysrhythmias	POS	I-NP
+.	POS	O
+All	POS	O
+patients	POS	O
+developed	POS	O
+cardiocirculatory	POS	B-NP
+arrest	POS	I-NP
+associated	POS	O
+with	POS	O
+extreme	POS	O
+hypotension	POS	B-NP
+and	POS	O
+dysrhythmias	POS	B-NP
+within	POS	O
+the	POS	O
+first	POS	O
+48	POS	O
+hours	POS	O
+of	POS	O
+their	POS	O
+admission	POS	O
+to	POS	O
+the	POS	O
+pediatric	POS	O
+intensive	POS	O
+care	POS	O
+unit	POS	O
+(	POS	O
+PICU	POS	O
+)	POS	O
+.	POS	O
+Right	POS	O
+ventricular	POS	O
+pacemaker	POS	O
+wires	POS	O
+were	POS	O
+inserted	POS	O
+in	POS	O
+all	POS	O
+of	POS	O
+them	POS	O
+during	POS	O
+cardiopulmonary	POS	O
+resuscitation	POS	O
+(	POS	O
+CPR	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+four	POS	O
+patients	POS	O
+,	POS	O
+cardiac	POS	O
+pacing	POS	O
+was	POS	O
+used	POS	O
+,	POS	O
+resulting	POS	O
+in	POS	O
+a	POS	O
+temporary	POS	O
+captured	POS	O
+rhythm	POS	O
+and	POS	O
+restoration	POS	O
+of	POS	O
+their	POS	O
+cardiac	POS	O
+output	POS	O
+.	POS	O
+These	POS	O
+patients	POS	O
+had	POS	O
+a	POS	O
+second	POS	O
+event	POS	O
+of	POS	O
+cardiac	POS	B-NP
+arrest	POS	I-NP
+,	POS	O
+resulting	POS	O
+in	POS	O
+death	POS	O
+,	POS	O
+within	POS	O
+10	POS	O
+to	POS	O
+60	POS	O
+minutes	POS	O
+.	POS	O
+In	POS	O
+one	POS	O
+patient	POS	O
+,	POS	O
+cardiac	POS	O
+pacing	POS	O
+was	POS	O
+not	POS	O
+used	POS	O
+,	POS	O
+because	POS	O
+he	POS	O
+converted	POS	O
+to	POS	O
+normal	POS	O
+sinus	POS	O
+rhythm	POS	O
+by	POS	O
+electrical	POS	O
+defibrillation	POS	O
+within	POS	O
+three	POS	O
+minutes	POS	O
+of	POS	O
+initiating	POS	O
+CPR	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+cardiac	POS	O
+pacing	POS	O
+during	POS	O
+resuscitative	POS	O
+efforts	POS	O
+in	POS	O
+pediatric	POS	O
+patients	POS	O
+suffering	POS	O
+from	POS	O
+acute	POS	O
+myocardial	POS	B-NP
+dysfunction	POS	I-NP
+may	POS	O
+not	POS	O
+have	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+value	POS	O
+in	POS	O
+and	POS	O
+of	POS	O
+itself	POS	O
+;	POS	O
+however	POS	O
+,	POS	O
+if	POS	O
+temporary	POS	O
+hemodynamic	POS	O
+stability	POS	O
+is	POS	O
+achieved	POS	O
+by	POS	O
+this	POS	O
+procedure	POS	O
+,	POS	O
+it	POS	O
+may	POS	O
+provide	POS	O
+additional	POS	O
+time	POS	O
+needed	POS	O
+to	POS	O
+institute	POS	O
+other	POS	O
+therapeutic	POS	O
+modalities	POS	O
+.	POS	O
+Efficacy	POS	O
+and	POS	O
+safety	POS	O
+of	POS	O
+granisetron	POS	O
+,	POS	O
+a	POS	O
+selective	POS	O
+5	POS	O
+-	POS	O
+hydroxytryptamine	POS	O
+-	POS	O
+3	POS	O
+receptor	POS	O
+antagonist	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+prevention	POS	O
+of	POS	O
+nausea	POS	B-NP
+and	POS	O
+vomiting	POS	B-NP
+induced	POS	O
+by	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+cisplatin	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+To	POS	O
+assess	POS	O
+the	POS	O
+antiemetic	POS	O
+effects	POS	O
+and	POS	O
+safety	POS	O
+profile	POS	O
+of	POS	O
+four	POS	O
+different	POS	O
+doses	POS	O
+of	POS	O
+granisetron	POS	O
+(	POS	O
+Kytril	POS	O
+;	POS	O
+SmithKline	POS	O
+Beecham	POS	O
+Pharmaceuticals	POS	O
+,	POS	O
+Philadelphia	POS	O
+,	POS	O
+PA	POS	O
+)	POS	O
+when	POS	O
+administered	POS	O
+as	POS	O
+a	POS	O
+single	POS	O
+intravenous	POS	O
+(	POS	O
+IV	POS	O
+)	POS	O
+dose	POS	O
+for	POS	O
+prophylaxis	POS	O
+of	POS	O
+cisplatin	POS	O
+-	POS	O
+induced	POS	O
+nausea	POS	B-NP
+and	POS	O
+vomiting	POS	B-NP
+.	POS	O
+PATIENTS	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+One	POS	O
+hundred	POS	O
+eighty	POS	O
+-	POS	O
+four	POS	O
+chemotherapy	POS	O
+-	POS	O
+naive	POS	O
+patients	POS	O
+receiving	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+cisplatin	POS	O
+(	POS	O
+81	POS	O
+to	POS	O
+120	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+)	POS	O
+were	POS	O
+randomized	POS	O
+to	POS	O
+receive	POS	O
+one	POS	O
+of	POS	O
+four	POS	O
+granisetron	POS	O
+doses	POS	O
+(	POS	O
+5	POS	O
+,	POS	O
+10	POS	O
+,	POS	O
+20	POS	O
+,	POS	O
+or	POS	O
+40	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+administered	POS	O
+before	POS	O
+chemotherapy	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+observed	POS	O
+on	POS	O
+an	POS	O
+inpatient	POS	O
+basis	POS	O
+for	POS	O
+18	POS	O
+to	POS	O
+24	POS	O
+hours	POS	O
+,	POS	O
+and	POS	O
+vital	POS	O
+signs	POS	O
+,	POS	O
+nausea	POS	B-NP
+,	POS	O
+vomiting	POS	B-NP
+,	POS	O
+retching	POS	B-NP
+,	POS	O
+and	POS	O
+appetite	POS	B-NP
+were	POS	O
+assessed	POS	O
+.	POS	O
+Safety	POS	O
+analyses	POS	O
+included	POS	O
+incidence	POS	O
+of	POS	O
+adverse	POS	O
+experiences	POS	O
+and	POS	O
+laboratory	POS	O
+parameter	POS	O
+changes	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+After	POS	O
+granisetron	POS	O
+doses	POS	O
+of	POS	O
+5	POS	O
+,	POS	O
+10	POS	O
+,	POS	O
+20	POS	O
+,	POS	O
+and	POS	O
+40	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+a	POS	O
+major	POS	O
+response	POS	O
+(	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+two	POS	O
+vomiting	POS	B-NP
+or	POS	O
+retching	POS	B-NP
+episodes	POS	O
+,	POS	O
+and	POS	O
+no	POS	O
+antiemetic	POS	O
+rescue	POS	O
+)	POS	O
+was	POS	O
+recorded	POS	O
+in	POS	O
+23	POS	O
+%	POS	O
+,	POS	O
+57	POS	O
+%	POS	O
+,	POS	O
+58	POS	O
+%	POS	O
+,	POS	O
+and	POS	O
+60	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+complete	POS	O
+response	POS	O
+(	POS	O
+no	POS	O
+vomiting	POS	B-NP
+or	POS	O
+retching	POS	B-NP
+,	POS	O
+and	POS	O
+no	POS	O
+antiemetic	POS	O
+rescue	POS	O
+)	POS	O
+in	POS	O
+18	POS	O
+%	POS	O
+,	POS	O
+41	POS	O
+%	POS	O
+,	POS	O
+40	POS	O
+%	POS	O
+,	POS	O
+and	POS	O
+47	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+a	POS	O
+statistically	POS	O
+longer	POS	O
+time	POS	O
+to	POS	O
+first	POS	O
+episode	POS	O
+of	POS	O
+nausea	POS	B-NP
+(	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+0015	POS	O
+)	POS	O
+and	POS	O
+vomiting	POS	B-NP
+(	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+0001	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+fewer	POS	O
+patients	POS	O
+were	POS	O
+administered	POS	O
+additional	POS	O
+antiemetic	POS	O
+medication	POS	O
+in	POS	O
+the	POS	O
+10	POS	O
+-	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+dosing	POS	O
+groups	POS	O
+than	POS	O
+in	POS	O
+the	POS	O
+5	POS	O
+-	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+dosing	POS	O
+group	POS	O
+.	POS	O
+As	POS	O
+granisetron	POS	O
+dose	POS	O
+increased	POS	O
+,	POS	O
+appetite	POS	O
+return	POS	O
+increased	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+040	POS	O
+)	POS	O
+.	POS	O
+Headache	POS	B-NP
+was	POS	O
+the	POS	O
+most	POS	O
+frequently	POS	O
+reported	POS	O
+adverse	POS	O
+event	POS	O
+(	POS	O
+20	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+A	POS	O
+single	POS	O
+10	POS	O
+-	POS	O
+,	POS	O
+20	POS	O
+-	POS	O
+,	POS	O
+or	POS	O
+40	POS	O
+-	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+dose	POS	O
+of	POS	O
+granisetron	POS	O
+was	POS	O
+effective	POS	O
+in	POS	O
+controlling	POS	O
+vomiting	POS	B-NP
+in	POS	O
+57	POS	O
+%	POS	O
+to	POS	O
+60	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+who	POS	O
+received	POS	O
+cisplatin	POS	O
+at	POS	O
+doses	POS	O
+greater	POS	O
+than	POS	O
+81	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+and	POS	O
+totally	POS	O
+prevented	POS	O
+vomiting	POS	B-NP
+in	POS	O
+40	POS	O
+%	POS	O
+to	POS	O
+47	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+no	POS	O
+statistically	POS	O
+significant	POS	O
+differences	POS	O
+in	POS	O
+efficacy	POS	O
+between	POS	O
+the	POS	O
+10	POS	O
+-	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+dose	POS	O
+and	POS	O
+the	POS	O
+20	POS	O
+-	POS	O
+and	POS	O
+40	POS	O
+-	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+doses	POS	O
+.	POS	O
+Granisetron	POS	O
+was	POS	O
+well	POS	O
+tolerated	POS	O
+at	POS	O
+all	POS	O
+doses	POS	O
+.	POS	O
+Adverse	POS	O
+interaction	POS	O
+between	POS	O
+clonidine	POS	O
+and	POS	O
+verapamil	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+report	POS	O
+two	POS	O
+cases	POS	O
+of	POS	O
+a	POS	O
+possible	POS	O
+adverse	POS	O
+interaction	POS	O
+between	POS	O
+clonidine	POS	O
+and	POS	O
+verapamil	POS	O
+resulting	POS	O
+in	POS	O
+atrioventricular	POS	B-NP
+(	POS	I-NP
+AV	POS	I-NP
+)	POS	I-NP
+block	POS	I-NP
+in	POS	O
+both	POS	O
+patients	POS	O
+and	POS	O
+severe	POS	O
+hypotension	POS	B-NP
+in	POS	O
+one	POS	O
+patient	POS	O
+.	POS	O
+CASE	POS	O
+SUMMARIES	POS	O
+:	POS	O
+A	POS	O
+54	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+with	POS	O
+hyperaldosteronism	POS	B-NP
+was	POS	O
+treated	POS	O
+with	POS	O
+verapamil	POS	O
+480	POS	O
+mg	POS	O
+/	POS	O
+d	POS	O
+and	POS	O
+spironolactone	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+d	POS	O
+.	POS	O
+After	POS	O
+the	POS	O
+addition	POS	O
+of	POS	O
+a	POS	O
+minimal	POS	O
+dose	POS	O
+of	POS	O
+clonidine	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+15	POS	O
+mg	POS	O
+bid	POS	O
+)	POS	O
+,	POS	O
+she	POS	O
+developed	POS	O
+complete	POS	O
+AV	POS	B-NP
+block	POS	I-NP
+and	POS	O
+severe	POS	O
+hypotension	POS	B-NP
+,	POS	O
+which	POS	O
+resolved	POS	O
+upon	POS	O
+cessation	POS	O
+of	POS	O
+all	POS	O
+medications	POS	O
+.	POS	O
+A	POS	O
+65	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+was	POS	O
+treated	POS	O
+with	POS	O
+extended	POS	O
+-	POS	O
+release	POS	O
+verapamil	POS	O
+240	POS	O
+mg	POS	O
+/	POS	O
+d	POS	O
+.	POS	O
+After	POS	O
+the	POS	O
+addition	POS	O
+of	POS	O
+clonidine	POS	O
+0	POS	O
+.	POS	O
+15	POS	O
+mg	POS	O
+bid	POS	O
+she	POS	O
+developed	POS	O
+complete	POS	O
+AV	POS	B-NP
+block	POS	I-NP
+,	POS	O
+which	POS	O
+resolved	POS	O
+after	POS	O
+all	POS	O
+therapy	POS	O
+was	POS	O
+stopped	POS	O
+.	POS	O
+DISCUSSION	POS	O
+:	POS	O
+An	POS	O
+adverse	POS	O
+interaction	POS	O
+between	POS	O
+clonidine	POS	O
+and	POS	O
+verapamil	POS	O
+has	POS	O
+not	POS	O
+been	POS	O
+reported	POS	O
+previously	POS	O
+.	POS	O
+We	POS	O
+describe	POS	O
+two	POS	O
+such	POS	O
+cases	POS	O
+and	POS	O
+discuss	POS	O
+the	POS	O
+various	POS	O
+mechanisms	POS	O
+that	POS	O
+might	POS	O
+cause	POS	O
+such	POS	O
+an	POS	O
+interaction	POS	O
+.	POS	O
+Clinicians	POS	O
+should	POS	O
+be	POS	O
+acquainted	POS	O
+with	POS	O
+this	POS	O
+possibly	POS	O
+fatal	POS	O
+interaction	POS	O
+between	POS	O
+two	POS	O
+commonly	POS	O
+used	POS	O
+antihypertensive	POS	O
+drugs	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Caution	POS	O
+is	POS	O
+recommended	POS	O
+in	POS	O
+combining	POS	O
+clonidine	POS	O
+and	POS	O
+verapamil	POS	O
+therapy	POS	O
+,	POS	O
+even	POS	O
+in	POS	O
+patients	POS	O
+who	POS	O
+do	POS	O
+not	POS	O
+have	POS	O
+sinus	POS	O
+or	POS	O
+AV	POS	B-NP
+node	POS	I-NP
+dysfunction	POS	I-NP
+.	POS	O
+The	POS	O
+two	POS	O
+drugs	POS	O
+may	POS	O
+act	POS	O
+synergistically	POS	O
+on	POS	O
+both	POS	O
+the	POS	O
+AV	POS	O
+node	POS	O
+and	POS	O
+the	POS	O
+peripheral	POS	O
+circulation	POS	O
+.	POS	O
+Pharmacological	POS	O
+studies	POS	O
+on	POS	O
+a	POS	O
+new	POS	O
+dihydrothienopyridine	POS	O
+calcium	POS	O
+antagonist	POS	O
+,	POS	O
+S	POS	O
+-	POS	O
+312	POS	O
+-	POS	O
+d	POS	O
+.	POS	O
+5th	POS	O
+communication	POS	O
+:	POS	O
+anticonvulsant	POS	O
+effects	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+S	POS	O
+-	POS	O
+312	POS	O
+,	POS	O
+S	POS	O
+-	POS	O
+312	POS	O
+-	POS	O
+d	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+S	POS	O
+-	POS	O
+312	POS	O
+-	POS	O
+l	POS	O
+,	POS	O
+L	POS	O
+-	POS	O
+type	POS	O
+calcium	POS	O
+channel	POS	O
+antagonists	POS	O
+,	POS	O
+showed	POS	O
+anticonvulsant	POS	O
+effects	POS	O
+on	POS	O
+the	POS	O
+audiogenic	POS	O
+tonic	POS	O
+convulsions	POS	B-NP
+in	POS	O
+DBA	POS	O
+/	POS	O
+2	POS	O
+mice	POS	O
+;	POS	O
+and	POS	O
+their	POS	O
+ED50	POS	O
+values	POS	O
+were	POS	O
+18	POS	O
+.	POS	O
+4	POS	O
+(	POS	O
+12	POS	O
+.	POS	O
+8	POS	O
+-	POS	O
+27	POS	O
+.	POS	O
+1	POS	O
+)	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+p	POS	O
+.	POS	O
+o	POS	O
+.	POS	O
+and	POS	O
+15	POS	O
+.	POS	O
+0	POS	O
+(	POS	O
+10	POS	O
+.	POS	O
+2	POS	O
+-	POS	O
+23	POS	O
+.	POS	O
+7	POS	O
+)	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+p	POS	O
+.	POS	O
+o	POS	O
+.	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+while	POS	O
+that	POS	O
+of	POS	O
+flunarizine	POS	O
+was	POS	O
+34	POS	O
+.	POS	O
+0	POS	O
+(	POS	O
+26	POS	O
+.	POS	O
+0	POS	O
+-	POS	O
+44	POS	O
+.	POS	O
+8	POS	O
+)	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+p	POS	O
+.	POS	O
+o	POS	O
+.	POS	O
+Although	POS	O
+moderate	POS	O
+anticonvulsant	POS	O
+effects	POS	O
+of	POS	O
+S	POS	O
+-	POS	O
+312	POS	O
+-	POS	O
+d	POS	O
+in	POS	O
+higher	POS	O
+doses	POS	O
+were	POS	O
+observed	POS	O
+against	POS	O
+the	POS	O
+clonic	POS	O
+convulsions	POS	B-NP
+induced	POS	O
+by	POS	O
+pentylenetetrazole	POS	O
+(	POS	O
+85	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+s	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+)	POS	O
+or	POS	O
+bemegride	POS	O
+(	POS	O
+40	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+s	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+)	POS	O
+,	POS	O
+no	POS	O
+effects	POS	O
+were	POS	O
+observed	POS	O
+in	POS	O
+convulsions	POS	B-NP
+induced	POS	O
+by	POS	O
+N	POS	O
+-	POS	O
+methyl	POS	O
+-	POS	O
+D	POS	O
+-	POS	O
+aspartate	POS	O
+,	POS	O
+picrotoxin	POS	O
+,	POS	O
+or	POS	O
+electroshock	POS	O
+in	POS	O
+Slc	POS	O
+:	POS	O
+ddY	POS	O
+mice	POS	O
+.	POS	O
+S	POS	O
+-	POS	O
+312	POS	O
+-	POS	O
+d	POS	O
+may	POS	O
+be	POS	O
+useful	POS	O
+in	POS	O
+the	POS	O
+therapy	POS	O
+of	POS	O
+certain	POS	O
+types	POS	O
+of	POS	O
+human	POS	O
+epilepsy	POS	B-NP
+.	POS	O
+Transmural	POS	B-NP
+myocardial	POS	I-NP
+infarction	POS	I-NP
+with	POS	O
+sumatriptan	POS	O
+.	POS	O
+For	POS	O
+sumatriptan	POS	O
+,	POS	O
+tightness	POS	B-NP
+in	POS	O
+the	POS	O
+chest	POS	O
+caused	POS	O
+by	POS	O
+an	POS	O
+unknown	POS	O
+mechanism	POS	O
+has	POS	O
+been	POS	O
+reported	POS	O
+in	POS	O
+3	POS	O
+-	POS	O
+5	POS	O
+%	POS	O
+of	POS	O
+users	POS	O
+.	POS	O
+We	POS	O
+describe	POS	O
+a	POS	O
+47	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+with	POS	O
+an	POS	O
+acute	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+after	POS	O
+administration	POS	O
+of	POS	O
+sumatriptan	POS	O
+6	POS	O
+mg	POS	O
+subcutaneously	POS	O
+for	POS	O
+cluster	POS	B-NP
+headache	POS	I-NP
+.	POS	O
+The	POS	O
+patient	POS	O
+had	POS	O
+no	POS	O
+history	POS	O
+of	POS	O
+underlying	POS	O
+ischaemic	POS	B-NP
+heart	POS	I-NP
+disease	POS	I-NP
+or	POS	O
+Prinzmetal	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+angina	POS	I-NP
+.	POS	O
+She	POS	O
+recovered	POS	O
+without	POS	O
+complications	POS	O
+.	POS	O
+Flumazenil	POS	O
+induces	POS	O
+seizures	POS	B-NP
+and	POS	O
+death	POS	B-NP
+in	POS	O
+mixed	POS	O
+cocaine	POS	O
+-	POS	O
+diazepam	POS	O
+intoxications	POS	O
+.	POS	O
+STUDY	POS	O
+HYPOTHESIS	POS	O
+:	POS	O
+Administration	POS	O
+of	POS	O
+the	POS	O
+benzodiazepine	POS	O
+antagonist	POS	O
+flumazenil	POS	O
+may	POS	O
+unmask	POS	O
+seizures	POS	B-NP
+in	POS	O
+mixed	POS	O
+cocaine	POS	O
+-	POS	O
+benzodiazepine	POS	O
+intoxication	POS	O
+.	POS	O
+DESIGN	POS	O
+:	POS	O
+Male	POS	O
+Sprague	POS	O
+-	POS	O
+Dawley	POS	O
+rats	POS	O
+received	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+cocaine	POS	O
+IP	POS	O
+alone	POS	O
+,	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+diazepam	POS	O
+alone	POS	O
+,	POS	O
+or	POS	O
+a	POS	O
+combination	POS	O
+of	POS	O
+diazepam	POS	O
+and	POS	O
+cocaine	POS	O
+.	POS	O
+Three	POS	O
+minutes	POS	O
+later	POS	O
+,	POS	O
+groups	POS	O
+were	POS	O
+challenged	POS	O
+with	POS	O
+vehicle	POS	O
+or	POS	O
+flumazenil	POS	O
+5	POS	O
+or	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+IP	POS	O
+.	POS	O
+Animal	POS	O
+behavior	POS	O
+,	POS	O
+seizures	POS	B-NP
+(	POS	O
+time	POS	O
+to	POS	O
+and	POS	O
+incidence	POS	O
+)	POS	O
+,	POS	O
+death	POS	B-NP
+(	POS	O
+time	POS	O
+to	POS	O
+and	POS	O
+incidence	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+cortical	POS	O
+EEG	POS	O
+tracings	POS	O
+were	POS	O
+recorded	POS	O
+.	POS	O
+INTERVENTIONS	POS	O
+:	POS	O
+Administration	POS	O
+of	POS	O
+flumazenil	POS	O
+to	POS	O
+animals	POS	O
+after	POS	O
+they	POS	O
+had	POS	O
+received	POS	O
+a	POS	O
+combination	POS	O
+dose	POS	O
+of	POS	O
+cocaine	POS	O
+and	POS	O
+diazepam	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+In	POS	O
+group	POS	O
+1	POS	O
+,	POS	O
+animals	POS	O
+received	POS	O
+cocaine	POS	O
+followed	POS	O
+by	POS	O
+vehicle	POS	O
+.	POS	O
+This	POS	O
+resulted	POS	O
+in	POS	O
+100	POS	O
+%	POS	O
+developing	POS	O
+seizures	POS	B-NP
+and	POS	O
+death	POS	B-NP
+.	POS	O
+Group	POS	O
+2	POS	O
+received	POS	O
+diazepam	POS	O
+alone	POS	O
+followed	POS	O
+by	POS	O
+vehicle	POS	O
+.	POS	O
+Animals	POS	O
+became	POS	O
+somnolent	POS	O
+and	POS	O
+none	POS	O
+died	POS	O
+.	POS	O
+Group	POS	O
+3	POS	O
+received	POS	O
+diazepam	POS	O
+followed	POS	O
+by	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+flumazenil	POS	O
+.	POS	O
+Animals	POS	O
+became	POS	O
+somnolent	POS	O
+after	POS	O
+diazepam	POS	O
+and	POS	O
+then	POS	O
+active	POS	O
+after	POS	O
+flumazenil	POS	O
+administration	POS	O
+.	POS	O
+In	POS	O
+group	POS	O
+4	POS	O
+,	POS	O
+a	POS	O
+combination	POS	O
+of	POS	O
+cocaine	POS	O
+and	POS	O
+diazepam	POS	O
+was	POS	O
+administered	POS	O
+simultaneously	POS	O
+.	POS	O
+This	POS	O
+resulted	POS	O
+in	POS	O
+no	POS	O
+overt	POS	O
+or	POS	O
+EEG	POS	O
+-	POS	O
+detectable	POS	O
+seizures	POS	B-NP
+and	POS	O
+a	POS	O
+50	POS	O
+%	POS	O
+incidence	POS	O
+of	POS	O
+death	POS	B-NP
+.	POS	O
+Group	POS	O
+5	POS	O
+received	POS	O
+a	POS	O
+similar	POS	O
+combination	POS	O
+of	POS	O
+cocaine	POS	O
+and	POS	O
+diazepam	POS	O
+,	POS	O
+followed	POS	O
+later	POS	O
+by	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+flumazenil	POS	O
+.	POS	O
+This	POS	O
+resulted	POS	O
+in	POS	O
+an	POS	O
+increased	POS	O
+incidence	POS	O
+of	POS	O
+seizures	POS	B-NP
+,	POS	O
+90	POS	O
+%	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+death	POS	O
+,	POS	O
+100	POS	O
+%	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+,	POS	O
+compared	POS	O
+with	POS	O
+group	POS	O
+4	POS	O
+.	POS	O
+Group	POS	O
+6	POS	O
+received	POS	O
+cocaine	POS	O
+and	POS	O
+diazepam	POS	O
+followed	POS	O
+by	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+flumazenil	POS	O
+.	POS	O
+This	POS	O
+also	POS	O
+resulted	POS	O
+in	POS	O
+an	POS	O
+increased	POS	O
+incidence	POS	O
+of	POS	O
+seizures	POS	B-NP
+,	POS	O
+90	POS	O
+%	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+death	POS	O
+,	POS	O
+90	POS	O
+%	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+,	POS	O
+compared	POS	O
+with	POS	O
+group	POS	O
+4	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Flumazenil	POS	O
+can	POS	O
+unmask	POS	O
+seizures	POS	B-NP
+and	POS	O
+increase	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+death	POS	B-NP
+in	POS	O
+a	POS	O
+model	POS	O
+of	POS	O
+combined	POS	O
+cocaine	POS	O
+-	POS	O
+diazepam	POS	O
+intoxications	POS	O
+.	POS	O
+Mechanisms	POS	O
+for	POS	O
+protective	POS	O
+effects	POS	O
+of	POS	O
+free	POS	O
+radical	POS	O
+scavengers	POS	O
+on	POS	O
+gentamicin	POS	O
+-	POS	O
+mediated	POS	O
+nephropathy	POS	B-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+Studies	POS	O
+were	POS	O
+performed	POS	O
+to	POS	O
+examine	POS	O
+the	POS	O
+mechanisms	POS	O
+for	POS	O
+the	POS	O
+protective	POS	O
+effects	POS	O
+of	POS	O
+free	POS	O
+radical	POS	O
+scavengers	POS	O
+on	POS	O
+gentamicin	POS	O
+(	POS	O
+GM	POS	O
+)	POS	O
+-	POS	O
+mediated	POS	O
+nephropathy	POS	B-NP
+.	POS	O
+Administration	POS	O
+of	POS	O
+GM	POS	O
+at	POS	O
+40	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+sc	POS	O
+for	POS	O
+13	POS	O
+days	POS	O
+to	POS	O
+rats	POS	O
+induced	POS	O
+a	POS	O
+significant	POS	O
+reduction	POS	O
+in	POS	O
+renal	POS	O
+blood	POS	O
+flow	POS	O
+(	POS	O
+RBF	POS	O
+)	POS	O
+and	POS	O
+inulin	POS	O
+clearance	POS	O
+(	POS	O
+CIn	POS	O
+)	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+marked	POS	O
+tubular	POS	O
+damage	POS	O
+.	POS	O
+A	POS	O
+significant	POS	O
+reduction	POS	O
+in	POS	O
+urinary	POS	O
+guanosine	POS	O
+3	POS	O
+'	POS	O
+,	POS	O
+5	POS	O
+'	POS	O
+-	POS	O
+cyclic	POS	O
+monophosphate	POS	O
+(	POS	O
+cGMP	POS	O
+)	POS	O
+excretion	POS	O
+and	POS	O
+a	POS	O
+significant	POS	O
+increase	POS	O
+in	POS	O
+renal	POS	O
+cortical	POS	O
+renin	POS	O
+and	POS	O
+endothelin	POS	O
+-	POS	O
+1	POS	O
+contents	POS	O
+were	POS	O
+also	POS	O
+observed	POS	O
+in	POS	O
+GM	POS	O
+-	POS	O
+mediated	POS	O
+nephropathy	POS	B-NP
+.	POS	O
+Superoxide	POS	O
+dismutase	POS	O
+(	POS	O
+SOD	POS	O
+)	POS	O
+or	POS	O
+dimethylthiourea	POS	O
+(	POS	O
+DMTU	POS	O
+)	POS	O
+significantly	POS	O
+lessened	POS	O
+the	POS	O
+GM	POS	O
+-	POS	O
+induced	POS	O
+decrement	POS	O
+in	POS	O
+CIn	POS	O
+.	POS	O
+The	POS	O
+SOD	POS	O
+-	POS	O
+induced	POS	O
+increase	POS	O
+in	POS	O
+glomerular	POS	O
+filtration	POS	O
+rate	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+a	POS	O
+marked	POS	O
+improvement	POS	O
+in	POS	O
+RBF	POS	O
+,	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+urinary	POS	O
+cGMP	POS	O
+excretion	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+renal	POS	O
+renin	POS	O
+and	POS	O
+endothelin	POS	O
+-	POS	O
+1	POS	O
+content	POS	O
+.	POS	O
+SOD	POS	O
+did	POS	O
+not	POS	O
+attenuate	POS	O
+the	POS	O
+tubular	POS	O
+damage	POS	O
+.	POS	O
+In	POS	O
+contrast	POS	O
+,	POS	O
+DMTU	POS	O
+significantly	POS	O
+reduced	POS	O
+the	POS	O
+tubular	POS	O
+damage	POS	O
+and	POS	O
+lipid	POS	O
+peroxidation	POS	O
+,	POS	O
+but	POS	O
+it	POS	O
+did	POS	O
+not	POS	O
+affect	POS	O
+renal	POS	O
+hemodynamics	POS	O
+and	POS	O
+vasoactive	POS	O
+substances	POS	O
+.	POS	O
+Neither	POS	O
+SOD	POS	O
+nor	POS	O
+DMTU	POS	O
+affected	POS	O
+the	POS	O
+renal	POS	O
+cortical	POS	O
+GM	POS	O
+content	POS	O
+in	POS	O
+GM	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+1	POS	O
+)	POS	O
+both	POS	O
+SOD	POS	O
+and	POS	O
+DMTU	POS	O
+have	POS	O
+protective	POS	O
+effects	POS	O
+on	POS	O
+GM	POS	O
+-	POS	O
+mediated	POS	O
+nephropathy	POS	B-NP
+,	POS	O
+2	POS	O
+)	POS	O
+the	POS	O
+mechanisms	POS	O
+for	POS	O
+the	POS	O
+protective	POS	O
+effects	POS	O
+differ	POS	O
+for	POS	O
+SOD	POS	O
+and	POS	O
+DMTU	POS	O
+,	POS	O
+and	POS	O
+3	POS	O
+)	POS	O
+superoxide	POS	O
+anions	POS	O
+play	POS	O
+a	POS	O
+critical	POS	O
+role	POS	O
+in	POS	O
+GM	POS	O
+-	POS	O
+induced	POS	O
+renal	POS	O
+vasoconstriction	POS	O
+.	POS	O
+Cephalothin	POS	O
+-	POS	O
+induced	POS	O
+immune	POS	O
+hemolytic	POS	B-NP
+anemia	POS	I-NP
+.	POS	O
+A	POS	O
+patient	POS	O
+with	POS	O
+renal	POS	B-NP
+disease	POS	I-NP
+developed	POS	O
+Coombs	POS	B-NP
+-	POS	O
+positive	POS	O
+hemolytic	POS	B-NP
+anemia	POS	I-NP
+while	POS	O
+receiving	POS	O
+cephalothin	POS	O
+therapy	POS	O
+.	POS	O
+An	POS	O
+anti	POS	O
+-	POS	O
+cephalothin	POS	O
+IgG	POS	O
+antibody	POS	O
+was	POS	O
+detected	POS	O
+in	POS	O
+the	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+serum	POS	O
+and	POS	O
+in	POS	O
+the	POS	O
+eluates	POS	O
+from	POS	O
+her	POS	O
+erythrocytes	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+nonimmunologic	POS	O
+binding	POS	O
+of	POS	O
+normal	POS	O
+and	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+serum	POS	O
+proteins	POS	O
+to	POS	O
+her	POS	O
+own	POS	O
+and	POS	O
+cephalothin	POS	O
+-	POS	O
+coated	POS	O
+normal	POS	O
+red	POS	O
+cells	POS	O
+was	POS	O
+demonstrated	POS	O
+.	POS	O
+Skin	POS	O
+tests	POS	O
+and	POS	O
+in	POS	O
+vitro	POS	O
+lymphocyte	POS	O
+stimulation	POS	O
+revealed	POS	O
+that	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+sensitized	POS	O
+to	POS	O
+cephalothin	POS	O
+and	POS	O
+also	POS	O
+to	POS	O
+ampicillin	POS	O
+.	POS	O
+Careful	POS	O
+investigation	POS	O
+of	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+hemolytic	POS	B-NP
+anemias	POS	I-NP
+reveals	POS	O
+the	POS	O
+complexity	POS	O
+of	POS	O
+the	POS	O
+immune	POS	O
+mechanisms	POS	O
+involved	POS	O
+.	POS	O
+Assessment	POS	O
+of	POS	O
+cardiomyocyte	POS	O
+DNA	POS	O
+synthesis	POS	O
+during	POS	O
+hypertrophy	POS	B-NP
+in	POS	O
+adult	POS	O
+mice	POS	O
+.	POS	O
+The	POS	O
+ability	POS	O
+of	POS	O
+cardiomyocytes	POS	O
+to	POS	O
+synthesize	POS	O
+DNA	POS	O
+in	POS	O
+response	POS	O
+to	POS	O
+experimentally	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+hypertrophy	POS	I-NP
+was	POS	O
+assessed	POS	O
+in	POS	O
+adult	POS	O
+mice	POS	O
+.	POS	O
+Isoproterenol	POS	O
+delivered	POS	O
+by	POS	O
+osmotic	POS	O
+minipump	POS	O
+implantation	POS	O
+in	POS	O
+adult	POS	O
+C3Heb	POS	O
+/	POS	O
+FeJ	POS	O
+mice	POS	O
+resulted	POS	O
+in	POS	O
+a	POS	O
+46	POS	O
+%	POS	O
+increase	POS	O
+in	POS	O
+heart	POS	O
+weight	POS	O
+and	POS	O
+a	POS	O
+19	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+increase	POS	O
+in	POS	O
+cardiomyocyte	POS	O
+area	POS	O
+.	POS	O
+No	POS	O
+DNA	POS	O
+synthesis	POS	O
+,	POS	O
+as	POS	O
+assessed	POS	O
+by	POS	O
+autoradiographic	POS	O
+analysis	POS	O
+of	POS	O
+isolated	POS	O
+cardiomyocytes	POS	O
+,	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+control	POS	O
+or	POS	O
+hypertrophic	POS	O
+hearts	POS	O
+.	POS	O
+A	POS	O
+survey	POS	O
+of	POS	O
+15	POS	O
+independent	POS	O
+inbred	POS	O
+strains	POS	O
+of	POS	O
+mice	POS	O
+revealed	POS	O
+that	POS	O
+ventricular	POS	O
+cardiomyocyte	POS	O
+nuclear	POS	O
+number	POS	O
+ranged	POS	O
+from	POS	O
+3	POS	O
+to	POS	O
+13	POS	O
+%	POS	O
+mononucleate	POS	O
+,	POS	O
+suggesting	POS	O
+that	POS	O
+cardiomyocyte	POS	O
+terminal	POS	O
+differentiation	POS	O
+is	POS	O
+influenced	POS	O
+directly	POS	O
+or	POS	O
+indirectly	POS	O
+by	POS	O
+genetic	POS	O
+background	POS	O
+.	POS	O
+To	POS	O
+determine	POS	O
+whether	POS	O
+the	POS	O
+capacity	POS	O
+for	POS	O
+reactive	POS	O
+DNA	POS	O
+synthesis	POS	O
+was	POS	O
+also	POS	O
+subject	POS	O
+to	POS	O
+genetic	POS	O
+regulation	POS	O
+,	POS	O
+cardiac	POS	B-NP
+hypertrophy	POS	I-NP
+was	POS	O
+induced	POS	O
+in	POS	O
+the	POS	O
+strains	POS	O
+of	POS	O
+mice	POS	O
+comprising	POS	O
+the	POS	O
+extremes	POS	O
+of	POS	O
+the	POS	O
+nuclear	POS	O
+number	POS	O
+survey	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+indicate	POS	O
+that	POS	O
+adult	POS	O
+mouse	POS	O
+atrial	POS	O
+and	POS	O
+ventricular	POS	O
+cardiomyocytes	POS	O
+do	POS	O
+not	POS	O
+synthesize	POS	O
+DNA	POS	O
+in	POS	O
+response	POS	O
+to	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+hypertrophy	POS	I-NP
+.	POS	O
+Central	POS	O
+cardiovascular	POS	O
+effects	POS	O
+of	POS	O
+AVP	POS	O
+and	POS	O
+ANP	POS	O
+in	POS	O
+normotensive	POS	O
+and	POS	O
+spontaneously	POS	O
+hypertensive	POS	B-NP
+rats	POS	O
+.	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+compare	POS	O
+influence	POS	O
+of	POS	O
+central	POS	O
+arginine	POS	O
+vasopressin	POS	O
+(	POS	O
+AVP	POS	O
+)	POS	O
+and	POS	O
+of	POS	O
+atrial	POS	O
+natriuretic	POS	O
+peptide	POS	O
+(	POS	O
+ANP	POS	O
+)	POS	O
+on	POS	O
+control	POS	O
+of	POS	O
+arterial	POS	O
+blood	POS	O
+pressure	POS	O
+(	POS	O
+MAP	POS	O
+)	POS	O
+and	POS	O
+heart	POS	O
+rate	POS	O
+(	POS	O
+HR	POS	O
+)	POS	O
+in	POS	O
+normotensive	POS	O
+(	POS	O
+WKY	POS	O
+)	POS	O
+and	POS	O
+spontaneously	POS	O
+hypertensive	POS	B-NP
+(	POS	O
+SHR	POS	O
+)	POS	O
+rats	POS	O
+.	POS	O
+Three	POS	O
+series	POS	O
+of	POS	O
+experiments	POS	O
+were	POS	O
+performed	POS	O
+on	POS	O
+30	POS	O
+WKY	POS	O
+and	POS	O
+30	POS	O
+SHR	POS	O
+,	POS	O
+chronically	POS	O
+instrumented	POS	O
+with	POS	O
+guide	POS	O
+tubes	POS	O
+in	POS	O
+the	POS	O
+lateral	POS	O
+ventricle	POS	O
+(	POS	O
+LV	POS	O
+)	POS	O
+and	POS	O
+arterial	POS	O
+and	POS	O
+venous	POS	O
+catheters	POS	O
+.	POS	O
+MAP	POS	O
+and	POS	O
+HR	POS	O
+were	POS	O
+monitored	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+injections	POS	O
+of	POS	O
+either	POS	O
+vehicle	POS	O
+or	POS	O
+1	POS	O
+,	POS	O
+10	POS	O
+and	POS	O
+50	POS	O
+ng	POS	O
+of	POS	O
+AVP	POS	O
+and	POS	O
+25	POS	O
+,	POS	O
+125	POS	O
+and	POS	O
+500	POS	O
+ng	POS	O
+of	POS	O
+ANP	POS	O
+.	POS	O
+Sensitivity	POS	O
+of	POS	O
+cardiac	POS	O
+component	POS	O
+of	POS	O
+baroreflex	POS	O
+(	POS	O
+CCB	POS	O
+)	POS	O
+,	POS	O
+expressed	POS	O
+as	POS	O
+a	POS	O
+slope	POS	O
+of	POS	O
+the	POS	O
+regression	POS	O
+line	POS	O
+was	POS	O
+determined	POS	O
+from	POS	O
+relationships	POS	O
+between	POS	O
+systolic	POS	O
+arterial	POS	O
+pressure	POS	O
+(	POS	O
+SAP	POS	O
+)	POS	O
+and	POS	O
+HR	POS	O
+period	POS	O
+(	POS	O
+HRp	POS	O
+)	POS	O
+during	POS	O
+phenylephrine	POS	O
+(	POS	O
+Phe	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+and	POS	O
+sodium	POS	O
+nitroprusside	POS	O
+(	POS	O
+SN	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+.	POS	O
+CCB	POS	O
+was	POS	O
+measured	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+administration	POS	O
+of	POS	O
+either	POS	O
+vehicle	POS	O
+,	POS	O
+AVP	POS	O
+,	POS	O
+ANP	POS	O
+,	POS	O
+or	POS	O
+both	POS	O
+peptides	POS	O
+together	POS	O
+.	POS	O
+Increases	POS	O
+of	POS	O
+MAP	POS	O
+occurred	POS	O
+after	POS	O
+LV	POS	O
+administration	POS	O
+of	POS	O
+1	POS	O
+,	POS	O
+10	POS	O
+and	POS	O
+50	POS	O
+ng	POS	O
+of	POS	O
+AVP	POS	O
+in	POS	O
+WKY	POS	O
+and	POS	O
+of	POS	O
+10	POS	O
+and	POS	O
+50	POS	O
+ng	POS	O
+in	POS	O
+SHR	POS	O
+.	POS	O
+ANP	POS	O
+did	POS	O
+not	POS	O
+cause	POS	O
+significant	POS	O
+changes	POS	O
+in	POS	O
+MAP	POS	O
+in	POS	O
+both	POS	O
+strains	POS	O
+as	POS	O
+compared	POS	O
+to	POS	O
+vehicle	POS	O
+,	POS	O
+but	POS	O
+it	POS	O
+abolished	POS	O
+AVP	POS	O
+-	POS	O
+induced	POS	O
+MAP	POS	O
+increase	POS	O
+in	POS	O
+WKY	POS	O
+and	POS	O
+SHR	POS	O
+.	POS	O
+CCB	POS	O
+was	POS	O
+reduced	POS	O
+in	POS	O
+WKY	POS	O
+and	POS	O
+SHR	POS	O
+after	POS	O
+LV	POS	O
+administration	POS	O
+of	POS	O
+AVP	POS	O
+during	POS	O
+SN	POS	O
+-	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+.	POS	O
+In	POS	O
+SHR	POS	O
+but	POS	O
+not	POS	O
+in	POS	O
+WKY	POS	O
+administration	POS	O
+of	POS	O
+ANP	POS	O
+,	POS	O
+AVP	POS	O
+and	POS	O
+ANP	POS	O
++	POS	O
+AVP	POS	O
+decreased	POS	O
+CCB	POS	O
+during	POS	O
+Phe	POS	O
+-	POS	O
+induced	POS	O
+MAP	POS	O
+elevation	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+centrally	POS	O
+applied	POS	O
+AVP	POS	O
+and	POS	O
+ANP	POS	O
+exert	POS	O
+differential	POS	O
+effects	POS	O
+on	POS	O
+blood	POS	O
+pressure	POS	O
+and	POS	O
+baroreflex	POS	O
+control	POS	O
+of	POS	O
+heart	POS	O
+rate	POS	O
+in	POS	O
+WKY	POS	O
+and	POS	O
+SHR	POS	O
+and	POS	O
+suggest	POS	O
+interaction	POS	O
+of	POS	O
+these	POS	O
+two	POS	O
+peptides	POS	O
+in	POS	O
+blood	POS	O
+pressure	POS	O
+regulation	POS	O
+at	POS	O
+the	POS	O
+level	POS	O
+of	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+.	POS	O
+Cutaneous	POS	O
+exposure	POS	O
+to	POS	O
+warfarin	POS	O
+-	POS	O
+like	POS	O
+anticoagulant	POS	O
+causing	POS	O
+an	POS	O
+intracerebral	POS	B-NP
+hemorrhage	POS	I-NP
+:	POS	O
+a	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+intercerebral	POS	O
+hematoma	POS	B-NP
+due	POS	O
+to	POS	O
+warfarin	POS	O
+-	POS	O
+induced	POS	O
+coagulopathy	POS	B-NP
+is	POS	O
+presented	POS	O
+.	POS	O
+The	POS	O
+39	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+had	POS	O
+spread	POS	O
+a	POS	O
+warfarin	POS	O
+-	POS	O
+type	POS	O
+rat	POS	O
+poison	POS	O
+around	POS	O
+her	POS	O
+house	POS	O
+weekly	POS	O
+using	POS	O
+her	POS	O
+bare	POS	O
+hands	POS	O
+,	POS	O
+with	POS	O
+no	POS	O
+washing	POS	O
+post	POS	O
+application	POS	O
+.	POS	O
+Percutaneous	POS	O
+absorption	POS	O
+of	POS	O
+warfarin	POS	O
+causing	POS	O
+coagulopathy	POS	B-NP
+,	POS	O
+reported	POS	O
+three	POS	O
+times	POS	O
+in	POS	O
+the	POS	O
+past	POS	O
+,	POS	O
+is	POS	O
+a	POS	O
+significant	POS	O
+risk	POS	O
+if	POS	O
+protective	POS	O
+measures	POS	O
+,	POS	O
+such	POS	O
+as	POS	O
+gloves	POS	O
+,	POS	O
+are	POS	O
+not	POS	O
+used	POS	O
+.	POS	O
+An	POS	O
+adverse	POS	O
+drug	POS	O
+interaction	POS	O
+with	POS	O
+piroxicam	POS	O
+,	POS	O
+which	POS	O
+she	POS	O
+took	POS	O
+occasionally	POS	O
+,	POS	O
+may	POS	O
+have	POS	O
+exacerbated	POS	O
+the	POS	O
+coagulopathy	POS	B-NP
+.	POS	O
+Pediatric	POS	O
+heart	POS	O
+transplantation	POS	O
+without	POS	O
+chronic	POS	O
+maintenance	POS	O
+steroids	POS	O
+.	POS	O
+From	POS	O
+1986	POS	O
+to	POS	O
+February	POS	O
+1993	POS	O
+,	POS	O
+40	POS	O
+children	POS	O
+aged	POS	O
+2	POS	O
+months	POS	O
+to	POS	O
+18	POS	O
+years	POS	O
+(	POS	O
+average	POS	O
+age	POS	O
+10	POS	O
+.	POS	O
+4	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+5	POS	O
+.	POS	O
+8	POS	O
+years	POS	O
+)	POS	O
+underwent	POS	O
+heart	POS	O
+transplantation	POS	O
+.	POS	O
+Indications	POS	O
+for	POS	O
+transplantation	POS	O
+were	POS	O
+idiopathic	POS	B-NP
+cardiomyopathy	POS	I-NP
+(	POS	O
+52	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+congenital	POS	B-NP
+heart	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+35	POS	O
+%	POS	O
+)	POS	O
+with	POS	O
+and	POS	O
+without	POS	O
+prior	POS	O
+repair	POS	O
+(	POS	O
+71	POS	O
+%	POS	O
+and	POS	O
+29	POS	O
+%	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+,	POS	O
+hypertrophic	POS	B-NP
+cardiomyopathy	POS	I-NP
+(	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+valvular	POS	B-NP
+heart	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+3	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+doxorubicin	POS	O
+cardiomyopathy	POS	B-NP
+(	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+managed	POS	O
+with	POS	O
+cyclosporine	POS	O
+and	POS	O
+azathioprine	POS	O
+.	POS	O
+No	POS	O
+prophylaxis	POS	O
+with	POS	O
+antilymphocyte	POS	O
+globulin	POS	O
+was	POS	O
+used	POS	O
+.	POS	O
+Steroids	POS	O
+were	POS	O
+given	POS	O
+to	POS	O
+39	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+for	POS	O
+refractory	POS	O
+rejection	POS	O
+,	POS	O
+but	POS	O
+weaning	POS	O
+was	POS	O
+always	POS	O
+attempted	POS	O
+and	POS	O
+generally	POS	O
+successful	POS	O
+(	POS	O
+64	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Five	POS	O
+patients	POS	O
+(	POS	O
+14	POS	O
+%	POS	O
+)	POS	O
+received	POS	O
+maintenance	POS	O
+steroids	POS	O
+.	POS	O
+Four	POS	O
+patients	POS	O
+died	POS	O
+in	POS	O
+the	POS	O
+perioperative	POS	O
+period	POS	O
+and	POS	O
+one	POS	O
+died	POS	O
+4	POS	O
+months	POS	O
+later	POS	O
+.	POS	O
+There	POS	O
+have	POS	O
+been	POS	O
+no	POS	O
+deaths	POS	O
+related	POS	O
+to	POS	O
+rejection	POS	O
+or	POS	O
+infection	POS	O
+.	POS	O
+Average	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+was	POS	O
+36	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+19	POS	O
+months	POS	O
+(	POS	O
+range	POS	O
+1	POS	O
+to	POS	O
+65	POS	O
+months	POS	O
+)	POS	O
+.	POS	O
+Cumulative	POS	O
+survival	POS	O
+is	POS	O
+88	POS	O
+%	POS	O
+at	POS	O
+5	POS	O
+years	POS	O
+.	POS	O
+In	POS	O
+patients	POS	O
+less	POS	O
+than	POS	O
+7	POS	O
+years	POS	O
+of	POS	O
+age	POS	O
+,	POS	O
+rejection	POS	O
+was	POS	O
+monitored	POS	O
+noninvasively	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+first	POS	O
+postoperative	POS	O
+month	POS	O
+,	POS	O
+89	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+were	POS	O
+treated	POS	O
+for	POS	O
+rejection	POS	O
+.	POS	O
+Freedom	POS	O
+from	POS	O
+serious	POS	O
+infections	POS	B-NP
+was	POS	O
+83	POS	O
+%	POS	O
+at	POS	O
+1	POS	O
+month	POS	O
+and	POS	O
+65	POS	O
+%	POS	O
+at	POS	O
+1	POS	O
+year	POS	O
+.	POS	O
+Cytomegalovirus	POS	B-NP
+infections	POS	I-NP
+were	POS	O
+treated	POS	O
+successfully	POS	O
+with	POS	O
+ganciclovir	POS	O
+in	POS	O
+11	POS	O
+patients	POS	O
+.	POS	O
+No	POS	O
+impairment	POS	O
+of	POS	O
+growth	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+children	POS	O
+who	POS	O
+underwent	POS	O
+transplantation	POS	O
+compared	POS	O
+with	POS	O
+a	POS	O
+control	POS	O
+population	POS	O
+.	POS	O
+Twenty	POS	O
+-	POS	O
+one	POS	O
+patients	POS	O
+(	POS	O
+60	POS	O
+%	POS	O
+)	POS	O
+have	POS	O
+undergone	POS	O
+annual	POS	O
+catheterizations	POS	O
+and	POS	O
+no	POS	O
+sign	POS	O
+of	POS	O
+graft	POS	O
+atherosclerosis	POS	B-NP
+has	POS	O
+been	POS	O
+observed	POS	O
+.	POS	O
+Seizures	POS	B-NP
+occurred	POS	O
+in	POS	O
+five	POS	O
+patients	POS	O
+(	POS	O
+14	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+hypertension	POS	B-NP
+was	POS	O
+treated	POS	O
+in	POS	O
+10	POS	O
+patients	POS	O
+(	POS	O
+28	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+No	POS	O
+patient	POS	O
+was	POS	O
+disabled	POS	O
+and	POS	O
+no	POS	O
+lymphoproliferative	POS	B-NP
+disorder	POS	I-NP
+was	POS	O
+observed	POS	O
+.	POS	O
+(	POS	O
+ABSTRACT	POS	O
+TRUNCATED	POS	O
+AT	POS	O
+250	POS	O
+WORDS	POS	O
+)	POS	O
+Delirium	POS	B-NP
+during	POS	O
+fluoxetine	POS	O
+treatment	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+The	POS	O
+correlation	POS	O
+between	POS	O
+high	POS	O
+serum	POS	O
+tricyclic	POS	O
+antidepressant	POS	O
+concentrations	POS	O
+and	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+side	POS	O
+effects	POS	O
+has	POS	O
+been	POS	O
+well	POS	O
+established	POS	O
+.	POS	O
+Only	POS	O
+a	POS	O
+few	POS	O
+reports	POS	O
+exist	POS	O
+,	POS	O
+however	POS	O
+,	POS	O
+on	POS	O
+the	POS	O
+relationship	POS	O
+between	POS	O
+the	POS	O
+serum	POS	O
+concentrations	POS	O
+of	POS	O
+selective	POS	O
+serotonin	POS	O
+reuptake	POS	O
+inhibitors	POS	O
+(	POS	O
+SSRIs	POS	O
+)	POS	O
+and	POS	O
+their	POS	O
+toxic	POS	O
+effects	POS	O
+.	POS	O
+In	POS	O
+some	POS	O
+cases	POS	O
+,	POS	O
+a	POS	O
+high	POS	O
+serum	POS	O
+concentration	POS	O
+of	POS	O
+citalopram	POS	O
+(	POS	O
+>	POS	O
+600	POS	O
+nmol	POS	O
+/	POS	O
+L	POS	O
+)	POS	O
+in	POS	O
+elderly	POS	O
+patients	POS	O
+has	POS	O
+been	POS	O
+associated	POS	O
+with	POS	O
+increased	POS	O
+somnolence	POS	B-NP
+and	POS	O
+movement	POS	B-NP
+difficulties	POS	I-NP
+.	POS	O
+Widespread	POS	B-NP
+cognitive	POS	I-NP
+disorders	POS	I-NP
+,	POS	O
+such	POS	O
+as	POS	O
+delirium	POS	B-NP
+,	POS	O
+have	POS	O
+not	POS	O
+been	POS	O
+previously	POS	O
+linked	POS	O
+with	POS	O
+high	POS	O
+blood	POS	O
+levels	POS	O
+of	POS	O
+SSRIs	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+report	POS	O
+,	POS	O
+we	POS	O
+describe	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+acute	POS	O
+hyperkinetic	POS	B-NP
+delirium	POS	I-NP
+connected	POS	O
+with	POS	O
+a	POS	O
+high	POS	O
+serum	POS	O
+total	POS	O
+fluoxetine	POS	O
+(	POS	O
+fluoxetine	POS	O
+plus	POS	O
+desmethylfluoxetine	POS	O
+)	POS	O
+concentration	POS	O
+.	POS	O
+Pulmonary	POS	B-NP
+edema	POS	I-NP
+and	POS	O
+shock	POS	B-NP
+after	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+aracytine	POS	O
+-	POS	O
+C	POS	O
+for	POS	O
+lymphoma	POS	B-NP
+;	POS	O
+possible	POS	O
+role	POS	O
+of	POS	O
+TNF	POS	O
+-	POS	O
+alpha	POS	O
+and	POS	O
+PAF	POS	O
+.	POS	O
+Four	POS	O
+out	POS	O
+of	POS	O
+23	POS	O
+consecutive	POS	O
+patients	POS	O
+treated	POS	O
+with	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+Ara	POS	O
+-	POS	O
+C	POS	O
+for	POS	O
+lymphomas	POS	B-NP
+in	POS	O
+our	POS	O
+institution	POS	O
+developed	POS	O
+a	POS	O
+strikingly	POS	O
+similar	POS	O
+syndrome	POS	O
+during	POS	O
+the	POS	O
+perfusion	POS	O
+.	POS	O
+It	POS	O
+was	POS	O
+characterized	POS	O
+by	POS	O
+the	POS	O
+onset	POS	O
+of	POS	O
+fever	POS	B-NP
+,	POS	O
+diarrhea	POS	B-NP
+,	POS	O
+shock	POS	B-NP
+,	POS	O
+pulmonary	POS	B-NP
+edema	POS	I-NP
+,	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+,	POS	O
+metabolic	POS	B-NP
+acidosis	POS	I-NP
+,	POS	O
+weight	POS	B-NP
+gain	POS	I-NP
+and	POS	O
+leukocytosis	POS	B-NP
+.	POS	O
+Thorough	POS	O
+bacteriological	POS	O
+screening	POS	O
+failed	POS	O
+to	POS	O
+provide	POS	O
+evidence	POS	O
+of	POS	O
+infection	POS	O
+.	POS	O
+Sequential	POS	O
+biological	POS	O
+assays	POS	O
+of	POS	O
+IL	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+IL	POS	O
+-	POS	O
+2	POS	O
+,	POS	O
+TNF	POS	O
+and	POS	O
+PAF	POS	O
+were	POS	O
+performed	POS	O
+during	POS	O
+Ara	POS	O
+-	POS	O
+C	POS	O
+infusion	POS	O
+to	POS	O
+ten	POS	O
+patients	POS	O
+,	POS	O
+including	POS	O
+the	POS	O
+four	POS	O
+who	POS	O
+developed	POS	O
+the	POS	O
+syndrome	POS	O
+.	POS	O
+TNF	POS	O
+and	POS	O
+PAF	POS	O
+activity	POS	O
+was	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+serum	POS	O
+of	POS	O
+respectively	POS	O
+two	POS	O
+and	POS	O
+four	POS	O
+of	POS	O
+the	POS	O
+cases	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+in	POS	O
+the	POS	O
+six	POS	O
+controls	POS	O
+.	POS	O
+As	POS	O
+TNF	POS	O
+and	POS	O
+PAF	POS	O
+are	POS	O
+thought	POS	O
+to	POS	O
+be	POS	O
+involved	POS	O
+in	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+septic	POS	B-NP
+shock	POS	I-NP
+and	POS	O
+adult	POS	O
+respiratory	POS	B-NP
+distress	POS	I-NP
+syndrome	POS	I-NP
+,	POS	O
+we	POS	O
+hypothesize	POS	O
+that	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+Ara	POS	O
+-	POS	O
+C	POS	O
+may	POS	O
+be	POS	O
+associated	POS	O
+with	POS	O
+cytokine	POS	O
+release	POS	O
+.	POS	O
+Protective	POS	O
+effect	POS	O
+of	POS	O
+clentiazem	POS	O
+against	POS	O
+epinephrine	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+injury	POS	I-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+We	POS	O
+investigated	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+clentiazem	POS	O
+,	POS	O
+a	POS	O
+1	POS	O
+,	POS	O
+5	POS	O
+-	POS	O
+benzothiazepine	POS	O
+calcium	POS	O
+antagonist	POS	O
+,	POS	O
+on	POS	O
+epinephrine	POS	O
+-	POS	O
+induced	POS	O
+cardiomyopathy	POS	B-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+With	POS	O
+2	POS	O
+-	POS	O
+week	POS	O
+chronic	POS	O
+epinephrine	POS	O
+infusion	POS	O
+,	POS	O
+16	POS	O
+of	POS	O
+30	POS	O
+rats	POS	O
+died	POS	O
+within	POS	O
+4	POS	O
+days	POS	O
+,	POS	O
+and	POS	O
+severe	POS	O
+ischemic	POS	B-NP
+lesions	POS	I-NP
+and	POS	O
+fibrosis	POS	B-NP
+of	POS	O
+the	POS	O
+left	POS	O
+ventricles	POS	O
+were	POS	O
+observed	POS	O
+.	POS	O
+In	POS	O
+epinephrine	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+,	POS	O
+left	POS	O
+atrial	POS	O
+and	POS	O
+left	POS	O
+ventricular	POS	O
+papillary	POS	O
+muscle	POS	O
+contractile	POS	O
+responses	POS	O
+to	POS	O
+isoproterenol	POS	O
+were	POS	O
+reduced	POS	O
+,	POS	O
+but	POS	O
+responses	POS	O
+to	POS	O
+calcium	POS	O
+were	POS	O
+normal	POS	O
+or	POS	O
+enhanced	POS	O
+compared	POS	O
+to	POS	O
+controls	POS	O
+.	POS	O
+Left	POS	O
+ventricular	POS	O
+alpha	POS	O
+and	POS	O
+beta	POS	O
+adrenoceptor	POS	O
+densities	POS	O
+were	POS	O
+also	POS	O
+reduced	POS	O
+compared	POS	O
+to	POS	O
+controls	POS	O
+.	POS	O
+Treatment	POS	O
+with	POS	O
+clentiazem	POS	O
+prevented	POS	O
+epinephrine	POS	O
+-	POS	O
+induced	POS	O
+death	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+attenuated	POS	O
+the	POS	O
+ventricular	POS	B-NP
+ischemic	POS	I-NP
+lesions	POS	I-NP
+and	POS	O
+fibrosis	POS	B-NP
+,	POS	O
+in	POS	O
+a	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+manner	POS	O
+.	POS	O
+Left	POS	O
+atrial	POS	O
+and	POS	O
+left	POS	O
+ventricular	POS	O
+papillary	POS	O
+muscle	POS	O
+contractile	POS	O
+responses	POS	O
+to	POS	O
+isoproterenol	POS	O
+were	POS	O
+reduced	POS	O
+compared	POS	O
+to	POS	O
+controls	POS	O
+in	POS	O
+groups	POS	O
+treated	POS	O
+with	POS	O
+clentiazem	POS	O
+alone	POS	O
+,	POS	O
+but	POS	O
+combined	POS	O
+with	POS	O
+epinephrine	POS	O
+,	POS	O
+clentiazem	POS	O
+restored	POS	O
+left	POS	O
+atrial	POS	O
+responses	POS	O
+and	POS	O
+enhanced	POS	O
+left	POS	O
+ventricular	POS	O
+papillary	POS	O
+responses	POS	O
+to	POS	O
+isoproterenol	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+other	POS	O
+hand	POS	O
+clentiazem	POS	O
+did	POS	O
+not	POS	O
+prevent	POS	O
+epinephrine	POS	O
+-	POS	O
+induced	POS	O
+down	POS	O
+-	POS	O
+regulation	POS	O
+of	POS	O
+alpha	POS	O
+and	POS	O
+beta	POS	O
+adrenoceptors	POS	O
+.	POS	O
+Interestingly	POS	O
+,	POS	O
+clentiazem	POS	O
+,	POS	O
+infused	POS	O
+alone	POS	O
+,	POS	O
+resulted	POS	O
+in	POS	O
+decreased	POS	O
+adrenergic	POS	O
+receptor	POS	O
+densities	POS	O
+in	POS	O
+the	POS	O
+left	POS	O
+ventricle	POS	O
+.	POS	O
+Clentiazem	POS	O
+also	POS	O
+did	POS	O
+not	POS	O
+prevent	POS	O
+the	POS	O
+enhanced	POS	O
+responses	POS	O
+to	POS	O
+calcium	POS	O
+seen	POS	O
+in	POS	O
+the	POS	O
+epinephrine	POS	O
+-	POS	O
+treated	POS	O
+animals	POS	O
+,	POS	O
+although	POS	O
+the	POS	O
+high	POS	O
+dose	POS	O
+of	POS	O
+clentiazem	POS	O
+partially	POS	O
+attenuated	POS	O
+the	POS	O
+maximal	POS	O
+response	POS	O
+to	POS	O
+calcium	POS	O
+compared	POS	O
+to	POS	O
+epinephrine	POS	O
+-	POS	O
+treated	POS	O
+animals	POS	O
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+clentiazem	POS	O
+attenuated	POS	O
+epinephrine	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+injury	POS	I-NP
+,	POS	O
+possibly	POS	O
+through	POS	O
+its	POS	O
+effect	POS	O
+on	POS	O
+the	POS	O
+adrenergic	POS	O
+pathway	POS	O
+.	POS	O
+Kaliuretic	POS	O
+effect	POS	O
+of	POS	O
+L	POS	O
+-	POS	O
+dopa	POS	O
+treatment	POS	O
+in	POS	O
+parkinsonian	POS	B-NP
+patients	POS	O
+.	POS	O
+Hypokalemia	POS	B-NP
+,	POS	O
+sometimes	POS	O
+severe	POS	O
+,	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+some	POS	O
+L	POS	O
+-	POS	O
+dopa	POS	O
+-	POS	O
+treated	POS	O
+parkinsonian	POS	B-NP
+patients	POS	O
+.	POS	O
+The	POS	O
+influence	POS	O
+of	POS	O
+L	POS	O
+-	POS	O
+dopa	POS	O
+on	POS	O
+the	POS	O
+renal	POS	O
+excretion	POS	O
+of	POS	O
+potassium	POS	O
+was	POS	O
+studied	POS	O
+in	POS	O
+3	POS	O
+patients	POS	O
+with	POS	O
+hypokalemia	POS	B-NP
+and	POS	O
+in	POS	O
+5	POS	O
+normokalemic	POS	B-NP
+patients	POS	O
+by	POS	O
+determination	POS	O
+of	POS	O
+renal	POS	O
+plasma	POS	O
+flow	POS	O
+,	POS	O
+glomerular	POS	O
+filtration	POS	O
+rate	POS	O
+,	POS	O
+plasma	POS	O
+concentration	POS	O
+of	POS	O
+potassium	POS	O
+and	POS	O
+sodium	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+urinary	POS	O
+excretion	POS	O
+of	POS	O
+potassium	POS	O
+,	POS	O
+sodium	POS	O
+and	POS	O
+aldosterone	POS	O
+.	POS	O
+L	POS	O
+-	POS	O
+Dopa	POS	O
+intake	POS	O
+was	POS	O
+found	POS	O
+to	POS	O
+cause	POS	O
+an	POS	O
+increased	POS	O
+excretion	POS	O
+of	POS	O
+potassium	POS	O
+,	POS	O
+and	POS	O
+sometimes	POS	O
+also	POS	O
+of	POS	O
+sodium	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+hypokalemic	POS	B-NP
+but	POS	O
+not	POS	O
+in	POS	O
+the	POS	O
+normokalemic	POS	B-NP
+patients	POS	O
+.	POS	O
+This	POS	O
+effect	POS	O
+on	POS	O
+the	POS	O
+renal	POS	O
+function	POS	O
+could	POS	O
+be	POS	O
+prohibited	POS	O
+by	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+a	POS	O
+peripheral	POS	O
+dopa	POS	O
+decarbodylase	POS	O
+inhibitor	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+not	POS	O
+known	POS	O
+why	POS	O
+this	POS	O
+effect	POS	O
+occurred	POS	O
+in	POS	O
+some	POS	O
+individuals	POS	O
+but	POS	O
+not	POS	O
+in	POS	O
+others	POS	O
+,	POS	O
+but	POS	O
+our	POS	O
+results	POS	O
+indicate	POS	O
+a	POS	O
+correlation	POS	O
+between	POS	O
+aldosterone	POS	O
+production	POS	O
+and	POS	O
+this	POS	O
+renal	POS	O
+effect	POS	O
+of	POS	O
+L	POS	O
+-	POS	O
+dopa	POS	O
+.	POS	O
+Cocaine	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+ischemia	POS	I-NP
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+myocardial	POS	B-NP
+ischemia	POS	I-NP
+induced	POS	O
+by	POS	O
+cocaine	POS	O
+.	POS	O
+The	POS	O
+ischemia	POS	B-NP
+probably	POS	O
+induced	POS	O
+by	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+spasm	POS	I-NP
+was	POS	O
+reversed	POS	O
+by	POS	O
+nitroglycerin	POS	O
+and	POS	O
+calcium	POS	O
+blocking	POS	O
+agents	POS	O
+.	POS	O
+Doxorubicin	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+monitored	POS	O
+by	POS	O
+ECG	POS	O
+in	POS	O
+freely	POS	O
+moving	POS	O
+mice	POS	O
+.	POS	O
+A	POS	O
+new	POS	O
+model	POS	O
+to	POS	O
+test	POS	O
+potential	POS	O
+protectors	POS	O
+.	POS	O
+In	POS	O
+laboratory	POS	O
+animals	POS	O
+,	POS	O
+histology	POS	O
+is	POS	O
+most	POS	O
+commonly	POS	O
+used	POS	O
+to	POS	O
+study	POS	O
+doxorubicin	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+However	POS	O
+,	POS	O
+for	POS	O
+monitoring	POS	O
+during	POS	O
+treatment	POS	O
+,	POS	O
+large	POS	O
+numbers	POS	O
+of	POS	O
+animals	POS	O
+are	POS	O
+needed	POS	O
+.	POS	O
+Recently	POS	O
+we	POS	O
+developed	POS	O
+a	POS	O
+new	POS	O
+method	POS	O
+to	POS	O
+measure	POS	O
+ECG	POS	O
+values	POS	O
+in	POS	O
+freely	POS	O
+moving	POS	O
+mice	POS	O
+by	POS	O
+telemetry	POS	O
+.	POS	O
+With	POS	O
+this	POS	O
+model	POS	O
+we	POS	O
+investigated	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+chronic	POS	O
+doxorubicin	POS	O
+administration	POS	O
+on	POS	O
+the	POS	O
+ECG	POS	O
+of	POS	O
+freely	POS	O
+moving	POS	O
+BALB	POS	O
+/	POS	O
+c	POS	O
+mice	POS	O
+and	POS	O
+the	POS	O
+efficacy	POS	O
+of	POS	O
+ICRF	POS	O
+-	POS	O
+187	POS	O
+as	POS	O
+a	POS	O
+protective	POS	O
+agent	POS	O
+.	POS	O
+The	POS	O
+ST	POS	O
+interval	POS	O
+significantly	POS	O
+widened	POS	O
+from	POS	O
+15	POS	O
+.	POS	O
+0	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+to	POS	O
+56	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+11	POS	O
+.	POS	O
+8	POS	O
+ms	POS	O
+in	POS	O
+week	POS	O
+10	POS	O
+(	POS	O
+7	POS	O
+weekly	POS	O
+doses	POS	O
+of	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+doxorubicin	POS	O
+given	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+plus	POS	O
+3	POS	O
+weeks	POS	O
+of	POS	O
+observation	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+ECG	POS	O
+of	POS	O
+the	POS	O
+control	POS	O
+animals	POS	O
+did	POS	O
+not	POS	O
+change	POS	O
+during	POS	O
+the	POS	O
+entire	POS	O
+study	POS	O
+.	POS	O
+After	POS	O
+sacrifice	POS	O
+the	POS	O
+hearts	POS	O
+of	POS	O
+doxorubicin	POS	O
+-	POS	O
+treated	POS	O
+animals	POS	O
+were	POS	O
+enlarged	POS	O
+and	POS	O
+the	POS	O
+atria	POS	O
+were	POS	O
+hypertrophic	POS	B-NP
+.	POS	O
+As	POS	O
+this	POS	O
+schedule	POS	O
+exerted	POS	O
+more	POS	O
+toxicity	POS	B-NP
+than	POS	O
+needed	POS	O
+to	POS	O
+investigate	POS	O
+protective	POS	O
+agents	POS	O
+,	POS	O
+the	POS	O
+protection	POS	O
+of	POS	O
+ICRF	POS	O
+-	POS	O
+187	POS	O
+was	POS	O
+determined	POS	O
+using	POS	O
+a	POS	O
+dose	POS	O
+schedule	POS	O
+with	POS	O
+lower	POS	O
+general	POS	O
+toxicity	POS	B-NP
+(	POS	O
+6	POS	O
+weekly	POS	O
+doses	POS	O
+of	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+doxorubicin	POS	O
+given	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+plus	POS	O
+2	POS	O
+weeks	POS	O
+of	POS	O
+observation	POS	O
+)	POS	O
+.	POS	O
+On	POS	O
+this	POS	O
+schedule	POS	O
+,	POS	O
+the	POS	O
+animals	POS	O
+'	POS	O
+hearts	POS	O
+appeared	POS	O
+normal	POS	O
+after	POS	O
+sacrifice	POS	O
+and	POS	O
+ICRF	POS	O
+-	POS	O
+187	POS	O
+(	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+given	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+1	POS	O
+h	POS	O
+before	POS	O
+doxorubicin	POS	O
+)	POS	O
+provided	POS	O
+almost	POS	O
+full	POS	O
+protection	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+were	POS	O
+confirmed	POS	O
+by	POS	O
+histology	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+this	POS	O
+new	POS	O
+model	POS	O
+is	POS	O
+very	POS	O
+sensitive	POS	O
+and	POS	O
+enables	POS	O
+monitoring	POS	O
+of	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+cardiotoxicity	POS	B-NP
+with	POS	O
+time	POS	O
+.	POS	O
+These	POS	O
+findings	POS	O
+result	POS	O
+in	POS	O
+a	POS	O
+model	POS	O
+that	POS	O
+allows	POS	O
+the	POS	O
+testing	POS	O
+of	POS	O
+protectors	POS	O
+against	POS	O
+doxorubicin	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+as	POS	O
+demonstrated	POS	O
+by	POS	O
+the	POS	O
+protection	POS	O
+provided	POS	O
+by	POS	O
+ICRF	POS	O
+-	POS	O
+187	POS	O
+.	POS	O
+Epinephrine	POS	O
+dysrhythmogenicity	POS	O
+is	POS	O
+not	POS	O
+enhanced	POS	O
+by	POS	O
+subtoxic	POS	O
+bupivacaine	POS	O
+in	POS	O
+dogs	POS	O
+.	POS	O
+Since	POS	O
+bupivacaine	POS	O
+and	POS	O
+epinephrine	POS	O
+may	POS	O
+both	POS	O
+precipitate	POS	O
+dysrhythmias	POS	B-NP
+,	POS	O
+circulating	POS	O
+bupivacaine	POS	O
+during	POS	O
+regional	POS	O
+anesthesia	POS	O
+could	POS	O
+potentiate	POS	O
+dysrhythmogenic	POS	O
+effects	POS	O
+of	POS	O
+epinephrine	POS	O
+.	POS	O
+We	POS	O
+therefore	POS	O
+examined	POS	O
+whether	POS	O
+bupivacaine	POS	O
+alters	POS	O
+the	POS	O
+dysrhythmogenicity	POS	O
+of	POS	O
+subsequent	POS	O
+administration	POS	O
+of	POS	O
+epinephrine	POS	O
+in	POS	O
+conscious	POS	O
+,	POS	O
+healthy	POS	O
+dogs	POS	O
+and	POS	O
+in	POS	O
+anesthetized	POS	O
+dogs	POS	O
+with	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+Forty	POS	O
+-	POS	O
+one	POS	O
+conscious	POS	O
+dogs	POS	O
+received	POS	O
+10	POS	O
+micrograms	POS	O
+.	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+min	POS	O
+-	POS	O
+1	POS	O
+epinephrine	POS	O
+.	POS	O
+Seventeen	POS	O
+animals	POS	O
+responded	POS	O
+with	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+(	POS	O
+VT	POS	B-NP
+)	POS	O
+within	POS	O
+3	POS	O
+min	POS	O
+.	POS	O
+After	POS	O
+3	POS	O
+h	POS	O
+,	POS	O
+these	POS	O
+responders	POS	O
+randomly	POS	O
+received	POS	O
+1	POS	O
+or	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+bupivacaine	POS	O
+or	POS	O
+saline	POS	O
+over	POS	O
+5	POS	O
+min	POS	O
+,	POS	O
+followed	POS	O
+by	POS	O
+10	POS	O
+micrograms	POS	O
+.	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+min	POS	O
+-	POS	O
+1	POS	O
+epinephrine	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+bupivacaine	POS	O
+groups	POS	O
+,	POS	O
+epinephrine	POS	O
+caused	POS	O
+fewer	POS	O
+prodysrhythmic	POS	O
+effects	POS	O
+than	POS	O
+without	POS	O
+bupivacaine	POS	O
+.	POS	O
+VT	POS	B-NP
+appeared	POS	O
+in	POS	O
+fewer	POS	O
+dogs	POS	O
+and	POS	O
+at	POS	O
+a	POS	O
+later	POS	O
+time	POS	O
+,	POS	O
+and	POS	O
+there	POS	O
+were	POS	O
+more	POS	O
+sinoatrial	POS	O
+beats	POS	O
+and	POS	O
+less	POS	O
+ectopies	POS	O
+.	POS	O
+Epinephrine	POS	O
+shortened	POS	O
+QT	POS	O
+less	POS	O
+after	POS	O
+bupivacaine	POS	O
+than	POS	O
+in	POS	O
+control	POS	O
+animals	POS	O
+.	POS	O
+One	POS	O
+day	POS	O
+after	POS	O
+experimental	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+,	POS	O
+six	POS	O
+additional	POS	O
+halothane	POS	O
+-	POS	O
+anesthetized	POS	O
+dogs	POS	O
+received	POS	O
+4	POS	O
+micrograms	POS	O
+.	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+min	POS	O
+-	POS	O
+1	POS	O
+epinephrine	POS	O
+until	POS	O
+VT	POS	O
+appeared	POS	O
+.	POS	O
+After	POS	O
+45	POS	O
+min	POS	O
+,	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+bupivacaine	POS	O
+was	POS	O
+injected	POS	O
+over	POS	O
+5	POS	O
+min	POS	O
+,	POS	O
+again	POS	O
+followed	POS	O
+by	POS	O
+4	POS	O
+micrograms	POS	O
+.	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+min	POS	O
+-	POS	O
+1	POS	O
+epinephrine	POS	O
+.	POS	O
+In	POS	O
+these	POS	O
+dogs	POS	O
+,	POS	O
+the	POS	O
+prodysrhythmic	POS	O
+response	POS	O
+to	POS	O
+epinephrine	POS	O
+was	POS	O
+also	POS	O
+mitigated	POS	O
+by	POS	O
+preceding	POS	O
+bupivacaine	POS	O
+.	POS	O
+Bupivacaine	POS	O
+antagonizes	POS	O
+epinephrine	POS	O
+dysrhythmogenicity	POS	O
+in	POS	O
+conscious	POS	O
+dogs	POS	O
+susceptible	POS	O
+to	POS	O
+VT	POS	B-NP
+and	POS	O
+in	POS	O
+anesthetized	POS	O
+dogs	POS	O
+with	POS	O
+spontaneous	POS	O
+postinfarct	POS	B-NP
+dysrhythmias	POS	I-NP
+.	POS	O
+There	POS	O
+is	POS	O
+no	POS	O
+evidence	POS	O
+that	POS	O
+systemic	POS	O
+subtoxic	POS	O
+bupivacaine	POS	O
+administration	POS	O
+enhances	POS	O
+the	POS	O
+dysrhythmogenicity	POS	O
+of	POS	O
+subsequent	POS	O
+epinephrine	POS	O
+.	POS	O
+Milk	POS	O
+-	POS	O
+alkali	POS	O
+syndrome	POS	O
+induced	POS	O
+by	POS	O
+1	POS	O
+,	POS	O
+25	POS	O
+(	POS	O
+OH	POS	O
+)	POS	O
+2D	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+hypoparathyroidism	POS	B-NP
+.	POS	O
+Milk	POS	B-NP
+-	POS	I-NP
+alkali	POS	I-NP
+syndrome	POS	I-NP
+was	POS	O
+first	POS	O
+described	POS	O
+70	POS	O
+years	POS	O
+ago	POS	O
+in	POS	O
+the	POS	O
+context	POS	O
+of	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+peptic	POS	B-NP
+ulcer	POS	I-NP
+disease	POS	I-NP
+with	POS	O
+large	POS	O
+amounts	POS	O
+of	POS	O
+calcium	POS	O
+and	POS	O
+alkali	POS	O
+.	POS	O
+Although	POS	O
+with	POS	O
+current	POS	O
+ulcer	POS	O
+therapy	POS	O
+(	POS	O
+H	POS	O
+-	POS	O
+2	POS	O
+blockers	POS	O
+,	POS	O
+omeprazole	POS	O
+,	POS	O
+and	POS	O
+sucralfate	POS	O
+)	POS	O
+,	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+milk	POS	O
+-	POS	O
+alkali	POS	O
+syndrome	POS	O
+has	POS	O
+decreased	POS	O
+significantly	POS	O
+,	POS	O
+the	POS	O
+classic	POS	O
+triad	POS	O
+of	POS	O
+hypercalcemia	POS	B-NP
+,	POS	O
+alkalosis	POS	B-NP
+,	POS	O
+and	POS	O
+renal	POS	B-NP
+impairment	POS	I-NP
+remains	POS	O
+the	POS	O
+hallmark	POS	O
+of	POS	O
+the	POS	O
+syndrome	POS	O
+.	POS	O
+Milk	POS	B-NP
+-	POS	I-NP
+alkali	POS	I-NP
+syndrome	POS	I-NP
+can	POS	O
+present	POS	O
+serious	POS	O
+and	POS	O
+occasionally	POS	O
+life	POS	O
+-	POS	O
+threatening	POS	O
+illness	POS	O
+unless	POS	O
+diagnosed	POS	O
+and	POS	O
+treated	POS	O
+appropriately	POS	O
+.	POS	O
+This	POS	O
+article	POS	O
+presents	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+hypoparathyroidism	POS	B-NP
+who	POS	O
+was	POS	O
+treated	POS	O
+with	POS	O
+calcium	POS	O
+carbonate	POS	O
+and	POS	O
+calcitriol	POS	O
+resulting	POS	O
+in	POS	O
+two	POS	O
+admissions	POS	O
+to	POS	O
+the	POS	O
+hospital	POS	O
+for	POS	O
+milk	POS	B-NP
+-	POS	I-NP
+alkali	POS	I-NP
+syndrome	POS	I-NP
+.	POS	O
+The	POS	O
+patient	POS	O
+was	POS	O
+successfully	POS	O
+treated	POS	O
+with	POS	O
+intravenous	POS	O
+pamidronate	POS	O
+on	POS	O
+his	POS	O
+first	POS	O
+admission	POS	O
+and	POS	O
+with	POS	O
+hydrocortisone	POS	O
+on	POS	O
+the	POS	O
+second	POS	O
+.	POS	O
+This	POS	O
+illustrates	POS	O
+intravenous	POS	O
+pamidronate	POS	O
+as	POS	O
+a	POS	O
+valuable	POS	O
+therapeutic	POS	O
+tool	POS	O
+when	POS	O
+milk	POS	B-NP
+-	POS	I-NP
+alkali	POS	I-NP
+syndrome	POS	I-NP
+presents	POS	O
+as	POS	O
+hypercalcemic	POS	B-NP
+emergency	POS	O
+.	POS	O
+Famotidine	POS	O
+-	POS	O
+associated	POS	O
+delirium	POS	B-NP
+.	POS	O
+A	POS	O
+series	POS	O
+of	POS	O
+six	POS	O
+cases	POS	O
+.	POS	O
+Famotidine	POS	O
+is	POS	O
+a	POS	O
+histamine	POS	O
+H2	POS	O
+-	POS	O
+receptor	POS	O
+antagonist	POS	O
+used	POS	O
+in	POS	O
+inpatient	POS	O
+settings	POS	O
+for	POS	O
+prevention	POS	O
+of	POS	O
+stress	POS	B-NP
+ulcers	POS	I-NP
+and	POS	O
+is	POS	O
+showing	POS	O
+increasing	POS	O
+popularity	POS	O
+because	POS	O
+of	POS	O
+its	POS	O
+low	POS	O
+cost	POS	O
+.	POS	O
+Although	POS	O
+all	POS	O
+of	POS	O
+the	POS	O
+currently	POS	O
+available	POS	O
+H2	POS	O
+-	POS	O
+receptor	POS	O
+antagonists	POS	O
+have	POS	O
+shown	POS	O
+the	POS	O
+propensity	POS	O
+to	POS	O
+cause	POS	O
+delirium	POS	B-NP
+,	POS	O
+only	POS	O
+two	POS	O
+previously	POS	O
+reported	POS	O
+cases	POS	O
+have	POS	O
+been	POS	O
+associated	POS	O
+with	POS	O
+famotidine	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+report	POS	O
+on	POS	O
+six	POS	O
+cases	POS	O
+of	POS	O
+famotidine	POS	O
+-	POS	O
+associated	POS	O
+delirium	POS	B-NP
+in	POS	O
+hospitalized	POS	O
+patients	POS	O
+who	POS	O
+cleared	POS	O
+completely	POS	O
+upon	POS	O
+removal	POS	O
+of	POS	O
+famotidine	POS	O
+.	POS	O
+The	POS	O
+pharmacokinetics	POS	O
+of	POS	O
+famotidine	POS	O
+are	POS	O
+reviewed	POS	O
+,	POS	O
+with	POS	O
+no	POS	O
+change	POS	O
+in	POS	O
+its	POS	O
+metabolism	POS	O
+in	POS	O
+the	POS	O
+elderly	POS	O
+population	POS	O
+seen	POS	O
+.	POS	O
+The	POS	O
+implications	POS	O
+of	POS	O
+using	POS	O
+famotidine	POS	O
+in	POS	O
+elderly	POS	O
+persons	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+Encephalopathy	POS	B-NP
+during	POS	O
+amitriptyline	POS	O
+therapy	POS	O
+:	POS	O
+are	POS	O
+neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+and	POS	O
+serotonin	POS	B-NP
+syndrome	POS	I-NP
+spectrum	POS	I-NP
+disorders	POS	I-NP
+?	POS	O
+This	POS	O
+report	POS	O
+describes	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+encephalopathy	POS	B-NP
+developed	POS	O
+in	POS	O
+the	POS	O
+course	POS	O
+of	POS	O
+amitriptyline	POS	O
+therapy	POS	O
+,	POS	O
+during	POS	O
+a	POS	O
+remission	POS	O
+of	POS	O
+unipolar	POS	B-NP
+depression	POS	I-NP
+.	POS	O
+This	POS	O
+patient	POS	O
+could	POS	O
+have	POS	O
+been	POS	O
+diagnosed	POS	O
+as	POS	O
+having	POS	O
+either	POS	O
+neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+(	POS	O
+NMS	POS	B-NP
+)	POS	O
+or	POS	O
+serotonin	POS	B-NP
+syndrome	POS	I-NP
+(	POS	O
+SS	POS	B-NP
+)	POS	O
+.	POS	O
+The	POS	O
+major	POS	O
+determinant	POS	O
+of	POS	O
+the	POS	O
+symptoms	POS	O
+may	POS	O
+have	POS	O
+been	POS	O
+dopamine	POS	O
+/	POS	O
+serotonin	POS	O
+imbalance	POS	O
+in	POS	O
+the	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+.	POS	O
+The	POS	O
+NMS	POS	B-NP
+-	POS	O
+like	POS	O
+encephalopathy	POS	B-NP
+that	POS	O
+develops	POS	O
+in	POS	O
+association	POS	O
+with	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+antidepressants	POS	O
+indicates	POS	O
+that	POS	O
+NMS	POS	B-NP
+and	POS	O
+SS	POS	B-NP
+are	POS	O
+spectrum	POS	O
+disorders	POS	O
+induced	POS	O
+by	POS	O
+drugs	POS	O
+with	POS	O
+both	POS	O
+antidopaminergic	POS	O
+and	POS	O
+serotonergic	POS	O
+effects	POS	O
+.	POS	O
+Genetic	POS	O
+separation	POS	O
+of	POS	O
+tumor	POS	B-NP
+growth	POS	O
+and	POS	O
+hemorrhagic	POS	B-NP
+phenotypes	POS	O
+in	POS	O
+an	POS	O
+estrogen	POS	O
+-	POS	O
+induced	POS	O
+tumor	POS	B-NP
+.	POS	O
+Chronic	POS	O
+administration	POS	O
+of	POS	O
+estrogen	POS	O
+to	POS	O
+the	POS	O
+Fischer	POS	O
+344	POS	O
+(	POS	O
+F344	POS	O
+)	POS	O
+rat	POS	O
+induces	POS	O
+growth	POS	O
+of	POS	O
+large	POS	O
+,	POS	O
+hemorrhagic	POS	B-NP
+pituitary	POS	I-NP
+tumors	POS	I-NP
+.	POS	O
+Ten	POS	O
+weeks	POS	O
+of	POS	O
+diethylstilbestrol	POS	O
+(	POS	O
+DES	POS	O
+)	POS	O
+treatment	POS	O
+caused	POS	O
+female	POS	O
+F344	POS	O
+rat	POS	O
+pituitaries	POS	O
+to	POS	O
+grow	POS	O
+to	POS	O
+an	POS	O
+average	POS	O
+of	POS	O
+109	POS	O
+.	POS	O
+2	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+3	POS	O
+mg	POS	O
+(	POS	O
+mean	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+SE	POS	O
+)	POS	O
+versus	POS	O
+11	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+4	POS	O
+mg	POS	O
+for	POS	O
+untreated	POS	O
+rats	POS	O
+,	POS	O
+and	POS	O
+to	POS	O
+become	POS	O
+highly	POS	O
+hemorrhagic	POS	B-NP
+.	POS	O
+The	POS	O
+same	POS	O
+DES	POS	O
+treatment	POS	O
+produced	POS	O
+no	POS	O
+significant	POS	O
+growth	POS	O
+(	POS	O
+8	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+for	POS	O
+treated	POS	O
+females	POS	O
+versus	POS	O
+8	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+1	POS	O
+for	POS	O
+untreated	POS	O
+females	POS	O
+)	POS	O
+or	POS	O
+morphological	POS	O
+changes	POS	O
+in	POS	O
+Brown	POS	O
+Norway	POS	O
+(	POS	O
+BN	POS	O
+)	POS	O
+rat	POS	O
+pituitaries	POS	O
+.	POS	O
+An	POS	O
+F1	POS	O
+hybrid	POS	O
+of	POS	O
+F344	POS	O
+and	POS	O
+BN	POS	O
+exhibited	POS	O
+significant	POS	O
+pituitary	POS	B-NP
+growth	POS	I-NP
+after	POS	O
+10	POS	O
+weeks	POS	O
+of	POS	O
+DES	POS	O
+treatment	POS	O
+with	POS	O
+an	POS	O
+average	POS	O
+mass	POS	O
+of	POS	O
+26	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+mg	POS	O
+compared	POS	O
+with	POS	O
+8	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+mg	POS	O
+for	POS	O
+untreated	POS	O
+rats	POS	O
+.	POS	O
+Surprisingly	POS	O
+,	POS	O
+the	POS	O
+F1	POS	O
+hybrid	POS	O
+tumors	POS	B-NP
+were	POS	O
+not	POS	O
+hemorrhagic	POS	B-NP
+and	POS	O
+had	POS	O
+hemoglobin	POS	O
+content	POS	O
+and	POS	O
+outward	POS	O
+appearance	POS	O
+identical	POS	O
+to	POS	O
+that	POS	O
+of	POS	O
+BN	POS	O
+.	POS	O
+Expression	POS	O
+of	POS	O
+both	POS	O
+growth	POS	O
+and	POS	O
+morphological	POS	O
+changes	POS	O
+is	POS	O
+due	POS	O
+to	POS	O
+multiple	POS	O
+genes	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+while	POS	O
+DES	POS	O
+-	POS	O
+induced	POS	O
+pituitary	POS	O
+growth	POS	O
+exhibited	POS	O
+quantitative	POS	O
+,	POS	O
+additive	POS	O
+inheritance	POS	O
+,	POS	O
+the	POS	O
+hemorrhagic	POS	B-NP
+phenotype	POS	O
+exhibited	POS	O
+recessive	POS	O
+,	POS	O
+epistatic	POS	O
+inheritance	POS	O
+.	POS	O
+Only	POS	O
+5	POS	O
+of	POS	O
+the	POS	O
+160	POS	O
+F2	POS	O
+pituitaries	POS	O
+exhibited	POS	O
+the	POS	O
+hemorrhagic	POS	B-NP
+phenotype	POS	O
+;	POS	O
+36	POS	O
+of	POS	O
+the	POS	O
+160	POS	O
+F2	POS	O
+pituitaries	POS	O
+were	POS	O
+in	POS	O
+the	POS	O
+F344	POS	O
+range	POS	O
+of	POS	O
+mass	POS	O
+,	POS	O
+but	POS	O
+31	POS	O
+of	POS	O
+these	POS	O
+were	POS	O
+not	POS	O
+hemorrhagic	POS	B-NP
+,	POS	O
+indicating	POS	O
+that	POS	O
+the	POS	O
+hemorrhagic	POS	B-NP
+phenotype	POS	O
+is	POS	O
+not	POS	O
+merely	POS	O
+a	POS	O
+consequence	POS	O
+of	POS	O
+extensive	POS	O
+growth	POS	O
+.	POS	O
+The	POS	O
+hemorrhagic	POS	B-NP
+F2	POS	O
+pituitaries	POS	O
+were	POS	O
+all	POS	O
+among	POS	O
+the	POS	O
+most	POS	O
+massive	POS	O
+,	POS	O
+indicating	POS	O
+that	POS	O
+some	POS	O
+of	POS	O
+the	POS	O
+genes	POS	O
+regulate	POS	O
+both	POS	O
+phenotypes	POS	O
+.	POS	O
+Increased	POS	O
+expression	POS	O
+of	POS	O
+neuronal	POS	O
+nitric	POS	O
+oxide	POS	O
+synthase	POS	O
+in	POS	O
+bladder	POS	O
+afferent	POS	O
+pathways	POS	O
+following	POS	O
+chronic	POS	B-NP
+bladder	POS	I-NP
+irritation	POS	I-NP
+.	POS	O
+Immunocytochemical	POS	O
+techniques	POS	O
+were	POS	O
+used	POS	O
+to	POS	O
+examine	POS	O
+alterations	POS	O
+in	POS	O
+the	POS	O
+expression	POS	O
+of	POS	O
+neuronal	POS	O
+nitric	POS	O
+oxide	POS	O
+synthase	POS	O
+(	POS	O
+NOS	POS	O
+)	POS	O
+in	POS	O
+bladder	POS	O
+pathways	POS	O
+following	POS	O
+acute	POS	O
+and	POS	O
+chronic	POS	O
+irritation	POS	O
+of	POS	O
+the	POS	O
+urinary	POS	O
+tract	POS	O
+of	POS	O
+the	POS	O
+rat	POS	O
+.	POS	O
+Chemical	POS	O
+cystitis	POS	B-NP
+was	POS	O
+induced	POS	O
+by	POS	O
+cyclophosphamide	POS	O
+(	POS	O
+CYP	POS	O
+)	POS	O
+which	POS	O
+is	POS	O
+metabolized	POS	O
+to	POS	O
+acrolein	POS	O
+,	POS	O
+an	POS	O
+irritant	POS	O
+eliminated	POS	O
+in	POS	O
+the	POS	O
+urine	POS	O
+.	POS	O
+Injection	POS	O
+of	POS	O
+CYP	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+10	POS	O
+,	POS	O
+75	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+2	POS	O
+hours	POS	O
+prior	POS	O
+to	POS	O
+perfusion	POS	O
+(	POS	O
+acute	POS	O
+treatment	POS	O
+)	POS	O
+of	POS	O
+the	POS	O
+animals	POS	O
+increased	POS	O
+Fos	POS	O
+-	POS	O
+immunoreactivity	POS	O
+(	POS	O
+IR	POS	O
+)	POS	O
+in	POS	O
+neurons	POS	O
+in	POS	O
+the	POS	O
+dorsal	POS	O
+commissure	POS	O
+,	POS	O
+dorsal	POS	O
+horn	POS	O
+,	POS	O
+and	POS	O
+autonomic	POS	O
+regions	POS	O
+of	POS	O
+spinal	POS	O
+segments	POS	O
+(	POS	O
+L1	POS	O
+-	POS	O
+L2	POS	O
+and	POS	O
+L6	POS	O
+-	POS	O
+S1	POS	O
+)	POS	O
+which	POS	O
+receive	POS	O
+afferent	POS	O
+inputs	POS	O
+from	POS	O
+the	POS	O
+bladder	POS	O
+,	POS	O
+urethra	POS	O
+,	POS	O
+and	POS	O
+ureter	POS	O
+.	POS	O
+Fos	POS	O
+-	POS	O
+IR	POS	O
+in	POS	O
+the	POS	O
+spinal	POS	O
+cord	POS	O
+was	POS	O
+not	POS	O
+changed	POS	O
+in	POS	O
+rats	POS	O
+receiving	POS	O
+chronic	POS	O
+CYP	POS	O
+treatment	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+15	POS	O
+,	POS	O
+75	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+,	POS	O
+every	POS	O
+3rd	POS	O
+day	POS	O
+for	POS	O
+2	POS	O
+weeks	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+control	POS	O
+animals	POS	O
+and	POS	O
+in	POS	O
+animals	POS	O
+treated	POS	O
+acutely	POS	O
+with	POS	O
+CYP	POS	O
+,	POS	O
+only	POS	O
+small	POS	O
+numbers	POS	O
+of	POS	O
+NOS	POS	O
+-	POS	O
+IR	POS	O
+cells	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+cell	POS	O
+profiles	POS	O
+/	POS	O
+sections	POS	O
+)	POS	O
+were	POS	O
+detected	POS	O
+in	POS	O
+the	POS	O
+L6	POS	O
+-	POS	O
+S1	POS	O
+dorsal	POS	O
+root	POS	O
+ganglia	POS	O
+(	POS	O
+DRG	POS	O
+)	POS	O
+.	POS	O
+Chronic	POS	O
+CYP	POS	O
+administration	POS	O
+significantly	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+.	POS	O
+002	POS	O
+)	POS	O
+increased	POS	O
+bladder	POS	O
+weight	POS	O
+by	POS	O
+60	POS	O
+%	POS	O
+and	POS	O
+increased	POS	O
+(	POS	O
+7	POS	O
+-	POS	O
+to	POS	O
+11	POS	O
+-	POS	O
+fold	POS	O
+)	POS	O
+the	POS	O
+numbers	POS	O
+of	POS	O
+NOS	POS	O
+-	POS	O
+immunoreactive	POS	O
+(	POS	O
+IR	POS	O
+)	POS	O
+afferent	POS	O
+neurons	POS	O
+in	POS	O
+the	POS	O
+L6	POS	O
+-	POS	O
+S1	POS	O
+DRG	POS	O
+.	POS	O
+A	POS	O
+small	POS	O
+increase	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+fold	POS	O
+)	POS	O
+also	POS	O
+occurred	POS	O
+in	POS	O
+the	POS	O
+L1	POS	O
+DRG	POS	O
+,	POS	O
+but	POS	O
+no	POS	O
+change	POS	O
+was	POS	O
+detected	POS	O
+in	POS	O
+the	POS	O
+L2	POS	O
+and	POS	O
+L5	POS	O
+DRG	POS	O
+.	POS	O
+Bladder	POS	O
+afferent	POS	O
+cells	POS	O
+in	POS	O
+the	POS	O
+L6	POS	O
+-	POS	O
+S1	POS	O
+DRG	POS	O
+labeled	POS	O
+by	POS	O
+Fluorogold	POS	O
+(	POS	O
+40	POS	O
+microliters	POS	O
+)	POS	O
+injected	POS	O
+into	POS	O
+the	POS	O
+bladder	POS	O
+wall	POS	O
+did	POS	O
+not	POS	O
+exhibit	POS	O
+NOS	POS	O
+-	POS	O
+IR	POS	O
+in	POS	O
+control	POS	O
+animals	POS	O
+;	POS	O
+however	POS	O
+,	POS	O
+following	POS	O
+chronic	POS	O
+CYP	POS	O
+administration	POS	O
+,	POS	O
+a	POS	O
+significant	POS	O
+percentage	POS	O
+of	POS	O
+bladder	POS	O
+afferent	POS	O
+neurons	POS	O
+were	POS	O
+NOS	POS	O
+-	POS	O
+IR	POS	O
+:	POS	O
+L6	POS	O
+(	POS	O
+19	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+S1	POS	O
+(	POS	O
+25	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+neuronal	POS	O
+gene	POS	O
+expression	POS	O
+in	POS	O
+visceral	POS	O
+sensory	POS	O
+pathways	POS	O
+can	POS	O
+be	POS	O
+upregulated	POS	O
+by	POS	O
+chemical	POS	O
+irritation	POS	O
+of	POS	O
+afferent	POS	O
+receptors	POS	O
+in	POS	O
+the	POS	O
+urinary	POS	O
+tract	POS	O
+and	POS	O
+/	POS	O
+or	POS	O
+that	POS	O
+pathological	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+urinary	POS	O
+tract	POS	O
+can	POS	O
+initiate	POS	O
+chemical	POS	O
+signals	POS	O
+that	POS	O
+alter	POS	O
+the	POS	O
+chemical	POS	O
+properties	POS	O
+of	POS	O
+visceral	POS	O
+afferent	POS	O
+neurons	POS	O
+.	POS	O
+Effects	POS	O
+of	POS	O
+a	POS	O
+new	POS	O
+calcium	POS	O
+antagonist	POS	O
+,	POS	O
+CD	POS	O
+-	POS	O
+832	POS	O
+,	POS	O
+on	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+ischemia	POS	I-NP
+in	POS	O
+dogs	POS	O
+with	POS	O
+partial	POS	O
+coronary	POS	B-NP
+stenosis	POS	I-NP
+.	POS	O
+Effects	POS	O
+of	POS	O
+CD	POS	O
+-	POS	O
+832	POS	O
+on	POS	O
+isoproterenol	POS	O
+(	POS	O
+ISO	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+ischemia	POS	I-NP
+were	POS	O
+studied	POS	O
+in	POS	O
+dogs	POS	O
+with	POS	O
+partial	POS	O
+coronary	POS	B-NP
+stenosis	POS	I-NP
+of	POS	O
+the	POS	O
+left	POS	O
+circumflex	POS	O
+coronary	POS	O
+artery	POS	O
+and	POS	O
+findings	POS	O
+were	POS	O
+compared	POS	O
+with	POS	O
+those	POS	O
+for	POS	O
+nifedipine	POS	O
+or	POS	O
+diltiazem	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+stenosis	POS	I-NP
+,	POS	O
+3	POS	O
+-	POS	O
+min	POS	O
+periods	POS	O
+of	POS	O
+intracoronary	POS	O
+ISO	POS	O
+infusion	POS	O
+(	POS	O
+10	POS	O
+ng	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+)	POS	O
+increased	POS	O
+heart	POS	O
+rate	POS	O
+and	POS	O
+maximal	POS	O
+rate	POS	O
+of	POS	O
+left	POS	O
+ventricular	POS	O
+pressure	POS	O
+rise	POS	O
+,	POS	O
+which	POS	O
+resulted	POS	O
+in	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+percentage	POS	O
+segmental	POS	O
+shortening	POS	O
+and	POS	O
+ST	POS	O
+-	POS	O
+segment	POS	O
+elevation	POS	O
+of	POS	O
+the	POS	O
+epicardial	POS	O
+electrocardiogram	POS	O
+.	POS	O
+After	POS	O
+the	POS	O
+control	POS	O
+ISO	POS	O
+infusion	POS	O
+with	POS	O
+stenosis	POS	B-NP
+was	POS	O
+performed	POS	O
+,	POS	O
+equihypotensive	POS	O
+doses	POS	O
+of	POS	O
+CD	POS	O
+-	POS	O
+832	POS	O
+(	POS	O
+3	POS	O
+and	POS	O
+10	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+,	POS	O
+n	POS	O
+=	POS	O
+7	POS	O
+)	POS	O
+,	POS	O
+nifedipine	POS	O
+(	POS	O
+1	POS	O
+and	POS	O
+3	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+,	POS	O
+n	POS	O
+=	POS	O
+9	POS	O
+)	POS	O
+or	POS	O
+diltiazem	POS	O
+(	POS	O
+10	POS	O
+and	POS	O
+30	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+,	POS	O
+n	POS	O
+=	POS	O
+7	POS	O
+)	POS	O
+were	POS	O
+infused	POS	O
+5	POS	O
+min	POS	O
+before	POS	O
+and	POS	O
+during	POS	O
+the	POS	O
+second	POS	O
+and	POS	O
+third	POS	O
+ISO	POS	O
+infusion	POS	O
+.	POS	O
+Both	POS	O
+CD	POS	O
+-	POS	O
+832	POS	O
+and	POS	O
+diltiazem	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+nifedipine	POS	O
+,	POS	O
+significantly	POS	O
+reduced	POS	O
+the	POS	O
+increase	POS	O
+in	POS	O
+heart	POS	O
+rate	POS	O
+induced	POS	O
+by	POS	O
+ISO	POS	O
+infusion	POS	O
+.	POS	O
+In	POS	O
+contrast	POS	O
+to	POS	O
+nifedipine	POS	O
+,	POS	O
+CD	POS	O
+-	POS	O
+832	POS	O
+(	POS	O
+10	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+)	POS	O
+prevented	POS	O
+the	POS	O
+decrease	POS	O
+in	POS	O
+percentage	POS	O
+segmental	POS	O
+shortening	POS	O
+from	POS	O
+32	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+12	POS	O
+%	POS	O
+to	POS	O
+115	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+26	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+control	POS	O
+value	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+and	POS	O
+ST	POS	O
+-	POS	O
+segment	POS	O
+elevation	POS	O
+from	POS	O
+5	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+0	POS	O
+mV	POS	O
+to	POS	O
+1	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+mV	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+at	POS	O
+3	POS	O
+min	POS	O
+after	POS	O
+ISO	POS	O
+infusion	POS	O
+with	POS	O
+stenosis	POS	O
+.	POS	O
+Diltiazem	POS	O
+(	POS	O
+30	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+)	POS	O
+also	POS	O
+prevented	POS	O
+the	POS	O
+decrease	POS	O
+in	POS	O
+percentage	POS	O
+segmental	POS	O
+shortening	POS	O
+from	POS	O
+34	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+14	POS	O
+%	POS	O
+to	POS	O
+63	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+18	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+control	POS	O
+value	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+and	POS	O
+ST	POS	O
+-	POS	O
+segment	POS	O
+elevation	POS	O
+from	POS	O
+4	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+mV	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+1	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+mV	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+at	POS	O
+3	POS	O
+min	POS	O
+after	POS	O
+ISO	POS	O
+infusion	POS	O
+with	POS	O
+stenosis	POS	B-NP
+.	POS	O
+These	POS	O
+data	POS	O
+show	POS	O
+that	POS	O
+CD	POS	O
+-	POS	O
+832	POS	O
+improves	POS	O
+myocardial	POS	B-NP
+ischemia	POS	I-NP
+during	POS	O
+ISO	POS	O
+infusion	POS	O
+with	POS	O
+stenosis	POS	B-NP
+and	POS	O
+suggest	POS	O
+that	POS	O
+the	POS	O
+negative	POS	O
+chronotropic	POS	O
+property	POS	O
+of	POS	O
+CD	POS	O
+-	POS	O
+832	POS	O
+plays	POS	O
+a	POS	O
+major	POS	O
+role	POS	O
+in	POS	O
+the	POS	O
+beneficial	POS	O
+effects	POS	O
+of	POS	O
+CD	POS	O
+-	POS	O
+832	POS	O
+.	POS	O
+The	POS	O
+effect	POS	O
+of	POS	O
+recombinant	POS	O
+human	POS	O
+insulin	POS	O
+-	POS	O
+like	POS	O
+growth	POS	O
+factor	POS	O
+-	POS	O
+I	POS	O
+on	POS	O
+chronic	POS	O
+puromycin	POS	O
+aminonucleoside	POS	O
+nephropathy	POS	B-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+We	POS	O
+recently	POS	O
+demonstrated	POS	O
+that	POS	O
+recombinant	POS	O
+hGH	POS	O
+exacerbates	POS	O
+renal	POS	O
+functional	POS	O
+and	POS	O
+structural	POS	O
+injury	POS	O
+in	POS	O
+chronic	POS	O
+puromycin	POS	O
+aminonucleoside	POS	O
+(	POS	O
+PAN	POS	O
+)	POS	O
+nephropathy	POS	B-NP
+,	POS	O
+an	POS	O
+experimental	POS	O
+model	POS	O
+of	POS	O
+glomerular	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+Therefore	POS	O
+,	POS	O
+we	POS	O
+examined	POS	O
+whether	POS	O
+recombinant	POS	O
+human	POS	O
+(	POS	O
+rh	POS	O
+)	POS	O
+IGF	POS	O
+-	POS	O
+I	POS	O
+is	POS	O
+a	POS	O
+safer	POS	O
+alternative	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+growth	POS	B-NP
+failure	POS	I-NP
+in	POS	O
+rats	POS	O
+with	POS	O
+chronic	POS	O
+PAN	POS	O
+nephropathy	POS	B-NP
+.	POS	O
+The	POS	O
+glomerulopathy	POS	B-NP
+was	POS	O
+induced	POS	O
+by	POS	O
+seven	POS	O
+serial	POS	O
+injections	POS	O
+of	POS	O
+PAN	POS	O
+over	POS	O
+12	POS	O
+wk	POS	O
+.	POS	O
+Experimental	POS	O
+animals	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+6	POS	O
+)	POS	O
+received	POS	O
+rhIGF	POS	O
+-	POS	O
+I	POS	O
+,	POS	O
+400	POS	O
+micrograms	POS	O
+/	POS	O
+d	POS	O
+,	POS	O
+whereas	POS	O
+control	POS	O
+rats	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+6	POS	O
+)	POS	O
+received	POS	O
+the	POS	O
+vehicle	POS	O
+.	POS	O
+rhIGF	POS	O
+-	POS	O
+I	POS	O
+improved	POS	O
+weight	POS	O
+gain	POS	O
+by	POS	O
+14	POS	O
+%	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+,	POS	O
+without	POS	O
+altering	POS	O
+hematocrit	POS	O
+or	POS	O
+blood	POS	O
+pressure	POS	O
+in	POS	O
+rats	POS	O
+with	POS	O
+renal	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+Urinary	POS	O
+protein	POS	O
+excretion	POS	O
+was	POS	O
+unaltered	POS	O
+by	POS	O
+rhIGF	POS	O
+-	POS	O
+I	POS	O
+treatment	POS	O
+in	POS	O
+rats	POS	O
+with	POS	O
+chronic	POS	O
+PAN	POS	O
+nephropathy	POS	B-NP
+.	POS	O
+After	POS	O
+12	POS	O
+wk	POS	O
+,	POS	O
+the	POS	O
+inulin	POS	O
+clearance	POS	O
+was	POS	O
+higher	POS	O
+in	POS	O
+rhIGF	POS	O
+-	POS	O
+I	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+48	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+08	POS	O
+versus	POS	O
+0	POS	O
+.	POS	O
+24	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+06	POS	O
+mL	POS	O
+/	POS	O
+min	POS	O
+/	POS	O
+100	POS	O
+g	POS	O
+of	POS	O
+body	POS	O
+weight	POS	O
+in	POS	O
+untreated	POS	O
+PAN	POS	O
+nephropathy	POS	B-NP
+animals	POS	O
+,	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+.	POS	O
+The	POS	O
+improvement	POS	O
+in	POS	O
+GFR	POS	O
+was	POS	O
+not	POS	O
+associated	POS	O
+with	POS	O
+enhanced	POS	O
+glomerular	POS	B-NP
+hypertrophy	POS	I-NP
+or	POS	O
+increased	POS	O
+segmental	POS	O
+glomerulosclerosis	POS	B-NP
+,	POS	O
+tubulointerstitial	POS	B-NP
+injury	POS	I-NP
+,	POS	O
+or	POS	O
+renal	POS	O
+cortical	POS	O
+malondialdehyde	POS	O
+content	POS	O
+.	POS	O
+In	POS	O
+rats	POS	O
+with	POS	O
+PAN	POS	O
+nephropathy	POS	B-NP
+,	POS	O
+administration	POS	O
+of	POS	O
+rhIGF	POS	O
+-	POS	O
+I	POS	O
+increased	POS	O
+IGF	POS	O
+-	POS	O
+I	POS	O
+and	POS	O
+GH	POS	O
+receptor	POS	O
+gene	POS	O
+expression	POS	O
+,	POS	O
+without	POS	O
+altering	POS	O
+the	POS	O
+steady	POS	O
+state	POS	O
+level	POS	O
+of	POS	O
+IGF	POS	O
+-	POS	O
+I	POS	O
+receptor	POS	O
+mRNA	POS	O
+.	POS	O
+In	POS	O
+normal	POS	O
+rats	POS	O
+with	POS	O
+intact	POS	O
+kidneys	POS	O
+,	POS	O
+rhIGF	POS	O
+-	POS	O
+I	POS	O
+administration	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+4	POS	O
+)	POS	O
+did	POS	O
+not	POS	O
+alter	POS	O
+weight	POS	O
+gain	POS	O
+,	POS	O
+blood	POS	O
+pressure	POS	O
+,	POS	O
+proteinuria	POS	B-NP
+,	POS	O
+GFR	POS	O
+,	POS	O
+glomerular	POS	O
+planar	POS	O
+area	POS	O
+,	POS	O
+renal	POS	O
+cortical	POS	O
+malondialdehyde	POS	O
+content	POS	O
+,	POS	O
+or	POS	O
+glomerular	POS	O
+or	POS	O
+tubulointerstitial	POS	B-NP
+damage	POS	I-NP
+,	POS	O
+compared	POS	O
+with	POS	O
+untreated	POS	O
+animals	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+4	POS	O
+)	POS	O
+.	POS	O
+rhIGF	POS	O
+-	POS	O
+I	POS	O
+treatment	POS	O
+reduced	POS	O
+the	POS	O
+steady	POS	O
+state	POS	O
+renal	POS	O
+IGF	POS	O
+-	POS	O
+I	POS	O
+mRNA	POS	O
+level	POS	O
+but	POS	O
+did	POS	O
+not	POS	O
+modify	POS	O
+gene	POS	O
+expression	POS	O
+of	POS	O
+the	POS	O
+IGF	POS	O
+-	POS	O
+I	POS	O
+or	POS	O
+GH	POS	O
+receptors	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+:	POS	O
+1	POS	O
+)	POS	O
+administration	POS	O
+of	POS	O
+rhIGF	POS	O
+-	POS	O
+I	POS	O
+improves	POS	O
+growth	POS	O
+and	POS	O
+GFR	POS	O
+in	POS	O
+rats	POS	O
+with	POS	O
+chronic	POS	O
+PAN	POS	O
+nephropathy	POS	B-NP
+and	POS	O
+2	POS	O
+)	POS	O
+unlike	POS	O
+rhGH	POS	O
+,	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+use	POS	O
+of	POS	O
+rhIGF	POS	O
+-	POS	O
+I	POS	O
+does	POS	O
+not	POS	O
+worsen	POS	O
+renal	POS	O
+functional	POS	O
+and	POS	O
+structural	POS	O
+injury	POS	O
+in	POS	O
+this	POS	O
+disease	POS	O
+model	POS	O
+.	POS	O
+Nefiracetam	POS	O
+(	POS	O
+DM	POS	B-NP
+-	POS	O
+9384	POS	O
+)	POS	O
+reverses	POS	O
+apomorphine	POS	O
+-	POS	O
+induced	POS	O
+amnesia	POS	B-NP
+of	POS	O
+a	POS	O
+passive	POS	O
+avoidance	POS	O
+response	POS	O
+:	POS	O
+delayed	POS	O
+emergence	POS	O
+of	POS	O
+the	POS	O
+memory	POS	O
+retention	POS	O
+effects	POS	O
+.	POS	O
+Nefiracetam	POS	O
+is	POS	O
+a	POS	O
+novel	POS	O
+pyrrolidone	POS	O
+derivative	POS	O
+which	POS	O
+attenuates	POS	O
+scopolamine	POS	O
+-	POS	O
+induced	POS	O
+learning	POS	O
+and	POS	O
+post	POS	O
+-	POS	O
+training	POS	O
+consolidation	POS	O
+deficits	POS	O
+.	POS	O
+Given	POS	O
+that	POS	O
+apomorphine	POS	O
+inhibits	POS	O
+passive	POS	O
+avoidance	POS	O
+retention	POS	O
+when	POS	O
+given	POS	O
+during	POS	O
+training	POS	O
+or	POS	O
+in	POS	O
+a	POS	O
+defined	POS	O
+10	POS	O
+-	POS	O
+12h	POS	O
+post	POS	O
+-	POS	O
+training	POS	O
+period	POS	O
+,	POS	O
+we	POS	O
+evaluated	POS	O
+the	POS	O
+ability	POS	O
+of	POS	O
+nefiracetam	POS	O
+to	POS	O
+attenuate	POS	O
+amnesia	POS	B-NP
+induced	POS	O
+by	POS	O
+dopaminergic	POS	O
+agonism	POS	O
+.	POS	O
+A	POS	O
+step	POS	O
+-	POS	O
+down	POS	O
+passive	POS	O
+avoidance	POS	O
+paradigm	POS	O
+was	POS	O
+employed	POS	O
+and	POS	O
+nefiracetam	POS	O
+(	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+and	POS	O
+apomorphine	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+were	POS	O
+given	POS	O
+alone	POS	O
+or	POS	O
+in	POS	O
+combination	POS	O
+during	POS	O
+training	POS	O
+and	POS	O
+at	POS	O
+the	POS	O
+10	POS	O
+-	POS	O
+12h	POS	O
+post	POS	O
+-	POS	O
+training	POS	O
+period	POS	O
+of	POS	O
+consolidation	POS	O
+.	POS	O
+Co	POS	O
+-	POS	O
+administration	POS	O
+of	POS	O
+nefiracetam	POS	O
+and	POS	O
+apomorphine	POS	O
+during	POS	O
+training	POS	O
+or	POS	O
+10h	POS	O
+thereafter	POS	O
+produced	POS	O
+no	POS	O
+significant	POS	O
+anti	POS	O
+-	POS	O
+amnesic	POS	O
+effect	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+administration	POS	O
+of	POS	O
+nefiracetam	POS	O
+during	POS	O
+training	POS	O
+completely	POS	O
+reversed	POS	O
+the	POS	O
+amnesia	POS	B-NP
+induced	POS	O
+by	POS	O
+apomorphine	POS	O
+at	POS	O
+the	POS	O
+10h	POS	O
+post	POS	O
+-	POS	O
+training	POS	O
+time	POS	O
+and	POS	O
+the	POS	O
+converse	POS	O
+was	POS	O
+also	POS	O
+true	POS	O
+.	POS	O
+These	POS	O
+effects	POS	O
+were	POS	O
+not	POS	O
+mediated	POS	O
+by	POS	O
+a	POS	O
+dopaminergic	POS	O
+mechanism	POS	O
+as	POS	O
+nefiracetam	POS	O
+,	POS	O
+at	POS	O
+millimolar	POS	O
+concentrations	POS	O
+,	POS	O
+failed	POS	O
+to	POS	O
+displace	POS	O
+either	POS	O
+[	POS	O
+3H	POS	O
+]	POS	O
+SCH	POS	O
+23390	POS	O
+or	POS	O
+[	POS	O
+3H	POS	O
+]	POS	O
+spiperone	POS	O
+binding	POS	O
+from	POS	O
+D1	POS	O
+or	POS	O
+D2	POS	O
+dopamine	POS	O
+receptor	POS	O
+subtypes	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+suggested	POS	O
+that	POS	O
+nefiracetam	POS	O
+augments	POS	O
+molecular	POS	O
+processes	POS	O
+in	POS	O
+the	POS	O
+early	POS	O
+stages	POS	O
+of	POS	O
+events	POS	O
+which	POS	O
+ultimately	POS	O
+lead	POS	O
+to	POS	O
+consolidation	POS	O
+of	POS	O
+memory	POS	O
+.	POS	O
+Phenytoin	POS	O
+encephalopathy	POS	B-NP
+as	POS	O
+probable	POS	O
+idiosyncratic	POS	O
+reaction	POS	O
+:	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+phenytoin	POS	O
+(	POS	O
+DPH	POS	O
+)	POS	O
+encephalopathy	POS	B-NP
+with	POS	O
+increasing	POS	O
+seizures	POS	B-NP
+and	POS	O
+EEG	POS	O
+and	POS	O
+mental	POS	O
+changes	POS	O
+is	POS	O
+described	POS	O
+.	POS	O
+Despite	POS	O
+adequate	POS	O
+oral	POS	O
+dosage	POS	O
+of	POS	O
+DPH	POS	O
+(	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+daily	POS	O
+)	POS	O
+the	POS	O
+plasma	POS	O
+level	POS	O
+was	POS	O
+very	POS	O
+low	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+8	POS	O
+microgramg	POS	O
+/	POS	O
+ml	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+encephalopathy	POS	B-NP
+was	POS	O
+probably	POS	O
+an	POS	O
+idiosyncratic	POS	O
+and	POS	O
+not	POS	O
+toxic	POS	O
+or	POS	O
+allergic	POS	B-NP
+reaction	POS	I-NP
+.	POS	O
+In	POS	O
+fact	POS	O
+the	POS	O
+concentration	POS	O
+of	POS	O
+free	POS	O
+DPH	POS	O
+was	POS	O
+normal	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+presented	POS	O
+a	POS	O
+retarded	POS	O
+morbilliform	POS	B-NP
+rash	POS	I-NP
+during	POS	O
+DPH	POS	B-NP
+treatment	POS	O
+,	POS	O
+the	POS	O
+protidogram	POS	O
+was	POS	O
+normal	POS	O
+,	POS	O
+and	POS	O
+an	POS	O
+intradermic	POS	O
+DPH	POS	O
+injection	POS	O
+had	POS	O
+no	POS	O
+local	POS	O
+effect	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+conclude	POS	O
+that	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+starting	POS	O
+DPH	POS	O
+treatment	POS	O
+an	POS	O
+unexpected	POS	O
+increase	POS	O
+in	POS	O
+seizures	POS	B-NP
+,	POS	O
+with	POS	O
+EEG	POS	O
+and	POS	O
+mental	POS	O
+changes	POS	O
+occurring	POS	O
+simultaneously	POS	O
+,	POS	O
+should	POS	O
+alert	POS	O
+the	POS	O
+physician	POS	O
+to	POS	O
+the	POS	O
+possible	POS	O
+need	POS	O
+for	POS	O
+eliminating	POS	O
+DPH	POS	O
+from	POS	O
+the	POS	O
+therapeutic	POS	O
+regimen	POS	O
+,	POS	O
+even	POS	O
+if	POS	O
+plasma	POS	O
+concentrations	POS	O
+are	POS	O
+low	POS	O
+.	POS	O
+Prevention	POS	O
+and	POS	O
+treatment	POS	O
+of	POS	O
+endometrial	POS	B-NP
+disease	POS	I-NP
+in	POS	O
+climacteric	POS	B-NP
+women	POS	O
+receiving	POS	O
+oestrogen	POS	O
+therapy	POS	O
+.	POS	O
+The	POS	O
+treatment	POS	O
+regimens	POS	O
+are	POS	O
+described	POS	O
+in	POS	O
+74	POS	O
+patients	POS	O
+with	POS	O
+endometrial	POS	B-NP
+disease	POS	I-NP
+among	POS	O
+850	POS	O
+climacteric	POS	B-NP
+women	POS	O
+receiving	POS	O
+oestrogen	POS	O
+therapy	POS	O
+.	POS	O
+Cystic	POS	B-NP
+hyperplasia	POS	I-NP
+was	POS	O
+associated	POS	O
+with	POS	O
+unopposed	POS	O
+oestrogen	POS	O
+therapy	POS	O
+without	POS	O
+progestagen	POS	O
+.	POS	O
+Two	POS	O
+courses	POS	O
+of	POS	O
+21	POS	O
+days	POS	O
+of	POS	O
+5	POS	O
+mg	POS	O
+norethisterone	POS	O
+daily	POS	O
+caused	POS	O
+reversion	POS	O
+to	POS	O
+normal	POS	O
+in	POS	O
+all	POS	O
+57	POS	O
+cases	POS	O
+of	POS	O
+cystic	POS	B-NP
+hyperplasia	POS	I-NP
+and	POS	O
+6	POS	O
+of	POS	O
+the	POS	O
+8	POS	O
+cases	POS	O
+of	POS	O
+atypical	POS	O
+hyperplasia	POS	B-NP
+.	POS	O
+4	POS	O
+cases	POS	O
+of	POS	O
+endometrial	POS	B-NP
+carcinoma	POS	I-NP
+referred	POS	O
+from	POS	O
+elsewhere	POS	O
+demonstrated	POS	O
+the	POS	O
+problems	POS	O
+of	POS	O
+inappropriate	POS	O
+and	POS	O
+unsupervised	POS	O
+unopposed	POS	O
+oestrogen	POS	O
+therapy	POS	O
+and	POS	O
+the	POS	O
+difficulty	POS	O
+in	POS	O
+distinguishing	POS	O
+severe	POS	O
+hyperplasia	POS	B-NP
+from	POS	O
+malignancy	POS	B-NP
+.	POS	O
+Cyclical	POS	O
+low	POS	O
+-	POS	O
+dose	POS	O
+oestrogen	POS	O
+therapy	POS	O
+with	POS	O
+7	POS	O
+-	POS	O
+-	POS	O
+13	POS	O
+days	POS	O
+of	POS	O
+progestagen	POS	O
+does	POS	O
+not	POS	O
+seem	POS	O
+to	POS	O
+increase	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+endometrial	POS	B-NP
+hyperplasia	POS	I-NP
+or	POS	O
+carcinoma	POS	B-NP
+.	POS	O
+Effects	POS	O
+of	POS	O
+exercise	POS	O
+on	POS	O
+the	POS	O
+severity	POS	O
+of	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+The	POS	O
+effect	POS	O
+of	POS	O
+exercise	POS	O
+on	POS	O
+the	POS	O
+severity	POS	O
+of	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+was	POS	O
+studied	POS	O
+in	POS	O
+male	POS	O
+rats	POS	O
+.	POS	O
+Ninety	POS	O
+-	POS	O
+three	POS	O
+rats	POS	O
+were	POS	O
+randomly	POS	O
+divided	POS	O
+into	POS	O
+three	POS	O
+groups	POS	O
+.	POS	O
+The	POS	O
+exercise	POS	O
+-	POS	O
+isoproterenol	POS	O
+(	POS	O
+E	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+and	POS	O
+exercise	POS	O
+control	POS	O
+(	POS	O
+EC	POS	O
+)	POS	O
+groups	POS	O
+exercised	POS	O
+daily	POS	O
+for	POS	O
+thirty	POS	O
+days	POS	O
+on	POS	O
+a	POS	O
+treadmill	POS	O
+at	POS	O
+1	POS	O
+mph	POS	O
+,	POS	O
+2	POS	O
+%	POS	O
+grade	POS	O
+while	POS	O
+animals	POS	O
+of	POS	O
+the	POS	O
+sedentary	POS	O
+-	POS	O
+isoproterenol	POS	O
+(	POS	O
+S	POS	O
+-	POS	O
+I	POS	O
+)	POS	O
+group	POS	O
+remained	POS	O
+sedentary	POS	O
+.	POS	O
+Eight	POS	O
+animals	POS	O
+were	POS	O
+assigned	POS	O
+to	POS	O
+the	POS	O
+sedentary	POS	O
+control	POS	O
+(	POS	O
+SC	POS	O
+)	POS	O
+group	POS	O
+which	POS	O
+remained	POS	O
+sedentary	POS	O
+throughout	POS	O
+the	POS	O
+experimental	POS	O
+period	POS	O
+.	POS	O
+Forty	POS	O
+-	POS	O
+eight	POS	O
+hours	POS	O
+after	POS	O
+the	POS	O
+final	POS	O
+exercise	POS	O
+period	POS	O
+,	POS	O
+S	POS	O
+-	POS	O
+I	POS	O
+and	POS	O
+E	POS	O
+-	POS	O
+I	POS	O
+animals	POS	O
+received	POS	O
+a	POS	O
+single	POS	O
+subcutaneous	POS	O
+injection	POS	O
+of	POS	O
+isoproterenol	POS	O
+(	POS	O
+250	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+body	POS	O
+weight	POS	O
+)	POS	O
+.	POS	O
+Animals	POS	O
+of	POS	O
+the	POS	O
+S	POS	O
+-	POS	O
+I	POS	O
+group	POS	O
+exhibited	POS	O
+significantly	POS	O
+(	POS	O
+Pp	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+greater	POS	O
+mortality	POS	O
+from	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+isoproterenol	POS	O
+than	POS	O
+animals	POS	O
+of	POS	O
+the	POS	O
+E	POS	O
+-	POS	O
+I	POS	O
+group	POS	O
+.	POS	O
+Serum	POS	O
+CPK	POS	O
+activity	POS	O
+for	POS	O
+E	POS	O
+-	POS	O
+I	POS	O
+animals	POS	O
+was	POS	O
+significantly	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+greater	POS	O
+than	POS	O
+for	POS	O
+animals	POS	O
+in	POS	O
+the	POS	O
+S	POS	O
+-	POS	O
+I	POS	O
+and	POS	O
+EC	POS	O
+groups	POS	O
+twenty	POS	O
+hours	POS	O
+following	POS	O
+isoproterenol	POS	O
+injection	POS	O
+.	POS	O
+No	POS	O
+statistically	POS	O
+significant	POS	O
+differences	POS	O
+were	POS	O
+observed	POS	O
+between	POS	O
+the	POS	O
+two	POS	O
+isoproterenol	POS	O
+treated	POS	O
+groups	POS	O
+for	POS	O
+severity	POS	O
+of	POS	O
+the	POS	O
+induced	POS	O
+lesions	POS	B-NP
+,	POS	O
+changes	POS	O
+in	POS	O
+heart	POS	O
+weight	POS	O
+,	POS	O
+or	POS	O
+heart	POS	O
+weight	POS	O
+to	POS	O
+body	POS	O
+weight	POS	O
+ratios	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+indicated	POS	O
+that	POS	O
+exercise	POS	O
+reduced	POS	O
+the	POS	O
+mortality	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+large	POS	O
+dosages	POS	O
+of	POS	O
+isoproterenol	POS	O
+but	POS	O
+had	POS	O
+little	POS	O
+on	POS	O
+the	POS	O
+severity	POS	O
+of	POS	O
+the	POS	O
+infarction	POS	B-NP
+.	POS	O
+Human	POS	O
+corticotropin	POS	O
+-	POS	O
+releasing	POS	O
+hormone	POS	O
+and	POS	O
+thyrotropin	POS	O
+-	POS	O
+releasing	POS	O
+hormone	POS	O
+modulate	POS	O
+the	POS	O
+hypercapnic	POS	O
+ventilatory	POS	O
+response	POS	O
+in	POS	O
+humans	POS	O
+.	POS	O
+Human	POS	O
+corticotropin	POS	O
+-	POS	O
+releasing	POS	O
+hormone	POS	O
+(	POS	O
+hCRH	POS	O
+)	POS	O
+and	POS	O
+thyrotropin	POS	O
+-	POS	O
+releasing	POS	O
+hormone	POS	O
+(	POS	O
+TRH	POS	O
+)	POS	O
+are	POS	O
+known	POS	O
+to	POS	O
+stimulate	POS	O
+ventilation	POS	O
+after	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+administration	POS	O
+in	POS	O
+humans	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+,	POS	O
+single	POS	O
+-	POS	O
+blind	POS	O
+study	POS	O
+we	POS	O
+aimed	POS	O
+to	POS	O
+clarify	POS	O
+if	POS	O
+both	POS	O
+peptides	POS	O
+act	POS	O
+by	POS	O
+altering	POS	O
+central	POS	O
+chemosensitivity	POS	O
+.	POS	O
+Two	POS	O
+subsequent	POS	O
+CO2	POS	O
+-	POS	O
+rebreathing	POS	O
+tests	POS	O
+were	POS	O
+performed	POS	O
+in	POS	O
+healthy	POS	O
+young	POS	O
+volunteers	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+first	POS	O
+test	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+NaCl	POS	O
+was	POS	O
+given	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+;	POS	O
+during	POS	O
+the	POS	O
+second	POS	O
+test	POS	O
+200	POS	O
+micrograms	POS	O
+of	POS	O
+hCRH	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+12	POS	O
+)	POS	O
+or	POS	O
+400	POS	O
+micrograms	POS	O
+of	POS	O
+TRH	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+6	POS	O
+)	POS	O
+was	POS	O
+administered	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+Nine	POS	O
+subjects	POS	O
+received	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+NaCl	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+during	POS	O
+both	POS	O
+rebreathing	POS	O
+manoeuvres	POS	O
+.	POS	O
+The	POS	O
+CO2	POS	O
+-	POS	O
+response	POS	O
+curves	POS	O
+for	POS	O
+the	POS	O
+two	POS	O
+tests	POS	O
+were	POS	O
+compared	POS	O
+within	POS	O
+the	POS	O
+same	POS	O
+subject	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+hCRH	POS	O
+group	POS	O
+a	POS	O
+marked	POS	O
+parallel	POS	O
+shift	POS	O
+of	POS	O
+the	POS	O
+CO2	POS	O
+-	POS	O
+response	POS	O
+curve	POS	O
+to	POS	O
+the	POS	O
+left	POS	O
+was	POS	O
+observed	POS	O
+after	POS	O
+hCRH	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+same	POS	O
+effect	POS	O
+occurred	POS	O
+following	POS	O
+TRH	POS	O
+but	POS	O
+was	POS	O
+less	POS	O
+striking	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+hCRH	POS	O
+and	POS	O
+TRH	POS	O
+caused	POS	O
+a	POS	O
+reduction	POS	O
+in	POS	O
+the	POS	O
+CO2	POS	O
+threshold	POS	O
+.	POS	O
+The	POS	O
+CO2	POS	O
+-	POS	O
+response	POS	O
+curves	POS	O
+in	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+were	POS	O
+nearly	POS	O
+identical	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+indicate	POS	O
+an	POS	O
+additive	POS	O
+effect	POS	O
+of	POS	O
+both	POS	O
+releasing	POS	O
+hormones	POS	O
+on	POS	O
+the	POS	O
+hypercapnic	POS	O
+ventilatory	POS	O
+response	POS	O
+in	POS	O
+humans	POS	O
+,	POS	O
+presumably	POS	O
+independent	POS	O
+of	POS	O
+central	POS	O
+chemosensitivity	POS	O
+.	POS	O
+Lamivudine	POS	O
+is	POS	O
+effective	POS	O
+in	POS	O
+suppressing	POS	O
+hepatitis	POS	O
+B	POS	O
+virus	POS	O
+DNA	POS	O
+in	POS	O
+Chinese	POS	O
+hepatitis	POS	O
+B	POS	O
+surface	POS	O
+antigen	POS	O
+carriers	POS	O
+:	POS	O
+a	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+trial	POS	O
+.	POS	O
+Lamivudine	POS	O
+is	POS	O
+a	POS	O
+novel	POS	O
+2	POS	O
+'	POS	O
+,	POS	O
+3	POS	O
+'	POS	O
+-	POS	O
+dideoxy	POS	O
+cytosine	POS	O
+analogue	POS	O
+that	POS	O
+has	POS	O
+potent	POS	O
+inhibitory	POS	O
+effects	POS	O
+on	POS	O
+hepatitis	POS	O
+B	POS	O
+virus	POS	O
+replication	POS	O
+in	POS	O
+vitro	POS	O
+and	POS	O
+in	POS	O
+vivo	POS	O
+.	POS	O
+We	POS	O
+performed	POS	O
+a	POS	O
+single	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+study	POS	O
+to	POS	O
+assess	POS	O
+its	POS	O
+effectiveness	POS	O
+and	POS	O
+safety	POS	O
+in	POS	O
+Chinese	POS	O
+hepatitis	POS	O
+B	POS	O
+surface	POS	O
+antigen	POS	O
+(	POS	O
+HBsAg	POS	O
+)	POS	O
+carriers	POS	O
+.	POS	O
+Forty	POS	O
+-	POS	O
+two	POS	O
+Chinese	POS	O
+HBsAg	POS	O
+carriers	POS	O
+were	POS	O
+randomized	POS	O
+to	POS	O
+receive	POS	O
+placebo	POS	O
+(	POS	O
+6	POS	O
+patients	POS	O
+)	POS	O
+or	POS	O
+lamivudine	POS	O
+orally	POS	O
+in	POS	O
+dosages	POS	O
+of	POS	O
+25	POS	O
+mg	POS	O
+,	POS	O
+100	POS	O
+mg	POS	O
+,	POS	O
+or	POS	O
+300	POS	O
+mg	POS	O
+daily	POS	O
+(	POS	O
+12	POS	O
+patients	POS	O
+for	POS	O
+each	POS	O
+dosage	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+drug	POS	O
+was	POS	O
+given	POS	O
+for	POS	O
+4	POS	O
+weeks	POS	O
+.	POS	O
+The	POS	O
+patients	POS	O
+were	POS	O
+closely	POS	O
+monitored	POS	O
+clinically	POS	O
+,	POS	O
+biochemically	POS	O
+,	POS	O
+and	POS	O
+serologically	POS	O
+up	POS	O
+to	POS	O
+4	POS	O
+weeks	POS	O
+after	POS	O
+drug	POS	O
+treatment	POS	O
+.	POS	O
+All	POS	O
+36	POS	O
+patients	POS	O
+receiving	POS	O
+lamivudine	POS	O
+had	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+hepatitis	POS	B-NP
+B	POS	I-NP
+virus	POS	O
+(	POS	O
+HBV	POS	O
+)	POS	O
+DNA	POS	O
+values	POS	O
+of	POS	O
+>	POS	O
+90	POS	O
+%	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+001	POS	O
+compared	POS	O
+with	POS	O
+placebo	POS	O
+)	POS	O
+.	POS	O
+Although	POS	O
+25	POS	O
+mg	POS	O
+of	POS	O
+lamivudine	POS	O
+was	POS	O
+slightly	POS	O
+less	POS	O
+effective	POS	O
+than	POS	O
+100	POS	O
+mg	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+011	POS	O
+)	POS	O
+and	POS	O
+300	POS	O
+mg	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+005	POS	O
+)	POS	O
+,	POS	O
+it	POS	O
+still	POS	O
+induced	POS	O
+94	POS	O
+%	POS	O
+suppression	POS	O
+of	POS	O
+HBV	POS	O
+DNA	POS	O
+after	POS	O
+the	POS	O
+fourth	POS	O
+week	POS	O
+of	POS	O
+therapy	POS	O
+.	POS	O
+HBV	POS	O
+DNA	POS	O
+values	POS	O
+returned	POS	O
+to	POS	O
+pretreatment	POS	O
+levels	POS	O
+within	POS	O
+4	POS	O
+weeks	POS	O
+of	POS	O
+cessation	POS	O
+of	POS	O
+therapy	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+change	POS	O
+in	POS	O
+the	POS	O
+hepatitis	POS	O
+B	POS	O
+e	POS	O
+antigen	POS	O
+status	POS	O
+or	POS	O
+in	POS	O
+aminotransferase	POS	O
+levels	POS	O
+.	POS	O
+No	POS	O
+serious	POS	O
+adverse	POS	O
+events	POS	O
+were	POS	O
+observed	POS	O
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+a	POS	O
+4	POS	O
+-	POS	O
+week	POS	O
+course	POS	O
+of	POS	O
+lamivudine	POS	O
+was	POS	O
+safe	POS	O
+and	POS	O
+effective	POS	O
+in	POS	O
+suppression	POS	O
+of	POS	O
+HBV	POS	O
+DNA	POS	O
+in	POS	O
+Chinese	POS	O
+HBsAg	POS	O
+carriers	POS	O
+.	POS	O
+The	POS	O
+suppression	POS	O
+was	POS	O
+>	POS	O
+90	POS	O
+%	POS	O
+but	POS	O
+reversible	POS	O
+.	POS	O
+Studies	POS	O
+with	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+lamivudine	POS	O
+administration	POS	O
+should	POS	O
+be	POS	O
+performed	POS	O
+to	POS	O
+determine	POS	O
+if	POS	O
+prolonged	POS	O
+suppression	POS	O
+of	POS	O
+HBV	POS	O
+DNA	POS	O
+can	POS	O
+be	POS	O
+achieved	POS	O
+.	POS	O
+Population	POS	O
+-	POS	O
+based	POS	O
+study	POS	O
+of	POS	O
+risk	POS	O
+of	POS	O
+venous	POS	B-NP
+thromboembolism	POS	I-NP
+associated	POS	O
+with	POS	O
+various	POS	O
+oral	POS	O
+contraceptives	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Four	POS	O
+studies	POS	O
+published	POS	O
+since	POS	O
+December	POS	O
+,	POS	O
+1995	POS	O
+,	POS	O
+reported	POS	O
+that	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+venous	POS	B-NP
+thromboembolism	POS	I-NP
+(	POS	O
+VTE	POS	B-NP
+)	POS	O
+was	POS	O
+higher	POS	O
+in	POS	O
+women	POS	O
+who	POS	O
+used	POS	O
+oral	POS	O
+contraceptives	POS	O
+(	POS	O
+OCs	POS	O
+)	POS	O
+containing	POS	O
+the	POS	O
+third	POS	O
+-	POS	O
+generation	POS	O
+progestagens	POS	O
+gestodene	POS	O
+or	POS	O
+desogestrel	POS	O
+than	POS	O
+in	POS	O
+users	POS	O
+of	POS	O
+OCs	POS	O
+containing	POS	O
+second	POS	O
+-	POS	O
+generation	POS	O
+progestagens	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+confounding	POS	O
+and	POS	O
+bias	POS	O
+in	POS	O
+the	POS	O
+design	POS	O
+of	POS	O
+these	POS	O
+studies	POS	O
+may	POS	O
+have	POS	O
+affected	POS	O
+the	POS	O
+findings	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+our	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+re	POS	O
+-	POS	O
+examine	POS	O
+the	POS	O
+association	POS	O
+between	POS	O
+risk	POS	O
+of	POS	O
+VTE	POS	B-NP
+and	POS	O
+OC	POS	O
+use	POS	O
+with	POS	O
+a	POS	O
+different	POS	O
+study	POS	O
+design	POS	O
+and	POS	O
+analysis	POS	O
+to	POS	O
+avoid	POS	O
+some	POS	O
+of	POS	O
+the	POS	O
+bias	POS	O
+and	POS	O
+confounding	POS	O
+of	POS	O
+the	POS	O
+earlier	POS	O
+studies	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+used	POS	O
+computer	POS	O
+records	POS	O
+of	POS	O
+patients	POS	O
+from	POS	O
+143	POS	O
+general	POS	O
+practices	POS	O
+in	POS	O
+the	POS	O
+UK	POS	O
+.	POS	O
+The	POS	O
+study	POS	O
+was	POS	O
+based	POS	O
+on	POS	O
+the	POS	O
+medical	POS	O
+records	POS	O
+of	POS	O
+about	POS	O
+540	POS	O
+,	POS	O
+000	POS	O
+women	POS	O
+born	POS	O
+between	POS	O
+1941	POS	O
+and	POS	O
+1981	POS	O
+.	POS	O
+All	POS	O
+women	POS	O
+who	POS	O
+had	POS	O
+a	POS	O
+recorded	POS	O
+diagnosis	POS	O
+of	POS	O
+deep	POS	B-NP
+-	POS	I-NP
+vein	POS	I-NP
+thrombosis	POS	I-NP
+,	POS	O
+venous	POS	B-NP
+thrombosis	POS	I-NP
+not	POS	O
+otherwise	POS	O
+specified	POS	O
+,	POS	O
+or	POS	O
+pulmonary	POS	B-NP
+embolus	POS	I-NP
+during	POS	O
+the	POS	O
+study	POS	O
+period	POS	O
+,	POS	O
+and	POS	O
+who	POS	O
+had	POS	O
+been	POS	O
+treated	POS	O
+with	POS	O
+an	POS	O
+anticoagulant	POS	O
+were	POS	O
+identified	POS	O
+as	POS	O
+potential	POS	O
+cases	POS	O
+of	POS	O
+VTE	POS	B-NP
+.	POS	O
+We	POS	O
+did	POS	O
+a	POS	O
+cohort	POS	O
+analysis	POS	O
+to	POS	O
+estimate	POS	O
+and	POS	O
+compare	POS	O
+incidence	POS	O
+of	POS	O
+VTE	POS	B-NP
+in	POS	O
+users	POS	O
+of	POS	O
+the	POS	O
+main	POS	O
+OC	POS	O
+preparations	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+nested	POS	O
+case	POS	O
+-	POS	O
+control	POS	O
+study	POS	O
+to	POS	O
+calculate	POS	O
+the	POS	O
+odds	POS	O
+ratios	POS	O
+of	POS	O
+VTE	POS	B-NP
+associated	POS	O
+with	POS	O
+use	POS	O
+of	POS	O
+different	POS	O
+types	POS	O
+of	POS	O
+OC	POS	O
+,	POS	O
+after	POS	O
+adjustment	POS	O
+for	POS	O
+potential	POS	O
+confounding	POS	O
+factors	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+case	POS	O
+-	POS	O
+control	POS	O
+study	POS	O
+,	POS	O
+we	POS	O
+matched	POS	O
+cases	POS	O
+to	POS	O
+controls	POS	O
+by	POS	O
+exact	POS	O
+year	POS	O
+of	POS	O
+birth	POS	O
+,	POS	O
+practice	POS	O
+,	POS	O
+and	POS	O
+current	POS	O
+use	POS	O
+of	POS	O
+OCs	POS	O
+.	POS	O
+We	POS	O
+used	POS	O
+a	POS	O
+multiple	POS	O
+logistic	POS	O
+regression	POS	O
+model	POS	O
+that	POS	O
+included	POS	O
+body	POS	O
+-	POS	O
+mass	POS	O
+index	POS	O
+,	POS	O
+number	POS	O
+of	POS	O
+cycles	POS	O
+,	POS	O
+change	POS	O
+in	POS	O
+type	POS	O
+of	POS	O
+OC	POS	O
+prescribed	POS	O
+within	POS	O
+3	POS	O
+months	POS	O
+of	POS	O
+the	POS	O
+event	POS	O
+,	POS	O
+previous	POS	O
+pregnancy	POS	O
+,	POS	O
+and	POS	O
+concurrent	POS	O
+disease	POS	O
+.	POS	O
+FINDINGS	POS	O
+:	POS	O
+85	POS	O
+women	POS	O
+met	POS	O
+the	POS	O
+inclusion	POS	O
+criteria	POS	O
+for	POS	O
+VTE	POS	B-NP
+,	POS	O
+two	POS	O
+of	POS	O
+whom	POS	O
+were	POS	O
+users	POS	O
+of	POS	O
+progestagen	POS	O
+-	POS	O
+only	POS	O
+OCs	POS	O
+.	POS	O
+Of	POS	O
+the	POS	O
+83	POS	O
+cases	POS	O
+of	POS	O
+VTE	POS	B-NP
+associated	POS	O
+with	POS	O
+use	POS	O
+of	POS	O
+combined	POS	O
+OCs	POS	O
+,	POS	O
+43	POS	O
+were	POS	O
+recorded	POS	O
+as	POS	O
+deep	POS	B-NP
+-	POS	I-NP
+vein	POS	I-NP
+thrombosis	POS	I-NP
+,	POS	O
+35	POS	O
+as	POS	O
+pulmonary	POS	B-NP
+thrombosis	POS	I-NP
+,	POS	O
+and	POS	O
+five	POS	O
+as	POS	O
+venous	POS	B-NP
+thrombosis	POS	I-NP
+not	POS	O
+otherwise	POS	O
+specified	POS	O
+.	POS	O
+The	POS	O
+crude	POS	O
+rate	POS	O
+of	POS	O
+VTE	POS	B-NP
+per	POS	O
+10	POS	O
+,	POS	O
+000	POS	O
+woman	POS	O
+-	POS	O
+years	POS	O
+was	POS	O
+4	POS	O
+.	POS	O
+10	POS	O
+in	POS	O
+current	POS	O
+users	POS	O
+of	POS	O
+any	POS	O
+OC	POS	O
+,	POS	O
+3	POS	O
+.	POS	O
+10	POS	O
+in	POS	O
+users	POS	O
+of	POS	O
+second	POS	O
+-	POS	O
+generation	POS	O
+OCs	POS	O
+,	POS	O
+and	POS	O
+4	POS	O
+.	POS	O
+96	POS	O
+in	POS	O
+users	POS	O
+of	POS	O
+third	POS	O
+-	POS	O
+generation	POS	O
+preparations	POS	O
+.	POS	O
+After	POS	O
+adjustment	POS	O
+for	POS	O
+age	POS	O
+,	POS	O
+the	POS	O
+rate	POS	O
+ratio	POS	O
+of	POS	O
+VTE	POS	B-NP
+in	POS	O
+users	POS	O
+of	POS	O
+third	POS	O
+-	POS	O
+generation	POS	O
+relative	POS	O
+to	POS	O
+second	POS	O
+-	POS	O
+generation	POS	O
+OCs	POS	O
+was	POS	O
+1	POS	O
+.	POS	O
+68	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+1	POS	O
+.	POS	O
+04	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+75	POS	O
+)	POS	O
+.	POS	O
+Logistic	POS	O
+regression	POS	O
+showed	POS	O
+no	POS	O
+significant	POS	O
+difference	POS	O
+in	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+VTE	POS	B-NP
+between	POS	O
+users	POS	O
+of	POS	O
+third	POS	O
+-	POS	O
+generation	POS	O
+and	POS	O
+second	POS	O
+-	POS	O
+generation	POS	O
+OCs	POS	O
+.	POS	O
+Among	POS	O
+users	POS	O
+of	POS	O
+third	POS	O
+-	POS	O
+generation	POS	O
+progestagens	POS	O
+,	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+VTE	POS	B-NP
+was	POS	O
+higher	POS	O
+in	POS	O
+users	POS	O
+of	POS	O
+desogestrel	POS	O
+with	POS	O
+20	POS	O
+g	POS	O
+ethinyloestradiol	POS	O
+than	POS	O
+in	POS	O
+users	POS	O
+of	POS	O
+gestodene	POS	O
+or	POS	O
+desogestrel	POS	O
+with	POS	O
+30	POS	O
+g	POS	O
+ethinyloestradiol	POS	O
+.	POS	O
+With	POS	O
+all	POS	O
+second	POS	O
+-	POS	O
+generation	POS	O
+OCs	POS	O
+as	POS	O
+the	POS	O
+reference	POS	O
+,	POS	O
+the	POS	O
+odds	POS	O
+ratios	POS	O
+for	POS	O
+VTE	POS	B-NP
+were	POS	O
+3	POS	O
+.	POS	O
+49	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+21	POS	O
+-	POS	O
+10	POS	O
+.	POS	O
+12	POS	O
+)	POS	O
+for	POS	O
+desogestrel	POS	O
+plus	POS	O
+20	POS	O
+g	POS	O
+ethinyloestradiol	POS	O
+and	POS	O
+1	POS	O
+.	POS	O
+18	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+66	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+17	POS	O
+)	POS	O
+for	POS	O
+the	POS	O
+other	POS	O
+third	POS	O
+-	POS	O
+generation	POS	O
+progestagens	POS	O
+.	POS	O
+INTERPRETATION	POS	O
+:	POS	O
+The	POS	O
+previously	POS	O
+reported	POS	O
+increase	POS	O
+in	POS	O
+odds	POS	O
+ratio	POS	O
+associated	POS	O
+with	POS	O
+third	POS	O
+-	POS	O
+generation	POS	O
+OCs	POS	O
+when	POS	O
+compared	POS	O
+with	POS	O
+second	POS	O
+-	POS	O
+generation	POS	O
+products	POS	O
+is	POS	O
+likely	POS	O
+to	POS	O
+have	POS	O
+been	POS	O
+the	POS	O
+result	POS	O
+of	POS	O
+residual	POS	O
+confounding	POS	O
+by	POS	O
+age	POS	O
+.	POS	O
+The	POS	O
+increased	POS	O
+odds	POS	O
+ratio	POS	O
+associated	POS	O
+with	POS	O
+products	POS	O
+containing	POS	O
+20	POS	O
+micrograms	POS	O
+ethinyloestradiol	POS	O
+and	POS	O
+desogestrel	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+30	POS	O
+micrograms	POS	O
+product	POS	O
+is	POS	O
+biologically	POS	O
+implausible	POS	O
+,	POS	O
+and	POS	O
+is	POS	O
+likely	POS	O
+to	POS	O
+be	POS	O
+the	POS	O
+result	POS	O
+of	POS	O
+preferential	POS	O
+prescribing	POS	O
+and	POS	O
+,	POS	O
+thus	POS	O
+,	POS	O
+confounding	POS	O
+.	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+augments	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+electrographic	POS	O
+seizure	POS	B-NP
+but	POS	O
+protects	POS	O
+against	POS	O
+brain	POS	B-NP
+damage	POS	I-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+1	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+examined	POS	O
+the	POS	O
+anticonvulsant	POS	O
+effects	POS	O
+of	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+on	POS	O
+the	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+seizure	POS	B-NP
+model	POS	O
+.	POS	O
+Intraperitoneal	POS	O
+injection	POS	O
+of	POS	O
+pilocarpine	POS	O
+(	POS	O
+400	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+induced	POS	O
+tonic	POS	O
+and	POS	O
+clonic	POS	B-NP
+seizure	POS	B-NP
+.	POS	O
+Scopolamine	POS	O
+(	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+and	POS	O
+pentobarbital	POS	O
+(	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+prevented	POS	O
+development	POS	O
+of	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+behavioral	POS	O
+seizure	POS	B-NP
+but	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+did	POS	O
+not	POS	O
+.	POS	O
+2	POS	O
+.	POS	O
+An	POS	O
+electrical	POS	O
+seizure	POS	B-NP
+measured	POS	O
+with	POS	O
+hippocampal	POS	O
+EEG	POS	O
+appeared	POS	O
+in	POS	O
+the	POS	O
+pilocarpine	POS	O
+-	POS	O
+treated	POS	O
+group	POS	O
+.	POS	O
+Scopolamine	POS	O
+and	POS	O
+pentobarbital	POS	O
+blocked	POS	O
+the	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+electrographic	POS	B-NP
+seizure	POS	I-NP
+,	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+treatment	POS	O
+augmented	POS	O
+the	POS	O
+electrographic	POS	O
+seizure	POS	B-NP
+induced	POS	O
+by	POS	O
+pilocarpine	POS	O
+.	POS	O
+3	POS	O
+.	POS	O
+Brain	POS	B-NP
+damage	POS	I-NP
+was	POS	O
+assessed	POS	O
+by	POS	O
+examining	POS	O
+the	POS	O
+hippocampus	POS	O
+microscopically	POS	O
+.	POS	O
+Pilocarpine	POS	O
+produced	POS	O
+neuronal	POS	O
+death	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+,	POS	O
+which	POS	O
+showed	POS	O
+pyknotic	POS	O
+changes	POS	O
+.	POS	O
+Pentobarbital	POS	O
+,	POS	O
+scopolamine	POS	O
+and	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+protected	POS	O
+the	POS	O
+brain	POS	O
+damage	POS	O
+by	POS	O
+pilocarpine	POS	O
+,	POS	O
+though	POS	O
+in	POS	O
+the	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+-	POS	O
+treated	POS	O
+group	POS	O
+,	POS	O
+the	POS	O
+pyramidal	POS	O
+cells	POS	O
+of	POS	O
+hippocampus	POS	O
+appeared	POS	O
+darker	POS	O
+than	POS	O
+normal	POS	O
+.	POS	O
+In	POS	O
+all	POS	O
+treatments	POS	O
+,	POS	O
+granule	POS	O
+cells	POS	O
+of	POS	O
+the	POS	O
+dentate	POS	O
+gyrus	POS	O
+were	POS	O
+not	POS	O
+affected	POS	O
+.	POS	O
+4	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+induced	POS	O
+by	POS	O
+pilocarpine	POS	O
+is	POS	O
+initiated	POS	O
+by	POS	O
+cholinergic	POS	O
+overstimulation	POS	O
+and	POS	O
+propagated	POS	O
+by	POS	O
+glutamatergic	POS	O
+transmission	POS	O
+,	POS	O
+the	POS	O
+elevation	POS	O
+of	POS	O
+which	POS	O
+may	POS	O
+cause	POS	O
+brain	POS	O
+damage	POS	O
+through	POS	O
+an	POS	O
+excitatory	POS	O
+NMDA	POS	O
+receptor	POS	O
+-	POS	O
+mediated	POS	O
+mechanism	POS	O
+.	POS	O
+Paclitaxel	POS	O
+,	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+,	POS	O
+and	POS	O
+folinic	POS	O
+acid	POS	O
+in	POS	O
+metastatic	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+:	POS	O
+BRE	POS	O
+-	POS	O
+26	POS	O
+,	POS	O
+a	POS	O
+phase	POS	O
+II	POS	O
+trial	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+Fluorouracil	POS	O
+plus	POS	O
+folinic	POS	O
+acid	POS	O
+and	POS	O
+paclitaxel	POS	O
+(	POS	O
+Taxol	POS	O
+;	POS	O
+Bristol	POS	O
+-	POS	O
+Myers	POS	O
+Squibb	POS	O
+Company	POS	O
+,	POS	O
+Princeton	POS	O
+,	POS	O
+NJ	POS	O
+)	POS	O
+are	POS	O
+effective	POS	O
+salvage	POS	O
+therapies	POS	O
+for	POS	O
+metastatic	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+patients	POS	O
+.	POS	O
+Paclitaxel	POS	O
+and	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+have	POS	O
+additive	POS	O
+cytotoxicity	POS	B-NP
+in	POS	O
+MCF	POS	O
+-	POS	O
+7	POS	O
+cell	POS	O
+lines	POS	O
+.	POS	O
+We	POS	O
+performed	POS	O
+a	POS	O
+phase	POS	O
+II	POS	O
+trial	POS	O
+of	POS	O
+paclitaxel	POS	O
+175	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+over	POS	O
+3	POS	O
+hours	POS	O
+on	POS	O
+day	POS	O
+I	POS	O
+followed	POS	O
+by	POS	O
+folinic	POS	O
+acid	POS	O
+300	POS	O
+mg	POS	O
+over	POS	O
+1	POS	O
+hour	POS	O
+before	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+350	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+on	POS	O
+days	POS	O
+1	POS	O
+to	POS	O
+3	POS	O
+every	POS	O
+28	POS	O
+days	POS	O
+(	POS	O
+TFL	POS	O
+)	POS	O
+in	POS	O
+women	POS	O
+with	POS	O
+metastatic	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+Analysis	POS	O
+is	POS	O
+reported	POS	O
+on	POS	O
+37	POS	O
+patients	POS	O
+with	POS	O
+a	POS	O
+minimum	POS	O
+of	POS	O
+6	POS	O
+months	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+who	POS	O
+received	POS	O
+a	POS	O
+total	POS	O
+of	POS	O
+192	POS	O
+cycles	POS	O
+of	POS	O
+TFL	POS	O
+:	POS	O
+nine	POS	O
+cycles	POS	O
+(	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+were	POS	O
+associated	POS	O
+with	POS	O
+grade	POS	O
+3	POS	O
+/	POS	O
+4	POS	O
+neutropenia	POS	B-NP
+requiring	POS	O
+hospitalization	POS	O
+;	POS	O
+seven	POS	O
+(	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+cycles	POS	O
+in	POS	O
+two	POS	O
+patients	POS	O
+required	POS	O
+granulocyte	POS	O
+colony	POS	O
+-	POS	O
+stimulating	POS	O
+factor	POS	O
+due	POS	O
+to	POS	O
+neutropenia	POS	B-NP
+;	POS	O
+no	POS	O
+patient	POS	O
+required	POS	O
+platelet	POS	B-NP
+transfusions	POS	I-NP
+.	POS	O
+Grade	POS	O
+3	POS	O
+/	POS	O
+4	POS	O
+nonhematologic	POS	O
+toxicities	POS	B-NP
+were	POS	O
+uncommon	POS	O
+.	POS	O
+Among	POS	O
+the	POS	O
+34	POS	O
+patients	POS	O
+evaluable	POS	O
+for	POS	O
+response	POS	O
+,	POS	O
+there	POS	O
+were	POS	O
+three	POS	O
+complete	POS	O
+responses	POS	O
+(	POS	O
+9	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+18	POS	O
+partial	POS	O
+responses	POS	O
+(	POS	O
+53	POS	O
+%	POS	O
+)	POS	O
+for	POS	O
+an	POS	O
+overall	POS	O
+response	POS	O
+rate	POS	O
+of	POS	O
+62	POS	O
+%	POS	O
+.	POS	O
+Of	POS	O
+the	POS	O
+19	POS	O
+evaluable	POS	O
+patients	POS	O
+with	POS	O
+prior	POS	O
+doxorubicin	POS	O
+exposure	POS	O
+,	POS	O
+11	POS	O
+(	POS	O
+58	POS	O
+%	POS	O
+)	POS	O
+responded	POS	O
+compared	POS	O
+with	POS	O
+nine	POS	O
+of	POS	O
+15	POS	O
+(	POS	O
+60	POS	O
+%	POS	O
+)	POS	O
+without	POS	O
+prior	POS	O
+doxorubicin	POS	O
+.	POS	O
+Plasma	POS	O
+paclitaxel	POS	O
+concentrations	POS	O
+were	POS	O
+measured	POS	O
+at	POS	O
+the	POS	O
+completion	POS	O
+of	POS	O
+paclitaxel	POS	O
+infusion	POS	O
+and	POS	O
+at	POS	O
+24	POS	O
+hours	POS	O
+in	POS	O
+19	POS	O
+patients	POS	O
+.	POS	O
+TFL	POS	O
+is	POS	O
+an	POS	O
+active	POS	O
+,	POS	O
+well	POS	O
+-	POS	O
+tolerated	POS	O
+regimen	POS	O
+in	POS	O
+metastatic	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+Efficacy	POS	O
+and	POS	O
+proarrhythmia	POS	B-NP
+with	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+for	POS	O
+sustained	POS	O
+ventricular	POS	B-NP
+tachyarrhythmias	POS	I-NP
+.	POS	O
+This	POS	O
+study	POS	O
+prospectively	POS	O
+evaluated	POS	O
+the	POS	O
+clinical	POS	O
+efficacy	POS	O
+,	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+,	POS	O
+and	POS	O
+the	POS	O
+presumable	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+in	POS	O
+patients	POS	O
+treated	POS	O
+with	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+for	POS	O
+sustained	POS	O
+ventricular	POS	B-NP
+tachyarrhythmias	POS	I-NP
+.	POS	O
+Eighty	POS	O
+-	POS	O
+one	POS	O
+consecutive	POS	O
+patients	POS	O
+(	POS	O
+54	POS	O
+with	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+,	POS	O
+and	POS	O
+20	POS	O
+with	POS	O
+dilated	POS	B-NP
+cardiomyopathy	POS	I-NP
+)	POS	O
+with	POS	O
+inducible	POS	O
+sustained	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+or	POS	O
+ventricular	POS	B-NP
+fibrillation	POS	I-NP
+received	POS	O
+oral	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+to	POS	O
+prevent	POS	O
+induction	POS	O
+of	POS	O
+the	POS	O
+ventricular	POS	B-NP
+tachyarrhythmia	POS	I-NP
+.	POS	O
+During	POS	O
+oral	POS	O
+loading	POS	O
+with	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+,	POS	O
+continuous	POS	O
+electrocardiographic	POS	O
+(	POS	O
+ECG	POS	O
+)	POS	O
+monitoring	POS	O
+was	POS	O
+performed	POS	O
+.	POS	O
+Those	POS	O
+patients	POS	O
+in	POS	O
+whom	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+prevented	POS	O
+induction	POS	O
+of	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+or	POS	O
+ventricular	POS	B-NP
+fibrillation	POS	I-NP
+were	POS	O
+discharged	POS	O
+with	POS	O
+the	POS	O
+drug	POS	O
+and	POS	O
+followed	POS	O
+up	POS	O
+on	POS	O
+an	POS	O
+outpatient	POS	O
+basis	POS	O
+for	POS	O
+21	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+18	POS	O
+months	POS	O
+.	POS	O
+Induction	POS	O
+of	POS	O
+the	POS	O
+ventricular	POS	B-NP
+tachyarrhythmia	POS	I-NP
+was	POS	O
+prevented	POS	O
+by	POS	O
+oral	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+in	POS	O
+35	POS	O
+(	POS	O
+43	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+;	POS	O
+the	POS	O
+ventricular	POS	B-NP
+tachyarrhythmia	POS	I-NP
+remained	POS	O
+inducible	POS	O
+in	POS	O
+40	POS	O
+(	POS	O
+49	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+;	POS	O
+and	POS	O
+two	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+did	POS	O
+not	POS	O
+tolerate	POS	O
+even	POS	O
+40	POS	O
+mg	POS	O
+of	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+once	POS	O
+daily	POS	O
+.	POS	O
+Four	POS	O
+(	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+had	POS	O
+from	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+during	POS	O
+the	POS	O
+initial	POS	O
+oral	POS	O
+treatment	POS	O
+with	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+.	POS	O
+Neither	POS	O
+ECG	POS	O
+[	POS	O
+sinus	POS	O
+-	POS	O
+cycle	POS	O
+length	POS	O
+(	POS	O
+SCL	POS	O
+)	POS	O
+,	POS	O
+QT	POS	O
+or	POS	O
+QTc	POS	O
+interval	POS	O
+,	POS	O
+or	POS	O
+U	POS	O
+wave	POS	O
+]	POS	O
+nor	POS	O
+clinical	POS	O
+parameters	POS	O
+identified	POS	O
+patients	POS	O
+at	POS	O
+risk	POS	O
+for	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+oral	POS	O
+dose	POS	O
+of	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+was	POS	O
+significantly	POS	O
+lower	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+(	POS	O
+200	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+46	POS	O
+vs	POS	O
+.	POS	O
+328	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+53	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+;	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+0017	POS	O
+)	POS	O
+.	POS	O
+Risk	POS	O
+factors	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+were	POS	O
+the	POS	O
+appearance	POS	O
+of	POS	O
+an	POS	O
+U	POS	O
+wave	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+049	POS	O
+)	POS	O
+,	POS	O
+female	POS	O
+gender	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+015	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+significant	POS	O
+dose	POS	O
+-	POS	O
+corrected	POS	O
+changes	POS	O
+of	POS	O
+SCL	POS	O
+,	POS	O
+QT	POS	O
+interval	POS	O
+,	POS	O
+and	POS	O
+QTc	POS	O
+interval	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+During	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+,	POS	O
+seven	POS	O
+(	POS	O
+20	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+had	POS	O
+a	POS	O
+nonfatal	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+recurrence	POS	O
+,	POS	O
+and	POS	O
+two	POS	O
+(	POS	O
+6	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+died	POS	O
+suddenly	POS	O
+.	POS	O
+One	POS	O
+female	POS	O
+patient	POS	O
+with	POS	O
+stable	POS	O
+cardiac	POS	B-NP
+disease	POS	I-NP
+had	POS	O
+recurrent	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+after	POS	O
+2	POS	O
+years	POS	O
+of	POS	O
+successful	POS	O
+treatment	POS	O
+with	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+.	POS	O
+Torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+occurred	POS	O
+early	POS	O
+during	POS	O
+treatment	POS	O
+even	POS	O
+with	POS	O
+low	POS	O
+doses	POS	O
+of	POS	O
+oral	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+.	POS	O
+Pronounced	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+surface	POS	O
+ECG	POS	O
+(	POS	O
+cycle	POS	O
+length	POS	O
+,	POS	O
+QT	POS	O
+,	POS	O
+and	POS	O
+QTc	POS	O
+)	POS	O
+in	POS	O
+relation	POS	O
+to	POS	O
+the	POS	O
+dose	POS	O
+of	POS	O
+oral	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+might	POS	O
+identify	POS	O
+a	POS	O
+subgroup	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+an	POS	O
+increased	POS	O
+risk	POS	O
+for	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+.	POS	O
+Other	POS	O
+ECG	POS	O
+parameters	POS	O
+before	POS	O
+the	POS	O
+application	POS	O
+of	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+did	POS	O
+not	POS	O
+identify	POS	O
+patients	POS	O
+at	POS	O
+increased	POS	O
+risk	POS	O
+for	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+.	POS	O
+Recurrence	POS	O
+rates	POS	O
+of	POS	O
+ventricular	POS	B-NP
+tachyarrhythmias	POS	I-NP
+are	POS	O
+high	POS	O
+despite	POS	O
+complete	POS	O
+suppression	POS	O
+of	POS	O
+the	POS	O
+arrhythmia	POS	B-NP
+during	POS	O
+programmed	POS	O
+stimulation	POS	O
+.	POS	O
+Therefore	POS	O
+programmed	POS	O
+electrical	POS	O
+stimulation	POS	O
+in	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+seems	POS	O
+to	POS	O
+be	POS	O
+of	POS	O
+limited	POS	O
+prognostic	POS	O
+value	POS	O
+.	POS	O
+Chronic	POS	O
+hyperprolactinemia	POS	B-NP
+and	POS	O
+changes	POS	O
+in	POS	O
+dopamine	POS	O
+neurons	POS	O
+.	POS	O
+The	POS	O
+tuberoinfundibular	POS	O
+dopaminergic	POS	O
+(	POS	O
+TIDA	POS	O
+)	POS	O
+system	POS	O
+is	POS	O
+known	POS	O
+to	POS	O
+inhibit	POS	O
+prolactin	POS	O
+(	POS	O
+PRL	POS	O
+)	POS	O
+secretion	POS	O
+.	POS	O
+In	POS	O
+young	POS	O
+animals	POS	O
+this	POS	O
+system	POS	O
+responds	POS	O
+to	POS	O
+acute	POS	O
+elevations	POS	O
+in	POS	O
+serum	POS	O
+PRL	POS	O
+by	POS	O
+increasing	POS	O
+its	POS	O
+activity	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+this	POS	O
+responsiveness	POS	O
+is	POS	O
+lost	POS	O
+in	POS	O
+aging	POS	O
+rats	POS	O
+with	POS	O
+chronically	POS	O
+high	POS	O
+serum	POS	O
+PRL	POS	O
+levels	POS	O
+.	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+induce	POS	O
+hyperprolactinemia	POS	B-NP
+in	POS	O
+rats	POS	O
+for	POS	O
+extended	POS	O
+periods	POS	O
+of	POS	O
+time	POS	O
+and	POS	O
+examine	POS	O
+its	POS	O
+effects	POS	O
+on	POS	O
+dopaminergic	POS	O
+systems	POS	O
+in	POS	O
+the	POS	O
+brain	POS	O
+.	POS	O
+Hyperprolactinemia	POS	B-NP
+was	POS	O
+induced	POS	O
+by	POS	O
+treatment	POS	O
+with	POS	O
+haloperidol	POS	O
+,	POS	O
+a	POS	O
+dopamine	POS	O
+receptor	POS	O
+antagonist	POS	O
+,	POS	O
+and	POS	O
+Palkovits	POS	O
+'	POS	O
+microdissection	POS	O
+technique	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+high	POS	O
+-	POS	O
+performance	POS	O
+liquid	POS	O
+chromatography	POS	O
+was	POS	O
+used	POS	O
+to	POS	O
+measure	POS	O
+neurotransmitter	POS	O
+concentrations	POS	O
+in	POS	O
+several	POS	O
+areas	POS	O
+of	POS	O
+the	POS	O
+brain	POS	O
+.	POS	O
+After	POS	O
+6	POS	O
+months	POS	O
+of	POS	O
+hyperprolactinemia	POS	B-NP
+,	POS	O
+dopamine	POS	O
+(	POS	O
+DA	POS	O
+)	POS	O
+concentrations	POS	O
+in	POS	O
+the	POS	O
+median	POS	O
+eminence	POS	O
+(	POS	O
+ME	POS	O
+)	POS	O
+increased	POS	O
+by	POS	O
+84	POS	O
+%	POS	O
+over	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+.	POS	O
+Nine	POS	O
+months	POS	O
+of	POS	O
+hyperprolactinemia	POS	B-NP
+produced	POS	O
+a	POS	O
+50	POS	O
+%	POS	O
+increase	POS	O
+in	POS	O
+DA	POS	O
+concentrations	POS	O
+in	POS	O
+the	POS	O
+ME	POS	O
+over	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+DA	POS	O
+response	POS	O
+was	POS	O
+lost	POS	O
+if	POS	O
+a	POS	O
+9	POS	O
+-	POS	O
+month	POS	O
+long	POS	O
+haloperidol	POS	O
+-	POS	O
+induced	POS	O
+hyperprolactinemia	POS	B-NP
+was	POS	O
+followed	POS	O
+by	POS	O
+a	POS	O
+1	POS	O
+1	POS	O
+/	POS	O
+2	POS	O
+month	POS	O
+-	POS	O
+long	POS	O
+extremely	POS	O
+high	POS	O
+increase	POS	O
+in	POS	O
+serum	POS	O
+PRL	POS	O
+levels	POS	O
+produced	POS	O
+by	POS	O
+implantation	POS	O
+of	POS	O
+MMQ	POS	O
+cells	POS	O
+under	POS	O
+the	POS	O
+kidney	POS	O
+capsule	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+change	POS	O
+in	POS	O
+the	POS	O
+levels	POS	O
+of	POS	O
+DA	POS	O
+,	POS	O
+norepinephrine	POS	O
+(	POS	O
+NE	POS	O
+)	POS	O
+,	POS	O
+serotonin	POS	O
+(	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+)	POS	O
+,	POS	O
+or	POS	O
+their	POS	O
+metabolites	POS	O
+in	POS	O
+the	POS	O
+arcuate	POS	O
+nucleus	POS	O
+(	POS	O
+AN	POS	O
+)	POS	O
+,	POS	O
+medial	POS	O
+preoptic	POS	O
+area	POS	O
+(	POS	O
+MPA	POS	O
+)	POS	O
+,	POS	O
+caudate	POS	O
+putamen	POS	O
+(	POS	O
+CP	POS	O
+)	POS	O
+,	POS	O
+substantia	POS	O
+nigra	POS	O
+(	POS	O
+SN	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+zona	POS	O
+incerta	POS	O
+(	POS	O
+ZI	POS	O
+)	POS	O
+,	POS	O
+except	POS	O
+for	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+5	POS	O
+-	POS	O
+hydroxyindoleacetic	POS	O
+acid	POS	O
+(	POS	O
+5	POS	O
+-	POS	O
+HIAA	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+AN	POS	O
+after	POS	O
+6	POS	O
+-	POS	O
+months	POS	O
+of	POS	O
+hyperprolactinemia	POS	B-NP
+and	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+DA	POS	O
+concentrations	POS	O
+in	POS	O
+the	POS	O
+AN	POS	B-NP
+after	POS	O
+9	POS	O
+-	POS	O
+months	POS	O
+of	POS	O
+hyperprolactinemia	POS	B-NP
+.	POS	O
+These	POS	O
+results	POS	O
+demonstrate	POS	O
+that	POS	O
+hyperprolactinemia	POS	B-NP
+specifically	POS	O
+affects	POS	O
+TIDA	POS	O
+neurons	POS	O
+and	POS	O
+these	POS	O
+effects	POS	O
+vary	POS	O
+,	POS	O
+depending	POS	O
+on	POS	O
+the	POS	O
+duration	POS	O
+and	POS	O
+intensity	POS	O
+of	POS	O
+hyperprolactinemia	POS	B-NP
+.	POS	O
+The	POS	O
+age	POS	O
+-	POS	O
+related	POS	O
+decrease	POS	O
+in	POS	O
+hypothalamic	POS	O
+dopamine	POS	O
+function	POS	O
+may	POS	O
+be	POS	O
+associated	POS	O
+with	POS	O
+increases	POS	O
+in	POS	O
+PRL	POS	O
+secretion	POS	O
+.	POS	O
+Treatment	POS	O
+-	POS	O
+related	POS	O
+disseminated	POS	O
+necrotizing	POS	B-NP
+leukoencephalopathy	POS	I-NP
+with	POS	O
+characteristic	POS	O
+contrast	POS	O
+enhancement	POS	O
+of	POS	O
+the	POS	O
+white	POS	O
+matter	POS	O
+.	POS	O
+This	POS	O
+report	POS	O
+describes	POS	O
+unique	POS	O
+contrast	POS	O
+enhancement	POS	O
+of	POS	O
+the	POS	O
+white	POS	O
+matter	POS	O
+on	POS	O
+T1	POS	O
+-	POS	O
+weighted	POS	O
+magnetic	POS	O
+resonance	POS	O
+images	POS	O
+of	POS	O
+two	POS	O
+patients	POS	O
+with	POS	O
+disseminated	POS	O
+necrotizing	POS	B-NP
+leukoencephalopathy	POS	I-NP
+,	POS	O
+which	POS	O
+developed	POS	O
+from	POS	O
+acute	POS	B-NP
+lymphoblastic	POS	I-NP
+leukemia	POS	I-NP
+treated	POS	O
+with	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+methotrexate	POS	O
+.	POS	O
+In	POS	O
+both	POS	O
+patients	POS	O
+,	POS	O
+the	POS	O
+enhancement	POS	O
+was	POS	O
+more	POS	O
+pronounced	POS	O
+near	POS	O
+the	POS	O
+base	POS	O
+of	POS	O
+the	POS	O
+brain	POS	O
+than	POS	O
+at	POS	O
+the	POS	O
+vertex	POS	O
+.	POS	O
+Necropsy	POS	O
+of	POS	O
+the	POS	O
+first	POS	O
+case	POS	O
+revealed	POS	O
+loss	POS	O
+of	POS	O
+myelination	POS	O
+and	POS	O
+necrosis	POS	B-NP
+of	POS	O
+the	POS	O
+white	POS	O
+matter	POS	O
+.	POS	O
+Possible	POS	O
+mechanisms	POS	O
+causing	POS	O
+such	POS	O
+a	POS	O
+leukoencephalopathy	POS	B-NP
+are	POS	O
+discussed	POS	O
+.	POS	O
+Thrombotic	POS	B-NP
+complications	POS	I-NP
+in	POS	O
+acute	POS	B-NP
+promyelocytic	POS	I-NP
+leukemia	POS	I-NP
+during	POS	O
+all	POS	O
+-	POS	O
+trans	POS	O
+-	POS	O
+retinoic	POS	O
+acid	POS	O
+therapy	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+,	POS	O
+due	POS	O
+to	POS	O
+occlusion	POS	O
+of	POS	O
+renal	POS	O
+vessels	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+acute	POS	B-NP
+promyelocytic	POS	I-NP
+leukemia	POS	I-NP
+(	POS	O
+APL	POS	B-NP
+)	POS	O
+treated	POS	O
+with	POS	O
+all	POS	O
+-	POS	O
+trans	POS	O
+-	POS	O
+retinoic	POS	O
+acid	POS	O
+(	POS	O
+ATRA	POS	O
+)	POS	O
+and	POS	O
+tranexamic	POS	O
+acid	POS	O
+has	POS	O
+been	POS	O
+described	POS	O
+recently	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+in	POS	O
+an	POS	O
+APL	POS	B-NP
+patient	POS	O
+treated	POS	O
+with	POS	O
+ATRA	POS	O
+alone	POS	O
+.	POS	O
+This	POS	O
+case	POS	O
+further	POS	O
+supports	POS	O
+the	POS	O
+concern	POS	O
+about	POS	O
+thromboembolic	POS	B-NP
+complications	POS	I-NP
+associated	POS	O
+with	POS	O
+ATRA	POS	O
+therapy	POS	O
+in	POS	O
+APL	POS	B-NP
+patients	POS	O
+.	POS	O
+The	POS	O
+patients	POS	O
+,	POS	O
+a	POS	O
+43	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+,	POS	O
+presented	POS	O
+all	POS	O
+the	POS	O
+signs	POS	O
+and	POS	O
+symptoms	POS	O
+of	POS	O
+APL	POS	B-NP
+and	POS	O
+was	POS	O
+included	POS	O
+in	POS	O
+a	POS	O
+treatment	POS	O
+protocol	POS	O
+with	POS	O
+ATRA	POS	O
+.	POS	O
+After	POS	O
+10	POS	O
+days	POS	O
+of	POS	O
+treatment	POS	O
+,	POS	O
+he	POS	O
+developed	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+that	POS	O
+was	POS	O
+completely	POS	O
+reversible	POS	O
+after	POS	O
+complete	POS	O
+remission	POS	O
+of	POS	O
+APL	POS	B-NP
+was	POS	O
+achieved	POS	O
+and	POS	O
+therapy	POS	O
+discontinued	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+ATRA	POS	O
+is	POS	O
+a	POS	O
+valid	POS	O
+therapeutic	POS	O
+choice	POS	O
+for	POS	O
+patients	POS	O
+with	POS	O
+APL	POS	B-NP
+,	POS	O
+although	POS	O
+the	POS	O
+procoagulant	POS	O
+tendency	POS	O
+is	POS	O
+not	POS	O
+completely	POS	O
+corrected	POS	O
+.	POS	O
+Thrombotic	POS	B-NP
+events	POS	I-NP
+,	POS	O
+however	POS	O
+,	POS	O
+could	POS	O
+be	POS	O
+avoided	POS	O
+by	POS	O
+using	POS	O
+low	POS	O
+-	POS	O
+dose	POS	O
+heparin	POS	O
+.	POS	O
+Pupillary	POS	O
+changes	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+stimulant	POS	O
+-	POS	O
+induced	POS	O
+mania	POS	B-NP
+:	POS	O
+a	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+A	POS	O
+30	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+cocaine	POS	O
+-	POS	O
+dependent	POS	O
+man	POS	O
+who	POS	O
+was	POS	O
+a	POS	O
+subject	POS	O
+in	POS	O
+a	POS	O
+study	POS	O
+evaluating	POS	O
+the	POS	O
+anticraving	POS	O
+efficacy	POS	O
+of	POS	O
+the	POS	O
+stimulant	POS	O
+medication	POS	O
+diethylpropion	POS	O
+(	POS	O
+DEP	POS	O
+)	POS	O
+became	POS	O
+manic	POS	B-NP
+during	POS	O
+his	POS	O
+second	POS	O
+week	POS	O
+on	POS	O
+the	POS	O
+study	POS	O
+drug	POS	O
+.	POS	O
+Pupillometric	POS	O
+changes	POS	O
+while	POS	O
+on	POS	O
+DEP	POS	O
+,	POS	O
+especially	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+total	POS	O
+power	POS	O
+of	POS	O
+pupillary	POS	O
+oscillation	POS	O
+,	POS	O
+were	POS	O
+dramatically	POS	O
+different	POS	O
+than	POS	O
+those	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+eight	POS	O
+other	POS	O
+study	POS	O
+subjects	POS	O
+who	POS	O
+did	POS	O
+not	POS	O
+become	POS	O
+manic	POS	B-NP
+.	POS	O
+The	POS	O
+large	POS	O
+changes	POS	O
+in	POS	O
+total	POS	O
+power	POS	O
+of	POS	O
+pupillary	POS	B-NP
+oscillation	POS	I-NP
+occurred	POS	O
+a	POS	O
+few	POS	O
+days	POS	O
+before	POS	O
+the	POS	O
+patient	POS	O
+became	POS	O
+fully	POS	O
+manic	POS	B-NP
+.	POS	O
+Such	POS	O
+medication	POS	O
+-	POS	O
+associated	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+total	POS	O
+power	POS	O
+of	POS	O
+pupillary	POS	O
+oscillation	POS	O
+might	POS	O
+be	POS	O
+of	POS	O
+utility	POS	O
+in	POS	O
+identifying	POS	O
+persons	POS	O
+at	POS	O
+risk	POS	O
+for	POS	O
+manic	POS	B-NP
+-	POS	O
+like	POS	O
+adverse	POS	O
+effects	POS	O
+during	POS	O
+the	POS	O
+medical	POS	O
+use	POS	O
+of	POS	O
+psychomotor	POS	O
+stimulants	POS	O
+or	POS	O
+sympathomimetic	POS	O
+agents	POS	O
+.	POS	O
+Fetal	POS	O
+risks	POS	O
+due	POS	O
+to	POS	O
+warfarin	POS	O
+therapy	POS	O
+during	POS	O
+pregnancy	POS	O
+.	POS	O
+Two	POS	O
+mothers	POS	O
+with	POS	O
+heart	POS	B-NP
+valve	POS	I-NP
+prosthesis	POS	I-NP
+were	POS	O
+treated	POS	O
+with	POS	O
+warfarin	POS	O
+during	POS	O
+pregnancy	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+first	POS	O
+case	POS	O
+a	POS	O
+caesarean	POS	O
+section	POS	O
+was	POS	O
+done	POS	O
+one	POS	O
+week	POS	O
+after	POS	O
+replacement	POS	O
+of	POS	O
+warfarin	POS	O
+with	POS	O
+heparin	POS	O
+.	POS	O
+The	POS	O
+baby	POS	O
+died	POS	O
+of	POS	O
+cerebral	POS	O
+and	POS	O
+pulmonary	POS	B-NP
+hemorrhage	POS	I-NP
+.	POS	O
+The	POS	O
+second	POS	O
+mother	POS	O
+had	POS	O
+a	POS	O
+male	POS	O
+infant	POS	O
+by	POS	O
+caesarean	POS	O
+section	POS	O
+.	POS	O
+The	POS	O
+baby	POS	O
+showed	POS	O
+warfarin	POS	O
+-	POS	O
+induced	POS	O
+embryopathy	POS	B-NP
+with	POS	O
+nasal	POS	B-NP
+hypoplasia	POS	I-NP
+and	POS	O
+stippled	POS	B-NP
+epiphyses	POS	I-NP
+(	POS	O
+chondrodysplasia	POS	B-NP
+punctata	POS	I-NP
+)	POS	O
+.	POS	O
+Nasal	POS	B-NP
+hypoplasia	POS	I-NP
+with	POS	O
+or	POS	O
+without	POS	O
+stippled	POS	O
+epiphyses	POS	O
+has	POS	O
+now	POS	O
+been	POS	O
+reported	POS	O
+in	POS	O
+11	POS	O
+infants	POS	O
+born	POS	O
+to	POS	O
+mothers	POS	O
+treated	POS	O
+with	POS	O
+warfarin	POS	O
+during	POS	O
+the	POS	O
+first	POS	O
+trimester	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+causal	POS	O
+association	POS	O
+is	POS	O
+probable	POS	O
+.	POS	O
+In	POS	O
+view	POS	O
+of	POS	O
+the	POS	O
+risks	POS	O
+to	POS	O
+both	POS	O
+mother	POS	O
+and	POS	O
+fetus	POS	O
+in	POS	O
+women	POS	O
+with	POS	O
+prosthetic	POS	O
+cardiac	POS	O
+valves	POS	O
+it	POS	O
+is	POS	O
+recommended	POS	O
+that	POS	O
+therapeutic	POS	O
+abortion	POS	O
+be	POS	O
+advised	POS	O
+as	POS	O
+the	POS	O
+first	POS	O
+alternative	POS	O
+.	POS	O
+The	POS	O
+negative	POS	O
+mucosal	POS	O
+potential	POS	O
+:	POS	O
+separating	POS	O
+central	POS	O
+and	POS	O
+peripheral	POS	O
+effects	POS	O
+of	POS	O
+NSAIDs	POS	O
+in	POS	O
+man	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+We	POS	O
+wanted	POS	O
+to	POS	O
+test	POS	O
+whether	POS	O
+assessment	POS	O
+of	POS	O
+both	POS	O
+a	POS	O
+central	POS	O
+pain	POS	O
+-	POS	O
+related	POS	O
+signal	POS	O
+(	POS	O
+chemo	POS	O
+-	POS	O
+somatosensory	POS	O
+evoked	POS	O
+potential	POS	O
+,	POS	O
+CSSEP	POS	O
+)	POS	O
+and	POS	O
+a	POS	O
+concomitantly	POS	O
+recorded	POS	O
+peripheral	POS	O
+signal	POS	O
+(	POS	O
+negative	POS	O
+mucosal	POS	O
+potential	POS	O
+,	POS	O
+NMP	POS	O
+)	POS	O
+allows	POS	O
+for	POS	O
+separation	POS	O
+of	POS	O
+central	POS	O
+and	POS	O
+peripheral	POS	O
+effects	POS	O
+of	POS	O
+NSAIDs	POS	O
+.	POS	O
+For	POS	O
+this	POS	O
+purpose	POS	O
+,	POS	O
+experimental	POS	O
+conditions	POS	O
+were	POS	O
+created	POS	O
+in	POS	O
+which	POS	O
+NSAIDs	POS	O
+had	POS	O
+previously	POS	O
+been	POS	O
+observed	POS	O
+to	POS	O
+produce	POS	O
+effects	POS	O
+on	POS	O
+phasic	POS	O
+and	POS	O
+tonic	POS	O
+pain	POS	B-NP
+by	POS	O
+either	POS	O
+central	POS	O
+or	POS	O
+peripheral	POS	O
+mechanisms	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+According	POS	O
+to	POS	O
+a	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+randomised	POS	O
+,	POS	O
+controlled	POS	O
+,	POS	O
+threefold	POS	O
+cross	POS	O
+-	POS	O
+over	POS	O
+design	POS	O
+,	POS	O
+18	POS	O
+healthy	POS	O
+subjects	POS	O
+(	POS	O
+11	POS	O
+males	POS	O
+,	POS	O
+7	POS	O
+females	POS	O
+;	POS	O
+mean	POS	O
+age	POS	O
+26	POS	O
+years	POS	O
+)	POS	O
+received	POS	O
+either	POS	O
+placebo	POS	O
+,	POS	O
+400	POS	O
+mg	POS	O
+ibuprofen	POS	O
+,	POS	O
+or	POS	O
+800	POS	O
+mg	POS	O
+ibuprofen	POS	O
+.	POS	O
+Phasic	POS	O
+pain	POS	B-NP
+was	POS	O
+applied	POS	O
+by	POS	O
+means	POS	O
+of	POS	O
+short	POS	O
+pulses	POS	O
+of	POS	O
+CO2	POS	O
+to	POS	O
+the	POS	O
+nasal	POS	O
+mucosa	POS	O
+(	POS	O
+stimulus	POS	O
+duration	POS	O
+500	POS	O
+ms	POS	O
+,	POS	O
+interval	POS	O
+approximately	POS	O
+60	POS	O
+s	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+tonic	POS	O
+pain	POS	B-NP
+was	POS	O
+induced	POS	O
+in	POS	O
+the	POS	O
+nasal	POS	O
+cavity	POS	O
+by	POS	O
+means	POS	O
+of	POS	O
+dry	POS	O
+air	POS	O
+of	POS	O
+controlled	POS	O
+temperature	POS	O
+,	POS	O
+humidity	POS	O
+and	POS	O
+flow	POS	O
+rate	POS	O
+(	POS	O
+22	POS	O
+degrees	POS	O
+C	POS	O
+,	POS	O
+0	POS	O
+%	POS	O
+relative	POS	O
+humidity	POS	O
+,	POS	O
+145	POS	O
+ml	POS	O
+.	POS	O
+s	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+.	POS	O
+Both	POS	O
+CSSEPs	POS	O
+as	POS	O
+central	POS	O
+and	POS	O
+NMPs	POS	O
+as	POS	O
+peripheral	POS	O
+correlates	POS	O
+of	POS	O
+pain	POS	B-NP
+were	POS	O
+obtained	POS	O
+in	POS	O
+response	POS	O
+to	POS	O
+the	POS	O
+CO2	POS	O
+stimuli	POS	O
+.	POS	O
+Additionally	POS	O
+,	POS	O
+the	POS	O
+subjects	POS	O
+rated	POS	O
+the	POS	O
+intensity	POS	O
+of	POS	O
+both	POS	O
+phasic	POS	O
+and	POS	O
+tonic	POS	O
+pain	POS	B-NP
+by	POS	O
+means	POS	O
+of	POS	O
+visual	POS	O
+analogue	POS	O
+scales	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+As	POS	O
+described	POS	O
+earlier	POS	O
+,	POS	O
+administration	POS	O
+of	POS	O
+ibuprofen	POS	O
+was	POS	O
+followed	POS	O
+by	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+tonic	POS	O
+pain	POS	B-NP
+but	POS	O
+-	POS	O
+relative	POS	O
+to	POS	O
+placebo	POS	O
+-	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+correlates	POS	O
+of	POS	O
+phasic	POS	B-NP
+pain	POS	I-NP
+,	POS	O
+indicating	POS	O
+a	POS	O
+specific	POS	O
+effect	POS	O
+of	POS	O
+ibuprofen	POS	O
+on	POS	O
+the	POS	O
+interaction	POS	O
+between	POS	O
+the	POS	O
+pain	POS	B-NP
+stimuli	POS	O
+under	POS	O
+these	POS	O
+special	POS	O
+experimental	POS	O
+conditions	POS	O
+.	POS	O
+Based	POS	O
+on	POS	O
+the	POS	O
+similar	POS	O
+behaviour	POS	O
+of	POS	O
+CSSEP	POS	O
+and	POS	O
+NMP	POS	O
+,	POS	O
+it	POS	O
+was	POS	O
+concluded	POS	O
+that	POS	O
+the	POS	O
+pharmacological	POS	O
+process	POS	O
+underlying	POS	O
+this	POS	O
+phenomenon	POS	O
+was	POS	O
+localised	POS	O
+in	POS	O
+the	POS	O
+periphery	POS	O
+.	POS	O
+By	POS	O
+means	POS	O
+of	POS	O
+the	POS	O
+simultaneous	POS	O
+recording	POS	O
+of	POS	O
+interrelated	POS	O
+peripheral	POS	O
+and	POS	O
+central	POS	O
+electrophysiologic	POS	O
+correlates	POS	O
+of	POS	O
+nociception	POS	O
+,	POS	O
+it	POS	O
+was	POS	O
+possible	POS	O
+to	POS	O
+separate	POS	O
+central	POS	O
+and	POS	O
+peripheral	POS	O
+effects	POS	O
+of	POS	O
+an	POS	O
+NSAID	POS	O
+.	POS	O
+The	POS	O
+major	POS	O
+advantage	POS	O
+of	POS	O
+this	POS	O
+pain	POS	B-NP
+model	POS	O
+is	POS	O
+the	POS	O
+possibility	POS	O
+of	POS	O
+obtaining	POS	O
+peripheral	POS	O
+pain	POS	O
+-	POS	O
+related	POS	O
+activity	POS	O
+directly	POS	O
+using	POS	O
+a	POS	O
+non	POS	O
+-	POS	O
+invasive	POS	O
+technique	POS	O
+in	POS	O
+humans	POS	O
+.	POS	O
+Effect	POS	O
+of	POS	O
+D	POS	O
+-	POS	O
+Glucarates	POS	O
+on	POS	O
+basic	POS	O
+antibiotic	POS	O
+-	POS	O
+induced	POS	O
+renal	POS	B-NP
+damage	POS	I-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+Dehydrated	POS	O
+rats	POS	O
+regularly	POS	O
+develop	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+following	POS	O
+single	POS	O
+injection	POS	O
+of	POS	O
+aminoglycoside	POS	O
+antibiotics	POS	O
+combined	POS	O
+with	POS	O
+dextran	POS	O
+or	POS	O
+of	POS	O
+antibiotics	POS	O
+only	POS	O
+.	POS	O
+Oral	POS	O
+administration	POS	O
+of	POS	O
+2	POS	O
+,	POS	O
+5	POS	O
+-	POS	O
+di	POS	O
+-	POS	O
+O	POS	O
+-	POS	O
+acetyl	POS	O
+-	POS	O
+D	POS	O
+-	POS	O
+glucaro	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+4	POS	O
+-	POS	O
+6	POS	O
+,	POS	O
+3	POS	O
+-	POS	O
+dilactone	POS	O
+protected	POS	O
+rats	POS	O
+against	POS	O
+renal	POS	B-NP
+failure	POS	I-NP
+induced	POS	O
+by	POS	O
+kanamycin	POS	O
+-	POS	O
+dextran	POS	O
+.	POS	O
+The	POS	O
+protective	POS	O
+effect	POS	O
+was	POS	O
+prevalent	POS	O
+among	POS	O
+D	POS	O
+-	POS	O
+glucarates	POS	O
+,	POS	O
+and	POS	O
+also	POS	O
+to	POS	O
+other	POS	O
+saccharic	POS	O
+acid	POS	O
+,	POS	O
+hexauronic	POS	O
+acids	POS	O
+and	POS	O
+hexaaldonic	POS	O
+acids	POS	O
+,	POS	O
+although	POS	O
+to	POS	O
+a	POS	O
+lesser	POS	O
+degree	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+to	POS	O
+a	POS	O
+hexaaldose	POS	O
+,	POS	O
+sugar	POS	O
+alcohols	POS	O
+,	POS	O
+substances	POS	O
+inthe	POS	O
+TCA	POS	O
+cycle	POS	O
+and	POS	O
+other	POS	O
+acidic	POS	O
+compounds	POS	O
+.	POS	O
+D	POS	O
+-	POS	O
+Glucarates	POS	O
+were	POS	O
+effective	POS	O
+against	POS	O
+renal	POS	O
+damage	POS	O
+induced	POS	O
+by	POS	O
+peptide	POS	O
+antibiotics	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+various	POS	O
+aminoglycoside	POS	O
+antibitocis	POS	O
+.	POS	O
+Dose	POS	O
+-	POS	O
+responses	POS	O
+were	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+protective	POS	O
+effect	POS	O
+of	POS	O
+D	POS	O
+-	POS	O
+Glucarates	POS	O
+.	POS	O
+With	POS	O
+a	POS	O
+D	POS	O
+-	POS	O
+glucarate	POS	O
+of	POS	O
+a	POS	O
+fixed	POS	O
+size	POS	O
+of	POS	O
+dose	POS	O
+,	POS	O
+approximately	POS	O
+the	POS	O
+same	POS	O
+degree	POS	O
+of	POS	O
+protection	POS	O
+was	POS	O
+obtained	POS	O
+against	POS	O
+renal	POS	O
+damages	POS	O
+induced	POS	O
+by	POS	O
+different	POS	O
+basic	POS	O
+antibiotics	POS	O
+despite	POS	O
+large	POS	O
+disparities	POS	O
+in	POS	O
+administration	POS	O
+doses	POS	O
+of	POS	O
+different	POS	O
+antibiotics	POS	O
+.	POS	O
+D	POS	O
+-	POS	O
+Glucarates	POS	O
+had	POS	O
+the	POS	O
+ability	POS	O
+to	POS	O
+prevent	POS	O
+renal	POS	B-NP
+damage	POS	I-NP
+but	POS	O
+not	POS	O
+to	POS	O
+cure	POS	O
+it	POS	O
+.	POS	O
+Rats	POS	O
+excreted	POS	O
+acidic	POS	O
+urine	POS	O
+when	POS	O
+they	POS	O
+were	POS	O
+spared	POS	O
+from	POS	O
+renal	POS	B-NP
+lesions	POS	I-NP
+by	POS	O
+monosaccharides	POS	O
+.	POS	O
+The	POS	O
+reduction	POS	O
+effect	POS	O
+of	POS	O
+D	POS	O
+-	POS	O
+glucarates	POS	O
+against	POS	O
+nephrotoxicity	POS	B-NP
+of	POS	O
+basic	POS	O
+antibiotics	POS	O
+was	POS	O
+discussed	POS	O
+.	POS	O
+Acute	POS	O
+severe	POS	O
+depression	POS	B-NP
+following	POS	O
+peri	POS	O
+-	POS	O
+operative	POS	O
+ondansetron	POS	O
+.	POS	O
+A	POS	O
+41	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+with	POS	O
+a	POS	O
+strong	POS	O
+history	POS	O
+of	POS	O
+postoperative	POS	B-NP
+nausea	POS	I-NP
+and	POS	O
+vomiting	POS	B-NP
+presented	POS	O
+for	POS	O
+abdominal	POS	O
+hysterectomy	POS	O
+3	POS	O
+months	POS	O
+after	POS	O
+a	POS	O
+previous	POS	O
+anaesthetic	POS	O
+where	POS	O
+ondansetron	POS	O
+prophylaxis	POS	B-NP
+had	POS	O
+been	POS	O
+used	POS	O
+.	POS	O
+She	POS	O
+had	POS	O
+developed	POS	O
+a	POS	O
+severe	POS	O
+acute	POS	O
+major	POS	O
+depression	POS	B-NP
+disorder	POS	O
+almost	POS	O
+immediately	POS	O
+thereafter	POS	O
+,	POS	O
+possibly	POS	O
+related	POS	O
+to	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+a	POS	O
+serotonin	POS	O
+antagonist	POS	O
+.	POS	O
+Nine	POS	O
+years	POS	O
+before	POS	O
+she	POS	O
+had	POS	O
+experienced	POS	O
+a	POS	O
+self	POS	O
+-	POS	O
+limited	POS	O
+puerperal	POS	B-NP
+depressive	POS	I-NP
+episode	POS	O
+.	POS	O
+Anaesthesia	POS	B-NP
+with	POS	O
+a	POS	O
+propofol	POS	O
+infusion	POS	O
+and	POS	O
+avoidance	POS	O
+of	POS	O
+serotonin	POS	O
+antagonists	POS	O
+provided	POS	O
+a	POS	O
+nausea	POS	B-NP
+-	POS	O
+free	POS	O
+postoperative	POS	O
+course	POS	O
+without	POS	O
+exacerbation	POS	O
+of	POS	O
+the	POS	O
+depression	POS	B-NP
+disorder	POS	I-NP
+.	POS	O
+Hypertensive	POS	B-NP
+response	POS	O
+during	POS	O
+dobutamine	POS	O
+stress	POS	O
+echocardiography	POS	O
+.	POS	O
+Among	POS	O
+3	POS	O
+,	POS	O
+129	POS	O
+dobutamine	POS	O
+stress	POS	O
+echocardiographic	POS	O
+studies	POS	O
+,	POS	O
+a	POS	O
+hypertensive	POS	B-NP
+response	POS	O
+,	POS	O
+defined	POS	O
+as	POS	O
+systolic	POS	O
+blood	POS	O
+pressure	POS	O
+(	POS	O
+BP	POS	O
+)	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+220	POS	O
+mm	POS	O
+Hg	POS	O
+and	POS	O
+/	POS	O
+or	POS	O
+diastolic	POS	O
+BP	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+110	POS	O
+mm	POS	O
+Hg	POS	O
+,	POS	O
+occurred	POS	O
+in	POS	O
+30	POS	O
+patients	POS	O
+(	POS	O
+1	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+this	POS	O
+response	POS	O
+more	POS	O
+often	POS	O
+had	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+hypertension	POS	B-NP
+and	POS	O
+had	POS	O
+higher	POS	O
+resting	POS	O
+systolic	POS	O
+and	POS	O
+diastolic	POS	O
+BP	POS	O
+before	POS	O
+dobutamine	POS	O
+infusion	POS	O
+.	POS	O
+Continuously	POS	O
+nebulized	POS	O
+albuterol	POS	O
+in	POS	O
+severe	POS	O
+exacerbations	POS	O
+of	POS	O
+asthma	POS	B-NP
+in	POS	O
+adults	POS	O
+:	POS	O
+a	POS	O
+case	POS	O
+-	POS	O
+controlled	POS	O
+study	POS	O
+.	POS	O
+A	POS	O
+retrospective	POS	O
+,	POS	O
+case	POS	O
+-	POS	O
+controlled	POS	O
+analysis	POS	O
+comparing	POS	O
+patients	POS	O
+admitted	POS	O
+to	POS	O
+a	POS	O
+medical	POS	O
+intensive	POS	O
+care	POS	O
+unit	POS	O
+with	POS	O
+severe	POS	O
+exacerbations	POS	B-NP
+of	POS	O
+asthma	POS	B-NP
+who	POS	O
+received	POS	O
+continuously	POS	O
+nebulized	POS	O
+albuterol	POS	O
+(	POS	O
+CNA	POS	O
+)	POS	O
+versus	POS	O
+intermittent	POS	O
+albuterol	POS	O
+(	POS	O
+INA	POS	O
+)	POS	O
+treatments	POS	O
+is	POS	O
+reported	POS	O
+.	POS	O
+Forty	POS	O
+matched	POS	O
+pairs	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+asthma	POS	B-NP
+are	POS	O
+compared	POS	O
+.	POS	O
+CNA	POS	O
+was	POS	O
+administered	POS	O
+for	POS	O
+a	POS	O
+mean	POS	O
+of	POS	O
+11	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+10	POS	O
+hr	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+cardiac	POS	B-NP
+dysrhythmias	POS	I-NP
+was	POS	O
+similar	POS	O
+between	POS	O
+groups	POS	O
+.	POS	O
+Symptomatic	POS	O
+hypokalemia	POS	B-NP
+did	POS	O
+not	POS	O
+occur	POS	O
+.	POS	O
+CNA	POS	O
+patients	POS	O
+had	POS	O
+higher	POS	O
+heart	POS	O
+rates	POS	O
+during	POS	O
+treatment	POS	O
+,	POS	O
+which	POS	O
+may	POS	O
+reflect	POS	O
+severity	POS	O
+of	POS	O
+illness	POS	B-NP
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+intubation	POS	O
+was	POS	O
+similar	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+CNA	POS	O
+and	POS	O
+INA	POS	O
+demonstrated	POS	O
+similar	POS	O
+profiles	POS	O
+with	POS	O
+regard	POS	O
+to	POS	O
+safety	POS	O
+,	POS	O
+morbidity	POS	O
+,	POS	O
+and	POS	O
+mortality	POS	O
+.	POS	O
+Paraplegia	POS	B-NP
+following	POS	O
+intrathecal	POS	O
+methotrexate	POS	O
+:	POS	O
+report	POS	O
+of	POS	O
+a	POS	O
+case	POS	O
+and	POS	O
+review	POS	O
+of	POS	O
+the	POS	O
+literature	POS	O
+.	POS	O
+A	POS	O
+patient	POS	O
+who	POS	O
+developed	POS	O
+paraplegia	POS	B-NP
+following	POS	O
+the	POS	O
+intrathecal	POS	O
+instillation	POS	O
+of	POS	O
+methotrexate	POS	O
+is	POS	O
+discribed	POS	O
+.	POS	O
+The	POS	O
+ten	POS	O
+previously	POS	O
+reported	POS	O
+cases	POS	O
+of	POS	O
+this	POS	O
+unusual	POS	O
+complication	POS	O
+are	POS	O
+reviewed	POS	O
+.	POS	O
+The	POS	O
+following	POS	O
+factors	POS	O
+appear	POS	O
+to	POS	O
+predispose	POS	O
+to	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+this	POS	O
+complication	POS	O
+:	POS	O
+abnormal	POS	O
+cerebrospinal	POS	O
+dynamics	POS	O
+related	POS	O
+to	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+central	POS	B-NP
+nervous	POS	I-NP
+system	POS	I-NP
+leukemia	POS	I-NP
+,	POS	O
+and	POS	O
+epidural	POS	O
+cerebrospinal	POS	O
+leakage	POS	O
+;	POS	O
+elevated	POS	O
+cerebrospinal	POS	O
+fluid	POS	O
+methothexate	POS	O
+concentration	POS	O
+related	POS	O
+to	POS	O
+abnormal	POS	O
+cerebrospinal	POS	O
+fluid	POS	O
+dynamics	POS	O
+and	POS	O
+to	POS	O
+inappropriately	POS	O
+high	POS	O
+methotrexate	POS	O
+doses	POS	O
+based	POS	O
+on	POS	O
+body	POS	O
+surface	POS	O
+area	POS	O
+calculations	POS	O
+in	POS	O
+older	POS	O
+children	POS	O
+and	POS	O
+adults	POS	O
+;	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+neurotoxic	POS	O
+preservatives	POS	O
+in	POS	O
+commercially	POS	O
+available	POS	O
+methotrexate	POS	O
+preparations	POS	O
+and	POS	O
+diluents	POS	O
+;	POS	O
+and	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+methotrexate	POS	O
+diluents	POS	O
+of	POS	O
+unphysiologic	POS	O
+pH	POS	O
+,	POS	O
+ionic	POS	O
+content	POS	O
+and	POS	O
+osmolarity	POS	O
+.	POS	O
+The	POS	O
+role	POS	O
+of	POS	O
+methotrexate	POS	O
+contaminants	POS	O
+,	POS	O
+local	POS	O
+folate	POS	B-NP
+deficiency	POS	I-NP
+,	POS	O
+and	POS	O
+cranial	POS	O
+irradiation	POS	O
+in	POS	O
+the	POS	O
+pathogenesis	POS	O
+of	POS	O
+intrathecal	POS	O
+methotrexate	POS	O
+toxicity	POS	B-NP
+is	POS	O
+unclear	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+neurotoxicity	POS	B-NP
+may	POS	O
+be	POS	O
+reduced	POS	O
+by	POS	O
+employing	POS	O
+lower	POS	O
+doses	POS	O
+of	POS	O
+methotrexate	POS	O
+in	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+central	POS	B-NP
+nervous	POS	I-NP
+system	POS	I-NP
+leukemia	POS	I-NP
+,	POS	O
+in	POS	O
+older	POS	O
+children	POS	O
+and	POS	O
+adults	POS	O
+,	POS	O
+and	POS	O
+in	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+epidural	POS	O
+leakage	POS	O
+.	POS	O
+Only	POS	O
+preservative	POS	O
+-	POS	O
+free	POS	O
+methotrexate	POS	O
+in	POS	O
+Elliott	POS	O
+'	POS	O
+s	POS	O
+B	POS	O
+Solution	POS	O
+at	POS	O
+a	POS	O
+concentration	POS	O
+of	POS	O
+not	POS	O
+more	POS	O
+than	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+ml	POS	O
+should	POS	O
+be	POS	O
+used	POS	O
+for	POS	O
+intrathecal	POS	O
+administration	POS	O
+.	POS	O
+Periodic	POS	O
+monitoring	POS	O
+of	POS	O
+cerebruspinal	POS	O
+fluid	POS	O
+methotrexate	POS	O
+levels	POS	O
+may	POS	O
+be	POS	O
+predictive	POS	O
+of	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+serious	POS	O
+neurotoxicity	POS	B-NP
+.	POS	O
+Hyperosmolar	POS	B-NP
+nonketotic	POS	I-NP
+coma	POS	I-NP
+precipitated	POS	O
+by	POS	O
+lithium	POS	O
+-	POS	O
+induced	POS	O
+nephrogenic	POS	B-NP
+diabetes	POS	I-NP
+insipidus	POS	I-NP
+.	POS	O
+A	POS	O
+45	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+,	POS	O
+with	POS	O
+a	POS	O
+10	POS	O
+-	POS	O
+year	POS	O
+history	POS	O
+of	POS	O
+manic	POS	B-NP
+depression	POS	I-NP
+treated	POS	O
+with	POS	O
+lithium	POS	O
+,	POS	O
+was	POS	O
+admitted	POS	O
+with	POS	O
+hyperosmolar	POS	B-NP
+,	POS	O
+nonketotic	POS	B-NP
+coma	POS	I-NP
+.	POS	O
+He	POS	O
+gave	POS	O
+a	POS	O
+five	POS	O
+-	POS	O
+year	POS	O
+history	POS	O
+of	POS	O
+polyuria	POS	B-NP
+and	POS	O
+polydipsia	POS	B-NP
+,	POS	O
+during	POS	O
+which	POS	O
+time	POS	O
+urinalysis	POS	O
+had	POS	O
+been	POS	O
+negative	POS	O
+for	POS	O
+glucose	POS	O
+.	POS	O
+After	POS	O
+recovery	POS	O
+from	POS	O
+hyperglycaemia	POS	B-NP
+,	POS	O
+he	POS	O
+remained	POS	O
+polyuric	POS	B-NP
+despite	POS	O
+normal	POS	O
+blood	POS	O
+glucose	POS	O
+concentrations	POS	O
+;	POS	O
+water	POS	O
+deprivation	POS	O
+testing	POS	O
+indicated	POS	O
+nephrogenic	POS	B-NP
+diabetes	POS	I-NP
+insipidus	POS	I-NP
+,	POS	O
+likely	POS	O
+to	POS	O
+be	POS	O
+lithium	POS	O
+-	POS	O
+induced	POS	O
+.	POS	O
+We	POS	O
+hypothesize	POS	O
+that	POS	O
+when	POS	O
+this	POS	O
+man	POS	O
+developed	POS	O
+type	POS	B-NP
+2	POS	I-NP
+diabetes	POS	I-NP
+,	POS	O
+chronic	POS	B-NP
+polyuria	POS	I-NP
+due	POS	O
+to	POS	O
+nephrogenic	POS	B-NP
+diabetes	POS	I-NP
+insipidus	POS	I-NP
+was	POS	O
+sufficient	POS	O
+to	POS	O
+precipitate	POS	O
+hyperosmolar	POS	B-NP
+dehydration	POS	I-NP
+.	POS	O
+Effects	POS	O
+of	POS	O
+the	POS	O
+intracoronary	POS	O
+infusion	POS	O
+of	POS	O
+cocaine	POS	O
+on	POS	O
+left	POS	O
+ventricular	POS	O
+systolic	POS	O
+and	POS	O
+diastolic	POS	O
+function	POS	O
+in	POS	O
+humans	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+In	POS	O
+dogs	POS	O
+,	POS	O
+a	POS	O
+large	POS	O
+amount	POS	O
+of	POS	O
+intravenous	POS	O
+cocaine	POS	O
+causes	POS	O
+a	POS	O
+profound	POS	O
+deterioration	POS	O
+of	POS	O
+left	POS	O
+ventricular	POS	O
+(	POS	O
+LV	POS	O
+)	POS	O
+systolic	POS	O
+function	POS	O
+and	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+LV	POS	O
+end	POS	O
+-	POS	O
+diastolic	POS	O
+pressure	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+was	POS	O
+done	POS	O
+to	POS	O
+assess	POS	O
+the	POS	O
+influence	POS	O
+of	POS	O
+a	POS	O
+high	POS	O
+intracoronary	POS	O
+cocaine	POS	O
+concentration	POS	O
+on	POS	O
+LV	POS	O
+systolic	POS	O
+and	POS	O
+diastolic	POS	O
+function	POS	O
+in	POS	O
+humans	POS	O
+.	POS	O
+METHODS	POS	O
+AND	POS	O
+RESULTS	POS	O
+:	POS	O
+In	POS	O
+20	POS	O
+patients	POS	O
+(	POS	O
+14	POS	O
+men	POS	O
+and	POS	O
+6	POS	O
+women	POS	O
+aged	POS	O
+39	POS	O
+to	POS	O
+72	POS	O
+years	POS	O
+)	POS	O
+referred	POS	O
+for	POS	O
+cardiac	POS	O
+catheterization	POS	O
+for	POS	O
+the	POS	O
+evaluation	POS	O
+of	POS	O
+chest	POS	B-NP
+pain	POS	I-NP
+,	POS	O
+we	POS	O
+measured	POS	O
+heart	POS	O
+rate	POS	O
+,	POS	O
+systemic	POS	O
+arterial	POS	O
+pressure	POS	O
+,	POS	O
+LV	POS	O
+pressure	POS	O
+and	POS	O
+its	POS	O
+first	POS	O
+derivative	POS	O
+(	POS	O
+dP	POS	O
+/	POS	O
+dt	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+LV	POS	O
+volumes	POS	O
+and	POS	O
+ejection	POS	O
+fraction	POS	O
+before	POS	O
+and	POS	O
+during	POS	O
+the	POS	O
+final	POS	O
+2	POS	O
+to	POS	O
+3	POS	O
+minutes	POS	O
+of	POS	O
+a	POS	O
+15	POS	O
+-	POS	O
+minute	POS	O
+intracoronary	POS	O
+infusion	POS	O
+of	POS	O
+saline	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+10	POS	O
+,	POS	O
+control	POS	O
+subjects	POS	O
+)	POS	O
+or	POS	O
+cocaine	POS	O
+hydrochloride	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+min	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+10	POS	O
+)	POS	O
+.	POS	O
+No	POS	O
+variable	POS	O
+changed	POS	O
+with	POS	O
+saline	POS	O
+.	POS	O
+With	POS	O
+cocaine	POS	O
+,	POS	O
+the	POS	O
+drug	POS	O
+concentration	POS	O
+in	POS	O
+blood	POS	O
+obtained	POS	O
+from	POS	O
+the	POS	O
+coronary	POS	O
+sinus	POS	O
+was	POS	O
+3	POS	O
+.	POS	O
+0	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+4	POS	O
+(	POS	O
+mean	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+SD	POS	O
+)	POS	O
+mg	POS	O
+/	POS	O
+L	POS	O
+,	POS	O
+similar	POS	O
+in	POS	O
+magnitude	POS	O
+to	POS	O
+the	POS	O
+blood	POS	O
+cocaine	POS	O
+concentration	POS	O
+reported	POS	O
+in	POS	O
+abusers	POS	O
+dying	POS	O
+of	POS	O
+cocaine	POS	B-NP
+intoxication	POS	I-NP
+.	POS	O
+Cocaine	POS	O
+induced	POS	O
+no	POS	O
+significant	POS	O
+change	POS	O
+in	POS	O
+heart	POS	O
+rate	POS	O
+,	POS	O
+LV	POS	O
+dP	POS	O
+/	POS	O
+dt	POS	O
+(	POS	O
+positive	POS	O
+or	POS	O
+negative	POS	O
+)	POS	O
+,	POS	O
+or	POS	O
+LV	POS	O
+end	POS	O
+-	POS	O
+diastolic	POS	O
+volume	POS	O
+,	POS	O
+but	POS	O
+it	POS	O
+caused	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+systolic	POS	O
+and	POS	O
+mean	POS	O
+arterial	POS	O
+pressures	POS	O
+,	POS	O
+LV	POS	O
+end	POS	O
+-	POS	O
+diastolic	POS	O
+pressure	POS	O
+,	POS	O
+and	POS	O
+LV	POS	O
+end	POS	O
+-	POS	O
+systolic	POS	O
+volume	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+LV	POS	O
+ejection	POS	O
+fraction	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+In	POS	O
+humans	POS	O
+,	POS	O
+the	POS	O
+intracoronary	POS	O
+infusion	POS	O
+of	POS	O
+cocaine	POS	O
+sufficient	POS	O
+in	POS	O
+amount	POS	O
+to	POS	O
+achieve	POS	O
+a	POS	O
+high	POS	O
+drug	POS	O
+concentration	POS	O
+in	POS	O
+coronary	POS	O
+sinus	POS	O
+blood	POS	O
+causes	POS	O
+a	POS	O
+deterioration	POS	O
+of	POS	O
+LV	POS	O
+systolic	POS	O
+and	POS	O
+diastolic	POS	O
+performance	POS	O
+.	POS	O
+Ascending	POS	O
+dose	POS	O
+tolerance	POS	O
+study	POS	O
+of	POS	O
+intramuscular	POS	O
+carbetocin	POS	O
+administered	POS	O
+after	POS	O
+normal	POS	O
+vaginal	POS	O
+birth	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+determine	POS	O
+the	POS	O
+maximum	POS	O
+tolerated	POS	O
+dose	POS	O
+(	POS	O
+MTD	POS	O
+)	POS	O
+of	POS	O
+carbetocin	POS	O
+(	POS	O
+a	POS	O
+long	POS	O
+-	POS	O
+acting	POS	O
+synthetic	POS	O
+analogue	POS	O
+of	POS	O
+oxytocin	POS	O
+)	POS	O
+,	POS	O
+when	POS	O
+administered	POS	O
+immediately	POS	O
+after	POS	O
+vaginal	POS	O
+delivery	POS	O
+at	POS	O
+term	POS	O
+.	POS	O
+MATERIALS	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+Carbetocin	POS	O
+was	POS	O
+given	POS	O
+as	POS	O
+an	POS	O
+intramuscular	POS	O
+injection	POS	O
+immediately	POS	O
+after	POS	O
+the	POS	O
+birth	POS	O
+of	POS	O
+the	POS	O
+infant	POS	O
+in	POS	O
+45	POS	O
+healthy	POS	O
+women	POS	O
+with	POS	O
+normal	POS	B-NP
+singleton	POS	O
+pregnancies	POS	O
+who	POS	O
+delivered	POS	O
+vaginally	POS	O
+at	POS	O
+term	POS	O
+.	POS	O
+Dosage	POS	O
+groups	POS	O
+of	POS	O
+15	POS	O
+,	POS	O
+30	POS	O
+,	POS	O
+50	POS	O
+,	POS	O
+75	POS	O
+,	POS	O
+100	POS	O
+,	POS	O
+125	POS	O
+,	POS	O
+150	POS	O
+,	POS	O
+175	POS	O
+or	POS	O
+200	POS	O
+microg	POS	O
+carbetocin	POS	O
+were	POS	O
+assigned	POS	O
+to	POS	O
+blocks	POS	O
+of	POS	O
+three	POS	O
+women	POS	O
+according	POS	O
+to	POS	O
+the	POS	O
+continual	POS	O
+reassessment	POS	O
+method	POS	O
+(	POS	O
+CRM	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+All	POS	O
+dosage	POS	O
+groups	POS	O
+consisted	POS	O
+of	POS	O
+three	POS	O
+women	POS	O
+,	POS	O
+except	POS	O
+those	POS	O
+with	POS	O
+100	POS	O
+microg	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+6	POS	O
+)	POS	O
+and	POS	O
+200	POS	O
+microg	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+18	POS	O
+)	POS	O
+.	POS	O
+Recorded	POS	O
+were	POS	O
+dose	POS	O
+-	POS	O
+limiting	POS	O
+adverse	POS	O
+events	POS	O
+:	POS	O
+hyper	POS	O
+-	POS	O
+or	POS	O
+hypotension	POS	B-NP
+(	POS	O
+three	POS	O
+)	POS	O
+,	POS	O
+severe	POS	O
+abdominal	POS	B-NP
+pain	POS	I-NP
+(	POS	O
+0	POS	O
+)	POS	O
+,	POS	O
+vomiting	POS	B-NP
+(	POS	O
+0	POS	O
+)	POS	O
+and	POS	O
+retained	POS	O
+placenta	POS	O
+(	POS	O
+four	POS	O
+)	POS	O
+.	POS	O
+Serious	POS	O
+adverse	POS	O
+events	POS	O
+occurred	POS	O
+in	POS	O
+seven	POS	O
+women	POS	O
+:	POS	O
+six	POS	O
+cases	POS	O
+with	POS	O
+blood	POS	B-NP
+loss	POS	I-NP
+>	POS	O
+or	POS	O
+=	POS	O
+1000	POS	O
+ml	POS	O
+,	POS	O
+four	POS	O
+cases	POS	O
+of	POS	O
+manual	POS	O
+placenta	POS	O
+removal	POS	O
+,	POS	O
+five	POS	O
+cases	POS	O
+of	POS	O
+additional	POS	O
+oxytocics	POS	O
+administration	POS	O
+and	POS	O
+five	POS	O
+cases	POS	O
+of	POS	O
+blood	POS	O
+transfusion	POS	O
+.	POS	O
+Maximum	POS	O
+blood	POS	O
+loss	POS	O
+was	POS	O
+greatest	POS	O
+at	POS	O
+the	POS	O
+upper	POS	O
+and	POS	O
+lower	POS	O
+dose	POS	O
+levels	POS	O
+,	POS	O
+and	POS	O
+lowest	POS	O
+in	POS	O
+the	POS	O
+70	POS	O
+-	POS	O
+125	POS	O
+microg	POS	O
+dose	POS	O
+range	POS	O
+.	POS	O
+Four	POS	O
+out	POS	O
+of	POS	O
+six	POS	O
+cases	POS	O
+with	POS	O
+blood	POS	O
+loss	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+1000	POS	O
+ml	POS	O
+occurred	POS	O
+in	POS	O
+the	POS	O
+200	POS	O
+microg	POS	O
+group	POS	O
+.	POS	O
+The	POS	O
+majority	POS	O
+of	POS	O
+additional	POS	O
+administration	POS	O
+of	POS	O
+oxytocics	POS	O
+(	POS	O
+4	POS	O
+/	POS	O
+5	POS	O
+)	POS	O
+and	POS	O
+blood	POS	O
+transfusion	POS	O
+(	POS	O
+3	POS	O
+/	POS	O
+5	POS	O
+)	POS	O
+occurred	POS	O
+in	POS	O
+the	POS	O
+dose	POS	O
+groups	POS	O
+of	POS	O
+200	POS	O
+microg	POS	O
+.	POS	O
+All	POS	O
+retained	POS	O
+placentae	POS	O
+were	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+group	POS	O
+of	POS	O
+200	POS	O
+microg	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+The	POS	O
+MTD	POS	O
+was	POS	O
+calculated	POS	O
+to	POS	O
+be	POS	O
+at	POS	O
+200	POS	O
+microg	POS	O
+carbetocin	POS	O
+.	POS	O
+Heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+,	POS	O
+paradoxical	POS	B-NP
+thromboembolism	POS	I-NP
+,	POS	O
+and	POS	O
+other	POS	O
+side	POS	O
+effects	POS	O
+of	POS	O
+heparin	POS	O
+therapy	POS	O
+.	POS	O
+Although	POS	O
+several	POS	O
+new	POS	O
+anticoagulant	POS	O
+drugs	POS	O
+are	POS	O
+in	POS	O
+development	POS	O
+,	POS	O
+heparin	POS	O
+remains	POS	O
+the	POS	O
+drug	POS	O
+of	POS	O
+choice	POS	O
+for	POS	O
+most	POS	O
+anticoagulation	POS	O
+needs	POS	O
+.	POS	O
+The	POS	O
+clinical	POS	O
+effects	POS	O
+of	POS	O
+heparin	POS	O
+are	POS	O
+meritorious	POS	O
+,	POS	O
+but	POS	O
+side	POS	O
+effects	POS	O
+do	POS	O
+exist	POS	O
+.	POS	O
+Important	POS	O
+untoward	POS	O
+effects	POS	O
+of	POS	O
+heparin	POS	O
+therapy	POS	O
+including	POS	O
+heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+,	POS	O
+heparin	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+osteoporosis	POS	I-NP
+,	POS	O
+eosinophilia	POS	B-NP
+,	POS	O
+skin	POS	B-NP
+reactions	POS	I-NP
+,	POS	O
+allergic	POS	B-NP
+reactions	POS	I-NP
+other	POS	O
+than	POS	O
+thrombocytopenia	POS	B-NP
+and	POS	O
+alopecia	POS	B-NP
+will	POS	O
+be	POS	O
+discussed	POS	O
+in	POS	O
+this	POS	O
+article	POS	O
+.	POS	O
+Nonopaque	POS	O
+crystal	POS	O
+deposition	POS	O
+causing	POS	O
+ureteric	POS	B-NP
+obstruction	POS	I-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+HIV	POS	O
+undergoing	POS	O
+indinavir	POS	O
+therapy	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+We	POS	O
+describe	POS	O
+the	POS	O
+unique	POS	O
+CT	POS	O
+features	POS	O
+of	POS	O
+ureteric	POS	O
+calculi	POS	O
+in	POS	O
+six	POS	O
+HIV	POS	O
+-	POS	O
+infected	POS	O
+patients	POS	O
+receiving	POS	O
+indinavir	POS	O
+,	POS	O
+the	POS	O
+most	POS	O
+commonly	POS	O
+used	POS	O
+HIV	POS	O
+protease	POS	O
+inhibitor	POS	O
+,	POS	O
+which	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+increased	POS	O
+incidence	POS	O
+of	POS	O
+urolithiasis	POS	B-NP
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Ureteric	POS	B-NP
+obstruction	POS	I-NP
+caused	POS	O
+by	POS	O
+precipitated	POS	O
+indinavir	POS	O
+crystals	POS	O
+may	POS	O
+be	POS	O
+difficult	POS	O
+to	POS	O
+diagnose	POS	O
+with	POS	O
+unenhanced	POS	O
+CT	POS	O
+.	POS	O
+The	POS	O
+calculi	POS	O
+are	POS	O
+not	POS	O
+opaque	POS	O
+,	POS	O
+and	POS	O
+secondary	POS	O
+signs	POS	O
+of	POS	O
+obstruction	POS	O
+may	POS	O
+be	POS	O
+absent	POS	O
+or	POS	O
+minimal	POS	O
+and	POS	O
+should	POS	O
+be	POS	O
+sought	POS	O
+carefully	POS	O
+.	POS	O
+Images	POS	O
+may	POS	O
+need	POS	O
+to	POS	O
+be	POS	O
+obtained	POS	O
+using	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+contrast	POS	O
+material	POS	O
+to	POS	O
+enable	POS	O
+diagnosis	POS	O
+of	POS	O
+ureteric	POS	B-NP
+stones	POS	I-NP
+or	POS	O
+obstruction	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+HIV	POS	B-NP
+infection	POS	I-NP
+who	POS	O
+receive	POS	O
+indinavir	POS	O
+therapy	POS	O
+.	POS	O
+Ischemic	POS	B-NP
+colitis	POS	I-NP
+and	POS	O
+sumatriptan	POS	O
+use	POS	O
+.	POS	O
+Sumatriptan	POS	O
+succinate	POS	O
+,	POS	O
+a	POS	O
+serotonin	POS	O
+-	POS	O
+1	POS	O
+(	POS	O
+5	POS	O
+-	POS	O
+hydroxytryptamine	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+receptor	POS	O
+agonist	POS	O
+,	POS	O
+is	POS	O
+an	POS	O
+antimigraine	POS	O
+drug	POS	O
+that	POS	O
+is	POS	O
+reported	POS	O
+to	POS	O
+act	POS	O
+by	POS	O
+selectively	POS	O
+constricting	POS	O
+intracranial	POS	O
+arteries	POS	O
+.	POS	O
+Recently	POS	O
+,	POS	O
+vasopressor	POS	O
+responses	POS	O
+that	POS	O
+are	POS	O
+distinct	POS	O
+from	POS	O
+the	POS	O
+cranial	POS	O
+circulation	POS	O
+have	POS	O
+been	POS	O
+demonstrated	POS	O
+to	POS	O
+occur	POS	O
+in	POS	O
+the	POS	O
+systemic	POS	O
+,	POS	O
+pulmonary	POS	O
+,	POS	O
+and	POS	O
+coronary	POS	B-NP
+circulations	POS	I-NP
+.	POS	O
+Cases	POS	O
+have	POS	O
+been	POS	O
+published	POS	O
+of	POS	O
+coronary	POS	B-NP
+vasospasm	POS	I-NP
+,	POS	O
+myocardial	POS	B-NP
+ischemia	POS	I-NP
+,	POS	O
+and	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+occurring	POS	O
+after	POS	O
+sumatriptan	POS	O
+use	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+on	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+8	POS	O
+serious	POS	O
+cases	POS	O
+of	POS	O
+ischemic	POS	B-NP
+colitis	POS	I-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+migraine	POS	B-NP
+treated	POS	O
+with	POS	O
+sumatriptan	POS	O
+.	POS	O
+Pallidotomy	POS	B-NP
+with	POS	O
+the	POS	O
+gamma	POS	O
+knife	POS	O
+:	POS	O
+a	POS	O
+positive	POS	O
+experience	POS	O
+.	POS	O
+51	POS	O
+patients	POS	O
+with	POS	O
+medically	POS	O
+refractory	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+underwent	POS	O
+stereotactic	POS	O
+posteromedial	POS	O
+pallidotomy	POS	O
+between	POS	O
+August	POS	O
+1993	POS	O
+and	POS	O
+February	POS	O
+1997	POS	O
+for	POS	O
+treatment	POS	O
+of	POS	O
+bradykinesia	POS	B-NP
+,	POS	O
+rigidity	POS	B-NP
+,	POS	O
+and	POS	O
+L	POS	O
+-	POS	O
+DOPA	POS	O
+-	POS	O
+induced	POS	O
+dyskinesias	POS	B-NP
+.	POS	O
+In	POS	O
+29	POS	O
+patients	POS	O
+,	POS	O
+the	POS	O
+pallidotomies	POS	O
+were	POS	O
+performed	POS	O
+with	POS	O
+the	POS	O
+Leksell	POS	O
+Gamma	POS	O
+Knife	POS	O
+and	POS	O
+in	POS	O
+22	POS	O
+they	POS	O
+were	POS	O
+performed	POS	O
+with	POS	O
+the	POS	O
+standard	POS	O
+radiofrequency	POS	O
+(	POS	O
+RF	POS	O
+)	POS	O
+method	POS	O
+.	POS	O
+Clinical	POS	O
+assessment	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+blinded	POS	O
+ratings	POS	O
+of	POS	O
+Unified	POS	O
+Parkinson	POS	O
+'	POS	O
+s	POS	O
+Disease	POS	O
+Rating	POS	O
+Scale	POS	O
+(	POS	O
+UPDRS	POS	O
+)	POS	O
+scores	POS	O
+were	POS	O
+carried	POS	O
+out	POS	O
+pre	POS	O
+-	POS	O
+and	POS	O
+postoperatively	POS	O
+.	POS	O
+Mean	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+time	POS	O
+is	POS	O
+20	POS	O
+.	POS	O
+6	POS	O
+months	POS	O
+(	POS	O
+range	POS	O
+6	POS	O
+-	POS	O
+48	POS	O
+)	POS	O
+and	POS	O
+all	POS	O
+except	POS	O
+4	POS	O
+patients	POS	O
+have	POS	O
+been	POS	O
+followed	POS	O
+more	POS	O
+than	POS	O
+one	POS	O
+year	POS	O
+.	POS	O
+85	POS	O
+percent	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+dyskinesias	POS	B-NP
+were	POS	O
+relieved	POS	O
+of	POS	O
+symptoms	POS	O
+,	POS	O
+regardless	POS	O
+of	POS	O
+whether	POS	O
+the	POS	O
+pallidotomies	POS	O
+were	POS	O
+performed	POS	O
+with	POS	O
+the	POS	O
+Gamma	POS	O
+Knife	POS	O
+or	POS	O
+radiofrequency	POS	O
+methods	POS	O
+.	POS	O
+About	POS	O
+2	POS	O
+/	POS	O
+3	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+in	POS	O
+both	POS	O
+Gamma	POS	O
+Knife	POS	O
+and	POS	O
+radiofrequency	POS	O
+groups	POS	O
+showed	POS	O
+improvements	POS	O
+in	POS	O
+bradykinesia	POS	B-NP
+and	POS	O
+rigidity	POS	B-NP
+,	POS	O
+although	POS	O
+when	POS	O
+considered	POS	O
+as	POS	O
+a	POS	O
+group	POS	O
+neither	POS	O
+the	POS	O
+Gamma	POS	O
+Knife	POS	O
+nor	POS	O
+the	POS	O
+radiofrequency	POS	O
+group	POS	O
+showed	POS	O
+statistically	POS	O
+significant	POS	O
+improvements	POS	O
+in	POS	O
+UPDRS	POS	O
+scores	POS	O
+.	POS	O
+One	POS	O
+patient	POS	O
+in	POS	O
+the	POS	O
+Gamma	POS	O
+Knife	POS	O
+group	POS	O
+(	POS	O
+3	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+developed	POS	O
+a	POS	O
+homonymous	POS	B-NP
+hemianopsia	POS	I-NP
+9	POS	O
+months	POS	O
+following	POS	O
+treatment	POS	O
+and	POS	O
+5	POS	O
+patients	POS	O
+(	POS	O
+27	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+radiofrequency	POS	O
+group	POS	O
+became	POS	O
+transiently	POS	O
+confused	POS	O
+postoperatively	POS	O
+.	POS	O
+No	POS	O
+other	POS	O
+complications	POS	O
+were	POS	O
+seen	POS	O
+.	POS	O
+Gamma	POS	O
+Knife	POS	O
+pallidotomy	POS	O
+is	POS	O
+as	POS	O
+effective	POS	O
+as	POS	O
+radiofrequency	POS	O
+pallidotomy	POS	O
+in	POS	O
+controlling	POS	O
+certain	POS	O
+of	POS	O
+the	POS	O
+symptoms	POS	O
+of	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+It	POS	O
+may	POS	O
+be	POS	O
+the	POS	O
+only	POS	O
+practical	POS	O
+technique	POS	O
+available	POS	O
+in	POS	O
+certain	POS	O
+patients	POS	O
+,	POS	O
+such	POS	O
+as	POS	O
+those	POS	O
+who	POS	O
+take	POS	O
+anticoagulants	POS	O
+,	POS	O
+have	POS	O
+bleeding	POS	B-NP
+diatheses	POS	I-NP
+or	POS	O
+serious	POS	O
+systemic	POS	O
+medical	POS	O
+illnesses	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+a	POS	O
+viable	POS	O
+option	POS	O
+for	POS	O
+other	POS	O
+patients	POS	O
+as	POS	O
+well	POS	O
+.	POS	O
+Centrally	POS	O
+mediated	POS	O
+cardiovascular	POS	O
+effects	POS	O
+of	POS	O
+intracisternal	POS	O
+application	POS	O
+of	POS	O
+carbachol	POS	O
+in	POS	O
+anesthetized	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+pressor	POS	O
+response	POS	O
+to	POS	O
+the	POS	O
+intracisternal	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+)	POS	O
+injection	POS	O
+of	POS	O
+carbachol	POS	O
+(	POS	O
+1	POS	O
+mug	POS	O
+)	POS	O
+in	POS	O
+anesthetized	POS	O
+rats	POS	O
+was	POS	O
+analyzed	POS	O
+.	POS	O
+This	POS	O
+response	POS	O
+was	POS	O
+significantly	POS	O
+reduced	POS	O
+by	POS	O
+the	POS	O
+intravenous	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+)	POS	O
+injection	POS	O
+of	POS	O
+guanethidine	POS	O
+(	POS	O
+5	POS	O
+mg	POS	O
+)	POS	O
+,	POS	O
+hexamethonium	POS	O
+(	POS	O
+10	POS	O
+mg	POS	O
+)	POS	O
+or	POS	O
+phentolamine	POS	O
+(	POS	O
+5	POS	O
+mg	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+conversely	POS	O
+,	POS	O
+potentiated	POS	O
+by	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+desmethylimipramine	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+mg	POS	O
+)	POS	O
+,	POS	O
+while	POS	O
+propranolol	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+)	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+selectively	POS	O
+inhibited	POS	O
+the	POS	O
+enlargement	POS	O
+of	POS	O
+pulse	POS	O
+pressure	POS	O
+and	POS	O
+the	POS	O
+tachycardia	POS	B-NP
+following	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+carbachol	POS	O
+(	POS	O
+1	POS	O
+mug	POS	O
+)	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+other	POS	O
+hand	POS	O
+,	POS	O
+the	POS	O
+pressor	POS	O
+response	POS	O
+to	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+carbachol	POS	O
+(	POS	O
+1	POS	O
+mug	POS	O
+)	POS	O
+was	POS	O
+almost	POS	O
+completely	POS	O
+blocked	POS	O
+by	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+atropine	POS	O
+(	POS	O
+3	POS	O
+mug	POS	O
+)	POS	O
+or	POS	O
+hexamethonium	POS	O
+(	POS	O
+500	POS	O
+mug	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+significantly	POS	O
+reduced	POS	O
+by	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+chlorpromazine	POS	O
+(	POS	O
+50	POS	O
+mug	POS	O
+)	POS	O
+but	POS	O
+significantly	POS	O
+potentiated	POS	O
+by	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+desmethylimipramine	POS	O
+(	POS	O
+30	POS	O
+mug	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+pressor	POS	O
+response	POS	O
+to	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+carbachol	POS	O
+(	POS	O
+1	POS	O
+mug	POS	O
+)	POS	O
+remained	POS	O
+unchanged	POS	O
+after	POS	O
+sectioning	POS	O
+of	POS	O
+the	POS	O
+bilateral	POS	O
+cervical	POS	O
+vagal	POS	O
+nerves	POS	O
+but	POS	O
+disappeared	POS	O
+after	POS	O
+sectioning	POS	O
+of	POS	O
+the	POS	O
+spinal	POS	O
+cord	POS	O
+(	POS	O
+C7	POS	O
+-	POS	O
+C8	POS	O
+)	POS	O
+.	POS	O
+From	POS	O
+the	POS	O
+above	POS	O
+result	POS	O
+it	POS	O
+is	POS	O
+suggested	POS	O
+that	POS	O
+the	POS	O
+pressor	POS	O
+response	POS	O
+to	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+carbachol	POS	O
+ortral	POS	O
+and	POS	O
+peripheral	POS	O
+adrenergic	POS	O
+mechanisms	POS	O
+,	POS	O
+and	POS	O
+that	POS	O
+the	POS	O
+sympathetic	POS	O
+trunk	POS	O
+is	POS	O
+the	POS	O
+main	POS	O
+pathway	POS	O
+.	POS	O
+Neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+and	POS	O
+methylphenidate	POS	O
+.	POS	O
+A	POS	O
+1	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+female	POS	O
+presented	POS	O
+with	POS	O
+neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+probably	POS	O
+caused	POS	O
+by	POS	O
+methylphenidate	POS	O
+.	POS	O
+She	POS	O
+had	POS	O
+defects	POS	O
+in	POS	O
+the	POS	O
+supratentorial	POS	O
+brain	POS	O
+including	POS	O
+the	POS	O
+basal	POS	O
+ganglia	POS	O
+and	POS	O
+the	POS	O
+striatum	POS	O
+(	POS	O
+multicystic	POS	B-NP
+encephalomalacia	POS	I-NP
+)	POS	O
+due	POS	O
+to	POS	O
+severe	POS	O
+perinatal	POS	O
+hypoxic	POS	O
+-	POS	O
+ischemic	POS	B-NP
+encephalopathy	POS	I-NP
+,	POS	O
+which	POS	O
+was	POS	O
+considered	POS	O
+to	POS	O
+be	POS	O
+a	POS	O
+possible	POS	O
+predisposing	POS	O
+factor	POS	O
+causing	POS	O
+neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+.	POS	O
+A	POS	O
+dopaminergic	POS	O
+blockade	POS	O
+mechanism	POS	O
+generally	POS	O
+is	POS	O
+accepted	POS	O
+as	POS	O
+the	POS	O
+pathogenesis	POS	O
+of	POS	O
+this	POS	O
+syndrome	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+methylphenidate	POS	O
+is	POS	O
+a	POS	O
+dopamine	POS	O
+agonist	POS	O
+via	POS	O
+the	POS	O
+inhibition	POS	O
+of	POS	O
+uptake	POS	O
+of	POS	O
+dopamine	POS	O
+,	POS	O
+and	POS	O
+therefore	POS	O
+dopaminergic	POS	O
+systems	POS	O
+in	POS	O
+the	POS	O
+brainstem	POS	O
+(	POS	O
+mainly	POS	O
+the	POS	O
+midbrain	POS	O
+)	POS	O
+and	POS	O
+the	POS	O
+spinal	POS	O
+cord	POS	O
+were	POS	O
+unlikely	POS	O
+to	POS	O
+participate	POS	O
+in	POS	O
+the	POS	O
+onset	POS	O
+of	POS	O
+this	POS	O
+syndrome	POS	O
+.	POS	O
+A	POS	O
+relative	POS	O
+gamma	POS	O
+-	POS	O
+aminobutyric	POS	O
+acid	POS	O
+-	POS	O
+ergic	POS	O
+deficiency	POS	O
+might	POS	O
+occur	POS	O
+because	POS	O
+diazepam	POS	O
+,	POS	O
+a	POS	O
+gamma	POS	O
+-	POS	O
+aminobutyric	POS	O
+acid	POS	O
+-	POS	O
+mimetic	POS	O
+agent	POS	O
+,	POS	O
+was	POS	O
+strikingly	POS	O
+effective	POS	O
+.	POS	O
+This	POS	O
+is	POS	O
+the	POS	O
+first	POS	O
+reported	POS	O
+patient	POS	O
+with	POS	O
+neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+probably	POS	O
+caused	POS	O
+by	POS	O
+methylphenidate	POS	O
+.	POS	O
+Differential	POS	O
+effects	POS	O
+of	POS	O
+17alpha	POS	O
+-	POS	O
+ethinylestradiol	POS	O
+on	POS	O
+the	POS	O
+neutral	POS	O
+and	POS	O
+acidic	POS	O
+pathways	POS	O
+of	POS	O
+bile	POS	O
+salt	POS	O
+synthesis	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+.	POS	O
+Effects	POS	O
+of	POS	O
+17alpha	POS	O
+-	POS	O
+ethinylestradiol	POS	O
+(	POS	O
+EE	POS	O
+)	POS	O
+on	POS	O
+the	POS	O
+neutral	POS	O
+and	POS	O
+acidic	POS	O
+biosynthetic	POS	O
+pathways	POS	O
+of	POS	O
+bile	POS	O
+salt	POS	O
+(	POS	O
+BS	POS	O
+)	POS	O
+synthesis	POS	O
+were	POS	O
+evaluated	POS	O
+in	POS	O
+rats	POS	O
+with	POS	O
+an	POS	O
+intact	POS	O
+enterohepatic	POS	O
+circulation	POS	O
+and	POS	O
+in	POS	O
+rats	POS	O
+with	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+bile	POS	O
+diversion	POS	O
+to	POS	O
+induce	POS	O
+BS	POS	O
+synthesis	POS	O
+.	POS	O
+For	POS	O
+this	POS	O
+purpose	POS	O
+,	POS	O
+bile	POS	O
+salt	POS	O
+pool	POS	O
+composition	POS	O
+,	POS	O
+synthesis	POS	O
+of	POS	O
+individual	POS	O
+BS	POS	O
+in	POS	O
+vivo	POS	O
+,	POS	O
+hepatic	POS	O
+activities	POS	O
+,	POS	O
+and	POS	O
+expression	POS	O
+levels	POS	O
+of	POS	O
+cholesterol	POS	O
+7alpha	POS	O
+-	POS	O
+hydroxylase	POS	O
+(	POS	O
+CYP7A	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+sterol	POS	O
+27	POS	O
+-	POS	O
+hydroxylase	POS	O
+(	POS	O
+CYP27	POS	O
+)	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+of	POS	O
+other	POS	O
+enzymes	POS	O
+involved	POS	O
+in	POS	O
+BS	POS	O
+synthesis	POS	O
+,	POS	O
+were	POS	O
+analyzed	POS	O
+in	POS	O
+rats	POS	O
+treated	POS	O
+with	POS	O
+EE	POS	O
+(	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+3	POS	O
+days	POS	O
+)	POS	O
+or	POS	O
+its	POS	O
+vehicle	POS	O
+.	POS	O
+BS	POS	O
+pool	POS	O
+size	POS	O
+was	POS	O
+decreased	POS	O
+by	POS	O
+27	POS	O
+%	POS	O
+but	POS	O
+total	POS	O
+BS	POS	O
+synthesis	POS	O
+was	POS	O
+not	POS	O
+affected	POS	O
+by	POS	O
+EE	POS	O
+in	POS	O
+intact	POS	O
+rats	POS	O
+.	POS	O
+Synthesis	POS	O
+of	POS	O
+cholate	POS	O
+was	POS	O
+reduced	POS	O
+by	POS	O
+68	POS	O
+%	POS	O
+in	POS	O
+EE	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+,	POS	O
+while	POS	O
+that	POS	O
+of	POS	O
+chenodeoxycholate	POS	O
+was	POS	O
+increased	POS	O
+by	POS	O
+60	POS	O
+%	POS	O
+.	POS	O
+The	POS	O
+recently	POS	O
+identified	POS	O
+Delta22	POS	O
+-	POS	O
+isomer	POS	O
+of	POS	O
+beta	POS	O
+-	POS	O
+muricholate	POS	O
+contributed	POS	O
+for	POS	O
+5	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+and	POS	O
+18	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+to	POS	O
+the	POS	O
+pool	POS	O
+in	POS	O
+control	POS	O
+and	POS	O
+EE	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+but	POS	O
+could	POS	O
+not	POS	O
+be	POS	O
+detected	POS	O
+in	POS	O
+bile	POS	O
+after	POS	O
+exhaustion	POS	O
+of	POS	O
+the	POS	O
+pool	POS	O
+.	POS	O
+A	POS	O
+clear	POS	O
+reduction	POS	O
+of	POS	O
+BS	POS	O
+synthesis	POS	O
+was	POS	O
+found	POS	O
+in	POS	O
+bile	POS	O
+-	POS	O
+diverted	POS	O
+rats	POS	O
+treated	POS	O
+with	POS	O
+EE	POS	O
+,	POS	O
+yet	POS	O
+biliary	POS	O
+BS	POS	O
+composition	POS	O
+was	POS	O
+only	POS	O
+minimally	POS	O
+affected	POS	O
+.	POS	O
+Activity	POS	O
+of	POS	O
+CYP7A	POS	O
+was	POS	O
+decreased	POS	O
+by	POS	O
+EE	POS	O
+in	POS	O
+both	POS	O
+intact	POS	O
+and	POS	O
+bile	POS	O
+-	POS	O
+diverted	POS	O
+rats	POS	O
+,	POS	O
+whereas	POS	O
+the	POS	O
+activity	POS	O
+of	POS	O
+the	POS	O
+CYP27	POS	O
+was	POS	O
+not	POS	O
+affected	POS	O
+.	POS	O
+Hepatic	POS	O
+mRNA	POS	O
+levels	POS	O
+of	POS	O
+CYP7A	POS	O
+were	POS	O
+significantly	POS	O
+reduced	POS	O
+by	POS	O
+EE	POS	O
+in	POS	O
+bile	POS	O
+-	POS	O
+diverted	POS	O
+rats	POS	O
+only	POS	O
+;	POS	O
+CYP27	POS	O
+mRNA	POS	O
+levels	POS	O
+were	POS	O
+not	POS	O
+affected	POS	O
+by	POS	O
+EE	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+mRNA	POS	O
+levels	POS	O
+of	POS	O
+sterol	POS	O
+12alpha	POS	O
+-	POS	O
+hydroxylase	POS	O
+and	POS	O
+lithocholate	POS	O
+6beta	POS	O
+-	POS	O
+hydroxylase	POS	O
+were	POS	O
+increased	POS	O
+by	POS	O
+bile	POS	O
+diversion	POS	O
+and	POS	O
+suppressed	POS	O
+by	POS	O
+EE	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+shows	POS	O
+that	POS	O
+17alpha	POS	O
+-	POS	O
+ethinylestradiol	POS	O
+(	POS	O
+EE	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+intrahepatic	POS	B-NP
+cholestasis	POS	I-NP
+in	POS	O
+rats	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+selective	POS	O
+inhibition	POS	O
+of	POS	O
+the	POS	O
+neutral	POS	O
+pathway	POS	O
+of	POS	O
+bile	POS	O
+salt	POS	O
+(	POS	O
+BS	POS	O
+)	POS	O
+synthesis	POS	O
+.	POS	O
+Simultaneous	POS	O
+impairment	POS	O
+of	POS	O
+other	POS	O
+enzymes	POS	O
+in	POS	O
+the	POS	O
+BS	POS	O
+biosynthetic	POS	O
+pathways	POS	O
+may	POS	O
+contribute	POS	O
+to	POS	O
+overall	POS	O
+effects	POS	O
+of	POS	O
+EE	POS	O
+on	POS	O
+BS	POS	O
+synthesis	POS	O
+.	POS	O
+Glibenclamide	POS	O
+-	POS	O
+sensitive	POS	O
+hypotension	POS	B-NP
+produced	POS	O
+by	POS	O
+helodermin	POS	O
+assessed	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+helodermin	POS	O
+,	POS	O
+a	POS	O
+basic	POS	O
+35	POS	O
+-	POS	O
+amino	POS	O
+acid	POS	O
+peptide	POS	O
+isolated	POS	O
+from	POS	O
+the	POS	O
+venom	POS	O
+of	POS	O
+a	POS	O
+lizard	POS	O
+salivary	POS	O
+gland	POS	O
+,	POS	O
+on	POS	O
+arterial	POS	O
+blood	POS	O
+pressure	POS	O
+and	POS	O
+heart	POS	O
+rate	POS	O
+were	POS	O
+examined	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+,	POS	O
+focusing	POS	O
+on	POS	O
+the	POS	O
+possibility	POS	O
+that	POS	O
+activation	POS	O
+of	POS	O
+ATP	POS	O
+sensitive	POS	O
+K	POS	O
++	POS	O
+(	POS	O
+K	POS	O
+(	POS	O
+ATP	POS	O
+)	POS	O
+)	POS	O
+channels	POS	O
+is	POS	O
+involved	POS	O
+in	POS	O
+the	POS	O
+responses	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+were	POS	O
+also	POS	O
+compared	POS	O
+with	POS	O
+those	POS	O
+of	POS	O
+vasoactive	POS	O
+intestinal	POS	O
+polypeptide	POS	O
+(	POS	O
+VIP	POS	O
+)	POS	O
+.	POS	O
+Helodermin	POS	O
+produced	POS	O
+hypotension	POS	B-NP
+in	POS	O
+a	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+manner	POS	O
+with	POS	O
+approximately	POS	O
+similar	POS	O
+potency	POS	O
+and	POS	O
+duration	POS	O
+to	POS	O
+VIP	POS	O
+.	POS	O
+Hypotension	POS	B-NP
+induced	POS	O
+by	POS	O
+both	POS	O
+peptides	POS	O
+was	POS	O
+significantly	POS	O
+attenuated	POS	O
+by	POS	O
+glibenclamide	POS	O
+,	POS	O
+which	POS	O
+abolished	POS	O
+a	POS	O
+levcromakalim	POS	O
+-	POS	O
+produced	POS	O
+decrease	POS	O
+in	POS	O
+arterial	POS	O
+blood	POS	O
+pressure	POS	O
+.	POS	O
+Oxyhemoglobin	POS	O
+did	POS	O
+not	POS	O
+affect	POS	O
+helodermin	POS	O
+-	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+,	POS	O
+whereas	POS	O
+it	POS	O
+shortened	POS	O
+the	POS	O
+duration	POS	O
+of	POS	O
+acetylcholine	POS	O
+(	POS	O
+ACh	POS	O
+)	POS	O
+-	POS	O
+produced	POS	O
+hypotension	POS	B-NP
+.	POS	O
+These	POS	O
+findings	POS	O
+suggest	POS	O
+that	POS	O
+helodermin	POS	O
+-	POS	O
+produced	POS	O
+hypotension	POS	B-NP
+is	POS	O
+partly	POS	O
+attributable	POS	O
+to	POS	O
+the	POS	O
+activation	POS	O
+of	POS	O
+glibenclamide	POS	O
+-	POS	O
+sensitive	POS	O
+K	POS	O
++	POS	O
+channels	POS	O
+(	POS	O
+K	POS	O
+(	POS	O
+ATP	POS	O
+)	POS	O
+channels	POS	O
+)	POS	O
+,	POS	O
+which	POS	O
+presumably	POS	O
+exist	POS	O
+on	POS	O
+arterial	POS	O
+smooth	POS	O
+muscle	POS	O
+cells	POS	O
+.	POS	O
+EDRF	POS	O
+(	POS	O
+endothelium	POS	O
+-	POS	O
+derived	POS	O
+relaxing	POS	O
+factor	POS	O
+)	POS	O
+/	POS	O
+nitric	POS	O
+oxide	POS	O
+does	POS	O
+not	POS	O
+seem	POS	O
+to	POS	O
+play	POS	O
+an	POS	O
+important	POS	O
+role	POS	O
+in	POS	O
+the	POS	O
+peptide	POS	O
+-	POS	O
+produced	POS	O
+hypotension	POS	B-NP
+.	POS	O
+Long	POS	O
+-	POS	O
+term	POS	O
+efficacy	POS	O
+and	POS	O
+adverse	POS	O
+event	POS	O
+of	POS	O
+nifedipine	POS	O
+sustained	POS	O
+-	POS	O
+release	POS	O
+tablets	POS	O
+for	POS	O
+cyclosporin	POS	O
+A	POS	O
+-	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+psoriasis	POS	B-NP
+.	POS	O
+Thirteen	POS	O
+psoriatic	POS	B-NP
+patients	POS	O
+with	POS	O
+hypertension	POS	B-NP
+during	POS	O
+the	POS	O
+course	POS	O
+of	POS	O
+cyclosporin	POS	O
+A	POS	O
+therapy	POS	O
+were	POS	O
+treated	POS	O
+for	POS	O
+25	POS	O
+months	POS	O
+with	POS	O
+a	POS	O
+calcium	POS	O
+channel	POS	O
+blocker	POS	O
+,	POS	O
+sustained	POS	O
+-	POS	O
+release	POS	O
+nifedipine	POS	O
+,	POS	O
+to	POS	O
+study	POS	O
+the	POS	O
+clinical	POS	O
+antihypertensive	POS	O
+effects	POS	O
+and	POS	O
+adverse	POS	O
+events	POS	O
+during	POS	O
+treatment	POS	O
+with	POS	O
+both	POS	O
+drugs	POS	O
+.	POS	O
+Seven	POS	O
+of	POS	O
+the	POS	O
+13	POS	O
+patients	POS	O
+had	POS	O
+exhibited	POS	O
+a	POS	O
+subclinical	POS	O
+hypertensive	POS	B-NP
+state	POS	O
+before	POS	O
+cyclosporin	POS	O
+A	POS	O
+therapy	POS	O
+.	POS	O
+Both	POS	O
+systolic	POS	O
+and	POS	O
+diastolic	POS	O
+blood	POS	O
+pressures	POS	O
+of	POS	O
+these	POS	O
+13	POS	O
+patients	POS	O
+were	POS	O
+decreased	POS	O
+significantly	POS	O
+after	POS	O
+4	POS	O
+weeks	POS	O
+of	POS	O
+nifedipine	POS	O
+therapy	POS	O
+,	POS	O
+and	POS	O
+blood	POS	O
+pressure	POS	O
+was	POS	O
+maintained	POS	O
+within	POS	O
+the	POS	O
+normal	POS	O
+range	POS	O
+thereafter	POS	O
+for	POS	O
+25	POS	O
+months	POS	O
+.	POS	O
+The	POS	O
+adverse	POS	O
+events	POS	O
+during	POS	O
+combined	POS	O
+therapy	POS	O
+with	POS	O
+cyclosporin	POS	O
+A	POS	O
+and	POS	O
+nifedipine	POS	O
+included	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+blood	POS	O
+urea	POS	O
+nitrogen	POS	O
+levels	POS	O
+in	POS	O
+9	POS	O
+of	POS	O
+the	POS	O
+13	POS	O
+patients	POS	O
+and	POS	O
+development	POS	O
+of	POS	O
+gingival	POS	B-NP
+hyperplasia	POS	I-NP
+in	POS	O
+2	POS	O
+of	POS	O
+the	POS	O
+13	POS	O
+patients	POS	O
+.	POS	O
+Our	POS	O
+findings	POS	O
+indicate	POS	O
+that	POS	O
+sustained	POS	O
+-	POS	O
+release	POS	O
+nifedipine	POS	O
+is	POS	O
+useful	POS	O
+for	POS	O
+hypertensive	POS	B-NP
+psoriatic	POS	I-NP
+patients	POS	O
+under	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+treatment	POS	O
+with	POS	O
+cyclosporin	POS	O
+A	POS	O
+,	POS	O
+but	POS	O
+that	POS	O
+these	POS	O
+patients	POS	O
+should	POS	O
+be	POS	O
+monitored	POS	O
+for	POS	O
+gingival	POS	B-NP
+hyperplasia	POS	I-NP
+.	POS	O
+
diff --git a/helper/.DS_Store b/helper/.DS_Store
new file mode 100644
index 0000000..0f4aad2
Binary files /dev/null and b/helper/.DS_Store differ
diff --git a/helper/evaluation/.DS_Store b/helper/evaluation/.DS_Store
new file mode 100644
index 0000000..baf56d1
Binary files /dev/null and b/helper/evaluation/.DS_Store differ
diff --git a/helper/evaluation/OUTPUT.tsv b/helper/evaluation/OUTPUT.tsv
new file mode 100644
index 0000000..b7c82bd
--- /dev/null
+++ b/helper/evaluation/OUTPUT.tsv
@@ -0,0 +1,124751 @@
+Torsade	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+ventricular	POS	I-NP
+tachycardia	POS	I-NP
+during	POS	O
+low	POS	O
+dose	POS	O
+intermittent	POS	O
+dobutamine	POS	O
+treatment	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+dilated	POS	B-NP
+cardiomyopathy	POS	I-NP
+and	POS	O
+congestive	POS	B-NP
+heart	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+The	POS	O
+authors	POS	O
+describe	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+56	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+with	POS	O
+chronic	POS	O
+,	POS	O
+severe	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+secondary	POS	O
+to	POS	O
+dilated	POS	B-NP
+cardiomyopathy	POS	I-NP
+and	POS	O
+absence	POS	O
+of	POS	O
+significant	POS	O
+ventricular	POS	B-NP
+arrhythmias	POS	I-NP
+who	POS	O
+developed	POS	O
+QT	POS	B-NP
+prolongation	POS	I-NP
+and	POS	O
+torsade	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+ventricular	POS	I-NP
+tachycardia	POS	I-NP
+during	POS	O
+one	POS	O
+cycle	POS	O
+of	POS	O
+intermittent	POS	O
+low	POS	O
+dose	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mcg	POS	O
+/	POS	O
+kg	POS	O
+per	POS	O
+min	POS	O
+)	POS	O
+dobutamine	POS	O
+.	POS	O
+This	POS	O
+report	POS	O
+of	POS	O
+torsade	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+ventricular	POS	I-NP
+tachycardia	POS	I-NP
+during	POS	O
+intermittent	POS	O
+dobutamine	POS	O
+supports	POS	O
+the	POS	O
+hypothesis	POS	O
+that	POS	O
+unpredictable	POS	O
+fatal	POS	O
+arrhythmias	POS	B-NP
+may	POS	O
+occur	POS	O
+even	POS	O
+with	POS	O
+low	POS	O
+doses	POS	O
+and	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+no	POS	O
+history	POS	O
+of	POS	O
+significant	POS	O
+rhythm	POS	B-NP
+disturbances	POS	I-NP
+.	POS	O
+The	POS	O
+mechanisms	POS	O
+of	POS	O
+proarrhythmic	POS	O
+effects	POS	O
+of	POS	O
+Dubutamine	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+Positive	POS	O
+skin	POS	O
+tests	POS	O
+in	POS	O
+late	POS	O
+reactions	POS	O
+to	POS	O
+radiographic	POS	O
+contrast	POS	O
+media	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+last	POS	O
+few	POS	O
+years	POS	O
+delayed	POS	O
+reactions	POS	O
+several	POS	O
+hours	POS	O
+after	POS	O
+the	POS	O
+injection	POS	O
+of	POS	O
+radiographic	POS	O
+and	POS	O
+contrast	POS	O
+materials	POS	O
+(	POS	O
+PRC	POS	O
+)	POS	O
+have	POS	O
+been	POS	O
+described	POS	O
+with	POS	O
+increasing	POS	O
+frequency	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+report	POS	O
+two	POS	O
+observations	POS	O
+on	POS	O
+patients	POS	O
+with	POS	O
+delayed	POS	O
+reactions	POS	O
+in	POS	O
+whom	POS	O
+intradermoreactions	POS	O
+(	POS	O
+IDR	POS	O
+)	POS	O
+and	POS	O
+patch	POS	O
+tests	POS	O
+to	POS	O
+a	POS	O
+series	POS	O
+of	POS	O
+ionic	POS	O
+and	POS	O
+non	POS	O
+ionic	POS	O
+PRC	POS	O
+were	POS	O
+studied	POS	O
+.	POS	O
+After	POS	O
+angiography	POS	O
+by	POS	O
+the	POS	O
+venous	POS	O
+route	POS	O
+in	POS	O
+patient	POS	O
+n	POS	O
+degree	POS	O
+1	POS	O
+a	POS	O
+biphasic	POS	O
+reaction	POS	O
+with	POS	O
+an	POS	O
+immediate	POS	O
+reaction	POS	O
+(	POS	O
+dyspnea	POS	B-NP
+,	POS	O
+loss	POS	B-NP
+of	POS	I-NP
+consciousness	POS	I-NP
+)	POS	O
+and	POS	O
+delayed	POS	O
+macro	POS	O
+-	POS	O
+papular	POS	B-NP
+rash	POS	I-NP
+appeared	POS	O
+,	POS	O
+whilst	POS	O
+patient	POS	O
+n	POS	O
+degree	POS	O
+2	POS	O
+developed	POS	O
+a	POS	O
+generalised	POS	B-NP
+sensation	POS	I-NP
+of	POS	I-NP
+heat	POS	I-NP
+,	POS	O
+persistent	POS	O
+pain	POS	B-NP
+at	POS	O
+the	POS	O
+site	POS	O
+of	POS	O
+injection	POS	O
+immediately	POS	O
+and	POS	O
+a	POS	O
+generalised	POS	O
+macro	POS	O
+-	POS	O
+papular	POS	B-NP
+reaction	POS	I-NP
+after	POS	O
+24	POS	O
+hours	POS	O
+.	POS	O
+The	POS	O
+skin	POS	O
+tests	POS	O
+revealed	POS	O
+positive	POS	O
+delayed	POS	O
+reactions	POS	O
+of	POS	O
+24	POS	O
+hours	POS	O
+and	POS	O
+48	POS	O
+hours	POS	O
+by	POS	O
+IDR	POS	O
+and	POS	O
+patch	POS	O
+tests	POS	O
+to	POS	O
+only	POS	O
+some	POS	O
+PRC	POS	O
+with	POS	O
+common	POS	O
+chains	POS	O
+in	POS	O
+their	POS	O
+structures	POS	O
+.	POS	O
+The	POS	O
+positive	POS	O
+skin	POS	O
+tests	POS	O
+are	POS	O
+in	POS	O
+favour	POS	O
+of	POS	O
+immunological	POS	O
+reactions	POS	O
+and	POS	O
+may	POS	O
+help	POS	O
+in	POS	O
+diagnosis	POS	O
+of	POS	O
+allergy	POS	B-NP
+in	POS	O
+the	POS	O
+patients	POS	O
+.	POS	O
+Risk	POS	O
+of	POS	O
+transient	POS	O
+hyperammonemic	POS	B-NP
+encephalopathy	POS	I-NP
+in	POS	O
+cancer	POS	B-NP
+patients	POS	O
+who	POS	O
+received	POS	O
+continuous	POS	O
+infusion	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+with	POS	O
+the	POS	O
+complication	POS	O
+of	POS	O
+dehydration	POS	B-NP
+and	POS	O
+infection	POS	O
+.	POS	O
+From	POS	O
+1986	POS	O
+to	POS	O
+1998	POS	O
+,	POS	O
+29	POS	O
+cancer	POS	B-NP
+patients	POS	O
+who	POS	O
+had	POS	O
+32	POS	O
+episodes	POS	O
+of	POS	O
+transient	POS	O
+hyperammonemic	POS	B-NP
+encephalopathy	POS	I-NP
+related	POS	O
+to	POS	O
+continuous	POS	O
+infusion	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+(	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+)	POS	O
+were	POS	O
+identified	POS	O
+.	POS	O
+None	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+had	POS	O
+decompensated	POS	B-NP
+liver	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+Onset	POS	O
+of	POS	O
+hyperammonemic	POS	B-NP
+encephalopathy	POS	I-NP
+varied	POS	O
+from	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+to	POS	O
+5	POS	O
+days	POS	O
+(	POS	O
+mean	POS	O
+:	POS	O
+2	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+days	POS	O
+)	POS	O
+after	POS	O
+the	POS	O
+initiation	POS	O
+of	POS	O
+chemotherapy	POS	O
+.	POS	O
+Plasma	POS	O
+ammonium	POS	O
+level	POS	O
+ranged	POS	O
+from	POS	O
+248	POS	O
+to	POS	O
+2387	POS	O
+microg	POS	O
+%	POS	O
+(	POS	O
+mean	POS	O
+:	POS	O
+626	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+431	POS	O
+microg	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Among	POS	O
+the	POS	O
+32	POS	O
+episodes	POS	O
+,	POS	O
+26	POS	O
+(	POS	O
+81	POS	O
+%	POS	O
+)	POS	O
+had	POS	O
+various	POS	O
+degrees	POS	O
+of	POS	O
+azotemia	POS	B-NP
+,	POS	O
+18	POS	O
+(	POS	O
+56	POS	O
+%	POS	O
+)	POS	O
+occurred	POS	O
+during	POS	O
+bacterial	POS	B-NP
+infections	POS	I-NP
+and	POS	O
+14	POS	O
+(	POS	O
+44	POS	O
+%	POS	O
+)	POS	O
+without	POS	O
+infection	POS	O
+occurred	POS	O
+during	POS	O
+periods	POS	O
+of	POS	O
+dehydration	POS	B-NP
+.	POS	O
+Higher	POS	O
+plasma	POS	O
+ammonium	POS	O
+levels	POS	O
+and	POS	O
+more	POS	O
+rapid	POS	O
+onset	POS	O
+of	POS	O
+hyperammonemia	POS	B-NP
+were	POS	O
+seen	POS	O
+in	POS	O
+18	POS	O
+patients	POS	O
+with	POS	O
+bacterial	POS	B-NP
+infections	POS	I-NP
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+003	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+0006	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+and	POS	O
+in	POS	O
+nine	POS	O
+patients	POS	O
+receiving	POS	O
+high	POS	O
+daily	POS	O
+doses	POS	O
+(	POS	O
+2600	POS	O
+or	POS	O
+1800	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+)	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+0001	POS	O
+and	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+0001	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+25	POS	O
+out	POS	O
+of	POS	O
+32	POS	O
+episodes	POS	O
+(	POS	O
+78	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+plasma	POS	O
+ammonium	POS	O
+levels	POS	O
+and	POS	O
+mental	POS	O
+status	POS	O
+returned	POS	O
+to	POS	O
+normal	POS	O
+within	POS	O
+2	POS	O
+days	POS	O
+after	POS	O
+adequate	POS	O
+management	POS	O
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+hyperammonemic	POS	B-NP
+encephalopathy	POS	I-NP
+can	POS	O
+occur	POS	O
+in	POS	O
+patients	POS	O
+receiving	POS	O
+continuous	POS	O
+infusion	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+.	POS	O
+Azotemia	POS	B-NP
+,	POS	O
+body	POS	B-NP
+fluid	POS	I-NP
+insufficiency	POS	I-NP
+and	POS	O
+bacterial	POS	B-NP
+infections	POS	I-NP
+were	POS	O
+frequently	POS	O
+found	POS	O
+in	POS	O
+these	POS	O
+patients	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+therefore	POS	O
+important	POS	O
+to	POS	O
+recognize	POS	O
+this	POS	O
+condition	POS	O
+in	POS	O
+patients	POS	O
+receiving	POS	O
+continuous	POS	O
+infusion	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+quinine	POS	O
+and	POS	O
+4	POS	O
+-	POS	O
+aminopyridine	POS	O
+on	POS	O
+conditioned	POS	O
+place	POS	O
+preference	POS	O
+and	POS	O
+changes	POS	O
+in	POS	O
+motor	POS	O
+activity	POS	O
+induced	POS	O
+by	POS	O
+morphine	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+1	POS	O
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+two	POS	O
+unselective	POS	O
+potassium	POS	O
+(	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+)	POS	O
+channel	POS	O
+blockers	POS	O
+,	POS	O
+quinine	POS	O
+(	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+,	POS	O
+25	POS	O
+and	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+and	POS	O
+4	POS	O
+-	POS	O
+aminopyridine	POS	O
+(	POS	O
+1	POS	O
+and	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+,	POS	O
+on	POS	O
+conditioned	POS	O
+place	POS	O
+preference	POS	O
+and	POS	O
+biphasic	POS	O
+changes	POS	O
+in	POS	O
+motor	POS	O
+activity	POS	O
+induced	POS	O
+by	POS	O
+morphine	POS	O
+(	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+were	POS	O
+tested	POS	O
+in	POS	O
+Wistar	POS	O
+rats	POS	O
+.	POS	O
+Quinine	POS	O
+is	POS	O
+known	POS	O
+to	POS	O
+block	POS	O
+voltage	POS	O
+-	POS	O
+,	POS	O
+calcium	POS	O
+-	POS	O
+and	POS	O
+ATP	POS	O
+-	POS	O
+sensitive	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+channels	POS	O
+while	POS	O
+4	POS	O
+-	POS	O
+aminopyridine	POS	O
+is	POS	O
+known	POS	O
+to	POS	O
+block	POS	O
+voltage	POS	O
+-	POS	O
+sensitive	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+channels	POS	O
+.	POS	O
+2	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+counterbalanced	POS	O
+method	POS	O
+,	POS	O
+quinine	POS	O
+attenuated	POS	O
+morphine	POS	O
+-	POS	O
+induced	POS	O
+place	POS	O
+preference	POS	O
+,	POS	O
+whereas	POS	O
+4	POS	O
+-	POS	O
+aminopyridine	POS	O
+was	POS	O
+ineffective	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+motor	POS	O
+activity	POS	O
+test	POS	O
+measured	POS	O
+with	POS	O
+an	POS	O
+Animex	POS	O
+-	POS	O
+activity	POS	O
+meter	POS	O
+neither	POS	O
+of	POS	O
+the	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+channel	POS	O
+blockers	POS	O
+affected	POS	O
+morphine	POS	O
+-	POS	O
+induced	POS	O
+hypoactivity	POS	O
+,	POS	O
+but	POS	O
+both	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+channel	POS	O
+blockers	POS	O
+prevented	POS	O
+morphine	POS	O
+-	POS	O
+induced	POS	O
+secondary	POS	O
+hyperactivity	POS	B-NP
+.	POS	O
+3	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+the	POS	O
+involvement	POS	O
+of	POS	O
+quinine	POS	O
+-	POS	O
+sensitive	POS	O
+but	POS	O
+not	POS	O
+4	POS	O
+-	POS	O
+aminopyridine	POS	O
+-	POS	O
+sensitive	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+channels	POS	O
+in	POS	O
+morphine	POS	O
+reward	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+also	POS	O
+suggested	POS	O
+that	POS	O
+the	POS	O
+blockade	POS	O
+of	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+channels	POS	O
+sensitive	POS	O
+to	POS	O
+these	POS	O
+blockers	POS	O
+is	POS	O
+not	POS	O
+sufficient	POS	O
+to	POS	O
+prevent	POS	O
+morphine	POS	O
+-	POS	O
+induced	POS	O
+hypoactivity	POS	O
+whereas	POS	O
+morphine	POS	O
+-	POS	O
+induced	POS	O
+hyperactivity	POS	B-NP
+seems	POS	O
+to	POS	O
+be	POS	O
+connected	POS	O
+to	POS	O
+both	POS	O
+quinine	POS	O
+-	POS	O
+and	POS	O
+4	POS	O
+-	POS	O
+aminopyridine	POS	O
+-	POS	O
+sensitive	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+channels	POS	O
+.	POS	O
+Nociceptin	POS	O
+/	POS	O
+orphanin	POS	O
+FQ	POS	O
+and	POS	O
+nocistatin	POS	O
+on	POS	O
+learning	POS	O
+and	POS	O
+memory	POS	B-NP
+impairment	POS	I-NP
+induced	POS	O
+by	POS	O
+scopolamine	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+1	POS	O
+.	POS	O
+Nociceptin	POS	O
+,	POS	O
+also	POS	O
+known	POS	O
+as	POS	O
+orphanin	POS	O
+FQ	POS	O
+,	POS	O
+is	POS	O
+an	POS	O
+endogenous	POS	O
+ligand	POS	O
+for	POS	O
+the	POS	O
+orphan	POS	O
+opioid	POS	O
+receptor	POS	O
+-	POS	O
+like	POS	O
+receptor	POS	O
+1	POS	O
+(	POS	O
+ORL1	POS	O
+)	POS	O
+and	POS	O
+involves	POS	O
+in	POS	O
+various	POS	O
+functions	POS	O
+in	POS	O
+the	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+(	POS	O
+CNS	POS	O
+)	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+other	POS	O
+hand	POS	O
+,	POS	O
+nocistatin	POS	O
+is	POS	O
+recently	POS	O
+isolated	POS	O
+from	POS	O
+the	POS	O
+same	POS	O
+precursor	POS	O
+as	POS	O
+nociceptin	POS	O
+and	POS	O
+blocks	POS	O
+nociceptin	POS	O
+-	POS	O
+induced	POS	O
+allodynia	POS	B-NP
+and	POS	O
+hyperalgesia	POS	B-NP
+.	POS	O
+2	POS	O
+.	POS	O
+Although	POS	O
+ORL1	POS	O
+receptors	POS	O
+which	POS	O
+display	POS	O
+a	POS	O
+high	POS	O
+degree	POS	O
+of	POS	O
+sequence	POS	O
+homology	POS	O
+with	POS	O
+classical	POS	O
+opioid	POS	O
+receptors	POS	O
+are	POS	O
+abundant	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+,	POS	O
+little	POS	O
+is	POS	O
+known	POS	O
+regarding	POS	O
+their	POS	O
+role	POS	O
+in	POS	O
+learning	POS	O
+and	POS	O
+memory	POS	O
+.	POS	O
+3	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+designed	POS	O
+to	POS	O
+investigate	POS	O
+whether	POS	O
+nociceptin	POS	O
+/	POS	O
+orphanin	POS	O
+FQ	POS	O
+and	POS	O
+nocistatin	POS	O
+could	POS	O
+modulate	POS	O
+impairment	POS	O
+of	POS	O
+learning	POS	O
+and	POS	O
+memory	POS	O
+induced	POS	O
+by	POS	O
+scopolamine	POS	O
+,	POS	O
+a	POS	O
+muscarinic	POS	O
+cholinergic	POS	O
+receptor	POS	O
+antagonist	POS	O
+,	POS	O
+using	POS	O
+spontaneous	POS	O
+alternation	POS	O
+of	POS	O
+Y	POS	O
+-	POS	O
+maze	POS	O
+and	POS	O
+step	POS	O
+-	POS	O
+down	POS	O
+type	POS	O
+passive	POS	O
+avoidance	POS	O
+tasks	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+4	POS	O
+.	POS	O
+While	POS	O
+nocistatin	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+5	POS	O
+.	POS	O
+0	POS	O
+nmol	POS	O
+mouse	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+)	POS	O
+administered	POS	O
+30	POS	O
+min	POS	O
+before	POS	O
+spontaneous	POS	O
+alternation	POS	O
+performance	POS	O
+or	POS	O
+the	POS	O
+training	POS	O
+session	POS	O
+of	POS	O
+the	POS	O
+passive	POS	O
+avoidance	POS	O
+task	POS	O
+,	POS	O
+had	POS	O
+no	POS	O
+effect	POS	O
+on	POS	O
+spontaneous	POS	O
+alternation	POS	O
+or	POS	O
+passive	POS	O
+avoidance	POS	O
+behaviours	POS	O
+,	POS	O
+a	POS	O
+lower	POS	O
+per	POS	O
+cent	POS	O
+alternation	POS	O
+and	POS	O
+shorter	POS	O
+median	POS	O
+step	POS	O
+-	POS	O
+down	POS	O
+latency	POS	O
+in	POS	O
+the	POS	O
+retention	POS	O
+test	POS	O
+were	POS	O
+obtained	POS	O
+in	POS	O
+nociceptin	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+and	POS	O
+/	POS	O
+or	POS	O
+5	POS	O
+.	POS	O
+0	POS	O
+nmol	POS	O
+mouse	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+)	POS	O
+-	POS	O
+treated	POS	O
+normal	POS	O
+mice	POS	O
+.	POS	O
+5	POS	O
+.	POS	O
+Administration	POS	O
+of	POS	O
+nocistatin	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+and	POS	O
+/	POS	O
+or	POS	O
+5	POS	O
+.	POS	O
+0	POS	O
+nmol	POS	O
+mouse	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+)	POS	O
+30	POS	O
+min	POS	O
+before	POS	O
+spontaneous	POS	O
+alternation	POS	O
+performance	POS	O
+or	POS	O
+the	POS	O
+training	POS	O
+session	POS	O
+of	POS	O
+the	POS	O
+passive	POS	O
+avoidance	POS	O
+task	POS	O
+,	POS	O
+attenuated	POS	O
+the	POS	O
+scopolamine	POS	O
+-	POS	O
+induced	POS	O
+impairment	POS	O
+of	POS	O
+spontaneous	POS	O
+alternation	POS	O
+and	POS	O
+passive	POS	O
+avoidance	POS	O
+behaviours	POS	O
+.	POS	O
+6	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+indicated	POS	O
+that	POS	O
+nocistatin	POS	O
+,	POS	O
+a	POS	O
+new	POS	O
+biologically	POS	O
+active	POS	O
+peptide	POS	O
+,	POS	O
+ameliorates	POS	O
+impairments	POS	O
+of	POS	O
+spontaneous	POS	O
+alternation	POS	O
+and	POS	O
+passive	POS	O
+avoidance	POS	O
+induced	POS	O
+by	POS	O
+scopolamine	POS	O
+,	POS	O
+and	POS	O
+suggested	POS	O
+that	POS	O
+these	POS	O
+peptides	POS	O
+play	POS	O
+opposite	POS	O
+roles	POS	O
+in	POS	O
+learning	POS	O
+and	POS	O
+memory	POS	O
+.	POS	O
+Meloxicam	POS	O
+-	POS	O
+induced	POS	O
+liver	POS	B-NP
+toxicity	POS	I-NP
+.	POS	O
+We	POS	O
+report	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+female	POS	O
+patient	POS	O
+with	POS	O
+rheumatoid	POS	B-NP
+arthritis	POS	I-NP
+who	POS	O
+developed	POS	O
+acute	POS	B-NP
+cytolytic	POS	I-NP
+hepatitis	POS	I-NP
+due	POS	O
+to	POS	O
+meloxicam	POS	O
+.	POS	O
+Recently	POS	O
+introduced	POS	O
+in	POS	O
+Belgium	POS	O
+,	POS	O
+meloxicam	POS	O
+is	POS	O
+the	POS	O
+first	POS	O
+nonsteroidal	POS	O
+antiinflammatory	POS	O
+drug	POS	O
+with	POS	O
+selective	POS	O
+action	POS	O
+on	POS	O
+the	POS	O
+inducible	POS	O
+form	POS	O
+of	POS	O
+cyclooxygenase	POS	O
+2	POS	O
+.	POS	O
+The	POS	O
+acute	POS	O
+cytolytic	POS	B-NP
+hepatitis	POS	I-NP
+occurred	POS	O
+rapidly	POS	O
+after	POS	O
+meloxicam	POS	O
+administration	POS	O
+and	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+antinuclear	POS	O
+antibodies	POS	O
+suggesting	POS	O
+a	POS	O
+hypersensitivity	POS	B-NP
+mechanism	POS	O
+.	POS	O
+This	POS	O
+first	POS	O
+case	POS	O
+of	POS	O
+meloxicam	POS	O
+related	POS	O
+liver	POS	B-NP
+toxicity	POS	I-NP
+demonstrates	POS	O
+the	POS	O
+potential	POS	O
+of	POS	O
+this	POS	O
+drug	POS	O
+to	POS	O
+induce	POS	O
+hepatic	POS	B-NP
+damage	POS	I-NP
+.	POS	O
+Induction	POS	O
+of	POS	O
+apoptosis	POS	O
+by	POS	O
+remoxipride	POS	O
+metabolites	POS	O
+in	POS	O
+HL60	POS	O
+and	POS	O
+CD34	POS	O
++	POS	O
+/	POS	O
+CD19	POS	O
+-	POS	O
+human	POS	O
+bone	POS	O
+marrow	POS	O
+progenitor	POS	O
+cells	POS	O
+:	POS	O
+potential	POS	O
+relevance	POS	O
+to	POS	O
+remoxipride	POS	O
+-	POS	O
+induced	POS	O
+aplastic	POS	B-NP
+anemia	POS	I-NP
+.	POS	O
+The	POS	O
+antipsychotic	POS	O
+agent	POS	O
+,	POS	O
+remoxipride	POS	O
+[	POS	O
+(	POS	O
+S	POS	O
+)	POS	O
+-	POS	O
+(	POS	O
+-	POS	O
+)	POS	O
+-	POS	O
+3	POS	O
+-	POS	O
+bromo	POS	O
+-	POS	O
+N	POS	O
+-	POS	O
+[	POS	O
+(	POS	O
+1	POS	O
+-	POS	O
+ethyl	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+pyrrolidinyl	POS	O
+)	POS	O
+methyl	POS	O
+]	POS	O
+-	POS	O
+2	POS	O
+,	POS	O
+6	POS	O
+-	POS	O
+dimethoxybenz	POS	O
+amide	POS	O
+]	POS	O
+has	POS	O
+been	POS	O
+associated	POS	O
+with	POS	O
+acquired	POS	O
+aplastic	POS	B-NP
+anemia	POS	I-NP
+.	POS	O
+We	POS	O
+have	POS	O
+examined	POS	O
+the	POS	O
+ability	POS	O
+of	POS	O
+remoxipride	POS	O
+,	POS	O
+three	POS	O
+pyrrolidine	POS	O
+ring	POS	O
+metabolites	POS	O
+and	POS	O
+five	POS	O
+aromatic	POS	O
+ring	POS	O
+metabolites	POS	O
+of	POS	O
+the	POS	O
+parent	POS	O
+compound	POS	O
+to	POS	O
+induce	POS	O
+apoptosis	POS	O
+in	POS	O
+HL60	POS	O
+cells	POS	O
+and	POS	O
+human	POS	O
+bone	POS	O
+marrow	POS	O
+progenitor	POS	O
+(	POS	O
+HBMP	POS	O
+)	POS	O
+cells	POS	O
+.	POS	O
+Cells	POS	O
+were	POS	O
+treated	POS	O
+for	POS	O
+0	POS	O
+-	POS	O
+24	POS	O
+h	POS	O
+with	POS	O
+each	POS	O
+compound	POS	O
+(	POS	O
+0	POS	O
+-	POS	O
+200	POS	O
+microM	POS	O
+)	POS	O
+.	POS	O
+Apoptosis	POS	O
+was	POS	O
+assessed	POS	O
+by	POS	O
+fluorescence	POS	O
+microscopy	POS	O
+in	POS	O
+Hoechst	POS	O
+33342	POS	O
+-	POS	O
+and	POS	O
+propidium	POS	O
+iodide	POS	O
+stained	POS	O
+cell	POS	O
+samples	POS	O
+.	POS	O
+Results	POS	O
+were	POS	O
+confirmed	POS	O
+by	POS	O
+determination	POS	O
+of	POS	O
+internucleosomal	POS	O
+DNA	POS	O
+fragmentation	POS	O
+using	POS	O
+gel	POS	O
+electrophoresis	POS	O
+for	POS	O
+HL60	POS	O
+cell	POS	O
+samples	POS	O
+and	POS	O
+terminal	POS	O
+deoxynucleotidyl	POS	O
+transferase	POS	O
+assay	POS	O
+in	POS	O
+HBMP	POS	O
+cells	POS	O
+.	POS	O
+The	POS	O
+catechol	POS	O
+and	POS	O
+hydroquinone	POS	O
+metabolites	POS	O
+,	POS	O
+NCQ436	POS	O
+and	POS	O
+NCQ344	POS	O
+,	POS	O
+induced	POS	O
+apoptosis	POS	O
+in	POS	O
+HL60	POS	O
+and	POS	O
+HBMP	POS	O
+cells	POS	O
+in	POS	O
+a	POS	O
+time	POS	O
+-	POS	O
+and	POS	O
+concentration	POS	O
+dependent	POS	O
+manner	POS	O
+,	POS	O
+while	POS	O
+the	POS	O
+phenols	POS	O
+,	POS	O
+NCR181	POS	O
+,	POS	O
+FLA873	POS	O
+,	POS	O
+and	POS	O
+FLA797	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+derivatives	POS	O
+formed	POS	O
+by	POS	O
+oxidation	POS	O
+of	POS	O
+the	POS	O
+pyrrolidine	POS	O
+ring	POS	O
+,	POS	O
+FLA838	POS	O
+,	POS	O
+NCM001	POS	O
+,	POS	O
+and	POS	O
+NCL118	POS	O
+,	POS	O
+had	POS	O
+no	POS	O
+effect	POS	O
+.	POS	O
+No	POS	O
+necrosis	POS	B-NP
+was	POS	O
+observed	POS	O
+in	POS	O
+cells	POS	O
+treated	POS	O
+with	POS	O
+NCQ436	POS	O
+but	POS	O
+NCQ344	POS	O
+had	POS	O
+a	POS	O
+biphasic	POS	O
+effect	POS	O
+in	POS	O
+both	POS	O
+cell	POS	O
+types	POS	O
+,	POS	O
+inducing	POS	O
+apoptosis	POS	O
+at	POS	O
+lower	POS	O
+concentrations	POS	O
+and	POS	O
+necrosis	POS	B-NP
+at	POS	O
+higher	POS	O
+concentrations	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+show	POS	O
+that	POS	O
+the	POS	O
+catechol	POS	O
+and	POS	O
+hydroquinone	POS	O
+metabolites	POS	O
+of	POS	O
+remoxipride	POS	O
+have	POS	O
+direct	POS	O
+toxic	POS	O
+effects	POS	O
+in	POS	O
+HL60	POS	O
+and	POS	O
+HBMP	POS	O
+cells	POS	O
+,	POS	O
+leading	POS	O
+to	POS	O
+apoptosis	POS	O
+,	POS	O
+while	POS	O
+the	POS	O
+phenol	POS	O
+metabolites	POS	O
+were	POS	O
+inactive	POS	O
+.	POS	O
+Similarly	POS	O
+,	POS	O
+benzene	POS	O
+-	POS	O
+derived	POS	O
+catechol	POS	O
+and	POS	O
+hydroquinone	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+phenol	POS	O
+,	POS	O
+induce	POS	O
+apoptosis	POS	O
+in	POS	O
+HBMP	POS	O
+cells	POS	O
+[	POS	O
+Moran	POS	O
+et	POS	O
+al	POS	O
+.	POS	O
+,	POS	O
+Mol	POS	O
+.	POS	O
+Pharmacol	POS	O
+.	POS	O
+,	POS	O
+50	POS	O
+(	POS	O
+1996	POS	O
+)	POS	O
+610	POS	O
+-	POS	O
+615	POS	O
+]	POS	O
+.	POS	O
+We	POS	O
+propose	POS	O
+that	POS	O
+remoxipride	POS	O
+and	POS	O
+benzene	POS	O
+may	POS	O
+induce	POS	O
+aplastic	POS	B-NP
+anemia	POS	I-NP
+via	POS	O
+production	POS	O
+of	POS	O
+similar	POS	O
+reactive	POS	O
+metabolites	POS	O
+and	POS	O
+that	POS	O
+the	POS	O
+ability	POS	O
+of	POS	O
+NCQ436	POS	O
+and	POS	O
+NCQ344	POS	O
+to	POS	O
+induce	POS	O
+apoptosis	POS	O
+in	POS	O
+HBMP	POS	O
+cells	POS	O
+may	POS	O
+contribute	POS	O
+to	POS	O
+the	POS	O
+mechanism	POS	O
+underlying	POS	O
+acquired	POS	O
+aplastic	POS	B-NP
+anemia	POS	I-NP
+that	POS	O
+has	POS	O
+been	POS	O
+associated	POS	O
+with	POS	O
+remoxipride	POS	O
+.	POS	O
+Synthesis	POS	O
+and	POS	O
+preliminary	POS	O
+pharmacological	POS	O
+investigations	POS	O
+of	POS	O
+1	POS	O
+-	POS	O
+(	POS	O
+1	POS	O
+,	POS	O
+2	POS	O
+-	POS	O
+dihydro	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+acenaphthylenyl	POS	O
+)	POS	O
+piperazine	POS	O
+derivatives	POS	O
+as	POS	O
+potential	POS	O
+atypical	POS	O
+antipsychotic	POS	O
+agents	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+In	POS	O
+research	POS	O
+towards	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+new	POS	O
+atypical	POS	O
+antipsychotic	POS	O
+agents	POS	O
+,	POS	O
+one	POS	O
+strategy	POS	O
+is	POS	O
+that	POS	O
+the	POS	O
+dopaminergic	POS	O
+system	POS	O
+can	POS	O
+be	POS	O
+modulated	POS	O
+through	POS	O
+manipulation	POS	O
+of	POS	O
+the	POS	O
+serotonergic	POS	O
+system	POS	O
+.	POS	O
+The	POS	O
+synthesis	POS	O
+and	POS	O
+preliminary	POS	O
+pharmacological	POS	O
+evaluation	POS	O
+of	POS	O
+a	POS	O
+series	POS	O
+of	POS	O
+potential	POS	O
+atypical	POS	O
+antipsychotic	POS	O
+agents	POS	O
+based	POS	O
+on	POS	O
+the	POS	O
+structure	POS	O
+of	POS	O
+1	POS	O
+-	POS	O
+(	POS	O
+1	POS	O
+,	POS	O
+2	POS	O
+-	POS	O
+dihydro	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+acenaphthylenyl	POS	O
+)	POS	O
+piperazine	POS	O
+(	POS	O
+7	POS	O
+)	POS	O
+is	POS	O
+described	POS	O
+.	POS	O
+Compound	POS	O
+7e	POS	O
+,	POS	O
+5	POS	O
+-	POS	O
+{	POS	O
+2	POS	O
+-	POS	O
+[	POS	O
+4	POS	O
+-	POS	O
+(	POS	O
+1	POS	O
+,	POS	O
+2	POS	O
+-	POS	O
+dihydro	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+acenaphthylenyl	POS	O
+)	POS	O
+piperazinyl	POS	O
+]	POS	O
+ethyl	POS	O
+}	POS	O
+-	POS	O
+2	POS	O
+,	POS	O
+3	POS	O
+-	POS	O
+dihy	POS	O
+dro	POS	O
+-	POS	O
+1H	POS	O
+-	POS	O
+indol	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+one	POS	O
+,	POS	O
+from	POS	O
+this	POS	O
+series	POS	O
+showed	POS	O
+significant	POS	O
+affinities	POS	O
+at	POS	O
+the	POS	O
+5	POS	O
+-	POS	O
+HT1A	POS	O
+and	POS	O
+5	POS	O
+-	POS	O
+HT2A	POS	O
+receptors	POS	O
+and	POS	O
+moderate	POS	O
+affinity	POS	O
+at	POS	O
+the	POS	O
+D2	POS	O
+receptor	POS	O
+.	POS	O
+7e	POS	O
+exhibits	POS	O
+a	POS	O
+high	POS	O
+reversal	POS	O
+of	POS	O
+catalepsy	POS	B-NP
+induced	POS	O
+by	POS	O
+haloperidol	POS	O
+indicating	POS	O
+its	POS	O
+atypical	POS	O
+antipsychotic	POS	O
+nature	POS	O
+.	POS	O
+Sub	POS	O
+-	POS	O
+chronic	POS	O
+inhibition	POS	O
+of	POS	O
+nitric	POS	O
+-	POS	O
+oxide	POS	O
+synthesis	POS	O
+modifies	POS	O
+haloperidol	POS	O
+-	POS	O
+induced	POS	O
+catalepsy	POS	B-NP
+and	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+NADPH	POS	O
+-	POS	O
+diaphorase	POS	O
+neurons	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+RATIONALE	POS	O
+:	POS	O
+NG	POS	O
+-	POS	O
+nitro	POS	O
+-	POS	O
+L	POS	O
+-	POS	O
+arginine	POS	O
+(	POS	O
+L	POS	O
+-	POS	O
+NOARG	POS	O
+)	POS	O
+,	POS	O
+an	POS	O
+inhibitor	POS	O
+of	POS	O
+nitric	POS	O
+-	POS	O
+oxide	POS	O
+synthase	POS	O
+(	POS	O
+NOS	POS	O
+)	POS	O
+,	POS	O
+induces	POS	O
+catalepsy	POS	B-NP
+in	POS	O
+mice	POS	O
+.	POS	O
+This	POS	O
+effect	POS	O
+undergoes	POS	O
+rapid	POS	O
+tolerance	POS	O
+,	POS	O
+showing	POS	O
+a	POS	O
+significant	POS	O
+decrease	POS	O
+after	POS	O
+2	POS	O
+days	POS	O
+of	POS	O
+sub	POS	O
+-	POS	O
+chronic	POS	O
+L	POS	O
+-	POS	O
+NOARG	POS	O
+treatment	POS	O
+.	POS	O
+Nitric	POS	O
+oxide	POS	O
+(	POS	O
+NO	POS	O
+)	POS	O
+has	POS	O
+been	POS	O
+shown	POS	O
+to	POS	O
+influence	POS	O
+dopaminergic	POS	O
+neurotransmission	POS	O
+in	POS	O
+the	POS	O
+striatum	POS	O
+.	POS	O
+Neuroleptic	POS	B-NP
+drugs	POS	O
+such	POS	O
+as	POS	O
+haloperidol	POS	O
+,	POS	O
+which	POS	O
+block	POS	O
+dopamine	POS	O
+receptors	POS	O
+,	POS	O
+also	POS	O
+cause	POS	O
+catalepsy	POS	B-NP
+in	POS	O
+rodents	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+To	POS	O
+investigate	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+subchronic	POS	O
+L	POS	O
+-	POS	O
+NOARG	POS	O
+treatment	POS	O
+in	POS	O
+haloperidol	POS	O
+-	POS	O
+induced	POS	O
+catalepsy	POS	B-NP
+and	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+NOS	POS	O
+neurons	POS	O
+in	POS	O
+areas	POS	O
+related	POS	O
+to	POS	O
+motor	POS	O
+control	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Male	POS	O
+albino	POS	O
+Swiss	POS	O
+mice	POS	O
+were	POS	O
+treated	POS	O
+sub	POS	O
+-	POS	O
+chronically	POS	O
+(	POS	O
+twice	POS	O
+a	POS	O
+day	POS	O
+for	POS	O
+4	POS	O
+days	POS	O
+)	POS	O
+with	POS	O
+L	POS	O
+-	POS	O
+NOARG	POS	O
+(	POS	O
+40	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+or	POS	O
+haloperidol	POS	O
+(	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+.	POS	O
+Catalepsy	POS	B-NP
+was	POS	O
+evaluated	POS	O
+at	POS	O
+the	POS	O
+beginning	POS	O
+and	POS	O
+the	POS	O
+end	POS	O
+of	POS	O
+the	POS	O
+treatments	POS	O
+.	POS	O
+Reduced	POS	O
+nicotinamide	POS	O
+adenine	POS	O
+dinucleotide	POS	O
+phosphate	POS	O
+-	POS	O
+diaphorase	POS	O
+(	POS	O
+NADPH	POS	O
+-	POS	O
+d	POS	O
+)	POS	O
+histochemistry	POS	O
+was	POS	O
+also	POS	O
+employed	POS	O
+to	POS	O
+visualize	POS	O
+NOS	POS	O
+as	POS	O
+an	POS	O
+index	POS	O
+of	POS	O
+enzyme	POS	O
+expression	POS	O
+in	POS	O
+mice	POS	O
+brain	POS	O
+regions	POS	O
+related	POS	O
+to	POS	O
+motor	POS	O
+control	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+L	POS	O
+-	POS	O
+NOARG	POS	O
+sub	POS	O
+-	POS	O
+chronic	POS	O
+administration	POS	O
+produced	POS	O
+tolerance	POS	O
+of	POS	O
+L	POS	O
+-	POS	O
+NOARG	POS	O
+and	POS	O
+of	POS	O
+haloperidol	POS	O
+-	POS	O
+induced	POS	O
+catalepsy	POS	B-NP
+.	POS	O
+It	POS	O
+also	POS	O
+induced	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+NADPH	POS	O
+-	POS	O
+d	POS	O
+-	POS	O
+positive	POS	O
+cells	POS	O
+in	POS	O
+the	POS	O
+dorsal	POS	O
+part	POS	O
+of	POS	O
+the	POS	O
+caudate	POS	O
+and	POS	O
+accumbens	POS	O
+nuclei	POS	O
+compared	POS	O
+with	POS	O
+haloperidol	POS	O
+and	POS	O
+in	POS	O
+the	POS	O
+pedunculopontine	POS	O
+tegmental	POS	O
+nucleus	POS	O
+compared	POS	O
+with	POS	O
+saline	POS	O
+.	POS	O
+In	POS	O
+contrast	POS	O
+,	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+NADPH	POS	O
+-	POS	O
+d	POS	O
+neuron	POS	O
+number	POS	O
+in	POS	O
+the	POS	O
+substantia	POS	O
+nigra	POS	O
+,	POS	O
+pars	POS	O
+compacta	POS	O
+in	POS	O
+both	POS	O
+haloperidol	POS	O
+-	POS	O
+treated	POS	O
+and	POS	O
+L	POS	O
+-	POS	O
+NOARG	POS	O
+-	POS	O
+treated	POS	O
+animals	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+results	POS	O
+give	POS	O
+further	POS	O
+support	POS	O
+to	POS	O
+the	POS	O
+hypothesis	POS	O
+that	POS	O
+NO	POS	O
+plays	POS	O
+a	POS	O
+role	POS	O
+in	POS	O
+motor	POS	O
+behavior	POS	O
+control	POS	O
+and	POS	O
+suggest	POS	O
+that	POS	O
+it	POS	O
+may	POS	O
+take	POS	O
+part	POS	O
+in	POS	O
+the	POS	O
+synaptic	POS	O
+changes	POS	O
+produced	POS	O
+by	POS	O
+antipsychotic	POS	O
+treatment	POS	O
+.	POS	O
+Prolonged	POS	O
+left	POS	O
+ventricular	POS	B-NP
+dysfunction	POS	I-NP
+occurs	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+after	POS	O
+both	POS	O
+dobutamine	POS	O
+and	POS	O
+exercise	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+ischaemia	POS	I-NP
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+determine	POS	O
+whether	POS	O
+pharmacological	POS	O
+stress	POS	O
+leads	POS	O
+to	POS	O
+prolonged	POS	O
+but	POS	O
+reversible	POS	O
+left	POS	O
+ventricular	POS	B-NP
+dysfunction	POS	I-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+,	POS	O
+similar	POS	O
+to	POS	O
+that	POS	O
+seen	POS	O
+after	POS	O
+exercise	POS	O
+.	POS	O
+DESIGN	POS	O
+:	POS	O
+A	POS	O
+randomised	POS	O
+crossover	POS	O
+study	POS	O
+of	POS	O
+recovery	POS	O
+time	POS	O
+of	POS	O
+systolic	POS	O
+and	POS	O
+diastolic	POS	O
+left	POS	O
+ventricular	POS	O
+function	POS	O
+after	POS	O
+exercise	POS	O
+and	POS	O
+dobutamine	POS	O
+induced	POS	O
+ischaemia	POS	B-NP
+.	POS	O
+SUBJECTS	POS	O
+:	POS	O
+10	POS	O
+patients	POS	O
+with	POS	O
+stable	POS	O
+angina	POS	B-NP
+,	POS	O
+angiographically	POS	B-NP
+proven	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+,	POS	O
+and	POS	O
+normal	POS	B-NP
+left	POS	I-NP
+ventricular	POS	I-NP
+function	POS	I-NP
+.	POS	O
+INTERVENTIONS	POS	O
+:	POS	O
+Treadmill	POS	O
+exercise	POS	O
+and	POS	O
+dobutamine	POS	O
+stress	POS	O
+were	POS	O
+performed	POS	O
+on	POS	O
+different	POS	O
+days	POS	O
+.	POS	O
+Quantitative	POS	O
+assessment	POS	O
+of	POS	O
+systolic	POS	O
+and	POS	O
+diastolic	POS	O
+left	POS	O
+ventricular	POS	O
+function	POS	O
+was	POS	O
+performed	POS	O
+using	POS	O
+transthoracic	POS	O
+echocardiography	POS	O
+at	POS	O
+baseline	POS	O
+and	POS	O
+at	POS	O
+regular	POS	O
+intervals	POS	O
+after	POS	O
+each	POS	O
+test	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Both	POS	O
+forms	POS	O
+of	POS	O
+stress	POS	O
+led	POS	O
+to	POS	O
+prolonged	POS	O
+but	POS	O
+reversible	POS	O
+systolic	POS	O
+and	POS	O
+diastolic	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+difference	POS	O
+in	POS	O
+the	POS	O
+maximum	POS	O
+double	POS	O
+product	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+53	POS	O
+)	POS	O
+or	POS	O
+ST	POS	B-NP
+depression	POS	I-NP
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+63	POS	O
+)	POS	O
+with	POS	O
+either	POS	O
+form	POS	O
+of	POS	O
+stress	POS	O
+.	POS	O
+After	POS	O
+exercise	POS	O
+,	POS	O
+ejection	POS	O
+fraction	POS	O
+was	POS	O
+reduced	POS	O
+at	POS	O
+15	POS	O
+and	POS	O
+30	POS	O
+minutes	POS	O
+compared	POS	O
+with	POS	O
+baseline	POS	O
+(	POS	O
+mean	POS	O
+(	POS	O
+SEM	POS	O
+)	POS	O
+,	POS	O
+-	POS	O
+5	POS	O
+.	POS	O
+6	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+)	POS	O
+%	POS	O
+,	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+;	POS	O
+and	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+1	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+2	POS	O
+)	POS	O
+%	POS	O
+,	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+at	POS	O
+30	POS	O
+and	POS	O
+45	POS	O
+minutes	POS	O
+after	POS	O
+dobutamine	POS	O
+(	POS	O
+-	POS	O
+10	POS	O
+.	POS	O
+8	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+8	POS	O
+)	POS	O
+%	POS	O
+and	POS	O
+-	POS	O
+5	POS	O
+.	POS	O
+5	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+8	POS	O
+)	POS	O
+%	POS	O
+,	POS	O
+both	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+Regional	POS	O
+analysis	POS	O
+showed	POS	O
+a	POS	O
+reduction	POS	O
+in	POS	O
+the	POS	O
+worst	POS	O
+affected	POS	O
+segment	POS	O
+15	POS	O
+and	POS	O
+30	POS	O
+minutes	POS	O
+after	POS	O
+exercise	POS	O
+(	POS	O
+-	POS	O
+27	POS	O
+.	POS	O
+9	POS	O
+(	POS	O
+7	POS	O
+.	POS	O
+2	POS	O
+)	POS	O
+%	POS	O
+and	POS	O
+-	POS	O
+28	POS	O
+.	POS	O
+6	POS	O
+(	POS	O
+5	POS	O
+.	POS	O
+7	POS	O
+)	POS	O
+%	POS	O
+,	POS	O
+both	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+at	POS	O
+30	POS	O
+minutes	POS	O
+after	POS	O
+dobutamine	POS	O
+(	POS	O
+-	POS	O
+32	POS	O
+(	POS	O
+5	POS	O
+.	POS	O
+3	POS	O
+)	POS	O
+%	POS	O
+,	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+isovolumic	POS	O
+relaxation	POS	O
+period	POS	O
+was	POS	O
+prolonged	POS	O
+45	POS	O
+minutes	POS	O
+after	POS	O
+each	POS	O
+form	POS	O
+of	POS	O
+stress	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+In	POS	O
+patients	POS	O
+with	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+,	POS	O
+dobutamine	POS	O
+induced	POS	O
+ischaemia	POS	B-NP
+results	POS	O
+in	POS	O
+prolonged	POS	O
+reversible	POS	O
+left	POS	O
+ventricular	POS	B-NP
+dysfunction	POS	I-NP
+,	POS	O
+presumed	POS	O
+to	POS	O
+be	POS	O
+myocardial	POS	B-NP
+stunning	POS	I-NP
+,	POS	O
+similar	POS	O
+to	POS	O
+that	POS	O
+seen	POS	O
+after	POS	O
+exercise	POS	O
+.	POS	O
+Dobutamine	POS	O
+induced	POS	O
+ischaemia	POS	B-NP
+could	POS	O
+therefore	POS	O
+be	POS	O
+used	POS	O
+to	POS	O
+study	POS	O
+the	POS	O
+pathophysiology	POS	O
+of	POS	O
+this	POS	O
+phenomenon	POS	O
+further	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+Anorexigens	POS	O
+and	POS	O
+pulmonary	POS	B-NP
+hypertension	POS	I-NP
+in	POS	O
+the	POS	O
+United	POS	O
+States	POS	O
+:	POS	O
+results	POS	O
+from	POS	O
+the	POS	O
+surveillance	POS	O
+of	POS	O
+North	POS	O
+American	POS	O
+pulmonary	POS	B-NP
+hypertension	POS	I-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+The	POS	O
+use	POS	O
+of	POS	O
+appetite	POS	O
+suppressants	POS	O
+in	POS	O
+Europe	POS	O
+has	POS	O
+been	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+primary	POS	O
+pulmonary	POS	B-NP
+hypertension	POS	I-NP
+(	POS	O
+PPH	POS	B-NP
+)	POS	O
+.	POS	O
+Recently	POS	O
+,	POS	O
+fenfluramine	POS	O
+appetite	POS	O
+suppressants	POS	O
+became	POS	O
+widely	POS	O
+used	POS	O
+in	POS	O
+the	POS	O
+United	POS	O
+States	POS	O
+but	POS	O
+were	POS	O
+withdrawn	POS	O
+in	POS	O
+September	POS	O
+1997	POS	O
+because	POS	O
+of	POS	O
+concerns	POS	O
+over	POS	O
+adverse	POS	O
+effects	POS	O
+.	POS	O
+MATERIALS	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+conducted	POS	O
+a	POS	O
+prospective	POS	O
+surveillance	POS	O
+study	POS	O
+on	POS	O
+patients	POS	O
+diagnosed	POS	O
+with	POS	O
+pulmonary	POS	B-NP
+hypertension	POS	I-NP
+at	POS	O
+12	POS	O
+large	POS	O
+referral	POS	O
+centers	POS	O
+in	POS	O
+North	POS	O
+America	POS	O
+.	POS	O
+Data	POS	O
+collected	POS	O
+on	POS	O
+patients	POS	O
+seen	POS	O
+from	POS	O
+September	POS	O
+1	POS	O
+,	POS	O
+1996	POS	O
+,	POS	O
+to	POS	O
+December	POS	O
+31	POS	O
+,	POS	O
+1997	POS	O
+,	POS	O
+included	POS	O
+the	POS	O
+cause	POS	O
+of	POS	O
+the	POS	O
+pulmonary	POS	B-NP
+hypertension	POS	I-NP
+and	POS	O
+its	POS	O
+severity	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+no	POS	O
+identifiable	POS	O
+cause	POS	O
+of	POS	O
+pulmonary	POS	B-NP
+hypertension	POS	I-NP
+were	POS	O
+classed	POS	O
+as	POS	O
+PPH	POS	B-NP
+.	POS	O
+A	POS	O
+history	POS	O
+of	POS	O
+drug	POS	O
+exposure	POS	O
+also	POS	O
+was	POS	O
+taken	POS	O
+with	POS	O
+special	POS	O
+attention	POS	O
+on	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+antidepressants	POS	O
+,	POS	O
+anorexigens	POS	O
+,	POS	O
+and	POS	O
+amphetamines	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Five	POS	O
+hundred	POS	O
+seventy	POS	O
+-	POS	O
+nine	POS	O
+patients	POS	O
+were	POS	O
+studied	POS	O
+,	POS	O
+205	POS	O
+with	POS	O
+PPH	POS	B-NP
+and	POS	O
+374	POS	O
+with	POS	O
+pulmonary	POS	B-NP
+hypertension	POS	I-NP
+from	POS	O
+other	POS	O
+causes	POS	O
+(	POS	O
+secondary	POS	O
+pulmonary	POS	B-NP
+hypertension	POS	I-NP
+[	POS	O
+SPH	POS	O
+]	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+use	POS	O
+of	POS	O
+anorexigens	POS	O
+was	POS	O
+common	POS	O
+in	POS	O
+both	POS	O
+groups	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+of	POS	O
+the	POS	O
+medications	POS	O
+surveyed	POS	O
+,	POS	O
+only	POS	O
+the	POS	O
+fenfluramines	POS	O
+had	POS	O
+a	POS	O
+significant	POS	O
+preferential	POS	O
+association	POS	O
+with	POS	O
+PPH	POS	B-NP
+as	POS	O
+compared	POS	O
+with	POS	O
+SPH	POS	B-NP
+(	POS	O
+adjusted	POS	O
+odds	POS	O
+ratio	POS	O
+for	POS	O
+use	POS	O
+>	POS	O
+6	POS	O
+months	POS	O
+,	POS	O
+7	POS	O
+.	POS	O
+5	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+7	POS	O
+to	POS	O
+32	POS	O
+.	POS	O
+4	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+association	POS	O
+was	POS	O
+stronger	POS	O
+with	POS	O
+longer	POS	O
+duration	POS	O
+of	POS	O
+use	POS	O
+when	POS	O
+compared	POS	O
+to	POS	O
+shorter	POS	O
+duration	POS	O
+of	POS	O
+use	POS	O
+and	POS	O
+was	POS	O
+more	POS	O
+pronounced	POS	O
+in	POS	O
+recent	POS	O
+users	POS	O
+than	POS	O
+in	POS	O
+remote	POS	O
+users	POS	O
+.	POS	O
+An	POS	O
+unexpectedly	POS	O
+high	POS	O
+(	POS	O
+11	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+number	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+SPH	POS	B-NP
+had	POS	O
+used	POS	O
+anorexigens	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+The	POS	O
+magnitude	POS	O
+of	POS	O
+the	POS	O
+association	POS	O
+with	POS	O
+PPH	POS	B-NP
+,	POS	O
+the	POS	O
+increase	POS	O
+of	POS	O
+association	POS	O
+with	POS	O
+increasing	POS	O
+duration	POS	O
+of	POS	O
+use	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+specificity	POS	O
+for	POS	O
+fenfluramines	POS	O
+are	POS	O
+consistent	POS	O
+with	POS	O
+previous	POS	O
+studies	POS	O
+indicating	POS	O
+that	POS	O
+fenfluramines	POS	O
+are	POS	O
+causally	POS	O
+related	POS	O
+to	POS	O
+PPH	POS	B-NP
+.	POS	O
+The	POS	O
+high	POS	O
+prevalence	POS	O
+of	POS	O
+anorexigen	POS	O
+use	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+SPH	POS	B-NP
+also	POS	O
+raises	POS	O
+the	POS	O
+possibility	POS	O
+that	POS	O
+these	POS	O
+drugs	POS	O
+precipitate	POS	O
+pulmonary	POS	B-NP
+hypertension	POS	I-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+underlying	POS	O
+conditions	POS	O
+associated	POS	O
+with	POS	O
+SPH	POS	B-NP
+.	POS	O
+Clinical	POS	O
+aspects	POS	O
+of	POS	O
+heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+and	POS	O
+thrombosis	POS	B-NP
+and	POS	O
+other	POS	O
+side	POS	O
+effects	POS	O
+of	POS	O
+heparin	POS	O
+therapy	POS	O
+.	POS	O
+Heparin	POS	O
+,	POS	O
+first	POS	O
+used	POS	O
+to	POS	O
+prevent	POS	O
+the	POS	O
+clotting	POS	O
+of	POS	O
+blood	POS	O
+in	POS	O
+vitro	POS	O
+,	POS	O
+has	POS	O
+been	POS	O
+clinically	POS	O
+used	POS	O
+to	POS	O
+treat	POS	O
+thrombosis	POS	B-NP
+for	POS	O
+more	POS	O
+than	POS	O
+50	POS	O
+years	POS	O
+.	POS	O
+Although	POS	O
+several	POS	O
+new	POS	O
+anticoagulant	POS	O
+drugs	POS	O
+are	POS	O
+in	POS	O
+development	POS	O
+,	POS	O
+heparin	POS	O
+remains	POS	O
+the	POS	O
+anticoagulant	POS	O
+of	POS	O
+choice	POS	O
+to	POS	O
+treat	POS	O
+acute	POS	O
+thrombotic	POS	B-NP
+episodes	POS	O
+.	POS	O
+The	POS	O
+clinical	POS	O
+effects	POS	O
+of	POS	O
+heparin	POS	O
+are	POS	O
+meritorious	POS	O
+,	POS	O
+but	POS	O
+side	POS	O
+effects	POS	O
+do	POS	O
+exist	POS	O
+.	POS	O
+Bleeding	POS	O
+is	POS	O
+the	POS	O
+primary	POS	O
+untoward	POS	O
+effect	POS	O
+of	POS	O
+heparin	POS	O
+.	POS	O
+Major	POS	O
+bleeding	POS	B-NP
+is	POS	O
+of	POS	O
+primary	POS	O
+concern	POS	O
+in	POS	O
+patients	POS	O
+receiving	POS	O
+heparin	POS	O
+therapy	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+additional	POS	O
+important	POS	O
+untoward	POS	O
+effects	POS	O
+of	POS	O
+heparin	POS	O
+therapy	POS	O
+include	POS	O
+heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+,	POS	O
+heparin	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+osteoporosis	POS	I-NP
+,	POS	O
+eosinophilia	POS	B-NP
+,	POS	O
+skin	POS	B-NP
+reactions	POS	I-NP
+,	POS	O
+allergic	POS	B-NP
+reactions	POS	I-NP
+other	POS	O
+than	POS	O
+thrombocytopenia	POS	B-NP
+,	POS	O
+alopecia	POS	B-NP
+,	POS	O
+transaminasemia	POS	B-NP
+,	POS	O
+hyperkalemia	POS	B-NP
+,	POS	O
+hypoaldosteronism	POS	B-NP
+,	POS	O
+and	POS	O
+priapism	POS	B-NP
+.	POS	O
+These	POS	O
+side	POS	O
+effects	POS	O
+are	POS	O
+relatively	POS	O
+rare	POS	O
+in	POS	O
+a	POS	O
+given	POS	O
+individual	POS	O
+,	POS	O
+but	POS	O
+given	POS	O
+the	POS	O
+extremely	POS	O
+widespread	POS	O
+use	POS	O
+of	POS	O
+heparin	POS	O
+,	POS	O
+some	POS	O
+are	POS	O
+quite	POS	O
+common	POS	O
+,	POS	O
+particularly	POS	O
+HITT	POS	B-NP
+and	POS	O
+osteoporosis	POS	B-NP
+.	POS	O
+Although	POS	O
+reasonable	POS	O
+incidences	POS	O
+of	POS	O
+many	POS	O
+of	POS	O
+these	POS	O
+side	POS	O
+effects	POS	O
+can	POS	O
+be	POS	O
+"	POS	O
+softly	POS	O
+"	POS	O
+deduced	POS	O
+from	POS	O
+current	POS	O
+reports	POS	O
+dealing	POS	O
+with	POS	O
+unfractionated	POS	O
+heparin	POS	O
+,	POS	O
+at	POS	O
+present	POS	O
+the	POS	O
+incidences	POS	O
+of	POS	O
+these	POS	O
+side	POS	O
+effects	POS	O
+with	POS	O
+newer	POS	O
+low	POS	O
+molecular	POS	O
+weight	POS	O
+heparins	POS	O
+appear	POS	O
+to	POS	O
+be	POS	O
+much	POS	O
+less	POS	O
+common	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+only	POS	O
+longer	POS	O
+experience	POS	O
+will	POS	O
+more	POS	O
+clearly	POS	O
+define	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+each	POS	O
+side	POS	O
+effect	POS	O
+with	POS	O
+low	POS	O
+molecular	POS	O
+weight	POS	O
+preparations	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+bilateral	POS	O
+optic	POS	B-NP
+neuropathy	POS	I-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+on	POS	O
+tacrolimus	POS	O
+(	POS	O
+FK506	POS	O
+)	POS	O
+therapy	POS	O
+after	POS	O
+liver	POS	O
+transplantation	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+To	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+bilateral	POS	O
+optic	POS	B-NP
+neuropathy	POS	I-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+receiving	POS	O
+tacrolimus	POS	O
+(	POS	O
+FK	POS	O
+506	POS	O
+,	POS	O
+Prograf	POS	O
+;	POS	O
+Fujisawa	POS	O
+USA	POS	O
+,	POS	O
+Inc	POS	O
+,	POS	O
+Deerfield	POS	O
+,	POS	O
+Illinois	POS	O
+)	POS	O
+for	POS	O
+immunosuppression	POS	O
+after	POS	O
+orthotropic	POS	O
+liver	POS	O
+transplantation	POS	O
+.	POS	O
+METHOD	POS	O
+:	POS	O
+Case	POS	O
+report	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+58	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+receiving	POS	O
+tacrolimus	POS	O
+after	POS	O
+orthotropic	POS	O
+liver	POS	O
+transplantation	POS	O
+,	POS	O
+serial	POS	O
+neuro	POS	O
+-	POS	O
+ophthalmologic	POS	O
+examinations	POS	O
+and	POS	O
+laboratory	POS	O
+studies	POS	O
+were	POS	O
+performed	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+patient	POS	O
+had	POS	O
+episodic	POS	B-NP
+deterioration	POS	I-NP
+of	POS	I-NP
+vision	POS	I-NP
+in	POS	I-NP
+both	POS	I-NP
+eyes	POS	I-NP
+,	POS	O
+with	POS	O
+clinical	POS	O
+features	POS	O
+resembling	POS	O
+ischemic	POS	B-NP
+optic	POS	I-NP
+neuropathies	POS	I-NP
+.	POS	O
+Deterioration	POS	B-NP
+of	POS	I-NP
+vision	POS	I-NP
+occurred	POS	O
+despite	POS	O
+discontinuation	POS	O
+of	POS	O
+the	POS	O
+tacrolimus	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Tacrolimus	POS	O
+and	POS	O
+other	POS	O
+immunosuppressive	POS	O
+agents	POS	O
+may	POS	O
+be	POS	O
+associated	POS	O
+with	POS	O
+optic	POS	B-NP
+nerve	POS	I-NP
+toxicity	POS	I-NP
+.	POS	O
+Hypercalcemia	POS	B-NP
+,	POS	O
+arrhythmia	POS	B-NP
+,	POS	O
+and	POS	O
+mood	POS	O
+stabilizers	POS	O
+.	POS	O
+Recent	POS	O
+findings	POS	O
+in	POS	O
+a	POS	O
+bipolar	POS	B-NP
+patient	POS	O
+receiving	POS	O
+maintenance	POS	O
+lithium	POS	O
+therapy	POS	O
+who	POS	O
+developed	POS	O
+hypercalcemia	POS	B-NP
+and	POS	O
+severe	POS	O
+bradyarrhythmia	POS	B-NP
+prompted	POS	O
+the	POS	O
+authors	POS	O
+to	POS	O
+conduct	POS	O
+a	POS	O
+retrospective	POS	O
+study	POS	O
+of	POS	O
+bipolar	POS	B-NP
+patients	POS	O
+with	POS	O
+lithium	POS	O
+-	POS	O
+associated	POS	O
+hypercalcemia	POS	B-NP
+.	POS	O
+A	POS	O
+printout	POS	O
+of	POS	O
+all	POS	O
+cases	POS	O
+of	POS	O
+hypercalcemia	POS	B-NP
+that	POS	O
+presented	POS	O
+during	POS	O
+a	POS	O
+1	POS	O
+-	POS	O
+year	POS	O
+period	POS	O
+was	POS	O
+generated	POS	O
+.	POS	O
+After	POS	O
+eliminating	POS	O
+spurious	POS	O
+hypercalcemias	POS	B-NP
+or	POS	O
+those	POS	O
+associated	POS	O
+with	POS	O
+intravenous	POS	O
+fluids	POS	O
+,	POS	O
+the	POS	O
+authors	POS	O
+identified	POS	O
+18	POS	O
+non	POS	O
+-	POS	O
+lithium	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+with	POS	O
+hypercalcemias	POS	B-NP
+related	POS	O
+to	POS	O
+malignancies	POS	B-NP
+and	POS	O
+other	POS	O
+medical	POS	O
+conditions	POS	O
+(	POS	O
+group	POS	O
+A	POS	O
+)	POS	O
+and	POS	O
+12	POS	O
+patients	POS	O
+with	POS	O
+lithium	POS	O
+-	POS	O
+associated	POS	O
+hypercalcemia	POS	B-NP
+(	POS	O
+group	POS	O
+B	POS	O
+)	POS	O
+.	POS	O
+Patients	POS	O
+in	POS	O
+group	POS	O
+B	POS	O
+were	POS	O
+not	POS	O
+comparable	POS	O
+to	POS	O
+those	POS	O
+in	POS	O
+group	POS	O
+A	POS	O
+,	POS	O
+as	POS	O
+the	POS	O
+latter	POS	O
+were	POS	O
+medically	POS	O
+compromised	POS	O
+and	POS	O
+were	POS	O
+receiving	POS	O
+multiple	POS	O
+pharmacotherapies	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+two	POS	O
+control	POS	O
+groups	POS	O
+were	POS	O
+generated	POS	O
+:	POS	O
+group	POS	O
+C1	POS	O
+,	POS	O
+which	POS	O
+included	POS	O
+age	POS	O
+-	POS	O
+and	POS	O
+sex	POS	O
+-	POS	O
+comparable	POS	O
+lithium	POS	O
+-	POS	O
+treated	POS	O
+bipolar	POS	O
+normocalcemic	POS	O
+patients	POS	O
+,	POS	O
+and	POS	O
+group	POS	O
+C2	POS	O
+,	POS	O
+which	POS	O
+included	POS	O
+bipolar	POS	B-NP
+normocalcemic	POS	I-NP
+patients	POS	O
+treated	POS	O
+with	POS	O
+anticonvulsant	POS	O
+mood	POS	O
+stabilizers	POS	O
+.	POS	O
+The	POS	O
+electrocardiographic	POS	O
+(	POS	O
+ECG	POS	O
+)	POS	O
+findings	POS	O
+for	POS	O
+patients	POS	O
+in	POS	O
+group	POS	O
+B	POS	O
+were	POS	O
+compared	POS	O
+with	POS	O
+those	POS	O
+of	POS	O
+patients	POS	O
+in	POS	O
+groups	POS	O
+C1	POS	O
+and	POS	O
+C2	POS	O
+.	POS	O
+It	POS	O
+was	POS	O
+found	POS	O
+that	POS	O
+these	POS	O
+groups	POS	O
+did	POS	O
+not	POS	O
+differ	POS	O
+in	POS	O
+their	POS	O
+overall	POS	O
+frequency	POS	O
+of	POS	O
+ECG	POS	B-NP
+abnormalities	POS	I-NP
+;	POS	O
+however	POS	O
+,	POS	O
+there	POS	O
+were	POS	O
+significant	POS	O
+differences	POS	O
+in	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+conduction	POS	B-NP
+defects	POS	I-NP
+.	POS	O
+Patients	POS	O
+with	POS	O
+hypercalcemia	POS	B-NP
+resulting	POS	O
+from	POS	O
+medical	POS	O
+diseases	POS	O
+and	POS	O
+bipolar	POS	B-NP
+patients	POS	O
+with	POS	O
+lithium	POS	O
+-	POS	O
+associated	POS	O
+hypercalcemia	POS	B-NP
+had	POS	O
+significantly	POS	O
+higher	POS	O
+frequencies	POS	O
+of	POS	O
+conduction	POS	B-NP
+defects	POS	I-NP
+.	POS	O
+Patients	POS	O
+in	POS	O
+group	POS	O
+A	POS	O
+had	POS	O
+significant	POS	O
+mortality	POS	O
+at	POS	O
+2	POS	O
+-	POS	O
+year	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+(	POS	O
+28	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+in	POS	O
+contrast	POS	O
+to	POS	O
+zero	POS	O
+mortality	POS	O
+in	POS	O
+the	POS	O
+other	POS	O
+three	POS	O
+groups	POS	O
+.	POS	O
+The	POS	O
+clinical	POS	O
+implications	POS	O
+of	POS	O
+these	POS	O
+findings	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+Attenuation	POS	O
+of	POS	O
+nephrotoxicity	POS	B-NP
+by	POS	O
+a	POS	O
+novel	POS	O
+lipid	POS	O
+nanosphere	POS	O
+(	POS	O
+NS	POS	O
+-	POS	O
+718	POS	O
+)	POS	O
+incorporating	POS	O
+amphotericin	POS	O
+B	POS	O
+.	POS	O
+NS	POS	O
+-	POS	O
+718	POS	O
+,	POS	O
+a	POS	O
+lipid	POS	O
+nanosphere	POS	O
+incorporating	POS	O
+amphotericin	POS	O
+B	POS	O
+,	POS	O
+is	POS	O
+effective	POS	O
+against	POS	O
+pathogenic	POS	O
+fungi	POS	O
+and	POS	O
+has	POS	O
+low	POS	B-NP
+toxicity	POS	I-NP
+.	POS	O
+We	POS	O
+compared	POS	O
+the	POS	O
+toxicity	POS	B-NP
+of	POS	O
+NS	POS	O
+-	POS	O
+718	POS	O
+with	POS	O
+that	POS	O
+of	POS	O
+Fungizone	POS	O
+(	POS	O
+amphotericin	POS	O
+B	POS	O
+-	POS	O
+sodium	POS	O
+deoxycholate	POS	O
+;	POS	O
+D	POS	O
+-	POS	O
+AmB	POS	O
+)	POS	O
+in	POS	O
+vitro	POS	O
+using	POS	O
+renal	POS	O
+cell	POS	O
+cultures	POS	O
+and	POS	O
+in	POS	O
+vivo	POS	O
+by	POS	O
+biochemical	POS	O
+analysis	POS	O
+,	POS	O
+histopathological	POS	O
+study	POS	O
+of	POS	O
+the	POS	O
+kidney	POS	O
+and	POS	O
+pharmacokinetic	POS	O
+study	POS	O
+of	POS	O
+amphotericin	POS	O
+B	POS	O
+following	POS	O
+intravenous	POS	O
+infusion	POS	O
+of	POS	O
+the	POS	O
+formulation	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+Incubation	POS	O
+with	POS	O
+NS	POS	O
+-	POS	O
+718	POS	O
+resulted	POS	O
+in	POS	O
+significantly	POS	O
+less	POS	O
+damage	POS	O
+of	POS	O
+cultured	POS	O
+human	POS	O
+renal	POS	O
+proximal	POS	O
+tubular	POS	O
+epithelial	POS	O
+cells	POS	O
+compared	POS	O
+with	POS	O
+D	POS	O
+-	POS	O
+AmB	POS	O
+.	POS	O
+Serum	POS	O
+blood	POS	O
+urea	POS	O
+and	POS	O
+creatinine	POS	O
+concentrations	POS	O
+increased	POS	O
+significantly	POS	O
+in	POS	O
+rats	POS	O
+given	POS	O
+an	POS	O
+iv	POS	O
+infusion	POS	O
+of	POS	O
+D	POS	O
+-	POS	O
+AmB	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+but	POS	O
+not	POS	O
+in	POS	O
+those	POS	O
+given	POS	O
+the	POS	O
+same	POS	O
+dose	POS	O
+of	POS	O
+NS	POS	O
+-	POS	O
+718	POS	O
+.	POS	O
+Histopathological	POS	O
+examination	POS	O
+of	POS	O
+the	POS	O
+kidney	POS	O
+showed	POS	O
+tubular	POS	O
+necrosis	POS	B-NP
+in	POS	O
+D	POS	O
+-	POS	O
+AmB	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+but	POS	O
+no	POS	O
+change	POS	O
+in	POS	O
+NS	POS	O
+-	POS	O
+718	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+.	POS	O
+Amphotericin	POS	O
+B	POS	O
+concentrations	POS	O
+in	POS	O
+the	POS	O
+kidney	POS	O
+in	POS	O
+NS	POS	O
+-	POS	O
+718	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+were	POS	O
+higher	POS	O
+than	POS	O
+those	POS	O
+in	POS	O
+D	POS	O
+-	POS	O
+AmB	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+.	POS	O
+Our	POS	O
+in	POS	O
+vitro	POS	O
+and	POS	O
+in	POS	O
+vivo	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+incorporation	POS	O
+of	POS	O
+amphotericin	POS	O
+B	POS	O
+into	POS	O
+lipid	POS	O
+nanospheres	POS	O
+of	POS	O
+NS	POS	O
+-	POS	O
+718	POS	O
+attenuates	POS	O
+the	POS	O
+nephrotoxicity	POS	B-NP
+of	POS	O
+amphotericin	POS	O
+B	POS	O
+.	POS	O
+Patterns	POS	O
+of	POS	O
+sulfadiazine	POS	O
+acute	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+Sulfadiazine	POS	O
+acute	POS	O
+nephrotoxicity	POS	B-NP
+is	POS	O
+reviving	POS	O
+specially	POS	O
+because	POS	O
+of	POS	O
+its	POS	O
+use	POS	O
+in	POS	O
+toxoplasmosis	POS	B-NP
+in	POS	O
+HIV	POS	B-NP
+-	POS	I-NP
+positive	POS	I-NP
+patients	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+4	POS	O
+cases	POS	O
+,	POS	O
+one	POS	O
+of	POS	O
+them	POS	O
+in	POS	O
+a	POS	O
+previously	POS	O
+healthy	POS	O
+person	POS	O
+.	POS	O
+Under	POS	O
+treatment	POS	O
+with	POS	O
+sulfadiazine	POS	O
+they	POS	O
+developed	POS	O
+oliguria	POS	B-NP
+,	POS	O
+abdominal	POS	B-NP
+pain	POS	I-NP
+,	POS	O
+renal	POS	B-NP
+failure	POS	I-NP
+and	POS	O
+showed	POS	O
+multiple	POS	B-NP
+radiolucent	POS	I-NP
+renal	POS	I-NP
+calculi	POS	I-NP
+in	POS	O
+echography	POS	O
+.	POS	O
+All	POS	O
+patients	POS	O
+recovered	POS	O
+their	POS	O
+previous	POS	O
+normal	POS	O
+renal	POS	O
+function	POS	O
+after	POS	O
+adequate	POS	O
+hydration	POS	O
+and	POS	O
+alcalinization	POS	O
+.	POS	O
+A	POS	O
+nephrostomy	POS	O
+tube	POS	O
+had	POS	O
+to	POS	O
+be	POS	O
+placed	POS	O
+in	POS	O
+one	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+for	POS	O
+ureteral	POS	B-NP
+lithiasis	POS	I-NP
+in	POS	O
+a	POS	O
+single	POS	O
+functional	POS	O
+kidney	POS	O
+.	POS	O
+None	POS	O
+of	POS	O
+them	POS	O
+needed	POS	O
+dialysis	POS	O
+or	POS	O
+a	POS	O
+renal	POS	O
+biopsy	POS	O
+because	POS	O
+of	POS	O
+a	POS	O
+typical	POS	O
+benign	POS	O
+course	POS	O
+.	POS	O
+Treatment	POS	O
+with	POS	O
+sulfadiazine	POS	O
+requires	POS	O
+exquisite	POS	O
+control	POS	O
+of	POS	O
+renal	POS	O
+function	POS	O
+,	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+water	POS	O
+ingestion	POS	O
+and	POS	O
+possibly	POS	O
+the	POS	O
+alcalinization	POS	O
+of	POS	O
+the	POS	O
+urine	POS	O
+.	POS	O
+We	POS	O
+communicate	POS	O
+a	POS	O
+case	POS	O
+in	POS	O
+a	POS	O
+previously	POS	O
+healthy	POS	O
+person	POS	O
+,	POS	O
+a	POS	O
+fact	POS	O
+not	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+recent	POS	O
+literature	POS	O
+.	POS	O
+Probably	POS	O
+many	POS	O
+more	POS	O
+cases	POS	O
+are	POS	O
+not	POS	O
+detected	POS	O
+.	POS	O
+We	POS	O
+think	POS	O
+that	POS	O
+a	POS	O
+prospective	POS	O
+study	POS	O
+would	POS	O
+be	POS	O
+useful	POS	O
+.	POS	O
+Downbeat	POS	B-NP
+nystagmus	POS	I-NP
+associated	POS	O
+with	POS	O
+intravenous	POS	O
+patient	POS	O
+-	POS	O
+controlled	POS	O
+administration	POS	O
+of	POS	O
+morphine	POS	O
+.	POS	O
+IMPLICATIONS	POS	O
+:	POS	O
+This	POS	O
+case	POS	O
+documents	POS	O
+a	POS	O
+patient	POS	O
+who	POS	O
+developed	POS	O
+dizziness	POS	B-NP
+with	POS	O
+downbeating	POS	B-NP
+nystagmus	POS	I-NP
+while	POS	O
+receiving	POS	O
+a	POS	O
+relatively	POS	O
+large	POS	O
+dose	POS	O
+of	POS	O
+IV	POS	O
+patient	POS	O
+-	POS	O
+controlled	POS	O
+analgesia	POS	O
+morphine	POS	O
+.	POS	O
+Although	POS	O
+there	POS	O
+have	POS	O
+been	POS	O
+case	POS	O
+reports	POS	O
+of	POS	O
+epidural	POS	O
+morphine	POS	O
+with	POS	O
+these	POS	O
+symptoms	POS	O
+and	POS	O
+signs	POS	O
+,	POS	O
+this	POS	O
+has	POS	O
+not	POS	O
+been	POS	O
+previously	POS	O
+documented	POS	O
+with	POS	O
+IV	POS	O
+or	POS	O
+patient	POS	O
+-	POS	O
+controlled	POS	O
+analgesia	POS	O
+morphine	POS	O
+.	POS	O
+Hemodynamic	POS	O
+and	POS	O
+antiadrenergic	POS	O
+effects	POS	O
+of	POS	O
+dronedarone	POS	O
+and	POS	O
+amiodarone	POS	O
+in	POS	O
+animals	POS	O
+with	POS	O
+a	POS	O
+healed	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+The	POS	O
+hemodynamic	POS	O
+and	POS	O
+antiadrenergic	POS	O
+effects	POS	O
+of	POS	O
+dronedarone	POS	O
+,	POS	O
+a	POS	O
+noniodinated	POS	O
+compound	POS	O
+structurally	POS	O
+related	POS	O
+to	POS	O
+amiodarone	POS	O
+,	POS	O
+were	POS	O
+compared	POS	O
+with	POS	O
+those	POS	O
+of	POS	O
+amiodarone	POS	O
+after	POS	O
+prolonged	POS	O
+oral	POS	O
+administration	POS	O
+,	POS	O
+both	POS	O
+at	POS	O
+rest	POS	O
+and	POS	O
+during	POS	O
+sympathetic	POS	O
+stimulation	POS	O
+in	POS	O
+conscious	POS	O
+dogs	POS	O
+with	POS	O
+a	POS	O
+healed	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+All	POS	O
+dogs	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+6	POS	O
+)	POS	O
+randomly	POS	O
+received	POS	O
+orally	POS	O
+dronedarone	POS	O
+(	POS	O
+10	POS	O
+and	POS	O
+30	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+,	POS	O
+amiodarone	POS	O
+(	POS	O
+10	POS	O
+and	POS	O
+30	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+placebo	POS	O
+twice	POS	O
+daily	POS	O
+for	POS	O
+7	POS	O
+days	POS	O
+,	POS	O
+with	POS	O
+a	POS	O
+3	POS	O
+-	POS	O
+week	POS	O
+washout	POS	O
+between	POS	O
+consecutive	POS	O
+treatments	POS	O
+.	POS	O
+Heart	POS	O
+rate	POS	O
+(	POS	O
+HR	POS	O
+)	POS	O
+,	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+(	POS	O
+MBP	POS	O
+)	POS	O
+,	POS	O
+positive	POS	O
+rate	POS	O
+of	POS	O
+increase	POS	O
+of	POS	O
+left	POS	O
+ventricular	POS	O
+pressure	POS	O
+(	POS	O
++	POS	O
+LVdP	POS	O
+/	POS	O
+dt	POS	O
+)	POS	O
+,	POS	O
+echocardiographically	POS	O
+assessed	POS	O
+left	POS	O
+ventricular	POS	O
+ejection	POS	O
+fraction	POS	O
+(	POS	O
+LVEF	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+fractional	POS	O
+shortening	POS	O
+(	POS	O
+FS	POS	O
+)	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+chronotropic	POS	O
+response	POS	O
+to	POS	O
+isoproterenol	POS	O
+and	POS	O
+exercise	POS	O
+-	POS	O
+induced	POS	O
+sympathetic	POS	O
+stimulation	POS	O
+were	POS	O
+evaluated	POS	O
+under	POS	O
+baseline	POS	O
+and	POS	O
+posttreatment	POS	O
+conditions	POS	O
+.	POS	O
+Resting	POS	O
+values	POS	O
+of	POS	O
+LVEF	POS	O
+,	POS	O
+FS	POS	O
+,	POS	O
++	POS	O
+LVdP	POS	O
+/	POS	O
+dt	POS	O
+,	POS	O
+and	POS	O
+MBP	POS	O
+remained	POS	O
+unchanged	POS	O
+whatever	POS	O
+the	POS	O
+drug	POS	O
+and	POS	O
+the	POS	O
+dosing	POS	O
+regimen	POS	O
+,	POS	O
+whereas	POS	O
+resting	POS	O
+HR	POS	O
+was	POS	O
+significantly	POS	O
+and	POS	O
+dose	POS	O
+-	POS	O
+dependently	POS	O
+lowered	POS	O
+after	POS	O
+dronedarone	POS	O
+and	POS	O
+to	POS	O
+a	POS	O
+lesser	POS	O
+extent	POS	O
+after	POS	O
+amiodarone	POS	O
+.	POS	O
+Both	POS	O
+dronedarone	POS	O
+and	POS	O
+amiodarone	POS	O
+significantly	POS	O
+reduced	POS	O
+the	POS	O
+exercise	POS	O
+-	POS	O
+induced	POS	O
+tachycardia	POS	B-NP
+and	POS	O
+,	POS	O
+at	POS	O
+the	POS	O
+highest	POS	O
+dose	POS	O
+,	POS	O
+decreased	POS	O
+the	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+tachycardia	POS	B-NP
+.	POS	O
+Thus	POS	O
+,	POS	O
+dronedarone	POS	O
+and	POS	O
+amiodarone	POS	O
+displayed	POS	O
+a	POS	O
+similar	POS	O
+level	POS	O
+of	POS	O
+antiadrenergic	POS	O
+effect	POS	O
+and	POS	O
+did	POS	O
+not	POS	O
+impair	POS	O
+the	POS	O
+resting	POS	O
+left	POS	O
+ventricular	POS	O
+function	POS	O
+.	POS	O
+Consequently	POS	O
+,	POS	O
+dronedarone	POS	O
+might	POS	O
+be	POS	O
+particularly	POS	O
+suitable	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+and	POS	O
+prevention	POS	O
+of	POS	O
+various	POS	O
+clinical	POS	O
+arrhythmias	POS	B-NP
+,	POS	O
+without	POS	O
+compromising	POS	O
+the	POS	O
+left	POS	O
+ventricular	POS	O
+function	POS	O
+.	POS	O
+Phase	POS	O
+2	POS	O
+trial	POS	O
+of	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+(	POS	O
+40	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+)	POS	O
+in	POS	O
+platinum	POS	O
+/	POS	O
+paclitaxel	POS	O
+-	POS	O
+refractory	POS	O
+ovarian	POS	O
+and	POS	O
+fallopian	POS	B-NP
+tube	POS	I-NP
+cancers	POS	I-NP
+and	POS	O
+primary	POS	O
+carcinoma	POS	B-NP
+of	POS	O
+the	POS	O
+peritoneum	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Several	POS	O
+studies	POS	O
+have	POS	O
+demonstrated	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+(	POS	O
+Doxil	POS	O
+)	POS	O
+to	POS	O
+be	POS	O
+an	POS	O
+active	POS	O
+antineoplastic	POS	O
+agent	POS	O
+in	POS	O
+platinum	POS	O
+-	POS	O
+resistant	POS	O
+ovarian	POS	B-NP
+cancer	POS	I-NP
+,	POS	O
+with	POS	O
+dose	POS	O
+limiting	POS	O
+toxicity	POS	B-NP
+of	POS	O
+the	POS	O
+standard	POS	O
+dosing	POS	O
+regimen	POS	O
+(	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+q	POS	O
+4	POS	O
+weeks	POS	O
+)	POS	O
+being	POS	O
+severe	POS	O
+erythrodysesthesia	POS	B-NP
+(	POS	O
+"	POS	B-NP
+hand	POS	I-NP
+-	POS	I-NP
+foot	POS	I-NP
+syndrome	POS	I-NP
+"	POS	O
+)	POS	O
+and	POS	O
+stomatitis	POS	B-NP
+.	POS	O
+We	POS	O
+wished	POS	O
+to	POS	O
+develop	POS	O
+a	POS	O
+more	POS	O
+tolerable	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+treatment	POS	O
+regimen	POS	O
+and	POS	O
+document	POS	O
+its	POS	O
+level	POS	O
+of	POS	O
+activity	POS	O
+in	POS	O
+a	POS	O
+well	POS	O
+-	POS	O
+defined	POS	O
+patient	POS	O
+population	POS	O
+with	POS	O
+platinum	POS	O
+/	POS	O
+paclitaxel	POS	O
+-	POS	O
+refractory	POS	O
+disease	POS	O
+.	POS	O
+METHODS	POS	O
+AND	POS	O
+MATERIALS	POS	O
+:	POS	O
+Patients	POS	O
+with	POS	O
+ovarian	POS	B-NP
+or	POS	I-NP
+fallopian	POS	I-NP
+tube	POS	I-NP
+cancers	POS	I-NP
+or	POS	O
+primary	POS	B-NP
+peritoneal	POS	I-NP
+carcinoma	POS	I-NP
+with	POS	O
+platinum	POS	O
+/	POS	O
+paclitaxel	POS	O
+-	POS	O
+refractory	POS	O
+disease	POS	O
+(	POS	O
+stable	POS	O
+or	POS	O
+progressive	POS	O
+disease	POS	O
+following	POS	O
+treatment	POS	O
+with	POS	O
+these	POS	O
+agents	POS	O
+or	POS	O
+previous	POS	O
+objective	POS	O
+response	POS	O
+<	POS	O
+3	POS	O
+months	POS	O
+in	POS	O
+duration	POS	O
+)	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+40	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+q	POS	O
+4	POS	O
+weeks	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+49	POS	O
+patients	POS	O
+(	POS	O
+median	POS	O
+age	POS	O
+:	POS	O
+60	POS	O
+;	POS	O
+range	POS	O
+41	POS	O
+-	POS	O
+81	POS	O
+)	POS	O
+entered	POS	O
+this	POS	O
+phase	POS	O
+2	POS	O
+trial	POS	O
+.	POS	O
+The	POS	O
+median	POS	O
+number	POS	O
+of	POS	O
+prior	POS	O
+regimens	POS	O
+was	POS	O
+2	POS	O
+(	POS	O
+range	POS	O
+:	POS	O
+1	POS	O
+-	POS	O
+6	POS	O
+)	POS	O
+.	POS	O
+Six	POS	O
+(	POS	O
+12	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+4	POS	O
+(	POS	O
+8	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+experienced	POS	O
+grade	POS	B-NP
+2	POS	I-NP
+hand	POS	I-NP
+-	POS	I-NP
+foot	POS	I-NP
+syndrome	POS	I-NP
+and	POS	O
+stomatitis	POS	B-NP
+,	POS	O
+respectively	POS	O
+(	POS	O
+no	POS	O
+episodes	POS	O
+of	POS	O
+grade	POS	O
+3	POS	O
+)	POS	O
+.	POS	O
+One	POS	O
+patient	POS	O
+developed	POS	O
+grade	POS	O
+3	POS	O
+diarrhea	POS	B-NP
+requiring	POS	O
+hospitalization	POS	O
+for	POS	O
+hydration	POS	O
+.	POS	O
+Six	POS	O
+(	POS	O
+12	POS	O
+%	POS	O
+)	POS	O
+individuals	POS	O
+required	POS	O
+dose	POS	O
+reductions	POS	O
+.	POS	O
+The	POS	O
+median	POS	O
+number	POS	O
+of	POS	O
+courses	POS	O
+of	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+administered	POS	O
+on	POS	O
+this	POS	O
+protocol	POS	O
+was	POS	O
+2	POS	O
+(	POS	O
+range	POS	O
+:	POS	O
+1	POS	O
+-	POS	O
+12	POS	O
+)	POS	O
+.	POS	O
+Four	POS	O
+of	POS	O
+44	POS	O
+patients	POS	O
+(	POS	O
+9	POS	O
+%	POS	O
+)	POS	O
+evaluable	POS	O
+for	POS	O
+response	POS	O
+exhibited	POS	O
+objective	POS	O
+and	POS	O
+subjective	POS	O
+evidence	POS	O
+of	POS	O
+an	POS	O
+antineoplastic	POS	O
+effect	POS	O
+of	POS	O
+therapy	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+This	POS	O
+modified	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+regimen	POS	O
+results	POS	O
+in	POS	O
+less	POS	O
+toxicity	POS	B-NP
+(	POS	O
+stomatitis	POS	B-NP
+,	POS	O
+hand	POS	B-NP
+-	POS	I-NP
+foot	POS	I-NP
+syndrome	POS	I-NP
+)	POS	O
+than	POS	O
+the	POS	O
+standard	POS	O
+FDA	POS	O
+-	POS	O
+approved	POS	O
+dose	POS	O
+schedule	POS	O
+.	POS	O
+Definite	POS	O
+,	POS	O
+although	POS	O
+limited	POS	O
+,	POS	O
+antineoplastic	POS	O
+activity	POS	O
+is	POS	O
+observed	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+well	POS	O
+-	POS	O
+defined	POS	O
+platinum	POS	O
+-	POS	O
+and	POS	O
+paclitaxel	POS	O
+-	POS	O
+refractory	POS	O
+ovarian	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+Efficacy	POS	O
+of	POS	O
+olanzapine	POS	O
+in	POS	O
+acute	POS	B-NP
+bipolar	POS	I-NP
+mania	POS	I-NP
+:	POS	O
+a	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+study	POS	O
+.	POS	O
+The	POS	O
+Olanzipine	POS	O
+HGGW	POS	O
+Study	POS	O
+Group	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+We	POS	O
+compared	POS	O
+the	POS	O
+efficacy	POS	O
+and	POS	O
+safety	POS	O
+of	POS	O
+olanzapine	POS	O
+vs	POS	O
+placebo	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+acute	POS	B-NP
+bipolar	POS	I-NP
+mania	POS	I-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Four	POS	O
+-	POS	O
+week	POS	O
+,	POS	O
+randomized	POS	O
+,	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+parallel	POS	O
+study	POS	O
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+115	POS	O
+patients	POS	O
+with	POS	O
+a	POS	O
+DSM	POS	O
+-	POS	O
+IV	POS	O
+diagnosis	POS	O
+of	POS	O
+bipolar	POS	B-NP
+disorder	POS	I-NP
+,	POS	O
+manic	POS	B-NP
+or	POS	O
+mixed	POS	O
+,	POS	O
+were	POS	O
+randomized	POS	O
+to	POS	O
+olanzapine	POS	O
+,	POS	O
+5	POS	O
+to	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+d	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+55	POS	O
+)	POS	O
+,	POS	O
+or	POS	O
+placebo	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+60	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+primary	POS	O
+efficacy	POS	O
+measure	POS	O
+was	POS	O
+the	POS	O
+Young	POS	O
+-	POS	O
+Mania	POS	O
+Rating	POS	O
+Scale	POS	O
+(	POS	O
+Y	POS	O
+-	POS	O
+MRS	POS	O
+)	POS	O
+total	POS	O
+score	POS	O
+.	POS	O
+Response	POS	O
+and	POS	O
+euthymia	POS	B-NP
+were	POS	O
+defined	POS	O
+,	POS	O
+a	POS	O
+priori	POS	O
+,	POS	O
+as	POS	O
+at	POS	O
+least	POS	O
+a	POS	O
+50	POS	O
+%	POS	O
+improvement	POS	O
+from	POS	O
+baseline	POS	O
+to	POS	O
+end	POS	O
+point	POS	O
+and	POS	O
+as	POS	O
+a	POS	O
+score	POS	O
+of	POS	O
+no	POS	O
+less	POS	O
+than	POS	O
+12	POS	O
+at	POS	O
+end	POS	O
+point	POS	O
+in	POS	O
+the	POS	O
+Y	POS	O
+-	POS	O
+MRS	POS	O
+total	POS	O
+score	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Safety	POS	O
+was	POS	O
+assessed	POS	O
+using	POS	O
+adverse	POS	O
+events	POS	O
+,	POS	O
+Extrapyramidal	POS	B-NP
+Symptom	POS	I-NP
+(	POS	O
+EPS	POS	B-NP
+)	POS	O
+rating	POS	O
+scales	POS	O
+,	POS	O
+laboratory	POS	O
+values	POS	O
+,	POS	O
+electrocardiograms	POS	O
+,	POS	O
+vital	POS	O
+signs	POS	O
+,	POS	O
+and	POS	O
+weight	POS	O
+change	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Olanzapine	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+demonstrated	POS	O
+a	POS	O
+statistically	POS	O
+significant	POS	O
+greater	POS	O
+mean	POS	O
+(	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+SD	POS	O
+)	POS	O
+improvement	POS	O
+in	POS	O
+Y	POS	O
+-	POS	O
+MRS	POS	O
+total	POS	O
+score	POS	O
+than	POS	O
+placebo	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+(	POS	O
+-	POS	O
+14	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+and	POS	O
+-	POS	O
+8	POS	O
+.	POS	O
+1	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+12	POS	O
+.	POS	O
+7	POS	O
+,	POS	O
+respectively	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+which	POS	O
+was	POS	O
+evident	POS	O
+at	POS	O
+the	POS	O
+first	POS	O
+postbaseline	POS	O
+observation	POS	O
+1	POS	O
+week	POS	O
+after	POS	O
+randomization	POS	O
+and	POS	O
+was	POS	O
+maintained	POS	O
+throughout	POS	O
+the	POS	O
+study	POS	O
+(	POS	O
+last	POS	O
+observation	POS	O
+carried	POS	O
+forward	POS	O
+)	POS	O
+.	POS	O
+Olanzapine	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+demonstrated	POS	O
+a	POS	O
+higher	POS	O
+rate	POS	O
+of	POS	O
+response	POS	O
+(	POS	O
+65	POS	O
+%	POS	O
+vs	POS	O
+43	POS	O
+%	POS	O
+,	POS	O
+respectively	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+and	POS	O
+euthymia	POS	B-NP
+(	POS	O
+61	POS	O
+%	POS	O
+vs	POS	O
+36	POS	O
+%	POS	O
+,	POS	O
+respectively	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+than	POS	O
+placebo	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+no	POS	O
+statistically	POS	O
+significant	POS	O
+differences	POS	O
+in	POS	O
+EPSs	POS	O
+between	POS	O
+groups	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+olanzapine	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+had	POS	O
+a	POS	O
+statistically	POS	O
+significant	POS	O
+greater	POS	O
+mean	POS	O
+(	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+SD	POS	O
+)	POS	O
+weight	POS	O
+gain	POS	O
+than	POS	O
+placebo	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+1	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+8	POS	O
+vs	POS	O
+0	POS	O
+.	POS	O
+45	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
+kg	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+and	POS	O
+also	POS	O
+experienced	POS	O
+more	POS	O
+treatment	POS	O
+-	POS	O
+emergent	POS	O
+somnolence	POS	B-NP
+(	POS	O
+21	POS	O
+patients	POS	O
+[	POS	O
+38	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+]	POS	O
+vs	POS	O
+5	POS	O
+[	POS	O
+8	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+]	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Olanzapine	POS	O
+demonstrated	POS	O
+greater	POS	O
+efficacy	POS	O
+than	POS	O
+placebo	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+acute	POS	O
+bipolar	POS	B-NP
+mania	POS	I-NP
+and	POS	O
+was	POS	O
+generally	POS	O
+well	POS	O
+tolerated	POS	O
+.	POS	O
+The	POS	O
+effect	POS	O
+of	POS	O
+pupil	POS	O
+dilation	POS	O
+with	POS	O
+tropicamide	POS	O
+on	POS	O
+vision	POS	O
+and	POS	O
+driving	POS	O
+simulator	POS	O
+performance	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+To	POS	O
+assess	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+pupil	POS	O
+dilation	POS	O
+on	POS	O
+vision	POS	O
+and	POS	O
+driving	POS	O
+ability	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+A	POS	O
+series	POS	O
+of	POS	O
+tests	POS	O
+on	POS	O
+various	POS	O
+parameters	POS	O
+of	POS	O
+visual	POS	O
+function	POS	O
+and	POS	O
+driving	POS	O
+simulator	POS	O
+performance	POS	O
+were	POS	O
+performed	POS	O
+on	POS	O
+12	POS	O
+healthy	POS	O
+drivers	POS	O
+,	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+pupil	POS	O
+dilation	POS	O
+using	POS	O
+guttae	POS	O
+tropicamide	POS	O
+1	POS	O
+%	POS	O
+.	POS	O
+A	POS	O
+driving	POS	O
+simulator	POS	O
+(	POS	O
+Transport	POS	O
+Research	POS	O
+Laboratory	POS	O
+)	POS	O
+was	POS	O
+used	POS	O
+to	POS	O
+measure	POS	O
+reaction	POS	O
+time	POS	O
+(	POS	O
+RT	POS	O
+)	POS	O
+,	POS	O
+speed	POS	O
+maintenance	POS	O
+and	POS	O
+steering	POS	O
+accuracy	POS	O
+.	POS	O
+Tests	POS	O
+of	POS	O
+basic	POS	O
+visual	POS	O
+function	POS	O
+included	POS	O
+high	POS	O
+-	POS	O
+and	POS	O
+low	POS	O
+-	POS	O
+contrast	POS	O
+visual	POS	O
+acuity	POS	O
+(	POS	O
+HCVA	POS	O
+and	POS	O
+LCVA	POS	O
+)	POS	O
+,	POS	O
+Pelli	POS	O
+-	POS	O
+Robson	POS	O
+contrast	POS	O
+threshold	POS	O
+(	POS	O
+CT	POS	O
+)	POS	O
+and	POS	O
+Goldmann	POS	O
+perimetry	POS	O
+(	POS	O
+FIELDS	POS	O
+)	POS	O
+.	POS	O
+Useful	POS	O
+Field	POS	O
+of	POS	O
+View	POS	O
+(	POS	O
+UFOV	POS	O
+-	POS	O
+-	POS	O
+a	POS	O
+test	POS	O
+of	POS	O
+visual	POS	O
+attention	POS	O
+)	POS	O
+was	POS	O
+also	POS	O
+undertaken	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+differences	POS	O
+in	POS	O
+the	POS	O
+pre	POS	O
+-	POS	O
+and	POS	O
+post	POS	O
+-	POS	O
+dilatation	POS	O
+measurements	POS	O
+were	POS	O
+tested	POS	O
+for	POS	O
+statistical	POS	O
+significance	POS	O
+at	POS	O
+the	POS	O
+95	POS	O
+%	POS	O
+level	POS	O
+using	POS	O
+one	POS	O
+-	POS	O
+tail	POS	O
+paired	POS	O
+t	POS	O
+-	POS	O
+tests	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Pupillary	POS	O
+dilation	POS	O
+resulted	POS	O
+in	POS	O
+a	POS	O
+statistically	POS	O
+significant	POS	O
+deterioration	POS	O
+in	POS	O
+CT	POS	O
+and	POS	O
+HCVA	POS	O
+only	POS	O
+.	POS	O
+Five	POS	O
+of	POS	O
+12	POS	O
+drivers	POS	O
+also	POS	O
+exhibited	POS	O
+deterioration	POS	O
+in	POS	O
+LCVA	POS	O
+,	POS	O
+CT	POS	O
+and	POS	O
+RT	POS	O
+.	POS	O
+Little	POS	O
+evidence	POS	O
+emerged	POS	O
+for	POS	O
+deterioration	POS	O
+in	POS	O
+FIELDS	POS	O
+and	POS	O
+UFOV	POS	O
+.	POS	O
+Also	POS	O
+,	POS	O
+7	POS	O
+of	POS	O
+12	POS	O
+drivers	POS	O
+appeared	POS	O
+to	POS	O
+adjust	POS	O
+their	POS	O
+driving	POS	O
+behaviour	POS	O
+by	POS	O
+reducing	POS	O
+their	POS	O
+speed	POS	O
+on	POS	O
+the	POS	O
+driving	POS	O
+simulator	POS	O
+,	POS	O
+leading	POS	O
+to	POS	O
+improved	POS	O
+steering	POS	O
+accuracy	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Pupillary	POS	O
+dilation	POS	O
+may	POS	O
+lead	POS	O
+to	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+vision	POS	O
+and	POS	O
+daylight	POS	O
+driving	POS	O
+performance	POS	O
+in	POS	O
+young	POS	O
+people	POS	O
+.	POS	O
+A	POS	O
+larger	POS	O
+study	POS	O
+,	POS	O
+including	POS	O
+a	POS	O
+broader	POS	O
+spectrum	POS	O
+of	POS	O
+subjects	POS	O
+,	POS	O
+is	POS	O
+warranted	POS	O
+before	POS	O
+guidelines	POS	O
+can	POS	O
+be	POS	O
+recommended	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+isotretinoin	POS	O
+embryopathy	POS	B-NP
+with	POS	O
+bilateral	POS	B-NP
+anotia	POS	I-NP
+and	POS	O
+Taussig	POS	B-NP
+-	POS	I-NP
+Bing	POS	I-NP
+malformation	POS	I-NP
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+newborn	POS	O
+infant	POS	O
+with	POS	O
+multiple	POS	B-NP
+congenital	POS	I-NP
+anomalies	POS	I-NP
+(	POS	O
+anotia	POS	B-NP
+and	POS	O
+Taussig	POS	B-NP
+-	POS	I-NP
+Bing	POS	I-NP
+malformation	POS	I-NP
+)	POS	O
+due	POS	O
+to	POS	O
+exposure	POS	O
+to	POS	O
+isotretinoin	POS	O
+within	POS	O
+the	POS	O
+first	POS	O
+trimester	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+paper	POS	O
+we	POS	O
+aim	POS	O
+to	POS	O
+draw	POS	O
+to	POS	O
+the	POS	O
+fact	POS	O
+that	POS	O
+caution	POS	O
+is	POS	O
+needed	POS	O
+when	POS	O
+prescribing	POS	O
+vitamin	POS	O
+A	POS	O
+-	POS	O
+containing	POS	O
+drugs	POS	O
+to	POS	O
+women	POS	O
+of	POS	O
+childbearing	POS	O
+years	POS	O
+.	POS	O
+Effect	POS	O
+of	POS	O
+methoxamine	POS	O
+on	POS	O
+maximum	POS	O
+urethral	POS	O
+pressure	POS	O
+in	POS	O
+women	POS	O
+with	POS	O
+genuine	POS	O
+stress	POS	B-NP
+incontinence	POS	I-NP
+:	POS	O
+a	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+,	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+crossover	POS	O
+study	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+the	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+potential	POS	O
+role	POS	O
+for	POS	O
+a	POS	O
+selective	POS	O
+alpha1	POS	O
+-	POS	O
+adrenoceptor	POS	O
+agonist	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+urinary	POS	B-NP
+stress	POS	I-NP
+incontinence	POS	I-NP
+.	POS	O
+A	POS	O
+randomised	POS	O
+,	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+,	POS	O
+crossover	POS	O
+study	POS	O
+design	POS	O
+was	POS	O
+employed	POS	O
+.	POS	O
+Half	POS	O
+log	POS	O
+incremental	POS	O
+doses	POS	O
+of	POS	O
+intravenous	POS	O
+methoxamine	POS	O
+or	POS	O
+placebo	POS	O
+(	POS	O
+saline	POS	O
+)	POS	O
+were	POS	O
+administered	POS	O
+to	POS	O
+a	POS	O
+group	POS	O
+of	POS	O
+women	POS	O
+with	POS	O
+genuine	POS	O
+stress	POS	B-NP
+incontinence	POS	I-NP
+while	POS	O
+measuring	POS	O
+maximum	POS	O
+urethral	POS	O
+pressure	POS	O
+(	POS	O
+MUP	POS	O
+)	POS	O
+,	POS	O
+blood	POS	O
+pressure	POS	O
+,	POS	O
+heart	POS	O
+rate	POS	O
+,	POS	O
+and	POS	O
+symptomatic	POS	O
+side	POS	O
+effects	POS	O
+.	POS	O
+Methoxamine	POS	O
+evoked	POS	O
+non	POS	O
+-	POS	O
+significant	POS	O
+increases	POS	O
+in	POS	O
+MUP	POS	O
+and	POS	O
+diastolic	POS	O
+blood	POS	O
+pressure	POS	O
+but	POS	O
+caused	POS	O
+a	POS	O
+significant	POS	O
+rise	POS	O
+in	POS	O
+systolic	POS	O
+blood	POS	O
+pressure	POS	O
+and	POS	O
+significant	POS	O
+fall	POS	O
+in	POS	O
+heart	POS	O
+rate	POS	O
+at	POS	O
+maximum	POS	O
+dosage	POS	O
+.	POS	O
+Systemic	POS	O
+side	POS	O
+effects	POS	O
+including	POS	O
+piloerection	POS	B-NP
+,	POS	O
+headache	POS	B-NP
+,	POS	O
+and	POS	O
+cold	POS	B-NP
+extremities	POS	I-NP
+were	POS	O
+experienced	POS	O
+in	POS	O
+all	POS	O
+subjects	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+the	POS	O
+clinical	POS	O
+usefulness	POS	O
+of	POS	O
+direct	POS	O
+,	POS	O
+peripherally	POS	O
+acting	POS	O
+sub	POS	O
+-	POS	O
+type	POS	O
+-	POS	O
+selective	POS	O
+alpha1	POS	O
+-	POS	O
+adrenoceptor	POS	O
+agonists	POS	O
+in	POS	O
+the	POS	O
+medical	POS	O
+treatment	POS	O
+of	POS	O
+stress	POS	B-NP
+incontinence	POS	I-NP
+may	POS	O
+be	POS	O
+limited	POS	O
+by	POS	O
+associated	POS	O
+piloerection	POS	O
+and	POS	O
+cardiovascular	POS	B-NP
+side	POS	I-NP
+effects	POS	I-NP
+.	POS	O
+Hyperglycemic	POS	B-NP
+effect	POS	O
+of	POS	O
+amino	POS	O
+compounds	POS	O
+structurally	POS	O
+related	POS	O
+to	POS	O
+caproate	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+chronic	POS	O
+feeding	POS	O
+of	POS	O
+small	POS	O
+amounts	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+-	POS	O
+3	POS	O
+%	POS	O
+of	POS	O
+diet	POS	O
+weight	POS	O
+)	POS	O
+of	POS	O
+certain	POS	O
+amino	POS	O
+derivatives	POS	O
+of	POS	O
+caproate	POS	O
+resulted	POS	O
+in	POS	O
+hyperglycemia	POS	B-NP
+,	POS	O
+an	POS	O
+elevated	POS	O
+glucose	POS	O
+tolerance	POS	O
+curve	POS	O
+and	POS	O
+,	POS	O
+occasionally	POS	O
+,	POS	O
+glucosuria	POS	B-NP
+.	POS	O
+Effective	POS	O
+compounds	POS	O
+included	POS	O
+norleucine	POS	O
+,	POS	O
+norvaline	POS	O
+,	POS	O
+glutamate	POS	O
+,	POS	O
+epsilon	POS	O
+-	POS	O
+aminocaproate	POS	O
+,	POS	O
+methionine	POS	O
+,	POS	O
+and	POS	O
+leucine	POS	O
+.	POS	O
+Toleration	POS	O
+of	POS	O
+high	POS	O
+doses	POS	O
+of	POS	O
+angiotensin	POS	O
+-	POS	O
+converting	POS	O
+enzyme	POS	O
+inhibitors	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+chronic	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+:	POS	O
+results	POS	O
+from	POS	O
+the	POS	O
+ATLAS	POS	O
+trial	POS	O
+.	POS	O
+The	POS	O
+Assessment	POS	O
+of	POS	O
+Treatment	POS	O
+with	POS	O
+Lisinopril	POS	O
+and	POS	O
+Survival	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Treatment	POS	O
+with	POS	O
+angiotensin	POS	O
+-	POS	O
+converting	POS	O
+enzyme	POS	O
+(	POS	O
+ACE	POS	O
+)	POS	O
+inhibitors	POS	O
+reduces	POS	O
+mortality	POS	O
+and	POS	O
+morbidity	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+chronic	POS	B-NP
+heart	POS	I-NP
+failure	POS	I-NP
+(	POS	O
+CHF	POS	B-NP
+)	POS	O
+,	POS	O
+but	POS	O
+most	POS	O
+affected	POS	O
+patients	POS	O
+are	POS	O
+not	POS	O
+receiving	POS	O
+these	POS	O
+agents	POS	O
+or	POS	O
+are	POS	O
+being	POS	O
+treated	POS	O
+with	POS	O
+doses	POS	O
+lower	POS	O
+than	POS	O
+those	POS	O
+found	POS	O
+to	POS	O
+be	POS	O
+efficacious	POS	O
+in	POS	O
+trials	POS	O
+,	POS	O
+primarily	POS	O
+because	POS	O
+of	POS	O
+concerns	POS	O
+about	POS	O
+the	POS	O
+safety	POS	O
+and	POS	O
+tolerability	POS	O
+of	POS	O
+these	POS	O
+agents	POS	O
+,	POS	O
+especially	POS	O
+at	POS	O
+the	POS	O
+recommended	POS	O
+doses	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+examines	POS	O
+the	POS	O
+safety	POS	O
+and	POS	O
+tolerability	POS	O
+of	POS	O
+high	POS	O
+-	POS	O
+compared	POS	O
+with	POS	O
+low	POS	O
+-	POS	O
+dose	POS	O
+lisinopril	POS	O
+in	POS	O
+CHF	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+The	POS	O
+Assessment	POS	O
+of	POS	O
+Lisinopril	POS	O
+and	POS	O
+Survival	POS	O
+study	POS	O
+was	POS	O
+a	POS	O
+multicenter	POS	O
+,	POS	O
+randomized	POS	O
+,	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+trial	POS	O
+in	POS	O
+which	POS	O
+patients	POS	O
+with	POS	O
+or	POS	O
+without	POS	O
+previous	POS	O
+ACE	POS	O
+inhibitor	POS	O
+treatment	POS	O
+were	POS	O
+stabilized	POS	O
+receiving	POS	O
+medium	POS	O
+-	POS	O
+dose	POS	O
+lisinopril	POS	O
+(	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+or	POS	O
+15	POS	O
+.	POS	O
+0	POS	O
+mg	POS	O
+once	POS	O
+daily	POS	O
+[	POS	O
+OD	POS	O
+]	POS	O
+)	POS	O
+for	POS	O
+2	POS	O
+to	POS	O
+4	POS	O
+weeks	POS	O
+and	POS	O
+then	POS	O
+randomized	POS	O
+to	POS	O
+high	POS	O
+-	POS	O
+(	POS	O
+35	POS	O
+.	POS	O
+0	POS	O
+or	POS	O
+32	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+OD	POS	O
+)	POS	O
+or	POS	O
+low	POS	O
+-	POS	O
+dose	POS	O
+(	POS	O
+5	POS	O
+.	POS	O
+0	POS	O
+or	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+OD	POS	O
+)	POS	O
+groups	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+New	POS	O
+York	POS	O
+Heart	POS	O
+Association	POS	O
+classes	POS	O
+II	POS	O
+to	POS	O
+IV	POS	O
+CHF	POS	B-NP
+and	POS	O
+left	POS	O
+ventricular	POS	O
+ejection	POS	O
+fractions	POS	O
+of	POS	O
+no	POS	O
+greater	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+30	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+3164	POS	O
+)	POS	O
+were	POS	O
+randomized	POS	O
+and	POS	O
+followed	POS	O
+up	POS	O
+for	POS	O
+a	POS	O
+median	POS	O
+of	POS	O
+46	POS	O
+months	POS	O
+.	POS	O
+We	POS	O
+examined	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+adverse	POS	O
+events	POS	O
+and	POS	O
+the	POS	O
+need	POS	O
+for	POS	O
+discontinuation	POS	O
+and	POS	O
+dose	POS	O
+reduction	POS	O
+during	POS	O
+treatment	POS	O
+,	POS	O
+with	POS	O
+a	POS	O
+focus	POS	O
+on	POS	O
+hypotension	POS	B-NP
+and	POS	O
+renal	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Of	POS	O
+405	POS	O
+patients	POS	O
+not	POS	O
+previously	POS	O
+receiving	POS	O
+an	POS	O
+ACE	POS	O
+inhibitor	POS	O
+,	POS	O
+doses	POS	O
+in	POS	O
+only	POS	O
+4	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+could	POS	O
+not	POS	O
+be	POS	O
+titrated	POS	O
+to	POS	O
+the	POS	O
+medium	POS	O
+doses	POS	O
+required	POS	O
+for	POS	O
+randomization	POS	O
+because	POS	O
+of	POS	O
+symptoms	POS	O
+possibly	POS	O
+related	POS	O
+to	POS	O
+hypotension	POS	B-NP
+(	POS	O
+2	POS	O
+.	POS	O
+0	POS	O
+%	POS	O
+)	POS	O
+or	POS	O
+because	POS	O
+of	POS	O
+renal	POS	B-NP
+dysfunction	POS	I-NP
+or	POS	O
+hyperkalemia	POS	B-NP
+(	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Doses	POS	O
+in	POS	O
+more	POS	O
+than	POS	O
+90	POS	O
+%	POS	O
+of	POS	O
+randomized	POS	O
+patients	POS	O
+in	POS	O
+the	POS	O
+high	POS	O
+-	POS	O
+and	POS	O
+low	POS	O
+-	POS	O
+dose	POS	O
+groups	POS	O
+were	POS	O
+titrated	POS	O
+to	POS	O
+their	POS	O
+assigned	POS	O
+target	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+mean	POS	O
+doses	POS	O
+of	POS	O
+blinded	POS	O
+medication	POS	O
+in	POS	O
+both	POS	O
+groups	POS	O
+remained	POS	O
+similar	POS	O
+throughout	POS	O
+the	POS	O
+study	POS	O
+.	POS	O
+Withdrawals	POS	B-NP
+occurred	POS	O
+in	POS	O
+27	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+high	POS	O
+-	POS	O
+and	POS	O
+30	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+low	POS	O
+-	POS	O
+dose	POS	O
+groups	POS	O
+.	POS	O
+Subgroups	POS	O
+presumed	POS	O
+to	POS	O
+be	POS	O
+at	POS	O
+higher	POS	O
+risk	POS	O
+for	POS	O
+ACE	POS	O
+inhibitor	POS	O
+intolerance	POS	O
+(	POS	O
+blood	POS	O
+pressure	POS	O
+,	POS	O
+<	POS	O
+120	POS	O
+mm	POS	O
+Hg	POS	O
+;	POS	O
+creatinine	POS	O
+,	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+132	POS	O
+.	POS	O
+6	POS	O
+micromol	POS	O
+/	POS	O
+L	POS	O
+[	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+]	POS	O
+;	POS	O
+age	POS	O
+,	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+70	POS	O
+years	POS	O
+;	POS	O
+and	POS	O
+patients	POS	O
+with	POS	O
+diabetes	POS	B-NP
+)	POS	O
+generally	POS	O
+tolerated	POS	O
+the	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+strategy	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+These	POS	O
+findings	POS	O
+demonstrate	POS	O
+that	POS	O
+ACE	POS	O
+inhibitor	POS	O
+therapy	POS	O
+in	POS	O
+most	POS	O
+patients	POS	O
+with	POS	O
+CHF	POS	B-NP
+can	POS	O
+be	POS	O
+successfully	POS	O
+titrated	POS	O
+to	POS	O
+and	POS	O
+maintained	POS	O
+at	POS	O
+high	POS	O
+doses	POS	O
+,	POS	O
+and	POS	O
+that	POS	O
+more	POS	O
+aggressive	POS	O
+use	POS	O
+of	POS	O
+these	POS	O
+agents	POS	O
+is	POS	O
+warranted	POS	O
+.	POS	O
+Cocaine	POS	O
+,	POS	O
+ethanol	POS	O
+,	POS	O
+and	POS	O
+cocaethylene	POS	O
+cardiotoxity	POS	O
+in	POS	O
+an	POS	O
+animal	POS	O
+model	POS	O
+of	POS	O
+cocaine	POS	O
+and	POS	O
+ethanol	POS	O
+abuse	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+Simultaneous	POS	O
+abuse	POS	O
+of	POS	O
+cocaine	POS	O
+and	POS	O
+ethanol	POS	O
+affects	POS	O
+12	POS	O
+million	POS	O
+Americans	POS	O
+annually	POS	O
+.	POS	O
+In	POS	O
+combination	POS	O
+,	POS	O
+these	POS	O
+substances	POS	O
+are	POS	O
+substantially	POS	O
+more	POS	O
+toxic	POS	O
+than	POS	O
+either	POS	O
+drug	POS	O
+alone	POS	O
+.	POS	O
+Their	POS	O
+combined	POS	O
+cardiac	POS	B-NP
+toxicity	POS	I-NP
+may	POS	O
+be	POS	O
+due	POS	O
+to	POS	O
+independent	POS	O
+effects	POS	O
+of	POS	O
+each	POS	O
+drug	POS	O
+;	POS	O
+however	POS	O
+,	POS	O
+they	POS	O
+may	POS	O
+also	POS	O
+be	POS	O
+due	POS	O
+to	POS	O
+cocaethylene	POS	O
+(	POS	O
+CE	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+cocaine	POS	O
+metabolite	POS	O
+formed	POS	O
+only	POS	O
+in	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+ethanol	POS	O
+.	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+delineate	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+CE	POS	O
+in	POS	O
+the	POS	O
+combined	POS	O
+cardiotoxicity	POS	B-NP
+of	POS	O
+cocaine	POS	O
+and	POS	O
+ethanol	POS	O
+in	POS	O
+a	POS	O
+model	POS	O
+simulating	POS	O
+their	POS	O
+abuse	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Twenty	POS	O
+-	POS	O
+three	POS	O
+dogs	POS	O
+were	POS	O
+randomized	POS	O
+to	POS	O
+receive	POS	O
+either	POS	O
+1	POS	O
+)	POS	O
+three	POS	O
+intravenous	POS	O
+(	POS	O
+IV	POS	O
+)	POS	O
+boluses	POS	O
+of	POS	O
+cocaine	POS	O
+7	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+with	POS	O
+ethanol	POS	O
+(	POS	O
+1	POS	O
+g	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+as	POS	O
+an	POS	O
+IV	POS	O
+infusion	POS	O
+(	POS	O
+C	POS	O
++	POS	O
+E	POS	O
+,	POS	O
+n	POS	O
+=	POS	O
+8	POS	O
+)	POS	O
+,	POS	O
+2	POS	O
+)	POS	O
+three	POS	O
+cocaine	POS	O
+boluses	POS	O
+only	POS	O
+(	POS	O
+C	POS	O
+,	POS	O
+n	POS	O
+=	POS	O
+6	POS	O
+)	POS	O
+,	POS	O
+3	POS	O
+)	POS	O
+ethanol	POS	O
+infusion	POS	O
+only	POS	O
+(	POS	O
+E	POS	O
+,	POS	O
+n	POS	O
+=	POS	O
+5	POS	O
+)	POS	O
+,	POS	O
+or	POS	O
+4	POS	O
+)	POS	O
+placebo	POS	O
+boluses	POS	O
+and	POS	O
+infusion	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+4	POS	O
+)	POS	O
+.	POS	O
+Hemodynamic	POS	O
+measurements	POS	O
+,	POS	O
+electrocardiograms	POS	O
+,	POS	O
+and	POS	O
+serum	POS	O
+drug	POS	O
+concentrations	POS	O
+were	POS	O
+obtained	POS	O
+at	POS	O
+baseline	POS	O
+,	POS	O
+and	POS	O
+then	POS	O
+at	POS	O
+fixed	POS	O
+time	POS	O
+intervals	POS	O
+after	POS	O
+each	POS	O
+drug	POS	O
+was	POS	O
+administered	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Two	POS	O
+of	POS	O
+eight	POS	O
+dogs	POS	O
+in	POS	O
+the	POS	O
+C	POS	O
++	POS	O
+E	POS	O
+group	POS	O
+experienced	POS	O
+cardiovascular	POS	B-NP
+collapse	POS	I-NP
+.	POS	O
+The	POS	O
+most	POS	O
+dramatic	POS	O
+hemodynamic	POS	O
+changes	POS	O
+occurred	POS	O
+after	POS	O
+each	POS	O
+cocaine	POS	O
+bolus	POS	O
+in	POS	O
+the	POS	O
+C	POS	O
++	POS	O
+E	POS	O
+and	POS	O
+C	POS	O
+only	POS	O
+groups	POS	O
+;	POS	O
+however	POS	O
+,	POS	O
+persistent	POS	O
+hemodynamic	POS	O
+changes	POS	O
+occurred	POS	O
+in	POS	O
+the	POS	O
+C	POS	O
++	POS	O
+E	POS	O
+group	POS	O
+.	POS	O
+Peak	POS	O
+CE	POS	O
+levels	POS	O
+were	POS	O
+associated	POS	O
+with	POS	O
+a	POS	O
+45	POS	O
+%	POS	O
+(	POS	O
+SD	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+22	POS	O
+%	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+22	POS	O
+%	POS	O
+to	POS	O
+69	POS	O
+%	POS	O
+)	POS	O
+decrease	POS	O
+in	POS	O
+cardiac	POS	O
+output	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+56	POS	O
+%	POS	O
+(	POS	O
+SD	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+23	POS	O
+%	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+32	POS	O
+%	POS	O
+to	POS	O
+80	POS	O
+%	POS	O
+)	POS	O
+decrease	POS	O
+in	POS	O
+dP	POS	O
+/	POS	O
+dt	POS	O
+(	POS	O
+max	POS	O
+)	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+.	POS	O
+006	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+23	POS	O
+%	POS	O
+(	POS	O
+SD	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+15	POS	O
+%	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+7	POS	O
+%	POS	O
+to	POS	O
+49	POS	O
+%	POS	O
+)	POS	O
+decrease	POS	O
+in	POS	O
+SVO	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+025	POS	O
+)	POS	O
+.	POS	O
+Ventricular	POS	B-NP
+arrhythmias	POS	I-NP
+were	POS	O
+primarily	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+C	POS	O
++	POS	O
+E	POS	O
+group	POS	O
+,	POS	O
+in	POS	O
+which	POS	O
+four	POS	O
+of	POS	O
+eight	POS	O
+dogs	POS	O
+experienced	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Cocaine	POS	O
+and	POS	O
+ethanol	POS	O
+in	POS	O
+combination	POS	O
+were	POS	O
+more	POS	O
+toxic	POS	O
+than	POS	O
+either	POS	O
+substance	POS	O
+alone	POS	O
+.	POS	O
+Co	POS	O
+-	POS	O
+administration	POS	O
+resulted	POS	O
+in	POS	O
+prolonged	POS	O
+cardiac	POS	B-NP
+toxicity	POS	I-NP
+and	POS	O
+was	POS	O
+dysrhythmogenic	POS	O
+.	POS	O
+Peak	POS	O
+serum	POS	O
+cocaethylene	POS	O
+concentrations	POS	O
+were	POS	O
+associated	POS	O
+with	POS	O
+prolonged	POS	O
+myocardial	POS	B-NP
+depression	POS	I-NP
+.	POS	O
+Worsening	POS	O
+of	POS	O
+Parkinsonism	POS	B-NP
+after	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+veralipride	POS	O
+for	POS	O
+treatment	POS	O
+of	POS	O
+menopause	POS	O
+:	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+We	POS	O
+describe	POS	O
+a	POS	O
+female	POS	O
+patient	POS	O
+with	POS	O
+stable	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+who	POS	O
+has	POS	O
+shown	POS	O
+a	POS	O
+marked	POS	O
+worsening	POS	O
+of	POS	O
+her	POS	O
+motor	POS	O
+functions	POS	O
+following	POS	O
+therapy	POS	O
+of	POS	O
+menopause	POS	O
+related	POS	O
+symptoms	POS	O
+with	POS	O
+veralipride	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+the	POS	O
+improvement	POS	O
+of	POS	O
+her	POS	O
+symptoms	POS	O
+back	POS	O
+to	POS	O
+baseline	POS	O
+after	POS	O
+discontinuation	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+.	POS	O
+We	POS	O
+emphasize	POS	O
+the	POS	O
+anti	POS	O
+-	POS	O
+dopaminergic	POS	O
+effect	POS	O
+of	POS	O
+veralipride	POS	O
+.	POS	O
+Viracept	POS	O
+and	POS	O
+irregular	POS	O
+heartbeat	POS	O
+warning	POS	O
+.	POS	O
+A	POS	O
+group	POS	O
+of	POS	O
+doctors	POS	O
+in	POS	O
+Boston	POS	O
+warn	POS	O
+that	POS	O
+the	POS	O
+protease	POS	O
+inhibitor	POS	O
+Viracept	POS	O
+may	POS	O
+cause	POS	O
+an	POS	O
+irregular	POS	O
+heart	POS	O
+beat	POS	O
+,	POS	O
+known	POS	O
+as	POS	O
+bradycardia	POS	B-NP
+,	POS	O
+in	POS	O
+people	POS	O
+with	POS	O
+HIV	POS	B-NP
+.	POS	O
+Bradycardia	POS	B-NP
+occurred	POS	O
+in	POS	O
+a	POS	O
+45	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+male	POS	O
+patient	POS	O
+who	POS	O
+was	POS	O
+Viracept	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+other	POS	O
+anti	POS	O
+-	POS	O
+HIV	POS	O
+drugs	POS	O
+.	POS	O
+The	POS	O
+symptoms	POS	O
+ceased	POS	O
+after	POS	O
+switching	POS	O
+to	POS	O
+another	POS	O
+drug	POS	O
+combination	POS	O
+.	POS	O
+Frequency	POS	O
+of	POS	O
+appearance	POS	O
+of	POS	O
+myeloperoxidase	POS	O
+-	POS	O
+antineutrophil	POS	O
+cytoplasmic	POS	O
+antibody	POS	O
+(	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	O
+)	POS	O
+in	POS	O
+Graves	POS	B-NP
+'	POS	I-NP
+disease	POS	I-NP
+patients	POS	O
+treated	POS	O
+with	POS	O
+propylthiouracil	POS	O
+and	POS	O
+the	POS	O
+relationship	POS	O
+between	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	B-NP
+and	POS	O
+clinical	POS	O
+manifestations	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+Myeloperoxidase	POS	O
+antineutrophil	POS	O
+cytoplasmic	POS	O
+antibody	POS	O
+(	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	O
+)	POS	O
+-	POS	O
+positive	POS	O
+vasculitis	POS	B-NP
+has	POS	O
+been	POS	O
+reported	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+Graves	POS	B-NP
+'	POS	I-NP
+disease	POS	I-NP
+who	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+propylthiouracil	POS	O
+(	POS	O
+PTU	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+appearance	POS	O
+of	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	B-NP
+in	POS	O
+these	POS	O
+cases	POS	O
+was	POS	O
+suspected	POS	O
+of	POS	O
+being	POS	O
+related	POS	O
+to	POS	O
+PTU	POS	B-NP
+because	POS	O
+the	POS	O
+titres	POS	O
+of	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	O
+decreased	POS	O
+when	POS	O
+PTU	POS	B-NP
+was	POS	O
+stopped	POS	O
+.	POS	O
+Nevertheless	POS	O
+,	POS	O
+there	POS	O
+have	POS	O
+been	POS	O
+no	POS	O
+studies	POS	O
+on	POS	O
+the	POS	O
+temporal	POS	O
+relationship	POS	O
+between	POS	O
+the	POS	O
+appearance	POS	O
+of	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	B-NP
+and	POS	O
+vasculitis	POS	B-NP
+during	POS	O
+PTU	POS	O
+therapy	POS	O
+,	POS	O
+or	POS	O
+on	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	B-NP
+in	POS	O
+untreated	POS	O
+Graves	POS	B-NP
+'	POS	I-NP
+disease	POS	I-NP
+patients	POS	O
+.	POS	O
+Therefore	POS	O
+,	POS	O
+we	POS	O
+sought	POS	O
+to	POS	O
+address	POS	O
+these	POS	O
+parameters	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+Graves	POS	B-NP
+'	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+PATIENTS	POS	O
+:	POS	O
+We	POS	O
+investigated	POS	O
+102	POS	O
+untreated	POS	O
+patients	POS	O
+with	POS	O
+hyperthyroidism	POS	B-NP
+due	POS	O
+to	POS	O
+Graves	POS	B-NP
+'	POS	I-NP
+disease	POS	I-NP
+for	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	B-NP
+,	POS	O
+and	POS	O
+for	POS	O
+the	POS	O
+development	POS	O
+vasculitis	POS	B-NP
+after	POS	O
+starting	POS	O
+PTU	POS	O
+therapy	POS	O
+.	POS	O
+Twenty	POS	O
+-	POS	O
+nine	POS	O
+of	POS	O
+them	POS	O
+were	POS	O
+later	POS	O
+excluded	POS	O
+because	POS	O
+of	POS	O
+adverse	POS	O
+effects	POS	O
+of	POS	O
+PTU	POS	B-NP
+or	POS	O
+because	POS	O
+the	POS	O
+observation	POS	O
+period	POS	O
+was	POS	O
+less	POS	O
+than	POS	O
+3	POS	O
+months	POS	O
+.	POS	O
+The	POS	O
+remaining	POS	O
+73	POS	O
+patients	POS	O
+(	POS	O
+55	POS	O
+women	POS	O
+and	POS	O
+18	POS	O
+men	POS	O
+)	POS	O
+,	POS	O
+all	POS	O
+of	POS	O
+whom	POS	O
+were	POS	O
+examined	POS	O
+for	POS	O
+more	POS	O
+than	POS	O
+3	POS	O
+months	POS	O
+,	POS	O
+were	POS	O
+adopted	POS	O
+as	POS	O
+the	POS	O
+subjects	POS	O
+of	POS	O
+the	POS	O
+investigation	POS	O
+.	POS	O
+The	POS	O
+median	POS	O
+observation	POS	O
+period	POS	O
+was	POS	O
+23	POS	O
+.	POS	O
+6	POS	O
+months	POS	O
+(	POS	O
+range	POS	O
+:	POS	O
+3	POS	O
+-	POS	O
+37	POS	O
+months	POS	O
+)	POS	O
+.	POS	O
+MEASUREMENTS	POS	O
+:	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	B-NP
+was	POS	O
+measured	POS	O
+at	POS	O
+intervals	POS	O
+of	POS	O
+2	POS	O
+-	POS	O
+6	POS	O
+months	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Before	POS	O
+treatment	POS	O
+,	POS	O
+the	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	O
+titres	POS	O
+of	POS	O
+all	POS	O
+102	POS	O
+untreated	POS	O
+Graves	POS	B-NP
+'	POS	I-NP
+disease	POS	I-NP
+patients	POS	O
+were	POS	O
+within	POS	O
+the	POS	O
+reference	POS	O
+range	POS	O
+(	POS	O
+below	POS	O
+10	POS	O
+U	POS	O
+/	POS	O
+ml	POS	O
+)	POS	O
+.	POS	O
+Three	POS	O
+(	POS	O
+4	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+)	POS	O
+of	POS	O
+the	POS	O
+73	POS	O
+patients	POS	O
+were	POS	O
+positive	POS	O
+for	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	B-NP
+at	POS	O
+13	POS	O
+,	POS	O
+16	POS	O
+and	POS	O
+17	POS	O
+months	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+after	POS	O
+the	POS	O
+start	POS	O
+of	POS	O
+PTU	POS	O
+therapy	POS	O
+.	POS	O
+In	POS	O
+two	POS	O
+of	POS	O
+them	POS	O
+,	POS	O
+the	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	O
+titres	POS	O
+transiently	POS	O
+increased	POS	O
+to	POS	O
+12	POS	O
+.	POS	O
+8	POS	O
+and	POS	O
+15	POS	O
+.	POS	O
+0	POS	O
+U	POS	O
+/	POS	O
+ml	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+despite	POS	O
+continued	POS	O
+PTU	POS	O
+therapy	POS	O
+,	POS	O
+but	POS	O
+no	POS	O
+vasculitic	POS	B-NP
+disorders	POS	I-NP
+developed	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+third	POS	O
+patient	POS	O
+,	POS	O
+the	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	O
+titre	POS	O
+increased	POS	O
+to	POS	O
+204	POS	O
+U	POS	O
+/	POS	O
+ml	POS	O
+and	POS	O
+she	POS	O
+developed	POS	O
+a	POS	O
+higher	POS	O
+fever	POS	B-NP
+,	POS	O
+oral	POS	B-NP
+ulcers	POS	I-NP
+and	POS	O
+polyarthralgia	POS	B-NP
+,	POS	O
+but	POS	O
+the	POS	O
+symptoms	POS	O
+resolved	POS	O
+2	POS	O
+weeks	POS	O
+after	POS	O
+stopping	POS	O
+PTU	POS	O
+therapy	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	O
+titre	POS	O
+decreased	POS	O
+to	POS	O
+20	POS	O
+.	POS	O
+7	POS	O
+U	POS	O
+/	POS	O
+ml	POS	O
+by	POS	O
+4	POS	O
+months	POS	O
+after	POS	O
+discontinuing	POS	O
+PTU	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+PTU	POS	O
+therapy	POS	O
+may	POS	O
+be	POS	O
+related	POS	O
+to	POS	O
+the	POS	O
+appearance	POS	O
+of	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	B-NP
+,	POS	O
+but	POS	O
+MPO	POS	O
+-	POS	O
+ANCA	POS	O
+does	POS	O
+not	POS	O
+appear	POS	O
+to	POS	O
+be	POS	O
+closely	POS	O
+related	POS	O
+to	POS	O
+vasculitis	POS	B-NP
+.	POS	O
+Prevalence	POS	O
+of	POS	O
+heart	POS	B-NP
+disease	POS	I-NP
+in	POS	O
+asymptomatic	POS	O
+chronic	POS	O
+cocaine	POS	O
+users	POS	O
+.	POS	O
+To	POS	O
+determine	POS	O
+the	POS	O
+prevalence	POS	O
+of	POS	O
+heart	POS	B-NP
+disease	POS	I-NP
+in	POS	O
+outpatient	POS	O
+young	POS	O
+asymptomatic	POS	O
+chronic	POS	O
+cocaine	POS	O
+users	POS	O
+,	POS	O
+35	POS	O
+cocaine	POS	O
+users	POS	O
+and	POS	O
+32	POS	O
+age	POS	O
+-	POS	O
+matched	POS	O
+controls	POS	O
+underwent	POS	O
+resting	POS	O
+and	POS	O
+exercise	POS	O
+electrocardiography	POS	O
+(	POS	O
+ECG	POS	O
+)	POS	O
+and	POS	O
+Doppler	POS	O
+echocardiography	POS	O
+.	POS	O
+Findings	POS	O
+consistent	POS	O
+with	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+were	POS	O
+detected	POS	O
+in	POS	O
+12	POS	O
+(	POS	O
+34	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+and	POS	O
+3	POS	O
+(	POS	O
+9	POS	O
+%	POS	O
+)	POS	O
+controls	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+Decreased	POS	O
+left	POS	O
+ventricular	POS	O
+systolic	POS	O
+function	POS	O
+was	POS	O
+demonstrated	POS	O
+in	POS	O
+5	POS	O
+(	POS	O
+14	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+,	POS	O
+but	POS	O
+in	POS	O
+none	POS	O
+of	POS	O
+the	POS	O
+controls	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+055	POS	O
+)	POS	O
+.	POS	O
+Finally	POS	O
+,	POS	O
+resting	POS	O
+and	POS	O
+peak	POS	O
+exercise	POS	O
+abnormal	POS	O
+left	POS	O
+ventricular	POS	O
+filling	POS	O
+was	POS	O
+detected	POS	O
+in	POS	O
+38	POS	O
+and	POS	O
+35	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+as	POS	O
+compared	POS	O
+to	POS	O
+19	POS	O
+and	POS	O
+9	POS	O
+%	POS	O
+of	POS	O
+controls	POS	O
+,	POS	O
+respectively	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+11	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+coronary	POS	O
+artery	POS	O
+or	POS	O
+myocardial	POS	B-NP
+disease	POS	I-NP
+is	POS	O
+common	POS	O
+(	POS	O
+38	POS	O
+%	POS	O
+)	POS	O
+in	POS	O
+young	POS	O
+asymptomatic	POS	O
+chronic	POS	O
+cocaine	POS	O
+users	POS	O
+.	POS	O
+Therefore	POS	O
+,	POS	O
+screening	POS	O
+ECG	POS	O
+and	POS	O
+echocardiography	POS	O
+may	POS	O
+be	POS	O
+warranted	POS	O
+in	POS	O
+these	POS	O
+patients	POS	O
+.	POS	O
+Cardioprotective	POS	O
+effects	POS	O
+of	POS	O
+Picrorrhiza	POS	O
+kurroa	POS	O
+against	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+myocardial	POS	O
+stress	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+cardioprotective	POS	O
+effect	POS	O
+of	POS	O
+the	POS	O
+ethanol	POS	O
+extract	POS	O
+of	POS	O
+Picrorrhiza	POS	O
+kurroa	POS	O
+rhizomes	POS	O
+and	POS	O
+roots	POS	O
+(	POS	O
+PK	POS	O
+)	POS	O
+on	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+in	POS	O
+rats	POS	O
+with	POS	O
+respect	POS	O
+to	POS	O
+lipid	POS	O
+metabolism	POS	O
+in	POS	O
+serum	POS	O
+and	POS	O
+heart	POS	O
+tissue	POS	O
+has	POS	O
+been	POS	O
+investigated	POS	O
+.	POS	O
+Oral	POS	O
+pre	POS	O
+-	POS	O
+treatment	POS	O
+with	POS	O
+PK	POS	O
+(	POS	O
+80	POS	O
+mg	POS	O
+kg	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+day	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+for	POS	O
+15	POS	O
+days	POS	O
+)	POS	O
+significantly	POS	O
+prevented	POS	O
+the	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+and	POS	O
+maintained	POS	O
+the	POS	O
+rats	POS	O
+at	POS	O
+near	POS	O
+normal	POS	O
+status	POS	O
+.	POS	O
+Phase	POS	O
+2	POS	O
+early	POS	O
+afterdepolarization	POS	B-NP
+as	POS	O
+a	POS	O
+trigger	POS	O
+of	POS	O
+polymorphic	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+in	POS	O
+acquired	POS	B-NP
+long	POS	I-NP
+-	POS	I-NP
+QT	POS	I-NP
+syndrome	POS	I-NP
+:	POS	O
+direct	POS	O
+evidence	POS	O
+from	POS	O
+intracellular	POS	O
+recordings	POS	O
+in	POS	O
+the	POS	O
+intact	POS	O
+left	POS	O
+ventricular	POS	O
+wall	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+This	POS	O
+study	POS	O
+examined	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+phase	POS	O
+2	POS	O
+early	POS	O
+afterdepolarization	POS	B-NP
+(	POS	O
+EAD	POS	B-NP
+)	POS	O
+in	POS	O
+producing	POS	O
+a	POS	O
+trigger	POS	O
+to	POS	O
+initiate	POS	O
+torsade	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+(	POS	O
+TdP	POS	B-NP
+)	POS	O
+with	POS	O
+QT	POS	B-NP
+prolongation	POS	I-NP
+induced	POS	O
+by	POS	O
+dl	POS	O
+-	POS	O
+sotalol	POS	O
+and	POS	O
+azimilide	POS	O
+.	POS	O
+The	POS	O
+contribution	POS	O
+of	POS	O
+transmural	POS	O
+dispersion	POS	O
+of	POS	O
+repolarization	POS	O
+(	POS	O
+TDR	POS	O
+)	POS	O
+to	POS	O
+transmural	POS	O
+propagation	POS	O
+of	POS	O
+EAD	POS	B-NP
+and	POS	O
+the	POS	O
+maintenance	POS	O
+of	POS	O
+TdP	POS	B-NP
+was	POS	O
+also	POS	O
+evaluated	POS	O
+.	POS	O
+METHODS	POS	O
+AND	POS	O
+RESULTS	POS	O
+:	POS	O
+Transmembrane	POS	O
+action	POS	O
+potentials	POS	O
+from	POS	O
+epicardium	POS	O
+,	POS	O
+midmyocardium	POS	O
+,	POS	O
+and	POS	O
+endocardium	POS	O
+were	POS	O
+recorded	POS	O
+simultaneously	POS	O
+,	POS	O
+together	POS	O
+with	POS	O
+a	POS	O
+transmural	POS	O
+ECG	POS	O
+,	POS	O
+in	POS	O
+arterially	POS	O
+perfused	POS	O
+canine	POS	O
+and	POS	O
+rabbit	POS	O
+left	POS	O
+ventricular	POS	O
+preparations	POS	O
+.	POS	O
+dl	POS	O
+-	POS	O
+Sotalol	POS	O
+preferentially	POS	O
+prolonged	POS	O
+action	POS	O
+potential	POS	O
+duration	POS	O
+(	POS	O
+APD	POS	O
+)	POS	O
+in	POS	O
+M	POS	O
+cells	POS	O
+dose	POS	O
+-	POS	O
+dependently	POS	O
+(	POS	O
+1	POS	O
+to	POS	O
+100	POS	O
+micromol	POS	O
+/	POS	O
+L	POS	O
+)	POS	O
+,	POS	O
+leading	POS	O
+to	POS	O
+QT	POS	O
+prolongation	POS	O
+and	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+TDR	POS	O
+.	POS	O
+Azimilide	POS	O
+,	POS	O
+however	POS	O
+,	POS	O
+significantly	POS	O
+prolonged	POS	O
+APD	POS	O
+and	POS	O
+QT	POS	O
+interval	POS	O
+at	POS	O
+concentrations	POS	O
+from	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+to	POS	O
+10	POS	O
+micromol	POS	O
+/	POS	O
+L	POS	O
+but	POS	O
+shortened	POS	O
+them	POS	O
+at	POS	O
+30	POS	O
+micromol	POS	O
+/	POS	O
+L	POS	O
+.	POS	O
+Unlike	POS	O
+dl	POS	O
+-	POS	O
+sotalol	POS	O
+,	POS	O
+azimilide	POS	O
+(	POS	O
+>	POS	O
+3	POS	O
+micromol	POS	O
+/	POS	O
+L	POS	O
+)	POS	O
+increased	POS	O
+epicardial	POS	O
+APD	POS	O
+markedly	POS	O
+,	POS	O
+causing	POS	O
+a	POS	O
+diminished	POS	O
+TDR	POS	O
+.	POS	O
+Although	POS	O
+both	POS	O
+dl	POS	O
+-	POS	O
+sotalol	POS	O
+and	POS	O
+azimilide	POS	O
+rarely	POS	O
+induced	POS	O
+EADs	POS	B-NP
+in	POS	O
+canine	POS	O
+left	POS	O
+ventricles	POS	O
+,	POS	O
+they	POS	O
+produced	POS	O
+frequent	POS	O
+EADs	POS	B-NP
+in	POS	O
+rabbits	POS	O
+,	POS	O
+in	POS	O
+which	POS	O
+more	POS	O
+pronounced	POS	O
+QT	POS	B-NP
+prolongation	POS	I-NP
+was	POS	O
+seen	POS	O
+.	POS	O
+An	POS	O
+increase	POS	O
+in	POS	O
+TDR	POS	O
+by	POS	O
+dl	POS	O
+-	POS	O
+sotalol	POS	O
+facilitated	POS	O
+transmural	POS	O
+propagation	POS	O
+of	POS	O
+EADs	POS	B-NP
+that	POS	O
+initiated	POS	O
+multiple	POS	O
+episodes	POS	O
+of	POS	O
+spontaneous	POS	O
+TdP	POS	B-NP
+in	POS	O
+3	POS	O
+of	POS	O
+6	POS	O
+rabbit	POS	O
+left	POS	O
+ventricles	POS	O
+.	POS	O
+Of	POS	O
+note	POS	O
+,	POS	O
+although	POS	O
+azimilide	POS	O
+(	POS	O
+3	POS	O
+to	POS	O
+10	POS	O
+micromol	POS	O
+/	POS	O
+L	POS	O
+)	POS	O
+increased	POS	O
+APD	POS	O
+more	POS	O
+than	POS	O
+dl	POS	O
+-	POS	O
+sotalol	POS	O
+,	POS	O
+its	POS	O
+EADs	POS	B-NP
+often	POS	O
+failed	POS	O
+to	POS	O
+propagate	POS	O
+transmurally	POS	O
+,	POS	O
+probably	POS	O
+because	POS	O
+of	POS	O
+a	POS	O
+diminished	POS	O
+TDR	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+This	POS	O
+study	POS	O
+provides	POS	O
+the	POS	O
+first	POS	O
+direct	POS	O
+evidence	POS	O
+from	POS	O
+intracellular	POS	O
+action	POS	O
+potential	POS	O
+recordings	POS	O
+that	POS	O
+phase	POS	O
+2	POS	O
+EAD	POS	B-NP
+can	POS	O
+be	POS	O
+generated	POS	O
+from	POS	O
+intact	POS	O
+ventricular	POS	O
+wall	POS	O
+and	POS	O
+produce	POS	O
+a	POS	O
+trigger	POS	O
+to	POS	O
+initiate	POS	O
+the	POS	O
+onset	POS	O
+of	POS	O
+TdP	POS	B-NP
+under	POS	O
+QT	POS	O
+prolongation	POS	O
+.	POS	O
+A	POS	O
+pilot	POS	O
+study	POS	O
+to	POS	O
+assess	POS	O
+the	POS	O
+safety	POS	O
+of	POS	O
+dobutamine	POS	O
+stress	POS	O
+echocardiography	POS	O
+in	POS	O
+the	POS	O
+emergency	POS	O
+department	POS	O
+evaluation	POS	O
+of	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+.	POS	O
+STUDY	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+Chest	POS	B-NP
+pain	POS	I-NP
+in	POS	O
+the	POS	O
+setting	POS	O
+of	POS	O
+cocaine	POS	O
+use	POS	O
+poses	POS	O
+a	POS	O
+diagnostic	POS	O
+dilemma	POS	O
+.	POS	O
+Dobutamine	POS	O
+stress	POS	O
+echocardiography	POS	O
+(	POS	O
+DSE	POS	O
+)	POS	O
+is	POS	O
+a	POS	O
+widely	POS	O
+available	POS	O
+and	POS	O
+sensitive	POS	O
+test	POS	O
+for	POS	O
+evaluating	POS	O
+cardiac	POS	B-NP
+ischemia	POS	I-NP
+.	POS	O
+Because	POS	O
+of	POS	O
+the	POS	O
+theoretical	POS	O
+concern	POS	O
+regarding	POS	O
+administration	POS	O
+of	POS	O
+dobutamine	POS	O
+in	POS	O
+the	POS	O
+setting	POS	O
+of	POS	O
+cocaine	POS	O
+use	POS	O
+,	POS	O
+we	POS	O
+conducted	POS	O
+a	POS	O
+pilot	POS	O
+study	POS	O
+to	POS	O
+assess	POS	O
+the	POS	O
+safety	POS	O
+of	POS	O
+DSE	POS	O
+in	POS	O
+emergency	POS	O
+department	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+A	POS	O
+prospective	POS	O
+case	POS	O
+series	POS	O
+was	POS	O
+conducted	POS	O
+in	POS	O
+the	POS	O
+intensive	POS	O
+diagnostic	POS	O
+and	POS	O
+treatment	POS	O
+unit	POS	O
+in	POS	O
+the	POS	O
+ED	POS	O
+of	POS	O
+an	POS	O
+urban	POS	O
+tertiary	POS	O
+-	POS	O
+care	POS	O
+teaching	POS	O
+hospital	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+eligible	POS	O
+for	POS	O
+DSE	POS	B-NP
+if	POS	O
+they	POS	O
+had	POS	O
+used	POS	O
+cocaine	POS	O
+within	POS	O
+24	POS	O
+hours	POS	O
+preceding	POS	O
+the	POS	O
+onset	POS	O
+of	POS	O
+chest	POS	B-NP
+pain	POS	I-NP
+and	POS	O
+had	POS	O
+a	POS	O
+normal	POS	O
+ECG	POS	O
+and	POS	O
+tropinin	POS	O
+I	POS	O
+level	POS	O
+.	POS	O
+Patients	POS	O
+exhibiting	POS	O
+signs	POS	O
+of	POS	O
+continuing	POS	O
+cocaine	POS	B-NP
+toxicity	POS	I-NP
+were	POS	O
+excluded	POS	O
+from	POS	O
+the	POS	O
+study	POS	O
+.	POS	O
+All	POS	O
+patients	POS	O
+were	POS	O
+admitted	POS	O
+to	POS	O
+the	POS	O
+hospital	POS	O
+for	POS	O
+serial	POS	O
+testing	POS	O
+after	POS	O
+the	POS	O
+DSE	POS	O
+testing	POS	O
+in	POS	O
+the	POS	O
+intensive	POS	O
+diagnostic	POS	O
+and	POS	O
+treatment	POS	O
+unit	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Twenty	POS	O
+-	POS	O
+four	POS	O
+patients	POS	O
+were	POS	O
+enrolled	POS	O
+.	POS	O
+Two	POS	O
+patients	POS	O
+had	POS	O
+inadequate	POS	O
+resting	POS	O
+images	POS	O
+,	POS	O
+one	POS	O
+DSE	POS	O
+was	POS	O
+terminated	POS	O
+because	POS	O
+of	POS	O
+inferior	POS	B-NP
+hypokinesis	POS	I-NP
+,	POS	O
+another	POS	O
+DSE	POS	O
+was	POS	O
+terminated	POS	O
+because	POS	O
+of	POS	O
+a	POS	O
+rate	POS	O
+-	POS	O
+related	POS	O
+atrial	POS	B-NP
+conduction	POS	I-NP
+deficit	POS	I-NP
+,	POS	O
+and	POS	O
+1	POS	O
+patient	POS	O
+did	POS	O
+not	POS	O
+reach	POS	O
+the	POS	O
+target	POS	O
+heart	POS	O
+rate	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+19	POS	O
+patients	POS	O
+completed	POS	O
+a	POS	O
+DSE	POS	O
+and	POS	O
+reached	POS	O
+their	POS	O
+target	POS	O
+heart	POS	O
+rates	POS	O
+.	POS	O
+None	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+experienced	POS	O
+signs	POS	O
+of	POS	O
+exaggerated	POS	O
+adrenergic	POS	O
+response	POS	O
+,	POS	O
+which	POS	O
+was	POS	O
+defined	POS	O
+as	POS	O
+a	POS	O
+systolic	POS	O
+blood	POS	O
+pressure	POS	O
+of	POS	O
+greater	POS	O
+than	POS	O
+200	POS	O
+mm	POS	O
+Hg	POS	O
+or	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+tachydysrhythmias	POS	B-NP
+(	POS	O
+excluding	POS	O
+sinus	POS	B-NP
+tachycardia	POS	I-NP
+)	POS	O
+.	POS	O
+Further	POS	O
+suggesting	POS	O
+lack	POS	O
+of	POS	O
+exaggerated	POS	O
+adrenergic	POS	O
+response	POS	O
+,	POS	O
+13	POS	O
+(	POS	O
+65	POS	O
+%	POS	O
+)	POS	O
+of	POS	O
+20	POS	O
+patients	POS	O
+required	POS	O
+supplemental	POS	O
+atropine	POS	O
+to	POS	O
+reach	POS	O
+their	POS	O
+target	POS	O
+heart	POS	O
+rates	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+No	POS	O
+exaggerated	POS	O
+adrenergic	POS	O
+response	POS	O
+was	POS	O
+detected	POS	O
+when	POS	O
+dobutamine	POS	O
+was	POS	O
+administered	POS	O
+to	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+related	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+.	POS	O
+Prenatal	POS	O
+cocaine	POS	O
+exposure	POS	O
+and	POS	O
+cranial	POS	O
+sonographic	POS	O
+findings	POS	O
+in	POS	O
+preterm	POS	B-NP
+infants	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+Prenatal	POS	O
+cocaine	POS	O
+exposure	POS	O
+has	POS	O
+been	POS	O
+linked	POS	O
+with	POS	O
+subependymal	POS	B-NP
+hemorrhage	POS	I-NP
+and	POS	O
+the	POS	O
+formation	POS	O
+of	POS	O
+cysts	POS	B-NP
+that	POS	O
+are	POS	O
+detectable	POS	O
+on	POS	O
+cranial	POS	O
+sonography	POS	O
+in	POS	O
+neonates	POS	O
+born	POS	O
+at	POS	O
+term	POS	O
+.	POS	O
+We	POS	O
+sought	POS	O
+to	POS	O
+determine	POS	O
+if	POS	O
+prenatal	POS	O
+cocaine	POS	O
+exposure	POS	O
+increases	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+subependymal	POS	B-NP
+cysts	POS	I-NP
+in	POS	O
+preterm	POS	B-NP
+infants	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+retrospectively	POS	O
+reviewed	POS	O
+the	POS	O
+medical	POS	O
+records	POS	O
+and	POS	O
+cranial	POS	O
+sonograms	POS	O
+obtained	POS	O
+during	POS	O
+a	POS	O
+1	POS	O
+-	POS	O
+year	POS	O
+period	POS	O
+on	POS	O
+122	POS	O
+premature	POS	O
+(	POS	O
+<	POS	O
+36	POS	O
+weeks	POS	O
+of	POS	O
+gestation	POS	O
+)	POS	O
+infants	POS	O
+.	POS	O
+Infants	POS	O
+were	POS	O
+categorized	POS	O
+into	POS	O
+1	POS	O
+of	POS	O
+2	POS	O
+groups	POS	O
+:	POS	O
+those	POS	O
+exposed	POS	O
+to	POS	O
+cocaine	POS	O
+and	POS	O
+those	POS	O
+not	POS	O
+exposed	POS	O
+to	POS	O
+cocaine	POS	O
+.	POS	O
+Infants	POS	O
+were	POS	O
+assigned	POS	O
+to	POS	O
+the	POS	O
+cocaine	POS	O
+-	POS	O
+exposed	POS	O
+group	POS	O
+if	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+maternal	POS	O
+history	POS	O
+of	POS	O
+cocaine	POS	B-NP
+abuse	POS	I-NP
+during	POS	O
+pregnancy	POS	O
+or	POS	O
+if	POS	O
+maternal	POS	O
+or	POS	O
+neonatal	POS	O
+urine	POS	O
+toxicology	POS	O
+results	POS	O
+were	POS	O
+positive	POS	O
+at	POS	O
+the	POS	O
+time	POS	O
+of	POS	O
+delivery	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Five	POS	O
+of	POS	O
+the	POS	O
+122	POS	O
+infants	POS	O
+were	POS	O
+excluded	POS	O
+from	POS	O
+the	POS	O
+study	POS	O
+because	POS	O
+of	POS	O
+insufficient	POS	O
+medical	POS	O
+and	POS	O
+drug	POS	O
+histories	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+subependymal	POS	B-NP
+cysts	POS	I-NP
+in	POS	O
+the	POS	O
+117	POS	O
+remaining	POS	O
+infants	POS	O
+was	POS	O
+14	POS	O
+%	POS	O
+(	POS	O
+16	POS	O
+of	POS	O
+117	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+subependymal	POS	B-NP
+cysts	POS	I-NP
+in	POS	O
+infants	POS	O
+exposed	POS	O
+to	POS	O
+cocaine	POS	O
+prenatally	POS	O
+was	POS	O
+44	POS	O
+%	POS	O
+(	POS	O
+8	POS	O
+of	POS	O
+18	POS	O
+)	POS	O
+compared	POS	O
+with	POS	O
+8	POS	O
+%	POS	O
+(	POS	O
+8	POS	O
+of	POS	O
+99	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+unexposed	POS	O
+group	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+We	POS	O
+found	POS	O
+an	POS	O
+increased	POS	O
+incidence	POS	O
+of	POS	O
+subependymal	POS	B-NP
+cyst	POS	I-NP
+formation	POS	O
+in	POS	O
+preterm	POS	B-NP
+infants	POS	O
+who	POS	O
+were	POS	O
+exposed	POS	O
+to	POS	O
+cocaine	POS	O
+prenatally	POS	O
+.	POS	O
+This	POS	O
+result	POS	O
+is	POS	O
+consistent	POS	O
+with	POS	O
+results	POS	O
+of	POS	O
+similar	POS	O
+studies	POS	O
+in	POS	O
+term	POS	O
+infants	POS	O
+.	POS	O
+Thalidomide	POS	B-NP
+neuropathy	POS	I-NP
+in	POS	O
+patients	POS	O
+treated	POS	O
+for	POS	O
+metastatic	POS	B-NP
+prostate	POS	I-NP
+cancer	POS	I-NP
+.	POS	O
+We	POS	O
+prospectively	POS	O
+evaluated	POS	O
+thalidomide	POS	O
+-	POS	O
+induced	POS	O
+neuropathy	POS	B-NP
+using	POS	O
+electrodiagnostic	POS	O
+studies	POS	O
+.	POS	O
+Sixty	POS	O
+-	POS	O
+seven	POS	O
+men	POS	O
+with	POS	O
+metastatic	POS	B-NP
+androgen	POS	I-NP
+-	POS	I-NP
+independent	POS	I-NP
+prostate	POS	I-NP
+cancer	POS	I-NP
+in	POS	O
+an	POS	O
+open	POS	O
+-	POS	O
+label	POS	O
+trial	POS	O
+of	POS	O
+oral	POS	O
+thalidomide	POS	O
+underwent	POS	O
+neurologic	POS	O
+examinations	POS	O
+and	POS	O
+nerve	POS	O
+conduction	POS	O
+studies	POS	O
+(	POS	O
+NCS	POS	O
+)	POS	O
+prior	POS	O
+to	POS	O
+and	POS	O
+at	POS	O
+3	POS	O
+-	POS	O
+month	POS	O
+intervals	POS	O
+during	POS	O
+treatment	POS	O
+.	POS	O
+NCS	POS	O
+included	POS	O
+recording	POS	O
+of	POS	O
+sensory	POS	O
+nerve	POS	O
+action	POS	O
+potentials	POS	O
+(	POS	O
+SNAPs	POS	O
+)	POS	O
+from	POS	O
+median	POS	O
+,	POS	O
+radial	POS	O
+,	POS	O
+ulnar	POS	O
+,	POS	O
+and	POS	O
+sural	POS	O
+nerves	POS	O
+.	POS	O
+SNAP	POS	O
+amplitudes	POS	O
+for	POS	O
+each	POS	O
+nerve	POS	O
+were	POS	O
+expressed	POS	O
+as	POS	O
+the	POS	O
+percentage	POS	O
+of	POS	O
+its	POS	O
+baseline	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+mean	POS	O
+of	POS	O
+the	POS	O
+four	POS	O
+was	POS	O
+termed	POS	O
+the	POS	O
+SNAP	POS	O
+index	POS	O
+.	POS	O
+A	POS	O
+40	POS	O
+%	POS	O
+decline	POS	O
+in	POS	O
+the	POS	O
+SNAP	POS	O
+index	POS	O
+was	POS	O
+considered	POS	O
+clinically	POS	O
+significant	POS	O
+.	POS	O
+Thalidomide	POS	B-NP
+was	POS	O
+discontinued	POS	O
+in	POS	O
+55	POS	O
+patients	POS	O
+for	POS	O
+lack	POS	O
+of	POS	O
+therapeutic	POS	O
+response	POS	O
+.	POS	O
+Of	POS	O
+67	POS	O
+patients	POS	O
+initially	POS	O
+enrolled	POS	O
+,	POS	O
+24	POS	O
+remained	POS	O
+on	POS	O
+thalidomide	POS	O
+for	POS	O
+3	POS	O
+months	POS	O
+,	POS	O
+8	POS	O
+remained	POS	O
+at	POS	O
+6	POS	O
+months	POS	O
+,	POS	O
+and	POS	O
+3	POS	O
+remained	POS	O
+at	POS	O
+9	POS	O
+months	POS	O
+.	POS	O
+Six	POS	O
+patients	POS	O
+developed	POS	O
+neuropathy	POS	B-NP
+.	POS	O
+Clinical	POS	O
+symptoms	POS	O
+and	POS	O
+a	POS	O
+decline	POS	O
+in	POS	O
+the	POS	O
+SNAP	POS	O
+index	POS	O
+occurred	POS	O
+concurrently	POS	O
+.	POS	O
+Older	POS	O
+age	POS	O
+and	POS	O
+cumulative	POS	O
+dose	POS	O
+were	POS	O
+possible	POS	O
+contributing	POS	O
+factors	POS	O
+.	POS	O
+Neuropathy	POS	B-NP
+may	POS	O
+thus	POS	O
+be	POS	O
+a	POS	O
+common	POS	O
+complication	POS	O
+of	POS	O
+thalidomide	POS	O
+in	POS	O
+older	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+SNAP	POS	O
+index	POS	O
+can	POS	O
+be	POS	O
+used	POS	O
+to	POS	O
+monitor	POS	O
+peripheral	POS	B-NP
+neuropathy	POS	I-NP
+,	POS	O
+but	POS	O
+not	POS	O
+for	POS	O
+early	POS	O
+detection	POS	O
+.	POS	O
+Overexpression	POS	O
+of	POS	O
+copper	POS	O
+/	POS	O
+zinc	POS	O
+-	POS	O
+superoxide	POS	O
+dismutase	POS	O
+protects	POS	O
+from	POS	O
+kanamycin	POS	O
+-	POS	O
+induced	POS	O
+hearing	POS	B-NP
+loss	POS	I-NP
+.	POS	O
+The	POS	O
+participation	POS	O
+of	POS	O
+reactive	POS	O
+oxygen	POS	O
+species	POS	O
+in	POS	O
+aminoglycoside	POS	O
+-	POS	O
+induced	POS	O
+ototoxicity	POS	B-NP
+has	POS	O
+been	POS	O
+deduced	POS	O
+from	POS	O
+observations	POS	O
+that	POS	O
+aminoglycoside	POS	O
+-	POS	O
+iron	POS	O
+complexes	POS	O
+catalyze	POS	O
+the	POS	O
+formation	POS	O
+of	POS	O
+superoxide	POS	O
+radicals	POS	O
+in	POS	O
+vitro	POS	O
+and	POS	O
+that	POS	O
+antioxidants	POS	O
+attenuate	POS	O
+ototoxicity	POS	B-NP
+in	POS	O
+vivo	POS	O
+.	POS	O
+We	POS	O
+therefore	POS	O
+hypothesized	POS	O
+that	POS	O
+overexpression	POS	O
+of	POS	O
+Cu	POS	O
+/	POS	O
+Zn	POS	O
+-	POS	O
+superoxide	POS	O
+dismutase	POS	O
+(	POS	O
+h	POS	O
+-	POS	O
+SOD1	POS	O
+)	POS	O
+should	POS	O
+protect	POS	O
+transgenic	POS	O
+mice	POS	O
+from	POS	O
+ototoxicity	POS	B-NP
+.	POS	O
+Immunocytochemistry	POS	O
+confirmed	POS	O
+expression	POS	O
+of	POS	O
+h	POS	O
+-	POS	O
+SOD1	POS	O
+in	POS	O
+inner	POS	O
+ear	POS	O
+tissues	POS	O
+of	POS	O
+transgenic	POS	O
+C57BL	POS	O
+/	POS	O
+6	POS	O
+-	POS	O
+TgN	POS	O
+[	POS	O
+SOD1	POS	O
+]	POS	O
+3Cje	POS	O
+mice	POS	O
+.	POS	O
+Transgenic	POS	O
+and	POS	O
+nontransgenic	POS	O
+littermates	POS	O
+received	POS	O
+kanamycin	POS	O
+(	POS	O
+400	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+body	POS	O
+weight	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+for	POS	O
+10	POS	O
+days	POS	O
+beginning	POS	O
+on	POS	O
+day	POS	O
+10	POS	O
+after	POS	O
+birth	POS	O
+.	POS	O
+Auditory	POS	O
+thresholds	POS	O
+were	POS	O
+tested	POS	O
+by	POS	O
+evoked	POS	O
+auditory	POS	O
+brain	POS	O
+stem	POS	O
+responses	POS	O
+at	POS	O
+1	POS	O
+month	POS	O
+after	POS	O
+birth	POS	O
+.	POS	O
+In	POS	O
+nontransgenic	POS	O
+animals	POS	O
+,	POS	O
+the	POS	O
+threshold	POS	O
+in	POS	O
+the	POS	O
+kanamycin	POS	O
+-	POS	O
+treated	POS	O
+group	POS	O
+was	POS	O
+45	POS	O
+-	POS	O
+50	POS	O
+dB	POS	O
+higher	POS	O
+than	POS	O
+in	POS	O
+saline	POS	O
+-	POS	O
+injected	POS	O
+controls	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+transgenic	POS	O
+group	POS	O
+,	POS	O
+kanamycin	POS	O
+increased	POS	O
+the	POS	O
+threshold	POS	O
+by	POS	O
+only	POS	O
+15	POS	O
+dB	POS	O
+over	POS	O
+the	POS	O
+respective	POS	O
+controls	POS	O
+.	POS	O
+The	POS	O
+effects	POS	O
+were	POS	O
+similar	POS	O
+at	POS	O
+12	POS	O
+and	POS	O
+24	POS	O
+kHz	POS	O
+.	POS	O
+The	POS	O
+protection	POS	O
+by	POS	O
+overexpression	POS	O
+of	POS	O
+superoxide	POS	O
+dismutase	POS	O
+supports	POS	O
+the	POS	O
+hypothesis	POS	O
+that	POS	O
+oxidant	POS	O
+stress	POS	O
+plays	POS	O
+a	POS	O
+significant	POS	O
+role	POS	O
+in	POS	O
+aminoglycoside	POS	O
+-	POS	O
+induced	POS	O
+ototoxicity	POS	B-NP
+.	POS	O
+The	POS	O
+results	POS	O
+also	POS	O
+suggest	POS	O
+transgenic	POS	O
+animals	POS	O
+as	POS	O
+suitable	POS	O
+models	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+underlying	POS	O
+mechanisms	POS	O
+and	POS	O
+possible	POS	O
+strategies	POS	O
+for	POS	O
+prevention	POS	O
+.	POS	O
+Fatty	POS	O
+liver	POS	O
+induced	POS	O
+by	POS	O
+tetracycline	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+.	POS	O
+Dose	POS	O
+-	POS	O
+response	POS	O
+relationships	POS	O
+and	POS	O
+effect	POS	O
+of	POS	O
+sex	POS	O
+.	POS	O
+Dose	POS	O
+-	POS	O
+response	POS	O
+relationships	POS	O
+,	POS	O
+biochemical	POS	O
+mechanisms	POS	O
+,	POS	O
+and	POS	O
+sex	POS	O
+differences	POS	O
+in	POS	O
+the	POS	O
+experimental	POS	O
+fatty	POS	O
+liver	POS	O
+induced	POS	O
+by	POS	O
+tetracycline	POS	O
+were	POS	O
+studied	POS	O
+in	POS	O
+the	POS	O
+intact	POS	O
+rat	POS	O
+and	POS	O
+with	POS	O
+the	POS	O
+isolated	POS	O
+perfused	POS	O
+rat	POS	O
+liver	POS	O
+in	POS	O
+vitro	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+intact	POS	O
+male	POS	O
+and	POS	O
+female	POS	O
+rat	POS	O
+,	POS	O
+no	POS	O
+direct	POS	O
+relationship	POS	O
+was	POS	O
+observed	POS	O
+between	POS	O
+dose	POS	O
+of	POS	O
+tetracycline	POS	O
+and	POS	O
+hepatic	POS	O
+accumulation	POS	O
+of	POS	O
+triglyceride	POS	O
+.	POS	O
+With	POS	O
+provision	POS	O
+of	POS	O
+adequate	POS	O
+oleic	POS	O
+acid	POS	O
+as	POS	O
+a	POS	O
+substrate	POS	O
+for	POS	O
+the	POS	O
+isolated	POS	O
+perfused	POS	O
+liver	POS	O
+,	POS	O
+a	POS	O
+direct	POS	O
+relationship	POS	O
+was	POS	O
+observed	POS	O
+between	POS	O
+dose	POS	O
+of	POS	O
+tetracycline	POS	O
+and	POS	O
+both	POS	O
+accumulation	POS	O
+of	POS	O
+triglyceride	POS	O
+in	POS	O
+the	POS	O
+liver	POS	O
+and	POS	O
+depression	POS	B-NP
+of	POS	O
+output	POS	O
+of	POS	O
+triglyceride	POS	O
+by	POS	O
+livers	POS	O
+from	POS	O
+male	POS	O
+and	POS	O
+female	POS	O
+rats	POS	O
+.	POS	O
+Marked	POS	O
+differences	POS	O
+were	POS	O
+observed	POS	O
+between	POS	O
+female	POS	O
+and	POS	O
+male	POS	O
+rats	POS	O
+with	POS	O
+regard	POS	O
+to	POS	O
+base	POS	O
+line	POS	O
+(	POS	O
+control	POS	O
+)	POS	O
+hepatic	POS	O
+concentration	POS	O
+of	POS	O
+triglyceride	POS	O
+and	POS	O
+output	POS	O
+of	POS	O
+triglyceride	POS	O
+.	POS	O
+Accumulation	POS	O
+of	POS	O
+hepatic	POS	O
+triglyceride	POS	O
+,	POS	O
+as	POS	O
+a	POS	O
+per	POS	O
+cent	POS	O
+of	POS	O
+control	POS	O
+values	POS	O
+,	POS	O
+in	POS	O
+response	POS	O
+to	POS	O
+graded	POS	O
+doses	POS	O
+of	POS	O
+tetracycline	POS	O
+,	POS	O
+did	POS	O
+not	POS	O
+differ	POS	O
+significantly	POS	O
+between	POS	O
+male	POS	O
+,	POS	O
+female	POS	O
+and	POS	O
+pregnant	POS	O
+rat	POS	O
+livers	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+livers	POS	O
+from	POS	O
+female	POS	O
+,	POS	O
+and	POS	O
+especially	POS	O
+pregnant	POS	O
+female	POS	O
+rats	POS	O
+,	POS	O
+were	POS	O
+strikingly	POS	O
+resistant	POS	O
+to	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+tetracycline	POS	O
+on	POS	O
+depression	POS	B-NP
+of	POS	O
+output	POS	O
+of	POS	O
+triglyceride	POS	O
+under	POS	O
+these	POS	O
+experimental	POS	O
+conditions	POS	O
+.	POS	O
+These	POS	O
+differences	POS	O
+between	POS	O
+the	POS	O
+sexes	POS	O
+could	POS	O
+not	POS	O
+be	POS	O
+related	POS	O
+to	POS	O
+altered	POS	O
+disposition	POS	O
+of	POS	O
+tetracycline	POS	O
+or	POS	O
+altered	POS	O
+uptake	POS	O
+of	POS	O
+oleic	POS	O
+acid	POS	O
+.	POS	O
+Depressed	POS	O
+hepatic	POS	O
+secretion	POS	O
+of	POS	O
+triglyceride	POS	O
+accounted	POS	O
+only	POS	O
+for	POS	O
+30	POS	O
+to	POS	O
+50	POS	O
+%	POS	O
+of	POS	O
+accumulated	POS	O
+hepatic	POS	O
+triglyceride	POS	O
+,	POS	O
+indicating	POS	O
+that	POS	O
+additional	POS	O
+mechanisms	POS	O
+must	POS	O
+be	POS	O
+involved	POS	O
+in	POS	O
+the	POS	O
+production	POS	O
+of	POS	O
+the	POS	O
+triglyceride	POS	O
+-	POS	O
+rich	POS	O
+fatty	POS	O
+liver	POS	O
+in	POS	O
+response	POS	O
+to	POS	O
+tetracycline	POS	O
+.	POS	O
+Prednisone	POS	O
+induces	POS	O
+anxiety	POS	B-NP
+and	POS	O
+glial	POS	O
+cerebral	POS	O
+changes	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+assess	POS	O
+whether	POS	O
+prednisone	POS	O
+(	POS	O
+PDN	POS	O
+)	POS	O
+produces	POS	O
+anxiety	POS	B-NP
+and	POS	O
+/	POS	O
+or	POS	O
+cerebral	POS	O
+glial	POS	O
+changes	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Male	POS	O
+Wistar	POS	O
+rats	POS	O
+were	POS	O
+studied	POS	O
+and	POS	O
+3	POS	O
+groups	POS	O
+were	POS	O
+formed	POS	O
+(	POS	O
+8	POS	O
+rats	POS	O
+per	POS	O
+group	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+moderate	POS	O
+-	POS	O
+dose	POS	O
+group	POS	O
+received	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+PDN	POS	O
+released	POS	O
+from	POS	O
+a	POS	O
+subcutaneous	POS	O
+implant	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+group	POS	O
+,	POS	O
+implants	POS	O
+containing	POS	O
+PDN	POS	O
+equivalent	POS	O
+to	POS	O
+60	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+were	POS	O
+applied	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+implants	POS	O
+contained	POS	O
+no	POS	O
+PDN	POS	O
+.	POS	O
+Anxiety	POS	O
+was	POS	O
+assessed	POS	O
+using	POS	O
+an	POS	O
+open	POS	O
+field	POS	O
+and	POS	O
+elevated	POS	O
+plus	POS	O
+-	POS	O
+maze	POS	O
+devices	POS	O
+.	POS	O
+The	POS	O
+number	POS	O
+of	POS	O
+cells	POS	O
+and	POS	O
+cytoplasmic	POS	O
+transformation	POS	O
+of	POS	O
+astrocytes	POS	O
+and	POS	O
+microglia	POS	O
+cells	POS	O
+were	POS	O
+assessed	POS	O
+by	POS	O
+immunohistochemical	POS	O
+analyses	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Anxiety	POS	B-NP
+was	POS	O
+documented	POS	O
+in	POS	O
+both	POS	O
+groups	POS	O
+of	POS	O
+PDN	POS	O
+treated	POS	O
+rats	POS	O
+compared	POS	O
+with	POS	O
+controls	POS	O
+.	POS	O
+The	POS	O
+magnitude	POS	O
+of	POS	O
+transformation	POS	O
+of	POS	O
+the	POS	O
+microglia	POS	O
+assessed	POS	O
+by	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+intersections	POS	O
+was	POS	O
+significantly	POS	O
+higher	POS	O
+in	POS	O
+the	POS	O
+PDN	POS	O
+groups	POS	O
+than	POS	O
+in	POS	O
+controls	POS	O
+in	POS	O
+the	POS	O
+prefrontal	POS	O
+cortex	POS	O
+(	POS	O
+moderate	POS	O
+-	POS	O
+dose	POS	O
+,	POS	O
+24	POS	O
+.	POS	O
+1	POS	O
+;	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+,	POS	O
+23	POS	O
+.	POS	O
+6	POS	O
+;	POS	O
+controls	POS	O
+18	POS	O
+.	POS	O
+7	POS	O
+;	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+and	POS	O
+striatum	POS	O
+(	POS	O
+moderate	POS	O
+-	POS	O
+dose	POS	O
+25	POS	O
+.	POS	O
+6	POS	O
+;	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+26	POS	O
+.	POS	O
+3	POS	O
+;	POS	O
+controls	POS	O
+18	POS	O
+.	POS	O
+9	POS	O
+;	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+in	POS	O
+hippocampus	POS	O
+.	POS	O
+The	POS	O
+number	POS	O
+of	POS	O
+stained	POS	O
+microglia	POS	O
+cells	POS	O
+was	POS	O
+significantly	POS	O
+higher	POS	O
+in	POS	O
+the	POS	O
+PDN	POS	O
+treated	POS	O
+groups	POS	O
+in	POS	O
+the	POS	O
+prefrontal	POS	O
+cortex	POS	O
+than	POS	O
+in	POS	O
+controls	POS	O
+(	POS	O
+moderate	POS	O
+-	POS	O
+dose	POS	O
+,	POS	O
+29	POS	O
+.	POS	O
+1	POS	O
+;	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+,	POS	O
+28	POS	O
+.	POS	O
+4	POS	O
+;	POS	O
+control	POS	O
+,	POS	O
+17	POS	O
+.	POS	O
+7	POS	O
+cells	POS	O
+per	POS	O
+field	POS	O
+;	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+Stained	POS	O
+microglia	POS	O
+cells	POS	O
+were	POS	O
+significantly	POS	O
+more	POS	O
+numerous	POS	O
+striatum	POS	O
+and	POS	O
+hippocampus	POS	O
+in	POS	O
+the	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+group	POS	O
+compared	POS	O
+to	POS	O
+controls	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Subacute	POS	O
+exposure	POS	O
+to	POS	O
+PDN	POS	O
+induced	POS	O
+anxiety	POS	B-NP
+and	POS	O
+reactivity	POS	O
+of	POS	O
+microglia	POS	O
+.	POS	O
+The	POS	O
+relevance	POS	O
+of	POS	O
+these	POS	O
+features	POS	O
+for	POS	O
+patients	POS	O
+using	POS	O
+PDN	POS	B-NP
+remains	POS	O
+to	POS	O
+be	POS	O
+elucidated	POS	O
+.	POS	O
+Phase	POS	O
+II	POS	O
+study	POS	O
+of	POS	O
+carboplatin	POS	O
+and	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+recurrent	POS	O
+squamous	POS	B-NP
+cell	POS	I-NP
+carcinoma	POS	I-NP
+of	POS	I-NP
+the	POS	I-NP
+cervix	POS	I-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+The	POS	O
+activity	POS	O
+of	POS	O
+the	POS	O
+combination	POS	O
+of	POS	O
+carboplatin	POS	O
+and	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+was	POS	O
+tested	POS	O
+in	POS	O
+a	POS	O
+Phase	POS	O
+II	POS	O
+study	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+recurrent	POS	O
+cervical	POS	B-NP
+carcinoma	POS	I-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+The	POS	O
+combination	POS	O
+of	POS	O
+carboplatin	POS	O
+(	POS	O
+area	POS	O
+under	POS	O
+the	POS	O
+concentration	POS	O
+curve	POS	O
+[	POS	O
+AUC	POS	O
+]	POS	O
+,	POS	O
+5	POS	O
+)	POS	O
+and	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+(	POS	O
+Doxil	POS	O
+;	POS	O
+starting	POS	O
+dose	POS	O
+,	POS	O
+40	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+)	POS	O
+was	POS	O
+administered	POS	O
+intravenously	POS	O
+every	POS	O
+28	POS	O
+days	POS	O
+to	POS	O
+37	POS	O
+patients	POS	O
+with	POS	O
+recurrent	POS	O
+squamous	POS	B-NP
+cell	POS	I-NP
+cervical	POS	I-NP
+carcinoma	POS	I-NP
+to	POS	O
+determine	POS	O
+antitumor	POS	O
+activity	POS	O
+and	POS	O
+toxicity	POS	B-NP
+profile	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Twenty	POS	O
+-	POS	O
+nine	POS	O
+patients	POS	O
+were	POS	O
+assessable	POS	O
+for	POS	O
+response	POS	O
+,	POS	O
+and	POS	O
+35	POS	O
+patients	POS	O
+were	POS	O
+assessable	POS	O
+for	POS	O
+toxicity	POS	B-NP
+.	POS	O
+The	POS	O
+overall	POS	O
+response	POS	O
+rate	POS	O
+was	POS	O
+38	POS	O
+%	POS	O
+,	POS	O
+the	POS	O
+median	POS	O
+time	POS	O
+to	POS	O
+response	POS	O
+was	POS	O
+10	POS	O
+weeks	POS	O
+,	POS	O
+the	POS	O
+median	POS	O
+duration	POS	O
+of	POS	O
+response	POS	O
+was	POS	O
+26	POS	O
+weeks	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+median	POS	O
+survival	POS	O
+was	POS	O
+37	POS	O
+weeks	POS	O
+.	POS	O
+The	POS	O
+main	POS	O
+toxic	POS	O
+effect	POS	O
+was	POS	O
+myelosuppression	POS	B-NP
+,	POS	O
+with	POS	O
+Grade	POS	O
+3	POS	O
+and	POS	O
+4	POS	O
+neutropenia	POS	B-NP
+in	POS	O
+16	POS	O
+patients	POS	O
+,	POS	O
+anemia	POS	B-NP
+in	POS	O
+12	POS	O
+patients	POS	O
+,	POS	O
+thrombocytopenia	POS	B-NP
+in	POS	O
+11	POS	O
+patients	POS	O
+,	POS	O
+and	POS	O
+neutropenic	POS	B-NP
+fever	POS	I-NP
+in	POS	O
+3	POS	O
+patients	POS	O
+.	POS	O
+Four	POS	O
+patients	POS	O
+had	POS	O
+five	POS	O
+infusion	POS	O
+-	POS	O
+related	POS	O
+reactions	POS	O
+during	POS	O
+the	POS	O
+infusion	POS	O
+of	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+,	POS	O
+leading	POS	O
+to	POS	O
+treatment	POS	O
+discontinuation	POS	O
+in	POS	O
+three	POS	O
+patients	POS	O
+.	POS	O
+Grade	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+2	POS	O
+nonhematologic	POS	O
+toxicity	POS	B-NP
+included	POS	O
+nausea	POS	B-NP
+in	POS	O
+17	POS	O
+patients	POS	O
+,	POS	O
+emesis	POS	B-NP
+in	POS	O
+14	POS	O
+patients	POS	O
+,	POS	O
+fatigue	POS	B-NP
+in	POS	O
+9	POS	O
+patients	POS	O
+,	POS	O
+mucositis	POS	B-NP
+and	POS	O
+/	POS	O
+or	POS	O
+stomatitis	POS	B-NP
+in	POS	O
+8	POS	O
+patients	POS	O
+,	POS	O
+constipation	POS	B-NP
+in	POS	O
+6	POS	O
+patients	POS	O
+,	POS	O
+weight	POS	B-NP
+loss	POS	I-NP
+in	POS	O
+5	POS	O
+patients	POS	O
+,	POS	O
+hand	POS	B-NP
+-	POS	I-NP
+foot	POS	I-NP
+syndrome	POS	I-NP
+in	POS	O
+2	POS	O
+patients	POS	O
+,	POS	O
+and	POS	O
+skin	POS	B-NP
+reactions	POS	I-NP
+in	POS	O
+3	POS	O
+patients	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+combination	POS	O
+of	POS	O
+carboplatin	POS	O
+and	POS	O
+liposomal	POS	O
+doxorubicin	POS	O
+has	POS	O
+modest	POS	O
+activity	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+recurrent	POS	O
+cervical	POS	B-NP
+carcinoma	POS	I-NP
+.	POS	O
+Antimicrobial	POS	O
+-	POS	O
+induced	POS	O
+mania	POS	B-NP
+(	POS	O
+antibiomania	POS	B-NP
+)	POS	O
+:	POS	O
+a	POS	O
+review	POS	O
+of	POS	O
+spontaneous	POS	O
+reports	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+reviewed	POS	O
+reported	POS	O
+cases	POS	O
+of	POS	O
+antibiotic	POS	O
+-	POS	O
+induced	POS	O
+manic	POS	B-NP
+episodes	POS	O
+by	POS	O
+means	POS	O
+of	POS	O
+a	POS	O
+MEDLINE	POS	O
+and	POS	O
+PsychLit	POS	O
+search	POS	O
+for	POS	O
+reports	POS	O
+of	POS	O
+antibiotic	POS	O
+-	POS	O
+induced	POS	O
+mania	POS	B-NP
+.	POS	O
+Unpublished	POS	O
+reports	POS	O
+were	POS	O
+requested	POS	O
+from	POS	O
+the	POS	O
+World	POS	O
+Health	POS	O
+Organization	POS	O
+(	POS	O
+WHO	POS	O
+)	POS	O
+and	POS	O
+the	POS	O
+Food	POS	O
+and	POS	O
+Drug	POS	O
+Administration	POS	O
+(	POS	O
+FDA	POS	O
+)	POS	O
+.	POS	O
+Twenty	POS	O
+-	POS	O
+one	POS	O
+reports	POS	O
+of	POS	O
+antimicrobial	POS	O
+-	POS	O
+induced	POS	O
+mania	POS	B-NP
+were	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+literature	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+6	POS	O
+cases	POS	O
+implicating	POS	O
+clarithromycin	POS	O
+,	POS	O
+13	POS	O
+implicating	POS	O
+isoniazid	POS	O
+,	POS	O
+and	POS	O
+1	POS	O
+case	POS	O
+each	POS	O
+implicating	POS	O
+erythromycin	POS	O
+and	POS	O
+amoxicillin	POS	O
+.	POS	O
+The	POS	O
+WHO	POS	O
+reported	POS	O
+82	POS	O
+cases	POS	O
+.	POS	O
+Of	POS	O
+these	POS	O
+,	POS	O
+clarithromycin	POS	O
+was	POS	O
+implicated	POS	O
+in	POS	O
+23	POS	O
+(	POS	O
+27	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+)	POS	O
+cases	POS	O
+,	POS	O
+ciprofloxacin	POS	O
+in	POS	O
+12	POS	O
+(	POS	O
+14	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+cases	POS	O
+,	POS	O
+and	POS	O
+ofloxacin	POS	O
+in	POS	O
+10	POS	O
+(	POS	O
+12	POS	O
+%	POS	O
+)	POS	O
+cases	POS	O
+.	POS	O
+Cotrimoxazole	POS	O
+,	POS	O
+metronidazole	POS	O
+,	POS	O
+and	POS	O
+erythromycin	POS	O
+were	POS	O
+involved	POS	O
+in	POS	O
+15	POS	O
+reported	POS	O
+manic	POS	B-NP
+episodes	POS	O
+.	POS	O
+Cases	POS	O
+reported	POS	O
+by	POS	O
+the	POS	O
+FDA	POS	O
+showed	POS	O
+clarithromycin	POS	O
+and	POS	O
+ciprofloxacin	POS	O
+to	POS	O
+be	POS	O
+the	POS	O
+most	POS	O
+frequently	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+mania	POS	B-NP
+.	POS	O
+Statistical	POS	O
+analysis	POS	O
+of	POS	O
+the	POS	O
+data	POS	O
+would	POS	O
+not	POS	O
+have	POS	O
+demonstrated	POS	O
+a	POS	O
+significant	POS	O
+statistical	POS	O
+correlative	POS	O
+risk	POS	O
+and	POS	O
+was	POS	O
+therefore	POS	O
+not	POS	O
+undertaken	POS	O
+.	POS	O
+Patients	POS	O
+have	POS	O
+an	POS	O
+increased	POS	O
+risk	POS	O
+of	POS	O
+developing	POS	O
+mania	POS	B-NP
+while	POS	O
+being	POS	O
+treated	POS	O
+with	POS	O
+antimicrobials	POS	O
+.	POS	O
+Although	POS	O
+this	POS	O
+is	POS	O
+not	POS	O
+a	POS	O
+statistically	POS	O
+significant	POS	O
+risk	POS	O
+,	POS	O
+physicians	POS	O
+must	POS	O
+be	POS	O
+aware	POS	O
+of	POS	O
+the	POS	O
+effect	POS	O
+and	POS	O
+reversibility	POS	O
+.	POS	O
+Further	POS	O
+research	POS	O
+clearly	POS	O
+is	POS	O
+required	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+antimicrobial	POS	O
+-	POS	O
+induced	POS	O
+mania	POS	B-NP
+,	POS	O
+the	POS	O
+relative	POS	O
+risk	POS	O
+factors	POS	O
+of	POS	O
+developing	POS	O
+an	POS	O
+antimicrobial	POS	O
+-	POS	O
+induced	POS	O
+manic	POS	B-NP
+episode	POS	O
+among	POS	O
+various	POS	O
+demographic	POS	O
+populations	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+patients	POS	O
+who	POS	O
+continue	POS	O
+to	POS	O
+have	POS	O
+persistent	POS	O
+affective	POS	B-NP
+disorders	POS	I-NP
+once	POS	O
+the	POS	O
+initial	POS	O
+episode	POS	O
+,	POS	O
+which	POS	O
+occurs	POS	O
+while	POS	O
+the	POS	O
+patient	POS	O
+is	POS	O
+taking	POS	O
+antibiotics	POS	O
+,	POS	O
+subsides	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+elected	POS	O
+to	POS	O
+name	POS	O
+this	POS	O
+syndrome	POS	O
+"	POS	O
+antibiomania	POS	B-NP
+.	POS	O
+"	POS	O
+Levodopa	POS	O
+-	POS	O
+induced	POS	O
+ocular	POS	B-NP
+dyskinesias	POS	I-NP
+in	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+Levodopa	POS	O
+-	POS	O
+induced	POS	O
+ocular	POS	B-NP
+dyskinesias	POS	I-NP
+are	POS	O
+very	POS	O
+uncommon	POS	O
+.	POS	O
+Usually	POS	O
+they	POS	O
+occur	POS	O
+simultaneously	POS	O
+with	POS	O
+limb	POS	O
+peak	POS	O
+-	POS	O
+dose	POS	O
+choreatic	POS	B-NP
+dyskinesias	POS	I-NP
+.	POS	O
+We	POS	O
+report	POS	O
+on	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+leftward	POS	O
+and	POS	O
+upward	POS	O
+deviations	POS	O
+of	POS	O
+gaze	POS	O
+during	POS	O
+the	POS	O
+peak	POS	O
+effect	POS	O
+of	POS	O
+levodopa	POS	O
+,	POS	O
+and	POS	O
+hypothesize	POS	O
+that	POS	O
+a	POS	O
+severe	POS	O
+dopaminergic	POS	O
+denervation	POS	O
+in	POS	O
+the	POS	O
+caudate	POS	O
+nucleus	POS	O
+is	POS	O
+needed	POS	O
+for	POS	O
+the	POS	O
+appearance	POS	O
+of	POS	O
+these	POS	O
+levodopa	POS	O
+-	POS	O
+induce	POS	O
+ocular	POS	O
+dyskinesias	POS	B-NP
+.	POS	O
+A	POS	O
+comparison	POS	O
+of	POS	O
+glyceryl	POS	O
+trinitrate	POS	O
+with	POS	O
+diclofenac	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+primary	POS	O
+dysmenorrhea	POS	B-NP
+:	POS	O
+an	POS	O
+open	POS	O
+,	POS	O
+randomized	POS	O
+,	POS	O
+cross	POS	O
+-	POS	O
+over	POS	O
+trial	POS	O
+.	POS	O
+Primary	POS	B-NP
+dysmenorrhea	POS	I-NP
+is	POS	O
+a	POS	O
+syndrome	POS	O
+characterized	POS	O
+by	POS	O
+painful	POS	B-NP
+uterine	POS	I-NP
+contractility	POS	I-NP
+caused	POS	O
+by	POS	O
+a	POS	O
+hypersecretion	POS	O
+of	POS	O
+endometrial	POS	O
+prostaglandins	POS	O
+;	POS	O
+non	POS	O
+-	POS	O
+steroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+are	POS	O
+the	POS	O
+first	POS	O
+choice	POS	O
+for	POS	O
+its	POS	O
+treatment	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+in	POS	O
+vivo	POS	O
+and	POS	O
+in	POS	O
+vitro	POS	O
+studies	POS	O
+have	POS	O
+demonstrated	POS	O
+that	POS	O
+myometrial	POS	O
+cells	POS	O
+are	POS	O
+also	POS	O
+targets	POS	O
+of	POS	O
+the	POS	O
+relaxant	POS	O
+effects	POS	O
+of	POS	O
+nitric	POS	O
+oxide	POS	O
+(	POS	O
+NO	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+efficacy	POS	O
+of	POS	O
+glyceryl	POS	O
+trinitrate	POS	O
+(	POS	O
+GTN	POS	O
+)	POS	O
+,	POS	O
+an	POS	O
+NO	POS	O
+donor	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+resolution	POS	O
+of	POS	O
+primary	POS	O
+dysmenorrhea	POS	B-NP
+in	POS	O
+comparison	POS	O
+with	POS	O
+diclofenac	POS	O
+(	POS	O
+DCF	POS	O
+)	POS	O
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+24	POS	O
+patients	POS	O
+with	POS	O
+the	POS	O
+diagnosis	POS	O
+of	POS	O
+severe	POS	O
+primary	POS	O
+dysmenorrhea	POS	B-NP
+were	POS	O
+studied	POS	O
+during	POS	O
+two	POS	O
+consecutive	POS	O
+menstrual	POS	O
+cycles	POS	O
+.	POS	O
+In	POS	O
+an	POS	O
+open	POS	O
+,	POS	O
+cross	POS	O
+-	POS	O
+over	POS	O
+,	POS	O
+controlled	POS	O
+design	POS	O
+,	POS	O
+patients	POS	O
+were	POS	O
+randomized	POS	O
+to	POS	O
+receive	POS	O
+either	POS	O
+DCF	POS	O
+per	POS	O
+os	POS	O
+or	POS	O
+GTN	POS	O
+patches	POS	O
+the	POS	O
+first	POS	O
+days	POS	O
+of	POS	O
+menses	POS	O
+,	POS	O
+when	POS	O
+menstrual	POS	B-NP
+cramps	POS	I-NP
+became	POS	O
+unendurable	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+subsequent	POS	O
+cycle	POS	O
+the	POS	O
+other	POS	O
+treatment	POS	O
+was	POS	O
+used	POS	O
+.	POS	O
+Patients	POS	O
+received	POS	O
+up	POS	O
+to	POS	O
+3	POS	O
+doses	POS	O
+/	POS	O
+day	POS	O
+of	POS	O
+50	POS	O
+mg	POS	O
+DCF	POS	O
+or	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+24	POS	O
+h	POS	O
+transdermal	POS	O
+GTN	POS	O
+for	POS	O
+the	POS	O
+first	POS	O
+3	POS	O
+days	POS	O
+of	POS	O
+the	POS	O
+cycle	POS	O
+,	POS	O
+according	POS	O
+to	POS	O
+their	POS	O
+needs	POS	O
+.	POS	O
+The	POS	O
+participants	POS	O
+recorded	POS	O
+menstrual	POS	O
+symptoms	POS	O
+and	POS	O
+possible	POS	O
+side	POS	O
+-	POS	O
+effects	POS	O
+at	POS	O
+different	POS	O
+times	POS	O
+(	POS	O
+0	POS	O
+,	POS	O
+30	POS	O
+,	POS	O
+60	POS	O
+,	POS	O
+120	POS	O
+minutes	POS	O
+)	POS	O
+after	POS	O
+the	POS	O
+first	POS	O
+dose	POS	O
+of	POS	O
+medication	POS	O
+on	POS	O
+the	POS	O
+first	POS	O
+day	POS	O
+of	POS	O
+the	POS	O
+cycle	POS	O
+,	POS	O
+with	POS	O
+both	POS	O
+drugs	POS	O
+.	POS	O
+The	POS	O
+difference	POS	O
+in	POS	O
+pain	POS	B-NP
+intensity	POS	O
+score	POS	O
+(	POS	O
+DPI	POS	O
+)	POS	O
+was	POS	O
+the	POS	O
+main	POS	O
+outcome	POS	O
+variable	POS	O
+.	POS	O
+Both	POS	O
+treatments	POS	O
+significantly	POS	O
+reduced	POS	O
+DPI	POS	O
+by	POS	O
+the	POS	O
+30th	POS	O
+minute	POS	O
+(	POS	O
+GTN	POS	O
+,	POS	O
+-	POS	O
+12	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+17	POS	O
+.	POS	O
+9	POS	O
+;	POS	O
+DCF	POS	O
+,	POS	O
+-	POS	O
+18	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+16	POS	O
+.	POS	O
+6	POS	O
+)	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+DCF	POS	O
+continued	POS	O
+to	POS	O
+be	POS	O
+effective	POS	O
+in	POS	O
+reducing	POS	O
+pelvic	POS	B-NP
+pain	POS	I-NP
+for	POS	O
+two	POS	O
+hours	POS	O
+,	POS	O
+whereas	POS	O
+GTN	POS	O
+scores	POS	O
+remained	POS	O
+more	POS	O
+or	POS	O
+less	POS	O
+stable	POS	O
+after	POS	O
+30	POS	O
+min	POS	O
+and	POS	O
+significantly	POS	O
+higher	POS	O
+than	POS	O
+those	POS	O
+for	POS	O
+DFC	POS	B-NP
+(	POS	O
+after	POS	O
+one	POS	O
+hour	POS	O
+:	POS	O
+GTN	POS	O
+,	POS	O
+-	POS	O
+12	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+17	POS	O
+.	POS	O
+9	POS	O
+;	POS	O
+DFC	POS	O
+,	POS	O
+-	POS	O
+18	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+16	POS	O
+.	POS	O
+6	POS	O
+and	POS	O
+after	POS	O
+two	POS	O
+hours	POS	O
+:	POS	O
+GTN	POS	O
+,	POS	O
+-	POS	O
+23	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+20	POS	O
+.	POS	O
+5	POS	O
+;	POS	O
+DFC	POS	O
+,	POS	O
+-	POS	O
+59	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+17	POS	O
+.	POS	O
+9	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+0001	POS	O
+)	POS	O
+.	POS	O
+Low	POS	B-NP
+back	POS	I-NP
+pain	POS	I-NP
+was	POS	O
+also	POS	O
+relieved	POS	O
+by	POS	O
+both	POS	O
+drugs	POS	O
+.	POS	O
+Headache	POS	B-NP
+was	POS	O
+significantly	POS	O
+increased	POS	O
+by	POS	O
+GTN	POS	O
+but	POS	O
+not	POS	O
+by	POS	O
+DCF	POS	O
+.	POS	O
+Eight	POS	O
+patients	POS	O
+stopped	POS	O
+using	POS	O
+GTN	POS	O
+because	POS	O
+headache	POS	B-NP
+-	POS	O
+-	POS	O
+attributed	POS	O
+to	POS	O
+its	POS	O
+use	POS	O
+-	POS	O
+-	POS	O
+became	POS	O
+intolerable	POS	O
+.	POS	O
+These	POS	O
+findings	POS	O
+indicate	POS	O
+that	POS	O
+GTN	POS	O
+has	POS	O
+a	POS	O
+reduced	POS	O
+efficacy	POS	O
+and	POS	O
+tolerability	POS	O
+by	POS	O
+comparison	POS	O
+with	POS	O
+DCF	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+primary	POS	O
+dysmenorrhea	POS	B-NP
+.	POS	O
+Temocapril	POS	O
+,	POS	O
+a	POS	O
+long	POS	O
+-	POS	O
+acting	POS	O
+non	POS	O
+-	POS	O
+SH	POS	O
+group	POS	O
+angiotensin	POS	O
+converting	POS	O
+enzyme	POS	O
+inhibitor	POS	O
+,	POS	O
+modulates	POS	O
+glomerular	POS	B-NP
+injury	POS	I-NP
+in	POS	O
+chronic	POS	O
+puromycin	POS	O
+aminonucleoside	POS	O
+nephrosis	POS	B-NP
+.	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+determine	POS	O
+whether	POS	O
+chronic	POS	O
+administration	POS	O
+of	POS	O
+temocapril	POS	O
+,	POS	O
+a	POS	O
+long	POS	O
+-	POS	O
+acting	POS	O
+non	POS	O
+-	POS	O
+SH	POS	O
+group	POS	O
+angiotensin	POS	O
+converting	POS	O
+enzyme	POS	O
+(	POS	O
+ACE	POS	O
+)	POS	O
+inhibitor	POS	O
+,	POS	O
+reduced	POS	O
+proteinuria	POS	B-NP
+,	POS	O
+inhibited	POS	O
+glomerular	POS	B-NP
+hypertrophy	POS	I-NP
+and	POS	O
+prevented	POS	O
+glomerulosclerosis	POS	B-NP
+in	POS	O
+chronic	POS	O
+puromycin	POS	O
+aminonucleoside	POS	O
+(	POS	O
+PAN	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+nephrotic	POS	B-NP
+rats	POS	O
+.	POS	O
+Nephrosis	POS	B-NP
+was	POS	O
+induced	POS	O
+by	POS	O
+injection	POS	O
+of	POS	O
+PAN	POS	O
+(	POS	O
+15mg	POS	O
+/	POS	O
+100g	POS	O
+body	POS	O
+weight	POS	O
+)	POS	O
+in	POS	O
+male	POS	O
+Sprague	POS	O
+-	POS	O
+Dawley	POS	O
+(	POS	O
+SD	POS	O
+)	POS	O
+rats	POS	O
+.	POS	O
+Four	POS	O
+groups	POS	O
+were	POS	O
+used	POS	O
+,	POS	O
+i	POS	O
+)	POS	O
+the	POS	O
+PAN	POS	O
+group	POS	O
+(	POS	O
+14	POS	O
+)	POS	O
+,	POS	O
+ii	POS	O
+)	POS	O
+PAN	POS	O
+/	POS	O
+temocapril	POS	O
+(	POS	O
+13	POS	O
+)	POS	O
+,	POS	O
+iii	POS	O
+)	POS	O
+temocapril	POS	O
+(	POS	O
+14	POS	O
+)	POS	O
+and	POS	O
+iv	POS	O
+)	POS	O
+untreated	POS	O
+controls	POS	O
+(	POS	O
+15	POS	O
+)	POS	O
+.	POS	O
+Temocapril	POS	O
+(	POS	O
+8	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+was	POS	O
+administered	POS	O
+to	POS	O
+the	POS	O
+rats	POS	O
+which	POS	O
+were	POS	O
+killed	POS	O
+at	POS	O
+weeks	POS	O
+4	POS	O
+,	POS	O
+14	POS	O
+or	POS	O
+20	POS	O
+.	POS	O
+At	POS	O
+each	POS	O
+time	POS	O
+point	POS	O
+,	POS	O
+systolic	POS	O
+blood	POS	O
+pressure	POS	O
+(	POS	O
+BP	POS	O
+)	POS	O
+,	POS	O
+urinary	POS	O
+protein	POS	O
+excretion	POS	O
+and	POS	O
+renal	POS	O
+histopathological	POS	O
+findings	POS	O
+were	POS	O
+evaluated	POS	O
+,	POS	O
+and	POS	O
+morphometric	POS	O
+image	POS	O
+analysis	POS	O
+was	POS	O
+done	POS	O
+.	POS	O
+Systolic	POS	O
+BP	POS	O
+in	POS	O
+the	POS	O
+PAN	POS	O
+group	POS	O
+was	POS	O
+significantly	POS	O
+high	POS	O
+at	POS	O
+4	POS	O
+,	POS	O
+14	POS	O
+and	POS	O
+20	POS	O
+weeks	POS	O
+,	POS	O
+but	POS	O
+was	POS	O
+normal	POS	O
+in	POS	O
+the	POS	O
+PAN	POS	O
+/	POS	O
+temocapril	POS	O
+group	POS	O
+.	POS	O
+Urinary	POS	O
+protein	POS	O
+excretion	POS	O
+in	POS	O
+the	POS	O
+PAN	POS	O
+group	POS	O
+increased	POS	O
+significantly	POS	O
+,	POS	O
+peaking	POS	O
+at	POS	O
+8	POS	O
+days	POS	O
+,	POS	O
+then	POS	O
+decreased	POS	O
+at	POS	O
+4	POS	O
+weeks	POS	O
+,	POS	O
+but	POS	O
+rose	POS	O
+again	POS	O
+significantly	POS	O
+at	POS	O
+14	POS	O
+and	POS	O
+20	POS	O
+weeks	POS	O
+.	POS	O
+Temocapril	POS	O
+did	POS	O
+not	POS	O
+attenuate	POS	O
+proteinuria	POS	B-NP
+at	POS	O
+8	POS	O
+days	POS	O
+,	POS	O
+but	POS	O
+it	POS	O
+did	POS	O
+markedly	POS	O
+lower	POS	O
+it	POS	O
+from	POS	O
+weeks	POS	O
+4	POS	O
+to	POS	O
+20	POS	O
+.	POS	O
+The	POS	O
+glomerulosclerosis	POS	B-NP
+index	POS	O
+(	POS	O
+GSI	POS	O
+)	POS	O
+was	POS	O
+6	POS	O
+.	POS	O
+21	POS	O
+%	POS	O
+at	POS	O
+4	POS	O
+weeks	POS	O
+and	POS	O
+respectively	POS	O
+25	POS	O
+.	POS	O
+35	POS	O
+%	POS	O
+and	POS	O
+30	POS	O
+.	POS	O
+49	POS	O
+%	POS	O
+at	POS	O
+14	POS	O
+and	POS	O
+20	POS	O
+weeks	POS	O
+in	POS	O
+the	POS	O
+PAN	POS	O
+group	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+correlation	POS	O
+between	POS	O
+urinary	POS	O
+protein	POS	O
+excretion	POS	O
+and	POS	O
+GSI	POS	O
+(	POS	O
+r	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+808	POS	O
+,	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+0001	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+ratio	POS	O
+of	POS	O
+glomerular	POS	O
+tuft	POS	O
+area	POS	O
+to	POS	O
+the	POS	O
+area	POS	O
+of	POS	O
+Bowman	POS	O
+'	POS	O
+s	POS	O
+capsules	POS	O
+(	POS	O
+GT	POS	O
+/	POS	O
+BC	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+PAN	POS	O
+group	POS	O
+was	POS	O
+significantly	POS	O
+increased	POS	O
+,	POS	O
+but	POS	O
+it	POS	O
+was	POS	O
+significantly	POS	O
+lower	POS	O
+in	POS	O
+the	POS	O
+PAN	POS	O
+/	POS	O
+temocapril	POS	O
+group	POS	O
+.	POS	O
+It	POS	O
+appears	POS	O
+that	POS	O
+temocapril	POS	O
+was	POS	O
+effective	POS	O
+in	POS	O
+retarding	POS	O
+renal	POS	O
+progression	POS	O
+and	POS	O
+protected	POS	O
+renal	POS	O
+function	POS	O
+in	POS	O
+PAN	POS	O
+neprotic	POS	O
+rats	POS	O
+.	POS	O
+Pulmonary	POS	B-NP
+hypertension	POS	I-NP
+after	POS	O
+ibuprofen	POS	O
+prophylaxis	POS	B-NP
+in	POS	O
+very	POS	O
+preterm	POS	B-NP
+infants	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+three	POS	O
+cases	POS	O
+of	POS	O
+severe	POS	O
+hypoxaemia	POS	B-NP
+after	POS	O
+ibuprofen	POS	O
+administration	POS	O
+during	POS	O
+a	POS	O
+randomised	POS	O
+controlled	POS	O
+trial	POS	O
+of	POS	O
+prophylactic	POS	O
+treatment	POS	O
+of	POS	O
+patent	POS	O
+ductus	POS	B-NP
+arteriosus	POS	I-NP
+with	POS	O
+ibuprofen	POS	O
+in	POS	O
+premature	POS	O
+infants	POS	O
+born	POS	O
+at	POS	O
+less	POS	O
+than	POS	O
+28	POS	O
+weeks	POS	O
+of	POS	O
+gestation	POS	O
+.	POS	O
+Echocardiography	POS	O
+showed	POS	O
+severely	POS	O
+decreased	POS	O
+pulmonary	POS	O
+blood	POS	O
+flow	POS	O
+.	POS	O
+Hypoxaemia	POS	B-NP
+resolved	POS	O
+quickly	POS	O
+on	POS	O
+inhaled	POS	O
+nitric	POS	O
+oxide	POS	O
+therapy	POS	O
+.	POS	O
+We	POS	O
+suggest	POS	O
+that	POS	O
+investigators	POS	O
+involved	POS	O
+in	POS	O
+similar	POS	O
+trials	POS	O
+pay	POS	O
+close	POS	O
+attention	POS	O
+to	POS	O
+pulmonary	POS	O
+pressure	POS	O
+if	POS	O
+hypoxaemia	POS	B-NP
+occurs	POS	O
+after	POS	O
+prophylactic	POS	O
+administration	POS	O
+of	POS	O
+ibuprofen	POS	O
+.	POS	O
+Hyponatremia	POS	B-NP
+and	POS	O
+syndrome	POS	O
+of	POS	O
+inappropriate	POS	O
+anti	POS	O
+-	POS	O
+diuretic	POS	O
+hormone	POS	O
+reported	POS	O
+with	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+Vincristine	POS	O
+:	POS	O
+an	POS	O
+over	POS	O
+-	POS	O
+representation	POS	O
+of	POS	O
+Asians	POS	O
+?	POS	O
+PURPOSE	POS	O
+:	POS	O
+This	POS	O
+retrospective	POS	O
+study	POS	O
+used	POS	O
+a	POS	O
+pharmaceutical	POS	O
+company	POS	O
+'	POS	O
+s	POS	O
+global	POS	O
+safety	POS	O
+database	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+reporting	POS	O
+rate	POS	O
+of	POS	O
+hyponatremia	POS	B-NP
+and	POS	O
+/	POS	O
+or	POS	O
+syndrome	POS	O
+of	POS	O
+inappropriate	POS	O
+secretion	POS	O
+of	POS	O
+anti	POS	O
+-	POS	O
+diuretic	POS	O
+hormone	POS	O
+(	POS	O
+SIADH	POS	B-NP
+)	POS	O
+among	POS	O
+vincristine	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+and	POS	O
+to	POS	O
+explore	POS	O
+the	POS	O
+possibility	POS	O
+of	POS	O
+at	POS	O
+-	POS	O
+risk	POS	O
+population	POS	O
+subgroups	POS	O
+.	POS	O
+METHOD	POS	O
+:	POS	O
+We	POS	O
+searched	POS	O
+the	POS	O
+Eli	POS	O
+Lilly	POS	O
+and	POS	O
+Company	POS	O
+'	POS	O
+s	POS	O
+computerized	POS	O
+adverse	POS	O
+event	POS	O
+database	POS	O
+for	POS	O
+all	POS	O
+reported	POS	O
+cases	POS	O
+of	POS	O
+hyponatremia	POS	B-NP
+and	POS	O
+/	POS	O
+or	POS	O
+SIADH	POS	B-NP
+as	POS	O
+of	POS	O
+1	POS	O
+November	POS	O
+1999	POS	O
+that	POS	O
+had	POS	O
+been	POS	O
+reported	POS	O
+during	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+vincristine	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+76	POS	O
+cases	POS	O
+of	POS	O
+hyponatremia	POS	B-NP
+and	POS	O
+/	POS	O
+or	POS	O
+SIADH	POS	B-NP
+associated	POS	O
+with	POS	O
+vincristine	POS	O
+use	POS	O
+were	POS	O
+identified	POS	O
+.	POS	O
+The	POS	O
+overall	POS	O
+reporting	POS	O
+rate	POS	O
+was	POS	O
+estimated	POS	O
+to	POS	O
+be	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+/	POS	O
+100	POS	O
+,	POS	O
+000	POS	O
+treated	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+average	POS	O
+age	POS	O
+of	POS	O
+patients	POS	O
+was	POS	O
+35	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+28	POS	O
+.	POS	O
+3	POS	O
+years	POS	O
+,	POS	O
+and	POS	O
+62	POS	O
+%	POS	O
+were	POS	O
+males	POS	O
+.	POS	O
+Approximately	POS	O
+75	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+were	POS	O
+receiving	POS	O
+treatment	POS	O
+for	POS	O
+leukemia	POS	B-NP
+or	POS	O
+lymphoma	POS	B-NP
+.	POS	O
+Among	POS	O
+the	POS	O
+39	POS	O
+reports	POS	O
+that	POS	O
+included	POS	O
+information	POS	O
+on	POS	O
+race	POS	O
+,	POS	O
+the	POS	O
+racial	POS	O
+distribution	POS	O
+was	POS	O
+:	POS	O
+1	POS	O
+Black	POS	O
+,	POS	O
+3	POS	O
+Caucasian	POS	O
+,	POS	O
+and	POS	O
+35	POS	O
+Asian	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Our	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+Asian	POS	O
+patients	POS	O
+may	POS	O
+be	POS	O
+at	POS	O
+increased	POS	O
+risk	POS	O
+of	POS	O
+hyponatremia	POS	B-NP
+and	POS	O
+/	POS	O
+or	POS	O
+SIADH	POS	B-NP
+associated	POS	O
+with	POS	O
+vincristine	POS	O
+use	POS	O
+.	POS	O
+Although	POS	O
+the	POS	O
+overall	POS	O
+reported	POS	O
+rate	POS	O
+of	POS	O
+SIADH	POS	B-NP
+associated	POS	O
+with	POS	O
+vincristine	POS	O
+is	POS	O
+very	POS	O
+low	POS	O
+,	POS	O
+physicians	POS	O
+caring	POS	O
+for	POS	O
+Asian	POS	O
+oncology	POS	O
+patients	POS	O
+should	POS	O
+be	POS	O
+aware	POS	O
+of	POS	O
+this	POS	O
+potential	POS	O
+serious	POS	O
+but	POS	O
+reversible	POS	O
+adverse	POS	O
+event	POS	O
+.	POS	O
+Delayed	POS	B-NP
+toxicity	POS	I-NP
+of	POS	O
+cyclophosphamide	POS	O
+on	POS	O
+the	POS	O
+bladder	POS	O
+of	POS	O
+DBA	POS	O
+/	POS	O
+2	POS	O
+and	POS	O
+C57BL	POS	O
+/	POS	O
+6	POS	O
+female	POS	O
+mouse	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+describes	POS	O
+the	POS	O
+delayed	POS	O
+development	POS	O
+of	POS	O
+a	POS	O
+severe	POS	O
+bladder	POS	B-NP
+pathology	POS	I-NP
+in	POS	O
+a	POS	O
+susceptible	POS	O
+strain	POS	O
+of	POS	O
+mice	POS	O
+(	POS	O
+DBA	POS	O
+/	POS	O
+2	POS	O
+)	POS	O
+but	POS	O
+not	POS	O
+in	POS	O
+a	POS	O
+resistant	POS	O
+strain	POS	O
+(	POS	O
+C57BL	POS	O
+/	POS	O
+6	POS	O
+)	POS	O
+when	POS	O
+both	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+a	POS	O
+single	POS	O
+300	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+dose	POS	O
+of	POS	O
+cyclophosphamide	POS	O
+(	POS	O
+CY	POS	O
+)	POS	O
+.	POS	O
+Inbred	POS	O
+DBA	POS	O
+/	POS	O
+2	POS	O
+and	POS	O
+C57BL	POS	O
+/	POS	O
+6	POS	O
+female	POS	O
+mice	POS	O
+were	POS	O
+injected	POS	O
+with	POS	O
+CY	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+on	POS	O
+the	POS	O
+bladder	POS	O
+was	POS	O
+assessed	POS	O
+during	POS	O
+100	POS	O
+days	POS	O
+by	POS	O
+light	POS	O
+microscopy	POS	O
+using	POS	O
+different	POS	O
+staining	POS	O
+procedures	POS	O
+,	POS	O
+and	POS	O
+after	POS	O
+30	POS	O
+days	POS	O
+by	POS	O
+conventional	POS	O
+electron	POS	O
+microscopy	POS	O
+.	POS	O
+Early	POS	O
+CY	POS	O
+toxicity	POS	B-NP
+caused	POS	O
+a	POS	O
+typical	POS	O
+haemorrhagic	POS	B-NP
+cystitis	POS	I-NP
+in	POS	O
+both	POS	O
+strains	POS	O
+that	POS	O
+was	POS	O
+completely	POS	O
+repaired	POS	O
+in	POS	O
+about	POS	O
+7	POS	O
+-	POS	O
+10	POS	O
+days	POS	O
+.	POS	O
+After	POS	O
+30	POS	O
+days	POS	O
+of	POS	O
+CY	POS	O
+injection	POS	O
+ulcerous	POS	B-NP
+and	POS	O
+non	POS	O
+-	POS	O
+ulcerous	POS	O
+forms	POS	O
+of	POS	O
+chronic	POS	B-NP
+cystitis	POS	I-NP
+appeared	POS	O
+in	POS	O
+86	POS	O
+%	POS	O
+of	POS	O
+DBA	POS	O
+/	POS	O
+2	POS	O
+mice	POS	O
+but	POS	O
+only	POS	O
+in	POS	O
+4	POS	O
+%	POS	O
+of	POS	O
+C57BL	POS	O
+/	POS	O
+6	POS	O
+mice	POS	O
+.	POS	O
+Delayed	POS	O
+cystitis	POS	B-NP
+was	POS	O
+characterized	POS	O
+by	POS	O
+infiltration	POS	O
+and	POS	O
+transepithelial	POS	O
+passage	POS	O
+into	POS	O
+the	POS	O
+lumen	POS	O
+of	POS	O
+inflammatory	POS	O
+cells	POS	O
+and	POS	O
+by	POS	O
+frequent	POS	O
+exfoliation	POS	O
+of	POS	O
+the	POS	O
+urothelium	POS	O
+.	POS	O
+Mast	POS	O
+cells	POS	O
+appeared	POS	O
+in	POS	O
+the	POS	O
+connective	POS	O
+and	POS	O
+muscular	POS	O
+layers	POS	O
+of	POS	O
+the	POS	O
+bladder	POS	O
+at	POS	O
+a	POS	O
+much	POS	O
+higher	POS	O
+number	POS	O
+in	POS	O
+DBA	POS	O
+/	POS	O
+2	POS	O
+mice	POS	O
+than	POS	O
+in	POS	O
+C57BL	POS	O
+/	POS	O
+6	POS	O
+mice	POS	O
+or	POS	O
+untreated	POS	O
+controls	POS	O
+.	POS	O
+Electron	POS	O
+microscopy	POS	O
+disclosed	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+the	POS	O
+typical	POS	O
+discoidal	POS	O
+vesicles	POS	O
+normally	POS	O
+present	POS	O
+in	POS	O
+the	POS	O
+cytoplasm	POS	O
+of	POS	O
+surface	POS	O
+cells	POS	O
+.	POS	O
+Instead	POS	O
+,	POS	O
+numerous	POS	O
+abnormal	POS	O
+vesicles	POS	O
+containing	POS	O
+one	POS	O
+or	POS	O
+several	POS	O
+dark	POS	O
+granules	POS	O
+were	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+cytoplasm	POS	O
+of	POS	O
+cells	POS	O
+from	POS	O
+all	POS	O
+the	POS	O
+epithelial	POS	O
+layers	POS	O
+.	POS	O
+Delayed	POS	O
+cystitis	POS	B-NP
+still	POS	O
+persisted	POS	O
+in	POS	O
+DBA	POS	O
+/	POS	O
+2	POS	O
+mice	POS	O
+100	POS	O
+days	POS	O
+after	POS	O
+treatment	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+delayed	POS	O
+toxicity	POS	B-NP
+of	POS	O
+CY	POS	O
+in	POS	O
+female	POS	O
+DBA	POS	O
+/	POS	O
+2	POS	O
+mice	POS	O
+causes	POS	O
+a	POS	O
+bladder	POS	O
+pathology	POS	O
+that	POS	O
+is	POS	O
+not	POS	O
+observed	POS	O
+in	POS	O
+C57BL	POS	O
+/	POS	O
+6	POS	O
+mice	POS	O
+.	POS	O
+This	POS	O
+pathology	POS	O
+resembles	POS	O
+interstitial	POS	B-NP
+cystitis	POS	I-NP
+in	POS	O
+humans	POS	O
+and	POS	O
+could	POS	O
+perhaps	POS	O
+be	POS	O
+used	POS	O
+as	POS	O
+an	POS	O
+animal	POS	O
+model	POS	O
+for	POS	O
+studies	POS	O
+on	POS	O
+the	POS	O
+disease	POS	O
+.	POS	O
+High	POS	O
+-	POS	O
+dose	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+/	POS	O
+folinic	POS	O
+acid	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+three	POS	O
+-	POS	O
+weekly	POS	O
+mitomycin	POS	O
+C	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+advanced	POS	O
+gastric	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+A	POS	O
+phase	POS	O
+II	POS	O
+study	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+The	POS	O
+24	POS	O
+-	POS	O
+hour	POS	O
+continuous	POS	O
+infusion	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+(	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+)	POS	O
+and	POS	O
+folinic	POS	O
+acid	POS	O
+(	POS	O
+FA	POS	O
+)	POS	O
+as	POS	O
+part	POS	O
+of	POS	O
+several	POS	O
+new	POS	O
+multidrug	POS	O
+chemotherapy	POS	O
+regimens	POS	O
+in	POS	O
+advanced	POS	O
+gastric	POS	B-NP
+cancer	POS	I-NP
+(	POS	O
+AGC	POS	O
+)	POS	O
+has	POS	O
+shown	POS	O
+to	POS	O
+be	POS	O
+effective	POS	O
+,	POS	O
+with	POS	O
+low	POS	B-NP
+toxicity	POS	I-NP
+.	POS	O
+In	POS	O
+a	POS	O
+previous	POS	O
+phase	POS	O
+II	POS	O
+study	POS	O
+with	POS	O
+3	POS	O
+-	POS	O
+weekly	POS	O
+bolus	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+,	POS	O
+FA	POS	O
+and	POS	O
+mitomycin	POS	O
+C	POS	O
+(	POS	O
+MMC	POS	O
+)	POS	O
+we	POS	O
+found	POS	O
+a	POS	O
+low	POS	O
+toxicity	POS	B-NP
+rate	POS	O
+and	POS	O
+response	POS	O
+rates	POS	O
+comparable	POS	O
+to	POS	O
+those	POS	O
+of	POS	O
+regimens	POS	O
+such	POS	O
+as	POS	O
+ELF	POS	O
+,	POS	O
+FAM	POS	O
+or	POS	O
+FAMTX	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+promising	POS	O
+median	POS	O
+overall	POS	O
+survival	POS	O
+.	POS	O
+In	POS	O
+order	POS	O
+to	POS	O
+improve	POS	O
+this	POS	O
+MMC	POS	O
+-	POS	O
+dependent	POS	O
+schedule	POS	O
+we	POS	O
+initiated	POS	O
+a	POS	O
+phase	POS	O
+II	POS	O
+study	POS	O
+with	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+/	POS	O
+FA	POS	O
+and	POS	O
+3	POS	O
+-	POS	O
+weekly	POS	O
+bolus	POS	O
+MMC	POS	O
+.	POS	O
+PATIENTS	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+From	POS	O
+February	POS	O
+,	POS	O
+1998	POS	O
+to	POS	O
+September	POS	O
+,	POS	O
+2000	POS	O
+we	POS	O
+recruited	POS	O
+33	POS	O
+patients	POS	O
+with	POS	O
+AGC	POS	O
+to	POS	O
+receive	POS	O
+weekly	POS	O
+24	POS	O
+-	POS	O
+hour	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+2	POS	O
+,	POS	O
+600	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+preceded	POS	O
+by	POS	O
+2	POS	O
+-	POS	O
+hour	POS	O
+FA	POS	O
+500	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+for	POS	O
+6	POS	O
+weeks	POS	O
+,	POS	O
+followed	POS	O
+by	POS	O
+a	POS	O
+2	POS	O
+-	POS	O
+week	POS	O
+rest	POS	O
+period	POS	O
+.	POS	O
+Bolus	POS	O
+MMC	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+was	POS	O
+added	POS	O
+in	POS	O
+3	POS	O
+-	POS	O
+weekly	POS	O
+intervals	POS	O
+.	POS	O
+Treatment	POS	O
+given	POS	O
+on	POS	O
+an	POS	O
+outpatient	POS	O
+basis	POS	O
+,	POS	O
+using	POS	O
+portable	POS	O
+pump	POS	O
+systems	POS	O
+,	POS	O
+was	POS	O
+repeated	POS	O
+on	POS	O
+day	POS	O
+57	POS	O
+.	POS	O
+Patients	POS	O
+'	POS	O
+characteristics	POS	O
+were	POS	O
+:	POS	O
+male	POS	O
+/	POS	O
+female	POS	O
+ratio	POS	O
+20	POS	O
+/	POS	O
+13	POS	O
+;	POS	O
+median	POS	O
+age	POS	O
+57	POS	O
+(	POS	O
+27	POS	O
+-	POS	O
+75	POS	O
+)	POS	O
+years	POS	O
+;	POS	O
+median	POS	O
+WHO	POS	O
+status	POS	O
+1	POS	O
+(	POS	O
+0	POS	O
+-	POS	O
+2	POS	O
+)	POS	O
+.	POS	O
+18	POS	O
+patients	POS	O
+had	POS	O
+a	POS	O
+primary	POS	O
+AGC	POS	O
+,	POS	O
+and	POS	O
+15	POS	O
+showed	POS	O
+a	POS	O
+relapsed	POS	O
+AGC	POS	O
+.	POS	O
+Median	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+was	POS	O
+11	POS	O
+.	POS	O
+8	POS	O
+months	POS	O
+(	POS	O
+range	POS	O
+of	POS	O
+those	POS	O
+surviving	POS	O
+:	POS	O
+2	POS	O
+.	POS	O
+7	POS	O
+-	POS	O
+11	POS	O
+.	POS	O
+8	POS	O
+months	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+32	POS	O
+patients	POS	O
+were	POS	O
+evaluable	POS	O
+for	POS	O
+response	POS	O
+-	POS	O
+complete	POS	O
+remission	POS	O
+9	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+3	POS	O
+)	POS	O
+,	POS	O
+partial	POS	O
+remission	POS	O
+45	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+15	POS	O
+)	POS	O
+,	POS	O
+no	POS	O
+change	POS	O
+27	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+9	POS	O
+)	POS	O
+,	POS	O
+progressive	POS	O
+disease	POS	O
+15	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+5	POS	O
+)	POS	O
+.	POS	O
+Median	POS	O
+overall	POS	O
+survival	POS	O
+time	POS	O
+was	POS	O
+10	POS	O
+.	POS	O
+2	POS	O
+months	POS	O
+[	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+(	POS	O
+CI	POS	O
+)	POS	O
+:	POS	O
+8	POS	O
+.	POS	O
+7	POS	O
+-	POS	O
+11	POS	O
+.	POS	O
+6	POS	O
+]	POS	O
+,	POS	O
+and	POS	O
+median	POS	O
+progression	POS	O
+-	POS	O
+free	POS	O
+survival	POS	O
+time	POS	O
+was	POS	O
+7	POS	O
+.	POS	O
+6	POS	O
+months	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+:	POS	O
+4	POS	O
+.	POS	O
+4	POS	O
+-	POS	O
+10	POS	O
+.	POS	O
+9	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+worst	POS	O
+toxicities	POS	B-NP
+(	POS	O
+%	POS	O
+)	POS	O
+observed	POS	O
+were	POS	O
+(	POS	O
+CTC	POS	O
+-	POS	O
+NCI	POS	O
+1	POS	O
+/	POS	O
+2	POS	O
+/	POS	O
+3	POS	O
+)	POS	O
+:	POS	O
+leukopenia	POS	B-NP
+45	POS	O
+.	POS	O
+5	POS	O
+/	POS	O
+18	POS	O
+.	POS	O
+2	POS	O
+/	POS	O
+6	POS	O
+.	POS	O
+1	POS	O
+,	POS	O
+thrombocytopenia	POS	B-NP
+33	POS	O
+.	POS	O
+3	POS	O
+/	POS	O
+9	POS	O
+.	POS	O
+1	POS	O
+/	POS	O
+6	POS	O
+.	POS	O
+1	POS	O
+,	POS	O
+vomitus	POS	O
+24	POS	O
+.	POS	O
+2	POS	O
+/	POS	O
+9	POS	O
+.	POS	O
+1	POS	O
+/	POS	O
+0	POS	O
+,	POS	O
+diarrhea	POS	B-NP
+36	POS	O
+.	POS	O
+4	POS	O
+/	POS	O
+6	POS	O
+.	POS	O
+1	POS	O
+/	POS	O
+3	POS	O
+.	POS	O
+0	POS	O
+,	POS	O
+stomatitis	POS	B-NP
+18	POS	O
+.	POS	O
+2	POS	O
+/	POS	O
+9	POS	O
+.	POS	O
+1	POS	O
+/	POS	O
+0	POS	O
+,	POS	O
+hand	POS	O
+-	POS	O
+foot	POS	B-NP
+syndrome	POS	I-NP
+12	POS	O
+.	POS	O
+1	POS	O
+/	POS	O
+0	POS	O
+/	POS	O
+0	POS	O
+.	POS	O
+Two	POS	O
+patients	POS	O
+developed	POS	O
+hemolytic	POS	B-NP
+-	POS	I-NP
+uremic	POS	I-NP
+syndrome	POS	I-NP
+(	POS	O
+HUS	POS	B-NP
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+High	POS	O
+-	POS	O
+dose	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+/	POS	O
+FA	POS	O
+/	POS	O
+MMC	POS	O
+is	POS	O
+an	POS	O
+effective	POS	O
+and	POS	O
+well	POS	O
+-	POS	O
+tolerated	POS	O
+outpatient	POS	O
+regimen	POS	O
+for	POS	O
+AGC	POS	O
+(	POS	O
+objective	POS	O
+response	POS	O
+rate	POS	O
+54	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+It	POS	O
+may	POS	O
+serve	POS	O
+as	POS	O
+an	POS	O
+alternative	POS	O
+to	POS	O
+cisplatin	POS	O
+-	POS	O
+containing	POS	O
+regimens	POS	O
+;	POS	O
+however	POS	O
+,	POS	O
+it	POS	O
+has	POS	O
+to	POS	O
+be	POS	O
+considered	POS	O
+that	POS	O
+possibly	POS	O
+HUS	POS	B-NP
+may	POS	O
+occur	POS	O
+.	POS	O
+Persistent	POS	O
+sterile	POS	O
+leukocyturia	POS	B-NP
+is	POS	O
+associated	POS	O
+with	POS	O
+impaired	POS	B-NP
+renal	POS	I-NP
+function	POS	I-NP
+in	POS	I-NP
+human	POS	I-NP
+immunodeficiency	POS	I-NP
+virus	POS	I-NP
+type	POS	I-NP
+1	POS	I-NP
+-	POS	I-NP
+infected	POS	I-NP
+children	POS	O
+treated	POS	O
+with	POS	O
+indinavir	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Prolonged	POS	O
+administration	POS	O
+of	POS	O
+indinavir	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+a	POS	O
+variety	POS	O
+of	POS	O
+renal	POS	B-NP
+complications	POS	I-NP
+in	POS	O
+adults	POS	O
+.	POS	O
+These	POS	O
+well	POS	O
+-	POS	O
+documented	POS	O
+side	POS	O
+effects	POS	O
+have	POS	O
+restricted	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+this	POS	O
+potent	POS	O
+protease	POS	O
+inhibitor	POS	O
+in	POS	O
+children	POS	O
+.	POS	O
+DESIGN	POS	O
+:	POS	O
+A	POS	O
+prospective	POS	O
+study	POS	O
+to	POS	O
+monitor	POS	O
+indinavir	POS	O
+-	POS	O
+related	POS	O
+nephrotoxicity	POS	B-NP
+in	POS	O
+a	POS	O
+cohort	POS	O
+of	POS	O
+30	POS	O
+human	POS	O
+immunodeficiency	POS	B-NP
+virus	POS	I-NP
+type	POS	I-NP
+1	POS	I-NP
+-	POS	I-NP
+infected	POS	I-NP
+children	POS	O
+treated	POS	O
+with	POS	O
+indinavir	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Urinary	POS	O
+pH	POS	O
+,	POS	O
+albumin	POS	O
+,	POS	O
+creatinine	POS	O
+,	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+erythrocytes	POS	O
+,	POS	O
+leukocytes	POS	O
+,	POS	O
+bacteria	POS	O
+and	POS	O
+crystals	POS	O
+,	POS	O
+and	POS	O
+culture	POS	O
+were	POS	O
+analyzed	POS	O
+every	POS	O
+3	POS	O
+months	POS	O
+for	POS	O
+96	POS	O
+weeks	POS	O
+.	POS	O
+Serum	POS	O
+creatinine	POS	O
+levels	POS	O
+were	POS	O
+routinely	POS	O
+determined	POS	O
+at	POS	O
+the	POS	O
+same	POS	O
+time	POS	O
+points	POS	O
+.	POS	O
+Steady	POS	O
+-	POS	O
+state	POS	O
+pharmacokinetics	POS	O
+of	POS	O
+indinavir	POS	O
+were	POS	O
+done	POS	O
+at	POS	O
+week	POS	O
+4	POS	O
+after	POS	O
+the	POS	O
+initiation	POS	O
+of	POS	O
+indinavir	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+cumulative	POS	O
+incidence	POS	O
+of	POS	O
+persistent	POS	O
+sterile	POS	O
+leukocyturia	POS	B-NP
+(	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+75	POS	O
+cells	POS	O
+/	POS	O
+micro	POS	O
+L	POS	O
+in	POS	O
+at	POS	O
+least	POS	O
+2	POS	O
+consecutive	POS	O
+visits	POS	O
+)	POS	O
+after	POS	O
+96	POS	O
+weeks	POS	O
+was	POS	O
+53	POS	O
+%	POS	O
+.	POS	O
+Persistent	POS	O
+sterile	POS	O
+leukocyturia	POS	B-NP
+was	POS	O
+frequently	POS	O
+associated	POS	O
+with	POS	O
+a	POS	O
+mild	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+urine	POS	O
+albumin	POS	O
+/	POS	O
+creatinine	POS	O
+ratio	POS	O
+and	POS	O
+by	POS	O
+microscopic	POS	O
+hematuria	POS	B-NP
+.	POS	O
+The	POS	O
+cumulative	POS	O
+incidence	POS	O
+of	POS	O
+serum	POS	O
+creatinine	POS	O
+levels	POS	O
+>	POS	O
+50	POS	O
+%	POS	O
+above	POS	O
+normal	POS	B-NP
+was	POS	O
+33	POS	O
+%	POS	O
+after	POS	O
+96	POS	O
+weeks	POS	O
+.	POS	O
+Children	POS	O
+with	POS	O
+persistent	POS	O
+sterile	POS	O
+leukocyturia	POS	B-NP
+more	POS	O
+frequently	POS	O
+had	POS	O
+serum	POS	O
+creatinine	POS	O
+levels	POS	O
+of	POS	O
+50	POS	O
+%	POS	O
+above	POS	O
+normal	POS	B-NP
+than	POS	O
+those	POS	O
+children	POS	O
+without	POS	O
+persistent	POS	O
+sterile	POS	O
+leukocyturia	POS	B-NP
+.	POS	O
+In	POS	O
+children	POS	O
+younger	POS	O
+than	POS	O
+5	POS	O
+.	POS	O
+6	POS	O
+years	POS	O
+,	POS	O
+persistent	POS	O
+sterile	POS	O
+leukocyturia	POS	B-NP
+was	POS	O
+significantly	POS	O
+more	POS	O
+frequent	POS	O
+than	POS	O
+in	POS	O
+older	POS	O
+children	POS	O
+.	POS	O
+A	POS	O
+higher	POS	O
+cumulative	POS	O
+incidence	POS	O
+of	POS	O
+persistent	POS	O
+leukocyturia	POS	B-NP
+was	POS	O
+found	POS	O
+in	POS	O
+children	POS	O
+with	POS	O
+an	POS	O
+area	POS	O
+under	POS	O
+the	POS	O
+curve	POS	O
+>	POS	O
+19	POS	O
+mg	POS	O
+/	POS	O
+L	POS	O
+x	POS	O
+h	POS	O
+or	POS	O
+a	POS	O
+peak	POS	O
+serum	POS	O
+level	POS	O
+of	POS	O
+indinavir	POS	O
+>	POS	O
+12	POS	O
+mg	POS	O
+/	POS	O
+L	POS	O
+.	POS	O
+In	POS	O
+4	POS	O
+children	POS	O
+,	POS	O
+indinavir	POS	O
+was	POS	O
+discontinued	POS	O
+because	POS	O
+of	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+Subsequently	POS	O
+,	POS	O
+the	POS	O
+serum	POS	O
+creatinine	POS	O
+levels	POS	O
+decreased	POS	O
+,	POS	O
+the	POS	O
+urine	POS	O
+albumin	POS	O
+/	POS	O
+creatinine	POS	O
+ratios	POS	O
+returned	POS	O
+to	POS	O
+zero	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+leukocyturia	POS	B-NP
+disappeared	POS	O
+within	POS	O
+3	POS	O
+months	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Children	POS	O
+treated	POS	O
+with	POS	O
+indinavir	POS	O
+have	POS	O
+a	POS	O
+high	POS	O
+cumulative	POS	O
+incidence	POS	O
+of	POS	O
+persistent	POS	O
+sterile	POS	O
+leukocyturia	POS	B-NP
+.	POS	O
+Children	POS	O
+with	POS	O
+persistent	POS	O
+sterile	POS	O
+leukocyturia	POS	B-NP
+more	POS	O
+frequently	POS	O
+had	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+serum	POS	O
+creatinine	POS	O
+levels	POS	O
+of	POS	O
+>	POS	O
+50	POS	O
+%	POS	O
+above	POS	O
+normal	POS	B-NP
+.	POS	O
+Younger	POS	O
+children	POS	O
+have	POS	O
+an	POS	O
+additional	POS	O
+risk	POS	O
+for	POS	O
+renal	POS	B-NP
+complications	POS	I-NP
+.	POS	O
+The	POS	O
+impairment	POS	B-NP
+of	POS	I-NP
+the	POS	I-NP
+renal	POS	I-NP
+function	POS	I-NP
+in	POS	O
+these	POS	O
+children	POS	O
+occurred	POS	O
+in	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+clinical	POS	O
+symptoms	POS	O
+of	POS	O
+nephrolithiasis	POS	B-NP
+.	POS	O
+Indinavir	POS	O
+-	POS	O
+associated	POS	O
+nephrotoxicity	POS	B-NP
+must	POS	O
+be	POS	O
+monitored	POS	O
+closely	POS	O
+,	POS	O
+especially	POS	O
+in	POS	O
+children	POS	O
+with	POS	O
+risk	POS	O
+factors	POS	O
+such	POS	O
+as	POS	O
+persistent	POS	O
+sterile	POS	O
+leukocyturia	POS	B-NP
+,	POS	O
+age	POS	O
+<	POS	O
+5	POS	O
+.	POS	O
+6	POS	O
+years	POS	O
+,	POS	O
+an	POS	O
+area	POS	O
+under	POS	O
+the	POS	O
+curve	POS	O
+of	POS	O
+indinavir	POS	O
+>	POS	O
+19	POS	O
+mg	POS	O
+/	POS	O
+L	POS	O
+x	POS	O
+h	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+C	POS	O
+(	POS	O
+max	POS	O
+)	POS	O
+>	POS	O
+12	POS	O
+mg	POS	O
+/	POS	O
+L	POS	O
+.	POS	O
+Utility	POS	O
+of	POS	O
+troponin	POS	O
+I	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+.	POS	O
+Baseline	POS	B-NP
+electrocardiogram	POS	I-NP
+abnormalities	POS	I-NP
+and	POS	O
+market	POS	O
+elevations	POS	O
+not	POS	O
+associated	POS	O
+with	POS	O
+myocardial	POS	B-NP
+necrosis	POS	I-NP
+make	POS	O
+accurate	POS	O
+diagnosis	POS	O
+of	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+(	POS	O
+MI	POS	B-NP
+)	POS	O
+difficult	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+.	POS	O
+Troponin	POS	O
+sampling	POS	O
+may	POS	O
+offer	POS	O
+greater	POS	O
+diagnostic	POS	O
+utility	POS	O
+in	POS	O
+these	POS	O
+patients	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+assess	POS	O
+outcomes	POS	O
+based	POS	O
+on	POS	O
+troponin	POS	O
+positivity	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	B-NP
+chest	POS	I-NP
+pain	POS	I-NP
+admitted	POS	O
+for	POS	O
+exclusion	POS	O
+of	POS	O
+MI	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Outcomes	POS	O
+were	POS	O
+examined	POS	O
+in	POS	O
+patients	POS	O
+admitted	POS	O
+for	POS	O
+possible	POS	O
+MI	POS	B-NP
+after	POS	O
+cocaine	POS	O
+use	POS	O
+.	POS	O
+All	POS	O
+patients	POS	O
+underwent	POS	O
+a	POS	O
+rapid	POS	O
+rule	POS	O
+-	POS	O
+in	POS	O
+protocol	POS	O
+that	POS	O
+included	POS	O
+serial	POS	O
+sampling	POS	O
+of	POS	O
+creatine	POS	O
+kinase	POS	O
+(	POS	O
+CK	POS	O
+)	POS	O
+,	POS	O
+CK	POS	O
+-	POS	O
+MB	POS	O
+,	POS	O
+and	POS	O
+cardiac	POS	B-NP
+troponin	POS	I-NP
+I	POS	I-NP
+(	POS	O
+cTnI	POS	O
+)	POS	O
+over	POS	O
+eight	POS	O
+hours	POS	O
+.	POS	O
+Outcomes	POS	O
+included	POS	O
+CK	POS	O
+-	POS	O
+MB	POS	B-NP
+MI	POS	I-NP
+(	POS	O
+CK	POS	O
+-	POS	O
+MB	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+8	POS	O
+ng	POS	O
+/	POS	O
+mL	POS	O
+with	POS	O
+a	POS	O
+relative	POS	O
+index	POS	O
+[	POS	O
+(	POS	O
+CK	POS	O
+-	POS	O
+MB	POS	O
+x	POS	O
+100	POS	O
+)	POS	O
+/	POS	O
+total	POS	O
+CK	POS	O
+]	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+4	POS	O
+,	POS	O
+cardiac	POS	B-NP
+death	POS	I-NP
+,	POS	O
+and	POS	O
+significant	POS	O
+coronary	POS	B-NP
+disease	POS	I-NP
+(	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+50	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Of	POS	O
+the	POS	O
+246	POS	O
+admitted	POS	O
+patients	POS	O
+,	POS	O
+34	POS	O
+(	POS	O
+14	POS	O
+%	POS	O
+)	POS	O
+met	POS	O
+CK	POS	O
+-	POS	O
+MB	POS	O
+criteria	POS	O
+for	POS	O
+MI	POS	B-NP
+and	POS	O
+38	POS	O
+(	POS	O
+16	POS	O
+%	POS	O
+)	POS	O
+had	POS	O
+cTnI	POS	O
+elevations	POS	O
+.	POS	O
+Angiography	POS	O
+was	POS	O
+performed	POS	O
+in	POS	O
+29	POS	O
+of	POS	O
+38	POS	O
+patients	POS	O
+who	POS	O
+were	POS	O
+cTnI	POS	O
+-	POS	O
+positive	POS	O
+,	POS	O
+with	POS	O
+significant	POS	O
+disease	POS	O
+present	POS	O
+in	POS	O
+25	POS	O
+(	POS	O
+86	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Three	POS	O
+of	POS	O
+the	POS	O
+four	POS	O
+patients	POS	O
+without	POS	O
+significant	POS	O
+disease	POS	O
+who	POS	O
+had	POS	O
+cTnI	POS	O
+elevations	POS	O
+met	POS	O
+CK	POS	O
+-	POS	O
+MB	POS	O
+criteria	POS	O
+for	POS	O
+MI	POS	B-NP
+,	POS	O
+and	POS	O
+the	POS	O
+other	POS	O
+had	POS	O
+a	POS	O
+peak	POS	O
+CK	POS	O
+-	POS	O
+MB	POS	O
+level	POS	O
+of	POS	O
+13	POS	O
+ng	POS	O
+/	POS	O
+mL	POS	O
+.	POS	O
+Sensitivities	POS	O
+,	POS	O
+specificities	POS	O
+,	POS	O
+and	POS	O
+positive	POS	O
+and	POS	O
+negative	POS	O
+likelihood	POS	O
+ratios	POS	O
+for	POS	O
+predicting	POS	O
+cardiac	POS	B-NP
+death	POS	I-NP
+or	POS	O
+significant	POS	O
+disease	POS	O
+were	POS	O
+high	POS	O
+for	POS	O
+both	POS	O
+CK	POS	O
+-	POS	O
+MB	POS	B-NP
+MI	POS	I-NP
+and	POS	O
+cTnI	POS	O
+and	POS	O
+were	POS	O
+not	POS	O
+significantly	POS	O
+different	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Most	POS	O
+patients	POS	O
+with	POS	O
+cTnI	POS	O
+elevations	POS	O
+meet	POS	O
+CK	POS	O
+-	POS	O
+MB	POS	O
+criteria	POS	O
+for	POS	O
+MI	POS	B-NP
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+have	POS	O
+a	POS	O
+high	POS	O
+incidence	POS	O
+of	POS	O
+underlying	POS	O
+significant	POS	O
+disease	POS	O
+.	POS	O
+Troponin	POS	O
+appears	POS	O
+to	POS	O
+have	POS	O
+an	POS	O
+equivalent	POS	O
+diagnostic	POS	O
+accuracy	POS	O
+compared	POS	O
+with	POS	O
+CK	POS	O
+-	POS	O
+MB	POS	O
+for	POS	O
+diagnosing	POS	O
+necrosis	POS	B-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+and	POS	O
+suspected	POS	O
+MI	POS	B-NP
+.	POS	O
+Acute	POS	B-NP
+interstitial	POS	I-NP
+nephritis	POS	I-NP
+due	POS	O
+to	POS	O
+nicergoline	POS	O
+(	POS	O
+Sermion	POS	O
+)	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+acute	POS	O
+interstitial	POS	B-NP
+nephritis	POS	I-NP
+(	POS	O
+AIN	POS	B-NP
+)	POS	O
+due	POS	O
+to	POS	O
+nicergoline	POS	O
+(	POS	O
+Sermion	POS	O
+)	POS	O
+.	POS	O
+A	POS	O
+50	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+patient	POS	O
+admitted	POS	O
+to	POS	O
+our	POS	O
+hospital	POS	O
+for	POS	O
+fever	POS	B-NP
+and	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+Before	POS	O
+admission	POS	O
+,	POS	O
+he	POS	O
+had	POS	O
+been	POS	O
+taking	POS	O
+nicergoline	POS	O
+and	POS	O
+bendazac	POS	O
+lysine	POS	O
+due	POS	O
+to	POS	O
+retinal	POS	B-NP
+vein	POS	I-NP
+occlusion	POS	I-NP
+at	POS	O
+ophthalmologic	POS	O
+department	POS	O
+.	POS	O
+Thereafter	POS	O
+,	POS	O
+he	POS	O
+experienced	POS	O
+intermittent	POS	B-NP
+fever	POS	I-NP
+and	POS	O
+skin	POS	B-NP
+rash	POS	I-NP
+.	POS	O
+On	POS	O
+admission	POS	O
+,	POS	O
+clinical	POS	O
+symptoms	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+e	POS	O
+.	POS	O
+arthralgia	POS	B-NP
+and	POS	O
+fever	POS	B-NP
+)	POS	O
+and	POS	O
+laboratory	POS	O
+findings	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+e	POS	O
+.	POS	O
+eosinophilia	POS	B-NP
+and	POS	O
+renal	POS	B-NP
+failure	POS	I-NP
+)	POS	O
+suggested	POS	O
+AIN	POS	B-NP
+,	POS	O
+and	POS	O
+which	POS	O
+was	POS	O
+confirmed	POS	O
+by	POS	O
+pathologic	POS	O
+findings	POS	O
+on	POS	O
+renal	POS	O
+biopsy	POS	O
+.	POS	O
+A	POS	O
+lymphocyte	POS	O
+transformation	POS	O
+test	POS	O
+demonstrated	POS	O
+a	POS	O
+positive	POS	O
+result	POS	O
+against	POS	O
+nicergoline	POS	O
+.	POS	O
+Treatment	POS	O
+was	POS	O
+consisted	POS	O
+of	POS	O
+withdrawal	POS	O
+of	POS	O
+nicergoline	POS	O
+and	POS	O
+intravenous	POS	O
+methylprednisolone	POS	O
+,	POS	O
+and	POS	O
+his	POS	O
+renal	POS	O
+function	POS	O
+was	POS	O
+completely	POS	O
+recovered	POS	O
+.	POS	O
+To	POS	O
+our	POS	O
+knowledge	POS	O
+,	POS	O
+this	POS	O
+is	POS	O
+the	POS	O
+first	POS	O
+report	POS	O
+of	POS	O
+nicergoline	POS	O
+-	POS	O
+associated	POS	O
+AIN	POS	B-NP
+.	POS	O
+Neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+complicated	POS	O
+by	POS	O
+massive	POS	O
+intestinal	POS	B-NP
+bleeding	POS	I-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+chronic	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+A	POS	O
+patient	POS	O
+with	POS	O
+chronic	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+(	POS	O
+CRF	POS	B-NP
+)	POS	O
+developed	POS	O
+neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+(	POS	O
+NMS	POS	B-NP
+)	POS	O
+after	POS	O
+administration	POS	O
+of	POS	O
+risperidone	POS	O
+and	POS	O
+levomepromazine	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+to	POS	O
+the	POS	O
+typical	POS	O
+symptoms	POS	O
+of	POS	O
+NMS	POS	B-NP
+,	POS	O
+massive	POS	O
+intestinal	POS	B-NP
+bleeding	POS	I-NP
+was	POS	O
+observed	POS	O
+during	POS	O
+the	POS	O
+episode	POS	O
+.	POS	O
+This	POS	O
+report	POS	O
+suggests	POS	O
+that	POS	O
+NMS	POS	B-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+CRF	POS	B-NP
+may	POS	O
+be	POS	O
+complicated	POS	O
+by	POS	O
+intestinal	POS	B-NP
+bleeding	POS	I-NP
+and	POS	O
+needs	POS	O
+special	POS	O
+caution	POS	O
+for	POS	O
+this	POS	O
+complication	POS	O
+.	POS	O
+Blood	POS	O
+brain	POS	O
+barrier	POS	O
+in	POS	O
+right	POS	O
+-	POS	O
+and	POS	O
+left	POS	O
+-	POS	O
+pawed	POS	O
+female	POS	O
+rats	POS	O
+assessed	POS	O
+by	POS	O
+a	POS	O
+new	POS	O
+staining	POS	O
+method	POS	O
+.	POS	O
+The	POS	O
+asymmetrical	POS	O
+breakdown	POS	O
+of	POS	O
+the	POS	O
+blood	POS	O
+-	POS	O
+brain	POS	O
+barrier	POS	O
+(	POS	O
+BBB	POS	O
+)	POS	O
+was	POS	O
+studied	POS	O
+in	POS	O
+female	POS	O
+rats	POS	O
+.	POS	O
+Paw	POS	O
+preference	POS	O
+was	POS	O
+assessed	POS	O
+by	POS	O
+a	POS	O
+food	POS	O
+reaching	POS	O
+test	POS	O
+.	POS	O
+Adrenaline	POS	O
+-	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+was	POS	O
+used	POS	O
+to	POS	O
+destroy	POS	O
+the	POS	O
+BBB	POS	O
+,	POS	O
+which	POS	O
+was	POS	O
+evaluated	POS	O
+using	POS	O
+triphenyltetrazolium	POS	O
+(	POS	O
+TTC	POS	O
+)	POS	O
+staining	POS	O
+of	POS	O
+the	POS	O
+brain	POS	O
+slices	POS	O
+just	POS	O
+after	POS	O
+giving	POS	O
+adrenaline	POS	O
+for	POS	O
+30	POS	O
+s	POS	O
+.	POS	O
+In	POS	O
+normal	POS	O
+rats	POS	O
+,	POS	O
+the	POS	O
+whole	POS	O
+brain	POS	O
+sections	POS	O
+exhibited	POS	O
+complete	POS	O
+staining	POS	O
+with	POS	O
+TTC	POS	O
+.	POS	O
+After	POS	O
+adrenaline	POS	O
+infusion	POS	O
+for	POS	O
+30	POS	O
+s	POS	O
+,	POS	O
+there	POS	O
+were	POS	O
+large	POS	O
+unstained	POS	O
+areas	POS	O
+in	POS	O
+the	POS	O
+left	POS	O
+brain	POS	O
+in	POS	O
+right	POS	O
+-	POS	O
+pawed	POS	O
+animals	POS	O
+,	POS	O
+and	POS	O
+vice	POS	O
+versa	POS	O
+in	POS	O
+left	POS	O
+-	POS	O
+pawed	POS	O
+animals	POS	O
+.	POS	O
+Similar	POS	O
+results	POS	O
+were	POS	O
+obtained	POS	O
+in	POS	O
+seizure	POS	B-NP
+-	POS	O
+induced	POS	O
+breakdown	POS	O
+of	POS	O
+BBB	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+were	POS	O
+explained	POS	O
+by	POS	O
+an	POS	O
+asymmetric	POS	O
+cerebral	POS	O
+blood	POS	O
+flow	POS	O
+depending	POS	O
+upon	POS	O
+the	POS	O
+paw	POS	O
+preference	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+It	POS	O
+was	POS	O
+suggested	POS	O
+that	POS	O
+this	POS	O
+new	POS	O
+method	POS	O
+and	POS	O
+the	POS	O
+results	POS	O
+are	POS	O
+consistent	POS	O
+with	POS	O
+contralateral	POS	O
+motor	POS	O
+control	POS	O
+that	POS	O
+may	POS	O
+be	POS	O
+important	POS	O
+in	POS	O
+determining	POS	O
+the	POS	O
+dominant	POS	O
+cerebral	POS	O
+hemisphere	POS	O
+in	POS	O
+animals	POS	O
+.	POS	O
+Carvedilol	POS	O
+protects	POS	O
+against	POS	O
+doxorubicin	POS	O
+-	POS	O
+induced	POS	O
+mitochondrial	POS	B-NP
+cardiomyopathy	POS	I-NP
+.	POS	O
+Several	POS	O
+cytopathic	POS	B-NP
+mechanisms	POS	O
+have	POS	O
+been	POS	O
+suggested	POS	O
+to	POS	O
+mediate	POS	O
+the	POS	O
+dose	POS	O
+-	POS	O
+limiting	POS	O
+cumulative	POS	O
+and	POS	O
+irreversible	POS	O
+cardiomyopathy	POS	B-NP
+caused	POS	O
+by	POS	O
+doxorubicin	POS	O
+.	POS	O
+Recent	POS	O
+evidence	POS	O
+indicates	POS	O
+that	POS	O
+oxidative	POS	O
+stress	POS	O
+and	POS	O
+mitochondrial	POS	B-NP
+dysfunction	POS	I-NP
+are	POS	O
+key	POS	O
+factors	POS	O
+in	POS	O
+the	POS	O
+pathogenic	POS	O
+process	POS	O
+.	POS	O
+The	POS	O
+objective	POS	O
+of	POS	O
+this	POS	O
+investigation	POS	O
+was	POS	O
+to	POS	O
+test	POS	O
+the	POS	O
+hypothesis	POS	O
+that	POS	O
+carvedilol	POS	O
+,	POS	O
+a	POS	O
+nonselective	POS	O
+beta	POS	O
+-	POS	O
+adrenergic	POS	O
+receptor	POS	O
+antagonist	POS	O
+with	POS	O
+potent	POS	O
+antioxidant	POS	O
+properties	POS	O
+,	POS	O
+protects	POS	O
+against	POS	O
+the	POS	O
+cardiac	POS	O
+and	POS	O
+hepatic	POS	O
+mitochondrial	POS	O
+bioenergetic	POS	O
+dysfunction	POS	O
+associated	POS	O
+with	POS	O
+subchronic	POS	O
+doxorubicin	POS	O
+toxicity	POS	B-NP
+.	POS	O
+Heart	POS	O
+and	POS	O
+liver	POS	O
+mitochondria	POS	O
+were	POS	O
+isolated	POS	O
+from	POS	O
+rats	POS	O
+treated	POS	O
+for	POS	O
+7	POS	O
+weeks	POS	O
+with	POS	O
+doxorubicin	POS	O
+(	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+sc	POS	O
+/	POS	O
+week	POS	O
+)	POS	O
+,	POS	O
+carvedilol	POS	O
+(	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+ip	POS	O
+/	POS	O
+week	POS	O
+)	POS	O
+,	POS	O
+or	POS	O
+the	POS	O
+combination	POS	O
+of	POS	O
+the	POS	O
+two	POS	O
+drugs	POS	O
+.	POS	O
+Heart	POS	O
+mitochondria	POS	O
+isolated	POS	O
+from	POS	O
+doxorubicin	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+exhibited	POS	O
+depressed	POS	O
+rates	POS	O
+for	POS	O
+state	POS	O
+3	POS	O
+respiration	POS	O
+(	POS	O
+336	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+26	POS	O
+versus	POS	O
+425	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+53	POS	O
+natom	POS	O
+O	POS	O
+/	POS	O
+min	POS	O
+/	POS	O
+mg	POS	O
+protein	POS	O
+)	POS	O
+and	POS	O
+a	POS	O
+lower	POS	O
+respiratory	POS	O
+control	POS	O
+ratio	POS	O
+(	POS	O
+RCR	POS	O
+)	POS	O
+(	POS	O
+4	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+6	POS	O
+versus	POS	O
+5	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+4	POS	O
+)	POS	O
+compared	POS	O
+with	POS	O
+cardiac	POS	O
+mitochondria	POS	O
+isolated	POS	O
+from	POS	O
+saline	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+.	POS	O
+Mitochondrial	POS	O
+calcium	POS	O
+-	POS	O
+loading	POS	O
+capacity	POS	O
+and	POS	O
+the	POS	O
+activity	POS	O
+of	POS	O
+NADH	POS	O
+-	POS	O
+dehydrogenase	POS	O
+were	POS	O
+also	POS	O
+suppressed	POS	O
+in	POS	O
+cardiac	POS	O
+mitochondria	POS	O
+from	POS	O
+doxorubicin	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+.	POS	O
+Doxorubicin	POS	O
+treatment	POS	O
+also	POS	O
+caused	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+RCR	POS	O
+for	POS	O
+liver	POS	O
+mitochondria	POS	O
+(	POS	O
+3	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+versus	POS	O
+5	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+for	POS	O
+control	POS	O
+rats	POS	O
+)	POS	O
+and	POS	O
+inhibition	POS	O
+of	POS	O
+hepatic	POS	O
+cytochrome	POS	O
+oxidase	POS	O
+activity	POS	O
+.	POS	O
+Coadministration	POS	O
+of	POS	O
+carvedilol	POS	O
+decreased	POS	O
+the	POS	O
+extent	POS	O
+of	POS	O
+cellular	POS	O
+vacuolization	POS	O
+in	POS	O
+cardiac	POS	O
+myocytes	POS	O
+and	POS	O
+prevented	POS	O
+the	POS	O
+inhibitory	POS	O
+effect	POS	O
+of	POS	O
+doxorubicin	POS	O
+on	POS	O
+mitochondrial	POS	O
+respiration	POS	O
+in	POS	O
+both	POS	O
+heart	POS	O
+and	POS	O
+liver	POS	O
+.	POS	O
+Carvedilol	POS	O
+also	POS	O
+prevented	POS	O
+the	POS	O
+decrease	POS	O
+in	POS	O
+mitochondrial	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+loading	POS	O
+capacity	POS	O
+and	POS	O
+the	POS	O
+inhibition	POS	O
+of	POS	O
+the	POS	O
+respiratory	POS	O
+complexes	POS	O
+of	POS	O
+heart	POS	O
+mitochondria	POS	O
+caused	POS	O
+by	POS	O
+doxorubicin	POS	O
+.	POS	O
+Carvedilol	POS	O
+by	POS	O
+itself	POS	O
+did	POS	O
+not	POS	O
+affect	POS	O
+any	POS	O
+of	POS	O
+the	POS	O
+parameters	POS	O
+measured	POS	O
+for	POS	O
+heart	POS	O
+or	POS	O
+liver	POS	O
+mitochondria	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+concluded	POS	O
+that	POS	O
+this	POS	O
+protection	POS	O
+by	POS	O
+carvedilol	POS	O
+against	POS	O
+both	POS	O
+the	POS	O
+structural	POS	O
+and	POS	O
+functional	POS	O
+cardiac	POS	O
+tissue	POS	O
+damage	POS	O
+may	POS	O
+afford	POS	O
+significant	POS	O
+clinical	POS	O
+advantage	POS	O
+in	POS	O
+minimizing	POS	O
+the	POS	O
+dose	POS	O
+-	POS	O
+limiting	POS	O
+mitochondrial	POS	B-NP
+dysfunction	POS	I-NP
+and	POS	O
+cardiomyopathy	POS	B-NP
+that	POS	O
+accompanies	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+doxorubicin	POS	O
+therapy	POS	O
+in	POS	O
+cancer	POS	B-NP
+patients	POS	O
+.	POS	O
+Cocaine	POS	O
+-	POS	O
+induced	POS	O
+hyperactivity	POS	B-NP
+is	POS	O
+more	POS	O
+influenced	POS	O
+by	POS	O
+adenosine	POS	O
+receptor	POS	O
+agonists	POS	O
+than	POS	O
+amphetamine	POS	O
+-	POS	O
+induced	POS	O
+hyperactivity	POS	B-NP
+.	POS	O
+The	POS	O
+influence	POS	O
+of	POS	O
+adenosine	POS	O
+receptor	POS	O
+agonists	POS	O
+and	POS	O
+antagonists	POS	O
+on	POS	O
+cocaine	POS	O
+-	POS	O
+and	POS	O
+amphetamine	POS	O
+-	POS	O
+induced	POS	O
+hyperactivity	POS	B-NP
+was	POS	O
+examined	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+All	POS	O
+adenosine	POS	O
+receptor	POS	O
+agonists	POS	O
+significantly	POS	O
+decreased	POS	O
+the	POS	O
+locomotor	POS	O
+activity	POS	O
+in	POS	O
+mice	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+effects	POS	O
+were	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+.	POS	O
+It	POS	O
+seems	POS	O
+that	POS	O
+adenosine	POS	O
+A1	POS	O
+and	POS	O
+A2	POS	O
+receptors	POS	O
+might	POS	O
+be	POS	O
+involved	POS	O
+in	POS	O
+this	POS	O
+reaction	POS	O
+.	POS	O
+Moreover	POS	O
+,	POS	O
+all	POS	O
+adenosine	POS	O
+receptor	POS	O
+agonists	POS	O
+:	POS	O
+2	POS	O
+-	POS	O
+p	POS	O
+-	POS	O
+(	POS	O
+2	POS	O
+-	POS	O
+carboxyethyl	POS	O
+)	POS	O
+phenethylamino	POS	O
+-	POS	O
+5	POS	O
+'	POS	O
+-	POS	O
+N	POS	O
+-	POS	O
+ethylcarboxamidoadenosine	POS	O
+(	POS	O
+CGS	POS	O
+21680	POS	O
+)	POS	O
+,	POS	O
+A2A	POS	O
+receptor	POS	O
+agonist	POS	O
+,	POS	O
+N6	POS	O
+-	POS	O
+cyclopentyladenosine	POS	O
+(	POS	O
+CPA	POS	O
+)	POS	O
+,	POS	O
+A1	POS	O
+receptor	POS	O
+agonist	POS	O
+,	POS	O
+and	POS	O
+5	POS	O
+'	POS	O
+-	POS	O
+N	POS	O
+-	POS	O
+ethylcarboxamidoadenosine	POS	O
+(	POS	O
+NECA	POS	O
+)	POS	O
+,	POS	O
+A2	POS	O
+/	POS	O
+A1	POS	O
+receptor	POS	O
+agonist	POS	O
+significantly	POS	O
+and	POS	O
+dose	POS	O
+-	POS	O
+dependently	POS	O
+decreased	POS	O
+cocaine	POS	O
+-	POS	O
+induced	POS	O
+locomotor	POS	O
+activity	POS	O
+.	POS	O
+CPA	POS	O
+reduced	POS	O
+cocaine	POS	O
+action	POS	O
+at	POS	O
+the	POS	O
+doses	POS	O
+which	POS	O
+,	POS	O
+given	POS	O
+alone	POS	O
+,	POS	O
+did	POS	O
+not	POS	O
+influence	POS	O
+motility	POS	O
+,	POS	O
+while	POS	O
+CGS	POS	O
+21680	POS	O
+and	POS	O
+NECA	POS	O
+decreased	POS	O
+the	POS	O
+action	POS	O
+of	POS	O
+cocaine	POS	O
+at	POS	O
+the	POS	O
+doses	POS	O
+which	POS	O
+,	POS	O
+given	POS	O
+alone	POS	O
+,	POS	O
+decreased	POS	O
+locomotor	POS	O
+activity	POS	O
+in	POS	O
+animals	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+the	POS	O
+involvement	POS	O
+of	POS	O
+both	POS	O
+adenosine	POS	O
+receptors	POS	O
+in	POS	O
+the	POS	O
+action	POS	O
+of	POS	O
+cocaine	POS	O
+although	POS	O
+agonists	POS	O
+of	POS	O
+A1	POS	O
+receptors	POS	O
+seem	POS	O
+to	POS	O
+have	POS	O
+stronger	POS	O
+influence	POS	O
+on	POS	O
+it	POS	O
+.	POS	O
+The	POS	O
+selective	POS	O
+blockade	POS	O
+of	POS	O
+A2	POS	O
+adenosine	POS	O
+receptor	POS	O
+by	POS	O
+DMPX	POS	O
+(	POS	O
+3	POS	O
+,	POS	O
+7	POS	O
+-	POS	O
+dimethyl	POS	O
+-	POS	O
+1	POS	O
+-	POS	O
+propargylxanthine	POS	O
+)	POS	O
+significantly	POS	O
+enhanced	POS	O
+cocaine	POS	O
+-	POS	O
+induced	POS	O
+locomotor	POS	O
+activity	POS	O
+of	POS	O
+animals	POS	O
+.	POS	O
+Caffeine	POS	O
+had	POS	O
+similar	POS	O
+action	POS	O
+but	POS	O
+the	POS	O
+effect	POS	O
+was	POS	O
+not	POS	O
+significant	POS	O
+.	POS	O
+CPT	POS	O
+(	POS	O
+8	POS	O
+-	POS	O
+cyclopentyltheophylline	POS	O
+)	POS	O
+-	POS	O
+-	POS	O
+A1	POS	O
+receptor	POS	O
+antagonist	POS	O
+,	POS	O
+did	POS	O
+not	POS	O
+show	POS	O
+any	POS	O
+influence	POS	O
+in	POS	O
+this	POS	O
+test	POS	O
+.	POS	O
+Similarly	POS	O
+,	POS	O
+all	POS	O
+adenosine	POS	O
+receptor	POS	O
+agonists	POS	O
+decreased	POS	O
+amphetamine	POS	O
+-	POS	O
+induced	POS	O
+hyperactivity	POS	B-NP
+,	POS	O
+but	POS	O
+at	POS	O
+the	POS	O
+higher	POS	O
+doses	POS	O
+than	POS	O
+those	POS	O
+which	POS	O
+were	POS	O
+active	POS	O
+in	POS	O
+cocaine	POS	O
+-	POS	O
+induced	POS	O
+hyperactivity	POS	B-NP
+.	POS	O
+The	POS	O
+selective	POS	O
+blockade	POS	O
+of	POS	O
+A2	POS	O
+adenosine	POS	O
+receptors	POS	O
+(	POS	O
+DMPX	POS	O
+)	POS	O
+and	POS	O
+non	POS	O
+-	POS	O
+selective	POS	O
+blockade	POS	O
+of	POS	O
+adenosine	POS	O
+receptors	POS	O
+(	POS	O
+caffeine	POS	O
+)	POS	O
+significantly	POS	O
+increased	POS	O
+the	POS	O
+action	POS	O
+of	POS	O
+amphetamine	POS	O
+in	POS	O
+the	POS	O
+locomotor	POS	O
+activity	POS	O
+test	POS	O
+.	POS	O
+Our	POS	O
+results	POS	O
+have	POS	O
+shown	POS	O
+that	POS	O
+all	POS	O
+adenosine	POS	O
+receptor	POS	O
+agonists	POS	O
+(	POS	O
+A1	POS	O
+and	POS	O
+A2	POS	O
+)	POS	O
+reduce	POS	O
+cocaine	POS	O
+-	POS	O
+and	POS	O
+amphetamine	POS	O
+-	POS	O
+induced	POS	O
+locomotor	POS	O
+activity	POS	O
+and	POS	O
+indicate	POS	O
+that	POS	O
+cocaine	POS	O
+-	POS	O
+induced	POS	O
+hyperactivity	POS	B-NP
+is	POS	O
+more	POS	O
+influenced	POS	O
+by	POS	O
+adenosine	POS	O
+receptor	POS	O
+agonists	POS	O
+(	POS	O
+particularly	POS	O
+A1	POS	O
+receptors	POS	O
+)	POS	O
+than	POS	O
+amphetamine	POS	O
+-	POS	O
+induced	POS	O
+hyperactivity	POS	B-NP
+.	POS	O
+Amiodarone	POS	O
+and	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+bradyarrhythmia	POS	B-NP
+requiring	POS	O
+permanent	POS	O
+pacemaker	POS	O
+in	POS	O
+elderly	POS	O
+patients	POS	O
+with	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+and	POS	O
+prior	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+determine	POS	O
+whether	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+amiodarone	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+(	POS	O
+AF	POS	B-NP
+)	POS	O
+increases	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+bradyarrhythmia	POS	B-NP
+requiring	POS	O
+a	POS	O
+permanent	POS	O
+pacemaker	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Reports	POS	O
+of	POS	O
+severe	POS	O
+bradyarrhythmia	POS	B-NP
+during	POS	O
+amiodarone	POS	O
+therapy	POS	O
+are	POS	O
+infrequent	POS	O
+and	POS	O
+limited	POS	O
+to	POS	O
+studies	POS	O
+assessing	POS	O
+the	POS	O
+therapy	POS	O
+'	POS	O
+s	POS	O
+use	POS	O
+in	POS	O
+the	POS	O
+management	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+ventricular	POS	B-NP
+arrhythmias	POS	I-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+A	POS	O
+study	POS	O
+cohort	POS	O
+of	POS	O
+8	POS	O
+,	POS	O
+770	POS	O
+patients	POS	O
+age	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+65	POS	O
+years	POS	O
+with	POS	O
+a	POS	O
+new	POS	O
+diagnosis	POS	O
+of	POS	O
+AF	POS	B-NP
+was	POS	O
+identified	POS	O
+from	POS	O
+a	POS	O
+provincewide	POS	O
+database	POS	O
+of	POS	O
+Quebec	POS	O
+residents	POS	O
+with	POS	O
+a	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+(	POS	O
+MI	POS	B-NP
+)	POS	O
+between	POS	O
+1991	POS	O
+and	POS	O
+1999	POS	O
+.	POS	O
+Using	POS	O
+a	POS	O
+nested	POS	O
+case	POS	O
+-	POS	O
+control	POS	O
+design	POS	O
+,	POS	O
+477	POS	O
+cases	POS	O
+of	POS	O
+bradyarrhythmia	POS	B-NP
+requiring	POS	O
+a	POS	O
+permanent	POS	O
+pacemaker	POS	O
+were	POS	O
+matched	POS	O
+(	POS	O
+1	POS	O
+:	POS	O
+4	POS	O
+)	POS	O
+to	POS	O
+1	POS	O
+,	POS	O
+908	POS	O
+controls	POS	O
+.	POS	O
+Multivariable	POS	O
+logistic	POS	O
+regression	POS	O
+was	POS	O
+used	POS	O
+to	POS	O
+estimate	POS	O
+the	POS	O
+odds	POS	O
+ratio	POS	O
+(	POS	O
+OR	POS	O
+)	POS	O
+of	POS	O
+pacemaker	POS	O
+insertion	POS	O
+associated	POS	O
+with	POS	O
+amiodarone	POS	O
+use	POS	O
+,	POS	O
+controlling	POS	O
+for	POS	O
+baseline	POS	O
+risk	POS	O
+factors	POS	O
+and	POS	O
+exposure	POS	O
+to	POS	O
+sotalol	POS	O
+,	POS	O
+Class	POS	O
+I	POS	O
+antiarrhythmic	POS	O
+agents	POS	O
+,	POS	O
+beta	POS	O
+-	POS	O
+blockers	POS	O
+,	POS	O
+calcium	POS	O
+channel	POS	O
+blockers	POS	O
+,	POS	O
+and	POS	O
+digoxin	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+amiodarone	POS	O
+use	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+increased	POS	O
+risk	POS	O
+of	POS	O
+pacemaker	POS	O
+insertion	POS	O
+(	POS	O
+OR	POS	O
+:	POS	O
+2	POS	O
+.	POS	O
+14	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+[	POS	O
+CI	POS	O
+]	POS	O
+:	POS	O
+1	POS	O
+.	POS	O
+30	POS	O
+to	POS	O
+3	POS	O
+.	POS	O
+54	POS	O
+)	POS	O
+.	POS	O
+This	POS	O
+effect	POS	O
+was	POS	O
+modified	POS	O
+by	POS	O
+gender	POS	O
+,	POS	O
+with	POS	O
+a	POS	O
+greater	POS	O
+risk	POS	O
+in	POS	O
+women	POS	O
+versus	POS	O
+men	POS	O
+(	POS	O
+OR	POS	O
+:	POS	O
+3	POS	O
+.	POS	O
+86	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+:	POS	O
+1	POS	O
+.	POS	O
+70	POS	O
+to	POS	O
+8	POS	O
+.	POS	O
+75	POS	O
+vs	POS	O
+.	POS	O
+OR	POS	O
+:	POS	O
+1	POS	O
+.	POS	O
+52	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+:	POS	O
+0	POS	O
+.	POS	O
+80	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+89	POS	O
+)	POS	O
+.	POS	O
+Digoxin	POS	O
+was	POS	O
+the	POS	O
+only	POS	O
+other	POS	O
+medication	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+increased	POS	O
+risk	POS	O
+of	POS	O
+pacemaker	POS	O
+insertion	POS	O
+(	POS	O
+OR	POS	O
+:	POS	O
+1	POS	O
+.	POS	O
+78	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+:	POS	O
+1	POS	O
+.	POS	O
+37	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+31	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+This	POS	O
+study	POS	O
+suggests	POS	O
+that	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+amiodarone	POS	O
+in	POS	O
+elderly	POS	O
+patients	POS	O
+with	POS	O
+AF	POS	B-NP
+and	POS	O
+a	POS	O
+previous	POS	O
+MI	POS	B-NP
+increases	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+bradyarrhythmia	POS	B-NP
+requiring	POS	O
+a	POS	O
+permanent	POS	O
+pacemaker	POS	O
+.	POS	O
+The	POS	O
+finding	POS	O
+of	POS	O
+an	POS	O
+augmented	POS	O
+risk	POS	O
+of	POS	O
+pacemaker	POS	O
+insertion	POS	O
+in	POS	O
+elderly	POS	O
+women	POS	O
+receiving	POS	O
+amiodarone	POS	O
+requires	POS	O
+further	POS	O
+investigation	POS	O
+.	POS	O
+Indomethacin	POS	O
+-	POS	O
+induced	POS	O
+morphologic	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+urinary	POS	O
+bladder	POS	O
+epithelium	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+To	POS	O
+evaluate	POS	O
+the	POS	O
+morphologic	POS	O
+changes	POS	O
+in	POS	O
+rat	POS	O
+urothelium	POS	O
+induced	POS	O
+by	POS	O
+indomethacin	POS	O
+.	POS	O
+Nonsteroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+cystitis	POS	B-NP
+is	POS	O
+a	POS	O
+poorly	POS	O
+recognized	POS	O
+and	POS	O
+under	POS	O
+-	POS	O
+reported	POS	O
+condition	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+to	POS	O
+tiaprofenic	POS	O
+acid	POS	O
+,	POS	O
+indomethacin	POS	O
+has	POS	O
+been	POS	O
+reported	POS	O
+to	POS	O
+be	POS	O
+associated	POS	O
+with	POS	O
+this	POS	O
+condition	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Three	POS	O
+groups	POS	O
+were	POS	O
+established	POS	O
+:	POS	O
+a	POS	O
+control	POS	O
+group	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+10	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+group	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+10	POS	O
+)	POS	O
+,	POS	O
+treated	POS	O
+with	POS	O
+one	POS	O
+intraperitoneal	POS	O
+injection	POS	O
+of	POS	O
+indomethacin	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+therapeutic	POS	O
+dose	POS	O
+group	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+10	POS	O
+)	POS	O
+in	POS	O
+which	POS	O
+oral	POS	O
+indomethacin	POS	O
+was	POS	O
+administered	POS	O
+3	POS	O
+.	POS	O
+25	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+body	POS	O
+weight	POS	O
+daily	POS	O
+for	POS	O
+3	POS	O
+weeks	POS	O
+.	POS	O
+The	POS	O
+animals	POS	O
+were	POS	O
+then	POS	O
+killed	POS	O
+and	POS	O
+the	POS	O
+bladders	POS	O
+removed	POS	O
+for	POS	O
+light	POS	O
+and	POS	O
+electron	POS	O
+microscopic	POS	O
+studies	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+light	POS	O
+microscopic	POS	O
+findings	POS	O
+showed	POS	O
+some	POS	O
+focal	POS	O
+epithelial	POS	O
+degeneration	POS	O
+that	POS	O
+was	POS	O
+more	POS	O
+prominent	POS	O
+in	POS	O
+the	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+group	POS	O
+.	POS	O
+When	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+,	POS	O
+both	POS	O
+indomethacin	POS	O
+groups	POS	O
+revealed	POS	O
+statistically	POS	O
+increased	POS	O
+numbers	POS	O
+of	POS	O
+mast	POS	O
+cells	POS	O
+in	POS	O
+the	POS	O
+mucosa	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+0001	POS	O
+)	POS	O
+and	POS	O
+penetration	POS	O
+of	POS	O
+lanthanum	POS	O
+nitrate	POS	O
+through	POS	O
+intercellular	POS	O
+areas	POS	O
+of	POS	O
+the	POS	O
+epithelium	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+the	POS	O
+difference	POS	O
+in	POS	O
+mast	POS	O
+cell	POS	O
+counts	POS	O
+between	POS	O
+the	POS	O
+high	POS	O
+and	POS	O
+therapeutic	POS	O
+dose	POS	O
+groups	POS	O
+was	POS	O
+also	POS	O
+statistically	POS	O
+significant	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+0001	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Indomethacin	POS	O
+resulted	POS	O
+in	POS	O
+histopathologic	POS	O
+findings	POS	O
+typical	POS	O
+of	POS	O
+interstitial	POS	B-NP
+cystitis	POS	I-NP
+,	POS	O
+such	POS	O
+as	POS	O
+leaky	POS	B-NP
+bladder	POS	I-NP
+epithelium	POS	I-NP
+and	POS	O
+mucosal	POS	B-NP
+mastocytosis	POS	I-NP
+.	POS	O
+The	POS	O
+true	POS	O
+incidence	POS	O
+of	POS	O
+nonsteroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+cystitis	POS	B-NP
+in	POS	O
+humans	POS	O
+must	POS	O
+be	POS	O
+clarified	POS	O
+by	POS	O
+prospective	POS	O
+clinical	POS	O
+trials	POS	O
+.	POS	O
+An	POS	O
+open	POS	O
+-	POS	O
+label	POS	O
+phase	POS	O
+II	POS	O
+study	POS	O
+of	POS	O
+low	POS	O
+-	POS	O
+dose	POS	O
+thalidomide	POS	O
+in	POS	O
+androgen	POS	O
+-	POS	O
+independent	POS	O
+prostate	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+The	POS	O
+antiangiogenic	POS	O
+effects	POS	O
+of	POS	O
+thalidomide	POS	O
+have	POS	O
+been	POS	O
+assessed	POS	O
+in	POS	O
+clinical	POS	O
+trials	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+various	POS	O
+solid	POS	O
+and	POS	O
+haematological	POS	O
+malignancies	POS	O
+.	POS	O
+Thalidomide	POS	O
+blocks	POS	O
+the	POS	O
+activity	POS	O
+of	POS	O
+angiogenic	POS	O
+agents	POS	O
+including	POS	O
+bFGF	POS	O
+,	POS	O
+VEGF	POS	O
+and	POS	O
+IL	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+We	POS	O
+undertook	POS	O
+an	POS	O
+open	POS	O
+-	POS	O
+label	POS	O
+study	POS	O
+using	POS	O
+thalidomide	POS	O
+100	POS	O
+mg	POS	O
+once	POS	O
+daily	POS	O
+for	POS	O
+up	POS	O
+to	POS	O
+6	POS	O
+months	POS	O
+in	POS	O
+20	POS	O
+men	POS	O
+with	POS	O
+androgen	POS	O
+-	POS	O
+independent	POS	O
+prostate	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+The	POS	O
+mean	POS	O
+time	POS	O
+of	POS	O
+study	POS	O
+was	POS	O
+109	POS	O
+days	POS	O
+(	POS	O
+median	POS	O
+107	POS	O
+,	POS	O
+range	POS	O
+4	POS	O
+-	POS	O
+184	POS	O
+days	POS	O
+)	POS	O
+.	POS	O
+Patients	POS	O
+underwent	POS	O
+regular	POS	O
+measurement	POS	O
+of	POS	O
+prostate	POS	O
+-	POS	O
+specific	POS	O
+antigen	POS	O
+(	POS	O
+PSA	POS	O
+)	POS	O
+,	POS	O
+urea	POS	O
+and	POS	O
+electrolytes	POS	O
+,	POS	O
+serum	POS	O
+bFGF	POS	O
+and	POS	O
+VEGF	POS	O
+.	POS	O
+Three	POS	O
+men	POS	O
+(	POS	O
+15	POS	O
+%	POS	O
+)	POS	O
+showed	POS	O
+a	POS	O
+decline	POS	O
+in	POS	O
+serum	POS	O
+PSA	POS	O
+of	POS	O
+at	POS	O
+least	POS	O
+50	POS	O
+%	POS	O
+,	POS	O
+sustained	POS	O
+throughout	POS	O
+treatment	POS	O
+.	POS	O
+Of	POS	O
+16	POS	O
+men	POS	O
+treated	POS	O
+for	POS	O
+at	POS	O
+least	POS	O
+2	POS	O
+months	POS	O
+,	POS	O
+six	POS	O
+(	POS	O
+37	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+showed	POS	O
+a	POS	O
+fall	POS	O
+in	POS	O
+absolute	POS	O
+PSA	POS	O
+by	POS	O
+a	POS	O
+median	POS	O
+of	POS	O
+48	POS	O
+%	POS	O
+.	POS	O
+Increasing	POS	O
+levels	POS	O
+of	POS	O
+serum	POS	O
+bFGF	POS	O
+and	POS	O
+VEGF	POS	O
+were	POS	O
+associated	POS	O
+with	POS	O
+progressive	POS	O
+disease	POS	O
+;	POS	O
+five	POS	O
+of	POS	O
+six	POS	O
+men	POS	O
+who	POS	O
+demonstrated	POS	O
+a	POS	O
+fall	POS	O
+in	POS	O
+PSA	POS	O
+also	POS	O
+showed	POS	O
+a	POS	O
+decline	POS	O
+in	POS	O
+bFGF	POS	O
+and	POS	O
+VEGF	POS	O
+levels	POS	O
+,	POS	O
+and	POS	O
+three	POS	O
+of	POS	O
+four	POS	O
+men	POS	O
+with	POS	O
+a	POS	O
+rising	POS	O
+PSA	POS	O
+showed	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+both	POS	O
+growth	POS	O
+factors	POS	O
+.	POS	O
+Adverse	POS	O
+effects	POS	O
+included	POS	O
+constipation	POS	B-NP
+,	POS	O
+morning	POS	B-NP
+drowsiness	POS	I-NP
+,	POS	O
+dizziness	POS	B-NP
+and	POS	O
+rash	POS	B-NP
+,	POS	O
+and	POS	O
+resulted	POS	O
+in	POS	O
+withdrawal	POS	O
+from	POS	O
+the	POS	O
+study	POS	O
+by	POS	O
+three	POS	O
+men	POS	O
+.	POS	O
+Evidence	POS	O
+of	POS	O
+peripheral	POS	B-NP
+sensory	POS	I-NP
+neuropathy	POS	I-NP
+was	POS	O
+found	POS	O
+in	POS	O
+nine	POS	O
+of	POS	O
+13	POS	O
+men	POS	O
+before	POS	O
+treatment	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+seven	POS	O
+men	POS	O
+who	POS	O
+completed	POS	O
+six	POS	O
+months	POS	O
+on	POS	O
+thalidomide	POS	O
+,	POS	O
+subclinical	POS	O
+evidence	POS	O
+of	POS	O
+peripheral	POS	B-NP
+neuropathy	POS	I-NP
+was	POS	O
+found	POS	O
+in	POS	O
+four	POS	O
+before	POS	O
+treatment	POS	O
+,	POS	O
+but	POS	O
+in	POS	O
+all	POS	O
+seven	POS	O
+at	POS	O
+repeat	POS	O
+testing	POS	O
+.	POS	O
+The	POS	O
+findings	POS	O
+indicate	POS	O
+that	POS	O
+thalidomide	POS	O
+may	POS	O
+be	POS	O
+an	POS	O
+option	POS	O
+for	POS	O
+patients	POS	O
+who	POS	O
+have	POS	O
+failed	POS	O
+other	POS	O
+forms	POS	O
+of	POS	O
+therapy	POS	O
+,	POS	O
+provided	POS	O
+close	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+is	POS	O
+maintained	POS	O
+for	POS	O
+development	POS	O
+of	POS	O
+peripheral	POS	B-NP
+neuropathy	POS	I-NP
+.	POS	O
+Central	POS	B-NP
+nervous	POS	I-NP
+system	POS	I-NP
+toxicity	POS	I-NP
+following	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+levobupivacaine	POS	O
+for	POS	O
+lumbar	POS	B-NP
+plexus	POS	I-NP
+block	POS	I-NP
+:	POS	O
+A	POS	O
+report	POS	O
+of	POS	O
+two	POS	O
+cases	POS	O
+.	POS	O
+BACKGROUND	POS	O
+AND	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+Central	POS	O
+nervous	POS	O
+system	POS	O
+and	POS	O
+cardiac	POS	B-NP
+toxicity	POS	I-NP
+following	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+local	POS	O
+anesthetics	POS	O
+is	POS	O
+a	POS	O
+recognized	POS	O
+complication	POS	O
+of	POS	O
+regional	POS	O
+anesthesia	POS	O
+.	POS	O
+Levobupivacaine	POS	O
+,	POS	O
+the	POS	O
+pure	POS	O
+S	POS	O
+(	POS	O
+-	POS	O
+)	POS	O
+enantiomer	POS	O
+of	POS	O
+bupivacaine	POS	O
+,	POS	O
+was	POS	O
+developed	POS	O
+to	POS	O
+improve	POS	O
+the	POS	O
+cardiac	POS	O
+safety	POS	O
+profile	POS	O
+of	POS	O
+bupivacaine	POS	O
+.	POS	O
+We	POS	O
+describe	POS	O
+2	POS	O
+cases	POS	O
+of	POS	O
+grand	POS	O
+mal	POS	O
+seizures	POS	B-NP
+following	POS	O
+accidental	POS	O
+intravascular	POS	O
+injection	POS	O
+of	POS	O
+levobupivacaine	POS	O
+.	POS	O
+CASE	POS	O
+REPORT	POS	O
+:	POS	O
+Two	POS	O
+patients	POS	O
+presenting	POS	O
+for	POS	O
+elective	POS	O
+orthopedic	POS	O
+surgery	POS	O
+of	POS	O
+the	POS	O
+lower	POS	O
+limb	POS	O
+underwent	POS	O
+blockade	POS	O
+of	POS	O
+the	POS	O
+lumbar	POS	O
+plexus	POS	O
+via	POS	O
+the	POS	O
+posterior	POS	O
+approach	POS	O
+.	POS	O
+Immediately	POS	O
+after	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+levobupivacaine	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+with	POS	O
+epinephrine	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+microgram	POS	O
+/	POS	O
+mL	POS	O
+,	POS	O
+the	POS	O
+patients	POS	O
+developed	POS	O
+grand	POS	O
+mal	POS	O
+seizures	POS	B-NP
+,	POS	O
+despite	POS	O
+negative	POS	O
+aspiration	POS	O
+for	POS	O
+blood	POS	O
+and	POS	O
+no	POS	O
+clinical	POS	O
+signs	POS	O
+of	POS	O
+intravenous	POS	O
+epinephrine	POS	O
+administration	POS	O
+.	POS	O
+The	POS	O
+seizures	POS	B-NP
+were	POS	O
+successfully	POS	O
+treated	POS	O
+with	POS	O
+sodium	POS	O
+thiopental	POS	O
+in	POS	O
+addition	POS	O
+to	POS	O
+succinylcholine	POS	O
+in	POS	O
+1	POS	O
+patient	POS	O
+.	POS	O
+Neither	POS	O
+patient	POS	O
+developed	POS	O
+signs	POS	O
+of	POS	O
+cardiovascular	POS	B-NP
+toxicity	POS	I-NP
+.	POS	O
+Both	POS	O
+patients	POS	O
+were	POS	O
+treated	POS	O
+preoperatively	POS	O
+with	POS	O
+beta	POS	O
+-	POS	O
+adrenergic	POS	O
+antagonist	POS	O
+medications	POS	O
+,	POS	O
+which	POS	O
+may	POS	O
+have	POS	O
+masked	POS	O
+the	POS	O
+cardiovascular	POS	O
+signs	POS	O
+of	POS	O
+the	POS	O
+unintentional	POS	O
+intravascular	POS	O
+administration	POS	O
+of	POS	O
+levobupivacaine	POS	O
+with	POS	O
+epinephrine	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Although	POS	O
+levobupivacaine	POS	O
+may	POS	O
+have	POS	O
+a	POS	O
+safer	POS	O
+cardiac	POS	B-NP
+toxicity	POS	I-NP
+profile	POS	O
+than	POS	O
+racemic	POS	O
+bupivacaine	POS	O
+,	POS	O
+if	POS	O
+adequate	POS	O
+amounts	POS	O
+of	POS	O
+levobupivacaine	POS	O
+reach	POS	O
+the	POS	O
+circulation	POS	O
+,	POS	O
+it	POS	O
+will	POS	O
+result	POS	O
+in	POS	O
+convulsions	POS	B-NP
+.	POS	O
+Plasma	POS	O
+concentrations	POS	O
+sufficient	POS	O
+to	POS	O
+result	POS	O
+in	POS	O
+central	POS	B-NP
+nervous	POS	I-NP
+system	POS	I-NP
+toxicity	POS	I-NP
+did	POS	O
+not	POS	O
+produce	POS	O
+manifestations	POS	O
+of	POS	O
+cardiac	POS	B-NP
+toxicity	POS	I-NP
+in	POS	O
+these	POS	O
+2	POS	O
+patients	POS	O
+.	POS	O
+Amiodarone	POS	O
+-	POS	O
+induced	POS	O
+torsade	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+during	POS	O
+bladder	POS	O
+irrigation	POS	O
+:	POS	O
+an	POS	O
+unusual	POS	O
+presentation	POS	O
+-	POS	O
+-	POS	O
+a	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+present	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+early	POS	O
+(	POS	O
+within	POS	O
+4	POS	O
+days	POS	O
+)	POS	O
+development	POS	O
+of	POS	O
+torsade	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+(	POS	O
+TdP	POS	B-NP
+)	POS	O
+associated	POS	O
+with	POS	O
+oral	POS	O
+amiodarone	POS	O
+therapy	POS	O
+.	POS	O
+Consistent	POS	O
+with	POS	O
+other	POS	O
+reports	POS	O
+this	POS	O
+case	POS	O
+of	POS	O
+TdP	POS	B-NP
+occurred	POS	O
+in	POS	O
+the	POS	O
+context	POS	O
+of	POS	O
+multiple	POS	O
+exacerbating	POS	O
+factors	POS	O
+including	POS	O
+hypokalemia	POS	B-NP
+and	POS	O
+digoxin	POS	O
+excess	POS	O
+.	POS	O
+Transient	POS	O
+prolongation	POS	O
+of	POS	O
+the	POS	O
+QT	POS	O
+during	POS	O
+bladder	POS	O
+irrigation	POS	O
+prompted	POS	O
+the	POS	O
+episode	POS	O
+of	POS	O
+TdP	POS	B-NP
+.	POS	O
+It	POS	O
+is	POS	O
+well	POS	O
+known	POS	O
+that	POS	O
+bradycardia	POS	B-NP
+exacerbates	POS	O
+acquired	POS	O
+TdP	POS	B-NP
+.	POS	O
+The	POS	O
+authors	POS	O
+speculate	POS	O
+that	POS	O
+the	POS	O
+increased	POS	O
+vagal	POS	O
+tone	POS	O
+during	POS	O
+bladder	POS	O
+irrigation	POS	O
+,	POS	O
+a	POS	O
+vagal	POS	O
+maneuver	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+context	POS	O
+of	POS	O
+amiodarone	POS	O
+therapy	POS	O
+resulted	POS	O
+in	POS	O
+amiodarone	POS	O
+-	POS	O
+induced	POS	O
+proarrhythmia	POS	B-NP
+.	POS	O
+In	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+amiodarone	POS	O
+therapy	POS	O
+,	POS	O
+a	POS	O
+second	POS	O
+bladder	POS	O
+irrigation	POS	O
+did	POS	O
+not	POS	O
+induce	POS	O
+TdP	POS	B-NP
+despite	POS	O
+hypokalemia	POS	B-NP
+and	POS	O
+hypomagnesemia	POS	B-NP
+.	POS	O
+Anaesthetic	POS	B-NP
+complications	POS	I-NP
+associated	POS	O
+with	POS	O
+myotonia	POS	B-NP
+congenita	POS	I-NP
+:	POS	O
+case	POS	O
+study	POS	O
+and	POS	O
+comparison	POS	O
+with	POS	O
+other	POS	O
+myotonic	POS	B-NP
+disorders	POS	I-NP
+.	POS	O
+Myotonia	POS	B-NP
+congenita	POS	I-NP
+(	POS	O
+MC	POS	B-NP
+)	POS	O
+is	POS	O
+caused	POS	O
+by	POS	O
+a	POS	O
+defect	POS	O
+in	POS	O
+the	POS	O
+skeletal	POS	O
+muscle	POS	O
+chloride	POS	O
+channel	POS	O
+function	POS	O
+,	POS	O
+which	POS	O
+may	POS	O
+cause	POS	O
+sustained	POS	O
+membrane	POS	O
+depolarisation	POS	O
+.	POS	O
+We	POS	O
+describe	POS	O
+a	POS	O
+previously	POS	O
+healthy	POS	O
+32	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+who	POS	O
+developed	POS	O
+a	POS	O
+life	POS	O
+-	POS	O
+threatening	POS	O
+muscle	POS	B-NP
+spasm	POS	I-NP
+and	POS	O
+secondary	POS	O
+ventilation	POS	O
+difficulties	POS	O
+following	POS	O
+a	POS	O
+preoperative	POS	O
+injection	POS	O
+of	POS	O
+suxamethonium	POS	O
+.	POS	O
+The	POS	O
+muscle	POS	B-NP
+spasms	POS	I-NP
+disappeared	POS	O
+spontaneously	POS	O
+and	POS	O
+the	POS	O
+surgery	POS	O
+proceeded	POS	O
+without	POS	O
+further	POS	O
+problems	POS	O
+.	POS	O
+When	POS	O
+subsequently	POS	O
+questioned	POS	O
+,	POS	O
+she	POS	O
+reported	POS	O
+minor	POS	O
+symptoms	POS	O
+suggesting	POS	O
+a	POS	O
+myotonic	POS	B-NP
+condition	POS	O
+.	POS	O
+Myotonia	POS	B-NP
+was	POS	O
+found	POS	O
+on	POS	O
+clinical	POS	O
+examination	POS	O
+and	POS	O
+EMG	POS	O
+.	POS	O
+The	POS	O
+diagnosis	POS	O
+MC	POS	O
+was	POS	O
+confirmed	POS	O
+genetically	POS	O
+.	POS	O
+Neither	POS	O
+the	POS	O
+patient	POS	O
+nor	POS	O
+the	POS	O
+anaesthetist	POS	O
+were	POS	O
+aware	POS	O
+of	POS	O
+the	POS	O
+diagnosis	POS	O
+before	POS	O
+this	POS	O
+potentially	POS	O
+lethal	POS	O
+complication	POS	O
+occurred	POS	O
+.	POS	O
+We	POS	O
+give	POS	O
+a	POS	O
+brief	POS	O
+overview	POS	O
+of	POS	O
+ion	POS	O
+channel	POS	O
+disorders	POS	O
+including	POS	O
+malignant	POS	B-NP
+hyperthermia	POS	I-NP
+and	POS	O
+their	POS	O
+anaesthetic	POS	O
+considerations	POS	O
+.	POS	O
+Respiratory	POS	O
+pattern	POS	O
+in	POS	O
+a	POS	O
+rat	POS	O
+model	POS	O
+of	POS	O
+epilepsy	POS	B-NP
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+Apnea	POS	B-NP
+is	POS	O
+known	POS	O
+to	POS	O
+occur	POS	O
+during	POS	O
+seizures	POS	B-NP
+,	POS	O
+but	POS	O
+systematic	POS	O
+studies	POS	O
+of	POS	O
+ictal	POS	O
+respiratory	POS	O
+changes	POS	O
+in	POS	O
+adults	POS	O
+are	POS	O
+few	POS	O
+.	POS	O
+Data	POS	O
+regarding	POS	O
+respiratory	POS	B-NP
+pattern	POS	I-NP
+defects	POS	I-NP
+during	POS	O
+interictal	POS	O
+periods	POS	O
+also	POS	O
+are	POS	O
+scarce	POS	O
+.	POS	O
+Here	POS	O
+we	POS	O
+sought	POS	O
+to	POS	O
+generate	POS	O
+information	POS	O
+with	POS	O
+regard	POS	O
+to	POS	O
+the	POS	O
+interictal	POS	O
+period	POS	O
+in	POS	O
+animals	POS	O
+with	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+epilepsy	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Twelve	POS	O
+rats	POS	O
+(	POS	O
+six	POS	O
+chronically	POS	O
+epileptic	POS	B-NP
+animals	POS	O
+and	POS	O
+six	POS	O
+controls	POS	O
+)	POS	O
+were	POS	O
+anesthetized	POS	O
+,	POS	O
+given	POS	O
+tracheotomies	POS	O
+,	POS	O
+and	POS	O
+subjected	POS	O
+to	POS	O
+hyperventilation	POS	B-NP
+or	POS	O
+hypoventilation	POS	B-NP
+conditions	POS	O
+.	POS	O
+Breathing	POS	O
+movements	POS	O
+caused	POS	O
+changes	POS	O
+in	POS	O
+thoracic	POS	O
+volume	POS	O
+and	POS	O
+forced	POS	O
+air	POS	O
+to	POS	O
+flow	POS	O
+tidally	POS	O
+through	POS	O
+a	POS	O
+pneumotachograph	POS	O
+.	POS	O
+This	POS	O
+flow	POS	O
+was	POS	O
+measured	POS	O
+by	POS	O
+using	POS	O
+a	POS	O
+differential	POS	O
+pressure	POS	O
+transducer	POS	O
+,	POS	O
+passed	POS	O
+through	POS	O
+a	POS	O
+polygraph	POS	O
+,	POS	O
+and	POS	O
+from	POS	O
+this	POS	O
+to	POS	O
+a	POS	O
+computer	POS	O
+with	POS	O
+custom	POS	O
+software	POS	O
+that	POS	O
+derived	POS	O
+ventilation	POS	O
+(	POS	O
+VE	POS	O
+)	POS	O
+,	POS	O
+tidal	POS	O
+volume	POS	O
+(	POS	O
+VT	POS	O
+)	POS	O
+,	POS	O
+inspiratory	POS	O
+time	POS	O
+(	POS	O
+TI	POS	O
+)	POS	O
+,	POS	O
+expiratory	POS	O
+time	POS	O
+(	POS	O
+TE	POS	O
+)	POS	O
+,	POS	O
+breathing	POS	O
+frequency	POS	O
+(	POS	O
+f	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+mean	POS	O
+inspiratory	POS	O
+flow	POS	O
+(	POS	O
+VT	POS	O
+/	POS	O
+TI	POS	O
+)	POS	O
+on	POS	O
+a	POS	O
+breath	POS	O
+-	POS	O
+by	POS	O
+-	POS	O
+breath	POS	O
+basis	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+hyperventilation	POS	O
+maneuver	POS	O
+caused	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+spontaneous	POS	O
+ventilation	POS	O
+in	POS	O
+pilocarpine	POS	O
+-	POS	O
+treated	POS	O
+and	POS	O
+control	POS	O
+rats	POS	O
+.	POS	O
+Although	POS	O
+VE	POS	O
+had	POS	O
+a	POS	O
+similar	POS	O
+decrease	POS	O
+in	POS	O
+both	POS	O
+groups	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+epileptic	POS	B-NP
+group	POS	O
+,	POS	O
+the	POS	O
+decrease	POS	O
+in	POS	O
+VE	POS	O
+was	POS	O
+due	POS	O
+to	POS	O
+a	POS	O
+significant	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+increase	POS	O
+in	POS	O
+TE	POS	O
+peak	POS	O
+in	POS	O
+relation	POS	O
+to	POS	O
+that	POS	O
+of	POS	O
+the	POS	O
+control	POS	O
+animals	POS	O
+.	POS	O
+The	POS	O
+hypoventilation	POS	B-NP
+maneuver	POS	O
+led	POS	O
+to	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+arterial	POS	O
+Paco2	POS	O
+,	POS	O
+followed	POS	O
+by	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+VE	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+epileptic	POS	B-NP
+group	POS	O
+,	POS	O
+the	POS	O
+increase	POS	O
+in	POS	O
+VE	POS	O
+was	POS	O
+mediated	POS	O
+by	POS	O
+a	POS	O
+significant	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+decrease	POS	O
+in	POS	O
+TE	POS	O
+peak	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+.	POS	O
+Systemic	POS	O
+application	POS	O
+of	POS	O
+KCN	POS	O
+,	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+peripheral	POS	O
+chemoreception	POS	O
+activation	POS	O
+on	POS	O
+ventilation	POS	O
+,	POS	O
+led	POS	O
+to	POS	O
+a	POS	O
+similar	POS	O
+increase	POS	O
+in	POS	O
+VE	POS	O
+for	POS	O
+both	POS	O
+groups	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+data	POS	O
+indicate	POS	O
+that	POS	O
+pilocarpine	POS	O
+-	POS	O
+treated	POS	O
+animals	POS	O
+have	POS	O
+an	POS	O
+altered	POS	O
+ability	POS	O
+to	POS	O
+react	POS	O
+to	POS	O
+(	POS	O
+or	POS	O
+compensate	POS	O
+for	POS	O
+)	POS	O
+blood	POS	O
+gas	POS	O
+changes	POS	O
+with	POS	O
+changes	POS	O
+in	POS	O
+ventilation	POS	O
+and	POS	O
+suggest	POS	O
+that	POS	O
+it	POS	O
+is	POS	O
+centrally	POS	O
+determined	POS	O
+.	POS	O
+We	POS	O
+speculate	POS	O
+on	POS	O
+the	POS	O
+possible	POS	O
+relation	POS	O
+of	POS	O
+the	POS	O
+current	POS	O
+findings	POS	O
+on	POS	O
+treating	POS	O
+different	POS	O
+epilepsy	POS	B-NP
+-	POS	O
+associated	POS	O
+conditions	POS	O
+.	POS	O
+Fatal	POS	O
+myeloencephalopathy	POS	B-NP
+due	POS	O
+to	POS	O
+intrathecal	POS	O
+vincristine	POS	O
+administration	POS	O
+.	POS	O
+Vincristine	POS	O
+was	POS	O
+accidentally	POS	O
+given	POS	O
+intrathecally	POS	O
+to	POS	O
+a	POS	O
+child	POS	O
+with	POS	O
+leukaemia	POS	B-NP
+,	POS	O
+producing	POS	O
+sensory	POS	O
+and	POS	O
+motor	POS	O
+dysfunction	POS	O
+followed	POS	O
+by	POS	O
+encephalopathy	POS	B-NP
+and	POS	O
+death	POS	B-NP
+.	POS	O
+Separate	POS	O
+times	POS	O
+for	POS	O
+administering	POS	O
+vincristine	POS	O
+and	POS	O
+intrathecal	POS	O
+therapy	POS	O
+is	POS	O
+recommended	POS	O
+.	POS	O
+Progesterone	POS	O
+potentiation	POS	O
+of	POS	O
+bupivacaine	POS	O
+arrhythmogenicity	POS	O
+in	POS	O
+pentobarbital	POS	O
+-	POS	O
+anesthetized	POS	O
+rats	POS	O
+and	POS	O
+beating	POS	O
+rat	POS	O
+heart	POS	O
+cell	POS	O
+cultures	POS	O
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+progesterone	POS	O
+treatment	POS	O
+on	POS	O
+bupivacaine	POS	O
+arrhythmogenicity	POS	O
+in	POS	O
+beating	POS	O
+rat	POS	O
+heart	POS	O
+myocyte	POS	O
+cultures	POS	O
+and	POS	O
+on	POS	O
+anesthetized	POS	O
+rats	POS	O
+were	POS	O
+determined	POS	O
+.	POS	O
+After	POS	O
+determining	POS	O
+the	POS	O
+bupivacaine	POS	O
+AD50	POS	O
+(	POS	O
+the	POS	O
+concentration	POS	O
+of	POS	O
+bupivacaine	POS	O
+that	POS	O
+caused	POS	O
+50	POS	O
+%	POS	O
+of	POS	O
+all	POS	O
+beating	POS	O
+rat	POS	O
+heart	POS	O
+myocyte	POS	O
+cultures	POS	O
+to	POS	O
+become	POS	O
+arrhythmic	POS	O
+)	POS	O
+,	POS	O
+we	POS	O
+determined	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+1	POS	O
+-	POS	O
+hour	POS	O
+progesterone	POS	O
+HCl	POS	O
+exposure	POS	O
+on	POS	O
+myocyte	POS	O
+contractile	POS	O
+rhythm	POS	O
+.	POS	O
+Each	POS	O
+concentration	POS	O
+of	POS	O
+progesterone	POS	O
+(	POS	O
+6	POS	O
+.	POS	O
+25	POS	O
+,	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+,	POS	O
+25	POS	O
+,	POS	O
+and	POS	O
+50	POS	O
+micrograms	POS	O
+/	POS	O
+ml	POS	O
+)	POS	O
+caused	POS	O
+a	POS	O
+significant	POS	O
+and	POS	O
+concentration	POS	O
+-	POS	O
+dependent	POS	O
+reduction	POS	O
+in	POS	O
+the	POS	O
+AD50	POS	O
+for	POS	O
+bupivacaine	POS	O
+.	POS	O
+Estradiol	POS	O
+treatment	POS	O
+also	POS	O
+increased	POS	O
+the	POS	O
+arrhythmogenicity	POS	O
+of	POS	O
+bupivacaine	POS	O
+in	POS	O
+myocyte	POS	O
+cultures	POS	O
+,	POS	O
+but	POS	O
+was	POS	O
+only	POS	O
+one	POS	O
+fourth	POS	O
+as	POS	O
+potent	POS	O
+as	POS	O
+progesterone	POS	O
+.	POS	O
+Neither	POS	O
+progesterone	POS	O
+nor	POS	O
+estradiol	POS	O
+effects	POS	O
+on	POS	O
+bupivacaine	POS	O
+arrhythmogenicity	POS	O
+were	POS	O
+potentiated	POS	O
+by	POS	O
+epinephrine	POS	O
+.	POS	O
+Chronic	POS	O
+progesterone	POS	O
+pretreatment	POS	O
+(	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+for	POS	O
+21	POS	O
+days	POS	O
+)	POS	O
+caused	POS	O
+a	POS	O
+significant	POS	O
+increase	POS	O
+in	POS	O
+bupivacaine	POS	O
+arrhythmogenicity	POS	O
+in	POS	O
+intact	POS	O
+pentobarbital	POS	O
+-	POS	O
+anesthetized	POS	O
+rats	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+decrease	POS	O
+in	POS	O
+the	POS	O
+time	POS	O
+to	POS	O
+onset	POS	O
+of	POS	O
+arrhythmia	POS	B-NP
+as	POS	O
+compared	POS	O
+with	POS	O
+control	POS	O
+nonprogesterone	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+(	POS	O
+6	POS	O
+.	POS	O
+2	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+vs	POS	O
+.	POS	O
+30	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+min	POS	O
+,	POS	O
+mean	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+SE	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+indicate	POS	O
+that	POS	O
+progesterone	POS	O
+can	POS	O
+potentiate	POS	O
+bupivacaine	POS	O
+arrhythmogenicity	POS	O
+both	POS	O
+in	POS	O
+vivo	POS	O
+and	POS	O
+in	POS	O
+vitro	POS	O
+.	POS	O
+Potentiation	POS	O
+of	POS	O
+bupivacaine	POS	O
+arrhythmia	POS	B-NP
+in	POS	O
+myocyte	POS	O
+cultures	POS	O
+suggests	POS	O
+that	POS	O
+this	POS	O
+effect	POS	O
+is	POS	O
+at	POS	O
+least	POS	O
+partly	POS	O
+mediated	POS	O
+at	POS	O
+the	POS	O
+myocyte	POS	O
+level	POS	O
+.	POS	O
+Increased	POS	O
+serum	POS	O
+soluble	POS	O
+Fas	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+due	POS	O
+to	POS	O
+paracetamol	POS	O
+overdose	POS	B-NP
+.	POS	O
+BACKGROUND	POS	O
+/	POS	O
+AIMS	POS	O
+:	POS	O
+Experimental	POS	O
+studies	POS	O
+have	POS	O
+suggested	POS	O
+that	POS	O
+apoptosis	POS	O
+via	POS	O
+the	POS	O
+Fas	POS	O
+/	POS	O
+Fas	POS	O
+Ligand	POS	O
+signaling	POS	O
+system	POS	O
+may	POS	O
+play	POS	O
+an	POS	O
+important	POS	O
+role	POS	O
+in	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+the	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+soluble	POS	O
+form	POS	O
+of	POS	O
+Fas	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+METHODOLOGY	POS	O
+:	POS	O
+Serum	POS	O
+levels	POS	O
+of	POS	O
+sFas	POS	O
+(	POS	O
+soluble	POS	O
+Fas	POS	O
+)	POS	O
+were	POS	O
+measured	POS	O
+by	POS	O
+ELISA	POS	O
+in	POS	O
+24	POS	O
+patients	POS	O
+with	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+and	POS	O
+10	POS	O
+normal	POS	B-NP
+control	POS	O
+subjects	POS	O
+.	POS	O
+Serum	POS	O
+levels	POS	O
+of	POS	O
+tumor	POS	B-NP
+necrosis	POS	O
+factor	POS	O
+-	POS	O
+alpha	POS	O
+and	POS	O
+interferon	POS	O
+-	POS	O
+gamma	POS	O
+were	POS	O
+also	POS	O
+determined	POS	O
+by	POS	O
+ELISA	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Serum	POS	O
+sFas	POS	O
+was	POS	O
+significantly	POS	O
+increased	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+(	POS	O
+median	POS	O
+,	POS	O
+26	POS	O
+.	POS	O
+8	POS	O
+U	POS	O
+/	POS	O
+mL	POS	O
+;	POS	O
+range	POS	O
+,	POS	O
+6	POS	O
+.	POS	O
+9	POS	O
+-	POS	O
+52	POS	O
+.	POS	O
+7	POS	O
+U	POS	O
+/	POS	O
+mL	POS	O
+)	POS	O
+compared	POS	O
+to	POS	O
+the	POS	O
+normal	POS	O
+controls	POS	O
+(	POS	O
+median	POS	O
+,	POS	O
+8	POS	O
+.	POS	O
+6	POS	O
+U	POS	O
+/	POS	O
+mL	POS	O
+;	POS	O
+range	POS	O
+,	POS	O
+6	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+12	POS	O
+.	POS	O
+0	POS	O
+U	POS	O
+/	POS	O
+mL	POS	O
+,	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+0001	POS	O
+)	POS	O
+.	POS	O
+Levels	POS	O
+were	POS	O
+significantly	POS	O
+greater	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+due	POS	O
+to	POS	O
+paracetamol	POS	O
+overdose	POS	B-NP
+(	POS	O
+median	POS	O
+,	POS	O
+28	POS	O
+.	POS	O
+7	POS	O
+U	POS	O
+/	POS	O
+mL	POS	O
+;	POS	O
+range	POS	O
+,	POS	O
+12	POS	O
+.	POS	O
+8	POS	O
+-	POS	O
+52	POS	O
+.	POS	O
+7	POS	O
+U	POS	O
+/	POS	O
+mL	POS	O
+,	POS	O
+n	POS	O
+=	POS	O
+17	POS	O
+)	POS	O
+than	POS	O
+those	POS	O
+due	POS	O
+to	POS	O
+non	POS	O
+-	POS	O
+A	POS	O
+to	POS	O
+E	POS	O
+hepatitis	POS	B-NP
+(	POS	O
+median	POS	O
+,	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+U	POS	O
+/	POS	O
+mL	POS	O
+;	POS	O
+range	POS	O
+,	POS	O
+6	POS	O
+.	POS	O
+9	POS	O
+-	POS	O
+46	POS	O
+.	POS	O
+0	POS	O
+U	POS	O
+/	POS	O
+mL	POS	O
+,	POS	O
+n	POS	O
+=	POS	O
+7	POS	O
+,	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+relationship	POS	O
+of	POS	O
+sFas	POS	O
+to	POS	O
+eventual	POS	O
+outcome	POS	O
+in	POS	O
+the	POS	O
+patients	POS	O
+.	POS	O
+A	POS	O
+significant	POS	O
+correlation	POS	O
+was	POS	O
+observed	POS	O
+between	POS	O
+serum	POS	O
+sFas	POS	O
+levels	POS	O
+and	POS	O
+aspartate	POS	O
+aminotransferase	POS	O
+(	POS	O
+r	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+613	POS	O
+,	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+increased	POS	O
+concentration	POS	O
+of	POS	O
+sFas	POS	O
+in	POS	O
+serum	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+may	POS	O
+reflect	POS	O
+activation	POS	O
+of	POS	O
+Fas	POS	O
+-	POS	O
+mediated	POS	O
+apoptosis	POS	O
+in	POS	O
+the	POS	O
+liver	POS	O
+and	POS	O
+this	POS	O
+together	POS	O
+with	POS	O
+increased	POS	O
+tumor	POS	B-NP
+necrosis	POS	O
+factor	POS	O
+-	POS	O
+alpha	POS	O
+may	POS	O
+be	POS	O
+an	POS	O
+important	POS	O
+factor	POS	O
+in	POS	O
+liver	POS	B-NP
+cell	POS	I-NP
+loss	POS	I-NP
+.	POS	O
+Bilateral	POS	O
+subthalamic	POS	O
+nucleus	POS	O
+stimulation	POS	O
+for	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+High	POS	O
+frequency	POS	O
+stimulation	POS	O
+of	POS	O
+the	POS	O
+subthalamic	POS	O
+nucleus	POS	O
+(	POS	O
+STN	POS	O
+)	POS	O
+is	POS	O
+known	POS	O
+to	POS	O
+ameliorate	POS	O
+the	POS	O
+signs	POS	O
+and	POS	O
+symptoms	POS	O
+of	POS	O
+advanced	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+AIM	POS	O
+:	POS	O
+We	POS	O
+studied	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+high	POS	O
+frequency	POS	O
+STN	POS	O
+stimulation	POS	O
+in	POS	O
+23	POS	O
+patients	POS	O
+.	POS	O
+METHOD	POS	O
+:	POS	O
+Twenty	POS	O
+-	POS	O
+three	POS	O
+patients	POS	O
+suffering	POS	O
+from	POS	O
+severe	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+Stages	POS	O
+III	POS	O
+-	POS	O
+V	POS	O
+on	POS	O
+Hoehn	POS	O
+and	POS	O
+Yahr	POS	O
+scale	POS	O
+)	POS	O
+and	POS	O
+,	POS	O
+particularly	POS	O
+bradykinesia	POS	B-NP
+,	POS	O
+rigidity	POS	B-NP
+,	POS	O
+and	POS	O
+levodopa	POS	O
+-	POS	O
+induced	POS	O
+dyskinesias	POS	B-NP
+underwent	POS	O
+bilateral	POS	O
+implantation	POS	O
+of	POS	O
+electrodes	POS	O
+in	POS	O
+the	POS	O
+STN	POS	O
+.	POS	O
+Preoperative	POS	O
+and	POS	O
+postoperative	POS	O
+assessments	POS	O
+of	POS	O
+these	POS	O
+patients	POS	O
+at	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+,	POS	O
+6	POS	O
+and	POS	O
+12	POS	O
+months	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+,	POS	O
+in	POS	O
+"	POS	O
+on	POS	O
+"	POS	O
+and	POS	O
+"	POS	O
+off	POS	O
+"	POS	O
+drug	POS	O
+conditions	POS	O
+,	POS	O
+was	POS	O
+carried	POS	O
+out	POS	O
+using	POS	O
+Unified	POS	O
+Parkinson	POS	O
+'	POS	O
+s	POS	O
+Disease	POS	O
+Rating	POS	O
+Scale	POS	O
+,	POS	O
+Hoehn	POS	B-NP
+and	POS	O
+Yahr	POS	O
+staging	POS	O
+,	POS	O
+England	POS	O
+activities	POS	O
+of	POS	O
+daily	POS	O
+living	POS	O
+score	POS	O
+and	POS	O
+video	POS	O
+recordings	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+After	POS	O
+one	POS	O
+year	POS	O
+of	POS	O
+electrical	POS	O
+stimulation	POS	O
+of	POS	O
+the	POS	O
+STN	POS	O
+,	POS	O
+the	POS	O
+patients	POS	O
+'	POS	O
+scores	POS	O
+for	POS	O
+activities	POS	O
+of	POS	O
+daily	POS	O
+living	POS	O
+and	POS	O
+motor	POS	O
+examination	POS	O
+scores	POS	O
+(	POS	O
+Unified	POS	O
+Parkinson	POS	O
+'	POS	O
+s	POS	O
+Disease	POS	O
+Rating	POS	O
+Scale	POS	O
+parts	POS	O
+II	POS	O
+and	POS	O
+III	POS	O
+)	POS	O
+off	POS	O
+medication	POS	O
+improved	POS	O
+by	POS	O
+62	POS	O
+%	POS	O
+and	POS	O
+61	POS	O
+%	POS	O
+respectively	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+0005	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+subscores	POS	O
+for	POS	O
+the	POS	O
+akinesia	POS	B-NP
+,	POS	O
+rigidity	POS	B-NP
+,	POS	O
+tremor	POS	B-NP
+and	POS	O
+gait	POS	O
+also	POS	O
+improved	POS	O
+.	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+0005	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+average	POS	O
+levodopa	POS	O
+dose	POS	O
+decreased	POS	O
+from	POS	O
+813	POS	O
+mg	POS	O
+to	POS	O
+359	POS	O
+mg	POS	O
+.	POS	O
+The	POS	O
+cognitive	POS	O
+functions	POS	O
+remained	POS	O
+unchanged	POS	O
+.	POS	O
+Two	POS	O
+patients	POS	O
+developed	POS	O
+device	POS	O
+-	POS	O
+related	POS	O
+complications	POS	O
+and	POS	O
+two	POS	O
+patients	POS	O
+experienced	POS	O
+abnormal	POS	B-NP
+weight	POS	I-NP
+gain	POS	I-NP
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Bilateral	POS	O
+subthalamic	POS	O
+nucleus	POS	O
+stimulation	POS	O
+is	POS	O
+an	POS	O
+effective	POS	O
+treatment	POS	O
+for	POS	O
+advanced	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+It	POS	O
+reduces	POS	O
+the	POS	O
+severity	POS	O
+of	POS	O
+"	POS	O
+off	POS	O
+"	POS	O
+phase	POS	O
+symptoms	POS	O
+,	POS	O
+improves	POS	O
+the	POS	O
+axial	POS	O
+symptoms	POS	O
+and	POS	O
+reduces	POS	O
+levodopa	POS	O
+requirements	POS	O
+.	POS	O
+The	POS	O
+reduction	POS	O
+in	POS	O
+the	POS	O
+levodopa	POS	O
+dose	POS	O
+is	POS	O
+useful	POS	O
+in	POS	O
+controlling	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+dyskinesias	POS	B-NP
+.	POS	O
+Acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+occurring	POS	O
+during	POS	O
+intravenous	POS	O
+desferrioxamine	POS	O
+therapy	POS	O
+:	POS	O
+recovery	POS	O
+after	POS	O
+haemodialysis	POS	O
+.	POS	O
+A	POS	O
+patient	POS	O
+with	POS	O
+transfusion	POS	B-NP
+-	POS	I-NP
+dependent	POS	I-NP
+thalassemia	POS	I-NP
+was	POS	O
+undergoing	POS	O
+home	POS	O
+intravenous	POS	O
+desferrioxamine	POS	O
+(	POS	O
+DFX	POS	O
+)	POS	O
+treatment	POS	O
+by	POS	O
+means	POS	O
+of	POS	O
+a	POS	O
+totally	POS	O
+implanted	POS	O
+system	POS	O
+because	POS	O
+of	POS	O
+his	POS	O
+poor	POS	O
+compliance	POS	O
+with	POS	O
+the	POS	O
+nightly	POS	O
+subcutaneous	POS	O
+therapy	POS	O
+.	POS	O
+Due	POS	O
+to	POS	O
+an	POS	O
+accidental	POS	O
+malfunctioning	POS	O
+of	POS	O
+the	POS	O
+infusion	POS	O
+pump	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+inadvertently	POS	O
+administered	POS	O
+a	POS	O
+toxic	POS	O
+dosage	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+which	POS	O
+caused	POS	O
+renal	POS	B-NP
+insufficiency	POS	I-NP
+.	POS	O
+Given	POS	O
+the	POS	O
+progressive	POS	O
+deterioration	POS	O
+of	POS	O
+the	POS	O
+symptoms	POS	O
+and	POS	O
+of	POS	O
+the	POS	O
+laboratory	POS	O
+values	POS	O
+,	POS	O
+despite	POS	O
+adequate	POS	O
+medical	POS	O
+treatment	POS	O
+,	POS	O
+a	POS	O
+decision	POS	O
+was	POS	O
+made	POS	O
+to	POS	O
+introduce	POS	O
+haemodialytical	POS	O
+therapy	POS	O
+in	POS	O
+order	POS	O
+to	POS	O
+remove	POS	O
+the	POS	O
+drug	POS	O
+and	POS	O
+therapy	POS	O
+reduce	POS	O
+the	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+From	POS	O
+the	POS	O
+results	POS	O
+obtained	POS	O
+,	POS	O
+haemodialysis	POS	O
+can	POS	O
+therefore	POS	O
+be	POS	O
+suggested	POS	O
+as	POS	O
+a	POS	O
+useful	POS	O
+therapy	POS	O
+in	POS	O
+rare	POS	O
+cases	POS	O
+of	POS	O
+progressive	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+caused	POS	O
+by	POS	O
+desferrioxamine	POS	O
+.	POS	O
+Ocular	POS	B-NP
+motility	POS	I-NP
+changes	POS	O
+after	POS	O
+subtenon	POS	O
+carboplatin	POS	O
+chemotherapy	POS	O
+for	POS	O
+retinoblastoma	POS	B-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Focal	POS	O
+subtenon	POS	O
+carboplatin	POS	O
+injections	POS	O
+have	POS	O
+recently	POS	O
+been	POS	O
+used	POS	O
+as	POS	O
+a	POS	O
+presumably	POS	O
+toxicity	POS	O
+-	POS	O
+free	POS	O
+adjunct	POS	O
+to	POS	O
+systemic	POS	O
+chemotherapy	POS	O
+for	POS	O
+intraocular	POS	B-NP
+retinoblastoma	POS	I-NP
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+report	POS	O
+our	POS	O
+clinical	POS	O
+experience	POS	O
+with	POS	O
+abnormal	POS	B-NP
+ocular	POS	I-NP
+motility	POS	I-NP
+in	POS	O
+patients	POS	O
+treated	POS	O
+with	POS	O
+subtenon	POS	O
+carboplatin	POS	O
+chemotherapy	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+noted	POS	O
+abnormal	POS	B-NP
+ocular	POS	I-NP
+motility	POS	I-NP
+in	POS	O
+10	POS	O
+consecutive	POS	O
+patients	POS	O
+with	POS	O
+retinoblastoma	POS	B-NP
+who	POS	O
+had	POS	O
+received	POS	O
+subtenon	POS	O
+carboplatin	POS	O
+.	POS	O
+During	POS	O
+ocular	POS	O
+manipulation	POS	O
+under	POS	O
+general	POS	O
+anesthesia	POS	O
+,	POS	O
+we	POS	O
+assessed	POS	O
+their	POS	O
+eyes	POS	O
+by	POS	O
+forced	POS	O
+duction	POS	O
+testing	POS	O
+,	POS	O
+comparing	POS	O
+ocular	POS	O
+motility	POS	O
+after	POS	O
+tumor	POS	B-NP
+control	POS	O
+with	POS	O
+ocular	POS	B-NP
+motility	POS	I-NP
+at	POS	O
+diagnosis	POS	O
+.	POS	O
+Eyes	POS	O
+subsequently	POS	O
+enucleated	POS	O
+because	POS	O
+of	POS	O
+treatment	POS	O
+failure	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+4	POS	O
+)	POS	O
+were	POS	O
+examined	POS	O
+histologically	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Limitation	POS	O
+of	POS	O
+ocular	POS	B-NP
+motility	POS	I-NP
+was	POS	O
+detected	POS	O
+in	POS	O
+all	POS	O
+12	POS	O
+eyes	POS	O
+of	POS	O
+10	POS	O
+patients	POS	O
+treated	POS	O
+for	POS	O
+intraocular	POS	B-NP
+retinoblastoma	POS	I-NP
+with	POS	O
+1	POS	O
+to	POS	O
+6	POS	O
+injections	POS	O
+of	POS	O
+subtenon	POS	O
+carboplatin	POS	O
+as	POS	O
+part	POS	O
+of	POS	O
+multimodality	POS	O
+therapy	POS	O
+.	POS	O
+Histopathological	POS	O
+examination	POS	O
+revealed	POS	O
+many	POS	O
+lipophages	POS	O
+in	POS	O
+the	POS	O
+periorbital	POS	O
+fat	POS	O
+surrounding	POS	O
+the	POS	O
+optic	POS	O
+nerve	POS	O
+in	POS	O
+1	POS	O
+eye	POS	O
+,	POS	O
+indicative	POS	O
+of	POS	O
+phagocytosis	POS	O
+of	POS	O
+previously	POS	O
+existing	POS	O
+fat	POS	O
+cells	POS	O
+and	POS	O
+suggesting	POS	O
+prior	POS	O
+fat	POS	O
+necrosis	POS	B-NP
+.	POS	O
+The	POS	O
+enucleations	POS	O
+were	POS	O
+technically	POS	O
+difficult	POS	O
+and	POS	O
+hazardous	POS	O
+for	POS	O
+globe	POS	O
+rupture	POS	O
+because	POS	O
+of	POS	O
+extensive	POS	O
+orbital	POS	O
+soft	POS	O
+tissue	POS	O
+adhesions	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Subtenon	POS	O
+carboplatin	POS	O
+chemotherapy	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+significant	POS	O
+fibrosis	POS	B-NP
+of	POS	O
+orbital	POS	O
+soft	POS	O
+tissues	POS	O
+,	POS	O
+leading	POS	O
+to	POS	O
+mechanical	POS	O
+restriction	POS	O
+of	POS	O
+eye	POS	O
+movements	POS	O
+and	POS	O
+making	POS	O
+subsequent	POS	O
+enucleation	POS	O
+difficult	POS	O
+.	POS	O
+Subtenon	POS	O
+carboplatin	POS	O
+is	POS	O
+not	POS	O
+free	POS	O
+of	POS	O
+toxicity	POS	B-NP
+,	POS	O
+and	POS	O
+its	POS	O
+use	POS	O
+is	POS	O
+best	POS	O
+restricted	POS	O
+to	POS	O
+specific	POS	O
+indications	POS	O
+.	POS	O
+Ethambutol	POS	O
+and	POS	O
+optic	POS	B-NP
+neuropathy	POS	I-NP
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+To	POS	O
+demonstrate	POS	O
+the	POS	O
+association	POS	O
+between	POS	O
+ethambutol	POS	O
+and	POS	O
+optic	POS	B-NP
+neuropathy	POS	I-NP
+.	POS	O
+METHOD	POS	O
+:	POS	O
+Thirteen	POS	O
+patients	POS	O
+who	POS	O
+developed	POS	O
+optic	POS	B-NP
+neuropathy	POS	I-NP
+after	POS	O
+being	POS	O
+treated	POS	O
+with	POS	O
+ethambutol	POS	O
+for	POS	O
+tuberculosis	POS	B-NP
+of	POS	O
+the	POS	O
+lung	POS	O
+or	POS	O
+lymph	POS	O
+node	POS	O
+at	POS	O
+Siriraj	POS	O
+Hospital	POS	O
+between	POS	O
+1997	POS	O
+and	POS	O
+2001	POS	O
+were	POS	O
+retrospectively	POS	O
+reviewed	POS	O
+.	POS	O
+The	POS	O
+clinical	POS	O
+characteristics	POS	O
+and	POS	O
+initial	POS	O
+and	POS	O
+final	POS	O
+visual	POS	O
+acuity	POS	O
+were	POS	O
+analyzed	POS	O
+to	POS	O
+determine	POS	O
+visual	POS	O
+outcome	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+All	POS	O
+patients	POS	O
+had	POS	O
+optic	POS	B-NP
+neuropathy	POS	I-NP
+between	POS	O
+1	POS	O
+to	POS	O
+6	POS	O
+months	POS	O
+(	POS	O
+mean	POS	O
+=	POS	O
+2	POS	O
+.	POS	O
+9	POS	O
+months	POS	O
+)	POS	O
+after	POS	O
+starting	POS	O
+ethambutol	POS	O
+therapy	POS	O
+at	POS	O
+a	POS	O
+dosage	POS	O
+ranging	POS	O
+from	POS	O
+13	POS	O
+to	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+(	POS	O
+mean	POS	O
+=	POS	O
+17	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+.	POS	O
+Seven	POS	O
+(	POS	O
+54	POS	O
+%	POS	O
+)	POS	O
+of	POS	O
+the	POS	O
+13	POS	O
+patients	POS	O
+experienced	POS	O
+visual	POS	O
+recovery	POS	O
+after	POS	O
+stopping	POS	O
+the	POS	O
+drug	POS	O
+.	POS	O
+Of	POS	O
+6	POS	O
+patients	POS	O
+with	POS	O
+irreversible	POS	O
+visual	POS	B-NP
+impairment	POS	I-NP
+,	POS	O
+4	POS	O
+patients	POS	O
+had	POS	O
+diabetes	POS	B-NP
+mellitus	POS	I-NP
+,	POS	O
+glaucoma	POS	B-NP
+and	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+heavy	POS	O
+smoking	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Early	POS	O
+recognition	POS	O
+of	POS	O
+optic	POS	B-NP
+neuropathy	POS	I-NP
+should	POS	O
+be	POS	O
+considered	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+ethambutol	POS	O
+therapy	POS	O
+.	POS	O
+A	POS	O
+low	POS	O
+dose	POS	O
+and	POS	O
+prompt	POS	O
+discontinuation	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+is	POS	O
+recommended	POS	O
+particularly	POS	O
+in	POS	O
+individuals	POS	O
+with	POS	O
+diabetes	POS	B-NP
+mellitus	POS	I-NP
+,	POS	O
+glaucoma	POS	B-NP
+or	POS	O
+who	POS	O
+are	POS	O
+heavy	POS	O
+smokers	POS	O
+.	POS	O
+Treatment	POS	O
+of	POS	O
+compensatory	POS	O
+gustatory	POS	B-NP
+hyperhidrosis	POS	I-NP
+with	POS	O
+topical	POS	O
+glycopyrrolate	POS	O
+.	POS	O
+Gustatory	POS	B-NP
+hyperhidrosis	POS	I-NP
+is	POS	O
+facial	POS	B-NP
+sweating	POS	I-NP
+usually	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+eating	POS	O
+of	POS	O
+hot	POS	O
+spicy	POS	O
+food	POS	O
+or	POS	O
+even	POS	O
+smelling	POS	O
+this	POS	O
+food	POS	O
+.	POS	O
+Current	POS	O
+options	POS	O
+of	POS	O
+treatment	POS	O
+include	POS	O
+oral	POS	O
+anticholinergic	POS	O
+drugs	POS	O
+,	POS	O
+the	POS	O
+topical	POS	O
+application	POS	O
+of	POS	O
+anticholinergics	POS	O
+or	POS	O
+aluminum	POS	O
+chloride	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+injection	POS	O
+of	POS	O
+botulinum	POS	O
+toxin	POS	O
+.	POS	O
+Thirteen	POS	O
+patients	POS	O
+have	POS	O
+been	POS	O
+treated	POS	O
+to	POS	O
+date	POS	O
+with	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+or	POS	O
+2	POS	O
+%	POS	O
+topical	POS	O
+glycopyrrolate	POS	O
+.	POS	O
+All	POS	O
+patients	POS	O
+had	POS	O
+gustatory	POS	B-NP
+hyperhidrosis	POS	I-NP
+,	POS	O
+which	POS	O
+interfered	POS	O
+with	POS	O
+their	POS	O
+social	POS	O
+activities	POS	O
+,	POS	O
+after	POS	O
+transthroacic	POS	O
+endoscopic	POS	O
+sympathectomy	POS	O
+,	POS	O
+and	POS	O
+which	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+compensatory	POS	O
+focal	POS	O
+hyperhidrosis	POS	B-NP
+.	POS	O
+After	POS	O
+applying	POS	O
+topical	POS	O
+glycopyrrolate	POS	O
+,	POS	O
+the	POS	O
+subjective	POS	O
+effect	POS	O
+was	POS	O
+excellent	POS	O
+(	POS	O
+no	POS	O
+sweating	POS	O
+after	POS	O
+eating	POS	O
+hot	POS	O
+spicy	POS	O
+food	POS	O
+)	POS	O
+in	POS	O
+10	POS	O
+patients	POS	O
+(	POS	O
+77	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+fair	POS	O
+(	POS	O
+clearly	POS	O
+reduced	POS	O
+sweating	POS	O
+)	POS	O
+in	POS	O
+3	POS	O
+patients	POS	O
+(	POS	O
+23	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+All	POS	O
+had	POS	O
+reported	POS	O
+incidents	POS	O
+of	POS	O
+being	POS	O
+very	POS	O
+embarrassed	POS	O
+whilst	POS	O
+eating	POS	O
+hot	POS	O
+spicy	POS	O
+foods	POS	O
+.	POS	O
+Adverse	POS	O
+effects	POS	O
+included	POS	O
+a	POS	O
+mildly	POS	O
+dry	POS	B-NP
+mouth	POS	I-NP
+and	POS	O
+a	POS	O
+sore	POS	B-NP
+throat	POS	I-NP
+in	POS	O
+2	POS	O
+patients	POS	O
+(	POS	O
+2	POS	O
+%	POS	O
+glycopyrrolate	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+light	POS	O
+headache	POS	B-NP
+in	POS	O
+1	POS	O
+patient	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+glycopyrrolate	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+topical	POS	O
+application	POS	O
+of	POS	O
+a	POS	O
+glycopyrrolate	POS	O
+pad	POS	O
+appeared	POS	O
+to	POS	O
+be	POS	O
+safe	POS	O
+,	POS	O
+efficacious	POS	O
+,	POS	O
+well	POS	O
+tolerated	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+convenient	POS	O
+method	POS	O
+of	POS	O
+treatment	POS	O
+for	POS	O
+moderate	POS	O
+to	POS	O
+severe	POS	O
+symptoms	POS	O
+of	POS	O
+gustatory	POS	B-NP
+hyperhidrosis	POS	I-NP
+in	POS	O
+post	POS	O
+transthoracic	POS	O
+endoscopic	POS	O
+sympathectomy	POS	O
+or	POS	O
+sympathicotomy	POS	O
+patients	POS	O
+,	POS	O
+with	POS	O
+few	POS	O
+side	POS	O
+effects	POS	O
+.	POS	O
+Neuroleptic	POS	B-NP
+-	POS	O
+associated	POS	O
+hyperprolactinemia	POS	B-NP
+.	POS	O
+Can	POS	O
+it	POS	O
+be	POS	O
+treated	POS	O
+with	POS	O
+bromocriptine	POS	O
+?	POS	O
+Six	POS	O
+stable	POS	O
+psychiatric	POS	O
+outpatients	POS	O
+with	POS	O
+hyperprolactinemia	POS	B-NP
+and	POS	O
+amenorrhea	POS	B-NP
+/	POS	O
+oligomenorrhea	POS	B-NP
+associated	POS	O
+with	POS	O
+their	POS	O
+neuroleptic	POS	O
+medications	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+bromocriptine	POS	O
+.	POS	O
+Daily	POS	O
+dosages	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+10	POS	O
+mg	POS	O
+corrected	POS	O
+the	POS	O
+hyperprolactinemia	POS	B-NP
+and	POS	O
+restored	POS	O
+menstruation	POS	O
+in	POS	O
+four	POS	O
+of	POS	O
+the	POS	O
+six	POS	O
+patients	POS	O
+.	POS	O
+One	POS	O
+woman	POS	O
+,	POS	O
+however	POS	O
+,	POS	O
+developed	POS	O
+worsened	POS	O
+psychiatric	POS	B-NP
+symptoms	POS	I-NP
+while	POS	O
+taking	POS	O
+bromocriptine	POS	O
+,	POS	O
+and	POS	O
+it	POS	O
+was	POS	O
+discontinued	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+three	POS	O
+of	POS	O
+six	POS	O
+patients	POS	O
+had	POS	O
+their	POS	O
+menstrual	POS	O
+irregularity	POS	O
+successfully	POS	O
+corrected	POS	O
+with	POS	O
+bromocriptine	POS	O
+.	POS	O
+This	POS	O
+suggests	POS	O
+that	POS	O
+bromocriptine	POS	O
+should	POS	O
+be	POS	O
+further	POS	O
+evaluated	POS	O
+as	POS	O
+potential	POS	O
+therapy	POS	O
+for	POS	O
+neuroleptic	POS	O
+-	POS	O
+associated	POS	O
+hyperprolactinemia	POS	B-NP
+and	POS	O
+amenorrhea	POS	B-NP
+/	POS	O
+galactorrhea	POS	B-NP
+.	POS	O
+Ethacrynic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+convulsions	POS	B-NP
+and	POS	O
+brain	POS	O
+neurotransmitters	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+Intracerebroventricular	POS	O
+injection	POS	O
+of	POS	O
+ethacrynic	POS	O
+acid	POS	O
+(	POS	O
+50	POS	O
+%	POS	O
+convulsive	POS	B-NP
+dose	POS	O
+;	POS	O
+50	POS	O
+micrograms	POS	O
+/	POS	O
+mouse	POS	O
+)	POS	O
+accelerated	POS	O
+the	POS	O
+synthesis	POS	O
+/	POS	O
+turnover	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+hydroxytryptamine	POS	O
+(	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+)	POS	O
+but	POS	O
+suppressed	POS	O
+the	POS	O
+synthesis	POS	O
+of	POS	O
+gamma	POS	O
+-	POS	O
+aminobutyric	POS	O
+acid	POS	O
+and	POS	O
+acetylcholine	POS	O
+in	POS	O
+mouse	POS	O
+brain	POS	O
+.	POS	O
+These	POS	O
+effects	POS	O
+were	POS	O
+completely	POS	O
+antagonized	POS	O
+by	POS	O
+pretreatment	POS	O
+with	POS	O
+a	POS	O
+glutamate	POS	O
+/	POS	O
+N	POS	O
+-	POS	O
+methyl	POS	O
+-	POS	O
+D	POS	O
+-	POS	O
+aspartate	POS	O
+antagonist	POS	O
+,	POS	O
+aminophosphonovaleric	POS	O
+acid	POS	O
+.	POS	O
+In	POS	O
+ethacrynic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+convulsions	POS	B-NP
+,	POS	O
+these	POS	O
+neurotransmitter	POS	O
+systems	POS	O
+may	POS	O
+be	POS	O
+differentially	POS	O
+modulated	POS	O
+,	POS	O
+probably	POS	O
+through	POS	O
+activation	POS	O
+of	POS	O
+glutaminergic	POS	O
+neurons	POS	O
+in	POS	O
+the	POS	O
+brain	POS	O
+.	POS	O
+Pharmacology	POS	O
+of	POS	O
+gamma	POS	O
+-	POS	O
+aminobutyric	POS	O
+acidA	POS	O
+receptor	POS	O
+complex	POS	O
+after	POS	O
+the	POS	O
+in	POS	O
+vivo	POS	O
+administration	POS	O
+of	POS	O
+the	POS	O
+anxioselective	POS	O
+and	POS	O
+anticonvulsant	POS	O
+beta	POS	O
+-	POS	O
+carboline	POS	O
+derivative	POS	O
+abecarnil	POS	O
+.	POS	O
+In	POS	O
+rodents	POS	O
+,	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+the	POS	O
+beta	POS	O
+-	POS	O
+carboline	POS	O
+derivative	POS	O
+isopropyl	POS	O
+-	POS	O
+6	POS	O
+-	POS	O
+benzyloxy	POS	O
+-	POS	O
+4	POS	O
+-	POS	O
+methoxymethyl	POS	O
+-	POS	O
+beta	POS	O
+-	POS	O
+carboline	POS	O
+-	POS	O
+3	POS	O
+-	POS	O
+carboxylate	POS	O
+(	POS	O
+abecarrnil	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+new	POS	O
+ligand	POS	O
+for	POS	O
+benzodiazepine	POS	O
+receptors	POS	O
+possessing	POS	O
+anxiolytic	POS	O
+and	POS	O
+anticonvulsant	POS	O
+properties	POS	O
+,	POS	O
+was	POS	O
+evaluated	POS	O
+on	POS	O
+the	POS	O
+function	POS	O
+of	POS	O
+central	POS	O
+gamma	POS	O
+-	POS	O
+aminobutyric	POS	O
+acid	POS	O
+(	POS	O
+GABA	POS	O
+)	POS	O
+A	POS	O
+receptor	POS	O
+complex	POS	O
+,	POS	O
+both	POS	O
+in	POS	O
+vitro	POS	O
+and	POS	O
+in	POS	O
+vivo	POS	O
+.	POS	O
+Added	POS	O
+in	POS	O
+vitro	POS	O
+to	POS	O
+rat	POS	O
+cortical	POS	O
+membrane	POS	O
+preparation	POS	O
+,	POS	O
+abecarnil	POS	O
+increased	POS	O
+[	POS	O
+3H	POS	O
+]	POS	O
+GABA	POS	O
+binding	POS	O
+,	POS	O
+enhanced	POS	O
+muscimol	POS	O
+-	POS	O
+stimulated	POS	O
+36Cl	POS	O
+-	POS	O
+uptake	POS	O
+and	POS	O
+reduced	POS	O
+the	POS	O
+binding	POS	O
+of	POS	O
+t	POS	O
+-	POS	O
+[	POS	O
+35S	POS	O
+]	POS	O
+butylbicyclophosphorothionate	POS	O
+(	POS	O
+[	POS	O
+35S	POS	O
+]	POS	O
+TBPS	POS	O
+)	POS	O
+.	POS	O
+These	POS	O
+effects	POS	O
+were	POS	O
+similar	POS	O
+to	POS	O
+those	POS	O
+induced	POS	O
+by	POS	O
+diazepam	POS	O
+,	POS	O
+whereas	POS	O
+the	POS	O
+partial	POS	O
+agonist	POS	O
+Ro	POS	O
+16	POS	O
+-	POS	O
+6028	POS	O
+(	POS	O
+tert	POS	O
+-	POS	O
+butyl	POS	O
+-	POS	O
+(	POS	O
+S	POS	O
+)	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+bromo	POS	O
+-	POS	O
+11	POS	O
+,	POS	O
+12	POS	O
+,	POS	O
+13	POS	O
+,	POS	O
+13a	POS	O
+-	POS	O
+tetrahydro	POS	O
+-	POS	O
+9	POS	O
+-	POS	O
+oxo	POS	O
+-	POS	O
+9H	POS	O
+-	POS	O
+imidazo	POS	O
+[	POS	O
+1	POS	O
+,	POS	O
+5	POS	O
+-	POS	O
+a	POS	O
+]	POS	O
+-	POS	O
+pyrrolo	POS	O
+-	POS	O
+[	POS	O
+2	POS	O
+,	POS	O
+1	POS	O
+-	POS	O
+c	POS	O
+]	POS	O
+[	POS	O
+1	POS	O
+,	POS	O
+4	POS	O
+]	POS	O
+benzodiazepine	POS	O
+-	POS	O
+1	POS	O
+-	POS	O
+carboxylate	POS	O
+)	POS	O
+showed	POS	O
+very	POS	O
+weak	POS	O
+efficacy	POS	O
+in	POS	O
+these	POS	O
+biochemical	POS	O
+tests	POS	O
+.	POS	O
+After	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+injection	POS	O
+to	POS	O
+rats	POS	O
+,	POS	O
+abecarnil	POS	O
+and	POS	O
+diazepam	POS	O
+decreased	POS	O
+in	POS	O
+a	POS	O
+time	POS	O
+-	POS	O
+dependent	POS	O
+and	POS	O
+dose	POS	O
+-	POS	O
+related	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+25	POS	O
+-	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+manner	POS	O
+[	POS	O
+35S	POS	O
+]	POS	O
+TBPS	POS	O
+binding	POS	O
+measured	POS	O
+ex	POS	O
+vivo	POS	O
+in	POS	O
+the	POS	O
+cerebral	POS	O
+cortex	POS	O
+.	POS	O
+Moreover	POS	O
+,	POS	O
+both	POS	O
+drugs	POS	O
+at	POS	O
+the	POS	O
+dose	POS	O
+of	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+antagonized	POS	O
+completely	POS	O
+the	POS	O
+convulsant	POS	O
+activity	POS	O
+and	POS	O
+the	POS	O
+increase	POS	O
+of	POS	O
+[	POS	O
+35S	POS	O
+]	POS	O
+TBPS	POS	O
+binding	POS	O
+induced	POS	O
+by	POS	O
+isoniazide	POS	O
+(	POS	O
+350	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+s	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+)	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+the	POS	O
+increase	POS	O
+of	POS	O
+[	POS	O
+35S	POS	O
+]	POS	O
+TBPS	POS	O
+binding	POS	O
+induced	POS	O
+by	POS	O
+foot	POS	O
+-	POS	O
+shock	POS	O
+stress	POS	O
+.	POS	O
+To	POS	O
+better	POS	O
+correlate	POS	O
+the	POS	O
+biochemical	POS	O
+and	POS	O
+the	POS	O
+pharmacological	POS	O
+effects	POS	O
+,	POS	O
+we	POS	O
+studied	POS	O
+the	POS	O
+action	POS	O
+of	POS	O
+abecarnil	POS	O
+on	POS	O
+[	POS	O
+35S	POS	O
+]	POS	O
+TBPS	POS	O
+binding	POS	O
+,	POS	O
+exploratory	POS	O
+motility	POS	O
+and	POS	O
+on	POS	O
+isoniazid	POS	O
+-	POS	O
+induced	POS	O
+biochemical	POS	O
+and	POS	O
+pharmacological	POS	O
+effects	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+In	POS	O
+these	POS	O
+animals	POS	O
+,	POS	O
+abecarnil	POS	O
+produced	POS	O
+a	POS	O
+paralleled	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+-	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+reduction	POS	O
+of	POS	O
+both	POS	O
+motor	POS	O
+behavior	POS	O
+and	POS	O
+cortical	POS	O
+[	POS	O
+35S	POS	O
+]	POS	O
+TBPS	POS	O
+binding	POS	O
+.	POS	O
+Moreover	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+of	POS	O
+this	POS	O
+beta	POS	O
+-	POS	O
+carboline	POS	O
+reduced	POS	O
+markedly	POS	O
+the	POS	O
+increase	POS	O
+of	POS	O
+[	POS	O
+35S	POS	O
+]	POS	O
+TBPS	POS	O
+binding	POS	O
+and	POS	O
+the	POS	O
+convulsions	POS	B-NP
+induced	POS	O
+by	POS	O
+isoniazid	POS	O
+(	POS	O
+200	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+s	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+)	POS	O
+.	POS	O
+(	POS	O
+ABSTRACT	POS	O
+TRUNCATED	POS	O
+AT	POS	O
+250	POS	O
+WORDS	POS	O
+)	POS	O
+Recurrent	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+in	POS	O
+a	POS	O
+postpartum	POS	O
+patient	POS	O
+receiving	POS	O
+bromocriptine	POS	O
+.	POS	O
+Myocardial	POS	B-NP
+infarction	POS	I-NP
+in	POS	O
+puerperium	POS	B-NP
+is	POS	O
+infrequently	POS	O
+reported	POS	O
+.	POS	O
+Spasm	POS	B-NP
+,	POS	O
+coronary	POS	B-NP
+dissection	POS	I-NP
+,	POS	O
+or	POS	O
+atheromatous	POS	B-NP
+etiology	POS	O
+has	POS	O
+been	POS	O
+described	POS	O
+.	POS	O
+Bromocriptine	POS	O
+has	POS	O
+been	POS	O
+implicated	POS	O
+in	POS	O
+several	POS	O
+previous	POS	O
+case	POS	O
+reports	POS	O
+of	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+in	POS	O
+the	POS	O
+puerperium	POS	O
+.	POS	O
+Our	POS	O
+case	POS	O
+(	POS	O
+including	POS	O
+an	POS	O
+inadvertent	POS	O
+rechallenge	POS	O
+)	POS	O
+suggests	POS	O
+such	POS	O
+a	POS	O
+relationship	POS	O
+.	POS	O
+Although	POS	O
+generally	POS	O
+regarded	POS	O
+as	POS	O
+"	POS	O
+safe	POS	O
+,	POS	O
+"	POS	O
+possible	POS	O
+serious	POS	O
+cardiac	POS	O
+effects	POS	O
+of	POS	O
+bromocriptine	POS	O
+should	POS	O
+be	POS	O
+acknowledged	POS	O
+.	POS	O
+Asterixis	POS	B-NP
+induced	POS	O
+by	POS	O
+carbamazepine	POS	O
+therapy	POS	O
+.	POS	O
+There	POS	O
+are	POS	O
+very	POS	O
+few	POS	O
+reports	POS	O
+about	POS	O
+asterixis	POS	B-NP
+as	POS	O
+a	POS	O
+side	POS	O
+effect	POS	O
+of	POS	O
+treatment	POS	O
+with	POS	O
+psychopharmacologic	POS	O
+agents	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+report	POS	O
+we	POS	O
+present	POS	O
+four	POS	O
+patients	POS	O
+treated	POS	O
+with	POS	O
+a	POS	O
+combination	POS	O
+of	POS	O
+different	POS	O
+psychotropic	POS	O
+drugs	POS	O
+,	POS	O
+in	POS	O
+whom	POS	O
+asterixis	POS	B-NP
+was	POS	O
+triggered	POS	O
+either	POS	O
+by	POS	O
+adding	POS	O
+carbamazepine	POS	O
+(	POS	O
+CBZ	POS	O
+)	POS	O
+to	POS	O
+a	POS	O
+treatment	POS	O
+regimen	POS	O
+,	POS	O
+or	POS	O
+by	POS	O
+increasing	POS	O
+its	POS	O
+dosage	POS	O
+.	POS	O
+Neither	POS	O
+dosage	POS	O
+nor	POS	O
+serum	POS	O
+levels	POS	O
+of	POS	O
+CBZ	POS	O
+were	POS	O
+in	POS	O
+a	POS	O
+higher	POS	O
+range	POS	O
+.	POS	O
+We	POS	O
+consider	POS	O
+asterixis	POS	B-NP
+to	POS	O
+be	POS	O
+an	POS	O
+easily	POS	O
+overlooked	POS	O
+sign	POS	O
+of	POS	O
+neurotoxicity	POS	B-NP
+,	POS	O
+which	POS	O
+may	POS	O
+occur	POS	O
+even	POS	O
+at	POS	O
+low	POS	O
+or	POS	O
+moderate	POS	O
+dosage	POS	O
+levels	POS	O
+,	POS	O
+if	POS	O
+certain	POS	O
+drugs	POS	O
+as	POS	O
+lithium	POS	O
+or	POS	O
+clozapine	POS	O
+are	POS	O
+used	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+CBZ	POS	O
+.	POS	O
+Pharmacodynamics	POS	O
+of	POS	O
+the	POS	O
+hypotensive	POS	B-NP
+effect	POS	O
+of	POS	O
+levodopa	POS	O
+in	POS	O
+parkinsonian	POS	B-NP
+patients	POS	O
+.	POS	O
+Blood	POS	O
+pressure	POS	O
+effects	POS	O
+of	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+levodopa	POS	O
+were	POS	O
+examined	POS	O
+in	POS	O
+parkinsonian	POS	B-NP
+patients	POS	O
+with	POS	O
+stable	POS	O
+and	POS	O
+fluctuating	POS	O
+responses	POS	O
+to	POS	O
+levodopa	POS	O
+.	POS	O
+The	POS	O
+magnitude	POS	O
+of	POS	O
+the	POS	O
+hypotensive	POS	B-NP
+effect	POS	O
+of	POS	O
+levodopa	POS	O
+was	POS	O
+concentration	POS	O
+dependent	POS	O
+and	POS	O
+was	POS	O
+fit	POS	O
+to	POS	O
+an	POS	O
+Emax	POS	O
+model	POS	O
+in	POS	O
+fluctuating	POS	O
+responders	POS	O
+.	POS	O
+Stable	POS	O
+responders	POS	O
+demonstrated	POS	O
+a	POS	O
+small	POS	O
+hypotensive	POS	B-NP
+response	POS	O
+.	POS	O
+Baseline	POS	O
+blood	POS	O
+pressures	POS	O
+were	POS	O
+higher	POS	O
+in	POS	O
+fluctuating	POS	O
+patients	POS	O
+;	POS	O
+a	POS	O
+higher	POS	O
+baseline	POS	O
+blood	POS	O
+pressure	POS	O
+correlated	POS	O
+with	POS	O
+greater	POS	O
+hypotensive	POS	B-NP
+effects	POS	O
+.	POS	O
+Antiparkinsonian	POS	O
+effects	POS	O
+of	POS	O
+levodopa	POS	O
+temporally	POS	O
+correlated	POS	O
+with	POS	O
+blood	POS	O
+pressure	POS	O
+changes	POS	O
+.	POS	O
+Phenylalanine	POS	O
+,	POS	O
+a	POS	O
+large	POS	O
+neutral	POS	O
+amino	POS	O
+acid	POS	O
+(	POS	O
+LNAA	POS	O
+)	POS	O
+competing	POS	O
+with	POS	O
+levodopa	POS	O
+for	POS	O
+transport	POS	O
+across	POS	O
+the	POS	O
+blood	POS	O
+-	POS	O
+brain	POS	O
+barrier	POS	O
+,	POS	O
+reduced	POS	O
+the	POS	O
+hypotensive	POS	B-NP
+and	POS	O
+antiparkinsonian	POS	O
+effects	POS	O
+of	POS	O
+levodopa	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+levodopa	POS	O
+has	POS	O
+a	POS	O
+central	POS	O
+hypotensive	POS	B-NP
+action	POS	O
+that	POS	O
+parallels	POS	O
+the	POS	O
+motor	POS	O
+effects	POS	O
+in	POS	O
+fluctuating	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+hypotensive	POS	B-NP
+effect	POS	O
+appears	POS	O
+to	POS	O
+be	POS	O
+related	POS	O
+to	POS	O
+the	POS	O
+higher	POS	O
+baseline	POS	O
+blood	POS	O
+pressure	POS	O
+we	POS	O
+observed	POS	O
+in	POS	O
+fluctuating	POS	O
+patients	POS	O
+relative	POS	O
+to	POS	O
+stable	POS	O
+patients	POS	O
+.	POS	O
+Syndrome	POS	B-NP
+of	POS	I-NP
+inappropriate	POS	I-NP
+secretion	POS	I-NP
+of	POS	I-NP
+antidiuretic	POS	I-NP
+hormone	POS	I-NP
+after	POS	O
+infusional	POS	O
+vincristine	POS	O
+.	POS	O
+A	POS	O
+77	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+with	POS	O
+refractory	POS	O
+multiple	POS	B-NP
+myeloma	POS	I-NP
+was	POS	O
+treated	POS	O
+with	POS	O
+a	POS	O
+4	POS	O
+-	POS	O
+day	POS	O
+continuous	POS	O
+intravenous	POS	O
+infusion	POS	O
+of	POS	O
+vincristine	POS	O
+and	POS	O
+doxorubicin	POS	O
+and	POS	O
+4	POS	O
+days	POS	O
+of	POS	O
+oral	POS	O
+dexamethasone	POS	O
+.	POS	O
+Nine	POS	O
+days	POS	O
+after	POS	O
+her	POS	O
+second	POS	O
+cycle	POS	O
+she	POS	O
+presented	POS	O
+with	POS	O
+lethargy	POS	B-NP
+and	POS	O
+weakness	POS	B-NP
+associated	POS	O
+with	POS	O
+hyponatremia	POS	B-NP
+.	POS	O
+Evaluation	POS	O
+revealed	POS	O
+the	POS	O
+syndrome	POS	O
+of	POS	O
+inappropriate	POS	O
+secretion	POS	O
+of	POS	O
+antidiuretic	POS	O
+hormone	POS	O
+,	POS	O
+which	POS	O
+was	POS	O
+attributed	POS	O
+to	POS	O
+the	POS	O
+vincristine	POS	O
+infusion	POS	O
+.	POS	O
+After	POS	O
+normal	POS	O
+serum	POS	O
+sodium	POS	O
+levels	POS	O
+returned	POS	O
+,	POS	O
+further	POS	O
+doxorubicin	POS	O
+and	POS	O
+dexamethasone	POS	O
+chemotherapy	POS	O
+without	POS	O
+vincristine	POS	O
+did	POS	O
+not	POS	O
+produce	POS	O
+this	POS	O
+complication	POS	O
+.	POS	O
+Heart	POS	B-NP
+failure	POS	I-NP
+:	POS	O
+to	POS	O
+digitalise	POS	O
+or	POS	O
+not	POS	O
+?	POS	O
+The	POS	O
+view	POS	O
+against	POS	O
+.	POS	O
+Despite	POS	O
+extensive	POS	O
+clinical	POS	O
+experience	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+digoxin	POS	O
+is	POS	O
+still	POS	O
+not	POS	O
+well	POS	O
+defined	POS	O
+.	POS	O
+In	POS	O
+patients	POS	O
+with	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+digoxin	POS	O
+is	POS	O
+beneficial	POS	O
+for	POS	O
+ventricular	POS	O
+rate	POS	O
+control	POS	O
+.	POS	O
+For	POS	O
+patients	POS	O
+in	POS	O
+sinus	POS	O
+rhythm	POS	O
+and	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+the	POS	O
+situation	POS	O
+is	POS	O
+less	POS	O
+clear	POS	O
+.	POS	O
+Digoxin	POS	O
+has	POS	O
+a	POS	O
+narrow	POS	O
+therapeutic	POS	O
+:	POS	O
+toxic	POS	O
+ratio	POS	O
+and	POS	O
+concentrations	POS	O
+are	POS	O
+affected	POS	O
+by	POS	O
+a	POS	O
+number	POS	O
+of	POS	O
+drugs	POS	O
+.	POS	O
+Also	POS	O
+,	POS	O
+digoxin	POS	O
+has	POS	O
+undesirable	POS	O
+effects	POS	O
+such	POS	O
+as	POS	O
+increasing	POS	O
+peripheral	POS	O
+resistance	POS	O
+and	POS	O
+myocardial	POS	O
+demands	POS	O
+,	POS	O
+and	POS	O
+causing	POS	O
+arrhythmias	POS	B-NP
+.	POS	O
+There	POS	O
+is	POS	O
+a	POS	O
+paucity	POS	O
+of	POS	O
+data	POS	O
+from	POS	O
+well	POS	O
+-	POS	O
+designed	POS	O
+trials	POS	O
+.	POS	O
+The	POS	O
+trials	POS	O
+that	POS	O
+are	POS	O
+available	POS	O
+are	POS	O
+generally	POS	O
+small	POS	O
+with	POS	O
+limitations	POS	O
+in	POS	O
+design	POS	O
+and	POS	O
+these	POS	O
+show	POS	O
+variation	POS	O
+in	POS	O
+patient	POS	O
+benefit	POS	O
+.	POS	O
+More	POS	O
+convincing	POS	O
+evidence	POS	O
+is	POS	O
+required	POS	O
+showing	POS	O
+that	POS	O
+digoxin	POS	O
+improves	POS	O
+symptoms	POS	O
+or	POS	O
+exercise	POS	O
+capacity	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+no	POS	O
+trial	POS	O
+has	POS	O
+had	POS	O
+sufficient	POS	O
+power	POS	O
+to	POS	O
+evaluate	POS	O
+mortality	POS	O
+.	POS	O
+Pooled	POS	O
+analysis	POS	O
+of	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+other	POS	O
+inotropic	POS	O
+drugs	POS	O
+shows	POS	O
+an	POS	O
+excess	POS	O
+mortality	POS	O
+and	POS	O
+there	POS	O
+is	POS	O
+a	POS	O
+possibility	POS	O
+that	POS	O
+digoxin	POS	O
+may	POS	O
+increase	POS	O
+mortality	POS	O
+after	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+(	POS	O
+MI	POS	B-NP
+)	POS	O
+.	POS	O
+Angiotensin	POS	O
+-	POS	O
+converting	POS	O
+enzyme	POS	O
+(	POS	O
+ACE	POS	O
+)	POS	O
+inhibitors	POS	O
+should	POS	O
+be	POS	O
+used	POS	O
+first	POS	O
+as	POS	O
+they	POS	O
+are	POS	O
+safer	POS	O
+,	POS	O
+do	POS	O
+not	POS	O
+require	POS	O
+blood	POS	O
+level	POS	O
+monitoring	POS	O
+,	POS	O
+modify	POS	O
+progression	POS	O
+of	POS	O
+disease	POS	O
+,	POS	O
+relieve	POS	O
+symptoms	POS	O
+,	POS	O
+improve	POS	O
+exercise	POS	B-NP
+tolerance	POS	I-NP
+and	POS	O
+reduce	POS	O
+mortality	POS	O
+.	POS	O
+Caution	POS	O
+should	POS	O
+be	POS	O
+exercised	POS	O
+in	POS	O
+using	POS	O
+digoxin	POS	O
+until	POS	O
+large	POS	O
+mortality	POS	O
+trials	POS	O
+are	POS	O
+completed	POS	O
+showing	POS	O
+either	POS	O
+benefit	POS	O
+or	POS	O
+harm	POS	O
+.	POS	O
+Until	POS	O
+then	POS	O
+digoxin	POS	O
+should	POS	O
+be	POS	O
+considered	POS	O
+a	POS	O
+third	POS	O
+-	POS	O
+line	POS	O
+therapy	POS	O
+.	POS	O
+Isradipine	POS	O
+treatment	POS	O
+for	POS	O
+hypertension	POS	B-NP
+in	POS	O
+general	POS	O
+practice	POS	O
+in	POS	O
+Hong	POS	O
+Kong	POS	O
+.	POS	O
+A	POS	O
+6	POS	O
+-	POS	O
+week	POS	O
+open	POS	O
+study	POS	O
+of	POS	O
+the	POS	O
+introduction	POS	O
+of	POS	O
+isradipine	POS	O
+treatment	POS	O
+was	POS	O
+conducted	POS	O
+in	POS	O
+general	POS	O
+practice	POS	O
+in	POS	O
+Hong	POS	O
+Kong	POS	O
+.	POS	O
+303	POS	O
+Chinese	POS	O
+patients	POS	O
+with	POS	O
+mild	POS	O
+to	POS	O
+moderate	POS	O
+hypertension	POS	B-NP
+entered	POS	O
+the	POS	O
+study	POS	O
+.	POS	O
+Side	POS	O
+effects	POS	O
+were	POS	O
+reported	POS	O
+in	POS	O
+21	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+and	POS	O
+caused	POS	O
+withdrawal	POS	O
+from	POS	O
+the	POS	O
+study	POS	O
+in	POS	O
+3	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+main	POS	O
+side	POS	O
+-	POS	O
+effects	POS	O
+were	POS	O
+headache	POS	B-NP
+,	POS	O
+dizziness	POS	B-NP
+,	POS	O
+palpitation	POS	B-NP
+and	POS	O
+flushing	POS	B-NP
+and	POS	O
+these	POS	O
+were	POS	O
+not	POS	O
+more	POS	O
+frequent	POS	O
+than	POS	O
+reported	POS	O
+in	POS	O
+other	POS	O
+studies	POS	O
+with	POS	O
+isradipine	POS	O
+or	POS	O
+with	POS	O
+placebo	POS	O
+.	POS	O
+Supine	POS	O
+blood	POS	O
+pressure	POS	O
+was	POS	O
+reduced	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+from	POS	O
+170	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+20	POS	O
+/	POS	O
+102	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+mmHg	POS	O
+to	POS	O
+153	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+19	POS	O
+/	POS	O
+92	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+8	POS	O
+,	POS	O
+147	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+18	POS	O
+/	POS	O
+88	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+7	POS	O
+and	POS	O
+144	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+14	POS	O
+/	POS	O
+87	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+mmHg	POS	O
+at	POS	O
+2	POS	O
+,	POS	O
+4	POS	O
+and	POS	O
+6	POS	O
+weeks	POS	O
+respectively	POS	O
+in	POS	O
+evaluable	POS	O
+patients	POS	O
+.	POS	O
+Similar	POS	O
+reductions	POS	O
+occurred	POS	O
+in	POS	O
+standing	POS	O
+blood	POS	O
+pressure	POS	O
+and	POS	O
+there	POS	O
+was	POS	O
+no	POS	O
+evidence	POS	O
+of	POS	O
+postural	POS	B-NP
+hypotension	POS	I-NP
+.	POS	O
+Normalization	POS	O
+and	POS	O
+responder	POS	O
+rates	POS	O
+at	POS	O
+6	POS	O
+weeks	POS	O
+were	POS	O
+86	POS	O
+%	POS	O
+and	POS	O
+69	POS	O
+%	POS	O
+respectively	POS	O
+.	POS	O
+Dosage	POS	O
+was	POS	O
+increased	POS	O
+from	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+b	POS	O
+.	POS	O
+d	POS	O
+.	POS	O
+to	POS	O
+5	POS	O
+mg	POS	O
+b	POS	O
+.	POS	O
+d	POS	O
+.	POS	O
+at	POS	O
+4	POS	O
+weeks	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+diastolic	POS	O
+blood	POS	O
+pressure	POS	O
+greater	POS	O
+than	POS	O
+90	POS	O
+mmHg	POS	O
+and	POS	O
+their	POS	O
+further	POS	O
+response	POS	O
+was	POS	O
+greater	POS	O
+than	POS	O
+those	POS	O
+remaining	POS	O
+on	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+b	POS	O
+.	POS	O
+d	POS	O
+.	POS	O
+Pharmacological	POS	O
+characteristics	POS	O
+and	POS	O
+side	POS	O
+effects	POS	O
+of	POS	O
+a	POS	O
+new	POS	O
+galenic	POS	O
+formulation	POS	O
+of	POS	O
+propofol	POS	O
+without	POS	O
+soyabean	POS	O
+oil	POS	O
+.	POS	O
+We	POS	O
+compared	POS	O
+the	POS	O
+pharmacokinetics	POS	O
+,	POS	O
+pharmacodynamics	POS	O
+and	POS	O
+safety	POS	O
+profile	POS	O
+of	POS	O
+a	POS	O
+new	POS	O
+galenic	POS	O
+formulation	POS	O
+of	POS	O
+propofol	POS	O
+(	POS	O
+AM149	POS	O
+1	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+which	POS	O
+does	POS	O
+not	POS	O
+contain	POS	O
+soyabean	POS	O
+oil	POS	O
+,	POS	O
+with	POS	O
+a	POS	O
+standard	POS	O
+formulation	POS	O
+of	POS	O
+propofol	POS	O
+(	POS	O
+Disoprivan	POS	O
+1	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+randomised	POS	O
+,	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+cross	POS	O
+-	POS	O
+over	POS	O
+study	POS	O
+,	POS	O
+30	POS	O
+healthy	POS	O
+volunteers	POS	O
+received	POS	O
+a	POS	O
+single	POS	O
+intravenous	POS	O
+bolus	POS	O
+injection	POS	O
+of	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+.	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+propofol	POS	O
+.	POS	O
+Plasma	POS	O
+propofol	POS	O
+levels	POS	O
+were	POS	O
+measured	POS	O
+for	POS	O
+48	POS	O
+h	POS	O
+following	POS	O
+drug	POS	O
+administration	POS	O
+and	POS	O
+evaluated	POS	O
+according	POS	O
+to	POS	O
+a	POS	O
+three	POS	O
+-	POS	O
+compartment	POS	O
+model	POS	O
+.	POS	O
+The	POS	O
+pharmacodynamic	POS	O
+parameters	POS	O
+assessed	POS	O
+included	POS	O
+induction	POS	O
+and	POS	O
+emergence	POS	O
+times	POS	O
+,	POS	O
+respiratory	POS	O
+and	POS	O
+cardiovascular	POS	O
+effects	POS	O
+,	POS	O
+and	POS	O
+pain	POS	B-NP
+on	POS	O
+injection	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+monitored	POS	O
+for	POS	O
+side	POS	O
+effects	POS	O
+over	POS	O
+48	POS	O
+h	POS	O
+.	POS	O
+Owing	POS	O
+to	POS	O
+a	POS	O
+high	POS	O
+incidence	POS	O
+of	POS	O
+thrombophlebitis	POS	B-NP
+,	POS	O
+the	POS	O
+study	POS	O
+was	POS	O
+terminated	POS	O
+prematurely	POS	O
+and	POS	O
+only	POS	O
+the	POS	O
+data	POS	O
+of	POS	O
+the	POS	O
+two	POS	O
+parallel	POS	O
+treatment	POS	O
+groups	POS	O
+(	POS	O
+15	POS	O
+patients	POS	O
+in	POS	O
+each	POS	O
+group	POS	O
+)	POS	O
+were	POS	O
+analysed	POS	O
+.	POS	O
+Plasma	POS	O
+concentrations	POS	O
+did	POS	O
+not	POS	O
+differ	POS	O
+significantly	POS	O
+between	POS	O
+the	POS	O
+two	POS	O
+formulations	POS	O
+.	POS	O
+Anaesthesia	POS	B-NP
+induction	POS	O
+and	POS	O
+emergence	POS	O
+times	POS	O
+,	POS	O
+respiratory	POS	O
+and	POS	O
+cardiovascular	POS	O
+variables	POS	O
+showed	POS	O
+no	POS	O
+significant	POS	O
+differences	POS	O
+between	POS	O
+the	POS	O
+two	POS	O
+treatment	POS	O
+groups	POS	O
+.	POS	O
+Pain	POS	B-NP
+on	POS	O
+injection	POS	O
+(	POS	O
+80	POS	O
+vs	POS	O
+.	POS	O
+20	POS	O
+%	POS	O
+,	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+and	POS	O
+thrombophlebitis	POS	B-NP
+(	POS	O
+93	POS	O
+.	POS	O
+3	POS	O
+vs	POS	O
+.	POS	O
+6	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+,	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+occurred	POS	O
+more	POS	O
+frequently	POS	O
+with	POS	O
+AM149	POS	O
+than	POS	O
+with	POS	O
+Disoprivan	POS	O
+.	POS	O
+Although	POS	O
+both	POS	O
+formulations	POS	O
+had	POS	O
+similar	POS	O
+pharmacokinetic	POS	O
+and	POS	O
+pharmacodynamic	POS	O
+profiles	POS	O
+the	POS	O
+new	POS	O
+formulation	POS	O
+is	POS	O
+not	POS	O
+suitable	POS	O
+for	POS	O
+clinical	POS	O
+use	POS	O
+due	POS	O
+to	POS	O
+the	POS	O
+high	POS	O
+incidence	POS	O
+of	POS	O
+thrombophlebitis	POS	B-NP
+produced	POS	O
+.	POS	O
+Pure	POS	B-NP
+red	POS	I-NP
+cell	POS	I-NP
+aplasia	POS	I-NP
+,	POS	O
+toxic	POS	B-NP
+dermatitis	POS	I-NP
+and	POS	O
+lymphadenopathy	POS	B-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+taking	POS	O
+diphenylhydantoin	POS	O
+.	POS	O
+A	POS	O
+patient	POS	O
+taking	POS	O
+diphenylhydantoin	POS	O
+for	POS	O
+3	POS	O
+weeks	POS	O
+developed	POS	O
+a	POS	O
+generalized	POS	O
+skin	POS	B-NP
+rash	POS	I-NP
+,	POS	O
+lymphadenopathy	POS	B-NP
+and	POS	O
+pure	POS	B-NP
+red	POS	I-NP
+cell	POS	I-NP
+aplasia	POS	I-NP
+.	POS	O
+After	POS	O
+withdrawal	POS	O
+of	POS	O
+the	POS	O
+pharmacon	POS	O
+all	POS	O
+symptoms	POS	O
+disappeared	POS	O
+spontaneously	POS	O
+.	POS	O
+Skin	POS	B-NP
+rash	POS	I-NP
+is	POS	O
+a	POS	O
+well	POS	O
+-	POS	O
+known	POS	O
+complication	POS	O
+of	POS	O
+diphenylhydantoin	POS	O
+treatment	POS	O
+as	POS	O
+is	POS	O
+benign	POS	O
+and	POS	O
+malignant	POS	B-NP
+lymphadenopathy	POS	I-NP
+.	POS	O
+Pure	POS	B-NP
+red	POS	I-NP
+cell	POS	I-NP
+aplasia	POS	I-NP
+associated	POS	O
+with	POS	O
+diphenylhydantoin	POS	O
+medication	POS	O
+has	POS	O
+been	POS	O
+reported	POS	O
+in	POS	O
+3	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+exact	POS	O
+mechanism	POS	O
+by	POS	O
+which	POS	O
+diphenylhydantoin	POS	O
+exerts	POS	O
+its	POS	O
+toxic	POS	O
+effects	POS	O
+is	POS	O
+not	POS	O
+known	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+patient	POS	O
+the	POS	O
+time	POS	O
+relation	POS	O
+between	POS	O
+the	POS	O
+ingestion	POS	O
+of	POS	O
+diphenylhydantoin	POS	O
+and	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+the	POS	O
+skin	POS	B-NP
+rash	POS	I-NP
+,	POS	O
+lymphadenopathy	POS	B-NP
+and	POS	O
+pure	POS	B-NP
+red	POS	I-NP
+cell	POS	I-NP
+aplasia	POS	I-NP
+is	POS	O
+very	POS	O
+suggestive	POS	O
+of	POS	O
+a	POS	O
+direct	POS	O
+connection	POS	O
+.	POS	O
+Vinorelbine	POS	O
+-	POS	O
+related	POS	O
+cardiac	POS	O
+events	POS	O
+:	POS	O
+a	POS	O
+meta	POS	O
+-	POS	O
+analysis	POS	O
+of	POS	O
+randomized	POS	O
+clinical	POS	O
+trials	POS	O
+.	POS	O
+Several	POS	O
+cases	POS	O
+of	POS	O
+cardiac	POS	B-NP
+adverse	POS	I-NP
+reactions	POS	I-NP
+related	POS	O
+to	POS	O
+vinorelbine	POS	O
+(	POS	O
+VNR	POS	O
+)	POS	O
+have	POS	O
+been	POS	O
+reported	POS	O
+in	POS	O
+the	POS	O
+literature	POS	O
+.	POS	O
+In	POS	O
+order	POS	O
+to	POS	O
+quantify	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+these	POS	O
+cardiac	POS	O
+events	POS	O
+,	POS	O
+we	POS	O
+performed	POS	O
+a	POS	O
+meta	POS	O
+-	POS	O
+analysis	POS	O
+of	POS	O
+clinical	POS	O
+trials	POS	O
+comparing	POS	O
+VNR	POS	O
+with	POS	O
+other	POS	O
+chemotherapeutic	POS	O
+agents	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+various	POS	O
+malignancies	POS	B-NP
+.	POS	O
+Randomized	POS	O
+clinical	POS	O
+trials	POS	O
+comparing	POS	O
+VNR	POS	O
+with	POS	O
+other	POS	O
+drugs	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+cancer	POS	B-NP
+were	POS	O
+searched	POS	O
+in	POS	O
+Medline	POS	O
+,	POS	O
+Embase	POS	O
+,	POS	O
+Evidence	POS	O
+-	POS	O
+based	POS	O
+Medicine	POS	O
+Reviews	POS	O
+databases	POS	O
+and	POS	O
+the	POS	O
+Cochrane	POS	O
+library	POS	O
+from	POS	O
+1987	POS	O
+to	POS	O
+2002	POS	O
+.	POS	O
+Outcomes	POS	O
+of	POS	O
+interest	POS	O
+were	POS	O
+severe	POS	O
+cardiac	POS	B-NP
+events	POS	I-NP
+,	POS	O
+toxic	POS	B-NP
+deaths	POS	I-NP
+and	POS	O
+cardiac	POS	B-NP
+event	POS	I-NP
+-	POS	I-NP
+related	POS	I-NP
+deaths	POS	I-NP
+reported	POS	O
+in	POS	O
+each	POS	O
+publication	POS	O
+.	POS	O
+We	POS	O
+found	POS	O
+19	POS	O
+trials	POS	O
+,	POS	O
+involving	POS	O
+2441	POS	O
+patients	POS	O
+treated	POS	O
+by	POS	O
+VNR	POS	O
+and	POS	O
+2050	POS	O
+control	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+cardiac	POS	B-NP
+events	POS	I-NP
+with	POS	O
+VNR	POS	O
+was	POS	O
+1	POS	O
+.	POS	O
+19	POS	O
+%	POS	O
+[	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+(	POS	O
+CI	POS	O
+)	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+75	POS	O
+;	POS	O
+1	POS	O
+.	POS	O
+67	POS	O
+)	POS	O
+]	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+difference	POS	O
+in	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+cardiac	POS	O
+events	POS	O
+between	POS	O
+VNR	POS	O
+and	POS	O
+other	POS	O
+drugs	POS	O
+[	POS	O
+odds	POS	O
+ratio	POS	O
+:	POS	O
+0	POS	O
+.	POS	O
+92	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+54	POS	O
+;	POS	O
+1	POS	O
+.	POS	O
+55	POS	O
+)	POS	O
+]	POS	O
+.	POS	O
+The	POS	O
+risk	POS	O
+of	POS	O
+VNR	POS	O
+cardiac	POS	O
+events	POS	O
+was	POS	O
+similar	POS	O
+to	POS	O
+vindesine	POS	O
+(	POS	O
+VDS	POS	O
+)	POS	O
+and	POS	O
+other	POS	O
+cardiotoxic	POS	B-NP
+drugs	POS	O
+[	POS	O
+fluorouracil	POS	O
+,	POS	O
+anthracyclines	POS	O
+,	POS	O
+gemcitabine	POS	O
+(	POS	O
+GEM	POS	O
+)	POS	O
+em	POS	O
+leader	POS	O
+]	POS	O
+.	POS	O
+Even	POS	O
+if	POS	O
+it	POS	O
+did	POS	O
+not	POS	O
+reach	POS	O
+statistical	POS	O
+significance	POS	O
+because	POS	O
+of	POS	O
+a	POS	O
+few	POS	O
+number	POS	O
+of	POS	O
+cases	POS	O
+,	POS	O
+the	POS	O
+risk	POS	O
+was	POS	O
+lower	POS	O
+in	POS	O
+trials	POS	O
+excluding	POS	O
+patients	POS	O
+with	POS	O
+cardiac	POS	B-NP
+history	POS	I-NP
+,	POS	O
+and	POS	O
+seemed	POS	O
+to	POS	O
+be	POS	O
+higher	POS	O
+in	POS	O
+trials	POS	O
+including	POS	O
+patients	POS	O
+with	POS	O
+pre	POS	O
+-	POS	O
+existing	POS	O
+cardiac	POS	B-NP
+diseases	POS	I-NP
+.	POS	O
+Vinorelbine	POS	O
+-	POS	O
+related	POS	O
+cardiac	POS	O
+events	POS	O
+concern	POS	O
+about	POS	O
+1	POS	O
+%	POS	O
+of	POS	O
+treated	POS	O
+patients	POS	O
+in	POS	O
+clinical	POS	O
+trials	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+risk	POS	O
+associated	POS	O
+with	POS	O
+VNR	POS	O
+seems	POS	O
+to	POS	O
+be	POS	O
+similar	POS	O
+to	POS	O
+that	POS	O
+of	POS	O
+other	POS	O
+chemotherapeutic	POS	O
+agents	POS	O
+in	POS	O
+the	POS	O
+same	POS	O
+indications	POS	O
+.	POS	O
+MRI	POS	O
+findings	POS	O
+of	POS	O
+hypoxic	POS	O
+cortical	POS	O
+laminar	POS	O
+necrosis	POS	B-NP
+in	POS	O
+a	POS	O
+child	POS	O
+with	POS	O
+hemolytic	POS	B-NP
+anemia	POS	I-NP
+crisis	POS	O
+.	POS	O
+We	POS	O
+present	POS	O
+magnetic	POS	O
+resonance	POS	O
+imaging	POS	O
+findings	POS	O
+of	POS	O
+a	POS	O
+5	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+girl	POS	O
+who	POS	O
+had	POS	O
+a	POS	O
+rapidly	POS	O
+installing	POS	O
+hemolytic	POS	B-NP
+anemia	POS	I-NP
+crisis	POS	O
+induced	POS	O
+by	POS	O
+trimethoprim	POS	O
+-	POS	O
+sulfomethoxazole	POS	O
+,	POS	O
+resulting	POS	O
+in	POS	O
+cerebral	POS	B-NP
+anoxia	POS	I-NP
+leading	POS	O
+to	POS	O
+permanent	POS	O
+damage	POS	O
+.	POS	O
+Magnetic	POS	O
+Resonance	POS	O
+imaging	POS	O
+revealed	POS	O
+cortical	POS	O
+laminar	POS	O
+necrosis	POS	B-NP
+in	POS	O
+arterial	POS	O
+border	POS	O
+zones	POS	O
+in	POS	O
+both	POS	O
+cerebral	POS	O
+hemispheres	POS	O
+,	POS	O
+ischemic	POS	O
+changes	POS	O
+in	POS	O
+subcortical	POS	O
+white	POS	O
+matter	POS	O
+of	POS	O
+left	POS	O
+cerebral	POS	O
+hemisphere	POS	O
+,	POS	O
+and	POS	O
+in	POS	O
+the	POS	O
+left	POS	O
+putamen	POS	O
+.	POS	O
+Although	POS	O
+cortical	POS	O
+laminar	POS	O
+necrosis	POS	B-NP
+is	POS	O
+a	POS	O
+classic	POS	O
+entity	POS	O
+in	POS	O
+adulthood	POS	O
+related	POS	O
+to	POS	O
+conditions	POS	O
+of	POS	O
+energy	POS	O
+depletions	POS	O
+,	POS	O
+there	POS	O
+are	POS	O
+few	POS	O
+reports	POS	O
+available	POS	O
+in	POS	O
+children	POS	O
+.	POS	O
+A	POS	O
+wide	POS	O
+review	POS	O
+of	POS	O
+the	POS	O
+literature	POS	O
+is	POS	O
+also	POS	O
+presented	POS	O
+.	POS	O
+The	POS	O
+natural	POS	O
+history	POS	O
+of	POS	O
+Vigabatrin	POS	B-NP
+associated	POS	I-NP
+visual	POS	I-NP
+field	POS	I-NP
+defects	POS	I-NP
+in	POS	O
+patients	POS	O
+electing	POS	O
+to	POS	O
+continue	POS	O
+their	POS	O
+medication	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+To	POS	O
+determine	POS	O
+the	POS	O
+natural	POS	O
+history	POS	O
+of	POS	O
+visual	POS	B-NP
+field	POS	I-NP
+defects	POS	I-NP
+in	POS	O
+a	POS	O
+group	POS	O
+of	POS	O
+patients	POS	O
+known	POS	O
+to	POS	O
+have	POS	O
+Vigabatrin	POS	O
+-	POS	O
+associated	POS	O
+changes	POS	O
+who	POS	O
+elected	POS	O
+to	POS	O
+continue	POS	O
+the	POS	O
+medication	POS	O
+because	POS	O
+of	POS	O
+good	POS	O
+seizure	POS	B-NP
+control	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+All	POS	O
+patients	POS	O
+taking	POS	O
+Vigabatrin	POS	O
+alone	POS	O
+or	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+other	POS	O
+antiepileptic	POS	O
+drugs	POS	O
+for	POS	O
+at	POS	O
+least	POS	O
+5	POS	O
+years	POS	O
+(	POS	O
+range	POS	O
+5	POS	O
+-	POS	O
+12	POS	O
+years	POS	O
+)	POS	O
+were	POS	O
+entered	POS	O
+into	POS	O
+a	POS	O
+visual	POS	O
+surveillance	POS	O
+programme	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+followed	POS	O
+up	POS	O
+at	POS	O
+6	POS	O
+-	POS	O
+monthly	POS	O
+intervals	POS	O
+for	POS	O
+not	POS	O
+less	POS	O
+than	POS	O
+18	POS	O
+months	POS	O
+(	POS	O
+range	POS	O
+18	POS	O
+-	POS	O
+43	POS	O
+months	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+all	POS	O
+,	POS	O
+16	POS	O
+patients	POS	O
+with	POS	O
+unequivocal	POS	O
+defects	POS	O
+continued	POS	O
+the	POS	O
+medication	POS	O
+.	POS	O
+Following	POS	O
+already	POS	O
+published	POS	O
+methodology	POS	O
+(	POS	O
+Eye	POS	O
+2002	POS	O
+;	POS	O
+16	POS	O
+;	POS	O
+567	POS	O
+-	POS	O
+571	POS	O
+)	POS	O
+monocular	POS	O
+mean	POS	O
+radial	POS	O
+degrees	POS	O
+(	POS	O
+MRDs	POS	O
+)	POS	O
+to	POS	O
+the	POS	O
+I	POS	O
+/	POS	O
+4e	POS	O
+isopter	POS	O
+on	POS	O
+Goldmann	POS	O
+perimetry	POS	O
+was	POS	O
+calculated	POS	O
+for	POS	O
+the	POS	O
+right	POS	O
+eye	POS	O
+at	POS	O
+the	POS	O
+time	POS	O
+of	POS	O
+discovery	POS	O
+of	POS	O
+a	POS	O
+visual	POS	B-NP
+field	POS	I-NP
+defect	POS	I-NP
+and	POS	O
+again	POS	O
+after	POS	O
+not	POS	O
+less	POS	O
+than	POS	O
+18	POS	O
+months	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Mean	POS	O
+right	POS	O
+eye	POS	O
+MRD	POS	O
+at	POS	O
+presentation	POS	O
+was	POS	O
+36	POS	O
+.	POS	O
+98	POS	O
+degrees	POS	O
+(	POS	O
+range	POS	O
+22	POS	O
+.	POS	O
+25	POS	O
+-	POS	O
+51	POS	O
+.	POS	O
+0	POS	O
+)	POS	O
+,	POS	O
+compared	POS	O
+to	POS	O
+38	POS	O
+.	POS	O
+40	POS	O
+degrees	POS	O
+(	POS	O
+range	POS	O
+22	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+49	POS	O
+.	POS	O
+75	POS	O
+)	POS	O
+after	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+338	POS	O
+unpaired	POS	O
+t	POS	O
+-	POS	O
+test	POS	O
+.	POS	O
+Only	POS	O
+one	POS	O
+patient	POS	O
+demonstrated	POS	O
+a	POS	O
+deterioration	POS	O
+in	POS	O
+visual	POS	O
+field	POS	O
+during	POS	O
+the	POS	O
+study	POS	O
+period	POS	O
+and	POS	O
+discontinued	POS	O
+treatment	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Established	POS	O
+visual	POS	B-NP
+field	POS	I-NP
+defects	POS	I-NP
+presumed	POS	O
+to	POS	O
+be	POS	O
+due	POS	O
+to	POS	O
+Vigabatrin	POS	O
+therapy	POS	O
+did	POS	O
+not	POS	O
+usually	POS	O
+progress	POS	O
+in	POS	O
+spite	POS	O
+of	POS	O
+continuing	POS	O
+use	POS	O
+of	POS	O
+the	POS	O
+medication	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+give	POS	O
+support	POS	O
+to	POS	O
+the	POS	O
+hypothesis	POS	O
+that	POS	O
+the	POS	O
+pathogenesis	POS	O
+of	POS	O
+Vigabatrin	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+visual	POS	I-NP
+field	POS	I-NP
+defects	POS	I-NP
+may	POS	O
+be	POS	O
+an	POS	O
+idiosyncratic	POS	O
+adverse	POS	O
+drug	POS	O
+reaction	POS	O
+rather	POS	O
+than	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+toxicity	POS	B-NP
+.	POS	O
+Induction	POS	O
+of	POS	O
+rosaceiform	POS	B-NP
+dermatitis	POS	I-NP
+during	POS	O
+treatment	POS	O
+of	POS	O
+facial	POS	B-NP
+inflammatory	POS	I-NP
+dermatoses	POS	I-NP
+with	POS	O
+tacrolimus	POS	O
+ointment	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Tacrolimus	POS	O
+ointment	POS	O
+is	POS	O
+increasingly	POS	O
+used	POS	O
+for	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+treatment	POS	O
+of	POS	O
+sensitive	POS	O
+areas	POS	O
+such	POS	O
+as	POS	O
+the	POS	O
+face	POS	O
+,	POS	O
+and	POS	O
+recent	POS	O
+observations	POS	O
+indicate	POS	O
+that	POS	O
+the	POS	O
+treatment	POS	O
+is	POS	O
+effective	POS	O
+in	POS	O
+steroid	POS	O
+-	POS	O
+aggravated	POS	O
+rosacea	POS	B-NP
+and	POS	O
+perioral	POS	B-NP
+dermatitis	POS	I-NP
+.	POS	O
+We	POS	O
+report	POS	O
+on	POS	O
+rosaceiform	POS	B-NP
+dermatitis	POS	I-NP
+as	POS	O
+a	POS	O
+complication	POS	O
+of	POS	O
+treatment	POS	O
+with	POS	O
+tacrolimus	POS	O
+ointment	POS	O
+.	POS	O
+OBSERVATIONS	POS	O
+:	POS	O
+Six	POS	O
+adult	POS	O
+patients	POS	O
+with	POS	O
+inflammatory	POS	B-NP
+facial	POS	I-NP
+dermatoses	POS	I-NP
+were	POS	O
+treated	POS	O
+with	POS	O
+tacrolimus	POS	O
+ointment	POS	O
+because	POS	O
+of	POS	O
+the	POS	O
+ineffectiveness	POS	O
+of	POS	O
+standard	POS	O
+treatments	POS	O
+.	POS	O
+Within	POS	O
+2	POS	O
+to	POS	O
+3	POS	O
+weeks	POS	O
+of	POS	O
+initially	POS	O
+effective	POS	O
+and	POS	O
+well	POS	O
+-	POS	O
+tolerated	POS	O
+treatment	POS	O
+,	POS	O
+3	POS	O
+patients	POS	O
+with	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+rosacea	POS	B-NP
+and	POS	O
+1	POS	O
+with	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+acne	POS	B-NP
+experienced	POS	O
+sudden	POS	B-NP
+worsening	POS	I-NP
+with	POS	O
+pustular	POS	B-NP
+rosaceiform	POS	I-NP
+lesions	POS	I-NP
+.	POS	O
+Biopsy	POS	B-NP
+revealed	POS	O
+an	POS	O
+abundance	POS	O
+of	POS	O
+Demodex	POS	O
+mites	POS	O
+in	POS	O
+2	POS	O
+of	POS	O
+these	POS	O
+patients	POS	O
+.	POS	O
+In	POS	O
+1	POS	O
+patient	POS	O
+with	POS	O
+eyelid	POS	B-NP
+eczema	POS	I-NP
+,	POS	O
+rosaceiform	POS	B-NP
+periocular	POS	I-NP
+dermatitis	POS	I-NP
+gradually	POS	O
+appeared	POS	O
+after	POS	O
+3	POS	O
+weeks	POS	O
+of	POS	O
+treatment	POS	O
+.	POS	O
+In	POS	O
+1	POS	O
+patient	POS	O
+with	POS	O
+atopic	POS	B-NP
+dermatitis	POS	I-NP
+,	POS	O
+telangiectatic	POS	B-NP
+and	POS	O
+papular	POS	B-NP
+rosacea	POS	I-NP
+insidiously	POS	I-NP
+appeared	POS	O
+after	POS	O
+5	POS	O
+months	POS	O
+of	POS	O
+treatment	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Our	POS	O
+observations	POS	O
+suggest	POS	O
+that	POS	O
+the	POS	O
+spectrum	POS	O
+of	POS	O
+rosaceiform	POS	B-NP
+dermatitis	POS	I-NP
+as	POS	O
+a	POS	O
+complication	POS	O
+of	POS	O
+treatment	POS	O
+with	POS	O
+tacrolimus	POS	O
+ointment	POS	O
+is	POS	O
+heterogeneous	POS	O
+.	POS	O
+A	POS	O
+variety	POS	O
+of	POS	O
+factors	POS	O
+,	POS	O
+such	POS	O
+as	POS	O
+vasoactive	POS	O
+properties	POS	O
+of	POS	O
+tacrolimus	POS	O
+,	POS	O
+proliferation	POS	O
+of	POS	O
+Demodex	POS	O
+due	POS	O
+to	POS	O
+local	POS	O
+immunosuppression	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+occlusive	POS	O
+properties	POS	O
+of	POS	O
+the	POS	O
+ointment	POS	O
+,	POS	O
+may	POS	O
+be	POS	O
+involved	POS	O
+in	POS	O
+the	POS	O
+observed	POS	O
+phenomena	POS	O
+.	POS	O
+Future	POS	O
+studies	POS	O
+are	POS	O
+needed	POS	O
+to	POS	O
+identify	POS	O
+individual	POS	O
+risk	POS	O
+factors	POS	O
+.	POS	O
+Intravascular	POS	B-NP
+hemolysis	POS	I-NP
+and	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+following	POS	O
+intermittent	POS	O
+rifampin	POS	O
+therapy	POS	O
+.	POS	O
+Renal	POS	B-NP
+failure	POS	I-NP
+is	POS	O
+a	POS	O
+rare	POS	O
+complication	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+rifampin	POS	O
+.	POS	O
+Intravascular	POS	B-NP
+hemolysis	POS	I-NP
+leading	POS	O
+to	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+following	POS	O
+rifampin	POS	O
+therapy	POS	O
+is	POS	O
+extremely	POS	O
+rare	POS	O
+.	POS	O
+Two	POS	O
+patients	POS	O
+with	POS	O
+leprosy	POS	B-NP
+who	POS	O
+developed	POS	O
+hemolysis	POS	B-NP
+and	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+following	POS	O
+rifampin	POS	O
+are	POS	O
+reported	POS	O
+.	POS	O
+Structural	POS	B-NP
+abnormalities	POS	I-NP
+in	POS	O
+the	POS	O
+brains	POS	O
+of	POS	O
+human	POS	O
+subjects	POS	O
+who	POS	O
+use	POS	O
+methamphetamine	POS	O
+.	POS	O
+We	POS	O
+visualize	POS	O
+,	POS	O
+for	POS	O
+the	POS	O
+first	POS	O
+time	POS	O
+,	POS	O
+the	POS	O
+profile	POS	O
+of	POS	O
+structural	POS	O
+deficits	POS	O
+in	POS	O
+the	POS	O
+human	POS	O
+brain	POS	O
+associated	POS	O
+with	POS	O
+chronic	POS	O
+methamphetamine	POS	O
+(	POS	O
+MA	POS	O
+)	POS	O
+abuse	POS	O
+.	POS	O
+Studies	POS	O
+of	POS	O
+human	POS	O
+subjects	POS	O
+who	POS	O
+have	POS	O
+used	POS	O
+MA	POS	O
+chronically	POS	O
+have	POS	O
+revealed	POS	O
+deficits	POS	O
+in	POS	O
+dopaminergic	POS	O
+and	POS	O
+serotonergic	POS	O
+systems	POS	O
+and	POS	O
+cerebral	POS	O
+metabolic	POS	O
+abnormalities	POS	O
+.	POS	O
+Using	POS	O
+magnetic	POS	O
+resonance	POS	O
+imaging	POS	O
+(	POS	O
+MRI	POS	O
+)	POS	O
+and	POS	O
+new	POS	O
+computational	POS	O
+brain	POS	O
+-	POS	O
+mapping	POS	O
+techniques	POS	O
+,	POS	O
+we	POS	O
+determined	POS	O
+the	POS	O
+pattern	POS	O
+of	POS	O
+structural	POS	O
+brain	POS	O
+alterations	POS	O
+associated	POS	O
+with	POS	O
+chronic	POS	O
+MA	POS	O
+abuse	POS	O
+in	POS	O
+human	POS	O
+subjects	POS	O
+and	POS	O
+related	POS	O
+these	POS	O
+deficits	POS	O
+to	POS	O
+cognitive	POS	B-NP
+impairment	POS	I-NP
+.	POS	O
+We	POS	O
+used	POS	O
+high	POS	O
+-	POS	O
+resolution	POS	O
+MRI	POS	O
+and	POS	O
+surface	POS	O
+-	POS	O
+based	POS	O
+computational	POS	O
+image	POS	O
+analyses	POS	O
+to	POS	O
+map	POS	O
+regional	POS	O
+abnormalities	POS	O
+in	POS	O
+the	POS	O
+cortex	POS	O
+,	POS	O
+hippocampus	POS	O
+,	POS	O
+white	POS	O
+matter	POS	O
+,	POS	O
+and	POS	O
+ventricles	POS	O
+in	POS	O
+22	POS	O
+human	POS	O
+subjects	POS	O
+who	POS	O
+used	POS	O
+MA	POS	O
+and	POS	O
+21	POS	O
+age	POS	O
+-	POS	O
+matched	POS	O
+,	POS	O
+healthy	POS	O
+controls	POS	O
+.	POS	O
+Cortical	POS	O
+maps	POS	O
+revealed	POS	O
+severe	POS	O
+gray	POS	B-NP
+-	POS	I-NP
+matter	POS	I-NP
+deficits	POS	I-NP
+in	POS	O
+the	POS	O
+cingulate	POS	O
+,	POS	O
+limbic	POS	O
+,	POS	O
+and	POS	O
+paralimbic	POS	O
+cortices	POS	O
+of	POS	O
+MA	POS	O
+abusers	POS	O
+(	POS	O
+averaging	POS	O
+11	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+below	POS	O
+control	POS	O
+;	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+On	POS	O
+average	POS	O
+,	POS	O
+MA	POS	O
+abusers	POS	O
+had	POS	O
+7	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+smaller	POS	O
+hippocampal	POS	O
+volumes	POS	O
+than	POS	O
+control	POS	O
+subjects	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+;	POS	O
+left	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+;	POS	O
+right	POS	O
+,	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+and	POS	O
+significant	POS	O
+white	POS	B-NP
+-	POS	I-NP
+matter	POS	I-NP
+hypertrophy	POS	I-NP
+(	POS	O
+7	POS	O
+.	POS	O
+0	POS	O
+%	POS	O
+;	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+Hippocampal	POS	B-NP
+deficits	POS	I-NP
+were	POS	O
+mapped	POS	O
+and	POS	O
+correlated	POS	O
+with	POS	O
+memory	POS	O
+performance	POS	O
+on	POS	O
+a	POS	O
+word	POS	O
+-	POS	O
+recall	POS	O
+test	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+MRI	POS	O
+-	POS	O
+based	POS	O
+maps	POS	O
+suggest	POS	O
+that	POS	O
+chronic	POS	O
+methamphetamine	POS	O
+abuse	POS	O
+causes	POS	O
+a	POS	O
+selective	POS	O
+pattern	POS	O
+of	POS	O
+cerebral	POS	B-NP
+deterioration	POS	I-NP
+that	POS	O
+contributes	POS	O
+to	POS	O
+impaired	POS	O
+memory	POS	O
+performance	POS	O
+.	POS	O
+MA	POS	O
+may	POS	O
+selectively	POS	O
+damage	POS	O
+the	POS	O
+medial	POS	O
+temporal	POS	O
+lobe	POS	O
+and	POS	O
+,	POS	O
+consistent	POS	O
+with	POS	O
+metabolic	POS	O
+studies	POS	O
+,	POS	O
+the	POS	O
+cingulate	POS	O
+-	POS	O
+limbic	POS	O
+cortex	POS	O
+,	POS	O
+inducing	POS	O
+neuroadaptation	POS	O
+,	POS	O
+neuropil	POS	O
+reduction	POS	O
+,	POS	O
+or	POS	O
+cell	POS	O
+death	POS	O
+.	POS	O
+Prominent	POS	O
+white	POS	O
+-	POS	O
+matter	POS	O
+hypertrophy	POS	B-NP
+may	POS	O
+result	POS	O
+from	POS	O
+altered	POS	O
+myelination	POS	O
+and	POS	O
+adaptive	POS	O
+glial	POS	O
+changes	POS	O
+,	POS	O
+including	POS	O
+gliosis	POS	B-NP
+secondary	POS	O
+to	POS	O
+neuronal	POS	B-NP
+damage	POS	I-NP
+.	POS	O
+These	POS	O
+brain	POS	O
+substrates	POS	O
+may	POS	O
+help	POS	O
+account	POS	O
+for	POS	O
+the	POS	O
+symptoms	POS	O
+of	POS	O
+MA	POS	O
+abuse	POS	O
+,	POS	O
+providing	POS	O
+therapeutic	POS	O
+targets	POS	O
+for	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+brain	POS	B-NP
+injury	POS	I-NP
+.	POS	O
+Disruption	POS	O
+of	POS	O
+hepatic	POS	O
+lipid	POS	O
+homeostasis	POS	O
+in	POS	O
+mice	POS	O
+after	POS	O
+amiodarone	POS	O
+treatment	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+peroxisome	POS	O
+proliferator	POS	O
+-	POS	O
+activated	POS	O
+receptor	POS	O
+-	POS	O
+alpha	POS	O
+target	POS	O
+gene	POS	O
+activation	POS	O
+.	POS	O
+Amiodarone	POS	O
+,	POS	O
+an	POS	O
+efficacious	POS	O
+and	POS	O
+widely	POS	O
+used	POS	O
+antiarrhythmic	POS	O
+agent	POS	O
+,	POS	O
+has	POS	O
+been	POS	O
+reported	POS	O
+to	POS	O
+cause	POS	O
+hepatotoxicity	POS	B-NP
+in	POS	O
+some	POS	O
+patients	POS	O
+.	POS	O
+To	POS	O
+gain	POS	O
+insight	POS	O
+into	POS	O
+the	POS	O
+mechanism	POS	O
+of	POS	O
+this	POS	O
+unwanted	POS	O
+effect	POS	O
+,	POS	O
+mice	POS	O
+were	POS	O
+administered	POS	O
+various	POS	O
+doses	POS	O
+of	POS	O
+amiodarone	POS	O
+and	POS	O
+examined	POS	O
+for	POS	O
+changes	POS	O
+in	POS	O
+hepatic	POS	O
+histology	POS	O
+and	POS	O
+gene	POS	O
+regulation	POS	O
+.	POS	O
+Amiodarone	POS	O
+induced	POS	O
+hepatomegaly	POS	B-NP
+,	POS	O
+hepatocyte	POS	O
+microvesicular	POS	O
+lipid	POS	O
+accumulation	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+significant	POS	O
+decrease	POS	O
+in	POS	O
+serum	POS	O
+triglycerides	POS	O
+and	POS	O
+glucose	POS	O
+.	POS	O
+Northern	POS	O
+blot	POS	O
+analysis	POS	O
+of	POS	O
+hepatic	POS	O
+RNA	POS	O
+revealed	POS	O
+a	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+expression	POS	O
+of	POS	O
+a	POS	O
+number	POS	O
+of	POS	O
+genes	POS	O
+critical	POS	O
+for	POS	O
+fatty	POS	O
+acid	POS	O
+oxidation	POS	O
+,	POS	O
+lipoprotein	POS	O
+assembly	POS	O
+,	POS	O
+and	POS	O
+lipid	POS	O
+transport	POS	O
+.	POS	O
+Many	POS	O
+of	POS	O
+these	POS	O
+genes	POS	O
+are	POS	O
+regulated	POS	O
+by	POS	O
+the	POS	O
+peroxisome	POS	O
+proliferator	POS	O
+-	POS	O
+activated	POS	O
+receptor	POS	O
+-	POS	O
+alpha	POS	O
+(	POS	O
+PPARalpha	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+ligand	POS	O
+-	POS	O
+activated	POS	O
+nuclear	POS	O
+hormone	POS	O
+receptor	POS	O
+transcription	POS	O
+factor	POS	O
+.	POS	O
+The	POS	O
+absence	POS	O
+of	POS	O
+induction	POS	O
+of	POS	O
+these	POS	O
+genes	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+hepatomegaly	POS	B-NP
+in	POS	O
+PPARalpha	POS	O
+knockout	POS	O
+[	POS	O
+PPARalpha	POS	O
+-	POS	O
+/	POS	O
+-	POS	O
+]	POS	O
+mice	POS	O
+indicated	POS	O
+that	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+amiodarone	POS	O
+were	POS	O
+dependent	POS	O
+upon	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+a	POS	O
+functional	POS	O
+PPARalpha	POS	O
+gene	POS	O
+.	POS	O
+Compared	POS	O
+to	POS	O
+wild	POS	O
+-	POS	O
+type	POS	O
+mice	POS	O
+,	POS	O
+treatment	POS	O
+of	POS	O
+PPARalpha	POS	O
+-	POS	O
+/	POS	O
+-	POS	O
+mice	POS	O
+with	POS	O
+amiodarone	POS	O
+resulted	POS	O
+in	POS	O
+an	POS	O
+increased	POS	O
+rate	POS	O
+and	POS	O
+extent	POS	O
+of	POS	O
+total	POS	O
+body	POS	O
+weight	POS	O
+loss	POS	O
+.	POS	O
+The	POS	O
+inability	POS	O
+of	POS	O
+amiodarone	POS	O
+to	POS	O
+directly	POS	O
+activate	POS	O
+either	POS	O
+human	POS	O
+or	POS	O
+mouse	POS	O
+PPARalpha	POS	O
+transiently	POS	O
+expressed	POS	O
+in	POS	O
+human	POS	O
+HepG2	POS	O
+hepatoma	POS	O
+cells	POS	O
+indicates	POS	O
+that	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+amiodarone	POS	O
+on	POS	O
+the	POS	O
+function	POS	O
+of	POS	O
+this	POS	O
+receptor	POS	O
+were	POS	O
+indirect	POS	O
+.	POS	O
+Based	POS	O
+upon	POS	O
+these	POS	O
+results	POS	O
+,	POS	O
+we	POS	O
+conclude	POS	O
+that	POS	O
+amiodarone	POS	O
+disrupts	POS	O
+hepatic	POS	O
+lipid	POS	O
+homeostasis	POS	O
+and	POS	O
+that	POS	O
+the	POS	O
+increased	POS	O
+expression	POS	O
+of	POS	O
+PPARalpha	POS	O
+target	POS	O
+genes	POS	O
+is	POS	O
+secondary	POS	O
+to	POS	O
+this	POS	O
+toxic	POS	O
+effect	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+provide	POS	O
+important	POS	O
+new	POS	O
+mechanistic	POS	O
+information	POS	O
+regarding	POS	O
+the	POS	O
+hepatotoxic	POS	B-NP
+effects	POS	O
+of	POS	O
+amiodarone	POS	O
+and	POS	O
+indicate	POS	O
+that	POS	O
+PPARalpha	POS	O
+protects	POS	O
+against	POS	O
+amiodarone	POS	O
+-	POS	O
+induced	POS	O
+hepatotoxicity	POS	B-NP
+.	POS	O
+Safety	POS	O
+and	POS	O
+compliance	POS	O
+with	POS	O
+once	POS	O
+-	POS	O
+daily	POS	O
+niacin	POS	O
+extended	POS	O
+-	POS	O
+release	POS	O
+/	POS	O
+lovastatin	POS	O
+as	POS	O
+initial	POS	O
+therapy	POS	O
+in	POS	O
+the	POS	O
+Impact	POS	O
+of	POS	O
+Medical	POS	O
+Subspecialty	POS	O
+on	POS	O
+Patient	POS	O
+Compliance	POS	O
+to	POS	O
+Treatment	POS	O
+(	POS	O
+IMPACT	POS	O
+)	POS	O
+study	POS	O
+.	POS	O
+Niacin	POS	O
+extended	POS	O
+-	POS	O
+release	POS	O
+/	POS	O
+lovastatin	POS	O
+is	POS	O
+a	POS	O
+new	POS	O
+combination	POS	O
+product	POS	O
+approved	POS	O
+for	POS	O
+treatment	POS	O
+of	POS	O
+primary	POS	O
+hypercholesterolemia	POS	B-NP
+and	POS	O
+mixed	POS	O
+dyslipidemia	POS	B-NP
+.	POS	O
+This	POS	O
+open	POS	O
+-	POS	O
+labeled	POS	O
+,	POS	O
+multicenter	POS	O
+study	POS	O
+evaluated	POS	O
+the	POS	O
+safety	POS	O
+of	POS	O
+bedtime	POS	O
+niacin	POS	O
+extended	POS	O
+-	POS	O
+release	POS	O
+/	POS	O
+lovastatin	POS	O
+when	POS	O
+dosed	POS	O
+as	POS	O
+initial	POS	O
+therapy	POS	O
+and	POS	O
+patient	POS	O
+compliance	POS	O
+to	POS	O
+treatment	POS	O
+in	POS	O
+various	POS	O
+clinical	POS	O
+practice	POS	O
+settings	POS	O
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+4	POS	O
+,	POS	O
+499	POS	O
+patients	POS	O
+with	POS	O
+dyslipidemia	POS	B-NP
+requiring	POS	O
+drug	POS	O
+intervention	POS	O
+was	POS	O
+enrolled	POS	O
+at	POS	O
+1	POS	O
+,	POS	O
+081	POS	O
+sites	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+1	POS	O
+tablet	POS	O
+(	POS	O
+500	POS	O
+mg	POS	O
+of	POS	O
+niacin	POS	O
+extended	POS	O
+-	POS	O
+release	POS	O
+/	POS	O
+20	POS	O
+mg	POS	O
+of	POS	O
+lovastatin	POS	O
+)	POS	O
+once	POS	O
+nightly	POS	O
+for	POS	O
+4	POS	O
+weeks	POS	O
+and	POS	O
+then	POS	O
+2	POS	O
+tablets	POS	O
+for	POS	O
+8	POS	O
+weeks	POS	O
+.	POS	O
+Patients	POS	O
+also	POS	O
+received	POS	O
+dietary	POS	O
+counseling	POS	O
+,	POS	O
+educational	POS	O
+materials	POS	O
+,	POS	O
+and	POS	O
+reminders	POS	O
+to	POS	O
+call	POS	O
+a	POS	O
+toll	POS	O
+-	POS	O
+free	POS	O
+number	POS	O
+that	POS	O
+provided	POS	O
+further	POS	O
+education	POS	O
+about	POS	O
+dyslipidemia	POS	B-NP
+and	POS	O
+niacin	POS	O
+extended	POS	O
+-	POS	O
+release	POS	O
+/	POS	O
+lovastatin	POS	O
+.	POS	O
+Primary	POS	O
+end	POS	O
+points	POS	O
+were	POS	O
+study	POS	O
+compliance	POS	O
+,	POS	O
+increases	POS	O
+in	POS	O
+liver	POS	O
+transaminases	POS	O
+to	POS	O
+>	POS	O
+3	POS	O
+times	POS	O
+the	POS	O
+upper	POS	O
+limit	POS	O
+of	POS	O
+normal	POS	O
+,	POS	O
+and	POS	O
+clinical	POS	O
+myopathy	POS	B-NP
+.	POS	O
+Final	POS	O
+study	POS	O
+status	POS	O
+was	POS	O
+available	POS	O
+for	POS	O
+4	POS	O
+,	POS	O
+217	POS	O
+patients	POS	O
+(	POS	O
+94	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Compliance	POS	O
+to	POS	O
+niacin	POS	O
+extended	POS	O
+-	POS	O
+release	POS	O
+/	POS	O
+lovastatin	POS	O
+was	POS	O
+77	POS	O
+%	POS	O
+,	POS	O
+with	POS	O
+3	POS	O
+,	POS	O
+245	POS	O
+patients	POS	O
+completing	POS	O
+the	POS	O
+study	POS	O
+.	POS	O
+Patients	POS	O
+in	POS	O
+the	POS	O
+southeast	POS	O
+and	POS	O
+those	POS	O
+enrolled	POS	O
+by	POS	O
+endocrinologists	POS	O
+had	POS	O
+the	POS	O
+lowest	POS	O
+compliance	POS	O
+and	POS	O
+highest	POS	O
+adverse	POS	O
+event	POS	O
+rates	POS	O
+.	POS	O
+Flushing	POS	O
+was	POS	O
+the	POS	O
+most	POS	O
+common	POS	O
+adverse	POS	O
+event	POS	O
+,	POS	O
+reported	POS	O
+by	POS	O
+18	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+and	POS	O
+leading	POS	O
+to	POS	O
+discontinuation	POS	O
+by	POS	O
+6	POS	O
+%	POS	O
+.	POS	O
+Incidence	POS	O
+of	POS	O
+increased	POS	O
+aspartate	POS	O
+aminotransferase	POS	O
+and	POS	O
+/	POS	O
+or	POS	O
+alanine	POS	O
+aminotransferase	POS	O
+>	POS	O
+3	POS	O
+times	POS	O
+the	POS	O
+upper	POS	O
+limit	POS	O
+of	POS	O
+normal	POS	O
+was	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+.	POS	O
+An	POS	O
+increase	POS	O
+of	POS	O
+creatine	POS	O
+phosphokinase	POS	O
+to	POS	O
+>	POS	O
+5	POS	O
+times	POS	O
+the	POS	O
+upper	POS	O
+limit	POS	O
+of	POS	O
+normal	POS	O
+occurred	POS	O
+in	POS	O
+0	POS	O
+.	POS	O
+24	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+,	POS	O
+and	POS	O
+no	POS	O
+cases	POS	O
+of	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+myopathy	POS	B-NP
+were	POS	O
+observed	POS	O
+.	POS	O
+Niacin	POS	O
+extended	POS	O
+-	POS	O
+release	POS	O
+/	POS	O
+lovastatin	POS	O
+1	POS	O
+,	POS	O
+000	POS	O
+/	POS	O
+40	POS	O
+mg	POS	O
+,	POS	O
+dosed	POS	O
+as	POS	O
+initial	POS	O
+therapy	POS	O
+,	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+good	POS	O
+compliance	POS	O
+and	POS	O
+safety	POS	O
+and	POS	O
+had	POS	O
+very	POS	O
+low	POS	O
+incidences	POS	O
+of	POS	O
+increased	POS	O
+liver	POS	O
+and	POS	O
+muscle	POS	O
+enzymes	POS	O
+.	POS	O
+Protective	POS	O
+effect	POS	O
+of	POS	O
+Terminalia	POS	O
+chebula	POS	O
+against	POS	O
+experimental	POS	O
+myocardial	POS	B-NP
+injury	POS	I-NP
+induced	POS	O
+by	POS	O
+isoproterenol	POS	O
+.	POS	O
+Cardioprotective	POS	O
+effect	POS	O
+of	POS	O
+ethanolic	POS	O
+extract	POS	O
+of	POS	O
+Terminalia	POS	O
+chebula	POS	O
+fruits	POS	O
+(	POS	O
+500	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+body	POS	O
+wt	POS	O
+)	POS	O
+was	POS	O
+examined	POS	O
+in	POS	O
+isoproterenol	POS	O
+(	POS	O
+200	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+body	POS	O
+wt	POS	O
+)	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+damage	POS	I-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+In	POS	O
+isoproterenol	POS	O
+administered	POS	O
+rats	POS	O
+,	POS	O
+the	POS	O
+level	POS	O
+of	POS	O
+lipid	POS	O
+peroxides	POS	O
+increased	POS	O
+significantly	POS	O
+in	POS	O
+the	POS	O
+serum	POS	O
+and	POS	O
+heart	POS	O
+.	POS	O
+A	POS	O
+significant	POS	O
+decrease	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+activity	POS	O
+of	POS	O
+the	POS	O
+myocardial	POS	O
+marker	POS	O
+enzymes	POS	O
+with	POS	O
+a	POS	O
+concomitant	POS	O
+increase	POS	O
+in	POS	O
+their	POS	O
+activity	POS	O
+in	POS	O
+serum	POS	O
+.	POS	O
+Histopathological	POS	O
+examination	POS	O
+was	POS	O
+carried	POS	O
+out	POS	O
+to	POS	O
+confirm	POS	O
+the	POS	O
+myocardial	POS	B-NP
+necrosis	POS	I-NP
+.	POS	O
+T	POS	O
+.	POS	O
+chebula	POS	O
+extract	POS	O
+pretreatment	POS	O
+was	POS	O
+found	POS	O
+to	POS	O
+ameliorate	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+isoproterenol	POS	O
+on	POS	O
+lipid	POS	O
+peroxide	POS	O
+formation	POS	O
+and	POS	O
+retained	POS	O
+the	POS	O
+activities	POS	O
+of	POS	O
+the	POS	O
+diagnostic	POS	O
+marker	POS	O
+enzymes	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+postoperative	POS	B-NP
+anxiety	POS	I-NP
+due	POS	O
+to	POS	O
+low	POS	O
+dose	POS	O
+droperidol	POS	O
+used	POS	O
+with	POS	O
+patient	POS	O
+-	POS	O
+controlled	POS	O
+analgesia	POS	B-NP
+.	POS	O
+A	POS	O
+multiparous	POS	O
+woman	POS	O
+in	POS	O
+good	POS	O
+psychological	POS	O
+health	POS	O
+underwent	POS	O
+urgent	POS	O
+caesarean	POS	O
+section	POS	O
+in	POS	O
+labour	POS	O
+.	POS	O
+Postoperatively	POS	O
+,	POS	O
+she	POS	O
+was	POS	O
+given	POS	O
+a	POS	O
+patient	POS	O
+-	POS	O
+controlled	POS	O
+analgesia	POS	O
+device	POS	O
+delivering	POS	O
+boluses	POS	O
+of	POS	O
+diamorphine	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+and	POS	O
+droperidol	POS	O
+0	POS	O
+.	POS	O
+025	POS	O
+mg	POS	O
+.	POS	O
+Whilst	POS	O
+using	POS	O
+the	POS	O
+device	POS	O
+she	POS	O
+gradually	POS	O
+became	POS	O
+anxious	POS	B-NP
+,	POS	O
+the	POS	O
+feeling	POS	O
+worsening	POS	O
+after	POS	O
+each	POS	O
+bolus	POS	O
+.	POS	O
+The	POS	O
+diagnosis	POS	O
+of	POS	O
+droperidol	POS	O
+-	POS	O
+induced	POS	O
+psychological	POS	O
+disturbance	POS	O
+was	POS	O
+not	POS	O
+made	POS	O
+straight	POS	O
+away	POS	O
+although	POS	O
+on	POS	O
+subsequent	POS	O
+close	POS	O
+questioning	POS	O
+the	POS	O
+patient	POS	O
+gave	POS	O
+a	POS	O
+very	POS	O
+clear	POS	O
+history	POS	O
+.	POS	O
+After	POS	O
+she	POS	O
+had	POS	O
+received	POS	O
+a	POS	O
+total	POS	O
+of	POS	O
+only	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+mg	POS	O
+droperidol	POS	O
+,	POS	O
+a	POS	O
+syringe	POS	O
+containing	POS	O
+diamorphine	POS	O
+only	POS	O
+was	POS	O
+substituted	POS	O
+and	POS	O
+her	POS	O
+unease	POS	O
+resolved	POS	O
+completely	POS	O
+.	POS	O
+We	POS	O
+feel	POS	O
+that	POS	O
+,	POS	O
+although	POS	O
+the	POS	O
+dramatic	POS	O
+extrapyramidal	POS	O
+side	POS	O
+effects	POS	O
+of	POS	O
+dopaminergic	POS	O
+antiemetics	POS	O
+are	POS	O
+well	POS	O
+known	POS	O
+,	POS	O
+more	POS	O
+subtle	POS	O
+manifestations	POS	O
+may	POS	O
+easily	POS	O
+be	POS	O
+overlooked	POS	O
+.	POS	O
+Accurate	POS	O
+patient	POS	O
+history	POS	O
+contributes	POS	O
+to	POS	O
+differentiating	POS	O
+diabetes	POS	B-NP
+insipidus	POS	I-NP
+:	POS	O
+a	POS	O
+case	POS	O
+study	POS	O
+.	POS	O
+This	POS	O
+case	POS	O
+study	POS	O
+highlights	POS	O
+the	POS	O
+important	POS	O
+contribution	POS	O
+of	POS	O
+nursing	POS	O
+in	POS	O
+obtaining	POS	O
+an	POS	O
+accurate	POS	O
+health	POS	O
+history	POS	O
+.	POS	O
+The	POS	O
+case	POS	O
+discussed	POS	O
+herein	POS	O
+initially	POS	O
+appeared	POS	O
+to	POS	O
+be	POS	O
+neurogenic	POS	B-NP
+diabetes	POS	I-NP
+insipidus	POS	I-NP
+(	POS	O
+DI	POS	B-NP
+)	POS	O
+secondary	POS	O
+to	POS	O
+a	POS	O
+traumatic	POS	B-NP
+brain	POS	I-NP
+injury	POS	I-NP
+.	POS	O
+The	POS	O
+nursing	POS	O
+staff	POS	O
+,	POS	O
+by	POS	O
+reviewing	POS	O
+the	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+health	POS	O
+history	POS	O
+with	POS	O
+his	POS	O
+family	POS	O
+,	POS	O
+discovered	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+polydipsia	POS	B-NP
+and	POS	O
+long	POS	O
+-	POS	O
+standing	POS	O
+lithium	POS	O
+use	POS	O
+.	POS	O
+Lithium	POS	O
+is	POS	O
+implicated	POS	O
+in	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+nephrogenic	POS	B-NP
+DI	POS	I-NP
+,	POS	O
+and	POS	O
+because	POS	O
+the	POS	O
+patient	POS	O
+had	POS	O
+not	POS	O
+received	POS	O
+lithium	POS	O
+since	POS	O
+being	POS	O
+admitted	POS	O
+to	POS	O
+the	POS	O
+hospital	POS	O
+,	POS	O
+his	POS	O
+treatment	POS	O
+changed	POS	O
+to	POS	O
+focus	POS	O
+on	POS	O
+nephrogenic	POS	B-NP
+DI	POS	I-NP
+.	POS	O
+By	POS	O
+combining	POS	O
+information	POS	O
+from	POS	O
+the	POS	O
+patient	POS	O
+history	POS	O
+,	POS	O
+the	POS	O
+physical	POS	O
+examination	POS	O
+,	POS	O
+and	POS	O
+radiologic	POS	O
+and	POS	O
+laboratory	POS	O
+studies	POS	O
+,	POS	O
+the	POS	O
+critical	POS	O
+care	POS	O
+team	POS	O
+demonstrated	POS	O
+that	POS	O
+the	POS	O
+patient	POS	O
+had	POS	O
+been	POS	O
+self	POS	O
+-	POS	O
+treating	POS	O
+his	POS	O
+lithium	POS	O
+-	POS	O
+induced	POS	O
+nephrogenic	POS	B-NP
+DI	POS	I-NP
+and	POS	O
+developed	POS	O
+neurogenic	POS	O
+DI	POS	O
+secondary	POS	O
+to	POS	O
+brain	POS	B-NP
+trauma	POS	I-NP
+.	POS	O
+Thus	POS	O
+successful	POS	O
+treatment	POS	O
+required	POS	O
+that	POS	O
+nephrogenic	POS	B-NP
+and	POS	O
+neurogenic	POS	B-NP
+DI	POS	I-NP
+be	POS	O
+treated	POS	O
+concomitantly	POS	O
+.	POS	O
+Factors	POS	O
+contributing	POS	O
+to	POS	O
+ribavirin	POS	O
+-	POS	O
+induced	POS	O
+anemia	POS	B-NP
+.	POS	O
+BACKGROUND	POS	O
+AND	POS	O
+AIM	POS	O
+:	POS	O
+Interferon	POS	O
+and	POS	O
+ribavirin	POS	O
+combination	POS	O
+therapy	POS	O
+for	POS	O
+chronic	POS	O
+hepatitis	POS	O
+C	POS	O
+produces	POS	O
+hemolytic	POS	B-NP
+anemia	POS	I-NP
+.	POS	O
+This	POS	O
+study	POS	O
+was	POS	O
+conducted	POS	O
+to	POS	O
+identify	POS	O
+the	POS	O
+factors	POS	O
+contributing	POS	O
+to	POS	O
+ribavirin	POS	O
+-	POS	O
+induced	POS	O
+anemia	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Eighty	POS	O
+-	POS	O
+eight	POS	O
+patients	POS	O
+with	POS	O
+chronic	POS	B-NP
+hepatitis	POS	I-NP
+C	POS	I-NP
+who	POS	O
+received	POS	O
+interferon	POS	O
+-	POS	O
+alpha	POS	O
+-	POS	O
+2b	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+6	POS	O
+MU	POS	O
+administered	POS	O
+intramuscularly	POS	O
+for	POS	O
+24	POS	O
+weeks	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+ribavirin	POS	O
+administered	POS	O
+orally	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+600	POS	O
+mg	POS	O
+or	POS	O
+800	POS	O
+mg	POS	O
+participated	POS	O
+in	POS	O
+the	POS	O
+study	POS	O
+.	POS	O
+A	POS	O
+hemoglobin	POS	O
+concentration	POS	O
+of	POS	O
+<	POS	O
+10	POS	O
+g	POS	O
+/	POS	O
+dL	POS	O
+was	POS	O
+defined	POS	O
+as	POS	O
+ribavirin	POS	O
+-	POS	O
+induced	POS	O
+anemia	POS	B-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Ribavirin	POS	O
+-	POS	O
+induced	POS	O
+anemia	POS	B-NP
+occurred	POS	O
+in	POS	O
+18	POS	O
+(	POS	O
+20	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+during	POS	O
+treatment	POS	O
+.	POS	O
+A	POS	O
+2	POS	O
+g	POS	O
+/	POS	O
+dL	POS	O
+decrease	POS	O
+in	POS	O
+hemoglobin	POS	O
+concentrations	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+anemia	POS	B-NP
+was	POS	O
+observed	POS	O
+at	POS	O
+week	POS	O
+2	POS	O
+after	POS	O
+the	POS	O
+start	POS	O
+of	POS	O
+treatment	POS	O
+.	POS	O
+The	POS	O
+hemoglobin	POS	O
+concentration	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+2	POS	O
+g	POS	O
+/	POS	O
+dL	POS	O
+decrease	POS	O
+at	POS	O
+week	POS	O
+2	POS	O
+was	POS	O
+observed	POS	O
+to	POS	O
+be	POS	O
+significantly	POS	O
+lower	POS	O
+even	POS	O
+after	POS	O
+week	POS	O
+2	POS	O
+than	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+<	POS	O
+2	POS	O
+g	POS	O
+/	POS	O
+dL	POS	O
+decrease	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+A	POS	O
+significant	POS	O
+relationship	POS	O
+was	POS	O
+observed	POS	O
+between	POS	O
+the	POS	O
+rate	POS	O
+of	POS	O
+reduction	POS	O
+of	POS	O
+hemoglobin	POS	O
+concentrations	POS	O
+at	POS	O
+week	POS	O
+2	POS	O
+and	POS	O
+the	POS	O
+severity	POS	O
+of	POS	O
+anemia	POS	B-NP
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+Such	POS	O
+factors	POS	O
+as	POS	O
+sex	POS	O
+(	POS	O
+female	POS	O
+)	POS	O
+,	POS	O
+age	POS	O
+(	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+60	POS	O
+years	POS	O
+old	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+ribavirin	POS	O
+dose	POS	O
+by	POS	O
+body	POS	O
+weight	POS	O
+(	POS	O
+12	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+or	POS	O
+more	POS	O
+)	POS	O
+were	POS	O
+significant	POS	O
+by	POS	O
+univariate	POS	O
+analysis	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Careful	POS	O
+administration	POS	O
+is	POS	O
+necessary	POS	O
+in	POS	O
+patients	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+60	POS	O
+years	POS	O
+old	POS	O
+,	POS	O
+in	POS	O
+female	POS	O
+patients	POS	O
+,	POS	O
+and	POS	O
+in	POS	O
+patients	POS	O
+receiving	POS	O
+a	POS	O
+ribavirin	POS	O
+dose	POS	O
+of	POS	O
+12	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+or	POS	O
+more	POS	O
+.	POS	O
+Patients	POS	O
+who	POS	O
+experience	POS	O
+a	POS	O
+fall	POS	O
+in	POS	O
+hemoglobin	POS	O
+concentrations	POS	O
+of	POS	O
+2	POS	O
+g	POS	O
+/	POS	O
+dL	POS	O
+or	POS	O
+more	POS	O
+at	POS	O
+week	POS	O
+2	POS	O
+after	POS	O
+the	POS	O
+start	POS	O
+of	POS	O
+treatment	POS	O
+should	POS	O
+be	POS	O
+monitored	POS	O
+with	POS	O
+particular	POS	O
+care	POS	O
+.	POS	O
+Zidovudine	POS	O
+-	POS	O
+induced	POS	O
+hepatitis	POS	B-NP
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+acute	POS	B-NP
+hepatitis	POS	I-NP
+induced	POS	O
+by	POS	O
+zidovudine	POS	O
+in	POS	O
+a	POS	O
+38	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+patient	POS	O
+with	POS	O
+AIDS	POS	B-NP
+is	POS	O
+presented	POS	O
+.	POS	O
+The	POS	O
+mechanism	POS	O
+whereby	POS	O
+the	POS	O
+hepatitis	POS	B-NP
+was	POS	O
+induced	POS	O
+is	POS	O
+not	POS	O
+known	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+tolerated	POS	O
+well	POS	O
+an	POS	O
+alternative	POS	O
+reverse	POS	O
+transcriptase	POS	O
+inhibitor	POS	O
+,	POS	O
+2	POS	O
+'	POS	O
+3	POS	O
+'	POS	O
+dideoxyinosine	POS	O
+.	POS	O
+Physicians	POS	O
+caring	POS	O
+for	POS	O
+patients	POS	O
+with	POS	O
+AIDS	POS	B-NP
+should	POS	O
+be	POS	O
+aware	POS	O
+of	POS	O
+this	POS	O
+hitherto	POS	O
+rarely	POS	O
+reported	POS	O
+complication	POS	O
+.	POS	O
+Oxidative	POS	O
+damage	POS	O
+precedes	POS	O
+nitrative	POS	O
+damage	POS	O
+in	POS	O
+adriamycin	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+mitochondrial	POS	I-NP
+injury	POS	I-NP
+.	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+determine	POS	O
+if	POS	O
+elevated	POS	O
+reactive	POS	O
+oxygen	POS	O
+(	POS	O
+ROS	POS	O
+)	POS	O
+/	POS	O
+nitrogen	POS	O
+species	POS	O
+(	POS	O
+RNS	POS	O
+)	POS	O
+reported	POS	O
+to	POS	O
+be	POS	O
+present	POS	O
+in	POS	O
+adriamycin	POS	O
+(	POS	O
+ADR	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+actually	POS	O
+resulted	POS	O
+in	POS	O
+cardiomyocyte	POS	O
+oxidative	POS	O
+/	POS	O
+nitrative	POS	O
+damage	POS	O
+,	POS	O
+and	POS	O
+to	POS	O
+quantitatively	POS	O
+determine	POS	O
+the	POS	O
+time	POS	O
+course	POS	O
+and	POS	O
+subcellular	POS	O
+localization	POS	O
+of	POS	O
+these	POS	O
+postulated	POS	O
+damage	POS	O
+products	POS	O
+using	POS	O
+an	POS	O
+in	POS	O
+vivo	POS	O
+approach	POS	O
+.	POS	O
+B6C3	POS	O
+mice	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+a	POS	O
+single	POS	O
+dose	POS	O
+of	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+ADR	POS	O
+.	POS	O
+Ultrastructural	POS	O
+damage	POS	O
+and	POS	O
+levels	POS	O
+of	POS	O
+4	POS	O
+-	POS	O
+hydroxy	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+nonenal	POS	O
+(	POS	O
+4HNE	POS	O
+)	POS	O
+-	POS	O
+protein	POS	O
+adducts	POS	O
+and	POS	O
+3	POS	O
+-	POS	O
+nitrotyrosine	POS	O
+(	POS	O
+3NT	POS	O
+)	POS	O
+were	POS	O
+analyzed	POS	O
+.	POS	O
+Quantitative	POS	O
+ultrastructural	POS	O
+damage	POS	O
+using	POS	O
+computerized	POS	O
+image	POS	O
+techniques	POS	O
+showed	POS	O
+cardiomyocyte	POS	B-NP
+injury	POS	I-NP
+as	POS	O
+early	POS	O
+as	POS	O
+3	POS	O
+hours	POS	O
+,	POS	O
+with	POS	O
+mitochondria	POS	O
+being	POS	O
+the	POS	O
+most	POS	O
+extensively	POS	O
+and	POS	O
+progressively	POS	O
+injured	POS	O
+subcellular	POS	O
+organelle	POS	O
+.	POS	O
+Analysis	POS	O
+of	POS	O
+4HNE	POS	O
+protein	POS	O
+adducts	POS	O
+by	POS	O
+immunogold	POS	O
+electron	POS	O
+microscopy	POS	O
+showed	POS	O
+appearance	POS	O
+of	POS	O
+4HNE	POS	O
+protein	POS	O
+adducts	POS	O
+in	POS	O
+mitochondria	POS	O
+as	POS	O
+early	POS	O
+as	POS	O
+3	POS	O
+hours	POS	O
+,	POS	O
+with	POS	O
+a	POS	O
+peak	POS	O
+at	POS	O
+6	POS	O
+hours	POS	O
+and	POS	O
+subsequent	POS	O
+decline	POS	O
+at	POS	O
+24	POS	O
+hours	POS	O
+.	POS	O
+3NT	POS	O
+levels	POS	O
+were	POS	O
+significantly	POS	O
+increased	POS	O
+in	POS	O
+all	POS	O
+subcellular	POS	O
+compartments	POS	O
+at	POS	O
+6	POS	O
+hours	POS	O
+and	POS	O
+subsequently	POS	O
+declined	POS	O
+at	POS	O
+24	POS	O
+hours	POS	O
+.	POS	O
+Our	POS	O
+data	POS	O
+showed	POS	O
+ADR	POS	O
+induced	POS	O
+4HNE	POS	O
+-	POS	O
+protein	POS	O
+adducts	POS	O
+in	POS	O
+mitochondria	POS	O
+at	POS	O
+the	POS	O
+same	POS	O
+time	POS	O
+point	POS	O
+as	POS	O
+when	POS	O
+mitochondrial	POS	B-NP
+injury	POS	I-NP
+initially	POS	O
+appeared	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+document	POS	O
+for	POS	O
+the	POS	O
+first	POS	O
+time	POS	O
+in	POS	O
+vivo	POS	O
+that	POS	O
+mitochondrial	POS	O
+oxidative	POS	O
+damage	POS	O
+precedes	POS	O
+nitrative	POS	O
+damage	POS	O
+.	POS	O
+The	POS	O
+progressive	POS	O
+nature	POS	O
+of	POS	O
+mitochondrial	POS	B-NP
+injury	POS	I-NP
+suggests	POS	O
+that	POS	O
+mitochondria	POS	O
+,	POS	O
+not	POS	O
+other	POS	O
+subcellular	POS	O
+organelles	POS	O
+,	POS	O
+are	POS	O
+the	POS	O
+major	POS	O
+site	POS	O
+of	POS	O
+intracellular	POS	O
+injury	POS	O
+.	POS	O
+Sotalol	POS	O
+-	POS	O
+induced	POS	O
+coronary	POS	B-NP
+spasm	POS	I-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+dilated	POS	B-NP
+cardiomyopathy	POS	I-NP
+associated	POS	O
+with	POS	O
+sustained	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+.	POS	O
+A	POS	O
+54	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+with	POS	O
+severe	POS	O
+left	POS	B-NP
+ventricular	POS	I-NP
+dysfunction	POS	I-NP
+due	POS	O
+to	POS	O
+dilated	POS	B-NP
+cardiomyopathy	POS	I-NP
+was	POS	O
+referred	POS	O
+to	POS	O
+our	POS	O
+hospital	POS	O
+for	POS	O
+symptomatic	POS	O
+incessant	POS	O
+sustained	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+(	POS	O
+VT	POS	B-NP
+)	POS	O
+.	POS	O
+After	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+nifekalant	POS	O
+hydrochloride	POS	O
+,	POS	O
+sustained	POS	O
+VT	POS	B-NP
+was	POS	O
+terminated	POS	O
+.	POS	O
+An	POS	O
+alternate	POS	O
+class	POS	O
+III	POS	O
+agent	POS	O
+,	POS	O
+sotalol	POS	O
+,	POS	O
+was	POS	O
+also	POS	O
+effective	POS	O
+for	POS	O
+the	POS	O
+prevention	POS	O
+of	POS	O
+VT	POS	B-NP
+.	POS	O
+However	POS	O
+,	POS	O
+one	POS	O
+month	POS	O
+after	POS	O
+switching	POS	O
+over	POS	O
+nifekalant	POS	O
+to	POS	O
+sotalol	POS	O
+,	POS	O
+a	POS	O
+short	POS	O
+duration	POS	O
+of	POS	O
+ST	POS	O
+elevation	POS	O
+was	POS	O
+documented	POS	O
+in	POS	O
+ECG	POS	O
+monitoring	POS	O
+at	POS	O
+almost	POS	O
+the	POS	O
+same	POS	O
+time	POS	O
+for	POS	O
+three	POS	O
+consecutive	POS	O
+days	POS	O
+.	POS	O
+ST	POS	O
+elevation	POS	O
+with	POS	O
+chest	POS	B-NP
+discomfort	POS	I-NP
+disappeared	POS	O
+since	POS	O
+he	POS	O
+began	POS	O
+taking	POS	O
+long	POS	O
+-	POS	O
+acting	POS	O
+diltiazem	POS	O
+.	POS	O
+Coronary	POS	B-NP
+vasospasm	POS	I-NP
+may	POS	O
+be	POS	O
+induced	POS	O
+by	POS	O
+the	POS	O
+non	POS	O
+-	POS	O
+selective	POS	O
+beta	POS	O
+-	POS	O
+blocking	POS	O
+properties	POS	O
+of	POS	O
+sotalol	POS	O
+.	POS	O
+Effects	POS	O
+of	POS	O
+the	POS	O
+antidepressant	POS	O
+trazodone	POS	O
+,	POS	O
+a	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+2A	POS	O
+/	POS	O
+2C	POS	O
+receptor	POS	O
+antagonist	POS	O
+,	POS	O
+on	POS	O
+dopamine	POS	O
+-	POS	O
+dependent	POS	O
+behaviors	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+RATIONALE	POS	O
+:	POS	O
+5	POS	O
+-	POS	O
+Hydroxytryptamine	POS	O
+,	POS	O
+via	POS	O
+stimulation	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+2C	POS	O
+receptors	POS	O
+,	POS	O
+exerts	POS	O
+a	POS	O
+tonic	POS	O
+inhibitory	POS	O
+influence	POS	O
+on	POS	O
+dopaminergic	POS	O
+neurotransmission	POS	O
+,	POS	O
+whereas	POS	O
+activation	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+2A	POS	O
+receptors	POS	O
+enhances	POS	O
+stimulated	POS	O
+DAergic	POS	O
+neurotransmission	POS	O
+.	POS	O
+The	POS	O
+antidepressant	POS	O
+trazodone	POS	O
+is	POS	O
+a	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+2A	POS	O
+/	POS	O
+2C	POS	O
+receptor	POS	O
+antagonist	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+To	POS	O
+evaluate	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+trazodone	POS	O
+treatment	POS	O
+on	POS	O
+behaviors	POS	O
+dependent	POS	O
+on	POS	O
+the	POS	O
+functional	POS	O
+status	POS	O
+of	POS	O
+the	POS	O
+nigrostriatal	POS	O
+DAergic	POS	O
+system	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+The	POS	O
+effect	POS	O
+of	POS	O
+pretreatment	POS	O
+with	POS	O
+trazodone	POS	O
+on	POS	O
+dexamphetamine	POS	O
+-	POS	O
+and	POS	O
+apomorphine	POS	O
+-	POS	O
+induced	POS	O
+oral	POS	O
+stereotypies	POS	B-NP
+,	POS	O
+on	POS	O
+catalepsy	POS	B-NP
+induced	POS	O
+by	POS	O
+haloperidol	POS	O
+and	POS	O
+apomorphine	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+,	POS	O
+on	POS	O
+ergometrine	POS	O
+-	POS	O
+induced	POS	O
+wet	POS	O
+dog	POS	O
+shake	POS	O
+(	POS	O
+WDS	POS	O
+)	POS	O
+behavior	POS	O
+and	POS	O
+fluoxetine	POS	O
+-	POS	O
+induced	POS	O
+penile	POS	O
+erections	POS	O
+was	POS	O
+studied	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+We	POS	O
+also	POS	O
+investigated	POS	O
+whether	POS	O
+trazodone	POS	O
+induces	POS	O
+catalepsy	POS	B-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Trazodone	POS	O
+at	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+did	POS	O
+not	POS	O
+induce	POS	O
+catalepsy	POS	B-NP
+,	POS	O
+and	POS	O
+did	POS	O
+not	POS	O
+antagonize	POS	O
+apomorphine	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+and	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+stereotypy	POS	O
+and	POS	O
+apomorphine	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+catalepsy	POS	B-NP
+.	POS	O
+However	POS	O
+,	POS	O
+pretreatment	POS	O
+with	POS	O
+5	POS	O
+,	POS	O
+10	POS	O
+and	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+trazodone	POS	O
+enhanced	POS	O
+dexamphetamine	POS	O
+stereotypy	POS	B-NP
+,	POS	O
+and	POS	O
+antagonized	POS	O
+haloperidol	POS	O
+catalepsy	POS	B-NP
+,	POS	O
+ergometrine	POS	O
+-	POS	O
+induced	POS	O
+WDS	POS	O
+behavior	POS	O
+and	POS	O
+fluoxetine	POS	O
+-	POS	O
+induced	POS	O
+penile	POS	O
+erections	POS	O
+.	POS	O
+Trazodone	POS	O
+at	POS	O
+30	POS	O
+,	POS	O
+40	POS	O
+and	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+induced	POS	O
+catalepsy	POS	B-NP
+and	POS	O
+antagonized	POS	O
+apomorphine	POS	O
+and	POS	O
+dexamphetamine	POS	O
+stereotypies	POS	B-NP
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Our	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+trazodone	POS	O
+at	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+does	POS	O
+not	POS	O
+block	POS	O
+pre	POS	O
+-	POS	O
+and	POS	O
+postsynaptic	POS	O
+striatal	POS	O
+D2	POS	O
+DA	POS	O
+receptors	POS	O
+,	POS	O
+while	POS	O
+at	POS	O
+30	POS	O
+,	POS	O
+40	POS	O
+and	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+it	POS	O
+blocks	POS	O
+postsynaptic	POS	O
+striatal	POS	O
+D2	POS	O
+DA	POS	O
+receptors	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+at	POS	O
+5	POS	O
+,	POS	O
+10	POS	O
+and	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+trazodone	POS	O
+blocks	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+2A	POS	O
+and	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+2C	POS	O
+receptors	POS	O
+.	POS	O
+We	POS	O
+suggest	POS	O
+that	POS	O
+trazodone	POS	O
+(	POS	O
+5	POS	O
+,	POS	O
+10	POS	O
+and	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+,	POS	O
+by	POS	O
+blocking	POS	O
+the	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+2C	POS	O
+receptors	POS	O
+,	POS	O
+releases	POS	O
+the	POS	O
+nigrostriatal	POS	O
+DAergic	POS	O
+neurons	POS	O
+from	POS	O
+tonic	POS	O
+inhibition	POS	O
+caused	POS	O
+by	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+,	POS	O
+and	POS	O
+thereby	POS	O
+potentiates	POS	O
+dexamphetamine	POS	O
+stereotypy	POS	O
+and	POS	O
+antagonizes	POS	O
+haloperidol	POS	O
+catalepsy	POS	B-NP
+.	POS	O
+Swallowing	POS	B-NP
+abnormalities	POS	I-NP
+and	POS	O
+dyskinesia	POS	B-NP
+in	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+Gastrointestinal	POS	B-NP
+abnormalities	POS	I-NP
+in	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+PD	POS	B-NP
+)	POS	O
+have	POS	O
+been	POS	O
+known	POS	O
+for	POS	O
+almost	POS	O
+two	POS	O
+centuries	POS	O
+,	POS	O
+but	POS	O
+many	POS	O
+aspects	POS	O
+concerning	POS	O
+their	POS	O
+pathophysiology	POS	O
+have	POS	O
+not	POS	O
+been	POS	O
+completely	POS	O
+clarified	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+characterize	POS	O
+the	POS	O
+oropharyngeal	POS	O
+dynamics	POS	O
+in	POS	O
+PD	POS	B-NP
+patients	POS	O
+with	POS	O
+and	POS	O
+without	POS	O
+levodopa	POS	O
+-	POS	O
+induced	POS	O
+dyskinesia	POS	B-NP
+.	POS	O
+Fifteen	POS	O
+dyskinetic	POS	B-NP
+,	POS	O
+12	POS	O
+nondyskinetic	POS	B-NP
+patients	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+control	POS	O
+group	POS	O
+were	POS	O
+included	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+asked	POS	O
+about	POS	O
+dysphagia	POS	B-NP
+and	POS	O
+evaluated	POS	O
+with	POS	O
+the	POS	O
+Unified	POS	O
+Parkinson	POS	O
+'	POS	O
+s	POS	O
+Disease	POS	O
+Rating	POS	O
+Scale	POS	O
+Parts	POS	O
+II	POS	O
+and	POS	O
+III	POS	O
+and	POS	O
+the	POS	O
+Hoehn	POS	B-NP
+and	POS	O
+Yahr	POS	O
+scale	POS	O
+.	POS	O
+Deglutition	POS	B-NP
+was	POS	O
+assessed	POS	O
+using	POS	O
+modified	POS	O
+barium	POS	O
+swallow	POS	O
+with	POS	O
+videofluoroscopy	POS	O
+.	POS	O
+Nondyskinetic	POS	B-NP
+patients	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+the	POS	O
+dyskinetic	POS	B-NP
+ones	POS	O
+,	POS	O
+showed	POS	O
+less	POS	O
+oropharyngeal	POS	O
+swallowing	POS	O
+efficiency	POS	O
+(	POS	O
+OPSE	POS	O
+)	POS	O
+for	POS	O
+liquid	POS	O
+food	POS	O
+than	POS	O
+controls	POS	O
+(	POS	O
+Dunnett	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+.	POS	O
+Dyskinetic	POS	B-NP
+patients	POS	O
+tended	POS	O
+to	POS	O
+have	POS	O
+a	POS	O
+greater	POS	O
+OPSE	POS	O
+than	POS	O
+nondyskinetic	POS	O
+(	POS	O
+Dunnett	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+06	POS	O
+)	POS	O
+.	POS	O
+Patients	POS	O
+who	POS	O
+were	POS	O
+using	POS	O
+a	POS	O
+higher	POS	O
+dose	POS	O
+of	POS	O
+levodopa	POS	O
+had	POS	O
+a	POS	O
+greater	POS	O
+OPSE	POS	O
+and	POS	O
+a	POS	O
+trend	POS	O
+toward	POS	O
+a	POS	O
+smaller	POS	O
+oral	POS	O
+transit	POS	O
+time	POS	O
+(	POS	O
+Pearson	POS	O
+'	POS	O
+s	POS	O
+correlation	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+08	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+.	POS	O
+Neither	POS	O
+the	POS	O
+report	POS	O
+of	POS	O
+dysphagia	POS	B-NP
+nor	POS	O
+any	POS	O
+of	POS	O
+the	POS	O
+PD	POS	B-NP
+severity	POS	O
+parameters	POS	O
+correlated	POS	O
+to	POS	O
+the	POS	O
+videofluoroscopic	POS	O
+variables	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+current	POS	O
+study	POS	O
+,	POS	O
+dyskinetic	POS	B-NP
+patients	POS	O
+performed	POS	O
+better	POS	O
+in	POS	O
+swallowing	POS	O
+function	POS	O
+,	POS	O
+which	POS	O
+could	POS	O
+be	POS	O
+explained	POS	O
+on	POS	O
+the	POS	O
+basis	POS	O
+of	POS	O
+a	POS	O
+greater	POS	O
+levodopa	POS	O
+dose	POS	O
+.	POS	O
+Our	POS	O
+results	POS	O
+suggest	POS	O
+a	POS	O
+role	POS	O
+for	POS	O
+levodopa	POS	O
+in	POS	O
+the	POS	O
+oral	POS	O
+phase	POS	O
+of	POS	O
+deglutition	POS	O
+and	POS	O
+confirm	POS	O
+that	POS	O
+dysphagia	POS	B-NP
+is	POS	O
+not	POS	O
+a	POS	O
+good	POS	O
+predictor	POS	O
+of	POS	O
+deglutition	POS	O
+alterations	POS	O
+in	POS	O
+PD	POS	B-NP
+.	POS	O
+Inhibition	POS	O
+of	POS	O
+nuclear	POS	O
+factor	POS	O
+-	POS	O
+kappaB	POS	O
+activation	POS	O
+attenuates	POS	O
+tubulointerstitial	POS	B-NP
+nephritis	POS	I-NP
+induced	POS	O
+by	POS	O
+gentamicin	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Animals	POS	O
+treated	POS	O
+with	POS	O
+gentamicin	POS	O
+can	POS	O
+show	POS	O
+residual	POS	O
+areas	POS	O
+of	POS	O
+interstitial	POS	B-NP
+fibrosis	POS	I-NP
+in	POS	O
+the	POS	O
+renal	POS	O
+cortex	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+investigated	POS	O
+the	POS	O
+expression	POS	O
+of	POS	O
+nuclear	POS	O
+factor	POS	O
+-	POS	O
+kappaB	POS	O
+(	POS	O
+NF	POS	O
+-	POS	O
+kappaB	POS	O
+)	POS	O
+,	POS	O
+mitogen	POS	O
+-	POS	O
+activated	POS	O
+protein	POS	O
+(	POS	O
+MAP	POS	O
+)	POS	O
+kinases	POS	O
+and	POS	O
+macrophages	POS	O
+in	POS	O
+the	POS	O
+renal	POS	O
+cortex	POS	O
+and	POS	O
+structural	POS	O
+and	POS	O
+functional	POS	O
+renal	POS	O
+changes	POS	O
+of	POS	O
+rats	POS	O
+treated	POS	O
+with	POS	O
+gentamicin	POS	O
+or	POS	O
+gentamicin	POS	O
++	POS	O
+pyrrolidine	POS	O
+dithiocarbamate	POS	O
+(	POS	O
+PDTC	POS	O
+)	POS	O
+,	POS	O
+an	POS	O
+NF	POS	O
+-	POS	O
+kappaB	POS	O
+inhibitor	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+38	POS	O
+female	POS	O
+Wistar	POS	O
+rats	POS	O
+were	POS	O
+injected	POS	O
+with	POS	O
+gentamicin	POS	O
+,	POS	O
+40	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+twice	POS	O
+a	POS	O
+day	POS	O
+for	POS	O
+9	POS	O
+days	POS	O
+,	POS	O
+38	POS	O
+with	POS	O
+gentamicin	POS	O
++	POS	O
+PDTC	POS	O
+,	POS	O
+and	POS	O
+28	POS	O
+with	POS	O
+0	POS	O
+.	POS	O
+15	POS	O
+M	POS	O
+NaCl	POS	O
+solution	POS	O
+.	POS	O
+The	POS	O
+animals	POS	O
+were	POS	O
+killed	POS	O
+5	POS	O
+and	POS	O
+30	POS	O
+days	POS	O
+after	POS	O
+these	POS	O
+injections	POS	O
+and	POS	O
+the	POS	O
+kidneys	POS	O
+were	POS	O
+removed	POS	O
+for	POS	O
+histological	POS	O
+and	POS	O
+immunohistochemical	POS	O
+studies	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+of	POS	O
+the	POS	O
+immunohistochemical	POS	O
+studies	POS	O
+were	POS	O
+scored	POS	O
+according	POS	O
+to	POS	O
+the	POS	O
+extent	POS	O
+of	POS	O
+staining	POS	O
+.	POS	O
+The	POS	O
+fractional	POS	O
+interstitial	POS	O
+area	POS	O
+was	POS	O
+determined	POS	O
+by	POS	O
+morphometry	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Gentamicin	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+presented	POS	O
+a	POS	O
+transitory	POS	O
+increase	POS	O
+in	POS	O
+plasma	POS	O
+creatinine	POS	O
+levels	POS	O
+.	POS	O
+Increased	POS	O
+ED	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+MAP	POS	O
+kinases	POS	O
+and	POS	O
+NF	POS	O
+-	POS	O
+kappaB	POS	O
+staining	POS	O
+were	POS	O
+also	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+renal	POS	O
+cortex	POS	O
+from	POS	O
+all	POS	O
+gentamicin	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+compared	POS	O
+to	POS	O
+control	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+animals	POS	O
+killed	POS	O
+on	POS	O
+day	POS	O
+30	POS	O
+also	POS	O
+presented	POS	O
+fibrosis	POS	B-NP
+in	POS	O
+the	POS	O
+renal	POS	O
+cortex	POS	O
+despite	POS	O
+the	POS	O
+recovery	POS	O
+of	POS	O
+renal	POS	O
+function	POS	O
+.	POS	O
+Treatment	POS	O
+with	POS	O
+PDTC	POS	O
+reduced	POS	O
+the	POS	O
+functional	POS	O
+and	POS	O
+structural	POS	O
+changes	POS	O
+induced	POS	O
+by	POS	O
+gentamicin	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+These	POS	O
+data	POS	O
+show	POS	O
+that	POS	O
+inhibition	POS	O
+of	POS	O
+NF	POS	O
+-	POS	O
+kappaB	POS	O
+activation	POS	O
+attenuates	POS	O
+tubulointerstitial	POS	B-NP
+nephritis	POS	I-NP
+induced	POS	O
+by	POS	O
+gentamicin	POS	O
+.	POS	O
+Glucose	POS	O
+metabolism	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+schizophrenia	POS	B-NP
+treated	POS	O
+with	POS	O
+atypical	POS	O
+antipsychotic	POS	O
+agents	POS	O
+:	POS	O
+a	POS	O
+frequently	POS	O
+sampled	POS	O
+intravenous	POS	O
+glucose	POS	O
+tolerance	POS	O
+test	POS	O
+and	POS	O
+minimal	POS	O
+model	POS	O
+analysis	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+While	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+new	POS	O
+-	POS	O
+onset	POS	O
+diabetes	POS	B-NP
+mellitus	POS	I-NP
+may	POS	O
+be	POS	O
+increasing	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+schizophrenia	POS	B-NP
+treated	POS	O
+with	POS	O
+certain	POS	O
+atypical	POS	O
+antipsychotic	POS	O
+agents	POS	O
+,	POS	O
+it	POS	O
+remains	POS	O
+unclear	POS	O
+whether	POS	O
+atypical	POS	O
+agents	POS	O
+are	POS	O
+directly	POS	O
+affecting	POS	O
+glucose	POS	O
+metabolism	POS	O
+or	POS	O
+simply	POS	O
+increasing	POS	O
+known	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+diabetes	POS	B-NP
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+study	POS	O
+the	POS	O
+2	POS	O
+drugs	POS	O
+most	POS	O
+clearly	POS	O
+implicated	POS	O
+(	POS	O
+clozapine	POS	O
+and	POS	O
+olanzapine	POS	O
+)	POS	O
+and	POS	O
+risperidone	POS	O
+using	POS	O
+a	POS	O
+frequently	POS	O
+sampled	POS	O
+intravenous	POS	O
+glucose	POS	O
+tolerance	POS	O
+test	POS	O
+.	POS	O
+DESIGN	POS	O
+:	POS	O
+A	POS	O
+cross	POS	O
+-	POS	O
+sectional	POS	O
+design	POS	O
+in	POS	O
+stable	POS	O
+,	POS	O
+treated	POS	O
+patients	POS	O
+with	POS	O
+schizophrenia	POS	B-NP
+evaluated	POS	O
+using	POS	O
+a	POS	O
+frequently	POS	O
+sampled	POS	O
+intravenous	POS	O
+glucose	POS	O
+tolerance	POS	O
+test	POS	O
+and	POS	O
+the	POS	O
+Bergman	POS	O
+minimal	POS	O
+model	POS	O
+analysis	POS	O
+.	POS	O
+SETTING	POS	O
+:	POS	O
+Subjects	POS	O
+were	POS	O
+recruited	POS	O
+from	POS	O
+an	POS	O
+urban	POS	O
+community	POS	O
+mental	POS	O
+health	POS	O
+clinic	POS	O
+and	POS	O
+were	POS	O
+studied	POS	O
+at	POS	O
+a	POS	O
+general	POS	O
+clinical	POS	O
+research	POS	O
+center	POS	O
+.	POS	O
+Patients	POS	O
+Fifty	POS	O
+subjects	POS	O
+signed	POS	O
+informed	POS	O
+consent	POS	O
+and	POS	O
+41	POS	O
+underwent	POS	O
+the	POS	O
+frequently	POS	O
+sampled	POS	O
+intravenous	POS	O
+glucose	POS	O
+tolerance	POS	O
+test	POS	O
+.	POS	O
+Thirty	POS	O
+-	POS	O
+six	POS	O
+nonobese	POS	O
+subjects	POS	O
+with	POS	O
+schizophrenia	POS	B-NP
+or	POS	O
+schizoaffective	POS	B-NP
+disorder	POS	I-NP
+,	POS	O
+matched	POS	O
+by	POS	O
+body	POS	O
+mass	POS	O
+index	POS	O
+and	POS	O
+treated	POS	O
+with	POS	O
+either	POS	O
+clozapine	POS	O
+,	POS	O
+olanzapine	POS	O
+,	POS	O
+or	POS	O
+risperidone	POS	O
+,	POS	O
+were	POS	O
+included	POS	O
+in	POS	O
+the	POS	O
+analysis	POS	O
+.	POS	O
+MAIN	POS	O
+OUTCOME	POS	O
+MEASURES	POS	O
+:	POS	O
+Fasting	POS	O
+plasma	POS	O
+glucose	POS	O
+and	POS	O
+fasting	POS	O
+serum	POS	O
+insulin	POS	O
+levels	POS	O
+,	POS	O
+insulin	POS	O
+sensitivity	POS	O
+index	POS	O
+,	POS	O
+homeostasis	POS	O
+model	POS	O
+assessment	POS	O
+of	POS	O
+insulin	POS	B-NP
+resistance	POS	I-NP
+,	POS	O
+and	POS	O
+glucose	POS	O
+effectiveness	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+mean	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+SD	POS	O
+duration	POS	O
+of	POS	O
+treatment	POS	O
+with	POS	O
+the	POS	O
+identified	POS	O
+atypical	POS	O
+antipsychotic	POS	O
+agent	POS	O
+was	POS	O
+68	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+28	POS	O
+.	POS	O
+9	POS	O
+months	POS	O
+(	POS	O
+clozapine	POS	O
+)	POS	O
+,	POS	O
+29	POS	O
+.	POS	O
+5	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+17	POS	O
+.	POS	O
+5	POS	O
+months	POS	O
+(	POS	O
+olanzapine	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+40	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+33	POS	O
+.	POS	O
+7	POS	O
+(	POS	O
+risperidone	POS	O
+)	POS	O
+.	POS	O
+Fasting	POS	O
+serum	POS	O
+insulin	POS	O
+concentrations	POS	O
+differed	POS	O
+among	POS	O
+groups	POS	O
+(	POS	O
+F	POS	O
+(	POS	O
+33	POS	O
+)	POS	O
+=	POS	O
+3	POS	O
+.	POS	O
+35	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+047	POS	O
+)	POS	O
+(	POS	O
+clozapine	POS	O
+>	POS	O
+olanzapine	POS	O
+>	POS	O
+risperidone	POS	O
+)	POS	O
+with	POS	O
+significant	POS	O
+differences	POS	O
+between	POS	O
+clozapine	POS	O
+and	POS	O
+risperidone	POS	O
+(	POS	O
+t	POS	O
+(	POS	O
+33	POS	O
+)	POS	O
+=	POS	O
+2	POS	O
+.	POS	O
+32	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+03	POS	O
+)	POS	O
+and	POS	O
+olanzapine	POS	O
+and	POS	O
+risperidone	POS	O
+(	POS	O
+t	POS	O
+(	POS	O
+33	POS	O
+)	POS	O
+=	POS	O
+2	POS	O
+.	POS	O
+15	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+04	POS	O
+)	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+difference	POS	O
+in	POS	O
+insulin	POS	O
+sensitivity	POS	O
+index	POS	O
+among	POS	O
+groups	POS	O
+(	POS	O
+F	POS	O
+(	POS	O
+33	POS	O
+)	POS	O
+=	POS	O
+10	POS	O
+.	POS	O
+66	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+(	POS	O
+clozapine	POS	O
+<	POS	O
+olanzapine	POS	O
+<	POS	O
+risperidone	POS	O
+)	POS	O
+,	POS	O
+with	POS	O
+subjects	POS	O
+who	POS	O
+received	POS	O
+clozapine	POS	O
+and	POS	O
+olanzapine	POS	O
+exhibiting	POS	O
+significant	POS	O
+insulin	POS	B-NP
+resistance	POS	I-NP
+compared	POS	O
+with	POS	O
+subjects	POS	O
+who	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+risperidone	POS	O
+(	POS	O
+clozapine	POS	O
+vs	POS	O
+risperidone	POS	O
+,	POS	O
+t	POS	O
+(	POS	O
+33	POS	O
+)	POS	O
+=	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+29	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+001	POS	O
+;	POS	O
+olanzapine	POS	O
+vs	POS	O
+risperidone	POS	O
+,	POS	O
+t	POS	O
+(	POS	O
+33	POS	O
+)	POS	O
+=	POS	O
+-	POS	O
+3	POS	O
+.	POS	O
+62	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+001	POS	O
+[	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+001	POS	O
+]	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+homeostasis	POS	O
+model	POS	O
+assessment	POS	O
+of	POS	O
+insulin	POS	O
+resistance	POS	O
+also	POS	O
+differed	POS	O
+significantly	POS	O
+among	POS	O
+groups	POS	O
+(	POS	O
+F	POS	O
+(	POS	O
+33	POS	O
+)	POS	O
+=	POS	O
+4	POS	O
+.	POS	O
+92	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+(	POS	O
+clozapine	POS	O
+>	POS	O
+olanzapine	POS	O
+>	POS	O
+risperidone	POS	O
+)	POS	O
+(	POS	O
+clozapine	POS	O
+vs	POS	O
+risperidone	POS	O
+,	POS	O
+t	POS	O
+(	POS	O
+33	POS	O
+)	POS	O
+=	POS	O
+2	POS	O
+.	POS	O
+94	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+006	POS	O
+;	POS	O
+olanzapine	POS	O
+vs	POS	O
+risperidone	POS	O
+,	POS	O
+t	POS	O
+(	POS	O
+33	POS	O
+)	POS	O
+=	POS	O
+2	POS	O
+.	POS	O
+42	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+difference	POS	O
+among	POS	O
+groups	POS	O
+in	POS	O
+glucose	POS	O
+effectiveness	POS	O
+(	POS	O
+F	POS	O
+(	POS	O
+30	POS	O
+)	POS	O
+=	POS	O
+4	POS	O
+.	POS	O
+18	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+(	POS	O
+clozapine	POS	O
+<	POS	O
+olanzapine	POS	O
+<	POS	O
+risperidone	POS	O
+)	POS	O
+with	POS	O
+significant	POS	O
+differences	POS	O
+between	POS	O
+clozapine	POS	O
+and	POS	O
+risperidone	POS	O
+(	POS	O
+t	POS	O
+(	POS	O
+30	POS	O
+)	POS	O
+=	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+59	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+and	POS	O
+olanzapine	POS	O
+and	POS	O
+risperidone	POS	O
+(	POS	O
+t	POS	O
+(	POS	O
+30	POS	O
+)	POS	O
+=	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+34	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+03	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Both	POS	O
+nonobese	POS	O
+clozapine	POS	O
+-	POS	O
+and	POS	O
+olanzapine	POS	O
+-	POS	O
+treated	POS	O
+groups	POS	O
+displayed	POS	O
+significant	POS	O
+insulin	POS	B-NP
+resistance	POS	I-NP
+and	POS	O
+impairment	POS	O
+of	POS	O
+glucose	POS	O
+effectiveness	POS	O
+compared	POS	O
+with	POS	O
+risperidone	POS	O
+-	POS	O
+treated	POS	O
+subjects	POS	O
+.	POS	O
+Patients	POS	O
+taking	POS	O
+clozapine	POS	O
+and	POS	O
+olanzapine	POS	O
+must	POS	O
+be	POS	O
+examined	POS	O
+for	POS	O
+insulin	POS	B-NP
+resistance	POS	I-NP
+and	POS	O
+its	POS	O
+consequences	POS	O
+.	POS	O
+Thoracic	POS	B-NP
+hematomyelia	POS	I-NP
+secondary	POS	O
+to	POS	O
+coumadin	POS	O
+anticoagulant	POS	O
+therapy	POS	O
+:	POS	O
+a	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+thoracic	POS	B-NP
+hematomyelia	POS	I-NP
+secondary	POS	O
+to	POS	O
+anticoagulant	POS	O
+therapy	POS	O
+is	POS	O
+presented	POS	O
+.	POS	O
+Clinical	POS	O
+features	POS	O
+,	POS	O
+similar	POS	O
+to	POS	O
+2	POS	O
+other	POS	O
+previously	POS	O
+reported	POS	O
+cases	POS	O
+,	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+A	POS	O
+high	POS	O
+index	POS	O
+of	POS	O
+suspicion	POS	O
+may	POS	O
+lead	POS	O
+to	POS	O
+a	POS	O
+quick	POS	O
+diagnostic	POS	O
+procedure	POS	O
+and	POS	O
+successful	POS	O
+decompressive	POS	O
+surgery	POS	O
+.	POS	O
+Mania	POS	B-NP
+associated	POS	O
+with	POS	O
+fluoxetine	POS	O
+treatment	POS	O
+in	POS	O
+adolescents	POS	O
+.	POS	O
+Fluoxetine	POS	O
+,	POS	O
+a	POS	O
+selective	POS	O
+serotonin	POS	O
+reuptake	POS	O
+inhibitor	POS	O
+,	POS	O
+is	POS	O
+gaining	POS	O
+increased	POS	O
+acceptance	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+adolescent	POS	B-NP
+depression	POS	I-NP
+.	POS	O
+Generally	POS	O
+safe	POS	O
+and	POS	O
+well	POS	O
+tolerated	POS	O
+by	POS	O
+adults	POS	O
+,	POS	O
+fluoxetine	POS	O
+has	POS	O
+been	POS	O
+reported	POS	O
+to	POS	O
+induce	POS	O
+mania	POS	B-NP
+.	POS	O
+The	POS	O
+cases	POS	O
+of	POS	O
+five	POS	O
+depressed	POS	B-NP
+adolescents	POS	O
+,	POS	O
+14	POS	O
+-	POS	O
+16	POS	O
+years	POS	O
+of	POS	O
+age	POS	O
+,	POS	O
+who	POS	O
+developed	POS	O
+mania	POS	B-NP
+during	POS	O
+pharmacotherapy	POS	O
+with	POS	O
+fluoxetine	POS	O
+,	POS	O
+are	POS	O
+reported	POS	O
+here	POS	O
+.	POS	O
+Apparent	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+mania	POS	B-NP
+or	POS	O
+hypomania	POS	B-NP
+during	POS	O
+fluoxetine	POS	O
+pharmacotherapy	POS	O
+in	POS	O
+this	POS	O
+population	POS	O
+were	POS	O
+the	POS	O
+combination	POS	O
+of	POS	O
+attention	POS	B-NP
+-	POS	I-NP
+deficit	POS	I-NP
+hyperactivity	POS	I-NP
+disorder	POS	I-NP
+and	POS	O
+affective	POS	B-NP
+instability	POS	I-NP
+;	POS	O
+major	POS	B-NP
+depression	POS	I-NP
+with	POS	O
+psychotic	POS	B-NP
+features	POS	O
+;	POS	O
+a	POS	O
+family	POS	O
+history	POS	O
+of	POS	O
+affective	POS	B-NP
+disorder	POS	I-NP
+,	POS	O
+especially	POS	O
+bipolar	POS	B-NP
+disorder	POS	I-NP
+;	POS	O
+and	POS	O
+a	POS	O
+diagnosis	POS	O
+of	POS	O
+bipolar	POS	B-NP
+disorder	POS	I-NP
+.	POS	O
+Further	POS	O
+study	POS	O
+is	POS	O
+needed	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+optimal	POS	O
+dosage	POS	O
+and	POS	O
+to	POS	O
+identify	POS	O
+risk	POS	O
+factors	POS	O
+that	POS	O
+increase	POS	O
+individual	POS	O
+vulnerability	POS	O
+to	POS	O
+fluoxetine	POS	O
+induced	POS	O
+mania	POS	B-NP
+in	POS	O
+adolescents	POS	O
+.	POS	O
+Acute	POS	B-NP
+renal	POS	I-NP
+insufficiency	POS	I-NP
+after	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+melphalan	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+primary	POS	O
+systemic	POS	B-NP
+amyloidosis	POS	I-NP
+during	POS	O
+stem	POS	O
+cell	POS	O
+transplantation	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Patients	POS	O
+with	POS	O
+primary	POS	O
+systemic	POS	B-NP
+amyloidosis	POS	I-NP
+(	POS	O
+AL	POS	O
+)	POS	O
+have	POS	O
+a	POS	O
+poor	POS	O
+prognosis	POS	O
+.	POS	O
+Median	POS	O
+survival	POS	O
+time	POS	O
+from	POS	O
+standard	POS	O
+treatments	POS	O
+is	POS	O
+only	POS	O
+17	POS	O
+months	POS	O
+.	POS	O
+High	POS	O
+-	POS	O
+dose	POS	O
+intravenous	POS	O
+melphalan	POS	O
+followed	POS	O
+by	POS	O
+peripheral	POS	O
+blood	POS	O
+stem	POS	O
+cell	POS	O
+transplant	POS	O
+(	POS	O
+PBSCT	POS	O
+)	POS	O
+appears	POS	O
+to	POS	O
+be	POS	O
+the	POS	O
+most	POS	O
+promising	POS	O
+therapy	POS	O
+,	POS	O
+but	POS	O
+treatment	POS	O
+mortality	POS	O
+can	POS	O
+be	POS	O
+high	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+have	POS	O
+noted	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+insufficiency	POS	I-NP
+immediately	POS	O
+after	POS	O
+melphalan	POS	O
+conditioning	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+was	POS	O
+undertaken	POS	O
+to	POS	O
+further	POS	O
+examine	POS	O
+its	POS	O
+risk	POS	O
+factors	POS	O
+and	POS	O
+impact	POS	O
+on	POS	O
+posttransplant	POS	O
+mortality	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Consecutive	POS	O
+AL	POS	O
+patients	POS	O
+who	POS	O
+underwent	POS	O
+PBSCT	POS	O
+were	POS	O
+studied	POS	O
+retrospectively	POS	O
+.	POS	O
+Acute	POS	B-NP
+renal	POS	I-NP
+insufficiency	POS	I-NP
+(	POS	O
+ARI	POS	B-NP
+)	POS	O
+after	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+melphalan	POS	O
+was	POS	O
+defined	POS	O
+by	POS	O
+a	POS	O
+minimum	POS	O
+increase	POS	O
+of	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+(	POS	O
+44	POS	O
+micromol	POS	O
+/	POS	O
+L	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+serum	POS	O
+creatinine	POS	O
+level	POS	O
+that	POS	O
+is	POS	O
+greater	POS	O
+than	POS	O
+50	POS	O
+%	POS	O
+of	POS	O
+baseline	POS	O
+immediately	POS	O
+after	POS	O
+conditioning	POS	O
+.	POS	O
+Urine	POS	O
+sediment	POS	O
+score	POS	O
+was	POS	O
+the	POS	O
+sum	POS	O
+of	POS	O
+the	POS	O
+individual	POS	O
+types	POS	O
+of	POS	O
+sediment	POS	O
+identified	POS	O
+on	POS	O
+urine	POS	O
+microscopy	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Of	POS	O
+the	POS	O
+80	POS	O
+patients	POS	O
+studied	POS	O
+,	POS	O
+ARI	POS	B-NP
+developed	POS	O
+in	POS	O
+18	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+after	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+melphalan	POS	O
+.	POS	O
+Univariate	POS	O
+analysis	POS	O
+identified	POS	O
+age	POS	O
+,	POS	O
+hypoalbuminemia	POS	B-NP
+,	POS	O
+heavy	POS	O
+proteinuria	POS	B-NP
+,	POS	O
+diuretic	POS	O
+use	POS	O
+,	POS	O
+and	POS	O
+urine	POS	O
+sediment	POS	O
+score	POS	O
+(	POS	O
+>	POS	O
+3	POS	O
+)	POS	O
+as	POS	O
+risk	POS	O
+factors	POS	O
+.	POS	O
+Age	POS	O
+and	POS	O
+urine	POS	O
+sediment	POS	O
+score	POS	O
+remained	POS	O
+independently	POS	O
+significant	POS	O
+risk	POS	O
+factors	POS	O
+in	POS	O
+the	POS	O
+multivariate	POS	O
+analysis	POS	O
+.	POS	O
+Patients	POS	O
+who	POS	O
+had	POS	O
+ARI	POS	B-NP
+after	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+melphalan	POS	O
+underwent	POS	O
+dialysis	POS	O
+more	POS	O
+often	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+007	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+had	POS	O
+a	POS	O
+worse	POS	O
+1	POS	O
+-	POS	O
+year	POS	O
+survival	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+03	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+The	POS	O
+timing	POS	O
+of	POS	O
+renal	POS	B-NP
+injury	POS	I-NP
+strongly	POS	O
+suggests	POS	O
+melphalan	POS	O
+as	POS	O
+the	POS	O
+causative	POS	O
+agent	POS	O
+.	POS	O
+Ongoing	POS	O
+tubular	POS	B-NP
+injury	POS	I-NP
+may	POS	O
+be	POS	O
+a	POS	O
+prerequisite	POS	O
+for	POS	O
+renal	POS	B-NP
+injury	POS	I-NP
+by	POS	O
+melphalan	POS	O
+as	POS	O
+evidenced	POS	O
+by	POS	O
+the	POS	O
+active	POS	O
+urinary	POS	O
+sediment	POS	O
+.	POS	O
+Development	POS	O
+of	POS	O
+ARI	POS	O
+adversely	POS	O
+affected	POS	O
+the	POS	O
+outcome	POS	O
+after	POS	O
+PBSCT	POS	O
+.	POS	O
+Effective	POS	O
+preventive	POS	O
+measures	POS	O
+may	POS	O
+help	POS	O
+decrease	POS	O
+the	POS	O
+treatment	POS	O
+mortality	POS	O
+of	POS	O
+PBSCT	POS	O
+in	POS	O
+AL	POS	O
+patients	POS	O
+.	POS	O
+Focal	POS	B-NP
+cerebral	POS	I-NP
+ischemia	POS	I-NP
+in	POS	O
+rats	POS	O
+:	POS	O
+effect	POS	O
+of	POS	O
+phenylephrine	POS	O
+-	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+during	POS	O
+reperfusion	POS	O
+.	POS	O
+After	POS	O
+180	POS	O
+min	POS	O
+of	POS	O
+temporary	POS	O
+middle	POS	O
+cerebral	POS	B-NP
+artery	POS	I-NP
+occlusion	POS	I-NP
+in	POS	O
+spontaneously	POS	O
+hypertensive	POS	B-NP
+rats	POS	O
+,	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+phenylephrine	POS	O
+-	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+on	POS	O
+ischemic	POS	B-NP
+brain	POS	I-NP
+injury	POS	I-NP
+and	POS	O
+blood	POS	O
+-	POS	O
+brain	POS	O
+barrier	POS	O
+permeability	POS	O
+was	POS	O
+determined	POS	O
+.	POS	O
+Blood	POS	O
+pressure	POS	O
+was	POS	O
+manipulated	POS	O
+by	POS	O
+one	POS	O
+of	POS	O
+the	POS	O
+following	POS	O
+schedules	POS	O
+during	POS	O
+120	POS	O
+min	POS	O
+of	POS	O
+reperfusion	POS	O
+:	POS	O
+Control	POS	O
+,	POS	O
+normotensive	POS	O
+reperfusion	POS	O
+;	POS	O
+90	POS	O
+/	POS	O
+hypertension	POS	B-NP
+(	POS	O
+90	POS	O
+/	POS	O
+HTN	POS	O
+)	POS	O
+,	POS	O
+blood	POS	O
+pressure	POS	O
+was	POS	O
+increased	POS	O
+by	POS	O
+35	POS	O
+mm	POS	O
+Hg	POS	O
+during	POS	O
+the	POS	O
+initial	POS	O
+90	POS	O
+min	POS	O
+of	POS	O
+reperfusion	POS	O
+only	POS	O
+;	POS	O
+15	POS	O
+/	POS	O
+hypertension	POS	B-NP
+(	POS	O
+15	POS	O
+/	POS	O
+HTN	POS	O
+)	POS	O
+,	POS	O
+normotensive	POS	O
+reperfusion	POS	O
+for	POS	O
+30	POS	O
+min	POS	O
+followed	POS	O
+by	POS	O
+15	POS	O
+min	POS	O
+of	POS	O
+hypertension	POS	B-NP
+and	POS	O
+75	POS	O
+min	POS	O
+of	POS	O
+normotension	POS	O
+.	POS	O
+Part	POS	O
+A	POS	O
+,	POS	O
+for	POS	O
+eight	POS	O
+rats	POS	O
+in	POS	O
+each	POS	O
+group	POS	O
+brain	POS	B-NP
+injury	POS	I-NP
+was	POS	O
+evaluated	POS	O
+by	POS	O
+staining	POS	O
+tissue	POS	O
+using	POS	O
+2	POS	O
+,	POS	O
+3	POS	O
+,	POS	O
+5	POS	O
+-	POS	O
+triphenyltetrazolium	POS	O
+chloride	POS	O
+and	POS	O
+edema	POS	B-NP
+was	POS	O
+evaluated	POS	O
+by	POS	O
+microgravimetry	POS	O
+.	POS	O
+Part	POS	O
+B	POS	O
+,	POS	O
+for	POS	O
+eight	POS	O
+different	POS	O
+rats	POS	O
+in	POS	O
+each	POS	O
+group	POS	O
+blood	POS	O
+-	POS	O
+brain	POS	O
+barrier	POS	O
+permeability	POS	O
+was	POS	O
+evaluated	POS	O
+by	POS	O
+measuring	POS	O
+the	POS	O
+amount	POS	O
+and	POS	O
+extent	POS	O
+of	POS	O
+extravasation	POS	O
+of	POS	O
+Evans	POS	O
+Blue	POS	O
+dye	POS	O
+.	POS	O
+Brain	POS	O
+injury	POS	O
+(	POS	O
+percentage	POS	O
+of	POS	O
+the	POS	O
+ischemic	POS	O
+hemisphere	POS	O
+)	POS	O
+was	POS	O
+less	POS	O
+in	POS	O
+the	POS	O
+15	POS	O
+/	POS	O
+HTN	POS	O
+group	POS	O
+(	POS	O
+16	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+,	POS	O
+mean	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+SD	POS	O
+)	POS	O
+versus	POS	O
+the	POS	O
+90	POS	O
+/	POS	O
+HTN	POS	O
+group	POS	O
+(	POS	O
+30	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+)	POS	O
+,	POS	O
+which	POS	O
+was	POS	O
+in	POS	O
+turn	POS	O
+less	POS	O
+than	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+(	POS	O
+42	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+5	POS	O
+)	POS	O
+.	POS	O
+Specific	POS	O
+gravity	POS	O
+was	POS	O
+greater	POS	O
+in	POS	O
+the	POS	O
+15	POS	O
+/	POS	O
+HTN	POS	O
+group	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+043	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+002	POS	O
+)	POS	O
+versus	POS	O
+the	POS	O
+90	POS	O
+/	POS	O
+HTN	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+036	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+003	POS	O
+)	POS	O
+and	POS	O
+control	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+037	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+003	POS	O
+)	POS	O
+groups	POS	O
+.	POS	O
+Evans	POS	O
+Blue	POS	O
+(	POS	O
+mug	POS	O
+g	POS	O
+-	POS	O
+1	POS	O
+of	POS	O
+brain	POS	O
+tissue	POS	O
+)	POS	O
+was	POS	O
+greater	POS	O
+in	POS	O
+the	POS	O
+90	POS	O
+/	POS	O
+HTN	POS	O
+group	POS	O
+(	POS	O
+24	POS	O
+.	POS	O
+4	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+0	POS	O
+)	POS	O
+versus	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+(	POS	O
+12	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+1	POS	O
+)	POS	O
+,	POS	O
+which	POS	O
+was	POS	O
+in	POS	O
+turn	POS	O
+greater	POS	O
+than	POS	O
+the	POS	O
+15	POS	O
+/	POS	O
+HTN	POS	O
+group	POS	O
+(	POS	O
+7	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+3	POS	O
+.	POS	O
+2	POS	O
+)	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+supports	POS	O
+a	POS	O
+hypothesis	POS	O
+that	POS	O
+during	POS	O
+reperfusion	POS	O
+,	POS	O
+a	POS	O
+short	POS	O
+interval	POS	O
+of	POS	O
+hypertension	POS	B-NP
+decreases	POS	O
+brain	POS	B-NP
+injury	POS	I-NP
+and	POS	O
+edema	POS	B-NP
+;	POS	O
+and	POS	O
+that	POS	O
+sustained	POS	O
+hypertension	POS	B-NP
+increases	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+vasogenic	POS	B-NP
+edema	POS	I-NP
+.	POS	O
+People	POS	O
+aged	POS	O
+over	POS	O
+75	POS	O
+in	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+on	POS	O
+warfarin	POS	O
+:	POS	O
+the	POS	O
+rate	POS	O
+of	POS	O
+major	POS	O
+hemorrhage	POS	B-NP
+and	POS	O
+stroke	POS	B-NP
+in	POS	O
+more	POS	O
+than	POS	O
+500	POS	O
+patient	POS	O
+-	POS	O
+years	POS	O
+of	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+To	POS	O
+determine	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+major	POS	O
+hemorrhage	POS	B-NP
+and	POS	O
+stroke	POS	B-NP
+in	POS	O
+people	POS	O
+aged	POS	O
+76	POS	O
+and	POS	O
+older	POS	O
+with	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+on	POS	O
+adjusted	POS	O
+-	POS	O
+dose	POS	O
+warfarin	POS	O
+who	POS	O
+had	POS	O
+been	POS	O
+recently	POS	O
+been	POS	O
+admitted	POS	O
+to	POS	O
+hospital	POS	O
+.	POS	O
+DESIGN	POS	O
+:	POS	O
+A	POS	O
+retrospective	POS	O
+observational	POS	O
+cohort	POS	O
+study	POS	O
+.	POS	O
+SETTING	POS	O
+:	POS	O
+A	POS	O
+major	POS	O
+healthcare	POS	O
+network	POS	O
+involving	POS	O
+four	POS	O
+tertiary	POS	O
+hospitals	POS	O
+.	POS	O
+PARTICIPANTS	POS	O
+:	POS	O
+Two	POS	O
+hundred	POS	O
+thirty	POS	O
+-	POS	O
+five	POS	O
+patients	POS	O
+aged	POS	O
+76	POS	O
+and	POS	O
+older	POS	O
+admitted	POS	O
+to	POS	O
+a	POS	O
+major	POS	O
+healthcare	POS	O
+network	POS	O
+between	POS	O
+July	POS	O
+1	POS	O
+,	POS	O
+2001	POS	O
+,	POS	O
+and	POS	O
+June	POS	O
+30	POS	O
+,	POS	O
+2002	POS	O
+,	POS	O
+with	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+on	POS	O
+warfarin	POS	O
+were	POS	O
+enrolled	POS	O
+.	POS	O
+MEASUREMENTS	POS	O
+:	POS	O
+Information	POS	O
+regarding	POS	O
+major	POS	O
+bleeding	POS	B-NP
+episodes	POS	O
+,	POS	O
+strokes	POS	B-NP
+,	POS	O
+and	POS	O
+warfarin	POS	O
+use	POS	O
+was	POS	O
+obtained	POS	O
+from	POS	O
+patients	POS	O
+,	POS	O
+relatives	POS	O
+,	POS	O
+primary	POS	O
+physicians	POS	O
+,	POS	O
+and	POS	O
+medical	POS	O
+records	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Two	POS	O
+hundred	POS	O
+twenty	POS	O
+-	POS	O
+eight	POS	O
+patients	POS	O
+(	POS	O
+42	POS	O
+%	POS	O
+men	POS	O
+)	POS	O
+with	POS	O
+a	POS	O
+mean	POS	O
+age	POS	O
+of	POS	O
+81	POS	O
+.	POS	O
+1	POS	O
+(	POS	O
+range	POS	O
+76	POS	O
+-	POS	O
+94	POS	O
+)	POS	O
+were	POS	O
+included	POS	O
+in	POS	O
+the	POS	O
+analysis	POS	O
+.	POS	O
+Total	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+on	POS	O
+warfarin	POS	O
+was	POS	O
+530	POS	O
+years	POS	O
+(	POS	O
+mean	POS	O
+28	POS	O
+months	POS	O
+)	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+53	POS	O
+major	POS	O
+hemorrhages	POS	B-NP
+,	POS	O
+for	POS	O
+an	POS	O
+annual	POS	O
+rate	POS	O
+of	POS	O
+10	POS	O
+.	POS	O
+0	POS	O
+%	POS	O
+,	POS	O
+including	POS	O
+24	POS	O
+(	POS	O
+45	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+)	POS	O
+life	POS	O
+-	POS	O
+threatening	POS	O
+and	POS	O
+five	POS	O
+(	POS	O
+9	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+fatal	POS	O
+bleeds	POS	B-NP
+.	POS	O
+The	POS	O
+annual	POS	O
+stroke	POS	B-NP
+rate	POS	O
+after	POS	O
+initiation	POS	O
+of	POS	O
+warfarin	POS	O
+was	POS	O
+2	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+The	POS	O
+rate	POS	O
+of	POS	O
+major	POS	O
+hemorrhage	POS	B-NP
+was	POS	O
+high	POS	O
+in	POS	O
+this	POS	O
+old	POS	O
+,	POS	O
+frail	POS	O
+group	POS	O
+,	POS	O
+but	POS	O
+excluding	POS	O
+fatalities	POS	B-NP
+,	POS	O
+resulted	POS	O
+in	POS	O
+no	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+sequelae	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+stroke	POS	B-NP
+rate	POS	O
+on	POS	O
+warfarin	POS	O
+was	POS	O
+low	POS	O
+,	POS	O
+demonstrating	POS	O
+how	POS	O
+effective	POS	O
+warfarin	POS	O
+treatment	POS	O
+is	POS	O
+.	POS	O
+Safety	POS	O
+of	POS	O
+celecoxib	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+adverse	POS	O
+skin	POS	O
+reactions	POS	O
+to	POS	O
+acetaminophen	POS	O
+(	POS	O
+paracetamol	POS	O
+)	POS	O
+and	POS	O
+nimesulide	POS	O
+associated	POS	O
+or	POS	O
+not	POS	O
+with	POS	O
+common	POS	O
+non	POS	O
+-	POS	O
+steroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Acetaminophen	POS	O
+(	POS	O
+paracetamol	POS	O
+-	POS	O
+-	POS	O
+P	POS	O
+)	POS	O
+and	POS	O
+Nimesulide	POS	O
+(	POS	O
+N	POS	O
+)	POS	O
+are	POS	O
+widely	POS	O
+used	POS	O
+analgesic	POS	O
+-	POS	O
+antipyretic	POS	O
+/	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+.	POS	O
+The	POS	O
+rate	POS	O
+of	POS	O
+adverse	POS	O
+hypersensitivity	POS	B-NP
+reactions	POS	O
+to	POS	O
+these	POS	O
+agents	POS	O
+is	POS	O
+generally	POS	O
+low	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+contrary	POS	O
+non	POS	O
+-	POS	O
+steroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+(	POS	O
+NSAIDs	POS	O
+)	POS	O
+are	POS	O
+commonly	POS	O
+involved	POS	O
+in	POS	O
+such	POS	O
+reactions	POS	O
+.	POS	O
+Celecoxib	POS	O
+(	POS	O
+CE	POS	O
+)	POS	O
+is	POS	O
+a	POS	O
+novel	POS	O
+drug	POS	O
+,	POS	O
+with	POS	O
+high	POS	O
+selectivity	POS	O
+and	POS	O
+affinity	POS	O
+for	POS	O
+COX	POS	O
+-	POS	O
+2	POS	O
+enzyme	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+We	POS	O
+evaluated	POS	O
+the	POS	O
+tolerability	POS	O
+of	POS	O
+CE	POS	O
+in	POS	O
+a	POS	O
+group	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+documented	POS	O
+history	POS	O
+of	POS	O
+adverse	POS	O
+cutaneous	POS	O
+reactions	POS	O
+to	POS	O
+P	POS	O
+and	POS	O
+N	POS	O
+associated	POS	O
+or	POS	O
+not	POS	O
+to	POS	O
+classic	POS	O
+NSAIDs	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+studied	POS	O
+9	POS	O
+patients	POS	O
+with	POS	O
+hypersensitivity	POS	B-NP
+to	POS	O
+P	POS	O
+and	POS	O
+N	POS	O
+with	POS	O
+or	POS	O
+without	POS	O
+associated	POS	O
+reactions	POS	O
+to	POS	O
+classic	POS	O
+NSAIDs	POS	O
+.	POS	O
+The	POS	O
+diagnosis	POS	O
+of	POS	O
+P	POS	O
+and	POS	O
+N	POS	O
+-	POS	O
+induced	POS	O
+skin	POS	O
+reactions	POS	O
+was	POS	O
+based	POS	O
+in	POS	O
+vivo	POS	O
+challenge	POS	O
+.	POS	O
+The	POS	O
+placebo	POS	O
+was	POS	O
+blindly	POS	O
+administered	POS	O
+at	POS	O
+the	POS	O
+beginning	POS	O
+of	POS	O
+each	POS	O
+challenge	POS	O
+.	POS	O
+After	POS	O
+three	POS	O
+days	POS	O
+,	POS	O
+a	POS	O
+cumulative	POS	O
+dosage	POS	O
+of	POS	O
+200	POS	O
+mg	POS	O
+of	POS	O
+CE	POS	O
+in	POS	O
+refracted	POS	O
+doses	POS	O
+were	POS	O
+given	POS	O
+.	POS	O
+After	POS	O
+2	POS	O
+-	POS	O
+3	POS	O
+days	POS	O
+,	POS	O
+a	POS	O
+single	POS	O
+dose	POS	O
+of	POS	O
+200	POS	O
+mg	POS	O
+was	POS	O
+administered	POS	O
+.	POS	O
+All	POS	O
+patients	POS	O
+were	POS	O
+observed	POS	O
+for	POS	O
+6	POS	O
+hours	POS	O
+after	POS	O
+each	POS	O
+challenge	POS	O
+,	POS	O
+and	POS	O
+controlled	POS	O
+again	POS	O
+after	POS	O
+24	POS	O
+hours	POS	O
+to	POS	O
+exclude	POS	O
+delayed	POS	O
+reactions	POS	O
+.	POS	O
+The	POS	O
+challenge	POS	O
+was	POS	O
+considered	POS	O
+positive	POS	O
+if	POS	O
+one	POS	O
+or	POS	O
+more	POS	O
+of	POS	O
+the	POS	O
+following	POS	O
+appeared	POS	O
+:	POS	O
+erythema	POS	B-NP
+,	POS	O
+rush	POS	B-NP
+or	POS	O
+urticaria	POS	B-NP
+-	POS	O
+angioedema	POS	B-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+No	POS	O
+reaction	POS	O
+was	POS	O
+observed	POS	O
+with	POS	O
+placebo	POS	O
+and	POS	O
+eight	POS	O
+patients	POS	O
+(	POS	O
+88	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+)	POS	O
+tolerated	POS	O
+CE	POS	O
+.	POS	O
+Only	POS	O
+one	POS	O
+patient	POS	O
+developed	POS	O
+a	POS	O
+moderate	POS	O
+angioedema	POS	B-NP
+of	POS	I-NP
+the	POS	I-NP
+lips	POS	I-NP
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Only	POS	O
+one	POS	O
+hypersensitivity	POS	B-NP
+reaction	POS	O
+to	POS	O
+CE	POS	O
+was	POS	O
+documented	POS	O
+among	POS	O
+9	POS	O
+P	POS	O
+and	POS	O
+N	POS	O
+-	POS	O
+highly	POS	O
+NSAIDs	POS	O
+intolerant	POS	O
+patients	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+we	POS	O
+conclude	POS	O
+that	POS	O
+CE	POS	O
+is	POS	O
+a	POS	O
+reasonably	POS	O
+safe	POS	O
+alternative	POS	O
+to	POS	O
+be	POS	O
+used	POS	O
+in	POS	O
+subjects	POS	O
+who	POS	O
+do	POS	O
+not	POS	O
+tolerate	POS	O
+P	POS	O
+and	POS	O
+N	POS	O
+.	POS	O
+Case	POS	O
+-	POS	O
+control	POS	O
+study	POS	O
+of	POS	O
+regular	POS	O
+analgesic	POS	O
+and	POS	O
+nonsteroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+use	POS	O
+and	POS	O
+end	POS	O
+-	POS	O
+stage	POS	O
+renal	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Studies	POS	O
+on	POS	O
+the	POS	O
+association	POS	O
+between	POS	O
+the	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+use	POS	O
+of	POS	O
+aspirin	POS	O
+and	POS	O
+other	POS	O
+analgesic	POS	O
+and	POS	O
+nonsteroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+(	POS	O
+NSAIDs	POS	O
+)	POS	O
+and	POS	O
+end	POS	O
+-	POS	O
+stage	POS	O
+renal	POS	B-NP
+disease	POS	I-NP
+(	POS	O
+ESRD	POS	B-NP
+)	POS	O
+have	POS	O
+given	POS	O
+conflicting	POS	O
+results	POS	O
+.	POS	O
+In	POS	O
+order	POS	O
+to	POS	O
+examine	POS	O
+this	POS	O
+association	POS	O
+,	POS	O
+a	POS	O
+case	POS	O
+-	POS	O
+control	POS	O
+study	POS	O
+with	POS	O
+incident	POS	O
+cases	POS	O
+of	POS	O
+ESRD	POS	B-NP
+was	POS	O
+carried	POS	O
+out	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+The	POS	O
+cases	POS	O
+were	POS	O
+all	POS	O
+patients	POS	O
+entering	POS	O
+the	POS	O
+local	POS	O
+dialysis	POS	O
+program	POS	O
+because	POS	O
+of	POS	O
+ESRD	POS	B-NP
+in	POS	O
+the	POS	O
+study	POS	O
+area	POS	O
+between	POS	O
+June	POS	O
+1	POS	O
+,	POS	O
+1995	POS	O
+and	POS	O
+November	POS	O
+30	POS	O
+,	POS	O
+1997	POS	O
+.	POS	O
+They	POS	O
+were	POS	O
+classified	POS	O
+according	POS	O
+to	POS	O
+the	POS	O
+underlying	POS	O
+disease	POS	O
+,	POS	O
+which	POS	O
+had	POS	O
+presumably	POS	O
+led	POS	O
+them	POS	O
+to	POS	O
+ESRD	POS	B-NP
+.	POS	O
+Controls	POS	O
+were	POS	O
+patients	POS	O
+admitted	POS	O
+to	POS	O
+the	POS	O
+same	POS	O
+hospitals	POS	O
+from	POS	O
+where	POS	O
+the	POS	O
+cases	POS	O
+arose	POS	O
+,	POS	O
+also	POS	O
+matched	POS	O
+by	POS	O
+age	POS	O
+and	POS	O
+sex	POS	O
+.	POS	O
+Odds	POS	O
+ratios	POS	O
+were	POS	O
+calculated	POS	O
+using	POS	O
+a	POS	O
+conditional	POS	O
+logistic	POS	O
+model	POS	O
+,	POS	O
+including	POS	O
+potential	POS	O
+confounding	POS	O
+factors	POS	O
+,	POS	O
+both	POS	O
+for	POS	O
+the	POS	O
+whole	POS	O
+study	POS	O
+population	POS	O
+and	POS	O
+for	POS	O
+the	POS	O
+various	POS	O
+underlying	POS	O
+diseases	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Five	POS	O
+hundred	POS	O
+and	POS	O
+eighty	POS	O
+-	POS	O
+three	POS	O
+cases	POS	O
+and	POS	O
+1190	POS	O
+controls	POS	O
+were	POS	O
+included	POS	O
+in	POS	O
+the	POS	O
+analysis	POS	O
+.	POS	O
+Long	POS	O
+-	POS	O
+term	POS	O
+use	POS	O
+of	POS	O
+any	POS	O
+analgesic	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+overall	POS	O
+odds	POS	O
+ratio	POS	O
+of	POS	O
+1	POS	O
+.	POS	O
+22	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+89	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+66	POS	O
+)	POS	O
+.	POS	O
+For	POS	O
+specific	POS	O
+groups	POS	O
+of	POS	O
+drugs	POS	O
+,	POS	O
+the	POS	O
+risks	POS	O
+were	POS	O
+1	POS	O
+.	POS	O
+56	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+05	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+30	POS	O
+)	POS	O
+for	POS	O
+aspirin	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+03	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+60	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+76	POS	O
+)	POS	O
+for	POS	O
+pyrazolones	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+80	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+39	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+63	POS	O
+)	POS	O
+for	POS	O
+paracetamol	POS	O
+,	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+94	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+57	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+56	POS	O
+)	POS	O
+for	POS	O
+nonaspirin	POS	O
+NSAIDs	POS	O
+.	POS	O
+The	POS	O
+risk	POS	O
+of	POS	O
+ESRD	POS	B-NP
+associated	POS	O
+with	POS	O
+aspirin	POS	O
+was	POS	O
+related	POS	O
+to	POS	O
+the	POS	O
+cumulated	POS	O
+dose	POS	O
+and	POS	O
+duration	POS	O
+of	POS	O
+use	POS	O
+,	POS	O
+and	POS	O
+it	POS	O
+was	POS	O
+particularly	POS	O
+high	POS	O
+among	POS	O
+the	POS	O
+subset	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+vascular	POS	B-NP
+nephropathy	POS	I-NP
+as	POS	O
+underlying	POS	O
+disease	POS	O
+[	POS	O
+2	POS	O
+.	POS	O
+35	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+17	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+72	POS	O
+)	POS	O
+]	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Our	POS	O
+data	POS	O
+indicate	POS	O
+that	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+use	POS	O
+of	POS	O
+nonaspirin	POS	O
+analgesic	POS	O
+drugs	POS	O
+and	POS	O
+NSAIDs	POS	O
+is	POS	O
+not	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+increased	POS	O
+risk	POS	O
+of	POS	O
+ESRD	POS	B-NP
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+chronic	POS	O
+use	POS	O
+of	POS	O
+aspirin	POS	O
+may	POS	O
+increase	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+ESRD	POS	B-NP
+.	POS	O
+Two	POS	O
+cases	POS	O
+of	POS	O
+amisulpride	POS	O
+overdose	POS	B-NP
+:	POS	O
+a	POS	O
+cause	POS	O
+for	POS	O
+prolonged	POS	O
+QT	POS	B-NP
+syndrome	POS	I-NP
+.	POS	O
+Two	POS	O
+cases	POS	O
+of	POS	O
+deliberate	POS	B-NP
+self	POS	I-NP
+-	POS	I-NP
+poisoning	POS	I-NP
+with	POS	O
+5	POS	O
+g	POS	O
+and	POS	O
+3	POS	O
+.	POS	O
+6	POS	O
+g	POS	O
+of	POS	O
+amisulpride	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+are	POS	O
+reported	POS	O
+.	POS	O
+In	POS	O
+both	POS	O
+cases	POS	O
+,	POS	O
+QT	POS	B-NP
+prolongation	POS	I-NP
+and	POS	O
+hypocalcaemia	POS	B-NP
+were	POS	O
+noted	POS	O
+.	POS	O
+The	POS	O
+QT	POS	O
+prolongation	POS	O
+appeared	POS	O
+to	POS	O
+respond	POS	O
+to	POS	O
+administration	POS	O
+of	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+calcium	POS	O
+gluconate	POS	O
+.	POS	O
+Growth	POS	O
+-	POS	O
+associated	POS	O
+protein	POS	O
+43	POS	O
+expression	POS	O
+in	POS	O
+hippocampal	POS	O
+molecular	POS	O
+layer	POS	O
+of	POS	O
+chronic	POS	O
+epileptic	POS	B-NP
+rats	POS	O
+treated	POS	O
+with	POS	O
+cycloheximide	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+GAP43	POS	O
+has	POS	O
+been	POS	O
+thought	POS	O
+to	POS	O
+be	POS	O
+linked	POS	O
+with	POS	O
+mossy	POS	O
+fiber	POS	O
+sprouting	POS	O
+(	POS	O
+MFS	POS	B-NP
+)	POS	O
+in	POS	O
+various	POS	O
+experimental	POS	O
+models	POS	O
+of	POS	O
+epilepsy	POS	B-NP
+.	POS	O
+To	POS	O
+investigate	POS	O
+how	POS	O
+GAP43	POS	O
+expression	POS	O
+(	POS	O
+GAP43	POS	O
+-	POS	O
+ir	POS	O
+)	POS	O
+correlates	POS	O
+with	POS	O
+MFS	POS	B-NP
+,	POS	O
+we	POS	O
+assessed	POS	O
+the	POS	O
+intensity	POS	O
+(	POS	O
+densitometry	POS	O
+)	POS	O
+and	POS	O
+extension	POS	O
+(	POS	O
+width	POS	O
+)	POS	O
+of	POS	O
+GAP43	POS	O
+-	POS	O
+ir	POS	O
+in	POS	O
+the	POS	O
+inner	POS	O
+molecular	POS	O
+layer	POS	O
+of	POS	O
+the	POS	O
+dentate	POS	O
+gyrus	POS	O
+(	POS	O
+IML	POS	O
+)	POS	O
+of	POS	O
+rats	POS	O
+subject	POS	O
+to	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+induced	POS	O
+by	POS	O
+pilocarpine	POS	O
+(	POS	O
+Pilo	POS	O
+)	POS	O
+,	POS	O
+previously	POS	O
+injected	POS	O
+or	POS	O
+not	POS	O
+with	POS	O
+cycloheximide	POS	O
+(	POS	O
+CHX	POS	O
+)	POS	O
+,	POS	O
+which	POS	O
+has	POS	O
+been	POS	O
+shown	POS	O
+to	POS	O
+inhibit	POS	O
+MFS	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+CHX	POS	O
+was	POS	O
+injected	POS	O
+before	POS	O
+the	POS	O
+Pilo	POS	O
+injection	POS	O
+in	POS	O
+adult	POS	O
+Wistar	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+Pilo	POS	O
+group	POS	O
+was	POS	O
+injected	POS	O
+with	POS	O
+the	POS	O
+same	POS	O
+drugs	POS	O
+,	POS	O
+except	POS	O
+for	POS	O
+CHX	POS	O
+.	POS	O
+Animals	POS	O
+were	POS	O
+killed	POS	O
+between	POS	O
+30	POS	O
+and	POS	O
+60	POS	O
+days	POS	O
+later	POS	O
+,	POS	O
+and	POS	O
+brain	POS	O
+sections	POS	O
+were	POS	O
+processed	POS	O
+for	POS	O
+GAP43	POS	O
+immunohistochemistry	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Densitometry	POS	O
+showed	POS	O
+no	POS	O
+significant	POS	O
+difference	POS	O
+regarding	POS	O
+GAP43	POS	O
+-	POS	O
+ir	POS	O
+in	POS	O
+the	POS	O
+IML	POS	O
+between	POS	O
+Pilo	POS	O
+,	POS	O
+CHX	POS	O
++	POS	O
+Pilo	POS	O
+,	POS	O
+and	POS	O
+control	POS	O
+groups	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+results	POS	O
+of	POS	O
+the	POS	O
+width	POS	O
+of	POS	O
+the	POS	O
+GAP43	POS	O
+-	POS	O
+ir	POS	O
+band	POS	O
+in	POS	O
+the	POS	O
+IML	POS	O
+showed	POS	O
+that	POS	O
+CHX	POS	O
++	POS	O
+Pilo	POS	O
+and	POS	O
+control	POS	O
+animals	POS	O
+had	POS	O
+a	POS	O
+significantly	POS	O
+larger	POS	O
+band	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+03	POS	O
+)	POS	O
+as	POS	O
+compared	POS	O
+with	POS	O
+that	POS	O
+in	POS	O
+the	POS	O
+Pilo	POS	O
+group	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Our	POS	O
+current	POS	O
+finding	POS	O
+that	POS	O
+animals	POS	O
+in	POS	O
+the	POS	O
+CHX	POS	O
++	POS	O
+Pilo	POS	O
+group	POS	O
+have	POS	O
+a	POS	O
+GAP43	POS	O
+-	POS	O
+ir	POS	O
+band	POS	O
+in	POS	O
+the	POS	O
+IML	POS	O
+,	POS	O
+similar	POS	O
+to	POS	O
+that	POS	O
+of	POS	O
+controls	POS	O
+,	POS	O
+reinforces	POS	O
+prior	POS	O
+data	POS	O
+on	POS	O
+the	POS	O
+blockade	POS	O
+of	POS	O
+MFS	POS	B-NP
+in	POS	O
+these	POS	O
+animals	POS	O
+.	POS	O
+The	POS	O
+change	POS	O
+in	POS	O
+GAP43	POS	O
+-	POS	O
+ir	POS	O
+present	POS	O
+in	POS	O
+Pilo	POS	O
+-	POS	O
+treated	POS	O
+animals	POS	O
+was	POS	O
+a	POS	O
+thinning	POS	O
+of	POS	O
+the	POS	O
+band	POS	O
+to	POS	O
+a	POS	O
+very	POS	O
+narrow	POS	O
+layer	POS	O
+just	POS	O
+above	POS	O
+the	POS	O
+granule	POS	O
+cell	POS	O
+layer	POS	O
+that	POS	O
+is	POS	O
+likely	POS	O
+to	POS	O
+be	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+loss	POS	O
+of	POS	O
+hilar	POS	O
+cell	POS	O
+projections	POS	O
+that	POS	O
+express	POS	O
+GAP	POS	O
+-	POS	O
+43	POS	O
+.	POS	O
+Nicotine	POS	O
+antagonizes	POS	O
+caffeine	POS	O
+-	POS	O
+but	POS	O
+not	POS	O
+pentylenetetrazole	POS	O
+-	POS	O
+induced	POS	O
+anxiogenic	POS	O
+effect	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+RATIONALE	POS	O
+:	POS	O
+Nicotine	POS	O
+and	POS	O
+caffeine	POS	O
+are	POS	O
+widely	POS	O
+consumed	POS	O
+licit	POS	O
+psychoactive	POS	O
+drugs	POS	O
+worldwide	POS	O
+.	POS	O
+Epidemiological	POS	O
+studies	POS	O
+showed	POS	O
+that	POS	O
+they	POS	O
+were	POS	O
+generally	POS	O
+used	POS	O
+concurrently	POS	O
+.	POS	O
+Although	POS	O
+some	POS	O
+studies	POS	O
+in	POS	O
+experimental	POS	O
+animals	POS	O
+indicate	POS	O
+clear	POS	O
+pharmacological	POS	O
+interactions	POS	O
+between	POS	O
+them	POS	O
+,	POS	O
+no	POS	O
+studies	POS	O
+have	POS	O
+shown	POS	O
+a	POS	O
+specific	POS	O
+interaction	POS	O
+on	POS	O
+anxiety	POS	B-NP
+responses	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+investigates	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+nicotine	POS	O
+on	POS	O
+anxiety	POS	B-NP
+induced	POS	O
+by	POS	O
+caffeine	POS	O
+and	POS	O
+another	POS	O
+anxiogenic	POS	O
+drug	POS	O
+,	POS	O
+pentylenetetrazole	POS	O
+,	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+The	POS	O
+elevated	POS	O
+plus	POS	O
+-	POS	O
+maze	POS	O
+(	POS	O
+EPM	POS	O
+)	POS	O
+test	POS	O
+was	POS	O
+used	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+drugs	POS	O
+on	POS	O
+anxiety	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Adult	POS	O
+male	POS	O
+Swiss	POS	O
+Webster	POS	O
+mice	POS	O
+(	POS	O
+25	POS	O
+-	POS	O
+32	POS	O
+g	POS	O
+)	POS	O
+were	POS	O
+given	POS	O
+nicotine	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+25	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+s	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+)	POS	O
+or	POS	O
+saline	POS	O
+10	POS	O
+min	POS	O
+before	POS	O
+caffeine	POS	O
+(	POS	O
+70	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+or	POS	O
+pentylenetetrazole	POS	O
+(	POS	O
+15	POS	O
+and	POS	O
+30	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+injections	POS	O
+.	POS	O
+After	POS	O
+15	POS	O
+min	POS	O
+,	POS	O
+mice	POS	O
+were	POS	O
+evaluated	POS	O
+for	POS	O
+their	POS	O
+open	POS	O
+-	POS	O
+and	POS	O
+closed	POS	O
+-	POS	O
+arm	POS	O
+time	POS	O
+and	POS	O
+entries	POS	O
+on	POS	O
+the	POS	O
+EPM	POS	O
+for	POS	O
+a	POS	O
+10	POS	O
+-	POS	O
+min	POS	O
+session	POS	O
+.	POS	O
+Locomotor	POS	O
+activity	POS	O
+was	POS	O
+recorded	POS	O
+for	POS	O
+individual	POS	O
+groups	POS	O
+by	POS	O
+using	POS	O
+the	POS	O
+same	POS	O
+treatment	POS	O
+protocol	POS	O
+with	POS	O
+the	POS	O
+EPM	POS	O
+test	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Nicotine	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+25	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+itself	POS	O
+did	POS	O
+not	POS	O
+produce	POS	O
+any	POS	O
+significant	POS	O
+effect	POS	O
+in	POS	O
+the	POS	O
+EPM	POS	O
+test	POS	O
+,	POS	O
+whereas	POS	O
+caffeine	POS	O
+(	POS	O
+70	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+and	POS	O
+pentylenetetrazole	POS	O
+(	POS	O
+30	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+produced	POS	O
+an	POS	O
+anxiogenic	POS	O
+effect	POS	O
+,	POS	O
+apparent	POS	O
+with	POS	O
+decreases	POS	O
+in	POS	O
+open	POS	O
+-	POS	O
+arm	POS	O
+time	POS	O
+and	POS	O
+entry	POS	O
+.	POS	O
+Nicotine	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+25	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+pretreatment	POS	O
+blocked	POS	O
+the	POS	O
+caffeine	POS	O
+-	POS	O
+but	POS	O
+not	POS	O
+pentylenetetrazole	POS	O
+-	POS	O
+induced	POS	O
+anxiety	POS	B-NP
+.	POS	O
+Administration	POS	O
+of	POS	O
+each	POS	O
+drug	POS	O
+and	POS	O
+their	POS	O
+combinations	POS	O
+did	POS	O
+not	POS	O
+produce	POS	O
+any	POS	O
+effect	POS	O
+on	POS	O
+locomotor	POS	O
+activity	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Our	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+the	POS	O
+antagonistic	POS	O
+effect	POS	O
+of	POS	O
+nicotine	POS	O
+on	POS	O
+caffeine	POS	O
+-	POS	O
+induced	POS	O
+anxiety	POS	B-NP
+is	POS	O
+specific	POS	O
+to	POS	O
+caffeine	POS	O
+,	POS	O
+instead	POS	O
+of	POS	O
+a	POS	O
+non	POS	O
+-	POS	O
+specific	POS	O
+anxiolytic	POS	O
+effect	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+it	POS	O
+may	POS	O
+extend	POS	O
+the	POS	O
+current	POS	O
+findings	POS	O
+on	POS	O
+the	POS	O
+interaction	POS	O
+between	POS	O
+nicotine	POS	O
+and	POS	O
+caffeine	POS	O
+.	POS	O
+Long	POS	O
+term	POS	O
+hormone	POS	O
+therapy	POS	O
+for	POS	O
+perimenopausal	POS	O
+and	POS	O
+postmenopausal	POS	O
+women	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Hormone	POS	O
+therapy	POS	O
+(	POS	O
+HT	POS	O
+)	POS	O
+is	POS	O
+widely	POS	O
+used	POS	O
+for	POS	O
+controlling	POS	O
+menopausal	POS	O
+symptoms	POS	O
+.	POS	O
+It	POS	O
+has	POS	O
+also	POS	O
+been	POS	O
+used	POS	O
+for	POS	O
+the	POS	O
+management	POS	O
+and	POS	O
+prevention	POS	O
+of	POS	O
+cardiovascular	POS	B-NP
+disease	POS	I-NP
+,	POS	O
+osteoporosis	POS	B-NP
+and	POS	O
+dementia	POS	B-NP
+in	POS	O
+older	POS	O
+women	POS	O
+but	POS	O
+the	POS	O
+evidence	POS	O
+supporting	POS	O
+its	POS	O
+use	POS	O
+for	POS	O
+these	POS	O
+indications	POS	O
+is	POS	O
+largely	POS	O
+observational	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+To	POS	O
+assess	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+HT	POS	O
+on	POS	O
+mortality	POS	O
+,	POS	O
+heart	POS	B-NP
+disease	POS	I-NP
+,	POS	O
+venous	POS	B-NP
+thromboembolism	POS	I-NP
+,	POS	O
+stroke	POS	B-NP
+,	POS	O
+transient	POS	B-NP
+ischaemic	POS	I-NP
+attacks	POS	I-NP
+,	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+,	POS	O
+colorectal	POS	B-NP
+cancer	POS	I-NP
+,	POS	O
+ovarian	POS	B-NP
+cancer	POS	I-NP
+,	POS	O
+endometrial	POS	B-NP
+cancer	POS	I-NP
+,	POS	O
+gallbladder	POS	B-NP
+disease	POS	I-NP
+,	POS	O
+cognitive	POS	B-NP
+function	POS	I-NP
+,	POS	O
+dementia	POS	B-NP
+,	POS	O
+fractures	POS	B-NP
+and	POS	O
+quality	POS	O
+of	POS	O
+life	POS	O
+.	POS	O
+SEARCH	POS	O
+STRATEGY	POS	O
+:	POS	O
+We	POS	O
+searched	POS	O
+the	POS	O
+following	POS	O
+databases	POS	O
+up	POS	O
+to	POS	O
+November	POS	O
+2004	POS	O
+:	POS	O
+the	POS	O
+Cochrane	POS	O
+Menstrual	POS	O
+Disorders	POS	O
+and	POS	O
+Subfertility	POS	O
+Group	POS	O
+Trials	POS	O
+Register	POS	O
+,	POS	O
+Cochrane	POS	O
+Central	POS	O
+Register	POS	O
+of	POS	O
+Controlled	POS	O
+Trials	POS	O
+(	POS	O
+CENTRAL	POS	O
+)	POS	O
+,	POS	O
+MEDLINE	POS	O
+,	POS	O
+EMBASE	POS	O
+,	POS	O
+Biological	POS	O
+Abstracts	POS	O
+.	POS	O
+Relevant	POS	O
+non	POS	O
+-	POS	O
+indexed	POS	O
+journals	POS	O
+and	POS	O
+conference	POS	O
+abstracts	POS	O
+were	POS	O
+also	POS	O
+searched	POS	O
+.	POS	O
+SELECTION	POS	O
+CRITERIA	POS	O
+:	POS	O
+Randomised	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+trials	POS	O
+of	POS	O
+HT	POS	O
+(	POS	O
+oestrogens	POS	O
+with	POS	O
+or	POS	O
+without	POS	O
+progestogens	POS	O
+)	POS	O
+versus	POS	O
+placebo	POS	O
+,	POS	O
+taken	POS	O
+for	POS	O
+at	POS	O
+least	POS	O
+one	POS	O
+year	POS	O
+by	POS	O
+perimenopausal	POS	O
+or	POS	O
+postmenopausal	POS	O
+women	POS	O
+.	POS	O
+DATA	POS	O
+COLLECTION	POS	O
+AND	POS	O
+ANALYSIS	POS	O
+:	POS	O
+Fifteen	POS	O
+RCTs	POS	O
+were	POS	O
+included	POS	O
+.	POS	O
+Trials	POS	O
+were	POS	O
+assessed	POS	O
+for	POS	O
+quality	POS	O
+and	POS	O
+two	POS	O
+review	POS	O
+authors	POS	O
+extracted	POS	O
+data	POS	O
+independently	POS	O
+.	POS	O
+They	POS	O
+calculated	POS	O
+risk	POS	O
+ratios	POS	O
+for	POS	O
+dichotomous	POS	O
+outcomes	POS	O
+and	POS	O
+weighted	POS	O
+mean	POS	O
+differences	POS	O
+for	POS	O
+continuous	POS	O
+outcomes	POS	O
+.	POS	O
+Clinical	POS	O
+heterogeneity	POS	O
+precluded	POS	O
+meta	POS	O
+-	POS	O
+analysis	POS	O
+for	POS	O
+most	POS	O
+outcomes	POS	O
+.	POS	O
+MAIN	POS	O
+RESULTS	POS	O
+:	POS	O
+All	POS	O
+the	POS	O
+statistically	POS	O
+significant	POS	O
+results	POS	O
+were	POS	O
+derived	POS	O
+from	POS	O
+the	POS	O
+two	POS	O
+biggest	POS	O
+trials	POS	O
+.	POS	O
+In	POS	O
+relatively	POS	O
+healthy	POS	O
+women	POS	O
+,	POS	O
+combined	POS	O
+continuous	POS	O
+HT	POS	O
+significantly	POS	O
+increased	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+venous	POS	B-NP
+thromboembolism	POS	I-NP
+or	POS	O
+coronary	POS	B-NP
+event	POS	I-NP
+(	POS	O
+after	POS	O
+one	POS	O
+year	POS	O
+'	POS	O
+s	POS	O
+use	POS	O
+)	POS	O
+,	POS	O
+stroke	POS	B-NP
+(	POS	O
+after	POS	O
+3	POS	O
+years	POS	O
+)	POS	O
+,	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+(	POS	O
+after	POS	O
+5	POS	O
+years	POS	O
+)	POS	O
+and	POS	O
+gallbladder	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+Long	POS	O
+-	POS	O
+term	POS	O
+oestrogen	POS	O
+-	POS	O
+only	POS	O
+HT	POS	O
+also	POS	O
+significantly	POS	O
+increased	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+stroke	POS	B-NP
+and	POS	O
+gallbladder	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+Overall	POS	O
+,	POS	O
+the	POS	O
+only	POS	O
+statistically	POS	O
+significant	POS	O
+benefits	POS	O
+of	POS	O
+HT	POS	O
+were	POS	O
+a	POS	O
+decreased	POS	O
+incidence	POS	O
+of	POS	O
+fractures	POS	B-NP
+and	POS	O
+colon	POS	B-NP
+cancer	POS	I-NP
+with	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+use	POS	O
+.	POS	O
+Among	POS	O
+relatively	POS	O
+healthy	POS	O
+women	POS	O
+over	POS	O
+65	POS	O
+years	POS	O
+taking	POS	O
+continuous	POS	O
+combined	POS	O
+HT	POS	O
+,	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+statistically	POS	O
+significant	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+dementia	POS	B-NP
+.	POS	O
+Among	POS	O
+women	POS	O
+with	POS	O
+cardiovascular	POS	B-NP
+disease	POS	I-NP
+,	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+use	POS	O
+of	POS	O
+combined	POS	O
+continuous	POS	O
+HT	POS	O
+significantly	POS	O
+increased	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+venous	POS	B-NP
+thromboembolism	POS	I-NP
+.	POS	O
+No	POS	O
+trials	POS	O
+focussed	POS	O
+specifically	POS	O
+on	POS	O
+younger	POS	O
+women	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+one	POS	O
+trial	POS	O
+analysed	POS	O
+subgroups	POS	O
+of	POS	O
+2839	POS	O
+relatively	POS	O
+healthy	POS	O
+50	POS	O
+to	POS	O
+59	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+women	POS	O
+taking	POS	O
+combined	POS	O
+continuous	POS	O
+HT	POS	O
+and	POS	O
+1637	POS	O
+taking	POS	O
+oestrogen	POS	O
+-	POS	O
+only	POS	O
+HT	POS	O
+,	POS	O
+versus	POS	O
+similar	POS	O
+-	POS	O
+sized	POS	O
+placebo	POS	O
+groups	POS	O
+.	POS	O
+The	POS	O
+only	POS	O
+significantly	POS	O
+increased	POS	O
+risk	POS	O
+reported	POS	O
+was	POS	O
+for	POS	O
+venous	POS	B-NP
+thromboembolism	POS	I-NP
+in	POS	O
+women	POS	O
+taking	POS	O
+combined	POS	O
+continuous	POS	O
+HT	POS	O
+;	POS	O
+their	POS	O
+absolute	POS	O
+risk	POS	O
+remained	POS	O
+very	POS	O
+low	POS	O
+.	POS	O
+AUTHORS	POS	O
+'	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+HT	POS	O
+is	POS	O
+not	POS	O
+indicated	POS	O
+for	POS	O
+the	POS	O
+routine	POS	O
+management	POS	O
+of	POS	O
+chronic	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+We	POS	O
+need	POS	O
+more	POS	O
+evidence	POS	O
+on	POS	O
+the	POS	O
+safety	POS	O
+of	POS	O
+HT	POS	O
+for	POS	O
+menopausal	POS	O
+symptom	POS	O
+control	POS	O
+,	POS	O
+though	POS	O
+short	POS	O
+-	POS	O
+term	POS	O
+use	POS	O
+appears	POS	O
+to	POS	O
+be	POS	O
+relatively	POS	O
+safe	POS	O
+for	POS	O
+healthy	POS	O
+younger	POS	O
+women	POS	O
+.	POS	O
+Drug	POS	O
+-	POS	O
+induced	POS	O
+liver	POS	B-NP
+injury	POS	I-NP
+:	POS	O
+an	POS	O
+analysis	POS	O
+of	POS	O
+461	POS	O
+incidences	POS	O
+submitted	POS	O
+to	POS	O
+the	POS	O
+Spanish	POS	O
+registry	POS	O
+over	POS	O
+a	POS	O
+10	POS	O
+-	POS	O
+year	POS	O
+period	POS	O
+.	POS	O
+BACKGROUND	POS	O
+&	POS	O
+AIMS	POS	O
+:	POS	O
+Progress	POS	O
+in	POS	O
+the	POS	O
+understanding	POS	O
+of	POS	O
+susceptibility	POS	O
+factors	POS	O
+to	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+liver	POS	B-NP
+injury	POS	I-NP
+(	POS	O
+DILI	POS	B-NP
+)	POS	O
+and	POS	O
+outcome	POS	O
+predictability	POS	O
+are	POS	O
+hampered	POS	O
+by	POS	O
+the	POS	O
+lack	POS	O
+of	POS	O
+systematic	POS	O
+programs	POS	O
+to	POS	O
+detect	POS	O
+bona	POS	O
+fide	POS	O
+cases	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+A	POS	O
+cooperative	POS	O
+network	POS	O
+was	POS	O
+created	POS	O
+in	POS	O
+1994	POS	O
+in	POS	O
+Spain	POS	O
+to	POS	O
+identify	POS	O
+all	POS	O
+suspicions	POS	O
+of	POS	O
+DILI	POS	B-NP
+following	POS	O
+a	POS	O
+prospective	POS	O
+structured	POS	O
+report	POS	O
+form	POS	O
+.	POS	O
+The	POS	O
+liver	POS	B-NP
+damage	POS	I-NP
+was	POS	O
+characterized	POS	O
+according	POS	O
+to	POS	O
+hepatocellular	POS	B-NP
+,	POS	O
+cholestatic	POS	B-NP
+,	POS	O
+and	POS	O
+mixed	POS	O
+laboratory	POS	O
+criteria	POS	O
+and	POS	O
+to	POS	O
+histologic	POS	O
+criteria	POS	O
+when	POS	O
+available	POS	O
+.	POS	O
+Further	POS	O
+evaluation	POS	O
+of	POS	O
+causality	POS	O
+assessment	POS	O
+was	POS	O
+centrally	POS	O
+performed	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Since	POS	O
+April	POS	O
+1994	POS	O
+to	POS	O
+August	POS	O
+2004	POS	O
+,	POS	O
+461	POS	O
+out	POS	O
+of	POS	O
+570	POS	O
+submitted	POS	O
+cases	POS	O
+,	POS	O
+involving	POS	O
+505	POS	O
+drugs	POS	O
+,	POS	O
+were	POS	O
+deemed	POS	O
+to	POS	O
+be	POS	O
+related	POS	O
+to	POS	O
+DILI	POS	B-NP
+.	POS	O
+The	POS	O
+antiinfective	POS	O
+group	POS	O
+of	POS	O
+drugs	POS	O
+was	POS	O
+the	POS	O
+more	POS	O
+frequently	POS	O
+incriminated	POS	O
+,	POS	O
+amoxicillin	POS	O
+-	POS	O
+clavulanate	POS	O
+accounting	POS	O
+for	POS	O
+the	POS	O
+12	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+whole	POS	O
+series	POS	O
+.	POS	O
+The	POS	O
+hepatocellular	POS	O
+pattern	POS	O
+of	POS	O
+damage	POS	O
+was	POS	O
+the	POS	O
+most	POS	O
+common	POS	O
+(	POS	O
+58	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+was	POS	O
+inversely	POS	O
+correlated	POS	O
+with	POS	O
+age	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+0001	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+had	POS	O
+the	POS	O
+worst	POS	O
+outcome	POS	O
+(	POS	O
+Cox	POS	O
+regression	POS	O
+,	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+034	POS	O
+)	POS	O
+.	POS	O
+Indeed	POS	O
+,	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+liver	POS	O
+transplantation	POS	O
+and	POS	O
+death	POS	O
+in	POS	O
+this	POS	O
+group	POS	O
+was	POS	O
+11	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+if	POS	O
+patients	POS	O
+had	POS	O
+jaundice	POS	B-NP
+at	POS	O
+presentation	POS	O
+,	POS	O
+whereas	POS	O
+the	POS	O
+corresponding	POS	O
+figure	POS	O
+was	POS	O
+3	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+in	POS	O
+nonjaundiced	POS	O
+patients	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+04	POS	O
+)	POS	O
+.	POS	O
+Factors	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+fulminant	POS	B-NP
+hepatic	POS	I-NP
+failure	POS	I-NP
+were	POS	O
+female	POS	O
+sex	POS	O
+(	POS	O
+OR	POS	O
+=	POS	O
+25	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+:	POS	O
+4	POS	O
+.	POS	O
+1	POS	O
+-	POS	O
+151	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+0001	POS	O
+)	POS	O
+,	POS	O
+hepatocellular	POS	B-NP
+damage	POS	I-NP
+(	POS	O
+OR	POS	O
+=	POS	O
+7	POS	O
+.	POS	O
+9	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+:	POS	O
+1	POS	O
+.	POS	O
+6	POS	O
+-	POS	O
+37	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+009	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+higher	POS	O
+baseline	POS	O
+plasma	POS	O
+bilirubin	POS	O
+value	POS	O
+(	POS	O
+OR	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+15	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+:	POS	O
+1	POS	O
+.	POS	O
+09	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+22	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+0001	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Patients	POS	O
+with	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+hepatocellular	POS	B-NP
+jaundice	POS	I-NP
+have	POS	O
+11	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+chance	POS	O
+of	POS	O
+progressing	POS	O
+to	POS	O
+death	POS	O
+or	POS	O
+transplantation	POS	O
+.	POS	O
+Amoxicillin	POS	O
+-	POS	O
+clavulanate	POS	O
+stands	POS	O
+out	POS	O
+as	POS	O
+the	POS	O
+most	POS	O
+common	POS	O
+drug	POS	O
+related	POS	O
+to	POS	O
+DILI	POS	B-NP
+.	POS	O
+Morphological	POS	O
+evaluation	POS	O
+of	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+d	POS	O
+-	POS	O
+ribose	POS	O
+on	POS	O
+adriamycin	POS	O
+-	POS	O
+evoked	POS	O
+cardiotoxicity	POS	B-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+influence	POS	O
+of	POS	O
+d	POS	O
+-	POS	O
+ribose	POS	O
+on	POS	O
+adriamycin	POS	O
+-	POS	O
+induced	POS	O
+myocardiopathy	POS	B-NP
+in	POS	O
+rats	POS	O
+was	POS	O
+studied	POS	O
+.	POS	O
+Adriamycin	POS	O
+in	POS	O
+the	POS	O
+cumulative	POS	O
+dose	POS	O
+of	POS	O
+25	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+evoked	POS	O
+fully	POS	O
+developed	POS	O
+cardiac	POS	B-NP
+toxicity	POS	I-NP
+.	POS	O
+D	POS	O
+-	POS	O
+ribose	POS	O
+in	POS	O
+the	POS	O
+multiple	POS	O
+doses	POS	O
+of	POS	O
+200	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+did	POS	O
+not	POS	O
+influence	POS	O
+ADR	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+In	POS	O
+vivo	POS	O
+evidences	POS	O
+suggesting	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+oxidative	POS	O
+stress	POS	O
+in	POS	O
+pathogenesis	POS	O
+of	POS	O
+vancomycin	POS	O
+-	POS	O
+induced	POS	O
+nephrotoxicity	POS	B-NP
+:	POS	O
+protection	POS	O
+by	POS	O
+erdosteine	POS	O
+.	POS	O
+The	POS	O
+aims	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+were	POS	O
+to	POS	O
+examine	POS	O
+vancomycin	POS	O
+(	POS	O
+VCM	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+oxidative	POS	O
+stress	POS	O
+that	POS	O
+promotes	POS	O
+production	POS	O
+of	POS	O
+reactive	POS	O
+oxygen	POS	O
+species	POS	O
+(	POS	O
+ROS	POS	O
+)	POS	O
+and	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+erdosteine	POS	O
+,	POS	O
+an	POS	O
+expectorant	POS	O
+agent	POS	O
+,	POS	O
+which	POS	O
+has	POS	O
+also	POS	O
+antioxidant	POS	O
+properties	POS	O
+,	POS	O
+on	POS	O
+kidney	POS	O
+tissue	POS	O
+against	POS	O
+the	POS	O
+possible	POS	O
+VCM	POS	O
+-	POS	O
+induced	POS	O
+renal	POS	B-NP
+impairment	POS	I-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+Rats	POS	O
+were	POS	O
+divided	POS	O
+into	POS	O
+three	POS	O
+groups	POS	O
+:	POS	O
+sham	POS	O
+,	POS	O
+VCM	POS	O
+and	POS	O
+VCM	POS	O
+plus	POS	O
+erdosteine	POS	O
+.	POS	O
+VCM	POS	O
+was	POS	O
+administrated	POS	O
+intraperitoneally	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+with	POS	O
+200mgkg	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+twice	POS	O
+daily	POS	O
+for	POS	O
+7	POS	O
+days	POS	O
+.	POS	O
+Erdosteine	POS	O
+was	POS	O
+administered	POS	O
+orally	POS	O
+.	POS	O
+VCM	POS	O
+administration	POS	O
+to	POS	O
+control	POS	O
+rats	POS	O
+significantly	POS	O
+increased	POS	O
+renal	POS	O
+malondialdehyde	POS	O
+(	POS	O
+MDA	POS	O
+)	POS	O
+and	POS	O
+urinary	POS	O
+N	POS	O
+-	POS	O
+acetyl	POS	O
+-	POS	O
+beta	POS	O
+-	POS	O
+d	POS	O
+-	POS	O
+glucosaminidase	POS	O
+(	POS	O
+NAG	POS	O
+,	POS	O
+a	POS	O
+marker	POS	O
+of	POS	O
+renal	POS	B-NP
+tubular	POS	I-NP
+injury	POS	I-NP
+)	POS	O
+excretion	POS	O
+but	POS	O
+decreased	POS	O
+superoxide	POS	O
+dismutase	POS	O
+(	POS	O
+SOD	POS	O
+)	POS	O
+and	POS	O
+catalase	POS	O
+(	POS	O
+CAT	POS	O
+)	POS	O
+activities	POS	O
+.	POS	O
+Erdosteine	POS	O
+administration	POS	O
+with	POS	O
+VCM	POS	O
+injections	POS	O
+caused	POS	O
+significantly	POS	O
+decreased	POS	O
+renal	POS	O
+MDA	POS	O
+and	POS	O
+urinary	POS	O
+NAG	POS	O
+excretion	POS	O
+,	POS	O
+and	POS	O
+increased	POS	O
+SOD	POS	O
+activity	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+CAT	POS	O
+activity	POS	O
+in	POS	O
+renal	POS	O
+tissue	POS	O
+when	POS	O
+compared	POS	O
+with	POS	O
+VCM	POS	O
+alone	POS	O
+.	POS	O
+Erdosteine	POS	O
+showed	POS	O
+histopathological	POS	O
+protection	POS	O
+against	POS	O
+VCM	POS	O
+-	POS	O
+induced	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+There	POS	O
+were	POS	O
+a	POS	O
+significant	POS	O
+dilatation	POS	B-NP
+of	POS	I-NP
+tubular	POS	I-NP
+lumens	POS	I-NP
+,	POS	O
+extensive	POS	O
+epithelial	POS	O
+cell	POS	O
+vacuolization	POS	O
+,	POS	O
+atrophy	POS	B-NP
+,	POS	O
+desquamation	POS	B-NP
+,	POS	O
+and	POS	O
+necrosis	POS	B-NP
+in	POS	O
+VCM	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+more	POS	O
+than	POS	O
+those	POS	O
+of	POS	O
+the	POS	O
+control	POS	O
+and	POS	O
+the	POS	O
+erdosteine	POS	O
+groups	POS	O
+.	POS	O
+Erdosteine	POS	O
+caused	POS	O
+a	POS	O
+marked	POS	O
+reduction	POS	O
+in	POS	O
+the	POS	O
+extent	POS	O
+of	POS	O
+tubular	POS	B-NP
+damage	POS	I-NP
+.	POS	O
+It	POS	O
+is	POS	O
+concluded	POS	O
+that	POS	O
+oxidative	POS	O
+tubular	POS	O
+damage	POS	O
+plays	POS	O
+an	POS	O
+important	POS	O
+role	POS	O
+in	POS	O
+the	POS	O
+VCM	POS	O
+-	POS	O
+induced	POS	O
+nephrotoxicity	POS	B-NP
+and	POS	O
+the	POS	O
+modulation	POS	O
+of	POS	O
+oxidative	POS	O
+stress	POS	O
+with	POS	O
+erdosteine	POS	O
+reduces	POS	O
+the	POS	O
+VCM	POS	O
+-	POS	O
+induced	POS	O
+kidney	POS	O
+damage	POS	O
+both	POS	O
+at	POS	O
+the	POS	O
+biochemical	POS	O
+and	POS	O
+histological	POS	O
+levels	POS	O
+.	POS	O
+Gemfibrozil	POS	O
+-	POS	O
+lovastatin	POS	O
+therapy	POS	O
+for	POS	O
+primary	POS	O
+hyperlipoproteinemias	POS	B-NP
+.	POS	O
+The	POS	O
+specific	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+retrospective	POS	O
+,	POS	O
+observational	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+assess	POS	O
+safety	POS	O
+and	POS	O
+efficacy	POS	O
+of	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+(	POS	O
+21	POS	O
+months	POS	O
+/	POS	O
+patient	POS	O
+)	POS	O
+,	POS	O
+open	POS	O
+-	POS	O
+label	POS	O
+,	POS	O
+gemfibrozil	POS	O
+-	POS	O
+lovastatin	POS	O
+treatment	POS	O
+in	POS	O
+80	POS	O
+patients	POS	O
+with	POS	O
+primary	POS	O
+mixed	POS	O
+hyperlipidemia	POS	B-NP
+(	POS	O
+68	POS	O
+%	POS	O
+of	POS	O
+whom	POS	O
+had	POS	O
+atherosclerotic	POS	B-NP
+vascular	POS	I-NP
+disease	POS	I-NP
+)	POS	O
+.	POS	O
+Because	POS	O
+ideal	POS	O
+lipid	POS	O
+targets	POS	O
+were	POS	O
+not	POS	O
+reached	POS	O
+(	POS	O
+low	POS	O
+-	POS	O
+density	POS	O
+lipoprotein	POS	O
+(	POS	O
+LDL	POS	O
+)	POS	O
+cholesterol	POS	O
+less	POS	O
+than	POS	O
+130	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+,	POS	O
+high	POS	O
+-	POS	O
+density	POS	O
+lipoprotein	POS	O
+(	POS	O
+HDL	POS	O
+)	POS	O
+cholesterol	POS	O
+greater	POS	O
+than	POS	O
+35	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+,	POS	O
+or	POS	O
+total	POS	O
+cholesterol	POS	O
+/	POS	O
+HDL	POS	O
+cholesterol	POS	O
+less	POS	O
+than	POS	O
+4	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+)	POS	O
+with	POS	O
+diet	POS	O
+plus	POS	O
+a	POS	O
+single	POS	O
+drug	POS	O
+,	POS	O
+gemfibrozil	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+g	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+-	POS	O
+lovastatin	POS	O
+(	POS	O
+primarily	POS	O
+20	POS	O
+or	POS	O
+40	POS	O
+mg	POS	O
+)	POS	O
+treatment	POS	O
+was	POS	O
+given	POS	O
+.	POS	O
+Follow	POS	O
+-	POS	O
+up	POS	O
+visits	POS	O
+were	POS	O
+scheduled	POS	O
+with	POS	O
+2	POS	O
+-	POS	O
+drug	POS	O
+therapy	POS	O
+every	POS	O
+6	POS	O
+to	POS	O
+8	POS	O
+weeks	POS	O
+,	POS	O
+an	POS	O
+average	POS	O
+of	POS	O
+10	POS	O
+.	POS	O
+3	POS	O
+visits	POS	O
+per	POS	O
+patient	POS	O
+,	POS	O
+with	POS	O
+741	POS	O
+batteries	POS	O
+of	POS	O
+6	POS	O
+liver	POS	O
+function	POS	O
+tests	POS	O
+and	POS	O
+714	POS	O
+creatine	POS	O
+phosphokinase	POS	O
+levels	POS	O
+measured	POS	O
+.	POS	O
+Only	POS	O
+1	POS	O
+of	POS	O
+the	POS	O
+4	POS	O
+,	POS	O
+446	POS	O
+liver	POS	O
+function	POS	O
+tests	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+gamma	POS	O
+glutamyl	POS	O
+transferase	POS	O
+,	POS	O
+was	POS	O
+greater	POS	O
+than	POS	O
+or	POS	O
+equal	POS	O
+to	POS	O
+3	POS	O
+times	POS	O
+the	POS	O
+upper	POS	O
+normal	POS	O
+limit	POS	O
+.	POS	O
+Of	POS	O
+the	POS	O
+714	POS	O
+creatine	POS	O
+phosphokinase	POS	O
+levels	POS	O
+,	POS	O
+9	POS	O
+%	POS	O
+were	POS	O
+high	POS	O
+;	POS	O
+only	POS	O
+1	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+)	POS	O
+was	POS	O
+greater	POS	O
+than	POS	O
+or	POS	O
+equal	POS	O
+to	POS	O
+3	POS	O
+times	POS	O
+the	POS	O
+upper	POS	O
+normal	POS	O
+limit	POS	O
+.	POS	O
+With	POS	O
+2	POS	O
+-	POS	O
+drug	POS	O
+therapy	POS	O
+,	POS	O
+mean	POS	O
+total	POS	O
+cholesterol	POS	O
+decreased	POS	O
+22	POS	O
+%	POS	O
+from	POS	O
+255	POS	O
+to	POS	O
+200	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+,	POS	O
+triglyceride	POS	O
+levels	POS	O
+decreased	POS	O
+35	POS	O
+%	POS	O
+from	POS	O
+236	POS	O
+to	POS	O
+154	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+,	POS	O
+LDL	POS	O
+cholesterol	POS	O
+decreased	POS	O
+26	POS	O
+%	POS	O
+from	POS	O
+176	POS	O
+to	POS	O
+131	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+total	POS	O
+cholesterol	POS	O
+/	POS	O
+HDL	POS	O
+cholesterol	POS	O
+ratio	POS	O
+decreased	POS	O
+24	POS	O
+%	POS	O
+from	POS	O
+7	POS	O
+.	POS	O
+1	POS	O
+to	POS	O
+5	POS	O
+.	POS	O
+4	POS	O
+,	POS	O
+all	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+or	POS	O
+equal	POS	O
+to	POS	O
+0	POS	O
+.	POS	O
+0001	POS	O
+.	POS	O
+Myositis	POS	B-NP
+,	POS	O
+attributable	POS	O
+to	POS	O
+the	POS	O
+drug	POS	O
+combination	POS	O
+and	POS	O
+symptomatic	POS	O
+enough	POS	O
+to	POS	O
+discontinue	POS	O
+it	POS	O
+,	POS	O
+occurred	POS	O
+in	POS	O
+3	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+,	POS	O
+and	POS	O
+in	POS	O
+1	POS	O
+%	POS	O
+with	POS	O
+concurrent	POS	O
+high	POS	O
+creatine	POS	O
+phosphokinase	POS	O
+(	POS	O
+769	POS	O
+U	POS	O
+/	POS	O
+liter	POS	O
+)	POS	O
+;	POS	O
+no	POS	O
+patients	POS	O
+had	POS	O
+rhabdomyolysis	POS	B-NP
+or	POS	O
+myoglobinuria	POS	B-NP
+.	POS	O
+(	POS	O
+ABSTRACT	POS	O
+TRUNCATED	POS	O
+AT	POS	O
+250	POS	O
+WORDS	POS	O
+)	POS	O
+Does	POS	O
+domperidone	POS	O
+potentiate	POS	O
+mirtazapine	POS	O
+-	POS	O
+associated	POS	O
+restless	POS	B-NP
+legs	POS	I-NP
+syndrome	POS	I-NP
+?	POS	O
+There	POS	O
+is	POS	O
+now	POS	O
+evidence	POS	O
+to	POS	O
+suggest	POS	O
+a	POS	O
+central	POS	O
+role	POS	O
+for	POS	O
+the	POS	O
+dopaminergic	POS	O
+system	POS	O
+in	POS	O
+restless	POS	B-NP
+legs	POS	I-NP
+syndrome	POS	I-NP
+(	POS	O
+RLS	POS	B-NP
+)	POS	O
+.	POS	O
+For	POS	O
+example	POS	O
+,	POS	O
+the	POS	O
+symptoms	POS	O
+of	POS	O
+RLS	POS	B-NP
+can	POS	O
+be	POS	O
+dramatically	POS	O
+improved	POS	O
+by	POS	O
+levodopa	POS	O
+and	POS	O
+dopamine	POS	O
+agonists	POS	O
+,	POS	O
+whereas	POS	O
+central	POS	O
+dopamine	POS	O
+D2	POS	O
+receptor	POS	O
+antagonists	POS	O
+can	POS	O
+induce	POS	O
+or	POS	O
+aggravate	POS	O
+RLS	POS	B-NP
+symptoms	POS	O
+.	POS	O
+To	POS	O
+our	POS	O
+knowledge	POS	O
+,	POS	O
+there	POS	O
+is	POS	O
+no	POS	O
+previous	POS	O
+report	POS	O
+regarding	POS	O
+whether	POS	O
+domperidone	POS	O
+,	POS	O
+a	POS	O
+peripheral	POS	O
+dopamine	POS	O
+D2	POS	O
+receptor	POS	O
+antagonist	POS	O
+,	POS	O
+can	POS	O
+also	POS	O
+induce	POS	O
+or	POS	O
+aggravate	POS	O
+symptoms	POS	O
+of	POS	O
+RLS	POS	B-NP
+.	POS	O
+Mirtazapine	POS	O
+,	POS	O
+the	POS	O
+first	POS	O
+noradrenergic	POS	O
+and	POS	O
+specific	POS	O
+serotonergic	POS	O
+antidepressant	POS	O
+(	POS	O
+NaSSA	POS	O
+)	POS	O
+,	POS	O
+has	POS	O
+been	POS	O
+associated	POS	O
+with	POS	O
+RLS	POS	B-NP
+in	POS	O
+several	POS	O
+recent	POS	O
+publications	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+report	POS	O
+here	POS	O
+a	POS	O
+depressed	POS	B-NP
+patient	POS	O
+comorbid	POS	O
+with	POS	O
+postprandial	POS	B-NP
+dyspepsia	POS	I-NP
+who	POS	O
+developed	POS	O
+RLS	POS	B-NP
+after	POS	O
+mirtazapine	POS	O
+had	POS	O
+been	POS	O
+added	POS	O
+to	POS	O
+his	POS	O
+domperidone	POS	O
+therapy	POS	O
+.	POS	O
+Our	POS	O
+patient	POS	O
+started	POS	O
+to	POS	O
+have	POS	O
+symptoms	POS	O
+of	POS	O
+RLS	POS	B-NP
+only	POS	O
+after	POS	O
+he	POS	O
+had	POS	O
+been	POS	O
+treated	POS	O
+with	POS	O
+mirtazapine	POS	O
+,	POS	O
+and	POS	O
+his	POS	O
+RLS	POS	B-NP
+symptoms	POS	O
+resolved	POS	O
+completely	POS	O
+upon	POS	O
+discontinuation	POS	O
+of	POS	O
+his	POS	O
+mirtazapine	POS	O
+.	POS	O
+Such	POS	O
+a	POS	O
+temporal	POS	O
+relationship	POS	O
+between	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+mirtazapine	POS	O
+and	POS	O
+the	POS	O
+symptoms	POS	O
+of	POS	O
+RLS	POS	B-NP
+in	POS	O
+our	POS	O
+patient	POS	O
+did	POS	O
+not	POS	O
+support	POS	O
+a	POS	O
+potentiating	POS	O
+effect	POS	O
+of	POS	O
+domperione	POS	O
+on	POS	O
+mirtazapine	POS	O
+-	POS	O
+associated	POS	O
+RLS	POS	B-NP
+.	POS	O
+However	POS	O
+,	POS	O
+physicians	POS	O
+should	POS	O
+be	POS	O
+aware	POS	O
+of	POS	O
+the	POS	O
+possibility	POS	O
+that	POS	O
+mirtazapine	POS	O
+can	POS	O
+be	POS	O
+associated	POS	O
+with	POS	O
+RLS	POS	B-NP
+in	POS	O
+some	POS	O
+individuals	POS	O
+,	POS	O
+especially	POS	O
+those	POS	O
+receiving	POS	O
+concomitant	POS	O
+dopamine	POS	O
+D2	POS	O
+receptor	POS	O
+antagonists	POS	O
+.	POS	O
+Antiandrogenic	POS	O
+therapy	POS	O
+can	POS	O
+cause	POS	O
+coronary	POS	B-NP
+arterial	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+AIM	POS	O
+:	POS	O
+To	POS	O
+study	POS	O
+the	POS	O
+change	POS	O
+of	POS	O
+lipid	POS	O
+metabolism	POS	O
+by	POS	O
+antiandrogen	POS	O
+therapy	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+prostate	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+MATERIALS	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+studied	POS	O
+with	POS	O
+a	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+years	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+the	POS	O
+changes	POS	O
+in	POS	O
+plasma	POS	O
+cholesterols	POS	O
+(	POS	O
+C	POS	O
+)	POS	O
+,	POS	O
+triglycerides	POS	O
+(	POS	O
+TG	POS	O
+)	POS	O
+,	POS	O
+lipoproteins	POS	O
+(	POS	O
+LP	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+apolipoproteins	POS	O
+(	POS	O
+Apo	POS	O
+)	POS	O
+B	POS	O
+-	POS	O
+100	POS	O
+,	POS	O
+A	POS	O
+-	POS	O
+I	POS	O
+,	POS	O
+and	POS	O
+A	POS	O
+-	POS	O
+II	POS	O
+pro	POS	O
+fi	POS	O
+les	POS	O
+in	POS	O
+24	POS	O
+patients	POS	O
+of	POS	O
+mean	POS	O
+age	POS	O
+60	POS	O
+years	POS	O
+with	POS	O
+low	POS	O
+risk	POS	O
+prostate	POS	B-NP
+cancer	POS	I-NP
+(	POS	O
+stage	POS	O
+:	POS	O
+T1cN0M0	POS	O
+,	POS	O
+Gleason	POS	O
+score	POS	O
+:	POS	O
+2	POS	O
+-	POS	O
+5	POS	O
+)	POS	O
+during	POS	O
+treatment	POS	O
+with	POS	O
+cyproterone	POS	O
+acetate	POS	O
+(	POS	O
+CPA	POS	O
+)	POS	O
+without	POS	O
+surgical	POS	O
+management	POS	O
+or	POS	O
+radiation	POS	O
+therapy	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Significant	POS	O
+decreases	POS	O
+of	POS	O
+HDL	POS	O
+-	POS	O
+C	POS	O
+,	POS	O
+Apo	POS	O
+A	POS	O
+-	POS	O
+I	POS	O
+and	POS	O
+Apo	POS	O
+A	POS	O
+-	POS	O
+II	POS	O
+and	POS	O
+an	POS	O
+increase	POS	O
+of	POS	O
+triglyceride	POS	O
+levels	POS	O
+in	POS	O
+VLDL	POS	O
+were	POS	O
+induced	POS	O
+by	POS	O
+CPA	POS	O
+.	POS	O
+After	POS	O
+a	POS	O
+period	POS	O
+of	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+years	POS	O
+on	POS	O
+CPA	POS	O
+treatment	POS	O
+,	POS	O
+four	POS	O
+patients	POS	O
+out	POS	O
+of	POS	O
+twenty	POS	O
+-	POS	O
+four	POS	O
+were	POS	O
+found	POS	O
+to	POS	O
+be	POS	O
+affected	POS	O
+by	POS	O
+coronary	POS	B-NP
+heart	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Ischaemic	POS	B-NP
+coronary	POS	I-NP
+arteriosclerosis	POS	I-NP
+with	POS	O
+an	POS	O
+incidence	POS	O
+rate	POS	O
+of	POS	O
+16	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+as	POS	O
+caused	POS	O
+by	POS	O
+prolonged	POS	O
+CPA	POS	O
+therapy	POS	O
+is	POS	O
+mediated	POS	O
+through	POS	O
+changes	POS	O
+in	POS	O
+HDL	POS	O
+cholesterol	POS	O
+,	POS	O
+Apo	POS	O
+A	POS	O
+-	POS	O
+I	POS	O
+and	POS	O
+Apo	POS	O
+A	POS	O
+-	POS	O
+II	POS	O
+pro	POS	O
+fi	POS	O
+les	POS	O
+,	POS	O
+other	POS	O
+than	POS	O
+the	POS	O
+well	POS	O
+-	POS	O
+known	POS	O
+hyperglyceridemic	POS	O
+effect	POS	O
+caused	POS	O
+by	POS	O
+estrogen	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+Fluorouracil	POS	O
+cardiotoxicity	POS	B-NP
+induced	POS	O
+by	POS	O
+alpha	POS	O
+-	POS	O
+fluoro	POS	O
+-	POS	O
+beta	POS	O
+-	POS	O
+alanine	POS	O
+.	POS	O
+Cardiotoxicity	POS	B-NP
+is	POS	O
+a	POS	O
+rare	POS	O
+complication	POS	O
+occurring	POS	O
+during	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+(	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+)	POS	O
+treatment	POS	O
+for	POS	O
+malignancies	POS	B-NP
+.	POS	O
+We	POS	O
+herein	POS	O
+report	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+70	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+with	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+,	POS	O
+in	POS	O
+whom	POS	O
+a	POS	O
+high	POS	O
+serum	POS	O
+level	POS	O
+of	POS	O
+alpha	POS	O
+-	POS	O
+fluoro	POS	O
+-	POS	O
+beta	POS	O
+-	POS	O
+alanine	POS	O
+(	POS	O
+FBAL	POS	O
+)	POS	O
+was	POS	O
+observed	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+,	POS	O
+who	POS	O
+had	POS	O
+unresectable	POS	O
+colon	POS	B-NP
+cancer	POS	I-NP
+metastases	POS	O
+to	POS	O
+the	POS	O
+liver	POS	O
+and	POS	O
+lung	POS	O
+,	POS	O
+was	POS	O
+referred	POS	O
+to	POS	O
+us	POS	O
+for	POS	O
+chemotherapy	POS	O
+from	POS	O
+an	POS	O
+affiliated	POS	O
+hospital	POS	O
+;	POS	O
+he	POS	O
+had	POS	O
+no	POS	O
+cardiac	POS	B-NP
+history	POS	I-NP
+.	POS	O
+After	POS	O
+admission	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+received	POS	O
+a	POS	O
+continuous	POS	O
+intravenous	POS	O
+infusion	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+(	POS	O
+1000	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+,	POS	O
+during	POS	O
+which	POS	O
+precordial	POS	B-NP
+pain	POS	I-NP
+with	POS	O
+right	POS	B-NP
+bundle	POS	I-NP
+branch	POS	I-NP
+block	POS	I-NP
+occurred	POS	O
+concomitantly	POS	O
+with	POS	O
+a	POS	O
+high	POS	O
+serum	POS	O
+FBAL	POS	O
+concentration	POS	O
+of	POS	O
+1955	POS	O
+ng	POS	O
+/	POS	O
+ml	POS	O
+.	POS	O
+Both	POS	O
+the	POS	O
+precordial	POS	B-NP
+pain	POS	I-NP
+and	POS	O
+the	POS	O
+electrocardiographic	POS	O
+changes	POS	O
+disappeared	POS	O
+spontaneously	POS	O
+after	POS	O
+the	POS	O
+discontinuation	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+.	POS	O
+As	POS	O
+the	POS	O
+precordial	POS	B-NP
+pain	POS	I-NP
+in	POS	O
+this	POS	O
+patient	POS	O
+was	POS	O
+considered	POS	O
+to	POS	O
+have	POS	O
+been	POS	O
+due	POS	O
+to	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+,	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+was	POS	O
+abandoned	POS	O
+.	POS	O
+Instead	POS	O
+,	POS	O
+oral	POS	O
+administration	POS	O
+of	POS	O
+S	POS	O
+-	POS	O
+1	POS	O
+(	POS	O
+a	POS	O
+derivative	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+)	POS	O
+,	POS	O
+at	POS	O
+200	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+twice	POS	O
+a	POS	O
+week	POS	O
+,	POS	O
+was	POS	O
+instituted	POS	O
+,	POS	O
+because	POS	O
+S	POS	O
+-	POS	O
+1	POS	O
+has	POS	O
+a	POS	O
+strong	POS	O
+inhibitory	POS	O
+effect	POS	O
+on	POS	O
+dihydropyrimidine	POS	O
+dehydrogenase	POS	O
+,	POS	O
+which	POS	O
+catalyzes	POS	O
+the	POS	O
+degradative	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+into	POS	O
+FBAL	POS	O
+.	POS	O
+The	POS	O
+serum	POS	O
+FBAL	POS	O
+concentration	POS	O
+subsequently	POS	O
+decreased	POS	O
+to	POS	O
+352	POS	O
+ng	POS	O
+/	POS	O
+ml	POS	O
+,	POS	O
+the	POS	O
+same	POS	O
+as	POS	O
+the	POS	O
+value	POS	O
+measured	POS	O
+on	POS	O
+the	POS	O
+first	POS	O
+day	POS	O
+of	POS	O
+S	POS	O
+-	POS	O
+1	POS	O
+administration	POS	O
+.	POS	O
+Thereafter	POS	O
+,	POS	O
+no	POS	O
+cardiac	POS	O
+symptoms	POS	O
+were	POS	O
+observed	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+achieved	POS	O
+a	POS	O
+partial	POS	O
+response	POS	O
+6	POS	O
+months	POS	O
+after	POS	O
+the	POS	O
+initiation	POS	O
+of	POS	O
+the	POS	O
+S	POS	O
+-	POS	O
+1	POS	O
+treatment	POS	O
+.	POS	O
+The	POS	O
+experience	POS	O
+of	POS	O
+this	POS	O
+case	POS	O
+,	POS	O
+together	POS	O
+with	POS	O
+a	POS	O
+review	POS	O
+of	POS	O
+the	POS	O
+literature	POS	O
+,	POS	O
+suggests	POS	O
+that	POS	O
+FBAL	POS	O
+is	POS	O
+related	POS	O
+to	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+S	POS	O
+-	POS	O
+1	POS	O
+may	POS	O
+be	POS	O
+administered	POS	O
+safely	POS	O
+to	POS	O
+patients	POS	O
+with	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+Hepatocellular	POS	B-NP
+carcinoma	POS	I-NP
+in	POS	O
+Fanconi	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+anemia	POS	I-NP
+treated	POS	O
+with	POS	O
+androgen	POS	O
+and	POS	O
+corticosteroid	POS	O
+.	POS	O
+The	POS	O
+case	POS	O
+of	POS	O
+an	POS	O
+11	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+boy	POS	O
+is	POS	O
+reported	POS	O
+who	POS	O
+was	POS	O
+known	POS	O
+to	POS	O
+have	POS	O
+Fanconi	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+anemia	POS	I-NP
+for	POS	O
+3	POS	O
+years	POS	O
+and	POS	O
+was	POS	O
+treated	POS	O
+with	POS	O
+androgens	POS	O
+,	POS	O
+corticosteroids	POS	O
+and	POS	O
+transfusions	POS	O
+.	POS	O
+Two	POS	O
+weeks	POS	O
+before	POS	O
+his	POS	O
+death	POS	O
+he	POS	O
+was	POS	O
+readmitted	POS	O
+because	POS	O
+of	POS	O
+aplastic	POS	B-NP
+crisis	POS	I-NP
+with	POS	O
+septicemia	POS	B-NP
+and	POS	O
+marked	POS	O
+abnormalities	POS	O
+in	POS	O
+liver	POS	O
+function	POS	O
+and	POS	O
+died	POS	O
+of	POS	O
+hemorrhagic	POS	B-NP
+bronchopneumonia	POS	I-NP
+.	POS	O
+At	POS	O
+autopsy	POS	O
+peliosis	POS	B-NP
+and	POS	O
+multiple	POS	B-NP
+hepatic	POS	I-NP
+tumors	POS	I-NP
+were	POS	O
+found	POS	O
+which	POS	O
+histologically	POS	O
+proved	POS	O
+to	POS	O
+be	POS	O
+well	POS	O
+-	POS	O
+differentiated	POS	O
+hepatocellular	POS	O
+carcinoma	POS	B-NP
+.	POS	O
+This	POS	O
+case	POS	O
+contributes	POS	O
+to	POS	O
+the	POS	O
+previous	POS	O
+observations	POS	O
+that	POS	O
+non	POS	B-NP
+-	POS	I-NP
+metastasizing	POS	I-NP
+hepatic	POS	I-NP
+neoplasms	POS	I-NP
+and	POS	O
+peliosis	POS	B-NP
+can	POS	O
+develop	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+androgen	POS	O
+-	POS	O
+and	POS	O
+corticosteroid	POS	O
+-	POS	O
+treated	POS	O
+Fanconi	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+anemia	POS	I-NP
+.	POS	O
+The	POS	O
+influence	POS	O
+of	POS	O
+the	POS	O
+time	POS	O
+interval	POS	O
+between	POS	O
+monoHER	POS	O
+and	POS	O
+doxorubicin	POS	O
+administration	POS	O
+on	POS	O
+the	POS	O
+protection	POS	O
+against	POS	O
+doxorubicin	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+in	POS	O
+mice	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+Despite	POS	O
+its	POS	O
+well	POS	O
+-	POS	O
+known	POS	O
+cardiotoxicity	POS	B-NP
+,	POS	O
+the	POS	O
+anthracyclin	POS	O
+doxorubicin	POS	O
+(	POS	O
+DOX	POS	O
+)	POS	O
+continues	POS	O
+to	POS	O
+be	POS	O
+an	POS	O
+effective	POS	O
+and	POS	O
+widely	POS	O
+used	POS	O
+chemotherapeutic	POS	O
+agent	POS	O
+.	POS	O
+DOX	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+damage	POS	I-NP
+presumably	POS	O
+results	POS	O
+from	POS	O
+the	POS	O
+formation	POS	O
+of	POS	O
+free	POS	O
+radicals	POS	O
+by	POS	O
+DOX	POS	O
+.	POS	O
+Reactive	POS	O
+oxygen	POS	O
+species	POS	O
+particularly	POS	O
+affect	POS	O
+the	POS	O
+cardiac	POS	O
+myocytes	POS	O
+because	POS	O
+these	POS	O
+cells	POS	O
+seem	POS	O
+to	POS	O
+have	POS	O
+a	POS	O
+relatively	POS	O
+poor	POS	O
+antioxidant	POS	O
+defense	POS	O
+system	POS	O
+.	POS	O
+The	POS	O
+semisynthetic	POS	O
+flavonoid	POS	O
+monohydroxyethylrutoside	POS	O
+(	POS	O
+monoHER	POS	O
+)	POS	O
+showed	POS	O
+cardioprotection	POS	O
+against	POS	O
+DOX	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+through	POS	O
+its	POS	O
+radical	POS	O
+scavenging	POS	O
+and	POS	O
+iron	POS	O
+chelating	POS	O
+properties	POS	O
+.	POS	O
+Because	POS	O
+of	POS	O
+the	POS	O
+relatively	POS	O
+short	POS	O
+final	POS	O
+half	POS	O
+-	POS	O
+life	POS	O
+of	POS	O
+monoHER	POS	O
+(	POS	O
+about	POS	O
+30	POS	O
+min	POS	O
+)	POS	O
+,	POS	O
+it	POS	O
+is	POS	O
+expected	POS	O
+that	POS	O
+the	POS	O
+time	POS	O
+interval	POS	O
+between	POS	O
+monoHER	POS	O
+and	POS	O
+DOX	POS	O
+might	POS	O
+be	POS	O
+of	POS	O
+influence	POS	O
+on	POS	O
+the	POS	O
+cardioprotective	POS	O
+effect	POS	O
+of	POS	O
+monoHER	POS	O
+.	POS	O
+Therefore	POS	O
+,	POS	O
+the	POS	O
+aim	POS	O
+of	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+investigate	POS	O
+this	POS	O
+possible	POS	O
+effect	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Six	POS	O
+groups	POS	O
+of	POS	O
+6	POS	O
+BALB	POS	O
+/	POS	O
+c	POS	O
+mice	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+saline	POS	O
+,	POS	O
+DOX	POS	O
+alone	POS	O
+or	POS	O
+DOX	POS	O
+(	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+)	POS	O
+preceded	POS	O
+by	POS	O
+monoHER	POS	O
+(	POS	O
+500	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+with	POS	O
+an	POS	O
+interval	POS	O
+of	POS	O
+10	POS	O
+,	POS	O
+30	POS	O
+,	POS	O
+60	POS	O
+or	POS	O
+120	POS	O
+min	POS	O
+.	POS	O
+After	POS	O
+a	POS	O
+6	POS	O
+-	POS	O
+week	POS	O
+treatment	POS	O
+period	POS	O
+and	POS	O
+additional	POS	O
+observation	POS	O
+for	POS	O
+2	POS	O
+weeks	POS	O
+,	POS	O
+the	POS	O
+mice	POS	O
+were	POS	O
+sacrificed	POS	O
+.	POS	O
+Their	POS	O
+cardiac	POS	O
+tissues	POS	O
+were	POS	O
+processed	POS	O
+for	POS	O
+light	POS	O
+microscopy	POS	O
+,	POS	O
+after	POS	O
+which	POS	O
+cardiomyocyte	POS	O
+damage	POS	O
+was	POS	O
+evaluated	POS	O
+according	POS	O
+to	POS	O
+Billingham	POS	O
+(	POS	O
+in	POS	O
+Cancer	POS	O
+Treat	POS	O
+Rep	POS	O
+62	POS	O
+(	POS	O
+6	POS	O
+)	POS	O
+:	POS	O
+865	POS	O
+-	POS	O
+872	POS	O
+,	POS	O
+1978	POS	O
+)	POS	O
+.	POS	O
+Microscopic	POS	O
+evaluation	POS	O
+revealed	POS	O
+that	POS	O
+treatment	POS	O
+with	POS	O
+DOX	POS	O
+alone	POS	O
+induced	POS	O
+significant	POS	O
+cardiac	POS	B-NP
+damage	POS	I-NP
+in	POS	O
+comparison	POS	O
+to	POS	O
+the	POS	O
+saline	POS	O
+control	POS	O
+group	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+number	POS	O
+of	POS	O
+damaged	POS	O
+cardiomyocytes	POS	O
+was	POS	O
+9	POS	O
+.	POS	O
+6	POS	O
+-	POS	O
+fold	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+4	POS	O
+.	POS	O
+4	POS	O
+-	POS	O
+21	POS	O
+.	POS	O
+0	POS	O
+)	POS	O
+higher	POS	O
+in	POS	O
+mice	POS	O
+treated	POS	O
+with	POS	O
+DOX	POS	O
+alone	POS	O
+than	POS	O
+that	POS	O
+in	POS	O
+animals	POS	O
+of	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+.	POS	O
+The	POS	O
+ratio	POS	O
+of	POS	O
+aberrant	POS	O
+cardiomyocytes	POS	O
+in	POS	O
+mice	POS	O
+treated	POS	O
+with	POS	O
+DOX	POS	O
+preceded	POS	O
+by	POS	O
+monoHER	POS	O
+and	POS	O
+those	POS	O
+in	POS	O
+mice	POS	O
+treated	POS	O
+with	POS	O
+saline	POS	O
+ranged	POS	O
+from	POS	O
+1	POS	O
+.	POS	O
+6	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+8	POS	O
+(	POS	O
+mean	POS	O
+2	POS	O
+.	POS	O
+2	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+1	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+019	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+protective	POS	O
+effect	POS	O
+by	POS	O
+adding	POS	O
+monoHER	POS	O
+before	POS	O
+DOX	POS	O
+led	POS	O
+to	POS	O
+a	POS	O
+significant	POS	O
+4	POS	O
+.	POS	O
+4	POS	O
+-	POS	O
+fold	POS	O
+reduction	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
+-	POS	O
+8	POS	O
+.	POS	O
+2	POS	O
+)	POS	O
+of	POS	O
+abnormal	POS	O
+cardiomyocytes	POS	O
+.	POS	O
+This	POS	O
+protective	POS	O
+effect	POS	O
+did	POS	O
+not	POS	O
+depend	POS	O
+on	POS	O
+the	POS	O
+time	POS	O
+interval	POS	O
+between	POS	O
+monoHER	POS	O
+and	POS	O
+DOX	POS	O
+administration	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+345	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+The	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+in	POS	O
+an	POS	O
+outpatient	POS	O
+clinical	POS	O
+setting	POS	O
+monoHER	POS	O
+may	POS	O
+be	POS	O
+administered	POS	O
+shortly	POS	O
+before	POS	O
+DOX	POS	O
+.	POS	O
+Clinical	POS	O
+evaluation	POS	O
+of	POS	O
+adverse	POS	O
+effects	POS	O
+during	POS	O
+bepridil	POS	O
+administration	POS	O
+for	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+and	POS	O
+flutter	POS	B-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Bepridil	POS	O
+hydrochloride	POS	O
+(	POS	O
+Bpd	POS	O
+)	POS	O
+has	POS	O
+attracted	POS	O
+attention	POS	O
+as	POS	O
+an	POS	O
+effective	POS	O
+drug	POS	O
+for	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+(	POS	O
+AF	POS	B-NP
+)	POS	O
+and	POS	O
+atrial	POS	B-NP
+flutter	POS	I-NP
+(	POS	O
+AFL	POS	B-NP
+)	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+serious	POS	O
+adverse	POS	O
+effects	POS	O
+,	POS	O
+including	POS	O
+torsade	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+(	POS	O
+Tdp	POS	B-NP
+)	POS	O
+,	POS	O
+have	POS	O
+been	POS	O
+reported	POS	O
+.	POS	O
+METHODS	POS	O
+AND	POS	O
+RESULTS	POS	O
+:	POS	O
+Adverse	POS	O
+effects	POS	O
+of	POS	O
+Bpd	POS	O
+requiring	POS	O
+discontinuation	POS	O
+of	POS	O
+treatment	POS	O
+were	POS	O
+evaluated	POS	O
+.	POS	O
+Bpd	POS	O
+was	POS	O
+administered	POS	O
+to	POS	O
+459	POS	O
+patients	POS	O
+(	POS	O
+361	POS	O
+males	POS	O
+,	POS	O
+63	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+12	POS	O
+years	POS	O
+old	POS	O
+)	POS	O
+comprising	POS	O
+378	POS	O
+AF	POS	B-NP
+and	POS	O
+81	POS	O
+AFL	POS	B-NP
+cases	POS	O
+.	POS	O
+Mean	POS	O
+left	POS	O
+ventricular	POS	O
+ejection	POS	O
+fraction	POS	O
+and	POS	O
+atrial	POS	O
+dimension	POS	O
+(	POS	O
+LAD	POS	O
+)	POS	O
+were	POS	O
+66	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+11	POS	O
+%	POS	O
+and	POS	O
+40	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+mm	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Adverse	POS	O
+effects	POS	O
+were	POS	O
+observed	POS	O
+in	POS	O
+19	POS	O
+patients	POS	O
+(	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+during	POS	O
+an	POS	O
+average	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+of	POS	O
+20	POS	O
+months	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+marked	POS	O
+QT	POS	O
+prolongation	POS	O
+greater	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+55	POS	O
+s	POS	O
+in	POS	O
+13	POS	O
+patients	POS	O
+,	POS	O
+bradycardia	POS	B-NP
+less	POS	O
+than	POS	O
+40	POS	O
+beats	POS	O
+/	POS	O
+min	POS	O
+in	POS	O
+6	POS	O
+patients	POS	O
+,	POS	O
+dizziness	POS	B-NP
+and	POS	O
+general	POS	B-NP
+fatigue	POS	I-NP
+in	POS	O
+1	POS	O
+patient	POS	O
+each	POS	O
+.	POS	O
+In	POS	O
+4	POS	O
+of	POS	O
+13	POS	O
+patients	POS	O
+with	POS	O
+QT	POS	B-NP
+prolongation	POS	I-NP
+,	POS	O
+Tdp	POS	B-NP
+occurred	POS	O
+.	POS	O
+The	POS	O
+major	POS	O
+triggering	POS	O
+factors	POS	O
+of	POS	O
+Tdp	POS	O
+were	POS	O
+hypokalemia	POS	B-NP
+and	POS	O
+sudden	POS	O
+decrease	POS	O
+in	POS	O
+heart	POS	O
+rate	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+no	POS	O
+differences	POS	O
+in	POS	O
+the	POS	O
+clinical	POS	O
+backgrounds	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+with	POS	O
+and	POS	O
+without	POS	O
+Tdp	POS	O
+other	POS	O
+than	POS	O
+LAD	POS	O
+and	POS	O
+age	POS	O
+,	POS	O
+which	POS	O
+were	POS	O
+larger	POS	O
+and	POS	O
+older	POS	O
+in	POS	O
+the	POS	O
+patients	POS	O
+with	POS	O
+Tdp	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Careful	POS	O
+observation	POS	O
+of	POS	O
+serum	POS	O
+potassium	POS	O
+concentration	POS	O
+and	POS	O
+the	POS	O
+ECG	POS	O
+should	POS	O
+always	POS	O
+be	POS	O
+done	POS	O
+during	POS	O
+Bpd	POS	O
+administration	POS	O
+,	POS	O
+particularly	POS	O
+in	POS	O
+elderly	POS	O
+patients	POS	O
+.	POS	O
+Enhanced	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+hypertrophy	POS	I-NP
+in	POS	O
+transgenic	POS	O
+rats	POS	O
+with	POS	O
+low	POS	O
+brain	POS	O
+angiotensinogen	POS	O
+.	POS	O
+We	POS	O
+have	POS	O
+previously	POS	O
+shown	POS	O
+that	POS	O
+a	POS	O
+permanent	POS	B-NP
+deficiency	POS	I-NP
+in	POS	I-NP
+the	POS	I-NP
+brain	POS	I-NP
+renin	POS	I-NP
+-	POS	I-NP
+angiotensin	POS	I-NP
+system	POS	I-NP
+(	POS	O
+RAS	POS	O
+)	POS	O
+may	POS	O
+increase	POS	O
+the	POS	O
+sensitivity	POS	O
+of	POS	O
+the	POS	O
+baroreflex	POS	O
+control	POS	O
+of	POS	O
+heart	POS	O
+rate	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+we	POS	O
+aimed	POS	O
+at	POS	O
+studying	POS	O
+the	POS	O
+involvement	POS	O
+of	POS	O
+the	POS	O
+brain	POS	O
+RAS	POS	O
+in	POS	O
+the	POS	O
+cardiac	POS	O
+reactivity	POS	O
+to	POS	O
+the	POS	O
+beta	POS	O
+-	POS	O
+adrenoceptor	POS	O
+(	POS	O
+beta	POS	O
+-	POS	O
+AR	POS	O
+)	POS	O
+agonist	POS	O
+isoproterenol	POS	O
+(	POS	O
+Iso	POS	O
+)	POS	O
+.	POS	O
+Transgenic	POS	O
+rats	POS	O
+with	POS	O
+low	POS	O
+brain	POS	O
+angiotensinogen	POS	O
+(	POS	O
+TGR	POS	O
+)	POS	O
+were	POS	O
+used	POS	O
+.	POS	O
+In	POS	O
+isolated	POS	O
+hearts	POS	O
+,	POS	O
+Iso	POS	O
+induced	POS	O
+a	POS	O
+significantly	POS	O
+greater	POS	O
+increase	POS	O
+in	POS	O
+left	POS	O
+ventricular	POS	O
+(	POS	O
+LV	POS	O
+)	POS	O
+pressure	POS	O
+and	POS	O
+maximal	POS	O
+contraction	POS	O
+(	POS	O
++	POS	O
+dP	POS	O
+/	POS	O
+dt	POS	O
+(	POS	O
+max	POS	O
+)	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+TGR	POS	O
+than	POS	O
+in	POS	O
+the	POS	O
+Sprague	POS	O
+-	POS	O
+Dawley	POS	O
+(	POS	O
+SD	POS	O
+)	POS	O
+rats	POS	O
+.	POS	O
+LV	POS	B-NP
+hypertrophy	POS	I-NP
+induced	POS	O
+by	POS	O
+Iso	POS	O
+treatment	POS	O
+was	POS	O
+significantly	POS	O
+higher	POS	O
+in	POS	O
+TGR	POS	O
+than	POS	O
+in	POS	O
+SD	POS	O
+rats	POS	O
+(	POS	O
+in	POS	O
+g	POS	O
+LV	POS	O
+wt	POS	O
+/	POS	O
+100	POS	O
+g	POS	O
+body	POS	O
+wt	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+28	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+004	POS	O
+vs	POS	O
+.	POS	O
+0	POS	O
+.	POS	O
+24	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+004	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+greater	POS	O
+LV	POS	B-NP
+hypertrophy	POS	I-NP
+in	POS	O
+TGR	POS	O
+rats	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+more	POS	O
+pronounced	POS	O
+downregulation	POS	O
+of	POS	O
+beta	POS	O
+-	POS	O
+AR	POS	O
+and	POS	O
+upregulation	POS	O
+of	POS	O
+LV	POS	O
+beta	POS	O
+-	POS	O
+AR	POS	O
+kinase	POS	O
+-	POS	O
+1	POS	O
+mRNA	POS	O
+levels	POS	O
+compared	POS	O
+with	POS	O
+those	POS	O
+in	POS	O
+SD	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+decrease	POS	O
+in	POS	O
+the	POS	O
+heart	POS	O
+rate	POS	O
+(	POS	O
+HR	POS	O
+)	POS	O
+induced	POS	O
+by	POS	O
+the	POS	O
+beta	POS	O
+-	POS	O
+AR	POS	O
+antagonist	POS	O
+metoprolol	POS	O
+in	POS	O
+conscious	POS	O
+rats	POS	O
+was	POS	O
+significantly	POS	O
+attenuated	POS	O
+in	POS	O
+TGR	POS	O
+compared	POS	O
+with	POS	O
+SD	POS	O
+rats	POS	O
+(	POS	O
+-	POS	O
+9	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+vs	POS	O
+.	POS	O
+-	POS	O
+18	POS	O
+.	POS	O
+1	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+whereas	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+parasympathetic	POS	O
+blockade	POS	O
+by	POS	O
+atropine	POS	O
+on	POS	O
+HR	POS	O
+was	POS	O
+similar	POS	O
+in	POS	O
+both	POS	O
+strains	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+TGR	POS	O
+are	POS	O
+more	POS	O
+sensitive	POS	O
+to	POS	O
+beta	POS	O
+-	POS	O
+AR	POS	O
+agonist	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	O
+inotropic	POS	O
+response	POS	O
+and	POS	O
+hypertrophy	POS	B-NP
+,	POS	O
+possibly	POS	O
+due	POS	O
+to	POS	O
+chronically	POS	O
+low	POS	O
+sympathetic	POS	O
+outflow	POS	O
+directed	POS	O
+to	POS	O
+the	POS	O
+heart	POS	O
+.	POS	O
+Drug	POS	O
+-	POS	O
+induced	POS	O
+long	POS	O
+QT	POS	B-NP
+syndrome	POS	I-NP
+in	POS	O
+injection	POS	O
+drug	POS	O
+users	POS	O
+receiving	POS	O
+methadone	POS	O
+:	POS	O
+high	POS	O
+frequency	POS	O
+in	POS	O
+hospitalized	POS	O
+patients	POS	O
+and	POS	O
+risk	POS	O
+factors	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Drug	POS	O
+-	POS	O
+induced	POS	O
+long	POS	O
+QT	POS	B-NP
+syndrome	POS	I-NP
+is	POS	O
+a	POS	O
+serious	POS	O
+adverse	POS	O
+drug	POS	O
+reaction	POS	O
+.	POS	O
+Methadone	POS	O
+prolongs	POS	O
+the	POS	O
+QT	POS	O
+interval	POS	O
+in	POS	O
+vitro	POS	O
+in	POS	O
+a	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+manner	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+inpatient	POS	O
+setting	POS	O
+,	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+QT	POS	O
+interval	POS	O
+prolongation	POS	O
+with	POS	O
+methadone	POS	O
+treatment	POS	O
+,	POS	O
+its	POS	O
+dose	POS	O
+dependence	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+importance	POS	O
+of	POS	O
+cofactors	POS	O
+such	POS	O
+as	POS	O
+drug	POS	O
+-	POS	O
+drug	POS	O
+interactions	POS	O
+remain	POS	O
+unknown	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+performed	POS	O
+a	POS	O
+systematic	POS	O
+,	POS	O
+retrospective	POS	O
+study	POS	O
+comparing	POS	O
+active	POS	O
+or	POS	O
+former	POS	O
+intravenous	POS	O
+drug	POS	O
+users	POS	O
+receiving	POS	O
+methadone	POS	O
+and	POS	O
+those	POS	O
+not	POS	O
+receiving	POS	O
+methadone	POS	O
+among	POS	O
+all	POS	O
+patients	POS	O
+hospitalized	POS	O
+over	POS	O
+a	POS	O
+5	POS	O
+-	POS	O
+year	POS	O
+period	POS	O
+in	POS	O
+a	POS	O
+tertiary	POS	O
+care	POS	O
+hospital	POS	O
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+167	POS	O
+patients	POS	O
+receiving	POS	O
+methadone	POS	O
+fulfilled	POS	O
+the	POS	O
+inclusion	POS	O
+criteria	POS	O
+and	POS	O
+were	POS	O
+compared	POS	O
+with	POS	O
+a	POS	O
+control	POS	O
+group	POS	O
+of	POS	O
+80	POS	O
+injection	POS	O
+drug	POS	O
+users	POS	O
+not	POS	O
+receiving	POS	O
+methadone	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+to	POS	O
+methadone	POS	O
+dose	POS	O
+,	POS	O
+15	POS	O
+demographic	POS	O
+,	POS	O
+biological	POS	O
+,	POS	O
+and	POS	O
+pharmacological	POS	O
+variables	POS	O
+were	POS	O
+considered	POS	O
+as	POS	O
+potential	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+QT	POS	B-NP
+prolongation	POS	I-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Among	POS	O
+167	POS	O
+methadone	POS	O
+maintenance	POS	O
+patients	POS	O
+,	POS	O
+the	POS	O
+prevalence	POS	O
+of	POS	O
+QTc	POS	O
+prolongation	POS	O
+to	POS	O
+0	POS	O
+.	POS	O
+50	POS	O
+second	POS	O
+(	POS	O
+(	POS	O
+1	POS	O
+/	POS	O
+2	POS	O
+)	POS	O
+)	POS	O
+or	POS	O
+longer	POS	O
+was	POS	O
+16	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+compared	POS	O
+with	POS	O
+0	POS	O
+%	POS	O
+in	POS	O
+80	POS	O
+control	POS	O
+subjects	POS	O
+.	POS	O
+Six	POS	O
+patients	POS	O
+(	POS	O
+3	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+methadone	POS	O
+group	POS	O
+presented	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+.	POS	O
+QTc	POS	O
+length	POS	O
+was	POS	O
+weakly	POS	O
+but	POS	O
+significantly	POS	O
+associated	POS	O
+with	POS	O
+methadone	POS	O
+daily	POS	O
+dose	POS	O
+(	POS	O
+Spearman	POS	O
+rank	POS	O
+correlation	POS	O
+coefficient	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+20	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+Multivariate	POS	O
+regression	POS	O
+analysis	POS	O
+allowed	POS	O
+attribution	POS	O
+of	POS	O
+31	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+of	POS	O
+QTc	POS	O
+variability	POS	O
+to	POS	O
+methadone	POS	O
+dose	POS	O
+,	POS	O
+cytochrome	POS	O
+P	POS	O
+-	POS	O
+450	POS	O
+3A4	POS	O
+drug	POS	O
+-	POS	O
+drug	POS	O
+interactions	POS	O
+,	POS	O
+hypokalemia	POS	B-NP
+,	POS	O
+and	POS	O
+altered	POS	B-NP
+liver	POS	I-NP
+function	POS	I-NP
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+QT	POS	O
+interval	POS	O
+prolongation	POS	O
+in	POS	O
+methadone	POS	O
+maintenance	POS	O
+patients	POS	O
+hospitalized	POS	O
+in	POS	O
+a	POS	O
+tertiary	POS	O
+care	POS	O
+center	POS	O
+is	POS	O
+a	POS	O
+frequent	POS	O
+finding	POS	O
+.	POS	O
+Methadone	POS	O
+dose	POS	O
+,	POS	O
+presence	POS	O
+of	POS	O
+cytochrome	POS	O
+P	POS	O
+-	POS	O
+450	POS	O
+3A4	POS	O
+inhibitors	POS	O
+,	POS	O
+potassium	POS	O
+level	POS	O
+,	POS	O
+and	POS	O
+liver	POS	O
+function	POS	O
+contribute	POS	O
+to	POS	O
+QT	POS	B-NP
+prolongation	POS	I-NP
+.	POS	O
+Long	POS	B-NP
+QT	POS	I-NP
+syndrome	POS	I-NP
+can	POS	O
+occur	POS	O
+with	POS	O
+low	POS	O
+doses	POS	O
+of	POS	O
+methadone	POS	O
+.	POS	O
+Mechanisms	POS	O
+of	POS	O
+hypertension	POS	B-NP
+induced	POS	O
+by	POS	O
+nitric	POS	O
+oxide	POS	O
+(	POS	O
+NO	POS	O
+)	POS	O
+deficiency	POS	O
+:	POS	O
+focus	POS	O
+on	POS	O
+venous	POS	O
+function	POS	O
+.	POS	O
+Loss	POS	O
+of	POS	O
+endothelial	POS	O
+cell	POS	O
+-	POS	O
+derived	POS	O
+nitric	POS	O
+oxide	POS	O
+(	POS	O
+NO	POS	O
+)	POS	O
+in	POS	O
+hypertension	POS	B-NP
+is	POS	O
+a	POS	O
+hallmark	POS	O
+of	POS	O
+arterial	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+Experimental	POS	O
+hypertension	POS	B-NP
+created	POS	O
+by	POS	O
+the	POS	O
+removal	POS	O
+of	POS	O
+NO	POS	O
+,	POS	O
+however	POS	O
+,	POS	O
+involves	POS	O
+mechanisms	POS	O
+in	POS	O
+addition	POS	O
+to	POS	O
+decreased	POS	O
+arterial	POS	O
+vasodilator	POS	O
+activity	POS	O
+.	POS	O
+These	POS	O
+include	POS	O
+augmented	POS	O
+endothelin	POS	O
+-	POS	O
+1	POS	O
+(	POS	O
+ET	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+release	POS	O
+,	POS	O
+increased	POS	O
+sympathetic	POS	O
+nervous	POS	O
+system	POS	O
+activity	POS	O
+,	POS	O
+and	POS	O
+elevated	POS	O
+tissue	POS	O
+oxidative	POS	O
+stress	POS	O
+.	POS	O
+We	POS	O
+hypothesized	POS	O
+that	POS	O
+increased	POS	O
+venous	POS	O
+smooth	POS	O
+muscle	POS	O
+(	POS	O
+venomotor	POS	O
+)	POS	O
+tone	POS	O
+plays	POS	O
+a	POS	O
+role	POS	O
+in	POS	O
+Nomega	POS	O
+-	POS	O
+nitro	POS	O
+-	POS	O
+L	POS	O
+-	POS	O
+arginine	POS	O
+(	POS	O
+LNNA	POS	O
+)	POS	O
+hypertension	POS	B-NP
+through	POS	O
+these	POS	O
+mechanisms	POS	O
+.	POS	O
+Rats	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+the	POS	O
+NO	POS	O
+synthase	POS	O
+inhibitor	POS	O
+LNNA	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+g	POS	O
+/	POS	O
+L	POS	O
+in	POS	O
+drinking	POS	O
+water	POS	O
+)	POS	O
+for	POS	O
+2	POS	O
+weeks	POS	O
+.	POS	O
+Mean	POS	O
+arterial	POS	O
+pressure	POS	O
+of	POS	O
+conscious	POS	O
+rats	POS	O
+was	POS	O
+119	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+2	POS	O
+mm	POS	O
+Hg	POS	O
+in	POS	O
+control	POS	O
+and	POS	O
+194	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+5	POS	O
+mm	POS	O
+Hg	POS	O
+in	POS	O
+LNNA	POS	O
+rats	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+Carotid	POS	O
+arteries	POS	O
+and	POS	O
+vena	POS	O
+cava	POS	O
+were	POS	O
+removed	POS	O
+for	POS	O
+measurement	POS	O
+of	POS	O
+isometric	POS	O
+contraction	POS	O
+.	POS	O
+Maximal	POS	O
+contraction	POS	O
+to	POS	O
+norepinephrine	POS	O
+was	POS	O
+modestly	POS	O
+reduced	POS	O
+in	POS	O
+arteries	POS	O
+from	POS	O
+LNNA	POS	O
+compared	POS	O
+with	POS	O
+control	POS	O
+rats	POS	O
+whereas	POS	O
+the	POS	O
+maximum	POS	O
+contraction	POS	O
+to	POS	O
+ET	POS	O
+-	POS	O
+1	POS	O
+was	POS	O
+significantly	POS	O
+reduced	POS	O
+(	POS	O
+54	POS	O
+%	POS	O
+control	POS	O
+)	POS	O
+.	POS	O
+Maximum	POS	O
+contraction	POS	O
+of	POS	O
+vena	POS	O
+cava	POS	O
+to	POS	O
+norepinephrine	POS	O
+(	POS	O
+37	POS	O
+%	POS	O
+control	POS	O
+)	POS	O
+also	POS	O
+was	POS	O
+reduced	POS	O
+but	POS	O
+no	POS	O
+change	POS	O
+in	POS	O
+response	POS	O
+to	POS	O
+ET	POS	O
+-	POS	O
+1	POS	O
+was	POS	O
+observed	POS	O
+.	POS	O
+Mean	POS	O
+circulatory	POS	O
+filling	POS	O
+pressure	POS	O
+,	POS	O
+an	POS	O
+in	POS	O
+vivo	POS	O
+measure	POS	O
+of	POS	O
+venomotor	POS	O
+tone	POS	O
+,	POS	O
+was	POS	O
+not	POS	O
+elevated	POS	O
+in	POS	O
+LNNA	POS	O
+hypertension	POS	B-NP
+at	POS	O
+1	POS	O
+or	POS	O
+2	POS	O
+weeks	POS	O
+after	POS	O
+LNNA	POS	O
+.	POS	O
+The	POS	O
+superoxide	POS	O
+scavenger	POS	O
+tempol	POS	O
+(	POS	O
+30	POS	O
+,	POS	O
+100	POS	O
+,	POS	O
+and	POS	O
+300	POS	O
+micromol	POS	O
+kg	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+,	POS	O
+IV	POS	O
+)	POS	O
+did	POS	O
+not	POS	O
+change	POS	O
+arterial	POS	O
+pressure	POS	O
+in	POS	O
+control	POS	O
+rats	POS	O
+but	POS	O
+caused	POS	O
+a	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+decrease	POS	O
+in	POS	O
+LNNA	POS	O
+rats	POS	O
+(	POS	O
+-	POS	O
+18	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+8	POS	O
+,	POS	O
+-	POS	O
+26	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+15	POS	O
+,	POS	O
+and	POS	O
+-	POS	O
+54	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+11	POS	O
+mm	POS	O
+Hg	POS	O
+)	POS	O
+.	POS	O
+Similarly	POS	O
+,	POS	O
+ganglionic	POS	O
+blockade	POS	O
+with	POS	O
+hexamethonium	POS	O
+caused	POS	O
+a	POS	O
+significantly	POS	O
+greater	POS	O
+fall	POS	O
+in	POS	O
+LNNA	POS	O
+hypertensive	POS	B-NP
+rats	POS	O
+(	POS	O
+76	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+9	POS	O
+mm	POS	O
+Hg	POS	O
+)	POS	O
+compared	POS	O
+with	POS	O
+control	POS	O
+rats	POS	O
+(	POS	O
+35	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+10	POS	O
+mm	POS	O
+Hg	POS	O
+)	POS	O
+.	POS	O
+Carotid	POS	O
+arteries	POS	O
+,	POS	O
+vena	POS	O
+cava	POS	O
+,	POS	O
+and	POS	O
+sympathetic	POS	O
+ganglia	POS	O
+from	POS	O
+LNNA	POS	O
+rats	POS	O
+had	POS	O
+higher	POS	O
+basal	POS	O
+levels	POS	O
+of	POS	O
+superoxide	POS	O
+compared	POS	O
+with	POS	O
+those	POS	O
+from	POS	O
+control	POS	O
+rats	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+while	POS	O
+NO	POS	O
+deficiency	POS	O
+increases	POS	O
+oxidative	POS	O
+stress	POS	O
+and	POS	O
+sympathetic	POS	O
+activity	POS	O
+in	POS	O
+both	POS	O
+arterial	POS	O
+and	POS	O
+venous	POS	O
+vessels	POS	O
+,	POS	O
+the	POS	O
+impact	POS	O
+on	POS	O
+veins	POS	O
+does	POS	O
+not	POS	O
+make	POS	O
+a	POS	O
+major	POS	O
+contribution	POS	O
+to	POS	O
+this	POS	O
+form	POS	O
+of	POS	O
+hypertension	POS	B-NP
+.	POS	O
+Association	POS	O
+of	POS	O
+DRD2	POS	O
+polymorphisms	POS	O
+and	POS	O
+chlorpromazine	POS	O
+-	POS	O
+induced	POS	O
+extrapyramidal	POS	B-NP
+syndrome	POS	I-NP
+in	POS	O
+Chinese	POS	O
+schizophrenic	POS	B-NP
+patients	POS	O
+.	POS	O
+AIM	POS	B-NP
+:	POS	O
+Extrapyramidal	POS	B-NP
+syndrome	POS	I-NP
+(	POS	O
+EPS	POS	B-NP
+)	POS	O
+is	POS	O
+most	POS	O
+commonly	POS	O
+affected	POS	O
+by	POS	O
+typical	POS	O
+antipsychotic	POS	O
+drugs	POS	O
+that	POS	O
+have	POS	O
+a	POS	O
+high	POS	O
+affinity	POS	O
+with	POS	O
+the	POS	O
+D2	POS	O
+receptor	POS	O
+.	POS	O
+Recently	POS	O
+,	POS	O
+many	POS	O
+research	POS	O
+groups	POS	O
+have	POS	O
+reported	POS	O
+on	POS	O
+the	POS	O
+positive	POS	O
+relationship	POS	O
+between	POS	O
+the	POS	O
+genetic	POS	O
+variations	POS	O
+in	POS	O
+the	POS	O
+DRD2	POS	O
+gene	POS	O
+and	POS	O
+the	POS	O
+therapeutic	POS	O
+response	POS	O
+in	POS	O
+schizophrenia	POS	B-NP
+patients	POS	O
+as	POS	O
+a	POS	O
+result	POS	O
+of	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+variations	POS	O
+in	POS	O
+the	POS	O
+receptor	POS	O
+in	POS	O
+modulating	POS	O
+receptor	POS	O
+expression	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+,	POS	O
+we	POS	O
+evaluate	POS	O
+the	POS	O
+role	POS	O
+DRD2	POS	O
+plays	POS	O
+in	POS	O
+chlorpromazine	POS	O
+-	POS	O
+induced	POS	O
+EPS	POS	B-NP
+in	POS	O
+schizophrenic	POS	B-NP
+patients	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+identified	POS	O
+seven	POS	O
+SNP	POS	O
+(	POS	O
+single	POS	O
+nucleotide	POS	O
+polymorphism	POS	O
+)	POS	O
+(	POS	O
+-	POS	O
+141Cins	POS	O
+>	POS	O
+del	POS	O
+,	POS	O
+TaqIB	POS	O
+,	POS	O
+TaqID	POS	O
+,	POS	O
+Ser311Cys	POS	O
+,	POS	O
+rs6275	POS	O
+,	POS	O
+rs6277	POS	O
+and	POS	O
+TaqIA	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+DRD2	POS	O
+gene	POS	O
+in	POS	O
+146	POS	O
+schizophrenic	POS	B-NP
+inpatients	POS	O
+(	POS	O
+59	POS	O
+with	POS	O
+EPS	POS	B-NP
+and	POS	O
+87	POS	O
+without	POS	O
+EPS	POS	B-NP
+according	POS	O
+to	POS	O
+the	POS	O
+Simpson	POS	O
+-	POS	O
+Angus	POS	O
+Scale	POS	O
+)	POS	O
+treated	POS	O
+with	POS	O
+chlorpromazine	POS	O
+after	POS	O
+8	POS	O
+weeks	POS	O
+.	POS	O
+The	POS	O
+alleles	POS	O
+of	POS	O
+all	POS	O
+loci	POS	O
+were	POS	O
+determined	POS	O
+by	POS	O
+PCR	POS	O
+(	POS	O
+polymerase	POS	O
+chain	POS	O
+reaction	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Polymorphisms	POS	O
+TaqID	POS	O
+,	POS	O
+Ser311Cys	POS	O
+and	POS	O
+rs6277	POS	O
+were	POS	O
+not	POS	O
+polymorphic	POS	O
+in	POS	O
+the	POS	O
+population	POS	O
+recruited	POS	O
+in	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+.	POS	O
+No	POS	O
+statistical	POS	O
+significance	POS	O
+was	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+allele	POS	O
+distribution	POS	O
+of	POS	O
+-	POS	O
+141Cins	POS	O
+>	POS	O
+del	POS	O
+,	POS	O
+TaqIB	POS	O
+,	POS	O
+rs6275	POS	O
+and	POS	O
+TaqIA	POS	O
+or	POS	O
+in	POS	O
+the	POS	O
+estimated	POS	O
+haplotypes	POS	O
+(	POS	O
+constituted	POS	O
+by	POS	O
+TaqIB	POS	O
+,	POS	O
+rs6275	POS	O
+and	POS	O
+TaqIA	POS	O
+)	POS	O
+in	POS	O
+linkage	POS	O
+disequilibrium	POS	O
+between	POS	O
+the	POS	O
+two	POS	O
+groups	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Our	POS	O
+results	POS	O
+did	POS	O
+not	POS	O
+lend	POS	O
+strong	POS	O
+support	POS	O
+to	POS	O
+the	POS	O
+view	POS	O
+that	POS	O
+the	POS	O
+genetic	POS	O
+variation	POS	O
+of	POS	O
+the	POS	O
+DRD2	POS	O
+gene	POS	O
+plays	POS	O
+a	POS	O
+major	POS	O
+role	POS	O
+in	POS	O
+the	POS	O
+individually	POS	O
+variable	POS	O
+adverse	POS	O
+effect	POS	O
+induced	POS	O
+by	POS	O
+chlorpromazine	POS	O
+,	POS	O
+at	POS	O
+least	POS	O
+in	POS	O
+Chinese	POS	O
+patients	POS	O
+with	POS	O
+schizophrenia	POS	B-NP
+.	POS	O
+Our	POS	O
+results	POS	O
+confirmed	POS	O
+a	POS	O
+previous	POS	O
+study	POS	O
+on	POS	O
+the	POS	O
+relationship	POS	O
+between	POS	O
+DRD2	POS	O
+and	POS	O
+EPS	POS	B-NP
+in	POS	O
+Caucasians	POS	O
+.	POS	O
+Physical	POS	O
+training	POS	O
+decreases	POS	O
+susceptibility	POS	O
+to	POS	O
+subsequent	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+in	POS	O
+the	POS	O
+rat	POS	O
+.	POS	O
+Regular	POS	O
+motor	POS	O
+activity	POS	O
+has	POS	O
+many	POS	O
+benefits	POS	O
+for	POS	O
+mental	POS	O
+and	POS	O
+physical	POS	O
+condition	POS	O
+but	POS	O
+its	POS	O
+implications	POS	O
+for	POS	O
+epilepsy	POS	B-NP
+are	POS	O
+still	POS	O
+controversial	POS	O
+.	POS	O
+In	POS	O
+order	POS	O
+to	POS	O
+elucidate	POS	O
+this	POS	O
+problem	POS	O
+,	POS	O
+we	POS	O
+have	POS	O
+studied	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+physical	POS	O
+activity	POS	O
+on	POS	O
+susceptibility	POS	O
+to	POS	O
+subsequent	POS	O
+seizures	POS	B-NP
+.	POS	O
+Male	POS	O
+Wistar	POS	O
+rats	POS	O
+were	POS	O
+subjected	POS	O
+to	POS	O
+repeated	POS	O
+training	POS	O
+sessions	POS	O
+in	POS	O
+a	POS	O
+treadmill	POS	O
+and	POS	O
+swimming	POS	O
+pool	POS	O
+.	POS	O
+Thereafter	POS	O
+,	POS	O
+seizures	POS	B-NP
+were	POS	O
+induced	POS	O
+by	POS	O
+pilocarpine	POS	O
+injections	POS	O
+in	POS	O
+trained	POS	O
+and	POS	O
+non	POS	O
+-	POS	O
+trained	POS	O
+control	POS	O
+groups	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+acute	POS	O
+period	POS	O
+of	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+,	POS	O
+we	POS	O
+measured	POS	O
+:	POS	O
+(	POS	O
+1	POS	O
+)	POS	O
+the	POS	O
+latency	POS	O
+of	POS	O
+the	POS	O
+first	POS	O
+motor	POS	O
+sign	POS	O
+,	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+the	POS	O
+intensity	POS	O
+of	POS	O
+seizures	POS	B-NP
+,	POS	O
+(	POS	O
+3	POS	O
+)	POS	O
+the	POS	O
+time	POS	O
+when	POS	O
+it	POS	O
+occurred	POS	O
+within	POS	O
+the	POS	O
+6	POS	O
+-	POS	O
+h	POS	O
+observation	POS	O
+period	POS	O
+,	POS	O
+and	POS	O
+(	POS	O
+4	POS	O
+)	POS	O
+the	POS	O
+time	POS	O
+when	POS	O
+the	POS	O
+acute	POS	O
+period	POS	O
+ended	POS	O
+.	POS	O
+All	POS	O
+these	POS	O
+behavioral	POS	O
+parameters	POS	O
+showed	POS	O
+statistically	POS	O
+significant	POS	O
+changes	POS	O
+suggesting	POS	O
+that	POS	O
+regular	POS	O
+physical	POS	O
+exercises	POS	O
+decrease	POS	O
+susceptibility	POS	O
+to	POS	O
+subsequently	POS	O
+induced	POS	O
+seizures	POS	B-NP
+and	POS	O
+ameliorate	POS	O
+the	POS	O
+course	POS	O
+of	POS	O
+experimentally	POS	O
+induced	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+.	POS	O
+Tonic	POS	O
+dopaminergic	POS	O
+stimulation	POS	O
+impairs	POS	O
+associative	POS	O
+learning	POS	O
+in	POS	O
+healthy	POS	O
+subjects	POS	O
+.	POS	O
+Endogenous	POS	O
+dopamine	POS	O
+plays	POS	O
+a	POS	O
+central	POS	O
+role	POS	O
+in	POS	O
+salience	POS	O
+coding	POS	O
+during	POS	O
+associative	POS	O
+learning	POS	O
+.	POS	O
+Administration	POS	O
+of	POS	O
+the	POS	O
+dopamine	POS	O
+precursor	POS	O
+levodopa	POS	O
+enhances	POS	O
+learning	POS	O
+in	POS	O
+healthy	POS	O
+subjects	POS	O
+and	POS	O
+stroke	POS	B-NP
+patients	POS	O
+.	POS	O
+Because	POS	O
+levodopa	POS	O
+increases	POS	O
+both	POS	O
+phasic	POS	O
+and	POS	O
+tonic	POS	O
+dopaminergic	POS	O
+neurotransmission	POS	O
+,	POS	O
+the	POS	O
+critical	POS	O
+mechanism	POS	O
+mediating	POS	O
+the	POS	O
+enhancement	POS	O
+of	POS	O
+learning	POS	O
+is	POS	O
+unresolved	POS	O
+.	POS	O
+We	POS	O
+here	POS	O
+probed	POS	O
+how	POS	O
+selective	POS	O
+tonic	POS	O
+dopaminergic	POS	O
+stimulation	POS	O
+affects	POS	O
+associative	POS	O
+learning	POS	O
+.	POS	O
+Forty	POS	O
+healthy	POS	O
+subjects	POS	O
+were	POS	O
+trained	POS	O
+in	POS	O
+a	POS	O
+novel	POS	O
+vocabulary	POS	O
+of	POS	O
+45	POS	O
+concrete	POS	O
+nouns	POS	O
+over	POS	O
+the	POS	O
+course	POS	O
+of	POS	O
+5	POS	O
+consecutive	POS	O
+training	POS	O
+days	POS	O
+in	POS	O
+a	POS	O
+prospective	POS	O
+,	POS	O
+randomized	POS	O
+,	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+design	POS	O
+.	POS	O
+Subjects	POS	O
+received	POS	O
+the	POS	O
+tonically	POS	O
+stimulating	POS	O
+dopamine	POS	O
+-	POS	O
+receptor	POS	O
+agonist	POS	O
+pergolide	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+mg	POS	O
+)	POS	O
+vs	POS	O
+placebo	POS	O
+120	POS	O
+min	POS	O
+before	POS	O
+training	POS	O
+on	POS	O
+each	POS	O
+training	POS	O
+day	POS	O
+.	POS	O
+The	POS	O
+dopamine	POS	O
+agonist	POS	O
+significantly	POS	O
+impaired	POS	O
+novel	POS	O
+word	POS	O
+learning	POS	O
+compared	POS	O
+to	POS	O
+placebo	POS	O
+.	POS	O
+This	POS	O
+learning	POS	O
+decrement	POS	O
+persisted	POS	O
+up	POS	O
+to	POS	O
+the	POS	O
+last	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+4	POS	O
+weeks	POS	O
+post	POS	O
+-	POS	O
+training	POS	O
+.	POS	O
+Subjects	POS	O
+treated	POS	O
+with	POS	O
+pergolide	POS	O
+also	POS	O
+showed	POS	O
+restricted	POS	O
+emotional	POS	O
+responses	POS	O
+compared	POS	O
+to	POS	O
+the	POS	O
+PLACEBO	POS	O
+group	POS	O
+.	POS	O
+The	POS	O
+extent	POS	O
+of	POS	O
+'	POS	O
+flattened	POS	O
+'	POS	O
+affect	POS	O
+with	POS	O
+pergolide	POS	O
+was	POS	O
+related	POS	O
+to	POS	O
+the	POS	O
+degree	POS	O
+of	POS	O
+learning	POS	O
+inhibition	POS	O
+.	POS	O
+These	POS	O
+findings	POS	O
+suggest	POS	O
+that	POS	O
+tonic	POS	O
+occupation	POS	O
+of	POS	O
+dopamine	POS	O
+receptors	POS	O
+impairs	POS	O
+learning	POS	O
+by	POS	O
+competition	POS	O
+with	POS	O
+phasic	POS	O
+dopamine	POS	O
+signals	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+phasic	POS	O
+signaling	POS	O
+seems	POS	O
+to	POS	O
+be	POS	O
+the	POS	O
+critical	POS	O
+mechanism	POS	O
+by	POS	O
+which	POS	O
+dopamine	POS	O
+enhances	POS	O
+associative	POS	O
+learning	POS	O
+in	POS	O
+healthy	POS	O
+subjects	POS	O
+and	POS	O
+stroke	POS	B-NP
+patients	POS	O
+.	POS	O
+Minocycline	POS	O
+-	POS	O
+induced	POS	O
+vasculitis	POS	B-NP
+fulfilling	POS	O
+the	POS	O
+criteria	POS	O
+of	POS	O
+polyarteritis	POS	B-NP
+nodosa	POS	I-NP
+.	POS	O
+A	POS	O
+47	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+who	POS	O
+had	POS	O
+been	POS	O
+taking	POS	O
+minocycline	POS	O
+for	POS	O
+palmoplantar	POS	B-NP
+pustulosis	POS	I-NP
+developed	POS	O
+fever	POS	B-NP
+,	POS	O
+myalgias	POS	B-NP
+,	POS	O
+polyneuropathy	POS	B-NP
+,	POS	O
+and	POS	O
+testicular	POS	B-NP
+pain	POS	I-NP
+,	POS	O
+with	POS	O
+elevated	POS	B-NP
+C	POS	I-NP
+-	POS	I-NP
+reactive	POS	I-NP
+protein	POS	I-NP
+(	POS	O
+CRP	POS	O
+)	POS	O
+.	POS	O
+Neither	POS	O
+myeloperoxidase	POS	O
+-	POS	O
+nor	POS	O
+proteinase	POS	O
+-	POS	O
+3	POS	O
+-	POS	O
+antineutrophil	POS	O
+cytoplasmic	POS	O
+antibody	POS	O
+was	POS	O
+positive	POS	O
+.	POS	O
+These	POS	O
+manifestations	POS	O
+met	POS	O
+the	POS	O
+American	POS	O
+College	POS	O
+of	POS	O
+Rheumatology	POS	O
+1990	POS	O
+criteria	POS	O
+for	POS	O
+the	POS	O
+classification	POS	O
+of	POS	O
+polyarteritis	POS	B-NP
+nodosa	POS	I-NP
+.	POS	O
+Stopping	POS	O
+minocycline	POS	O
+led	POS	O
+to	POS	O
+amelioration	POS	O
+of	POS	O
+symptoms	POS	O
+and	POS	O
+normalization	POS	O
+of	POS	O
+CRP	POS	O
+level	POS	O
+.	POS	O
+To	POS	O
+our	POS	O
+knowledge	POS	O
+,	POS	O
+this	POS	O
+is	POS	O
+the	POS	O
+second	POS	O
+case	POS	O
+of	POS	O
+minocycline	POS	O
+-	POS	O
+induced	POS	O
+vasculitis	POS	B-NP
+satisfying	POS	O
+the	POS	O
+criteria	POS	O
+.	POS	O
+Differential	POS	O
+diagnosis	POS	O
+for	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+disease	POS	O
+is	POS	O
+invaluable	POS	O
+even	POS	O
+for	POS	O
+patients	POS	O
+with	POS	O
+classical	POS	O
+polyarteritis	POS	B-NP
+nodosa	POS	I-NP
+.	POS	O
+Intramuscular	POS	B-NP
+hepatitis	POS	I-NP
+B	POS	I-NP
+immune	POS	O
+globulin	POS	O
+combined	POS	O
+with	POS	O
+lamivudine	POS	O
+in	POS	O
+prevention	POS	O
+of	POS	O
+hepatitis	POS	B-NP
+B	POS	I-NP
+recurrence	POS	O
+after	POS	O
+liver	POS	O
+transplantation	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Combined	POS	O
+hepatitis	POS	B-NP
+B	POS	I-NP
+immune	POS	O
+globulin	POS	O
+(	POS	O
+HBIg	POS	O
+)	POS	O
+and	POS	O
+lamivudine	POS	O
+in	POS	O
+prophylaxis	POS	O
+of	POS	O
+the	POS	O
+recurrence	POS	O
+of	POS	O
+hepatitis	POS	B-NP
+B	POS	I-NP
+after	POS	O
+liver	POS	O
+transplantation	POS	O
+has	POS	O
+significantly	POS	O
+improved	POS	O
+the	POS	O
+survival	POS	O
+of	POS	O
+HBsAg	POS	O
+positive	POS	O
+patients	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+was	POS	O
+undertaken	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+outcomes	POS	O
+of	POS	O
+liver	POS	O
+transplantation	POS	O
+for	POS	O
+patients	POS	O
+with	POS	O
+hepatitis	POS	B-NP
+B	POS	I-NP
+virus	POS	O
+(	POS	O
+HBV	POS	O
+)	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+A	POS	O
+retrospective	POS	O
+chart	POS	O
+analysis	POS	O
+and	POS	O
+a	POS	O
+review	POS	O
+of	POS	O
+the	POS	O
+organ	POS	O
+transplant	POS	O
+database	POS	O
+identified	POS	O
+51	POS	O
+patients	POS	O
+(	POS	O
+43	POS	O
+men	POS	O
+and	POS	O
+8	POS	O
+women	POS	O
+)	POS	O
+transplanted	POS	O
+for	POS	O
+benign	POS	O
+HBV	POS	O
+-	POS	O
+related	POS	O
+cirrhotic	POS	B-NP
+diseases	POS	I-NP
+between	POS	O
+June	POS	O
+2002	POS	O
+and	POS	O
+December	POS	O
+2004	POS	O
+who	POS	O
+had	POS	O
+survived	POS	O
+more	POS	O
+than	POS	O
+3	POS	O
+months	POS	O
+.	POS	O
+HBIg	POS	O
+was	POS	O
+administered	POS	O
+intravenously	POS	O
+during	POS	O
+the	POS	O
+first	POS	O
+week	POS	O
+and	POS	O
+intramuscularly	POS	O
+thereafter	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+At	POS	O
+a	POS	O
+median	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+of	POS	O
+14	POS	O
+.	POS	O
+1	POS	O
+months	POS	O
+,	POS	O
+the	POS	O
+overall	POS	O
+recurrence	POS	O
+rate	POS	O
+in	POS	O
+the	POS	O
+51	POS	O
+patients	POS	O
+was	POS	O
+3	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+(	POS	O
+2	POS	O
+/	POS	O
+51	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+overall	POS	O
+patient	POS	O
+survival	POS	O
+was	POS	O
+88	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+,	POS	O
+and	POS	O
+82	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+after	POS	O
+1	POS	O
+and	POS	O
+2	POS	O
+years	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+A	POS	O
+daily	POS	O
+oral	POS	O
+dose	POS	O
+of	POS	O
+100	POS	O
+mg	POS	O
+lamivudine	POS	O
+for	POS	O
+2	POS	O
+weeks	POS	O
+before	POS	O
+transplantation	POS	O
+for	POS	O
+10	POS	O
+patients	POS	O
+enabled	POS	O
+57	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+(	POS	O
+4	POS	O
+/	POS	O
+7	POS	O
+)	POS	O
+and	POS	O
+62	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+(	POS	O
+5	POS	O
+/	POS	O
+8	POS	O
+)	POS	O
+of	POS	O
+HBV	POS	O
+-	POS	O
+DNA	POS	O
+and	POS	O
+HBeAg	POS	O
+positive	POS	O
+patients	POS	O
+respectively	POS	O
+to	POS	O
+convert	POS	O
+to	POS	O
+be	POS	O
+negative	POS	O
+.	POS	O
+Intramuscular	POS	O
+HBIg	POS	O
+was	POS	O
+well	POS	O
+tolerated	POS	O
+in	POS	O
+all	POS	O
+patients	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Lamivudine	POS	O
+combined	POS	O
+with	POS	O
+intramuscular	POS	O
+HBIg	POS	O
+can	POS	O
+effectively	POS	O
+prevent	POS	O
+allograft	POS	O
+from	POS	O
+the	POS	O
+recurrence	POS	O
+of	POS	O
+HBV	POS	O
+after	POS	O
+liver	POS	O
+transplantation	POS	O
+.	POS	O
+Anticonvulsant	POS	O
+effect	POS	O
+of	POS	O
+eslicarbazepine	POS	O
+acetate	POS	O
+(	POS	O
+BIA	POS	O
+2	POS	O
+-	POS	O
+093	POS	O
+)	POS	O
+on	POS	O
+seizures	POS	B-NP
+induced	POS	O
+by	POS	O
+microperfusion	POS	O
+of	POS	O
+picrotoxin	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+of	POS	O
+freely	POS	O
+moving	POS	O
+rats	POS	O
+.	POS	O
+Eslicarbazepine	POS	O
+acetate	POS	O
+(	POS	O
+BIA	POS	O
+2	POS	O
+-	POS	O
+093	POS	O
+,	POS	O
+S	POS	O
+-	POS	O
+(	POS	O
+-	POS	O
+)	POS	O
+-	POS	O
+10	POS	O
+-	POS	O
+acetoxy	POS	O
+-	POS	O
+10	POS	O
+,	POS	O
+11	POS	O
+-	POS	O
+dihydro	POS	O
+-	POS	O
+5H	POS	O
+-	POS	O
+dibenzo	POS	O
+/	POS	O
+b	POS	O
+,	POS	O
+f	POS	O
+/	POS	O
+azepine	POS	O
+-	POS	O
+5	POS	O
+-	POS	O
+carboxamide	POS	O
+)	POS	O
+is	POS	O
+a	POS	O
+novel	POS	O
+antiepileptic	POS	O
+drug	POS	O
+,	POS	O
+now	POS	O
+in	POS	O
+Phase	POS	O
+III	POS	O
+clinical	POS	O
+trials	POS	O
+,	POS	O
+designed	POS	O
+with	POS	O
+the	POS	O
+aim	POS	O
+of	POS	O
+improving	POS	O
+efficacy	POS	O
+and	POS	O
+safety	POS	O
+in	POS	O
+comparison	POS	O
+with	POS	O
+the	POS	O
+structurally	POS	O
+related	POS	O
+drugs	POS	O
+carbamazepine	POS	O
+(	POS	O
+CBZ	POS	O
+)	POS	O
+and	POS	O
+oxcarbazepine	POS	O
+(	POS	O
+OXC	POS	O
+)	POS	O
+.	POS	O
+We	POS	O
+have	POS	O
+studied	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+oral	POS	O
+treatment	POS	O
+with	POS	O
+eslicarbazepine	POS	O
+acetate	POS	O
+on	POS	O
+a	POS	O
+whole	POS	O
+-	POS	O
+animal	POS	O
+model	POS	O
+in	POS	O
+which	POS	O
+partial	POS	O
+seizures	POS	B-NP
+can	POS	O
+be	POS	O
+elicited	POS	O
+repeatedly	POS	O
+on	POS	O
+different	POS	O
+days	POS	O
+without	POS	O
+changes	POS	O
+in	POS	O
+threshold	POS	O
+or	POS	O
+seizure	POS	B-NP
+patterns	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+animals	POS	O
+treated	POS	O
+with	POS	O
+threshold	POS	O
+doses	POS	O
+of	POS	O
+picrotoxin	POS	O
+,	POS	O
+the	POS	O
+average	POS	O
+number	POS	O
+of	POS	O
+seizures	POS	B-NP
+was	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+,	POS	O
+and	POS	O
+average	POS	O
+seizure	POS	B-NP
+duration	POS	O
+was	POS	O
+39	POS	O
+.	POS	O
+5	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+8	POS	O
+.	POS	O
+4s	POS	O
+.	POS	O
+Pre	POS	O
+-	POS	O
+treatment	POS	O
+with	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+30	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+2h	POS	O
+before	POS	O
+picrotoxin	POS	O
+microperfusion	POS	O
+prevented	POS	O
+seizures	POS	B-NP
+in	POS	O
+the	POS	O
+75	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+rats	POS	O
+.	POS	O
+Lower	POS	O
+doses	POS	O
+(	POS	O
+3	POS	O
+and	POS	O
+10mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+did	POS	O
+not	POS	O
+suppress	POS	O
+seizures	POS	B-NP
+,	POS	O
+however	POS	O
+,	POS	O
+after	POS	O
+administration	POS	O
+of	POS	O
+10mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+significant	POS	O
+reductions	POS	O
+in	POS	O
+seizures	POS	B-NP
+duration	POS	O
+(	POS	O
+24	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+8s	POS	O
+)	POS	O
+and	POS	O
+seizure	POS	B-NP
+number	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+34	POS	O
+)	POS	O
+were	POS	O
+found	POS	O
+.	POS	O
+No	POS	O
+adverse	POS	O
+effects	POS	O
+of	POS	O
+eslicarbazepine	POS	O
+acetate	POS	O
+were	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+behavioral	POS	O
+/	POS	O
+EEG	POS	O
+patterns	POS	O
+studied	POS	O
+,	POS	O
+including	POS	O
+sleep	POS	O
+/	POS	O
+wakefulness	POS	O
+cycle	POS	O
+,	POS	O
+at	POS	O
+the	POS	O
+doses	POS	O
+studied	POS	O
+.	POS	O
+Acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+associated	POS	O
+with	POS	O
+prolonged	POS	O
+intake	POS	O
+of	POS	O
+slimming	POS	O
+pills	POS	O
+containing	POS	O
+anthraquinones	POS	O
+.	POS	O
+Chinese	POS	O
+herbal	POS	O
+medicine	POS	O
+preparations	POS	O
+are	POS	O
+widely	POS	O
+available	POS	O
+and	POS	O
+often	POS	O
+regarded	POS	O
+by	POS	O
+the	POS	O
+public	POS	O
+as	POS	O
+natural	POS	O
+and	POS	O
+safe	POS	O
+remedies	POS	O
+for	POS	O
+a	POS	O
+variety	POS	O
+of	POS	O
+medical	POS	O
+conditions	POS	O
+.	POS	O
+Nephropathy	POS	B-NP
+caused	POS	O
+by	POS	O
+Chinese	POS	O
+herbs	POS	O
+has	POS	O
+previously	POS	O
+been	POS	O
+reported	POS	O
+,	POS	O
+usually	POS	O
+involving	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+aristolochic	POS	O
+acids	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+23	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+who	POS	O
+developed	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+following	POS	O
+prolonged	POS	O
+use	POS	O
+of	POS	O
+a	POS	O
+proprietary	POS	O
+Chinese	POS	O
+herbal	POS	O
+slimming	POS	O
+pill	POS	O
+that	POS	O
+contained	POS	O
+anthraquinone	POS	O
+derivatives	POS	O
+,	POS	O
+extracted	POS	O
+from	POS	O
+Rhizoma	POS	O
+Rhei	POS	O
+(	POS	O
+rhubarb	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+renal	POS	B-NP
+injury	POS	I-NP
+was	POS	O
+probably	POS	O
+aggravated	POS	O
+by	POS	O
+the	POS	O
+concomitant	POS	O
+intake	POS	O
+of	POS	O
+a	POS	O
+non	POS	O
+-	POS	O
+steroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drug	POS	O
+,	POS	O
+diclofenac	POS	O
+.	POS	O
+Renal	POS	O
+pathology	POS	O
+was	POS	O
+that	POS	O
+of	POS	O
+hypocellular	POS	B-NP
+interstitial	POS	I-NP
+fibrosis	POS	I-NP
+.	POS	O
+Spontaneous	POS	B-NP
+renal	POS	I-NP
+recovery	POS	I-NP
+occurred	POS	O
+upon	POS	O
+cessation	POS	O
+of	POS	O
+the	POS	O
+slimming	POS	O
+pills	POS	O
+,	POS	O
+but	POS	O
+mild	POS	O
+interstitial	POS	B-NP
+fibrosis	POS	I-NP
+and	POS	O
+tubular	POS	B-NP
+atrophy	POS	I-NP
+was	POS	O
+still	POS	O
+evident	POS	O
+histologically	POS	O
+4	POS	O
+months	POS	O
+later	POS	O
+.	POS	O
+Although	POS	O
+a	POS	O
+causal	POS	O
+relationship	POS	O
+between	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+an	POS	O
+anthraquinone	POS	O
+-	POS	O
+containing	POS	O
+herbal	POS	O
+agent	POS	O
+and	POS	O
+renal	POS	B-NP
+injury	POS	I-NP
+remains	POS	O
+to	POS	O
+be	POS	O
+proven	POS	O
+,	POS	O
+phytotherapy	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+interstitial	POS	I-NP
+nephropathy	POS	I-NP
+should	POS	O
+be	POS	O
+considered	POS	O
+in	POS	O
+patients	POS	O
+who	POS	O
+present	POS	O
+with	POS	O
+unexplained	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+Chloroacetaldehyde	POS	O
+as	POS	O
+a	POS	O
+sulfhydryl	POS	O
+reagent	POS	O
+:	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+critical	POS	O
+thiol	POS	O
+groups	POS	O
+in	POS	O
+ifosfamide	POS	O
+nephropathy	POS	B-NP
+.	POS	O
+Chloroacetaldehyde	POS	O
+(	POS	O
+CAA	POS	O
+)	POS	O
+is	POS	O
+a	POS	O
+metabolite	POS	O
+of	POS	O
+the	POS	O
+alkylating	POS	O
+agent	POS	O
+ifosfamide	POS	O
+(	POS	O
+IFO	POS	O
+)	POS	O
+and	POS	O
+putatively	POS	O
+responsible	POS	O
+for	POS	O
+renal	POS	O
+damage	POS	O
+following	POS	O
+anti	POS	O
+-	POS	O
+tumor	POS	O
+therapy	POS	O
+with	POS	O
+IFO	POS	O
+.	POS	O
+Depletion	POS	O
+of	POS	O
+sulfhydryl	POS	O
+(	POS	O
+SH	POS	O
+)	POS	O
+groups	POS	O
+has	POS	O
+been	POS	O
+reported	POS	O
+from	POS	O
+cell	POS	O
+culture	POS	O
+,	POS	O
+animal	POS	O
+and	POS	O
+clinical	POS	O
+studies	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+work	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+CAA	POS	O
+on	POS	O
+human	POS	O
+proximal	POS	O
+tubule	POS	O
+cells	POS	O
+in	POS	O
+primary	POS	O
+culture	POS	O
+(	POS	O
+hRPTEC	POS	O
+)	POS	O
+was	POS	O
+investigated	POS	O
+.	POS	O
+Toxicity	POS	O
+of	POS	O
+CAA	POS	O
+was	POS	O
+determined	POS	O
+by	POS	O
+protein	POS	O
+content	POS	O
+,	POS	O
+cell	POS	O
+number	POS	O
+,	POS	O
+LDH	POS	O
+release	POS	O
+,	POS	O
+trypan	POS	O
+blue	POS	O
+exclusion	POS	O
+assay	POS	O
+and	POS	O
+caspase	POS	O
+-	POS	O
+3	POS	O
+activity	POS	O
+.	POS	O
+Free	POS	O
+thiols	POS	O
+were	POS	O
+measured	POS	O
+by	POS	O
+the	POS	O
+method	POS	O
+of	POS	O
+Ellman	POS	O
+.	POS	O
+CAA	POS	O
+reduced	POS	O
+hRPTEC	POS	O
+cell	POS	O
+number	POS	O
+and	POS	O
+protein	POS	O
+,	POS	O
+induced	POS	O
+a	POS	O
+loss	POS	O
+in	POS	O
+free	POS	O
+intracellular	POS	O
+thiols	POS	O
+and	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+necrosis	POS	B-NP
+markers	POS	O
+.	POS	O
+CAA	POS	O
+but	POS	O
+not	POS	O
+acrolein	POS	O
+inhibited	POS	O
+the	POS	O
+cysteine	POS	O
+proteases	POS	O
+caspase	POS	O
+-	POS	O
+3	POS	O
+,	POS	O
+caspase	POS	O
+-	POS	O
+8	POS	O
+and	POS	O
+cathepsin	POS	O
+B	POS	O
+.	POS	O
+Caspase	POS	O
+activation	POS	O
+by	POS	O
+cisplatin	POS	O
+was	POS	O
+inhibited	POS	O
+by	POS	O
+CAA	POS	O
+.	POS	O
+In	POS	O
+cells	POS	O
+stained	POS	O
+with	POS	O
+fluorescent	POS	O
+dyes	POS	O
+targeting	POS	O
+lysosomes	POS	O
+,	POS	O
+CAA	POS	O
+induced	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+lysosomal	POS	O
+size	POS	O
+and	POS	O
+lysosomal	POS	O
+leakage	POS	O
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+CAA	POS	O
+on	POS	O
+cysteine	POS	O
+protease	POS	O
+activities	POS	O
+and	POS	O
+thiols	POS	O
+could	POS	O
+be	POS	O
+reproduced	POS	O
+in	POS	O
+cell	POS	O
+lysate	POS	O
+.	POS	O
+Acidification	POS	O
+,	POS	O
+which	POS	O
+slowed	POS	O
+the	POS	O
+reaction	POS	O
+of	POS	O
+CAA	POS	O
+with	POS	O
+thiol	POS	O
+donors	POS	O
+,	POS	O
+could	POS	O
+also	POS	O
+attenuate	POS	O
+effects	POS	O
+of	POS	O
+CAA	POS	O
+on	POS	O
+necrosis	POS	O
+markers	POS	O
+,	POS	O
+thiol	POS	O
+depletion	POS	O
+and	POS	O
+cysteine	POS	O
+protease	POS	O
+inhibition	POS	O
+in	POS	O
+living	POS	O
+cells	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+CAA	POS	O
+directly	POS	O
+reacts	POS	O
+with	POS	O
+cellular	POS	O
+protein	POS	O
+and	POS	O
+non	POS	O
+-	POS	O
+protein	POS	O
+thiols	POS	O
+,	POS	O
+mediating	POS	O
+its	POS	O
+toxicity	POS	O
+on	POS	O
+hRPTEC	POS	O
+.	POS	O
+This	POS	O
+effect	POS	O
+can	POS	O
+be	POS	O
+reduced	POS	O
+by	POS	O
+acidification	POS	O
+.	POS	O
+Therefore	POS	O
+,	POS	O
+urinary	POS	O
+acidification	POS	O
+could	POS	O
+be	POS	O
+an	POS	O
+option	POS	O
+to	POS	O
+prevent	POS	O
+IFO	POS	O
+nephropathy	POS	B-NP
+in	POS	O
+patients	POS	O
+.	POS	O
+Stereological	POS	O
+methods	POS	O
+reveal	POS	O
+the	POS	O
+robust	POS	O
+size	POS	O
+and	POS	O
+stability	POS	O
+of	POS	O
+ectopic	POS	O
+hilar	POS	O
+granule	POS	O
+cells	POS	O
+after	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+in	POS	O
+the	POS	O
+adult	POS	O
+rat	POS	O
+.	POS	O
+Following	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+in	POS	O
+the	POS	O
+rat	POS	O
+,	POS	O
+dentate	POS	O
+granule	POS	O
+cell	POS	O
+neurogenesis	POS	O
+increases	POS	O
+greatly	POS	O
+,	POS	O
+and	POS	O
+many	POS	O
+of	POS	O
+the	POS	O
+new	POS	O
+neurons	POS	O
+appear	POS	O
+to	POS	O
+develop	POS	O
+ectopically	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+hilar	POS	O
+region	POS	O
+of	POS	O
+the	POS	O
+hippocampal	POS	O
+formation	POS	O
+.	POS	O
+It	POS	O
+has	POS	O
+been	POS	O
+suggested	POS	O
+that	POS	O
+the	POS	O
+ectopic	POS	O
+hilar	POS	O
+granule	POS	O
+cells	POS	O
+could	POS	O
+contribute	POS	O
+to	POS	O
+the	POS	O
+spontaneous	POS	O
+seizures	POS	B-NP
+that	POS	O
+ultimately	POS	O
+develop	POS	O
+after	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+population	POS	O
+has	POS	O
+never	POS	O
+been	POS	O
+quantified	POS	O
+,	POS	O
+so	POS	O
+it	POS	O
+is	POS	O
+unclear	POS	O
+whether	POS	O
+it	POS	O
+is	POS	O
+substantial	POS	O
+enough	POS	O
+to	POS	O
+have	POS	O
+a	POS	O
+strong	POS	O
+influence	POS	O
+on	POS	O
+epileptogenesis	POS	B-NP
+.	POS	O
+To	POS	O
+quantify	POS	O
+this	POS	O
+population	POS	O
+,	POS	O
+the	POS	O
+total	POS	O
+number	POS	O
+of	POS	O
+ectopic	POS	O
+hilar	POS	O
+granule	POS	O
+cells	POS	O
+was	POS	O
+estimated	POS	O
+using	POS	O
+unbiased	POS	O
+stereology	POS	O
+at	POS	O
+different	POS	O
+times	POS	O
+after	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+.	POS	O
+The	POS	O
+number	POS	O
+of	POS	O
+hilar	POS	O
+neurons	POS	O
+immunoreactive	POS	O
+for	POS	O
+Prox	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+a	POS	O
+granule	POS	O
+-	POS	O
+cell	POS	O
+-	POS	O
+specific	POS	O
+marker	POS	O
+,	POS	O
+was	POS	O
+estimated	POS	O
+using	POS	O
+the	POS	O
+optical	POS	O
+fractionator	POS	O
+method	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+the	POS	O
+size	POS	O
+of	POS	O
+the	POS	O
+hilar	POS	O
+ectopic	POS	O
+granule	POS	O
+cell	POS	O
+population	POS	O
+after	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+is	POS	O
+substantial	POS	O
+,	POS	O
+and	POS	O
+stable	POS	O
+over	POS	O
+time	POS	O
+.	POS	O
+Interestingly	POS	O
+,	POS	O
+the	POS	O
+size	POS	O
+of	POS	O
+the	POS	O
+population	POS	O
+appears	POS	O
+to	POS	O
+be	POS	O
+correlated	POS	O
+with	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+behavioral	POS	O
+seizures	POS	B-NP
+,	POS	O
+because	POS	O
+animals	POS	O
+with	POS	O
+more	POS	O
+ectopic	POS	O
+granule	POS	O
+cells	POS	O
+in	POS	O
+the	POS	O
+hilus	POS	O
+have	POS	O
+more	POS	O
+frequent	POS	O
+behavioral	POS	O
+seizures	POS	B-NP
+.	POS	O
+The	POS	O
+hilar	POS	O
+ectopic	POS	O
+granule	POS	O
+cell	POS	O
+population	POS	O
+does	POS	O
+not	POS	O
+appear	POS	O
+to	POS	O
+vary	POS	O
+systematically	POS	O
+across	POS	O
+the	POS	O
+septotemporal	POS	O
+axis	POS	O
+,	POS	O
+although	POS	O
+it	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+volume	POS	O
+of	POS	O
+the	POS	O
+hilus	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+provide	POS	O
+new	POS	O
+insight	POS	O
+into	POS	O
+the	POS	O
+potential	POS	O
+role	POS	O
+of	POS	O
+ectopic	POS	O
+hilar	POS	O
+granule	POS	O
+cells	POS	O
+in	POS	O
+the	POS	O
+pilocarpine	POS	O
+model	POS	O
+of	POS	O
+temporal	POS	B-NP
+lobe	POS	I-NP
+epilepsy	POS	I-NP
+.	POS	O
+A	POS	O
+prospective	POS	O
+,	POS	O
+open	POS	O
+-	POS	O
+label	POS	O
+trial	POS	O
+of	POS	O
+galantamine	POS	O
+in	POS	O
+autistic	POS	B-NP
+disorder	POS	I-NP
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+Post	POS	O
+-	POS	O
+mortem	POS	O
+studies	POS	O
+have	POS	O
+reported	POS	O
+abnormalities	POS	O
+of	POS	O
+the	POS	O
+cholinergic	POS	O
+system	POS	O
+in	POS	O
+autism	POS	B-NP
+.	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+assess	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+galantamine	POS	O
+,	POS	O
+an	POS	O
+acetylcholinesterase	POS	O
+inhibitor	POS	O
+and	POS	O
+nicotinic	POS	O
+receptor	POS	O
+modulator	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+interfering	POS	O
+behaviors	POS	O
+in	POS	O
+children	POS	O
+with	POS	O
+autism	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Thirteen	POS	O
+medication	POS	O
+-	POS	O
+free	POS	O
+children	POS	O
+with	POS	O
+autism	POS	B-NP
+(	POS	O
+mean	POS	O
+age	POS	O
+,	POS	O
+8	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+3	POS	O
+.	POS	O
+5	POS	O
+years	POS	O
+)	POS	O
+participated	POS	O
+in	POS	O
+a	POS	O
+12	POS	O
+-	POS	O
+week	POS	O
+,	POS	O
+open	POS	O
+-	POS	O
+label	POS	O
+trial	POS	O
+of	POS	O
+galantamine	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+rated	POS	O
+monthly	POS	O
+by	POS	O
+parents	POS	O
+on	POS	O
+the	POS	O
+Aberrant	POS	O
+Behavior	POS	O
+Checklist	POS	O
+(	POS	O
+ABC	POS	O
+)	POS	O
+and	POS	O
+the	POS	O
+Conners	POS	O
+'	POS	O
+Parent	POS	O
+Rating	POS	O
+Scale	POS	O
+-	POS	O
+Revised	POS	O
+,	POS	O
+and	POS	O
+by	POS	O
+a	POS	O
+physician	POS	O
+using	POS	O
+the	POS	O
+Children	POS	O
+'	POS	O
+s	POS	O
+Psychiatric	POS	O
+Rating	POS	O
+Scale	POS	O
+and	POS	O
+the	POS	O
+Clinical	POS	O
+Global	POS	O
+Impressions	POS	O
+scale	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Patients	POS	O
+showed	POS	O
+a	POS	O
+significant	POS	O
+reduction	POS	O
+in	POS	O
+parent	POS	O
+-	POS	O
+rated	POS	O
+irritability	POS	B-NP
+and	POS	O
+social	POS	O
+withdrawal	POS	O
+on	POS	O
+the	POS	O
+ABC	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+significant	POS	O
+improvements	POS	O
+in	POS	O
+emotional	POS	O
+lability	POS	O
+and	POS	O
+inattention	POS	B-NP
+on	POS	O
+the	POS	O
+Conners	POS	O
+'	POS	O
+Parent	POS	O
+Rating	POS	O
+Scale	POS	O
+-	POS	O
+-	POS	O
+Revised	POS	O
+.	POS	O
+Similarly	POS	O
+,	POS	O
+clinician	POS	O
+ratings	POS	O
+showed	POS	O
+reductions	POS	O
+in	POS	O
+the	POS	O
+anger	POS	O
+subscale	POS	O
+of	POS	O
+the	POS	O
+Children	POS	O
+'	POS	O
+s	POS	O
+Psychiatric	POS	O
+Rating	POS	O
+Scale	POS	O
+.	POS	O
+Eight	POS	O
+of	POS	O
+13	POS	O
+participants	POS	O
+were	POS	O
+rated	POS	O
+as	POS	O
+responders	POS	O
+on	POS	O
+the	POS	O
+basis	POS	O
+of	POS	O
+their	POS	O
+improvement	POS	O
+scores	POS	O
+on	POS	O
+the	POS	O
+Clinical	POS	O
+Global	POS	O
+Impressions	POS	O
+scale	POS	O
+.	POS	O
+Overall	POS	O
+,	POS	O
+galantamine	POS	O
+was	POS	O
+well	POS	O
+-	POS	O
+tolerated	POS	O
+,	POS	O
+with	POS	O
+no	POS	O
+significant	POS	O
+adverse	POS	O
+effects	POS	O
+apart	POS	O
+from	POS	O
+headaches	POS	B-NP
+in	POS	O
+one	POS	O
+patient	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+In	POS	O
+this	POS	O
+open	POS	O
+trial	POS	O
+,	POS	O
+galantamine	POS	O
+was	POS	O
+well	POS	O
+-	POS	O
+tolerated	POS	O
+and	POS	O
+appeared	POS	O
+to	POS	O
+be	POS	O
+beneficial	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+interfering	POS	O
+behaviors	POS	O
+in	POS	O
+children	POS	O
+with	POS	O
+autism	POS	B-NP
+,	POS	O
+particularly	POS	O
+aggression	POS	B-NP
+,	POS	O
+behavioral	POS	B-NP
+dyscontrol	POS	I-NP
+,	POS	O
+and	POS	O
+inattention	POS	B-NP
+.	POS	O
+Further	POS	O
+controlled	POS	O
+trials	POS	O
+are	POS	O
+warranted	POS	O
+.	POS	O
+Randomized	POS	O
+comparison	POS	O
+of	POS	O
+olanzapine	POS	O
+versus	POS	O
+risperidone	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+first	POS	O
+-	POS	O
+episode	POS	O
+schizophrenia	POS	B-NP
+:	POS	O
+4	POS	O
+-	POS	O
+month	POS	O
+outcomes	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+The	POS	O
+authors	POS	O
+compared	POS	O
+4	POS	O
+-	POS	O
+month	POS	O
+treatment	POS	O
+outcomes	POS	O
+for	POS	O
+olanzapine	POS	O
+versus	POS	O
+risperidone	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+first	POS	O
+-	POS	O
+episode	POS	O
+schizophrenia	POS	B-NP
+spectrum	POS	O
+disorders	POS	O
+.	POS	O
+METHOD	POS	O
+:	POS	O
+One	POS	O
+hundred	POS	O
+twelve	POS	O
+subjects	POS	O
+(	POS	O
+70	POS	O
+%	POS	O
+male	POS	O
+;	POS	O
+mean	POS	O
+age	POS	O
+=	POS	O
+23	POS	O
+.	POS	O
+3	POS	O
+years	POS	O
+[	POS	O
+SD	POS	O
+=	POS	O
+5	POS	O
+.	POS	O
+1	POS	O
+]	POS	O
+)	POS	O
+with	POS	O
+first	POS	O
+-	POS	O
+episode	POS	O
+schizophrenia	POS	B-NP
+(	POS	O
+75	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+schizophreniform	POS	B-NP
+disorder	POS	I-NP
+(	POS	O
+17	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+or	POS	O
+schizoaffective	POS	B-NP
+disorder	POS	I-NP
+(	POS	O
+8	POS	O
+%	POS	O
+)	POS	O
+were	POS	O
+randomly	POS	O
+assigned	POS	O
+to	POS	O
+treatment	POS	O
+with	POS	O
+olanzapine	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+or	POS	O
+risperidone	POS	O
+(	POS	O
+1	POS	O
+-	POS	O
+6	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Response	POS	O
+rates	POS	O
+did	POS	O
+not	POS	O
+significantly	POS	O
+differ	POS	O
+between	POS	O
+olanzapine	POS	O
+(	POS	O
+43	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+28	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+-	POS	O
+58	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+risperidone	POS	O
+(	POS	O
+54	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+39	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+-	POS	O
+68	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Among	POS	O
+those	POS	O
+responding	POS	O
+to	POS	O
+treatment	POS	O
+,	POS	O
+more	POS	O
+subjects	POS	O
+in	POS	O
+the	POS	O
+olanzapine	POS	O
+group	POS	O
+(	POS	O
+40	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+16	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+-	POS	O
+65	POS	O
+.	POS	O
+0	POS	O
+%	POS	O
+)	POS	O
+than	POS	O
+in	POS	O
+the	POS	O
+risperidone	POS	O
+group	POS	O
+(	POS	O
+18	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+0	POS	O
+%	POS	O
+-	POS	O
+39	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+)	POS	O
+had	POS	O
+subsequent	POS	O
+ratings	POS	O
+not	POS	O
+meeting	POS	O
+response	POS	O
+criteria	POS	O
+.	POS	O
+Negative	POS	O
+symptom	POS	O
+outcomes	POS	O
+and	POS	O
+measures	POS	O
+of	POS	O
+parkinsonism	POS	B-NP
+and	POS	O
+akathisia	POS	B-NP
+did	POS	O
+not	POS	O
+differ	POS	O
+between	POS	O
+medications	POS	O
+.	POS	O
+Extrapyramidal	POS	B-NP
+symptom	POS	I-NP
+severity	POS	O
+scores	POS	O
+were	POS	O
+1	POS	O
+.	POS	O
+4	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+6	POS	O
+)	POS	O
+with	POS	O
+risperidone	POS	O
+and	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+0	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+4	POS	O
+)	POS	O
+with	POS	O
+olanzapine	POS	O
+.	POS	O
+Significantly	POS	O
+more	POS	O
+weight	POS	O
+gain	POS	O
+occurred	POS	O
+with	POS	O
+olanzapine	POS	O
+than	POS	O
+with	POS	O
+risperidone	POS	O
+:	POS	O
+the	POS	O
+increase	POS	O
+in	POS	O
+weight	POS	O
+at	POS	O
+4	POS	O
+months	POS	O
+relative	POS	O
+to	POS	O
+baseline	POS	O
+weight	POS	O
+was	POS	O
+17	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+14	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+-	POS	O
+20	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+with	POS	O
+olanzapine	POS	O
+and	POS	O
+11	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+8	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+-	POS	O
+14	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+)	POS	O
+with	POS	O
+risperidone	POS	O
+.	POS	O
+Body	POS	O
+mass	POS	O
+index	POS	O
+at	POS	O
+baseline	POS	O
+and	POS	O
+at	POS	O
+4	POS	O
+months	POS	O
+was	POS	O
+24	POS	O
+.	POS	O
+3	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+22	POS	O
+.	POS	O
+8	POS	O
+-	POS	O
+25	POS	O
+.	POS	O
+7	POS	O
+)	POS	O
+versus	POS	O
+28	POS	O
+.	POS	O
+2	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+26	POS	O
+.	POS	O
+7	POS	O
+-	POS	O
+29	POS	O
+.	POS	O
+7	POS	O
+)	POS	O
+with	POS	O
+olanzapine	POS	O
+and	POS	O
+23	POS	O
+.	POS	O
+9	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+22	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+25	POS	O
+.	POS	O
+3	POS	O
+)	POS	O
+versus	POS	O
+26	POS	O
+.	POS	O
+7	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+25	POS	O
+.	POS	O
+2	POS	O
+-	POS	O
+28	POS	O
+.	POS	O
+2	POS	O
+)	POS	O
+with	POS	O
+risperidone	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Clinical	POS	O
+outcomes	POS	O
+with	POS	O
+risperidone	POS	O
+were	POS	O
+equal	POS	O
+to	POS	O
+those	POS	O
+with	POS	O
+olanzapine	POS	O
+,	POS	O
+and	POS	O
+response	POS	O
+may	POS	O
+be	POS	O
+more	POS	O
+stable	POS	O
+.	POS	O
+Olanzapine	POS	O
+may	POS	O
+have	POS	O
+an	POS	O
+advantage	POS	O
+for	POS	O
+motor	POS	O
+side	POS	O
+effects	POS	O
+.	POS	O
+Both	POS	O
+medications	POS	O
+caused	POS	O
+substantial	POS	O
+rapid	POS	O
+weight	POS	O
+gain	POS	O
+,	POS	O
+but	POS	O
+weight	POS	B-NP
+gain	POS	I-NP
+was	POS	O
+greater	POS	O
+with	POS	O
+olanzapine	POS	O
+.	POS	O
+Early	POS	B-NP
+paracentral	POS	I-NP
+visual	POS	I-NP
+field	POS	I-NP
+loss	POS	I-NP
+in	POS	O
+patients	POS	O
+taking	POS	O
+hydroxychloroquine	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+review	POS	O
+the	POS	O
+natural	POS	O
+history	POS	O
+and	POS	O
+ocular	POS	O
+and	POS	O
+systemic	POS	O
+adverse	POS	O
+effects	POS	O
+of	POS	O
+patients	POS	O
+taking	POS	O
+hydroxychloroquine	POS	O
+sulfate	POS	O
+who	POS	O
+attended	POS	O
+an	POS	O
+ophthalmic	POS	O
+screening	POS	O
+program	POS	O
+.	POS	O
+DESIGN	POS	O
+:	POS	O
+Retrospective	POS	O
+study	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Records	POS	O
+of	POS	O
+262	POS	O
+patients	POS	O
+who	POS	O
+were	POS	O
+taking	POS	O
+hydroxychloroquine	POS	O
+and	POS	O
+screened	POS	O
+in	POS	O
+the	POS	O
+Department	POS	O
+of	POS	O
+Ophthalmology	POS	O
+were	POS	O
+reviewed	POS	O
+.	POS	O
+Of	POS	O
+the	POS	O
+262	POS	O
+patients	POS	O
+,	POS	O
+14	POS	O
+(	POS	O
+18	POS	O
+%	POS	O
+)	POS	O
+of	POS	O
+76	POS	O
+who	POS	O
+had	POS	O
+stopped	POS	O
+treatment	POS	O
+at	POS	O
+the	POS	O
+time	POS	O
+of	POS	O
+the	POS	O
+study	POS	O
+experienced	POS	O
+documented	POS	O
+adverse	POS	O
+effects	POS	O
+.	POS	O
+Systemic	POS	O
+adverse	POS	O
+effects	POS	O
+occurred	POS	O
+in	POS	O
+8	POS	O
+patients	POS	O
+(	POS	O
+10	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+ocular	POS	O
+adverse	POS	O
+effects	POS	O
+,	POS	O
+in	POS	O
+5	POS	O
+(	POS	O
+6	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Thirty	POS	O
+-	POS	O
+five	POS	O
+patients	POS	O
+(	POS	O
+13	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+had	POS	O
+visual	POS	B-NP
+field	POS	I-NP
+abnormalities	POS	I-NP
+,	POS	O
+which	POS	O
+were	POS	O
+attributed	POS	O
+to	POS	O
+hydroxychloroquine	POS	O
+treatment	POS	O
+in	POS	O
+4	POS	O
+patients	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Three	POS	O
+of	POS	O
+the	POS	O
+4	POS	O
+patients	POS	O
+were	POS	O
+taking	POS	O
+less	POS	O
+than	POS	O
+6	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+per	POS	O
+day	POS	O
+and	POS	O
+all	POS	O
+patients	POS	O
+had	POS	O
+normal	POS	O
+renal	POS	O
+and	POS	O
+liver	POS	O
+function	POS	O
+test	POS	O
+results	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+current	POS	O
+study	POS	O
+used	POS	O
+a	POS	O
+protocol	POS	O
+of	POS	O
+visual	POS	O
+acuity	POS	O
+and	POS	O
+color	POS	O
+vision	POS	O
+assessment	POS	O
+,	POS	O
+funduscopy	POS	O
+,	POS	O
+and	POS	O
+Humphrey	POS	O
+10	POS	O
+-	POS	O
+2	POS	O
+visual	POS	O
+field	POS	O
+testing	POS	O
+and	POS	O
+shows	POS	O
+that	POS	O
+visual	POS	B-NP
+field	POS	I-NP
+defects	POS	I-NP
+appeared	POS	O
+before	POS	O
+any	POS	O
+corresponding	POS	O
+changes	POS	O
+in	POS	O
+any	POS	O
+other	POS	O
+tested	POS	O
+clinical	POS	O
+parameters	POS	O
+;	POS	O
+the	POS	O
+defects	POS	O
+were	POS	O
+reproducible	POS	O
+and	POS	O
+the	POS	O
+test	POS	O
+parameters	POS	O
+were	POS	O
+reliable	POS	O
+.	POS	O
+Patients	POS	O
+taking	POS	O
+hydroxychloroquine	POS	O
+can	POS	O
+demonstrate	POS	O
+a	POS	O
+toxic	POS	O
+reaction	POS	O
+in	POS	O
+the	POS	O
+retina	POS	O
+despite	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+known	POS	O
+risk	POS	O
+factors	POS	O
+.	POS	O
+Screening	POS	O
+,	POS	O
+including	POS	O
+Humphrey	POS	O
+10	POS	O
+-	POS	O
+2	POS	O
+visual	POS	O
+field	POS	O
+assessment	POS	O
+,	POS	O
+is	POS	O
+recommended	POS	O
+2	POS	O
+years	POS	O
+after	POS	O
+the	POS	O
+initial	POS	O
+baseline	POS	O
+and	POS	O
+yearly	POS	O
+thereafter	POS	O
+.	POS	O
+Peri	POS	O
+-	POS	O
+operative	POS	O
+atrioventricular	POS	B-NP
+block	POS	I-NP
+as	POS	O
+a	POS	O
+result	POS	O
+of	POS	O
+chemotherapy	POS	O
+with	POS	O
+epirubicin	POS	O
+and	POS	O
+paclitaxel	POS	O
+.	POS	O
+A	POS	O
+47	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+presented	POS	O
+for	POS	O
+mastectomy	POS	O
+and	POS	O
+immediate	POS	O
+latissimus	POS	O
+dorsi	POS	O
+flap	POS	O
+reconstruction	POS	O
+having	POS	O
+been	POS	O
+diagnosed	POS	O
+with	POS	O
+carcinoma	POS	B-NP
+of	POS	O
+the	POS	O
+breast	POS	O
+6	POS	O
+months	POS	O
+previously	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+preceding	POS	O
+months	POS	O
+she	POS	O
+had	POS	O
+received	POS	O
+neo	POS	O
+-	POS	O
+adjuvant	POS	O
+chemotherapy	POS	O
+with	POS	O
+epirubicin	POS	O
+,	POS	O
+paclitaxel	POS	O
+(	POS	O
+Taxol	POS	O
+)	POS	O
+and	POS	O
+cyclophosphamide	POS	O
+.	POS	O
+This	POS	O
+had	POS	O
+been	POS	O
+apparently	POS	O
+uncomplicated	POS	O
+and	POS	O
+she	POS	O
+had	POS	O
+maintained	POS	O
+a	POS	O
+remarkably	POS	O
+high	POS	O
+level	POS	O
+of	POS	O
+physical	POS	O
+activity	POS	O
+.	POS	O
+She	POS	O
+was	POS	O
+found	POS	O
+to	POS	O
+be	POS	O
+bradycardic	POS	O
+at	POS	O
+pre	POS	O
+-	POS	O
+operative	POS	O
+assessment	POS	O
+but	POS	O
+had	POS	O
+no	POS	O
+cardiac	POS	B-NP
+symptoms	POS	I-NP
+.	POS	O
+Second	POS	O
+degree	POS	O
+Mobitz	POS	B-NP
+type	POS	I-NP
+II	POS	I-NP
+atrioventricular	POS	I-NP
+block	POS	I-NP
+was	POS	O
+diagnosed	POS	O
+on	POS	O
+electrocardiogram	POS	O
+,	POS	O
+and	POS	O
+temporary	POS	O
+transvenous	POS	O
+ventricular	POS	O
+pacing	POS	O
+instituted	POS	O
+in	POS	O
+the	POS	O
+peri	POS	O
+-	POS	O
+operative	POS	O
+period	POS	O
+.	POS	O
+We	POS	O
+discuss	POS	O
+how	POS	O
+evidence	POS	O
+-	POS	O
+based	POS	O
+guidelines	POS	O
+would	POS	O
+not	POS	O
+have	POS	O
+been	POS	O
+helpful	POS	O
+in	POS	O
+this	POS	O
+case	POS	O
+,	POS	O
+and	POS	O
+how	POS	O
+chemotherapy	POS	O
+can	POS	O
+exhibit	POS	O
+substantial	POS	O
+cardiotoxicity	POS	B-NP
+that	POS	O
+may	POS	O
+develop	POS	O
+over	POS	O
+many	POS	O
+years	POS	O
+.	POS	O
+We	POS	O
+suggest	POS	O
+that	POS	O
+patients	POS	O
+who	POS	O
+have	POS	O
+received	POS	O
+chemotherapy	POS	O
+at	POS	O
+any	POS	O
+time	POS	O
+should	POS	O
+have	POS	O
+a	POS	O
+pre	POS	O
+-	POS	O
+operative	POS	O
+electrocardiogram	POS	O
+even	POS	O
+if	POS	O
+they	POS	O
+are	POS	O
+asymptomatic	POS	O
+.	POS	O
+Risks	POS	O
+and	POS	O
+benefits	POS	O
+of	POS	O
+COX	POS	O
+-	POS	O
+2	POS	O
+inhibitors	POS	O
+vs	POS	O
+non	POS	O
+-	POS	O
+selective	POS	O
+NSAIDs	POS	O
+:	POS	O
+does	POS	O
+their	POS	O
+cardiovascular	POS	O
+risk	POS	O
+exceed	POS	O
+their	POS	O
+gastrointestinal	POS	O
+benefit	POS	O
+?	POS	O
+A	POS	O
+retrospective	POS	O
+cohort	POS	O
+study	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+The	POS	O
+risk	POS	O
+of	POS	O
+acute	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+(	POS	O
+AMI	POS	B-NP
+)	POS	O
+with	POS	O
+COX	POS	O
+-	POS	O
+2	POS	O
+inhibitors	POS	O
+may	POS	O
+offset	POS	O
+their	POS	O
+gastrointestinal	POS	O
+(	POS	O
+GI	POS	O
+)	POS	O
+benefit	POS	O
+compared	POS	O
+with	POS	O
+non	POS	O
+-	POS	O
+selective	POS	O
+(	POS	O
+NS	POS	O
+)	POS	O
+non	POS	O
+-	POS	O
+steroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+(	POS	O
+NSAIDs	POS	O
+)	POS	O
+.	POS	O
+We	POS	O
+aimed	POS	O
+to	POS	O
+compare	POS	O
+the	POS	O
+risks	POS	O
+of	POS	O
+hospitalization	POS	O
+for	POS	O
+AMI	POS	B-NP
+and	POS	O
+GI	POS	B-NP
+bleeding	POS	I-NP
+among	POS	O
+elderly	POS	O
+patients	POS	O
+using	POS	O
+COX	POS	O
+-	POS	O
+2	POS	O
+inhibitors	POS	O
+,	POS	O
+NS	POS	O
+-	POS	O
+NSAIDs	POS	O
+and	POS	O
+acetaminophen	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+conducted	POS	O
+a	POS	O
+retrospective	POS	O
+cohort	POS	O
+study	POS	O
+using	POS	O
+administrative	POS	O
+data	POS	O
+of	POS	O
+patients	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+65	POS	O
+years	POS	O
+of	POS	O
+age	POS	O
+who	POS	O
+filled	POS	O
+a	POS	O
+prescription	POS	O
+for	POS	O
+NSAID	POS	O
+or	POS	O
+acetaminophen	POS	O
+during	POS	O
+1999	POS	O
+-	POS	O
+2002	POS	O
+.	POS	O
+Outcomes	POS	O
+were	POS	O
+compared	POS	O
+using	POS	O
+Cox	POS	O
+regression	POS	O
+models	POS	O
+with	POS	O
+time	POS	O
+-	POS	O
+dependent	POS	O
+exposures	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Person	POS	O
+-	POS	O
+years	POS	O
+of	POS	O
+exposure	POS	O
+among	POS	O
+non	POS	O
+-	POS	O
+users	POS	O
+of	POS	O
+aspirin	POS	O
+were	POS	O
+:	POS	O
+75	POS	O
+,	POS	O
+761	POS	O
+to	POS	O
+acetaminophen	POS	O
+,	POS	O
+42	POS	O
+,	POS	O
+671	POS	O
+to	POS	O
+rofecoxib	POS	O
+65	POS	O
+,	POS	O
+860	POS	O
+to	POS	O
+celecoxib	POS	O
+,	POS	O
+and	POS	O
+37	POS	O
+,	POS	O
+495	POS	O
+to	POS	O
+NS	POS	O
+-	POS	O
+NSAIDs	POS	O
+.	POS	O
+Among	POS	O
+users	POS	O
+of	POS	O
+aspirin	POS	O
+,	POS	O
+they	POS	O
+were	POS	O
+:	POS	O
+14	POS	O
+,	POS	O
+671	POS	O
+to	POS	O
+rofecoxib	POS	O
+,	POS	O
+22	POS	O
+,	POS	O
+875	POS	O
+to	POS	O
+celecoxib	POS	O
+,	POS	O
+9	POS	O
+,	POS	O
+832	POS	O
+to	POS	O
+NS	POS	O
+-	POS	O
+NSAIDs	POS	O
+and	POS	O
+38	POS	O
+,	POS	O
+048	POS	O
+to	POS	O
+acetaminophen	POS	O
+.	POS	O
+Among	POS	O
+non	POS	O
+-	POS	O
+users	POS	O
+of	POS	O
+aspirin	POS	O
+,	POS	O
+the	POS	O
+adjusted	POS	O
+hazard	POS	O
+ratios	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+)	POS	O
+of	POS	O
+hospitalization	POS	O
+for	POS	O
+AMI	POS	B-NP
+/	POS	O
+GI	POS	O
+vs	POS	O
+the	POS	O
+acetaminophen	POS	O
+(	POS	O
+with	POS	O
+no	POS	O
+aspirin	POS	O
+)	POS	O
+group	POS	O
+were	POS	O
+:	POS	O
+rofecoxib	POS	O
+1	POS	O
+.	POS	O
+27	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+13	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+42	POS	O
+)	POS	O
+,	POS	O
+celecoxib	POS	O
+0	POS	O
+.	POS	O
+93	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+83	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+03	POS	O
+)	POS	O
+,	POS	O
+naproxen	POS	O
+1	POS	O
+.	POS	O
+59	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+31	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+93	POS	O
+)	POS	O
+,	POS	O
+diclofenac	POS	O
+1	POS	O
+.	POS	O
+17	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+99	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+38	POS	O
+)	POS	O
+and	POS	O
+ibuprofen	POS	O
+1	POS	O
+.	POS	O
+05	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+74	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+51	POS	O
+)	POS	O
+.	POS	O
+Among	POS	O
+users	POS	O
+of	POS	O
+aspirin	POS	O
+,	POS	O
+they	POS	O
+were	POS	O
+:	POS	O
+rofecoxib	POS	O
+1	POS	O
+.	POS	O
+73	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+52	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+98	POS	O
+)	POS	O
+,	POS	O
+celecoxib	POS	O
+1	POS	O
+.	POS	O
+34	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+19	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+52	POS	O
+)	POS	O
+,	POS	O
+ibuprofen	POS	O
+1	POS	O
+.	POS	O
+51	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+95	POS	O
+,	POS	O
+2	POS	O
+.	POS	O
+41	POS	O
+)	POS	O
+,	POS	O
+diclofenac	POS	O
+1	POS	O
+.	POS	O
+69	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+35	POS	O
+,	POS	O
+2	POS	O
+.	POS	O
+10	POS	O
+)	POS	O
+,	POS	O
+naproxen	POS	O
+1	POS	O
+.	POS	O
+35	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+97	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+88	POS	O
+)	POS	O
+and	POS	O
+acetaminophen	POS	O
+1	POS	O
+.	POS	O
+29	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+17	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+42	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Among	POS	O
+non	POS	O
+-	POS	O
+users	POS	O
+of	POS	O
+aspirin	POS	O
+,	POS	O
+naproxen	POS	O
+seemed	POS	O
+to	POS	O
+carry	POS	O
+the	POS	O
+highest	POS	O
+risk	POS	O
+for	POS	O
+AMI	POS	B-NP
+/	POS	O
+GI	POS	B-NP
+bleeding	POS	I-NP
+.	POS	O
+The	POS	O
+AMI	POS	O
+/	POS	O
+GI	POS	B-NP
+toxicity	POS	I-NP
+of	POS	O
+celecoxib	POS	O
+was	POS	O
+similar	POS	O
+to	POS	O
+that	POS	O
+of	POS	O
+acetaminophen	POS	O
+and	POS	O
+seemed	POS	O
+to	POS	O
+be	POS	O
+better	POS	O
+than	POS	O
+those	POS	O
+of	POS	O
+rofecoxib	POS	O
+and	POS	O
+NS	POS	O
+-	POS	O
+NSAIDs	POS	O
+.	POS	O
+Among	POS	O
+users	POS	O
+of	POS	O
+aspirin	POS	O
+,	POS	O
+both	POS	O
+celecoxib	POS	O
+and	POS	O
+naproxen	POS	O
+seemed	POS	O
+to	POS	O
+be	POS	O
+the	POS	O
+least	POS	O
+toxic	POS	O
+.	POS	O
+Quinine	POS	O
+-	POS	O
+induced	POS	O
+arrhythmia	POS	B-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+severe	POS	O
+malaria	POS	B-NP
+.	POS	O
+It	POS	O
+was	POS	O
+reported	POS	O
+that	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+severe	POS	O
+malaria	POS	B-NP
+patient	POS	O
+with	POS	O
+jaundice	POS	B-NP
+who	POS	O
+presented	POS	O
+with	POS	O
+arrhythmia	POS	B-NP
+(	POS	O
+premature	POS	B-NP
+ventricular	POS	I-NP
+contraction	POS	I-NP
+)	POS	O
+while	POS	O
+getting	POS	O
+quinine	POS	O
+infusion	POS	O
+was	POS	O
+reported	POS	O
+.	POS	O
+A	POS	O
+man	POS	O
+,	POS	O
+25	POS	O
+years	POS	O
+old	POS	O
+,	POS	O
+was	POS	O
+admitted	POS	O
+to	POS	O
+hospital	POS	O
+with	POS	O
+high	POS	B-NP
+fever	POS	I-NP
+,	POS	O
+chill	POS	B-NP
+,	POS	O
+vomiting	POS	B-NP
+,	POS	O
+jaundice	POS	B-NP
+.	POS	O
+The	POS	O
+patient	POS	O
+was	POS	O
+fully	POS	O
+conscious	POS	O
+,	POS	O
+blood	POS	O
+pressure	POS	O
+120	POS	O
+/	POS	O
+80	POS	O
+mmHg	POS	O
+,	POS	O
+pulse	POS	O
+rate	POS	O
+100	POS	O
+x	POS	O
+/	POS	O
+minute	POS	O
+,	POS	O
+regular	POS	O
+.	POS	O
+On	POS	O
+admission	POS	O
+,	POS	O
+laboratory	POS	O
+examination	POS	O
+showed	POS	O
+Plasmodium	POS	O
+falciparum	POS	O
+(	POS	O
++	POS	O
++	POS	O
++	POS	O
++	POS	O
+)	POS	O
+,	POS	O
+total	POS	O
+bilirubin	POS	O
+8	POS	O
+.	POS	O
+25	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+,	POS	O
+conjugated	POS	O
+bilirubin	POS	O
+4	POS	O
+.	POS	O
+36	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+,	POS	O
+unconjugated	POS	O
+bilirubin	POS	O
+3	POS	O
+.	POS	O
+89	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+,	POS	O
+potassium	POS	O
+3	POS	O
+.	POS	O
+52	POS	O
+meq	POS	O
+/	POS	O
+L	POS	O
+Patient	POS	O
+was	POS	O
+diagnosed	POS	O
+as	POS	O
+severe	POS	O
+malaria	POS	B-NP
+with	POS	O
+jaundice	POS	B-NP
+and	POS	O
+got	POS	O
+quinine	POS	O
+infusion	POS	O
+in	POS	O
+dextrose	POS	O
+5	POS	O
+%	POS	O
+500	POS	O
+mg	POS	O
+/	POS	O
+8	POS	O
+hour	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+second	POS	O
+day	POS	O
+the	POS	O
+patient	POS	O
+had	POS	O
+vomitus	POS	B-NP
+,	POS	O
+diarrhea	POS	B-NP
+,	POS	O
+tinnitus	POS	B-NP
+,	POS	O
+loss	POS	B-NP
+of	POS	I-NP
+hearing	POS	I-NP
+.	POS	O
+After	POS	O
+30	POS	O
+hours	POS	O
+of	POS	O
+quinine	POS	O
+infusion	POS	O
+the	POS	O
+patient	POS	O
+felt	POS	O
+palpitation	POS	B-NP
+and	POS	O
+electrocardiography	POS	O
+(	POS	O
+ECG	POS	O
+)	POS	O
+recording	POS	O
+showed	POS	O
+premature	POS	B-NP
+ventricular	POS	I-NP
+contraction	POS	I-NP
+(	POS	O
+PVC	POS	O
+)	POS	O
+>	POS	O
+5	POS	O
+x	POS	O
+/	POS	O
+minute	POS	O
+,	POS	O
+trigemini	POS	O
+,	POS	O
+constant	POS	O
+type	POS	O
+-	POS	O
+-	POS	O
+sinoatrial	POS	O
+block	POS	O
+,	POS	O
+positive	POS	O
+U	POS	O
+wave	POS	O
+.	POS	O
+He	POS	O
+was	POS	O
+treated	POS	O
+with	POS	O
+lidocaine	POS	O
+50	POS	O
+mg	POS	O
+intravenously	POS	O
+followed	POS	O
+by	POS	O
+infusion	POS	O
+1500	POS	O
+mg	POS	O
+in	POS	O
+dextrose	POS	O
+5	POS	O
+%	POS	O
+/	POS	O
+24	POS	O
+hour	POS	O
+and	POS	O
+potassium	POS	O
+aspartate	POS	O
+tablet	POS	O
+.	POS	O
+Quinine	POS	O
+infusion	POS	O
+was	POS	O
+discontinued	POS	O
+and	POS	O
+changed	POS	O
+with	POS	O
+sulfate	POS	O
+quinine	POS	O
+tablets	POS	O
+.	POS	O
+Three	POS	O
+hours	POS	O
+later	POS	O
+the	POS	O
+patient	POS	O
+felt	POS	O
+better	POS	O
+,	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+PVC	POS	O
+reduced	POS	O
+to	POS	O
+4	POS	O
+-	POS	O
+5	POS	O
+x	POS	O
+/	POS	O
+minute	POS	O
+and	POS	O
+on	POS	O
+the	POS	O
+third	POS	O
+day	POS	O
+ECG	POS	O
+was	POS	O
+normal	POS	O
+,	POS	O
+potassium	POS	O
+level	POS	O
+was	POS	O
+3	POS	O
+.	POS	O
+34	POS	O
+meq	POS	O
+/	POS	O
+L	POS	O
+.	POS	O
+He	POS	O
+was	POS	O
+discharged	POS	O
+on	POS	O
+7th	POS	O
+day	POS	O
+in	POS	O
+good	POS	O
+condition	POS	O
+.	POS	O
+Quinine	POS	O
+,	POS	O
+like	POS	O
+quinidine	POS	O
+,	POS	O
+is	POS	O
+a	POS	O
+chincona	POS	O
+alkaloid	POS	O
+that	POS	O
+has	POS	O
+anti	POS	O
+-	POS	O
+arrhythmic	POS	O
+property	POS	O
+,	POS	O
+although	POS	O
+it	POS	O
+also	POS	O
+pro	POS	O
+-	POS	O
+arrhythmic	POS	O
+that	POS	O
+can	POS	O
+cause	POS	O
+various	POS	O
+arrhythmias	POS	B-NP
+,	POS	O
+including	POS	O
+severe	POS	O
+arrhythmia	POS	B-NP
+such	POS	O
+as	POS	O
+multiple	POS	O
+PVC	POS	O
+.	POS	O
+Administration	POS	O
+of	POS	O
+parenteral	POS	O
+quinine	POS	O
+must	POS	O
+be	POS	O
+done	POS	O
+carefully	POS	O
+and	POS	O
+with	POS	O
+good	POS	O
+observation	POS	O
+because	POS	O
+of	POS	O
+its	POS	O
+pro	POS	O
+-	POS	O
+arrhythmic	POS	O
+effect	POS	O
+,	POS	O
+especially	POS	O
+in	POS	O
+older	POS	O
+patients	POS	O
+who	POS	O
+have	POS	O
+heart	POS	B-NP
+diseases	POS	I-NP
+or	POS	O
+patients	POS	O
+with	POS	O
+electrolyte	POS	B-NP
+disorder	POS	I-NP
+(	POS	O
+hypokalemia	POS	B-NP
+)	POS	O
+which	POS	O
+frequently	POS	O
+occurs	POS	O
+due	POS	O
+to	POS	O
+vomiting	POS	B-NP
+and	POS	O
+or	POS	O
+diarrhea	POS	B-NP
+in	POS	O
+malaria	POS	B-NP
+cases	POS	O
+.	POS	O
+Penicillamine	POS	B-NP
+-	POS	I-NP
+related	POS	I-NP
+lichenoid	POS	I-NP
+dermatitis	POS	I-NP
+and	POS	O
+utility	POS	O
+of	POS	O
+zinc	POS	O
+acetate	POS	O
+in	POS	O
+a	POS	O
+Wilson	POS	B-NP
+disease	POS	I-NP
+patient	POS	O
+with	POS	O
+hepatic	POS	B-NP
+presentation	POS	I-NP
+,	POS	O
+anxiety	POS	B-NP
+and	POS	O
+SPECT	POS	B-NP
+abnormalities	POS	I-NP
+.	POS	O
+Wilson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+is	POS	O
+an	POS	O
+autosomal	POS	B-NP
+recessive	POS	I-NP
+disorder	POS	I-NP
+of	POS	I-NP
+hepatic	POS	I-NP
+copper	POS	I-NP
+metabolism	POS	I-NP
+with	POS	O
+consequent	POS	O
+copper	POS	O
+accumulation	POS	O
+and	POS	O
+toxicity	POS	B-NP
+in	POS	O
+many	POS	O
+tissues	POS	O
+and	POS	O
+consequent	POS	O
+hepatic	POS	O
+,	POS	O
+neurologic	POS	O
+and	POS	O
+psychiatric	POS	B-NP
+disorders	POS	I-NP
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+Wilson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+with	POS	O
+chronic	POS	B-NP
+liver	POS	I-NP
+disease	POS	I-NP
+;	POS	O
+moreover	POS	O
+,	POS	O
+in	POS	O
+our	POS	O
+patient	POS	O
+,	POS	O
+presenting	POS	O
+also	POS	O
+with	POS	O
+high	POS	O
+levels	POS	O
+of	POS	O
+state	POS	O
+anxiety	POS	B-NP
+without	POS	O
+depression	POS	B-NP
+,	POS	O
+99mTc	POS	O
+-	POS	O
+ECD	POS	O
+-	POS	O
+SPECT	POS	O
+showed	POS	O
+cortical	POS	O
+hypoperfusion	POS	O
+in	POS	O
+frontal	POS	O
+lobes	POS	O
+,	POS	O
+more	POS	O
+marked	POS	O
+on	POS	O
+the	POS	O
+left	POS	O
+frontal	POS	O
+lobe	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+of	POS	O
+our	POS	O
+patient	POS	O
+,	POS	O
+penicillamine	POS	O
+was	POS	O
+interrupted	POS	O
+after	POS	O
+the	POS	O
+appearance	POS	O
+of	POS	O
+a	POS	O
+lichenoid	POS	B-NP
+dermatitis	POS	I-NP
+,	POS	O
+and	POS	O
+zinc	POS	O
+acetate	POS	O
+permitted	POS	O
+to	POS	O
+continue	POS	O
+the	POS	O
+successful	POS	O
+treatment	POS	O
+of	POS	O
+the	POS	O
+patient	POS	O
+without	POS	O
+side	POS	O
+-	POS	O
+effects	POS	O
+.	POS	O
+In	POS	O
+our	POS	O
+case	POS	O
+the	POS	O
+therapy	POS	O
+with	POS	O
+zinc	POS	O
+acetate	POS	O
+represented	POS	O
+an	POS	O
+effective	POS	O
+treatment	POS	O
+for	POS	O
+a	POS	O
+Wilson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+patient	POS	O
+in	POS	O
+which	POS	O
+penicillamine	POS	O
+-	POS	O
+related	POS	O
+side	POS	O
+effects	POS	O
+appeared	POS	O
+.	POS	O
+The	POS	O
+safety	POS	O
+of	POS	O
+the	POS	O
+zinc	POS	O
+acetate	POS	O
+allowed	POS	O
+us	POS	O
+to	POS	O
+avoid	POS	O
+other	POS	O
+potentially	POS	O
+toxic	POS	O
+chelating	POS	O
+drugs	POS	O
+;	POS	O
+this	POS	O
+observation	POS	O
+is	POS	O
+in	POS	O
+line	POS	O
+with	POS	O
+the	POS	O
+growing	POS	O
+evidence	POS	O
+on	POS	O
+the	POS	O
+efficacy	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+Wilson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+Since	POS	O
+most	POS	O
+of	POS	O
+Wilson	POS	O
+'	POS	O
+s	POS	O
+disease	POS	O
+penicillamine	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+do	POS	O
+not	POS	O
+seem	POS	O
+to	POS	O
+develop	POS	O
+this	POS	O
+skin	POS	B-NP
+lesion	POS	I-NP
+,	POS	O
+it	POS	O
+could	POS	O
+be	POS	O
+conceivable	POS	O
+that	POS	O
+a	POS	O
+specific	POS	O
+genetic	POS	O
+factor	POS	O
+is	POS	O
+involved	POS	O
+in	POS	O
+drug	POS	O
+response	POS	O
+.	POS	O
+Further	POS	O
+studies	POS	O
+are	POS	O
+needed	POS	O
+for	POS	O
+a	POS	O
+better	POS	O
+clarification	POS	O
+of	POS	O
+Wilson	POS	O
+'	POS	O
+s	POS	O
+disease	POS	O
+therapy	POS	O
+,	POS	O
+and	POS	O
+in	POS	O
+particular	POS	O
+to	POS	O
+differentiate	POS	O
+specific	POS	O
+therapies	POS	O
+for	POS	O
+different	POS	O
+Wilson	POS	O
+'	POS	O
+s	POS	O
+disease	POS	O
+phenotypes	POS	O
+.	POS	O
+A	POS	O
+dramatic	POS	O
+drop	POS	O
+in	POS	O
+blood	POS	O
+pressure	POS	O
+following	POS	O
+prehospital	POS	O
+GTN	POS	O
+administration	POS	O
+.	POS	O
+A	POS	O
+male	POS	O
+in	POS	O
+his	POS	O
+sixties	POS	O
+with	POS	O
+no	POS	O
+history	POS	O
+of	POS	O
+cardiac	POS	B-NP
+chest	POS	I-NP
+pain	POS	I-NP
+awoke	POS	O
+with	POS	O
+chest	POS	B-NP
+pain	POS	I-NP
+following	POS	O
+an	POS	O
+afternoon	POS	O
+sleep	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+did	POS	O
+not	POS	O
+self	POS	O
+medicate	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+observations	POS	O
+were	POS	O
+within	POS	O
+normal	POS	O
+limits	POS	O
+,	POS	O
+he	POS	O
+was	POS	O
+administered	POS	O
+oxygen	POS	O
+via	POS	O
+a	POS	O
+face	POS	O
+mask	POS	O
+and	POS	O
+glyceryl	POS	O
+trinitrate	POS	O
+(	POS	O
+GTN	POS	O
+)	POS	O
+.	POS	O
+Several	POS	O
+minutes	POS	O
+after	POS	O
+the	POS	O
+GTN	POS	O
+the	POS	O
+patient	POS	O
+experienced	POS	O
+a	POS	O
+sudden	POS	O
+drop	POS	O
+in	POS	O
+blood	POS	O
+pressure	POS	O
+and	POS	O
+heart	POS	O
+rate	POS	O
+,	POS	O
+this	POS	O
+was	POS	O
+rectified	POS	O
+by	POS	O
+atropine	POS	O
+sulphate	POS	O
+and	POS	O
+a	POS	O
+fluid	POS	O
+challenge	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+further	POS	O
+deterioration	POS	O
+in	POS	O
+the	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+condition	POS	O
+during	POS	O
+transport	POS	O
+to	POS	O
+hospital	POS	O
+.	POS	O
+There	POS	O
+are	POS	O
+very	POS	O
+few	POS	O
+documented	POS	O
+case	POS	O
+like	POS	O
+this	POS	O
+in	POS	O
+the	POS	O
+prehospital	POS	O
+scientific	POS	O
+literature	POS	O
+.	POS	O
+The	POS	O
+cause	POS	O
+appears	POS	O
+to	POS	O
+be	POS	O
+the	POS	O
+Bezold	POS	O
+-	POS	O
+Jarish	POS	O
+reflex	POS	O
+,	POS	O
+stimulation	POS	O
+of	POS	O
+the	POS	O
+ventricular	POS	O
+walls	POS	O
+which	POS	O
+in	POS	O
+turn	POS	O
+decreases	POS	O
+sympathetic	POS	O
+outflow	POS	O
+from	POS	O
+the	POS	O
+vasomotor	POS	O
+centre	POS	O
+.	POS	O
+Prehospital	POS	O
+care	POS	O
+providers	POS	O
+who	POS	O
+are	POS	O
+managing	POS	O
+any	POS	O
+patient	POS	O
+with	POS	O
+a	POS	O
+syncopal	POS	B-NP
+episode	POS	O
+that	POS	O
+fails	POS	O
+to	POS	O
+recover	POS	O
+within	POS	O
+a	POS	O
+reasonable	POS	O
+time	POS	O
+frame	POS	O
+should	POS	O
+consider	POS	O
+the	POS	O
+Bezold	POS	O
+-	POS	O
+Jarisch	POS	O
+reflex	POS	O
+as	POS	O
+the	POS	O
+cause	POS	O
+and	POS	O
+manage	POS	O
+the	POS	O
+patient	POS	O
+accordingly	POS	O
+.	POS	O
+Chronic	POS	O
+lesion	POS	O
+of	POS	O
+rostral	POS	O
+ventrolateral	POS	O
+medulla	POS	O
+in	POS	O
+spontaneously	POS	O
+hypertensive	POS	B-NP
+rats	POS	O
+.	POS	O
+We	POS	O
+studied	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+chronic	POS	O
+selective	POS	O
+neuronal	POS	O
+lesion	POS	O
+of	POS	O
+rostral	POS	O
+ventrolateral	POS	O
+medulla	POS	O
+on	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+,	POS	O
+heart	POS	O
+rate	POS	O
+,	POS	O
+and	POS	O
+neurogenic	POS	O
+tone	POS	O
+in	POS	O
+conscious	POS	O
+,	POS	O
+unrestrained	POS	O
+spontaneously	POS	O
+hypertensive	POS	B-NP
+rats	POS	O
+.	POS	O
+The	POS	O
+lesions	POS	O
+were	POS	O
+placed	POS	O
+via	POS	O
+bilateral	POS	O
+microinjections	POS	O
+of	POS	O
+30	POS	O
+nmol	POS	O
+/	POS	O
+200	POS	O
+nl	POS	O
+N	POS	O
+-	POS	O
+methyl	POS	O
+-	POS	O
+D	POS	O
+-	POS	O
+aspartic	POS	O
+acid	POS	O
+.	POS	O
+The	POS	O
+restimulation	POS	O
+of	POS	O
+this	POS	O
+area	POS	O
+with	POS	O
+N	POS	O
+-	POS	O
+methyl	POS	O
+-	POS	O
+D	POS	O
+-	POS	O
+aspartic	POS	O
+acid	POS	O
+15	POS	O
+days	POS	O
+postlesion	POS	O
+failed	POS	O
+to	POS	O
+produce	POS	O
+a	POS	O
+pressor	POS	O
+response	POS	O
+.	POS	O
+One	POS	O
+day	POS	O
+postlesion	POS	O
+,	POS	O
+the	POS	O
+resting	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+was	POS	O
+significantly	POS	O
+decreased	POS	O
+in	POS	O
+lesioned	POS	O
+rats	POS	O
+when	POS	O
+compared	POS	O
+with	POS	O
+sham	POS	O
+rats	POS	O
+(	POS	O
+100	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+7	POS	O
+versus	POS	O
+173	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+mm	POS	O
+Hg	POS	O
+,	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+Fifteen	POS	O
+days	POS	O
+later	POS	O
+,	POS	O
+the	POS	O
+lesioned	POS	O
+group	POS	O
+still	POS	O
+showed	POS	O
+values	POS	O
+significantly	POS	O
+lower	POS	O
+than	POS	O
+the	POS	O
+sham	POS	O
+group	POS	O
+(	POS	O
+150	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+versus	POS	O
+167	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+5	POS	O
+mm	POS	O
+Hg	POS	O
+,	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+No	POS	O
+significant	POS	O
+heart	POS	O
+rate	POS	O
+differences	POS	O
+were	POS	O
+observed	POS	O
+between	POS	O
+the	POS	O
+sham	POS	O
+and	POS	O
+lesioned	POS	O
+groups	POS	O
+.	POS	O
+The	POS	O
+ganglionic	POS	O
+blocker	POS	O
+trimethaphan	POS	O
+(	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+)	POS	O
+caused	POS	O
+similar	POS	O
+reductions	POS	O
+in	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+in	POS	O
+both	POS	O
+lesioned	POS	O
+and	POS	O
+sham	POS	O
+groups	POS	O
+.	POS	O
+The	POS	O
+trimethaphan	POS	O
+-	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+was	POS	O
+accompanied	POS	O
+by	POS	O
+a	POS	O
+significant	POS	O
+bradycardia	POS	B-NP
+in	POS	O
+lesioned	POS	O
+rats	POS	O
+(	POS	O
+-	POS	O
+32	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+13	POS	O
+beats	POS	O
+per	POS	O
+minute	POS	O
+)	POS	O
+but	POS	O
+a	POS	O
+tachycardia	POS	B-NP
+in	POS	O
+sham	POS	O
+rats	POS	O
+(	POS	O
++	POS	O
+33	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+12	POS	O
+beats	POS	O
+per	POS	O
+minute	POS	O
+)	POS	O
+1	POS	O
+day	POS	O
+postlesion	POS	O
+.	POS	O
+Therefore	POS	O
+,	POS	O
+rostral	POS	O
+ventrolateral	POS	O
+medulla	POS	O
+neurons	POS	O
+appear	POS	O
+to	POS	O
+play	POS	O
+a	POS	O
+significant	POS	O
+role	POS	O
+in	POS	O
+maintaining	POS	O
+hypertension	POS	B-NP
+in	POS	O
+conscious	POS	O
+spontaneously	POS	O
+hypertensive	POS	B-NP
+rats	POS	O
+.	POS	O
+Spinal	POS	O
+or	POS	O
+suprabulbar	POS	O
+structures	POS	O
+could	POS	O
+be	POS	O
+responsible	POS	O
+for	POS	O
+the	POS	O
+gradual	POS	O
+recovery	POS	O
+of	POS	O
+the	POS	O
+hypertension	POS	B-NP
+in	POS	O
+the	POS	O
+lesioned	POS	O
+rats	POS	O
+.	POS	O
+Acute	POS	O
+encephalopathy	POS	B-NP
+and	POS	O
+cerebral	POS	B-NP
+vasospasm	POS	I-NP
+after	POS	O
+multiagent	POS	O
+chemotherapy	POS	O
+including	POS	O
+PEG	POS	O
+-	POS	O
+asparaginase	POS	O
+and	POS	O
+intrathecal	POS	O
+cytarabine	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+acute	POS	B-NP
+lymphoblastic	POS	I-NP
+leukemia	POS	I-NP
+.	POS	O
+A	POS	O
+7	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+girl	POS	O
+with	POS	O
+an	POS	O
+unusual	POS	O
+reaction	POS	O
+to	POS	O
+induction	POS	O
+chemotherapy	POS	O
+for	POS	O
+precursor	POS	B-NP
+B	POS	I-NP
+-	POS	I-NP
+cell	POS	I-NP
+acute	POS	I-NP
+lymphoblastic	POS	I-NP
+leukemia	POS	I-NP
+(	POS	O
+ALL	POS	B-NP
+)	POS	O
+is	POS	O
+described	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+developed	POS	O
+acute	POS	O
+encephalopathy	POS	B-NP
+evidenced	POS	O
+by	POS	O
+behavioral	POS	O
+changes	POS	O
+,	POS	O
+aphasia	POS	B-NP
+,	POS	O
+incontinence	POS	B-NP
+,	POS	O
+visual	POS	B-NP
+hallucinations	POS	I-NP
+,	POS	O
+and	POS	O
+right	POS	B-NP
+-	POS	I-NP
+sided	POS	I-NP
+weakness	POS	I-NP
+with	POS	O
+diffuse	POS	B-NP
+cerebral	POS	I-NP
+vasospasm	POS	I-NP
+on	POS	O
+magnetic	POS	O
+resonance	POS	O
+angiography	POS	O
+after	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+intrathecal	POS	O
+cytarabine	POS	O
+.	POS	O
+Vincristine	POS	O
+,	POS	O
+dexamethasone	POS	O
+,	POS	O
+and	POS	O
+polyethylene	POS	O
+glycol	POS	O
+-	POS	O
+asparaginase	POS	O
+were	POS	O
+also	POS	O
+administered	POS	O
+before	POS	O
+the	POS	O
+episode	POS	O
+as	POS	O
+part	POS	O
+of	POS	O
+induction	POS	O
+therapy	POS	O
+.	POS	O
+Neurologic	POS	O
+status	POS	O
+returned	POS	O
+to	POS	O
+baseline	POS	O
+within	POS	O
+10	POS	O
+days	POS	O
+of	POS	O
+the	POS	O
+acute	POS	O
+event	POS	O
+,	POS	O
+and	POS	O
+magnetic	POS	O
+resonance	POS	O
+angiography	POS	O
+findings	POS	O
+returned	POS	O
+to	POS	O
+normal	POS	O
+4	POS	O
+months	POS	O
+later	POS	O
+.	POS	O
+Comparison	POS	O
+of	POS	O
+valsartan	POS	O
+/	POS	O
+hydrochlorothiazide	POS	O
+combination	POS	O
+therapy	POS	O
+at	POS	O
+doses	POS	O
+up	POS	O
+to	POS	O
+320	POS	O
+/	POS	O
+25	POS	O
+mg	POS	O
+versus	POS	O
+monotherapy	POS	O
+:	POS	O
+a	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+study	POS	O
+followed	POS	O
+by	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+combination	POS	O
+therapy	POS	O
+in	POS	O
+hypertensive	POS	B-NP
+adults	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+One	POS	O
+third	POS	O
+of	POS	O
+patients	POS	O
+treated	POS	O
+for	POS	O
+hypertension	POS	B-NP
+attain	POS	O
+adequate	POS	O
+blood	POS	O
+pressure	POS	O
+(	POS	O
+BP	POS	O
+)	POS	O
+control	POS	O
+,	POS	O
+and	POS	O
+multidrug	POS	O
+regimens	POS	O
+are	POS	O
+often	POS	O
+required	POS	O
+.	POS	O
+Given	POS	O
+the	POS	O
+lifelong	POS	O
+nature	POS	O
+of	POS	O
+hypertension	POS	B-NP
+,	POS	O
+there	POS	O
+is	POS	O
+a	POS	O
+need	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+efficacy	POS	O
+and	POS	O
+tolerability	POS	O
+of	POS	O
+higher	POS	O
+doses	POS	O
+of	POS	O
+combination	POS	O
+anti	POS	O
+-	POS	O
+hypertensive	POS	O
+therapies	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+This	POS	O
+study	POS	O
+investigated	POS	O
+the	POS	O
+efficacy	POS	O
+and	POS	O
+tolerability	POS	O
+of	POS	O
+valsartan	POS	O
+(	POS	O
+VAL	POS	O
+)	POS	O
+or	POS	O
+hydrochlorothiazide	POS	O
+(	POS	O
+HCTZ	POS	O
+)	POS	O
+-	POS	O
+monotherapy	POS	O
+and	POS	O
+higher	POS	O
+-	POS	O
+dose	POS	O
+combinations	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+essential	POS	O
+hypertension	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+The	POS	O
+first	POS	O
+part	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+an	POS	O
+8	POS	O
+-	POS	O
+week	POS	O
+,	POS	O
+multicenter	POS	O
+,	POS	O
+randomized	POS	O
+,	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+placebo	POS	O
+controlled	POS	O
+,	POS	O
+parallel	POS	O
+-	POS	O
+group	POS	O
+trial	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+essential	POS	O
+hypertension	POS	B-NP
+(	POS	O
+mean	POS	O
+sitting	POS	O
+diastolic	POS	O
+BP	POS	O
+[	POS	O
+MSDBP	POS	O
+]	POS	O
+,	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+95	POS	O
+mm	POS	O
+Hg	POS	O
+and	POS	O
+<	POS	O
+110	POS	O
+mm	POS	O
+Hg	POS	O
+)	POS	O
+were	POS	O
+randomized	POS	O
+to	POS	O
+1	POS	O
+of	POS	O
+8	POS	O
+treatment	POS	O
+groups	POS	O
+:	POS	O
+VAL	POS	O
+160	POS	O
+or	POS	O
+320	POS	O
+mg	POS	O
+;	POS	O
+HCTZ	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+or	POS	O
+25	POS	O
+mg	POS	O
+;	POS	O
+VAL	POS	O
+/	POS	O
+HCTZ	POS	O
+160	POS	O
+/	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+,	POS	O
+320	POS	O
+/	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+,	POS	O
+or	POS	O
+320	POS	O
+/	POS	O
+25	POS	O
+mg	POS	O
+;	POS	O
+or	POS	O
+placebo	POS	O
+.	POS	O
+Mean	POS	O
+changes	POS	O
+in	POS	O
+MSDBP	POS	O
+and	POS	O
+mean	POS	O
+sitting	POS	O
+systolic	POS	O
+BP	POS	O
+(	POS	O
+MSSBP	POS	O
+)	POS	O
+were	POS	O
+analyzed	POS	O
+at	POS	O
+the	POS	O
+8	POS	O
+-	POS	O
+week	POS	O
+core	POS	O
+study	POS	O
+end	POS	O
+point	POS	O
+.	POS	O
+VAL	POS	O
+/	POS	O
+HCTZ	POS	O
+320	POS	O
+/	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+and	POS	O
+320	POS	O
+/	POS	O
+25	POS	O
+mg	POS	O
+were	POS	O
+further	POS	O
+investigated	POS	O
+in	POS	O
+a	POS	O
+54	POS	O
+-	POS	O
+week	POS	O
+,	POS	O
+open	POS	O
+-	POS	O
+label	POS	O
+extension	POS	O
+.	POS	O
+Response	POS	O
+was	POS	O
+defined	POS	O
+as	POS	O
+MSDBP	POS	O
+<	POS	O
+90	POS	O
+mm	POS	O
+Hg	POS	O
+or	POS	O
+a	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+10	POS	O
+mm	POS	O
+Hg	POS	O
+decrease	POS	O
+compared	POS	O
+to	POS	O
+baseline	POS	O
+.	POS	O
+Control	POS	O
+was	POS	O
+defined	POS	O
+as	POS	O
+MSDBP	POS	O
+<	POS	O
+90	POS	O
+mm	POS	O
+Hg	POS	O
+compared	POS	O
+with	POS	O
+baseline	POS	O
+.	POS	O
+Tolerability	POS	O
+was	POS	O
+assessed	POS	O
+by	POS	O
+monitoring	POS	O
+adverse	POS	O
+events	POS	O
+at	POS	O
+randomization	POS	O
+and	POS	O
+all	POS	O
+subsequent	POS	O
+study	POS	O
+visits	POS	O
+and	POS	O
+regular	POS	O
+evaluation	POS	O
+of	POS	O
+hematology	POS	O
+and	POS	O
+blood	POS	O
+chemistry	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+1346	POS	O
+patients	POS	O
+were	POS	O
+randomized	POS	O
+into	POS	O
+the	POS	O
+8	POS	O
+-	POS	O
+week	POS	O
+core	POS	O
+study	POS	O
+(	POS	O
+734	POS	O
+men	POS	O
+,	POS	O
+612	POS	O
+women	POS	O
+;	POS	O
+924	POS	O
+white	POS	O
+,	POS	O
+291	POS	O
+black	POS	O
+,	POS	O
+23	POS	O
+Asian	POS	O
+,	POS	O
+108	POS	O
+other	POS	O
+;	POS	O
+mean	POS	O
+age	POS	O
+,	POS	O
+52	POS	O
+.	POS	O
+7	POS	O
+years	POS	O
+;	POS	O
+mean	POS	O
+weight	POS	O
+,	POS	O
+92	POS	O
+.	POS	O
+6	POS	O
+kg	POS	O
+)	POS	O
+.	POS	O
+All	POS	O
+active	POS	O
+treatments	POS	O
+were	POS	O
+associated	POS	O
+with	POS	O
+significantly	POS	O
+reduced	POS	O
+MSSBP	POS	O
+and	POS	O
+MSDBP	POS	O
+during	POS	O
+the	POS	O
+core	POS	O
+8	POS	O
+-	POS	O
+week	POS	O
+study	POS	O
+,	POS	O
+with	POS	O
+each	POS	O
+monotherapy	POS	O
+significantly	POS	O
+contributing	POS	O
+to	POS	O
+the	POS	O
+overall	POS	O
+effect	POS	O
+of	POS	O
+combination	POS	O
+therapy	POS	O
+(	POS	O
+VAL	POS	O
+and	POS	O
+HCTZ	POS	O
+,	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+Each	POS	O
+combination	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+significantly	POS	O
+greater	POS	O
+reductions	POS	O
+in	POS	O
+MSSBP	POS	O
+and	POS	O
+MSDBP	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+monotherapies	POS	O
+and	POS	O
+placebo	POS	O
+(	POS	O
+all	POS	O
+,	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+reduction	POS	O
+in	POS	O
+MSSBP	POS	O
+/	POS	O
+MSDBP	POS	O
+with	POS	O
+VAL	POS	O
+/	POS	O
+HCTZ	POS	O
+320	POS	O
+/	POS	O
+25	POS	O
+mg	POS	O
+was	POS	O
+24	POS	O
+.	POS	O
+7	POS	O
+/	POS	O
+16	POS	O
+.	POS	O
+6	POS	O
+mm	POS	O
+Hg	POS	O
+,	POS	O
+compared	POS	O
+with	POS	O
+5	POS	O
+.	POS	O
+9	POS	O
+/	POS	O
+7	POS	O
+.	POS	O
+0	POS	O
+mm	POS	O
+Hg	POS	O
+with	POS	O
+placebo	POS	O
+.	POS	O
+The	POS	O
+reduction	POS	O
+in	POS	O
+MSSBP	POS	O
+was	POS	O
+significantly	POS	O
+greater	POS	O
+with	POS	O
+VAL	POS	O
+/	POS	O
+HCTZ	POS	O
+320	POS	O
+/	POS	O
+25	POS	O
+mg	POS	O
+compared	POS	O
+with	POS	O
+VAL	POS	O
+/	POS	O
+HCTZ	POS	O
+160	POS	O
+/	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+002	POS	O
+)	POS	O
+.	POS	O
+Rates	POS	O
+of	POS	O
+response	POS	O
+and	POS	O
+BP	POS	O
+control	POS	O
+were	POS	O
+significantly	POS	O
+higher	POS	O
+in	POS	O
+the	POS	O
+groups	POS	O
+that	POS	O
+received	POS	O
+combination	POS	O
+treatment	POS	O
+compared	POS	O
+with	POS	O
+those	POS	O
+that	POS	O
+received	POS	O
+monotherapy	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+hypokalemia	POS	B-NP
+was	POS	O
+lower	POS	O
+with	POS	O
+VAL	POS	O
+/	POS	O
+HCTZ	POS	O
+combinations	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+)	POS	O
+than	POS	O
+with	POS	O
+HCTZ	POS	O
+monotherapies	POS	O
+(	POS	O
+7	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+-	POS	O
+13	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+majority	POS	O
+of	POS	O
+adverse	POS	O
+events	POS	O
+in	POS	O
+the	POS	O
+core	POS	O
+study	POS	O
+were	POS	O
+of	POS	O
+mild	POS	O
+to	POS	O
+moderate	POS	O
+severity	POS	O
+.	POS	O
+The	POS	O
+efficacy	POS	O
+and	POS	O
+tolerability	POS	O
+of	POS	O
+VAL	POS	O
+/	POS	O
+HCTZ	POS	O
+combinations	POS	O
+were	POS	O
+maintained	POS	O
+during	POS	O
+the	POS	O
+extension	POS	O
+(	POS	O
+797	POS	O
+patients	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+population	POS	O
+,	POS	O
+combination	POS	O
+therapies	POS	O
+with	POS	O
+VAL	POS	O
+/	POS	O
+HCTZ	POS	O
+were	POS	O
+associated	POS	O
+with	POS	O
+significantly	POS	O
+greater	POS	O
+BP	POS	O
+reductions	POS	O
+compared	POS	O
+with	POS	O
+either	POS	O
+monotherapy	POS	O
+,	POS	O
+were	POS	O
+well	POS	O
+tolerated	POS	O
+,	POS	O
+and	POS	O
+were	POS	O
+associated	POS	O
+with	POS	O
+less	POS	O
+hypokalemia	POS	B-NP
+than	POS	O
+HCTZ	POS	O
+alone	POS	O
+.	POS	O
+Succimer	POS	O
+chelation	POS	O
+improves	POS	O
+learning	POS	O
+,	POS	O
+attention	POS	O
+,	POS	O
+and	POS	O
+arousal	POS	O
+regulation	POS	O
+in	POS	O
+lead	POS	O
+-	POS	O
+exposed	POS	O
+rats	POS	O
+but	POS	O
+produces	POS	O
+lasting	POS	O
+cognitive	POS	B-NP
+impairment	POS	I-NP
+in	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+lead	POS	O
+exposure	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+There	POS	O
+is	POS	O
+growing	POS	O
+pressure	POS	O
+for	POS	O
+clinicians	POS	O
+to	POS	O
+prescribe	POS	O
+chelation	POS	O
+therapy	POS	O
+at	POS	O
+only	POS	O
+slightly	POS	O
+elevated	POS	O
+blood	POS	O
+lead	POS	O
+levels	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+very	POS	O
+few	POS	O
+studies	POS	O
+have	POS	O
+evaluated	POS	O
+whether	POS	O
+chelation	POS	O
+improves	POS	O
+cognitive	POS	O
+outcomes	POS	O
+in	POS	O
+Pb	POS	O
+-	POS	O
+exposed	POS	O
+children	POS	O
+,	POS	O
+or	POS	O
+whether	POS	O
+these	POS	O
+agents	POS	O
+have	POS	O
+adverse	POS	O
+effects	POS	O
+that	POS	O
+may	POS	O
+affect	POS	O
+brain	POS	O
+development	POS	O
+in	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+Pb	POS	O
+exposure	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+designed	POS	O
+to	POS	O
+answer	POS	O
+these	POS	O
+questions	POS	O
+,	POS	O
+using	POS	O
+a	POS	O
+rodent	POS	O
+model	POS	O
+of	POS	O
+early	POS	O
+childhood	POS	O
+Pb	POS	O
+exposure	POS	O
+and	POS	O
+treatment	POS	O
+with	POS	O
+succimer	POS	O
+,	POS	O
+a	POS	O
+widely	POS	O
+used	POS	O
+chelating	POS	O
+agent	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+Pb	POS	B-NP
+poisoning	POS	I-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Pb	POS	O
+exposure	POS	O
+produced	POS	O
+lasting	POS	O
+impairments	POS	O
+in	POS	O
+learning	POS	O
+,	POS	O
+attention	POS	O
+,	POS	O
+inhibitory	POS	O
+control	POS	O
+,	POS	O
+and	POS	O
+arousal	POS	O
+regulation	POS	O
+,	POS	O
+paralleling	POS	O
+the	POS	O
+areas	POS	O
+of	POS	O
+dysfunction	POS	O
+seen	POS	O
+in	POS	O
+Pb	POS	O
+-	POS	O
+exposed	POS	O
+children	POS	O
+.	POS	O
+Succimer	POS	O
+treatment	POS	O
+of	POS	O
+the	POS	O
+Pb	POS	O
+-	POS	O
+exposed	POS	O
+rats	POS	O
+significantly	POS	O
+improved	POS	O
+learning	POS	O
+,	POS	O
+attention	POS	O
+,	POS	O
+and	POS	O
+arousal	POS	O
+regulation	POS	O
+,	POS	O
+although	POS	O
+the	POS	O
+efficacy	POS	O
+of	POS	O
+the	POS	O
+treatment	POS	O
+varied	POS	O
+as	POS	O
+a	POS	O
+function	POS	O
+of	POS	O
+the	POS	O
+Pb	POS	O
+exposure	POS	O
+level	POS	O
+and	POS	O
+the	POS	O
+specific	POS	O
+functional	POS	O
+deficit	POS	O
+.	POS	O
+In	POS	O
+contrast	POS	O
+,	POS	O
+succimer	POS	O
+treatment	POS	O
+of	POS	O
+rats	POS	O
+not	POS	O
+previously	POS	O
+exposed	POS	O
+to	POS	O
+Pb	POS	O
+produced	POS	O
+lasting	POS	O
+and	POS	O
+pervasive	POS	O
+cognitive	POS	O
+and	POS	O
+affective	POS	B-NP
+dysfunction	POS	I-NP
+comparable	POS	O
+in	POS	O
+magnitude	POS	O
+to	POS	O
+that	POS	O
+produced	POS	O
+by	POS	O
+the	POS	O
+higher	POS	O
+Pb	POS	O
+exposure	POS	O
+regimen	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+These	POS	O
+are	POS	O
+the	POS	O
+first	POS	O
+data	POS	O
+,	POS	O
+to	POS	O
+our	POS	O
+knowledge	POS	O
+,	POS	O
+to	POS	O
+show	POS	O
+that	POS	O
+treatment	POS	O
+with	POS	O
+any	POS	O
+chelating	POS	O
+agent	POS	O
+can	POS	O
+alleviate	POS	O
+cognitive	POS	B-NP
+deficits	POS	I-NP
+due	POS	O
+to	POS	O
+Pb	POS	O
+exposure	POS	O
+.	POS	O
+These	POS	O
+findings	POS	O
+suggest	POS	O
+that	POS	O
+it	POS	O
+may	POS	O
+be	POS	O
+possible	POS	O
+to	POS	O
+identify	POS	O
+a	POS	O
+succimer	POS	O
+treatment	POS	O
+protocol	POS	O
+that	POS	O
+improves	POS	O
+cognitive	POS	O
+outcomes	POS	O
+in	POS	O
+Pb	POS	O
+-	POS	O
+exposed	POS	O
+children	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+they	POS	O
+also	POS	O
+suggest	POS	O
+that	POS	O
+succimer	POS	O
+treatment	POS	O
+should	POS	O
+be	POS	O
+strongly	POS	O
+discouraged	POS	O
+for	POS	O
+children	POS	O
+who	POS	O
+do	POS	O
+not	POS	O
+have	POS	O
+elevated	POS	O
+tissue	POS	O
+levels	POS	O
+of	POS	O
+Pb	POS	O
+or	POS	O
+other	POS	O
+heavy	POS	O
+metals	POS	O
+.	POS	O
+Caffeine	POS	O
+challenge	POS	O
+test	POS	O
+in	POS	O
+panic	POS	B-NP
+disorder	POS	I-NP
+and	POS	O
+depression	POS	B-NP
+with	POS	O
+panic	POS	B-NP
+attacks	POS	I-NP
+.	POS	O
+Our	POS	O
+aim	POS	O
+was	POS	O
+to	POS	O
+observe	POS	O
+if	POS	O
+patients	POS	O
+with	POS	O
+panic	POS	B-NP
+disorder	POS	I-NP
+(	POS	O
+PD	POS	B-NP
+)	POS	O
+and	POS	O
+patients	POS	O
+with	POS	O
+major	POS	O
+depression	POS	B-NP
+with	POS	O
+panic	POS	B-NP
+attacks	POS	I-NP
+(	POS	O
+MDP	POS	O
+)	POS	O
+(	POS	O
+Diagnostic	POS	O
+and	POS	O
+Statistical	POS	O
+Manual	POS	O
+of	POS	O
+Mental	POS	O
+Disorders	POS	O
+,	POS	O
+Fourth	POS	O
+Edition	POS	O
+criteria	POS	O
+)	POS	O
+respond	POS	O
+in	POS	O
+a	POS	O
+similar	POS	O
+way	POS	O
+to	POS	O
+the	POS	O
+induction	POS	O
+of	POS	O
+panic	POS	B-NP
+attacks	POS	I-NP
+by	POS	O
+an	POS	O
+oral	POS	O
+caffeine	POS	O
+challenge	POS	O
+test	POS	O
+.	POS	O
+We	POS	O
+randomly	POS	O
+selected	POS	O
+29	POS	O
+patients	POS	O
+with	POS	O
+PD	POS	B-NP
+,	POS	O
+27	POS	O
+with	POS	O
+MDP	POS	O
+,	POS	O
+25	POS	O
+with	POS	O
+major	POS	O
+depression	POS	B-NP
+without	POS	O
+panic	POS	B-NP
+attacks	POS	I-NP
+(	POS	O
+MD	POS	B-NP
+)	POS	O
+,	POS	O
+and	POS	O
+28	POS	O
+healthy	POS	O
+volunteers	POS	O
+.	POS	O
+The	POS	O
+patients	POS	O
+had	POS	O
+no	POS	O
+psychotropic	POS	O
+drug	POS	O
+for	POS	O
+at	POS	O
+least	POS	O
+a	POS	O
+4	POS	O
+-	POS	O
+week	POS	O
+period	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+randomized	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+experiment	POS	O
+performed	POS	O
+in	POS	O
+2	POS	O
+occasions	POS	O
+7	POS	O
+days	POS	O
+apart	POS	O
+,	POS	O
+480	POS	O
+mg	POS	O
+caffeine	POS	O
+and	POS	O
+a	POS	O
+caffeine	POS	O
+-	POS	O
+free	POS	O
+(	POS	O
+placebo	POS	O
+)	POS	O
+solution	POS	O
+were	POS	O
+administered	POS	O
+in	POS	O
+a	POS	O
+coffee	POS	O
+form	POS	O
+and	POS	O
+anxiety	POS	B-NP
+scales	POS	O
+were	POS	O
+applied	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+each	POS	O
+test	POS	O
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+58	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+17	POS	O
+)	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+PD	POS	B-NP
+,	POS	O
+44	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+12	POS	O
+)	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+MDP	POS	O
+,	POS	O
+12	POS	O
+.	POS	O
+0	POS	O
+%	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+3	POS	O
+)	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+MD	POS	B-NP
+,	POS	O
+and	POS	O
+7	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+2	POS	O
+)	POS	O
+of	POS	O
+control	POS	O
+subjects	POS	O
+had	POS	O
+a	POS	O
+panic	POS	B-NP
+attack	POS	O
+after	POS	O
+the	POS	O
+480	POS	O
+-	POS	O
+mg	POS	O
+caffeine	POS	O
+challenge	POS	O
+test	POS	O
+(	POS	O
+chi	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+(	POS	O
+3	POS	O
+)	POS	O
+=	POS	O
+16	POS	O
+.	POS	O
+22	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+patients	POS	O
+with	POS	O
+PD	POS	B-NP
+and	POS	O
+MDP	POS	O
+were	POS	O
+more	POS	O
+sensitive	POS	O
+to	POS	O
+caffeine	POS	O
+than	POS	O
+were	POS	O
+patients	POS	O
+with	POS	O
+MD	POS	B-NP
+and	POS	O
+healthy	POS	O
+volunteers	POS	O
+.	POS	O
+No	POS	O
+panic	POS	B-NP
+attack	POS	O
+was	POS	O
+observed	POS	O
+after	POS	O
+the	POS	O
+caffeine	POS	O
+-	POS	O
+free	POS	O
+solution	POS	O
+intake	POS	O
+.	POS	O
+The	POS	O
+patients	POS	O
+with	POS	O
+MD	POS	B-NP
+had	POS	O
+a	POS	O
+lower	POS	O
+heart	POS	O
+rate	POS	O
+response	POS	O
+to	POS	O
+the	POS	O
+test	POS	O
+than	POS	O
+all	POS	O
+the	POS	O
+other	POS	O
+groups	POS	O
+(	POS	O
+2	POS	O
+-	POS	O
+way	POS	O
+analysis	POS	O
+of	POS	O
+variance	POS	O
+,	POS	O
+group	POS	O
+by	POS	O
+time	POS	O
+interaction	POS	O
+with	POS	O
+Greenhouse	POS	O
+-	POS	O
+Geisser	POS	O
+correction	POS	O
+:	POS	O
+F	POS	O
+(	POS	O
+3	POS	O
+,	POS	O
+762	POS	O
+)	POS	O
+=	POS	O
+2	POS	O
+.	POS	O
+85	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+026	POS	O
+)	POS	O
+.	POS	O
+Our	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+there	POS	O
+is	POS	O
+an	POS	O
+association	POS	O
+between	POS	O
+panic	POS	B-NP
+attacks	POS	I-NP
+,	POS	O
+no	POS	O
+matter	POS	O
+if	POS	O
+associated	POS	O
+with	POS	O
+PD	POS	B-NP
+or	POS	O
+MDP	POS	O
+,	POS	O
+and	POS	O
+hyperreactivity	POS	B-NP
+to	POS	O
+an	POS	O
+oral	POS	O
+caffeine	POS	O
+challenge	POS	O
+test	POS	O
+.	POS	O
+Mitral	POS	O
+annuloplasty	POS	O
+as	POS	O
+a	POS	O
+ventricular	POS	O
+restoration	POS	O
+method	POS	O
+for	POS	O
+the	POS	O
+failing	POS	O
+left	POS	O
+ventricle	POS	O
+:	POS	O
+a	POS	O
+pilot	POS	O
+study	POS	O
+.	POS	O
+BACKGROUND	POS	O
+AND	POS	O
+AIM	POS	O
+OF	POS	O
+THE	POS	O
+STUDY	POS	O
+:	POS	O
+Undersized	POS	O
+mitral	POS	O
+annuloplasty	POS	O
+(	POS	O
+MAP	POS	O
+)	POS	O
+is	POS	O
+effective	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+dilated	POS	B-NP
+cardiomyopathy	POS	I-NP
+and	POS	O
+functional	POS	B-NP
+mitral	POS	I-NP
+regurgitation	POS	I-NP
+(	POS	O
+MR	POS	O
+)	POS	O
+since	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+addressing	POS	O
+the	POS	O
+MR	POS	O
+,	POS	O
+the	POS	O
+MAP	POS	O
+may	POS	O
+also	POS	O
+reshape	POS	O
+the	POS	O
+dilated	POS	O
+left	POS	O
+ventricular	POS	O
+(	POS	O
+LV	POS	O
+)	POS	O
+base	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+direct	POS	O
+benefits	POS	O
+of	POS	O
+this	POS	O
+possible	POS	O
+reshaping	POS	O
+on	POS	O
+LV	POS	O
+function	POS	O
+in	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+underlying	POS	O
+MR	POS	O
+remain	POS	O
+incompletely	POS	O
+understood	POS	O
+.	POS	O
+The	POS	O
+study	POS	O
+aim	POS	O
+was	POS	O
+to	POS	O
+identify	POS	O
+these	POS	O
+benefits	POS	O
+in	POS	O
+a	POS	O
+canine	POS	O
+model	POS	O
+of	POS	O
+acute	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Six	POS	O
+dogs	POS	O
+underwent	POS	O
+MAP	POS	O
+with	POS	O
+a	POS	O
+prosthetic	POS	O
+band	POS	O
+on	POS	O
+the	POS	O
+posterior	POS	O
+mitral	POS	O
+annulus	POS	O
+,	POS	O
+using	POS	O
+four	POS	O
+mattress	POS	O
+sutures	POS	O
+.	POS	O
+The	POS	O
+sutures	POS	O
+were	POS	O
+passed	POS	O
+individually	POS	O
+through	POS	O
+four	POS	O
+tourniquets	POS	O
+and	POS	O
+exteriorized	POS	O
+untied	POS	O
+via	POS	O
+the	POS	O
+left	POS	O
+atriotomy	POS	O
+.	POS	O
+Sonomicrometry	POS	O
+crystals	POS	O
+were	POS	O
+implanted	POS	O
+around	POS	O
+the	POS	O
+mitral	POS	O
+annulus	POS	O
+and	POS	O
+left	POS	O
+ventricle	POS	O
+to	POS	O
+measure	POS	O
+geometry	POS	O
+and	POS	O
+regional	POS	O
+function	POS	O
+.	POS	O
+Acute	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+was	POS	O
+induced	POS	O
+by	POS	O
+propranolol	POS	O
+and	POS	O
+volume	POS	O
+loading	POS	O
+after	POS	O
+weaning	POS	O
+from	POS	O
+cardiopulmonary	POS	O
+bypass	POS	O
+;	POS	O
+an	POS	O
+absence	POS	O
+of	POS	O
+MR	POS	O
+was	POS	O
+confirmed	POS	O
+by	POS	O
+echocardiography	POS	O
+.	POS	O
+MAP	POS	O
+was	POS	O
+accomplished	POS	O
+by	POS	O
+cinching	POS	O
+the	POS	O
+tourniquets	POS	O
+.	POS	O
+Data	POS	O
+were	POS	O
+acquired	POS	O
+at	POS	O
+baseline	POS	O
+,	POS	O
+after	POS	O
+induction	POS	O
+of	POS	O
+acute	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+,	POS	O
+and	POS	O
+after	POS	O
+MAP	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+MAP	POS	O
+decreased	POS	O
+mitral	POS	O
+annular	POS	O
+dimensions	POS	O
+in	POS	O
+both	POS	O
+commissure	POS	O
+-	POS	O
+commissure	POS	O
+and	POS	O
+septal	POS	O
+-	POS	O
+lateral	POS	O
+directions	POS	O
+.	POS	O
+Concomitantly	POS	O
+,	POS	O
+the	POS	O
+diastolic	POS	O
+diameter	POS	O
+of	POS	O
+the	POS	O
+LV	POS	O
+base	POS	O
+and	POS	O
+LV	POS	O
+sphericity	POS	O
+decreased	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+e	POS	O
+.	POS	O
+,	POS	O
+improved	POS	O
+)	POS	O
+from	POS	O
+37	POS	O
+.	POS	O
+4	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+9	POS	O
+.	POS	O
+3	POS	O
+to	POS	O
+35	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+10	POS	O
+mm	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+063	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+from	POS	O
+67	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+18	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+to	POS	O
+65	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+18	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+016	POS	O
+)	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Decreases	POS	O
+were	POS	O
+evident	POS	O
+in	POS	O
+both	POS	O
+LV	POS	O
+end	POS	O
+-	POS	O
+diastolic	POS	O
+pressure	POS	O
+(	POS	O
+from	POS	O
+17	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+7	POS	O
+to	POS	O
+15	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+mmHg	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+0480	POS	O
+and	POS	O
+Tau	POS	O
+(	POS	O
+from	POS	O
+48	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+8	POS	O
+to	POS	O
+45	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+8	POS	O
+ms	POS	O
+,	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+,	POS	O
+while	POS	O
+fractional	POS	O
+shortening	POS	O
+at	POS	O
+the	POS	O
+LV	POS	O
+base	POS	O
+increased	POS	O
+from	POS	O
+7	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+to	POS	O
+9	POS	O
+.	POS	O
+4	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+045	POS	O
+)	POS	O
+.	POS	O
+After	POS	O
+MAP	POS	O
+,	POS	O
+increases	POS	O
+were	POS	O
+identified	POS	O
+in	POS	O
+both	POS	O
+cardiac	POS	O
+output	POS	O
+(	POS	O
+from	POS	O
+1	POS	O
+.	POS	O
+54	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+57	POS	O
+to	POS	O
+1	POS	O
+.	POS	O
+65	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+57	POS	O
+1	POS	O
+/	POS	O
+min	POS	O
+)	POS	O
+and	POS	O
+Emax	POS	O
+(	POS	O
+from	POS	O
+1	POS	O
+.	POS	O
+86	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+41	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+31	POS	O
+mmHg	POS	O
+/	POS	O
+ml	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+The	POS	O
+data	POS	O
+acquired	POS	O
+suggest	POS	O
+that	POS	O
+isolated	POS	O
+MAP	POS	O
+may	POS	O
+have	POS	O
+certain	POS	O
+benefits	POS	O
+on	POS	O
+LV	POS	O
+dimension	POS	O
+/	POS	O
+function	POS	O
+in	POS	O
+acute	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+,	POS	O
+even	POS	O
+in	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+MR	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+further	POS	O
+investigations	POS	O
+are	POS	O
+warranted	POS	O
+in	POS	O
+a	POS	O
+model	POS	O
+of	POS	O
+chronic	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+.	POS	O
+Piperacillin	POS	O
+/	POS	O
+tazobactam	POS	O
+-	POS	O
+induced	POS	O
+seizure	POS	B-NP
+rapidly	POS	O
+reversed	POS	O
+by	POS	O
+high	POS	O
+flux	POS	O
+hemodialysis	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+on	POS	O
+peritoneal	POS	O
+dialysis	POS	O
+.	POS	O
+Despite	POS	O
+popular	POS	O
+use	POS	O
+of	POS	O
+piperacillin	POS	O
+,	POS	O
+the	POS	O
+dire	POS	O
+neurotoxicity	POS	B-NP
+associated	POS	O
+with	POS	O
+piperacillin	POS	O
+still	POS	O
+goes	POS	O
+unrecognized	POS	O
+,	POS	O
+leading	POS	O
+to	POS	O
+a	POS	O
+delay	POS	O
+in	POS	O
+appropriate	POS	O
+management	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+57	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+with	POS	O
+end	POS	O
+-	POS	O
+stage	POS	O
+renal	POS	B-NP
+disease	POS	I-NP
+receiving	POS	O
+continuous	POS	O
+ambulatory	POS	O
+peritoneal	POS	O
+dialysis	POS	O
+(	POS	O
+CAPD	POS	O
+)	POS	O
+,	POS	O
+who	POS	O
+developed	POS	O
+slurred	POS	B-NP
+speech	POS	I-NP
+,	POS	O
+tremor	POS	B-NP
+,	POS	O
+bizarre	POS	B-NP
+behavior	POS	I-NP
+,	POS	O
+progressive	POS	B-NP
+mental	POS	I-NP
+confusion	POS	I-NP
+,	POS	O
+and	POS	O
+2	POS	O
+episodes	POS	O
+of	POS	O
+generalized	POS	O
+tonic	POS	O
+-	POS	O
+clonic	POS	B-NP
+seizure	POS	I-NP
+(	POS	O
+GTCS	POS	B-NP
+)	POS	O
+after	POS	O
+5	POS	O
+doses	POS	O
+of	POS	O
+piperacillin	POS	O
+/	POS	O
+tazobactam	POS	O
+(	POS	O
+2	POS	O
+g	POS	O
+/	POS	O
+250	POS	O
+mg	POS	O
+)	POS	O
+were	POS	O
+given	POS	O
+for	POS	O
+bronchiectasis	POS	B-NP
+with	POS	O
+secondary	POS	B-NP
+infection	POS	I-NP
+.	POS	O
+The	POS	O
+laboratory	POS	O
+data	POS	O
+revealed	POS	O
+normal	POS	O
+plasma	POS	O
+electrolyte	POS	O
+and	POS	O
+ammonia	POS	O
+levels	POS	O
+but	POS	O
+leukocytosis	POS	B-NP
+.	POS	O
+Neurologic	POS	O
+examinations	POS	O
+showed	POS	O
+dysarthria	POS	B-NP
+and	POS	O
+bilateral	POS	B-NP
+Babinski	POS	I-NP
+sign	POS	O
+.	POS	O
+Computed	POS	O
+tomography	POS	O
+of	POS	O
+brain	POS	O
+and	POS	O
+electroencephalogram	POS	O
+were	POS	O
+unremarkable	POS	O
+.	POS	O
+Despite	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+antiepileptic	POS	O
+agents	POS	O
+,	POS	O
+another	POS	O
+GTCS	POS	B-NP
+episode	POS	O
+recurred	POS	O
+after	POS	O
+the	POS	O
+sixth	POS	O
+dose	POS	O
+of	POS	O
+piperacillin	POS	O
+/	POS	O
+tazobactam	POS	O
+.	POS	O
+Brain	POS	O
+magnetic	POS	O
+resonance	POS	O
+imaging	POS	O
+did	POS	O
+not	POS	O
+demonstrate	POS	O
+acute	POS	B-NP
+infarction	POS	I-NP
+and	POS	O
+organic	POS	B-NP
+brain	POS	I-NP
+lesions	POS	I-NP
+.	POS	O
+Initiation	POS	O
+of	POS	O
+high	POS	O
+-	POS	O
+flux	POS	O
+hemodialysis	POS	O
+rapidly	POS	O
+reversed	POS	O
+the	POS	O
+neurologic	POS	O
+symptoms	POS	O
+within	POS	O
+4	POS	O
+hours	POS	O
+.	POS	O
+Piperacillin	POS	O
+-	POS	O
+induced	POS	O
+encephalopathy	POS	B-NP
+should	POS	O
+be	POS	O
+considered	POS	O
+in	POS	O
+any	POS	O
+uremic	POS	B-NP
+patients	POS	O
+with	POS	O
+unexplained	POS	O
+neurological	POS	B-NP
+manifestations	POS	I-NP
+.	POS	O
+CAPD	POS	B-NP
+is	POS	O
+inefficient	POS	O
+in	POS	O
+removing	POS	O
+piperacillin	POS	O
+,	POS	O
+whereas	POS	O
+hemodialysis	POS	O
+can	POS	O
+rapidly	POS	O
+terminate	POS	O
+the	POS	O
+piperacillin	POS	O
+-	POS	O
+induced	POS	O
+encephalopathy	POS	B-NP
+.	POS	O
+Frequency	POS	O
+of	POS	O
+transient	POS	O
+ipsilateral	POS	O
+vocal	POS	B-NP
+cord	POS	I-NP
+paralysis	POS	I-NP
+in	POS	O
+patients	POS	O
+undergoing	POS	O
+carotid	POS	O
+endarterectomy	POS	O
+under	POS	O
+local	POS	O
+anesthesia	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Especially	POS	O
+because	POS	O
+of	POS	O
+improvements	POS	O
+in	POS	O
+clinical	POS	O
+neurologic	POS	O
+monitoring	POS	O
+,	POS	O
+carotid	POS	O
+endarterectomy	POS	O
+done	POS	O
+under	POS	O
+local	POS	O
+anesthesia	POS	O
+has	POS	O
+become	POS	O
+the	POS	O
+technique	POS	O
+of	POS	O
+choice	POS	O
+in	POS	O
+several	POS	O
+centers	POS	O
+.	POS	O
+Temporary	POS	O
+ipsilateral	POS	O
+vocal	POS	B-NP
+nerve	POS	I-NP
+palsies	POS	I-NP
+due	POS	O
+to	POS	O
+local	POS	O
+anesthetics	POS	O
+have	POS	O
+been	POS	O
+described	POS	O
+,	POS	O
+however	POS	O
+.	POS	O
+Such	POS	O
+complications	POS	O
+are	POS	O
+most	POS	O
+important	POS	O
+in	POS	O
+situations	POS	O
+where	POS	O
+there	POS	O
+is	POS	O
+a	POS	O
+pre	POS	O
+-	POS	O
+existing	POS	O
+contralateral	POS	O
+paralysis	POS	B-NP
+.	POS	O
+We	POS	O
+therefore	POS	O
+examined	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+local	POS	O
+anesthesia	POS	O
+on	POS	O
+vocal	POS	O
+cord	POS	O
+function	POS	O
+to	POS	O
+better	POS	O
+understand	POS	O
+its	POS	O
+possible	POS	O
+consequences	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+This	POS	O
+prospective	POS	O
+study	POS	O
+included	POS	O
+28	POS	O
+patients	POS	O
+undergoing	POS	O
+carotid	POS	O
+endarterectomy	POS	O
+under	POS	O
+local	POS	O
+anesthesia	POS	O
+.	POS	O
+Vocal	POS	O
+cord	POS	O
+function	POS	O
+was	POS	O
+evaluated	POS	O
+before	POS	O
+,	POS	O
+during	POS	O
+,	POS	O
+and	POS	O
+after	POS	O
+surgery	POS	O
+(	POS	O
+postoperative	POS	O
+day	POS	O
+1	POS	O
+)	POS	O
+using	POS	O
+flexible	POS	O
+laryngoscopy	POS	O
+.	POS	O
+Anesthesia	POS	O
+was	POS	O
+performed	POS	O
+by	POS	O
+injecting	POS	O
+20	POS	O
+to	POS	O
+40	POS	O
+mL	POS	O
+of	POS	O
+a	POS	O
+mixture	POS	O
+of	POS	O
+long	POS	O
+-	POS	O
+acting	POS	O
+(	POS	O
+ropivacaine	POS	O
+)	POS	O
+and	POS	O
+short	POS	O
+-	POS	O
+acting	POS	O
+(	POS	O
+prilocaine	POS	O
+)	POS	O
+anesthetic	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+All	POS	O
+patients	POS	O
+had	POS	O
+normal	POS	O
+vocal	POS	O
+cord	POS	O
+function	POS	O
+preoperatively	POS	O
+.	POS	O
+Twelve	POS	O
+patients	POS	O
+(	POS	O
+43	POS	O
+%	POS	O
+)	POS	O
+were	POS	O
+found	POS	O
+to	POS	O
+have	POS	O
+intraoperative	POS	O
+ipsilateral	POS	O
+vocal	POS	B-NP
+cord	POS	I-NP
+paralysis	POS	I-NP
+.	POS	O
+It	POS	O
+resolved	POS	O
+in	POS	O
+all	POS	O
+cases	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+24	POS	O
+hours	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+no	POS	O
+significant	POS	O
+differences	POS	O
+in	POS	O
+operating	POS	O
+time	POS	O
+or	POS	O
+volume	POS	O
+or	POS	O
+frequency	POS	O
+of	POS	O
+anesthetic	POS	O
+administration	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+temporary	POS	O
+vocal	POS	B-NP
+cord	POS	I-NP
+paralysis	POS	I-NP
+compared	POS	O
+with	POS	O
+those	POS	O
+without	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Local	POS	O
+anesthesia	POS	O
+led	POS	O
+to	POS	O
+temporary	POS	O
+ipsilateral	POS	O
+vocal	POS	B-NP
+cord	POS	I-NP
+paralysis	POS	I-NP
+in	POS	O
+almost	POS	O
+half	POS	O
+of	POS	O
+these	POS	O
+patients	POS	O
+.	POS	O
+Because	POS	O
+pre	POS	O
+-	POS	O
+existing	POS	O
+paralysis	POS	B-NP
+is	POS	O
+of	POS	O
+a	POS	O
+relevant	POS	O
+frequency	POS	O
+(	POS	O
+up	POS	O
+to	POS	O
+3	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+preoperative	POS	O
+evaluation	POS	O
+of	POS	O
+vocal	POS	O
+cord	POS	O
+function	POS	O
+before	POS	O
+carotid	POS	O
+endarterectomy	POS	O
+under	POS	O
+local	POS	O
+anesthesia	POS	O
+is	POS	O
+recommended	POS	O
+to	POS	O
+avoid	POS	O
+intraoperative	POS	B-NP
+bilateral	POS	I-NP
+paralysis	POS	I-NP
+.	POS	O
+In	POS	O
+patients	POS	O
+with	POS	O
+preoperative	POS	B-NP
+contralateral	POS	I-NP
+vocal	POS	I-NP
+cord	POS	I-NP
+paralysis	POS	I-NP
+,	POS	O
+surgery	POS	O
+under	POS	O
+general	POS	O
+anesthesia	POS	O
+should	POS	O
+be	POS	O
+considered	POS	O
+.	POS	O
+Impaired	POS	O
+fear	POS	O
+recognition	POS	O
+in	POS	O
+regular	POS	O
+recreational	POS	O
+cocaine	POS	O
+users	POS	O
+.	POS	O
+INTRODUCTION	POS	O
+:	POS	O
+The	POS	O
+ability	POS	O
+to	POS	O
+read	POS	O
+facial	POS	O
+expressions	POS	O
+is	POS	O
+essential	POS	O
+for	POS	O
+normal	POS	O
+human	POS	O
+social	POS	O
+interaction	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+conduct	POS	O
+the	POS	O
+first	POS	O
+investigation	POS	O
+of	POS	O
+facial	POS	O
+expression	POS	O
+recognition	POS	O
+performance	POS	O
+in	POS	O
+recreational	POS	O
+cocaine	POS	O
+users	POS	O
+.	POS	O
+MATERIALS	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+Three	POS	O
+groups	POS	O
+,	POS	O
+comprised	POS	O
+of	POS	O
+21	POS	O
+cocaine	POS	O
+naive	POS	O
+participants	POS	O
+(	POS	O
+CN	POS	O
+)	POS	O
+,	POS	O
+30	POS	O
+occasional	POS	O
+cocaine	POS	O
+(	POS	O
+OC	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+48	POS	O
+regular	POS	O
+recreational	POS	O
+cocaine	POS	O
+(	POS	O
+RC	POS	O
+)	POS	O
+users	POS	O
+,	POS	O
+were	POS	O
+compared	POS	O
+.	POS	O
+An	POS	O
+emotional	POS	O
+facial	POS	O
+expression	POS	O
+(	POS	O
+EFE	POS	O
+)	POS	O
+task	POS	O
+consisting	POS	O
+of	POS	O
+a	POS	O
+male	POS	O
+and	POS	O
+female	POS	O
+face	POS	O
+expressing	POS	O
+six	POS	O
+basic	POS	O
+emotions	POS	O
+(	POS	O
+happiness	POS	O
+,	POS	O
+surprise	POS	O
+,	POS	O
+sadness	POS	O
+,	POS	O
+anger	POS	O
+,	POS	O
+fear	POS	O
+,	POS	O
+and	POS	O
+disgust	POS	O
+)	POS	O
+was	POS	O
+administered	POS	O
+.	POS	O
+Mean	POS	O
+percent	POS	O
+accuracy	POS	O
+and	POS	O
+latencies	POS	O
+for	POS	O
+correct	POS	O
+responses	POS	O
+across	POS	O
+eight	POS	O
+presentations	POS	O
+of	POS	O
+each	POS	O
+basic	POS	O
+emotion	POS	O
+were	POS	O
+derived	POS	O
+.	POS	O
+Participants	POS	O
+were	POS	O
+also	POS	O
+assessed	POS	O
+with	POS	O
+the	POS	O
+"	POS	O
+Eyes	POS	O
+task	POS	O
+"	POS	O
+to	POS	O
+investigate	POS	O
+their	POS	O
+ability	POS	O
+to	POS	O
+recognize	POS	O
+more	POS	O
+complex	POS	O
+emotional	POS	O
+states	POS	O
+and	POS	O
+the	POS	O
+Symptom	POS	O
+CheckList	POS	O
+-	POS	O
+90	POS	O
+-	POS	O
+Revised	POS	O
+to	POS	O
+measure	POS	O
+psychopathology	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+There	POS	O
+were	POS	O
+no	POS	O
+group	POS	O
+differences	POS	O
+in	POS	O
+psychopathology	POS	O
+or	POS	O
+"	POS	O
+eyes	POS	O
+task	POS	O
+"	POS	O
+performance	POS	O
+,	POS	O
+but	POS	O
+the	POS	O
+RC	POS	O
+group	POS	O
+,	POS	O
+who	POS	O
+otherwise	POS	O
+had	POS	O
+similar	POS	O
+illicit	POS	O
+substance	POS	O
+use	POS	O
+histories	POS	O
+to	POS	O
+the	POS	O
+OC	POS	O
+group	POS	O
+,	POS	O
+exhibited	POS	O
+impaired	POS	O
+fear	POS	O
+recognition	POS	O
+accuracy	POS	O
+compared	POS	O
+to	POS	O
+the	POS	O
+OC	POS	O
+and	POS	O
+CN	POS	O
+groups	POS	O
+.	POS	O
+The	POS	O
+RC	POS	O
+group	POS	O
+also	POS	O
+correctly	POS	O
+identified	POS	O
+anger	POS	O
+,	POS	O
+fear	POS	O
+,	POS	O
+happiness	POS	O
+,	POS	O
+and	POS	O
+surprise	POS	O
+,	POS	O
+more	POS	O
+slowly	POS	O
+than	POS	O
+CN	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+OC	POS	O
+participants	POS	O
+.	POS	O
+The	POS	O
+OC	POS	O
+group	POS	O
+was	POS	O
+slower	POS	O
+than	POS	O
+CN	POS	O
+when	POS	O
+correctly	POS	O
+identifying	POS	O
+disgust	POS	O
+.	POS	O
+The	POS	O
+selective	POS	O
+deficit	POS	O
+in	POS	O
+fear	POS	O
+recognition	POS	O
+accuracy	POS	O
+manifested	POS	O
+by	POS	O
+the	POS	O
+RC	POS	O
+group	POS	O
+cannot	POS	O
+be	POS	O
+explained	POS	O
+by	POS	O
+the	POS	O
+subacute	POS	O
+effects	POS	O
+of	POS	O
+cocaine	POS	O
+,	POS	O
+or	POS	O
+ecstasy	POS	O
+,	POS	O
+because	POS	O
+recent	POS	O
+and	POS	O
+less	POS	O
+recent	POS	O
+users	POS	O
+of	POS	O
+these	POS	O
+drugs	POS	O
+within	POS	O
+this	POS	O
+group	POS	O
+were	POS	O
+similarly	POS	O
+impaired	POS	O
+.	POS	O
+Possible	POS	O
+parallels	POS	O
+between	POS	O
+RC	POS	O
+users	POS	O
+and	POS	O
+psychopaths	POS	O
+with	POS	O
+respect	POS	O
+to	POS	O
+impaired	POS	O
+fear	POS	O
+recognition	POS	O
+,	POS	O
+amygdala	POS	B-NP
+dysfunction	POS	I-NP
+,	POS	O
+and	POS	O
+etiology	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+Damage	POS	O
+of	POS	O
+substantia	POS	O
+nigra	POS	O
+pars	POS	O
+reticulata	POS	O
+during	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+in	POS	O
+the	POS	O
+rat	POS	O
+:	POS	O
+immunohistochemical	POS	O
+study	POS	O
+of	POS	O
+neurons	POS	O
+,	POS	O
+astrocytes	POS	O
+and	POS	O
+serum	POS	O
+-	POS	O
+protein	POS	O
+extravasation	POS	O
+.	POS	O
+The	POS	O
+substantia	POS	O
+nigra	POS	O
+has	POS	O
+a	POS	O
+gating	POS	O
+function	POS	O
+controlling	POS	O
+the	POS	O
+spread	POS	O
+of	POS	O
+epileptic	POS	B-NP
+seizure	POS	I-NP
+activity	POS	O
+.	POS	O
+Additionally	POS	O
+,	POS	O
+in	POS	O
+models	POS	O
+of	POS	O
+prolonged	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+the	POS	O
+pars	POS	O
+reticulata	POS	O
+of	POS	O
+substantia	POS	O
+nigra	POS	O
+(	POS	O
+SNR	POS	O
+)	POS	O
+suffers	POS	O
+from	POS	O
+a	POS	O
+massive	POS	O
+lesion	POS	O
+which	POS	O
+may	POS	O
+arise	POS	O
+from	POS	O
+a	POS	O
+massive	POS	O
+metabolic	POS	O
+derangement	POS	O
+and	POS	O
+hyperexcitation	POS	B-NP
+developing	POS	O
+in	POS	O
+the	POS	O
+activated	POS	O
+SNR	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+,	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+was	POS	O
+induced	POS	O
+by	POS	O
+systemic	POS	O
+injection	POS	O
+of	POS	O
+pilocarpine	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+neuropathology	POS	O
+of	POS	O
+SNR	POS	O
+was	POS	O
+investigated	POS	O
+using	POS	O
+immunohistochemical	POS	O
+techniques	POS	O
+with	POS	O
+the	POS	O
+major	POS	O
+emphasis	POS	O
+on	POS	O
+the	POS	O
+time	POS	O
+-	POS	O
+course	POS	O
+of	POS	O
+changes	POS	O
+in	POS	O
+neurons	POS	O
+and	POS	O
+astrocytes	POS	O
+.	POS	O
+Animals	POS	O
+surviving	POS	O
+20	POS	O
+,	POS	O
+30	POS	O
+,	POS	O
+40	POS	O
+,	POS	O
+60	POS	O
+min	POS	O
+,	POS	O
+2	POS	O
+,	POS	O
+3	POS	O
+,	POS	O
+6	POS	O
+hours	POS	O
+,	POS	O
+1	POS	O
+,	POS	O
+2	POS	O
+,	POS	O
+and	POS	O
+3	POS	O
+days	POS	O
+after	POS	O
+induction	POS	O
+of	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+were	POS	O
+perfusion	POS	O
+-	POS	O
+fixed	POS	O
+,	POS	O
+and	POS	O
+brains	POS	O
+processed	POS	O
+for	POS	O
+immunohistochemical	POS	O
+staining	POS	O
+of	POS	O
+SNR	POS	O
+.	POS	O
+Nissl	POS	O
+-	POS	O
+staining	POS	O
+and	POS	O
+antibodies	POS	O
+against	POS	O
+the	POS	O
+neuron	POS	O
+-	POS	O
+specific	POS	O
+calcium	POS	O
+-	POS	O
+binding	POS	O
+protein	POS	O
+,	POS	O
+parvalbumin	POS	O
+,	POS	O
+served	POS	O
+to	POS	O
+detect	POS	O
+neuronal	POS	O
+damage	POS	O
+in	POS	O
+SNR	POS	O
+.	POS	O
+Antibodies	POS	O
+against	POS	O
+the	POS	O
+astroglia	POS	O
+-	POS	O
+specific	POS	O
+cytoskeletal	POS	O
+protein	POS	O
+,	POS	O
+glial	POS	O
+fibrillary	POS	O
+acidic	POS	O
+protein	POS	O
+(	POS	O
+GFAP	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+against	POS	O
+the	POS	O
+glial	POS	O
+calcium	POS	O
+-	POS	O
+binding	POS	O
+protein	POS	O
+,	POS	O
+S	POS	O
+-	POS	O
+100	POS	O
+protein	POS	O
+,	POS	O
+were	POS	O
+used	POS	O
+to	POS	O
+assess	POS	O
+the	POS	O
+status	POS	O
+of	POS	O
+astrocytes	POS	O
+.	POS	O
+Immunohistochemical	POS	O
+staining	POS	O
+for	POS	O
+serum	POS	O
+-	POS	O
+albumin	POS	O
+and	POS	O
+immunoglobulins	POS	O
+in	POS	O
+brain	POS	O
+tissue	POS	O
+was	POS	O
+taken	POS	O
+as	POS	O
+indicator	POS	O
+of	POS	O
+blood	POS	O
+-	POS	O
+brain	POS	O
+barrier	POS	O
+disturbances	POS	O
+and	POS	O
+vasogenic	POS	B-NP
+edema	POS	I-NP
+formation	POS	O
+.	POS	O
+Immunohistochemical	POS	O
+staining	POS	O
+indicated	POS	O
+loss	POS	O
+of	POS	O
+GFAP	POS	O
+-	POS	O
+staining	POS	O
+already	POS	O
+at	POS	O
+30	POS	O
+min	POS	O
+after	POS	O
+induction	POS	O
+of	POS	O
+seizures	POS	B-NP
+in	POS	O
+an	POS	O
+oval	POS	O
+focus	POS	O
+situated	POS	O
+in	POS	O
+the	POS	O
+center	POS	O
+of	POS	O
+SNR	POS	O
+while	POS	O
+sparing	POS	O
+medial	POS	O
+and	POS	O
+lateral	POS	O
+aspects	POS	O
+.	POS	O
+At	POS	O
+1	POS	O
+h	POS	O
+there	POS	O
+was	POS	O
+additional	POS	O
+vacuolation	POS	O
+in	POS	O
+S	POS	O
+-	POS	O
+100	POS	O
+protein	POS	O
+staining	POS	O
+.	POS	O
+By	POS	O
+2	POS	O
+hours	POS	O
+,	POS	O
+parvalbumin	POS	O
+-	POS	O
+staining	POS	O
+changed	POS	O
+in	POS	O
+the	POS	O
+central	POS	O
+SNR	POS	O
+indicating	POS	O
+neuronal	POS	O
+damage	POS	O
+,	POS	O
+and	POS	O
+Nissl	POS	O
+-	POS	O
+staining	POS	O
+visualized	POS	O
+some	POS	O
+neuronal	POS	O
+distortion	POS	O
+.	POS	O
+Staining	POS	O
+for	POS	O
+serum	POS	O
+-	POS	O
+proteins	POS	O
+occurred	POS	O
+in	POS	O
+a	POS	O
+patchy	POS	O
+manner	POS	O
+throughout	POS	O
+the	POS	O
+forebrain	POS	O
+during	POS	O
+the	POS	O
+first	POS	O
+hours	POS	O
+.	POS	O
+By	POS	O
+6	POS	O
+h	POS	O
+,	POS	O
+vasogenic	POS	O
+edema	POS	B-NP
+covered	POS	O
+the	POS	O
+lesioned	POS	O
+SNR	POS	O
+.	POS	O
+By	POS	O
+24	POS	O
+h	POS	O
+,	POS	O
+glial	POS	O
+and	POS	O
+neuronal	POS	O
+markers	POS	O
+indicated	POS	O
+a	POS	O
+massive	POS	O
+lesion	POS	O
+in	POS	O
+the	POS	O
+center	POS	O
+of	POS	O
+SNR	POS	O
+.	POS	O
+By	POS	O
+48	POS	O
+-	POS	O
+72	POS	O
+h	POS	O
+,	POS	O
+astrocytes	POS	O
+surrounding	POS	O
+the	POS	O
+lesion	POS	O
+increased	POS	O
+in	POS	O
+size	POS	O
+,	POS	O
+and	POS	O
+polymorphic	POS	O
+phagocytotic	POS	O
+cells	POS	O
+invaded	POS	O
+the	POS	O
+damaged	POS	O
+area	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+further	POS	O
+group	POS	O
+of	POS	O
+animals	POS	O
+surviving	POS	O
+1	POS	O
+to	POS	O
+5	POS	O
+days	POS	O
+,	POS	O
+conventional	POS	O
+paraffin	POS	O
+-	POS	O
+sections	POS	O
+confirmed	POS	O
+the	POS	O
+neuronal	POS	O
+and	POS	O
+glial	POS	O
+damage	POS	O
+of	POS	O
+SNR	POS	O
+.	POS	O
+Additional	POS	O
+pathology	POS	O
+of	POS	O
+similar	POS	O
+quality	POS	O
+was	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+globus	POS	O
+pallidus	POS	O
+.	POS	O
+Since	POS	O
+astrocytes	POS	O
+were	POS	O
+always	POS	O
+damaged	POS	O
+in	POS	O
+parallel	POS	O
+with	POS	O
+neurons	POS	O
+in	POS	O
+SNR	POS	O
+it	POS	O
+is	POS	O
+proposed	POS	O
+that	POS	O
+the	POS	O
+anatomical	POS	O
+and	POS	O
+functional	POS	O
+interrelationship	POS	O
+between	POS	O
+neurons	POS	O
+and	POS	O
+astrocytes	POS	O
+is	POS	O
+particularly	POS	O
+tight	POS	O
+in	POS	O
+SNR	POS	O
+.	POS	O
+Both	POS	O
+cell	POS	O
+elements	POS	O
+may	POS	O
+suffer	POS	O
+in	POS	O
+common	POS	O
+from	POS	O
+metabolic	POS	O
+disturbance	POS	O
+and	POS	O
+neurotransmitter	POS	B-NP
+dysfunction	POS	I-NP
+as	POS	O
+occur	POS	O
+during	POS	O
+massive	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+.	POS	O
+Neuroprotective	POS	O
+effects	POS	O
+of	POS	O
+melatonin	POS	O
+upon	POS	O
+the	POS	O
+offspring	POS	O
+cerebellar	POS	O
+cortex	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+model	POS	O
+of	POS	O
+BCNU	POS	O
+-	POS	O
+induced	POS	O
+cortical	POS	B-NP
+dysplasia	POS	I-NP
+.	POS	O
+Cortical	POS	B-NP
+dysplasia	POS	I-NP
+is	POS	O
+a	POS	O
+malformation	POS	B-NP
+characterized	POS	O
+by	POS	O
+defects	POS	O
+in	POS	O
+proliferation	POS	O
+,	POS	O
+migration	POS	O
+and	POS	O
+maturation	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+was	POS	O
+designed	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+alterations	POS	O
+in	POS	O
+offspring	POS	O
+rat	POS	O
+cerebellum	POS	O
+induced	POS	O
+by	POS	O
+maternal	POS	O
+exposure	POS	O
+to	POS	O
+carmustine	POS	O
+-	POS	O
+[	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+-	POS	O
+bis	POS	O
+(	POS	O
+2	POS	O
+-	POS	O
+chloroethyl	POS	O
+)	POS	O
+-	POS	O
+1	POS	O
+-	POS	O
+nitrosoure	POS	O
+]	POS	O
+(	POS	O
+BCNU	POS	O
+)	POS	O
+and	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+exogenous	POS	O
+melatonin	POS	O
+upon	POS	O
+cerebellar	POS	O
+BCNU	POS	O
+-	POS	O
+induced	POS	O
+cortical	POS	B-NP
+dysplasia	POS	I-NP
+,	POS	O
+using	POS	O
+histological	POS	O
+and	POS	O
+biochemical	POS	O
+analyses	POS	O
+.	POS	O
+Pregnant	POS	O
+Wistar	POS	O
+rats	POS	O
+were	POS	O
+assigned	POS	O
+to	POS	O
+five	POS	O
+groups	POS	O
+:	POS	O
+intact	POS	O
+-	POS	O
+control	POS	O
+,	POS	O
+saline	POS	O
+-	POS	O
+control	POS	O
+,	POS	O
+melatonin	POS	O
+-	POS	O
+treated	POS	O
+,	POS	O
+BCNU	POS	O
+-	POS	O
+exposed	POS	O
+and	POS	O
+BCNU	POS	O
+-	POS	O
+exposed	POS	O
+plus	POS	O
+melatonin	POS	O
+.	POS	O
+Rats	POS	O
+were	POS	O
+exposed	POS	O
+to	POS	O
+BCNU	POS	O
+on	POS	O
+embryonic	POS	O
+day	POS	O
+15	POS	O
+and	POS	O
+melatonin	POS	O
+was	POS	O
+given	POS	O
+until	POS	O
+delivery	POS	O
+.	POS	O
+Immuno	POS	O
+/	POS	O
+histochemistry	POS	O
+and	POS	O
+electron	POS	O
+microscopy	POS	O
+were	POS	O
+carried	POS	O
+out	POS	O
+on	POS	O
+the	POS	O
+offspring	POS	O
+cerebellum	POS	O
+,	POS	O
+and	POS	O
+levels	POS	O
+of	POS	O
+malondialdehyde	POS	O
+and	POS	O
+superoxide	POS	O
+dismutase	POS	O
+were	POS	O
+determined	POS	O
+.	POS	O
+Histopathologically	POS	O
+,	POS	O
+typical	POS	O
+findings	POS	O
+were	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+cerebella	POS	O
+from	POS	O
+the	POS	O
+control	POS	O
+groups	POS	O
+,	POS	O
+but	POS	O
+the	POS	O
+findings	POS	O
+consistent	POS	O
+with	POS	O
+early	POS	O
+embryonic	POS	O
+development	POS	O
+were	POS	O
+noted	POS	O
+in	POS	O
+BCNU	POS	O
+-	POS	O
+exposed	POS	O
+cortical	POS	B-NP
+dysplasia	POS	I-NP
+group	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+a	POS	O
+marked	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+TUNEL	POS	O
+positive	POS	O
+cells	POS	O
+and	POS	O
+nestin	POS	O
+positive	POS	O
+cells	POS	O
+in	POS	O
+BCNU	POS	O
+-	POS	O
+exposed	POS	O
+group	POS	O
+,	POS	O
+but	POS	O
+a	POS	O
+decreased	POS	O
+immunoreactivity	POS	O
+to	POS	O
+glial	POS	O
+fibrillary	POS	O
+acidic	POS	O
+protein	POS	O
+,	POS	O
+synaptophysin	POS	O
+and	POS	O
+transforming	POS	O
+growth	POS	O
+factor	POS	O
+beta1	POS	O
+was	POS	O
+observed	POS	O
+,	POS	O
+indicating	POS	O
+a	POS	O
+delayed	POS	O
+maturation	POS	O
+,	POS	O
+and	POS	O
+melatonin	POS	O
+significantly	POS	O
+reversed	POS	O
+these	POS	O
+changes	POS	O
+.	POS	O
+Malondialdehyde	POS	O
+level	POS	O
+in	POS	O
+BCNU	POS	O
+-	POS	O
+exposed	POS	O
+group	POS	O
+was	POS	O
+higher	POS	O
+than	POS	O
+those	POS	O
+in	POS	O
+control	POS	O
+groups	POS	O
+and	POS	O
+melatonin	POS	O
+decreased	POS	O
+malondialdehyde	POS	O
+levels	POS	O
+in	POS	O
+BCNU	POS	O
+group	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+,	POS	O
+while	POS	O
+there	POS	O
+were	POS	O
+no	POS	O
+significant	POS	O
+differences	POS	O
+in	POS	O
+the	POS	O
+superoxide	POS	O
+dismutase	POS	O
+levels	POS	O
+between	POS	O
+these	POS	O
+groups	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+exposure	POS	O
+of	POS	O
+animals	POS	O
+to	POS	O
+BCNU	POS	O
+during	POS	O
+pregnancy	POS	O
+leads	POS	O
+to	POS	O
+delayed	POS	O
+maturation	POS	O
+of	POS	O
+offspring	POS	O
+cerebellum	POS	O
+and	POS	O
+melatonin	POS	O
+protects	POS	O
+the	POS	O
+cerebellum	POS	O
+against	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+BCNU	POS	O
+.	POS	O
+Reduced	POS	O
+cardiotoxicity	POS	B-NP
+of	POS	O
+doxorubicin	POS	O
+given	POS	O
+in	POS	O
+the	POS	O
+form	POS	O
+of	POS	O
+N	POS	O
+-	POS	O
+(	POS	O
+2	POS	O
+-	POS	O
+hydroxypropyl	POS	O
+)	POS	O
+methacrylamide	POS	O
+conjugates	POS	O
+:	POS	O
+and	POS	O
+experimental	POS	O
+study	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+.	POS	O
+A	POS	O
+rat	POS	O
+model	POS	O
+was	POS	O
+used	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+general	POS	O
+acute	POS	B-NP
+toxicity	POS	I-NP
+and	POS	O
+the	POS	O
+late	POS	O
+cardiotoxicity	POS	B-NP
+of	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+doxorubicin	POS	O
+(	POS	O
+DOX	POS	O
+)	POS	O
+given	POS	O
+either	POS	O
+as	POS	O
+free	POS	O
+drug	POS	O
+or	POS	O
+in	POS	O
+the	POS	O
+form	POS	O
+of	POS	O
+three	POS	O
+N	POS	O
+-	POS	O
+(	POS	O
+2	POS	O
+-	POS	O
+hydroxypropyl	POS	O
+)	POS	O
+methacrylamide	POS	O
+(	POS	O
+HPMA	POS	O
+)	POS	O
+copolymer	POS	O
+conjugates	POS	O
+.	POS	O
+In	POS	O
+these	POS	O
+HPMA	POS	O
+copolymers	POS	O
+,	POS	O
+DOX	POS	O
+was	POS	O
+covalently	POS	O
+bound	POS	O
+via	POS	O
+peptide	POS	O
+linkages	POS	O
+that	POS	O
+were	POS	O
+either	POS	O
+non	POS	O
+-	POS	O
+biodegradable	POS	O
+(	POS	O
+Gly	POS	O
+-	POS	O
+Gly	POS	O
+)	POS	O
+or	POS	O
+degradable	POS	O
+by	POS	O
+lysosomal	POS	O
+proteinases	POS	O
+(	POS	O
+Gly	POS	O
+-	POS	O
+Phe	POS	O
+-	POS	O
+Leu	POS	O
+-	POS	O
+Gly	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+one	POS	O
+biodegradable	POS	O
+conjugate	POS	O
+containing	POS	O
+galactosamine	POS	O
+was	POS	O
+used	POS	O
+;	POS	O
+this	POS	O
+residue	POS	O
+was	POS	O
+targeted	POS	O
+to	POS	O
+the	POS	O
+liver	POS	O
+.	POS	O
+Over	POS	O
+the	POS	O
+first	POS	O
+3	POS	O
+weeks	POS	O
+after	POS	O
+the	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+administration	POS	O
+of	POS	O
+free	POS	O
+and	POS	O
+polymer	POS	O
+-	POS	O
+bound	POS	O
+DOX	POS	O
+,	POS	O
+all	POS	O
+animals	POS	O
+showed	POS	O
+a	POS	O
+transient	POS	O
+reduction	POS	O
+in	POS	O
+body	POS	O
+weight	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+maximal	POS	O
+reduction	POS	O
+in	POS	O
+body	POS	O
+weight	POS	O
+seen	POS	O
+in	POS	O
+animals	POS	O
+that	POS	O
+received	POS	O
+polymer	POS	O
+-	POS	O
+bound	POS	O
+DOX	POS	O
+(	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+was	POS	O
+significantly	POS	O
+lower	POS	O
+than	POS	O
+that	POS	O
+observed	POS	O
+in	POS	O
+those	POS	O
+that	POS	O
+received	POS	O
+free	POS	O
+DOX	POS	O
+(	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+or	POS	O
+a	POS	O
+mixture	POS	O
+of	POS	O
+the	POS	O
+unmodified	POS	O
+parent	POS	O
+HPMA	POS	O
+copolymer	POS	O
+and	POS	O
+free	POS	O
+DOX	POS	O
+(	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+;	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+Throughout	POS	O
+the	POS	O
+study	POS	O
+(	POS	O
+20	POS	O
+weeks	POS	O
+)	POS	O
+,	POS	O
+deaths	POS	O
+related	POS	O
+to	POS	O
+cardiotoxicity	POS	B-NP
+were	POS	O
+observed	POS	O
+only	POS	O
+in	POS	O
+animals	POS	O
+that	POS	O
+received	POS	O
+either	POS	O
+free	POS	O
+DOX	POS	O
+or	POS	O
+the	POS	O
+mixture	POS	O
+of	POS	O
+HPMA	POS	O
+copolymer	POS	O
+and	POS	O
+free	POS	O
+DOX	POS	O
+;	POS	O
+in	POS	O
+these	POS	O
+cases	POS	O
+,	POS	O
+histological	POS	O
+investigations	POS	O
+revealed	POS	O
+marked	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+heart	POS	O
+that	POS	O
+were	POS	O
+consistent	POS	O
+with	POS	O
+DOX	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+Sequential	POS	O
+measurements	POS	O
+of	POS	O
+cardiac	POS	O
+output	POS	O
+in	POS	O
+surviving	POS	O
+animals	POS	O
+that	POS	O
+received	POS	O
+either	POS	O
+free	POS	O
+DOX	POS	O
+or	POS	O
+the	POS	O
+mixture	POS	O
+of	POS	O
+HPMA	POS	O
+copolymer	POS	O
+and	POS	O
+free	POS	O
+DOX	POS	O
+showed	POS	O
+a	POS	O
+reduction	POS	O
+of	POS	O
+approximately	POS	O
+30	POS	O
+%	POS	O
+in	POS	O
+function	POS	O
+beginning	POS	O
+at	POS	O
+the	POS	O
+4th	POS	O
+week	POS	O
+after	POS	O
+drug	POS	O
+administration	POS	O
+.	POS	O
+The	POS	O
+heart	POS	O
+rate	POS	O
+in	POS	O
+these	POS	O
+animals	POS	O
+was	POS	O
+approximately	POS	O
+12	POS	O
+%	POS	O
+lower	POS	O
+than	POS	O
+that	POS	O
+measured	POS	O
+in	POS	O
+age	POS	O
+-	POS	O
+matched	POS	O
+control	POS	O
+rats	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+Animals	POS	O
+that	POS	O
+were	POS	O
+given	POS	O
+the	POS	O
+HPMA	POS	O
+copolymer	POS	O
+conjugates	POS	O
+containing	POS	O
+DOX	POS	O
+exhibited	POS	O
+no	POS	O
+significant	POS	O
+change	POS	O
+in	POS	O
+cardiac	POS	O
+output	POS	O
+throughout	POS	O
+the	POS	O
+study	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+no	POS	O
+significant	POS	O
+histological	POS	O
+change	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+heart	POS	O
+of	POS	O
+animals	POS	O
+that	POS	O
+received	POS	O
+DOX	POS	O
+in	POS	O
+the	POS	O
+form	POS	O
+of	POS	O
+HPMA	POS	O
+copolymer	POS	O
+conjugates	POS	O
+and	POS	O
+were	POS	O
+killed	POS	O
+at	POS	O
+the	POS	O
+end	POS	O
+of	POS	O
+the	POS	O
+study	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+these	POS	O
+animals	POS	O
+had	POS	O
+shown	POS	O
+a	POS	O
+significant	POS	O
+increase	POS	O
+in	POS	O
+heart	POS	O
+rate	POS	O
+beginning	POS	O
+at	POS	O
+8	POS	O
+weeks	POS	O
+after	POS	O
+drug	POS	O
+administration	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+(	POS	O
+ABSTRACT	POS	O
+TRUNCATED	POS	O
+AT	POS	O
+400	POS	O
+WORDS	POS	O
+)	POS	O
+Corneal	POS	B-NP
+ulcers	POS	I-NP
+associated	POS	O
+with	POS	O
+aerosolized	POS	O
+crack	POS	O
+cocaine	POS	O
+use	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+We	POS	O
+report	POS	O
+4	POS	O
+cases	POS	O
+of	POS	O
+corneal	POS	B-NP
+ulcers	POS	I-NP
+associated	POS	O
+with	POS	O
+drug	POS	B-NP
+abuse	POS	I-NP
+.	POS	O
+The	POS	O
+pathogenesis	POS	O
+of	POS	O
+these	POS	O
+ulcers	POS	B-NP
+and	POS	O
+management	POS	O
+of	POS	O
+these	POS	O
+patients	POS	O
+are	POS	O
+also	POS	O
+reviewed	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Review	POS	O
+of	POS	O
+all	POS	O
+cases	POS	O
+of	POS	O
+corneal	POS	B-NP
+ulcers	POS	I-NP
+associated	POS	O
+with	POS	O
+drug	POS	B-NP
+abuse	POS	I-NP
+seen	POS	O
+at	POS	O
+our	POS	O
+institution	POS	O
+from	POS	O
+July	POS	O
+2006	POS	O
+to	POS	O
+December	POS	O
+2006	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Four	POS	O
+patients	POS	O
+with	POS	O
+corneal	POS	B-NP
+ulcers	POS	I-NP
+associated	POS	O
+with	POS	O
+crack	POS	O
+cocaine	POS	O
+use	POS	O
+were	POS	O
+reviewed	POS	O
+.	POS	O
+All	POS	O
+corneal	POS	B-NP
+ulcers	POS	I-NP
+were	POS	O
+cultured	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+patients	POS	O
+were	POS	O
+admitted	POS	O
+to	POS	O
+the	POS	O
+hospital	POS	O
+for	POS	O
+intensive	POS	O
+topical	POS	O
+antibiotic	POS	O
+treatment	POS	O
+.	POS	O
+Each	POS	O
+patient	POS	O
+received	POS	O
+comprehensive	POS	O
+health	POS	O
+care	POS	O
+,	POS	O
+including	POS	O
+medical	POS	O
+and	POS	O
+substance	POS	O
+abuse	POS	O
+consultations	POS	O
+.	POS	O
+Streptococcal	POS	O
+organisms	POS	O
+were	POS	O
+found	POS	O
+in	POS	O
+3	POS	O
+cases	POS	O
+and	POS	O
+Capnocytophaga	POS	O
+and	POS	O
+Brevibacterium	POS	O
+casei	POS	O
+in	POS	O
+1	POS	O
+patient	POS	O
+.	POS	O
+The	POS	O
+infections	POS	O
+responded	POS	O
+to	POS	O
+antibiotic	POS	O
+treatment	POS	O
+.	POS	O
+Two	POS	O
+patients	POS	O
+needed	POS	O
+a	POS	O
+lateral	POS	O
+tarsorrhaphy	POS	O
+for	POS	O
+persistent	POS	O
+epithelial	POS	B-NP
+defects	POS	I-NP
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Aerosolized	POS	O
+crack	POS	O
+cocaine	POS	O
+use	POS	O
+can	POS	O
+be	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+corneal	POS	B-NP
+ulcers	POS	I-NP
+.	POS	O
+Drug	POS	O
+abuse	POS	O
+provides	POS	O
+additional	POS	O
+challenges	POS	O
+for	POS	O
+management	POS	O
+.	POS	O
+Not	POS	O
+only	POS	O
+treatment	POS	O
+of	POS	O
+their	POS	O
+infections	POS	O
+but	POS	O
+also	POS	O
+the	POS	O
+overall	POS	O
+poor	POS	O
+health	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+and	POS	O
+increased	POS	O
+risk	POS	O
+of	POS	O
+noncompliance	POS	O
+need	POS	O
+to	POS	O
+be	POS	O
+addressed	POS	O
+.	POS	O
+Comprehensive	POS	O
+care	POS	O
+may	POS	O
+provide	POS	O
+the	POS	O
+patient	POS	O
+the	POS	O
+opportunity	POS	O
+to	POS	O
+discontinue	POS	O
+their	POS	O
+substance	POS	B-NP
+abuse	POS	I-NP
+,	POS	O
+improve	POS	O
+their	POS	O
+overall	POS	O
+health	POS	O
+,	POS	O
+and	POS	O
+prevent	POS	O
+future	POS	O
+corneal	POS	B-NP
+complications	POS	I-NP
+.	POS	O
+Topical	POS	O
+0	POS	O
+.	POS	O
+025	POS	O
+%	POS	O
+capsaicin	POS	O
+in	POS	O
+chronic	POS	O
+post	POS	O
+-	POS	O
+herpetic	POS	B-NP
+neuralgia	POS	I-NP
+:	POS	O
+efficacy	POS	O
+,	POS	O
+predictors	POS	O
+of	POS	O
+response	POS	O
+and	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+course	POS	O
+.	POS	O
+In	POS	O
+order	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+efficacy	POS	O
+,	POS	O
+time	POS	O
+-	POS	O
+course	POS	O
+of	POS	O
+action	POS	O
+and	POS	O
+predictors	POS	O
+of	POS	O
+response	POS	O
+to	POS	O
+topical	POS	O
+capsaicin	POS	O
+,	POS	O
+39	POS	O
+patients	POS	O
+with	POS	O
+chronic	POS	B-NP
+post	POS	I-NP
+-	POS	I-NP
+herpetic	POS	I-NP
+neuralgia	POS	I-NP
+(	POS	O
+PHN	POS	B-NP
+)	POS	O
+,	POS	O
+median	POS	O
+duration	POS	O
+24	POS	O
+months	POS	O
+,	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+0	POS	O
+.	POS	O
+025	POS	O
+%	POS	O
+capsaicin	POS	O
+cream	POS	O
+for	POS	O
+8	POS	O
+weeks	POS	O
+.	POS	O
+During	POS	O
+therapy	POS	O
+the	POS	O
+patients	POS	O
+rated	POS	O
+their	POS	O
+pain	POS	B-NP
+on	POS	O
+a	POS	O
+visual	POS	O
+analogue	POS	O
+scale	POS	O
+(	POS	O
+VAS	POS	O
+)	POS	O
+and	POS	O
+a	POS	O
+verbal	POS	O
+outcome	POS	O
+scale	POS	O
+.	POS	O
+A	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+investigation	POS	O
+was	POS	O
+performed	POS	O
+10	POS	O
+-	POS	O
+12	POS	O
+months	POS	O
+after	POS	O
+study	POS	O
+onset	POS	O
+on	POS	O
+the	POS	O
+patients	POS	O
+who	POS	O
+had	POS	O
+improved	POS	O
+.	POS	O
+Nineteen	POS	O
+patients	POS	O
+(	POS	O
+48	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+)	POS	O
+substantially	POS	O
+improved	POS	O
+after	POS	O
+the	POS	O
+8	POS	O
+-	POS	O
+week	POS	O
+trial	POS	O
+;	POS	O
+5	POS	O
+(	POS	O
+12	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+)	POS	O
+discontinued	POS	O
+therapy	POS	O
+due	POS	O
+to	POS	O
+side	POS	O
+-	POS	O
+effects	POS	O
+such	POS	O
+as	POS	O
+intolerable	POS	O
+capsaicin	POS	O
+-	POS	O
+induced	POS	O
+burning	POS	O
+sensations	POS	O
+(	POS	O
+4	POS	O
+)	POS	O
+or	POS	O
+mastitis	POS	B-NP
+(	POS	O
+1	POS	O
+)	POS	O
+;	POS	O
+15	POS	O
+(	POS	O
+38	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+reported	POS	O
+no	POS	O
+benefit	POS	O
+.	POS	O
+The	POS	O
+decrease	POS	O
+in	POS	O
+VAS	POS	O
+ratings	POS	O
+was	POS	O
+significant	POS	O
+after	POS	O
+2	POS	O
+weeks	POS	O
+of	POS	O
+continuous	POS	O
+application	POS	O
+.	POS	O
+Of	POS	O
+the	POS	O
+responders	POS	O
+72	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+were	POS	O
+still	POS	O
+improved	POS	O
+at	POS	O
+the	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+;	POS	O
+only	POS	O
+one	POS	O
+-	POS	O
+third	POS	O
+of	POS	O
+them	POS	O
+had	POS	O
+continued	POS	O
+application	POS	O
+irregularly	POS	O
+.	POS	O
+Treatment	POS	O
+effect	POS	O
+was	POS	O
+not	POS	O
+dependent	POS	O
+on	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+age	POS	O
+,	POS	O
+duration	POS	O
+or	POS	O
+localization	POS	O
+of	POS	O
+PHN	POS	B-NP
+(	POS	O
+trigeminal	POS	O
+involvement	POS	O
+was	POS	O
+excluded	POS	O
+)	POS	O
+,	POS	O
+sensory	POS	B-NP
+disturbance	POS	I-NP
+or	POS	O
+pain	POS	B-NP
+character	POS	O
+.	POS	O
+Treatment	POS	O
+response	POS	O
+was	POS	O
+not	POS	O
+correlated	POS	O
+with	POS	O
+the	POS	O
+incidence	POS	O
+,	POS	O
+time	POS	O
+-	POS	O
+course	POS	O
+or	POS	O
+severity	POS	O
+of	POS	O
+capsaicin	POS	O
+-	POS	O
+induced	POS	O
+burning	POS	O
+.	POS	O
+If	POS	O
+confirmed	POS	O
+in	POS	O
+controlled	POS	O
+trials	POS	O
+,	POS	O
+the	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+results	POS	O
+of	POS	O
+this	POS	O
+open	POS	O
+,	POS	O
+non	POS	O
+-	POS	O
+randomized	POS	O
+study	POS	O
+might	POS	O
+indicate	POS	O
+that	POS	O
+the	POS	O
+analgesic	POS	O
+effect	POS	O
+of	POS	O
+capsaicin	POS	O
+in	POS	O
+PHN	POS	B-NP
+is	POS	O
+mediated	POS	O
+by	POS	O
+both	POS	O
+interference	POS	O
+with	POS	O
+neuropeptide	POS	O
+metabolism	POS	O
+and	POS	O
+morphological	POS	O
+changes	POS	O
+(	POS	O
+perhaps	POS	O
+degeneration	POS	O
+)	POS	O
+of	POS	O
+nociceptive	POS	O
+afferents	POS	O
+.	POS	O
+Myo	POS	O
+-	POS	O
+inositol	POS	O
+-	POS	O
+1	POS	O
+-	POS	O
+phosphate	POS	O
+(	POS	O
+MIP	POS	O
+)	POS	O
+synthase	POS	O
+inhibition	POS	O
+:	POS	O
+in	POS	O
+-	POS	O
+vivo	POS	O
+study	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+Lithium	POS	O
+and	POS	O
+valproate	POS	O
+are	POS	O
+the	POS	O
+prototypic	POS	O
+mood	POS	O
+stabilizers	POS	O
+and	POS	O
+have	POS	O
+diverse	POS	O
+structures	POS	O
+and	POS	O
+targets	POS	O
+.	POS	O
+Both	POS	O
+drugs	POS	O
+influence	POS	O
+inositol	POS	O
+metabolism	POS	O
+.	POS	O
+Lithium	POS	O
+inhibits	POS	O
+IMPase	POS	O
+and	POS	O
+valproate	POS	O
+inhibits	POS	O
+MIP	POS	O
+synthase	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+shows	POS	O
+that	POS	O
+MIP	POS	O
+synthase	POS	O
+inhibition	POS	O
+does	POS	O
+not	POS	O
+replicate	POS	O
+or	POS	O
+augment	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+lithium	POS	O
+in	POS	O
+the	POS	O
+inositol	POS	O
+sensitive	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+model	POS	O
+.	POS	O
+This	POS	O
+lack	POS	O
+of	POS	O
+effects	POS	O
+may	POS	O
+stem	POS	O
+from	POS	O
+the	POS	O
+low	POS	O
+contribution	POS	O
+of	POS	O
+de	POS	O
+-	POS	O
+novo	POS	O
+synthesis	POS	O
+to	POS	O
+cellular	POS	O
+inositol	POS	O
+supply	POS	O
+or	POS	O
+to	POS	O
+the	POS	O
+inhibition	POS	O
+of	POS	O
+the	POS	O
+de	POS	O
+-	POS	O
+novo	POS	O
+synthesis	POS	O
+by	POS	O
+lithium	POS	O
+itself	POS	O
+.	POS	O
+Non	POS	O
+-	POS	O
+steroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+-	POS	O
+associated	POS	O
+acute	POS	O
+interstitial	POS	B-NP
+nephritis	POS	I-NP
+with	POS	O
+granular	POS	B-NP
+tubular	POS	I-NP
+basement	POS	I-NP
+membrane	POS	I-NP
+deposits	POS	I-NP
+.	POS	O
+Acute	POS	O
+tubulo	POS	O
+-	POS	O
+interstitial	POS	B-NP
+nephritis	POS	I-NP
+(	POS	O
+ATIN	POS	B-NP
+)	POS	O
+is	POS	O
+an	POS	O
+important	POS	O
+cause	POS	O
+of	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+resulting	POS	O
+from	POS	O
+a	POS	O
+variety	POS	O
+of	POS	O
+insults	POS	O
+,	POS	O
+including	POS	O
+immune	POS	O
+complex	POS	O
+-	POS	O
+mediated	POS	O
+tubulo	POS	O
+-	POS	O
+interstitial	POS	B-NP
+injury	POS	I-NP
+,	POS	O
+but	POS	O
+drugs	POS	O
+such	POS	O
+as	POS	O
+non	POS	O
+-	POS	O
+steroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+(	POS	O
+NSAIDs	POS	O
+)	POS	O
+are	POS	O
+a	POS	O
+far	POS	O
+more	POS	O
+frequent	POS	O
+cause	POS	O
+.	POS	O
+Overall	POS	O
+,	POS	O
+as	POS	O
+an	POS	O
+entity	POS	O
+,	POS	O
+ATIN	POS	B-NP
+remains	POS	O
+under	POS	O
+-	POS	O
+diagnosed	POS	O
+,	POS	O
+as	POS	O
+symptoms	POS	O
+resolve	POS	O
+spontaneously	POS	O
+if	POS	O
+the	POS	O
+medication	POS	O
+is	POS	O
+stopped	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+on	POS	O
+a	POS	O
+14	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+boy	POS	O
+who	POS	O
+developed	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+2	POS	O
+weeks	POS	O
+after	POS	O
+aortic	POS	O
+valve	POS	O
+surgery	POS	O
+.	POS	O
+He	POS	O
+was	POS	O
+put	POS	O
+on	POS	O
+aspirin	POS	O
+following	POS	O
+surgery	POS	O
+and	POS	O
+took	POS	O
+ibuprofen	POS	O
+for	POS	O
+fever	POS	B-NP
+for	POS	O
+nearly	POS	O
+a	POS	O
+week	POS	O
+prior	POS	O
+to	POS	O
+presentation	POS	O
+.	POS	O
+He	POS	O
+then	POS	O
+presented	POS	O
+to	POS	O
+the	POS	O
+emergency	POS	O
+department	POS	O
+feeling	POS	O
+quite	POS	O
+ill	POS	O
+and	POS	O
+was	POS	O
+found	POS	O
+to	POS	O
+have	POS	O
+a	POS	O
+blood	POS	O
+urea	POS	O
+nitrogen	POS	O
+(	POS	O
+BUN	POS	O
+)	POS	O
+concentration	POS	O
+of	POS	O
+of	POS	O
+147	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+,	POS	O
+creatinine	POS	O
+of	POS	O
+15	POS	O
+.	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+and	POS	O
+serum	POS	O
+potassium	POS	O
+of	POS	O
+8	POS	O
+.	POS	O
+7	POS	O
+mEq	POS	O
+/	POS	O
+l	POS	O
+.	POS	O
+Dialysis	POS	O
+was	POS	O
+immediately	POS	O
+initiated	POS	O
+.	POS	O
+A	POS	O
+kidney	POS	O
+biopsy	POS	O
+showed	POS	O
+inflammatory	POS	O
+infiltrate	POS	O
+consistent	POS	O
+with	POS	O
+ATIN	POS	B-NP
+.	POS	O
+However	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+tubular	POS	O
+basement	POS	O
+membrane	POS	O
+(	POS	O
+TBM	POS	O
+)	POS	O
+,	POS	O
+very	POS	O
+intense	POS	O
+granular	POS	O
+deposits	POS	O
+of	POS	O
+polyclonal	POS	O
+IgG	POS	O
+and	POS	O
+C3	POS	O
+were	POS	O
+noted	POS	O
+.	POS	O
+He	POS	O
+needed	POS	O
+dialysis	POS	O
+for	POS	O
+2	POS	O
+weeks	POS	O
+and	POS	O
+was	POS	O
+treated	POS	O
+successfully	POS	O
+with	POS	O
+steroids	POS	O
+for	POS	O
+6	POS	O
+months	POS	O
+.	POS	O
+His	POS	O
+renal	POS	O
+recovery	POS	O
+and	POS	O
+disappearance	POS	O
+of	POS	O
+proteinuria	POS	B-NP
+took	POS	O
+a	POS	O
+year	POS	O
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+this	POS	O
+is	POS	O
+a	POS	O
+first	POS	O
+report	POS	O
+of	POS	O
+NSAIDs	POS	O
+-	POS	O
+associated	POS	O
+ATIN	POS	B-NP
+,	POS	O
+showing	POS	O
+deposits	POS	O
+of	POS	O
+granular	POS	O
+immune	POS	O
+complex	POS	O
+present	POS	O
+only	POS	O
+in	POS	O
+the	POS	O
+TBM	POS	B-NP
+and	POS	O
+not	POS	O
+in	POS	O
+the	POS	O
+glomeruli	POS	O
+.	POS	O
+Rifampicin	POS	O
+-	POS	O
+associated	POS	O
+segmental	POS	O
+necrotizing	POS	B-NP
+glomerulonephritis	POS	I-NP
+in	POS	O
+staphylococcal	POS	B-NP
+endocarditis	POS	I-NP
+.	POS	O
+Segmental	POS	B-NP
+necrotising	POS	I-NP
+glomerulonephritis	POS	I-NP
+has	POS	O
+been	POS	O
+reported	POS	O
+as	POS	O
+complication	POS	O
+of	POS	O
+rifampicin	POS	O
+therapy	POS	O
+in	POS	O
+patients	POS	O
+receiving	POS	O
+treatment	POS	O
+for	POS	O
+tuberculosis	POS	B-NP
+.	POS	O
+Changing	POS	O
+epidemiology	POS	O
+of	POS	O
+infections	POS	O
+such	POS	O
+as	POS	O
+infective	POS	B-NP
+endocarditis	POS	I-NP
+(	POS	O
+IE	POS	B-NP
+)	POS	O
+has	POS	O
+led	POS	O
+to	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+rifampicin	POS	O
+for	POS	O
+Staphylococcal	POS	B-NP
+infections	POS	I-NP
+.	POS	O
+We	POS	O
+describe	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+Staphylococcal	POS	B-NP
+IE	POS	I-NP
+who	POS	O
+developed	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+secondary	POS	O
+to	POS	O
+a	POS	O
+segmental	POS	O
+necrotising	POS	B-NP
+glomerulonephritis	POS	I-NP
+while	POS	O
+being	POS	O
+treated	POS	O
+with	POS	O
+rifampicin	POS	O
+,	POS	O
+and	POS	O
+review	POS	O
+the	POS	O
+literature	POS	O
+regarding	POS	O
+this	POS	O
+complication	POS	O
+of	POS	O
+rifampicin	POS	O
+therapy	POS	O
+.	POS	O
+Rate	POS	O
+of	POS	O
+YMDD	POS	O
+motif	POS	O
+mutants	POS	O
+in	POS	O
+lamivudine	POS	O
+-	POS	O
+untreated	POS	O
+Iranian	POS	O
+patients	POS	O
+with	POS	O
+chronic	POS	B-NP
+hepatitis	POS	I-NP
+B	POS	I-NP
+virus	POS	I-NP
+infection	POS	I-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Lamivudine	POS	O
+is	POS	O
+used	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+chronic	POS	B-NP
+hepatitis	POS	I-NP
+B	POS	I-NP
+patients	POS	O
+.	POS	O
+Recent	POS	O
+studies	POS	O
+show	POS	O
+that	POS	O
+the	POS	O
+YMDD	POS	O
+motif	POS	O
+mutants	POS	O
+(	POS	O
+resistant	POS	O
+hepatitis	POS	O
+B	POS	O
+virus	POS	O
+)	POS	O
+occur	POS	O
+as	POS	O
+natural	POS	O
+genome	POS	O
+variability	POS	O
+in	POS	O
+lamivudine	POS	O
+-	POS	O
+untreated	POS	O
+chronic	POS	O
+hepatitis	POS	B-NP
+B	POS	I-NP
+patients	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+we	POS	O
+aimed	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+rate	POS	O
+of	POS	O
+YMDD	POS	O
+motif	POS	O
+mutants	POS	O
+in	POS	O
+lamivudine	POS	O
+-	POS	O
+untreated	POS	O
+chronic	POS	O
+hepatitis	POS	B-NP
+B	POS	I-NP
+patients	POS	O
+in	POS	O
+Iran	POS	O
+.	POS	O
+PATIENTS	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+77	POS	O
+chronic	POS	O
+hepatitis	POS	B-NP
+B	POS	I-NP
+patients	POS	O
+who	POS	O
+had	POS	O
+not	POS	O
+been	POS	O
+treated	POS	O
+with	POS	O
+lamivudine	POS	O
+were	POS	O
+included	POS	O
+in	POS	O
+the	POS	O
+study	POS	O
+.	POS	O
+Serum	POS	O
+samples	POS	O
+from	POS	O
+patients	POS	O
+were	POS	O
+tested	POS	O
+by	POS	O
+polymerase	POS	O
+chain	POS	O
+reaction	POS	O
+-	POS	O
+restriction	POS	O
+fragment	POS	O
+length	POS	O
+polymorphism	POS	O
+(	POS	O
+PCR	POS	O
+-	POS	O
+RFLP	POS	O
+)	POS	O
+for	POS	O
+detection	POS	O
+of	POS	O
+YMDD	POS	O
+motif	POS	O
+mutants	POS	O
+.	POS	O
+All	POS	O
+patients	POS	O
+were	POS	O
+also	POS	O
+tested	POS	O
+for	POS	O
+liver	POS	O
+enzymes	POS	O
+,	POS	O
+anti	POS	O
+-	POS	O
+HCV	POS	O
+,	POS	O
+HBeAg	POS	O
+,	POS	O
+and	POS	O
+anti	POS	O
+-	POS	O
+HBe	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Of	POS	O
+the	POS	O
+77	POS	O
+patients	POS	O
+enrolled	POS	O
+in	POS	O
+the	POS	O
+study	POS	O
+,	POS	O
+73	POS	O
+%	POS	O
+were	POS	O
+male	POS	O
+and	POS	O
+27	POS	O
+%	POS	O
+were	POS	O
+female	POS	O
+.	POS	O
+Mean	POS	O
+ALT	POS	O
+and	POS	O
+AST	POS	O
+levels	POS	O
+were	POS	O
+124	POS	O
+.	POS	O
+4	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+73	POS	O
+.	POS	O
+4	POS	O
+and	POS	O
+103	POS	O
+.	POS	O
+1	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+81	POS	O
+IU	POS	O
+/	POS	O
+l	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+HBeAg	POS	O
+was	POS	O
+positive	POS	O
+in	POS	O
+40	POS	O
+%	POS	O
+and	POS	O
+anti	POS	O
+-	POS	O
+HBe	POS	O
+in	POS	O
+60	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+.	POS	O
+Anti	POS	O
+-	POS	O
+HCV	POS	O
+was	POS	O
+negative	POS	O
+in	POS	O
+all	POS	O
+of	POS	O
+them	POS	O
+.	POS	O
+YMDD	POS	O
+motif	POS	O
+mutants	POS	O
+were	POS	O
+not	POS	O
+detected	POS	O
+in	POS	O
+any	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+despite	POS	O
+the	POS	O
+liver	POS	O
+enzyme	POS	O
+levels	POS	O
+and	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+HBeAg	POS	O
+or	POS	O
+anti	POS	O
+-	POS	O
+HBe	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Although	POS	O
+the	POS	O
+natural	POS	O
+occurrence	POS	O
+of	POS	O
+YMDD	POS	O
+motif	POS	O
+mutants	POS	O
+in	POS	O
+lamivudine	POS	O
+-	POS	O
+untreated	POS	O
+patients	POS	O
+with	POS	O
+chronic	POS	B-NP
+hepatitis	POS	I-NP
+B	POS	I-NP
+has	POS	O
+been	POS	O
+reported	POS	O
+,	POS	O
+these	POS	O
+mutants	POS	O
+were	POS	O
+not	POS	O
+detected	POS	O
+in	POS	O
+Iranian	POS	O
+lamivudine	POS	O
+-	POS	O
+untreated	POS	O
+chronic	POS	O
+hepatitis	POS	B-NP
+B	POS	I-NP
+patients	POS	O
+.	POS	O
+Branch	POS	B-NP
+retinal	POS	I-NP
+vein	POS	I-NP
+occlusion	POS	I-NP
+and	POS	O
+fluoxetine	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+branch	POS	O
+retinal	POS	B-NP
+vein	POS	I-NP
+occlusion	POS	I-NP
+associated	POS	O
+with	POS	O
+fluoxetine	POS	O
+-	POS	O
+induced	POS	O
+secondary	POS	O
+hypertension	POS	B-NP
+is	POS	O
+described	POS	O
+.	POS	O
+Although	POS	O
+an	POS	O
+infrequent	POS	O
+complication	POS	O
+of	POS	O
+selective	POS	O
+serotonin	POS	O
+reuptake	POS	O
+inhibitor	POS	O
+therapy	POS	O
+,	POS	O
+it	POS	O
+is	POS	O
+important	POS	O
+that	POS	O
+ophthalmologists	POS	O
+are	POS	O
+aware	POS	O
+that	POS	O
+these	POS	O
+agents	POS	O
+can	POS	O
+cause	POS	O
+hypertension	POS	B-NP
+because	POS	O
+this	POS	O
+class	POS	O
+of	POS	O
+drugs	POS	O
+is	POS	O
+widely	POS	O
+prescribed	POS	O
+.	POS	O
+The	POS	O
+differential	POS	O
+effects	POS	O
+of	POS	O
+bupivacaine	POS	O
+and	POS	O
+lidocaine	POS	O
+on	POS	O
+prostaglandin	POS	O
+E2	POS	O
+release	POS	O
+,	POS	O
+cyclooxygenase	POS	O
+gene	POS	O
+expression	POS	O
+and	POS	O
+pain	POS	B-NP
+in	POS	O
+a	POS	O
+clinical	POS	O
+pain	POS	B-NP
+model	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+In	POS	O
+addition	POS	O
+to	POS	O
+blocking	POS	O
+nociceptive	POS	O
+input	POS	O
+from	POS	O
+surgical	POS	O
+sites	POS	O
+,	POS	O
+long	POS	O
+-	POS	O
+acting	POS	O
+local	POS	O
+anesthetics	POS	O
+might	POS	O
+directly	POS	O
+modulate	POS	O
+inflammation	POS	B-NP
+.	POS	O
+In	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+,	POS	O
+we	POS	O
+describe	POS	O
+the	POS	O
+proinflammatory	POS	O
+effects	POS	O
+of	POS	O
+bupivacaine	POS	O
+on	POS	O
+local	POS	O
+prostaglandin	POS	O
+E2	POS	O
+(	POS	O
+PGE2	POS	O
+)	POS	O
+production	POS	O
+and	POS	O
+cyclooxygenase	POS	O
+(	POS	O
+COX	POS	O
+)	POS	O
+gene	POS	O
+expression	POS	O
+that	POS	O
+increases	POS	O
+postoperative	POS	B-NP
+pain	POS	I-NP
+in	POS	O
+human	POS	O
+subjects	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Subjects	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+114	POS	O
+)	POS	O
+undergoing	POS	O
+extraction	POS	O
+of	POS	O
+impacted	POS	O
+third	POS	O
+molars	POS	O
+received	POS	O
+either	POS	O
+2	POS	O
+%	POS	O
+lidocaine	POS	O
+or	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+bupivacaine	POS	O
+before	POS	O
+surgery	POS	O
+and	POS	O
+either	POS	O
+rofecoxib	POS	O
+50	POS	O
+mg	POS	O
+or	POS	O
+placebo	POS	O
+orally	POS	O
+90	POS	O
+min	POS	O
+before	POS	O
+surgery	POS	O
+and	POS	O
+for	POS	O
+the	POS	O
+following	POS	O
+48	POS	O
+h	POS	O
+.	POS	O
+Oral	POS	O
+mucosal	POS	O
+biopsies	POS	O
+were	POS	O
+taken	POS	O
+before	POS	O
+surgery	POS	O
+and	POS	O
+48	POS	O
+h	POS	O
+after	POS	O
+surgery	POS	O
+.	POS	O
+After	POS	O
+extraction	POS	O
+,	POS	O
+a	POS	O
+microdialysis	POS	O
+probe	POS	O
+was	POS	O
+placed	POS	O
+at	POS	O
+the	POS	O
+surgical	POS	O
+site	POS	O
+for	POS	O
+PGE2	POS	O
+and	POS	O
+thromboxane	POS	O
+B2	POS	O
+(	POS	O
+TXB2	POS	O
+)	POS	O
+measurements	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+bupivacaine	POS	O
+/	POS	O
+rofecoxib	POS	O
+group	POS	O
+reported	POS	O
+significantly	POS	O
+less	POS	O
+pain	POS	B-NP
+,	POS	O
+as	POS	O
+assessed	POS	O
+by	POS	O
+a	POS	O
+visual	POS	O
+analog	POS	O
+scale	POS	O
+,	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+other	POS	O
+three	POS	O
+treatment	POS	O
+groups	POS	O
+over	POS	O
+the	POS	O
+first	POS	O
+4	POS	O
+h	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+bupivacaine	POS	O
+/	POS	O
+placebo	POS	O
+group	POS	O
+reported	POS	O
+significantly	POS	O
+more	POS	O
+pain	POS	B-NP
+at	POS	O
+24	POS	O
+h	POS	O
+and	POS	O
+PGE2	POS	O
+levels	POS	O
+during	POS	O
+the	POS	O
+first	POS	O
+4	POS	O
+h	POS	O
+were	POS	O
+significantly	POS	O
+higher	POS	O
+than	POS	O
+the	POS	O
+other	POS	O
+three	POS	O
+treatment	POS	O
+groups	POS	O
+.	POS	O
+Moreover	POS	O
+,	POS	O
+bupivacaine	POS	O
+significantly	POS	O
+increased	POS	O
+COX	POS	O
+-	POS	O
+2	POS	O
+gene	POS	O
+expression	POS	O
+at	POS	O
+48	POS	O
+h	POS	O
+as	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+lidocaine	POS	O
+/	POS	O
+placebo	POS	O
+group	POS	O
+.	POS	O
+Thromboxane	POS	O
+levels	POS	O
+were	POS	O
+not	POS	O
+significantly	POS	O
+affected	POS	O
+by	POS	O
+any	POS	O
+of	POS	O
+the	POS	O
+treatments	POS	O
+,	POS	O
+indicating	POS	O
+that	POS	O
+the	POS	O
+effects	POS	O
+seen	POS	O
+were	POS	O
+attributable	POS	O
+to	POS	O
+inhibition	POS	O
+of	POS	O
+COX	POS	O
+-	POS	O
+2	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+COX	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+bupivacaine	POS	O
+stimulates	POS	O
+COX	POS	O
+-	POS	O
+2	POS	O
+gene	POS	O
+expression	POS	O
+after	POS	O
+tissue	POS	O
+injury	POS	O
+,	POS	O
+which	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+higher	POS	O
+PGE2	POS	O
+production	POS	O
+and	POS	O
+pain	POS	B-NP
+after	POS	O
+the	POS	O
+local	POS	O
+anesthetic	POS	O
+effect	POS	O
+dissipates	POS	O
+.	POS	O
+p75NTR	POS	O
+expression	POS	O
+in	POS	O
+rat	POS	O
+urinary	POS	O
+bladder	POS	O
+sensory	POS	O
+neurons	POS	O
+and	POS	O
+spinal	POS	O
+cord	POS	O
+with	POS	O
+cyclophosphamide	POS	O
+-	POS	O
+induced	POS	O
+cystitis	POS	B-NP
+.	POS	O
+A	POS	O
+role	POS	O
+for	POS	O
+nerve	POS	O
+growth	POS	O
+factor	POS	O
+(	POS	O
+NGF	POS	O
+)	POS	O
+in	POS	O
+contributing	POS	O
+to	POS	O
+increased	POS	O
+voiding	POS	O
+frequency	POS	O
+and	POS	O
+altered	POS	O
+sensation	POS	O
+from	POS	O
+the	POS	O
+urinary	POS	O
+bladder	POS	O
+has	POS	O
+been	POS	O
+suggested	POS	O
+.	POS	O
+Previous	POS	O
+studies	POS	O
+have	POS	O
+examined	POS	O
+the	POS	O
+expression	POS	O
+and	POS	O
+regulation	POS	O
+of	POS	O
+tyrosine	POS	O
+kinase	POS	O
+receptors	POS	O
+(	POS	O
+Trks	POS	O
+)	POS	O
+in	POS	O
+micturition	POS	O
+reflexes	POS	O
+with	POS	O
+urinary	POS	B-NP
+bladder	POS	I-NP
+inflammation	POS	I-NP
+.	POS	O
+The	POS	O
+present	POS	O
+studies	POS	O
+examine	POS	O
+the	POS	O
+expression	POS	O
+and	POS	O
+regulation	POS	O
+of	POS	O
+another	POS	O
+receptor	POS	O
+known	POS	O
+to	POS	O
+bind	POS	O
+NGF	POS	O
+,	POS	O
+p75	POS	O
+(	POS	O
+NTR	POS	O
+)	POS	O
+,	POS	O
+after	POS	O
+various	POS	O
+durations	POS	O
+of	POS	O
+bladder	POS	B-NP
+inflammation	POS	I-NP
+induced	POS	O
+by	POS	O
+cyclophosphamide	POS	O
+(	POS	O
+CYP	POS	O
+)	POS	O
+.	POS	O
+CYP	POS	O
+-	POS	O
+induced	POS	O
+cystitis	POS	B-NP
+increased	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+p75	POS	O
+(	POS	O
+NTR	POS	O
+)	POS	O
+expression	POS	O
+in	POS	O
+the	POS	O
+superficial	POS	O
+lateral	POS	O
+and	POS	O
+medial	POS	O
+dorsal	POS	O
+horn	POS	O
+in	POS	O
+L1	POS	O
+-	POS	O
+L2	POS	O
+and	POS	O
+L6	POS	O
+-	POS	O
+S1	POS	O
+spinal	POS	O
+segments	POS	O
+.	POS	O
+The	POS	O
+number	POS	O
+of	POS	O
+p75	POS	O
+(	POS	O
+NTR	POS	O
+)	POS	O
+-	POS	O
+immunoreactive	POS	O
+(	POS	O
+-	POS	O
+IR	POS	O
+)	POS	O
+cells	POS	O
+in	POS	O
+the	POS	O
+lumbosacral	POS	O
+dorsal	POS	O
+root	POS	O
+ganglia	POS	O
+(	POS	O
+DRG	POS	O
+)	POS	O
+also	POS	O
+increased	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+with	POS	O
+CYP	POS	O
+-	POS	O
+induced	POS	O
+cystitis	POS	B-NP
+(	POS	O
+acute	POS	O
+,	POS	O
+intermediate	POS	O
+,	POS	O
+and	POS	O
+chronic	POS	O
+)	POS	O
+.	POS	O
+Quantitative	POS	O
+,	POS	O
+real	POS	O
+-	POS	O
+time	POS	O
+polymerase	POS	O
+chain	POS	O
+reaction	POS	O
+also	POS	O
+demonstrated	POS	O
+significant	POS	O
+increases	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+in	POS	O
+p75	POS	O
+(	POS	O
+NTR	POS	O
+)	POS	O
+mRNA	POS	O
+in	POS	O
+DRG	POS	O
+with	POS	O
+intermediate	POS	O
+and	POS	O
+chronic	POS	O
+CYP	POS	O
+-	POS	O
+induced	POS	O
+cystitis	POS	B-NP
+.	POS	O
+Retrograde	POS	O
+dye	POS	O
+-	POS	O
+tracing	POS	O
+techniques	POS	O
+with	POS	O
+Fastblue	POS	O
+were	POS	O
+used	POS	O
+to	POS	O
+identify	POS	O
+presumptive	POS	O
+bladder	POS	O
+afferent	POS	O
+cells	POS	O
+in	POS	O
+the	POS	O
+lumbosacral	POS	O
+DRG	POS	O
+.	POS	O
+In	POS	O
+bladder	POS	O
+afferent	POS	O
+cells	POS	O
+in	POS	O
+DRG	POS	O
+,	POS	O
+p75	POS	O
+(	POS	O
+NTR	POS	O
+)	POS	O
+-	POS	O
+IR	POS	O
+was	POS	O
+also	POS	O
+increased	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+with	POS	O
+cystitis	POS	B-NP
+.	POS	O
+In	POS	O
+addition	POS	O
+to	POS	O
+increases	POS	O
+in	POS	O
+p75	POS	O
+(	POS	O
+NTR	POS	O
+)	POS	O
+-	POS	O
+IR	POS	O
+in	POS	O
+DRG	POS	O
+cell	POS	O
+bodies	POS	O
+,	POS	O
+increases	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+in	POS	O
+pericellular	POS	O
+(	POS	O
+encircling	POS	O
+DRG	POS	O
+cells	POS	O
+)	POS	O
+p75	POS	O
+(	POS	O
+NTR	POS	O
+)	POS	O
+-	POS	O
+IR	POS	O
+in	POS	O
+DRG	POS	O
+also	POS	O
+increased	POS	O
+.	POS	O
+Confocal	POS	O
+analyses	POS	O
+demonstrated	POS	O
+that	POS	O
+pericellular	POS	O
+p75	POS	O
+(	POS	O
+NTR	POS	O
+)	POS	O
+-	POS	O
+IR	POS	O
+was	POS	O
+not	POS	O
+colocalized	POS	O
+with	POS	O
+the	POS	O
+glial	POS	O
+marker	POS	O
+,	POS	O
+glial	POS	O
+fibrillary	POS	O
+acidic	POS	O
+protein	POS	O
+(	POS	O
+GFAP	POS	O
+)	POS	O
+.	POS	O
+These	POS	O
+studies	POS	O
+demonstrate	POS	O
+that	POS	O
+p75	POS	O
+(	POS	O
+NTR	POS	O
+)	POS	O
+expression	POS	O
+in	POS	O
+micturition	POS	O
+reflexes	POS	O
+is	POS	O
+present	POS	O
+constitutively	POS	O
+and	POS	O
+modified	POS	O
+by	POS	O
+bladder	POS	B-NP
+inflammation	POS	I-NP
+.	POS	O
+The	POS	O
+functional	POS	O
+significance	POS	O
+of	POS	O
+p75	POS	O
+(	POS	O
+NTR	POS	O
+)	POS	O
+expression	POS	O
+in	POS	O
+micturition	POS	B-NP
+reflexes	POS	I-NP
+remains	POS	O
+to	POS	O
+be	POS	O
+determined	POS	O
+.	POS	O
+Azathioprine	POS	O
+-	POS	O
+induced	POS	O
+suicidal	POS	B-NP
+erythrocyte	POS	I-NP
+death	POS	I-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Azathioprine	POS	O
+is	POS	O
+widely	POS	O
+used	POS	O
+as	POS	O
+an	POS	O
+immunosuppressive	POS	O
+drug	POS	O
+.	POS	O
+The	POS	O
+side	POS	O
+effects	POS	O
+of	POS	O
+azathioprine	POS	O
+include	POS	O
+anemia	POS	B-NP
+,	POS	O
+which	POS	O
+has	POS	O
+been	POS	O
+attributed	POS	O
+to	POS	O
+bone	POS	O
+marrow	POS	O
+suppression	POS	O
+.	POS	O
+Alternatively	POS	O
+,	POS	O
+anemia	POS	B-NP
+could	POS	O
+result	POS	O
+from	POS	O
+accelerated	POS	O
+suicidal	POS	O
+erythrocyte	POS	O
+death	POS	O
+or	POS	O
+eryptosis	POS	O
+,	POS	O
+which	POS	O
+is	POS	O
+characterized	POS	O
+by	POS	O
+exposure	POS	O
+of	POS	O
+phosphatidylserine	POS	O
+(	POS	O
+PS	POS	O
+)	POS	O
+at	POS	O
+the	POS	O
+erythrocyte	POS	O
+surface	POS	O
+and	POS	O
+by	POS	O
+cell	POS	O
+shrinkage	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+The	POS	O
+present	POS	O
+experiments	POS	O
+explored	POS	O
+whether	POS	O
+azathioprine	POS	O
+influences	POS	O
+eryptosis	POS	O
+.	POS	O
+According	POS	O
+to	POS	O
+annexin	POS	O
+V	POS	O
+binding	POS	O
+,	POS	O
+erythrocytes	POS	O
+from	POS	O
+patients	POS	O
+indeed	POS	O
+showed	POS	O
+a	POS	O
+significant	POS	O
+increase	POS	O
+of	POS	O
+PS	POS	O
+exposure	POS	O
+within	POS	O
+1	POS	O
+week	POS	O
+of	POS	O
+treatment	POS	O
+with	POS	O
+azathioprine	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+second	POS	O
+series	POS	O
+,	POS	O
+cytosolic	POS	O
+Ca2	POS	O
++	POS	O
+activity	POS	O
+(	POS	O
+Fluo3	POS	O
+fluorescence	POS	O
+)	POS	O
+,	POS	O
+cell	POS	O
+volume	POS	O
+(	POS	O
+forward	POS	O
+scatter	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+PS	POS	O
+-	POS	O
+exposure	POS	O
+(	POS	O
+annexin	POS	O
+V	POS	O
+binding	POS	O
+)	POS	O
+were	POS	O
+determined	POS	O
+by	POS	O
+FACS	POS	O
+analysis	POS	O
+in	POS	O
+erythrocytes	POS	O
+from	POS	O
+healthy	POS	O
+volunteers	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Exposure	POS	O
+to	POS	O
+azathioprine	POS	O
+(	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+2	POS	O
+microg	POS	O
+/	POS	O
+mL	POS	O
+)	POS	O
+for	POS	O
+48	POS	O
+hours	POS	O
+increased	POS	O
+cytosolic	POS	O
+Ca2	POS	O
++	POS	O
+activity	POS	O
+and	POS	O
+annexin	POS	O
+V	POS	O
+binding	POS	O
+and	POS	O
+decreased	POS	O
+forward	POS	O
+scatter	POS	O
+.	POS	O
+The	POS	O
+effect	POS	O
+of	POS	O
+azathioprine	POS	O
+on	POS	O
+both	POS	O
+annexin	POS	O
+V	POS	O
+binding	POS	O
+and	POS	O
+forward	POS	O
+scatter	POS	O
+was	POS	O
+significantly	POS	O
+blunted	POS	O
+in	POS	O
+the	POS	O
+nominal	POS	O
+absence	POS	O
+of	POS	O
+extracellular	POS	O
+Ca2	POS	O
++	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Azathioprine	POS	O
+triggers	POS	O
+suicidal	POS	O
+erythrocyte	POS	O
+death	POS	O
+,	POS	O
+an	POS	O
+effect	POS	O
+presumably	POS	O
+contributing	POS	O
+to	POS	O
+azathioprine	POS	O
+-	POS	O
+induced	POS	O
+anemia	POS	B-NP
+.	POS	O
+Levetiracetam	POS	O
+as	POS	O
+an	POS	O
+adjunct	POS	O
+to	POS	O
+phenobarbital	POS	O
+treatment	POS	O
+in	POS	O
+cats	POS	O
+with	POS	O
+suspected	POS	O
+idiopathic	POS	B-NP
+epilepsy	POS	I-NP
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+assess	POS	O
+pharmacokinetics	POS	O
+,	POS	O
+efficacy	POS	O
+,	POS	O
+and	POS	O
+tolerability	POS	O
+of	POS	O
+oral	POS	O
+levetiracetam	POS	O
+administered	POS	O
+as	POS	O
+an	POS	O
+adjunct	POS	O
+to	POS	O
+phenobarbital	POS	O
+treatment	POS	O
+in	POS	O
+cats	POS	O
+with	POS	O
+poorly	POS	O
+controlled	POS	O
+suspected	POS	O
+idiopathic	POS	B-NP
+epilepsy	POS	I-NP
+.	POS	O
+DESIGN	POS	O
+-	POS	O
+Open	POS	O
+-	POS	O
+label	POS	O
+,	POS	O
+noncomparative	POS	O
+clinical	POS	O
+trial	POS	O
+.	POS	O
+ANIMALS	POS	O
+:	POS	O
+12	POS	O
+cats	POS	O
+suspected	POS	O
+to	POS	O
+have	POS	O
+idiopathic	POS	B-NP
+epilepsy	POS	I-NP
+that	POS	O
+was	POS	O
+poorly	POS	O
+controlled	POS	O
+with	POS	O
+phenobarbital	POS	O
+or	POS	O
+that	POS	O
+had	POS	O
+unacceptable	POS	O
+adverse	POS	O
+effects	POS	O
+when	POS	O
+treated	POS	O
+with	POS	O
+phenobarbital	POS	O
+.	POS	O
+PROCEDURES	POS	O
+:	POS	O
+Cats	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+levetiracetam	POS	O
+(	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+[	POS	O
+9	POS	O
+.	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+lb	POS	O
+]	POS	O
+,	POS	O
+PO	POS	O
+,	POS	O
+q	POS	O
+8	POS	O
+h	POS	O
+)	POS	O
+.	POS	O
+After	POS	O
+a	POS	O
+minimum	POS	O
+of	POS	O
+1	POS	O
+week	POS	O
+of	POS	O
+treatment	POS	O
+,	POS	O
+serum	POS	O
+levetiracetam	POS	O
+concentrations	POS	O
+were	POS	O
+measured	POS	O
+before	POS	O
+and	POS	O
+2	POS	O
+,	POS	O
+4	POS	O
+,	POS	O
+and	POS	O
+6	POS	O
+hours	POS	O
+after	POS	O
+drug	POS	O
+administration	POS	O
+,	POS	O
+and	POS	O
+maximum	POS	O
+and	POS	O
+minimum	POS	O
+serum	POS	O
+concentrations	POS	O
+and	POS	O
+elimination	POS	O
+half	POS	O
+-	POS	O
+life	POS	O
+were	POS	O
+calculated	POS	O
+.	POS	O
+Seizure	POS	B-NP
+frequencies	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+initiation	POS	O
+of	POS	O
+levetiracetam	POS	O
+treatment	POS	O
+were	POS	O
+compared	POS	O
+,	POS	O
+and	POS	O
+adverse	POS	O
+effects	POS	O
+were	POS	O
+recorded	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Median	POS	O
+maximum	POS	O
+serum	POS	O
+levetiracetam	POS	O
+concentration	POS	O
+was	POS	O
+25	POS	O
+.	POS	O
+5	POS	O
+microg	POS	O
+/	POS	O
+mL	POS	O
+,	POS	O
+median	POS	O
+minimum	POS	O
+serum	POS	O
+levetiracetam	POS	O
+concentration	POS	O
+was	POS	O
+8	POS	O
+.	POS	O
+3	POS	O
+microg	POS	O
+/	POS	O
+mL	POS	O
+,	POS	O
+and	POS	O
+median	POS	O
+elimination	POS	O
+half	POS	O
+-	POS	O
+life	POS	O
+was	POS	O
+2	POS	O
+.	POS	O
+9	POS	O
+hours	POS	O
+.	POS	O
+Median	POS	O
+seizure	POS	B-NP
+frequency	POS	O
+prior	POS	O
+to	POS	O
+treatment	POS	O
+with	POS	O
+levetiracetam	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+1	POS	O
+seizures	POS	B-NP
+/	POS	O
+mo	POS	O
+)	POS	O
+was	POS	O
+significantly	POS	O
+higher	POS	O
+than	POS	O
+median	POS	O
+seizure	POS	B-NP
+frequency	POS	O
+after	POS	O
+initiation	POS	O
+of	POS	O
+levetiracetam	POS	O
+treatment	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+42	POS	O
+seizures	POS	B-NP
+/	POS	O
+mo	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+7	POS	O
+of	POS	O
+10	POS	O
+cats	POS	O
+were	POS	O
+classified	POS	O
+as	POS	O
+having	POS	O
+responded	POS	O
+to	POS	O
+levetiracetam	POS	O
+treatment	POS	O
+(	POS	O
+ie	POS	O
+,	POS	O
+reduction	POS	O
+in	POS	O
+seizure	POS	B-NP
+frequency	POS	O
+of	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+50	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Two	POS	O
+cats	POS	O
+had	POS	O
+transient	POS	O
+lethargy	POS	B-NP
+and	POS	O
+inappetence	POS	B-NP
+.	POS	O
+CONCLUSIONS	POS	O
+AND	POS	O
+CLINICAL	POS	O
+RELEVANCE	POS	O
+:	POS	O
+Results	POS	O
+suggested	POS	O
+that	POS	O
+levetiracetam	POS	O
+is	POS	O
+well	POS	O
+tolerated	POS	O
+in	POS	O
+cats	POS	O
+and	POS	O
+may	POS	O
+be	POS	O
+useful	POS	O
+as	POS	O
+an	POS	O
+adjunct	POS	O
+to	POS	O
+phenobarbital	POS	O
+treatment	POS	O
+in	POS	O
+cats	POS	O
+with	POS	O
+idiopathic	POS	B-NP
+epilepsy	POS	I-NP
+.	POS	O
+Serotonin	POS	O
+reuptake	POS	O
+inhibitors	POS	O
+,	POS	O
+paranoia	POS	B-NP
+,	POS	O
+and	POS	O
+the	POS	O
+ventral	POS	O
+basal	POS	O
+ganglia	POS	O
+.	POS	O
+Antidepressants	POS	O
+have	POS	O
+previously	POS	O
+been	POS	O
+associated	POS	O
+with	POS	O
+paranoid	POS	O
+reactions	POS	O
+in	POS	O
+psychiatric	POS	B-NP
+patients	POS	O
+.	POS	O
+Five	POS	O
+cases	POS	O
+of	POS	O
+paranoid	POS	B-NP
+exacerbation	POS	I-NP
+with	POS	O
+the	POS	O
+serotonin	POS	O
+reuptake	POS	O
+inhibitors	POS	O
+fluoxetine	POS	O
+and	POS	O
+amitriptyline	POS	O
+are	POS	O
+reported	POS	O
+here	POS	O
+.	POS	O
+Elements	POS	O
+common	POS	O
+to	POS	O
+these	POS	O
+cases	POS	O
+included	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+paranoid	POS	O
+symptomatology	POS	O
+and	POS	O
+the	POS	O
+concomitant	POS	O
+occurrence	POS	O
+of	POS	O
+depressive	POS	B-NP
+and	POS	O
+psychotic	POS	B-NP
+symptoms	POS	I-NP
+.	POS	O
+Complicated	POS	B-NP
+depressive	POS	I-NP
+disorders	POS	I-NP
+(	POS	O
+including	POS	O
+atypicality	POS	O
+of	POS	O
+course	POS	O
+and	POS	O
+symptomatology	POS	O
+,	POS	O
+chronicity	POS	B-NP
+,	POS	O
+psychosis	POS	B-NP
+,	POS	O
+bipolarity	POS	B-NP
+,	POS	O
+and	POS	O
+secondary	POS	O
+onset	POS	O
+in	POS	O
+the	POS	O
+course	POS	O
+of	POS	O
+a	POS	O
+primary	POS	O
+psychosis	POS	B-NP
+)	POS	O
+may	POS	O
+present	POS	O
+particular	POS	O
+vulnerability	POS	O
+to	POS	O
+paranoid	POS	B-NP
+exacerbations	POS	I-NP
+associated	POS	O
+with	POS	O
+serotonin	POS	O
+reuptake	POS	O
+inhibitors	POS	O
+.	POS	O
+Although	POS	O
+the	POS	O
+pharmacology	POS	O
+and	POS	O
+neurobiology	POS	O
+of	POS	O
+paranoia	POS	B-NP
+remain	POS	O
+cryptic	POS	O
+,	POS	O
+several	POS	O
+mechanisms	POS	O
+,	POS	O
+including	POS	O
+5HT3	POS	O
+receptor	POS	O
+-	POS	O
+mediated	POS	O
+dopamine	POS	O
+release	POS	O
+,	POS	O
+beta	POS	O
+-	POS	O
+noradrenergic	POS	O
+receptor	POS	O
+downregulation	POS	O
+,	POS	O
+or	POS	O
+GABAB	POS	O
+receptor	POS	O
+upregulation	POS	O
+acting	POS	O
+in	POS	O
+the	POS	O
+vicinity	POS	O
+of	POS	O
+the	POS	O
+ventral	POS	O
+basal	POS	O
+ganglia	POS	O
+(	POS	O
+possibly	POS	O
+in	POS	O
+lateral	POS	O
+orbitofrontal	POS	O
+or	POS	O
+anterior	POS	O
+cingulate	POS	O
+circuits	POS	O
+)	POS	O
+,	POS	O
+might	POS	O
+apply	POS	O
+to	POS	O
+this	POS	O
+phenomenon	POS	O
+.	POS	O
+These	POS	O
+cases	POS	O
+call	POS	O
+attention	POS	O
+to	POS	O
+possible	POS	O
+paranoid	POS	B-NP
+exacerbations	POS	I-NP
+with	POS	O
+serotonin	POS	O
+reuptake	POS	O
+blockers	POS	O
+in	POS	O
+select	POS	O
+patients	POS	O
+and	POS	O
+raise	POS	O
+neurobiological	POS	O
+considerations	POS	O
+regarding	POS	O
+paranoia	POS	B-NP
+.	POS	O
+Clinical	POS	O
+comparison	POS	O
+of	POS	O
+cardiorespiratory	POS	B-NP
+effects	POS	I-NP
+during	POS	O
+unilateral	POS	O
+and	POS	O
+conventional	POS	O
+spinal	POS	O
+anaesthesia	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Spinal	POS	O
+anaesthesia	POS	O
+is	POS	O
+widely	POS	O
+employed	POS	O
+in	POS	O
+clinical	POS	O
+practice	POS	O
+but	POS	O
+has	POS	O
+the	POS	O
+main	POS	O
+drawback	POS	O
+of	POS	O
+post	POS	O
+-	POS	O
+spinal	POS	O
+block	POS	O
+hypotension	POS	B-NP
+.	POS	O
+Efforts	POS	O
+must	POS	O
+therefore	POS	O
+continue	POS	O
+to	POS	O
+be	POS	O
+made	POS	O
+to	POS	O
+obviate	POS	O
+this	POS	O
+setback	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+evaluate	POS	O
+the	POS	O
+cardiovascular	POS	O
+and	POS	O
+respiratory	POS	O
+changes	POS	O
+during	POS	O
+unilateral	POS	O
+and	POS	O
+conventional	POS	O
+spinal	POS	O
+anaesthesia	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+With	POS	O
+ethical	POS	O
+approval	POS	O
+,	POS	O
+we	POS	O
+studied	POS	O
+74	POS	O
+American	POS	O
+Society	POS	O
+of	POS	O
+Anesthesiologists	POS	O
+(	POS	O
+ASA	POS	O
+)	POS	O
+,	POS	O
+physical	POS	O
+status	POS	O
+class	POS	O
+1	POS	O
+and	POS	O
+2	POS	O
+patients	POS	O
+scheduled	POS	O
+for	POS	O
+elective	POS	O
+unilateral	POS	O
+lower	POS	O
+limb	POS	O
+surgery	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+randomly	POS	O
+allocated	POS	O
+into	POS	O
+one	POS	O
+of	POS	O
+two	POS	O
+groups	POS	O
+:	POS	O
+lateral	POS	O
+and	POS	O
+conventional	POS	O
+spinal	POS	O
+anaesthesia	POS	O
+groups	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+lateral	POS	O
+position	POS	O
+with	POS	O
+operative	POS	O
+side	POS	O
+down	POS	O
+,	POS	O
+patients	POS	O
+recived	POS	O
+10	POS	O
+mg	POS	O
+(	POS	O
+2mls	POS	O
+)	POS	O
+of	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+hyperbaric	POS	O
+bupivacaine	POS	O
+through	POS	O
+a	POS	O
+25	POS	O
+-	POS	O
+gauge	POS	O
+spinal	POS	O
+needle	POS	O
+.	POS	O
+Patients	POS	O
+in	POS	O
+the	POS	O
+unilateral	POS	O
+group	POS	O
+were	POS	O
+maintained	POS	O
+in	POS	O
+the	POS	O
+lateral	POS	O
+position	POS	O
+for	POS	O
+15	POS	O
+minutes	POS	O
+following	POS	O
+spinal	POS	O
+injection	POS	O
+while	POS	O
+those	POS	O
+in	POS	O
+the	POS	O
+conventional	POS	O
+group	POS	O
+were	POS	O
+turned	POS	O
+supine	POS	O
+immediately	POS	O
+after	POS	O
+injection	POS	O
+.	POS	O
+Blood	POS	O
+pressure	POS	O
+,	POS	O
+heart	POS	O
+rate	POS	O
+,	POS	O
+respiratory	POS	O
+rate	POS	O
+and	POS	O
+oxygen	POS	O
+saturation	POS	O
+were	POS	O
+monitored	POS	O
+over	POS	O
+1	POS	O
+hour	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Three	POS	O
+patients	POS	O
+(	POS	O
+8	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+unilateral	POS	O
+group	POS	O
+and	POS	O
+5	POS	O
+(	POS	O
+13	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+conventional	POS	O
+group	POS	O
+developed	POS	O
+hypotension	POS	B-NP
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+71	POS	O
+.	POS	O
+Four	POS	O
+(	POS	O
+10	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+in	POS	O
+the	POS	O
+conventional	POS	O
+group	POS	O
+and	POS	O
+1	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+unilateral	POS	O
+group	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+17	POS	O
+required	POS	O
+epinephrine	POS	O
+infusion	POS	O
+to	POS	O
+treat	POS	O
+hypotension	POS	B-NP
+.	POS	O
+Patients	POS	O
+in	POS	O
+the	POS	O
+conventional	POS	O
+group	POS	O
+had	POS	O
+statistically	POS	O
+significant	POS	O
+greater	POS	O
+fall	POS	O
+in	POS	O
+the	POS	O
+systolic	POS	O
+blood	POS	O
+pressures	POS	O
+at	POS	O
+15	POS	O
+,	POS	O
+30	POS	O
+and	POS	O
+45	POS	O
+minutes	POS	O
+when	POS	O
+compared	POS	O
+to	POS	O
+the	POS	O
+baseline	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+003	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+004	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+respiratory	POS	O
+rate	POS	O
+and	POS	O
+oxygen	POS	O
+saturations	POS	O
+in	POS	O
+the	POS	O
+two	POS	O
+groups	POS	O
+were	POS	O
+similar	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Compared	POS	O
+to	POS	O
+conventional	POS	O
+spinal	POS	O
+anaesthesia	POS	O
+,	POS	O
+unilateral	POS	O
+spinal	POS	O
+anaesthesia	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+fewer	POS	O
+cardiovascular	POS	B-NP
+perturbations	POS	I-NP
+.	POS	O
+Also	POS	O
+,	POS	O
+the	POS	O
+type	POS	O
+of	POS	O
+spinal	POS	O
+block	POS	O
+instituted	POS	O
+affected	POS	O
+neither	POS	O
+the	POS	O
+respiratory	POS	O
+rate	POS	O
+nor	POS	O
+the	POS	O
+arterial	POS	O
+oxygen	POS	O
+saturation	POS	O
+.	POS	O
+Spectrum	POS	O
+of	POS	O
+adverse	POS	O
+events	POS	O
+after	POS	O
+generic	POS	O
+HAART	POS	O
+in	POS	O
+southern	POS	O
+Indian	POS	O
+HIV	POS	O
+-	POS	O
+infected	POS	O
+patients	POS	O
+.	POS	O
+To	POS	O
+determine	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+clinically	POS	O
+significant	POS	O
+adverse	POS	O
+events	POS	O
+after	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+,	POS	O
+fixed	POS	O
+-	POS	O
+dose	POS	O
+,	POS	O
+generic	POS	O
+highly	POS	O
+active	POS	O
+antiretroviral	POS	O
+therapy	POS	O
+(	POS	O
+HAART	POS	O
+)	POS	O
+use	POS	O
+among	POS	O
+HIV	POS	O
+-	POS	O
+infected	POS	O
+individuals	POS	O
+in	POS	O
+South	POS	O
+India	POS	O
+,	POS	O
+we	POS	O
+examined	POS	O
+the	POS	O
+experiences	POS	O
+of	POS	O
+3154	POS	O
+HIV	POS	O
+-	POS	O
+infected	POS	O
+individuals	POS	O
+who	POS	O
+received	POS	O
+a	POS	O
+minimum	POS	O
+of	POS	O
+3	POS	O
+months	POS	O
+of	POS	O
+generic	POS	O
+HAART	POS	O
+between	POS	O
+February	POS	O
+1996	POS	O
+and	POS	O
+December	POS	O
+2006	POS	O
+at	POS	O
+a	POS	O
+tertiary	POS	O
+HIV	POS	O
+care	POS	O
+referral	POS	O
+center	POS	O
+in	POS	O
+South	POS	O
+India	POS	O
+.	POS	O
+The	POS	O
+most	POS	O
+common	POS	O
+regimens	POS	O
+were	POS	O
+3TC	POS	O
++	POS	O
+d4T	POS	O
++	POS	O
+nevirapine	POS	O
+(	POS	O
+NVP	POS	O
+)	POS	O
+(	POS	O
+54	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+zidovudine	POS	O
+(	POS	O
+AZT	POS	O
+)	POS	O
++	POS	O
+3TC	POS	O
++	POS	O
+NVP	POS	O
+(	POS	O
+14	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+3TC	POS	O
++	POS	O
+d4T	POS	O
++	POS	O
+efavirenz	POS	O
+(	POS	O
+EFV	POS	O
+)	POS	O
+(	POS	O
+20	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+AZT	POS	O
++	POS	O
+3TC	POS	O
++	POS	O
+EFV	POS	O
+(	POS	O
+5	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+most	POS	O
+common	POS	O
+adverse	POS	O
+events	POS	O
+and	POS	O
+median	POS	O
+CD4	POS	O
+at	POS	O
+time	POS	O
+of	POS	O
+event	POS	O
+were	POS	O
+rash	POS	B-NP
+(	POS	O
+15	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+;	POS	O
+CD4	POS	O
+,	POS	O
+285	POS	O
+cells	POS	O
+/	POS	O
+microL	POS	O
+)	POS	O
+and	POS	O
+peripheral	POS	B-NP
+neuropathy	POS	I-NP
+(	POS	O
+9	POS	O
+.	POS	O
+0	POS	O
+%	POS	O
+and	POS	O
+348	POS	O
+cells	POS	O
+/	POS	O
+microL	POS	O
+)	POS	O
+.	POS	O
+Clinically	POS	O
+significant	POS	O
+anemia	POS	B-NP
+(	POS	O
+hemoglobin	POS	O
+<	POS	O
+7	POS	O
+g	POS	O
+/	POS	O
+dL	POS	O
+)	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+5	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+(	POS	O
+CD4	POS	O
+,	POS	O
+165	POS	O
+cells	POS	O
+/	POS	O
+microL	POS	O
+)	POS	O
+and	POS	O
+hepatitis	POS	B-NP
+(	POS	O
+clinical	POS	O
+jaundice	POS	B-NP
+with	POS	O
+alanine	POS	O
+aminotransferase	POS	O
+>	POS	O
+5	POS	O
+times	POS	O
+upper	POS	O
+limits	POS	O
+of	POS	O
+normal	POS	O
+)	POS	O
+in	POS	O
+3	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+(	POS	O
+CD4	POS	O
+,	POS	O
+260	POS	O
+cells	POS	O
+/	POS	O
+microL	POS	O
+)	POS	O
+.	POS	O
+Women	POS	O
+were	POS	O
+significantly	POS	O
+more	POS	O
+likely	POS	O
+to	POS	O
+experience	POS	O
+lactic	POS	B-NP
+acidosis	POS	I-NP
+,	POS	O
+while	POS	O
+men	POS	O
+were	POS	O
+significantly	POS	O
+more	POS	O
+likely	POS	O
+to	POS	O
+experience	POS	O
+immune	POS	B-NP
+reconstitution	POS	I-NP
+syndrome	POS	I-NP
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+Among	POS	O
+the	POS	O
+patients	POS	O
+with	POS	O
+1	POS	O
+year	POS	O
+of	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+,	POS	O
+NVP	POS	O
+therapy	POS	O
+was	POS	O
+significantly	POS	O
+associated	POS	O
+with	POS	O
+developing	POS	O
+rash	POS	B-NP
+and	POS	O
+d4T	POS	O
+therapy	POS	O
+with	POS	O
+developing	POS	O
+peripheral	POS	B-NP
+neuropathy	POS	I-NP
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+Anemia	POS	B-NP
+and	POS	O
+hepatitis	POS	B-NP
+often	POS	O
+occur	POS	O
+within	POS	O
+12	POS	O
+weeks	POS	O
+of	POS	O
+initiating	POS	O
+generic	POS	O
+HAART	POS	O
+.	POS	O
+Frequent	POS	O
+and	POS	O
+early	POS	O
+monitoring	POS	O
+for	POS	O
+these	POS	O
+toxicities	POS	B-NP
+is	POS	O
+warranted	POS	O
+in	POS	O
+developing	POS	O
+countries	POS	O
+where	POS	O
+generic	POS	O
+HAART	POS	O
+is	POS	O
+increasingly	POS	O
+available	POS	O
+.	POS	O
+Thalidomide	POS	O
+and	POS	O
+sensory	POS	B-NP
+neurotoxicity	POS	I-NP
+:	POS	O
+a	POS	O
+neurophysiological	POS	O
+study	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Recent	POS	O
+studies	POS	O
+confirmed	POS	O
+a	POS	O
+high	POS	O
+incidence	POS	O
+of	POS	O
+sensory	POS	B-NP
+axonal	POS	I-NP
+neuropathy	POS	I-NP
+in	POS	O
+patients	POS	O
+treated	POS	O
+with	POS	O
+different	POS	O
+doses	POS	O
+of	POS	O
+thalidomide	POS	O
+.	POS	O
+The	POS	O
+study	POS	O
+'	POS	O
+s	POS	O
+aims	POS	O
+were	POS	O
+to	POS	O
+measure	POS	O
+variations	POS	O
+in	POS	O
+sural	POS	O
+nerve	POS	O
+sensory	POS	O
+action	POS	O
+potential	POS	O
+(	POS	O
+SAP	POS	O
+)	POS	O
+amplitude	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+refractory	POS	O
+cutaneous	POS	B-NP
+lupus	POS	I-NP
+erythematosus	POS	I-NP
+(	POS	O
+CLE	POS	B-NP
+)	POS	O
+treated	POS	O
+with	POS	O
+thalidomide	POS	O
+and	POS	O
+use	POS	O
+these	POS	O
+findings	POS	O
+to	POS	O
+identify	POS	O
+the	POS	O
+neurotoxic	POS	B-NP
+potential	POS	O
+of	POS	O
+thalidomide	POS	O
+and	POS	O
+the	POS	O
+recovery	POS	O
+capacity	POS	O
+of	POS	O
+sensory	POS	O
+fibres	POS	O
+after	POS	O
+discontinuation	POS	O
+of	POS	O
+treatment	POS	O
+.	POS	O
+PATIENTS	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+Clinical	POS	O
+and	POS	O
+electrophysiological	POS	O
+data	POS	O
+in	POS	O
+12	POS	O
+female	POS	O
+patients	POS	O
+with	POS	O
+CLE	POS	B-NP
+during	POS	O
+treatment	POS	O
+with	POS	O
+thalidomide	POS	O
+and	POS	O
+up	POS	O
+to	POS	O
+47	POS	O
+months	POS	O
+after	POS	O
+discontinuation	POS	O
+of	POS	O
+treatment	POS	O
+were	POS	O
+analysed	POS	O
+.	POS	O
+Sural	POS	O
+nerve	POS	O
+SAP	POS	O
+amplitude	POS	O
+reduction	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+40	POS	O
+%	POS	O
+was	POS	O
+the	POS	O
+criteria	POS	O
+for	POS	O
+discontinuing	POS	O
+therapy	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+During	POS	O
+treatment	POS	O
+,	POS	O
+11	POS	O
+patients	POS	O
+showed	POS	O
+a	POS	O
+reduction	POS	O
+in	POS	O
+sural	POS	O
+nerve	POS	O
+SAP	POS	O
+amplitude	POS	O
+compared	POS	O
+to	POS	O
+baseline	POS	O
+values	POS	O
+(	POS	O
+9	POS	O
+with	POS	O
+a	POS	O
+reduction	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+50	POS	O
+%	POS	O
+and	POS	O
+2	POS	O
+<	POS	O
+50	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+One	POS	O
+patient	POS	O
+showed	POS	O
+no	POS	O
+changes	POS	O
+in	POS	O
+SAP	POS	O
+amplitude	POS	O
+.	POS	O
+Five	POS	O
+patients	POS	O
+complained	POS	O
+of	POS	O
+paresthesias	POS	B-NP
+and	POS	O
+leg	POS	B-NP
+cramps	POS	I-NP
+.	POS	O
+After	POS	O
+thalidomide	POS	O
+treatment	POS	O
+,	POS	O
+sural	POS	O
+SAP	POS	O
+amplitude	POS	O
+recovered	POS	O
+in	POS	O
+3	POS	O
+patients	POS	O
+.	POS	O
+At	POS	O
+detection	POS	O
+of	POS	O
+reduction	POS	O
+in	POS	O
+sural	POS	O
+nerve	POS	O
+SAP	POS	O
+amplitude	POS	O
+,	POS	O
+the	POS	O
+median	POS	O
+thalidomide	POS	O
+cumulative	POS	O
+dose	POS	O
+was	POS	O
+21	POS	O
+.	POS	O
+4	POS	O
+g	POS	O
+.	POS	O
+The	POS	O
+threshold	POS	O
+neurotoxic	POS	B-NP
+dosage	POS	O
+is	POS	O
+lower	POS	O
+than	POS	O
+previously	POS	O
+reported	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Sural	POS	O
+nerve	POS	O
+SAP	POS	O
+amplitude	POS	O
+reduction	POS	O
+is	POS	O
+a	POS	O
+reliable	POS	O
+and	POS	O
+sensitive	POS	O
+marker	POS	O
+of	POS	O
+degeneration	POS	O
+and	POS	O
+recovery	POS	O
+of	POS	O
+sensory	POS	O
+fibres	POS	O
+.	POS	O
+This	POS	O
+electrophysiological	POS	O
+parameter	POS	O
+provides	POS	O
+information	POS	O
+about	POS	O
+subclinical	POS	O
+neurotoxic	POS	B-NP
+potential	POS	O
+of	POS	O
+thalidomide	POS	O
+but	POS	O
+is	POS	O
+not	POS	O
+helpful	POS	O
+in	POS	O
+predicting	POS	O
+the	POS	O
+appearance	POS	O
+of	POS	O
+sensory	POS	B-NP
+symptoms	POS	I-NP
+.	POS	O
+Five	POS	O
+cases	POS	O
+of	POS	O
+encephalitis	POS	B-NP
+during	POS	O
+treatment	POS	O
+of	POS	O
+loiasis	POS	B-NP
+with	POS	O
+diethylcarbamazine	POS	O
+.	POS	O
+Five	POS	O
+cases	POS	O
+of	POS	O
+encephalitis	POS	B-NP
+following	POS	O
+treatment	POS	O
+with	POS	O
+diethylcarbamazine	POS	O
+(	POS	O
+DEC	POS	O
+)	POS	O
+were	POS	O
+observed	POS	O
+in	POS	O
+Congolese	POS	O
+patients	POS	O
+with	POS	O
+Loa	POS	B-NP
+loa	POS	I-NP
+filariasis	POS	I-NP
+.	POS	O
+Two	POS	O
+cases	POS	O
+had	POS	O
+a	POS	O
+fatal	POS	O
+outcome	POS	O
+and	POS	O
+one	POS	O
+resulted	POS	O
+in	POS	O
+severe	POS	O
+sequelae	POS	O
+.	POS	O
+The	POS	O
+notable	POS	O
+fact	POS	O
+was	POS	O
+that	POS	O
+this	POS	O
+complication	POS	O
+occurred	POS	O
+in	POS	O
+three	POS	O
+patients	POS	O
+hospitalized	POS	O
+before	POS	O
+treatment	POS	O
+began	POS	O
+,	POS	O
+with	POS	O
+whom	POS	O
+particularly	POS	O
+strict	POS	O
+therapeutic	POS	O
+precautions	POS	O
+were	POS	O
+taken	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+e	POS	O
+.	POS	O
+,	POS	O
+initial	POS	O
+dose	POS	O
+less	POS	O
+than	POS	O
+10	POS	O
+mg	POS	O
+of	POS	O
+DEC	POS	O
+,	POS	O
+very	POS	O
+gradual	POS	O
+dose	POS	O
+increases	POS	O
+,	POS	O
+and	POS	O
+associated	POS	O
+anti	POS	O
+-	POS	O
+allergic	POS	O
+treatment	POS	O
+.	POS	O
+This	POS	O
+type	POS	O
+of	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+complication	POS	O
+may	POS	O
+not	POS	O
+be	POS	O
+that	POS	O
+uncommon	POS	O
+in	POS	O
+highly	POS	O
+endemic	POS	O
+regions	POS	O
+.	POS	O
+It	POS	O
+occurs	POS	O
+primarily	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+exclusively	POS	O
+,	POS	O
+in	POS	O
+subjects	POS	O
+presenting	POS	O
+with	POS	O
+a	POS	O
+high	POS	O
+microfilarial	POS	O
+load	POS	O
+.	POS	O
+The	POS	O
+relationship	POS	O
+between	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+encephalitis	POS	B-NP
+and	POS	O
+the	POS	O
+decrease	POS	O
+in	POS	O
+microfilaremia	POS	B-NP
+is	POS	O
+evident	POS	O
+.	POS	O
+The	POS	O
+pathophysiological	POS	O
+mechanisms	POS	O
+are	POS	O
+discussed	POS	O
+in	POS	O
+the	POS	O
+light	POS	O
+of	POS	O
+these	POS	O
+observations	POS	O
+and	POS	O
+the	POS	O
+few	POS	O
+other	POS	O
+comments	POS	O
+on	POS	O
+this	POS	O
+subject	POS	O
+published	POS	O
+in	POS	O
+the	POS	O
+literature	POS	O
+.	POS	O
+Amiodarone	POS	O
+-	POS	O
+related	POS	O
+pulmonary	POS	O
+mass	POS	O
+and	POS	O
+unique	POS	O
+membranous	POS	B-NP
+glomerulonephritis	POS	I-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+valvular	POS	B-NP
+heart	POS	I-NP
+disease	POS	I-NP
+:	POS	O
+Diagnostic	POS	O
+pitfall	POS	O
+and	POS	O
+new	POS	O
+findings	POS	O
+.	POS	O
+Amiodarone	POS	O
+is	POS	O
+an	POS	O
+anti	POS	O
+-	POS	O
+arrhythmic	POS	O
+drug	POS	O
+for	POS	O
+life	POS	O
+-	POS	O
+threatening	POS	O
+tachycardia	POS	B-NP
+,	POS	O
+but	POS	O
+various	POS	O
+adverse	POS	O
+effects	POS	O
+have	POS	O
+been	POS	O
+reported	POS	O
+.	POS	O
+Reported	POS	O
+herein	POS	O
+is	POS	O
+an	POS	O
+autopsy	POS	O
+case	POS	O
+of	POS	O
+valvular	POS	B-NP
+heart	POS	I-NP
+disease	POS	I-NP
+,	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+who	POS	O
+developed	POS	O
+a	POS	O
+lung	POS	O
+mass	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+cm	POS	O
+in	POS	O
+diameter	POS	O
+)	POS	O
+and	POS	O
+proteinuria	POS	B-NP
+(	POS	O
+2	POS	O
+.	POS	O
+76	POS	O
+g	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+after	POS	O
+treatment	POS	O
+with	POS	O
+amiodarone	POS	O
+for	POS	O
+a	POS	O
+long	POS	O
+time	POS	O
+.	POS	O
+The	POS	O
+lung	POS	O
+mass	POS	O
+was	POS	O
+highly	POS	O
+suspected	POS	O
+to	POS	O
+be	POS	O
+lung	POS	B-NP
+cancer	POS	I-NP
+on	POS	O
+CT	POS	O
+and	POS	O
+positron	POS	O
+emission	POS	O
+tomography	POS	O
+,	POS	O
+but	POS	O
+histologically	POS	O
+the	POS	O
+lesion	POS	O
+was	POS	O
+composed	POS	O
+of	POS	O
+lymphoplasmacytic	POS	O
+infiltrates	POS	O
+in	POS	O
+alveolar	POS	O
+walls	POS	O
+and	POS	O
+intra	POS	O
+-	POS	O
+alveolar	POS	O
+accumulation	POS	O
+of	POS	O
+foamy	POS	O
+macrophages	POS	O
+containing	POS	O
+characteristic	POS	O
+myelinoid	POS	O
+bodies	POS	O
+,	POS	O
+indicating	POS	O
+that	POS	O
+it	POS	O
+was	POS	O
+an	POS	O
+amiodarone	POS	O
+-	POS	O
+related	POS	O
+lesion	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+the	POS	O
+lung	POS	O
+tissue	POS	O
+had	POS	O
+unevenly	POS	O
+distributed	POS	O
+hemosiderin	POS	O
+deposition	POS	O
+,	POS	O
+and	POS	O
+abnormally	POS	O
+tortuous	POS	O
+capillaries	POS	O
+were	POS	O
+seen	POS	O
+in	POS	O
+the	POS	O
+mass	POS	O
+and	POS	O
+in	POS	O
+heavily	POS	O
+hemosiderotic	POS	O
+lung	POS	O
+portions	POS	O
+outside	POS	O
+the	POS	O
+mass	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+kidneys	POS	O
+,	POS	O
+glomeruli	POS	O
+had	POS	O
+membrane	POS	O
+spikes	POS	O
+,	POS	O
+prominent	POS	O
+swelling	POS	O
+of	POS	O
+podocytes	POS	O
+and	POS	O
+subepithelial	POS	O
+deposits	POS	O
+,	POS	O
+which	POS	O
+were	POS	O
+sometimes	POS	O
+large	POS	O
+and	POS	O
+hump	POS	O
+-	POS	O
+like	POS	O
+.	POS	O
+Autoimmune	POS	B-NP
+diseases	POS	I-NP
+,	POS	O
+viral	POS	B-NP
+hepatitis	POS	I-NP
+,	POS	O
+malignant	POS	B-NP
+neoplasms	POS	I-NP
+or	POS	O
+other	POS	O
+diseases	POS	O
+with	POS	O
+a	POS	O
+known	POS	O
+relationship	POS	O
+to	POS	O
+membranous	POS	O
+glomerulonephritis	POS	B-NP
+were	POS	O
+not	POS	O
+found	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+case	POS	O
+highlights	POS	O
+the	POS	O
+possibility	POS	O
+that	POS	O
+differential	POS	O
+diagnosis	POS	O
+between	POS	O
+an	POS	O
+amiodarone	POS	O
+-	POS	O
+related	POS	O
+pulmonary	POS	B-NP
+lesion	POS	I-NP
+and	POS	O
+a	POS	O
+neoplasm	POS	B-NP
+can	POS	O
+be	POS	O
+very	POS	O
+difficult	POS	O
+radiologically	POS	O
+,	POS	O
+and	POS	O
+suggests	POS	O
+that	POS	O
+membranous	POS	O
+glomerulonephritis	POS	B-NP
+might	POS	O
+be	POS	O
+another	POS	O
+possible	POS	O
+complication	POS	O
+of	POS	O
+amiodarone	POS	O
+treatment	POS	O
+.	POS	O
+Risk	POS	O
+of	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+associated	POS	O
+with	POS	O
+initial	POS	O
+sulphonylurea	POS	O
+treatment	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+type	POS	B-NP
+2	POS	I-NP
+diabetes	POS	I-NP
+:	POS	O
+a	POS	O
+matched	POS	O
+case	POS	O
+-	POS	O
+control	POS	O
+study	POS	O
+.	POS	O
+AIMS	POS	O
+:	POS	O
+This	POS	O
+study	POS	O
+sought	POS	O
+to	POS	O
+assess	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+developing	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+CAD	POS	B-NP
+)	POS	O
+associated	POS	O
+with	POS	O
+initial	POS	O
+treatment	POS	O
+of	POS	O
+type	POS	B-NP
+2	POS	I-NP
+diabetes	POS	I-NP
+with	POS	O
+different	POS	O
+sulphonylureas	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+In	POS	O
+type	POS	B-NP
+2	POS	I-NP
+diabetic	POS	I-NP
+patients	POS	O
+,	POS	O
+cases	POS	O
+who	POS	O
+developed	POS	O
+CAD	POS	B-NP
+were	POS	O
+compared	POS	O
+retrospectively	POS	O
+with	POS	O
+controls	POS	O
+that	POS	O
+did	POS	O
+not	POS	O
+.	POS	O
+The	POS	O
+20	POS	O
+-	POS	O
+year	POS	O
+risk	POS	O
+of	POS	O
+CAD	POS	B-NP
+at	POS	O
+diagnosis	POS	O
+of	POS	O
+diabetes	POS	B-NP
+,	POS	O
+using	POS	O
+the	POS	O
+UKPDS	POS	B-NP
+risk	POS	O
+engine	POS	O
+,	POS	O
+was	POS	O
+used	POS	O
+to	POS	O
+match	POS	O
+cases	POS	O
+with	POS	O
+controls	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+76	POS	O
+cases	POS	O
+of	POS	O
+CAD	POS	B-NP
+were	POS	O
+compared	POS	O
+with	POS	O
+152	POS	O
+controls	POS	O
+.	POS	O
+The	POS	O
+hazard	POS	O
+of	POS	O
+developing	POS	O
+CAD	POS	B-NP
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+)	POS	O
+associated	POS	O
+with	POS	O
+initial	POS	O
+treatment	POS	O
+increased	POS	O
+by	POS	O
+2	POS	O
+.	POS	O
+4	POS	O
+-	POS	O
+fold	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+3	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+004	POS	O
+)	POS	O
+with	POS	O
+glibenclamide	POS	O
+;	POS	O
+2	POS	O
+-	POS	O
+fold	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+6	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+099	POS	O
+)	POS	O
+with	POS	O
+glipizide	POS	O
+;	POS	O
+2	POS	O
+.	POS	O
+9	POS	O
+-	POS	O
+fold	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+6	POS	O
+-	POS	O
+5	POS	O
+.	POS	O
+1	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+000	POS	O
+)	POS	O
+with	POS	O
+either	POS	O
+,	POS	O
+and	POS	O
+was	POS	O
+unchanged	POS	O
+with	POS	O
+metformin	POS	O
+.	POS	O
+The	POS	O
+hazard	POS	O
+decreased	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+-	POS	O
+fold	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+7	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+385	POS	O
+)	POS	O
+with	POS	O
+glimepiride	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+4	POS	O
+-	POS	O
+fold	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+192	POS	O
+)	POS	O
+with	POS	O
+gliclazide	POS	O
+,	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+4	POS	O
+-	POS	O
+fold	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+1	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+09	POS	O
+)	POS	O
+with	POS	O
+either	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Initiating	POS	O
+treatment	POS	O
+of	POS	O
+type	POS	B-NP
+2	POS	I-NP
+diabetes	POS	I-NP
+with	POS	O
+glibenclamide	POS	O
+or	POS	O
+glipizide	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+increased	POS	O
+risk	POS	O
+of	POS	O
+CAD	POS	B-NP
+in	POS	O
+comparison	POS	O
+to	POS	O
+gliclazide	POS	O
+or	POS	O
+glimepiride	POS	O
+.	POS	O
+If	POS	O
+confirmed	POS	O
+,	POS	O
+this	POS	O
+may	POS	O
+be	POS	O
+important	POS	O
+because	POS	O
+most	POS	O
+Indian	POS	O
+patients	POS	O
+receive	POS	O
+the	POS	O
+cheaper	POS	O
+older	POS	O
+sulphonylureas	POS	O
+,	POS	O
+and	POS	O
+present	POS	O
+guidelines	POS	O
+do	POS	O
+not	POS	O
+distinguish	POS	O
+between	POS	O
+individual	POS	O
+agents	POS	O
+.	POS	O
+Reduced	POS	O
+progression	POS	O
+of	POS	O
+adriamycin	POS	O
+nephropathy	POS	B-NP
+in	POS	O
+spontaneously	POS	O
+hypertensive	POS	B-NP
+rats	POS	O
+treated	POS	O
+by	POS	O
+losartan	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+the	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+antihypertensive	POS	O
+effects	POS	O
+of	POS	O
+angiotensin	POS	O
+II	POS	O
+type	POS	O
+-	POS	O
+1	POS	O
+receptor	POS	O
+blocker	POS	O
+,	POS	O
+losartan	POS	O
+,	POS	O
+and	POS	O
+its	POS	O
+potential	POS	O
+in	POS	O
+slowing	POS	O
+down	POS	O
+renal	POS	O
+disease	POS	O
+progression	POS	O
+in	POS	O
+spontaneously	POS	O
+hypertensive	POS	B-NP
+rats	POS	O
+(	POS	O
+SHR	POS	O
+)	POS	O
+with	POS	O
+adriamycin	POS	O
+(	POS	O
+ADR	POS	O
+)	POS	O
+nephropathy	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Six	POS	O
+-	POS	O
+month	POS	O
+-	POS	O
+old	POS	O
+female	POS	O
+SHR	POS	O
+were	POS	O
+randomly	POS	O
+selected	POS	O
+in	POS	O
+six	POS	O
+groups	POS	O
+.	POS	O
+Two	POS	O
+control	POS	O
+groups	POS	O
+(	POS	O
+SH	POS	O
+(	POS	O
+6	POS	O
+)	POS	O
+,	POS	O
+SH	POS	O
+(	POS	O
+12	POS	O
+)	POS	O
+)	POS	O
+received	POS	O
+vehicle	POS	O
+.	POS	O
+Groups	POS	O
+ADR	POS	O
+(	POS	O
+6	POS	O
+)	POS	O
+,	POS	O
+ADR	POS	O
++	POS	O
+LOS	POS	O
+(	POS	O
+6	POS	O
+)	POS	O
+and	POS	O
+ADR	POS	O
+(	POS	O
+12	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+ADR	POS	O
++	POS	O
+LOS	POS	O
+(	POS	O
+12	POS	O
+)	POS	O
+received	POS	O
+ADR	POS	O
+(	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+b	POS	O
+.	POS	O
+w	POS	O
+.	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+)	POS	O
+twice	POS	O
+in	POS	O
+a	POS	O
+3	POS	O
+-	POS	O
+week	POS	O
+interval	POS	O
+.	POS	O
+Group	POS	O
+ADR	POS	O
++	POS	O
+LOS	POS	O
+(	POS	O
+6	POS	O
+)	POS	O
+received	POS	O
+losartan	POS	O
+(	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+b	POS	O
+.	POS	O
+w	POS	O
+.	POS	O
+/	POS	O
+day	POS	O
+by	POS	O
+gavages	POS	O
+)	POS	O
+for	POS	O
+6	POS	O
+weeks	POS	O
+and	POS	O
+group	POS	O
+ADR	POS	O
++	POS	O
+LOS	POS	O
+(	POS	O
+12	POS	O
+)	POS	O
+for	POS	O
+12	POS	O
+weeks	POS	O
+after	POS	O
+second	POS	O
+injection	POS	O
+of	POS	O
+ADR	POS	O
+.	POS	O
+Animals	POS	O
+were	POS	O
+killed	POS	O
+after	POS	O
+6	POS	O
+or	POS	O
+12	POS	O
+weeks	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Haemodynamic	POS	O
+measurements	POS	O
+were	POS	O
+performed	POS	O
+on	POS	O
+anaesthetized	POS	O
+animals	POS	O
+,	POS	O
+blood	POS	O
+and	POS	O
+urine	POS	O
+samples	POS	O
+were	POS	O
+taken	POS	O
+for	POS	O
+biochemical	POS	O
+analysis	POS	O
+and	POS	O
+the	POS	O
+left	POS	O
+kidney	POS	O
+was	POS	O
+processed	POS	O
+for	POS	O
+morphological	POS	O
+studies	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Short	POS	O
+-	POS	O
+term	POS	O
+losartan	POS	O
+treatment	POS	O
+,	POS	O
+besides	POS	O
+antihypertensive	POS	O
+effect	POS	O
+,	POS	O
+improved	POS	O
+glomerular	POS	O
+filtration	POS	O
+rate	POS	O
+and	POS	O
+ameliorated	POS	O
+glomerulosclerosis	POS	B-NP
+resulting	POS	O
+in	POS	O
+decreased	POS	O
+proteinuria	POS	B-NP
+.	POS	O
+Prolonged	POS	O
+treatment	POS	O
+with	POS	O
+losartan	POS	O
+showed	POS	O
+further	POS	O
+reduction	POS	O
+of	POS	O
+glomerulosclerosis	POS	B-NP
+associated	POS	O
+with	POS	O
+reduced	POS	O
+progression	POS	O
+of	POS	O
+tubular	POS	B-NP
+atrophy	POS	I-NP
+and	POS	O
+interstitial	POS	B-NP
+fibrosis	POS	I-NP
+,	POS	O
+thus	POS	O
+preventing	POS	O
+heavy	POS	O
+proteinuria	POS	B-NP
+and	POS	O
+chronic	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+Losartan	POS	O
+reduced	POS	O
+uraemia	POS	B-NP
+and	POS	O
+increased	POS	O
+urea	POS	O
+clearance	POS	O
+in	POS	O
+advanced	POS	O
+ADR	POS	O
+nephropathy	POS	B-NP
+in	POS	O
+SHR	POS	O
+.	POS	O
+Histological	POS	O
+examination	POS	O
+showed	POS	O
+that	POS	O
+losartan	POS	O
+could	POS	O
+prevent	POS	O
+tubular	POS	B-NP
+atrophy	POS	I-NP
+,	POS	O
+interstitial	POS	B-NP
+infiltration	POS	I-NP
+and	POS	O
+fibrosis	POS	B-NP
+in	POS	O
+ADR	POS	B-NP
+nephropathy	POS	I-NP
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Losartan	POS	O
+reduces	POS	O
+the	POS	O
+rate	POS	O
+of	POS	O
+progression	POS	O
+of	POS	O
+ADR	POS	O
+-	POS	O
+induced	POS	O
+focal	POS	O
+segmental	POS	O
+glomerulosclerosis	POS	B-NP
+to	POS	O
+end	POS	O
+-	POS	O
+stage	POS	O
+renal	POS	B-NP
+disease	POS	I-NP
+in	POS	O
+SHR	POS	O
+.	POS	O
+The	POS	O
+risks	POS	O
+of	POS	O
+aprotinin	POS	O
+and	POS	O
+tranexamic	POS	O
+acid	POS	O
+in	POS	O
+cardiac	POS	O
+surgery	POS	O
+:	POS	O
+a	POS	O
+one	POS	O
+-	POS	O
+year	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+of	POS	O
+1188	POS	O
+consecutive	POS	O
+patients	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Our	POS	O
+aim	POS	O
+was	POS	O
+to	POS	O
+investigate	POS	O
+postoperative	POS	B-NP
+complications	POS	I-NP
+and	POS	O
+mortality	POS	O
+after	POS	O
+administration	POS	O
+of	POS	O
+aprotinin	POS	O
+compared	POS	O
+to	POS	O
+tranexamic	POS	O
+acid	POS	O
+in	POS	O
+an	POS	O
+unselected	POS	O
+,	POS	O
+consecutive	POS	O
+cohort	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Perioperative	POS	O
+data	POS	O
+from	POS	O
+consecutive	POS	O
+cardiac	POS	O
+surgery	POS	O
+patients	POS	O
+were	POS	O
+prospectively	POS	O
+collected	POS	O
+between	POS	O
+September	POS	O
+2005	POS	O
+and	POS	O
+June	POS	O
+2006	POS	O
+in	POS	O
+a	POS	O
+university	POS	O
+-	POS	O
+affiliated	POS	O
+clinic	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+1188	POS	O
+)	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+first	POS	O
+5	POS	O
+mo	POS	O
+,	POS	O
+596	POS	O
+patients	POS	O
+received	POS	O
+aprotinin	POS	O
+(	POS	O
+Group	POS	O
+A	POS	O
+)	POS	O
+;	POS	O
+in	POS	O
+the	POS	O
+next	POS	O
+5	POS	O
+mo	POS	O
+,	POS	O
+592	POS	O
+patients	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+tranexamic	POS	O
+acid	POS	O
+(	POS	O
+Group	POS	O
+T	POS	O
+)	POS	O
+.	POS	O
+Except	POS	O
+for	POS	O
+antifibrinolytic	POS	O
+therapy	POS	O
+,	POS	O
+the	POS	O
+anesthetic	POS	O
+and	POS	O
+surgical	POS	O
+protocols	POS	O
+remained	POS	O
+unchanged	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+pre	POS	O
+-	POS	O
+and	POS	O
+intraoperative	POS	O
+variables	POS	O
+were	POS	O
+comparable	POS	O
+between	POS	O
+the	POS	O
+treatment	POS	O
+groups	POS	O
+.	POS	O
+Postoperatively	POS	O
+,	POS	O
+a	POS	O
+significantly	POS	O
+higher	POS	O
+incidence	POS	O
+of	POS	O
+seizures	POS	B-NP
+was	POS	O
+found	POS	O
+in	POS	O
+Group	POS	O
+T	POS	O
+(	POS	O
+4	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+vs	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+,	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+This	POS	O
+difference	POS	O
+was	POS	O
+also	POS	O
+significant	POS	O
+in	POS	O
+the	POS	O
+primary	POS	O
+valve	POS	O
+surgery	POS	O
+and	POS	O
+the	POS	O
+high	POS	O
+risk	POS	O
+surgery	POS	O
+subgroups	POS	O
+(	POS	O
+7	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+vs	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+003	POS	O
+;	POS	O
+7	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+vs	POS	O
+2	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+035	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+.	POS	O
+Persistent	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+(	POS	O
+7	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+vs	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+020	POS	O
+)	POS	O
+and	POS	O
+renal	POS	B-NP
+failure	POS	I-NP
+(	POS	O
+9	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+vs	POS	O
+1	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+002	POS	O
+)	POS	O
+were	POS	O
+also	POS	O
+more	POS	O
+common	POS	O
+in	POS	O
+Group	POS	O
+T	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+primary	POS	O
+valve	POS	O
+surgery	POS	O
+subgroup	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+contrary	POS	O
+,	POS	O
+among	POS	O
+primary	POS	O
+coronary	POS	O
+artery	POS	O
+bypass	POS	O
+surgery	POS	O
+patients	POS	O
+,	POS	O
+there	POS	O
+were	POS	O
+more	POS	O
+acute	POS	O
+myocardial	POS	B-NP
+infarctions	POS	I-NP
+and	POS	O
+renal	POS	B-NP
+dysfunction	POS	I-NP
+in	POS	O
+Group	POS	O
+A	POS	O
+(	POS	O
+5	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+vs	POS	O
+2	POS	O
+.	POS	O
+0	POS	O
+%	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+027	POS	O
+;	POS	O
+22	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+vs	POS	O
+15	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+036	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+1	POS	O
+-	POS	O
+yr	POS	O
+mortality	POS	O
+was	POS	O
+significantly	POS	O
+higher	POS	O
+after	POS	O
+aprotinin	POS	O
+treatment	POS	O
+in	POS	O
+the	POS	O
+high	POS	O
+risk	POS	O
+surgery	POS	O
+group	POS	O
+(	POS	O
+17	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+vs	POS	O
+9	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+034	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Both	POS	O
+antifibrinolytic	POS	O
+drugs	POS	O
+bear	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+adverse	POS	O
+outcome	POS	O
+depending	POS	O
+on	POS	O
+the	POS	O
+type	POS	O
+of	POS	O
+cardiac	POS	O
+surgery	POS	O
+.	POS	O
+Administration	POS	O
+of	POS	O
+aprotinin	POS	O
+should	POS	O
+be	POS	O
+avoided	POS	O
+in	POS	O
+coronary	POS	O
+artery	POS	O
+bypass	POS	O
+graft	POS	O
+and	POS	O
+high	POS	O
+risk	POS	O
+patients	POS	O
+,	POS	O
+whereas	POS	O
+administration	POS	O
+of	POS	O
+tranexamic	POS	O
+acid	POS	O
+is	POS	O
+not	POS	O
+recommended	POS	O
+in	POS	O
+valve	POS	O
+surgery	POS	O
+.	POS	O
+Delirium	POS	B-NP
+in	POS	O
+an	POS	O
+elderly	POS	O
+woman	POS	O
+possibly	POS	O
+associated	POS	O
+with	POS	O
+administration	POS	O
+of	POS	O
+misoprostol	POS	O
+.	POS	O
+Misoprostol	POS	O
+has	POS	O
+been	POS	O
+associated	POS	O
+with	POS	O
+adverse	POS	O
+reactions	POS	O
+,	POS	O
+including	POS	O
+gastrointestinal	POS	B-NP
+symptoms	POS	I-NP
+,	POS	O
+gynecologic	POS	B-NP
+problems	POS	I-NP
+,	POS	O
+and	POS	O
+headache	POS	B-NP
+.	POS	O
+Changes	POS	B-NP
+in	POS	I-NP
+mental	POS	I-NP
+status	POS	I-NP
+,	POS	O
+however	POS	O
+,	POS	O
+have	POS	O
+not	POS	O
+been	POS	O
+reported	POS	O
+.	POS	O
+We	POS	O
+present	POS	O
+a	POS	O
+case	POS	O
+in	POS	O
+which	POS	O
+an	POS	O
+89	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+in	POS	O
+a	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+care	POS	O
+facility	POS	O
+became	POS	O
+confused	POS	O
+after	POS	O
+the	POS	O
+initiation	POS	O
+of	POS	O
+misoprostol	POS	O
+therapy	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+change	POS	O
+in	POS	O
+mental	POS	O
+status	POS	O
+was	POS	O
+first	POS	O
+reported	POS	O
+nine	POS	O
+days	POS	O
+after	POS	O
+the	POS	O
+initiation	POS	O
+of	POS	O
+therapy	POS	O
+.	POS	O
+Her	POS	O
+delirium	POS	B-NP
+significantly	POS	O
+improved	POS	O
+after	POS	O
+misoprostol	POS	O
+was	POS	O
+discontinued	POS	O
+and	POS	O
+her	POS	O
+mental	POS	O
+status	POS	O
+returned	POS	O
+to	POS	O
+normal	POS	O
+within	POS	O
+a	POS	O
+week	POS	O
+.	POS	O
+Because	POS	O
+no	POS	O
+other	POS	O
+factors	POS	O
+related	POS	O
+to	POS	O
+this	POS	O
+patient	POS	O
+changed	POS	O
+significantly	POS	O
+,	POS	O
+the	POS	O
+delirium	POS	B-NP
+experienced	POS	O
+by	POS	O
+this	POS	O
+patient	POS	O
+possibly	POS	O
+resulted	POS	O
+from	POS	O
+misoprostol	POS	O
+therapy	POS	O
+.	POS	O
+The	POS	O
+biological	POS	O
+properties	POS	O
+of	POS	O
+the	POS	O
+optical	POS	O
+isomers	POS	O
+of	POS	O
+propranolol	POS	O
+and	POS	O
+their	POS	O
+effects	POS	O
+on	POS	O
+cardiac	POS	B-NP
+arrhythmias	POS	I-NP
+.	POS	O
+1	POS	O
+.	POS	O
+The	POS	O
+optical	POS	O
+isomers	POS	O
+of	POS	O
+propranolol	POS	O
+have	POS	O
+been	POS	O
+compared	POS	O
+for	POS	O
+their	POS	O
+beta	POS	O
+-	POS	O
+blocking	POS	O
+and	POS	O
+antiarrhythmic	POS	O
+activities	POS	O
+.	POS	O
+2	POS	O
+.	POS	O
+In	POS	O
+blocking	POS	O
+the	POS	O
+positive	POS	O
+inotropic	POS	O
+and	POS	O
+chronotropic	POS	O
+responses	POS	O
+to	POS	O
+isoprenaline	POS	O
+,	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+propranolol	POS	O
+had	POS	O
+less	POS	O
+than	POS	O
+one	POS	O
+hundredth	POS	O
+the	POS	O
+potency	POS	O
+of	POS	O
+(	POS	O
+-	POS	O
+)	POS	O
+-	POS	O
+propranolol	POS	O
+.	POS	O
+At	POS	O
+dose	POS	O
+levels	POS	O
+of	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+propranolol	POS	O
+which	POS	O
+attenuated	POS	O
+the	POS	O
+responses	POS	O
+to	POS	O
+isoprenaline	POS	O
+,	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+prolongation	POS	O
+of	POS	O
+the	POS	O
+PR	POS	O
+interval	POS	O
+of	POS	O
+the	POS	O
+electrocardiogram	POS	O
+.	POS	O
+3	POS	O
+.	POS	O
+The	POS	O
+metabolic	POS	O
+responses	POS	O
+to	POS	O
+isoprenaline	POS	O
+in	POS	O
+dogs	POS	O
+(	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+circulating	POS	O
+glucose	POS	O
+,	POS	O
+lactate	POS	O
+and	POS	O
+free	POS	O
+fatty	POS	O
+acids	POS	O
+)	POS	O
+were	POS	O
+all	POS	O
+blocked	POS	O
+by	POS	O
+(	POS	O
+-	POS	O
+)	POS	O
+-	POS	O
+propranolol	POS	O
+.	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+Propranolol	POS	O
+had	POS	O
+no	POS	O
+effect	POS	O
+on	POS	O
+fatty	POS	O
+acid	POS	O
+mobilization	POS	O
+but	POS	O
+significantly	POS	O
+reduced	POS	O
+the	POS	O
+increments	POS	O
+in	POS	O
+both	POS	O
+lactate	POS	O
+and	POS	O
+glucose	POS	O
+.	POS	O
+4	POS	O
+.	POS	O
+Both	POS	O
+isomers	POS	O
+of	POS	O
+propranolol	POS	O
+possessed	POS	O
+similar	POS	O
+depressant	POS	O
+potency	POS	O
+on	POS	O
+isolated	POS	O
+atrial	POS	O
+muscle	POS	O
+taken	POS	O
+from	POS	O
+guinea	POS	O
+-	POS	O
+pigs	POS	O
+.	POS	O
+5	POS	O
+.	POS	O
+The	POS	O
+isomers	POS	O
+of	POS	O
+propranolol	POS	O
+exhibited	POS	O
+similar	POS	O
+local	POS	O
+anaesthetic	POS	O
+potencies	POS	O
+on	POS	O
+an	POS	O
+isolated	POS	O
+frog	POS	O
+nerve	POS	O
+preparation	POS	O
+at	POS	O
+a	POS	O
+level	POS	O
+approximately	POS	O
+three	POS	O
+times	POS	O
+that	POS	O
+of	POS	O
+procaine	POS	O
+.	POS	O
+The	POS	O
+racemic	POS	O
+compound	POS	O
+was	POS	O
+significantly	POS	O
+less	POS	O
+potent	POS	O
+than	POS	O
+either	POS	O
+isomer	POS	O
+.	POS	O
+6	POS	O
+.	POS	O
+Both	POS	O
+isomers	POS	O
+of	POS	O
+propranolol	POS	O
+were	POS	O
+capable	POS	O
+of	POS	O
+preventing	POS	O
+adrenaline	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+arrhythmias	POS	I-NP
+in	POS	O
+cats	POS	O
+anaesthetized	POS	O
+with	POS	O
+halothane	POS	O
+,	POS	O
+but	POS	O
+the	POS	O
+mean	POS	O
+dose	POS	O
+of	POS	O
+(	POS	O
+-	POS	O
+)	POS	O
+-	POS	O
+propranolol	POS	O
+was	POS	O
+0	POS	O
+.	POS	O
+09	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+whereas	POS	O
+that	POS	O
+of	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+propranolol	POS	O
+was	POS	O
+4	POS	O
+.	POS	O
+2	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+At	POS	O
+the	POS	O
+effective	POS	O
+dose	POS	O
+level	POS	O
+of	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+propranolol	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+prolongation	POS	O
+of	POS	O
+the	POS	O
+PR	POS	O
+interval	POS	O
+of	POS	O
+the	POS	O
+electrocardiogram	POS	O
+.	POS	O
+Blockade	POS	O
+of	POS	O
+arrhythmias	POS	B-NP
+with	POS	O
+both	POS	O
+isomers	POS	O
+was	POS	O
+surmountable	POS	O
+by	POS	O
+increasing	POS	O
+the	POS	O
+dose	POS	O
+of	POS	O
+adrenaline	POS	O
+.	POS	O
+7	POS	O
+.	POS	O
+Both	POS	O
+isomers	POS	O
+of	POS	O
+propranolol	POS	O
+were	POS	O
+also	POS	O
+capable	POS	O
+of	POS	O
+reversing	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+caused	POS	O
+by	POS	O
+ouabain	POS	O
+in	POS	O
+anaesthetized	POS	O
+cats	POS	O
+and	POS	O
+dogs	POS	O
+.	POS	O
+The	POS	O
+dose	POS	O
+of	POS	O
+(	POS	O
+-	POS	O
+)	POS	O
+-	POS	O
+propranolol	POS	O
+was	POS	O
+significantly	POS	O
+smaller	POS	O
+than	POS	O
+that	POS	O
+of	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+propranolol	POS	O
+in	POS	O
+both	POS	O
+species	POS	O
+but	POS	O
+much	POS	O
+higher	POS	O
+than	POS	O
+that	POS	O
+required	POS	O
+to	POS	O
+produce	POS	O
+evidence	POS	O
+of	POS	O
+beta	POS	O
+-	POS	O
+blockade	POS	O
+.	POS	O
+8	POS	O
+.	POS	O
+The	POS	O
+implications	POS	O
+of	POS	O
+these	POS	O
+results	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+Topotecan	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+radiotherapy	POS	O
+in	POS	O
+unresectable	POS	O
+glioblastoma	POS	B-NP
+:	POS	O
+a	POS	O
+phase	POS	O
+2	POS	O
+study	POS	O
+.	POS	O
+Improving	POS	O
+glioblastoma	POS	B-NP
+multiforme	POS	I-NP
+(	POS	O
+GBM	POS	B-NP
+)	POS	O
+treatment	POS	O
+with	POS	O
+radio	POS	O
+-	POS	O
+chemotherapy	POS	O
+remains	POS	O
+a	POS	O
+challenge	POS	O
+.	POS	O
+Topotecan	POS	O
+is	POS	O
+an	POS	O
+attractive	POS	O
+option	POS	O
+as	POS	O
+it	POS	O
+exhibits	POS	O
+growth	POS	O
+inhibition	POS	O
+of	POS	O
+human	POS	O
+glioma	POS	B-NP
+as	POS	O
+well	POS	O
+as	POS	O
+brain	POS	O
+penetration	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+assessed	POS	O
+the	POS	O
+combination	POS	O
+of	POS	O
+radiotherapy	POS	O
+(	POS	O
+60	POS	O
+Gy	POS	O
+/	POS	O
+30	POS	O
+fractions	POS	O
+/	POS	O
+40	POS	O
+days	POS	O
+)	POS	O
+and	POS	O
+topotecan	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+/	POS	O
+day	POS	O
+on	POS	O
+days	POS	O
+1	POS	O
+-	POS	O
+5	POS	O
+on	POS	O
+weeks	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+and	POS	O
+5	POS	O
+)	POS	O
+in	POS	O
+50	POS	O
+adults	POS	O
+with	POS	O
+histologically	POS	O
+proven	POS	O
+and	POS	O
+untreated	POS	O
+GBM	POS	B-NP
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+non	POS	B-NP
+-	POS	I-NP
+hematological	POS	I-NP
+toxicities	POS	I-NP
+was	POS	O
+low	POS	O
+and	POS	O
+grade	POS	O
+3	POS	O
+-	POS	O
+4	POS	O
+hematological	POS	B-NP
+toxicities	POS	I-NP
+were	POS	O
+reported	POS	O
+in	POS	O
+20	POS	O
+patients	POS	O
+(	POS	O
+mainly	POS	O
+lymphopenia	POS	B-NP
+and	POS	O
+neutropenia	POS	B-NP
+)	POS	O
+.	POS	O
+Partial	POS	O
+response	POS	O
+and	POS	O
+stabilization	POS	O
+rates	POS	O
+were	POS	O
+2	POS	O
+%	POS	O
+and	POS	O
+32	POS	O
+%	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+with	POS	O
+an	POS	O
+overall	POS	O
+time	POS	O
+to	POS	O
+progression	POS	O
+of	POS	O
+12	POS	O
+weeks	POS	O
+.	POS	O
+One	POS	O
+-	POS	O
+year	POS	O
+overall	POS	O
+survival	POS	O
+(	POS	O
+OS	POS	O
+)	POS	O
+rate	POS	O
+was	POS	O
+42	POS	O
+%	POS	O
+,	POS	O
+with	POS	O
+a	POS	O
+median	POS	O
+OS	POS	O
+of	POS	O
+40	POS	O
+weeks	POS	O
+.	POS	O
+Topotecan	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+radiotherapy	POS	O
+was	POS	O
+well	POS	O
+tolerated	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+while	POS	O
+response	POS	O
+and	POS	O
+stabilization	POS	O
+concerned	POS	O
+one	POS	O
+-	POS	O
+third	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+,	POS	O
+the	POS	O
+study	POS	O
+did	POS	O
+not	POS	O
+show	POS	O
+increased	POS	O
+benefits	POS	O
+in	POS	O
+terms	POS	O
+of	POS	O
+survival	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+unresectable	POS	O
+GBM	POS	B-NP
+.	POS	O
+Long	POS	O
+-	POS	O
+term	POS	O
+lithium	POS	O
+therapy	POS	O
+leading	POS	O
+to	POS	O
+hyperparathyroidism	POS	B-NP
+:	POS	O
+a	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+This	POS	O
+paper	POS	O
+reviews	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+chronic	POS	O
+lithium	POS	O
+therapy	POS	O
+on	POS	O
+serum	POS	O
+calcium	POS	O
+level	POS	O
+and	POS	O
+parathyroid	POS	O
+glands	POS	O
+,	POS	O
+its	POS	O
+pathogenesis	POS	O
+,	POS	O
+and	POS	O
+treatment	POS	O
+options	POS	O
+.	POS	O
+We	POS	O
+examined	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+lithium	POS	O
+-	POS	O
+treated	POS	O
+patient	POS	O
+who	POS	O
+had	POS	O
+recurrent	POS	O
+hypercalcemia	POS	B-NP
+to	POS	O
+better	POS	O
+understand	POS	O
+the	POS	O
+disease	POS	O
+process	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Primary	POS	B-NP
+hyperparathyroidism	POS	I-NP
+is	POS	O
+a	POS	O
+rare	POS	O
+but	POS	O
+potentially	POS	O
+life	POS	O
+-	POS	O
+threatening	POS	O
+side	POS	O
+effect	POS	O
+of	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+lithium	POS	O
+therapy	POS	O
+.	POS	O
+Careful	POS	O
+patient	POS	O
+selection	POS	O
+and	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+can	POS	O
+reduce	POS	O
+morbidity	POS	O
+.	POS	O
+PRACTICAL	POS	O
+IMPLICATIONS	POS	O
+:	POS	O
+As	POS	O
+much	POS	O
+as	POS	O
+15	POS	O
+%	POS	O
+of	POS	O
+lithium	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+become	POS	O
+hypercalcemic	POS	B-NP
+.	POS	O
+By	POS	O
+routinely	POS	O
+monitoring	POS	O
+serum	POS	O
+calcium	POS	O
+levels	POS	O
+,	POS	O
+healthcare	POS	O
+providers	POS	O
+can	POS	O
+improve	POS	O
+the	POS	O
+quality	POS	O
+of	POS	O
+life	POS	O
+of	POS	O
+this	POS	O
+patient	POS	O
+group	POS	O
+.	POS	O
+Comparison	POS	O
+of	POS	O
+laryngeal	POS	O
+mask	POS	O
+with	POS	O
+endotracheal	POS	O
+tube	POS	O
+for	POS	O
+anesthesia	POS	O
+in	POS	O
+endoscopic	POS	O
+sinus	POS	O
+surgery	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+compare	POS	O
+surgical	POS	O
+conditions	POS	O
+,	POS	O
+including	POS	O
+the	POS	O
+amount	POS	O
+of	POS	O
+intraoperative	POS	O
+bleeding	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+intraoperative	POS	O
+blood	POS	O
+pressure	POS	O
+,	POS	O
+during	POS	O
+functional	POS	O
+endoscopic	POS	O
+sinus	POS	O
+surgery	POS	O
+(	POS	O
+FESS	POS	O
+)	POS	O
+using	POS	O
+flexible	POS	O
+reinforced	POS	O
+laryngeal	POS	O
+mask	POS	O
+airway	POS	O
+(	POS	O
+FRLMA	POS	O
+)	POS	O
+versus	POS	O
+endotracheal	POS	O
+tube	POS	O
+(	POS	O
+ETT	POS	O
+)	POS	O
+in	POS	O
+maintaining	POS	O
+controlled	POS	O
+hypotension	POS	B-NP
+anesthesia	POS	O
+induced	POS	O
+by	POS	O
+propofol	POS	O
+-	POS	O
+remifentanil	POS	O
+total	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+anesthesia	POS	O
+(	POS	O
+TIVA	POS	O
+)	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Sixty	POS	O
+normotensive	POS	O
+American	POS	O
+Society	POS	O
+of	POS	O
+Anesthesiologists	POS	O
+I	POS	O
+-	POS	O
+II	POS	O
+adult	POS	O
+patients	POS	O
+undergoing	POS	O
+FESS	POS	B-NP
+under	POS	O
+controlled	POS	O
+hypotension	POS	B-NP
+anesthesia	POS	O
+caused	POS	O
+by	POS	O
+propofol	POS	O
+-	POS	O
+remifentanil	POS	O
+-	POS	O
+TIVA	POS	O
+were	POS	O
+randomly	POS	O
+assigned	POS	O
+into	POS	O
+two	POS	O
+groups	POS	O
+:	POS	O
+group	POS	O
+I	POS	O
+,	POS	O
+FRLMA	POS	O
+;	POS	O
+group	POS	O
+II	POS	O
+,	POS	O
+ETT	POS	O
+.	POS	O
+Hemorrhage	POS	O
+was	POS	O
+measured	POS	O
+and	POS	O
+the	POS	O
+visibility	POS	O
+of	POS	O
+the	POS	O
+operative	POS	O
+field	POS	O
+was	POS	O
+evaluated	POS	O
+according	POS	O
+to	POS	O
+a	POS	O
+six	POS	O
+-	POS	O
+point	POS	O
+scale	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Controlled	POS	O
+hypotension	POS	B-NP
+was	POS	O
+achieved	POS	O
+within	POS	O
+a	POS	O
+shorter	POS	O
+period	POS	O
+using	POS	O
+laryngeal	POS	O
+mask	POS	O
+using	POS	O
+lower	POS	O
+rates	POS	O
+of	POS	O
+remifentanil	POS	O
+infusion	POS	O
+and	POS	O
+lower	POS	O
+total	POS	O
+dose	POS	O
+of	POS	O
+remifentanil	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+In	POS	O
+summary	POS	O
+,	POS	O
+our	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+airway	POS	O
+management	POS	O
+using	POS	O
+FRLMA	POS	O
+during	POS	O
+controlled	POS	O
+hypotension	POS	B-NP
+anesthesia	POS	O
+provided	POS	O
+better	POS	O
+surgical	POS	O
+conditions	POS	O
+in	POS	O
+terms	POS	O
+of	POS	O
+quality	POS	O
+of	POS	O
+operative	POS	O
+field	POS	O
+and	POS	O
+blood	POS	O
+loss	POS	O
+and	POS	O
+allowed	POS	O
+for	POS	O
+convenient	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+with	POS	O
+low	POS	O
+doses	POS	O
+of	POS	O
+remifentanil	POS	O
+during	POS	O
+TIVA	POS	O
+in	POS	O
+patients	POS	O
+undergoing	POS	O
+FESS	POS	B-NP
+.	POS	O
+Nonalcoholic	POS	B-NP
+fatty	POS	I-NP
+liver	POS	I-NP
+disease	POS	I-NP
+during	POS	O
+valproate	POS	O
+therapy	POS	O
+.	POS	O
+Valproic	POS	O
+acid	POS	O
+(	POS	O
+VPA	POS	O
+)	POS	O
+is	POS	O
+effective	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+many	POS	O
+types	POS	O
+of	POS	O
+epilepsy	POS	B-NP
+,	POS	O
+but	POS	O
+its	POS	O
+use	POS	O
+can	POS	O
+be	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+body	POS	O
+weight	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+nonalcoholic	POS	B-NP
+fatty	POS	I-NP
+liver	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+NAFLD	POS	B-NP
+)	POS	O
+arising	POS	O
+in	POS	O
+a	POS	O
+child	POS	O
+who	POS	O
+developed	POS	O
+obesity	POS	B-NP
+during	POS	O
+VPA	POS	O
+treatment	POS	O
+.	POS	O
+Laboratory	POS	O
+data	POS	O
+revealed	POS	O
+hyperinsulinemia	POS	B-NP
+with	POS	O
+insulin	POS	B-NP
+resistance	POS	I-NP
+.	POS	O
+After	POS	O
+the	POS	O
+withdrawal	POS	O
+of	POS	O
+VPA	POS	O
+therapy	POS	O
+,	POS	O
+our	POS	O
+patient	POS	O
+showed	POS	O
+a	POS	O
+significant	POS	O
+weight	POS	B-NP
+loss	POS	I-NP
+,	POS	O
+a	POS	O
+decrease	POS	O
+of	POS	O
+body	POS	O
+mass	POS	O
+index	POS	O
+,	POS	O
+and	POS	O
+normalization	POS	O
+of	POS	O
+metabolic	POS	O
+and	POS	O
+endocrine	POS	O
+parameters	POS	O
+;	POS	O
+moreover	POS	O
+,	POS	O
+ultrasound	POS	O
+measurements	POS	O
+showed	POS	O
+a	POS	O
+complete	POS	O
+normalization	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+case	POS	O
+suggests	POS	O
+that	POS	O
+obesity	POS	B-NP
+,	POS	O
+hyperinsulinemia	POS	B-NP
+,	POS	O
+insulin	POS	B-NP
+resistance	POS	I-NP
+,	POS	O
+and	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+treatment	POS	O
+with	POS	O
+VPA	POS	O
+may	POS	O
+be	POS	O
+all	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+NAFLD	POS	B-NP
+;	POS	O
+this	POS	O
+side	POS	O
+effect	POS	O
+is	POS	O
+reversible	POS	O
+after	POS	O
+VPA	POS	O
+withdrawal	POS	O
+.	POS	O
+Carbimazole	POS	O
+induced	POS	O
+ANCA	POS	B-NP
+positive	POS	O
+vasculitis	POS	B-NP
+.	POS	O
+Anti	POS	O
+-	POS	O
+thyroid	POS	O
+drugs	POS	O
+,	POS	O
+like	POS	O
+carbimazole	POS	O
+and	POS	O
+propylthiouracil	POS	O
+(	POS	O
+PTU	POS	B-NP
+)	POS	O
+are	POS	O
+commonly	POS	O
+prescribed	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+hyperthyroidism	POS	B-NP
+.	POS	O
+One	POS	O
+should	POS	O
+be	POS	O
+aware	POS	O
+of	POS	O
+the	POS	O
+side	POS	O
+effects	POS	O
+of	POS	O
+antithyroid	POS	O
+medications	POS	O
+.	POS	O
+Antineutrophil	POS	O
+cytoplasmic	POS	O
+antibody	POS	O
+(	POS	O
+ANCA	POS	B-NP
+)	POS	I-NP
+-	POS	I-NP
+-	POS	I-NP
+associated	POS	I-NP
+vasculitis	POS	I-NP
+is	POS	O
+a	POS	O
+potentially	POS	O
+life	POS	O
+-	POS	O
+threatening	POS	O
+adverse	POS	O
+effect	POS	O
+of	POS	O
+antithyroidmedications	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+Graves	POS	B-NP
+'	POS	I-NP
+disease	POS	I-NP
+who	POS	O
+developed	POS	O
+ANCA	POS	B-NP
+positive	POS	O
+carbimazole	POS	O
+induced	POS	O
+vasculitis	POS	B-NP
+.	POS	O
+The	POS	O
+episode	POS	O
+was	POS	O
+characterized	POS	O
+by	POS	O
+a	POS	O
+vasculitic	POS	B-NP
+skin	POS	I-NP
+rash	POS	I-NP
+associated	POS	O
+with	POS	O
+large	POS	O
+joint	POS	B-NP
+arthritis	POS	I-NP
+,	POS	O
+pyrexia	POS	B-NP
+and	POS	O
+parotiditis	POS	B-NP
+but	POS	O
+no	POS	O
+renal	POS	O
+or	POS	O
+pulmonary	POS	B-NP
+involvement	POS	I-NP
+.	POS	O
+He	POS	O
+was	POS	O
+referred	POS	O
+to	POS	O
+us	POS	O
+for	POS	O
+neurological	POS	O
+evaluation	POS	O
+because	POS	O
+he	POS	O
+had	POS	O
+difficulty	POS	O
+in	POS	O
+getting	POS	O
+up	POS	O
+from	POS	O
+squatting	POS	O
+position	POS	O
+and	POS	O
+was	POS	O
+suspected	POS	O
+to	POS	O
+have	POS	O
+myositis	POS	B-NP
+.	POS	O
+Carbimazole	POS	O
+and	POS	O
+methimazole	POS	O
+have	POS	O
+a	POS	O
+lower	POS	O
+incidence	POS	O
+of	POS	O
+reported	POS	O
+ANCA	POS	B-NP
+positive	POS	O
+side	POS	O
+effects	POS	O
+than	POS	O
+PUT	POS	O
+.	POS	O
+To	POS	O
+the	POS	O
+best	POS	O
+of	POS	O
+our	POS	O
+knowledge	POS	O
+this	POS	O
+is	POS	O
+the	POS	O
+first	POS	O
+ANCA	POS	B-NP
+positive	POS	O
+carbimazole	POS	O
+induced	POS	O
+vasculitis	POS	B-NP
+case	POS	O
+reported	POS	O
+from	POS	O
+India	POS	O
+.	POS	O
+Aspirin	POS	O
+for	POS	O
+the	POS	O
+primary	POS	O
+prevention	POS	O
+of	POS	O
+cardiovascular	POS	O
+events	POS	O
+:	POS	O
+an	POS	O
+update	POS	O
+of	POS	O
+the	POS	O
+evidence	POS	O
+for	POS	O
+the	POS	O
+U	POS	O
+.	POS	O
+S	POS	O
+.	POS	O
+Preventive	POS	O
+Services	POS	O
+Task	POS	O
+Force	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Coronary	POS	B-NP
+heart	POS	I-NP
+disease	POS	I-NP
+and	POS	O
+cerebrovascular	POS	B-NP
+disease	POS	I-NP
+are	POS	O
+leading	POS	O
+causes	POS	O
+of	POS	O
+death	POS	O
+in	POS	O
+the	POS	O
+United	POS	O
+States	POS	O
+.	POS	O
+In	POS	O
+2002	POS	O
+,	POS	O
+the	POS	O
+U	POS	O
+.	POS	O
+S	POS	O
+.	POS	O
+Preventive	POS	O
+Services	POS	O
+Task	POS	O
+Force	POS	O
+(	POS	O
+USPSTF	POS	O
+)	POS	O
+strongly	POS	O
+recommended	POS	O
+that	POS	O
+clinicians	POS	O
+discuss	POS	O
+aspirin	POS	O
+with	POS	O
+adults	POS	O
+who	POS	O
+are	POS	O
+at	POS	O
+increased	POS	O
+risk	POS	O
+for	POS	O
+coronary	POS	B-NP
+heart	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+To	POS	O
+determine	POS	O
+the	POS	O
+benefits	POS	O
+and	POS	O
+harms	POS	O
+of	POS	O
+taking	POS	O
+aspirin	POS	O
+for	POS	O
+the	POS	O
+primary	POS	O
+prevention	POS	O
+of	POS	O
+myocardial	POS	B-NP
+infarctions	POS	I-NP
+,	POS	O
+strokes	POS	B-NP
+,	POS	O
+and	POS	O
+death	POS	O
+.	POS	O
+DATA	POS	O
+SOURCES	POS	O
+:	POS	O
+MEDLINE	POS	O
+and	POS	O
+Cochrane	POS	O
+Library	POS	O
+(	POS	O
+search	POS	O
+dates	POS	O
+,	POS	O
+1	POS	O
+January	POS	O
+2001	POS	O
+to	POS	O
+28	POS	O
+August	POS	O
+2008	POS	O
+)	POS	O
+,	POS	O
+recent	POS	O
+systematic	POS	O
+reviews	POS	O
+,	POS	O
+reference	POS	O
+lists	POS	O
+of	POS	O
+retrieved	POS	O
+articles	POS	O
+,	POS	O
+and	POS	O
+suggestions	POS	O
+from	POS	O
+experts	POS	O
+.	POS	O
+STUDY	POS	O
+SELECTION	POS	O
+:	POS	O
+English	POS	O
+-	POS	O
+language	POS	O
+randomized	POS	O
+,	POS	O
+controlled	POS	O
+trials	POS	O
+(	POS	O
+RCTs	POS	O
+)	POS	O
+;	POS	O
+case	POS	O
+-	POS	O
+control	POS	O
+studies	POS	O
+;	POS	O
+meta	POS	O
+-	POS	O
+analyses	POS	O
+;	POS	O
+and	POS	O
+systematic	POS	O
+reviews	POS	O
+of	POS	O
+aspirin	POS	O
+versus	POS	O
+control	POS	O
+for	POS	O
+the	POS	O
+primary	POS	O
+prevention	POS	O
+of	POS	O
+cardiovascular	POS	B-NP
+disease	POS	I-NP
+(	POS	O
+CVD	POS	B-NP
+)	POS	O
+were	POS	O
+selected	POS	O
+to	POS	O
+answer	POS	O
+the	POS	O
+following	POS	O
+questions	POS	O
+:	POS	O
+Does	POS	O
+aspirin	POS	O
+decrease	POS	O
+coronary	POS	B-NP
+heart	POS	I-NP
+events	POS	I-NP
+,	POS	O
+strokes	POS	B-NP
+,	POS	O
+death	POS	B-NP
+from	POS	O
+coronary	POS	B-NP
+heart	POS	I-NP
+events	POS	I-NP
+or	POS	O
+stroke	POS	B-NP
+,	POS	O
+or	POS	O
+all	POS	O
+-	POS	O
+cause	POS	O
+mortality	POS	O
+in	POS	O
+adults	POS	O
+without	POS	O
+known	POS	O
+CVD	POS	B-NP
+?	POS	O
+Does	POS	O
+aspirin	POS	O
+increase	POS	O
+gastrointestinal	POS	B-NP
+bleeding	POS	I-NP
+or	POS	O
+hemorrhagic	POS	B-NP
+strokes	POS	I-NP
+?	POS	O
+DATA	POS	O
+EXTRACTION	POS	O
+:	POS	O
+All	POS	O
+studies	POS	O
+were	POS	O
+reviewed	POS	O
+,	POS	O
+abstracted	POS	O
+,	POS	O
+and	POS	O
+rated	POS	O
+for	POS	O
+quality	POS	O
+by	POS	O
+using	POS	O
+predefined	POS	O
+USPSTF	POS	O
+criteria	POS	O
+.	POS	O
+DATA	POS	O
+SYNTHESIS	POS	O
+:	POS	O
+New	POS	O
+evidence	POS	O
+from	POS	O
+1	POS	O
+good	POS	O
+-	POS	O
+quality	POS	O
+RCT	POS	O
+,	POS	O
+1	POS	O
+good	POS	O
+-	POS	O
+quality	POS	O
+meta	POS	O
+-	POS	O
+analysis	POS	O
+,	POS	O
+and	POS	O
+2	POS	O
+fair	POS	O
+-	POS	O
+quality	POS	O
+subanalyses	POS	O
+of	POS	O
+RCTs	POS	O
+demonstrates	POS	O
+that	POS	O
+aspirin	POS	O
+use	POS	O
+reduces	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+CVD	POS	B-NP
+events	POS	O
+in	POS	O
+patients	POS	O
+without	POS	O
+known	POS	O
+CVD	POS	B-NP
+.	POS	O
+Men	POS	O
+in	POS	O
+these	POS	O
+studies	POS	O
+experienced	POS	O
+fewer	POS	O
+myocardial	POS	B-NP
+infarctions	POS	I-NP
+and	POS	O
+women	POS	O
+experienced	POS	O
+fewer	POS	O
+ischemic	POS	B-NP
+strokes	POS	I-NP
+.	POS	O
+Aspirin	POS	B-NP
+does	POS	O
+not	POS	O
+seem	POS	O
+to	POS	O
+affect	POS	O
+CVD	POS	B-NP
+mortality	POS	O
+or	POS	O
+all	POS	O
+-	POS	O
+cause	POS	O
+mortality	POS	O
+in	POS	O
+either	POS	O
+men	POS	O
+or	POS	O
+women	POS	O
+.	POS	O
+The	POS	O
+use	POS	O
+of	POS	O
+aspirin	POS	O
+for	POS	O
+primary	POS	O
+prevention	POS	O
+increases	POS	O
+the	POS	O
+risk	POS	O
+for	POS	O
+major	POS	O
+bleeding	POS	O
+events	POS	O
+,	POS	O
+primarily	POS	O
+gastrointestinal	POS	B-NP
+bleeding	POS	I-NP
+events	POS	O
+,	POS	O
+in	POS	O
+both	POS	O
+men	POS	O
+and	POS	O
+women	POS	O
+.	POS	O
+Men	POS	O
+have	POS	O
+an	POS	O
+increased	POS	O
+risk	POS	O
+for	POS	O
+hemorrhagic	POS	B-NP
+strokes	POS	I-NP
+with	POS	O
+aspirin	POS	O
+use	POS	O
+.	POS	O
+A	POS	O
+new	POS	O
+RCT	POS	O
+and	POS	O
+meta	POS	O
+-	POS	O
+analysis	POS	O
+suggest	POS	O
+that	POS	O
+the	POS	O
+risk	POS	O
+for	POS	O
+hemorrhagic	POS	B-NP
+strokes	POS	I-NP
+in	POS	O
+women	POS	O
+is	POS	O
+not	POS	O
+statistically	POS	O
+significantly	POS	O
+increased	POS	O
+.	POS	O
+LIMITATIONS	POS	O
+:	POS	O
+New	POS	O
+evidence	POS	O
+on	POS	O
+aspirin	POS	O
+for	POS	O
+the	POS	O
+primary	POS	O
+prevention	POS	O
+of	POS	O
+CVD	POS	B-NP
+is	POS	O
+limited	POS	O
+.	POS	O
+The	POS	O
+dose	POS	O
+of	POS	O
+aspirin	POS	O
+used	POS	O
+in	POS	O
+the	POS	O
+RCTs	POS	O
+varied	POS	O
+,	POS	O
+which	POS	O
+prevented	POS	O
+the	POS	O
+estimation	POS	O
+of	POS	O
+the	POS	O
+most	POS	O
+appropriate	POS	O
+dose	POS	O
+for	POS	O
+primary	POS	O
+prevention	POS	O
+.	POS	O
+Several	POS	O
+of	POS	O
+the	POS	O
+RCTs	POS	O
+were	POS	O
+conducted	POS	O
+within	POS	O
+populations	POS	O
+of	POS	O
+health	POS	O
+professionals	POS	O
+,	POS	O
+which	POS	O
+potentially	POS	O
+limits	POS	O
+generalizability	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Aspirin	POS	O
+reduces	POS	O
+the	POS	O
+risk	POS	O
+for	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+in	POS	O
+men	POS	O
+and	POS	O
+strokes	POS	B-NP
+in	POS	O
+women	POS	O
+.	POS	O
+Aspirin	POS	O
+use	POS	O
+increases	POS	O
+the	POS	O
+risk	POS	O
+for	POS	O
+serious	POS	O
+bleeding	POS	B-NP
+events	POS	O
+.	POS	O
+Reducing	POS	O
+harm	POS	O
+associated	POS	O
+with	POS	O
+anticoagulation	POS	O
+:	POS	O
+practical	POS	O
+considerations	POS	O
+of	POS	O
+argatroban	POS	O
+therapy	POS	O
+in	POS	O
+heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+.	POS	O
+Argatroban	POS	O
+is	POS	O
+a	POS	O
+hepatically	POS	O
+metabolized	POS	O
+,	POS	O
+direct	POS	O
+thrombin	POS	O
+inhibitor	POS	O
+used	POS	O
+for	POS	O
+prophylaxis	POS	O
+or	POS	O
+treatment	POS	O
+of	POS	O
+thrombosis	POS	B-NP
+in	POS	O
+heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+(	POS	O
+HIT	POS	B-NP
+)	POS	O
+and	POS	O
+for	POS	O
+patients	POS	O
+with	POS	O
+or	POS	O
+at	POS	O
+risk	POS	O
+of	POS	O
+HIT	POS	B-NP
+undergoing	POS	O
+percutaneous	POS	O
+coronary	POS	O
+intervention	POS	O
+(	POS	O
+PCI	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+objective	POS	O
+of	POS	O
+this	POS	O
+review	POS	O
+is	POS	O
+to	POS	O
+summarize	POS	O
+practical	POS	O
+considerations	POS	O
+of	POS	O
+argatroban	POS	O
+therapy	POS	O
+in	POS	O
+HIT	POS	B-NP
+.	POS	O
+The	POS	O
+US	POS	O
+FDA	POS	O
+-	POS	O
+recommended	POS	O
+argatroban	POS	O
+dose	POS	O
+in	POS	O
+HIT	POS	B-NP
+is	POS	O
+2	POS	O
+microg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+(	POS	O
+reduced	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+hepatic	POS	B-NP
+impairment	POS	I-NP
+and	POS	O
+in	POS	O
+paediatric	POS	O
+patients	POS	O
+)	POS	O
+,	POS	O
+adjusted	POS	O
+to	POS	O
+achieve	POS	O
+activated	POS	O
+partial	POS	O
+thromboplastin	POS	O
+times	POS	O
+(	POS	O
+aPTTs	POS	O
+)	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+3	POS	O
+times	POS	O
+baseline	POS	O
+(	POS	O
+not	POS	O
+>	POS	O
+100	POS	O
+seconds	POS	O
+)	POS	O
+.	POS	O
+Contemporary	POS	O
+experiences	POS	O
+indicate	POS	O
+that	POS	O
+reduced	POS	O
+doses	POS	O
+are	POS	O
+also	POS	O
+needed	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+conditions	POS	O
+associated	POS	O
+with	POS	O
+hepatic	POS	B-NP
+hypoperfusion	POS	I-NP
+,	POS	O
+e	POS	O
+.	POS	O
+g	POS	O
+.	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+,	POS	O
+yet	POS	O
+are	POS	O
+unnecessary	POS	O
+for	POS	O
+renal	POS	B-NP
+dysfunction	POS	I-NP
+,	POS	O
+adult	POS	O
+age	POS	O
+,	POS	O
+sex	POS	O
+,	POS	O
+race	POS	O
+/	POS	O
+ethnicity	POS	O
+or	POS	O
+obesity	POS	B-NP
+.	POS	O
+Argatroban	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+microg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+typically	POS	O
+supports	POS	O
+therapeutic	POS	O
+aPTTs	POS	O
+.	POS	O
+The	POS	O
+FDA	POS	O
+-	POS	O
+recommended	POS	O
+dose	POS	O
+during	POS	O
+PCI	POS	O
+is	POS	O
+25	POS	O
+microg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+(	POS	O
+350	POS	O
+microg	POS	O
+/	POS	O
+kg	POS	O
+initial	POS	O
+bolus	POS	O
+)	POS	O
+,	POS	O
+adjusted	POS	O
+to	POS	O
+achieve	POS	O
+activated	POS	O
+clotting	POS	O
+times	POS	O
+(	POS	O
+ACTs	POS	O
+)	POS	O
+of	POS	O
+300	POS	O
+-	POS	O
+450	POS	O
+sec	POS	O
+.	POS	O
+For	POS	O
+PCI	POS	O
+,	POS	O
+argatroban	POS	O
+has	POS	O
+not	POS	O
+been	POS	O
+investigated	POS	O
+in	POS	O
+hepatically	POS	O
+impaired	POS	O
+patients	POS	O
+;	POS	O
+dose	POS	O
+adjustment	POS	O
+is	POS	O
+unnecessary	POS	O
+for	POS	O
+adult	POS	O
+age	POS	O
+,	POS	O
+sex	POS	O
+,	POS	O
+race	POS	O
+/	POS	O
+ethnicity	POS	O
+or	POS	O
+obesity	POS	B-NP
+,	POS	O
+and	POS	O
+lesser	POS	O
+doses	POS	O
+may	POS	O
+be	POS	O
+adequate	POS	O
+with	POS	O
+concurrent	POS	O
+glycoprotein	POS	O
+IIb	POS	O
+/	POS	O
+IIIa	POS	O
+inhibition	POS	O
+.	POS	O
+Argatroban	POS	O
+prolongs	POS	O
+the	POS	O
+International	POS	O
+Normalized	POS	O
+Ratio	POS	O
+,	POS	O
+and	POS	O
+published	POS	O
+approaches	POS	O
+for	POS	O
+monitoring	POS	O
+the	POS	O
+argatroban	POS	O
+-	POS	O
+to	POS	O
+-	POS	O
+warfarin	POS	O
+transition	POS	O
+should	POS	O
+be	POS	O
+followed	POS	O
+.	POS	O
+Major	POS	O
+bleeding	POS	O
+with	POS	O
+argatroban	POS	O
+is	POS	O
+0	POS	O
+-	POS	O
+10	POS	O
+%	POS	O
+in	POS	O
+the	POS	O
+non	POS	O
+-	POS	O
+interventional	POS	O
+setting	POS	O
+and	POS	O
+0	POS	O
+-	POS	O
+5	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+periprocedurally	POS	O
+.	POS	O
+Argatroban	POS	O
+has	POS	O
+no	POS	O
+specific	POS	O
+antidote	POS	O
+,	POS	O
+and	POS	O
+if	POS	O
+excessive	POS	O
+anticoagulation	POS	O
+occurs	POS	O
+,	POS	O
+argatroban	POS	O
+infusion	POS	O
+should	POS	O
+be	POS	O
+stopped	POS	O
+or	POS	O
+reduced	POS	O
+.	POS	O
+Improved	POS	O
+familiarity	POS	O
+of	POS	O
+healthcare	POS	O
+professionals	POS	O
+with	POS	O
+argatroban	POS	O
+therapy	POS	O
+in	POS	O
+HIT	POS	B-NP
+,	POS	O
+including	POS	O
+in	POS	O
+special	POS	O
+populations	POS	O
+and	POS	O
+during	POS	O
+PCI	POS	O
+,	POS	O
+may	POS	O
+facilitate	POS	O
+reduction	POS	O
+of	POS	O
+harm	POS	O
+associated	POS	O
+with	POS	O
+HIT	POS	B-NP
+(	POS	O
+e	POS	O
+.	POS	O
+g	POS	O
+.	POS	O
+fewer	POS	O
+thromboses	POS	B-NP
+)	POS	O
+or	POS	O
+its	POS	O
+treatment	POS	O
+(	POS	O
+e	POS	O
+.	POS	O
+g	POS	O
+.	POS	O
+fewer	POS	O
+argatroban	POS	O
+medication	POS	O
+errors	POS	O
+)	POS	O
+.	POS	O
+Rhabdomyolysis	POS	B-NP
+and	POS	O
+brain	POS	B-NP
+ischemic	POS	I-NP
+stroke	POS	I-NP
+in	POS	O
+a	POS	O
+heroin	POS	O
+-	POS	O
+dependent	POS	O
+male	POS	O
+under	POS	O
+methadone	POS	O
+maintenance	POS	O
+therapy	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+There	POS	O
+are	POS	O
+several	POS	O
+complications	POS	O
+associated	POS	O
+with	POS	O
+heroin	POS	B-NP
+abuse	POS	I-NP
+,	POS	O
+some	POS	O
+of	POS	O
+which	POS	O
+are	POS	O
+life	POS	O
+-	POS	O
+threatening	POS	O
+.	POS	O
+Methadone	POS	O
+may	POS	O
+aggravate	POS	O
+this	POS	O
+problem	POS	O
+.	POS	O
+METHOD	POS	O
+:	POS	O
+A	POS	O
+clinical	POS	O
+case	POS	O
+description	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+A	POS	O
+33	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+presented	POS	O
+with	POS	O
+rhabdomyolysis	POS	B-NP
+and	POS	O
+cerebral	POS	B-NP
+ischemic	POS	I-NP
+stroke	POS	I-NP
+after	POS	O
+intravenous	POS	O
+heroin	POS	O
+.	POS	O
+He	POS	O
+had	POS	O
+used	POS	O
+heroin	POS	O
+since	POS	O
+age	POS	O
+20	POS	O
+,	POS	O
+and	POS	O
+had	POS	O
+used	POS	O
+150	POS	O
+mg	POS	O
+methadone	POS	O
+daily	POS	O
+for	POS	O
+6	POS	O
+months	POS	O
+.	POS	O
+He	POS	O
+was	POS	O
+found	POS	O
+unconsciousness	POS	B-NP
+at	POS	O
+home	POS	O
+and	POS	O
+was	POS	O
+sent	POS	O
+to	POS	O
+our	POS	O
+hospital	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+ER	POS	O
+,	POS	O
+his	POS	O
+opiate	POS	O
+level	POS	O
+was	POS	O
+4497	POS	O
+ng	POS	O
+/	POS	O
+ml	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+ICU	POS	O
+,	POS	O
+we	POS	O
+found	POS	O
+rhabdomyolysis	POS	B-NP
+,	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+and	POS	O
+acute	POS	B-NP
+respiratory	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+After	POS	O
+transfer	POS	O
+to	POS	O
+an	POS	O
+internal	POS	O
+ward	POS	O
+,	POS	O
+we	POS	O
+noted	POS	O
+aphasia	POS	B-NP
+and	POS	O
+weakness	POS	B-NP
+of	POS	I-NP
+his	POS	I-NP
+left	POS	I-NP
+limbs	POS	I-NP
+.	POS	O
+After	POS	O
+MRI	POS	O
+,	POS	O
+we	POS	O
+found	POS	O
+cerebral	POS	B-NP
+ischemic	POS	I-NP
+infarction	POS	I-NP
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Those	POS	O
+using	POS	O
+methadone	POS	O
+and	POS	O
+heroin	POS	O
+simultaneously	POS	O
+may	POS	O
+increase	POS	O
+risk	POS	O
+of	POS	O
+rhabdomyolysis	POS	B-NP
+and	POS	O
+ischemic	POS	B-NP
+stroke	POS	I-NP
+.	POS	O
+Patients	POS	O
+under	POS	O
+methadone	POS	O
+maintenance	POS	O
+therapy	POS	O
+should	POS	O
+be	POS	O
+warned	POS	O
+regarding	POS	O
+these	POS	O
+serious	POS	O
+adverse	POS	O
+events	POS	O
+.	POS	O
+Hypotheses	POS	O
+of	POS	O
+heroin	POS	O
+-	POS	O
+related	POS	O
+rhabdomyolysis	POS	B-NP
+and	POS	O
+stroke	POS	B-NP
+in	POS	O
+heroin	POS	O
+abusers	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+Increased	POS	O
+vulnerability	POS	O
+to	POS	O
+6	POS	O
+-	POS	O
+hydroxydopamine	POS	O
+lesion	POS	O
+and	POS	O
+reduced	POS	O
+development	POS	O
+of	POS	O
+dyskinesias	POS	B-NP
+in	POS	O
+mice	POS	O
+lacking	POS	O
+CB1	POS	O
+cannabinoid	POS	O
+receptors	POS	O
+.	POS	O
+Motor	POS	B-NP
+impairment	POS	I-NP
+,	POS	O
+dopamine	POS	O
+(	POS	O
+DA	POS	O
+)	POS	O
+neuronal	POS	O
+activity	POS	O
+and	POS	O
+proenkephalin	POS	O
+(	POS	O
+PENK	POS	O
+)	POS	O
+gene	POS	O
+expression	POS	O
+in	POS	O
+the	POS	O
+caudate	POS	O
+-	POS	O
+putamen	POS	O
+(	POS	O
+CPu	POS	O
+)	POS	O
+were	POS	O
+measured	POS	O
+in	POS	O
+6	POS	O
+-	POS	O
+OHDA	POS	O
+-	POS	O
+lesioned	POS	O
+and	POS	O
+treated	POS	O
+(	POS	O
+L	POS	O
+-	POS	O
+DOPA	POS	O
++	POS	O
+benserazide	POS	O
+)	POS	O
+CB1	POS	O
+KO	POS	O
+and	POS	O
+WT	POS	O
+mice	POS	O
+.	POS	O
+A	POS	O
+lesion	POS	O
+induced	POS	O
+by	POS	O
+6	POS	O
+-	POS	O
+OHDA	POS	O
+produced	POS	O
+more	POS	O
+severe	POS	O
+motor	POS	O
+deterioration	POS	O
+in	POS	O
+CB1	POS	O
+KO	POS	O
+mice	POS	O
+accompanied	POS	O
+by	POS	O
+more	POS	O
+loss	POS	O
+of	POS	O
+DA	POS	O
+neurons	POS	O
+and	POS	O
+increased	POS	O
+PENK	POS	O
+gene	POS	O
+expression	POS	O
+in	POS	O
+the	POS	O
+CPu	POS	O
+.	POS	O
+Oxidative	POS	O
+/	POS	O
+nitrosative	POS	O
+and	POS	O
+neuroinflammatory	POS	O
+parameters	POS	O
+were	POS	O
+estimated	POS	O
+in	POS	O
+the	POS	O
+CPu	POS	O
+and	POS	O
+cingulate	POS	O
+cortex	POS	O
+(	POS	O
+Cg	POS	O
+)	POS	O
+.	POS	O
+CB1	POS	O
+KO	POS	O
+mice	POS	O
+exhibited	POS	O
+higher	POS	O
+MDA	POS	O
+levels	POS	O
+and	POS	O
+iNOS	POS	O
+protein	POS	O
+expression	POS	O
+in	POS	O
+the	POS	O
+CPu	POS	O
+and	POS	O
+Cg	POS	O
+compared	POS	O
+to	POS	O
+WT	POS	O
+mice	POS	O
+.	POS	O
+Treatment	POS	O
+with	POS	O
+L	POS	O
+-	POS	O
+DOPA	POS	O
++	POS	O
+benserazide	POS	O
+(	POS	O
+12	POS	O
+weeks	POS	O
+)	POS	O
+resulted	POS	O
+in	POS	O
+less	POS	O
+severe	POS	O
+dyskinesias	POS	B-NP
+in	POS	O
+CB1	POS	O
+KO	POS	O
+than	POS	O
+in	POS	O
+WT	POS	O
+mice	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+revealed	POS	O
+that	POS	O
+the	POS	O
+lack	POS	O
+of	POS	O
+cannabinoid	POS	O
+CB1	POS	O
+receptors	POS	O
+increased	POS	O
+the	POS	O
+severity	POS	O
+of	POS	O
+motor	POS	O
+impairment	POS	O
+and	POS	O
+DA	POS	O
+lesion	POS	O
+,	POS	O
+and	POS	O
+reduced	POS	O
+L	POS	O
+-	POS	O
+DOPA	POS	O
+-	POS	O
+induced	POS	O
+dyskinesias	POS	B-NP
+.	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+activation	POS	O
+of	POS	O
+CB1	POS	O
+receptors	POS	O
+offers	POS	O
+neuroprotection	POS	O
+against	POS	O
+dopaminergic	POS	O
+lesion	POS	O
+and	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+L	POS	O
+-	POS	O
+DOPA	POS	O
+-	POS	O
+induced	POS	O
+dyskinesias	POS	B-NP
+.	POS	O
+Hepatocellular	POS	O
+oxidant	POS	O
+stress	POS	O
+following	POS	O
+intestinal	POS	B-NP
+ischemia	POS	I-NP
+-	POS	O
+reperfusion	POS	B-NP
+injury	POS	I-NP
+.	POS	O
+Reperfusion	POS	O
+of	POS	O
+ischemic	POS	O
+intestine	POS	O
+results	POS	O
+in	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+dysfunction	POS	I-NP
+characterized	POS	O
+by	POS	O
+hepatocellular	POS	O
+enzyme	POS	O
+release	POS	O
+into	POS	O
+plasma	POS	O
+,	POS	O
+reduction	POS	O
+in	POS	O
+bile	POS	O
+flow	POS	O
+rate	POS	O
+,	POS	O
+and	POS	O
+neutrophil	POS	O
+sequestration	POS	O
+within	POS	O
+the	POS	O
+liver	POS	O
+.	POS	O
+The	POS	O
+pathophysiology	POS	O
+underlying	POS	O
+this	POS	O
+acute	POS	O
+hepatic	POS	B-NP
+injury	POS	I-NP
+is	POS	O
+unknown	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+was	POS	O
+undertaken	POS	O
+to	POS	O
+determine	POS	O
+whether	POS	O
+oxidants	POS	O
+are	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+hepatic	POS	B-NP
+injury	POS	I-NP
+and	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+relative	POS	O
+value	POS	O
+of	POS	O
+several	POS	O
+indirect	POS	O
+methods	POS	O
+of	POS	O
+assessing	POS	O
+oxidant	POS	O
+exposure	POS	O
+in	POS	O
+vivo	POS	O
+.	POS	O
+Rats	POS	O
+were	POS	O
+subjected	POS	O
+to	POS	O
+a	POS	O
+standardized	POS	O
+intestinal	POS	O
+ischemia	POS	B-NP
+-	POS	O
+reperfusion	POS	B-NP
+injury	POS	I-NP
+.	POS	O
+Hepatic	POS	O
+tissue	POS	O
+was	POS	O
+assayed	POS	O
+for	POS	O
+lipid	POS	O
+peroxidation	POS	O
+products	POS	O
+and	POS	O
+oxidized	POS	O
+and	POS	O
+reduced	POS	O
+glutathione	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+change	POS	O
+in	POS	O
+hepatic	POS	O
+tissue	POS	O
+total	POS	O
+glutathione	POS	O
+following	POS	O
+intestinal	POS	O
+ischemia	POS	B-NP
+-	POS	O
+reperfusion	POS	B-NP
+injury	POS	I-NP
+.	POS	O
+Oxidized	POS	O
+glutathione	POS	O
+(	POS	O
+GSSG	POS	O
+)	POS	O
+increased	POS	O
+significantly	POS	O
+following	POS	O
+30	POS	O
+and	POS	O
+60	POS	O
+min	POS	O
+of	POS	O
+reperfusion	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+increase	POS	O
+in	POS	O
+any	POS	O
+of	POS	O
+the	POS	O
+products	POS	O
+of	POS	O
+lipid	POS	O
+peroxidation	POS	O
+associated	POS	O
+with	POS	O
+this	POS	O
+injury	POS	O
+.	POS	O
+An	POS	O
+increase	POS	O
+in	POS	O
+GSSG	POS	O
+within	POS	O
+hepatic	POS	O
+tissue	POS	O
+during	POS	O
+intestinal	POS	O
+reperfusion	POS	O
+suggests	POS	O
+exposure	POS	O
+of	POS	O
+hepatocytes	POS	O
+to	POS	O
+an	POS	O
+oxidant	POS	O
+stress	POS	O
+.	POS	O
+The	POS	O
+lack	POS	O
+of	POS	O
+a	POS	O
+significant	POS	O
+increase	POS	O
+in	POS	O
+products	POS	O
+of	POS	O
+lipid	POS	O
+peroxidation	POS	O
+suggests	POS	O
+that	POS	O
+the	POS	O
+oxidant	POS	O
+stress	POS	O
+is	POS	O
+of	POS	O
+insufficient	POS	O
+magnitude	POS	O
+to	POS	O
+result	POS	O
+in	POS	O
+irreversible	POS	O
+injury	POS	O
+to	POS	O
+hepatocyte	POS	O
+cell	POS	O
+membranes	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+also	POS	O
+suggest	POS	O
+that	POS	O
+the	POS	O
+measurement	POS	O
+of	POS	O
+tissue	POS	O
+GSSG	POS	O
+may	POS	O
+be	POS	O
+a	POS	O
+more	POS	O
+sensitive	POS	O
+indicator	POS	O
+of	POS	O
+oxidant	POS	O
+stress	POS	O
+than	POS	O
+measurement	POS	O
+of	POS	O
+products	POS	O
+of	POS	O
+lipid	POS	O
+peroxidation	POS	O
+.	POS	O
+Animal	POS	O
+model	POS	O
+of	POS	O
+mania	POS	B-NP
+induced	POS	O
+by	POS	O
+ouabain	POS	O
+:	POS	O
+Evidence	POS	O
+of	POS	O
+oxidative	POS	O
+stress	POS	O
+in	POS	O
+submitochondrial	POS	O
+particles	POS	O
+of	POS	O
+the	POS	O
+rat	POS	O
+brain	POS	O
+.	POS	O
+The	POS	O
+intracerebroventricular	POS	O
+(	POS	O
+ICV	POS	O
+)	POS	O
+administration	POS	O
+of	POS	O
+ouabain	POS	O
+(	POS	O
+a	POS	O
+Na	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+/	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+ATPase	POS	O
+inhibitor	POS	O
+)	POS	O
+in	POS	O
+rats	POS	O
+has	POS	O
+been	POS	O
+suggested	POS	O
+to	POS	O
+mimic	POS	O
+some	POS	O
+symptoms	POS	O
+of	POS	O
+human	POS	O
+bipolar	POS	B-NP
+mania	POS	I-NP
+.	POS	O
+Clinical	POS	O
+studies	POS	O
+have	POS	O
+shown	POS	O
+that	POS	O
+bipolar	POS	B-NP
+disorder	POS	I-NP
+may	POS	O
+be	POS	O
+related	POS	O
+to	POS	O
+mitochondrial	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+Herein	POS	O
+,	POS	O
+we	POS	O
+investigated	POS	O
+the	POS	O
+behavioral	POS	O
+and	POS	O
+biochemical	POS	O
+effects	POS	O
+induced	POS	O
+by	POS	O
+the	POS	O
+ICV	POS	O
+administration	POS	O
+of	POS	O
+ouabain	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+To	POS	O
+achieve	POS	O
+this	POS	O
+aim	POS	O
+,	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+ouabain	POS	O
+injection	POS	O
+immediately	POS	O
+after	POS	O
+and	POS	O
+7	POS	O
+days	POS	O
+following	POS	O
+a	POS	O
+single	POS	O
+ICV	POS	O
+administration	POS	O
+(	POS	O
+at	POS	O
+concentrations	POS	O
+of	POS	O
+10	POS	O
+(	POS	O
+-	POS	O
+2	POS	O
+)	POS	O
+and	POS	O
+10	POS	O
+(	POS	O
+-	POS	O
+3	POS	O
+)	POS	O
+M	POS	O
+)	POS	O
+on	POS	O
+locomotion	POS	O
+was	POS	O
+measured	POS	O
+using	POS	O
+the	POS	O
+open	POS	O
+-	POS	O
+field	POS	O
+test	POS	O
+.	POS	O
+Additionally	POS	O
+,	POS	O
+thiobarbituric	POS	O
+acid	POS	O
+reactive	POS	O
+substances	POS	O
+(	POS	O
+TBARSs	POS	O
+)	POS	O
+and	POS	O
+superoxide	POS	O
+production	POS	O
+were	POS	O
+measured	POS	O
+in	POS	O
+submitochondrial	POS	O
+particles	POS	O
+of	POS	O
+the	POS	O
+prefrontal	POS	O
+cortex	POS	O
+,	POS	O
+hippocampus	POS	O
+,	POS	O
+striatum	POS	O
+and	POS	O
+amygdala	POS	O
+.	POS	O
+Our	POS	O
+findings	POS	O
+demonstrated	POS	O
+that	POS	O
+ouabain	POS	O
+at	POS	O
+10	POS	O
+(	POS	O
+-	POS	O
+2	POS	O
+)	POS	O
+and	POS	O
+10	POS	O
+(	POS	O
+-	POS	O
+3	POS	O
+)	POS	O
+M	POS	O
+induced	POS	O
+hyperlocomotion	POS	B-NP
+in	POS	O
+rats	POS	O
+,	POS	O
+and	POS	O
+this	POS	O
+response	POS	O
+remained	POS	O
+up	POS	O
+to	POS	O
+7	POS	O
+days	POS	O
+following	POS	O
+a	POS	O
+single	POS	O
+ICV	POS	O
+injection	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+we	POS	O
+observed	POS	O
+that	POS	O
+the	POS	O
+persistent	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+spontaneous	POS	O
+locomotion	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+increased	POS	O
+TBARS	POS	O
+levels	POS	O
+and	POS	O
+superoxide	POS	O
+generation	POS	O
+in	POS	O
+submitochondrial	POS	O
+particles	POS	O
+in	POS	O
+the	POS	O
+prefrontal	POS	O
+cortex	POS	O
+,	POS	O
+striatum	POS	O
+and	POS	O
+amygdala	POS	O
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+ouabain	POS	O
+-	POS	O
+induced	POS	O
+mania	POS	B-NP
+-	POS	O
+like	POS	O
+behavior	POS	O
+may	POS	O
+provide	POS	O
+a	POS	O
+useful	POS	O
+animal	POS	O
+model	POS	O
+to	POS	O
+test	POS	O
+the	POS	O
+hypothesis	POS	O
+of	POS	O
+the	POS	O
+involvement	POS	O
+of	POS	O
+oxidative	POS	O
+stress	POS	O
+in	POS	O
+bipolar	POS	B-NP
+disorder	POS	I-NP
+.	POS	O
+Intraoperative	POS	O
+dialysis	POS	O
+during	POS	O
+liver	POS	O
+transplantation	POS	O
+with	POS	O
+citrate	POS	O
+dialysate	POS	O
+.	POS	O
+Liver	POS	O
+transplantation	POS	O
+for	POS	O
+acutely	POS	O
+ill	POS	O
+patients	POS	O
+with	POS	O
+fulminant	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+carries	POS	O
+high	POS	O
+intraoperative	POS	O
+and	POS	O
+immediate	POS	O
+postoperative	POS	O
+risks	POS	O
+.	POS	O
+These	POS	O
+are	POS	O
+increased	POS	O
+with	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+concomitant	POS	O
+acute	POS	B-NP
+kidney	POS	I-NP
+injury	POS	I-NP
+(	POS	O
+AKI	POS	B-NP
+)	POS	O
+and	POS	O
+intraoperative	POS	O
+dialysis	POS	O
+is	POS	O
+sometimes	POS	O
+required	POS	O
+to	POS	O
+allow	POS	O
+the	POS	O
+transplant	POS	O
+to	POS	O
+proceed	POS	O
+.	POS	O
+The	POS	O
+derangements	POS	O
+in	POS	O
+the	POS	O
+procoagulant	POS	O
+and	POS	O
+anticoagulant	POS	O
+pathways	POS	O
+during	POS	O
+fulminant	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+can	POS	O
+lead	POS	O
+to	POS	O
+difficulties	POS	O
+with	POS	O
+anticoagulation	POS	O
+during	POS	O
+dialysis	POS	O
+,	POS	O
+especially	POS	O
+when	POS	O
+continued	POS	O
+in	POS	O
+the	POS	O
+operating	POS	O
+room	POS	O
+.	POS	O
+Systemic	POS	O
+anticoagulation	POS	O
+is	POS	O
+unsafe	POS	O
+and	POS	O
+regional	POS	O
+citrate	POS	O
+anticoagulation	POS	O
+in	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+a	POS	O
+functional	POS	O
+liver	POS	O
+carries	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+citrate	POS	O
+toxicity	POS	O
+.	POS	O
+Citrate	POS	O
+dialysate	POS	O
+,	POS	O
+a	POS	O
+new	POS	O
+dialysate	POS	O
+with	POS	O
+citric	POS	O
+acid	POS	O
+can	POS	O
+be	POS	O
+used	POS	O
+for	POS	O
+anticoagulation	POS	O
+in	POS	O
+patients	POS	O
+who	POS	O
+cannot	POS	O
+tolerate	POS	O
+heparin	POS	O
+or	POS	O
+regional	POS	O
+citrate	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+40	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+female	POS	O
+with	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+fulminant	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+with	POS	O
+associated	POS	O
+AKI	POS	B-NP
+who	POS	O
+underwent	POS	O
+intraoperative	POS	O
+dialytic	POS	O
+support	POS	O
+during	POS	O
+liver	POS	O
+transplantation	POS	O
+anticoagulated	POS	O
+with	POS	O
+citrate	POS	O
+dialysate	POS	O
+during	POS	O
+the	POS	O
+entire	POS	O
+procedure	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+tolerated	POS	O
+the	POS	O
+procedure	POS	O
+well	POS	O
+without	POS	O
+any	POS	O
+signs	POS	O
+of	POS	O
+citrate	POS	O
+toxicity	POS	B-NP
+and	POS	O
+maintained	POS	O
+adequate	POS	O
+anticoagulation	POS	O
+for	POS	O
+patency	POS	O
+of	POS	O
+the	POS	O
+dialysis	POS	O
+circuit	POS	O
+.	POS	O
+Citrate	POS	O
+dialysate	POS	O
+is	POS	O
+a	POS	O
+safe	POS	O
+alternative	POS	O
+for	POS	O
+intradialytic	POS	O
+support	POS	O
+of	POS	O
+liver	POS	O
+transplantation	POS	O
+in	POS	O
+fulminant	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+Delirium	POS	B-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+toxic	POS	O
+flecainide	POS	O
+plasma	POS	O
+concentrations	POS	O
+:	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+a	POS	O
+pharmacokinetic	POS	O
+drug	POS	O
+interaction	POS	O
+with	POS	O
+paroxetine	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+describe	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+flecainide	POS	O
+-	POS	O
+induced	POS	O
+delirium	POS	B-NP
+associated	POS	O
+with	POS	O
+a	POS	O
+pharmacokinetic	POS	O
+drug	POS	O
+interaction	POS	O
+with	POS	O
+paroxetine	POS	O
+.	POS	O
+CASE	POS	O
+SUMMARY	POS	O
+:	POS	O
+A	POS	O
+69	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+white	POS	O
+female	POS	O
+presented	POS	O
+to	POS	O
+the	POS	O
+emergency	POS	O
+department	POS	O
+with	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+confusion	POS	B-NP
+and	POS	O
+paranoia	POS	B-NP
+over	POS	O
+the	POS	O
+past	POS	O
+several	POS	O
+days	POS	O
+.	POS	O
+On	POS	O
+admission	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+taking	POS	O
+carvedilol	POS	O
+12	POS	O
+mg	POS	O
+twice	POS	O
+daily	POS	O
+,	POS	O
+warfarin	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+,	POS	O
+folic	POS	O
+acid	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+,	POS	O
+levothyroxine	POS	O
+100	POS	O
+microg	POS	O
+/	POS	O
+day	POS	O
+,	POS	O
+pantoprazole	POS	O
+40	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+,	POS	O
+paroxetine	POS	O
+40	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+,	POS	O
+and	POS	O
+flecainide	POS	O
+100	POS	O
+mg	POS	O
+twice	POS	O
+daily	POS	O
+.	POS	O
+Flecainide	POS	O
+had	POS	O
+been	POS	O
+started	POS	O
+2	POS	O
+weeks	POS	O
+prior	POS	O
+for	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+.	POS	O
+Laboratory	POS	O
+test	POS	O
+findings	POS	O
+on	POS	O
+admission	POS	O
+were	POS	O
+notable	POS	O
+only	POS	O
+for	POS	O
+a	POS	O
+flecainide	POS	O
+plasma	POS	O
+concentration	POS	O
+of	POS	O
+1360	POS	O
+microg	POS	O
+/	POS	O
+L	POS	O
+(	POS	O
+reference	POS	O
+range	POS	O
+200	POS	O
+-	POS	O
+1000	POS	O
+)	POS	O
+.	POS	O
+A	POS	O
+metabolic	POS	O
+drug	POS	O
+interaction	POS	O
+between	POS	O
+flecainide	POS	O
+and	POS	O
+paroxetine	POS	O
+,	POS	O
+which	POS	O
+the	POS	O
+patient	POS	O
+had	POS	O
+been	POS	O
+taking	POS	O
+for	POS	O
+more	POS	O
+than	POS	O
+5	POS	O
+years	POS	O
+,	POS	O
+was	POS	O
+considered	POS	O
+.	POS	O
+Paroxetine	POS	O
+was	POS	O
+discontinued	POS	O
+and	POS	O
+the	POS	O
+dose	POS	O
+of	POS	O
+flecainide	POS	O
+was	POS	O
+reduced	POS	O
+to	POS	O
+50	POS	O
+mg	POS	O
+twice	POS	O
+daily	POS	O
+.	POS	O
+Her	POS	O
+delirium	POS	B-NP
+resolved	POS	O
+3	POS	O
+days	POS	O
+later	POS	O
+.	POS	O
+DISCUSSION	POS	O
+:	POS	O
+Flecainide	POS	O
+and	POS	O
+pharmacologically	POS	O
+similar	POS	O
+agents	POS	O
+that	POS	O
+interact	POS	O
+with	POS	O
+sodium	POS	O
+channels	POS	O
+may	POS	O
+cause	POS	O
+delirium	POS	B-NP
+in	POS	O
+susceptible	POS	O
+patients	POS	O
+.	POS	O
+A	POS	O
+MEDLINE	POS	O
+search	POS	O
+(	POS	O
+1966	POS	O
+-	POS	O
+January	POS	O
+2009	POS	O
+)	POS	O
+revealed	POS	O
+one	POS	O
+in	POS	O
+vivo	POS	O
+pharmacokinetic	POS	O
+study	POS	O
+on	POS	O
+the	POS	O
+interaction	POS	O
+between	POS	O
+flecainide	POS	O
+,	POS	O
+a	POS	O
+CYP2D6	POS	O
+substrate	POS	O
+,	POS	O
+and	POS	O
+paroxetine	POS	O
+,	POS	O
+a	POS	O
+CYP2D6	POS	O
+inhibitor	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+3	POS	O
+case	POS	O
+reports	POS	O
+of	POS	O
+flecainide	POS	O
+-	POS	O
+induced	POS	O
+delirium	POS	B-NP
+.	POS	O
+According	POS	O
+to	POS	O
+the	POS	O
+Naranjo	POS	O
+probability	POS	O
+scale	POS	O
+,	POS	O
+flecainide	POS	O
+was	POS	O
+the	POS	O
+probable	POS	O
+cause	POS	O
+of	POS	O
+the	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+delirium	POS	B-NP
+;	POS	O
+the	POS	O
+Horn	POS	O
+Drug	POS	O
+Interaction	POS	O
+Probability	POS	O
+Scale	POS	O
+indicates	POS	O
+a	POS	O
+possible	POS	O
+pharmacokinetic	POS	O
+drug	POS	O
+interaction	POS	O
+between	POS	O
+flecainide	POS	O
+and	POS	O
+paroxetine	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Supratherapeutic	POS	O
+flecainide	POS	O
+plasma	POS	O
+concentrations	POS	O
+may	POS	O
+cause	POS	O
+delirium	POS	B-NP
+.	POS	O
+Because	POS	O
+toxicity	POS	B-NP
+may	POS	O
+occur	POS	O
+when	POS	O
+flecainide	POS	O
+is	POS	O
+prescribed	POS	O
+with	POS	O
+paroxetine	POS	O
+and	POS	O
+other	POS	O
+potent	POS	O
+CYP2D6	POS	O
+inhibitors	POS	O
+,	POS	O
+flecainide	POS	O
+plasma	POS	O
+concentrations	POS	O
+should	POS	O
+be	POS	O
+monitored	POS	O
+closely	POS	O
+with	POS	O
+commencement	POS	O
+of	POS	O
+CYP2D6	POS	O
+inhibitors	POS	O
+.	POS	O
+Efficacy	POS	O
+of	POS	O
+everolimus	POS	O
+(	POS	O
+RAD001	POS	O
+)	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+advanced	POS	O
+NSCLC	POS	B-NP
+previously	POS	O
+treated	POS	O
+with	POS	O
+chemotherapy	POS	O
+alone	POS	O
+or	POS	O
+with	POS	O
+chemotherapy	POS	O
+and	POS	O
+EGFR	POS	O
+inhibitors	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Treatment	POS	O
+options	POS	O
+are	POS	O
+scarce	POS	O
+in	POS	O
+pretreated	POS	O
+advanced	POS	O
+non	POS	B-NP
+-	POS	I-NP
+small	POS	I-NP
+-	POS	I-NP
+cell	POS	I-NP
+lung	POS	I-NP
+cancer	POS	I-NP
+(	POS	O
+NSCLC	POS	B-NP
+)	POS	O
+patients	POS	O
+.	POS	O
+RAD001	POS	O
+,	POS	O
+an	POS	O
+oral	POS	O
+inhibitor	POS	O
+of	POS	O
+the	POS	O
+mammalian	POS	O
+target	POS	O
+of	POS	O
+rapamycin	POS	O
+(	POS	O
+mTOR	POS	O
+)	POS	O
+,	POS	O
+has	POS	O
+shown	POS	O
+phase	POS	O
+I	POS	O
+efficacy	POS	O
+in	POS	O
+NSCLC	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Stage	POS	O
+IIIb	POS	O
+or	POS	O
+IV	POS	O
+NSCLC	POS	B-NP
+patients	POS	O
+,	POS	O
+with	POS	O
+two	POS	O
+or	POS	O
+fewer	POS	O
+prior	POS	O
+chemotherapy	POS	O
+regimens	POS	O
+,	POS	O
+one	POS	O
+platinum	POS	O
+based	POS	O
+(	POS	O
+stratum	POS	O
+1	POS	O
+)	POS	O
+or	POS	O
+both	POS	O
+chemotherapy	POS	O
+and	POS	O
+epidermal	POS	O
+growth	POS	O
+factor	POS	O
+receptor	POS	O
+tyrosine	POS	O
+kinase	POS	O
+inhibitors	POS	O
+(	POS	O
+stratum	POS	O
+2	POS	O
+)	POS	O
+,	POS	O
+received	POS	O
+RAD001	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+until	POS	O
+progression	POS	O
+or	POS	O
+unacceptable	POS	O
+toxicity	POS	B-NP
+.	POS	O
+Primary	POS	O
+objective	POS	O
+was	POS	O
+overall	POS	O
+response	POS	O
+rate	POS	O
+(	POS	O
+ORR	POS	O
+)	POS	O
+.	POS	O
+Analyses	POS	O
+of	POS	O
+markers	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+mTOR	POS	O
+pathway	POS	O
+were	POS	O
+carried	POS	O
+out	POS	O
+on	POS	O
+archival	POS	O
+tumor	POS	B-NP
+from	POS	O
+a	POS	O
+subgroup	POS	O
+using	POS	O
+immunohistochemistry	POS	O
+(	POS	O
+IHC	POS	O
+)	POS	O
+and	POS	O
+direct	POS	O
+mutation	POS	O
+sequencing	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Eighty	POS	O
+-	POS	O
+five	POS	O
+patients	POS	O
+were	POS	O
+enrolled	POS	O
+,	POS	O
+42	POS	O
+in	POS	O
+stratum	POS	O
+1	POS	O
+and	POS	O
+43	POS	O
+in	POS	O
+stratum	POS	O
+.	POS	O
+ORR	POS	O
+was	POS	O
+4	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+(	POS	O
+7	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+stratum	POS	O
+1	POS	O
+;	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+stratum	POS	O
+2	POS	O
+)	POS	O
+.	POS	O
+Overall	POS	O
+disease	POS	O
+control	POS	O
+rate	POS	O
+was	POS	O
+47	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+.	POS	O
+Median	POS	O
+progression	POS	O
+-	POS	O
+free	POS	O
+survivals	POS	O
+(	POS	O
+PFSs	POS	O
+)	POS	O
+were	POS	O
+2	POS	O
+.	POS	O
+6	POS	O
+(	POS	O
+stratum	POS	O
+1	POS	O
+)	POS	O
+and	POS	O
+2	POS	O
+.	POS	O
+7	POS	O
+months	POS	O
+(	POS	O
+stratum	POS	O
+2	POS	O
+)	POS	O
+.	POS	O
+Common	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+grade	POS	O
+3	POS	O
+events	POS	O
+were	POS	O
+fatigue	POS	B-NP
+,	POS	O
+dyspnea	POS	B-NP
+,	POS	O
+stomatitis	POS	B-NP
+,	POS	O
+anemia	POS	B-NP
+,	POS	O
+and	POS	O
+thrombocytopenia	POS	B-NP
+.	POS	O
+Pneumonitis	POS	B-NP
+,	POS	O
+probably	POS	O
+or	POS	O
+possibly	POS	O
+related	POS	O
+,	POS	O
+mainly	POS	O
+grade	POS	O
+1	POS	O
+/	POS	O
+2	POS	O
+,	POS	O
+occurred	POS	O
+in	POS	O
+25	POS	O
+%	POS	O
+.	POS	O
+Cox	POS	O
+regression	POS	O
+analysis	POS	O
+of	POS	O
+IHC	POS	O
+scores	POS	O
+found	POS	O
+that	POS	O
+only	POS	O
+phospho	POS	O
+AKT	POS	O
+(	POS	O
+pAKT	POS	O
+)	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+independent	POS	O
+predictor	POS	O
+of	POS	O
+worse	POS	O
+PFS	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+RAD001	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+was	POS	O
+well	POS	O
+tolerated	POS	O
+,	POS	O
+showing	POS	O
+modest	POS	O
+clinical	POS	O
+activity	POS	O
+in	POS	O
+pretreated	POS	O
+NSCLC	POS	B-NP
+.	POS	O
+Evaluation	POS	O
+of	POS	O
+RAD001	POS	O
+plus	POS	O
+standard	POS	O
+therapy	POS	O
+for	POS	O
+metastatic	POS	O
+NSCLC	POS	B-NP
+continues	POS	O
+.	POS	O
+Posttransplant	POS	B-NP
+anemia	POS	I-NP
+:	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+sirolimus	POS	O
+.	POS	O
+Posttransplant	POS	B-NP
+anemia	POS	I-NP
+is	POS	O
+a	POS	O
+common	POS	O
+problem	POS	O
+that	POS	O
+may	POS	O
+hinder	POS	O
+patients	POS	O
+'	POS	O
+quality	POS	O
+of	POS	O
+life	POS	O
+.	POS	O
+It	POS	O
+occurs	POS	O
+in	POS	O
+12	POS	O
+to	POS	O
+76	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+,	POS	O
+and	POS	O
+is	POS	O
+most	POS	O
+common	POS	O
+in	POS	O
+the	POS	O
+immediate	POS	O
+posttransplant	POS	O
+period	POS	O
+.	POS	O
+A	POS	O
+variety	POS	O
+of	POS	O
+factors	POS	O
+have	POS	O
+been	POS	O
+identified	POS	O
+that	POS	O
+increase	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+posttransplant	POS	O
+anemia	POS	B-NP
+,	POS	O
+of	POS	O
+which	POS	O
+the	POS	O
+level	POS	O
+of	POS	O
+renal	POS	O
+function	POS	O
+is	POS	O
+most	POS	O
+important	POS	O
+.	POS	O
+Sirolimus	POS	O
+,	POS	O
+a	POS	O
+mammalian	POS	O
+target	POS	O
+of	POS	O
+rapamycin	POS	O
+inhibitor	POS	O
+,	POS	O
+has	POS	O
+been	POS	O
+implicated	POS	O
+as	POS	O
+playing	POS	O
+a	POS	O
+special	POS	O
+role	POS	O
+in	POS	O
+posttransplant	POS	O
+anemia	POS	B-NP
+.	POS	O
+This	POS	O
+review	POS	O
+considers	POS	O
+anemia	POS	B-NP
+associated	POS	O
+with	POS	O
+sirolimus	POS	O
+,	POS	O
+including	POS	O
+its	POS	O
+presentation	POS	O
+,	POS	O
+mechanisms	POS	O
+,	POS	O
+and	POS	O
+management	POS	O
+.	POS	O
+Coronary	POS	O
+computerized	POS	O
+tomography	POS	O
+angiography	POS	O
+for	POS	O
+rapid	POS	O
+discharge	POS	O
+of	POS	O
+low	POS	O
+-	POS	O
+risk	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Most	POS	O
+patients	POS	O
+presenting	POS	O
+to	POS	O
+emergency	POS	O
+departments	POS	O
+(	POS	O
+EDs	POS	O
+)	POS	O
+with	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+are	POS	O
+admitted	POS	O
+for	POS	O
+at	POS	O
+least	POS	O
+12	POS	O
+hours	POS	O
+and	POS	O
+receive	POS	O
+a	POS	O
+"	POS	O
+rule	POS	O
+out	POS	O
+acute	POS	O
+coronary	POS	B-NP
+syndrome	POS	I-NP
+"	POS	O
+protocol	POS	O
+,	POS	O
+often	POS	O
+with	POS	O
+noninvasive	POS	O
+testing	POS	O
+prior	POS	O
+to	POS	O
+discharge	POS	O
+.	POS	O
+In	POS	O
+patients	POS	O
+without	POS	O
+cocaine	POS	O
+use	POS	O
+,	POS	O
+coronary	POS	O
+computerized	POS	O
+tomography	POS	O
+angiography	POS	O
+(	POS	O
+CTA	POS	O
+)	POS	O
+has	POS	O
+been	POS	O
+shown	POS	O
+to	POS	O
+be	POS	O
+useful	POS	O
+for	POS	O
+identifying	POS	O
+a	POS	O
+group	POS	O
+of	POS	O
+patients	POS	O
+at	POS	O
+low	POS	O
+risk	POS	O
+for	POS	O
+cardiac	POS	B-NP
+events	POS	I-NP
+who	POS	O
+can	POS	O
+be	POS	O
+safely	POS	O
+discharged	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+unclear	POS	O
+whether	POS	O
+a	POS	O
+coronary	POS	O
+CTA	POS	O
+strategy	POS	O
+would	POS	O
+be	POS	O
+efficacious	POS	O
+in	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+,	POS	O
+as	POS	O
+coronary	POS	B-NP
+vasospasm	POS	I-NP
+may	POS	O
+account	POS	O
+for	POS	O
+some	POS	O
+of	POS	O
+the	POS	O
+ischemia	POS	B-NP
+.	POS	O
+We	POS	O
+studied	POS	O
+whether	POS	O
+a	POS	O
+negative	POS	O
+coronary	POS	O
+CTA	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+could	POS	O
+identify	POS	O
+a	POS	O
+subset	POS	O
+safe	POS	O
+for	POS	O
+discharge	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+prospectively	POS	O
+evaluated	POS	O
+the	POS	O
+safety	POS	O
+of	POS	O
+coronary	POS	O
+CTA	POS	O
+for	POS	O
+low	POS	O
+-	POS	O
+risk	POS	O
+patients	POS	O
+who	POS	O
+presented	POS	O
+to	POS	O
+the	POS	O
+ED	POS	O
+with	POS	O
+cocaineassociated	POS	B-NP
+chest	POS	I-NP
+pain	POS	I-NP
+(	POS	O
+self	POS	O
+-	POS	O
+reported	POS	O
+or	POS	O
+positive	POS	O
+urine	POS	O
+test	POS	O
+)	POS	O
+.	POS	O
+Consecutive	POS	O
+patients	POS	O
+received	POS	O
+either	POS	O
+immediate	POS	O
+coronary	POS	O
+CTA	POS	O
+in	POS	O
+the	POS	O
+ED	POS	O
+(	POS	O
+without	POS	O
+serial	POS	O
+markers	POS	O
+)	POS	O
+or	POS	O
+underwent	POS	O
+coronary	POS	O
+CTA	POS	O
+after	POS	O
+a	POS	O
+brief	POS	O
+observation	POS	O
+period	POS	O
+with	POS	O
+serial	POS	O
+cardiac	POS	O
+marker	POS	O
+measurements	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+negative	POS	O
+coronary	POS	O
+CTA	POS	O
+(	POS	O
+maximal	POS	O
+stenosis	POS	B-NP
+less	POS	O
+than	POS	O
+50	POS	O
+%	POS	O
+)	POS	O
+were	POS	O
+discharged	POS	O
+.	POS	O
+The	POS	O
+main	POS	O
+outcome	POS	O
+was	POS	O
+30	POS	O
+-	POS	O
+day	POS	O
+cardiovascular	POS	O
+death	POS	O
+or	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+59	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+chest	POS	I-NP
+pain	POS	I-NP
+were	POS	O
+evaluated	POS	O
+.	POS	O
+Patients	POS	O
+had	POS	O
+a	POS	O
+mean	POS	O
+age	POS	O
+of	POS	O
+45	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+6	POS	O
+yrs	POS	O
+and	POS	O
+were	POS	O
+86	POS	O
+%	POS	O
+black	POS	O
+,	POS	O
+66	POS	O
+%	POS	O
+male	POS	O
+.	POS	O
+Seventy	POS	O
+-	POS	O
+nine	POS	O
+percent	POS	O
+had	POS	O
+a	POS	O
+normal	POS	O
+or	POS	O
+nonspecific	POS	O
+ECG	POS	O
+and	POS	O
+85	POS	O
+%	POS	O
+had	POS	O
+a	POS	O
+TIMI	POS	B-NP
+score	POS	O
+<	POS	O
+2	POS	O
+.	POS	O
+Twenty	POS	O
+patients	POS	O
+received	POS	O
+coronary	POS	O
+CTA	POS	O
+immediately	POS	O
+in	POS	O
+the	POS	O
+ED	POS	O
+,	POS	O
+18	POS	O
+of	POS	O
+whom	POS	O
+were	POS	O
+discharged	POS	O
+following	POS	O
+CTA	POS	O
+(	POS	O
+90	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Thirty	POS	O
+-	POS	O
+nine	POS	O
+received	POS	O
+coronary	POS	O
+CTA	POS	O
+after	POS	O
+a	POS	O
+brief	POS	O
+observation	POS	O
+period	POS	O
+,	POS	O
+with	POS	O
+37	POS	O
+discharged	POS	O
+home	POS	O
+following	POS	O
+CTA	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Six	POS	O
+patients	POS	O
+had	POS	O
+coronary	POS	B-NP
+stenosis	POS	I-NP
+>	POS	O
+or	POS	O
+=	POS	O
+50	POS	O
+%	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+30	POS	O
+-	POS	O
+day	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+period	POS	O
+,	POS	O
+no	POS	O
+patients	POS	O
+died	POS	O
+of	POS	O
+a	POS	O
+cardiovascular	POS	B-NP
+event	POS	I-NP
+(	POS	O
+0	POS	O
+%	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+,	POS	O
+0	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+no	POS	O
+patient	POS	O
+sustained	POS	O
+a	POS	O
+nonfatal	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+(	POS	O
+0	POS	O
+%	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+,	POS	O
+0	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Although	POS	O
+cocaine	POS	O
+-	POS	O
+associated	POS	O
+myocardial	POS	B-NP
+ischemia	POS	I-NP
+can	POS	O
+result	POS	O
+from	POS	O
+coronary	POS	B-NP
+vasoconstriction	POS	I-NP
+,	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	O
+associated	POS	O
+chest	POS	B-NP
+pain	POS	I-NP
+,	POS	O
+a	POS	O
+non	POS	B-NP
+-	POS	I-NP
+ischemic	POS	I-NP
+ECG	POS	I-NP
+,	POS	O
+and	POS	O
+a	POS	O
+TIMI	POS	B-NP
+risk	POS	O
+score	POS	O
+<	POS	O
+2	POS	O
+may	POS	O
+be	POS	O
+safely	POS	O
+discharged	POS	O
+from	POS	O
+the	POS	O
+ED	POS	O
+after	POS	O
+a	POS	O
+negative	POS	O
+coronary	POS	O
+CTA	POS	O
+with	POS	O
+a	POS	O
+low	POS	O
+risk	POS	O
+of	POS	O
+30	POS	O
+-	POS	O
+day	POS	O
+adverse	POS	O
+events	POS	O
+.	POS	O
+Bilateral	POS	O
+haemorrhagic	POS	B-NP
+infarction	POS	I-NP
+of	POS	O
+the	POS	O
+globus	POS	O
+pallidus	POS	O
+after	POS	O
+cocaine	POS	O
+and	POS	O
+alcohol	POS	B-NP
+intoxication	POS	I-NP
+.	POS	O
+Cocaine	POS	O
+is	POS	O
+a	POS	O
+risk	POS	O
+factor	POS	O
+for	POS	O
+both	POS	O
+ischemic	POS	B-NP
+and	POS	O
+haemorrhagic	POS	B-NP
+stroke	POS	I-NP
+.	POS	O
+We	POS	O
+present	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+31	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+with	POS	O
+bilateral	POS	B-NP
+ischemia	POS	I-NP
+of	POS	O
+the	POS	O
+globus	POS	O
+pallidus	POS	O
+after	POS	O
+excessive	POS	O
+alcohol	POS	O
+and	POS	O
+intranasal	POS	O
+cocaine	POS	O
+use	POS	O
+.	POS	O
+Drug	POS	O
+-	POS	O
+related	POS	O
+globus	POS	O
+pallidus	POS	O
+infarctions	POS	O
+are	POS	O
+most	POS	O
+often	POS	O
+associated	POS	O
+with	POS	O
+heroin	POS	O
+.	POS	O
+Bilateral	POS	O
+basal	POS	O
+ganglia	POS	O
+infarcts	POS	B-NP
+after	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+cocaine	POS	O
+,	POS	O
+without	POS	O
+concurrent	POS	O
+heroin	POS	O
+use	POS	O
+,	POS	O
+have	POS	O
+never	POS	O
+been	POS	O
+reported	POS	O
+.	POS	O
+In	POS	O
+our	POS	O
+patient	POS	O
+,	POS	O
+transient	POS	O
+cardiac	POS	B-NP
+arrhythmia	POS	I-NP
+or	POS	O
+respiratory	POS	B-NP
+dysfunction	POS	I-NP
+related	POS	O
+to	POS	O
+cocaine	POS	O
+and	POS	O
+/	POS	O
+or	POS	O
+ethanol	POS	O
+use	POS	O
+were	POS	O
+the	POS	O
+most	POS	O
+likely	POS	O
+causes	POS	O
+of	POS	O
+cerebral	POS	B-NP
+hypoperfusion	POS	I-NP
+.	POS	O
+Late	POS	O
+fulminant	POS	O
+posterior	POS	O
+reversible	POS	O
+encephalopathy	POS	B-NP
+syndrome	POS	I-NP
+after	POS	O
+liver	POS	O
+transplant	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+Posterior	POS	B-NP
+leukoencephalopathy	POS	I-NP
+due	POS	O
+to	POS	O
+calcineurin	POS	O
+-	POS	O
+inhibitor	POS	O
+-	POS	O
+related	POS	O
+neurotoxicity	POS	B-NP
+is	POS	O
+a	POS	O
+rare	POS	O
+but	POS	O
+severe	POS	O
+complication	POS	O
+that	POS	O
+results	POS	O
+from	POS	O
+treatment	POS	O
+with	POS	O
+immunosuppressive	POS	O
+agents	POS	O
+(	POS	O
+primarily	POS	O
+those	POS	O
+administered	POS	O
+after	POS	O
+a	POS	O
+liver	POS	O
+or	POS	O
+kidney	POS	O
+transplant	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+pathophysiologic	POS	O
+mechanisms	POS	O
+of	POS	O
+that	POS	O
+disorder	POS	O
+remain	POS	O
+unknown	POS	O
+.	POS	O
+CASE	POS	O
+:	POS	O
+We	POS	O
+report	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+46	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+who	POS	O
+received	POS	O
+a	POS	O
+liver	POS	O
+transplant	POS	O
+in	POS	O
+our	POS	O
+center	POS	O
+as	POS	O
+treatment	POS	O
+for	POS	O
+alcoholic	POS	O
+cirrhosis	POS	B-NP
+and	POS	O
+in	POS	O
+whom	POS	O
+either	POS	O
+a	POS	O
+fulminant	POS	B-NP
+course	POS	O
+of	POS	O
+posterior	POS	B-NP
+leukoencephalopathy	POS	I-NP
+or	POS	O
+posterior	POS	O
+reversible	POS	O
+encephalopathy	POS	B-NP
+syndrome	POS	I-NP
+developed	POS	O
+110	POS	O
+days	POS	O
+after	POS	O
+transplant	POS	O
+.	POS	O
+After	POS	O
+an	POS	O
+initially	POS	O
+uneventful	POS	O
+course	POS	O
+after	POS	O
+the	POS	O
+transplant	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+rapidly	POS	O
+fell	POS	O
+into	POS	O
+deep	POS	O
+coma	POS	B-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Cerebral	POS	O
+MRI	POS	O
+scan	POS	O
+showed	POS	O
+typical	POS	O
+signs	POS	O
+of	POS	O
+enhancement	POS	O
+in	POS	O
+the	POS	O
+pontine	POS	O
+and	POS	O
+posterior	POS	O
+regions	POS	O
+.	POS	O
+Switching	POS	O
+the	POS	O
+immunosuppressive	POS	O
+regimen	POS	O
+from	POS	O
+tacrolimus	POS	O
+to	POS	O
+cyclosporine	POS	O
+did	POS	O
+not	POS	O
+improve	POS	O
+the	POS	O
+clinical	POS	O
+situation	POS	O
+.	POS	O
+The	POS	O
+termination	POS	O
+of	POS	O
+treatment	POS	O
+with	POS	O
+any	POS	O
+calcineurin	POS	O
+inhibitor	POS	O
+resulted	POS	O
+in	POS	O
+a	POS	O
+complete	POS	O
+resolution	POS	O
+of	POS	O
+that	POS	O
+complication	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Posterior	POS	O
+reversible	POS	O
+encephalopathy	POS	B-NP
+syndrome	POS	I-NP
+after	POS	O
+liver	POS	O
+transplant	POS	O
+is	POS	O
+rare	POS	O
+.	POS	O
+We	POS	O
+recommend	POS	O
+a	POS	O
+complete	POS	O
+cessation	POS	O
+of	POS	O
+any	POS	O
+calcineurin	POS	O
+inhibitor	POS	O
+rather	POS	O
+than	POS	O
+a	POS	O
+dose	POS	O
+reduction	POS	O
+.	POS	O
+Prolonged	POS	O
+hypothermia	POS	B-NP
+as	POS	O
+a	POS	O
+bridge	POS	O
+to	POS	O
+recovery	POS	O
+for	POS	O
+cerebral	POS	B-NP
+edema	POS	I-NP
+and	POS	O
+intracranial	POS	B-NP
+hypertension	POS	I-NP
+associated	POS	O
+with	POS	O
+fulminant	POS	B-NP
+hepatic	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+To	POS	O
+review	POS	O
+evidence	POS	O
+-	POS	O
+based	POS	O
+treatment	POS	O
+options	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+cerebral	POS	B-NP
+edema	POS	I-NP
+complicating	POS	O
+fulminant	POS	B-NP
+hepatic	POS	I-NP
+failure	POS	I-NP
+(	POS	O
+FHF	POS	B-NP
+)	POS	O
+and	POS	O
+discuss	POS	O
+the	POS	O
+potential	POS	O
+applications	POS	O
+of	POS	O
+hypothermia	POS	B-NP
+.	POS	O
+METHOD	POS	O
+:	POS	O
+Case	POS	O
+-	POS	O
+based	POS	O
+observations	POS	O
+from	POS	O
+a	POS	O
+medical	POS	O
+intensive	POS	O
+care	POS	O
+unit	POS	O
+(	POS	O
+MICU	POS	O
+)	POS	O
+in	POS	O
+a	POS	O
+tertiary	POS	O
+care	POS	O
+facility	POS	O
+in	POS	O
+a	POS	O
+27	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+female	POS	O
+with	POS	O
+FHF	POS	B-NP
+from	POS	O
+acetaminophen	POS	O
+and	POS	O
+resultant	POS	O
+cerebral	POS	B-NP
+edema	POS	I-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Our	POS	O
+patient	POS	O
+was	POS	O
+admitted	POS	O
+to	POS	O
+the	POS	O
+MICU	POS	O
+after	POS	O
+being	POS	O
+found	POS	O
+unresponsive	POS	O
+with	POS	O
+presumed	POS	O
+toxicity	POS	B-NP
+from	POS	O
+acetaminophen	POS	O
+which	POS	O
+was	POS	O
+ingested	POS	O
+over	POS	O
+a	POS	O
+2	POS	O
+-	POS	O
+day	POS	O
+period	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+had	POS	O
+depressed	POS	O
+of	POS	O
+mental	POS	O
+status	POS	O
+lasting	POS	O
+at	POS	O
+least	POS	O
+24	POS	O
+h	POS	O
+prior	POS	O
+to	POS	O
+admission	POS	O
+.	POS	O
+Initial	POS	O
+evaluation	POS	O
+confirmed	POS	O
+FHF	POS	B-NP
+from	POS	O
+acetaminophen	POS	O
+and	POS	O
+cerebral	POS	B-NP
+edema	POS	I-NP
+.	POS	O
+The	POS	O
+patient	POS	O
+was	POS	O
+treated	POS	O
+with	POS	O
+hyperosmolar	POS	O
+therapy	POS	O
+,	POS	O
+hyperventilation	POS	B-NP
+,	POS	O
+sedation	POS	O
+,	POS	O
+and	POS	O
+chemical	POS	O
+paralysis	POS	B-NP
+.	POS	O
+Her	POS	O
+intracranial	POS	O
+pressure	POS	O
+remained	POS	O
+elevated	POS	O
+despite	POS	O
+maximal	POS	O
+medical	POS	O
+therapy	POS	O
+.	POS	O
+We	POS	O
+then	POS	O
+initiated	POS	O
+therapeutic	POS	O
+hypothermia	POS	B-NP
+which	POS	O
+was	POS	O
+continued	POS	O
+for	POS	O
+5	POS	O
+days	POS	O
+.	POS	O
+At	POS	O
+re	POS	O
+-	POS	O
+warming	POS	O
+,	POS	O
+patient	POS	O
+had	POS	O
+resolution	POS	O
+of	POS	O
+her	POS	O
+cerebral	POS	B-NP
+edema	POS	I-NP
+and	POS	O
+intracranial	POS	B-NP
+hypertension	POS	I-NP
+.	POS	O
+At	POS	O
+discharge	POS	O
+,	POS	O
+she	POS	O
+had	POS	O
+complete	POS	O
+recovery	POS	O
+of	POS	O
+neurological	POS	O
+and	POS	O
+hepatic	POS	O
+functions	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+In	POS	O
+patients	POS	O
+with	POS	O
+FHF	POS	B-NP
+and	POS	O
+cerebral	POS	B-NP
+edema	POS	I-NP
+from	POS	O
+acetaminophen	POS	O
+overdose	POS	B-NP
+,	POS	O
+prolonged	POS	O
+therapeutic	POS	O
+hypothermia	POS	B-NP
+could	POS	O
+potentially	POS	O
+be	POS	O
+used	POS	O
+as	POS	O
+a	POS	O
+life	POS	O
+saving	POS	O
+therapy	POS	O
+and	POS	O
+a	POS	O
+bridge	POS	O
+to	POS	O
+hepatic	POS	O
+and	POS	O
+neurological	POS	O
+recovery	POS	O
+.	POS	O
+A	POS	O
+clinical	POS	O
+trial	POS	O
+of	POS	O
+hypothermia	POS	B-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+this	POS	O
+condition	POS	O
+is	POS	O
+warranted	POS	O
+.	POS	O
+Binasal	POS	B-NP
+visual	POS	I-NP
+field	POS	I-NP
+defects	POS	I-NP
+are	POS	O
+not	POS	O
+specific	POS	O
+to	POS	O
+vigabatrin	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+investigated	POS	O
+the	POS	O
+visual	POS	B-NP
+defects	POS	I-NP
+associated	POS	O
+with	POS	O
+the	POS	O
+antiepileptic	POS	O
+drug	POS	O
+vigabatrin	POS	O
+(	POS	O
+VGB	POS	O
+)	POS	O
+.	POS	O
+Two	POS	O
+hundred	POS	O
+four	POS	O
+people	POS	O
+with	POS	O
+epilepsy	POS	B-NP
+were	POS	O
+grouped	POS	O
+on	POS	O
+the	POS	O
+basis	POS	O
+of	POS	O
+antiepileptic	POS	O
+drug	POS	O
+therapy	POS	O
+(	POS	O
+current	POS	O
+,	POS	O
+previous	POS	O
+,	POS	O
+or	POS	O
+no	POS	O
+exposure	POS	O
+to	POS	O
+VGB	POS	O
+)	POS	O
+.	POS	O
+Groups	POS	O
+were	POS	O
+matched	POS	O
+with	POS	O
+respect	POS	O
+to	POS	O
+age	POS	O
+,	POS	O
+gender	POS	O
+,	POS	O
+and	POS	O
+seizure	POS	B-NP
+frequency	POS	O
+.	POS	O
+All	POS	O
+patients	POS	O
+underwent	POS	O
+objective	POS	O
+assessment	POS	O
+of	POS	O
+electrophysiological	POS	O
+function	POS	O
+(	POS	O
+wide	POS	O
+-	POS	O
+field	POS	O
+multifocal	POS	O
+electroretinography	POS	O
+)	POS	O
+and	POS	O
+conventional	POS	O
+visual	POS	O
+field	POS	O
+testing	POS	O
+(	POS	O
+static	POS	O
+perimetry	POS	O
+)	POS	O
+.	POS	O
+Bilateral	POS	B-NP
+visual	POS	I-NP
+field	POS	I-NP
+constriction	POS	I-NP
+was	POS	O
+observed	POS	O
+in	POS	O
+59	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+currently	POS	O
+taking	POS	O
+VGB	POS	O
+,	POS	O
+43	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+who	POS	O
+previously	POS	O
+took	POS	O
+VGB	POS	O
+,	POS	O
+and	POS	O
+24	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+no	POS	O
+exposure	POS	O
+to	POS	O
+VGB	POS	O
+.	POS	O
+Assessment	POS	O
+of	POS	O
+retinal	POS	O
+function	POS	O
+revealed	POS	O
+abnormal	POS	O
+responses	POS	O
+in	POS	O
+48	POS	O
+%	POS	O
+of	POS	O
+current	POS	O
+VGB	POS	O
+users	POS	O
+and	POS	O
+22	POS	O
+%	POS	O
+of	POS	O
+prior	POS	O
+VGB	POS	O
+users	POS	O
+,	POS	O
+but	POS	O
+in	POS	O
+none	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+without	POS	O
+previous	POS	O
+exposure	POS	O
+to	POS	O
+VGB	POS	B-NP
+.	POS	O
+Bilateral	POS	B-NP
+visual	POS	I-NP
+field	POS	I-NP
+abnormalities	POS	I-NP
+are	POS	O
+common	POS	O
+in	POS	O
+the	POS	O
+treated	POS	O
+epilepsy	POS	B-NP
+population	POS	O
+,	POS	O
+irrespective	POS	O
+of	POS	O
+drug	POS	O
+history	POS	O
+.	POS	O
+Assessment	POS	O
+by	POS	O
+conventional	POS	O
+static	POS	O
+perimetry	POS	O
+may	POS	O
+neither	POS	O
+be	POS	O
+sufficiently	POS	O
+sensitive	POS	O
+nor	POS	O
+specific	POS	O
+to	POS	O
+reliably	POS	O
+identify	POS	O
+retinal	POS	B-NP
+toxicity	POS	I-NP
+associated	POS	O
+with	POS	O
+VGB	POS	B-NP
+.	POS	O
+Smoking	POS	O
+of	POS	O
+crack	POS	O
+cocaine	POS	O
+as	POS	O
+a	POS	O
+risk	POS	O
+factor	POS	O
+for	POS	O
+HIV	POS	B-NP
+infection	POS	I-NP
+among	POS	O
+people	POS	O
+who	POS	O
+use	POS	O
+injection	POS	O
+drugs	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Little	POS	O
+is	POS	O
+known	POS	O
+about	POS	O
+the	POS	O
+possible	POS	O
+role	POS	O
+that	POS	O
+smoking	POS	O
+crack	POS	O
+cocaine	POS	O
+has	POS	O
+on	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+HIV	POS	B-NP
+infection	POS	I-NP
+.	POS	O
+Given	POS	O
+the	POS	O
+increasing	POS	O
+use	POS	O
+of	POS	O
+crack	POS	O
+cocaine	POS	O
+,	POS	O
+we	POS	O
+sought	POS	O
+to	POS	O
+examine	POS	O
+whether	POS	O
+use	POS	O
+of	POS	O
+this	POS	O
+illicit	POS	O
+drug	POS	O
+has	POS	O
+become	POS	O
+a	POS	O
+risk	POS	O
+factor	POS	O
+for	POS	O
+HIV	POS	B-NP
+infection	POS	I-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+included	POS	O
+data	POS	O
+from	POS	O
+people	POS	O
+participating	POS	O
+in	POS	O
+the	POS	O
+Vancouver	POS	O
+Injection	POS	O
+Drug	POS	O
+Users	POS	O
+Study	POS	O
+who	POS	O
+reported	POS	O
+injecting	POS	O
+illicit	POS	O
+drugs	POS	O
+at	POS	O
+least	POS	O
+once	POS	O
+in	POS	O
+the	POS	O
+month	POS	O
+before	POS	O
+enrolment	POS	O
+,	POS	O
+lived	POS	O
+in	POS	O
+the	POS	O
+greater	POS	O
+Vancouver	POS	O
+area	POS	O
+,	POS	O
+were	POS	O
+HIV	POS	O
+-	POS	O
+negative	POS	O
+at	POS	O
+enrolment	POS	O
+and	POS	O
+completed	POS	O
+at	POS	O
+least	POS	O
+1	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+study	POS	O
+visit	POS	O
+.	POS	O
+To	POS	O
+determine	POS	O
+whether	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+HIV	POS	B-NP
+seroconversion	POS	I-NP
+among	POS	O
+daily	POS	O
+smokers	POS	O
+of	POS	O
+crack	POS	O
+cocaine	POS	O
+changed	POS	O
+over	POS	O
+time	POS	O
+,	POS	O
+we	POS	O
+used	POS	O
+Cox	POS	O
+proportional	POS	O
+hazards	POS	O
+regression	POS	O
+and	POS	O
+divided	POS	O
+the	POS	O
+study	POS	O
+into	POS	O
+3	POS	O
+periods	POS	O
+:	POS	O
+May	POS	O
+1	POS	O
+,	POS	O
+1996	POS	O
+-	POS	O
+Nov	POS	O
+.	POS	O
+30	POS	O
+,	POS	O
+1999	POS	O
+(	POS	O
+period	POS	O
+1	POS	O
+)	POS	O
+,	POS	O
+Dec	POS	O
+.	POS	O
+1	POS	O
+,	POS	O
+1999	POS	O
+-	POS	O
+Nov	POS	O
+.	POS	O
+30	POS	O
+,	POS	O
+2002	POS	O
+(	POS	O
+period	POS	O
+2	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+Dec	POS	O
+.	POS	O
+1	POS	O
+,	POS	O
+2002	POS	O
+-	POS	O
+Dec	POS	O
+.	POS	O
+30	POS	O
+,	POS	O
+2005	POS	O
+(	POS	O
+period	POS	O
+3	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Overall	POS	O
+,	POS	O
+1048	POS	O
+eligible	POS	O
+injection	POS	O
+drug	POS	O
+users	POS	O
+were	POS	O
+included	POS	O
+in	POS	O
+our	POS	O
+study	POS	O
+.	POS	O
+Of	POS	O
+these	POS	O
+,	POS	O
+137	POS	O
+acquired	POS	O
+HIV	POS	B-NP
+infection	POS	I-NP
+during	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+proportion	POS	O
+of	POS	O
+participants	POS	O
+who	POS	O
+reported	POS	O
+daily	POS	O
+smoking	POS	O
+of	POS	O
+crack	POS	O
+cocaine	POS	O
+increased	POS	O
+from	POS	O
+11	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+in	POS	O
+period	POS	O
+1	POS	O
+to	POS	O
+39	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+in	POS	O
+period	POS	O
+3	POS	O
+.	POS	O
+After	POS	O
+adjusting	POS	O
+for	POS	O
+potential	POS	O
+confounders	POS	O
+,	POS	O
+we	POS	O
+found	POS	O
+that	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+HIV	POS	B-NP
+seroconversion	POS	I-NP
+among	POS	O
+participants	POS	O
+who	POS	O
+were	POS	O
+daily	POS	O
+smokers	POS	O
+of	POS	O
+crack	POS	O
+cocaine	POS	O
+increased	POS	O
+over	POS	O
+time	POS	O
+(	POS	O
+period	POS	O
+1	POS	O
+:	POS	O
+hazard	POS	O
+ratio	POS	O
+[	POS	O
+HR	POS	O
+]	POS	O
+1	POS	O
+.	POS	O
+03	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+[	POS	O
+CI	POS	O
+]	POS	O
+0	POS	O
+.	POS	O
+57	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+85	POS	O
+;	POS	O
+period	POS	O
+2	POS	O
+:	POS	O
+HR	POS	O
+1	POS	O
+.	POS	O
+68	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+1	POS	O
+.	POS	O
+01	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+80	POS	O
+;	POS	O
+and	POS	O
+period	POS	O
+3	POS	O
+:	POS	O
+HR	POS	O
+2	POS	O
+.	POS	O
+74	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+1	POS	O
+.	POS	O
+06	POS	O
+-	POS	O
+7	POS	O
+.	POS	O
+11	POS	O
+)	POS	O
+.	POS	O
+INTERPRETATION	POS	O
+:	POS	O
+Smoking	POS	O
+of	POS	O
+crack	POS	O
+cocaine	POS	O
+was	POS	O
+found	POS	O
+to	POS	O
+be	POS	O
+an	POS	O
+independent	POS	O
+risk	POS	O
+factor	POS	O
+for	POS	O
+HIV	POS	B-NP
+seroconversion	POS	I-NP
+among	POS	O
+people	POS	O
+who	POS	O
+were	POS	O
+injection	POS	O
+drug	POS	O
+users	POS	O
+.	POS	O
+This	POS	O
+finding	POS	O
+points	POS	O
+to	POS	O
+the	POS	O
+urgent	POS	O
+need	POS	O
+for	POS	O
+evidence	POS	O
+-	POS	O
+based	POS	O
+public	POS	O
+health	POS	O
+initiatives	POS	O
+targeted	POS	O
+at	POS	O
+people	POS	O
+who	POS	O
+smoke	POS	O
+crack	POS	O
+cocaine	POS	O
+.	POS	O
+Fluoxetine	POS	O
+improves	POS	O
+the	POS	O
+memory	POS	B-NP
+deficits	POS	I-NP
+caused	POS	O
+by	POS	O
+the	POS	O
+chemotherapy	POS	O
+agent	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+.	POS	O
+Cancer	POS	B-NP
+patients	POS	O
+who	POS	O
+have	POS	O
+been	POS	O
+treated	POS	O
+with	POS	O
+systemic	POS	O
+adjuvant	POS	O
+chemotherapy	POS	O
+have	POS	O
+described	POS	O
+experiencing	POS	O
+deteriorations	POS	O
+in	POS	O
+cognition	POS	O
+.	POS	O
+A	POS	O
+widely	POS	O
+used	POS	O
+chemotherapeutic	POS	O
+agent	POS	O
+,	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+(	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+)	POS	O
+,	POS	O
+readily	POS	O
+crosses	POS	O
+the	POS	O
+blood	POS	O
+-	POS	O
+brain	POS	O
+barrier	POS	O
+and	POS	O
+so	POS	O
+could	POS	O
+have	POS	O
+a	POS	O
+direct	POS	O
+effect	POS	O
+on	POS	O
+brain	POS	O
+function	POS	O
+.	POS	O
+In	POS	O
+particular	POS	O
+this	POS	O
+anti	POS	O
+mitotic	POS	O
+drug	POS	O
+could	POS	O
+reduce	POS	O
+cell	POS	O
+proliferation	POS	O
+in	POS	O
+the	POS	O
+neurogenic	POS	O
+regions	POS	O
+of	POS	O
+the	POS	O
+adult	POS	O
+brain	POS	O
+.	POS	O
+In	POS	O
+contrast	POS	O
+reports	POS	O
+indicate	POS	O
+that	POS	O
+hippocampal	POS	O
+dependent	POS	O
+neurogenesis	POS	O
+and	POS	O
+cognition	POS	O
+are	POS	O
+enhanced	POS	O
+by	POS	O
+the	POS	O
+SSRI	POS	O
+antidepressant	POS	O
+Fluoxetine	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+investigation	POS	O
+the	POS	O
+behavioural	POS	O
+effects	POS	O
+of	POS	O
+chronic	POS	O
+(	POS	O
+two	POS	O
+week	POS	O
+)	POS	O
+treatment	POS	O
+with	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+and	POS	O
+(	POS	O
+three	POS	O
+weeks	POS	O
+)	POS	O
+with	POS	O
+Fluoxetine	POS	O
+either	POS	O
+separately	POS	O
+or	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+were	POS	O
+tested	POS	O
+on	POS	O
+adult	POS	O
+Lister	POS	O
+hooded	POS	O
+rats	POS	O
+.	POS	O
+Behavioural	POS	O
+effects	POS	O
+were	POS	O
+tested	POS	O
+using	POS	O
+a	POS	O
+context	POS	O
+dependent	POS	O
+conditioned	POS	O
+emotional	POS	O
+response	POS	O
+test	POS	O
+(	POS	O
+CER	POS	O
+)	POS	O
+which	POS	O
+showed	POS	O
+that	POS	O
+animals	POS	O
+treated	POS	O
+with	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+had	POS	O
+a	POS	O
+significant	POS	O
+reduction	POS	O
+in	POS	O
+freezing	POS	O
+time	POS	O
+compared	POS	O
+to	POS	O
+controls	POS	O
+.	POS	O
+A	POS	O
+separate	POS	O
+group	POS	O
+of	POS	O
+animals	POS	O
+was	POS	O
+tested	POS	O
+using	POS	O
+a	POS	O
+hippocampal	POS	O
+dependent	POS	O
+spatial	POS	O
+working	POS	O
+memory	POS	O
+test	POS	O
+,	POS	O
+the	POS	O
+object	POS	O
+location	POS	O
+recognition	POS	O
+test	POS	O
+(	POS	O
+OLR	POS	O
+)	POS	O
+.	POS	O
+Animals	POS	O
+treated	POS	O
+only	POS	O
+with	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+showed	POS	O
+significant	POS	O
+deficits	POS	O
+in	POS	O
+their	POS	O
+ability	POS	O
+to	POS	O
+carry	POS	O
+out	POS	O
+the	POS	O
+OLR	POS	O
+task	POS	O
+but	POS	O
+co	POS	O
+administration	POS	O
+of	POS	O
+Fluoxetine	POS	O
+improved	POS	O
+their	POS	O
+performance	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+chemotherapy	POS	O
+caused	POS	O
+a	POS	O
+significant	POS	O
+reduction	POS	O
+in	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+proliferating	POS	O
+cells	POS	O
+in	POS	O
+the	POS	O
+sub	POS	O
+granular	POS	O
+zone	POS	O
+of	POS	O
+the	POS	O
+dentate	POS	O
+gyrus	POS	O
+compared	POS	O
+to	POS	O
+controls	POS	O
+.	POS	O
+This	POS	O
+reduction	POS	O
+was	POS	O
+eliminated	POS	O
+when	POS	O
+Fluoxetine	POS	O
+was	POS	O
+co	POS	O
+administered	POS	O
+with	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+.	POS	O
+Fluoxetine	POS	O
+on	POS	O
+its	POS	O
+own	POS	O
+had	POS	O
+no	POS	O
+effect	POS	O
+on	POS	O
+proliferating	POS	O
+cell	POS	O
+number	POS	O
+or	POS	O
+behaviour	POS	O
+.	POS	O
+These	POS	O
+findings	POS	O
+suggest	POS	O
+that	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+can	POS	O
+negatively	POS	O
+affect	POS	O
+both	POS	O
+cell	POS	O
+proliferation	POS	O
+and	POS	O
+hippocampal	POS	O
+dependent	POS	O
+working	POS	O
+memory	POS	O
+and	POS	O
+that	POS	O
+these	POS	O
+deficits	POS	O
+can	POS	O
+be	POS	O
+reversed	POS	O
+by	POS	O
+the	POS	O
+simultaneous	POS	O
+administration	POS	O
+of	POS	O
+the	POS	O
+antidepressant	POS	O
+Fluoxetine	POS	O
+.	POS	O
+Liver	POS	O
+-	POS	O
+specific	POS	O
+ablation	POS	O
+of	POS	O
+integrin	POS	O
+-	POS	O
+linked	POS	O
+kinase	POS	O
+in	POS	O
+mice	POS	O
+results	POS	O
+in	POS	O
+enhanced	POS	O
+and	POS	O
+prolonged	POS	O
+cell	POS	O
+proliferation	POS	O
+and	POS	O
+hepatomegaly	POS	B-NP
+after	POS	O
+phenobarbital	POS	O
+administration	POS	O
+.	POS	O
+We	POS	O
+have	POS	O
+recently	POS	O
+demonstrated	POS	O
+that	POS	O
+disruption	POS	O
+of	POS	O
+extracellular	POS	O
+matrix	POS	O
+(	POS	O
+ECM	POS	O
+)	POS	O
+/	POS	O
+integrin	POS	O
+signaling	POS	O
+via	POS	O
+elimination	POS	O
+of	POS	O
+integrin	POS	O
+-	POS	O
+linked	POS	O
+kinase	POS	O
+(	POS	O
+ILK	POS	O
+)	POS	O
+in	POS	O
+hepatocytes	POS	O
+interferes	POS	O
+with	POS	O
+signals	POS	O
+leading	POS	O
+to	POS	O
+termination	POS	O
+of	POS	O
+liver	POS	O
+regeneration	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+investigates	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+ILK	POS	O
+in	POS	O
+liver	POS	B-NP
+enlargement	POS	I-NP
+induced	POS	O
+by	POS	O
+phenobarbital	POS	O
+(	POS	O
+PB	POS	O
+)	POS	O
+.	POS	O
+Wild	POS	O
+-	POS	O
+type	POS	O
+(	POS	O
+WT	POS	O
+)	POS	O
+and	POS	O
+ILK	POS	O
+:	POS	O
+liver	POS	O
+-	POS	O
+/	POS	O
+-	POS	O
+mice	POS	O
+were	POS	O
+given	POS	O
+PB	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+in	POS	O
+drinking	POS	O
+water	POS	O
+)	POS	O
+for	POS	O
+10	POS	O
+days	POS	O
+.	POS	O
+Livers	POS	O
+were	POS	O
+harvested	POS	O
+on	POS	O
+2	POS	O
+,	POS	O
+5	POS	O
+,	POS	O
+and	POS	O
+10	POS	O
+days	POS	O
+during	POS	O
+PB	POS	O
+administration	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+hepatocyte	POS	O
+-	POS	O
+specific	POS	O
+ILK	POS	O
+/	POS	O
+liver	POS	O
+-	POS	O
+/	POS	O
+-	POS	O
+mice	POS	O
+,	POS	O
+the	POS	O
+liver	POS	O
+:	POS	O
+body	POS	O
+weight	POS	O
+ratio	POS	O
+was	POS	O
+more	POS	O
+than	POS	O
+double	POS	O
+as	POS	O
+compared	POS	O
+to	POS	O
+0	POS	O
+h	POS	O
+at	POS	O
+day	POS	O
+2	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+times	POS	O
+)	POS	O
+,	POS	O
+while	POS	O
+at	POS	O
+days	POS	O
+5	POS	O
+and	POS	O
+10	POS	O
+,	POS	O
+it	POS	O
+was	POS	O
+enlarged	POS	O
+three	POS	O
+times	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+WT	POS	O
+mice	POS	O
+,	POS	O
+the	POS	O
+increase	POS	O
+was	POS	O
+as	POS	O
+expected	POS	O
+from	POS	O
+previous	POS	O
+literature	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+8	POS	O
+times	POS	O
+)	POS	O
+and	POS	O
+seems	POS	O
+to	POS	O
+have	POS	O
+leveled	POS	O
+off	POS	O
+after	POS	O
+day	POS	O
+2	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+slightly	POS	O
+increased	POS	O
+proliferating	POS	O
+cell	POS	O
+nuclear	POS	O
+antigen	POS	O
+-	POS	O
+positive	POS	O
+cells	POS	O
+in	POS	O
+the	POS	O
+ILK	POS	O
+/	POS	O
+liver	POS	O
+-	POS	O
+/	POS	O
+-	POS	O
+animals	POS	O
+at	POS	O
+day	POS	O
+2	POS	O
+as	POS	O
+compared	POS	O
+to	POS	O
+WT	POS	O
+after	POS	O
+PB	POS	O
+administration	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+WT	POS	O
+animals	POS	O
+,	POS	O
+the	POS	O
+proliferative	POS	O
+response	POS	O
+had	POS	O
+come	POS	O
+back	POS	O
+to	POS	O
+normal	POS	O
+by	POS	O
+days	POS	O
+5	POS	O
+and	POS	O
+10	POS	O
+.	POS	O
+Hepatocytes	POS	O
+of	POS	O
+the	POS	O
+ILK	POS	O
+/	POS	O
+liver	POS	O
+-	POS	O
+/	POS	O
+-	POS	O
+mice	POS	O
+continued	POS	O
+to	POS	O
+proliferate	POS	O
+up	POS	O
+until	POS	O
+day	POS	O
+10	POS	O
+.	POS	O
+ILK	POS	O
+/	POS	O
+liver	POS	O
+-	POS	O
+/	POS	O
+-	POS	O
+mice	POS	O
+also	POS	O
+showed	POS	O
+increased	POS	O
+expression	POS	O
+of	POS	O
+key	POS	O
+genes	POS	O
+involved	POS	O
+in	POS	O
+hepatocyte	POS	O
+proliferation	POS	O
+at	POS	O
+different	POS	O
+time	POS	O
+points	POS	O
+during	POS	O
+PB	POS	O
+administration	POS	O
+.	POS	O
+In	POS	O
+summary	POS	O
+,	POS	O
+ECM	POS	O
+proteins	POS	O
+communicate	POS	O
+with	POS	O
+the	POS	O
+signaling	POS	O
+machinery	POS	O
+of	POS	O
+dividing	POS	O
+cells	POS	O
+via	POS	O
+ILK	POS	O
+to	POS	O
+regulate	POS	O
+hepatocyte	POS	O
+proliferation	POS	O
+and	POS	O
+termination	POS	O
+of	POS	O
+the	POS	O
+proliferative	POS	O
+response	POS	O
+.	POS	O
+Lack	POS	O
+of	POS	O
+ILK	POS	O
+in	POS	O
+the	POS	O
+hepatocytes	POS	O
+imparts	POS	O
+prolonged	POS	O
+proliferative	POS	O
+response	POS	O
+not	POS	O
+only	POS	O
+to	POS	O
+stimuli	POS	O
+related	POS	O
+to	POS	O
+liver	POS	O
+regeneration	POS	O
+but	POS	O
+also	POS	O
+to	POS	O
+xenobiotic	POS	O
+chemical	POS	O
+mitogens	POS	O
+,	POS	O
+such	POS	O
+as	POS	O
+PB	POS	O
+.	POS	O
+Decreased	POS	O
+Expression	POS	O
+of	POS	O
+Na	POS	O
+/	POS	O
+K	POS	O
+-	POS	O
+ATPase	POS	O
+,	POS	O
+NHE3	POS	O
+,	POS	O
+NBC1	POS	O
+,	POS	O
+AQP1	POS	O
+and	POS	O
+OAT	POS	O
+in	POS	O
+Gentamicin	POS	O
+-	POS	O
+induced	POS	O
+Nephropathy	POS	B-NP
+.	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+aimed	POS	O
+to	POS	O
+determine	POS	O
+whether	POS	O
+there	POS	O
+is	POS	O
+an	POS	O
+altered	POS	O
+regulation	POS	O
+of	POS	O
+tubular	POS	O
+transporters	POS	O
+in	POS	O
+gentamicin	POS	O
+-	POS	O
+induced	POS	O
+nephropathy	POS	B-NP
+.	POS	O
+Sprague	POS	O
+-	POS	O
+Dawley	POS	O
+male	POS	O
+rats	POS	O
+(	POS	O
+200	POS	O
+~	POS	O
+250	POS	O
+g	POS	O
+)	POS	O
+were	POS	O
+subcutaneously	POS	O
+injected	POS	O
+with	POS	O
+gentamicin	POS	O
+(	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+per	POS	O
+day	POS	O
+)	POS	O
+for	POS	O
+7	POS	O
+days	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+expression	POS	O
+of	POS	O
+tubular	POS	O
+transporters	POS	O
+was	POS	O
+determined	POS	O
+by	POS	O
+immunoblotting	POS	O
+and	POS	O
+immunohistochemistry	POS	O
+.	POS	O
+The	POS	O
+mRNA	POS	O
+and	POS	O
+protein	POS	O
+expression	POS	O
+of	POS	O
+OAT	POS	O
+was	POS	O
+also	POS	O
+determined	POS	O
+.	POS	O
+Gentamicin	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+exhibited	POS	O
+significantly	POS	O
+decreased	POS	O
+creatinine	POS	O
+clearance	POS	O
+along	POS	O
+with	POS	O
+increased	POS	O
+plasma	POS	O
+creatinine	POS	O
+levels	POS	O
+.	POS	O
+Accordingly	POS	O
+,	POS	O
+the	POS	O
+fractional	POS	O
+excretion	POS	O
+of	POS	O
+sodium	POS	O
+increased	POS	O
+.	POS	O
+Urine	POS	O
+volume	POS	O
+was	POS	O
+increased	POS	O
+,	POS	O
+while	POS	O
+urine	POS	O
+osmolality	POS	O
+and	POS	O
+free	POS	O
+water	POS	O
+reabsorption	POS	O
+were	POS	O
+decreased	POS	O
+.	POS	O
+Immunoblotting	POS	O
+and	POS	O
+immunohistochemistry	POS	O
+revealed	POS	O
+decreased	POS	O
+expression	POS	O
+of	POS	O
+Na	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+/	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+ATPase	POS	O
+,	POS	O
+NHE3	POS	O
+,	POS	O
+NBC1	POS	O
+,	POS	O
+and	POS	O
+AQP1	POS	O
+in	POS	O
+the	POS	O
+kidney	POS	O
+of	POS	O
+gentamicin	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+expression	POS	O
+of	POS	O
+OAT1	POS	O
+and	POS	O
+OAT3	POS	O
+was	POS	O
+also	POS	O
+decreased	POS	O
+.	POS	O
+Gentamicin	POS	O
+-	POS	O
+induced	POS	O
+nephropathy	POS	B-NP
+may	POS	O
+at	POS	O
+least	POS	O
+in	POS	O
+part	POS	O
+be	POS	O
+causally	POS	O
+related	POS	O
+with	POS	O
+a	POS	O
+decreased	POS	O
+expression	POS	O
+of	POS	O
+Na	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+/	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+-	POS	O
+ATPase	POS	O
+,	POS	O
+NHE3	POS	O
+,	POS	O
+NBC1	POS	O
+,	POS	O
+AQP1	POS	O
+and	POS	O
+OAT	POS	O
+.	POS	O
+Acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+after	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+methotrexate	POS	O
+therapy	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+ileostomy	POS	O
+.	POS	O
+High	POS	O
+-	POS	O
+dose	POS	O
+methotrexate	POS	O
+(	POS	O
+HD	POS	B-NP
+-	POS	O
+MTX	POS	O
+)	POS	O
+is	POS	O
+an	POS	O
+important	POS	O
+treatment	POS	O
+for	POS	O
+Burkitt	POS	B-NP
+lymphoma	POS	I-NP
+,	POS	O
+but	POS	O
+can	POS	O
+cause	POS	O
+hepatic	POS	B-NP
+and	POS	I-NP
+renal	POS	I-NP
+toxicity	POS	I-NP
+when	POS	O
+its	POS	O
+clearance	POS	O
+is	POS	O
+delayed	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+after	POS	O
+HD	POS	B-NP
+-	POS	O
+MTX	POS	O
+therapy	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+ileostomy	POS	O
+,	POS	O
+The	POS	O
+patient	POS	O
+was	POS	O
+a	POS	O
+3	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+boy	POS	O
+who	POS	O
+had	POS	O
+received	POS	O
+a	POS	O
+living	POS	O
+-	POS	O
+related	POS	O
+liver	POS	O
+transplantation	POS	O
+for	POS	O
+congenital	POS	B-NP
+biliary	POS	I-NP
+atresia	POS	I-NP
+.	POS	O
+At	POS	O
+day	POS	O
+833	POS	O
+after	POS	O
+the	POS	O
+transplantation	POS	O
+,	POS	O
+he	POS	O
+was	POS	O
+diagnosed	POS	O
+with	POS	O
+PTLD	POS	B-NP
+(	POS	O
+post	POS	B-NP
+-	POS	I-NP
+transplantation	POS	I-NP
+lymphoproliferative	POS	I-NP
+disorder	POS	I-NP
+,	POS	O
+Burkitt	POS	B-NP
+-	POS	I-NP
+type	POS	I-NP
+malignant	POS	I-NP
+lymphoma	POS	I-NP
+)	POS	O
+.	POS	O
+During	POS	O
+induction	POS	O
+therapy	POS	O
+,	POS	O
+he	POS	O
+suffered	POS	O
+ileal	POS	B-NP
+perforation	POS	I-NP
+and	POS	O
+ileostomy	POS	B-NP
+was	POS	O
+performed	POS	O
+.	POS	O
+Subsequent	POS	O
+HD	POS	B-NP
+-	POS	O
+MTX	POS	O
+therapy	POS	O
+caused	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+that	POS	O
+required	POS	O
+continuous	POS	O
+hemodialysis	POS	O
+.	POS	O
+We	POS	O
+supposed	POS	O
+that	POS	O
+intravascular	POS	B-NP
+hypovolemia	POS	I-NP
+due	POS	O
+to	POS	O
+substantial	POS	O
+drainage	POS	O
+from	POS	O
+the	POS	O
+ileostoma	POS	B-NP
+caused	POS	O
+acute	POS	B-NP
+prerenal	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+After	POS	O
+recovery	POS	O
+of	POS	O
+his	POS	O
+renal	POS	O
+function	POS	O
+,	POS	O
+we	POS	O
+could	POS	O
+safely	POS	O
+treat	POS	O
+the	POS	O
+patient	POS	O
+with	POS	O
+HD	POS	B-NP
+-	POS	O
+MTX	POS	O
+therapy	POS	O
+by	POS	O
+controlling	POS	O
+drainage	POS	O
+from	POS	O
+ileostoma	POS	B-NP
+with	POS	O
+total	POS	O
+parenteral	POS	O
+nutrition	POS	O
+.	POS	O
+Longitudinal	POS	O
+association	POS	O
+of	POS	O
+alcohol	POS	O
+use	POS	O
+with	POS	O
+HIV	POS	B-NP
+disease	POS	I-NP
+progression	POS	O
+and	POS	O
+psychological	POS	O
+health	POS	O
+of	POS	O
+women	POS	O
+with	POS	O
+HIV	POS	B-NP
+.	POS	O
+We	POS	O
+evaluated	POS	O
+the	POS	O
+association	POS	O
+of	POS	O
+alcohol	POS	O
+consumption	POS	O
+and	POS	O
+depression	POS	B-NP
+,	POS	O
+and	POS	O
+their	POS	O
+effects	POS	O
+on	POS	O
+HIV	POS	B-NP
+disease	POS	I-NP
+progression	POS	O
+among	POS	O
+women	POS	O
+with	POS	O
+HIV	POS	B-NP
+.	POS	O
+The	POS	O
+study	POS	O
+included	POS	O
+871	POS	O
+women	POS	O
+with	POS	O
+HIV	POS	B-NP
+who	POS	O
+were	POS	O
+recruited	POS	O
+from	POS	O
+1993	POS	O
+-	POS	O
+1995	POS	O
+in	POS	O
+four	POS	O
+US	POS	O
+cities	POS	O
+.	POS	O
+The	POS	O
+participants	POS	O
+had	POS	O
+physical	POS	O
+examination	POS	O
+,	POS	O
+medical	POS	O
+record	POS	O
+extraction	POS	O
+,	POS	O
+and	POS	O
+venipuncture	POS	O
+,	POS	O
+CD4	POS	O
++	POS	O
+T	POS	O
+-	POS	O
+cell	POS	O
+counts	POS	O
+determination	POS	O
+,	POS	O
+measurement	POS	O
+of	POS	O
+depression	POS	B-NP
+symptoms	POS	O
+(	POS	O
+using	POS	O
+the	POS	O
+self	POS	O
+-	POS	O
+report	POS	O
+Center	POS	O
+for	POS	O
+Epidemiological	POS	O
+Studies	POS	O
+-	POS	O
+Depression	POS	O
+Scale	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+alcohol	POS	O
+use	POS	O
+assessment	POS	O
+at	POS	O
+enrollment	POS	O
+,	POS	O
+and	POS	O
+semiannually	POS	O
+until	POS	O
+March	POS	O
+2000	POS	O
+.	POS	O
+Multilevel	POS	O
+random	POS	O
+coefficient	POS	O
+ordinal	POS	O
+models	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+multilevel	POS	O
+models	POS	O
+with	POS	O
+joint	POS	O
+responses	POS	O
+were	POS	O
+used	POS	O
+in	POS	O
+the	POS	O
+analysis	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+significant	POS	O
+association	POS	O
+between	POS	O
+level	POS	O
+of	POS	O
+alcohol	POS	O
+use	POS	O
+and	POS	O
+CD4	POS	O
++	POS	O
+T	POS	O
+-	POS	O
+cell	POS	O
+counts	POS	O
+.	POS	O
+When	POS	O
+participants	POS	O
+were	POS	O
+stratified	POS	O
+by	POS	O
+antiretroviral	POS	O
+therapy	POS	O
+(	POS	O
+ART	POS	O
+)	POS	O
+use	POS	O
+,	POS	O
+the	POS	O
+association	POS	O
+between	POS	O
+alcohol	POS	O
+and	POS	O
+CD4	POS	O
++	POS	O
+T	POS	O
+-	POS	O
+cell	POS	O
+did	POS	O
+not	POS	O
+reach	POS	O
+statistical	POS	O
+significance	POS	O
+.	POS	O
+The	POS	O
+association	POS	O
+between	POS	O
+alcohol	POS	O
+consumption	POS	O
+and	POS	O
+depression	POS	B-NP
+was	POS	O
+significant	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+Depression	POS	B-NP
+had	POS	O
+a	POS	O
+significant	POS	O
+negative	POS	O
+effect	POS	O
+on	POS	O
+CD4	POS	O
++	POS	O
+T	POS	O
+-	POS	O
+cell	POS	O
+counts	POS	O
+over	POS	O
+time	POS	O
+regardless	POS	O
+of	POS	O
+ART	POS	O
+use	POS	O
+.	POS	O
+Our	POS	O
+findings	POS	O
+suggest	POS	O
+that	POS	O
+alcohol	POS	O
+consumption	POS	O
+has	POS	O
+a	POS	O
+direct	POS	O
+association	POS	O
+with	POS	O
+depression	POS	B-NP
+.	POS	O
+Moreover	POS	O
+,	POS	O
+depression	POS	B-NP
+is	POS	O
+associated	POS	O
+with	POS	O
+HIV	POS	B-NP
+disease	POS	I-NP
+progression	POS	O
+.	POS	O
+Our	POS	O
+findings	POS	O
+have	POS	O
+implications	POS	O
+for	POS	O
+the	POS	O
+provision	POS	O
+of	POS	O
+alcohol	POS	O
+use	POS	O
+interventions	POS	O
+and	POS	O
+psychological	POS	O
+resources	POS	O
+to	POS	O
+improve	POS	O
+the	POS	O
+health	POS	O
+of	POS	O
+women	POS	O
+with	POS	O
+HIV	POS	O
+.	POS	O
+Chemokine	POS	O
+CCL2	POS	O
+and	POS	O
+its	POS	O
+receptor	POS	O
+CCR2	POS	O
+are	POS	O
+increased	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+following	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Neuroinflammation	POS	O
+occurs	POS	O
+after	POS	O
+seizures	POS	B-NP
+and	POS	O
+is	POS	O
+implicated	POS	O
+in	POS	O
+epileptogenesis	POS	B-NP
+.	POS	O
+CCR2	POS	O
+is	POS	O
+a	POS	O
+chemokine	POS	O
+receptor	POS	O
+for	POS	O
+CCL2	POS	O
+and	POS	O
+their	POS	O
+interaction	POS	O
+mediates	POS	O
+monocyte	POS	O
+infiltration	POS	O
+in	POS	O
+the	POS	O
+neuroinflammatory	POS	O
+cascade	POS	O
+triggered	POS	O
+in	POS	O
+different	POS	O
+brain	POS	B-NP
+pathologies	POS	I-NP
+.	POS	O
+In	POS	O
+this	POS	O
+work	POS	O
+CCR2	POS	O
+and	POS	O
+CCL2	POS	O
+expression	POS	O
+were	POS	O
+examined	POS	O
+following	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+(	POS	O
+SE	POS	B-NP
+)	POS	O
+induced	POS	O
+by	POS	O
+pilocarpine	POS	O
+injection	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+SE	POS	B-NP
+was	POS	O
+induced	POS	O
+by	POS	O
+pilocarpine	POS	O
+injection	POS	O
+.	POS	O
+Control	POS	O
+rats	POS	O
+were	POS	O
+injected	POS	O
+with	POS	O
+saline	POS	O
+instead	POS	O
+of	POS	O
+pilocarpine	POS	O
+.	POS	O
+Five	POS	O
+days	POS	O
+after	POS	O
+SE	POS	O
+,	POS	O
+CCR2	POS	O
+staining	POS	O
+in	POS	O
+neurons	POS	O
+and	POS	O
+glial	POS	O
+cells	POS	O
+was	POS	O
+examined	POS	O
+using	POS	O
+imunohistochemical	POS	O
+analyses	POS	O
+.	POS	O
+The	POS	O
+number	POS	O
+of	POS	O
+CCR2	POS	O
+positive	POS	O
+cells	POS	O
+was	POS	O
+determined	POS	O
+using	POS	O
+stereology	POS	O
+probes	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+.	POS	O
+CCL2	POS	O
+expression	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+was	POS	O
+examined	POS	O
+by	POS	O
+molecular	POS	O
+assay	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Increased	POS	O
+CCR2	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+after	POS	O
+SE	POS	B-NP
+.	POS	O
+Seizures	POS	B-NP
+also	POS	O
+resulted	POS	O
+in	POS	O
+alterations	POS	O
+to	POS	O
+the	POS	O
+cell	POS	O
+types	POS	O
+expressing	POS	O
+CCR2	POS	O
+.	POS	O
+Increased	POS	O
+numbers	POS	O
+of	POS	O
+neurons	POS	O
+that	POS	O
+expressed	POS	O
+CCR2	POS	O
+was	POS	O
+observed	POS	O
+following	POS	O
+SE	POS	B-NP
+.	POS	O
+Microglial	POS	O
+cells	POS	O
+were	POS	O
+more	POS	O
+closely	POS	O
+apposed	POS	O
+to	POS	O
+the	POS	O
+CCR2	POS	O
+-	POS	O
+labeled	POS	O
+cells	POS	O
+in	POS	O
+SE	POS	O
+rats	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+rats	POS	O
+that	POS	O
+experienced	POS	O
+SE	POS	O
+exhibited	POS	O
+CCR2	POS	O
+-	POS	O
+labeling	POS	O
+in	POS	O
+populations	POS	O
+of	POS	O
+hypertrophied	POS	O
+astrocytes	POS	O
+,	POS	O
+especially	POS	O
+in	POS	O
+CA1	POS	O
+and	POS	O
+dentate	POS	O
+gyrus	POS	O
+.	POS	O
+These	POS	O
+CCR2	POS	O
++	POS	O
+astroctytes	POS	O
+were	POS	O
+not	POS	O
+observed	POS	O
+in	POS	O
+control	POS	O
+rats	POS	O
+.	POS	O
+Examination	POS	O
+of	POS	O
+CCL2	POS	O
+expression	POS	O
+showed	POS	O
+that	POS	O
+it	POS	O
+was	POS	O
+elevated	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+following	POS	O
+SE	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+The	POS	O
+data	POS	O
+show	POS	O
+that	POS	O
+CCR2	POS	O
+and	POS	O
+CCL2	POS	O
+are	POS	O
+up	POS	O
+-	POS	O
+regulated	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+after	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+SE	POS	B-NP
+.	POS	O
+Seizures	POS	B-NP
+also	POS	O
+result	POS	O
+in	POS	O
+changes	POS	O
+to	POS	O
+CCR2	POS	O
+receptor	POS	O
+expression	POS	O
+in	POS	O
+neurons	POS	O
+and	POS	O
+astrocytes	POS	O
+.	POS	O
+These	POS	O
+changes	POS	O
+might	POS	O
+be	POS	O
+involved	POS	O
+in	POS	O
+detrimental	POS	O
+neuroplasticity	POS	O
+and	POS	O
+neuroinflammatory	POS	O
+changes	POS	O
+that	POS	O
+occur	POS	O
+following	POS	O
+seizures	POS	B-NP
+.	POS	O
+Metallothionein	POS	O
+induction	POS	O
+reduces	POS	O
+caspase	POS	O
+-	POS	O
+3	POS	O
+activity	POS	O
+and	POS	O
+TNFalpha	POS	O
+levels	POS	O
+with	POS	O
+preservation	POS	O
+of	POS	O
+cognitive	POS	O
+function	POS	O
+and	POS	O
+intact	POS	O
+hippocampal	POS	O
+neurons	POS	O
+in	POS	O
+carmustine	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+.	POS	O
+Hippocampal	POS	O
+integrity	POS	O
+is	POS	O
+essential	POS	O
+for	POS	O
+cognitive	POS	O
+functions	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+other	POS	O
+hand	POS	O
+,	POS	O
+induction	POS	O
+of	POS	O
+metallothionein	POS	O
+(	POS	O
+MT	POS	O
+)	POS	O
+by	POS	O
+ZnSO	POS	O
+(	POS	O
+4	POS	O
+)	POS	O
+and	POS	O
+its	POS	O
+role	POS	O
+in	POS	O
+neuroprotection	POS	O
+has	POS	O
+been	POS	O
+documented	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+aimed	POS	O
+to	POS	O
+explore	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+MT	POS	O
+induction	POS	O
+on	POS	O
+carmustine	POS	O
+(	POS	O
+BCNU	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+hippocampal	POS	B-NP
+cognitive	POS	I-NP
+dysfunction	POS	I-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+60	POS	O
+male	POS	O
+Wistar	POS	O
+albino	POS	O
+rats	POS	O
+were	POS	O
+randomly	POS	O
+divided	POS	O
+into	POS	O
+four	POS	O
+groups	POS	O
+(	POS	O
+15	POS	O
+/	POS	O
+group	POS	O
+)	POS	O
+:	POS	O
+The	POS	O
+control	POS	O
+group	POS	O
+injected	POS	O
+with	POS	O
+single	POS	O
+doses	POS	O
+of	POS	O
+normal	POS	O
+saline	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+)	POS	O
+followed	POS	O
+24	POS	O
+h	POS	O
+later	POS	O
+by	POS	O
+BCNU	POS	O
+solvent	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+second	POS	O
+group	POS	O
+administered	POS	O
+ZnSO	POS	O
+(	POS	O
+4	POS	O
+)	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+micromol	POS	O
+/	POS	O
+10	POS	O
+microl	POS	O
+normal	POS	O
+saline	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+,	POS	O
+once	POS	O
+)	POS	O
+then	POS	O
+BCNU	POS	O
+solvent	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+)	POS	O
+after	POS	O
+24	POS	O
+h	POS	O
+.	POS	O
+Third	POS	O
+group	POS	O
+received	POS	O
+BCNU	POS	O
+(	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+,	POS	O
+once	POS	O
+)	POS	O
+24	POS	O
+h	POS	O
+after	POS	O
+injection	POS	O
+with	POS	O
+normal	POS	O
+saline	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+)	POS	O
+.	POS	O
+Fourth	POS	O
+group	POS	O
+received	POS	O
+a	POS	O
+single	POS	O
+dose	POS	O
+of	POS	O
+ZnSO	POS	O
+(	POS	O
+4	POS	O
+)	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+micromol	POS	O
+/	POS	O
+10	POS	O
+microl	POS	O
+normal	POS	O
+saline	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+)	POS	O
+then	POS	O
+BCNU	POS	O
+(	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+,	POS	O
+once	POS	O
+)	POS	O
+after	POS	O
+24	POS	O
+h	POS	O
+.	POS	O
+The	POS	O
+obtained	POS	O
+data	POS	O
+revealed	POS	O
+that	POS	O
+BCNU	POS	O
+administration	POS	O
+resulted	POS	O
+in	POS	O
+deterioration	POS	O
+of	POS	O
+learning	POS	O
+and	POS	O
+short	POS	O
+-	POS	O
+term	POS	O
+memory	POS	O
+(	POS	O
+STM	POS	O
+)	POS	O
+,	POS	O
+as	POS	O
+measured	POS	O
+by	POS	O
+using	POS	O
+radial	POS	O
+arm	POS	O
+water	POS	O
+maze	POS	O
+,	POS	O
+accompanied	POS	O
+with	POS	O
+decreased	POS	O
+hippocampal	POS	O
+glutathione	POS	O
+reductase	POS	O
+(	POS	O
+GR	POS	O
+)	POS	O
+activity	POS	O
+and	POS	O
+reduced	POS	O
+glutathione	POS	O
+(	POS	O
+GSH	POS	O
+)	POS	O
+content	POS	O
+.	POS	O
+Also	POS	O
+,	POS	O
+BCNU	POS	O
+administration	POS	O
+increased	POS	O
+serum	POS	O
+tumor	POS	O
+necrosis	POS	O
+factor	POS	O
+-	POS	O
+alpha	POS	O
+(	POS	O
+TNFalpha	POS	O
+)	POS	O
+,	POS	O
+hippocampal	POS	O
+MT	POS	O
+and	POS	O
+malondialdehyde	POS	O
+(	POS	O
+MDA	POS	O
+)	POS	O
+contents	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+caspase	POS	O
+-	POS	O
+3	POS	O
+activity	POS	O
+in	POS	O
+addition	POS	O
+to	POS	O
+histological	POS	O
+alterations	POS	O
+.	POS	O
+ZnSO	POS	O
+(	POS	O
+4	POS	O
+)	POS	O
+pretreatment	POS	O
+counteracted	POS	O
+BCNU	POS	O
+-	POS	O
+induced	POS	O
+inhibition	POS	O
+of	POS	O
+GR	POS	O
+and	POS	O
+depletion	POS	O
+of	POS	O
+GSH	POS	O
+and	POS	O
+resulted	POS	O
+in	POS	O
+significant	POS	O
+reduction	POS	O
+in	POS	O
+the	POS	O
+levels	POS	O
+of	POS	O
+MDA	POS	O
+and	POS	O
+TNFalpha	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+the	POS	O
+activity	POS	O
+of	POS	O
+caspase	POS	O
+-	POS	O
+3	POS	O
+.	POS	O
+The	POS	O
+histological	POS	O
+features	POS	O
+were	POS	O
+improved	POS	O
+in	POS	O
+hippocampus	POS	O
+of	POS	O
+rats	POS	O
+treated	POS	O
+with	POS	O
+ZnSO	POS	O
+(	POS	O
+4	POS	O
+)	POS	O
++	POS	O
+BCNU	POS	O
+compared	POS	O
+to	POS	O
+only	POS	O
+BCNU	POS	O
+-	POS	O
+treated	POS	O
+animals	POS	O
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+MT	POS	O
+induction	POS	O
+halts	POS	O
+BCNU	POS	O
+-	POS	O
+induced	POS	O
+hippocampal	POS	B-NP
+toxicity	POS	I-NP
+as	POS	O
+it	POS	O
+prevented	POS	O
+GR	POS	O
+inhibition	POS	O
+and	POS	O
+GSH	POS	O
+depletion	POS	O
+and	POS	O
+counteracted	POS	O
+the	POS	O
+increased	POS	O
+levels	POS	O
+of	POS	O
+TNFalpha	POS	O
+,	POS	O
+MDA	POS	O
+and	POS	O
+caspase	POS	O
+-	POS	O
+3	POS	O
+activity	POS	O
+with	POS	O
+subsequent	POS	O
+preservation	POS	O
+of	POS	O
+cognition	POS	O
+.	POS	O
+Fatal	POS	O
+carbamazepine	POS	O
+induced	POS	O
+fulminant	POS	B-NP
+eosinophilic	POS	I-NP
+(	POS	O
+hypersensitivity	POS	B-NP
+)	POS	O
+myocarditis	POS	B-NP
+:	POS	O
+emphasis	POS	O
+on	POS	O
+anatomical	POS	O
+and	POS	O
+histological	POS	O
+characteristics	POS	O
+,	POS	O
+mechanisms	POS	O
+and	POS	O
+genetics	POS	O
+of	POS	O
+drug	POS	O
+hypersensitivity	POS	B-NP
+and	POS	O
+differential	POS	O
+diagnosis	POS	O
+.	POS	O
+The	POS	O
+most	POS	O
+severe	POS	O
+adverse	POS	O
+reactions	POS	O
+to	POS	O
+carbamazepine	POS	O
+have	POS	O
+been	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+haemopoietic	POS	O
+system	POS	O
+,	POS	O
+the	POS	O
+liver	POS	O
+and	POS	O
+the	POS	O
+cardiovascular	POS	O
+system	POS	O
+.	POS	O
+A	POS	O
+frequently	POS	O
+fatal	POS	O
+,	POS	O
+although	POS	O
+exceptionally	POS	O
+rare	POS	O
+side	POS	O
+effect	POS	O
+of	POS	O
+carbamazepine	POS	O
+is	POS	O
+necrotizing	POS	B-NP
+eosinophilic	POS	I-NP
+(	POS	O
+hypersensitivity	POS	B-NP
+)	POS	O
+myocarditis	POS	B-NP
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+hypersensitivity	POS	B-NP
+myocarditis	POS	I-NP
+secondary	POS	O
+to	POS	O
+administration	POS	O
+of	POS	O
+carbamazepine	POS	O
+.	POS	O
+Acute	POS	O
+hypersensitivity	POS	B-NP
+myocarditis	POS	I-NP
+was	POS	O
+not	POS	O
+suspected	POS	O
+clinically	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+diagnosis	POS	O
+was	POS	O
+made	POS	O
+post	POS	O
+-	POS	O
+mortem	POS	O
+.	POS	O
+Histology	POS	O
+revealed	POS	O
+diffuse	POS	O
+infiltration	POS	O
+of	POS	O
+the	POS	O
+myocardium	POS	O
+by	POS	O
+eosinophils	POS	O
+and	POS	O
+lymphocytes	POS	O
+with	POS	O
+myocyte	POS	B-NP
+damage	POS	I-NP
+.	POS	O
+Clinically	POS	O
+,	POS	O
+death	POS	B-NP
+was	POS	O
+due	POS	O
+to	POS	O
+cardiogenic	POS	B-NP
+shock	POS	I-NP
+.	POS	O
+To	POS	O
+best	POS	O
+of	POS	O
+our	POS	O
+knowledge	POS	O
+this	POS	O
+is	POS	O
+the	POS	O
+second	POS	O
+case	POS	O
+of	POS	O
+fatal	POS	O
+carbamazepine	POS	O
+induced	POS	O
+myocarditis	POS	B-NP
+reported	POS	O
+in	POS	O
+English	POS	O
+literature	POS	O
+.	POS	O
+Neuropsychiatric	POS	O
+behaviors	POS	O
+in	POS	O
+the	POS	O
+MPTP	POS	O
+marmoset	POS	O
+model	POS	O
+of	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+Neuropsychiatric	POS	B-NP
+symptoms	POS	I-NP
+are	POS	O
+increasingly	POS	O
+recognised	POS	O
+as	POS	O
+a	POS	O
+significant	POS	O
+problem	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+PD	POS	B-NP
+)	POS	O
+.	POS	O
+These	POS	O
+symptoms	POS	O
+may	POS	O
+be	POS	O
+due	POS	O
+to	POS	O
+'	POS	O
+sensitisation	POS	O
+'	POS	O
+following	POS	O
+repeated	POS	O
+levodopa	POS	O
+treatment	POS	O
+or	POS	O
+a	POS	O
+direct	POS	O
+effect	POS	O
+of	POS	O
+dopamine	POS	O
+on	POS	O
+the	POS	O
+disease	POS	O
+state	POS	O
+.	POS	O
+The	POS	O
+levodopa	POS	O
+-	POS	O
+treated	POS	O
+MPTP	POS	O
+-	POS	O
+lesioned	POS	O
+marmoset	POS	O
+was	POS	O
+used	POS	O
+as	POS	O
+a	POS	O
+model	POS	O
+of	POS	O
+neuropsychiatric	POS	B-NP
+symptoms	POS	I-NP
+in	POS	O
+PD	POS	B-NP
+patients	POS	O
+.	POS	O
+Here	POS	O
+we	POS	O
+compare	POS	O
+the	POS	O
+time	POS	O
+course	POS	O
+of	POS	O
+levodopa	POS	O
+-	POS	O
+induced	POS	O
+motor	POS	O
+fluctuations	POS	O
+and	POS	O
+neuropsychiatric	POS	O
+-	POS	O
+like	POS	O
+behaviors	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+relationship	POS	O
+between	POS	O
+duration	POS	O
+of	POS	O
+treatment	POS	O
+and	POS	O
+onset	POS	O
+of	POS	O
+symptoms	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Marmosets	POS	O
+were	POS	O
+administered	POS	O
+1	POS	O
+-	POS	O
+methyl	POS	O
+-	POS	O
+4	POS	O
+-	POS	O
+phenyl	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+2	POS	O
+,	POS	O
+3	POS	O
+,	POS	O
+6	POS	O
+-	POS	O
+tetrahydropyridine	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+0	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+s	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+)	POS	O
+for	POS	O
+five	POS	O
+days	POS	O
+,	POS	O
+resulting	POS	O
+in	POS	O
+stable	POS	O
+parkinsonism	POS	B-NP
+.	POS	O
+Levodopa	POS	O
+(	POS	O
+15	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+and	POS	O
+benserazide	POS	O
+,	POS	O
+3	POS	O
+.	POS	O
+75	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+p	POS	O
+.	POS	O
+o	POS	O
+.	POS	O
+b	POS	O
+.	POS	O
+i	POS	O
+.	POS	O
+d	POS	O
+,	POS	O
+was	POS	O
+administered	POS	O
+for	POS	O
+30	POS	O
+days	POS	O
+.	POS	O
+Animals	POS	O
+were	POS	O
+evaluated	POS	O
+for	POS	O
+parkinsonian	POS	B-NP
+disability	POS	I-NP
+,	POS	O
+dyskinesia	POS	B-NP
+and	POS	O
+on	POS	O
+-	POS	O
+time	POS	O
+(	POS	O
+motor	POS	O
+fluctuations	POS	O
+)	POS	O
+and	POS	O
+neuropsychiatric	POS	O
+-	POS	O
+like	POS	O
+behaviors	POS	O
+on	POS	O
+Day	POS	O
+0	POS	O
+(	POS	O
+prior	POS	O
+to	POS	O
+levodopa	POS	O
+)	POS	O
+and	POS	O
+on	POS	O
+Days	POS	O
+1	POS	O
+,	POS	O
+7	POS	O
+,	POS	O
+13	POS	O
+,	POS	O
+27	POS	O
+and	POS	O
+30	POS	O
+of	POS	O
+treatment	POS	O
+using	POS	O
+post	POS	O
+hoc	POS	O
+DVD	POS	O
+analysis	POS	O
+by	POS	O
+a	POS	O
+trained	POS	O
+rater	POS	O
+,	POS	O
+blind	POS	O
+to	POS	O
+the	POS	O
+treatment	POS	O
+day	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+neuropsychiatric	POS	O
+-	POS	O
+like	POS	O
+behavior	POS	O
+rating	POS	O
+scale	POS	O
+demonstrated	POS	O
+high	POS	O
+interrater	POS	O
+reliability	POS	O
+between	POS	O
+three	POS	O
+trained	POS	O
+raters	POS	O
+of	POS	O
+differing	POS	O
+professional	POS	O
+backgrounds	POS	O
+.	POS	O
+As	POS	O
+anticipated	POS	O
+,	POS	O
+animals	POS	O
+exhibited	POS	O
+a	POS	O
+progressive	POS	O
+increase	POS	O
+in	POS	O
+levodopa	POS	O
+-	POS	O
+induced	POS	O
+motor	POS	O
+fluctuations	POS	O
+,	POS	O
+dyskinesia	POS	B-NP
+and	POS	O
+wearing	POS	O
+-	POS	O
+off	POS	O
+,	POS	O
+that	POS	O
+correlated	POS	O
+with	POS	O
+the	POS	O
+duration	POS	O
+of	POS	O
+levodopa	POS	O
+therapy	POS	O
+.	POS	O
+In	POS	O
+contrast	POS	O
+,	POS	O
+levodopa	POS	O
+-	POS	O
+induced	POS	O
+neuropsychiatric	POS	B-NP
+-	POS	I-NP
+like	POS	I-NP
+behaviors	POS	I-NP
+were	POS	O
+present	POS	O
+on	POS	O
+Day	POS	O
+1	POS	O
+of	POS	O
+levodopa	POS	O
+treatment	POS	O
+and	POS	O
+their	POS	O
+severity	POS	O
+did	POS	O
+not	POS	O
+correlate	POS	O
+with	POS	O
+duration	POS	O
+of	POS	O
+treatment	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+neuropsychiatric	POS	B-NP
+disorders	POS	I-NP
+in	POS	O
+PD	POS	B-NP
+are	POS	O
+more	POS	O
+likely	POS	O
+an	POS	O
+interaction	POS	O
+between	POS	O
+levodopa	POS	O
+and	POS	O
+the	POS	O
+disease	POS	O
+state	POS	O
+than	POS	O
+a	POS	O
+consequence	POS	O
+of	POS	O
+sensitisation	POS	O
+to	POS	O
+repeated	POS	O
+dopaminergic	POS	O
+therapy	POS	O
+.	POS	O
+Contrast	POS	O
+medium	POS	O
+nephrotoxicity	POS	B-NP
+after	POS	O
+renal	POS	O
+artery	POS	O
+and	POS	O
+coronary	POS	B-NP
+angioplasty	POS	I-NP
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Renal	POS	B-NP
+dysfunction	POS	I-NP
+induced	POS	O
+by	POS	O
+iodinated	POS	O
+contrast	POS	O
+medium	POS	O
+(	POS	O
+CM	POS	O
+)	POS	O
+administration	POS	O
+can	POS	O
+minimize	POS	O
+the	POS	O
+benefit	POS	O
+of	POS	O
+the	POS	O
+interventional	POS	O
+procedure	POS	O
+in	POS	O
+patients	POS	O
+undergoing	POS	O
+renal	POS	O
+angioplasty	POS	O
+(	POS	O
+PTRA	POS	O
+)	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+To	POS	O
+compare	POS	O
+the	POS	O
+susceptibility	POS	O
+to	POS	O
+nephrotoxic	POS	B-NP
+effect	POS	O
+of	POS	O
+CM	POS	B-NP
+in	POS	O
+patients	POS	O
+undergoing	POS	O
+PTRA	POS	O
+with	POS	O
+that	POS	O
+of	POS	O
+patients	POS	O
+submitted	POS	O
+to	POS	O
+percutaneous	POS	O
+coronary	POS	O
+intervention	POS	O
+(	POS	O
+PCI	POS	O
+)	POS	O
+.	POS	O
+MATERIAL	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+33	POS	O
+patients	POS	O
+successfully	POS	O
+treated	POS	O
+with	POS	O
+PTRA	POS	O
+(	POS	O
+PTRA	POS	O
+group	POS	O
+,	POS	O
+mean	POS	O
+age	POS	O
+70	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+12	POS	O
+years	POS	O
+,	POS	O
+23	POS	O
+female	POS	O
+,	POS	O
+basal	POS	O
+creatinine	POS	O
+1	POS	O
+.	POS	O
+46	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+79	POS	O
+,	POS	O
+range	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+9	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+)	POS	O
+were	POS	O
+compared	POS	O
+with	POS	O
+33	POS	O
+patients	POS	O
+undergoing	POS	O
+successful	POS	O
+PCI	POS	O
+(	POS	O
+PCI	POS	O
+group	POS	O
+)	POS	O
+,	POS	O
+matched	POS	O
+for	POS	O
+basal	POS	O
+creatinine	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+44	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+6	POS	O
+,	POS	O
+range	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+-	POS	O
+3	POS	O
+.	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+)	POS	O
+,	POS	O
+gender	POS	O
+,	POS	O
+and	POS	O
+age	POS	O
+.	POS	O
+In	POS	O
+both	POS	O
+groups	POS	O
+postprocedural	POS	O
+(	POS	O
+48	POS	O
+h	POS	O
+)	POS	O
+serum	POS	O
+creatinine	POS	O
+was	POS	O
+measured	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Postprocedural	POS	O
+creatinine	POS	O
+level	POS	O
+decreased	POS	O
+nonsignificantly	POS	O
+in	POS	O
+the	POS	O
+PTRA	POS	O
+group	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+46	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+8	POS	O
+vs	POS	O
+.	POS	O
+1	POS	O
+.	POS	O
+34	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+NS	POS	O
+)	POS	O
+and	POS	O
+increased	POS	O
+significantly	POS	O
+in	POS	O
+the	POS	O
+PCI	POS	O
+group	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+44	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+6	POS	O
+vs	POS	O
+.	POS	O
+1	POS	O
+.	POS	O
+57	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+,	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+.	POS	O
+Changes	POS	O
+in	POS	O
+serum	POS	O
+creatinine	POS	O
+after	POS	O
+intervention	POS	O
+(	POS	O
+after	POS	O
+-	POS	O
+before	POS	O
+)	POS	O
+were	POS	O
+significantly	POS	O
+different	POS	O
+between	POS	O
+the	POS	O
+PTRA	POS	O
+and	POS	O
+PCI	POS	O
+groups	POS	O
+(	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+12	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+vs	POS	O
+.	POS	O
+0	POS	O
+.	POS	O
+13	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+014	POS	O
+)	POS	O
+.	POS	O
+This	POS	O
+difference	POS	O
+was	POS	O
+not	POS	O
+related	POS	O
+to	POS	O
+either	POS	O
+a	POS	O
+different	POS	O
+clinical	POS	O
+risk	POS	O
+profile	POS	O
+or	POS	O
+to	POS	O
+the	POS	O
+volume	POS	O
+of	POS	O
+CM	POS	O
+administered	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+In	POS	O
+this	POS	O
+preliminary	POS	O
+study	POS	O
+patients	POS	O
+submitted	POS	O
+to	POS	O
+PTRA	POS	O
+showed	POS	O
+a	POS	O
+lower	POS	O
+susceptibility	POS	O
+to	POS	O
+renal	POS	B-NP
+damage	POS	I-NP
+induced	POS	O
+by	POS	O
+CM	POS	O
+administration	POS	O
+than	POS	O
+PCI	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+effectiveness	POS	O
+of	POS	O
+PTRA	POS	O
+on	POS	O
+renal	POS	O
+function	POS	O
+seems	POS	O
+to	POS	O
+be	POS	O
+barely	POS	O
+influenced	POS	O
+by	POS	O
+CM	POS	B-NP
+toxicity	POS	I-NP
+.	POS	O
+Diphenhydramine	POS	O
+prevents	POS	O
+the	POS	O
+haemodynamic	POS	O
+changes	POS	O
+of	POS	O
+cimetidine	POS	O
+in	POS	O
+ICU	POS	O
+patients	POS	O
+.	POS	O
+Cimetidine	POS	O
+,	POS	O
+a	POS	O
+histamine	POS	O
+2	POS	O
+(	POS	O
+H2	POS	O
+)	POS	O
+antagonist	POS	O
+,	POS	O
+produces	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+arterial	POS	O
+pressure	POS	O
+due	POS	O
+to	POS	O
+vasodilatation	POS	O
+,	POS	O
+especially	POS	O
+in	POS	O
+critically	POS	O
+ill	POS	O
+patients	POS	O
+.	POS	O
+This	POS	O
+may	POS	O
+be	POS	O
+because	POS	O
+cimetidine	POS	O
+acts	POS	O
+as	POS	O
+a	POS	O
+histamine	POS	O
+agonist	POS	O
+.	POS	O
+We	POS	O
+,	POS	O
+therefore	POS	O
+,	POS	O
+investigated	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+the	POS	O
+histamine	POS	O
+1	POS	O
+(	POS	O
+H1	POS	O
+)	POS	O
+receptor	POS	O
+antagonist	POS	O
+,	POS	O
+diphenhydramine	POS	O
+,	POS	O
+on	POS	O
+the	POS	O
+haemodynamic	POS	O
+changes	POS	O
+observed	POS	O
+after	POS	O
+cimetidine	POS	O
+in	POS	O
+ICU	POS	O
+patients	POS	O
+.	POS	O
+Each	POS	O
+patient	POS	O
+was	POS	O
+studied	POS	O
+on	POS	O
+two	POS	O
+separate	POS	O
+days	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+random	POS	O
+fashion	POS	O
+,	POS	O
+they	POS	O
+received	POS	O
+cimetidine	POS	O
+200	POS	O
+mg	POS	O
+iv	POS	O
+on	POS	O
+one	POS	O
+day	POS	O
+,	POS	O
+and	POS	O
+on	POS	O
+the	POS	O
+other	POS	O
+,	POS	O
+a	POS	O
+pretreatment	POS	O
+of	POS	O
+diphenhydramine	POS	O
+40	POS	O
+mg	POS	O
+iv	POS	O
+with	POS	O
+cimetidine	POS	O
+200	POS	O
+mg	POS	O
+iv	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+non	POS	O
+-	POS	O
+pretreatment	POS	O
+group	POS	O
+,	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+(	POS	O
+MAP	POS	O
+)	POS	O
+decreased	POS	O
+from	POS	O
+107	POS	O
+.	POS	O
+4	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+8	POS	O
+.	POS	O
+4	POS	O
+mmHg	POS	O
+to	POS	O
+86	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+11	POS	O
+.	POS	O
+4	POS	O
+mmHg	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+two	POS	O
+minutes	POS	O
+after	POS	O
+cimetidine	POS	O
+.	POS	O
+Also	POS	O
+,	POS	O
+systemic	POS	O
+vascular	POS	O
+resistance	POS	O
+(	POS	O
+SVR	POS	O
+)	POS	O
+decreased	POS	O
+during	POS	O
+the	POS	O
+eight	POS	O
+-	POS	O
+minute	POS	O
+observation	POS	O
+period	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+contrast	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+pretreatment	POS	O
+group	POS	O
+,	POS	O
+little	POS	O
+haemodynamic	POS	O
+change	POS	O
+was	POS	O
+seen	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+an	POS	O
+H1	POS	O
+antagonist	POS	O
+may	POS	O
+be	POS	O
+useful	POS	O
+in	POS	O
+preventing	POS	O
+hypotension	POS	B-NP
+caused	POS	O
+by	POS	O
+iv	POS	O
+cimetidine	POS	O
+,	POS	O
+since	POS	O
+the	POS	O
+vasodilating	POS	O
+activity	POS	O
+of	POS	O
+cimetidine	POS	O
+is	POS	O
+mediated	POS	O
+,	POS	O
+in	POS	O
+part	POS	O
+,	POS	O
+through	POS	O
+the	POS	O
+H1	POS	O
+receptor	POS	O
+.	POS	O
+Medical	POS	O
+and	POS	O
+psychiatric	POS	O
+outcomes	POS	O
+for	POS	O
+patients	POS	O
+transplanted	POS	O
+for	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+:	POS	O
+a	POS	O
+case	POS	O
+-	POS	O
+control	POS	O
+study	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+hepatotoxicity	POS	B-NP
+is	POS	O
+the	POS	O
+most	POS	O
+common	POS	O
+cause	POS	O
+of	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+(	POS	O
+ALF	POS	B-NP
+)	POS	O
+in	POS	O
+the	POS	O
+UK	POS	O
+.	POS	O
+Patients	POS	O
+often	POS	O
+consume	POS	O
+the	POS	O
+drug	POS	O
+with	POS	O
+suicidal	POS	O
+intent	POS	O
+or	POS	O
+with	POS	O
+a	POS	O
+background	POS	O
+of	POS	O
+substance	POS	O
+dependence	POS	O
+.	POS	O
+AIMS	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+compared	POS	O
+the	POS	O
+severity	POS	O
+of	POS	O
+pretransplant	POS	B-NP
+illness	POS	I-NP
+,	POS	O
+psychiatric	POS	O
+co	POS	O
+-	POS	O
+morbidity	POS	O
+,	POS	O
+medical	POS	O
+and	POS	O
+psychosocial	POS	O
+outcomes	POS	O
+of	POS	O
+all	POS	O
+patients	POS	O
+who	POS	O
+had	POS	O
+undergone	POS	O
+liver	POS	O
+transplantation	POS	O
+(	POS	O
+LT	POS	O
+)	POS	O
+emergently	POS	O
+between	POS	O
+1999	POS	O
+-	POS	O
+2004	POS	O
+for	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+ALF	POS	B-NP
+(	POS	O
+n	POS	O
+=	POS	O
+36	POS	O
+)	POS	O
+with	POS	O
+age	POS	O
+-	POS	O
+and	POS	O
+sex	POS	O
+-	POS	O
+matched	POS	O
+patients	POS	O
+undergoing	POS	O
+emergent	POS	O
+LT	POS	O
+for	POS	O
+non	POS	O
+-	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+ALF	POS	B-NP
+(	POS	O
+n	POS	O
+=	POS	O
+35	POS	O
+)	POS	O
+and	POS	O
+elective	POS	O
+LT	POS	O
+for	POS	O
+chronic	POS	B-NP
+liver	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+CLD	POS	B-NP
+,	POS	O
+n	POS	O
+=	POS	O
+34	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+ALF	POS	B-NP
+patients	POS	O
+undergoing	POS	O
+LT	POS	O
+had	POS	O
+a	POS	O
+greater	POS	O
+severity	POS	O
+of	POS	O
+pre	POS	O
+-	POS	O
+LT	POS	O
+illness	POS	O
+reflected	POS	O
+by	POS	O
+higher	POS	O
+Acute	POS	O
+Physiology	POS	O
+and	POS	O
+Chronic	POS	O
+Health	POS	O
+Evaluation	POS	O
+II	POS	O
+scores	POS	O
+and	POS	O
+requirement	POS	O
+for	POS	O
+organ	POS	O
+support	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+other	POS	O
+two	POS	O
+groups	POS	O
+.	POS	O
+Twenty	POS	O
+(	POS	O
+56	POS	O
+%	POS	O
+)	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+ALF	POS	B-NP
+patients	POS	O
+had	POS	O
+a	POS	O
+formal	POS	O
+psychiatric	POS	O
+diagnosis	POS	O
+before	POS	O
+LT	POS	O
+(	POS	O
+non	POS	O
+-	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+ALF	POS	B-NP
+=	POS	O
+0	POS	O
+/	POS	O
+35	POS	O
+,	POS	O
+CLD	POS	B-NP
+=	POS	O
+2	POS	O
+/	POS	O
+34	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+for	POS	O
+all	POS	O
+)	POS	O
+and	POS	O
+nine	POS	O
+(	POS	O
+25	POS	O
+%	POS	O
+)	POS	O
+had	POS	O
+a	POS	O
+previous	POS	O
+suicide	POS	O
+attempt	POS	O
+.	POS	O
+During	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+(	POS	O
+median	POS	O
+5	POS	O
+years	POS	O
+)	POS	O
+,	POS	O
+there	POS	O
+were	POS	O
+no	POS	O
+significant	POS	O
+differences	POS	O
+in	POS	O
+rejection	POS	O
+(	POS	O
+acute	POS	O
+and	POS	O
+chronic	POS	O
+)	POS	O
+,	POS	O
+graft	POS	B-NP
+failure	POS	I-NP
+or	POS	O
+survival	POS	O
+between	POS	O
+the	POS	O
+groups	POS	O
+(	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+ALF	POS	B-NP
+1	POS	O
+year	POS	O
+87	POS	O
+%	POS	O
+,	POS	O
+5	POS	O
+years	POS	O
+75	POS	O
+%	POS	O
+;	POS	O
+non	POS	O
+-	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+ALF	POS	B-NP
+88	POS	O
+%	POS	O
+,	POS	O
+78	POS	O
+%	POS	O
+;	POS	O
+CLD	POS	B-NP
+93	POS	O
+%	POS	O
+,	POS	O
+82	POS	O
+%	POS	O
+:	POS	O
+P	POS	O
+>	POS	O
+0	POS	O
+.	POS	O
+6	POS	O
+log	POS	O
+rank	POS	O
+)	POS	O
+.	POS	O
+Two	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+ALF	POS	B-NP
+patients	POS	O
+reattempted	POS	O
+suicide	POS	O
+post	POS	O
+-	POS	O
+LT	POS	O
+(	POS	O
+one	POS	O
+died	POS	O
+8	POS	O
+years	POS	O
+post	POS	O
+-	POS	O
+LT	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Despite	POS	O
+a	POS	O
+high	POS	O
+prevalence	POS	O
+of	POS	O
+psychiatric	POS	B-NP
+disturbance	POS	I-NP
+,	POS	O
+outcomes	POS	O
+for	POS	O
+patients	POS	O
+transplanted	POS	O
+emergently	POS	O
+for	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+ALF	POS	B-NP
+were	POS	O
+comparable	POS	O
+to	POS	O
+those	POS	O
+transplanted	POS	O
+for	POS	O
+non	POS	O
+-	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+ALF	POS	B-NP
+and	POS	O
+electively	POS	O
+for	POS	O
+CLD	POS	B-NP
+.	POS	O
+Multidisciplinary	POS	O
+approaches	POS	O
+with	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+psychiatric	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+may	POS	O
+contribute	POS	O
+to	POS	O
+low	POS	O
+post	POS	O
+-	POS	O
+transplant	POS	O
+suicide	POS	O
+rates	POS	O
+seen	POS	O
+and	POS	O
+low	POS	O
+rates	POS	O
+of	POS	O
+graft	POS	B-NP
+loss	POS	I-NP
+because	POS	O
+of	POS	O
+non	POS	O
+-	POS	O
+compliance	POS	O
+.	POS	O
+Antithrombotic	POS	O
+drug	POS	O
+use	POS	O
+,	POS	O
+cerebral	POS	B-NP
+microbleeds	POS	I-NP
+,	POS	O
+and	POS	O
+intracerebral	POS	B-NP
+hemorrhage	POS	I-NP
+:	POS	O
+a	POS	O
+systematic	POS	O
+review	POS	O
+of	POS	O
+published	POS	O
+and	POS	O
+unpublished	POS	O
+studies	POS	O
+.	POS	O
+BACKGROUND	POS	O
+AND	POS	O
+PURPOSE	POS	O
+:	POS	O
+Cerebral	POS	B-NP
+microbleeds	POS	I-NP
+(	POS	O
+MB	POS	B-NP
+)	POS	O
+are	POS	O
+potential	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+intracerebral	POS	B-NP
+hemorrhage	POS	I-NP
+(	POS	O
+ICH	POS	B-NP
+)	POS	O
+,	POS	O
+but	POS	O
+it	POS	O
+is	POS	O
+unclear	POS	O
+if	POS	O
+they	POS	O
+are	POS	O
+a	POS	O
+contraindication	POS	O
+to	POS	O
+using	POS	O
+antithrombotic	POS	O
+drugs	POS	O
+.	POS	O
+Insights	POS	O
+could	POS	O
+be	POS	O
+gained	POS	O
+by	POS	O
+pooling	POS	O
+data	POS	O
+on	POS	O
+MB	POS	B-NP
+frequency	POS	O
+stratified	POS	O
+by	POS	O
+antithrombotic	POS	O
+use	POS	O
+in	POS	O
+cohorts	POS	O
+with	POS	O
+ICH	POS	B-NP
+and	POS	O
+ischemic	POS	B-NP
+stroke	POS	I-NP
+(	POS	O
+IS	POS	O
+)	POS	O
+/	POS	O
+transient	POS	O
+ischemic	POS	B-NP
+attack	POS	I-NP
+(	POS	O
+TIA	POS	B-NP
+)	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+performed	POS	O
+a	POS	O
+systematic	POS	O
+review	POS	O
+of	POS	O
+published	POS	O
+and	POS	O
+unpublished	POS	O
+data	POS	O
+from	POS	O
+cohorts	POS	O
+with	POS	O
+stroke	POS	B-NP
+or	POS	O
+TIA	POS	B-NP
+to	POS	O
+compare	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+MB	POS	B-NP
+in	POS	O
+:	POS	O
+(	POS	O
+1	POS	O
+)	POS	O
+antithrombotic	POS	O
+users	POS	O
+vs	POS	O
+nonantithrombotic	POS	O
+users	POS	O
+with	POS	O
+ICH	POS	B-NP
+;	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+antithrombotic	POS	O
+users	POS	O
+vs	POS	O
+nonusers	POS	O
+with	POS	O
+IS	POS	O
+/	POS	O
+TIA	POS	B-NP
+;	POS	O
+and	POS	O
+(	POS	O
+3	POS	O
+)	POS	O
+ICH	POS	B-NP
+vs	POS	O
+ischemic	POS	B-NP
+events	POS	O
+stratified	POS	O
+by	POS	O
+antithrombotic	POS	O
+use	POS	O
+.	POS	O
+We	POS	O
+also	POS	O
+analyzed	POS	O
+published	POS	O
+and	POS	O
+unpublished	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+data	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+ICH	POS	B-NP
+in	POS	O
+antithrombotic	POS	O
+users	POS	O
+with	POS	O
+MB	POS	B-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+In	POS	O
+a	POS	O
+pooled	POS	O
+analysis	POS	O
+of	POS	O
+1460	POS	O
+ICH	POS	B-NP
+and	POS	O
+3817	POS	O
+IS	POS	O
+/	POS	O
+TIA	POS	B-NP
+,	POS	O
+MB	POS	B-NP
+were	POS	O
+more	POS	O
+frequent	POS	O
+in	POS	O
+ICH	POS	B-NP
+vs	POS	O
+IS	POS	O
+/	POS	O
+TIA	POS	B-NP
+in	POS	O
+all	POS	O
+treatment	POS	O
+groups	POS	O
+,	POS	O
+but	POS	O
+the	POS	O
+excess	POS	O
+increased	POS	O
+from	POS	O
+2	POS	O
+.	POS	O
+8	POS	O
+(	POS	O
+odds	POS	O
+ratio	POS	O
+;	POS	O
+range	POS	O
+,	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
+-	POS	O
+3	POS	O
+.	POS	O
+5	POS	O
+)	POS	O
+in	POS	O
+nonantithrombotic	POS	O
+users	POS	O
+to	POS	O
+5	POS	O
+.	POS	O
+7	POS	O
+(	POS	O
+range	POS	O
+,	POS	O
+3	POS	O
+.	POS	O
+4	POS	O
+-	POS	O
+9	POS	O
+.	POS	O
+7	POS	O
+)	POS	O
+in	POS	O
+antiplatelet	POS	O
+users	POS	O
+and	POS	O
+8	POS	O
+.	POS	O
+0	POS	O
+(	POS	O
+range	POS	O
+,	POS	O
+3	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+17	POS	O
+.	POS	O
+8	POS	O
+)	POS	O
+in	POS	O
+warfarin	POS	O
+users	POS	O
+(	POS	O
+P	POS	O
+difference	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+also	POS	O
+an	POS	O
+excess	POS	O
+of	POS	O
+MB	POS	B-NP
+in	POS	O
+warfarin	POS	O
+users	POS	O
+vs	POS	O
+nonusers	POS	O
+with	POS	O
+ICH	POS	B-NP
+(	POS	O
+OR	POS	O
+,	POS	O
+2	POS	O
+.	POS	O
+7	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+6	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+4	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+but	POS	O
+none	POS	O
+in	POS	O
+warfarin	POS	O
+users	POS	O
+with	POS	O
+IS	POS	O
+/	POS	O
+TIA	POS	B-NP
+(	POS	O
+OR	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+7	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+33	POS	O
+;	POS	O
+P	POS	O
+difference	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+a	POS	O
+smaller	POS	O
+excess	POS	O
+of	POS	O
+MB	POS	B-NP
+in	POS	O
+antiplatelet	POS	O
+users	POS	O
+vs	POS	O
+nonusers	POS	O
+with	POS	O
+ICH	POS	B-NP
+(	POS	O
+OR	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+7	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+but	POS	O
+findings	POS	O
+were	POS	O
+similar	POS	O
+for	POS	O
+antiplatelet	POS	O
+users	POS	O
+with	POS	O
+IS	POS	O
+/	POS	O
+TIA	POS	B-NP
+(	POS	O
+OR	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+4	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+7	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+;	POS	O
+P	POS	O
+difference	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+25	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+pooled	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+data	POS	O
+for	POS	O
+768	POS	O
+antithrombotic	POS	O
+users	POS	O
+,	POS	O
+presence	POS	O
+of	POS	O
+MB	POS	B-NP
+at	POS	O
+baseline	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+a	POS	O
+substantially	POS	O
+increased	POS	O
+risk	POS	O
+of	POS	O
+subsequent	POS	O
+ICH	POS	B-NP
+(	POS	O
+OR	POS	O
+,	POS	O
+12	POS	O
+.	POS	O
+1	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+,	POS	O
+3	POS	O
+.	POS	O
+4	POS	O
+-	POS	O
+42	POS	O
+.	POS	O
+5	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+excess	POS	O
+of	POS	O
+MB	POS	B-NP
+in	POS	O
+warfarin	POS	O
+users	POS	O
+with	POS	O
+ICH	POS	B-NP
+compared	POS	O
+to	POS	O
+other	POS	O
+groups	POS	O
+suggests	POS	O
+that	POS	O
+MB	POS	B-NP
+increase	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+warfarin	POS	O
+-	POS	O
+associated	POS	O
+ICH	POS	B-NP
+.	POS	O
+Limited	POS	O
+prospective	POS	O
+data	POS	O
+corroborate	POS	O
+these	POS	O
+findings	POS	O
+,	POS	O
+but	POS	O
+larger	POS	O
+prospective	POS	O
+studies	POS	O
+are	POS	O
+urgently	POS	O
+required	POS	O
+.	POS	O
+Studies	POS	O
+of	POS	O
+synergy	POS	O
+between	POS	O
+morphine	POS	O
+and	POS	O
+a	POS	O
+novel	POS	O
+sodium	POS	O
+channel	POS	O
+blocker	POS	O
+,	POS	O
+CNSB002	POS	O
+,	POS	O
+in	POS	O
+rat	POS	O
+models	POS	O
+of	POS	O
+inflammatory	POS	O
+and	POS	O
+neuropathic	POS	B-NP
+pain	POS	I-NP
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+This	POS	O
+study	POS	O
+determined	POS	O
+the	POS	O
+antihyperalgesic	POS	O
+effect	POS	O
+of	POS	O
+CNSB002	POS	O
+,	POS	O
+a	POS	O
+sodium	POS	O
+channel	POS	O
+blocker	POS	O
+with	POS	O
+antioxidant	POS	O
+properties	POS	O
+given	POS	O
+alone	POS	O
+and	POS	O
+in	POS	O
+combinations	POS	O
+with	POS	O
+morphine	POS	O
+in	POS	O
+rat	POS	O
+models	POS	O
+of	POS	O
+inflammatory	POS	O
+and	POS	O
+neuropathic	POS	B-NP
+pain	POS	I-NP
+.	POS	O
+DESIGN	POS	O
+:	POS	O
+Dose	POS	O
+response	POS	O
+curves	POS	O
+for	POS	O
+nonsedating	POS	O
+doses	POS	O
+of	POS	O
+morphine	POS	O
+and	POS	O
+CNSB002	POS	O
+given	POS	O
+intraperitoneally	POS	O
+alone	POS	O
+and	POS	O
+together	POS	O
+in	POS	O
+combinations	POS	O
+were	POS	O
+constructed	POS	O
+for	POS	O
+antihyperalgesic	POS	O
+effect	POS	O
+using	POS	O
+paw	POS	O
+withdrawal	POS	O
+from	POS	O
+noxious	POS	O
+heat	POS	O
+in	POS	O
+two	POS	O
+rat	POS	O
+pain	POS	B-NP
+models	POS	O
+:	POS	O
+carrageenan	POS	O
+-	POS	O
+induced	POS	O
+paw	POS	O
+inflammation	POS	B-NP
+and	POS	O
+streptozotocin	POS	O
+(	POS	O
+STZ	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+diabetic	POS	B-NP
+neuropathy	POS	I-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+maximum	POS	O
+nonsedating	POS	O
+doses	POS	O
+were	POS	O
+:	POS	O
+morphine	POS	O
+,	POS	O
+3	POS	O
+.	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+;	POS	O
+CNSB002	POS	O
+10	POS	O
+.	POS	O
+0	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+;	POS	O
+5	POS	O
+.	POS	O
+0	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+CNSB002	POS	O
+with	POS	O
+morphine	POS	O
+3	POS	O
+.	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+in	POS	O
+combination	POS	O
+.	POS	O
+The	POS	O
+doses	POS	O
+calculated	POS	O
+to	POS	O
+cause	POS	O
+50	POS	O
+%	POS	O
+reversal	POS	O
+of	POS	O
+hyperalgesia	POS	B-NP
+(	POS	O
+ED50	POS	O
+)	POS	O
+were	POS	O
+7	POS	O
+.	POS	O
+54	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+81	POS	O
+)	POS	O
+and	POS	O
+4	POS	O
+.	POS	O
+83	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+54	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+carrageenan	POS	O
+model	POS	O
+and	POS	O
+44	POS	O
+.	POS	O
+18	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+37	POS	O
+)	POS	O
+and	POS	O
+9	POS	O
+.	POS	O
+14	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+24	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+STZ	POS	O
+-	POS	O
+induced	POS	O
+neuropathy	POS	B-NP
+model	POS	O
+for	POS	O
+CNSB002	POS	O
+and	POS	O
+morphine	POS	O
+,	POS	O
+respectively	POS	O
+(	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+;	POS	O
+mean	POS	O
+,	POS	O
+SEM	POS	O
+)	POS	O
+.	POS	O
+These	POS	O
+values	POS	O
+were	POS	O
+greater	POS	O
+than	POS	O
+the	POS	O
+maximum	POS	O
+nonsedating	POS	O
+doses	POS	O
+.	POS	O
+The	POS	O
+ED50	POS	O
+values	POS	O
+for	POS	O
+morphine	POS	O
+when	POS	O
+given	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+CNSB002	POS	O
+(	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+were	POS	O
+less	POS	O
+than	POS	O
+the	POS	O
+maximum	POS	O
+nonsedating	POS	O
+dose	POS	O
+:	POS	O
+0	POS	O
+.	POS	O
+56	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+55	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+carrageenan	POS	O
+model	POS	O
+and	POS	O
+1	POS	O
+.	POS	O
+37	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+23	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+neuropathy	POS	B-NP
+model	POS	O
+(	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+;	POS	O
+mean	POS	O
+,	POS	O
+SEM	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+antinociception	POS	O
+after	POS	O
+morphine	POS	O
+(	POS	O
+3	POS	O
+.	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+was	POS	O
+increased	POS	O
+by	POS	O
+co	POS	O
+-	POS	O
+administration	POS	O
+with	POS	O
+CNSB002	POS	O
+from	POS	O
+28	POS	O
+.	POS	O
+0	POS	O
+and	POS	O
+31	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+to	POS	O
+114	POS	O
+.	POS	O
+6	POS	O
+and	POS	O
+56	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+reversal	POS	O
+of	POS	O
+hyperalgesia	POS	B-NP
+in	POS	O
+the	POS	O
+inflammatory	POS	O
+and	POS	O
+neuropathic	POS	B-NP
+models	POS	O
+,	POS	O
+respectively	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+;	POS	O
+one	POS	O
+-	POS	O
+way	POS	O
+analysis	POS	O
+of	POS	O
+variance	POS	O
+-	POS	O
+significantly	POS	O
+greater	POS	O
+than	POS	O
+either	POS	O
+drug	POS	O
+given	POS	O
+alone	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+maximum	POS	O
+antihyperalgesic	POS	O
+effect	POS	O
+achievable	POS	O
+with	POS	O
+nonsedating	POS	O
+doses	POS	O
+of	POS	O
+morphine	POS	O
+may	POS	O
+be	POS	O
+increased	POS	O
+significantly	POS	O
+when	POS	O
+the	POS	O
+drug	POS	O
+is	POS	O
+used	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+CNSB002	POS	O
+.	POS	O
+Heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+:	POS	O
+a	POS	O
+practical	POS	O
+review	POS	O
+.	POS	O
+Heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+(	POS	O
+HIT	POS	B-NP
+)	POS	O
+remains	POS	O
+under	POS	O
+-	POS	O
+recognized	POS	O
+despite	POS	O
+its	POS	O
+potentially	POS	O
+devastating	POS	O
+outcomes	POS	O
+.	POS	O
+It	POS	O
+begins	POS	O
+when	POS	O
+heparin	POS	O
+exposure	POS	O
+stimulates	POS	O
+the	POS	O
+formation	POS	O
+of	POS	O
+heparin	POS	O
+-	POS	O
+platelet	POS	O
+factor	POS	O
+4	POS	O
+antibodies	POS	O
+,	POS	O
+which	POS	O
+in	POS	O
+turn	POS	O
+triggers	POS	O
+the	POS	O
+release	POS	O
+of	POS	O
+procoagulant	POS	O
+platelet	POS	O
+particles	POS	O
+.	POS	O
+Thrombosis	POS	B-NP
+and	POS	O
+thrombocytopenia	POS	B-NP
+that	POS	O
+follow	POS	O
+comprise	POS	O
+the	POS	O
+2	POS	O
+hallmark	POS	O
+traits	POS	O
+of	POS	O
+HIT	POS	B-NP
+,	POS	O
+with	POS	O
+the	POS	O
+former	POS	O
+largely	POS	O
+responsible	POS	O
+for	POS	O
+significant	POS	O
+vascular	POS	B-NP
+complications	POS	I-NP
+.	POS	O
+The	POS	O
+prevalence	POS	O
+of	POS	O
+HIT	POS	B-NP
+varies	POS	O
+among	POS	O
+several	POS	O
+subgroups	POS	O
+,	POS	O
+with	POS	O
+greater	POS	O
+incidence	POS	O
+in	POS	O
+surgical	POS	O
+as	POS	O
+compared	POS	O
+with	POS	O
+medical	POS	O
+populations	POS	O
+.	POS	O
+HIT	POS	B-NP
+must	POS	O
+be	POS	O
+acknowledged	POS	O
+for	POS	O
+its	POS	O
+intense	POS	O
+predilection	POS	O
+for	POS	O
+thrombosis	POS	B-NP
+and	POS	O
+suspected	POS	O
+whenever	POS	O
+thrombosis	POS	B-NP
+occurs	POS	O
+after	POS	O
+heparin	POS	O
+exposure	POS	O
+.	POS	O
+Early	POS	O
+recognition	POS	O
+that	POS	O
+incorporates	POS	O
+the	POS	O
+clinical	POS	O
+and	POS	O
+serologic	POS	O
+clues	POS	O
+is	POS	O
+paramount	POS	O
+to	POS	O
+timely	POS	O
+institution	POS	O
+of	POS	O
+treatment	POS	O
+,	POS	O
+as	POS	O
+its	POS	O
+delay	POS	O
+may	POS	O
+result	POS	O
+in	POS	O
+catastrophic	POS	O
+outcomes	POS	O
+.	POS	O
+The	POS	O
+treatment	POS	O
+of	POS	O
+HIT	POS	B-NP
+mandates	POS	O
+an	POS	O
+immediate	POS	O
+cessation	POS	O
+of	POS	O
+all	POS	O
+heparin	POS	O
+exposure	POS	O
+and	POS	O
+the	POS	O
+institution	POS	O
+of	POS	O
+an	POS	O
+antithrombotic	POS	O
+therapy	POS	O
+,	POS	O
+most	POS	O
+commonly	POS	O
+using	POS	O
+a	POS	O
+direct	POS	O
+thrombin	POS	O
+inhibitor	POS	O
+.	POS	O
+Current	POS	O
+"	POS	O
+diagnostic	POS	O
+"	POS	O
+tests	POS	O
+,	POS	O
+which	POS	O
+primarily	POS	O
+include	POS	O
+functional	POS	O
+and	POS	O
+antigenic	POS	O
+assays	POS	O
+,	POS	O
+have	POS	O
+more	POS	O
+of	POS	O
+a	POS	O
+confirmatory	POS	O
+than	POS	O
+diagnostic	POS	O
+role	POS	O
+in	POS	O
+the	POS	O
+management	POS	O
+of	POS	O
+HIT	POS	B-NP
+.	POS	O
+Special	POS	O
+attention	POS	O
+must	POS	O
+be	POS	O
+paid	POS	O
+to	POS	O
+cardiac	POS	O
+patients	POS	O
+who	POS	O
+are	POS	O
+often	POS	O
+exposed	POS	O
+to	POS	O
+heparin	POS	O
+multiple	POS	O
+times	POS	O
+during	POS	O
+their	POS	O
+course	POS	O
+of	POS	O
+treatment	POS	O
+.	POS	O
+Direct	POS	O
+thrombin	POS	O
+inhibitors	POS	O
+are	POS	O
+appropriate	POS	O
+,	POS	O
+evidence	POS	O
+-	POS	O
+based	POS	O
+alternatives	POS	O
+to	POS	O
+heparin	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+HIT	POS	B-NP
+,	POS	O
+who	POS	O
+need	POS	O
+to	POS	O
+undergo	POS	O
+percutaneous	POS	O
+coronary	POS	O
+intervention	POS	O
+.	POS	O
+As	POS	O
+heparin	POS	O
+remains	POS	O
+one	POS	O
+of	POS	O
+the	POS	O
+most	POS	O
+frequently	POS	O
+used	POS	O
+medications	POS	O
+today	POS	O
+with	POS	O
+potential	POS	O
+for	POS	O
+HIT	POS	B-NP
+with	POS	O
+every	POS	O
+heparin	POS	O
+exposure	POS	O
+,	POS	O
+a	POS	O
+close	POS	O
+vigilance	POS	O
+of	POS	O
+platelet	POS	O
+counts	POS	O
+must	POS	O
+be	POS	O
+practiced	POS	O
+whenever	POS	O
+heparin	POS	O
+is	POS	O
+initiated	POS	O
+.	POS	O
+Abductor	POS	B-NP
+paralysis	POS	I-NP
+after	POS	O
+botox	POS	O
+injection	POS	O
+for	POS	O
+adductor	POS	B-NP
+spasmodic	POS	I-NP
+dysphonia	POS	I-NP
+.	POS	O
+OBJECTIVES	POS	O
+/	POS	O
+HYPOTHESIS	POS	O
+:	POS	O
+Botulinum	POS	O
+toxin	POS	O
+(	POS	O
+Botox	POS	O
+)	POS	O
+injections	POS	O
+into	POS	O
+the	POS	O
+thyroarytenoid	POS	O
+muscles	POS	O
+are	POS	O
+the	POS	O
+current	POS	O
+standard	POS	O
+of	POS	O
+care	POS	O
+for	POS	O
+adductor	POS	B-NP
+spasmodic	POS	I-NP
+dysphonia	POS	I-NP
+(	POS	O
+ADSD	POS	B-NP
+)	POS	O
+.	POS	O
+Reported	POS	O
+adverse	POS	O
+effects	POS	O
+include	POS	O
+a	POS	O
+period	POS	O
+of	POS	O
+breathiness	POS	B-NP
+,	POS	O
+throat	POS	B-NP
+pain	POS	I-NP
+,	POS	O
+and	POS	O
+difficulty	POS	O
+with	POS	O
+swallowing	POS	O
+liquids	POS	O
+.	POS	O
+Here	POS	O
+we	POS	O
+report	POS	O
+multiple	POS	O
+cases	POS	O
+of	POS	O
+bilateral	POS	B-NP
+abductor	POS	I-NP
+paralysis	POS	I-NP
+following	POS	O
+Botox	POS	O
+injections	POS	O
+for	POS	O
+ADSD	POS	B-NP
+,	POS	O
+a	POS	O
+complication	POS	O
+previously	POS	O
+unreported	POS	O
+.	POS	O
+STUDY	POS	O
+DESIGN	POS	O
+:	POS	O
+Retrospective	POS	O
+case	POS	O
+series	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Patients	POS	O
+that	POS	O
+received	POS	O
+Botox	POS	O
+injections	POS	O
+for	POS	O
+spasmodic	POS	B-NP
+dysphonia	POS	I-NP
+between	POS	O
+January	POS	O
+2000	POS	O
+and	POS	O
+October	POS	O
+2009	POS	O
+were	POS	O
+evaluated	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+ADSD	POS	B-NP
+were	POS	O
+identified	POS	O
+.	POS	O
+The	POS	O
+number	POS	O
+of	POS	O
+treatments	POS	O
+received	POS	O
+and	POS	O
+adverse	POS	O
+effects	POS	O
+were	POS	O
+noted	POS	O
+.	POS	O
+For	POS	O
+patients	POS	O
+with	POS	O
+bilateral	POS	B-NP
+abductor	POS	I-NP
+paralysis	POS	I-NP
+,	POS	O
+age	POS	O
+,	POS	O
+sex	POS	O
+,	POS	O
+paralytic	POS	B-NP
+Botox	POS	I-NP
+dose	POS	O
+,	POS	O
+prior	POS	O
+Botox	POS	O
+dose	POS	O
+,	POS	O
+and	POS	O
+course	POS	O
+following	POS	O
+paralysis	POS	B-NP
+were	POS	O
+noted	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+From	POS	O
+a	POS	O
+database	POS	O
+of	POS	O
+452	POS	O
+patients	POS	O
+receiving	POS	O
+Botox	POS	O
+,	POS	O
+352	POS	O
+patients	POS	O
+had	POS	O
+been	POS	O
+diagnosed	POS	O
+with	POS	O
+ADSD	POS	B-NP
+.	POS	O
+Of	POS	O
+these	POS	O
+352	POS	O
+patients	POS	O
+,	POS	O
+eight	POS	O
+patients	POS	O
+suffered	POS	O
+bilateral	POS	B-NP
+abductor	POS	I-NP
+paralysis	POS	I-NP
+,	POS	O
+and	POS	O
+two	POS	O
+suffered	POS	O
+this	POS	O
+complication	POS	O
+twice	POS	O
+.	POS	O
+All	POS	O
+affected	POS	B-NP
+patients	POS	O
+were	POS	O
+females	POS	O
+over	POS	O
+the	POS	O
+age	POS	O
+of	POS	O
+50	POS	O
+years	POS	O
+.	POS	O
+Most	POS	O
+patients	POS	O
+had	POS	O
+received	POS	O
+treatments	POS	O
+prior	POS	O
+to	POS	O
+abductor	POS	B-NP
+paralysis	POS	I-NP
+and	POS	O
+continued	POS	O
+receiving	POS	O
+after	POS	O
+paralysis	POS	B-NP
+.	POS	O
+Seven	POS	O
+patients	POS	O
+recovered	POS	O
+after	POS	O
+a	POS	O
+brief	POS	O
+period	POS	O
+of	POS	O
+activity	POS	O
+restrictions	POS	O
+,	POS	O
+and	POS	O
+one	POS	O
+underwent	POS	O
+a	POS	O
+tracheotomy	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+abductor	POS	B-NP
+paralysis	POS	I-NP
+after	POS	O
+Botox	POS	O
+injection	POS	O
+for	POS	O
+ADSD	POS	B-NP
+was	POS	O
+0	POS	O
+.	POS	O
+34	POS	O
+%	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Bilateral	POS	O
+abductor	POS	B-NP
+paralysis	POS	I-NP
+is	POS	O
+a	POS	O
+rare	POS	O
+complication	POS	O
+of	POS	O
+Botox	POS	O
+injections	POS	O
+for	POS	O
+ADSD	POS	B-NP
+,	POS	O
+causing	POS	O
+difficulty	POS	O
+with	POS	O
+breathing	POS	B-NP
+upon	POS	I-NP
+exertion	POS	I-NP
+.	POS	O
+The	POS	O
+likely	POS	O
+mechanism	POS	O
+of	POS	O
+paralysis	POS	B-NP
+is	POS	O
+diffusion	POS	O
+of	POS	O
+Botox	POS	O
+around	POS	O
+the	POS	O
+muscular	POS	O
+process	POS	O
+of	POS	O
+the	POS	O
+arytenoid	POS	O
+to	POS	O
+the	POS	O
+posterior	POS	O
+cricoarytenoid	POS	O
+muscles	POS	O
+.	POS	O
+The	POS	O
+paralysis	POS	B-NP
+is	POS	O
+temporary	POS	O
+,	POS	O
+and	POS	O
+watchful	POS	O
+waiting	POS	O
+with	POS	O
+restriction	POS	O
+of	POS	O
+activity	POS	O
+is	POS	O
+the	POS	O
+recommended	POS	O
+management	POS	O
+.	POS	O
+Mitochondrial	POS	B-NP
+impairment	POS	I-NP
+contributes	POS	O
+to	POS	O
+cocaine	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+dysfunction	POS	I-NP
+:	POS	O
+Prevention	POS	O
+by	POS	O
+the	POS	O
+targeted	POS	O
+antioxidant	POS	O
+MitoQ	POS	O
+.	POS	O
+The	POS	O
+goal	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+assess	POS	O
+mitochondrial	POS	O
+function	POS	O
+and	POS	O
+ROS	POS	O
+production	POS	O
+in	POS	O
+an	POS	O
+experimental	POS	O
+model	POS	O
+of	POS	O
+cocaine	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+We	POS	O
+hypothesized	POS	O
+that	POS	O
+cocaine	POS	B-NP
+abuse	POS	I-NP
+may	POS	O
+lead	POS	O
+to	POS	O
+altered	POS	O
+mitochondrial	POS	O
+function	POS	O
+that	POS	O
+in	POS	O
+turn	POS	O
+may	POS	O
+cause	POS	O
+left	POS	O
+ventricular	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+Seven	POS	O
+days	POS	O
+of	POS	O
+cocaine	POS	O
+administration	POS	O
+to	POS	O
+rats	POS	O
+led	POS	O
+to	POS	O
+an	POS	O
+increased	POS	O
+oxygen	POS	O
+consumption	POS	O
+detected	POS	O
+in	POS	O
+cardiac	POS	O
+fibers	POS	O
+,	POS	O
+specifically	POS	O
+through	POS	O
+complex	POS	O
+I	POS	O
+and	POS	O
+complex	POS	O
+III	POS	O
+.	POS	O
+ROS	POS	O
+levels	POS	O
+were	POS	O
+increased	POS	O
+,	POS	O
+specifically	POS	O
+in	POS	O
+interfibrillar	POS	O
+mitochondria	POS	O
+.	POS	O
+In	POS	O
+parallel	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+ATP	POS	O
+synthesis	POS	O
+,	POS	O
+whereas	POS	O
+no	POS	O
+difference	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+subsarcolemmal	POS	O
+mitochondria	POS	O
+.	POS	O
+This	POS	O
+uncoupling	POS	O
+effect	POS	O
+on	POS	O
+oxidative	POS	O
+phosphorylation	POS	O
+was	POS	O
+not	POS	O
+detectable	POS	O
+after	POS	O
+short	POS	O
+-	POS	O
+term	POS	O
+exposure	POS	O
+to	POS	O
+cocaine	POS	O
+,	POS	O
+suggesting	POS	O
+that	POS	O
+these	POS	O
+mitochondrial	POS	B-NP
+abnormalities	POS	I-NP
+were	POS	O
+a	POS	O
+late	POS	O
+rather	POS	O
+than	POS	O
+a	POS	O
+primary	POS	O
+event	POS	O
+in	POS	O
+the	POS	O
+pathological	POS	O
+response	POS	O
+to	POS	O
+cocaine	POS	O
+.	POS	O
+MitoQ	POS	O
+,	POS	O
+a	POS	O
+mitochondrial	POS	O
+-	POS	O
+targeted	POS	O
+antioxidant	POS	O
+,	POS	O
+was	POS	O
+shown	POS	O
+to	POS	O
+completely	POS	O
+prevent	POS	O
+these	POS	O
+mitochondrial	POS	O
+abnormalities	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+cardiac	POS	B-NP
+dysfunction	POS	I-NP
+characterized	POS	O
+here	POS	O
+by	POS	O
+a	POS	O
+diastolic	POS	B-NP
+dysfunction	POS	I-NP
+studied	POS	O
+with	POS	O
+a	POS	O
+conductance	POS	O
+catheter	POS	O
+to	POS	O
+obtain	POS	O
+pressure	POS	O
+-	POS	O
+volume	POS	O
+data	POS	O
+.	POS	O
+Taken	POS	O
+together	POS	O
+,	POS	O
+these	POS	O
+results	POS	O
+extend	POS	O
+previous	POS	O
+studies	POS	O
+and	POS	O
+demonstrate	POS	O
+that	POS	O
+cocaine	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+dysfunction	POS	I-NP
+may	POS	O
+be	POS	O
+due	POS	O
+to	POS	O
+a	POS	O
+mitochondrial	POS	B-NP
+defect	POS	I-NP
+.	POS	O
+Trimethoprim	POS	O
+-	POS	O
+induced	POS	O
+immune	POS	O
+hemolytic	POS	B-NP
+anemia	POS	I-NP
+in	POS	O
+a	POS	O
+pediatric	POS	O
+oncology	POS	O
+patient	POS	O
+presenting	POS	O
+as	POS	O
+an	POS	O
+acute	POS	B-NP
+hemolytic	POS	I-NP
+transfusion	POS	I-NP
+reaction	POS	I-NP
+.	POS	O
+A	POS	O
+10	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+male	POS	O
+with	POS	O
+acute	POS	B-NP
+leukemia	POS	I-NP
+presented	POS	O
+with	POS	O
+post	POS	O
+-	POS	O
+chemotherapy	POS	O
+anemia	POS	B-NP
+.	POS	O
+During	POS	O
+red	POS	O
+cell	POS	O
+transfusion	POS	O
+,	POS	O
+he	POS	O
+developed	POS	O
+hemoglobinuria	POS	B-NP
+.	POS	O
+Transfusion	POS	O
+reaction	POS	O
+workup	POS	O
+was	POS	O
+negative	POS	O
+.	POS	O
+Drug	POS	O
+-	POS	O
+induced	POS	O
+immune	POS	O
+hemolytic	POS	B-NP
+anemia	POS	I-NP
+was	POS	O
+suspected	POS	O
+because	POS	O
+of	POS	O
+positive	POS	O
+direct	POS	O
+antiglobulin	POS	O
+test	POS	O
+,	POS	O
+negative	POS	O
+eluate	POS	O
+,	POS	O
+and	POS	O
+microspherocytes	POS	O
+on	POS	O
+smear	POS	O
+pre	POS	O
+-	POS	O
+and	POS	O
+post	POS	O
+-	POS	O
+transfusion	POS	O
+.	POS	O
+Drug	POS	O
+studies	POS	O
+using	POS	O
+the	POS	O
+indirect	POS	O
+antiglobulin	POS	O
+test	POS	O
+were	POS	O
+strongly	POS	O
+positive	POS	O
+with	POS	O
+trimethoprim	POS	O
+and	POS	O
+trimethoprim	POS	O
+-	POS	O
+sulfamethoxazole	POS	O
+but	POS	O
+negative	POS	O
+with	POS	O
+sulfamethoxazole	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+recovered	POS	O
+after	POS	O
+discontinuing	POS	O
+the	POS	O
+drug	POS	O
+,	POS	O
+with	POS	O
+no	POS	O
+recurrence	POS	O
+in	POS	O
+2	POS	O
+years	POS	O
+.	POS	O
+Other	POS	O
+causes	POS	O
+of	POS	O
+anemia	POS	B-NP
+should	POS	O
+be	POS	O
+considered	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+worse	POS	O
+-	POS	O
+than	POS	O
+-	POS	O
+expected	POS	O
+anemia	POS	B-NP
+after	POS	O
+chemotherapy	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+hemolysis	POS	B-NP
+during	POS	O
+transfusion	POS	O
+is	POS	O
+not	POS	O
+always	POS	O
+a	POS	O
+transfusion	POS	O
+reaction	POS	O
+.	POS	O
+Verapamil	POS	O
+stimulation	POS	O
+test	POS	O
+in	POS	O
+hyperprolactinemia	POS	B-NP
+:	POS	O
+loss	POS	O
+of	POS	O
+prolactin	POS	O
+response	POS	O
+in	POS	O
+anatomic	POS	O
+or	POS	O
+functional	POS	O
+stalk	POS	O
+effect	POS	O
+.	POS	O
+AIM	POS	O
+:	POS	O
+Verapamil	POS	O
+stimulation	POS	O
+test	POS	O
+was	POS	O
+previously	POS	O
+investigated	POS	O
+as	POS	O
+a	POS	O
+tool	POS	O
+for	POS	O
+differential	POS	O
+diagnosis	POS	O
+of	POS	O
+hyperprolactinemia	POS	B-NP
+,	POS	O
+but	POS	O
+with	POS	O
+conflicting	POS	O
+results	POS	O
+.	POS	O
+Macroprolactinemia	POS	B-NP
+was	POS	O
+never	POS	O
+considered	POS	O
+in	POS	O
+those	POS	O
+previous	POS	O
+studies	POS	O
+.	POS	O
+Here	POS	O
+,	POS	O
+we	POS	O
+aimed	POS	O
+to	POS	O
+re	POS	O
+-	POS	O
+investigate	POS	O
+the	POS	O
+diagnostic	POS	O
+value	POS	O
+of	POS	O
+verapamil	POS	O
+in	POS	O
+a	POS	O
+population	POS	O
+who	POS	O
+were	POS	O
+all	POS	O
+screened	POS	O
+for	POS	O
+macroprolactinemia	POS	B-NP
+.	POS	O
+Prolactin	POS	O
+responses	POS	O
+to	POS	O
+verapamil	POS	O
+in	POS	O
+65	POS	O
+female	POS	O
+patients	POS	O
+(	POS	O
+age	POS	O
+:	POS	O
+29	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+8	POS	O
+.	POS	O
+1	POS	O
+years	POS	O
+)	POS	O
+with	POS	O
+hyperprolactinemia	POS	B-NP
+were	POS	O
+tested	POS	O
+in	POS	O
+a	POS	O
+descriptive	POS	O
+,	POS	O
+matched	POS	O
+case	POS	O
+-	POS	O
+control	POS	O
+study	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Verapamil	POS	O
+80	POS	O
+mg	POS	O
+,	POS	O
+p	POS	O
+.	POS	O
+o	POS	O
+.	POS	O
+was	POS	O
+administered	POS	O
+,	POS	O
+and	POS	O
+then	POS	O
+PRL	POS	O
+levels	POS	O
+were	POS	O
+measured	POS	O
+at	POS	O
+8th	POS	O
+and	POS	O
+16th	POS	O
+hours	POS	O
+,	POS	O
+by	POS	O
+immunometric	POS	O
+chemiluminescence	POS	O
+.	POS	O
+Verapamil	POS	O
+responsiveness	POS	O
+was	POS	O
+determined	POS	O
+by	POS	O
+peak	POS	O
+percent	POS	O
+change	POS	O
+in	POS	O
+basal	POS	O
+prolactin	POS	O
+levels	POS	O
+(	POS	O
+PRL	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Verapamil	POS	O
+significantly	POS	O
+increased	POS	O
+PRL	POS	O
+levels	POS	O
+in	POS	O
+healthy	POS	O
+controls	POS	O
+(	POS	O
+N	POS	O
+.	POS	O
+8	POS	O
+,	POS	O
+PRL	POS	O
+:	POS	O
+183	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+macroprolactinoma	POS	B-NP
+(	POS	O
+N	POS	O
+.	POS	O
+8	POS	O
+,	POS	O
+PRL	POS	O
+:	POS	O
+7	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+microprolactinoma	POS	B-NP
+(	POS	O
+N	POS	O
+.	POS	O
+19	POS	O
+,	POS	O
+PRL	POS	O
+:	POS	O
+21	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+macroprolactinemia	POS	B-NP
+(	POS	O
+N	POS	O
+.	POS	O
+23	POS	O
+,	POS	O
+PRL	POS	O
+:	POS	O
+126	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+in	POS	O
+pseudoprolactinoma	POS	B-NP
+(	POS	O
+N	POS	O
+.	POS	O
+8	POS	O
+,	POS	O
+PRL	POS	O
+:	POS	O
+0	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+risperidone	POS	O
+-	POS	O
+induced	POS	O
+hyperprolactinemia	POS	B-NP
+(	POS	O
+N	POS	O
+.	POS	O
+7	POS	O
+,	POS	O
+PRL	POS	O
+:	POS	O
+3	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+ROC	POS	O
+curve	POS	O
+analysis	POS	O
+revealed	POS	O
+that	POS	O
+unresponsiveness	POS	O
+to	POS	O
+verapamil	POS	O
+defined	POS	O
+as	POS	O
+PRL	POS	O
+<	POS	O
+7	POS	O
+%	POS	O
+,	POS	O
+discriminated	POS	O
+anatomical	POS	O
+or	POS	O
+functional	POS	O
+stalk	POS	O
+effect	POS	O
+(	POS	O
+sensitivity	POS	O
+:	POS	O
+74	POS	O
+%	POS	O
+,	POS	O
+specificity	POS	O
+:	POS	O
+73	POS	O
+%	POS	O
+,	POS	O
+AUC	POS	O
+:	POS	O
+0	POS	O
+.	POS	O
+855	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+04	POS	O
+,	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+,	POS	O
+CI	POS	O
+:	POS	O
+0	POS	O
+.	POS	O
+768	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+942	POS	O
+)	POS	O
+associated	POS	O
+with	POS	O
+pseudoprolactinoma	POS	O
+or	POS	O
+risperidone	POS	O
+-	POS	O
+induced	POS	O
+hyperprolactinemia	POS	B-NP
+,	POS	O
+respectively	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Verapamil	POS	O
+responsiveness	POS	O
+is	POS	O
+not	POS	O
+a	POS	O
+reliable	POS	O
+finding	POS	O
+for	POS	O
+the	POS	O
+differential	POS	O
+diagnosis	POS	O
+of	POS	O
+hyperprolactinemia	POS	B-NP
+.	POS	O
+However	POS	O
+,	POS	O
+verapamil	POS	O
+unresponsiveness	POS	O
+discriminates	POS	O
+stalk	POS	O
+effect	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+e	POS	O
+.	POS	O
+,	POS	O
+anatomically	POS	O
+or	POS	O
+functionally	POS	O
+inhibited	POS	O
+dopaminergic	POS	O
+tonus	POS	O
+)	POS	O
+from	POS	O
+other	POS	O
+causes	POS	O
+of	POS	O
+hyperprolactinemia	POS	B-NP
+with	POS	O
+varying	POS	O
+degrees	POS	O
+of	POS	O
+responsiveness	POS	O
+.	POS	O
+Blockade	POS	O
+of	POS	O
+endothelial	POS	O
+-	POS	O
+mesenchymal	POS	O
+transition	POS	O
+by	POS	O
+a	POS	O
+Smad3	POS	O
+inhibitor	POS	O
+delays	POS	O
+the	POS	O
+early	POS	O
+development	POS	O
+of	POS	O
+streptozotocin	POS	O
+-	POS	O
+induced	POS	O
+diabetic	POS	B-NP
+nephropathy	POS	I-NP
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+A	POS	O
+multicenter	POS	O
+,	POS	O
+controlled	POS	O
+trial	POS	O
+showed	POS	O
+that	POS	O
+early	POS	O
+blockade	POS	O
+of	POS	O
+the	POS	O
+renin	POS	O
+-	POS	O
+angiotensin	POS	O
+system	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+type	POS	B-NP
+1	POS	I-NP
+diabetes	POS	I-NP
+and	POS	O
+normoalbuminuria	POS	B-NP
+did	POS	O
+not	POS	O
+retard	POS	O
+the	POS	O
+progression	POS	O
+of	POS	O
+nephropathy	POS	B-NP
+,	POS	O
+suggesting	POS	O
+that	POS	O
+other	POS	O
+mechanism	POS	O
+(	POS	O
+s	POS	O
+)	POS	O
+are	POS	O
+involved	POS	O
+in	POS	O
+the	POS	O
+pathogenesis	POS	O
+of	POS	O
+early	POS	O
+diabetic	POS	B-NP
+nephropathy	POS	I-NP
+(	POS	O
+diabetic	POS	B-NP
+nephropathy	POS	I-NP
+)	POS	O
+.	POS	O
+We	POS	O
+have	POS	O
+previously	POS	O
+demonstrated	POS	O
+that	POS	O
+endothelial	POS	O
+-	POS	O
+mesenchymal	POS	O
+-	POS	O
+transition	POS	O
+(	POS	O
+EndoMT	POS	O
+)	POS	O
+contributes	POS	O
+to	POS	O
+the	POS	O
+early	POS	O
+development	POS	O
+of	POS	O
+renal	POS	B-NP
+interstitial	POS	I-NP
+fibrosis	POS	I-NP
+independently	POS	O
+of	POS	O
+microalbuminuria	POS	B-NP
+in	POS	O
+mice	POS	O
+with	POS	O
+streptozotocin	POS	O
+(	POS	O
+STZ	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+diabetes	POS	B-NP
+.	POS	O
+In	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+,	POS	O
+we	POS	O
+hypothesized	POS	O
+that	POS	O
+blocking	POS	O
+EndoMT	POS	O
+reduces	POS	O
+the	POS	O
+early	POS	O
+development	POS	O
+of	POS	O
+diabetic	POS	B-NP
+nephropathy	POS	I-NP
+.	POS	O
+RESEARCH	POS	O
+DESIGN	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+EndoMT	POS	O
+was	POS	O
+induced	POS	O
+in	POS	O
+a	POS	O
+mouse	POS	O
+pancreatic	POS	O
+microvascular	POS	O
+endothelial	POS	O
+cell	POS	O
+line	POS	O
+(	POS	O
+MMEC	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+advanced	POS	O
+glycation	POS	O
+end	POS	O
+products	POS	O
+(	POS	O
+AGEs	POS	O
+)	POS	O
+and	POS	O
+in	POS	O
+the	POS	O
+endothelial	POS	O
+lineage	POS	O
+-	POS	O
+traceble	POS	O
+mouse	POS	O
+line	POS	O
+Tie2	POS	O
+-	POS	O
+Cre	POS	O
+;	POS	O
+Loxp	POS	O
+-	POS	O
+EGFP	POS	O
+by	POS	O
+administration	POS	O
+of	POS	O
+AGEs	POS	O
+,	POS	O
+with	POS	O
+nonglycated	POS	O
+mouse	POS	O
+albumin	POS	O
+serving	POS	O
+as	POS	O
+a	POS	O
+control	POS	O
+.	POS	O
+Phosphorylated	POS	O
+Smad3	POS	O
+was	POS	O
+detected	POS	O
+by	POS	O
+immunoprecipitation	POS	O
+/	POS	O
+Western	POS	O
+blotting	POS	O
+and	POS	O
+confocal	POS	O
+microscopy	POS	O
+.	POS	O
+Blocking	POS	O
+studies	POS	O
+using	POS	O
+receptor	POS	O
+for	POS	O
+AGE	POS	O
+siRNA	POS	O
+and	POS	O
+a	POS	O
+specific	POS	O
+inhibitor	POS	O
+of	POS	O
+Smad3	POS	O
+(	POS	O
+SIS3	POS	O
+)	POS	O
+were	POS	O
+performed	POS	O
+in	POS	O
+MMECs	POS	O
+and	POS	O
+in	POS	O
+STZ	POS	O
+-	POS	O
+induced	POS	O
+diabetic	POS	B-NP
+nephropathy	POS	I-NP
+in	POS	O
+Tie2	POS	O
+-	POS	O
+Cre	POS	O
+;	POS	O
+Loxp	POS	O
+-	POS	O
+EGFP	POS	O
+mice	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Confocal	POS	O
+microscopy	POS	O
+and	POS	O
+real	POS	O
+-	POS	O
+time	POS	O
+PCR	POS	O
+demonstrated	POS	O
+that	POS	O
+AGEs	POS	O
+induced	POS	O
+EndoMT	POS	O
+in	POS	O
+MMECs	POS	O
+and	POS	O
+in	POS	O
+Tie2	POS	O
+-	POS	O
+Cre	POS	O
+;	POS	O
+Loxp	POS	O
+-	POS	O
+EGFP	POS	O
+mice	POS	O
+.	POS	O
+Immunoprecipitation	POS	O
+/	POS	O
+Western	POS	O
+blotting	POS	O
+showed	POS	O
+that	POS	O
+Smad3	POS	O
+was	POS	O
+activated	POS	O
+by	POS	O
+AGEs	POS	O
+but	POS	O
+was	POS	O
+inhibited	POS	O
+by	POS	O
+SIS3	POS	O
+in	POS	O
+MMECs	POS	O
+and	POS	O
+in	POS	O
+STZ	POS	O
+-	POS	O
+induced	POS	O
+diabetic	POS	B-NP
+nephropathy	POS	I-NP
+.	POS	O
+Confocal	POS	O
+microscopy	POS	O
+and	POS	O
+real	POS	O
+-	POS	O
+time	POS	O
+PCR	POS	O
+further	POS	O
+demonstrated	POS	O
+that	POS	O
+SIS3	POS	O
+abrogated	POS	O
+EndoMT	POS	O
+,	POS	O
+reduced	POS	O
+renal	POS	B-NP
+fibrosis	POS	I-NP
+,	POS	O
+and	POS	O
+retarded	POS	O
+progression	POS	O
+of	POS	O
+nephropathy	POS	B-NP
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+EndoMT	POS	O
+is	POS	O
+a	POS	O
+novel	POS	O
+pathway	POS	O
+leading	POS	O
+to	POS	O
+early	POS	O
+development	POS	O
+of	POS	O
+diabetic	POS	B-NP
+nephropathy	POS	I-NP
+.	POS	O
+Blockade	POS	O
+of	POS	O
+EndoMT	POS	O
+by	POS	O
+SIS3	POS	O
+may	POS	O
+provide	POS	O
+a	POS	O
+new	POS	O
+strategy	POS	O
+to	POS	O
+retard	POS	O
+the	POS	O
+progression	POS	O
+of	POS	O
+diabetic	POS	B-NP
+nephropathy	POS	I-NP
+and	POS	O
+other	POS	O
+diabetes	POS	B-NP
+complications	POS	O
+.	POS	O
+Cytostatic	POS	O
+and	POS	O
+anti	POS	O
+-	POS	O
+angiogenic	POS	O
+effects	POS	O
+of	POS	O
+temsirolimus	POS	O
+in	POS	O
+refractory	POS	O
+mantle	POS	B-NP
+cell	POS	I-NP
+lymphoma	POS	I-NP
+.	POS	O
+Mantle	POS	B-NP
+cell	POS	I-NP
+lymphoma	POS	I-NP
+(	POS	O
+MCL	POS	B-NP
+)	POS	O
+is	POS	O
+a	POS	O
+rare	POS	O
+and	POS	O
+aggressive	POS	B-NP
+type	POS	I-NP
+of	POS	I-NP
+B	POS	I-NP
+-	POS	I-NP
+cell	POS	I-NP
+non	POS	I-NP
+-	POS	I-NP
+Hodgkin	POS	I-NP
+'	POS	I-NP
+s	POS	I-NP
+lymphoma	POS	I-NP
+.	POS	O
+Patients	POS	O
+become	POS	O
+progressively	POS	O
+refractory	POS	O
+to	POS	O
+conventional	POS	O
+chemotherapy	POS	O
+,	POS	O
+and	POS	O
+their	POS	O
+prognosis	POS	O
+is	POS	O
+poor	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+a	POS	O
+38	POS	O
+%	POS	O
+remission	POS	O
+rate	POS	O
+has	POS	O
+been	POS	O
+recently	POS	O
+reported	POS	O
+in	POS	O
+refractory	POS	O
+MCL	POS	O
+treated	POS	O
+with	POS	O
+temsirolimus	POS	O
+,	POS	O
+a	POS	O
+mTOR	POS	O
+inhibitor	POS	O
+.	POS	O
+Here	POS	O
+we	POS	O
+had	POS	O
+the	POS	O
+opportunity	POS	O
+to	POS	O
+study	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+refractory	POS	O
+MCL	POS	B-NP
+who	POS	O
+had	POS	O
+tumor	POS	B-NP
+regression	POS	O
+two	POS	O
+months	POS	O
+after	POS	O
+temsirolimus	POS	O
+treatment	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+progression	POS	O
+-	POS	O
+free	POS	O
+survival	POS	O
+of	POS	O
+10	POS	O
+months	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+case	POS	O
+,	POS	O
+lymph	POS	O
+node	POS	O
+biopsies	POS	O
+were	POS	O
+performed	POS	O
+before	POS	O
+and	POS	O
+six	POS	O
+months	POS	O
+after	POS	O
+temsirolimus	POS	O
+therapy	POS	O
+.	POS	O
+Comparison	POS	O
+of	POS	O
+the	POS	O
+two	POS	O
+biopsies	POS	O
+showed	POS	O
+that	POS	O
+temsirolimus	POS	O
+inhibited	POS	O
+tumor	POS	B-NP
+cell	POS	I-NP
+proliferation	POS	I-NP
+through	POS	I-NP
+cell	POS	I-NP
+cycle	POS	I-NP
+arrest	POS	I-NP
+,	POS	O
+but	POS	O
+did	POS	O
+not	POS	O
+induce	POS	O
+any	POS	O
+change	POS	O
+in	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+apoptotic	POS	O
+tumor	POS	B-NP
+cells	POS	O
+.	POS	O
+Apart	POS	O
+from	POS	O
+this	POS	O
+cytostatic	POS	O
+effect	POS	O
+,	POS	O
+temsirolimus	POS	O
+had	POS	O
+an	POS	O
+antiangiogenic	POS	O
+effect	POS	O
+with	POS	O
+decrease	POS	O
+of	POS	O
+tumor	POS	B-NP
+microvessel	POS	O
+density	POS	O
+and	POS	O
+of	POS	O
+VEGF	POS	O
+expression	POS	O
+.	POS	O
+Moreover	POS	O
+,	POS	O
+numerous	POS	O
+patchy	POS	O
+,	POS	O
+well	POS	O
+-	POS	O
+limited	POS	O
+fibrotic	POS	O
+areas	POS	O
+,	POS	O
+compatible	POS	O
+with	POS	O
+post	POS	O
+-	POS	O
+necrotic	POS	O
+tissue	POS	O
+repair	POS	O
+,	POS	O
+were	POS	O
+found	POS	O
+after	POS	O
+6	POS	O
+-	POS	O
+month	POS	O
+temsirolimus	POS	O
+therapy	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+temsirolimus	POS	O
+reduced	POS	O
+tumor	POS	B-NP
+burden	POS	O
+through	POS	O
+associated	POS	O
+cytostatic	POS	O
+and	POS	O
+anti	POS	O
+-	POS	O
+angiogenic	POS	O
+effects	POS	O
+.	POS	O
+This	POS	O
+dual	POS	O
+effect	POS	O
+of	POS	O
+temsirolimus	POS	O
+on	POS	O
+tumor	POS	B-NP
+tissue	POS	O
+could	POS	O
+contribute	POS	O
+to	POS	O
+its	POS	O
+recently	POS	O
+reported	POS	O
+efficiency	POS	O
+in	POS	O
+refractory	POS	O
+MCL	POS	B-NP
+resistant	POS	O
+to	POS	O
+conventional	POS	O
+chemotherapy	POS	O
+.	POS	O
+Acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+due	POS	O
+to	POS	O
+rifampicin	POS	O
+.	POS	O
+A	POS	O
+23	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+male	POS	O
+patient	POS	O
+with	POS	O
+bacteriologically	POS	O
+proven	POS	O
+pulmonary	POS	B-NP
+tuberculosis	POS	I-NP
+was	POS	O
+treated	POS	O
+with	POS	O
+the	POS	O
+various	POS	O
+regimens	POS	O
+of	POS	O
+antituberculosis	POS	O
+drugs	POS	O
+for	POS	O
+nearly	POS	O
+15	POS	O
+months	POS	O
+.	POS	O
+Rifampicin	POS	O
+was	POS	O
+administered	POS	O
+thrice	POS	O
+as	POS	O
+one	POS	O
+of	POS	O
+the	POS	O
+3	POS	O
+-	POS	O
+4	POS	O
+drug	POS	O
+regimen	POS	O
+and	POS	O
+each	POS	O
+time	POS	O
+he	POS	O
+developed	POS	O
+untoward	POS	O
+side	POS	O
+effects	POS	O
+like	POS	O
+nausea	POS	B-NP
+,	POS	O
+vomiting	POS	B-NP
+and	POS	O
+fever	POS	B-NP
+with	POS	O
+chills	POS	B-NP
+and	POS	O
+rigors	POS	B-NP
+.	POS	O
+The	POS	O
+last	POS	O
+such	POS	O
+episode	POS	O
+was	POS	O
+of	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+at	POS	O
+which	POS	O
+stage	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+seen	POS	O
+by	POS	O
+the	POS	O
+authors	POS	O
+of	POS	O
+this	POS	O
+report	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+,	POS	O
+however	POS	O
+,	POS	O
+made	POS	O
+a	POS	O
+full	POS	O
+recovery	POS	O
+.	POS	O
+Syncope	POS	B-NP
+caused	POS	O
+by	POS	O
+hyperkalemia	POS	B-NP
+during	POS	O
+use	POS	O
+of	POS	O
+a	POS	O
+combined	POS	O
+therapy	POS	O
+with	POS	O
+the	POS	O
+angiotensin	POS	O
+-	POS	O
+converting	POS	O
+enzyme	POS	O
+inhibitor	POS	O
+and	POS	O
+spironolactone	POS	O
+.	POS	O
+A	POS	O
+76	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+with	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+coronary	POS	O
+artery	POS	O
+bypass	POS	O
+grafting	POS	O
+and	POS	O
+prior	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+was	POS	O
+transferred	POS	O
+to	POS	O
+the	POS	O
+emergency	POS	O
+room	POS	O
+with	POS	O
+loss	POS	O
+of	POS	O
+consciousness	POS	O
+due	POS	O
+to	POS	O
+marked	POS	O
+bradycardia	POS	B-NP
+caused	POS	O
+by	POS	O
+hyperkalemia	POS	B-NP
+.	POS	O
+The	POS	O
+concentration	POS	O
+of	POS	O
+serum	POS	O
+potassium	POS	O
+was	POS	O
+high	POS	O
+,	POS	O
+and	POS	O
+normal	POS	O
+sinus	POS	O
+rhythm	POS	O
+was	POS	O
+restored	POS	O
+after	POS	O
+correction	POS	O
+of	POS	O
+the	POS	O
+serum	POS	O
+potassium	POS	O
+level	POS	O
+.	POS	O
+The	POS	O
+cause	POS	O
+of	POS	O
+hyperkalemia	POS	B-NP
+was	POS	O
+considered	POS	O
+to	POS	O
+be	POS	O
+several	POS	O
+doses	POS	O
+of	POS	O
+spiranolactone	POS	O
+,	POS	O
+an	POS	O
+aldosterone	POS	O
+antagonist	POS	O
+,	POS	O
+in	POS	O
+addition	POS	O
+to	POS	O
+the	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+intake	POS	O
+of	POS	O
+ramipril	POS	O
+,	POS	O
+an	POS	O
+ACE	POS	O
+inhibitor	POS	O
+.	POS	O
+This	POS	O
+case	POS	O
+is	POS	O
+a	POS	O
+good	POS	O
+example	POS	O
+of	POS	O
+electrolyte	POS	O
+imbalance	POS	O
+causing	POS	O
+acute	POS	O
+life	POS	O
+-	POS	O
+threatening	POS	O
+cardiac	POS	O
+events	POS	O
+.	POS	O
+Clinicians	POS	O
+should	POS	O
+be	POS	O
+alert	POS	O
+to	POS	O
+the	POS	O
+possibility	POS	O
+of	POS	O
+hyperkalemia	POS	B-NP
+,	POS	O
+especially	POS	O
+in	POS	O
+elderly	POS	O
+patients	POS	O
+using	POS	O
+ACE	POS	O
+/	POS	O
+ARB	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+potassium	POS	O
+sparing	POS	O
+agents	POS	O
+and	POS	O
+who	POS	O
+have	POS	O
+mild	POS	O
+renal	POS	B-NP
+disturbance	POS	I-NP
+.	POS	O
+Diffuse	POS	B-NP
+skeletal	POS	I-NP
+pain	POS	I-NP
+after	POS	O
+administration	POS	O
+of	POS	O
+alendronate	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Osteoporosis	POS	B-NP
+is	POS	O
+caused	POS	O
+by	POS	O
+bone	POS	O
+resorption	POS	O
+in	POS	O
+excess	POS	O
+of	POS	O
+bone	POS	O
+formation	POS	O
+,	POS	O
+and	POS	O
+bisphosphonates	POS	O
+,	POS	O
+are	POS	O
+used	POS	O
+to	POS	O
+inhibit	POS	O
+bone	POS	O
+resorption	POS	O
+.	POS	O
+Alendronate	POS	O
+,	POS	O
+a	POS	O
+biphosphonate	POS	O
+,	POS	O
+is	POS	O
+effective	POS	O
+for	POS	O
+both	POS	O
+the	POS	O
+treatment	POS	O
+and	POS	O
+prevention	POS	O
+of	POS	O
+osteoporosis	POS	B-NP
+in	POS	O
+postmenopausal	POS	O
+women	POS	O
+.	POS	O
+Side	POS	O
+effects	POS	O
+are	POS	O
+relatively	POS	O
+few	POS	O
+and	POS	O
+prominently	POS	O
+gastrointestinal	POS	O
+.	POS	O
+Musculoskeletal	POS	B-NP
+pain	POS	I-NP
+may	POS	O
+be	POS	O
+an	POS	O
+important	POS	O
+side	POS	O
+effect	POS	O
+in	POS	O
+these	POS	O
+patients	POS	O
+.	POS	O
+We	POS	O
+presented	POS	O
+a	POS	O
+patient	POS	O
+admitted	POS	O
+to	POS	O
+our	POS	O
+out	POS	O
+-	POS	O
+patient	POS	O
+clinic	POS	O
+with	POS	O
+diffuse	POS	O
+skeletal	POS	B-NP
+pain	POS	I-NP
+after	POS	O
+three	POS	O
+consecutive	POS	O
+administration	POS	O
+of	POS	O
+alendronate	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+patients	POS	O
+with	POS	O
+osteoporosis	POS	B-NP
+can	POS	O
+report	POS	O
+pain	POS	B-NP
+,	POS	O
+and	POS	O
+bisphosphonate	POS	B-NP
+-	POS	I-NP
+related	POS	I-NP
+pain	POS	I-NP
+should	POS	O
+also	POS	O
+be	POS	O
+considered	POS	O
+before	POS	O
+ascribing	POS	O
+this	POS	O
+complaint	POS	O
+to	POS	O
+osteoporosis	POS	B-NP
+.	POS	O
+Cerebrospinal	POS	O
+fluid	POS	O
+penetration	POS	O
+of	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+daptomycin	POS	O
+in	POS	O
+suspected	POS	O
+Staphylococcus	POS	O
+aureus	POS	O
+meningitis	POS	B-NP
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+methicillin	POS	O
+-	POS	O
+sensitive	POS	O
+Staphylococcus	POS	O
+aureus	POS	O
+(	POS	O
+MSSA	POS	O
+)	POS	O
+bacteremia	POS	B-NP
+with	POS	O
+suspected	POS	O
+MSSA	POS	B-NP
+meningitis	POS	I-NP
+treated	POS	O
+with	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+daptomycin	POS	O
+assessed	POS	O
+with	POS	O
+concurrent	POS	O
+serum	POS	O
+and	POS	O
+cerebrospinal	POS	O
+fluid	POS	O
+(	POS	O
+CSF	POS	O
+)	POS	O
+concentrations	POS	O
+.	POS	O
+CASE	POS	O
+SUMMARY	POS	O
+:	POS	O
+A	POS	O
+54	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+male	POS	O
+presented	POS	O
+to	POS	O
+the	POS	O
+emergency	POS	O
+department	POS	O
+with	POS	O
+generalized	POS	B-NP
+weakness	POS	I-NP
+and	POS	O
+presumed	POS	O
+health	POS	O
+-	POS	O
+care	POS	O
+-	POS	O
+associated	POS	O
+pneumonia	POS	B-NP
+shown	POS	O
+on	POS	O
+chest	POS	O
+radiograph	POS	O
+.	POS	O
+Treatment	POS	O
+was	POS	O
+empirically	POS	O
+initiated	POS	O
+with	POS	O
+vancomycin	POS	O
+,	POS	O
+levofloxacin	POS	O
+,	POS	O
+and	POS	O
+piperacillin	POS	O
+/	POS	O
+tazobactam	POS	O
+.	POS	O
+Blood	POS	O
+cultures	POS	O
+revealed	POS	O
+S	POS	O
+.	POS	O
+aureus	POS	O
+susceptible	POS	O
+to	POS	O
+oxacillin	POS	O
+.	POS	O
+Empiric	POS	O
+antibiotic	POS	O
+treatment	POS	O
+was	POS	O
+narrowed	POS	O
+to	POS	O
+nafcillin	POS	O
+on	POS	O
+day	POS	O
+4	POS	O
+.	POS	O
+On	POS	O
+day	POS	O
+8	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+developed	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+(	POS	O
+serum	POS	O
+creatinine	POS	O
+1	POS	O
+.	POS	O
+9	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+,	POS	O
+increased	POS	O
+from	POS	O
+1	POS	O
+.	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+the	POS	O
+previous	POS	O
+day	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+8	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+on	POS	O
+admission	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+Glasgow	POS	O
+Coma	POS	B-NP
+Score	POS	O
+was	POS	O
+3	POS	O
+,	POS	O
+with	POS	O
+normal	POS	O
+findings	POS	O
+shown	POS	O
+on	POS	O
+computed	POS	O
+tomography	POS	O
+scan	POS	O
+of	POS	O
+the	POS	O
+head	POS	O
+72	POS	O
+hours	POS	O
+following	POS	O
+an	POS	O
+episode	POS	O
+of	POS	O
+cardiac	POS	B-NP
+arrest	POS	I-NP
+on	POS	O
+day	POS	O
+10	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+experienced	POS	O
+relapsing	POS	O
+MSSA	POS	B-NP
+bacteremia	POS	B-NP
+on	POS	O
+day	POS	O
+9	POS	O
+,	POS	O
+increasing	POS	O
+the	POS	O
+suspicion	POS	O
+for	POS	O
+a	POS	O
+central	POS	B-NP
+nervous	POS	I-NP
+system	POS	I-NP
+(	POS	I-NP
+CNS	POS	I-NP
+)	POS	I-NP
+infection	POS	I-NP
+.	POS	O
+Nafcillin	POS	O
+was	POS	O
+discontinued	POS	O
+and	POS	O
+daptomycin	POS	O
+9	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+daily	POS	O
+was	POS	O
+initiated	POS	O
+for	POS	O
+suspected	POS	O
+meningitis	POS	B-NP
+and	POS	O
+was	POS	O
+continued	POS	O
+until	POS	O
+the	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+death	POS	O
+on	POS	O
+day	POS	O
+16	POS	O
+.	POS	O
+Daptomycin	POS	O
+serum	POS	O
+and	POS	O
+CSF	POS	O
+trough	POS	O
+concentrations	POS	O
+were	POS	O
+11	POS	O
+.	POS	O
+21	POS	O
+ug	POS	O
+/	POS	O
+mL	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+52	POS	O
+ug	POS	O
+/	POS	O
+mL	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+prior	POS	O
+to	POS	O
+the	POS	O
+third	POS	O
+dose	POS	O
+.	POS	O
+Lumbar	POS	O
+puncture	POS	O
+results	POS	O
+were	POS	O
+inconclusive	POS	O
+and	POS	O
+no	POS	O
+further	POS	O
+blood	POS	O
+cultures	POS	O
+were	POS	O
+positive	POS	O
+for	POS	O
+MSSA	POS	O
+.	POS	O
+Creatine	POS	O
+kinase	POS	O
+levels	POS	O
+were	POS	O
+normal	POS	O
+prior	POS	O
+to	POS	O
+daptomycin	POS	O
+therapy	POS	O
+and	POS	O
+were	POS	O
+not	POS	O
+reassessed	POS	O
+.	POS	O
+DISCUSSION	POS	O
+:	POS	O
+Daptomycin	POS	O
+was	POS	O
+initiated	POS	O
+in	POS	O
+our	POS	O
+patient	POS	O
+secondary	POS	O
+to	POS	O
+possible	POS	O
+nafcillin	POS	O
+-	POS	O
+induced	POS	O
+acute	POS	O
+interstitial	POS	B-NP
+nephritis	POS	I-NP
+and	POS	O
+relapsing	POS	B-NP
+bacteremia	POS	I-NP
+.	POS	O
+At	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+9	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+resultant	POS	O
+penetration	POS	O
+of	POS	O
+5	POS	O
+%	POS	O
+was	POS	O
+higher	POS	O
+than	POS	O
+in	POS	O
+previous	POS	O
+reports	POS	O
+,	POS	O
+more	POS	O
+consistent	POS	O
+with	POS	O
+inflamed	POS	O
+meninges	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+High	POS	O
+-	POS	O
+dose	POS	O
+daptomycin	POS	O
+may	POS	O
+be	POS	O
+an	POS	O
+alternative	POS	O
+option	POS	O
+for	POS	O
+MSSA	POS	O
+bacteremia	POS	B-NP
+with	POS	O
+or	POS	O
+without	POS	O
+a	POS	O
+CNS	POS	O
+source	POS	O
+in	POS	O
+patients	POS	O
+who	POS	O
+have	POS	O
+failed	POS	O
+or	POS	O
+cannot	POS	O
+tolerate	POS	O
+standard	POS	O
+therapy	POS	O
+.	POS	O
+Further	POS	O
+clinical	POS	O
+evaluation	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+confirmed	POS	O
+meningitis	POS	B-NP
+is	POS	O
+warranted	POS	O
+.	POS	O
+The	POS	O
+role	POS	O
+of	POS	O
+nitric	POS	O
+oxide	POS	O
+in	POS	O
+convulsions	POS	B-NP
+induced	POS	O
+by	POS	O
+lindane	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+Lindane	POS	O
+is	POS	O
+an	POS	O
+organochloride	POS	O
+pesticide	POS	O
+and	POS	O
+scabicide	POS	O
+.	POS	O
+It	POS	O
+evokes	POS	O
+convulsions	POS	B-NP
+mainly	POS	O
+trough	POS	O
+the	POS	O
+blockage	POS	O
+of	POS	O
+GABA	POS	O
+(	POS	O
+A	POS	O
+)	POS	O
+receptors	POS	O
+.	POS	O
+Nitric	POS	O
+oxide	POS	O
+(	POS	O
+NO	POS	O
+)	POS	O
+,	POS	O
+gaseous	POS	O
+neurotransmitter	POS	O
+,	POS	O
+has	POS	O
+contradictor	POS	O
+role	POS	O
+in	POS	O
+epileptogenesis	POS	B-NP
+due	POS	O
+to	POS	O
+opposite	POS	O
+effects	POS	O
+of	POS	O
+L	POS	O
+-	POS	O
+arginine	POS	O
+,	POS	O
+precursor	POS	O
+of	POS	O
+NO	POS	O
+syntheses	POS	O
+(	POS	O
+NOS	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+L	POS	O
+-	POS	O
+NAME	POS	O
+(	POS	O
+NOS	POS	O
+inhibitor	POS	O
+)	POS	O
+observed	POS	O
+in	POS	O
+different	POS	O
+epilepsy	POS	B-NP
+models	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+the	POS	O
+current	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+NO	POS	O
+on	POS	O
+the	POS	O
+behavioral	POS	O
+and	POS	O
+EEG	POS	O
+characteristics	POS	O
+of	POS	O
+lindane	POS	O
+-	POS	O
+induced	POS	O
+epilepsy	POS	B-NP
+in	POS	O
+male	POS	O
+Wistar	POS	O
+albino	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+administration	POS	O
+of	POS	O
+L	POS	O
+-	POS	O
+arginine	POS	O
+(	POS	O
+600	POS	O
+,	POS	O
+800	POS	O
+and	POS	O
+1000	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+in	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+manner	POS	O
+significantly	POS	O
+increased	POS	O
+convulsion	POS	B-NP
+incidence	POS	O
+and	POS	O
+severity	POS	O
+and	POS	O
+shortened	POS	O
+latency	POS	O
+time	POS	O
+to	POS	O
+first	POS	O
+convulsion	POS	B-NP
+elicited	POS	O
+by	POS	O
+lower	POS	O
+lindane	POS	O
+dose	POS	O
+(	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+contrary	POS	O
+,	POS	O
+pretreatment	POS	O
+with	POS	O
+L	POS	O
+-	POS	O
+NAME	POS	O
+(	POS	O
+500	POS	O
+,	POS	O
+700	POS	O
+and	POS	O
+900	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+decreased	POS	O
+convulsion	POS	B-NP
+incidence	POS	O
+and	POS	O
+severity	POS	O
+and	POS	O
+prolonged	POS	O
+latency	POS	O
+time	POS	O
+to	POS	O
+convulsion	POS	B-NP
+following	POS	O
+injection	POS	O
+with	POS	O
+a	POS	O
+convulsive	POS	B-NP
+dose	POS	O
+of	POS	O
+lindane	POS	O
+(	POS	O
+8	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+.	POS	O
+EEG	POS	O
+analyses	POS	O
+showed	POS	O
+increase	POS	O
+of	POS	O
+number	POS	O
+and	POS	O
+duration	POS	O
+of	POS	O
+ictal	POS	O
+periods	POS	O
+in	POS	O
+EEG	POS	O
+of	POS	O
+rats	POS	O
+receiving	POS	O
+l	POS	O
+-	POS	O
+arginine	POS	O
+prior	POS	O
+to	POS	O
+lindane	POS	O
+and	POS	O
+decrease	POS	O
+of	POS	O
+this	POS	O
+number	POS	O
+in	POS	O
+rats	POS	O
+pretreated	POS	O
+with	POS	O
+L	POS	O
+-	POS	O
+NAME	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+support	POS	O
+the	POS	O
+conclusion	POS	O
+that	POS	O
+NO	POS	O
+plays	POS	O
+a	POS	O
+role	POS	O
+of	POS	O
+endogenous	POS	O
+convulsant	POS	O
+in	POS	O
+rat	POS	O
+model	POS	O
+of	POS	O
+lindane	POS	O
+seizures	POS	B-NP
+.	POS	O
+Severe	POS	B-NP
+polyneuropathy	POS	I-NP
+and	POS	O
+motor	POS	B-NP
+loss	POS	I-NP
+after	POS	O
+intrathecal	POS	O
+thiotepa	POS	O
+combination	POS	O
+chemotherapy	POS	O
+:	POS	O
+description	POS	O
+of	POS	O
+two	POS	O
+cases	POS	O
+.	POS	O
+Two	POS	O
+cases	POS	O
+of	POS	O
+severe	POS	O
+delayed	POS	O
+neurologic	POS	B-NP
+toxicity	POS	I-NP
+related	POS	O
+to	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+intrathecal	POS	O
+(	POS	O
+IT	POS	O
+)	POS	O
+combination	POS	O
+chemotherapy	POS	O
+including	POS	O
+thiotepa	POS	O
+(	POS	O
+TSPA	POS	O
+)	POS	O
+are	POS	O
+presented	POS	O
+.	POS	O
+Both	POS	O
+cases	POS	O
+developed	POS	O
+axonal	POS	B-NP
+neuropathy	POS	I-NP
+with	POS	O
+motor	POS	O
+predominance	POS	O
+in	POS	O
+the	POS	O
+lower	POS	O
+extremities	POS	O
+1	POS	O
+and	POS	O
+6	POS	O
+months	POS	O
+after	POS	O
+IT	POS	O
+chemotherapy	POS	O
+was	POS	O
+administered	POS	O
+.	POS	O
+Neurologic	POS	B-NP
+toxicities	POS	I-NP
+have	POS	O
+been	POS	O
+described	POS	O
+with	POS	O
+IT	POS	O
+-	POS	O
+methotrexate	POS	O
+,	POS	O
+IT	POS	O
+-	POS	O
+cytosine	POS	O
+arabinoside	POS	O
+and	POS	O
+IT	POS	O
+-	POS	O
+TSPA	POS	O
+.	POS	O
+To	POS	O
+our	POS	O
+knowledge	POS	O
+,	POS	O
+however	POS	O
+,	POS	O
+axonal	POS	B-NP
+neuropathy	POS	I-NP
+following	POS	O
+administration	POS	O
+of	POS	O
+these	POS	O
+three	POS	O
+agents	POS	O
+has	POS	O
+not	POS	O
+been	POS	O
+previously	POS	O
+described	POS	O
+.	POS	O
+In	POS	O
+spite	POS	O
+of	POS	O
+the	POS	O
+fact	POS	O
+that	POS	O
+TSPA	POS	O
+is	POS	O
+a	POS	O
+useful	POS	O
+IT	POS	O
+agent	POS	O
+,	POS	O
+its	POS	O
+combination	POS	O
+with	POS	O
+MTX	POS	O
+,	POS	O
+ara	POS	O
+-	POS	O
+C	POS	O
+and	POS	O
+radiotherapy	POS	O
+could	POS	O
+cause	POS	O
+severe	POS	O
+neurotoxicity	POS	B-NP
+.	POS	O
+This	POS	O
+unexpected	POS	O
+complication	POS	O
+indicates	POS	O
+the	POS	O
+need	POS	O
+for	POS	O
+further	POS	O
+toxicology	POS	O
+research	POS	O
+on	POS	O
+IT	POS	O
+-	POS	O
+TSPA	POS	O
+.	POS	O
+Effects	POS	O
+of	POS	O
+cromakalim	POS	O
+and	POS	O
+pinacidil	POS	O
+on	POS	O
+large	POS	O
+epicardial	POS	O
+and	POS	O
+small	POS	O
+coronary	POS	O
+arteries	POS	O
+in	POS	O
+conscious	POS	O
+dogs	POS	O
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+bolus	POS	O
+administration	POS	O
+of	POS	O
+cromakalim	POS	O
+(	POS	O
+1	POS	O
+-	POS	O
+10	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+and	POS	O
+pinacidil	POS	O
+(	POS	O
+3	POS	O
+-	POS	O
+100	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+on	POS	O
+large	POS	O
+(	POS	O
+circumflex	POS	O
+artery	POS	O
+)	POS	O
+and	POS	O
+small	POS	O
+coronary	POS	O
+arteries	POS	O
+and	POS	O
+on	POS	O
+systemic	POS	O
+hemodynamics	POS	O
+were	POS	O
+investigated	POS	O
+in	POS	O
+chronically	POS	O
+instrumented	POS	O
+conscious	POS	O
+dogs	POS	O
+and	POS	O
+compared	POS	O
+to	POS	O
+those	POS	O
+of	POS	O
+nitroglycerin	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+03	POS	O
+-	POS	O
+10	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+.	POS	O
+Nitroglycerin	POS	O
+,	POS	O
+up	POS	O
+to	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+selectively	POS	O
+increased	POS	O
+circumflex	POS	O
+artery	POS	O
+diameter	POS	O
+(	POS	O
+CxAD	POS	O
+)	POS	O
+without	POS	O
+simultaneously	POS	O
+affecting	POS	O
+any	POS	O
+other	POS	O
+cardiac	POS	O
+or	POS	O
+systemic	POS	O
+hemodynamic	POS	O
+parameter	POS	O
+.	POS	O
+In	POS	O
+contrast	POS	O
+,	POS	O
+cromakalim	POS	O
+and	POS	O
+pinacidil	POS	O
+at	POS	O
+all	POS	O
+doses	POS	O
+and	POS	O
+nitroglycerin	POS	O
+at	POS	O
+doses	POS	O
+higher	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+simultaneously	POS	O
+and	POS	O
+dose	POS	O
+-	POS	O
+dependently	POS	O
+increased	POS	O
+CxAD	POS	O
+,	POS	O
+coronary	POS	O
+blood	POS	O
+flow	POS	O
+and	POS	O
+heart	POS	O
+rate	POS	O
+and	POS	O
+decreased	POS	O
+coronary	POS	O
+vascular	POS	O
+resistance	POS	O
+and	POS	O
+aortic	POS	O
+pressure	POS	O
+.	POS	O
+Cromakalim	POS	O
+was	POS	O
+approximately	POS	O
+8	POS	O
+-	POS	O
+to	POS	O
+9	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+fold	POS	O
+more	POS	O
+potent	POS	O
+than	POS	O
+pinacidil	POS	O
+in	POS	O
+increasing	POS	O
+CxAD	POS	O
+.	POS	O
+Vasodilation	POS	O
+of	POS	O
+large	POS	O
+and	POS	O
+small	POS	O
+coronary	POS	O
+vessels	POS	O
+and	POS	O
+hypotension	POS	B-NP
+induced	POS	O
+by	POS	O
+cromakalim	POS	O
+and	POS	O
+pinacidil	POS	O
+were	POS	O
+not	POS	O
+affected	POS	O
+by	POS	O
+prior	POS	O
+combined	POS	O
+beta	POS	O
+adrenergic	POS	O
+and	POS	O
+muscarinic	POS	O
+receptors	POS	O
+blockade	POS	O
+but	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+tachycardia	POS	B-NP
+was	POS	O
+abolished	POS	O
+.	POS	O
+When	POS	O
+circumflex	POS	O
+artery	POS	O
+blood	POS	O
+flow	POS	O
+was	POS	O
+maintained	POS	O
+constant	POS	O
+,	POS	O
+the	POS	O
+increases	POS	O
+in	POS	O
+CxAD	POS	O
+induced	POS	O
+by	POS	O
+cromakalim	POS	O
+(	POS	O
+10	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+,	POS	O
+pinacidil	POS	O
+(	POS	O
+30	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+and	POS	O
+nitroglycerin	POS	O
+(	POS	O
+10	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+were	POS	O
+reduced	POS	O
+by	POS	O
+68	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+7	POS	O
+,	POS	O
+54	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+9	POS	O
+and	POS	O
+1	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+%	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+whereas	POS	O
+nitroglycerin	POS	O
+preferentially	POS	O
+and	POS	O
+flow	POS	O
+-	POS	O
+independently	POS	O
+dilates	POS	O
+large	POS	O
+coronary	POS	O
+arteries	POS	O
+,	POS	O
+cromakalim	POS	O
+and	POS	O
+pinacidil	POS	O
+dilate	POS	O
+both	POS	O
+large	POS	O
+and	POS	O
+small	POS	O
+coronary	POS	O
+arteries	POS	O
+and	POS	O
+this	POS	O
+effect	POS	O
+is	POS	O
+not	POS	O
+dependent	POS	O
+upon	POS	O
+the	POS	O
+simultaneous	POS	O
+beta	POS	O
+adrenoceptors	POS	O
+-	POS	O
+mediated	POS	O
+rise	POS	O
+in	POS	O
+myocardial	POS	O
+metabolic	POS	O
+demand	POS	O
+.	POS	O
+Finally	POS	O
+,	POS	O
+two	POS	O
+mechanisms	POS	O
+at	POS	O
+least	POS	O
+,	POS	O
+direct	POS	O
+vasodilation	POS	O
+and	POS	O
+flow	POS	O
+dependency	POS	O
+,	POS	O
+are	POS	O
+involved	POS	O
+in	POS	O
+the	POS	O
+cromakalim	POS	O
+-	POS	O
+and	POS	O
+pinacidil	POS	O
+-	POS	O
+induced	POS	O
+increase	POS	O
+in	POS	O
+CxAD	POS	O
+.	POS	O
+Mefenamic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+neutropenia	POS	B-NP
+and	POS	O
+renal	POS	B-NP
+failure	POS	I-NP
+in	POS	O
+elderly	POS	O
+females	POS	O
+with	POS	O
+hypothyroidism	POS	B-NP
+.	POS	O
+We	POS	O
+report	POS	O
+mefenamic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+non	POS	B-NP
+-	POS	I-NP
+oliguric	POS	I-NP
+renal	POS	I-NP
+failure	POS	I-NP
+and	POS	O
+severe	POS	O
+neutropenia	POS	B-NP
+occurring	POS	O
+simultaneously	POS	O
+in	POS	O
+two	POS	O
+elderly	POS	O
+females	POS	O
+.	POS	O
+The	POS	O
+neutropenia	POS	B-NP
+was	POS	O
+due	POS	O
+to	POS	O
+maturation	POS	O
+arrest	POS	O
+of	POS	O
+the	POS	O
+myeloid	POS	O
+series	POS	O
+in	POS	O
+one	POS	O
+patient	POS	O
+.	POS	O
+Both	POS	O
+patients	POS	O
+were	POS	O
+also	POS	O
+hypothyroid	POS	B-NP
+,	POS	O
+but	POS	O
+it	POS	O
+is	POS	O
+not	POS	O
+clear	POS	O
+whether	POS	O
+this	POS	O
+was	POS	O
+a	POS	O
+predisposing	POS	O
+factor	POS	O
+to	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+these	POS	O
+adverse	POS	O
+reactions	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+it	POS	O
+would	POS	O
+seem	POS	O
+prudent	POS	O
+not	POS	O
+to	POS	O
+use	POS	O
+mefenamic	POS	O
+acid	POS	O
+in	POS	O
+hypothyroid	POS	B-NP
+patients	POS	O
+until	POS	O
+the	POS	O
+hypothyroidism	POS	B-NP
+has	POS	O
+been	POS	O
+corrected	POS	O
+.	POS	O
+Etiology	POS	O
+of	POS	O
+hypercalcemia	POS	B-NP
+in	POS	O
+hemodialysis	POS	B-NP
+patients	POS	O
+on	POS	O
+calcium	POS	O
+carbonate	POS	O
+therapy	POS	O
+.	POS	O
+Fourteen	POS	O
+of	POS	O
+39	POS	O
+dialysis	POS	O
+patients	POS	O
+(	POS	O
+36	POS	O
+%	POS	O
+)	POS	O
+became	POS	O
+hypercalcemic	POS	B-NP
+after	POS	O
+switching	POS	O
+to	POS	O
+calcium	POS	O
+carbonate	POS	O
+as	POS	O
+their	POS	O
+principal	POS	O
+phosphate	POS	O
+binder	POS	O
+.	POS	O
+In	POS	O
+order	POS	O
+to	POS	O
+identify	POS	O
+risk	POS	O
+factors	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+hypercalcemia	POS	B-NP
+,	POS	O
+indirect	POS	O
+parameters	POS	O
+of	POS	O
+intestinal	POS	O
+calcium	POS	O
+reabsorption	POS	O
+and	POS	O
+bone	POS	O
+turnover	POS	O
+rate	POS	O
+in	POS	O
+these	POS	O
+14	POS	O
+patients	POS	O
+were	POS	O
+compared	POS	O
+with	POS	O
+results	POS	O
+in	POS	O
+14	POS	O
+eucalcemic	POS	O
+patients	POS	O
+matched	POS	O
+for	POS	O
+age	POS	O
+,	POS	O
+sex	POS	O
+,	POS	O
+length	POS	O
+of	POS	O
+time	POS	O
+on	POS	O
+dialysis	POS	O
+,	POS	O
+and	POS	O
+etiology	POS	O
+of	POS	O
+renal	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+In	POS	O
+addition	POS	O
+to	POS	O
+experiencing	POS	O
+hypercalcemic	POS	B-NP
+episodes	POS	O
+with	POS	O
+peak	POS	O
+calcium	POS	O
+values	POS	O
+of	POS	O
+2	POS	O
+.	POS	O
+7	POS	O
+to	POS	O
+3	POS	O
+.	POS	O
+8	POS	O
+mmol	POS	O
+/	POS	O
+L	POS	O
+(	POS	O
+10	POS	O
+.	POS	O
+7	POS	O
+to	POS	O
+15	POS	O
+.	POS	O
+0	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+)	POS	O
+,	POS	O
+patients	POS	O
+in	POS	O
+the	POS	O
+hypercalcemic	POS	B-NP
+group	POS	O
+exhibited	POS	O
+a	POS	O
+significant	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+mean	POS	O
+calcium	POS	O
+concentration	POS	O
+obtained	POS	O
+during	POS	O
+6	POS	O
+months	POS	O
+before	POS	O
+the	POS	O
+switch	POS	O
+,	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+mean	POS	O
+value	POS	O
+obtained	POS	O
+during	POS	O
+the	POS	O
+7	POS	O
+months	POS	O
+of	POS	O
+observation	POS	O
+after	POS	O
+the	POS	O
+switch	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+4	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+03	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+03	POS	O
+mmol	POS	O
+/	POS	O
+L	POS	O
+[	POS	O
+9	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+2	POS	O
+to	POS	O
+10	POS	O
+.	POS	O
+2	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+]	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+006	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+contrast	POS	O
+,	POS	O
+eucalcemic	POS	O
+patients	POS	O
+exhibited	POS	O
+no	POS	O
+change	POS	O
+in	POS	O
+mean	POS	O
+calcium	POS	O
+values	POS	O
+over	POS	O
+the	POS	O
+same	POS	O
+time	POS	O
+period	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+mmol	POS	O
+/	POS	O
+L	POS	O
+[	POS	O
+9	POS	O
+.	POS	O
+2	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+2	POS	O
+to	POS	O
+9	POS	O
+.	POS	O
+2	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+]	POS	O
+)	POS	O
+.	POS	O
+CaCO3	POS	O
+dosage	POS	O
+,	POS	O
+calculated	POS	O
+dietary	POS	O
+calcium	POS	O
+intake	POS	O
+,	POS	O
+and	POS	O
+circulating	POS	O
+levels	POS	O
+of	POS	O
+vitamin	POS	O
+D	POS	O
+metabolites	POS	O
+were	POS	O
+similar	POS	O
+in	POS	O
+both	POS	O
+groups	POS	O
+.	POS	O
+Physical	POS	O
+activity	POS	O
+index	POS	O
+and	POS	O
+predialysis	POS	O
+serum	POS	O
+bicarbonate	POS	O
+levels	POS	O
+also	POS	O
+were	POS	O
+similar	POS	O
+in	POS	O
+both	POS	O
+groups	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+difference	POS	O
+in	POS	O
+parameters	POS	O
+reflecting	POS	O
+bone	POS	O
+turnover	POS	O
+rates	POS	O
+between	POS	O
+groups	POS	O
+.	POS	O
+(	POS	O
+ABSTRACT	POS	O
+TRUNCATED	POS	O
+AT	POS	O
+250	POS	O
+WORDS	POS	O
+)	POS	O
+Late	POS	O
+-	POS	O
+onset	POS	O
+scleroderma	POS	B-NP
+renal	POS	I-NP
+crisis	POS	I-NP
+induced	POS	O
+by	POS	O
+tacrolimus	POS	O
+and	POS	O
+prednisolone	POS	O
+:	POS	O
+a	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+Scleroderma	POS	B-NP
+renal	POS	I-NP
+crisis	POS	I-NP
+(	POS	O
+SRC	POS	B-NP
+)	POS	O
+is	POS	O
+a	POS	O
+rare	POS	O
+complication	POS	O
+of	POS	O
+systemic	POS	B-NP
+sclerosis	POS	I-NP
+(	POS	O
+SSc	POS	B-NP
+)	POS	O
+but	POS	O
+can	POS	O
+be	POS	O
+severe	POS	O
+enough	POS	O
+to	POS	O
+require	POS	O
+temporary	POS	O
+or	POS	O
+permanent	POS	O
+renal	POS	O
+replacement	POS	O
+therapy	POS	O
+.	POS	O
+Moderate	POS	O
+to	POS	O
+high	POS	O
+dose	POS	O
+corticosteroid	POS	O
+use	POS	O
+is	POS	O
+recognized	POS	O
+as	POS	O
+a	POS	O
+major	POS	O
+risk	POS	O
+factor	POS	O
+for	POS	O
+SRC	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+there	POS	O
+have	POS	O
+been	POS	O
+reports	POS	O
+of	POS	O
+thrombotic	POS	B-NP
+microangiopathy	POS	I-NP
+precipitated	POS	O
+by	POS	O
+cyclosporine	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+SSc	POS	B-NP
+.	POS	O
+In	POS	O
+this	POS	O
+article	POS	O
+,	POS	O
+we	POS	O
+report	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+SRC	POS	B-NP
+induced	POS	O
+by	POS	O
+tacrolimus	POS	O
+and	POS	O
+corticosteroids	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+work	POS	O
+is	POS	O
+to	POS	O
+call	POS	O
+attention	POS	O
+to	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+tacrolimus	POS	O
+use	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+SSc	POS	B-NP
+.	POS	O
+Methyldopa	POS	O
+-	POS	O
+induced	POS	O
+hemolytic	POS	B-NP
+anemia	POS	I-NP
+in	POS	O
+a	POS	O
+15	POS	O
+year	POS	O
+old	POS	O
+presenting	POS	O
+as	POS	O
+near	POS	B-NP
+-	POS	I-NP
+syncope	POS	I-NP
+.	POS	O
+Methyldopa	POS	B-NP
+is	POS	O
+an	POS	O
+antihypertensive	POS	O
+medication	POS	O
+which	POS	O
+is	POS	O
+available	POS	O
+generically	POS	O
+and	POS	O
+under	POS	O
+the	POS	O
+trade	POS	O
+name	POS	O
+Aldomet	POS	O
+that	POS	O
+is	POS	O
+widely	POS	O
+prescribed	POS	O
+in	POS	O
+the	POS	O
+adult	POS	O
+population	POS	O
+and	POS	O
+infrequently	POS	O
+used	POS	O
+in	POS	O
+children	POS	O
+.	POS	O
+Methyldopa	POS	B-NP
+causes	POS	O
+an	POS	O
+autoimmune	POS	B-NP
+hemolytic	POS	I-NP
+anemia	POS	I-NP
+in	POS	O
+a	POS	O
+small	POS	O
+percentage	POS	O
+of	POS	O
+patients	POS	O
+who	POS	O
+take	POS	O
+the	POS	O
+drug	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+methyldopa	POS	O
+-	POS	O
+induced	POS	O
+hemolytic	POS	B-NP
+anemia	POS	I-NP
+in	POS	O
+a	POS	O
+15	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+boy	POS	O
+who	POS	O
+presented	POS	O
+to	POS	O
+the	POS	O
+emergency	POS	O
+department	POS	O
+with	POS	O
+near	POS	O
+-	POS	O
+syncope	POS	B-NP
+.	POS	O
+The	POS	O
+boy	POS	O
+had	POS	O
+been	POS	O
+treated	POS	O
+with	POS	O
+intravenous	POS	O
+methyldopa	POS	O
+during	POS	O
+a	POS	O
+trauma	POS	B-NP
+admission	POS	O
+seven	POS	O
+weeks	POS	O
+prior	POS	O
+to	POS	O
+presentation	POS	O
+.	POS	O
+Evaluation	POS	O
+revealed	POS	O
+a	POS	O
+hemoglobin	POS	O
+of	POS	O
+three	POS	O
+grams	POS	O
+,	POS	O
+3	POS	O
++	POS	O
+Coombs	POS	O
+'	POS	O
+test	POS	O
+with	POS	O
+polyspecific	POS	O
+anti	POS	O
+-	POS	O
+human	POS	O
+globulin	POS	O
+and	POS	O
+monospecific	POS	O
+IgG	POS	O
+reagents	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+warm	POS	O
+reacting	POS	O
+autoantibody	POS	O
+.	POS	O
+Transfusion	POS	O
+and	POS	O
+corticosteroid	POS	O
+therapy	POS	O
+resulted	POS	O
+in	POS	O
+a	POS	O
+complete	POS	O
+recovery	POS	O
+of	POS	O
+the	POS	O
+patient	POS	O
+.	POS	O
+Emergency	POS	O
+physicians	POS	O
+treating	POS	O
+children	POS	O
+must	POS	O
+be	POS	O
+aware	POS	O
+of	POS	O
+this	POS	O
+syndrome	POS	O
+in	POS	O
+order	POS	O
+to	POS	O
+diagnose	POS	O
+and	POS	O
+treat	POS	O
+it	POS	O
+correctly	POS	O
+.	POS	O
+A	POS	O
+brief	POS	O
+review	POS	O
+of	POS	O
+autoimmune	POS	O
+and	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+hemolytic	POS	B-NP
+anemias	POS	I-NP
+is	POS	O
+provided	POS	O
+.	POS	O
+The	POS	O
+risk	POS	O
+and	POS	O
+associated	POS	O
+factors	POS	O
+of	POS	O
+methamphetamine	POS	O
+psychosis	POS	B-NP
+in	POS	O
+methamphetamine	POS	O
+-	POS	O
+dependent	POS	O
+patients	POS	O
+in	POS	O
+Malaysia	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+The	POS	O
+objective	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+lifetime	POS	O
+and	POS	O
+current	POS	O
+methamphetamine	POS	O
+-	POS	O
+induced	POS	O
+psychosis	POS	B-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+methamphetamine	POS	O
+dependence	POS	O
+.	POS	O
+The	POS	O
+association	POS	O
+between	POS	O
+psychiatric	POS	O
+co	POS	O
+-	POS	O
+morbidity	POS	O
+and	POS	O
+methamphetamine	POS	O
+-	POS	O
+induced	POS	O
+psychosis	POS	B-NP
+was	POS	O
+also	POS	O
+studied	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+This	POS	O
+was	POS	O
+a	POS	O
+cross	POS	O
+-	POS	O
+sectional	POS	O
+study	POS	O
+conducted	POS	O
+concurrently	POS	O
+at	POS	O
+a	POS	O
+teaching	POS	O
+hospital	POS	O
+and	POS	O
+a	POS	O
+drug	POS	O
+rehabilitation	POS	O
+center	POS	O
+in	POS	O
+Malaysia	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+the	POS	O
+diagnosis	POS	O
+of	POS	O
+methamphetamine	POS	O
+based	POS	O
+on	POS	O
+DSM	POS	O
+-	POS	O
+IV	POS	O
+were	POS	O
+interviewed	POS	O
+using	POS	O
+the	POS	O
+Mini	POS	O
+International	POS	O
+Neuropsychiatric	POS	O
+Interview	POS	O
+(	POS	O
+M	POS	O
+.	POS	O
+I	POS	O
+.	POS	O
+N	POS	O
+.	POS	O
+I	POS	O
+.	POS	O
+)	POS	O
+for	POS	O
+methamphetamine	POS	O
+-	POS	O
+induced	POS	O
+psychosis	POS	B-NP
+and	POS	O
+other	POS	O
+Axis	POS	B-NP
+I	POS	I-NP
+psychiatric	POS	I-NP
+disorders	POS	I-NP
+.	POS	O
+The	POS	O
+information	POS	O
+on	POS	O
+sociodemographic	POS	O
+background	POS	O
+and	POS	O
+drug	POS	O
+use	POS	O
+history	POS	O
+was	POS	O
+obtained	POS	O
+from	POS	O
+interview	POS	O
+or	POS	O
+medical	POS	O
+records	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Of	POS	O
+292	POS	O
+subjects	POS	O
+,	POS	O
+47	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+subjects	POS	O
+had	POS	O
+a	POS	O
+past	POS	O
+history	POS	O
+of	POS	O
+psychotic	POS	B-NP
+symptoms	POS	I-NP
+and	POS	O
+13	POS	O
+.	POS	O
+0	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+were	POS	O
+having	POS	O
+current	POS	O
+psychotic	POS	B-NP
+symptoms	POS	I-NP
+.	POS	O
+Co	POS	O
+-	POS	O
+morbid	POS	O
+major	POS	O
+depressive	POS	B-NP
+disorder	POS	I-NP
+(	POS	O
+OR	POS	O
+=	POS	O
+7	POS	O
+.	POS	O
+18	POS	O
+,	POS	O
+95	POS	O
+CI	POS	O
+=	POS	O
+2	POS	O
+.	POS	O
+612	POS	O
+-	POS	O
+19	POS	O
+.	POS	O
+708	POS	O
+)	POS	O
+,	POS	O
+bipolar	POS	B-NP
+disorder	POS	I-NP
+(	POS	O
+OR	POS	O
+=	POS	O
+13	POS	O
+.	POS	O
+807	POS	O
+,	POS	O
+95	POS	O
+CI	POS	O
+=	POS	O
+5	POS	O
+.	POS	O
+194	POS	O
+-	POS	O
+36	POS	O
+.	POS	O
+706	POS	O
+)	POS	O
+,	POS	O
+antisocial	POS	B-NP
+personality	POS	I-NP
+disorder	POS	I-NP
+(	POS	O
+OR	POS	O
+=	POS	O
+12	POS	O
+.	POS	O
+619	POS	O
+,	POS	O
+95	POS	O
+CI	POS	O
+=	POS	O
+6	POS	O
+.	POS	O
+702	POS	O
+-	POS	O
+23	POS	O
+.	POS	O
+759	POS	O
+)	POS	O
+and	POS	O
+heavy	POS	O
+methamphetamine	POS	O
+uses	POS	O
+were	POS	O
+significantly	POS	O
+associated	POS	O
+with	POS	O
+lifetime	POS	O
+methamphetamine	POS	O
+-	POS	O
+induced	POS	O
+psychosis	POS	B-NP
+after	POS	O
+adjusted	POS	O
+for	POS	O
+other	POS	O
+factors	POS	O
+.	POS	O
+Major	POS	O
+depressive	POS	B-NP
+disorder	POS	I-NP
+(	POS	O
+OR	POS	O
+=	POS	O
+2	POS	O
+.	POS	O
+870	POS	O
+,	POS	O
+CI	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+154	POS	O
+-	POS	O
+7	POS	O
+.	POS	O
+142	POS	O
+)	POS	O
+and	POS	O
+antisocial	POS	B-NP
+personality	POS	I-NP
+disorder	POS	I-NP
+(	POS	O
+OR	POS	O
+=	POS	O
+3	POS	O
+.	POS	O
+299	POS	O
+,	POS	O
+95	POS	O
+CI	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+375	POS	O
+-	POS	O
+7	POS	O
+.	POS	O
+914	POS	O
+)	POS	O
+were	POS	O
+the	POS	O
+only	POS	O
+factors	POS	O
+associated	POS	O
+with	POS	O
+current	POS	O
+psychosis	POS	B-NP
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+There	POS	O
+was	POS	O
+a	POS	O
+high	POS	O
+risk	POS	O
+of	POS	O
+psychosis	POS	B-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+methamphetamine	POS	B-NP
+dependence	POS	I-NP
+.	POS	O
+It	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+co	POS	B-NP
+-	POS	I-NP
+morbid	POS	I-NP
+affective	POS	I-NP
+disorder	POS	I-NP
+,	POS	O
+antisocial	POS	B-NP
+personality	POS	I-NP
+,	POS	O
+and	POS	O
+heavy	POS	O
+methamphetamine	POS	O
+use	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+recommended	POS	O
+that	POS	O
+all	POS	O
+cases	POS	O
+of	POS	O
+methamphetamine	POS	O
+dependence	POS	O
+should	POS	O
+be	POS	O
+screened	POS	O
+for	POS	O
+psychotic	POS	B-NP
+symptoms	POS	I-NP
+.	POS	O
+Cerebellar	POS	O
+sensory	POS	O
+processing	POS	O
+alterations	POS	O
+impact	POS	O
+motor	POS	O
+cortical	POS	O
+plasticity	POS	O
+in	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+:	POS	O
+clues	POS	O
+from	POS	O
+dyskinetic	POS	B-NP
+patients	POS	O
+.	POS	O
+The	POS	O
+plasticity	POS	O
+of	POS	O
+primary	POS	O
+motor	POS	O
+cortex	POS	O
+(	POS	O
+M1	POS	O
+)	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+PD	POS	B-NP
+)	POS	O
+and	POS	O
+levodopa	POS	O
+-	POS	O
+induced	POS	O
+dyskinesias	POS	B-NP
+(	POS	O
+LIDs	POS	B-NP
+)	POS	O
+is	POS	O
+severely	POS	O
+impaired	POS	O
+.	POS	O
+We	POS	O
+recently	POS	O
+reported	POS	O
+in	POS	O
+young	POS	O
+healthy	POS	O
+subjects	POS	O
+that	POS	O
+inhibitory	POS	O
+cerebellar	POS	O
+stimulation	POS	O
+enhanced	POS	O
+the	POS	O
+sensorimotor	POS	O
+plasticity	POS	O
+of	POS	O
+M1	POS	O
+that	POS	O
+was	POS	O
+induced	POS	O
+by	POS	O
+paired	POS	O
+associative	POS	O
+stimulation	POS	O
+(	POS	O
+PAS	POS	O
+)	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+demonstrates	POS	O
+that	POS	O
+the	POS	O
+deficient	POS	O
+sensorimotor	POS	O
+M1	POS	O
+plasticity	POS	O
+in	POS	O
+16	POS	O
+patients	POS	O
+with	POS	O
+LIDs	POS	B-NP
+could	POS	O
+be	POS	O
+reinstated	POS	O
+by	POS	O
+a	POS	O
+single	POS	O
+session	POS	O
+of	POS	O
+real	POS	O
+inhibitory	POS	O
+cerebellar	POS	O
+stimulation	POS	O
+but	POS	O
+not	POS	O
+sham	POS	O
+stimulation	POS	O
+.	POS	O
+This	POS	O
+was	POS	O
+evident	POS	O
+only	POS	O
+when	POS	O
+a	POS	O
+sensory	POS	O
+component	POS	O
+was	POS	O
+involved	POS	O
+in	POS	O
+the	POS	O
+induction	POS	O
+of	POS	O
+plasticity	POS	O
+,	POS	O
+indicating	POS	O
+that	POS	O
+cerebellar	POS	O
+sensory	POS	O
+processing	POS	O
+function	POS	O
+is	POS	O
+involved	POS	O
+in	POS	O
+the	POS	O
+resurgence	POS	O
+of	POS	O
+M1	POS	O
+plasticity	POS	O
+.	POS	O
+The	POS	O
+benefit	POS	O
+of	POS	O
+inhibitory	POS	O
+cerebellar	POS	O
+stimulation	POS	O
+on	POS	O
+LIDs	POS	B-NP
+is	POS	O
+known	POS	O
+.	POS	O
+To	POS	O
+explore	POS	O
+whether	POS	O
+this	POS	O
+benefit	POS	O
+is	POS	O
+linked	POS	O
+to	POS	O
+the	POS	O
+restoration	POS	O
+of	POS	O
+sensorimotor	POS	O
+plasticity	POS	O
+of	POS	O
+M1	POS	O
+,	POS	O
+we	POS	O
+conducted	POS	O
+an	POS	O
+additional	POS	O
+study	POS	O
+looking	POS	O
+at	POS	O
+changes	POS	O
+in	POS	O
+LIDs	POS	B-NP
+and	POS	O
+PAS	POS	O
+-	POS	O
+induced	POS	O
+plasticity	POS	O
+after	POS	O
+10	POS	O
+sessions	POS	O
+of	POS	O
+either	POS	O
+bilateral	POS	O
+,	POS	O
+real	POS	O
+inhibitory	POS	O
+cerebellar	POS	O
+stimulation	POS	O
+or	POS	O
+sham	POS	O
+stimulation	POS	O
+.	POS	O
+Only	POS	O
+real	POS	O
+and	POS	O
+not	POS	O
+sham	POS	O
+stimulation	POS	O
+had	POS	O
+an	POS	O
+antidyskinetic	POS	O
+effect	POS	O
+and	POS	O
+it	POS	O
+was	POS	O
+paralleled	POS	O
+by	POS	O
+a	POS	O
+resurgence	POS	O
+in	POS	O
+the	POS	O
+sensorimotor	POS	O
+plasticity	POS	O
+of	POS	O
+M1	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+alterations	POS	O
+in	POS	O
+cerebellar	POS	O
+sensory	POS	O
+processing	POS	O
+function	POS	O
+,	POS	O
+occurring	POS	O
+secondary	POS	O
+to	POS	O
+abnormal	POS	O
+basal	POS	O
+ganglia	POS	O
+signals	POS	O
+reaching	POS	O
+it	POS	O
+,	POS	O
+may	POS	O
+be	POS	O
+an	POS	O
+important	POS	O
+element	POS	O
+contributing	POS	O
+to	POS	O
+the	POS	O
+maladaptive	POS	O
+sensorimotor	POS	O
+plasticity	POS	O
+of	POS	O
+M1	POS	O
+and	POS	O
+the	POS	O
+emergence	POS	O
+of	POS	O
+abnormal	POS	B-NP
+involuntary	POS	I-NP
+movements	POS	I-NP
+.	POS	O
+The	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+safety	POS	O
+of	POS	O
+danazol	POS	O
+in	POS	O
+women	POS	O
+with	POS	O
+hereditary	POS	B-NP
+angioedema	POS	I-NP
+.	POS	O
+Although	POS	O
+the	POS	O
+short	POS	O
+-	POS	O
+term	POS	O
+safety	POS	O
+(	POS	O
+less	POS	O
+than	POS	O
+or	POS	O
+equal	POS	O
+to	POS	O
+6	POS	O
+months	POS	O
+)	POS	O
+of	POS	O
+danazol	POS	O
+has	POS	O
+been	POS	O
+established	POS	O
+in	POS	O
+a	POS	O
+variety	POS	O
+of	POS	O
+settings	POS	O
+,	POS	O
+no	POS	O
+information	POS	O
+exists	POS	O
+as	POS	O
+to	POS	O
+its	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+safety	POS	O
+.	POS	O
+We	POS	O
+therefore	POS	O
+investigated	POS	O
+the	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+safety	POS	O
+of	POS	O
+danazol	POS	O
+by	POS	O
+performing	POS	O
+a	POS	O
+retrospective	POS	O
+chart	POS	O
+review	POS	O
+of	POS	O
+60	POS	O
+female	POS	O
+patients	POS	O
+with	POS	O
+hereditary	POS	B-NP
+angioedema	POS	I-NP
+treated	POS	O
+with	POS	O
+danazol	POS	O
+for	POS	O
+a	POS	O
+continuous	POS	O
+period	POS	O
+of	POS	O
+6	POS	O
+months	POS	O
+or	POS	O
+longer	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+age	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+was	POS	O
+35	POS	O
+.	POS	O
+2	POS	O
+years	POS	O
+and	POS	O
+the	POS	O
+mean	POS	O
+duration	POS	O
+of	POS	O
+therapy	POS	O
+was	POS	O
+59	POS	O
+.	POS	O
+7	POS	O
+months	POS	O
+.	POS	O
+Virtually	POS	O
+all	POS	O
+patients	POS	O
+experienced	POS	O
+one	POS	O
+or	POS	O
+more	POS	O
+adverse	POS	O
+reactions	POS	O
+.	POS	O
+Menstrual	POS	B-NP
+abnormalities	POS	I-NP
+(	POS	O
+79	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+weight	POS	B-NP
+gain	POS	I-NP
+(	POS	O
+60	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+muscle	POS	B-NP
+cramps	POS	I-NP
+/	POS	O
+myalgias	POS	B-NP
+(	POS	O
+40	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+transaminase	POS	O
+elevations	POS	O
+(	POS	O
+40	POS	O
+%	POS	O
+)	POS	O
+were	POS	O
+the	POS	O
+most	POS	O
+common	POS	O
+adverse	POS	O
+reactions	POS	O
+.	POS	O
+The	POS	O
+drug	POS	O
+was	POS	O
+discontinued	POS	O
+due	POS	O
+to	POS	O
+adverse	POS	O
+reactions	POS	O
+in	POS	O
+8	POS	O
+patients	POS	O
+.	POS	O
+No	POS	O
+patient	POS	O
+has	POS	O
+died	POS	O
+or	POS	O
+suffered	POS	O
+any	POS	O
+apparent	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+sequelae	POS	O
+that	POS	O
+were	POS	O
+directly	POS	O
+attributable	POS	O
+to	POS	O
+the	POS	O
+drug	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+,	POS	O
+despite	POS	O
+a	POS	O
+relatively	POS	O
+high	POS	O
+incidence	POS	O
+of	POS	O
+adverse	POS	O
+reactions	POS	O
+,	POS	O
+danazol	POS	O
+has	POS	O
+proven	POS	O
+to	POS	O
+be	POS	O
+remarkably	POS	O
+safe	POS	O
+over	POS	O
+the	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+in	POS	O
+this	POS	O
+group	POS	O
+of	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+function	POS	O
+of	POS	O
+P2X3	POS	O
+receptor	POS	O
+and	POS	O
+NK1	POS	O
+receptor	POS	O
+antagonists	POS	O
+on	POS	O
+cyclophosphamide	POS	O
+-	POS	O
+induced	POS	O
+cystitis	POS	B-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+the	POS	O
+study	POS	O
+is	POS	O
+to	POS	O
+explore	POS	O
+the	POS	O
+function	POS	O
+of	POS	O
+P2X3	POS	O
+and	POS	O
+NK1	POS	O
+receptors	POS	O
+antagonists	POS	O
+on	POS	O
+cyclophosphamide	POS	O
+(	POS	O
+CYP	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+cystitis	POS	B-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Sixty	POS	O
+female	POS	O
+Sprague	POS	O
+-	POS	O
+Dawley	POS	O
+(	POS	O
+SD	POS	O
+)	POS	O
+rats	POS	O
+were	POS	O
+randomly	POS	O
+divided	POS	O
+into	POS	O
+three	POS	O
+groups	POS	O
+.	POS	O
+The	POS	O
+rats	POS	O
+in	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+were	POS	O
+intraperitoneally	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+injected	POS	O
+with	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+saline	POS	O
+(	POS	O
+4	POS	O
+ml	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+;	POS	O
+the	POS	O
+rats	POS	O
+in	POS	O
+the	POS	O
+model	POS	O
+group	POS	O
+were	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+injected	POS	O
+with	POS	O
+CYP	POS	O
+(	POS	O
+150	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+;	POS	O
+and	POS	O
+the	POS	O
+rats	POS	O
+in	POS	O
+the	POS	O
+intervention	POS	O
+group	POS	O
+were	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+injected	POS	O
+with	POS	O
+CYP	POS	O
+with	POS	O
+subsequently	POS	O
+perfusion	POS	O
+of	POS	O
+bladder	POS	O
+with	POS	O
+P2X3	POS	O
+and	POS	O
+NK1	POS	O
+receptors	POS	O
+'	POS	O
+antagonists	POS	O
+,	POS	O
+Suramin	POS	O
+and	POS	O
+GR	POS	O
+82334	POS	O
+.	POS	O
+Spontaneous	POS	O
+pain	POS	O
+behaviors	POS	O
+following	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+CYP	POS	O
+were	POS	O
+observed	POS	O
+.	POS	O
+Urodynamic	POS	O
+parameters	POS	O
+,	POS	O
+bladder	POS	O
+pressure	POS	O
+-	POS	O
+volume	POS	O
+curve	POS	O
+,	POS	O
+maximum	POS	O
+voiding	POS	O
+pressure	POS	O
+(	POS	O
+MVP	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+maximum	POS	O
+cystometric	POS	O
+capacity	POS	O
+(	POS	O
+MCC	POS	O
+)	POS	O
+,	POS	O
+were	POS	O
+recorded	POS	O
+.	POS	O
+Pathological	POS	O
+changes	POS	O
+in	POS	O
+bladder	POS	O
+tissue	POS	O
+were	POS	O
+observed	POS	O
+.	POS	O
+Immunofluorescence	POS	O
+was	POS	O
+used	POS	O
+to	POS	O
+detect	POS	O
+the	POS	O
+expression	POS	O
+of	POS	O
+P2X3	POS	O
+and	POS	O
+NK1	POS	O
+receptors	POS	O
+in	POS	O
+bladder	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Cyclophosphamide	POS	O
+treatment	POS	O
+increased	POS	O
+the	POS	O
+spontaneous	POS	O
+pain	POS	B-NP
+behaviors	POS	O
+scores	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+bladder	POS	B-NP
+instability	POS	I-NP
+during	POS	O
+urine	POS	O
+storage	POS	O
+period	POS	O
+of	POS	O
+model	POS	O
+group	POS	O
+was	POS	O
+significantly	POS	O
+higher	POS	O
+than	POS	O
+intervention	POS	O
+group	POS	O
+(	POS	O
+X	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+=	POS	O
+7	POS	O
+.	POS	O
+619	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+007	POS	O
+)	POS	O
+and	POS	O
+control	POS	O
+group	POS	O
+(	POS	O
+X	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+=	POS	O
+13	POS	O
+.	POS	O
+755	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+000	POS	O
+)	POS	O
+.	POS	O
+MCC	POS	O
+in	POS	O
+the	POS	O
+model	POS	O
+group	POS	O
+was	POS	O
+lower	POS	O
+than	POS	O
+the	POS	O
+control	POS	O
+and	POS	O
+intervention	POS	O
+groups	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+Histological	POS	O
+changes	POS	O
+evident	POS	O
+in	POS	O
+model	POS	O
+and	POS	O
+intervention	POS	O
+groups	POS	O
+rats	POS	O
+'	POS	O
+bladder	POS	O
+included	POS	O
+edema	POS	B-NP
+,	POS	O
+vasodilation	POS	B-NP
+,	POS	O
+and	POS	O
+infiltration	POS	O
+of	POS	O
+inflammatory	POS	O
+cells	POS	O
+.	POS	O
+In	POS	O
+model	POS	O
+group	POS	O
+,	POS	O
+the	POS	O
+expression	POS	O
+of	POS	O
+P2X3	POS	O
+receptor	POS	O
+increased	POS	O
+in	POS	O
+urothelium	POS	O
+and	POS	O
+suburothelium	POS	O
+,	POS	O
+and	POS	O
+NK1	POS	O
+receptor	POS	O
+increased	POS	O
+in	POS	O
+suburothelium	POS	O
+,	POS	O
+while	POS	O
+the	POS	O
+expression	POS	O
+of	POS	O
+them	POS	O
+in	POS	O
+intervention	POS	O
+group	POS	O
+was	POS	O
+lower	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+In	POS	O
+CYP	POS	O
+-	POS	O
+induced	POS	O
+cystitis	POS	B-NP
+,	POS	O
+the	POS	O
+expression	POS	O
+of	POS	O
+P2X3	POS	O
+and	POS	O
+NK1	POS	O
+receptors	POS	O
+increased	POS	O
+in	POS	O
+urothelium	POS	O
+and	POS	O
+/	POS	O
+or	POS	O
+suburothelium	POS	O
+.	POS	O
+Perfusion	POS	O
+of	POS	O
+bladder	POS	O
+with	POS	O
+P2X3	POS	O
+and	POS	O
+NK1	POS	O
+receptors	POS	O
+antagonists	POS	O
+ameliorated	POS	O
+the	POS	O
+bladder	POS	O
+function	POS	O
+.	POS	O
+Patient	POS	O
+tolerance	POS	O
+study	POS	O
+of	POS	O
+topical	POS	O
+chlorhexidine	POS	O
+diphosphanilate	POS	O
+:	POS	O
+a	POS	O
+new	POS	O
+topical	POS	O
+agent	POS	O
+for	POS	O
+burns	POS	O
+.	POS	O
+Effective	POS	O
+topical	POS	O
+antimicrobial	POS	O
+agents	POS	O
+decrease	POS	O
+infection	POS	O
+and	POS	O
+mortality	POS	O
+in	POS	O
+burn	POS	O
+patients	POS	O
+.	POS	O
+Chlorhexidine	POS	O
+phosphanilate	POS	O
+(	POS	O
+CHP	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+new	POS	O
+broad	POS	O
+-	POS	O
+spectrum	POS	O
+antimicrobial	POS	O
+agent	POS	O
+,	POS	O
+has	POS	O
+been	POS	O
+evaluated	POS	O
+as	POS	O
+a	POS	O
+topical	POS	O
+burn	POS	O
+wound	POS	O
+dressing	POS	O
+in	POS	O
+cream	POS	O
+form	POS	O
+,	POS	O
+but	POS	O
+preliminary	POS	O
+clinical	POS	O
+trials	POS	O
+reported	POS	O
+that	POS	O
+it	POS	O
+was	POS	O
+painful	POS	O
+upon	POS	O
+application	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+compared	POS	O
+various	POS	O
+concentrations	POS	O
+of	POS	O
+CHP	POS	O
+to	POS	O
+determine	POS	O
+if	POS	O
+a	POS	O
+tolerable	POS	O
+concentration	POS	O
+could	POS	O
+be	POS	O
+identified	POS	O
+with	POS	O
+retention	POS	O
+of	POS	O
+antimicrobial	POS	O
+efficacy	POS	O
+.	POS	O
+Twenty	POS	O
+-	POS	O
+nine	POS	O
+burn	POS	B-NP
+patients	POS	O
+,	POS	O
+each	POS	O
+with	POS	O
+two	POS	O
+similar	POS	O
+burns	POS	B-NP
+which	POS	O
+could	POS	O
+be	POS	O
+separately	POS	O
+treated	POS	O
+,	POS	O
+were	POS	O
+given	POS	O
+pairs	POS	O
+of	POS	O
+treatments	POS	O
+at	POS	O
+successive	POS	O
+12	POS	O
+-	POS	O
+h	POS	O
+intervals	POS	O
+over	POS	O
+a	POS	O
+3	POS	O
+-	POS	O
+day	POS	O
+period	POS	O
+.	POS	O
+One	POS	O
+burn	POS	O
+site	POS	O
+was	POS	O
+treated	POS	O
+with	POS	O
+each	POS	O
+of	POS	O
+four	POS	O
+different	POS	O
+CHP	POS	O
+concentrations	POS	O
+,	POS	O
+from	POS	O
+0	POS	O
+.	POS	O
+25	POS	O
+per	POS	O
+cent	POS	O
+to	POS	O
+2	POS	O
+per	POS	O
+cent	POS	O
+,	POS	O
+their	POS	O
+vehicle	POS	O
+,	POS	O
+and	POS	O
+1	POS	O
+per	POS	O
+cent	POS	O
+silver	POS	O
+sulphadiazine	POS	O
+(	POS	O
+AgSD	POS	O
+)	POS	O
+cream	POS	O
+,	POS	O
+an	POS	O
+antimicrobial	POS	O
+agent	POS	O
+frequently	POS	O
+used	POS	O
+for	POS	O
+topical	POS	O
+treatment	POS	O
+of	POS	O
+burn	POS	B-NP
+wounds	POS	I-NP
+.	POS	O
+The	POS	O
+other	POS	O
+site	POS	O
+was	POS	O
+always	POS	O
+treated	POS	O
+with	POS	O
+AgSD	POS	O
+cream	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+a	POS	O
+direct	POS	O
+relationship	POS	O
+between	POS	O
+CHP	POS	O
+concentration	POS	O
+and	POS	O
+patients	POS	O
+'	POS	O
+ratings	POS	O
+of	POS	O
+pain	POS	B-NP
+on	POS	O
+an	POS	O
+analogue	POS	O
+scale	POS	O
+.	POS	O
+The	POS	O
+0	POS	O
+.	POS	O
+25	POS	O
+per	POS	O
+cent	POS	O
+CHP	POS	O
+cream	POS	O
+was	POS	O
+closest	POS	O
+to	POS	O
+AgSD	POS	O
+in	POS	O
+pain	POS	B-NP
+tolerance	POS	I-NP
+;	POS	O
+however	POS	O
+,	POS	O
+none	POS	O
+of	POS	O
+the	POS	O
+treatments	POS	O
+differed	POS	O
+statistically	POS	O
+from	POS	O
+AgSD	POS	B-NP
+or	POS	O
+from	POS	O
+each	POS	O
+other	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+ease	POS	O
+of	POS	O
+application	POS	O
+of	POS	O
+CHP	POS	O
+creams	POS	O
+was	POS	O
+less	POS	O
+satisfactory	POS	O
+than	POS	O
+that	POS	O
+of	POS	O
+AgSD	POS	B-NP
+.	POS	O
+It	POS	O
+was	POS	O
+concluded	POS	O
+that	POS	O
+formulations	POS	O
+at	POS	O
+or	POS	O
+below	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+per	POS	O
+cent	POS	O
+CHP	POS	O
+may	POS	O
+prove	POS	O
+acceptable	POS	O
+for	POS	O
+wound	POS	O
+care	POS	O
+,	POS	O
+but	POS	O
+the	POS	O
+vehicle	POS	O
+system	POS	O
+needs	POS	O
+pharmaceutical	POS	O
+improvement	POS	O
+to	POS	O
+render	POS	O
+it	POS	O
+more	POS	O
+tolerable	POS	O
+and	POS	O
+easier	POS	O
+to	POS	O
+use	POS	O
+.	POS	O
+Acute	POS	O
+hepatitis	POS	B-NP
+associated	POS	O
+with	POS	O
+clopidogrel	POS	O
+:	POS	O
+a	POS	O
+case	POS	O
+report	POS	O
+and	POS	O
+review	POS	O
+of	POS	O
+the	POS	O
+literature	POS	O
+.	POS	O
+Drug	POS	O
+-	POS	O
+induced	POS	O
+hepatotoxicity	POS	B-NP
+is	POS	O
+a	POS	O
+common	POS	O
+cause	POS	O
+of	POS	O
+acute	POS	B-NP
+hepatitis	POS	I-NP
+,	POS	O
+and	POS	O
+the	POS	O
+recognition	POS	O
+of	POS	O
+the	POS	O
+responsible	POS	O
+drug	POS	O
+may	POS	O
+be	POS	O
+difficult	POS	O
+.	POS	O
+We	POS	O
+describe	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+clopidogrel	POS	O
+-	POS	O
+related	POS	O
+acute	POS	O
+hepatitis	POS	B-NP
+.	POS	O
+The	POS	O
+diagnosis	POS	O
+is	POS	O
+strongly	POS	O
+suggested	POS	O
+by	POS	O
+an	POS	O
+accurate	POS	O
+medical	POS	O
+history	POS	O
+and	POS	O
+liver	POS	O
+biopsy	POS	O
+.	POS	O
+Reports	POS	O
+about	POS	O
+cases	POS	O
+of	POS	O
+hepatotoxicity	POS	B-NP
+due	POS	O
+to	POS	O
+clopidogrel	POS	O
+are	POS	O
+increasing	POS	O
+in	POS	O
+the	POS	O
+last	POS	O
+few	POS	O
+years	POS	O
+,	POS	O
+after	POS	O
+the	POS	O
+increased	POS	O
+use	POS	O
+of	POS	O
+this	POS	O
+drug	POS	O
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+we	POS	O
+believe	POS	O
+that	POS	O
+physicians	POS	O
+should	POS	O
+carefully	POS	O
+consider	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+hepatic	POS	B-NP
+injury	POS	I-NP
+when	POS	O
+clopidogrel	POS	O
+is	POS	O
+prescribed	POS	O
+.	POS	O
+Bortezomib	POS	O
+and	POS	O
+dexamethasone	POS	O
+as	POS	O
+salvage	POS	O
+therapy	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+relapsed	POS	B-NP
+/	POS	I-NP
+refractory	POS	I-NP
+multiple	POS	I-NP
+myeloma	POS	I-NP
+:	POS	O
+analysis	POS	O
+of	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+clinical	POS	O
+outcomes	POS	O
+.	POS	O
+Bortezomib	POS	O
+(	POS	O
+bort	POS	O
+)	POS	O
+-	POS	O
+dexamethasone	POS	O
+(	POS	O
+dex	POS	O
+)	POS	O
+is	POS	O
+an	POS	O
+effective	POS	O
+therapy	POS	O
+for	POS	O
+relapsed	POS	B-NP
+/	POS	I-NP
+refractory	POS	I-NP
+(	POS	I-NP
+R	POS	I-NP
+/	POS	I-NP
+R	POS	I-NP
+)	POS	I-NP
+multiple	POS	I-NP
+myeloma	POS	I-NP
+(	POS	O
+MM	POS	B-NP
+)	POS	O
+.	POS	O
+This	POS	O
+retrospective	POS	O
+study	POS	O
+investigated	POS	O
+the	POS	O
+combination	POS	O
+of	POS	O
+bort	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+on	POS	O
+days	POS	O
+1	POS	O
+,	POS	O
+4	POS	O
+,	POS	O
+8	POS	O
+,	POS	O
+and	POS	O
+11	POS	O
+every	POS	O
+3	POS	O
+weeks	POS	O
+)	POS	O
+and	POS	O
+dex	POS	O
+(	POS	O
+20	POS	O
+mg	POS	O
+on	POS	O
+the	POS	O
+day	POS	O
+of	POS	O
+and	POS	O
+the	POS	O
+day	POS	O
+after	POS	O
+bort	POS	O
+)	POS	O
+as	POS	O
+salvage	POS	O
+treatment	POS	O
+in	POS	O
+85	POS	O
+patients	POS	O
+with	POS	O
+R	POS	O
+/	POS	O
+R	POS	O
+MM	POS	O
+after	POS	O
+prior	POS	O
+autologous	POS	O
+stem	POS	O
+cell	POS	O
+transplantation	POS	O
+or	POS	O
+conventional	POS	O
+chemotherapy	POS	O
+.	POS	O
+The	POS	O
+median	POS	O
+number	POS	O
+of	POS	O
+prior	POS	O
+lines	POS	O
+of	POS	O
+therapy	POS	O
+was	POS	O
+2	POS	O
+.	POS	O
+Eighty	POS	O
+-	POS	O
+seven	POS	O
+percent	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+had	POS	O
+received	POS	O
+immunomodulatory	POS	O
+drugs	POS	O
+included	POS	O
+in	POS	O
+some	POS	O
+line	POS	O
+of	POS	O
+therapy	POS	O
+before	POS	O
+bort	POS	O
+-	POS	O
+dex	POS	O
+.	POS	O
+The	POS	O
+median	POS	O
+number	POS	O
+of	POS	O
+bort	POS	O
+-	POS	O
+dex	POS	O
+cycles	POS	O
+was	POS	O
+6	POS	O
+,	POS	O
+up	POS	O
+to	POS	O
+a	POS	O
+maximum	POS	O
+of	POS	O
+12	POS	O
+cycles	POS	O
+.	POS	O
+On	POS	O
+an	POS	O
+intention	POS	O
+-	POS	O
+to	POS	O
+-	POS	O
+treat	POS	O
+basis	POS	O
+,	POS	O
+55	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+achieved	POS	O
+at	POS	O
+least	POS	O
+partial	POS	O
+response	POS	O
+,	POS	O
+including	POS	O
+19	POS	O
+%	POS	O
+CR	POS	O
+and	POS	O
+35	POS	O
+%	POS	O
+achieved	POS	O
+at	POS	O
+least	POS	O
+very	POS	O
+good	POS	O
+partial	POS	O
+response	POS	O
+.	POS	O
+Median	POS	O
+durations	POS	O
+of	POS	O
+response	POS	O
+,	POS	O
+time	POS	O
+to	POS	O
+next	POS	O
+therapy	POS	O
+and	POS	O
+treatment	POS	O
+-	POS	O
+free	POS	O
+interval	POS	O
+were	POS	O
+8	POS	O
+,	POS	O
+11	POS	O
+.	POS	O
+2	POS	O
+,	POS	O
+and	POS	O
+5	POS	O
+.	POS	O
+1	POS	O
+months	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+The	POS	O
+most	POS	O
+relevant	POS	O
+adverse	POS	O
+event	POS	O
+was	POS	O
+peripheral	POS	B-NP
+neuropathy	POS	I-NP
+,	POS	O
+which	POS	O
+occurred	POS	O
+in	POS	O
+78	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+(	POS	O
+grade	POS	O
+II	POS	O
+,	POS	O
+38	POS	O
+%	POS	O
+;	POS	O
+grade	POS	O
+III	POS	O
+,	POS	O
+21	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+led	POS	O
+to	POS	O
+treatment	POS	O
+discontinuation	POS	O
+in	POS	O
+6	POS	O
+%	POS	O
+.	POS	O
+With	POS	O
+a	POS	O
+median	POS	O
+follow	POS	O
+up	POS	O
+of	POS	O
+22	POS	O
+months	POS	O
+,	POS	O
+median	POS	O
+time	POS	O
+to	POS	O
+progression	POS	O
+,	POS	O
+progression	POS	O
+-	POS	O
+free	POS	O
+survival	POS	O
+(	POS	O
+PFS	POS	O
+)	POS	O
+and	POS	O
+overall	POS	O
+survival	POS	O
+(	POS	O
+OS	POS	O
+)	POS	O
+were	POS	O
+8	POS	O
+.	POS	O
+9	POS	O
+,	POS	O
+8	POS	O
+.	POS	O
+7	POS	O
+,	POS	O
+and	POS	O
+22	POS	O
+months	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Prolonged	POS	O
+PFS	POS	O
+and	POS	O
+OS	POS	O
+were	POS	O
+observed	POS	O
+in	POS	O
+patients	POS	O
+achieving	POS	O
+CR	POS	O
+and	POS	O
+receiving	POS	O
+bort	POS	O
+-	POS	O
+dex	POS	O
+a	POS	O
+single	POS	O
+line	POS	O
+of	POS	O
+prior	POS	O
+therapy	POS	O
+.	POS	O
+Bort	POS	O
+-	POS	O
+dex	POS	O
+was	POS	O
+an	POS	O
+effective	POS	O
+salvage	POS	O
+treatment	POS	O
+for	POS	O
+MM	POS	B-NP
+patients	POS	O
+,	POS	O
+particularly	POS	O
+for	POS	O
+those	POS	O
+in	POS	O
+first	POS	O
+relapse	POS	O
+.	POS	O
+Pubertal	POS	O
+exposure	POS	O
+to	POS	O
+Bisphenol	POS	O
+A	POS	O
+increases	POS	O
+anxiety	POS	B-NP
+-	POS	O
+like	POS	O
+behavior	POS	O
+and	POS	O
+decreases	POS	O
+acetylcholinesterase	POS	O
+activity	POS	O
+of	POS	O
+hippocampus	POS	O
+in	POS	O
+adult	POS	O
+male	POS	O
+mice	POS	O
+.	POS	O
+The	POS	O
+negative	POS	O
+effects	POS	O
+of	POS	O
+Bisphenol	POS	O
+A	POS	O
+(	POS	O
+BPA	POS	O
+)	POS	O
+on	POS	O
+neurodevelopment	POS	O
+and	POS	O
+behaviors	POS	O
+have	POS	O
+been	POS	O
+well	POS	O
+established	POS	O
+.	POS	O
+Acetylcholinesterase	POS	O
+(	POS	O
+AChE	POS	O
+)	POS	O
+is	POS	O
+a	POS	O
+regulatory	POS	O
+enzyme	POS	O
+which	POS	O
+is	POS	O
+involved	POS	O
+in	POS	O
+anxiety	POS	B-NP
+-	POS	O
+like	POS	O
+behavior	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+investigated	POS	O
+behavioral	POS	O
+phenotypes	POS	O
+and	POS	O
+AChE	POS	O
+activity	POS	O
+in	POS	O
+male	POS	O
+mice	POS	O
+following	POS	O
+BPA	POS	O
+exposure	POS	O
+during	POS	O
+puberty	POS	B-NP
+.	POS	O
+On	POS	O
+postnatal	POS	O
+day	POS	O
+(	POS	O
+PND	POS	O
+)	POS	O
+35	POS	O
+,	POS	O
+male	POS	O
+mice	POS	O
+were	POS	O
+exposed	POS	O
+to	POS	O
+50mg	POS	O
+BPA	POS	O
+/	POS	O
+kg	POS	O
+diet	POS	O
+per	POS	O
+day	POS	O
+for	POS	O
+a	POS	O
+period	POS	O
+of	POS	O
+35	POS	O
+days	POS	O
+.	POS	O
+On	POS	O
+PND71	POS	O
+,	POS	O
+a	POS	O
+behavioral	POS	O
+assay	POS	O
+was	POS	O
+performed	POS	O
+using	POS	O
+the	POS	O
+elevated	POS	O
+plus	POS	O
+maze	POS	O
+(	POS	O
+EPM	POS	O
+)	POS	O
+and	POS	O
+the	POS	O
+light	POS	O
+/	POS	O
+dark	POS	O
+test	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+AChE	POS	O
+activity	POS	O
+was	POS	O
+measured	POS	O
+in	POS	O
+the	POS	O
+prefrontal	POS	O
+cortex	POS	O
+,	POS	O
+hypothalamus	POS	O
+,	POS	O
+cerebellum	POS	O
+and	POS	O
+hippocampus	POS	O
+.	POS	O
+Results	POS	O
+from	POS	O
+our	POS	O
+behavioral	POS	O
+phenotyping	POS	O
+indicated	POS	O
+that	POS	O
+anxiety	POS	B-NP
+-	POS	O
+like	POS	O
+behavior	POS	O
+was	POS	O
+increased	POS	O
+in	POS	O
+mice	POS	O
+exposed	POS	O
+to	POS	O
+BPA	POS	O
+.	POS	O
+AChE	POS	O
+activity	POS	O
+was	POS	O
+significantly	POS	O
+decreased	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+of	POS	O
+mice	POS	O
+with	POS	O
+BPA	POS	O
+compared	POS	O
+to	POS	O
+control	POS	O
+mice	POS	O
+,	POS	O
+whereas	POS	O
+no	POS	O
+difference	POS	O
+was	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+prefrontal	POS	O
+cortex	POS	O
+,	POS	O
+hypothalamus	POS	O
+and	POS	O
+cerebellum	POS	O
+.	POS	O
+Our	POS	O
+findings	POS	O
+showed	POS	O
+that	POS	O
+pubertal	POS	O
+BPA	POS	O
+exposure	POS	O
+increased	POS	O
+anxiety	POS	B-NP
+-	POS	O
+like	POS	O
+behavior	POS	O
+,	POS	O
+which	POS	O
+may	POS	O
+be	POS	O
+associated	POS	O
+with	POS	O
+decreased	POS	O
+AChE	POS	O
+activity	POS	O
+of	POS	O
+the	POS	O
+hippocampus	POS	O
+in	POS	O
+adult	POS	O
+male	POS	O
+mice	POS	O
+.	POS	O
+Further	POS	O
+studies	POS	O
+are	POS	O
+necessary	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+cholinergic	POS	O
+signaling	POS	O
+of	POS	O
+the	POS	O
+hippocampus	POS	O
+in	POS	O
+PBE	POS	O
+induced	POS	O
+anxiety	POS	B-NP
+-	POS	O
+like	POS	O
+behaviors	POS	O
+.	POS	O
+Biochemical	POS	O
+effects	POS	O
+of	POS	O
+Solidago	POS	O
+virgaurea	POS	O
+extract	POS	O
+on	POS	O
+experimental	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+Cardiovascular	POS	B-NP
+diseases	POS	I-NP
+(	POS	O
+CVDs	POS	B-NP
+)	POS	O
+are	POS	O
+the	POS	O
+major	POS	O
+health	POS	O
+problem	POS	O
+of	POS	O
+advanced	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+developing	POS	O
+countries	POS	O
+of	POS	O
+the	POS	O
+world	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+protective	POS	O
+effect	POS	O
+of	POS	O
+the	POS	O
+Solidago	POS	O
+virgaurea	POS	O
+extract	POS	O
+on	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+subcutaneous	POS	O
+injection	POS	O
+of	POS	O
+isoproterenol	POS	O
+(	POS	O
+30	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+into	POS	O
+rats	POS	O
+twice	POS	O
+at	POS	O
+an	POS	O
+interval	POS	O
+of	POS	O
+24	POS	O
+h	POS	O
+,	POS	O
+for	POS	O
+two	POS	O
+consecutive	POS	O
+days	POS	O
+,	POS	O
+led	POS	O
+to	POS	O
+a	POS	O
+significant	POS	O
+increase	POS	O
+in	POS	O
+serum	POS	O
+lactate	POS	O
+dehydrogenase	POS	O
+,	POS	O
+creatine	POS	O
+phosphokinase	POS	O
+,	POS	O
+alanine	POS	O
+transaminase	POS	O
+,	POS	O
+aspartate	POS	O
+transaminase	POS	O
+,	POS	O
+and	POS	O
+angiotensin	POS	O
+-	POS	O
+converting	POS	O
+enzyme	POS	O
+activities	POS	O
+,	POS	O
+total	POS	O
+cholesterol	POS	O
+,	POS	O
+triglycerides	POS	O
+,	POS	O
+free	POS	O
+serum	POS	O
+fatty	POS	O
+acid	POS	O
+,	POS	O
+cardiac	POS	O
+tissue	POS	O
+malondialdehyde	POS	O
+(	POS	O
+MDA	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+nitric	POS	O
+oxide	POS	O
+levels	POS	O
+and	POS	O
+a	POS	O
+significant	POS	O
+decrease	POS	O
+in	POS	O
+levels	POS	O
+of	POS	O
+glutathione	POS	O
+and	POS	O
+superoxide	POS	O
+dismutase	POS	O
+in	POS	O
+cardiac	POS	O
+tissue	POS	O
+as	POS	O
+compared	POS	O
+to	POS	O
+the	POS	O
+normal	POS	O
+control	POS	O
+group	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+Pretreatment	POS	O
+with	POS	O
+S	POS	O
+.	POS	O
+virgaurea	POS	O
+extract	POS	O
+for	POS	O
+5	POS	O
+weeks	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+250	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+followed	POS	O
+by	POS	O
+isoproterenol	POS	O
+injection	POS	O
+significantly	POS	O
+prevented	POS	O
+the	POS	O
+observed	POS	O
+alterations	POS	O
+.	POS	O
+Captopril	POS	O
+(	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+,	POS	O
+given	POS	O
+orally	POS	O
+)	POS	O
+,	POS	O
+an	POS	O
+inhibitor	POS	O
+of	POS	O
+angiotensin	POS	O
+-	POS	O
+converting	POS	O
+enzyme	POS	O
+used	POS	O
+as	POS	O
+a	POS	O
+standard	POS	O
+cardioprotective	POS	O
+drug	POS	O
+,	POS	O
+was	POS	O
+used	POS	O
+as	POS	O
+a	POS	O
+positive	POS	O
+control	POS	O
+in	POS	O
+this	POS	O
+study	POS	O
+.	POS	O
+The	POS	O
+data	POS	O
+of	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+suggest	POS	O
+that	POS	O
+S	POS	O
+.	POS	O
+virgaurea	POS	O
+extract	POS	O
+exerts	POS	O
+its	POS	O
+protective	POS	O
+effect	POS	O
+by	POS	O
+decreasing	POS	O
+MDA	POS	O
+level	POS	O
+and	POS	O
+increasing	POS	O
+the	POS	O
+antioxidant	POS	O
+status	POS	O
+in	POS	O
+isoproterenol	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+study	POS	O
+emphasizes	POS	O
+the	POS	O
+beneficial	POS	O
+action	POS	O
+of	POS	O
+S	POS	O
+.	POS	O
+virgaurea	POS	O
+extract	POS	O
+as	POS	O
+a	POS	O
+cardioprotective	POS	O
+agent	POS	O
+.	POS	O
+"	POS	O
+Real	POS	O
+-	POS	O
+world	POS	O
+"	POS	O
+data	POS	O
+on	POS	O
+the	POS	O
+efficacy	POS	O
+and	POS	O
+safety	POS	O
+of	POS	O
+lenalidomide	POS	O
+and	POS	O
+dexamethasone	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+relapsed	POS	B-NP
+/	POS	I-NP
+refractory	POS	I-NP
+multiple	POS	I-NP
+myeloma	POS	I-NP
+who	POS	O
+were	POS	O
+treated	POS	O
+according	POS	O
+to	POS	O
+the	POS	O
+standard	POS	O
+clinical	POS	O
+practice	POS	O
+:	POS	O
+a	POS	O
+study	POS	O
+of	POS	O
+the	POS	O
+Greek	POS	O
+Myeloma	POS	B-NP
+Study	POS	O
+Group	POS	O
+.	POS	O
+Lenalidomide	POS	O
+and	POS	O
+dexamethasone	POS	O
+(	POS	O
+RD	POS	O
+)	POS	O
+is	POS	O
+a	POS	O
+standard	POS	O
+of	POS	O
+care	POS	O
+for	POS	O
+relapsed	POS	B-NP
+/	POS	I-NP
+refractory	POS	I-NP
+multiple	POS	I-NP
+myeloma	POS	I-NP
+(	POS	O
+RRMM	POS	O
+)	POS	O
+,	POS	O
+but	POS	O
+there	POS	O
+is	POS	O
+limited	POS	O
+published	POS	O
+data	POS	O
+on	POS	O
+its	POS	O
+efficacy	POS	O
+and	POS	O
+safety	POS	O
+in	POS	O
+the	POS	O
+"	POS	O
+real	POS	O
+world	POS	O
+"	POS	O
+(	POS	O
+RW	POS	O
+)	POS	O
+,	POS	O
+according	POS	O
+to	POS	O
+the	POS	O
+International	POS	O
+Society	POS	O
+of	POS	O
+Pharmacoeconomics	POS	O
+and	POS	O
+Outcomes	POS	O
+Research	POS	O
+definition	POS	O
+.	POS	O
+We	POS	O
+studied	POS	O
+212	POS	O
+RRMM	POS	O
+patients	POS	O
+who	POS	O
+received	POS	O
+RD	POS	O
+in	POS	O
+RW	POS	O
+.	POS	O
+Objective	POS	O
+response	POS	O
+(	POS	O
+>	POS	O
+PR	POS	O
+(	POS	O
+partial	POS	O
+response	POS	O
+)	POS	O
+)	POS	O
+rate	POS	O
+was	POS	O
+77	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+(	POS	O
+complete	POS	O
+response	POS	O
+(	POS	O
+CR	POS	O
+)	POS	O
+,	POS	O
+20	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Median	POS	O
+time	POS	O
+to	POS	O
+first	POS	O
+and	POS	O
+best	POS	O
+response	POS	O
+was	POS	O
+2	POS	O
+and	POS	O
+5	POS	O
+months	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Median	POS	O
+time	POS	O
+to	POS	O
+CR	POS	O
+when	POS	O
+RD	POS	O
+was	POS	O
+given	POS	O
+as	POS	O
+2nd	POS	O
+or	POS	O
+>	POS	O
+2	POS	O
+(	POS	O
+nd	POS	O
+)	POS	O
+-	POS	O
+line	POS	O
+treatment	POS	O
+at	POS	O
+4	POS	O
+and	POS	O
+11	POS	O
+months	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Quality	POS	O
+of	POS	O
+response	POS	O
+was	POS	O
+independent	POS	O
+of	POS	O
+previous	POS	O
+lines	POS	O
+of	POS	O
+therapies	POS	O
+or	POS	O
+previous	POS	O
+exposure	POS	O
+to	POS	O
+thalidomide	POS	O
+or	POS	O
+bortezomib	POS	O
+.	POS	O
+Median	POS	O
+duration	POS	O
+of	POS	O
+response	POS	O
+was	POS	O
+34	POS	O
+.	POS	O
+4	POS	O
+months	POS	O
+,	POS	O
+and	POS	O
+it	POS	O
+was	POS	O
+higher	POS	O
+in	POS	O
+patients	POS	O
+who	POS	O
+received	POS	O
+RD	POS	B-NP
+until	POS	O
+progression	POS	O
+(	POS	O
+not	POS	O
+reached	POS	O
+versus	POS	O
+19	POS	O
+months	POS	O
+,	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+Improvement	POS	O
+of	POS	O
+humoral	POS	O
+immunity	POS	O
+occurred	POS	O
+in	POS	O
+60	POS	O
+%	POS	O
+of	POS	O
+responders	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+and	POS	O
+in	POS	O
+the	POS	O
+majority	POS	O
+of	POS	O
+patients	POS	O
+who	POS	O
+achieved	POS	O
+stable	POS	O
+disease	POS	O
+.	POS	O
+Adverse	POS	O
+events	POS	O
+were	POS	O
+reported	POS	O
+in	POS	O
+68	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+(	POS	O
+myelosuppression	POS	B-NP
+in	POS	O
+49	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+12	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+needed	POS	O
+hospitalization	POS	O
+.	POS	O
+Peripheral	POS	B-NP
+neuropathy	POS	I-NP
+was	POS	O
+observed	POS	O
+only	POS	O
+in	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+and	POS	O
+deep	POS	O
+vein	POS	B-NP
+thrombosis	POS	I-NP
+in	POS	O
+5	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+.	POS	O
+Dose	POS	O
+reductions	POS	O
+were	POS	O
+needed	POS	O
+in	POS	O
+31	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+and	POS	O
+permanent	POS	O
+discontinuation	POS	O
+in	POS	O
+38	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+.	POS	O
+Median	POS	O
+time	POS	O
+to	POS	O
+treatment	POS	O
+discontinuation	POS	O
+was	POS	O
+16	POS	O
+.	POS	O
+8	POS	O
+months	POS	O
+.	POS	O
+Performance	POS	O
+status	POS	O
+(	POS	O
+PS	POS	O
+)	POS	O
+and	POS	O
+initial	POS	O
+lenalidomide	POS	O
+dose	POS	O
+predicted	POS	O
+for	POS	O
+treatment	POS	O
+discontinuation	POS	O
+.	POS	O
+Extra	POS	B-NP
+-	POS	I-NP
+medullary	POS	I-NP
+relapses	POS	I-NP
+occurred	POS	O
+in	POS	O
+3	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+.	POS	O
+Our	POS	O
+study	POS	O
+confirms	POS	O
+that	POS	O
+RD	POS	O
+is	POS	O
+effective	POS	O
+and	POS	O
+safe	POS	O
+in	POS	O
+RRMM	POS	O
+in	POS	O
+the	POS	O
+RW	POS	O
+;	POS	O
+it	POS	O
+produces	POS	O
+durable	POS	O
+responses	POS	O
+especially	POS	O
+in	POS	O
+patients	POS	O
+who	POS	O
+continue	POS	O
+on	POS	O
+treatment	POS	O
+till	POS	O
+progression	POS	O
+and	POS	O
+improves	POS	O
+humoral	POS	O
+immunity	POS	O
+even	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+stable	POS	O
+disease	POS	O
+.	POS	O
+The	POS	O
+cytogenetic	POS	O
+action	POS	O
+of	POS	O
+ifosfamide	POS	O
+,	POS	O
+mesna	POS	O
+,	POS	O
+and	POS	O
+their	POS	O
+combination	POS	O
+on	POS	O
+peripheral	POS	O
+rabbit	POS	O
+lymphocytes	POS	O
+:	POS	O
+an	POS	O
+in	POS	O
+vivo	POS	O
+/	POS	O
+in	POS	O
+vitro	POS	O
+cytogenetic	POS	O
+study	POS	O
+.	POS	O
+Ifosfamide	POS	O
+(	POS	O
+IFO	POS	O
+)	POS	O
+is	POS	O
+an	POS	O
+alkylating	POS	O
+nitrogen	POS	O
+mustard	POS	O
+,	POS	O
+administrated	POS	O
+as	POS	O
+an	POS	O
+antineoplasmic	POS	O
+agent	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+characterized	POS	O
+by	POS	O
+its	POS	O
+intense	POS	O
+urotoxic	POS	O
+action	POS	O
+,	POS	O
+leading	POS	O
+to	POS	O
+hemorrhagic	POS	B-NP
+cystitis	POS	I-NP
+.	POS	O
+This	POS	O
+side	POS	O
+effect	POS	O
+of	POS	O
+IFO	POS	O
+raises	POS	O
+the	POS	O
+requirement	POS	O
+for	POS	O
+the	POS	O
+co	POS	O
+-	POS	O
+administration	POS	O
+with	POS	O
+sodium	POS	O
+2	POS	O
+-	POS	O
+sulfanylethanesulfonate	POS	O
+(	POS	O
+Mesna	POS	O
+)	POS	O
+aiming	POS	O
+to	POS	O
+avoid	POS	O
+or	POS	O
+minimize	POS	O
+this	POS	O
+effect	POS	O
+.	POS	O
+IFO	POS	O
+and	POS	O
+Mesna	POS	O
+were	POS	O
+administrated	POS	O
+separately	POS	O
+on	POS	O
+rabbit	POS	O
+'	POS	O
+s	POS	O
+lymphocytes	POS	O
+in	POS	O
+vivo	POS	O
+,	POS	O
+which	POS	O
+were	POS	O
+later	POS	O
+developed	POS	O
+in	POS	O
+vitro	POS	O
+.	POS	O
+Cytogenetic	POS	O
+markers	POS	O
+for	POS	O
+sister	POS	O
+chromatid	POS	O
+exchanges	POS	O
+(	POS	O
+SCEs	POS	O
+)	POS	O
+,	POS	O
+proliferation	POS	O
+rate	POS	O
+index	POS	O
+(	POS	O
+PRI	POS	O
+)	POS	O
+and	POS	O
+Mitotic	POS	O
+Index	POS	O
+were	POS	O
+recorded	POS	O
+.	POS	O
+Mesna	POS	O
+'	POS	O
+s	POS	O
+action	POS	O
+,	POS	O
+in	POS	O
+conjunction	POS	O
+with	POS	O
+IFO	POS	O
+reduces	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+SCEs	POS	O
+,	POS	O
+in	POS	O
+comparison	POS	O
+with	POS	O
+the	POS	O
+SCEs	POS	O
+recordings	POS	O
+obtained	POS	O
+when	POS	O
+IFO	POS	O
+is	POS	O
+administered	POS	O
+alone	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+to	POS	O
+this	POS	O
+,	POS	O
+when	POS	O
+high	POS	O
+concentrations	POS	O
+of	POS	O
+Mesna	POS	O
+were	POS	O
+administered	POS	O
+alone	POS	O
+significant	POS	O
+reductions	POS	O
+of	POS	O
+the	POS	O
+PRI	POS	O
+were	POS	O
+noted	POS	O
+,	POS	O
+than	POS	O
+with	POS	O
+IFO	POS	O
+acting	POS	O
+at	POS	O
+the	POS	O
+same	POS	O
+concentration	POS	O
+on	POS	O
+the	POS	O
+lymphocytes	POS	O
+.	POS	O
+Mesna	POS	O
+significantly	POS	O
+reduces	POS	O
+IFO	POS	O
+'	POS	O
+s	POS	O
+genotoxicity	POS	B-NP
+,	POS	O
+while	POS	O
+when	POS	O
+administered	POS	O
+in	POS	O
+high	POS	O
+concentrations	POS	O
+it	POS	O
+acts	POS	O
+in	POS	O
+an	POS	O
+inhibitory	POS	O
+fashion	POS	O
+on	POS	O
+the	POS	O
+cytostatic	POS	O
+action	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+.	POS	O
+Risk	POS	O
+factors	POS	O
+and	POS	O
+predictors	POS	O
+of	POS	O
+levodopa	POS	O
+-	POS	O
+induced	POS	O
+dyskinesia	POS	B-NP
+among	POS	O
+multiethnic	POS	O
+Malaysians	POS	O
+with	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+Chronic	POS	O
+pulsatile	POS	O
+levodopa	POS	O
+therapy	POS	O
+for	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+PD	POS	B-NP
+)	POS	O
+leads	POS	O
+to	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+motor	POS	O
+fluctuations	POS	O
+and	POS	O
+dyskinesia	POS	B-NP
+.	POS	O
+We	POS	O
+studied	POS	O
+the	POS	O
+prevalence	POS	O
+and	POS	O
+predictors	POS	O
+of	POS	O
+levodopa	POS	O
+-	POS	O
+induced	POS	O
+dyskinesia	POS	B-NP
+among	POS	O
+multiethnic	POS	O
+Malaysian	POS	O
+patients	POS	O
+with	POS	O
+PD	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+This	POS	O
+is	POS	O
+a	POS	O
+cross	POS	O
+-	POS	O
+sectional	POS	O
+study	POS	O
+involving	POS	O
+95	POS	O
+patients	POS	O
+with	POS	O
+PD	POS	B-NP
+on	POS	O
+uninterrupted	POS	O
+levodopa	POS	O
+therapy	POS	O
+for	POS	O
+at	POS	O
+least	POS	O
+6	POS	O
+months	POS	O
+.	POS	O
+The	POS	O
+instrument	POS	O
+used	POS	O
+was	POS	O
+the	POS	O
+UPDRS	POS	O
+questionnaires	POS	O
+.	POS	O
+The	POS	O
+predictors	POS	O
+of	POS	O
+dyskinesia	POS	B-NP
+were	POS	O
+determined	POS	O
+using	POS	O
+multivariate	POS	O
+logistic	POS	O
+regression	POS	O
+analysis	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+mean	POS	O
+age	POS	O
+was	POS	O
+65	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+8	POS	O
+.	POS	O
+5	POS	O
+years	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+onset	POS	O
+age	POS	O
+was	POS	O
+58	POS	O
+.	POS	O
+5	POS	O
++	POS	O
+9	POS	O
+.	POS	O
+8	POS	O
+years	POS	O
+.	POS	O
+The	POS	O
+median	POS	O
+disease	POS	O
+duration	POS	O
+was	POS	O
+6	POS	O
+(	POS	O
+7	POS	O
+)	POS	O
+years	POS	O
+.	POS	O
+Dyskinesia	POS	B-NP
+was	POS	O
+present	POS	O
+in	POS	O
+44	POS	O
+%	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+42	POS	O
+)	POS	O
+with	POS	O
+median	POS	O
+levodopa	POS	O
+therapy	POS	O
+of	POS	O
+3	POS	O
+years	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+64	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+Chinese	POS	O
+,	POS	O
+31	POS	O
+%	POS	O
+Malays	POS	O
+,	POS	O
+and	POS	O
+3	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+Indians	POS	O
+and	POS	O
+other	POS	O
+ethnic	POS	O
+groups	POS	O
+.	POS	O
+Eighty	POS	O
+-	POS	O
+one	POS	O
+percent	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+dyskinesia	POS	B-NP
+had	POS	O
+clinical	POS	O
+fluctuations	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+dyskinesia	POS	B-NP
+had	POS	O
+lower	POS	O
+onset	POS	O
+age	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+longer	POS	O
+duration	POS	O
+of	POS	O
+levodopa	POS	O
+therapy	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+longer	POS	O
+disease	POS	O
+duration	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+higher	POS	O
+total	POS	O
+daily	POS	O
+levodopa	POS	O
+dose	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+higher	POS	O
+total	POS	O
+UPDRS	POS	O
+scores	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+005	POS	O
+)	POS	O
+than	POS	O
+patients	POS	O
+without	POS	O
+dyskinesia	POS	B-NP
+.	POS	O
+The	POS	O
+three	POS	O
+significant	POS	O
+predictors	POS	O
+of	POS	O
+dyskinesia	POS	B-NP
+were	POS	O
+duration	POS	O
+of	POS	O
+levodopa	POS	O
+therapy	POS	O
+,	POS	O
+onset	POS	O
+age	POS	O
+,	POS	O
+and	POS	O
+total	POS	O
+daily	POS	O
+levodopa	POS	O
+dose	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+prevalence	POS	O
+of	POS	O
+levodopa	POS	O
+-	POS	O
+induced	POS	O
+dyskinesia	POS	B-NP
+in	POS	O
+our	POS	O
+patients	POS	O
+was	POS	O
+44	POS	O
+%	POS	O
+.	POS	O
+The	POS	O
+most	POS	O
+significant	POS	O
+predictors	POS	O
+were	POS	O
+duration	POS	O
+of	POS	O
+levodopa	POS	O
+therapy	POS	O
+,	POS	O
+total	POS	O
+daily	POS	O
+levodopa	POS	O
+dose	POS	O
+,	POS	O
+and	POS	O
+onset	POS	O
+age	POS	O
+.	POS	O
+Dose	POS	O
+-	POS	O
+dependent	POS	O
+neurotoxicity	POS	B-NP
+of	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+busulfan	POS	O
+in	POS	O
+children	POS	O
+:	POS	O
+a	POS	O
+clinical	POS	O
+and	POS	O
+pharmacological	POS	O
+study	POS	O
+.	POS	O
+Busulfan	POS	O
+is	POS	O
+known	POS	O
+to	POS	O
+be	POS	O
+neurotoxic	POS	B-NP
+in	POS	O
+animals	POS	O
+and	POS	O
+humans	POS	O
+,	POS	O
+but	POS	O
+its	POS	O
+acute	POS	O
+neurotoxicity	POS	B-NP
+remains	POS	O
+poorly	POS	O
+characterized	POS	O
+in	POS	O
+children	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+here	POS	O
+a	POS	O
+retrospective	POS	O
+study	POS	O
+of	POS	O
+123	POS	O
+children	POS	O
+(	POS	O
+median	POS	O
+age	POS	O
+,	POS	O
+6	POS	O
+.	POS	O
+5	POS	O
+years	POS	O
+)	POS	O
+receiving	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+busulfan	POS	O
+in	POS	O
+combined	POS	O
+chemotherapy	POS	O
+before	POS	O
+bone	POS	O
+marrow	POS	O
+transplantation	POS	O
+for	POS	O
+malignant	POS	B-NP
+solid	POS	I-NP
+tumors	POS	I-NP
+,	POS	O
+brain	POS	B-NP
+tumors	POS	I-NP
+excluded	POS	O
+.	POS	O
+Busulfan	POS	O
+was	POS	O
+given	POS	O
+p	POS	O
+.	POS	O
+o	POS	O
+.	POS	O
+,	POS	O
+every	POS	O
+6	POS	O
+hours	POS	O
+for	POS	O
+16	POS	O
+doses	POS	O
+over	POS	O
+4	POS	O
+days	POS	O
+.	POS	O
+Two	POS	O
+total	POS	O
+doses	POS	O
+were	POS	O
+consecutively	POS	O
+used	POS	O
+:	POS	O
+16	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+then	POS	O
+600	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+.	POS	O
+The	POS	O
+dose	POS	O
+calculation	POS	O
+on	POS	O
+the	POS	O
+basis	POS	O
+of	POS	O
+body	POS	O
+surface	POS	O
+area	POS	O
+results	POS	O
+in	POS	O
+higher	POS	O
+doses	POS	O
+in	POS	O
+young	POS	O
+children	POS	O
+than	POS	O
+in	POS	O
+older	POS	O
+patients	POS	O
+(	POS	O
+16	POS	O
+to	POS	O
+28	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+.	POS	O
+Ninety	POS	O
+-	POS	O
+six	POS	O
+patients	POS	O
+were	POS	O
+not	POS	O
+given	POS	O
+anticonvulsive	POS	O
+prophylaxis	POS	B-NP
+;	POS	O
+7	POS	O
+(	POS	O
+7	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+developed	POS	O
+seizures	POS	B-NP
+during	POS	O
+the	POS	O
+4	POS	O
+days	POS	O
+of	POS	O
+the	POS	O
+busulfan	POS	O
+course	POS	O
+or	POS	O
+within	POS	O
+24	POS	O
+h	POS	O
+after	POS	O
+the	POS	O
+last	POS	O
+dosing	POS	O
+.	POS	O
+When	POS	O
+the	POS	O
+total	POS	O
+busulfan	POS	O
+dose	POS	O
+was	POS	O
+taken	POS	O
+into	POS	O
+account	POS	O
+,	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+difference	POS	O
+in	POS	O
+terms	POS	O
+of	POS	O
+neurotoxicity	POS	B-NP
+incidence	POS	O
+among	POS	O
+patients	POS	O
+under	POS	O
+16	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+1	POS	O
+of	POS	O
+57	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+patients	POS	O
+under	POS	O
+600	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+(	POS	O
+6	POS	O
+of	POS	O
+39	POS	O
+,	POS	O
+15	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+.	POS	O
+Twenty	POS	O
+-	POS	O
+seven	POS	O
+patients	POS	O
+were	POS	O
+given	POS	O
+a	POS	O
+600	POS	O
+-	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+busulfan	POS	O
+total	POS	O
+dose	POS	O
+with	POS	O
+continuous	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+infusion	POS	O
+of	POS	O
+clonazepam	POS	O
+;	POS	O
+none	POS	O
+had	POS	O
+any	POS	O
+neurological	POS	O
+symptoms	POS	O
+.	POS	O
+Busulfan	POS	O
+levels	POS	O
+were	POS	O
+measured	POS	O
+by	POS	O
+a	POS	O
+gas	POS	O
+chromatographic	POS	O
+-	POS	O
+mass	POS	O
+spectrometry	POS	O
+assay	POS	O
+in	POS	O
+the	POS	O
+plasma	POS	O
+and	POS	O
+cerebrospinal	POS	O
+fluid	POS	O
+of	POS	O
+9	POS	O
+children	POS	O
+without	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+disease	POS	O
+under	POS	O
+600	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+busulfan	POS	O
+with	POS	O
+clonazepam	POS	O
+:	POS	O
+busulfan	POS	O
+cerebrospinal	POS	O
+fluid	POS	O
+:	POS	O
+plasma	POS	O
+ratio	POS	O
+was	POS	O
+1	POS	O
+.	POS	O
+39	POS	O
+.	POS	O
+This	POS	O
+was	POS	O
+significantly	POS	O
+different	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+from	POS	O
+the	POS	O
+cerebrospinal	POS	O
+fluid	POS	O
+:	POS	O
+plasma	POS	O
+ratio	POS	O
+previously	POS	O
+defined	POS	O
+in	POS	O
+children	POS	O
+receiving	POS	O
+a	POS	O
+16	POS	O
+-	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+total	POS	O
+dose	POS	O
+of	POS	O
+busulfan	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+shows	POS	O
+that	POS	O
+busulfan	POS	O
+neurotoxicity	POS	B-NP
+is	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+in	POS	O
+children	POS	O
+and	POS	O
+efficiently	POS	O
+prevented	POS	O
+by	POS	O
+clonazepam	POS	O
+.	POS	O
+A	POS	O
+busulfan	POS	O
+dose	POS	O
+calculated	POS	O
+on	POS	O
+the	POS	O
+basis	POS	O
+of	POS	O
+body	POS	O
+surface	POS	O
+area	POS	O
+,	POS	O
+resulting	POS	O
+in	POS	O
+higher	POS	O
+doses	POS	O
+in	POS	O
+young	POS	O
+children	POS	O
+,	POS	O
+was	POS	O
+followed	POS	O
+by	POS	O
+increased	POS	O
+neurotoxicity	POS	B-NP
+,	POS	O
+close	POS	O
+to	POS	O
+neurotoxicity	POS	B-NP
+incidence	POS	O
+observed	POS	O
+in	POS	O
+adults	POS	O
+.	POS	O
+Since	POS	O
+plasma	POS	O
+pharmacokinetic	POS	O
+studies	POS	O
+showed	POS	O
+a	POS	O
+faster	POS	O
+busulfan	POS	O
+clearance	POS	O
+in	POS	O
+children	POS	O
+than	POS	O
+in	POS	O
+adults	POS	O
+,	POS	O
+this	POS	O
+new	POS	O
+dose	POS	O
+may	POS	O
+approximate	POS	O
+more	POS	O
+closely	POS	O
+the	POS	O
+adult	POS	O
+systemic	POS	O
+exposure	POS	O
+obtained	POS	O
+after	POS	O
+the	POS	O
+usual	POS	O
+16	POS	O
+-	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+total	POS	O
+dose	POS	O
+,	POS	O
+with	POS	O
+potential	POS	O
+inferences	POS	O
+in	POS	O
+terms	POS	O
+of	POS	O
+anticancer	POS	O
+or	POS	O
+myeloablative	POS	O
+effects	POS	O
+.	POS	O
+The	POS	O
+busulfan	POS	O
+dose	POS	O
+in	POS	O
+children	POS	O
+and	POS	O
+infants	POS	O
+undergoing	POS	O
+bone	POS	O
+marrow	POS	O
+transplantation	POS	O
+should	POS	O
+be	POS	O
+reconsidered	POS	O
+on	POS	O
+the	POS	O
+basis	POS	O
+of	POS	O
+pharmacokinetic	POS	O
+studies	POS	O
+.	POS	O
+An	POS	O
+unexpected	POS	O
+diagnosis	POS	O
+in	POS	O
+a	POS	O
+renal	POS	O
+-	POS	O
+transplant	POS	O
+patient	POS	O
+with	POS	O
+proteinuria	POS	B-NP
+treated	POS	O
+with	POS	O
+everolimus	POS	O
+:	POS	O
+AL	POS	O
+amyloidosis	POS	B-NP
+.	POS	O
+Proteinuria	POS	B-NP
+is	POS	O
+an	POS	O
+expected	POS	O
+complication	POS	O
+in	POS	O
+transplant	POS	O
+patients	POS	O
+treated	POS	O
+with	POS	O
+mammalian	POS	O
+target	POS	O
+of	POS	O
+rapamycin	POS	O
+inhibitors	POS	O
+(	POS	O
+mTOR	POS	O
+-	POS	O
+i	POS	O
+)	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+clinical	POS	O
+suspicion	POS	O
+should	POS	O
+always	POS	O
+be	POS	O
+supported	POS	O
+by	POS	O
+histological	POS	O
+evidence	POS	O
+in	POS	O
+order	POS	O
+to	POS	O
+investigate	POS	O
+potential	POS	O
+alternate	POS	O
+diagnoses	POS	O
+such	POS	O
+as	POS	O
+acute	POS	O
+or	POS	O
+chronic	POS	B-NP
+rejection	POS	I-NP
+,	POS	O
+interstitial	POS	B-NP
+fibrosis	POS	I-NP
+and	POS	O
+tubular	POS	B-NP
+atrophy	POS	I-NP
+,	POS	O
+or	POS	O
+recurrent	POS	O
+or	POS	O
+de	POS	O
+novo	POS	O
+glomerulopathy	POS	B-NP
+.	POS	O
+In	POS	O
+this	POS	O
+case	POS	O
+we	POS	O
+report	POS	O
+the	POS	O
+unexpected	POS	O
+diagnosis	POS	O
+of	POS	O
+amyloidosis	POS	B-NP
+in	POS	O
+a	POS	O
+renal	POS	O
+-	POS	O
+transplant	POS	O
+patient	POS	O
+with	POS	O
+pre	POS	O
+-	POS	O
+transplant	POS	O
+monoclonal	POS	O
+gammapathy	POS	O
+of	POS	O
+undetermined	POS	O
+significance	POS	O
+who	POS	O
+developed	POS	O
+proteinuria	POS	B-NP
+after	POS	O
+conversion	POS	O
+from	POS	O
+tacrolimus	POS	O
+to	POS	O
+everolimus	POS	O
+.	POS	O
+Long	POS	O
+-	POS	O
+term	POS	O
+oral	POS	O
+galactose	POS	O
+treatment	POS	O
+prevents	POS	O
+cognitive	POS	B-NP
+deficits	POS	I-NP
+in	POS	O
+male	POS	O
+Wistar	POS	O
+rats	POS	O
+treated	POS	O
+intracerebroventricularly	POS	O
+with	POS	O
+streptozotocin	POS	O
+.	POS	O
+Basic	POS	O
+and	POS	O
+clinical	POS	O
+research	POS	O
+has	POS	O
+demonstrated	POS	O
+that	POS	O
+dementia	POS	B-NP
+of	POS	O
+sporadic	POS	O
+Alzheimer	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+sAD	POS	B-NP
+)	POS	O
+type	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+dysfunction	POS	O
+of	POS	O
+the	POS	O
+insulin	POS	O
+-	POS	O
+receptor	POS	O
+(	POS	O
+IR	POS	O
+)	POS	O
+system	POS	O
+followed	POS	O
+by	POS	O
+decreased	POS	O
+glucose	POS	O
+transport	POS	O
+via	POS	O
+glucose	POS	O
+transporter	POS	O
+GLUT4	POS	O
+and	POS	O
+decreased	POS	O
+glucose	POS	O
+metabolism	POS	O
+in	POS	O
+brain	POS	O
+cells	POS	O
+.	POS	O
+An	POS	O
+alternative	POS	O
+source	POS	O
+of	POS	O
+energy	POS	O
+is	POS	O
+d	POS	O
+-	POS	O
+galactose	POS	O
+(	POS	O
+the	POS	O
+C	POS	O
+-	POS	O
+4	POS	O
+-	POS	O
+epimer	POS	O
+of	POS	O
+d	POS	O
+-	POS	O
+glucose	POS	O
+)	POS	O
+which	POS	O
+is	POS	O
+transported	POS	O
+into	POS	O
+the	POS	O
+brain	POS	O
+by	POS	O
+insulin	POS	O
+-	POS	O
+independent	POS	O
+GLUT3	POS	O
+transporter	POS	O
+where	POS	O
+it	POS	O
+might	POS	O
+be	POS	O
+metabolized	POS	O
+to	POS	O
+glucose	POS	O
+via	POS	O
+the	POS	O
+Leloir	POS	O
+pathway	POS	O
+.	POS	O
+Exclusively	POS	O
+parenteral	POS	O
+daily	POS	O
+injections	POS	O
+of	POS	O
+galactose	POS	O
+induce	POS	O
+memory	POS	O
+deterioration	POS	O
+in	POS	O
+rodents	POS	O
+and	POS	O
+are	POS	O
+used	POS	O
+to	POS	O
+generate	POS	O
+animal	POS	O
+aging	POS	O
+model	POS	O
+,	POS	O
+but	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+oral	POS	O
+galactose	POS	O
+treatment	POS	O
+on	POS	O
+cognitive	POS	O
+functions	POS	O
+have	POS	O
+never	POS	O
+been	POS	O
+tested	POS	O
+.	POS	O
+We	POS	O
+have	POS	O
+investigated	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+continuous	POS	O
+daily	POS	O
+oral	POS	O
+galactose	POS	O
+(	POS	O
+200	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+treatment	POS	O
+on	POS	O
+cognitive	POS	B-NP
+deficits	POS	I-NP
+in	POS	O
+streptozotocin	POS	O
+-	POS	O
+induced	POS	O
+(	POS	O
+STZ	POS	O
+-	POS	O
+icv	POS	O
+)	POS	O
+rat	POS	O
+model	POS	O
+of	POS	O
+sAD	POS	O
+,	POS	O
+tested	POS	O
+by	POS	O
+Morris	POS	O
+Water	POS	O
+Maze	POS	O
+and	POS	O
+Passive	POS	O
+Avoidance	POS	O
+test	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+One	POS	O
+month	POS	O
+of	POS	O
+oral	POS	O
+galactose	POS	O
+treatment	POS	O
+initiated	POS	O
+immediately	POS	O
+after	POS	O
+the	POS	O
+STZ	POS	O
+-	POS	O
+icv	POS	O
+administration	POS	O
+,	POS	O
+successfully	POS	O
+prevented	POS	O
+development	POS	O
+of	POS	O
+the	POS	O
+STZ	POS	O
+-	POS	O
+icv	POS	O
+-	POS	O
+induced	POS	O
+cognitive	POS	B-NP
+deficits	POS	I-NP
+.	POS	O
+Beneficial	POS	O
+effect	POS	O
+of	POS	O
+oral	POS	O
+galactose	POS	O
+was	POS	O
+independent	POS	O
+of	POS	O
+the	POS	O
+rat	POS	O
+age	POS	O
+and	POS	O
+of	POS	O
+the	POS	O
+galactose	POS	O
+dose	POS	O
+ranging	POS	O
+from	POS	O
+100	POS	O
+to	POS	O
+300	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+.	POS	O
+Additionally	POS	O
+,	POS	O
+oral	POS	O
+galactose	POS	O
+administration	POS	O
+led	POS	O
+to	POS	O
+the	POS	O
+appearance	POS	O
+of	POS	O
+galactose	POS	O
+in	POS	O
+the	POS	O
+blood	POS	O
+.	POS	O
+The	POS	O
+increase	POS	O
+of	POS	O
+galactose	POS	O
+concentration	POS	O
+in	POS	O
+the	POS	O
+cerebrospinal	POS	O
+fluid	POS	O
+was	POS	O
+several	POS	O
+times	POS	O
+lower	POS	O
+after	POS	O
+oral	POS	O
+than	POS	O
+after	POS	O
+parenteral	POS	O
+administration	POS	O
+of	POS	O
+the	POS	O
+same	POS	O
+galactose	POS	O
+dose	POS	O
+.	POS	O
+Oral	POS	O
+galactose	POS	O
+exposure	POS	O
+might	POS	O
+have	POS	O
+beneficial	POS	O
+effects	POS	O
+on	POS	O
+learning	POS	O
+and	POS	O
+memory	POS	O
+ability	POS	O
+and	POS	O
+could	POS	O
+be	POS	O
+worth	POS	O
+investigating	POS	O
+for	POS	O
+improvement	POS	O
+of	POS	O
+cognitive	POS	B-NP
+deficits	POS	I-NP
+associated	POS	O
+with	POS	O
+glucose	POS	B-NP
+hypometabolism	POS	I-NP
+in	POS	O
+AD	POS	B-NP
+.	POS	O
+An	POS	O
+investigation	POS	O
+of	POS	O
+the	POS	O
+pattern	POS	O
+of	POS	O
+kidney	POS	B-NP
+injury	POS	I-NP
+in	POS	O
+HIV	POS	O
+-	POS	O
+positive	POS	O
+persons	POS	O
+exposed	POS	O
+to	POS	O
+tenofovir	POS	O
+disoproxil	POS	O
+fumarate	POS	O
+:	POS	O
+an	POS	O
+examination	POS	O
+of	POS	O
+a	POS	O
+large	POS	O
+population	POS	O
+database	POS	O
+(	POS	O
+MHRA	POS	O
+database	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+potential	POS	O
+for	POS	O
+tenofovir	POS	O
+to	POS	O
+cause	POS	O
+a	POS	O
+range	POS	O
+of	POS	O
+kidney	POS	B-NP
+syndromes	POS	I-NP
+has	POS	O
+been	POS	O
+established	POS	O
+from	POS	O
+mechanistic	POS	O
+and	POS	O
+randomised	POS	O
+clinical	POS	O
+trials	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+exact	POS	O
+pattern	POS	O
+of	POS	O
+kidney	POS	O
+involvement	POS	O
+is	POS	O
+still	POS	O
+uncertain	POS	O
+.	POS	O
+We	POS	O
+undertook	POS	O
+a	POS	O
+descriptive	POS	O
+analysis	POS	O
+of	POS	O
+Yellow	POS	O
+Card	POS	O
+records	POS	O
+of	POS	O
+407	POS	O
+HIV	POS	O
+-	POS	O
+positive	POS	O
+persons	POS	O
+taking	POS	O
+tenofovir	POS	O
+disoproxil	POS	O
+fumarate	POS	O
+(	POS	O
+TDF	POS	O
+)	POS	O
+as	POS	O
+part	POS	O
+of	POS	O
+their	POS	O
+antiretroviral	POS	O
+therapy	POS	O
+regimen	POS	O
+and	POS	O
+submitted	POS	O
+to	POS	O
+the	POS	O
+Medicines	POS	O
+and	POS	O
+Healthcare	POS	O
+Products	POS	O
+Regulatory	POS	O
+Agency	POS	O
+(	POS	O
+MHRA	POS	O
+)	POS	O
+with	POS	O
+suspected	POS	O
+kidney	POS	O
+adverse	POS	O
+effects	POS	O
+.	POS	O
+Reports	POS	O
+that	POS	O
+satisfy	POS	O
+defined	POS	O
+criteria	POS	O
+were	POS	O
+classified	POS	O
+as	POS	O
+acute	POS	B-NP
+kidney	POS	I-NP
+injury	POS	I-NP
+,	POS	O
+kidney	POS	B-NP
+tubular	POS	I-NP
+dysfunction	POS	I-NP
+and	POS	O
+Fanconi	POS	B-NP
+syndrome	POS	I-NP
+.	POS	O
+Of	POS	O
+the	POS	O
+407	POS	O
+Yellow	POS	O
+Card	POS	O
+records	POS	O
+analysed	POS	O
+,	POS	O
+106	POS	O
+satisfied	POS	O
+criteria	POS	O
+for	POS	O
+TDF	POS	O
+-	POS	O
+related	POS	O
+kidney	POS	B-NP
+disease	POS	I-NP
+,	POS	O
+of	POS	O
+which	POS	O
+53	POS	O
+(	POS	O
+50	POS	O
+%	POS	O
+)	POS	O
+had	POS	O
+features	POS	O
+of	POS	O
+kidney	POS	B-NP
+tubular	POS	I-NP
+dysfunction	POS	I-NP
+,	POS	O
+35	POS	O
+(	POS	O
+33	POS	O
+%	POS	O
+)	POS	O
+were	POS	O
+found	POS	O
+to	POS	O
+have	POS	O
+features	POS	O
+of	POS	O
+glomerular	POS	B-NP
+dysfunction	POS	I-NP
+and	POS	O
+18	POS	O
+(	POS	O
+17	POS	O
+%	POS	O
+)	POS	O
+had	POS	O
+Fanconi	POS	B-NP
+syndrome	POS	I-NP
+.	POS	O
+The	POS	O
+median	POS	O
+TDF	POS	O
+exposure	POS	O
+was	POS	O
+316	POS	O
+days	POS	O
+(	POS	O
+interquartile	POS	O
+range	POS	O
+120	POS	O
+-	POS	O
+740	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+hospitalisation	POS	O
+for	POS	O
+TDF	POS	O
+kidney	POS	O
+adverse	POS	O
+effects	POS	O
+was	POS	O
+high	POS	O
+,	POS	O
+particularly	POS	O
+amongst	POS	O
+patients	POS	O
+with	POS	O
+features	POS	O
+of	POS	O
+Fanconi	POS	B-NP
+syndrome	POS	I-NP
+.	POS	O
+The	POS	O
+pattern	POS	O
+of	POS	O
+kidney	POS	B-NP
+syndromes	POS	I-NP
+in	POS	O
+this	POS	O
+population	POS	O
+series	POS	O
+mirrors	POS	O
+that	POS	O
+reported	POS	O
+in	POS	O
+randomised	POS	O
+clinical	POS	O
+trials	POS	O
+.	POS	O
+Cessation	POS	O
+of	POS	O
+TDF	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+complete	POS	O
+restoration	POS	O
+of	POS	O
+kidney	POS	O
+function	POS	O
+in	POS	O
+up	POS	O
+half	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+in	POS	O
+this	POS	O
+report	POS	O
+.	POS	O
+Incidence	POS	O
+of	POS	O
+postoperative	POS	B-NP
+delirium	POS	I-NP
+is	POS	O
+high	POS	O
+even	POS	O
+in	POS	O
+a	POS	O
+population	POS	O
+without	POS	O
+known	POS	O
+risk	POS	O
+factors	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+Postoperative	POS	O
+delirium	POS	B-NP
+is	POS	O
+a	POS	O
+recognized	POS	O
+complication	POS	O
+in	POS	O
+populations	POS	O
+at	POS	O
+risk	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+is	POS	O
+to	POS	O
+assess	POS	O
+the	POS	O
+prevalence	POS	O
+of	POS	O
+early	POS	O
+postoperative	POS	B-NP
+delirium	POS	I-NP
+in	POS	O
+a	POS	O
+population	POS	O
+without	POS	O
+known	POS	O
+risk	POS	O
+factors	POS	O
+admitted	POS	O
+to	POS	O
+the	POS	O
+ICU	POS	O
+for	POS	O
+postoperative	POS	O
+monitoring	POS	O
+after	POS	O
+elective	POS	O
+major	POS	O
+surgery	POS	O
+.	POS	O
+The	POS	O
+secondary	POS	O
+outcome	POS	O
+investigated	POS	O
+is	POS	O
+to	POS	O
+identify	POS	O
+eventual	POS	O
+independent	POS	O
+risk	POS	O
+factors	POS	O
+among	POS	O
+demographic	POS	O
+data	POS	O
+and	POS	O
+anesthetic	POS	O
+drugs	POS	O
+used	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+An	POS	O
+observational	POS	O
+,	POS	O
+prospective	POS	O
+study	POS	O
+was	POS	O
+conducted	POS	O
+on	POS	O
+a	POS	O
+consecutive	POS	O
+cohort	POS	O
+of	POS	O
+patients	POS	O
+admitted	POS	O
+to	POS	O
+our	POS	O
+ICU	POS	O
+within	POS	O
+and	POS	O
+for	POS	O
+at	POS	O
+least	POS	O
+24	POS	O
+h	POS	O
+after	POS	O
+major	POS	O
+surgical	POS	O
+procedures	POS	O
+.	POS	O
+Exclusion	POS	O
+criteria	POS	O
+were	POS	O
+any	POS	O
+preexisting	POS	O
+predisposing	POS	O
+factor	POS	O
+for	POS	O
+delirium	POS	B-NP
+or	POS	O
+other	POS	O
+potentially	POS	O
+confounding	POS	O
+neurological	POS	B-NP
+dysfunctions	POS	I-NP
+.	POS	O
+Patients	POS	O
+were	POS	O
+assessed	POS	O
+daily	POS	O
+using	POS	O
+the	POS	O
+confusion	POS	B-NP
+assessment	POS	O
+method	POS	O
+for	POS	O
+the	POS	O
+ICU	POS	O
+scale	POS	O
+for	POS	O
+3	POS	O
+days	POS	O
+after	POS	O
+the	POS	O
+surgical	POS	O
+procedure	POS	O
+.	POS	O
+Early	POS	O
+postoperative	POS	B-NP
+delirium	POS	I-NP
+incidence	POS	O
+risk	POS	O
+factors	POS	O
+were	POS	O
+then	POS	O
+assessed	POS	O
+through	POS	O
+three	POS	O
+different	POS	O
+multiple	POS	O
+regression	POS	O
+models	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+According	POS	O
+to	POS	O
+the	POS	O
+confusion	POS	B-NP
+assessment	POS	O
+method	POS	O
+for	POS	O
+the	POS	O
+ICU	POS	O
+scale	POS	O
+,	POS	O
+28	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+were	POS	O
+diagnosed	POS	O
+with	POS	O
+early	POS	O
+postoperative	POS	B-NP
+delirium	POS	I-NP
+.	POS	O
+The	POS	O
+use	POS	O
+of	POS	O
+thiopentone	POS	O
+was	POS	O
+significantly	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+eight	POS	O
+-	POS	O
+fold	POS	O
+-	POS	O
+higher	POS	O
+risk	POS	O
+for	POS	O
+delirium	POS	B-NP
+compared	POS	O
+to	POS	O
+propofol	POS	O
+(	POS	O
+57	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+vs	POS	O
+.	POS	O
+7	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+,	POS	O
+RR	POS	O
+=	POS	O
+8	POS	O
+.	POS	O
+0	POS	O
+,	POS	O
+X2	POS	O
+=	POS	O
+4	POS	O
+.	POS	O
+256	POS	O
+;	POS	O
+df	POS	O
+=	POS	O
+1	POS	O
+;	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+<	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+early	POS	O
+postoperative	POS	B-NP
+delirium	POS	I-NP
+was	POS	O
+found	POS	O
+to	POS	O
+be	POS	O
+a	POS	O
+very	POS	O
+common	POS	O
+complication	POS	O
+after	POS	O
+major	POS	O
+surgery	POS	O
+,	POS	O
+even	POS	O
+in	POS	O
+a	POS	O
+population	POS	O
+without	POS	O
+known	POS	O
+risk	POS	O
+factors	POS	O
+.	POS	O
+Thiopentone	POS	O
+was	POS	O
+independently	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+its	POS	O
+relative	POS	O
+risk	POS	O
+.	POS	O
+A	POS	O
+single	POS	O
+neurotoxic	POS	B-NP
+dose	POS	O
+of	POS	O
+methamphetamine	POS	O
+induces	POS	O
+a	POS	O
+long	POS	O
+-	POS	O
+lasting	POS	O
+depressive	POS	O
+-	POS	O
+like	POS	O
+behaviour	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+Methamphetamine	POS	O
+(	POS	O
+METH	POS	O
+)	POS	O
+triggers	POS	O
+a	POS	O
+disruption	POS	O
+of	POS	O
+the	POS	O
+monoaminergic	POS	O
+system	POS	O
+and	POS	O
+METH	POS	O
+abuse	POS	O
+leads	POS	O
+to	POS	O
+negative	POS	O
+emotional	POS	O
+states	POS	O
+including	POS	O
+depressive	POS	B-NP
+symptoms	POS	I-NP
+during	POS	O
+drug	POS	O
+withdrawal	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+it	POS	O
+is	POS	O
+currently	POS	O
+unknown	POS	O
+if	POS	O
+the	POS	O
+acute	POS	O
+toxic	POS	O
+dosage	POS	O
+of	POS	O
+METH	POS	O
+also	POS	O
+causes	POS	O
+a	POS	O
+long	POS	O
+-	POS	O
+lasting	POS	O
+depressive	POS	B-NP
+phenotype	POS	O
+and	POS	O
+persistent	POS	O
+monoaminergic	POS	B-NP
+deficits	POS	I-NP
+.	POS	O
+Thus	POS	O
+,	POS	O
+we	POS	O
+now	POS	O
+assessed	POS	O
+the	POS	O
+depressive	POS	O
+-	POS	O
+like	POS	O
+behaviour	POS	O
+in	POS	O
+mice	POS	O
+at	POS	O
+early	POS	O
+and	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+periods	POS	O
+following	POS	O
+a	POS	O
+single	POS	O
+high	POS	O
+METH	POS	O
+dose	POS	O
+(	POS	O
+30	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+.	POS	O
+METH	POS	O
+did	POS	O
+not	POS	O
+alter	POS	O
+the	POS	O
+motor	POS	O
+function	POS	O
+and	POS	O
+procedural	POS	O
+memory	POS	O
+of	POS	O
+mice	POS	O
+as	POS	O
+assessed	POS	O
+by	POS	O
+swimming	POS	O
+speed	POS	O
+and	POS	O
+escape	POS	O
+latency	POS	O
+to	POS	O
+find	POS	O
+the	POS	O
+platform	POS	O
+in	POS	O
+a	POS	O
+cued	POS	O
+version	POS	O
+of	POS	O
+the	POS	O
+water	POS	O
+maze	POS	O
+task	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+METH	POS	O
+significantly	POS	O
+increased	POS	O
+the	POS	O
+immobility	POS	O
+time	POS	O
+in	POS	O
+the	POS	O
+tail	POS	O
+suspension	POS	O
+test	POS	O
+at	POS	O
+3	POS	O
+and	POS	O
+49	POS	O
+days	POS	O
+post	POS	O
+-	POS	O
+administration	POS	O
+.	POS	O
+This	POS	O
+depressive	POS	O
+-	POS	O
+like	POS	O
+profile	POS	O
+induced	POS	O
+by	POS	O
+METH	POS	O
+was	POS	O
+accompanied	POS	O
+by	POS	O
+a	POS	O
+marked	POS	O
+depletion	POS	O
+of	POS	O
+frontostriatal	POS	O
+dopaminergic	POS	O
+and	POS	O
+serotonergic	POS	O
+neurotransmission	POS	O
+,	POS	O
+indicated	POS	O
+by	POS	O
+a	POS	O
+reduction	POS	O
+in	POS	O
+the	POS	O
+levels	POS	O
+of	POS	O
+dopamine	POS	O
+,	POS	O
+DOPAC	POS	O
+and	POS	O
+HVA	POS	O
+,	POS	O
+tyrosine	POS	O
+hydroxylase	POS	O
+and	POS	O
+serotonin	POS	O
+,	POS	O
+observed	POS	O
+at	POS	O
+both	POS	O
+3	POS	O
+and	POS	O
+49	POS	O
+days	POS	O
+post	POS	O
+-	POS	O
+administration	POS	O
+.	POS	O
+In	POS	O
+parallel	POS	O
+,	POS	O
+another	POS	O
+neurochemical	POS	O
+feature	POS	O
+of	POS	O
+depression	POS	B-NP
+-	POS	O
+-	POS	O
+astroglial	POS	O
+dysfunction	POS	O
+-	POS	O
+-	POS	O
+was	POS	O
+unaffected	POS	O
+in	POS	O
+the	POS	O
+cortex	POS	O
+and	POS	O
+the	POS	O
+striatal	POS	O
+levels	POS	O
+of	POS	O
+the	POS	O
+astrocytic	POS	O
+protein	POS	O
+marker	POS	O
+,	POS	O
+glial	POS	O
+fibrillary	POS	O
+acidic	POS	O
+protein	POS	O
+,	POS	O
+were	POS	O
+only	POS	O
+transiently	POS	O
+increased	POS	O
+at	POS	O
+3	POS	O
+days	POS	O
+.	POS	O
+These	POS	O
+findings	POS	O
+demonstrate	POS	O
+for	POS	O
+the	POS	O
+first	POS	O
+time	POS	O
+that	POS	O
+a	POS	O
+single	POS	O
+high	POS	O
+dose	POS	O
+of	POS	O
+METH	POS	O
+induces	POS	O
+long	POS	O
+-	POS	O
+lasting	POS	O
+depressive	POS	O
+-	POS	O
+like	POS	O
+behaviour	POS	O
+in	POS	O
+mice	POS	O
+associated	POS	O
+with	POS	O
+a	POS	O
+persistent	POS	O
+disruption	POS	O
+of	POS	O
+frontostriatal	POS	O
+dopaminergic	POS	O
+and	POS	O
+serotonergic	POS	O
+homoeostasis	POS	O
+.	POS	O
+Linezolid	POS	O
+-	POS	O
+induced	POS	O
+optic	POS	B-NP
+neuropathy	POS	I-NP
+.	POS	O
+Many	POS	O
+systemic	POS	O
+antimicrobials	POS	O
+have	POS	O
+been	POS	O
+implicated	POS	O
+to	POS	O
+cause	POS	O
+ocular	POS	O
+adverse	POS	O
+effects	POS	O
+.	POS	O
+This	POS	O
+is	POS	O
+especially	POS	O
+relevant	POS	O
+in	POS	O
+multidrug	POS	O
+therapy	POS	O
+where	POS	O
+more	POS	O
+than	POS	O
+one	POS	O
+drug	POS	O
+can	POS	O
+cause	POS	O
+a	POS	O
+similar	POS	O
+ocular	POS	O
+adverse	POS	O
+effect	POS	O
+.	POS	O
+We	POS	O
+describe	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+progressive	POS	O
+loss	POS	O
+of	POS	O
+vision	POS	O
+associated	POS	O
+with	POS	O
+linezolid	POS	O
+therapy	POS	O
+.	POS	O
+A	POS	O
+45	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+male	POS	O
+patient	POS	O
+who	POS	O
+was	POS	O
+on	POS	O
+treatment	POS	O
+with	POS	O
+multiple	POS	O
+second	POS	O
+-	POS	O
+line	POS	O
+anti	POS	O
+-	POS	O
+tuberculous	POS	O
+drugs	POS	O
+including	POS	O
+linezolid	POS	O
+and	POS	O
+ethambutol	POS	O
+for	POS	O
+extensively	POS	O
+drug	POS	O
+-	POS	O
+resistant	POS	O
+tuberculosis	POS	B-NP
+(	POS	O
+XDR	POS	O
+-	POS	O
+TB	POS	O
+)	POS	O
+presented	POS	O
+to	POS	O
+us	POS	O
+with	POS	O
+painless	POS	O
+progressive	POS	O
+loss	POS	O
+of	POS	O
+vision	POS	O
+in	POS	O
+both	POS	O
+eyes	POS	O
+.	POS	O
+Color	POS	B-NP
+vision	POS	I-NP
+was	POS	O
+defective	POS	O
+and	POS	O
+fundus	POS	O
+examination	POS	O
+revealed	POS	O
+optic	POS	B-NP
+disc	POS	I-NP
+edema	POS	I-NP
+in	POS	O
+both	POS	O
+eyes	POS	O
+.	POS	O
+Ethambutol	POS	O
+-	POS	O
+induced	POS	O
+toxic	POS	O
+optic	POS	B-NP
+neuropathy	POS	I-NP
+was	POS	O
+suspected	POS	O
+and	POS	O
+tablet	POS	O
+ethambutol	POS	O
+was	POS	O
+withdrawn	POS	O
+.	POS	O
+Deterioration	POS	B-NP
+of	POS	I-NP
+vision	POS	I-NP
+occurred	POS	O
+despite	POS	O
+withdrawal	POS	O
+of	POS	O
+ethambutol	POS	O
+.	POS	O
+Discontinuation	POS	O
+of	POS	O
+linezolid	POS	O
+resulted	POS	O
+in	POS	O
+marked	POS	O
+improvement	POS	O
+of	POS	O
+vision	POS	O
+.	POS	O
+Our	POS	O
+report	POS	O
+emphasizes	POS	O
+the	POS	O
+need	POS	O
+for	POS	O
+monitoring	POS	O
+of	POS	O
+visual	POS	O
+function	POS	O
+in	POS	O
+patients	POS	O
+on	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+linezolid	POS	O
+treatment	POS	O
+.	POS	O
+Resuscitation	POS	O
+with	POS	O
+lipid	POS	O
+,	POS	O
+epinephrine	POS	O
+,	POS	O
+or	POS	O
+both	POS	O
+in	POS	O
+levobupivacaine	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+toxicity	POS	I-NP
+in	POS	O
+newborn	POS	O
+piglets	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+The	POS	O
+optimal	POS	O
+dosing	POS	O
+regimens	POS	O
+of	POS	O
+lipid	POS	O
+emulsion	POS	O
+,	POS	O
+epinephrine	POS	O
+,	POS	O
+or	POS	O
+both	POS	O
+are	POS	O
+not	POS	O
+yet	POS	O
+determined	POS	O
+in	POS	O
+neonates	POS	O
+in	POS	O
+cases	POS	O
+of	POS	O
+local	POS	O
+anaesthetic	POS	O
+systemic	POS	B-NP
+toxicity	POS	I-NP
+(	POS	O
+LAST	POS	O
+)	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Newborn	POS	O
+piglets	POS	O
+received	POS	O
+levobupivacaine	POS	O
+until	POS	O
+cardiovascular	POS	B-NP
+collapse	POS	I-NP
+occurred	POS	O
+.	POS	O
+Standard	POS	O
+cardiopulmonary	POS	O
+resuscitation	POS	O
+was	POS	O
+started	POS	O
+and	POS	O
+electrocardiogram	POS	O
+(	POS	O
+ECG	POS	O
+)	POS	O
+was	POS	O
+monitored	POS	O
+for	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+,	POS	O
+fibrillation	POS	B-NP
+,	POS	O
+or	POS	O
+QRS	POS	B-NP
+prolongation	POS	I-NP
+.	POS	O
+Piglets	POS	O
+were	POS	O
+then	POS	O
+randomly	POS	O
+allocated	POS	O
+to	POS	O
+four	POS	O
+groups	POS	O
+:	POS	O
+control	POS	O
+(	POS	O
+saline	POS	O
+)	POS	O
+,	POS	O
+Intralipid	POS	O
+(	POS	O
+)	POS	O
+alone	POS	O
+,	POS	O
+epinephrine	POS	O
+alone	POS	O
+,	POS	O
+or	POS	O
+a	POS	O
+combination	POS	O
+of	POS	O
+Intralipd	POS	O
+plus	POS	O
+epinephrine	POS	O
+.	POS	O
+Resuscitation	POS	O
+continued	POS	O
+for	POS	O
+30	POS	O
+min	POS	O
+or	POS	O
+until	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+return	POS	O
+of	POS	O
+spontaneous	POS	O
+circulation	POS	O
+(	POS	O
+ROSC	POS	O
+)	POS	O
+accompanied	POS	O
+by	POS	O
+a	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+at	POS	O
+or	POS	O
+superior	POS	O
+to	POS	O
+the	POS	O
+baseline	POS	O
+pressure	POS	O
+and	POS	O
+normal	POS	O
+sinus	POS	O
+rhythm	POS	O
+for	POS	O
+a	POS	O
+period	POS	O
+of	POS	O
+30	POS	O
+min	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+ROSC	POS	O
+was	POS	O
+achieved	POS	O
+in	POS	O
+only	POS	O
+one	POS	O
+of	POS	O
+the	POS	O
+control	POS	O
+piglets	POS	O
+compared	POS	O
+with	POS	O
+most	POS	O
+of	POS	O
+the	POS	O
+treated	POS	O
+piglets	POS	O
+.	POS	O
+Mortality	POS	O
+was	POS	O
+not	POS	O
+significantly	POS	O
+different	POS	O
+between	POS	O
+the	POS	O
+three	POS	O
+treatment	POS	O
+groups	POS	O
+,	POS	O
+but	POS	O
+was	POS	O
+significantly	POS	O
+lower	POS	O
+in	POS	O
+all	POS	O
+the	POS	O
+treatment	POS	O
+groups	POS	O
+compared	POS	O
+with	POS	O
+control	POS	O
+.	POS	O
+The	POS	O
+number	POS	O
+of	POS	O
+ECG	POS	B-NP
+abnormalities	POS	I-NP
+was	POS	O
+zero	POS	O
+in	POS	O
+the	POS	O
+Intralipid	POS	O
+only	POS	O
+group	POS	O
+,	POS	O
+but	POS	O
+14	POS	O
+and	POS	O
+17	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+epinephrine	POS	O
+and	POS	O
+epinephrine	POS	O
+plus	POS	O
+lipid	POS	O
+groups	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Lipid	POS	O
+emulsion	POS	O
+with	POS	O
+or	POS	O
+without	POS	O
+epinephrine	POS	O
+,	POS	O
+or	POS	O
+epinephrine	POS	O
+alone	POS	O
+were	POS	O
+equally	POS	O
+effective	POS	O
+in	POS	O
+achieving	POS	O
+a	POS	O
+return	POS	O
+to	POS	O
+spontaneous	POS	O
+circulation	POS	O
+in	POS	O
+this	POS	O
+model	POS	O
+of	POS	O
+LAST	POS	O
+.	POS	O
+Epinephrine	POS	O
+alone	POS	O
+or	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+lipid	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+increased	POS	O
+number	POS	O
+of	POS	O
+ECG	POS	B-NP
+abnormalities	POS	I-NP
+compared	POS	O
+with	POS	O
+lipid	POS	O
+emulsion	POS	O
+alone	POS	O
+.	POS	O
+Incidence	POS	O
+of	POS	O
+heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+type	POS	O
+II	POS	O
+and	POS	O
+postoperative	POS	O
+recovery	POS	O
+of	POS	O
+platelet	POS	O
+count	POS	O
+in	POS	O
+liver	POS	O
+graft	POS	O
+recipients	POS	O
+:	POS	O
+a	POS	O
+retrospective	POS	O
+cohort	POS	O
+analysis	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Thrombocytopenia	POS	B-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+end	POS	O
+-	POS	O
+stage	POS	O
+liver	POS	B-NP
+disease	POS	I-NP
+is	POS	O
+a	POS	O
+common	POS	O
+disorder	POS	O
+caused	POS	O
+mainly	POS	O
+by	POS	O
+portal	POS	O
+hypertension	POS	B-NP
+,	POS	O
+low	POS	O
+levels	POS	O
+of	POS	O
+thrombopoetin	POS	O
+,	POS	O
+and	POS	O
+endotoxemia	POS	B-NP
+.	POS	O
+The	POS	O
+impact	POS	O
+of	POS	O
+immune	POS	O
+-	POS	O
+mediated	POS	O
+heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+type	POS	O
+II	POS	O
+(	POS	O
+HIT	POS	B-NP
+type	POS	O
+II	POS	O
+)	POS	O
+as	POS	O
+a	POS	O
+cause	POS	O
+of	POS	O
+thrombocytopenia	POS	B-NP
+after	POS	O
+liver	POS	O
+transplantation	POS	O
+is	POS	O
+not	POS	O
+yet	POS	O
+understood	POS	O
+,	POS	O
+with	POS	O
+few	POS	O
+literature	POS	O
+citations	POS	O
+reporting	POS	O
+contradictory	POS	O
+results	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+our	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+demonstrate	POS	O
+the	POS	O
+perioperative	POS	O
+course	POS	O
+of	POS	O
+thrombocytopenia	POS	B-NP
+after	POS	O
+liver	POS	O
+transplantation	POS	O
+and	POS	O
+determine	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+clinical	POS	O
+HIT	POS	B-NP
+type	POS	O
+II	POS	O
+.	POS	O
+METHOD	POS	O
+:	POS	O
+We	POS	O
+retrospectively	POS	O
+evaluated	POS	O
+the	POS	O
+medical	POS	O
+records	POS	O
+of	POS	O
+205	POS	O
+consecutive	POS	O
+adult	POS	O
+patients	POS	O
+who	POS	O
+underwent	POS	O
+full	POS	O
+-	POS	O
+size	POS	O
+liver	POS	O
+transplantation	POS	O
+between	POS	O
+January	POS	O
+2006	POS	O
+and	POS	O
+December	POS	O
+2010	POS	O
+due	POS	O
+to	POS	O
+end	POS	O
+-	POS	O
+stage	POS	O
+or	POS	O
+malignant	POS	B-NP
+liver	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+Preoperative	POS	O
+platelet	POS	O
+count	POS	O
+,	POS	O
+postoperative	POS	O
+course	POS	O
+of	POS	O
+platelets	POS	O
+,	POS	O
+and	POS	O
+clinical	POS	O
+signs	POS	O
+of	POS	O
+HIT	POS	B-NP
+type	POS	O
+II	POS	O
+were	POS	O
+analyzed	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+155	POS	O
+(	POS	O
+75	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+)	POS	O
+of	POS	O
+205	POS	O
+patients	POS	O
+had	POS	O
+thrombocytopenia	POS	B-NP
+before	POS	O
+transplantation	POS	O
+,	POS	O
+significantly	POS	O
+influenced	POS	O
+by	POS	O
+Model	POS	O
+of	POS	O
+End	POS	O
+-	POS	O
+Stage	POS	O
+Liver	POS	O
+Disease	POS	O
+score	POS	O
+and	POS	O
+liver	POS	B-NP
+cirrhosis	POS	I-NP
+.	POS	O
+The	POS	O
+platelet	POS	O
+count	POS	O
+exceeded	POS	O
+100	POS	O
+,	POS	O
+000	POS	O
+/	POS	O
+uL	POS	O
+in	POS	O
+most	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+193	POS	O
+)	POS	O
+at	POS	O
+a	POS	O
+medium	POS	O
+of	POS	O
+7	POS	O
+d	POS	O
+.	POS	O
+Regarding	POS	O
+HIT	POS	B-NP
+II	POS	O
+,	POS	O
+there	POS	O
+were	POS	O
+four	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+95	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+with	POS	O
+a	POS	O
+background	POS	O
+of	POS	O
+HIT	POS	B-NP
+type	POS	O
+II	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+HIT	POS	B-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+end	POS	O
+-	POS	O
+stage	POS	O
+hepatic	POS	B-NP
+failure	POS	I-NP
+is	POS	O
+,	POS	O
+with	POS	O
+about	POS	O
+1	POS	O
+.	POS	O
+95	POS	O
+%	POS	O
+,	POS	O
+rare	POS	O
+.	POS	O
+For	POS	O
+further	POS	O
+reduction	POS	O
+of	POS	O
+HIT	POS	B-NP
+type	POS	O
+II	POS	O
+,	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+intravenous	POS	O
+heparin	POS	O
+should	POS	O
+be	POS	O
+avoided	POS	O
+and	POS	O
+the	POS	O
+prophylactic	POS	O
+anticoagulation	POS	O
+should	POS	O
+be	POS	O
+performed	POS	O
+with	POS	O
+low	POS	O
+-	POS	O
+molecular	POS	O
+-	POS	O
+weight	POS	O
+heparin	POS	O
+after	POS	O
+normalization	POS	O
+of	POS	O
+platelet	POS	O
+count	POS	O
+.	POS	O
+Takotsubo	POS	B-NP
+syndrome	POS	I-NP
+(	POS	O
+or	POS	O
+apical	POS	B-NP
+ballooning	POS	I-NP
+syndrome	POS	I-NP
+)	POS	O
+secondary	POS	O
+to	POS	O
+Zolmitriptan	POS	O
+.	POS	O
+Takotsubo	POS	B-NP
+syndrome	POS	I-NP
+(	POS	O
+TS	POS	B-NP
+)	POS	O
+,	POS	O
+also	POS	O
+known	POS	O
+as	POS	O
+broken	POS	O
+heart	POS	B-NP
+syndrome	POS	I-NP
+,	POS	O
+is	POS	O
+characterized	POS	O
+by	POS	O
+left	POS	B-NP
+ventricle	POS	I-NP
+apical	POS	I-NP
+ballooning	POS	I-NP
+with	POS	O
+elevated	POS	O
+cardiac	POS	O
+biomarkers	POS	O
+and	POS	O
+electrocardiographic	POS	O
+changes	POS	O
+suggestive	POS	O
+of	POS	O
+an	POS	O
+acute	POS	O
+coronary	POS	B-NP
+syndrome	POS	I-NP
+(	POS	O
+ie	POS	O
+,	POS	O
+ST	POS	B-NP
+-	POS	I-NP
+segment	POS	I-NP
+elevation	POS	I-NP
+,	POS	O
+T	POS	O
+wave	POS	O
+inversions	POS	O
+,	POS	O
+and	POS	O
+pathologic	POS	O
+Q	POS	O
+waves	POS	O
+)	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+54	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+with	POS	O
+medical	POS	O
+history	POS	O
+of	POS	O
+mitral	POS	B-NP
+valve	POS	I-NP
+prolapse	POS	I-NP
+and	POS	O
+migraines	POS	B-NP
+,	POS	O
+who	POS	O
+was	POS	O
+admitted	POS	O
+to	POS	O
+the	POS	O
+hospital	POS	O
+for	POS	O
+substernal	POS	B-NP
+chest	POS	I-NP
+pain	POS	I-NP
+and	POS	O
+electrocardiogram	POS	O
+demonstrated	POS	O
+1	POS	O
+/	POS	O
+2	POS	O
+mm	POS	O
+ST	POS	O
+-	POS	O
+segment	POS	O
+elevation	POS	O
+in	POS	O
+leads	POS	O
+II	POS	O
+,	POS	O
+III	POS	O
+,	POS	O
+aVF	POS	O
+,	POS	O
+V5	POS	O
+,	POS	O
+and	POS	O
+V6	POS	O
+and	POS	O
+positive	POS	O
+troponin	POS	O
+I	POS	O
+.	POS	O
+Emergent	POS	O
+coronary	POS	O
+angiogram	POS	O
+revealed	POS	O
+normal	POS	O
+coronary	POS	O
+arteries	POS	O
+with	POS	O
+moderately	POS	O
+reduced	POS	O
+left	POS	O
+ventricular	POS	O
+ejection	POS	O
+fraction	POS	O
+with	POS	O
+wall	POS	O
+motion	POS	O
+abnormalities	POS	O
+consistent	POS	O
+with	POS	O
+TS	POS	B-NP
+.	POS	O
+Detailed	POS	O
+history	POS	O
+obtained	POS	O
+retrospectively	POS	O
+revealed	POS	O
+that	POS	O
+the	POS	O
+patient	POS	O
+took	POS	O
+zolmitriptan	POS	O
+sparingly	POS	O
+only	POS	O
+when	POS	O
+she	POS	O
+had	POS	O
+migraines	POS	B-NP
+.	POS	O
+But	POS	O
+before	POS	O
+this	POS	O
+event	POS	O
+,	POS	O
+she	POS	O
+was	POS	O
+taking	POS	O
+zolmitriptan	POS	O
+2	POS	O
+-	POS	O
+3	POS	O
+times	POS	O
+daily	POS	O
+for	POS	O
+several	POS	O
+days	POS	O
+because	POS	O
+of	POS	O
+a	POS	O
+persistent	POS	O
+migraine	POS	B-NP
+headache	POS	I-NP
+.	POS	O
+She	POS	O
+otherwise	POS	O
+reported	POS	O
+that	POS	O
+she	POS	O
+is	POS	O
+quite	POS	O
+active	POS	O
+,	POS	O
+rides	POS	O
+horses	POS	O
+,	POS	O
+and	POS	O
+does	POS	O
+show	POS	O
+jumping	POS	O
+without	POS	O
+any	POS	O
+limitations	POS	O
+in	POS	O
+her	POS	O
+physical	POS	O
+activity	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+evidence	POS	O
+of	POS	O
+any	POS	O
+recent	POS	O
+stress	POS	O
+or	POS	O
+status	POS	B-NP
+migrainosus	POS	I-NP
+.	POS	O
+Extensive	POS	O
+literature	POS	O
+search	POS	O
+revealed	POS	O
+multiple	POS	O
+cases	POS	O
+of	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+vasospasm	POS	I-NP
+secondary	POS	O
+to	POS	O
+zolmitriptan	POS	O
+,	POS	O
+but	POS	O
+none	POS	O
+of	POS	O
+the	POS	O
+cases	POS	O
+were	POS	O
+associated	POS	O
+with	POS	O
+TS	POS	B-NP
+.	POS	O
+Depression	POS	B-NP
+,	POS	O
+impulsiveness	POS	B-NP
+,	POS	O
+sleep	POS	O
+,	POS	O
+and	POS	O
+memory	POS	O
+in	POS	O
+past	POS	O
+and	POS	O
+present	POS	O
+polydrug	POS	O
+users	POS	O
+of	POS	O
+3	POS	O
+,	POS	O
+4	POS	O
+-	POS	O
+methylenedioxymethamphetamine	POS	O
+(	POS	O
+MDMA	POS	O
+,	POS	O
+ecstasy	POS	O
+)	POS	O
+.	POS	O
+RATIONALE	POS	O
+:	POS	O
+Ecstasy	POS	O
+(	POS	O
+3	POS	O
+,	POS	O
+4	POS	O
+-	POS	O
+methylenedioxymethamphetamine	POS	O
+,	POS	O
+MDMA	POS	O
+)	POS	O
+is	POS	O
+a	POS	O
+worldwide	POS	O
+recreational	POS	O
+drug	POS	O
+of	POS	O
+abuse	POS	O
+.	POS	O
+Unfortunately	POS	O
+,	POS	O
+the	POS	O
+results	POS	O
+from	POS	O
+human	POS	O
+research	POS	O
+investigating	POS	O
+its	POS	O
+psychological	POS	O
+effects	POS	O
+have	POS	O
+been	POS	O
+inconsistent	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+aimed	POS	O
+to	POS	O
+be	POS	O
+the	POS	O
+largest	POS	O
+to	POS	O
+date	POS	O
+in	POS	O
+sample	POS	O
+size	POS	O
+and	POS	O
+5HT	POS	O
+-	POS	O
+related	POS	O
+behaviors	POS	O
+;	POS	O
+the	POS	O
+first	POS	O
+to	POS	O
+compare	POS	O
+present	POS	O
+ecstasy	POS	O
+users	POS	O
+with	POS	O
+past	POS	O
+users	POS	O
+after	POS	O
+an	POS	O
+abstinence	POS	O
+of	POS	O
+4	POS	O
+or	POS	O
+more	POS	O
+years	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+first	POS	O
+to	POS	O
+include	POS	O
+robust	POS	O
+controls	POS	O
+for	POS	O
+other	POS	O
+recreational	POS	O
+substances	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+A	POS	O
+sample	POS	O
+of	POS	O
+997	POS	O
+participants	POS	O
+(	POS	O
+52	POS	O
+%	POS	O
+male	POS	O
+)	POS	O
+was	POS	O
+recruited	POS	O
+to	POS	O
+four	POS	O
+control	POS	O
+groups	POS	O
+(	POS	O
+non	POS	O
+-	POS	O
+drug	POS	O
+(	POS	O
+ND	POS	O
+)	POS	O
+,	POS	O
+alcohol	POS	O
+/	POS	O
+nicotine	POS	O
+(	POS	O
+AN	POS	O
+)	POS	O
+,	POS	O
+cannabis	POS	O
+/	POS	O
+alcohol	POS	O
+/	POS	O
+nicotine	POS	O
+(	POS	O
+CAN	POS	O
+)	POS	O
+,	POS	O
+non	POS	B-NP
+-	POS	I-NP
+ecstasy	POS	I-NP
+polydrug	POS	I-NP
+(	POS	O
+PD	POS	B-NP
+)	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+two	POS	O
+ecstasy	POS	O
+polydrug	POS	O
+groups	POS	O
+(	POS	O
+present	POS	O
+(	POS	O
+MDMA	POS	O
+)	POS	O
+and	POS	O
+past	POS	O
+users	POS	O
+(	POS	O
+EX	POS	O
+-	POS	O
+MDMA	POS	O
+)	POS	O
+.	POS	O
+Participants	POS	O
+completed	POS	O
+a	POS	O
+drug	POS	O
+history	POS	O
+questionnaire	POS	O
+,	POS	O
+Beck	POS	O
+Depression	POS	O
+Inventory	POS	O
+,	POS	O
+Barratt	POS	O
+Impulsiveness	POS	O
+Scale	POS	O
+,	POS	O
+Pittsburgh	POS	O
+Sleep	POS	O
+Quality	POS	O
+Index	POS	O
+,	POS	O
+and	POS	O
+Wechsler	POS	O
+Memory	POS	O
+Scale	POS	O
+-	POS	O
+Revised	POS	O
+which	POS	O
+,	POS	O
+in	POS	O
+total	POS	O
+,	POS	O
+provided	POS	O
+13	POS	O
+psychometric	POS	O
+measures	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+While	POS	O
+the	POS	O
+CAN	POS	O
+and	POS	O
+PD	POS	B-NP
+groups	POS	O
+tended	POS	O
+to	POS	O
+record	POS	O
+greater	POS	O
+deficits	POS	O
+than	POS	O
+the	POS	O
+non	POS	O
+-	POS	O
+drug	POS	O
+controls	POS	O
+,	POS	O
+the	POS	O
+MDMA	POS	O
+and	POS	O
+EX	POS	O
+-	POS	O
+MDMA	POS	O
+groups	POS	O
+recorded	POS	O
+greater	POS	O
+deficits	POS	O
+than	POS	O
+all	POS	O
+the	POS	O
+control	POS	O
+groups	POS	O
+on	POS	O
+ten	POS	O
+of	POS	O
+the	POS	O
+13	POS	O
+psychometric	POS	O
+measures	POS	O
+.	POS	O
+Strikingly	POS	O
+,	POS	O
+despite	POS	O
+prolonged	POS	O
+abstinence	POS	O
+(	POS	O
+mean	POS	O
+,	POS	O
+4	POS	O
+.	POS	O
+98	POS	O
+;	POS	O
+range	POS	O
+,	POS	O
+4	POS	O
+-	POS	O
+9	POS	O
+years	POS	O
+)	POS	O
+,	POS	O
+past	POS	O
+ecstasy	POS	O
+users	POS	O
+showed	POS	O
+few	POS	O
+signs	POS	O
+of	POS	O
+recovery	POS	O
+.	POS	O
+Compared	POS	O
+with	POS	O
+present	POS	O
+ecstasy	POS	O
+users	POS	O
+,	POS	O
+the	POS	O
+past	POS	O
+users	POS	O
+showed	POS	O
+no	POS	O
+change	POS	O
+for	POS	O
+ten	POS	O
+measures	POS	O
+,	POS	O
+increased	POS	O
+impairment	POS	O
+for	POS	O
+two	POS	O
+measures	POS	O
+,	POS	O
+and	POS	O
+improvement	POS	O
+on	POS	O
+just	POS	O
+one	POS	O
+measure	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Given	POS	O
+this	POS	O
+record	POS	O
+of	POS	O
+impaired	POS	B-NP
+memory	POS	I-NP
+and	POS	O
+clinically	POS	O
+significant	POS	O
+levels	POS	O
+of	POS	O
+depression	POS	B-NP
+,	POS	O
+impulsiveness	POS	B-NP
+,	POS	O
+and	POS	O
+sleep	POS	B-NP
+disturbance	POS	I-NP
+,	POS	O
+the	POS	O
+prognosis	POS	O
+for	POS	O
+the	POS	O
+current	POS	O
+generation	POS	O
+of	POS	O
+ecstasy	POS	O
+users	POS	O
+is	POS	O
+a	POS	O
+major	POS	O
+cause	POS	O
+for	POS	O
+concern	POS	O
+.	POS	O
+Association	POS	O
+of	POS	O
+common	POS	O
+genetic	POS	O
+variants	POS	O
+of	POS	O
+HOMER1	POS	O
+gene	POS	O
+with	POS	O
+levodopa	POS	O
+adverse	POS	O
+effects	POS	O
+in	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+patients	POS	O
+.	POS	O
+Levodopa	POS	B-NP
+is	POS	O
+the	POS	O
+most	POS	O
+effective	POS	O
+symptomatic	POS	O
+therapy	POS	O
+for	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+,	POS	O
+but	POS	O
+its	POS	O
+chronic	POS	O
+use	POS	O
+could	POS	O
+lead	POS	O
+to	POS	O
+chronic	POS	O
+adverse	POS	O
+outcomes	POS	O
+,	POS	O
+such	POS	O
+as	POS	O
+motor	POS	O
+fluctuations	POS	O
+,	POS	O
+dyskinesia	POS	B-NP
+and	POS	O
+visual	POS	B-NP
+hallucinations	POS	I-NP
+.	POS	O
+HOMER1	POS	O
+is	POS	O
+a	POS	O
+protein	POS	O
+with	POS	O
+pivotal	POS	O
+function	POS	O
+in	POS	O
+glutamate	POS	O
+transmission	POS	O
+,	POS	O
+which	POS	O
+has	POS	O
+been	POS	O
+related	POS	O
+to	POS	O
+the	POS	O
+pathogenesis	POS	O
+of	POS	O
+these	POS	O
+complications	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+investigates	POS	O
+whether	POS	O
+polymorphisms	POS	O
+in	POS	O
+the	POS	O
+HOMER1	POS	O
+gene	POS	O
+promoter	POS	O
+region	POS	O
+are	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+the	POS	O
+chronic	POS	O
+complications	POS	O
+of	POS	O
+levodopa	POS	O
+therapy	POS	O
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+205	POS	O
+patients	POS	O
+with	POS	O
+idiopathic	POS	B-NP
+Parkinson	POS	I-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+were	POS	O
+investigated	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+genotyped	POS	O
+for	POS	O
+rs4704559	POS	O
+,	POS	O
+rs10942891	POS	O
+and	POS	O
+rs4704560	POS	O
+by	POS	O
+allelic	POS	O
+discrimination	POS	O
+with	POS	O
+Taqman	POS	O
+assays	POS	O
+.	POS	O
+The	POS	O
+rs4704559	POS	O
+G	POS	O
+allele	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+a	POS	O
+lower	POS	O
+prevalence	POS	O
+of	POS	O
+dyskinesia	POS	B-NP
+(	POS	O
+prevalence	POS	O
+ratio	POS	O
+(	POS	O
+PR	POS	O
+)	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+615	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+(	POS	O
+CI	POS	O
+)	POS	O
+0	POS	O
+.	POS	O
+426	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+887	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+009	POS	O
+)	POS	O
+and	POS	O
+visual	POS	B-NP
+hallucinations	POS	I-NP
+(	POS	O
+PR	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+515	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+0	POS	O
+.	POS	O
+295	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+899	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+020	POS	O
+)	POS	O
+.	POS	O
+Our	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+HOMER1	POS	O
+rs4704559	POS	O
+G	POS	O
+allele	POS	O
+has	POS	O
+a	POS	O
+protective	POS	O
+role	POS	O
+for	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+levodopa	POS	O
+adverse	POS	O
+effects	POS	O
+.	POS	O
+Crocin	POS	O
+improves	POS	O
+lipid	POS	O
+dysregulation	POS	O
+in	POS	O
+subacute	POS	O
+diazinon	POS	O
+exposure	POS	O
+through	POS	O
+ERK1	POS	O
+/	POS	O
+2	POS	O
+pathway	POS	O
+in	POS	O
+rat	POS	O
+liver	POS	O
+.	POS	O
+INTRODUCTION	POS	O
+:	POS	O
+Diazinon	POS	O
+Yis	POS	O
+one	POS	O
+of	POS	O
+the	POS	O
+most	POS	O
+broadly	POS	O
+used	POS	O
+organophosphorus	POS	O
+insecticides	POS	O
+in	POS	O
+agriculture	POS	O
+.	POS	O
+It	POS	O
+has	POS	O
+been	POS	O
+shown	POS	O
+that	POS	O
+exposure	POS	O
+to	POS	O
+diazinon	POS	O
+may	POS	O
+interfere	POS	O
+with	POS	O
+lipid	POS	O
+metabolism	POS	O
+.	POS	O
+Moreover	POS	O
+,	POS	O
+the	POS	O
+hypolipidemic	POS	O
+effect	POS	O
+of	POS	O
+crocin	POS	O
+has	POS	O
+been	POS	O
+established	POS	O
+.	POS	O
+Earlier	POS	O
+studies	POS	O
+revealed	POS	O
+the	POS	O
+major	POS	O
+role	POS	O
+of	POS	O
+Extracellular	POS	O
+signal	POS	O
+-	POS	O
+regulated	POS	O
+kinase	POS	O
+(	POS	O
+ERK	POS	O
+)	POS	O
+pathways	POS	O
+in	POS	O
+low	POS	O
+-	POS	O
+density	POS	O
+lipoprotein	POS	O
+receptor	POS	O
+(	POS	O
+LDLr	POS	O
+)	POS	O
+expression	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+evaluate	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+regulation	POS	O
+of	POS	O
+lipid	POS	O
+metabolism	POS	O
+,	POS	O
+ERK	POS	O
+and	POS	O
+LDLr	POS	O
+expression	POS	O
+in	POS	O
+the	POS	O
+liver	POS	O
+of	POS	O
+rats	POS	O
+exposed	POS	O
+to	POS	O
+subacute	POS	O
+diazinon	POS	O
+.	POS	O
+Furthermore	POS	O
+ameliorating	POS	O
+effect	POS	O
+of	POS	O
+crocin	POS	O
+on	POS	O
+diazinon	POS	O
+induced	POS	O
+disturbed	POS	O
+cholesterol	POS	O
+homeostasis	POS	O
+was	POS	O
+studied	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+24	POS	O
+Rats	POS	O
+were	POS	O
+divided	POS	O
+into	POS	O
+4	POS	O
+groups	POS	O
+and	POS	O
+received	POS	O
+following	POS	O
+treatments	POS	O
+for	POS	O
+4	POS	O
+weeks	POS	O
+;	POS	O
+Corn	POS	O
+oil	POS	O
+(	POS	O
+control	POS	O
+)	POS	O
+,	POS	O
+diazinon	POS	O
+(	POS	O
+15mg	POS	O
+/	POS	O
+kg	POS	O
+per	POS	O
+day	POS	O
+,	POS	O
+orally	POS	O
+)	POS	O
+and	POS	O
+crocin	POS	O
+(	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+and	POS	O
+25mg	POS	O
+/	POS	O
+kg	POS	O
+per	POS	O
+day	POS	O
+,	POS	O
+intraperitoneally	POS	O
+)	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+diazinon	POS	O
+(	POS	O
+15	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+levels	POS	O
+of	POS	O
+cholesterol	POS	O
+,	POS	O
+triglyceride	POS	O
+and	POS	O
+LDL	POS	O
+in	POS	O
+blood	POS	O
+of	POS	O
+rats	POS	O
+were	POS	O
+analyzed	POS	O
+.	POS	O
+Moreover	POS	O
+mRNA	POS	O
+levels	POS	O
+of	POS	O
+LDLr	POS	O
+and	POS	O
+ERK1	POS	O
+/	POS	O
+2	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+protein	POS	O
+levels	POS	O
+of	POS	O
+total	POS	O
+and	POS	O
+activated	POS	O
+forms	POS	O
+of	POS	O
+ERK1	POS	O
+/	POS	O
+2	POS	O
+in	POS	O
+rat	POS	O
+liver	POS	O
+were	POS	O
+evaluated	POS	O
+by	POS	O
+Western	POS	O
+blotting	POS	O
+and	POS	O
+quantitative	POS	O
+real	POS	O
+time	POS	O
+polymerase	POS	O
+chain	POS	O
+reaction	POS	O
+analysis	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Our	POS	O
+data	POS	O
+showed	POS	O
+that	POS	O
+subacute	POS	O
+exposure	POS	O
+to	POS	O
+diazinon	POS	O
+significantly	POS	O
+increased	POS	O
+concentrations	POS	O
+of	POS	O
+cholesterol	POS	O
+,	POS	O
+triglyceride	POS	O
+and	POS	O
+LDL	POS	O
+.	POS	O
+Moreover	POS	O
+diazinon	POS	O
+decreased	POS	O
+ERK1	POS	O
+/	POS	O
+2	POS	O
+protein	POS	O
+phosphorylation	POS	O
+and	POS	O
+LDLr	POS	O
+transcript	POS	O
+.	POS	O
+Crocin	POS	O
+reduced	POS	O
+inhibition	POS	O
+of	POS	O
+ERK	POS	O
+activation	POS	O
+and	POS	O
+diazinon	POS	O
+-	POS	O
+induced	POS	O
+hyperlipemia	POS	B-NP
+and	POS	O
+increased	POS	O
+levels	POS	O
+of	POS	O
+LDLr	POS	O
+transcript	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Crocin	POS	O
+may	POS	O
+be	POS	O
+considered	POS	O
+as	POS	O
+a	POS	O
+novel	POS	O
+protective	POS	O
+agent	POS	O
+in	POS	O
+diazinon	POS	O
+-	POS	O
+induced	POS	O
+hyperlipemia	POS	B-NP
+through	POS	O
+modulating	POS	O
+of	POS	O
+ERK	POS	O
+pathway	POS	O
+and	POS	O
+increase	POS	O
+of	POS	O
+LDLr	POS	O
+expression	POS	O
+.	POS	O
+GEM	POS	O
+-	POS	O
+P	POS	O
+chemotherapy	POS	O
+is	POS	O
+active	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+relapsed	POS	B-NP
+Hodgkin	POS	I-NP
+lymphoma	POS	I-NP
+.	POS	O
+Hodgkin	POS	B-NP
+lymphoma	POS	I-NP
+(	POS	O
+HL	POS	B-NP
+)	POS	O
+is	POS	O
+a	POS	O
+relatively	POS	O
+chemosensitive	POS	B-NP
+malignancy	POS	I-NP
+.	POS	O
+However	POS	O
+,	POS	O
+for	POS	O
+those	POS	O
+who	POS	O
+relapse	POS	O
+,	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+chemotherapy	POS	O
+with	POS	O
+autologous	POS	O
+stem	POS	O
+cell	POS	O
+transplant	POS	O
+is	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+choice	POS	O
+which	POS	O
+relies	POS	O
+on	POS	O
+adequate	POS	O
+disease	POS	O
+control	POS	O
+with	POS	O
+salvage	POS	O
+chemotherapy	POS	O
+.	POS	O
+Regimens	POS	O
+commonly	POS	O
+used	POS	O
+often	POS	O
+require	POS	O
+inpatient	POS	O
+administration	POS	O
+and	POS	O
+can	POS	O
+be	POS	O
+difficult	POS	O
+to	POS	O
+deliver	POS	O
+due	POS	O
+to	POS	O
+toxicity	POS	B-NP
+.	POS	O
+Gemcitabine	POS	O
+and	POS	O
+cisplatin	POS	O
+have	POS	O
+activity	POS	O
+in	POS	O
+HL	POS	B-NP
+,	POS	O
+non	POS	B-NP
+-	POS	I-NP
+overlapping	POS	I-NP
+toxicity	POS	I-NP
+with	POS	O
+first	POS	O
+-	POS	O
+line	POS	O
+chemotherapeutics	POS	O
+,	POS	O
+and	POS	O
+may	POS	O
+be	POS	O
+delivered	POS	O
+in	POS	O
+an	POS	O
+outpatient	POS	O
+setting	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+retrospective	POS	O
+single	POS	O
+-	POS	O
+centre	POS	O
+analysis	POS	O
+,	POS	O
+patients	POS	O
+with	POS	O
+relapsed	POS	O
+or	POS	O
+refractory	POS	O
+HL	POS	B-NP
+treated	POS	O
+with	POS	O
+gemcitabine	POS	O
+1	POS	O
+,	POS	O
+000	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+day	POS	O
+(	POS	O
+D	POS	O
+)	POS	O
+1	POS	O
+,	POS	O
+D8	POS	O
+and	POS	O
+D15	POS	O
+;	POS	O
+methylprednisolone	POS	O
+1	POS	O
+,	POS	O
+000	POS	O
+mg	POS	O
+D1	POS	O
+-	POS	O
+5	POS	O
+;	POS	O
+and	POS	O
+cisplatin	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+D15	POS	O
+,	POS	O
+every	POS	O
+28	POS	O
+days	POS	O
+(	POS	O
+GEM	POS	O
+-	POS	O
+P	POS	O
+)	POS	O
+were	POS	O
+included	POS	O
+.	POS	O
+Demographic	POS	O
+,	POS	O
+survival	POS	O
+,	POS	O
+response	POS	O
+and	POS	O
+toxicity	POS	B-NP
+data	POS	O
+were	POS	O
+recorded	POS	O
+.	POS	O
+Forty	POS	O
+-	POS	O
+one	POS	O
+eligible	POS	O
+patients	POS	O
+were	POS	O
+identified	POS	O
+:	POS	O
+median	POS	O
+age	POS	O
+27	POS	O
+.	POS	O
+One	POS	O
+hundred	POS	O
+and	POS	O
+twenty	POS	O
+-	POS	O
+two	POS	O
+cycles	POS	O
+of	POS	O
+GEM	POS	O
+-	POS	O
+P	POS	O
+were	POS	O
+administered	POS	O
+in	POS	O
+total	POS	O
+(	POS	O
+median	POS	O
+3	POS	O
+cycles	POS	O
+;	POS	O
+range	POS	O
+1	POS	O
+-	POS	O
+6	POS	O
+)	POS	O
+.	POS	O
+Twenty	POS	O
+of	POS	O
+41	POS	O
+(	POS	O
+48	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+received	POS	O
+GEM	POS	O
+-	POS	O
+P	POS	O
+as	POS	O
+second	POS	O
+-	POS	O
+line	POS	O
+treatment	POS	O
+and	POS	O
+11	POS	O
+/	POS	O
+41	POS	O
+(	POS	O
+27	POS	O
+%	POS	O
+)	POS	O
+as	POS	O
+third	POS	O
+-	POS	O
+line	POS	O
+therapy	POS	O
+.	POS	O
+Overall	POS	O
+response	POS	O
+rate	POS	O
+(	POS	O
+ORR	POS	O
+)	POS	O
+to	POS	O
+GEM	POS	O
+-	POS	O
+P	POS	O
+in	POS	O
+the	POS	O
+entire	POS	O
+cohort	POS	O
+was	POS	O
+80	POS	O
+%	POS	O
+(	POS	O
+complete	POS	O
+response	POS	O
+(	POS	O
+CR	POS	O
+)	POS	O
+37	POS	O
+%	POS	O
+,	POS	O
+partial	POS	O
+response	POS	O
+44	POS	O
+%	POS	O
+)	POS	O
+with	POS	O
+14	POS	O
+/	POS	O
+15	POS	O
+CR	POS	O
+confirmed	POS	O
+as	POS	O
+a	POS	O
+metabolic	POS	O
+CR	POS	O
+on	POS	O
+PET	POS	O
+and	POS	O
+ORR	POS	O
+of	POS	O
+85	POS	O
+%	POS	O
+in	POS	O
+the	POS	O
+20	POS	O
+second	POS	O
+-	POS	O
+line	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+most	POS	O
+common	POS	O
+grade	POS	O
+3	POS	O
+/	POS	O
+4	POS	O
+toxicities	POS	B-NP
+were	POS	O
+haematological	POS	B-NP
+:	POS	O
+neutropenia	POS	B-NP
+54	POS	O
+%	POS	O
+and	POS	O
+thrombocytopenia	POS	B-NP
+51	POS	O
+%	POS	O
+.	POS	O
+Median	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+from	POS	O
+the	POS	O
+start	POS	O
+of	POS	O
+GEM	POS	O
+-	POS	O
+P	POS	O
+was	POS	O
+4	POS	O
+.	POS	O
+5	POS	O
+years	POS	O
+.	POS	O
+Following	POS	O
+GEM	POS	O
+-	POS	O
+P	POS	O
+,	POS	O
+5	POS	O
+-	POS	O
+year	POS	O
+progression	POS	O
+-	POS	O
+free	POS	O
+survival	POS	O
+was	POS	O
+46	POS	O
+%	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+(	POS	O
+CI	POS	O
+)	POS	O
+,	POS	O
+30	POS	O
+-	POS	O
+62	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+5	POS	O
+-	POS	O
+year	POS	O
+overall	POS	O
+survival	POS	O
+was	POS	O
+59	POS	O
+%	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+,	POS	O
+43	POS	O
+-	POS	O
+74	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Fourteen	POS	O
+of	POS	O
+41	POS	O
+patients	POS	O
+proceeded	POS	O
+directly	POS	O
+to	POS	O
+autologous	POS	O
+transplant	POS	O
+.	POS	O
+GEM	POS	O
+-	POS	O
+P	POS	O
+is	POS	O
+a	POS	O
+salvage	POS	O
+chemotherapy	POS	O
+with	POS	O
+relatively	POS	O
+high	POS	O
+response	POS	O
+rates	POS	O
+,	POS	O
+leading	POS	O
+to	POS	O
+successful	POS	O
+transplantation	POS	O
+in	POS	O
+appropriate	POS	O
+patients	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+relapsed	POS	O
+or	POS	O
+refractory	POS	O
+HL	POS	B-NP
+.	POS	O
+Basal	POS	B-NP
+functioning	POS	I-NP
+of	POS	I-NP
+the	POS	I-NP
+hypothalamic	POS	I-NP
+-	POS	I-NP
+pituitary	POS	I-NP
+-	POS	I-NP
+adrenal	POS	I-NP
+(	POS	I-NP
+HPA	POS	I-NP
+)	POS	I-NP
+axis	POS	I-NP
+and	POS	I-NP
+psychological	POS	I-NP
+distress	POS	I-NP
+in	POS	O
+recreational	POS	O
+ecstasy	POS	O
+polydrug	POS	O
+users	POS	O
+.	POS	O
+RATIONALE	POS	O
+:	POS	O
+Ecstasy	POS	O
+(	POS	O
+MDMA	POS	O
+)	POS	O
+is	POS	O
+a	POS	O
+psychostimulant	POS	O
+drug	POS	O
+which	POS	O
+is	POS	O
+increasingly	POS	O
+associated	POS	O
+with	POS	O
+psychobiological	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+While	POS	O
+some	POS	O
+recent	POS	O
+studies	POS	O
+suggest	POS	O
+acute	POS	O
+changes	POS	O
+in	POS	O
+neuroendocrine	POS	O
+function	POS	O
+,	POS	O
+less	POS	O
+is	POS	O
+known	POS	O
+about	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+changes	POS	O
+in	POS	O
+HPA	POS	O
+functionality	POS	O
+in	POS	O
+recreational	POS	O
+users	POS	O
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+The	POS	O
+current	POS	O
+study	POS	O
+is	POS	O
+the	POS	O
+first	POS	O
+to	POS	O
+explore	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+ecstasy	POS	O
+-	POS	O
+polydrug	POS	O
+use	POS	O
+on	POS	O
+psychological	POS	O
+distress	POS	O
+and	POS	O
+basal	POS	O
+functioning	POS	O
+of	POS	O
+the	POS	O
+HPA	POS	O
+axis	POS	O
+through	POS	O
+assessing	POS	O
+the	POS	O
+secretion	POS	O
+of	POS	O
+cortisol	POS	O
+across	POS	O
+the	POS	O
+diurnal	POS	O
+period	POS	O
+.	POS	O
+METHOD	POS	O
+:	POS	O
+Seventy	POS	O
+-	POS	O
+six	POS	O
+participants	POS	O
+(	POS	O
+21	POS	O
+nonusers	POS	O
+,	POS	O
+29	POS	O
+light	POS	O
+ecstasy	POS	O
+-	POS	O
+polydrug	POS	O
+users	POS	O
+,	POS	O
+26	POS	O
+heavy	POS	O
+ecstasy	POS	O
+-	POS	O
+polydrug	POS	O
+users	POS	O
+)	POS	O
+completed	POS	O
+a	POS	O
+substance	POS	O
+use	POS	O
+inventory	POS	O
+and	POS	O
+measures	POS	O
+of	POS	O
+psychological	POS	O
+distress	POS	O
+at	POS	O
+baseline	POS	O
+,	POS	O
+then	POS	O
+two	POS	O
+consecutive	POS	O
+days	POS	O
+of	POS	O
+cortisol	POS	O
+sampling	POS	O
+(	POS	O
+on	POS	O
+awakening	POS	O
+,	POS	O
+30	POS	O
+min	POS	O
+post	POS	O
+awakening	POS	O
+,	POS	O
+between	POS	O
+1400	POS	O
+and	POS	O
+1600	POS	O
+hours	POS	O
+and	POS	O
+pre	POS	O
+bedtime	POS	O
+)	POS	O
+.	POS	O
+On	POS	O
+day	POS	O
+2	POS	O
+,	POS	O
+participants	POS	O
+also	POS	O
+attended	POS	O
+the	POS	O
+laboratory	POS	O
+to	POS	O
+complete	POS	O
+a	POS	O
+20	POS	O
+-	POS	O
+min	POS	O
+multitasking	POS	O
+stressor	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Both	POS	O
+user	POS	O
+groups	POS	O
+exhibited	POS	O
+significantly	POS	O
+greater	POS	O
+levels	POS	O
+of	POS	O
+anxiety	POS	B-NP
+and	POS	O
+depression	POS	B-NP
+than	POS	O
+nonusers	POS	O
+.	POS	O
+On	POS	O
+day	POS	O
+1	POS	O
+,	POS	O
+all	POS	O
+participants	POS	O
+exhibited	POS	O
+a	POS	O
+typical	POS	O
+cortisol	POS	O
+profile	POS	O
+,	POS	O
+though	POS	O
+light	POS	O
+users	POS	O
+had	POS	O
+significantly	POS	O
+elevated	POS	O
+levels	POS	O
+pre	POS	O
+-	POS	O
+bed	POS	O
+.	POS	O
+On	POS	O
+day	POS	O
+2	POS	O
+,	POS	O
+heavy	POS	O
+users	POS	O
+demonstrated	POS	O
+elevated	POS	O
+levels	POS	O
+upon	POS	O
+awakening	POS	O
+and	POS	O
+all	POS	O
+ecstasy	POS	O
+-	POS	O
+polydrug	POS	O
+users	POS	O
+demonstrated	POS	O
+elevated	POS	O
+pre	POS	O
+-	POS	O
+bed	POS	O
+levels	POS	O
+compared	POS	O
+to	POS	O
+non	POS	O
+-	POS	O
+users	POS	O
+.	POS	O
+Significant	POS	O
+between	POS	O
+group	POS	O
+differences	POS	O
+were	POS	O
+also	POS	O
+observed	POS	O
+in	POS	O
+afternoon	POS	O
+cortisol	POS	O
+levels	POS	O
+and	POS	O
+in	POS	O
+overall	POS	O
+cortisol	POS	O
+secretion	POS	O
+across	POS	O
+the	POS	O
+day	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+increases	POS	O
+in	POS	O
+anxiety	POS	B-NP
+and	POS	O
+depression	POS	B-NP
+are	POS	O
+in	POS	O
+line	POS	O
+with	POS	O
+previous	POS	O
+observations	POS	O
+in	POS	O
+recreational	POS	O
+ecstasy	POS	O
+-	POS	O
+polydrug	POS	O
+users	POS	O
+.	POS	O
+Dysregulated	POS	O
+diurnal	POS	O
+cortisol	POS	O
+may	POS	O
+be	POS	O
+indicative	POS	O
+of	POS	O
+inappropriate	POS	O
+anticipation	POS	O
+of	POS	O
+forthcoming	POS	O
+demands	POS	O
+and	POS	O
+hypersecretion	POS	B-NP
+may	POS	O
+lead	POS	O
+to	POS	O
+the	POS	O
+increased	POS	O
+psychological	POS	O
+and	POS	O
+physical	POS	O
+morbidity	POS	O
+associated	POS	O
+with	POS	O
+heavy	POS	O
+recreational	POS	O
+use	POS	O
+of	POS	O
+ecstasy	POS	O
+.	POS	O
+Ifosfamide	POS	O
+related	POS	O
+encephalopathy	POS	B-NP
+:	POS	O
+the	POS	O
+need	POS	O
+for	POS	O
+a	POS	O
+timely	POS	O
+EEG	POS	O
+evaluation	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Ifosfamide	POS	O
+is	POS	O
+an	POS	O
+alkylating	POS	O
+agent	POS	O
+useful	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+a	POS	O
+wide	POS	O
+range	POS	O
+of	POS	O
+cancers	POS	B-NP
+including	POS	O
+sarcomas	POS	B-NP
+,	POS	O
+lymphoma	POS	B-NP
+,	POS	O
+gynecologic	POS	B-NP
+and	POS	O
+testicular	POS	B-NP
+cancers	POS	I-NP
+.	POS	O
+Encephalopathy	POS	B-NP
+has	POS	O
+been	POS	O
+reported	POS	O
+in	POS	O
+10	POS	O
+-	POS	O
+40	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+receiving	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+IV	POS	O
+ifosfamide	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+highlight	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+electroencephalogram	POS	O
+(	POS	O
+EEG	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+early	POS	O
+detection	POS	O
+and	POS	O
+management	POS	O
+of	POS	O
+ifosfamide	POS	O
+related	POS	O
+encephalopathy	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Retrospective	POS	O
+chart	POS	O
+review	POS	O
+including	POS	O
+clinical	POS	O
+data	POS	O
+and	POS	O
+EEG	POS	O
+recordings	POS	O
+was	POS	O
+done	POS	O
+on	POS	O
+five	POS	O
+patients	POS	O
+,	POS	O
+admitted	POS	O
+to	POS	O
+MD	POS	O
+Anderson	POS	O
+Cancer	POS	O
+Center	POS	O
+between	POS	O
+years	POS	O
+2009	POS	O
+and	POS	O
+2012	POS	O
+,	POS	O
+who	POS	O
+developed	POS	O
+ifosfamide	POS	O
+related	POS	O
+acute	POS	B-NP
+encephalopathy	POS	I-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+All	POS	O
+five	POS	O
+patients	POS	O
+experienced	POS	O
+symptoms	POS	O
+of	POS	O
+encephalopathy	POS	B-NP
+soon	POS	O
+after	POS	O
+(	POS	O
+within	POS	O
+12	POS	O
+h	POS	O
+-	POS	O
+2	POS	O
+days	POS	O
+)	POS	O
+receiving	POS	O
+ifosfamide	POS	O
+.	POS	O
+Two	POS	O
+patients	POS	O
+developed	POS	O
+generalized	POS	O
+convulsions	POS	B-NP
+while	POS	O
+one	POS	O
+patient	POS	O
+developed	POS	O
+continuous	POS	O
+non	POS	O
+-	POS	O
+convulsive	POS	B-NP
+status	POS	I-NP
+epilepticus	POS	I-NP
+(	POS	O
+NCSE	POS	B-NP
+)	POS	O
+that	POS	O
+required	POS	O
+ICU	POS	O
+admission	POS	O
+and	POS	O
+intubation	POS	O
+.	POS	O
+Initial	POS	O
+EEG	POS	O
+showed	POS	O
+epileptiform	POS	O
+discharges	POS	O
+in	POS	O
+three	POS	O
+patients	POS	O
+;	POS	O
+run	POS	O
+of	POS	O
+triphasic	POS	O
+waves	POS	O
+in	POS	O
+one	POS	O
+patient	POS	O
+and	POS	O
+moderate	POS	O
+degree	POS	O
+diffuse	POS	O
+generalized	POS	O
+slowing	POS	O
+.	POS	O
+Mixed	POS	O
+pattern	POS	O
+with	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+both	POS	O
+sharps	POS	O
+and	POS	O
+triphasic	POS	O
+waves	POS	O
+were	POS	O
+also	POS	O
+noted	POS	O
+.	POS	O
+Repeat	POS	O
+EEGs	POS	O
+within	POS	O
+24	POS	O
+_	POS	O
+h	POS	O
+of	POS	O
+symptom	POS	O
+onset	POS	O
+showed	POS	O
+marked	POS	O
+improvement	POS	O
+that	POS	O
+was	POS	O
+correlated	POS	O
+with	POS	O
+clinical	POS	O
+improvement	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Severity	POS	O
+of	POS	O
+ifosfamide	POS	O
+related	POS	O
+encephalopathy	POS	B-NP
+correlates	POS	O
+with	POS	O
+EEG	POS	O
+changes	POS	O
+.	POS	O
+We	POS	O
+suggest	POS	O
+a	POS	O
+timely	POS	O
+EEG	POS	O
+evaluation	POS	O
+for	POS	O
+patients	POS	O
+receiving	POS	O
+ifosfamide	POS	O
+who	POS	O
+develop	POS	O
+features	POS	O
+of	POS	O
+encephalopathy	POS	B-NP
+.	POS	O
+Incidence	POS	O
+of	POS	O
+contrast	POS	O
+-	POS	O
+induced	POS	O
+nephropathy	POS	B-NP
+in	POS	O
+hospitalised	POS	O
+patients	POS	O
+with	POS	O
+cancer	POS	B-NP
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+To	POS	O
+determine	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+and	POS	O
+possible	POS	O
+factors	POS	O
+related	POS	O
+to	POS	O
+contrast	POS	O
+-	POS	O
+induced	POS	O
+nephropathy	POS	B-NP
+(	POS	O
+CIN	POS	B-NP
+)	POS	O
+in	POS	O
+hospitalised	POS	O
+patients	POS	O
+with	POS	O
+cancer	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Ninety	POS	O
+adult	POS	O
+patients	POS	O
+were	POS	O
+enrolled	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+were	POS	O
+excluded	POS	O
+.	POS	O
+Blood	POS	O
+samples	POS	O
+were	POS	O
+examined	POS	O
+the	POS	O
+day	POS	O
+before	POS	O
+contrast	POS	O
+-	POS	O
+enhanced	POS	O
+computed	POS	O
+tomography	POS	O
+(	POS	O
+CT	POS	O
+)	POS	O
+and	POS	O
+serially	POS	O
+for	POS	O
+3	POS	O
+days	POS	O
+thereafter	POS	O
+.	POS	O
+CIN	POS	B-NP
+was	POS	O
+defined	POS	O
+as	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+serum	POS	O
+creatinine	POS	O
+(	POS	O
+Cr	POS	O
+)	POS	O
+of	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+or	POS	O
+more	POS	O
+,	POS	O
+or	POS	O
+elevation	POS	O
+of	POS	O
+Cr	POS	O
+to	POS	O
+25	POS	O
+%	POS	O
+over	POS	O
+baseline	POS	O
+.	POS	O
+Relationships	POS	O
+between	POS	O
+CIN	POS	B-NP
+and	POS	O
+possible	POS	O
+risk	POS	O
+factors	POS	O
+were	POS	O
+investigated	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+CIN	POS	B-NP
+was	POS	O
+detected	POS	O
+in	POS	O
+18	POS	O
+/	POS	O
+90	POS	O
+(	POS	O
+20	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+.	POS	O
+CIN	POS	B-NP
+developed	POS	O
+in	POS	O
+25	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+patients	POS	O
+who	POS	O
+underwent	POS	O
+chemotherapy	POS	O
+and	POS	O
+in	POS	O
+11	POS	O
+%	POS	O
+patients	POS	O
+who	POS	O
+did	POS	O
+not	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+)	POS	O
+.	POS	O
+CIN	POS	B-NP
+more	POS	O
+frequently	POS	O
+developed	POS	O
+in	POS	O
+patients	POS	O
+who	POS	O
+had	POS	O
+undergone	POS	O
+CT	POS	O
+within	POS	O
+45	POS	O
+days	POS	O
+after	POS	O
+the	POS	O
+last	POS	O
+chemotherapy	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+005	POS	O
+)	POS	O
+;	POS	O
+it	POS	O
+was	POS	O
+also	POS	O
+an	POS	O
+independent	POS	O
+risk	POS	O
+factor	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+017	POS	O
+)	POS	O
+.	POS	O
+CIN	POS	B-NP
+was	POS	O
+significantly	POS	O
+more	POS	O
+after	POS	O
+treatment	POS	O
+with	POS	O
+bevacizumab	POS	O
+/	POS	O
+irinotecan	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+021	POS	O
+)	POS	O
+and	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+hypertension	POS	B-NP
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+044	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+CIN	POS	B-NP
+after	POS	O
+CT	POS	O
+in	POS	O
+hospitalised	POS	O
+oncological	POS	O
+patients	POS	O
+was	POS	O
+20	POS	O
+%	POS	O
+.	POS	O
+CIN	POS	B-NP
+developed	POS	O
+4	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+times	POS	O
+more	POS	O
+frequently	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+cancer	POS	B-NP
+who	POS	O
+had	POS	O
+undergone	POS	O
+recent	POS	O
+chemotherapy	POS	O
+.	POS	O
+Hypertension	POS	B-NP
+and	POS	O
+the	POS	O
+combination	POS	O
+of	POS	O
+bevacizumab	POS	O
+/	POS	O
+irinotecan	POS	O
+may	POS	O
+be	POS	O
+additional	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+CIN	POS	B-NP
+development	POS	O
+.	POS	O
+KEY	POS	O
+POINTS	POS	O
+:	POS	O
+.	POS	O
+Contrast	POS	O
+-	POS	O
+induced	POS	O
+nephropathy	POS	B-NP
+(	POS	O
+CIN	POS	B-NP
+)	POS	O
+is	POS	O
+a	POS	O
+concern	POS	O
+for	POS	O
+oncological	POS	O
+patients	POS	O
+undergoing	POS	O
+CT	POS	O
+.	POS	O
+.	POS	O
+CIN	POS	B-NP
+occurs	POS	O
+more	POS	O
+often	POS	O
+when	POS	O
+CT	POS	O
+is	POS	O
+performed	POS	O
+<	POS	O
+45	POS	O
+days	POS	O
+after	POS	O
+chemotherapy	POS	O
+.	POS	O
+.	POS	O
+Hypertension	POS	B-NP
+and	POS	O
+treatment	POS	O
+with	POS	O
+bevacizumab	POS	O
+appear	POS	O
+to	POS	O
+be	POS	O
+additional	POS	O
+risk	POS	O
+factors	POS	O
+.	POS	O
+Syndrome	POS	B-NP
+of	POS	I-NP
+inappropriate	POS	I-NP
+antidiuretic	POS	I-NP
+hormone	POS	I-NP
+secretion	POS	I-NP
+associated	POS	O
+with	POS	O
+desvenlafaxine	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+syndrome	POS	O
+of	POS	O
+inappropriate	POS	O
+anti	POS	O
+-	POS	O
+diuretic	POS	O
+hormone	POS	O
+(	POS	O
+SIADH	POS	B-NP
+)	POS	O
+secretion	POS	O
+associated	POS	O
+with	POS	O
+desvenlafaxine	POS	O
+.	POS	O
+CASE	POS	O
+SUMMARY	POS	O
+:	POS	O
+A	POS	O
+57	POS	O
+-	POS	O
+year	POS	O
+old	POS	O
+female	POS	O
+with	POS	O
+hyponatraemia	POS	B-NP
+.	POS	O
+Her	POS	O
+medications	POS	O
+included	POS	O
+desvenlafaxine	POS	O
+,	POS	O
+and	POS	O
+symptoms	POS	O
+included	POS	O
+nausea	POS	B-NP
+,	POS	O
+anxiety	POS	B-NP
+and	POS	O
+confusion	POS	B-NP
+.	POS	O
+The	POS	O
+serum	POS	O
+sodium	POS	O
+at	POS	O
+this	POS	O
+time	POS	O
+was	POS	O
+120	POS	O
+mmol	POS	O
+/	POS	O
+L	POS	O
+,	POS	O
+serum	POS	O
+osmolality	POS	O
+was	POS	O
+263	POS	O
+mosmol	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+urine	POS	O
+osmolality	POS	O
+410	POS	O
+mosmol	POS	O
+/	POS	O
+kg	POS	O
+and	POS	O
+urine	POS	O
+sodium	POS	O
+63	POS	O
+mmol	POS	O
+/	POS	O
+L	POS	O
+,	POS	O
+consistent	POS	O
+with	POS	O
+a	POS	O
+diagnosis	POS	O
+of	POS	O
+SIADH	POS	B-NP
+.	POS	O
+Desvenlafaxine	POS	O
+was	POS	O
+ceased	POS	O
+and	POS	O
+fluid	POS	O
+restriction	POS	O
+implemented	POS	O
+.	POS	O
+After	POS	O
+4	POS	O
+days	POS	O
+the	POS	O
+sodium	POS	O
+increased	POS	O
+to	POS	O
+128	POS	O
+mmol	POS	O
+/	POS	O
+L	POS	O
+and	POS	O
+fluid	POS	O
+restriction	POS	O
+was	POS	O
+relaxed	POS	O
+.	POS	O
+During	POS	O
+her	POS	O
+further	POS	O
+3	POS	O
+weeks	POS	O
+inpatient	POS	O
+admission	POS	O
+the	POS	O
+serum	POS	O
+sodium	POS	O
+ranged	POS	O
+from	POS	O
+134	POS	O
+to	POS	O
+137	POS	O
+mmol	POS	O
+/	POS	O
+L	POS	O
+during	POS	O
+treatment	POS	O
+with	POS	O
+mirtazapine	POS	O
+.	POS	O
+DISCUSSION	POS	O
+:	POS	O
+SIADH	POS	B-NP
+has	POS	O
+been	POS	O
+widely	POS	O
+reported	POS	O
+with	POS	O
+a	POS	O
+range	POS	O
+of	POS	O
+antidepressants	POS	O
+.	POS	O
+This	POS	O
+case	POS	O
+report	POS	O
+suggests	POS	O
+that	POS	O
+desvenlafaxine	POS	O
+might	POS	O
+cause	POS	O
+clinically	POS	O
+significant	POS	O
+hyponatremia	POS	B-NP
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Clinicians	POS	O
+should	POS	O
+be	POS	O
+aware	POS	O
+of	POS	O
+the	POS	O
+potential	POS	O
+for	POS	O
+antidepressants	POS	O
+to	POS	O
+cause	POS	O
+hyponatremia	POS	B-NP
+,	POS	O
+and	POS	O
+take	POS	O
+appropriate	POS	O
+corrective	POS	O
+action	POS	O
+where	POS	O
+necessary	POS	O
+.	POS	O
+Oxidative	POS	O
+stress	POS	O
+on	POS	O
+cardiotoxicity	POS	B-NP
+after	POS	O
+treatment	POS	O
+with	POS	O
+single	POS	O
+and	POS	O
+multiple	POS	O
+doses	POS	O
+of	POS	O
+doxorubicin	POS	O
+.	POS	O
+The	POS	O
+mechanism	POS	O
+of	POS	O
+doxorubicin	POS	O
+(	POS	O
+DOX	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+remains	POS	O
+controversial	POS	O
+.	POS	O
+Wistar	POS	O
+rats	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+66	POS	O
+)	POS	O
+received	POS	O
+DOX	POS	O
+injections	POS	O
+intraperitoneally	POS	O
+and	POS	O
+were	POS	O
+randomly	POS	O
+assigned	POS	O
+to	POS	O
+2	POS	O
+experimental	POS	O
+protocols	POS	O
+:	POS	O
+(	POS	O
+1	POS	O
+)	POS	O
+rats	POS	O
+were	POS	O
+killed	POS	O
+before	POS	O
+(	POS	O
+-	POS	O
+24	POS	O
+h	POS	O
+,	POS	O
+n	POS	O
+=	POS	O
+8	POS	O
+)	POS	O
+and	POS	O
+24	POS	O
+h	POS	O
+after	POS	O
+(	POS	O
++	POS	O
+24	POS	O
+h	POS	O
+,	POS	O
+n	POS	O
+=	POS	O
+8	POS	O
+)	POS	O
+a	POS	O
+single	POS	O
+dose	POS	O
+of	POS	O
+DOX	POS	O
+(	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+body	POS	O
+weight	POS	O
+)	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+DOX	POS	O
+acute	POS	O
+effect	POS	O
+and	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+rats	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+58	POS	O
+)	POS	O
+received	POS	O
+4	POS	O
+injections	POS	O
+of	POS	O
+DOX	POS	O
+(	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+body	POS	O
+weight	POS	O
+/	POS	O
+week	POS	O
+)	POS	O
+and	POS	O
+were	POS	O
+killed	POS	O
+before	POS	O
+the	POS	O
+first	POS	O
+injection	POS	O
+(	POS	O
+M0	POS	O
+)	POS	O
+and	POS	O
+1	POS	O
+week	POS	O
+after	POS	O
+each	POS	O
+injection	POS	O
+(	POS	O
+M1	POS	O
+,	POS	O
+M2	POS	O
+,	POS	O
+M3	POS	O
+,	POS	O
+and	POS	O
+M4	POS	O
+)	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+chronological	POS	O
+effects	POS	O
+.	POS	O
+Animals	POS	O
+used	POS	O
+at	POS	O
+M0	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+8	POS	O
+)	POS	O
+were	POS	O
+also	POS	O
+used	POS	O
+at	POS	O
+moment	POS	O
+-	POS	O
+24	POS	O
+h	POS	O
+of	POS	O
+acute	POS	O
+study	POS	O
+.	POS	O
+Cardiac	POS	O
+total	POS	O
+antioxidant	POS	O
+performance	POS	O
+(	POS	O
+TAP	POS	O
+)	POS	O
+,	POS	O
+DNA	POS	O
+damage	POS	O
+,	POS	O
+and	POS	O
+morphology	POS	O
+analyses	POS	O
+were	POS	O
+carried	POS	O
+out	POS	O
+at	POS	O
+each	POS	O
+time	POS	O
+point	POS	O
+.	POS	O
+Single	POS	O
+dose	POS	O
+of	POS	O
+DOX	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+increased	POS	O
+cardiac	POS	B-NP
+disarrangement	POS	I-NP
+,	POS	O
+necrosis	POS	B-NP
+,	POS	O
+and	POS	O
+DNA	POS	O
+damage	POS	O
+(	POS	O
+strand	POS	O
+breaks	POS	O
+(	POS	O
+SBs	POS	O
+)	POS	O
+and	POS	O
+oxidized	POS	O
+pyrimidines	POS	O
+)	POS	O
+and	POS	O
+decreased	POS	O
+TAP	POS	O
+.	POS	O
+The	POS	O
+chronological	POS	O
+study	POS	O
+showed	POS	O
+an	POS	O
+effect	POS	O
+of	POS	O
+a	POS	O
+cumulative	POS	O
+dose	POS	O
+on	POS	O
+body	POS	O
+weight	POS	O
+(	POS	O
+R	POS	O
+=	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+99	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+011	POS	O
+)	POS	O
+,	POS	O
+necrosis	POS	B-NP
+(	POS	O
+R	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+00	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+004	POS	O
+)	POS	O
+,	POS	O
+TAP	POS	O
+(	POS	O
+R	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+95	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+049	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+DNA	POS	O
+SBs	POS	O
+(	POS	O
+R	POS	O
+=	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+95	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+049	POS	O
+)	POS	O
+.	POS	O
+DNA	POS	O
+SBs	POS	O
+damage	POS	O
+was	POS	O
+negatively	POS	O
+associated	POS	O
+with	POS	O
+TAP	POS	O
+(	POS	O
+R	POS	O
+=	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+98	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+018	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+necrosis	POS	B-NP
+(	POS	O
+R	POS	O
+=	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+97	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+027	POS	O
+)	POS	O
+.	POS	O
+Our	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+oxidative	POS	O
+damage	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+acute	POS	O
+cardiotoxicity	POS	B-NP
+induced	POS	O
+by	POS	O
+a	POS	O
+single	POS	O
+dose	POS	O
+of	POS	O
+DOX	POS	O
+only	POS	O
+.	POS	O
+Increased	POS	O
+resistance	POS	O
+to	POS	O
+the	POS	O
+oxidative	POS	O
+stress	POS	O
+is	POS	O
+plausible	POS	O
+for	POS	O
+the	POS	O
+multiple	POS	O
+dose	POS	O
+of	POS	O
+DOX	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+different	POS	O
+mechanisms	POS	O
+may	POS	O
+be	POS	O
+involved	POS	O
+in	POS	O
+acute	POS	B-NP
+toxicity	POS	I-NP
+versus	POS	O
+chronic	POS	B-NP
+toxicity	POS	I-NP
+.	POS	O
+Tacrolimus	POS	O
+-	POS	O
+related	POS	O
+seizure	POS	B-NP
+after	POS	O
+pediatric	POS	O
+liver	POS	O
+transplantation	POS	O
+-	POS	O
+-	POS	O
+a	POS	O
+single	POS	O
+-	POS	O
+center	POS	O
+experience	POS	O
+.	POS	O
+To	POS	O
+identify	POS	O
+the	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+new	POS	O
+-	POS	O
+onset	POS	O
+seizures	POS	B-NP
+after	POS	O
+pediatric	POS	O
+LT	POS	O
+and	POS	O
+to	POS	O
+assess	POS	O
+their	POS	O
+clinical	POS	O
+implications	POS	O
+and	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+prognosis	POS	O
+.	POS	O
+The	POS	O
+clinical	POS	O
+and	POS	O
+laboratory	POS	O
+data	POS	O
+of	POS	O
+27	POS	O
+consecutive	POS	O
+children	POS	O
+who	POS	O
+underwent	POS	O
+LT	POS	O
+from	POS	O
+January	POS	O
+2007	POS	O
+to	POS	O
+December	POS	O
+2010	POS	O
+in	POS	O
+our	POS	O
+center	POS	O
+were	POS	O
+analyzed	POS	O
+retrospectively	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+divided	POS	O
+into	POS	O
+seizures	POS	B-NP
+group	POS	O
+and	POS	O
+a	POS	O
+non	POS	O
+-	POS	O
+seizures	POS	B-NP
+group	POS	O
+.	POS	O
+Pre	POS	O
+-	POS	O
+operative	POS	O
+,	POS	O
+intra	POS	O
+-	POS	O
+operative	POS	O
+,	POS	O
+and	POS	O
+post	POS	O
+-	POS	O
+operative	POS	O
+data	POS	O
+were	POS	O
+collected	POS	O
+.	POS	O
+Seizures	POS	B-NP
+occurred	POS	O
+in	POS	O
+four	POS	O
+children	POS	O
+,	POS	O
+an	POS	O
+incidence	POS	O
+of	POS	O
+14	POS	O
+.	POS	O
+8	POS	O
+%	POS	O
+.	POS	O
+All	POS	O
+exhibited	POS	O
+generalized	POS	O
+tonic	POS	O
+-	POS	O
+clonic	POS	B-NP
+seizures	POS	B-NP
+within	POS	O
+the	POS	O
+first	POS	O
+two	POS	O
+wk	POS	O
+after	POS	O
+LT	POS	O
+.	POS	O
+Univariate	POS	O
+analysis	POS	O
+showed	POS	O
+that	POS	O
+the	POS	O
+risk	POS	O
+factors	POS	O
+associated	POS	O
+with	POS	O
+seizures	POS	B-NP
+after	POS	O
+pediatric	POS	O
+LT	POS	O
+included	POS	O
+gender	POS	O
+,	POS	O
+pediatric	POS	B-NP
+end	POS	I-NP
+-	POS	I-NP
+stage	POS	I-NP
+liver	POS	I-NP
+disease	POS	I-NP
+score	POS	O
+before	POS	O
+surgery	POS	O
+,	POS	O
+Child	POS	O
+-	POS	O
+Pugh	POS	O
+score	POS	O
+before	POS	O
+surgery	POS	O
+,	POS	O
+serum	POS	O
+total	POS	O
+bilirubin	POS	O
+after	POS	O
+surgery	POS	O
+,	POS	O
+and	POS	O
+trough	POS	O
+TAC	POS	O
+level	POS	O
+.	POS	O
+Multivariate	POS	O
+analysis	POS	O
+showed	POS	O
+that	POS	O
+trough	POS	O
+TAC	POS	O
+level	POS	O
+was	POS	O
+the	POS	O
+only	POS	O
+independent	POS	O
+risk	POS	O
+factor	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+seizures	POS	B-NP
+.	POS	O
+All	POS	O
+children	POS	O
+who	POS	O
+experienced	POS	O
+seizures	POS	B-NP
+survived	POS	O
+with	POS	O
+good	POS	O
+graft	POS	O
+function	POS	O
+and	POS	O
+remained	POS	O
+seizure	POS	B-NP
+-	POS	O
+free	POS	O
+without	POS	O
+anti	POS	O
+-	POS	O
+epileptic	POS	B-NP
+drugs	POS	O
+over	POS	O
+a	POS	O
+mean	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+period	POS	O
+of	POS	O
+33	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+14	POS	O
+.	POS	O
+6	POS	O
+months	POS	O
+.	POS	O
+High	POS	O
+trough	POS	O
+TAC	POS	O
+level	POS	O
+was	POS	O
+the	POS	O
+predominant	POS	O
+factor	POS	O
+that	POS	O
+contributed	POS	O
+to	POS	O
+seizures	POS	B-NP
+in	POS	O
+the	POS	O
+early	POS	O
+post	POS	O
+-	POS	O
+operative	POS	O
+period	POS	O
+after	POS	O
+pediatric	POS	O
+LT	POS	O
+.	POS	O
+High	POS	O
+PELD	POS	O
+and	POS	O
+Child	POS	O
+-	POS	O
+Pugh	POS	O
+scores	POS	O
+before	POS	O
+LT	POS	O
+and	POS	O
+high	POS	O
+post	POS	O
+-	POS	O
+operative	POS	O
+serum	POS	O
+Tbil	POS	O
+may	POS	O
+be	POS	O
+contributory	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+TAC	POS	O
+-	POS	O
+related	POS	O
+seizures	POS	B-NP
+.	POS	O
+The	POS	O
+flavonoid	POS	O
+apigenin	POS	O
+delays	POS	O
+forgetting	POS	O
+of	POS	O
+passive	POS	O
+avoidance	POS	O
+conditioning	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+experiments	POS	O
+were	POS	O
+performed	POS	O
+to	POS	O
+study	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+the	POS	O
+flavonoid	POS	O
+apigenin	POS	O
+(	POS	O
+20	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+intraperitoneally	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+,	POS	O
+1	POS	O
+h	POS	O
+before	POS	O
+acquisition	POS	O
+)	POS	O
+,	POS	O
+on	POS	O
+24	POS	O
+h	POS	O
+retention	POS	O
+performance	POS	O
+and	POS	O
+forgetting	POS	O
+of	POS	O
+a	POS	O
+step	POS	O
+-	POS	O
+through	POS	O
+passive	POS	O
+avoidance	POS	O
+task	POS	O
+,	POS	O
+in	POS	O
+young	POS	O
+male	POS	O
+Wistar	POS	O
+rats	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+no	POS	O
+differences	POS	O
+between	POS	O
+saline	POS	O
+-	POS	O
+and	POS	O
+apigenin	POS	O
+-	POS	O
+treated	POS	O
+groups	POS	O
+in	POS	O
+the	POS	O
+24	POS	O
+h	POS	O
+retention	POS	O
+trial	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+apigenin	POS	O
+did	POS	O
+not	POS	O
+prevent	POS	O
+the	POS	O
+amnesia	POS	B-NP
+induced	POS	O
+by	POS	O
+scopolamine	POS	O
+(	POS	O
+1mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+,	POS	O
+30	POS	O
+min	POS	O
+before	POS	O
+the	POS	O
+acquisition	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+saline	POS	O
+-	POS	O
+and	POS	O
+apigenin	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+that	POS	O
+did	POS	O
+not	POS	O
+step	POS	O
+through	POS	O
+into	POS	O
+the	POS	O
+dark	POS	O
+compartment	POS	O
+during	POS	O
+the	POS	O
+cut	POS	O
+-	POS	O
+off	POS	O
+time	POS	O
+(	POS	O
+540	POS	O
+s	POS	O
+)	POS	O
+were	POS	O
+retested	POS	O
+weekly	POS	O
+for	POS	O
+up	POS	O
+to	POS	O
+eight	POS	O
+weeks	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+saline	POS	O
+treated	POS	O
+group	POS	O
+,	POS	O
+the	POS	O
+first	POS	O
+significant	POS	O
+decline	POS	O
+in	POS	O
+passive	POS	O
+avoidance	POS	O
+response	POS	O
+was	POS	O
+observed	POS	O
+at	POS	O
+four	POS	O
+weeks	POS	O
+,	POS	O
+and	POS	O
+complete	POS	O
+memory	POS	B-NP
+loss	POS	I-NP
+was	POS	O
+found	POS	O
+five	POS	O
+weeks	POS	O
+after	POS	O
+the	POS	O
+acquisition	POS	O
+of	POS	O
+the	POS	O
+passive	POS	O
+avoidance	POS	O
+task	POS	O
+.	POS	O
+At	POS	O
+the	POS	O
+end	POS	O
+of	POS	O
+the	POS	O
+experimental	POS	O
+period	POS	O
+,	POS	O
+60	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+animals	POS	O
+treated	POS	O
+with	POS	O
+apigenin	POS	O
+still	POS	O
+did	POS	O
+not	POS	O
+step	POS	O
+through	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+1	POS	O
+)	POS	O
+apigenin	POS	O
+delays	POS	O
+the	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+forgetting	POS	O
+but	POS	O
+did	POS	O
+not	POS	O
+modulate	POS	O
+the	POS	O
+24	POS	O
+h	POS	O
+retention	POS	O
+of	POS	O
+fear	POS	O
+memory	POS	O
+and	POS	O
+2	POS	O
+)	POS	O
+the	POS	O
+obtained	POS	O
+beneficial	POS	O
+effect	POS	O
+of	POS	O
+apigenin	POS	O
+on	POS	O
+the	POS	O
+passive	POS	O
+avoidance	POS	O
+conditioning	POS	O
+is	POS	O
+mediated	POS	O
+by	POS	O
+mechanisms	POS	O
+that	POS	O
+do	POS	O
+not	POS	O
+implicate	POS	O
+its	POS	O
+action	POS	O
+on	POS	O
+the	POS	O
+muscarinic	POS	O
+cholinergic	POS	O
+system	POS	O
+.	POS	O
+Histamine	POS	O
+antagonists	POS	O
+and	POS	O
+d	POS	O
+-	POS	O
+tubocurarine	POS	O
+-	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+in	POS	O
+cardiac	POS	O
+surgical	POS	O
+patients	POS	O
+.	POS	O
+Hemodynamic	POS	O
+effects	POS	O
+and	POS	O
+histamine	POS	O
+release	POS	O
+by	POS	O
+bolus	POS	O
+injection	POS	O
+of	POS	O
+0	POS	O
+.	POS	O
+35	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+of	POS	O
+d	POS	O
+-	POS	O
+tubocurarine	POS	O
+were	POS	O
+studied	POS	O
+in	POS	O
+24	POS	O
+patients	POS	O
+.	POS	O
+H1	POS	O
+-	POS	O
+and	POS	O
+H2	POS	O
+-	POS	O
+histamine	POS	O
+antagonists	POS	O
+or	POS	O
+placebo	POS	O
+were	POS	O
+given	POS	O
+before	POS	O
+dosing	POS	O
+with	POS	O
+d	POS	O
+-	POS	O
+tubocurarine	POS	O
+in	POS	O
+a	POS	O
+randomized	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+fashion	POS	O
+to	POS	O
+four	POS	O
+groups	POS	O
+:	POS	O
+group	POS	O
+1	POS	O
+-	POS	O
+-	POS	O
+placebo	POS	O
+;	POS	O
+group	POS	O
+2	POS	O
+-	POS	O
+-	POS	O
+cimetidine	POS	O
+,	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+plus	POS	O
+placebo	POS	O
+;	POS	O
+group	POS	O
+3	POS	O
+-	POS	O
+-	POS	O
+chlorpheniramine	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+plus	POS	O
+placebo	POS	O
+;	POS	O
+and	POS	O
+group	POS	O
+4	POS	O
+-	POS	O
+-	POS	O
+cimetidine	POS	O
+plus	POS	O
+chlorpheniramine	POS	O
+.	POS	O
+Histamine	POS	O
+release	POS	O
+occurred	POS	O
+in	POS	O
+most	POS	O
+patients	POS	O
+,	POS	O
+the	POS	O
+highest	POS	O
+level	POS	O
+2	POS	O
+minutes	POS	O
+after	POS	O
+d	POS	O
+-	POS	O
+tubocurarine	POS	O
+dosing	POS	O
+.	POS	O
+Group	POS	O
+1	POS	O
+had	POS	O
+a	POS	O
+moderate	POS	O
+negative	POS	O
+correlation	POS	O
+between	POS	O
+plasma	POS	O
+histamine	POS	O
+change	POS	O
+and	POS	O
+systemic	POS	O
+vascular	POS	O
+resistance	POS	O
+(	POS	O
+r	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+58	POS	O
+;	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+not	POS	O
+present	POS	O
+in	POS	O
+group	POS	O
+4	POS	O
+.	POS	O
+Prior	POS	O
+dosing	POS	O
+with	POS	O
+antagonists	POS	O
+partially	POS	O
+prevented	POS	O
+the	POS	O
+fall	POS	O
+in	POS	O
+systemic	POS	O
+vascular	POS	O
+resistance	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+demonstrate	POS	O
+that	POS	O
+the	POS	O
+hemodynamic	POS	O
+changes	POS	O
+associated	POS	O
+with	POS	O
+d	POS	O
+-	POS	O
+tubocurarine	POS	O
+dosing	POS	O
+are	POS	O
+only	POS	O
+partially	POS	O
+explained	POS	O
+by	POS	O
+histamine	POS	O
+release	POS	O
+.	POS	O
+Thus	POS	O
+prior	POS	O
+dosing	POS	O
+with	POS	O
+H1	POS	O
+-	POS	O
+and	POS	O
+H2	POS	O
+-	POS	O
+antagonists	POS	O
+provides	POS	O
+only	POS	O
+partial	POS	O
+protection	POS	O
+.	POS	O
+Cholecystokinin	POS	O
+-	POS	O
+octapeptide	POS	O
+restored	POS	O
+morphine	POS	O
+-	POS	O
+induced	POS	O
+hippocampal	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+potentiation	POS	O
+impairment	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+Cholecystokinin	POS	O
+-	POS	O
+octapeptide	POS	O
+(	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+)	POS	O
+,	POS	O
+which	POS	O
+is	POS	O
+a	POS	O
+typical	POS	O
+brain	POS	O
+-	POS	O
+gut	POS	O
+peptide	POS	O
+,	POS	O
+exerts	POS	O
+a	POS	O
+wide	POS	O
+range	POS	O
+of	POS	O
+biological	POS	O
+activities	POS	O
+on	POS	O
+the	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+.	POS	O
+We	POS	O
+have	POS	O
+previously	POS	O
+reported	POS	O
+that	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+significantly	POS	O
+alleviated	POS	O
+morphine	POS	O
+-	POS	O
+induced	POS	O
+amnesia	POS	B-NP
+and	POS	O
+reversed	POS	O
+spine	POS	O
+density	POS	O
+decreases	POS	O
+in	POS	O
+the	POS	O
+CA1	POS	O
+region	POS	O
+of	POS	O
+the	POS	O
+hippocampus	POS	O
+in	POS	O
+morphine	POS	O
+-	POS	O
+treated	POS	O
+animals	POS	O
+.	POS	O
+Here	POS	O
+,	POS	O
+we	POS	O
+investigated	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+on	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+potentiation	POS	O
+(	POS	O
+LTP	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+lateral	POS	O
+perforant	POS	O
+path	POS	O
+(	POS	O
+LPP	POS	O
+)	POS	O
+-	POS	O
+granule	POS	O
+cell	POS	O
+synapse	POS	O
+of	POS	O
+rat	POS	O
+dentate	POS	O
+gyrus	POS	O
+(	POS	O
+DG	POS	O
+)	POS	O
+in	POS	O
+acute	POS	O
+saline	POS	O
+or	POS	O
+morphine	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+.	POS	O
+Population	POS	O
+spikes	POS	O
+(	POS	O
+PS	POS	O
+)	POS	O
+,	POS	O
+which	POS	O
+were	POS	O
+evoked	POS	O
+by	POS	O
+stimulation	POS	O
+of	POS	O
+the	POS	O
+LPP	POS	O
+,	POS	O
+were	POS	O
+recorded	POS	O
+in	POS	O
+the	POS	O
+DG	POS	O
+region	POS	O
+.	POS	O
+Acute	POS	O
+morphine	POS	O
+(	POS	O
+30mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+s	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+)	POS	O
+treatment	POS	O
+significantly	POS	O
+attenuated	POS	O
+hippocampal	POS	O
+LTP	POS	O
+and	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+(	POS	O
+1ug	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+)	POS	O
+restored	POS	O
+the	POS	O
+amplitude	POS	O
+of	POS	O
+PS	POS	O
+that	POS	O
+was	POS	O
+attenuated	POS	O
+by	POS	O
+morphine	POS	O
+injection	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+microinjection	POS	O
+of	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+and	POS	O
+1ug	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+)	POS	O
+also	POS	O
+significantly	POS	O
+augmented	POS	O
+hippocampal	POS	O
+LTP	POS	O
+in	POS	O
+saline	POS	O
+-	POS	O
+treated	POS	O
+(	POS	O
+1ml	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+s	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+)	POS	O
+rats	POS	O
+.	POS	O
+Pre	POS	O
+-	POS	O
+treatment	POS	O
+of	POS	O
+the	POS	O
+CCK2	POS	O
+receptor	POS	O
+antagonist	POS	O
+L	POS	O
+-	POS	O
+365	POS	O
+,	POS	O
+260	POS	O
+(	POS	O
+10ug	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+)	POS	O
+reversed	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+,	POS	O
+but	POS	O
+the	POS	O
+CCK1	POS	O
+receptor	POS	O
+antagonist	POS	O
+L	POS	O
+-	POS	O
+364	POS	O
+,	POS	O
+718	POS	O
+(	POS	O
+10ug	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+v	POS	O
+)	POS	O
+did	POS	O
+not	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+results	POS	O
+demonstrate	POS	O
+that	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+attenuates	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+morphine	POS	O
+on	POS	O
+hippocampal	POS	O
+LTP	POS	O
+through	POS	O
+CCK2	POS	O
+receptors	POS	O
+and	POS	O
+suggest	POS	O
+an	POS	O
+ameliorative	POS	O
+function	POS	O
+of	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+on	POS	O
+morphine	POS	O
+-	POS	O
+induced	POS	O
+memory	POS	B-NP
+impairment	POS	I-NP
+.	POS	O
+Glial	POS	O
+activation	POS	O
+and	POS	O
+post	POS	O
+-	POS	O
+synaptic	POS	O
+neurotoxicity	POS	B-NP
+:	POS	O
+the	POS	O
+key	POS	O
+events	POS	O
+in	POS	O
+Streptozotocin	POS	O
+(	POS	O
+ICV	POS	O
+)	POS	O
+induced	POS	O
+memory	POS	B-NP
+impairment	POS	I-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+glial	POS	O
+activation	POS	O
+and	POS	O
+post	POS	O
+synaptic	POS	B-NP
+toxicity	POS	I-NP
+in	POS	O
+ICV	POS	O
+Streptozotocin	POS	O
+(	POS	O
+STZ	POS	O
+)	POS	O
+induced	POS	O
+memory	POS	O
+impaired	POS	O
+rats	POS	O
+was	POS	O
+explored	POS	O
+.	POS	O
+In	POS	O
+experiment	POS	O
+set	POS	O
+up	POS	O
+1	POS	O
+:	POS	O
+Memory	POS	B-NP
+deficit	POS	I-NP
+was	POS	O
+found	POS	O
+in	POS	O
+Morris	POS	O
+water	POS	O
+maze	POS	O
+test	POS	O
+on	POS	O
+14	POS	O
+-	POS	O
+16	POS	O
+days	POS	O
+after	POS	O
+STZ	POS	O
+(	POS	O
+ICV	POS	O
+;	POS	O
+3mg	POS	O
+/	POS	O
+Kg	POS	O
+)	POS	O
+administration	POS	O
+.	POS	O
+STZ	POS	O
+causes	POS	O
+increased	POS	O
+expression	POS	O
+of	POS	O
+GFAP	POS	O
+,	POS	O
+CD11b	POS	O
+and	POS	O
+TNF	POS	O
+-	POS	O
+a	POS	O
+indicating	POS	O
+glial	POS	O
+activation	POS	O
+and	POS	O
+neuroinflammation	POS	O
+.	POS	O
+STZ	POS	O
+also	POS	O
+significantly	POS	O
+increased	POS	O
+the	POS	O
+level	POS	O
+of	POS	O
+ROS	POS	O
+,	POS	O
+nitrite	POS	O
+,	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+and	POS	O
+reduced	POS	O
+the	POS	O
+mitochondrial	POS	O
+activity	POS	O
+in	POS	O
+synaptosomal	POS	O
+preparation	POS	O
+illustrating	POS	O
+free	POS	O
+radical	POS	O
+generation	POS	O
+and	POS	O
+excitotoxicity	POS	O
+.	POS	O
+Increased	POS	O
+expression	POS	O
+and	POS	O
+activity	POS	O
+of	POS	O
+Caspase	POS	O
+-	POS	O
+3	POS	O
+was	POS	O
+also	POS	O
+observed	POS	O
+in	POS	O
+STZ	POS	O
+treated	POS	O
+rat	POS	O
+which	POS	O
+specify	POS	O
+apoptotic	POS	O
+cell	POS	O
+death	POS	O
+in	POS	O
+hippocampus	POS	O
+and	POS	O
+cortex	POS	O
+.	POS	O
+STZ	POS	O
+treatment	POS	O
+showed	POS	O
+decrease	POS	O
+expression	POS	O
+of	POS	O
+post	POS	O
+synaptic	POS	O
+markers	POS	O
+CaMKIIa	POS	O
+and	POS	O
+PSD	POS	O
+-	POS	O
+95	POS	O
+,	POS	O
+while	POS	O
+,	POS	O
+expression	POS	O
+of	POS	O
+pre	POS	O
+synaptic	POS	O
+markers	POS	O
+(	POS	O
+synaptophysin	POS	O
+and	POS	O
+SNAP	POS	O
+-	POS	O
+25	POS	O
+)	POS	O
+remains	POS	O
+unaltered	POS	O
+indicating	POS	O
+selective	POS	O
+post	POS	O
+synaptic	POS	O
+neurotoxicity	POS	B-NP
+.	POS	O
+Oral	POS	O
+treatment	POS	O
+with	POS	O
+Memantine	POS	O
+(	POS	O
+10mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+and	POS	O
+Ibuprofen	POS	O
+(	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+daily	POS	O
+for	POS	O
+13	POS	O
+days	POS	O
+attenuated	POS	O
+STZ	POS	O
+induced	POS	O
+glial	POS	O
+activation	POS	O
+,	POS	O
+apoptotic	POS	O
+cell	POS	O
+death	POS	O
+and	POS	O
+post	POS	O
+synaptic	POS	O
+neurotoxicity	POS	B-NP
+in	POS	O
+rat	POS	O
+brain	POS	O
+.	POS	O
+Further	POS	O
+,	POS	O
+in	POS	O
+experiment	POS	O
+set	POS	O
+up	POS	O
+2	POS	O
+:	POS	O
+where	POS	O
+memory	POS	O
+function	POS	O
+was	POS	O
+not	POS	O
+affected	POS	O
+i	POS	O
+.	POS	O
+e	POS	O
+.	POS	O
+7	POS	O
+-	POS	O
+9	POS	O
+days	POS	O
+after	POS	O
+STZ	POS	O
+treatment	POS	O
+.	POS	O
+The	POS	O
+level	POS	O
+of	POS	O
+GFAP	POS	O
+,	POS	O
+CD11b	POS	O
+,	POS	O
+TNF	POS	O
+-	POS	O
+a	POS	O
+,	POS	O
+ROS	POS	O
+and	POS	O
+nitrite	POS	O
+levels	POS	O
+were	POS	O
+increased	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+other	POS	O
+hand	POS	O
+,	POS	O
+apoptotic	POS	O
+marker	POS	O
+,	POS	O
+synaptic	POS	O
+markers	POS	O
+,	POS	O
+mitochondrial	POS	O
+activity	POS	O
+and	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+levels	POS	O
+remained	POS	O
+unaffected	POS	B-NP
+.	POS	O
+Collective	POS	O
+data	POS	O
+indicates	POS	O
+that	POS	O
+neuroinflammatory	POS	O
+process	POS	O
+and	POS	O
+oxidative	POS	O
+stress	POS	O
+occurs	POS	O
+earlier	POS	O
+to	POS	O
+apoptosis	POS	O
+and	POS	O
+does	POS	O
+not	POS	O
+affect	POS	O
+memory	POS	O
+function	POS	O
+.	POS	O
+Present	POS	O
+study	POS	O
+clearly	POS	O
+suggests	POS	O
+that	POS	O
+glial	POS	O
+activation	POS	O
+and	POS	O
+post	POS	O
+synaptic	POS	O
+neurotoxicity	POS	B-NP
+are	POS	O
+the	POS	O
+key	POS	O
+factors	POS	O
+in	POS	O
+STZ	POS	O
+induced	POS	O
+memory	POS	B-NP
+impairment	POS	I-NP
+and	POS	O
+neuronal	POS	B-NP
+cell	POS	I-NP
+death	POS	I-NP
+.	POS	O
+Comparison	POS	O
+of	POS	O
+effects	POS	O
+of	POS	O
+isotonic	POS	O
+sodium	POS	O
+chloride	POS	O
+with	POS	O
+diltiazem	POS	O
+in	POS	O
+prevention	POS	O
+of	POS	O
+contrast	POS	O
+-	POS	O
+induced	POS	O
+nephropathy	POS	B-NP
+.	POS	O
+INTRODUCTION	POS	O
+AND	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+Contrast	POS	O
+-	POS	O
+induced	POS	O
+nephropathy	POS	B-NP
+(	POS	O
+CIN	POS	B-NP
+)	POS	O
+significantly	POS	O
+increases	POS	O
+the	POS	O
+morbidity	POS	O
+and	POS	O
+mortality	POS	O
+of	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+is	POS	O
+to	POS	O
+investigate	POS	O
+and	POS	O
+compare	POS	O
+the	POS	O
+protective	POS	O
+effects	POS	O
+of	POS	O
+isotonic	POS	O
+sodium	POS	O
+chloride	POS	O
+with	POS	O
+sodium	POS	O
+bicarbonate	POS	O
+infusion	POS	O
+and	POS	O
+isotonic	POS	O
+sodium	POS	O
+chloride	POS	O
+infusion	POS	O
+with	POS	O
+diltiazem	POS	O
+,	POS	O
+a	POS	O
+calcium	POS	O
+channel	POS	O
+blocker	POS	O
+,	POS	O
+in	POS	O
+preventing	POS	O
+CIN	POS	O
+.	POS	O
+MATERIALS	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+Our	POS	O
+study	POS	O
+included	POS	O
+patients	POS	O
+who	POS	O
+were	POS	O
+administered	POS	O
+30	POS	O
+-	POS	O
+60	POS	O
+mL	POS	O
+of	POS	O
+iodinated	POS	O
+contrast	POS	O
+agent	POS	O
+for	POS	O
+percutaneous	POS	O
+coronary	POS	O
+angiography	POS	O
+(	POS	O
+PCAG	POS	O
+)	POS	O
+,	POS	O
+all	POS	O
+with	POS	O
+creatinine	POS	O
+values	POS	O
+between	POS	O
+1	POS	O
+.	POS	O
+1	POS	O
+and	POS	O
+3	POS	O
+.	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+dL	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+divided	POS	O
+into	POS	O
+three	POS	O
+groups	POS	O
+and	POS	O
+each	POS	O
+group	POS	O
+had	POS	O
+20	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+first	POS	O
+group	POS	O
+of	POS	O
+patients	POS	O
+was	POS	O
+administered	POS	O
+isotonic	POS	O
+sodium	POS	O
+chloride	POS	O
+;	POS	O
+the	POS	O
+second	POS	O
+group	POS	O
+was	POS	O
+administered	POS	O
+a	POS	O
+solution	POS	O
+that	POS	O
+of	POS	O
+5	POS	O
+%	POS	O
+dextrose	POS	O
+and	POS	O
+sodium	POS	O
+bicarbonate	POS	O
+,	POS	O
+while	POS	O
+the	POS	O
+third	POS	O
+group	POS	O
+was	POS	O
+administered	POS	O
+isotonic	POS	O
+sodium	POS	O
+chloride	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+the	POS	O
+contrast	POS	O
+injection	POS	O
+.	POS	O
+The	POS	O
+third	POS	O
+group	POS	O
+received	POS	O
+an	POS	O
+additional	POS	O
+injection	POS	O
+of	POS	O
+diltiazem	POS	O
+the	POS	O
+day	POS	O
+before	POS	O
+and	POS	O
+first	POS	O
+2	POS	O
+days	POS	O
+after	POS	O
+the	POS	O
+contrast	POS	O
+injection	POS	O
+.	POS	O
+All	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+'	POS	O
+plasma	POS	O
+blood	POS	O
+urea	POS	O
+nitrogen	POS	O
+(	POS	O
+BUN	POS	O
+)	POS	O
+and	POS	O
+creatinine	POS	O
+levels	POS	O
+were	POS	O
+measured	POS	O
+on	POS	O
+the	POS	O
+second	POS	O
+and	POS	O
+seventh	POS	O
+day	POS	O
+after	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+intravenous	POS	O
+contrast	POS	O
+material	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+basal	POS	O
+creatinine	POS	O
+levels	POS	O
+were	POS	O
+similar	POS	O
+for	POS	O
+all	POS	O
+three	POS	O
+groups	POS	O
+(	POS	O
+p	POS	O
+>	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+Among	POS	O
+a	POS	O
+total	POS	O
+of	POS	O
+60	POS	O
+patients	POS	O
+included	POS	O
+in	POS	O
+the	POS	O
+study	POS	O
+,	POS	O
+16	POS	O
+patients	POS	O
+developed	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+(	POS	O
+ARF	POS	B-NP
+)	POS	O
+on	POS	O
+the	POS	O
+second	POS	O
+day	POS	O
+after	POS	O
+contrast	POS	O
+material	POS	O
+was	POS	O
+injected	POS	O
+(	POS	O
+26	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+number	POS	O
+of	POS	O
+patients	POS	O
+who	POS	O
+developed	POS	O
+ARF	POS	B-NP
+on	POS	O
+the	POS	O
+second	POS	O
+day	POS	O
+after	POS	O
+the	POS	O
+injection	POS	O
+in	POS	O
+the	POS	O
+first	POS	O
+group	POS	O
+was	POS	O
+five	POS	O
+(	POS	O
+25	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+second	POS	O
+group	POS	O
+was	POS	O
+six	POS	O
+(	POS	O
+30	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+the	POS	O
+third	POS	O
+group	POS	O
+was	POS	O
+five	POS	O
+(	POS	O
+25	POS	O
+%	POS	O
+)	POS	O
+(	POS	O
+p	POS	O
+>	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+significant	POS	O
+difference	POS	O
+between	POS	O
+isotonic	POS	O
+sodium	POS	O
+chloride	POS	O
+,	POS	O
+sodium	POS	O
+bicarbonate	POS	O
+and	POS	O
+isotonic	POS	O
+sodium	POS	O
+chloride	POS	O
+with	POS	O
+diltiazem	POS	O
+application	POS	O
+in	POS	O
+prevention	POS	O
+of	POS	O
+CIN	POS	B-NP
+.	POS	O
+Neurocognitive	POS	O
+and	POS	O
+neuroradiologic	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+late	POS	O
+effects	POS	O
+in	POS	O
+children	POS	O
+treated	POS	O
+on	POS	O
+Pediatric	POS	O
+Oncology	POS	O
+Group	POS	O
+(	POS	O
+POG	POS	O
+)	POS	O
+P9605	POS	O
+(	POS	O
+standard	POS	O
+risk	POS	O
+)	POS	O
+and	POS	O
+P9201	POS	O
+(	POS	O
+lesser	POS	O
+risk	POS	O
+)	POS	O
+acute	POS	B-NP
+lymphoblastic	POS	I-NP
+leukemia	POS	I-NP
+protocols	POS	O
+(	POS	O
+ACCL0131	POS	O
+)	POS	O
+:	POS	O
+a	POS	O
+methotrexate	POS	O
+consequence	POS	O
+?	POS	O
+A	POS	O
+report	POS	O
+from	POS	O
+the	POS	O
+Children	POS	O
+'	POS	O
+s	POS	O
+Oncology	POS	O
+Group	POS	O
+.	POS	O
+Concerns	POS	O
+about	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+methotrexate	POS	O
+(	POS	O
+MTX	POS	O
+)	POS	O
+neurotoxicity	POS	B-NP
+in	POS	O
+the	POS	O
+1990s	POS	O
+led	POS	O
+to	POS	O
+modifications	POS	O
+in	POS	O
+intrathecal	POS	O
+(	POS	O
+IT	POS	O
+)	POS	O
+therapy	POS	O
+,	POS	O
+leucovorin	POS	O
+rescue	POS	O
+,	POS	O
+and	POS	O
+frequency	POS	O
+of	POS	O
+systemic	POS	O
+MTX	POS	O
+administration	POS	O
+in	POS	O
+children	POS	O
+with	POS	O
+acute	POS	B-NP
+lymphoblastic	POS	I-NP
+leukemia	POS	I-NP
+.	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+,	POS	O
+neurocognitive	POS	O
+outcomes	POS	O
+and	POS	O
+neuroradiologic	POS	O
+evidence	POS	O
+of	POS	O
+leukoencephalopathy	POS	B-NP
+were	POS	O
+compared	POS	O
+in	POS	O
+children	POS	O
+treated	POS	O
+with	POS	O
+intense	POS	B-NP
+central	POS	I-NP
+nervous	POS	I-NP
+system	POS	I-NP
+(	POS	O
+CNS	POS	O
+)	POS	O
+-	POS	O
+directed	POS	O
+therapy	POS	O
+(	POS	O
+P9605	POS	O
+)	POS	O
+versus	POS	O
+those	POS	O
+receiving	POS	O
+fewer	POS	O
+CNS	POS	O
+-	POS	O
+directed	POS	O
+treatment	POS	O
+days	POS	O
+during	POS	O
+intensive	POS	O
+consolidation	POS	O
+(	POS	O
+P9201	POS	O
+)	POS	O
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+66	POS	O
+children	POS	O
+from	POS	O
+16	POS	O
+Pediatric	POS	O
+Oncology	POS	O
+Group	POS	O
+institutions	POS	O
+with	POS	O
+"	POS	O
+standard	POS	O
+-	POS	O
+risk	POS	O
+"	POS	O
+acute	POS	B-NP
+lymphoblastic	POS	I-NP
+leukemia	POS	I-NP
+,	POS	O
+1	POS	O
+.	POS	O
+00	POS	O
+to	POS	O
+9	POS	O
+.	POS	O
+99	POS	O
+years	POS	O
+at	POS	O
+diagnosis	POS	O
+,	POS	O
+without	POS	O
+evidence	POS	O
+of	POS	O
+CNS	POS	B-NP
+leukemia	POS	I-NP
+at	POS	O
+diagnosis	POS	O
+were	POS	O
+enrolled	POS	O
+on	POS	O
+ACCL0131	POS	O
+:	POS	O
+28	POS	O
+from	POS	O
+P9201	POS	O
+and	POS	O
+38	POS	O
+from	POS	O
+P9605	POS	O
+.	POS	O
+Magnetic	POS	O
+resonance	POS	O
+imaging	POS	O
+scans	POS	O
+and	POS	O
+standard	POS	O
+neuropsychological	POS	O
+tests	POS	O
+were	POS	O
+performed	POS	O
+>	POS	O
+2	POS	O
+.	POS	O
+6	POS	O
+years	POS	O
+after	POS	O
+the	POS	O
+end	POS	O
+of	POS	O
+treatment	POS	O
+.	POS	O
+Significantly	POS	O
+more	POS	O
+P9605	POS	O
+patients	POS	O
+developed	POS	O
+leukoencephalopathy	POS	B-NP
+compared	POS	O
+with	POS	O
+P9201	POS	O
+patients	POS	O
+(	POS	O
+68	POS	O
+%	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+49	POS	O
+%	POS	O
+-	POS	O
+83	POS	O
+%	POS	O
+vs	POS	O
+.	POS	O
+22	POS	O
+%	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+5	POS	O
+%	POS	O
+-	POS	O
+44	POS	O
+%	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+identified	POS	O
+as	POS	O
+late	POS	O
+as	POS	O
+7	POS	O
+.	POS	O
+7	POS	O
+years	POS	O
+after	POS	O
+the	POS	O
+end	POS	O
+of	POS	O
+treatment	POS	O
+.	POS	O
+Overall	POS	O
+,	POS	O
+40	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+scored	POS	O
+<	POS	O
+85	POS	O
+on	POS	O
+either	POS	O
+Verbal	POS	O
+or	POS	O
+Performance	POS	O
+IQ	POS	O
+.	POS	O
+Children	POS	O
+on	POS	O
+both	POS	O
+studies	POS	O
+had	POS	O
+significant	POS	O
+attention	POS	B-NP
+problems	POS	I-NP
+,	POS	O
+but	POS	O
+P9605	POS	O
+children	POS	O
+scored	POS	O
+below	POS	O
+average	POS	O
+on	POS	O
+more	POS	O
+neurocognitive	POS	O
+measures	POS	O
+than	POS	O
+those	POS	O
+treated	POS	O
+on	POS	O
+P9201	POS	O
+(	POS	O
+82	POS	O
+%	POS	O
+,	POS	O
+14	POS	O
+/	POS	O
+17	POS	O
+measures	POS	O
+vs	POS	O
+.	POS	O
+24	POS	O
+%	POS	O
+,	POS	O
+4	POS	O
+/	POS	O
+17	POS	O
+measures	POS	O
+)	POS	O
+.	POS	O
+This	POS	O
+supports	POS	O
+ongoing	POS	O
+concerns	POS	O
+about	POS	O
+intensive	POS	O
+MTX	POS	O
+exposure	POS	O
+as	POS	O
+a	POS	O
+major	POS	O
+contributor	POS	O
+to	POS	O
+CNS	POS	O
+late	POS	O
+effects	POS	O
+.	POS	O
+Tranexamic	POS	O
+acid	POS	O
+overdosage	POS	O
+-	POS	O
+induced	POS	O
+generalized	POS	O
+seizure	POS	B-NP
+in	POS	O
+renal	POS	B-NP
+failure	POS	I-NP
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+45	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+lady	POS	O
+with	POS	O
+chronic	POS	B-NP
+kidney	POS	I-NP
+disease	POS	I-NP
+stage	POS	O
+4	POS	O
+due	POS	O
+to	POS	O
+chronic	POS	O
+tubulointerstial	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+She	POS	O
+was	POS	O
+admitted	POS	O
+to	POS	O
+our	POS	O
+center	POS	O
+for	POS	O
+severe	POS	O
+anemia	POS	B-NP
+due	POS	O
+to	POS	O
+menorrhagia	POS	B-NP
+and	POS	O
+deterioration	POS	B-NP
+of	POS	I-NP
+renal	POS	I-NP
+function	POS	I-NP
+.	POS	O
+She	POS	O
+was	POS	O
+infused	POS	O
+three	POS	O
+units	POS	O
+of	POS	O
+packed	POS	O
+cells	POS	O
+during	POS	O
+a	POS	O
+session	POS	O
+of	POS	O
+hemodialysis	POS	O
+.	POS	O
+Tranexamic	POS	O
+acid	POS	O
+(	POS	O
+TNA	POS	O
+)	POS	O
+1	POS	O
+g	POS	O
+8	POS	O
+-	POS	O
+hourly	POS	O
+was	POS	O
+administered	POS	O
+to	POS	O
+her	POS	O
+to	POS	O
+control	POS	O
+bleeding	POS	O
+per	POS	O
+vaginum	POS	O
+.	POS	O
+Two	POS	O
+hours	POS	O
+after	POS	O
+the	POS	O
+sixth	POS	O
+dose	POS	O
+of	POS	O
+TNA	POS	O
+,	POS	O
+she	POS	O
+had	POS	O
+an	POS	O
+episode	POS	O
+of	POS	O
+generalized	POS	O
+tonic	POS	O
+clonic	POS	B-NP
+convulsions	POS	B-NP
+.	POS	O
+TNA	POS	O
+was	POS	O
+discontinued	POS	O
+.	POS	O
+Investigations	POS	O
+of	POS	O
+the	POS	O
+patient	POS	O
+revealed	POS	O
+no	POS	O
+biochemical	POS	O
+or	POS	O
+structural	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+abnormalities	POS	O
+that	POS	O
+could	POS	O
+have	POS	O
+provoked	POS	O
+the	POS	O
+convulsions	POS	B-NP
+.	POS	O
+She	POS	O
+did	POS	O
+not	POS	O
+require	POS	O
+any	POS	O
+further	POS	O
+dialytic	POS	O
+support	POS	O
+.	POS	O
+She	POS	O
+had	POS	O
+no	POS	O
+further	POS	O
+episodes	POS	O
+of	POS	O
+convulsion	POS	B-NP
+till	POS	O
+dis	POS	O
+-	POS	O
+charge	POS	O
+and	POS	O
+during	POS	O
+the	POS	O
+two	POS	O
+months	POS	O
+of	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+the	POS	O
+precipitating	POS	O
+cause	POS	O
+of	POS	O
+convulsions	POS	B-NP
+was	POS	O
+believed	POS	O
+to	POS	O
+be	POS	O
+an	POS	O
+overdose	POS	B-NP
+of	POS	O
+TNA	POS	O
+.	POS	O
+Pre	POS	O
+-	POS	O
+treatment	POS	O
+of	POS	O
+bupivacaine	POS	O
+-	POS	O
+induced	POS	O
+cardiovascular	POS	B-NP
+depression	POS	I-NP
+using	POS	O
+different	POS	O
+lipid	POS	O
+formulations	POS	O
+of	POS	O
+propofol	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Pre	POS	O
+-	POS	O
+treatment	POS	O
+with	POS	O
+lipid	POS	O
+emulsions	POS	O
+has	POS	O
+been	POS	O
+shown	POS	O
+to	POS	O
+increase	POS	O
+lethal	POS	O
+doses	POS	O
+of	POS	O
+bupivacaine	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+lipid	POS	O
+content	POS	O
+of	POS	O
+propofol	POS	O
+may	POS	O
+alleviate	POS	O
+bupivacaine	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+is	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+propofol	POS	O
+in	POS	O
+intralipid	POS	O
+or	POS	O
+medialipid	POS	O
+emulsions	POS	O
+on	POS	O
+bupivacaine	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Rats	POS	O
+were	POS	O
+anaesthetised	POS	O
+with	POS	O
+ketamine	POS	O
+and	POS	O
+were	POS	O
+given	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+propofol	POS	O
+in	POS	O
+intralipid	POS	O
+(	POS	O
+Group	POS	O
+P	POS	O
+)	POS	O
+,	POS	O
+propofol	POS	O
+in	POS	O
+medialipid	POS	O
+(	POS	O
+Group	POS	O
+L	POS	O
+)	POS	O
+,	POS	O
+or	POS	O
+saline	POS	O
+(	POS	O
+Group	POS	O
+C	POS	O
+)	POS	O
+over	POS	O
+20	POS	O
+min	POS	O
+.	POS	O
+Thereafter	POS	O
+,	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+bupivacaine	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+was	POS	O
+infused	POS	O
+.	POS	O
+We	POS	O
+recorded	POS	O
+time	POS	O
+to	POS	O
+first	POS	O
+dysrhythmia	POS	B-NP
+occurrence	POS	O
+,	POS	O
+respective	POS	O
+times	POS	O
+to	POS	O
+25	POS	O
+%	POS	O
+and	POS	O
+50	POS	O
+%	POS	O
+reduction	POS	O
+of	POS	O
+the	POS	O
+heart	POS	O
+rate	POS	O
+(	POS	O
+HR	POS	O
+)	POS	O
+and	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+,	POS	O
+and	POS	O
+time	POS	O
+to	POS	O
+asystole	POS	B-NP
+and	POS	O
+total	POS	O
+amount	POS	O
+of	POS	O
+bupivacaine	POS	O
+consumption	POS	O
+.	POS	O
+Blood	POS	O
+and	POS	O
+tissue	POS	O
+samples	POS	O
+were	POS	O
+collected	POS	O
+following	POS	O
+asystole	POS	B-NP
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+time	POS	O
+to	POS	O
+first	POS	O
+dysrhythmia	POS	B-NP
+occurrence	POS	O
+,	POS	O
+time	POS	O
+to	POS	O
+25	POS	O
+%	POS	O
+and	POS	O
+50	POS	O
+%	POS	O
+reductions	POS	O
+in	POS	O
+HR	POS	O
+,	POS	O
+and	POS	O
+time	POS	O
+to	POS	O
+asystole	POS	B-NP
+were	POS	O
+longer	POS	O
+in	POS	O
+Group	POS	O
+P	POS	O
+than	POS	O
+the	POS	O
+other	POS	O
+groups	POS	O
+.	POS	O
+The	POS	O
+cumulative	POS	O
+bupivacaine	POS	O
+dose	POS	O
+given	POS	O
+at	POS	O
+those	POS	O
+time	POS	O
+points	POS	O
+was	POS	O
+higher	POS	O
+in	POS	O
+Group	POS	O
+P	POS	O
+.	POS	O
+Plasma	POS	O
+bupivacaine	POS	O
+levels	POS	O
+were	POS	O
+significantly	POS	O
+lower	POS	O
+in	POS	O
+Group	POS	O
+P	POS	O
+than	POS	O
+in	POS	O
+Group	POS	O
+C	POS	O
+.	POS	O
+Bupivacaine	POS	O
+levels	POS	O
+in	POS	O
+the	POS	O
+brain	POS	O
+and	POS	O
+heart	POS	O
+were	POS	O
+significantly	POS	O
+lower	POS	O
+in	POS	O
+Group	POS	O
+P	POS	O
+and	POS	O
+Group	POS	O
+L	POS	O
+than	POS	O
+in	POS	O
+Group	POS	O
+C	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+pre	POS	O
+-	POS	O
+treatment	POS	O
+with	POS	O
+propofol	POS	O
+in	POS	O
+intralipid	POS	O
+,	POS	O
+compared	POS	O
+with	POS	O
+propofol	POS	O
+in	POS	O
+medialipid	POS	O
+or	POS	O
+saline	POS	O
+,	POS	O
+delayed	POS	O
+the	POS	O
+onset	POS	O
+of	POS	O
+bupivacaine	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxic	POS	B-NP
+effects	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+reduced	POS	O
+plasma	POS	O
+bupivacaine	POS	O
+levels	POS	O
+.	POS	O
+Further	POS	O
+studies	POS	O
+are	POS	O
+needed	POS	O
+to	POS	O
+explore	POS	O
+tissue	POS	O
+bupivacaine	POS	O
+levels	POS	O
+of	POS	O
+propofol	POS	O
+in	POS	O
+medialipid	POS	O
+and	POS	O
+adapt	POS	O
+these	POS	O
+results	POS	O
+to	POS	O
+clinical	POS	O
+practice	POS	O
+.	POS	O
+Drug	POS	O
+-	POS	O
+Induced	POS	O
+Acute	POS	O
+Liver	POS	B-NP
+Injury	POS	I-NP
+Within	POS	O
+12	POS	O
+Hours	POS	O
+After	POS	O
+Fluvastatin	POS	O
+Therapy	POS	O
+.	POS	O
+Although	POS	O
+statins	POS	O
+are	POS	O
+generally	POS	O
+well	POS	O
+-	POS	O
+tolerated	POS	O
+drugs	POS	O
+,	POS	O
+recent	POS	O
+cases	POS	O
+of	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+liver	POS	B-NP
+injury	POS	I-NP
+associated	POS	O
+with	POS	O
+their	POS	O
+use	POS	O
+have	POS	O
+been	POS	O
+reported	POS	O
+.	POS	O
+A	POS	O
+52	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+Chinese	POS	O
+man	POS	O
+reported	POS	O
+with	POS	O
+liver	POS	B-NP
+damage	POS	I-NP
+,	POS	O
+which	POS	O
+appeared	POS	O
+12	POS	O
+hours	POS	O
+after	POS	O
+beginning	POS	O
+treatment	POS	O
+with	POS	O
+fluvastatin	POS	O
+.	POS	O
+Patient	POS	O
+presented	POS	O
+with	POS	O
+complaints	POS	O
+of	POS	O
+increasing	POS	O
+nausea	POS	B-NP
+,	POS	O
+anorexia	POS	B-NP
+,	POS	O
+and	POS	O
+upper	POS	B-NP
+abdominal	POS	I-NP
+pain	POS	I-NP
+.	POS	O
+His	POS	O
+laboratory	POS	O
+values	POS	O
+showed	POS	O
+elevated	POS	O
+creatine	POS	O
+kinase	POS	O
+and	POS	O
+transaminases	POS	O
+.	POS	O
+Testing	POS	O
+for	POS	O
+autoantibodies	POS	O
+was	POS	O
+also	POS	O
+negative	POS	O
+.	POS	O
+The	POS	O
+liver	POS	O
+biochemistries	POS	O
+eventually	POS	O
+normalized	POS	O
+within	POS	O
+3	POS	O
+weeks	POS	O
+of	POS	O
+stopping	POS	O
+the	POS	O
+fluvastatin	POS	O
+.	POS	O
+Therefore	POS	O
+,	POS	O
+when	POS	O
+prescribing	POS	O
+statins	POS	O
+,	POS	O
+the	POS	O
+possibility	POS	O
+of	POS	O
+hepatic	POS	B-NP
+damage	POS	I-NP
+should	POS	O
+be	POS	O
+taken	POS	O
+into	POS	O
+account	POS	O
+.	POS	O
+Fluconazole	POS	O
+associated	POS	O
+agranulocytosis	POS	B-NP
+and	POS	O
+thrombocytopenia	POS	B-NP
+.	POS	O
+CASE	POS	O
+:	POS	O
+We	POS	O
+describe	POS	O
+a	POS	O
+second	POS	O
+case	POS	O
+of	POS	O
+fluconazole	POS	O
+associated	POS	O
+agranulocytosis	POS	B-NP
+with	POS	O
+thrombocytopenia	POS	B-NP
+and	POS	O
+recovery	POS	O
+upon	POS	O
+discontinuation	POS	O
+of	POS	O
+therapy	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+began	POS	O
+to	POS	O
+have	POS	O
+changes	POS	O
+in	POS	O
+white	POS	O
+blood	POS	O
+cells	POS	O
+and	POS	O
+platelets	POS	O
+within	POS	O
+48	POS	O
+h	POS	O
+of	POS	O
+administration	POS	O
+of	POS	O
+fluconazole	POS	O
+and	POS	O
+began	POS	O
+to	POS	O
+recover	POS	O
+with	POS	O
+48	POS	O
+h	POS	O
+of	POS	O
+discontinuation	POS	O
+.	POS	O
+This	POS	O
+case	POS	O
+highlights	POS	O
+that	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+blood	POS	B-NP
+dyscrasias	POS	I-NP
+can	POS	O
+occur	POS	O
+unexpectedly	POS	O
+as	POS	O
+a	POS	O
+result	POS	O
+of	POS	O
+treatment	POS	O
+with	POS	O
+a	POS	O
+commonly	POS	O
+used	POS	O
+drug	POS	O
+thought	POS	O
+to	POS	O
+be	POS	O
+"	POS	O
+safe	POS	O
+"	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+According	POS	O
+to	POS	O
+Naranjo	POS	O
+'	POS	O
+s	POS	O
+algorithm	POS	O
+the	POS	O
+likelihood	POS	O
+that	POS	O
+our	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+agranulocytosis	POS	B-NP
+and	POS	O
+thrombocytopenia	POS	B-NP
+occurred	POS	O
+as	POS	O
+a	POS	O
+result	POS	O
+of	POS	O
+therapy	POS	O
+with	POS	O
+fluconazole	POS	O
+is	POS	O
+probable	POS	O
+,	POS	O
+with	POS	O
+a	POS	O
+total	POS	O
+of	POS	O
+six	POS	O
+points	POS	O
+.	POS	O
+We	POS	O
+feel	POS	O
+that	POS	O
+the	POS	O
+weight	POS	O
+of	POS	O
+the	POS	O
+overall	POS	O
+evidence	POS	O
+of	POS	O
+this	POS	O
+evidence	POS	O
+is	POS	O
+strong	POS	O
+.	POS	O
+In	POS	O
+particular	POS	O
+the	POS	O
+temporal	POS	O
+relationship	POS	O
+of	POS	O
+bone	POS	O
+marrow	POS	O
+suppression	POS	O
+to	POS	O
+the	POS	O
+initiation	POS	O
+of	POS	O
+fluconazole	POS	O
+and	POS	O
+the	POS	O
+abatement	POS	O
+of	POS	O
+symptoms	POS	O
+that	POS	O
+rapidly	POS	O
+reversed	POS	O
+immediately	POS	O
+following	POS	O
+discontinuation	POS	O
+.	POS	O
+Two	POS	O
+-	POS	O
+dimensional	POS	O
+speckle	POS	O
+tracking	POS	O
+echocardiography	POS	O
+combined	POS	O
+with	POS	O
+high	POS	O
+-	POS	O
+sensitive	POS	O
+cardiac	POS	O
+troponin	POS	O
+T	POS	O
+in	POS	O
+early	POS	O
+detection	POS	O
+and	POS	O
+prediction	POS	O
+of	POS	O
+cardiotoxicity	POS	B-NP
+during	POS	O
+epirubicine	POS	O
+-	POS	O
+based	POS	O
+chemotherapy	POS	O
+.	POS	O
+AIMS	POS	O
+:	POS	O
+To	POS	O
+investigate	POS	O
+whether	POS	O
+alterations	POS	O
+of	POS	O
+myocardial	POS	O
+strain	POS	O
+and	POS	O
+high	POS	O
+-	POS	O
+sensitive	POS	O
+cardiac	POS	O
+troponin	POS	O
+T	POS	O
+(	POS	O
+cTnT	POS	O
+)	POS	O
+could	POS	O
+predict	POS	O
+future	POS	O
+cardiac	POS	B-NP
+dysfunction	POS	I-NP
+in	POS	O
+patients	POS	O
+after	POS	O
+epirubicin	POS	O
+exposure	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Seventy	POS	O
+-	POS	O
+five	POS	O
+patients	POS	O
+with	POS	O
+non	POS	B-NP
+-	POS	I-NP
+Hodgkin	POS	I-NP
+lymphoma	POS	I-NP
+treated	POS	O
+with	POS	O
+epirubicin	POS	O
+were	POS	O
+studied	POS	O
+.	POS	O
+Blood	POS	O
+collection	POS	O
+and	POS	O
+echocardiography	POS	O
+were	POS	O
+performed	POS	O
+at	POS	O
+baseline	POS	O
+,	POS	O
+1	POS	O
+day	POS	O
+after	POS	O
+the	POS	O
+third	POS	O
+cycle	POS	O
+,	POS	O
+and	POS	O
+1	POS	O
+day	POS	O
+after	POS	O
+completion	POS	O
+of	POS	O
+chemotherapy	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+studied	POS	O
+using	POS	O
+echocardiography	POS	O
+during	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+.	POS	O
+Global	POS	O
+longitudinal	POS	O
+(	POS	O
+GLS	POS	O
+)	POS	O
+,	POS	O
+circumferential	POS	O
+(	POS	O
+GCS	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+radial	POS	O
+strain	POS	O
+(	POS	O
+GRS	POS	O
+)	POS	O
+were	POS	O
+calculated	POS	O
+using	POS	O
+speckle	POS	O
+tracking	POS	O
+echocardiography	POS	O
+.	POS	O
+Left	POS	O
+ventricular	POS	O
+ejection	POS	O
+fraction	POS	O
+was	POS	O
+analysed	POS	O
+by	POS	O
+real	POS	O
+-	POS	O
+time	POS	O
+3D	POS	O
+echocardiography	POS	O
+.	POS	O
+Cardiotoxicity	POS	B-NP
+was	POS	O
+defined	POS	O
+as	POS	O
+a	POS	O
+reduction	POS	O
+of	POS	O
+the	POS	O
+LVEF	POS	O
+of	POS	O
+>	POS	O
+5	POS	O
+%	POS	O
+to	POS	O
+<	POS	O
+55	POS	O
+%	POS	O
+with	POS	O
+symptoms	POS	O
+of	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+or	POS	O
+an	POS	O
+asymptomatic	POS	O
+reduction	POS	O
+of	POS	O
+the	POS	O
+LVEF	POS	O
+of	POS	O
+>	POS	O
+10	POS	O
+%	POS	O
+to	POS	O
+<	POS	O
+55	POS	O
+%	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Fourteen	POS	O
+patients	POS	O
+(	POS	O
+18	POS	O
+.	POS	O
+67	POS	O
+%	POS	O
+)	POS	O
+developed	POS	O
+cardiotoxicity	POS	B-NP
+after	POS	O
+treatment	POS	O
+.	POS	O
+GLS	POS	O
+(	POS	O
+-	POS	O
+18	POS	O
+.	POS	O
+48	POS	O
++	POS	O
+1	POS	O
+.	POS	O
+72	POS	O
+%	POS	O
+vs	POS	O
+.	POS	O
+-	POS	O
+15	POS	O
+.	POS	O
+96	POS	O
++	POS	O
+1	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+GCS	POS	B-NP
+(	POS	O
+-	POS	O
+20	POS	O
+.	POS	O
+93	POS	O
++	POS	O
+2	POS	O
+.	POS	O
+86	POS	O
+%	POS	O
+vs	POS	O
+.	POS	O
+-	POS	O
+19	POS	O
+.	POS	O
+20	POS	O
++	POS	O
+3	POS	O
+.	POS	O
+21	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+GRS	POS	O
+(	POS	O
+39	POS	O
+.	POS	O
+23	POS	O
++	POS	O
+6	POS	O
+.	POS	O
+44	POS	O
+%	POS	O
+vs	POS	O
+.	POS	O
+34	POS	O
+.	POS	O
+98	POS	O
++	POS	O
+6	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+)	POS	O
+were	POS	O
+markedly	POS	O
+reduced	POS	O
+and	POS	O
+cTnT	POS	O
+was	POS	O
+elevated	POS	O
+from	POS	O
+0	POS	O
+.	POS	O
+0010	POS	O
++	POS	O
+0	POS	O
+.	POS	O
+0020	POS	O
+to	POS	O
+0	POS	O
+.	POS	O
+0073	POS	O
++	POS	O
+0	POS	O
+.	POS	O
+0038	POS	O
+ng	POS	O
+/	POS	O
+mL	POS	O
+(	POS	O
+P	POS	O
+all	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+at	POS	O
+the	POS	O
+completion	POS	O
+of	POS	O
+chemotherapy	POS	O
+compared	POS	O
+with	POS	O
+baseline	POS	O
+values	POS	O
+.	POS	O
+A	POS	O
+>	POS	O
+15	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+decrease	POS	O
+in	POS	O
+GLS	POS	O
+[	POS	O
+sensitivity	POS	O
+,	POS	O
+86	POS	O
+%	POS	O
+;	POS	O
+specificity	POS	O
+,	POS	O
+75	POS	O
+%	POS	O
+;	POS	O
+area	POS	O
+under	POS	O
+the	POS	O
+curve	POS	O
+(	POS	O
+AUC	POS	O
+)	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+815	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+]	POS	O
+and	POS	O
+a	POS	O
+>	POS	O
+0	POS	O
+.	POS	O
+004	POS	O
+ng	POS	O
+/	POS	O
+mL	POS	O
+elevation	POS	O
+in	POS	O
+cTnT	POS	O
+(	POS	O
+sensitivity	POS	O
+,	POS	O
+79	POS	O
+%	POS	O
+;	POS	O
+specificity	POS	O
+,	POS	O
+64	POS	O
+%	POS	O
+;	POS	O
+AUC	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+757	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+005	POS	O
+)	POS	O
+from	POS	O
+baseline	POS	O
+to	POS	O
+the	POS	O
+third	POS	O
+cycle	POS	O
+of	POS	O
+chemotherapy	POS	O
+predicted	POS	O
+later	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+The	POS	O
+decrease	POS	O
+in	POS	O
+GLS	POS	O
+remained	POS	O
+the	POS	O
+only	POS	O
+independent	POS	O
+predictor	POS	O
+of	POS	O
+cardiotoxicity	POS	B-NP
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+000	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+GLS	POS	O
+combined	POS	O
+with	POS	O
+cTnT	POS	O
+may	POS	O
+provide	POS	O
+a	POS	O
+reliable	POS	O
+and	POS	O
+non	POS	O
+-	POS	O
+invasive	POS	O
+method	POS	O
+to	POS	O
+predict	POS	O
+cardiac	POS	B-NP
+dysfunction	POS	I-NP
+in	POS	O
+patients	POS	O
+receiving	POS	O
+anthracycline	POS	O
+-	POS	O
+based	POS	O
+chemotherapy	POS	O
+.	POS	O
+Prevention	POS	O
+of	POS	O
+etomidate	POS	O
+-	POS	O
+induced	POS	O
+myoclonus	POS	B-NP
+:	POS	O
+which	POS	O
+is	POS	O
+superior	POS	O
+:	POS	O
+Fentanyl	POS	O
+,	POS	O
+midazolam	POS	O
+,	POS	O
+or	POS	O
+a	POS	O
+combination	POS	O
+?	POS	O
+A	POS	O
+Retrospective	POS	O
+comparative	POS	O
+study	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+In	POS	O
+this	POS	O
+retrospective	POS	O
+comparative	POS	O
+study	POS	O
+,	POS	O
+we	POS	O
+aimed	POS	O
+to	POS	O
+compare	POS	O
+the	POS	O
+effectiveness	POS	O
+of	POS	O
+fentanyl	POS	O
+,	POS	O
+midazolam	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+combination	POS	O
+of	POS	O
+fentanyl	POS	O
+and	POS	O
+midazolam	POS	O
+to	POS	O
+prevent	POS	O
+etomidate	POS	O
+-	POS	O
+induced	POS	O
+myoclonus	POS	B-NP
+.	POS	O
+MATERIAL	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+This	POS	O
+study	POS	O
+was	POS	O
+performed	POS	O
+based	POS	O
+on	POS	O
+anesthesia	POS	O
+records	POS	O
+.	POS	O
+Depending	POS	O
+on	POS	O
+the	POS	O
+drugs	POS	O
+that	POS	O
+would	POS	O
+be	POS	O
+given	POS	O
+before	POS	O
+the	POS	O
+induction	POS	O
+of	POS	O
+anesthesia	POS	O
+with	POS	O
+etomidate	POS	O
+,	POS	O
+the	POS	O
+patients	POS	O
+were	POS	O
+separated	POS	O
+into	POS	O
+4	POS	O
+groups	POS	O
+:	POS	O
+no	POS	O
+pretreatment	POS	O
+(	POS	O
+Group	POS	O
+NP	POS	O
+)	POS	O
+,	POS	O
+fentanyl	POS	O
+1	POS	O
+ug	POS	O
+.	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+(	POS	O
+Group	POS	O
+F	POS	O
+)	POS	O
+,	POS	O
+midazolam	POS	O
+0	POS	O
+.	POS	O
+03	POS	O
+mg	POS	O
+.	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+(	POS	O
+Group	POS	O
+M	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+midazolam	POS	O
+0	POS	O
+.	POS	O
+015	POS	O
+mg	POS	O
+.	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
++	POS	O
+fentanyl	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+ug	POS	O
+.	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+(	POS	O
+Group	POS	O
+FM	POS	O
+)	POS	O
+.	POS	O
+Patients	POS	O
+who	POS	O
+received	POS	O
+the	POS	O
+same	POS	O
+anesthetic	POS	O
+procedure	POS	O
+were	POS	O
+selected	POS	O
+:	POS	O
+2	POS	O
+minutes	POS	O
+after	POS	O
+intravenous	POS	O
+injections	POS	O
+of	POS	O
+the	POS	O
+pretreatment	POS	O
+drugs	POS	O
+,	POS	O
+anesthesia	POS	O
+is	POS	O
+induced	POS	O
+with	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+mg	POS	O
+.	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+etomidate	POS	O
+injected	POS	O
+intravenously	POS	O
+over	POS	O
+a	POS	O
+period	POS	O
+of	POS	O
+20	POS	O
+-	POS	O
+30	POS	O
+seconds	POS	O
+.	POS	O
+Myoclonic	POS	B-NP
+movements	POS	I-NP
+are	POS	O
+evaluated	POS	O
+,	POS	O
+which	POS	O
+were	POS	O
+observed	POS	O
+and	POS	O
+graded	POS	O
+according	POS	O
+to	POS	O
+clinical	POS	O
+severity	POS	O
+during	POS	O
+the	POS	O
+2	POS	O
+minutes	POS	O
+after	POS	O
+etomidate	POS	O
+injection	POS	O
+.	POS	O
+The	POS	O
+severity	POS	O
+of	POS	O
+pain	POS	B-NP
+due	POS	O
+to	POS	O
+etomidate	POS	O
+injection	POS	O
+,	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+,	POS	O
+heart	POS	O
+rate	POS	O
+,	POS	O
+and	POS	O
+adverse	POS	O
+effects	POS	O
+were	POS	O
+also	POS	O
+evaluated	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Study	POS	O
+results	POS	O
+showed	POS	O
+that	POS	O
+myoclonus	POS	B-NP
+incidence	POS	O
+was	POS	O
+85	POS	O
+%	POS	O
+,	POS	O
+40	POS	O
+%	POS	O
+,	POS	O
+70	POS	O
+%	POS	O
+,	POS	O
+and	POS	O
+25	POS	O
+%	POS	O
+in	POS	O
+Group	POS	O
+NP	POS	O
+,	POS	O
+Group	POS	O
+F	POS	O
+,	POS	O
+Group	POS	O
+M	POS	O
+,	POS	O
+and	POS	O
+Group	POS	O
+FM	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+and	POS	O
+were	POS	O
+significantly	POS	O
+lower	POS	O
+in	POS	O
+Group	POS	O
+F	POS	O
+and	POS	O
+Group	POS	O
+FM	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+pretreatment	POS	O
+with	POS	O
+fentanyl	POS	O
+or	POS	O
+combination	POS	O
+of	POS	O
+fentanyl	POS	O
+and	POS	O
+midazolam	POS	O
+was	POS	O
+effective	POS	O
+in	POS	O
+preventing	POS	O
+etomidate	POS	O
+-	POS	O
+induced	POS	O
+myoclonus	POS	B-NP
+.	POS	O
+Convulsant	POS	O
+effect	POS	O
+of	POS	O
+lindane	POS	O
+and	POS	O
+regional	POS	O
+brain	POS	O
+concentration	POS	O
+of	POS	O
+GABA	POS	O
+and	POS	O
+dopamine	POS	O
+.	POS	O
+Lindane	POS	O
+(	POS	O
+gamma	POS	O
+-	POS	O
+hexachlorocyclohexane	POS	O
+)	POS	O
+is	POS	O
+an	POS	O
+organochlorine	POS	O
+insecticide	POS	O
+with	POS	O
+known	POS	O
+neurotoxic	POS	B-NP
+effects	POS	O
+.	POS	O
+Its	POS	O
+mechanism	POS	O
+of	POS	O
+action	POS	O
+is	POS	O
+not	POS	O
+well	POS	O
+understood	POS	O
+although	POS	O
+it	POS	O
+has	POS	O
+been	POS	O
+proposed	POS	O
+that	POS	O
+lindane	POS	O
+acts	POS	O
+as	POS	O
+a	POS	O
+non	POS	O
+-	POS	O
+competitive	POS	O
+antagonist	POS	O
+at	POS	O
+the	POS	O
+gamma	POS	O
+-	POS	O
+aminobutyric	POS	O
+acid	POS	O
+(	POS	O
+GABA	POS	O
+)	POS	O
+-	POS	O
+A	POS	O
+receptor	POS	O
+.	POS	O
+We	POS	O
+studied	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+lindane	POS	O
+(	POS	O
+150	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+on	POS	O
+the	POS	O
+GABAergic	POS	O
+and	POS	O
+dopaminergic	POS	O
+systems	POS	O
+by	POS	O
+measuring	POS	O
+the	POS	O
+concentration	POS	O
+of	POS	O
+GABA	POS	O
+,	POS	O
+dopamine	POS	O
+and	POS	O
+its	POS	O
+metabolites	POS	O
+in	POS	O
+7	POS	O
+brain	POS	O
+areas	POS	O
+at	POS	O
+the	POS	O
+onset	POS	O
+of	POS	O
+seizures	POS	B-NP
+.	POS	O
+All	POS	O
+animals	POS	O
+suffered	POS	O
+tonic	POS	O
+convulsions	POS	B-NP
+at	POS	O
+18	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+4	POS	O
+min	POS	O
+after	POS	O
+lindane	POS	O
+administration	POS	O
+.	POS	O
+The	POS	O
+concentration	POS	O
+of	POS	O
+GABA	POS	O
+was	POS	O
+only	POS	O
+slightly	POS	O
+but	POS	O
+significantly	POS	O
+decreased	POS	O
+in	POS	O
+the	POS	O
+colliculi	POS	O
+without	POS	O
+modifications	POS	O
+in	POS	O
+the	POS	O
+other	POS	O
+areas	POS	O
+.	POS	O
+The	POS	O
+concentration	POS	O
+of	POS	O
+dopamine	POS	O
+was	POS	O
+increased	POS	O
+in	POS	O
+the	POS	O
+mesencephalon	POS	O
+and	POS	O
+that	POS	O
+of	POS	O
+its	POS	O
+metabolite	POS	O
+DOPAC	POS	O
+was	POS	O
+also	POS	O
+increased	POS	O
+in	POS	O
+the	POS	O
+mesencephalon	POS	O
+and	POS	O
+the	POS	O
+striatum	POS	O
+.	POS	O
+Cholestatic	POS	O
+presentation	POS	O
+of	POS	O
+yellow	POS	O
+phosphorus	POS	O
+poisoning	POS	O
+.	POS	O
+Yellow	POS	O
+phosphorus	POS	O
+,	POS	O
+a	POS	O
+component	POS	O
+of	POS	O
+certain	POS	O
+pesticide	POS	O
+pastes	POS	O
+and	POS	O
+fireworks	POS	O
+,	POS	O
+is	POS	O
+well	POS	O
+known	POS	O
+to	POS	O
+cause	POS	O
+hepatotoxicity	POS	B-NP
+.	POS	O
+Poisoning	POS	O
+with	POS	O
+yellow	POS	O
+phosphorus	POS	O
+classically	POS	O
+manifests	POS	O
+with	POS	O
+acute	POS	B-NP
+hepatitis	POS	I-NP
+leading	POS	O
+to	POS	O
+acute	POS	B-NP
+liver	POS	I-NP
+failure	POS	I-NP
+which	POS	O
+may	POS	O
+need	POS	O
+liver	POS	O
+transplantation	POS	O
+.	POS	O
+We	POS	O
+present	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+yellow	POS	O
+phosphorus	POS	O
+poisoning	POS	B-NP
+in	POS	O
+which	POS	O
+a	POS	O
+patient	POS	O
+presented	POS	O
+with	POS	O
+florid	POS	O
+clinical	POS	O
+features	POS	O
+of	POS	O
+cholestasis	POS	B-NP
+highlighting	POS	O
+the	POS	O
+fact	POS	O
+that	POS	O
+cholestasis	POS	B-NP
+can	POS	O
+rarely	POS	O
+be	POS	O
+a	POS	O
+presenting	POS	O
+feature	POS	O
+of	POS	O
+yellow	POS	O
+phosphorus	POS	O
+hepatotoxicity	POS	B-NP
+.	POS	O
+Vasovagal	POS	B-NP
+syncope	POS	I-NP
+and	POS	O
+severe	POS	O
+bradycardia	POS	B-NP
+following	POS	O
+intranasal	POS	O
+dexmedetomidine	POS	O
+for	POS	O
+pediatric	POS	O
+procedural	POS	O
+sedation	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+syncope	POS	B-NP
+and	POS	O
+bradycardia	POS	B-NP
+in	POS	O
+an	POS	O
+11	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+girl	POS	O
+following	POS	O
+administration	POS	O
+of	POS	O
+intranasal	POS	O
+dexmedetomidine	POS	O
+for	POS	O
+sedation	POS	O
+for	POS	O
+a	POS	O
+voiding	POS	O
+cystourethrogram	POS	O
+.	POS	O
+Following	POS	O
+successful	POS	O
+completion	POS	O
+of	POS	O
+VCUG	POS	O
+and	POS	O
+a	POS	O
+60	POS	O
+-	POS	O
+min	POS	O
+recovery	POS	O
+period	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+level	POS	O
+of	POS	O
+consciousness	POS	O
+and	POS	O
+vital	POS	O
+signs	POS	O
+returned	POS	O
+to	POS	O
+presedation	POS	O
+levels	POS	O
+.	POS	O
+Upon	POS	O
+leaving	POS	O
+the	POS	O
+sedation	POS	O
+area	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+collapsed	POS	O
+,	POS	O
+with	POS	O
+no	POS	O
+apparent	POS	O
+inciting	POS	O
+event	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+quickly	POS	O
+regained	POS	O
+consciousness	POS	O
+and	POS	O
+no	POS	O
+injury	POS	O
+occurred	POS	O
+.	POS	O
+The	POS	O
+primary	POS	O
+abnormality	POS	O
+found	POS	O
+was	POS	O
+persistent	POS	O
+bradycardia	POS	B-NP
+,	POS	O
+and	POS	O
+she	POS	O
+was	POS	O
+admitted	POS	O
+to	POS	O
+the	POS	O
+hospital	POS	O
+for	POS	O
+telemetric	POS	O
+observation	POS	O
+.	POS	O
+The	POS	O
+bradycardia	POS	B-NP
+lasted	POS	O
+~	POS	O
+2	POS	O
+h	POS	O
+,	POS	O
+and	POS	O
+further	POS	O
+cardiac	POS	O
+workup	POS	O
+revealed	POS	O
+no	POS	O
+underlying	POS	O
+abnormality	POS	O
+.	POS	O
+Unanticipated	POS	O
+and	POS	O
+previously	POS	O
+unreported	POS	O
+outcomes	POS	O
+may	POS	O
+be	POS	O
+witnessed	POS	O
+as	POS	O
+we	POS	O
+expand	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+certain	POS	O
+sedatives	POS	O
+to	POS	O
+alternative	POS	O
+routes	POS	O
+of	POS	O
+administration	POS	O
+.	POS	O
+Paradoxical	POS	O
+severe	POS	O
+agitation	POS	B-NP
+induced	POS	O
+by	POS	O
+add	POS	O
+-	POS	O
+on	POS	O
+high	POS	O
+-	POS	O
+doses	POS	O
+quetiapine	POS	O
+in	POS	O
+schizo	POS	B-NP
+-	POS	I-NP
+affective	POS	I-NP
+disorder	POS	I-NP
+.	POS	O
+We	POS	O
+report	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+35	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+patient	POS	O
+suffering	POS	O
+from	POS	O
+schizo	POS	B-NP
+-	POS	I-NP
+affective	POS	I-NP
+disorder	POS	I-NP
+since	POS	O
+the	POS	O
+age	POS	O
+of	POS	O
+19	POS	O
+years	POS	O
+,	POS	O
+treated	POS	O
+by	POS	O
+a	POS	O
+combination	POS	O
+of	POS	O
+first	POS	O
+-	POS	O
+generation	POS	O
+antipsychotics	POS	O
+,	POS	O
+zuclopenthixol	POS	O
+(	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+and	POS	O
+lithium	POS	O
+(	POS	O
+1200	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+(	POS	O
+serum	POS	O
+lithium	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+85	POS	O
+mEq	POS	O
+/	POS	O
+l	POS	O
+)	POS	O
+.	POS	O
+This	POS	O
+patient	POS	O
+had	POS	O
+no	POS	O
+associated	POS	O
+personality	POS	B-NP
+disorder	POS	I-NP
+(	POS	O
+particularly	POS	O
+no	POS	O
+antisocial	POS	B-NP
+disorder	POS	I-NP
+)	POS	O
+and	POS	O
+no	POS	O
+substance	POS	B-NP
+abuse	POS	I-NP
+disorder	POS	I-NP
+.	POS	O
+Within	POS	O
+the	POS	O
+48	POS	O
+h	POS	O
+following	POS	O
+the	POS	O
+gradual	POS	O
+introduction	POS	O
+of	POS	O
+quetiapine	POS	O
+(	POS	O
+up	POS	O
+to	POS	O
+600	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+presented	POS	O
+severe	POS	O
+agitation	POS	B-NP
+without	POS	O
+an	POS	O
+environmental	POS	O
+explanation	POS	O
+,	POS	O
+contrasting	POS	O
+with	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+aggressiveness	POS	B-NP
+or	POS	O
+personality	POS	B-NP
+disorder	POS	I-NP
+.	POS	O
+The	POS	O
+diagnoses	POS	O
+of	POS	O
+manic	POS	B-NP
+shift	POS	O
+and	POS	O
+akathisia	POS	B-NP
+were	POS	O
+dismissed	POS	O
+.	POS	O
+The	POS	O
+withdrawal	POS	O
+and	POS	O
+the	POS	O
+gradual	POS	O
+reintroduction	POS	O
+of	POS	O
+quetiapine	POS	O
+2	POS	O
+weeks	POS	O
+later	POS	O
+,	POS	O
+which	POS	O
+led	POS	O
+to	POS	O
+another	POS	O
+severe	POS	O
+agitation	POS	B-NP
+,	POS	O
+enabled	POS	O
+us	POS	O
+to	POS	O
+attribute	POS	O
+the	POS	O
+agitation	POS	B-NP
+specifically	POS	O
+to	POS	O
+quetiapine	POS	O
+.	POS	O
+Antioxidant	POS	O
+effects	POS	O
+of	POS	O
+bovine	POS	O
+lactoferrin	POS	O
+on	POS	O
+dexamethasone	POS	O
+-	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+in	POS	O
+rat	POS	O
+.	POS	O
+Dexamethasone	POS	O
+-	POS	O
+(	POS	O
+Dex	POS	O
+-	POS	O
+)	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+is	POS	O
+associated	POS	O
+with	POS	O
+enhanced	POS	O
+oxidative	POS	O
+stress	POS	O
+.	POS	O
+Lactoferrin	POS	O
+(	POS	O
+LF	POS	O
+)	POS	O
+is	POS	O
+an	POS	O
+iron	POS	O
+-	POS	O
+binding	POS	O
+glycoprotein	POS	O
+with	POS	O
+antihypertensive	POS	O
+properties	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+,	POS	O
+we	POS	O
+investigated	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+chronic	POS	O
+administration	POS	O
+of	POS	O
+LF	POS	O
+on	POS	O
+oxidative	POS	O
+stress	POS	O
+and	POS	O
+hypertension	POS	B-NP
+upon	POS	O
+Dex	POS	O
+administration	POS	O
+.	POS	O
+Male	POS	O
+Wistar	POS	O
+rats	POS	O
+were	POS	O
+treated	POS	O
+by	POS	O
+Dex	POS	O
+(	POS	O
+30	POS	O
+u	POS	O
+g	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+subcutaneously	POS	O
+)	POS	O
+or	POS	O
+saline	POS	O
+for	POS	O
+14	POS	O
+days	POS	O
+.	POS	O
+Oral	POS	O
+bovine	POS	O
+LF	POS	O
+(	POS	O
+30	POS	O
+,	POS	O
+100	POS	O
+,	POS	O
+300	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+was	POS	O
+given	POS	O
+from	POS	O
+day	POS	O
+8	POS	O
+to	POS	O
+14	POS	O
+in	POS	O
+a	POS	O
+reversal	POS	O
+study	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+prevention	POS	O
+study	POS	O
+,	POS	O
+rats	POS	O
+received	POS	O
+4	POS	O
+days	POS	O
+of	POS	O
+LF	POS	O
+treatment	POS	O
+followed	POS	O
+by	POS	O
+Dex	POS	O
+and	POS	O
+continued	POS	O
+during	POS	O
+the	POS	O
+test	POS	O
+period	POS	O
+.	POS	O
+Systolic	POS	O
+blood	POS	O
+pressure	POS	O
+(	POS	O
+SBP	POS	O
+)	POS	O
+was	POS	O
+measured	POS	O
+using	POS	O
+tail	POS	O
+-	POS	O
+cuff	POS	O
+method	POS	O
+.	POS	O
+Thymus	POS	O
+weight	POS	O
+was	POS	O
+used	POS	O
+as	POS	O
+a	POS	O
+marker	POS	O
+of	POS	O
+glucocorticoid	POS	O
+activity	POS	O
+.	POS	O
+Plasma	POS	O
+hydrogen	POS	O
+peroxide	POS	O
+(	POS	O
+H2O2	POS	O
+)	POS	O
+concentration	POS	O
+and	POS	O
+ferric	POS	O
+reducing	POS	O
+antioxidant	POS	O
+power	POS	O
+(	POS	O
+FRAP	POS	O
+)	POS	O
+value	POS	O
+were	POS	O
+determined	POS	O
+.	POS	O
+Dexamethasone	POS	O
+significantly	POS	O
+increased	POS	O
+SBP	POS	O
+and	POS	O
+plasma	POS	O
+H2O2	POS	O
+level	POS	O
+and	POS	O
+decreased	POS	O
+thymus	POS	O
+and	POS	O
+body	POS	O
+weights	POS	O
+.	POS	O
+LF	POS	O
+lowered	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+and	POS	O
+dose	POS	O
+dependently	POS	O
+prevented	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+Dex	POS	O
+-	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+.	POS	O
+LF	POS	O
+prevented	POS	O
+body	POS	O
+weight	POS	O
+loss	POS	O
+and	POS	O
+significantly	POS	O
+reduced	POS	O
+the	POS	O
+elevated	POS	O
+plasma	POS	O
+H2O2	POS	O
+and	POS	O
+increased	POS	O
+FRAP	POS	O
+values	POS	O
+.	POS	O
+Chronic	POS	O
+administration	POS	O
+of	POS	O
+LF	POS	O
+strongly	POS	O
+reduced	POS	O
+the	POS	O
+blood	POS	O
+pressure	POS	O
+and	POS	O
+production	POS	O
+of	POS	O
+ROS	POS	O
+and	POS	O
+improved	POS	O
+antioxidant	POS	O
+capacity	POS	O
+in	POS	O
+Dex	POS	O
+-	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+,	POS	O
+suggesting	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+inhibition	POS	O
+of	POS	O
+oxidative	POS	O
+stress	POS	O
+as	POS	O
+another	POS	O
+mechanism	POS	O
+of	POS	O
+antihypertensive	POS	O
+action	POS	O
+of	POS	O
+LF	POS	O
+.	POS	O
+The	POS	O
+association	POS	O
+between	POS	O
+tranexamic	POS	O
+acid	POS	O
+and	POS	O
+convulsive	POS	B-NP
+seizures	POS	I-NP
+after	POS	O
+cardiac	POS	O
+surgery	POS	O
+:	POS	O
+a	POS	O
+multivariate	POS	O
+analysis	POS	O
+in	POS	O
+11	POS	O
+529	POS	O
+patients	POS	O
+.	POS	O
+Because	POS	O
+of	POS	O
+a	POS	O
+lack	POS	O
+of	POS	O
+contemporary	POS	O
+data	POS	O
+regarding	POS	O
+seizures	POS	B-NP
+after	POS	O
+cardiac	POS	O
+surgery	POS	O
+,	POS	O
+we	POS	O
+undertook	POS	O
+a	POS	O
+retrospective	POS	O
+analysis	POS	O
+of	POS	O
+prospectively	POS	O
+collected	POS	O
+data	POS	O
+from	POS	O
+11	POS	O
+529	POS	O
+patients	POS	O
+in	POS	O
+whom	POS	O
+cardiopulmonary	POS	O
+bypass	POS	O
+was	POS	O
+used	POS	O
+from	POS	O
+January	POS	O
+2004	POS	O
+to	POS	O
+December	POS	O
+2010	POS	O
+.	POS	O
+A	POS	O
+convulsive	POS	O
+seizure	POS	B-NP
+was	POS	O
+defined	POS	O
+as	POS	O
+a	POS	O
+transient	POS	O
+episode	POS	O
+of	POS	O
+disturbed	POS	O
+brain	POS	O
+function	POS	O
+characterised	POS	O
+by	POS	O
+abnormal	POS	B-NP
+involuntary	POS	I-NP
+motor	POS	I-NP
+movements	POS	I-NP
+.	POS	O
+Multivariate	POS	O
+regression	POS	O
+analysis	POS	O
+was	POS	O
+performed	POS	O
+to	POS	O
+identify	POS	O
+independent	POS	O
+predictors	POS	O
+of	POS	O
+postoperative	POS	B-NP
+seizures	POS	I-NP
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+100	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+developed	POS	O
+postoperative	POS	B-NP
+convulsive	POS	I-NP
+seizures	POS	I-NP
+.	POS	O
+Generalised	POS	O
+and	POS	O
+focal	POS	O
+seizures	POS	B-NP
+were	POS	O
+identified	POS	O
+in	POS	O
+68	POS	O
+and	POS	O
+32	POS	O
+patients	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+The	POS	O
+median	POS	O
+(	POS	O
+IQR	POS	O
+[	POS	O
+range	POS	O
+]	POS	O
+)	POS	O
+time	POS	O
+after	POS	O
+surgery	POS	O
+when	POS	O
+the	POS	O
+seizure	POS	B-NP
+occurred	POS	O
+was	POS	O
+7	POS	O
+(	POS	O
+6	POS	O
+-	POS	O
+12	POS	O
+[	POS	O
+1	POS	O
+-	POS	O
+216	POS	O
+]	POS	O
+)	POS	O
+h	POS	O
+and	POS	O
+8	POS	O
+(	POS	O
+6	POS	O
+-	POS	O
+11	POS	O
+[	POS	O
+4	POS	O
+-	POS	O
+18	POS	O
+]	POS	O
+)	POS	O
+h	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Epileptiform	POS	O
+findings	POS	O
+on	POS	O
+electroencephalography	POS	O
+were	POS	O
+seen	POS	O
+in	POS	O
+19	POS	O
+patients	POS	O
+.	POS	O
+Independent	POS	O
+predictors	POS	O
+of	POS	O
+postoperative	POS	O
+seizures	POS	B-NP
+included	POS	O
+age	POS	O
+,	POS	O
+female	POS	O
+sex	POS	O
+,	POS	O
+redo	POS	O
+cardiac	POS	O
+surgery	POS	O
+,	POS	O
+calcification	POS	B-NP
+of	POS	I-NP
+ascending	POS	I-NP
+aorta	POS	I-NP
+,	POS	O
+congestive	POS	B-NP
+heart	POS	I-NP
+failure	POS	I-NP
+,	POS	O
+deep	POS	O
+hypothermic	POS	B-NP
+circulatory	POS	I-NP
+arrest	POS	I-NP
+,	POS	O
+duration	POS	O
+of	POS	O
+aortic	POS	O
+cross	POS	O
+-	POS	O
+clamp	POS	O
+and	POS	O
+tranexamic	POS	O
+acid	POS	O
+.	POS	O
+When	POS	O
+tested	POS	O
+in	POS	O
+a	POS	O
+multivariate	POS	O
+regression	POS	O
+analysis	POS	O
+,	POS	O
+tranexamic	POS	O
+acid	POS	O
+was	POS	O
+a	POS	O
+strong	POS	O
+independent	POS	O
+predictor	POS	O
+of	POS	O
+seizures	POS	B-NP
+(	POS	O
+OR	POS	O
+14	POS	O
+.	POS	O
+3	POS	O
+,	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+5	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+36	POS	O
+.	POS	O
+7	POS	O
+;	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+convulsive	POS	B-NP
+seizures	POS	I-NP
+had	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+times	POS	O
+higher	POS	O
+in	POS	O
+-	POS	O
+hospital	POS	O
+mortality	POS	O
+rates	POS	O
+and	POS	O
+twice	POS	O
+the	POS	O
+length	POS	O
+of	POS	O
+hospital	POS	O
+stay	POS	O
+compared	POS	O
+with	POS	O
+patients	POS	O
+without	POS	O
+convulsive	POS	B-NP
+seizures	POS	I-NP
+.	POS	O
+Mean	POS	O
+(	POS	O
+IQR	POS	O
+[	POS	O
+range	POS	O
+]	POS	O
+)	POS	O
+length	POS	O
+of	POS	O
+stay	POS	O
+in	POS	O
+the	POS	O
+intensive	POS	O
+care	POS	O
+unit	POS	O
+was	POS	O
+115	POS	O
+(	POS	O
+49	POS	O
+-	POS	O
+228	POS	O
+[	POS	O
+32	POS	O
+-	POS	O
+481	POS	O
+]	POS	O
+)	POS	O
+h	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+convulsive	POS	B-NP
+seizures	POS	I-NP
+compared	POS	O
+with	POS	O
+26	POS	O
+(	POS	O
+22	POS	O
+-	POS	O
+69	POS	O
+[	POS	O
+14	POS	O
+-	POS	O
+1080	POS	O
+]	POS	O
+)	POS	O
+h	POS	O
+in	POS	O
+patients	POS	O
+without	POS	O
+seizures	POS	B-NP
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+Convulsive	POS	B-NP
+seizures	POS	I-NP
+are	POS	O
+a	POS	O
+serious	POS	O
+postoperative	POS	O
+complication	POS	O
+after	POS	O
+cardiac	POS	O
+surgery	POS	O
+.	POS	O
+As	POS	O
+tranexamic	POS	O
+acid	POS	O
+is	POS	O
+the	POS	O
+only	POS	O
+modifiable	POS	O
+factor	POS	O
+,	POS	O
+its	POS	O
+administration	POS	O
+,	POS	O
+particularly	POS	O
+in	POS	O
+doses	POS	O
+exceeding	POS	O
+80	POS	O
+mg	POS	O
+.	POS	O
+kg	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+,	POS	O
+should	POS	O
+be	POS	O
+weighed	POS	O
+against	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+postoperative	POS	B-NP
+seizures	POS	I-NP
+.	POS	O
+Dysfunctional	POS	O
+overnight	POS	O
+memory	POS	O
+consolidation	POS	O
+in	POS	O
+ecstasy	POS	O
+users	POS	O
+.	POS	O
+Sleep	POS	O
+plays	POS	O
+an	POS	O
+important	POS	O
+role	POS	O
+in	POS	O
+the	POS	O
+consolidation	POS	O
+and	POS	O
+integration	POS	O
+of	POS	O
+memory	POS	O
+in	POS	O
+a	POS	O
+process	POS	O
+called	POS	O
+overnight	POS	O
+memory	POS	O
+consolidation	POS	O
+.	POS	O
+Previous	POS	O
+studies	POS	O
+indicate	POS	O
+that	POS	O
+ecstasy	POS	O
+users	POS	O
+have	POS	O
+marked	POS	O
+and	POS	O
+persistent	POS	O
+neurocognitive	POS	O
+and	POS	O
+sleep	POS	B-NP
+-	POS	I-NP
+related	POS	I-NP
+impairments	POS	I-NP
+.	POS	O
+We	POS	O
+extend	POS	O
+past	POS	O
+research	POS	O
+by	POS	O
+examining	POS	O
+overnight	POS	O
+memory	POS	O
+consolidation	POS	O
+among	POS	O
+regular	POS	O
+ecstasy	POS	O
+users	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+12	POS	O
+)	POS	O
+and	POS	O
+drug	POS	O
+naive	POS	O
+healthy	POS	O
+controls	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+26	POS	O
+)	POS	O
+.	POS	O
+Memory	POS	O
+recall	POS	O
+of	POS	O
+word	POS	O
+pairs	POS	O
+was	POS	O
+evaluated	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+a	POS	O
+period	POS	O
+of	POS	O
+sleep	POS	O
+,	POS	O
+with	POS	O
+and	POS	O
+without	POS	O
+interference	POS	O
+prior	POS	O
+to	POS	O
+testing	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+we	POS	O
+assessed	POS	O
+neurocognitive	POS	O
+performances	POS	O
+across	POS	O
+tasks	POS	O
+of	POS	O
+learning	POS	O
+,	POS	O
+memory	POS	O
+and	POS	O
+executive	POS	O
+functioning	POS	O
+.	POS	O
+Ecstasy	POS	O
+users	POS	O
+demonstrated	POS	O
+impaired	POS	O
+overnight	POS	O
+memory	POS	O
+consolidation	POS	O
+,	POS	O
+a	POS	O
+finding	POS	O
+that	POS	O
+was	POS	O
+more	POS	O
+pronounced	POS	O
+following	POS	O
+associative	POS	O
+interference	POS	O
+.	POS	O
+Additionally	POS	O
+,	POS	O
+ecstasy	POS	O
+users	POS	O
+demonstrated	POS	O
+impairments	POS	O
+on	POS	O
+tasks	POS	O
+recruiting	POS	O
+frontostriatal	POS	O
+and	POS	O
+hippocampal	POS	O
+neural	POS	O
+circuitry	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+domains	POS	O
+of	POS	O
+proactive	POS	O
+interference	POS	O
+memory	POS	O
+,	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+memory	POS	O
+,	POS	O
+encoding	POS	O
+,	POS	O
+working	POS	O
+memory	POS	O
+and	POS	O
+complex	POS	O
+planning	POS	O
+.	POS	O
+We	POS	O
+suggest	POS	O
+that	POS	O
+ecstasy	POS	O
+-	POS	O
+associated	POS	O
+dysfunction	POS	O
+in	POS	O
+fronto	POS	O
+-	POS	O
+temporal	POS	O
+circuitry	POS	O
+may	POS	O
+underlie	POS	O
+overnight	POS	O
+consolidation	POS	O
+memory	POS	B-NP
+impairments	POS	I-NP
+in	POS	O
+regular	POS	O
+ecstasy	POS	O
+users	POS	O
+.	POS	O
+Normoammonemic	POS	B-NP
+encephalopathy	POS	I-NP
+:	POS	O
+solely	POS	O
+valproate	POS	O
+induced	POS	O
+or	POS	O
+multiple	POS	O
+mechanisms	POS	O
+?	POS	O
+A	POS	O
+77	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+presented	POS	O
+with	POS	O
+subacute	POS	O
+onset	POS	O
+progressive	POS	O
+confusion	POS	B-NP
+,	POS	O
+aggression	POS	B-NP
+,	POS	O
+auditory	POS	B-NP
+hallucinations	POS	I-NP
+and	POS	O
+delusions	POS	B-NP
+.	POS	O
+In	POS	O
+the	POS	O
+preceding	POS	O
+months	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+had	POS	O
+a	POS	O
+number	POS	O
+of	POS	O
+admissions	POS	O
+with	POS	O
+transient	POS	O
+unilateral	POS	B-NP
+hemiparesis	POS	I-NP
+with	POS	O
+facial	POS	B-NP
+droop	POS	I-NP
+,	POS	O
+and	POS	O
+had	POS	O
+been	POS	O
+started	POS	O
+on	POS	O
+valproate	POS	O
+for	POS	O
+presumed	POS	O
+hemiplegic	POS	B-NP
+migraine	POS	I-NP
+.	POS	O
+Valproate	POS	B-NP
+was	POS	O
+withdrawn	POS	O
+soon	POS	O
+after	POS	O
+admission	POS	O
+and	POS	O
+her	POS	O
+cognitive	POS	O
+abilities	POS	O
+have	POS	O
+gradually	POS	O
+improved	POS	O
+over	POS	O
+3	POS	O
+months	POS	O
+of	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+.	POS	O
+Valproate	POS	O
+levels	POS	O
+taken	POS	O
+prior	POS	O
+to	POS	O
+withdrawal	POS	O
+were	POS	O
+subtherapeutic	POS	O
+and	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+normoammonaemic	POS	O
+.	POS	O
+EEG	POS	O
+undertaken	POS	O
+during	POS	O
+inpatient	POS	O
+stay	POS	O
+showed	POS	O
+changes	POS	O
+consistent	POS	O
+with	POS	O
+encephalopathy	POS	B-NP
+,	POS	O
+and	POS	O
+low	POS	O
+titre	POS	O
+N	POS	O
+-	POS	O
+methyl	POS	O
+-	POS	O
+D	POS	O
+-	POS	O
+aspartate	POS	O
+(	POS	O
+NMDA	POS	O
+)	POS	O
+receptor	POS	O
+antibodies	POS	O
+were	POS	O
+present	POS	O
+in	POS	O
+this	POS	O
+patient	POS	O
+.	POS	O
+The	POS	O
+possible	POS	O
+aetiologies	POS	O
+of	POS	O
+valproate	POS	O
+-	POS	O
+induced	POS	O
+encephalopathy	POS	B-NP
+and	POS	O
+NMDA	POS	O
+receptor	POS	O
+-	POS	O
+associated	POS	O
+encephalitis	POS	B-NP
+present	POS	O
+a	POS	O
+diagnostic	POS	O
+dilemma	POS	O
+.	POS	O
+We	POS	O
+present	POS	O
+a	POS	O
+putative	POS	O
+combinatorial	POS	O
+hypothesis	POS	O
+to	POS	O
+explain	POS	O
+this	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+symptoms	POS	O
+.	POS	O
+Cerebellar	POS	O
+and	POS	O
+oculomotor	POS	B-NP
+dysfunction	POS	I-NP
+induced	POS	O
+by	POS	O
+rapid	POS	O
+infusion	POS	O
+of	POS	O
+pethidine	POS	O
+.	POS	O
+Pethidine	POS	O
+is	POS	O
+an	POS	O
+opioid	POS	O
+that	POS	O
+gains	POS	O
+its	POS	O
+popularity	POS	O
+for	POS	O
+the	POS	O
+effective	POS	O
+pain	POS	B-NP
+control	POS	O
+through	POS	O
+acting	POS	O
+on	POS	O
+the	POS	O
+opioid	POS	O
+-	POS	O
+receptors	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+rapid	POS	O
+pain	POS	B-NP
+relief	POS	O
+sometimes	POS	O
+brings	POS	O
+about	POS	O
+unfavourable	POS	O
+side	POS	O
+effects	POS	O
+that	POS	O
+largely	POS	O
+limit	POS	O
+its	POS	O
+clinical	POS	O
+utility	POS	O
+.	POS	O
+Common	POS	O
+side	POS	O
+effects	POS	O
+include	POS	O
+nausea	POS	B-NP
+,	POS	O
+vomiting	POS	B-NP
+and	POS	O
+hypotension	POS	B-NP
+.	POS	O
+In	POS	O
+patients	POS	O
+with	POS	O
+impaired	POS	B-NP
+renal	POS	I-NP
+and	POS	I-NP
+liver	POS	I-NP
+function	POS	I-NP
+,	POS	O
+and	POS	O
+those	POS	O
+who	POS	O
+need	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+pain	POS	B-NP
+control	POS	O
+,	POS	O
+pethidine	POS	O
+may	POS	O
+cause	POS	O
+excitatory	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+(	POS	O
+CNS	POS	O
+)	POS	O
+effects	POS	O
+through	POS	O
+its	POS	O
+neurotoxic	POS	O
+metabolite	POS	O
+,	POS	O
+norpethidine	POS	O
+,	POS	O
+resulting	POS	O
+in	POS	O
+irritability	POS	B-NP
+and	POS	O
+seizure	POS	B-NP
+attack	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+contrary	POS	O
+,	POS	O
+though	POS	O
+not	POS	O
+clinically	POS	O
+apparent	POS	O
+,	POS	O
+pethidine	POS	O
+potentially	POS	O
+causes	POS	O
+inhibitory	POS	O
+impacts	POS	O
+on	POS	O
+the	POS	O
+CNS	POS	O
+and	POS	O
+impairs	POS	O
+normal	POS	O
+cerebellar	POS	O
+and	POS	O
+oculomotor	POS	O
+function	POS	O
+in	POS	O
+the	POS	O
+short	POS	O
+term	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+case	POS	O
+report	POS	O
+,	POS	O
+we	POS	O
+highlight	POS	O
+opioid	POS	O
+'	POS	O
+s	POS	O
+inhibitory	POS	O
+side	POS	O
+effects	POS	O
+on	POS	O
+the	POS	O
+cerebellar	POS	O
+structure	POS	O
+that	POS	O
+causes	POS	O
+dysmetria	POS	B-NP
+,	POS	O
+dysarthria	POS	B-NP
+,	POS	O
+reduced	POS	O
+smooth	POS	O
+pursuit	POS	O
+gain	POS	O
+and	POS	O
+decreased	POS	O
+saccadic	POS	O
+velocity	POS	O
+.	POS	O
+Baboon	POS	B-NP
+syndrome	POS	I-NP
+induced	POS	O
+by	POS	O
+ketoconazole	POS	O
+.	POS	O
+A	POS	O
+27	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+male	POS	O
+patient	POS	O
+presented	POS	O
+with	POS	O
+a	POS	O
+maculopapular	POS	B-NP
+eruption	POS	I-NP
+on	POS	O
+the	POS	O
+flexural	POS	O
+areas	POS	O
+and	POS	O
+buttocks	POS	O
+after	POS	O
+using	POS	O
+oral	POS	O
+ketoconazole	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+was	POS	O
+diagnosed	POS	O
+with	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+baboon	POS	B-NP
+syndrome	POS	I-NP
+based	POS	O
+on	POS	O
+his	POS	O
+history	POS	O
+,	POS	O
+which	POS	O
+included	POS	O
+prior	POS	O
+sensitivity	POS	O
+to	POS	O
+topical	POS	O
+ketoconazole	POS	O
+,	POS	O
+a	POS	O
+physical	POS	O
+examination	POS	O
+,	POS	O
+and	POS	O
+histopathological	POS	O
+findings	POS	O
+.	POS	O
+Baboon	POS	B-NP
+syndrome	POS	I-NP
+is	POS	O
+a	POS	O
+drug	POS	O
+-	POS	O
+or	POS	O
+contact	POS	O
+allergen	POS	O
+-	POS	O
+related	POS	O
+maculopapular	POS	B-NP
+eruption	POS	I-NP
+that	POS	O
+typically	POS	O
+involves	POS	O
+the	POS	O
+flexural	POS	O
+and	POS	O
+gluteal	POS	O
+areas	POS	O
+.	POS	O
+To	POS	O
+the	POS	O
+best	POS	O
+of	POS	O
+our	POS	O
+knowledge	POS	O
+,	POS	O
+this	POS	O
+is	POS	O
+the	POS	O
+first	POS	O
+reported	POS	O
+case	POS	O
+of	POS	O
+ketoconazole	POS	O
+-	POS	O
+induced	POS	O
+baboon	POS	B-NP
+syndrome	POS	I-NP
+in	POS	O
+the	POS	O
+English	POS	O
+literature	POS	O
+.	POS	O
+A	POS	O
+Case	POS	O
+of	POS	O
+Sudden	POS	B-NP
+Cardiac	POS	I-NP
+Death	POS	I-NP
+due	POS	O
+to	POS	O
+Pilsicainide	POS	O
+-	POS	O
+Induced	POS	O
+Torsades	POS	O
+de	POS	O
+Pointes	POS	B-NP
+.	POS	O
+An	POS	O
+84	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+male	POS	O
+received	POS	O
+oral	POS	O
+pilsicainide	POS	O
+,	POS	O
+a	POS	O
+pure	POS	O
+sodium	POS	O
+channel	POS	O
+blocker	POS	O
+with	POS	O
+slow	POS	O
+recovery	POS	O
+kinetics	POS	O
+,	POS	O
+to	POS	O
+convert	POS	O
+his	POS	O
+paroxysmal	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+to	POS	O
+a	POS	O
+sinus	POS	O
+rhythm	POS	O
+;	POS	O
+the	POS	O
+patient	POS	O
+developed	POS	O
+sudden	POS	O
+cardiac	POS	B-NP
+death	POS	I-NP
+two	POS	O
+days	POS	O
+later	POS	O
+.	POS	O
+The	POS	O
+Holter	POS	O
+electrocardiogram	POS	O
+,	POS	O
+which	POS	O
+was	POS	O
+worn	POS	O
+by	POS	O
+chance	POS	O
+,	POS	O
+revealed	POS	O
+torsade	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+with	POS	O
+gradually	POS	O
+prolonged	POS	O
+QT	POS	O
+intervals	POS	O
+.	POS	O
+This	POS	O
+drug	POS	O
+is	POS	O
+rapidly	POS	O
+absorbed	POS	O
+from	POS	O
+the	POS	O
+gastrointestinal	POS	O
+tract	POS	O
+,	POS	O
+and	POS	O
+most	POS	O
+of	POS	O
+it	POS	O
+is	POS	O
+excreted	POS	O
+from	POS	O
+the	POS	O
+kidney	POS	O
+.	POS	O
+Although	POS	O
+the	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+renal	POS	O
+function	POS	O
+was	POS	O
+not	POS	O
+highly	POS	O
+impaired	POS	O
+and	POS	O
+the	POS	O
+dose	POS	O
+of	POS	O
+pilsicainide	POS	O
+was	POS	O
+low	POS	O
+,	POS	O
+the	POS	O
+plasma	POS	O
+concentration	POS	O
+of	POS	O
+pilsicainide	POS	O
+may	POS	O
+have	POS	O
+been	POS	O
+high	POS	O
+,	POS	O
+which	POS	O
+can	POS	O
+produce	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+in	POS	O
+the	POS	O
+octogenarian	POS	O
+.	POS	O
+Although	POS	O
+the	POS	O
+oral	POS	O
+administration	POS	O
+of	POS	O
+class	POS	O
+IC	POS	O
+drugs	POS	O
+,	POS	O
+including	POS	O
+pilsicainide	POS	O
+,	POS	O
+is	POS	O
+effective	POS	O
+to	POS	O
+terminate	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+,	POS	O
+careful	POS	O
+consideration	POS	O
+must	POS	O
+be	POS	O
+taken	POS	O
+before	POS	O
+giving	POS	O
+these	POS	O
+drugs	POS	O
+to	POS	O
+octogenarians	POS	O
+.	POS	O
+All	POS	O
+-	POS	O
+trans	POS	O
+retinoic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+inflammatory	POS	B-NP
+myositis	POS	I-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+acute	POS	B-NP
+promyelocytic	POS	I-NP
+leukemia	POS	I-NP
+.	POS	O
+All	POS	O
+-	POS	O
+trans	POS	O
+retinoic	POS	O
+acid	POS	O
+(	POS	O
+ATRA	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+component	POS	O
+of	POS	O
+standard	POS	O
+therapy	POS	O
+for	POS	O
+acute	POS	B-NP
+promyelocytic	POS	I-NP
+leukemia	POS	I-NP
+(	POS	O
+APL	POS	B-NP
+)	POS	O
+,	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+potentially	POS	O
+serious	POS	O
+but	POS	O
+treatable	POS	O
+adverse	POS	O
+effects	POS	O
+involving	POS	O
+numerous	POS	O
+organ	POS	O
+systems	POS	O
+,	POS	O
+including	POS	O
+rare	POS	O
+skeletal	POS	O
+muscle	POS	O
+involvement	POS	O
+.	POS	O
+Only	POS	O
+a	POS	O
+handful	POS	O
+of	POS	O
+cases	POS	O
+of	POS	O
+ATRA	POS	O
+-	POS	O
+induced	POS	O
+myositis	POS	B-NP
+in	POS	O
+children	POS	O
+have	POS	O
+been	POS	O
+reported	POS	O
+,	POS	O
+and	POS	O
+none	POS	O
+in	POS	O
+the	POS	O
+radiology	POS	O
+literature	POS	O
+.	POS	O
+We	POS	O
+present	POS	O
+such	POS	O
+a	POS	O
+case	POS	O
+in	POS	O
+a	POS	O
+15	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+boy	POS	O
+with	POS	O
+APL	POS	B-NP
+,	POS	O
+where	POS	O
+recognition	POS	O
+of	POS	O
+imaging	POS	O
+findings	POS	O
+played	POS	O
+a	POS	O
+crucial	POS	O
+role	POS	O
+in	POS	O
+making	POS	O
+the	POS	O
+diagnosis	POS	O
+and	POS	O
+facilitated	POS	O
+prompt	POS	O
+,	POS	O
+effective	POS	O
+treatment	POS	O
+.	POS	O
+Tolerability	POS	O
+of	POS	O
+lomustine	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+cyclophosphamide	POS	O
+in	POS	O
+dogs	POS	O
+with	POS	O
+lymphoma	POS	B-NP
+.	POS	O
+This	POS	O
+retrospective	POS	O
+study	POS	O
+describes	POS	O
+toxicity	POS	B-NP
+associated	POS	O
+with	POS	O
+a	POS	O
+protocol	POS	O
+of	POS	O
+lomustine	POS	O
+(	POS	O
+CCNU	POS	O
+)	POS	O
+and	POS	O
+cyclophosphamide	POS	O
+(	POS	O
+CTX	POS	O
+)	POS	O
+in	POS	O
+dogs	POS	O
+with	POS	O
+lymphoma	POS	B-NP
+.	POS	O
+CCNU	POS	O
+was	POS	O
+administered	POS	O
+per	POS	O
+os	POS	O
+(	POS	O
+PO	POS	O
+)	POS	O
+at	POS	O
+a	POS	O
+targeted	POS	O
+dosage	POS	O
+of	POS	O
+60	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+body	POS	O
+surface	POS	O
+area	POS	O
+on	POS	O
+day	POS	O
+0	POS	O
+,	POS	O
+CTX	POS	O
+was	POS	O
+administered	POS	O
+PO	POS	O
+at	POS	O
+a	POS	O
+targeted	POS	O
+dosage	POS	O
+of	POS	O
+250	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+divided	POS	O
+over	POS	O
+days	POS	O
+0	POS	O
+through	POS	O
+4	POS	O
+,	POS	O
+and	POS	O
+all	POS	O
+dogs	POS	O
+received	POS	O
+prophylactic	POS	O
+antibiotics	POS	O
+.	POS	O
+Ninety	POS	O
+treatments	POS	O
+were	POS	O
+given	POS	O
+to	POS	O
+the	POS	O
+57	POS	O
+dogs	POS	O
+included	POS	O
+in	POS	O
+the	POS	O
+study	POS	O
+.	POS	O
+Neutropenia	POS	B-NP
+was	POS	O
+the	POS	O
+principal	POS	O
+toxic	POS	O
+effect	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+overall	POS	O
+frequency	POS	O
+of	POS	O
+grade	POS	O
+4	POS	O
+neutropenia	POS	B-NP
+after	POS	O
+the	POS	O
+first	POS	O
+treatment	POS	O
+of	POS	O
+CCNU	POS	O
+/	POS	O
+CTX	POS	B-NP
+was	POS	O
+30	POS	O
+%	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+,	POS	O
+19	POS	O
+-	POS	O
+43	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+body	POS	O
+weight	POS	O
+of	POS	O
+dogs	POS	O
+with	POS	O
+grade	POS	O
+4	POS	O
+neutropenia	POS	B-NP
+(	POS	O
+19	POS	O
+.	POS	O
+7	POS	O
+kg	POS	O
++	POS	O
+13	POS	O
+.	POS	O
+4	POS	O
+kg	POS	O
+)	POS	O
+was	POS	O
+significantly	POS	O
+less	POS	O
+than	POS	O
+the	POS	O
+mean	POS	O
+body	POS	O
+weight	POS	O
+of	POS	O
+dogs	POS	O
+that	POS	O
+did	POS	O
+not	POS	O
+develop	POS	O
+grade	POS	O
+4	POS	O
+neutropenia	POS	B-NP
+(	POS	O
+31	POS	O
+.	POS	O
+7	POS	O
+kg	POS	O
++	POS	O
+12	POS	O
+.	POS	O
+4	POS	O
+kg	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+005	POS	O
+)	POS	O
+.	POS	O
+One	POS	O
+dog	POS	O
+(	POS	O
+3	POS	O
+%	POS	O
+)	POS	O
+developed	POS	O
+hematologic	POS	O
+changes	POS	O
+suggestive	POS	O
+of	POS	O
+hepatotoxicity	POS	B-NP
+.	POS	O
+No	POS	O
+dogs	POS	O
+had	POS	O
+evidence	POS	O
+of	POS	O
+either	POS	O
+renal	POS	B-NP
+toxicity	POS	I-NP
+or	POS	O
+hemorrhagic	POS	B-NP
+cystitis	POS	I-NP
+.	POS	O
+Adverse	POS	O
+gastrointestinal	POS	O
+effects	POS	O
+were	POS	O
+uncommon	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+basis	POS	O
+of	POS	O
+the	POS	O
+findings	POS	O
+reported	POS	O
+herein	POS	O
+,	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+60	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+of	POS	O
+CCNU	POS	O
+combined	POS	O
+with	POS	O
+250	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+of	POS	O
+CTX	POS	B-NP
+(	POS	O
+divided	POS	O
+over	POS	O
+5	POS	O
+days	POS	O
+)	POS	O
+q	POS	O
+4	POS	O
+wk	POS	O
+is	POS	O
+tolerable	POS	O
+in	POS	O
+tumor	POS	B-NP
+-	POS	O
+bearing	POS	O
+dogs	POS	O
+.	POS	O
+Nelarabine	POS	O
+neurotoxicity	POS	B-NP
+with	POS	O
+concurrent	POS	O
+intrathecal	POS	O
+chemotherapy	POS	O
+:	POS	O
+Case	POS	O
+report	POS	O
+and	POS	O
+review	POS	O
+of	POS	O
+literature	POS	O
+.	POS	O
+Severe	POS	O
+nelarabine	POS	O
+neurotoxicity	POS	B-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+who	POS	O
+received	POS	O
+concurrent	POS	O
+intrathecal	POS	O
+(	POS	O
+IT	POS	O
+)	POS	O
+chemotherapy	POS	O
+is	POS	O
+reported	POS	O
+.	POS	O
+A	POS	O
+37	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+Caucasian	POS	O
+woman	POS	O
+with	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+T	POS	B-NP
+-	POS	I-NP
+cell	POS	I-NP
+lymphoblastic	POS	I-NP
+lymphoma	POS	I-NP
+was	POS	O
+admitted	POS	O
+for	POS	O
+relapsed	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+She	POS	O
+was	POS	O
+originally	POS	O
+treated	POS	O
+with	POS	O
+induction	POS	O
+chemotherapy	POS	O
+followed	POS	O
+by	POS	O
+an	POS	O
+autologous	POS	O
+transplant	POS	O
+.	POS	O
+She	POS	O
+developed	POS	O
+relapsed	POS	B-NP
+disease	POS	I-NP
+10	POS	O
+months	POS	O
+later	POS	O
+with	POS	O
+leukemic	POS	B-NP
+involvement	POS	I-NP
+.	POS	O
+She	POS	O
+was	POS	O
+re	POS	O
+-	POS	O
+induced	POS	O
+with	POS	O
+nelarabine	POS	O
+1500	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+on	POS	O
+days	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+,	POS	O
+and	POS	O
+5	POS	O
+with	POS	O
+1	POS	O
+dose	POS	O
+of	POS	O
+IT	POS	O
+cytarabine	POS	O
+100	POS	O
+mg	POS	O
+on	POS	O
+day	POS	O
+2	POS	O
+as	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+(	POS	O
+CNS	POS	O
+)	POS	O
+prophylaxis	POS	O
+.	POS	O
+At	POS	O
+the	POS	O
+time	POS	O
+of	POS	O
+treatment	POS	O
+,	POS	O
+she	POS	O
+was	POS	O
+on	POS	O
+continuous	POS	O
+renal	POS	O
+replacement	POS	O
+therapy	POS	O
+due	POS	O
+to	POS	O
+sequelae	POS	O
+of	POS	O
+tumor	POS	B-NP
+lysis	POS	I-NP
+syndrome	POS	I-NP
+(	POS	O
+TLS	POS	O
+)	POS	O
+.	POS	O
+She	POS	O
+tolerated	POS	O
+therapy	POS	O
+well	POS	O
+,	POS	O
+entered	POS	O
+a	POS	O
+complete	POS	O
+remission	POS	O
+,	POS	O
+and	POS	O
+recovered	POS	O
+her	POS	O
+renal	POS	O
+function	POS	O
+.	POS	O
+She	POS	O
+received	POS	O
+a	POS	O
+second	POS	O
+cycle	POS	O
+of	POS	O
+nelarabine	POS	O
+without	POS	O
+additional	POS	O
+IT	POS	O
+prophylaxis	POS	O
+one	POS	O
+month	POS	O
+later	POS	O
+.	POS	O
+A	POS	O
+week	POS	O
+after	POS	O
+this	POS	O
+second	POS	O
+cycle	POS	O
+,	POS	O
+she	POS	O
+noted	POS	O
+numbness	POS	B-NP
+in	POS	O
+her	POS	O
+lower	POS	O
+extremities	POS	O
+.	POS	O
+Predominantly	POS	O
+sensory	POS	O
+,	POS	O
+though	POS	O
+also	POS	O
+motor	POS	O
+and	POS	O
+autonomic	POS	O
+,	POS	O
+peripheral	POS	B-NP
+neuropathy	POS	I-NP
+started	POS	O
+in	POS	O
+her	POS	O
+feet	POS	O
+,	POS	O
+ascended	POS	O
+proximally	POS	O
+to	POS	O
+the	POS	O
+mid	POS	O
+-	POS	O
+thoracic	POS	O
+region	POS	O
+,	POS	O
+and	POS	O
+eventually	POS	O
+included	POS	O
+her	POS	O
+distal	POS	O
+upper	POS	O
+extremities	POS	O
+.	POS	O
+A	POS	O
+magnetic	POS	O
+resonance	POS	O
+imaging	POS	O
+(	POS	O
+MRI	POS	O
+)	POS	O
+of	POS	O
+her	POS	O
+spine	POS	O
+demonstrated	POS	O
+changes	POS	O
+from	POS	O
+C2	POS	O
+to	POS	O
+C6	POS	O
+consistent	POS	O
+with	POS	O
+subacute	POS	O
+combined	POS	O
+degeneration	POS	O
+.	POS	O
+Nelarabine	POS	O
+was	POS	O
+felt	POS	O
+to	POS	O
+be	POS	O
+the	POS	O
+cause	POS	O
+of	POS	O
+her	POS	O
+symptoms	POS	O
+.	POS	O
+Her	POS	B-NP
+neuropathy	POS	I-NP
+stabilized	POS	O
+and	POS	O
+showed	POS	O
+slight	POS	O
+improvement	POS	O
+and	POS	O
+ultimately	POS	O
+received	POS	O
+an	POS	O
+unrelated	POS	O
+,	POS	O
+reduced	POS	O
+-	POS	O
+intensity	POS	O
+allogeneic	POS	O
+transplant	POS	O
+while	POS	O
+in	POS	O
+complete	POS	O
+remission	POS	O
+,	POS	O
+but	POS	O
+relapsed	POS	B-NP
+disease	POS	I-NP
+10	POS	O
+weeks	POS	O
+later	POS	O
+.	POS	O
+She	POS	O
+is	POS	O
+currently	POS	O
+being	POS	O
+treated	POS	O
+with	POS	O
+best	POS	O
+supportive	POS	O
+care	POS	O
+.	POS	O
+To	POS	O
+our	POS	O
+knowledge	POS	O
+,	POS	O
+this	POS	O
+is	POS	O
+the	POS	O
+first	POS	O
+published	POS	O
+case	POS	O
+report	POS	O
+of	POS	O
+severe	POS	O
+neurotoxicity	POS	B-NP
+caused	POS	O
+by	POS	O
+nelarabine	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+who	POS	O
+received	POS	O
+concurrent	POS	O
+IT	POS	O
+chemotherapy	POS	O
+.	POS	O
+Valproate	POS	O
+-	POS	O
+induced	POS	O
+hyperammonemic	POS	B-NP
+encephalopathy	POS	I-NP
+in	POS	O
+a	POS	O
+renal	POS	O
+transplanted	POS	O
+patient	POS	O
+.	POS	O
+Neurological	POS	B-NP
+complications	POS	I-NP
+after	POS	O
+renal	POS	O
+transplantation	POS	O
+constitute	POS	O
+an	POS	O
+important	POS	O
+cause	POS	O
+of	POS	O
+morbidity	POS	O
+and	POS	O
+mortality	POS	O
+.	POS	O
+Their	POS	O
+differential	POS	O
+diagnosis	POS	O
+is	POS	O
+difficult	POS	O
+and	POS	O
+essential	POS	O
+for	POS	O
+subsequent	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+management	POS	O
+.	POS	O
+Valproate	POS	O
+-	POS	O
+induced	POS	O
+hyperammonemic	POS	B-NP
+encephalopathy	POS	I-NP
+is	POS	O
+an	POS	O
+uncommon	POS	O
+but	POS	O
+serious	POS	O
+effect	POS	O
+of	POS	O
+valproate	POS	O
+treatment	POS	O
+.	POS	O
+Here	POS	O
+,	POS	O
+we	POS	O
+describe	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+15	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+girl	POS	O
+who	POS	O
+was	POS	O
+on	POS	O
+a	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+therapy	POS	O
+with	POS	O
+valproate	POS	O
+due	POS	O
+to	POS	O
+epilepsy	POS	B-NP
+and	POS	O
+revealed	POS	O
+impaired	POS	B-NP
+consciousness	POS	I-NP
+with	POS	O
+hyperammonemia	POS	B-NP
+12	POS	O
+days	POS	O
+after	POS	O
+renal	POS	O
+transplantation	POS	O
+.	POS	O
+After	POS	O
+withdraw	POS	O
+of	POS	O
+valproate	POS	O
+,	POS	O
+patients	POS	O
+'	POS	O
+symptoms	POS	O
+resolved	POS	O
+within	POS	O
+24	POS	O
+h	POS	O
+.	POS	O
+Clinicians	POS	O
+should	POS	O
+increase	POS	O
+their	POS	O
+awareness	POS	O
+for	POS	O
+potential	POS	O
+complication	POS	O
+of	POS	O
+valproate	POS	O
+,	POS	O
+especially	POS	O
+in	POS	O
+transplanted	POS	O
+patients	POS	O
+.	POS	O
+Necrotising	POS	B-NP
+fasciitis	POS	I-NP
+after	POS	O
+bortezomib	POS	O
+and	POS	O
+dexamethasone	POS	O
+-	POS	O
+containing	POS	O
+regimen	POS	O
+in	POS	O
+an	POS	O
+elderly	POS	O
+patient	POS	O
+of	POS	O
+Waldenstrom	POS	B-NP
+macroglobulinaemia	POS	I-NP
+.	POS	O
+Bortezomib	POS	O
+and	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+dexamethasone	POS	O
+-	POS	O
+containing	POS	O
+regimens	POS	O
+are	POS	O
+considered	POS	O
+to	POS	O
+be	POS	O
+generally	POS	O
+tolerable	POS	O
+with	POS	O
+few	POS	O
+severe	POS	O
+bacterial	POS	B-NP
+infections	POS	I-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+B	POS	B-NP
+-	POS	I-NP
+cell	POS	I-NP
+malignancies	POS	I-NP
+.	POS	O
+However	POS	O
+,	POS	O
+information	POS	O
+is	POS	O
+limited	POS	O
+concerning	POS	O
+the	POS	O
+safety	POS	O
+of	POS	O
+the	POS	O
+regimen	POS	O
+in	POS	O
+elderly	POS	O
+patients	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+76	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+with	POS	O
+Waldenstrom	POS	B-NP
+macroglobulinaemia	POS	I-NP
+who	POS	O
+suffered	POS	O
+necrotising	POS	B-NP
+fasciitis	POS	I-NP
+without	POS	O
+neutropenia	POS	B-NP
+after	POS	O
+the	POS	O
+combination	POS	O
+treatment	POS	O
+with	POS	O
+bortezomib	POS	O
+,	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+dexamethasone	POS	O
+and	POS	O
+rituximab	POS	O
+.	POS	O
+Despite	POS	O
+immediate	POS	O
+intravenous	POS	O
+antimicrobial	POS	O
+therapy	POS	O
+,	POS	O
+he	POS	O
+succumbed	POS	O
+23	POS	O
+h	POS	O
+after	POS	O
+the	POS	O
+onset	POS	O
+.	POS	O
+Physicians	POS	O
+should	POS	O
+recognise	POS	O
+the	POS	O
+possibility	POS	O
+of	POS	O
+fatal	POS	O
+bacterial	POS	B-NP
+infections	POS	I-NP
+related	POS	O
+to	POS	O
+bortezomib	POS	O
+plus	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+dexamethasone	POS	O
+in	POS	O
+elderly	POS	O
+patients	POS	O
+,	POS	O
+and	POS	O
+we	POS	O
+believe	POS	O
+this	POS	O
+case	POS	O
+warrants	POS	O
+further	POS	O
+investigation	POS	O
+.	POS	O
+An	POS	O
+integrated	POS	O
+characterization	POS	O
+of	POS	O
+serological	POS	O
+,	POS	O
+pathological	POS	O
+,	POS	O
+and	POS	O
+functional	POS	O
+events	POS	O
+in	POS	O
+doxorubicin	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+Many	POS	O
+efficacious	POS	O
+cancer	POS	B-NP
+treatments	POS	O
+cause	POS	O
+significant	POS	O
+cardiac	POS	B-NP
+morbidity	POS	I-NP
+,	POS	O
+yet	POS	O
+biomarkers	POS	O
+or	POS	O
+functional	POS	O
+indices	POS	O
+of	POS	O
+early	POS	O
+damage	POS	O
+,	POS	O
+which	POS	O
+would	POS	O
+allow	POS	O
+monitoring	POS	O
+and	POS	O
+intervention	POS	O
+,	POS	O
+are	POS	O
+lacking	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+,	POS	O
+we	POS	O
+have	POS	O
+utilized	POS	O
+a	POS	O
+rat	POS	O
+model	POS	O
+of	POS	O
+progressive	POS	O
+doxorubicin	POS	O
+(	POS	O
+DOX	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+cardiomyopathy	POS	B-NP
+,	POS	O
+applying	POS	O
+multiple	POS	O
+approaches	POS	O
+,	POS	O
+including	POS	O
+cardiac	POS	O
+magnetic	POS	O
+resonance	POS	O
+imaging	POS	O
+(	POS	O
+MRI	POS	O
+)	POS	O
+,	POS	O
+to	POS	O
+provide	POS	O
+the	POS	O
+most	POS	O
+comprehensive	POS	O
+characterization	POS	O
+to	POS	O
+date	POS	O
+of	POS	O
+the	POS	O
+timecourse	POS	O
+of	POS	O
+serological	POS	O
+,	POS	O
+pathological	POS	O
+,	POS	O
+and	POS	O
+functional	POS	O
+events	POS	O
+underlying	POS	O
+this	POS	O
+toxicity	POS	B-NP
+.	POS	O
+Hannover	POS	O
+Wistar	POS	O
+rats	POS	O
+were	POS	O
+dosed	POS	O
+with	POS	O
+1	POS	O
+.	POS	O
+25	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+DOX	POS	O
+weekly	POS	O
+for	POS	O
+8	POS	O
+weeks	POS	O
+followed	POS	O
+by	POS	O
+a	POS	O
+4	POS	O
+week	POS	O
+off	POS	O
+-	POS	O
+dosing	POS	O
+"	POS	O
+recovery	POS	O
+"	POS	O
+period	POS	O
+.	POS	O
+Electron	POS	O
+microscopy	POS	O
+of	POS	O
+the	POS	O
+myocardium	POS	O
+revealed	POS	O
+subcellular	POS	O
+degeneration	POS	O
+and	POS	O
+marked	POS	O
+mitochondrial	POS	O
+changes	POS	O
+after	POS	O
+a	POS	O
+single	POS	O
+dose	POS	O
+.	POS	O
+Histopathological	POS	O
+analysis	POS	O
+revealed	POS	O
+progressive	POS	O
+cardiomyocyte	POS	B-NP
+degeneration	POS	I-NP
+,	POS	O
+hypertrophy	POS	B-NP
+/	POS	I-NP
+cytomegaly	POS	I-NP
+,	POS	O
+and	POS	O
+extensive	POS	O
+vacuolation	POS	O
+after	POS	O
+two	POS	O
+doses	POS	O
+.	POS	O
+Extensive	POS	O
+replacement	POS	O
+fibrosis	POS	B-NP
+(	POS	O
+quantified	POS	O
+by	POS	O
+Sirius	POS	O
+red	POS	O
+staining	POS	O
+)	POS	O
+developed	POS	O
+during	POS	O
+the	POS	O
+off	POS	O
+-	POS	O
+dosing	POS	O
+period	POS	O
+.	POS	O
+Functional	POS	O
+indices	POS	O
+assessed	POS	O
+by	POS	O
+cardiac	POS	O
+MRI	POS	O
+(	POS	O
+including	POS	O
+left	POS	O
+ventricular	POS	O
+ejection	POS	O
+fraction	POS	O
+(	POS	O
+LVEF	POS	O
+)	POS	O
+,	POS	O
+cardiac	POS	O
+output	POS	O
+,	POS	O
+and	POS	O
+E	POS	O
+/	POS	O
+A	POS	O
+ratio	POS	O
+)	POS	O
+declined	POS	O
+progressively	POS	O
+,	POS	O
+reaching	POS	O
+statistical	POS	O
+significance	POS	O
+after	POS	O
+two	POS	O
+doses	POS	O
+and	POS	O
+culminating	POS	O
+in	POS	O
+"	POS	O
+clinical	POS	O
+"	POS	O
+LV	POS	B-NP
+dysfunction	POS	I-NP
+by	POS	O
+12	POS	O
+weeks	POS	O
+.	POS	O
+Significant	POS	O
+increases	POS	O
+in	POS	O
+peak	POS	O
+myocardial	POS	O
+contrast	POS	O
+enhancement	POS	O
+and	POS	O
+serological	POS	O
+cardiac	POS	O
+troponin	POS	O
+I	POS	O
+(	POS	O
+cTnI	POS	O
+)	POS	O
+emerged	POS	O
+after	POS	O
+eight	POS	O
+doses	POS	O
+,	POS	O
+importantly	POS	O
+preceding	POS	O
+the	POS	O
+LVEF	POS	O
+decline	POS	O
+to	POS	O
+<	POS	O
+50	POS	O
+%	POS	O
+.	POS	O
+Troponin	POS	O
+I	POS	O
+levels	POS	O
+positively	POS	O
+correlated	POS	O
+with	POS	O
+delayed	POS	O
+and	POS	O
+peak	POS	O
+gadolinium	POS	O
+contrast	POS	O
+enhancement	POS	O
+,	POS	O
+histopathological	POS	O
+grading	POS	O
+,	POS	O
+and	POS	O
+diastolic	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+In	POS	O
+summary	POS	O
+,	POS	O
+subcellular	POS	O
+cardiomyocyte	POS	B-NP
+degeneration	POS	I-NP
+was	POS	O
+the	POS	O
+earliest	POS	O
+marker	POS	O
+,	POS	O
+followed	POS	O
+by	POS	O
+progressive	POS	O
+functional	POS	O
+decline	POS	O
+and	POS	O
+histopathological	POS	O
+manifestations	POS	O
+.	POS	O
+Myocardial	POS	O
+contrast	POS	O
+enhancement	POS	O
+and	POS	O
+elevations	POS	O
+in	POS	O
+cTnI	POS	O
+occurred	POS	O
+later	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+all	POS	O
+indices	POS	O
+predated	POS	O
+"	POS	O
+clinical	POS	O
+"	POS	O
+LV	POS	B-NP
+dysfunction	POS	I-NP
+and	POS	O
+thus	POS	O
+warrant	POS	O
+further	POS	O
+evaluation	POS	O
+as	POS	O
+predictive	POS	O
+biomarkers	POS	O
+.	POS	O
+Intradermal	POS	O
+glutamate	POS	O
+and	POS	O
+capsaicin	POS	O
+injections	POS	O
+:	POS	O
+intra	POS	O
+-	POS	O
+and	POS	O
+interindividual	POS	O
+variability	POS	O
+of	POS	O
+provoked	POS	O
+hyperalgesia	POS	B-NP
+and	POS	O
+allodynia	POS	B-NP
+.	POS	O
+Intradermal	POS	O
+injections	POS	O
+of	POS	O
+glutamate	POS	O
+and	POS	O
+capsaicin	POS	O
+are	POS	O
+attractive	POS	O
+to	POS	O
+use	POS	O
+in	POS	O
+human	POS	O
+experimental	POS	O
+pain	POS	B-NP
+models	POS	O
+because	POS	O
+hyperalgesia	POS	B-NP
+and	POS	O
+allodynia	POS	B-NP
+mimic	POS	O
+isolated	POS	O
+aspects	POS	O
+of	POS	O
+clinical	POS	O
+pain	POS	B-NP
+disorders	POS	I-NP
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+reproducibility	POS	O
+of	POS	O
+these	POS	O
+models	POS	O
+.	POS	O
+Twenty	POS	O
+healthy	POS	O
+male	POS	O
+volunteers	POS	O
+(	POS	O
+mean	POS	O
+age	POS	O
+24	POS	O
+years	POS	O
+;	POS	O
+range	POS	O
+18	POS	O
+-	POS	O
+38	POS	O
+years	POS	O
+)	POS	O
+received	POS	O
+intradermal	POS	O
+injections	POS	O
+of	POS	O
+glutamate	POS	O
+and	POS	O
+capsaicin	POS	O
+in	POS	O
+the	POS	O
+volar	POS	O
+forearm	POS	O
+.	POS	O
+Magnitudes	POS	O
+of	POS	O
+secondary	POS	O
+pinprick	POS	O
+hyperalgesia	POS	B-NP
+and	POS	O
+brush	POS	O
+-	POS	O
+evoked	POS	O
+allodynia	POS	B-NP
+were	POS	O
+investigated	POS	O
+using	POS	O
+von	POS	O
+Frey	POS	O
+filaments	POS	O
+(	POS	O
+gauges	POS	O
+10	POS	O
+,	POS	O
+15	POS	O
+,	POS	O
+60	POS	O
+and	POS	O
+100	POS	O
+g	POS	O
+)	POS	O
+and	POS	O
+brush	POS	O
+strokes	POS	B-NP
+.	POS	O
+Areas	POS	O
+of	POS	O
+secondary	POS	O
+hyperalgesia	POS	B-NP
+and	POS	O
+allodynia	POS	B-NP
+were	POS	O
+quantified	POS	O
+immediately	POS	O
+after	POS	O
+injection	POS	O
+and	POS	O
+after	POS	O
+15	POS	O
+,	POS	O
+30	POS	O
+and	POS	O
+60	POS	O
+min	POS	O
+.	POS	O
+Two	POS	O
+identical	POS	O
+experiments	POS	O
+separated	POS	O
+by	POS	O
+at	POS	O
+least	POS	O
+7	POS	O
+days	POS	O
+were	POS	O
+performed	POS	O
+.	POS	O
+Reproducibility	POS	O
+across	POS	O
+and	POS	O
+within	POS	O
+volunteers	POS	O
+(	POS	O
+inter	POS	O
+-	POS	O
+and	POS	O
+intra	POS	O
+-	POS	O
+individual	POS	O
+variation	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+was	POS	O
+assessed	POS	O
+using	POS	O
+intraclass	POS	O
+correlation	POS	O
+coefficient	POS	O
+(	POS	O
+ICC	POS	O
+)	POS	O
+and	POS	O
+coefficient	POS	O
+of	POS	O
+variation	POS	O
+(	POS	O
+CV	POS	O
+)	POS	O
+.	POS	O
+Secondary	POS	B-NP
+pinprick	POS	I-NP
+hyperalgesia	POS	I-NP
+was	POS	O
+observed	POS	O
+as	POS	O
+a	POS	O
+marked	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+visual	POS	O
+analogue	POS	O
+scale	POS	O
+(	POS	O
+VAS	POS	O
+)	POS	O
+response	POS	O
+to	POS	O
+von	POS	O
+Frey	POS	O
+gauges	POS	O
+60	POS	O
+and	POS	O
+100	POS	O
+g	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+after	POS	O
+glutamate	POS	O
+injection	POS	O
+.	POS	O
+For	POS	O
+capsaicin	POS	O
+,	POS	O
+secondary	POS	O
+pinprick	POS	O
+hyperalgesia	POS	B-NP
+was	POS	O
+detected	POS	O
+with	POS	O
+all	POS	O
+von	POS	O
+Frey	POS	O
+gauges	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+Glutamate	POS	O
+evoked	POS	O
+reproducible	POS	O
+VAS	POS	O
+response	POS	O
+to	POS	O
+all	POS	O
+von	POS	O
+Frey	POS	O
+gauges	POS	O
+(	POS	O
+ICC	POS	O
+>	POS	O
+0	POS	O
+.	POS	O
+60	POS	O
+)	POS	O
+and	POS	O
+brush	POS	O
+strokes	POS	B-NP
+(	POS	O
+ICC	POS	O
+>	POS	O
+0	POS	O
+.	POS	O
+83	POS	O
+)	POS	O
+.	POS	O
+Capsaicin	POS	O
+injection	POS	O
+was	POS	O
+reproducible	POS	O
+for	POS	O
+secondary	POS	O
+hyperalgesia	POS	B-NP
+(	POS	O
+ICC	POS	O
+>	POS	O
+0	POS	O
+.	POS	O
+70	POS	O
+)	POS	O
+and	POS	O
+allodynia	POS	B-NP
+(	POS	O
+ICC	POS	O
+>	POS	O
+0	POS	O
+.	POS	O
+71	POS	O
+)	POS	O
+.	POS	O
+Intra	POS	O
+-	POS	O
+individual	POS	O
+variability	POS	O
+was	POS	O
+generally	POS	O
+lower	POS	O
+for	POS	O
+the	POS	O
+VAS	POS	O
+response	POS	O
+to	POS	O
+von	POS	O
+Frey	POS	O
+and	POS	O
+brush	POS	O
+compared	POS	O
+with	POS	O
+areas	POS	O
+of	POS	O
+secondary	POS	O
+hyperalgesia	POS	B-NP
+and	POS	O
+allodynia	POS	B-NP
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+glutamate	POS	O
+and	POS	O
+capsaicin	POS	O
+yield	POS	O
+reproducible	POS	O
+hyperalgesic	POS	B-NP
+and	POS	O
+allodynic	POS	O
+responses	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+present	POS	O
+model	POS	O
+is	POS	O
+well	POS	O
+suited	POS	O
+for	POS	O
+basic	POS	O
+research	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+for	POS	O
+assessing	POS	O
+the	POS	O
+modulation	POS	O
+of	POS	O
+central	POS	O
+phenomena	POS	O
+.	POS	O
+Ocular	POS	O
+-	POS	O
+specific	POS	O
+ER	POS	O
+stress	POS	O
+reduction	POS	O
+rescues	POS	O
+glaucoma	POS	B-NP
+in	POS	O
+murine	POS	O
+glucocorticoid	POS	O
+-	POS	O
+induced	POS	O
+glaucoma	POS	B-NP
+.	POS	O
+Administration	POS	O
+of	POS	O
+glucocorticoids	POS	O
+induces	POS	O
+ocular	POS	O
+hypertension	POS	B-NP
+in	POS	O
+some	POS	O
+patients	POS	O
+.	POS	O
+If	POS	O
+untreated	POS	O
+,	POS	O
+these	POS	O
+patients	POS	O
+can	POS	O
+develop	POS	O
+a	POS	O
+secondary	POS	O
+glaucoma	POS	B-NP
+that	POS	O
+resembles	POS	O
+primary	POS	O
+open	POS	O
+-	POS	O
+angle	POS	O
+glaucoma	POS	B-NP
+(	POS	O
+POAG	POS	B-NP
+)	POS	O
+.	POS	O
+The	POS	O
+underlying	POS	O
+pathology	POS	O
+of	POS	O
+glucocorticoid	POS	O
+-	POS	O
+induced	POS	O
+glaucoma	POS	B-NP
+is	POS	O
+not	POS	O
+fully	POS	O
+understood	POS	O
+,	POS	O
+due	POS	O
+in	POS	O
+part	POS	O
+to	POS	O
+lack	POS	O
+of	POS	O
+an	POS	O
+appropriate	POS	O
+animal	POS	O
+model	POS	O
+.	POS	O
+Here	POS	O
+,	POS	O
+we	POS	O
+developed	POS	O
+a	POS	O
+murine	POS	O
+model	POS	O
+of	POS	O
+glucocorticoid	POS	O
+-	POS	O
+induced	POS	O
+glaucoma	POS	B-NP
+that	POS	O
+exhibits	POS	O
+glaucoma	POS	B-NP
+features	POS	O
+that	POS	O
+are	POS	O
+observed	POS	O
+in	POS	O
+patients	POS	O
+.	POS	O
+Treatment	POS	O
+of	POS	O
+WT	POS	O
+mice	POS	O
+with	POS	O
+topical	POS	O
+ocular	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+%	POS	O
+dexamethasone	POS	O
+led	POS	O
+to	POS	O
+elevation	POS	O
+of	POS	O
+intraocular	POS	O
+pressure	POS	O
+(	POS	O
+IOP	POS	O
+)	POS	O
+,	POS	O
+functional	POS	O
+and	POS	O
+structural	POS	O
+loss	POS	O
+of	POS	O
+retinal	POS	O
+ganglion	POS	O
+cells	POS	O
+,	POS	O
+and	POS	O
+axonal	POS	B-NP
+degeneration	POS	I-NP
+,	POS	O
+resembling	POS	O
+glucocorticoid	POS	O
+-	POS	O
+induced	POS	O
+glaucoma	POS	B-NP
+in	POS	O
+human	POS	O
+patients	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+dexamethasone	POS	O
+-	POS	O
+induced	POS	O
+ocular	POS	O
+hypertension	POS	B-NP
+was	POS	O
+associated	POS	O
+with	POS	O
+chronic	POS	O
+ER	POS	O
+stress	POS	O
+of	POS	O
+the	POS	O
+trabecular	POS	O
+meshwork	POS	O
+(	POS	O
+TM	POS	O
+)	POS	O
+.	POS	O
+Similar	POS	O
+to	POS	O
+patients	POS	O
+,	POS	O
+withdrawal	POS	O
+of	POS	O
+dexamethasone	POS	O
+treatment	POS	O
+reduced	POS	O
+elevated	POS	O
+IOP	POS	O
+and	POS	O
+ER	POS	O
+stress	POS	O
+in	POS	O
+this	POS	O
+animal	POS	O
+model	POS	O
+.	POS	O
+Dexamethasone	POS	O
+induced	POS	O
+the	POS	O
+transcriptional	POS	O
+factor	POS	O
+CHOP	POS	O
+,	POS	O
+a	POS	O
+marker	POS	O
+for	POS	O
+chronic	POS	O
+ER	POS	O
+stress	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+anterior	POS	O
+segment	POS	O
+tissues	POS	O
+,	POS	O
+and	POS	O
+Chop	POS	O
+deletion	POS	O
+reduced	POS	O
+ER	POS	O
+stress	POS	O
+in	POS	O
+these	POS	O
+tissues	POS	O
+and	POS	O
+prevented	POS	O
+dexamethasone	POS	O
+-	POS	O
+induced	POS	O
+ocular	POS	O
+hypertension	POS	B-NP
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+reduction	POS	B-NP
+of	POS	I-NP
+ER	POS	I-NP
+stress	POS	I-NP
+in	POS	O
+the	POS	O
+TM	POS	O
+with	POS	O
+sodium	POS	O
+4	POS	O
+-	POS	O
+phenylbutyrate	POS	O
+prevented	POS	O
+dexamethasone	POS	O
+-	POS	O
+induced	POS	O
+ocular	POS	O
+hypertension	POS	B-NP
+in	POS	O
+WT	POS	O
+mice	POS	O
+.	POS	O
+Our	POS	O
+data	POS	O
+indicate	POS	O
+that	POS	O
+ER	POS	O
+stress	POS	O
+contributes	POS	O
+to	POS	O
+glucocorticoid	POS	O
+-	POS	O
+induced	POS	O
+ocular	POS	O
+hypertension	POS	B-NP
+and	POS	O
+suggest	POS	O
+that	POS	O
+reducing	POS	O
+ER	POS	O
+stress	POS	O
+has	POS	O
+potential	POS	O
+as	POS	O
+a	POS	O
+therapeutic	POS	O
+strategy	POS	O
+for	POS	O
+treating	POS	O
+glucocorticoid	POS	O
+-	POS	O
+induced	POS	O
+glaucoma	POS	B-NP
+.	POS	O
+Effects	POS	O
+of	POS	O
+ginsenosides	POS	O
+on	POS	O
+opioid	POS	O
+-	POS	O
+induced	POS	O
+hyperalgesia	POS	B-NP
+in	POS	O
+mice	POS	O
+.	POS	O
+Opioid	POS	O
+-	POS	O
+induced	POS	O
+hyperalgesia	POS	B-NP
+(	POS	O
+OIH	POS	O
+)	POS	O
+is	POS	O
+characterized	POS	O
+by	POS	O
+nociceptive	POS	O
+sensitization	POS	O
+caused	POS	O
+by	POS	O
+the	POS	O
+cessation	POS	O
+of	POS	O
+chronic	POS	O
+opioid	POS	O
+use	POS	O
+.	POS	O
+OIH	POS	O
+can	POS	O
+limit	POS	O
+the	POS	O
+clinical	POS	O
+use	POS	O
+of	POS	O
+opioid	POS	O
+analgesics	POS	O
+and	POS	O
+complicate	POS	O
+withdrawal	POS	O
+from	POS	O
+opioid	POS	O
+addiction	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+,	POS	O
+we	POS	O
+investigated	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+Re	POS	O
+,	POS	O
+Rg1	POS	O
+,	POS	O
+and	POS	O
+Rb1	POS	O
+ginsenosides	POS	O
+,	POS	O
+the	POS	O
+bioactive	POS	O
+components	POS	O
+of	POS	O
+ginseng	POS	O
+,	POS	O
+on	POS	O
+OIH	POS	O
+.	POS	O
+OIH	POS	O
+was	POS	O
+achieved	POS	O
+in	POS	O
+mice	POS	O
+after	POS	O
+subcutaneous	POS	O
+administration	POS	O
+of	POS	O
+morphine	POS	O
+for	POS	O
+7	POS	O
+consecutive	POS	O
+days	POS	O
+three	POS	O
+times	POS	O
+per	POS	O
+day	POS	O
+.	POS	O
+During	POS	O
+withdrawal	POS	O
+(	POS	O
+days	POS	O
+8	POS	O
+and	POS	O
+9	POS	O
+)	POS	O
+,	POS	O
+these	POS	O
+mice	POS	O
+were	POS	O
+administered	POS	O
+Re	POS	O
+,	POS	O
+Rg1	POS	O
+,	POS	O
+or	POS	O
+Rb1	POS	O
+intragastrically	POS	O
+two	POS	O
+times	POS	O
+per	POS	O
+day	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+test	POS	O
+day	POS	O
+(	POS	O
+day	POS	O
+10	POS	O
+)	POS	O
+,	POS	O
+mice	POS	O
+were	POS	O
+subjected	POS	O
+to	POS	O
+the	POS	O
+thermal	POS	O
+sensitivity	POS	O
+test	POS	O
+and	POS	O
+the	POS	O
+acetic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+writhing	POS	O
+test	POS	O
+.	POS	O
+Re	POS	O
+(	POS	O
+300	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+inhibited	POS	O
+OIH	POS	O
+in	POS	O
+both	POS	O
+the	POS	O
+thermal	POS	O
+sensitivity	POS	O
+test	POS	O
+and	POS	O
+the	POS	O
+acetic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+writhing	POS	O
+test	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+Rg1	POS	O
+and	POS	O
+Rb1	POS	O
+ginsenosides	POS	O
+failed	POS	O
+to	POS	O
+prevent	POS	O
+OIH	POS	O
+in	POS	O
+either	POS	O
+test	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+Rg1	POS	O
+showed	POS	O
+a	POS	O
+tendency	POS	O
+to	POS	O
+aggravate	POS	O
+OIH	POS	O
+in	POS	O
+the	POS	O
+acetic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+writhing	POS	O
+test	POS	O
+.	POS	O
+Our	POS	O
+data	POS	O
+suggested	POS	O
+that	POS	O
+the	POS	O
+ginsenoside	POS	O
+Re	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+Rg1	POS	O
+or	POS	O
+Rb1	POS	O
+,	POS	O
+may	POS	O
+contribute	POS	O
+toward	POS	O
+reversal	POS	O
+of	POS	O
+OIH	POS	O
+.	POS	O
+A	POS	O
+comparison	POS	O
+of	POS	O
+severe	POS	O
+hemodynamic	POS	B-NP
+disturbances	POS	I-NP
+between	POS	O
+dexmedetomidine	POS	O
+and	POS	O
+propofol	POS	O
+for	POS	O
+sedation	POS	O
+in	POS	O
+neurocritical	POS	O
+care	POS	O
+patients	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+Dexmedetomidine	POS	O
+and	POS	O
+propofol	POS	O
+are	POS	O
+commonly	POS	O
+used	POS	O
+sedatives	POS	O
+in	POS	O
+neurocritical	POS	O
+care	POS	O
+as	POS	O
+they	POS	O
+allow	POS	O
+for	POS	O
+frequent	POS	O
+neurologic	POS	O
+examinations	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+both	POS	O
+agents	POS	O
+are	POS	O
+associated	POS	O
+with	POS	O
+significant	POS	O
+hemodynamic	POS	O
+side	POS	O
+effects	POS	O
+.	POS	O
+The	POS	O
+primary	POS	O
+objective	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+is	POS	O
+to	POS	O
+compare	POS	O
+the	POS	O
+prevalence	POS	O
+of	POS	O
+severe	POS	O
+hemodynamic	POS	O
+effects	POS	O
+in	POS	O
+neurocritical	POS	O
+care	POS	O
+patients	POS	O
+receiving	POS	O
+dexmedetomidine	POS	O
+and	POS	O
+propofol	POS	O
+.	POS	O
+DESIGN	POS	O
+:	POS	O
+Multicenter	POS	O
+,	POS	O
+retrospective	POS	O
+,	POS	O
+propensity	POS	O
+-	POS	O
+matched	POS	O
+cohort	POS	O
+study	POS	O
+.	POS	O
+SETTING	POS	O
+:	POS	O
+Neurocritical	POS	O
+care	POS	O
+units	POS	O
+at	POS	O
+two	POS	O
+academic	POS	O
+medical	POS	O
+centers	POS	O
+with	POS	O
+dedicated	POS	O
+neurocritical	POS	O
+care	POS	O
+teams	POS	O
+and	POS	O
+board	POS	O
+-	POS	O
+certified	POS	O
+neurointensivists	POS	O
+.	POS	O
+PATIENTS	POS	O
+:	POS	O
+Neurocritical	POS	O
+care	POS	O
+patients	POS	O
+admitted	POS	O
+between	POS	O
+July	POS	O
+2009	POS	O
+and	POS	O
+September	POS	O
+2012	POS	O
+were	POS	O
+evaluated	POS	O
+and	POS	O
+then	POS	O
+matched	POS	O
+1	POS	O
+:	POS	O
+1	POS	O
+based	POS	O
+on	POS	O
+propensity	POS	O
+scoring	POS	O
+of	POS	O
+baseline	POS	O
+characteristics	POS	O
+.	POS	O
+INTERVENTIONS	POS	O
+:	POS	O
+Continuous	POS	O
+sedation	POS	O
+with	POS	O
+dexmedetomidine	POS	O
+or	POS	O
+propofol	POS	O
+.	POS	O
+MEASUREMENTS	POS	O
+AND	POS	O
+MAIN	POS	O
+RESULTS	POS	O
+:	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+342	POS	O
+patients	POS	O
+(	POS	O
+105	POS	O
+dexmedetomidine	POS	O
+and	POS	O
+237	POS	O
+propofol	POS	O
+)	POS	O
+were	POS	O
+included	POS	O
+in	POS	O
+the	POS	O
+analysis	POS	O
+,	POS	O
+with	POS	O
+190	POS	O
+matched	POS	O
+(	POS	O
+95	POS	O
+in	POS	O
+each	POS	O
+group	POS	O
+)	POS	O
+by	POS	O
+propensity	POS	O
+score	POS	O
+.	POS	O
+The	POS	O
+primary	POS	O
+outcome	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+a	POS	O
+composite	POS	O
+of	POS	O
+severe	POS	O
+hypotension	POS	B-NP
+(	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+<	POS	O
+60	POS	O
+mm	POS	O
+Hg	POS	O
+)	POS	O
+and	POS	O
+bradycardia	POS	B-NP
+(	POS	O
+heart	POS	O
+rate	POS	O
+<	POS	O
+50	POS	O
+beats	POS	O
+/	POS	O
+min	POS	O
+)	POS	O
+during	POS	O
+sedative	POS	O
+infusion	POS	O
+.	POS	O
+No	POS	O
+difference	POS	O
+in	POS	O
+the	POS	O
+primary	POS	O
+composite	POS	O
+outcome	POS	O
+in	POS	O
+both	POS	O
+the	POS	O
+unmatched	POS	O
+(	POS	O
+30	POS	O
+%	POS	O
+vs	POS	O
+30	POS	O
+%	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+94	POS	O
+)	POS	O
+or	POS	O
+matched	POS	O
+cohorts	POS	O
+(	POS	O
+28	POS	O
+%	POS	O
+vs	POS	O
+34	POS	O
+%	POS	O
+,	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+35	POS	O
+)	POS	O
+could	POS	O
+be	POS	O
+found	POS	O
+.	POS	O
+When	POS	O
+analyzed	POS	O
+separately	POS	O
+,	POS	O
+no	POS	O
+differences	POS	O
+could	POS	O
+be	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+prevalence	POS	O
+of	POS	O
+severe	POS	O
+hypotension	POS	B-NP
+or	POS	O
+bradycardia	POS	B-NP
+in	POS	O
+either	POS	O
+the	POS	O
+unmatched	POS	O
+or	POS	O
+matched	POS	O
+cohorts	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Severe	POS	O
+hypotension	POS	B-NP
+and	POS	O
+bradycardia	POS	B-NP
+occur	POS	O
+at	POS	O
+similar	POS	O
+prevalence	POS	O
+in	POS	O
+neurocritical	POS	O
+care	POS	O
+patients	POS	O
+who	POS	O
+receive	POS	O
+dexmedetomidine	POS	O
+or	POS	O
+propofol	POS	O
+.	POS	O
+Providers	POS	O
+should	POS	O
+similarly	POS	O
+consider	POS	O
+the	POS	O
+likelihood	POS	O
+of	POS	O
+hypotension	POS	B-NP
+or	POS	O
+bradycardia	POS	B-NP
+before	POS	O
+starting	POS	O
+either	POS	O
+sedative	POS	O
+.	POS	O
+Hydroxytyrosol	POS	O
+ameliorates	POS	O
+oxidative	POS	O
+stress	POS	O
+and	POS	O
+mitochondrial	POS	B-NP
+dysfunction	POS	I-NP
+in	POS	O
+doxorubicin	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+in	POS	O
+rats	POS	O
+with	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+Oxidative	POS	O
+stress	POS	O
+is	POS	O
+involved	POS	O
+in	POS	O
+several	POS	O
+processes	POS	O
+including	POS	O
+cancer	POS	B-NP
+,	POS	O
+aging	POS	O
+and	POS	O
+cardiovascular	POS	B-NP
+disease	POS	I-NP
+,	POS	O
+and	POS	O
+has	POS	O
+been	POS	O
+shown	POS	O
+to	POS	O
+potentiate	POS	O
+the	POS	O
+therapeutic	POS	O
+effect	POS	O
+of	POS	O
+drugs	POS	O
+such	POS	O
+as	POS	O
+doxorubicin	POS	O
+.	POS	O
+Doxorubicin	POS	O
+causes	POS	O
+significant	POS	O
+cardiotoxicity	POS	B-NP
+characterized	POS	O
+by	POS	O
+marked	POS	O
+increases	POS	O
+in	POS	O
+oxidative	POS	O
+stress	POS	O
+and	POS	O
+mitochondrial	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+Herein	POS	O
+,	POS	O
+we	POS	O
+investigate	POS	O
+whether	POS	O
+doxorubicin	POS	O
+-	POS	O
+associated	POS	O
+chronic	POS	O
+cardiac	POS	B-NP
+toxicity	POS	I-NP
+can	POS	O
+be	POS	O
+ameliorated	POS	O
+with	POS	O
+the	POS	O
+antioxidant	POS	O
+hydroxytyrosol	POS	O
+in	POS	O
+rats	POS	O
+with	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+Thirty	POS	O
+-	POS	O
+six	POS	O
+rats	POS	O
+bearing	POS	O
+breast	POS	B-NP
+tumors	POS	I-NP
+induced	POS	O
+chemically	POS	O
+were	POS	O
+divided	POS	O
+into	POS	O
+4	POS	O
+groups	POS	O
+:	POS	O
+control	POS	O
+,	POS	O
+hydroxytyrosol	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+5mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+5days	POS	O
+/	POS	O
+week	POS	O
+)	POS	O
+,	POS	O
+doxorubicin	POS	O
+(	POS	O
+1mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+week	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+doxorubicin	POS	O
+plus	POS	O
+hydroxytyrosol	POS	O
+.	POS	O
+Cardiac	POS	O
+disturbances	POS	O
+at	POS	O
+the	POS	O
+cellular	POS	O
+and	POS	O
+mitochondrial	POS	O
+level	POS	O
+,	POS	O
+mitochondrial	POS	O
+electron	POS	O
+transport	POS	O
+chain	POS	O
+complexes	POS	O
+I	POS	O
+-	POS	O
+IV	POS	O
+and	POS	O
+apoptosis	POS	O
+-	POS	O
+inducing	POS	O
+factor	POS	O
+,	POS	O
+and	POS	O
+oxidative	POS	O
+stress	POS	O
+markers	POS	O
+have	POS	O
+been	POS	O
+analyzed	POS	O
+.	POS	O
+Hydroxytyrosol	POS	O
+improved	POS	O
+the	POS	O
+cardiac	POS	B-NP
+disturbances	POS	I-NP
+enhanced	POS	O
+by	POS	O
+doxorubicin	POS	O
+by	POS	O
+significantly	POS	O
+reducing	POS	O
+the	POS	O
+percentage	POS	O
+of	POS	O
+altered	POS	O
+mitochondria	POS	O
+and	POS	O
+oxidative	POS	O
+damage	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+hydroxytyrosol	POS	O
+improve	POS	O
+the	POS	O
+mitochondrial	POS	O
+electron	POS	O
+transport	POS	O
+chain	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+demonstrates	POS	O
+that	POS	O
+hydroxytyrosol	POS	O
+protect	POS	O
+rat	POS	O
+heart	POS	O
+damage	POS	O
+provoked	POS	O
+by	POS	O
+doxorubicin	POS	O
+decreasing	POS	O
+oxidative	POS	O
+damage	POS	O
+and	POS	O
+mitochondrial	POS	O
+alterations	POS	O
+.	POS	O
+Amiodarone	POS	O
+-	POS	O
+induced	POS	O
+myxoedema	POS	B-NP
+coma	POS	I-NP
+.	POS	O
+A	POS	O
+62	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+was	POS	O
+found	POS	O
+to	POS	O
+have	POS	O
+bradycardia	POS	B-NP
+,	POS	O
+hypothermia	POS	B-NP
+and	POS	O
+respiratory	POS	B-NP
+failure	POS	I-NP
+3	POS	O
+weeks	POS	O
+after	POS	O
+initiation	POS	O
+of	POS	O
+amiodarone	POS	O
+therapy	POS	O
+for	POS	O
+atrial	POS	B-NP
+fibrillation	POS	I-NP
+.	POS	O
+Thyroid	POS	O
+-	POS	O
+stimulating	POS	O
+hormone	POS	O
+was	POS	O
+found	POS	O
+to	POS	O
+be	POS	O
+168	POS	O
+uIU	POS	O
+/	POS	O
+mL	POS	O
+(	POS	O
+nl	POS	O
+.	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+-	POS	O
+5	POS	O
+uIU	POS	O
+/	POS	O
+mL	POS	O
+)	POS	O
+and	POS	O
+free	POS	O
+thyroxine	POS	O
+(	POS	O
+FT4	POS	O
+)	POS	O
+was	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+2	POS	O
+ng	POS	O
+/	POS	O
+dL	POS	O
+(	POS	O
+nl	POS	O
+.	POS	O
+0	POS	O
+.	POS	O
+8	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+8	POS	O
+ng	POS	O
+/	POS	O
+dL	POS	O
+)	POS	O
+.	POS	O
+He	POS	O
+received	POS	O
+intravenous	POS	O
+fluids	POS	O
+,	POS	O
+vasopressor	POS	O
+therapy	POS	O
+and	POS	O
+stress	POS	O
+dose	POS	O
+steroids	POS	O
+;	POS	O
+he	POS	O
+was	POS	O
+intubated	POS	O
+and	POS	O
+admitted	POS	O
+to	POS	O
+the	POS	O
+intensive	POS	O
+care	POS	O
+unit	POS	O
+.	POS	O
+He	POS	O
+received	POS	O
+500	POS	O
+ug	POS	O
+of	POS	O
+intravenous	POS	O
+levothyroxine	POS	O
+in	POS	O
+the	POS	O
+first	POS	O
+18	POS	O
+h	POS	O
+of	POS	O
+therapy	POS	O
+,	POS	O
+and	POS	O
+150	POS	O
+ug	POS	O
+intravenous	POS	O
+daily	POS	O
+thereafter	POS	O
+.	POS	O
+Haemodynamic	POS	O
+improvement	POS	O
+,	POS	O
+along	POS	O
+with	POS	O
+complete	POS	O
+recovery	POS	O
+of	POS	O
+mental	POS	O
+status	POS	O
+,	POS	O
+occurred	POS	O
+after	POS	O
+48	POS	O
+h	POS	O
+.	POS	O
+Twelve	POS	O
+hours	POS	O
+after	POS	O
+the	POS	O
+initiation	POS	O
+of	POS	O
+therapy	POS	O
+,	POS	O
+FT4	POS	O
+was	POS	O
+0	POS	O
+.	POS	O
+96	POS	O
+ng	POS	O
+/	POS	O
+dL	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+was	POS	O
+maintained	POS	O
+on	POS	O
+levothyroxine	POS	O
+175	POS	O
+(	POS	O
+g	POS	O
+POorally	POS	O
+daily	POS	O
+.	POS	O
+A	POS	O
+thyroid	POS	O
+ultrasound	POS	O
+showed	POS	O
+diffuse	POS	O
+heterogeneity	POS	O
+.	POS	O
+The	POS	O
+24	POS	O
+hour	POS	O
+excretion	POS	O
+of	POS	O
+iodine	POS	O
+was	POS	O
+3657	POS	O
+(	POS	O
+mcg	POS	O
+(	POS	O
+25	POS	O
+-	POS	O
+756	POS	O
+(	POS	O
+mcg	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+only	POS	O
+two	POS	O
+cases	POS	O
+of	POS	O
+amiodarone	POS	O
+-	POS	O
+induced	POS	O
+myxoedema	POS	B-NP
+coma	POS	I-NP
+in	POS	O
+the	POS	O
+literature	POS	O
+report	POS	O
+patient	POS	O
+death	POS	B-NP
+despite	POS	O
+supportive	POS	O
+therapy	POS	O
+and	POS	O
+thyroid	POS	O
+hormone	POS	O
+replacement	POS	O
+.	POS	O
+This	POS	O
+case	POS	O
+represents	POS	O
+the	POS	O
+most	POS	O
+thoroughly	POS	O
+investigated	POS	O
+case	POS	O
+of	POS	O
+amiodarone	POS	O
+-	POS	O
+induced	POS	O
+myxoedema	POS	B-NP
+coma	POS	I-NP
+with	POS	O
+a	POS	O
+history	POS	O
+significant	POS	O
+for	POS	O
+subclinical	POS	B-NP
+thyroid	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+Use	POS	O
+of	POS	O
+argatroban	POS	O
+and	POS	O
+catheter	POS	O
+-	POS	O
+directed	POS	O
+thrombolysis	POS	B-NP
+with	POS	O
+alteplase	POS	O
+in	POS	O
+an	POS	O
+oncology	POS	O
+patient	POS	O
+with	POS	O
+heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+with	POS	O
+thrombosis	POS	B-NP
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+The	POS	O
+case	POS	O
+of	POS	O
+an	POS	O
+oncology	POS	O
+patient	POS	O
+who	POS	O
+developed	POS	O
+heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+with	POS	O
+thrombosis	POS	B-NP
+(	POS	O
+HITT	POS	B-NP
+)	POS	O
+and	POS	O
+was	POS	O
+treated	POS	O
+with	POS	O
+argatroban	POS	O
+plus	POS	O
+catheter	POS	O
+-	POS	O
+directed	POS	O
+thrombolysis	POS	B-NP
+(	POS	O
+CDT	POS	O
+)	POS	O
+with	POS	O
+alteplase	POS	O
+is	POS	O
+presented	POS	O
+.	POS	O
+SUMMARY	POS	O
+:	POS	O
+A	POS	O
+63	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+Caucasian	POS	O
+man	POS	O
+with	POS	O
+renal	POS	B-NP
+amyloidosis	POS	I-NP
+undergoing	POS	O
+peripheral	POS	O
+blood	POS	O
+stem	POS	O
+cell	POS	O
+collection	POS	O
+for	POS	O
+an	POS	O
+autologous	POS	O
+stem	POS	O
+cell	POS	O
+transplant	POS	O
+developed	POS	O
+extensive	POS	O
+bilateral	POS	B-NP
+upper	POS	I-NP
+-	POS	I-NP
+extremity	POS	I-NP
+deep	POS	I-NP
+venous	POS	I-NP
+thrombosis	POS	I-NP
+(	POS	O
+DVT	POS	B-NP
+)	POS	O
+and	POS	O
+pulmonary	POS	B-NP
+embolism	POS	I-NP
+secondary	POS	O
+to	POS	O
+heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+.	POS	O
+A	POS	O
+continuous	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+infusion	POS	O
+of	POS	O
+argatroban	POS	O
+was	POS	O
+initiated	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+managed	POS	O
+on	POS	O
+the	POS	O
+general	POS	O
+medical	POS	O
+floor	POS	O
+.	POS	O
+After	POS	O
+one	POS	O
+week	POS	O
+of	POS	O
+therapy	POS	O
+,	POS	O
+he	POS	O
+was	POS	O
+transferred	POS	O
+to	POS	O
+the	POS	O
+intensive	POS	O
+care	POS	O
+unit	POS	O
+with	POS	O
+cardiopulmonary	POS	O
+compromise	POS	O
+related	POS	O
+to	POS	O
+superior	POS	B-NP
+vena	POS	I-NP
+cava	POS	I-NP
+(	POS	I-NP
+SVC	POS	I-NP
+)	POS	I-NP
+syndrome	POS	I-NP
+.	POS	O
+A	POS	O
+percutaneous	POS	O
+mechanical	POS	O
+thrombectomy	POS	O
+and	POS	O
+CDT	POS	O
+with	POS	O
+alteplase	POS	O
+were	POS	O
+attempted	POS	O
+,	POS	O
+but	POS	O
+the	POS	O
+procedure	POS	O
+was	POS	O
+aborted	POS	O
+due	POS	O
+to	POS	O
+epistaxis	POS	B-NP
+.	POS	O
+The	POS	O
+epistaxis	POS	B-NP
+resolved	POS	O
+the	POS	O
+next	POS	O
+day	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+restarted	POS	O
+on	POS	O
+argatroban	POS	O
+.	POS	O
+A	POS	O
+second	POS	O
+percutaneous	POS	O
+mechanical	POS	O
+thrombectomy	POS	O
+was	POS	O
+performed	POS	O
+six	POS	O
+days	POS	O
+later	POS	O
+and	POS	O
+resulted	POS	O
+in	POS	O
+partial	POS	O
+revascularization	POS	O
+of	POS	O
+the	POS	O
+SVC	POS	O
+and	POS	O
+central	POS	O
+veins	POS	O
+.	POS	O
+Postthrombectomy	POS	O
+continuous	POS	O
+CDT	POS	O
+with	POS	O
+alteplase	POS	O
+was	POS	O
+commenced	POS	O
+while	POS	O
+argatroban	POS	O
+was	POS	O
+withheld	POS	O
+,	POS	O
+and	POS	O
+complete	POS	O
+patency	POS	O
+of	POS	O
+the	POS	O
+SVC	POS	O
+and	POS	O
+central	POS	O
+veins	POS	O
+was	POS	O
+achieved	POS	O
+after	POS	O
+three	POS	O
+days	POS	O
+of	POS	O
+therapy	POS	O
+.	POS	O
+Alteplase	POS	O
+was	POS	O
+discontinued	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+reinitiated	POS	O
+on	POS	O
+argatroban	POS	O
+;	POS	O
+ultimately	POS	O
+,	POS	O
+he	POS	O
+was	POS	O
+transitioned	POS	O
+to	POS	O
+warfarin	POS	O
+for	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+anticoagulation	POS	O
+.	POS	O
+Although	POS	O
+the	POS	O
+patient	POS	O
+recovered	POS	O
+,	POS	O
+he	POS	O
+experienced	POS	O
+permanent	POS	O
+vision	POS	O
+and	POS	O
+hearing	POS	B-NP
+loss	POS	I-NP
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+end	POS	O
+-	POS	O
+stage	POS	O
+renal	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+A	POS	O
+63	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+with	POS	O
+renal	POS	B-NP
+amyloidosis	POS	I-NP
+and	POS	O
+SVC	POS	B-NP
+syndrome	POS	I-NP
+secondary	POS	O
+to	POS	O
+HITT	POS	B-NP
+was	POS	O
+successfully	POS	O
+treated	POS	O
+with	POS	O
+argatroban	POS	O
+and	POS	O
+CDT	POS	O
+with	POS	O
+alteplase	POS	O
+.	POS	O
+Effects	POS	O
+of	POS	O
+dehydroepiandrosterone	POS	O
+in	POS	O
+amphetamine	POS	O
+-	POS	O
+induced	POS	O
+schizophrenia	POS	B-NP
+models	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+examine	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+dehydroepiandrosterone	POS	O
+(	POS	O
+DHEA	POS	O
+)	POS	O
+on	POS	O
+animal	POS	O
+models	POS	O
+of	POS	O
+schizophrenia	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Seventy	POS	O
+Swiss	POS	O
+albino	POS	O
+female	POS	O
+mice	POS	O
+(	POS	O
+25	POS	O
+-	POS	O
+35	POS	O
+g	POS	O
+)	POS	O
+were	POS	O
+divided	POS	O
+into	POS	O
+4	POS	O
+groups	POS	O
+:	POS	O
+amphetamine	POS	O
+-	POS	O
+free	POS	O
+(	POS	O
+control	POS	O
+)	POS	O
+,	POS	O
+amphetamine	POS	O
+,	POS	O
+50	POS	O
+,	POS	O
+and	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+DHEA	POS	O
+.	POS	O
+The	POS	O
+DHEA	POS	O
+was	POS	O
+administered	POS	O
+intraperitoneally	POS	O
+(	POS	O
+ip	POS	O
+)	POS	O
+for	POS	O
+5	POS	O
+days	POS	O
+.	POS	O
+Amphetamine	POS	O
+(	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+ip	POS	O
+)	POS	O
+induced	POS	O
+hyper	POS	O
+locomotion	POS	O
+,	POS	O
+apomorphine	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+subcutaneously	POS	O
+[	POS	O
+sc	POS	O
+]	POS	O
+)	POS	O
+induced	POS	O
+climbing	POS	O
+,	POS	O
+and	POS	O
+haloperidol	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+sc	POS	O
+)	POS	O
+induced	POS	O
+catalepsy	POS	B-NP
+tests	POS	O
+were	POS	O
+used	POS	O
+as	POS	O
+animal	POS	O
+models	POS	O
+of	POS	O
+schizophrenia	POS	B-NP
+.	POS	O
+The	POS	O
+study	POS	O
+was	POS	O
+conducted	POS	O
+at	POS	O
+the	POS	O
+Animal	POS	O
+Experiment	POS	O
+Laboratories	POS	O
+,	POS	O
+Department	POS	O
+of	POS	O
+Pharmacology	POS	O
+,	POS	O
+Medical	POS	O
+School	POS	O
+,	POS	O
+Eskisehir	POS	O
+Osmangazi	POS	O
+University	POS	O
+,	POS	O
+Eskisehir	POS	O
+,	POS	O
+Turkey	POS	O
+between	POS	O
+March	POS	O
+and	POS	O
+May	POS	O
+2012	POS	O
+.	POS	O
+Statistical	POS	O
+analysis	POS	O
+was	POS	O
+carried	POS	O
+out	POS	O
+using	POS	O
+Kruskal	POS	O
+-	POS	O
+Wallis	POS	O
+test	POS	O
+for	POS	O
+hyper	POS	O
+locomotion	POS	O
+,	POS	O
+and	POS	O
+one	POS	O
+-	POS	O
+way	POS	O
+ANOVA	POS	O
+for	POS	O
+climbing	POS	O
+and	POS	O
+catalepsy	POS	B-NP
+tests	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+In	POS	O
+the	POS	O
+amphetamine	POS	O
+-	POS	O
+induced	POS	O
+locomotion	POS	O
+test	POS	O
+,	POS	O
+there	POS	O
+were	POS	O
+significant	POS	O
+increases	POS	O
+in	POS	O
+all	POS	O
+movements	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+amphetamine	POS	O
+-	POS	O
+free	POS	O
+group	POS	O
+.	POS	O
+Both	POS	O
+DHEA	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+significantly	POS	O
+decreased	POS	O
+all	POS	O
+movements	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+amphetamine	POS	O
+-	POS	O
+induced	POS	O
+locomotion	POS	O
+group	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+difference	POS	O
+between	POS	O
+groups	POS	O
+in	POS	O
+the	POS	O
+haloperidol	POS	O
+-	POS	O
+induced	POS	O
+catalepsy	POS	B-NP
+test	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+significant	POS	O
+difference	POS	O
+between	POS	O
+groups	POS	O
+in	POS	O
+terms	POS	O
+of	POS	O
+total	POS	O
+climbing	POS	O
+time	POS	O
+in	POS	O
+the	POS	O
+apomorphine	POS	O
+-	POS	O
+induced	POS	O
+climbing	POS	O
+test	POS	O
+(	POS	O
+p	POS	O
+>	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+We	POS	O
+observed	POS	O
+that	POS	O
+DHEA	POS	O
+reduced	POS	O
+locomotor	POS	O
+activity	POS	O
+and	POS	O
+increased	POS	O
+catalepsy	POS	B-NP
+at	POS	O
+both	POS	O
+doses	POS	O
+,	POS	O
+while	POS	O
+it	POS	O
+had	POS	O
+no	POS	O
+effect	POS	O
+on	POS	O
+climbing	POS	O
+behavior	POS	O
+.	POS	O
+We	POS	O
+suggest	POS	O
+that	POS	O
+DHEA	POS	O
+displays	POS	O
+typical	POS	O
+neuroleptic	POS	O
+-	POS	O
+like	POS	O
+effects	POS	O
+,	POS	O
+and	POS	O
+may	POS	O
+be	POS	O
+used	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+schizophrenia	POS	B-NP
+.	POS	O
+Availability	POS	O
+of	POS	O
+human	POS	O
+induced	POS	O
+pluripotent	POS	O
+stem	POS	O
+cell	POS	O
+-	POS	O
+derived	POS	O
+cardiomyocytes	POS	O
+in	POS	O
+assessment	POS	O
+of	POS	O
+drug	POS	O
+potential	POS	O
+for	POS	O
+QT	POS	O
+prolongation	POS	O
+.	POS	O
+Field	POS	O
+potential	POS	O
+duration	POS	O
+(	POS	O
+FPD	POS	O
+)	POS	O
+in	POS	O
+human	POS	O
+-	POS	O
+induced	POS	O
+pluripotent	POS	O
+stem	POS	O
+cell	POS	O
+-	POS	O
+derived	POS	O
+cardiomyocytes	POS	O
+(	POS	O
+hiPS	POS	O
+-	POS	O
+CMs	POS	O
+)	POS	O
+,	POS	O
+which	POS	O
+can	POS	O
+express	POS	O
+QT	POS	O
+interval	POS	O
+in	POS	O
+an	POS	O
+electrocardiogram	POS	O
+,	POS	O
+is	POS	O
+reported	POS	O
+to	POS	O
+be	POS	O
+a	POS	O
+useful	POS	O
+tool	POS	O
+to	POS	O
+predict	POS	O
+K	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+channel	POS	O
+and	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+channel	POS	O
+blocker	POS	O
+effects	POS	O
+on	POS	O
+QT	POS	O
+interval	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+there	POS	O
+is	POS	O
+no	POS	O
+report	POS	O
+showing	POS	O
+that	POS	O
+this	POS	O
+technique	POS	O
+can	POS	O
+be	POS	O
+used	POS	O
+to	POS	O
+predict	POS	O
+multichannel	POS	O
+blocker	POS	O
+potential	POS	O
+for	POS	O
+QT	POS	O
+prolongation	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+is	POS	O
+to	POS	O
+show	POS	O
+that	POS	O
+FPD	POS	O
+from	POS	O
+MEA	POS	O
+(	POS	O
+Multielectrode	POS	O
+array	POS	O
+)	POS	O
+of	POS	O
+hiPS	POS	O
+-	POS	O
+CMs	POS	O
+can	POS	O
+detect	POS	O
+QT	POS	O
+prolongation	POS	O
+induced	POS	O
+by	POS	O
+multichannel	POS	O
+blockers	POS	O
+.	POS	O
+hiPS	POS	O
+-	POS	O
+CMs	POS	O
+were	POS	O
+seeded	POS	O
+onto	POS	O
+MEA	POS	O
+and	POS	O
+FPD	POS	O
+was	POS	O
+measured	POS	O
+for	POS	O
+2min	POS	O
+every	POS	O
+10min	POS	O
+for	POS	O
+30min	POS	O
+after	POS	O
+drug	POS	O
+exposure	POS	O
+for	POS	O
+the	POS	O
+vehicle	POS	O
+and	POS	O
+each	POS	O
+drug	POS	O
+concentration	POS	O
+.	POS	O
+IKr	POS	O
+and	POS	O
+IKs	POS	O
+blockers	POS	O
+concentration	POS	O
+-	POS	O
+dependently	POS	O
+prolonged	POS	O
+corrected	POS	O
+FPD	POS	O
+(	POS	O
+FPDc	POS	O
+)	POS	O
+,	POS	O
+whereas	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+channel	POS	O
+blockers	POS	O
+concentration	POS	O
+-	POS	O
+dependently	POS	O
+shortened	POS	O
+FPDc	POS	O
+.	POS	O
+Also	POS	O
+,	POS	O
+the	POS	O
+multichannel	POS	O
+blockers	POS	O
+Amiodarone	POS	O
+,	POS	O
+Paroxetine	POS	O
+,	POS	O
+Terfenadine	POS	O
+and	POS	O
+Citalopram	POS	O
+prolonged	POS	O
+FPDc	POS	O
+in	POS	O
+a	POS	O
+concentration	POS	O
+dependent	POS	O
+manner	POS	O
+.	POS	O
+Finally	POS	O
+,	POS	O
+the	POS	O
+IKr	POS	O
+blockers	POS	O
+,	POS	O
+Terfenadine	POS	O
+and	POS	O
+Citalopram	POS	O
+,	POS	O
+which	POS	O
+are	POS	O
+reported	POS	O
+to	POS	O
+cause	POS	O
+Torsade	POS	B-NP
+de	POS	I-NP
+Pointes	POS	I-NP
+(	POS	O
+TdP	POS	B-NP
+)	POS	O
+in	POS	O
+clinical	POS	O
+practice	POS	O
+,	POS	O
+produced	POS	O
+early	POS	O
+afterdepolarization	POS	B-NP
+(	POS	O
+EAD	POS	B-NP
+)	POS	O
+.	POS	O
+hiPS	POS	O
+-	POS	O
+CMs	POS	O
+using	POS	O
+MEA	POS	O
+system	POS	O
+and	POS	O
+FPDc	POS	O
+can	POS	O
+predict	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+drug	POS	O
+candidates	POS	O
+on	POS	O
+QT	POS	O
+interval	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+also	POS	O
+shows	POS	O
+that	POS	O
+this	POS	O
+assay	POS	O
+can	POS	O
+help	POS	O
+detect	POS	O
+EAD	POS	B-NP
+for	POS	O
+drugs	POS	O
+with	POS	O
+TdP	POS	B-NP
+potential	POS	O
+.	POS	O
+Dermal	POS	B-NP
+developmental	POS	I-NP
+toxicity	POS	I-NP
+of	POS	O
+N	POS	O
+-	POS	O
+phenylimide	POS	O
+herbicides	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+S	POS	O
+-	POS	O
+53482	POS	O
+and	POS	O
+S	POS	O
+-	POS	O
+23121	POS	O
+are	POS	O
+N	POS	O
+-	POS	O
+phenylimide	POS	O
+herbicides	POS	O
+and	POS	O
+produced	POS	O
+embryolethality	POS	B-NP
+,	POS	O
+teratogenicity	POS	B-NP
+(	POS	O
+mainly	POS	O
+ventricular	POS	B-NP
+septal	POS	I-NP
+defects	POS	I-NP
+and	POS	O
+wavy	POS	O
+ribs	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+growth	POS	B-NP
+retardation	POS	I-NP
+in	POS	O
+rats	POS	O
+in	POS	O
+conventional	POS	O
+oral	POS	O
+developmental	POS	O
+toxicity	POS	B-NP
+studies	POS	O
+.	POS	O
+Our	POS	O
+objective	POS	O
+in	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+investigate	POS	O
+whether	POS	O
+the	POS	O
+compounds	POS	O
+induce	POS	O
+developmental	POS	O
+toxicity	POS	O
+via	POS	O
+the	POS	O
+dermal	POS	O
+route	POS	O
+,	POS	O
+which	POS	O
+is	POS	O
+more	POS	O
+relevant	POS	O
+to	POS	O
+occupational	POS	O
+exposure	POS	O
+,	POS	O
+hence	POS	O
+better	POS	O
+addressing	POS	O
+human	POS	O
+health	POS	O
+risks	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+S	POS	O
+-	POS	O
+53482	POS	O
+was	POS	O
+administered	POS	O
+dermally	POS	O
+to	POS	O
+rats	POS	O
+at	POS	O
+30	POS	O
+,	POS	O
+100	POS	O
+,	POS	O
+and	POS	O
+300	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+during	POS	O
+organogenesis	POS	O
+,	POS	O
+and	POS	O
+S	POS	O
+-	POS	O
+23121	POS	O
+was	POS	O
+administered	POS	O
+at	POS	O
+200	POS	O
+,	POS	O
+400	POS	O
+,	POS	O
+and	POS	O
+800	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+the	POS	O
+maximum	POS	O
+applicable	POS	O
+dose	POS	O
+level	POS	O
+)	POS	O
+.	POS	O
+Fetuses	POS	O
+were	POS	O
+obtained	POS	O
+by	POS	O
+a	POS	O
+Cesarean	POS	O
+section	POS	O
+and	POS	O
+examined	POS	O
+for	POS	O
+external	POS	O
+,	POS	O
+visceral	POS	O
+,	POS	O
+and	POS	O
+skeletal	POS	O
+alterations	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Dermal	POS	O
+exposure	POS	O
+of	POS	O
+rats	POS	O
+to	POS	O
+S	POS	O
+-	POS	O
+53482	POS	O
+at	POS	O
+300	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+produced	POS	O
+patterns	POS	O
+of	POS	O
+developmental	POS	O
+toxicity	POS	B-NP
+similar	POS	O
+to	POS	O
+those	POS	O
+resulting	POS	O
+from	POS	O
+oral	POS	O
+exposure	POS	O
+.	POS	O
+Toxicity	POS	O
+included	POS	O
+embryolethality	POS	B-NP
+,	POS	O
+teratogenicity	POS	B-NP
+,	POS	O
+and	POS	O
+growth	POS	B-NP
+retardation	POS	I-NP
+.	POS	O
+Dermal	POS	O
+administration	POS	O
+of	POS	O
+S	POS	O
+-	POS	O
+23121	POS	O
+at	POS	O
+800	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+resulted	POS	O
+in	POS	O
+an	POS	O
+increased	POS	O
+incidence	POS	O
+of	POS	O
+embryonic	POS	B-NP
+death	POS	I-NP
+and	POS	O
+ventricular	POS	B-NP
+septal	POS	I-NP
+defect	POS	I-NP
+,	POS	O
+but	POS	O
+retarded	POS	O
+fetal	POS	O
+growth	POS	O
+was	POS	O
+not	POS	O
+observed	POS	O
+as	POS	O
+it	POS	O
+was	POS	O
+following	POS	O
+oral	POS	O
+exposure	POS	O
+to	POS	O
+S	POS	O
+-	POS	O
+23121	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Based	POS	O
+on	POS	O
+the	POS	O
+results	POS	O
+,	POS	O
+S	POS	O
+-	POS	O
+53482	POS	O
+and	POS	O
+S	POS	O
+-	POS	O
+23121	POS	O
+were	POS	O
+teratogenic	POS	O
+when	POS	O
+administered	POS	O
+dermally	POS	O
+to	POS	O
+pregnant	POS	O
+rats	POS	O
+as	POS	O
+were	POS	O
+the	POS	O
+compounds	POS	O
+administered	POS	O
+orally	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+investigation	POS	O
+of	POS	O
+the	POS	O
+mechanism	POS	O
+and	POS	O
+its	POS	O
+human	POS	O
+relevancy	POS	O
+become	POS	O
+more	POS	O
+important	POS	O
+.	POS	O
+Rates	POS	O
+of	POS	O
+Renal	POS	O
+Toxicity	POS	O
+in	POS	O
+Cancer	POS	O
+Patients	POS	O
+Receiving	POS	O
+Cisplatin	POS	O
+With	POS	O
+and	POS	O
+Without	POS	O
+Mannitol	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Cisplatin	POS	O
+is	POS	O
+a	POS	O
+widely	POS	O
+used	POS	O
+antineoplastic	POS	O
+.	POS	O
+One	POS	O
+of	POS	O
+the	POS	O
+major	POS	O
+complications	POS	O
+of	POS	O
+cisplatin	POS	O
+use	POS	O
+is	POS	O
+dose	POS	O
+-	POS	O
+limiting	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+There	POS	O
+are	POS	O
+many	POS	O
+strategies	POS	O
+to	POS	O
+prevent	POS	O
+this	POS	O
+toxicity	POS	B-NP
+,	POS	O
+including	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+mannitol	POS	O
+as	POS	O
+a	POS	O
+nephroprotectant	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+hydration	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+We	POS	O
+aimed	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+rates	POS	O
+of	POS	O
+cisplatin	POS	O
+-	POS	O
+induced	POS	O
+nephrotoxicity	POS	B-NP
+in	POS	O
+cancer	POS	B-NP
+patients	POS	O
+receiving	POS	O
+single	POS	O
+-	POS	O
+agent	POS	O
+cisplatin	POS	O
+with	POS	O
+and	POS	O
+without	POS	O
+mannitol	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+This	POS	O
+single	POS	O
+-	POS	O
+center	POS	O
+retrospective	POS	O
+analysis	POS	O
+was	POS	O
+a	POS	O
+quasi	POS	O
+experiment	POS	O
+created	POS	O
+by	POS	O
+the	POS	O
+national	POS	O
+mannitol	POS	O
+shortage	POS	O
+.	POS	O
+Data	POS	O
+were	POS	O
+collected	POS	O
+on	POS	O
+adult	POS	O
+cancer	POS	B-NP
+patients	POS	O
+receiving	POS	O
+single	POS	O
+-	POS	O
+agent	POS	O
+cisplatin	POS	O
+as	POS	O
+an	POS	O
+outpatient	POS	O
+from	POS	O
+January	POS	O
+2011	POS	O
+to	POS	O
+September	POS	O
+2012	POS	O
+.	POS	O
+The	POS	O
+primary	POS	O
+outcome	POS	O
+was	POS	O
+acute	POS	B-NP
+kidney	POS	I-NP
+injury	POS	I-NP
+(	POS	O
+AKI	POS	B-NP
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+We	POS	O
+evaluated	POS	O
+143	POS	O
+patients	POS	O
+who	POS	O
+received	POS	O
+single	POS	O
+-	POS	O
+agent	POS	O
+cisplatin	POS	O
+;	POS	O
+97	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+had	POS	O
+head	POS	B-NP
+and	POS	I-NP
+neck	POS	I-NP
+cancer	POS	I-NP
+as	POS	O
+their	POS	O
+primary	POS	B-NP
+malignancy	POS	I-NP
+.	POS	O
+Patients	POS	O
+who	POS	O
+did	POS	O
+not	POS	O
+receive	POS	O
+mannitol	POS	O
+were	POS	O
+more	POS	O
+likely	POS	O
+to	POS	O
+develop	POS	O
+nephrotoxicity	POS	B-NP
+:	POS	O
+odds	POS	O
+ratio	POS	O
+[	POS	O
+OR	POS	O
+]	POS	O
+=	POS	O
+2	POS	O
+.	POS	O
+646	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+008	POS	O
+,	POS	O
+6	POS	O
+.	POS	O
+944	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+048	POS	O
+)	POS	O
+.	POS	O
+Patients	POS	O
+who	POS	O
+received	POS	O
+the	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+dosing	POS	O
+and	POS	O
+patients	POS	O
+who	POS	O
+had	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+hypertension	POS	B-NP
+also	POS	O
+had	POS	O
+a	POS	O
+higher	POS	O
+likelihood	POS	O
+of	POS	O
+developing	POS	O
+nephrotoxicity	POS	B-NP
+:	POS	O
+OR	POS	O
+=	POS	O
+11	POS	O
+.	POS	O
+494	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+4	POS	O
+.	POS	O
+149	POS	O
+,	POS	O
+32	POS	O
+.	POS	O
+258	POS	O
+;	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+0001	POS	O
+)	POS	O
+and	POS	O
+OR	POS	O
+=	POS	O
+3	POS	O
+.	POS	O
+219	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+228	POS	O
+,	POS	O
+8	POS	O
+.	POS	O
+439	POS	O
+;	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+017	POS	O
+)	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+When	POS	O
+limited	POS	O
+quantities	POS	O
+of	POS	O
+mannitol	POS	O
+are	POS	O
+available	POS	O
+,	POS	O
+it	POS	O
+should	POS	O
+preferentially	POS	O
+be	POS	O
+given	POS	O
+to	POS	O
+patients	POS	O
+at	POS	O
+particularly	POS	O
+high	POS	O
+risk	POS	O
+of	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+Our	POS	O
+analysis	POS	O
+suggests	POS	O
+that	POS	O
+those	POS	O
+patients	POS	O
+receiving	POS	O
+the	POS	O
+dosing	POS	O
+schedule	POS	O
+of	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+cisplatin	POS	O
+every	POS	O
+3	POS	O
+weeks	POS	O
+and	POS	O
+those	POS	O
+with	POS	O
+hypertension	POS	B-NP
+are	POS	O
+at	POS	O
+the	POS	O
+greatest	POS	O
+risk	POS	O
+of	POS	O
+nephrotoxicity	POS	B-NP
+and	POS	O
+would	POS	O
+benefit	POS	O
+from	POS	O
+the	POS	O
+addition	POS	O
+of	POS	O
+mannitol	POS	O
+.	POS	O
+Metformin	POS	O
+protects	POS	O
+against	POS	O
+seizures	POS	B-NP
+,	POS	O
+learning	POS	B-NP
+and	POS	I-NP
+memory	POS	I-NP
+impairments	POS	I-NP
+and	POS	O
+oxidative	POS	O
+damage	POS	O
+induced	POS	O
+by	POS	O
+pentylenetetrazole	POS	O
+-	POS	O
+induced	POS	O
+kindling	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+Cognitive	POS	B-NP
+impairment	POS	I-NP
+,	POS	O
+the	POS	O
+most	POS	O
+common	POS	O
+and	POS	O
+severe	POS	O
+comorbidity	POS	O
+of	POS	O
+epilepsy	POS	B-NP
+,	POS	O
+greatly	POS	O
+diminishes	POS	O
+the	POS	O
+quality	POS	O
+of	POS	O
+life	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+current	POS	O
+therapeutic	POS	O
+interventions	POS	O
+for	POS	O
+epilepsy	POS	B-NP
+can	POS	O
+also	POS	O
+cause	POS	O
+untoward	POS	O
+cognitive	POS	O
+effects	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+there	POS	O
+is	POS	O
+an	POS	O
+urgent	POS	O
+need	POS	O
+for	POS	O
+new	POS	O
+kinds	POS	O
+of	POS	O
+agents	POS	O
+targeting	POS	O
+both	POS	O
+seizures	POS	B-NP
+and	POS	O
+cognition	POS	B-NP
+deficits	POS	I-NP
+.	POS	O
+Oxidative	POS	O
+stress	POS	O
+is	POS	O
+considered	POS	O
+to	POS	O
+play	POS	O
+an	POS	O
+important	POS	O
+role	POS	O
+in	POS	O
+epileptogenesis	POS	B-NP
+and	POS	O
+cognitive	POS	B-NP
+deficits	POS	I-NP
+,	POS	O
+and	POS	O
+antioxidants	POS	O
+have	POS	O
+a	POS	O
+putative	POS	O
+antiepileptic	POS	O
+potential	POS	O
+.	POS	O
+Metformin	POS	O
+,	POS	O
+the	POS	O
+most	POS	O
+commonly	POS	O
+prescribed	POS	O
+antidiabetic	POS	O
+oral	POS	O
+drug	POS	O
+,	POS	O
+has	POS	O
+antioxidant	POS	O
+properties	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+was	POS	O
+designed	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+ameliorative	POS	O
+effects	POS	O
+of	POS	O
+metformin	POS	O
+on	POS	O
+seizures	POS	B-NP
+,	POS	O
+cognitive	POS	B-NP
+impairment	POS	I-NP
+and	POS	O
+brain	POS	O
+oxidative	POS	O
+stress	POS	O
+markers	POS	O
+observed	POS	O
+in	POS	O
+pentylenetetrazole	POS	O
+-	POS	O
+induced	POS	O
+kindling	POS	O
+animals	POS	O
+.	POS	O
+Male	POS	O
+C57BL	POS	O
+/	POS	O
+6	POS	O
+mice	POS	O
+were	POS	O
+administered	POS	O
+with	POS	O
+subconvulsive	POS	O
+dose	POS	O
+of	POS	O
+pentylenetetrazole	POS	O
+(	POS	O
+37	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+every	POS	O
+other	POS	O
+day	POS	O
+for	POS	O
+14	POS	O
+injections	POS	O
+.	POS	O
+Metformin	POS	O
+was	POS	O
+injected	POS	O
+intraperitoneally	POS	O
+in	POS	O
+dose	POS	O
+of	POS	O
+200mg	POS	O
+/	POS	O
+kg	POS	O
+along	POS	O
+with	POS	O
+alternate	POS	O
+-	POS	O
+day	POS	O
+PTZ	POS	O
+.	POS	O
+We	POS	O
+found	POS	O
+that	POS	O
+metformin	POS	O
+suppressed	POS	O
+the	POS	O
+progression	POS	O
+of	POS	O
+kindling	POS	O
+,	POS	O
+ameliorated	POS	O
+the	POS	O
+cognitive	POS	B-NP
+impairment	POS	I-NP
+and	POS	O
+decreased	POS	O
+brain	POS	O
+oxidative	POS	O
+stress	POS	O
+.	POS	O
+Thus	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+concluded	POS	O
+that	POS	O
+metformin	POS	O
+may	POS	O
+be	POS	O
+a	POS	O
+potential	POS	O
+agent	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+epilepsy	POS	B-NP
+as	POS	O
+well	POS	O
+as	POS	O
+a	POS	O
+protective	POS	O
+medicine	POS	O
+against	POS	O
+cognitive	POS	B-NP
+impairment	POS	I-NP
+induced	POS	O
+by	POS	O
+seizures	POS	B-NP
+.	POS	O
+P53	POS	O
+inhibition	POS	O
+exacerbates	POS	O
+late	POS	O
+-	POS	O
+stage	POS	O
+anthracycline	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+AIMS	POS	O
+:	POS	O
+Doxorubicin	POS	O
+(	POS	O
+DOX	POS	O
+)	POS	O
+is	POS	O
+an	POS	O
+effective	POS	O
+anti	POS	O
+-	POS	O
+cancer	POS	O
+therapeutic	POS	O
+,	POS	O
+but	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+both	POS	O
+acute	POS	O
+and	POS	O
+late	POS	O
+-	POS	O
+stage	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+Children	POS	O
+are	POS	O
+particularly	POS	O
+sensitive	POS	O
+to	POS	O
+DOX	POS	O
+-	POS	O
+induced	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+.	POS	O
+Here	POS	O
+,	POS	O
+the	POS	O
+impact	POS	O
+of	POS	O
+p53	POS	O
+inhibition	POS	O
+on	POS	O
+acute	POS	O
+vs	POS	O
+.	POS	O
+late	POS	O
+-	POS	O
+stage	POS	O
+DOX	POS	O
+cardiotoxicity	POS	B-NP
+was	POS	O
+examined	POS	O
+in	POS	O
+a	POS	O
+juvenile	POS	O
+model	POS	O
+.	POS	O
+METHODS	POS	O
+AND	POS	O
+RESULTS	POS	O
+:	POS	O
+Two	POS	O
+-	POS	O
+week	POS	O
+-	POS	O
+old	POS	O
+MHC	POS	O
+-	POS	O
+CB7	POS	O
+mice	POS	O
+(	POS	O
+which	POS	O
+express	POS	O
+dominant	POS	O
+-	POS	O
+interfering	POS	O
+p53	POS	O
+in	POS	O
+cardiomyocytes	POS	O
+)	POS	O
+and	POS	O
+their	POS	O
+non	POS	O
+-	POS	O
+transgenic	POS	O
+(	POS	O
+NON	POS	O
+-	POS	O
+TXG	POS	O
+)	POS	O
+littermates	POS	O
+received	POS	O
+weekly	POS	O
+DOX	POS	O
+injections	POS	O
+for	POS	O
+5	POS	O
+weeks	POS	O
+(	POS	O
+25	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+cumulative	POS	O
+dose	POS	O
+)	POS	O
+.	POS	O
+One	POS	O
+week	POS	O
+after	POS	O
+the	POS	O
+last	POS	O
+DOX	POS	O
+treatment	POS	O
+(	POS	O
+acute	POS	O
+stage	POS	O
+)	POS	O
+,	POS	O
+MHC	POS	O
+-	POS	O
+CB7	POS	O
+mice	POS	O
+exhibited	POS	O
+improved	POS	O
+cardiac	POS	O
+function	POS	O
+and	POS	O
+lower	POS	O
+levels	POS	O
+of	POS	O
+cardiomyocyte	POS	O
+apoptosis	POS	O
+when	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+NON	POS	O
+-	POS	O
+TXG	POS	O
+mice	POS	O
+.	POS	O
+Surprisingly	POS	O
+,	POS	O
+by	POS	O
+13	POS	O
+weeks	POS	O
+following	POS	O
+the	POS	O
+last	POS	O
+DOX	POS	O
+treatment	POS	O
+(	POS	O
+late	POS	O
+stage	POS	O
+)	POS	O
+,	POS	O
+MHC	POS	O
+-	POS	O
+CB7	POS	O
+exhibited	POS	O
+a	POS	O
+progressive	POS	O
+decrease	POS	O
+in	POS	O
+cardiac	POS	O
+function	POS	O
+and	POS	O
+higher	POS	O
+rates	POS	O
+of	POS	O
+cardiomyocyte	POS	O
+apoptosis	POS	O
+when	POS	O
+compared	POS	O
+with	POS	O
+NON	POS	O
+-	POS	O
+TXG	POS	O
+mice	POS	O
+.	POS	O
+p53	POS	O
+inhibition	POS	O
+blocked	POS	O
+transient	POS	O
+DOX	POS	O
+-	POS	O
+induced	POS	O
+STAT3	POS	O
+activation	POS	O
+in	POS	O
+MHC	POS	O
+-	POS	O
+CB7	POS	O
+mice	POS	O
+,	POS	O
+which	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+enhanced	POS	O
+induction	POS	O
+of	POS	O
+the	POS	O
+DNA	POS	O
+repair	POS	O
+proteins	POS	O
+Ku70	POS	O
+and	POS	O
+Ku80	POS	O
+.	POS	O
+Mice	POS	O
+with	POS	O
+cardiomyocyte	POS	O
+-	POS	O
+restricted	POS	O
+deletion	POS	O
+of	POS	O
+STAT3	POS	O
+exhibited	POS	O
+worse	POS	O
+cardiac	POS	O
+function	POS	O
+,	POS	O
+higher	POS	O
+levels	POS	O
+of	POS	O
+cardiomyocyte	POS	O
+apoptosis	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+greater	POS	O
+induction	POS	O
+of	POS	O
+Ku70	POS	O
+and	POS	O
+Ku80	POS	O
+in	POS	O
+response	POS	O
+to	POS	O
+DOX	POS	O
+treatment	POS	O
+during	POS	O
+the	POS	O
+acute	POS	O
+stage	POS	O
+when	POS	O
+compared	POS	O
+with	POS	O
+control	POS	O
+animals	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+These	POS	O
+data	POS	O
+support	POS	O
+a	POS	O
+model	POS	O
+wherein	POS	O
+a	POS	O
+p53	POS	O
+-	POS	O
+dependent	POS	O
+cardioprotective	POS	O
+pathway	POS	O
+,	POS	O
+mediated	POS	O
+via	POS	O
+STAT3	POS	O
+activation	POS	O
+,	POS	O
+mitigates	POS	O
+DOX	POS	O
+-	POS	O
+induced	POS	O
+myocardial	POS	O
+stress	POS	O
+during	POS	O
+drug	POS	O
+delivery	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+these	POS	O
+data	POS	O
+suggest	POS	O
+an	POS	O
+explanation	POS	O
+as	POS	O
+to	POS	O
+how	POS	O
+p53	POS	O
+inhibition	POS	O
+can	POS	O
+result	POS	O
+in	POS	O
+cardioprotection	POS	O
+during	POS	O
+drug	POS	O
+treatment	POS	O
+and	POS	O
+,	POS	O
+paradoxically	POS	O
+,	POS	O
+enhanced	POS	O
+cardiotoxicity	POS	B-NP
+long	POS	O
+after	POS	O
+the	POS	O
+cessation	POS	O
+of	POS	O
+drug	POS	O
+treatment	POS	O
+.	POS	O
+Metronidazole	POS	O
+-	POS	O
+induced	POS	O
+encephalopathy	POS	B-NP
+:	POS	O
+an	POS	O
+uncommon	POS	O
+scenario	POS	O
+.	POS	O
+Metronidazole	POS	O
+can	POS	O
+produce	POS	O
+neurological	POS	B-NP
+complications	POS	I-NP
+although	POS	O
+it	POS	O
+is	POS	O
+not	POS	O
+a	POS	O
+common	POS	O
+scenario	POS	O
+.	POS	O
+We	POS	O
+present	POS	O
+a	POS	O
+case	POS	O
+where	POS	O
+a	POS	O
+patient	POS	O
+developed	POS	O
+features	POS	O
+of	POS	O
+encephalopathy	POS	B-NP
+following	POS	O
+prolonged	POS	O
+metronidazole	POS	O
+intake	POS	O
+.	POS	O
+Magnetic	POS	O
+resonance	POS	O
+imaging	POS	O
+(	POS	O
+MRI	POS	O
+)	POS	O
+brain	POS	O
+showed	POS	O
+abnormal	POS	O
+signal	POS	O
+intensity	POS	O
+involving	POS	O
+both	POS	O
+dentate	POS	O
+nuclei	POS	O
+of	POS	O
+cerebellum	POS	O
+and	POS	O
+splenium	POS	O
+of	POS	O
+corpus	POS	O
+callosum	POS	O
+.	POS	O
+The	POS	O
+diagnosis	POS	O
+of	POS	O
+metronidazole	POS	O
+toxicity	POS	B-NP
+was	POS	O
+made	POS	O
+by	POS	O
+the	POS	O
+MRI	POS	O
+findings	POS	O
+and	POS	O
+supported	POS	O
+clinically	POS	O
+.	POS	O
+Aconitine	POS	O
+-	POS	O
+induced	POS	O
+Ca2	POS	O
++	POS	O
+overload	POS	O
+causes	POS	O
+arrhythmia	POS	B-NP
+and	POS	O
+triggers	POS	O
+apoptosis	POS	O
+through	POS	O
+p38	POS	O
+MAPK	POS	O
+signaling	POS	O
+pathway	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+Aconitine	POS	O
+is	POS	O
+a	POS	O
+major	POS	O
+bioactive	POS	O
+diterpenoid	POS	O
+alkaloid	POS	O
+with	POS	O
+high	POS	O
+content	POS	O
+derived	POS	O
+from	POS	O
+herbal	POS	O
+aconitum	POS	O
+plants	POS	O
+.	POS	O
+Emerging	POS	O
+evidence	POS	O
+indicates	POS	O
+that	POS	O
+voltage	POS	O
+-	POS	O
+dependent	POS	O
+Na	POS	O
+(	POS	O
++	POS	O
+)	POS	O
+channels	POS	O
+have	POS	O
+pivotal	POS	O
+roles	POS	O
+in	POS	O
+the	POS	O
+cardiotoxicity	POS	B-NP
+of	POS	O
+aconitine	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+no	POS	O
+reports	POS	O
+are	POS	O
+available	POS	O
+on	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+in	POS	O
+aconitine	POS	B-NP
+poisoning	POS	I-NP
+.	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+,	POS	O
+we	POS	O
+explored	POS	O
+the	POS	O
+importance	POS	O
+of	POS	O
+pathological	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+signaling	POS	O
+in	POS	O
+aconitine	POS	O
+poisoning	POS	B-NP
+in	POS	O
+vitro	POS	O
+and	POS	O
+in	POS	O
+vivo	POS	O
+.	POS	O
+We	POS	O
+found	POS	O
+that	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+overload	POS	O
+lead	POS	O
+to	POS	O
+accelerated	POS	O
+beating	POS	O
+rhythm	POS	O
+in	POS	O
+adult	POS	O
+rat	POS	O
+ventricular	POS	O
+myocytes	POS	O
+and	POS	O
+caused	POS	O
+arrhythmia	POS	B-NP
+in	POS	O
+conscious	POS	O
+freely	POS	O
+moving	POS	O
+rats	POS	O
+.	POS	O
+To	POS	O
+investigate	POS	O
+effects	POS	O
+of	POS	O
+aconitine	POS	O
+on	POS	O
+myocardial	POS	B-NP
+injury	POS	I-NP
+,	POS	O
+we	POS	O
+performed	POS	O
+cytotoxicity	POS	B-NP
+assay	POS	O
+in	POS	O
+neonatal	POS	O
+rat	POS	O
+ventricular	POS	O
+myocytes	POS	O
+(	POS	O
+NRVMs	POS	O
+)	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+measured	POS	O
+lactate	POS	O
+dehydrogenase	POS	O
+level	POS	O
+in	POS	O
+the	POS	O
+culture	POS	O
+medium	POS	O
+of	POS	O
+NRVMs	POS	O
+and	POS	O
+activities	POS	O
+of	POS	O
+serum	POS	O
+cardiac	POS	O
+enzymes	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+showed	POS	O
+that	POS	O
+aconitine	POS	O
+resulted	POS	O
+in	POS	O
+myocardial	POS	B-NP
+injury	POS	I-NP
+and	POS	O
+reduced	POS	O
+NRVMs	POS	O
+viability	POS	O
+dose	POS	O
+-	POS	O
+dependently	POS	O
+.	POS	O
+To	POS	O
+confirm	POS	O
+the	POS	O
+pro	POS	O
+-	POS	O
+apoptotic	POS	O
+effects	POS	O
+,	POS	O
+we	POS	O
+performed	POS	O
+flow	POS	O
+cytometric	POS	O
+detection	POS	O
+,	POS	O
+cardiac	POS	O
+histology	POS	O
+,	POS	O
+transmission	POS	O
+electron	POS	O
+microscopy	POS	O
+and	POS	O
+terminal	POS	O
+deoxynucleotidyl	POS	O
+transferase	POS	O
+-	POS	O
+mediated	POS	O
+dUTP	POS	O
+-	POS	O
+biotin	POS	O
+nick	POS	O
+end	POS	O
+labeling	POS	O
+assay	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+showed	POS	O
+that	POS	O
+aconitine	POS	O
+stimulated	POS	O
+apoptosis	POS	O
+time	POS	O
+-	POS	O
+dependently	POS	O
+.	POS	O
+The	POS	O
+expression	POS	O
+analysis	POS	O
+of	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+handling	POS	O
+proteins	POS	O
+demonstrated	POS	O
+that	POS	O
+aconitine	POS	O
+promoted	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+overload	POS	O
+through	POS	O
+the	POS	O
+expression	POS	O
+regulation	POS	O
+of	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+handling	POS	O
+proteins	POS	O
+.	POS	O
+The	POS	O
+expression	POS	O
+analysis	POS	O
+of	POS	O
+apoptosis	POS	O
+-	POS	O
+related	POS	O
+proteins	POS	O
+revealed	POS	O
+that	POS	O
+pro	POS	O
+-	POS	O
+apoptotic	POS	O
+protein	POS	O
+expression	POS	O
+was	POS	O
+upregulated	POS	O
+,	POS	O
+and	POS	O
+anti	POS	O
+-	POS	O
+apoptotic	POS	O
+protein	POS	O
+BCL	POS	O
+-	POS	O
+2	POS	O
+expression	POS	O
+was	POS	O
+downregulated	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+increased	POS	O
+phosphorylation	POS	O
+of	POS	O
+MAPK	POS	O
+family	POS	O
+members	POS	O
+,	POS	O
+especially	POS	O
+the	POS	O
+P	POS	O
+-	POS	O
+P38	POS	O
+/	POS	O
+P38	POS	O
+ratio	POS	O
+was	POS	O
+found	POS	O
+in	POS	O
+cardiac	POS	O
+tissues	POS	O
+.	POS	O
+Hence	POS	O
+,	POS	O
+our	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+aconitine	POS	O
+significantly	POS	O
+aggravates	POS	O
+Ca	POS	O
+(	POS	O
+2	POS	O
++	POS	O
+)	POS	O
+overload	POS	O
+and	POS	O
+causes	POS	O
+arrhythmia	POS	B-NP
+and	POS	O
+finally	POS	O
+promotes	POS	O
+apoptotic	POS	O
+development	POS	O
+via	POS	O
+phosphorylation	POS	O
+of	POS	O
+P38	POS	O
+mitogen	POS	O
+-	POS	O
+activated	POS	O
+protein	POS	O
+kinase	POS	O
+.	POS	O
+Chronic	POS	O
+treatment	POS	O
+with	POS	O
+metformin	POS	O
+suppresses	POS	O
+toll	POS	O
+-	POS	O
+like	POS	O
+receptor	POS	O
+4	POS	O
+signaling	POS	O
+and	POS	O
+attenuates	POS	O
+left	POS	O
+ventricular	POS	B-NP
+dysfunction	POS	I-NP
+following	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+Acute	POS	O
+treatment	POS	O
+with	POS	O
+metformin	POS	O
+has	POS	O
+a	POS	O
+protective	POS	O
+effect	POS	O
+in	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+by	POS	O
+suppression	POS	O
+of	POS	O
+inflammatory	POS	O
+responses	POS	O
+due	POS	O
+to	POS	O
+activation	POS	O
+of	POS	O
+AMP	POS	O
+-	POS	O
+activated	POS	O
+protein	POS	O
+kinase	POS	O
+(	POS	O
+AMPK	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+,	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+chronic	POS	O
+pre	POS	O
+-	POS	O
+treatment	POS	O
+with	POS	O
+metformin	POS	O
+on	POS	O
+cardiac	POS	B-NP
+dysfunction	POS	I-NP
+and	POS	O
+toll	POS	O
+-	POS	O
+like	POS	O
+receptor	POS	O
+4	POS	O
+(	POS	O
+TLR4	POS	O
+)	POS	O
+activities	POS	O
+following	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+and	POS	O
+their	POS	O
+relation	POS	O
+with	POS	O
+AMPK	POS	O
+were	POS	O
+assessed	POS	O
+.	POS	O
+Male	POS	O
+Wistar	POS	O
+rats	POS	O
+were	POS	O
+randomly	POS	O
+assigned	POS	O
+to	POS	O
+one	POS	O
+of	POS	O
+5	POS	O
+groups	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+6	POS	O
+)	POS	O
+:	POS	O
+normal	POS	O
+control	POS	O
+and	POS	O
+groups	POS	O
+were	POS	O
+injected	POS	O
+isoproterenol	POS	O
+after	POS	O
+chronic	POS	O
+pre	POS	O
+-	POS	O
+treatment	POS	O
+with	POS	O
+0	POS	O
+,	POS	O
+25	POS	O
+,	POS	O
+50	POS	O
+,	POS	O
+or	POS	O
+100mg	POS	O
+/	POS	O
+kg	POS	O
+of	POS	O
+metformin	POS	O
+twice	POS	O
+daily	POS	O
+for	POS	O
+14	POS	O
+days	POS	O
+.	POS	O
+Isoproterenol	POS	O
+(	POS	O
+100mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+was	POS	O
+injected	POS	O
+subcutaneously	POS	O
+on	POS	O
+the	POS	O
+13th	POS	O
+and	POS	O
+14th	POS	O
+days	POS	O
+to	POS	O
+induce	POS	O
+acute	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+Isoproterenol	POS	O
+alone	POS	O
+decreased	POS	O
+left	POS	O
+ventricular	POS	O
+systolic	POS	O
+pressure	POS	O
+and	POS	O
+myocardial	POS	O
+contractility	POS	O
+indexed	POS	O
+as	POS	O
+LVdp	POS	O
+/	POS	O
+dtmax	POS	O
+and	POS	O
+LVdp	POS	O
+/	POS	O
+dtmin	POS	O
+.	POS	O
+The	POS	O
+left	POS	O
+ventricular	POS	B-NP
+dysfunction	POS	I-NP
+was	POS	O
+significantly	POS	O
+lower	POS	O
+in	POS	O
+the	POS	O
+groups	POS	O
+treated	POS	O
+with	POS	O
+25	POS	O
+and	POS	O
+50mg	POS	O
+/	POS	O
+kg	POS	O
+of	POS	O
+metformin	POS	O
+.	POS	O
+Metfromin	POS	O
+markedly	POS	O
+lowered	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+elevation	POS	O
+in	POS	O
+the	POS	O
+levels	POS	O
+of	POS	O
+TLR4	POS	O
+mRNA	POS	O
+,	POS	O
+myeloid	POS	O
+differentiation	POS	O
+protein	POS	O
+88	POS	O
+(	POS	O
+MyD88	POS	O
+)	POS	O
+,	POS	O
+tumor	POS	B-NP
+necrosis	POS	I-NP
+factor	POS	O
+-	POS	O
+alpha	POS	O
+(	POS	O
+TNF	POS	O
+-	POS	O
+a	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+interleukin	POS	O
+6	POS	O
+(	POS	O
+IL	POS	O
+-	POS	O
+6	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+heart	POS	O
+tissues	POS	O
+.	POS	O
+Similar	POS	O
+changes	POS	O
+were	POS	O
+also	POS	O
+seen	POS	O
+in	POS	O
+the	POS	O
+serum	POS	O
+levels	POS	O
+of	POS	O
+TNF	POS	O
+-	POS	O
+a	POS	O
+and	POS	O
+IL	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+lower	POS	O
+doses	POS	O
+of	POS	O
+25	POS	O
+and	POS	O
+50mg	POS	O
+/	POS	O
+kg	POS	O
+were	POS	O
+more	POS	O
+effective	POS	O
+than	POS	O
+100mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+Phosphorylated	POS	O
+AMPKa	POS	O
+(	POS	O
+p	POS	O
+-	POS	O
+AMPK	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+myocardium	POS	O
+was	POS	O
+significantly	POS	O
+elevated	POS	O
+by	POS	O
+25mg	POS	O
+/	POS	O
+kg	POS	O
+of	POS	O
+metformin	POS	O
+,	POS	O
+slightly	POS	O
+by	POS	O
+50mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+by	POS	O
+100mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+Chronic	POS	O
+pre	POS	O
+-	POS	O
+treatment	POS	O
+with	POS	O
+metformin	POS	O
+reduces	POS	O
+post	POS	O
+-	POS	O
+myocardial	POS	O
+infarction	POS	O
+cardiac	POS	O
+dysfunction	POS	O
+and	POS	O
+suppresses	POS	O
+inflammatory	POS	O
+responses	POS	O
+,	POS	O
+possibly	POS	O
+through	POS	O
+inhibition	POS	O
+of	POS	O
+TLR4	POS	O
+activities	POS	O
+.	POS	O
+This	POS	O
+mechanism	POS	O
+can	POS	O
+be	POS	O
+considered	POS	O
+as	POS	O
+a	POS	O
+target	POS	O
+to	POS	O
+protect	POS	O
+infarcted	POS	O
+myocardium	POS	O
+.	POS	O
+Unusual	POS	O
+complications	POS	O
+of	POS	O
+antithyroid	POS	O
+drug	POS	O
+therapy	POS	O
+:	POS	O
+four	POS	O
+case	POS	O
+reports	POS	O
+and	POS	O
+review	POS	O
+of	POS	O
+literature	POS	O
+.	POS	O
+Two	POS	O
+cases	POS	O
+of	POS	O
+propylthiouracil	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+acute	POS	I-NP
+hepatitis	POS	I-NP
+,	POS	O
+one	POS	O
+case	POS	O
+of	POS	O
+fatal	POS	O
+methimazole	POS	O
+-	POS	O
+associated	POS	O
+hepatocellular	POS	B-NP
+necrosis	POS	I-NP
+and	POS	O
+one	POS	O
+case	POS	O
+of	POS	O
+propylthiouracil	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+lupus	POS	I-NP
+-	POS	I-NP
+like	POS	I-NP
+syndrome	POS	I-NP
+are	POS	O
+described	POS	O
+.	POS	O
+The	POS	O
+literature	POS	O
+related	POS	O
+to	POS	O
+antithyroid	POS	O
+drug	POS	O
+side	POS	O
+effects	POS	O
+and	POS	O
+the	POS	O
+mechanisms	POS	O
+for	POS	O
+their	POS	O
+occurrence	POS	O
+are	POS	O
+reviewed	POS	O
+and	POS	O
+the	POS	O
+efficacy	POS	O
+and	POS	O
+complications	POS	O
+of	POS	O
+thyroidectomy	POS	O
+and	POS	O
+radioiodine	POS	O
+compared	POS	O
+to	POS	O
+those	POS	O
+of	POS	O
+antithyroid	POS	O
+drugs	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+concluded	POS	O
+that	POS	O
+in	POS	O
+most	POS	O
+circumstances	POS	O
+131I	POS	O
+is	POS	O
+the	POS	O
+therapy	POS	O
+of	POS	O
+choice	POS	O
+for	POS	O
+hyperthyroidism	POS	B-NP
+.	POS	O
+Neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+induced	POS	O
+by	POS	O
+combination	POS	O
+therapy	POS	O
+with	POS	O
+tetrabenazine	POS	O
+and	POS	O
+tiapride	POS	O
+in	POS	O
+a	POS	O
+Japanese	POS	O
+patient	POS	O
+with	POS	O
+Huntington	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+at	POS	O
+the	POS	O
+terminal	POS	O
+stage	POS	O
+of	POS	O
+recurrent	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+We	POS	O
+herein	POS	O
+describe	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+an	POS	O
+81	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+Japanese	POS	O
+woman	POS	O
+with	POS	O
+neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+that	POS	O
+occurred	POS	O
+36	POS	O
+days	POS	O
+after	POS	O
+the	POS	O
+initiation	POS	O
+of	POS	O
+combination	POS	O
+therapy	POS	O
+with	POS	O
+tiapride	POS	O
+(	POS	O
+75	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+and	POS	O
+tetrabenazine	POS	O
+(	POS	O
+12	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+for	POS	O
+Huntington	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+The	POS	O
+patient	POS	O
+had	POS	O
+been	POS	O
+treated	POS	O
+with	POS	O
+tiapride	POS	O
+or	POS	O
+tetrabenazine	POS	O
+alone	POS	O
+without	POS	O
+any	POS	O
+adverse	POS	O
+effects	POS	O
+before	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+the	POS	O
+combination	POS	O
+therapy	POS	O
+.	POS	O
+She	POS	O
+also	POS	O
+had	POS	O
+advanced	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+when	POS	O
+the	POS	O
+combination	POS	O
+therapy	POS	O
+was	POS	O
+initiated	POS	O
+.	POS	O
+To	POS	O
+the	POS	O
+best	POS	O
+of	POS	O
+our	POS	O
+knowledge	POS	O
+,	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+due	POS	O
+to	POS	O
+combination	POS	O
+therapy	POS	O
+with	POS	O
+tetrabenazine	POS	O
+and	POS	O
+tiapride	POS	O
+has	POS	O
+not	POS	O
+been	POS	O
+previously	POS	O
+reported	POS	O
+.	POS	O
+Tetrabenazine	POS	O
+should	POS	O
+be	POS	O
+administered	POS	O
+very	POS	O
+carefully	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+other	POS	O
+neuroleptic	POS	O
+drugs	POS	O
+,	POS	O
+particularly	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+a	POS	O
+worsening	POS	O
+general	POS	O
+condition	POS	O
+.	POS	O
+A	POS	O
+metoprolol	POS	O
+-	POS	O
+terbinafine	POS	O
+combination	POS	O
+induced	POS	O
+bradycardia	POS	B-NP
+.	POS	O
+To	POS	O
+report	POS	O
+a	POS	O
+sinus	POS	B-NP
+bradycardia	POS	I-NP
+induced	POS	O
+by	POS	O
+metoprolol	POS	O
+and	POS	O
+terbinafine	POS	O
+drug	POS	O
+-	POS	O
+drug	POS	O
+interaction	POS	O
+and	POS	O
+its	POS	O
+management	POS	O
+.	POS	O
+A	POS	O
+63	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+Caucasian	POS	O
+man	POS	O
+on	POS	O
+metoprolol	POS	O
+200	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+for	POS	O
+stable	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+was	POS	O
+prescribed	POS	O
+a	POS	O
+90	POS	O
+-	POS	O
+day	POS	O
+course	POS	O
+of	POS	O
+oral	POS	O
+terbinafine	POS	O
+250	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+for	POS	O
+onychomycosis	POS	B-NP
+.	POS	O
+On	POS	O
+the	POS	O
+49th	POS	O
+day	POS	O
+of	POS	O
+terbinafine	POS	O
+therapy	POS	O
+,	POS	O
+he	POS	O
+was	POS	O
+brought	POS	O
+to	POS	O
+the	POS	O
+emergency	POS	O
+room	POS	O
+for	POS	O
+a	POS	O
+decrease	POS	O
+of	POS	O
+his	POS	O
+global	POS	O
+health	POS	O
+status	POS	O
+,	POS	O
+confusion	POS	B-NP
+and	POS	O
+falls	POS	O
+.	POS	O
+The	POS	O
+electrocardiogram	POS	O
+revealed	POS	O
+a	POS	O
+37	POS	O
+beats	POS	O
+/	POS	O
+min	POS	O
+sinus	POS	O
+bradycardia	POS	B-NP
+.	POS	O
+A	POS	O
+score	POS	O
+of	POS	O
+7	POS	O
+on	POS	O
+the	POS	O
+Naranjo	POS	O
+adverse	POS	O
+drug	POS	O
+reaction	POS	O
+probability	POS	O
+scale	POS	O
+indicates	POS	O
+a	POS	O
+probable	POS	O
+relationship	POS	O
+between	POS	O
+the	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+sinus	POS	O
+bradycardia	POS	B-NP
+and	POS	O
+the	POS	O
+drug	POS	O
+interaction	POS	O
+between	POS	O
+metoprolol	POS	O
+and	POS	O
+terbinafine	POS	O
+.	POS	O
+The	POS	O
+heart	POS	O
+rate	POS	O
+ameliorated	POS	O
+first	POS	O
+with	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+the	POS	O
+dose	POS	O
+of	POS	O
+metoprolol	POS	O
+.	POS	O
+It	POS	O
+was	POS	O
+subsequently	POS	O
+changed	POS	O
+to	POS	O
+bisoprolol	POS	O
+and	POS	O
+the	POS	O
+heart	POS	O
+rate	POS	O
+remained	POS	O
+normal	POS	O
+.	POS	O
+By	POS	O
+inhibiting	POS	O
+the	POS	O
+cytochrome	POS	O
+P450	POS	O
+2D6	POS	O
+,	POS	O
+terbinafine	POS	O
+had	POS	O
+decreased	POS	O
+metoprolol	POS	O
+'	POS	O
+s	POS	O
+clearance	POS	O
+,	POS	O
+leading	POS	O
+in	POS	O
+metoprolol	POS	O
+accumulation	POS	O
+which	POS	O
+has	POS	O
+resulted	POS	O
+in	POS	O
+clinically	POS	O
+significant	POS	O
+sinus	POS	B-NP
+bradycardia	POS	I-NP
+.	POS	O
+Optochiasmatic	POS	B-NP
+and	POS	O
+peripheral	POS	B-NP
+neuropathy	POS	I-NP
+due	POS	O
+to	POS	O
+ethambutol	POS	O
+overtreatment	POS	O
+.	POS	O
+Ethambutol	POS	O
+is	POS	O
+known	POS	O
+to	POS	O
+cause	POS	O
+optic	POS	B-NP
+neuropathy	POS	I-NP
+and	POS	O
+,	POS	O
+more	POS	O
+rarely	POS	O
+,	POS	O
+axonal	POS	B-NP
+polyneuropathy	POS	I-NP
+.	POS	O
+We	POS	O
+characterize	POS	O
+the	POS	O
+clinical	POS	O
+,	POS	O
+neurophysiological	POS	O
+,	POS	O
+and	POS	O
+neuroimaging	POS	O
+findings	POS	O
+in	POS	O
+a	POS	O
+72	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+who	POS	O
+developed	POS	O
+visual	POS	B-NP
+loss	POS	I-NP
+and	POS	O
+paresthesias	POS	B-NP
+after	POS	O
+11	POS	O
+weeks	POS	O
+of	POS	O
+exposure	POS	O
+to	POS	O
+a	POS	O
+supratherapeutic	POS	O
+dose	POS	O
+of	POS	O
+ethambutol	POS	O
+.	POS	O
+This	POS	O
+case	POS	O
+demonstrates	POS	O
+the	POS	O
+selective	POS	O
+vulnerability	POS	O
+of	POS	O
+the	POS	O
+anterior	POS	O
+visual	POS	O
+pathways	POS	O
+and	POS	O
+peripheral	POS	O
+nerves	POS	O
+to	POS	O
+ethambutol	POS	O
+toxicity	POS	B-NP
+.	POS	O
+Testosterone	POS	O
+ameliorates	POS	O
+streptozotocin	POS	O
+-	POS	O
+induced	POS	O
+memory	POS	B-NP
+impairment	POS	I-NP
+in	POS	O
+male	POS	O
+rats	POS	O
+.	POS	O
+AIM	POS	O
+:	POS	O
+To	POS	O
+study	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+testosterone	POS	O
+on	POS	O
+streptozotocin	POS	O
+(	POS	O
+STZ	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+memory	POS	B-NP
+impairment	POS	I-NP
+in	POS	O
+male	POS	O
+rats	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Adult	POS	O
+male	POS	O
+Wistar	POS	O
+rats	POS	O
+were	POS	O
+intracerebroventricularly	POS	O
+(	POS	O
+icv	POS	O
+)	POS	O
+infused	POS	O
+with	POS	O
+STZ	POS	O
+(	POS	O
+750	POS	O
+ug	POS	O
+)	POS	O
+on	POS	O
+d	POS	O
+1	POS	O
+and	POS	O
+d	POS	O
+3	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+passive	POS	O
+avoidance	POS	O
+task	POS	O
+was	POS	O
+assessed	POS	O
+2	POS	O
+weeks	POS	O
+after	POS	O
+the	POS	O
+first	POS	O
+injection	POS	O
+of	POS	O
+STZ	POS	O
+.	POS	O
+Castration	POS	O
+surgery	POS	O
+was	POS	O
+performed	POS	O
+in	POS	O
+another	POS	O
+group	POS	O
+of	POS	O
+rats	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+passive	POS	O
+avoidance	POS	O
+task	POS	O
+was	POS	O
+assessed	POS	O
+4	POS	O
+weeks	POS	O
+after	POS	O
+the	POS	O
+operation	POS	O
+.	POS	O
+Testosterone	POS	O
+(	POS	O
+1	POS	O
+mg	POS	O
+.	POS	O
+kg	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+.	POS	O
+d	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+,	POS	O
+sc	POS	O
+)	POS	O
+,	POS	O
+the	POS	O
+androgen	POS	O
+receptor	POS	O
+antagonist	POS	O
+flutamide	POS	O
+(	POS	O
+10	POS	O
+mg	POS	O
+.	POS	O
+kg	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+.	POS	O
+d	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+,	POS	O
+ip	POS	O
+)	POS	O
+,	POS	O
+the	POS	O
+estrogen	POS	O
+receptor	POS	O
+antagonist	POS	O
+tamoxifen	POS	O
+(	POS	O
+1	POS	O
+mg	POS	O
+.	POS	O
+kg	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+.	POS	O
+d	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+,	POS	O
+ip	POS	O
+)	POS	O
+or	POS	O
+the	POS	O
+aromatase	POS	O
+inhibitor	POS	O
+letrozole	POS	O
+(	POS	O
+4	POS	O
+mg	POS	O
+.	POS	O
+kg	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+.	POS	O
+d	POS	O
+(	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+,	POS	O
+ip	POS	O
+)	POS	O
+were	POS	O
+administered	POS	O
+for	POS	O
+6	POS	O
+d	POS	O
+after	POS	O
+the	POS	O
+first	POS	O
+injection	POS	O
+of	POS	O
+STZ	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+STZ	POS	O
+administration	POS	O
+and	POS	O
+castration	POS	O
+markedly	POS	O
+decreased	POS	O
+both	POS	O
+STL1	POS	O
+(	POS	O
+the	POS	O
+short	POS	O
+memory	POS	O
+)	POS	O
+and	POS	O
+STL2	POS	O
+(	POS	O
+the	POS	O
+long	POS	O
+memory	POS	O
+)	POS	O
+in	POS	O
+passive	POS	O
+avoidance	POS	O
+tests	POS	O
+.	POS	O
+Testosterone	POS	O
+replacement	POS	O
+almost	POS	O
+restored	POS	O
+the	POS	O
+STL1	POS	O
+and	POS	O
+STL2	POS	O
+in	POS	O
+castrated	POS	O
+rats	POS	O
+,	POS	O
+and	POS	O
+significantly	POS	O
+prolonged	POS	O
+the	POS	O
+STL1	POS	O
+and	POS	O
+STL2	POS	O
+in	POS	O
+STZ	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+.	POS	O
+Administration	POS	O
+of	POS	O
+flutamide	POS	O
+,	POS	O
+letrozole	POS	O
+or	POS	O
+tamoxifen	POS	O
+significantly	POS	O
+impaired	POS	O
+the	POS	O
+memory	POS	O
+in	POS	O
+intact	POS	O
+rats	POS	O
+,	POS	O
+and	POS	O
+significantly	POS	O
+attenuated	POS	O
+the	POS	O
+testosterone	POS	O
+replacement	POS	O
+in	POS	O
+improving	POS	O
+STZ	POS	O
+-	POS	O
+and	POS	O
+castration	POS	O
+-	POS	O
+induced	POS	O
+memory	POS	B-NP
+impairment	POS	I-NP
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Testosterone	POS	O
+administration	POS	O
+ameliorates	POS	O
+STZ	POS	O
+-	POS	O
+and	POS	O
+castration	POS	O
+-	POS	O
+induced	POS	O
+memory	POS	B-NP
+impairment	POS	I-NP
+in	POS	O
+male	POS	O
+Wistar	POS	O
+rats	POS	O
+.	POS	O
+Behavioral	POS	O
+and	POS	O
+neurochemical	POS	O
+studies	POS	O
+in	POS	O
+mice	POS	O
+pretreated	POS	O
+with	POS	O
+garcinielliptone	POS	O
+FC	POS	O
+in	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+.	POS	O
+Garcinielliptone	POS	O
+FC	POS	O
+(	POS	O
+GFC	POS	O
+)	POS	O
+isolated	POS	O
+from	POS	O
+hexanic	POS	O
+fraction	POS	O
+seed	POS	O
+extract	POS	O
+of	POS	O
+species	POS	O
+Platonia	POS	O
+insignis	POS	O
+Mart	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+widely	POS	O
+used	POS	O
+in	POS	O
+folk	POS	O
+medicine	POS	O
+to	POS	O
+treat	POS	O
+skin	POS	B-NP
+diseases	POS	I-NP
+in	POS	O
+both	POS	O
+humans	POS	O
+and	POS	O
+animals	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+the	POS	O
+seed	POS	O
+decoction	POS	O
+has	POS	O
+been	POS	O
+used	POS	O
+to	POS	O
+treat	POS	O
+diarrheas	POS	B-NP
+and	POS	O
+inflammatory	POS	B-NP
+diseases	POS	I-NP
+.	POS	O
+However	POS	O
+,	POS	O
+there	POS	O
+is	POS	O
+no	POS	O
+research	POS	O
+on	POS	O
+GFC	POS	O
+effects	POS	O
+in	POS	O
+the	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+of	POS	O
+rodents	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+aimed	POS	O
+to	POS	O
+evaluate	POS	O
+the	POS	O
+GFC	POS	O
+effects	POS	O
+at	POS	O
+doses	POS	O
+of	POS	O
+25	POS	O
+,	POS	O
+50	POS	O
+or	POS	O
+75	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+on	POS	O
+seizure	POS	B-NP
+parameters	POS	O
+to	POS	O
+determine	POS	O
+their	POS	O
+anticonvulsant	POS	O
+activity	POS	O
+and	POS	O
+its	POS	O
+effects	POS	O
+on	POS	O
+amino	POS	O
+acid	POS	O
+(	POS	O
+r	POS	O
+-	POS	O
+aminobutyric	POS	O
+acid	POS	O
+(	POS	O
+GABA	POS	O
+)	POS	O
+,	POS	O
+glutamine	POS	O
+,	POS	O
+aspartate	POS	O
+and	POS	O
+glutathione	POS	O
+)	POS	O
+levels	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+on	POS	O
+acetylcholinesterase	POS	O
+(	POS	O
+AChE	POS	O
+)	POS	O
+activity	POS	O
+in	POS	O
+mice	POS	O
+hippocampus	POS	O
+after	POS	O
+seizures	POS	B-NP
+.	POS	O
+GFC	POS	O
+produced	POS	O
+an	POS	O
+increased	POS	O
+latency	POS	O
+to	POS	O
+first	POS	O
+seizure	POS	B-NP
+,	POS	O
+at	POS	O
+doses	POS	O
+25mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+20	POS	O
+.	POS	O
+12	POS	O
++	POS	O
+2	POS	O
+.	POS	O
+20	POS	O
+min	POS	O
+)	POS	O
+,	POS	O
+50mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+20	POS	O
+.	POS	O
+95	POS	O
++	POS	O
+2	POS	O
+.	POS	O
+21	POS	O
+min	POS	O
+)	POS	O
+or	POS	O
+75	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+23	POS	O
+.	POS	O
+43	POS	O
++	POS	O
+1	POS	O
+.	POS	O
+99	POS	O
+min	POS	O
+)	POS	O
+when	POS	O
+compared	POS	O
+with	POS	O
+seized	POS	O
+mice	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+GABA	POS	O
+content	POS	O
+of	POS	O
+mice	POS	O
+hippocampus	POS	O
+treated	POS	O
+with	POS	O
+GFC75	POS	O
+plus	POS	O
+P400	POS	O
+showed	POS	O
+an	POS	O
+increase	POS	O
+of	POS	O
+46	POS	O
+.	POS	O
+90	POS	O
+%	POS	O
+when	POS	O
+compared	POS	O
+with	POS	O
+seized	POS	O
+mice	POS	O
+.	POS	O
+In	POS	O
+aspartate	POS	O
+,	POS	O
+glutamine	POS	O
+and	POS	O
+glutamate	POS	O
+levels	POS	O
+detected	POS	O
+a	POS	O
+decrease	POS	O
+of	POS	O
+5	POS	O
+.	POS	O
+21	POS	O
+%	POS	O
+,	POS	O
+13	POS	O
+.	POS	O
+55	POS	O
+%	POS	O
+and	POS	O
+21	POS	O
+.	POS	O
+80	POS	O
+%	POS	O
+,	POS	O
+respectively	POS	O
+in	POS	O
+mice	POS	O
+hippocampus	POS	O
+treated	POS	O
+with	POS	O
+GFC75	POS	O
+plus	POS	O
+P400	POS	O
+when	POS	O
+compared	POS	O
+with	POS	O
+seized	POS	O
+mice	POS	O
+.	POS	O
+Hippocampus	POS	O
+mice	POS	O
+treated	POS	O
+with	POS	O
+GFC75	POS	O
+plus	POS	O
+P400	POS	O
+showed	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+AChE	POS	O
+activity	POS	O
+(	POS	O
+63	POS	O
+.	POS	O
+30	POS	O
+%	POS	O
+)	POS	O
+when	POS	O
+compared	POS	O
+with	POS	O
+seized	POS	O
+mice	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+GFC	POS	O
+can	POS	O
+exert	POS	O
+anticonvulsant	POS	O
+activity	POS	O
+and	POS	O
+reduce	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+installation	POS	O
+of	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+,	POS	O
+as	POS	O
+demonstrated	POS	O
+by	POS	O
+increase	POS	O
+in	POS	O
+latency	POS	O
+to	POS	O
+first	POS	O
+seizure	POS	B-NP
+and	POS	O
+decrease	POS	O
+in	POS	O
+mortality	POS	O
+rate	POS	O
+of	POS	O
+animals	POS	O
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+our	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+GFC	POS	O
+may	POS	O
+influence	POS	O
+in	POS	O
+epileptogenesis	POS	B-NP
+and	POS	O
+promote	POS	O
+anticonvulsant	POS	O
+actions	POS	O
+in	POS	O
+pilocarpine	POS	O
+model	POS	O
+by	POS	O
+modulating	POS	O
+the	POS	O
+GABA	POS	O
+and	POS	O
+glutamate	POS	O
+contents	POS	O
+and	POS	O
+of	POS	O
+AChE	POS	O
+activity	POS	O
+in	POS	O
+seized	POS	O
+mice	POS	O
+hippocampus	POS	O
+.	POS	O
+This	POS	O
+compound	POS	O
+may	POS	O
+be	POS	O
+useful	POS	O
+to	POS	O
+produce	POS	O
+neuronal	POS	O
+protection	POS	O
+and	POS	O
+it	POS	O
+can	POS	O
+be	POS	O
+considered	POS	O
+as	POS	O
+an	POS	O
+anticonvulsant	POS	O
+agent	POS	O
+.	POS	O
+Standard	POS	O
+operating	POS	O
+procedures	POS	O
+for	POS	O
+antibiotic	POS	O
+therapy	POS	O
+and	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+acute	POS	B-NP
+kidney	POS	I-NP
+injury	POS	I-NP
+:	POS	O
+a	POS	O
+prospective	POS	O
+,	POS	O
+clinical	POS	O
+,	POS	O
+non	POS	O
+-	POS	O
+interventional	POS	O
+,	POS	O
+observational	POS	O
+study	POS	O
+.	POS	O
+INTRODUCTION	POS	O
+:	POS	O
+Acute	POS	B-NP
+kidney	POS	I-NP
+injury	POS	I-NP
+(	POS	O
+AKI	POS	B-NP
+)	POS	O
+occurs	POS	O
+in	POS	O
+7	POS	O
+%	POS	O
+of	POS	O
+hospitalized	POS	O
+and	POS	O
+66	POS	O
+%	POS	O
+of	POS	O
+Intensive	POS	O
+Care	POS	O
+Unit	POS	O
+(	POS	O
+ICU	POS	O
+)	POS	O
+patients	POS	O
+.	POS	O
+It	POS	O
+increases	POS	O
+mortality	POS	O
+,	POS	O
+hospital	POS	O
+length	POS	O
+of	POS	O
+stay	POS	O
+,	POS	O
+and	POS	O
+costs	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+investigate	POS	O
+,	POS	O
+whether	POS	O
+there	POS	O
+is	POS	O
+an	POS	O
+association	POS	O
+between	POS	O
+adherence	POS	O
+to	POS	O
+guidelines	POS	O
+(	POS	O
+standard	POS	O
+operating	POS	O
+procedures	POS	O
+(	POS	O
+SOP	POS	O
+)	POS	O
+)	POS	O
+for	POS	O
+potentially	POS	O
+nephrotoxic	POS	B-NP
+antibiotics	POS	O
+and	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+AKI	POS	B-NP
+.	POS	O
+METHODS	POS	O
+:	POS	O
+This	POS	O
+study	POS	O
+was	POS	O
+carried	POS	O
+out	POS	O
+as	POS	O
+a	POS	O
+prospective	POS	O
+,	POS	O
+clinical	POS	O
+,	POS	O
+non	POS	O
+-	POS	O
+interventional	POS	O
+,	POS	O
+observational	POS	O
+study	POS	O
+.	POS	O
+Data	POS	O
+collection	POS	O
+was	POS	O
+performed	POS	O
+over	POS	O
+a	POS	O
+total	POS	O
+of	POS	O
+170	POS	O
+days	POS	O
+in	POS	O
+three	POS	O
+ICUs	POS	O
+at	POS	O
+Charite	POS	O
+-	POS	O
+Universitaetsmedizin	POS	O
+Berlin	POS	O
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+675	POS	O
+patients	POS	O
+were	POS	O
+included	POS	O
+;	POS	O
+163	POS	O
+of	POS	O
+these	POS	O
+had	POS	O
+therapy	POS	O
+with	POS	O
+vancomycin	POS	O
+,	POS	O
+gentamicin	POS	O
+,	POS	O
+or	POS	O
+tobramycin	POS	O
+;	POS	O
+were	POS	O
+>	POS	O
+18	POS	O
+years	POS	O
+;	POS	O
+and	POS	O
+treated	POS	O
+in	POS	O
+the	POS	O
+ICU	POS	O
+for	POS	O
+>	POS	O
+24	POS	O
+hours	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+an	POS	O
+adherence	POS	O
+to	POS	O
+SOP	POS	O
+>	POS	O
+70	POS	O
+%	POS	O
+were	POS	O
+classified	POS	O
+into	POS	O
+the	POS	O
+high	POS	O
+adherence	POS	O
+group	POS	O
+(	POS	O
+HAG	POS	O
+)	POS	O
+and	POS	O
+patients	POS	O
+with	POS	O
+an	POS	O
+adherence	POS	O
+of	POS	O
+<	POS	O
+70	POS	O
+%	POS	O
+into	POS	O
+the	POS	O
+low	POS	O
+adherence	POS	O
+group	POS	O
+(	POS	O
+LAG	POS	O
+)	POS	O
+.	POS	O
+AKI	POS	B-NP
+was	POS	O
+defined	POS	O
+according	POS	O
+to	POS	O
+RIFLE	POS	O
+criteria	POS	O
+.	POS	O
+Adherence	POS	O
+to	POS	O
+SOPs	POS	O
+was	POS	O
+evaluated	POS	O
+by	POS	O
+retrospective	POS	O
+expert	POS	O
+audit	POS	O
+.	POS	O
+Development	POS	O
+of	POS	O
+AKI	POS	B-NP
+was	POS	O
+compared	POS	O
+between	POS	O
+groups	POS	O
+with	POS	O
+exact	POS	O
+Chi2	POS	O
+-	POS	O
+test	POS	O
+and	POS	O
+multivariate	POS	O
+logistic	POS	O
+regression	POS	O
+analysis	POS	O
+(	POS	O
+two	POS	O
+-	POS	O
+sided	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+LAG	POS	O
+consisted	POS	O
+of	POS	O
+75	POS	O
+patients	POS	O
+(	POS	O
+46	POS	O
+%	POS	O
+)	POS	O
+versus	POS	O
+88	POS	O
+HAG	POS	O
+patients	POS	O
+(	POS	O
+54	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+AKI	POS	B-NP
+occurred	POS	O
+significantly	POS	O
+more	POS	O
+often	POS	O
+in	POS	O
+LAG	POS	O
+with	POS	O
+36	POS	O
+%	POS	O
+versus	POS	O
+21	POS	O
+%	POS	O
+in	POS	O
+HAG	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+035	POS	O
+)	POS	O
+.	POS	O
+Basic	POS	O
+characteristics	POS	O
+were	POS	O
+comparable	POS	O
+,	POS	O
+except	POS	O
+an	POS	O
+increased	POS	O
+rate	POS	O
+of	POS	O
+soft	POS	B-NP
+tissue	POS	I-NP
+infections	POS	I-NP
+in	POS	O
+LAG	POS	O
+.	POS	O
+Multivariate	POS	O
+analysis	POS	O
+revealed	POS	O
+an	POS	O
+odds	POS	O
+ratio	POS	O
+of	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+fold	POS	O
+for	POS	O
+LAG	POS	O
+to	POS	O
+develop	POS	O
+AKI	POS	B-NP
+compared	POS	O
+with	POS	O
+HAG	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+1	POS	O
+.	POS	O
+195	POS	O
+to	POS	O
+5	POS	O
+.	POS	O
+124	POS	O
+,	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+039	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Low	POS	O
+adherence	POS	O
+to	POS	O
+SOPs	POS	O
+for	POS	O
+potentially	POS	O
+nephrotoxic	POS	B-NP
+antibiotics	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+a	POS	O
+higher	POS	O
+occurrence	POS	O
+of	POS	O
+AKI	POS	B-NP
+.	POS	O
+TRIAL	POS	O
+REGISTRATION	POS	O
+:	POS	O
+Current	POS	O
+Controlled	POS	O
+Trials	POS	O
+ISRCTN54598675	POS	O
+.	POS	O
+Registered	POS	O
+17	POS	O
+August	POS	O
+2007	POS	O
+.	POS	O
+Rhabdomyolysis	POS	B-NP
+in	POS	O
+a	POS	O
+hepatitis	POS	B-NP
+C	POS	I-NP
+virus	POS	I-NP
+infected	POS	I-NP
+patient	POS	O
+treated	POS	O
+with	POS	O
+telaprevir	POS	O
+and	POS	O
+simvastatin	POS	O
+.	POS	O
+A	POS	O
+46	POS	O
+-	POS	O
+year	POS	O
+old	POS	O
+man	POS	O
+with	POS	O
+a	POS	O
+chronic	POS	B-NP
+hepatitis	POS	I-NP
+C	POS	I-NP
+virus	POS	I-NP
+infection	POS	I-NP
+received	POS	O
+triple	POS	O
+therapy	POS	O
+with	POS	O
+ribavirin	POS	O
+,	POS	O
+pegylated	POS	O
+interferon	POS	O
+and	POS	O
+telaprevir	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+also	POS	O
+received	POS	O
+simvastatin	POS	O
+.	POS	O
+One	POS	O
+month	POS	O
+after	POS	O
+starting	POS	O
+the	POS	O
+antiviral	POS	O
+therapy	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+admitted	POS	O
+to	POS	O
+the	POS	O
+hospital	POS	O
+because	POS	O
+he	POS	O
+developed	POS	O
+rhabdomyolysis	POS	B-NP
+.	POS	O
+At	POS	O
+admission	POS	O
+simvastatin	POS	O
+and	POS	O
+all	POS	O
+antiviral	POS	O
+drugs	POS	O
+were	POS	O
+discontinued	POS	O
+because	POS	O
+toxicity	POS	B-NP
+due	POS	O
+to	POS	O
+a	POS	O
+drug	POS	O
+-	POS	O
+drug	POS	O
+interaction	POS	O
+was	POS	O
+suspected	POS	O
+.	POS	O
+The	POS	O
+creatine	POS	O
+kinase	POS	O
+peaked	POS	O
+at	POS	O
+62	POS	O
+,	POS	O
+246	POS	O
+IU	POS	O
+/	POS	O
+L	POS	O
+and	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+treated	POS	O
+with	POS	O
+intravenous	POS	O
+normal	POS	O
+saline	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+renal	POS	O
+function	POS	O
+remained	POS	O
+unaffected	POS	B-NP
+.	POS	O
+Fourteen	POS	O
+days	POS	O
+after	POS	O
+hospitalization	POS	O
+,	POS	O
+creatine	POS	O
+kinase	POS	O
+level	POS	O
+had	POS	O
+returned	POS	O
+to	POS	O
+230	POS	O
+IU	POS	O
+/	POS	O
+L	POS	O
+and	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+discharged	POS	O
+.	POS	O
+Telaprevir	POS	O
+was	POS	O
+considered	POS	O
+the	POS	O
+probable	POS	O
+causative	POS	O
+agent	POS	O
+of	POS	O
+an	POS	O
+interaction	POS	O
+with	POS	O
+simvastatin	POS	O
+according	POS	O
+to	POS	O
+the	POS	O
+Drug	POS	O
+Interaction	POS	O
+Probability	POS	O
+Scale	POS	O
+.	POS	O
+The	POS	O
+interaction	POS	O
+is	POS	O
+due	POS	O
+to	POS	O
+inhibition	POS	O
+of	POS	O
+CYP3A4	POS	O
+-	POS	O
+mediated	POS	O
+simvastatin	POS	O
+clearance	POS	O
+.	POS	O
+Simvastatin	POS	O
+plasma	POS	O
+concentration	POS	O
+increased	POS	O
+30	POS	O
+times	POS	O
+in	POS	O
+this	POS	O
+patient	POS	O
+and	POS	O
+statin	POS	O
+induced	POS	O
+muscle	POS	B-NP
+toxicity	POS	I-NP
+is	POS	O
+related	POS	O
+to	POS	O
+the	POS	O
+concentration	POS	O
+of	POS	O
+the	POS	O
+statin	POS	O
+in	POS	O
+blood	POS	O
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+with	POS	O
+this	POS	O
+case	POS	O
+we	POS	O
+illustrate	POS	O
+that	POS	O
+telaprevir	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+statins	POS	O
+are	POS	O
+susceptible	POS	O
+to	POS	O
+clinical	POS	O
+relevant	POS	O
+drug	POS	O
+-	POS	O
+drug	POS	O
+interactions	POS	O
+.	POS	O
+Combination	POS	O
+of	POS	O
+bortezomib	POS	O
+,	POS	O
+thalidomide	POS	O
+,	POS	O
+and	POS	O
+dexamethasone	POS	O
+(	POS	O
+VTD	POS	O
+)	POS	O
+as	POS	O
+a	POS	O
+consolidation	POS	O
+therapy	POS	O
+after	POS	O
+autologous	POS	O
+stem	POS	O
+cell	POS	O
+transplantation	POS	O
+for	POS	O
+symptomatic	POS	O
+multiple	POS	O
+myeloma	POS	B-NP
+in	POS	O
+Japanese	POS	O
+patients	POS	O
+.	POS	O
+Consolidation	POS	O
+therapy	POS	O
+for	POS	O
+patients	POS	O
+with	POS	O
+multiple	POS	B-NP
+myeloma	POS	I-NP
+(	POS	O
+MM	POS	B-NP
+)	POS	O
+has	POS	O
+been	POS	O
+widely	POS	O
+adopted	POS	O
+to	POS	O
+improve	POS	O
+treatment	POS	O
+response	POS	O
+following	POS	O
+autologous	POS	O
+stem	POS	O
+cell	POS	O
+transplantation	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+study	POS	O
+,	POS	O
+we	POS	O
+retrospectively	POS	O
+analyzed	POS	O
+the	POS	O
+safety	POS	O
+and	POS	O
+efficacy	POS	O
+of	POS	O
+combination	POS	O
+regimen	POS	O
+of	POS	O
+bortezomib	POS	O
+,	POS	O
+thalidomide	POS	O
+,	POS	O
+and	POS	O
+dexamethasone	POS	O
+(	POS	O
+VTD	POS	O
+)	POS	O
+as	POS	O
+consolidation	POS	O
+therapy	POS	O
+in	POS	O
+24	POS	O
+Japanese	POS	O
+patients	POS	O
+with	POS	O
+newly	POS	O
+diagnosed	POS	O
+MM	POS	B-NP
+.	POS	O
+VTD	POS	B-NP
+consisted	POS	O
+of	POS	O
+bortezomib	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+m	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+and	POS	O
+dexamethasone	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+40	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+on	POS	O
+days	POS	O
+1	POS	O
+,	POS	O
+8	POS	O
+,	POS	O
+15	POS	O
+,	POS	O
+and	POS	O
+22	POS	O
+of	POS	O
+a	POS	O
+35	POS	O
+-	POS	O
+day	POS	O
+cycle	POS	O
+,	POS	O
+with	POS	O
+daily	POS	O
+oral	POS	O
+thalidomide	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+.	POS	O
+Grade	POS	O
+3	POS	O
+-	POS	O
+4	POS	O
+neutropenia	POS	B-NP
+and	POS	O
+thrombocytopenia	POS	B-NP
+were	POS	O
+documented	POS	O
+in	POS	O
+four	POS	O
+and	POS	O
+three	POS	O
+patients	POS	O
+(	POS	O
+17	POS	O
+and	POS	O
+13	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+but	POS	O
+drug	POS	O
+dose	POS	O
+reduction	POS	O
+due	POS	O
+to	POS	O
+cytopenia	POS	B-NP
+was	POS	O
+not	POS	O
+required	POS	O
+in	POS	O
+any	POS	O
+case	POS	O
+.	POS	O
+Peripheral	POS	B-NP
+neuropathy	POS	I-NP
+was	POS	O
+common	POS	O
+(	POS	O
+63	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+but	POS	O
+severe	POS	O
+grade	POS	O
+3	POS	O
+-	POS	O
+4	POS	O
+peripheral	POS	B-NP
+neuropathy	POS	I-NP
+was	POS	O
+not	POS	O
+observed	POS	O
+.	POS	O
+Very	POS	O
+good	POS	O
+partial	POS	O
+response	POS	O
+or	POS	O
+better	POS	O
+response	POS	O
+(	POS	O
+>	POS	O
+VGPR	POS	O
+)	POS	O
+rates	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+consolidation	POS	O
+therapy	POS	O
+were	POS	O
+54	POS	O
+and	POS	O
+79	POS	O
+%	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Patients	POS	O
+had	POS	O
+a	POS	O
+significant	POS	O
+probability	POS	O
+of	POS	O
+improving	POS	O
+from	POS	O
+<	POS	O
+VGPR	POS	O
+before	POS	O
+consolidation	POS	O
+therapy	POS	O
+to	POS	O
+>	POS	O
+VGPR	POS	O
+after	POS	O
+consolidation	POS	O
+therapy	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+041	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+VTD	POS	O
+regimen	POS	O
+may	POS	O
+be	POS	O
+safe	POS	O
+and	POS	O
+effective	POS	O
+as	POS	O
+a	POS	O
+consolidation	POS	O
+therapy	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+MM	POS	B-NP
+in	POS	O
+Japanese	POS	O
+population	POS	O
+.	POS	O
+Conversion	POS	O
+to	POS	O
+sirolimus	POS	O
+ameliorates	POS	O
+cyclosporine	POS	O
+-	POS	O
+induced	POS	O
+nephropathy	POS	B-NP
+in	POS	O
+the	POS	O
+rat	POS	O
+:	POS	O
+focus	POS	O
+on	POS	O
+serum	POS	O
+,	POS	O
+urine	POS	O
+,	POS	O
+gene	POS	O
+,	POS	O
+and	POS	O
+protein	POS	O
+renal	POS	O
+expression	POS	O
+biomarkers	POS	O
+.	POS	O
+Protocols	POS	O
+of	POS	O
+conversion	POS	O
+from	POS	O
+cyclosporin	POS	O
+A	POS	O
+(	POS	O
+CsA	POS	O
+)	POS	O
+to	POS	O
+sirolimus	POS	O
+(	POS	O
+SRL	POS	O
+)	POS	O
+have	POS	O
+been	POS	O
+widely	POS	O
+used	POS	O
+in	POS	O
+immunotherapy	POS	O
+after	POS	O
+transplantation	POS	O
+to	POS	O
+prevent	POS	O
+CsA	POS	O
+-	POS	O
+induced	POS	O
+nephropathy	POS	B-NP
+,	POS	O
+but	POS	O
+the	POS	O
+molecular	POS	O
+mechanisms	POS	O
+underlying	POS	O
+these	POS	O
+protocols	POS	O
+remain	POS	O
+nuclear	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+aimed	POS	O
+to	POS	O
+identify	POS	O
+the	POS	O
+molecular	POS	O
+pathways	POS	O
+and	POS	O
+putative	POS	O
+biomarkers	POS	O
+of	POS	O
+CsA	POS	O
+-	POS	O
+to	POS	O
+-	POS	O
+SRL	POS	O
+conversion	POS	O
+in	POS	O
+a	POS	O
+rat	POS	O
+model	POS	O
+.	POS	O
+Four	POS	O
+animal	POS	O
+groups	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+6	POS	O
+)	POS	O
+were	POS	O
+tested	POS	O
+during	POS	O
+9	POS	O
+weeks	POS	O
+:	POS	O
+control	POS	O
+,	POS	O
+CsA	POS	O
+,	POS	O
+SRL	POS	O
+,	POS	O
+and	POS	O
+conversion	POS	O
+(	POS	O
+CsA	POS	O
+for	POS	O
+3	POS	O
+weeks	POS	O
+followed	POS	O
+by	POS	O
+SRL	POS	O
+for	POS	O
+6	POS	O
+weeks	POS	O
+)	POS	O
+.	POS	O
+Classical	POS	O
+and	POS	O
+emergent	POS	O
+serum	POS	O
+,	POS	O
+urinary	POS	O
+,	POS	O
+and	POS	O
+kidney	POS	O
+tissue	POS	O
+(	POS	O
+gene	POS	O
+and	POS	O
+protein	POS	O
+expression	POS	O
+)	POS	O
+markers	POS	O
+were	POS	O
+assessed	POS	O
+.	POS	O
+Renal	POS	B-NP
+lesions	POS	I-NP
+were	POS	O
+analyzed	POS	O
+in	POS	O
+hematoxylin	POS	O
+and	POS	O
+eosin	POS	O
+,	POS	O
+periodic	POS	O
+acid	POS	O
+-	POS	O
+Schiff	POS	O
+,	POS	O
+and	POS	O
+Masson	POS	O
+'	POS	O
+s	POS	O
+trichrome	POS	O
+stains	POS	O
+.	POS	O
+SRL	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+presented	POS	O
+proteinuria	POS	B-NP
+and	POS	O
+NGAL	POS	O
+(	POS	O
+serum	POS	O
+and	POS	O
+urinary	POS	O
+)	POS	O
+as	POS	O
+the	POS	O
+best	POS	O
+markers	POS	O
+of	POS	O
+renal	POS	B-NP
+impairment	POS	I-NP
+.	POS	O
+Short	POS	O
+CsA	POS	O
+treatment	POS	O
+presented	POS	O
+slight	POS	O
+or	POS	O
+even	POS	O
+absent	POS	O
+kidney	POS	O
+lesions	POS	O
+and	POS	O
+TGF	POS	O
+-	POS	O
+b	POS	O
+,	POS	O
+NF	POS	O
+-	POS	O
+kb	POS	O
+,	POS	O
+mTOR	POS	O
+,	POS	O
+PCNA	POS	O
+,	POS	O
+TP53	POS	O
+,	POS	O
+KIM	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+and	POS	O
+CTGF	POS	O
+as	POS	O
+relevant	POS	O
+gene	POS	O
+and	POS	O
+protein	POS	O
+changes	POS	O
+.	POS	O
+Prolonged	POS	O
+CsA	POS	O
+exposure	POS	O
+aggravated	POS	O
+renal	POS	B-NP
+damage	POS	I-NP
+,	POS	O
+without	POS	O
+clear	POS	O
+changes	POS	O
+on	POS	O
+the	POS	O
+traditional	POS	O
+markers	POS	O
+,	POS	O
+but	POS	O
+with	POS	O
+changes	POS	O
+in	POS	O
+serums	POS	O
+TGF	POS	O
+-	POS	O
+b	POS	O
+and	POS	O
+IL	POS	O
+-	POS	O
+7	POS	O
+,	POS	O
+TBARs	POS	O
+clearance	POS	O
+,	POS	O
+and	POS	O
+kidney	POS	O
+TGF	POS	O
+-	POS	O
+b	POS	O
+and	POS	O
+mTOR	POS	O
+.	POS	O
+Conversion	POS	O
+to	POS	O
+SRL	POS	O
+prevented	POS	O
+CsA	POS	O
+-	POS	O
+induced	POS	O
+renal	POS	O
+damage	POS	O
+evolution	POS	O
+(	POS	O
+absent	POS	O
+/	POS	O
+mild	POS	O
+grade	POS	O
+lesions	POS	B-NP
+)	POS	O
+,	POS	O
+while	POS	O
+NGAL	POS	O
+(	POS	O
+serum	POS	O
+versus	POS	O
+urine	POS	O
+)	POS	O
+seems	POS	O
+to	POS	O
+be	POS	O
+a	POS	O
+feasible	POS	O
+biomarker	POS	O
+of	POS	O
+CsA	POS	O
+replacement	POS	O
+to	POS	O
+SRL	POS	O
+.	POS	O
+Kinin	POS	O
+B2	POS	O
+receptor	POS	O
+deletion	POS	O
+and	POS	O
+blockage	POS	O
+ameliorates	POS	O
+cisplatin	POS	O
+-	POS	O
+induced	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+injury	POS	I-NP
+.	POS	O
+Cisplatin	POS	O
+treatment	POS	O
+has	POS	O
+been	POS	O
+adopted	POS	O
+in	POS	O
+some	POS	O
+chemotherapies	POS	O
+;	POS	O
+however	POS	O
+,	POS	O
+this	POS	O
+drug	POS	O
+can	POS	O
+induce	POS	O
+acute	POS	B-NP
+kidney	POS	I-NP
+injury	POS	I-NP
+due	POS	O
+its	POS	O
+ability	POS	O
+to	POS	O
+negatively	POS	O
+affect	POS	O
+renal	POS	O
+function	POS	O
+,	POS	O
+augment	POS	O
+serum	POS	O
+levels	POS	O
+of	POS	O
+creatinine	POS	O
+and	POS	O
+urea	POS	O
+,	POS	O
+increase	POS	O
+the	POS	O
+acute	POS	O
+tubular	POS	O
+necrosis	POS	O
+score	POS	O
+and	POS	O
+up	POS	O
+-	POS	O
+regulate	POS	O
+cytokines	POS	O
+(	POS	O
+e	POS	O
+.	POS	O
+g	POS	O
+.	POS	O
+,	POS	O
+IL	POS	O
+-	POS	O
+1b	POS	O
+and	POS	O
+TNF	POS	O
+-	POS	O
+a	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+kinin	POS	O
+B2	POS	O
+receptor	POS	O
+has	POS	O
+been	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+inflammation	POS	O
+process	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+the	POS	O
+regulation	POS	O
+of	POS	O
+cytokine	POS	O
+expression	POS	O
+,	POS	O
+and	POS	O
+its	POS	O
+deletion	POS	O
+resulted	POS	O
+in	POS	O
+an	POS	O
+improvement	POS	O
+in	POS	O
+the	POS	O
+diabetic	POS	B-NP
+nephropathy	POS	I-NP
+status	POS	O
+.	POS	O
+To	POS	O
+examine	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+the	POS	O
+kinin	POS	O
+B2	POS	O
+receptor	POS	O
+in	POS	O
+cisplatin	POS	O
+-	POS	O
+induced	POS	O
+acute	POS	B-NP
+kidney	POS	I-NP
+injury	POS	I-NP
+,	POS	O
+kinin	POS	O
+B2	POS	O
+receptor	POS	O
+knockout	POS	O
+mice	POS	O
+were	POS	O
+challenged	POS	O
+with	POS	O
+cisplatin	POS	O
+.	POS	O
+Additionally	POS	O
+,	POS	O
+WT	POS	O
+mice	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+a	POS	O
+B2	POS	O
+receptor	POS	O
+antagonist	POS	O
+after	POS	O
+cisplatin	POS	O
+administration	POS	O
+.	POS	O
+B2	POS	O
+receptor	POS	O
+-	POS	O
+deficient	POS	O
+mice	POS	O
+were	POS	O
+less	POS	O
+sensitive	POS	O
+to	POS	O
+this	POS	O
+drug	POS	O
+than	POS	O
+the	POS	O
+WT	POS	O
+mice	POS	O
+,	POS	O
+as	POS	O
+shown	POS	O
+by	POS	O
+reduced	POS	O
+weight	POS	O
+loss	POS	O
+,	POS	O
+better	POS	O
+preservation	POS	O
+of	POS	O
+kidney	POS	O
+function	POS	O
+,	POS	O
+down	POS	O
+regulation	POS	O
+of	POS	O
+inflammatory	POS	O
+cytokines	POS	O
+and	POS	O
+less	POS	O
+acute	POS	O
+tubular	POS	O
+necrosis	POS	B-NP
+.	POS	O
+Moreover	POS	O
+,	POS	O
+treatment	POS	O
+with	POS	O
+the	POS	O
+kinin	POS	O
+B2	POS	O
+receptor	POS	O
+antagonist	POS	O
+effectively	POS	O
+reduced	POS	O
+the	POS	O
+levels	POS	O
+of	POS	O
+serum	POS	O
+creatinine	POS	O
+and	POS	O
+blood	POS	O
+urea	POS	O
+after	POS	O
+cisplatin	POS	O
+administration	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+our	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+the	POS	O
+kinin	POS	O
+B2	POS	O
+receptor	POS	O
+is	POS	O
+involved	POS	O
+in	POS	O
+cisplatin	POS	O
+-	POS	O
+induced	POS	O
+acute	POS	B-NP
+kidney	POS	I-NP
+injury	POS	I-NP
+by	POS	O
+mediating	POS	O
+the	POS	O
+necrotic	POS	O
+process	POS	O
+and	POS	O
+the	POS	O
+expression	POS	O
+of	POS	O
+inflammatory	POS	O
+cytokines	POS	O
+,	POS	O
+thus	POS	O
+resulting	POS	O
+in	POS	O
+declined	POS	O
+renal	POS	O
+function	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+highlight	POS	O
+the	POS	O
+kinin	POS	O
+B2	POS	O
+receptor	POS	O
+antagonist	POS	O
+treatment	POS	O
+in	POS	O
+amelioration	POS	O
+of	POS	O
+nephrotoxicity	POS	B-NP
+induced	POS	O
+by	POS	O
+cisplatin	POS	O
+therapy	POS	O
+.	POS	O
+Safety	POS	O
+and	POS	O
+efficacy	POS	O
+of	POS	O
+fluocinolone	POS	O
+acetonide	POS	O
+intravitreal	POS	O
+implant	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+59	POS	O
+mg	POS	O
+)	POS	O
+in	POS	O
+birdshot	POS	B-NP
+retinochoroidopathy	POS	I-NP
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+To	POS	O
+report	POS	O
+the	POS	O
+treatment	POS	O
+outcomes	POS	O
+of	POS	O
+the	POS	O
+fluocinolone	POS	O
+acetonide	POS	O
+intravitreal	POS	O
+implant	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+59	POS	O
+mg	POS	O
+)	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+birdshot	POS	B-NP
+retinochoroidopathy	POS	I-NP
+whose	POS	I-NP
+disease	POS	I-NP
+is	POS	O
+refractory	POS	O
+or	POS	O
+intolerant	POS	O
+to	POS	O
+conventional	POS	O
+immunomodulatory	POS	O
+therapy	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+A	POS	O
+retrospective	POS	O
+case	POS	O
+series	POS	O
+involving	POS	O
+11	POS	O
+birdshot	POS	O
+retinochoroidopathy	POS	B-NP
+patients	POS	O
+(	POS	O
+11	POS	O
+eyes	POS	O
+)	POS	O
+.	POS	O
+Eleven	POS	O
+patients	POS	O
+(	POS	O
+11	POS	O
+eyes	POS	O
+)	POS	O
+underwent	POS	O
+surgery	POS	O
+for	POS	O
+fluocinolone	POS	O
+acetonide	POS	O
+implant	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+59	POS	O
+mg	POS	O
+)	POS	O
+.	POS	O
+Treatment	POS	O
+outcomes	POS	O
+of	POS	O
+interest	POS	O
+were	POS	O
+noted	POS	O
+at	POS	O
+baseline	POS	O
+,	POS	O
+before	POS	O
+fluocinolone	POS	O
+acetonide	POS	O
+implant	POS	O
+,	POS	O
+and	POS	O
+then	POS	O
+at	POS	O
+6	POS	O
+months	POS	O
+,	POS	O
+1	POS	O
+year	POS	O
+,	POS	O
+2	POS	O
+years	POS	O
+,	POS	O
+3	POS	O
+years	POS	O
+,	POS	O
+and	POS	O
+beyond	POS	O
+3	POS	O
+years	POS	O
+.	POS	O
+Disease	POS	O
+activity	POS	O
+markers	POS	O
+,	POS	O
+including	POS	O
+signs	POS	O
+of	POS	O
+ocular	POS	B-NP
+inflammation	POS	I-NP
+,	POS	O
+evidence	POS	O
+of	POS	O
+retinal	POS	B-NP
+vasculitis	POS	I-NP
+,	POS	O
+Swedish	POS	O
+interactive	POS	O
+threshold	POS	O
+algorithm	POS	O
+-	POS	O
+short	POS	O
+wavelength	POS	O
+automated	POS	O
+perimetry	POS	O
+Humphrey	POS	O
+visual	POS	O
+field	POS	O
+analysis	POS	O
+,	POS	O
+electroretinographic	POS	O
+parameters	POS	O
+,	POS	O
+and	POS	O
+optical	POS	O
+coherence	POS	O
+tomography	POS	O
+were	POS	O
+recorded	POS	O
+.	POS	O
+Data	POS	O
+on	POS	O
+occurrence	POS	O
+of	POS	O
+cataract	POS	B-NP
+and	POS	O
+raised	POS	O
+intraocular	POS	O
+pressure	POS	O
+were	POS	O
+collected	POS	O
+in	POS	O
+all	POS	O
+eyes	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Intraocular	POS	B-NP
+inflammation	POS	I-NP
+was	POS	O
+present	POS	O
+in	POS	O
+54	POS	O
+.	POS	O
+5	POS	O
+,	POS	O
+9	POS	O
+.	POS	O
+9	POS	O
+,	POS	O
+11	POS	O
+.	POS	O
+1	POS	O
+,	POS	O
+and	POS	O
+0	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+at	POS	O
+baseline	POS	O
+,	POS	O
+6	POS	O
+months	POS	O
+,	POS	O
+1	POS	O
+year	POS	O
+,	POS	O
+2	POS	O
+years	POS	O
+,	POS	O
+3	POS	O
+years	POS	O
+,	POS	O
+and	POS	O
+beyond	POS	O
+3	POS	O
+years	POS	O
+after	POS	O
+receiving	POS	O
+the	POS	O
+implant	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Active	POS	O
+vasculitis	POS	B-NP
+was	POS	O
+noted	POS	O
+in	POS	O
+36	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+patients	POS	O
+at	POS	O
+baseline	POS	O
+and	POS	O
+0	POS	O
+%	POS	O
+at	POS	O
+3	POS	O
+years	POS	O
+of	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+.	POS	O
+More	POS	O
+than	POS	O
+20	POS	O
+%	POS	O
+(	POS	O
+47	POS	O
+.	POS	O
+61	POS	O
+-	POS	O
+67	POS	O
+.	POS	O
+2	POS	O
+%	POS	O
+)	POS	O
+reduction	POS	O
+in	POS	O
+central	POS	O
+retinal	POS	O
+thickness	POS	O
+was	POS	O
+noted	POS	O
+in	POS	O
+all	POS	O
+patients	POS	O
+with	POS	O
+cystoid	POS	B-NP
+macular	POS	I-NP
+edema	POS	I-NP
+at	POS	O
+6	POS	O
+months	POS	O
+,	POS	O
+1	POS	O
+year	POS	O
+,	POS	O
+2	POS	O
+years	POS	O
+,	POS	O
+and	POS	O
+3	POS	O
+years	POS	O
+postimplant	POS	O
+.	POS	O
+At	POS	O
+baseline	POS	O
+,	POS	O
+54	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+patients	POS	O
+were	POS	O
+on	POS	O
+immunomodulatory	POS	O
+agents	POS	O
+.	POS	O
+This	POS	O
+percentage	POS	O
+decreased	POS	O
+to	POS	O
+45	POS	O
+.	POS	O
+45	POS	O
+,	POS	O
+44	POS	O
+.	POS	O
+4	POS	O
+,	POS	O
+and	POS	O
+14	POS	O
+.	POS	O
+28	POS	O
+%	POS	O
+at	POS	O
+1	POS	O
+year	POS	O
+,	POS	O
+2	POS	O
+years	POS	O
+,	POS	O
+and	POS	O
+3	POS	O
+years	POS	O
+postimplant	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Adverse	POS	O
+events	POS	O
+included	POS	O
+increased	POS	O
+intraocular	POS	O
+pressure	POS	O
+(	POS	O
+54	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+cataract	POS	B-NP
+formation	POS	O
+(	POS	O
+100	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+The	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+fluocinolone	POS	O
+acetonide	POS	O
+implant	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+59	POS	O
+mg	POS	O
+)	POS	O
+helps	POS	O
+to	POS	O
+control	POS	O
+inflammation	POS	B-NP
+in	POS	O
+otherwise	POS	O
+treatment	POS	O
+-	POS	O
+refractory	POS	O
+cases	POS	O
+of	POS	O
+birdshot	POS	B-NP
+retinochoroidopathy	POS	I-NP
+.	POS	O
+It	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+significant	POS	O
+side	POS	O
+effects	POS	O
+of	POS	O
+cataract	POS	B-NP
+and	POS	O
+ocular	POS	B-NP
+hypertension	POS	I-NP
+requiring	POS	O
+treatment	POS	O
+.	POS	O
+Optimal	POS	O
+precurarizing	POS	O
+dose	POS	O
+of	POS	O
+rocuronium	POS	O
+to	POS	O
+decrease	POS	O
+fasciculation	POS	B-NP
+and	POS	O
+myalgia	POS	B-NP
+following	POS	O
+succinylcholine	POS	O
+administration	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Succinylcholine	POS	O
+commonly	POS	O
+produces	POS	O
+frequent	POS	O
+adverse	POS	O
+effects	POS	O
+,	POS	O
+including	POS	O
+muscle	POS	B-NP
+fasciculation	POS	I-NP
+and	POS	O
+myalgia	POS	B-NP
+.	POS	O
+The	POS	O
+current	POS	O
+study	POS	O
+identified	POS	O
+the	POS	O
+optimal	POS	O
+dose	POS	O
+of	POS	O
+rocuronium	POS	O
+to	POS	O
+prevent	POS	O
+succinylcholine	POS	O
+-	POS	O
+induced	POS	O
+fasciculation	POS	B-NP
+and	POS	O
+myalgia	POS	B-NP
+and	POS	O
+evaluated	POS	O
+the	POS	O
+influence	POS	O
+of	POS	O
+rocuronium	POS	O
+on	POS	O
+the	POS	O
+speed	POS	O
+of	POS	O
+onset	POS	O
+produced	POS	O
+by	POS	O
+succinylcholine	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+This	POS	O
+randomized	POS	O
+,	POS	O
+double	POS	O
+-	POS	O
+blinded	POS	O
+study	POS	O
+was	POS	O
+conducted	POS	O
+in	POS	O
+100	POS	O
+patients	POS	O
+randomly	POS	O
+allocated	POS	O
+into	POS	O
+five	POS	O
+groups	POS	O
+of	POS	O
+20	POS	O
+patients	POS	O
+each	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+randomized	POS	O
+to	POS	O
+receive	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+03	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+04	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+06	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+rocuronium	POS	O
+as	POS	O
+a	POS	O
+precurarizing	POS	O
+dose	POS	O
+.	POS	O
+Neuromuscular	POS	O
+monitoring	POS	O
+after	POS	O
+each	POS	O
+precurarizing	POS	O
+dose	POS	O
+was	POS	O
+recorded	POS	O
+from	POS	O
+the	POS	O
+adductor	POS	O
+pollicis	POS	O
+muscle	POS	O
+using	POS	O
+acceleromyography	POS	O
+with	POS	O
+train	POS	O
+-	POS	O
+of	POS	O
+-	POS	O
+four	POS	O
+stimulation	POS	O
+of	POS	O
+the	POS	O
+ulnar	POS	O
+nerve	POS	O
+.	POS	O
+All	POS	O
+patients	POS	O
+received	POS	O
+succinylcholine	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+at	POS	O
+2	POS	O
+minutes	POS	O
+after	POS	O
+the	POS	O
+precurarization	POS	O
+,	POS	O
+and	POS	O
+were	POS	O
+assessed	POS	O
+the	POS	O
+incidence	POS	O
+and	POS	O
+severity	POS	O
+of	POS	O
+fasciculations	POS	B-NP
+,	POS	O
+while	POS	O
+myalgia	POS	B-NP
+was	POS	O
+assessed	POS	O
+at	POS	O
+24	POS	O
+hours	POS	O
+after	POS	O
+surgery	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+incidence	POS	O
+and	POS	O
+severity	POS	O
+of	POS	O
+visible	POS	O
+muscle	POS	B-NP
+fasciculation	POS	I-NP
+was	POS	O
+significantly	POS	O
+less	POS	O
+with	POS	O
+increasing	POS	O
+the	POS	O
+amount	POS	O
+of	POS	O
+precurarizing	POS	O
+dose	POS	O
+of	POS	O
+rocuronium	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+Those	POS	O
+of	POS	O
+myalgia	POS	B-NP
+tend	POS	O
+to	POS	O
+decrease	POS	O
+according	POS	O
+to	POS	O
+increasing	POS	O
+the	POS	O
+amount	POS	O
+of	POS	O
+precurarizing	POS	O
+dose	POS	O
+of	POS	O
+rocuronium	POS	O
+,	POS	O
+but	POS	O
+there	POS	O
+was	POS	O
+no	POS	O
+significance	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+072	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+onset	POS	O
+time	POS	O
+of	POS	O
+succinylcholine	POS	O
+was	POS	O
+significantly	POS	O
+longer	POS	O
+with	POS	O
+increasing	POS	O
+the	POS	O
+amount	POS	O
+of	POS	O
+precurarizing	POS	O
+dose	POS	O
+of	POS	O
+rocuronium	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Precurarization	POS	O
+with	POS	O
+0	POS	O
+.	POS	O
+04	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+rocuronium	POS	O
+was	POS	O
+the	POS	O
+optimal	POS	O
+dose	POS	O
+considering	POS	O
+the	POS	O
+reduction	POS	O
+in	POS	O
+the	POS	O
+incidence	POS	O
+and	POS	O
+severity	POS	O
+of	POS	O
+fasciculation	POS	B-NP
+and	POS	O
+myalgia	POS	B-NP
+with	POS	O
+acceptable	POS	O
+onset	POS	O
+time	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+safe	POS	O
+and	POS	O
+effective	POS	O
+precurarization	POS	O
+.	POS	O
+Absence	POS	O
+of	POS	O
+PKC	POS	O
+-	POS	O
+alpha	POS	O
+attenuates	POS	O
+lithium	POS	O
+-	POS	O
+induced	POS	O
+nephrogenic	POS	B-NP
+diabetes	POS	I-NP
+insipidus	POS	I-NP
+.	POS	O
+Lithium	POS	B-NP
+,	POS	O
+an	POS	O
+effective	POS	O
+antipsychotic	POS	O
+,	POS	O
+induces	POS	O
+nephrogenic	POS	B-NP
+diabetes	POS	I-NP
+insipidus	POS	I-NP
+(	POS	O
+NDI	POS	B-NP
+)	POS	O
+in	POS	O
+40	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+decreased	POS	O
+capacity	POS	O
+to	POS	O
+concentrate	POS	O
+urine	POS	O
+is	POS	O
+likely	POS	O
+due	POS	O
+to	POS	O
+lithium	POS	O
+acutely	POS	O
+disrupting	POS	O
+the	POS	O
+cAMP	POS	O
+pathway	POS	O
+and	POS	O
+chronically	POS	O
+reducing	POS	O
+urea	POS	O
+transporter	POS	O
+(	POS	O
+UT	POS	O
+-	POS	O
+A1	POS	O
+)	POS	O
+and	POS	O
+water	POS	O
+channel	POS	O
+(	POS	O
+AQP2	POS	O
+)	POS	O
+expression	POS	O
+in	POS	O
+the	POS	O
+inner	POS	O
+medulla	POS	O
+.	POS	O
+Targeting	POS	O
+an	POS	O
+alternative	POS	O
+signaling	POS	O
+pathway	POS	O
+,	POS	O
+such	POS	O
+as	POS	O
+PKC	POS	O
+-	POS	O
+mediated	POS	O
+signaling	POS	O
+,	POS	O
+may	POS	O
+be	POS	O
+an	POS	O
+effective	POS	O
+method	POS	O
+of	POS	O
+treating	POS	O
+lithium	POS	O
+-	POS	O
+induced	POS	O
+polyuria	POS	B-NP
+.	POS	O
+PKC	POS	O
+-	POS	O
+alpha	POS	O
+null	POS	O
+mice	POS	O
+(	POS	O
+PKCa	POS	O
+KO	POS	O
+)	POS	O
+and	POS	O
+strain	POS	O
+-	POS	O
+matched	POS	O
+wild	POS	O
+type	POS	O
+(	POS	O
+WT	POS	O
+)	POS	O
+controls	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+lithium	POS	O
+for	POS	O
+0	POS	O
+,	POS	O
+3	POS	O
+or	POS	O
+5	POS	O
+days	POS	O
+.	POS	O
+WT	POS	O
+mice	POS	O
+had	POS	O
+increased	POS	O
+urine	POS	O
+output	POS	O
+and	POS	O
+lowered	POS	O
+urine	POS	O
+osmolality	POS	O
+after	POS	O
+3	POS	O
+and	POS	O
+5	POS	O
+days	POS	O
+of	POS	O
+treatment	POS	O
+whereas	POS	O
+PKCa	POS	O
+KO	POS	O
+mice	POS	O
+had	POS	O
+no	POS	O
+change	POS	O
+in	POS	O
+urine	POS	O
+output	POS	O
+or	POS	O
+concentration	POS	O
+.	POS	O
+Western	POS	O
+blot	POS	O
+analysis	POS	O
+revealed	POS	O
+that	POS	O
+AQP2	POS	O
+expression	POS	O
+in	POS	O
+medullary	POS	O
+tissues	POS	O
+was	POS	O
+lowered	POS	O
+after	POS	O
+3	POS	O
+and	POS	O
+5	POS	O
+days	POS	O
+in	POS	O
+WT	POS	O
+mice	POS	O
+;	POS	O
+however	POS	O
+,	POS	O
+AQP2	POS	O
+was	POS	O
+unchanged	POS	O
+in	POS	O
+PKCa	POS	O
+KO	POS	O
+.	POS	O
+Similar	POS	O
+results	POS	O
+were	POS	O
+observed	POS	O
+with	POS	O
+UT	POS	O
+-	POS	O
+A1	POS	O
+expression	POS	O
+.	POS	O
+Animals	POS	O
+were	POS	O
+also	POS	O
+treated	POS	O
+with	POS	O
+lithium	POS	O
+for	POS	O
+6	POS	O
+weeks	POS	O
+.	POS	O
+Lithium	POS	O
+-	POS	O
+treated	POS	O
+WT	POS	O
+mice	POS	O
+had	POS	O
+19	POS	O
+-	POS	O
+fold	POS	O
+increased	POS	O
+urine	POS	O
+output	POS	O
+whereas	POS	O
+treated	POS	O
+PKCa	POS	O
+KO	POS	O
+animals	POS	O
+had	POS	O
+a	POS	O
+4	POS	O
+-	POS	O
+fold	POS	O
+increase	POS	O
+in	POS	O
+output	POS	O
+.	POS	O
+AQP2	POS	O
+and	POS	O
+UT	POS	O
+-	POS	O
+A1	POS	O
+expression	POS	O
+was	POS	O
+lowered	POS	O
+in	POS	O
+6	POS	O
+week	POS	O
+lithium	POS	O
+-	POS	O
+treated	POS	O
+WT	POS	O
+animals	POS	O
+whereas	POS	O
+in	POS	O
+treated	POS	O
+PKCa	POS	O
+KO	POS	O
+mice	POS	O
+,	POS	O
+AQP2	POS	O
+was	POS	O
+only	POS	O
+reduced	POS	O
+by	POS	O
+2	POS	O
+-	POS	O
+fold	POS	O
+and	POS	O
+UT	POS	O
+-	POS	O
+A1	POS	O
+expression	POS	O
+was	POS	O
+unaffected	POS	O
+.	POS	O
+Urinary	POS	O
+sodium	POS	O
+,	POS	O
+potassium	POS	O
+and	POS	O
+calcium	POS	O
+were	POS	O
+elevated	POS	O
+in	POS	O
+lithium	POS	O
+-	POS	O
+fed	POS	O
+WT	POS	O
+but	POS	O
+not	POS	O
+in	POS	O
+lithium	POS	O
+-	POS	O
+fed	POS	O
+PKCa	POS	O
+KO	POS	O
+mice	POS	O
+.	POS	O
+Our	POS	O
+data	POS	O
+show	POS	O
+that	POS	O
+ablation	POS	O
+of	POS	O
+PKCa	POS	O
+preserves	POS	O
+AQP2	POS	O
+and	POS	O
+UT	POS	O
+-	POS	O
+A1	POS	O
+protein	POS	O
+expression	POS	O
+and	POS	O
+localization	POS	O
+in	POS	O
+lithium	POS	O
+-	POS	O
+induced	POS	O
+NDI	POS	O
+,	POS	O
+and	POS	O
+prevents	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+the	POS	O
+severe	POS	O
+polyuria	POS	B-NP
+associated	POS	O
+with	POS	O
+lithium	POS	O
+therapy	POS	O
+.	POS	O
+Is	POS	O
+Dysguesia	POS	B-NP
+Going	POS	O
+to	POS	O
+be	POS	O
+a	POS	O
+Rare	POS	O
+or	POS	O
+a	POS	O
+Common	POS	O
+Side	POS	O
+-	POS	O
+effect	POS	O
+of	POS	O
+Amlodipine	POS	O
+?	POS	O
+A	POS	O
+very	POS	O
+rare	POS	O
+side	POS	O
+-	POS	O
+effect	POS	O
+of	POS	O
+amlodipine	POS	O
+is	POS	O
+dysguesia	POS	B-NP
+.	POS	O
+A	POS	O
+review	POS	O
+of	POS	O
+the	POS	O
+literature	POS	O
+produced	POS	O
+only	POS	O
+one	POS	O
+case	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+about	POS	O
+a	POS	O
+female	POS	O
+with	POS	O
+essential	POS	O
+hypertension	POS	B-NP
+on	POS	O
+drug	POS	O
+treatment	POS	O
+with	POS	O
+amlodipine	POS	O
+developed	POS	O
+loss	POS	B-NP
+of	POS	I-NP
+taste	POS	I-NP
+sensation	POS	I-NP
+.	POS	O
+Condition	POS	O
+moderately	POS	O
+improved	POS	O
+on	POS	O
+stoppage	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+for	POS	O
+25	POS	O
+days	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+amlodipine	POS	O
+can	POS	O
+cause	POS	O
+dysguesia	POS	B-NP
+.	POS	O
+Here	POS	O
+,	POS	O
+we	POS	O
+describe	POS	O
+the	POS	O
+clinical	POS	O
+presentation	POS	O
+and	POS	O
+review	POS	O
+the	POS	O
+relevant	POS	O
+literature	POS	O
+on	POS	O
+amlodipine	POS	O
+and	POS	O
+dysguesia	POS	B-NP
+.	POS	O
+Rhabdomyolysis	POS	B-NP
+in	POS	O
+association	POS	O
+with	POS	O
+simvastatin	POS	O
+and	POS	O
+dosage	POS	O
+increment	POS	O
+in	POS	O
+clarithromycin	POS	O
+.	POS	O
+Clarithromycin	POS	O
+is	POS	O
+the	POS	O
+most	POS	O
+documented	POS	O
+cytochrome	POS	O
+P450	POS	O
+3A4	POS	O
+(	POS	O
+CYP3A4	POS	O
+)	POS	O
+inhibitor	POS	O
+to	POS	O
+cause	POS	O
+an	POS	O
+adverse	POS	O
+interaction	POS	O
+with	POS	O
+simvastatin	POS	O
+.	POS	O
+This	POS	O
+particular	POS	O
+case	POS	O
+is	POS	O
+of	POS	O
+interest	POS	O
+as	POS	O
+rhabdomyolysis	POS	B-NP
+only	POS	O
+occurred	POS	O
+after	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+dose	POS	O
+of	POS	O
+clarithromycin	POS	O
+.	POS	O
+The	POS	O
+patient	POS	O
+developed	POS	O
+raised	POS	O
+cardiac	POS	O
+biomarkers	POS	O
+without	POS	O
+any	POS	O
+obvious	POS	O
+cardiac	POS	O
+issues	POS	O
+,	POS	O
+a	POS	O
+phenomenon	POS	O
+that	POS	O
+has	POS	O
+been	POS	O
+linked	POS	O
+to	POS	O
+rhabdomyolysis	POS	B-NP
+previously	POS	O
+.	POS	O
+To	POS	O
+date	POS	O
+,	POS	O
+there	POS	O
+has	POS	O
+been	POS	O
+no	POS	O
+reported	POS	O
+effect	POS	O
+of	POS	O
+rhabdomyolysis	POS	B-NP
+on	POS	O
+the	POS	O
+structure	POS	O
+and	POS	O
+function	POS	O
+of	POS	O
+cardiac	POS	O
+muscle	POS	O
+.	POS	O
+Clinicians	POS	O
+need	POS	O
+to	POS	O
+be	POS	O
+aware	POS	O
+of	POS	O
+prescribing	POS	O
+concomitant	POS	O
+medications	POS	O
+that	POS	O
+increase	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+myopathy	POS	B-NP
+or	POS	O
+inhibit	POS	O
+the	POS	O
+CYP3A4	POS	O
+enzyme	POS	O
+.	POS	O
+Our	POS	O
+case	POS	O
+suggests	POS	O
+that	POS	O
+troponin	POS	O
+elevation	POS	O
+could	POS	O
+be	POS	O
+associated	POS	O
+with	POS	O
+statin	POS	O
+induced	POS	O
+rhabdomyolysis	POS	B-NP
+,	POS	O
+which	POS	O
+may	POS	O
+warrant	POS	O
+further	POS	O
+studies	POS	O
+.	POS	O
+Characterization	POS	O
+of	POS	O
+a	POS	O
+novel	POS	O
+BCHE	POS	O
+"	POS	O
+silent	POS	O
+"	POS	O
+allele	POS	O
+:	POS	O
+point	POS	O
+mutation	POS	O
+(	POS	O
+p	POS	O
+.	POS	O
+Val204Asp	POS	O
+)	POS	O
+causes	POS	O
+loss	POS	O
+of	POS	O
+activity	POS	O
+and	POS	O
+prolonged	POS	O
+apnea	POS	B-NP
+with	POS	O
+suxamethonium	POS	O
+.	POS	O
+Butyrylcholinesterase	POS	B-NP
+deficiency	POS	I-NP
+is	POS	O
+characterized	POS	O
+by	POS	O
+prolonged	POS	O
+apnea	POS	B-NP
+after	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+muscle	POS	O
+relaxants	POS	O
+(	POS	O
+suxamethonium	POS	O
+or	POS	O
+mivacurium	POS	O
+)	POS	O
+in	POS	O
+patients	POS	O
+who	POS	O
+have	POS	O
+mutations	POS	O
+in	POS	O
+the	POS	O
+BCHE	POS	O
+gene	POS	O
+.	POS	O
+Here	POS	O
+,	POS	O
+we	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+prolonged	POS	O
+neuromuscular	POS	B-NP
+block	POS	I-NP
+after	POS	O
+administration	POS	O
+of	POS	O
+suxamethonium	POS	O
+leading	POS	O
+to	POS	O
+the	POS	O
+discovery	POS	O
+of	POS	O
+a	POS	O
+novel	POS	O
+BCHE	POS	O
+variant	POS	O
+(	POS	O
+c	POS	O
+.	POS	O
+695T	POS	O
+>	POS	O
+A	POS	O
+,	POS	O
+p	POS	O
+.	POS	O
+Val204Asp	POS	O
+)	POS	O
+.	POS	O
+Inhibition	POS	O
+studies	POS	O
+,	POS	O
+kinetic	POS	O
+analysis	POS	O
+and	POS	O
+molecular	POS	O
+dynamics	POS	O
+were	POS	O
+undertaken	POS	O
+to	POS	O
+understand	POS	O
+how	POS	O
+this	POS	O
+mutation	POS	O
+disrupts	POS	O
+the	POS	O
+catalytic	POS	O
+triad	POS	O
+and	POS	O
+determines	POS	O
+a	POS	O
+"	POS	O
+silent	POS	O
+"	POS	O
+phenotype	POS	O
+.	POS	O
+Low	POS	O
+activity	POS	O
+of	POS	O
+patient	POS	O
+plasma	POS	O
+butyrylcholinesterase	POS	O
+with	POS	O
+butyrylthiocholine	POS	O
+(	POS	O
+BTC	POS	O
+)	POS	O
+and	POS	O
+benzoylcholine	POS	O
+,	POS	O
+and	POS	O
+values	POS	O
+of	POS	O
+dibucaine	POS	O
+and	POS	O
+fluoride	POS	O
+numbers	POS	O
+fit	POS	O
+with	POS	O
+heterozygous	POS	O
+atypical	POS	O
+silent	POS	O
+genotype	POS	O
+.	POS	O
+Electrophoretic	POS	O
+analysis	POS	O
+of	POS	O
+plasma	POS	O
+BChE	POS	O
+of	POS	O
+the	POS	O
+proband	POS	O
+and	POS	O
+his	POS	O
+mother	POS	O
+showed	POS	O
+that	POS	O
+patient	POS	O
+has	POS	O
+a	POS	O
+reduced	POS	O
+amount	POS	O
+of	POS	O
+tetrameric	POS	O
+enzyme	POS	O
+in	POS	O
+plasma	POS	O
+and	POS	O
+that	POS	O
+minor	POS	O
+fast	POS	O
+-	POS	O
+moving	POS	O
+BChE	POS	O
+components	POS	O
+:	POS	O
+monomer	POS	O
+,	POS	O
+dimer	POS	O
+,	POS	O
+and	POS	O
+monomer	POS	O
+-	POS	O
+albumin	POS	O
+conjugate	POS	O
+are	POS	O
+missing	POS	O
+.	POS	O
+Kinetic	POS	O
+analysis	POS	O
+showed	POS	O
+that	POS	O
+the	POS	O
+p	POS	O
+.	POS	O
+Val204Asp	POS	O
+/	POS	O
+p	POS	O
+.	POS	O
+Asp70Gly	POS	O
+-	POS	O
+p	POS	O
+.	POS	O
+Ala539Thr	POS	O
+BChE	POS	O
+displays	POS	O
+a	POS	O
+pure	POS	O
+Michaelian	POS	O
+behavior	POS	O
+with	POS	O
+BTC	POS	O
+as	POS	O
+the	POS	O
+substrate	POS	O
+.	POS	O
+Both	POS	O
+catalytic	POS	O
+parameters	POS	O
+Km	POS	O
+=	POS	O
+265	POS	O
+uM	POS	O
+for	POS	O
+BTC	POS	O
+,	POS	O
+two	POS	O
+times	POS	O
+higher	POS	O
+than	POS	O
+that	POS	O
+of	POS	O
+the	POS	O
+atypical	POS	O
+enzyme	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+low	POS	O
+Vmax	POS	O
+are	POS	O
+consistent	POS	O
+with	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+activity	POS	O
+against	POS	O
+suxamethonium	POS	O
+.	POS	O
+Molecular	POS	O
+dynamic	POS	O
+(	POS	O
+MD	POS	O
+)	POS	O
+simulations	POS	O
+showed	POS	O
+that	POS	O
+the	POS	O
+overall	POS	O
+effect	POS	O
+of	POS	O
+the	POS	O
+mutation	POS	O
+p	POS	O
+.	POS	O
+Val204Asp	POS	O
+is	POS	O
+disruption	POS	O
+of	POS	O
+hydrogen	POS	O
+bonding	POS	O
+between	POS	O
+Gln223	POS	O
+and	POS	O
+Glu441	POS	O
+,	POS	O
+leading	POS	O
+Ser198	POS	O
+and	POS	O
+His438	POS	O
+to	POS	O
+move	POS	O
+away	POS	O
+from	POS	O
+each	POS	O
+other	POS	O
+with	POS	O
+subsequent	POS	O
+disruption	POS	O
+of	POS	O
+the	POS	O
+catalytic	POS	O
+triad	POS	O
+functionality	POS	O
+regardless	POS	O
+of	POS	O
+the	POS	O
+type	POS	O
+of	POS	O
+substrate	POS	O
+.	POS	O
+MD	POS	O
+also	POS	O
+showed	POS	O
+that	POS	O
+the	POS	O
+enzyme	POS	O
+volume	POS	O
+is	POS	O
+increased	POS	O
+,	POS	O
+suggesting	POS	O
+a	POS	O
+pre	POS	O
+-	POS	O
+denaturation	POS	O
+state	POS	O
+.	POS	O
+This	POS	O
+fits	POS	O
+with	POS	O
+the	POS	O
+reduced	POS	O
+concentration	POS	O
+of	POS	O
+p	POS	O
+.	POS	O
+Ala204Asp	POS	O
+/	POS	O
+p	POS	O
+.	POS	O
+Asp70Gly	POS	O
+-	POS	O
+p	POS	O
+.	POS	O
+Ala539Thr	POS	O
+tetrameric	POS	O
+enzyme	POS	O
+in	POS	O
+the	POS	O
+plasma	POS	O
+and	POS	O
+non	POS	O
+-	POS	O
+detectable	POS	O
+fast	POS	O
+moving	POS	O
+-	POS	O
+bands	POS	O
+on	POS	O
+electrophoresis	POS	O
+gels	POS	O
+.	POS	O
+Delayed	POS	O
+anemia	POS	B-NP
+after	POS	O
+treatment	POS	O
+with	POS	O
+injectable	POS	O
+artesunate	POS	O
+in	POS	O
+the	POS	O
+Democratic	POS	O
+Republic	POS	O
+of	POS	O
+the	POS	O
+Congo	POS	O
+:	POS	O
+a	POS	O
+manageable	POS	O
+issue	POS	O
+.	POS	O
+Cases	POS	O
+of	POS	O
+delayed	POS	O
+hemolytic	POS	B-NP
+anemia	POS	I-NP
+have	POS	O
+been	POS	O
+described	POS	O
+after	POS	O
+treatment	POS	O
+with	POS	O
+injectable	POS	O
+artesunate	POS	O
+,	POS	O
+the	POS	O
+current	POS	O
+World	POS	O
+Health	POS	O
+Organization	POS	O
+(	POS	O
+WHO	POS	O
+)	POS	O
+-	POS	O
+recommended	POS	O
+first	POS	O
+-	POS	O
+line	POS	O
+drug	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+severe	POS	O
+malaria	POS	B-NP
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+350	POS	O
+patients	POS	O
+(	POS	O
+215	POS	O
+[	POS	O
+61	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+]	POS	O
+<	POS	O
+5	POS	O
+years	POS	O
+of	POS	O
+age	POS	O
+and	POS	O
+135	POS	O
+[	POS	O
+38	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+]	POS	O
+>	POS	O
+5	POS	O
+years	POS	O
+of	POS	O
+age	POS	O
+)	POS	O
+were	POS	O
+followed	POS	O
+-	POS	O
+up	POS	O
+after	POS	O
+treatment	POS	O
+with	POS	O
+injectable	POS	O
+artesunate	POS	O
+for	POS	O
+severe	POS	O
+malaria	POS	B-NP
+in	POS	O
+hospitals	POS	O
+and	POS	O
+health	POS	O
+centers	POS	O
+of	POS	O
+the	POS	O
+Democratic	POS	O
+Republic	POS	O
+of	POS	O
+the	POS	O
+Congo	POS	O
+.	POS	O
+Complete	POS	O
+series	POS	O
+of	POS	O
+hemoglobin	POS	O
+(	POS	O
+Hb	POS	O
+)	POS	O
+measurements	POS	O
+were	POS	O
+available	POS	O
+for	POS	O
+201	POS	O
+patients	POS	O
+.	POS	O
+A	POS	O
+decrease	POS	O
+in	POS	O
+Hb	POS	O
+levels	POS	O
+between	POS	O
+2	POS	O
+and	POS	O
+5	POS	O
+g	POS	O
+/	POS	O
+dL	POS	O
+was	POS	O
+detected	POS	O
+in	POS	O
+23	POS	O
+(	POS	O
+11	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+during	POS	O
+the	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+period	POS	O
+.	POS	O
+For	POS	O
+five	POS	O
+patients	POS	O
+,	POS	O
+Hb	POS	O
+levels	POS	O
+decreased	POS	O
+below	POS	O
+5	POS	O
+g	POS	O
+/	POS	O
+dL	POS	O
+during	POS	O
+at	POS	O
+least	POS	O
+one	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+visit	POS	O
+.	POS	O
+All	POS	O
+cases	POS	O
+of	POS	O
+delayed	POS	O
+anemia	POS	B-NP
+were	POS	O
+clinically	POS	O
+manageable	POS	O
+and	POS	O
+resolved	POS	O
+within	POS	O
+one	POS	O
+month	POS	O
+.	POS	O
+Regulation	POS	O
+of	POS	O
+signal	POS	O
+transducer	POS	O
+and	POS	O
+activator	POS	O
+of	POS	O
+transcription	POS	O
+3	POS	O
+and	POS	O
+apoptotic	POS	O
+pathways	POS	O
+by	POS	O
+betaine	POS	O
+attenuates	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+acute	POS	O
+myocardial	POS	B-NP
+injury	POS	I-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+designed	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+cardioprotective	POS	O
+effects	POS	O
+of	POS	O
+betaine	POS	O
+on	POS	O
+acute	POS	O
+myocardial	POS	B-NP
+ischemia	POS	I-NP
+induced	POS	O
+experimentally	POS	O
+in	POS	O
+rats	POS	O
+focusing	POS	O
+on	POS	O
+regulation	POS	O
+of	POS	O
+signal	POS	O
+transducer	POS	O
+and	POS	O
+activator	POS	O
+of	POS	O
+transcription	POS	O
+3	POS	O
+(	POS	O
+STAT3	POS	O
+)	POS	O
+and	POS	O
+apoptotic	POS	O
+pathways	POS	O
+as	POS	O
+the	POS	O
+potential	POS	O
+mechanism	POS	O
+underlying	POS	O
+the	POS	O
+drug	POS	O
+effect	POS	O
+.	POS	O
+Male	POS	O
+Sprague	POS	O
+Dawley	POS	O
+rats	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+betaine	POS	O
+(	POS	O
+100	POS	O
+,	POS	O
+200	POS	O
+,	POS	O
+and	POS	O
+400	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+orally	POS	O
+for	POS	O
+40	POS	O
+days	POS	O
+.	POS	O
+Acute	POS	O
+myocardial	POS	B-NP
+ischemic	POS	I-NP
+injury	POS	I-NP
+was	POS	O
+induced	POS	O
+in	POS	O
+rats	POS	O
+by	POS	O
+subcutaneous	POS	O
+injection	POS	O
+of	POS	O
+isoproterenol	POS	O
+(	POS	O
+85	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+,	POS	O
+for	POS	O
+two	POS	O
+consecutive	POS	O
+days	POS	O
+.	POS	O
+Serum	POS	O
+cardiac	POS	O
+marker	POS	O
+enzyme	POS	O
+,	POS	O
+histopathological	POS	O
+variables	POS	O
+and	POS	O
+expression	POS	O
+of	POS	O
+protein	POS	O
+levels	POS	O
+were	POS	O
+analyzed	POS	O
+.	POS	O
+Oral	POS	O
+administration	POS	O
+of	POS	O
+betaine	POS	O
+(	POS	O
+200	POS	O
+and	POS	O
+400	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+significantly	POS	O
+reduced	POS	O
+the	POS	O
+level	POS	O
+of	POS	O
+cardiac	POS	O
+marker	POS	O
+enzyme	POS	O
+in	POS	O
+the	POS	O
+serum	POS	O
+and	POS	O
+prevented	POS	O
+left	POS	O
+ventricular	POS	O
+remodeling	POS	O
+.	POS	O
+Western	POS	O
+blot	POS	O
+analysis	POS	O
+showed	POS	O
+that	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+phosphorylation	POS	O
+of	POS	O
+STAT3	POS	O
+was	POS	O
+maintained	POS	O
+or	POS	O
+further	POS	O
+enhanced	POS	O
+by	POS	O
+betaine	POS	O
+treatment	POS	O
+in	POS	O
+myocardium	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+betaine	POS	O
+(	POS	O
+200	POS	O
+and	POS	O
+400	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+treatment	POS	O
+increased	POS	O
+the	POS	O
+ventricular	POS	O
+expression	POS	O
+of	POS	O
+Bcl	POS	O
+-	POS	O
+2	POS	O
+and	POS	O
+reduced	POS	O
+the	POS	O
+level	POS	O
+of	POS	O
+Bax	POS	O
+,	POS	O
+therefore	POS	O
+causing	POS	O
+a	POS	O
+significant	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+ratio	POS	O
+of	POS	O
+Bcl	POS	O
+-	POS	O
+2	POS	O
+/	POS	O
+Bax	POS	O
+.	POS	O
+The	POS	O
+protective	POS	O
+role	POS	O
+of	POS	O
+betaine	POS	O
+on	POS	O
+myocardial	POS	B-NP
+damage	POS	I-NP
+was	POS	O
+further	POS	O
+confirmed	POS	O
+by	POS	O
+histopathological	POS	O
+examination	POS	O
+.	POS	O
+In	POS	O
+summary	POS	O
+,	POS	O
+our	POS	O
+results	POS	O
+showed	POS	O
+that	POS	O
+betaine	POS	O
+pretreatment	POS	O
+attenuated	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+acute	POS	O
+myocardial	POS	B-NP
+ischemia	POS	I-NP
+via	POS	O
+the	POS	O
+regulation	POS	O
+of	POS	O
+STAT3	POS	O
+and	POS	O
+apoptotic	POS	O
+pathways	POS	O
+.	POS	O
+Quetiapine	POS	O
+-	POS	O
+induced	POS	O
+neutropenia	POS	B-NP
+in	POS	O
+a	POS	O
+bipolar	POS	O
+patient	POS	O
+with	POS	O
+hepatocellular	POS	B-NP
+carcinoma	POS	I-NP
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+Quetiapine	POS	O
+is	POS	O
+a	POS	O
+dibenzothiazepine	POS	O
+derivative	POS	O
+,	POS	O
+similar	POS	O
+to	POS	O
+clozapine	POS	O
+,	POS	O
+which	POS	O
+has	POS	O
+the	POS	O
+highest	POS	O
+risk	POS	O
+of	POS	O
+causing	POS	O
+blood	POS	B-NP
+dyscrasias	POS	I-NP
+,	POS	O
+especially	POS	O
+neutropenia	POS	B-NP
+.	POS	O
+There	POS	O
+are	POS	O
+some	POS	O
+case	POS	O
+reports	POS	O
+about	POS	O
+this	POS	O
+side	POS	O
+effect	POS	O
+of	POS	O
+quetiapine	POS	O
+,	POS	O
+but	POS	O
+possible	POS	O
+risk	POS	O
+factors	POS	O
+are	POS	O
+seldom	POS	O
+discussed	POS	O
+and	POS	O
+identified	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+hepatocellular	POS	B-NP
+carcinoma	POS	I-NP
+that	POS	O
+developed	POS	O
+neutropenia	POS	B-NP
+after	POS	O
+treatment	POS	O
+with	POS	O
+quetiapine	POS	O
+is	POS	O
+described	POS	O
+here	POS	O
+.	POS	O
+CASE	POS	O
+REPORT	POS	O
+:	POS	O
+A	POS	O
+62	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+Taiwanese	POS	O
+widow	POS	O
+with	POS	O
+bipolar	POS	B-NP
+disorder	POS	I-NP
+was	POS	O
+diagnosed	POS	O
+with	POS	O
+hepatocellular	POS	B-NP
+carcinoma	POS	I-NP
+at	POS	O
+age	POS	O
+60	POS	O
+.	POS	O
+She	POS	O
+developed	POS	O
+leucopenia	POS	B-NP
+after	POS	O
+being	POS	O
+treated	POS	O
+with	POS	O
+quetiapine	POS	O
+.	POS	O
+After	POS	O
+quetiapine	POS	O
+was	POS	O
+discontinued	POS	O
+,	POS	O
+her	POS	O
+white	POS	O
+blood	POS	O
+cell	POS	O
+count	POS	O
+returned	POS	O
+to	POS	O
+normal	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Although	POS	O
+neutropenia	POS	B-NP
+is	POS	O
+not	POS	O
+a	POS	O
+common	POS	O
+side	POS	O
+effect	POS	O
+of	POS	O
+quetiapine	POS	O
+,	POS	O
+physicians	POS	O
+should	POS	O
+be	POS	O
+cautious	POS	O
+about	POS	O
+its	POS	O
+presentation	POS	O
+and	POS	O
+associated	POS	O
+risk	POS	O
+factors	POS	O
+.	POS	O
+Hepatic	POS	B-NP
+dysfunction	POS	I-NP
+may	POS	O
+be	POS	O
+one	POS	O
+of	POS	O
+the	POS	O
+possible	POS	O
+risk	POS	O
+factors	POS	O
+,	POS	O
+and	POS	O
+concomitant	POS	O
+fever	POS	B-NP
+may	POS	O
+be	POS	O
+a	POS	O
+diagnostic	POS	O
+marker	POS	O
+for	POS	O
+adverse	POS	O
+reaction	POS	O
+to	POS	O
+quetiapine	POS	O
+.	POS	O
+Lateral	POS	B-NP
+antebrachial	POS	I-NP
+cutaneous	POS	I-NP
+neuropathy	POS	I-NP
+after	POS	O
+steroid	POS	O
+injection	POS	O
+at	POS	O
+lateral	POS	O
+epicondyle	POS	O
+.	POS	O
+BACKGROUND	POS	O
+AND	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+This	POS	O
+report	POS	O
+aimed	POS	O
+to	POS	O
+present	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+lateral	POS	B-NP
+antebrachial	POS	I-NP
+cutaneous	POS	I-NP
+neuropathy	POS	I-NP
+(	POS	O
+LACNP	POS	B-NP
+)	POS	O
+that	POS	O
+occurred	POS	O
+after	POS	O
+a	POS	O
+steroid	POS	O
+injection	POS	O
+in	POS	O
+the	POS	O
+lateral	POS	O
+epicondyle	POS	O
+to	POS	O
+treat	POS	O
+lateral	POS	B-NP
+epicondylitis	POS	I-NP
+in	POS	O
+a	POS	O
+40	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+.	POS	O
+MATERIAL	POS	O
+AND	POS	O
+METHOD	POS	O
+:	POS	O
+A	POS	O
+40	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+presented	POS	O
+with	POS	O
+decreased	POS	B-NP
+sensation	POS	I-NP
+and	POS	O
+paresthesia	POS	B-NP
+over	POS	O
+her	POS	O
+right	POS	O
+lateral	POS	O
+forearm	POS	O
+;	POS	O
+the	POS	O
+paresthesia	POS	B-NP
+had	POS	O
+occurred	POS	O
+after	POS	O
+a	POS	O
+steroid	POS	O
+injection	POS	O
+in	POS	O
+the	POS	O
+right	POS	O
+lateral	POS	O
+epicondyle	POS	O
+3	POS	O
+months	POS	O
+before	POS	O
+.	POS	O
+Her	POS	O
+sensation	POS	O
+of	POS	O
+light	POS	O
+touch	POS	O
+and	POS	O
+pain	POS	B-NP
+was	POS	O
+diminished	POS	O
+over	POS	O
+the	POS	O
+lateral	POS	O
+side	POS	O
+of	POS	O
+the	POS	O
+right	POS	O
+forearm	POS	O
+and	POS	O
+wrist	POS	O
+area	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+The	POS	O
+sensory	POS	O
+action	POS	O
+potential	POS	O
+amplitude	POS	O
+of	POS	O
+the	POS	O
+right	POS	O
+lateral	POS	O
+antebrachial	POS	O
+cutaneous	POS	O
+nerve	POS	O
+(	POS	O
+LACN	POS	O
+)	POS	O
+(	POS	O
+6	POS	O
+.	POS	O
+2	POS	O
+uV	POS	O
+)	POS	O
+was	POS	O
+lower	POS	O
+than	POS	O
+that	POS	O
+of	POS	O
+the	POS	O
+left	POS	O
+(	POS	O
+13	POS	O
+.	POS	O
+1	POS	O
+uV	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+difference	POS	O
+of	POS	O
+amplitude	POS	O
+between	POS	O
+both	POS	O
+sides	POS	O
+was	POS	O
+significant	POS	O
+because	POS	O
+there	POS	O
+was	POS	O
+more	POS	O
+than	POS	O
+a	POS	O
+50	POS	O
+%	POS	O
+reduction	POS	O
+.	POS	O
+She	POS	O
+was	POS	O
+diagnosed	POS	O
+with	POS	O
+right	POS	O
+LACNP	POS	O
+(	POS	O
+mainly	POS	O
+axonal	POS	O
+involvement	POS	O
+)	POS	O
+on	POS	O
+the	POS	O
+basis	POS	O
+of	POS	O
+the	POS	O
+clinical	POS	O
+manifestation	POS	O
+and	POS	O
+the	POS	O
+electrodiagnostic	POS	O
+findings	POS	O
+.	POS	O
+Her	POS	O
+symptoms	POS	O
+improved	POS	O
+through	POS	O
+physical	POS	O
+therapy	POS	O
+but	POS	O
+persisted	POS	O
+to	POS	O
+some	POS	O
+degree	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+This	POS	O
+report	POS	O
+describes	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+a	POS	O
+woman	POS	O
+with	POS	O
+LACNP	POS	B-NP
+that	POS	O
+developed	POS	O
+after	POS	O
+a	POS	O
+steroid	POS	O
+injection	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+lateral	POS	B-NP
+epicondylitis	POS	I-NP
+.	POS	O
+An	POS	O
+electrodiagnostic	POS	O
+study	POS	O
+,	POS	O
+including	POS	O
+a	POS	O
+nerve	POS	O
+conduction	POS	O
+study	POS	O
+of	POS	O
+the	POS	O
+LACN	POS	O
+,	POS	O
+was	POS	O
+helpful	POS	O
+to	POS	O
+diagnose	POS	O
+right	POS	O
+LACNP	POS	O
+and	POS	O
+to	POS	O
+find	POS	O
+the	POS	O
+passage	POS	O
+of	POS	O
+the	POS	O
+LACN	POS	O
+on	POS	O
+the	POS	O
+lateral	POS	O
+epicondyle	POS	O
+.	POS	O
+Curcumin	POS	O
+prevents	POS	O
+maleate	POS	O
+-	POS	O
+induced	POS	O
+nephrotoxicity	POS	B-NP
+:	POS	O
+relation	POS	O
+to	POS	O
+hemodynamic	POS	O
+alterations	POS	O
+,	POS	O
+oxidative	POS	O
+stress	POS	O
+,	POS	O
+mitochondrial	POS	O
+oxygen	POS	O
+consumption	POS	O
+and	POS	O
+activity	POS	O
+of	POS	O
+respiratory	POS	O
+complex	POS	O
+I	POS	O
+.	POS	O
+The	POS	O
+potential	POS	O
+protective	POS	O
+effect	POS	O
+of	POS	O
+the	POS	O
+dietary	POS	O
+antioxidant	POS	O
+curcumin	POS	O
+(	POS	O
+120	POS	O
+mg	POS	O
+/	POS	O
+Kg	POS	O
+/	POS	O
+day	POS	O
+for	POS	O
+6	POS	O
+days	POS	O
+)	POS	O
+against	POS	O
+the	POS	O
+renal	POS	B-NP
+injury	POS	I-NP
+induced	POS	O
+by	POS	O
+maleate	POS	O
+was	POS	O
+evaluated	POS	O
+.	POS	O
+Tubular	POS	O
+proteinuria	POS	B-NP
+and	POS	O
+oxidative	POS	O
+stress	POS	O
+were	POS	O
+induced	POS	O
+by	POS	O
+a	POS	O
+single	POS	O
+injection	POS	O
+of	POS	O
+maleate	POS	O
+(	POS	O
+400	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+Maleate	POS	O
+-	POS	O
+induced	POS	O
+renal	POS	B-NP
+injury	POS	I-NP
+included	POS	O
+increase	POS	B-NP
+in	POS	I-NP
+renal	POS	I-NP
+vascular	POS	I-NP
+resistance	POS	I-NP
+and	POS	O
+in	POS	O
+the	POS	O
+urinary	POS	O
+excretion	POS	O
+of	POS	O
+total	POS	O
+protein	POS	O
+,	POS	O
+glucose	POS	O
+,	POS	O
+sodium	POS	O
+,	POS	O
+neutrophil	POS	O
+gelatinase	POS	O
+-	POS	O
+associated	POS	O
+lipocalin	POS	O
+(	POS	O
+NGAL	POS	O
+)	POS	O
+and	POS	O
+N	POS	O
+-	POS	O
+acetyl	POS	O
+b	POS	O
+-	POS	O
+D	POS	O
+-	POS	O
+glucosaminidase	POS	O
+(	POS	O
+NAG	POS	O
+)	POS	O
+,	POS	O
+upregulation	POS	O
+of	POS	O
+kidney	POS	O
+injury	POS	O
+molecule	POS	O
+(	POS	O
+KIM	POS	O
+)	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+decrease	POS	O
+in	POS	O
+renal	POS	O
+blood	POS	O
+flow	POS	O
+and	POS	O
+claudin	POS	O
+-	POS	O
+2	POS	O
+expression	POS	O
+besides	POS	O
+of	POS	O
+necrosis	POS	B-NP
+and	POS	O
+apoptosis	POS	O
+of	POS	O
+tubular	POS	O
+cells	POS	O
+on	POS	O
+24	POS	O
+h	POS	O
+.	POS	O
+Oxidative	POS	O
+stress	POS	O
+was	POS	O
+determined	POS	O
+by	POS	O
+measuring	POS	O
+the	POS	O
+oxidation	POS	O
+of	POS	O
+lipids	POS	O
+and	POS	O
+proteins	POS	O
+and	POS	O
+diminution	POS	O
+in	POS	O
+renal	POS	O
+Nrf2	POS	O
+levels	POS	O
+.	POS	O
+Studies	POS	O
+were	POS	O
+also	POS	O
+conducted	POS	O
+in	POS	O
+renal	POS	O
+epithelial	POS	O
+LLC	POS	O
+-	POS	O
+PK1	POS	O
+cells	POS	O
+and	POS	O
+in	POS	O
+mitochondria	POS	O
+isolated	POS	O
+from	POS	O
+kidneys	POS	O
+of	POS	O
+all	POS	O
+the	POS	O
+experimental	POS	O
+groups	POS	O
+.	POS	O
+Maleate	POS	O
+induced	POS	O
+cell	POS	O
+damage	POS	O
+and	POS	O
+reactive	POS	O
+oxygen	POS	O
+species	POS	O
+(	POS	O
+ROS	POS	O
+)	POS	O
+production	POS	O
+in	POS	O
+LLC	POS	O
+-	POS	O
+PK1	POS	O
+cells	POS	O
+in	POS	O
+culture	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+maleate	POS	O
+treatment	POS	O
+reduced	POS	O
+oxygen	POS	O
+consumption	POS	O
+in	POS	O
+ADP	POS	O
+-	POS	O
+stimulated	POS	O
+mitochondria	POS	O
+and	POS	O
+diminished	POS	O
+respiratory	POS	O
+control	POS	O
+index	POS	O
+when	POS	O
+using	POS	O
+malate	POS	O
+/	POS	O
+glutamate	POS	O
+as	POS	O
+substrate	POS	O
+.	POS	O
+The	POS	O
+activities	POS	O
+of	POS	O
+both	POS	O
+complex	POS	O
+I	POS	O
+and	POS	O
+aconitase	POS	O
+were	POS	O
+also	POS	O
+diminished	POS	O
+.	POS	O
+All	POS	O
+the	POS	O
+above	POS	O
+-	POS	O
+described	POS	O
+alterations	POS	O
+were	POS	O
+prevented	POS	O
+by	POS	O
+curcumin	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+concluded	POS	O
+that	POS	O
+curcumin	POS	O
+is	POS	O
+able	POS	O
+to	POS	O
+attenuate	POS	O
+in	POS	O
+vivo	POS	O
+maleate	POS	O
+-	POS	O
+induced	POS	O
+nephropathy	POS	B-NP
+and	POS	O
+in	POS	O
+vitro	POS	O
+cell	POS	O
+damage	POS	O
+.	POS	O
+The	POS	O
+in	POS	O
+vivo	POS	O
+protection	POS	O
+was	POS	O
+associated	POS	O
+to	POS	O
+the	POS	O
+prevention	POS	O
+of	POS	O
+oxidative	POS	O
+stress	POS	O
+and	POS	O
+preservation	POS	O
+of	POS	O
+mitochondrial	POS	O
+oxygen	POS	O
+consumption	POS	O
+and	POS	O
+activity	POS	O
+of	POS	O
+respiratory	POS	O
+complex	POS	O
+I	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+in	POS	O
+vitro	POS	O
+protection	POS	O
+was	POS	O
+associated	POS	O
+to	POS	O
+the	POS	O
+prevention	POS	O
+of	POS	O
+ROS	POS	O
+production	POS	O
+.	POS	O
+Anticonvulsant	POS	O
+actions	POS	O
+of	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+on	POS	O
+the	POS	O
+lithium	POS	O
+-	POS	O
+pilocarpine	POS	O
+model	POS	O
+of	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+,	POS	O
+a	POS	O
+noncompetitive	POS	O
+N	POS	O
+-	POS	O
+methyl	POS	O
+-	POS	O
+D	POS	O
+-	POS	O
+aspartate	POS	O
+(	POS	O
+NMDA	POS	O
+)	POS	O
+receptor	POS	O
+antagonist	POS	O
+,	POS	O
+was	POS	O
+tested	POS	O
+for	POS	O
+anticonvulsant	POS	O
+effects	POS	O
+in	POS	O
+rats	POS	O
+using	POS	O
+two	POS	O
+seizure	POS	B-NP
+models	POS	O
+,	POS	O
+coadministration	POS	O
+of	POS	O
+lithium	POS	O
+and	POS	O
+pilocarpine	POS	O
+and	POS	O
+administration	POS	O
+of	POS	O
+a	POS	O
+high	POS	O
+dose	POS	O
+of	POS	O
+pilocarpine	POS	O
+alone	POS	O
+.	POS	O
+Three	POS	O
+major	POS	O
+results	POS	O
+are	POS	O
+reported	POS	O
+.	POS	O
+First	POS	O
+,	POS	O
+pretreatment	POS	O
+with	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+produced	POS	O
+an	POS	O
+effective	POS	O
+and	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+anticonvulsant	POS	O
+action	POS	O
+with	POS	O
+the	POS	O
+lithium	POS	O
+-	POS	O
+pilocarpine	POS	O
+model	POS	O
+but	POS	O
+not	POS	O
+with	POS	O
+rats	POS	O
+treated	POS	O
+with	POS	O
+pilocarpine	POS	O
+alone	POS	O
+,	POS	O
+suggesting	POS	O
+that	POS	O
+different	POS	O
+biochemical	POS	O
+mechanisms	POS	O
+control	POS	O
+seizures	POS	B-NP
+in	POS	O
+these	POS	O
+two	POS	O
+models	POS	O
+.	POS	O
+Second	POS	O
+,	POS	O
+the	POS	O
+anticonvulsant	POS	O
+effect	POS	O
+of	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+in	POS	O
+the	POS	O
+lithium	POS	O
+-	POS	O
+pilocarpine	POS	O
+model	POS	O
+only	POS	O
+occurred	POS	O
+after	POS	O
+initial	POS	O
+periods	POS	O
+of	POS	O
+seizure	POS	B-NP
+activity	POS	O
+.	POS	O
+This	POS	O
+observation	POS	O
+is	POS	O
+suggested	POS	O
+to	POS	O
+be	POS	O
+an	POS	O
+in	POS	O
+vivo	POS	O
+demonstration	POS	O
+of	POS	O
+the	POS	O
+conclusion	POS	O
+derived	POS	O
+from	POS	O
+in	POS	O
+vitro	POS	O
+experiments	POS	O
+that	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+binding	POS	O
+requires	POS	O
+agonist	POS	O
+-	POS	O
+induced	POS	O
+opening	POS	O
+of	POS	O
+the	POS	O
+channel	POS	O
+sites	POS	O
+of	POS	O
+the	POS	O
+NMDA	POS	O
+receptor	POS	O
+.	POS	O
+Third	POS	O
+,	POS	O
+although	POS	O
+it	POS	O
+is	POS	O
+relatively	POS	O
+easy	POS	O
+to	POS	O
+block	POS	O
+seizures	POS	B-NP
+induced	POS	O
+by	POS	O
+lithium	POS	O
+and	POS	O
+pilocarpine	POS	O
+by	POS	O
+administration	POS	O
+of	POS	O
+anticonvulsants	POS	O
+prior	POS	O
+to	POS	O
+pilocarpine	POS	O
+,	POS	O
+it	POS	O
+is	POS	O
+more	POS	O
+difficult	POS	O
+to	POS	O
+terminate	POS	O
+ongoing	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+and	POS	O
+block	POS	O
+the	POS	O
+lethality	POS	O
+of	POS	O
+the	POS	O
+seizures	POS	B-NP
+.	POS	O
+Administration	POS	O
+of	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+30	POS	O
+or	POS	O
+60	POS	O
+min	POS	O
+after	POS	O
+pilocarpine	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+e	POS	O
+.	POS	O
+,	POS	O
+during	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+,	POS	O
+gradually	POS	O
+reduced	POS	O
+electrical	POS	O
+and	POS	O
+behavioral	POS	O
+seizure	POS	B-NP
+activity	POS	O
+and	POS	O
+greatly	POS	O
+enhanced	POS	O
+the	POS	O
+survival	POS	O
+rate	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+activation	POS	O
+of	POS	O
+NMDA	POS	O
+receptors	POS	O
+plays	POS	O
+an	POS	O
+important	POS	O
+role	POS	O
+in	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+and	POS	O
+brain	POS	B-NP
+damage	POS	I-NP
+in	POS	O
+the	POS	O
+lithium	POS	O
+-	POS	O
+pilocarpine	POS	O
+model	POS	O
+.	POS	O
+This	POS	O
+was	POS	O
+further	POS	O
+supported	POS	O
+by	POS	O
+results	POS	O
+showing	POS	O
+that	POS	O
+nonconvulsive	POS	B-NP
+doses	POS	O
+of	POS	O
+NMDA	POS	O
+and	POS	O
+pilocarpine	POS	O
+were	POS	O
+synergistic	POS	O
+,	POS	O
+resulting	POS	O
+in	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+and	POS	O
+subsequent	POS	O
+mortality	POS	O
+.	POS	O
+Continuous	POS	O
+infusion	POS	O
+tobramycin	POS	O
+combined	POS	O
+with	POS	O
+carbenicillin	POS	O
+for	POS	O
+infections	POS	O
+in	POS	O
+cancer	POS	B-NP
+patients	POS	O
+.	POS	O
+The	POS	O
+cure	POS	O
+rate	POS	O
+of	POS	O
+infections	POS	B-NP
+in	POS	O
+cancer	POS	B-NP
+patients	POS	O
+is	POS	O
+adversely	POS	O
+affected	POS	O
+by	POS	O
+neutropenia	POS	B-NP
+(	POS	O
+less	POS	O
+than	POS	O
+1	POS	O
+,	POS	O
+000	POS	O
+/	POS	O
+mm3	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+particular	POS	O
+,	POS	O
+patients	POS	O
+with	POS	O
+severe	POS	O
+neutropenia	POS	B-NP
+(	POS	O
+less	POS	O
+than	POS	O
+100	POS	O
+/	POS	O
+mm3	POS	O
+)	POS	O
+have	POS	O
+shown	POS	O
+a	POS	O
+poor	POS	O
+response	POS	O
+to	POS	O
+antibiotics	POS	O
+.	POS	O
+To	POS	O
+overcome	POS	O
+the	POS	O
+adverse	POS	O
+effects	POS	O
+of	POS	O
+neutropenia	POS	B-NP
+,	POS	O
+tobramycin	POS	O
+was	POS	O
+given	POS	O
+by	POS	O
+continuous	POS	O
+infusion	POS	O
+and	POS	O
+combined	POS	O
+with	POS	O
+intermittent	POS	O
+carbenicillin	POS	O
+.	POS	O
+Tobramycin	POS	O
+was	POS	O
+given	POS	O
+to	POS	O
+a	POS	O
+total	POS	O
+daily	POS	O
+dose	POS	O
+of	POS	O
+300	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+and	POS	O
+carbenicillin	POS	O
+was	POS	O
+given	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+5	POS	O
+gm	POS	O
+every	POS	O
+four	POS	O
+hours	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+125	POS	O
+infectious	POS	O
+episodes	POS	O
+in	POS	O
+116	POS	O
+cancer	POS	B-NP
+patients	POS	O
+receiving	POS	O
+myelosuppressive	POS	O
+chemotherapy	POS	O
+.	POS	O
+The	POS	O
+overall	POS	O
+cure	POS	O
+rate	POS	O
+was	POS	O
+70	POS	O
+%	POS	O
+.	POS	O
+Pneumonia	POS	B-NP
+was	POS	O
+the	POS	O
+most	POS	O
+common	POS	O
+infection	POS	O
+and	POS	O
+61	POS	O
+%	POS	O
+of	POS	O
+59	POS	O
+episodes	POS	O
+were	POS	O
+cured	POS	O
+.	POS	O
+Gram	POS	O
+-	POS	O
+negative	POS	O
+bacilli	POS	O
+were	POS	O
+the	POS	O
+most	POS	O
+common	POS	O
+causative	POS	O
+organisms	POS	O
+and	POS	O
+69	POS	O
+%	POS	O
+of	POS	O
+these	POS	O
+infections	POS	B-NP
+were	POS	O
+cured	POS	O
+.	POS	O
+The	POS	O
+most	POS	O
+common	POS	O
+pathogen	POS	O
+was	POS	O
+Klebsiella	POS	O
+pneumoniae	POS	O
+and	POS	O
+this	POS	O
+,	POS	O
+together	POS	O
+with	POS	O
+Escherichia	POS	O
+coli	POS	O
+and	POS	O
+Pseudomonas	POS	O
+aeruginosa	POS	O
+,	POS	O
+accounted	POS	O
+for	POS	O
+74	POS	O
+%	POS	O
+of	POS	O
+all	POS	O
+gram	POS	O
+-	POS	O
+negative	POS	O
+bacillary	POS	B-NP
+infections	POS	I-NP
+.	POS	O
+Response	POS	O
+was	POS	O
+not	POS	O
+influenced	POS	O
+by	POS	O
+the	POS	O
+initial	POS	O
+neutrophil	POS	O
+count	POS	O
+,	POS	O
+with	POS	O
+a	POS	O
+62	POS	O
+%	POS	O
+cure	POS	O
+rate	POS	O
+for	POS	O
+39	POS	O
+episodes	POS	O
+associated	POS	O
+with	POS	O
+severe	POS	O
+neutropenia	POS	B-NP
+.	POS	O
+However	POS	O
+,	POS	O
+failure	POS	O
+of	POS	O
+the	POS	O
+neutrophil	POS	O
+count	POS	O
+to	POS	O
+increase	POS	O
+during	POS	O
+therapy	POS	O
+adversely	POS	O
+affected	POS	O
+response	POS	O
+.	POS	O
+Azotemia	POS	B-NP
+was	POS	O
+the	POS	O
+major	POS	O
+side	POS	O
+effect	POS	O
+recognized	POS	O
+,	POS	O
+and	POS	O
+it	POS	O
+occurred	POS	O
+in	POS	O
+11	POS	O
+%	POS	O
+of	POS	O
+episodes	POS	O
+.	POS	O
+Major	POS	O
+azotemia	POS	B-NP
+(	POS	O
+serum	POS	O
+creatinine	POS	O
+greater	POS	O
+than	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+or	POS	O
+BUN	POS	O
+greater	POS	O
+than	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+dl	POS	O
+)	POS	O
+occurred	POS	O
+in	POS	O
+only	POS	O
+2	POS	O
+%	POS	O
+.	POS	O
+Azotemia	POS	B-NP
+was	POS	O
+not	POS	O
+related	POS	O
+to	POS	O
+duration	POS	O
+of	POS	O
+therapy	POS	O
+or	POS	O
+serum	POS	O
+tobramycin	POS	O
+concentration	POS	O
+.	POS	O
+This	POS	O
+antibiotic	POS	O
+regimen	POS	O
+showed	POS	O
+both	POS	O
+therapeutic	POS	O
+efficacy	POS	O
+and	POS	O
+acceptable	POS	O
+renal	POS	B-NP
+toxicity	POS	I-NP
+for	POS	O
+these	POS	O
+patients	POS	O
+.	POS	O
+Incidence	POS	O
+of	POS	O
+solid	POS	O
+tumours	POS	B-NP
+among	POS	O
+pesticide	POS	O
+applicators	POS	O
+exposed	POS	O
+to	POS	O
+the	POS	O
+organophosphate	POS	O
+insecticide	POS	O
+diazinon	POS	O
+in	POS	O
+the	POS	O
+Agricultural	POS	O
+Health	POS	O
+Study	POS	O
+:	POS	O
+an	POS	O
+updated	POS	O
+analysis	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+Diazinon	POS	O
+,	POS	O
+a	POS	O
+common	POS	O
+organophosphate	POS	O
+insecticide	POS	O
+with	POS	O
+genotoxic	POS	O
+properties	POS	O
+,	POS	O
+was	POS	O
+previously	POS	O
+associated	POS	O
+with	POS	O
+lung	POS	B-NP
+cancer	POS	I-NP
+in	POS	O
+the	POS	O
+Agricultural	POS	O
+Health	POS	O
+Study	POS	O
+(	POS	O
+AHS	POS	O
+)	POS	O
+cohort	POS	O
+,	POS	O
+but	POS	O
+few	POS	O
+other	POS	O
+epidemiological	POS	O
+studies	POS	O
+have	POS	O
+examined	POS	O
+diazinon	POS	O
+-	POS	O
+associated	POS	O
+cancer	POS	B-NP
+risk	POS	O
+.	POS	O
+We	POS	O
+used	POS	O
+updated	POS	O
+diazinon	POS	O
+exposure	POS	O
+and	POS	O
+cancer	POS	B-NP
+incidence	POS	O
+information	POS	O
+to	POS	O
+evaluate	POS	O
+solid	POS	O
+tumour	POS	B-NP
+risk	POS	O
+in	POS	O
+the	POS	O
+AHS	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+Male	POS	O
+pesticide	POS	O
+applicators	POS	O
+in	POS	O
+Iowa	POS	O
+and	POS	O
+North	POS	O
+Carolina	POS	O
+reported	POS	O
+lifetime	POS	O
+diazinon	POS	O
+use	POS	O
+at	POS	O
+enrolment	POS	O
+(	POS	O
+1993	POS	O
+-	POS	O
+1997	POS	O
+)	POS	O
+and	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+(	POS	O
+1998	POS	O
+-	POS	O
+2005	POS	O
+)	POS	O
+;	POS	O
+cancer	POS	B-NP
+incidence	POS	O
+was	POS	O
+assessed	POS	O
+through	POS	O
+2010	POS	O
+(	POS	O
+North	POS	O
+Carolina	POS	O
+)	POS	O
+/	POS	O
+2011	POS	O
+(	POS	O
+Iowa	POS	O
+)	POS	O
+.	POS	O
+Among	POS	O
+applicators	POS	O
+with	POS	O
+usage	POS	O
+information	POS	O
+sufficient	POS	O
+to	POS	O
+evaluate	POS	O
+exposure	POS	O
+-	POS	O
+response	POS	O
+patterns	POS	O
+,	POS	O
+we	POS	O
+used	POS	O
+Poisson	POS	O
+regression	POS	O
+to	POS	O
+estimate	POS	O
+adjusted	POS	O
+rate	POS	O
+ratios	POS	O
+(	POS	O
+RRs	POS	O
+)	POS	O
+and	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+for	POS	O
+cancer	POS	B-NP
+sites	POS	O
+with	POS	O
+>	POS	O
+10	POS	O
+exposed	POS	O
+cases	POS	O
+for	POS	O
+both	POS	O
+lifetime	POS	O
+(	POS	O
+LT	POS	O
+)	POS	O
+exposure	POS	O
+days	POS	O
+and	POS	O
+intensity	POS	O
+-	POS	O
+weighted	POS	O
+(	POS	O
+IW	POS	O
+)	POS	O
+lifetime	POS	O
+exposure	POS	O
+days	POS	O
+(	POS	O
+accounting	POS	O
+for	POS	O
+factors	POS	O
+impacting	POS	O
+exposure	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+We	POS	O
+observed	POS	O
+elevated	POS	O
+lung	POS	B-NP
+cancer	POS	I-NP
+risks	POS	O
+(	POS	O
+N	POS	O
+=	POS	O
+283	POS	O
+)	POS	O
+among	POS	O
+applicators	POS	O
+with	POS	O
+the	POS	O
+greatest	POS	O
+number	POS	O
+of	POS	O
+LT	POS	O
+(	POS	O
+RR	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+60	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+1	POS	O
+.	POS	O
+11	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+31	POS	O
+;	POS	O
+Ptrend	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+and	POS	O
+IW	POS	O
+days	POS	O
+of	POS	O
+diazinon	POS	O
+use	POS	O
+(	POS	O
+RR	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+41	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+0	POS	O
+.	POS	O
+98	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+04	POS	O
+;	POS	O
+Ptrend	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+08	POS	O
+)	POS	O
+.	POS	O
+Kidney	POS	B-NP
+cancer	POS	I-NP
+(	POS	O
+N	POS	O
+=	POS	O
+94	POS	O
+)	POS	O
+risks	POS	O
+were	POS	O
+non	POS	O
+-	POS	O
+significantly	POS	O
+elevated	POS	O
+(	POS	O
+RRLT	POS	O
+days	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+77	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+0	POS	O
+.	POS	O
+90	POS	O
+to	POS	O
+3	POS	O
+.	POS	O
+51	POS	O
+;	POS	O
+Ptrend	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+09	POS	O
+;	POS	O
+RRIW	POS	O
+days	POS	O
+1	POS	O
+.	POS	O
+37	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+0	POS	O
+.	POS	O
+64	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+92	POS	O
+;	POS	O
+Ptrend	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+50	POS	O
+)	POS	O
+,	POS	O
+as	POS	O
+were	POS	O
+risks	POS	O
+for	POS	O
+aggressive	POS	O
+prostate	POS	B-NP
+cancer	POS	I-NP
+(	POS	O
+N	POS	O
+=	POS	O
+656	POS	O
+)	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Our	POS	O
+updated	POS	O
+evaluation	POS	O
+of	POS	O
+diazinon	POS	O
+provides	POS	O
+additional	POS	O
+evidence	POS	O
+of	POS	O
+an	POS	O
+association	POS	O
+with	POS	O
+lung	POS	B-NP
+cancer	POS	I-NP
+risk	POS	O
+.	POS	O
+Newly	POS	O
+identified	POS	O
+links	POS	O
+to	POS	O
+kidney	POS	B-NP
+cancer	POS	I-NP
+and	POS	O
+associations	POS	O
+with	POS	O
+aggressive	POS	O
+prostate	POS	B-NP
+cancer	POS	I-NP
+require	POS	O
+further	POS	O
+evaluation	POS	O
+.	POS	O
+Associations	POS	O
+of	POS	O
+Ozone	POS	O
+and	POS	O
+PM2	POS	O
+.	POS	O
+5	POS	O
+Concentrations	POS	O
+With	POS	O
+Parkinson	POS	O
+'	POS	O
+s	POS	O
+Disease	POS	O
+Among	POS	O
+Participants	POS	O
+in	POS	O
+the	POS	O
+Agricultural	POS	O
+Health	POS	O
+Study	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+This	POS	O
+study	POS	O
+describes	POS	O
+associations	POS	O
+of	POS	O
+ozone	POS	O
+and	POS	O
+fine	POS	O
+particulate	POS	O
+matter	POS	O
+with	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+observed	POS	O
+among	POS	O
+farmers	POS	O
+in	POS	O
+North	POS	O
+Carolina	POS	O
+and	POS	O
+Iowa	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+used	POS	O
+logistic	POS	O
+regression	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+associations	POS	O
+of	POS	O
+these	POS	O
+pollutants	POS	O
+with	POS	O
+self	POS	O
+-	POS	O
+reported	POS	O
+,	POS	O
+doctor	POS	O
+-	POS	O
+diagnosed	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+Daily	POS	O
+predicted	POS	O
+pollutant	POS	O
+concentrations	POS	O
+were	POS	O
+used	POS	O
+to	POS	O
+derive	POS	O
+surrogates	POS	O
+of	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+exposure	POS	O
+and	POS	O
+link	POS	O
+them	POS	O
+to	POS	O
+study	POS	O
+participants	POS	O
+'	POS	O
+geocoded	POS	O
+addresses	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+We	POS	O
+observed	POS	O
+positive	POS	O
+associations	POS	O
+of	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+with	POS	O
+ozone	POS	O
+(	POS	O
+odds	POS	O
+ratio	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+39	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+:	POS	O
+0	POS	O
+.	POS	O
+98	POS	O
+to	POS	O
+1	POS	O
+.	POS	O
+98	POS	O
+)	POS	O
+and	POS	O
+fine	POS	O
+particulate	POS	O
+matter	POS	O
+(	POS	O
+odds	POS	O
+ratio	POS	O
+=	POS	O
+1	POS	O
+.	POS	O
+34	POS	O
+;	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+:	POS	O
+0	POS	O
+.	POS	O
+93	POS	O
+to	POS	O
+1	POS	O
+.	POS	O
+93	POS	O
+)	POS	O
+in	POS	O
+North	POS	O
+Carolina	POS	O
+but	POS	O
+not	POS	O
+in	POS	O
+Iowa	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+The	POS	O
+plausibility	POS	O
+of	POS	O
+an	POS	O
+effect	POS	O
+of	POS	O
+ambient	POS	O
+concentrations	POS	O
+of	POS	O
+these	POS	O
+pollutants	POS	O
+on	POS	O
+Parkinson	POS	O
+'	POS	O
+s	POS	O
+disease	POS	O
+risk	POS	O
+is	POS	O
+supported	POS	O
+by	POS	O
+experimental	POS	O
+data	POS	O
+demonstrating	POS	O
+damage	POS	O
+to	POS	O
+dopaminergic	POS	O
+neurons	POS	O
+at	POS	O
+relevant	POS	O
+concentrations	POS	O
+.	POS	O
+Additional	POS	O
+studies	POS	O
+are	POS	O
+needed	POS	O
+to	POS	O
+address	POS	O
+uncertainties	POS	O
+related	POS	O
+to	POS	O
+confounding	POS	O
+and	POS	O
+to	POS	O
+examine	POS	O
+temporal	POS	O
+aspects	POS	O
+of	POS	O
+the	POS	O
+associations	POS	O
+we	POS	O
+observed	POS	O
+.	POS	O
+Low	POS	O
+functional	POS	O
+programming	POS	O
+of	POS	O
+renal	POS	O
+AT2R	POS	O
+mediates	POS	O
+the	POS	O
+developmental	POS	O
+origin	POS	O
+of	POS	O
+glomerulosclerosis	POS	B-NP
+in	POS	O
+adult	POS	O
+offspring	POS	O
+induced	POS	O
+by	POS	O
+prenatal	POS	O
+caffeine	POS	O
+exposure	POS	O
+.	POS	O
+UNASSIGNED	POS	O
+:	POS	O
+Our	POS	O
+previous	POS	O
+study	POS	O
+has	POS	O
+indicated	POS	O
+that	POS	O
+prenatal	POS	O
+caffeine	POS	O
+exposure	POS	O
+(	POS	O
+PCE	POS	O
+)	POS	O
+could	POS	O
+induce	POS	O
+intrauterine	POS	B-NP
+growth	POS	I-NP
+retardation	POS	I-NP
+(	POS	O
+IUGR	POS	B-NP
+)	POS	O
+of	POS	O
+offspring	POS	O
+.	POS	O
+Recent	POS	O
+research	POS	O
+suggested	POS	O
+that	POS	O
+IUGR	POS	B-NP
+is	POS	O
+a	POS	O
+risk	POS	O
+factor	POS	O
+for	POS	O
+glomerulosclerosis	POS	B-NP
+.	POS	O
+However	POS	O
+,	POS	O
+whether	POS	O
+PCE	POS	O
+could	POS	O
+induce	POS	O
+glomerulosclerosis	POS	B-NP
+and	POS	O
+its	POS	O
+underlying	POS	O
+mechanisms	POS	O
+remain	POS	O
+unknown	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+aimed	POS	O
+to	POS	O
+demonstrate	POS	O
+the	POS	O
+induction	POS	O
+to	POS	O
+glomerulosclerosis	POS	B-NP
+in	POS	O
+adult	POS	O
+offspring	POS	O
+by	POS	O
+PCE	POS	O
+and	POS	O
+its	POS	O
+intrauterine	POS	O
+programming	POS	O
+mechanisms	POS	O
+.	POS	O
+A	POS	O
+rat	POS	O
+model	POS	O
+of	POS	O
+IUGR	POS	B-NP
+was	POS	O
+established	POS	O
+by	POS	O
+PCE	POS	O
+,	POS	O
+male	POS	O
+fetuses	POS	O
+and	POS	O
+adult	POS	O
+offspring	POS	O
+at	POS	O
+the	POS	O
+age	POS	O
+of	POS	O
+postnatal	POS	O
+week	POS	O
+24	POS	O
+were	POS	O
+euthanized	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+revealed	POS	O
+that	POS	O
+the	POS	O
+adult	POS	O
+offspring	POS	O
+kidneys	POS	O
+in	POS	O
+the	POS	O
+PCE	POS	O
+group	POS	O
+exhibited	POS	O
+glomerulosclerosis	POS	B-NP
+as	POS	O
+well	POS	O
+as	POS	O
+interstitial	POS	B-NP
+fibrosis	POS	I-NP
+,	POS	O
+accompanied	POS	O
+by	POS	O
+elevated	POS	O
+levels	POS	O
+of	POS	O
+serum	POS	O
+creatinine	POS	O
+and	POS	O
+urine	POS	O
+protein	POS	O
+.	POS	O
+Renal	POS	O
+angiotensin	POS	O
+II	POS	O
+receptor	POS	O
+type	POS	O
+2	POS	O
+(	POS	O
+AT2R	POS	O
+)	POS	O
+gene	POS	O
+expression	POS	O
+in	POS	O
+adult	POS	O
+offspring	POS	O
+was	POS	O
+reduced	POS	O
+by	POS	O
+PCE	POS	O
+,	POS	O
+whereas	POS	O
+the	POS	O
+renal	POS	O
+angiotensin	POS	O
+II	POS	O
+receptor	POS	O
+type	POS	O
+1a	POS	O
+(	POS	O
+AT1aR	POS	O
+)	POS	O
+/	POS	O
+AT2R	POS	O
+expression	POS	O
+ratio	POS	O
+was	POS	O
+increased	POS	O
+.	POS	O
+The	POS	O
+fetal	POS	O
+kidneys	POS	O
+in	POS	O
+the	POS	O
+PCE	POS	O
+group	POS	O
+displayed	POS	O
+an	POS	O
+enlarged	POS	O
+Bowman	POS	O
+'	POS	O
+s	POS	O
+space	POS	O
+and	POS	O
+a	POS	O
+shrunken	POS	O
+glomerular	POS	O
+tuft	POS	O
+,	POS	O
+accompanied	POS	O
+by	POS	O
+a	POS	O
+reduced	POS	O
+cortex	POS	O
+width	POS	O
+and	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+nephrogenic	POS	O
+zone	POS	O
+/	POS	O
+cortical	POS	O
+zone	POS	O
+ratio	POS	O
+.	POS	O
+Observation	POS	O
+by	POS	O
+electronic	POS	O
+microscope	POS	O
+revealed	POS	O
+structural	POS	O
+damage	POS	O
+of	POS	O
+podocytes	POS	O
+;	POS	O
+the	POS	O
+reduced	POS	O
+expression	POS	O
+level	POS	O
+of	POS	O
+podocyte	POS	O
+marker	POS	O
+genes	POS	O
+,	POS	O
+nephrin	POS	O
+and	POS	O
+podocin	POS	O
+,	POS	O
+was	POS	O
+also	POS	O
+detected	POS	O
+by	POS	O
+q	POS	O
+-	POS	O
+PCR	POS	O
+.	POS	O
+Moreover	POS	O
+,	POS	O
+AT2R	POS	O
+gene	POS	O
+and	POS	O
+protein	POS	O
+expressions	POS	O
+in	POS	O
+fetal	POS	O
+kidneys	POS	O
+were	POS	O
+inhibited	POS	O
+by	POS	O
+PCE	POS	O
+,	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+repression	POS	O
+of	POS	O
+the	POS	O
+gene	POS	O
+expression	POS	O
+of	POS	O
+glial	POS	O
+-	POS	O
+cell	POS	O
+-	POS	O
+line	POS	O
+-	POS	O
+derived	POS	O
+neurotrophic	POS	O
+factor	POS	O
+(	POS	O
+GDNF	POS	O
+)	POS	O
+/	POS	O
+tyrosine	POS	O
+kinase	POS	O
+receptor	POS	O
+(	POS	O
+c	POS	O
+-	POS	O
+Ret	POS	O
+)	POS	O
+signaling	POS	O
+pathway	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+demonstrated	POS	O
+that	POS	O
+PCE	POS	O
+could	POS	O
+induce	POS	O
+dysplasia	POS	B-NP
+of	POS	O
+fetal	POS	O
+kidneys	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+glomerulosclerosis	POS	B-NP
+of	POS	O
+adult	POS	O
+offspring	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+low	POS	O
+functional	POS	O
+programming	POS	O
+of	POS	O
+renal	POS	O
+AT2R	POS	O
+might	POS	O
+mediate	POS	O
+the	POS	O
+developmental	POS	O
+origin	POS	O
+of	POS	O
+adult	POS	O
+glomerulosclerosis	POS	B-NP
+.	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+-	POS	O
+Butadiene	POS	O
+,	POS	O
+CML	POS	B-NP
+and	POS	O
+the	POS	O
+t	POS	O
+(	POS	O
+9	POS	O
+:	POS	O
+22	POS	O
+)	POS	O
+translocation	POS	O
+:	POS	O
+A	POS	O
+reality	POS	O
+check	POS	O
+.	POS	O
+UNASSIGNED	POS	O
+:	POS	O
+Epidemiological	POS	O
+studies	POS	O
+of	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+-	POS	O
+butadiene	POS	O
+have	POS	O
+suggest	POS	O
+that	POS	O
+exposures	POS	O
+to	POS	O
+humans	POS	O
+are	POS	O
+associated	POS	O
+with	POS	O
+chronic	POS	B-NP
+myeloid	POS	I-NP
+leukemia	POS	I-NP
+(	POS	O
+CML	POS	B-NP
+)	POS	O
+.	POS	O
+CML	POS	B-NP
+has	POS	O
+a	POS	O
+well	POS	O
+-	POS	O
+documented	POS	O
+association	POS	O
+with	POS	O
+ionizing	POS	O
+radiation	POS	O
+,	POS	O
+but	POS	O
+reports	POS	O
+of	POS	O
+associations	POS	O
+with	POS	O
+chemical	POS	O
+exposures	POS	O
+have	POS	O
+been	POS	O
+questioned	POS	O
+.	POS	O
+Ionizing	POS	O
+radiation	POS	O
+is	POS	O
+capable	POS	O
+of	POS	O
+inducing	POS	O
+the	POS	O
+requisite	POS	O
+CML	POS	O
+-	POS	O
+associated	POS	O
+t	POS	O
+(	POS	O
+9	POS	O
+:	POS	O
+22	POS	O
+)	POS	O
+translocation	POS	O
+(	POS	O
+Philadelphia	POS	O
+chromosome	POS	O
+)	POS	O
+in	POS	O
+appropriate	POS	O
+cells	POS	O
+in	POS	O
+vitro	POS	O
+but	POS	O
+,	POS	O
+thus	POS	O
+far	POS	O
+,	POS	O
+chemicals	POS	O
+have	POS	O
+not	POS	O
+shown	POS	O
+this	POS	O
+capacity	POS	O
+.	POS	O
+We	POS	O
+have	POS	O
+proposed	POS	O
+that	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+-	POS	O
+butadiene	POS	O
+metabolites	POS	O
+be	POS	O
+so	POS	O
+tested	POS	O
+as	POS	O
+a	POS	O
+reality	POS	O
+check	POS	O
+on	POS	O
+the	POS	O
+epidemiological	POS	O
+reports	POS	O
+.	POS	O
+In	POS	O
+order	POS	O
+to	POS	O
+conduct	POS	O
+reliable	POS	O
+testing	POS	O
+in	POS	O
+this	POS	O
+regard	POS	O
+,	POS	O
+it	POS	O
+is	POS	O
+essential	POS	O
+that	POS	O
+a	POS	O
+positive	POS	O
+control	POS	O
+for	POS	O
+induction	POS	O
+be	POS	O
+available	POS	O
+.	POS	O
+We	POS	O
+have	POS	O
+used	POS	O
+ionizing	POS	O
+radiation	POS	O
+to	POS	O
+develop	POS	O
+such	POS	O
+a	POS	O
+control	POS	O
+.	POS	O
+Results	POS	O
+described	POS	O
+here	POS	O
+demonstrate	POS	O
+that	POS	O
+this	POS	O
+agent	POS	O
+does	POS	O
+in	POS	O
+fact	POS	O
+induce	POS	O
+pathogenic	POS	O
+t	POS	O
+(	POS	O
+9	POS	O
+:	POS	O
+22	POS	O
+)	POS	O
+translocations	POS	O
+in	POS	O
+a	POS	O
+human	POS	O
+myeloid	POS	O
+cell	POS	O
+line	POS	O
+in	POS	O
+vitro	POS	O
+,	POS	O
+but	POS	O
+does	POS	O
+so	POS	O
+at	POS	O
+low	POS	O
+frequencies	POS	O
+.	POS	O
+Conditions	POS	O
+that	POS	O
+will	POS	O
+be	POS	O
+required	POS	O
+for	POS	O
+studies	POS	O
+of	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+-	POS	O
+butadiene	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+Cancer	POS	O
+incidence	POS	O
+and	POS	O
+metolachlor	POS	O
+use	POS	O
+in	POS	O
+the	POS	O
+Agricultural	POS	O
+Health	POS	O
+Study	POS	O
+:	POS	O
+An	POS	O
+update	POS	O
+.	POS	O
+UNASSIGNED	POS	O
+:	POS	O
+Metolachlor	POS	O
+,	POS	O
+a	POS	O
+widely	POS	O
+used	POS	O
+herbicide	POS	O
+,	POS	O
+is	POS	O
+classified	POS	O
+as	POS	O
+a	POS	O
+Group	POS	O
+C	POS	O
+carcinogen	POS	O
+by	POS	O
+the	POS	O
+U	POS	O
+.	POS	O
+S	POS	O
+.	POS	O
+Environmental	POS	O
+Protection	POS	O
+Agency	POS	O
+based	POS	O
+on	POS	O
+increased	POS	O
+liver	POS	B-NP
+neoplasms	POS	I-NP
+in	POS	O
+female	POS	O
+rats	POS	O
+.	POS	O
+Epidemiologic	POS	O
+studies	POS	O
+of	POS	O
+the	POS	O
+health	POS	O
+effects	POS	O
+of	POS	O
+metolachlor	POS	O
+have	POS	O
+been	POS	O
+limited	POS	O
+.	POS	O
+The	POS	O
+Agricultural	POS	O
+Health	POS	O
+Study	POS	O
+(	POS	O
+AHS	POS	O
+)	POS	O
+is	POS	O
+a	POS	O
+prospective	POS	O
+cohort	POS	O
+study	POS	O
+including	POS	O
+licensed	POS	O
+private	POS	O
+and	POS	O
+commercial	POS	O
+pesticide	POS	O
+applicators	POS	O
+in	POS	O
+Iowa	POS	O
+and	POS	O
+North	POS	O
+Carolina	POS	O
+enrolled	POS	O
+1993	POS	O
+-	POS	O
+1997	POS	O
+.	POS	O
+We	POS	O
+evaluated	POS	O
+cancer	POS	B-NP
+incidence	POS	O
+through	POS	O
+2010	POS	O
+/	POS	O
+2011	POS	O
+(	POS	O
+NC	POS	O
+/	POS	O
+IA	POS	O
+)	POS	O
+for	POS	O
+49	POS	O
+,	POS	O
+616	POS	O
+applicators	POS	O
+,	POS	O
+53	POS	O
+%	POS	O
+of	POS	O
+whom	POS	O
+reported	POS	O
+ever	POS	O
+using	POS	O
+metolachlor	POS	O
+.	POS	O
+We	POS	O
+used	POS	O
+Poisson	POS	O
+regression	POS	O
+to	POS	O
+evaluate	POS	O
+relations	POS	O
+between	POS	O
+two	POS	O
+metrics	POS	O
+of	POS	O
+metolachlor	POS	O
+use	POS	O
+(	POS	O
+lifetime	POS	O
+days	POS	O
+,	POS	O
+intensity	POS	O
+-	POS	O
+weighted	POS	O
+lifetime	POS	O
+days	POS	O
+)	POS	O
+and	POS	O
+cancer	POS	B-NP
+incidence	POS	O
+.	POS	O
+We	POS	O
+saw	POS	O
+no	POS	O
+association	POS	O
+between	POS	O
+metolachlor	POS	O
+use	POS	O
+and	POS	O
+incidence	POS	O
+of	POS	O
+all	POS	O
+cancers	POS	B-NP
+combined	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+5	POS	O
+,	POS	O
+701	POS	O
+with	POS	O
+a	POS	O
+5	POS	O
+-	POS	O
+year	POS	O
+lag	POS	O
+)	POS	O
+or	POS	O
+most	POS	O
+site	POS	O
+-	POS	O
+specific	POS	O
+cancers	POS	B-NP
+.	POS	O
+For	POS	O
+liver	POS	B-NP
+cancer	POS	I-NP
+,	POS	O
+in	POS	O
+analyses	POS	O
+restricted	POS	O
+to	POS	O
+exposed	POS	O
+workers	POS	O
+,	POS	O
+elevations	POS	O
+observed	POS	O
+at	POS	O
+higher	POS	O
+categories	POS	O
+of	POS	O
+use	POS	O
+were	POS	O
+not	POS	O
+statistically	POS	O
+significant	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+trends	POS	O
+for	POS	O
+both	POS	O
+lifetime	POS	O
+and	POS	O
+intensity	POS	O
+-	POS	O
+weighted	POS	O
+lifetime	POS	O
+days	POS	O
+of	POS	O
+metolachor	POS	O
+use	POS	O
+were	POS	O
+positive	POS	O
+and	POS	O
+statistically	POS	O
+significant	POS	O
+with	POS	O
+an	POS	O
+unexposed	POS	O
+reference	POS	O
+group	POS	O
+.	POS	O
+A	POS	O
+similar	POS	O
+pattern	POS	O
+was	POS	O
+observed	POS	O
+for	POS	O
+follicular	POS	B-NP
+cell	POS	I-NP
+lymphoma	POS	I-NP
+,	POS	O
+but	POS	O
+no	POS	O
+other	POS	O
+lymphoma	POS	B-NP
+subtypes	POS	O
+.	POS	O
+An	POS	O
+earlier	POS	O
+suggestion	POS	O
+of	POS	O
+increased	POS	O
+lung	POS	B-NP
+cancer	POS	I-NP
+risk	POS	O
+at	POS	O
+high	POS	O
+levels	POS	O
+of	POS	O
+metolachlor	POS	O
+use	POS	O
+in	POS	O
+this	POS	O
+cohort	POS	O
+was	POS	O
+not	POS	O
+confirmed	POS	O
+in	POS	O
+this	POS	O
+update	POS	O
+.	POS	O
+This	POS	O
+suggestion	POS	O
+of	POS	O
+an	POS	O
+association	POS	O
+between	POS	O
+metolachlor	POS	O
+and	POS	O
+liver	POS	B-NP
+cancer	POS	I-NP
+among	POS	O
+pesticide	POS	O
+applicators	POS	O
+is	POS	O
+a	POS	O
+novel	POS	O
+finding	POS	O
+and	POS	O
+echoes	POS	O
+observation	POS	O
+of	POS	O
+increased	POS	O
+liver	POS	B-NP
+neoplasms	POS	I-NP
+in	POS	O
+some	POS	O
+animal	POS	O
+studies	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+our	POS	O
+findings	POS	O
+for	POS	O
+both	POS	O
+liver	POS	B-NP
+cancer	POS	I-NP
+and	POS	O
+follicular	POS	B-NP
+cell	POS	I-NP
+lymphoma	POS	I-NP
+warrant	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+to	POS	O
+better	POS	O
+differentiate	POS	O
+effects	POS	O
+of	POS	O
+metolachlor	POS	O
+use	POS	O
+from	POS	O
+other	POS	O
+factors	POS	O
+.	POS	O
+Mechanisms	POS	O
+Underlying	POS	O
+Latent	POS	O
+Disease	POS	O
+Risk	POS	O
+Associated	POS	O
+with	POS	O
+Early	POS	O
+-	POS	O
+Life	POS	O
+Arsenic	POS	O
+Exposure	POS	O
+:	POS	O
+Current	POS	O
+Research	POS	O
+Trends	POS	O
+and	POS	O
+Scientific	POS	O
+Gaps	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Millions	POS	O
+of	POS	O
+individuals	POS	O
+worldwide	POS	O
+,	POS	O
+particularly	POS	O
+those	POS	O
+living	POS	O
+in	POS	O
+rural	POS	O
+and	POS	O
+developing	POS	O
+areas	POS	O
+,	POS	O
+are	POS	O
+exposed	POS	O
+to	POS	O
+harmful	POS	O
+levels	POS	O
+of	POS	O
+inorganic	POS	O
+arsenic	POS	O
+(	POS	O
+iAs	POS	O
+)	POS	O
+in	POS	O
+their	POS	O
+drinking	POS	O
+water	POS	O
+.	POS	O
+Inorganic	POS	O
+As	POS	O
+exposure	POS	O
+during	POS	O
+key	POS	O
+developmental	POS	O
+periods	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+a	POS	O
+variety	POS	O
+of	POS	O
+adverse	POS	O
+health	POS	O
+effects	POS	O
+including	POS	O
+those	POS	O
+that	POS	O
+are	POS	O
+evident	POS	O
+in	POS	O
+adulthood	POS	O
+.	POS	O
+There	POS	O
+is	POS	O
+considerable	POS	O
+interest	POS	O
+in	POS	O
+identifying	POS	O
+the	POS	O
+molecular	POS	O
+mechanisms	POS	O
+that	POS	O
+relate	POS	O
+early	POS	O
+-	POS	O
+life	POS	O
+iAs	POS	O
+exposure	POS	O
+to	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+these	POS	O
+latent	POS	B-NP
+diseases	POS	I-NP
+,	POS	O
+particularly	POS	O
+in	POS	O
+relationship	POS	O
+to	POS	O
+cancer	POS	B-NP
+.	POS	O
+OBJECTIVES	POS	O
+:	POS	O
+This	POS	O
+work	POS	O
+summarizes	POS	O
+research	POS	O
+on	POS	O
+the	POS	O
+molecular	POS	O
+mechanisms	POS	O
+that	POS	O
+underlie	POS	O
+the	POS	O
+increased	POS	O
+risk	POS	O
+of	POS	O
+cancer	POS	B-NP
+development	POS	O
+in	POS	O
+adulthood	POS	O
+that	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+early	POS	O
+-	POS	O
+life	POS	O
+iAs	POS	O
+exposure	POS	O
+.	POS	O
+DISCUSSION	POS	O
+:	POS	O
+Epigenetic	POS	O
+reprogramming	POS	O
+that	POS	O
+imparts	POS	O
+functional	POS	O
+changes	POS	O
+in	POS	O
+gene	POS	O
+expression	POS	O
+,	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+cancer	POS	B-NP
+stem	POS	O
+cells	POS	O
+,	POS	O
+and	POS	O
+immunomodulation	POS	O
+are	POS	O
+plausible	POS	O
+underlying	POS	O
+mechanisms	POS	O
+by	POS	O
+which	POS	O
+early	POS	O
+-	POS	O
+life	POS	O
+iAs	POS	O
+exposure	POS	O
+elicits	POS	O
+latent	POS	O
+carcinogenic	POS	O
+effects	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Evidence	POS	O
+is	POS	O
+mounting	POS	O
+that	POS	O
+relates	POS	O
+early	POS	O
+-	POS	O
+life	POS	O
+iAs	POS	O
+exposure	POS	O
+and	POS	O
+cancer	POS	B-NP
+development	POS	O
+later	POS	O
+in	POS	O
+life	POS	O
+.	POS	O
+Future	POS	O
+research	POS	O
+should	POS	O
+include	POS	O
+animal	POS	O
+studies	POS	O
+that	POS	O
+address	POS	O
+mechanistic	POS	O
+hypotheses	POS	O
+and	POS	O
+studies	POS	O
+of	POS	O
+human	POS	O
+populations	POS	O
+that	POS	O
+integrate	POS	O
+early	POS	O
+-	POS	O
+life	POS	O
+exposure	POS	O
+,	POS	O
+molecular	POS	O
+alterations	POS	O
+,	POS	O
+and	POS	O
+latent	POS	O
+disease	POS	O
+outcomes	POS	O
+.	POS	O
+Nifedipine	POS	O
+induced	POS	O
+bradycardia	POS	B-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+autonomic	POS	B-NP
+neuropathy	POS	I-NP
+.	POS	O
+An	POS	O
+80	POS	O
+year	POS	O
+old	POS	O
+diabetic	POS	O
+male	POS	O
+with	POS	O
+evidence	POS	O
+of	POS	O
+peripheral	POS	O
+and	POS	O
+autonomic	POS	B-NP
+neuropathy	POS	I-NP
+was	POS	O
+admitted	POS	O
+with	POS	O
+chest	POS	B-NP
+pain	POS	I-NP
+.	POS	O
+He	POS	O
+was	POS	O
+found	POS	O
+to	POS	O
+have	POS	O
+atrial	POS	B-NP
+flutter	POS	I-NP
+at	POS	O
+a	POS	O
+ventricular	POS	O
+rate	POS	O
+of	POS	O
+70	POS	O
+/	POS	O
+min	POS	O
+which	POS	O
+slowed	POS	O
+down	POS	O
+to	POS	O
+30	POS	O
+-	POS	O
+40	POS	O
+/	POS	O
+min	POS	O
+when	POS	O
+nifedipine	POS	O
+(	POS	O
+60	POS	O
+mg	POS	O
+)	POS	O
+in	POS	O
+3	POS	O
+divided	POS	O
+doses	POS	O
+,	POS	O
+during	POS	O
+which	POS	O
+he	POS	O
+was	POS	O
+paced	POS	O
+at	POS	O
+a	POS	O
+rate	POS	O
+of	POS	O
+70	POS	O
+/	POS	O
+min	POS	O
+.	POS	O
+This	POS	O
+is	POS	O
+inconsistent	POS	O
+with	POS	O
+the	POS	O
+well	POS	O
+-	POS	O
+established	POS	O
+finding	POS	O
+that	POS	O
+nifedipine	POS	O
+induces	POS	O
+tachycardia	POS	B-NP
+in	POS	O
+normally	POS	O
+innervated	POS	O
+hearts	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+in	POS	O
+hearts	POS	O
+deprived	POS	O
+of	POS	O
+compensatory	POS	O
+sympathetic	POS	O
+drive	POS	O
+,	POS	O
+it	POS	O
+may	POS	O
+lead	POS	O
+to	POS	O
+bradycardia	POS	B-NP
+.	POS	O
+The	POS	O
+effect	POS	O
+of	POS	O
+haloperidol	POS	O
+in	POS	O
+cocaine	POS	O
+and	POS	O
+amphetamine	POS	O
+intoxication	POS	O
+.	POS	O
+The	POS	O
+effectiveness	POS	O
+of	POS	O
+haloperidol	POS	O
+pretreatment	POS	O
+in	POS	O
+preventing	POS	O
+the	POS	O
+toxic	POS	O
+effects	POS	O
+of	POS	O
+high	POS	O
+doses	POS	O
+of	POS	O
+amphetamine	POS	O
+and	POS	O
+cocaine	POS	O
+was	POS	O
+studied	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+model	POS	O
+,	POS	O
+toxic	POS	O
+effects	POS	O
+were	POS	O
+induced	POS	O
+by	POS	O
+intraperitoneal	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+injection	POS	O
+of	POS	O
+amphetamine	POS	O
+75	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+100	POS	O
+%	POS	O
+death	POS	O
+rate	POS	O
+)	POS	O
+or	POS	O
+cocaine	POS	O
+70	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+82	POS	O
+%	POS	O
+death	POS	O
+rate	POS	O
+)	POS	O
+.	POS	O
+Haloperidol	POS	O
+failed	POS	O
+to	POS	O
+prevent	POS	O
+amphetamine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+,	POS	O
+but	POS	O
+did	POS	O
+lower	POS	O
+the	POS	O
+mortality	POS	O
+rate	POS	O
+at	POS	O
+most	POS	O
+doses	POS	O
+tested	POS	O
+.	POS	O
+Haloperidol	POS	O
+decreased	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+cocaine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+at	POS	O
+the	POS	O
+two	POS	O
+highest	POS	O
+doses	POS	O
+,	POS	O
+but	POS	O
+the	POS	O
+lowering	POS	O
+of	POS	O
+the	POS	O
+mortality	POS	O
+rate	POS	O
+did	POS	O
+not	POS	O
+reach	POS	O
+statistical	POS	O
+significance	POS	O
+at	POS	O
+any	POS	O
+dose	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+suggest	POS	O
+a	POS	O
+protective	POS	O
+role	POS	O
+for	POS	O
+the	POS	O
+central	POS	O
+dopamine	POS	O
+blocker	POS	O
+haloperidol	POS	O
+against	POS	O
+death	POS	O
+from	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+amphetamine	POS	O
+exposure	POS	O
+without	POS	O
+reducing	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+seizures	POS	B-NP
+.	POS	O
+In	POS	O
+contrast	POS	O
+,	POS	O
+haloperidol	POS	O
+demonstrated	POS	O
+an	POS	O
+ability	POS	O
+to	POS	O
+reduce	POS	O
+cocaine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+without	POS	O
+significantly	POS	O
+reducing	POS	O
+mortality	POS	O
+.	POS	O
+Autoradiographic	POS	O
+evidence	POS	O
+of	POS	O
+estrogen	POS	O
+binding	POS	O
+sites	POS	O
+in	POS	O
+nuclei	POS	O
+of	POS	O
+diethylstilbesterol	POS	O
+induced	POS	O
+hamster	POS	B-NP
+renal	POS	I-NP
+carcinomas	POS	I-NP
+.	POS	O
+Estrogen	POS	O
+binding	POS	O
+sites	POS	O
+were	POS	O
+demonstrated	POS	O
+by	POS	O
+autoradiography	POS	O
+in	POS	O
+one	POS	O
+transplantable	POS	O
+and	POS	O
+five	POS	O
+primary	POS	O
+diethylstilbesterol	POS	O
+induced	POS	O
+renal	POS	B-NP
+carcinomas	POS	I-NP
+in	POS	O
+three	POS	O
+hamsters	POS	O
+.	POS	O
+Radiolabelling	POS	O
+,	POS	O
+following	POS	O
+the	POS	O
+in	POS	O
+vivo	POS	O
+injection	POS	O
+of	POS	O
+3H	POS	O
+-	POS	O
+17	POS	O
+beta	POS	O
+estradiol	POS	O
+,	POS	O
+was	POS	O
+increased	POS	O
+only	POS	O
+over	POS	O
+the	POS	O
+nuclei	POS	O
+of	POS	O
+tumor	POS	B-NP
+cells	POS	O
+;	POS	O
+stereologic	POS	O
+analysis	POS	O
+revealed	POS	O
+a	POS	O
+4	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+to	POS	O
+6	POS	O
+.	POS	O
+7	POS	O
+-	POS	O
+times	POS	O
+higher	POS	O
+concentration	POS	O
+of	POS	O
+reduced	POS	O
+silver	POS	O
+grains	POS	O
+over	POS	O
+nuclei	POS	O
+than	POS	O
+cytoplasm	POS	O
+of	POS	O
+these	POS	O
+cells	POS	O
+.	POS	O
+Despite	POS	O
+rapid	POS	O
+tubular	POS	O
+excretion	POS	O
+of	POS	O
+estradiol	POS	O
+which	POS	O
+peaked	POS	O
+in	POS	O
+less	POS	O
+than	POS	O
+1	POS	O
+h	POS	O
+,	POS	O
+the	POS	O
+normal	POS	O
+cells	POS	O
+did	POS	O
+not	POS	O
+appear	POS	O
+to	POS	O
+bind	POS	O
+the	POS	O
+ligand	POS	O
+.	POS	O
+This	POS	O
+is	POS	O
+the	POS	O
+first	POS	O
+published	POS	O
+report	POS	O
+documenting	POS	O
+the	POS	O
+preferential	POS	O
+in	POS	O
+vivo	POS	O
+binding	POS	O
+of	POS	O
+estrogen	POS	O
+to	POS	O
+nuclei	POS	O
+of	POS	O
+cells	POS	O
+in	POS	O
+estrogen	POS	O
+induced	POS	O
+hamster	POS	O
+renal	POS	O
+carcinomas	POS	B-NP
+.	POS	O
+Bradycardia	POS	B-NP
+due	POS	O
+to	POS	O
+biperiden	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+38	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+male	POS	O
+patient	POS	O
+suffering	POS	O
+from	POS	O
+a	POS	O
+severe	POS	O
+postzosteric	POS	O
+trigeminal	POS	B-NP
+neuralgia	POS	I-NP
+,	POS	O
+intravenous	POS	O
+application	POS	O
+of	POS	O
+10	POS	O
+mg	POS	O
+biperiden	POS	O
+lactate	POS	O
+led	POS	O
+to	POS	O
+a	POS	O
+long	POS	O
+-	POS	O
+lasting	POS	O
+paradoxical	POS	O
+reaction	POS	O
+characterized	POS	O
+by	POS	O
+considerable	POS	O
+bradycardia	POS	B-NP
+,	POS	O
+dysarthria	POS	B-NP
+,	POS	O
+and	POS	O
+dysphagia	POS	B-NP
+.	POS	O
+The	POS	O
+heart	POS	O
+rate	POS	O
+was	POS	O
+back	POS	O
+to	POS	O
+normal	POS	O
+within	POS	O
+12	POS	O
+hours	POS	O
+upon	POS	O
+administration	POS	O
+of	POS	O
+orciprenaline	POS	O
+under	POS	O
+cardiac	POS	O
+monitoring	POS	O
+in	POS	O
+an	POS	O
+intensive	POS	O
+care	POS	O
+unit	POS	O
+.	POS	O
+Bradycardia	POS	B-NP
+induced	POS	O
+by	POS	O
+biperiden	POS	O
+is	POS	O
+attributed	POS	O
+to	POS	O
+the	POS	O
+speed	POS	O
+of	POS	O
+injection	POS	O
+and	POS	O
+to	POS	O
+a	POS	O
+dose	POS	O
+-	POS	O
+related	POS	O
+dual	POS	O
+effect	POS	O
+of	POS	O
+atropine	POS	O
+-	POS	O
+like	POS	O
+drugs	POS	O
+on	POS	O
+muscarine	POS	O
+receptors	POS	O
+.	POS	O
+Deliberate	POS	O
+hypotension	POS	B-NP
+induced	POS	O
+by	POS	O
+labetalol	POS	O
+with	POS	O
+halothane	POS	O
+,	POS	O
+enflurane	POS	O
+or	POS	O
+isoflurane	POS	O
+for	POS	O
+middle	POS	O
+-	POS	O
+ear	POS	O
+surgery	POS	O
+.	POS	O
+The	POS	O
+feasibility	POS	O
+of	POS	O
+using	POS	O
+labetalol	POS	O
+,	POS	O
+an	POS	O
+alpha	POS	O
+-	POS	O
+and	POS	O
+beta	POS	O
+-	POS	O
+adrenergic	POS	O
+blocking	POS	O
+agent	POS	O
+,	POS	O
+as	POS	O
+a	POS	O
+hypotensive	POS	B-NP
+agent	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+inhalation	POS	O
+anaesthetics	POS	O
+(	POS	O
+halothane	POS	O
+,	POS	O
+enflurane	POS	O
+or	POS	O
+isoflurane	POS	O
+)	POS	O
+was	POS	O
+studied	POS	O
+in	POS	O
+23	POS	O
+adult	POS	O
+patients	POS	O
+undergoing	POS	O
+middle	POS	O
+-	POS	O
+ear	POS	O
+surgery	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+was	POS	O
+decreased	POS	O
+from	POS	O
+86	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+5	POS	O
+(	POS	O
+s	POS	O
+.	POS	O
+e	POS	O
+.	POS	O
+mean	POS	O
+)	POS	O
+mmHg	POS	O
+to	POS	O
+52	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+mmHg	POS	O
+(	POS	O
+11	POS	O
+.	POS	O
+5	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+to	POS	O
+6	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+kPa	POS	O
+)	POS	O
+for	POS	O
+98	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+10	POS	O
+min	POS	O
+in	POS	O
+the	POS	O
+halothane	POS	O
+(	POS	O
+H	POS	O
+)	POS	O
+group	POS	O
+,	POS	O
+from	POS	O
+79	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+5	POS	O
+to	POS	O
+53	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+mmHg	POS	O
+(	POS	O
+10	POS	O
+.	POS	O
+5	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+to	POS	O
+7	POS	O
+.	POS	O
+1	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+kPa	POS	O
+)	POS	O
+for	POS	O
+129	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+11	POS	O
+min	POS	O
+in	POS	O
+the	POS	O
+enflurane	POS	O
+(	POS	O
+E	POS	O
+)	POS	O
+group	POS	O
+,	POS	O
+and	POS	O
+from	POS	O
+80	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+to	POS	O
+49	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+mmHg	POS	O
+(	POS	O
+10	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+to	POS	O
+6	POS	O
+.	POS	O
+5	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+kPa	POS	O
+)	POS	O
+for	POS	O
+135	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+15	POS	O
+min	POS	O
+in	POS	O
+the	POS	O
+isoflurane	POS	O
+(	POS	O
+I	POS	O
+)	POS	O
+group	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+H	POS	O
+concentration	POS	O
+during	POS	O
+hypotension	POS	B-NP
+in	POS	O
+the	POS	O
+inspiratory	POS	O
+gas	POS	O
+was	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+vol	POS	O
+%	POS	O
+,	POS	O
+the	POS	O
+mean	POS	O
+E	POS	O
+concentration	POS	O
+1	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+2	POS	O
+vol	POS	O
+%	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+mean	POS	O
+I	POS	O
+concentration	POS	O
+1	POS	O
+.	POS	O
+0	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+vol	POS	O
+%	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+the	POS	O
+patients	POS	O
+received	POS	O
+fentanyl	POS	O
+and	POS	O
+d	POS	O
+-	POS	O
+tubocurarine	POS	O
+.	POS	O
+The	POS	O
+initial	POS	O
+dose	POS	O
+of	POS	O
+labetalol	POS	O
+for	POS	O
+lowering	POS	O
+blood	POS	O
+pressure	POS	O
+was	POS	O
+similar	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+52	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+59	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+in	POS	O
+all	POS	O
+the	POS	O
+groups	POS	O
+.	POS	O
+During	POS	O
+hypotension	POS	B-NP
+,	POS	O
+the	POS	O
+heart	POS	O
+rate	POS	O
+was	POS	O
+stable	POS	O
+without	POS	O
+tachy	POS	O
+-	POS	O
+or	POS	O
+bradycardia	POS	B-NP
+.	POS	O
+The	POS	O
+operating	POS	O
+conditions	POS	O
+regarding	POS	O
+bleeding	POS	B-NP
+were	POS	O
+estimated	POS	O
+in	POS	O
+a	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+manner	POS	O
+,	POS	O
+and	POS	O
+did	POS	O
+not	POS	O
+differ	POS	O
+significantly	POS	O
+between	POS	O
+the	POS	O
+groups	POS	O
+.	POS	O
+During	POS	O
+hypotension	POS	B-NP
+,	POS	O
+the	POS	O
+serum	POS	O
+creatinine	POS	O
+concentration	POS	O
+rose	POS	O
+significantly	POS	O
+in	POS	O
+all	POS	O
+groups	POS	O
+from	POS	O
+the	POS	O
+values	POS	O
+before	POS	O
+hypotension	POS	B-NP
+and	POS	O
+returned	POS	O
+postoperatively	POS	O
+to	POS	O
+the	POS	O
+initial	POS	O
+level	POS	O
+in	POS	O
+the	POS	O
+other	POS	O
+groups	POS	O
+,	POS	O
+except	POS	O
+the	POS	O
+isoflurane	POS	O
+group	POS	O
+.	POS	O
+After	POS	O
+hypotension	POS	B-NP
+there	POS	O
+was	POS	O
+no	POS	O
+rebound	POS	O
+phenomenon	POS	O
+in	POS	O
+either	POS	O
+blood	POS	O
+pressure	POS	O
+or	POS	O
+heart	POS	O
+rate	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+labetalol	POS	O
+induces	POS	O
+easily	POS	O
+adjustable	POS	O
+hypotension	POS	B-NP
+without	POS	O
+compensatory	POS	O
+tachycardia	POS	B-NP
+and	POS	O
+rebound	POS	O
+hypertension	POS	B-NP
+.	POS	O
+Convulsion	POS	B-NP
+following	POS	O
+intravenous	POS	O
+fluorescein	POS	O
+angiography	POS	O
+.	POS	O
+Tonic	POS	O
+-	POS	O
+clonic	POS	O
+seizures	POS	B-NP
+followed	POS	O
+intravenous	POS	O
+fluorescein	POS	O
+injection	POS	O
+for	POS	O
+fundus	POS	O
+angiography	POS	O
+in	POS	O
+a	POS	O
+47	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+male	POS	O
+.	POS	O
+Despite	POS	O
+precautions	POS	O
+this	POS	O
+adverse	POS	O
+reaction	POS	O
+recurred	POS	O
+on	POS	O
+re	POS	O
+-	POS	O
+exposure	POS	O
+to	POS	O
+intravenous	POS	O
+fluorescein	POS	O
+.	POS	O
+Pharmacology	POS	O
+of	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+(	POS	O
+phenytoin	POS	O
+prodrug	POS	O
+)	POS	O
+.	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+,	POS	O
+the	POS	O
+disodium	POS	O
+phosphate	POS	O
+ester	POS	O
+of	POS	O
+3	POS	O
+-	POS	O
+hydroxymethyl	POS	O
+-	POS	O
+5	POS	O
+,	POS	O
+5	POS	O
+-	POS	O
+diphenylhydantoin	POS	O
+,	POS	O
+is	POS	O
+a	POS	O
+prodrug	POS	O
+of	POS	O
+phenytoin	POS	O
+with	POS	O
+advantageous	POS	O
+physicochemical	POS	O
+properties	POS	O
+.	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+is	POS	O
+rapidly	POS	O
+converted	POS	O
+enzymatically	POS	O
+to	POS	O
+phenytoin	POS	O
+in	POS	O
+vivo	POS	O
+.	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+and	POS	O
+phenytoin	POS	O
+sodium	POS	O
+have	POS	O
+equivalent	POS	O
+anticonvulsant	POS	O
+activity	POS	O
+against	POS	O
+seizures	POS	B-NP
+induced	POS	O
+by	POS	O
+maximal	POS	O
+electroshock	POS	O
+(	POS	O
+MES	POS	O
+)	POS	O
+in	POS	O
+mice	POS	O
+following	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+,	POS	O
+oral	POS	O
+,	POS	O
+or	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+administration	POS	O
+.	POS	O
+The	POS	O
+ED50	POS	O
+doses	POS	O
+were	POS	O
+16	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+for	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+and	POS	O
+8	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+for	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+phenytoin	POS	O
+sodium	POS	O
+.	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+and	POS	O
+phenytoin	POS	O
+sodium	POS	O
+have	POS	O
+similar	POS	O
+antiarrhythmic	POS	O
+activity	POS	O
+against	POS	O
+ouabain	POS	O
+-	POS	O
+induced	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+in	POS	O
+anesthetized	POS	O
+dogs	POS	O
+.	POS	O
+The	POS	O
+total	POS	O
+doses	POS	O
+of	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+or	POS	O
+phenytoin	POS	O
+sodium	POS	O
+necessary	POS	O
+to	POS	O
+convert	POS	O
+the	POS	O
+arrhythmia	POS	B-NP
+to	POS	O
+a	POS	O
+normal	POS	O
+sinus	POS	O
+rhythm	POS	O
+were	POS	O
+24	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+and	POS	O
+14	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Only	POS	O
+phenytoin	POS	O
+sodium	POS	O
+displayed	POS	O
+in	POS	O
+vitro	POS	O
+antiarrhythmic	POS	O
+activity	POS	O
+against	POS	O
+strophanthidin	POS	O
+-	POS	O
+induced	POS	O
+arrhythmias	POS	B-NP
+in	POS	O
+guinea	POS	O
+pig	POS	O
+right	POS	O
+atria	POS	O
+.	POS	O
+In	POS	O
+anesthetized	POS	O
+dogs	POS	O
+,	POS	O
+a	POS	O
+high	POS	O
+dose	POS	O
+of	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+(	POS	O
+31	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+was	POS	O
+infused	POS	O
+over	POS	O
+15	POS	O
+,	POS	O
+20	POS	O
+,	POS	O
+and	POS	O
+30	POS	O
+min	POS	O
+and	POS	O
+the	POS	O
+responses	POS	O
+were	POS	O
+compared	POS	O
+to	POS	O
+an	POS	O
+equimolar	POS	O
+dose	POS	O
+of	POS	O
+phenytoin	POS	O
+sodium	POS	O
+(	POS	O
+21	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+and	POS	O
+phenytoin	POS	O
+sodium	POS	O
+treatments	POS	O
+produced	POS	O
+similar	POS	O
+marked	POS	O
+reductions	POS	O
+in	POS	O
+diastolic	POS	O
+blood	POS	O
+pressure	POS	O
+and	POS	O
+contractile	POS	O
+force	POS	O
+(	POS	O
+LVdP	POS	O
+/	POS	O
+dt	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+maximum	POS	O
+effects	POS	O
+of	POS	O
+each	POS	O
+treatment	POS	O
+occurred	POS	O
+at	POS	O
+the	POS	O
+time	POS	O
+of	POS	O
+maximum	POS	O
+phenytoin	POS	O
+sodium	POS	O
+levels	POS	O
+.	POS	O
+Acute	POS	B-NP
+toxicity	POS	I-NP
+studies	POS	O
+of	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+and	POS	O
+phenytoin	POS	O
+sodium	POS	O
+were	POS	O
+carried	POS	O
+out	POS	O
+in	POS	O
+mice	POS	O
+,	POS	O
+rats	POS	O
+,	POS	O
+rabbits	POS	O
+,	POS	O
+and	POS	O
+dogs	POS	O
+by	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+m	POS	O
+.	POS	O
+,	POS	O
+and	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+routes	POS	O
+of	POS	O
+administration	POS	O
+.	POS	O
+The	POS	O
+systemic	POS	O
+toxic	POS	O
+signs	POS	O
+of	POS	O
+both	POS	O
+agents	POS	O
+were	POS	O
+similar	POS	O
+and	POS	O
+occurred	POS	O
+at	POS	O
+approximately	POS	O
+equivalent	POS	O
+doses	POS	O
+.	POS	O
+Importantly	POS	O
+,	POS	O
+the	POS	O
+local	POS	O
+irritation	POS	O
+of	POS	O
+ACC	POS	O
+-	POS	O
+9653	POS	O
+was	POS	O
+markedly	POS	O
+less	POS	O
+than	POS	O
+phenytoin	POS	O
+sodium	POS	O
+following	POS	O
+i	POS	O
+.	POS	O
+m	POS	O
+.	POS	O
+administration	POS	O
+.	POS	O
+(	POS	O
+ABSTRACT	POS	O
+TRUNCATED	POS	O
+AT	POS	O
+250	POS	O
+WORDS	POS	O
+)	POS	O
+Tachyphylaxis	POS	O
+to	POS	O
+systemic	POS	O
+but	POS	O
+not	POS	O
+to	POS	O
+airway	POS	O
+responses	POS	O
+during	POS	O
+prolonged	POS	O
+therapy	POS	O
+with	POS	O
+high	POS	O
+dose	POS	O
+inhaled	POS	O
+salbutamol	POS	O
+in	POS	O
+asthmatics	POS	O
+.	POS	O
+High	POS	O
+doses	POS	O
+of	POS	O
+inhaled	POS	O
+salbutamol	POS	O
+produce	POS	O
+substantial	POS	O
+improvements	POS	O
+in	POS	O
+airway	POS	O
+response	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+asthma	POS	B-NP
+,	POS	O
+and	POS	O
+are	POS	O
+associated	POS	O
+with	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+systemic	POS	O
+beta	POS	O
+-	POS	O
+adrenoceptor	POS	O
+responses	POS	O
+.	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+investigate	POS	O
+whether	POS	O
+tachyphylaxis	POS	B-NP
+occurs	POS	O
+during	POS	O
+prolonged	POS	O
+treatment	POS	O
+with	POS	O
+high	POS	O
+dose	POS	O
+inhaled	POS	O
+salbutamol	POS	O
+.	POS	O
+Twelve	POS	O
+asthmatic	POS	B-NP
+patients	POS	O
+(	POS	O
+FEV1	POS	O
+,	POS	O
+81	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+%	POS	O
+predicted	POS	O
+)	POS	O
+,	POS	O
+requiring	POS	O
+only	POS	O
+occasional	POS	O
+inhaled	POS	O
+beta	POS	O
+-	POS	O
+agonists	POS	O
+as	POS	O
+their	POS	O
+sole	POS	O
+therapy	POS	O
+,	POS	O
+were	POS	O
+given	POS	O
+a	POS	O
+14	POS	O
+-	POS	O
+day	POS	O
+treatment	POS	O
+with	POS	O
+high	POS	O
+dose	POS	O
+inhaled	POS	O
+salbutamol	POS	O
+(	POS	O
+HDS	POS	O
+)	POS	O
+,	POS	O
+4	POS	O
+,	POS	O
+000	POS	O
+micrograms	POS	O
+daily	POS	O
+,	POS	O
+low	POS	O
+dose	POS	O
+inhaled	POS	O
+salbutamol	POS	O
+(	POS	O
+LDS	POS	O
+)	POS	O
+,	POS	O
+800	POS	O
+micrograms	POS	O
+daily	POS	O
+,	POS	O
+or	POS	O
+placebo	POS	O
+(	POS	O
+PI	POS	O
+)	POS	O
+by	POS	O
+metered	POS	O
+-	POS	O
+dose	POS	O
+inhaler	POS	O
+in	POS	O
+a	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+randomized	POS	O
+crossover	POS	O
+design	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+14	POS	O
+-	POS	O
+day	POS	O
+run	POS	O
+-	POS	O
+in	POS	O
+and	POS	O
+during	POS	O
+washout	POS	O
+periods	POS	O
+,	POS	O
+inhaled	POS	O
+beta	POS	O
+-	POS	O
+agonists	POS	O
+were	POS	O
+withheld	POS	O
+and	POS	O
+ipratropium	POS	O
+bromide	POS	O
+was	POS	O
+substituted	POS	O
+for	POS	O
+rescue	POS	O
+purposes	POS	O
+.	POS	O
+At	POS	O
+the	POS	O
+end	POS	O
+of	POS	O
+each	POS	O
+14	POS	O
+-	POS	O
+day	POS	O
+treatment	POS	O
+,	POS	O
+a	POS	O
+dose	POS	O
+-	POS	O
+response	POS	O
+curve	POS	O
+(	POS	O
+DRC	POS	O
+)	POS	O
+was	POS	O
+performed	POS	O
+,	POS	O
+and	POS	O
+airway	POS	O
+(	POS	O
+FEV1	POS	O
+,	POS	O
+FEF25	POS	O
+-	POS	O
+75	POS	O
+)	POS	O
+chronotropic	POS	O
+(	POS	O
+HR	POS	O
+)	POS	O
+,	POS	O
+tremor	POS	B-NP
+,	POS	O
+and	POS	O
+metabolic	POS	O
+(	POS	O
+K	POS	O
+,	POS	O
+Glu	POS	O
+)	POS	O
+responses	POS	O
+were	POS	O
+measured	POS	O
+at	POS	O
+each	POS	O
+step	POS	O
+(	POS	O
+from	POS	O
+100	POS	O
+to	POS	O
+4	POS	O
+,	POS	O
+000	POS	O
+micrograms	POS	O
+)	POS	O
+.	POS	O
+Treatment	POS	O
+had	POS	O
+no	POS	O
+significant	POS	O
+effect	POS	O
+on	POS	O
+baseline	POS	O
+values	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+increases	POS	O
+in	POS	O
+FEV1	POS	O
+and	POS	O
+FEF25	POS	O
+-	POS	O
+75	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+pretreatment	POS	O
+with	POS	O
+HDS	POS	O
+did	POS	O
+not	POS	O
+displace	POS	O
+the	POS	O
+DRC	POS	O
+to	POS	O
+the	POS	O
+right	POS	O
+.	POS	O
+DRC	POS	O
+for	POS	O
+HR	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+K	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+Glu	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+005	POS	O
+)	POS	O
+were	POS	O
+attenuated	POS	O
+after	POS	O
+treatment	POS	O
+with	POS	O
+HDS	POS	B-NP
+compared	POS	O
+with	POS	O
+PI	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+also	POS	O
+differences	POS	O
+between	POS	O
+HDS	POS	O
+and	POS	O
+LDS	POS	O
+for	POS	O
+HR	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+and	POS	O
+Glu	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+responses	POS	O
+.	POS	O
+Frequency	POS	O
+and	POS	O
+severity	POS	O
+of	POS	O
+subjective	POS	O
+adverse	POS	O
+effects	POS	O
+were	POS	O
+also	POS	O
+reduced	POS	O
+after	POS	O
+HDS	POS	B-NP
+:	POS	O
+tremor	POS	B-NP
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+palpitations	POS	B-NP
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+(	POS	O
+ABSTRACT	POS	O
+TRUNCATED	POS	O
+AT	POS	O
+250	POS	O
+WORDS	POS	O
+)	POS	O
+Phenytoin	POS	O
+induced	POS	O
+fatal	POS	O
+hepatic	POS	B-NP
+injury	POS	I-NP
+.	POS	O
+A	POS	O
+61	POS	O
+year	POS	O
+old	POS	O
+female	POS	O
+developed	POS	O
+fatal	POS	O
+hepatic	POS	B-NP
+failure	POS	I-NP
+after	POS	O
+phenytoin	POS	O
+administration	POS	O
+.	POS	O
+A	POS	O
+typical	POS	O
+multisystem	POS	O
+clinical	POS	O
+pattern	POS	O
+precedes	POS	O
+the	POS	O
+manifestations	POS	O
+of	POS	O
+hepatic	POS	B-NP
+injury	POS	I-NP
+.	POS	O
+The	POS	O
+hematologic	POS	O
+,	POS	O
+biochemical	POS	O
+and	POS	O
+pathologic	POS	O
+features	POS	O
+indicate	POS	O
+a	POS	O
+mixed	POS	O
+hepatocellular	POS	B-NP
+damage	POS	I-NP
+due	POS	O
+to	POS	O
+drug	POS	O
+hypersensitivity	POS	B-NP
+.	POS	O
+In	POS	O
+a	POS	O
+patient	POS	O
+receiving	POS	O
+phenytoin	POS	O
+who	POS	O
+presents	POS	O
+a	POS	O
+viral	POS	B-NP
+-	POS	I-NP
+like	POS	I-NP
+illness	POS	I-NP
+,	POS	O
+early	POS	O
+recognition	POS	O
+and	POS	O
+discontinuation	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+are	POS	O
+mandatory	POS	O
+.	POS	O
+Treatment	POS	O
+of	POS	O
+lethal	POS	O
+pertussis	POS	O
+vaccine	POS	O
+reaction	POS	O
+with	POS	O
+histamine	POS	O
+H1	POS	O
+antagonists	POS	O
+.	POS	O
+We	POS	O
+studied	POS	O
+mortality	POS	O
+after	POS	O
+pertussis	POS	O
+immunization	POS	O
+in	POS	O
+the	POS	O
+mouse	POS	O
+.	POS	O
+Without	POS	O
+treatment	POS	O
+,	POS	O
+73	POS	O
+of	POS	O
+92	POS	O
+animals	POS	O
+(	POS	O
+80	POS	O
+%	POS	O
+)	POS	O
+died	POS	O
+after	POS	O
+injection	POS	O
+of	POS	O
+bovine	POS	O
+serum	POS	O
+albumin	POS	O
+(	POS	O
+BSA	POS	O
+)	POS	O
+on	POS	O
+day	POS	O
++	POS	O
+7	POS	O
+of	POS	O
+pertussis	POS	O
+immunization	POS	O
+.	POS	O
+After	POS	O
+pretreatment	POS	O
+with	POS	O
+3	POS	O
+mg	POS	O
+of	POS	O
+cyproheptadine	POS	O
+,	POS	O
+2	POS	O
+mg	POS	O
+mianserin	POS	O
+,	POS	O
+or	POS	O
+2	POS	O
+mg	POS	O
+chlorpheniramine	POS	O
+,	POS	O
+only	POS	O
+5	POS	O
+of	POS	O
+105	POS	O
+animals	POS	O
+(	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+died	POS	O
+after	POS	O
+receiving	POS	O
+BSA	POS	O
+on	POS	O
+day	POS	O
++	POS	O
+7	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+Blockade	POS	O
+of	POS	O
+histamine	POS	O
+H1	POS	O
+receptors	POS	O
+may	POS	O
+reduce	POS	O
+mortality	POS	O
+in	POS	O
+pertussis	POS	O
+immunization	POS	O
+-	POS	O
+induced	POS	O
+encephalopathy	POS	B-NP
+in	POS	O
+mice	POS	O
+.	POS	O
+Support	POS	O
+for	POS	O
+adrenaline	POS	O
+-	POS	O
+hypertension	POS	B-NP
+hypothesis	POS	O
+:	POS	O
+18	POS	O
+hour	POS	O
+pressor	POS	O
+effect	POS	O
+after	POS	O
+6	POS	O
+hours	POS	O
+adrenaline	POS	O
+infusion	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+double	POS	O
+blind	POS	O
+,	POS	O
+crossover	POS	O
+study	POS	O
+6	POS	O
+h	POS	O
+infusions	POS	O
+of	POS	O
+adrenaline	POS	O
+(	POS	O
+15	POS	O
+ng	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+;	POS	O
+1	POS	O
+ng	POS	O
+=	POS	O
+5	POS	O
+.	POS	O
+458	POS	O
+pmol	POS	O
+)	POS	O
+,	POS	O
+noradrenaline	POS	O
+(	POS	O
+30	POS	O
+ng	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+;	POS	O
+1	POS	O
+ng	POS	O
+=	POS	O
+5	POS	O
+.	POS	O
+911	POS	O
+pmol	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+5	POS	O
+%	POS	O
+dextrose	POS	O
+solution	POS	O
+(	POS	O
+5	POS	O
+.	POS	O
+4	POS	O
+ml	POS	O
+/	POS	O
+h	POS	O
+)	POS	O
+,	POS	O
+were	POS	O
+given	POS	O
+to	POS	O
+ten	POS	O
+healthy	POS	O
+volunteers	POS	O
+in	POS	O
+random	POS	O
+order	POS	O
+2	POS	O
+weeks	POS	O
+apart	POS	O
+.	POS	O
+By	POS	O
+means	POS	O
+of	POS	O
+intra	POS	O
+-	POS	O
+arterial	POS	O
+ambulatory	POS	O
+monitoring	POS	O
+the	POS	O
+haemodynamic	POS	O
+effects	POS	O
+were	POS	O
+followed	POS	O
+for	POS	O
+18	POS	O
+h	POS	O
+after	POS	O
+the	POS	O
+infusions	POS	O
+were	POS	O
+stopped	POS	O
+.	POS	O
+Adrenaline	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+noradrenaline	POS	O
+,	POS	O
+caused	POS	O
+a	POS	O
+delayed	POS	O
+and	POS	O
+protracted	POS	O
+pressor	POS	O
+effect	POS	O
+.	POS	O
+Over	POS	O
+the	POS	O
+total	POS	O
+postinfusion	POS	O
+period	POS	O
+systolic	POS	O
+and	POS	O
+diastolic	POS	O
+arterial	POS	O
+pressure	POS	O
+were	POS	O
+6	POS	O
+(	POS	O
+SEM	POS	O
+2	POS	O
+)	POS	O
+%	POS	O
+and	POS	O
+7	POS	O
+(	POS	O
+2	POS	O
+)	POS	O
+%	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+higher	POS	O
+than	POS	O
+after	POS	O
+dextrose	POS	O
+infusion	POS	O
+(	POS	O
+ANOVA	POS	O
+,	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+"	POS	O
+stress	POS	O
+"	POS	O
+levels	POS	O
+of	POS	O
+adrenaline	POS	O
+(	POS	O
+230	POS	O
+pg	POS	O
+/	POS	O
+ml	POS	O
+)	POS	O
+for	POS	O
+6	POS	O
+h	POS	O
+cause	POS	O
+a	POS	O
+delayed	POS	O
+and	POS	O
+protracted	POS	O
+pressor	POS	O
+effect	POS	O
+.	POS	O
+These	POS	O
+findings	POS	O
+are	POS	O
+strong	POS	O
+support	POS	O
+for	POS	O
+the	POS	O
+adrenaline	POS	O
+-	POS	O
+hypertension	POS	B-NP
+hypothesis	POS	O
+in	POS	O
+man	POS	O
+.	POS	O
+Effect	POS	O
+of	POS	O
+alkylxanthines	POS	O
+on	POS	O
+gentamicin	POS	O
+-	POS	O
+induced	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+in	POS	O
+the	POS	O
+rat	POS	O
+.	POS	O
+Adenosine	POS	O
+antagonists	POS	O
+have	POS	O
+been	POS	O
+previously	POS	O
+shown	POS	O
+to	POS	O
+be	POS	O
+of	POS	O
+benefit	POS	O
+in	POS	O
+some	POS	O
+ischaemic	POS	B-NP
+and	POS	O
+nephrotoxic	POS	B-NP
+models	POS	O
+of	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+(	POS	O
+ARF	POS	B-NP
+)	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+,	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+three	POS	O
+alkylxanthines	POS	O
+with	POS	O
+different	POS	O
+potencies	POS	O
+as	POS	O
+adenosine	POS	O
+antagonists	POS	O
+8	POS	O
+-	POS	O
+phenyltheophylline	POS	O
+,	POS	O
+theophylline	POS	O
+and	POS	O
+enprofylline	POS	O
+,	POS	O
+were	POS	O
+examined	POS	O
+in	POS	O
+rats	POS	O
+developing	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+after	POS	O
+4	POS	O
+daily	POS	O
+injections	POS	O
+of	POS	O
+gentamicin	POS	O
+(	POS	O
+200	POS	O
+mg	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+.	POS	O
+Renal	POS	O
+function	POS	O
+was	POS	O
+assessed	POS	O
+by	POS	O
+biochemical	POS	O
+(	POS	O
+plasma	POS	O
+urea	POS	O
+and	POS	O
+creatinine	POS	O
+)	POS	O
+,	POS	O
+functional	POS	O
+(	POS	O
+urine	POS	O
+analysis	POS	O
+and	POS	O
+[	POS	O
+3H	POS	O
+]	POS	O
+inulin	POS	O
+and	POS	O
+[	POS	O
+14C	POS	O
+]	POS	O
+p	POS	O
+-	POS	O
+aminohippuric	POS	O
+acid	POS	O
+clearances	POS	O
+)	POS	O
+and	POS	O
+morphological	POS	O
+(	POS	O
+degree	POS	O
+of	POS	O
+necrosis	POS	B-NP
+)	POS	O
+indices	POS	O
+.	POS	O
+The	POS	O
+various	POS	O
+drug	POS	O
+treatments	POS	O
+produced	POS	O
+improvements	POS	O
+in	POS	O
+some	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+all	POS	O
+,	POS	O
+measurements	POS	O
+of	POS	O
+renal	POS	O
+function	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+any	POS	O
+improvement	POS	O
+produced	POS	O
+by	POS	O
+drug	POS	O
+treatment	POS	O
+was	POS	O
+largely	POS	O
+a	POS	O
+result	POS	O
+of	POS	O
+a	POS	O
+beneficial	POS	O
+effect	POS	O
+exerted	POS	O
+by	POS	O
+its	POS	O
+vehicle	POS	O
+(	POS	O
+polyethylene	POS	O
+glycol	POS	O
+and	POS	O
+NaOH	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+lack	POS	O
+of	POS	O
+any	POS	O
+consistent	POS	O
+protective	POS	O
+effect	POS	O
+noted	POS	O
+with	POS	O
+the	POS	O
+alkylxanthines	POS	O
+tested	POS	O
+in	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+indicates	POS	O
+that	POS	O
+adenosine	POS	O
+plays	POS	O
+little	POS	O
+,	POS	O
+if	POS	O
+any	POS	O
+,	POS	O
+pathophysiological	POS	O
+role	POS	O
+in	POS	O
+gentamicin	POS	O
+-	POS	O
+induced	POS	O
+ARF	POS	B-NP
+.	POS	O
+Adverse	POS	O
+ocular	POS	O
+reactions	POS	O
+possibly	POS	O
+associated	POS	O
+with	POS	O
+isotretinoin	POS	O
+.	POS	O
+A	POS	O
+total	POS	O
+of	POS	O
+261	POS	O
+adverse	POS	O
+ocular	POS	B-NP
+reactions	POS	I-NP
+occurred	POS	O
+in	POS	O
+237	POS	O
+patients	POS	O
+who	POS	O
+received	POS	O
+isotretinoin	POS	O
+,	POS	O
+a	POS	O
+commonly	POS	O
+used	POS	O
+drug	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+severe	POS	O
+cystic	POS	B-NP
+acne	POS	I-NP
+.	POS	O
+Blepharoconjunctivitis	POS	B-NP
+,	POS	O
+subjective	POS	O
+complaints	POS	O
+of	POS	O
+dry	POS	B-NP
+eyes	POS	I-NP
+,	POS	O
+blurred	POS	B-NP
+vision	POS	I-NP
+,	POS	O
+contact	POS	B-NP
+lens	POS	I-NP
+intolerance	POS	I-NP
+,	POS	O
+and	POS	O
+photodermatitis	POS	B-NP
+are	POS	O
+reversible	POS	O
+side	POS	O
+effects	POS	O
+.	POS	O
+More	POS	O
+serious	POS	O
+ocular	POS	O
+adverse	POS	O
+reactions	POS	O
+include	POS	O
+papilledema	POS	B-NP
+,	POS	O
+pseudotumor	POS	B-NP
+cerebri	POS	I-NP
+,	POS	O
+and	POS	O
+white	POS	O
+or	POS	O
+gray	POS	O
+subepithelial	POS	O
+corneal	POS	O
+opacities	POS	O
+;	POS	O
+all	POS	O
+of	POS	O
+these	POS	O
+are	POS	O
+reversible	POS	O
+if	POS	O
+the	POS	O
+drug	POS	O
+is	POS	O
+discontinued	POS	O
+.	POS	O
+Reported	POS	O
+cases	POS	O
+of	POS	O
+decreased	POS	O
+dark	POS	O
+adaptation	POS	O
+are	POS	O
+under	POS	O
+investigation	POS	O
+.	POS	O
+Isotretinoin	POS	O
+is	POS	O
+contraindicated	POS	O
+in	POS	O
+pregnancy	POS	O
+because	POS	O
+of	POS	O
+the	POS	O
+many	POS	O
+reported	POS	O
+congenital	POS	B-NP
+abnormalities	POS	I-NP
+after	POS	O
+maternal	POS	O
+use	POS	O
+(	POS	O
+including	POS	O
+microphthalmos	POS	B-NP
+,	POS	O
+orbital	POS	B-NP
+hypertelorism	POS	I-NP
+,	POS	O
+and	POS	O
+optic	POS	B-NP
+nerve	POS	I-NP
+hypoplasia	POS	I-NP
+)	POS	O
+.	POS	O
+Procaterol	POS	O
+and	POS	O
+terbutaline	POS	O
+in	POS	O
+bronchial	POS	B-NP
+asthma	POS	I-NP
+.	POS	O
+A	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+,	POS	O
+cross	POS	O
+-	POS	O
+over	POS	O
+study	POS	O
+.	POS	O
+Procaterol	POS	O
+,	POS	O
+a	POS	O
+new	POS	O
+beta	POS	O
+-	POS	O
+2	POS	O
+adrenoceptor	POS	O
+stimulant	POS	O
+,	POS	O
+was	POS	O
+studied	POS	O
+in	POS	O
+a	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+,	POS	O
+cross	POS	O
+-	POS	O
+over	POS	O
+trial	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+bronchial	POS	B-NP
+asthma	POS	I-NP
+.	POS	O
+Oral	POS	O
+procaterol	POS	O
+50	POS	O
+micrograms	POS	O
+b	POS	O
+.	POS	O
+d	POS	O
+.	POS	O
+,	POS	O
+procaterol	POS	O
+100	POS	O
+micrograms	POS	O
+b	POS	O
+.	POS	O
+d	POS	O
+.	POS	O
+,	POS	O
+and	POS	O
+terbutaline	POS	O
+5	POS	O
+mg	POS	O
+t	POS	O
+.	POS	O
+i	POS	O
+.	POS	O
+d	POS	O
+.	POS	O
+,	POS	O
+were	POS	O
+compared	POS	O
+when	POS	O
+given	POS	O
+randomly	POS	O
+in	POS	O
+1	POS	O
+-	POS	O
+week	POS	O
+treatment	POS	O
+periods	POS	O
+.	POS	O
+The	POS	O
+best	POS	O
+clinical	POS	O
+effect	POS	O
+was	POS	O
+found	POS	O
+with	POS	O
+terbutaline	POS	O
+.	POS	O
+Both	POS	O
+anti	POS	O
+-	POS	O
+asthmatic	POS	O
+and	POS	O
+tremorgenic	POS	O
+effects	POS	O
+of	POS	O
+procaterol	POS	O
+were	POS	O
+dose	POS	O
+-	POS	O
+related	POS	O
+.	POS	O
+Procaterol	POS	O
+appeared	POS	O
+effective	POS	O
+in	POS	O
+the	POS	O
+doses	POS	O
+tested	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+twice	POS	O
+daily	POS	O
+regimen	POS	O
+would	POS	O
+appear	POS	O
+to	POS	O
+be	POS	O
+suitable	POS	O
+with	POS	O
+this	POS	O
+drug	POS	O
+.	POS	O
+Subacute	POS	O
+effects	POS	O
+of	POS	O
+propranolol	POS	O
+and	POS	O
+B	POS	O
+24	POS	O
+/	POS	O
+76	POS	O
+on	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+rat	POS	O
+heart	POS	B-NP
+hypertrophy	POS	I-NP
+in	POS	O
+correlation	POS	O
+with	POS	O
+blood	POS	O
+pressure	POS	O
+.	POS	O
+We	POS	O
+compared	POS	O
+the	POS	O
+potential	POS	O
+beta	POS	O
+-	POS	O
+receptor	POS	O
+blocker	POS	O
+,	POS	O
+B	POS	O
+24	POS	O
+/	POS	O
+76	POS	O
+i	POS	O
+.	POS	O
+e	POS	O
+.	POS	O
+1	POS	O
+-	POS	O
+(	POS	O
+2	POS	O
+,	POS	O
+4	POS	O
+-	POS	O
+dichlorophenoxy	POS	O
+)	POS	O
+-	POS	O
+3	POS	O
+[	POS	O
+2	POS	O
+-	POS	O
+3	POS	O
+,	POS	O
+4	POS	O
+-	POS	O
+dimethoxyphenyl	POS	O
+)	POS	O
+ethanolamino	POS	O
+]	POS	O
+-	POS	O
+prop	POS	O
+an	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+ol	POS	O
+,	POS	O
+which	POS	O
+is	POS	O
+characterized	POS	O
+by	POS	O
+beta	POS	O
+1	POS	O
+-	POS	O
+adrenoceptor	POS	O
+blocking	POS	O
+and	POS	O
+beta	POS	O
+2	POS	O
+-	POS	O
+adrenoceptor	POS	O
+stimulating	POS	O
+properties	POS	O
+with	POS	O
+propranolol	POS	O
+.	POS	O
+The	POS	O
+studies	POS	O
+were	POS	O
+performed	POS	O
+using	POS	O
+an	POS	O
+experimental	POS	O
+model	POS	O
+of	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+heart	POS	B-NP
+hypertrophy	POS	I-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+A	POS	O
+correlation	POS	O
+of	POS	O
+the	POS	O
+blood	POS	O
+pressure	POS	O
+was	POS	O
+neither	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+development	POS	O
+nor	POS	O
+in	POS	O
+the	POS	O
+attempt	POS	O
+to	POS	O
+suppress	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+heart	POS	B-NP
+hypertrophy	POS	I-NP
+with	POS	O
+the	POS	O
+two	POS	O
+beta	POS	O
+-	POS	O
+receptor	POS	O
+blockers	POS	O
+.	POS	O
+Both	POS	O
+beta	POS	O
+-	POS	O
+blockers	POS	O
+influenced	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+hypertrophy	POS	B-NP
+to	POS	O
+a	POS	O
+different	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+reproducible	POS	O
+extent	POS	O
+.	POS	O
+It	POS	O
+was	POS	O
+possible	POS	O
+to	POS	O
+suppress	POS	O
+the	POS	O
+increased	POS	O
+ornithine	POS	O
+decarboxylase	POS	O
+activity	POS	O
+with	POS	O
+both	POS	O
+beta	POS	O
+-	POS	O
+blockers	POS	O
+in	POS	O
+hypertrophied	POS	O
+hearts	POS	O
+,	POS	O
+but	POS	O
+there	POS	O
+was	POS	O
+no	POS	O
+effect	POS	O
+on	POS	O
+the	POS	O
+heart	POS	O
+mass	POS	O
+.	POS	O
+Neither	POS	O
+propranolol	POS	O
+nor	POS	O
+B	POS	O
+24	POS	O
+/	POS	O
+76	POS	O
+could	POS	O
+stop	POS	O
+the	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+characteristic	POS	O
+myosin	POS	O
+isoenzyme	POS	O
+pattern	POS	O
+of	POS	O
+the	POS	O
+hypertrophied	POS	O
+rat	POS	O
+heart	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+the	POS	O
+investigations	POS	O
+did	POS	O
+not	POS	O
+provide	POS	O
+any	POS	O
+evidence	POS	O
+that	POS	O
+the	POS	O
+beta	POS	O
+-	POS	O
+receptor	POS	O
+blockers	POS	O
+propranolol	POS	O
+and	POS	O
+B	POS	O
+24	POS	O
+/	POS	O
+76	POS	O
+have	POS	O
+the	POS	O
+potency	POS	O
+to	POS	O
+prevent	POS	O
+isoproterenol	POS	O
+from	POS	O
+producing	POS	O
+heart	POS	B-NP
+hypertrophy	POS	I-NP
+.	POS	O
+Increased	POS	O
+anxiogenic	POS	O
+effects	POS	O
+of	POS	O
+caffeine	POS	O
+in	POS	O
+panic	POS	B-NP
+disorders	POS	I-NP
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+oral	POS	O
+administration	POS	O
+of	POS	O
+caffeine	POS	O
+(	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+on	POS	O
+behavioral	POS	O
+ratings	POS	O
+,	POS	O
+somatic	POS	O
+symptoms	POS	O
+,	POS	O
+blood	POS	O
+pressure	POS	O
+and	POS	O
+plasma	POS	O
+levels	POS	O
+of	POS	O
+3	POS	O
+-	POS	O
+methoxy	POS	O
+-	POS	O
+4	POS	O
+-	POS	O
+hydroxyphenethyleneglycol	POS	O
+(	POS	O
+MHPG	POS	O
+)	POS	O
+and	POS	O
+cortisol	POS	O
+were	POS	O
+determined	POS	O
+in	POS	O
+17	POS	O
+healthy	POS	O
+subjects	POS	O
+and	POS	O
+21	POS	O
+patients	POS	O
+meeting	POS	O
+DSM	POS	O
+-	POS	O
+III	POS	O
+criteria	POS	O
+for	POS	O
+agoraphobia	POS	B-NP
+with	POS	O
+panic	POS	B-NP
+attacks	POS	I-NP
+or	POS	O
+panic	POS	B-NP
+disorder	POS	I-NP
+.	POS	O
+Caffeine	POS	O
+produced	POS	O
+significantly	POS	O
+greater	POS	O
+increases	POS	O
+in	POS	O
+subject	POS	O
+-	POS	O
+rated	POS	O
+anxiety	POS	B-NP
+,	POS	O
+nervousness	POS	B-NP
+,	POS	O
+fear	POS	B-NP
+,	POS	O
+nausea	POS	B-NP
+,	POS	O
+palpitations	POS	B-NP
+,	POS	O
+restlessness	POS	B-NP
+,	POS	O
+and	POS	O
+tremors	POS	B-NP
+in	POS	O
+the	POS	O
+patients	POS	O
+compared	POS	O
+with	POS	O
+healthy	POS	O
+subjects	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+patients	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+the	POS	O
+healthy	POS	O
+subjects	POS	O
+,	POS	O
+these	POS	O
+symptoms	POS	O
+were	POS	O
+significantly	POS	O
+correlated	POS	O
+with	POS	O
+plasma	POS	O
+caffeine	POS	O
+levels	POS	O
+.	POS	O
+Seventy	POS	O
+-	POS	O
+one	POS	O
+percent	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+reported	POS	O
+that	POS	O
+the	POS	O
+behavioral	POS	O
+effects	POS	O
+of	POS	O
+caffeine	POS	O
+were	POS	O
+similar	POS	O
+to	POS	O
+those	POS	O
+experienced	POS	O
+during	POS	O
+panic	POS	B-NP
+attacks	POS	I-NP
+.	POS	O
+Caffeine	POS	O
+did	POS	O
+not	POS	O
+alter	POS	O
+plasma	POS	O
+MHPG	POS	O
+levels	POS	O
+in	POS	O
+either	POS	O
+the	POS	O
+healthy	POS	O
+subjects	POS	O
+or	POS	O
+patients	POS	O
+.	POS	O
+Caffeine	POS	O
+increased	POS	O
+plasma	POS	O
+cortisol	POS	O
+levels	POS	O
+equally	POS	O
+in	POS	O
+the	POS	O
+patient	POS	O
+and	POS	O
+healthy	POS	O
+groups	POS	O
+.	POS	O
+Because	POS	O
+caffeine	POS	O
+is	POS	O
+an	POS	O
+adenosine	POS	O
+receptor	POS	O
+antagonist	POS	O
+,	POS	O
+these	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+some	POS	O
+panic	POS	B-NP
+disorder	POS	I-NP
+patients	POS	O
+may	POS	O
+have	POS	O
+abnormalities	POS	O
+in	POS	O
+neuronal	POS	O
+systems	POS	O
+involving	POS	O
+adenosine	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+anxiety	POS	B-NP
+disorders	POS	I-NP
+may	POS	O
+benefit	POS	O
+by	POS	O
+avoiding	POS	O
+caffeine	POS	O
+-	POS	O
+containing	POS	O
+foods	POS	O
+and	POS	O
+beverages	POS	O
+.	POS	O
+Comparison	POS	O
+of	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+oxitropium	POS	O
+bromide	POS	O
+and	POS	O
+of	POS	O
+slow	POS	O
+-	POS	O
+release	POS	O
+theophylline	POS	O
+on	POS	O
+nocturnal	POS	O
+asthma	POS	B-NP
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+a	POS	O
+new	POS	O
+inhaled	POS	O
+antimuscarinic	POS	O
+drug	POS	O
+,	POS	O
+oxitropium	POS	O
+bromide	POS	O
+,	POS	O
+and	POS	O
+of	POS	O
+a	POS	O
+slow	POS	O
+-	POS	O
+release	POS	O
+theophylline	POS	O
+preparation	POS	O
+upon	POS	O
+nocturnal	POS	O
+asthma	POS	B-NP
+were	POS	O
+compared	POS	O
+in	POS	O
+a	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+study	POS	O
+.	POS	O
+Two	POS	O
+samples	POS	O
+were	POS	O
+studied	POS	O
+:	POS	O
+12	POS	O
+patients	POS	O
+received	POS	O
+oxitropium	POS	O
+at	POS	O
+600	POS	O
+micrograms	POS	O
+(	POS	O
+6	POS	O
+subjects	POS	O
+)	POS	O
+or	POS	O
+at	POS	O
+400	POS	O
+micrograms	POS	O
+t	POS	O
+.	POS	O
+i	POS	O
+.	POS	O
+d	POS	O
+.	POS	O
+(	POS	O
+6	POS	O
+subjects	POS	O
+)	POS	O
+whereas	POS	O
+11	POS	O
+received	POS	O
+theophylline	POS	O
+at	POS	O
+300	POS	O
+mg	POS	O
+b	POS	O
+.	POS	O
+i	POS	O
+.	POS	O
+d	POS	O
+.	POS	O
+Morning	POS	O
+dipping	POS	O
+,	POS	O
+assessed	POS	O
+by	POS	O
+the	POS	O
+fall	POS	O
+in	POS	O
+peak	POS	O
+flow	POS	O
+overnight	POS	O
+,	POS	O
+was	POS	O
+significantly	POS	O
+reduced	POS	O
+in	POS	O
+the	POS	O
+periods	POS	O
+when	POS	O
+either	POS	O
+active	POS	O
+drug	POS	O
+was	POS	O
+taken	POS	O
+,	POS	O
+whereas	POS	O
+no	POS	O
+difference	POS	O
+was	POS	O
+noticed	POS	O
+during	POS	O
+the	POS	O
+placebo	POS	O
+administration	POS	O
+.	POS	O
+No	POS	O
+significant	POS	O
+difference	POS	O
+was	POS	O
+noticed	POS	O
+between	POS	O
+results	POS	O
+obtained	POS	O
+with	POS	O
+either	POS	O
+active	POS	O
+drug	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+with	POS	O
+either	POS	O
+dosage	POS	O
+of	POS	O
+oxitropium	POS	O
+.	POS	O
+No	POS	O
+subject	POS	O
+reported	POS	O
+side	POS	O
+effects	POS	O
+of	POS	O
+oxitropium	POS	O
+,	POS	O
+as	POS	O
+compared	POS	O
+to	POS	O
+three	POS	O
+subjects	POS	O
+reporting	POS	O
+nausea	POS	B-NP
+,	POS	O
+vomiting	POS	B-NP
+and	POS	O
+tremors	POS	B-NP
+after	POS	O
+theophylline	POS	O
+.	POS	O
+Oxitropium	POS	O
+proves	POS	O
+to	POS	O
+be	POS	O
+a	POS	O
+valuable	POS	O
+alternative	POS	O
+to	POS	O
+theophylline	POS	O
+in	POS	O
+nocturnal	POS	B-NP
+asthma	POS	I-NP
+,	POS	O
+since	POS	O
+it	POS	O
+is	POS	O
+equally	POS	O
+potent	POS	O
+,	POS	O
+safer	POS	O
+and	POS	O
+does	POS	O
+not	POS	O
+require	POS	O
+the	POS	O
+titration	POS	O
+of	POS	O
+dosage	POS	O
+.	POS	O
+Penicillin	POS	O
+anaphylaxis	POS	B-NP
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+oral	POS	O
+penicillin	POS	O
+anaphylaxis	POS	B-NP
+is	POS	O
+described	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+terminology	POS	O
+,	POS	O
+occurrence	POS	O
+,	POS	O
+clinical	POS	O
+manifestations	POS	O
+,	POS	O
+pathogenesis	POS	O
+,	POS	O
+prevention	POS	O
+,	POS	O
+and	POS	O
+treatment	POS	O
+of	POS	O
+anaphylaxis	POS	B-NP
+are	POS	O
+reviewed	POS	O
+.	POS	O
+Emergency	POS	O
+physicians	POS	O
+should	POS	O
+be	POS	O
+aware	POS	O
+of	POS	O
+oral	POS	O
+penicillin	POS	O
+anaphylaxis	POS	B-NP
+in	POS	O
+order	POS	O
+to	POS	O
+prevent	POS	O
+its	POS	O
+occurrence	POS	O
+by	POS	O
+prescribing	POS	O
+the	POS	O
+antibiotic	POS	O
+judiciously	POS	O
+and	POS	O
+knowledgeably	POS	O
+and	POS	O
+to	POS	O
+offer	POS	O
+optimal	POS	O
+medical	POS	O
+therapy	POS	O
+once	POS	O
+this	POS	O
+life	POS	O
+-	POS	O
+threatening	POS	O
+reaction	POS	O
+has	POS	O
+begun	POS	O
+.	POS	O
+Reversible	POS	O
+valproic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+dementia	POS	B-NP
+:	POS	O
+a	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+Reversible	POS	O
+valproic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+dementia	POS	B-NP
+was	POS	O
+documented	POS	O
+in	POS	O
+a	POS	O
+21	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+with	POS	O
+epilepsy	POS	B-NP
+who	POS	O
+had	POS	O
+a	POS	O
+3	POS	O
+-	POS	O
+year	POS	O
+history	POS	O
+of	POS	O
+insidious	POS	O
+progressive	POS	O
+decline	POS	O
+in	POS	O
+global	POS	O
+cognitive	POS	O
+abilities	POS	O
+documented	POS	O
+by	POS	O
+serial	POS	O
+neuropsychological	POS	O
+studies	POS	O
+.	POS	O
+Repeat	POS	O
+neuropsychological	POS	O
+testing	POS	O
+7	POS	O
+weeks	POS	O
+after	POS	O
+discontinuation	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+revealed	POS	O
+dramatic	POS	O
+improvement	POS	O
+in	POS	O
+IQ	POS	O
+,	POS	O
+memory	POS	O
+,	POS	O
+naming	POS	O
+,	POS	O
+and	POS	O
+other	POS	O
+tasks	POS	O
+commensurate	POS	O
+with	POS	O
+clinical	POS	O
+recovery	POS	O
+in	POS	O
+his	POS	O
+intellectual	POS	O
+capacity	POS	O
+.	POS	O
+Possible	POS	O
+pathophysiological	POS	O
+mechanisms	POS	O
+which	POS	O
+may	POS	O
+have	POS	O
+been	POS	O
+operative	POS	O
+in	POS	O
+this	POS	O
+case	POS	O
+include	POS	O
+:	POS	O
+a	POS	O
+direct	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+(	POS	O
+CNS	POS	O
+)	POS	O
+toxic	POS	O
+effect	POS	O
+of	POS	O
+valproic	POS	O
+acid	POS	O
+;	POS	O
+a	POS	O
+paradoxical	POS	O
+epileptogenic	POS	O
+effect	POS	O
+secondary	POS	O
+to	POS	O
+the	POS	O
+drug	POS	O
+;	POS	O
+and	POS	O
+an	POS	O
+indirect	POS	O
+CNS	POS	O
+toxic	POS	O
+effect	POS	O
+mediated	POS	O
+through	POS	O
+valproic	POS	O
+acid	POS	O
+-	POS	O
+induced	POS	O
+hyperammonemia	POS	B-NP
+.	POS	O
+Reversal	POS	O
+of	POS	O
+scopolamine	POS	O
+-	POS	O
+induced	POS	O
+amnesia	POS	B-NP
+of	POS	O
+passive	POS	O
+avoidance	POS	O
+by	POS	O
+pre	POS	O
+-	POS	O
+and	POS	O
+post	POS	O
+-	POS	O
+training	POS	O
+naloxone	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+series	POS	O
+of	POS	O
+five	POS	O
+experiments	POS	O
+,	POS	O
+the	POS	O
+modulating	POS	O
+role	POS	O
+of	POS	O
+naloxone	POS	O
+on	POS	O
+a	POS	O
+scopolamine	POS	O
+-	POS	O
+induced	POS	O
+retention	POS	O
+deficit	POS	O
+in	POS	O
+a	POS	O
+passive	POS	O
+avoidance	POS	O
+paradigm	POS	O
+was	POS	O
+investigated	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+Scopolamine	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+methyl	POS	O
+scopolamine	POS	O
+(	POS	O
+1	POS	O
+and	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+,	POS	O
+induced	POS	O
+an	POS	O
+amnesia	POS	B-NP
+as	POS	O
+measured	POS	O
+by	POS	O
+latency	POS	O
+and	POS	O
+duration	POS	O
+parameters	POS	O
+.	POS	O
+Naloxone	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+,	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+,	POS	O
+and	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+injected	POS	O
+prior	POS	O
+to	POS	O
+training	POS	O
+attenuated	POS	O
+the	POS	O
+retention	POS	O
+deficit	POS	O
+with	POS	O
+a	POS	O
+peak	POS	O
+of	POS	O
+activity	POS	O
+at	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+The	POS	O
+effect	POS	O
+of	POS	O
+naloxone	POS	O
+could	POS	O
+be	POS	O
+antagonized	POS	O
+with	POS	O
+morphine	POS	O
+(	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+,	POS	O
+and	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+,	POS	O
+demonstrating	POS	O
+the	POS	O
+opioid	POS	O
+specificity	POS	O
+of	POS	O
+the	POS	O
+naloxone	POS	O
+effect	POS	O
+.	POS	O
+Post	POS	O
+-	POS	O
+training	POS	O
+administration	POS	O
+of	POS	O
+naloxone	POS	O
+(	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+as	POS	O
+a	POS	O
+single	POS	O
+or	POS	O
+as	POS	O
+a	POS	O
+split	POS	O
+dose	POS	O
+also	POS	O
+attenuated	POS	O
+the	POS	O
+scopolamine	POS	O
+-	POS	O
+induced	POS	O
+amnesia	POS	B-NP
+.	POS	O
+Control	POS	O
+experiments	POS	O
+indicated	POS	O
+that	POS	O
+neither	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+pain	POS	B-NP
+sensitivity	POS	O
+(	POS	O
+pre	POS	O
+-	POS	O
+training	POS	O
+naloxone	POS	O
+)	POS	O
+nor	POS	O
+an	POS	O
+induced	POS	O
+aversive	POS	O
+state	POS	O
+(	POS	O
+post	POS	O
+-	POS	O
+training	POS	O
+naloxone	POS	O
+)	POS	O
+appear	POS	O
+to	POS	O
+be	POS	O
+responsible	POS	O
+for	POS	O
+the	POS	O
+influence	POS	O
+of	POS	O
+naloxone	POS	O
+on	POS	O
+the	POS	O
+scopolamine	POS	O
+-	POS	O
+induced	POS	O
+retention	POS	B-NP
+deficit	POS	I-NP
+.	POS	O
+These	POS	O
+results	POS	O
+extend	POS	O
+previous	POS	O
+findings	POS	O
+implicating	POS	O
+a	POS	O
+cholinergic	POS	O
+-	POS	O
+opioid	POS	O
+interaction	POS	O
+in	POS	O
+memory	POS	O
+processes	POS	O
+.	POS	O
+A	POS	O
+possible	POS	O
+mechanism	POS	O
+for	POS	O
+this	POS	O
+interaction	POS	O
+involving	POS	O
+the	POS	O
+septo	POS	O
+-	POS	O
+hippocampal	POS	O
+cholinergic	POS	O
+pathway	POS	O
+is	POS	O
+discussed	POS	O
+.	POS	O
+Electron	POS	O
+microscopic	POS	O
+investigations	POS	O
+of	POS	O
+the	POS	O
+cyclophosphamide	POS	O
+-	POS	O
+induced	POS	O
+lesions	POS	O
+of	POS	O
+the	POS	O
+urinary	POS	O
+bladder	POS	O
+of	POS	O
+the	POS	O
+rat	POS	O
+and	POS	O
+their	POS	O
+prevention	POS	O
+by	POS	O
+mesna	POS	O
+.	POS	O
+Fully	POS	O
+developed	POS	O
+cyclophosphamide	POS	O
+-	POS	O
+induced	POS	O
+cystitis	POS	B-NP
+is	POS	O
+characterized	POS	O
+by	POS	O
+nearly	POS	O
+complete	POS	O
+detachment	POS	B-NP
+of	POS	I-NP
+the	POS	I-NP
+urothelium	POS	I-NP
+,	POS	O
+severe	POS	O
+submucosal	POS	B-NP
+edema	POS	I-NP
+owing	POS	O
+to	POS	O
+damage	POS	O
+to	POS	O
+the	POS	O
+microvascular	POS	O
+bed	POS	O
+and	POS	O
+focal	POS	O
+muscle	POS	B-NP
+necroses	POS	I-NP
+.	POS	O
+The	POS	O
+initial	POS	O
+response	POS	O
+to	POS	O
+the	POS	O
+primary	POS	O
+attack	POS	O
+by	POS	O
+the	POS	O
+cyclophosphamide	POS	O
+metabolites	POS	O
+seems	POS	O
+to	POS	O
+be	POS	O
+fragmentation	POS	O
+of	POS	O
+the	POS	O
+luminal	POS	O
+membrane	POS	O
+.	POS	O
+This	POS	O
+damages	POS	O
+the	POS	O
+cellular	POS	O
+barrier	POS	O
+against	POS	O
+the	POS	O
+hypertonic	POS	O
+urine	POS	O
+.	POS	O
+Subsequent	POS	O
+breaks	POS	O
+in	POS	O
+the	POS	O
+lateral	POS	O
+cell	POS	O
+membranes	POS	O
+of	POS	O
+the	POS	O
+superficial	POS	O
+cells	POS	O
+and	POS	O
+in	POS	O
+all	POS	O
+the	POS	O
+plasma	POS	O
+membranes	POS	O
+of	POS	O
+the	POS	O
+intermediate	POS	O
+and	POS	O
+basal	POS	O
+cells	POS	O
+,	POS	O
+intercellular	POS	O
+and	POS	O
+intracellular	POS	O
+edema	POS	B-NP
+and	POS	O
+disintegration	POS	O
+of	POS	O
+the	POS	O
+desmosomes	POS	O
+and	POS	O
+hemidesmosomes	POS	O
+lead	POS	O
+to	POS	O
+progressive	POS	O
+degeneration	POS	O
+and	POS	O
+detachment	POS	O
+of	POS	O
+the	POS	O
+epithelial	POS	O
+cells	POS	O
+with	POS	O
+exposure	POS	O
+and	POS	O
+splitting	POS	O
+of	POS	O
+the	POS	O
+basal	POS	O
+membrane	POS	O
+.	POS	O
+The	POS	O
+morphological	POS	O
+changes	POS	O
+of	POS	O
+the	POS	O
+endothelial	POS	O
+cells	POS	O
+,	POS	O
+which	POS	O
+become	POS	O
+more	POS	O
+pronounced	POS	O
+in	POS	O
+the	POS	O
+later	POS	O
+stages	POS	O
+of	POS	O
+the	POS	O
+experiment	POS	O
+,	POS	O
+the	POS	O
+involvement	POS	O
+of	POS	O
+blood	POS	O
+vessels	POS	O
+regardless	POS	O
+of	POS	O
+their	POS	O
+diameter	POS	O
+and	POS	O
+the	POS	O
+location	POS	O
+-	POS	O
+dependent	POS	O
+extent	POS	O
+of	POS	O
+the	POS	O
+damage	POS	O
+indicate	POS	O
+a	POS	O
+direct	POS	O
+type	POS	O
+of	POS	O
+damage	POS	O
+which	POS	O
+is	POS	O
+preceded	POS	O
+by	POS	O
+a	POS	O
+mediator	POS	O
+-	POS	O
+induced	POS	O
+increase	POS	O
+in	POS	O
+permeability	POS	O
+,	POS	O
+the	POS	O
+morphological	POS	O
+correlate	POS	O
+of	POS	O
+which	POS	O
+is	POS	O
+the	POS	O
+formation	POS	O
+of	POS	O
+gaps	POS	O
+in	POS	O
+the	POS	O
+interendothelial	POS	O
+cell	POS	O
+connections	POS	O
+on	POS	O
+the	POS	O
+venules	POS	O
+.	POS	O
+These	POS	O
+changes	POS	O
+can	POS	O
+be	POS	O
+effectively	POS	O
+prevented	POS	O
+by	POS	O
+mesna	POS	O
+.	POS	O
+The	POS	O
+only	POS	O
+sign	POS	O
+of	POS	O
+a	POS	O
+possible	POS	O
+involvement	POS	O
+is	POS	O
+the	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+specific	POS	O
+granules	POS	O
+with	POS	O
+a	POS	O
+presumed	POS	O
+lysosomal	POS	O
+function	POS	O
+in	POS	O
+the	POS	O
+superficial	POS	O
+cells	POS	O
+.	POS	O
+Increase	POS	O
+in	POS	O
+intragastric	POS	O
+pressure	POS	O
+during	POS	O
+suxamethonium	POS	O
+-	POS	O
+induced	POS	O
+muscle	POS	B-NP
+fasciculations	POS	I-NP
+in	POS	O
+children	POS	O
+:	POS	O
+inhibition	POS	O
+by	POS	O
+alfentanil	POS	O
+.	POS	O
+Changes	POS	O
+in	POS	O
+intragastric	POS	O
+pressure	POS	O
+after	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+suxamethonium	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+were	POS	O
+studied	POS	O
+in	POS	O
+32	POS	O
+children	POS	O
+(	POS	O
+mean	POS	O
+age	POS	O
+6	POS	O
+.	POS	O
+9	POS	O
+yr	POS	O
+)	POS	O
+pretreated	POS	O
+with	POS	O
+either	POS	O
+physiological	POS	O
+saline	POS	O
+or	POS	O
+alfentanil	POS	O
+50	POS	O
+micrograms	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+Anaesthesia	POS	B-NP
+was	POS	O
+induced	POS	O
+with	POS	O
+thiopentone	POS	O
+5	POS	O
+mg	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+and	POS	O
+intensity	POS	O
+of	POS	O
+muscle	POS	B-NP
+fasciculations	POS	I-NP
+caused	POS	O
+by	POS	O
+suxamethonium	POS	O
+were	POS	O
+significantly	POS	O
+greater	POS	O
+in	POS	O
+the	POS	O
+control	POS	O
+than	POS	O
+in	POS	O
+the	POS	O
+alfentanil	POS	O
+group	POS	O
+.	POS	O
+The	POS	O
+intragastric	POS	O
+pressure	POS	O
+during	POS	O
+muscle	POS	B-NP
+fasciculations	POS	I-NP
+was	POS	O
+significantly	POS	O
+higher	POS	O
+in	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+(	POS	O
+16	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+(	POS	O
+SEM	POS	O
+)	POS	O
+cm	POS	O
+H2O	POS	O
+)	POS	O
+than	POS	O
+in	POS	O
+the	POS	O
+alfentanil	POS	O
+group	POS	O
+(	POS	O
+7	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+(	POS	O
+SEM	POS	O
+)	POS	O
+cm	POS	O
+H2O	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+increase	POS	O
+in	POS	O
+intragastric	POS	O
+pressure	POS	O
+was	POS	O
+directly	POS	O
+related	POS	O
+to	POS	O
+the	POS	O
+intensity	POS	O
+of	POS	O
+muscle	POS	B-NP
+fasciculations	POS	I-NP
+(	POS	O
+regression	POS	O
+line	POS	O
+:	POS	O
+y	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
++	POS	O
+4	POS	O
+.	POS	O
+78x	POS	O
+with	POS	O
+r	POS	O
+of	POS	O
+0	POS	O
+.	POS	O
+78	POS	O
+)	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+concluded	POS	O
+that	POS	O
+intragastric	POS	O
+pressure	POS	O
+increases	POS	O
+significantly	POS	O
+during	POS	O
+muscle	POS	B-NP
+fasciculations	POS	I-NP
+caused	POS	O
+by	POS	O
+suxamethonium	POS	O
+in	POS	O
+healthy	POS	O
+children	POS	O
+.	POS	O
+Alfentanil	POS	O
+50	POS	O
+micrograms	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+effectively	POS	O
+inhibits	POS	O
+the	POS	O
+incidence	POS	O
+and	POS	O
+intensity	POS	O
+of	POS	O
+suxamethonium	POS	O
+-	POS	O
+induced	POS	O
+muscle	POS	B-NP
+fasciculations	POS	I-NP
+;	POS	O
+moreover	POS	O
+,	POS	O
+intragastric	POS	O
+pressure	POS	O
+remains	POS	O
+at	POS	O
+its	POS	O
+control	POS	O
+value	POS	O
+.	POS	O
+Acute	POS	O
+insulin	POS	O
+treatment	POS	O
+normalizes	POS	O
+the	POS	O
+resistance	POS	O
+to	POS	O
+the	POS	O
+cardiotoxic	POS	B-NP
+effect	POS	O
+of	POS	O
+isoproterenol	POS	O
+in	POS	O
+streptozotocin	POS	O
+diabetic	POS	O
+rats	POS	O
+.	POS	O
+A	POS	O
+morphometric	POS	O
+study	POS	O
+of	POS	O
+isoproterenol	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+fibrosis	POS	I-NP
+.	POS	O
+The	POS	O
+acute	POS	O
+effect	POS	O
+of	POS	O
+insulin	POS	O
+treatment	POS	O
+on	POS	O
+the	POS	O
+earlier	POS	O
+reported	POS	O
+protective	POS	O
+effect	POS	O
+of	POS	O
+streptozotocin	POS	O
+diabetes	POS	B-NP
+against	POS	O
+the	POS	O
+cardiotoxic	POS	B-NP
+effect	POS	O
+of	POS	O
+high	POS	O
+doses	POS	O
+of	POS	O
+isoproterenol	POS	O
+(	POS	O
+ISO	POS	O
+)	POS	O
+was	POS	O
+investigated	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+Thirty	POS	O
+to	POS	O
+135	POS	O
+min	POS	O
+after	POS	O
+the	POS	O
+injection	POS	O
+of	POS	O
+crystalline	POS	O
+insulin	POS	O
+,	POS	O
+ISO	POS	O
+was	POS	O
+given	POS	O
+subcutaneously	POS	O
+and	POS	O
+when	POS	O
+ISO	POS	O
+induced	POS	O
+fibrosis	POS	B-NP
+in	POS	O
+the	POS	O
+myocardium	POS	O
+was	POS	O
+morphometrically	POS	O
+analyzed	POS	O
+7	POS	O
+days	POS	O
+later	POS	O
+,	POS	O
+a	POS	O
+highly	POS	O
+significant	POS	O
+correlation	POS	O
+(	POS	O
+r	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+83	POS	O
+,	POS	O
+2	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+006	POS	O
+)	POS	O
+to	POS	O
+the	POS	O
+slope	POS	O
+of	POS	O
+the	POS	O
+fall	POS	O
+in	POS	O
+blood	POS	O
+glucose	POS	O
+after	POS	O
+insulin	POS	O
+treatment	POS	O
+appeared	POS	O
+.	POS	O
+The	POS	O
+myocardial	POS	O
+content	POS	O
+of	POS	O
+catecholamines	POS	O
+was	POS	O
+estimated	POS	O
+in	POS	O
+these	POS	O
+8	POS	O
+day	POS	O
+diabetic	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+norepinephrine	POS	O
+content	POS	O
+was	POS	O
+significantly	POS	O
+increased	POS	O
+while	POS	O
+epinephrine	POS	O
+remained	POS	O
+unchanged	POS	O
+.	POS	O
+An	POS	O
+enhanced	POS	O
+sympathetic	POS	O
+nervous	POS	O
+system	POS	O
+activity	POS	O
+with	POS	O
+a	POS	O
+consequent	POS	O
+down	POS	O
+regulation	POS	O
+of	POS	O
+the	POS	O
+myocardial	POS	O
+beta	POS	O
+-	POS	O
+adrenergic	POS	O
+receptors	POS	O
+could	POS	O
+,	POS	O
+therefore	POS	O
+,	POS	O
+explain	POS	O
+this	POS	O
+catecholamine	POS	O
+resistance	POS	O
+.	POS	O
+The	POS	O
+rapid	POS	O
+reversion	POS	O
+after	POS	O
+insulin	POS	O
+treatment	POS	O
+excludes	POS	O
+the	POS	O
+possibility	POS	O
+that	POS	O
+streptozotocin	POS	O
+in	POS	O
+itself	POS	O
+causes	POS	O
+the	POS	O
+ISO	POS	O
+resistance	POS	O
+and	POS	O
+points	POS	O
+towards	POS	O
+a	POS	O
+direct	POS	O
+insulin	POS	O
+effect	POS	O
+on	POS	O
+myocardial	POS	O
+catecholamine	POS	O
+sensitivity	POS	O
+in	POS	O
+diabetic	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+phenomenon	POS	O
+described	POS	O
+might	POS	O
+elucidate	POS	O
+pathogenetic	POS	O
+mechanisms	POS	O
+behind	POS	O
+toxic	POS	O
+myocardial	POS	B-NP
+cell	POS	I-NP
+degeneration	POS	I-NP
+and	POS	O
+may	POS	O
+possibly	POS	O
+have	POS	O
+relevance	POS	O
+for	POS	O
+acute	POS	O
+cardiovascular	POS	O
+complications	POS	O
+in	POS	O
+diabetic	POS	B-NP
+patients	POS	O
+.	POS	O
+Differential	POS	O
+effects	POS	O
+of	POS	O
+non	POS	O
+-	POS	O
+steroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+on	POS	O
+seizures	POS	B-NP
+produced	POS	O
+by	POS	O
+pilocarpine	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+muscarinic	POS	O
+cholinergic	POS	O
+agonist	POS	O
+pilocarpine	POS	O
+induces	POS	O
+in	POS	O
+rats	POS	O
+seizures	POS	B-NP
+and	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+followed	POS	O
+by	POS	O
+widespread	POS	O
+damage	POS	O
+to	POS	O
+the	POS	O
+forebrain	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+designed	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+5	POS	O
+non	POS	O
+-	POS	O
+steroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+,	POS	O
+sodium	POS	O
+salicylate	POS	O
+,	POS	O
+phenylbutazone	POS	O
+,	POS	O
+indomethacin	POS	O
+,	POS	O
+ibuprofen	POS	O
+and	POS	O
+mefenamic	POS	O
+acid	POS	O
+,	POS	O
+on	POS	O
+seizures	POS	B-NP
+produced	POS	O
+by	POS	O
+pilocarpine	POS	O
+.	POS	O
+Pretreatment	POS	O
+of	POS	O
+rats	POS	O
+with	POS	O
+sodium	POS	O
+salicylate	POS	O
+,	POS	O
+ED50	POS	O
+103	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+60	POS	O
+-	POS	O
+174	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+phenylbutazone	POS	O
+,	POS	O
+59	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+50	POS	O
+-	POS	O
+70	POS	O
+)	POS	O
+converted	POS	O
+the	POS	O
+non	POS	O
+-	POS	O
+convulsant	POS	O
+dose	POS	O
+of	POS	O
+pilocarpine	POS	O
+,	POS	O
+200	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+to	POS	O
+a	POS	O
+convulsant	POS	O
+one	POS	O
+.	POS	O
+Indomethacin	POS	O
+,	POS	O
+1	POS	O
+-	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+and	POS	O
+ibuprofen	POS	O
+,	POS	O
+10	POS	O
+-	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+failed	POS	O
+to	POS	O
+modulate	POS	O
+seizures	POS	B-NP
+produced	POS	O
+by	POS	O
+pilocarpine	POS	O
+.	POS	O
+Mefenamic	POS	O
+acid	POS	O
+,	POS	O
+26	POS	O
+(	POS	O
+22	POS	O
+-	POS	O
+30	POS	O
+)	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+prevented	POS	O
+seizures	POS	B-NP
+and	POS	O
+protected	POS	O
+rats	POS	O
+from	POS	O
+seizure	POS	B-NP
+-	POS	O
+related	POS	O
+brain	POS	B-NP
+damage	POS	I-NP
+induced	POS	O
+by	POS	O
+pilocarpine	POS	O
+,	POS	O
+380	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+non	POS	O
+-	POS	O
+steroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drugs	POS	O
+differentially	POS	O
+modulate	POS	O
+the	POS	O
+threshold	POS	O
+for	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+.	POS	O
+Acute	POS	B-NP
+neurologic	POS	I-NP
+dysfunction	POS	I-NP
+after	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+etoposide	POS	O
+therapy	POS	O
+for	POS	O
+malignant	POS	B-NP
+glioma	POS	I-NP
+.	POS	O
+Etoposide	POS	O
+(	POS	O
+VP	POS	O
+-	POS	O
+16	POS	O
+-	POS	O
+213	POS	O
+)	POS	O
+has	POS	O
+been	POS	O
+used	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+many	POS	O
+solid	POS	O
+tumors	POS	B-NP
+and	POS	O
+hematologic	POS	B-NP
+malignancies	POS	I-NP
+.	POS	O
+When	POS	O
+used	POS	O
+in	POS	O
+high	POS	O
+doses	POS	O
+and	POS	O
+in	POS	O
+conjunction	POS	O
+with	POS	O
+autologous	POS	O
+bone	POS	O
+marrow	POS	O
+transplantation	POS	O
+,	POS	O
+this	POS	O
+agent	POS	O
+has	POS	O
+activity	POS	O
+against	POS	O
+several	POS	O
+treatment	POS	O
+-	POS	O
+resistant	POS	O
+cancers	POS	B-NP
+including	POS	O
+malignant	POS	B-NP
+glioma	POS	I-NP
+.	POS	O
+In	POS	O
+six	POS	O
+of	POS	O
+eight	POS	O
+patients	POS	O
+(	POS	O
+75	POS	O
+%	POS	O
+)	POS	O
+who	POS	O
+we	POS	O
+treated	POS	O
+for	POS	O
+recurrent	POS	O
+or	POS	O
+resistant	POS	O
+glioma	POS	B-NP
+,	POS	O
+sudden	POS	O
+severe	POS	O
+neurologic	POS	B-NP
+deterioration	POS	I-NP
+occurred	POS	O
+.	POS	O
+This	POS	O
+developed	POS	O
+a	POS	O
+median	POS	O
+of	POS	O
+9	POS	O
+days	POS	O
+after	POS	O
+initiation	POS	O
+of	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+etoposide	POS	O
+therapy	POS	O
+.	POS	O
+Significant	POS	O
+clinical	POS	O
+manifestations	POS	O
+have	POS	O
+included	POS	O
+confusion	POS	B-NP
+,	POS	O
+papilledema	POS	B-NP
+,	POS	O
+somnolence	POS	B-NP
+,	POS	O
+exacerbation	POS	B-NP
+of	POS	I-NP
+motor	POS	I-NP
+deficits	POS	I-NP
+,	POS	O
+and	POS	O
+sharp	POS	O
+increase	POS	O
+in	POS	O
+seizure	POS	B-NP
+activity	POS	O
+.	POS	O
+These	POS	O
+abnormalities	POS	O
+resolved	POS	O
+rapidly	POS	O
+after	POS	O
+initiation	POS	O
+of	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+intravenous	POS	O
+dexamethasone	POS	O
+therapy	POS	O
+.	POS	O
+In	POS	O
+all	POS	O
+patients	POS	O
+,	POS	O
+computerized	POS	O
+tomographic	POS	O
+(	POS	O
+CT	POS	O
+)	POS	O
+brain	POS	O
+scans	POS	O
+demonstrated	POS	O
+stability	POS	O
+in	POS	O
+tumor	POS	B-NP
+size	POS	O
+and	POS	O
+peritumor	POS	B-NP
+edema	POS	I-NP
+when	POS	O
+compared	POS	O
+with	POS	O
+pretransplant	POS	O
+scans	POS	O
+.	POS	O
+This	POS	O
+complication	POS	O
+appears	POS	O
+to	POS	O
+represent	POS	O
+a	POS	O
+significant	POS	O
+new	POS	O
+toxicity	POS	B-NP
+of	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+etoposide	POS	O
+therapy	POS	O
+for	POS	O
+malignant	POS	B-NP
+glioma	POS	I-NP
+.	POS	O
+Progressive	POS	B-NP
+bile	POS	I-NP
+duct	POS	I-NP
+injury	POS	I-NP
+after	POS	O
+thiabendazole	POS	O
+administration	POS	O
+.	POS	O
+A	POS	O
+27	POS	O
+-	POS	O
+yr	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+developed	POS	O
+jaundice	POS	B-NP
+2	POS	O
+wk	POS	O
+after	POS	O
+exposure	POS	O
+to	POS	O
+thiabendazole	POS	O
+.	POS	O
+Cholestasis	POS	B-NP
+persisted	POS	O
+for	POS	O
+3	POS	O
+yr	POS	O
+,	POS	O
+at	POS	O
+which	POS	O
+time	POS	O
+a	POS	O
+liver	POS	O
+transplant	POS	O
+was	POS	O
+performed	POS	O
+.	POS	O
+Two	POS	O
+liver	POS	O
+biopsy	POS	O
+specimens	POS	O
+and	POS	O
+the	POS	O
+hepatectomy	POS	O
+specimen	POS	O
+were	POS	O
+remarkable	POS	O
+for	POS	O
+almost	POS	O
+complete	POS	O
+disappearance	POS	O
+of	POS	O
+interlobular	POS	O
+bile	POS	O
+ducts	POS	O
+.	POS	O
+Prominent	POS	O
+fibrosis	POS	B-NP
+and	POS	O
+hepatocellular	POS	B-NP
+regeneration	POS	I-NP
+were	POS	O
+also	POS	O
+present	POS	O
+;	POS	O
+however	POS	O
+,	POS	O
+the	POS	O
+lobular	POS	O
+architecture	POS	O
+was	POS	O
+preserved	POS	O
+.	POS	O
+This	POS	O
+case	POS	O
+represents	POS	O
+an	POS	O
+example	POS	O
+of	POS	O
+"	POS	O
+idiosyncratic	POS	O
+"	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+liver	POS	B-NP
+damage	POS	I-NP
+in	POS	O
+which	POS	O
+the	POS	O
+primary	POS	O
+target	POS	O
+of	POS	O
+injury	POS	O
+is	POS	O
+the	POS	O
+bile	POS	O
+duct	POS	O
+.	POS	O
+An	POS	O
+autoimmune	POS	O
+pathogenesis	POS	O
+of	POS	O
+the	POS	O
+bile	POS	O
+duct	POS	O
+destruction	POS	O
+is	POS	O
+suggested	POS	O
+.	POS	O
+Differential	POS	O
+effects	POS	O
+of	POS	O
+1	POS	O
+,	POS	O
+4	POS	O
+-	POS	O
+dihydropyridine	POS	O
+calcium	POS	O
+channel	POS	O
+blockers	POS	O
+:	POS	O
+therapeutic	POS	O
+implications	POS	O
+.	POS	O
+Increasing	POS	O
+recognition	POS	O
+of	POS	O
+the	POS	O
+importance	POS	O
+of	POS	O
+calcium	POS	O
+in	POS	O
+the	POS	O
+pathogenesis	POS	O
+of	POS	O
+cardiovascular	POS	B-NP
+disease	POS	I-NP
+has	POS	O
+stimulated	POS	O
+research	POS	O
+into	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+calcium	POS	O
+channel	POS	O
+blocking	POS	O
+agents	POS	O
+for	POS	O
+treatment	POS	O
+of	POS	O
+a	POS	O
+variety	POS	O
+of	POS	O
+cardiovascular	POS	B-NP
+diseases	POS	I-NP
+.	POS	O
+The	POS	O
+favorable	POS	O
+efficacy	POS	O
+and	POS	O
+tolerability	POS	O
+profiles	POS	O
+of	POS	O
+these	POS	O
+agents	POS	O
+make	POS	O
+them	POS	O
+attractive	POS	O
+therapeutic	POS	O
+modalities	POS	O
+.	POS	O
+Clinical	POS	O
+applications	POS	O
+of	POS	O
+calcium	POS	O
+channel	POS	O
+blockers	POS	O
+parallel	POS	O
+their	POS	O
+tissue	POS	O
+selectivity	POS	O
+.	POS	O
+In	POS	O
+contrast	POS	O
+to	POS	O
+verapamil	POS	O
+and	POS	O
+diltiazem	POS	O
+,	POS	O
+which	POS	O
+are	POS	O
+roughly	POS	O
+equipotent	POS	O
+in	POS	O
+their	POS	O
+actions	POS	O
+on	POS	O
+the	POS	O
+heart	POS	O
+and	POS	O
+vascular	POS	O
+smooth	POS	O
+muscle	POS	O
+,	POS	O
+the	POS	O
+dihydropyridine	POS	O
+calcium	POS	O
+channel	POS	O
+blockers	POS	O
+are	POS	O
+a	POS	O
+group	POS	O
+of	POS	O
+potent	POS	O
+peripheral	POS	O
+vasodilator	POS	O
+agents	POS	O
+that	POS	O
+exert	POS	O
+minimal	POS	O
+electrophysiologic	POS	O
+effects	POS	O
+on	POS	O
+cardiac	POS	O
+nodal	POS	O
+or	POS	O
+conduction	POS	O
+tissue	POS	O
+.	POS	O
+As	POS	O
+the	POS	O
+first	POS	O
+dihydropyridine	POS	O
+available	POS	O
+for	POS	O
+use	POS	O
+in	POS	O
+the	POS	O
+United	POS	O
+States	POS	O
+,	POS	O
+nifedipine	POS	O
+controls	POS	O
+angina	POS	B-NP
+and	POS	O
+hypertension	POS	B-NP
+with	POS	O
+minimal	POS	O
+depression	POS	B-NP
+of	POS	O
+cardiac	POS	B-NP
+function	POS	I-NP
+.	POS	O
+Additional	POS	O
+members	POS	O
+of	POS	O
+this	POS	O
+group	POS	O
+of	POS	O
+calcium	POS	O
+channel	POS	O
+blockers	POS	O
+have	POS	O
+been	POS	O
+studied	POS	O
+for	POS	O
+a	POS	O
+variety	POS	O
+of	POS	O
+indications	POS	O
+for	POS	O
+which	POS	O
+they	POS	O
+may	POS	O
+offer	POS	O
+advantages	POS	O
+over	POS	O
+current	POS	O
+therapy	POS	O
+.	POS	O
+Once	POS	O
+or	POS	O
+twice	POS	O
+daily	POS	O
+dosage	POS	O
+possible	POS	O
+with	POS	O
+nitrendipine	POS	O
+and	POS	O
+nisoldipine	POS	O
+offers	POS	O
+a	POS	O
+convenient	POS	O
+administration	POS	O
+schedule	POS	O
+,	POS	O
+which	POS	O
+encourages	POS	O
+patient	POS	O
+compliance	POS	O
+in	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+therapy	POS	O
+of	POS	O
+hypertension	POS	B-NP
+.	POS	O
+The	POS	O
+coronary	POS	O
+vasodilating	POS	O
+properties	POS	O
+of	POS	O
+nisoldipine	POS	O
+have	POS	O
+led	POS	O
+to	POS	O
+the	POS	O
+investigation	POS	O
+of	POS	O
+this	POS	O
+agent	POS	O
+for	POS	O
+use	POS	O
+in	POS	O
+angina	POS	B-NP
+.	POS	O
+Selectivity	POS	O
+for	POS	O
+the	POS	O
+cerebrovascular	POS	O
+bed	POS	O
+makes	POS	O
+nimodipine	POS	O
+potentially	POS	O
+useful	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+subarachnoid	POS	B-NP
+hemorrhage	POS	I-NP
+,	POS	O
+migraine	POS	B-NP
+headache	POS	I-NP
+,	POS	O
+dementia	POS	B-NP
+,	POS	O
+and	POS	O
+stroke	POS	B-NP
+.	POS	O
+In	POS	O
+general	POS	O
+,	POS	O
+the	POS	O
+dihydropyridine	POS	O
+calcium	POS	O
+channel	POS	O
+blockers	POS	O
+are	POS	O
+usually	POS	O
+well	POS	O
+tolerated	POS	O
+,	POS	O
+with	POS	O
+headache	POS	B-NP
+,	POS	O
+facial	POS	B-NP
+flushing	POS	I-NP
+,	POS	O
+palpitations	POS	B-NP
+,	POS	O
+edema	POS	B-NP
+,	POS	O
+nausea	POS	B-NP
+,	POS	O
+anorexia	POS	B-NP
+,	POS	O
+and	POS	O
+dizziness	POS	B-NP
+being	POS	O
+the	POS	O
+more	POS	O
+common	POS	O
+adverse	POS	O
+effects	POS	O
+.	POS	O
+The	POS	O
+enhancement	POS	O
+of	POS	O
+aminonucleoside	POS	O
+nephrosis	POS	B-NP
+by	POS	O
+the	POS	O
+co	POS	O
+-	POS	O
+administration	POS	O
+of	POS	O
+protamine	POS	O
+.	POS	O
+An	POS	O
+experimental	POS	O
+model	POS	O
+of	POS	O
+focal	POS	O
+segmental	POS	O
+glomerular	POS	B-NP
+sclerosis	POS	I-NP
+(	POS	O
+FSGS	POS	B-NP
+)	POS	O
+was	POS	O
+developed	POS	O
+in	POS	O
+rats	POS	O
+by	POS	O
+the	POS	O
+combined	POS	O
+administration	POS	O
+of	POS	O
+puromycin	POS	O
+-	POS	O
+aminonucleoside	POS	O
+(	POS	O
+AMNS	POS	O
+)	POS	O
+and	POS	O
+protamine	POS	O
+sulfate	POS	O
+(	POS	O
+PS	POS	O
+)	POS	O
+.	POS	O
+Male	POS	O
+Sprague	POS	O
+-	POS	O
+Dawley	POS	O
+rats	POS	O
+,	POS	O
+uninephrectomized	POS	O
+three	POS	O
+weeks	POS	O
+before	POS	O
+,	POS	O
+received	POS	O
+daily	POS	O
+injections	POS	O
+of	POS	O
+subcutaneous	POS	O
+AMNS	POS	O
+(	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+100	POS	O
+g	POS	O
+body	POS	O
+wt	POS	O
+)	POS	O
+and	POS	O
+intravenous	POS	O
+PS	POS	O
+(	POS	O
+2	POS	O
+separated	POS	O
+doses	POS	O
+of	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+100	POS	O
+g	POS	O
+body	POS	O
+wt	POS	O
+)	POS	O
+for	POS	O
+four	POS	O
+days	POS	O
+.	POS	O
+The	POS	O
+series	POS	O
+of	POS	O
+injections	POS	O
+were	POS	O
+repeated	POS	O
+another	POS	O
+three	POS	O
+times	POS	O
+at	POS	O
+10	POS	O
+day	POS	O
+intervals	POS	O
+.	POS	O
+The	POS	O
+animals	POS	O
+were	POS	O
+sacrificed	POS	O
+on	POS	O
+days	POS	O
+24	POS	O
+,	POS	O
+52	POS	O
+,	POS	O
+and	POS	O
+80	POS	O
+.	POS	O
+They	POS	O
+developed	POS	O
+nephrotic	POS	B-NP
+syndrome	POS	I-NP
+and	POS	O
+finally	POS	O
+renal	POS	B-NP
+failure	POS	I-NP
+.	POS	O
+The	POS	O
+time	POS	O
+-	POS	O
+course	POS	O
+curve	POS	O
+of	POS	O
+creatinine	POS	O
+clearance	POS	O
+dropped	POS	O
+and	POS	O
+showed	POS	O
+significant	POS	O
+difference	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+from	POS	O
+that	POS	O
+of	POS	O
+each	POS	O
+control	POS	O
+group	POS	O
+,	POS	O
+such	POS	O
+as	POS	O
+,	POS	O
+AMNS	POS	O
+alone	POS	O
+,	POS	O
+PS	POS	O
+alone	POS	O
+or	POS	O
+saline	POS	O
+injected	POS	O
+.	POS	O
+Their	POS	O
+glomeruli	POS	O
+showed	POS	O
+changes	POS	O
+of	POS	O
+progressive	POS	O
+FSGS	POS	B-NP
+.	POS	O
+The	POS	O
+ultrastructural	POS	O
+studies	POS	O
+in	POS	O
+the	POS	O
+initial	POS	O
+stage	POS	O
+revealed	POS	O
+significant	POS	O
+lack	POS	O
+of	POS	O
+particles	POS	O
+of	POS	O
+perfused	POS	O
+ruthenium	POS	O
+red	POS	O
+on	POS	O
+the	POS	O
+lamina	POS	O
+rara	POS	O
+externa	POS	O
+and	POS	O
+marked	POS	O
+changes	POS	O
+in	POS	O
+epithelial	POS	O
+cell	POS	O
+cytoplasm	POS	O
+.	POS	O
+Therefore	POS	O
+,	POS	O
+it	POS	O
+is	POS	O
+suggested	POS	O
+that	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+PS	POS	O
+enhances	POS	O
+the	POS	O
+toxicity	POS	O
+of	POS	O
+AMNS	POS	O
+on	POS	O
+the	POS	O
+glomerulus	POS	O
+and	POS	O
+readily	POS	O
+produces	POS	O
+progressive	POS	O
+FSGS	POS	B-NP
+in	POS	O
+rats	POS	O
+resulting	POS	O
+in	POS	O
+the	POS	O
+end	POS	O
+-	POS	O
+stage	POS	O
+renal	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+Theophylline	POS	O
+neurotoxicity	POS	B-NP
+in	POS	O
+pregnant	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+this	POS	O
+investigation	POS	O
+was	POS	O
+to	POS	O
+determine	POS	O
+whether	POS	O
+the	POS	O
+neurotoxicity	POS	B-NP
+of	POS	O
+theophylline	POS	O
+is	POS	O
+altered	POS	O
+in	POS	O
+advanced	POS	O
+pregnancy	POS	O
+.	POS	O
+Sprague	POS	O
+-	POS	O
+Dawley	POS	O
+rats	POS	O
+that	POS	O
+were	POS	O
+20	POS	O
+days	POS	O
+pregnant	POS	O
+and	POS	O
+nonpregnant	POS	O
+rats	POS	O
+of	POS	O
+the	POS	O
+same	POS	O
+age	POS	O
+and	POS	O
+strain	POS	O
+received	POS	O
+infusions	POS	O
+of	POS	O
+aminophylline	POS	O
+until	POS	O
+onset	POS	O
+of	POS	O
+maximal	POS	O
+seizures	POS	B-NP
+which	POS	O
+occurred	POS	O
+after	POS	O
+28	POS	O
+and	POS	O
+30	POS	O
+minutes	POS	O
+respectively	POS	O
+.	POS	O
+Theophylline	POS	O
+concentrations	POS	O
+at	POS	O
+this	POS	O
+endpoint	POS	O
+in	POS	O
+serum	POS	O
+(	POS	O
+total	POS	O
+)	POS	O
+and	POS	O
+CSF	POS	O
+were	POS	O
+similar	POS	O
+but	POS	O
+serum	POS	O
+(	POS	O
+free	POS	O
+)	POS	O
+and	POS	O
+brain	POS	O
+concentrations	POS	O
+were	POS	O
+slightly	POS	O
+different	POS	O
+in	POS	O
+pregnant	POS	O
+rats	POS	O
+.	POS	O
+Theophylline	POS	O
+serum	POS	O
+protein	POS	O
+binding	POS	O
+determined	POS	O
+by	POS	O
+equilibrium	POS	O
+dialysis	POS	O
+was	POS	O
+lower	POS	O
+in	POS	O
+pregnant	POS	O
+rats	POS	O
+.	POS	O
+Fetal	POS	O
+serum	POS	O
+concentrations	POS	O
+at	POS	O
+onset	POS	O
+of	POS	O
+seizures	POS	B-NP
+in	POS	O
+the	POS	O
+mother	POS	O
+were	POS	O
+similar	POS	O
+to	POS	O
+maternal	POS	O
+brain	POS	O
+and	POS	O
+CSF	POS	O
+concentrations	POS	O
+and	POS	O
+correlated	POS	O
+significantly	POS	O
+with	POS	O
+the	POS	O
+former	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+concluded	POS	O
+that	POS	O
+advanced	POS	O
+pregnancy	POS	O
+has	POS	O
+a	POS	O
+negligible	POS	O
+effect	POS	O
+on	POS	O
+the	POS	O
+neurotoxic	POS	B-NP
+response	POS	O
+to	POS	O
+theophylline	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+Hyperkalemia	POS	B-NP
+induced	POS	O
+by	POS	O
+indomethacin	POS	O
+and	POS	O
+naproxen	POS	O
+and	POS	O
+reversed	POS	O
+by	POS	O
+fludrocortisone	POS	O
+.	POS	O
+We	POS	O
+have	POS	O
+described	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+severe	POS	O
+rheumatoid	POS	B-NP
+arthritis	POS	I-NP
+and	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+mefenamic	POS	O
+acid	POS	O
+nephropathy	POS	B-NP
+in	POS	O
+whom	POS	O
+hyperkalemia	POS	B-NP
+and	POS	O
+inappropriate	POS	O
+hypoaldosteronism	POS	B-NP
+were	POS	O
+caused	POS	O
+by	POS	O
+both	POS	O
+indomethacin	POS	O
+and	POS	O
+naproxen	POS	O
+,	POS	O
+without	POS	O
+major	POS	O
+decline	POS	O
+in	POS	O
+renal	POS	O
+function	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+likely	POS	O
+that	POS	O
+preexisting	POS	O
+renal	POS	B-NP
+disease	POS	I-NP
+predisposed	POS	O
+this	POS	O
+patient	POS	O
+to	POS	O
+type	POS	B-NP
+IV	POS	I-NP
+renal	POS	I-NP
+tubular	POS	I-NP
+acidosis	POS	I-NP
+with	POS	O
+prostaglandin	POS	O
+synthetase	POS	O
+inhibitors	POS	O
+.	POS	O
+Because	POS	O
+he	POS	O
+was	POS	O
+unable	POS	O
+to	POS	O
+discontinue	POS	O
+nonsteroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+drug	POS	O
+therapy	POS	O
+,	POS	O
+fludrocortisone	POS	O
+was	POS	O
+added	POS	O
+,	POS	O
+correcting	POS	O
+the	POS	O
+hyperkalemia	POS	B-NP
+and	POS	O
+allowing	POS	O
+indomethacin	POS	O
+therapy	POS	O
+to	POS	O
+be	POS	O
+continued	POS	O
+safely	POS	O
+.	POS	O
+Hypotension	POS	B-NP
+as	POS	O
+a	POS	O
+manifestation	POS	O
+of	POS	O
+cardiotoxicity	POS	B-NP
+in	POS	O
+three	POS	O
+patients	POS	O
+receiving	POS	O
+cisplatin	POS	O
+and	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+.	POS	O
+Cardiac	POS	B-NP
+symptoms	POS	I-NP
+,	POS	O
+including	POS	O
+hypotension	POS	B-NP
+,	POS	O
+developed	POS	O
+in	POS	O
+three	POS	O
+patients	POS	O
+with	POS	O
+advanced	POS	O
+colorectal	POS	B-NP
+carcinoma	POS	B-NP
+while	POS	O
+being	POS	O
+treated	POS	O
+with	POS	O
+cisplatin	POS	O
+(	POS	O
+CDDP	POS	O
+)	POS	O
+and	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+(	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+two	POS	O
+patients	POS	O
+,	POS	O
+hypotension	POS	B-NP
+was	POS	O
+associated	POS	O
+with	POS	O
+severe	POS	O
+left	POS	O
+ventricular	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+All	POS	O
+three	POS	O
+patients	POS	O
+required	POS	O
+therapy	POS	O
+discontinuation	POS	O
+.	POS	O
+Cardiac	POS	O
+enzymes	POS	O
+remained	POS	O
+normal	POS	O
+despite	POS	O
+transient	POS	O
+electrocardiographic	POS	O
+(	POS	O
+EKG	POS	O
+)	POS	O
+changes	POS	O
+.	POS	O
+The	POS	O
+presentation	POS	O
+and	POS	O
+cardiac	POS	O
+evaluation	POS	O
+(	POS	O
+hemodynamic	POS	O
+,	POS	O
+echocardiographic	POS	O
+,	POS	O
+and	POS	O
+scintigraphic	POS	O
+)	POS	O
+of	POS	O
+these	POS	O
+patients	POS	O
+suggest	POS	O
+new	POS	O
+manifestations	POS	O
+of	POS	O
+5	POS	O
+-	POS	O
+FU	POS	O
+cardiotoxicity	POS	B-NP
+that	POS	O
+may	POS	O
+be	POS	O
+influenced	POS	O
+by	POS	O
+CDDP	POS	O
+.	POS	O
+The	POS	O
+possible	POS	O
+pathophysiologic	POS	O
+mechanisms	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+Fatal	POS	O
+aplastic	POS	B-NP
+anemia	POS	I-NP
+in	POS	O
+a	POS	O
+patient	POS	O
+treated	POS	O
+with	POS	O
+carbamazepine	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+fatal	POS	O
+aplastic	POS	B-NP
+anemia	POS	I-NP
+due	POS	O
+to	POS	O
+carbamazepine	POS	O
+treatment	POS	O
+in	POS	O
+an	POS	O
+epileptic	POS	B-NP
+woman	POS	O
+is	POS	O
+reported	POS	O
+.	POS	O
+Despite	POS	O
+concerns	POS	O
+of	POS	O
+fatal	POS	O
+bone	POS	B-NP
+marrow	POS	I-NP
+toxicity	POS	I-NP
+due	POS	O
+to	POS	O
+carbamazepine	POS	O
+,	POS	O
+this	POS	O
+is	POS	O
+only	POS	O
+the	POS	O
+fourth	POS	O
+documented	POS	O
+and	POS	O
+published	POS	O
+report	POS	O
+.	POS	O
+Carbamazepine	POS	O
+is	POS	O
+a	POS	O
+safe	POS	O
+drug	POS	O
+,	POS	O
+but	POS	O
+physicians	POS	O
+and	POS	O
+patients	POS	O
+should	POS	O
+be	POS	O
+aware	POS	O
+of	POS	O
+the	POS	O
+exceedingly	POS	O
+rare	POS	O
+but	POS	O
+potentially	POS	O
+fatal	POS	O
+side	POS	O
+effects	POS	O
+,	POS	O
+better	POS	O
+prevented	POS	O
+by	POS	O
+clinical	POS	O
+than	POS	O
+by	POS	O
+laboratory	POS	O
+monitoring	POS	O
+.	POS	O
+Participation	POS	O
+of	POS	O
+a	POS	O
+bulbospinal	POS	O
+serotonergic	POS	O
+pathway	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+brain	POS	O
+in	POS	O
+clonidine	POS	O
+-	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+and	POS	O
+bradycardia	POS	B-NP
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+microinjection	POS	O
+of	POS	O
+clonidine	POS	O
+(	POS	O
+1	POS	O
+-	POS	O
+10	POS	O
+micrograms	POS	O
+in	POS	O
+1	POS	O
+microliter	POS	O
+)	POS	O
+into	POS	O
+a	POS	O
+region	POS	O
+adjacent	POS	O
+to	POS	O
+the	POS	O
+ventrolateral	POS	O
+surface	POS	O
+of	POS	O
+the	POS	O
+medulla	POS	O
+oblongata	POS	O
+on	POS	O
+cardiovascular	POS	O
+function	POS	O
+were	POS	O
+assessed	POS	O
+in	POS	O
+urethane	POS	O
+-	POS	O
+anesthetized	POS	O
+rats	POS	O
+.	POS	O
+Intramedullary	POS	O
+administration	POS	O
+of	POS	O
+clonidine	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+saline	POS	O
+vehicle	POS	O
+,	POS	O
+caused	POS	O
+a	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+decrease	POS	O
+in	POS	O
+both	POS	O
+the	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+and	POS	O
+the	POS	O
+heart	POS	O
+rate	POS	O
+.	POS	O
+The	POS	O
+clonidine	POS	O
+-	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+was	POS	O
+antagonized	POS	O
+by	POS	O
+prior	POS	O
+spinal	POS	O
+transection	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+bilateral	POS	O
+vagotomy	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+other	POS	O
+hand	POS	O
+,	POS	O
+the	POS	O
+clonidine	POS	O
+-	POS	O
+induced	POS	O
+bradycardia	POS	B-NP
+was	POS	O
+antagonized	POS	O
+by	POS	O
+prior	POS	O
+bilateral	POS	O
+vagotomy	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+spinal	POS	O
+transection	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+selective	POS	O
+destruction	POS	O
+of	POS	O
+the	POS	O
+spinal	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+nerves	POS	O
+,	POS	O
+produced	POS	O
+by	POS	O
+bilateral	POS	O
+spinal	POS	O
+injection	POS	O
+of	POS	O
+5	POS	O
+,	POS	O
+7	POS	O
+-	POS	O
+dihydroxytryptamine	POS	O
+,	POS	O
+reduced	POS	O
+the	POS	O
+magnitude	POS	O
+of	POS	O
+the	POS	O
+vasodepressor	POS	O
+or	POS	O
+the	POS	O
+bradycardiac	POS	O
+responses	POS	O
+to	POS	O
+clonidine	POS	O
+microinjected	POS	O
+into	POS	O
+the	POS	O
+area	POS	O
+near	POS	O
+the	POS	O
+ventrolateral	POS	O
+surface	POS	O
+of	POS	O
+the	POS	O
+medulla	POS	O
+oblongata	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+data	POS	O
+indicate	POS	O
+that	POS	O
+a	POS	O
+bulbospinal	POS	O
+serotonergic	POS	O
+pathway	POS	O
+is	POS	O
+involved	POS	O
+in	POS	O
+development	POS	O
+of	POS	O
+clonidine	POS	O
+-	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+and	POS	O
+bradycardia	POS	B-NP
+.	POS	O
+The	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+is	POS	O
+brought	POS	O
+about	POS	O
+by	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+sympathetic	POS	O
+efferent	POS	O
+activity	POS	O
+,	POS	O
+whereas	POS	O
+the	POS	O
+induced	POS	O
+bradycardia	POS	B-NP
+was	POS	O
+due	POS	O
+to	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+vagal	POS	O
+efferent	POS	O
+activity	POS	O
+.	POS	O
+Hypertension	POS	B-NP
+in	POS	O
+neuroblastoma	POS	B-NP
+induced	POS	O
+by	POS	O
+imipramine	POS	O
+.	POS	O
+Hypertension	POS	B-NP
+is	POS	O
+a	POS	O
+well	POS	O
+-	POS	O
+known	POS	O
+finding	POS	O
+in	POS	O
+some	POS	O
+patients	POS	O
+with	POS	O
+neuroblastoma	POS	B-NP
+.	POS	O
+However	POS	O
+,	POS	O
+it	POS	O
+has	POS	O
+not	POS	O
+previously	POS	O
+been	POS	O
+described	POS	O
+in	POS	O
+association	POS	O
+with	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+Imipramine	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+severe	POS	O
+hypertension	POS	B-NP
+(	POS	O
+blood	POS	O
+pressure	POS	O
+190	POS	O
+/	POS	O
+160	POS	O
+)	POS	O
+in	POS	O
+a	POS	O
+4	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+girl	POS	O
+with	POS	O
+neuroblastoma	POS	B-NP
+who	POS	O
+was	POS	O
+given	POS	O
+Imipramine	POS	O
+to	POS	O
+control	POS	O
+a	POS	O
+behavior	POS	B-NP
+disorder	POS	I-NP
+.	POS	O
+It	POS	O
+was	POS	O
+determined	POS	O
+later	POS	O
+that	POS	O
+this	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+tumor	POS	B-NP
+was	POS	O
+recurring	POS	O
+at	POS	O
+the	POS	O
+time	POS	O
+of	POS	O
+her	POS	O
+hypertensive	POS	B-NP
+episode	POS	O
+.	POS	O
+Since	POS	O
+she	POS	O
+had	POS	O
+no	POS	O
+blood	POS	O
+pressure	POS	O
+elevation	POS	O
+at	POS	O
+initial	POS	O
+diagnosis	POS	O
+and	POS	O
+none	POS	O
+following	POS	O
+discontinuation	POS	O
+of	POS	O
+the	POS	O
+Imipramine	POS	O
+(	POS	O
+when	POS	O
+she	POS	O
+was	POS	O
+in	POS	O
+florid	POS	O
+relapse	POS	O
+)	POS	O
+,	POS	O
+we	POS	O
+believe	POS	O
+that	POS	O
+this	POS	O
+drug	POS	O
+rather	POS	O
+than	POS	O
+her	POS	O
+underlying	POS	O
+disease	POS	O
+alone	POS	O
+caused	POS	O
+her	POS	O
+hypertension	POS	B-NP
+.	POS	O
+The	POS	O
+mechanism	POS	O
+for	POS	O
+this	POS	O
+reaction	POS	O
+is	POS	O
+believed	POS	O
+to	POS	O
+be	POS	O
+increased	POS	O
+levels	POS	O
+of	POS	O
+vasoactive	POS	O
+catecholamines	POS	O
+due	POS	O
+to	POS	O
+interference	POS	O
+of	POS	O
+their	POS	O
+physiologic	POS	O
+inactivation	POS	O
+by	POS	O
+Imipramine	POS	O
+.	POS	O
+From	POS	O
+this	POS	O
+experience	POS	O
+,	POS	O
+we	POS	O
+urge	POS	O
+extreme	POS	O
+caution	POS	O
+in	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+tricyclic	POS	O
+antidepressants	POS	O
+in	POS	O
+children	POS	O
+with	POS	O
+active	POS	O
+neuroblastoma	POS	B-NP
+.	POS	O
+Rechallenge	POS	O
+of	POS	O
+patients	POS	O
+who	POS	O
+developed	POS	O
+oral	POS	O
+candidiasis	POS	B-NP
+or	POS	O
+hoarseness	POS	B-NP
+with	POS	O
+beclomethasone	POS	O
+dipropionate	POS	O
+.	POS	O
+Of	POS	O
+158	POS	O
+asthmatic	POS	B-NP
+patients	POS	O
+who	POS	O
+were	POS	O
+placed	POS	O
+on	POS	O
+inhaled	POS	O
+beclomethasone	POS	O
+,	POS	O
+15	POS	O
+(	POS	O
+9	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+developed	POS	O
+either	POS	O
+hoarseness	POS	B-NP
+(	POS	O
+8	POS	O
+)	POS	O
+,	POS	O
+oral	POS	O
+thrush	POS	B-NP
+(	POS	O
+6	POS	O
+)	POS	O
+,	POS	O
+or	POS	O
+both	POS	O
+(	POS	O
+1	POS	O
+)	POS	O
+.	POS	O
+When	POS	O
+their	POS	O
+adverse	POS	O
+reactions	POS	O
+subsided	POS	O
+,	POS	O
+seven	POS	O
+of	POS	O
+these	POS	O
+15	POS	O
+patients	POS	O
+were	POS	O
+rechallenged	POS	O
+with	POS	O
+inhaled	POS	O
+beclomethasone	POS	O
+.	POS	O
+These	POS	O
+included	POS	O
+five	POS	O
+cases	POS	O
+who	POS	O
+developed	POS	O
+hoarseness	POS	B-NP
+and	POS	O
+three	POS	O
+who	POS	O
+developed	POS	O
+Candidiasis	POS	B-NP
+.	POS	O
+One	POS	O
+patient	POS	O
+had	POS	O
+both	POS	O
+.	POS	O
+Oral	POS	O
+thrush	POS	B-NP
+did	POS	O
+not	POS	O
+recur	POS	O
+,	POS	O
+but	POS	O
+60	POS	O
+%	POS	O
+(	POS	O
+3	POS	O
+/	POS	O
+5	POS	O
+)	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+hoarseness	POS	B-NP
+had	POS	O
+recurrence	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+patients	POS	O
+may	POS	O
+be	POS	O
+restarted	POS	O
+on	POS	O
+inhaled	POS	O
+beclomethasone	POS	O
+when	POS	O
+clinically	POS	O
+indicated	POS	O
+;	POS	O
+however	POS	O
+,	POS	O
+because	POS	O
+of	POS	O
+the	POS	O
+high	POS	O
+recurrence	POS	O
+rate	POS	O
+,	POS	O
+patients	POS	O
+who	POS	O
+develop	POS	O
+hoarseness	POS	B-NP
+should	POS	O
+not	POS	O
+be	POS	O
+re	POS	O
+-	POS	O
+challenged	POS	O
+.	POS	O
+Concomitant	POS	O
+use	POS	O
+of	POS	O
+oral	POS	O
+prednisone	POS	O
+and	POS	O
+topical	POS	O
+beclomethasone	POS	O
+may	POS	O
+increase	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+developing	POS	O
+hoarseness	POS	B-NP
+or	POS	O
+candidiasis	POS	B-NP
+.	POS	O
+Cyclophosphamide	POS	B-NP
+cardiotoxicity	POS	I-NP
+:	POS	O
+an	POS	O
+analysis	POS	O
+of	POS	O
+dosing	POS	O
+as	POS	O
+a	POS	O
+risk	POS	O
+factor	POS	O
+.	POS	O
+Patients	POS	O
+who	POS	O
+undergo	POS	O
+bone	POS	O
+marrow	POS	O
+transplantation	POS	O
+are	POS	O
+generally	POS	O
+immunosuppressed	POS	O
+with	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+cyclophosphamide	POS	O
+(	POS	O
+CYA	POS	O
+)	POS	O
+which	POS	O
+is	POS	O
+usually	POS	O
+calculated	POS	O
+based	POS	O
+on	POS	O
+the	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+weight	POS	O
+.	POS	O
+At	POS	O
+these	POS	O
+high	POS	O
+doses	POS	O
+of	POS	O
+CYA	POS	O
+,	POS	O
+serious	POS	O
+cardiotoxicity	POS	B-NP
+may	POS	O
+occur	POS	O
+,	POS	O
+but	POS	O
+definitive	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+such	POS	O
+cardiotoxicity	POS	B-NP
+have	POS	O
+not	POS	O
+been	POS	O
+described	POS	O
+.	POS	O
+Since	POS	O
+chemotherapeutic	POS	O
+agent	POS	O
+toxicity	POS	B-NP
+generally	POS	O
+correlates	POS	O
+with	POS	O
+dose	POS	O
+per	POS	O
+body	POS	O
+surface	POS	O
+area	POS	O
+,	POS	O
+we	POS	O
+retrospectively	POS	O
+calculated	POS	O
+the	POS	O
+dose	POS	O
+of	POS	O
+CYA	POS	O
+in	POS	O
+patients	POS	O
+transplanted	POS	O
+at	POS	O
+our	POS	O
+institution	POS	O
+to	POS	O
+determine	POS	O
+whether	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+CYA	POS	O
+cardiotoxicity	POS	B-NP
+correlated	POS	O
+with	POS	O
+the	POS	O
+dose	POS	O
+per	POS	O
+body	POS	O
+surface	POS	O
+area	POS	O
+.	POS	O
+Eighty	POS	O
+patients	POS	O
+who	POS	O
+were	POS	O
+to	POS	O
+receive	POS	O
+CYA	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+d	POS	O
+for	POS	O
+four	POS	O
+days	POS	O
+as	POS	O
+preparation	POS	O
+for	POS	O
+marrow	POS	O
+grafting	POS	O
+underwent	POS	O
+a	POS	O
+total	POS	O
+of	POS	O
+84	POS	O
+transplants	POS	O
+for	POS	O
+aplastic	POS	B-NP
+anemia	POS	I-NP
+,	POS	O
+Wiskott	POS	B-NP
+-	POS	I-NP
+Aldrich	POS	I-NP
+syndrome	POS	I-NP
+,	POS	O
+or	POS	O
+severe	POS	O
+combined	POS	O
+immunodeficiency	POS	B-NP
+syndrome	POS	I-NP
+.	POS	O
+Fourteen	POS	O
+of	POS	O
+84	POS	O
+(	POS	O
+17	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+had	POS	O
+symptoms	POS	O
+and	POS	O
+signs	POS	O
+consistent	POS	O
+with	POS	O
+CYA	POS	O
+cardiotoxicity	POS	B-NP
+within	POS	O
+ten	POS	O
+days	POS	O
+of	POS	O
+receiving	POS	O
+1	POS	O
+to	POS	O
+4	POS	O
+doses	POS	O
+of	POS	O
+CYA	POS	O
+.	POS	O
+Six	POS	O
+of	POS	O
+the	POS	O
+14	POS	O
+patients	POS	O
+died	POS	O
+with	POS	O
+congestive	POS	B-NP
+heart	POS	I-NP
+failure	POS	I-NP
+.	POS	O
+The	POS	O
+dose	POS	O
+of	POS	O
+CYA	POS	O
+per	POS	O
+body	POS	O
+surface	POS	O
+area	POS	O
+was	POS	O
+calculated	POS	O
+for	POS	O
+all	POS	O
+patients	POS	O
+and	POS	O
+the	POS	O
+patients	POS	O
+were	POS	O
+divided	POS	O
+into	POS	O
+two	POS	O
+groups	POS	O
+based	POS	O
+on	POS	O
+daily	POS	O
+CYA	POS	O
+dose	POS	O
+:	POS	O
+Group	POS	O
+1	POS	O
+,	POS	O
+CYA	POS	O
+less	POS	O
+than	POS	O
+or	POS	O
+equal	POS	O
+to	POS	O
+1	POS	O
+.	POS	O
+55	POS	O
+g	POS	O
+/	POS	O
+m2	POS	O
+/	POS	O
+d	POS	O
+;	POS	O
+Group	POS	O
+2	POS	O
+,	POS	O
+CYA	POS	O
+greater	POS	O
+than	POS	O
+1	POS	O
+.	POS	O
+55	POS	O
+g	POS	O
+/	POS	O
+m2	POS	O
+/	POS	O
+d	POS	O
+.	POS	O
+Cardiotoxicity	POS	B-NP
+that	POS	O
+was	POS	O
+thought	POS	O
+to	POS	O
+be	POS	O
+related	POS	O
+to	POS	O
+CYA	POS	O
+occurred	POS	O
+in	POS	O
+1	POS	O
+/	POS	O
+32	POS	O
+(	POS	O
+3	POS	O
+%	POS	O
+)	POS	O
+of	POS	O
+patients	POS	O
+in	POS	O
+Group	POS	O
+1	POS	O
+and	POS	O
+in	POS	O
+13	POS	O
+/	POS	O
+52	POS	O
+(	POS	O
+25	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+in	POS	O
+Group	POS	O
+2	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+025	POS	O
+)	POS	O
+.	POS	O
+Congestive	POS	B-NP
+heart	POS	I-NP
+failure	POS	I-NP
+caused	POS	O
+or	POS	O
+contributed	POS	O
+to	POS	O
+death	POS	O
+in	POS	O
+0	POS	O
+/	POS	O
+32	POS	O
+patients	POS	O
+in	POS	O
+Group	POS	O
+1	POS	O
+v	POS	O
+6	POS	O
+/	POS	O
+52	POS	O
+(	POS	O
+12	POS	O
+%	POS	O
+)	POS	O
+of	POS	O
+patients	POS	O
+in	POS	O
+Group	POS	O
+2	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+25	POS	O
+)	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+difference	POS	O
+in	POS	O
+the	POS	O
+rate	POS	O
+of	POS	O
+engraftment	POS	O
+of	POS	O
+evaluable	POS	O
+patients	POS	O
+in	POS	O
+the	POS	O
+two	POS	O
+groups	POS	O
+(	POS	O
+P	POS	O
+greater	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+)	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+the	POS	O
+CYA	POS	O
+cardiotoxicity	POS	B-NP
+correlates	POS	O
+with	POS	O
+CYA	POS	O
+dosage	POS	O
+as	POS	O
+calculated	POS	O
+by	POS	O
+body	POS	O
+surface	POS	O
+area	POS	O
+,	POS	O
+and	POS	O
+that	POS	O
+patients	POS	O
+with	POS	O
+aplastic	POS	B-NP
+anemia	POS	I-NP
+and	POS	O
+immunodeficiencies	POS	B-NP
+can	POS	O
+be	POS	O
+effectively	POS	O
+prepared	POS	O
+for	POS	O
+bone	POS	O
+marrow	POS	O
+grafting	POS	O
+at	POS	O
+a	POS	O
+CYA	POS	O
+dose	POS	O
+of	POS	O
+1	POS	O
+.	POS	O
+55	POS	O
+g	POS	O
+/	POS	O
+m2	POS	O
+/	POS	O
+d	POS	O
+for	POS	O
+four	POS	O
+days	POS	O
+with	POS	O
+a	POS	O
+lower	POS	O
+incidence	POS	O
+of	POS	O
+cardiotoxicity	POS	B-NP
+than	POS	O
+patients	POS	O
+whose	POS	O
+CYA	POS	O
+dosage	POS	O
+is	POS	O
+calculated	POS	O
+based	POS	O
+on	POS	O
+weight	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+reaffirms	POS	O
+the	POS	O
+principle	POS	O
+that	POS	O
+drug	POS	O
+toxicity	POS	B-NP
+correlates	POS	O
+with	POS	O
+dose	POS	O
+per	POS	O
+body	POS	O
+surface	POS	O
+area	POS	O
+.	POS	O
+Studies	POS	O
+of	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+aminoglycoside	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+The	POS	O
+epidemiology	POS	O
+of	POS	O
+aminoglycoside	POS	O
+-	POS	O
+induced	POS	O
+nephrotoxicity	POS	B-NP
+is	POS	O
+not	POS	O
+fully	POS	O
+understood	POS	O
+.	POS	O
+Experimental	POS	O
+studies	POS	O
+in	POS	O
+healthy	POS	O
+human	POS	O
+volunteers	POS	O
+indicate	POS	O
+aminoglycosides	POS	O
+cause	POS	O
+proximal	POS	O
+tubular	POS	B-NP
+damage	POS	I-NP
+in	POS	O
+most	POS	O
+patients	POS	O
+,	POS	O
+but	POS	O
+rarely	POS	O
+,	POS	O
+if	POS	O
+ever	POS	O
+,	POS	O
+cause	POS	O
+glomerular	POS	B-NP
+or	POS	I-NP
+tubular	POS	I-NP
+dysfunction	POS	I-NP
+.	POS	O
+Clinical	POS	O
+trials	POS	O
+of	POS	O
+aminoglycosides	POS	O
+in	POS	O
+seriously	POS	O
+ill	POS	O
+patients	POS	O
+indicate	POS	O
+that	POS	O
+the	POS	O
+relative	POS	O
+risk	POS	O
+for	POS	O
+developing	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+during	POS	O
+therapy	POS	O
+ranges	POS	O
+from	POS	O
+8	POS	O
+to	POS	O
+10	POS	O
+and	POS	O
+that	POS	O
+the	POS	O
+attributable	POS	O
+risk	POS	O
+is	POS	O
+70	POS	O
+%	POS	O
+to	POS	O
+80	POS	O
+%	POS	O
+.	POS	O
+Further	POS	O
+analysis	POS	O
+of	POS	O
+these	POS	O
+data	POS	O
+suggests	POS	O
+that	POS	O
+the	POS	O
+duration	POS	O
+of	POS	O
+therapy	POS	O
+,	POS	O
+plasma	POS	O
+aminoglycoside	POS	O
+levels	POS	O
+,	POS	O
+liver	POS	B-NP
+disease	POS	I-NP
+,	POS	O
+advanced	POS	O
+age	POS	O
+,	POS	O
+high	POS	O
+initial	POS	O
+estimated	POS	O
+creatinine	POS	O
+clearance	POS	O
+and	POS	O
+,	POS	O
+possibly	POS	O
+,	POS	O
+female	POS	O
+gender	POS	O
+all	POS	O
+increase	POS	O
+the	POS	O
+risk	POS	O
+for	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+Other	POS	O
+causes	POS	O
+of	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+,	POS	O
+such	POS	O
+as	POS	O
+shock	POS	B-NP
+,	POS	O
+appear	POS	O
+to	POS	O
+have	POS	O
+an	POS	O
+additive	POS	O
+effect	POS	O
+.	POS	O
+Predictive	POS	O
+models	POS	O
+have	POS	O
+been	POS	O
+developed	POS	O
+from	POS	O
+these	POS	O
+analyses	POS	O
+that	POS	O
+should	POS	O
+be	POS	O
+useful	POS	O
+for	POS	O
+identifying	POS	O
+patients	POS	O
+at	POS	O
+high	POS	O
+risk	POS	O
+.	POS	O
+These	POS	O
+models	POS	O
+may	POS	O
+also	POS	O
+be	POS	O
+useful	POS	O
+in	POS	O
+developing	POS	O
+insights	POS	O
+into	POS	O
+the	POS	O
+pathophysiology	POS	O
+of	POS	O
+aminoglycoside	POS	O
+-	POS	O
+induced	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+Central	POS	O
+action	POS	O
+of	POS	O
+narcotic	POS	O
+analgesics	POS	O
+.	POS	O
+Part	POS	O
+IV	POS	O
+.	POS	O
+Noradrenergic	POS	O
+influences	POS	O
+on	POS	O
+the	POS	O
+activity	POS	O
+of	POS	O
+analgesics	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+effect	POS	O
+of	POS	O
+clonidine	POS	O
+,	POS	O
+naphazoline	POS	O
+and	POS	O
+xylometazoline	POS	O
+on	POS	O
+analgesia	POS	O
+induced	POS	O
+by	POS	O
+morphine	POS	O
+,	POS	O
+codeine	POS	O
+,	POS	O
+fentanyl	POS	O
+and	POS	O
+pentazocine	POS	O
+,	POS	O
+and	POS	O
+on	POS	O
+cataleptic	POS	O
+effect	POS	O
+of	POS	O
+morphine	POS	O
+,	POS	O
+codine	POS	O
+and	POS	O
+fentanyl	POS	O
+was	POS	O
+studied	POS	O
+in	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+biochemical	POS	O
+assays	POS	O
+on	POS	O
+the	POS	O
+influence	POS	O
+of	POS	O
+four	POS	O
+analgesics	POS	O
+on	POS	O
+the	POS	O
+brain	POS	O
+concentration	POS	O
+and	POS	O
+turnover	POS	O
+of	POS	O
+noradrenaline	POS	O
+(	POS	O
+NA	POS	O
+)	POS	O
+were	POS	O
+also	POS	O
+performed	POS	O
+.	POS	O
+It	POS	O
+was	POS	O
+found	POS	O
+that	POS	O
+three	POS	O
+drugs	POS	O
+stimulating	POS	O
+central	POS	O
+NA	POS	O
+receptors	POS	O
+failed	POS	O
+to	POS	O
+affect	POS	O
+the	POS	O
+analgesic	POS	O
+ED50	POS	O
+of	POS	O
+all	POS	O
+antinociceptive	POS	O
+agents	POS	O
+and	POS	O
+they	POS	O
+enhanced	POS	O
+catalepsy	POS	B-NP
+induced	POS	O
+by	POS	O
+morphine	POS	O
+and	POS	O
+fentanyl	POS	O
+.	POS	O
+Codeine	POS	O
+catalepsy	POS	B-NP
+was	POS	O
+increased	POS	O
+by	POS	O
+clonidine	POS	O
+and	POS	O
+decreased	POS	O
+by	POS	O
+naphazoline	POS	O
+and	POS	O
+xylometazoline	POS	O
+.	POS	O
+The	POS	O
+brain	POS	O
+concentration	POS	O
+of	POS	O
+NA	POS	O
+was	POS	O
+not	POS	O
+changed	POS	O
+by	POS	O
+morphine	POS	O
+and	POS	O
+fentanyl	POS	O
+,	POS	O
+but	POS	O
+one	POS	O
+of	POS	O
+the	POS	O
+doses	POS	O
+of	POS	O
+codeine	POS	O
+(	POS	O
+45	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+slightly	POS	O
+enhanced	POS	O
+it	POS	O
+.	POS	O
+Pentazocine	POS	O
+dose	POS	O
+-	POS	O
+dependently	POS	O
+decreased	POS	O
+the	POS	O
+brain	POS	O
+level	POS	O
+of	POS	O
+NA	POS	O
+.	POS	O
+The	POS	O
+rate	POS	O
+of	POS	O
+NA	POS	O
+turnover	POS	O
+was	POS	O
+not	POS	O
+altered	POS	O
+by	POS	O
+analgesics	POS	O
+except	POS	O
+for	POS	O
+the	POS	O
+higher	POS	O
+dose	POS	O
+of	POS	O
+fentanyl	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+following	POS	O
+which	POS	O
+the	POS	O
+disappearance	POS	O
+of	POS	O
+NA	POS	O
+from	POS	O
+the	POS	O
+brain	POS	O
+was	POS	O
+diminished	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+are	POS	O
+discussed	POS	O
+in	POS	O
+the	POS	O
+light	POS	O
+of	POS	O
+various	POS	O
+and	POS	O
+non	POS	O
+-	POS	O
+uniform	POS	O
+data	POS	O
+from	POS	O
+the	POS	O
+literature	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+suggested	POS	O
+that	POS	O
+in	POS	O
+rats	POS	O
+the	POS	O
+brain	POS	O
+NA	POS	O
+plays	POS	O
+a	POS	O
+less	POS	O
+important	POS	O
+function	POS	O
+than	POS	O
+the	POS	O
+other	POS	O
+monoamines	POS	O
+in	POS	O
+the	POS	O
+behavioural	POS	O
+activity	POS	O
+of	POS	O
+potent	POS	O
+analgesics	POS	O
+.	POS	O
+Flurothyl	POS	O
+seizure	POS	B-NP
+thresholds	POS	O
+in	POS	O
+mice	POS	O
+treated	POS	O
+neonatally	POS	O
+with	POS	O
+a	POS	O
+single	POS	O
+injection	POS	O
+of	POS	O
+monosodium	POS	O
+glutamate	POS	O
+(	POS	O
+MSG	POS	O
+)	POS	O
+:	POS	O
+evaluation	POS	O
+of	POS	O
+experimental	POS	O
+parameters	POS	O
+in	POS	O
+flurothyl	POS	O
+seizure	POS	B-NP
+testing	POS	O
+.	POS	O
+Monosodium	POS	O
+glutamate	POS	O
+(	POS	O
+MSG	POS	O
+)	POS	O
+administration	POS	O
+to	POS	O
+neonatal	POS	O
+rodents	POS	O
+produces	POS	O
+convulsions	POS	B-NP
+and	POS	O
+results	POS	O
+in	POS	O
+numerous	POS	O
+biochemical	POS	O
+and	POS	O
+behavioral	POS	B-NP
+deficits	POS	I-NP
+.	POS	O
+These	POS	O
+studies	POS	O
+were	POS	O
+undertaken	POS	O
+to	POS	O
+determine	POS	O
+if	POS	O
+neonatal	POS	O
+administration	POS	O
+of	POS	O
+MSG	POS	O
+produced	POS	O
+permanent	POS	O
+alterations	POS	O
+in	POS	O
+seizure	POS	B-NP
+susceptibility	POS	O
+,	POS	O
+since	POS	O
+previous	POS	O
+investigations	POS	O
+were	POS	O
+inconclusive	POS	O
+.	POS	O
+A	POS	O
+flurothyl	POS	O
+ether	POS	O
+seizure	POS	B-NP
+screening	POS	O
+technique	POS	O
+was	POS	O
+used	POS	O
+to	POS	O
+evaluate	POS	O
+seizure	POS	B-NP
+susceptibility	POS	O
+in	POS	O
+adult	POS	O
+mice	POS	O
+that	POS	O
+received	POS	O
+neonatal	POS	O
+injections	POS	O
+of	POS	O
+MSG	POS	O
+(	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+g	POS	O
+and	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+g	POS	O
+)	POS	O
+.	POS	O
+MSG	POS	O
+treatment	POS	O
+resulted	POS	O
+in	POS	O
+significant	POS	O
+reductions	POS	O
+in	POS	O
+whole	POS	O
+brain	POS	O
+weight	POS	O
+but	POS	O
+did	POS	O
+not	POS	O
+alter	POS	O
+seizure	POS	B-NP
+threshold	POS	O
+.	POS	O
+A	POS	O
+naloxone	POS	O
+(	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+challenge	POS	O
+was	POS	O
+also	POS	O
+ineffective	POS	O
+in	POS	O
+altering	POS	O
+the	POS	O
+seizure	POS	B-NP
+thresholds	POS	O
+of	POS	O
+either	POS	O
+control	POS	O
+of	POS	O
+MSG	POS	O
+-	POS	O
+treated	POS	O
+mice	POS	O
+.	POS	O
+Flurothyl	POS	O
+ether	POS	O
+produced	POS	O
+hypothermia	POS	B-NP
+which	POS	O
+was	POS	O
+correlated	POS	O
+with	POS	O
+the	POS	O
+duration	POS	O
+of	POS	O
+flurothyl	POS	O
+exposure	POS	O
+;	POS	O
+however	POS	O
+,	POS	O
+the	POS	O
+relationship	POS	O
+of	POS	O
+hypothermia	POS	B-NP
+to	POS	O
+seizure	POS	B-NP
+induction	POS	O
+was	POS	O
+unclear	POS	O
+.	POS	O
+Flurothyl	POS	O
+seizure	POS	B-NP
+testing	POS	O
+proved	POS	O
+to	POS	O
+be	POS	O
+a	POS	O
+rapid	POS	O
+and	POS	O
+reliable	POS	O
+technique	POS	O
+with	POS	O
+which	POS	O
+to	POS	O
+evaluate	POS	O
+seizure	POS	B-NP
+susceptibility	POS	O
+.	POS	O
+Susceptibility	POS	O
+to	POS	O
+seizures	POS	B-NP
+produced	POS	O
+by	POS	O
+pilocarpine	POS	O
+in	POS	O
+rats	POS	O
+after	POS	O
+microinjection	POS	O
+of	POS	O
+isoniazid	POS	O
+or	POS	O
+gamma	POS	O
+-	POS	O
+vinyl	POS	O
+-	POS	O
+GABA	POS	O
+into	POS	O
+the	POS	O
+substantia	POS	O
+nigra	POS	O
+.	POS	O
+Pilocarpine	POS	O
+,	POS	O
+given	POS	O
+intraperitoneally	POS	O
+to	POS	O
+rats	POS	O
+,	POS	O
+reproduces	POS	O
+the	POS	O
+neuropathological	POS	O
+sequelae	POS	O
+of	POS	O
+temporal	POS	B-NP
+lobe	POS	I-NP
+epilepsy	POS	I-NP
+and	POS	O
+provides	POS	O
+a	POS	O
+relevant	POS	O
+animal	POS	O
+model	POS	O
+for	POS	O
+studying	POS	O
+mechanisms	POS	O
+of	POS	O
+buildup	POS	O
+of	POS	O
+convulsive	POS	B-NP
+activity	POS	O
+and	POS	O
+pathways	POS	O
+operative	POS	O
+in	POS	O
+the	POS	O
+generalization	POS	O
+and	POS	O
+propagation	POS	O
+of	POS	O
+seizures	POS	B-NP
+within	POS	O
+the	POS	O
+forebrain	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+,	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+manipulating	POS	O
+the	POS	O
+activity	POS	O
+of	POS	O
+the	POS	O
+gamma	POS	O
+-	POS	O
+aminobutyric	POS	O
+acid	POS	O
+(	POS	O
+GABA	POS	O
+)	POS	O
+-	POS	O
+mediated	POS	O
+synaptic	POS	O
+inhibition	POS	O
+within	POS	O
+the	POS	O
+substantia	POS	O
+nigra	POS	O
+on	POS	O
+seizures	POS	B-NP
+produced	POS	O
+by	POS	O
+pilocarpine	POS	O
+in	POS	O
+rats	POS	O
+,	POS	O
+were	POS	O
+investigated	POS	O
+.	POS	O
+In	POS	O
+animals	POS	O
+pretreated	POS	O
+with	POS	O
+microinjections	POS	O
+of	POS	O
+isoniazid	POS	O
+,	POS	O
+150	POS	O
+micrograms	POS	O
+,	POS	O
+an	POS	O
+inhibitor	POS	O
+of	POS	O
+activity	POS	O
+of	POS	O
+the	POS	O
+GABA	POS	O
+-	POS	O
+synthesizing	POS	O
+enzyme	POS	O
+,	POS	O
+L	POS	O
+-	POS	O
+glutamic	POS	O
+acid	POS	O
+decarboxylase	POS	O
+,	POS	O
+into	POS	O
+the	POS	O
+substantia	POS	O
+nigra	POS	O
+pars	POS	O
+reticulata	POS	O
+(	POS	O
+SNR	POS	O
+)	POS	O
+,	POS	O
+bilaterally	POS	O
+,	POS	O
+non	POS	O
+-	POS	O
+convulsant	POS	O
+doses	POS	O
+of	POS	O
+pilocarpine	POS	O
+,	POS	O
+100	POS	O
+and	POS	O
+200	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+resulted	POS	O
+in	POS	O
+severe	POS	O
+motor	POS	B-NP
+limbic	POS	I-NP
+seizures	POS	I-NP
+and	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+.	POS	O
+Electroencephalographic	POS	O
+and	POS	O
+behavioral	POS	O
+monitoring	POS	O
+revealed	POS	O
+a	POS	O
+profound	POS	O
+reduction	POS	O
+of	POS	O
+the	POS	O
+threshold	POS	O
+for	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+convulsions	POS	B-NP
+.	POS	O
+Morphological	POS	O
+analysis	POS	O
+of	POS	O
+frontal	POS	O
+forebrain	POS	O
+sections	POS	O
+with	POS	O
+light	POS	O
+microscopy	POS	O
+revealed	POS	O
+seizure	POS	B-NP
+-	POS	O
+related	POS	O
+damage	POS	O
+to	POS	O
+the	POS	O
+hippocampal	POS	O
+formation	POS	O
+,	POS	O
+thalamus	POS	O
+,	POS	O
+amygdala	POS	O
+,	POS	O
+olfactory	POS	O
+cortex	POS	O
+,	POS	O
+substantia	POS	O
+nigra	POS	O
+and	POS	O
+neocortex	POS	O
+,	POS	O
+which	POS	O
+is	POS	O
+typically	POS	O
+observed	POS	O
+with	POS	O
+pilocarpine	POS	O
+in	POS	O
+doses	POS	O
+exceeding	POS	O
+350	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+Bilateral	POS	O
+intrastriatal	POS	O
+injections	POS	O
+of	POS	O
+isoniazid	POS	O
+did	POS	O
+not	POS	O
+augment	POS	O
+seizures	POS	B-NP
+produced	POS	O
+by	POS	O
+pilocarpine	POS	O
+,	POS	O
+200	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+Application	POS	O
+of	POS	O
+an	POS	O
+irreversible	POS	O
+inhibitor	POS	O
+of	POS	O
+GABA	POS	O
+transaminase	POS	O
+,	POS	O
+gamma	POS	O
+-	POS	O
+vinyl	POS	O
+-	POS	O
+GABA	POS	O
+(	POS	O
+D	POS	O
+,	POS	O
+L	POS	O
+-	POS	O
+4	POS	O
+-	POS	O
+amino	POS	O
+-	POS	O
+hex	POS	O
+-	POS	O
+5	POS	O
+-	POS	O
+enoic	POS	O
+acid	POS	O
+)	POS	O
+,	POS	O
+5	POS	O
+micrograms	POS	O
+,	POS	O
+into	POS	O
+the	POS	O
+SNR	POS	O
+,	POS	O
+bilaterally	POS	O
+,	POS	O
+suppressed	POS	O
+the	POS	O
+appearance	POS	O
+of	POS	O
+electrographic	POS	O
+and	POS	O
+behavioral	POS	O
+seizures	POS	B-NP
+produced	POS	O
+by	POS	O
+pilocarpine	POS	O
+,	POS	O
+380	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+This	POS	O
+treatment	POS	O
+was	POS	O
+also	POS	O
+sufficient	POS	O
+to	POS	O
+protect	POS	O
+animals	POS	O
+from	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+brain	POS	O
+damage	POS	O
+.	POS	O
+Microinjections	POS	O
+of	POS	O
+gamma	POS	O
+-	POS	O
+vinyl	POS	O
+-	POS	O
+GABA	POS	O
+,	POS	O
+5	POS	O
+micrograms	POS	O
+,	POS	O
+into	POS	O
+the	POS	O
+dorsal	POS	O
+striatum	POS	O
+,	POS	O
+bilaterally	POS	O
+,	POS	O
+failed	POS	O
+to	POS	O
+prevent	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+convulsions	POS	B-NP
+produced	POS	O
+by	POS	O
+pilocarpine	POS	O
+,	POS	O
+380	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+demonstrate	POS	O
+that	POS	O
+the	POS	O
+threshold	POS	O
+for	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+in	POS	O
+rats	POS	O
+is	POS	O
+subjected	POS	O
+to	POS	O
+the	POS	O
+regulation	POS	O
+of	POS	O
+the	POS	O
+GABA	POS	O
+-	POS	O
+mediated	POS	O
+synaptic	POS	O
+inhibition	POS	O
+within	POS	O
+the	POS	O
+substantia	POS	O
+nigra	POS	O
+.	POS	O
+Human	POS	O
+and	POS	O
+canine	POS	O
+ventricular	POS	O
+vasoactive	POS	O
+intestinal	POS	O
+polypeptide	POS	O
+:	POS	O
+decrease	POS	O
+with	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+.	POS	O
+Vasoactive	POS	O
+intestinal	POS	O
+polypeptide	POS	O
+(	POS	O
+VIP	POS	O
+)	POS	O
+is	POS	O
+a	POS	O
+systemic	POS	O
+and	POS	O
+coronary	POS	O
+vasodilator	POS	O
+that	POS	O
+may	POS	O
+have	POS	O
+positive	POS	O
+inotropic	POS	O
+properties	POS	O
+.	POS	O
+Myocardial	POS	O
+levels	POS	O
+of	POS	O
+VIP	POS	O
+were	POS	O
+assayed	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+in	POS	O
+two	POS	O
+canine	POS	O
+models	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+first	POS	O
+,	POS	O
+cobalt	POS	O
+cardiomyopathy	POS	B-NP
+was	POS	O
+induced	POS	O
+in	POS	O
+eight	POS	O
+dogs	POS	O
+;	POS	O
+VIP	POS	O
+(	POS	O
+by	POS	O
+radioimmunoassay	POS	O
+)	POS	O
+decreased	POS	O
+from	POS	O
+35	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+11	POS	O
+pg	POS	O
+/	POS	O
+mg	POS	O
+protein	POS	O
+(	POS	O
+mean	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+SD	POS	O
+)	POS	O
+to	POS	O
+5	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+pg	POS	O
+/	POS	O
+mg	POS	O
+protein	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+six	POS	O
+dogs	POS	O
+with	POS	O
+doxorubicin	POS	O
+-	POS	O
+induced	POS	O
+heart	POS	B-NP
+failure	POS	I-NP
+,	POS	O
+VIP	POS	O
+decreased	POS	O
+from	POS	O
+31	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+7	POS	O
+to	POS	O
+11	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+pg	POS	O
+/	POS	O
+mg	POS	O
+protein	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+VIP	POS	O
+content	POS	O
+of	POS	O
+left	POS	O
+ventricular	POS	O
+muscle	POS	O
+of	POS	O
+resected	POS	O
+failing	POS	O
+hearts	POS	O
+in	POS	O
+10	POS	O
+patients	POS	O
+receiving	POS	O
+a	POS	O
+heart	POS	O
+transplant	POS	O
+was	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+papillary	POS	O
+muscles	POS	O
+in	POS	O
+14	POS	O
+patients	POS	O
+(	POS	O
+five	POS	O
+with	POS	O
+rheumatic	POS	B-NP
+disease	POS	I-NP
+,	POS	O
+nine	POS	O
+with	POS	O
+myxomatous	POS	B-NP
+degeneration	POS	I-NP
+)	POS	O
+receiving	POS	O
+mitral	POS	B-NP
+valve	POS	I-NP
+prostheses	POS	I-NP
+.	POS	O
+The	POS	O
+lowest	POS	O
+myocardial	POS	O
+VIP	POS	O
+concentration	POS	O
+was	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+hearts	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+coronary	POS	B-NP
+disease	POS	I-NP
+(	POS	O
+one	POS	O
+patient	POS	O
+receiving	POS	O
+a	POS	O
+transplant	POS	O
+and	POS	O
+three	POS	O
+receiving	POS	O
+mitral	POS	O
+prostheses	POS	O
+)	POS	O
+(	POS	O
+6	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+9	POS	O
+pg	POS	O
+/	POS	O
+mg	POS	O
+protein	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+other	POS	O
+patients	POS	O
+undergoing	POS	O
+transplantation	POS	O
+had	POS	O
+an	POS	O
+average	POS	O
+ejection	POS	O
+fraction	POS	O
+of	POS	O
+17	POS	O
+%	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+%	POS	O
+and	POS	O
+a	POS	O
+VIP	POS	O
+level	POS	O
+of	POS	O
+8	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+3	POS	O
+.	POS	O
+9	POS	O
+pg	POS	O
+/	POS	O
+mg	POS	O
+protein	POS	O
+.	POS	O
+The	POS	O
+hearts	POS	O
+without	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+average	POS	O
+ejection	POS	O
+fraction	POS	O
+of	POS	O
+this	POS	O
+group	POS	O
+62	POS	O
+%	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+10	POS	O
+%	POS	O
+)	POS	O
+had	POS	O
+a	POS	O
+VIP	POS	O
+concentration	POS	O
+of	POS	O
+14	POS	O
+.	POS	O
+1	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+7	POS	O
+.	POS	O
+9	POS	O
+pg	POS	O
+/	POS	O
+mg	POS	O
+protein	POS	O
+,	POS	O
+and	POS	O
+this	POS	O
+was	POS	O
+greater	POS	O
+than	POS	O
+in	POS	O
+hearts	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+with	POS	O
+coronary	POS	B-NP
+disease	POS	I-NP
+and	POS	O
+the	POS	O
+hearts	POS	O
+of	POS	O
+patients	POS	O
+receiving	POS	O
+a	POS	O
+transplant	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+Myocardial	POS	O
+catecholamines	POS	O
+were	POS	O
+also	POS	O
+determined	POS	O
+in	POS	O
+14	POS	O
+subjects	POS	O
+;	POS	O
+a	POS	O
+weak	POS	O
+correlation	POS	O
+(	POS	O
+r	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+57	POS	O
+,	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+between	POS	O
+the	POS	O
+tissue	POS	O
+concentrations	POS	O
+of	POS	O
+VIP	POS	O
+and	POS	O
+norepinephrine	POS	O
+was	POS	O
+noted	POS	O
+.	POS	O
+(	POS	O
+ABSTRACT	POS	O
+TRUNCATED	POS	O
+AT	POS	O
+250	POS	O
+WORDS	POS	O
+)	POS	O
+Non	POS	O
+-	POS	O
+invasive	POS	O
+detection	POS	O
+of	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+by	POS	O
+body	POS	O
+surface	POS	O
+electrocardiographic	POS	O
+mapping	POS	O
+after	POS	O
+dipyridamole	POS	O
+infusion	POS	O
+.	POS	O
+Electrocardiographic	POS	O
+changes	POS	O
+after	POS	O
+dipyridamole	POS	O
+infusion	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+568	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+4	POS	O
+min	POS	O
+)	POS	O
+were	POS	O
+studied	POS	O
+in	POS	O
+41	POS	O
+patients	POS	O
+with	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+and	POS	O
+compared	POS	O
+with	POS	O
+those	POS	O
+after	POS	O
+submaximal	POS	O
+treadmill	POS	O
+exercise	POS	O
+by	POS	O
+use	POS	O
+of	POS	O
+the	POS	O
+body	POS	O
+surface	POS	O
+mapping	POS	O
+technique	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+divided	POS	O
+into	POS	O
+three	POS	O
+groups	POS	O
+;	POS	O
+19	POS	O
+patients	POS	O
+without	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+(	POS	O
+non	POS	B-NP
+-	POS	I-NP
+MI	POS	I-NP
+group	POS	O
+)	POS	O
+,	POS	O
+14	POS	O
+with	POS	O
+anterior	POS	B-NP
+infarction	POS	I-NP
+(	POS	O
+ANT	POS	B-NP
+-	POS	I-NP
+MI	POS	I-NP
+)	POS	O
+and	POS	O
+eight	POS	O
+with	POS	O
+inferior	POS	B-NP
+infarction	POS	I-NP
+(	POS	O
+INF	POS	B-NP
+-	POS	I-NP
+MI	POS	I-NP
+)	POS	O
+.	POS	O
+Eighty	POS	O
+-	POS	O
+seven	POS	O
+unipolar	POS	O
+electrocardiograms	POS	O
+(	POS	O
+ECGs	POS	O
+)	POS	O
+distributed	POS	O
+over	POS	O
+the	POS	O
+entire	POS	O
+thoracic	POS	O
+surface	POS	O
+were	POS	O
+simultaneously	POS	O
+recorded	POS	O
+.	POS	O
+After	POS	O
+dipyridamole	POS	O
+,	POS	O
+ischemic	POS	B-NP
+ST	POS	I-NP
+-	POS	I-NP
+segment	POS	I-NP
+depression	POS	I-NP
+(	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+mV	POS	O
+or	POS	O
+more	POS	O
+)	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+84	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+non	POS	O
+-	POS	O
+MI	POS	B-NP
+group	POS	O
+,	POS	O
+29	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+ANT	POS	O
+-	POS	O
+MI	POS	B-NP
+group	POS	O
+,	POS	O
+63	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+INF	POS	O
+-	POS	O
+MI	POS	B-NP
+group	POS	O
+and	POS	O
+61	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+total	POS	O
+population	POS	O
+.	POS	O
+Exercise	POS	O
+-	POS	O
+induced	POS	O
+ST	POS	B-NP
+depression	POS	I-NP
+was	POS	O
+observed	POS	O
+in	POS	O
+84	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+non	POS	O
+-	POS	O
+MI	POS	B-NP
+group	POS	O
+,	POS	O
+43	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+ANT	POS	O
+-	POS	O
+MI	POS	B-NP
+group	POS	O
+,	POS	O
+38	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+INF	POS	O
+-	POS	O
+MI	POS	B-NP
+group	POS	O
+and	POS	O
+61	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+total	POS	O
+.	POS	O
+For	POS	O
+individual	POS	O
+patients	POS	O
+,	POS	O
+there	POS	O
+were	POS	O
+no	POS	O
+obvious	POS	O
+differences	POS	O
+between	POS	O
+the	POS	O
+body	POS	O
+surface	POS	O
+distribution	POS	O
+of	POS	O
+ST	POS	O
+depression	POS	B-NP
+in	POS	O
+both	POS	O
+tests	POS	O
+.	POS	O
+The	POS	O
+increase	POS	O
+in	POS	O
+pressure	POS	O
+rate	POS	O
+product	POS	O
+after	POS	O
+dipyridamole	POS	O
+was	POS	O
+significantly	POS	O
+less	POS	O
+than	POS	O
+that	POS	O
+during	POS	O
+the	POS	O
+treadmill	POS	O
+exercise	POS	O
+.	POS	O
+The	POS	O
+data	POS	O
+suggest	POS	O
+that	POS	O
+the	POS	O
+dipyridamole	POS	O
+-	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+ischemia	POS	I-NP
+is	POS	O
+caused	POS	O
+by	POS	O
+the	POS	O
+inhomogenous	POS	O
+distribution	POS	O
+of	POS	O
+myocardial	POS	O
+blood	POS	O
+flow	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+the	POS	O
+dipyridamole	POS	O
+ECG	POS	O
+test	POS	O
+is	POS	O
+as	POS	O
+useful	POS	O
+as	POS	O
+the	POS	O
+exercise	POS	O
+ECG	POS	O
+test	POS	O
+for	POS	O
+the	POS	O
+assessment	POS	O
+of	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+Bradycardia	POS	B-NP
+after	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+intravenous	POS	O
+methylprednisolone	POS	O
+therapy	POS	O
+.	POS	O
+In	POS	O
+5	POS	O
+consecutive	POS	O
+patients	POS	O
+with	POS	O
+rheumatoid	POS	B-NP
+arthritis	POS	I-NP
+who	POS	O
+received	POS	O
+intravenous	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+methylprednisolone	POS	O
+(	POS	O
+MP	POS	O
+)	POS	O
+therapy	POS	O
+(	POS	O
+1	POS	O
+g	POS	O
+daily	POS	O
+for	POS	O
+2	POS	O
+or	POS	O
+3	POS	O
+consecutive	POS	O
+days	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+decline	POS	O
+in	POS	O
+pulse	POS	O
+rate	POS	O
+was	POS	O
+observed	POS	O
+,	POS	O
+most	POS	O
+pronounced	POS	O
+on	POS	O
+day	POS	O
+4	POS	O
+.	POS	O
+In	POS	O
+one	POS	O
+of	POS	O
+the	POS	O
+5	POS	O
+patients	POS	O
+the	POS	O
+bradycardia	POS	B-NP
+was	POS	O
+associated	POS	O
+with	POS	O
+complaints	POS	O
+of	POS	O
+substernal	POS	O
+pressure	POS	O
+.	POS	O
+Reversal	POS	O
+to	POS	O
+normal	POS	O
+heart	POS	O
+rate	POS	O
+was	POS	O
+found	POS	O
+on	POS	O
+day	POS	O
+7	POS	O
+.	POS	O
+Electrocardiographic	POS	O
+registrations	POS	O
+showed	POS	O
+sinus	POS	B-NP
+bradycardia	POS	I-NP
+in	POS	O
+all	POS	O
+cases	POS	O
+.	POS	O
+No	POS	O
+significant	POS	O
+changes	POS	O
+in	POS	O
+plasma	POS	O
+concentrations	POS	O
+of	POS	O
+electrolytes	POS	O
+were	POS	O
+found	POS	O
+.	POS	O
+Careful	POS	O
+observation	POS	O
+of	POS	O
+patients	POS	O
+receiving	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+MP	POS	O
+is	POS	O
+recommended	POS	O
+.	POS	O
+High	POS	O
+-	POS	O
+dose	POS	O
+MP	POS	O
+may	POS	O
+be	POS	O
+contraindicated	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+known	POS	O
+heart	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+Two	POS	O
+cases	POS	O
+of	POS	O
+downbeat	POS	B-NP
+nystagmus	POS	I-NP
+and	POS	O
+oscillopsia	POS	B-NP
+associated	POS	O
+with	POS	O
+carbamazepine	POS	O
+.	POS	O
+Downbeat	POS	B-NP
+nystagmus	POS	I-NP
+is	POS	O
+often	POS	O
+associated	POS	O
+with	POS	O
+structural	POS	O
+lesions	POS	O
+at	POS	O
+the	POS	O
+craniocervical	POS	O
+junction	POS	O
+,	POS	O
+but	POS	O
+has	POS	O
+occasionally	POS	O
+been	POS	O
+reported	POS	O
+as	POS	O
+a	POS	O
+manifestation	POS	O
+of	POS	O
+metabolic	POS	O
+imbalance	POS	O
+or	POS	O
+drug	POS	O
+intoxication	POS	O
+.	POS	O
+We	POS	O
+recorded	POS	O
+the	POS	O
+eye	POS	O
+movements	POS	O
+of	POS	O
+two	POS	O
+patients	POS	O
+with	POS	O
+reversible	POS	O
+downbeat	POS	B-NP
+nystagmus	POS	I-NP
+related	POS	O
+to	POS	O
+carbamazepine	POS	O
+therapy	POS	O
+.	POS	O
+The	POS	O
+nystagmus	POS	B-NP
+of	POS	O
+both	POS	O
+patients	POS	O
+resolved	POS	O
+after	POS	O
+reduction	POS	O
+of	POS	O
+the	POS	O
+serum	POS	O
+carbamazepine	POS	O
+levels	POS	O
+.	POS	O
+Neuroradiologic	POS	O
+investigations	POS	O
+including	POS	O
+magnetic	POS	O
+resonance	POS	O
+imaging	POS	O
+scans	POS	O
+in	POS	O
+both	POS	O
+patients	POS	O
+showed	POS	O
+no	POS	O
+evidence	POS	O
+of	POS	O
+intracranial	POS	B-NP
+abnormality	POS	I-NP
+.	POS	O
+In	POS	O
+patients	POS	O
+with	POS	O
+downbeat	POS	B-NP
+nystagmus	POS	I-NP
+who	POS	O
+are	POS	O
+taking	POS	O
+anticonvulsant	POS	O
+medications	POS	O
+,	POS	O
+consideration	POS	O
+should	POS	O
+be	POS	O
+given	POS	O
+to	POS	O
+reduction	POS	O
+in	POS	O
+dose	POS	O
+before	POS	O
+further	POS	O
+investigation	POS	O
+is	POS	O
+undertaken	POS	O
+.	POS	O
+Improvement	POS	O
+by	POS	O
+denopamine	POS	O
+(	POS	O
+TA	POS	O
+-	POS	O
+064	POS	O
+)	POS	O
+of	POS	O
+pentobarbital	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+failure	POS	I-NP
+in	POS	O
+the	POS	O
+dog	POS	O
+heart	POS	O
+-	POS	O
+lung	POS	O
+preparation	POS	O
+.	POS	O
+The	POS	O
+efficacy	POS	O
+of	POS	O
+denopamine	POS	O
+,	POS	O
+an	POS	O
+orally	POS	O
+active	POS	O
+beta	POS	O
+1	POS	O
+-	POS	O
+adrenoceptor	POS	O
+agonist	POS	O
+,	POS	O
+in	POS	O
+improving	POS	O
+cardiac	POS	B-NP
+failure	POS	I-NP
+was	POS	O
+assessed	POS	O
+in	POS	O
+dog	POS	O
+heart	POS	O
+-	POS	O
+lung	POS	O
+preparations	POS	O
+.	POS	O
+Cardiac	POS	O
+functions	POS	O
+depressed	POS	O
+by	POS	O
+pentobarbital	POS	O
+(	POS	O
+118	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+28	POS	O
+mg	POS	O
+;	POS	O
+mean	POS	O
+value	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+SD	POS	O
+)	POS	O
+such	POS	O
+that	POS	O
+cardiac	POS	O
+output	POS	O
+and	POS	O
+maximum	POS	O
+rate	POS	O
+of	POS	O
+rise	POS	O
+of	POS	O
+left	POS	O
+ventricular	POS	O
+pressure	POS	O
+(	POS	O
+LV	POS	O
+dP	POS	O
+/	POS	O
+dt	POS	O
+max	POS	O
+)	POS	O
+had	POS	O
+been	POS	O
+reduced	POS	O
+by	POS	O
+about	POS	O
+35	POS	O
+%	POS	O
+and	POS	O
+26	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+respective	POS	O
+controls	POS	O
+were	POS	O
+improved	POS	O
+by	POS	O
+denopamine	POS	O
+(	POS	O
+10	POS	O
+-	POS	O
+300	POS	O
+micrograms	POS	O
+)	POS	O
+in	POS	O
+a	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+manner	POS	O
+.	POS	O
+With	POS	O
+100	POS	O
+micrograms	POS	O
+denopamine	POS	O
+,	POS	O
+almost	POS	O
+complete	POS	O
+restoration	POS	O
+of	POS	O
+cardiac	POS	O
+performance	POS	O
+was	POS	O
+attained	POS	O
+,	POS	O
+associated	POS	O
+with	POS	O
+a	POS	O
+slight	POS	O
+increase	POS	O
+in	POS	O
+heart	POS	O
+rate	POS	O
+.	POS	O
+No	POS	O
+arrhythmias	POS	B-NP
+were	POS	O
+induced	POS	O
+by	POS	O
+these	POS	O
+doses	POS	O
+of	POS	O
+denopamine	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+warrant	POS	O
+clinical	POS	O
+trials	POS	O
+of	POS	O
+denopamine	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+cardiac	POS	B-NP
+failure	POS	I-NP
+.	POS	O
+Clonazepam	POS	O
+monotherapy	POS	O
+for	POS	O
+epilepsy	POS	B-NP
+in	POS	O
+childhood	POS	O
+.	POS	O
+Sixty	POS	O
+patients	POS	O
+(	POS	O
+age	POS	O
+-	POS	O
+range	POS	O
+one	POS	O
+month	POS	O
+to	POS	O
+14	POS	O
+years	POS	O
+)	POS	O
+with	POS	O
+other	POS	O
+types	POS	O
+of	POS	O
+epilepsy	POS	B-NP
+than	POS	O
+infantile	POS	B-NP
+spasms	POS	I-NP
+were	POS	O
+treated	POS	O
+with	POS	O
+clonazepam	POS	O
+.	POS	O
+Disappearance	POS	O
+of	POS	O
+seizures	POS	B-NP
+and	POS	O
+normalization	POS	O
+of	POS	O
+abnormal	POS	O
+EEG	POS	O
+with	POS	O
+disappearance	POS	O
+of	POS	O
+seizures	POS	B-NP
+were	POS	O
+recognized	POS	O
+in	POS	O
+77	POS	O
+%	POS	O
+and	POS	O
+50	POS	O
+%	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+Seizures	POS	B-NP
+disappeared	POS	O
+in	POS	O
+71	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+with	POS	O
+generalized	POS	O
+seizures	POS	B-NP
+and	POS	O
+89	POS	O
+%	POS	O
+of	POS	O
+partial	POS	O
+seizures	POS	B-NP
+.	POS	O
+Improvement	POS	O
+of	POS	O
+abnormal	POS	O
+EEG	POS	O
+was	POS	O
+noticed	POS	O
+in	POS	O
+76	POS	O
+%	POS	O
+of	POS	O
+diffuse	POS	O
+paroxysms	POS	B-NP
+and	POS	O
+in	POS	O
+67	POS	O
+%	POS	O
+of	POS	O
+focal	POS	O
+paroxysms	POS	B-NP
+.	POS	O
+In	POS	O
+excellent	POS	O
+cases	POS	O
+,	POS	O
+mean	POS	O
+effective	POS	O
+dosages	POS	O
+were	POS	O
+0	POS	O
+.	POS	O
+086	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+021	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+in	POS	O
+infants	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+057	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+022	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+day	POS	O
+in	POS	O
+schoolchildren	POS	O
+,	POS	O
+this	POS	O
+difference	POS	O
+was	POS	O
+statistically	POS	O
+significant	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+005	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+side	POS	O
+effects	POS	O
+such	POS	O
+as	POS	O
+drowsiness	POS	B-NP
+and	POS	O
+ataxia	POS	B-NP
+was	POS	O
+only	POS	O
+5	POS	O
+%	POS	O
+.	POS	O
+Postmarketing	POS	O
+study	POS	O
+of	POS	O
+timolol	POS	O
+-	POS	O
+hydrochlorothiazide	POS	O
+antihypertensive	POS	O
+therapy	POS	O
+.	POS	O
+A	POS	O
+postmarketing	POS	O
+surveillance	POS	O
+study	POS	O
+was	POS	O
+conducted	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+safety	POS	O
+and	POS	O
+efficacy	POS	O
+of	POS	O
+a	POS	O
+fixed	POS	O
+-	POS	O
+ratio	POS	O
+combination	POS	O
+containing	POS	O
+10	POS	O
+mg	POS	O
+of	POS	O
+timolol	POS	O
+maleate	POS	O
+and	POS	O
+25	POS	O
+mg	POS	O
+of	POS	O
+hydrochlorothiazide	POS	O
+,	POS	O
+administered	POS	O
+twice	POS	O
+daily	POS	O
+for	POS	O
+one	POS	O
+month	POS	O
+to	POS	O
+hypertensive	POS	B-NP
+patients	POS	O
+.	POS	O
+Data	POS	O
+on	POS	O
+9	POS	O
+,	POS	O
+037	POS	O
+patients	POS	O
+were	POS	O
+collected	POS	O
+by	POS	O
+1	POS	O
+,	POS	O
+455	POS	O
+participating	POS	O
+physicians	POS	O
+.	POS	O
+Mean	POS	O
+systolic	POS	O
+blood	POS	O
+pressure	POS	O
+decreased	POS	O
+25	POS	O
+mmHg	POS	O
+and	POS	O
+mean	POS	O
+diastolic	POS	O
+blood	POS	O
+pressure	POS	O
+declined	POS	O
+15	POS	O
+mmHg	POS	O
+after	POS	O
+one	POS	O
+month	POS	O
+of	POS	O
+timolol	POS	O
+-	POS	O
+hydrochlorothiazide	POS	O
+therapy	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+,	POS	O
+both	POS	O
+comparisons	POS	O
+)	POS	O
+.	POS	O
+Age	POS	O
+,	POS	O
+race	POS	O
+,	POS	O
+and	POS	O
+sex	POS	O
+appeared	POS	O
+to	POS	O
+have	POS	O
+no	POS	O
+influence	POS	O
+on	POS	O
+the	POS	O
+decrease	POS	O
+in	POS	O
+blood	POS	O
+pressure	POS	O
+.	POS	O
+The	POS	O
+antihypertensive	POS	O
+effect	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+was	POS	O
+greater	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+more	POS	O
+severe	POS	O
+hypertension	POS	B-NP
+.	POS	O
+Overall	POS	O
+,	POS	O
+1	POS	O
+,	POS	O
+453	POS	O
+patients	POS	O
+experienced	POS	O
+a	POS	O
+total	POS	O
+of	POS	O
+2	POS	O
+,	POS	O
+658	POS	O
+adverse	POS	O
+events	POS	O
+,	POS	O
+the	POS	O
+most	POS	O
+common	POS	O
+being	POS	O
+fatigue	POS	B-NP
+,	POS	O
+dizziness	POS	B-NP
+,	POS	O
+and	POS	O
+weakness	POS	B-NP
+.	POS	O
+Treatment	POS	O
+in	POS	O
+590	POS	O
+patients	POS	O
+was	POS	O
+discontinued	POS	O
+because	POS	O
+of	POS	O
+adverse	POS	O
+events	POS	O
+.	POS	O
+Salicylate	POS	O
+nephropathy	POS	B-NP
+in	POS	O
+the	POS	O
+Gunn	POS	O
+rat	POS	O
+:	POS	O
+potential	POS	O
+role	POS	O
+of	POS	O
+prostaglandins	POS	O
+.	POS	O
+We	POS	O
+examined	POS	O
+the	POS	O
+potential	POS	O
+role	POS	O
+of	POS	O
+prostaglandins	POS	O
+in	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+analgesic	POS	O
+nephropathy	POS	B-NP
+in	POS	O
+the	POS	O
+Gunn	POS	O
+strain	POS	O
+of	POS	O
+rat	POS	O
+.	POS	O
+The	POS	O
+homozygous	POS	O
+Gunn	POS	O
+rats	POS	O
+have	POS	O
+unconjugated	POS	O
+hyperbilirubinemia	POS	B-NP
+due	POS	O
+to	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+glucuronyl	POS	O
+transferase	POS	O
+,	POS	O
+leading	POS	O
+to	POS	O
+marked	POS	O
+bilirubin	POS	O
+deposition	POS	O
+in	POS	O
+renal	POS	O
+medulla	POS	O
+and	POS	O
+papilla	POS	O
+.	POS	O
+These	POS	O
+rats	POS	O
+are	POS	O
+also	POS	O
+highly	POS	O
+susceptible	POS	O
+to	POS	O
+develop	POS	O
+papillary	POS	B-NP
+necrosis	POS	I-NP
+with	POS	O
+analgesic	POS	O
+administration	POS	O
+.	POS	O
+We	POS	O
+used	POS	O
+homozygous	POS	O
+(	POS	O
+jj	POS	O
+)	POS	O
+and	POS	O
+phenotypically	POS	O
+normal	POS	B-NP
+heterozygous	POS	O
+(	POS	O
+jJ	POS	O
+)	POS	O
+animals	POS	O
+.	POS	O
+Four	POS	O
+groups	POS	O
+of	POS	O
+rats	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+7	POS	O
+)	POS	O
+were	POS	O
+studied	POS	O
+:	POS	O
+jj	POS	O
+and	POS	O
+jJ	POS	O
+rats	POS	O
+treated	POS	O
+either	POS	O
+with	POS	O
+aspirin	POS	O
+300	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+every	POS	O
+other	POS	O
+day	POS	O
+or	POS	O
+sham	POS	O
+-	POS	O
+treated	POS	O
+.	POS	O
+After	POS	O
+one	POS	O
+week	POS	O
+,	POS	O
+slices	POS	O
+of	POS	O
+cortex	POS	O
+,	POS	O
+outer	POS	O
+and	POS	O
+inner	POS	O
+medulla	POS	O
+from	POS	O
+one	POS	O
+kidney	POS	O
+were	POS	O
+incubated	POS	O
+in	POS	O
+buffer	POS	O
+and	POS	O
+prostaglandin	POS	O
+synthesis	POS	O
+was	POS	O
+determined	POS	O
+by	POS	O
+radioimmunoassay	POS	O
+.	POS	O
+The	POS	O
+other	POS	O
+kidney	POS	O
+was	POS	O
+examined	POS	O
+histologically	POS	O
+.	POS	O
+A	POS	O
+marked	POS	O
+corticomedullary	POS	O
+gradient	POS	O
+of	POS	O
+prostaglandin	POS	O
+synthesis	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+all	POS	O
+groups	POS	O
+.	POS	O
+PGE2	POS	O
+synthesis	POS	O
+was	POS	O
+significantly	POS	O
+higher	POS	O
+in	POS	O
+outer	POS	O
+medulla	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+cortex	POS	O
+or	POS	O
+inner	POS	O
+medulla	POS	O
+,	POS	O
+of	POS	O
+jj	POS	O
+(	POS	O
+38	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+ng	POS	O
+/	POS	O
+mg	POS	O
+prot	POS	O
+)	POS	O
+than	POS	O
+jJ	POS	O
+rats	POS	O
+(	POS	O
+15	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+3	POS	O
+)	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+Aspirin	POS	O
+treatment	POS	O
+reduced	POS	O
+PGE2	POS	O
+synthesis	POS	O
+in	POS	O
+all	POS	O
+regions	POS	O
+,	POS	O
+but	POS	O
+outer	POS	O
+medullary	POS	O
+PGE2	POS	O
+remained	POS	O
+higher	POS	O
+in	POS	O
+jj	POS	O
+(	POS	O
+18	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+3	POS	O
+)	POS	O
+than	POS	O
+jJ	POS	O
+rats	POS	O
+(	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+2	POS	O
+)	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+PGF2	POS	O
+alpha	POS	O
+was	POS	O
+also	POS	O
+significantly	POS	O
+higher	POS	O
+in	POS	O
+the	POS	O
+outer	POS	O
+medulla	POS	O
+of	POS	O
+jj	POS	O
+rats	POS	O
+with	POS	O
+and	POS	O
+without	POS	O
+aspirin	POS	O
+administration	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+changes	POS	O
+in	POS	O
+renal	POS	O
+prostaglandin	POS	O
+synthesis	POS	O
+were	POS	O
+accompanied	POS	O
+by	POS	O
+evidence	POS	O
+of	POS	O
+renal	POS	B-NP
+damage	POS	I-NP
+in	POS	O
+aspirin	POS	O
+-	POS	O
+treated	POS	O
+jj	POS	O
+but	POS	O
+not	POS	O
+jJ	POS	O
+rats	POS	O
+as	POS	O
+evidenced	POS	O
+by	POS	O
+:	POS	O
+increased	POS	O
+incidence	POS	O
+and	POS	O
+severity	POS	O
+of	POS	O
+hematuria	POS	B-NP
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+;	POS	O
+increased	POS	O
+serum	POS	O
+creatinine	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+;	POS	O
+and	POS	O
+increase	POS	O
+in	POS	O
+outer	POS	O
+medullary	POS	O
+histopathologic	POS	O
+lesions	POS	B-NP
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+005	POS	O
+compared	POS	O
+to	POS	O
+either	POS	O
+sham	POS	O
+-	POS	O
+treated	POS	O
+jj	POS	O
+or	POS	O
+aspirin	POS	O
+-	POS	O
+treated	POS	O
+jJ	POS	O
+)	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+enhanced	POS	O
+prostaglandin	POS	O
+synthesis	POS	O
+contributes	POS	O
+to	POS	O
+maintenance	POS	O
+of	POS	O
+renal	POS	O
+function	POS	O
+and	POS	O
+morphological	POS	O
+integrity	POS	O
+,	POS	O
+and	POS	O
+that	POS	O
+inhibition	POS	O
+of	POS	O
+prostaglandin	POS	O
+synthesis	POS	O
+may	POS	O
+lead	POS	O
+to	POS	O
+pathological	POS	O
+renal	POS	B-NP
+medullary	POS	I-NP
+lesions	POS	I-NP
+and	POS	O
+deterioration	POS	B-NP
+of	POS	I-NP
+renal	POS	I-NP
+function	POS	I-NP
+.	POS	O
+Prophylactic	POS	O
+lidocaine	POS	O
+in	POS	O
+the	POS	O
+early	POS	O
+phase	POS	O
+of	POS	O
+suspected	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+Four	POS	O
+hundred	POS	O
+two	POS	O
+patients	POS	O
+with	POS	O
+suspected	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+seen	POS	O
+within	POS	O
+6	POS	O
+hours	POS	O
+of	POS	O
+the	POS	O
+onset	POS	O
+of	POS	O
+symptoms	POS	O
+entered	POS	O
+a	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+randomized	POS	O
+trial	POS	O
+of	POS	O
+lidocaine	POS	O
+vs	POS	O
+placebo	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+1	POS	O
+hour	POS	O
+after	POS	O
+administration	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+ventricular	POS	B-NP
+fibrillation	POS	I-NP
+or	POS	O
+sustained	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+among	POS	O
+the	POS	O
+204	POS	O
+patients	POS	O
+with	POS	O
+acute	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+was	POS	O
+low	POS	O
+,	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+.	POS	O
+Lidocaine	POS	O
+,	POS	O
+given	POS	O
+in	POS	O
+a	POS	O
+300	POS	O
+mg	POS	O
+dose	POS	O
+intramuscularly	POS	O
+followed	POS	O
+by	POS	O
+100	POS	O
+mg	POS	O
+intravenously	POS	O
+,	POS	O
+did	POS	O
+not	POS	O
+prevent	POS	O
+sustained	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+,	POS	O
+although	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+reduction	POS	O
+in	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+warning	POS	O
+arrhythmias	POS	B-NP
+between	POS	O
+15	POS	O
+and	POS	O
+45	POS	O
+minutes	POS	O
+after	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+lidocaine	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+average	POS	O
+plasma	POS	O
+lidocaine	POS	O
+level	POS	O
+10	POS	O
+minutes	POS	O
+after	POS	O
+administration	POS	O
+for	POS	O
+patients	POS	O
+without	POS	O
+a	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+was	POS	O
+significantly	POS	O
+higher	POS	O
+than	POS	O
+that	POS	O
+for	POS	O
+patients	POS	O
+with	POS	O
+an	POS	O
+acute	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+The	POS	O
+mean	POS	O
+plasma	POS	O
+lidocaine	POS	O
+level	POS	O
+of	POS	O
+patients	POS	O
+on	POS	O
+beta	POS	O
+-	POS	O
+blocking	POS	O
+agents	POS	O
+was	POS	O
+no	POS	O
+different	POS	O
+from	POS	O
+that	POS	O
+in	POS	O
+patients	POS	O
+not	POS	O
+on	POS	O
+beta	POS	O
+blocking	POS	O
+agents	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+1	POS	O
+-	POS	O
+hour	POS	O
+study	POS	O
+period	POS	O
+,	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+side	POS	O
+effects	POS	O
+was	POS	O
+significantly	POS	O
+greater	POS	O
+in	POS	O
+the	POS	O
+lidocaine	POS	O
+group	POS	O
+,	POS	O
+hypotension	POS	B-NP
+occurred	POS	O
+in	POS	O
+11	POS	O
+patients	POS	O
+,	POS	O
+nine	POS	O
+of	POS	O
+whom	POS	O
+had	POS	O
+received	POS	O
+lidocaine	POS	O
+,	POS	O
+and	POS	O
+four	POS	O
+patients	POS	O
+died	POS	O
+from	POS	O
+asystole	POS	B-NP
+,	POS	O
+three	POS	O
+of	POS	O
+whom	POS	O
+had	POS	O
+had	POS	O
+lidocaine	POS	O
+.	POS	O
+We	POS	O
+cannot	POS	O
+advocate	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+lidocaine	POS	O
+prophylactically	POS	O
+in	POS	O
+the	POS	O
+early	POS	O
+hours	POS	O
+of	POS	O
+suspected	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+Evidence	POS	O
+for	POS	O
+a	POS	O
+cholinergic	POS	O
+role	POS	O
+in	POS	O
+haloperidol	POS	O
+-	POS	O
+induced	POS	O
+catalepsy	POS	B-NP
+.	POS	O
+Experiments	POS	O
+in	POS	O
+mice	POS	O
+tested	POS	O
+previous	POS	O
+evidence	POS	O
+that	POS	O
+activation	POS	O
+of	POS	O
+cholinergic	POS	O
+systems	POS	O
+promotes	POS	O
+catalepsy	POS	B-NP
+and	POS	O
+that	POS	O
+cholinergic	POS	O
+mechanisms	POS	O
+need	POS	O
+to	POS	O
+be	POS	O
+intact	POS	O
+for	POS	O
+full	POS	O
+expression	POS	O
+of	POS	O
+neuroleptic	POS	O
+-	POS	O
+induced	POS	O
+catalepsy	POS	B-NP
+.	POS	O
+Large	POS	O
+doses	POS	O
+of	POS	O
+the	POS	O
+cholinomimetic	POS	O
+,	POS	O
+pilocarpine	POS	O
+,	POS	O
+could	POS	O
+induce	POS	O
+catalepsy	POS	B-NP
+when	POS	O
+peripheral	POS	O
+cholinergic	POS	O
+receptors	POS	O
+were	POS	O
+blocked	POS	O
+.	POS	O
+Low	POS	O
+doses	POS	O
+of	POS	O
+pilocarpine	POS	O
+caused	POS	O
+a	POS	O
+pronounced	POS	O
+enhancement	POS	O
+of	POS	O
+the	POS	O
+catalepsy	POS	B-NP
+that	POS	O
+was	POS	O
+induced	POS	O
+by	POS	O
+the	POS	O
+dopaminergic	POS	O
+blocker	POS	O
+,	POS	O
+haloperidol	POS	O
+.	POS	O
+A	POS	O
+muscarinic	POS	O
+receptor	POS	O
+blocker	POS	O
+,	POS	O
+atropine	POS	O
+,	POS	O
+disrupted	POS	O
+haloperidol	POS	O
+-	POS	O
+induced	POS	O
+catalepsy	POS	B-NP
+.	POS	O
+Intracranial	POS	O
+injection	POS	O
+of	POS	O
+an	POS	O
+acetylcholine	POS	O
+-	POS	O
+synthesis	POS	O
+inhibitor	POS	O
+,	POS	O
+hemicholinium	POS	O
+,	POS	O
+prevented	POS	O
+the	POS	O
+catalepsy	POS	B-NP
+that	POS	O
+is	POS	O
+usually	POS	O
+induced	POS	O
+by	POS	O
+haloperidol	POS	O
+.	POS	O
+These	POS	O
+findings	POS	O
+suggest	POS	O
+the	POS	O
+hypothesis	POS	O
+that	POS	O
+the	POS	O
+catalepsy	POS	B-NP
+that	POS	O
+is	POS	O
+produced	POS	O
+by	POS	O
+neuroleptics	POS	O
+such	POS	O
+as	POS	O
+haloperidol	POS	O
+is	POS	O
+actually	POS	O
+mediated	POS	O
+by	POS	O
+intrinsic	POS	O
+central	POS	O
+cholinergic	POS	O
+systems	POS	O
+.	POS	O
+Alternatively	POS	O
+,	POS	O
+activation	POS	O
+of	POS	O
+central	POS	O
+cholinergic	POS	O
+systems	POS	O
+could	POS	O
+promote	POS	O
+catalepsy	POS	B-NP
+by	POS	O
+suppression	POS	O
+of	POS	O
+dopaminergic	POS	O
+systems	POS	O
+.	POS	O
+Cardiovascular	POS	B-NP
+dysfunction	POS	I-NP
+and	POS	O
+hypersensitivity	POS	B-NP
+to	POS	O
+sodium	POS	O
+pentobarbital	POS	O
+induced	POS	O
+by	POS	O
+chronic	POS	O
+barium	POS	O
+chloride	POS	O
+ingestion	POS	O
+.	POS	O
+Barium	POS	O
+-	POS	O
+supplemented	POS	O
+Long	POS	O
+-	POS	O
+Evans	POS	O
+hooded	POS	O
+rats	POS	O
+were	POS	O
+characterized	POS	O
+by	POS	O
+a	POS	O
+persistent	POS	O
+hypertension	POS	B-NP
+that	POS	O
+was	POS	O
+evident	POS	O
+after	POS	O
+1	POS	O
+month	POS	O
+of	POS	O
+barium	POS	O
+(	POS	O
+100	POS	O
+micrograms	POS	O
+/	POS	O
+ml	POS	O
+mineral	POS	O
+fortified	POS	O
+water	POS	O
+)	POS	O
+treatment	POS	O
+.	POS	O
+Analysis	POS	O
+of	POS	O
+in	POS	O
+vivo	POS	O
+myocardial	POS	O
+excitability	POS	O
+,	POS	O
+contractility	POS	O
+,	POS	O
+and	POS	O
+metabolic	POS	O
+characteristics	POS	O
+at	POS	O
+16	POS	O
+months	POS	O
+revealed	POS	O
+other	POS	O
+significant	POS	O
+barium	POS	O
+-	POS	O
+induced	POS	O
+disturbances	POS	O
+within	POS	O
+the	POS	O
+cardiovascular	POS	O
+system	POS	O
+.	POS	O
+The	POS	O
+most	POS	O
+distinctive	POS	O
+aspect	POS	O
+of	POS	O
+the	POS	O
+barium	POS	O
+effect	POS	O
+was	POS	O
+a	POS	O
+demonstrated	POS	O
+hypersensitivity	POS	B-NP
+of	POS	I-NP
+the	POS	I-NP
+cardiovascular	POS	I-NP
+system	POS	I-NP
+to	POS	O
+sodium	POS	O
+pentobarbital	POS	O
+.	POS	O
+Under	POS	O
+barbiturate	POS	O
+anesthesia	POS	O
+,	POS	O
+virtually	POS	O
+all	POS	O
+of	POS	O
+the	POS	O
+myocardial	POS	O
+contractile	POS	O
+indices	POS	O
+were	POS	O
+depressed	POS	O
+significantly	POS	O
+in	POS	O
+barium	POS	O
+-	POS	O
+exposed	POS	O
+rats	POS	O
+relative	POS	O
+to	POS	O
+the	POS	O
+corresponding	POS	O
+control	POS	O
+-	POS	O
+fed	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+lack	POS	O
+of	POS	O
+a	POS	O
+similar	POS	O
+response	POS	O
+to	POS	O
+ketamine	POS	O
+and	POS	O
+xylazine	POS	O
+anesthesia	POS	O
+revealed	POS	O
+that	POS	O
+the	POS	O
+cardiovascular	POS	O
+actions	POS	O
+of	POS	O
+sodium	POS	O
+pentobarbital	POS	O
+in	POS	O
+barium	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+were	POS	O
+linked	POS	O
+specifically	POS	O
+to	POS	O
+this	POS	O
+anesthetic	POS	O
+,	POS	O
+and	POS	O
+were	POS	O
+not	POS	O
+representative	POS	O
+of	POS	O
+a	POS	O
+generalized	POS	O
+anesthetic	POS	O
+response	POS	O
+.	POS	O
+Other	POS	O
+myocardial	POS	O
+pathophysiologic	POS	O
+and	POS	O
+metabolic	POS	O
+changes	POS	O
+induced	POS	O
+by	POS	O
+barium	POS	O
+were	POS	O
+manifest	POS	O
+,	POS	O
+irrespective	POS	O
+of	POS	O
+the	POS	O
+anesthetic	POS	O
+employed	POS	O
+.	POS	O
+The	POS	O
+contractile	POS	O
+element	POS	O
+shortening	POS	O
+velocity	POS	O
+of	POS	O
+the	POS	O
+cardiac	POS	O
+muscle	POS	O
+fibers	POS	O
+was	POS	O
+significantly	POS	O
+slower	POS	O
+in	POS	O
+both	POS	O
+groups	POS	O
+of	POS	O
+barium	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+relative	POS	O
+to	POS	O
+the	POS	O
+control	POS	O
+groups	POS	O
+,	POS	O
+irrespective	POS	O
+of	POS	O
+the	POS	O
+anesthetic	POS	O
+regimen	POS	O
+.	POS	O
+Similarly	POS	O
+,	POS	O
+significant	POS	O
+disturbances	POS	O
+in	POS	O
+myocardial	POS	O
+energy	POS	O
+metabolism	POS	O
+were	POS	O
+detected	POS	O
+in	POS	O
+the	POS	O
+barium	POS	O
+-	POS	O
+exposed	POS	O
+rats	POS	O
+which	POS	O
+were	POS	O
+consistent	POS	O
+with	POS	O
+the	POS	O
+reduced	POS	O
+contractile	POS	O
+element	POS	O
+shortening	POS	O
+velocity	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+the	POS	O
+excitability	POS	O
+of	POS	O
+the	POS	O
+cardiac	POS	O
+conduction	POS	O
+system	POS	O
+was	POS	O
+depressed	POS	O
+preferentially	POS	O
+in	POS	O
+the	POS	O
+atrioventricular	POS	O
+nodal	POS	O
+region	POS	O
+of	POS	O
+hearts	POS	O
+from	POS	O
+barium	POS	O
+-	POS	O
+exposed	POS	O
+rats	POS	O
+.	POS	O
+Overall	POS	O
+,	POS	O
+the	POS	O
+altered	POS	O
+cardiac	POS	O
+contractility	POS	O
+and	POS	O
+excitability	POS	O
+characteristics	POS	O
+,	POS	O
+the	POS	O
+myocardial	POS	B-NP
+metabolic	POS	I-NP
+disturbances	POS	I-NP
+,	POS	O
+and	POS	O
+the	POS	O
+hypersensitivity	POS	B-NP
+of	POS	O
+the	POS	O
+cardiovascular	POS	O
+system	POS	O
+to	POS	O
+sodium	POS	O
+pentobarbital	POS	O
+suggest	POS	O
+the	POS	O
+existence	POS	O
+of	POS	O
+a	POS	O
+heretofore	POS	O
+undescribed	POS	O
+cardiomyopathic	POS	B-NP
+disorder	POS	I-NP
+induced	POS	O
+by	POS	O
+chronic	POS	O
+barium	POS	O
+exposure	POS	O
+.	POS	O
+These	POS	O
+experimental	POS	O
+findings	POS	O
+represent	POS	O
+the	POS	O
+first	POS	O
+indication	POS	O
+that	POS	O
+life	POS	O
+-	POS	O
+long	POS	O
+barium	POS	O
+ingestion	POS	O
+may	POS	O
+have	POS	O
+significant	POS	O
+adverse	POS	O
+effects	POS	O
+on	POS	O
+the	POS	O
+mammalian	POS	O
+cardiovascular	POS	O
+system	POS	O
+.	POS	O
+Propranolol	POS	O
+antagonism	POS	O
+of	POS	O
+phenylpropanolamine	POS	O
+-	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+.	POS	O
+Phenylpropanolamine	POS	B-NP
+(	POS	O
+PPA	POS	O
+)	POS	O
+overdose	POS	B-NP
+can	POS	O
+cause	POS	O
+severe	POS	O
+hypertension	POS	B-NP
+,	POS	O
+intracerebral	POS	B-NP
+hemorrhage	POS	I-NP
+,	POS	O
+and	POS	O
+death	POS	B-NP
+.	POS	O
+We	POS	O
+studied	POS	O
+the	POS	O
+efficacy	POS	O
+and	POS	O
+safety	POS	O
+of	POS	O
+propranolol	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+PPA	POS	O
+-	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+.	POS	O
+Subjects	POS	O
+received	POS	O
+propranolol	POS	O
+either	POS	O
+by	POS	O
+mouth	POS	O
+for	POS	O
+48	POS	O
+hours	POS	O
+before	POS	O
+PPA	POS	O
+or	POS	O
+as	POS	O
+a	POS	O
+rapid	POS	O
+intravenous	POS	O
+infusion	POS	O
+after	POS	O
+PPA	POS	O
+.	POS	O
+PPA	POS	O
+,	POS	O
+75	POS	O
+mg	POS	O
+alone	POS	O
+,	POS	O
+increased	POS	O
+blood	POS	O
+pressure	POS	O
+(	POS	O
+31	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+14	POS	O
+mm	POS	O
+Hg	POS	O
+systolic	POS	O
+,	POS	O
+20	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+5	POS	O
+mm	POS	O
+Hg	POS	O
+diastolic	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+propranolol	POS	O
+pretreatment	POS	O
+antagonized	POS	O
+this	POS	O
+increase	POS	O
+(	POS	O
+12	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+10	POS	O
+mm	POS	O
+Hg	POS	O
+systolic	POS	O
+,	POS	O
+10	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+7	POS	O
+mm	POS	O
+Hg	POS	O
+diastolic	POS	O
+)	POS	O
+.	POS	O
+Intravenous	POS	O
+propranolol	POS	O
+after	POS	O
+PPA	POS	O
+also	POS	O
+decreased	POS	O
+blood	POS	O
+pressure	POS	O
+.	POS	O
+Left	POS	O
+ventricular	POS	O
+function	POS	O
+(	POS	O
+assessed	POS	O
+by	POS	O
+echocardiography	POS	O
+)	POS	O
+showed	POS	O
+that	POS	O
+PPA	POS	O
+increased	POS	O
+the	POS	O
+stroke	POS	B-NP
+volume	POS	O
+30	POS	O
+%	POS	O
+(	POS	O
+from	POS	O
+62	POS	O
+.	POS	O
+5	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+20	POS	O
+.	POS	O
+9	POS	O
+to	POS	O
+80	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+22	POS	O
+.	POS	O
+4	POS	O
+ml	POS	O
+)	POS	O
+,	POS	O
+the	POS	O
+ejection	POS	O
+fraction	POS	O
+9	POS	O
+%	POS	O
+(	POS	O
+from	POS	O
+64	POS	O
+%	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+10	POS	O
+%	POS	O
+to	POS	O
+70	POS	O
+%	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+7	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+cardiac	POS	O
+output	POS	O
+14	POS	O
+%	POS	O
+(	POS	O
+from	POS	O
+3	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+6	POS	O
+to	POS	O
+4	POS	O
+.	POS	O
+1	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+0	POS	O
+L	POS	O
+/	POS	O
+min	POS	O
+)	POS	O
+.	POS	O
+Intravenous	POS	O
+propranolol	POS	O
+reversed	POS	O
+these	POS	O
+effects	POS	O
+.	POS	O
+Systemic	POS	O
+vascular	POS	O
+resistance	POS	O
+was	POS	O
+increased	POS	O
+by	POS	O
+PPA	POS	O
+28	POS	O
+%	POS	O
+(	POS	O
+from	POS	O
+1710	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+200	POS	O
+to	POS	O
+2190	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+700	POS	O
+dyne	POS	O
+X	POS	O
+sec	POS	O
+/	POS	O
+cm5	POS	O
+)	POS	O
+and	POS	O
+was	POS	O
+further	POS	O
+increased	POS	O
+by	POS	O
+propranolol	POS	O
+22	POS	O
+%	POS	O
+(	POS	O
+to	POS	O
+2660	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1200	POS	O
+dyne	POS	O
+X	POS	O
+sec	POS	O
+/	POS	O
+cm5	POS	O
+)	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+PPA	POS	O
+increases	POS	O
+blood	POS	O
+pressure	POS	O
+by	POS	O
+increasing	POS	O
+systemic	POS	O
+vascular	POS	O
+resistance	POS	O
+and	POS	O
+cardiac	POS	O
+output	POS	O
+,	POS	O
+and	POS	O
+that	POS	O
+propranolol	POS	O
+antagonizes	POS	O
+this	POS	O
+increase	POS	O
+by	POS	O
+reversing	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+PPA	POS	O
+on	POS	O
+cardiac	POS	O
+output	POS	O
+.	POS	O
+That	POS	O
+propranolol	POS	O
+antagonizes	POS	O
+the	POS	O
+pressor	POS	O
+effect	POS	O
+of	POS	O
+PPA	POS	O
+is	POS	O
+in	POS	O
+contrast	POS	O
+to	POS	O
+the	POS	O
+interaction	POS	O
+in	POS	O
+which	POS	O
+propranolol	POS	O
+enhances	POS	O
+the	POS	O
+pressor	POS	O
+effect	POS	O
+of	POS	O
+norepinephrine	POS	O
+.	POS	O
+This	POS	O
+is	POS	O
+probably	POS	O
+because	POS	O
+PPA	POS	O
+has	POS	O
+less	POS	O
+beta	POS	O
+2	POS	O
+activity	POS	O
+than	POS	O
+does	POS	O
+norepinephrine	POS	O
+.	POS	O
+Mesangial	POS	O
+function	POS	O
+and	POS	O
+glomerular	POS	B-NP
+sclerosis	POS	I-NP
+in	POS	O
+rats	POS	O
+with	POS	O
+aminonucleoside	POS	O
+nephrosis	POS	B-NP
+.	POS	O
+The	POS	O
+possible	POS	O
+relationship	POS	O
+between	POS	O
+mesangial	POS	B-NP
+dysfunction	POS	I-NP
+and	POS	O
+development	POS	O
+of	POS	O
+glomerular	POS	B-NP
+sclerosis	POS	I-NP
+was	POS	O
+studied	POS	O
+in	POS	O
+the	POS	O
+puromycin	POS	O
+aminonucleoside	POS	O
+(	POS	O
+PAN	POS	O
+)	POS	O
+model	POS	O
+.	POS	O
+Five	POS	O
+male	POS	O
+Wistar	POS	O
+rats	POS	O
+received	POS	O
+repeated	POS	O
+subcutaneous	POS	O
+PAN	POS	O
+injections	POS	O
+;	POS	O
+five	POS	O
+controls	POS	O
+received	POS	O
+saline	POS	O
+only	POS	O
+.	POS	O
+After	POS	O
+4	POS	O
+weeks	POS	O
+the	POS	O
+PAN	POS	O
+rats	POS	O
+were	POS	O
+severely	POS	O
+proteinuric	POS	O
+(	POS	O
+190	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+80	POS	O
+mg	POS	O
+/	POS	O
+24	POS	O
+hr	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+all	POS	O
+rats	POS	O
+were	POS	O
+given	POS	O
+colloidal	POS	O
+carbon	POS	O
+(	POS	O
+CC	POS	O
+)	POS	O
+intravenously	POS	O
+.	POS	O
+At	POS	O
+5	POS	O
+months	POS	O
+glomerular	POS	B-NP
+sclerosis	POS	I-NP
+was	POS	O
+found	POS	O
+in	POS	O
+7	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+3	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+glomeruli	POS	O
+of	POS	O
+PAN	POS	O
+rats	POS	O
+;	POS	O
+glomeruli	POS	O
+of	POS	O
+the	POS	O
+controls	POS	O
+were	POS	O
+normal	POS	O
+.	POS	O
+Glomeruli	POS	O
+of	POS	O
+PAN	POS	O
+rats	POS	O
+contained	POS	O
+significantly	POS	O
+more	POS	O
+CC	POS	O
+than	POS	O
+glomeruli	POS	O
+of	POS	O
+controls	POS	O
+.	POS	O
+Glomeruli	POS	O
+with	POS	O
+sclerosis	POS	B-NP
+contained	POS	O
+significantly	POS	O
+more	POS	O
+CC	POS	O
+than	POS	O
+non	POS	O
+-	POS	O
+sclerotic	POS	O
+glomeruli	POS	O
+in	POS	O
+the	POS	O
+same	POS	O
+kidneys	POS	O
+.	POS	O
+CC	POS	O
+was	POS	O
+preferentially	POS	O
+localized	POS	O
+within	POS	O
+the	POS	O
+sclerotic	POS	O
+areas	POS	O
+of	POS	O
+the	POS	O
+affected	POS	O
+glomeruli	POS	O
+.	POS	O
+Since	POS	O
+mesangial	POS	O
+CC	POS	O
+clearance	POS	O
+from	POS	O
+the	POS	O
+mesangium	POS	O
+did	POS	O
+not	POS	O
+change	POS	O
+during	POS	O
+chronic	POS	O
+PAN	POS	O
+treatment	POS	O
+,	POS	O
+we	POS	O
+conclude	POS	O
+that	POS	O
+this	POS	O
+preferential	POS	O
+CC	POS	O
+localization	POS	O
+within	POS	O
+the	POS	O
+lesions	POS	B-NP
+is	POS	O
+caused	POS	O
+by	POS	O
+an	POS	O
+increased	POS	O
+CC	POS	O
+uptake	POS	O
+shortly	POS	O
+after	POS	O
+injection	POS	O
+in	POS	O
+apparent	POS	O
+vulnerable	POS	O
+areas	POS	O
+where	POS	O
+sclerosis	POS	B-NP
+will	POS	O
+develop	POS	O
+subsequently	POS	O
+.	POS	O
+Cluster	POS	O
+analysis	POS	O
+showed	POS	O
+a	POS	O
+random	POS	O
+distribution	POS	O
+of	POS	O
+lesions	POS	B-NP
+in	POS	O
+the	POS	O
+PAN	POS	O
+glomeruli	POS	O
+in	POS	O
+concordance	POS	O
+with	POS	O
+the	POS	O
+random	POS	O
+localization	POS	O
+of	POS	O
+mesangial	POS	O
+areas	POS	O
+with	POS	O
+dysfunction	POS	O
+in	POS	O
+this	POS	O
+model	POS	O
+.	POS	O
+Similar	POS	O
+to	POS	O
+the	POS	O
+remnant	POS	O
+kidney	POS	O
+model	POS	O
+in	POS	O
+PAN	POS	O
+nephrosis	POS	B-NP
+the	POS	O
+development	POS	O
+of	POS	O
+glomerular	POS	B-NP
+sclerosis	POS	I-NP
+may	POS	O
+be	POS	O
+related	POS	O
+to	POS	O
+"	POS	O
+mesangial	POS	O
+overloading	POS	O
+.	POS	O
+"	POS	O
+Relationship	POS	O
+between	POS	O
+nicotine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+and	POS	O
+hippocampal	POS	O
+nicotinic	POS	O
+receptors	POS	O
+.	POS	O
+A	POS	O
+controversy	POS	O
+has	POS	O
+existed	POS	O
+for	POS	O
+several	POS	O
+years	POS	O
+concerning	POS	O
+the	POS	O
+physiological	POS	O
+relevance	POS	O
+of	POS	O
+the	POS	O
+nicotinic	POS	O
+receptor	POS	O
+measured	POS	O
+by	POS	O
+alpha	POS	O
+-	POS	O
+bungarotoxin	POS	O
+binding	POS	O
+.	POS	O
+Using	POS	O
+mice	POS	O
+derived	POS	O
+from	POS	O
+a	POS	O
+classical	POS	O
+F2	POS	O
+and	POS	O
+backcross	POS	O
+genetic	POS	O
+design	POS	O
+,	POS	O
+a	POS	O
+relationship	POS	O
+between	POS	O
+nicotine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+and	POS	O
+alpha	POS	O
+-	POS	O
+bungarotoxin	POS	O
+nicotinic	POS	O
+receptor	POS	O
+concentration	POS	O
+was	POS	O
+found	POS	O
+.	POS	O
+Mice	POS	O
+sensitive	POS	O
+to	POS	O
+the	POS	O
+convulsant	POS	O
+effects	POS	O
+of	POS	O
+nicotine	POS	O
+had	POS	O
+greater	POS	O
+alpha	POS	O
+-	POS	O
+bungarotoxin	POS	O
+binding	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+than	POS	O
+seizure	POS	B-NP
+insensitive	POS	O
+mice	POS	O
+.	POS	O
+The	POS	O
+binding	POS	O
+sites	POS	O
+from	POS	O
+seizure	POS	B-NP
+sensitive	POS	O
+and	POS	O
+resistant	POS	O
+mice	POS	O
+were	POS	O
+equally	POS	O
+affected	POS	O
+by	POS	O
+treatment	POS	O
+with	POS	O
+dithiothreitol	POS	O
+,	POS	O
+trypsin	POS	O
+or	POS	O
+heat	POS	O
+.	POS	O
+Thus	POS	O
+it	POS	O
+appears	POS	O
+that	POS	O
+the	POS	O
+difference	POS	O
+between	POS	O
+seizure	POS	B-NP
+sensitive	POS	O
+and	POS	O
+insensitive	POS	O
+animals	POS	O
+may	POS	O
+be	POS	O
+due	POS	O
+to	POS	O
+a	POS	O
+difference	POS	O
+in	POS	O
+hippocampal	POS	O
+nicotinic	POS	O
+receptor	POS	O
+concentration	POS	O
+as	POS	O
+measured	POS	O
+with	POS	O
+alpha	POS	O
+-	POS	O
+bungarotoxin	POS	O
+binding	POS	O
+.	POS	O
+The	POS	O
+role	POS	O
+of	POS	O
+p	POS	O
+-	POS	O
+aminophenol	POS	O
+in	POS	O
+acetaminophen	POS	O
+-	POS	O
+induced	POS	O
+nephrotoxicity	POS	B-NP
+:	POS	O
+effect	POS	O
+of	POS	O
+bis	POS	O
+(	POS	O
+p	POS	O
+-	POS	O
+nitrophenyl	POS	O
+)	POS	O
+phosphate	POS	O
+on	POS	O
+acetaminophen	POS	O
+and	POS	O
+p	POS	O
+-	POS	O
+aminophenol	POS	O
+nephrotoxicity	POS	B-NP
+and	POS	O
+metabolism	POS	O
+in	POS	O
+Fischer	POS	O
+344	POS	O
+rats	POS	O
+.	POS	O
+Acetaminophen	POS	O
+(	POS	O
+APAP	POS	O
+)	POS	O
+produces	POS	O
+proximal	POS	O
+tubular	POS	O
+necrosis	POS	B-NP
+in	POS	O
+Fischer	POS	O
+344	POS	O
+(	POS	O
+F344	POS	O
+)	POS	O
+rats	POS	O
+.	POS	O
+Recently	POS	O
+,	POS	O
+p	POS	O
+-	POS	O
+aminophenol	POS	O
+(	POS	O
+PAP	POS	O
+)	POS	O
+,	POS	O
+a	POS	O
+known	POS	O
+potent	POS	O
+nephrotoxicant	POS	O
+,	POS	O
+was	POS	O
+identified	POS	O
+as	POS	O
+a	POS	O
+metabolite	POS	O
+of	POS	O
+APAP	POS	O
+in	POS	O
+F344	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+determine	POS	O
+if	POS	O
+PAP	POS	O
+formation	POS	O
+is	POS	O
+a	POS	O
+requisite	POS	O
+step	POS	O
+in	POS	O
+APAP	POS	O
+-	POS	O
+induced	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+Therefore	POS	O
+,	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+bis	POS	O
+(	POS	O
+p	POS	O
+-	POS	O
+nitrophenyl	POS	O
+)	POS	O
+phosphate	POS	O
+(	POS	O
+BNPP	POS	O
+)	POS	O
+,	POS	O
+an	POS	O
+acylamidase	POS	O
+inhibitor	POS	O
+,	POS	O
+on	POS	O
+APAP	POS	O
+and	POS	O
+PAP	POS	O
+nephrotoxicity	POS	B-NP
+and	POS	O
+metabolism	POS	O
+was	POS	O
+determined	POS	O
+.	POS	O
+BNPP	POS	O
+(	POS	O
+1	POS	O
+to	POS	O
+8	POS	O
+mM	POS	O
+)	POS	O
+reduced	POS	O
+APAP	POS	O
+deacetylation	POS	O
+and	POS	O
+covalent	POS	O
+binding	POS	O
+in	POS	O
+F344	POS	O
+renal	POS	O
+cortical	POS	O
+homogenates	POS	O
+in	POS	O
+a	POS	O
+concentration	POS	O
+-	POS	O
+dependent	POS	O
+manner	POS	O
+.	POS	O
+Pretreatment	POS	O
+of	POS	O
+animals	POS	O
+with	POS	O
+BNPP	POS	O
+prior	POS	O
+to	POS	O
+APAP	POS	O
+or	POS	O
+PAP	POS	O
+administration	POS	O
+resulted	POS	O
+in	POS	O
+marked	POS	O
+reduction	POS	O
+of	POS	O
+APAP	POS	O
+(	POS	O
+900	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+nephrotoxicity	POS	B-NP
+but	POS	O
+not	POS	O
+PAP	POS	O
+nephrotoxicity	POS	B-NP
+.	POS	O
+This	POS	O
+result	POS	O
+was	POS	O
+not	POS	O
+due	POS	O
+to	POS	O
+altered	POS	O
+disposition	POS	O
+of	POS	O
+either	POS	O
+APAP	POS	O
+or	POS	O
+acetylated	POS	O
+metabolites	POS	O
+in	POS	O
+plasma	POS	O
+or	POS	O
+renal	POS	O
+cortical	POS	O
+and	POS	O
+hepatic	POS	O
+tissue	POS	O
+.	POS	O
+Rather	POS	O
+,	POS	O
+BNPP	POS	O
+pretreatment	POS	O
+reduced	POS	O
+the	POS	O
+fraction	POS	O
+of	POS	O
+APAP	POS	O
+excreted	POS	O
+as	POS	O
+PAP	POS	O
+by	POS	O
+64	POS	O
+and	POS	O
+75	POS	O
+%	POS	O
+after	POS	O
+APAP	POS	O
+doses	POS	O
+of	POS	O
+750	POS	O
+and	POS	O
+900	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+BNPP	POS	O
+did	POS	O
+not	POS	O
+alter	POS	O
+the	POS	O
+excretion	POS	O
+of	POS	O
+APAP	POS	O
+or	POS	O
+any	POS	O
+of	POS	O
+its	POS	O
+non	POS	O
+-	POS	O
+deacetylated	POS	O
+metabolites	POS	O
+nor	POS	O
+did	POS	O
+BNPP	POS	O
+alter	POS	O
+excretion	POS	O
+of	POS	O
+PAP	POS	O
+or	POS	O
+its	POS	O
+metabolites	POS	O
+after	POS	O
+PAP	POS	O
+doses	POS	O
+of	POS	O
+150	POS	O
+and	POS	O
+300	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+Therefore	POS	O
+,	POS	O
+the	POS	O
+BNPP	POS	O
+-	POS	O
+induced	POS	O
+reduction	POS	O
+in	POS	O
+APAP	POS	O
+-	POS	O
+induced	POS	O
+nephrotoxicity	POS	B-NP
+appears	POS	O
+to	POS	O
+be	POS	O
+due	POS	O
+to	POS	O
+inhibition	POS	O
+of	POS	O
+APAP	POS	O
+deacetylation	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+concluded	POS	O
+that	POS	O
+PAP	POS	O
+formation	POS	O
+,	POS	O
+in	POS	O
+vivo	POS	O
+,	POS	O
+accounts	POS	O
+,	POS	O
+at	POS	O
+least	POS	O
+in	POS	O
+part	POS	O
+,	POS	O
+for	POS	O
+APAP	POS	O
+-	POS	O
+induced	POS	O
+renal	POS	B-NP
+tubular	POS	I-NP
+necrosis	POS	I-NP
+.	POS	O
+Morphine	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+in	POS	O
+newborn	POS	O
+infants	POS	O
+.	POS	O
+Two	POS	O
+neonates	POS	O
+suffered	POS	O
+from	POS	O
+generalized	POS	O
+seizures	POS	B-NP
+during	POS	O
+the	POS	O
+course	POS	O
+of	POS	O
+intravenous	POS	O
+morphine	POS	O
+sulfate	POS	O
+for	POS	O
+post	POS	O
+-	POS	O
+operative	POS	O
+analgesia	POS	O
+.	POS	O
+They	POS	O
+received	POS	O
+morphine	POS	O
+in	POS	O
+doses	POS	O
+of	POS	O
+32	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+hr	POS	O
+and	POS	O
+40	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+hr	POS	O
+larger	POS	O
+than	POS	O
+a	POS	O
+group	POS	O
+of	POS	O
+10	POS	O
+neonates	POS	O
+who	POS	O
+received	POS	O
+6	POS	O
+-	POS	O
+24	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+hr	POS	O
+and	POS	O
+had	POS	O
+no	POS	O
+seizures	POS	B-NP
+.	POS	O
+Plasma	POS	O
+concentrations	POS	O
+of	POS	O
+morphine	POS	O
+in	POS	O
+these	POS	O
+neonates	POS	O
+was	POS	O
+excessive	POS	O
+(	POS	O
+60	POS	O
+and	POS	O
+90	POS	O
+mg	POS	O
+/	POS	O
+ml	POS	O
+)	POS	O
+.	POS	O
+Other	POS	O
+known	POS	O
+reasons	POS	O
+for	POS	O
+seizures	POS	B-NP
+were	POS	O
+ruled	POS	O
+out	POS	O
+and	POS	O
+the	POS	O
+convulsions	POS	B-NP
+stopped	POS	O
+a	POS	O
+few	POS	O
+hours	POS	O
+after	POS	O
+cessation	POS	O
+of	POS	O
+morphine	POS	O
+and	POS	O
+did	POS	O
+not	POS	O
+reoccur	POS	O
+in	POS	O
+the	POS	O
+subsequent	POS	O
+8	POS	O
+months	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+suggested	POS	O
+that	POS	O
+post	POS	O
+-	POS	O
+operative	POS	O
+intravenous	POS	O
+morphine	POS	O
+should	POS	O
+not	POS	O
+exceed	POS	O
+20	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+ml	POS	O
+in	POS	O
+neonates	POS	O
+.	POS	O
+Indomethacin	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+in	POS	O
+sodium	POS	O
+and	POS	O
+volume	POS	O
+depleted	POS	O
+rats	POS	O
+.	POS	O
+After	POS	O
+a	POS	O
+single	POS	O
+oral	POS	O
+dose	POS	O
+of	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+indomethacin	POS	O
+(	POS	O
+IDM	POS	O
+)	POS	O
+to	POS	O
+sodium	POS	O
+and	POS	O
+volume	POS	O
+depleted	POS	O
+rats	POS	O
+plasma	POS	O
+renin	POS	O
+activity	POS	O
+(	POS	O
+PRA	POS	O
+)	POS	O
+and	POS	O
+systolic	POS	O
+blood	POS	O
+pressure	POS	O
+fell	POS	O
+significantly	POS	O
+within	POS	O
+four	POS	O
+hours	POS	O
+.	POS	O
+In	POS	O
+sodium	POS	O
+repleted	POS	O
+animals	POS	O
+indomethacin	POS	O
+did	POS	O
+not	POS	O
+change	POS	O
+systolic	POS	O
+blood	POS	O
+pressure	POS	O
+(	POS	O
+BP	POS	O
+)	POS	O
+although	POS	O
+plasma	POS	O
+renin	POS	O
+activity	POS	O
+was	POS	O
+decreased	POS	O
+.	POS	O
+Thus	POS	O
+,	POS	O
+indomethacin	POS	O
+by	POS	O
+inhibition	POS	O
+of	POS	O
+prostaglandin	POS	O
+synthesis	POS	O
+may	POS	O
+diminish	POS	O
+the	POS	O
+blood	POS	O
+pressure	POS	O
+maintaining	POS	O
+effect	POS	O
+of	POS	O
+the	POS	O
+stimulated	POS	O
+renin	POS	O
+-	POS	O
+angiotensin	POS	O
+system	POS	O
+in	POS	O
+sodium	POS	O
+and	POS	O
+volume	POS	O
+depletion	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+antiarrhythmic	POS	O
+activity	POS	O
+of	POS	O
+one	POS	O
+N	POS	O
+-	POS	O
+substituted	POS	O
+piperazine	POS	O
+derivative	POS	O
+of	POS	O
+trans	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+amino	POS	O
+-	POS	O
+3	POS	O
+-	POS	O
+hydroxy	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+2	POS	O
+,	POS	O
+3	POS	O
+,	POS	O
+4	POS	O
+-	POS	O
+tetrahydroanaphthalene	POS	O
+.	POS	O
+The	POS	O
+antiarrhythmic	POS	O
+activity	POS	O
+of	POS	O
+the	POS	O
+compound	POS	O
+N	POS	O
+-	POS	O
+(	POS	O
+trans	POS	O
+-	POS	O
+3	POS	O
+-	POS	O
+hydroxy	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+2	POS	O
+,	POS	O
+3	POS	O
+,	POS	O
+4	POS	O
+-	POS	O
+tetrahydro	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+naphthyl	POS	O
+)	POS	O
+-	POS	O
+N	POS	O
+-	POS	O
+(	POS	O
+3	POS	O
+-	POS	O
+oxo	POS	O
+-	POS	O
+3	POS	O
+-	POS	O
+phenyl	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+methylpropyl	POS	O
+)	POS	O
+-	POS	O
+piperazine	POS	O
+hydrochloride	POS	O
+,	POS	O
+referred	POS	O
+to	POS	O
+as	POS	O
+P11	POS	O
+,	POS	O
+is	POS	O
+studied	POS	O
+on	POS	O
+anaesthesized	POS	O
+cats	POS	O
+and	POS	O
+Wistar	POS	O
+albino	POS	O
+rats	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+on	POS	O
+non	POS	O
+-	POS	O
+anaesthesized	POS	O
+rabbits	POS	O
+.	POS	O
+Four	POS	O
+types	POS	O
+of	POS	O
+experimental	POS	O
+arrhythmia	POS	B-NP
+are	POS	O
+used	POS	O
+-	POS	O
+-	POS	O
+with	POS	O
+BaCl2	POS	O
+,	POS	O
+with	POS	O
+chloroform	POS	O
+-	POS	O
+adrenaline	POS	O
+,	POS	O
+with	POS	O
+strophantine	POS	O
+G	POS	O
+and	POS	O
+with	POS	O
+aconitine	POS	O
+.	POS	O
+The	POS	O
+compound	POS	O
+P11	POS	O
+is	POS	O
+introduced	POS	O
+in	POS	O
+doses	POS	O
+of	POS	O
+0	POS	O
+.	POS	O
+25	POS	O
+and	POS	O
+0	POS	O
+.	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+intravenously	POS	O
+and	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+orally	POS	O
+.	POS	O
+The	POS	O
+compound	POS	O
+manifests	POS	O
+antiarrhythmic	POS	O
+activity	POS	O
+in	POS	O
+all	POS	O
+models	POS	O
+of	POS	O
+experimental	POS	O
+arrhythmia	POS	B-NP
+used	POS	O
+,	POS	O
+causing	POS	O
+greatest	POS	O
+inhibition	POS	O
+on	POS	O
+the	POS	O
+arrhythmia	POS	B-NP
+induced	POS	O
+by	POS	O
+chloroform	POS	O
+-	POS	O
+adrenaline	POS	O
+(	POS	O
+in	POS	O
+90	POS	O
+per	POS	O
+cent	POS	O
+)	POS	O
+and	POS	O
+with	POS	O
+BaCl2	POS	O
+(	POS	O
+in	POS	O
+84	POS	O
+per	POS	O
+cent	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+obtained	POS	O
+are	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+beta	POS	O
+-	POS	O
+adrenoblocking	POS	O
+and	POS	O
+with	POS	O
+the	POS	O
+membrane	POS	O
+-	POS	O
+stabilizing	POS	O
+action	POS	O
+of	POS	O
+the	POS	O
+compound	POS	O
+.	POS	O
+Recurrent	POS	O
+subarachnoid	POS	B-NP
+hemorrhage	POS	I-NP
+associated	POS	O
+with	POS	O
+aminocaproic	POS	O
+acid	POS	O
+therapy	POS	O
+and	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+artery	POS	I-NP
+thrombosis	POS	I-NP
+.	POS	O
+Case	POS	O
+report	POS	O
+.	POS	O
+Epsilon	POS	O
+aminocaproic	POS	O
+acid	POS	O
+(	POS	O
+EACA	POS	O
+)	POS	O
+has	POS	O
+been	POS	O
+used	POS	O
+to	POS	O
+prevent	POS	O
+rebleeding	POS	B-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+subarachnoid	POS	B-NP
+hemorrhage	POS	I-NP
+(	POS	O
+SAH	POS	B-NP
+)	POS	O
+.	POS	O
+Although	POS	O
+this	POS	O
+agent	POS	O
+does	POS	O
+decrease	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+rebleeding	POS	B-NP
+,	POS	O
+several	POS	O
+reports	POS	O
+have	POS	O
+described	POS	O
+thrombotic	POS	B-NP
+complications	POS	O
+of	POS	O
+EACA	POS	O
+therapy	POS	O
+.	POS	O
+These	POS	O
+complications	POS	O
+have	POS	O
+included	POS	O
+clinical	POS	O
+deterioration	POS	O
+and	POS	O
+intracranial	POS	B-NP
+vascular	POS	I-NP
+thrombosis	POS	I-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+SAH	POS	B-NP
+,	POS	O
+arteriolar	POS	O
+and	POS	O
+capillary	POS	O
+fibrin	POS	O
+thrombi	POS	B-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+fibrinolytic	POS	B-NP
+syndromes	POS	I-NP
+treated	POS	O
+with	POS	O
+EACA	POS	O
+,	POS	O
+or	POS	O
+other	POS	O
+thromboembolic	POS	B-NP
+phenomena	POS	I-NP
+.	POS	O
+Since	POS	O
+intravascular	POS	O
+fibrin	POS	O
+thrombi	POS	B-NP
+are	POS	O
+often	POS	O
+observed	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+fibrinolytic	POS	B-NP
+disorders	POS	I-NP
+,	POS	O
+EACA	POS	O
+should	POS	O
+not	POS	O
+be	POS	O
+implicated	POS	O
+in	POS	O
+the	POS	O
+pathogenesis	POS	O
+of	POS	O
+fibrin	POS	O
+thrombi	POS	B-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+disseminated	POS	B-NP
+intravascular	POS	I-NP
+coagulation	POS	I-NP
+or	POS	O
+other	POS	O
+"	POS	O
+consumption	POS	O
+coagulopathies	POS	B-NP
+.	POS	O
+"	POS	O
+This	POS	O
+report	POS	O
+describes	POS	O
+subtotal	POS	O
+infarction	POS	O
+of	POS	O
+the	POS	O
+kidney	POS	O
+due	POS	O
+to	POS	O
+thrombosis	POS	B-NP
+of	POS	O
+a	POS	O
+normal	POS	B-NP
+renal	POS	I-NP
+artery	POS	I-NP
+.	POS	O
+This	POS	O
+occlusion	POS	O
+occurred	POS	O
+after	POS	O
+EACA	POS	O
+therapy	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+SAH	POS	B-NP
+and	POS	O
+histopathological	POS	O
+documentation	POS	O
+of	POS	O
+recurrent	POS	O
+SAH	POS	B-NP
+.	POS	O
+The	POS	O
+corresponding	POS	O
+clinical	POS	O
+event	POS	O
+was	POS	O
+characterized	POS	O
+by	POS	O
+marked	POS	O
+hypertension	POS	B-NP
+and	POS	O
+abrupt	POS	O
+neurological	POS	B-NP
+deterioration	POS	I-NP
+.	POS	O
+Effect	POS	O
+of	POS	O
+vincristine	POS	O
+sulfate	POS	O
+on	POS	O
+Pseudomonas	POS	O
+infections	POS	O
+in	POS	O
+monkeys	POS	O
+.	POS	O
+In	POS	O
+rhesus	POS	O
+monkeys	POS	O
+,	POS	O
+intravenous	POS	O
+challenge	POS	O
+with	POS	O
+0	POS	O
+.	POS	O
+6	POS	O
+x	POS	O
+10	POS	O
+(	POS	O
+10	POS	O
+)	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+2	POS	O
+x	POS	O
+10	POS	O
+(	POS	O
+10	POS	O
+)	POS	O
+Pseudomonas	POS	O
+aeruginosa	POS	O
+organisms	POS	O
+caused	POS	O
+acute	POS	B-NP
+illness	POS	I-NP
+of	POS	O
+4	POS	O
+to	POS	O
+5	POS	O
+days	POS	O
+'	POS	O
+duration	POS	O
+with	POS	O
+spontaneous	POS	O
+recovery	POS	O
+in	POS	O
+13	POS	O
+of	POS	O
+15	POS	O
+monkeys	POS	O
+;	POS	O
+blood	POS	O
+cultures	POS	O
+became	POS	O
+negative	POS	O
+3	POS	O
+to	POS	O
+17	POS	O
+days	POS	O
+after	POS	O
+challenge	POS	O
+.	POS	O
+Leukocytosis	POS	B-NP
+was	POS	O
+observed	POS	O
+in	POS	O
+all	POS	O
+monkeys	POS	O
+.	POS	O
+Intravenous	POS	O
+or	POS	O
+intratracheal	POS	O
+inoculation	POS	O
+of	POS	O
+2	POS	O
+.	POS	O
+0	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+of	POS	O
+vincristine	POS	O
+sulfate	POS	O
+was	POS	O
+followed	POS	O
+by	POS	O
+leukopenia	POS	B-NP
+in	POS	O
+4	POS	O
+to	POS	O
+5	POS	O
+days	POS	O
+.	POS	O
+Intravenous	POS	O
+inoculation	POS	O
+of	POS	O
+4	POS	O
+.	POS	O
+2	POS	O
+x	POS	O
+10	POS	O
+(	POS	O
+10	POS	O
+)	POS	O
+to	POS	O
+7	POS	O
+.	POS	O
+8	POS	O
+x	POS	O
+10	POS	O
+(	POS	O
+10	POS	O
+)	POS	O
+pyocin	POS	O
+type	POS	O
+6	POS	O
+Pseudomonas	POS	O
+organisms	POS	O
+in	POS	O
+monkeys	POS	O
+given	POS	O
+vincristine	POS	O
+sulfate	POS	O
+4	POS	O
+days	POS	O
+previously	POS	O
+resulted	POS	O
+in	POS	O
+fatal	POS	O
+infection	POS	B-NP
+in	POS	O
+11	POS	O
+of	POS	O
+14	POS	O
+monkeys	POS	O
+,	POS	O
+whereas	POS	O
+none	POS	O
+of	POS	O
+four	POS	O
+receiving	POS	O
+Pseudomonas	POS	O
+alone	POS	O
+died	POS	O
+.	POS	O
+These	POS	O
+studies	POS	O
+suggest	POS	O
+that	POS	O
+an	POS	O
+antimetabolite	POS	O
+-	POS	O
+induced	POS	O
+leukopenia	POS	B-NP
+predisposes	POS	O
+to	POS	O
+severe	POS	O
+Pseudomonas	POS	B-NP
+sepsis	POS	I-NP
+and	POS	O
+that	POS	O
+such	POS	O
+monkeys	POS	O
+may	POS	O
+serve	POS	O
+as	POS	O
+a	POS	O
+biological	POS	O
+model	POS	O
+for	POS	O
+study	POS	O
+of	POS	O
+comparative	POS	O
+efficacy	POS	O
+of	POS	O
+antimicrobial	POS	O
+agents	POS	O
+.	POS	O
+Modification	POS	O
+by	POS	O
+propranolol	POS	O
+of	POS	O
+cardiovascular	POS	O
+effects	POS	O
+of	POS	O
+induced	POS	O
+hypoglycaemia	POS	B-NP
+.	POS	O
+The	POS	O
+cardiovascular	POS	O
+effects	POS	O
+of	POS	O
+hypoglycaemia	POS	B-NP
+,	POS	O
+with	POS	O
+and	POS	O
+without	POS	O
+beta	POS	O
+-	POS	O
+blockade	POS	O
+,	POS	O
+were	POS	O
+compared	POS	O
+in	POS	O
+fourteen	POS	O
+healthy	POS	O
+men	POS	O
+.	POS	O
+Eight	POS	O
+received	POS	O
+insulin	POS	O
+alone	POS	O
+,	POS	O
+and	POS	O
+eight	POS	O
+,	POS	O
+including	POS	O
+two	POS	O
+of	POS	O
+the	POS	O
+original	POS	O
+insulin	POS	O
+-	POS	O
+only	POS	O
+group	POS	O
+,	POS	O
+were	POS	O
+given	POS	O
+propranolol	POS	O
+and	POS	O
+insulin	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+insulin	POS	O
+-	POS	O
+group	POS	O
+the	POS	O
+period	POS	O
+of	POS	O
+hypoglycaemia	POS	B-NP
+was	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+heart	POS	O
+-	POS	O
+rate	POS	O
+and	POS	O
+a	POS	O
+fall	POS	O
+in	POS	O
+diastolic	POS	O
+blood	POS	O
+-	POS	O
+pressure	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+propranolol	POS	O
+-	POS	O
+insulin	POS	O
+group	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+fall	POS	O
+in	POS	O
+heart	POS	O
+-	POS	O
+rate	POS	O
+in	POS	O
+most	POS	O
+subjects	POS	O
+and	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+diastolic	POS	O
+pressure	POS	O
+.	POS	O
+Typical	POS	O
+S	POS	O
+-	POS	O
+T	POS	O
+/	POS	O
+T	POS	O
+changes	POS	O
+occurred	POS	O
+in	POS	O
+the	POS	O
+insulin	POS	O
+-	POS	O
+group	POS	O
+but	POS	O
+in	POS	O
+none	POS	O
+of	POS	O
+the	POS	O
+propranolol	POS	O
+-	POS	O
+insulin	POS	O
+group	POS	O
+.	POS	O
+Hypertension	POS	B-NP
+in	POS	O
+diabetics	POS	O
+prone	POS	O
+to	POS	O
+hypoglycaemia	POS	B-NP
+attacks	POS	O
+should	POS	O
+not	POS	O
+be	POS	O
+treated	POS	O
+with	POS	O
+beta	POS	O
+-	POS	O
+blockers	POS	O
+because	POS	O
+these	POS	O
+drugs	POS	O
+may	POS	O
+cause	POS	O
+a	POS	O
+sharp	POS	O
+rise	POS	O
+in	POS	O
+blood	POS	O
+-	POS	O
+pressure	POS	O
+in	POS	O
+such	POS	O
+patients	POS	O
+.	POS	O
+Long	POS	O
+-	POS	O
+term	POS	O
+propranolol	POS	O
+therapy	POS	O
+in	POS	O
+pregnancy	POS	O
+:	POS	O
+maternal	POS	O
+and	POS	O
+fetal	POS	O
+outcome	POS	O
+.	POS	O
+Propranolol	POS	O
+,	POS	O
+a	POS	O
+beta	POS	O
+-	POS	O
+adrenergic	POS	O
+blocking	POS	O
+agent	POS	O
+,	POS	O
+has	POS	O
+found	POS	O
+an	POS	O
+important	POS	O
+position	POS	O
+in	POS	O
+the	POS	O
+practice	POS	O
+of	POS	O
+medicine	POS	O
+.	POS	O
+Its	POS	O
+use	POS	O
+in	POS	O
+pregnancy	POS	O
+,	POS	O
+however	POS	O
+,	POS	O
+is	POS	O
+an	POS	O
+open	POS	O
+question	POS	O
+as	POS	O
+a	POS	O
+number	POS	O
+of	POS	O
+detrimental	POS	O
+side	POS	O
+effects	POS	O
+have	POS	O
+been	POS	O
+reported	POS	O
+in	POS	O
+the	POS	O
+fetus	POS	O
+and	POS	O
+neonate	POS	O
+.	POS	O
+Ten	POS	O
+patients	POS	O
+and	POS	O
+12	POS	O
+pregnancies	POS	O
+are	POS	O
+reported	POS	O
+where	POS	O
+chronic	POS	O
+propranolol	POS	O
+has	POS	O
+been	POS	O
+administered	POS	O
+.	POS	O
+Five	POS	O
+patients	POS	O
+with	POS	O
+serial	POS	O
+pregnancies	POS	O
+with	POS	O
+and	POS	O
+without	POS	O
+propranolol	POS	O
+therapy	POS	O
+are	POS	O
+also	POS	O
+examined	POS	O
+.	POS	O
+Maternal	POS	O
+,	POS	O
+fetal	POS	O
+,	POS	O
+and	POS	O
+neonatal	POS	B-NP
+complications	POS	I-NP
+are	POS	O
+examined	POS	O
+.	POS	O
+An	POS	O
+attempt	POS	O
+is	POS	O
+made	POS	O
+to	POS	O
+differentiate	POS	O
+drug	POS	O
+-	POS	O
+related	POS	O
+complications	POS	O
+from	POS	O
+maternal	POS	O
+disease	POS	O
+-	POS	O
+-	POS	O
+related	POS	O
+complications	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+previously	POS	O
+reported	POS	O
+hypoglycemia	POS	B-NP
+,	POS	O
+hyperbilirubinemia	POS	B-NP
+,	POS	O
+polycythemia	POS	B-NP
+,	POS	O
+neonatal	POS	B-NP
+apnea	POS	I-NP
+,	POS	O
+and	POS	O
+bradycardia	POS	B-NP
+are	POS	O
+not	POS	O
+invariable	POS	O
+and	POS	O
+cannot	POS	O
+be	POS	O
+statistically	POS	O
+correlated	POS	O
+with	POS	O
+chronic	POS	O
+propranolol	POS	O
+therapy	POS	O
+.	POS	O
+Growth	POS	B-NP
+retardation	POS	I-NP
+,	POS	O
+however	POS	O
+,	POS	O
+appears	POS	O
+to	POS	O
+be	POS	O
+significant	POS	O
+in	POS	O
+both	POS	O
+of	POS	O
+our	POS	O
+series	POS	O
+.	POS	O
+Central	POS	O
+excitatory	POS	O
+actions	POS	O
+of	POS	O
+flurazepam	POS	O
+.	POS	O
+Toxic	POS	O
+actions	POS	O
+of	POS	O
+flurazepam	POS	O
+(	POS	O
+FZP	POS	O
+)	POS	O
+were	POS	O
+studied	POS	O
+in	POS	O
+cats	POS	O
+,	POS	O
+mice	POS	O
+and	POS	O
+rats	POS	O
+.	POS	O
+High	POS	O
+doses	POS	O
+caused	POS	O
+an	POS	O
+apparent	POS	O
+central	POS	O
+excitation	POS	O
+,	POS	O
+most	POS	O
+clearly	POS	O
+seen	POS	O
+as	POS	O
+clonic	POS	B-NP
+convulsions	POS	B-NP
+,	POS	O
+superimposed	POS	O
+on	POS	O
+general	POS	O
+depression	POS	B-NP
+.	POS	O
+Following	POS	O
+a	POS	O
+lethal	POS	O
+dose	POS	O
+,	POS	O
+death	POS	B-NP
+was	POS	O
+always	POS	O
+associated	POS	O
+with	POS	O
+convulsions	POS	B-NP
+.	POS	O
+Comparing	POS	O
+the	POS	O
+relative	POS	O
+sensitivity	POS	O
+to	POS	O
+central	POS	O
+depression	POS	B-NP
+and	POS	O
+excitation	POS	O
+revealed	POS	O
+that	POS	O
+rats	POS	O
+were	POS	O
+least	POS	O
+likely	POS	O
+to	POS	O
+have	POS	O
+convulsions	POS	B-NP
+at	POS	O
+doses	POS	O
+that	POS	O
+did	POS	O
+not	POS	O
+first	POS	O
+cause	POS	O
+loss	POS	B-NP
+of	POS	I-NP
+consciousness	POS	I-NP
+,	POS	O
+while	POS	O
+cats	POS	O
+most	POS	O
+clearly	POS	O
+showed	POS	O
+marked	POS	O
+central	POS	O
+excitatory	POS	O
+actions	POS	O
+.	POS	O
+Signs	POS	O
+of	POS	O
+FZP	POS	O
+toxocity	POS	O
+in	POS	O
+cats	POS	O
+included	POS	O
+excessive	POS	O
+salivation	POS	B-NP
+,	POS	O
+extreme	POS	O
+apprehensive	POS	O
+behavior	POS	O
+,	POS	O
+retching	POS	B-NP
+,	POS	O
+muscle	POS	B-NP
+tremors	POS	I-NP
+and	POS	O
+convulsions	POS	B-NP
+.	POS	O
+An	POS	O
+interaction	POS	O
+between	POS	O
+FZP	POS	O
+and	POS	O
+pentylenetetrazol	POS	O
+(	POS	O
+PTZ	POS	O
+)	POS	O
+was	POS	O
+shown	POS	O
+by	POS	O
+pretreating	POS	O
+mice	POS	O
+with	POS	O
+FZP	POS	O
+before	POS	O
+PTZ	POS	O
+challenge	POS	O
+.	POS	O
+As	POS	O
+a	POS	O
+function	POS	O
+of	POS	O
+dose	POS	O
+,	POS	O
+FZP	POS	O
+first	POS	O
+protected	POS	O
+against	POS	O
+convulsions	POS	B-NP
+and	POS	O
+death	POS	B-NP
+.	POS	O
+At	POS	O
+higher	POS	O
+doses	POS	O
+,	POS	O
+however	POS	O
+,	POS	O
+convulsions	POS	B-NP
+again	POS	O
+emerged	POS	O
+.	POS	O
+These	POS	O
+doses	POS	O
+of	POS	O
+FZP	POS	O
+were	POS	O
+lower	POS	O
+than	POS	O
+those	POS	O
+that	POS	O
+would	POS	O
+alone	POS	O
+cause	POS	O
+convulsions	POS	B-NP
+.	POS	O
+These	POS	O
+results	POS	O
+may	POS	O
+be	POS	O
+relevant	POS	O
+to	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+FZP	POS	O
+in	POS	O
+clinical	POS	O
+situations	POS	O
+in	POS	O
+which	POS	O
+there	POS	O
+is	POS	O
+increased	POS	O
+neural	POS	O
+excitability	POS	O
+,	POS	O
+such	POS	O
+as	POS	O
+epilepsy	POS	B-NP
+or	POS	O
+sedative	POS	O
+-	POS	O
+hypnotic	POS	O
+drug	POS	O
+withdrawal	POS	O
+.	POS	O
+Use	POS	O
+of	POS	O
+propranolol	POS	O
+in	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+idiopathic	POS	B-NP
+orthostatic	POS	I-NP
+hypotension	POS	I-NP
+.	POS	O
+Five	POS	O
+patients	POS	O
+with	POS	O
+idiopathic	POS	B-NP
+orthostatic	POS	I-NP
+hypotension	POS	I-NP
+who	POS	O
+had	POS	O
+physiologic	POS	O
+and	POS	O
+biochemical	POS	O
+evidence	POS	O
+of	POS	O
+severe	POS	O
+autonomic	POS	B-NP
+dysfunction	POS	I-NP
+were	POS	O
+included	POS	O
+in	POS	O
+the	POS	O
+study	POS	O
+.	POS	O
+They	POS	O
+all	POS	O
+exhibited	POS	O
+markedly	POS	O
+reduced	POS	O
+plasma	POS	O
+catecholamines	POS	O
+and	POS	O
+plasma	POS	O
+renin	POS	O
+activity	POS	O
+in	POS	O
+both	POS	O
+recumbent	POS	O
+and	POS	O
+upright	POS	O
+positions	POS	O
+and	POS	O
+had	POS	O
+marked	POS	O
+hypersensitivity	POS	B-NP
+to	POS	O
+the	POS	O
+pressor	POS	O
+effects	POS	O
+of	POS	O
+infused	POS	O
+norepinephrine	POS	O
+.	POS	O
+Treatment	POS	O
+with	POS	O
+propanolol	POS	O
+administered	POS	O
+intravenously	POS	O
+(	POS	O
+1	POS	O
+-	POS	O
+5	POS	O
+mg	POS	O
+)	POS	O
+produced	POS	O
+increases	POS	O
+in	POS	O
+supine	POS	O
+and	POS	O
+upright	POS	O
+blood	POS	O
+pressure	POS	O
+in	POS	O
+4	POS	O
+of	POS	O
+the	POS	O
+5	POS	O
+individuals	POS	O
+with	POS	O
+rises	POS	O
+ranging	POS	O
+from	POS	O
+11	POS	O
+/	POS	O
+6	POS	O
+to	POS	O
+22	POS	O
+/	POS	O
+11	POS	O
+mmHg	POS	O
+.	POS	O
+Chronic	POS	O
+oral	POS	O
+administration	POS	O
+of	POS	O
+propranolol	POS	O
+(	POS	O
+40	POS	O
+-	POS	O
+160	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+)	POS	O
+also	POS	O
+elevated	POS	O
+the	POS	O
+blood	POS	O
+pressures	POS	O
+of	POS	O
+these	POS	O
+individuals	POS	O
+with	POS	O
+increases	POS	O
+in	POS	O
+the	POS	O
+order	POS	O
+of	POS	O
+20	POS	O
+-	POS	O
+35	POS	O
+/	POS	O
+15	POS	O
+-	POS	O
+25	POS	O
+mmg	POS	O
+being	POS	O
+observed	POS	O
+.	POS	O
+In	POS	O
+1	POS	O
+patient	POS	O
+,	POS	O
+marked	POS	O
+hypertension	POS	B-NP
+was	POS	O
+induced	POS	O
+by	POS	O
+propranolol	POS	O
+and	POS	O
+the	POS	O
+drug	POS	O
+had	POS	O
+to	POS	O
+be	POS	O
+withdrawn	POS	O
+.	POS	O
+It	POS	O
+otherwise	POS	O
+was	POS	O
+well	POS	O
+tolerated	POS	O
+and	POS	O
+no	POS	O
+important	POS	O
+side	POS	O
+effects	POS	O
+were	POS	O
+observed	POS	O
+.	POS	O
+Treatment	POS	O
+has	POS	O
+been	POS	O
+continued	POS	O
+in	POS	O
+3	POS	O
+individuals	POS	O
+for	POS	O
+6	POS	O
+-	POS	O
+13	POS	O
+months	POS	O
+with	POS	O
+persistence	POS	O
+of	POS	O
+the	POS	O
+pressor	POS	O
+effect	POS	O
+,	POS	O
+although	POS	O
+there	POS	O
+appears	POS	O
+to	POS	O
+have	POS	O
+been	POS	O
+some	POS	O
+decrease	POS	O
+in	POS	O
+the	POS	O
+degree	POS	O
+of	POS	O
+response	POS	O
+with	POS	O
+time	POS	O
+.	POS	O
+Hemodynamic	POS	O
+measurements	POS	O
+in	POS	O
+1	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+demonstrated	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+total	POS	O
+peripheral	POS	O
+resistance	POS	O
+and	POS	O
+essentially	POS	O
+no	POS	O
+change	POS	O
+in	POS	O
+cardiac	POS	O
+output	POS	O
+following	POS	O
+propranolol	POS	O
+therapy	POS	O
+.	POS	O
+The	POS	O
+studies	POS	O
+suggest	POS	O
+that	POS	O
+propranolol	POS	O
+is	POS	O
+a	POS	O
+useful	POS	O
+drug	POS	O
+in	POS	O
+selected	POS	O
+patients	POS	O
+with	POS	O
+severe	POS	O
+idiopathic	POS	B-NP
+orthostatic	POS	I-NP
+hypotension	POS	I-NP
+.	POS	O
+Total	POS	O
+intravenous	POS	O
+anesthesia	POS	O
+with	POS	O
+etomidate	POS	O
+.	POS	O
+III	POS	O
+.	POS	O
+Some	POS	O
+observations	POS	O
+in	POS	O
+adults	POS	O
+.	POS	O
+An	POS	O
+investigation	POS	O
+was	POS	O
+undertaken	POS	O
+to	POS	O
+determine	POS	O
+the	POS	O
+dosage	POS	O
+of	POS	O
+etomidate	POS	O
+required	POS	O
+to	POS	O
+maintain	POS	O
+sleep	POS	O
+in	POS	O
+adults	POS	O
+undergoing	POS	O
+surgery	POS	O
+under	POS	O
+regional	POS	O
+local	POS	O
+anesthesia	POS	O
+.	POS	O
+Premedication	POS	O
+of	POS	O
+diazepam	POS	O
+10	POS	O
+mg	POS	O
+and	POS	O
+atropine	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+was	POS	O
+given	POS	O
+,	POS	O
+and	POS	O
+sleep	POS	O
+was	POS	O
+induced	POS	O
+and	POS	O
+maintained	POS	O
+by	POS	O
+intermittent	POS	O
+intravenous	POS	O
+injections	POS	O
+of	POS	O
+etomidate	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+/	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+given	POS	O
+whenever	POS	O
+the	POS	O
+patient	POS	O
+would	POS	O
+open	POS	O
+his	POS	O
+eyes	POS	O
+on	POS	O
+request	POS	O
+.	POS	O
+A	POS	O
+mean	POS	O
+overall	POS	O
+dose	POS	O
+of	POS	O
+etomidate	POS	O
+17	POS	O
+.	POS	O
+4	POS	O
+microgram	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+.	POS	O
+was	POS	O
+required	POS	O
+to	POS	O
+maintain	POS	O
+sleep	POS	O
+,	POS	O
+but	POS	O
+great	POS	O
+individual	POS	O
+variation	POS	O
+occurred	POS	O
+,	POS	O
+with	POS	O
+older	POS	O
+patients	POS	O
+requiring	POS	O
+less	POS	O
+drug	POS	O
+.	POS	O
+The	POS	O
+investigation	POS	O
+was	POS	O
+discontinued	POS	O
+after	POS	O
+18	POS	O
+patients	POS	O
+because	POS	O
+of	POS	O
+the	POS	O
+frequency	POS	O
+and	POS	O
+intensity	POS	O
+of	POS	O
+side	POS	O
+-	POS	O
+effects	POS	O
+,	POS	O
+particularly	POS	O
+pain	POS	B-NP
+and	POS	O
+myoclonia	POS	B-NP
+,	POS	O
+which	POS	O
+caused	POS	O
+the	POS	O
+technique	POS	O
+to	POS	O
+be	POS	O
+abandoned	POS	O
+in	POS	O
+two	POS	O
+cases	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+considered	POS	O
+unlikely	POS	O
+that	POS	O
+etomidate	POS	O
+will	POS	O
+prove	POS	O
+to	POS	O
+be	POS	O
+the	POS	O
+hypnotic	POS	O
+of	POS	O
+choice	POS	O
+for	POS	O
+a	POS	O
+totally	POS	O
+intravenous	POS	O
+anesthetic	POS	O
+technique	POS	O
+in	POS	O
+adults	POS	O
+because	POS	O
+of	POS	O
+the	POS	O
+high	POS	O
+incidence	POS	O
+of	POS	O
+myoclonia	POS	B-NP
+after	POS	O
+prolonged	POS	O
+administration	POS	O
+.	POS	O
+In	POS	O
+several	POS	O
+patients	POS	O
+uncontrollable	POS	O
+muscle	POS	B-NP
+movements	POS	I-NP
+persisted	POS	O
+for	POS	O
+many	POS	O
+minutes	POS	O
+after	POS	O
+complete	POS	O
+recovery	POS	O
+of	POS	O
+consciousness	POS	O
+.	POS	O
+Evidence	POS	O
+for	POS	O
+cardiac	POS	O
+beta	POS	O
+2	POS	O
+-	POS	O
+adrenoceptors	POS	O
+in	POS	O
+man	POS	O
+.	POS	O
+We	POS	O
+compared	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+single	POS	O
+doses	POS	O
+of	POS	O
+50	POS	O
+mg	POS	O
+atenolol	POS	O
+(	POS	O
+cardioselective	POS	O
+)	POS	O
+,	POS	O
+40	POS	O
+mg	POS	O
+propranolol	POS	O
+(	POS	O
+nonselective	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+placebo	POS	O
+on	POS	O
+both	POS	O
+exercise	POS	O
+-	POS	O
+and	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+tachycardia	POS	B-NP
+in	POS	O
+two	POS	O
+experiments	POS	O
+involving	POS	O
+nine	POS	O
+normal	POS	O
+subjects	POS	O
+.	POS	O
+Maximal	POS	O
+exercise	POS	O
+heart	POS	O
+rate	POS	O
+was	POS	O
+reduced	POS	O
+from	POS	O
+187	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+(	POS	O
+SEM	POS	O
+)	POS	O
+after	POS	O
+placebo	POS	O
+to	POS	O
+146	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+7	POS	O
+bpm	POS	O
+after	POS	O
+atenolol	POS	O
+and	POS	O
+138	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+bpm	POS	O
+after	POS	O
+propranolol	POS	O
+,	POS	O
+but	POS	O
+there	POS	O
+were	POS	O
+no	POS	O
+differences	POS	O
+between	POS	O
+the	POS	O
+drugs	POS	O
+.	POS	O
+The	POS	O
+effects	POS	O
+on	POS	O
+isoproterenol	POS	O
+tachycardia	POS	B-NP
+were	POS	O
+determined	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+atropine	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+04	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+IV	POS	O
+)	POS	O
+.	POS	O
+Isoproterenol	POS	O
+sensitivity	POS	O
+was	POS	O
+determined	POS	O
+as	POS	O
+the	POS	O
+intravenous	POS	O
+dose	POS	O
+that	POS	O
+increased	POS	O
+heart	POS	O
+rate	POS	O
+by	POS	O
+25	POS	O
+bpm	POS	O
+(	POS	O
+CD25	POS	O
+)	POS	O
+and	POS	O
+this	POS	O
+was	POS	O
+increased	POS	O
+from	POS	O
+1	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+micrograms	POS	O
+after	POS	O
+placebo	POS	O
+to	POS	O
+38	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+8	POS	O
+.	POS	O
+3	POS	O
+micrograms	POS	O
+after	POS	O
+propranolol	POS	O
+and	POS	O
+8	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+7	POS	O
+micrograms	POS	O
+after	POS	O
+atenolol	POS	O
+.	POS	O
+The	POS	O
+difference	POS	O
+in	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+the	POS	O
+two	POS	O
+was	POS	O
+significant	POS	O
+.	POS	O
+After	POS	O
+atropine	POS	O
+the	POS	O
+CD25	POS	O
+was	POS	O
+unchanged	POS	O
+after	POS	O
+placebo	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+micrograms	POS	O
+)	POS	O
+and	POS	O
+atenolol	POS	O
+(	POS	O
+7	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+micrograms	POS	O
+)	POS	O
+;	POS	O
+it	POS	O
+was	POS	O
+reduced	POS	O
+after	POS	O
+propranolol	POS	O
+(	POS	O
+24	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+5	POS	O
+.	POS	O
+0	POS	O
+micrograms	POS	O
+)	POS	O
+,	POS	O
+but	POS	O
+remained	POS	O
+different	POS	O
+from	POS	O
+atenolol	POS	O
+.	POS	O
+This	POS	O
+change	POS	O
+with	POS	O
+propranolol	POS	O
+sensitivity	POS	O
+was	POS	O
+calculated	POS	O
+as	POS	O
+the	POS	O
+apparent	POS	O
+Ka	POS	O
+,	POS	O
+this	POS	O
+was	POS	O
+unchanged	POS	O
+by	POS	O
+atropine	POS	O
+(	POS	O
+11	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+1	POS	O
+and	POS	O
+10	POS	O
+.	POS	O
+1	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+ml	POS	O
+/	POS	O
+ng	POS	O
+)	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+are	POS	O
+consistent	POS	O
+with	POS	O
+the	POS	O
+hypothesis	POS	O
+that	POS	O
+exercise	POS	O
+-	POS	O
+induced	POS	O
+tachycardia	POS	B-NP
+results	POS	O
+largely	POS	O
+from	POS	O
+beta	POS	O
+1	POS	O
+-	POS	O
+receptor	POS	O
+activation	POS	O
+that	POS	O
+is	POS	O
+blocked	POS	O
+by	POS	O
+both	POS	O
+cardioselective	POS	O
+and	POS	O
+nonselective	POS	O
+drugs	POS	O
+,	POS	O
+whereas	POS	O
+isoproterenol	POS	O
+activates	POS	O
+both	POS	O
+beta	POS	O
+1	POS	O
+-	POS	O
+and	POS	O
+beta	POS	O
+2	POS	O
+-	POS	O
+receptors	POS	O
+so	POS	O
+that	POS	O
+after	POS	O
+cardioselective	POS	O
+blockade	POS	O
+there	POS	O
+remains	POS	O
+a	POS	O
+beta	POS	O
+2	POS	O
+-	POS	O
+component	POS	O
+that	POS	O
+can	POS	O
+be	POS	O
+blocked	POS	O
+with	POS	O
+a	POS	O
+nonselective	POS	O
+drug	POS	O
+.	POS	O
+While	POS	O
+there	POS	O
+appear	POS	O
+to	POS	O
+be	POS	O
+beta	POS	O
+2	POS	O
+-	POS	O
+receptors	POS	O
+in	POS	O
+the	POS	O
+human	POS	O
+heart	POS	O
+,	POS	O
+their	POS	O
+physiologic	POS	O
+or	POS	O
+pathologic	POS	O
+roles	POS	O
+remain	POS	O
+to	POS	O
+be	POS	O
+defined	POS	O
+.	POS	O
+Hormones	POS	O
+and	POS	O
+risk	POS	O
+of	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+This	POS	O
+paper	POS	O
+reports	POS	O
+the	POS	O
+results	POS	O
+of	POS	O
+a	POS	O
+study	POS	O
+of	POS	O
+50	POS	O
+menopausal	POS	O
+women	POS	O
+receiving	POS	O
+hormonal	POS	O
+replacement	POS	O
+therapy	POS	O
+.	POS	O
+The	POS	O
+majority	POS	O
+(	POS	O
+29	POS	O
+)	POS	O
+had	POS	O
+surgical	POS	O
+menopause	POS	O
+;	POS	O
+their	POS	O
+mean	POS	O
+age	POS	O
+was	POS	O
+45	POS	O
+.	POS	O
+7	POS	O
+years	POS	O
+.	POS	O
+It	POS	O
+was	POS	O
+hypothesized	POS	O
+that	POS	O
+progestins	POS	O
+could	POS	O
+equilibrate	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+the	POS	O
+estrogenic	POS	O
+stimulation	POS	O
+on	POS	O
+the	POS	O
+mammary	POS	O
+and	POS	O
+endometrial	POS	O
+target	POS	O
+tissues	POS	O
+of	POS	O
+women	POS	O
+on	POS	O
+hormonal	POS	O
+replacement	POS	O
+therapy	POS	O
+.	POS	O
+The	POS	O
+treatment	POS	O
+schedule	POS	O
+consisted	POS	O
+of	POS	O
+conjugated	POS	O
+estrogens	POS	O
+(	POS	O
+Premarin	POS	O
+)	POS	O
+1	POS	O
+.	POS	O
+25	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+for	POS	O
+21	POS	O
+days	POS	O
+and	POS	O
+Medroxyprogesterone	POS	O
+acetate	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+for	POS	O
+10	POS	O
+days	POS	O
+in	POS	O
+each	POS	O
+month	POS	O
+.	POS	O
+The	POS	O
+mean	POS	O
+treatment	POS	O
+period	POS	O
+was	POS	O
+18	POS	O
+months	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+period	POS	O
+,	POS	O
+attention	POS	O
+was	POS	O
+paid	POS	O
+to	POS	O
+breast	POS	O
+modifications	POS	O
+as	POS	O
+evidenced	POS	O
+by	POS	O
+symptomatology	POS	O
+,	POS	O
+physical	POS	O
+examination	POS	O
+,	POS	O
+and	POS	O
+plate	POS	O
+thermography	POS	O
+.	POS	O
+Mastodynia	POS	B-NP
+was	POS	O
+reported	POS	O
+by	POS	O
+21	POS	O
+patients	POS	O
+,	POS	O
+and	POS	O
+physical	POS	O
+examination	POS	O
+revealed	POS	O
+a	POS	O
+light	POS	O
+increase	POS	O
+in	POS	O
+breast	POS	O
+firmness	POS	O
+in	POS	O
+12	POS	O
+women	POS	O
+and	POS	O
+a	POS	O
+moderate	POS	O
+increase	POS	O
+in	POS	O
+breast	POS	B-NP
+nodularity	POS	I-NP
+in	POS	O
+2	POS	O
+women	POS	O
+.	POS	O
+Themography	POS	B-NP
+confirmed	POS	O
+the	POS	O
+existence	POS	O
+of	POS	O
+an	POS	O
+excessive	POS	O
+breast	POS	O
+stimulation	POS	O
+in	POS	O
+1	POS	O
+women	POS	O
+who	POS	O
+complained	POS	O
+of	POS	O
+moderate	POS	O
+mastodynia	POS	B-NP
+and	POS	O
+in	POS	O
+5	POS	O
+of	POS	O
+the	POS	O
+7	POS	O
+women	POS	O
+who	POS	O
+complained	POS	O
+of	POS	O
+severe	POS	O
+mastodynia	POS	B-NP
+.	POS	O
+Normalization	POS	O
+was	POS	O
+obtained	POS	O
+by	POS	O
+halving	POS	O
+the	POS	O
+estrogen	POS	O
+dose	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+hormonal	POS	O
+replacement	POS	O
+therapy	POS	O
+can	POS	O
+be	POS	O
+safely	POS	O
+prescribed	POS	O
+if	POS	O
+the	POS	O
+following	POS	O
+criteria	POS	O
+are	POS	O
+satisfied	POS	O
+:	POS	O
+1	POS	O
+)	POS	O
+preliminary	POS	O
+evaluation	POS	O
+of	POS	O
+patients	POS	O
+from	POS	O
+a	POS	O
+clinical	POS	O
+,	POS	O
+metabolic	POS	O
+,	POS	O
+cytologic	POS	O
+,	POS	O
+and	POS	O
+mammographic	POS	O
+perspective	POS	O
+;	POS	O
+2	POS	O
+)	POS	O
+cyclic	POS	O
+treatment	POS	O
+schedule	POS	O
+,	POS	O
+with	POS	O
+a	POS	O
+progestative	POS	O
+phase	POS	O
+of	POS	O
+10	POS	O
+days	POS	O
+;	POS	O
+and	POS	O
+3	POS	O
+)	POS	O
+periodic	POS	O
+complete	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+,	POS	O
+with	POS	O
+accurate	POS	O
+thermographic	POS	O
+evaluation	POS	O
+of	POS	O
+the	POS	O
+breast	POS	O
+target	POS	O
+tissues	POS	O
+.	POS	O
+Early	POS	O
+infections	POS	O
+in	POS	O
+kidney	POS	O
+,	POS	O
+heart	POS	O
+,	POS	O
+and	POS	O
+liver	POS	O
+transplant	POS	O
+recipients	POS	O
+on	POS	O
+cyclosporine	POS	O
+.	POS	O
+Eighty	POS	O
+-	POS	O
+one	POS	O
+renal	POS	O
+,	POS	O
+seventeen	POS	O
+heart	POS	O
+,	POS	O
+and	POS	O
+twenty	POS	O
+-	POS	O
+four	POS	O
+liver	POS	O
+transplant	POS	O
+patients	POS	O
+were	POS	O
+followed	POS	O
+for	POS	O
+infection	POS	O
+.	POS	O
+Seventeen	POS	O
+renal	POS	O
+patients	POS	O
+received	POS	O
+azathioprine	POS	O
+(	POS	O
+Aza	POS	O
+)	POS	O
+and	POS	O
+prednisone	POS	O
+as	POS	O
+part	POS	O
+of	POS	O
+a	POS	O
+randomized	POS	O
+trial	POS	O
+of	POS	O
+immunosuppression	POS	O
+with	POS	O
+21	POS	O
+cyclosporine	POS	O
+-	POS	O
+and	POS	O
+-	POS	O
+prednisone	POS	O
+-	POS	O
+treated	POS	O
+renal	POS	O
+transplant	POS	O
+patients	POS	O
+.	POS	O
+All	POS	O
+others	POS	O
+received	POS	O
+cyclosporine	POS	O
+and	POS	O
+prednisone	POS	O
+.	POS	O
+The	POS	O
+randomized	POS	O
+Aza	POS	O
+patients	POS	O
+had	POS	O
+more	POS	O
+overall	POS	O
+infections	POS	B-NP
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+and	POS	O
+more	POS	O
+nonviral	POS	B-NP
+infections	POS	I-NP
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+02	POS	O
+)	POS	O
+than	POS	O
+the	POS	O
+randomized	POS	O
+cyclosporine	POS	O
+patients	POS	O
+.	POS	O
+Heart	POS	O
+and	POS	O
+liver	POS	O
+patients	POS	O
+had	POS	O
+more	POS	O
+infections	POS	O
+than	POS	O
+cyclosporine	POS	O
+renal	POS	O
+patients	POS	O
+but	POS	O
+fewer	POS	O
+infections	POS	B-NP
+than	POS	O
+the	POS	O
+Aza	POS	O
+renal	POS	O
+patients	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+no	POS	O
+infectious	POS	B-NP
+deaths	POS	I-NP
+in	POS	O
+renal	POS	O
+transplant	POS	O
+patients	POS	O
+on	POS	O
+cyclosporine	POS	O
+or	POS	O
+Aza	POS	O
+,	POS	O
+but	POS	O
+infection	POS	O
+played	POS	O
+a	POS	O
+major	POS	O
+role	POS	O
+in	POS	O
+3	POS	O
+out	POS	O
+of	POS	O
+6	POS	O
+cardiac	POS	O
+transplant	POS	O
+deaths	POS	O
+and	POS	O
+in	POS	O
+8	POS	O
+out	POS	O
+of	POS	O
+9	POS	O
+liver	POS	B-NP
+transplant	POS	I-NP
+deaths	POS	I-NP
+.	POS	O
+Renal	POS	O
+patients	POS	O
+on	POS	O
+cyclosporine	POS	O
+had	POS	O
+the	POS	O
+fewest	POS	O
+bacteremias	POS	B-NP
+.	POS	O
+Analysis	POS	O
+of	POS	O
+site	POS	O
+of	POS	O
+infection	POS	O
+showed	POS	O
+a	POS	O
+preponderance	POS	O
+of	POS	O
+abdominal	POS	B-NP
+infections	POS	I-NP
+in	POS	O
+liver	POS	O
+patients	POS	O
+,	POS	O
+intrathoracic	POS	B-NP
+infections	POS	I-NP
+in	POS	O
+heart	POS	O
+patients	POS	O
+,	POS	O
+and	POS	O
+urinary	POS	B-NP
+tract	POS	I-NP
+infections	POS	I-NP
+in	POS	O
+renal	POS	O
+patients	POS	O
+.	POS	O
+Pulmonary	POS	B-NP
+infections	POS	I-NP
+were	POS	O
+less	POS	O
+common	POS	O
+in	POS	O
+cyclosporine	POS	O
+-	POS	O
+treated	POS	O
+renal	POS	O
+patients	POS	O
+than	POS	O
+in	POS	O
+Aza	POS	O
+-	POS	O
+treated	POS	O
+patients	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+Aza	POS	O
+patients	POS	O
+had	POS	O
+significantly	POS	O
+more	POS	O
+staphylococcal	POS	B-NP
+infections	POS	I-NP
+than	POS	O
+all	POS	O
+other	POS	O
+transplant	POS	O
+groups	POS	O
+(	POS	O
+P	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+005	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+systemic	POS	B-NP
+fungal	POS	I-NP
+infections	POS	I-NP
+occurred	POS	O
+only	POS	O
+in	POS	O
+the	POS	O
+liver	POS	O
+transplant	POS	O
+group	POS	O
+.	POS	O
+Cytomegalovirus	POS	O
+(	POS	O
+CMV	POS	O
+)	POS	O
+shedding	POS	O
+or	POS	O
+serological	POS	O
+rises	POS	O
+in	POS	O
+antibody	POS	O
+titer	POS	O
+,	POS	O
+or	POS	O
+both	POS	O
+occurred	POS	O
+in	POS	O
+78	POS	O
+%	POS	O
+of	POS	O
+cyclosporine	POS	O
+patients	POS	O
+and	POS	O
+76	POS	O
+%	POS	O
+of	POS	O
+Aza	POS	O
+patients	POS	O
+.	POS	O
+Of	POS	O
+the	POS	O
+cyclosporine	POS	O
+patients	POS	O
+,	POS	O
+15	POS	O
+%	POS	O
+had	POS	O
+symptoms	POS	O
+related	POS	O
+to	POS	O
+CMV	POS	B-NP
+infection	POS	I-NP
+.	POS	O
+Serological	POS	O
+evidence	POS	O
+for	POS	O
+Epstein	POS	B-NP
+Barr	POS	I-NP
+Virus	POS	I-NP
+infection	POS	I-NP
+was	POS	O
+found	POS	O
+in	POS	O
+20	POS	O
+%	POS	O
+of	POS	O
+65	POS	O
+cyclosporine	POS	O
+patients	POS	O
+studied	POS	O
+.	POS	O
+Three	POS	O
+had	POS	O
+associated	POS	O
+symptoms	POS	O
+,	POS	O
+and	POS	O
+one	POS	O
+developed	POS	O
+a	POS	O
+lymphoma	POS	B-NP
+.	POS	O
+Structure	POS	O
+-	POS	O
+activity	POS	O
+and	POS	O
+dose	POS	O
+-	POS	O
+effect	POS	O
+relationships	POS	O
+of	POS	O
+the	POS	O
+antagonism	POS	O
+of	POS	O
+picrotoxin	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+by	POS	O
+cholecystokinin	POS	O
+,	POS	O
+fragments	POS	O
+and	POS	O
+analogues	POS	O
+of	POS	O
+cholecystokinin	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+Intraperitoneal	POS	O
+administration	POS	O
+of	POS	O
+cholecystokinin	POS	O
+octapeptide	POS	O
+sulphate	POS	O
+ester	POS	O
+(	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+SE	POS	O
+)	POS	O
+and	POS	O
+nonsulphated	POS	O
+cholecystokinin	POS	O
+octapeptide	POS	O
+(	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+NS	POS	O
+)	POS	O
+enhanced	POS	O
+the	POS	O
+latency	POS	O
+of	POS	O
+seizures	POS	B-NP
+induced	POS	O
+by	POS	O
+picrotoxin	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+Experiments	POS	O
+with	POS	O
+N	POS	O
+-	POS	O
+and	POS	O
+C	POS	O
+-	POS	O
+terminal	POS	O
+fragments	POS	O
+revealed	POS	O
+that	POS	O
+the	POS	O
+C	POS	O
+-	POS	O
+terminal	POS	O
+tetrapeptide	POS	O
+(	POS	O
+CCK	POS	O
+-	POS	O
+5	POS	O
+-	POS	O
+8	POS	O
+)	POS	O
+was	POS	O
+the	POS	O
+active	POS	O
+centre	POS	O
+of	POS	O
+the	POS	O
+CCK	POS	O
+octapeptide	POS	O
+molecule	POS	O
+.	POS	O
+The	POS	O
+analogues	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+SE	POS	O
+and	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+NS	POS	O
+(	POS	O
+dose	POS	O
+range	POS	O
+0	POS	O
+.	POS	O
+2	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+4	POS	O
+mumol	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+and	POS	O
+caerulein	POS	O
+dose	POS	O
+range	POS	O
+0	POS	O
+.	POS	O
+1	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+8	POS	O
+mumol	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+showed	POS	O
+bell	POS	O
+-	POS	O
+shaped	POS	O
+dose	POS	O
+-	POS	O
+effect	POS	O
+curves	POS	O
+,	POS	O
+with	POS	O
+the	POS	O
+greatest	POS	O
+maximum	POS	O
+inhibition	POS	O
+for	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+NS	POS	O
+.	POS	O
+The	POS	O
+peptide	POS	O
+CCK	POS	O
+-	POS	O
+5	POS	O
+-	POS	O
+8	POS	O
+had	POS	O
+weak	POS	O
+anticonvulsant	POS	O
+activity	POS	O
+in	POS	O
+comparison	POS	O
+to	POS	O
+the	POS	O
+octapeptides	POS	O
+,	POS	O
+3	POS	O
+.	POS	O
+2	POS	O
+mumol	POS	O
+/	POS	O
+kg	POS	O
+and	POS	O
+larger	POS	O
+doses	POS	O
+of	POS	O
+the	POS	O
+reference	POS	O
+drug	POS	O
+,	POS	O
+diazepam	POS	O
+,	POS	O
+totally	POS	O
+prevented	POS	O
+picrotoxin	POS	O
+-	POS	O
+induced	POS	O
+seizures	POS	B-NP
+and	POS	O
+mortality	POS	O
+.	POS	O
+The	POS	O
+maximum	POS	O
+effect	POS	O
+of	POS	O
+the	POS	O
+peptides	POS	O
+tested	POS	O
+was	POS	O
+less	POS	O
+than	POS	O
+that	POS	O
+of	POS	O
+diazepam	POS	O
+.	POS	O
+Experiments	POS	O
+with	POS	O
+analogues	POS	O
+and	POS	O
+derivatives	POS	O
+of	POS	O
+CCK	POS	O
+-	POS	O
+5	POS	O
+-	POS	O
+8	POS	O
+demonstrated	POS	O
+that	POS	O
+the	POS	O
+effectiveness	POS	O
+of	POS	O
+the	POS	O
+beta	POS	O
+-	POS	O
+alanyl	POS	O
+derivatives	POS	O
+of	POS	O
+CCK	POS	O
+-	POS	O
+5	POS	O
+-	POS	O
+8	POS	O
+were	POS	O
+enhanced	POS	O
+and	POS	O
+that	POS	O
+they	POS	O
+were	POS	O
+equipotent	POS	O
+with	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+SE	POS	O
+.	POS	O
+Of	POS	O
+the	POS	O
+CCK	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+8	POS	O
+analogues	POS	O
+,	POS	O
+Ser	POS	O
+(	POS	O
+SO3H	POS	O
+)	POS	O
+7	POS	O
+-	POS	O
+Ac	POS	O
+-	POS	O
+CCK	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+SE	POS	O
+and	POS	O
+Thr	POS	O
+(	POS	O
+SO3H	POS	O
+)	POS	O
+7	POS	O
+-	POS	O
+Ac	POS	O
+-	POS	O
+CCK	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+SE	POS	O
+and	POS	O
+Hyp	POS	O
+(	POS	O
+SO3H	POS	O
+)	POS	O
+-	POS	O
+Ac	POS	O
+-	POS	O
+CCK	POS	O
+-	POS	O
+2	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+SE	POS	O
+were	POS	O
+slightly	POS	O
+more	POS	O
+active	POS	O
+than	POS	O
+CCK	POS	O
+-	POS	O
+8	POS	O
+-	POS	O
+SE	POS	O
+.	POS	O
+Vasopressin	POS	O
+as	POS	O
+a	POS	O
+possible	POS	O
+contributor	POS	O
+to	POS	O
+hypertension	POS	B-NP
+.	POS	O
+The	POS	O
+role	POS	O
+of	POS	O
+vasopressin	POS	O
+as	POS	O
+a	POS	O
+pressor	POS	O
+agent	POS	O
+to	POS	O
+the	POS	O
+hypertensive	POS	B-NP
+process	POS	O
+was	POS	O
+examined	POS	O
+.	POS	O
+Vasopressin	POS	O
+plays	POS	O
+a	POS	O
+major	POS	O
+role	POS	O
+in	POS	O
+the	POS	O
+pathogenesis	POS	O
+of	POS	O
+DOCA	POS	O
+-	POS	O
+salt	POS	O
+hypertension	POS	B-NP
+,	POS	O
+since	POS	O
+the	POS	O
+elevation	POS	O
+of	POS	O
+blood	POS	O
+pressure	POS	O
+was	POS	O
+not	POS	O
+substantial	POS	O
+in	POS	O
+the	POS	O
+rats	POS	O
+with	POS	O
+lithium	POS	O
+-	POS	O
+treated	POS	O
+diabetes	POS	B-NP
+insipidus	POS	I-NP
+after	POS	O
+DOCA	POS	O
+-	POS	O
+salt	POS	O
+treatment	POS	O
+.	POS	O
+Administration	POS	O
+of	POS	O
+DDAVP	POS	O
+which	POS	O
+has	POS	O
+antidiuretic	POS	O
+action	POS	O
+but	POS	O
+minimal	POS	O
+vasopressor	POS	O
+effect	POS	O
+failed	POS	O
+to	POS	O
+increase	POS	O
+blood	POS	O
+pressure	POS	O
+to	POS	O
+the	POS	O
+levels	POS	O
+observed	POS	O
+after	POS	O
+administration	POS	O
+of	POS	O
+AVP	POS	O
+.	POS	O
+Furthermore	POS	O
+,	POS	O
+the	POS	O
+pressor	POS	O
+action	POS	O
+of	POS	O
+vasopressin	POS	O
+appears	POS	O
+to	POS	O
+be	POS	O
+important	POS	O
+in	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+this	POS	O
+model	POS	O
+of	POS	O
+hypertension	POS	B-NP
+,	POS	O
+since	POS	O
+the	POS	O
+enhanced	POS	O
+pressor	POS	O
+responsiveness	POS	O
+to	POS	O
+the	POS	O
+hormone	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+initial	POS	O
+stage	POS	O
+of	POS	O
+hypertension	POS	B-NP
+.	POS	O
+Increased	POS	O
+secretion	POS	O
+of	POS	O
+vasopressin	POS	O
+from	POS	O
+neurohypophysis	POS	O
+also	POS	O
+promotes	POS	O
+the	POS	O
+function	POS	O
+of	POS	O
+the	POS	O
+hormone	POS	O
+as	POS	O
+a	POS	O
+pathogenetic	POS	O
+factor	POS	O
+in	POS	O
+hypertension	POS	B-NP
+.	POS	O
+An	POS	O
+unproportional	POS	O
+release	POS	O
+of	POS	O
+vasopressin	POS	O
+compared	POS	O
+to	POS	O
+plasma	POS	O
+osmolality	POS	O
+may	POS	O
+be	POS	O
+induced	POS	O
+by	POS	O
+the	POS	O
+absence	POS	O
+of	POS	O
+an	POS	O
+adjusting	POS	O
+control	POS	O
+of	POS	O
+angiotensin	POS	O
+II	POS	O
+forming	POS	O
+and	POS	O
+receptor	POS	O
+binding	POS	O
+capacity	POS	O
+for	POS	O
+sodium	POS	O
+balance	POS	O
+in	POS	O
+the	POS	O
+brain	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+role	POS	O
+of	POS	O
+vasopressin	POS	O
+remains	POS	O
+to	POS	O
+be	POS	O
+determined	POS	O
+in	POS	O
+human	POS	O
+essential	POS	O
+hypertension	POS	B-NP
+.	POS	O
+Toxic	POS	B-NP
+hepatitis	POS	I-NP
+induced	POS	O
+by	POS	O
+disulfiram	POS	O
+in	POS	O
+a	POS	O
+non	POS	O
+-	POS	O
+alcoholic	POS	O
+.	POS	O
+A	POS	O
+reversible	POS	O
+toxic	POS	B-NP
+liver	POS	I-NP
+damage	POS	I-NP
+was	POS	O
+observed	POS	O
+in	POS	O
+a	POS	O
+non	POS	O
+-	POS	O
+alcoholic	POS	O
+woman	POS	O
+treated	POS	O
+with	POS	O
+disulfiram	POS	O
+.	POS	O
+The	POS	O
+causative	POS	O
+relationship	POS	O
+was	POS	O
+proven	POS	O
+by	POS	O
+challenge	POS	O
+.	POS	O
+Atrial	POS	B-NP
+thrombosis	POS	I-NP
+involving	POS	O
+the	POS	O
+heart	POS	O
+of	POS	O
+F	POS	O
+-	POS	O
+344	POS	O
+rats	POS	O
+ingesting	POS	O
+quinacrine	POS	O
+hydrochloride	POS	O
+.	POS	O
+Quinacrine	POS	O
+hydrochloride	POS	O
+is	POS	O
+toxic	POS	O
+for	POS	O
+the	POS	O
+heart	POS	O
+of	POS	O
+F	POS	O
+-	POS	O
+344	POS	O
+rats	POS	O
+.	POS	O
+Rats	POS	O
+treated	POS	O
+with	POS	O
+500	POS	O
+ppm	POS	O
+quinacrine	POS	O
+hydrochloride	POS	O
+in	POS	O
+the	POS	O
+diet	POS	O
+all	POS	O
+developed	POS	O
+a	POS	O
+high	POS	O
+incidence	POS	O
+of	POS	O
+left	POS	O
+atrial	POS	B-NP
+thrombosis	POS	I-NP
+.	POS	O
+The	POS	O
+lesion	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+cardiac	POS	B-NP
+hypertrophy	POS	I-NP
+and	POS	O
+dilatation	POS	O
+and	POS	O
+focal	POS	O
+myocardial	POS	B-NP
+degeneration	POS	I-NP
+.	POS	O
+Rats	POS	O
+died	POS	O
+from	POS	O
+cardiac	POS	B-NP
+hypertrophy	POS	I-NP
+with	POS	O
+severe	POS	O
+acute	POS	O
+and	POS	O
+chronic	POS	O
+congestion	POS	O
+of	POS	O
+the	POS	O
+lungs	POS	O
+,	POS	O
+liver	POS	O
+,	POS	O
+and	POS	O
+other	POS	O
+organs	POS	O
+.	POS	O
+Seventy	POS	O
+percent	POS	O
+of	POS	O
+rats	POS	O
+given	POS	O
+250	POS	O
+ppm	POS	O
+quinacrine	POS	O
+hydrochloride	POS	O
+and	POS	O
+1	POS	O
+,	POS	O
+000	POS	O
+ppm	POS	O
+sodium	POS	O
+nitrite	POS	O
+simultaneously	POS	O
+in	POS	O
+the	POS	O
+diet	POS	O
+had	POS	O
+thrombosis	POS	B-NP
+of	POS	O
+the	POS	O
+atria	POS	O
+of	POS	O
+the	POS	O
+heart	POS	O
+,	POS	O
+while	POS	O
+untreated	POS	O
+control	POS	O
+rats	POS	O
+in	POS	O
+this	POS	O
+laboratory	POS	O
+did	POS	O
+not	POS	O
+have	POS	O
+atrial	POS	B-NP
+thrombosis	POS	I-NP
+.	POS	O
+Sodium	POS	O
+nitrite	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+quinacrine	POS	O
+hydrochloride	POS	O
+appeared	POS	O
+to	POS	O
+have	POS	O
+no	POS	O
+additional	POS	O
+effect	POS	O
+.	POS	O
+Alternating	POS	O
+sinus	POS	O
+rhythm	POS	O
+and	POS	O
+intermittent	POS	O
+sinoatrial	POS	B-NP
+block	POS	I-NP
+induced	POS	O
+by	POS	O
+propranolol	POS	O
+.	POS	O
+Alternating	POS	O
+sinus	POS	O
+rhythm	POS	O
+and	POS	O
+intermittent	POS	O
+sinoatrial	POS	O
+(	POS	O
+S	POS	O
+-	POS	O
+A	POS	O
+)	POS	O
+block	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+a	POS	O
+57	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+,	POS	O
+under	POS	O
+treatment	POS	O
+for	POS	O
+angina	POS	B-NP
+with	POS	O
+80	POS	O
+mg	POS	O
+propranolol	POS	O
+daily	POS	O
+.	POS	O
+The	POS	O
+electrocardiogram	POS	O
+showed	POS	O
+alternation	POS	O
+of	POS	O
+long	POS	O
+and	POS	O
+short	POS	O
+P	POS	O
+-	POS	O
+P	POS	O
+intervals	POS	O
+and	POS	O
+occasional	POS	O
+pauses	POS	O
+.	POS	O
+These	POS	O
+pauses	POS	O
+were	POS	O
+always	POS	O
+preceded	POS	O
+by	POS	O
+the	POS	O
+short	POS	O
+P	POS	O
+-	POS	O
+P	POS	O
+intervals	POS	O
+and	POS	O
+were	POS	O
+usually	POS	O
+followed	POS	O
+by	POS	O
+one	POS	O
+or	POS	O
+two	POS	O
+P	POS	O
+-	POS	O
+P	POS	O
+intervals	POS	O
+of	POS	O
+0	POS	O
+.	POS	O
+92	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+95	POS	O
+s	POS	O
+representing	POS	O
+the	POS	O
+basic	POS	O
+sinus	POS	O
+cycle	POS	O
+.	POS	O
+Following	POS	O
+these	POS	O
+basic	POS	O
+sinus	POS	O
+cycles	POS	O
+,	POS	O
+alternating	POS	O
+rhythm	POS	O
+started	POS	O
+with	POS	O
+the	POS	O
+longer	POS	O
+P	POS	O
+-	POS	O
+P	POS	O
+interval	POS	O
+.	POS	O
+The	POS	O
+long	POS	O
+P	POS	O
+-	POS	O
+P	POS	O
+intervals	POS	O
+ranged	POS	O
+between	POS	O
+1	POS	O
+.	POS	O
+04	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+12	POS	O
+s	POS	O
+and	POS	O
+the	POS	O
+short	POS	O
+P	POS	O
+-	POS	O
+P	POS	O
+intervals	POS	O
+between	POS	O
+0	POS	O
+.	POS	O
+80	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+84	POS	O
+s	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+The	POS	O
+duration	POS	O
+of	POS	O
+the	POS	O
+pauses	POS	O
+were	POS	O
+equal	POS	O
+or	POS	O
+almost	POS	O
+equal	POS	O
+to	POS	O
+one	POS	O
+short	POS	O
+plus	POS	O
+one	POS	O
+long	POS	O
+P	POS	O
+-	POS	O
+P	POS	O
+interval	POS	O
+or	POS	O
+to	POS	O
+twice	POS	O
+the	POS	O
+basic	POS	O
+sinus	POS	O
+cycle	POS	O
+.	POS	O
+In	POS	O
+one	POS	O
+recording	POS	O
+a	POS	O
+short	POS	O
+period	POS	O
+of	POS	O
+regular	POS	O
+sinus	POS	O
+rhythm	POS	O
+with	POS	O
+intermittent	POS	O
+2	POS	O
+/	POS	O
+1	POS	O
+S	POS	O
+-	POS	O
+A	POS	O
+block	POS	O
+was	POS	O
+observed	POS	O
+.	POS	O
+This	POS	O
+short	POS	O
+period	POS	O
+of	POS	O
+sinus	POS	O
+rhythm	POS	O
+was	POS	O
+interrupted	POS	O
+by	POS	O
+sudden	POS	O
+prolongation	POS	O
+of	POS	O
+the	POS	O
+P	POS	O
+-	POS	O
+P	POS	O
+interval	POS	O
+starting	POS	O
+the	POS	O
+alternative	POS	O
+rhythm	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+small	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+shape	POS	O
+of	POS	O
+the	POS	O
+P	POS	O
+waves	POS	O
+and	POS	O
+P	POS	O
+-	POS	O
+R	POS	O
+intervals	POS	O
+.	POS	O
+S	POS	O
+-	POS	O
+A	POS	O
+conduction	POS	O
+through	POS	O
+two	POS	O
+pathways	POS	O
+,	POS	O
+the	POS	O
+first	POS	O
+with	POS	O
+2	POS	O
+/	POS	O
+1	POS	O
+block	POS	O
+the	POS	O
+second	POS	O
+having	POS	O
+0	POS	O
+.	POS	O
+12	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+14	POS	O
+s	POS	O
+longer	POS	O
+conduction	POS	O
+time	POS	O
+and	POS	O
+with	POS	O
+occasional	POS	O
+2	POS	O
+/	POS	O
+1	POS	O
+block	POS	O
+was	POS	O
+proposed	POS	O
+for	POS	O
+the	POS	O
+explanation	POS	O
+of	POS	O
+the	POS	O
+alternating	POS	O
+P	POS	O
+-	POS	O
+P	POS	O
+interval	POS	O
+and	POS	O
+other	POS	O
+electrocardiographic	POS	O
+features	POS	O
+seen	POS	O
+.	POS	O
+Atropine	POS	O
+1	POS	O
+mg	POS	O
+given	POS	O
+intravenously	POS	O
+resulted	POS	O
+in	POS	O
+shortening	POS	O
+of	POS	O
+all	POS	O
+P	POS	O
+-	POS	O
+P	POS	O
+intervals	POS	O
+without	POS	O
+changing	POS	O
+the	POS	O
+rhythm	POS	O
+.	POS	O
+The	POS	O
+abnormal	POS	O
+rhythm	POS	O
+disappeared	POS	O
+with	POS	O
+the	POS	O
+withdrawal	POS	O
+of	POS	O
+propranolol	POS	O
+and	POS	O
+when	POS	O
+the	POS	O
+drug	POS	O
+was	POS	O
+restarted	POS	O
+a	POS	O
+2	POS	O
+/	POS	O
+1	POS	O
+S	POS	O
+-	POS	O
+A	POS	O
+block	POS	O
+was	POS	O
+seen	POS	O
+.	POS	O
+This	POS	O
+was	POS	O
+accepted	POS	O
+as	POS	O
+evidence	POS	O
+for	POS	O
+propranolol	POS	O
+being	POS	O
+the	POS	O
+cause	POS	O
+of	POS	O
+this	POS	O
+conduction	POS	O
+disorder	POS	O
+.	POS	O
+Antitumor	POS	B-NP
+effect	POS	I-NP
+,	POS	O
+cardiotoxicity	POS	B-NP
+,	POS	O
+and	POS	O
+nephrotoxicity	POS	B-NP
+of	POS	O
+doxorubicin	POS	O
+in	POS	O
+the	POS	O
+IgM	POS	O
+solid	POS	O
+immunocytoma	POS	O
+-	POS	O
+bearing	POS	O
+LOU	POS	O
+/	POS	O
+M	POS	O
+/	POS	O
+WSL	POS	O
+rat	POS	O
+.	POS	O
+Antitumor	POS	O
+activity	POS	O
+,	POS	O
+cardiotoxicity	POS	B-NP
+,	POS	O
+and	POS	O
+nephrotoxicity	POS	B-NP
+induced	POS	O
+by	POS	O
+doxorubicin	POS	O
+were	POS	O
+studied	POS	O
+in	POS	O
+LOU	POS	O
+/	POS	O
+M	POS	O
+/	POS	O
+WSL	POS	O
+inbred	POS	O
+rats	POS	O
+each	POS	O
+bearing	POS	O
+a	POS	O
+transplantable	POS	O
+solid	POS	O
+IgM	POS	O
+immunocytoma	POS	B-NP
+.	POS	O
+Animals	POS	O
+with	POS	O
+a	POS	O
+tumor	POS	B-NP
+(	POS	O
+diameter	POS	O
+,	POS	O
+15	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+3	POS	O
+.	POS	O
+3	POS	O
+mm	POS	O
+)	POS	O
+were	POS	O
+treated	POS	O
+with	POS	O
+iv	POS	O
+injections	POS	O
+of	POS	O
+doxorubicin	POS	O
+on	POS	O
+5	POS	O
+consecutive	POS	O
+days	POS	O
+,	POS	O
+followed	POS	O
+by	POS	O
+1	POS	O
+weekly	POS	O
+injection	POS	O
+for	POS	O
+7	POS	O
+weeks	POS	O
+(	POS	O
+dose	POS	O
+range	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+015	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+0	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+body	POS	O
+wt	POS	O
+)	POS	O
+.	POS	O
+Tumor	POS	B-NP
+regression	POS	O
+was	POS	O
+observed	POS	O
+with	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+doxorubicin	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+Complete	POS	O
+disappearance	POS	O
+of	POS	O
+the	POS	O
+tumor	POS	B-NP
+was	POS	O
+induced	POS	O
+with	POS	O
+1	POS	O
+.	POS	O
+0	POS	O
+mg	POS	O
+doxorubicin	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+Histologic	POS	O
+evidence	POS	O
+of	POS	O
+cardiotoxicity	POS	B-NP
+scored	POS	O
+as	POS	O
+grade	POS	O
+III	POS	O
+was	POS	O
+only	POS	O
+observed	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+1	POS	O
+.	POS	O
+0	POS	O
+mg	POS	O
+doxorubicin	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+Light	POS	O
+microscopic	POS	O
+evidence	POS	O
+of	POS	O
+renal	POS	B-NP
+damage	POS	I-NP
+was	POS	O
+seen	POS	O
+above	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+doxorubicin	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+which	POS	O
+resulted	POS	O
+in	POS	O
+albuminuria	POS	B-NP
+and	POS	O
+very	POS	O
+low	POS	O
+serum	POS	O
+albumin	POS	O
+levels	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+group	POS	O
+that	POS	O
+received	POS	O
+1	POS	O
+.	POS	O
+0	POS	O
+mg	POS	O
+doxorubicin	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+the	POS	O
+serum	POS	O
+albumin	POS	O
+level	POS	O
+decreased	POS	O
+from	POS	O
+33	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+1	POS	O
+to	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+g	POS	O
+/	POS	O
+liter	POS	O
+.	POS	O
+Ascites	POS	O
+and	POS	O
+hydrothorax	POS	B-NP
+were	POS	O
+observed	POS	O
+simultaneously	POS	O
+.	POS	O
+The	POS	O
+same	POS	O
+experiments	POS	O
+were	POS	O
+performed	POS	O
+with	POS	O
+non	POS	O
+-	POS	O
+tumor	POS	O
+-	POS	O
+bearing	POS	O
+rats	POS	O
+,	POS	O
+in	POS	O
+which	POS	O
+no	POS	O
+major	POS	O
+differences	POS	O
+were	POS	O
+observed	POS	O
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+antitumor	POS	O
+activity	POS	O
+,	POS	O
+cardiotoxicity	POS	B-NP
+,	POS	O
+and	POS	O
+nephrotoxicity	POS	B-NP
+were	POS	O
+studied	POS	O
+simultaneously	POS	O
+in	POS	O
+the	POS	O
+same	POS	O
+LOU	POS	O
+/	POS	O
+M	POS	O
+/	POS	O
+WSL	POS	O
+rat	POS	O
+.	POS	O
+Albuminuria	POS	B-NP
+due	POS	O
+to	POS	O
+renal	POS	B-NP
+damage	POS	I-NP
+led	POS	O
+to	POS	O
+extremely	POS	O
+low	POS	O
+serum	POS	O
+albumin	POS	O
+levels	POS	O
+,	POS	O
+so	POS	O
+ascites	POS	B-NP
+and	POS	O
+hydrothorax	POS	B-NP
+were	POS	O
+not	POS	O
+necessarily	POS	O
+a	POS	O
+consequence	POS	O
+of	POS	O
+the	POS	O
+observed	POS	O
+cardiomyopathy	POS	B-NP
+.	POS	O
+Intraoperative	POS	B-NP
+bradycardia	POS	I-NP
+and	POS	O
+hypotension	POS	B-NP
+associated	POS	O
+with	POS	O
+timolol	POS	O
+and	POS	O
+pilocarpine	POS	O
+eye	POS	O
+drops	POS	O
+.	POS	O
+A	POS	O
+69	POS	O
+-	POS	O
+yr	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+,	POS	O
+who	POS	O
+was	POS	O
+concurrently	POS	O
+being	POS	O
+treated	POS	O
+with	POS	O
+pilocarpine	POS	O
+nitrate	POS	O
+and	POS	O
+timolol	POS	O
+maleate	POS	O
+eye	POS	O
+drops	POS	O
+,	POS	O
+developed	POS	O
+a	POS	O
+bradycardia	POS	B-NP
+and	POS	O
+became	POS	O
+hypotensive	POS	B-NP
+during	POS	O
+halothane	POS	O
+anaesthesia	POS	O
+.	POS	O
+Both	POS	O
+timolol	POS	O
+and	POS	O
+pilocarpine	POS	O
+were	POS	O
+subsequently	POS	O
+identified	POS	O
+in	POS	O
+a	POS	O
+24	POS	O
+-	POS	O
+h	POS	O
+collection	POS	O
+of	POS	O
+urine	POS	O
+.	POS	O
+Timolol	POS	O
+(	POS	O
+but	POS	O
+not	POS	O
+pilocarpine	POS	O
+)	POS	O
+was	POS	O
+detected	POS	O
+in	POS	O
+a	POS	O
+sample	POS	O
+of	POS	O
+plasma	POS	O
+removed	POS	O
+during	POS	O
+surgery	POS	O
+;	POS	O
+the	POS	O
+plasma	POS	O
+concentration	POS	O
+of	POS	O
+timolol	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+6	POS	O
+ng	POS	O
+ml	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+was	POS	O
+consistent	POS	O
+with	POS	O
+partial	POS	O
+beta	POS	O
+-	POS	O
+adrenoceptor	POS	O
+blockade	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+postulated	POS	O
+that	POS	O
+this	POS	O
+action	POS	O
+may	POS	O
+have	POS	O
+been	POS	O
+enhanced	POS	O
+during	POS	O
+halothane	POS	O
+anaesthesia	POS	O
+with	POS	O
+resultant	POS	O
+bradycardia	POS	B-NP
+and	POS	O
+hypotension	POS	B-NP
+.	POS	O
+Pilocarpine	POS	O
+may	POS	O
+have	POS	O
+had	POS	O
+a	POS	O
+contributory	POS	O
+effect	POS	O
+.	POS	O
+Succinylcholine	POS	O
+apnoea	POS	B-NP
+:	POS	O
+attempted	POS	O
+reversal	POS	O
+with	POS	O
+anticholinesterases	POS	O
+.	POS	O
+Anticholinesterases	POS	O
+were	POS	O
+administered	POS	O
+in	POS	O
+an	POS	O
+attempt	POS	O
+to	POS	O
+antagonize	POS	O
+prolonged	POS	O
+neuromuscular	POS	O
+blockade	POS	O
+following	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+succinylcholine	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+later	POS	O
+found	POS	O
+to	POS	O
+be	POS	O
+homozygous	POS	O
+for	POS	O
+atypical	POS	O
+plasma	POS	O
+cholinesterase	POS	O
+.	POS	O
+Edrophonium	POS	O
+10	POS	O
+mg	POS	O
+,	POS	O
+given	POS	O
+74	POS	O
+min	POS	O
+after	POS	O
+succinylcholine	POS	O
+,	POS	O
+when	POS	O
+train	POS	O
+-	POS	O
+of	POS	O
+-	POS	O
+four	POS	O
+stimulation	POS	O
+was	POS	O
+characteristic	POS	O
+of	POS	O
+phase	POS	O
+II	POS	O
+block	POS	O
+,	POS	O
+produced	POS	O
+partial	POS	O
+antagonism	POS	O
+which	POS	O
+was	POS	O
+not	POS	O
+sustained	POS	O
+.	POS	O
+Repeated	POS	O
+doses	POS	O
+of	POS	O
+edrophonium	POS	O
+to	POS	O
+70	POS	O
+mg	POS	O
+and	POS	O
+neostigmine	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+did	POS	O
+not	POS	O
+antagonize	POS	O
+or	POS	O
+augment	POS	O
+the	POS	O
+block	POS	O
+.	POS	O
+Spontaneous	POS	O
+respiration	POS	O
+recommenced	POS	O
+200	POS	O
+min	POS	O
+after	POS	O
+succinylcholine	POS	O
+administration	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+concluded	POS	O
+that	POS	O
+anticholinesterases	POS	O
+are	POS	O
+only	POS	O
+partially	POS	O
+effective	POS	O
+in	POS	O
+restoring	POS	O
+neuromuscular	POS	O
+function	POS	O
+in	POS	O
+succinylcholine	POS	O
+apnoea	POS	B-NP
+despite	POS	O
+muscle	POS	O
+twitch	POS	O
+activity	POS	O
+typical	POS	O
+of	POS	O
+phase	POS	O
+II	POS	O
+block	POS	O
+.	POS	O
+Effect	POS	O
+of	POS	O
+doxorubicin	POS	O
+on	POS	O
+[	POS	O
+omega	POS	O
+-	POS	O
+I	POS	O
+-	POS	O
+131	POS	O
+]	POS	O
+heptadecanoic	POS	O
+acid	POS	O
+myocardial	POS	O
+scintigraphy	POS	O
+and	POS	O
+echocardiography	POS	O
+in	POS	O
+dogs	POS	O
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+serial	POS	O
+treatment	POS	O
+with	POS	O
+doxorubicin	POS	O
+on	POS	O
+dynamic	POS	O
+myocardial	POS	O
+scintigraphy	POS	O
+with	POS	O
+[	POS	O
+omega	POS	O
+-	POS	O
+I	POS	O
+-	POS	O
+131	POS	O
+]	POS	O
+heptadecanoic	POS	O
+acid	POS	O
+(	POS	O
+I	POS	O
+-	POS	O
+131	POS	O
+HA	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+on	POS	O
+global	POS	O
+left	POS	O
+-	POS	O
+ventricular	POS	O
+function	POS	O
+determined	POS	O
+echocardiographically	POS	O
+,	POS	O
+were	POS	O
+studied	POS	O
+in	POS	O
+a	POS	O
+group	POS	O
+of	POS	O
+nine	POS	O
+mongrel	POS	O
+dogs	POS	O
+.	POS	O
+Total	POS	O
+extractable	POS	O
+myocardial	POS	O
+lipid	POS	O
+was	POS	O
+compared	POS	O
+postmortem	POS	O
+between	POS	O
+a	POS	O
+group	POS	O
+of	POS	O
+control	POS	O
+dogs	POS	O
+and	POS	O
+doxorubicin	POS	O
+-	POS	O
+treated	POS	O
+dogs	POS	O
+.	POS	O
+A	POS	O
+significant	POS	O
+and	POS	O
+then	POS	O
+progressive	POS	O
+fall	POS	O
+in	POS	O
+global	POS	O
+LV	POS	O
+function	POS	O
+was	POS	O
+observed	POS	O
+at	POS	O
+a	POS	O
+cumulative	POS	O
+doxorubicin	POS	O
+dose	POS	O
+of	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+A	POS	O
+significant	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+myocardial	POS	O
+t1	POS	O
+/	POS	O
+2	POS	O
+of	POS	O
+the	POS	O
+I	POS	O
+-	POS	O
+131	POS	O
+HA	POS	O
+was	POS	O
+observed	POS	O
+only	POS	O
+at	POS	O
+a	POS	O
+higher	POS	O
+cumulative	POS	O
+dose	POS	O
+,	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+No	POS	O
+significant	POS	O
+alteration	POS	O
+in	POS	O
+total	POS	O
+extractable	POS	O
+myocardial	POS	O
+lipids	POS	O
+was	POS	O
+observed	POS	O
+between	POS	O
+control	POS	O
+dogs	POS	O
+and	POS	O
+those	POS	O
+treated	POS	O
+with	POS	O
+doxorubicin	POS	O
+.	POS	O
+Our	POS	O
+findings	POS	O
+suggest	POS	O
+that	POS	O
+the	POS	O
+changes	POS	O
+leading	POS	O
+to	POS	O
+an	POS	O
+alteration	POS	O
+of	POS	O
+myocardial	POS	O
+dynamic	POS	O
+imaging	POS	O
+with	POS	O
+I	POS	O
+-	POS	O
+131	POS	O
+HA	POS	O
+are	POS	O
+not	POS	O
+the	POS	O
+initiating	POS	O
+factor	POS	O
+in	POS	O
+doxorubicin	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+Hemodynamics	POS	O
+and	POS	O
+myocardial	POS	O
+metabolism	POS	O
+under	POS	O
+deliberate	POS	O
+hypotension	POS	B-NP
+.	POS	O
+An	POS	O
+experimental	POS	O
+study	POS	O
+in	POS	O
+dogs	POS	O
+.	POS	O
+Coronary	POS	O
+blood	POS	O
+flow	POS	O
+,	POS	O
+cardiac	POS	O
+work	POS	O
+and	POS	O
+metabolism	POS	O
+were	POS	O
+studied	POS	O
+in	POS	O
+dogs	POS	O
+under	POS	O
+sodium	POS	O
+nitroprusside	POS	O
+(	POS	O
+SNP	POS	O
+)	POS	O
+and	POS	O
+trimetaphan	POS	O
+(	POS	O
+TMP	POS	O
+)	POS	O
+deliberate	POS	O
+hypotension	POS	B-NP
+(	POS	O
+20	POS	O
+%	POS	O
+and	POS	O
+40	POS	O
+%	POS	O
+mean	POS	O
+pressure	POS	O
+decrease	POS	O
+from	POS	O
+baseline	POS	O
+)	POS	O
+.	POS	O
+Regarding	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+on	POS	O
+coronary	POS	O
+blood	POS	O
+flow	POS	O
+,	POS	O
+aortic	POS	O
+and	POS	O
+coronary	POS	O
+sinus	POS	O
+metabolic	POS	O
+data	POS	O
+(	POS	O
+pH	POS	O
+,	POS	O
+pO2	POS	O
+,	POS	O
+pCO2	POS	O
+)	POS	O
+we	POS	O
+could	POS	O
+confirm	POS	O
+that	POS	O
+nitroprusside	POS	O
+hypotension	POS	B-NP
+could	POS	O
+be	POS	O
+safely	POS	O
+used	POS	O
+to	POS	O
+30	POS	O
+%	POS	O
+mean	POS	O
+blood	POS	O
+pressure	POS	O
+decrease	POS	O
+from	POS	O
+control	POS	O
+,	POS	O
+trimetaphan	POS	O
+hypotension	POS	B-NP
+to	POS	O
+20	POS	O
+%	POS	O
+mean	POS	O
+blood	POS	O
+pressure	POS	O
+decrease	POS	O
+.	POS	O
+Cardiac	POS	O
+work	POS	O
+was	POS	O
+significantly	POS	O
+reduced	POS	O
+during	POS	O
+SNP	POS	O
+hypotension	POS	B-NP
+.	POS	O
+Myocardial	POS	O
+O2	POS	O
+consumption	POS	O
+and	POS	O
+O2	POS	O
+availability	POS	O
+were	POS	O
+directly	POS	O
+dependent	POS	O
+on	POS	O
+the	POS	O
+coronary	POS	O
+perfusion	POS	O
+.	POS	O
+Careful	POS	O
+invasive	POS	O
+monitoring	POS	O
+of	POS	O
+the	POS	O
+blood	POS	O
+pressure	POS	O
+,	POS	O
+blood	POS	O
+gases	POS	O
+and	POS	O
+of	POS	O
+the	POS	O
+ECG	POS	O
+ST	POS	O
+-	POS	O
+T	POS	O
+segment	POS	O
+is	POS	O
+mandatory	POS	O
+.	POS	O
+Evidence	POS	O
+for	POS	O
+a	POS	O
+selective	POS	O
+brain	POS	O
+noradrenergic	POS	O
+involvement	POS	O
+in	POS	O
+the	POS	O
+locomotor	POS	O
+stimulant	POS	O
+effects	POS	O
+of	POS	O
+amphetamine	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+.	POS	O
+Male	POS	O
+rats	POS	O
+received	POS	O
+the	POS	O
+noradrenaline	POS	O
+neurotoxin	POS	O
+DSP4	POS	O
+(	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+7	POS	O
+days	POS	O
+prior	POS	O
+to	POS	O
+injection	POS	O
+of	POS	O
+D	POS	O
+-	POS	O
+amphetamine	POS	O
+(	POS	O
+10	POS	O
+or	POS	O
+40	POS	O
+mumol	POS	O
+/	POS	O
+kg	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+hyperactivity	POS	B-NP
+induced	POS	O
+by	POS	O
+D	POS	O
+-	POS	O
+amphetamine	POS	O
+(	POS	O
+10	POS	O
+mumol	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+was	POS	O
+significantly	POS	O
+reduced	POS	O
+by	POS	O
+DSP4	POS	O
+pretreatment	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+increased	POS	O
+rearings	POS	O
+and	POS	O
+the	POS	O
+amphetamine	POS	O
+-	POS	O
+induced	POS	O
+stereotypies	POS	B-NP
+were	POS	O
+not	POS	O
+blocked	POS	O
+by	POS	O
+pretreatment	POS	O
+with	POS	O
+DSP4	POS	O
+.	POS	O
+The	POS	O
+reduction	POS	O
+of	POS	O
+amphetamine	POS	O
+hyperactivity	POS	B-NP
+induced	POS	O
+by	POS	O
+DSP4	POS	O
+was	POS	O
+blocked	POS	O
+by	POS	O
+pretreatment	POS	O
+with	POS	O
+the	POS	O
+noradrenaline	POS	O
+-	POS	O
+uptake	POS	O
+blocking	POS	O
+agent	POS	O
+,	POS	O
+desipramine	POS	O
+,	POS	O
+which	POS	O
+prevents	POS	O
+the	POS	O
+neurotoxic	POS	B-NP
+action	POS	O
+of	POS	O
+DSP4	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+results	POS	O
+suggest	POS	O
+a	POS	O
+selective	POS	O
+involvement	POS	O
+of	POS	O
+central	POS	O
+noradrenergic	POS	O
+neurones	POS	O
+in	POS	O
+the	POS	O
+locomotor	POS	O
+stimulant	POS	O
+effect	POS	O
+of	POS	O
+amphetamine	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+.	POS	O
+Accelerated	POS	O
+junctional	POS	O
+rhythms	POS	O
+during	POS	O
+oral	POS	O
+verapamil	POS	O
+therapy	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+examined	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+atrioventricular	POS	O
+(	POS	O
+AV	POS	O
+)	POS	O
+dissociation	POS	O
+and	POS	O
+accelerated	POS	O
+junctional	POS	O
+rhythms	POS	O
+in	POS	O
+59	POS	O
+patients	POS	O
+receiving	POS	O
+oral	POS	O
+verapamil	POS	O
+.	POS	O
+Accelerated	POS	O
+junctional	POS	O
+rhythms	POS	O
+and	POS	O
+AV	POS	O
+dissociation	POS	O
+were	POS	O
+frequent	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+supraventricular	POS	B-NP
+tachyarrhythmias	POS	I-NP
+,	POS	O
+particularly	POS	O
+AV	POS	B-NP
+nodal	POS	I-NP
+reentry	POS	I-NP
+.	POS	O
+Verapamil	POS	O
+administration	POS	O
+to	POS	O
+these	POS	O
+patients	POS	O
+led	POS	O
+to	POS	O
+an	POS	O
+asymptomatic	POS	O
+increase	POS	O
+in	POS	O
+activity	POS	O
+of	POS	O
+these	POS	O
+junctional	POS	O
+pacemakers	POS	O
+.	POS	O
+In	POS	O
+patients	POS	O
+with	POS	O
+various	POS	O
+chest	POS	B-NP
+pain	POS	I-NP
+syndromes	POS	I-NP
+,	POS	O
+verapamil	POS	O
+neither	POS	O
+increased	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+junctional	POS	O
+rhythms	POS	O
+nor	POS	O
+suppressed	POS	O
+their	POS	O
+role	POS	O
+as	POS	O
+escape	POS	O
+rhythms	POS	O
+under	POS	O
+physiologically	POS	O
+appropriate	POS	O
+circumstances	POS	O
+.	POS	O
+Interstrain	POS	O
+variation	POS	O
+in	POS	O
+acute	POS	O
+toxic	POS	O
+response	POS	O
+to	POS	O
+caffeine	POS	O
+among	POS	O
+inbred	POS	O
+mice	POS	O
+.	POS	O
+Acute	POS	O
+toxic	POS	O
+dosage	POS	O
+-	POS	O
+dependent	POS	O
+behavioral	POS	O
+effects	POS	O
+of	POS	O
+caffeine	POS	O
+were	POS	O
+compared	POS	O
+in	POS	O
+adult	POS	O
+males	POS	O
+from	POS	O
+seven	POS	O
+inbred	POS	O
+mouse	POS	O
+strains	POS	O
+(	POS	O
+A	POS	O
+/	POS	O
+J	POS	O
+,	POS	O
+BALB	POS	O
+/	POS	O
+cJ	POS	O
+,	POS	O
+CBA	POS	O
+/	POS	O
+J	POS	O
+,	POS	O
+C3H	POS	O
+/	POS	O
+HeJ	POS	O
+,	POS	O
+C57BL	POS	O
+/	POS	O
+6J	POS	O
+,	POS	O
+DBA	POS	O
+/	POS	O
+2J	POS	O
+,	POS	O
+SWR	POS	O
+/	POS	O
+J	POS	O
+)	POS	O
+.	POS	O
+C57BL	POS	O
+/	POS	O
+6J	POS	O
+,	POS	O
+chosen	POS	O
+as	POS	O
+a	POS	O
+"	POS	O
+prototypic	POS	O
+"	POS	O
+mouse	POS	O
+strain	POS	O
+,	POS	O
+was	POS	O
+used	POS	O
+to	POS	O
+determine	POS	O
+behavioral	POS	O
+responses	POS	O
+to	POS	O
+a	POS	O
+broad	POS	O
+range	POS	O
+(	POS	O
+5	POS	O
+-	POS	O
+500	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+of	POS	O
+caffeine	POS	O
+doses	POS	O
+.	POS	O
+Five	POS	O
+phenotypic	POS	O
+characteristics	POS	O
+-	POS	O
+-	POS	O
+locomotor	POS	O
+activity	POS	O
+,	POS	O
+righting	POS	O
+ability	POS	O
+,	POS	O
+clonic	POS	O
+seizure	POS	B-NP
+induction	POS	O
+,	POS	O
+stress	POS	B-NP
+-	POS	I-NP
+induced	POS	I-NP
+lethality	POS	I-NP
+,	POS	O
+death	POS	B-NP
+without	POS	O
+external	POS	O
+stress	POS	O
+-	POS	O
+-	POS	O
+were	POS	O
+scored	POS	O
+at	POS	O
+various	POS	O
+caffeine	POS	O
+doses	POS	O
+in	POS	O
+drug	POS	O
+-	POS	O
+naive	POS	O
+animals	POS	O
+under	POS	O
+empirically	POS	O
+optimized	POS	O
+,	POS	O
+rigidly	POS	O
+constant	POS	O
+experimental	POS	O
+conditions	POS	O
+.	POS	O
+Mice	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+12	POS	O
+for	POS	O
+each	POS	O
+point	POS	O
+)	POS	O
+received	POS	O
+single	POS	O
+IP	POS	O
+injections	POS	O
+of	POS	O
+a	POS	O
+fixed	POS	O
+volume	POS	O
+/	POS	O
+g	POS	O
+body	POS	O
+weight	POS	O
+of	POS	O
+physiological	POS	O
+saline	POS	O
+carrier	POS	O
+with	POS	O
+or	POS	O
+without	POS	O
+caffeine	POS	O
+in	POS	O
+doses	POS	O
+ranging	POS	O
+from	POS	O
+125	POS	O
+-	POS	O
+500	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+Loss	POS	O
+of	POS	O
+righting	POS	O
+ability	POS	O
+was	POS	O
+scored	POS	O
+at	POS	O
+1	POS	O
+,	POS	O
+3	POS	O
+,	POS	O
+5	POS	O
+min	POS	O
+post	POS	O
+dosing	POS	O
+and	POS	O
+at	POS	O
+5	POS	O
+min	POS	O
+intervals	POS	O
+thereafter	POS	O
+for	POS	O
+20	POS	O
+min	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+same	POS	O
+animals	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+clonic	POS	B-NP
+seizures	POS	B-NP
+was	POS	O
+scored	POS	O
+as	POS	O
+to	POS	O
+time	POS	O
+of	POS	O
+onset	POS	O
+and	POS	O
+severity	POS	O
+for	POS	O
+20	POS	O
+min	POS	O
+after	POS	O
+drug	POS	O
+administration	POS	O
+.	POS	O
+When	POS	O
+these	POS	O
+proceeded	POS	O
+to	POS	O
+tonic	POS	O
+seizures	POS	B-NP
+,	POS	O
+death	POS	B-NP
+occurred	POS	O
+in	POS	O
+less	POS	O
+than	POS	O
+20	POS	O
+min	POS	O
+.	POS	O
+Animals	POS	O
+surviving	POS	O
+for	POS	O
+20	POS	O
+min	POS	O
+were	POS	O
+immediately	POS	O
+stressed	POS	O
+by	POS	O
+a	POS	O
+swim	POS	O
+test	POS	O
+in	POS	O
+25	POS	O
+degrees	POS	O
+C	POS	O
+water	POS	O
+,	POS	O
+and	POS	O
+death	POS	O
+-	POS	O
+producing	POS	O
+tonic	POS	O
+seizures	POS	B-NP
+were	POS	O
+scored	POS	O
+for	POS	O
+2	POS	O
+min	POS	O
+.	POS	O
+In	POS	O
+other	POS	O
+animals	POS	O
+locomotor	POS	O
+activity	POS	O
+was	POS	O
+measured	POS	O
+15	POS	O
+or	POS	O
+60	POS	O
+min	POS	O
+after	POS	O
+caffeine	POS	O
+administration	POS	O
+.	POS	O
+By	POS	O
+any	POS	O
+single	POS	O
+behavioral	POS	O
+criterion	POS	O
+or	POS	O
+a	POS	O
+combination	POS	O
+of	POS	O
+these	POS	O
+criteria	POS	O
+,	POS	O
+marked	POS	O
+differences	POS	O
+in	POS	O
+response	POS	O
+to	POS	O
+toxic	POS	O
+caffeine	POS	O
+doses	POS	O
+were	POS	O
+observed	POS	O
+between	POS	O
+strains	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+behavioral	POS	B-NP
+toxicity	POS	I-NP
+testing	POS	O
+of	POS	O
+alkylxanthines	POS	O
+in	POS	O
+a	POS	O
+single	POS	O
+mouse	POS	O
+strain	POS	O
+may	POS	O
+be	POS	O
+misleading	POS	O
+and	POS	O
+suggest	POS	O
+that	POS	O
+toxic	POS	O
+responses	POS	O
+of	POS	O
+the	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+to	POS	O
+this	POS	O
+class	POS	O
+of	POS	O
+compounds	POS	O
+are	POS	O
+genetically	POS	O
+influenced	POS	O
+in	POS	O
+mammals	POS	O
+.	POS	O
+Treatment	POS	O
+of	POS	O
+ovarian	POS	B-NP
+cancer	POS	I-NP
+with	POS	O
+a	POS	O
+combination	POS	O
+of	POS	O
+cis	POS	O
+-	POS	O
+platinum	POS	O
+,	POS	O
+adriamycin	POS	O
+,	POS	O
+cyclophosphamide	POS	O
+and	POS	O
+hexamethylmelamine	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+last	POS	O
+2	POS	O
+1	POS	O
+/	POS	O
+2	POS	O
+years	POS	O
+,	POS	O
+38	POS	O
+patients	POS	O
+with	POS	O
+ovarian	POS	B-NP
+cancer	POS	I-NP
+were	POS	O
+treated	POS	O
+with	POS	O
+a	POS	O
+combination	POS	O
+of	POS	O
+cisplatinum	POS	O
+(	POS	O
+CPDD	POS	O
+)	POS	O
+,	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+,	POS	O
+adriamycin	POS	O
+,	POS	O
+30	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+,	POS	O
+cyclophosphamide	POS	O
+,	POS	O
+300	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+,	POS	O
+on	POS	O
+day	POS	O
+1	POS	O
+;	POS	O
+and	POS	O
+hexamethylmelamine	POS	O
+(	POS	O
+HMM	POS	O
+)	POS	O
+,	POS	O
+6	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+daily	POS	O
+,	POS	O
+for	POS	O
+14	POS	O
+days	POS	O
+.	POS	O
+Each	POS	O
+course	POS	O
+was	POS	O
+repeated	POS	O
+monthly	POS	O
+.	POS	O
+2	POS	O
+patients	POS	O
+had	POS	O
+stage	POS	O
+II	POS	O
+,	POS	O
+14	POS	O
+stage	POS	O
+III	POS	O
+and	POS	O
+22	POS	O
+stage	POS	O
+IV	POS	O
+disease	POS	O
+.	POS	O
+14	POS	O
+of	POS	O
+the	POS	O
+38	POS	O
+patients	POS	O
+were	POS	O
+previously	POS	O
+treated	POS	O
+with	POS	O
+chemotherapy	POS	O
+,	POS	O
+1	POS	O
+with	POS	O
+radiation	POS	O
+,	POS	O
+6	POS	O
+with	POS	O
+both	POS	O
+chemotherapy	POS	O
+and	POS	O
+radiation	POS	O
+,	POS	O
+and	POS	O
+17	POS	O
+did	POS	O
+not	POS	O
+have	POS	O
+any	POS	O
+treatment	POS	O
+before	POS	O
+CPDD	POS	B-NP
+combination	POS	O
+.	POS	O
+31	POS	O
+of	POS	O
+the	POS	O
+38	POS	O
+cases	POS	O
+(	POS	O
+81	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+demonstrated	POS	O
+objective	POS	O
+responses	POS	O
+lasting	POS	O
+for	POS	O
+2	POS	O
+months	POS	O
+or	POS	O
+more	POS	O
+.	POS	O
+These	POS	O
+responses	POS	O
+were	POS	O
+partial	POS	O
+in	POS	O
+19	POS	O
+and	POS	O
+complete	POS	O
+in	POS	O
+12	POS	O
+cases	POS	O
+.	POS	O
+Hematologic	POS	B-NP
+toxicity	POS	I-NP
+was	POS	O
+moderate	POS	O
+and	POS	O
+with	POS	O
+reversible	POS	O
+anemia	POS	B-NP
+developing	POS	O
+in	POS	O
+71	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+.	POS	O
+Gastrointestinal	POS	B-NP
+side	POS	I-NP
+effects	POS	I-NP
+from	POS	O
+CPDD	POS	B-NP
+were	POS	O
+universal	POS	O
+.	POS	O
+HMM	POS	O
+gastrointestinal	POS	B-NP
+toxicity	POS	I-NP
+necessitated	POS	O
+discontinuation	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+in	POS	O
+5	POS	O
+patients	POS	O
+.	POS	O
+Severe	POS	O
+nephrotoxicity	POS	B-NP
+was	POS	O
+observed	POS	O
+in	POS	O
+2	POS	O
+patients	POS	O
+but	POS	O
+was	POS	O
+reversible	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+no	POS	O
+drug	POS	O
+-	POS	O
+related	POS	O
+deaths	POS	O
+.	POS	O
+Nontraumatic	POS	B-NP
+dissecting	POS	I-NP
+aneurysm	POS	I-NP
+of	POS	I-NP
+the	POS	I-NP
+basilar	POS	I-NP
+artery	POS	I-NP
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+nontraumatic	POS	O
+dissecting	POS	O
+aneurysm	POS	B-NP
+of	POS	O
+the	POS	O
+basilar	POS	O
+artery	POS	O
+in	POS	O
+association	POS	O
+with	POS	O
+hypertension	POS	B-NP
+,	POS	O
+smoke	POS	O
+,	POS	O
+and	POS	O
+oral	POS	O
+contraceptives	POS	O
+is	POS	O
+reported	POS	O
+in	POS	O
+a	POS	O
+young	POS	O
+female	POS	O
+patient	POS	O
+with	POS	O
+a	POS	O
+locked	POS	O
+-	POS	O
+in	POS	O
+syndrome	POS	O
+.	POS	O
+A	POS	O
+method	POS	O
+for	POS	O
+the	POS	O
+measurement	POS	O
+of	POS	O
+tremor	POS	B-NP
+,	POS	O
+and	POS	O
+a	POS	O
+comparison	POS	O
+of	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+tocolytic	POS	O
+beta	POS	O
+-	POS	O
+mimetics	POS	O
+.	POS	O
+A	POS	O
+method	POS	O
+permitting	POS	O
+measurement	POS	O
+of	POS	O
+finger	POS	O
+tremor	POS	O
+as	POS	O
+a	POS	O
+displacement	POS	O
+-	POS	O
+time	POS	O
+curve	POS	O
+is	POS	O
+described	POS	O
+,	POS	O
+using	POS	O
+a	POS	O
+test	POS	O
+system	POS	O
+with	POS	O
+simple	POS	O
+amplitude	POS	O
+calibration	POS	O
+.	POS	O
+The	POS	O
+coordinates	POS	O
+of	POS	O
+the	POS	O
+inversion	POS	O
+points	POS	O
+of	POS	O
+the	POS	O
+displacement	POS	O
+-	POS	O
+time	POS	O
+curves	POS	O
+were	POS	O
+transferred	POS	O
+through	POS	O
+graphical	POS	O
+input	POS	O
+equipment	POS	O
+to	POS	O
+punched	POS	O
+tape	POS	O
+.	POS	O
+By	POS	O
+means	POS	O
+of	POS	O
+a	POS	O
+computer	POS	O
+program	POS	O
+,	POS	O
+periods	POS	O
+and	POS	O
+amplitudes	POS	O
+of	POS	O
+tremor	POS	B-NP
+oscillations	POS	O
+were	POS	O
+calculated	POS	O
+and	POS	O
+classified	POS	O
+.	POS	O
+The	POS	O
+event	POS	O
+frequency	POS	O
+for	POS	O
+each	POS	O
+class	POS	O
+of	POS	O
+periods	POS	O
+and	POS	O
+amplitudes	POS	O
+was	POS	O
+determined	POS	O
+.	POS	O
+The	POS	O
+actions	POS	O
+of	POS	O
+fenoterol	POS	O
+-	POS	O
+hydrobromide	POS	O
+,	POS	O
+ritodrin	POS	O
+-	POS	O
+HCl	POS	O
+and	POS	O
+placebo	POS	O
+given	POS	O
+to	POS	O
+10	POS	O
+healthy	POS	O
+subjects	POS	O
+by	POS	O
+intravenous	POS	O
+infusion	POS	O
+in	POS	O
+a	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+crossover	POS	O
+study	POS	O
+were	POS	O
+tested	POS	O
+by	POS	O
+this	POS	O
+method	POS	O
+.	POS	O
+At	POS	O
+therapeutic	POS	O
+doses	POS	O
+both	POS	O
+substances	POS	O
+raised	POS	O
+the	POS	O
+mean	POS	O
+tremor	POS	B-NP
+amplitude	POS	O
+to	POS	O
+about	POS	O
+three	POS	O
+times	POS	O
+the	POS	O
+control	POS	O
+level	POS	O
+.	POS	O
+At	POS	O
+the	POS	O
+same	POS	O
+time	POS	O
+,	POS	O
+the	POS	O
+mean	POS	O
+period	POS	O
+within	POS	O
+each	POS	O
+class	POS	O
+of	POS	O
+amplitudes	POS	O
+shortened	POS	O
+by	POS	O
+10	POS	O
+-	POS	O
+-	POS	O
+20	POS	O
+ms	POS	O
+,	POS	O
+whereas	POS	O
+the	POS	O
+mean	POS	O
+periods	POS	O
+calculated	POS	O
+from	POS	O
+all	POS	O
+oscillations	POS	O
+together	POS	O
+did	POS	O
+not	POS	O
+change	POS	O
+significantly	POS	O
+.	POS	O
+After	POS	O
+the	POS	O
+end	POS	O
+of	POS	O
+fenoterol	POS	O
+-	POS	O
+hydrobromide	POS	O
+infusion	POS	O
+,	POS	O
+tremor	POS	B-NP
+amplitudes	POS	O
+decreased	POS	O
+significantly	POS	O
+faster	POS	O
+than	POS	O
+those	POS	O
+following	POS	O
+ritodrin	POS	O
+-	POS	O
+HCl	POS	O
+infusion	POS	O
+.	POS	O
+Propylthiouracil	POS	O
+-	POS	O
+induced	POS	O
+hepatic	POS	B-NP
+damage	POS	I-NP
+.	POS	O
+Two	POS	O
+cases	POS	O
+of	POS	O
+propylthiouracil	POS	O
+-	POS	O
+induced	POS	O
+liver	POS	B-NP
+damage	POS	I-NP
+have	POS	O
+been	POS	O
+observed	POS	O
+.	POS	O
+The	POS	O
+first	POS	O
+case	POS	O
+is	POS	O
+of	POS	O
+an	POS	O
+acute	POS	O
+type	POS	O
+of	POS	O
+damage	POS	O
+,	POS	O
+proven	POS	O
+by	POS	O
+rechallenge	POS	O
+;	POS	O
+the	POS	O
+second	POS	O
+presents	POS	O
+a	POS	O
+clinical	POS	O
+and	POS	O
+histologic	POS	O
+picture	POS	O
+resembling	POS	O
+chronic	POS	O
+active	POS	O
+hepatitis	POS	B-NP
+,	POS	O
+with	POS	O
+spontaneous	POS	O
+remission	POS	O
+.	POS	O
+Studies	POS	O
+on	POS	O
+the	POS	O
+bradycardia	POS	B-NP
+induced	POS	O
+by	POS	O
+bepridil	POS	O
+.	POS	O
+Bepridil	POS	O
+,	POS	O
+a	POS	O
+novel	POS	O
+active	POS	O
+compound	POS	O
+for	POS	O
+prophylactic	POS	O
+treatment	POS	O
+of	POS	O
+anginal	POS	B-NP
+attacks	POS	I-NP
+,	POS	O
+induced	POS	O
+persistent	POS	O
+bradycardia	POS	B-NP
+and	POS	O
+a	POS	O
+non	POS	O
+-	POS	O
+specific	POS	O
+anti	POS	O
+-	POS	O
+tachycardial	POS	O
+effect	POS	O
+,	POS	O
+the	POS	O
+mechanisms	POS	O
+of	POS	O
+which	POS	O
+were	POS	O
+investigated	POS	O
+in	POS	O
+vitro	POS	O
+and	POS	O
+in	POS	O
+vivo	POS	O
+.	POS	O
+In	POS	O
+vitro	POS	O
+perfusion	POS	O
+of	POS	O
+bepridil	POS	O
+in	POS	O
+the	POS	O
+life	POS	O
+-	POS	O
+support	POS	O
+medium	POS	O
+for	POS	O
+isolated	POS	O
+sino	POS	O
+-	POS	O
+atrial	POS	O
+tissue	POS	O
+from	POS	O
+rabbit	POS	O
+heart	POS	O
+,	POS	O
+caused	POS	O
+a	POS	O
+reduction	POS	O
+in	POS	O
+action	POS	O
+potential	POS	O
+(	POS	O
+AP	POS	O
+)	POS	O
+spike	POS	O
+frequency	POS	O
+(	POS	O
+recorded	POS	O
+by	POS	O
+KCl	POS	O
+microelectrodes	POS	O
+)	POS	O
+starting	POS	O
+at	POS	O
+doses	POS	O
+of	POS	O
+5	POS	O
+X	POS	O
+10	POS	O
+(	POS	O
+-	POS	O
+6	POS	O
+)	POS	O
+M	POS	O
+.	POS	O
+This	POS	O
+effect	POS	O
+was	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+up	POS	O
+to	POS	O
+concentrations	POS	O
+of	POS	O
+5	POS	O
+X	POS	O
+10	POS	O
+(	POS	O
+-	POS	O
+5	POS	O
+)	POS	O
+M	POS	O
+,	POS	O
+whereupon	POS	O
+blockade	POS	O
+of	POS	O
+sinus	POS	O
+activity	POS	O
+set	POS	O
+in	POS	O
+.	POS	O
+Bepridil	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+5	POS	O
+X	POS	O
+10	POS	O
+(	POS	O
+-	POS	O
+6	POS	O
+)	POS	O
+M	POS	O
+,	POS	O
+induced	POS	O
+a	POS	O
+concomitant	POS	O
+reduction	POS	O
+in	POS	O
+AP	POS	O
+amplitude	POS	O
+(	POS	O
+falling	POS	O
+from	POS	O
+71	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+8	POS	O
+mV	POS	O
+to	POS	O
+47	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+mV	POS	O
+)	POS	O
+,	POS	O
+maximum	POS	O
+systolic	POS	O
+depolarization	POS	O
+velocity	POS	O
+(	POS	O
+phase	POS	O
+0	POS	O
+)	POS	O
+which	POS	O
+fell	POS	O
+from	POS	O
+1	POS	O
+.	POS	O
+85	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+35	POS	O
+V	POS	O
+/	POS	O
+s	POS	O
+to	POS	O
+0	POS	O
+.	POS	O
+84	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+28	POS	O
+V	POS	O
+/	POS	O
+s	POS	O
+,	POS	O
+together	POS	O
+with	POS	O
+maximum	POS	O
+diastolic	POS	O
+depolarization	POS	O
+velocity	POS	O
+(	POS	O
+phase	POS	O
+4	POS	O
+)	POS	O
+which	POS	O
+fell	POS	O
+from	POS	O
+38	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+3	POS	O
+mV	POS	O
+/	POS	O
+s	POS	O
+to	POS	O
+24	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+5	POS	O
+mV	POS	O
+/	POS	O
+s	POS	O
+.	POS	O
+In	POS	O
+vivo	POS	O
+injection	POS	O
+of	POS	O
+bepridil	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+)	POS	O
+into	POS	O
+6	POS	O
+anaesthetized	POS	O
+dogs	POS	O
+which	POS	O
+had	POS	O
+undergone	POS	O
+ablation	POS	O
+of	POS	O
+all	POS	O
+the	POS	O
+extrinsic	POS	O
+cardiac	POS	O
+afferent	POS	O
+nerve	POS	O
+supply	POS	O
+,	POS	O
+together	POS	O
+with	POS	O
+a	POS	O
+bilateral	POS	O
+medullo	POS	O
+-	POS	O
+adrenalectomy	POS	O
+,	POS	O
+caused	POS	O
+a	POS	O
+marked	POS	O
+reduction	POS	O
+in	POS	O
+heart	POS	O
+rate	POS	O
+which	POS	O
+fell	POS	O
+from	POS	O
+98	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+2	POS	O
+beats	POS	O
+/	POS	O
+min	POS	O
+to	POS	O
+76	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+5	POS	O
+.	POS	O
+3	POS	O
+beats	POS	O
+/	POS	O
+min	POS	O
+sustained	POS	O
+for	POS	O
+more	POS	O
+than	POS	O
+45	POS	O
+min	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+concluded	POS	O
+that	POS	O
+bepridil	POS	O
+reduces	POS	O
+heart	POS	O
+rate	POS	O
+by	POS	O
+acting	POS	O
+directly	POS	O
+on	POS	O
+the	POS	O
+sinus	POS	O
+node	POS	O
+.	POS	O
+This	POS	O
+effect	POS	O
+,	POS	O
+which	POS	O
+results	POS	O
+in	POS	O
+a	POS	O
+flattening	POS	O
+of	POS	O
+the	POS	O
+phase	POS	O
+0	POS	O
+and	POS	O
+phase	POS	O
+4	POS	O
+slope	POS	O
+,	POS	O
+together	POS	O
+with	POS	O
+a	POS	O
+longer	POS	O
+AP	POS	O
+duration	POS	O
+,	POS	O
+may	POS	O
+be	POS	O
+due	POS	O
+to	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+the	POS	O
+time	POS	O
+constants	POS	O
+of	POS	O
+slow	POS	O
+inward	POS	O
+ionic	POS	O
+currents	POS	O
+(	POS	O
+already	POS	O
+demonstrated	POS	O
+elsewhere	POS	O
+)	POS	O
+,	POS	O
+but	POS	O
+also	POS	O
+to	POS	O
+an	POS	O
+increased	POS	O
+time	POS	O
+constant	POS	O
+for	POS	O
+deactivation	POS	O
+of	POS	O
+the	POS	O
+outward	POS	O
+potassium	POS	O
+current	POS	O
+(	POS	O
+Ip	POS	O
+)	POS	O
+.	POS	O
+Hepatitis	POS	B-NP
+and	POS	I-NP
+renal	POS	I-NP
+tubular	POS	I-NP
+acidosis	POS	I-NP
+after	POS	O
+anesthesia	POS	O
+with	POS	O
+methoxyflurane	POS	O
+.	POS	O
+A	POS	O
+69	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+operated	POS	O
+for	POS	O
+acute	POS	B-NP
+cholecystitis	POS	I-NP
+under	POS	O
+methoxyflurane	POS	O
+anesthesia	POS	O
+developed	POS	O
+postoperatively	POS	O
+a	POS	O
+hepatic	POS	B-NP
+insufficiency	POS	I-NP
+syndrome	POS	I-NP
+and	POS	O
+renal	POS	B-NP
+tubular	POS	I-NP
+acidosis	POS	I-NP
+.	POS	O
+Massive	POS	B-NP
+bleeding	POS	I-NP
+appeared	POS	O
+during	POS	O
+surgery	POS	O
+which	POS	O
+lasted	POS	O
+for	POS	O
+six	POS	O
+hours	POS	O
+.	POS	O
+Postoperative	POS	O
+evolution	POS	O
+under	POS	O
+supportive	POS	O
+therapy	POS	O
+was	POS	O
+favourable	POS	O
+.	POS	O
+Complete	POS	O
+recovery	POS	O
+was	POS	O
+confirmed	POS	O
+by	POS	O
+repeated	POS	O
+controls	POS	O
+performed	POS	O
+over	POS	O
+a	POS	O
+period	POS	O
+of	POS	O
+one	POS	O
+year	POS	O
+after	POS	O
+surgery	POS	O
+.	POS	O
+Pituitary	POS	O
+response	POS	O
+to	POS	O
+luteinizing	POS	O
+hormone	POS	O
+-	POS	O
+releasing	POS	O
+hormone	POS	O
+during	POS	O
+haloperidol	POS	O
+-	POS	O
+induced	POS	O
+hyperprolactinemia	POS	B-NP
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+a	POS	O
+6	POS	O
+-	POS	O
+hour	POS	O
+infusion	POS	O
+with	POS	O
+haloperidol	POS	O
+on	POS	O
+serum	POS	O
+prolactin	POS	O
+and	POS	O
+luteinizing	POS	O
+hormone	POS	O
+(	POS	O
+LH	POS	O
+)	POS	O
+levels	POS	O
+was	POS	O
+studied	POS	O
+in	POS	O
+a	POS	O
+group	POS	O
+of	POS	O
+male	POS	O
+subjects	POS	O
+.	POS	O
+Five	POS	O
+hours	POS	O
+after	POS	O
+starting	POS	O
+the	POS	O
+infusions	POS	O
+,	POS	O
+a	POS	O
+study	POS	O
+of	POS	O
+the	POS	O
+pituitary	POS	O
+responses	POS	O
+to	POS	O
+LH	POS	O
+-	POS	O
+releasing	POS	O
+hormone	POS	O
+(	POS	O
+LH	POS	O
+-	POS	O
+RH	POS	O
+)	POS	O
+was	POS	O
+carried	POS	O
+out	POS	O
+.	POS	O
+Control	POS	O
+patients	POS	O
+received	POS	O
+infusions	POS	O
+of	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+NaCl	POS	O
+solution	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+course	POS	O
+of	POS	O
+haloperidol	POS	O
+infusions	POS	O
+,	POS	O
+significant	POS	O
+hyperprolactinemia	POS	B-NP
+was	POS	O
+found	POS	O
+,	POS	O
+together	POS	O
+with	POS	O
+an	POS	O
+abolished	POS	O
+pituitary	POS	O
+response	POS	O
+to	POS	O
+LH	POS	O
+-	POS	O
+RH	POS	O
+,	POS	O
+as	POS	O
+compared	POS	O
+with	POS	O
+responses	POS	O
+of	POS	O
+control	POS	O
+subjects	POS	O
+.	POS	O
+Antirifampicin	POS	O
+antibodies	POS	O
+in	POS	O
+acute	POS	O
+rifampicin	POS	O
+-	POS	O
+associated	POS	O
+renal	POS	B-NP
+failure	POS	I-NP
+.	POS	O
+5	POS	O
+patients	POS	O
+with	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+(	POS	O
+3	POS	O
+with	POS	O
+thrombopenia	POS	B-NP
+and	POS	O
+hemolysis	POS	B-NP
+)	POS	O
+induced	POS	O
+by	POS	O
+the	POS	O
+reintroduction	POS	O
+of	POS	O
+rifampicin	POS	O
+are	POS	O
+described	POS	O
+.	POS	O
+No	POS	O
+correlation	POS	O
+was	POS	O
+found	POS	O
+between	POS	O
+the	POS	O
+severity	POS	O
+of	POS	O
+clinical	POS	O
+manifestations	POS	O
+and	POS	O
+the	POS	O
+total	POS	O
+dose	POS	O
+taken	POS	O
+by	POS	O
+the	POS	O
+patients	POS	O
+.	POS	O
+In	POS	O
+all	POS	O
+but	POS	O
+1	POS	O
+patient	POS	O
+,	POS	O
+antirifampicin	POS	O
+antibodies	POS	O
+were	POS	O
+detected	POS	O
+.	POS	O
+Antibodies	POS	O
+suggested	POS	O
+to	POS	O
+be	POS	O
+of	POS	O
+the	POS	O
+IgM	POS	O
+class	POS	O
+were	POS	O
+detected	POS	O
+in	POS	O
+all	POS	O
+3	POS	O
+patients	POS	O
+with	POS	O
+hematological	POS	B-NP
+disorders	POS	I-NP
+.	POS	O
+The	POS	O
+pattern	POS	O
+of	POS	O
+non	POS	O
+-	POS	O
+specific	POS	O
+acute	POS	O
+tubular	POS	O
+necrosis	POS	B-NP
+found	POS	O
+in	POS	O
+the	POS	O
+2	POS	O
+biopsied	POS	O
+patients	POS	O
+,	POS	O
+indistinguishable	POS	O
+from	POS	O
+that	POS	O
+of	POS	O
+ischemic	POS	O
+origin	POS	O
+,	POS	O
+raised	POS	O
+the	POS	O
+possibility	POS	O
+of	POS	O
+a	POS	O
+vascular	POS	B-NP
+-	POS	I-NP
+mediated	POS	I-NP
+damage	POS	I-NP
+.	POS	O
+In	POS	O
+3	POS	O
+patients	POS	O
+,	POS	O
+the	POS	O
+possibility	POS	O
+of	POS	O
+a	POS	O
+triggering	POS	O
+immunoallergic	POS	O
+mechanism	POS	O
+is	POS	O
+discussed	POS	O
+.	POS	O
+Cardiovascular	POS	O
+effects	POS	O
+of	POS	O
+hypotension	POS	B-NP
+induced	POS	O
+by	POS	O
+adenosine	POS	O
+triphosphate	POS	O
+and	POS	O
+sodium	POS	O
+nitroprusside	POS	O
+on	POS	O
+dogs	POS	O
+with	POS	O
+denervated	POS	O
+hearts	POS	O
+.	POS	O
+Adenosine	POS	O
+triphosphate	POS	O
+(	POS	O
+ATP	POS	O
+)	POS	O
+and	POS	O
+sodium	POS	O
+nitroprusside	POS	O
+(	POS	O
+SNP	POS	O
+)	POS	O
+are	POS	O
+administered	POS	O
+to	POS	O
+patients	POS	O
+to	POS	O
+induce	POS	O
+and	POS	O
+control	POS	O
+hypotension	POS	B-NP
+during	POS	O
+anesthesia	POS	O
+.	POS	O
+SNP	POS	O
+is	POS	O
+authorized	POS	O
+for	POS	O
+clinical	POS	O
+use	POS	O
+in	POS	O
+USA	POS	O
+and	POS	O
+UK	POS	O
+,	POS	O
+and	POS	O
+ATP	POS	O
+is	POS	O
+clinically	POS	O
+used	POS	O
+in	POS	O
+other	POS	O
+countries	POS	O
+such	POS	O
+as	POS	O
+Japan	POS	O
+.	POS	O
+We	POS	O
+investigated	POS	O
+how	POS	O
+these	POS	O
+two	POS	O
+drugs	POS	O
+act	POS	O
+on	POS	O
+the	POS	O
+cardiovascular	POS	O
+systems	POS	O
+of	POS	O
+20	POS	O
+dogs	POS	O
+whose	POS	O
+hearts	POS	O
+had	POS	O
+been	POS	O
+denervated	POS	O
+by	POS	O
+a	POS	O
+procedure	POS	O
+we	POS	O
+had	POS	O
+devised	POS	O
+.	POS	O
+ATP	POS	O
+(	POS	O
+10	POS	O
+dogs	POS	O
+)	POS	O
+or	POS	O
+SNP	POS	O
+(	POS	O
+10	POS	O
+dogs	POS	O
+)	POS	O
+was	POS	O
+administered	POS	O
+to	POS	O
+reduce	POS	O
+mean	POS	O
+arterial	POS	O
+pressure	POS	O
+by	POS	O
+30	POS	O
+%	POS	O
+to	POS	O
+70	POS	O
+%	POS	O
+of	POS	O
+control	POS	O
+.	POS	O
+Before	POS	O
+,	POS	O
+during	POS	O
+and	POS	O
+after	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+,	POS	O
+we	POS	O
+measured	POS	O
+major	POS	O
+cardiovascular	POS	O
+parameters	POS	O
+.	POS	O
+Hypotension	POS	B-NP
+induced	POS	O
+by	POS	O
+ATP	POS	O
+was	POS	O
+accompanied	POS	O
+by	POS	O
+significant	POS	O
+decreases	POS	O
+in	POS	O
+mean	POS	O
+pulmonary	POS	O
+arterial	POS	O
+pressure	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+central	POS	O
+venous	POS	O
+pressure	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+left	POS	O
+ventricular	POS	O
+end	POS	O
+-	POS	O
+diastolic	POS	O
+pressure	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+total	POS	O
+peripheral	POS	O
+resistance	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+rate	POS	O
+pressure	POS	O
+product	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+total	POS	O
+body	POS	O
+oxygen	POS	O
+consumption	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+heart	POS	O
+rate	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+;	POS	O
+all	POS	O
+these	POS	O
+variables	POS	O
+returned	POS	O
+normal	POS	O
+within	POS	O
+30	POS	O
+min	POS	O
+after	POS	O
+ATP	POS	O
+was	POS	O
+stopped	POS	O
+.	POS	O
+Cardiac	POS	O
+output	POS	O
+did	POS	O
+not	POS	O
+change	POS	O
+.	POS	O
+During	POS	O
+hypotension	POS	B-NP
+produced	POS	O
+by	POS	O
+SNP	POS	O
+similar	POS	O
+decreases	POS	O
+were	POS	O
+observed	POS	O
+in	POS	O
+mean	POS	O
+pulmonary	POS	O
+arterial	POS	O
+pressure	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+,	POS	O
+central	POS	O
+venous	POS	O
+pressure	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+left	POS	O
+ventricular	POS	O
+end	POS	O
+-	POS	O
+diastolic	POS	O
+pressure	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+,	POS	O
+total	POS	O
+peripheral	POS	O
+resistance	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+rate	POS	O
+pressure	POS	O
+product	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+oxygen	POS	O
+content	POS	O
+difference	POS	O
+between	POS	O
+arterial	POS	O
+and	POS	O
+mixed	POS	O
+venous	POS	O
+blood	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+,	POS	O
+while	POS	O
+heart	POS	O
+rate	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+001	POS	O
+)	POS	O
+and	POS	O
+cardiac	POS	O
+output	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+were	POS	O
+increased	POS	O
+.	POS	O
+Recoveries	POS	O
+of	POS	O
+heart	POS	O
+rate	POS	O
+and	POS	O
+left	POS	O
+ventricular	POS	O
+end	POS	O
+-	POS	O
+diastolic	POS	O
+pressure	POS	O
+were	POS	O
+not	POS	O
+shown	POS	O
+within	POS	O
+60	POS	O
+min	POS	O
+after	POS	O
+SNP	POS	O
+had	POS	O
+been	POS	O
+stopped	POS	O
+.	POS	O
+Both	POS	O
+ATP	POS	O
+and	POS	O
+SNP	POS	O
+should	POS	O
+act	POS	O
+on	POS	O
+the	POS	O
+pacemaker	POS	O
+tissue	POS	O
+of	POS	O
+the	POS	O
+heart	POS	O
+.	POS	O
+Comparative	POS	O
+study	POS	O
+:	POS	O
+Endografine	POS	O
+(	POS	O
+diatrizoate	POS	O
+)	POS	O
+,	POS	O
+Vasurix	POS	O
+polyvidone	POS	O
+(	POS	O
+acetrizoate	POS	O
+)	POS	O
+,	POS	O
+Dimer	POS	O
+-	POS	O
+X	POS	O
+(	POS	O
+iocarmate	POS	O
+)	POS	O
+and	POS	O
+Hexabrix	POS	O
+(	POS	O
+ioxaglate	POS	O
+)	POS	O
+in	POS	O
+hysterosalpingography	POS	O
+.	POS	O
+Side	POS	O
+effects	POS	O
+of	POS	O
+hysterosalpingography	POS	O
+with	POS	O
+Dimer	POS	O
+-	POS	O
+X	POS	O
+,	POS	O
+Hexabrix	POS	O
+,	POS	O
+Vasurix	POS	O
+polyvidone	POS	O
+and	POS	O
+Endografine	POS	O
+in	POS	O
+142	POS	O
+consecutive	POS	O
+patients	POS	O
+,	POS	O
+receiving	POS	O
+one	POS	O
+of	POS	O
+the	POS	O
+four	POS	O
+tested	POS	O
+media	POS	O
+were	POS	O
+evaluated	POS	O
+from	POS	O
+replies	POS	O
+to	POS	O
+postal	POS	O
+questionnaires	POS	O
+.	POS	O
+The	POS	O
+Dimer	POS	O
+-	POS	O
+X	POS	O
+group	POS	O
+had	POS	O
+a	POS	O
+higher	POS	O
+incidence	POS	O
+of	POS	O
+nausea	POS	B-NP
+and	POS	O
+dizziness	POS	B-NP
+.	POS	O
+The	POS	O
+Endografine	POS	O
+group	POS	O
+had	POS	O
+a	POS	O
+higher	POS	O
+incidence	POS	O
+of	POS	O
+abdominal	POS	B-NP
+pain	POS	I-NP
+.	POS	O
+These	POS	O
+differences	POS	O
+occur	POS	O
+especially	POS	O
+in	POS	O
+the	POS	O
+age	POS	O
+groups	POS	O
+under	POS	O
+30	POS	O
+years	POS	O
+.	POS	O
+Hexabrix	POS	O
+and	POS	O
+Vasurix	POS	O
+polyvidone	POS	O
+are	POS	O
+considered	POS	O
+the	POS	O
+best	POS	O
+contrast	POS	O
+media	POS	O
+for	POS	O
+hysterosalpingography	POS	O
+and	POS	O
+perhaps	POS	O
+because	POS	O
+of	POS	O
+its	POS	O
+low	POS	O
+toxicity	POS	O
+Hexabrix	POS	O
+should	POS	O
+be	POS	O
+preferred	POS	O
+.	POS	O
+Post	POS	O
+-	POS	O
+suxamethonium	POS	O
+pains	POS	O
+in	POS	O
+Nigerian	POS	O
+surgical	POS	O
+patients	POS	O
+.	POS	O
+Contrary	POS	O
+to	POS	O
+an	POS	O
+earlier	POS	O
+report	POS	O
+by	POS	O
+Coxon	POS	O
+,	POS	O
+scoline	POS	O
+pain	POS	B-NP
+occurs	POS	O
+in	POS	O
+African	POS	O
+negroes	POS	O
+.	POS	O
+Its	POS	O
+incidence	POS	O
+was	POS	O
+determined	POS	O
+in	POS	O
+a	POS	O
+prospective	POS	O
+study	POS	O
+involving	POS	O
+a	POS	O
+total	POS	O
+of	POS	O
+100	POS	O
+Nigerian	POS	O
+patients	POS	O
+(	POS	O
+50	POS	O
+out	POS	O
+-	POS	O
+patients	POS	O
+and	POS	O
+50	POS	O
+in	POS	O
+-	POS	O
+patients	POS	O
+)	POS	O
+.	POS	O
+About	POS	O
+62	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+out	POS	O
+-	POS	O
+patients	POS	O
+developed	POS	O
+scoline	POS	B-NP
+pain	POS	I-NP
+as	POS	O
+compared	POS	O
+with	POS	O
+about	POS	O
+26	POS	O
+%	POS	O
+among	POS	O
+the	POS	O
+in	POS	O
+-	POS	O
+patients	POS	O
+.	POS	O
+The	POS	O
+abolition	POS	O
+of	POS	O
+muscle	POS	B-NP
+fasciculations	POS	I-NP
+(	POS	O
+by	POS	O
+0	POS	O
+.	POS	O
+075mg	POS	O
+/	POS	O
+kg	POS	O
+dose	POS	O
+of	POS	O
+Fazadinium	POS	O
+)	POS	O
+did	POS	O
+not	POS	O
+influence	POS	O
+the	POS	O
+occurrence	POS	O
+of	POS	O
+scoline	POS	O
+pain	POS	B-NP
+.	POS	O
+Neither	POS	O
+the	POS	O
+type	POS	O
+of	POS	O
+induction	POS	O
+agent	POS	O
+(	POS	O
+Althesin	POS	O
+or	POS	O
+Thiopentone	POS	O
+)	POS	O
+nor	POS	O
+the	POS	O
+salt	POS	O
+preparation	POS	O
+of	POS	O
+suxamethonium	POS	O
+used	POS	O
+(	POS	O
+chloride	POS	O
+or	POS	O
+bromide	POS	O
+)	POS	O
+,	POS	O
+affected	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+scoline	POS	B-NP
+pain	POS	I-NP
+.	POS	O
+Invasive	POS	B-NP
+carcinoma	POS	I-NP
+of	POS	I-NP
+the	POS	I-NP
+renal	POS	I-NP
+pelvis	POS	I-NP
+following	POS	O
+cyclophosphamide	POS	O
+therapy	POS	O
+for	POS	O
+nonmalignant	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+A	POS	O
+47	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+with	POS	O
+right	POS	O
+hydroureteronephrosis	POS	B-NP
+due	POS	O
+to	POS	O
+ureterovesical	POS	B-NP
+junction	POS	I-NP
+obstruction	POS	I-NP
+had	POS	O
+gross	POS	O
+hematuria	POS	B-NP
+after	POS	O
+being	POS	O
+treated	POS	O
+for	POS	O
+five	POS	O
+years	POS	O
+wtih	POS	O
+cyclophosphamide	POS	O
+for	POS	O
+cerebral	POS	B-NP
+vasculitis	POS	I-NP
+.	POS	O
+A	POS	O
+right	POS	O
+nephroureterectomy	POS	O
+was	POS	O
+required	POS	O
+for	POS	O
+control	POS	O
+of	POS	O
+bleeding	POS	B-NP
+.	POS	O
+The	POS	O
+pathology	POS	O
+specimen	POS	O
+contained	POS	O
+clinically	POS	O
+occult	POS	O
+invasive	POS	O
+carcinoma	POS	B-NP
+of	POS	I-NP
+the	POS	I-NP
+renal	POS	I-NP
+pelvis	POS	I-NP
+.	POS	O
+Although	POS	O
+the	POS	O
+ability	POS	O
+of	POS	O
+cyclophosphamide	POS	O
+to	POS	O
+cause	POS	O
+hemorrhagic	POS	B-NP
+cystitis	POS	I-NP
+and	POS	O
+urine	POS	O
+cytologic	POS	O
+abnormalities	POS	O
+indistinguishable	POS	O
+from	POS	O
+high	POS	O
+grade	POS	O
+carcinoma	POS	B-NP
+is	POS	O
+well	POS	O
+known	POS	O
+,	POS	O
+it	POS	O
+is	POS	O
+less	POS	O
+widely	POS	O
+appreciated	POS	O
+that	POS	O
+it	POS	O
+is	POS	O
+also	POS	O
+associated	POS	O
+with	POS	O
+carcinoma	POS	B-NP
+of	POS	I-NP
+the	POS	I-NP
+urinary	POS	I-NP
+tract	POS	I-NP
+.	POS	O
+Twenty	POS	O
+carcinomas	POS	B-NP
+of	POS	O
+the	POS	O
+urinary	POS	O
+bladder	POS	O
+and	POS	O
+one	POS	O
+carcinoma	POS	B-NP
+of	POS	O
+the	POS	O
+prostate	POS	O
+have	POS	O
+been	POS	O
+reported	POS	O
+in	POS	O
+association	POS	O
+with	POS	O
+its	POS	O
+use	POS	O
+.	POS	O
+The	POS	O
+present	POS	O
+case	POS	O
+is	POS	O
+the	POS	O
+first	POS	O
+carcinoma	POS	B-NP
+of	POS	I-NP
+the	POS	I-NP
+renal	POS	I-NP
+pelvis	POS	I-NP
+reported	POS	O
+in	POS	O
+association	POS	O
+with	POS	O
+cyclophosphamide	POS	O
+treatment	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+the	POS	O
+third	POS	O
+urinary	POS	B-NP
+tract	POS	I-NP
+cancer	POS	I-NP
+reported	POS	O
+in	POS	O
+association	POS	O
+with	POS	O
+cyclophosphamide	POS	O
+treatment	POS	O
+for	POS	O
+nonmalignant	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+The	POS	O
+association	POS	O
+of	POS	O
+the	POS	O
+tumor	POS	B-NP
+with	POS	O
+preexisting	POS	O
+hydroureteronephrosis	POS	B-NP
+suggests	POS	O
+that	POS	O
+stasis	POS	O
+prolonged	POS	O
+and	POS	O
+intensified	POS	O
+exposure	POS	O
+of	POS	O
+upper	POS	O
+urinary	POS	O
+tract	POS	O
+epithelium	POS	O
+to	POS	O
+cyclophosphamide	POS	O
+.	POS	O
+Patients	POS	O
+who	POS	O
+are	POS	O
+candidates	POS	O
+for	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+cyclophosphamide	POS	O
+treatment	POS	O
+should	POS	O
+be	POS	O
+routinely	POS	O
+evaluated	POS	O
+for	POS	O
+obstructive	POS	B-NP
+uropathy	POS	I-NP
+.	POS	O
+Medial	POS	O
+changes	POS	O
+in	POS	O
+arterial	POS	B-NP
+spasm	POS	I-NP
+induced	POS	O
+by	POS	O
+L	POS	O
+-	POS	O
+norepinephrine	POS	O
+.	POS	O
+In	POS	O
+normal	POS	O
+rats	POS	O
+,	POS	O
+the	POS	O
+media	POS	O
+of	POS	O
+small	POS	O
+arteries	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+4	POS	O
+-	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+2	POS	O
+mm	POS	O
+in	POS	O
+diameter	POS	O
+)	POS	O
+previously	POS	O
+was	POS	O
+shown	POS	O
+to	POS	O
+contain	POS	O
+intracellular	POS	O
+vacuoles	POS	O
+,	POS	O
+identified	POS	O
+ultrastructurally	POS	O
+as	POS	O
+herniations	POS	O
+of	POS	O
+one	POS	O
+smooth	POS	O
+muscle	POS	O
+cell	POS	O
+into	POS	O
+another	POS	O
+.	POS	O
+The	POS	O
+hypothesis	POS	O
+that	POS	O
+intense	POS	O
+vasoconstriction	POS	O
+would	POS	O
+increase	POS	O
+the	POS	O
+number	POS	O
+of	POS	O
+such	POS	O
+vacuoles	POS	O
+has	POS	O
+been	POS	O
+tested	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+media	POS	O
+of	POS	O
+the	POS	O
+saphenous	POS	O
+artery	POS	O
+and	POS	O
+its	POS	O
+distal	POS	O
+branch	POS	O
+,	POS	O
+vasoconstriction	POS	O
+induced	POS	O
+by	POS	O
+L	POS	O
+-	POS	O
+norepinephrine	POS	O
+produced	POS	O
+many	POS	O
+cell	POS	O
+-	POS	O
+to	POS	O
+-	POS	O
+cell	POS	O
+hernias	POS	O
+within	POS	O
+15	POS	O
+minutes	POS	O
+.	POS	O
+At	POS	O
+1	POS	O
+day	POS	O
+their	POS	O
+number	POS	O
+was	POS	O
+reduced	POS	O
+to	POS	O
+about	POS	O
+1	POS	O
+/	POS	O
+10	POS	O
+of	POS	O
+the	POS	O
+original	POS	O
+number	POS	O
+.	POS	O
+By	POS	O
+7	POS	O
+days	POS	O
+the	POS	O
+vessel	POS	O
+was	POS	O
+almost	POS	O
+restored	POS	O
+to	POS	O
+normal	POS	O
+.	POS	O
+Triple	POS	O
+stimulation	POS	O
+over	POS	O
+1	POS	O
+day	POS	O
+induced	POS	O
+more	POS	O
+severe	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+media	POS	O
+.	POS	O
+These	POS	O
+findings	POS	O
+suggest	POS	O
+that	POS	O
+smooth	POS	O
+muscle	POS	O
+cells	POS	O
+are	POS	O
+susceptible	POS	O
+to	POS	O
+damage	POS	O
+in	POS	O
+the	POS	O
+course	POS	O
+of	POS	O
+their	POS	O
+specific	POS	O
+function	POS	O
+.	POS	O
+The	POS	O
+experimental	POS	O
+data	POS	O
+are	POS	O
+discussed	POS	O
+in	POS	O
+relation	POS	O
+to	POS	O
+medial	POS	O
+changes	POS	O
+observed	POS	O
+in	POS	O
+other	POS	O
+instances	POS	O
+of	POS	O
+arterial	POS	B-NP
+spasm	POS	I-NP
+.	POS	O
+Endothelial	POS	O
+changes	POS	O
+that	POS	O
+developed	POS	O
+in	POS	O
+the	POS	O
+same	POS	O
+experimental	POS	O
+model	POS	O
+were	POS	O
+described	POS	O
+in	POS	O
+a	POS	O
+previous	POS	O
+paper	POS	O
+.	POS	O
+Bilateral	POS	O
+retinal	POS	O
+artery	POS	O
+and	POS	O
+choriocapillaris	POS	B-NP
+occlusion	POS	I-NP
+following	POS	O
+the	POS	O
+injection	POS	O
+of	POS	O
+long	POS	O
+-	POS	O
+acting	POS	O
+corticosteroid	POS	O
+suspensions	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+other	POS	O
+drugs	POS	O
+:	POS	O
+I	POS	O
+.	POS	O
+Clinical	POS	O
+studies	POS	O
+.	POS	O
+Two	POS	O
+well	POS	O
+-	POS	O
+documented	POS	O
+cases	POS	O
+of	POS	O
+bilateral	POS	O
+retinal	POS	O
+artery	POS	O
+and	POS	O
+choriocapillaris	POS	B-NP
+occlusions	POS	I-NP
+with	POS	O
+blindness	POS	B-NP
+following	POS	O
+head	POS	O
+and	POS	O
+neck	POS	O
+soft	POS	O
+-	POS	O
+tissue	POS	O
+injection	POS	O
+with	POS	O
+methylprednisolone	POS	O
+acetate	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+lidocaine	POS	O
+,	POS	O
+epinephrine	POS	O
+,	POS	O
+or	POS	O
+penicillin	POS	O
+are	POS	O
+reported	POS	O
+.	POS	O
+One	POS	O
+case	POS	O
+had	POS	O
+only	POS	O
+a	POS	O
+unilateral	POS	O
+injection	POS	O
+.	POS	O
+The	POS	O
+acute	POS	O
+observations	POS	O
+included	POS	O
+hazy	POS	B-NP
+sensorium	POS	I-NP
+,	POS	O
+superior	POS	B-NP
+gaze	POS	I-NP
+palsy	POS	I-NP
+,	POS	O
+pupillary	POS	B-NP
+abnormalities	POS	I-NP
+,	POS	O
+and	POS	O
+conjunctival	POS	B-NP
+hemorrhages	POS	I-NP
+with	POS	O
+edema	POS	B-NP
+.	POS	O
+Follow	POS	O
+-	POS	O
+up	POS	O
+changes	POS	O
+showed	POS	O
+marked	POS	O
+visual	POS	B-NP
+loss	POS	I-NP
+,	POS	O
+constricted	POS	O
+visual	POS	O
+fields	POS	O
+,	POS	O
+optic	POS	B-NP
+nerve	POS	I-NP
+pallor	POS	I-NP
+,	POS	O
+vascular	POS	B-NP
+attenuation	POS	I-NP
+,	POS	O
+and	POS	O
+chorioretinal	POS	B-NP
+atrophy	POS	I-NP
+.	POS	O
+The	POS	O
+literature	POS	O
+is	POS	O
+reviewed	POS	O
+,	POS	O
+and	POS	O
+possible	POS	O
+causes	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+Abnormalities	POS	O
+of	POS	O
+the	POS	O
+pupil	POS	O
+and	POS	O
+visual	POS	O
+-	POS	O
+evoked	POS	O
+potential	POS	O
+in	POS	O
+quinine	POS	O
+amblyopia	POS	B-NP
+.	POS	O
+Total	POS	B-NP
+blindness	POS	I-NP
+with	POS	O
+a	POS	O
+transient	POS	O
+tonic	POS	O
+pupillary	POS	O
+response	POS	O
+,	POS	O
+denervation	POS	O
+supersensitivity	POS	O
+,	POS	O
+and	POS	O
+abnormal	POS	O
+visual	POS	O
+-	POS	O
+evoked	POS	O
+potentials	POS	O
+developed	POS	O
+in	POS	O
+a	POS	O
+54	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+after	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+quinine	POS	O
+sulfate	POS	O
+for	POS	O
+leg	POS	B-NP
+cramps	POS	I-NP
+.	POS	O
+He	POS	O
+later	POS	O
+recovered	POS	O
+normal	POS	O
+visual	POS	O
+acuity	POS	O
+.	POS	O
+A	POS	O
+transient	POS	O
+tonic	POS	O
+pupillary	POS	O
+response	POS	O
+,	POS	O
+denervation	POS	O
+supersensitivity	POS	O
+,	POS	O
+and	POS	O
+abnormal	POS	O
+visual	POS	O
+-	POS	O
+evoked	POS	O
+potentials	POS	O
+in	POS	O
+quinine	POS	O
+toxicity	POS	B-NP
+,	POS	O
+to	POS	O
+our	POS	O
+knowledge	POS	O
+,	POS	O
+have	POS	O
+not	POS	O
+been	POS	O
+previously	POS	O
+reported	POS	O
+.	POS	O
+Suxamethonium	POS	B-NP
+-	POS	I-NP
+induced	POS	I-NP
+jaw	POS	I-NP
+stiffness	POS	I-NP
+and	POS	O
+myalgia	POS	B-NP
+associated	POS	O
+with	POS	O
+atypical	POS	O
+cholinesterase	POS	O
+:	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+An	POS	O
+11	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+boy	POS	O
+was	POS	O
+given	POS	O
+halothane	POS	O
+,	POS	O
+nitrous	POS	O
+oxide	POS	O
+and	POS	O
+oxygen	POS	O
+,	POS	O
+pancuronium	POS	O
+0	POS	O
+.	POS	O
+4	POS	O
+mg	POS	O
+and	POS	O
+suxamethonium	POS	O
+100	POS	O
+mg	POS	O
+for	POS	O
+induction	POS	O
+of	POS	O
+anaesthesia	POS	O
+.	POS	O
+In	POS	O
+response	POS	O
+to	POS	O
+this	POS	O
+a	POS	O
+marked	POS	O
+jaw	POS	B-NP
+stiffness	POS	I-NP
+occurred	POS	O
+which	POS	O
+lasted	POS	O
+for	POS	O
+two	POS	O
+minutes	POS	O
+and	POS	O
+the	POS	O
+anaesthesia	POS	O
+were	POS	O
+terminated	POS	O
+.	POS	O
+Four	POS	O
+hours	POS	O
+of	POS	O
+apnoea	POS	B-NP
+ensued	POS	O
+and	POS	O
+he	POS	O
+suffered	POS	O
+generalized	POS	O
+severe	POS	O
+myalgia	POS	B-NP
+lasting	POS	O
+for	POS	O
+one	POS	O
+week	POS	O
+.	POS	O
+He	POS	O
+was	POS	O
+found	POS	O
+to	POS	O
+have	POS	O
+atypical	POS	O
+plasma	POS	O
+cholinesterase	POS	O
+with	POS	O
+a	POS	O
+dibucaine	POS	O
+number	POS	O
+of	POS	O
+12	POS	O
+,	POS	O
+indicating	POS	O
+homozygocity	POS	O
+.	POS	O
+This	POS	O
+was	POS	O
+verified	POS	O
+by	POS	O
+study	POS	O
+of	POS	O
+the	POS	O
+family	POS	O
+.	POS	O
+The	POS	O
+case	POS	O
+shows	POS	O
+that	POS	O
+prolonged	POS	O
+jaw	POS	B-NP
+rigidity	POS	I-NP
+and	POS	O
+myalgia	POS	B-NP
+may	POS	O
+occur	POS	O
+after	POS	O
+suxamethonium	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+atypical	POS	O
+cholinesterase	POS	O
+despite	POS	O
+pretreatment	POS	O
+with	POS	O
+pancuronium	POS	O
+.	POS	O
+Indomethacin	POS	O
+-	POS	O
+induced	POS	O
+hyperkalemia	POS	B-NP
+in	POS	O
+three	POS	O
+patients	POS	O
+with	POS	O
+gouty	POS	B-NP
+arthritis	POS	I-NP
+.	POS	O
+We	POS	O
+describe	POS	O
+three	POS	O
+patients	POS	O
+in	POS	O
+whom	POS	O
+severe	POS	O
+,	POS	O
+life	POS	O
+-	POS	O
+threatening	POS	O
+hyperkalemia	POS	B-NP
+and	POS	O
+renal	POS	B-NP
+insufficiency	POS	I-NP
+developed	POS	O
+after	POS	O
+treatment	POS	O
+of	POS	O
+acute	POS	O
+gouty	POS	B-NP
+arthritis	POS	I-NP
+with	POS	O
+indomethacin	POS	O
+.	POS	O
+This	POS	O
+complication	POS	O
+may	POS	O
+result	POS	O
+from	POS	O
+an	POS	O
+inhibition	POS	O
+of	POS	O
+prostaglandin	POS	O
+synthesis	POS	O
+and	POS	O
+consequent	POS	O
+hyporeninemic	POS	B-NP
+hypoaidosteronism	POS	I-NP
+.	POS	O
+Careful	POS	O
+attention	POS	O
+to	POS	O
+renal	POS	O
+function	POS	O
+and	POS	O
+potassium	POS	O
+balance	POS	O
+in	POS	O
+patients	POS	O
+receiving	POS	O
+indomethacin	POS	O
+or	POS	O
+other	POS	O
+nonsteroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+agents	POS	O
+,	POS	O
+particularly	POS	O
+in	POS	O
+those	POS	O
+patients	POS	O
+with	POS	O
+diabetes	POS	B-NP
+mellitus	POS	I-NP
+or	POS	O
+preexisting	POS	B-NP
+renal	POS	I-NP
+disease	POS	I-NP
+,	POS	O
+will	POS	O
+help	POS	O
+prevent	POS	O
+this	POS	O
+potentially	POS	O
+serious	POS	O
+complication	POS	O
+.	POS	O
+Etomidate	POS	O
+:	POS	O
+a	POS	O
+foreshortened	POS	O
+clinical	POS	O
+trial	POS	O
+.	POS	O
+A	POS	O
+clinical	POS	O
+evaluation	POS	O
+of	POS	O
+etomidate	POS	O
+for	POS	O
+outpatient	POS	O
+cystoscopy	POS	O
+was	POS	O
+embarked	POS	O
+upon	POS	O
+.	POS	O
+Unpremedicated	POS	O
+patients	POS	O
+were	POS	O
+given	POS	O
+fentanyl	POS	O
+1	POS	O
+microgram	POS	O
+/	POS	O
+kg	POS	O
+followed	POS	O
+by	POS	O
+etomidate	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+.	POS	O
+Anaesthesia	POS	O
+was	POS	O
+maintained	POS	O
+with	POS	O
+intermittent	POS	O
+etomidate	POS	O
+in	POS	O
+2	POS	O
+-	POS	O
+4	POS	O
+mg	POS	O
+doses	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+interviewed	POS	O
+personally	POS	O
+later	POS	O
+the	POS	O
+same	POS	O
+day	POS	O
+,	POS	O
+and	POS	O
+by	POS	O
+questionnaire	POS	O
+three	POS	O
+to	POS	O
+four	POS	O
+weeks	POS	O
+later	POS	O
+.	POS	O
+The	POS	O
+trial	POS	O
+was	POS	O
+discontinued	POS	O
+after	POS	O
+20	POS	O
+cases	POS	O
+because	POS	O
+of	POS	O
+an	POS	O
+unacceptable	POS	O
+incidence	POS	O
+of	POS	O
+side	POS	O
+effects	POS	O
+.	POS	O
+Venous	POS	B-NP
+pain	POS	I-NP
+occurred	POS	O
+in	POS	O
+68	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+and	POS	O
+50	POS	O
+%	POS	O
+had	POS	O
+redness	POS	B-NP
+,	POS	O
+pain	POS	B-NP
+or	POS	O
+swelling	POS	B-NP
+related	POS	O
+to	POS	O
+the	POS	O
+injection	POS	O
+site	POS	O
+,	POS	O
+in	POS	O
+some	POS	O
+cases	POS	O
+lasting	POS	O
+up	POS	O
+to	POS	O
+three	POS	O
+weeks	POS	O
+after	POS	O
+anaesthesia	POS	O
+.	POS	O
+Skeletal	POS	B-NP
+movements	POS	I-NP
+occurred	POS	O
+in	POS	O
+50	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+;	POS	O
+30	POS	O
+%	POS	O
+experienced	POS	O
+respiratory	POS	B-NP
+upset	POS	I-NP
+,	POS	O
+one	POS	O
+sufficiently	POS	O
+severe	POS	O
+to	POS	O
+necessitate	POS	O
+abandoning	POS	O
+the	POS	O
+technique	POS	O
+.	POS	O
+Nausea	POS	B-NP
+and	POS	O
+vomiting	POS	B-NP
+occurred	POS	O
+in	POS	O
+40	POS	O
+%	POS	O
+and	POS	O
+25	POS	O
+%	POS	O
+had	POS	O
+disturbing	POS	O
+emergence	POS	O
+psychoses	POS	B-NP
+.	POS	O
+Levodopa	POS	O
+-	POS	O
+induced	POS	O
+dyskinesias	POS	B-NP
+are	POS	O
+improved	POS	O
+by	POS	O
+fluoxetine	POS	O
+.	POS	O
+We	POS	O
+evaluated	POS	O
+the	POS	O
+severity	POS	O
+of	POS	O
+motor	POS	B-NP
+disability	POS	I-NP
+and	POS	O
+dyskinesias	POS	B-NP
+in	POS	O
+seven	POS	O
+levodopa	POS	O
+-	POS	O
+responsive	POS	O
+patients	POS	O
+with	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+after	POS	O
+an	POS	O
+acute	POS	O
+challenge	POS	O
+with	POS	O
+the	POS	O
+mixed	POS	O
+dopamine	POS	O
+agonist	POS	O
+,	POS	O
+apomorphine	POS	O
+,	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+fluoxetine	POS	O
+(	POS	O
+20	POS	O
+mg	POS	O
+twice	POS	O
+per	POS	O
+day	POS	O
+)	POS	O
+for	POS	O
+11	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+days	POS	O
+.	POS	O
+After	POS	O
+fluoxetine	POS	O
+treatment	POS	O
+,	POS	O
+there	POS	O
+was	POS	O
+a	POS	O
+significant	POS	O
+47	POS	O
+%	POS	O
+improvement	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+of	POS	O
+apomorphine	POS	O
+-	POS	O
+induced	POS	O
+dyskinesias	POS	B-NP
+without	POS	O
+modification	POS	O
+of	POS	O
+parkinsonian	POS	B-NP
+motor	POS	I-NP
+disability	POS	I-NP
+.	POS	O
+The	POS	O
+dyskinesias	POS	B-NP
+were	POS	O
+reduced	POS	O
+predominantly	POS	O
+in	POS	O
+the	POS	O
+lower	POS	O
+limbs	POS	O
+during	POS	O
+the	POS	O
+onset	POS	O
+and	POS	O
+disappearance	POS	O
+of	POS	O
+dystonic	POS	B-NP
+dyskinesias	POS	I-NP
+(	POS	O
+onset	POS	O
+-	POS	O
+and	POS	O
+end	POS	O
+-	POS	O
+of	POS	O
+-	POS	O
+dose	POS	O
+dyskinesias	POS	B-NP
+)	POS	O
+and	POS	O
+in	POS	O
+the	POS	O
+upper	POS	O
+limbs	POS	O
+during	POS	O
+choreic	POS	B-NP
+mid	POS	O
+-	POS	O
+dose	POS	O
+dyskinesias	POS	B-NP
+.	POS	O
+The	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+increased	POS	O
+brain	POS	O
+serotoninergic	POS	O
+transmission	POS	O
+with	POS	O
+fluoxetine	POS	O
+may	POS	O
+reduce	POS	O
+levodopa	POS	O
+-	POS	O
+or	POS	O
+dopamine	POS	O
+agonist	POS	O
+-	POS	O
+induced	POS	O
+dyskinesias	POS	B-NP
+without	POS	O
+aggravating	POS	O
+parkinsonian	POS	B-NP
+motor	POS	I-NP
+disability	POS	I-NP
+.	POS	O
+A	POS	O
+large	POS	O
+population	POS	O
+-	POS	O
+based	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+study	POS	O
+of	POS	O
+trimethoprim	POS	O
+-	POS	O
+sulfamethoxazole	POS	O
+,	POS	O
+trimethoprim	POS	O
+,	POS	O
+and	POS	O
+cephalexin	POS	O
+for	POS	O
+uncommon	POS	O
+serious	POS	O
+drug	POS	B-NP
+toxicity	POS	I-NP
+.	POS	O
+We	POS	O
+conducted	POS	O
+a	POS	O
+population	POS	O
+-	POS	O
+based	POS	O
+45	POS	O
+-	POS	O
+day	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+study	POS	O
+of	POS	O
+232	POS	O
+,	POS	O
+390	POS	O
+people	POS	O
+who	POS	O
+were	POS	O
+prescribed	POS	O
+trimethoprim	POS	O
+-	POS	O
+sulfamethoxazole	POS	O
+(	POS	O
+TMP	POS	O
+-	POS	O
+SMZ	POS	O
+)	POS	O
+,	POS	O
+266	POS	O
+,	POS	O
+951	POS	O
+prescribed	POS	O
+trimethoprim	POS	O
+alone	POS	O
+,	POS	O
+and	POS	O
+196	POS	O
+,	POS	O
+397	POS	O
+prescribed	POS	O
+cephalexin	POS	O
+,	POS	O
+to	POS	O
+estimate	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+serious	POS	O
+liver	POS	O
+,	POS	O
+blood	POS	O
+,	POS	O
+skin	POS	O
+,	POS	O
+and	POS	O
+renal	POS	B-NP
+disorders	POS	I-NP
+resulting	POS	O
+in	POS	O
+referral	POS	O
+or	POS	O
+hospitalization	POS	O
+associated	POS	O
+with	POS	O
+these	POS	O
+drugs	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+were	POS	O
+based	POS	O
+on	POS	O
+information	POS	O
+recorded	POS	O
+on	POS	O
+office	POS	O
+computers	POS	O
+by	POS	O
+selected	POS	O
+general	POS	O
+practitioners	POS	O
+in	POS	O
+the	POS	O
+United	POS	O
+Kingdom	POS	O
+,	POS	O
+together	POS	O
+with	POS	O
+a	POS	O
+review	POS	O
+of	POS	O
+clinical	POS	O
+records	POS	O
+.	POS	O
+The	POS	O
+risk	POS	O
+of	POS	O
+clinically	POS	O
+important	POS	O
+idiopathic	POS	B-NP
+liver	POS	I-NP
+disease	POS	I-NP
+was	POS	O
+similar	POS	O
+for	POS	O
+persons	POS	O
+prescribed	POS	O
+TMP	POS	O
+-	POS	O
+SMZ	POS	O
+(	POS	O
+5	POS	O
+.	POS	O
+2	POS	O
+/	POS	O
+100	POS	O
+,	POS	O
+000	POS	O
+)	POS	O
+and	POS	O
+those	POS	O
+prescribed	POS	O
+trimethoprim	POS	O
+alone	POS	O
+(	POS	O
+3	POS	O
+.	POS	O
+8	POS	O
+/	POS	O
+100	POS	O
+,	POS	O
+000	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+risk	POS	O
+for	POS	O
+those	POS	O
+prescribed	POS	O
+cephalexin	POS	O
+was	POS	O
+somewhat	POS	O
+lower	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+0	POS	O
+/	POS	O
+100	POS	O
+,	POS	O
+000	POS	O
+)	POS	O
+.	POS	O
+Only	POS	O
+five	POS	O
+patients	POS	O
+experienced	POS	O
+blood	POS	B-NP
+disorders	POS	I-NP
+,	POS	O
+one	POS	O
+of	POS	O
+whom	POS	O
+was	POS	O
+exposed	POS	O
+to	POS	O
+TMP	POS	O
+-	POS	O
+SMZ	POS	O
+;	POS	O
+of	POS	O
+seven	POS	O
+with	POS	O
+erythema	POS	B-NP
+multiforme	POS	I-NP
+and	POS	O
+Stevens	POS	B-NP
+-	POS	I-NP
+Johnson	POS	I-NP
+syndrome	POS	I-NP
+,	POS	O
+four	POS	O
+were	POS	O
+exposed	POS	O
+to	POS	O
+TMP	POS	O
+-	POS	O
+SMZ	POS	O
+.	POS	O
+The	POS	O
+one	POS	O
+case	POS	O
+of	POS	O
+toxic	POS	O
+epidermal	POS	B-NP
+necrolysis	POS	I-NP
+occurred	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+who	POS	O
+took	POS	O
+cephalexin	POS	O
+.	POS	O
+Finally	POS	O
+,	POS	O
+only	POS	O
+five	POS	O
+cases	POS	O
+of	POS	O
+acute	POS	O
+parenchymal	POS	B-NP
+renal	POS	I-NP
+disease	POS	I-NP
+occurred	POS	O
+,	POS	O
+none	POS	O
+likely	POS	O
+to	POS	O
+be	POS	O
+caused	POS	O
+by	POS	O
+a	POS	O
+study	POS	O
+drug	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+the	POS	O
+serious	POS	O
+diseases	POS	O
+studied	POS	O
+is	POS	O
+small	POS	O
+for	POS	O
+the	POS	O
+three	POS	O
+agents	POS	O
+,	POS	O
+and	POS	O
+compares	POS	O
+reasonably	POS	O
+with	POS	O
+the	POS	O
+risk	POS	O
+for	POS	O
+many	POS	O
+other	POS	O
+antibiotics	POS	O
+.	POS	O
+Clinical	POS	O
+safety	POS	O
+of	POS	O
+lidocaine	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	O
+-	POS	O
+associated	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+STUDY	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+evaluate	POS	O
+the	POS	O
+safety	POS	O
+of	POS	O
+lidocaine	POS	O
+in	POS	O
+the	POS	O
+setting	POS	O
+of	POS	O
+cocaine	POS	O
+-	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+(	POS	O
+MI	POS	B-NP
+)	POS	O
+.	POS	O
+DESIGN	POS	O
+:	POS	O
+A	POS	O
+retrospective	POS	O
+,	POS	O
+multicenter	POS	O
+study	POS	O
+.	POS	O
+SETTING	POS	O
+:	POS	O
+Twenty	POS	O
+-	POS	O
+nine	POS	O
+university	POS	O
+,	POS	O
+university	POS	O
+-	POS	O
+affiliated	POS	O
+,	POS	O
+or	POS	O
+community	POS	O
+hospitals	POS	O
+during	POS	O
+a	POS	O
+6	POS	O
+-	POS	O
+year	POS	O
+period	POS	O
+(	POS	O
+total	POS	O
+of	POS	O
+117	POS	O
+cumulative	POS	O
+hospital	POS	O
+-	POS	O
+years	POS	O
+)	POS	O
+.	POS	O
+PARTICIPANTS	POS	O
+:	POS	O
+Patients	POS	O
+with	POS	O
+cocaine	POS	O
+-	POS	O
+associated	POS	O
+MI	POS	B-NP
+who	POS	O
+received	POS	O
+lidocaine	POS	O
+in	POS	O
+the	POS	O
+emergency	POS	O
+department	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+Of	POS	O
+29	POS	O
+patients	POS	O
+who	POS	O
+received	POS	O
+lidocaine	POS	O
+in	POS	O
+the	POS	O
+setting	POS	O
+of	POS	O
+cocaine	POS	O
+-	POS	O
+associated	POS	O
+MI	POS	B-NP
+,	POS	O
+no	POS	O
+patient	POS	O
+died	POS	O
+;	POS	O
+exhibited	POS	O
+bradydysrhythmias	POS	B-NP
+,	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+,	POS	O
+or	POS	O
+ventricular	POS	B-NP
+fibrillation	POS	I-NP
+;	POS	O
+or	POS	O
+experienced	POS	O
+seizures	POS	B-NP
+after	POS	O
+administration	POS	O
+of	POS	O
+lidocaine	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+confidence	POS	O
+interval	POS	O
+,	POS	O
+0	POS	O
+%	POS	O
+to	POS	O
+11	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Despite	POS	O
+theoretical	POS	O
+concerns	POS	O
+that	POS	O
+lidocaine	POS	O
+may	POS	O
+enhance	POS	O
+cocaine	POS	B-NP
+toxicity	POS	I-NP
+,	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+lidocaine	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+cocaine	POS	O
+-	POS	O
+associated	POS	O
+MI	POS	B-NP
+was	POS	O
+not	POS	O
+associated	POS	O
+with	POS	O
+significant	POS	O
+cardiovascular	POS	B-NP
+or	POS	I-NP
+central	POS	I-NP
+nervous	POS	I-NP
+system	POS	I-NP
+toxicity	POS	I-NP
+.	POS	O
+Experimental	POS	O
+progressive	POS	O
+muscular	POS	B-NP
+dystrophy	POS	I-NP
+and	POS	O
+its	POS	O
+treatment	POS	O
+with	POS	O
+high	POS	O
+doses	POS	O
+anabolizing	POS	O
+agents	POS	O
+.	POS	O
+We	POS	O
+are	POS	O
+still	POS	O
+a	POS	O
+long	POS	O
+way	POS	O
+from	POS	O
+discovering	POS	O
+an	POS	O
+unequivocal	POS	O
+pathogenetic	POS	O
+interpretation	POS	O
+of	POS	O
+progressive	POS	O
+muscular	POS	B-NP
+dystrophy	POS	I-NP
+in	POS	O
+man	POS	O
+.	POS	O
+Noteworthy	POS	O
+efforts	POS	O
+have	POS	O
+been	POS	O
+made	POS	O
+in	POS	O
+the	POS	O
+experimental	POS	O
+field	POS	O
+;	POS	O
+a	POS	O
+recessive	POS	B-NP
+autosomic	POS	I-NP
+form	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+mouse	POS	O
+seems	POS	O
+to	POS	O
+bear	POS	O
+the	POS	O
+closest	POS	O
+resemblance	POS	O
+to	POS	O
+the	POS	O
+human	POS	O
+form	POS	O
+from	POS	O
+the	POS	O
+genetic	POS	O
+point	POS	O
+of	POS	O
+view	POS	O
+.	POS	O
+Myopathy	POS	B-NP
+due	POS	O
+to	POS	O
+lack	POS	O
+of	POS	O
+vitamin	POS	O
+E	POS	O
+and	POS	O
+myopathy	POS	B-NP
+induced	POS	O
+by	POS	O
+certain	POS	O
+viruses	POS	O
+have	POS	O
+much	POS	O
+in	POS	O
+common	POS	O
+anatomically	POS	O
+and	POS	O
+pathologically	POS	O
+with	POS	O
+the	POS	O
+human	POS	O
+form	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+induced	POS	O
+myodystrophy	POS	B-NP
+in	POS	O
+the	POS	O
+rat	POS	O
+by	POS	O
+giving	POS	O
+it	POS	O
+a	POS	O
+diet	POS	O
+lacking	POS	O
+in	POS	O
+vitamin	POS	O
+E	POS	O
+.	POS	O
+The	POS	O
+pharmacological	POS	O
+characteristics	POS	O
+of	POS	O
+vitamin	POS	O
+E	POS	O
+and	POS	O
+the	POS	O
+degenerative	POS	O
+changes	POS	O
+brought	POS	O
+about	POS	O
+by	POS	O
+its	POS	O
+deficiency	POS	O
+,	POS	O
+especially	POS	O
+in	POS	O
+the	POS	O
+muscles	POS	O
+,	POS	O
+are	POS	O
+illustrated	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+thus	POS	O
+confirmed	POS	O
+that	POS	O
+the	POS	O
+histological	POS	O
+characteristics	POS	O
+of	POS	O
+myopathic	POS	O
+rat	POS	O
+muscle	POS	O
+induced	POS	O
+experimentally	POS	O
+are	POS	O
+extraordinarily	POS	O
+similar	POS	O
+to	POS	O
+those	POS	O
+of	POS	O
+human	POS	O
+myopathy	POS	B-NP
+as	POS	O
+confirmed	POS	O
+during	POS	O
+biopsies	POS	O
+performed	POS	O
+at	POS	O
+the	POS	O
+Orthopaedic	POS	O
+Traumatological	POS	O
+Centre	POS	O
+,	POS	O
+Florence	POS	O
+.	POS	O
+The	POS	O
+encouraging	POS	O
+results	POS	O
+obtained	POS	O
+in	POS	O
+various	POS	O
+authoratative	POS	O
+departments	POS	O
+in	POS	O
+myopathic	POS	B-NP
+patients	POS	O
+by	POS	O
+using	POS	O
+anabolizing	POS	O
+steroids	POS	O
+have	POS	O
+encouraged	POS	O
+the	POS	O
+authors	POS	O
+to	POS	O
+investigate	POS	O
+the	POS	O
+beneficial	POS	O
+effects	POS	O
+of	POS	O
+one	POS	O
+anabolizing	POS	O
+agent	POS	O
+(	POS	O
+Dianabol	POS	O
+,	POS	O
+CIBA	POS	O
+)	POS	O
+at	POS	O
+high	POS	O
+doses	POS	O
+in	POS	O
+rats	POS	O
+rendered	POS	O
+myopathic	POS	B-NP
+by	POS	O
+a	POS	O
+diet	POS	O
+deficient	POS	O
+in	POS	O
+vitamin	POS	O
+E	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+way	POS	O
+they	POS	O
+obtained	POS	O
+appreciable	POS	O
+changes	POS	O
+in	POS	O
+body	POS	O
+weight	POS	O
+(	POS	O
+increased	POS	O
+from	POS	O
+50	POS	O
+to	POS	O
+70	POS	O
+g	POS	O
+after	POS	O
+forty	POS	O
+days	POS	O
+at	POS	O
+a	POS	O
+dose	POS	O
+of	POS	O
+5	POS	O
+mg	POS	O
+per	POS	O
+day	POS	O
+of	POS	O
+anabolizing	POS	O
+agent	POS	O
+)	POS	O
+,	POS	O
+but	POS	O
+most	POS	O
+of	POS	O
+all	POS	O
+they	POS	O
+found	POS	O
+histological	POS	O
+changes	POS	O
+due	POS	O
+to	POS	O
+"	POS	O
+regenerative	POS	O
+"	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+muscle	POS	O
+tissue	POS	O
+,	POS	O
+which	POS	O
+however	POS	O
+maintained	POS	O
+its	POS	O
+myopathic	POS	B-NP
+characteristics	POS	O
+in	POS	O
+the	POS	O
+control	POS	O
+animals	POS	O
+that	POS	O
+were	POS	O
+not	POS	O
+treated	POS	O
+with	POS	O
+the	POS	O
+anabolizing	POS	O
+agent	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+conclude	POS	O
+by	POS	O
+affirming	POS	O
+the	POS	O
+undoubted	POS	O
+efficacy	POS	O
+of	POS	O
+the	POS	O
+anabolizing	POS	O
+steroids	POS	O
+in	POS	O
+experimental	POS	O
+myopathic	POS	B-NP
+disease	POS	I-NP
+,	POS	O
+but	POS	O
+they	POS	O
+have	POS	O
+reservations	POS	O
+as	POS	O
+to	POS	O
+the	POS	O
+transfer	POS	O
+of	POS	O
+the	POS	O
+results	POS	O
+into	POS	O
+the	POS	O
+human	POS	O
+field	POS	O
+,	POS	O
+where	POS	O
+high	POS	O
+dosage	POS	O
+cannot	POS	O
+be	POS	O
+carried	POS	O
+out	POS	O
+continuously	POS	O
+because	POS	O
+of	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+on	POS	O
+virility	POS	O
+;	POS	O
+because	POS	O
+the	POS	O
+tissue	POS	O
+injury	POS	O
+too	POS	O
+often	POS	O
+occurs	POS	O
+at	POS	O
+an	POS	O
+irreversible	POS	O
+stage	POS	O
+vis	POS	O
+-	POS	O
+a	POS	O
+-	POS	O
+vis	POS	O
+the	POS	O
+"	POS	O
+regeneration	POS	O
+"	POS	O
+of	POS	O
+the	POS	O
+muscle	POS	O
+tissue	POS	O
+;	POS	O
+and	POS	O
+finally	POS	O
+because	POS	O
+the	POS	O
+dystrophic	POS	O
+injurious	POS	O
+agent	POS	O
+is	POS	O
+certainly	POS	O
+not	POS	O
+the	POS	O
+lack	POS	O
+of	POS	O
+vitamin	POS	O
+E	POS	O
+but	POS	O
+something	POS	O
+as	POS	O
+yet	POS	O
+unknown	POS	O
+.	POS	O
+Paclitaxel	POS	O
+3	POS	O
+-	POS	O
+hour	POS	O
+infusion	POS	O
+given	POS	O
+alone	POS	O
+and	POS	O
+combined	POS	O
+with	POS	O
+carboplatin	POS	O
+:	POS	O
+preliminary	POS	O
+results	POS	O
+of	POS	O
+dose	POS	O
+-	POS	O
+escalation	POS	O
+trials	POS	O
+.	POS	O
+Paclitaxel	POS	O
+(	POS	O
+Taxol	POS	O
+;	POS	O
+Bristol	POS	O
+-	POS	O
+Myers	POS	O
+Squibb	POS	O
+Company	POS	O
+,	POS	O
+Princeton	POS	O
+,	POS	O
+NJ	POS	O
+)	POS	O
+by	POS	O
+3	POS	O
+-	POS	O
+hour	POS	O
+infusion	POS	O
+was	POS	O
+combined	POS	O
+with	POS	O
+carboplatin	POS	O
+in	POS	O
+a	POS	O
+phase	POS	O
+I	POS	O
+/	POS	O
+II	POS	O
+study	POS	O
+directed	POS	O
+to	POS	O
+patients	POS	O
+with	POS	O
+non	POS	B-NP
+-	POS	I-NP
+small	POS	I-NP
+cell	POS	I-NP
+lung	POS	I-NP
+cancer	POS	I-NP
+.	POS	O
+Carboplatin	POS	O
+was	POS	O
+given	POS	O
+at	POS	O
+a	POS	O
+fixed	POS	O
+target	POS	O
+area	POS	O
+under	POS	O
+the	POS	O
+concentration	POS	O
+-	POS	O
+time	POS	O
+curve	POS	O
+of	POS	O
+6	POS	O
+.	POS	O
+0	POS	O
+by	POS	O
+the	POS	O
+Calvert	POS	O
+formula	POS	O
+,	POS	O
+whereas	POS	O
+paclitaxel	POS	O
+was	POS	O
+escalated	POS	O
+in	POS	O
+patient	POS	O
+cohorts	POS	O
+from	POS	O
+150	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+(	POS	O
+dose	POS	O
+level	POS	O
+I	POS	O
+)	POS	O
+to	POS	O
+175	POS	O
+,	POS	O
+200	POS	O
+,	POS	O
+225	POS	O
+,	POS	O
+and	POS	O
+250	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+.	POS	O
+The	POS	O
+225	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+level	POS	O
+was	POS	O
+expanded	POS	O
+for	POS	O
+the	POS	O
+phase	POS	O
+II	POS	O
+study	POS	O
+since	POS	O
+the	POS	O
+highest	POS	O
+level	POS	O
+achieved	POS	O
+(	POS	O
+250	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+)	POS	O
+required	POS	O
+modification	POS	O
+because	POS	O
+of	POS	O
+nonhematologic	POS	O
+toxicities	POS	B-NP
+(	POS	O
+arthralgia	POS	B-NP
+and	POS	O
+sensory	POS	B-NP
+neuropathy	POS	I-NP
+)	POS	O
+.	POS	O
+Therapeutic	POS	O
+effects	POS	O
+were	POS	O
+noted	POS	O
+at	POS	O
+all	POS	O
+dose	POS	O
+levels	POS	O
+,	POS	O
+with	POS	O
+objective	POS	O
+responses	POS	O
+in	POS	O
+17	POS	O
+(	POS	O
+two	POS	O
+complete	POS	O
+and	POS	O
+15	POS	O
+partial	POS	O
+regressions	POS	O
+)	POS	O
+of	POS	O
+41	POS	O
+previously	POS	O
+untreated	POS	O
+patients	POS	O
+.	POS	O
+Toxicities	POS	B-NP
+were	POS	O
+compared	POS	O
+with	POS	O
+a	POS	O
+cohort	POS	O
+of	POS	O
+patients	POS	O
+in	POS	O
+a	POS	O
+phase	POS	O
+I	POS	O
+trial	POS	O
+of	POS	O
+paclitaxel	POS	O
+alone	POS	O
+at	POS	O
+identical	POS	O
+dose	POS	O
+levels	POS	O
+.	POS	O
+Carboplatin	POS	O
+did	POS	O
+not	POS	O
+appear	POS	O
+to	POS	O
+add	POS	O
+to	POS	O
+the	POS	O
+hematologic	POS	O
+toxicities	POS	B-NP
+observed	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+paclitaxel	POS	O
+/	POS	O
+carboplatin	POS	O
+combination	POS	O
+could	POS	O
+be	POS	O
+dosed	POS	O
+every	POS	O
+3	POS	O
+weeks	POS	O
+.	POS	O
+The	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+effect	POS	O
+of	POS	O
+misoprostol	POS	O
+on	POS	O
+indomethacin	POS	O
+-	POS	O
+induced	POS	O
+renal	POS	B-NP
+dysfunction	POS	I-NP
+in	POS	O
+well	POS	O
+compensated	POS	O
+cirrhosis	POS	B-NP
+.	POS	O
+Misoprostol	POS	O
+(	POS	O
+200	POS	O
+micrograms	POS	O
+)	POS	O
+has	POS	O
+been	POS	O
+shown	POS	O
+to	POS	O
+acutely	POS	O
+counteract	POS	O
+the	POS	O
+indomethacin	POS	O
+-	POS	O
+induced	POS	O
+renal	POS	B-NP
+dysfunction	POS	I-NP
+in	POS	O
+well	POS	O
+compensated	POS	O
+cirrhotic	POS	B-NP
+patients	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+determine	POS	O
+if	POS	O
+the	POS	O
+prophylactic	POS	O
+value	POS	O
+of	POS	O
+misoprostol	POS	O
+was	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+.	POS	O
+Parameters	POS	O
+of	POS	O
+renal	POS	O
+hemodynamics	POS	O
+and	POS	O
+tubular	POS	O
+sodium	POS	O
+and	POS	O
+water	POS	O
+handling	POS	O
+were	POS	O
+assessed	POS	O
+by	POS	O
+clearance	POS	O
+techniques	POS	O
+in	POS	O
+26	POS	O
+well	POS	O
+compensated	POS	O
+cirrhotic	POS	B-NP
+patients	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+an	POS	O
+oral	POS	O
+combination	POS	O
+of	POS	O
+50	POS	O
+mg	POS	O
+of	POS	O
+indomethacin	POS	O
+and	POS	O
+various	POS	O
+doses	POS	O
+of	POS	O
+misoprostol	POS	O
+.	POS	O
+The	POS	O
+200	POS	O
+-	POS	O
+micrograms	POS	O
+dose	POS	O
+was	POS	O
+able	POS	O
+to	POS	O
+totally	POS	O
+abolish	POS	O
+the	POS	O
+deleterious	POS	O
+renal	POS	O
+effects	POS	O
+of	POS	O
+indomethacin	POS	O
+,	POS	O
+whereas	POS	O
+the	POS	O
+800	POS	O
+-	POS	O
+micrograms	POS	O
+dose	POS	O
+resulted	POS	O
+in	POS	O
+significant	POS	O
+worsening	POS	O
+of	POS	O
+renal	POS	O
+hemodynamics	POS	O
+and	POS	O
+sodium	POS	O
+retention	POS	O
+.	POS	O
+These	POS	O
+changes	POS	O
+were	POS	O
+maximal	POS	O
+in	POS	O
+the	POS	O
+hour	POS	O
+immediately	POS	O
+after	POS	O
+medications	POS	O
+and	POS	O
+slowly	POS	O
+returned	POS	O
+toward	POS	O
+base	POS	O
+-	POS	O
+line	POS	O
+levels	POS	O
+thereafter	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+the	POS	O
+renal	POS	O
+protective	POS	O
+effects	POS	O
+of	POS	O
+misoprostol	POS	O
+is	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+until	POS	O
+this	POS	O
+apparent	POS	O
+ability	POS	O
+of	POS	O
+200	POS	O
+micrograms	POS	O
+of	POS	O
+misoprostol	POS	O
+to	POS	O
+prevent	POS	O
+the	POS	O
+adverse	POS	O
+effects	POS	O
+of	POS	O
+indomethacin	POS	O
+on	POS	O
+renal	POS	O
+function	POS	O
+is	POS	O
+confirmed	POS	O
+with	POS	O
+chronic	POS	O
+frequent	POS	O
+dosing	POS	O
+,	POS	O
+it	POS	O
+would	POS	O
+be	POS	O
+prudent	POS	O
+to	POS	O
+avoid	POS	O
+nonsteroidal	POS	O
+anti	POS	O
+-	POS	O
+inflammatory	POS	O
+therapy	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+cirrhosis	POS	B-NP
+.	POS	O
+Increased	POS	O
+frequency	POS	O
+and	POS	O
+severity	POS	O
+of	POS	O
+angio	POS	B-NP
+-	POS	I-NP
+oedema	POS	I-NP
+related	POS	O
+to	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+therapy	POS	O
+with	POS	O
+angiotensin	POS	O
+-	POS	O
+converting	POS	O
+enzyme	POS	O
+inhibitor	POS	O
+in	POS	O
+two	POS	O
+patients	POS	O
+.	POS	O
+Adverse	POS	O
+reactions	POS	O
+to	POS	O
+drugs	POS	O
+are	POS	O
+well	POS	O
+recognized	POS	O
+as	POS	O
+a	POS	O
+cause	POS	O
+of	POS	O
+acute	POS	O
+or	POS	O
+chronic	POS	O
+urticaria	POS	B-NP
+,	POS	O
+and	POS	O
+angio	POS	B-NP
+-	POS	I-NP
+oedema	POS	I-NP
+.	POS	O
+Angiotensin	POS	O
+-	POS	O
+converting	POS	O
+enzyme	POS	O
+(	POS	O
+ACE	POS	O
+)	POS	O
+inhibitors	POS	O
+,	POS	O
+used	POS	O
+to	POS	O
+treat	POS	O
+hypertension	POS	B-NP
+and	POS	O
+congestive	POS	B-NP
+heart	POS	I-NP
+failure	POS	I-NP
+,	POS	O
+were	POS	O
+introduced	POS	O
+in	POS	O
+Europe	POS	O
+in	POS	O
+the	POS	O
+middle	POS	O
+of	POS	O
+the	POS	O
+eighties	POS	O
+,	POS	O
+and	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+these	POS	O
+drugs	POS	O
+has	POS	O
+increased	POS	O
+progressively	POS	O
+.	POS	O
+Soon	POS	O
+after	POS	O
+the	POS	O
+introduction	POS	O
+of	POS	O
+ACE	POS	O
+inhibitors	POS	O
+,	POS	O
+acute	POS	O
+bouts	POS	O
+of	POS	O
+angio	POS	B-NP
+-	POS	I-NP
+oedema	POS	I-NP
+were	POS	O
+reported	POS	O
+in	POS	O
+association	POS	O
+with	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+these	POS	O
+drugs	POS	O
+.	POS	O
+We	POS	O
+wish	POS	O
+to	POS	O
+draw	POS	O
+attention	POS	O
+to	POS	O
+the	POS	O
+possibility	POS	O
+of	POS	O
+adverse	POS	O
+reactions	POS	O
+to	POS	O
+ACE	POS	O
+inhibitors	POS	O
+after	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+use	POS	O
+and	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+pre	POS	O
+-	POS	O
+existing	POS	O
+angio	POS	O
+-	POS	O
+oedema	POS	B-NP
+.	POS	O
+Myoclonus	POS	B-NP
+associated	POS	O
+with	POS	O
+lorazepam	POS	O
+therapy	POS	O
+in	POS	O
+very	POS	O
+-	POS	O
+low	POS	O
+-	POS	O
+birth	POS	O
+-	POS	O
+weight	POS	O
+infants	POS	O
+.	POS	O
+Lorazepam	POS	O
+is	POS	O
+being	POS	O
+used	POS	O
+with	POS	O
+increasing	POS	O
+frequency	POS	O
+as	POS	O
+a	POS	O
+sedative	POS	O
+in	POS	O
+the	POS	O
+newborn	POS	O
+and	POS	O
+the	POS	O
+young	POS	O
+infant	POS	O
+.	POS	O
+Concern	POS	O
+has	POS	O
+been	POS	O
+raised	POS	O
+with	POS	O
+regard	POS	O
+to	POS	O
+the	POS	O
+safety	POS	O
+of	POS	O
+lorazepam	POS	O
+in	POS	O
+this	POS	O
+age	POS	O
+group	POS	O
+,	POS	O
+especially	POS	O
+in	POS	O
+very	POS	O
+-	POS	O
+low	POS	O
+-	POS	O
+birth	POS	O
+-	POS	O
+weight	POS	O
+(	POS	O
+VLBW	POS	O
+;	POS	O
+<	POS	O
+1	POS	O
+,	POS	O
+500	POS	O
+g	POS	O
+)	POS	O
+infants	POS	O
+.	POS	O
+Three	POS	O
+young	POS	O
+infants	POS	O
+,	POS	O
+all	POS	O
+of	POS	O
+birth	POS	O
+weight	POS	O
+<	POS	O
+1	POS	O
+,	POS	O
+500	POS	O
+g	POS	O
+,	POS	O
+experienced	POS	O
+myoclonus	POS	B-NP
+following	POS	O
+the	POS	O
+intravenous	POS	O
+administration	POS	O
+of	POS	O
+lorazepam	POS	O
+.	POS	O
+The	POS	O
+potential	POS	O
+neurotoxic	POS	B-NP
+effects	POS	O
+of	POS	O
+the	POS	O
+drug	POS	O
+(	POS	O
+and	POS	O
+its	POS	O
+vehicle	POS	O
+)	POS	O
+in	POS	O
+this	POS	O
+population	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+Injectable	POS	O
+lorazepam	POS	O
+should	POS	O
+be	POS	O
+used	POS	O
+with	POS	O
+caution	POS	O
+in	POS	O
+VLBW	POS	O
+infants	POS	O
+.	POS	O
+Transvenous	POS	O
+right	POS	O
+ventricular	POS	O
+pacing	POS	O
+during	POS	O
+cardiopulmonary	POS	O
+resuscitation	POS	O
+of	POS	O
+pediatric	POS	O
+patients	POS	O
+with	POS	O
+acute	POS	B-NP
+cardiomyopathy	POS	I-NP
+.	POS	O
+We	POS	O
+describe	POS	O
+the	POS	O
+cardiopulmonary	POS	O
+resuscitation	POS	O
+efforts	POS	O
+on	POS	O
+five	POS	O
+patients	POS	O
+who	POS	O
+presented	POS	O
+in	POS	O
+acute	POS	B-NP
+circulatory	POS	I-NP
+failure	POS	I-NP
+from	POS	O
+myocardial	POS	B-NP
+dysfunction	POS	I-NP
+.	POS	O
+Three	POS	O
+patients	POS	O
+had	POS	O
+acute	POS	O
+viral	POS	O
+myocarditis	POS	B-NP
+,	POS	O
+one	POS	O
+had	POS	O
+a	POS	O
+carbamazepine	POS	O
+-	POS	O
+induced	POS	O
+acute	POS	O
+eosinophilic	POS	B-NP
+myocarditis	POS	I-NP
+,	POS	O
+and	POS	O
+one	POS	O
+had	POS	O
+cardiac	POS	B-NP
+hemosiderosis	POS	I-NP
+resulting	POS	O
+in	POS	O
+acute	POS	B-NP
+cardiogenic	POS	I-NP
+shock	POS	I-NP
+.	POS	O
+All	POS	O
+patients	POS	O
+were	POS	O
+continuously	POS	O
+monitored	POS	O
+with	POS	O
+central	POS	O
+venous	POS	O
+and	POS	O
+arterial	POS	O
+catheters	POS	O
+in	POS	O
+addition	POS	O
+to	POS	O
+routine	POS	O
+noninvasive	POS	O
+monitoring	POS	O
+.	POS	O
+An	POS	O
+introducer	POS	O
+sheath	POS	O
+,	POS	O
+a	POS	O
+pacemaker	POS	O
+,	POS	O
+and	POS	O
+sterile	POS	O
+pacing	POS	O
+wires	POS	O
+were	POS	O
+made	POS	O
+readily	POS	O
+available	POS	O
+for	POS	O
+the	POS	O
+patients	POS	O
+,	POS	O
+should	POS	O
+the	POS	O
+need	POS	O
+arise	POS	O
+to	POS	O
+terminate	POS	O
+resistant	POS	O
+cardiac	POS	B-NP
+dysrhythmias	POS	I-NP
+.	POS	O
+All	POS	O
+patients	POS	O
+developed	POS	O
+cardiocirculatory	POS	B-NP
+arrest	POS	I-NP
+associated	POS	O
+with	POS	O
+extreme	POS	O
+hypotension	POS	B-NP
+and	POS	O
+dysrhythmias	POS	B-NP
+within	POS	O
+the	POS	O
+first	POS	O
+48	POS	O
+hours	POS	O
+of	POS	O
+their	POS	O
+admission	POS	O
+to	POS	O
+the	POS	O
+pediatric	POS	O
+intensive	POS	O
+care	POS	O
+unit	POS	O
+(	POS	O
+PICU	POS	O
+)	POS	O
+.	POS	O
+Right	POS	O
+ventricular	POS	O
+pacemaker	POS	O
+wires	POS	O
+were	POS	O
+inserted	POS	O
+in	POS	O
+all	POS	O
+of	POS	O
+them	POS	O
+during	POS	O
+cardiopulmonary	POS	O
+resuscitation	POS	O
+(	POS	O
+CPR	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+four	POS	O
+patients	POS	O
+,	POS	O
+cardiac	POS	O
+pacing	POS	O
+was	POS	O
+used	POS	O
+,	POS	O
+resulting	POS	O
+in	POS	O
+a	POS	O
+temporary	POS	O
+captured	POS	O
+rhythm	POS	O
+and	POS	O
+restoration	POS	O
+of	POS	O
+their	POS	O
+cardiac	POS	O
+output	POS	O
+.	POS	O
+These	POS	O
+patients	POS	O
+had	POS	O
+a	POS	O
+second	POS	O
+event	POS	O
+of	POS	O
+cardiac	POS	B-NP
+arrest	POS	I-NP
+,	POS	O
+resulting	POS	O
+in	POS	O
+death	POS	O
+,	POS	O
+within	POS	O
+10	POS	O
+to	POS	O
+60	POS	O
+minutes	POS	O
+.	POS	O
+In	POS	O
+one	POS	O
+patient	POS	O
+,	POS	O
+cardiac	POS	O
+pacing	POS	O
+was	POS	O
+not	POS	O
+used	POS	O
+,	POS	O
+because	POS	O
+he	POS	O
+converted	POS	O
+to	POS	O
+normal	POS	O
+sinus	POS	O
+rhythm	POS	O
+by	POS	O
+electrical	POS	O
+defibrillation	POS	O
+within	POS	O
+three	POS	O
+minutes	POS	O
+of	POS	O
+initiating	POS	O
+CPR	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+cardiac	POS	O
+pacing	POS	O
+during	POS	O
+resuscitative	POS	O
+efforts	POS	O
+in	POS	O
+pediatric	POS	O
+patients	POS	O
+suffering	POS	O
+from	POS	O
+acute	POS	O
+myocardial	POS	B-NP
+dysfunction	POS	I-NP
+may	POS	O
+not	POS	O
+have	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+value	POS	O
+in	POS	O
+and	POS	O
+of	POS	O
+itself	POS	O
+;	POS	O
+however	POS	O
+,	POS	O
+if	POS	O
+temporary	POS	O
+hemodynamic	POS	O
+stability	POS	O
+is	POS	O
+achieved	POS	O
+by	POS	O
+this	POS	O
+procedure	POS	O
+,	POS	O
+it	POS	O
+may	POS	O
+provide	POS	O
+additional	POS	O
+time	POS	O
+needed	POS	O
+to	POS	O
+institute	POS	O
+other	POS	O
+therapeutic	POS	O
+modalities	POS	O
+.	POS	O
+Efficacy	POS	O
+and	POS	O
+safety	POS	O
+of	POS	O
+granisetron	POS	O
+,	POS	O
+a	POS	O
+selective	POS	O
+5	POS	O
+-	POS	O
+hydroxytryptamine	POS	O
+-	POS	O
+3	POS	O
+receptor	POS	O
+antagonist	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+prevention	POS	O
+of	POS	O
+nausea	POS	B-NP
+and	POS	O
+vomiting	POS	B-NP
+induced	POS	O
+by	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+cisplatin	POS	O
+.	POS	O
+PURPOSE	POS	O
+:	POS	O
+To	POS	O
+assess	POS	O
+the	POS	O
+antiemetic	POS	O
+effects	POS	O
+and	POS	O
+safety	POS	O
+profile	POS	O
+of	POS	O
+four	POS	O
+different	POS	O
+doses	POS	O
+of	POS	O
+granisetron	POS	O
+(	POS	O
+Kytril	POS	O
+;	POS	O
+SmithKline	POS	O
+Beecham	POS	O
+Pharmaceuticals	POS	O
+,	POS	O
+Philadelphia	POS	O
+,	POS	O
+PA	POS	O
+)	POS	O
+when	POS	O
+administered	POS	O
+as	POS	O
+a	POS	O
+single	POS	O
+intravenous	POS	O
+(	POS	O
+IV	POS	O
+)	POS	O
+dose	POS	O
+for	POS	O
+prophylaxis	POS	O
+of	POS	O
+cisplatin	POS	O
+-	POS	O
+induced	POS	O
+nausea	POS	B-NP
+and	POS	O
+vomiting	POS	B-NP
+.	POS	O
+PATIENTS	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+One	POS	O
+hundred	POS	O
+eighty	POS	O
+-	POS	O
+four	POS	O
+chemotherapy	POS	O
+-	POS	O
+naive	POS	O
+patients	POS	O
+receiving	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+cisplatin	POS	O
+(	POS	O
+81	POS	O
+to	POS	O
+120	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+)	POS	O
+were	POS	O
+randomized	POS	O
+to	POS	O
+receive	POS	O
+one	POS	O
+of	POS	O
+four	POS	O
+granisetron	POS	O
+doses	POS	O
+(	POS	O
+5	POS	O
+,	POS	O
+10	POS	O
+,	POS	O
+20	POS	O
+,	POS	O
+or	POS	O
+40	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+administered	POS	O
+before	POS	O
+chemotherapy	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+observed	POS	O
+on	POS	O
+an	POS	O
+inpatient	POS	O
+basis	POS	O
+for	POS	O
+18	POS	O
+to	POS	O
+24	POS	O
+hours	POS	O
+,	POS	O
+and	POS	O
+vital	POS	O
+signs	POS	O
+,	POS	O
+nausea	POS	B-NP
+,	POS	O
+vomiting	POS	B-NP
+,	POS	O
+retching	POS	B-NP
+,	POS	O
+and	POS	O
+appetite	POS	B-NP
+were	POS	O
+assessed	POS	O
+.	POS	O
+Safety	POS	O
+analyses	POS	O
+included	POS	O
+incidence	POS	O
+of	POS	O
+adverse	POS	O
+experiences	POS	O
+and	POS	O
+laboratory	POS	O
+parameter	POS	O
+changes	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+After	POS	O
+granisetron	POS	O
+doses	POS	O
+of	POS	O
+5	POS	O
+,	POS	O
+10	POS	O
+,	POS	O
+20	POS	O
+,	POS	O
+and	POS	O
+40	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+a	POS	O
+major	POS	O
+response	POS	O
+(	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+two	POS	O
+vomiting	POS	B-NP
+or	POS	O
+retching	POS	B-NP
+episodes	POS	O
+,	POS	O
+and	POS	O
+no	POS	O
+antiemetic	POS	O
+rescue	POS	O
+)	POS	O
+was	POS	O
+recorded	POS	O
+in	POS	O
+23	POS	O
+%	POS	O
+,	POS	O
+57	POS	O
+%	POS	O
+,	POS	O
+58	POS	O
+%	POS	O
+,	POS	O
+and	POS	O
+60	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+complete	POS	O
+response	POS	O
+(	POS	O
+no	POS	O
+vomiting	POS	B-NP
+or	POS	O
+retching	POS	B-NP
+,	POS	O
+and	POS	O
+no	POS	O
+antiemetic	POS	O
+rescue	POS	O
+)	POS	O
+in	POS	O
+18	POS	O
+%	POS	O
+,	POS	O
+41	POS	O
+%	POS	O
+,	POS	O
+40	POS	O
+%	POS	O
+,	POS	O
+and	POS	O
+47	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+a	POS	O
+statistically	POS	O
+longer	POS	O
+time	POS	O
+to	POS	O
+first	POS	O
+episode	POS	O
+of	POS	O
+nausea	POS	B-NP
+(	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+0015	POS	O
+)	POS	O
+and	POS	O
+vomiting	POS	B-NP
+(	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+0001	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+fewer	POS	O
+patients	POS	O
+were	POS	O
+administered	POS	O
+additional	POS	O
+antiemetic	POS	O
+medication	POS	O
+in	POS	O
+the	POS	O
+10	POS	O
+-	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+dosing	POS	O
+groups	POS	O
+than	POS	O
+in	POS	O
+the	POS	O
+5	POS	O
+-	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+dosing	POS	O
+group	POS	O
+.	POS	O
+As	POS	O
+granisetron	POS	O
+dose	POS	O
+increased	POS	O
+,	POS	O
+appetite	POS	O
+return	POS	O
+increased	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+040	POS	O
+)	POS	O
+.	POS	O
+Headache	POS	B-NP
+was	POS	O
+the	POS	O
+most	POS	O
+frequently	POS	O
+reported	POS	O
+adverse	POS	O
+event	POS	O
+(	POS	O
+20	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+A	POS	O
+single	POS	O
+10	POS	O
+-	POS	O
+,	POS	O
+20	POS	O
+-	POS	O
+,	POS	O
+or	POS	O
+40	POS	O
+-	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+dose	POS	O
+of	POS	O
+granisetron	POS	O
+was	POS	O
+effective	POS	O
+in	POS	O
+controlling	POS	O
+vomiting	POS	B-NP
+in	POS	O
+57	POS	O
+%	POS	O
+to	POS	O
+60	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+who	POS	O
+received	POS	O
+cisplatin	POS	O
+at	POS	O
+doses	POS	O
+greater	POS	O
+than	POS	O
+81	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+and	POS	O
+totally	POS	O
+prevented	POS	O
+vomiting	POS	B-NP
+in	POS	O
+40	POS	O
+%	POS	O
+to	POS	O
+47	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+.	POS	O
+There	POS	O
+were	POS	O
+no	POS	O
+statistically	POS	O
+significant	POS	O
+differences	POS	O
+in	POS	O
+efficacy	POS	O
+between	POS	O
+the	POS	O
+10	POS	O
+-	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+dose	POS	O
+and	POS	O
+the	POS	O
+20	POS	O
+-	POS	O
+and	POS	O
+40	POS	O
+-	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+doses	POS	O
+.	POS	O
+Granisetron	POS	O
+was	POS	O
+well	POS	O
+tolerated	POS	O
+at	POS	O
+all	POS	O
+doses	POS	O
+.	POS	O
+Adverse	POS	O
+interaction	POS	O
+between	POS	O
+clonidine	POS	O
+and	POS	O
+verapamil	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+report	POS	O
+two	POS	O
+cases	POS	O
+of	POS	O
+a	POS	O
+possible	POS	O
+adverse	POS	O
+interaction	POS	O
+between	POS	O
+clonidine	POS	O
+and	POS	O
+verapamil	POS	O
+resulting	POS	O
+in	POS	O
+atrioventricular	POS	B-NP
+(	POS	I-NP
+AV	POS	I-NP
+)	POS	I-NP
+block	POS	I-NP
+in	POS	O
+both	POS	O
+patients	POS	O
+and	POS	O
+severe	POS	O
+hypotension	POS	B-NP
+in	POS	O
+one	POS	O
+patient	POS	O
+.	POS	O
+CASE	POS	O
+SUMMARIES	POS	O
+:	POS	O
+A	POS	O
+54	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+with	POS	O
+hyperaldosteronism	POS	B-NP
+was	POS	O
+treated	POS	O
+with	POS	O
+verapamil	POS	O
+480	POS	O
+mg	POS	O
+/	POS	O
+d	POS	O
+and	POS	O
+spironolactone	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+d	POS	O
+.	POS	O
+After	POS	O
+the	POS	O
+addition	POS	O
+of	POS	O
+a	POS	O
+minimal	POS	O
+dose	POS	O
+of	POS	O
+clonidine	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+15	POS	O
+mg	POS	O
+bid	POS	O
+)	POS	O
+,	POS	O
+she	POS	O
+developed	POS	O
+complete	POS	O
+AV	POS	B-NP
+block	POS	I-NP
+and	POS	O
+severe	POS	O
+hypotension	POS	B-NP
+,	POS	O
+which	POS	O
+resolved	POS	O
+upon	POS	O
+cessation	POS	O
+of	POS	O
+all	POS	O
+medications	POS	O
+.	POS	O
+A	POS	O
+65	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+was	POS	O
+treated	POS	O
+with	POS	O
+extended	POS	O
+-	POS	O
+release	POS	O
+verapamil	POS	O
+240	POS	O
+mg	POS	O
+/	POS	O
+d	POS	O
+.	POS	O
+After	POS	O
+the	POS	O
+addition	POS	O
+of	POS	O
+clonidine	POS	O
+0	POS	O
+.	POS	O
+15	POS	O
+mg	POS	O
+bid	POS	O
+she	POS	O
+developed	POS	O
+complete	POS	O
+AV	POS	B-NP
+block	POS	I-NP
+,	POS	O
+which	POS	O
+resolved	POS	O
+after	POS	O
+all	POS	O
+therapy	POS	O
+was	POS	O
+stopped	POS	O
+.	POS	O
+DISCUSSION	POS	O
+:	POS	O
+An	POS	O
+adverse	POS	O
+interaction	POS	O
+between	POS	O
+clonidine	POS	O
+and	POS	O
+verapamil	POS	O
+has	POS	O
+not	POS	O
+been	POS	O
+reported	POS	O
+previously	POS	O
+.	POS	O
+We	POS	O
+describe	POS	O
+two	POS	O
+such	POS	O
+cases	POS	O
+and	POS	O
+discuss	POS	O
+the	POS	O
+various	POS	O
+mechanisms	POS	O
+that	POS	O
+might	POS	O
+cause	POS	O
+such	POS	O
+an	POS	O
+interaction	POS	O
+.	POS	O
+Clinicians	POS	O
+should	POS	O
+be	POS	O
+acquainted	POS	O
+with	POS	O
+this	POS	O
+possibly	POS	O
+fatal	POS	O
+interaction	POS	O
+between	POS	O
+two	POS	O
+commonly	POS	O
+used	POS	O
+antihypertensive	POS	O
+drugs	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+Caution	POS	O
+is	POS	O
+recommended	POS	O
+in	POS	O
+combining	POS	O
+clonidine	POS	O
+and	POS	O
+verapamil	POS	O
+therapy	POS	O
+,	POS	O
+even	POS	O
+in	POS	O
+patients	POS	O
+who	POS	O
+do	POS	O
+not	POS	O
+have	POS	O
+sinus	POS	O
+or	POS	O
+AV	POS	B-NP
+node	POS	I-NP
+dysfunction	POS	I-NP
+.	POS	O
+The	POS	O
+two	POS	O
+drugs	POS	O
+may	POS	O
+act	POS	O
+synergistically	POS	O
+on	POS	O
+both	POS	O
+the	POS	O
+AV	POS	O
+node	POS	O
+and	POS	O
+the	POS	O
+peripheral	POS	O
+circulation	POS	O
+.	POS	O
+Pharmacological	POS	O
+studies	POS	O
+on	POS	O
+a	POS	O
+new	POS	O
+dihydrothienopyridine	POS	O
+calcium	POS	O
+antagonist	POS	O
+,	POS	O
+S	POS	O
+-	POS	O
+312	POS	O
+-	POS	O
+d	POS	O
+.	POS	O
+5th	POS	O
+communication	POS	O
+:	POS	O
+anticonvulsant	POS	O
+effects	POS	O
+in	POS	O
+mice	POS	O
+.	POS	O
+S	POS	O
+-	POS	O
+312	POS	O
+,	POS	O
+S	POS	O
+-	POS	O
+312	POS	O
+-	POS	O
+d	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+S	POS	O
+-	POS	O
+312	POS	O
+-	POS	O
+l	POS	O
+,	POS	O
+L	POS	O
+-	POS	O
+type	POS	O
+calcium	POS	O
+channel	POS	O
+antagonists	POS	O
+,	POS	O
+showed	POS	O
+anticonvulsant	POS	O
+effects	POS	O
+on	POS	O
+the	POS	O
+audiogenic	POS	O
+tonic	POS	O
+convulsions	POS	B-NP
+in	POS	O
+DBA	POS	O
+/	POS	O
+2	POS	O
+mice	POS	O
+;	POS	O
+and	POS	O
+their	POS	O
+ED50	POS	O
+values	POS	O
+were	POS	O
+18	POS	O
+.	POS	O
+4	POS	O
+(	POS	O
+12	POS	O
+.	POS	O
+8	POS	O
+-	POS	O
+27	POS	O
+.	POS	O
+1	POS	O
+)	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+p	POS	O
+.	POS	O
+o	POS	O
+.	POS	O
+and	POS	O
+15	POS	O
+.	POS	O
+0	POS	O
+(	POS	O
+10	POS	O
+.	POS	O
+2	POS	O
+-	POS	O
+23	POS	O
+.	POS	O
+7	POS	O
+)	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+p	POS	O
+.	POS	O
+o	POS	O
+.	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+while	POS	O
+that	POS	O
+of	POS	O
+flunarizine	POS	O
+was	POS	O
+34	POS	O
+.	POS	O
+0	POS	O
+(	POS	O
+26	POS	O
+.	POS	O
+0	POS	O
+-	POS	O
+44	POS	O
+.	POS	O
+8	POS	O
+)	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+p	POS	O
+.	POS	O
+o	POS	O
+.	POS	O
+Although	POS	O
+moderate	POS	O
+anticonvulsant	POS	O
+effects	POS	O
+of	POS	O
+S	POS	O
+-	POS	O
+312	POS	O
+-	POS	O
+d	POS	O
+in	POS	O
+higher	POS	O
+doses	POS	O
+were	POS	O
+observed	POS	O
+against	POS	O
+the	POS	O
+clonic	POS	O
+convulsions	POS	B-NP
+induced	POS	O
+by	POS	O
+pentylenetetrazole	POS	O
+(	POS	O
+85	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+s	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+)	POS	O
+or	POS	O
+bemegride	POS	O
+(	POS	O
+40	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+s	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+)	POS	O
+,	POS	O
+no	POS	O
+effects	POS	O
+were	POS	O
+observed	POS	O
+in	POS	O
+convulsions	POS	B-NP
+induced	POS	O
+by	POS	O
+N	POS	O
+-	POS	O
+methyl	POS	O
+-	POS	O
+D	POS	O
+-	POS	O
+aspartate	POS	O
+,	POS	O
+picrotoxin	POS	O
+,	POS	O
+or	POS	O
+electroshock	POS	O
+in	POS	O
+Slc	POS	O
+:	POS	O
+ddY	POS	O
+mice	POS	O
+.	POS	O
+S	POS	O
+-	POS	O
+312	POS	O
+-	POS	O
+d	POS	O
+may	POS	O
+be	POS	O
+useful	POS	O
+in	POS	O
+the	POS	O
+therapy	POS	O
+of	POS	O
+certain	POS	O
+types	POS	O
+of	POS	O
+human	POS	O
+epilepsy	POS	B-NP
+.	POS	O
+Transmural	POS	B-NP
+myocardial	POS	I-NP
+infarction	POS	I-NP
+with	POS	O
+sumatriptan	POS	O
+.	POS	O
+For	POS	O
+sumatriptan	POS	O
+,	POS	O
+tightness	POS	B-NP
+in	POS	O
+the	POS	O
+chest	POS	O
+caused	POS	O
+by	POS	O
+an	POS	O
+unknown	POS	O
+mechanism	POS	O
+has	POS	O
+been	POS	O
+reported	POS	O
+in	POS	O
+3	POS	O
+-	POS	O
+5	POS	O
+%	POS	O
+of	POS	O
+users	POS	O
+.	POS	O
+We	POS	O
+describe	POS	O
+a	POS	O
+47	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+with	POS	O
+an	POS	O
+acute	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+after	POS	O
+administration	POS	O
+of	POS	O
+sumatriptan	POS	O
+6	POS	O
+mg	POS	O
+subcutaneously	POS	O
+for	POS	O
+cluster	POS	B-NP
+headache	POS	I-NP
+.	POS	O
+The	POS	O
+patient	POS	O
+had	POS	O
+no	POS	O
+history	POS	O
+of	POS	O
+underlying	POS	O
+ischaemic	POS	B-NP
+heart	POS	I-NP
+disease	POS	I-NP
+or	POS	O
+Prinzmetal	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+angina	POS	I-NP
+.	POS	O
+She	POS	O
+recovered	POS	O
+without	POS	O
+complications	POS	O
+.	POS	O
+Flumazenil	POS	O
+induces	POS	O
+seizures	POS	B-NP
+and	POS	O
+death	POS	B-NP
+in	POS	O
+mixed	POS	O
+cocaine	POS	O
+-	POS	O
+diazepam	POS	O
+intoxications	POS	O
+.	POS	O
+STUDY	POS	O
+HYPOTHESIS	POS	O
+:	POS	O
+Administration	POS	O
+of	POS	O
+the	POS	O
+benzodiazepine	POS	O
+antagonist	POS	O
+flumazenil	POS	O
+may	POS	O
+unmask	POS	O
+seizures	POS	B-NP
+in	POS	O
+mixed	POS	O
+cocaine	POS	O
+-	POS	O
+benzodiazepine	POS	O
+intoxication	POS	O
+.	POS	O
+DESIGN	POS	O
+:	POS	O
+Male	POS	O
+Sprague	POS	O
+-	POS	O
+Dawley	POS	O
+rats	POS	O
+received	POS	O
+100	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+cocaine	POS	O
+IP	POS	O
+alone	POS	O
+,	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+diazepam	POS	O
+alone	POS	O
+,	POS	O
+or	POS	O
+a	POS	O
+combination	POS	O
+of	POS	O
+diazepam	POS	O
+and	POS	O
+cocaine	POS	O
+.	POS	O
+Three	POS	O
+minutes	POS	O
+later	POS	O
+,	POS	O
+groups	POS	O
+were	POS	O
+challenged	POS	O
+with	POS	O
+vehicle	POS	O
+or	POS	O
+flumazenil	POS	O
+5	POS	O
+or	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+IP	POS	O
+.	POS	O
+Animal	POS	O
+behavior	POS	O
+,	POS	O
+seizures	POS	B-NP
+(	POS	O
+time	POS	O
+to	POS	O
+and	POS	O
+incidence	POS	O
+)	POS	O
+,	POS	O
+death	POS	B-NP
+(	POS	O
+time	POS	O
+to	POS	O
+and	POS	O
+incidence	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+cortical	POS	O
+EEG	POS	O
+tracings	POS	O
+were	POS	O
+recorded	POS	O
+.	POS	O
+INTERVENTIONS	POS	O
+:	POS	O
+Administration	POS	O
+of	POS	O
+flumazenil	POS	O
+to	POS	O
+animals	POS	O
+after	POS	O
+they	POS	O
+had	POS	O
+received	POS	O
+a	POS	O
+combination	POS	O
+dose	POS	O
+of	POS	O
+cocaine	POS	O
+and	POS	O
+diazepam	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+In	POS	O
+group	POS	O
+1	POS	O
+,	POS	O
+animals	POS	O
+received	POS	O
+cocaine	POS	O
+followed	POS	O
+by	POS	O
+vehicle	POS	O
+.	POS	O
+This	POS	O
+resulted	POS	O
+in	POS	O
+100	POS	O
+%	POS	O
+developing	POS	O
+seizures	POS	B-NP
+and	POS	O
+death	POS	B-NP
+.	POS	O
+Group	POS	O
+2	POS	O
+received	POS	O
+diazepam	POS	O
+alone	POS	O
+followed	POS	O
+by	POS	O
+vehicle	POS	O
+.	POS	O
+Animals	POS	O
+became	POS	O
+somnolent	POS	O
+and	POS	O
+none	POS	O
+died	POS	O
+.	POS	O
+Group	POS	O
+3	POS	O
+received	POS	O
+diazepam	POS	O
+followed	POS	O
+by	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+flumazenil	POS	O
+.	POS	O
+Animals	POS	O
+became	POS	O
+somnolent	POS	O
+after	POS	O
+diazepam	POS	O
+and	POS	O
+then	POS	O
+active	POS	O
+after	POS	O
+flumazenil	POS	O
+administration	POS	O
+.	POS	O
+In	POS	O
+group	POS	O
+4	POS	O
+,	POS	O
+a	POS	O
+combination	POS	O
+of	POS	O
+cocaine	POS	O
+and	POS	O
+diazepam	POS	O
+was	POS	O
+administered	POS	O
+simultaneously	POS	O
+.	POS	O
+This	POS	O
+resulted	POS	O
+in	POS	O
+no	POS	O
+overt	POS	O
+or	POS	O
+EEG	POS	O
+-	POS	O
+detectable	POS	O
+seizures	POS	B-NP
+and	POS	O
+a	POS	O
+50	POS	O
+%	POS	O
+incidence	POS	O
+of	POS	O
+death	POS	B-NP
+.	POS	O
+Group	POS	O
+5	POS	O
+received	POS	O
+a	POS	O
+similar	POS	O
+combination	POS	O
+of	POS	O
+cocaine	POS	O
+and	POS	O
+diazepam	POS	O
+,	POS	O
+followed	POS	O
+later	POS	O
+by	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+flumazenil	POS	O
+.	POS	O
+This	POS	O
+resulted	POS	O
+in	POS	O
+an	POS	O
+increased	POS	O
+incidence	POS	O
+of	POS	O
+seizures	POS	B-NP
+,	POS	O
+90	POS	O
+%	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+death	POS	O
+,	POS	O
+100	POS	O
+%	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+,	POS	O
+compared	POS	O
+with	POS	O
+group	POS	O
+4	POS	O
+.	POS	O
+Group	POS	O
+6	POS	O
+received	POS	O
+cocaine	POS	O
+and	POS	O
+diazepam	POS	O
+followed	POS	O
+by	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+flumazenil	POS	O
+.	POS	O
+This	POS	O
+also	POS	O
+resulted	POS	O
+in	POS	O
+an	POS	O
+increased	POS	O
+incidence	POS	O
+of	POS	O
+seizures	POS	B-NP
+,	POS	O
+90	POS	O
+%	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+death	POS	O
+,	POS	O
+90	POS	O
+%	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+,	POS	O
+compared	POS	O
+with	POS	O
+group	POS	O
+4	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Flumazenil	POS	O
+can	POS	O
+unmask	POS	O
+seizures	POS	B-NP
+and	POS	O
+increase	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+death	POS	B-NP
+in	POS	O
+a	POS	O
+model	POS	O
+of	POS	O
+combined	POS	O
+cocaine	POS	O
+-	POS	O
+diazepam	POS	O
+intoxications	POS	O
+.	POS	O
+Mechanisms	POS	O
+for	POS	O
+protective	POS	O
+effects	POS	O
+of	POS	O
+free	POS	O
+radical	POS	O
+scavengers	POS	O
+on	POS	O
+gentamicin	POS	O
+-	POS	O
+mediated	POS	O
+nephropathy	POS	B-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+Studies	POS	O
+were	POS	O
+performed	POS	O
+to	POS	O
+examine	POS	O
+the	POS	O
+mechanisms	POS	O
+for	POS	O
+the	POS	O
+protective	POS	O
+effects	POS	O
+of	POS	O
+free	POS	O
+radical	POS	O
+scavengers	POS	O
+on	POS	O
+gentamicin	POS	O
+(	POS	O
+GM	POS	O
+)	POS	O
+-	POS	O
+mediated	POS	O
+nephropathy	POS	B-NP
+.	POS	O
+Administration	POS	O
+of	POS	O
+GM	POS	O
+at	POS	O
+40	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+sc	POS	O
+for	POS	O
+13	POS	O
+days	POS	O
+to	POS	O
+rats	POS	O
+induced	POS	O
+a	POS	O
+significant	POS	O
+reduction	POS	O
+in	POS	O
+renal	POS	O
+blood	POS	O
+flow	POS	O
+(	POS	O
+RBF	POS	O
+)	POS	O
+and	POS	O
+inulin	POS	O
+clearance	POS	O
+(	POS	O
+CIn	POS	O
+)	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+marked	POS	O
+tubular	POS	O
+damage	POS	O
+.	POS	O
+A	POS	O
+significant	POS	O
+reduction	POS	O
+in	POS	O
+urinary	POS	O
+guanosine	POS	O
+3	POS	O
+'	POS	O
+,	POS	O
+5	POS	O
+'	POS	O
+-	POS	O
+cyclic	POS	O
+monophosphate	POS	O
+(	POS	O
+cGMP	POS	O
+)	POS	O
+excretion	POS	O
+and	POS	O
+a	POS	O
+significant	POS	O
+increase	POS	O
+in	POS	O
+renal	POS	O
+cortical	POS	O
+renin	POS	O
+and	POS	O
+endothelin	POS	O
+-	POS	O
+1	POS	O
+contents	POS	O
+were	POS	O
+also	POS	O
+observed	POS	O
+in	POS	O
+GM	POS	O
+-	POS	O
+mediated	POS	O
+nephropathy	POS	B-NP
+.	POS	O
+Superoxide	POS	O
+dismutase	POS	O
+(	POS	O
+SOD	POS	O
+)	POS	O
+or	POS	O
+dimethylthiourea	POS	O
+(	POS	O
+DMTU	POS	O
+)	POS	O
+significantly	POS	O
+lessened	POS	O
+the	POS	O
+GM	POS	O
+-	POS	O
+induced	POS	O
+decrement	POS	O
+in	POS	O
+CIn	POS	O
+.	POS	O
+The	POS	O
+SOD	POS	O
+-	POS	O
+induced	POS	O
+increase	POS	O
+in	POS	O
+glomerular	POS	O
+filtration	POS	O
+rate	POS	O
+was	POS	O
+associated	POS	O
+with	POS	O
+a	POS	O
+marked	POS	O
+improvement	POS	O
+in	POS	O
+RBF	POS	O
+,	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+urinary	POS	O
+cGMP	POS	O
+excretion	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+renal	POS	O
+renin	POS	O
+and	POS	O
+endothelin	POS	O
+-	POS	O
+1	POS	O
+content	POS	O
+.	POS	O
+SOD	POS	O
+did	POS	O
+not	POS	O
+attenuate	POS	O
+the	POS	O
+tubular	POS	O
+damage	POS	O
+.	POS	O
+In	POS	O
+contrast	POS	O
+,	POS	O
+DMTU	POS	O
+significantly	POS	O
+reduced	POS	O
+the	POS	O
+tubular	POS	O
+damage	POS	O
+and	POS	O
+lipid	POS	O
+peroxidation	POS	O
+,	POS	O
+but	POS	O
+it	POS	O
+did	POS	O
+not	POS	O
+affect	POS	O
+renal	POS	O
+hemodynamics	POS	O
+and	POS	O
+vasoactive	POS	O
+substances	POS	O
+.	POS	O
+Neither	POS	O
+SOD	POS	O
+nor	POS	O
+DMTU	POS	O
+affected	POS	O
+the	POS	O
+renal	POS	O
+cortical	POS	O
+GM	POS	O
+content	POS	O
+in	POS	O
+GM	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+suggest	POS	O
+that	POS	O
+1	POS	O
+)	POS	O
+both	POS	O
+SOD	POS	O
+and	POS	O
+DMTU	POS	O
+have	POS	O
+protective	POS	O
+effects	POS	O
+on	POS	O
+GM	POS	O
+-	POS	O
+mediated	POS	O
+nephropathy	POS	B-NP
+,	POS	O
+2	POS	O
+)	POS	O
+the	POS	O
+mechanisms	POS	O
+for	POS	O
+the	POS	O
+protective	POS	O
+effects	POS	O
+differ	POS	O
+for	POS	O
+SOD	POS	O
+and	POS	O
+DMTU	POS	O
+,	POS	O
+and	POS	O
+3	POS	O
+)	POS	O
+superoxide	POS	O
+anions	POS	O
+play	POS	O
+a	POS	O
+critical	POS	O
+role	POS	O
+in	POS	O
+GM	POS	O
+-	POS	O
+induced	POS	O
+renal	POS	O
+vasoconstriction	POS	O
+.	POS	O
+Cephalothin	POS	O
+-	POS	O
+induced	POS	O
+immune	POS	O
+hemolytic	POS	B-NP
+anemia	POS	I-NP
+.	POS	O
+A	POS	O
+patient	POS	O
+with	POS	O
+renal	POS	B-NP
+disease	POS	I-NP
+developed	POS	O
+Coombs	POS	B-NP
+-	POS	O
+positive	POS	O
+hemolytic	POS	B-NP
+anemia	POS	I-NP
+while	POS	O
+receiving	POS	O
+cephalothin	POS	O
+therapy	POS	O
+.	POS	O
+An	POS	O
+anti	POS	O
+-	POS	O
+cephalothin	POS	O
+IgG	POS	O
+antibody	POS	O
+was	POS	O
+detected	POS	O
+in	POS	O
+the	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+serum	POS	O
+and	POS	O
+in	POS	O
+the	POS	O
+eluates	POS	O
+from	POS	O
+her	POS	O
+erythrocytes	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+nonimmunologic	POS	O
+binding	POS	O
+of	POS	O
+normal	POS	O
+and	POS	O
+patient	POS	O
+'	POS	O
+s	POS	O
+serum	POS	O
+proteins	POS	O
+to	POS	O
+her	POS	O
+own	POS	O
+and	POS	O
+cephalothin	POS	O
+-	POS	O
+coated	POS	O
+normal	POS	O
+red	POS	O
+cells	POS	O
+was	POS	O
+demonstrated	POS	O
+.	POS	O
+Skin	POS	O
+tests	POS	O
+and	POS	O
+in	POS	O
+vitro	POS	O
+lymphocyte	POS	O
+stimulation	POS	O
+revealed	POS	O
+that	POS	O
+the	POS	O
+patient	POS	O
+was	POS	O
+sensitized	POS	O
+to	POS	O
+cephalothin	POS	O
+and	POS	O
+also	POS	O
+to	POS	O
+ampicillin	POS	O
+.	POS	O
+Careful	POS	O
+investigation	POS	O
+of	POS	O
+drug	POS	O
+-	POS	O
+induced	POS	O
+hemolytic	POS	B-NP
+anemias	POS	I-NP
+reveals	POS	O
+the	POS	O
+complexity	POS	O
+of	POS	O
+the	POS	O
+immune	POS	O
+mechanisms	POS	O
+involved	POS	O
+.	POS	O
+Assessment	POS	O
+of	POS	O
+cardiomyocyte	POS	O
+DNA	POS	O
+synthesis	POS	O
+during	POS	O
+hypertrophy	POS	B-NP
+in	POS	O
+adult	POS	O
+mice	POS	O
+.	POS	O
+The	POS	O
+ability	POS	O
+of	POS	O
+cardiomyocytes	POS	O
+to	POS	O
+synthesize	POS	O
+DNA	POS	O
+in	POS	O
+response	POS	O
+to	POS	O
+experimentally	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+hypertrophy	POS	I-NP
+was	POS	O
+assessed	POS	O
+in	POS	O
+adult	POS	O
+mice	POS	O
+.	POS	O
+Isoproterenol	POS	O
+delivered	POS	O
+by	POS	O
+osmotic	POS	O
+minipump	POS	O
+implantation	POS	O
+in	POS	O
+adult	POS	O
+C3Heb	POS	O
+/	POS	O
+FeJ	POS	O
+mice	POS	O
+resulted	POS	O
+in	POS	O
+a	POS	O
+46	POS	O
+%	POS	O
+increase	POS	O
+in	POS	O
+heart	POS	O
+weight	POS	O
+and	POS	O
+a	POS	O
+19	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+increase	POS	O
+in	POS	O
+cardiomyocyte	POS	O
+area	POS	O
+.	POS	O
+No	POS	O
+DNA	POS	O
+synthesis	POS	O
+,	POS	O
+as	POS	O
+assessed	POS	O
+by	POS	O
+autoradiographic	POS	O
+analysis	POS	O
+of	POS	O
+isolated	POS	O
+cardiomyocytes	POS	O
+,	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+control	POS	O
+or	POS	O
+hypertrophic	POS	O
+hearts	POS	O
+.	POS	O
+A	POS	O
+survey	POS	O
+of	POS	O
+15	POS	O
+independent	POS	O
+inbred	POS	O
+strains	POS	O
+of	POS	O
+mice	POS	O
+revealed	POS	O
+that	POS	O
+ventricular	POS	O
+cardiomyocyte	POS	O
+nuclear	POS	O
+number	POS	O
+ranged	POS	O
+from	POS	O
+3	POS	O
+to	POS	O
+13	POS	O
+%	POS	O
+mononucleate	POS	O
+,	POS	O
+suggesting	POS	O
+that	POS	O
+cardiomyocyte	POS	O
+terminal	POS	O
+differentiation	POS	O
+is	POS	O
+influenced	POS	O
+directly	POS	O
+or	POS	O
+indirectly	POS	O
+by	POS	O
+genetic	POS	O
+background	POS	O
+.	POS	O
+To	POS	O
+determine	POS	O
+whether	POS	O
+the	POS	O
+capacity	POS	O
+for	POS	O
+reactive	POS	O
+DNA	POS	O
+synthesis	POS	O
+was	POS	O
+also	POS	O
+subject	POS	O
+to	POS	O
+genetic	POS	O
+regulation	POS	O
+,	POS	O
+cardiac	POS	B-NP
+hypertrophy	POS	I-NP
+was	POS	O
+induced	POS	O
+in	POS	O
+the	POS	O
+strains	POS	O
+of	POS	O
+mice	POS	O
+comprising	POS	O
+the	POS	O
+extremes	POS	O
+of	POS	O
+the	POS	O
+nuclear	POS	O
+number	POS	O
+survey	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+indicate	POS	O
+that	POS	O
+adult	POS	O
+mouse	POS	O
+atrial	POS	O
+and	POS	O
+ventricular	POS	O
+cardiomyocytes	POS	O
+do	POS	O
+not	POS	O
+synthesize	POS	O
+DNA	POS	O
+in	POS	O
+response	POS	O
+to	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+hypertrophy	POS	I-NP
+.	POS	O
+Central	POS	O
+cardiovascular	POS	O
+effects	POS	O
+of	POS	O
+AVP	POS	O
+and	POS	O
+ANP	POS	O
+in	POS	O
+normotensive	POS	O
+and	POS	O
+spontaneously	POS	O
+hypertensive	POS	B-NP
+rats	POS	O
+.	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+the	POS	O
+present	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+compare	POS	O
+influence	POS	O
+of	POS	O
+central	POS	O
+arginine	POS	O
+vasopressin	POS	O
+(	POS	O
+AVP	POS	O
+)	POS	O
+and	POS	O
+of	POS	O
+atrial	POS	O
+natriuretic	POS	O
+peptide	POS	O
+(	POS	O
+ANP	POS	O
+)	POS	O
+on	POS	O
+control	POS	O
+of	POS	O
+arterial	POS	O
+blood	POS	O
+pressure	POS	O
+(	POS	O
+MAP	POS	O
+)	POS	O
+and	POS	O
+heart	POS	O
+rate	POS	O
+(	POS	O
+HR	POS	O
+)	POS	O
+in	POS	O
+normotensive	POS	O
+(	POS	O
+WKY	POS	O
+)	POS	O
+and	POS	O
+spontaneously	POS	O
+hypertensive	POS	B-NP
+(	POS	O
+SHR	POS	O
+)	POS	O
+rats	POS	O
+.	POS	O
+Three	POS	O
+series	POS	O
+of	POS	O
+experiments	POS	O
+were	POS	O
+performed	POS	O
+on	POS	O
+30	POS	O
+WKY	POS	O
+and	POS	O
+30	POS	O
+SHR	POS	O
+,	POS	O
+chronically	POS	O
+instrumented	POS	O
+with	POS	O
+guide	POS	O
+tubes	POS	O
+in	POS	O
+the	POS	O
+lateral	POS	O
+ventricle	POS	O
+(	POS	O
+LV	POS	O
+)	POS	O
+and	POS	O
+arterial	POS	O
+and	POS	O
+venous	POS	O
+catheters	POS	O
+.	POS	O
+MAP	POS	O
+and	POS	O
+HR	POS	O
+were	POS	O
+monitored	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+injections	POS	O
+of	POS	O
+either	POS	O
+vehicle	POS	O
+or	POS	O
+1	POS	O
+,	POS	O
+10	POS	O
+and	POS	O
+50	POS	O
+ng	POS	O
+of	POS	O
+AVP	POS	O
+and	POS	O
+25	POS	O
+,	POS	O
+125	POS	O
+and	POS	O
+500	POS	O
+ng	POS	O
+of	POS	O
+ANP	POS	O
+.	POS	O
+Sensitivity	POS	O
+of	POS	O
+cardiac	POS	O
+component	POS	O
+of	POS	O
+baroreflex	POS	O
+(	POS	O
+CCB	POS	O
+)	POS	O
+,	POS	O
+expressed	POS	O
+as	POS	O
+a	POS	O
+slope	POS	O
+of	POS	O
+the	POS	O
+regression	POS	O
+line	POS	O
+was	POS	O
+determined	POS	O
+from	POS	O
+relationships	POS	O
+between	POS	O
+systolic	POS	O
+arterial	POS	O
+pressure	POS	O
+(	POS	O
+SAP	POS	O
+)	POS	O
+and	POS	O
+HR	POS	O
+period	POS	O
+(	POS	O
+HRp	POS	O
+)	POS	O
+during	POS	O
+phenylephrine	POS	O
+(	POS	O
+Phe	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+and	POS	O
+sodium	POS	O
+nitroprusside	POS	O
+(	POS	O
+SN	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+.	POS	O
+CCB	POS	O
+was	POS	O
+measured	POS	O
+before	POS	O
+and	POS	O
+after	POS	O
+administration	POS	O
+of	POS	O
+either	POS	O
+vehicle	POS	O
+,	POS	O
+AVP	POS	O
+,	POS	O
+ANP	POS	O
+,	POS	O
+or	POS	O
+both	POS	O
+peptides	POS	O
+together	POS	O
+.	POS	O
+Increases	POS	O
+of	POS	O
+MAP	POS	O
+occurred	POS	O
+after	POS	O
+LV	POS	O
+administration	POS	O
+of	POS	O
+1	POS	O
+,	POS	O
+10	POS	O
+and	POS	O
+50	POS	O
+ng	POS	O
+of	POS	O
+AVP	POS	O
+in	POS	O
+WKY	POS	O
+and	POS	O
+of	POS	O
+10	POS	O
+and	POS	O
+50	POS	O
+ng	POS	O
+in	POS	O
+SHR	POS	O
+.	POS	O
+ANP	POS	O
+did	POS	O
+not	POS	O
+cause	POS	O
+significant	POS	O
+changes	POS	O
+in	POS	O
+MAP	POS	O
+in	POS	O
+both	POS	O
+strains	POS	O
+as	POS	O
+compared	POS	O
+to	POS	O
+vehicle	POS	O
+,	POS	O
+but	POS	O
+it	POS	O
+abolished	POS	O
+AVP	POS	O
+-	POS	O
+induced	POS	O
+MAP	POS	O
+increase	POS	O
+in	POS	O
+WKY	POS	O
+and	POS	O
+SHR	POS	O
+.	POS	O
+CCB	POS	O
+was	POS	O
+reduced	POS	O
+in	POS	O
+WKY	POS	O
+and	POS	O
+SHR	POS	O
+after	POS	O
+LV	POS	O
+administration	POS	O
+of	POS	O
+AVP	POS	O
+during	POS	O
+SN	POS	O
+-	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+.	POS	O
+In	POS	O
+SHR	POS	O
+but	POS	O
+not	POS	O
+in	POS	O
+WKY	POS	O
+administration	POS	O
+of	POS	O
+ANP	POS	O
+,	POS	O
+AVP	POS	O
+and	POS	O
+ANP	POS	O
++	POS	O
+AVP	POS	O
+decreased	POS	O
+CCB	POS	O
+during	POS	O
+Phe	POS	O
+-	POS	O
+induced	POS	O
+MAP	POS	O
+elevation	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+centrally	POS	O
+applied	POS	O
+AVP	POS	O
+and	POS	O
+ANP	POS	O
+exert	POS	O
+differential	POS	O
+effects	POS	O
+on	POS	O
+blood	POS	O
+pressure	POS	O
+and	POS	O
+baroreflex	POS	O
+control	POS	O
+of	POS	O
+heart	POS	O
+rate	POS	O
+in	POS	O
+WKY	POS	O
+and	POS	O
+SHR	POS	O
+and	POS	O
+suggest	POS	O
+interaction	POS	O
+of	POS	O
+these	POS	O
+two	POS	O
+peptides	POS	O
+in	POS	O
+blood	POS	O
+pressure	POS	O
+regulation	POS	O
+at	POS	O
+the	POS	O
+level	POS	O
+of	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+.	POS	O
+Cutaneous	POS	O
+exposure	POS	O
+to	POS	O
+warfarin	POS	O
+-	POS	O
+like	POS	O
+anticoagulant	POS	O
+causing	POS	O
+an	POS	O
+intracerebral	POS	B-NP
+hemorrhage	POS	I-NP
+:	POS	O
+a	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+intercerebral	POS	O
+hematoma	POS	B-NP
+due	POS	O
+to	POS	O
+warfarin	POS	O
+-	POS	O
+induced	POS	O
+coagulopathy	POS	B-NP
+is	POS	O
+presented	POS	O
+.	POS	O
+The	POS	O
+39	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+had	POS	O
+spread	POS	O
+a	POS	O
+warfarin	POS	O
+-	POS	O
+type	POS	O
+rat	POS	O
+poison	POS	O
+around	POS	O
+her	POS	O
+house	POS	O
+weekly	POS	O
+using	POS	O
+her	POS	O
+bare	POS	O
+hands	POS	O
+,	POS	O
+with	POS	O
+no	POS	O
+washing	POS	O
+post	POS	O
+application	POS	O
+.	POS	O
+Percutaneous	POS	O
+absorption	POS	O
+of	POS	O
+warfarin	POS	O
+causing	POS	O
+coagulopathy	POS	B-NP
+,	POS	O
+reported	POS	O
+three	POS	O
+times	POS	O
+in	POS	O
+the	POS	O
+past	POS	O
+,	POS	O
+is	POS	O
+a	POS	O
+significant	POS	O
+risk	POS	O
+if	POS	O
+protective	POS	O
+measures	POS	O
+,	POS	O
+such	POS	O
+as	POS	O
+gloves	POS	O
+,	POS	O
+are	POS	O
+not	POS	O
+used	POS	O
+.	POS	O
+An	POS	O
+adverse	POS	O
+drug	POS	O
+interaction	POS	O
+with	POS	O
+piroxicam	POS	O
+,	POS	O
+which	POS	O
+she	POS	O
+took	POS	O
+occasionally	POS	O
+,	POS	O
+may	POS	O
+have	POS	O
+exacerbated	POS	O
+the	POS	O
+coagulopathy	POS	B-NP
+.	POS	O
+Pediatric	POS	O
+heart	POS	O
+transplantation	POS	O
+without	POS	O
+chronic	POS	O
+maintenance	POS	O
+steroids	POS	O
+.	POS	O
+From	POS	O
+1986	POS	O
+to	POS	O
+February	POS	O
+1993	POS	O
+,	POS	O
+40	POS	O
+children	POS	O
+aged	POS	O
+2	POS	O
+months	POS	O
+to	POS	O
+18	POS	O
+years	POS	O
+(	POS	O
+average	POS	O
+age	POS	O
+10	POS	O
+.	POS	O
+4	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+5	POS	O
+.	POS	O
+8	POS	O
+years	POS	O
+)	POS	O
+underwent	POS	O
+heart	POS	O
+transplantation	POS	O
+.	POS	O
+Indications	POS	O
+for	POS	O
+transplantation	POS	O
+were	POS	O
+idiopathic	POS	B-NP
+cardiomyopathy	POS	I-NP
+(	POS	O
+52	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+congenital	POS	B-NP
+heart	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+35	POS	O
+%	POS	O
+)	POS	O
+with	POS	O
+and	POS	O
+without	POS	O
+prior	POS	O
+repair	POS	O
+(	POS	O
+71	POS	O
+%	POS	O
+and	POS	O
+29	POS	O
+%	POS	O
+,	POS	O
+respectively	POS	O
+)	POS	O
+,	POS	O
+hypertrophic	POS	B-NP
+cardiomyopathy	POS	I-NP
+(	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+valvular	POS	B-NP
+heart	POS	I-NP
+disease	POS	I-NP
+(	POS	O
+3	POS	O
+%	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+doxorubicin	POS	O
+cardiomyopathy	POS	B-NP
+(	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Patients	POS	O
+were	POS	O
+managed	POS	O
+with	POS	O
+cyclosporine	POS	O
+and	POS	O
+azathioprine	POS	O
+.	POS	O
+No	POS	O
+prophylaxis	POS	O
+with	POS	O
+antilymphocyte	POS	O
+globulin	POS	O
+was	POS	O
+used	POS	O
+.	POS	O
+Steroids	POS	O
+were	POS	O
+given	POS	O
+to	POS	O
+39	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+for	POS	O
+refractory	POS	O
+rejection	POS	O
+,	POS	O
+but	POS	O
+weaning	POS	O
+was	POS	O
+always	POS	O
+attempted	POS	O
+and	POS	O
+generally	POS	O
+successful	POS	O
+(	POS	O
+64	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Five	POS	O
+patients	POS	O
+(	POS	O
+14	POS	O
+%	POS	O
+)	POS	O
+received	POS	O
+maintenance	POS	O
+steroids	POS	O
+.	POS	O
+Four	POS	O
+patients	POS	O
+died	POS	O
+in	POS	O
+the	POS	O
+perioperative	POS	O
+period	POS	O
+and	POS	O
+one	POS	O
+died	POS	O
+4	POS	O
+months	POS	O
+later	POS	O
+.	POS	O
+There	POS	O
+have	POS	O
+been	POS	O
+no	POS	O
+deaths	POS	O
+related	POS	O
+to	POS	O
+rejection	POS	O
+or	POS	O
+infection	POS	O
+.	POS	O
+Average	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+was	POS	O
+36	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+19	POS	O
+months	POS	O
+(	POS	O
+range	POS	O
+1	POS	O
+to	POS	O
+65	POS	O
+months	POS	O
+)	POS	O
+.	POS	O
+Cumulative	POS	O
+survival	POS	O
+is	POS	O
+88	POS	O
+%	POS	O
+at	POS	O
+5	POS	O
+years	POS	O
+.	POS	O
+In	POS	O
+patients	POS	O
+less	POS	O
+than	POS	O
+7	POS	O
+years	POS	O
+of	POS	O
+age	POS	O
+,	POS	O
+rejection	POS	O
+was	POS	O
+monitored	POS	O
+noninvasively	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+first	POS	O
+postoperative	POS	O
+month	POS	O
+,	POS	O
+89	POS	O
+%	POS	O
+of	POS	O
+patients	POS	O
+were	POS	O
+treated	POS	O
+for	POS	O
+rejection	POS	O
+.	POS	O
+Freedom	POS	O
+from	POS	O
+serious	POS	O
+infections	POS	B-NP
+was	POS	O
+83	POS	O
+%	POS	O
+at	POS	O
+1	POS	O
+month	POS	O
+and	POS	O
+65	POS	O
+%	POS	O
+at	POS	O
+1	POS	O
+year	POS	O
+.	POS	O
+Cytomegalovirus	POS	B-NP
+infections	POS	I-NP
+were	POS	O
+treated	POS	O
+successfully	POS	O
+with	POS	O
+ganciclovir	POS	O
+in	POS	O
+11	POS	O
+patients	POS	O
+.	POS	O
+No	POS	O
+impairment	POS	O
+of	POS	O
+growth	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+children	POS	O
+who	POS	O
+underwent	POS	O
+transplantation	POS	O
+compared	POS	O
+with	POS	O
+a	POS	O
+control	POS	O
+population	POS	O
+.	POS	O
+Twenty	POS	O
+-	POS	O
+one	POS	O
+patients	POS	O
+(	POS	O
+60	POS	O
+%	POS	O
+)	POS	O
+have	POS	O
+undergone	POS	O
+annual	POS	O
+catheterizations	POS	O
+and	POS	O
+no	POS	O
+sign	POS	O
+of	POS	O
+graft	POS	O
+atherosclerosis	POS	B-NP
+has	POS	O
+been	POS	O
+observed	POS	O
+.	POS	O
+Seizures	POS	B-NP
+occurred	POS	O
+in	POS	O
+five	POS	O
+patients	POS	O
+(	POS	O
+14	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+hypertension	POS	B-NP
+was	POS	O
+treated	POS	O
+in	POS	O
+10	POS	O
+patients	POS	O
+(	POS	O
+28	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+No	POS	O
+patient	POS	O
+was	POS	O
+disabled	POS	O
+and	POS	O
+no	POS	O
+lymphoproliferative	POS	B-NP
+disorder	POS	I-NP
+was	POS	O
+observed	POS	O
+.	POS	O
+(	POS	O
+ABSTRACT	POS	O
+TRUNCATED	POS	O
+AT	POS	O
+250	POS	O
+WORDS	POS	O
+)	POS	O
+Delirium	POS	B-NP
+during	POS	O
+fluoxetine	POS	O
+treatment	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+The	POS	O
+correlation	POS	O
+between	POS	O
+high	POS	O
+serum	POS	O
+tricyclic	POS	O
+antidepressant	POS	O
+concentrations	POS	O
+and	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+side	POS	O
+effects	POS	O
+has	POS	O
+been	POS	O
+well	POS	O
+established	POS	O
+.	POS	O
+Only	POS	O
+a	POS	O
+few	POS	O
+reports	POS	O
+exist	POS	O
+,	POS	O
+however	POS	O
+,	POS	O
+on	POS	O
+the	POS	O
+relationship	POS	O
+between	POS	O
+the	POS	O
+serum	POS	O
+concentrations	POS	O
+of	POS	O
+selective	POS	O
+serotonin	POS	O
+reuptake	POS	O
+inhibitors	POS	O
+(	POS	O
+SSRIs	POS	O
+)	POS	O
+and	POS	O
+their	POS	O
+toxic	POS	O
+effects	POS	O
+.	POS	O
+In	POS	O
+some	POS	O
+cases	POS	O
+,	POS	O
+a	POS	O
+high	POS	O
+serum	POS	O
+concentration	POS	O
+of	POS	O
+citalopram	POS	O
+(	POS	O
+>	POS	O
+600	POS	O
+nmol	POS	O
+/	POS	O
+L	POS	O
+)	POS	O
+in	POS	O
+elderly	POS	O
+patients	POS	O
+has	POS	O
+been	POS	O
+associated	POS	O
+with	POS	O
+increased	POS	O
+somnolence	POS	B-NP
+and	POS	O
+movement	POS	B-NP
+difficulties	POS	I-NP
+.	POS	O
+Widespread	POS	B-NP
+cognitive	POS	I-NP
+disorders	POS	I-NP
+,	POS	O
+such	POS	O
+as	POS	O
+delirium	POS	B-NP
+,	POS	O
+have	POS	O
+not	POS	O
+been	POS	O
+previously	POS	O
+linked	POS	O
+with	POS	O
+high	POS	O
+blood	POS	O
+levels	POS	O
+of	POS	O
+SSRIs	POS	O
+.	POS	O
+In	POS	O
+this	POS	O
+report	POS	O
+,	POS	O
+we	POS	O
+describe	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+acute	POS	O
+hyperkinetic	POS	B-NP
+delirium	POS	I-NP
+connected	POS	O
+with	POS	O
+a	POS	O
+high	POS	O
+serum	POS	O
+total	POS	O
+fluoxetine	POS	O
+(	POS	O
+fluoxetine	POS	O
+plus	POS	O
+desmethylfluoxetine	POS	O
+)	POS	O
+concentration	POS	O
+.	POS	O
+Pulmonary	POS	B-NP
+edema	POS	I-NP
+and	POS	O
+shock	POS	B-NP
+after	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+aracytine	POS	O
+-	POS	O
+C	POS	O
+for	POS	O
+lymphoma	POS	B-NP
+;	POS	O
+possible	POS	O
+role	POS	O
+of	POS	O
+TNF	POS	O
+-	POS	O
+alpha	POS	O
+and	POS	O
+PAF	POS	O
+.	POS	O
+Four	POS	O
+out	POS	O
+of	POS	O
+23	POS	O
+consecutive	POS	O
+patients	POS	O
+treated	POS	O
+with	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+Ara	POS	O
+-	POS	O
+C	POS	O
+for	POS	O
+lymphomas	POS	B-NP
+in	POS	O
+our	POS	O
+institution	POS	O
+developed	POS	O
+a	POS	O
+strikingly	POS	O
+similar	POS	O
+syndrome	POS	O
+during	POS	O
+the	POS	O
+perfusion	POS	O
+.	POS	O
+It	POS	O
+was	POS	O
+characterized	POS	O
+by	POS	O
+the	POS	O
+onset	POS	O
+of	POS	O
+fever	POS	B-NP
+,	POS	O
+diarrhea	POS	B-NP
+,	POS	O
+shock	POS	B-NP
+,	POS	O
+pulmonary	POS	B-NP
+edema	POS	I-NP
+,	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+,	POS	O
+metabolic	POS	B-NP
+acidosis	POS	I-NP
+,	POS	O
+weight	POS	B-NP
+gain	POS	I-NP
+and	POS	O
+leukocytosis	POS	B-NP
+.	POS	O
+Thorough	POS	O
+bacteriological	POS	O
+screening	POS	O
+failed	POS	O
+to	POS	O
+provide	POS	O
+evidence	POS	O
+of	POS	O
+infection	POS	O
+.	POS	O
+Sequential	POS	O
+biological	POS	O
+assays	POS	O
+of	POS	O
+IL	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+IL	POS	O
+-	POS	O
+2	POS	O
+,	POS	O
+TNF	POS	O
+and	POS	O
+PAF	POS	O
+were	POS	O
+performed	POS	O
+during	POS	O
+Ara	POS	O
+-	POS	O
+C	POS	O
+infusion	POS	O
+to	POS	O
+ten	POS	O
+patients	POS	O
+,	POS	O
+including	POS	O
+the	POS	O
+four	POS	O
+who	POS	O
+developed	POS	O
+the	POS	O
+syndrome	POS	O
+.	POS	O
+TNF	POS	O
+and	POS	O
+PAF	POS	O
+activity	POS	O
+was	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+serum	POS	O
+of	POS	O
+respectively	POS	O
+two	POS	O
+and	POS	O
+four	POS	O
+of	POS	O
+the	POS	O
+cases	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+in	POS	O
+the	POS	O
+six	POS	O
+controls	POS	O
+.	POS	O
+As	POS	O
+TNF	POS	O
+and	POS	O
+PAF	POS	O
+are	POS	O
+thought	POS	O
+to	POS	O
+be	POS	O
+involved	POS	O
+in	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+septic	POS	B-NP
+shock	POS	I-NP
+and	POS	O
+adult	POS	O
+respiratory	POS	B-NP
+distress	POS	I-NP
+syndrome	POS	I-NP
+,	POS	O
+we	POS	O
+hypothesize	POS	O
+that	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+Ara	POS	O
+-	POS	O
+C	POS	O
+may	POS	O
+be	POS	O
+associated	POS	O
+with	POS	O
+cytokine	POS	O
+release	POS	O
+.	POS	O
+Protective	POS	O
+effect	POS	O
+of	POS	O
+clentiazem	POS	O
+against	POS	O
+epinephrine	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+injury	POS	I-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+We	POS	O
+investigated	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+clentiazem	POS	O
+,	POS	O
+a	POS	O
+1	POS	O
+,	POS	O
+5	POS	O
+-	POS	O
+benzothiazepine	POS	O
+calcium	POS	O
+antagonist	POS	O
+,	POS	O
+on	POS	O
+epinephrine	POS	O
+-	POS	O
+induced	POS	O
+cardiomyopathy	POS	B-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+With	POS	O
+2	POS	O
+-	POS	O
+week	POS	O
+chronic	POS	O
+epinephrine	POS	O
+infusion	POS	O
+,	POS	O
+16	POS	O
+of	POS	O
+30	POS	O
+rats	POS	O
+died	POS	O
+within	POS	O
+4	POS	O
+days	POS	O
+,	POS	O
+and	POS	O
+severe	POS	O
+ischemic	POS	B-NP
+lesions	POS	I-NP
+and	POS	O
+fibrosis	POS	B-NP
+of	POS	O
+the	POS	O
+left	POS	O
+ventricles	POS	O
+were	POS	O
+observed	POS	O
+.	POS	O
+In	POS	O
+epinephrine	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+,	POS	O
+left	POS	O
+atrial	POS	O
+and	POS	O
+left	POS	O
+ventricular	POS	O
+papillary	POS	O
+muscle	POS	O
+contractile	POS	O
+responses	POS	O
+to	POS	O
+isoproterenol	POS	O
+were	POS	O
+reduced	POS	O
+,	POS	O
+but	POS	O
+responses	POS	O
+to	POS	O
+calcium	POS	O
+were	POS	O
+normal	POS	O
+or	POS	O
+enhanced	POS	O
+compared	POS	O
+to	POS	O
+controls	POS	O
+.	POS	O
+Left	POS	O
+ventricular	POS	O
+alpha	POS	O
+and	POS	O
+beta	POS	O
+adrenoceptor	POS	O
+densities	POS	O
+were	POS	O
+also	POS	O
+reduced	POS	O
+compared	POS	O
+to	POS	O
+controls	POS	O
+.	POS	O
+Treatment	POS	O
+with	POS	O
+clentiazem	POS	O
+prevented	POS	O
+epinephrine	POS	O
+-	POS	O
+induced	POS	O
+death	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+attenuated	POS	O
+the	POS	O
+ventricular	POS	B-NP
+ischemic	POS	I-NP
+lesions	POS	I-NP
+and	POS	O
+fibrosis	POS	B-NP
+,	POS	O
+in	POS	O
+a	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+manner	POS	O
+.	POS	O
+Left	POS	O
+atrial	POS	O
+and	POS	O
+left	POS	O
+ventricular	POS	O
+papillary	POS	O
+muscle	POS	O
+contractile	POS	O
+responses	POS	O
+to	POS	O
+isoproterenol	POS	O
+were	POS	O
+reduced	POS	O
+compared	POS	O
+to	POS	O
+controls	POS	O
+in	POS	O
+groups	POS	O
+treated	POS	O
+with	POS	O
+clentiazem	POS	O
+alone	POS	O
+,	POS	O
+but	POS	O
+combined	POS	O
+with	POS	O
+epinephrine	POS	O
+,	POS	O
+clentiazem	POS	O
+restored	POS	O
+left	POS	O
+atrial	POS	O
+responses	POS	O
+and	POS	O
+enhanced	POS	O
+left	POS	O
+ventricular	POS	O
+papillary	POS	O
+responses	POS	O
+to	POS	O
+isoproterenol	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+other	POS	O
+hand	POS	O
+clentiazem	POS	O
+did	POS	O
+not	POS	O
+prevent	POS	O
+epinephrine	POS	O
+-	POS	O
+induced	POS	O
+down	POS	O
+-	POS	O
+regulation	POS	O
+of	POS	O
+alpha	POS	O
+and	POS	O
+beta	POS	O
+adrenoceptors	POS	O
+.	POS	O
+Interestingly	POS	O
+,	POS	O
+clentiazem	POS	O
+,	POS	O
+infused	POS	O
+alone	POS	O
+,	POS	O
+resulted	POS	O
+in	POS	O
+decreased	POS	O
+adrenergic	POS	O
+receptor	POS	O
+densities	POS	O
+in	POS	O
+the	POS	O
+left	POS	O
+ventricle	POS	O
+.	POS	O
+Clentiazem	POS	O
+also	POS	O
+did	POS	O
+not	POS	O
+prevent	POS	O
+the	POS	O
+enhanced	POS	O
+responses	POS	O
+to	POS	O
+calcium	POS	O
+seen	POS	O
+in	POS	O
+the	POS	O
+epinephrine	POS	O
+-	POS	O
+treated	POS	O
+animals	POS	O
+,	POS	O
+although	POS	O
+the	POS	O
+high	POS	O
+dose	POS	O
+of	POS	O
+clentiazem	POS	O
+partially	POS	O
+attenuated	POS	O
+the	POS	O
+maximal	POS	O
+response	POS	O
+to	POS	O
+calcium	POS	O
+compared	POS	O
+to	POS	O
+epinephrine	POS	O
+-	POS	O
+treated	POS	O
+animals	POS	O
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+clentiazem	POS	O
+attenuated	POS	O
+epinephrine	POS	O
+-	POS	O
+induced	POS	O
+cardiac	POS	B-NP
+injury	POS	I-NP
+,	POS	O
+possibly	POS	O
+through	POS	O
+its	POS	O
+effect	POS	O
+on	POS	O
+the	POS	O
+adrenergic	POS	O
+pathway	POS	O
+.	POS	O
+Kaliuretic	POS	O
+effect	POS	O
+of	POS	O
+L	POS	O
+-	POS	O
+dopa	POS	O
+treatment	POS	O
+in	POS	O
+parkinsonian	POS	B-NP
+patients	POS	O
+.	POS	O
+Hypokalemia	POS	B-NP
+,	POS	O
+sometimes	POS	O
+severe	POS	O
+,	POS	O
+was	POS	O
+observed	POS	O
+in	POS	O
+some	POS	O
+L	POS	O
+-	POS	O
+dopa	POS	O
+-	POS	O
+treated	POS	O
+parkinsonian	POS	B-NP
+patients	POS	O
+.	POS	O
+The	POS	O
+influence	POS	O
+of	POS	O
+L	POS	O
+-	POS	O
+dopa	POS	O
+on	POS	O
+the	POS	O
+renal	POS	O
+excretion	POS	O
+of	POS	O
+potassium	POS	O
+was	POS	O
+studied	POS	O
+in	POS	O
+3	POS	O
+patients	POS	O
+with	POS	O
+hypokalemia	POS	B-NP
+and	POS	O
+in	POS	O
+5	POS	O
+normokalemic	POS	B-NP
+patients	POS	O
+by	POS	O
+determination	POS	O
+of	POS	O
+renal	POS	O
+plasma	POS	O
+flow	POS	O
+,	POS	O
+glomerular	POS	O
+filtration	POS	O
+rate	POS	O
+,	POS	O
+plasma	POS	O
+concentration	POS	O
+of	POS	O
+potassium	POS	O
+and	POS	O
+sodium	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+urinary	POS	O
+excretion	POS	O
+of	POS	O
+potassium	POS	O
+,	POS	O
+sodium	POS	O
+and	POS	O
+aldosterone	POS	O
+.	POS	O
+L	POS	O
+-	POS	O
+Dopa	POS	O
+intake	POS	O
+was	POS	O
+found	POS	O
+to	POS	O
+cause	POS	O
+an	POS	O
+increased	POS	O
+excretion	POS	O
+of	POS	O
+potassium	POS	O
+,	POS	O
+and	POS	O
+sometimes	POS	O
+also	POS	O
+of	POS	O
+sodium	POS	O
+,	POS	O
+in	POS	O
+the	POS	O
+hypokalemic	POS	B-NP
+but	POS	O
+not	POS	O
+in	POS	O
+the	POS	O
+normokalemic	POS	B-NP
+patients	POS	O
+.	POS	O
+This	POS	O
+effect	POS	O
+on	POS	O
+the	POS	O
+renal	POS	O
+function	POS	O
+could	POS	O
+be	POS	O
+prohibited	POS	O
+by	POS	O
+the	POS	O
+administration	POS	O
+of	POS	O
+a	POS	O
+peripheral	POS	O
+dopa	POS	O
+decarbodylase	POS	O
+inhibitor	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+not	POS	O
+known	POS	O
+why	POS	O
+this	POS	O
+effect	POS	O
+occurred	POS	O
+in	POS	O
+some	POS	O
+individuals	POS	O
+but	POS	O
+not	POS	O
+in	POS	O
+others	POS	O
+,	POS	O
+but	POS	O
+our	POS	O
+results	POS	O
+indicate	POS	O
+a	POS	O
+correlation	POS	O
+between	POS	O
+aldosterone	POS	O
+production	POS	O
+and	POS	O
+this	POS	O
+renal	POS	O
+effect	POS	O
+of	POS	O
+L	POS	O
+-	POS	O
+dopa	POS	O
+.	POS	O
+Cocaine	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+ischemia	POS	I-NP
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+myocardial	POS	B-NP
+ischemia	POS	I-NP
+induced	POS	O
+by	POS	O
+cocaine	POS	O
+.	POS	O
+The	POS	O
+ischemia	POS	B-NP
+probably	POS	O
+induced	POS	O
+by	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+spasm	POS	I-NP
+was	POS	O
+reversed	POS	O
+by	POS	O
+nitroglycerin	POS	O
+and	POS	O
+calcium	POS	O
+blocking	POS	O
+agents	POS	O
+.	POS	O
+Doxorubicin	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+monitored	POS	O
+by	POS	O
+ECG	POS	O
+in	POS	O
+freely	POS	O
+moving	POS	O
+mice	POS	O
+.	POS	O
+A	POS	O
+new	POS	O
+model	POS	O
+to	POS	O
+test	POS	O
+potential	POS	O
+protectors	POS	O
+.	POS	O
+In	POS	O
+laboratory	POS	O
+animals	POS	O
+,	POS	O
+histology	POS	O
+is	POS	O
+most	POS	O
+commonly	POS	O
+used	POS	O
+to	POS	O
+study	POS	O
+doxorubicin	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+.	POS	O
+However	POS	O
+,	POS	O
+for	POS	O
+monitoring	POS	O
+during	POS	O
+treatment	POS	O
+,	POS	O
+large	POS	O
+numbers	POS	O
+of	POS	O
+animals	POS	O
+are	POS	O
+needed	POS	O
+.	POS	O
+Recently	POS	O
+we	POS	O
+developed	POS	O
+a	POS	O
+new	POS	O
+method	POS	O
+to	POS	O
+measure	POS	O
+ECG	POS	O
+values	POS	O
+in	POS	O
+freely	POS	O
+moving	POS	O
+mice	POS	O
+by	POS	O
+telemetry	POS	O
+.	POS	O
+With	POS	O
+this	POS	O
+model	POS	O
+we	POS	O
+investigated	POS	O
+the	POS	O
+effect	POS	O
+of	POS	O
+chronic	POS	O
+doxorubicin	POS	O
+administration	POS	O
+on	POS	O
+the	POS	O
+ECG	POS	O
+of	POS	O
+freely	POS	O
+moving	POS	O
+BALB	POS	O
+/	POS	O
+c	POS	O
+mice	POS	O
+and	POS	O
+the	POS	O
+efficacy	POS	O
+of	POS	O
+ICRF	POS	O
+-	POS	O
+187	POS	O
+as	POS	O
+a	POS	O
+protective	POS	O
+agent	POS	O
+.	POS	O
+The	POS	O
+ST	POS	O
+interval	POS	O
+significantly	POS	O
+widened	POS	O
+from	POS	O
+15	POS	O
+.	POS	O
+0	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+to	POS	O
+56	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+11	POS	O
+.	POS	O
+8	POS	O
+ms	POS	O
+in	POS	O
+week	POS	O
+10	POS	O
+(	POS	O
+7	POS	O
+weekly	POS	O
+doses	POS	O
+of	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+doxorubicin	POS	O
+given	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+plus	POS	O
+3	POS	O
+weeks	POS	O
+of	POS	O
+observation	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+ECG	POS	O
+of	POS	O
+the	POS	O
+control	POS	O
+animals	POS	O
+did	POS	O
+not	POS	O
+change	POS	O
+during	POS	O
+the	POS	O
+entire	POS	O
+study	POS	O
+.	POS	O
+After	POS	O
+sacrifice	POS	O
+the	POS	O
+hearts	POS	O
+of	POS	O
+doxorubicin	POS	O
+-	POS	O
+treated	POS	O
+animals	POS	O
+were	POS	O
+enlarged	POS	O
+and	POS	O
+the	POS	O
+atria	POS	O
+were	POS	O
+hypertrophic	POS	B-NP
+.	POS	O
+As	POS	O
+this	POS	O
+schedule	POS	O
+exerted	POS	O
+more	POS	O
+toxicity	POS	B-NP
+than	POS	O
+needed	POS	O
+to	POS	O
+investigate	POS	O
+protective	POS	O
+agents	POS	O
+,	POS	O
+the	POS	O
+protection	POS	O
+of	POS	O
+ICRF	POS	O
+-	POS	O
+187	POS	O
+was	POS	O
+determined	POS	O
+using	POS	O
+a	POS	O
+dose	POS	O
+schedule	POS	O
+with	POS	O
+lower	POS	O
+general	POS	O
+toxicity	POS	B-NP
+(	POS	O
+6	POS	O
+weekly	POS	O
+doses	POS	O
+of	POS	O
+4	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+doxorubicin	POS	O
+given	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+plus	POS	O
+2	POS	O
+weeks	POS	O
+of	POS	O
+observation	POS	O
+)	POS	O
+.	POS	O
+On	POS	O
+this	POS	O
+schedule	POS	O
+,	POS	O
+the	POS	O
+animals	POS	O
+'	POS	O
+hearts	POS	O
+appeared	POS	O
+normal	POS	O
+after	POS	O
+sacrifice	POS	O
+and	POS	O
+ICRF	POS	O
+-	POS	O
+187	POS	O
+(	POS	O
+50	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+given	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+1	POS	O
+h	POS	O
+before	POS	O
+doxorubicin	POS	O
+)	POS	O
+provided	POS	O
+almost	POS	O
+full	POS	O
+protection	POS	O
+.	POS	O
+These	POS	O
+data	POS	O
+were	POS	O
+confirmed	POS	O
+by	POS	O
+histology	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+this	POS	O
+new	POS	O
+model	POS	O
+is	POS	O
+very	POS	O
+sensitive	POS	O
+and	POS	O
+enables	POS	O
+monitoring	POS	O
+of	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+cardiotoxicity	POS	B-NP
+with	POS	O
+time	POS	O
+.	POS	O
+These	POS	O
+findings	POS	O
+result	POS	O
+in	POS	O
+a	POS	O
+model	POS	O
+that	POS	O
+allows	POS	O
+the	POS	O
+testing	POS	O
+of	POS	O
+protectors	POS	O
+against	POS	O
+doxorubicin	POS	O
+-	POS	O
+induced	POS	O
+cardiotoxicity	POS	B-NP
+as	POS	O
+demonstrated	POS	O
+by	POS	O
+the	POS	O
+protection	POS	O
+provided	POS	O
+by	POS	O
+ICRF	POS	O
+-	POS	O
+187	POS	O
+.	POS	O
+Epinephrine	POS	O
+dysrhythmogenicity	POS	O
+is	POS	O
+not	POS	O
+enhanced	POS	O
+by	POS	O
+subtoxic	POS	O
+bupivacaine	POS	O
+in	POS	O
+dogs	POS	O
+.	POS	O
+Since	POS	O
+bupivacaine	POS	O
+and	POS	O
+epinephrine	POS	O
+may	POS	O
+both	POS	O
+precipitate	POS	O
+dysrhythmias	POS	B-NP
+,	POS	O
+circulating	POS	O
+bupivacaine	POS	O
+during	POS	O
+regional	POS	O
+anesthesia	POS	O
+could	POS	O
+potentiate	POS	O
+dysrhythmogenic	POS	O
+effects	POS	O
+of	POS	O
+epinephrine	POS	O
+.	POS	O
+We	POS	O
+therefore	POS	O
+examined	POS	O
+whether	POS	O
+bupivacaine	POS	O
+alters	POS	O
+the	POS	O
+dysrhythmogenicity	POS	O
+of	POS	O
+subsequent	POS	O
+administration	POS	O
+of	POS	O
+epinephrine	POS	O
+in	POS	O
+conscious	POS	O
+,	POS	O
+healthy	POS	O
+dogs	POS	O
+and	POS	O
+in	POS	O
+anesthetized	POS	O
+dogs	POS	O
+with	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+Forty	POS	O
+-	POS	O
+one	POS	O
+conscious	POS	O
+dogs	POS	O
+received	POS	O
+10	POS	O
+micrograms	POS	O
+.	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+min	POS	O
+-	POS	O
+1	POS	O
+epinephrine	POS	O
+.	POS	O
+Seventeen	POS	O
+animals	POS	O
+responded	POS	O
+with	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+(	POS	O
+VT	POS	B-NP
+)	POS	O
+within	POS	O
+3	POS	O
+min	POS	O
+.	POS	O
+After	POS	O
+3	POS	O
+h	POS	O
+,	POS	O
+these	POS	O
+responders	POS	O
+randomly	POS	O
+received	POS	O
+1	POS	O
+or	POS	O
+2	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+bupivacaine	POS	O
+or	POS	O
+saline	POS	O
+over	POS	O
+5	POS	O
+min	POS	O
+,	POS	O
+followed	POS	O
+by	POS	O
+10	POS	O
+micrograms	POS	O
+.	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+min	POS	O
+-	POS	O
+1	POS	O
+epinephrine	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+bupivacaine	POS	O
+groups	POS	O
+,	POS	O
+epinephrine	POS	O
+caused	POS	O
+fewer	POS	O
+prodysrhythmic	POS	O
+effects	POS	O
+than	POS	O
+without	POS	O
+bupivacaine	POS	O
+.	POS	O
+VT	POS	B-NP
+appeared	POS	O
+in	POS	O
+fewer	POS	O
+dogs	POS	O
+and	POS	O
+at	POS	O
+a	POS	O
+later	POS	O
+time	POS	O
+,	POS	O
+and	POS	O
+there	POS	O
+were	POS	O
+more	POS	O
+sinoatrial	POS	O
+beats	POS	O
+and	POS	O
+less	POS	O
+ectopies	POS	O
+.	POS	O
+Epinephrine	POS	O
+shortened	POS	O
+QT	POS	O
+less	POS	O
+after	POS	O
+bupivacaine	POS	O
+than	POS	O
+in	POS	O
+control	POS	O
+animals	POS	O
+.	POS	O
+One	POS	O
+day	POS	O
+after	POS	O
+experimental	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+,	POS	O
+six	POS	O
+additional	POS	O
+halothane	POS	O
+-	POS	O
+anesthetized	POS	O
+dogs	POS	O
+received	POS	O
+4	POS	O
+micrograms	POS	O
+.	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+min	POS	O
+-	POS	O
+1	POS	O
+epinephrine	POS	O
+until	POS	O
+VT	POS	O
+appeared	POS	O
+.	POS	O
+After	POS	O
+45	POS	O
+min	POS	O
+,	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+bupivacaine	POS	O
+was	POS	O
+injected	POS	O
+over	POS	O
+5	POS	O
+min	POS	O
+,	POS	O
+again	POS	O
+followed	POS	O
+by	POS	O
+4	POS	O
+micrograms	POS	O
+.	POS	O
+kg	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+min	POS	O
+-	POS	O
+1	POS	O
+epinephrine	POS	O
+.	POS	O
+In	POS	O
+these	POS	O
+dogs	POS	O
+,	POS	O
+the	POS	O
+prodysrhythmic	POS	O
+response	POS	O
+to	POS	O
+epinephrine	POS	O
+was	POS	O
+also	POS	O
+mitigated	POS	O
+by	POS	O
+preceding	POS	O
+bupivacaine	POS	O
+.	POS	O
+Bupivacaine	POS	O
+antagonizes	POS	O
+epinephrine	POS	O
+dysrhythmogenicity	POS	O
+in	POS	O
+conscious	POS	O
+dogs	POS	O
+susceptible	POS	O
+to	POS	O
+VT	POS	B-NP
+and	POS	O
+in	POS	O
+anesthetized	POS	O
+dogs	POS	O
+with	POS	O
+spontaneous	POS	O
+postinfarct	POS	B-NP
+dysrhythmias	POS	I-NP
+.	POS	O
+There	POS	O
+is	POS	O
+no	POS	O
+evidence	POS	O
+that	POS	O
+systemic	POS	O
+subtoxic	POS	O
+bupivacaine	POS	O
+administration	POS	O
+enhances	POS	O
+the	POS	O
+dysrhythmogenicity	POS	O
+of	POS	O
+subsequent	POS	O
+epinephrine	POS	O
+.	POS	O
+Milk	POS	O
+-	POS	O
+alkali	POS	O
+syndrome	POS	O
+induced	POS	O
+by	POS	O
+1	POS	O
+,	POS	O
+25	POS	O
+(	POS	O
+OH	POS	O
+)	POS	O
+2D	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+hypoparathyroidism	POS	B-NP
+.	POS	O
+Milk	POS	B-NP
+-	POS	I-NP
+alkali	POS	I-NP
+syndrome	POS	I-NP
+was	POS	O
+first	POS	O
+described	POS	O
+70	POS	O
+years	POS	O
+ago	POS	O
+in	POS	O
+the	POS	O
+context	POS	O
+of	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+peptic	POS	B-NP
+ulcer	POS	I-NP
+disease	POS	I-NP
+with	POS	O
+large	POS	O
+amounts	POS	O
+of	POS	O
+calcium	POS	O
+and	POS	O
+alkali	POS	O
+.	POS	O
+Although	POS	O
+with	POS	O
+current	POS	O
+ulcer	POS	O
+therapy	POS	O
+(	POS	O
+H	POS	O
+-	POS	O
+2	POS	O
+blockers	POS	O
+,	POS	O
+omeprazole	POS	O
+,	POS	O
+and	POS	O
+sucralfate	POS	O
+)	POS	O
+,	POS	O
+the	POS	O
+frequency	POS	O
+of	POS	O
+milk	POS	O
+-	POS	O
+alkali	POS	O
+syndrome	POS	O
+has	POS	O
+decreased	POS	O
+significantly	POS	O
+,	POS	O
+the	POS	O
+classic	POS	O
+triad	POS	O
+of	POS	O
+hypercalcemia	POS	B-NP
+,	POS	O
+alkalosis	POS	B-NP
+,	POS	O
+and	POS	O
+renal	POS	B-NP
+impairment	POS	I-NP
+remains	POS	O
+the	POS	O
+hallmark	POS	O
+of	POS	O
+the	POS	O
+syndrome	POS	O
+.	POS	O
+Milk	POS	B-NP
+-	POS	I-NP
+alkali	POS	I-NP
+syndrome	POS	I-NP
+can	POS	O
+present	POS	O
+serious	POS	O
+and	POS	O
+occasionally	POS	O
+life	POS	O
+-	POS	O
+threatening	POS	O
+illness	POS	O
+unless	POS	O
+diagnosed	POS	O
+and	POS	O
+treated	POS	O
+appropriately	POS	O
+.	POS	O
+This	POS	O
+article	POS	O
+presents	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+hypoparathyroidism	POS	B-NP
+who	POS	O
+was	POS	O
+treated	POS	O
+with	POS	O
+calcium	POS	O
+carbonate	POS	O
+and	POS	O
+calcitriol	POS	O
+resulting	POS	O
+in	POS	O
+two	POS	O
+admissions	POS	O
+to	POS	O
+the	POS	O
+hospital	POS	O
+for	POS	O
+milk	POS	B-NP
+-	POS	I-NP
+alkali	POS	I-NP
+syndrome	POS	I-NP
+.	POS	O
+The	POS	O
+patient	POS	O
+was	POS	O
+successfully	POS	O
+treated	POS	O
+with	POS	O
+intravenous	POS	O
+pamidronate	POS	O
+on	POS	O
+his	POS	O
+first	POS	O
+admission	POS	O
+and	POS	O
+with	POS	O
+hydrocortisone	POS	O
+on	POS	O
+the	POS	O
+second	POS	O
+.	POS	O
+This	POS	O
+illustrates	POS	O
+intravenous	POS	O
+pamidronate	POS	O
+as	POS	O
+a	POS	O
+valuable	POS	O
+therapeutic	POS	O
+tool	POS	O
+when	POS	O
+milk	POS	B-NP
+-	POS	I-NP
+alkali	POS	I-NP
+syndrome	POS	I-NP
+presents	POS	O
+as	POS	O
+hypercalcemic	POS	B-NP
+emergency	POS	O
+.	POS	O
+Famotidine	POS	O
+-	POS	O
+associated	POS	O
+delirium	POS	B-NP
+.	POS	O
+A	POS	O
+series	POS	O
+of	POS	O
+six	POS	O
+cases	POS	O
+.	POS	O
+Famotidine	POS	O
+is	POS	O
+a	POS	O
+histamine	POS	O
+H2	POS	O
+-	POS	O
+receptor	POS	O
+antagonist	POS	O
+used	POS	O
+in	POS	O
+inpatient	POS	O
+settings	POS	O
+for	POS	O
+prevention	POS	O
+of	POS	O
+stress	POS	B-NP
+ulcers	POS	I-NP
+and	POS	O
+is	POS	O
+showing	POS	O
+increasing	POS	O
+popularity	POS	O
+because	POS	O
+of	POS	O
+its	POS	O
+low	POS	O
+cost	POS	O
+.	POS	O
+Although	POS	O
+all	POS	O
+of	POS	O
+the	POS	O
+currently	POS	O
+available	POS	O
+H2	POS	O
+-	POS	O
+receptor	POS	O
+antagonists	POS	O
+have	POS	O
+shown	POS	O
+the	POS	O
+propensity	POS	O
+to	POS	O
+cause	POS	O
+delirium	POS	B-NP
+,	POS	O
+only	POS	O
+two	POS	O
+previously	POS	O
+reported	POS	O
+cases	POS	O
+have	POS	O
+been	POS	O
+associated	POS	O
+with	POS	O
+famotidine	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+report	POS	O
+on	POS	O
+six	POS	O
+cases	POS	O
+of	POS	O
+famotidine	POS	O
+-	POS	O
+associated	POS	O
+delirium	POS	B-NP
+in	POS	O
+hospitalized	POS	O
+patients	POS	O
+who	POS	O
+cleared	POS	O
+completely	POS	O
+upon	POS	O
+removal	POS	O
+of	POS	O
+famotidine	POS	O
+.	POS	O
+The	POS	O
+pharmacokinetics	POS	O
+of	POS	O
+famotidine	POS	O
+are	POS	O
+reviewed	POS	O
+,	POS	O
+with	POS	O
+no	POS	O
+change	POS	O
+in	POS	O
+its	POS	O
+metabolism	POS	O
+in	POS	O
+the	POS	O
+elderly	POS	O
+population	POS	O
+seen	POS	O
+.	POS	O
+The	POS	O
+implications	POS	O
+of	POS	O
+using	POS	O
+famotidine	POS	O
+in	POS	O
+elderly	POS	O
+persons	POS	O
+are	POS	O
+discussed	POS	O
+.	POS	O
+Encephalopathy	POS	B-NP
+during	POS	O
+amitriptyline	POS	O
+therapy	POS	O
+:	POS	O
+are	POS	O
+neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+and	POS	O
+serotonin	POS	B-NP
+syndrome	POS	I-NP
+spectrum	POS	I-NP
+disorders	POS	I-NP
+?	POS	O
+This	POS	O
+report	POS	O
+describes	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+encephalopathy	POS	B-NP
+developed	POS	O
+in	POS	O
+the	POS	O
+course	POS	O
+of	POS	O
+amitriptyline	POS	O
+therapy	POS	O
+,	POS	O
+during	POS	O
+a	POS	O
+remission	POS	O
+of	POS	O
+unipolar	POS	B-NP
+depression	POS	I-NP
+.	POS	O
+This	POS	O
+patient	POS	O
+could	POS	O
+have	POS	O
+been	POS	O
+diagnosed	POS	O
+as	POS	O
+having	POS	O
+either	POS	O
+neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+(	POS	O
+NMS	POS	B-NP
+)	POS	O
+or	POS	O
+serotonin	POS	B-NP
+syndrome	POS	I-NP
+(	POS	O
+SS	POS	B-NP
+)	POS	O
+.	POS	O
+The	POS	O
+major	POS	O
+determinant	POS	O
+of	POS	O
+the	POS	O
+symptoms	POS	O
+may	POS	O
+have	POS	O
+been	POS	O
+dopamine	POS	O
+/	POS	O
+serotonin	POS	O
+imbalance	POS	O
+in	POS	O
+the	POS	O
+central	POS	O
+nervous	POS	O
+system	POS	O
+.	POS	O
+The	POS	O
+NMS	POS	B-NP
+-	POS	O
+like	POS	O
+encephalopathy	POS	B-NP
+that	POS	O
+develops	POS	O
+in	POS	O
+association	POS	O
+with	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+antidepressants	POS	O
+indicates	POS	O
+that	POS	O
+NMS	POS	B-NP
+and	POS	O
+SS	POS	B-NP
+are	POS	O
+spectrum	POS	O
+disorders	POS	O
+induced	POS	O
+by	POS	O
+drugs	POS	O
+with	POS	O
+both	POS	O
+antidopaminergic	POS	O
+and	POS	O
+serotonergic	POS	O
+effects	POS	O
+.	POS	O
+Genetic	POS	O
+separation	POS	O
+of	POS	O
+tumor	POS	B-NP
+growth	POS	O
+and	POS	O
+hemorrhagic	POS	B-NP
+phenotypes	POS	O
+in	POS	O
+an	POS	O
+estrogen	POS	O
+-	POS	O
+induced	POS	O
+tumor	POS	B-NP
+.	POS	O
+Chronic	POS	O
+administration	POS	O
+of	POS	O
+estrogen	POS	O
+to	POS	O
+the	POS	O
+Fischer	POS	O
+344	POS	O
+(	POS	O
+F344	POS	O
+)	POS	O
+rat	POS	O
+induces	POS	O
+growth	POS	O
+of	POS	O
+large	POS	O
+,	POS	O
+hemorrhagic	POS	B-NP
+pituitary	POS	I-NP
+tumors	POS	I-NP
+.	POS	O
+Ten	POS	O
+weeks	POS	O
+of	POS	O
+diethylstilbestrol	POS	O
+(	POS	O
+DES	POS	O
+)	POS	O
+treatment	POS	O
+caused	POS	O
+female	POS	O
+F344	POS	O
+rat	POS	O
+pituitaries	POS	O
+to	POS	O
+grow	POS	O
+to	POS	O
+an	POS	O
+average	POS	O
+of	POS	O
+109	POS	O
+.	POS	O
+2	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+6	POS	O
+.	POS	O
+3	POS	O
+mg	POS	O
+(	POS	O
+mean	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+SE	POS	O
+)	POS	O
+versus	POS	O
+11	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+4	POS	O
+mg	POS	O
+for	POS	O
+untreated	POS	O
+rats	POS	O
+,	POS	O
+and	POS	O
+to	POS	O
+become	POS	O
+highly	POS	O
+hemorrhagic	POS	B-NP
+.	POS	O
+The	POS	O
+same	POS	O
+DES	POS	O
+treatment	POS	O
+produced	POS	O
+no	POS	O
+significant	POS	O
+growth	POS	O
+(	POS	O
+8	POS	O
+.	POS	O
+9	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+for	POS	O
+treated	POS	O
+females	POS	O
+versus	POS	O
+8	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+1	POS	O
+for	POS	O
+untreated	POS	O
+females	POS	O
+)	POS	O
+or	POS	O
+morphological	POS	O
+changes	POS	O
+in	POS	O
+Brown	POS	O
+Norway	POS	O
+(	POS	O
+BN	POS	O
+)	POS	O
+rat	POS	O
+pituitaries	POS	O
+.	POS	O
+An	POS	O
+F1	POS	O
+hybrid	POS	O
+of	POS	O
+F344	POS	O
+and	POS	O
+BN	POS	O
+exhibited	POS	O
+significant	POS	O
+pituitary	POS	B-NP
+growth	POS	I-NP
+after	POS	O
+10	POS	O
+weeks	POS	O
+of	POS	O
+DES	POS	O
+treatment	POS	O
+with	POS	O
+an	POS	O
+average	POS	O
+mass	POS	O
+of	POS	O
+26	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+mg	POS	O
+compared	POS	O
+with	POS	O
+8	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+mg	POS	O
+for	POS	O
+untreated	POS	O
+rats	POS	O
+.	POS	O
+Surprisingly	POS	O
+,	POS	O
+the	POS	O
+F1	POS	O
+hybrid	POS	O
+tumors	POS	B-NP
+were	POS	O
+not	POS	O
+hemorrhagic	POS	B-NP
+and	POS	O
+had	POS	O
+hemoglobin	POS	O
+content	POS	O
+and	POS	O
+outward	POS	O
+appearance	POS	O
+identical	POS	O
+to	POS	O
+that	POS	O
+of	POS	O
+BN	POS	O
+.	POS	O
+Expression	POS	O
+of	POS	O
+both	POS	O
+growth	POS	O
+and	POS	O
+morphological	POS	O
+changes	POS	O
+is	POS	O
+due	POS	O
+to	POS	O
+multiple	POS	O
+genes	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+while	POS	O
+DES	POS	O
+-	POS	O
+induced	POS	O
+pituitary	POS	O
+growth	POS	O
+exhibited	POS	O
+quantitative	POS	O
+,	POS	O
+additive	POS	O
+inheritance	POS	O
+,	POS	O
+the	POS	O
+hemorrhagic	POS	B-NP
+phenotype	POS	O
+exhibited	POS	O
+recessive	POS	O
+,	POS	O
+epistatic	POS	O
+inheritance	POS	O
+.	POS	O
+Only	POS	O
+5	POS	O
+of	POS	O
+the	POS	O
+160	POS	O
+F2	POS	O
+pituitaries	POS	O
+exhibited	POS	O
+the	POS	O
+hemorrhagic	POS	B-NP
+phenotype	POS	O
+;	POS	O
+36	POS	O
+of	POS	O
+the	POS	O
+160	POS	O
+F2	POS	O
+pituitaries	POS	O
+were	POS	O
+in	POS	O
+the	POS	O
+F344	POS	O
+range	POS	O
+of	POS	O
+mass	POS	O
+,	POS	O
+but	POS	O
+31	POS	O
+of	POS	O
+these	POS	O
+were	POS	O
+not	POS	O
+hemorrhagic	POS	B-NP
+,	POS	O
+indicating	POS	O
+that	POS	O
+the	POS	O
+hemorrhagic	POS	B-NP
+phenotype	POS	O
+is	POS	O
+not	POS	O
+merely	POS	O
+a	POS	O
+consequence	POS	O
+of	POS	O
+extensive	POS	O
+growth	POS	O
+.	POS	O
+The	POS	O
+hemorrhagic	POS	B-NP
+F2	POS	O
+pituitaries	POS	O
+were	POS	O
+all	POS	O
+among	POS	O
+the	POS	O
+most	POS	O
+massive	POS	O
+,	POS	O
+indicating	POS	O
+that	POS	O
+some	POS	O
+of	POS	O
+the	POS	O
+genes	POS	O
+regulate	POS	O
+both	POS	O
+phenotypes	POS	O
+.	POS	O
+Increased	POS	O
+expression	POS	O
+of	POS	O
+neuronal	POS	O
+nitric	POS	O
+oxide	POS	O
+synthase	POS	O
+in	POS	O
+bladder	POS	O
+afferent	POS	O
+pathways	POS	O
+following	POS	O
+chronic	POS	B-NP
+bladder	POS	I-NP
+irritation	POS	I-NP
+.	POS	O
+Immunocytochemical	POS	O
+techniques	POS	O
+were	POS	O
+used	POS	O
+to	POS	O
+examine	POS	O
+alterations	POS	O
+in	POS	O
+the	POS	O
+expression	POS	O
+of	POS	O
+neuronal	POS	O
+nitric	POS	O
+oxide	POS	O
+synthase	POS	O
+(	POS	O
+NOS	POS	O
+)	POS	O
+in	POS	O
+bladder	POS	O
+pathways	POS	O
+following	POS	O
+acute	POS	O
+and	POS	O
+chronic	POS	O
+irritation	POS	O
+of	POS	O
+the	POS	O
+urinary	POS	O
+tract	POS	O
+of	POS	O
+the	POS	O
+rat	POS	O
+.	POS	O
+Chemical	POS	O
+cystitis	POS	B-NP
+was	POS	O
+induced	POS	O
+by	POS	O
+cyclophosphamide	POS	O
+(	POS	O
+CYP	POS	O
+)	POS	O
+which	POS	O
+is	POS	O
+metabolized	POS	O
+to	POS	O
+acrolein	POS	O
+,	POS	O
+an	POS	O
+irritant	POS	O
+eliminated	POS	O
+in	POS	O
+the	POS	O
+urine	POS	O
+.	POS	O
+Injection	POS	O
+of	POS	O
+CYP	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+10	POS	O
+,	POS	O
+75	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+)	POS	O
+2	POS	O
+hours	POS	O
+prior	POS	O
+to	POS	O
+perfusion	POS	O
+(	POS	O
+acute	POS	O
+treatment	POS	O
+)	POS	O
+of	POS	O
+the	POS	O
+animals	POS	O
+increased	POS	O
+Fos	POS	O
+-	POS	O
+immunoreactivity	POS	O
+(	POS	O
+IR	POS	O
+)	POS	O
+in	POS	O
+neurons	POS	O
+in	POS	O
+the	POS	O
+dorsal	POS	O
+commissure	POS	O
+,	POS	O
+dorsal	POS	O
+horn	POS	O
+,	POS	O
+and	POS	O
+autonomic	POS	O
+regions	POS	O
+of	POS	O
+spinal	POS	O
+segments	POS	O
+(	POS	O
+L1	POS	O
+-	POS	O
+L2	POS	O
+and	POS	O
+L6	POS	O
+-	POS	O
+S1	POS	O
+)	POS	O
+which	POS	O
+receive	POS	O
+afferent	POS	O
+inputs	POS	O
+from	POS	O
+the	POS	O
+bladder	POS	O
+,	POS	O
+urethra	POS	O
+,	POS	O
+and	POS	O
+ureter	POS	O
+.	POS	O
+Fos	POS	O
+-	POS	O
+IR	POS	O
+in	POS	O
+the	POS	O
+spinal	POS	O
+cord	POS	O
+was	POS	O
+not	POS	O
+changed	POS	O
+in	POS	O
+rats	POS	O
+receiving	POS	O
+chronic	POS	O
+CYP	POS	O
+treatment	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+15	POS	O
+,	POS	O
+75	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+i	POS	O
+.	POS	O
+p	POS	O
+.	POS	O
+,	POS	O
+every	POS	O
+3rd	POS	O
+day	POS	O
+for	POS	O
+2	POS	O
+weeks	POS	O
+)	POS	O
+.	POS	O
+In	POS	O
+control	POS	O
+animals	POS	O
+and	POS	O
+in	POS	O
+animals	POS	O
+treated	POS	O
+acutely	POS	O
+with	POS	O
+CYP	POS	O
+,	POS	O
+only	POS	O
+small	POS	O
+numbers	POS	O
+of	POS	O
+NOS	POS	O
+-	POS	O
+IR	POS	O
+cells	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+cell	POS	O
+profiles	POS	O
+/	POS	O
+sections	POS	O
+)	POS	O
+were	POS	O
+detected	POS	O
+in	POS	O
+the	POS	O
+L6	POS	O
+-	POS	O
+S1	POS	O
+dorsal	POS	O
+root	POS	O
+ganglia	POS	O
+(	POS	O
+DRG	POS	O
+)	POS	O
+.	POS	O
+Chronic	POS	O
+CYP	POS	O
+administration	POS	O
+significantly	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+or	POS	O
+=	POS	O
+.	POS	O
+002	POS	O
+)	POS	O
+increased	POS	O
+bladder	POS	O
+weight	POS	O
+by	POS	O
+60	POS	O
+%	POS	O
+and	POS	O
+increased	POS	O
+(	POS	O
+7	POS	O
+-	POS	O
+to	POS	O
+11	POS	O
+-	POS	O
+fold	POS	O
+)	POS	O
+the	POS	O
+numbers	POS	O
+of	POS	O
+NOS	POS	O
+-	POS	O
+immunoreactive	POS	O
+(	POS	O
+IR	POS	O
+)	POS	O
+afferent	POS	O
+neurons	POS	O
+in	POS	O
+the	POS	O
+L6	POS	O
+-	POS	O
+S1	POS	O
+DRG	POS	O
+.	POS	O
+A	POS	O
+small	POS	O
+increase	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+fold	POS	O
+)	POS	O
+also	POS	O
+occurred	POS	O
+in	POS	O
+the	POS	O
+L1	POS	O
+DRG	POS	O
+,	POS	O
+but	POS	O
+no	POS	O
+change	POS	O
+was	POS	O
+detected	POS	O
+in	POS	O
+the	POS	O
+L2	POS	O
+and	POS	O
+L5	POS	O
+DRG	POS	O
+.	POS	O
+Bladder	POS	O
+afferent	POS	O
+cells	POS	O
+in	POS	O
+the	POS	O
+L6	POS	O
+-	POS	O
+S1	POS	O
+DRG	POS	O
+labeled	POS	O
+by	POS	O
+Fluorogold	POS	O
+(	POS	O
+40	POS	O
+microliters	POS	O
+)	POS	O
+injected	POS	O
+into	POS	O
+the	POS	O
+bladder	POS	O
+wall	POS	O
+did	POS	O
+not	POS	O
+exhibit	POS	O
+NOS	POS	O
+-	POS	O
+IR	POS	O
+in	POS	O
+control	POS	O
+animals	POS	O
+;	POS	O
+however	POS	O
+,	POS	O
+following	POS	O
+chronic	POS	O
+CYP	POS	O
+administration	POS	O
+,	POS	O
+a	POS	O
+significant	POS	O
+percentage	POS	O
+of	POS	O
+bladder	POS	O
+afferent	POS	O
+neurons	POS	O
+were	POS	O
+NOS	POS	O
+-	POS	O
+IR	POS	O
+:	POS	O
+L6	POS	O
+(	POS	O
+19	POS	O
+.	POS	O
+8	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+4	POS	O
+.	POS	O
+6	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+S1	POS	O
+(	POS	O
+25	POS	O
+.	POS	O
+3	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+neuronal	POS	O
+gene	POS	O
+expression	POS	O
+in	POS	O
+visceral	POS	O
+sensory	POS	O
+pathways	POS	O
+can	POS	O
+be	POS	O
+upregulated	POS	O
+by	POS	O
+chemical	POS	O
+irritation	POS	O
+of	POS	O
+afferent	POS	O
+receptors	POS	O
+in	POS	O
+the	POS	O
+urinary	POS	O
+tract	POS	O
+and	POS	O
+/	POS	O
+or	POS	O
+that	POS	O
+pathological	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+urinary	POS	O
+tract	POS	O
+can	POS	O
+initiate	POS	O
+chemical	POS	O
+signals	POS	O
+that	POS	O
+alter	POS	O
+the	POS	O
+chemical	POS	O
+properties	POS	O
+of	POS	O
+visceral	POS	O
+afferent	POS	O
+neurons	POS	O
+.	POS	O
+Effects	POS	O
+of	POS	O
+a	POS	O
+new	POS	O
+calcium	POS	O
+antagonist	POS	O
+,	POS	O
+CD	POS	O
+-	POS	O
+832	POS	O
+,	POS	O
+on	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+ischemia	POS	I-NP
+in	POS	O
+dogs	POS	O
+with	POS	O
+partial	POS	O
+coronary	POS	B-NP
+stenosis	POS	I-NP
+.	POS	O
+Effects	POS	O
+of	POS	O
+CD	POS	O
+-	POS	O
+832	POS	O
+on	POS	O
+isoproterenol	POS	O
+(	POS	O
+ISO	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+ischemia	POS	I-NP
+were	POS	O
+studied	POS	O
+in	POS	O
+dogs	POS	O
+with	POS	O
+partial	POS	O
+coronary	POS	B-NP
+stenosis	POS	I-NP
+of	POS	O
+the	POS	O
+left	POS	O
+circumflex	POS	O
+coronary	POS	O
+artery	POS	O
+and	POS	O
+findings	POS	O
+were	POS	O
+compared	POS	O
+with	POS	O
+those	POS	O
+for	POS	O
+nifedipine	POS	O
+or	POS	O
+diltiazem	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+stenosis	POS	I-NP
+,	POS	O
+3	POS	O
+-	POS	O
+min	POS	O
+periods	POS	O
+of	POS	O
+intracoronary	POS	O
+ISO	POS	O
+infusion	POS	O
+(	POS	O
+10	POS	O
+ng	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+)	POS	O
+increased	POS	O
+heart	POS	O
+rate	POS	O
+and	POS	O
+maximal	POS	O
+rate	POS	O
+of	POS	O
+left	POS	O
+ventricular	POS	O
+pressure	POS	O
+rise	POS	O
+,	POS	O
+which	POS	O
+resulted	POS	O
+in	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+percentage	POS	O
+segmental	POS	O
+shortening	POS	O
+and	POS	O
+ST	POS	O
+-	POS	O
+segment	POS	O
+elevation	POS	O
+of	POS	O
+the	POS	O
+epicardial	POS	O
+electrocardiogram	POS	O
+.	POS	O
+After	POS	O
+the	POS	O
+control	POS	O
+ISO	POS	O
+infusion	POS	O
+with	POS	O
+stenosis	POS	B-NP
+was	POS	O
+performed	POS	O
+,	POS	O
+equihypotensive	POS	O
+doses	POS	O
+of	POS	O
+CD	POS	O
+-	POS	O
+832	POS	O
+(	POS	O
+3	POS	O
+and	POS	O
+10	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+,	POS	O
+n	POS	O
+=	POS	O
+7	POS	O
+)	POS	O
+,	POS	O
+nifedipine	POS	O
+(	POS	O
+1	POS	O
+and	POS	O
+3	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+,	POS	O
+n	POS	O
+=	POS	O
+9	POS	O
+)	POS	O
+or	POS	O
+diltiazem	POS	O
+(	POS	O
+10	POS	O
+and	POS	O
+30	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+,	POS	O
+n	POS	O
+=	POS	O
+7	POS	O
+)	POS	O
+were	POS	O
+infused	POS	O
+5	POS	O
+min	POS	O
+before	POS	O
+and	POS	O
+during	POS	O
+the	POS	O
+second	POS	O
+and	POS	O
+third	POS	O
+ISO	POS	O
+infusion	POS	O
+.	POS	O
+Both	POS	O
+CD	POS	O
+-	POS	O
+832	POS	O
+and	POS	O
+diltiazem	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+nifedipine	POS	O
+,	POS	O
+significantly	POS	O
+reduced	POS	O
+the	POS	O
+increase	POS	O
+in	POS	O
+heart	POS	O
+rate	POS	O
+induced	POS	O
+by	POS	O
+ISO	POS	O
+infusion	POS	O
+.	POS	O
+In	POS	O
+contrast	POS	O
+to	POS	O
+nifedipine	POS	O
+,	POS	O
+CD	POS	O
+-	POS	O
+832	POS	O
+(	POS	O
+10	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+)	POS	O
+prevented	POS	O
+the	POS	O
+decrease	POS	O
+in	POS	O
+percentage	POS	O
+segmental	POS	O
+shortening	POS	O
+from	POS	O
+32	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+12	POS	O
+%	POS	O
+to	POS	O
+115	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+26	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+control	POS	O
+value	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+and	POS	O
+ST	POS	O
+-	POS	O
+segment	POS	O
+elevation	POS	O
+from	POS	O
+5	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+0	POS	O
+mV	POS	O
+to	POS	O
+1	POS	O
+.	POS	O
+6	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+1	POS	O
+.	POS	O
+3	POS	O
+mV	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+at	POS	O
+3	POS	O
+min	POS	O
+after	POS	O
+ISO	POS	O
+infusion	POS	O
+with	POS	O
+stenosis	POS	O
+.	POS	O
+Diltiazem	POS	O
+(	POS	O
+30	POS	O
+micrograms	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+min	POS	O
+)	POS	O
+also	POS	O
+prevented	POS	O
+the	POS	O
+decrease	POS	O
+in	POS	O
+percentage	POS	O
+segmental	POS	O
+shortening	POS	O
+from	POS	O
+34	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+14	POS	O
+%	POS	O
+to	POS	O
+63	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+18	POS	O
+%	POS	O
+of	POS	O
+the	POS	O
+control	POS	O
+value	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+and	POS	O
+ST	POS	O
+-	POS	O
+segment	POS	O
+elevation	POS	O
+from	POS	O
+4	POS	O
+.	POS	O
+7	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+mV	POS	O
+to	POS	O
+2	POS	O
+.	POS	O
+1	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+7	POS	O
+mV	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+at	POS	O
+3	POS	O
+min	POS	O
+after	POS	O
+ISO	POS	O
+infusion	POS	O
+with	POS	O
+stenosis	POS	B-NP
+.	POS	O
+These	POS	O
+data	POS	O
+show	POS	O
+that	POS	O
+CD	POS	O
+-	POS	O
+832	POS	O
+improves	POS	O
+myocardial	POS	B-NP
+ischemia	POS	I-NP
+during	POS	O
+ISO	POS	O
+infusion	POS	O
+with	POS	O
+stenosis	POS	B-NP
+and	POS	O
+suggest	POS	O
+that	POS	O
+the	POS	O
+negative	POS	O
+chronotropic	POS	O
+property	POS	O
+of	POS	O
+CD	POS	O
+-	POS	O
+832	POS	O
+plays	POS	O
+a	POS	O
+major	POS	O
+role	POS	O
+in	POS	O
+the	POS	O
+beneficial	POS	O
+effects	POS	O
+of	POS	O
+CD	POS	O
+-	POS	O
+832	POS	O
+.	POS	O
+The	POS	O
+effect	POS	O
+of	POS	O
+recombinant	POS	O
+human	POS	O
+insulin	POS	O
+-	POS	O
+like	POS	O
+growth	POS	O
+factor	POS	O
+-	POS	O
+I	POS	O
+on	POS	O
+chronic	POS	O
+puromycin	POS	O
+aminonucleoside	POS	O
+nephropathy	POS	B-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+We	POS	O
+recently	POS	O
+demonstrated	POS	O
+that	POS	O
+recombinant	POS	O
+hGH	POS	O
+exacerbates	POS	O
+renal	POS	O
+functional	POS	O
+and	POS	O
+structural	POS	O
+injury	POS	O
+in	POS	O
+chronic	POS	O
+puromycin	POS	O
+aminonucleoside	POS	O
+(	POS	O
+PAN	POS	O
+)	POS	O
+nephropathy	POS	B-NP
+,	POS	O
+an	POS	O
+experimental	POS	O
+model	POS	O
+of	POS	O
+glomerular	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+Therefore	POS	O
+,	POS	O
+we	POS	O
+examined	POS	O
+whether	POS	O
+recombinant	POS	O
+human	POS	O
+(	POS	O
+rh	POS	O
+)	POS	O
+IGF	POS	O
+-	POS	O
+I	POS	O
+is	POS	O
+a	POS	O
+safer	POS	O
+alternative	POS	O
+for	POS	O
+the	POS	O
+treatment	POS	O
+of	POS	O
+growth	POS	B-NP
+failure	POS	I-NP
+in	POS	O
+rats	POS	O
+with	POS	O
+chronic	POS	O
+PAN	POS	O
+nephropathy	POS	B-NP
+.	POS	O
+The	POS	O
+glomerulopathy	POS	B-NP
+was	POS	O
+induced	POS	O
+by	POS	O
+seven	POS	O
+serial	POS	O
+injections	POS	O
+of	POS	O
+PAN	POS	O
+over	POS	O
+12	POS	O
+wk	POS	O
+.	POS	O
+Experimental	POS	O
+animals	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+6	POS	O
+)	POS	O
+received	POS	O
+rhIGF	POS	O
+-	POS	O
+I	POS	O
+,	POS	O
+400	POS	O
+micrograms	POS	O
+/	POS	O
+d	POS	O
+,	POS	O
+whereas	POS	O
+control	POS	O
+rats	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+6	POS	O
+)	POS	O
+received	POS	O
+the	POS	O
+vehicle	POS	O
+.	POS	O
+rhIGF	POS	O
+-	POS	O
+I	POS	O
+improved	POS	O
+weight	POS	O
+gain	POS	O
+by	POS	O
+14	POS	O
+%	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+,	POS	O
+without	POS	O
+altering	POS	O
+hematocrit	POS	O
+or	POS	O
+blood	POS	O
+pressure	POS	O
+in	POS	O
+rats	POS	O
+with	POS	O
+renal	POS	B-NP
+disease	POS	I-NP
+.	POS	O
+Urinary	POS	O
+protein	POS	O
+excretion	POS	O
+was	POS	O
+unaltered	POS	O
+by	POS	O
+rhIGF	POS	O
+-	POS	O
+I	POS	O
+treatment	POS	O
+in	POS	O
+rats	POS	O
+with	POS	O
+chronic	POS	O
+PAN	POS	O
+nephropathy	POS	B-NP
+.	POS	O
+After	POS	O
+12	POS	O
+wk	POS	O
+,	POS	O
+the	POS	O
+inulin	POS	O
+clearance	POS	O
+was	POS	O
+higher	POS	O
+in	POS	O
+rhIGF	POS	O
+-	POS	O
+I	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+,	POS	O
+0	POS	O
+.	POS	O
+48	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+08	POS	O
+versus	POS	O
+0	POS	O
+.	POS	O
+24	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+06	POS	O
+mL	POS	O
+/	POS	O
+min	POS	O
+/	POS	O
+100	POS	O
+g	POS	O
+of	POS	O
+body	POS	O
+weight	POS	O
+in	POS	O
+untreated	POS	O
+PAN	POS	O
+nephropathy	POS	B-NP
+animals	POS	O
+,	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+.	POS	O
+The	POS	O
+improvement	POS	O
+in	POS	O
+GFR	POS	O
+was	POS	O
+not	POS	O
+associated	POS	O
+with	POS	O
+enhanced	POS	O
+glomerular	POS	B-NP
+hypertrophy	POS	I-NP
+or	POS	O
+increased	POS	O
+segmental	POS	O
+glomerulosclerosis	POS	B-NP
+,	POS	O
+tubulointerstitial	POS	B-NP
+injury	POS	I-NP
+,	POS	O
+or	POS	O
+renal	POS	O
+cortical	POS	O
+malondialdehyde	POS	O
+content	POS	O
+.	POS	O
+In	POS	O
+rats	POS	O
+with	POS	O
+PAN	POS	O
+nephropathy	POS	B-NP
+,	POS	O
+administration	POS	O
+of	POS	O
+rhIGF	POS	O
+-	POS	O
+I	POS	O
+increased	POS	O
+IGF	POS	O
+-	POS	O
+I	POS	O
+and	POS	O
+GH	POS	O
+receptor	POS	O
+gene	POS	O
+expression	POS	O
+,	POS	O
+without	POS	O
+altering	POS	O
+the	POS	O
+steady	POS	O
+state	POS	O
+level	POS	O
+of	POS	O
+IGF	POS	O
+-	POS	O
+I	POS	O
+receptor	POS	O
+mRNA	POS	O
+.	POS	O
+In	POS	O
+normal	POS	O
+rats	POS	O
+with	POS	O
+intact	POS	O
+kidneys	POS	O
+,	POS	O
+rhIGF	POS	O
+-	POS	O
+I	POS	O
+administration	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+4	POS	O
+)	POS	O
+did	POS	O
+not	POS	O
+alter	POS	O
+weight	POS	O
+gain	POS	O
+,	POS	O
+blood	POS	O
+pressure	POS	O
+,	POS	O
+proteinuria	POS	B-NP
+,	POS	O
+GFR	POS	O
+,	POS	O
+glomerular	POS	O
+planar	POS	O
+area	POS	O
+,	POS	O
+renal	POS	O
+cortical	POS	O
+malondialdehyde	POS	O
+content	POS	O
+,	POS	O
+or	POS	O
+glomerular	POS	O
+or	POS	O
+tubulointerstitial	POS	B-NP
+damage	POS	I-NP
+,	POS	O
+compared	POS	O
+with	POS	O
+untreated	POS	O
+animals	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+4	POS	O
+)	POS	O
+.	POS	O
+rhIGF	POS	O
+-	POS	O
+I	POS	O
+treatment	POS	O
+reduced	POS	O
+the	POS	O
+steady	POS	O
+state	POS	O
+renal	POS	O
+IGF	POS	O
+-	POS	O
+I	POS	O
+mRNA	POS	O
+level	POS	O
+but	POS	O
+did	POS	O
+not	POS	O
+modify	POS	O
+gene	POS	O
+expression	POS	O
+of	POS	O
+the	POS	O
+IGF	POS	O
+-	POS	O
+I	POS	O
+or	POS	O
+GH	POS	O
+receptors	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+:	POS	O
+1	POS	O
+)	POS	O
+administration	POS	O
+of	POS	O
+rhIGF	POS	O
+-	POS	O
+I	POS	O
+improves	POS	O
+growth	POS	O
+and	POS	O
+GFR	POS	O
+in	POS	O
+rats	POS	O
+with	POS	O
+chronic	POS	O
+PAN	POS	O
+nephropathy	POS	B-NP
+and	POS	O
+2	POS	O
+)	POS	O
+unlike	POS	O
+rhGH	POS	O
+,	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+use	POS	O
+of	POS	O
+rhIGF	POS	O
+-	POS	O
+I	POS	O
+does	POS	O
+not	POS	O
+worsen	POS	O
+renal	POS	O
+functional	POS	O
+and	POS	O
+structural	POS	O
+injury	POS	O
+in	POS	O
+this	POS	O
+disease	POS	O
+model	POS	O
+.	POS	O
+Nefiracetam	POS	O
+(	POS	O
+DM	POS	B-NP
+-	POS	O
+9384	POS	O
+)	POS	O
+reverses	POS	O
+apomorphine	POS	O
+-	POS	O
+induced	POS	O
+amnesia	POS	B-NP
+of	POS	O
+a	POS	O
+passive	POS	O
+avoidance	POS	O
+response	POS	O
+:	POS	O
+delayed	POS	O
+emergence	POS	O
+of	POS	O
+the	POS	O
+memory	POS	O
+retention	POS	O
+effects	POS	O
+.	POS	O
+Nefiracetam	POS	O
+is	POS	O
+a	POS	O
+novel	POS	O
+pyrrolidone	POS	O
+derivative	POS	O
+which	POS	O
+attenuates	POS	O
+scopolamine	POS	O
+-	POS	O
+induced	POS	O
+learning	POS	O
+and	POS	O
+post	POS	O
+-	POS	O
+training	POS	O
+consolidation	POS	O
+deficits	POS	O
+.	POS	O
+Given	POS	O
+that	POS	O
+apomorphine	POS	O
+inhibits	POS	O
+passive	POS	O
+avoidance	POS	O
+retention	POS	O
+when	POS	O
+given	POS	O
+during	POS	O
+training	POS	O
+or	POS	O
+in	POS	O
+a	POS	O
+defined	POS	O
+10	POS	O
+-	POS	O
+12h	POS	O
+post	POS	O
+-	POS	O
+training	POS	O
+period	POS	O
+,	POS	O
+we	POS	O
+evaluated	POS	O
+the	POS	O
+ability	POS	O
+of	POS	O
+nefiracetam	POS	O
+to	POS	O
+attenuate	POS	O
+amnesia	POS	B-NP
+induced	POS	O
+by	POS	O
+dopaminergic	POS	O
+agonism	POS	O
+.	POS	O
+A	POS	O
+step	POS	O
+-	POS	O
+down	POS	O
+passive	POS	O
+avoidance	POS	O
+paradigm	POS	O
+was	POS	O
+employed	POS	O
+and	POS	O
+nefiracetam	POS	O
+(	POS	O
+3	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+and	POS	O
+apomorphine	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+were	POS	O
+given	POS	O
+alone	POS	O
+or	POS	O
+in	POS	O
+combination	POS	O
+during	POS	O
+training	POS	O
+and	POS	O
+at	POS	O
+the	POS	O
+10	POS	O
+-	POS	O
+12h	POS	O
+post	POS	O
+-	POS	O
+training	POS	O
+period	POS	O
+of	POS	O
+consolidation	POS	O
+.	POS	O
+Co	POS	O
+-	POS	O
+administration	POS	O
+of	POS	O
+nefiracetam	POS	O
+and	POS	O
+apomorphine	POS	O
+during	POS	O
+training	POS	O
+or	POS	O
+10h	POS	O
+thereafter	POS	O
+produced	POS	O
+no	POS	O
+significant	POS	O
+anti	POS	O
+-	POS	O
+amnesic	POS	O
+effect	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+administration	POS	O
+of	POS	O
+nefiracetam	POS	O
+during	POS	O
+training	POS	O
+completely	POS	O
+reversed	POS	O
+the	POS	O
+amnesia	POS	B-NP
+induced	POS	O
+by	POS	O
+apomorphine	POS	O
+at	POS	O
+the	POS	O
+10h	POS	O
+post	POS	O
+-	POS	O
+training	POS	O
+time	POS	O
+and	POS	O
+the	POS	O
+converse	POS	O
+was	POS	O
+also	POS	O
+true	POS	O
+.	POS	O
+These	POS	O
+effects	POS	O
+were	POS	O
+not	POS	O
+mediated	POS	O
+by	POS	O
+a	POS	O
+dopaminergic	POS	O
+mechanism	POS	O
+as	POS	O
+nefiracetam	POS	O
+,	POS	O
+at	POS	O
+millimolar	POS	O
+concentrations	POS	O
+,	POS	O
+failed	POS	O
+to	POS	O
+displace	POS	O
+either	POS	O
+[	POS	O
+3H	POS	O
+]	POS	O
+SCH	POS	O
+23390	POS	O
+or	POS	O
+[	POS	O
+3H	POS	O
+]	POS	O
+spiperone	POS	O
+binding	POS	O
+from	POS	O
+D1	POS	O
+or	POS	O
+D2	POS	O
+dopamine	POS	O
+receptor	POS	O
+subtypes	POS	O
+,	POS	O
+respectively	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+suggested	POS	O
+that	POS	O
+nefiracetam	POS	O
+augments	POS	O
+molecular	POS	O
+processes	POS	O
+in	POS	O
+the	POS	O
+early	POS	O
+stages	POS	O
+of	POS	O
+events	POS	O
+which	POS	O
+ultimately	POS	O
+lead	POS	O
+to	POS	O
+consolidation	POS	O
+of	POS	O
+memory	POS	O
+.	POS	O
+Phenytoin	POS	O
+encephalopathy	POS	B-NP
+as	POS	O
+probable	POS	O
+idiosyncratic	POS	O
+reaction	POS	O
+:	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+phenytoin	POS	O
+(	POS	O
+DPH	POS	O
+)	POS	O
+encephalopathy	POS	B-NP
+with	POS	O
+increasing	POS	O
+seizures	POS	B-NP
+and	POS	O
+EEG	POS	O
+and	POS	O
+mental	POS	O
+changes	POS	O
+is	POS	O
+described	POS	O
+.	POS	O
+Despite	POS	O
+adequate	POS	O
+oral	POS	O
+dosage	POS	O
+of	POS	O
+DPH	POS	O
+(	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+/	POS	O
+daily	POS	O
+)	POS	O
+the	POS	O
+plasma	POS	O
+level	POS	O
+was	POS	O
+very	POS	O
+low	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+8	POS	O
+microgramg	POS	O
+/	POS	O
+ml	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+encephalopathy	POS	B-NP
+was	POS	O
+probably	POS	O
+an	POS	O
+idiosyncratic	POS	O
+and	POS	O
+not	POS	O
+toxic	POS	O
+or	POS	O
+allergic	POS	B-NP
+reaction	POS	I-NP
+.	POS	O
+In	POS	O
+fact	POS	O
+the	POS	O
+concentration	POS	O
+of	POS	O
+free	POS	O
+DPH	POS	O
+was	POS	O
+normal	POS	O
+,	POS	O
+the	POS	O
+patient	POS	O
+presented	POS	O
+a	POS	O
+retarded	POS	O
+morbilliform	POS	B-NP
+rash	POS	I-NP
+during	POS	O
+DPH	POS	B-NP
+treatment	POS	O
+,	POS	O
+the	POS	O
+protidogram	POS	O
+was	POS	O
+normal	POS	O
+,	POS	O
+and	POS	O
+an	POS	O
+intradermic	POS	O
+DPH	POS	O
+injection	POS	O
+had	POS	O
+no	POS	O
+local	POS	O
+effect	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+conclude	POS	O
+that	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+starting	POS	O
+DPH	POS	O
+treatment	POS	O
+an	POS	O
+unexpected	POS	O
+increase	POS	O
+in	POS	O
+seizures	POS	B-NP
+,	POS	O
+with	POS	O
+EEG	POS	O
+and	POS	O
+mental	POS	O
+changes	POS	O
+occurring	POS	O
+simultaneously	POS	O
+,	POS	O
+should	POS	O
+alert	POS	O
+the	POS	O
+physician	POS	O
+to	POS	O
+the	POS	O
+possible	POS	O
+need	POS	O
+for	POS	O
+eliminating	POS	O
+DPH	POS	O
+from	POS	O
+the	POS	O
+therapeutic	POS	O
+regimen	POS	O
+,	POS	O
+even	POS	O
+if	POS	O
+plasma	POS	O
+concentrations	POS	O
+are	POS	O
+low	POS	O
+.	POS	O
+Prevention	POS	O
+and	POS	O
+treatment	POS	O
+of	POS	O
+endometrial	POS	B-NP
+disease	POS	I-NP
+in	POS	O
+climacteric	POS	B-NP
+women	POS	O
+receiving	POS	O
+oestrogen	POS	O
+therapy	POS	O
+.	POS	O
+The	POS	O
+treatment	POS	O
+regimens	POS	O
+are	POS	O
+described	POS	O
+in	POS	O
+74	POS	O
+patients	POS	O
+with	POS	O
+endometrial	POS	B-NP
+disease	POS	I-NP
+among	POS	O
+850	POS	O
+climacteric	POS	B-NP
+women	POS	O
+receiving	POS	O
+oestrogen	POS	O
+therapy	POS	O
+.	POS	O
+Cystic	POS	B-NP
+hyperplasia	POS	I-NP
+was	POS	O
+associated	POS	O
+with	POS	O
+unopposed	POS	O
+oestrogen	POS	O
+therapy	POS	O
+without	POS	O
+progestagen	POS	O
+.	POS	O
+Two	POS	O
+courses	POS	O
+of	POS	O
+21	POS	O
+days	POS	O
+of	POS	O
+5	POS	O
+mg	POS	O
+norethisterone	POS	O
+daily	POS	O
+caused	POS	O
+reversion	POS	O
+to	POS	O
+normal	POS	O
+in	POS	O
+all	POS	O
+57	POS	O
+cases	POS	O
+of	POS	O
+cystic	POS	B-NP
+hyperplasia	POS	I-NP
+and	POS	O
+6	POS	O
+of	POS	O
+the	POS	O
+8	POS	O
+cases	POS	O
+of	POS	O
+atypical	POS	O
+hyperplasia	POS	B-NP
+.	POS	O
+4	POS	O
+cases	POS	O
+of	POS	O
+endometrial	POS	B-NP
+carcinoma	POS	I-NP
+referred	POS	O
+from	POS	O
+elsewhere	POS	O
+demonstrated	POS	O
+the	POS	O
+problems	POS	O
+of	POS	O
+inappropriate	POS	O
+and	POS	O
+unsupervised	POS	O
+unopposed	POS	O
+oestrogen	POS	O
+therapy	POS	O
+and	POS	O
+the	POS	O
+difficulty	POS	O
+in	POS	O
+distinguishing	POS	O
+severe	POS	O
+hyperplasia	POS	B-NP
+from	POS	O
+malignancy	POS	B-NP
+.	POS	O
+Cyclical	POS	O
+low	POS	O
+-	POS	O
+dose	POS	O
+oestrogen	POS	O
+therapy	POS	O
+with	POS	O
+7	POS	O
+-	POS	O
+-	POS	O
+13	POS	O
+days	POS	O
+of	POS	O
+progestagen	POS	O
+does	POS	O
+not	POS	O
+seem	POS	O
+to	POS	O
+increase	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+endometrial	POS	B-NP
+hyperplasia	POS	I-NP
+or	POS	O
+carcinoma	POS	B-NP
+.	POS	O
+Effects	POS	O
+of	POS	O
+exercise	POS	O
+on	POS	O
+the	POS	O
+severity	POS	O
+of	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+.	POS	O
+The	POS	O
+effect	POS	O
+of	POS	O
+exercise	POS	O
+on	POS	O
+the	POS	O
+severity	POS	O
+of	POS	O
+isoproterenol	POS	O
+-	POS	O
+induced	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+was	POS	O
+studied	POS	O
+in	POS	O
+male	POS	O
+rats	POS	O
+.	POS	O
+Ninety	POS	O
+-	POS	O
+three	POS	O
+rats	POS	O
+were	POS	O
+randomly	POS	O
+divided	POS	O
+into	POS	O
+three	POS	O
+groups	POS	O
+.	POS	O
+The	POS	O
+exercise	POS	O
+-	POS	O
+isoproterenol	POS	O
+(	POS	O
+E	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+and	POS	O
+exercise	POS	O
+control	POS	O
+(	POS	O
+EC	POS	O
+)	POS	O
+groups	POS	O
+exercised	POS	O
+daily	POS	O
+for	POS	O
+thirty	POS	O
+days	POS	O
+on	POS	O
+a	POS	O
+treadmill	POS	O
+at	POS	O
+1	POS	O
+mph	POS	O
+,	POS	O
+2	POS	O
+%	POS	O
+grade	POS	O
+while	POS	O
+animals	POS	O
+of	POS	O
+the	POS	O
+sedentary	POS	O
+-	POS	O
+isoproterenol	POS	O
+(	POS	O
+S	POS	O
+-	POS	O
+I	POS	O
+)	POS	O
+group	POS	O
+remained	POS	O
+sedentary	POS	O
+.	POS	O
+Eight	POS	O
+animals	POS	O
+were	POS	O
+assigned	POS	O
+to	POS	O
+the	POS	O
+sedentary	POS	O
+control	POS	O
+(	POS	O
+SC	POS	O
+)	POS	O
+group	POS	O
+which	POS	O
+remained	POS	O
+sedentary	POS	O
+throughout	POS	O
+the	POS	O
+experimental	POS	O
+period	POS	O
+.	POS	O
+Forty	POS	O
+-	POS	O
+eight	POS	O
+hours	POS	O
+after	POS	O
+the	POS	O
+final	POS	O
+exercise	POS	O
+period	POS	O
+,	POS	O
+S	POS	O
+-	POS	O
+I	POS	O
+and	POS	O
+E	POS	O
+-	POS	O
+I	POS	O
+animals	POS	O
+received	POS	O
+a	POS	O
+single	POS	O
+subcutaneous	POS	O
+injection	POS	O
+of	POS	O
+isoproterenol	POS	O
+(	POS	O
+250	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+body	POS	O
+weight	POS	O
+)	POS	O
+.	POS	O
+Animals	POS	O
+of	POS	O
+the	POS	O
+S	POS	O
+-	POS	O
+I	POS	O
+group	POS	O
+exhibited	POS	O
+significantly	POS	O
+(	POS	O
+Pp	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+greater	POS	O
+mortality	POS	O
+from	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+isoproterenol	POS	O
+than	POS	O
+animals	POS	O
+of	POS	O
+the	POS	O
+E	POS	O
+-	POS	O
+I	POS	O
+group	POS	O
+.	POS	O
+Serum	POS	O
+CPK	POS	O
+activity	POS	O
+for	POS	O
+E	POS	O
+-	POS	O
+I	POS	O
+animals	POS	O
+was	POS	O
+significantly	POS	O
+(	POS	O
+p	POS	O
+less	POS	O
+than	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+greater	POS	O
+than	POS	O
+for	POS	O
+animals	POS	O
+in	POS	O
+the	POS	O
+S	POS	O
+-	POS	O
+I	POS	O
+and	POS	O
+EC	POS	O
+groups	POS	O
+twenty	POS	O
+hours	POS	O
+following	POS	O
+isoproterenol	POS	O
+injection	POS	O
+.	POS	O
+No	POS	O
+statistically	POS	O
+significant	POS	O
+differences	POS	O
+were	POS	O
+observed	POS	O
+between	POS	O
+the	POS	O
+two	POS	O
+isoproterenol	POS	O
+treated	POS	O
+groups	POS	O
+for	POS	O
+severity	POS	O
+of	POS	O
+the	POS	O
+induced	POS	O
+lesions	POS	B-NP
+,	POS	O
+changes	POS	O
+in	POS	O
+heart	POS	O
+weight	POS	O
+,	POS	O
+or	POS	O
+heart	POS	O
+weight	POS	O
+to	POS	O
+body	POS	O
+weight	POS	O
+ratios	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+indicated	POS	O
+that	POS	O
+exercise	POS	O
+reduced	POS	O
+the	POS	O
+mortality	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+effects	POS	O
+of	POS	O
+large	POS	O
+dosages	POS	O
+of	POS	O
+isoproterenol	POS	O
+but	POS	O
+had	POS	O
+little	POS	O
+on	POS	O
+the	POS	O
+severity	POS	O
+of	POS	O
+the	POS	O
+infarction	POS	B-NP
+.	POS	O
+Human	POS	O
+corticotropin	POS	O
+-	POS	O
+releasing	POS	O
+hormone	POS	O
+and	POS	O
+thyrotropin	POS	O
+-	POS	O
+releasing	POS	O
+hormone	POS	O
+modulate	POS	O
+the	POS	O
+hypercapnic	POS	O
+ventilatory	POS	O
+response	POS	O
+in	POS	O
+humans	POS	O
+.	POS	O
+Human	POS	O
+corticotropin	POS	O
+-	POS	O
+releasing	POS	O
+hormone	POS	O
+(	POS	O
+hCRH	POS	O
+)	POS	O
+and	POS	O
+thyrotropin	POS	O
+-	POS	O
+releasing	POS	O
+hormone	POS	O
+(	POS	O
+TRH	POS	O
+)	POS	O
+are	POS	O
+known	POS	O
+to	POS	O
+stimulate	POS	O
+ventilation	POS	O
+after	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+administration	POS	O
+in	POS	O
+humans	POS	O
+.	POS	O
+In	POS	O
+a	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+,	POS	O
+single	POS	O
+-	POS	O
+blind	POS	O
+study	POS	O
+we	POS	O
+aimed	POS	O
+to	POS	O
+clarify	POS	O
+if	POS	O
+both	POS	O
+peptides	POS	O
+act	POS	O
+by	POS	O
+altering	POS	O
+central	POS	O
+chemosensitivity	POS	O
+.	POS	O
+Two	POS	O
+subsequent	POS	O
+CO2	POS	O
+-	POS	O
+rebreathing	POS	O
+tests	POS	O
+were	POS	O
+performed	POS	O
+in	POS	O
+healthy	POS	O
+young	POS	O
+volunteers	POS	O
+.	POS	O
+During	POS	O
+the	POS	O
+first	POS	O
+test	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+NaCl	POS	O
+was	POS	O
+given	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+;	POS	O
+during	POS	O
+the	POS	O
+second	POS	O
+test	POS	O
+200	POS	O
+micrograms	POS	O
+of	POS	O
+hCRH	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+12	POS	O
+)	POS	O
+or	POS	O
+400	POS	O
+micrograms	POS	O
+of	POS	O
+TRH	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+6	POS	O
+)	POS	O
+was	POS	O
+administered	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+Nine	POS	O
+subjects	POS	O
+received	POS	O
+0	POS	O
+.	POS	O
+9	POS	O
+%	POS	O
+NaCl	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+during	POS	O
+both	POS	O
+rebreathing	POS	O
+manoeuvres	POS	O
+.	POS	O
+The	POS	O
+CO2	POS	O
+-	POS	O
+response	POS	O
+curves	POS	O
+for	POS	O
+the	POS	O
+two	POS	O
+tests	POS	O
+were	POS	O
+compared	POS	O
+within	POS	O
+the	POS	O
+same	POS	O
+subject	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+hCRH	POS	O
+group	POS	O
+a	POS	O
+marked	POS	O
+parallel	POS	O
+shift	POS	O
+of	POS	O
+the	POS	O
+CO2	POS	O
+-	POS	O
+response	POS	O
+curve	POS	O
+to	POS	O
+the	POS	O
+left	POS	O
+was	POS	O
+observed	POS	O
+after	POS	O
+hCRH	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+same	POS	O
+effect	POS	O
+occurred	POS	O
+following	POS	O
+TRH	POS	O
+but	POS	O
+was	POS	O
+less	POS	O
+striking	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+hCRH	POS	O
+and	POS	O
+TRH	POS	O
+caused	POS	O
+a	POS	O
+reduction	POS	O
+in	POS	O
+the	POS	O
+CO2	POS	O
+threshold	POS	O
+.	POS	O
+The	POS	O
+CO2	POS	O
+-	POS	O
+response	POS	O
+curves	POS	O
+in	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+were	POS	O
+nearly	POS	O
+identical	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+indicate	POS	O
+an	POS	O
+additive	POS	O
+effect	POS	O
+of	POS	O
+both	POS	O
+releasing	POS	O
+hormones	POS	O
+on	POS	O
+the	POS	O
+hypercapnic	POS	O
+ventilatory	POS	O
+response	POS	O
+in	POS	O
+humans	POS	O
+,	POS	O
+presumably	POS	O
+independent	POS	O
+of	POS	O
+central	POS	O
+chemosensitivity	POS	O
+.	POS	O
+Lamivudine	POS	O
+is	POS	O
+effective	POS	O
+in	POS	O
+suppressing	POS	O
+hepatitis	POS	O
+B	POS	O
+virus	POS	O
+DNA	POS	O
+in	POS	O
+Chinese	POS	O
+hepatitis	POS	O
+B	POS	O
+surface	POS	O
+antigen	POS	O
+carriers	POS	O
+:	POS	O
+a	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+trial	POS	O
+.	POS	O
+Lamivudine	POS	O
+is	POS	O
+a	POS	O
+novel	POS	O
+2	POS	O
+'	POS	O
+,	POS	O
+3	POS	O
+'	POS	O
+-	POS	O
+dideoxy	POS	O
+cytosine	POS	O
+analogue	POS	O
+that	POS	O
+has	POS	O
+potent	POS	O
+inhibitory	POS	O
+effects	POS	O
+on	POS	O
+hepatitis	POS	O
+B	POS	O
+virus	POS	O
+replication	POS	O
+in	POS	O
+vitro	POS	O
+and	POS	O
+in	POS	O
+vivo	POS	O
+.	POS	O
+We	POS	O
+performed	POS	O
+a	POS	O
+single	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+placebo	POS	O
+-	POS	O
+controlled	POS	O
+study	POS	O
+to	POS	O
+assess	POS	O
+its	POS	O
+effectiveness	POS	O
+and	POS	O
+safety	POS	O
+in	POS	O
+Chinese	POS	O
+hepatitis	POS	O
+B	POS	O
+surface	POS	O
+antigen	POS	O
+(	POS	O
+HBsAg	POS	O
+)	POS	O
+carriers	POS	O
+.	POS	O
+Forty	POS	O
+-	POS	O
+two	POS	O
+Chinese	POS	O
+HBsAg	POS	O
+carriers	POS	O
+were	POS	O
+randomized	POS	O
+to	POS	O
+receive	POS	O
+placebo	POS	O
+(	POS	O
+6	POS	O
+patients	POS	O
+)	POS	O
+or	POS	O
+lamivudine	POS	O
+orally	POS	O
+in	POS	O
+dosages	POS	O
+of	POS	O
+25	POS	O
+mg	POS	O
+,	POS	O
+100	POS	O
+mg	POS	O
+,	POS	O
+or	POS	O
+300	POS	O
+mg	POS	O
+daily	POS	O
+(	POS	O
+12	POS	O
+patients	POS	O
+for	POS	O
+each	POS	O
+dosage	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+drug	POS	O
+was	POS	O
+given	POS	O
+for	POS	O
+4	POS	O
+weeks	POS	O
+.	POS	O
+The	POS	O
+patients	POS	O
+were	POS	O
+closely	POS	O
+monitored	POS	O
+clinically	POS	O
+,	POS	O
+biochemically	POS	O
+,	POS	O
+and	POS	O
+serologically	POS	O
+up	POS	O
+to	POS	O
+4	POS	O
+weeks	POS	O
+after	POS	O
+drug	POS	O
+treatment	POS	O
+.	POS	O
+All	POS	O
+36	POS	O
+patients	POS	O
+receiving	POS	O
+lamivudine	POS	O
+had	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+hepatitis	POS	B-NP
+B	POS	I-NP
+virus	POS	O
+(	POS	O
+HBV	POS	O
+)	POS	O
+DNA	POS	O
+values	POS	O
+of	POS	O
+>	POS	O
+90	POS	O
+%	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+.	POS	O
+001	POS	O
+compared	POS	O
+with	POS	O
+placebo	POS	O
+)	POS	O
+.	POS	O
+Although	POS	O
+25	POS	O
+mg	POS	O
+of	POS	O
+lamivudine	POS	O
+was	POS	O
+slightly	POS	O
+less	POS	O
+effective	POS	O
+than	POS	O
+100	POS	O
+mg	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+011	POS	O
+)	POS	O
+and	POS	O
+300	POS	O
+mg	POS	O
+(	POS	O
+P	POS	O
+=	POS	O
+.	POS	O
+005	POS	O
+)	POS	O
+,	POS	O
+it	POS	O
+still	POS	O
+induced	POS	O
+94	POS	O
+%	POS	O
+suppression	POS	O
+of	POS	O
+HBV	POS	O
+DNA	POS	O
+after	POS	O
+the	POS	O
+fourth	POS	O
+week	POS	O
+of	POS	O
+therapy	POS	O
+.	POS	O
+HBV	POS	O
+DNA	POS	O
+values	POS	O
+returned	POS	O
+to	POS	O
+pretreatment	POS	O
+levels	POS	O
+within	POS	O
+4	POS	O
+weeks	POS	O
+of	POS	O
+cessation	POS	O
+of	POS	O
+therapy	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+change	POS	O
+in	POS	O
+the	POS	O
+hepatitis	POS	O
+B	POS	O
+e	POS	O
+antigen	POS	O
+status	POS	O
+or	POS	O
+in	POS	O
+aminotransferase	POS	O
+levels	POS	O
+.	POS	O
+No	POS	O
+serious	POS	O
+adverse	POS	O
+events	POS	O
+were	POS	O
+observed	POS	O
+.	POS	O
+In	POS	O
+conclusion	POS	O
+,	POS	O
+a	POS	O
+4	POS	O
+-	POS	O
+week	POS	O
+course	POS	O
+of	POS	O
+lamivudine	POS	O
+was	POS	O
+safe	POS	O
+and	POS	O
+effective	POS	O
+in	POS	O
+suppression	POS	O
+of	POS	O
+HBV	POS	O
+DNA	POS	O
+in	POS	O
+Chinese	POS	O
+HBsAg	POS	O
+carriers	POS	O
+.	POS	O
+The	POS	O
+suppression	POS	O
+was	POS	O
+>	POS	O
+90	POS	O
+%	POS	O
+but	POS	O
+reversible	POS	O
+.	POS	O
+Studies	POS	O
+with	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+lamivudine	POS	O
+administration	POS	O
+should	POS	O
+be	POS	O
+performed	POS	O
+to	POS	O
+determine	POS	O
+if	POS	O
+prolonged	POS	O
+suppression	POS	O
+of	POS	O
+HBV	POS	O
+DNA	POS	O
+can	POS	O
+be	POS	O
+achieved	POS	O
+.	POS	O
+Population	POS	O
+-	POS	O
+based	POS	O
+study	POS	O
+of	POS	O
+risk	POS	O
+of	POS	O
+venous	POS	B-NP
+thromboembolism	POS	I-NP
+associated	POS	O
+with	POS	O
+various	POS	O
+oral	POS	O
+contraceptives	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+Four	POS	O
+studies	POS	O
+published	POS	O
+since	POS	O
+December	POS	O
+,	POS	O
+1995	POS	O
+,	POS	O
+reported	POS	O
+that	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+venous	POS	B-NP
+thromboembolism	POS	I-NP
+(	POS	O
+VTE	POS	B-NP
+)	POS	O
+was	POS	O
+higher	POS	O
+in	POS	O
+women	POS	O
+who	POS	O
+used	POS	O
+oral	POS	O
+contraceptives	POS	O
+(	POS	O
+OCs	POS	O
+)	POS	O
+containing	POS	O
+the	POS	O
+third	POS	O
+-	POS	O
+generation	POS	O
+progestagens	POS	O
+gestodene	POS	O
+or	POS	O
+desogestrel	POS	O
+than	POS	O
+in	POS	O
+users	POS	O
+of	POS	O
+OCs	POS	O
+containing	POS	O
+second	POS	O
+-	POS	O
+generation	POS	O
+progestagens	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+confounding	POS	O
+and	POS	O
+bias	POS	O
+in	POS	O
+the	POS	O
+design	POS	O
+of	POS	O
+these	POS	O
+studies	POS	O
+may	POS	O
+have	POS	O
+affected	POS	O
+the	POS	O
+findings	POS	O
+.	POS	O
+The	POS	O
+aim	POS	O
+of	POS	O
+our	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+re	POS	O
+-	POS	O
+examine	POS	O
+the	POS	O
+association	POS	O
+between	POS	O
+risk	POS	O
+of	POS	O
+VTE	POS	B-NP
+and	POS	O
+OC	POS	O
+use	POS	O
+with	POS	O
+a	POS	O
+different	POS	O
+study	POS	O
+design	POS	O
+and	POS	O
+analysis	POS	O
+to	POS	O
+avoid	POS	O
+some	POS	O
+of	POS	O
+the	POS	O
+bias	POS	O
+and	POS	O
+confounding	POS	O
+of	POS	O
+the	POS	O
+earlier	POS	O
+studies	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+We	POS	O
+used	POS	O
+computer	POS	O
+records	POS	O
+of	POS	O
+patients	POS	O
+from	POS	O
+143	POS	O
+general	POS	O
+practices	POS	O
+in	POS	O
+the	POS	O
+UK	POS	O
+.	POS	O
+The	POS	O
+study	POS	O
+was	POS	O
+based	POS	O
+on	POS	O
+the	POS	O
+medical	POS	O
+records	POS	O
+of	POS	O
+about	POS	O
+540	POS	O
+,	POS	O
+000	POS	O
+women	POS	O
+born	POS	O
+between	POS	O
+1941	POS	O
+and	POS	O
+1981	POS	O
+.	POS	O
+All	POS	O
+women	POS	O
+who	POS	O
+had	POS	O
+a	POS	O
+recorded	POS	O
+diagnosis	POS	O
+of	POS	O
+deep	POS	B-NP
+-	POS	I-NP
+vein	POS	I-NP
+thrombosis	POS	I-NP
+,	POS	O
+venous	POS	B-NP
+thrombosis	POS	I-NP
+not	POS	O
+otherwise	POS	O
+specified	POS	O
+,	POS	O
+or	POS	O
+pulmonary	POS	B-NP
+embolus	POS	I-NP
+during	POS	O
+the	POS	O
+study	POS	O
+period	POS	O
+,	POS	O
+and	POS	O
+who	POS	O
+had	POS	O
+been	POS	O
+treated	POS	O
+with	POS	O
+an	POS	O
+anticoagulant	POS	O
+were	POS	O
+identified	POS	O
+as	POS	O
+potential	POS	O
+cases	POS	O
+of	POS	O
+VTE	POS	B-NP
+.	POS	O
+We	POS	O
+did	POS	O
+a	POS	O
+cohort	POS	O
+analysis	POS	O
+to	POS	O
+estimate	POS	O
+and	POS	O
+compare	POS	O
+incidence	POS	O
+of	POS	O
+VTE	POS	B-NP
+in	POS	O
+users	POS	O
+of	POS	O
+the	POS	O
+main	POS	O
+OC	POS	O
+preparations	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+nested	POS	O
+case	POS	O
+-	POS	O
+control	POS	O
+study	POS	O
+to	POS	O
+calculate	POS	O
+the	POS	O
+odds	POS	O
+ratios	POS	O
+of	POS	O
+VTE	POS	B-NP
+associated	POS	O
+with	POS	O
+use	POS	O
+of	POS	O
+different	POS	O
+types	POS	O
+of	POS	O
+OC	POS	O
+,	POS	O
+after	POS	O
+adjustment	POS	O
+for	POS	O
+potential	POS	O
+confounding	POS	O
+factors	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+case	POS	O
+-	POS	O
+control	POS	O
+study	POS	O
+,	POS	O
+we	POS	O
+matched	POS	O
+cases	POS	O
+to	POS	O
+controls	POS	O
+by	POS	O
+exact	POS	O
+year	POS	O
+of	POS	O
+birth	POS	O
+,	POS	O
+practice	POS	O
+,	POS	O
+and	POS	O
+current	POS	O
+use	POS	O
+of	POS	O
+OCs	POS	O
+.	POS	O
+We	POS	O
+used	POS	O
+a	POS	O
+multiple	POS	O
+logistic	POS	O
+regression	POS	O
+model	POS	O
+that	POS	O
+included	POS	O
+body	POS	O
+-	POS	O
+mass	POS	O
+index	POS	O
+,	POS	O
+number	POS	O
+of	POS	O
+cycles	POS	O
+,	POS	O
+change	POS	O
+in	POS	O
+type	POS	O
+of	POS	O
+OC	POS	O
+prescribed	POS	O
+within	POS	O
+3	POS	O
+months	POS	O
+of	POS	O
+the	POS	O
+event	POS	O
+,	POS	O
+previous	POS	O
+pregnancy	POS	O
+,	POS	O
+and	POS	O
+concurrent	POS	O
+disease	POS	O
+.	POS	O
+FINDINGS	POS	O
+:	POS	O
+85	POS	O
+women	POS	O
+met	POS	O
+the	POS	O
+inclusion	POS	O
+criteria	POS	O
+for	POS	O
+VTE	POS	B-NP
+,	POS	O
+two	POS	O
+of	POS	O
+whom	POS	O
+were	POS	O
+users	POS	O
+of	POS	O
+progestagen	POS	O
+-	POS	O
+only	POS	O
+OCs	POS	O
+.	POS	O
+Of	POS	O
+the	POS	O
+83	POS	O
+cases	POS	O
+of	POS	O
+VTE	POS	B-NP
+associated	POS	O
+with	POS	O
+use	POS	O
+of	POS	O
+combined	POS	O
+OCs	POS	O
+,	POS	O
+43	POS	O
+were	POS	O
+recorded	POS	O
+as	POS	O
+deep	POS	B-NP
+-	POS	I-NP
+vein	POS	I-NP
+thrombosis	POS	I-NP
+,	POS	O
+35	POS	O
+as	POS	O
+pulmonary	POS	B-NP
+thrombosis	POS	I-NP
+,	POS	O
+and	POS	O
+five	POS	O
+as	POS	O
+venous	POS	B-NP
+thrombosis	POS	I-NP
+not	POS	O
+otherwise	POS	O
+specified	POS	O
+.	POS	O
+The	POS	O
+crude	POS	O
+rate	POS	O
+of	POS	O
+VTE	POS	B-NP
+per	POS	O
+10	POS	O
+,	POS	O
+000	POS	O
+woman	POS	O
+-	POS	O
+years	POS	O
+was	POS	O
+4	POS	O
+.	POS	O
+10	POS	O
+in	POS	O
+current	POS	O
+users	POS	O
+of	POS	O
+any	POS	O
+OC	POS	O
+,	POS	O
+3	POS	O
+.	POS	O
+10	POS	O
+in	POS	O
+users	POS	O
+of	POS	O
+second	POS	O
+-	POS	O
+generation	POS	O
+OCs	POS	O
+,	POS	O
+and	POS	O
+4	POS	O
+.	POS	O
+96	POS	O
+in	POS	O
+users	POS	O
+of	POS	O
+third	POS	O
+-	POS	O
+generation	POS	O
+preparations	POS	O
+.	POS	O
+After	POS	O
+adjustment	POS	O
+for	POS	O
+age	POS	O
+,	POS	O
+the	POS	O
+rate	POS	O
+ratio	POS	O
+of	POS	O
+VTE	POS	B-NP
+in	POS	O
+users	POS	O
+of	POS	O
+third	POS	O
+-	POS	O
+generation	POS	O
+relative	POS	O
+to	POS	O
+second	POS	O
+-	POS	O
+generation	POS	O
+OCs	POS	O
+was	POS	O
+1	POS	O
+.	POS	O
+68	POS	O
+(	POS	O
+95	POS	O
+%	POS	O
+CI	POS	O
+1	POS	O
+.	POS	O
+04	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+75	POS	O
+)	POS	O
+.	POS	O
+Logistic	POS	O
+regression	POS	O
+showed	POS	O
+no	POS	O
+significant	POS	O
+difference	POS	O
+in	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+VTE	POS	B-NP
+between	POS	O
+users	POS	O
+of	POS	O
+third	POS	O
+-	POS	O
+generation	POS	O
+and	POS	O
+second	POS	O
+-	POS	O
+generation	POS	O
+OCs	POS	O
+.	POS	O
+Among	POS	O
+users	POS	O
+of	POS	O
+third	POS	O
+-	POS	O
+generation	POS	O
+progestagens	POS	O
+,	POS	O
+the	POS	O
+risk	POS	O
+of	POS	O
+VTE	POS	B-NP
+was	POS	O
+higher	POS	O
+in	POS	O
+users	POS	O
+of	POS	O
+desogestrel	POS	O
+with	POS	O
+20	POS	O
+g	POS	O
+ethinyloestradiol	POS	O
+than	POS	O
+in	POS	O
+users	POS	O
+of	POS	O
+gestodene	POS	O
+or	POS	O
+desogestrel	POS	O
+with	POS	O
+30	POS	O
+g	POS	O
+ethinyloestradiol	POS	O
+.	POS	O
+With	POS	O
+all	POS	O
+second	POS	O
+-	POS	O
+generation	POS	O
+OCs	POS	O
+as	POS	O
+the	POS	O
+reference	POS	O
+,	POS	O
+the	POS	O
+odds	POS	O
+ratios	POS	O
+for	POS	O
+VTE	POS	B-NP
+were	POS	O
+3	POS	O
+.	POS	O
+49	POS	O
+(	POS	O
+1	POS	O
+.	POS	O
+21	POS	O
+-	POS	O
+10	POS	O
+.	POS	O
+12	POS	O
+)	POS	O
+for	POS	O
+desogestrel	POS	O
+plus	POS	O
+20	POS	O
+g	POS	O
+ethinyloestradiol	POS	O
+and	POS	O
+1	POS	O
+.	POS	O
+18	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+66	POS	O
+-	POS	O
+2	POS	O
+.	POS	O
+17	POS	O
+)	POS	O
+for	POS	O
+the	POS	O
+other	POS	O
+third	POS	O
+-	POS	O
+generation	POS	O
+progestagens	POS	O
+.	POS	O
+INTERPRETATION	POS	O
+:	POS	O
+The	POS	O
+previously	POS	O
+reported	POS	O
+increase	POS	O
+in	POS	O
+odds	POS	O
+ratio	POS	O
+associated	POS	O
+with	POS	O
+third	POS	O
+-	POS	O
+generation	POS	O
+OCs	POS	O
+when	POS	O
+compared	POS	O
+with	POS	O
+second	POS	O
+-	POS	O
+generation	POS	O
+products	POS	O
+is	POS	O
+likely	POS	O
+to	POS	O
+have	POS	O
+been	POS	O
+the	POS	O
+result	POS	O
+of	POS	O
+residual	POS	O
+confounding	POS	O
+by	POS	O
+age	POS	O
+.	POS	O
+The	POS	O
+increased	POS	O
+odds	POS	O
+ratio	POS	O
+associated	POS	O
+with	POS	O
+products	POS	O
+containing	POS	O
+20	POS	O
+micrograms	POS	O
+ethinyloestradiol	POS	O
+and	POS	O
+desogestrel	POS	O
+compared	POS	O
+with	POS	O
+the	POS	O
+30	POS	O
+micrograms	POS	O
+product	POS	O
+is	POS	O
+biologically	POS	O
+implausible	POS	O
+,	POS	O
+and	POS	O
+is	POS	O
+likely	POS	O
+to	POS	O
+be	POS	O
+the	POS	O
+result	POS	O
+of	POS	O
+preferential	POS	O
+prescribing	POS	O
+and	POS	O
+,	POS	O
+thus	POS	O
+,	POS	O
+confounding	POS	O
+.	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+augments	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+electrographic	POS	O
+seizure	POS	B-NP
+but	POS	O
+protects	POS	O
+against	POS	O
+brain	POS	B-NP
+damage	POS	I-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+1	POS	O
+.	POS	O
+The	POS	O
+authors	POS	O
+examined	POS	O
+the	POS	O
+anticonvulsant	POS	O
+effects	POS	O
+of	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+on	POS	O
+the	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+seizure	POS	B-NP
+model	POS	O
+.	POS	O
+Intraperitoneal	POS	O
+injection	POS	O
+of	POS	O
+pilocarpine	POS	O
+(	POS	O
+400	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+induced	POS	O
+tonic	POS	O
+and	POS	O
+clonic	POS	B-NP
+seizure	POS	B-NP
+.	POS	O
+Scopolamine	POS	O
+(	POS	O
+10	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+and	POS	O
+pentobarbital	POS	O
+(	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+prevented	POS	O
+development	POS	O
+of	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+behavioral	POS	O
+seizure	POS	B-NP
+but	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+)	POS	O
+did	POS	O
+not	POS	O
+.	POS	O
+2	POS	O
+.	POS	O
+An	POS	O
+electrical	POS	O
+seizure	POS	B-NP
+measured	POS	O
+with	POS	O
+hippocampal	POS	O
+EEG	POS	O
+appeared	POS	O
+in	POS	O
+the	POS	O
+pilocarpine	POS	O
+-	POS	O
+treated	POS	O
+group	POS	O
+.	POS	O
+Scopolamine	POS	O
+and	POS	O
+pentobarbital	POS	O
+blocked	POS	O
+the	POS	O
+pilocarpine	POS	O
+-	POS	O
+induced	POS	O
+electrographic	POS	B-NP
+seizure	POS	I-NP
+,	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+treatment	POS	O
+augmented	POS	O
+the	POS	O
+electrographic	POS	O
+seizure	POS	B-NP
+induced	POS	O
+by	POS	O
+pilocarpine	POS	O
+.	POS	O
+3	POS	O
+.	POS	O
+Brain	POS	B-NP
+damage	POS	I-NP
+was	POS	O
+assessed	POS	O
+by	POS	O
+examining	POS	O
+the	POS	O
+hippocampus	POS	O
+microscopically	POS	O
+.	POS	O
+Pilocarpine	POS	O
+produced	POS	O
+neuronal	POS	O
+death	POS	O
+in	POS	O
+the	POS	O
+hippocampus	POS	O
+,	POS	O
+which	POS	O
+showed	POS	O
+pyknotic	POS	O
+changes	POS	O
+.	POS	O
+Pentobarbital	POS	O
+,	POS	O
+scopolamine	POS	O
+and	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+protected	POS	O
+the	POS	O
+brain	POS	O
+damage	POS	O
+by	POS	O
+pilocarpine	POS	O
+,	POS	O
+though	POS	O
+in	POS	O
+the	POS	O
+MK	POS	O
+-	POS	O
+801	POS	O
+-	POS	O
+treated	POS	O
+group	POS	O
+,	POS	O
+the	POS	O
+pyramidal	POS	O
+cells	POS	O
+of	POS	O
+hippocampus	POS	O
+appeared	POS	O
+darker	POS	O
+than	POS	O
+normal	POS	O
+.	POS	O
+In	POS	O
+all	POS	O
+treatments	POS	O
+,	POS	O
+granule	POS	O
+cells	POS	O
+of	POS	O
+the	POS	O
+dentate	POS	O
+gyrus	POS	O
+were	POS	O
+not	POS	O
+affected	POS	O
+.	POS	O
+4	POS	O
+.	POS	O
+These	POS	O
+results	POS	O
+indicate	POS	O
+that	POS	O
+status	POS	B-NP
+epilepticus	POS	I-NP
+induced	POS	O
+by	POS	O
+pilocarpine	POS	O
+is	POS	O
+initiated	POS	O
+by	POS	O
+cholinergic	POS	O
+overstimulation	POS	O
+and	POS	O
+propagated	POS	O
+by	POS	O
+glutamatergic	POS	O
+transmission	POS	O
+,	POS	O
+the	POS	O
+elevation	POS	O
+of	POS	O
+which	POS	O
+may	POS	O
+cause	POS	O
+brain	POS	O
+damage	POS	O
+through	POS	O
+an	POS	O
+excitatory	POS	O
+NMDA	POS	O
+receptor	POS	O
+-	POS	O
+mediated	POS	O
+mechanism	POS	O
+.	POS	O
+Paclitaxel	POS	O
+,	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+,	POS	O
+and	POS	O
+folinic	POS	O
+acid	POS	O
+in	POS	O
+metastatic	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+:	POS	O
+BRE	POS	O
+-	POS	O
+26	POS	O
+,	POS	O
+a	POS	O
+phase	POS	O
+II	POS	O
+trial	POS	O
+.	POS	O
+5	POS	O
+-	POS	O
+Fluorouracil	POS	O
+plus	POS	O
+folinic	POS	O
+acid	POS	O
+and	POS	O
+paclitaxel	POS	O
+(	POS	O
+Taxol	POS	O
+;	POS	O
+Bristol	POS	O
+-	POS	O
+Myers	POS	O
+Squibb	POS	O
+Company	POS	O
+,	POS	O
+Princeton	POS	O
+,	POS	O
+NJ	POS	O
+)	POS	O
+are	POS	O
+effective	POS	O
+salvage	POS	O
+therapies	POS	O
+for	POS	O
+metastatic	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+patients	POS	O
+.	POS	O
+Paclitaxel	POS	O
+and	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+have	POS	O
+additive	POS	O
+cytotoxicity	POS	B-NP
+in	POS	O
+MCF	POS	O
+-	POS	O
+7	POS	O
+cell	POS	O
+lines	POS	O
+.	POS	O
+We	POS	O
+performed	POS	O
+a	POS	O
+phase	POS	O
+II	POS	O
+trial	POS	O
+of	POS	O
+paclitaxel	POS	O
+175	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+over	POS	O
+3	POS	O
+hours	POS	O
+on	POS	O
+day	POS	O
+I	POS	O
+followed	POS	O
+by	POS	O
+folinic	POS	O
+acid	POS	O
+300	POS	O
+mg	POS	O
+over	POS	O
+1	POS	O
+hour	POS	O
+before	POS	O
+5	POS	O
+-	POS	O
+fluorouracil	POS	O
+350	POS	O
+mg	POS	O
+/	POS	O
+m2	POS	O
+on	POS	O
+days	POS	O
+1	POS	O
+to	POS	O
+3	POS	O
+every	POS	O
+28	POS	O
+days	POS	O
+(	POS	O
+TFL	POS	O
+)	POS	O
+in	POS	O
+women	POS	O
+with	POS	O
+metastatic	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+Analysis	POS	O
+is	POS	O
+reported	POS	O
+on	POS	O
+37	POS	O
+patients	POS	O
+with	POS	O
+a	POS	O
+minimum	POS	O
+of	POS	O
+6	POS	O
+months	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+who	POS	O
+received	POS	O
+a	POS	O
+total	POS	O
+of	POS	O
+192	POS	O
+cycles	POS	O
+of	POS	O
+TFL	POS	O
+:	POS	O
+nine	POS	O
+cycles	POS	O
+(	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+were	POS	O
+associated	POS	O
+with	POS	O
+grade	POS	O
+3	POS	O
+/	POS	O
+4	POS	O
+neutropenia	POS	B-NP
+requiring	POS	O
+hospitalization	POS	O
+;	POS	O
+seven	POS	O
+(	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+cycles	POS	O
+in	POS	O
+two	POS	O
+patients	POS	O
+required	POS	O
+granulocyte	POS	O
+colony	POS	O
+-	POS	O
+stimulating	POS	O
+factor	POS	O
+due	POS	O
+to	POS	O
+neutropenia	POS	B-NP
+;	POS	O
+no	POS	O
+patient	POS	O
+required	POS	O
+platelet	POS	B-NP
+transfusions	POS	I-NP
+.	POS	O
+Grade	POS	O
+3	POS	O
+/	POS	O
+4	POS	O
+nonhematologic	POS	O
+toxicities	POS	B-NP
+were	POS	O
+uncommon	POS	O
+.	POS	O
+Among	POS	O
+the	POS	O
+34	POS	O
+patients	POS	O
+evaluable	POS	O
+for	POS	O
+response	POS	O
+,	POS	O
+there	POS	O
+were	POS	O
+three	POS	O
+complete	POS	O
+responses	POS	O
+(	POS	O
+9	POS	O
+%	POS	O
+)	POS	O
+and	POS	O
+18	POS	O
+partial	POS	O
+responses	POS	O
+(	POS	O
+53	POS	O
+%	POS	O
+)	POS	O
+for	POS	O
+an	POS	O
+overall	POS	O
+response	POS	O
+rate	POS	O
+of	POS	O
+62	POS	O
+%	POS	O
+.	POS	O
+Of	POS	O
+the	POS	O
+19	POS	O
+evaluable	POS	O
+patients	POS	O
+with	POS	O
+prior	POS	O
+doxorubicin	POS	O
+exposure	POS	O
+,	POS	O
+11	POS	O
+(	POS	O
+58	POS	O
+%	POS	O
+)	POS	O
+responded	POS	O
+compared	POS	O
+with	POS	O
+nine	POS	O
+of	POS	O
+15	POS	O
+(	POS	O
+60	POS	O
+%	POS	O
+)	POS	O
+without	POS	O
+prior	POS	O
+doxorubicin	POS	O
+.	POS	O
+Plasma	POS	O
+paclitaxel	POS	O
+concentrations	POS	O
+were	POS	O
+measured	POS	O
+at	POS	O
+the	POS	O
+completion	POS	O
+of	POS	O
+paclitaxel	POS	O
+infusion	POS	O
+and	POS	O
+at	POS	O
+24	POS	O
+hours	POS	O
+in	POS	O
+19	POS	O
+patients	POS	O
+.	POS	O
+TFL	POS	O
+is	POS	O
+an	POS	O
+active	POS	O
+,	POS	O
+well	POS	O
+-	POS	O
+tolerated	POS	O
+regimen	POS	O
+in	POS	O
+metastatic	POS	O
+breast	POS	B-NP
+cancer	POS	I-NP
+.	POS	O
+Efficacy	POS	O
+and	POS	O
+proarrhythmia	POS	B-NP
+with	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+for	POS	O
+sustained	POS	O
+ventricular	POS	B-NP
+tachyarrhythmias	POS	I-NP
+.	POS	O
+This	POS	O
+study	POS	O
+prospectively	POS	O
+evaluated	POS	O
+the	POS	O
+clinical	POS	O
+efficacy	POS	O
+,	POS	O
+the	POS	O
+incidence	POS	O
+of	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+,	POS	O
+and	POS	O
+the	POS	O
+presumable	POS	O
+risk	POS	O
+factors	POS	O
+for	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+in	POS	O
+patients	POS	O
+treated	POS	O
+with	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+for	POS	O
+sustained	POS	O
+ventricular	POS	B-NP
+tachyarrhythmias	POS	I-NP
+.	POS	O
+Eighty	POS	O
+-	POS	O
+one	POS	O
+consecutive	POS	O
+patients	POS	O
+(	POS	O
+54	POS	O
+with	POS	O
+coronary	POS	B-NP
+artery	POS	I-NP
+disease	POS	I-NP
+,	POS	O
+and	POS	O
+20	POS	O
+with	POS	O
+dilated	POS	B-NP
+cardiomyopathy	POS	I-NP
+)	POS	O
+with	POS	O
+inducible	POS	O
+sustained	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+or	POS	O
+ventricular	POS	B-NP
+fibrillation	POS	I-NP
+received	POS	O
+oral	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+to	POS	O
+prevent	POS	O
+induction	POS	O
+of	POS	O
+the	POS	O
+ventricular	POS	B-NP
+tachyarrhythmia	POS	I-NP
+.	POS	O
+During	POS	O
+oral	POS	O
+loading	POS	O
+with	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+,	POS	O
+continuous	POS	O
+electrocardiographic	POS	O
+(	POS	O
+ECG	POS	O
+)	POS	O
+monitoring	POS	O
+was	POS	O
+performed	POS	O
+.	POS	O
+Those	POS	O
+patients	POS	O
+in	POS	O
+whom	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+prevented	POS	O
+induction	POS	O
+of	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+or	POS	O
+ventricular	POS	B-NP
+fibrillation	POS	I-NP
+were	POS	O
+discharged	POS	O
+with	POS	O
+the	POS	O
+drug	POS	O
+and	POS	O
+followed	POS	O
+up	POS	O
+on	POS	O
+an	POS	O
+outpatient	POS	O
+basis	POS	O
+for	POS	O
+21	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+18	POS	O
+months	POS	O
+.	POS	O
+Induction	POS	O
+of	POS	O
+the	POS	O
+ventricular	POS	B-NP
+tachyarrhythmia	POS	I-NP
+was	POS	O
+prevented	POS	O
+by	POS	O
+oral	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+in	POS	O
+35	POS	O
+(	POS	O
+43	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+;	POS	O
+the	POS	O
+ventricular	POS	B-NP
+tachyarrhythmia	POS	I-NP
+remained	POS	O
+inducible	POS	O
+in	POS	O
+40	POS	O
+(	POS	O
+49	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+;	POS	O
+and	POS	O
+two	POS	O
+(	POS	O
+2	POS	O
+.	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+did	POS	O
+not	POS	O
+tolerate	POS	O
+even	POS	O
+40	POS	O
+mg	POS	O
+of	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+once	POS	O
+daily	POS	O
+.	POS	O
+Four	POS	O
+(	POS	O
+5	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+had	POS	O
+from	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+during	POS	O
+the	POS	O
+initial	POS	O
+oral	POS	O
+treatment	POS	O
+with	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+.	POS	O
+Neither	POS	O
+ECG	POS	O
+[	POS	O
+sinus	POS	O
+-	POS	O
+cycle	POS	O
+length	POS	O
+(	POS	O
+SCL	POS	O
+)	POS	O
+,	POS	O
+QT	POS	O
+or	POS	O
+QTc	POS	O
+interval	POS	O
+,	POS	O
+or	POS	O
+U	POS	O
+wave	POS	O
+]	POS	O
+nor	POS	O
+clinical	POS	O
+parameters	POS	O
+identified	POS	O
+patients	POS	O
+at	POS	O
+risk	POS	O
+for	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+.	POS	O
+However	POS	O
+,	POS	O
+the	POS	O
+oral	POS	O
+dose	POS	O
+of	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+was	POS	O
+significantly	POS	O
+lower	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+(	POS	O
+200	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+46	POS	O
+vs	POS	O
+.	POS	O
+328	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+53	POS	O
+mg	POS	O
+/	POS	O
+day	POS	O
+;	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+0017	POS	O
+)	POS	O
+.	POS	O
+Risk	POS	O
+factors	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+were	POS	O
+the	POS	O
+appearance	POS	O
+of	POS	O
+an	POS	O
+U	POS	O
+wave	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+049	POS	O
+)	POS	O
+,	POS	O
+female	POS	O
+gender	POS	O
+(	POS	O
+p	POS	O
+=	POS	O
+0	POS	O
+.	POS	O
+015	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+significant	POS	O
+dose	POS	O
+-	POS	O
+corrected	POS	O
+changes	POS	O
+of	POS	O
+SCL	POS	O
+,	POS	O
+QT	POS	O
+interval	POS	O
+,	POS	O
+and	POS	O
+QTc	POS	O
+interval	POS	O
+(	POS	O
+p	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+05	POS	O
+)	POS	O
+.	POS	O
+During	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+,	POS	O
+seven	POS	O
+(	POS	O
+20	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+had	POS	O
+a	POS	O
+nonfatal	POS	O
+ventricular	POS	B-NP
+tachycardia	POS	I-NP
+recurrence	POS	O
+,	POS	O
+and	POS	O
+two	POS	O
+(	POS	O
+6	POS	O
+%	POS	O
+)	POS	O
+patients	POS	O
+died	POS	O
+suddenly	POS	O
+.	POS	O
+One	POS	O
+female	POS	O
+patient	POS	O
+with	POS	O
+stable	POS	O
+cardiac	POS	B-NP
+disease	POS	I-NP
+had	POS	O
+recurrent	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+after	POS	O
+2	POS	O
+years	POS	O
+of	POS	O
+successful	POS	O
+treatment	POS	O
+with	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+.	POS	O
+Torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+occurred	POS	O
+early	POS	O
+during	POS	O
+treatment	POS	O
+even	POS	O
+with	POS	O
+low	POS	O
+doses	POS	O
+of	POS	O
+oral	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+.	POS	O
+Pronounced	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+surface	POS	O
+ECG	POS	O
+(	POS	O
+cycle	POS	O
+length	POS	O
+,	POS	O
+QT	POS	O
+,	POS	O
+and	POS	O
+QTc	POS	O
+)	POS	O
+in	POS	O
+relation	POS	O
+to	POS	O
+the	POS	O
+dose	POS	O
+of	POS	O
+oral	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+might	POS	O
+identify	POS	O
+a	POS	O
+subgroup	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+an	POS	O
+increased	POS	O
+risk	POS	O
+for	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+.	POS	O
+Other	POS	O
+ECG	POS	O
+parameters	POS	O
+before	POS	O
+the	POS	O
+application	POS	O
+of	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+did	POS	O
+not	POS	O
+identify	POS	O
+patients	POS	O
+at	POS	O
+increased	POS	O
+risk	POS	O
+for	POS	O
+torsades	POS	B-NP
+de	POS	I-NP
+pointes	POS	I-NP
+.	POS	O
+Recurrence	POS	O
+rates	POS	O
+of	POS	O
+ventricular	POS	B-NP
+tachyarrhythmias	POS	I-NP
+are	POS	O
+high	POS	O
+despite	POS	O
+complete	POS	O
+suppression	POS	O
+of	POS	O
+the	POS	O
+arrhythmia	POS	B-NP
+during	POS	O
+programmed	POS	O
+stimulation	POS	O
+.	POS	O
+Therefore	POS	O
+programmed	POS	O
+electrical	POS	O
+stimulation	POS	O
+in	POS	O
+the	POS	O
+case	POS	O
+of	POS	O
+d	POS	O
+,	POS	O
+l	POS	O
+-	POS	O
+sotalol	POS	O
+seems	POS	O
+to	POS	O
+be	POS	O
+of	POS	O
+limited	POS	O
+prognostic	POS	O
+value	POS	O
+.	POS	O
+Chronic	POS	O
+hyperprolactinemia	POS	B-NP
+and	POS	O
+changes	POS	O
+in	POS	O
+dopamine	POS	O
+neurons	POS	O
+.	POS	O
+The	POS	O
+tuberoinfundibular	POS	O
+dopaminergic	POS	O
+(	POS	O
+TIDA	POS	O
+)	POS	O
+system	POS	O
+is	POS	O
+known	POS	O
+to	POS	O
+inhibit	POS	O
+prolactin	POS	O
+(	POS	O
+PRL	POS	O
+)	POS	O
+secretion	POS	O
+.	POS	O
+In	POS	O
+young	POS	O
+animals	POS	O
+this	POS	O
+system	POS	O
+responds	POS	O
+to	POS	O
+acute	POS	O
+elevations	POS	O
+in	POS	O
+serum	POS	O
+PRL	POS	O
+by	POS	O
+increasing	POS	O
+its	POS	O
+activity	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+this	POS	O
+responsiveness	POS	O
+is	POS	O
+lost	POS	O
+in	POS	O
+aging	POS	O
+rats	POS	O
+with	POS	O
+chronically	POS	O
+high	POS	O
+serum	POS	O
+PRL	POS	O
+levels	POS	O
+.	POS	O
+The	POS	O
+purpose	POS	O
+of	POS	O
+this	POS	O
+study	POS	O
+was	POS	O
+to	POS	O
+induce	POS	O
+hyperprolactinemia	POS	B-NP
+in	POS	O
+rats	POS	O
+for	POS	O
+extended	POS	O
+periods	POS	O
+of	POS	O
+time	POS	O
+and	POS	O
+examine	POS	O
+its	POS	O
+effects	POS	O
+on	POS	O
+dopaminergic	POS	O
+systems	POS	O
+in	POS	O
+the	POS	O
+brain	POS	O
+.	POS	O
+Hyperprolactinemia	POS	B-NP
+was	POS	O
+induced	POS	O
+by	POS	O
+treatment	POS	O
+with	POS	O
+haloperidol	POS	O
+,	POS	O
+a	POS	O
+dopamine	POS	O
+receptor	POS	O
+antagonist	POS	O
+,	POS	O
+and	POS	O
+Palkovits	POS	O
+'	POS	O
+microdissection	POS	O
+technique	POS	O
+in	POS	O
+combination	POS	O
+with	POS	O
+high	POS	O
+-	POS	O
+performance	POS	O
+liquid	POS	O
+chromatography	POS	O
+was	POS	O
+used	POS	O
+to	POS	O
+measure	POS	O
+neurotransmitter	POS	O
+concentrations	POS	O
+in	POS	O
+several	POS	O
+areas	POS	O
+of	POS	O
+the	POS	O
+brain	POS	O
+.	POS	O
+After	POS	O
+6	POS	O
+months	POS	O
+of	POS	O
+hyperprolactinemia	POS	B-NP
+,	POS	O
+dopamine	POS	O
+(	POS	O
+DA	POS	O
+)	POS	O
+concentrations	POS	O
+in	POS	O
+the	POS	O
+median	POS	O
+eminence	POS	O
+(	POS	O
+ME	POS	O
+)	POS	O
+increased	POS	O
+by	POS	O
+84	POS	O
+%	POS	O
+over	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+.	POS	O
+Nine	POS	O
+months	POS	O
+of	POS	O
+hyperprolactinemia	POS	B-NP
+produced	POS	O
+a	POS	O
+50	POS	O
+%	POS	O
+increase	POS	O
+in	POS	O
+DA	POS	O
+concentrations	POS	O
+in	POS	O
+the	POS	O
+ME	POS	O
+over	POS	O
+the	POS	O
+control	POS	O
+group	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+DA	POS	O
+response	POS	O
+was	POS	O
+lost	POS	O
+if	POS	O
+a	POS	O
+9	POS	O
+-	POS	O
+month	POS	O
+long	POS	O
+haloperidol	POS	O
+-	POS	O
+induced	POS	O
+hyperprolactinemia	POS	B-NP
+was	POS	O
+followed	POS	O
+by	POS	O
+a	POS	O
+1	POS	O
+1	POS	O
+/	POS	O
+2	POS	O
+month	POS	O
+-	POS	O
+long	POS	O
+extremely	POS	O
+high	POS	O
+increase	POS	O
+in	POS	O
+serum	POS	O
+PRL	POS	O
+levels	POS	O
+produced	POS	O
+by	POS	O
+implantation	POS	O
+of	POS	O
+MMQ	POS	O
+cells	POS	O
+under	POS	O
+the	POS	O
+kidney	POS	O
+capsule	POS	O
+.	POS	O
+There	POS	O
+was	POS	O
+no	POS	O
+change	POS	O
+in	POS	O
+the	POS	O
+levels	POS	O
+of	POS	O
+DA	POS	O
+,	POS	O
+norepinephrine	POS	O
+(	POS	O
+NE	POS	O
+)	POS	O
+,	POS	O
+serotonin	POS	O
+(	POS	O
+5	POS	O
+-	POS	O
+HT	POS	O
+)	POS	O
+,	POS	O
+or	POS	O
+their	POS	O
+metabolites	POS	O
+in	POS	O
+the	POS	O
+arcuate	POS	O
+nucleus	POS	O
+(	POS	O
+AN	POS	O
+)	POS	O
+,	POS	O
+medial	POS	O
+preoptic	POS	O
+area	POS	O
+(	POS	O
+MPA	POS	O
+)	POS	O
+,	POS	O
+caudate	POS	O
+putamen	POS	O
+(	POS	O
+CP	POS	O
+)	POS	O
+,	POS	O
+substantia	POS	O
+nigra	POS	O
+(	POS	O
+SN	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+zona	POS	O
+incerta	POS	O
+(	POS	O
+ZI	POS	O
+)	POS	O
+,	POS	O
+except	POS	O
+for	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+5	POS	O
+-	POS	O
+hydroxyindoleacetic	POS	O
+acid	POS	O
+(	POS	O
+5	POS	O
+-	POS	O
+HIAA	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+AN	POS	O
+after	POS	O
+6	POS	O
+-	POS	O
+months	POS	O
+of	POS	O
+hyperprolactinemia	POS	B-NP
+and	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+DA	POS	O
+concentrations	POS	O
+in	POS	O
+the	POS	O
+AN	POS	B-NP
+after	POS	O
+9	POS	O
+-	POS	O
+months	POS	O
+of	POS	O
+hyperprolactinemia	POS	B-NP
+.	POS	O
+These	POS	O
+results	POS	O
+demonstrate	POS	O
+that	POS	O
+hyperprolactinemia	POS	B-NP
+specifically	POS	O
+affects	POS	O
+TIDA	POS	O
+neurons	POS	O
+and	POS	O
+these	POS	O
+effects	POS	O
+vary	POS	O
+,	POS	O
+depending	POS	O
+on	POS	O
+the	POS	O
+duration	POS	O
+and	POS	O
+intensity	POS	O
+of	POS	O
+hyperprolactinemia	POS	B-NP
+.	POS	O
+The	POS	O
+age	POS	O
+-	POS	O
+related	POS	O
+decrease	POS	O
+in	POS	O
+hypothalamic	POS	O
+dopamine	POS	O
+function	POS	O
+may	POS	O
+be	POS	O
+associated	POS	O
+with	POS	O
+increases	POS	O
+in	POS	O
+PRL	POS	O
+secretion	POS	O
+.	POS	O
+Treatment	POS	O
+-	POS	O
+related	POS	O
+disseminated	POS	O
+necrotizing	POS	B-NP
+leukoencephalopathy	POS	I-NP
+with	POS	O
+characteristic	POS	O
+contrast	POS	O
+enhancement	POS	O
+of	POS	O
+the	POS	O
+white	POS	O
+matter	POS	O
+.	POS	O
+This	POS	O
+report	POS	O
+describes	POS	O
+unique	POS	O
+contrast	POS	O
+enhancement	POS	O
+of	POS	O
+the	POS	O
+white	POS	O
+matter	POS	O
+on	POS	O
+T1	POS	O
+-	POS	O
+weighted	POS	O
+magnetic	POS	O
+resonance	POS	O
+images	POS	O
+of	POS	O
+two	POS	O
+patients	POS	O
+with	POS	O
+disseminated	POS	O
+necrotizing	POS	B-NP
+leukoencephalopathy	POS	I-NP
+,	POS	O
+which	POS	O
+developed	POS	O
+from	POS	O
+acute	POS	B-NP
+lymphoblastic	POS	I-NP
+leukemia	POS	I-NP
+treated	POS	O
+with	POS	O
+high	POS	O
+-	POS	O
+dose	POS	O
+methotrexate	POS	O
+.	POS	O
+In	POS	O
+both	POS	O
+patients	POS	O
+,	POS	O
+the	POS	O
+enhancement	POS	O
+was	POS	O
+more	POS	O
+pronounced	POS	O
+near	POS	O
+the	POS	O
+base	POS	O
+of	POS	O
+the	POS	O
+brain	POS	O
+than	POS	O
+at	POS	O
+the	POS	O
+vertex	POS	O
+.	POS	O
+Necropsy	POS	O
+of	POS	O
+the	POS	O
+first	POS	O
+case	POS	O
+revealed	POS	O
+loss	POS	O
+of	POS	O
+myelination	POS	O
+and	POS	O
+necrosis	POS	B-NP
+of	POS	O
+the	POS	O
+white	POS	O
+matter	POS	O
+.	POS	O
+Possible	POS	O
+mechanisms	POS	O
+causing	POS	O
+such	POS	O
+a	POS	O
+leukoencephalopathy	POS	B-NP
+are	POS	O
+discussed	POS	O
+.	POS	O
+Thrombotic	POS	B-NP
+complications	POS	I-NP
+in	POS	O
+acute	POS	B-NP
+promyelocytic	POS	I-NP
+leukemia	POS	I-NP
+during	POS	O
+all	POS	O
+-	POS	O
+trans	POS	O
+-	POS	O
+retinoic	POS	O
+acid	POS	O
+therapy	POS	O
+.	POS	O
+A	POS	O
+case	POS	O
+of	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+,	POS	O
+due	POS	O
+to	POS	O
+occlusion	POS	O
+of	POS	O
+renal	POS	O
+vessels	POS	O
+in	POS	O
+a	POS	O
+patient	POS	O
+with	POS	O
+acute	POS	B-NP
+promyelocytic	POS	I-NP
+leukemia	POS	I-NP
+(	POS	O
+APL	POS	B-NP
+)	POS	O
+treated	POS	O
+with	POS	O
+all	POS	O
+-	POS	O
+trans	POS	O
+-	POS	O
+retinoic	POS	O
+acid	POS	O
+(	POS	O
+ATRA	POS	O
+)	POS	O
+and	POS	O
+tranexamic	POS	O
+acid	POS	O
+has	POS	O
+been	POS	O
+described	POS	O
+recently	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+a	POS	O
+case	POS	O
+of	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+in	POS	O
+an	POS	O
+APL	POS	B-NP
+patient	POS	O
+treated	POS	O
+with	POS	O
+ATRA	POS	O
+alone	POS	O
+.	POS	O
+This	POS	O
+case	POS	O
+further	POS	O
+supports	POS	O
+the	POS	O
+concern	POS	O
+about	POS	O
+thromboembolic	POS	B-NP
+complications	POS	I-NP
+associated	POS	O
+with	POS	O
+ATRA	POS	O
+therapy	POS	O
+in	POS	O
+APL	POS	B-NP
+patients	POS	O
+.	POS	O
+The	POS	O
+patients	POS	O
+,	POS	O
+a	POS	O
+43	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+,	POS	O
+presented	POS	O
+all	POS	O
+the	POS	O
+signs	POS	O
+and	POS	O
+symptoms	POS	O
+of	POS	O
+APL	POS	B-NP
+and	POS	O
+was	POS	O
+included	POS	O
+in	POS	O
+a	POS	O
+treatment	POS	O
+protocol	POS	O
+with	POS	O
+ATRA	POS	O
+.	POS	O
+After	POS	O
+10	POS	O
+days	POS	O
+of	POS	O
+treatment	POS	O
+,	POS	O
+he	POS	O
+developed	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+that	POS	O
+was	POS	O
+completely	POS	O
+reversible	POS	O
+after	POS	O
+complete	POS	O
+remission	POS	O
+of	POS	O
+APL	POS	B-NP
+was	POS	O
+achieved	POS	O
+and	POS	O
+therapy	POS	O
+discontinued	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+ATRA	POS	O
+is	POS	O
+a	POS	O
+valid	POS	O
+therapeutic	POS	O
+choice	POS	O
+for	POS	O
+patients	POS	O
+with	POS	O
+APL	POS	B-NP
+,	POS	O
+although	POS	O
+the	POS	O
+procoagulant	POS	O
+tendency	POS	O
+is	POS	O
+not	POS	O
+completely	POS	O
+corrected	POS	O
+.	POS	O
+Thrombotic	POS	B-NP
+events	POS	I-NP
+,	POS	O
+however	POS	O
+,	POS	O
+could	POS	O
+be	POS	O
+avoided	POS	O
+by	POS	O
+using	POS	O
+low	POS	O
+-	POS	O
+dose	POS	O
+heparin	POS	O
+.	POS	O
+Pupillary	POS	O
+changes	POS	O
+associated	POS	O
+with	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+stimulant	POS	O
+-	POS	O
+induced	POS	O
+mania	POS	B-NP
+:	POS	O
+a	POS	O
+case	POS	O
+report	POS	O
+.	POS	O
+A	POS	O
+30	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+cocaine	POS	O
+-	POS	O
+dependent	POS	O
+man	POS	O
+who	POS	O
+was	POS	O
+a	POS	O
+subject	POS	O
+in	POS	O
+a	POS	O
+study	POS	O
+evaluating	POS	O
+the	POS	O
+anticraving	POS	O
+efficacy	POS	O
+of	POS	O
+the	POS	O
+stimulant	POS	O
+medication	POS	O
+diethylpropion	POS	O
+(	POS	O
+DEP	POS	O
+)	POS	O
+became	POS	O
+manic	POS	B-NP
+during	POS	O
+his	POS	O
+second	POS	O
+week	POS	O
+on	POS	O
+the	POS	O
+study	POS	O
+drug	POS	O
+.	POS	O
+Pupillometric	POS	O
+changes	POS	O
+while	POS	O
+on	POS	O
+DEP	POS	O
+,	POS	O
+especially	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+total	POS	O
+power	POS	O
+of	POS	O
+pupillary	POS	O
+oscillation	POS	O
+,	POS	O
+were	POS	O
+dramatically	POS	O
+different	POS	O
+than	POS	O
+those	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+eight	POS	O
+other	POS	O
+study	POS	O
+subjects	POS	O
+who	POS	O
+did	POS	O
+not	POS	O
+become	POS	O
+manic	POS	B-NP
+.	POS	O
+The	POS	O
+large	POS	O
+changes	POS	O
+in	POS	O
+total	POS	O
+power	POS	O
+of	POS	O
+pupillary	POS	B-NP
+oscillation	POS	I-NP
+occurred	POS	O
+a	POS	O
+few	POS	O
+days	POS	O
+before	POS	O
+the	POS	O
+patient	POS	O
+became	POS	O
+fully	POS	O
+manic	POS	B-NP
+.	POS	O
+Such	POS	O
+medication	POS	O
+-	POS	O
+associated	POS	O
+changes	POS	O
+in	POS	O
+the	POS	O
+total	POS	O
+power	POS	O
+of	POS	O
+pupillary	POS	O
+oscillation	POS	O
+might	POS	O
+be	POS	O
+of	POS	O
+utility	POS	O
+in	POS	O
+identifying	POS	O
+persons	POS	O
+at	POS	O
+risk	POS	O
+for	POS	O
+manic	POS	B-NP
+-	POS	O
+like	POS	O
+adverse	POS	O
+effects	POS	O
+during	POS	O
+the	POS	O
+medical	POS	O
+use	POS	O
+of	POS	O
+psychomotor	POS	O
+stimulants	POS	O
+or	POS	O
+sympathomimetic	POS	O
+agents	POS	O
+.	POS	O
+Fetal	POS	O
+risks	POS	O
+due	POS	O
+to	POS	O
+warfarin	POS	O
+therapy	POS	O
+during	POS	O
+pregnancy	POS	O
+.	POS	O
+Two	POS	O
+mothers	POS	O
+with	POS	O
+heart	POS	B-NP
+valve	POS	I-NP
+prosthesis	POS	I-NP
+were	POS	O
+treated	POS	O
+with	POS	O
+warfarin	POS	O
+during	POS	O
+pregnancy	POS	O
+.	POS	O
+In	POS	O
+the	POS	O
+first	POS	O
+case	POS	O
+a	POS	O
+caesarean	POS	O
+section	POS	O
+was	POS	O
+done	POS	O
+one	POS	O
+week	POS	O
+after	POS	O
+replacement	POS	O
+of	POS	O
+warfarin	POS	O
+with	POS	O
+heparin	POS	O
+.	POS	O
+The	POS	O
+baby	POS	O
+died	POS	O
+of	POS	O
+cerebral	POS	O
+and	POS	O
+pulmonary	POS	B-NP
+hemorrhage	POS	I-NP
+.	POS	O
+The	POS	O
+second	POS	O
+mother	POS	O
+had	POS	O
+a	POS	O
+male	POS	O
+infant	POS	O
+by	POS	O
+caesarean	POS	O
+section	POS	O
+.	POS	O
+The	POS	O
+baby	POS	O
+showed	POS	O
+warfarin	POS	O
+-	POS	O
+induced	POS	O
+embryopathy	POS	B-NP
+with	POS	O
+nasal	POS	B-NP
+hypoplasia	POS	I-NP
+and	POS	O
+stippled	POS	B-NP
+epiphyses	POS	I-NP
+(	POS	O
+chondrodysplasia	POS	B-NP
+punctata	POS	I-NP
+)	POS	O
+.	POS	O
+Nasal	POS	B-NP
+hypoplasia	POS	I-NP
+with	POS	O
+or	POS	O
+without	POS	O
+stippled	POS	O
+epiphyses	POS	O
+has	POS	O
+now	POS	O
+been	POS	O
+reported	POS	O
+in	POS	O
+11	POS	O
+infants	POS	O
+born	POS	O
+to	POS	O
+mothers	POS	O
+treated	POS	O
+with	POS	O
+warfarin	POS	O
+during	POS	O
+the	POS	O
+first	POS	O
+trimester	POS	O
+,	POS	O
+and	POS	O
+a	POS	O
+causal	POS	O
+association	POS	O
+is	POS	O
+probable	POS	O
+.	POS	O
+In	POS	O
+view	POS	O
+of	POS	O
+the	POS	O
+risks	POS	O
+to	POS	O
+both	POS	O
+mother	POS	O
+and	POS	O
+fetus	POS	O
+in	POS	O
+women	POS	O
+with	POS	O
+prosthetic	POS	O
+cardiac	POS	O
+valves	POS	O
+it	POS	O
+is	POS	O
+recommended	POS	O
+that	POS	O
+therapeutic	POS	O
+abortion	POS	O
+be	POS	O
+advised	POS	O
+as	POS	O
+the	POS	O
+first	POS	O
+alternative	POS	O
+.	POS	O
+The	POS	O
+negative	POS	O
+mucosal	POS	O
+potential	POS	O
+:	POS	O
+separating	POS	O
+central	POS	O
+and	POS	O
+peripheral	POS	O
+effects	POS	O
+of	POS	O
+NSAIDs	POS	O
+in	POS	O
+man	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+We	POS	O
+wanted	POS	O
+to	POS	O
+test	POS	O
+whether	POS	O
+assessment	POS	O
+of	POS	O
+both	POS	O
+a	POS	O
+central	POS	O
+pain	POS	O
+-	POS	O
+related	POS	O
+signal	POS	O
+(	POS	O
+chemo	POS	O
+-	POS	O
+somatosensory	POS	O
+evoked	POS	O
+potential	POS	O
+,	POS	O
+CSSEP	POS	O
+)	POS	O
+and	POS	O
+a	POS	O
+concomitantly	POS	O
+recorded	POS	O
+peripheral	POS	O
+signal	POS	O
+(	POS	O
+negative	POS	O
+mucosal	POS	O
+potential	POS	O
+,	POS	O
+NMP	POS	O
+)	POS	O
+allows	POS	O
+for	POS	O
+separation	POS	O
+of	POS	O
+central	POS	O
+and	POS	O
+peripheral	POS	O
+effects	POS	O
+of	POS	O
+NSAIDs	POS	O
+.	POS	O
+For	POS	O
+this	POS	O
+purpose	POS	O
+,	POS	O
+experimental	POS	O
+conditions	POS	O
+were	POS	O
+created	POS	O
+in	POS	O
+which	POS	O
+NSAIDs	POS	O
+had	POS	O
+previously	POS	O
+been	POS	O
+observed	POS	O
+to	POS	O
+produce	POS	O
+effects	POS	O
+on	POS	O
+phasic	POS	O
+and	POS	O
+tonic	POS	O
+pain	POS	B-NP
+by	POS	O
+either	POS	O
+central	POS	O
+or	POS	O
+peripheral	POS	O
+mechanisms	POS	O
+.	POS	O
+METHODS	POS	O
+:	POS	O
+According	POS	O
+to	POS	O
+a	POS	O
+double	POS	O
+-	POS	O
+blind	POS	O
+,	POS	O
+randomised	POS	O
+,	POS	O
+controlled	POS	O
+,	POS	O
+threefold	POS	O
+cross	POS	O
+-	POS	O
+over	POS	O
+design	POS	O
+,	POS	O
+18	POS	O
+healthy	POS	O
+subjects	POS	O
+(	POS	O
+11	POS	O
+males	POS	O
+,	POS	O
+7	POS	O
+females	POS	O
+;	POS	O
+mean	POS	O
+age	POS	O
+26	POS	O
+years	POS	O
+)	POS	O
+received	POS	O
+either	POS	O
+placebo	POS	O
+,	POS	O
+400	POS	O
+mg	POS	O
+ibuprofen	POS	O
+,	POS	O
+or	POS	O
+800	POS	O
+mg	POS	O
+ibuprofen	POS	O
+.	POS	O
+Phasic	POS	O
+pain	POS	B-NP
+was	POS	O
+applied	POS	O
+by	POS	O
+means	POS	O
+of	POS	O
+short	POS	O
+pulses	POS	O
+of	POS	O
+CO2	POS	O
+to	POS	O
+the	POS	O
+nasal	POS	O
+mucosa	POS	O
+(	POS	O
+stimulus	POS	O
+duration	POS	O
+500	POS	O
+ms	POS	O
+,	POS	O
+interval	POS	O
+approximately	POS	O
+60	POS	O
+s	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+tonic	POS	O
+pain	POS	B-NP
+was	POS	O
+induced	POS	O
+in	POS	O
+the	POS	O
+nasal	POS	O
+cavity	POS	O
+by	POS	O
+means	POS	O
+of	POS	O
+dry	POS	O
+air	POS	O
+of	POS	O
+controlled	POS	O
+temperature	POS	O
+,	POS	O
+humidity	POS	O
+and	POS	O
+flow	POS	O
+rate	POS	O
+(	POS	O
+22	POS	O
+degrees	POS	O
+C	POS	O
+,	POS	O
+0	POS	O
+%	POS	O
+relative	POS	O
+humidity	POS	O
+,	POS	O
+145	POS	O
+ml	POS	O
+.	POS	O
+s	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+.	POS	O
+Both	POS	O
+CSSEPs	POS	O
+as	POS	O
+central	POS	O
+and	POS	O
+NMPs	POS	O
+as	POS	O
+peripheral	POS	O
+correlates	POS	O
+of	POS	O
+pain	POS	B-NP
+were	POS	O
+obtained	POS	O
+in	POS	O
+response	POS	O
+to	POS	O
+the	POS	O
+CO2	POS	O
+stimuli	POS	O
+.	POS	O
+Additionally	POS	O
+,	POS	O
+the	POS	O
+subjects	POS	O
+rated	POS	O
+the	POS	O
+intensity	POS	O
+of	POS	O
+both	POS	O
+phasic	POS	O
+and	POS	O
+tonic	POS	O
+pain	POS	B-NP
+by	POS	O
+means	POS	O
+of	POS	O
+visual	POS	O
+analogue	POS	O
+scales	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+As	POS	O
+described	POS	O
+earlier	POS	O
+,	POS	O
+administration	POS	O
+of	POS	O
+ibuprofen	POS	O
+was	POS	O
+followed	POS	O
+by	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+tonic	POS	O
+pain	POS	B-NP
+but	POS	O
+-	POS	O
+relative	POS	O
+to	POS	O
+placebo	POS	O
+-	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+correlates	POS	O
+of	POS	O
+phasic	POS	B-NP
+pain	POS	I-NP
+,	POS	O
+indicating	POS	O
+a	POS	O
+specific	POS	O
+effect	POS	O
+of	POS	O
+ibuprofen	POS	O
+on	POS	O
+the	POS	O
+interaction	POS	O
+between	POS	O
+the	POS	O
+pain	POS	B-NP
+stimuli	POS	O
+under	POS	O
+these	POS	O
+special	POS	O
+experimental	POS	O
+conditions	POS	O
+.	POS	O
+Based	POS	O
+on	POS	O
+the	POS	O
+similar	POS	O
+behaviour	POS	O
+of	POS	O
+CSSEP	POS	O
+and	POS	O
+NMP	POS	O
+,	POS	O
+it	POS	O
+was	POS	O
+concluded	POS	O
+that	POS	O
+the	POS	O
+pharmacological	POS	O
+process	POS	O
+underlying	POS	O
+this	POS	O
+phenomenon	POS	O
+was	POS	O
+localised	POS	O
+in	POS	O
+the	POS	O
+periphery	POS	O
+.	POS	O
+By	POS	O
+means	POS	O
+of	POS	O
+the	POS	O
+simultaneous	POS	O
+recording	POS	O
+of	POS	O
+interrelated	POS	O
+peripheral	POS	O
+and	POS	O
+central	POS	O
+electrophysiologic	POS	O
+correlates	POS	O
+of	POS	O
+nociception	POS	O
+,	POS	O
+it	POS	O
+was	POS	O
+possible	POS	O
+to	POS	O
+separate	POS	O
+central	POS	O
+and	POS	O
+peripheral	POS	O
+effects	POS	O
+of	POS	O
+an	POS	O
+NSAID	POS	O
+.	POS	O
+The	POS	O
+major	POS	O
+advantage	POS	O
+of	POS	O
+this	POS	O
+pain	POS	B-NP
+model	POS	O
+is	POS	O
+the	POS	O
+possibility	POS	O
+of	POS	O
+obtaining	POS	O
+peripheral	POS	O
+pain	POS	O
+-	POS	O
+related	POS	O
+activity	POS	O
+directly	POS	O
+using	POS	O
+a	POS	O
+non	POS	O
+-	POS	O
+invasive	POS	O
+technique	POS	O
+in	POS	O
+humans	POS	O
+.	POS	O
+Effect	POS	O
+of	POS	O
+D	POS	O
+-	POS	O
+Glucarates	POS	O
+on	POS	O
+basic	POS	O
+antibiotic	POS	O
+-	POS	O
+induced	POS	O
+renal	POS	B-NP
+damage	POS	I-NP
+in	POS	O
+rats	POS	O
+.	POS	O
+Dehydrated	POS	O
+rats	POS	O
+regularly	POS	O
+develop	POS	O
+acute	POS	B-NP
+renal	POS	I-NP
+failure	POS	I-NP
+following	POS	O
+single	POS	O
+injection	POS	O
+of	POS	O
+aminoglycoside	POS	O
+antibiotics	POS	O
+combined	POS	O
+with	POS	O
+dextran	POS	O
+or	POS	O
+of	POS	O
+antibiotics	POS	O
+only	POS	O
+.	POS	O
+Oral	POS	O
+administration	POS	O
+of	POS	O
+2	POS	O
+,	POS	O
+5	POS	O
+-	POS	O
+di	POS	O
+-	POS	O
+O	POS	O
+-	POS	O
+acetyl	POS	O
+-	POS	O
+D	POS	O
+-	POS	O
+glucaro	POS	O
+-	POS	O
+1	POS	O
+,	POS	O
+4	POS	O
+-	POS	O
+6	POS	O
+,	POS	O
+3	POS	O
+-	POS	O
+dilactone	POS	O
+protected	POS	O
+rats	POS	O
+against	POS	O
+renal	POS	B-NP
+failure	POS	I-NP
+induced	POS	O
+by	POS	O
+kanamycin	POS	O
+-	POS	O
+dextran	POS	O
+.	POS	O
+The	POS	O
+protective	POS	O
+effect	POS	O
+was	POS	O
+prevalent	POS	O
+among	POS	O
+D	POS	O
+-	POS	O
+glucarates	POS	O
+,	POS	O
+and	POS	O
+also	POS	O
+to	POS	O
+other	POS	O
+saccharic	POS	O
+acid	POS	O
+,	POS	O
+hexauronic	POS	O
+acids	POS	O
+and	POS	O
+hexaaldonic	POS	O
+acids	POS	O
+,	POS	O
+although	POS	O
+to	POS	O
+a	POS	O
+lesser	POS	O
+degree	POS	O
+,	POS	O
+but	POS	O
+not	POS	O
+to	POS	O
+a	POS	O
+hexaaldose	POS	O
+,	POS	O
+sugar	POS	O
+alcohols	POS	O
+,	POS	O
+substances	POS	O
+inthe	POS	O
+TCA	POS	O
+cycle	POS	O
+and	POS	O
+other	POS	O
+acidic	POS	O
+compounds	POS	O
+.	POS	O
+D	POS	O
+-	POS	O
+Glucarates	POS	O
+were	POS	O
+effective	POS	O
+against	POS	O
+renal	POS	O
+damage	POS	O
+induced	POS	O
+by	POS	O
+peptide	POS	O
+antibiotics	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+various	POS	O
+aminoglycoside	POS	O
+antibitocis	POS	O
+.	POS	O
+Dose	POS	O
+-	POS	O
+responses	POS	O
+were	POS	O
+observed	POS	O
+in	POS	O
+the	POS	O
+protective	POS	O
+effect	POS	O
+of	POS	O
+D	POS	O
+-	POS	O
+Glucarates	POS	O
+.	POS	O
+With	POS	O
+a	POS	O
+D	POS	O
+-	POS	O
+glucarate	POS	O
+of	POS	O
+a	POS	O
+fixed	POS	O
+size	POS	O
+of	POS	O
+dose	POS	O
+,	POS	O
+approximately	POS	O
+the	POS	O
+same	POS	O
+degree	POS	O
+of	POS	O
+protection	POS	O
+was	POS	O
+obtained	POS	O
+against	POS	O
+renal	POS	O
+damages	POS	O
+induced	POS	O
+by	POS	O
+different	POS	O
+basic	POS	O
+antibiotics	POS	O
+despite	POS	O
+large	POS	O
+disparities	POS	O
+in	POS	O
+administration	POS	O
+doses	POS	O
+of	POS	O
+different	POS	O
+antibiotics	POS	O
+.	POS	O
+D	POS	O
+-	POS	O
+Glucarates	POS	O
+had	POS	O
+the	POS	O
+ability	POS	O
+to	POS	O
+prevent	POS	O
+renal	POS	B-NP
+damage	POS	I-NP
+but	POS	O
+not	POS	O
+to	POS	O
+cure	POS	O
+it	POS	O
+.	POS	O
+Rats	POS	O
+excreted	POS	O
+acidic	POS	O
+urine	POS	O
+when	POS	O
+they	POS	O
+were	POS	O
+spared	POS	O
+from	POS	O
+renal	POS	B-NP
+lesions	POS	I-NP
+by	POS	O
+monosaccharides	POS	O
+.	POS	O
+The	POS	O
+reduction	POS	O
+effect	POS	O
+of	POS	O
+D	POS	O
+-	POS	O
+glucarates	POS	O
+against	POS	O
+nephrotoxicity	POS	B-NP
+of	POS	O
+basic	POS	O
+antibiotics	POS	O
+was	POS	O
+discussed	POS	O
+.	POS	O
+Acute	POS	O
+severe	POS	O
+depression	POS	B-NP
+following	POS	O
+peri	POS	O
+-	POS	O
+operative	POS	O
+ondansetron	POS	O
+.	POS	O
+A	POS	O
+41	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+woman	POS	O
+with	POS	O
+a	POS	O
+strong	POS	O
+history	POS	O
+of	POS	O
+postoperative	POS	B-NP
+nausea	POS	I-NP
+and	POS	O
+vomiting	POS	B-NP
+presented	POS	O
+for	POS	O
+abdominal	POS	O
+hysterectomy	POS	O
+3	POS	O
+months	POS	O
+after	POS	O
+a	POS	O
+previous	POS	O
+anaesthetic	POS	O
+where	POS	O
+ondansetron	POS	O
+prophylaxis	POS	B-NP
+had	POS	O
+been	POS	O
+used	POS	O
+.	POS	O
+She	POS	O
+had	POS	O
+developed	POS	O
+a	POS	O
+severe	POS	O
+acute	POS	O
+major	POS	O
+depression	POS	B-NP
+disorder	POS	O
+almost	POS	O
+immediately	POS	O
+thereafter	POS	O
+,	POS	O
+possibly	POS	O
+related	POS	O
+to	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+a	POS	O
+serotonin	POS	O
+antagonist	POS	O
+.	POS	O
+Nine	POS	O
+years	POS	O
+before	POS	O
+she	POS	O
+had	POS	O
+experienced	POS	O
+a	POS	O
+self	POS	O
+-	POS	O
+limited	POS	O
+puerperal	POS	B-NP
+depressive	POS	I-NP
+episode	POS	O
+.	POS	O
+Anaesthesia	POS	B-NP
+with	POS	O
+a	POS	O
+propofol	POS	O
+infusion	POS	O
+and	POS	O
+avoidance	POS	O
+of	POS	O
+serotonin	POS	O
+antagonists	POS	O
+provided	POS	O
+a	POS	O
+nausea	POS	B-NP
+-	POS	O
+free	POS	O
+postoperative	POS	O
+course	POS	O
+without	POS	O
+exacerbation	POS	O
+of	POS	O
+the	POS	O
+depression	POS	B-NP
+disorder	POS	I-NP
+.	POS	O
+Hypertensive	POS	B-NP
+response	POS	O
+during	POS	O
+dobutamine	POS	O
+stress	POS	O
+echocardiography	POS	O
+.	POS	O
+Among	POS	O
+3	POS	O
+,	POS	O
+129	POS	O
+dobutamine	POS	O
+stress	POS	O
+echocardiographic	POS	O
+studies	POS	O
+,	POS	O
+a	POS	O
+hypertensive	POS	B-NP
+response	POS	O
+,	POS	O
+defined	POS	O
+as	POS	O
+systolic	POS	O
+blood	POS	O
+pressure	POS	O
+(	POS	O
+BP	POS	O
+)	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+220	POS	O
+mm	POS	O
+Hg	POS	O
+and	POS	O
+/	POS	O
+or	POS	O
+diastolic	POS	O
+BP	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+110	POS	O
+mm	POS	O
+Hg	POS	O
+,	POS	O
+occurred	POS	O
+in	POS	O
+30	POS	O
+patients	POS	O
+(	POS	O
+1	POS	O
+%	POS	O
+)	POS	O
+.	POS	O
+Patients	POS	O
+with	POS	O
+this	POS	O
+response	POS	O
+more	POS	O
+often	POS	O
+had	POS	O
+a	POS	O
+history	POS	O
+of	POS	O
+hypertension	POS	B-NP
+and	POS	O
+had	POS	O
+higher	POS	O
+resting	POS	O
+systolic	POS	O
+and	POS	O
+diastolic	POS	O
+BP	POS	O
+before	POS	O
+dobutamine	POS	O
+infusion	POS	O
+.	POS	O
+Continuously	POS	O
+nebulized	POS	O
+albuterol	POS	O
+in	POS	O
+severe	POS	O
+exacerbations	POS	O
+of	POS	O
+asthma	POS	B-NP
+in	POS	O
+adults	POS	O
+:	POS	O
+a	POS	O
+case	POS	O
+-	POS	O
+controlled	POS	O
+study	POS	O
+.	POS	O
+A	POS	O
+retrospective	POS	O
+,	POS	O
+case	POS	O
+-	POS	O
+controlled	POS	O
+analysis	POS	O
+comparing	POS	O
+patients	POS	O
+admitted	POS	O
+to	POS	O
+a	POS	O
+medical	POS	O
+intensive	POS	O
+care	POS	O
+unit	POS	O
+with	POS	O
+severe	POS	O
+exacerbations	POS	B-NP
+of	POS	O
+asthma	POS	B-NP
+who	POS	O
+received	POS	O
+continuously	POS	O
+nebulized	POS	O
+albuterol	POS	O
+(	POS	O
+CNA	POS	O
+)	POS	O
+versus	POS	O
+intermittent	POS	O
+albuterol	POS	O
+(	POS	O
+INA	POS	O
+)	POS	O
+treatments	POS	O
+is	POS	O
+reported	POS	O
+.	POS	O
+Forty	POS	O
+matched	POS	O
+pairs	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+asthma	POS	B-NP
+are	POS	O
+compared	POS	O
+.	POS	O
+CNA	POS	O
+was	POS	O
+administered	POS	O
+for	POS	O
+a	POS	O
+mean	POS	O
+of	POS	O
+11	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+10	POS	O
+hr	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+cardiac	POS	B-NP
+dysrhythmias	POS	I-NP
+was	POS	O
+similar	POS	O
+between	POS	O
+groups	POS	O
+.	POS	O
+Symptomatic	POS	O
+hypokalemia	POS	B-NP
+did	POS	O
+not	POS	O
+occur	POS	O
+.	POS	O
+CNA	POS	O
+patients	POS	O
+had	POS	O
+higher	POS	O
+heart	POS	O
+rates	POS	O
+during	POS	O
+treatment	POS	O
+,	POS	O
+which	POS	O
+may	POS	O
+reflect	POS	O
+severity	POS	O
+of	POS	O
+illness	POS	B-NP
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+intubation	POS	O
+was	POS	O
+similar	POS	O
+.	POS	O
+We	POS	O
+conclude	POS	O
+that	POS	O
+CNA	POS	O
+and	POS	O
+INA	POS	O
+demonstrated	POS	O
+similar	POS	O
+profiles	POS	O
+with	POS	O
+regard	POS	O
+to	POS	O
+safety	POS	O
+,	POS	O
+morbidity	POS	O
+,	POS	O
+and	POS	O
+mortality	POS	O
+.	POS	O
+Paraplegia	POS	B-NP
+following	POS	O
+intrathecal	POS	O
+methotrexate	POS	O
+:	POS	O
+report	POS	O
+of	POS	O
+a	POS	O
+case	POS	O
+and	POS	O
+review	POS	O
+of	POS	O
+the	POS	O
+literature	POS	O
+.	POS	O
+A	POS	O
+patient	POS	O
+who	POS	O
+developed	POS	O
+paraplegia	POS	B-NP
+following	POS	O
+the	POS	O
+intrathecal	POS	O
+instillation	POS	O
+of	POS	O
+methotrexate	POS	O
+is	POS	O
+discribed	POS	O
+.	POS	O
+The	POS	O
+ten	POS	O
+previously	POS	O
+reported	POS	O
+cases	POS	O
+of	POS	O
+this	POS	O
+unusual	POS	O
+complication	POS	O
+are	POS	O
+reviewed	POS	O
+.	POS	O
+The	POS	O
+following	POS	O
+factors	POS	O
+appear	POS	O
+to	POS	O
+predispose	POS	O
+to	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+this	POS	O
+complication	POS	O
+:	POS	O
+abnormal	POS	O
+cerebrospinal	POS	O
+dynamics	POS	O
+related	POS	O
+to	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+central	POS	B-NP
+nervous	POS	I-NP
+system	POS	I-NP
+leukemia	POS	I-NP
+,	POS	O
+and	POS	O
+epidural	POS	O
+cerebrospinal	POS	O
+leakage	POS	O
+;	POS	O
+elevated	POS	O
+cerebrospinal	POS	O
+fluid	POS	O
+methothexate	POS	O
+concentration	POS	O
+related	POS	O
+to	POS	O
+abnormal	POS	O
+cerebrospinal	POS	O
+fluid	POS	O
+dynamics	POS	O
+and	POS	O
+to	POS	O
+inappropriately	POS	O
+high	POS	O
+methotrexate	POS	O
+doses	POS	O
+based	POS	O
+on	POS	O
+body	POS	O
+surface	POS	O
+area	POS	O
+calculations	POS	O
+in	POS	O
+older	POS	O
+children	POS	O
+and	POS	O
+adults	POS	O
+;	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+neurotoxic	POS	O
+preservatives	POS	O
+in	POS	O
+commercially	POS	O
+available	POS	O
+methotrexate	POS	O
+preparations	POS	O
+and	POS	O
+diluents	POS	O
+;	POS	O
+and	POS	O
+the	POS	O
+use	POS	O
+of	POS	O
+methotrexate	POS	O
+diluents	POS	O
+of	POS	O
+unphysiologic	POS	O
+pH	POS	O
+,	POS	O
+ionic	POS	O
+content	POS	O
+and	POS	O
+osmolarity	POS	O
+.	POS	O
+The	POS	O
+role	POS	O
+of	POS	O
+methotrexate	POS	O
+contaminants	POS	O
+,	POS	O
+local	POS	O
+folate	POS	B-NP
+deficiency	POS	I-NP
+,	POS	O
+and	POS	O
+cranial	POS	O
+irradiation	POS	O
+in	POS	O
+the	POS	O
+pathogenesis	POS	O
+of	POS	O
+intrathecal	POS	O
+methotrexate	POS	O
+toxicity	POS	B-NP
+is	POS	O
+unclear	POS	O
+.	POS	O
+The	POS	O
+incidence	POS	O
+of	POS	O
+neurotoxicity	POS	B-NP
+may	POS	O
+be	POS	O
+reduced	POS	O
+by	POS	O
+employing	POS	O
+lower	POS	O
+doses	POS	O
+of	POS	O
+methotrexate	POS	O
+in	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+central	POS	B-NP
+nervous	POS	I-NP
+system	POS	I-NP
+leukemia	POS	I-NP
+,	POS	O
+in	POS	O
+older	POS	O
+children	POS	O
+and	POS	O
+adults	POS	O
+,	POS	O
+and	POS	O
+in	POS	O
+the	POS	O
+presence	POS	O
+of	POS	O
+epidural	POS	O
+leakage	POS	O
+.	POS	O
+Only	POS	O
+preservative	POS	O
+-	POS	O
+free	POS	O
+methotrexate	POS	O
+in	POS	O
+Elliott	POS	O
+'	POS	O
+s	POS	O
+B	POS	O
+Solution	POS	O
+at	POS	O
+a	POS	O
+concentration	POS	O
+of	POS	O
+not	POS	O
+more	POS	O
+than	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+ml	POS	O
+should	POS	O
+be	POS	O
+used	POS	O
+for	POS	O
+intrathecal	POS	O
+administration	POS	O
+.	POS	O
+Periodic	POS	O
+monitoring	POS	O
+of	POS	O
+cerebruspinal	POS	O
+fluid	POS	O
+methotrexate	POS	O
+levels	POS	O
+may	POS	O
+be	POS	O
+predictive	POS	O
+of	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+serious	POS	O
+neurotoxicity	POS	B-NP
+.	POS	O
+Hyperosmolar	POS	B-NP
+nonketotic	POS	I-NP
+coma	POS	I-NP
+precipitated	POS	O
+by	POS	O
+lithium	POS	O
+-	POS	O
+induced	POS	O
+nephrogenic	POS	B-NP
+diabetes	POS	I-NP
+insipidus	POS	I-NP
+.	POS	O
+A	POS	O
+45	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+man	POS	O
+,	POS	O
+with	POS	O
+a	POS	O
+10	POS	O
+-	POS	O
+year	POS	O
+history	POS	O
+of	POS	O
+manic	POS	B-NP
+depression	POS	I-NP
+treated	POS	O
+with	POS	O
+lithium	POS	O
+,	POS	O
+was	POS	O
+admitted	POS	O
+with	POS	O
+hyperosmolar	POS	B-NP
+,	POS	O
+nonketotic	POS	B-NP
+coma	POS	I-NP
+.	POS	O
+He	POS	O
+gave	POS	O
+a	POS	O
+five	POS	O
+-	POS	O
+year	POS	O
+history	POS	O
+of	POS	O
+polyuria	POS	B-NP
+and	POS	O
+polydipsia	POS	B-NP
+,	POS	O
+during	POS	O
+which	POS	O
+time	POS	O
+urinalysis	POS	O
+had	POS	O
+been	POS	O
+negative	POS	O
+for	POS	O
+glucose	POS	O
+.	POS	O
+After	POS	O
+recovery	POS	O
+from	POS	O
+hyperglycaemia	POS	B-NP
+,	POS	O
+he	POS	O
+remained	POS	O
+polyuric	POS	B-NP
+despite	POS	O
+normal	POS	O
+blood	POS	O
+glucose	POS	O
+concentrations	POS	O
+;	POS	O
+water	POS	O
+deprivation	POS	O
+testing	POS	O
+indicated	POS	O
+nephrogenic	POS	B-NP
+diabetes	POS	I-NP
+insipidus	POS	I-NP
+,	POS	O
+likely	POS	O
+to	POS	O
+be	POS	O
+lithium	POS	O
+-	POS	O
+induced	POS	O
+.	POS	O
+We	POS	O
+hypothesize	POS	O
+that	POS	O
+when	POS	O
+this	POS	O
+man	POS	O
+developed	POS	O
+type	POS	B-NP
+2	POS	I-NP
+diabetes	POS	I-NP
+,	POS	O
+chronic	POS	B-NP
+polyuria	POS	I-NP
+due	POS	O
+to	POS	O
+nephrogenic	POS	B-NP
+diabetes	POS	I-NP
+insipidus	POS	I-NP
+was	POS	O
+sufficient	POS	O
+to	POS	O
+precipitate	POS	O
+hyperosmolar	POS	B-NP
+dehydration	POS	I-NP
+.	POS	O
+Effects	POS	O
+of	POS	O
+the	POS	O
+intracoronary	POS	O
+infusion	POS	O
+of	POS	O
+cocaine	POS	O
+on	POS	O
+left	POS	O
+ventricular	POS	O
+systolic	POS	O
+and	POS	O
+diastolic	POS	O
+function	POS	O
+in	POS	O
+humans	POS	O
+.	POS	O
+BACKGROUND	POS	O
+:	POS	O
+In	POS	O
+dogs	POS	O
+,	POS	O
+a	POS	O
+large	POS	O
+amount	POS	O
+of	POS	O
+intravenous	POS	O
+cocaine	POS	O
+causes	POS	O
+a	POS	O
+profound	POS	O
+deterioration	POS	O
+of	POS	O
+left	POS	O
+ventricular	POS	O
+(	POS	O
+LV	POS	O
+)	POS	O
+systolic	POS	O
+function	POS	O
+and	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+LV	POS	O
+end	POS	O
+-	POS	O
+diastolic	POS	O
+pressure	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+was	POS	O
+done	POS	O
+to	POS	O
+assess	POS	O
+the	POS	O
+influence	POS	O
+of	POS	O
+a	POS	O
+high	POS	O
+intracoronary	POS	O
+cocaine	POS	O
+concentration	POS	O
+on	POS	O
+LV	POS	O
+systolic	POS	O
+and	POS	O
+diastolic	POS	O
+function	POS	O
+in	POS	O
+humans	POS	O
+.	POS	O
+METHODS	POS	O
+AND	POS	O
+RESULTS	POS	O
+:	POS	O
+In	POS	O
+20	POS	O
+patients	POS	O
+(	POS	O
+14	POS	O
+men	POS	O
+and	POS	O
+6	POS	O
+women	POS	O
+aged	POS	O
+39	POS	O
+to	POS	O
+72	POS	O
+years	POS	O
+)	POS	O
+referred	POS	O
+for	POS	O
+cardiac	POS	O
+catheterization	POS	O
+for	POS	O
+the	POS	O
+evaluation	POS	O
+of	POS	O
+chest	POS	B-NP
+pain	POS	I-NP
+,	POS	O
+we	POS	O
+measured	POS	O
+heart	POS	O
+rate	POS	O
+,	POS	O
+systemic	POS	O
+arterial	POS	O
+pressure	POS	O
+,	POS	O
+LV	POS	O
+pressure	POS	O
+and	POS	O
+its	POS	O
+first	POS	O
+derivative	POS	O
+(	POS	O
+dP	POS	O
+/	POS	O
+dt	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+LV	POS	O
+volumes	POS	O
+and	POS	O
+ejection	POS	O
+fraction	POS	O
+before	POS	O
+and	POS	O
+during	POS	O
+the	POS	O
+final	POS	O
+2	POS	O
+to	POS	O
+3	POS	O
+minutes	POS	O
+of	POS	O
+a	POS	O
+15	POS	O
+-	POS	O
+minute	POS	O
+intracoronary	POS	O
+infusion	POS	O
+of	POS	O
+saline	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+10	POS	O
+,	POS	O
+control	POS	O
+subjects	POS	O
+)	POS	O
+or	POS	O
+cocaine	POS	O
+hydrochloride	POS	O
+1	POS	O
+mg	POS	O
+/	POS	O
+min	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+10	POS	O
+)	POS	O
+.	POS	O
+No	POS	O
+variable	POS	O
+changed	POS	O
+with	POS	O
+saline	POS	O
+.	POS	O
+With	POS	O
+cocaine	POS	O
+,	POS	O
+the	POS	O
+drug	POS	O
+concentration	POS	O
+in	POS	O
+blood	POS	O
+obtained	POS	O
+from	POS	O
+the	POS	O
+coronary	POS	O
+sinus	POS	O
+was	POS	O
+3	POS	O
+.	POS	O
+0	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+0	POS	O
+.	POS	O
+4	POS	O
+(	POS	O
+mean	POS	O
++	POS	O
+/	POS	O
+-	POS	O
+SD	POS	O
+)	POS	O
+mg	POS	O
+/	POS	O
+L	POS	O
+,	POS	O
+similar	POS	O
+in	POS	O
+magnitude	POS	O
+to	POS	O
+the	POS	O
+blood	POS	O
+cocaine	POS	O
+concentration	POS	O
+reported	POS	O
+in	POS	O
+abusers	POS	O
+dying	POS	O
+of	POS	O
+cocaine	POS	B-NP
+intoxication	POS	I-NP
+.	POS	O
+Cocaine	POS	O
+induced	POS	O
+no	POS	O
+significant	POS	O
+change	POS	O
+in	POS	O
+heart	POS	O
+rate	POS	O
+,	POS	O
+LV	POS	O
+dP	POS	O
+/	POS	O
+dt	POS	O
+(	POS	O
+positive	POS	O
+or	POS	O
+negative	POS	O
+)	POS	O
+,	POS	O
+or	POS	O
+LV	POS	O
+end	POS	O
+-	POS	O
+diastolic	POS	O
+volume	POS	O
+,	POS	O
+but	POS	O
+it	POS	O
+caused	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+systolic	POS	O
+and	POS	O
+mean	POS	O
+arterial	POS	O
+pressures	POS	O
+,	POS	O
+LV	POS	O
+end	POS	O
+-	POS	O
+diastolic	POS	O
+pressure	POS	O
+,	POS	O
+and	POS	O
+LV	POS	O
+end	POS	O
+-	POS	O
+systolic	POS	O
+volume	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+a	POS	O
+decrease	POS	O
+in	POS	O
+LV	POS	O
+ejection	POS	O
+fraction	POS	O
+.	POS	O
+CONCLUSIONS	POS	O
+:	POS	O
+In	POS	O
+humans	POS	O
+,	POS	O
+the	POS	O
+intracoronary	POS	O
+infusion	POS	O
+of	POS	O
+cocaine	POS	O
+sufficient	POS	O
+in	POS	O
+amount	POS	O
+to	POS	O
+achieve	POS	O
+a	POS	O
+high	POS	O
+drug	POS	O
+concentration	POS	O
+in	POS	O
+coronary	POS	O
+sinus	POS	O
+blood	POS	O
+causes	POS	O
+a	POS	O
+deterioration	POS	O
+of	POS	O
+LV	POS	O
+systolic	POS	O
+and	POS	O
+diastolic	POS	O
+performance	POS	O
+.	POS	O
+Ascending	POS	O
+dose	POS	O
+tolerance	POS	O
+study	POS	O
+of	POS	O
+intramuscular	POS	O
+carbetocin	POS	O
+administered	POS	O
+after	POS	O
+normal	POS	O
+vaginal	POS	O
+birth	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+To	POS	O
+determine	POS	O
+the	POS	O
+maximum	POS	O
+tolerated	POS	O
+dose	POS	O
+(	POS	O
+MTD	POS	O
+)	POS	O
+of	POS	O
+carbetocin	POS	O
+(	POS	O
+a	POS	O
+long	POS	O
+-	POS	O
+acting	POS	O
+synthetic	POS	O
+analogue	POS	O
+of	POS	O
+oxytocin	POS	O
+)	POS	O
+,	POS	O
+when	POS	O
+administered	POS	O
+immediately	POS	O
+after	POS	O
+vaginal	POS	O
+delivery	POS	O
+at	POS	O
+term	POS	O
+.	POS	O
+MATERIALS	POS	O
+AND	POS	O
+METHODS	POS	O
+:	POS	O
+Carbetocin	POS	O
+was	POS	O
+given	POS	O
+as	POS	O
+an	POS	O
+intramuscular	POS	O
+injection	POS	O
+immediately	POS	O
+after	POS	O
+the	POS	O
+birth	POS	O
+of	POS	O
+the	POS	O
+infant	POS	O
+in	POS	O
+45	POS	O
+healthy	POS	O
+women	POS	O
+with	POS	O
+normal	POS	B-NP
+singleton	POS	O
+pregnancies	POS	O
+who	POS	O
+delivered	POS	O
+vaginally	POS	O
+at	POS	O
+term	POS	O
+.	POS	O
+Dosage	POS	O
+groups	POS	O
+of	POS	O
+15	POS	O
+,	POS	O
+30	POS	O
+,	POS	O
+50	POS	O
+,	POS	O
+75	POS	O
+,	POS	O
+100	POS	O
+,	POS	O
+125	POS	O
+,	POS	O
+150	POS	O
+,	POS	O
+175	POS	O
+or	POS	O
+200	POS	O
+microg	POS	O
+carbetocin	POS	O
+were	POS	O
+assigned	POS	O
+to	POS	O
+blocks	POS	O
+of	POS	O
+three	POS	O
+women	POS	O
+according	POS	O
+to	POS	O
+the	POS	O
+continual	POS	O
+reassessment	POS	O
+method	POS	O
+(	POS	O
+CRM	POS	O
+)	POS	O
+.	POS	O
+RESULTS	POS	O
+:	POS	O
+All	POS	O
+dosage	POS	O
+groups	POS	O
+consisted	POS	O
+of	POS	O
+three	POS	O
+women	POS	O
+,	POS	O
+except	POS	O
+those	POS	O
+with	POS	O
+100	POS	O
+microg	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+6	POS	O
+)	POS	O
+and	POS	O
+200	POS	O
+microg	POS	O
+(	POS	O
+n	POS	O
+=	POS	O
+18	POS	O
+)	POS	O
+.	POS	O
+Recorded	POS	O
+were	POS	O
+dose	POS	O
+-	POS	O
+limiting	POS	O
+adverse	POS	O
+events	POS	O
+:	POS	O
+hyper	POS	O
+-	POS	O
+or	POS	O
+hypotension	POS	B-NP
+(	POS	O
+three	POS	O
+)	POS	O
+,	POS	O
+severe	POS	O
+abdominal	POS	B-NP
+pain	POS	I-NP
+(	POS	O
+0	POS	O
+)	POS	O
+,	POS	O
+vomiting	POS	B-NP
+(	POS	O
+0	POS	O
+)	POS	O
+and	POS	O
+retained	POS	O
+placenta	POS	O
+(	POS	O
+four	POS	O
+)	POS	O
+.	POS	O
+Serious	POS	O
+adverse	POS	O
+events	POS	O
+occurred	POS	O
+in	POS	O
+seven	POS	O
+women	POS	O
+:	POS	O
+six	POS	O
+cases	POS	O
+with	POS	O
+blood	POS	B-NP
+loss	POS	I-NP
+>	POS	O
+or	POS	O
+=	POS	O
+1000	POS	O
+ml	POS	O
+,	POS	O
+four	POS	O
+cases	POS	O
+of	POS	O
+manual	POS	O
+placenta	POS	O
+removal	POS	O
+,	POS	O
+five	POS	O
+cases	POS	O
+of	POS	O
+additional	POS	O
+oxytocics	POS	O
+administration	POS	O
+and	POS	O
+five	POS	O
+cases	POS	O
+of	POS	O
+blood	POS	O
+transfusion	POS	O
+.	POS	O
+Maximum	POS	O
+blood	POS	O
+loss	POS	O
+was	POS	O
+greatest	POS	O
+at	POS	O
+the	POS	O
+upper	POS	O
+and	POS	O
+lower	POS	O
+dose	POS	O
+levels	POS	O
+,	POS	O
+and	POS	O
+lowest	POS	O
+in	POS	O
+the	POS	O
+70	POS	O
+-	POS	O
+125	POS	O
+microg	POS	O
+dose	POS	O
+range	POS	O
+.	POS	O
+Four	POS	O
+out	POS	O
+of	POS	O
+six	POS	O
+cases	POS	O
+with	POS	O
+blood	POS	O
+loss	POS	O
+>	POS	O
+or	POS	O
+=	POS	O
+1000	POS	O
+ml	POS	O
+occurred	POS	O
+in	POS	O
+the	POS	O
+200	POS	O
+microg	POS	O
+group	POS	O
+.	POS	O
+The	POS	O
+majority	POS	O
+of	POS	O
+additional	POS	O
+administration	POS	O
+of	POS	O
+oxytocics	POS	O
+(	POS	O
+4	POS	O
+/	POS	O
+5	POS	O
+)	POS	O
+and	POS	O
+blood	POS	O
+transfusion	POS	O
+(	POS	O
+3	POS	O
+/	POS	O
+5	POS	O
+)	POS	O
+occurred	POS	O
+in	POS	O
+the	POS	O
+dose	POS	O
+groups	POS	O
+of	POS	O
+200	POS	O
+microg	POS	O
+.	POS	O
+All	POS	O
+retained	POS	O
+placentae	POS	O
+were	POS	O
+found	POS	O
+in	POS	O
+the	POS	O
+group	POS	O
+of	POS	O
+200	POS	O
+microg	POS	O
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+The	POS	O
+MTD	POS	O
+was	POS	O
+calculated	POS	O
+to	POS	O
+be	POS	O
+at	POS	O
+200	POS	O
+microg	POS	O
+carbetocin	POS	O
+.	POS	O
+Heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+,	POS	O
+paradoxical	POS	B-NP
+thromboembolism	POS	I-NP
+,	POS	O
+and	POS	O
+other	POS	O
+side	POS	O
+effects	POS	O
+of	POS	O
+heparin	POS	O
+therapy	POS	O
+.	POS	O
+Although	POS	O
+several	POS	O
+new	POS	O
+anticoagulant	POS	O
+drugs	POS	O
+are	POS	O
+in	POS	O
+development	POS	O
+,	POS	O
+heparin	POS	O
+remains	POS	O
+the	POS	O
+drug	POS	O
+of	POS	O
+choice	POS	O
+for	POS	O
+most	POS	O
+anticoagulation	POS	O
+needs	POS	O
+.	POS	O
+The	POS	O
+clinical	POS	O
+effects	POS	O
+of	POS	O
+heparin	POS	O
+are	POS	O
+meritorious	POS	O
+,	POS	O
+but	POS	O
+side	POS	O
+effects	POS	O
+do	POS	O
+exist	POS	O
+.	POS	O
+Important	POS	O
+untoward	POS	O
+effects	POS	O
+of	POS	O
+heparin	POS	O
+therapy	POS	O
+including	POS	O
+heparin	POS	O
+-	POS	O
+induced	POS	O
+thrombocytopenia	POS	B-NP
+,	POS	O
+heparin	POS	B-NP
+-	POS	I-NP
+associated	POS	I-NP
+osteoporosis	POS	I-NP
+,	POS	O
+eosinophilia	POS	B-NP
+,	POS	O
+skin	POS	B-NP
+reactions	POS	I-NP
+,	POS	O
+allergic	POS	B-NP
+reactions	POS	I-NP
+other	POS	O
+than	POS	O
+thrombocytopenia	POS	B-NP
+and	POS	O
+alopecia	POS	B-NP
+will	POS	O
+be	POS	O
+discussed	POS	O
+in	POS	O
+this	POS	O
+article	POS	O
+.	POS	O
+Nonopaque	POS	O
+crystal	POS	O
+deposition	POS	O
+causing	POS	O
+ureteric	POS	B-NP
+obstruction	POS	I-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+HIV	POS	O
+undergoing	POS	O
+indinavir	POS	O
+therapy	POS	O
+.	POS	O
+OBJECTIVE	POS	O
+:	POS	O
+We	POS	O
+describe	POS	O
+the	POS	O
+unique	POS	O
+CT	POS	O
+features	POS	O
+of	POS	O
+ureteric	POS	O
+calculi	POS	O
+in	POS	O
+six	POS	O
+HIV	POS	O
+-	POS	O
+infected	POS	O
+patients	POS	O
+receiving	POS	O
+indinavir	POS	O
+,	POS	O
+the	POS	O
+most	POS	O
+commonly	POS	O
+used	POS	O
+HIV	POS	O
+protease	POS	O
+inhibitor	POS	O
+,	POS	O
+which	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+an	POS	O
+increased	POS	O
+incidence	POS	O
+of	POS	O
+urolithiasis	POS	B-NP
+.	POS	O
+CONCLUSION	POS	O
+:	POS	O
+Ureteric	POS	B-NP
+obstruction	POS	I-NP
+caused	POS	O
+by	POS	O
+precipitated	POS	O
+indinavir	POS	O
+crystals	POS	O
+may	POS	O
+be	POS	O
+difficult	POS	O
+to	POS	O
+diagnose	POS	O
+with	POS	O
+unenhanced	POS	O
+CT	POS	O
+.	POS	O
+The	POS	O
+calculi	POS	O
+are	POS	O
+not	POS	O
+opaque	POS	O
+,	POS	O
+and	POS	O
+secondary	POS	O
+signs	POS	O
+of	POS	O
+obstruction	POS	O
+may	POS	O
+be	POS	O
+absent	POS	O
+or	POS	O
+minimal	POS	O
+and	POS	O
+should	POS	O
+be	POS	O
+sought	POS	O
+carefully	POS	O
+.	POS	O
+Images	POS	O
+may	POS	O
+need	POS	O
+to	POS	O
+be	POS	O
+obtained	POS	O
+using	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+contrast	POS	O
+material	POS	O
+to	POS	O
+enable	POS	O
+diagnosis	POS	O
+of	POS	O
+ureteric	POS	B-NP
+stones	POS	I-NP
+or	POS	O
+obstruction	POS	O
+in	POS	O
+patients	POS	O
+with	POS	O
+HIV	POS	B-NP
+infection	POS	I-NP
+who	POS	O
+receive	POS	O
+indinavir	POS	O
+therapy	POS	O
+.	POS	O
+Ischemic	POS	B-NP
+colitis	POS	I-NP
+and	POS	O
+sumatriptan	POS	O
+use	POS	O
+.	POS	O
+Sumatriptan	POS	O
+succinate	POS	O
+,	POS	O
+a	POS	O
+serotonin	POS	O
+-	POS	O
+1	POS	O
+(	POS	O
+5	POS	O
+-	POS	O
+hydroxytryptamine	POS	O
+-	POS	O
+1	POS	O
+)	POS	O
+receptor	POS	O
+agonist	POS	O
+,	POS	O
+is	POS	O
+an	POS	O
+antimigraine	POS	O
+drug	POS	O
+that	POS	O
+is	POS	O
+reported	POS	O
+to	POS	O
+act	POS	O
+by	POS	O
+selectively	POS	O
+constricting	POS	O
+intracranial	POS	O
+arteries	POS	O
+.	POS	O
+Recently	POS	O
+,	POS	O
+vasopressor	POS	O
+responses	POS	O
+that	POS	O
+are	POS	O
+distinct	POS	O
+from	POS	O
+the	POS	O
+cranial	POS	O
+circulation	POS	O
+have	POS	O
+been	POS	O
+demonstrated	POS	O
+to	POS	O
+occur	POS	O
+in	POS	O
+the	POS	O
+systemic	POS	O
+,	POS	O
+pulmonary	POS	O
+,	POS	O
+and	POS	O
+coronary	POS	B-NP
+circulations	POS	I-NP
+.	POS	O
+Cases	POS	O
+have	POS	O
+been	POS	O
+published	POS	O
+of	POS	O
+coronary	POS	B-NP
+vasospasm	POS	I-NP
+,	POS	O
+myocardial	POS	B-NP
+ischemia	POS	I-NP
+,	POS	O
+and	POS	O
+myocardial	POS	B-NP
+infarction	POS	I-NP
+occurring	POS	O
+after	POS	O
+sumatriptan	POS	O
+use	POS	O
+.	POS	O
+We	POS	O
+report	POS	O
+on	POS	O
+the	POS	O
+development	POS	O
+of	POS	O
+8	POS	O
+serious	POS	O
+cases	POS	O
+of	POS	O
+ischemic	POS	B-NP
+colitis	POS	I-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+migraine	POS	B-NP
+treated	POS	O
+with	POS	O
+sumatriptan	POS	O
+.	POS	O
+Pallidotomy	POS	B-NP
+with	POS	O
+the	POS	O
+gamma	POS	O
+knife	POS	O
+:	POS	O
+a	POS	O
+positive	POS	O
+experience	POS	O
+.	POS	O
+51	POS	O
+patients	POS	O
+with	POS	O
+medically	POS	O
+refractory	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+underwent	POS	O
+stereotactic	POS	O
+posteromedial	POS	O
+pallidotomy	POS	O
+between	POS	O
+August	POS	O
+1993	POS	O
+and	POS	O
+February	POS	O
+1997	POS	O
+for	POS	O
+treatment	POS	O
+of	POS	O
+bradykinesia	POS	B-NP
+,	POS	O
+rigidity	POS	B-NP
+,	POS	O
+and	POS	O
+L	POS	O
+-	POS	O
+DOPA	POS	O
+-	POS	O
+induced	POS	O
+dyskinesias	POS	B-NP
+.	POS	O
+In	POS	O
+29	POS	O
+patients	POS	O
+,	POS	O
+the	POS	O
+pallidotomies	POS	O
+were	POS	O
+performed	POS	O
+with	POS	O
+the	POS	O
+Leksell	POS	O
+Gamma	POS	O
+Knife	POS	O
+and	POS	O
+in	POS	O
+22	POS	O
+they	POS	O
+were	POS	O
+performed	POS	O
+with	POS	O
+the	POS	O
+standard	POS	O
+radiofrequency	POS	O
+(	POS	O
+RF	POS	O
+)	POS	O
+method	POS	O
+.	POS	O
+Clinical	POS	O
+assessment	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+blinded	POS	O
+ratings	POS	O
+of	POS	O
+Unified	POS	O
+Parkinson	POS	O
+'	POS	O
+s	POS	O
+Disease	POS	O
+Rating	POS	O
+Scale	POS	O
+(	POS	O
+UPDRS	POS	O
+)	POS	O
+scores	POS	O
+were	POS	O
+carried	POS	O
+out	POS	O
+pre	POS	O
+-	POS	O
+and	POS	O
+postoperatively	POS	O
+.	POS	O
+Mean	POS	O
+follow	POS	O
+-	POS	O
+up	POS	O
+time	POS	O
+is	POS	O
+20	POS	O
+.	POS	O
+6	POS	O
+months	POS	O
+(	POS	O
+range	POS	O
+6	POS	O
+-	POS	O
+48	POS	O
+)	POS	O
+and	POS	O
+all	POS	O
+except	POS	O
+4	POS	O
+patients	POS	O
+have	POS	O
+been	POS	O
+followed	POS	O
+more	POS	O
+than	POS	O
+one	POS	O
+year	POS	O
+.	POS	O
+85	POS	O
+percent	POS	O
+of	POS	O
+patients	POS	O
+with	POS	O
+dyskinesias	POS	B-NP
+were	POS	O
+relieved	POS	O
+of	POS	O
+symptoms	POS	O
+,	POS	O
+regardless	POS	O
+of	POS	O
+whether	POS	O
+the	POS	O
+pallidotomies	POS	O
+were	POS	O
+performed	POS	O
+with	POS	O
+the	POS	O
+Gamma	POS	O
+Knife	POS	O
+or	POS	O
+radiofrequency	POS	O
+methods	POS	O
+.	POS	O
+About	POS	O
+2	POS	O
+/	POS	O
+3	POS	O
+of	POS	O
+the	POS	O
+patients	POS	O
+in	POS	O
+both	POS	O
+Gamma	POS	O
+Knife	POS	O
+and	POS	O
+radiofrequency	POS	O
+groups	POS	O
+showed	POS	O
+improvements	POS	O
+in	POS	O
+bradykinesia	POS	B-NP
+and	POS	O
+rigidity	POS	B-NP
+,	POS	O
+although	POS	O
+when	POS	O
+considered	POS	O
+as	POS	O
+a	POS	O
+group	POS	O
+neither	POS	O
+the	POS	O
+Gamma	POS	O
+Knife	POS	O
+nor	POS	O
+the	POS	O
+radiofrequency	POS	O
+group	POS	O
+showed	POS	O
+statistically	POS	O
+significant	POS	O
+improvements	POS	O
+in	POS	O
+UPDRS	POS	O
+scores	POS	O
+.	POS	O
+One	POS	O
+patient	POS	O
+in	POS	O
+the	POS	O
+Gamma	POS	O
+Knife	POS	O
+group	POS	O
+(	POS	O
+3	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+)	POS	O
+developed	POS	O
+a	POS	O
+homonymous	POS	B-NP
+hemianopsia	POS	I-NP
+9	POS	O
+months	POS	O
+following	POS	O
+treatment	POS	O
+and	POS	O
+5	POS	O
+patients	POS	O
+(	POS	O
+27	POS	O
+.	POS	O
+7	POS	O
+%	POS	O
+)	POS	O
+in	POS	O
+the	POS	O
+radiofrequency	POS	O
+group	POS	O
+became	POS	O
+transiently	POS	O
+confused	POS	O
+postoperatively	POS	O
+.	POS	O
+No	POS	O
+other	POS	O
+complications	POS	O
+were	POS	O
+seen	POS	O
+.	POS	O
+Gamma	POS	O
+Knife	POS	O
+pallidotomy	POS	O
+is	POS	O
+as	POS	O
+effective	POS	O
+as	POS	O
+radiofrequency	POS	O
+pallidotomy	POS	O
+in	POS	O
+controlling	POS	O
+certain	POS	O
+of	POS	O
+the	POS	O
+symptoms	POS	O
+of	POS	O
+Parkinson	POS	B-NP
+'	POS	I-NP
+s	POS	I-NP
+disease	POS	I-NP
+.	POS	O
+It	POS	O
+may	POS	O
+be	POS	O
+the	POS	O
+only	POS	O
+practical	POS	O
+technique	POS	O
+available	POS	O
+in	POS	O
+certain	POS	O
+patients	POS	O
+,	POS	O
+such	POS	O
+as	POS	O
+those	POS	O
+who	POS	O
+take	POS	O
+anticoagulants	POS	O
+,	POS	O
+have	POS	O
+bleeding	POS	B-NP
+diatheses	POS	I-NP
+or	POS	O
+serious	POS	O
+systemic	POS	O
+medical	POS	O
+illnesses	POS	O
+.	POS	O
+It	POS	O
+is	POS	O
+a	POS	O
+viable	POS	O
+option	POS	O
+for	POS	O
+other	POS	O
+patients	POS	O
+as	POS	O
+well	POS	O
+.	POS	O
+Centrally	POS	O
+mediated	POS	O
+cardiovascular	POS	O
+effects	POS	O
+of	POS	O
+intracisternal	POS	O
+application	POS	O
+of	POS	O
+carbachol	POS	O
+in	POS	O
+anesthetized	POS	O
+rats	POS	O
+.	POS	O
+The	POS	O
+pressor	POS	O
+response	POS	O
+to	POS	O
+the	POS	O
+intracisternal	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+)	POS	O
+injection	POS	O
+of	POS	O
+carbachol	POS	O
+(	POS	O
+1	POS	O
+mug	POS	O
+)	POS	O
+in	POS	O
+anesthetized	POS	O
+rats	POS	O
+was	POS	O
+analyzed	POS	O
+.	POS	O
+This	POS	O
+response	POS	O
+was	POS	O
+significantly	POS	O
+reduced	POS	O
+by	POS	O
+the	POS	O
+intravenous	POS	O
+(	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+)	POS	O
+injection	POS	O
+of	POS	O
+guanethidine	POS	O
+(	POS	O
+5	POS	O
+mg	POS	O
+)	POS	O
+,	POS	O
+hexamethonium	POS	O
+(	POS	O
+10	POS	O
+mg	POS	O
+)	POS	O
+or	POS	O
+phentolamine	POS	O
+(	POS	O
+5	POS	O
+mg	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+conversely	POS	O
+,	POS	O
+potentiated	POS	O
+by	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+desmethylimipramine	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+3	POS	O
+mg	POS	O
+)	POS	O
+,	POS	O
+while	POS	O
+propranolol	POS	O
+(	POS	O
+0	POS	O
+.	POS	O
+5	POS	O
+mg	POS	O
+)	POS	O
+i	POS	O
+.	POS	O
+v	POS	O
+.	POS	O
+selectively	POS	O
+inhibited	POS	O
+the	POS	O
+enlargement	POS	O
+of	POS	O
+pulse	POS	O
+pressure	POS	O
+and	POS	O
+the	POS	O
+tachycardia	POS	B-NP
+following	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+carbachol	POS	O
+(	POS	O
+1	POS	O
+mug	POS	O
+)	POS	O
+.	POS	O
+On	POS	O
+the	POS	O
+other	POS	O
+hand	POS	O
+,	POS	O
+the	POS	O
+pressor	POS	O
+response	POS	O
+to	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+carbachol	POS	O
+(	POS	O
+1	POS	O
+mug	POS	O
+)	POS	O
+was	POS	O
+almost	POS	O
+completely	POS	O
+blocked	POS	O
+by	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+atropine	POS	O
+(	POS	O
+3	POS	O
+mug	POS	O
+)	POS	O
+or	POS	O
+hexamethonium	POS	O
+(	POS	O
+500	POS	O
+mug	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+significantly	POS	O
+reduced	POS	O
+by	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+chlorpromazine	POS	O
+(	POS	O
+50	POS	O
+mug	POS	O
+)	POS	O
+but	POS	O
+significantly	POS	O
+potentiated	POS	O
+by	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+desmethylimipramine	POS	O
+(	POS	O
+30	POS	O
+mug	POS	O
+)	POS	O
+.	POS	O
+The	POS	O
+pressor	POS	O
+response	POS	O
+to	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+carbachol	POS	O
+(	POS	O
+1	POS	O
+mug	POS	O
+)	POS	O
+remained	POS	O
+unchanged	POS	O
+after	POS	O
+sectioning	POS	O
+of	POS	O
+the	POS	O
+bilateral	POS	O
+cervical	POS	O
+vagal	POS	O
+nerves	POS	O
+but	POS	O
+disappeared	POS	O
+after	POS	O
+sectioning	POS	O
+of	POS	O
+the	POS	O
+spinal	POS	O
+cord	POS	O
+(	POS	O
+C7	POS	O
+-	POS	O
+C8	POS	O
+)	POS	O
+.	POS	O
+From	POS	O
+the	POS	O
+above	POS	O
+result	POS	O
+it	POS	O
+is	POS	O
+suggested	POS	O
+that	POS	O
+the	POS	O
+pressor	POS	O
+response	POS	O
+to	POS	O
+i	POS	O
+.	POS	O
+c	POS	O
+.	POS	O
+carbachol	POS	O
+ortral	POS	O
+and	POS	O
+peripheral	POS	O
+adrenergic	POS	O
+mechanisms	POS	O
+,	POS	O
+and	POS	O
+that	POS	O
+the	POS	O
+sympathetic	POS	O
+trunk	POS	O
+is	POS	O
+the	POS	O
+main	POS	O
+pathway	POS	O
+.	POS	O
+Neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+and	POS	O
+methylphenidate	POS	O
+.	POS	O
+A	POS	O
+1	POS	O
+-	POS	O
+year	POS	O
+-	POS	O
+old	POS	O
+female	POS	O
+presented	POS	O
+with	POS	O
+neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+probably	POS	O
+caused	POS	O
+by	POS	O
+methylphenidate	POS	O
+.	POS	O
+She	POS	O
+had	POS	O
+defects	POS	O
+in	POS	O
+the	POS	O
+supratentorial	POS	O
+brain	POS	O
+including	POS	O
+the	POS	O
+basal	POS	O
+ganglia	POS	O
+and	POS	O
+the	POS	O
+striatum	POS	O
+(	POS	O
+multicystic	POS	B-NP
+encephalomalacia	POS	I-NP
+)	POS	O
+due	POS	O
+to	POS	O
+severe	POS	O
+perinatal	POS	O
+hypoxic	POS	O
+-	POS	O
+ischemic	POS	B-NP
+encephalopathy	POS	I-NP
+,	POS	O
+which	POS	O
+was	POS	O
+considered	POS	O
+to	POS	O
+be	POS	O
+a	POS	O
+possible	POS	O
+predisposing	POS	O
+factor	POS	O
+causing	POS	O
+neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+.	POS	O
+A	POS	O
+dopaminergic	POS	O
+blockade	POS	O
+mechanism	POS	O
+generally	POS	O
+is	POS	O
+accepted	POS	O
+as	POS	O
+the	POS	O
+pathogenesis	POS	O
+of	POS	O
+this	POS	O
+syndrome	POS	O
+.	POS	O
+However	POS	O
+,	POS	O
+methylphenidate	POS	O
+is	POS	O
+a	POS	O
+dopamine	POS	O
+agonist	POS	O
+via	POS	O
+the	POS	O
+inhibition	POS	O
+of	POS	O
+uptake	POS	O
+of	POS	O
+dopamine	POS	O
+,	POS	O
+and	POS	O
+therefore	POS	O
+dopaminergic	POS	O
+systems	POS	O
+in	POS	O
+the	POS	O
+brainstem	POS	O
+(	POS	O
+mainly	POS	O
+the	POS	O
+midbrain	POS	O
+)	POS	O
+and	POS	O
+the	POS	O
+spinal	POS	O
+cord	POS	O
+were	POS	O
+unlikely	POS	O
+to	POS	O
+participate	POS	O
+in	POS	O
+the	POS	O
+onset	POS	O
+of	POS	O
+this	POS	O
+syndrome	POS	O
+.	POS	O
+A	POS	O
+relative	POS	O
+gamma	POS	O
+-	POS	O
+aminobutyric	POS	O
+acid	POS	O
+-	POS	O
+ergic	POS	O
+deficiency	POS	O
+might	POS	O
+occur	POS	O
+because	POS	O
+diazepam	POS	O
+,	POS	O
+a	POS	O
+gamma	POS	O
+-	POS	O
+aminobutyric	POS	O
+acid	POS	O
+-	POS	O
+mimetic	POS	O
+agent	POS	O
+,	POS	O
+was	POS	O
+strikingly	POS	O
+effective	POS	O
+.	POS	O
+This	POS	O
+is	POS	O
+the	POS	O
+first	POS	O
+reported	POS	O
+patient	POS	O
+with	POS	O
+neuroleptic	POS	B-NP
+malignant	POS	I-NP
+syndrome	POS	I-NP
+probably	POS	O
+caused	POS	O
+by	POS	O
+methylphenidate	POS	O
+.	POS	O
+Differential	POS	O
+effects	POS	O
+of	POS	O
+17alpha	POS	O
+-	POS	O
+ethinylestradiol	POS	O
+on	POS	O
+the	POS	O
+neutral	POS	O
+and	POS	O
+acidic	POS	O
+pathways	POS	O
+of	POS	O
+bile	POS	O
+salt	POS	O
+synthesis	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+.	POS	O
+Effects	POS	O
+of	POS	O
+17alpha	POS	O
+-	POS	O
+ethinylestradiol	POS	O
+(	POS	O
+EE	POS	O
+)	POS	O
+on	POS	O
+the	POS	O
+neutral	POS	O
+and	POS	O
+acidic	POS	O
+biosynthetic	POS	O
+pathways	POS	O
+of	POS	O
+bile	POS	O
+salt	POS	O
+(	POS	O
+BS	POS	O
+)	POS	O
+synthesis	POS	O
+were	POS	O
+evaluated	POS	O
+in	POS	O
+rats	POS	O
+with	POS	O
+an	POS	O
+intact	POS	O
+enterohepatic	POS	O
+circulation	POS	O
+and	POS	O
+in	POS	O
+rats	POS	O
+with	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+bile	POS	O
+diversion	POS	O
+to	POS	O
+induce	POS	O
+BS	POS	O
+synthesis	POS	O
+.	POS	O
+For	POS	O
+this	POS	O
+purpose	POS	O
+,	POS	O
+bile	POS	O
+salt	POS	O
+pool	POS	O
+composition	POS	O
+,	POS	O
+synthesis	POS	O
+of	POS	O
+individual	POS	O
+BS	POS	O
+in	POS	O
+vivo	POS	O
+,	POS	O
+hepatic	POS	O
+activities	POS	O
+,	POS	O
+and	POS	O
+expression	POS	O
+levels	POS	O
+of	POS	O
+cholesterol	POS	O
+7alpha	POS	O
+-	POS	O
+hydroxylase	POS	O
+(	POS	O
+CYP7A	POS	O
+)	POS	O
+,	POS	O
+and	POS	O
+sterol	POS	O
+27	POS	O
+-	POS	O
+hydroxylase	POS	O
+(	POS	O
+CYP27	POS	O
+)	POS	O
+,	POS	O
+as	POS	O
+well	POS	O
+as	POS	O
+of	POS	O
+other	POS	O
+enzymes	POS	O
+involved	POS	O
+in	POS	O
+BS	POS	O
+synthesis	POS	O
+,	POS	O
+were	POS	O
+analyzed	POS	O
+in	POS	O
+rats	POS	O
+treated	POS	O
+with	POS	O
+EE	POS	O
+(	POS	O
+5	POS	O
+mg	POS	O
+/	POS	O
+kg	POS	O
+,	POS	O
+3	POS	O
+days	POS	O
+)	POS	O
+or	POS	O
+its	POS	O
+vehicle	POS	O
+.	POS	O
+BS	POS	O
+pool	POS	O
+size	POS	O
+was	POS	O
+decreased	POS	O
+by	POS	O
+27	POS	O
+%	POS	O
+but	POS	O
+total	POS	O
+BS	POS	O
+synthesis	POS	O
+was	POS	O
+not	POS	O
+affected	POS	O
+by	POS	O
+EE	POS	O
+in	POS	O
+intact	POS	O
+rats	POS	O
+.	POS	O
+Synthesis	POS	O
+of	POS	O
+cholate	POS	O
+was	POS	O
+reduced	POS	O
+by	POS	O
+68	POS	O
+%	POS	O
+in	POS	O
+EE	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+,	POS	O
+while	POS	O
+that	POS	O
+of	POS	O
+chenodeoxycholate	POS	O
+was	POS	O
+increased	POS	O
+by	POS	O
+60	POS	O
+%	POS	O
+.	POS	O
+The	POS	O
+recently	POS	O
+identified	POS	O
+Delta22	POS	O
+-	POS	O
+isomer	POS	O
+of	POS	O
+beta	POS	O
+-	POS	O
+muricholate	POS	O
+contributed	POS	O
+for	POS	O
+5	POS	O
+.	POS	O
+4	POS	O
+%	POS	O
+and	POS	O
+18	POS	O
+.	POS	O
+3	POS	O
+%	POS	O
+(	POS	O
+P	POS	O
+<	POS	O
+0	POS	O
+.	POS	O
+01	POS	O
+)	POS	O
+to	POS	O
+the	POS	O
+pool	POS	O
+in	POS	O
+control	POS	O
+and	POS	O
+EE	POS	O
+-	POS	O
+treated	POS	O
+rats	POS	O
+,	POS	O
+respectively	POS	O
+,	POS	O
+but	POS	O
+could	POS	O
+not	POS	O
+be	POS	O
+detected	POS	O
+in	POS	O
+bile	POS	O
+after	POS	O
+exhaustion	POS	O
+of	POS	O
+the	POS	O
+pool	POS	O
+.	POS	O
+A	POS	O
+clear	POS	O
+reduction	POS	O
+of	POS	O
+BS	POS	O
+synthesis	POS	O
+was	POS	O
+found	POS	O
+in	POS	O
+bile	POS	O
+-	POS	O
+diverted	POS	O
+rats	POS	O
+treated	POS	O
+with	POS	O
+EE	POS	O
+,	POS	O
+yet	POS	O
+biliary	POS	O
+BS	POS	O
+composition	POS	O
+was	POS	O
+only	POS	O
+minimally	POS	O
+affected	POS	O
+.	POS	O
+Activity	POS	O
+of	POS	O
+CYP7A	POS	O
+was	POS	O
+decreased	POS	O
+by	POS	O
+EE	POS	O
+in	POS	O
+both	POS	O
+intact	POS	O
+and	POS	O
+bile	POS	O
+-	POS	O
+diverted	POS	O
+rats	POS	O
+,	POS	O
+whereas	POS	O
+the	POS	O
+activity	POS	O
+of	POS	O
+the	POS	O
+CYP27	POS	O
+was	POS	O
+not	POS	O
+affected	POS	O
+.	POS	O
+Hepatic	POS	O
+mRNA	POS	O
+levels	POS	O
+of	POS	O
+CYP7A	POS	O
+were	POS	O
+significantly	POS	O
+reduced	POS	O
+by	POS	O
+EE	POS	O
+in	POS	O
+bile	POS	O
+-	POS	O
+diverted	POS	O
+rats	POS	O
+only	POS	O
+;	POS	O
+CYP27	POS	O
+mRNA	POS	O
+levels	POS	O
+were	POS	O
+not	POS	O
+affected	POS	O
+by	POS	O
+EE	POS	O
+.	POS	O
+In	POS	O
+addition	POS	O
+,	POS	O
+mRNA	POS	O
+levels	POS	O
+of	POS	O
+sterol	POS	O
+12alpha	POS	O
+-	POS	O
+hydroxylase	POS	O
+and	POS	O
+lithocholate	POS	O
+6beta	POS	O
+-	POS	O
+hydroxylase	POS	O
+were	POS	O
+increased	POS	O
+by	POS	O
+bile	POS	O
+diversion	POS	O
+and	POS	O
+suppressed	POS	O
+by	POS	O
+EE	POS	O
+.	POS	O
+This	POS	O
+study	POS	O
+shows	POS	O
+that	POS	O
+17alpha	POS	O
+-	POS	O
+ethinylestradiol	POS	O
+(	POS	O
+EE	POS	O
+)	POS	O
+-	POS	O
+induced	POS	O
+intrahepatic	POS	B-NP
+cholestasis	POS	I-NP
+in	POS	O
+rats	POS	O
+is	POS	O
+associated	POS	O
+with	POS	O
+selective	POS	O
+inhibition	POS	O
+of	POS	O
+the	POS	O
+neutral	POS	O
+pathway	POS	O
+of	POS	O
+bile	POS	O
+salt	POS	O
+(	POS	O
+BS	POS	O
+)	POS	O
+synthesis	POS	O
+.	POS	O
+Simultaneous	POS	O
+impairment	POS	O
+of	POS	O
+other	POS	O
+enzymes	POS	O
+in	POS	O
+the	POS	O
+BS	POS	O
+biosynthetic	POS	O
+pathways	POS	O
+may	POS	O
+contribute	POS	O
+to	POS	O
+overall	POS	O
+effects	POS	O
+of	POS	O
+EE	POS	O
+on	POS	O
+BS	POS	O
+synthesis	POS	O
+.	POS	O
+Glibenclamide	POS	O
+-	POS	O
+sensitive	POS	O
+hypotension	POS	B-NP
+produced	POS	O
+by	POS	O
+helodermin	POS	O
+assessed	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+.	POS	O
+The	POS	O
+effects	POS	O
+of	POS	O
+helodermin	POS	O
+,	POS	O
+a	POS	O
+basic	POS	O
+35	POS	O
+-	POS	O
+amino	POS	O
+acid	POS	O
+peptide	POS	O
+isolated	POS	O
+from	POS	O
+the	POS	O
+venom	POS	O
+of	POS	O
+a	POS	O
+lizard	POS	O
+salivary	POS	O
+gland	POS	O
+,	POS	O
+on	POS	O
+arterial	POS	O
+blood	POS	O
+pressure	POS	O
+and	POS	O
+heart	POS	O
+rate	POS	O
+were	POS	O
+examined	POS	O
+in	POS	O
+the	POS	O
+rat	POS	O
+,	POS	O
+focusing	POS	O
+on	POS	O
+the	POS	O
+possibility	POS	O
+that	POS	O
+activation	POS	O
+of	POS	O
+ATP	POS	O
+sensitive	POS	O
+K	POS	O
++	POS	O
+(	POS	O
+K	POS	O
+(	POS	O
+ATP	POS	O
+)	POS	O
+)	POS	O
+channels	POS	O
+is	POS	O
+involved	POS	O
+in	POS	O
+the	POS	O
+responses	POS	O
+.	POS	O
+The	POS	O
+results	POS	O
+were	POS	O
+also	POS	O
+compared	POS	O
+with	POS	O
+those	POS	O
+of	POS	O
+vasoactive	POS	O
+intestinal	POS	O
+polypeptide	POS	O
+(	POS	O
+VIP	POS	O
+)	POS	O
+.	POS	O
+Helodermin	POS	O
+produced	POS	O
+hypotension	POS	B-NP
+in	POS	O
+a	POS	O
+dose	POS	O
+-	POS	O
+dependent	POS	O
+manner	POS	O
+with	POS	O
+approximately	POS	O
+similar	POS	O
+potency	POS	O
+and	POS	O
+duration	POS	O
+to	POS	O
+VIP	POS	O
+.	POS	O
+Hypotension	POS	B-NP
+induced	POS	O
+by	POS	O
+both	POS	O
+peptides	POS	O
+was	POS	O
+significantly	POS	O
+attenuated	POS	O
+by	POS	O
+glibenclamide	POS	O
+,	POS	O
+which	POS	O
+abolished	POS	O
+a	POS	O
+levcromakalim	POS	O
+-	POS	O
+produced	POS	O
+decrease	POS	O
+in	POS	O
+arterial	POS	O
+blood	POS	O
+pressure	POS	O
+.	POS	O
+Oxyhemoglobin	POS	O
+did	POS	O
+not	POS	O
+affect	POS	O
+helodermin	POS	O
+-	POS	O
+induced	POS	O
+hypotension	POS	B-NP
+,	POS	O
+whereas	POS	O
+it	POS	O
+shortened	POS	O
+the	POS	O
+duration	POS	O
+of	POS	O
+acetylcholine	POS	O
+(	POS	O
+ACh	POS	O
+)	POS	O
+-	POS	O
+produced	POS	O
+hypotension	POS	B-NP
+.	POS	O
+These	POS	O
+findings	POS	O
+suggest	POS	O
+that	POS	O
+helodermin	POS	O
+-	POS	O
+produced	POS	O
+hypotension	POS	B-NP
+is	POS	O
+partly	POS	O
+attributable	POS	O
+to	POS	O
+the	POS	O
+activation	POS	O
+of	POS	O
+glibenclamide	POS	O
+-	POS	O
+sensitive	POS	O
+K	POS	O
++	POS	O
+channels	POS	O
+(	POS	O
+K	POS	O
+(	POS	O
+ATP	POS	O
+)	POS	O
+channels	POS	O
+)	POS	O
+,	POS	O
+which	POS	O
+presumably	POS	O
+exist	POS	O
+on	POS	O
+arterial	POS	O
+smooth	POS	O
+muscle	POS	O
+cells	POS	O
+.	POS	O
+EDRF	POS	O
+(	POS	O
+endothelium	POS	O
+-	POS	O
+derived	POS	O
+relaxing	POS	O
+factor	POS	O
+)	POS	O
+/	POS	O
+nitric	POS	O
+oxide	POS	O
+does	POS	O
+not	POS	O
+seem	POS	O
+to	POS	O
+play	POS	O
+an	POS	O
+important	POS	O
+role	POS	O
+in	POS	O
+the	POS	O
+peptide	POS	O
+-	POS	O
+produced	POS	O
+hypotension	POS	B-NP
+.	POS	O
+Long	POS	O
+-	POS	O
+term	POS	O
+efficacy	POS	O
+and	POS	O
+adverse	POS	O
+event	POS	O
+of	POS	O
+nifedipine	POS	O
+sustained	POS	O
+-	POS	O
+release	POS	O
+tablets	POS	O
+for	POS	O
+cyclosporin	POS	O
+A	POS	O
+-	POS	O
+induced	POS	O
+hypertension	POS	B-NP
+in	POS	O
+patients	POS	O
+with	POS	O
+psoriasis	POS	B-NP
+.	POS	O
+Thirteen	POS	O
+psoriatic	POS	B-NP
+patients	POS	O
+with	POS	O
+hypertension	POS	B-NP
+during	POS	O
+the	POS	O
+course	POS	O
+of	POS	O
+cyclosporin	POS	O
+A	POS	O
+therapy	POS	O
+were	POS	O
+treated	POS	O
+for	POS	O
+25	POS	O
+months	POS	O
+with	POS	O
+a	POS	O
+calcium	POS	O
+channel	POS	O
+blocker	POS	O
+,	POS	O
+sustained	POS	O
+-	POS	O
+release	POS	O
+nifedipine	POS	O
+,	POS	O
+to	POS	O
+study	POS	O
+the	POS	O
+clinical	POS	O
+antihypertensive	POS	O
+effects	POS	O
+and	POS	O
+adverse	POS	O
+events	POS	O
+during	POS	O
+treatment	POS	O
+with	POS	O
+both	POS	O
+drugs	POS	O
+.	POS	O
+Seven	POS	O
+of	POS	O
+the	POS	O
+13	POS	O
+patients	POS	O
+had	POS	O
+exhibited	POS	O
+a	POS	O
+subclinical	POS	O
+hypertensive	POS	B-NP
+state	POS	O
+before	POS	O
+cyclosporin	POS	O
+A	POS	O
+therapy	POS	O
+.	POS	O
+Both	POS	O
+systolic	POS	O
+and	POS	O
+diastolic	POS	O
+blood	POS	O
+pressures	POS	O
+of	POS	O
+these	POS	O
+13	POS	O
+patients	POS	O
+were	POS	O
+decreased	POS	O
+significantly	POS	O
+after	POS	O
+4	POS	O
+weeks	POS	O
+of	POS	O
+nifedipine	POS	O
+therapy	POS	O
+,	POS	O
+and	POS	O
+blood	POS	O
+pressure	POS	O
+was	POS	O
+maintained	POS	O
+within	POS	O
+the	POS	O
+normal	POS	O
+range	POS	O
+thereafter	POS	O
+for	POS	O
+25	POS	O
+months	POS	O
+.	POS	O
+The	POS	O
+adverse	POS	O
+events	POS	O
+during	POS	O
+combined	POS	O
+therapy	POS	O
+with	POS	O
+cyclosporin	POS	O
+A	POS	O
+and	POS	O
+nifedipine	POS	O
+included	POS	O
+an	POS	O
+increase	POS	O
+in	POS	O
+blood	POS	O
+urea	POS	O
+nitrogen	POS	O
+levels	POS	O
+in	POS	O
+9	POS	O
+of	POS	O
+the	POS	O
+13	POS	O
+patients	POS	O
+and	POS	O
+development	POS	O
+of	POS	O
+gingival	POS	B-NP
+hyperplasia	POS	I-NP
+in	POS	O
+2	POS	O
+of	POS	O
+the	POS	O
+13	POS	O
+patients	POS	O
+.	POS	O
+Our	POS	O
+findings	POS	O
+indicate	POS	O
+that	POS	O
+sustained	POS	O
+-	POS	O
+release	POS	O
+nifedipine	POS	O
+is	POS	O
+useful	POS	O
+for	POS	O
+hypertensive	POS	B-NP
+psoriatic	POS	I-NP
+patients	POS	O
+under	POS	O
+long	POS	O
+-	POS	O
+term	POS	O
+treatment	POS	O
+with	POS	O
+cyclosporin	POS	O
+A	POS	O
+,	POS	O
+but	POS	O
+that	POS	O
+these	POS	O
+patients	POS	O
+should	POS	O
+be	POS	O
+monitored	POS	O
+for	POS	O
+gingival	POS	B-NP
+hyperplasia	POS	I-NP
+.	POS	O
+
diff --git a/helper/evaluation/evaluation.py b/helper/evaluation/evaluation.py
new file mode 100644
index 0000000..e44c966
--- /dev/null
+++ b/helper/evaluation/evaluation.py
@@ -0,0 +1,30 @@
+
+def evaluate(ground_truth, prediction):
+    from seqeval.metrics import classification_report
+    import csv
+    """
+    Read prediction and ground_truth labels and pass labels to
+    classification_report
+    """
+
+    y_pred = []
+    y_true = []
+    with open(ground_truth, 'r') as f:
+        r = csv.reader(f, delimiter='\t', quotechar=None)
+        lines = list(r)
+        for line in lines:
+            if len(line) > 0:
+                y_pred.append(line[2])
+
+    with open(prediction, 'r') as f2:
+        reader = csv.reader(f2, delimiter='\t', quotechar=None)
+        for row in reader:
+            if any(field.strip() for field in row):
+                y_true.append(row[1])
+
+    print('y_true count :', len(y_true))
+    print('y_pred count :', len(y_pred))
+    print(classification_report(y_true, y_pred))
+
+
+evaluate('OUTPUT.tsv', 'test.tsv')
\ No newline at end of file
diff --git a/helper/evaluation/test_modified.tsv b/helper/evaluation/test_modified.tsv
new file mode 100644
index 0000000..adef417
--- /dev/null
+++ b/helper/evaluation/test_modified.tsv
@@ -0,0 +1,129546 @@
+Torsade	B-NP
+de	I-NP
+pointes	I-NP
+ventricular	B-NP
+tachycardia	I-NP
+during	O
+low	O
+dose	O
+intermittent	O
+dobutamine	O
+treatment	O
+in	O
+a	O
+patient	O
+with	O
+dilated	B-NP
+cardiomyopathy	I-NP
+and	O
+congestive	B-NP
+heart	I-NP
+failure	I-NP
+.	O
+	
+The	O
+authors	O
+describe	O
+the	O
+case	O
+of	O
+a	O
+56	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+chronic	O
+","	O
+severe	O
+heart	B-NP
+failure	I-NP
+secondary	O
+to	O
+dilated	B-NP
+cardiomyopathy	I-NP
+and	O
+absence	O
+of	O
+significant	O
+ventricular	B-NP
+arrhythmias	I-NP
+who	O
+developed	O
+QT	B-NP
+prolongation	I-NP
+and	O
+torsade	B-NP
+de	I-NP
+pointes	I-NP
+ventricular	B-NP
+tachycardia	I-NP
+during	O
+one	O
+cycle	O
+of	O
+intermittent	O
+low	O
+dose	O
+(	O
+2	O
+.	O
+5	O
+mcg	O
+/	O
+kg	O
+per	O
+min	O
+)	O
+dobutamine	O
+.	O
+	
+This	O
+report	O
+of	O
+torsade	B-NP
+de	I-NP
+pointes	I-NP
+ventricular	B-NP
+tachycardia	I-NP
+during	O
+intermittent	O
+dobutamine	O
+supports	O
+the	O
+hypothesis	O
+that	O
+unpredictable	O
+fatal	O
+arrhythmias	B-NP
+may	O
+occur	O
+even	O
+with	O
+low	O
+doses	O
+and	O
+in	O
+patients	O
+with	O
+no	O
+history	O
+of	O
+significant	O
+rhythm	O
+disturbances	O
+.	O
+	
+The	O
+mechanisms	O
+of	O
+proarrhythmic	O
+effects	O
+of	O
+Dubutamine	O
+are	O
+discussed	O
+.	O
+	
+Positive	O
+skin	O
+tests	O
+in	O
+late	O
+reactions	O
+to	O
+radiographic	O
+contrast	O
+media	O
+.	O
+	
+In	O
+the	O
+last	O
+few	O
+years	O
+delayed	O
+reactions	O
+several	O
+hours	O
+after	O
+the	O
+injection	O
+of	O
+radiographic	O
+and	O
+contrast	O
+materials	O
+(	O
+PRC	O
+)	O
+have	O
+been	O
+described	O
+with	O
+increasing	O
+frequency	O
+.	O
+	
+The	O
+authors	O
+report	O
+two	O
+observations	O
+on	O
+patients	O
+with	O
+delayed	O
+reactions	O
+in	O
+whom	O
+intradermoreactions	O
+(	O
+IDR	O
+)	O
+and	O
+patch	O
+tests	O
+to	O
+a	O
+series	O
+of	O
+ionic	O
+and	O
+non	O
+ionic	O
+PRC	O
+were	O
+studied	O
+.	O
+	
+After	O
+angiography	O
+by	O
+the	O
+venous	O
+route	O
+in	O
+patient	O
+n	O
+degree	O
+1	O
+a	O
+biphasic	O
+reaction	O
+with	O
+an	O
+immediate	O
+reaction	O
+(	O
+dyspnea	B-NP
+","	O
+loss	B-NP
+of	I-NP
+consciousness	I-NP
+)	O
+and	O
+delayed	O
+macro	B-NP
+-	I-NP
+papular	I-NP
+rash	I-NP
+appeared	O
+","	O
+whilst	O
+patient	O
+n	O
+degree	O
+2	O
+developed	O
+a	O
+generalised	O
+sensation	O
+of	O
+heat	O
+","	O
+persistent	O
+pain	B-NP
+at	O
+the	O
+site	O
+of	O
+injection	O
+immediately	O
+and	O
+a	O
+generalised	O
+macro	O
+-	O
+papular	O
+reaction	O
+after	O
+24	O
+hours	O
+.	O
+	
+The	O
+skin	O
+tests	O
+revealed	O
+positive	O
+delayed	O
+reactions	O
+of	O
+24	O
+hours	O
+and	O
+48	O
+hours	O
+by	O
+IDR	O
+and	O
+patch	O
+tests	O
+to	O
+only	O
+some	O
+PRC	O
+with	O
+common	O
+chains	O
+in	O
+their	O
+structures	O
+.	O
+	
+The	O
+positive	O
+skin	O
+tests	O
+are	O
+in	O
+favour	O
+of	O
+immunological	O
+reactions	O
+and	O
+may	O
+help	O
+in	O
+diagnosis	O
+of	O
+allergy	B-NP
+in	O
+the	O
+patients	O
+.	O
+	
+Risk	O
+of	O
+transient	O
+hyperammonemic	B-NP
+encephalopathy	I-NP
+in	O
+cancer	B-NP
+patients	O
+who	O
+received	O
+continuous	O
+infusion	O
+of	O
+5	O
+-	O
+fluorouracil	O
+with	O
+the	O
+complication	O
+of	O
+dehydration	B-NP
+and	O
+infection	B-NP
+.	O
+	
+From	O
+1986	O
+to	O
+1998	O
+","	O
+29	O
+cancer	B-NP
+patients	O
+who	O
+had	O
+32	O
+episodes	O
+of	O
+transient	O
+hyperammonemic	B-NP
+encephalopathy	I-NP
+related	O
+to	O
+continuous	O
+infusion	O
+of	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+were	O
+identified	O
+.	O
+	
+None	O
+of	O
+the	O
+patients	O
+had	O
+decompensated	O
+liver	B-NP
+disease	I-NP
+.	O
+	
+Onset	O
+of	O
+hyperammonemic	B-NP
+encephalopathy	I-NP
+varied	O
+from	O
+0	O
+.	O
+5	O
+to	O
+5	O
+days	O
+(	O
+mean	O
+:	O
+2	O
+.	O
+6	O
++	O
+/	O
+-	O
+1	O
+.	O
+3	O
+days	O
+)	O
+after	O
+the	O
+initiation	O
+of	O
+chemotherapy	O
+.	O
+	
+Plasma	O
+ammonium	O
+level	O
+ranged	O
+from	O
+248	O
+to	O
+2387	O
+microg	O
+%	O
+(	O
+mean	O
+:	O
+626	O
++	O
+/	O
+-	O
+431	O
+microg	O
+%	O
+)	O
+.	O
+	
+Among	O
+the	O
+32	O
+episodes	O
+","	O
+26	O
+(	O
+81	O
+%	O
+)	O
+had	O
+various	O
+degrees	O
+of	O
+azotemia	B-NP
+","	O
+18	O
+(	O
+56	O
+%	O
+)	O
+occurred	O
+during	O
+bacterial	B-NP
+infections	I-NP
+and	O
+14	O
+(	O
+44	O
+%	O
+)	O
+without	O
+infection	B-NP
+occurred	O
+during	O
+periods	O
+of	O
+dehydration	B-NP
+.	O
+	
+Higher	O
+plasma	O
+ammonium	O
+levels	O
+and	O
+more	O
+rapid	O
+onset	O
+of	O
+hyperammonemia	B-NP
+were	O
+seen	O
+in	O
+18	O
+patients	O
+with	O
+bacterial	B-NP
+infections	I-NP
+(	O
+p	O
+=	O
+0	O
+.	O
+3	O
+and	O
+0	O
+.	O
+6	O
+","	O
+respectively	O
+)	O
+and	O
+in	O
+nine	O
+patients	O
+receiving	O
+high	O
+daily	O
+doses	O
+(	O
+2600	O
+or	O
+1800	O
+mg	O
+/	O
+m2	O
+)	O
+of	O
+5	O
+-	O
+FU	O
+(	O
+p	O
+=	O
+0	O
+.	O
+1	O
+and	O
+<	O
+0	O
+.	O
+1	O
+","	O
+respectively	O
+)	O
+.	O
+	
+In	O
+25	O
+out	O
+of	O
+32	O
+episodes	O
+(	O
+78	O
+%	O
+)	O
+","	O
+plasma	O
+ammonium	O
+levels	O
+and	O
+mental	O
+status	O
+returned	O
+to	O
+normal	O
+within	O
+2	O
+days	O
+after	O
+adequate	O
+management	O
+.	O
+	
+In	O
+conclusion	O
+","	O
+hyperammonemic	B-NP
+encephalopathy	I-NP
+can	O
+occur	O
+in	O
+patients	O
+receiving	O
+continuous	O
+infusion	O
+of	O
+5	O
+-	O
+FU	O
+.	O
+	
+Azotemia	B-NP
+","	O
+body	O
+fluid	O
+insufficiency	O
+and	O
+bacterial	B-NP
+infections	I-NP
+were	O
+frequently	O
+found	O
+in	O
+these	O
+patients	O
+.	O
+	
+It	O
+is	O
+therefore	O
+important	O
+to	O
+recognize	O
+this	O
+condition	O
+in	O
+patients	O
+receiving	O
+continuous	O
+infusion	O
+of	O
+5	O
+-	O
+FU	O
+.	O
+	
+The	O
+effects	O
+of	O
+quinine	O
+and	O
+4	O
+-	O
+aminopyridine	O
+on	O
+conditioned	O
+place	O
+preference	O
+and	O
+changes	O
+in	O
+motor	O
+activity	O
+induced	O
+by	O
+morphine	O
+in	O
+rats	O
+.	O
+	
+1	O
+.	O
+	
+The	O
+effects	O
+of	O
+two	O
+unselective	O
+potassium	O
+(	O
+K	O
+(	O
++	O
+)	O
+-	O
+)	O
+channel	O
+blockers	O
+","	O
+quinine	O
+(	O
+12	O
+.	O
+5	O
+","	O
+25	O
+and	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+4	O
+-	O
+aminopyridine	O
+(	O
+1	O
+and	O
+2	O
+mg	O
+/	O
+kg	O
+)	O
+","	O
+on	O
+conditioned	O
+place	O
+preference	O
+and	O
+biphasic	O
+changes	O
+in	O
+motor	O
+activity	O
+induced	O
+by	O
+morphine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+were	O
+tested	O
+in	O
+Wistar	O
+rats	O
+.	O
+	
+Quinine	O
+is	O
+known	O
+to	O
+block	O
+voltage	O
+-	O
+","	O
+calcium	O
+-	O
+and	O
+ATP	O
+-	O
+sensitive	O
+K	O
+(	O
++	O
+)	O
+-	O
+channels	O
+while	O
+4	O
+-	O
+aminopyridine	O
+is	O
+known	O
+to	O
+block	O
+voltage	O
+-	O
+sensitive	O
+K	O
+(	O
++	O
+)	O
+-	O
+channels	O
+.	O
+	
+2	O
+.	O
+	
+In	O
+the	O
+counterbalanced	O
+method	O
+","	O
+quinine	O
+attenuated	O
+morphine	O
+-	O
+induced	O
+place	O
+preference	O
+","	O
+whereas	O
+4	O
+-	O
+aminopyridine	O
+was	O
+ineffective	O
+.	O
+	
+In	O
+the	O
+motor	O
+activity	O
+test	O
+measured	O
+with	O
+an	O
+Animex	O
+-	O
+activity	O
+meter	O
+neither	O
+of	O
+the	O
+K	O
+(	O
++	O
+)	O
+-	O
+channel	O
+blockers	O
+affected	O
+morphine	O
+-	O
+induced	O
+hypoactivity	B-NP
+","	O
+but	O
+both	O
+K	O
+(	O
++	O
+)	O
+-	O
+channel	O
+blockers	O
+prevented	O
+morphine	O
+-	O
+induced	O
+secondary	O
+hyperactivity	B-NP
+.	O
+	
+3	O
+.	O
+	
+These	O
+results	O
+suggest	O
+the	O
+involvement	O
+of	O
+quinine	O
+-	O
+sensitive	O
+but	O
+not	O
+4	O
+-	O
+aminopyridine	O
+-	O
+sensitive	O
+K	O
+(	O
++	O
+)	O
+-	O
+channels	O
+in	O
+morphine	O
+reward	O
+.	O
+	
+It	O
+is	O
+also	O
+suggested	O
+that	O
+the	O
+blockade	O
+of	O
+K	O
+(	O
++	O
+)	O
+-	O
+channels	O
+sensitive	O
+to	O
+these	O
+blockers	O
+is	O
+not	O
+sufficient	O
+to	O
+prevent	O
+morphine	O
+-	O
+induced	O
+hypoactivity	B-NP
+whereas	O
+morphine	O
+-	O
+induced	O
+hyperactivity	B-NP
+seems	O
+to	O
+be	O
+connected	O
+to	O
+both	O
+quinine	O
+-	O
+and	O
+4	O
+-	O
+aminopyridine	O
+-	O
+sensitive	O
+K	O
+(	O
++	O
+)	O
+-	O
+channels	O
+.	O
+	
+Nociceptin	O
+/	O
+orphanin	O
+FQ	O
+and	O
+nocistatin	O
+on	O
+learning	B-NP
+and	I-NP
+memory	I-NP
+impairment	I-NP
+induced	O
+by	O
+scopolamine	O
+in	O
+mice	O
+.	O
+	
+1	O
+.	O
+	
+Nociceptin	O
+","	O
+also	O
+known	O
+as	O
+orphanin	O
+FQ	O
+","	O
+is	O
+an	O
+endogenous	O
+ligand	O
+for	O
+the	O
+orphan	O
+opioid	O
+receptor	O
+-	O
+like	O
+receptor	O
+1	O
+(	O
+ORL1	O
+)	O
+and	O
+involves	O
+in	O
+various	O
+functions	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+.	O
+	
+On	O
+the	O
+other	O
+hand	O
+","	O
+nocistatin	O
+is	O
+recently	O
+isolated	O
+from	O
+the	O
+same	O
+precursor	O
+as	O
+nociceptin	O
+and	O
+blocks	O
+nociceptin	O
+-	O
+induced	O
+allodynia	B-NP
+and	O
+hyperalgesia	B-NP
+.	O
+	
+2	O
+.	O
+	
+Although	O
+ORL1	O
+receptors	O
+which	O
+display	O
+a	O
+high	O
+degree	O
+of	O
+sequence	O
+homology	O
+with	O
+classical	O
+opioid	O
+receptors	O
+are	O
+abundant	O
+in	O
+the	O
+hippocampus	O
+","	O
+little	O
+is	O
+known	O
+regarding	O
+their	O
+role	O
+in	O
+learning	O
+and	O
+memory	O
+.	O
+	
+3	O
+.	O
+	
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+investigate	O
+whether	O
+nociceptin	O
+/	O
+orphanin	O
+FQ	O
+and	O
+nocistatin	O
+could	O
+modulate	O
+impairment	B-NP
+of	I-NP
+learning	I-NP
+and	I-NP
+memory	I-NP
+induced	O
+by	O
+scopolamine	O
+","	O
+a	O
+muscarinic	O
+cholinergic	O
+receptor	O
+antagonist	O
+","	O
+using	O
+spontaneous	O
+alternation	O
+of	O
+Y	O
+-	O
+maze	O
+and	O
+step	O
+-	O
+down	O
+type	O
+passive	O
+avoidance	O
+tasks	O
+in	O
+mice	O
+.	O
+	
+4	O
+.	O
+	
+While	O
+nocistatin	O
+(	O
+0	O
+.	O
+5	O
+-	O
+5	O
+.	O
+0	O
+nmol	O
+mouse	O
+-	O
+1	O
+","	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+administered	O
+30	O
+min	O
+before	O
+spontaneous	O
+alternation	O
+performance	O
+or	O
+the	O
+training	O
+session	O
+of	O
+the	O
+passive	O
+avoidance	O
+task	O
+","	O
+had	O
+no	O
+effect	O
+on	O
+spontaneous	O
+alternation	O
+or	O
+passive	O
+avoidance	O
+behaviours	O
+","	O
+a	O
+lower	O
+per	O
+cent	O
+alternation	O
+and	O
+shorter	O
+median	O
+step	O
+-	O
+down	O
+latency	O
+in	O
+the	O
+retention	O
+test	O
+were	O
+obtained	O
+in	O
+nociceptin	O
+(	O
+1	O
+.	O
+5	O
+and	O
+/	O
+or	O
+5	O
+.	O
+0	O
+nmol	O
+mouse	O
+-	O
+1	O
+","	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+-	O
+treated	O
+normal	O
+mice	O
+.	O
+	
+5	O
+.	O
+	
+Administration	O
+of	O
+nocistatin	O
+(	O
+1	O
+.	O
+5	O
+and	O
+/	O
+or	O
+5	O
+.	O
+0	O
+nmol	O
+mouse	O
+-	O
+1	O
+","	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+30	O
+min	O
+before	O
+spontaneous	O
+alternation	O
+performance	O
+or	O
+the	O
+training	O
+session	O
+of	O
+the	O
+passive	O
+avoidance	O
+task	O
+","	O
+attenuated	O
+the	O
+scopolamine	O
+-	O
+induced	O
+impairment	O
+of	O
+spontaneous	O
+alternation	O
+and	O
+passive	O
+avoidance	O
+behaviours	O
+.	O
+	
+6	O
+.	O
+	
+These	O
+results	O
+indicated	O
+that	O
+nocistatin	O
+","	O
+a	O
+new	O
+biologically	O
+active	O
+peptide	O
+","	O
+ameliorates	O
+impairments	O
+of	O
+spontaneous	O
+alternation	O
+and	O
+passive	O
+avoidance	O
+induced	O
+by	O
+scopolamine	O
+","	O
+and	O
+suggested	O
+that	O
+these	O
+peptides	O
+play	O
+opposite	O
+roles	O
+in	O
+learning	O
+and	O
+memory	O
+.	O
+	
+Meloxicam	O
+-	O
+induced	O
+liver	B-NP
+toxicity	I-NP
+.	O
+	
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+female	O
+patient	O
+with	O
+rheumatoid	B-NP
+arthritis	I-NP
+who	O
+developed	O
+acute	O
+cytolytic	O
+hepatitis	B-NP
+due	O
+to	O
+meloxicam	O
+.	O
+	
+Recently	O
+introduced	O
+in	O
+Belgium	O
+","	O
+meloxicam	O
+is	O
+the	O
+first	O
+nonsteroidal	O
+antiinflammatory	O
+drug	O
+with	O
+selective	O
+action	O
+on	O
+the	O
+inducible	O
+form	O
+of	O
+cyclooxygenase	O
+2	O
+.	O
+	
+The	O
+acute	O
+cytolytic	O
+hepatitis	B-NP
+occurred	O
+rapidly	O
+after	O
+meloxicam	O
+administration	O
+and	O
+was	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+antinuclear	O
+antibodies	O
+suggesting	O
+a	O
+hypersensitivity	B-NP
+mechanism	O
+.	O
+	
+This	O
+first	O
+case	O
+of	O
+meloxicam	O
+related	O
+liver	B-NP
+toxicity	I-NP
+demonstrates	O
+the	O
+potential	O
+of	O
+this	O
+drug	O
+to	O
+induce	O
+hepatic	B-NP
+damage	I-NP
+.	O
+	
+Induction	O
+of	O
+apoptosis	O
+by	O
+remoxipride	O
+metabolites	O
+in	O
+HL60	O
+and	O
+CD34	O
++	O
+/	O
+CD19	O
+-	O
+human	O
+bone	O
+marrow	O
+progenitor	O
+cells	O
+:	O
+potential	O
+relevance	O
+to	O
+remoxipride	O
+-	O
+induced	O
+aplastic	B-NP
+anemia	I-NP
+.	O
+	
+The	O
+antipsychotic	O
+agent	O
+","	O
+remoxipride	O
+[	O
+(	O
+S	O
+)	O
+-	O
+(	O
+-	O
+)	O
+-	O
+3	O
+-	O
+bromo	O
+-	O
+N	O
+-	O
+[	O
+(	O
+1	O
+-	O
+ethyl	O
+-	O
+2	O
+-	O
+pyrrolidinyl	O
+)	O
+methyl	O
+]	O
+-	O
+2	O
+","	O
+6	O
+-	O
+dimethoxybenz	O
+amide	O
+]	O
+has	O
+been	O
+associated	O
+with	O
+acquired	O
+aplastic	B-NP
+anemia	I-NP
+.	O
+	
+We	O
+have	O
+examined	O
+the	O
+ability	O
+of	O
+remoxipride	O
+","	O
+three	O
+pyrrolidine	O
+ring	O
+metabolites	O
+and	O
+five	O
+aromatic	O
+ring	O
+metabolites	O
+of	O
+the	O
+parent	O
+compound	O
+to	O
+induce	O
+apoptosis	O
+in	O
+HL60	O
+cells	O
+and	O
+human	O
+bone	O
+marrow	O
+progenitor	O
+(	O
+HBMP	O
+)	O
+cells	O
+.	O
+	
+Cells	O
+were	O
+treated	O
+for	O
+0	O
+-	O
+24	O
+h	O
+with	O
+each	O
+compound	O
+(	O
+0	O
+-	O
+200	O
+microM	O
+)	O
+.	O
+	
+Apoptosis	O
+was	O
+assessed	O
+by	O
+fluorescence	O
+microscopy	O
+in	O
+Hoechst	O
+33342	O
+-	O
+and	O
+propidium	O
+iodide	O
+stained	O
+cell	O
+samples	O
+.	O
+	
+Results	O
+were	O
+confirmed	O
+by	O
+determination	O
+of	O
+internucleosomal	O
+DNA	O
+fragmentation	O
+using	O
+gel	O
+electrophoresis	O
+for	O
+HL60	O
+cell	O
+samples	O
+and	O
+terminal	O
+deoxynucleotidyl	O
+transferase	O
+assay	O
+in	O
+HBMP	O
+cells	O
+.	O
+	
+The	O
+catechol	O
+and	O
+hydroquinone	O
+metabolites	O
+","	O
+NCQ436	O
+and	O
+NCQ344	O
+","	O
+induced	O
+apoptosis	O
+in	O
+HL60	O
+and	O
+HBMP	O
+cells	O
+in	O
+a	O
+time	O
+-	O
+and	O
+concentration	O
+dependent	O
+manner	O
+","	O
+while	O
+the	O
+phenols	O
+","	O
+NCR181	O
+","	O
+FLA873	O
+","	O
+and	O
+FLA797	O
+","	O
+and	O
+the	O
+derivatives	O
+formed	O
+by	O
+oxidation	O
+of	O
+the	O
+pyrrolidine	O
+ring	O
+","	O
+FLA838	O
+","	O
+NCM001	O
+","	O
+and	O
+NCL118	O
+","	O
+had	O
+no	O
+effect	O
+.	O
+	
+No	O
+necrosis	B-NP
+was	O
+observed	O
+in	O
+cells	O
+treated	O
+with	O
+NCQ436	O
+but	O
+NCQ344	O
+had	O
+a	O
+biphasic	O
+effect	O
+in	O
+both	O
+cell	O
+types	O
+","	O
+inducing	O
+apoptosis	O
+at	O
+lower	O
+concentrations	O
+and	O
+necrosis	B-NP
+at	O
+higher	O
+concentrations	O
+.	O
+	
+These	O
+data	O
+show	O
+that	O
+the	O
+catechol	O
+and	O
+hydroquinone	O
+metabolites	O
+of	O
+remoxipride	O
+have	O
+direct	O
+toxic	O
+effects	O
+in	O
+HL60	O
+and	O
+HBMP	O
+cells	O
+","	O
+leading	O
+to	O
+apoptosis	O
+","	O
+while	O
+the	O
+phenol	O
+metabolites	O
+were	O
+inactive	O
+.	O
+	
+Similarly	O
+","	O
+benzene	O
+-	O
+derived	O
+catechol	O
+and	O
+hydroquinone	O
+","	O
+but	O
+not	O
+phenol	O
+","	O
+induce	O
+apoptosis	O
+in	O
+HBMP	O
+cells	O
+[	O
+Moran	O
+et	O
+al	O
+.	O
+","	O
+Mol	O
+.	O
+Pharmacol	O
+.	O
+","	O
+50	O
+(	O
+1996	O
+)	O
+610	O
+-	O
+615	O
+]	O
+.	O
+	
+We	O
+propose	O
+that	O
+remoxipride	O
+and	O
+benzene	O
+may	O
+induce	O
+aplastic	B-NP
+anemia	I-NP
+via	O
+production	O
+of	O
+similar	O
+reactive	O
+metabolites	O
+and	O
+that	O
+the	O
+ability	O
+of	O
+NCQ436	O
+and	O
+NCQ344	O
+to	O
+induce	O
+apoptosis	O
+in	O
+HBMP	O
+cells	O
+may	O
+contribute	O
+to	O
+the	O
+mechanism	O
+underlying	O
+acquired	O
+aplastic	B-NP
+anemia	I-NP
+that	O
+has	O
+been	O
+associated	O
+with	O
+remoxipride	O
+.	O
+	
+Synthesis	O
+and	O
+preliminary	O
+pharmacological	O
+investigations	O
+of	O
+1	O
+-	O
+(	O
+1	O
+","	O
+2	O
+-	O
+dihydro	O
+-	O
+2	O
+-	O
+acenaphthylenyl	O
+)	O
+piperazine	O
+derivatives	O
+as	O
+potential	O
+atypical	O
+antipsychotic	O
+agents	O
+in	O
+mice	O
+.	O
+	
+In	O
+research	O
+towards	O
+the	O
+development	O
+of	O
+new	O
+atypical	O
+antipsychotic	O
+agents	O
+","	O
+one	O
+strategy	O
+is	O
+that	O
+the	O
+dopaminergic	O
+system	O
+can	O
+be	O
+modulated	O
+through	O
+manipulation	O
+of	O
+the	O
+serotonergic	O
+system	O
+.	O
+	
+The	O
+synthesis	O
+and	O
+preliminary	O
+pharmacological	O
+evaluation	O
+of	O
+a	O
+series	O
+of	O
+potential	O
+atypical	O
+antipsychotic	O
+agents	O
+based	O
+on	O
+the	O
+structure	O
+of	O
+1	O
+-	O
+(	O
+1	O
+","	O
+2	O
+-	O
+dihydro	O
+-	O
+2	O
+-	O
+acenaphthylenyl	O
+)	O
+piperazine	O
+(	O
+7	O
+)	O
+is	O
+described	O
+.	O
+	
+Compound	O
+7e	O
+","	O
+5	O
+-	O
+{	O
+2	O
+-	O
+[	O
+4	O
+-	O
+(	O
+1	O
+","	O
+2	O
+-	O
+dihydro	O
+-	O
+2	O
+-	O
+acenaphthylenyl	O
+)	O
+piperazinyl	O
+]	O
+ethyl	O
+}	O
+-	O
+2	O
+","	O
+3	O
+-	O
+dihy	O
+dro	O
+-	O
+1H	O
+-	O
+indol	O
+-	O
+2	O
+-	O
+one	O
+","	O
+from	O
+this	O
+series	O
+showed	O
+significant	O
+affinities	O
+at	O
+the	O
+5	O
+-	O
+HT1A	O
+and	O
+5	O
+-	O
+HT2A	O
+receptors	O
+and	O
+moderate	O
+affinity	O
+at	O
+the	O
+D2	O
+receptor	O
+.	O
+	
+7e	O
+exhibits	O
+a	O
+high	O
+reversal	O
+of	O
+catalepsy	B-NP
+induced	O
+by	O
+haloperidol	O
+indicating	O
+its	O
+atypical	O
+antipsychotic	O
+nature	O
+.	O
+	
+Sub	O
+-	O
+chronic	O
+inhibition	O
+of	O
+nitric	O
+-	O
+oxide	O
+synthesis	O
+modifies	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B-NP
+and	O
+the	O
+number	O
+of	O
+NADPH	O
+-	O
+diaphorase	O
+neurons	O
+in	O
+mice	O
+.	O
+	
+RATIONALE	O
+:	O
+NG	O
+-	O
+nitro	O
+-	O
+L	O
+-	O
+arginine	O
+(	O
+L	O
+-	O
+NOARG	O
+)	O
+","	O
+an	O
+inhibitor	O
+of	O
+nitric	O
+-	O
+oxide	O
+synthase	O
+(	O
+NOS	O
+)	O
+","	O
+induces	O
+catalepsy	B-NP
+in	O
+mice	O
+.	O
+	
+This	O
+effect	O
+undergoes	O
+rapid	O
+tolerance	O
+","	O
+showing	O
+a	O
+significant	O
+decrease	O
+after	O
+2	O
+days	O
+of	O
+sub	O
+-	O
+chronic	O
+L	O
+-	O
+NOARG	O
+treatment	O
+.	O
+	
+Nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+has	O
+been	O
+shown	O
+to	O
+influence	O
+dopaminergic	O
+neurotransmission	O
+in	O
+the	O
+striatum	O
+.	O
+	
+Neuroleptic	O
+drugs	O
+such	O
+as	O
+haloperidol	O
+","	O
+which	O
+block	O
+dopamine	O
+receptors	O
+","	O
+also	O
+cause	O
+catalepsy	B-NP
+in	O
+rodents	O
+.	O
+	
+OBJECTIVES	O
+:	O
+To	O
+investigate	O
+the	O
+effects	O
+of	O
+subchronic	O
+L	O
+-	O
+NOARG	O
+treatment	O
+in	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B-NP
+and	O
+the	O
+number	O
+of	O
+NOS	O
+neurons	O
+in	O
+areas	O
+related	O
+to	O
+motor	O
+control	O
+.	O
+	
+METHODS	O
+:	O
+Male	O
+albino	O
+Swiss	O
+mice	O
+were	O
+treated	O
+sub	O
+-	O
+chronically	O
+(	O
+twice	O
+a	O
+day	O
+for	O
+4	O
+days	O
+)	O
+with	O
+L	O
+-	O
+NOARG	O
+(	O
+40	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+or	O
+haloperidol	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+	
+Catalepsy	B-NP
+was	O
+evaluated	O
+at	O
+the	O
+beginning	O
+and	O
+the	O
+end	O
+of	O
+the	O
+treatments	O
+.	O
+	
+Reduced	O
+nicotinamide	O
+adenine	O
+dinucleotide	O
+phosphate	O
+-	O
+diaphorase	O
+(	O
+NADPH	O
+-	O
+d	O
+)	O
+histochemistry	O
+was	O
+also	O
+employed	O
+to	O
+visualize	O
+NOS	O
+as	O
+an	O
+index	O
+of	O
+enzyme	O
+expression	O
+in	O
+mice	O
+brain	O
+regions	O
+related	O
+to	O
+motor	O
+control	O
+.	O
+	
+RESULTS	O
+:	O
+L	O
+-	O
+NOARG	O
+sub	O
+-	O
+chronic	O
+administration	O
+produced	O
+tolerance	O
+of	O
+L	O
+-	O
+NOARG	O
+and	O
+of	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B-NP
+.	O
+	
+It	O
+also	O
+induced	O
+an	O
+increase	O
+in	O
+the	O
+number	O
+of	O
+NADPH	O
+-	O
+d	O
+-	O
+positive	O
+cells	O
+in	O
+the	O
+dorsal	O
+part	O
+of	O
+the	O
+caudate	O
+and	O
+accumbens	O
+nuclei	O
+compared	O
+with	O
+haloperidol	O
+and	O
+in	O
+the	O
+pedunculopontine	O
+tegmental	O
+nucleus	O
+compared	O
+with	O
+saline	O
+.	O
+	
+In	O
+contrast	O
+","	O
+there	O
+was	O
+a	O
+decrease	O
+in	O
+NADPH	O
+-	O
+d	O
+neuron	O
+number	O
+in	O
+the	O
+substantia	O
+nigra	O
+","	O
+pars	O
+compacta	O
+in	O
+both	O
+haloperidol	O
+-	O
+treated	O
+and	O
+L	O
+-	O
+NOARG	O
+-	O
+treated	O
+animals	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+results	O
+give	O
+further	O
+support	O
+to	O
+the	O
+hypothesis	O
+that	O
+NO	O
+plays	O
+a	O
+role	O
+in	O
+motor	O
+behavior	O
+control	O
+and	O
+suggest	O
+that	O
+it	O
+may	O
+take	O
+part	O
+in	O
+the	O
+synaptic	O
+changes	O
+produced	O
+by	O
+antipsychotic	O
+treatment	O
+.	O
+	
+Prolonged	O
+left	B-NP
+ventricular	I-NP
+dysfunction	I-NP
+occurs	O
+in	O
+patients	O
+with	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+after	O
+both	O
+dobutamine	O
+and	O
+exercise	O
+induced	O
+myocardial	B-NP
+ischaemia	I-NP
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+determine	O
+whether	O
+pharmacological	O
+stress	O
+leads	O
+to	O
+prolonged	O
+but	O
+reversible	O
+left	B-NP
+ventricular	I-NP
+dysfunction	I-NP
+in	O
+patients	O
+with	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+","	O
+similar	O
+to	O
+that	O
+seen	O
+after	O
+exercise	O
+.	O
+	
+DESIGN	O
+:	O
+A	O
+randomised	O
+crossover	O
+study	O
+of	O
+recovery	O
+time	O
+of	O
+systolic	O
+and	O
+diastolic	O
+left	O
+ventricular	O
+function	O
+after	O
+exercise	O
+and	O
+dobutamine	O
+induced	O
+ischaemia	B-NP
+.	O
+	
+SUBJECTS	O
+:	O
+10	O
+patients	O
+with	O
+stable	B-NP
+angina	I-NP
+","	O
+angiographically	O
+proven	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+","	O
+and	O
+normal	O
+left	O
+ventricular	O
+function	O
+.	O
+	
+INTERVENTIONS	O
+:	O
+Treadmill	O
+exercise	O
+and	O
+dobutamine	O
+stress	O
+were	O
+performed	O
+on	O
+different	O
+days	O
+.	O
+	
+Quantitative	O
+assessment	O
+of	O
+systolic	O
+and	O
+diastolic	O
+left	O
+ventricular	O
+function	O
+was	O
+performed	O
+using	O
+transthoracic	O
+echocardiography	O
+at	O
+baseline	O
+and	O
+at	O
+regular	O
+intervals	O
+after	O
+each	O
+test	O
+.	O
+	
+RESULTS	O
+:	O
+Both	O
+forms	O
+of	O
+stress	O
+led	O
+to	O
+prolonged	O
+but	O
+reversible	O
+systolic	O
+and	O
+diastolic	O
+dysfunction	O
+.	O
+	
+There	O
+was	O
+no	O
+difference	O
+in	O
+the	O
+maximum	O
+double	O
+product	O
+(	O
+p	O
+=	O
+0	O
+.	O
+53	O
+)	O
+or	O
+ST	O
+depression	B-NP
+(	O
+p	O
+=	O
+0	O
+.	O
+63	O
+)	O
+with	O
+either	O
+form	O
+of	O
+stress	O
+.	O
+	
+After	O
+exercise	O
+","	O
+ejection	O
+fraction	O
+was	O
+reduced	O
+at	O
+15	O
+and	O
+30	O
+minutes	O
+compared	O
+with	O
+baseline	O
+(	O
+mean	O
+(	O
+SEM	O
+)	O
+","	O
+-	O
+5	O
+.	O
+6	O
+(	O
+1	O
+.	O
+5	O
+)	O
+%	O
+","	O
+p	O
+<	O
+0	O
+.	O
+5	O
+;	O
+and	O
+-	O
+6	O
+.	O
+1	O
+(	O
+2	O
+.	O
+2	O
+)	O
+%	O
+","	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+","	O
+and	O
+at	O
+30	O
+and	O
+45	O
+minutes	O
+after	O
+dobutamine	O
+(	O
+-	O
+10	O
+.	O
+8	O
+(	O
+1	O
+.	O
+8	O
+)	O
+%	O
+and	O
+-	O
+5	O
+.	O
+5	O
+(	O
+1	O
+.	O
+8	O
+)	O
+%	O
+","	O
+both	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Regional	O
+analysis	O
+showed	O
+a	O
+reduction	O
+in	O
+the	O
+worst	O
+affected	O
+segment	O
+15	O
+and	O
+30	O
+minutes	O
+after	O
+exercise	O
+(	O
+-	O
+27	O
+.	O
+9	O
+(	O
+7	O
+.	O
+2	O
+)	O
+%	O
+and	O
+-	O
+28	O
+.	O
+6	O
+(	O
+5	O
+.	O
+7	O
+)	O
+%	O
+","	O
+both	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+","	O
+and	O
+at	O
+30	O
+minutes	O
+after	O
+dobutamine	O
+(	O
+-	O
+32	O
+(	O
+5	O
+.	O
+3	O
+)	O
+%	O
+","	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+The	O
+isovolumic	O
+relaxation	O
+period	O
+was	O
+prolonged	O
+45	O
+minutes	O
+after	O
+each	O
+form	O
+of	O
+stress	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+In	O
+patients	O
+with	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+","	O
+dobutamine	O
+induced	O
+ischaemia	B-NP
+results	O
+in	O
+prolonged	O
+reversible	O
+left	B-NP
+ventricular	I-NP
+dysfunction	I-NP
+","	O
+presumed	O
+to	O
+be	O
+myocardial	B-NP
+stunning	I-NP
+","	O
+similar	O
+to	O
+that	O
+seen	O
+after	O
+exercise	O
+.	O
+	
+Dobutamine	O
+induced	O
+ischaemia	B-NP
+could	O
+therefore	O
+be	O
+used	O
+to	O
+study	O
+the	O
+pathophysiology	O
+of	O
+this	O
+phenomenon	O
+further	O
+in	O
+patients	O
+with	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+.	O
+	
+Anorexigens	O
+and	O
+pulmonary	B-NP
+hypertension	I-NP
+in	O
+the	O
+United	O
+States	O
+:	O
+results	O
+from	O
+the	O
+surveillance	O
+of	O
+North	O
+American	O
+pulmonary	B-NP
+hypertension	I-NP
+.	O
+	
+BACKGROUND	O
+:	O
+The	O
+use	O
+of	O
+appetite	O
+suppressants	O
+in	O
+Europe	O
+has	O
+been	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+primary	B-NP
+pulmonary	I-NP
+hypertension	I-NP
+(	O
+PPH	B-NP
+)	O
+.	O
+	
+Recently	O
+","	O
+fenfluramine	O
+appetite	O
+suppressants	O
+became	O
+widely	O
+used	O
+in	O
+the	O
+United	O
+States	O
+but	O
+were	O
+withdrawn	O
+in	O
+September	O
+1997	O
+because	O
+of	O
+concerns	O
+over	O
+adverse	O
+effects	O
+.	O
+	
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+We	O
+conducted	O
+a	O
+prospective	O
+surveillance	O
+study	O
+on	O
+patients	O
+diagnosed	O
+with	O
+pulmonary	B-NP
+hypertension	I-NP
+at	O
+12	O
+large	O
+referral	O
+centers	O
+in	O
+North	O
+America	O
+.	O
+	
+Data	O
+collected	O
+on	O
+patients	O
+seen	O
+from	O
+September	O
+1	O
+","	O
+1996	O
+","	O
+to	O
+December	O
+31	O
+","	O
+1997	O
+","	O
+included	O
+the	O
+cause	O
+of	O
+the	O
+pulmonary	B-NP
+hypertension	I-NP
+and	O
+its	O
+severity	O
+.	O
+	
+Patients	O
+with	O
+no	O
+identifiable	O
+cause	O
+of	O
+pulmonary	B-NP
+hypertension	I-NP
+were	O
+classed	O
+as	O
+PPH	B-NP
+.	O
+	
+A	O
+history	O
+of	O
+drug	O
+exposure	O
+also	O
+was	O
+taken	O
+with	O
+special	O
+attention	O
+on	O
+the	O
+use	O
+of	O
+antidepressants	O
+","	O
+anorexigens	O
+","	O
+and	O
+amphetamines	O
+.	O
+	
+RESULTS	O
+:	O
+Five	O
+hundred	O
+seventy	O
+-	O
+nine	O
+patients	O
+were	O
+studied	O
+","	O
+205	O
+with	O
+PPH	B-NP
+and	O
+374	O
+with	O
+pulmonary	B-NP
+hypertension	I-NP
+from	O
+other	O
+causes	O
+(	O
+secondary	O
+pulmonary	B-NP
+hypertension	I-NP
+[	O
+SPH	O
+]	O
+)	O
+.	O
+	
+The	O
+use	O
+of	O
+anorexigens	O
+was	O
+common	O
+in	O
+both	O
+groups	O
+.	O
+	
+However	O
+","	O
+of	O
+the	O
+medications	O
+surveyed	O
+","	O
+only	O
+the	O
+fenfluramines	O
+had	O
+a	O
+significant	O
+preferential	O
+association	O
+with	O
+PPH	B-NP
+as	O
+compared	O
+with	O
+SPH	O
+(	O
+adjusted	O
+odds	O
+ratio	O
+for	O
+use	O
+>	O
+6	O
+months	O
+","	O
+7	O
+.	O
+5	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+","	O
+1	O
+.	O
+7	O
+to	O
+32	O
+.	O
+4	O
+)	O
+.	O
+	
+The	O
+association	O
+was	O
+stronger	O
+with	O
+longer	O
+duration	O
+of	O
+use	O
+when	O
+compared	O
+to	O
+shorter	O
+duration	O
+of	O
+use	O
+and	O
+was	O
+more	O
+pronounced	O
+in	O
+recent	O
+users	O
+than	O
+in	O
+remote	O
+users	O
+.	O
+	
+An	O
+unexpectedly	O
+high	O
+(	O
+11	O
+.	O
+4	O
+%	O
+)	O
+number	O
+of	O
+patients	O
+with	O
+SPH	O
+had	O
+used	O
+anorexigens	O
+.	O
+	
+CONCLUSION	O
+:	O
+The	O
+magnitude	O
+of	O
+the	O
+association	O
+with	O
+PPH	B-NP
+","	O
+the	O
+increase	O
+of	O
+association	O
+with	O
+increasing	O
+duration	O
+of	O
+use	O
+","	O
+and	O
+the	O
+specificity	O
+for	O
+fenfluramines	O
+are	O
+consistent	O
+with	O
+previous	O
+studies	O
+indicating	O
+that	O
+fenfluramines	O
+are	O
+causally	O
+related	O
+to	O
+PPH	B-NP
+.	O
+	
+The	O
+high	O
+prevalence	O
+of	O
+anorexigen	O
+use	O
+in	O
+patients	O
+with	O
+SPH	O
+also	O
+raises	O
+the	O
+possibility	O
+that	O
+these	O
+drugs	O
+precipitate	O
+pulmonary	B-NP
+hypertension	I-NP
+in	O
+patients	O
+with	O
+underlying	O
+conditions	O
+associated	O
+with	O
+SPH	O
+.	O
+	
+Clinical	O
+aspects	O
+of	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+and	O
+thrombosis	B-NP
+and	O
+other	O
+side	O
+effects	O
+of	O
+heparin	O
+therapy	O
+.	O
+	
+Heparin	O
+","	O
+first	O
+used	O
+to	O
+prevent	O
+the	O
+clotting	O
+of	O
+blood	O
+in	O
+vitro	O
+","	O
+has	O
+been	O
+clinically	O
+used	O
+to	O
+treat	O
+thrombosis	B-NP
+for	O
+more	O
+than	O
+50	O
+years	O
+.	O
+	
+Although	O
+several	O
+new	O
+anticoagulant	O
+drugs	O
+are	O
+in	O
+development	O
+","	O
+heparin	O
+remains	O
+the	O
+anticoagulant	O
+of	O
+choice	O
+to	O
+treat	O
+acute	O
+thrombotic	B-NP
+episodes	O
+.	O
+	
+The	O
+clinical	O
+effects	O
+of	O
+heparin	O
+are	O
+meritorious	O
+","	O
+but	O
+side	O
+effects	O
+do	O
+exist	O
+.	O
+	
+Bleeding	B-NP
+is	O
+the	O
+primary	O
+untoward	O
+effect	O
+of	O
+heparin	O
+.	O
+	
+Major	O
+bleeding	B-NP
+is	O
+of	O
+primary	O
+concern	O
+in	O
+patients	O
+receiving	O
+heparin	O
+therapy	O
+.	O
+	
+However	O
+","	O
+additional	O
+important	O
+untoward	O
+effects	O
+of	O
+heparin	O
+therapy	O
+include	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+","	O
+heparin	O
+-	O
+associated	O
+osteoporosis	B-NP
+","	O
+eosinophilia	B-NP
+","	O
+skin	B-NP
+reactions	I-NP
+","	O
+allergic	B-NP
+reactions	I-NP
+other	O
+than	O
+thrombocytopenia	B-NP
+","	O
+alopecia	B-NP
+","	O
+transaminasemia	O
+","	O
+hyperkalemia	B-NP
+","	O
+hypoaldosteronism	B-NP
+","	O
+and	O
+priapism	B-NP
+.	O
+	
+These	O
+side	O
+effects	O
+are	O
+relatively	O
+rare	O
+in	O
+a	O
+given	O
+individual	O
+","	O
+but	O
+given	O
+the	O
+extremely	O
+widespread	O
+use	O
+of	O
+heparin	O
+","	O
+some	O
+are	O
+quite	O
+common	O
+","	O
+particularly	O
+HITT	B-NP
+and	O
+osteoporosis	B-NP
+.	O
+	
+Although	O
+reasonable	O
+incidences	O
+of	O
+many	O
+of	O
+these	O
+side	O
+effects	O
+can	O
+be	O
+"	O
+softly	O
+"	O
+deduced	O
+from	O
+current	O
+reports	O
+dealing	O
+with	O
+unfractionated	O
+heparin	O
+","	O
+at	O
+present	O
+the	O
+incidences	O
+of	O
+these	O
+side	O
+effects	O
+with	O
+newer	O
+low	O
+molecular	O
+weight	O
+heparins	O
+appear	O
+to	O
+be	O
+much	O
+less	O
+common	O
+.	O
+	
+However	O
+","	O
+only	O
+longer	O
+experience	O
+will	O
+more	O
+clearly	O
+define	O
+the	O
+incidence	O
+of	O
+each	O
+side	O
+effect	O
+with	O
+low	O
+molecular	O
+weight	O
+preparations	O
+.	O
+	
+A	O
+case	O
+of	O
+bilateral	O
+optic	B-NP
+neuropathy	I-NP
+in	O
+a	O
+patient	O
+on	O
+tacrolimus	O
+(	O
+FK506	O
+)	O
+therapy	O
+after	O
+liver	O
+transplantation	O
+.	O
+	
+PURPOSE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+bilateral	O
+optic	B-NP
+neuropathy	I-NP
+in	O
+a	O
+patient	O
+receiving	O
+tacrolimus	O
+(	O
+FK	O
+506	O
+","	O
+Prograf	O
+;	O
+Fujisawa	O
+USA	O
+","	O
+Inc	O
+","	O
+Deerfield	O
+","	O
+Illinois	O
+)	O
+for	O
+immunosuppression	O
+after	O
+orthotropic	O
+liver	O
+transplantation	O
+.	O
+	
+METHOD	O
+:	O
+Case	O
+report	O
+.	O
+	
+In	O
+a	O
+58	O
+-	O
+year	O
+-	O
+old	O
+man	O
+receiving	O
+tacrolimus	O
+after	O
+orthotropic	O
+liver	O
+transplantation	O
+","	O
+serial	O
+neuro	O
+-	O
+ophthalmologic	O
+examinations	O
+and	O
+laboratory	O
+studies	O
+were	O
+performed	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+patient	O
+had	O
+episodic	O
+deterioration	O
+of	O
+vision	O
+in	O
+both	O
+eyes	O
+","	O
+with	O
+clinical	O
+features	O
+resembling	O
+ischemic	B-NP
+optic	I-NP
+neuropathies	I-NP
+.	O
+	
+Deterioration	B-NP
+of	I-NP
+vision	I-NP
+occurred	O
+despite	O
+discontinuation	O
+of	O
+the	O
+tacrolimus	O
+.	O
+	
+CONCLUSION	O
+:	O
+Tacrolimus	O
+and	O
+other	O
+immunosuppressive	O
+agents	O
+may	O
+be	O
+associated	O
+with	O
+optic	B-NP
+nerve	I-NP
+toxicity	I-NP
+.	O
+	
+Hypercalcemia	B-NP
+","	O
+arrhythmia	B-NP
+","	O
+and	O
+mood	O
+stabilizers	O
+.	O
+	
+Recent	O
+findings	O
+in	O
+a	O
+bipolar	B-NP
+patient	O
+receiving	O
+maintenance	O
+lithium	O
+therapy	O
+who	O
+developed	O
+hypercalcemia	B-NP
+and	O
+severe	O
+bradyarrhythmia	B-NP
+prompted	O
+the	O
+authors	O
+to	O
+conduct	O
+a	O
+retrospective	O
+study	O
+of	O
+bipolar	B-NP
+patients	O
+with	O
+lithium	O
+-	O
+associated	O
+hypercalcemia	B-NP
+.	O
+	
+A	O
+printout	O
+of	O
+all	O
+cases	O
+of	O
+hypercalcemia	B-NP
+that	O
+presented	O
+during	O
+a	O
+1	O
+-	O
+year	O
+period	O
+was	O
+generated	O
+.	O
+	
+After	O
+eliminating	O
+spurious	O
+hypercalcemias	B-NP
+or	O
+those	O
+associated	O
+with	O
+intravenous	O
+fluids	O
+","	O
+the	O
+authors	O
+identified	O
+18	O
+non	O
+-	O
+lithium	O
+-	O
+treated	O
+patients	O
+with	O
+hypercalcemias	B-NP
+related	O
+to	O
+malignancies	B-NP
+and	O
+other	O
+medical	O
+conditions	O
+(	O
+group	O
+A	O
+)	O
+and	O
+12	O
+patients	O
+with	O
+lithium	O
+-	O
+associated	O
+hypercalcemia	B-NP
+(	O
+group	O
+B	O
+)	O
+.	O
+	
+Patients	O
+in	O
+group	O
+B	O
+were	O
+not	O
+comparable	O
+to	O
+those	O
+in	O
+group	O
+A	O
+","	O
+as	O
+the	O
+latter	O
+were	O
+medically	O
+compromised	O
+and	O
+were	O
+receiving	O
+multiple	O
+pharmacotherapies	O
+.	O
+	
+Thus	O
+","	O
+two	O
+control	O
+groups	O
+were	O
+generated	O
+:	O
+group	O
+C1	O
+","	O
+which	O
+included	O
+age	O
+-	O
+and	O
+sex	O
+-	O
+comparable	O
+lithium	O
+-	O
+treated	O
+bipolar	B-NP
+normocalcemic	O
+patients	O
+","	O
+and	O
+group	O
+C2	O
+","	O
+which	O
+included	O
+bipolar	B-NP
+normocalcemic	O
+patients	O
+treated	O
+with	O
+anticonvulsant	O
+mood	O
+stabilizers	O
+.	O
+	
+The	O
+electrocardiographic	O
+(	O
+ECG	O
+)	O
+findings	O
+for	O
+patients	O
+in	O
+group	O
+B	O
+were	O
+compared	O
+with	O
+those	O
+of	O
+patients	O
+in	O
+groups	O
+C1	O
+and	O
+C2	O
+.	O
+	
+It	O
+was	O
+found	O
+that	O
+these	O
+groups	O
+did	O
+not	O
+differ	O
+in	O
+their	O
+overall	O
+frequency	O
+of	O
+ECG	O
+abnormalities	O
+;	O
+however	O
+","	O
+there	O
+were	O
+significant	O
+differences	O
+in	O
+the	O
+frequency	O
+of	O
+conduction	O
+defects	O
+.	O
+	
+Patients	O
+with	O
+hypercalcemia	B-NP
+resulting	O
+from	O
+medical	O
+diseases	O
+and	O
+bipolar	B-NP
+patients	O
+with	O
+lithium	O
+-	O
+associated	O
+hypercalcemia	B-NP
+had	O
+significantly	O
+higher	O
+frequencies	O
+of	O
+conduction	O
+defects	O
+.	O
+	
+Patients	O
+in	O
+group	O
+A	O
+had	O
+significant	O
+mortality	O
+at	O
+2	O
+-	O
+year	O
+follow	O
+-	O
+up	O
+(	O
+28	O
+%	O
+)	O
+","	O
+in	O
+contrast	O
+to	O
+zero	O
+mortality	O
+in	O
+the	O
+other	O
+three	O
+groups	O
+.	O
+	
+The	O
+clinical	O
+implications	O
+of	O
+these	O
+findings	O
+are	O
+discussed	O
+.	O
+	
+Attenuation	O
+of	O
+nephrotoxicity	B-NP
+by	O
+a	O
+novel	O
+lipid	O
+nanosphere	O
+(	O
+NS	O
+-	O
+718	O
+)	O
+incorporating	O
+amphotericin	O
+B	O
+.	O
+	
+NS	O
+-	O
+718	O
+","	O
+a	O
+lipid	O
+nanosphere	O
+incorporating	O
+amphotericin	O
+B	O
+","	O
+is	O
+effective	O
+against	O
+pathogenic	O
+fungi	O
+and	O
+has	O
+low	O
+toxicity	B-NP
+.	O
+	
+We	O
+compared	O
+the	O
+toxicity	B-NP
+of	O
+NS	O
+-	O
+718	O
+with	O
+that	O
+of	O
+Fungizone	O
+(	O
+amphotericin	O
+B	O
+-	O
+sodium	O
+deoxycholate	O
+;	O
+D	O
+-	O
+AmB	O
+)	O
+in	O
+vitro	O
+using	O
+renal	O
+cell	O
+cultures	O
+and	O
+in	O
+vivo	O
+by	O
+biochemical	O
+analysis	O
+","	O
+histopathological	O
+study	O
+of	O
+the	O
+kidney	O
+and	O
+pharmacokinetic	O
+study	O
+of	O
+amphotericin	O
+B	O
+following	O
+intravenous	O
+infusion	O
+of	O
+the	O
+formulation	O
+in	O
+rats	O
+.	O
+	
+Incubation	O
+with	O
+NS	O
+-	O
+718	O
+resulted	O
+in	O
+significantly	O
+less	O
+damage	O
+of	O
+cultured	O
+human	O
+renal	O
+proximal	O
+tubular	O
+epithelial	O
+cells	O
+compared	O
+with	O
+D	O
+-	O
+AmB	O
+.	O
+	
+Serum	O
+blood	O
+urea	O
+and	O
+creatinine	O
+concentrations	O
+increased	O
+significantly	O
+in	O
+rats	O
+given	O
+an	O
+iv	O
+infusion	O
+of	O
+D	O
+-	O
+AmB	O
+3	O
+mg	O
+/	O
+kg	O
+but	O
+not	O
+in	O
+those	O
+given	O
+the	O
+same	O
+dose	O
+of	O
+NS	O
+-	O
+718	O
+.	O
+	
+Histopathological	O
+examination	O
+of	O
+the	O
+kidney	O
+showed	O
+tubular	B-NP
+necrosis	I-NP
+in	O
+D	O
+-	O
+AmB	O
+-	O
+treated	O
+rats	O
+but	O
+no	O
+change	O
+in	O
+NS	O
+-	O
+718	O
+-	O
+treated	O
+rats	O
+.	O
+	
+Amphotericin	O
+B	O
+concentrations	O
+in	O
+the	O
+kidney	O
+in	O
+NS	O
+-	O
+718	O
+-	O
+treated	O
+rats	O
+were	O
+higher	O
+than	O
+those	O
+in	O
+D	O
+-	O
+AmB	O
+-	O
+treated	O
+rats	O
+.	O
+	
+Our	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+results	O
+suggest	O
+that	O
+incorporation	O
+of	O
+amphotericin	O
+B	O
+into	O
+lipid	O
+nanospheres	O
+of	O
+NS	O
+-	O
+718	O
+attenuates	O
+the	O
+nephrotoxicity	B-NP
+of	O
+amphotericin	O
+B	O
+.	O
+	
+Patterns	O
+of	O
+sulfadiazine	O
+acute	B-NP
+nephrotoxicity	I-NP
+.	O
+	
+Sulfadiazine	O
+acute	B-NP
+nephrotoxicity	I-NP
+is	O
+reviving	O
+specially	O
+because	O
+of	O
+its	O
+use	O
+in	O
+toxoplasmosis	B-NP
+in	O
+HIV	O
+-	O
+positive	O
+patients	O
+.	O
+	
+We	O
+report	O
+4	O
+cases	O
+","	O
+one	O
+of	O
+them	O
+in	O
+a	O
+previously	O
+healthy	O
+person	O
+.	O
+	
+Under	O
+treatment	O
+with	O
+sulfadiazine	O
+they	O
+developed	O
+oliguria	B-NP
+","	O
+abdominal	B-NP
+pain	I-NP
+","	O
+renal	B-NP
+failure	I-NP
+and	O
+showed	O
+multiple	O
+radiolucent	O
+renal	B-NP
+calculi	I-NP
+in	O
+echography	O
+.	O
+	
+All	O
+patients	O
+recovered	O
+their	O
+previous	O
+normal	O
+renal	O
+function	O
+after	O
+adequate	O
+hydration	O
+and	O
+alcalinization	O
+.	O
+	
+A	O
+nephrostomy	O
+tube	O
+had	O
+to	O
+be	O
+placed	O
+in	O
+one	O
+of	O
+the	O
+patients	O
+for	O
+ureteral	B-NP
+lithiasis	I-NP
+in	O
+a	O
+single	O
+functional	O
+kidney	O
+.	O
+	
+None	O
+of	O
+them	O
+needed	O
+dialysis	O
+or	O
+a	O
+renal	O
+biopsy	O
+because	O
+of	O
+a	O
+typical	O
+benign	O
+course	O
+.	O
+	
+Treatment	O
+with	O
+sulfadiazine	O
+requires	O
+exquisite	O
+control	O
+of	O
+renal	O
+function	O
+","	O
+an	O
+increase	O
+in	O
+water	O
+ingestion	O
+and	O
+possibly	O
+the	O
+alcalinization	O
+of	O
+the	O
+urine	O
+.	O
+	
+We	O
+communicate	O
+a	O
+case	O
+in	O
+a	O
+previously	O
+healthy	O
+person	O
+","	O
+a	O
+fact	O
+not	O
+found	O
+in	O
+the	O
+recent	O
+literature	O
+.	O
+	
+Probably	O
+many	O
+more	O
+cases	O
+are	O
+not	O
+detected	O
+.	O
+	
+We	O
+think	O
+that	O
+a	O
+prospective	O
+study	O
+would	O
+be	O
+useful	O
+.	O
+	
+Downbeat	B-NP
+nystagmus	I-NP
+associated	O
+with	O
+intravenous	O
+patient	O
+-	O
+controlled	O
+administration	O
+of	O
+morphine	O
+.	O
+	
+IMPLICATIONS	O
+:	O
+This	O
+case	O
+documents	O
+a	O
+patient	O
+who	O
+developed	O
+dizziness	B-NP
+with	O
+downbeating	B-NP
+nystagmus	I-NP
+while	O
+receiving	O
+a	O
+relatively	O
+large	O
+dose	O
+of	O
+IV	O
+patient	O
+-	O
+controlled	O
+analgesia	O
+morphine	O
+.	O
+	
+Although	O
+there	O
+have	O
+been	O
+case	O
+reports	O
+of	O
+epidural	O
+morphine	O
+with	O
+these	O
+symptoms	O
+and	O
+signs	O
+","	O
+this	O
+has	O
+not	O
+been	O
+previously	O
+documented	O
+with	O
+IV	O
+or	O
+patient	O
+-	O
+controlled	O
+analgesia	O
+morphine	O
+.	O
+	
+Hemodynamic	O
+and	O
+antiadrenergic	O
+effects	O
+of	O
+dronedarone	O
+and	O
+amiodarone	O
+in	O
+animals	O
+with	O
+a	O
+healed	O
+myocardial	B-NP
+infarction	I-NP
+.	O
+	
+The	O
+hemodynamic	O
+and	O
+antiadrenergic	O
+effects	O
+of	O
+dronedarone	O
+","	O
+a	O
+noniodinated	O
+compound	O
+structurally	O
+related	O
+to	O
+amiodarone	O
+","	O
+were	O
+compared	O
+with	O
+those	O
+of	O
+amiodarone	O
+after	O
+prolonged	O
+oral	O
+administration	O
+","	O
+both	O
+at	O
+rest	O
+and	O
+during	O
+sympathetic	O
+stimulation	O
+in	O
+conscious	O
+dogs	O
+with	O
+a	O
+healed	O
+myocardial	B-NP
+infarction	I-NP
+.	O
+	
+All	O
+dogs	O
+(	O
+n	O
+=	O
+6	O
+)	O
+randomly	O
+received	O
+orally	O
+dronedarone	O
+(	O
+10	O
+and	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+","	O
+amiodarone	O
+(	O
+10	O
+and	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+","	O
+and	O
+placebo	O
+twice	O
+daily	O
+for	O
+7	O
+days	O
+","	O
+with	O
+a	O
+3	O
+-	O
+week	O
+washout	O
+between	O
+consecutive	O
+treatments	O
+.	O
+	
+Heart	O
+rate	O
+(	O
+HR	O
+)	O
+","	O
+mean	O
+arterial	O
+pressure	O
+(	O
+MBP	O
+)	O
+","	O
+positive	O
+rate	O
+of	O
+increase	O
+of	O
+left	O
+ventricular	O
+pressure	O
+(	O
++	O
+LVdP	O
+/	O
+dt	O
+)	O
+","	O
+echocardiographically	O
+assessed	O
+left	O
+ventricular	O
+ejection	O
+fraction	O
+(	O
+LVEF	O
+)	O
+","	O
+and	O
+fractional	O
+shortening	O
+(	O
+FS	O
+)	O
+","	O
+as	O
+well	O
+as	O
+chronotropic	O
+response	O
+to	O
+isoproterenol	O
+and	O
+exercise	O
+-	O
+induced	O
+sympathetic	O
+stimulation	O
+were	O
+evaluated	O
+under	O
+baseline	O
+and	O
+posttreatment	O
+conditions	O
+.	O
+	
+Resting	O
+values	O
+of	O
+LVEF	O
+","	O
+FS	O
+","	O
++	O
+LVdP	O
+/	O
+dt	O
+","	O
+and	O
+MBP	O
+remained	O
+unchanged	O
+whatever	O
+the	O
+drug	O
+and	O
+the	O
+dosing	O
+regimen	O
+","	O
+whereas	O
+resting	O
+HR	O
+was	O
+significantly	O
+and	O
+dose	O
+-	O
+dependently	O
+lowered	O
+after	O
+dronedarone	O
+and	O
+to	O
+a	O
+lesser	O
+extent	O
+after	O
+amiodarone	O
+.	O
+	
+Both	O
+dronedarone	O
+and	O
+amiodarone	O
+significantly	O
+reduced	O
+the	O
+exercise	O
+-	O
+induced	O
+tachycardia	B-NP
+and	O
+","	O
+at	O
+the	O
+highest	O
+dose	O
+","	O
+decreased	O
+the	O
+isoproterenol	O
+-	O
+induced	O
+tachycardia	B-NP
+.	O
+	
+Thus	O
+","	O
+dronedarone	O
+and	O
+amiodarone	O
+displayed	O
+a	O
+similar	O
+level	O
+of	O
+antiadrenergic	O
+effect	O
+and	O
+did	O
+not	O
+impair	O
+the	O
+resting	O
+left	O
+ventricular	O
+function	O
+.	O
+	
+Consequently	O
+","	O
+dronedarone	O
+might	O
+be	O
+particularly	O
+suitable	O
+for	O
+the	O
+treatment	O
+and	O
+prevention	O
+of	O
+various	O
+clinical	O
+arrhythmias	B-NP
+","	O
+without	O
+compromising	O
+the	O
+left	O
+ventricular	O
+function	O
+.	O
+	
+Phase	O
+2	O
+trial	O
+of	O
+liposomal	O
+doxorubicin	O
+(	O
+40	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+)	O
+in	O
+platinum	O
+/	O
+paclitaxel	O
+-	O
+refractory	O
+ovarian	B-NP
+and	I-NP
+fallopian	I-NP
+tube	I-NP
+cancers	I-NP
+and	O
+primary	O
+carcinoma	B-NP
+of	I-NP
+the	I-NP
+peritoneum	I-NP
+.	O
+	
+BACKGROUND	O
+:	O
+Several	O
+studies	O
+have	O
+demonstrated	O
+liposomal	O
+doxorubicin	O
+(	O
+Doxil	O
+)	O
+to	O
+be	O
+an	O
+active	O
+antineoplastic	O
+agent	O
+in	O
+platinum	O
+-	O
+resistant	O
+ovarian	B-NP
+cancer	I-NP
+","	O
+with	O
+dose	O
+limiting	O
+toxicity	B-NP
+of	O
+the	O
+standard	O
+dosing	O
+regimen	O
+(	O
+50	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+q	O
+4	O
+weeks	O
+)	O
+being	O
+severe	O
+erythrodysesthesia	B-NP
+(	O
+"	O
+hand	B
+-	I
+foot	I
+syndrome	I
+"	O
+)	O
+and	O
+stomatitis	B-NP
+.	O
+	
+We	O
+wished	O
+to	O
+develop	O
+a	O
+more	O
+tolerable	O
+liposomal	O
+doxorubicin	O
+treatment	O
+regimen	O
+and	O
+document	O
+its	O
+level	O
+of	O
+activity	O
+in	O
+a	O
+well	O
+-	O
+defined	O
+patient	O
+population	O
+with	O
+platinum	O
+/	O
+paclitaxel	O
+-	O
+refractory	O
+disease	O
+.	O
+	
+METHODS	O
+AND	O
+MATERIALS	O
+:	O
+Patients	O
+with	O
+ovarian	B-NP
+or	I-NP
+fallopian	I-NP
+tube	I-NP
+cancers	I-NP
+or	O
+primary	O
+peritoneal	B-NP
+carcinoma	I-NP
+with	O
+platinum	O
+/	O
+paclitaxel	O
+-	O
+refractory	O
+disease	O
+(	O
+stable	O
+or	O
+progressive	O
+disease	O
+following	O
+treatment	O
+with	O
+these	O
+agents	O
+or	O
+previous	O
+objective	O
+response	O
+<	O
+3	O
+months	O
+in	O
+duration	O
+)	O
+were	O
+treated	O
+with	O
+liposomal	O
+doxorubicin	O
+at	O
+a	O
+dose	O
+of	O
+40	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+q	O
+4	O
+weeks	O
+.	O
+	
+RESULTS	O
+:	O
+A	O
+total	O
+of	O
+49	O
+patients	O
+(	O
+median	O
+age	O
+:	O
+60	O
+;	O
+range	O
+41	O
+-	O
+81	O
+)	O
+entered	O
+this	O
+phase	O
+2	O
+trial	O
+.	O
+	
+The	O
+median	O
+number	O
+of	O
+prior	O
+regimens	O
+was	O
+2	O
+(	O
+range	O
+:	O
+1	O
+-	O
+6	O
+)	O
+.	O
+	
+Six	O
+(	O
+12	O
+%	O
+)	O
+and	O
+4	O
+(	O
+8	O
+%	O
+)	O
+patients	O
+experienced	O
+grade	O
+2	O
+hand	B-NP
+-	I-NP
+foot	I-NP
+syndrome	I-NP
+and	O
+stomatitis	B-NP
+","	O
+respectively	O
+(	O
+no	O
+episodes	O
+of	O
+grade	O
+3	O
+)	O
+.	O
+	
+One	O
+patient	O
+developed	O
+grade	O
+3	O
+diarrhea	B-NP
+requiring	O
+hospitalization	O
+for	O
+hydration	O
+.	O
+	
+Six	O
+(	O
+12	O
+%	O
+)	O
+individuals	O
+required	O
+dose	O
+reductions	O
+.	O
+	
+The	O
+median	O
+number	O
+of	O
+courses	O
+of	O
+liposomal	O
+doxorubicin	O
+administered	O
+on	O
+this	O
+protocol	O
+was	O
+2	O
+(	O
+range	O
+:	O
+1	O
+-	O
+12	O
+)	O
+.	O
+	
+Four	O
+of	O
+44	O
+patients	O
+(	O
+9	O
+%	O
+)	O
+evaluable	O
+for	O
+response	O
+exhibited	O
+objective	O
+and	O
+subjective	O
+evidence	O
+of	O
+an	O
+antineoplastic	O
+effect	O
+of	O
+therapy	O
+.	O
+	
+CONCLUSION	O
+:	O
+This	O
+modified	O
+liposomal	O
+doxorubicin	O
+regimen	O
+results	O
+in	O
+less	O
+toxicity	B-NP
+(	O
+stomatitis	B-NP
+","	O
+hand	B-NP
+-	I-NP
+foot	I-NP
+syndrome	I-NP
+)	O
+than	O
+the	O
+standard	O
+FDA	O
+-	O
+approved	O
+dose	O
+schedule	O
+.	O
+	
+Definite	O
+","	O
+although	O
+limited	O
+","	O
+antineoplastic	O
+activity	O
+is	O
+observed	O
+in	O
+patients	O
+with	O
+well	O
+-	O
+defined	O
+platinum	O
+-	O
+and	O
+paclitaxel	O
+-	O
+refractory	O
+ovarian	B-NP
+cancer	I-NP
+.	O
+	
+Efficacy	O
+of	O
+olanzapine	O
+in	O
+acute	O
+bipolar	B-NP
+mania	I-NP
+:	O
+a	O
+double	O
+-	O
+blind	O
+","	O
+placebo	O
+-	O
+controlled	O
+study	O
+.	O
+	
+The	O
+Olanzipine	O
+HGGW	O
+Study	O
+Group	O
+.	O
+	
+BACKGROUND	O
+:	O
+We	O
+compared	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+olanzapine	O
+vs	O
+placebo	O
+for	O
+the	O
+treatment	O
+of	O
+acute	O
+bipolar	B-NP
+mania	I-NP
+.	O
+	
+METHODS	O
+:	O
+Four	O
+-	O
+week	O
+","	O
+randomized	O
+","	O
+double	O
+-	O
+blind	O
+","	O
+parallel	O
+study	O
+.	O
+	
+A	O
+total	O
+of	O
+115	O
+patients	O
+with	O
+a	O
+DSM	O
+-	O
+IV	O
+diagnosis	O
+of	O
+bipolar	B-NP
+disorder	I-NP
+","	O
+manic	B-NP
+or	O
+mixed	O
+","	O
+were	O
+randomized	O
+to	O
+olanzapine	O
+","	O
+5	O
+to	O
+20	O
+mg	O
+/	O
+d	O
+(	O
+n	O
+=	O
+55	O
+)	O
+","	O
+or	O
+placebo	O
+(	O
+n	O
+=	O
+60	O
+)	O
+.	O
+	
+The	O
+primary	O
+efficacy	O
+measure	O
+was	O
+the	O
+Young	O
+-	O
+Mania	B-NP
+Rating	O
+Scale	O
+(	O
+Y	O
+-	O
+MRS	O
+)	O
+total	O
+score	O
+.	O
+	
+Response	O
+and	O
+euthymia	O
+were	O
+defined	O
+","	O
+a	O
+priori	O
+","	O
+as	O
+at	O
+least	O
+a	O
+50	O
+%	O
+improvement	O
+from	O
+baseline	O
+to	O
+end	O
+point	O
+and	O
+as	O
+a	O
+score	O
+of	O
+no	O
+less	O
+than	O
+12	O
+at	O
+end	O
+point	O
+in	O
+the	O
+Y	O
+-	O
+MRS	O
+total	O
+score	O
+","	O
+respectively	O
+.	O
+	
+Safety	O
+was	O
+assessed	O
+using	O
+adverse	O
+events	O
+","	O
+Extrapyramidal	B-NP
+Symptom	I-NP
+(	O
+EPS	B-NP
+)	O
+rating	O
+scales	O
+","	O
+laboratory	O
+values	O
+","	O
+electrocardiograms	O
+","	O
+vital	O
+signs	O
+","	O
+and	O
+weight	O
+change	O
+.	O
+	
+RESULTS	O
+:	O
+Olanzapine	O
+-	O
+treated	O
+patients	O
+demonstrated	O
+a	O
+statistically	O
+significant	O
+greater	O
+mean	O
+(	O
++	O
+/	O
+-	O
+SD	O
+)	O
+improvement	O
+in	O
+Y	O
+-	O
+MRS	O
+total	O
+score	O
+than	O
+placebo	O
+-	O
+treated	O
+patients	O
+(	O
+-	O
+14	O
+.	O
+8	O
++	O
+/	O
+-	O
+12	O
+.	O
+5	O
+and	O
+-	O
+8	O
+.	O
+1	O
++	O
+/	O
+-	O
+12	O
+.	O
+7	O
+","	O
+respectively	O
+;	O
+P	O
+<	O
+.	O
+1	O
+)	O
+","	O
+which	O
+was	O
+evident	O
+at	O
+the	O
+first	O
+postbaseline	O
+observation	O
+1	O
+week	O
+after	O
+randomization	O
+and	O
+was	O
+maintained	O
+throughout	O
+the	O
+study	O
+(	O
+last	O
+observation	O
+carried	O
+forward	O
+)	O
+.	O
+	
+Olanzapine	O
+-	O
+treated	O
+patients	O
+demonstrated	O
+a	O
+higher	O
+rate	O
+of	O
+response	O
+(	O
+65	O
+%	O
+vs	O
+43	O
+%	O
+","	O
+respectively	O
+;	O
+P	O
+=	O
+.	O
+2	O
+)	O
+and	O
+euthymia	O
+(	O
+61	O
+%	O
+vs	O
+36	O
+%	O
+","	O
+respectively	O
+;	O
+P	O
+=	O
+.	O
+1	O
+)	O
+than	O
+placebo	O
+-	O
+treated	O
+patients	O
+.	O
+	
+There	O
+were	O
+no	O
+statistically	O
+significant	O
+differences	O
+in	O
+EPSs	B-NP
+between	O
+groups	O
+.	O
+	
+However	O
+","	O
+olanzapine	O
+-	O
+treated	O
+patients	O
+had	O
+a	O
+statistically	O
+significant	O
+greater	O
+mean	O
+(	O
++	O
+/	O
+-	O
+SD	O
+)	O
+weight	B-NP
+gain	I-NP
+than	O
+placebo	O
+-	O
+treated	O
+patients	O
+(	O
+2	O
+.	O
+1	O
++	O
+/	O
+-	O
+2	O
+.	O
+8	O
+vs	O
+0	O
+.	O
+45	O
++	O
+/	O
+-	O
+2	O
+.	O
+3	O
+kg	O
+","	O
+respectively	O
+)	O
+and	O
+also	O
+experienced	O
+more	O
+treatment	O
+-	O
+emergent	O
+somnolence	B-NP
+(	O
+21	O
+patients	O
+[	O
+38	O
+.	O
+2	O
+%	O
+]	O
+vs	O
+5	O
+[	O
+8	O
+.	O
+3	O
+%	O
+]	O
+","	O
+respectively	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+Olanzapine	O
+demonstrated	O
+greater	O
+efficacy	O
+than	O
+placebo	O
+in	O
+the	O
+treatment	O
+of	O
+acute	O
+bipolar	B-NP
+mania	I-NP
+and	O
+was	O
+generally	O
+well	O
+tolerated	O
+.	O
+	
+The	O
+effect	O
+of	O
+pupil	B-NP
+dilation	I-NP
+with	O
+tropicamide	O
+on	O
+vision	O
+and	O
+driving	O
+simulator	O
+performance	O
+.	O
+	
+PURPOSE	O
+:	O
+To	O
+assess	O
+the	O
+effect	O
+of	O
+pupil	B-NP
+dilation	I-NP
+on	O
+vision	O
+and	O
+driving	O
+ability	O
+.	O
+	
+METHODS	O
+:	O
+A	O
+series	O
+of	O
+tests	O
+on	O
+various	O
+parameters	O
+of	O
+visual	O
+function	O
+and	O
+driving	O
+simulator	O
+performance	O
+were	O
+performed	O
+on	O
+12	O
+healthy	O
+drivers	O
+","	O
+before	O
+and	O
+after	O
+pupil	B-NP
+dilation	I-NP
+using	O
+guttae	O
+tropicamide	O
+1	O
+%	O
+.	O
+	
+A	O
+driving	O
+simulator	O
+(	O
+Transport	O
+Research	O
+Laboratory	O
+)	O
+was	O
+used	O
+to	O
+measure	O
+reaction	O
+time	O
+(	O
+RT	O
+)	O
+","	O
+speed	O
+maintenance	O
+and	O
+steering	O
+accuracy	O
+.	O
+	
+Tests	O
+of	O
+basic	O
+visual	O
+function	O
+included	O
+high	O
+-	O
+and	O
+low	O
+-	O
+contrast	O
+visual	O
+acuity	O
+(	O
+HCVA	O
+and	O
+LCVA	O
+)	O
+","	O
+Pelli	O
+-	O
+Robson	O
+contrast	O
+threshold	O
+(	O
+CT	O
+)	O
+and	O
+Goldmann	O
+perimetry	O
+(	O
+FIELDS	O
+)	O
+.	O
+	
+Useful	O
+Field	O
+of	O
+View	O
+(	O
+UFOV	O
+-	O
+-	O
+a	O
+test	O
+of	O
+visual	O
+attention	O
+)	O
+was	O
+also	O
+undertaken	O
+.	O
+	
+The	O
+mean	O
+differences	O
+in	O
+the	O
+pre	O
+-	O
+and	O
+post	O
+-	O
+dilatation	O
+measurements	O
+were	O
+tested	O
+for	O
+statistical	O
+significance	O
+at	O
+the	O
+95	O
+%	O
+level	O
+using	O
+one	O
+-	O
+tail	O
+paired	O
+t	O
+-	O
+tests	O
+.	O
+	
+RESULTS	O
+:	O
+Pupillary	B-NP
+dilation	I-NP
+resulted	O
+in	O
+a	O
+statistically	O
+significant	O
+deterioration	O
+in	O
+CT	O
+and	O
+HCVA	O
+only	O
+.	O
+	
+Five	O
+of	O
+12	O
+drivers	O
+also	O
+exhibited	O
+deterioration	O
+in	O
+LCVA	O
+","	O
+CT	O
+and	O
+RT	O
+.	O
+	
+Little	O
+evidence	O
+emerged	O
+for	O
+deterioration	O
+in	O
+FIELDS	O
+and	O
+UFOV	O
+.	O
+	
+Also	O
+","	O
+7	O
+of	O
+12	O
+drivers	O
+appeared	O
+to	O
+adjust	O
+their	O
+driving	O
+behaviour	O
+by	O
+reducing	O
+their	O
+speed	O
+on	O
+the	O
+driving	O
+simulator	O
+","	O
+leading	O
+to	O
+improved	O
+steering	O
+accuracy	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Pupillary	B-NP
+dilation	I-NP
+may	O
+lead	O
+to	O
+a	O
+decrease	O
+in	O
+vision	O
+and	O
+daylight	O
+driving	O
+performance	O
+in	O
+young	O
+people	O
+.	O
+	
+A	O
+larger	O
+study	O
+","	O
+including	O
+a	O
+broader	O
+spectrum	O
+of	O
+subjects	O
+","	O
+is	O
+warranted	O
+before	O
+guidelines	O
+can	O
+be	O
+recommended	O
+.	O
+	
+A	O
+case	O
+of	O
+isotretinoin	B-NP
+embryopathy	I-NP
+with	O
+bilateral	O
+anotia	B-NP
+and	O
+Taussig	B-NP
+-	I-NP
+Bing	I-NP
+malformation	I-NP
+.	O
+	
+We	O
+report	O
+a	O
+newborn	O
+infant	O
+with	O
+multiple	O
+congenital	O
+anomalies	O
+(	O
+anotia	B-NP
+and	O
+Taussig	B-NP
+-	I-NP
+Bing	I-NP
+malformation	I-NP
+)	O
+due	O
+to	O
+exposure	O
+to	O
+isotretinoin	O
+within	O
+the	O
+first	O
+trimester	O
+.	O
+	
+In	O
+this	O
+paper	O
+we	O
+aim	O
+to	O
+draw	O
+to	O
+the	O
+fact	O
+that	O
+caution	O
+is	O
+needed	O
+when	O
+prescribing	O
+vitamin	O
+A	O
+-	O
+containing	O
+drugs	O
+to	O
+women	O
+of	O
+childbearing	O
+years	O
+.	O
+	
+Effect	O
+of	O
+methoxamine	O
+on	O
+maximum	O
+urethral	O
+pressure	O
+in	O
+women	O
+with	O
+genuine	O
+stress	B-NP
+incontinence	I-NP
+:	O
+a	O
+placebo	O
+-	O
+controlled	O
+","	O
+double	O
+-	O
+blind	O
+crossover	O
+study	O
+.	O
+	
+The	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+evaluate	O
+the	O
+potential	O
+role	O
+for	O
+a	O
+selective	O
+alpha1	O
+-	O
+adrenoceptor	O
+agonist	O
+in	O
+the	O
+treatment	O
+of	O
+urinary	B-NP
+stress	I-NP
+incontinence	I-NP
+.	O
+	
+A	O
+randomised	O
+","	O
+double	O
+-	O
+blind	O
+","	O
+placebo	O
+-	O
+controlled	O
+","	O
+crossover	O
+study	O
+design	O
+was	O
+employed	O
+.	O
+	
+Half	O
+log	O
+incremental	O
+doses	O
+of	O
+intravenous	O
+methoxamine	O
+or	O
+placebo	O
+(	O
+saline	O
+)	O
+were	O
+administered	O
+to	O
+a	O
+group	O
+of	O
+women	O
+with	O
+genuine	O
+stress	B-NP
+incontinence	I-NP
+while	O
+measuring	O
+maximum	O
+urethral	O
+pressure	O
+(	O
+MUP	O
+)	O
+","	O
+blood	O
+pressure	O
+","	O
+heart	O
+rate	O
+","	O
+and	O
+symptomatic	O
+side	O
+effects	O
+.	O
+	
+Methoxamine	O
+evoked	O
+non	O
+-	O
+significant	O
+increases	O
+in	O
+MUP	O
+and	O
+diastolic	O
+blood	O
+pressure	O
+but	O
+caused	O
+a	B-NP
+significant	I-NP
+rise	I-NP
+in	I-NP
+systolic	I-NP
+blood	I-NP
+pressure	I-NP
+and	O
+significant	O
+fall	O
+in	O
+heart	O
+rate	O
+at	O
+maximum	O
+dosage	O
+.	O
+	
+Systemic	O
+side	O
+effects	O
+including	O
+piloerection	O
+","	O
+headache	B-NP
+","	O
+and	O
+cold	O
+extremities	O
+were	O
+experienced	O
+in	O
+all	O
+subjects	O
+.	O
+	
+The	O
+results	O
+indicate	O
+that	O
+the	O
+clinical	O
+usefulness	O
+of	O
+direct	O
+","	O
+peripherally	O
+acting	O
+sub	O
+-	O
+type	O
+-	O
+selective	O
+alpha1	O
+-	O
+adrenoceptor	O
+agonists	O
+in	O
+the	O
+medical	O
+treatment	O
+of	O
+stress	B-NP
+incontinence	I-NP
+may	O
+be	O
+limited	O
+by	O
+associated	O
+piloerection	O
+and	O
+cardiovascular	O
+side	O
+effects	O
+.	O
+	
+Hyperglycemic	B-NP
+effect	O
+of	O
+amino	O
+compounds	O
+structurally	O
+related	O
+to	O
+caproate	O
+in	O
+rats	O
+.	O
+	
+The	O
+chronic	O
+feeding	O
+of	O
+small	O
+amounts	O
+(	O
+0	O
+.	O
+3	O
+-	O
+3	O
+%	O
+of	O
+diet	O
+weight	O
+)	O
+of	O
+certain	O
+amino	O
+derivatives	O
+of	O
+caproate	O
+resulted	O
+in	O
+hyperglycemia	B-NP
+","	O
+an	O
+elevated	O
+glucose	O
+tolerance	O
+curve	O
+and	O
+","	O
+occasionally	O
+","	O
+glucosuria	B-NP
+.	O
+	
+Effective	O
+compounds	O
+included	O
+norleucine	O
+","	O
+norvaline	O
+","	O
+glutamate	O
+","	O
+epsilon	O
+-	O
+aminocaproate	O
+","	O
+methionine	O
+","	O
+and	O
+leucine	O
+.	O
+	
+Toleration	O
+of	O
+high	O
+doses	O
+of	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitors	O
+in	O
+patients	O
+with	O
+chronic	O
+heart	B-NP
+failure	I-NP
+:	O
+results	O
+from	O
+the	O
+ATLAS	O
+trial	O
+.	O
+	
+The	O
+Assessment	O
+of	O
+Treatment	O
+with	O
+Lisinopril	O
+and	O
+Survival	O
+.	O
+	
+BACKGROUND	O
+:	O
+Treatment	O
+with	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+inhibitors	O
+reduces	O
+mortality	O
+and	O
+morbidity	O
+in	O
+patients	O
+with	O
+chronic	O
+heart	B-NP
+failure	I-NP
+(	O
+CHF	B-NP
+)	O
+","	O
+but	O
+most	O
+affected	O
+patients	O
+are	O
+not	O
+receiving	O
+these	O
+agents	O
+or	O
+are	O
+being	O
+treated	O
+with	O
+doses	O
+lower	O
+than	O
+those	O
+found	O
+to	O
+be	O
+efficacious	O
+in	O
+trials	O
+","	O
+primarily	O
+because	O
+of	O
+concerns	O
+about	O
+the	O
+safety	O
+and	O
+tolerability	O
+of	O
+these	O
+agents	O
+","	O
+especially	O
+at	O
+the	O
+recommended	O
+doses	O
+.	O
+	
+The	O
+present	O
+study	O
+examines	O
+the	O
+safety	O
+and	O
+tolerability	O
+of	O
+high	O
+-	O
+compared	O
+with	O
+low	O
+-	O
+dose	O
+lisinopril	O
+in	O
+CHF	B-NP
+.	O
+	
+METHODS	O
+:	O
+The	O
+Assessment	O
+of	O
+Lisinopril	O
+and	O
+Survival	O
+study	O
+was	O
+a	O
+multicenter	O
+","	O
+randomized	O
+","	O
+double	O
+-	O
+blind	O
+trial	O
+in	O
+which	O
+patients	O
+with	O
+or	O
+without	O
+previous	O
+ACE	O
+inhibitor	O
+treatment	O
+were	O
+stabilized	O
+receiving	O
+medium	O
+-	O
+dose	O
+lisinopril	O
+(	O
+12	O
+.	O
+5	O
+or	O
+15	O
+.	O
+0	O
+mg	O
+once	O
+daily	O
+[	O
+OD	O
+]	O
+)	O
+for	O
+2	O
+to	O
+4	O
+weeks	O
+and	O
+then	O
+randomized	O
+to	O
+high	O
+-	O
+(	O
+35	O
+.	O
+0	O
+or	O
+32	O
+.	O
+5	O
+mg	O
+OD	O
+)	O
+or	O
+low	O
+-	O
+dose	O
+(	O
+5	O
+.	O
+0	O
+or	O
+2	O
+.	O
+5	O
+mg	O
+OD	O
+)	O
+groups	O
+.	O
+	
+Patients	O
+with	O
+New	O
+York	O
+Heart	O
+Association	O
+classes	O
+II	O
+to	O
+IV	O
+CHF	B-NP
+and	O
+left	O
+ventricular	O
+ejection	O
+fractions	O
+of	O
+no	O
+greater	O
+than	O
+0	O
+.	O
+30	O
+(	O
+n	O
+=	O
+3164	O
+)	O
+were	O
+randomized	O
+and	O
+followed	O
+up	O
+for	O
+a	O
+median	O
+of	O
+46	O
+months	O
+.	O
+	
+We	O
+examined	O
+the	O
+occurrence	O
+of	O
+adverse	O
+events	O
+and	O
+the	O
+need	O
+for	O
+discontinuation	O
+and	O
+dose	O
+reduction	O
+during	O
+treatment	O
+","	O
+with	O
+a	O
+focus	O
+on	O
+hypotension	B-NP
+and	O
+renal	B-NP
+dysfunction	I-NP
+.	O
+	
+RESULTS	O
+:	O
+Of	O
+405	O
+patients	O
+not	O
+previously	O
+receiving	O
+an	O
+ACE	O
+inhibitor	O
+","	O
+doses	O
+in	O
+only	O
+4	O
+.	O
+2	O
+%	O
+could	O
+not	O
+be	O
+titrated	O
+to	O
+the	O
+medium	O
+doses	O
+required	O
+for	O
+randomization	O
+because	O
+of	O
+symptoms	O
+possibly	O
+related	O
+to	O
+hypotension	B-NP
+(	O
+2	O
+.	O
+0	O
+%	O
+)	O
+or	O
+because	O
+of	O
+renal	B-NP
+dysfunction	I-NP
+or	O
+hyperkalemia	B-NP
+(	O
+2	O
+.	O
+3	O
+%	O
+)	O
+.	O
+	
+Doses	O
+in	O
+more	O
+than	O
+90	O
+%	O
+of	O
+randomized	O
+patients	O
+in	O
+the	O
+high	O
+-	O
+and	O
+low	O
+-	O
+dose	O
+groups	O
+were	O
+titrated	O
+to	O
+their	O
+assigned	O
+target	O
+","	O
+and	O
+the	O
+mean	O
+doses	O
+of	O
+blinded	O
+medication	O
+in	O
+both	O
+groups	O
+remained	O
+similar	O
+throughout	O
+the	O
+study	O
+.	O
+	
+Withdrawals	O
+occurred	O
+in	O
+27	O
+.	O
+1	O
+%	O
+of	O
+the	O
+high	O
+-	O
+and	O
+30	O
+.	O
+7	O
+%	O
+of	O
+the	O
+low	O
+-	O
+dose	O
+groups	O
+.	O
+	
+Subgroups	O
+presumed	O
+to	O
+be	O
+at	O
+higher	O
+risk	O
+for	O
+ACE	O
+inhibitor	O
+intolerance	O
+(	O
+blood	O
+pressure	O
+","	O
+<	O
+120	O
+mm	O
+Hg	O
+;	O
+creatinine	O
+","	O
+>	O
+or	O
+=	O
+132	O
+.	O
+6	O
+micromol	O
+/	O
+L	O
+[	O
+>	O
+or	O
+=	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+dL	O
+]	O
+;	O
+age	O
+","	O
+>	O
+or	O
+=	O
+70	O
+years	O
+;	O
+and	O
+patients	O
+with	O
+diabetes	B-NP
+)	O
+generally	O
+tolerated	O
+the	O
+high	O
+-	O
+dose	O
+strategy	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+These	O
+findings	O
+demonstrate	O
+that	O
+ACE	O
+inhibitor	O
+therapy	O
+in	O
+most	O
+patients	O
+with	O
+CHF	B-NP
+can	O
+be	O
+successfully	O
+titrated	O
+to	O
+and	O
+maintained	O
+at	O
+high	O
+doses	O
+","	O
+and	O
+that	O
+more	O
+aggressive	O
+use	O
+of	O
+these	O
+agents	O
+is	O
+warranted	O
+.	O
+	
+Cocaine	O
+","	O
+ethanol	O
+","	O
+and	O
+cocaethylene	O
+cardiotoxity	B-NP
+in	O
+an	O
+animal	O
+model	O
+of	O
+cocaine	B-NP
+and	I-NP
+ethanol	I-NP
+abuse	I-NP
+.	O
+	
+OBJECTIVES	O
+:	O
+Simultaneous	O
+abuse	B-NP
+of	I-NP
+cocaine	I-NP
+and	I-NP
+ethanol	I-NP
+affects	O
+12	O
+million	O
+Americans	O
+annually	O
+.	O
+	
+In	O
+combination	O
+","	O
+these	O
+substances	O
+are	O
+substantially	O
+more	O
+toxic	O
+than	O
+either	O
+drug	O
+alone	O
+.	O
+	
+Their	O
+combined	O
+cardiac	B-NP
+toxicity	I-NP
+may	O
+be	O
+due	O
+to	O
+independent	O
+effects	O
+of	O
+each	O
+drug	O
+;	O
+however	O
+","	O
+they	O
+may	O
+also	O
+be	O
+due	O
+to	O
+cocaethylene	O
+(	O
+CE	O
+)	O
+","	O
+a	O
+cocaine	O
+metabolite	O
+formed	O
+only	O
+in	O
+the	O
+presence	O
+of	O
+ethanol	O
+.	O
+	
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+delineate	O
+the	O
+role	O
+of	O
+CE	O
+in	O
+the	O
+combined	O
+cardiotoxicity	B-NP
+of	O
+cocaine	O
+and	O
+ethanol	O
+in	O
+a	O
+model	O
+simulating	O
+their	O
+abuse	O
+.	O
+	
+METHODS	O
+:	O
+Twenty	O
+-	O
+three	O
+dogs	O
+were	O
+randomized	O
+to	O
+receive	O
+either	O
+1	O
+)	O
+three	O
+intravenous	O
+(	O
+IV	O
+)	O
+boluses	O
+of	O
+cocaine	O
+7	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+with	O
+ethanol	O
+(	O
+1	O
+g	O
+/	O
+kg	O
+)	O
+as	O
+an	O
+IV	O
+infusion	O
+(	O
+C	O
++	O
+E	O
+","	O
+n	O
+=	O
+8	O
+)	O
+","	O
+2	O
+)	O
+three	O
+cocaine	O
+boluses	O
+only	O
+(	O
+C	O
+","	O
+n	O
+=	O
+6	O
+)	O
+","	O
+3	O
+)	O
+ethanol	O
+infusion	O
+only	O
+(	O
+E	O
+","	O
+n	O
+=	O
+5	O
+)	O
+","	O
+or	O
+4	O
+)	O
+placebo	O
+boluses	O
+and	O
+infusion	O
+(	O
+n	O
+=	O
+4	O
+)	O
+.	O
+	
+Hemodynamic	O
+measurements	O
+","	O
+electrocardiograms	O
+","	O
+and	O
+serum	O
+drug	O
+concentrations	O
+were	O
+obtained	O
+at	O
+baseline	O
+","	O
+and	O
+then	O
+at	O
+fixed	O
+time	O
+intervals	O
+after	O
+each	O
+drug	O
+was	O
+administered	O
+.	O
+	
+RESULTS	O
+:	O
+Two	O
+of	O
+eight	O
+dogs	O
+in	O
+the	O
+C	O
++	O
+E	O
+group	O
+experienced	O
+cardiovascular	B-NP
+collapse	I-NP
+.	O
+	
+The	O
+most	O
+dramatic	O
+hemodynamic	O
+changes	O
+occurred	O
+after	O
+each	O
+cocaine	O
+bolus	O
+in	O
+the	O
+C	O
++	O
+E	O
+and	O
+C	O
+only	O
+groups	O
+;	O
+however	O
+","	O
+persistent	O
+hemodynamic	O
+changes	O
+occurred	O
+in	O
+the	O
+C	O
++	O
+E	O
+group	O
+.	O
+	
+Peak	O
+CE	O
+levels	O
+were	O
+associated	O
+with	O
+a	O
+45	O
+%	O
+(	O
+SD	O
++	O
+/	O
+-	O
+22	O
+%	O
+","	O
+95	O
+%	O
+CI	O
+=	O
+22	O
+%	O
+to	O
+69	O
+%	O
+)	O
+decrease	B-NP
+in	I-NP
+cardiac	I-NP
+output	I-NP
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+","	O
+a	O
+56	O
+%	O
+(	O
+SD	O
++	O
+/	O
+-	O
+23	O
+%	O
+","	O
+95	O
+%	O
+CI	O
+=	O
+32	O
+%	O
+to	O
+80	O
+%	O
+)	O
+decrease	O
+in	O
+dP	O
+/	O
+dt	O
+(	O
+max	O
+)	O
+(	O
+p	O
+<	O
+.	O
+6	O
+)	O
+","	O
+and	O
+a	O
+23	O
+%	O
+(	O
+SD	O
++	O
+/	O
+-	O
+15	O
+%	O
+","	O
+95	O
+%	O
+CI	O
+=	O
+7	O
+%	O
+to	O
+49	O
+%	O
+)	O
+decrease	O
+in	O
+SVO	O
+(	O
+2	O
+)	O
+(	O
+p	O
+<	O
+0	O
+.	O
+25	O
+)	O
+.	O
+	
+Ventricular	B-NP
+arrhythmias	I-NP
+were	O
+primarily	O
+observed	O
+in	O
+the	O
+C	O
++	O
+E	O
+group	O
+","	O
+in	O
+which	O
+four	O
+of	O
+eight	O
+dogs	O
+experienced	O
+ventricular	B-NP
+tachycardia	I-NP
+.	O
+	
+CONCLUSIONS	O
+:	O
+Cocaine	O
+and	O
+ethanol	O
+in	O
+combination	O
+were	O
+more	O
+toxic	O
+than	O
+either	O
+substance	O
+alone	O
+.	O
+	
+Co	O
+-	O
+administration	O
+resulted	O
+in	O
+prolonged	O
+cardiac	B-NP
+toxicity	I-NP
+and	O
+was	O
+dysrhythmogenic	O
+.	O
+	
+Peak	O
+serum	O
+cocaethylene	O
+concentrations	O
+were	O
+associated	O
+with	O
+prolonged	O
+myocardial	B-NP
+depression	I-NP
+.	O
+	
+Worsening	O
+of	O
+Parkinsonism	B-NP
+after	O
+the	O
+use	O
+of	O
+veralipride	O
+for	O
+treatment	O
+of	O
+menopause	O
+:	O
+case	O
+report	O
+.	O
+	
+We	O
+describe	O
+a	O
+female	O
+patient	O
+with	O
+stable	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+who	O
+has	O
+shown	O
+a	O
+marked	O
+worsening	O
+of	O
+her	O
+motor	O
+functions	O
+following	O
+therapy	O
+of	O
+menopause	O
+related	O
+symptoms	O
+with	O
+veralipride	O
+","	O
+as	O
+well	O
+as	O
+the	O
+improvement	O
+of	O
+her	O
+symptoms	O
+back	O
+to	O
+baseline	O
+after	O
+discontinuation	O
+of	O
+the	O
+drug	O
+.	O
+	
+We	O
+emphasize	O
+the	O
+anti	O
+-	O
+dopaminergic	O
+effect	O
+of	O
+veralipride	O
+.	O
+	
+Viracept	O
+and	O
+irregular	B-NP
+heartbeat	I-NP
+warning	O
+.	O
+	
+A	O
+group	O
+of	O
+doctors	O
+in	O
+Boston	O
+warn	O
+that	O
+the	O
+protease	O
+inhibitor	O
+Viracept	O
+may	O
+cause	O
+an	O
+irregular	B-NP
+heart	I-NP
+beat	I-NP
+","	O
+known	O
+as	O
+bradycardia	B-NP
+","	O
+in	O
+people	O
+with	O
+HIV	O
+.	O
+	
+Bradycardia	B-NP
+occurred	O
+in	O
+a	O
+45	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+who	O
+was	O
+Viracept	O
+in	O
+combination	O
+with	O
+other	O
+anti	O
+-	O
+HIV	O
+drugs	O
+.	O
+	
+The	O
+symptoms	O
+ceased	O
+after	O
+switching	O
+to	O
+another	O
+drug	O
+combination	O
+.	O
+	
+Frequency	O
+of	O
+appearance	O
+of	O
+myeloperoxidase	O
+-	O
+antineutrophil	O
+cytoplasmic	O
+antibody	O
+(	O
+MPO	O
+-	O
+ANCA	O
+)	O
+in	O
+Graves	B-NP
+'	I-NP
+disease	I-NP
+patients	O
+treated	O
+with	O
+propylthiouracil	O
+and	O
+the	O
+relationship	O
+between	O
+MPO	O
+-	O
+ANCA	O
+and	O
+clinical	O
+manifestations	O
+.	O
+	
+OBJECTIVE	O
+:	O
+Myeloperoxidase	O
+antineutrophil	O
+cytoplasmic	O
+antibody	O
+(	O
+MPO	O
+-	O
+ANCA	O
+)	O
+-	O
+positive	O
+vasculitis	B-NP
+has	O
+been	O
+reported	O
+in	O
+patients	O
+with	O
+Graves	B-NP
+'	I-NP
+disease	I-NP
+who	O
+were	O
+treated	O
+with	O
+propylthiouracil	O
+(	O
+PTU	O
+)	O
+.	O
+	
+The	O
+appearance	O
+of	O
+MPO	O
+-	O
+ANCA	O
+in	O
+these	O
+cases	O
+was	O
+suspected	O
+of	O
+being	O
+related	O
+to	O
+PTU	O
+because	O
+the	O
+titres	O
+of	O
+MPO	O
+-	O
+ANCA	O
+decreased	O
+when	O
+PTU	O
+was	O
+stopped	O
+.	O
+	
+Nevertheless	O
+","	O
+there	O
+have	O
+been	O
+no	O
+studies	O
+on	O
+the	O
+temporal	O
+relationship	O
+between	O
+the	O
+appearance	O
+of	O
+MPO	O
+-	O
+ANCA	O
+and	O
+vasculitis	B-NP
+during	O
+PTU	O
+therapy	O
+","	O
+or	O
+on	O
+the	O
+incidence	O
+of	O
+MPO	O
+-	O
+ANCA	O
+in	O
+untreated	O
+Graves	B-NP
+'	I-NP
+disease	I-NP
+patients	O
+.	O
+	
+Therefore	O
+","	O
+we	O
+sought	O
+to	O
+address	O
+these	O
+parameters	O
+in	O
+patients	O
+with	O
+Graves	B-NP
+'	I-NP
+disease	I-NP
+.	O
+	
+PATIENTS	O
+:	O
+We	O
+investigated	O
+102	O
+untreated	O
+patients	O
+with	O
+hyperthyroidism	B-NP
+due	O
+to	O
+Graves	B-NP
+'	I-NP
+disease	I-NP
+for	O
+the	O
+presence	O
+of	O
+MPO	O
+-	O
+ANCA	O
+","	O
+and	O
+for	O
+the	O
+development	O
+vasculitis	B-NP
+after	O
+starting	O
+PTU	O
+therapy	O
+.	O
+	
+Twenty	O
+-	O
+nine	O
+of	O
+them	O
+were	O
+later	O
+excluded	O
+because	O
+of	O
+adverse	O
+effects	O
+of	O
+PTU	O
+or	O
+because	O
+the	O
+observation	O
+period	O
+was	O
+less	O
+than	O
+3	O
+months	O
+.	O
+	
+The	O
+remaining	O
+73	O
+patients	O
+(	O
+55	O
+women	O
+and	O
+18	O
+men	O
+)	O
+","	O
+all	O
+of	O
+whom	O
+were	O
+examined	O
+for	O
+more	O
+than	O
+3	O
+months	O
+","	O
+were	O
+adopted	O
+as	O
+the	O
+subjects	O
+of	O
+the	O
+investigation	O
+.	O
+	
+The	O
+median	O
+observation	O
+period	O
+was	O
+23	O
+.	O
+6	O
+months	O
+(	O
+range	O
+:	O
+3	O
+-	O
+37	O
+months	O
+)	O
+.	O
+	
+MEASUREMENTS	O
+:	O
+MPO	O
+-	O
+ANCA	O
+was	O
+measured	O
+at	O
+intervals	O
+of	O
+2	O
+-	O
+6	O
+months	O
+.	O
+	
+RESULTS	O
+:	O
+Before	O
+treatment	O
+","	O
+the	O
+MPO	O
+-	O
+ANCA	O
+titres	O
+of	O
+all	O
+102	O
+untreated	O
+Graves	B-NP
+'	I-NP
+disease	I-NP
+patients	O
+were	O
+within	O
+the	O
+reference	O
+range	O
+(	O
+below	O
+10	O
+U	O
+/	O
+ml	O
+)	O
+.	O
+	
+Three	O
+(	O
+4	O
+.	O
+1	O
+%	O
+)	O
+of	O
+the	O
+73	O
+patients	O
+were	O
+positive	O
+for	O
+MPO	O
+-	O
+ANCA	O
+at	O
+13	O
+","	O
+16	O
+and	O
+17	O
+months	O
+","	O
+respectively	O
+","	O
+after	O
+the	O
+start	O
+of	O
+PTU	O
+therapy	O
+.	O
+	
+In	O
+two	O
+of	O
+them	O
+","	O
+the	O
+MPO	O
+-	O
+ANCA	O
+titres	O
+transiently	O
+increased	O
+to	O
+12	O
+.	O
+8	O
+and	O
+15	O
+.	O
+0	O
+U	O
+/	O
+ml	O
+","	O
+respectively	O
+","	O
+despite	O
+continued	O
+PTU	O
+therapy	O
+","	O
+but	O
+no	O
+vasculitic	B-NP
+disorders	I-NP
+developed	O
+.	O
+	
+In	O
+the	O
+third	O
+patient	O
+","	O
+the	O
+MPO	O
+-	O
+ANCA	O
+titre	O
+increased	O
+to	O
+204	O
+U	O
+/	O
+ml	O
+and	O
+she	O
+developed	O
+a	O
+higher	O
+fever	B-NP
+","	O
+oral	B-NP
+ulcers	I-NP
+and	O
+polyarthralgia	B-NP
+","	O
+but	O
+the	O
+symptoms	O
+resolved	O
+2	O
+weeks	O
+after	O
+stopping	O
+PTU	O
+therapy	O
+","	O
+and	O
+the	O
+MPO	O
+-	O
+ANCA	O
+titre	O
+decreased	O
+to	O
+20	O
+.	O
+7	O
+U	O
+/	O
+ml	O
+by	O
+4	O
+months	O
+after	O
+discontinuing	O
+PTU	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+PTU	O
+therapy	O
+may	O
+be	O
+related	O
+to	O
+the	O
+appearance	O
+of	O
+MPO	O
+-	O
+ANCA	O
+","	O
+but	O
+MPO	O
+-	O
+ANCA	O
+does	O
+not	O
+appear	O
+to	O
+be	O
+closely	O
+related	O
+to	O
+vasculitis	B-NP
+.	O
+	
+Prevalence	O
+of	O
+heart	B-NP
+disease	I-NP
+in	O
+asymptomatic	O
+chronic	O
+cocaine	O
+users	O
+.	O
+	
+To	O
+determine	O
+the	O
+prevalence	O
+of	O
+heart	B-NP
+disease	I-NP
+in	O
+outpatient	O
+young	O
+asymptomatic	O
+chronic	O
+cocaine	O
+users	O
+","	O
+35	O
+cocaine	O
+users	O
+and	O
+32	O
+age	O
+-	O
+matched	O
+controls	O
+underwent	O
+resting	O
+and	O
+exercise	O
+electrocardiography	O
+(	O
+ECG	O
+)	O
+and	O
+Doppler	O
+echocardiography	O
+.	O
+	
+Findings	O
+consistent	O
+with	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+were	O
+detected	O
+in	O
+12	O
+(	O
+34	O
+%	O
+)	O
+patients	O
+and	O
+3	O
+(	O
+9	O
+%	O
+)	O
+controls	O
+(	O
+p	O
+=	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Decreased	O
+left	O
+ventricular	O
+systolic	O
+function	O
+was	O
+demonstrated	O
+in	O
+5	O
+(	O
+14	O
+%	O
+)	O
+patients	O
+","	O
+but	O
+in	O
+none	O
+of	O
+the	O
+controls	O
+(	O
+p	O
+=	O
+0	O
+.	O
+55	O
+)	O
+.	O
+	
+Finally	O
+","	O
+resting	O
+and	O
+peak	O
+exercise	O
+abnormal	B-NP
+left	I-NP
+ventricular	I-NP
+filling	I-NP
+was	O
+detected	O
+in	O
+38	O
+and	O
+35	O
+%	O
+of	O
+patients	O
+as	O
+compared	O
+to	O
+19	O
+and	O
+9	O
+%	O
+of	O
+controls	O
+","	O
+respectively	O
+(	O
+p	O
+=	O
+0	O
+.	O
+11	O
+and	O
+0	O
+.	O
+2	O
+","	O
+respectively	O
+)	O
+.	O
+	
+We	O
+conclude	O
+that	O
+coronary	B-NP
+artery	I-NP
+or	I-NP
+myocardial	I-NP
+disease	I-NP
+is	O
+common	O
+(	O
+38	O
+%	O
+)	O
+in	O
+young	O
+asymptomatic	O
+chronic	O
+cocaine	O
+users	O
+.	O
+	
+Therefore	O
+","	O
+screening	O
+ECG	O
+and	O
+echocardiography	O
+may	O
+be	O
+warranted	O
+in	O
+these	O
+patients	O
+.	O
+	
+Cardioprotective	O
+effects	O
+of	O
+Picrorrhiza	O
+kurroa	O
+against	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	O
+stress	O
+in	O
+rats	O
+.	O
+	
+The	O
+cardioprotective	O
+effect	O
+of	O
+the	O
+ethanol	O
+extract	O
+of	O
+Picrorrhiza	O
+kurroa	O
+rhizomes	O
+and	O
+roots	O
+(	O
+PK	O
+)	O
+on	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B-NP
+infarction	I-NP
+in	O
+rats	O
+with	O
+respect	O
+to	O
+lipid	O
+metabolism	O
+in	O
+serum	O
+and	O
+heart	O
+tissue	O
+has	O
+been	O
+investigated	O
+.	O
+	
+Oral	O
+pre	O
+-	O
+treatment	O
+with	O
+PK	O
+(	O
+80	O
+mg	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+day	O
+(	O
+-	O
+1	O
+)	O
+for	O
+15	O
+days	O
+)	O
+significantly	O
+prevented	O
+the	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B-NP
+infarction	I-NP
+and	O
+maintained	O
+the	O
+rats	O
+at	O
+near	O
+normal	O
+status	O
+.	O
+	
+Phase	O
+2	O
+early	O
+afterdepolarization	O
+as	O
+a	O
+trigger	O
+of	O
+polymorphic	O
+ventricular	B-NP
+tachycardia	I-NP
+in	O
+acquired	O
+long	B-NP
+-	I-NP
+QT	I-NP
+syndrome	I-NP
+:	O
+direct	O
+evidence	O
+from	O
+intracellular	O
+recordings	O
+in	O
+the	O
+intact	O
+left	O
+ventricular	O
+wall	O
+.	O
+	
+BACKGROUND	O
+:	O
+This	O
+study	O
+examined	O
+the	O
+role	O
+of	O
+phase	O
+2	O
+early	O
+afterdepolarization	O
+(	O
+EAD	O
+)	O
+in	O
+producing	O
+a	O
+trigger	O
+to	O
+initiate	O
+torsade	B-NP
+de	I-NP
+pointes	I-NP
+(	O
+TdP	B-NP
+)	O
+with	O
+QT	B-NP
+prolongation	I-NP
+induced	O
+by	O
+dl	O
+-	O
+sotalol	O
+and	O
+azimilide	O
+.	O
+	
+The	O
+contribution	O
+of	O
+transmural	O
+dispersion	O
+of	O
+repolarization	O
+(	O
+TDR	O
+)	O
+to	O
+transmural	O
+propagation	O
+of	O
+EAD	O
+and	O
+the	O
+maintenance	O
+of	O
+TdP	B-NP
+was	O
+also	O
+evaluated	O
+.	O
+	
+METHODS	O
+AND	O
+RESULTS	O
+:	O
+Transmembrane	O
+action	O
+potentials	O
+from	O
+epicardium	O
+","	O
+midmyocardium	O
+","	O
+and	O
+endocardium	O
+were	O
+recorded	O
+simultaneously	O
+","	O
+together	O
+with	O
+a	O
+transmural	O
+ECG	O
+","	O
+in	O
+arterially	O
+perfused	O
+canine	O
+and	O
+rabbit	O
+left	O
+ventricular	O
+preparations	O
+.	O
+	
+dl	O
+-	O
+Sotalol	O
+preferentially	O
+prolonged	O
+action	O
+potential	O
+duration	O
+(	O
+APD	O
+)	O
+in	O
+M	O
+cells	O
+dose	O
+-	O
+dependently	O
+(	O
+1	O
+to	O
+100	O
+micromol	O
+/	O
+L	O
+)	O
+","	O
+leading	O
+to	O
+QT	B-NP
+prolongation	I-NP
+and	O
+an	O
+increase	O
+in	O
+TDR	O
+.	O
+	
+Azimilide	O
+","	O
+however	O
+","	O
+significantly	O
+prolonged	O
+APD	O
+and	O
+QT	O
+interval	O
+at	O
+concentrations	O
+from	O
+0	O
+.	O
+1	O
+to	O
+10	O
+micromol	O
+/	O
+L	O
+but	O
+shortened	O
+them	O
+at	O
+30	O
+micromol	O
+/	O
+L	O
+.	O
+	
+Unlike	O
+dl	O
+-	O
+sotalol	O
+","	O
+azimilide	O
+(	O
+>	O
+3	O
+micromol	O
+/	O
+L	O
+)	O
+increased	O
+epicardial	O
+APD	O
+markedly	O
+","	O
+causing	O
+a	O
+diminished	O
+TDR	O
+.	O
+	
+Although	O
+both	O
+dl	O
+-	O
+sotalol	O
+and	O
+azimilide	O
+rarely	O
+induced	O
+EADs	O
+in	O
+canine	O
+left	O
+ventricles	O
+","	O
+they	O
+produced	O
+frequent	O
+EADs	O
+in	O
+rabbits	O
+","	O
+in	O
+which	O
+more	O
+pronounced	O
+QT	B-NP
+prolongation	I-NP
+was	O
+seen	O
+.	O
+	
+An	O
+increase	O
+in	O
+TDR	O
+by	O
+dl	O
+-	O
+sotalol	O
+facilitated	O
+transmural	O
+propagation	O
+of	O
+EADs	O
+that	O
+initiated	O
+multiple	O
+episodes	O
+of	O
+spontaneous	O
+TdP	B-NP
+in	O
+3	O
+of	O
+6	O
+rabbit	O
+left	O
+ventricles	O
+.	O
+	
+Of	O
+note	O
+","	O
+although	O
+azimilide	O
+(	O
+3	O
+to	O
+10	O
+micromol	O
+/	O
+L	O
+)	O
+increased	O
+APD	O
+more	O
+than	O
+dl	O
+-	O
+sotalol	O
+","	O
+its	O
+EADs	O
+often	O
+failed	O
+to	O
+propagate	O
+transmurally	O
+","	O
+probably	O
+because	O
+of	O
+a	O
+diminished	O
+TDR	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+This	O
+study	O
+provides	O
+the	O
+first	O
+direct	O
+evidence	O
+from	O
+intracellular	O
+action	O
+potential	O
+recordings	O
+that	O
+phase	O
+2	O
+EAD	O
+can	O
+be	O
+generated	O
+from	O
+intact	O
+ventricular	O
+wall	O
+and	O
+produce	O
+a	O
+trigger	O
+to	O
+initiate	O
+the	O
+onset	O
+of	O
+TdP	B-NP
+under	O
+QT	B-NP
+prolongation	I-NP
+.	O
+	
+A	O
+pilot	O
+study	O
+to	O
+assess	O
+the	O
+safety	O
+of	O
+dobutamine	O
+stress	O
+echocardiography	O
+in	O
+the	O
+emergency	O
+department	O
+evaluation	O
+of	O
+cocaine	O
+-	O
+associated	O
+chest	B-NP
+pain	I-NP
+.	O
+	
+STUDY	O
+OBJECTIVE	O
+:	O
+Chest	B-NP
+pain	I-NP
+in	O
+the	O
+setting	O
+of	O
+cocaine	O
+use	O
+poses	O
+a	O
+diagnostic	O
+dilemma	O
+.	O
+	
+Dobutamine	O
+stress	O
+echocardiography	O
+(	O
+DSE	O
+)	O
+is	O
+a	O
+widely	O
+available	O
+and	O
+sensitive	O
+test	O
+for	O
+evaluating	O
+cardiac	O
+ischemia	B-NP
+.	O
+	
+Because	O
+of	O
+the	O
+theoretical	O
+concern	O
+regarding	O
+administration	O
+of	O
+dobutamine	O
+in	O
+the	O
+setting	O
+of	O
+cocaine	O
+use	O
+","	O
+we	O
+conducted	O
+a	O
+pilot	O
+study	O
+to	O
+assess	O
+the	O
+safety	O
+of	O
+DSE	O
+in	O
+emergency	O
+department	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B-NP
+pain	I-NP
+.	O
+	
+METHODS	O
+:	O
+A	O
+prospective	O
+case	O
+series	O
+was	O
+conducted	O
+in	O
+the	O
+intensive	O
+diagnostic	O
+and	O
+treatment	O
+unit	O
+in	O
+the	O
+ED	O
+of	O
+an	O
+urban	O
+tertiary	O
+-	O
+care	O
+teaching	O
+hospital	O
+.	O
+	
+Patients	O
+were	O
+eligible	O
+for	O
+DSE	O
+if	O
+they	O
+had	O
+used	O
+cocaine	O
+within	O
+24	O
+hours	O
+preceding	O
+the	O
+onset	O
+of	O
+chest	B-NP
+pain	I-NP
+and	O
+had	O
+a	O
+normal	O
+ECG	O
+and	O
+tropinin	O
+I	O
+level	O
+.	O
+	
+Patients	O
+exhibiting	O
+signs	O
+of	O
+continuing	O
+cocaine	O
+toxicity	B-NP
+were	O
+excluded	O
+from	O
+the	O
+study	O
+.	O
+	
+All	O
+patients	O
+were	O
+admitted	O
+to	O
+the	O
+hospital	O
+for	O
+serial	O
+testing	O
+after	O
+the	O
+DSE	O
+testing	O
+in	O
+the	O
+intensive	O
+diagnostic	O
+and	O
+treatment	O
+unit	O
+.	O
+	
+RESULTS	O
+:	O
+Twenty	O
+-	O
+four	O
+patients	O
+were	O
+enrolled	O
+.	O
+	
+Two	O
+patients	O
+had	O
+inadequate	O
+resting	O
+images	O
+","	O
+one	O
+DSE	O
+was	O
+terminated	O
+because	O
+of	O
+inferior	O
+hypokinesis	B-NP
+","	O
+another	O
+DSE	O
+was	O
+terminated	O
+because	O
+of	O
+a	O
+rate	O
+-	O
+related	O
+atrial	O
+conduction	O
+deficit	O
+","	O
+and	O
+1	O
+patient	O
+did	O
+not	O
+reach	O
+the	O
+target	O
+heart	O
+rate	O
+.	O
+	
+Thus	O
+","	O
+19	O
+patients	O
+completed	O
+a	O
+DSE	O
+and	O
+reached	O
+their	O
+target	O
+heart	O
+rates	O
+.	O
+	
+None	O
+of	O
+the	O
+patients	O
+experienced	O
+signs	O
+of	O
+exaggerated	O
+adrenergic	O
+response	O
+","	O
+which	O
+was	O
+defined	O
+as	O
+a	O
+systolic	O
+blood	O
+pressure	O
+of	O
+greater	O
+than	O
+200	O
+mm	O
+Hg	O
+or	O
+the	O
+occurrence	O
+of	O
+tachydysrhythmias	B-NP
+(	O
+excluding	O
+sinus	B-NP
+tachycardia	I-NP
+)	O
+.	O
+	
+Further	O
+suggesting	O
+lack	O
+of	O
+exaggerated	O
+adrenergic	O
+response	O
+","	O
+13	O
+(	O
+65	O
+%	O
+)	O
+of	O
+20	O
+patients	O
+required	O
+supplemental	O
+atropine	O
+to	O
+reach	O
+their	O
+target	O
+heart	O
+rates	O
+.	O
+	
+CONCLUSION	O
+:	O
+No	O
+exaggerated	O
+adrenergic	O
+response	O
+was	O
+detected	O
+when	O
+dobutamine	O
+was	O
+administered	O
+to	O
+patients	O
+with	O
+cocaine	O
+-	O
+related	O
+chest	B-NP
+pain	I-NP
+.	O
+	
+Prenatal	O
+cocaine	O
+exposure	O
+and	O
+cranial	O
+sonographic	O
+findings	O
+in	O
+preterm	B-NP
+infants	I-NP
+.	O
+	
+PURPOSE	O
+:	O
+Prenatal	O
+cocaine	O
+exposure	O
+has	O
+been	O
+linked	O
+with	O
+subependymal	O
+hemorrhage	B-NP
+and	O
+the	O
+formation	O
+of	O
+cysts	B-NP
+that	O
+are	O
+detectable	O
+on	O
+cranial	O
+sonography	O
+in	O
+neonates	O
+born	O
+at	O
+term	O
+.	O
+	
+We	O
+sought	O
+to	O
+determine	O
+if	O
+prenatal	O
+cocaine	O
+exposure	O
+increases	O
+the	O
+incidence	O
+of	O
+subependymal	B-NP
+cysts	I-NP
+in	O
+preterm	B-NP
+infants	I-NP
+.	O
+	
+METHODS	O
+:	O
+We	O
+retrospectively	O
+reviewed	O
+the	O
+medical	O
+records	O
+and	O
+cranial	O
+sonograms	O
+obtained	O
+during	O
+a	O
+1	O
+-	O
+year	O
+period	O
+on	O
+122	O
+premature	B-NP
+(	I-NP
+<	I-NP
+36	I-NP
+weeks	I-NP
+of	I-NP
+gestation	I-NP
+)	I-NP
+infants	I-NP
+.	O
+	
+Infants	O
+were	O
+categorized	O
+into	O
+1	O
+of	O
+2	O
+groups	O
+:	O
+those	O
+exposed	O
+to	O
+cocaine	O
+and	O
+those	O
+not	O
+exposed	O
+to	O
+cocaine	O
+.	O
+	
+Infants	O
+were	O
+assigned	O
+to	O
+the	O
+cocaine	O
+-	O
+exposed	O
+group	O
+if	O
+there	O
+was	O
+a	O
+maternal	O
+history	O
+of	O
+cocaine	B-NP
+abuse	I-NP
+during	O
+pregnancy	O
+or	O
+if	O
+maternal	O
+or	O
+neonatal	O
+urine	O
+toxicology	O
+results	O
+were	O
+positive	O
+at	O
+the	O
+time	O
+of	O
+delivery	O
+.	O
+	
+RESULTS	O
+:	O
+Five	O
+of	O
+the	O
+122	O
+infants	O
+were	O
+excluded	O
+from	O
+the	O
+study	O
+because	O
+of	O
+insufficient	O
+medical	O
+and	O
+drug	O
+histories	O
+.	O
+	
+The	O
+incidence	O
+of	O
+subependymal	B-NP
+cysts	I-NP
+in	O
+the	O
+117	O
+remaining	O
+infants	O
+was	O
+14	O
+%	O
+(	O
+16	O
+of	O
+117	O
+)	O
+.	O
+	
+The	O
+incidence	O
+of	O
+subependymal	B-NP
+cysts	I-NP
+in	O
+infants	O
+exposed	O
+to	O
+cocaine	O
+prenatally	O
+was	O
+44	O
+%	O
+(	O
+8	O
+of	O
+18	O
+)	O
+compared	O
+with	O
+8	O
+%	O
+(	O
+8	O
+of	O
+99	O
+)	O
+in	O
+the	O
+unexposed	O
+group	O
+(	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+We	O
+found	O
+an	O
+increased	O
+incidence	O
+of	O
+subependymal	B-NP
+cyst	I-NP
+formation	O
+in	O
+preterm	B-NP
+infants	I-NP
+who	O
+were	O
+exposed	O
+to	O
+cocaine	O
+prenatally	O
+.	O
+	
+This	O
+result	O
+is	O
+consistent	O
+with	O
+results	O
+of	O
+similar	O
+studies	O
+in	O
+term	O
+infants	O
+.	O
+	
+Thalidomide	O
+neuropathy	B-NP
+in	O
+patients	O
+treated	O
+for	O
+metastatic	O
+prostate	B-NP
+cancer	I-NP
+.	O
+	
+We	O
+prospectively	O
+evaluated	O
+thalidomide	O
+-	O
+induced	O
+neuropathy	B-NP
+using	O
+electrodiagnostic	O
+studies	O
+.	O
+	
+Sixty	O
+-	O
+seven	O
+men	O
+with	O
+metastatic	O
+androgen	O
+-	O
+independent	O
+prostate	B-NP
+cancer	I-NP
+in	O
+an	O
+open	O
+-	O
+label	O
+trial	O
+of	O
+oral	O
+thalidomide	O
+underwent	O
+neurologic	O
+examinations	O
+and	O
+nerve	O
+conduction	O
+studies	O
+(	O
+NCS	O
+)	O
+prior	O
+to	O
+and	O
+at	O
+3	O
+-	O
+month	O
+intervals	O
+during	O
+treatment	O
+.	O
+	
+NCS	O
+included	O
+recording	O
+of	O
+sensory	O
+nerve	O
+action	O
+potentials	O
+(	O
+SNAPs	O
+)	O
+from	O
+median	O
+","	O
+radial	O
+","	O
+ulnar	O
+","	O
+and	O
+sural	O
+nerves	O
+.	O
+	
+SNAP	O
+amplitudes	O
+for	O
+each	O
+nerve	O
+were	O
+expressed	O
+as	O
+the	O
+percentage	O
+of	O
+its	O
+baseline	O
+","	O
+and	O
+the	O
+mean	O
+of	O
+the	O
+four	O
+was	O
+termed	O
+the	O
+SNAP	O
+index	O
+.	O
+	
+A	O
+40	O
+%	O
+decline	O
+in	O
+the	O
+SNAP	O
+index	O
+was	O
+considered	O
+clinically	O
+significant	O
+.	O
+	
+Thalidomide	O
+was	O
+discontinued	O
+in	O
+55	O
+patients	O
+for	O
+lack	O
+of	O
+therapeutic	O
+response	O
+.	O
+	
+Of	O
+67	O
+patients	O
+initially	O
+enrolled	O
+","	O
+24	O
+remained	O
+on	O
+thalidomide	O
+for	O
+3	O
+months	O
+","	O
+8	O
+remained	O
+at	O
+6	O
+months	O
+","	O
+and	O
+3	O
+remained	O
+at	O
+9	O
+months	O
+.	O
+	
+Six	O
+patients	O
+developed	O
+neuropathy	B-NP
+.	O
+	
+Clinical	O
+symptoms	O
+and	O
+a	O
+decline	O
+in	O
+the	O
+SNAP	O
+index	O
+occurred	O
+concurrently	O
+.	O
+	
+Older	O
+age	O
+and	O
+cumulative	O
+dose	O
+were	O
+possible	O
+contributing	O
+factors	O
+.	O
+	
+Neuropathy	B-NP
+may	O
+thus	O
+be	O
+a	O
+common	O
+complication	O
+of	O
+thalidomide	O
+in	O
+older	O
+patients	O
+.	O
+	
+The	O
+SNAP	O
+index	O
+can	O
+be	O
+used	O
+to	O
+monitor	O
+peripheral	B-NP
+neuropathy	I-NP
+","	O
+but	O
+not	O
+for	O
+early	O
+detection	O
+.	O
+	
+Overexpression	O
+of	O
+copper	O
+/	O
+zinc	O
+-	O
+superoxide	O
+dismutase	O
+protects	O
+from	O
+kanamycin	O
+-	O
+induced	O
+hearing	B-NP
+loss	I-NP
+.	O
+	
+The	O
+participation	O
+of	O
+reactive	O
+oxygen	O
+species	O
+in	O
+aminoglycoside	O
+-	O
+induced	O
+ototoxicity	B-NP
+has	O
+been	O
+deduced	O
+from	O
+observations	O
+that	O
+aminoglycoside	O
+-	O
+iron	O
+complexes	O
+catalyze	O
+the	O
+formation	O
+of	O
+superoxide	O
+radicals	O
+in	O
+vitro	O
+and	O
+that	O
+antioxidants	O
+attenuate	O
+ototoxicity	B-NP
+in	O
+vivo	O
+.	O
+	
+We	O
+therefore	O
+hypothesized	O
+that	O
+overexpression	O
+of	O
+Cu	O
+/	O
+Zn	O
+-	O
+superoxide	O
+dismutase	O
+(	O
+h	O
+-	O
+SOD1	O
+)	O
+should	O
+protect	O
+transgenic	O
+mice	O
+from	O
+ototoxicity	B-NP
+.	O
+	
+Immunocytochemistry	O
+confirmed	O
+expression	O
+of	O
+h	O
+-	O
+SOD1	O
+in	O
+inner	O
+ear	O
+tissues	O
+of	O
+transgenic	O
+C57BL	O
+/	O
+6	O
+-	O
+TgN	O
+[	O
+SOD1	O
+]	O
+3Cje	O
+mice	O
+.	O
+	
+Transgenic	O
+and	O
+nontransgenic	O
+littermates	O
+received	O
+kanamycin	O
+(	O
+400	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+/	O
+day	O
+)	O
+for	O
+10	O
+days	O
+beginning	O
+on	O
+day	O
+10	O
+after	O
+birth	O
+.	O
+	
+Auditory	O
+thresholds	O
+were	O
+tested	O
+by	O
+evoked	O
+auditory	O
+brain	O
+stem	O
+responses	O
+at	O
+1	O
+month	O
+after	O
+birth	O
+.	O
+	
+In	O
+nontransgenic	O
+animals	O
+","	O
+the	O
+threshold	O
+in	O
+the	O
+kanamycin	O
+-	O
+treated	O
+group	O
+was	O
+45	O
+-	O
+50	O
+dB	O
+higher	O
+than	O
+in	O
+saline	O
+-	O
+injected	O
+controls	O
+.	O
+	
+In	O
+the	O
+transgenic	O
+group	O
+","	O
+kanamycin	O
+increased	O
+the	O
+threshold	O
+by	O
+only	O
+15	O
+dB	O
+over	O
+the	O
+respective	O
+controls	O
+.	O
+	
+The	O
+effects	O
+were	O
+similar	O
+at	O
+12	O
+and	O
+24	O
+kHz	O
+.	O
+	
+The	O
+protection	O
+by	O
+overexpression	O
+of	O
+superoxide	O
+dismutase	O
+supports	O
+the	O
+hypothesis	O
+that	O
+oxidant	O
+stress	O
+plays	O
+a	O
+significant	O
+role	O
+in	O
+aminoglycoside	O
+-	O
+induced	O
+ototoxicity	B-NP
+.	O
+	
+The	O
+results	O
+also	O
+suggest	O
+transgenic	O
+animals	O
+as	O
+suitable	O
+models	O
+to	O
+investigate	O
+the	O
+underlying	O
+mechanisms	O
+and	O
+possible	O
+strategies	O
+for	O
+prevention	O
+.	O
+	
+Fatty	B-NP
+liver	I-NP
+induced	O
+by	O
+tetracycline	O
+in	O
+the	O
+rat	O
+.	O
+	
+Dose	O
+-	O
+response	O
+relationships	O
+and	O
+effect	O
+of	O
+sex	O
+.	O
+	
+Dose	O
+-	O
+response	O
+relationships	O
+","	O
+biochemical	O
+mechanisms	O
+","	O
+and	O
+sex	O
+differences	O
+in	O
+the	O
+experimental	O
+fatty	B-NP
+liver	I-NP
+induced	O
+by	O
+tetracycline	O
+were	O
+studied	O
+in	O
+the	O
+intact	O
+rat	O
+and	O
+with	O
+the	O
+isolated	O
+perfused	O
+rat	O
+liver	O
+in	O
+vitro	O
+.	O
+	
+In	O
+the	O
+intact	O
+male	O
+and	O
+female	O
+rat	O
+","	O
+no	O
+direct	O
+relationship	O
+was	O
+observed	O
+between	O
+dose	O
+of	O
+tetracycline	O
+and	O
+hepatic	O
+accumulation	O
+of	O
+triglyceride	O
+.	O
+	
+With	O
+provision	O
+of	O
+adequate	O
+oleic	O
+acid	O
+as	O
+a	O
+substrate	O
+for	O
+the	O
+isolated	O
+perfused	O
+liver	O
+","	O
+a	O
+direct	O
+relationship	O
+was	O
+observed	O
+between	O
+dose	O
+of	O
+tetracycline	O
+and	O
+both	O
+accumulation	O
+of	O
+triglyceride	O
+in	O
+the	O
+liver	O
+and	O
+depression	B-NP
+of	O
+output	O
+of	O
+triglyceride	O
+by	O
+livers	O
+from	O
+male	O
+and	O
+female	O
+rats	O
+.	O
+	
+Marked	O
+differences	O
+were	O
+observed	O
+between	O
+female	O
+and	O
+male	O
+rats	O
+with	O
+regard	O
+to	O
+base	O
+line	O
+(	O
+control	O
+)	O
+hepatic	O
+concentration	O
+of	O
+triglyceride	O
+and	O
+output	O
+of	O
+triglyceride	O
+.	O
+	
+Accumulation	O
+of	O
+hepatic	O
+triglyceride	O
+","	O
+as	O
+a	O
+per	O
+cent	O
+of	O
+control	O
+values	O
+","	O
+in	O
+response	O
+to	O
+graded	O
+doses	O
+of	O
+tetracycline	O
+","	O
+did	O
+not	O
+differ	O
+significantly	O
+between	O
+male	O
+","	O
+female	O
+and	O
+pregnant	O
+rat	O
+livers	O
+.	O
+	
+However	O
+","	O
+livers	O
+from	O
+female	O
+","	O
+and	O
+especially	O
+pregnant	O
+female	O
+rats	O
+","	O
+were	O
+strikingly	O
+resistant	O
+to	O
+the	O
+effects	O
+of	O
+tetracycline	O
+on	O
+depression	B-NP
+of	O
+output	O
+of	O
+triglyceride	O
+under	O
+these	O
+experimental	O
+conditions	O
+.	O
+	
+These	O
+differences	O
+between	O
+the	O
+sexes	O
+could	O
+not	O
+be	O
+related	O
+to	O
+altered	O
+disposition	O
+of	O
+tetracycline	O
+or	O
+altered	O
+uptake	O
+of	O
+oleic	O
+acid	O
+.	O
+	
+Depressed	O
+hepatic	O
+secretion	O
+of	O
+triglyceride	O
+accounted	O
+only	O
+for	O
+30	O
+to	O
+50	O
+%	O
+of	O
+accumulated	O
+hepatic	O
+triglyceride	O
+","	O
+indicating	O
+that	O
+additional	O
+mechanisms	O
+must	O
+be	O
+involved	O
+in	O
+the	O
+production	O
+of	O
+the	O
+triglyceride	O
+-	O
+rich	O
+fatty	B-NP
+liver	I-NP
+in	O
+response	O
+to	O
+tetracycline	O
+.	O
+	
+Prednisone	O
+induces	O
+anxiety	B-NP
+and	O
+glial	O
+cerebral	O
+changes	O
+in	O
+rats	O
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+assess	O
+whether	O
+prednisone	O
+(	O
+PDN	O
+)	O
+produces	O
+anxiety	B-NP
+and	O
+/	O
+or	O
+cerebral	O
+glial	O
+changes	O
+in	O
+rats	O
+.	O
+	
+METHODS	O
+:	O
+Male	O
+Wistar	O
+rats	O
+were	O
+studied	O
+and	O
+3	O
+groups	O
+were	O
+formed	O
+(	O
+8	O
+rats	O
+per	O
+group	O
+)	O
+.	O
+	
+The	O
+moderate	O
+-	O
+dose	O
+group	O
+received	O
+5	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+PDN	O
+released	O
+from	O
+a	O
+subcutaneous	O
+implant	O
+.	O
+	
+In	O
+the	O
+high	O
+-	O
+dose	O
+group	O
+","	O
+implants	O
+containing	O
+PDN	O
+equivalent	O
+to	O
+60	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+were	O
+applied	O
+.	O
+	
+In	O
+the	O
+control	O
+group	O
+implants	O
+contained	O
+no	O
+PDN	O
+.	O
+	
+Anxiety	B-NP
+was	O
+assessed	O
+using	O
+an	O
+open	O
+field	O
+and	O
+elevated	O
+plus	O
+-	O
+maze	O
+devices	O
+.	O
+	
+The	O
+number	O
+of	O
+cells	O
+and	O
+cytoplasmic	O
+transformation	O
+of	O
+astrocytes	O
+and	O
+microglia	O
+cells	O
+were	O
+assessed	O
+by	O
+immunohistochemical	O
+analyses	O
+.	O
+	
+RESULTS	O
+:	O
+Anxiety	B-NP
+was	O
+documented	O
+in	O
+both	O
+groups	O
+of	O
+PDN	O
+treated	O
+rats	O
+compared	O
+with	O
+controls	O
+.	O
+	
+The	O
+magnitude	O
+of	O
+transformation	O
+of	O
+the	O
+microglia	O
+assessed	O
+by	O
+the	O
+number	O
+of	O
+intersections	O
+was	O
+significantly	O
+higher	O
+in	O
+the	O
+PDN	O
+groups	O
+than	O
+in	O
+controls	O
+in	O
+the	O
+prefrontal	O
+cortex	O
+(	O
+moderate	O
+-	O
+dose	O
+","	O
+24	O
+.	O
+1	O
+;	O
+high	O
+-	O
+dose	O
+","	O
+23	O
+.	O
+6	O
+;	O
+controls	O
+18	O
+.	O
+7	O
+;	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+and	O
+striatum	O
+(	O
+moderate	O
+-	O
+dose	O
+25	O
+.	O
+6	O
+;	O
+high	O
+-	O
+dose	O
+26	O
+.	O
+3	O
+;	O
+controls	O
+18	O
+.	O
+9	O
+;	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+","	O
+but	O
+not	O
+in	O
+hippocampus	O
+.	O
+	
+The	O
+number	O
+of	O
+stained	O
+microglia	O
+cells	O
+was	O
+significantly	O
+higher	O
+in	O
+the	O
+PDN	O
+treated	O
+groups	O
+in	O
+the	O
+prefrontal	O
+cortex	O
+than	O
+in	O
+controls	O
+(	O
+moderate	O
+-	O
+dose	O
+","	O
+29	O
+.	O
+1	O
+;	O
+high	O
+-	O
+dose	O
+","	O
+28	O
+.	O
+4	O
+;	O
+control	O
+","	O
+17	O
+.	O
+7	O
+cells	O
+per	O
+field	O
+;	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Stained	O
+microglia	O
+cells	O
+were	O
+significantly	O
+more	O
+numerous	O
+striatum	O
+and	O
+hippocampus	O
+in	O
+the	O
+high	O
+-	O
+dose	O
+group	O
+compared	O
+to	O
+controls	O
+.	O
+	
+CONCLUSION	O
+:	O
+Subacute	O
+exposure	O
+to	O
+PDN	O
+induced	O
+anxiety	B-NP
+and	O
+reactivity	O
+of	O
+microglia	O
+.	O
+	
+The	O
+relevance	O
+of	O
+these	O
+features	O
+for	O
+patients	O
+using	O
+PDN	O
+remains	O
+to	O
+be	O
+elucidated	O
+.	O
+	
+Phase	O
+II	O
+study	O
+of	O
+carboplatin	O
+and	O
+liposomal	O
+doxorubicin	O
+in	O
+patients	O
+with	O
+recurrent	O
+squamous	B-NP
+cell	I-NP
+carcinoma	I-NP
+of	I-NP
+the	I-NP
+cervix	I-NP
+.	O
+	
+BACKGROUND	O
+:	O
+The	O
+activity	O
+of	O
+the	O
+combination	O
+of	O
+carboplatin	O
+and	O
+liposomal	O
+doxorubicin	O
+was	O
+tested	O
+in	O
+a	O
+Phase	O
+II	O
+study	O
+of	O
+patients	O
+with	O
+recurrent	O
+cervical	B-NP
+carcinoma	I-NP
+.	O
+	
+METHODS	O
+:	O
+The	O
+combination	O
+of	O
+carboplatin	O
+(	O
+area	O
+under	O
+the	O
+concentration	O
+curve	O
+[	O
+AUC	O
+]	O
+","	O
+5	O
+)	O
+and	O
+liposomal	O
+doxorubicin	O
+(	O
+Doxil	O
+;	O
+starting	O
+dose	O
+","	O
+40	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+)	O
+was	O
+administered	O
+intravenously	O
+every	O
+28	O
+days	O
+to	O
+37	O
+patients	O
+with	O
+recurrent	O
+squamous	B-NP
+cell	I-NP
+cervical	I-NP
+carcinoma	I-NP
+to	O
+determine	O
+antitumor	O
+activity	O
+and	O
+toxicity	B-NP
+profile	O
+.	O
+	
+RESULTS	O
+:	O
+Twenty	O
+-	O
+nine	O
+patients	O
+were	O
+assessable	O
+for	O
+response	O
+","	O
+and	O
+35	O
+patients	O
+were	O
+assessable	O
+for	O
+toxicity	B-NP
+.	O
+	
+The	O
+overall	O
+response	O
+rate	O
+was	O
+38	O
+%	O
+","	O
+the	O
+median	O
+time	O
+to	O
+response	O
+was	O
+10	O
+weeks	O
+","	O
+the	O
+median	O
+duration	O
+of	O
+response	O
+was	O
+26	O
+weeks	O
+","	O
+and	O
+the	O
+median	O
+survival	O
+was	O
+37	O
+weeks	O
+.	O
+	
+The	O
+main	O
+toxic	O
+effect	O
+was	O
+myelosuppression	B-NP
+","	O
+with	O
+Grade	O
+3	O
+and	O
+4	O
+neutropenia	B-NP
+in	O
+16	O
+patients	O
+","	O
+anemia	B-NP
+in	O
+12	O
+patients	O
+","	O
+thrombocytopenia	B-NP
+in	O
+11	O
+patients	O
+","	O
+and	O
+neutropenic	B-NP
+fever	I-NP
+in	O
+3	O
+patients	O
+.	O
+	
+Four	O
+patients	O
+had	O
+five	O
+infusion	O
+-	O
+related	O
+reactions	O
+during	O
+the	O
+infusion	O
+of	O
+liposomal	O
+doxorubicin	O
+","	O
+leading	O
+to	O
+treatment	O
+discontinuation	O
+in	O
+three	O
+patients	O
+.	O
+	
+Grade	O
+>	O
+or	O
+=	O
+2	O
+nonhematologic	O
+toxicity	B-NP
+included	O
+nausea	B-NP
+in	O
+17	O
+patients	O
+","	O
+emesis	B-NP
+in	O
+14	O
+patients	O
+","	O
+fatigue	B-NP
+in	O
+9	O
+patients	O
+","	O
+mucositis	B-NP
+and	O
+/	O
+or	O
+stomatitis	B-NP
+in	O
+8	O
+patients	O
+","	O
+constipation	B-NP
+in	O
+6	O
+patients	O
+","	O
+weight	B-NP
+loss	I-NP
+in	O
+5	O
+patients	O
+","	O
+hand	B-NP
+-	I-NP
+foot	I-NP
+syndrome	I-NP
+in	O
+2	O
+patients	O
+","	O
+and	O
+skin	B-NP
+reactions	I-NP
+in	O
+3	O
+patients	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+combination	O
+of	O
+carboplatin	O
+and	O
+liposomal	O
+doxorubicin	O
+has	O
+modest	O
+activity	O
+in	O
+patients	O
+with	O
+recurrent	O
+cervical	B-NP
+carcinoma	I-NP
+.	O
+	
+Antimicrobial	O
+-	O
+induced	O
+mania	B-NP
+(	O
+antibiomania	B-NP
+)	O
+:	O
+a	O
+review	O
+of	O
+spontaneous	O
+reports	O
+.	O
+	
+The	O
+authors	O
+reviewed	O
+reported	O
+cases	O
+of	O
+antibiotic	O
+-	O
+induced	O
+manic	B-NP
+episodes	O
+by	O
+means	O
+of	O
+a	O
+MEDLINE	O
+and	O
+PsychLit	O
+search	O
+for	O
+reports	O
+of	O
+antibiotic	O
+-	O
+induced	O
+mania	B-NP
+.	O
+	
+Unpublished	O
+reports	O
+were	O
+requested	O
+from	O
+the	O
+World	O
+Health	O
+Organization	O
+(	O
+WHO	O
+)	O
+and	O
+the	O
+Food	O
+and	O
+Drug	O
+Administration	O
+(	O
+FDA	O
+)	O
+.	O
+	
+Twenty	O
+-	O
+one	O
+reports	O
+of	O
+antimicrobial	O
+-	O
+induced	O
+mania	B-NP
+were	O
+found	O
+in	O
+the	O
+literature	O
+.	O
+	
+There	O
+were	O
+6	O
+cases	O
+implicating	O
+clarithromycin	O
+","	O
+13	O
+implicating	O
+isoniazid	O
+","	O
+and	O
+1	O
+case	O
+each	O
+implicating	O
+erythromycin	O
+and	O
+amoxicillin	O
+.	O
+	
+The	O
+WHO	O
+reported	O
+82	O
+cases	O
+.	O
+	
+Of	O
+these	O
+","	O
+clarithromycin	O
+was	O
+implicated	O
+in	O
+23	O
+(	O
+27	O
+.	O
+6	O
+%	O
+)	O
+cases	O
+","	O
+ciprofloxacin	O
+in	O
+12	O
+(	O
+14	O
+.	O
+4	O
+%	O
+)	O
+cases	O
+","	O
+and	O
+ofloxacin	O
+in	O
+10	O
+(	O
+12	O
+%	O
+)	O
+cases	O
+.	O
+	
+Cotrimoxazole	O
+","	O
+metronidazole	O
+","	O
+and	O
+erythromycin	O
+were	O
+involved	O
+in	O
+15	O
+reported	O
+manic	B-NP
+episodes	O
+.	O
+	
+Cases	O
+reported	O
+by	O
+the	O
+FDA	O
+showed	O
+clarithromycin	O
+and	O
+ciprofloxacin	O
+to	O
+be	O
+the	O
+most	O
+frequently	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+mania	B-NP
+.	O
+	
+Statistical	O
+analysis	O
+of	O
+the	O
+data	O
+would	O
+not	O
+have	O
+demonstrated	O
+a	O
+significant	O
+statistical	O
+correlative	O
+risk	O
+and	O
+was	O
+therefore	O
+not	O
+undertaken	O
+.	O
+	
+Patients	O
+have	O
+an	O
+increased	O
+risk	O
+of	O
+developing	O
+mania	B-NP
+while	O
+being	O
+treated	O
+with	O
+antimicrobials	O
+.	O
+	
+Although	O
+this	O
+is	O
+not	O
+a	O
+statistically	O
+significant	O
+risk	O
+","	O
+physicians	O
+must	O
+be	O
+aware	O
+of	O
+the	O
+effect	O
+and	O
+reversibility	O
+.	O
+	
+Further	O
+research	O
+clearly	O
+is	O
+required	O
+to	O
+determine	O
+the	O
+incidence	O
+of	O
+antimicrobial	O
+-	O
+induced	O
+mania	B-NP
+","	O
+the	O
+relative	O
+risk	O
+factors	O
+of	O
+developing	O
+an	O
+antimicrobial	O
+-	O
+induced	O
+manic	B-NP
+episode	O
+among	O
+various	O
+demographic	O
+populations	O
+","	O
+and	O
+the	O
+incidence	O
+of	O
+patients	O
+who	O
+continue	O
+to	O
+have	O
+persistent	O
+affective	O
+disorders	O
+once	O
+the	O
+initial	O
+episode	O
+","	O
+which	O
+occurs	O
+while	O
+the	O
+patient	O
+is	O
+taking	O
+antibiotics	O
+","	O
+subsides	O
+.	O
+	
+The	O
+authors	O
+elected	O
+to	O
+name	O
+this	O
+syndrome	O
+"	O
+antibiomania	B
+.	O
+"	O
+	
+Levodopa	O
+-	O
+induced	O
+ocular	B-NP
+dyskinesias	I-NP
+in	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+Levodopa	O
+-	O
+induced	O
+ocular	B-NP
+dyskinesias	I-NP
+are	O
+very	O
+uncommon	O
+.	O
+	
+Usually	O
+they	O
+occur	O
+simultaneously	O
+with	O
+limb	O
+peak	O
+-	O
+dose	O
+choreatic	B-NP
+dyskinesias	I-NP
+.	O
+	
+We	O
+report	O
+on	O
+a	O
+patient	O
+with	O
+leftward	O
+and	O
+upward	O
+deviations	O
+of	O
+gaze	O
+during	O
+the	O
+peak	O
+effect	O
+of	O
+levodopa	O
+","	O
+and	O
+hypothesize	O
+that	O
+a	O
+severe	O
+dopaminergic	O
+denervation	O
+in	O
+the	O
+caudate	O
+nucleus	O
+is	O
+needed	O
+for	O
+the	O
+appearance	O
+of	O
+these	O
+levodopa	O
+-	O
+induce	O
+ocular	B-NP
+dyskinesias	I-NP
+.	O
+	
+A	O
+comparison	O
+of	O
+glyceryl	O
+trinitrate	O
+with	O
+diclofenac	O
+for	O
+the	O
+treatment	O
+of	O
+primary	O
+dysmenorrhea	B-NP
+:	O
+an	O
+open	O
+","	O
+randomized	O
+","	O
+cross	O
+-	O
+over	O
+trial	O
+.	O
+	
+Primary	O
+dysmenorrhea	B-NP
+is	O
+a	O
+syndrome	O
+characterized	O
+by	O
+painful	O
+uterine	O
+contractility	O
+caused	O
+by	O
+a	O
+hypersecretion	O
+of	O
+endometrial	O
+prostaglandins	O
+;	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+are	O
+the	O
+first	O
+choice	O
+for	O
+its	O
+treatment	O
+.	O
+	
+However	O
+","	O
+in	O
+vivo	O
+and	O
+in	O
+vitro	O
+studies	O
+have	O
+demonstrated	O
+that	O
+myometrial	O
+cells	O
+are	O
+also	O
+targets	O
+of	O
+the	O
+relaxant	O
+effects	O
+of	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+.	O
+	
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+efficacy	O
+of	O
+glyceryl	O
+trinitrate	O
+(	O
+GTN	O
+)	O
+","	O
+an	O
+NO	O
+donor	O
+","	O
+in	O
+the	O
+resolution	O
+of	O
+primary	O
+dysmenorrhea	B-NP
+in	O
+comparison	O
+with	O
+diclofenac	O
+(	O
+DCF	O
+)	O
+.	O
+	
+A	O
+total	O
+of	O
+24	O
+patients	O
+with	O
+the	O
+diagnosis	O
+of	O
+severe	O
+primary	O
+dysmenorrhea	B-NP
+were	O
+studied	O
+during	O
+two	O
+consecutive	O
+menstrual	O
+cycles	O
+.	O
+	
+In	O
+an	O
+open	O
+","	O
+cross	O
+-	O
+over	O
+","	O
+controlled	O
+design	O
+","	O
+patients	O
+were	O
+randomized	O
+to	O
+receive	O
+either	O
+DCF	O
+per	O
+os	O
+or	O
+GTN	O
+patches	O
+the	O
+first	O
+days	O
+of	O
+menses	O
+","	O
+when	O
+menstrual	O
+cramps	O
+became	O
+unendurable	O
+.	O
+	
+In	O
+the	O
+subsequent	O
+cycle	O
+the	O
+other	O
+treatment	O
+was	O
+used	O
+.	O
+	
+Patients	O
+received	O
+up	O
+to	O
+3	O
+doses	O
+/	O
+day	O
+of	O
+50	O
+mg	O
+DCF	O
+or	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+24	O
+h	O
+transdermal	O
+GTN	O
+for	O
+the	O
+first	O
+3	O
+days	O
+of	O
+the	O
+cycle	O
+","	O
+according	O
+to	O
+their	O
+needs	O
+.	O
+	
+The	O
+participants	O
+recorded	O
+menstrual	O
+symptoms	O
+and	O
+possible	O
+side	O
+-	O
+effects	O
+at	O
+different	O
+times	O
+(	O
+0	O
+","	O
+30	O
+","	O
+60	O
+","	O
+120	O
+minutes	O
+)	O
+after	O
+the	O
+first	O
+dose	O
+of	O
+medication	O
+on	O
+the	O
+first	O
+day	O
+of	O
+the	O
+cycle	O
+","	O
+with	O
+both	O
+drugs	O
+.	O
+	
+The	O
+difference	O
+in	O
+pain	B-NP
+intensity	O
+score	O
+(	O
+DPI	O
+)	O
+was	O
+the	O
+main	O
+outcome	O
+variable	O
+.	O
+	
+Both	O
+treatments	O
+significantly	O
+reduced	O
+DPI	O
+by	O
+the	O
+30th	O
+minute	O
+(	O
+GTN	O
+","	O
+-	O
+12	O
+.	O
+8	O
++	O
+/	O
+-	O
+17	O
+.	O
+9	O
+;	O
+DCF	O
+","	O
+-	O
+18	O
+.	O
+9	O
++	O
+/	O
+-	O
+16	O
+.	O
+6	O
+)	O
+.	O
+	
+However	O
+","	O
+DCF	O
+continued	O
+to	O
+be	O
+effective	O
+in	O
+reducing	O
+pelvic	B-NP
+pain	I-NP
+for	O
+two	O
+hours	O
+","	O
+whereas	O
+GTN	O
+scores	O
+remained	O
+more	O
+or	O
+less	O
+stable	O
+after	O
+30	O
+min	O
+and	O
+significantly	O
+higher	O
+than	O
+those	O
+for	O
+DFC	O
+(	O
+after	O
+one	O
+hour	O
+:	O
+GTN	O
+","	O
+-	O
+12	O
+.	O
+8	O
++	O
+/	O
+-	O
+17	O
+.	O
+9	O
+;	O
+DFC	O
+","	O
+-	O
+18	O
+.	O
+9	O
++	O
+/	O
+-	O
+16	O
+.	O
+6	O
+and	O
+after	O
+two	O
+hours	O
+:	O
+GTN	O
+","	O
+-	O
+23	O
+.	O
+7	O
++	O
+/	O
+-	O
+20	O
+.	O
+5	O
+;	O
+DFC	O
+","	O
+-	O
+59	O
+.	O
+7	O
++	O
+/	O
+-	O
+17	O
+.	O
+9	O
+","	O
+p	O
+=	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Low	B-NP
+back	I-NP
+pain	I-NP
+was	O
+also	O
+relieved	O
+by	O
+both	O
+drugs	O
+.	O
+	
+Headache	B-NP
+was	O
+significantly	O
+increased	O
+by	O
+GTN	O
+but	O
+not	O
+by	O
+DCF	O
+.	O
+	
+Eight	O
+patients	O
+stopped	O
+using	O
+GTN	O
+because	O
+headache	B-NP
+-	O
+-	O
+attributed	O
+to	O
+its	O
+use	O
+-	O
+-	O
+became	O
+intolerable	O
+.	O
+	
+These	O
+findings	O
+indicate	O
+that	O
+GTN	O
+has	O
+a	O
+reduced	O
+efficacy	O
+and	O
+tolerability	O
+by	O
+comparison	O
+with	O
+DCF	O
+in	O
+the	O
+treatment	O
+of	O
+primary	O
+dysmenorrhea	B-NP
+.	O
+	
+Temocapril	O
+","	O
+a	O
+long	O
+-	O
+acting	O
+non	O
+-	O
+SH	O
+group	O
+angiotensin	O
+converting	O
+enzyme	O
+inhibitor	O
+","	O
+modulates	O
+glomerular	B-NP
+injury	I-NP
+in	O
+chronic	O
+puromycin	O
+aminonucleoside	O
+nephrosis	B-NP
+.	O
+	
+The	O
+purpose	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+determine	O
+whether	O
+chronic	O
+administration	O
+of	O
+temocapril	O
+","	O
+a	O
+long	O
+-	O
+acting	O
+non	O
+-	O
+SH	O
+group	O
+angiotensin	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+inhibitor	O
+","	O
+reduced	O
+proteinuria	B-NP
+","	O
+inhibited	O
+glomerular	O
+hypertrophy	B-NP
+and	O
+prevented	O
+glomerulosclerosis	B-NP
+in	O
+chronic	O
+puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+)	O
+-	O
+induced	O
+nephrotic	B-NP
+rats	O
+.	O
+	
+Nephrosis	B-NP
+was	O
+induced	O
+by	O
+injection	O
+of	O
+PAN	O
+(	O
+15mg	O
+/	O
+100g	O
+body	O
+weight	O
+)	O
+in	O
+male	O
+Sprague	O
+-	O
+Dawley	O
+(	O
+SD	O
+)	O
+rats	O
+.	O
+	
+Four	O
+groups	O
+were	O
+used	O
+","	O
+i	O
+)	O
+the	O
+PAN	O
+group	O
+(	O
+14	O
+)	O
+","	O
+ii	O
+)	O
+PAN	O
+/	O
+temocapril	O
+(	O
+13	O
+)	O
+","	O
+iii	O
+)	O
+temocapril	O
+(	O
+14	O
+)	O
+and	O
+iv	O
+)	O
+untreated	O
+controls	O
+(	O
+15	O
+)	O
+.	O
+	
+Temocapril	O
+(	O
+8	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+)	O
+was	O
+administered	O
+to	O
+the	O
+rats	O
+which	O
+were	O
+killed	O
+at	O
+weeks	O
+4	O
+","	O
+14	O
+or	O
+20	O
+.	O
+	
+At	O
+each	O
+time	O
+point	O
+","	O
+systolic	O
+blood	O
+pressure	O
+(	O
+BP	O
+)	O
+","	O
+urinary	O
+protein	O
+excretion	O
+and	O
+renal	O
+histopathological	O
+findings	O
+were	O
+evaluated	O
+","	O
+and	O
+morphometric	O
+image	O
+analysis	O
+was	O
+done	O
+.	O
+	
+Systolic	O
+BP	O
+in	O
+the	O
+PAN	O
+group	O
+was	O
+significantly	O
+high	O
+at	O
+4	O
+","	O
+14	O
+and	O
+20	O
+weeks	O
+","	O
+but	O
+was	O
+normal	O
+in	O
+the	O
+PAN	O
+/	O
+temocapril	O
+group	O
+.	O
+	
+Urinary	O
+protein	O
+excretion	O
+in	O
+the	O
+PAN	O
+group	O
+increased	O
+significantly	O
+","	O
+peaking	O
+at	O
+8	O
+days	O
+","	O
+then	O
+decreased	O
+at	O
+4	O
+weeks	O
+","	O
+but	O
+rose	O
+again	O
+significantly	O
+at	O
+14	O
+and	O
+20	O
+weeks	O
+.	O
+	
+Temocapril	O
+did	O
+not	O
+attenuate	O
+proteinuria	B-NP
+at	O
+8	O
+days	O
+","	O
+but	O
+it	O
+did	O
+markedly	O
+lower	O
+it	O
+from	O
+weeks	O
+4	O
+to	O
+20	O
+.	O
+	
+The	O
+glomerulosclerosis	B-NP
+index	O
+(	O
+GSI	O
+)	O
+was	O
+6	O
+.	O
+21	O
+%	O
+at	O
+4	O
+weeks	O
+and	O
+respectively	O
+25	O
+.	O
+35	O
+%	O
+and	O
+30	O
+.	O
+49	O
+%	O
+at	O
+14	O
+and	O
+20	O
+weeks	O
+in	O
+the	O
+PAN	O
+group	O
+.	O
+	
+There	O
+was	O
+a	O
+significant	O
+correlation	O
+between	O
+urinary	O
+protein	O
+excretion	O
+and	O
+GSI	O
+(	O
+r	O
+=	O
+0	O
+.	O
+808	O
+","	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+The	O
+ratio	O
+of	O
+glomerular	O
+tuft	O
+area	O
+to	O
+the	O
+area	O
+of	O
+Bowman	O
+'	O
+s	O
+capsules	O
+(	O
+GT	O
+/	O
+BC	O
+)	O
+in	O
+the	O
+PAN	O
+group	O
+was	O
+significantly	O
+increased	O
+","	O
+but	O
+it	O
+was	O
+significantly	O
+lower	O
+in	O
+the	O
+PAN	O
+/	O
+temocapril	O
+group	O
+.	O
+	
+It	O
+appears	O
+that	O
+temocapril	O
+was	O
+effective	O
+in	O
+retarding	O
+renal	O
+progression	O
+and	O
+protected	O
+renal	O
+function	O
+in	O
+PAN	O
+neprotic	B-NP
+rats	O
+.	O
+	
+Pulmonary	B-NP
+hypertension	I-NP
+after	O
+ibuprofen	O
+prophylaxis	O
+in	O
+very	O
+preterm	O
+infants	O
+.	O
+	
+We	O
+report	O
+three	O
+cases	O
+of	O
+severe	O
+hypoxaemia	B-NP
+after	O
+ibuprofen	O
+administration	O
+during	O
+a	O
+randomised	O
+controlled	O
+trial	O
+of	O
+prophylactic	O
+treatment	O
+of	O
+patent	B-NP
+ductus	I-NP
+arteriosus	I-NP
+with	O
+ibuprofen	O
+in	O
+premature	O
+infants	O
+born	O
+at	O
+less	O
+than	O
+28	O
+weeks	O
+of	O
+gestation	O
+.	O
+	
+Echocardiography	O
+showed	O
+severely	O
+decreased	O
+pulmonary	O
+blood	O
+flow	O
+.	O
+	
+Hypoxaemia	B-NP
+resolved	O
+quickly	O
+on	O
+inhaled	O
+nitric	O
+oxide	O
+therapy	O
+.	O
+	
+We	O
+suggest	O
+that	O
+investigators	O
+involved	O
+in	O
+similar	O
+trials	O
+pay	O
+close	O
+attention	O
+to	O
+pulmonary	O
+pressure	O
+if	O
+hypoxaemia	B-NP
+occurs	O
+after	O
+prophylactic	O
+administration	O
+of	O
+ibuprofen	O
+.	O
+	
+Hyponatremia	B-NP
+and	O
+syndrome	B-NP
+of	I-NP
+inappropriate	I-NP
+anti	I-NP
+-	I-NP
+diuretic	I-NP
+hormone	I-NP
+reported	O
+with	O
+the	O
+use	O
+of	O
+Vincristine	O
+:	O
+an	O
+over	O
+-	O
+representation	O
+of	O
+Asians	O
+?	O
+	
+PURPOSE	O
+:	O
+This	O
+retrospective	O
+study	O
+used	O
+a	O
+pharmaceutical	O
+company	O
+'	O
+s	O
+global	O
+safety	O
+database	O
+to	O
+determine	O
+the	O
+reporting	O
+rate	O
+of	O
+hyponatremia	B-NP
+and	O
+/	O
+or	O
+syndrome	B-NP
+of	I-NP
+inappropriate	I-NP
+secretion	I-NP
+of	I-NP
+anti	I-NP
+-	I-NP
+diuretic	I-NP
+hormone	I-NP
+(	O
+SIADH	B-NP
+)	O
+among	O
+vincristine	O
+-	O
+treated	O
+patients	O
+and	O
+to	O
+explore	O
+the	O
+possibility	O
+of	O
+at	O
+-	O
+risk	O
+population	O
+subgroups	O
+.	O
+	
+METHOD	O
+:	O
+We	O
+searched	O
+the	O
+Eli	O
+Lilly	O
+and	O
+Company	O
+'	O
+s	O
+computerized	O
+adverse	O
+event	O
+database	O
+for	O
+all	O
+reported	O
+cases	O
+of	O
+hyponatremia	B-NP
+and	O
+/	O
+or	O
+SIADH	B-NP
+as	O
+of	O
+1	O
+November	O
+1999	O
+that	O
+had	O
+been	O
+reported	O
+during	O
+the	O
+use	O
+of	O
+vincristine	O
+.	O
+	
+RESULTS	O
+:	O
+A	O
+total	O
+of	O
+76	O
+cases	O
+of	O
+hyponatremia	B-NP
+and	O
+/	O
+or	O
+SIADH	B-NP
+associated	O
+with	O
+vincristine	O
+use	O
+were	O
+identified	O
+.	O
+	
+The	O
+overall	O
+reporting	O
+rate	O
+was	O
+estimated	O
+to	O
+be	O
+1	O
+.	O
+3	O
+/	O
+100	O
+","	O
+0	O
+treated	O
+patients	O
+.	O
+	
+The	O
+average	O
+age	O
+of	O
+patients	O
+was	O
+35	O
+.	O
+6	O
++	O
+/	O
+-	O
+28	O
+.	O
+3	O
+years	O
+","	O
+and	O
+62	O
+%	O
+were	O
+males	O
+.	O
+	
+Approximately	O
+75	O
+%	O
+of	O
+the	O
+patients	O
+were	O
+receiving	O
+treatment	O
+for	O
+leukemia	B-NP
+or	O
+lymphoma	B-NP
+.	O
+	
+Among	O
+the	O
+39	O
+reports	O
+that	O
+included	O
+information	O
+on	O
+race	O
+","	O
+the	O
+racial	O
+distribution	O
+was	O
+:	O
+1	O
+Black	O
+","	O
+3	O
+Caucasian	O
+","	O
+and	O
+35	O
+Asian	O
+.	O
+	
+CONCLUSION	O
+:	O
+Our	O
+data	O
+suggest	O
+that	O
+Asian	O
+patients	O
+may	O
+be	O
+at	O
+increased	O
+risk	O
+of	O
+hyponatremia	B-NP
+and	O
+/	O
+or	O
+SIADH	B-NP
+associated	O
+with	O
+vincristine	O
+use	O
+.	O
+	
+Although	O
+the	O
+overall	O
+reported	O
+rate	O
+of	O
+SIADH	B-NP
+associated	O
+with	O
+vincristine	O
+is	O
+very	O
+low	O
+","	O
+physicians	O
+caring	O
+for	O
+Asian	O
+oncology	O
+patients	O
+should	O
+be	O
+aware	O
+of	O
+this	O
+potential	O
+serious	O
+but	O
+reversible	O
+adverse	O
+event	O
+.	O
+	
+Delayed	O
+toxicity	B-NP
+of	O
+cyclophosphamide	O
+on	O
+the	O
+bladder	O
+of	O
+DBA	O
+/	O
+2	O
+and	O
+C57BL	O
+/	O
+6	O
+female	O
+mouse	O
+.	O
+	
+The	O
+present	O
+study	O
+describes	O
+the	O
+delayed	O
+development	O
+of	O
+a	O
+severe	O
+bladder	O
+pathology	O
+in	O
+a	O
+susceptible	O
+strain	O
+of	O
+mice	O
+(	O
+DBA	O
+/	O
+2	O
+)	O
+but	O
+not	O
+in	O
+a	O
+resistant	O
+strain	O
+(	O
+C57BL	O
+/	O
+6	O
+)	O
+when	O
+both	O
+were	O
+treated	O
+with	O
+a	O
+single	O
+300	O
+mg	O
+/	O
+kg	O
+dose	O
+of	O
+cyclophosphamide	O
+(	O
+CY	O
+)	O
+.	O
+	
+Inbred	O
+DBA	O
+/	O
+2	O
+and	O
+C57BL	O
+/	O
+6	O
+female	O
+mice	O
+were	O
+injected	O
+with	O
+CY	O
+","	O
+and	O
+the	O
+effect	O
+of	O
+the	O
+drug	O
+on	O
+the	O
+bladder	O
+was	O
+assessed	O
+during	O
+100	O
+days	O
+by	O
+light	O
+microscopy	O
+using	O
+different	O
+staining	O
+procedures	O
+","	O
+and	O
+after	O
+30	O
+days	O
+by	O
+conventional	O
+electron	O
+microscopy	O
+.	O
+	
+Early	O
+CY	O
+toxicity	B-NP
+caused	O
+a	O
+typical	O
+haemorrhagic	B-NP
+cystitis	B-NP
+in	O
+both	O
+strains	O
+that	O
+was	O
+completely	O
+repaired	O
+in	O
+about	O
+7	O
+-	O
+10	O
+days	O
+.	O
+	
+After	O
+30	O
+days	O
+of	O
+CY	O
+injection	O
+ulcerous	O
+and	O
+non	O
+-	O
+ulcerous	O
+forms	O
+of	O
+chronic	O
+cystitis	B-NP
+appeared	O
+in	O
+86	O
+%	O
+of	O
+DBA	O
+/	O
+2	O
+mice	O
+but	O
+only	O
+in	O
+4	O
+%	O
+of	O
+C57BL	O
+/	O
+6	O
+mice	O
+.	O
+	
+Delayed	O
+cystitis	B-NP
+was	O
+characterized	O
+by	O
+infiltration	O
+and	O
+transepithelial	O
+passage	O
+into	O
+the	O
+lumen	O
+of	O
+inflammatory	O
+cells	O
+and	O
+by	O
+frequent	O
+exfoliation	O
+of	O
+the	O
+urothelium	O
+.	O
+	
+Mast	O
+cells	O
+appeared	O
+in	O
+the	O
+connective	O
+and	O
+muscular	O
+layers	O
+of	O
+the	O
+bladder	O
+at	O
+a	O
+much	O
+higher	O
+number	O
+in	O
+DBA	O
+/	O
+2	O
+mice	O
+than	O
+in	O
+C57BL	O
+/	O
+6	O
+mice	O
+or	O
+untreated	O
+controls	O
+.	O
+	
+Electron	O
+microscopy	O
+disclosed	O
+the	O
+absence	O
+of	O
+the	O
+typical	O
+discoidal	O
+vesicles	O
+normally	O
+present	O
+in	O
+the	O
+cytoplasm	O
+of	O
+surface	O
+cells	O
+.	O
+	
+Instead	O
+","	O
+numerous	O
+abnormal	O
+vesicles	O
+containing	O
+one	O
+or	O
+several	O
+dark	O
+granules	O
+were	O
+observed	O
+in	O
+the	O
+cytoplasm	O
+of	O
+cells	O
+from	O
+all	O
+the	O
+epithelial	O
+layers	O
+.	O
+	
+Delayed	O
+cystitis	B-NP
+still	O
+persisted	O
+in	O
+DBA	O
+/	O
+2	O
+mice	O
+100	O
+days	O
+after	O
+treatment	O
+.	O
+	
+These	O
+results	O
+indicate	O
+that	O
+delayed	O
+toxicity	B-NP
+of	O
+CY	O
+in	O
+female	O
+DBA	O
+/	O
+2	O
+mice	O
+causes	O
+a	O
+bladder	O
+pathology	O
+that	O
+is	O
+not	O
+observed	O
+in	O
+C57BL	O
+/	O
+6	O
+mice	O
+.	O
+	
+This	O
+pathology	O
+resembles	O
+interstitial	B-NP
+cystitis	I-NP
+in	O
+humans	O
+and	O
+could	O
+perhaps	O
+be	O
+used	O
+as	O
+an	O
+animal	O
+model	O
+for	O
+studies	O
+on	O
+the	O
+disease	O
+.	O
+	
+High	O
+-	O
+dose	O
+5	O
+-	O
+fluorouracil	O
+/	O
+folinic	O
+acid	O
+in	O
+combination	O
+with	O
+three	O
+-	O
+weekly	O
+mitomycin	O
+C	O
+in	O
+the	O
+treatment	O
+of	O
+advanced	O
+gastric	B-NP
+cancer	I-NP
+.	O
+	
+A	O
+phase	O
+II	O
+study	O
+.	O
+	
+BACKGROUND	O
+:	O
+The	O
+24	O
+-	O
+hour	O
+continuous	O
+infusion	O
+of	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+and	O
+folinic	O
+acid	O
+(	O
+FA	O
+)	O
+as	O
+part	O
+of	O
+several	O
+new	O
+multidrug	O
+chemotherapy	O
+regimens	O
+in	O
+advanced	O
+gastric	B-NP
+cancer	I-NP
+(	O
+AGC	B-NP
+)	O
+has	O
+shown	O
+to	O
+be	O
+effective	O
+","	O
+with	O
+low	O
+toxicity	B-NP
+.	O
+	
+In	O
+a	O
+previous	O
+phase	O
+II	O
+study	O
+with	O
+3	O
+-	O
+weekly	O
+bolus	O
+5	O
+-	O
+FU	O
+","	O
+FA	O
+and	O
+mitomycin	O
+C	O
+(	O
+MMC	O
+)	O
+we	O
+found	O
+a	O
+low	O
+toxicity	B-NP
+rate	O
+and	O
+response	O
+rates	O
+comparable	O
+to	O
+those	O
+of	O
+regimens	O
+such	O
+as	O
+ELF	O
+","	O
+FAM	O
+or	O
+FAMTX	O
+","	O
+and	O
+a	O
+promising	O
+median	O
+overall	O
+survival	O
+.	O
+	
+In	O
+order	O
+to	O
+improve	O
+this	O
+MMC	O
+-	O
+dependent	O
+schedule	O
+we	O
+initiated	O
+a	O
+phase	O
+II	O
+study	O
+with	O
+high	O
+-	O
+dose	O
+5	O
+-	O
+FU	O
+/	O
+FA	O
+and	O
+3	O
+-	O
+weekly	O
+bolus	O
+MMC	O
+.	O
+	
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+From	O
+February	O
+","	O
+1998	O
+to	O
+September	O
+","	O
+2000	O
+we	O
+recruited	O
+33	O
+patients	O
+with	O
+AGC	B-NP
+to	O
+receive	O
+weekly	O
+24	O
+-	O
+hour	O
+5	O
+-	O
+FU	O
+2	O
+","	O
+600	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+preceded	O
+by	O
+2	O
+-	O
+hour	O
+FA	O
+500	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+for	O
+6	O
+weeks	O
+","	O
+followed	O
+by	O
+a	O
+2	O
+-	O
+week	O
+rest	O
+period	O
+.	O
+	
+Bolus	O
+MMC	O
+10	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+was	O
+added	O
+in	O
+3	O
+-	O
+weekly	O
+intervals	O
+.	O
+	
+Treatment	O
+given	O
+on	O
+an	O
+outpatient	O
+basis	O
+","	O
+using	O
+portable	O
+pump	O
+systems	O
+","	O
+was	O
+repeated	O
+on	O
+day	O
+57	O
+.	O
+	
+Patients	O
+'	O
+characteristics	O
+were	O
+:	O
+male	O
+/	O
+female	O
+ratio	O
+20	O
+/	O
+13	O
+;	O
+median	O
+age	O
+57	O
+(	O
+27	O
+-	O
+75	O
+)	O
+years	O
+;	O
+median	O
+WHO	O
+status	O
+1	O
+(	O
+0	O
+-	O
+2	O
+)	O
+.	O
+	
+18	O
+patients	O
+had	O
+a	O
+primary	O
+AGC	B-NP
+","	O
+and	O
+15	O
+showed	O
+a	O
+relapsed	O
+AGC	B-NP
+.	O
+	
+Median	O
+follow	O
+-	O
+up	O
+was	O
+11	O
+.	O
+8	O
+months	O
+(	O
+range	O
+of	O
+those	O
+surviving	O
+:	O
+2	O
+.	O
+7	O
+-	O
+11	O
+.	O
+8	O
+months	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+32	O
+patients	O
+were	O
+evaluable	O
+for	O
+response	O
+-	O
+complete	O
+remission	O
+9	O
+.	O
+1	O
+%	O
+(	O
+n	O
+=	O
+3	O
+)	O
+","	O
+partial	O
+remission	O
+45	O
+.	O
+5	O
+%	O
+(	O
+n	O
+=	O
+15	O
+)	O
+","	O
+no	O
+change	O
+27	O
+.	O
+3	O
+%	O
+(	O
+n	O
+=	O
+9	O
+)	O
+","	O
+progressive	O
+disease	O
+15	O
+.	O
+1	O
+%	O
+(	O
+n	O
+=	O
+5	O
+)	O
+.	O
+	
+Median	O
+overall	O
+survival	O
+time	O
+was	O
+10	O
+.	O
+2	O
+months	O
+[	O
+95	O
+%	O
+confidence	O
+interval	O
+(	O
+CI	O
+)	O
+:	O
+8	O
+.	O
+7	O
+-	O
+11	O
+.	O
+6	O
+]	O
+","	O
+and	O
+median	O
+progression	O
+-	O
+free	O
+survival	O
+time	O
+was	O
+7	O
+.	O
+6	O
+months	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+4	O
+.	O
+4	O
+-	O
+10	O
+.	O
+9	O
+)	O
+.	O
+	
+The	O
+worst	O
+toxicities	B-NP
+(	O
+%	O
+)	O
+observed	O
+were	O
+(	O
+CTC	O
+-	O
+NCI	O
+1	O
+/	O
+2	O
+/	O
+3	O
+)	O
+:	O
+leukopenia	B-NP
+45	O
+.	O
+5	O
+/	O
+18	O
+.	O
+2	O
+/	O
+6	O
+.	O
+1	O
+","	O
+thrombocytopenia	B-NP
+33	O
+.	O
+3	O
+/	O
+9	O
+.	O
+1	O
+/	O
+6	O
+.	O
+1	O
+","	O
+vomitus	B-NP
+24	O
+.	O
+2	O
+/	O
+9	O
+.	O
+1	O
+/	O
+0	O
+","	O
+diarrhea	B-NP
+36	O
+.	O
+4	O
+/	O
+6	O
+.	O
+1	O
+/	O
+3	O
+.	O
+0	O
+","	O
+stomatitis	B-NP
+18	O
+.	O
+2	O
+/	O
+9	O
+.	O
+1	O
+/	O
+0	O
+","	O
+hand	B-NP
+-	I-NP
+foot	I-NP
+syndrome	I-NP
+12	O
+.	O
+1	O
+/	O
+0	O
+/	O
+0	O
+.	O
+	
+Two	O
+patients	O
+developed	O
+hemolytic	B-NP
+-	I-NP
+uremic	I-NP
+syndrome	I-NP
+(	O
+HUS	B-NP
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+High	O
+-	O
+dose	O
+5	O
+-	O
+FU	O
+/	O
+FA	O
+/	O
+MMC	O
+is	O
+an	O
+effective	O
+and	O
+well	O
+-	O
+tolerated	O
+outpatient	O
+regimen	O
+for	O
+AGC	B-NP
+(	O
+objective	O
+response	O
+rate	O
+54	O
+.	O
+6	O
+%	O
+)	O
+.	O
+	
+It	O
+may	O
+serve	O
+as	O
+an	O
+alternative	O
+to	O
+cisplatin	O
+-	O
+containing	O
+regimens	O
+;	O
+however	O
+","	O
+it	O
+has	O
+to	O
+be	O
+considered	O
+that	O
+possibly	O
+HUS	B-NP
+may	O
+occur	O
+.	O
+	
+Persistent	O
+sterile	O
+leukocyturia	B-NP
+is	O
+associated	O
+with	O
+impaired	B-NP
+renal	I-NP
+function	I-NP
+in	O
+human	B-NP
+immunodeficiency	I-NP
+virus	I-NP
+type	I-NP
+1	I-NP
+-	I-NP
+infected	I-NP
+children	O
+treated	O
+with	O
+indinavir	O
+.	O
+	
+BACKGROUND	O
+:	O
+Prolonged	O
+administration	O
+of	O
+indinavir	O
+is	O
+associated	O
+with	O
+the	O
+occurrence	O
+of	O
+a	O
+variety	O
+of	O
+renal	O
+complications	O
+in	O
+adults	O
+.	O
+	
+These	O
+well	O
+-	O
+documented	O
+side	O
+effects	O
+have	O
+restricted	O
+the	O
+use	O
+of	O
+this	O
+potent	O
+protease	O
+inhibitor	O
+in	O
+children	O
+.	O
+	
+DESIGN	O
+:	O
+A	O
+prospective	O
+study	O
+to	O
+monitor	O
+indinavir	O
+-	O
+related	O
+nephrotoxicity	B-NP
+in	O
+a	O
+cohort	O
+of	O
+30	O
+human	B-NP
+immunodeficiency	I-NP
+virus	I-NP
+type	I-NP
+1	I-NP
+-	I-NP
+infected	I-NP
+children	O
+treated	O
+with	O
+indinavir	O
+.	O
+	
+METHODS	O
+:	O
+Urinary	O
+pH	O
+","	O
+albumin	O
+","	O
+creatinine	O
+","	O
+the	O
+presence	O
+of	O
+erythrocytes	O
+","	O
+leukocytes	O
+","	O
+bacteria	O
+and	O
+crystals	O
+","	O
+and	O
+culture	O
+were	O
+analyzed	O
+every	O
+3	O
+months	O
+for	O
+96	O
+weeks	O
+.	O
+	
+Serum	O
+creatinine	O
+levels	O
+were	O
+routinely	O
+determined	O
+at	O
+the	O
+same	O
+time	O
+points	O
+.	O
+	
+Steady	O
+-	O
+state	O
+pharmacokinetics	O
+of	O
+indinavir	O
+were	O
+done	O
+at	O
+week	O
+4	O
+after	O
+the	O
+initiation	O
+of	O
+indinavir	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+cumulative	O
+incidence	O
+of	O
+persistent	O
+sterile	O
+leukocyturia	B-NP
+(	O
+>	O
+or	O
+=	O
+75	O
+cells	O
+/	O
+micro	O
+L	O
+in	O
+at	O
+least	O
+2	O
+consecutive	O
+visits	O
+)	O
+after	O
+96	O
+weeks	O
+was	O
+53	O
+%	O
+.	O
+	
+Persistent	O
+sterile	O
+leukocyturia	B-NP
+was	O
+frequently	O
+associated	O
+with	O
+a	O
+mild	O
+increase	O
+in	O
+the	O
+urine	O
+albumin	O
+/	O
+creatinine	O
+ratio	O
+and	O
+by	O
+microscopic	O
+hematuria	B-NP
+.	O
+	
+The	O
+cumulative	O
+incidence	O
+of	O
+serum	O
+creatinine	O
+levels	O
+>	O
+50	O
+%	O
+above	O
+normal	O
+was	O
+33	O
+%	O
+after	O
+96	O
+weeks	O
+.	O
+	
+Children	O
+with	O
+persistent	O
+sterile	O
+leukocyturia	B-NP
+more	O
+frequently	O
+had	O
+serum	O
+creatinine	O
+levels	O
+of	O
+50	O
+%	O
+above	O
+normal	O
+than	O
+those	O
+children	O
+without	O
+persistent	O
+sterile	O
+leukocyturia	B-NP
+.	O
+	
+In	O
+children	O
+younger	O
+than	O
+5	O
+.	O
+6	O
+years	O
+","	O
+persistent	O
+sterile	O
+leukocyturia	B-NP
+was	O
+significantly	O
+more	O
+frequent	O
+than	O
+in	O
+older	O
+children	O
+.	O
+	
+A	O
+higher	O
+cumulative	O
+incidence	O
+of	O
+persistent	O
+leukocyturia	B-NP
+was	O
+found	O
+in	O
+children	O
+with	O
+an	O
+area	O
+under	O
+the	O
+curve	O
+>	O
+19	O
+mg	O
+/	O
+L	O
+x	O
+h	O
+or	O
+a	O
+peak	O
+serum	O
+level	O
+of	O
+indinavir	O
+>	O
+12	O
+mg	O
+/	O
+L	O
+.	O
+	
+In	O
+4	O
+children	O
+","	O
+indinavir	O
+was	O
+discontinued	O
+because	O
+of	O
+nephrotoxicity	B-NP
+.	O
+	
+Subsequently	O
+","	O
+the	O
+serum	O
+creatinine	O
+levels	O
+decreased	O
+","	O
+the	O
+urine	O
+albumin	O
+/	O
+creatinine	O
+ratios	O
+returned	O
+to	O
+zero	O
+","	O
+and	O
+the	O
+leukocyturia	B-NP
+disappeared	O
+within	O
+3	O
+months	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Children	O
+treated	O
+with	O
+indinavir	O
+have	O
+a	O
+high	O
+cumulative	O
+incidence	O
+of	O
+persistent	O
+sterile	O
+leukocyturia	B-NP
+.	O
+	
+Children	O
+with	O
+persistent	O
+sterile	O
+leukocyturia	B-NP
+more	O
+frequently	O
+had	O
+an	O
+increase	O
+in	O
+serum	O
+creatinine	O
+levels	O
+of	O
+>	O
+50	O
+%	O
+above	O
+normal	O
+.	O
+	
+Younger	O
+children	O
+have	O
+an	O
+additional	O
+risk	O
+for	O
+renal	O
+complications	O
+.	O
+	
+The	O
+impairment	B-NP
+of	I-NP
+the	I-NP
+renal	I-NP
+function	I-NP
+in	O
+these	O
+children	O
+occurred	O
+in	O
+the	O
+absence	O
+of	O
+clinical	O
+symptoms	O
+of	O
+nephrolithiasis	B-NP
+.	O
+	
+Indinavir	O
+-	O
+associated	O
+nephrotoxicity	B-NP
+must	O
+be	O
+monitored	O
+closely	O
+","	O
+especially	O
+in	O
+children	O
+with	O
+risk	O
+factors	O
+such	O
+as	O
+persistent	O
+sterile	O
+leukocyturia	B-NP
+","	O
+age	O
+<	O
+5	O
+.	O
+6	O
+years	O
+","	O
+an	O
+area	O
+under	O
+the	O
+curve	O
+of	O
+indinavir	O
+>	O
+19	O
+mg	O
+/	O
+L	O
+x	O
+h	O
+","	O
+and	O
+a	O
+C	O
+(	O
+max	O
+)	O
+>	O
+12	O
+mg	O
+/	O
+L	O
+.	O
+	
+Utility	O
+of	O
+troponin	O
+I	O
+in	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B-NP
+pain	I-NP
+.	O
+	
+Baseline	O
+electrocardiogram	O
+abnormalities	O
+and	O
+market	O
+elevations	O
+not	O
+associated	O
+with	O
+myocardial	B-NP
+necrosis	I-NP
+make	O
+accurate	O
+diagnosis	O
+of	O
+myocardial	B-NP
+infarction	I-NP
+(	O
+MI	B-NP
+)	O
+difficult	O
+in	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B-NP
+pain	I-NP
+.	O
+	
+Troponin	O
+sampling	O
+may	O
+offer	O
+greater	O
+diagnostic	O
+utility	O
+in	O
+these	O
+patients	O
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+assess	O
+outcomes	O
+based	O
+on	O
+troponin	O
+positivity	O
+in	O
+patients	O
+with	O
+cocaine	O
+chest	B-NP
+pain	I-NP
+admitted	O
+for	O
+exclusion	O
+of	O
+MI	B-NP
+.	O
+	
+METHODS	O
+:	O
+Outcomes	O
+were	O
+examined	O
+in	O
+patients	O
+admitted	O
+for	O
+possible	O
+MI	B-NP
+after	O
+cocaine	O
+use	O
+.	O
+	
+All	O
+patients	O
+underwent	O
+a	O
+rapid	O
+rule	O
+-	O
+in	O
+protocol	O
+that	O
+included	O
+serial	O
+sampling	O
+of	O
+creatine	O
+kinase	O
+(	O
+CK	O
+)	O
+","	O
+CK	O
+-	O
+MB	O
+","	O
+and	O
+cardiac	O
+troponin	O
+I	O
+(	O
+cTnI	O
+)	O
+over	O
+eight	O
+hours	O
+.	O
+	
+Outcomes	O
+included	O
+CK	O
+-	O
+MB	O
+MI	B-NP
+(	O
+CK	O
+-	O
+MB	O
+>	O
+or	O
+=	O
+8	O
+ng	O
+/	O
+mL	O
+with	O
+a	O
+relative	O
+index	O
+[	O
+(	O
+CK	O
+-	O
+MB	O
+x	O
+100	O
+)	O
+/	O
+total	O
+CK	O
+]	O
+>	O
+or	O
+=	O
+4	O
+","	O
+cardiac	B-NP
+death	I-NP
+","	O
+and	O
+significant	O
+coronary	B-NP
+disease	I-NP
+(	O
+>	O
+or	O
+=	O
+50	O
+%	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+Of	O
+the	O
+246	O
+admitted	O
+patients	O
+","	O
+34	O
+(	O
+14	O
+%	O
+)	O
+met	O
+CK	O
+-	O
+MB	O
+criteria	O
+for	O
+MI	B-NP
+and	O
+38	O
+(	O
+16	O
+%	O
+)	O
+had	O
+cTnI	O
+elevations	O
+.	O
+	
+Angiography	O
+was	O
+performed	O
+in	O
+29	O
+of	O
+38	O
+patients	O
+who	O
+were	O
+cTnI	O
+-	O
+positive	O
+","	O
+with	O
+significant	O
+disease	O
+present	O
+in	O
+25	O
+(	O
+86	O
+%	O
+)	O
+.	O
+	
+Three	O
+of	O
+the	O
+four	O
+patients	O
+without	O
+significant	O
+disease	O
+who	O
+had	O
+cTnI	O
+elevations	O
+met	O
+CK	O
+-	O
+MB	O
+criteria	O
+for	O
+MI	B-NP
+","	O
+and	O
+the	O
+other	O
+had	O
+a	O
+peak	O
+CK	O
+-	O
+MB	O
+level	O
+of	O
+13	O
+ng	O
+/	O
+mL	O
+.	O
+	
+Sensitivities	O
+","	O
+specificities	O
+","	O
+and	O
+positive	O
+and	O
+negative	O
+likelihood	O
+ratios	O
+for	O
+predicting	O
+cardiac	B-NP
+death	I-NP
+or	O
+significant	O
+disease	O
+were	O
+high	O
+for	O
+both	O
+CK	O
+-	O
+MB	O
+MI	B-NP
+and	O
+cTnI	O
+and	O
+were	O
+not	O
+significantly	O
+different	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Most	O
+patients	O
+with	O
+cTnI	O
+elevations	O
+meet	O
+CK	O
+-	O
+MB	O
+criteria	O
+for	O
+MI	B-NP
+","	O
+as	O
+well	O
+as	O
+have	O
+a	O
+high	O
+incidence	O
+of	O
+underlying	O
+significant	O
+disease	O
+.	O
+	
+Troponin	O
+appears	O
+to	O
+have	O
+an	O
+equivalent	O
+diagnostic	O
+accuracy	O
+compared	O
+with	O
+CK	O
+-	O
+MB	O
+for	O
+diagnosing	O
+necrosis	B-NP
+in	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B-NP
+pain	I-NP
+and	O
+suspected	O
+MI	B-NP
+.	O
+	
+Acute	O
+interstitial	B-NP
+nephritis	I-NP
+due	O
+to	O
+nicergoline	O
+(	O
+Sermion	O
+)	O
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+acute	O
+interstitial	B-NP
+nephritis	I-NP
+(	O
+AIN	B-NP
+)	O
+due	O
+to	O
+nicergoline	O
+(	O
+Sermion	O
+)	O
+.	O
+	
+A	O
+50	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+admitted	O
+to	O
+our	O
+hospital	O
+for	O
+fever	B-NP
+and	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+.	O
+	
+Before	O
+admission	O
+","	O
+he	O
+had	O
+been	O
+taking	O
+nicergoline	O
+and	O
+bendazac	O
+lysine	O
+due	O
+to	O
+retinal	B-NP
+vein	I-NP
+occlusion	I-NP
+at	O
+ophthalmologic	O
+department	O
+.	O
+	
+Thereafter	O
+","	O
+he	O
+experienced	O
+intermittent	O
+fever	B-NP
+and	O
+skin	B-NP
+rash	I-NP
+.	O
+	
+On	O
+admission	O
+","	O
+clinical	O
+symptoms	O
+(	O
+i	O
+.	O
+e	O
+.	O
+arthralgia	B-NP
+and	O
+fever	B-NP
+)	O
+and	O
+laboratory	O
+findings	O
+(	O
+i	O
+.	O
+e	O
+.	O
+eosinophilia	B-NP
+and	O
+renal	B-NP
+failure	I-NP
+)	O
+suggested	O
+AIN	B-NP
+","	O
+and	O
+which	O
+was	O
+confirmed	O
+by	O
+pathologic	O
+findings	O
+on	O
+renal	O
+biopsy	O
+.	O
+	
+A	O
+lymphocyte	O
+transformation	O
+test	O
+demonstrated	O
+a	O
+positive	O
+result	O
+against	O
+nicergoline	O
+.	O
+	
+Treatment	O
+was	O
+consisted	O
+of	O
+withdrawal	O
+of	O
+nicergoline	O
+and	O
+intravenous	O
+methylprednisolone	O
+","	O
+and	O
+his	O
+renal	O
+function	O
+was	O
+completely	O
+recovered	O
+.	O
+	
+To	O
+our	O
+knowledge	O
+","	O
+this	O
+is	O
+the	O
+first	O
+report	O
+of	O
+nicergoline	O
+-	O
+associated	O
+AIN	B-NP
+.	O
+	
+Neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+complicated	O
+by	O
+massive	O
+intestinal	O
+bleeding	B-NP
+in	O
+a	O
+patient	O
+with	O
+chronic	B-NP
+renal	I-NP
+failure	I-NP
+.	O
+	
+A	O
+patient	O
+with	O
+chronic	B-NP
+renal	I-NP
+failure	I-NP
+(	O
+CRF	B-NP
+)	O
+developed	O
+neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+(	O
+NMS	B-NP
+)	O
+after	O
+administration	O
+of	O
+risperidone	O
+and	O
+levomepromazine	O
+.	O
+	
+In	O
+addition	O
+to	O
+the	O
+typical	O
+symptoms	O
+of	O
+NMS	B-NP
+","	O
+massive	O
+intestinal	O
+bleeding	B-NP
+was	O
+observed	O
+during	O
+the	O
+episode	O
+.	O
+	
+This	O
+report	O
+suggests	O
+that	O
+NMS	B-NP
+in	O
+a	O
+patient	O
+with	O
+CRF	B-NP
+may	O
+be	O
+complicated	O
+by	O
+intestinal	O
+bleeding	B-NP
+and	O
+needs	O
+special	O
+caution	O
+for	O
+this	O
+complication	O
+.	O
+	
+Blood	O
+brain	O
+barrier	O
+in	O
+right	O
+-	O
+and	O
+left	O
+-	O
+pawed	O
+female	O
+rats	O
+assessed	O
+by	O
+a	O
+new	O
+staining	O
+method	O
+.	O
+	
+The	O
+asymmetrical	O
+breakdown	O
+of	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+(	O
+BBB	O
+)	O
+was	O
+studied	O
+in	O
+female	O
+rats	O
+.	O
+	
+Paw	O
+preference	O
+was	O
+assessed	O
+by	O
+a	O
+food	O
+reaching	O
+test	O
+.	O
+	
+Adrenaline	O
+-	O
+induced	O
+hypertension	B-NP
+was	O
+used	O
+to	O
+destroy	O
+the	O
+BBB	O
+","	O
+which	O
+was	O
+evaluated	O
+using	O
+triphenyltetrazolium	O
+(	O
+TTC	O
+)	O
+staining	O
+of	O
+the	O
+brain	O
+slices	O
+just	O
+after	O
+giving	O
+adrenaline	O
+for	O
+30	O
+s	O
+.	O
+	
+In	O
+normal	O
+rats	O
+","	O
+the	O
+whole	O
+brain	O
+sections	O
+exhibited	O
+complete	O
+staining	O
+with	O
+TTC	O
+.	O
+	
+After	O
+adrenaline	O
+infusion	O
+for	O
+30	O
+s	O
+","	O
+there	O
+were	O
+large	O
+unstained	O
+areas	O
+in	O
+the	O
+left	O
+brain	O
+in	O
+right	O
+-	O
+pawed	O
+animals	O
+","	O
+and	O
+vice	O
+versa	O
+in	O
+left	O
+-	O
+pawed	O
+animals	O
+.	O
+	
+Similar	O
+results	O
+were	O
+obtained	O
+in	O
+seizure	B-NP
+-	O
+induced	O
+breakdown	O
+of	O
+BBB	O
+.	O
+	
+These	O
+results	O
+were	O
+explained	O
+by	O
+an	O
+asymmetric	O
+cerebral	O
+blood	O
+flow	O
+depending	O
+upon	O
+the	O
+paw	O
+preference	O
+in	O
+rats	O
+.	O
+	
+It	O
+was	O
+suggested	O
+that	O
+this	O
+new	O
+method	O
+and	O
+the	O
+results	O
+are	O
+consistent	O
+with	O
+contralateral	O
+motor	O
+control	O
+that	O
+may	O
+be	O
+important	O
+in	O
+determining	O
+the	O
+dominant	O
+cerebral	O
+hemisphere	O
+in	O
+animals	O
+.	O
+	
+Carvedilol	O
+protects	O
+against	O
+doxorubicin	O
+-	O
+induced	O
+mitochondrial	O
+cardiomyopathy	B-NP
+.	O
+	
+Several	O
+cytopathic	O
+mechanisms	O
+have	O
+been	O
+suggested	O
+to	O
+mediate	O
+the	O
+dose	O
+-	O
+limiting	O
+cumulative	O
+and	O
+irreversible	O
+cardiomyopathy	B-NP
+caused	O
+by	O
+doxorubicin	O
+.	O
+	
+Recent	O
+evidence	O
+indicates	O
+that	O
+oxidative	O
+stress	O
+and	O
+mitochondrial	B-NP
+dysfunction	I-NP
+are	O
+key	O
+factors	O
+in	O
+the	O
+pathogenic	O
+process	O
+.	O
+	
+The	O
+objective	O
+of	O
+this	O
+investigation	O
+was	O
+to	O
+test	O
+the	O
+hypothesis	O
+that	O
+carvedilol	O
+","	O
+a	O
+nonselective	O
+beta	O
+-	O
+adrenergic	O
+receptor	O
+antagonist	O
+with	O
+potent	O
+antioxidant	O
+properties	O
+","	O
+protects	O
+against	O
+the	O
+cardiac	O
+and	O
+hepatic	O
+mitochondrial	O
+bioenergetic	O
+dysfunction	O
+associated	O
+with	O
+subchronic	O
+doxorubicin	O
+toxicity	B-NP
+.	O
+	
+Heart	O
+and	O
+liver	O
+mitochondria	O
+were	O
+isolated	O
+from	O
+rats	O
+treated	O
+for	O
+7	O
+weeks	O
+with	O
+doxorubicin	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+sc	O
+/	O
+week	O
+)	O
+","	O
+carvedilol	O
+(	O
+1	O
+mg	O
+/	O
+kg	O
+ip	O
+/	O
+week	O
+)	O
+","	O
+or	O
+the	O
+combination	O
+of	O
+the	O
+two	O
+drugs	O
+.	O
+	
+Heart	O
+mitochondria	O
+isolated	O
+from	O
+doxorubicin	O
+-	O
+treated	O
+rats	O
+exhibited	O
+depressed	O
+rates	O
+for	O
+state	O
+3	O
+respiration	O
+(	O
+336	O
++	O
+/	O
+-	O
+26	O
+versus	O
+425	O
++	O
+/	O
+-	O
+53	O
+natom	O
+O	O
+/	O
+min	O
+/	O
+mg	O
+protein	O
+)	O
+and	O
+a	O
+lower	O
+respiratory	O
+control	O
+ratio	O
+(	O
+RCR	O
+)	O
+(	O
+4	O
+.	O
+3	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+versus	O
+5	O
+.	O
+8	O
++	O
+/	O
+-	O
+0	O
+.	O
+4	O
+)	O
+compared	O
+with	O
+cardiac	O
+mitochondria	O
+isolated	O
+from	O
+saline	O
+-	O
+treated	O
+rats	O
+.	O
+	
+Mitochondrial	O
+calcium	O
+-	O
+loading	O
+capacity	O
+and	O
+the	O
+activity	O
+of	O
+NADH	O
+-	O
+dehydrogenase	O
+were	O
+also	O
+suppressed	O
+in	O
+cardiac	O
+mitochondria	O
+from	O
+doxorubicin	O
+-	O
+treated	O
+rats	O
+.	O
+	
+Doxorubicin	O
+treatment	O
+also	O
+caused	O
+a	O
+decrease	O
+in	O
+RCR	O
+for	O
+liver	O
+mitochondria	O
+(	O
+3	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+9	O
+versus	O
+5	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+for	O
+control	O
+rats	O
+)	O
+and	O
+inhibition	O
+of	O
+hepatic	O
+cytochrome	O
+oxidase	O
+activity	O
+.	O
+	
+Coadministration	O
+of	O
+carvedilol	O
+decreased	O
+the	O
+extent	O
+of	O
+cellular	O
+vacuolization	O
+in	O
+cardiac	O
+myocytes	O
+and	O
+prevented	O
+the	O
+inhibitory	O
+effect	O
+of	O
+doxorubicin	O
+on	O
+mitochondrial	O
+respiration	O
+in	O
+both	O
+heart	O
+and	O
+liver	O
+.	O
+	
+Carvedilol	O
+also	O
+prevented	O
+the	O
+decrease	O
+in	O
+mitochondrial	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+loading	O
+capacity	O
+and	O
+the	O
+inhibition	O
+of	O
+the	O
+respiratory	O
+complexes	O
+of	O
+heart	O
+mitochondria	O
+caused	O
+by	O
+doxorubicin	O
+.	O
+	
+Carvedilol	O
+by	O
+itself	O
+did	O
+not	O
+affect	O
+any	O
+of	O
+the	O
+parameters	O
+measured	O
+for	O
+heart	O
+or	O
+liver	O
+mitochondria	O
+.	O
+	
+It	O
+is	O
+concluded	O
+that	O
+this	O
+protection	O
+by	O
+carvedilol	O
+against	O
+both	O
+the	O
+structural	O
+and	O
+functional	O
+cardiac	O
+tissue	O
+damage	O
+may	O
+afford	O
+significant	O
+clinical	O
+advantage	O
+in	O
+minimizing	O
+the	O
+dose	O
+-	O
+limiting	O
+mitochondrial	B-NP
+dysfunction	I-NP
+and	O
+cardiomyopathy	B-NP
+that	O
+accompanies	O
+long	O
+-	O
+term	O
+doxorubicin	O
+therapy	O
+in	O
+cancer	B-NP
+patients	O
+.	O
+	
+Cocaine	O
+-	O
+induced	O
+hyperactivity	B-NP
+is	O
+more	O
+influenced	O
+by	O
+adenosine	O
+receptor	O
+agonists	O
+than	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B-NP
+.	O
+	
+The	O
+influence	O
+of	O
+adenosine	O
+receptor	O
+agonists	O
+and	O
+antagonists	O
+on	O
+cocaine	O
+-	O
+and	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B-NP
+was	O
+examined	O
+in	O
+mice	O
+.	O
+	
+All	O
+adenosine	O
+receptor	O
+agonists	O
+significantly	O
+decreased	B-NP
+the	I-NP
+locomotor	I-NP
+activity	I-NP
+in	O
+mice	O
+","	O
+and	O
+the	O
+effects	O
+were	O
+dose	O
+-	O
+dependent	O
+.	O
+	
+It	O
+seems	O
+that	O
+adenosine	O
+A1	O
+and	O
+A2	O
+receptors	O
+might	O
+be	O
+involved	O
+in	O
+this	O
+reaction	O
+.	O
+	
+Moreover	O
+","	O
+all	O
+adenosine	O
+receptor	O
+agonists	O
+:	O
+2	O
+-	O
+p	O
+-	O
+(	O
+2	O
+-	O
+carboxyethyl	O
+)	O
+phenethylamino	O
+-	O
+5	O
+'	O
+-	O
+N	O
+-	O
+ethylcarboxamidoadenosine	O
+(	O
+CGS	O
+21680	O
+)	O
+","	O
+A2A	O
+receptor	O
+agonist	O
+","	O
+N6	O
+-	O
+cyclopentyladenosine	O
+(	O
+CPA	O
+)	O
+","	O
+A1	O
+receptor	O
+agonist	O
+","	O
+and	O
+5	O
+'	O
+-	O
+N	O
+-	O
+ethylcarboxamidoadenosine	O
+(	O
+NECA	O
+)	O
+","	O
+A2	O
+/	O
+A1	O
+receptor	O
+agonist	O
+significantly	O
+and	O
+dose	O
+-	O
+dependently	O
+decreased	O
+cocaine	O
+-	O
+induced	O
+locomotor	O
+activity	O
+.	O
+	
+CPA	O
+reduced	O
+cocaine	O
+action	O
+at	O
+the	O
+doses	O
+which	O
+","	O
+given	O
+alone	O
+","	O
+did	O
+not	O
+influence	O
+motility	O
+","	O
+while	O
+CGS	O
+21680	O
+and	O
+NECA	O
+decreased	O
+the	O
+action	O
+of	O
+cocaine	O
+at	O
+the	O
+doses	O
+which	O
+","	O
+given	O
+alone	O
+","	O
+decreased	O
+locomotor	O
+activity	O
+in	O
+animals	O
+.	O
+	
+These	O
+results	O
+suggest	O
+the	O
+involvement	O
+of	O
+both	O
+adenosine	O
+receptors	O
+in	O
+the	O
+action	O
+of	O
+cocaine	O
+although	O
+agonists	O
+of	O
+A1	O
+receptors	O
+seem	O
+to	O
+have	O
+stronger	O
+influence	O
+on	O
+it	O
+.	O
+	
+The	O
+selective	O
+blockade	O
+of	O
+A2	O
+adenosine	O
+receptor	O
+by	O
+DMPX	O
+(	O
+3	O
+","	O
+7	O
+-	O
+dimethyl	O
+-	O
+1	O
+-	O
+propargylxanthine	O
+)	O
+significantly	O
+enhanced	O
+cocaine	O
+-	O
+induced	O
+locomotor	O
+activity	O
+of	O
+animals	O
+.	O
+	
+Caffeine	O
+had	O
+similar	O
+action	O
+but	O
+the	O
+effect	O
+was	O
+not	O
+significant	O
+.	O
+	
+CPT	O
+(	O
+8	O
+-	O
+cyclopentyltheophylline	O
+)	O
+-	O
+-	O
+A1	O
+receptor	O
+antagonist	O
+","	O
+did	O
+not	O
+show	O
+any	O
+influence	O
+in	O
+this	O
+test	O
+.	O
+	
+Similarly	O
+","	O
+all	O
+adenosine	O
+receptor	O
+agonists	O
+decreased	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B-NP
+","	O
+but	O
+at	O
+the	O
+higher	O
+doses	O
+than	O
+those	O
+which	O
+were	O
+active	O
+in	O
+cocaine	O
+-	O
+induced	O
+hyperactivity	B-NP
+.	O
+	
+The	O
+selective	O
+blockade	O
+of	O
+A2	O
+adenosine	O
+receptors	O
+(	O
+DMPX	O
+)	O
+and	O
+non	O
+-	O
+selective	O
+blockade	O
+of	O
+adenosine	O
+receptors	O
+(	O
+caffeine	O
+)	O
+significantly	O
+increased	O
+the	O
+action	O
+of	O
+amphetamine	O
+in	O
+the	O
+locomotor	O
+activity	O
+test	O
+.	O
+	
+Our	O
+results	O
+have	O
+shown	O
+that	O
+all	O
+adenosine	O
+receptor	O
+agonists	O
+(	O
+A1	O
+and	O
+A2	O
+)	O
+reduce	O
+cocaine	O
+-	O
+and	O
+amphetamine	O
+-	O
+induced	O
+locomotor	O
+activity	O
+and	O
+indicate	O
+that	O
+cocaine	O
+-	O
+induced	O
+hyperactivity	B-NP
+is	O
+more	O
+influenced	O
+by	O
+adenosine	O
+receptor	O
+agonists	O
+(	O
+particularly	O
+A1	O
+receptors	O
+)	O
+than	O
+amphetamine	O
+-	O
+induced	O
+hyperactivity	B-NP
+.	O
+	
+Amiodarone	O
+and	O
+the	O
+risk	O
+of	O
+bradyarrhythmia	B-NP
+requiring	O
+permanent	O
+pacemaker	O
+in	O
+elderly	O
+patients	O
+with	O
+atrial	B-NP
+fibrillation	I-NP
+and	O
+prior	O
+myocardial	B-NP
+infarction	I-NP
+.	O
+	
+OBJECTIVES	O
+:	O
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+whether	O
+the	O
+use	O
+of	O
+amiodarone	O
+in	O
+patients	O
+with	O
+atrial	B-NP
+fibrillation	I-NP
+(	O
+AF	B-NP
+)	O
+increases	O
+the	O
+risk	O
+of	O
+bradyarrhythmia	B-NP
+requiring	O
+a	O
+permanent	O
+pacemaker	O
+.	O
+	
+BACKGROUND	O
+:	O
+Reports	O
+of	O
+severe	O
+bradyarrhythmia	B-NP
+during	O
+amiodarone	O
+therapy	O
+are	O
+infrequent	O
+and	O
+limited	O
+to	O
+studies	O
+assessing	O
+the	O
+therapy	O
+'	O
+s	O
+use	O
+in	O
+the	O
+management	O
+of	O
+patients	O
+with	O
+ventricular	B-NP
+arrhythmias	I-NP
+.	O
+	
+METHODS	O
+:	O
+A	O
+study	O
+cohort	O
+of	O
+8	O
+","	O
+770	O
+patients	O
+age	O
+>	O
+or	O
+=	O
+65	O
+years	O
+with	O
+a	O
+new	O
+diagnosis	O
+of	O
+AF	B-NP
+was	O
+identified	O
+from	O
+a	O
+provincewide	O
+database	O
+of	O
+Quebec	O
+residents	O
+with	O
+a	O
+myocardial	B-NP
+infarction	I-NP
+(	O
+MI	B-NP
+)	O
+between	O
+1991	O
+and	O
+1999	O
+.	O
+	
+Using	O
+a	O
+nested	O
+case	O
+-	O
+control	O
+design	O
+","	O
+477	O
+cases	O
+of	O
+bradyarrhythmia	B-NP
+requiring	O
+a	O
+permanent	O
+pacemaker	O
+were	O
+matched	O
+(	O
+1	O
+:	O
+4	O
+)	O
+to	O
+1	O
+","	O
+908	O
+controls	O
+.	O
+	
+Multivariable	O
+logistic	O
+regression	O
+was	O
+used	O
+to	O
+estimate	O
+the	O
+odds	O
+ratio	O
+(	O
+OR	O
+)	O
+of	O
+pacemaker	O
+insertion	O
+associated	O
+with	O
+amiodarone	O
+use	O
+","	O
+controlling	O
+for	O
+baseline	O
+risk	O
+factors	O
+and	O
+exposure	O
+to	O
+sotalol	O
+","	O
+Class	O
+I	O
+antiarrhythmic	O
+agents	O
+","	O
+beta	O
+-	O
+blockers	O
+","	O
+calcium	O
+channel	O
+blockers	O
+","	O
+and	O
+digoxin	O
+.	O
+	
+RESULTS	O
+:	O
+amiodarone	O
+use	O
+was	O
+associated	O
+with	O
+an	O
+increased	O
+risk	O
+of	O
+pacemaker	O
+insertion	O
+(	O
+OR	O
+:	O
+2	O
+.	O
+14	O
+","	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+:	O
+1	O
+.	O
+30	O
+to	O
+3	O
+.	O
+54	O
+)	O
+.	O
+	
+This	O
+effect	O
+was	O
+modified	O
+by	O
+gender	O
+","	O
+with	O
+a	O
+greater	O
+risk	O
+in	O
+women	O
+versus	O
+men	O
+(	O
+OR	O
+:	O
+3	O
+.	O
+86	O
+","	O
+95	O
+%	O
+CI	O
+:	O
+1	O
+.	O
+70	O
+to	O
+8	O
+.	O
+75	O
+vs	O
+.	O
+OR	O
+:	O
+1	O
+.	O
+52	O
+","	O
+95	O
+%	O
+CI	O
+:	O
+0	O
+.	O
+80	O
+to	O
+2	O
+.	O
+89	O
+)	O
+.	O
+	
+Digoxin	O
+was	O
+the	O
+only	O
+other	O
+medication	O
+associated	O
+with	O
+an	O
+increased	O
+risk	O
+of	O
+pacemaker	O
+insertion	O
+(	O
+OR	O
+:	O
+1	O
+.	O
+78	O
+","	O
+95	O
+%	O
+CI	O
+:	O
+1	O
+.	O
+37	O
+to	O
+2	O
+.	O
+31	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+This	O
+study	O
+suggests	O
+that	O
+the	O
+use	O
+of	O
+amiodarone	O
+in	O
+elderly	O
+patients	O
+with	O
+AF	B-NP
+and	O
+a	O
+previous	O
+MI	B-NP
+increases	O
+the	O
+risk	O
+of	O
+bradyarrhythmia	B-NP
+requiring	O
+a	O
+permanent	O
+pacemaker	O
+.	O
+	
+The	O
+finding	O
+of	O
+an	O
+augmented	O
+risk	O
+of	O
+pacemaker	O
+insertion	O
+in	O
+elderly	O
+women	O
+receiving	O
+amiodarone	O
+requires	O
+further	O
+investigation	O
+.	O
+	
+Indomethacin	O
+-	O
+induced	O
+morphologic	O
+changes	O
+in	O
+the	O
+rat	O
+urinary	O
+bladder	O
+epithelium	O
+.	O
+	
+OBJECTIVES	O
+:	O
+To	O
+evaluate	O
+the	O
+morphologic	O
+changes	O
+in	O
+rat	O
+urothelium	O
+induced	O
+by	O
+indomethacin	O
+.	O
+	
+Nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drug	O
+-	O
+induced	O
+cystitis	B-NP
+is	O
+a	O
+poorly	O
+recognized	O
+and	O
+under	O
+-	O
+reported	O
+condition	O
+.	O
+	
+In	O
+addition	O
+to	O
+tiaprofenic	O
+acid	O
+","	O
+indomethacin	O
+has	O
+been	O
+reported	O
+to	O
+be	O
+associated	O
+with	O
+this	O
+condition	O
+.	O
+	
+METHODS	O
+:	O
+Three	O
+groups	O
+were	O
+established	O
+:	O
+a	O
+control	O
+group	O
+(	O
+n	O
+=	O
+10	O
+)	O
+","	O
+a	O
+high	O
+-	O
+dose	O
+group	O
+(	O
+n	O
+=	O
+10	O
+)	O
+","	O
+treated	O
+with	O
+one	O
+intraperitoneal	O
+injection	O
+of	O
+indomethacin	O
+20	O
+mg	O
+/	O
+kg	O
+","	O
+and	O
+a	O
+therapeutic	O
+dose	O
+group	O
+(	O
+n	O
+=	O
+10	O
+)	O
+in	O
+which	O
+oral	O
+indomethacin	O
+was	O
+administered	O
+3	O
+.	O
+25	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+daily	O
+for	O
+3	O
+weeks	O
+.	O
+	
+The	O
+animals	O
+were	O
+then	O
+killed	O
+and	O
+the	O
+bladders	O
+removed	O
+for	O
+light	O
+and	O
+electron	O
+microscopic	O
+studies	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+light	O
+microscopic	O
+findings	O
+showed	O
+some	O
+focal	O
+epithelial	O
+degeneration	O
+that	O
+was	O
+more	O
+prominent	O
+in	O
+the	O
+high	O
+-	O
+dose	O
+group	O
+.	O
+	
+When	O
+compared	O
+with	O
+the	O
+control	O
+group	O
+","	O
+both	O
+indomethacin	O
+groups	O
+revealed	O
+statistically	O
+increased	O
+numbers	O
+of	O
+mast	O
+cells	O
+in	O
+the	O
+mucosa	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+and	O
+penetration	O
+of	O
+lanthanum	O
+nitrate	O
+through	O
+intercellular	O
+areas	O
+of	O
+the	O
+epithelium	O
+.	O
+	
+Furthermore	O
+","	O
+the	O
+difference	O
+in	O
+mast	O
+cell	O
+counts	O
+between	O
+the	O
+high	O
+and	O
+therapeutic	O
+dose	O
+groups	O
+was	O
+also	O
+statistically	O
+significant	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Indomethacin	O
+resulted	O
+in	O
+histopathologic	O
+findings	O
+typical	O
+of	O
+interstitial	B-NP
+cystitis	I-NP
+","	O
+such	O
+as	O
+leaky	O
+bladder	O
+epithelium	O
+and	O
+mucosal	O
+mastocytosis	B-NP
+.	O
+	
+The	O
+TRUE	O
+incidence	O
+of	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drug	O
+-	O
+induced	O
+cystitis	B-NP
+in	O
+humans	O
+must	O
+be	O
+clarified	O
+by	O
+prospective	O
+clinical	O
+trials	O
+.	O
+	
+An	O
+open	O
+-	O
+label	O
+phase	O
+II	O
+study	O
+of	O
+low	O
+-	O
+dose	O
+thalidomide	O
+in	O
+androgen	O
+-	O
+independent	O
+prostate	B-NP
+cancer	I-NP
+.	O
+	
+The	O
+antiangiogenic	O
+effects	O
+of	O
+thalidomide	O
+have	O
+been	O
+assessed	O
+in	O
+clinical	O
+trials	O
+in	O
+patients	O
+with	O
+various	O
+solid	O
+and	O
+haematological	B-NP
+malignancies	I-NP
+.	O
+	
+Thalidomide	O
+blocks	O
+the	O
+activity	O
+of	O
+angiogenic	O
+agents	O
+including	O
+bFGF	O
+","	O
+VEGF	O
+and	O
+IL	O
+-	O
+6	O
+.	O
+	
+We	O
+undertook	O
+an	O
+open	O
+-	O
+label	O
+study	O
+using	O
+thalidomide	O
+100	O
+mg	O
+once	O
+daily	O
+for	O
+up	O
+to	O
+6	O
+months	O
+in	O
+20	O
+men	O
+with	O
+androgen	O
+-	O
+independent	O
+prostate	B-NP
+cancer	I-NP
+.	O
+	
+The	O
+mean	O
+time	O
+of	O
+study	O
+was	O
+109	O
+days	O
+(	O
+median	O
+107	O
+","	O
+range	O
+4	O
+-	O
+184	O
+days	O
+)	O
+.	O
+	
+Patients	O
+underwent	O
+regular	O
+measurement	O
+of	O
+prostate	O
+-	O
+specific	O
+antigen	O
+(	O
+PSA	O
+)	O
+","	O
+urea	O
+and	O
+electrolytes	O
+","	O
+serum	O
+bFGF	O
+and	O
+VEGF	O
+.	O
+	
+Three	O
+men	O
+(	O
+15	O
+%	O
+)	O
+showed	O
+a	O
+decline	O
+in	O
+serum	O
+PSA	O
+of	O
+at	O
+least	O
+50	O
+%	O
+","	O
+sustained	O
+throughout	O
+treatment	O
+.	O
+	
+Of	O
+16	O
+men	O
+treated	O
+for	O
+at	O
+least	O
+2	O
+months	O
+","	O
+six	O
+(	O
+37	O
+.	O
+5	O
+%	O
+)	O
+showed	O
+a	O
+fall	O
+in	O
+absolute	O
+PSA	O
+by	O
+a	O
+median	O
+of	O
+48	O
+%	O
+.	O
+	
+Increasing	O
+levels	O
+of	O
+serum	O
+bFGF	O
+and	O
+VEGF	O
+were	O
+associated	O
+with	O
+progressive	O
+disease	O
+;	O
+five	O
+of	O
+six	O
+men	O
+who	O
+demonstrated	O
+a	O
+fall	O
+in	O
+PSA	O
+also	O
+showed	O
+a	O
+decline	O
+in	O
+bFGF	O
+and	O
+VEGF	O
+levels	O
+","	O
+and	O
+three	O
+of	O
+four	O
+men	O
+with	O
+a	O
+rising	O
+PSA	O
+showed	O
+an	O
+increase	O
+in	O
+both	O
+growth	O
+factors	O
+.	O
+	
+Adverse	O
+effects	O
+included	O
+constipation	B-NP
+","	O
+morning	O
+drowsiness	B-NP
+","	O
+dizziness	B-NP
+and	O
+rash	B-NP
+","	O
+and	O
+resulted	O
+in	O
+withdrawal	O
+from	O
+the	O
+study	O
+by	O
+three	O
+men	O
+.	O
+	
+Evidence	O
+of	O
+peripheral	B-NP
+sensory	I-NP
+neuropathy	I-NP
+was	O
+found	O
+in	O
+nine	O
+of	O
+13	O
+men	O
+before	O
+treatment	O
+.	O
+	
+In	O
+the	O
+seven	O
+men	O
+who	O
+completed	O
+six	O
+months	O
+on	O
+thalidomide	O
+","	O
+subclinical	O
+evidence	O
+of	O
+peripheral	B-NP
+neuropathy	I-NP
+was	O
+found	O
+in	O
+four	O
+before	O
+treatment	O
+","	O
+but	O
+in	O
+all	O
+seven	O
+at	O
+repeat	O
+testing	O
+.	O
+	
+The	O
+findings	O
+indicate	O
+that	O
+thalidomide	O
+may	O
+be	O
+an	O
+option	O
+for	O
+patients	O
+who	O
+have	O
+failed	O
+other	O
+forms	O
+of	O
+therapy	O
+","	O
+provided	O
+close	O
+follow	O
+-	O
+up	O
+is	O
+maintained	O
+for	O
+development	O
+of	O
+peripheral	B-NP
+neuropathy	I-NP
+.	O
+	
+Central	B-NP
+nervous	I-NP
+system	I-NP
+toxicity	I-NP
+following	O
+the	O
+administration	O
+of	O
+levobupivacaine	O
+for	O
+lumbar	O
+plexus	O
+block	O
+:	O
+A	O
+report	O
+of	O
+two	O
+cases	O
+.	O
+	
+BACKGROUND	O
+AND	O
+OBJECTIVES	O
+:	O
+Central	B-NP
+nervous	I-NP
+system	I-NP
+and	I-NP
+cardiac	I-NP
+toxicity	I-NP
+following	O
+the	O
+administration	O
+of	O
+local	O
+anesthetics	O
+is	O
+a	O
+recognized	O
+complication	O
+of	O
+regional	O
+anesthesia	O
+.	O
+	
+Levobupivacaine	O
+","	O
+the	O
+pure	O
+S	O
+(	O
+-	O
+)	O
+enantiomer	O
+of	O
+bupivacaine	O
+","	O
+was	O
+developed	O
+to	O
+improve	O
+the	O
+cardiac	O
+safety	O
+profile	O
+of	O
+bupivacaine	O
+.	O
+	
+We	O
+describe	O
+2	O
+cases	O
+of	O
+grand	B-NP
+mal	I-NP
+seizures	I-NP
+following	O
+accidental	O
+intravascular	O
+injection	O
+of	O
+levobupivacaine	O
+.	O
+	
+CASE	O
+REPORT	O
+:	O
+Two	O
+patients	O
+presenting	O
+for	O
+elective	O
+orthopedic	O
+surgery	O
+of	O
+the	O
+lower	O
+limb	O
+underwent	O
+blockade	O
+of	O
+the	O
+lumbar	O
+plexus	O
+via	O
+the	O
+posterior	O
+approach	O
+.	O
+	
+Immediately	O
+after	O
+the	O
+administration	O
+of	O
+levobupivacaine	O
+0	O
+.	O
+5	O
+%	O
+with	O
+epinephrine	O
+2	O
+.	O
+5	O
+microgram	O
+/	O
+mL	O
+","	O
+the	O
+patients	O
+developed	O
+grand	B-NP
+mal	I-NP
+seizures	I-NP
+","	O
+despite	O
+negative	O
+aspiration	O
+for	O
+blood	O
+and	O
+no	O
+clinical	O
+signs	O
+of	O
+intravenous	O
+epinephrine	O
+administration	O
+.	O
+	
+The	O
+seizures	B-NP
+were	O
+successfully	O
+treated	O
+with	O
+sodium	O
+thiopental	O
+in	O
+addition	O
+to	O
+succinylcholine	O
+in	O
+1	O
+patient	O
+.	O
+	
+Neither	O
+patient	O
+developed	O
+signs	O
+of	O
+cardiovascular	B-NP
+toxicity	I-NP
+.	O
+	
+Both	O
+patients	O
+were	O
+treated	O
+preoperatively	O
+with	O
+beta	O
+-	O
+adrenergic	O
+antagonist	O
+medications	O
+","	O
+which	O
+may	O
+have	O
+masked	O
+the	O
+cardiovascular	O
+signs	O
+of	O
+the	O
+unintentional	O
+intravascular	O
+administration	O
+of	O
+levobupivacaine	O
+with	O
+epinephrine	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Although	O
+levobupivacaine	O
+may	O
+have	O
+a	O
+safer	O
+cardiac	B-NP
+toxicity	I-NP
+profile	O
+than	O
+racemic	O
+bupivacaine	O
+","	O
+if	O
+adequate	O
+amounts	O
+of	O
+levobupivacaine	O
+reach	O
+the	O
+circulation	O
+","	O
+it	O
+will	O
+result	O
+in	O
+convulsions	B-NP
+.	O
+	
+Plasma	O
+concentrations	O
+sufficient	O
+to	O
+result	O
+in	O
+central	B-NP
+nervous	I-NP
+system	I-NP
+toxicity	I-NP
+did	O
+not	O
+produce	O
+manifestations	O
+of	O
+cardiac	B-NP
+toxicity	I-NP
+in	O
+these	O
+2	O
+patients	O
+.	O
+	
+Amiodarone	O
+-	O
+induced	O
+torsade	B-NP
+de	I-NP
+pointes	I-NP
+during	O
+bladder	O
+irrigation	O
+:	O
+an	O
+unusual	O
+presentation	O
+-	O
+-	O
+a	O
+case	O
+report	O
+.	O
+	
+The	O
+authors	O
+present	O
+a	O
+case	O
+of	O
+early	O
+(	O
+within	O
+4	O
+days	O
+)	O
+development	O
+of	O
+torsade	B-NP
+de	I-NP
+pointes	I-NP
+(	O
+TdP	B-NP
+)	O
+associated	O
+with	O
+oral	O
+amiodarone	O
+therapy	O
+.	O
+	
+Consistent	O
+with	O
+other	O
+reports	O
+this	O
+case	O
+of	O
+TdP	B-NP
+occurred	O
+in	O
+the	O
+context	O
+of	O
+multiple	O
+exacerbating	O
+factors	O
+including	O
+hypokalemia	B-NP
+and	O
+digoxin	O
+excess	O
+.	O
+	
+Transient	O
+prolongation	O
+of	O
+the	O
+QT	O
+during	O
+bladder	O
+irrigation	O
+prompted	O
+the	O
+episode	O
+of	O
+TdP	B-NP
+.	O
+	
+It	O
+is	O
+well	O
+known	O
+that	O
+bradycardia	B-NP
+exacerbates	O
+acquired	O
+TdP	B-NP
+.	O
+	
+The	O
+authors	O
+speculate	O
+that	O
+the	O
+increased	O
+vagal	O
+tone	O
+during	O
+bladder	O
+irrigation	O
+","	O
+a	O
+vagal	O
+maneuver	O
+","	O
+in	O
+the	O
+context	O
+of	O
+amiodarone	O
+therapy	O
+resulted	O
+in	O
+amiodarone	O
+-	O
+induced	O
+proarrhythmia	B-NP
+.	O
+	
+In	O
+the	O
+absence	O
+of	O
+amiodarone	O
+therapy	O
+","	O
+a	O
+second	O
+bladder	O
+irrigation	O
+did	O
+not	O
+induce	O
+TdP	B-NP
+despite	O
+hypokalemia	B-NP
+and	O
+hypomagnesemia	B-NP
+.	O
+	
+Anaesthetic	O
+complications	O
+associated	O
+with	O
+myotonia	B-NP
+congenita	I-NP
+:	O
+case	O
+study	O
+and	O
+comparison	O
+with	O
+other	O
+myotonic	B-NP
+disorders	I-NP
+.	O
+	
+Myotonia	B-NP
+congenita	I-NP
+(	O
+MC	B-NP
+)	O
+is	O
+caused	O
+by	O
+a	O
+defect	O
+in	O
+the	O
+skeletal	O
+muscle	O
+chloride	O
+channel	O
+function	O
+","	O
+which	O
+may	O
+cause	O
+sustained	B-NP
+membrane	I-NP
+depolarisation	I-NP
+.	O
+	
+We	O
+describe	O
+a	O
+previously	O
+healthy	O
+32	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+who	O
+developed	O
+a	O
+life	O
+-	O
+threatening	O
+muscle	B-NP
+spasm	I-NP
+and	O
+secondary	O
+ventilation	O
+difficulties	O
+following	O
+a	O
+preoperative	O
+injection	O
+of	O
+suxamethonium	O
+.	O
+	
+The	O
+muscle	B-NP
+spasms	I-NP
+disappeared	O
+spontaneously	O
+and	O
+the	O
+surgery	O
+proceeded	O
+without	O
+further	O
+problems	O
+.	O
+	
+When	O
+subsequently	O
+questioned	O
+","	O
+she	O
+reported	O
+minor	O
+symptoms	O
+suggesting	O
+a	O
+myotonic	B-NP
+condition	I-NP
+.	O
+	
+Myotonia	B-NP
+was	O
+found	O
+on	O
+clinical	O
+examination	O
+and	O
+EMG	O
+.	O
+	
+The	O
+diagnosis	O
+MC	B-NP
+was	O
+confirmed	O
+genetically	O
+.	O
+	
+Neither	O
+the	O
+patient	O
+nor	O
+the	O
+anaesthetist	O
+were	O
+aware	O
+of	O
+the	O
+diagnosis	O
+before	O
+this	O
+potentially	O
+lethal	O
+complication	O
+occurred	O
+.	O
+	
+We	O
+give	O
+a	O
+brief	O
+overview	O
+of	O
+ion	B-NP
+channel	I-NP
+disorders	I-NP
+including	O
+malignant	B-NP
+hyperthermia	I-NP
+and	O
+their	O
+anaesthetic	O
+considerations	O
+.	O
+	
+Respiratory	O
+pattern	O
+in	O
+a	O
+rat	O
+model	O
+of	O
+epilepsy	B-NP
+.	O
+	
+PURPOSE	O
+:	O
+Apnea	B-NP
+is	O
+known	O
+to	O
+occur	O
+during	O
+seizures	B-NP
+","	O
+but	O
+systematic	O
+studies	O
+of	O
+ictal	O
+respiratory	O
+changes	O
+in	O
+adults	O
+are	O
+few	O
+.	O
+	
+Data	O
+regarding	O
+respiratory	O
+pattern	O
+defects	O
+during	O
+interictal	O
+periods	O
+also	O
+are	O
+scarce	O
+.	O
+	
+Here	O
+we	O
+sought	O
+to	O
+generate	O
+information	O
+with	O
+regard	O
+to	O
+the	O
+interictal	O
+period	O
+in	O
+animals	O
+with	O
+pilocarpine	O
+-	O
+induced	O
+epilepsy	B-NP
+.	O
+	
+METHODS	O
+:	O
+Twelve	O
+rats	O
+(	O
+six	O
+chronically	O
+epileptic	B-NP
+animals	O
+and	O
+six	O
+controls	O
+)	O
+were	O
+anesthetized	O
+","	O
+given	O
+tracheotomies	O
+","	O
+and	O
+subjected	O
+to	O
+hyperventilation	B-NP
+or	O
+hypoventilation	O
+conditions	O
+.	O
+	
+Breathing	O
+movements	O
+caused	O
+changes	O
+in	O
+thoracic	O
+volume	O
+and	O
+forced	O
+air	O
+to	O
+flow	O
+tidally	O
+through	O
+a	O
+pneumotachograph	O
+.	O
+	
+This	O
+flow	O
+was	O
+measured	O
+by	O
+using	O
+a	O
+differential	O
+pressure	O
+transducer	O
+","	O
+passed	O
+through	O
+a	O
+polygraph	O
+","	O
+and	O
+from	O
+this	O
+to	O
+a	O
+computer	O
+with	O
+custom	O
+software	O
+that	O
+derived	O
+ventilation	O
+(	O
+VE	O
+)	O
+","	O
+tidal	O
+volume	O
+(	O
+VT	O
+)	O
+","	O
+inspiratory	O
+time	O
+(	O
+TI	O
+)	O
+","	O
+expiratory	O
+time	O
+(	O
+TE	O
+)	O
+","	O
+breathing	O
+frequency	O
+(	O
+f	O
+)	O
+","	O
+and	O
+mean	O
+inspiratory	O
+flow	O
+(	O
+VT	O
+/	O
+TI	O
+)	O
+on	O
+a	O
+breath	O
+-	O
+by	O
+-	O
+breath	O
+basis	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+hyperventilation	B-NP
+maneuver	O
+caused	O
+a	O
+decrease	O
+in	O
+spontaneous	O
+ventilation	O
+in	O
+pilocarpine	O
+-	O
+treated	O
+and	O
+control	O
+rats	O
+.	O
+	
+Although	O
+VE	O
+had	O
+a	O
+similar	O
+decrease	O
+in	O
+both	O
+groups	O
+","	O
+in	O
+the	O
+epileptic	B-NP
+group	O
+","	O
+the	O
+decrease	O
+in	O
+VE	O
+was	O
+due	O
+to	O
+a	O
+significant	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+increase	O
+in	O
+TE	O
+peak	O
+in	O
+relation	O
+to	O
+that	O
+of	O
+the	O
+control	O
+animals	O
+.	O
+	
+The	O
+hypoventilation	O
+maneuver	O
+led	O
+to	O
+an	O
+increase	O
+in	O
+the	O
+arterial	O
+Paco2	O
+","	O
+followed	O
+by	O
+an	O
+increase	O
+in	O
+VE	O
+.	O
+	
+In	O
+the	O
+epileptic	B-NP
+group	O
+","	O
+the	O
+increase	O
+in	O
+VE	O
+was	O
+mediated	O
+by	O
+a	O
+significant	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+decrease	O
+in	O
+TE	O
+peak	O
+compared	O
+with	O
+the	O
+control	O
+group	O
+.	O
+	
+Systemic	O
+application	O
+of	O
+KCN	O
+","	O
+to	O
+evaluate	O
+the	O
+effects	O
+of	O
+peripheral	O
+chemoreception	O
+activation	O
+on	O
+ventilation	O
+","	O
+led	O
+to	O
+a	O
+similar	O
+increase	O
+in	O
+VE	O
+for	O
+both	O
+groups	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+data	O
+indicate	O
+that	O
+pilocarpine	O
+-	O
+treated	O
+animals	O
+have	O
+an	O
+altered	O
+ability	O
+to	O
+react	O
+to	O
+(	O
+or	O
+compensate	O
+for	O
+)	O
+blood	O
+gas	O
+changes	O
+with	O
+changes	O
+in	O
+ventilation	O
+and	O
+suggest	O
+that	O
+it	O
+is	O
+centrally	O
+determined	O
+.	O
+	
+We	O
+speculate	O
+on	O
+the	O
+possible	O
+relation	O
+of	O
+the	O
+current	O
+findings	O
+on	O
+treating	O
+different	O
+epilepsy	B-NP
+-	O
+associated	O
+conditions	O
+.	O
+	
+Fatal	O
+myeloencephalopathy	B-NP
+due	O
+to	O
+intrathecal	O
+vincristine	O
+administration	O
+.	O
+	
+Vincristine	O
+was	O
+accidentally	O
+given	O
+intrathecally	O
+to	O
+a	O
+child	O
+with	O
+leukaemia	B-NP
+","	O
+producing	O
+sensory	B-NP
+and	I-NP
+motor	I-NP
+dysfunction	I-NP
+followed	O
+by	O
+encephalopathy	B-NP
+and	O
+death	O
+.	O
+	
+Separate	O
+times	O
+for	O
+administering	O
+vincristine	O
+and	O
+intrathecal	O
+therapy	O
+is	O
+recommended	O
+.	O
+	
+Progesterone	O
+potentiation	O
+of	O
+bupivacaine	O
+arrhythmogenicity	O
+in	O
+pentobarbital	O
+-	O
+anesthetized	O
+rats	O
+and	O
+beating	O
+rat	O
+heart	O
+cell	O
+cultures	O
+.	O
+	
+The	O
+effects	O
+of	O
+progesterone	O
+treatment	O
+on	O
+bupivacaine	O
+arrhythmogenicity	O
+in	O
+beating	O
+rat	O
+heart	O
+myocyte	O
+cultures	O
+and	O
+on	O
+anesthetized	O
+rats	O
+were	O
+determined	O
+.	O
+	
+After	O
+determining	O
+the	O
+bupivacaine	O
+AD50	O
+(	O
+the	O
+concentration	O
+of	O
+bupivacaine	O
+that	O
+caused	O
+50	O
+%	O
+of	O
+all	O
+beating	O
+rat	O
+heart	O
+myocyte	O
+cultures	O
+to	O
+become	O
+arrhythmic	B-NP
+)	O
+","	O
+we	O
+determined	O
+the	O
+effect	O
+of	O
+1	O
+-	O
+hour	O
+progesterone	O
+HCl	O
+exposure	O
+on	O
+myocyte	O
+contractile	O
+rhythm	O
+.	O
+	
+Each	O
+concentration	O
+of	O
+progesterone	O
+(	O
+6	O
+.	O
+25	O
+","	O
+12	O
+.	O
+5	O
+","	O
+25	O
+","	O
+and	O
+50	O
+micrograms	O
+/	O
+ml	O
+)	O
+caused	O
+a	O
+significant	O
+and	O
+concentration	O
+-	O
+dependent	O
+reduction	O
+in	O
+the	O
+AD50	O
+for	O
+bupivacaine	O
+.	O
+	
+Estradiol	O
+treatment	O
+also	O
+increased	O
+the	O
+arrhythmogenicity	O
+of	O
+bupivacaine	O
+in	O
+myocyte	O
+cultures	O
+","	O
+but	O
+was	O
+only	O
+one	O
+fourth	O
+as	O
+potent	O
+as	O
+progesterone	O
+.	O
+	
+Neither	O
+progesterone	O
+nor	O
+estradiol	O
+effects	O
+on	O
+bupivacaine	O
+arrhythmogenicity	O
+were	O
+potentiated	O
+by	O
+epinephrine	O
+.	O
+	
+Chronic	O
+progesterone	O
+pretreatment	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+for	O
+21	O
+days	O
+)	O
+caused	O
+a	O
+significant	O
+increase	O
+in	O
+bupivacaine	O
+arrhythmogenicity	O
+in	O
+intact	O
+pentobarbital	O
+-	O
+anesthetized	O
+rats	O
+.	O
+	
+There	O
+was	O
+a	O
+significant	O
+decrease	O
+in	O
+the	O
+time	O
+to	O
+onset	O
+of	O
+arrhythmia	B-NP
+as	O
+compared	O
+with	O
+control	O
+nonprogesterone	O
+-	O
+treated	O
+rats	O
+(	O
+6	O
+.	O
+2	O
++	O
+/	O
+-	O
+1	O
+.	O
+3	O
+vs	O
+.	O
+30	O
+.	O
+8	O
++	O
+/	O
+-	O
+2	O
+.	O
+5	O
+min	O
+","	O
+mean	O
++	O
+/	O
+-	O
+SE	O
+)	O
+.	O
+	
+The	O
+results	O
+of	O
+this	O
+study	O
+indicate	O
+that	O
+progesterone	O
+can	O
+potentiate	O
+bupivacaine	O
+arrhythmogenicity	O
+both	O
+in	O
+vivo	O
+and	O
+in	O
+vitro	O
+.	O
+	
+Potentiation	O
+of	O
+bupivacaine	O
+arrhythmia	B-NP
+in	O
+myocyte	O
+cultures	O
+suggests	O
+that	O
+this	O
+effect	O
+is	O
+at	O
+least	O
+partly	O
+mediated	O
+at	O
+the	O
+myocyte	O
+level	O
+.	O
+	
+Increased	O
+serum	O
+soluble	O
+Fas	O
+in	O
+patients	O
+with	O
+acute	B-NP
+liver	I-NP
+failure	I-NP
+due	O
+to	O
+paracetamol	O
+overdose	B-NP
+.	O
+	
+BACKGROUND	O
+/	O
+AIMS	O
+:	O
+Experimental	O
+studies	O
+have	O
+suggested	O
+that	O
+apoptosis	O
+via	O
+the	O
+Fas	O
+/	O
+Fas	O
+Ligand	O
+signaling	O
+system	O
+may	O
+play	O
+an	O
+important	O
+role	O
+in	O
+the	O
+development	O
+of	O
+acute	B-NP
+liver	I-NP
+failure	I-NP
+.	O
+	
+The	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+soluble	O
+form	O
+of	O
+Fas	O
+in	O
+patients	O
+with	O
+acute	B-NP
+liver	I-NP
+failure	I-NP
+.	O
+	
+METHODOLOGY	O
+:	O
+Serum	O
+levels	O
+of	O
+sFas	O
+(	O
+soluble	O
+Fas	O
+)	O
+were	O
+measured	O
+by	O
+ELISA	O
+in	O
+24	O
+patients	O
+with	O
+acute	B-NP
+liver	I-NP
+failure	I-NP
+and	O
+10	O
+normal	O
+control	O
+subjects	O
+.	O
+	
+Serum	O
+levels	O
+of	O
+tumor	B-NP
+necrosis	B-NP
+factor	O
+-	O
+alpha	O
+and	O
+interferon	O
+-	O
+gamma	O
+were	O
+also	O
+determined	O
+by	O
+ELISA	O
+.	O
+	
+RESULTS	O
+:	O
+Serum	O
+sFas	O
+was	O
+significantly	O
+increased	O
+in	O
+patients	O
+with	O
+acute	B-NP
+liver	I-NP
+failure	I-NP
+(	O
+median	O
+","	O
+26	O
+.	O
+8	O
+U	O
+/	O
+mL	O
+;	O
+range	O
+","	O
+6	O
+.	O
+9	O
+-	O
+52	O
+.	O
+7	O
+U	O
+/	O
+mL	O
+)	O
+compared	O
+to	O
+the	O
+normal	O
+controls	O
+(	O
+median	O
+","	O
+8	O
+.	O
+6	O
+U	O
+/	O
+mL	O
+;	O
+range	O
+","	O
+6	O
+.	O
+5	O
+-	O
+12	O
+.	O
+0	O
+U	O
+/	O
+mL	O
+","	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Levels	O
+were	O
+significantly	O
+greater	O
+in	O
+patients	O
+with	O
+acute	B-NP
+liver	I-NP
+failure	I-NP
+due	O
+to	O
+paracetamol	O
+overdose	B-NP
+(	O
+median	O
+","	O
+28	O
+.	O
+7	O
+U	O
+/	O
+mL	O
+;	O
+range	O
+","	O
+12	O
+.	O
+8	O
+-	O
+52	O
+.	O
+7	O
+U	O
+/	O
+mL	O
+","	O
+n	O
+=	O
+17	O
+)	O
+than	O
+those	O
+due	O
+to	O
+non	O
+-	O
+A	O
+to	O
+E	O
+hepatitis	B-NP
+(	O
+median	O
+","	O
+12	O
+.	O
+5	O
+U	O
+/	O
+mL	O
+;	O
+range	O
+","	O
+6	O
+.	O
+9	O
+-	O
+46	O
+.	O
+0	O
+U	O
+/	O
+mL	O
+","	O
+n	O
+=	O
+7	O
+","	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+There	O
+was	O
+no	O
+relationship	O
+of	O
+sFas	O
+to	O
+eventual	O
+outcome	O
+in	O
+the	O
+patients	O
+.	O
+	
+A	O
+significant	O
+correlation	O
+was	O
+observed	O
+between	O
+serum	O
+sFas	O
+levels	O
+and	O
+aspartate	O
+aminotransferase	O
+(	O
+r	O
+=	O
+0	O
+.	O
+613	O
+","	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+increased	O
+concentration	O
+of	O
+sFas	O
+in	O
+serum	O
+of	O
+patients	O
+with	O
+acute	B-NP
+liver	I-NP
+failure	I-NP
+may	O
+reflect	O
+activation	O
+of	O
+Fas	O
+-	O
+mediated	O
+apoptosis	O
+in	O
+the	O
+liver	O
+and	O
+this	O
+together	O
+with	O
+increased	O
+tumor	B-NP
+necrosis	B-NP
+factor	O
+-	O
+alpha	O
+may	O
+be	O
+an	O
+important	O
+factor	O
+in	O
+liver	O
+cell	O
+loss	O
+.	O
+	
+Bilateral	O
+subthalamic	O
+nucleus	O
+stimulation	O
+for	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+High	O
+frequency	O
+stimulation	O
+of	O
+the	O
+subthalamic	O
+nucleus	O
+(	O
+STN	O
+)	O
+is	O
+known	O
+to	O
+ameliorate	O
+the	O
+signs	O
+and	O
+symptoms	O
+of	O
+advanced	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+AIM	O
+:	O
+We	O
+studied	O
+the	O
+effect	O
+of	O
+high	O
+frequency	O
+STN	O
+stimulation	O
+in	O
+23	O
+patients	O
+.	O
+	
+METHOD	O
+:	O
+Twenty	O
+-	O
+three	O
+patients	O
+suffering	O
+from	O
+severe	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+(	O
+Stages	O
+III	O
+-	O
+V	O
+on	O
+Hoehn	O
+and	O
+Yahr	O
+scale	O
+)	O
+and	O
+","	O
+particularly	O
+bradykinesia	B-NP
+","	O
+rigidity	B-NP
+","	O
+and	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B-NP
+underwent	O
+bilateral	O
+implantation	O
+of	O
+electrodes	O
+in	O
+the	O
+STN	O
+.	O
+	
+Preoperative	O
+and	O
+postoperative	O
+assessments	O
+of	O
+these	O
+patients	O
+at	O
+1	O
+","	O
+3	O
+","	O
+6	O
+and	O
+12	O
+months	O
+follow	O
+-	O
+up	O
+","	O
+in	O
+"	O
+on	O
+"	O
+and	O
+"	O
+off	O
+"	O
+drug	O
+conditions	O
+","	O
+was	O
+carried	O
+out	O
+using	O
+Unified	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+Disease	I-NP
+Rating	O
+Scale	O
+","	O
+Hoehn	O
+and	O
+Yahr	O
+staging	O
+","	O
+England	O
+activities	O
+of	O
+daily	O
+living	O
+score	O
+and	O
+video	O
+recordings	O
+.	O
+	
+RESULTS	O
+:	O
+After	O
+one	O
+year	O
+of	O
+electrical	O
+stimulation	O
+of	O
+the	O
+STN	O
+","	O
+the	O
+patients	O
+'	O
+scores	O
+for	O
+activities	O
+of	O
+daily	O
+living	O
+and	O
+motor	O
+examination	O
+scores	O
+(	O
+Unified	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+Disease	I-NP
+Rating	O
+Scale	O
+parts	O
+II	O
+and	O
+III	O
+)	O
+off	O
+medication	O
+improved	O
+by	O
+62	O
+%	O
+and	O
+61	O
+%	O
+respectively	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+The	O
+subscores	O
+for	O
+the	O
+akinesia	B-NP
+","	O
+rigidity	B-NP
+","	O
+tremor	B-NP
+and	O
+gait	O
+also	O
+improved	O
+.	O
+	
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+The	O
+average	O
+levodopa	O
+dose	O
+decreased	O
+from	O
+813	O
+mg	O
+to	O
+359	O
+mg	O
+.	O
+	
+The	O
+cognitive	O
+functions	O
+remained	O
+unchanged	O
+.	O
+	
+Two	O
+patients	O
+developed	O
+device	O
+-	O
+related	O
+complications	O
+and	O
+two	O
+patients	O
+experienced	O
+abnormal	O
+weight	O
+gain	O
+.	O
+	
+CONCLUSION	O
+:	O
+Bilateral	O
+subthalamic	O
+nucleus	O
+stimulation	O
+is	O
+an	O
+effective	O
+treatment	O
+for	O
+advanced	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+It	O
+reduces	O
+the	O
+severity	O
+of	O
+"	O
+off	O
+"	O
+phase	O
+symptoms	O
+","	O
+improves	O
+the	O
+axial	O
+symptoms	O
+and	O
+reduces	O
+levodopa	O
+requirements	O
+.	O
+	
+The	O
+reduction	O
+in	O
+the	O
+levodopa	O
+dose	O
+is	O
+useful	O
+in	O
+controlling	O
+drug	B-NP
+-	I-NP
+induced	I-NP
+dyskinesias	I-NP
+.	O
+	
+Acute	B-NP
+renal	I-NP
+failure	I-NP
+occurring	O
+during	O
+intravenous	O
+desferrioxamine	O
+therapy	O
+:	O
+recovery	O
+after	O
+haemodialysis	O
+.	O
+	
+A	O
+patient	O
+with	O
+transfusion	O
+-	O
+dependent	O
+thalassemia	B-NP
+was	O
+undergoing	O
+home	O
+intravenous	O
+desferrioxamine	O
+(	O
+DFX	O
+)	O
+treatment	O
+by	O
+means	O
+of	O
+a	O
+totally	O
+implanted	O
+system	O
+because	O
+of	O
+his	O
+poor	O
+compliance	O
+with	O
+the	O
+nightly	O
+subcutaneous	O
+therapy	O
+.	O
+	
+Due	O
+to	O
+an	O
+accidental	O
+malfunctioning	O
+of	O
+the	O
+infusion	O
+pump	O
+","	O
+the	O
+patient	O
+was	O
+inadvertently	O
+administered	O
+a	O
+toxic	O
+dosage	O
+of	O
+the	O
+drug	O
+which	O
+caused	O
+renal	B-NP
+insufficiency	I-NP
+.	O
+	
+Given	O
+the	O
+progressive	O
+deterioration	O
+of	O
+the	O
+symptoms	O
+and	O
+of	O
+the	O
+laboratory	O
+values	O
+","	O
+despite	O
+adequate	O
+medical	O
+treatment	O
+","	O
+a	O
+decision	O
+was	O
+made	O
+to	O
+introduce	O
+haemodialytical	O
+therapy	O
+in	O
+order	O
+to	O
+remove	O
+the	O
+drug	O
+and	O
+therapy	O
+reduce	O
+the	O
+nephrotoxicity	B-NP
+.	O
+	
+From	O
+the	O
+results	O
+obtained	O
+","	O
+haemodialysis	O
+can	O
+therefore	O
+be	O
+suggested	O
+as	O
+a	O
+useful	O
+therapy	O
+in	O
+rare	O
+cases	O
+of	O
+progressive	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+caused	O
+by	O
+desferrioxamine	O
+.	O
+	
+Ocular	O
+motility	O
+changes	O
+after	O
+subtenon	O
+carboplatin	O
+chemotherapy	O
+for	O
+retinoblastoma	B-NP
+.	O
+	
+BACKGROUND	O
+:	O
+Focal	O
+subtenon	O
+carboplatin	O
+injections	O
+have	O
+recently	O
+been	O
+used	O
+as	O
+a	O
+presumably	O
+toxicity	B-NP
+-	O
+free	O
+adjunct	O
+to	O
+systemic	O
+chemotherapy	O
+for	O
+intraocular	O
+retinoblastoma	B-NP
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+report	O
+our	O
+clinical	O
+experience	O
+with	O
+abnormal	B-NP
+ocular	I-NP
+motility	I-NP
+in	O
+patients	O
+treated	O
+with	O
+subtenon	O
+carboplatin	O
+chemotherapy	O
+.	O
+	
+METHODS	O
+:	O
+We	O
+noted	O
+abnormal	B-NP
+ocular	I-NP
+motility	I-NP
+in	O
+10	O
+consecutive	O
+patients	O
+with	O
+retinoblastoma	B-NP
+who	O
+had	O
+received	O
+subtenon	O
+carboplatin	O
+.	O
+	
+During	O
+ocular	O
+manipulation	O
+under	O
+general	O
+anesthesia	O
+","	O
+we	O
+assessed	O
+their	O
+eyes	O
+by	O
+forced	O
+duction	O
+testing	O
+","	O
+comparing	O
+ocular	O
+motility	O
+after	O
+tumor	B-NP
+control	O
+with	O
+ocular	O
+motility	O
+at	O
+diagnosis	O
+.	O
+	
+Eyes	O
+subsequently	O
+enucleated	O
+because	O
+of	O
+treatment	O
+failure	O
+(	O
+n	O
+=	O
+4	O
+)	O
+were	O
+examined	O
+histologically	O
+.	O
+	
+RESULTS	O
+:	O
+Limitation	O
+of	O
+ocular	O
+motility	O
+was	O
+detected	O
+in	O
+all	O
+12	O
+eyes	O
+of	O
+10	O
+patients	O
+treated	O
+for	O
+intraocular	O
+retinoblastoma	B-NP
+with	O
+1	O
+to	O
+6	O
+injections	O
+of	O
+subtenon	O
+carboplatin	O
+as	O
+part	O
+of	O
+multimodality	O
+therapy	O
+.	O
+	
+Histopathological	O
+examination	O
+revealed	O
+many	O
+lipophages	O
+in	O
+the	O
+periorbital	O
+fat	O
+surrounding	O
+the	O
+optic	O
+nerve	O
+in	O
+1	O
+eye	O
+","	O
+indicative	O
+of	O
+phagocytosis	O
+of	O
+previously	O
+existing	O
+fat	O
+cells	O
+and	O
+suggesting	O
+prior	O
+fat	O
+necrosis	B-NP
+.	O
+	
+The	O
+enucleations	O
+were	O
+technically	O
+difficult	O
+and	O
+hazardous	O
+for	O
+globe	O
+rupture	B-NP
+because	O
+of	O
+extensive	O
+orbital	O
+soft	O
+tissue	O
+adhesions	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Subtenon	O
+carboplatin	O
+chemotherapy	O
+is	O
+associated	O
+with	O
+significant	O
+fibrosis	B-NP
+of	O
+orbital	O
+soft	O
+tissues	O
+","	O
+leading	O
+to	O
+mechanical	O
+restriction	O
+of	O
+eye	O
+movements	O
+and	O
+making	O
+subsequent	O
+enucleation	O
+difficult	O
+.	O
+	
+Subtenon	O
+carboplatin	O
+is	O
+not	O
+free	O
+of	O
+toxicity	B-NP
+","	O
+and	O
+its	O
+use	O
+is	O
+best	O
+restricted	O
+to	O
+specific	O
+indications	O
+.	O
+	
+Ethambutol	O
+and	O
+optic	B-NP
+neuropathy	I-NP
+.	O
+	
+PURPOSE	O
+:	O
+To	O
+demonstrate	O
+the	O
+association	O
+between	O
+ethambutol	O
+and	O
+optic	B-NP
+neuropathy	I-NP
+.	O
+	
+METHOD	O
+:	O
+Thirteen	O
+patients	O
+who	O
+developed	O
+optic	B-NP
+neuropathy	I-NP
+after	O
+being	O
+treated	O
+with	O
+ethambutol	O
+for	O
+tuberculosis	B-NP
+of	I-NP
+the	I-NP
+lung	I-NP
+or	I-NP
+lymph	I-NP
+node	I-NP
+at	O
+Siriraj	O
+Hospital	O
+between	O
+1997	O
+and	O
+2001	O
+were	O
+retrospectively	O
+reviewed	O
+.	O
+	
+The	O
+clinical	O
+characteristics	O
+and	O
+initial	O
+and	O
+final	O
+visual	O
+acuity	O
+were	O
+analyzed	O
+to	O
+determine	O
+visual	O
+outcome	O
+.	O
+	
+RESULTS	O
+:	O
+All	O
+patients	O
+had	O
+optic	B-NP
+neuropathy	I-NP
+between	O
+1	O
+to	O
+6	O
+months	O
+(	O
+mean	O
+=	O
+2	O
+.	O
+9	O
+months	O
+)	O
+after	O
+starting	O
+ethambutol	O
+therapy	O
+at	O
+a	O
+dosage	O
+ranging	O
+from	O
+13	O
+to	O
+20	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+(	O
+mean	O
+=	O
+17	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+)	O
+.	O
+	
+Seven	O
+(	O
+54	O
+%	O
+)	O
+of	O
+the	O
+13	O
+patients	O
+experienced	O
+visual	O
+recovery	O
+after	O
+stopping	O
+the	O
+drug	O
+.	O
+	
+Of	O
+6	O
+patients	O
+with	O
+irreversible	O
+visual	B-NP
+impairment	I-NP
+","	O
+4	O
+patients	O
+had	O
+diabetes	B-NP
+mellitus	I-NP
+","	O
+glaucoma	B-NP
+and	O
+a	O
+history	O
+of	O
+heavy	O
+smoking	O
+.	O
+	
+CONCLUSION	O
+:	O
+Early	O
+recognition	O
+of	O
+optic	B-NP
+neuropathy	I-NP
+should	O
+be	O
+considered	O
+in	O
+patients	O
+with	O
+ethambutol	O
+therapy	O
+.	O
+	
+A	O
+low	O
+dose	O
+and	O
+prompt	O
+discontinuation	O
+of	O
+the	O
+drug	O
+is	O
+recommended	O
+particularly	O
+in	O
+individuals	O
+with	O
+diabetes	B-NP
+mellitus	I-NP
+","	O
+glaucoma	B-NP
+or	O
+who	O
+are	O
+heavy	O
+smokers	O
+.	O
+	
+Treatment	O
+of	O
+compensatory	O
+gustatory	B-NP
+hyperhidrosis	I-NP
+with	O
+topical	O
+glycopyrrolate	O
+.	O
+	
+Gustatory	B-NP
+hyperhidrosis	I-NP
+is	O
+facial	O
+sweating	B-NP
+usually	O
+associated	O
+with	O
+the	O
+eating	O
+of	O
+hot	O
+spicy	O
+food	O
+or	O
+even	O
+smelling	O
+this	O
+food	O
+.	O
+	
+Current	O
+options	O
+of	O
+treatment	O
+include	O
+oral	O
+anticholinergic	O
+drugs	O
+","	O
+the	O
+topical	O
+application	O
+of	O
+anticholinergics	O
+or	O
+aluminum	O
+chloride	O
+","	O
+and	O
+the	O
+injection	O
+of	O
+botulinum	O
+toxin	O
+.	O
+	
+Thirteen	O
+patients	O
+have	O
+been	O
+treated	O
+to	O
+date	O
+with	O
+1	O
+.	O
+5	O
+%	O
+or	O
+2	O
+%	O
+topical	O
+glycopyrrolate	O
+.	O
+	
+All	O
+patients	O
+had	O
+gustatory	B-NP
+hyperhidrosis	I-NP
+","	O
+which	O
+interfered	O
+with	O
+their	O
+social	O
+activities	O
+","	O
+after	O
+transthroacic	O
+endoscopic	O
+sympathectomy	O
+","	O
+and	O
+which	O
+was	O
+associated	O
+with	O
+compensatory	O
+focal	O
+hyperhidrosis	B-NP
+.	O
+	
+After	O
+applying	O
+topical	O
+glycopyrrolate	O
+","	O
+the	O
+subjective	O
+effect	O
+was	O
+excellent	O
+(	O
+no	O
+sweating	B-NP
+after	O
+eating	O
+hot	O
+spicy	O
+food	O
+)	O
+in	O
+10	O
+patients	O
+(	O
+77	O
+%	O
+)	O
+","	O
+and	O
+fair	O
+(	O
+clearly	O
+reduced	O
+sweating	B-NP
+)	O
+in	O
+3	O
+patients	O
+(	O
+23	O
+%	O
+)	O
+.	O
+	
+All	O
+had	O
+reported	O
+incidents	O
+of	O
+being	O
+very	O
+embarrassed	O
+whilst	O
+eating	O
+hot	O
+spicy	O
+foods	O
+.	O
+	
+Adverse	O
+effects	O
+included	O
+a	O
+mildly	O
+dry	B-NP
+mouth	I-NP
+and	O
+a	O
+sore	B-NP
+throat	I-NP
+in	O
+2	O
+patients	O
+(	O
+2	O
+%	O
+glycopyrrolate	O
+)	O
+","	O
+a	O
+light	O
+headache	B-NP
+in	O
+1	O
+patient	O
+(	O
+1	O
+.	O
+5	O
+%	O
+glycopyrrolate	O
+)	O
+.	O
+	
+The	O
+topical	O
+application	O
+of	O
+a	O
+glycopyrrolate	O
+pad	O
+appeared	O
+to	O
+be	O
+safe	O
+","	O
+efficacious	O
+","	O
+well	O
+tolerated	O
+","	O
+and	O
+a	O
+convenient	O
+method	O
+of	O
+treatment	O
+for	O
+moderate	O
+to	O
+severe	O
+symptoms	O
+of	O
+gustatory	B-NP
+hyperhidrosis	I-NP
+in	O
+post	O
+transthoracic	O
+endoscopic	O
+sympathectomy	O
+or	O
+sympathicotomy	O
+patients	O
+","	O
+with	O
+few	O
+side	O
+effects	O
+.	O
+	
+Neuroleptic	O
+-	O
+associated	O
+hyperprolactinemia	B-NP
+.	O
+	
+Can	O
+it	O
+be	O
+treated	O
+with	O
+bromocriptine	O
+?	O
+	
+Six	O
+stable	O
+psychiatric	O
+outpatients	O
+with	O
+hyperprolactinemia	B-NP
+and	O
+amenorrhea	B-NP
+/	O
+oligomenorrhea	B-NP
+associated	O
+with	O
+their	O
+neuroleptic	O
+medications	O
+were	O
+treated	O
+with	O
+bromocriptine	O
+.	O
+	
+Daily	O
+dosages	O
+of	O
+5	O
+-	O
+10	O
+mg	O
+corrected	O
+the	O
+hyperprolactinemia	B-NP
+and	O
+restored	O
+menstruation	O
+in	O
+four	O
+of	O
+the	O
+six	O
+patients	O
+.	O
+	
+One	O
+woman	O
+","	O
+however	O
+","	O
+developed	O
+worsened	O
+psychiatric	B-NP
+symptoms	I-NP
+while	O
+taking	O
+bromocriptine	O
+","	O
+and	O
+it	O
+was	O
+discontinued	O
+.	O
+	
+Thus	O
+","	O
+three	O
+of	O
+six	O
+patients	O
+had	O
+their	O
+menstrual	O
+irregularity	O
+successfully	O
+corrected	O
+with	O
+bromocriptine	O
+.	O
+	
+This	O
+suggests	O
+that	O
+bromocriptine	O
+should	O
+be	O
+further	O
+evaluated	O
+as	O
+potential	O
+therapy	O
+for	O
+neuroleptic	O
+-	O
+associated	O
+hyperprolactinemia	B-NP
+and	O
+amenorrhea	B-NP
+/	O
+galactorrhea	B-NP
+.	O
+	
+Ethacrynic	O
+acid	O
+-	O
+induced	O
+convulsions	B-NP
+and	O
+brain	O
+neurotransmitters	O
+in	O
+mice	O
+.	O
+	
+Intracerebroventricular	O
+injection	O
+of	O
+ethacrynic	O
+acid	O
+(	O
+50	O
+%	O
+convulsive	B-NP
+dose	O
+;	O
+50	O
+micrograms	O
+/	O
+mouse	O
+)	O
+accelerated	O
+the	O
+synthesis	O
+/	O
+turnover	O
+of	O
+5	O
+-	O
+hydroxytryptamine	O
+(	O
+5	O
+-	O
+HT	O
+)	O
+but	O
+suppressed	O
+the	O
+synthesis	O
+of	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+and	O
+acetylcholine	O
+in	O
+mouse	O
+brain	O
+.	O
+	
+These	O
+effects	O
+were	O
+completely	O
+antagonized	O
+by	O
+pretreatment	O
+with	O
+a	O
+glutamate	O
+/	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+antagonist	O
+","	O
+aminophosphonovaleric	O
+acid	O
+.	O
+	
+In	O
+ethacrynic	O
+acid	O
+-	O
+induced	O
+convulsions	B-NP
+","	O
+these	O
+neurotransmitter	O
+systems	O
+may	O
+be	O
+differentially	O
+modulated	O
+","	O
+probably	O
+through	O
+activation	O
+of	O
+glutaminergic	O
+neurons	O
+in	O
+the	O
+brain	O
+.	O
+	
+Pharmacology	O
+of	O
+gamma	O
+-	O
+aminobutyric	O
+acidA	O
+receptor	O
+complex	O
+after	O
+the	O
+in	O
+vivo	O
+administration	O
+of	O
+the	O
+anxioselective	O
+and	O
+anticonvulsant	O
+beta	O
+-	O
+carboline	O
+derivative	O
+abecarnil	O
+.	O
+	
+In	O
+rodents	O
+","	O
+the	O
+effect	O
+of	O
+the	O
+beta	O
+-	O
+carboline	O
+derivative	O
+isopropyl	O
+-	O
+6	O
+-	O
+benzyloxy	O
+-	O
+4	O
+-	O
+methoxymethyl	O
+-	O
+beta	O
+-	O
+carboline	O
+-	O
+3	O
+-	O
+carboxylate	O
+(	O
+abecarrnil	O
+)	O
+","	O
+a	O
+new	O
+ligand	O
+for	O
+benzodiazepine	O
+receptors	O
+possessing	O
+anxiolytic	O
+and	O
+anticonvulsant	O
+properties	O
+","	O
+was	O
+evaluated	O
+on	O
+the	O
+function	O
+of	O
+central	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+(	O
+GABA	O
+)	O
+A	O
+receptor	O
+complex	O
+","	O
+both	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+.	O
+	
+Added	O
+in	O
+vitro	O
+to	O
+rat	O
+cortical	O
+membrane	O
+preparation	O
+","	O
+abecarnil	O
+increased	O
+[	O
+3H	O
+]	O
+GABA	O
+binding	O
+","	O
+enhanced	O
+muscimol	O
+-	O
+stimulated	O
+36Cl	O
+-	O
+uptake	O
+and	O
+reduced	O
+the	O
+binding	O
+of	O
+t	O
+-	O
+[	O
+35S	O
+]	O
+butylbicyclophosphorothionate	O
+(	O
+[	O
+35S	O
+]	O
+TBPS	O
+)	O
+.	O
+	
+These	O
+effects	O
+were	O
+similar	O
+to	O
+those	O
+induced	O
+by	O
+diazepam	O
+","	O
+whereas	O
+the	O
+partial	O
+agonist	O
+Ro	O
+16	O
+-	O
+6028	O
+(	O
+tert	O
+-	O
+butyl	O
+-	O
+(	O
+S	O
+)	O
+-	O
+8	O
+-	O
+bromo	O
+-	O
+11	O
+","	O
+12	O
+","	O
+13	O
+","	O
+13a	O
+-	O
+tetrahydro	O
+-	O
+9	O
+-	O
+oxo	O
+-	O
+9H	O
+-	O
+imidazo	O
+[	O
+1	O
+","	O
+5	O
+-	O
+a	O
+]	O
+-	O
+pyrrolo	O
+-	O
+[	O
+2	O
+","	O
+1	O
+-	O
+c	O
+]	O
+[	O
+1	O
+","	O
+4	O
+]	O
+benzodiazepine	O
+-	O
+1	O
+-	O
+carboxylate	O
+)	O
+showed	O
+very	O
+weak	O
+efficacy	O
+in	O
+these	O
+biochemical	O
+tests	O
+.	O
+	
+After	O
+i	O
+.	O
+p	O
+.	O
+injection	O
+to	O
+rats	O
+","	O
+abecarnil	O
+and	O
+diazepam	O
+decreased	O
+in	O
+a	O
+time	O
+-	O
+dependent	O
+and	O
+dose	O
+-	O
+related	O
+(	O
+0	O
+.	O
+25	O
+-	O
+20	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+manner	O
+[	O
+35S	O
+]	O
+TBPS	O
+binding	O
+measured	O
+ex	O
+vivo	O
+in	O
+the	O
+cerebral	O
+cortex	O
+.	O
+	
+Moreover	O
+","	O
+both	O
+drugs	O
+at	O
+the	O
+dose	O
+of	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+antagonized	O
+completely	O
+the	O
+convulsant	O
+activity	O
+and	O
+the	O
+increase	O
+of	O
+[	O
+35S	O
+]	O
+TBPS	O
+binding	O
+induced	O
+by	O
+isoniazide	O
+(	O
+350	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+as	O
+well	O
+as	O
+the	O
+increase	O
+of	O
+[	O
+35S	O
+]	O
+TBPS	O
+binding	O
+induced	O
+by	O
+foot	O
+-	O
+shock	O
+stress	O
+.	O
+	
+To	O
+better	O
+correlate	O
+the	O
+biochemical	O
+and	O
+the	O
+pharmacological	O
+effects	O
+","	O
+we	O
+studied	O
+the	O
+action	O
+of	O
+abecarnil	O
+on	O
+[	O
+35S	O
+]	O
+TBPS	O
+binding	O
+","	O
+exploratory	O
+motility	O
+and	O
+on	O
+isoniazid	O
+-	O
+induced	O
+biochemical	O
+and	O
+pharmacological	O
+effects	O
+in	O
+mice	O
+.	O
+	
+In	O
+these	O
+animals	O
+","	O
+abecarnil	O
+produced	O
+a	O
+paralleled	O
+dose	O
+-	O
+dependent	O
+(	O
+0	O
+.	O
+5	O
+-	O
+1	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+reduction	O
+of	O
+both	O
+motor	O
+behavior	O
+and	O
+cortical	O
+[	O
+35S	O
+]	O
+TBPS	O
+binding	O
+.	O
+	
+Moreover	O
+","	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+of	O
+this	O
+beta	O
+-	O
+carboline	O
+reduced	O
+markedly	O
+the	O
+increase	O
+of	O
+[	O
+35S	O
+]	O
+TBPS	O
+binding	O
+and	O
+the	O
+convulsions	B-NP
+induced	O
+by	O
+isoniazid	O
+(	O
+200	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+	
+Recurrent	O
+myocardial	B-NP
+infarction	I-NP
+in	O
+a	O
+postpartum	O
+patient	O
+receiving	O
+bromocriptine	O
+.	O
+	
+Myocardial	B-NP
+infarction	I-NP
+in	O
+puerperium	O
+is	O
+infrequently	O
+reported	O
+.	O
+	
+Spasm	B-NP
+","	O
+coronary	O
+dissection	O
+","	O
+or	O
+atheromatous	O
+etiology	O
+has	O
+been	O
+described	O
+.	O
+	
+Bromocriptine	O
+has	O
+been	O
+implicated	O
+in	O
+several	O
+previous	O
+case	O
+reports	O
+of	O
+myocardial	B-NP
+infarction	I-NP
+in	O
+the	O
+puerperium	O
+.	O
+	
+Our	O
+case	O
+(	O
+including	O
+an	O
+inadvertent	O
+rechallenge	O
+)	O
+suggests	O
+such	O
+a	O
+relationship	O
+.	O
+	
+Although	O
+generally	O
+regarded	O
+as	O
+"	O
+safe	O
+,	O
+"	O
+possible	O
+serious	O
+cardiac	O
+effects	O
+of	O
+bromocriptine	O
+should	O
+be	O
+acknowledged	O
+.	O
+	
+Asterixis	B-NP
+induced	O
+by	O
+carbamazepine	O
+therapy	O
+.	O
+	
+There	O
+are	O
+very	O
+few	O
+reports	O
+about	O
+asterixis	B-NP
+as	O
+a	O
+side	O
+effect	O
+of	O
+treatment	O
+with	O
+psychopharmacologic	O
+agents	O
+.	O
+	
+In	O
+this	O
+report	O
+we	O
+present	O
+four	O
+patients	O
+treated	O
+with	O
+a	O
+combination	O
+of	O
+different	O
+psychotropic	O
+drugs	O
+","	O
+in	O
+whom	O
+asterixis	B-NP
+was	O
+triggered	O
+either	O
+by	O
+adding	O
+carbamazepine	O
+(	O
+CBZ	O
+)	O
+to	O
+a	O
+treatment	O
+regimen	O
+","	O
+or	O
+by	O
+increasing	O
+its	O
+dosage	O
+.	O
+	
+Neither	O
+dosage	O
+nor	O
+serum	O
+levels	O
+of	O
+CBZ	O
+were	O
+in	O
+a	O
+higher	O
+range	O
+.	O
+	
+We	O
+consider	O
+asterixis	B-NP
+to	O
+be	O
+an	O
+easily	O
+overlooked	O
+sign	O
+of	O
+neurotoxicity	B-NP
+","	O
+which	O
+may	O
+occur	O
+even	O
+at	O
+low	O
+or	O
+moderate	O
+dosage	O
+levels	O
+","	O
+if	O
+certain	O
+drugs	O
+as	O
+lithium	O
+or	O
+clozapine	O
+are	O
+used	O
+in	O
+combination	O
+with	O
+CBZ	O
+.	O
+	
+Pharmacodynamics	O
+of	O
+the	O
+hypotensive	B-NP
+effect	O
+of	O
+levodopa	O
+in	O
+parkinsonian	B-NP
+patients	O
+.	O
+	
+Blood	O
+pressure	O
+effects	O
+of	O
+i	O
+.	O
+v	O
+.	O
+levodopa	O
+were	O
+examined	O
+in	O
+parkinsonian	B-NP
+patients	O
+with	O
+stable	O
+and	O
+fluctuating	O
+responses	O
+to	O
+levodopa	O
+.	O
+	
+The	O
+magnitude	O
+of	O
+the	O
+hypotensive	B-NP
+effect	O
+of	O
+levodopa	O
+was	O
+concentration	O
+dependent	O
+and	O
+was	O
+fit	O
+to	O
+an	O
+Emax	O
+model	O
+in	O
+fluctuating	O
+responders	O
+.	O
+	
+Stable	O
+responders	O
+demonstrated	O
+a	O
+small	O
+hypotensive	B-NP
+response	O
+.	O
+	
+Baseline	O
+blood	O
+pressures	O
+were	O
+higher	O
+in	O
+fluctuating	O
+patients	O
+;	O
+a	O
+higher	O
+baseline	O
+blood	O
+pressure	O
+correlated	O
+with	O
+greater	O
+hypotensive	B-NP
+effects	O
+.	O
+	
+Antiparkinsonian	O
+effects	O
+of	O
+levodopa	O
+temporally	O
+correlated	O
+with	O
+blood	O
+pressure	O
+changes	O
+.	O
+	
+Phenylalanine	O
+","	O
+a	O
+large	O
+neutral	O
+amino	O
+acid	O
+(	O
+LNAA	O
+)	O
+competing	O
+with	O
+levodopa	O
+for	O
+transport	O
+across	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+","	O
+reduced	O
+the	O
+hypotensive	B-NP
+and	O
+antiparkinsonian	O
+effects	O
+of	O
+levodopa	O
+.	O
+	
+We	O
+conclude	O
+that	O
+levodopa	O
+has	O
+a	O
+central	O
+hypotensive	B-NP
+action	O
+that	O
+parallels	O
+the	O
+motor	O
+effects	O
+in	O
+fluctuating	O
+patients	O
+.	O
+	
+The	O
+hypotensive	B-NP
+effect	O
+appears	O
+to	O
+be	O
+related	O
+to	O
+the	O
+higher	O
+baseline	O
+blood	O
+pressure	O
+we	O
+observed	O
+in	O
+fluctuating	O
+patients	O
+relative	O
+to	O
+stable	O
+patients	O
+.	O
+	
+Syndrome	B-NP
+of	I-NP
+inappropriate	I-NP
+secretion	I-NP
+of	I-NP
+antidiuretic	I-NP
+hormone	I-NP
+after	O
+infusional	O
+vincristine	O
+.	O
+	
+A	O
+77	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+refractory	O
+multiple	B-NP
+myeloma	I-NP
+was	O
+treated	O
+with	O
+a	O
+4	O
+-	O
+day	O
+continuous	O
+intravenous	O
+infusion	O
+of	O
+vincristine	O
+and	O
+doxorubicin	O
+and	O
+4	O
+days	O
+of	O
+oral	O
+dexamethasone	O
+.	O
+	
+Nine	O
+days	O
+after	O
+her	O
+second	O
+cycle	O
+she	O
+presented	O
+with	O
+lethargy	B-NP
+and	O
+weakness	B-NP
+associated	O
+with	O
+hyponatremia	B-NP
+.	O
+	
+Evaluation	O
+revealed	O
+the	O
+syndrome	B-NP
+of	I-NP
+inappropriate	I-NP
+secretion	I-NP
+of	I-NP
+antidiuretic	I-NP
+hormone	I-NP
+","	O
+which	O
+was	O
+attributed	O
+to	O
+the	O
+vincristine	O
+infusion	O
+.	O
+	
+After	O
+normal	O
+serum	O
+sodium	O
+levels	O
+returned	O
+","	O
+further	O
+doxorubicin	O
+and	O
+dexamethasone	O
+chemotherapy	O
+without	O
+vincristine	O
+did	O
+not	O
+produce	O
+this	O
+complication	O
+.	O
+	
+Heart	B-NP
+failure	I-NP
+:	O
+to	O
+digitalise	O
+or	O
+not	O
+?	O
+	
+The	O
+view	O
+against	O
+.	O
+	
+Despite	O
+extensive	O
+clinical	O
+experience	O
+the	O
+role	O
+of	O
+digoxin	O
+is	O
+still	O
+not	O
+well	O
+defined	O
+.	O
+	
+In	O
+patients	O
+with	O
+atrial	B-NP
+fibrillation	I-NP
+digoxin	O
+is	O
+beneficial	O
+for	O
+ventricular	O
+rate	O
+control	O
+.	O
+	
+For	O
+patients	O
+in	O
+sinus	O
+rhythm	O
+and	O
+heart	B-NP
+failure	I-NP
+the	O
+situation	O
+is	O
+less	O
+clear	O
+.	O
+	
+Digoxin	O
+has	O
+a	O
+narrow	O
+therapeutic	O
+:	O
+toxic	O
+ratio	O
+and	O
+concentrations	O
+are	O
+affected	O
+by	O
+a	O
+number	O
+of	O
+drugs	O
+.	O
+	
+Also	O
+","	O
+digoxin	O
+has	O
+undesirable	O
+effects	O
+such	O
+as	O
+increasing	O
+peripheral	O
+resistance	O
+and	O
+myocardial	O
+demands	O
+","	O
+and	O
+causing	O
+arrhythmias	B-NP
+.	O
+	
+There	O
+is	O
+a	O
+paucity	O
+of	O
+data	O
+from	O
+well	O
+-	O
+designed	O
+trials	O
+.	O
+	
+The	O
+trials	O
+that	O
+are	O
+available	O
+are	O
+generally	O
+small	O
+with	O
+limitations	O
+in	O
+design	O
+and	O
+these	O
+show	O
+variation	O
+in	O
+patient	O
+benefit	O
+.	O
+	
+More	O
+convincing	O
+evidence	O
+is	O
+required	O
+showing	O
+that	O
+digoxin	O
+improves	O
+symptoms	O
+or	O
+exercise	O
+capacity	O
+.	O
+	
+Furthermore	O
+","	O
+no	O
+trial	O
+has	O
+had	O
+sufficient	O
+power	O
+to	O
+evaluate	O
+mortality	O
+.	O
+	
+Pooled	O
+analysis	O
+of	O
+the	O
+effects	O
+of	O
+other	O
+inotropic	O
+drugs	O
+shows	O
+an	O
+excess	O
+mortality	O
+and	O
+there	O
+is	O
+a	O
+possibility	O
+that	O
+digoxin	O
+may	O
+increase	O
+mortality	O
+after	O
+myocardial	B-NP
+infarction	I-NP
+(	O
+MI	B-NP
+)	O
+.	O
+	
+Angiotensin	O
+-	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+inhibitors	O
+should	O
+be	O
+used	O
+first	O
+as	O
+they	O
+are	O
+safer	O
+","	O
+do	O
+not	O
+require	O
+blood	O
+level	O
+monitoring	O
+","	O
+modify	O
+progression	O
+of	O
+disease	O
+","	O
+relieve	O
+symptoms	O
+","	O
+improve	O
+exercise	O
+tolerance	O
+and	O
+reduce	O
+mortality	O
+.	O
+	
+Caution	O
+should	O
+be	O
+exercised	O
+in	O
+using	O
+digoxin	O
+until	O
+large	O
+mortality	O
+trials	O
+are	O
+completed	O
+showing	O
+either	O
+benefit	O
+or	O
+harm	O
+.	O
+	
+Until	O
+then	O
+digoxin	O
+should	O
+be	O
+considered	O
+a	O
+third	O
+-	O
+line	O
+therapy	O
+.	O
+	
+Isradipine	O
+treatment	O
+for	O
+hypertension	B-NP
+in	O
+general	O
+practice	O
+in	O
+Hong	O
+Kong	O
+.	O
+	
+A	O
+6	O
+-	O
+week	O
+open	O
+study	O
+of	O
+the	O
+introduction	O
+of	O
+isradipine	O
+treatment	O
+was	O
+conducted	O
+in	O
+general	O
+practice	O
+in	O
+Hong	O
+Kong	O
+.	O
+	
+303	O
+Chinese	O
+patients	O
+with	O
+mild	O
+to	O
+moderate	O
+hypertension	B-NP
+entered	O
+the	O
+study	O
+.	O
+	
+Side	O
+effects	O
+were	O
+reported	O
+in	O
+21	O
+%	O
+of	O
+patients	O
+and	O
+caused	O
+withdrawal	O
+from	O
+the	O
+study	O
+in	O
+3	O
+patients	O
+.	O
+	
+The	O
+main	O
+side	O
+-	O
+effects	O
+were	O
+headache	B-NP
+","	O
+dizziness	B-NP
+","	O
+palpitation	B-NP
+and	O
+flushing	B-NP
+and	O
+these	O
+were	O
+not	O
+more	O
+frequent	O
+than	O
+reported	O
+in	O
+other	O
+studies	O
+with	O
+isradipine	O
+or	O
+with	O
+placebo	O
+.	O
+	
+Supine	O
+blood	O
+pressure	O
+was	O
+reduced	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+from	O
+170	O
++	O
+/	O
+-	O
+20	O
+/	O
+102	O
++	O
+/	O
+-	O
+6	O
+mmHg	O
+to	O
+153	O
++	O
+/	O
+-	O
+19	O
+/	O
+92	O
++	O
+/	O
+-	O
+8	O
+","	O
+147	O
++	O
+/	O
+-	O
+18	O
+/	O
+88	O
++	O
+/	O
+-	O
+7	O
+and	O
+144	O
++	O
+/	O
+-	O
+14	O
+/	O
+87	O
++	O
+/	O
+-	O
+6	O
+mmHg	O
+at	O
+2	O
+","	O
+4	O
+and	O
+6	O
+weeks	O
+respectively	O
+in	O
+evaluable	O
+patients	O
+.	O
+	
+Similar	O
+reductions	O
+occurred	O
+in	O
+standing	O
+blood	O
+pressure	O
+and	O
+there	O
+was	O
+no	O
+evidence	O
+of	O
+postural	B-NP
+hypotension	I-NP
+.	O
+	
+Normalization	O
+and	O
+responder	O
+rates	O
+at	O
+6	O
+weeks	O
+were	O
+86	O
+%	O
+and	O
+69	O
+%	O
+respectively	O
+.	O
+	
+Dosage	O
+was	O
+increased	O
+from	O
+2	O
+.	O
+5	O
+mg	O
+b	O
+.	O
+d	O
+.	O
+to	O
+5	O
+mg	O
+b	O
+.	O
+d	O
+.	O
+at	O
+4	O
+weeks	O
+in	O
+patients	O
+with	O
+diastolic	O
+blood	O
+pressure	O
+greater	O
+than	O
+90	O
+mmHg	O
+and	O
+their	O
+further	O
+response	O
+was	O
+greater	O
+than	O
+those	O
+remaining	O
+on	O
+2	O
+.	O
+5	O
+mg	O
+b	O
+.	O
+d	O
+.	O
+	
+Pharmacological	O
+characteristics	O
+and	O
+side	O
+effects	O
+of	O
+a	O
+new	O
+galenic	O
+formulation	O
+of	O
+propofol	O
+without	O
+soyabean	O
+oil	O
+.	O
+	
+We	O
+compared	O
+the	O
+pharmacokinetics	O
+","	O
+pharmacodynamics	O
+and	O
+safety	O
+profile	O
+of	O
+a	O
+new	O
+galenic	O
+formulation	O
+of	O
+propofol	O
+(	O
+AM149	O
+1	O
+%	O
+)	O
+","	O
+which	O
+does	O
+not	O
+contain	O
+soyabean	O
+oil	O
+","	O
+with	O
+a	O
+standard	O
+formulation	O
+of	O
+propofol	O
+(	O
+Disoprivan	O
+1	O
+%	O
+)	O
+.	O
+	
+In	O
+a	O
+randomised	O
+","	O
+double	O
+-	O
+blind	O
+","	O
+cross	O
+-	O
+over	O
+study	O
+","	O
+30	O
+healthy	O
+volunteers	O
+received	O
+a	O
+single	O
+intravenous	O
+bolus	O
+injection	O
+of	O
+2	O
+.	O
+5	O
+mg	O
+.	O
+kg	O
+-	O
+1	O
+propofol	O
+.	O
+	
+Plasma	O
+propofol	O
+levels	O
+were	O
+measured	O
+for	O
+48	O
+h	O
+following	O
+drug	O
+administration	O
+and	O
+evaluated	O
+according	O
+to	O
+a	O
+three	O
+-	O
+compartment	O
+model	O
+.	O
+	
+The	O
+pharmacodynamic	O
+parameters	O
+assessed	O
+included	O
+induction	O
+and	O
+emergence	O
+times	O
+","	O
+respiratory	O
+and	O
+cardiovascular	O
+effects	O
+","	O
+and	O
+pain	B-NP
+on	O
+injection	O
+.	O
+	
+Patients	O
+were	O
+monitored	O
+for	O
+side	O
+effects	O
+over	O
+48	O
+h	O
+.	O
+	
+Owing	O
+to	O
+a	O
+high	O
+incidence	O
+of	O
+thrombophlebitis	B-NP
+","	O
+the	O
+study	O
+was	O
+terminated	O
+prematurely	O
+and	O
+only	O
+the	O
+data	O
+of	O
+the	O
+two	O
+parallel	O
+treatment	O
+groups	O
+(	O
+15	O
+patients	O
+in	O
+each	O
+group	O
+)	O
+were	O
+analysed	O
+.	O
+	
+Plasma	O
+concentrations	O
+did	O
+not	O
+differ	O
+significantly	O
+between	O
+the	O
+two	O
+formulations	O
+.	O
+	
+Anaesthesia	O
+induction	O
+and	O
+emergence	O
+times	O
+","	O
+respiratory	O
+and	O
+cardiovascular	O
+variables	O
+showed	O
+no	O
+significant	O
+differences	O
+between	O
+the	O
+two	O
+treatment	O
+groups	O
+.	O
+	
+Pain	B-NP
+on	O
+injection	O
+(	O
+80	O
+vs	O
+.	O
+20	O
+%	O
+","	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+and	O
+thrombophlebitis	B-NP
+(	O
+93	O
+.	O
+3	O
+vs	O
+.	O
+6	O
+.	O
+6	O
+%	O
+","	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+occurred	O
+more	O
+frequently	O
+with	O
+AM149	O
+than	O
+with	O
+Disoprivan	O
+.	O
+	
+Although	O
+both	O
+formulations	O
+had	O
+similar	O
+pharmacokinetic	O
+and	O
+pharmacodynamic	O
+profiles	O
+the	O
+new	O
+formulation	O
+is	O
+not	O
+suitable	O
+for	O
+clinical	O
+use	O
+due	O
+to	O
+the	O
+high	O
+incidence	O
+of	O
+thrombophlebitis	B-NP
+produced	O
+.	O
+	
+Pure	B-NP
+red	I-NP
+cell	I-NP
+aplasia	I-NP
+","	O
+toxic	B-NP
+dermatitis	I-NP
+and	O
+lymphadenopathy	B-NP
+in	O
+a	O
+patient	O
+taking	O
+diphenylhydantoin	O
+.	O
+	
+A	O
+patient	O
+taking	O
+diphenylhydantoin	O
+for	O
+3	O
+weeks	O
+developed	O
+a	O
+generalized	O
+skin	B-NP
+rash	I-NP
+","	O
+lymphadenopathy	B-NP
+and	O
+pure	B-NP
+red	I-NP
+cell	I-NP
+aplasia	I-NP
+.	O
+	
+After	O
+withdrawal	O
+of	O
+the	O
+pharmacon	O
+all	O
+symptoms	O
+disappeared	O
+spontaneously	O
+.	O
+	
+Skin	B-NP
+rash	I-NP
+is	O
+a	O
+well	O
+-	O
+known	O
+complication	O
+of	O
+diphenylhydantoin	O
+treatment	O
+as	O
+is	O
+benign	O
+and	O
+malignant	O
+lymphadenopathy	B-NP
+.	O
+	
+Pure	B-NP
+red	I-NP
+cell	I-NP
+aplasia	I-NP
+associated	O
+with	O
+diphenylhydantoin	O
+medication	O
+has	O
+been	O
+reported	O
+in	O
+3	O
+patients	O
+.	O
+	
+The	O
+exact	O
+mechanism	O
+by	O
+which	O
+diphenylhydantoin	O
+exerts	O
+its	O
+toxic	O
+effects	O
+is	O
+not	O
+known	O
+.	O
+	
+In	O
+this	O
+patient	O
+the	O
+time	O
+relation	O
+between	O
+the	O
+ingestion	O
+of	O
+diphenylhydantoin	O
+and	O
+the	O
+occurrence	O
+of	O
+the	O
+skin	B-NP
+rash	I-NP
+","	O
+lymphadenopathy	B-NP
+and	O
+pure	B-NP
+red	I-NP
+cell	I-NP
+aplasia	I-NP
+is	O
+very	O
+suggestive	O
+of	O
+a	O
+direct	O
+connection	O
+.	O
+	
+Vinorelbine	O
+-	O
+related	O
+cardiac	O
+events	O
+:	O
+a	O
+meta	O
+-	O
+analysis	O
+of	O
+randomized	O
+clinical	O
+trials	O
+.	O
+	
+Several	O
+cases	O
+of	O
+cardiac	O
+adverse	O
+reactions	O
+related	O
+to	O
+vinorelbine	O
+(	O
+VNR	O
+)	O
+have	O
+been	O
+reported	O
+in	O
+the	O
+literature	O
+.	O
+	
+In	O
+order	O
+to	O
+quantify	O
+the	O
+incidence	O
+of	O
+these	O
+cardiac	O
+events	O
+","	O
+we	O
+performed	O
+a	O
+meta	O
+-	O
+analysis	O
+of	O
+clinical	O
+trials	O
+comparing	O
+VNR	O
+with	O
+other	O
+chemotherapeutic	O
+agents	O
+in	O
+the	O
+treatment	O
+of	O
+various	O
+malignancies	B-NP
+.	O
+	
+Randomized	O
+clinical	O
+trials	O
+comparing	O
+VNR	O
+with	O
+other	O
+drugs	O
+in	O
+the	O
+treatment	O
+of	O
+cancer	B-NP
+were	O
+searched	O
+in	O
+Medline	O
+","	O
+Embase	O
+","	O
+Evidence	O
+-	O
+based	O
+Medicine	O
+Reviews	O
+databases	O
+and	O
+the	O
+Cochrane	O
+library	O
+from	O
+1987	O
+to	O
+2002	O
+.	O
+	
+Outcomes	O
+of	O
+interest	O
+were	O
+severe	O
+cardiac	O
+events	O
+","	O
+toxic	O
+deaths	O
+and	O
+cardiac	O
+event	O
+-	O
+related	O
+deaths	O
+reported	O
+in	O
+each	O
+publication	O
+.	O
+	
+We	O
+found	O
+19	O
+trials	O
+","	O
+involving	O
+2441	O
+patients	O
+treated	O
+by	O
+VNR	O
+and	O
+2050	O
+control	O
+patients	O
+.	O
+	
+The	O
+incidence	O
+of	O
+cardiac	O
+events	O
+with	O
+VNR	O
+was	O
+1	O
+.	O
+19	O
+%	O
+[	O
+95	O
+%	O
+confidence	O
+interval	O
+(	O
+CI	O
+)	O
+(	O
+0	O
+.	O
+75	O
+;	O
+1	O
+.	O
+67	O
+)	O
+]	O
+.	O
+	
+There	O
+was	O
+no	O
+difference	O
+in	O
+the	O
+risk	O
+of	O
+cardiac	O
+events	O
+between	O
+VNR	O
+and	O
+other	O
+drugs	O
+[	O
+odds	O
+ratio	O
+:	O
+0	O
+.	O
+92	O
+","	O
+95	O
+%	O
+CI	O
+(	O
+0	O
+.	O
+54	O
+;	O
+1	O
+.	O
+55	O
+)	O
+]	O
+.	O
+	
+The	O
+risk	O
+of	O
+VNR	O
+cardiac	O
+events	O
+was	O
+similar	O
+to	O
+vindesine	O
+(	O
+VDS	O
+)	O
+and	O
+other	O
+cardiotoxic	B-NP
+drugs	O
+[	O
+fluorouracil	O
+","	O
+anthracyclines	O
+","	O
+gemcitabine	O
+(	O
+GEM	O
+)	O
+em	O
+leader	O
+]	O
+.	O
+	
+Even	O
+if	O
+it	O
+did	O
+not	O
+reach	O
+statistical	O
+significance	O
+because	O
+of	O
+a	O
+few	O
+number	O
+of	O
+cases	O
+","	O
+the	O
+risk	O
+was	O
+lower	O
+in	O
+trials	O
+excluding	O
+patients	O
+with	O
+cardiac	O
+history	O
+","	O
+and	O
+seemed	O
+to	O
+be	O
+higher	O
+in	O
+trials	O
+including	O
+patients	O
+with	O
+pre	O
+-	O
+existing	O
+cardiac	B-NP
+diseases	I-NP
+.	O
+	
+Vinorelbine	O
+-	O
+related	O
+cardiac	O
+events	O
+concern	O
+about	O
+1	O
+%	O
+of	O
+treated	O
+patients	O
+in	O
+clinical	O
+trials	O
+.	O
+	
+However	O
+","	O
+the	O
+risk	O
+associated	O
+with	O
+VNR	O
+seems	O
+to	O
+be	O
+similar	O
+to	O
+that	O
+of	O
+other	O
+chemotherapeutic	O
+agents	O
+in	O
+the	O
+same	O
+indications	O
+.	O
+	
+MRI	O
+findings	O
+of	O
+hypoxic	O
+cortical	O
+laminar	O
+necrosis	B-NP
+in	O
+a	O
+child	O
+with	O
+hemolytic	B-NP
+anemia	I-NP
+crisis	O
+.	O
+	
+We	O
+present	O
+magnetic	O
+resonance	O
+imaging	O
+findings	O
+of	O
+a	O
+5	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+who	O
+had	O
+a	O
+rapidly	O
+installing	O
+hemolytic	B-NP
+anemia	I-NP
+crisis	O
+induced	O
+by	O
+trimethoprim	O
+-	O
+sulfomethoxazole	O
+","	O
+resulting	O
+in	O
+cerebral	B-NP
+anoxia	I-NP
+leading	O
+to	O
+permanent	O
+damage	O
+.	O
+	
+Magnetic	O
+Resonance	O
+imaging	O
+revealed	O
+cortical	O
+laminar	O
+necrosis	B-NP
+in	O
+arterial	O
+border	O
+zones	O
+in	O
+both	O
+cerebral	O
+hemispheres	O
+","	O
+ischemic	O
+changes	O
+in	O
+subcortical	O
+white	O
+matter	O
+of	O
+left	O
+cerebral	O
+hemisphere	O
+","	O
+and	O
+in	O
+the	O
+left	O
+putamen	O
+.	O
+	
+Although	O
+cortical	O
+laminar	O
+necrosis	B-NP
+is	O
+a	O
+classic	O
+entity	O
+in	O
+adulthood	O
+related	O
+to	O
+conditions	O
+of	O
+energy	O
+depletions	O
+","	O
+there	O
+are	O
+few	O
+reports	O
+available	O
+in	O
+children	O
+.	O
+	
+A	O
+wide	O
+review	O
+of	O
+the	O
+literature	O
+is	O
+also	O
+presented	O
+.	O
+	
+The	O
+natural	O
+history	O
+of	O
+Vigabatrin	O
+associated	O
+visual	B-NP
+field	I-NP
+defects	I-NP
+in	O
+patients	O
+electing	O
+to	O
+continue	O
+their	O
+medication	O
+.	O
+	
+PURPOSE	O
+:	O
+To	O
+determine	O
+the	O
+natural	O
+history	O
+of	O
+visual	B-NP
+field	I-NP
+defects	I-NP
+in	O
+a	O
+group	O
+of	O
+patients	O
+known	O
+to	O
+have	O
+Vigabatrin	O
+-	O
+associated	O
+changes	O
+who	O
+elected	O
+to	O
+continue	O
+the	O
+medication	O
+because	O
+of	O
+good	O
+seizure	B-NP
+control	O
+.	O
+	
+METHODS	O
+:	O
+All	O
+patients	O
+taking	O
+Vigabatrin	O
+alone	O
+or	O
+in	O
+combination	O
+with	O
+other	O
+antiepileptic	O
+drugs	O
+for	O
+at	O
+least	O
+5	O
+years	O
+(	O
+range	O
+5	O
+-	O
+12	O
+years	O
+)	O
+were	O
+entered	O
+into	O
+a	O
+visual	O
+surveillance	O
+programme	O
+.	O
+	
+Patients	O
+were	O
+followed	O
+up	O
+at	O
+6	O
+-	O
+monthly	O
+intervals	O
+for	O
+not	O
+less	O
+than	O
+18	O
+months	O
+(	O
+range	O
+18	O
+-	O
+43	O
+months	O
+)	O
+.	O
+	
+In	O
+all	O
+","	O
+16	O
+patients	O
+with	O
+unequivocal	O
+defects	O
+continued	O
+the	O
+medication	O
+.	O
+	
+Following	O
+already	O
+published	O
+methodology	O
+(	O
+Eye	O
+2002	O
+;	O
+16	O
+;	O
+567	O
+-	O
+571	O
+)	O
+monocular	O
+mean	O
+radial	O
+degrees	O
+(	O
+MRDs	O
+)	O
+to	O
+the	O
+I	O
+/	O
+4e	O
+isopter	O
+on	O
+Goldmann	O
+perimetry	O
+was	O
+calculated	O
+for	O
+the	O
+right	O
+eye	O
+at	O
+the	O
+time	O
+of	O
+discovery	O
+of	O
+a	O
+visual	B-NP
+field	I-NP
+defect	I-NP
+and	O
+again	O
+after	O
+not	O
+less	O
+than	O
+18	O
+months	O
+follow	O
+-	O
+up	O
+.	O
+	
+RESULTS	O
+:	O
+Mean	O
+right	O
+eye	O
+MRD	O
+at	O
+presentation	O
+was	O
+36	O
+.	O
+98	O
+degrees	O
+(	O
+range	O
+22	O
+.	O
+25	O
+-	O
+51	O
+.	O
+0	O
+)	O
+","	O
+compared	O
+to	O
+38	O
+.	O
+40	O
+degrees	O
+(	O
+range	O
+22	O
+.	O
+5	O
+-	O
+49	O
+.	O
+75	O
+)	O
+after	O
+follow	O
+-	O
+up	O
+;	O
+P	O
+=	O
+0	O
+.	O
+338	O
+unpaired	O
+t	O
+-	O
+test	O
+.	O
+	
+Only	O
+one	O
+patient	O
+demonstrated	O
+a	O
+deterioration	B-NP
+in	I-NP
+visual	I-NP
+field	I-NP
+during	O
+the	O
+study	O
+period	O
+and	O
+discontinued	O
+treatment	O
+.	O
+	
+CONCLUSION	O
+:	O
+Established	O
+visual	B-NP
+field	I-NP
+defects	I-NP
+presumed	O
+to	O
+be	O
+due	O
+to	O
+Vigabatrin	O
+therapy	O
+did	O
+not	O
+usually	O
+progress	O
+in	O
+spite	O
+of	O
+continuing	O
+use	O
+of	O
+the	O
+medication	O
+.	O
+	
+These	O
+data	O
+give	O
+support	O
+to	O
+the	O
+hypothesis	O
+that	O
+the	O
+pathogenesis	O
+of	O
+Vigabatrin	O
+-	O
+associated	O
+visual	B-NP
+field	I-NP
+defects	I-NP
+may	O
+be	O
+an	O
+idiosyncratic	O
+adverse	O
+drug	O
+reaction	O
+rather	O
+than	O
+dose	O
+-	O
+dependent	O
+toxicity	B-NP
+.	O
+	
+Induction	O
+of	O
+rosaceiform	O
+dermatitis	B-NP
+during	O
+treatment	O
+of	O
+facial	B-NP
+inflammatory	I-NP
+dermatoses	I-NP
+with	O
+tacrolimus	O
+ointment	O
+.	O
+	
+BACKGROUND	O
+:	O
+Tacrolimus	O
+ointment	O
+is	O
+increasingly	O
+used	O
+for	O
+anti	O
+-	O
+inflammatory	O
+treatment	O
+of	O
+sensitive	O
+areas	O
+such	O
+as	O
+the	O
+face	O
+","	O
+and	O
+recent	O
+observations	O
+indicate	O
+that	O
+the	O
+treatment	O
+is	O
+effective	O
+in	O
+steroid	O
+-	O
+aggravated	O
+rosacea	B-NP
+and	O
+perioral	B-NP
+dermatitis	I-NP
+.	O
+	
+We	O
+report	O
+on	O
+rosaceiform	O
+dermatitis	B-NP
+as	O
+a	O
+complication	O
+of	O
+treatment	O
+with	O
+tacrolimus	O
+ointment	O
+.	O
+	
+OBSERVATIONS	O
+:	O
+Six	O
+adult	O
+patients	O
+with	O
+inflammatory	B-NP
+facial	I-NP
+dermatoses	I-NP
+were	O
+treated	O
+with	O
+tacrolimus	O
+ointment	O
+because	O
+of	O
+the	O
+ineffectiveness	O
+of	O
+standard	O
+treatments	O
+.	O
+	
+Within	O
+2	O
+to	O
+3	O
+weeks	O
+of	O
+initially	O
+effective	O
+and	O
+well	O
+-	O
+tolerated	O
+treatment	O
+","	O
+3	O
+patients	O
+with	O
+a	O
+history	O
+of	O
+rosacea	B-NP
+and	O
+1	O
+with	O
+a	O
+history	O
+of	O
+acne	B-NP
+experienced	O
+sudden	O
+worsening	O
+with	O
+pustular	O
+rosaceiform	O
+lesions	O
+.	O
+	
+Biopsy	O
+revealed	O
+an	O
+abundance	O
+of	O
+Demodex	O
+mites	O
+in	O
+2	O
+of	O
+these	O
+patients	O
+.	O
+	
+In	O
+1	O
+patient	O
+with	O
+eyelid	O
+eczema	B-NP
+","	O
+rosaceiform	O
+periocular	B-NP
+dermatitis	I-NP
+gradually	O
+appeared	O
+after	O
+3	O
+weeks	O
+of	O
+treatment	O
+.	O
+	
+In	O
+1	O
+patient	O
+with	O
+atopic	B-NP
+dermatitis	I-NP
+","	O
+telangiectatic	O
+and	O
+papular	B-NP
+rosacea	I-NP
+insidiously	O
+appeared	O
+after	O
+5	O
+months	O
+of	O
+treatment	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Our	O
+observations	O
+suggest	O
+that	O
+the	O
+spectrum	O
+of	O
+rosaceiform	O
+dermatitis	B-NP
+as	O
+a	O
+complication	O
+of	O
+treatment	O
+with	O
+tacrolimus	O
+ointment	O
+is	O
+heterogeneous	O
+.	O
+	
+A	O
+variety	O
+of	O
+factors	O
+","	O
+such	O
+as	O
+vasoactive	O
+properties	O
+of	O
+tacrolimus	O
+","	O
+proliferation	O
+of	O
+Demodex	O
+due	O
+to	O
+local	O
+immunosuppression	O
+","	O
+and	O
+the	O
+occlusive	O
+properties	O
+of	O
+the	O
+ointment	O
+","	O
+may	O
+be	O
+involved	O
+in	O
+the	O
+observed	O
+phenomena	O
+.	O
+	
+Future	O
+studies	O
+are	O
+needed	O
+to	O
+identify	O
+individual	O
+risk	O
+factors	O
+.	O
+	
+Intravascular	O
+hemolysis	B-NP
+and	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+following	O
+intermittent	O
+rifampin	O
+therapy	O
+.	O
+	
+Renal	B-NP
+failure	I-NP
+is	O
+a	O
+rare	O
+complication	O
+associated	O
+with	O
+the	O
+use	O
+of	O
+rifampin	O
+.	O
+	
+Intravascular	O
+hemolysis	B-NP
+leading	O
+to	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+following	O
+rifampin	O
+therapy	O
+is	O
+extremely	O
+rare	O
+.	O
+	
+Two	O
+patients	O
+with	O
+leprosy	B-NP
+who	O
+developed	O
+hemolysis	B-NP
+and	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+following	O
+rifampin	O
+are	O
+reported	O
+.	O
+	
+Structural	O
+abnormalities	O
+in	O
+the	O
+brains	O
+of	O
+human	O
+subjects	O
+who	O
+use	O
+methamphetamine	O
+.	O
+	
+We	O
+visualize	O
+","	O
+for	O
+the	O
+first	O
+time	O
+","	O
+the	O
+profile	O
+of	O
+structural	B-NP
+deficits	I-NP
+in	I-NP
+the	I-NP
+human	I-NP
+brain	I-NP
+associated	O
+with	O
+chronic	O
+methamphetamine	O
+(	O
+MA	O
+)	O
+abuse	O
+.	O
+	
+Studies	O
+of	O
+human	O
+subjects	O
+who	O
+have	O
+used	O
+MA	O
+chronically	O
+have	O
+revealed	O
+deficits	O
+in	O
+dopaminergic	O
+and	O
+serotonergic	O
+systems	O
+and	O
+cerebral	O
+metabolic	B-NP
+abnormalities	I-NP
+.	O
+	
+Using	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+and	O
+new	O
+computational	O
+brain	O
+-	O
+mapping	O
+techniques	O
+","	O
+we	O
+determined	O
+the	O
+pattern	O
+of	O
+structural	O
+brain	O
+alterations	O
+associated	O
+with	O
+chronic	O
+MA	O
+abuse	O
+in	O
+human	O
+subjects	O
+and	O
+related	O
+these	O
+deficits	O
+to	O
+cognitive	B-NP
+impairment	I-NP
+.	O
+	
+We	O
+used	O
+high	O
+-	O
+resolution	O
+MRI	O
+and	O
+surface	O
+-	O
+based	O
+computational	O
+image	O
+analyses	O
+to	O
+map	O
+regional	O
+abnormalities	B-NP
+in	I-NP
+the	I-NP
+cortex	I-NP
+","	I-NP
+hippocampus	I-NP
+","	I-NP
+white	I-NP
+matter	I-NP
+","	I-NP
+and	I-NP
+ventricles	I-NP
+in	O
+22	O
+human	O
+subjects	O
+who	O
+used	O
+MA	O
+and	O
+21	O
+age	O
+-	O
+matched	O
+","	O
+healthy	O
+controls	O
+.	O
+	
+Cortical	O
+maps	O
+revealed	O
+severe	O
+gray	O
+-	O
+matter	O
+deficits	O
+in	O
+the	O
+cingulate	O
+","	O
+limbic	O
+","	O
+and	O
+paralimbic	O
+cortices	O
+of	O
+MA	O
+abusers	O
+(	O
+averaging	O
+11	O
+.	O
+3	O
+%	O
+below	O
+control	O
+;	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+On	O
+average	O
+","	O
+MA	O
+abusers	O
+had	O
+7	O
+.	O
+8	O
+%	O
+smaller	O
+hippocampal	O
+volumes	O
+than	O
+control	O
+subjects	O
+(	O
+p	O
+<	O
+0	O
+.	O
+1	O
+;	O
+left	O
+","	O
+p	O
+=	O
+0	O
+.	O
+1	O
+;	O
+right	O
+","	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+and	O
+significant	O
+white	O
+-	O
+matter	O
+hypertrophy	B-NP
+(	O
+7	O
+.	O
+0	O
+%	O
+;	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Hippocampal	O
+deficits	O
+were	O
+mapped	O
+and	O
+correlated	O
+with	O
+memory	O
+performance	O
+on	O
+a	O
+word	O
+-	O
+recall	O
+test	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+MRI	O
+-	O
+based	O
+maps	O
+suggest	O
+that	O
+chronic	O
+methamphetamine	O
+abuse	O
+causes	O
+a	O
+selective	O
+pattern	O
+of	O
+cerebral	O
+deterioration	O
+that	O
+contributes	O
+to	O
+impaired	B-NP
+memory	I-NP
+performance	I-NP
+.	O
+	
+MA	O
+may	O
+selectively	O
+damage	O
+the	O
+medial	O
+temporal	O
+lobe	O
+and	O
+","	O
+consistent	O
+with	O
+metabolic	O
+studies	O
+","	O
+the	O
+cingulate	O
+-	O
+limbic	O
+cortex	O
+","	O
+inducing	O
+neuroadaptation	O
+","	O
+neuropil	O
+reduction	O
+","	O
+or	O
+cell	O
+death	O
+.	O
+	
+Prominent	O
+white	O
+-	O
+matter	O
+hypertrophy	B-NP
+may	O
+result	O
+from	O
+altered	O
+myelination	O
+and	O
+adaptive	O
+glial	O
+changes	O
+","	O
+including	O
+gliosis	B-NP
+secondary	O
+to	O
+neuronal	B-NP
+damage	I-NP
+.	O
+	
+These	O
+brain	O
+substrates	O
+may	O
+help	O
+account	O
+for	O
+the	O
+symptoms	O
+of	O
+MA	O
+abuse	O
+","	O
+providing	O
+therapeutic	O
+targets	O
+for	O
+drug	O
+-	O
+induced	O
+brain	B-NP
+injury	I-NP
+.	O
+	
+Disruption	O
+of	O
+hepatic	O
+lipid	O
+homeostasis	O
+in	O
+mice	O
+after	O
+amiodarone	O
+treatment	O
+is	O
+associated	O
+with	O
+peroxisome	O
+proliferator	O
+-	O
+activated	O
+receptor	O
+-	O
+alpha	O
+target	O
+gene	O
+activation	O
+.	O
+	
+Amiodarone	O
+","	O
+an	O
+efficacious	O
+and	O
+widely	O
+used	O
+antiarrhythmic	O
+agent	O
+","	O
+has	O
+been	O
+reported	O
+to	O
+cause	O
+hepatotoxicity	B-NP
+in	O
+some	O
+patients	O
+.	O
+	
+To	O
+gain	O
+insight	O
+into	O
+the	O
+mechanism	O
+of	O
+this	O
+unwanted	O
+effect	O
+","	O
+mice	O
+were	O
+administered	O
+various	O
+doses	O
+of	O
+amiodarone	O
+and	O
+examined	O
+for	O
+changes	O
+in	O
+hepatic	O
+histology	O
+and	O
+gene	O
+regulation	O
+.	O
+	
+Amiodarone	O
+induced	O
+hepatomegaly	B-NP
+","	O
+hepatocyte	O
+microvesicular	O
+lipid	O
+accumulation	O
+","	O
+and	O
+a	O
+significant	O
+decrease	O
+in	O
+serum	O
+triglycerides	O
+and	O
+glucose	O
+.	O
+	
+Northern	O
+blot	O
+analysis	O
+of	O
+hepatic	O
+RNA	O
+revealed	O
+a	O
+dose	O
+-	O
+dependent	O
+increase	O
+in	O
+the	O
+expression	O
+of	O
+a	O
+number	O
+of	O
+genes	O
+critical	O
+for	O
+fatty	O
+acid	O
+oxidation	O
+","	O
+lipoprotein	O
+assembly	O
+","	O
+and	O
+lipid	O
+transport	O
+.	O
+	
+Many	O
+of	O
+these	O
+genes	O
+are	O
+regulated	O
+by	O
+the	O
+peroxisome	O
+proliferator	O
+-	O
+activated	O
+receptor	O
+-	O
+alpha	O
+(	O
+PPARalpha	O
+)	O
+","	O
+a	O
+ligand	O
+-	O
+activated	O
+nuclear	O
+hormone	O
+receptor	O
+transcription	O
+factor	O
+.	O
+	
+The	O
+absence	O
+of	O
+induction	O
+of	O
+these	O
+genes	O
+as	O
+well	O
+as	O
+hepatomegaly	B-NP
+in	O
+PPARalpha	O
+knockout	O
+[	O
+PPARalpha	O
+-	O
+/	O
+-	O
+]	O
+mice	O
+indicated	O
+that	O
+the	O
+effects	O
+of	O
+amiodarone	O
+were	O
+dependent	O
+upon	O
+the	O
+presence	O
+of	O
+a	O
+functional	O
+PPARalpha	O
+gene	O
+.	O
+	
+Compared	O
+to	O
+wild	O
+-	O
+type	O
+mice	O
+","	O
+treatment	O
+of	O
+PPARalpha	O
+-	O
+/	O
+-	O
+mice	O
+with	O
+amiodarone	O
+resulted	O
+in	O
+an	O
+increased	O
+rate	O
+and	O
+extent	O
+of	O
+total	O
+body	O
+weight	B-NP
+loss	I-NP
+.	O
+	
+The	O
+inability	O
+of	O
+amiodarone	O
+to	O
+directly	O
+activate	O
+either	O
+human	O
+or	O
+mouse	O
+PPARalpha	O
+transiently	O
+expressed	O
+in	O
+human	O
+HepG2	O
+hepatoma	B-NP
+cells	O
+indicates	O
+that	O
+the	O
+effects	O
+of	O
+amiodarone	O
+on	O
+the	O
+function	O
+of	O
+this	O
+receptor	O
+were	O
+indirect	O
+.	O
+	
+Based	O
+upon	O
+these	O
+results	O
+","	O
+we	O
+conclude	O
+that	O
+amiodarone	O
+disrupts	O
+hepatic	O
+lipid	O
+homeostasis	O
+and	O
+that	O
+the	O
+increased	O
+expression	O
+of	O
+PPARalpha	O
+target	O
+genes	O
+is	O
+secondary	O
+to	O
+this	O
+toxic	O
+effect	O
+.	O
+	
+These	O
+results	O
+provide	O
+important	O
+new	O
+mechanistic	O
+information	O
+regarding	O
+the	O
+hepatotoxic	B-NP
+effects	O
+of	O
+amiodarone	O
+and	O
+indicate	O
+that	O
+PPARalpha	O
+protects	O
+against	O
+amiodarone	O
+-	O
+induced	O
+hepatotoxicity	B-NP
+.	O
+	
+Safety	O
+and	O
+compliance	O
+with	O
+once	O
+-	O
+daily	O
+niacin	O
+extended	O
+-	O
+release	O
+/	O
+lovastatin	O
+as	O
+initial	O
+therapy	O
+in	O
+the	O
+Impact	O
+of	O
+Medical	O
+Subspecialty	O
+on	O
+Patient	O
+Compliance	O
+to	O
+Treatment	O
+(	O
+IMPACT	O
+)	O
+study	O
+.	O
+	
+Niacin	O
+extended	O
+-	O
+release	O
+/	O
+lovastatin	O
+is	O
+a	O
+new	O
+combination	O
+product	O
+approved	O
+for	O
+treatment	O
+of	O
+primary	O
+hypercholesterolemia	B-NP
+and	O
+mixed	O
+dyslipidemia	B-NP
+.	O
+	
+This	O
+open	O
+-	O
+labeled	O
+","	O
+multicenter	O
+study	O
+evaluated	O
+the	O
+safety	O
+of	O
+bedtime	O
+niacin	O
+extended	O
+-	O
+release	O
+/	O
+lovastatin	O
+when	O
+dosed	O
+as	O
+initial	O
+therapy	O
+and	O
+patient	O
+compliance	O
+to	O
+treatment	O
+in	O
+various	O
+clinical	O
+practice	O
+settings	O
+.	O
+	
+A	O
+total	O
+of	O
+4	O
+","	O
+499	O
+patients	O
+with	O
+dyslipidemia	B-NP
+requiring	O
+drug	O
+intervention	O
+was	O
+enrolled	O
+at	O
+1	O
+","	O
+81	O
+sites	O
+.	O
+	
+Patients	O
+were	O
+treated	O
+with	O
+1	O
+tablet	O
+(	O
+500	O
+mg	O
+of	O
+niacin	O
+extended	O
+-	O
+release	O
+/	O
+20	O
+mg	O
+of	O
+lovastatin	O
+)	O
+once	O
+nightly	O
+for	O
+4	O
+weeks	O
+and	O
+then	O
+2	O
+tablets	O
+for	O
+8	O
+weeks	O
+.	O
+	
+Patients	O
+also	O
+received	O
+dietary	O
+counseling	O
+","	O
+educational	O
+materials	O
+","	O
+and	O
+reminders	O
+to	O
+call	O
+a	O
+toll	O
+-	O
+free	O
+number	O
+that	O
+provided	O
+further	O
+education	O
+about	O
+dyslipidemia	B-NP
+and	O
+niacin	O
+extended	O
+-	O
+release	O
+/	O
+lovastatin	O
+.	O
+	
+Primary	O
+end	O
+points	O
+were	O
+study	O
+compliance	O
+","	O
+increases	O
+in	O
+liver	O
+transaminases	O
+to	O
+>	O
+3	O
+times	O
+the	O
+upper	O
+limit	O
+of	O
+normal	O
+","	O
+and	O
+clinical	O
+myopathy	B-NP
+.	O
+	
+Final	O
+study	O
+status	O
+was	O
+available	O
+for	O
+4	O
+","	O
+217	O
+patients	O
+(	O
+94	O
+%	O
+)	O
+.	O
+	
+Compliance	O
+to	O
+niacin	O
+extended	O
+-	O
+release	O
+/	O
+lovastatin	O
+was	O
+77	O
+%	O
+","	O
+with	O
+3	O
+","	O
+245	O
+patients	O
+completing	O
+the	O
+study	O
+.	O
+	
+Patients	O
+in	O
+the	O
+southeast	O
+and	O
+those	O
+enrolled	O
+by	O
+endocrinologists	O
+had	O
+the	O
+lowest	O
+compliance	O
+and	O
+highest	O
+adverse	O
+event	O
+rates	O
+.	O
+	
+Flushing	B-NP
+was	O
+the	O
+most	O
+common	O
+adverse	O
+event	O
+","	O
+reported	O
+by	O
+18	O
+%	O
+of	O
+patients	O
+and	O
+leading	O
+to	O
+discontinuation	O
+by	O
+6	O
+%	O
+.	O
+	
+Incidence	O
+of	O
+increased	O
+aspartate	O
+aminotransferase	O
+and	O
+/	O
+or	O
+alanine	O
+aminotransferase	O
+>	O
+3	O
+times	O
+the	O
+upper	O
+limit	O
+of	O
+normal	O
+was	O
+<	O
+0	O
+.	O
+3	O
+%	O
+.	O
+	
+An	O
+increase	O
+of	O
+creatine	O
+phosphokinase	O
+to	O
+>	O
+5	O
+times	O
+the	O
+upper	O
+limit	O
+of	O
+normal	O
+occurred	O
+in	O
+0	O
+.	O
+24	O
+%	O
+of	O
+patients	O
+","	O
+and	O
+no	O
+cases	O
+of	O
+drug	O
+-	O
+induced	O
+myopathy	B-NP
+were	O
+observed	O
+.	O
+	
+Niacin	O
+extended	O
+-	O
+release	O
+/	O
+lovastatin	O
+1	O
+","	O
+0	O
+/	O
+40	O
+mg	O
+","	O
+dosed	O
+as	O
+initial	O
+therapy	O
+","	O
+was	O
+associated	O
+with	O
+good	O
+compliance	O
+and	O
+safety	O
+and	O
+had	O
+very	O
+low	O
+incidences	O
+of	O
+increased	O
+liver	O
+and	O
+muscle	O
+enzymes	O
+.	O
+	
+Protective	O
+effect	O
+of	O
+Terminalia	O
+chebula	O
+against	O
+experimental	O
+myocardial	B-NP
+injury	I-NP
+induced	O
+by	O
+isoproterenol	O
+.	O
+	
+Cardioprotective	O
+effect	O
+of	O
+ethanolic	O
+extract	O
+of	O
+Terminalia	O
+chebula	O
+fruits	O
+(	O
+500	O
+mg	O
+/	O
+kg	O
+body	O
+wt	O
+)	O
+was	O
+examined	O
+in	O
+isoproterenol	O
+(	O
+200	O
+mg	O
+/	O
+kg	O
+body	O
+wt	O
+)	O
+induced	O
+myocardial	B-NP
+damage	I-NP
+in	O
+rats	O
+.	O
+	
+In	O
+isoproterenol	O
+administered	O
+rats	O
+","	O
+the	O
+level	O
+of	O
+lipid	O
+peroxides	O
+increased	O
+significantly	O
+in	O
+the	O
+serum	O
+and	O
+heart	O
+.	O
+	
+A	O
+significant	O
+decrease	O
+was	O
+observed	O
+in	O
+the	O
+activity	O
+of	O
+the	O
+myocardial	O
+marker	O
+enzymes	O
+with	O
+a	O
+concomitant	O
+increase	O
+in	O
+their	O
+activity	O
+in	O
+serum	O
+.	O
+	
+Histopathological	O
+examination	O
+was	O
+carried	O
+out	O
+to	O
+confirm	O
+the	O
+myocardial	O
+necrosis	B-NP
+.	O
+	
+T	O
+.	O
+chebula	O
+extract	O
+pretreatment	O
+was	O
+found	O
+to	O
+ameliorate	O
+the	O
+effect	O
+of	O
+isoproterenol	O
+on	O
+lipid	O
+peroxide	O
+formation	O
+and	O
+retained	O
+the	O
+activities	O
+of	O
+the	O
+diagnostic	O
+marker	O
+enzymes	O
+.	O
+	
+A	O
+case	O
+of	O
+postoperative	O
+anxiety	B-NP
+due	O
+to	O
+low	O
+dose	O
+droperidol	O
+used	O
+with	O
+patient	O
+-	O
+controlled	O
+analgesia	O
+.	O
+	
+A	O
+multiparous	O
+woman	O
+in	O
+good	O
+psychological	O
+health	O
+underwent	O
+urgent	O
+caesarean	O
+section	O
+in	O
+labour	O
+.	O
+	
+Postoperatively	O
+","	O
+she	O
+was	O
+given	O
+a	O
+patient	O
+-	O
+controlled	O
+analgesia	O
+device	O
+delivering	O
+boluses	O
+of	O
+diamorphine	O
+0	O
+.	O
+5	O
+mg	O
+and	O
+droperidol	O
+0	O
+.	O
+25	O
+mg	O
+.	O
+	
+Whilst	O
+using	O
+the	O
+device	O
+she	O
+gradually	O
+became	O
+anxious	O
+","	O
+the	O
+feeling	O
+worsening	O
+after	O
+each	O
+bolus	O
+.	O
+	
+The	O
+diagnosis	O
+of	O
+droperidol	O
+-	O
+induced	O
+psychological	B-NP
+disturbance	I-NP
+was	O
+not	O
+made	O
+straight	O
+away	O
+although	O
+on	O
+subsequent	O
+close	O
+questioning	O
+the	O
+patient	O
+gave	O
+a	O
+very	O
+clear	O
+history	O
+.	O
+	
+After	O
+she	O
+had	O
+received	O
+a	O
+total	O
+of	O
+only	O
+0	O
+.	O
+9	O
+mg	O
+droperidol	O
+","	O
+a	O
+syringe	O
+containing	O
+diamorphine	O
+only	O
+was	O
+substituted	O
+and	O
+her	O
+unease	O
+resolved	O
+completely	O
+.	O
+	
+We	O
+feel	O
+that	O
+","	O
+although	O
+the	O
+dramatic	O
+extrapyramidal	O
+side	O
+effects	O
+of	O
+dopaminergic	O
+antiemetics	O
+are	O
+well	O
+known	O
+","	O
+more	O
+subtle	O
+manifestations	O
+may	O
+easily	O
+be	O
+overlooked	O
+.	O
+	
+Accurate	O
+patient	O
+history	O
+contributes	O
+to	O
+differentiating	O
+diabetes	B-NP
+insipidus	I-NP
+:	O
+a	O
+case	O
+study	O
+.	O
+	
+This	O
+case	O
+study	O
+highlights	O
+the	O
+important	O
+contribution	O
+of	O
+nursing	O
+in	O
+obtaining	O
+an	O
+accurate	O
+health	O
+history	O
+.	O
+	
+The	O
+case	O
+discussed	O
+herein	O
+initially	O
+appeared	O
+to	O
+be	O
+neurogenic	B-NP
+diabetes	I-NP
+insipidus	I-NP
+(	O
+DI	B-NP
+)	O
+secondary	O
+to	O
+a	O
+traumatic	B-NP
+brain	I-NP
+injury	I-NP
+.	O
+	
+The	O
+nursing	O
+staff	O
+","	O
+by	O
+reviewing	O
+the	O
+patient	O
+'	O
+s	O
+health	O
+history	O
+with	O
+his	O
+family	O
+","	O
+discovered	O
+a	O
+history	O
+of	O
+polydipsia	B-NP
+and	O
+long	O
+-	O
+standing	O
+lithium	O
+use	O
+.	O
+	
+Lithium	O
+is	O
+implicated	O
+in	O
+drug	O
+-	O
+induced	O
+nephrogenic	B-NP
+DI	I-NP
+","	O
+and	O
+because	O
+the	O
+patient	O
+had	O
+not	O
+received	O
+lithium	O
+since	O
+being	O
+admitted	O
+to	O
+the	O
+hospital	O
+","	O
+his	O
+treatment	O
+changed	O
+to	O
+focus	O
+on	O
+nephrogenic	B-NP
+DI	I-NP
+.	O
+	
+By	O
+combining	O
+information	O
+from	O
+the	O
+patient	O
+history	O
+","	O
+the	O
+physical	O
+examination	O
+","	O
+and	O
+radiologic	O
+and	O
+laboratory	O
+studies	O
+","	O
+the	O
+critical	O
+care	O
+team	O
+demonstrated	O
+that	O
+the	O
+patient	O
+had	O
+been	O
+self	O
+-	O
+treating	O
+his	O
+lithium	O
+-	O
+induced	O
+nephrogenic	B-NP
+DI	I-NP
+and	O
+developed	O
+neurogenic	B-NP
+DI	I-NP
+secondary	O
+to	O
+brain	B-NP
+trauma	I-NP
+.	O
+	
+Thus	O
+successful	O
+treatment	O
+required	O
+that	O
+nephrogenic	O
+and	O
+neurogenic	B-NP
+DI	I-NP
+be	O
+treated	O
+concomitantly	O
+.	O
+	
+Factors	O
+contributing	O
+to	O
+ribavirin	O
+-	O
+induced	O
+anemia	B-NP
+.	O
+	
+BACKGROUND	O
+AND	O
+AIM	O
+:	O
+Interferon	O
+and	O
+ribavirin	O
+combination	O
+therapy	O
+for	O
+chronic	B-NP
+hepatitis	I-NP
+C	I-NP
+produces	O
+hemolytic	B-NP
+anemia	I-NP
+.	O
+	
+This	O
+study	O
+was	O
+conducted	O
+to	O
+identify	O
+the	O
+factors	O
+contributing	O
+to	O
+ribavirin	O
+-	O
+induced	O
+anemia	B-NP
+.	O
+	
+METHODS	O
+:	O
+Eighty	O
+-	O
+eight	O
+patients	O
+with	O
+chronic	B-NP
+hepatitis	I-NP
+C	I-NP
+who	O
+received	O
+interferon	O
+-	O
+alpha	O
+-	O
+2b	O
+at	O
+a	O
+dose	O
+of	O
+6	O
+MU	O
+administered	O
+intramuscularly	O
+for	O
+24	O
+weeks	O
+in	O
+combination	O
+with	O
+ribavirin	O
+administered	O
+orally	O
+at	O
+a	O
+dose	O
+of	O
+600	O
+mg	O
+or	O
+800	O
+mg	O
+participated	O
+in	O
+the	O
+study	O
+.	O
+	
+A	O
+hemoglobin	O
+concentration	O
+of	O
+<	O
+10	O
+g	O
+/	O
+dL	O
+was	O
+defined	O
+as	O
+ribavirin	O
+-	O
+induced	O
+anemia	B-NP
+.	O
+	
+RESULTS	O
+:	O
+Ribavirin	O
+-	O
+induced	O
+anemia	B-NP
+occurred	O
+in	O
+18	O
+(	O
+20	O
+.	O
+5	O
+%	O
+)	O
+patients	O
+during	O
+treatment	O
+.	O
+	
+A	O
+2	O
+g	O
+/	O
+dL	O
+decrease	O
+in	O
+hemoglobin	O
+concentrations	O
+in	O
+patients	O
+with	O
+anemia	B-NP
+was	O
+observed	O
+at	O
+week	O
+2	O
+after	O
+the	O
+start	O
+of	O
+treatment	O
+.	O
+	
+The	O
+hemoglobin	O
+concentration	O
+in	O
+patients	O
+with	O
+>	O
+or	O
+=	O
+2	O
+g	O
+/	O
+dL	O
+decrease	O
+at	O
+week	O
+2	O
+was	O
+observed	O
+to	O
+be	O
+significantly	O
+lower	O
+even	O
+after	O
+week	O
+2	O
+than	O
+in	O
+patients	O
+with	O
+<	O
+2	O
+g	O
+/	O
+dL	O
+decrease	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+A	O
+significant	O
+relationship	O
+was	O
+observed	O
+between	O
+the	O
+rate	O
+of	O
+reduction	O
+of	O
+hemoglobin	O
+concentrations	O
+at	O
+week	O
+2	O
+and	O
+the	O
+severity	O
+of	O
+anemia	B-NP
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Such	O
+factors	O
+as	O
+sex	O
+(	O
+female	O
+)	O
+","	O
+age	O
+(	O
+>	O
+or	O
+=	O
+60	O
+years	O
+old	O
+)	O
+","	O
+and	O
+the	O
+ribavirin	O
+dose	O
+by	O
+body	O
+weight	O
+(	O
+12	O
+mg	O
+/	O
+kg	O
+or	O
+more	O
+)	O
+were	O
+significant	O
+by	O
+univariate	O
+analysis	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Careful	O
+administration	O
+is	O
+necessary	O
+in	O
+patients	O
+>	O
+or	O
+=	O
+60	O
+years	O
+old	O
+","	O
+in	O
+female	O
+patients	O
+","	O
+and	O
+in	O
+patients	O
+receiving	O
+a	O
+ribavirin	O
+dose	O
+of	O
+12	O
+mg	O
+/	O
+kg	O
+or	O
+more	O
+.	O
+	
+Patients	O
+who	O
+experience	O
+a	O
+fall	O
+in	O
+hemoglobin	O
+concentrations	O
+of	O
+2	O
+g	O
+/	O
+dL	O
+or	O
+more	O
+at	O
+week	O
+2	O
+after	O
+the	O
+start	O
+of	O
+treatment	O
+should	O
+be	O
+monitored	O
+with	O
+particular	O
+care	O
+.	O
+	
+Zidovudine	O
+-	O
+induced	O
+hepatitis	B-NP
+.	O
+	
+A	O
+case	O
+of	O
+acute	O
+hepatitis	B-NP
+induced	O
+by	O
+zidovudine	O
+in	O
+a	O
+38	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+with	O
+AIDS	B-NP
+is	O
+presented	O
+.	O
+	
+The	O
+mechanism	O
+whereby	O
+the	O
+hepatitis	B-NP
+was	O
+induced	O
+is	O
+not	O
+known	O
+.	O
+	
+However	O
+","	O
+the	O
+patient	O
+tolerated	O
+well	O
+an	O
+alternative	O
+reverse	O
+transcriptase	O
+inhibitor	O
+","	O
+2	O
+'	O
+3	O
+'	O
+dideoxyinosine	O
+.	O
+	
+Physicians	O
+caring	O
+for	O
+patients	O
+with	O
+AIDS	B-NP
+should	O
+be	O
+aware	O
+of	O
+this	O
+hitherto	O
+rarely	O
+reported	O
+complication	O
+.	O
+	
+Oxidative	O
+damage	O
+precedes	O
+nitrative	O
+damage	O
+in	O
+adriamycin	O
+-	O
+induced	O
+cardiac	O
+mitochondrial	B-NP
+injury	I-NP
+.	O
+	
+The	O
+purpose	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+determine	O
+if	O
+elevated	O
+reactive	O
+oxygen	O
+(	O
+ROS	O
+)	O
+/	O
+nitrogen	O
+species	O
+(	O
+RNS	O
+)	O
+reported	O
+to	O
+be	O
+present	O
+in	O
+adriamycin	O
+(	O
+ADR	O
+)	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+actually	O
+resulted	O
+in	O
+cardiomyocyte	O
+oxidative	O
+/	O
+nitrative	O
+damage	O
+","	O
+and	O
+to	O
+quantitatively	O
+determine	O
+the	O
+time	O
+course	O
+and	O
+subcellular	O
+localization	O
+of	O
+these	O
+postulated	O
+damage	O
+products	O
+using	O
+an	O
+in	O
+vivo	O
+approach	O
+.	O
+	
+B6C3	O
+mice	O
+were	O
+treated	O
+with	O
+a	O
+single	O
+dose	O
+of	O
+20	O
+mg	O
+/	O
+kg	O
+ADR	O
+.	O
+	
+Ultrastructural	O
+damage	O
+and	O
+levels	O
+of	O
+4	O
+-	O
+hydroxy	O
+-	O
+2	O
+-	O
+nonenal	O
+(	O
+4HNE	O
+)	O
+-	O
+protein	O
+adducts	O
+and	O
+3	O
+-	O
+nitrotyrosine	O
+(	O
+3NT	O
+)	O
+were	O
+analyzed	O
+.	O
+	
+Quantitative	O
+ultrastructural	O
+damage	O
+using	O
+computerized	O
+image	O
+techniques	O
+showed	O
+cardiomyocyte	O
+injury	O
+as	O
+early	O
+as	O
+3	O
+hours	O
+","	O
+with	O
+mitochondria	O
+being	O
+the	O
+most	O
+extensively	O
+and	O
+progressively	O
+injured	O
+subcellular	O
+organelle	O
+.	O
+	
+Analysis	O
+of	O
+4HNE	O
+protein	O
+adducts	O
+by	O
+immunogold	O
+electron	O
+microscopy	O
+showed	O
+appearance	O
+of	O
+4HNE	O
+protein	O
+adducts	O
+in	O
+mitochondria	O
+as	O
+early	O
+as	O
+3	O
+hours	O
+","	O
+with	O
+a	O
+peak	O
+at	O
+6	O
+hours	O
+and	O
+subsequent	O
+decline	O
+at	O
+24	O
+hours	O
+.	O
+	
+3NT	O
+levels	O
+were	O
+significantly	O
+increased	O
+in	O
+all	O
+subcellular	O
+compartments	O
+at	O
+6	O
+hours	O
+and	O
+subsequently	O
+declined	O
+at	O
+24	O
+hours	O
+.	O
+	
+Our	O
+data	O
+showed	O
+ADR	O
+induced	O
+4HNE	O
+-	O
+protein	O
+adducts	O
+in	O
+mitochondria	O
+at	O
+the	O
+same	O
+time	O
+point	O
+as	O
+when	O
+mitochondrial	B-NP
+injury	I-NP
+initially	O
+appeared	O
+.	O
+	
+These	O
+results	O
+document	O
+for	O
+the	O
+first	O
+time	O
+in	O
+vivo	O
+that	O
+mitochondrial	B-NP
+oxidative	I-NP
+damage	I-NP
+precedes	O
+nitrative	O
+damage	O
+.	O
+	
+The	O
+progressive	O
+nature	O
+of	O
+mitochondrial	B-NP
+injury	I-NP
+suggests	O
+that	O
+mitochondria	O
+","	O
+not	O
+other	O
+subcellular	O
+organelles	O
+","	O
+are	O
+the	O
+major	O
+site	O
+of	O
+intracellular	O
+injury	O
+.	O
+	
+Sotalol	O
+-	O
+induced	O
+coronary	B-NP
+spasm	I-NP
+in	O
+a	O
+patient	O
+with	O
+dilated	B-NP
+cardiomyopathy	I-NP
+associated	O
+with	O
+sustained	O
+ventricular	B-NP
+tachycardia	I-NP
+.	O
+	
+A	O
+54	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+severe	O
+left	O
+ventricular	B-NP
+dysfunction	I-NP
+due	O
+to	O
+dilated	B-NP
+cardiomyopathy	I-NP
+was	O
+referred	O
+to	O
+our	O
+hospital	O
+for	O
+symptomatic	O
+incessant	O
+sustained	O
+ventricular	B-NP
+tachycardia	I-NP
+(	O
+VT	B-NP
+)	O
+.	O
+	
+After	O
+the	O
+administration	O
+of	O
+nifekalant	O
+hydrochloride	O
+","	O
+sustained	O
+VT	B-NP
+was	O
+terminated	O
+.	O
+	
+An	O
+alternate	O
+class	O
+III	O
+agent	O
+","	O
+sotalol	O
+","	O
+was	O
+also	O
+effective	O
+for	O
+the	O
+prevention	O
+of	O
+VT	B-NP
+.	O
+	
+However	O
+","	O
+one	O
+month	O
+after	O
+switching	O
+over	O
+nifekalant	O
+to	O
+sotalol	O
+","	O
+a	O
+short	O
+duration	O
+of	O
+ST	O
+elevation	O
+was	O
+documented	O
+in	O
+ECG	O
+monitoring	O
+at	O
+almost	O
+the	O
+same	O
+time	O
+for	O
+three	O
+consecutive	O
+days	O
+.	O
+	
+ST	O
+elevation	O
+with	O
+chest	O
+discomfort	O
+disappeared	O
+since	O
+he	O
+began	O
+taking	O
+long	O
+-	O
+acting	O
+diltiazem	O
+.	O
+	
+Coronary	B-NP
+vasospasm	I-NP
+may	O
+be	O
+induced	O
+by	O
+the	O
+non	O
+-	O
+selective	O
+beta	O
+-	O
+blocking	O
+properties	O
+of	O
+sotalol	O
+.	O
+	
+Effects	O
+of	O
+the	O
+antidepressant	O
+trazodone	O
+","	O
+a	O
+5	O
+-	O
+HT	O
+2A	O
+/	O
+2C	O
+receptor	O
+antagonist	O
+","	O
+on	O
+dopamine	O
+-	O
+dependent	O
+behaviors	O
+in	O
+rats	O
+.	O
+	
+RATIONALE	O
+:	O
+5	O
+-	O
+Hydroxytryptamine	O
+","	O
+via	O
+stimulation	O
+of	O
+5	O
+-	O
+HT	O
+2C	O
+receptors	O
+","	O
+exerts	O
+a	O
+tonic	O
+inhibitory	O
+influence	O
+on	O
+dopaminergic	O
+neurotransmission	O
+","	O
+whereas	O
+activation	O
+of	O
+5	O
+-	O
+HT	O
+2A	O
+receptors	O
+enhances	O
+stimulated	O
+DAergic	O
+neurotransmission	O
+.	O
+	
+The	O
+antidepressant	O
+trazodone	O
+is	O
+a	O
+5	O
+-	O
+HT	O
+2A	O
+/	O
+2C	O
+receptor	O
+antagonist	O
+.	O
+	
+OBJECTIVES	O
+:	O
+To	O
+evaluate	O
+the	O
+effect	O
+of	O
+trazodone	O
+treatment	O
+on	O
+behaviors	O
+dependent	O
+on	O
+the	O
+functional	O
+status	O
+of	O
+the	O
+nigrostriatal	O
+DAergic	O
+system	O
+.	O
+	
+METHODS	O
+:	O
+The	O
+effect	O
+of	O
+pretreatment	O
+with	O
+trazodone	O
+on	O
+dexamphetamine	O
+-	O
+and	O
+apomorphine	O
+-	O
+induced	O
+oral	B-NP
+stereotypies	I-NP
+","	O
+on	O
+catalepsy	B-NP
+induced	O
+by	O
+haloperidol	O
+and	O
+apomorphine	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+p	O
+.	O
+)	O
+","	O
+on	O
+ergometrine	O
+-	O
+induced	O
+wet	O
+dog	O
+shake	O
+(	O
+WDS	O
+)	O
+behavior	O
+and	O
+fluoxetine	O
+-	O
+induced	O
+penile	O
+erections	O
+was	O
+studied	O
+in	O
+rats	O
+.	O
+	
+We	O
+also	O
+investigated	O
+whether	O
+trazodone	O
+induces	O
+catalepsy	B-NP
+in	O
+rats	O
+.	O
+	
+RESULTS	O
+:	O
+Trazodone	O
+at	O
+2	O
+.	O
+5	O
+-	O
+20	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+did	O
+not	O
+induce	O
+catalepsy	B-NP
+","	O
+and	O
+did	O
+not	O
+antagonize	O
+apomorphine	O
+(	O
+1	O
+.	O
+5	O
+and	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+stereotypy	O
+and	O
+apomorphine	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+-	O
+induced	O
+catalepsy	B-NP
+.	O
+	
+However	O
+","	O
+pretreatment	O
+with	O
+5	O
+","	O
+10	O
+and	O
+20	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+trazodone	O
+enhanced	O
+dexamphetamine	O
+stereotypy	O
+","	O
+and	O
+antagonized	O
+haloperidol	O
+catalepsy	B-NP
+","	O
+ergometrine	O
+-	O
+induced	O
+WDS	O
+behavior	O
+and	O
+fluoxetine	O
+-	O
+induced	O
+penile	O
+erections	O
+.	O
+	
+Trazodone	O
+at	O
+30	O
+","	O
+40	O
+and	O
+50	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+induced	O
+catalepsy	B-NP
+and	O
+antagonized	O
+apomorphine	O
+and	O
+dexamphetamine	O
+stereotypies	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Our	O
+results	O
+indicate	O
+that	O
+trazodone	O
+at	O
+2	O
+.	O
+5	O
+-	O
+20	O
+mg	O
+/	O
+kg	O
+does	O
+not	O
+block	O
+pre	O
+-	O
+and	O
+postsynaptic	O
+striatal	O
+D2	O
+DA	O
+receptors	O
+","	O
+while	O
+at	O
+30	O
+","	O
+40	O
+and	O
+50	O
+mg	O
+/	O
+kg	O
+it	O
+blocks	O
+postsynaptic	O
+striatal	O
+D2	O
+DA	O
+receptors	O
+.	O
+	
+Furthermore	O
+","	O
+at	O
+5	O
+","	O
+10	O
+and	O
+20	O
+mg	O
+/	O
+kg	O
+","	O
+trazodone	O
+blocks	O
+5	O
+-	O
+HT	O
+2A	O
+and	O
+5	O
+-	O
+HT	O
+2C	O
+receptors	O
+.	O
+	
+We	O
+suggest	O
+that	O
+trazodone	O
+(	O
+5	O
+","	O
+10	O
+and	O
+20	O
+mg	O
+/	O
+kg	O
+)	O
+","	O
+by	O
+blocking	O
+the	O
+5	O
+-	O
+HT	O
+2C	O
+receptors	O
+","	O
+releases	O
+the	O
+nigrostriatal	O
+DAergic	O
+neurons	O
+from	O
+tonic	O
+inhibition	O
+caused	O
+by	O
+5	O
+-	O
+HT	O
+","	O
+and	O
+thereby	O
+potentiates	O
+dexamphetamine	O
+stereotypy	O
+and	O
+antagonizes	O
+haloperidol	O
+catalepsy	B-NP
+.	O
+	
+Swallowing	B-NP
+abnormalities	I-NP
+and	O
+dyskinesia	B-NP
+in	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+Gastrointestinal	B-NP
+abnormalities	I-NP
+in	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+(	O
+PD	B-NP
+)	O
+have	O
+been	O
+known	O
+for	O
+almost	O
+two	O
+centuries	O
+","	O
+but	O
+many	O
+aspects	O
+concerning	O
+their	O
+pathophysiology	O
+have	O
+not	O
+been	O
+completely	O
+clarified	O
+.	O
+	
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+characterize	O
+the	O
+oropharyngeal	O
+dynamics	O
+in	O
+PD	B-NP
+patients	O
+with	O
+and	O
+without	O
+levodopa	O
+-	O
+induced	O
+dyskinesia	B-NP
+.	O
+	
+Fifteen	O
+dyskinetic	B-NP
+","	O
+12	O
+nondyskinetic	O
+patients	O
+","	O
+and	O
+a	O
+control	O
+group	O
+were	O
+included	O
+.	O
+	
+Patients	O
+were	O
+asked	O
+about	O
+dysphagia	B-NP
+and	O
+evaluated	O
+with	O
+the	O
+Unified	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+Disease	I-NP
+Rating	O
+Scale	O
+Parts	O
+II	O
+and	O
+III	O
+and	O
+the	O
+Hoehn	O
+and	O
+Yahr	O
+scale	O
+.	O
+	
+Deglutition	O
+was	O
+assessed	O
+using	O
+modified	O
+barium	O
+swallow	O
+with	O
+videofluoroscopy	O
+.	O
+	
+Nondyskinetic	O
+patients	O
+","	O
+but	O
+not	O
+the	O
+dyskinetic	B-NP
+ones	O
+","	O
+showed	O
+less	O
+oropharyngeal	O
+swallowing	O
+efficiency	O
+(	O
+OPSE	O
+)	O
+for	O
+liquid	O
+food	O
+than	O
+controls	O
+(	O
+Dunnett	O
+","	O
+P	O
+=	O
+0	O
+.	O
+2	O
+)	O
+.	O
+	
+Dyskinetic	B-NP
+patients	O
+tended	O
+to	O
+have	O
+a	O
+greater	O
+OPSE	O
+than	O
+nondyskinetic	O
+(	O
+Dunnett	O
+","	O
+P	O
+=	O
+0	O
+.	O
+6	O
+)	O
+.	O
+	
+Patients	O
+who	O
+were	O
+using	O
+a	O
+higher	O
+dose	O
+of	O
+levodopa	O
+had	O
+a	O
+greater	O
+OPSE	O
+and	O
+a	O
+trend	O
+toward	O
+a	O
+smaller	O
+oral	O
+transit	O
+time	O
+(	O
+Pearson	O
+'	O
+s	O
+correlation	O
+","	O
+P	O
+=	O
+0	O
+.	O
+1	O
+and	O
+0	O
+.	O
+8	O
+","	O
+respectively	O
+)	O
+.	O
+	
+Neither	O
+the	O
+report	O
+of	O
+dysphagia	B-NP
+nor	O
+any	O
+of	O
+the	O
+PD	B-NP
+severity	O
+parameters	O
+correlated	O
+to	O
+the	O
+videofluoroscopic	O
+variables	O
+.	O
+	
+In	O
+the	O
+current	O
+study	O
+","	O
+dyskinetic	B-NP
+patients	O
+performed	O
+better	O
+in	O
+swallowing	O
+function	O
+","	O
+which	O
+could	O
+be	O
+explained	O
+on	O
+the	O
+basis	O
+of	O
+a	O
+greater	O
+levodopa	O
+dose	O
+.	O
+	
+Our	O
+results	O
+suggest	O
+a	O
+role	O
+for	O
+levodopa	O
+in	O
+the	O
+oral	O
+phase	O
+of	O
+deglutition	O
+and	O
+confirm	O
+that	O
+dysphagia	B-NP
+is	O
+not	O
+a	O
+good	O
+predictor	O
+of	O
+deglutition	O
+alterations	O
+in	O
+PD	B-NP
+.	O
+	
+Inhibition	O
+of	O
+nuclear	O
+factor	O
+-	O
+kappaB	O
+activation	O
+attenuates	O
+tubulointerstitial	B-NP
+nephritis	I-NP
+induced	O
+by	O
+gentamicin	O
+.	O
+	
+BACKGROUND	O
+:	O
+Animals	O
+treated	O
+with	O
+gentamicin	O
+can	O
+show	O
+residual	O
+areas	O
+of	O
+interstitial	O
+fibrosis	B-NP
+in	O
+the	O
+renal	O
+cortex	O
+.	O
+	
+This	O
+study	O
+investigated	O
+the	O
+expression	O
+of	O
+nuclear	O
+factor	O
+-	O
+kappaB	O
+(	O
+NF	O
+-	O
+kappaB	O
+)	O
+","	O
+mitogen	O
+-	O
+activated	O
+protein	O
+(	O
+MAP	O
+)	O
+kinases	O
+and	O
+macrophages	O
+in	O
+the	O
+renal	O
+cortex	O
+and	O
+structural	O
+and	O
+functional	O
+renal	O
+changes	O
+of	O
+rats	O
+treated	O
+with	O
+gentamicin	O
+or	O
+gentamicin	O
++	O
+pyrrolidine	O
+dithiocarbamate	O
+(	O
+PDTC	O
+)	O
+","	O
+an	O
+NF	O
+-	O
+kappaB	O
+inhibitor	O
+.	O
+	
+METHODS	O
+:	O
+38	O
+female	O
+Wistar	O
+rats	O
+were	O
+injected	O
+with	O
+gentamicin	O
+","	O
+40	O
+mg	O
+/	O
+kg	O
+","	O
+twice	O
+a	O
+day	O
+for	O
+9	O
+days	O
+","	O
+38	O
+with	O
+gentamicin	O
++	O
+PDTC	O
+","	O
+and	O
+28	O
+with	O
+0	O
+.	O
+15	O
+M	O
+NaCl	O
+solution	O
+.	O
+	
+The	O
+animals	O
+were	O
+killed	O
+5	O
+and	O
+30	O
+days	O
+after	O
+these	O
+injections	O
+and	O
+the	O
+kidneys	O
+were	O
+removed	O
+for	O
+histological	O
+and	O
+immunohistochemical	O
+studies	O
+.	O
+	
+The	O
+results	O
+of	O
+the	O
+immunohistochemical	O
+studies	O
+were	O
+scored	O
+according	O
+to	O
+the	O
+extent	O
+of	O
+staining	O
+.	O
+	
+The	O
+fractional	O
+interstitial	O
+area	O
+was	O
+determined	O
+by	O
+morphometry	O
+.	O
+	
+RESULTS	O
+:	O
+Gentamicin	O
+-	O
+treated	O
+rats	O
+presented	O
+a	O
+transitory	O
+increase	O
+in	O
+plasma	O
+creatinine	O
+levels	O
+.	O
+	
+Increased	O
+ED	O
+-	O
+1	O
+","	O
+MAP	O
+kinases	O
+and	O
+NF	O
+-	O
+kappaB	O
+staining	O
+were	O
+also	O
+observed	O
+in	O
+the	O
+renal	O
+cortex	O
+from	O
+all	O
+gentamicin	O
+-	O
+treated	O
+rats	O
+compared	O
+to	O
+control	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+The	O
+animals	O
+killed	O
+on	O
+day	O
+30	O
+also	O
+presented	O
+fibrosis	B-NP
+in	O
+the	O
+renal	O
+cortex	O
+despite	O
+the	O
+recovery	O
+of	O
+renal	O
+function	O
+.	O
+	
+Treatment	O
+with	O
+PDTC	O
+reduced	O
+the	O
+functional	O
+and	O
+structural	O
+changes	O
+induced	O
+by	O
+gentamicin	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+These	O
+data	O
+show	O
+that	O
+inhibition	O
+of	O
+NF	O
+-	O
+kappaB	O
+activation	O
+attenuates	O
+tubulointerstitial	B-NP
+nephritis	I-NP
+induced	O
+by	O
+gentamicin	O
+.	O
+	
+Glucose	O
+metabolism	O
+in	O
+patients	O
+with	O
+schizophrenia	B-NP
+treated	O
+with	O
+atypical	O
+antipsychotic	O
+agents	O
+:	O
+a	O
+frequently	O
+sampled	O
+intravenous	O
+glucose	O
+tolerance	O
+test	O
+and	O
+minimal	O
+model	O
+analysis	O
+.	O
+	
+BACKGROUND	O
+:	O
+While	O
+the	O
+incidence	O
+of	O
+new	O
+-	O
+onset	O
+diabetes	B-NP
+mellitus	I-NP
+may	O
+be	O
+increasing	O
+in	O
+patients	O
+with	O
+schizophrenia	B-NP
+treated	O
+with	O
+certain	O
+atypical	O
+antipsychotic	O
+agents	O
+","	O
+it	O
+remains	O
+unclear	O
+whether	O
+atypical	O
+agents	O
+are	O
+directly	O
+affecting	O
+glucose	O
+metabolism	O
+or	O
+simply	O
+increasing	O
+known	O
+risk	O
+factors	O
+for	O
+diabetes	B-NP
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+study	O
+the	O
+2	O
+drugs	O
+most	O
+clearly	O
+implicated	O
+(	O
+clozapine	O
+and	O
+olanzapine	O
+)	O
+and	O
+risperidone	O
+using	O
+a	O
+frequently	O
+sampled	O
+intravenous	O
+glucose	O
+tolerance	O
+test	O
+.	O
+	
+DESIGN	O
+:	O
+A	O
+cross	O
+-	O
+sectional	O
+design	O
+in	O
+stable	O
+","	O
+treated	O
+patients	O
+with	O
+schizophrenia	B-NP
+evaluated	O
+using	O
+a	O
+frequently	O
+sampled	O
+intravenous	O
+glucose	O
+tolerance	O
+test	O
+and	O
+the	O
+Bergman	O
+minimal	O
+model	O
+analysis	O
+.	O
+	
+SETTING	O
+:	O
+Subjects	O
+were	O
+recruited	O
+from	O
+an	O
+urban	O
+community	O
+mental	O
+health	O
+clinic	O
+and	O
+were	O
+studied	O
+at	O
+a	O
+general	O
+clinical	O
+research	O
+center	O
+.	O
+	
+Patients	O
+Fifty	O
+subjects	O
+signed	O
+informed	O
+consent	O
+and	O
+41	O
+underwent	O
+the	O
+frequently	O
+sampled	O
+intravenous	O
+glucose	O
+tolerance	O
+test	O
+.	O
+	
+Thirty	O
+-	O
+six	O
+nonobese	O
+subjects	O
+with	O
+schizophrenia	B-NP
+or	O
+schizoaffective	B-NP
+disorder	I-NP
+","	O
+matched	O
+by	O
+body	O
+mass	O
+index	O
+and	O
+treated	O
+with	O
+either	O
+clozapine	O
+","	O
+olanzapine	O
+","	O
+or	O
+risperidone	O
+","	O
+were	O
+included	O
+in	O
+the	O
+analysis	O
+.	O
+	
+MAIN	O
+OUTCOME	O
+MEASURES	O
+:	O
+Fasting	O
+plasma	O
+glucose	O
+and	O
+fasting	O
+serum	O
+insulin	O
+levels	O
+","	O
+insulin	B-NP
+sensitivity	I-NP
+index	O
+","	O
+homeostasis	O
+model	O
+assessment	O
+of	O
+insulin	B-NP
+resistance	I-NP
+","	O
+and	O
+glucose	O
+effectiveness	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+duration	O
+of	O
+treatment	O
+with	O
+the	O
+identified	O
+atypical	O
+antipsychotic	O
+agent	O
+was	O
+68	O
+.	O
+3	O
++	O
+/	O
+-	O
+28	O
+.	O
+9	O
+months	O
+(	O
+clozapine	O
+)	O
+","	O
+29	O
+.	O
+5	O
++	O
+/	O
+-	O
+17	O
+.	O
+5	O
+months	O
+(	O
+olanzapine	O
+)	O
+","	O
+and	O
+40	O
+.	O
+9	O
++	O
+/	O
+-	O
+33	O
+.	O
+7	O
+(	O
+risperidone	O
+)	O
+.	O
+	
+Fasting	O
+serum	O
+insulin	O
+concentrations	O
+differed	O
+among	O
+groups	O
+(	O
+F	O
+(	O
+33	O
+)	O
+=	O
+3	O
+.	O
+35	O
+;	O
+P	O
+=	O
+.	O
+47	O
+)	O
+(	O
+clozapine	O
+>	O
+olanzapine	O
+>	O
+risperidone	O
+)	O
+with	O
+significant	O
+differences	O
+between	O
+clozapine	O
+and	O
+risperidone	O
+(	O
+t	O
+(	O
+33	O
+)	O
+=	O
+2	O
+.	O
+32	O
+;	O
+P	O
+=	O
+.	O
+3	O
+)	O
+and	O
+olanzapine	O
+and	O
+risperidone	O
+(	O
+t	O
+(	O
+33	O
+)	O
+=	O
+2	O
+.	O
+15	O
+;	O
+P	O
+=	O
+.	O
+4	O
+)	O
+.	O
+	
+There	O
+was	O
+a	O
+significant	O
+difference	O
+in	O
+insulin	B-NP
+sensitivity	I-NP
+index	O
+among	O
+groups	O
+(	O
+F	O
+(	O
+33	O
+)	O
+=	O
+10	O
+.	O
+66	O
+;	O
+P	O
+<	O
+.	O
+1	O
+)	O
+(	O
+clozapine	O
+<	O
+olanzapine	O
+<	O
+risperidone	O
+)	O
+","	O
+with	O
+subjects	O
+who	O
+received	O
+clozapine	O
+and	O
+olanzapine	O
+exhibiting	O
+significant	O
+insulin	B-NP
+resistance	I-NP
+compared	O
+with	O
+subjects	O
+who	O
+were	O
+treated	O
+with	O
+risperidone	O
+(	O
+clozapine	O
+vs	O
+risperidone	O
+","	O
+t	O
+(	O
+33	O
+)	O
+=	O
+-	O
+4	O
+.	O
+29	O
+;	O
+P	O
+<	O
+.	O
+1	O
+;	O
+olanzapine	O
+vs	O
+risperidone	O
+","	O
+t	O
+(	O
+33	O
+)	O
+=	O
+-	O
+3	O
+.	O
+62	O
+;	O
+P	O
+=	O
+.	O
+1	O
+[	O
+P	O
+<	O
+.	O
+1	O
+]	O
+)	O
+.	O
+	
+The	O
+homeostasis	O
+model	O
+assessment	O
+of	O
+insulin	B-NP
+resistance	I-NP
+also	O
+differed	O
+significantly	O
+among	O
+groups	O
+(	O
+F	O
+(	O
+33	O
+)	O
+=	O
+4	O
+.	O
+92	O
+;	O
+P	O
+=	O
+.	O
+1	O
+)	O
+(	O
+clozapine	O
+>	O
+olanzapine	O
+>	O
+risperidone	O
+)	O
+(	O
+clozapine	O
+vs	O
+risperidone	O
+","	O
+t	O
+(	O
+33	O
+)	O
+=	O
+2	O
+.	O
+94	O
+;	O
+P	O
+=	O
+.	O
+6	O
+;	O
+olanzapine	O
+vs	O
+risperidone	O
+","	O
+t	O
+(	O
+33	O
+)	O
+=	O
+2	O
+.	O
+42	O
+;	O
+P	O
+=	O
+.	O
+2	O
+)	O
+.	O
+	
+There	O
+was	O
+a	O
+significant	O
+difference	O
+among	O
+groups	O
+in	O
+glucose	O
+effectiveness	O
+(	O
+F	O
+(	O
+30	O
+)	O
+=	O
+4	O
+.	O
+18	O
+;	O
+P	O
+=	O
+.	O
+2	O
+)	O
+(	O
+clozapine	O
+<	O
+olanzapine	O
+<	O
+risperidone	O
+)	O
+with	O
+significant	O
+differences	O
+between	O
+clozapine	O
+and	O
+risperidone	O
+(	O
+t	O
+(	O
+30	O
+)	O
+=	O
+-	O
+2	O
+.	O
+59	O
+;	O
+P	O
+=	O
+.	O
+2	O
+)	O
+and	O
+olanzapine	O
+and	O
+risperidone	O
+(	O
+t	O
+(	O
+30	O
+)	O
+=	O
+-	O
+2	O
+.	O
+34	O
+","	O
+P	O
+=	O
+.	O
+3	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Both	O
+nonobese	O
+clozapine	O
+-	O
+and	O
+olanzapine	O
+-	O
+treated	O
+groups	O
+displayed	O
+significant	O
+insulin	B-NP
+resistance	I-NP
+and	O
+impairment	O
+of	O
+glucose	O
+effectiveness	O
+compared	O
+with	O
+risperidone	O
+-	O
+treated	O
+subjects	O
+.	O
+	
+Patients	O
+taking	O
+clozapine	O
+and	O
+olanzapine	O
+must	O
+be	O
+examined	O
+for	O
+insulin	B-NP
+resistance	I-NP
+and	O
+its	O
+consequences	O
+.	O
+	
+Thoracic	B-NP
+hematomyelia	I-NP
+secondary	O
+to	O
+coumadin	O
+anticoagulant	O
+therapy	O
+:	O
+a	O
+case	O
+report	O
+.	O
+	
+A	O
+case	O
+of	O
+thoracic	B-NP
+hematomyelia	I-NP
+secondary	O
+to	O
+anticoagulant	O
+therapy	O
+is	O
+presented	O
+.	O
+	
+Clinical	O
+features	O
+","	O
+similar	O
+to	O
+2	O
+other	O
+previously	O
+reported	O
+cases	O
+","	O
+are	O
+discussed	O
+.	O
+	
+A	O
+high	O
+index	O
+of	O
+suspicion	O
+may	O
+lead	O
+to	O
+a	O
+quick	O
+diagnostic	O
+procedure	O
+and	O
+successful	O
+decompressive	O
+surgery	O
+.	O
+	
+Mania	B-NP
+associated	O
+with	O
+fluoxetine	O
+treatment	O
+in	O
+adolescents	O
+.	O
+	
+Fluoxetine	O
+","	O
+a	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitor	O
+","	O
+is	O
+gaining	O
+increased	O
+acceptance	O
+in	O
+the	O
+treatment	O
+of	O
+adolescent	O
+depression	B-NP
+.	O
+	
+Generally	O
+safe	O
+and	O
+well	O
+tolerated	O
+by	O
+adults	O
+","	O
+fluoxetine	O
+has	O
+been	O
+reported	O
+to	O
+induce	O
+mania	B-NP
+.	O
+	
+The	O
+cases	O
+of	O
+five	O
+depressed	B-NP
+adolescents	O
+","	O
+14	O
+-	O
+16	O
+years	O
+of	O
+age	O
+","	O
+who	O
+developed	O
+mania	B-NP
+during	O
+pharmacotherapy	O
+with	O
+fluoxetine	O
+","	O
+are	O
+reported	O
+here	O
+.	O
+	
+Apparent	O
+risk	O
+factors	O
+for	O
+the	O
+development	O
+of	O
+mania	B-NP
+or	O
+hypomania	B-NP
+during	O
+fluoxetine	O
+pharmacotherapy	O
+in	O
+this	O
+population	O
+were	O
+the	O
+combination	O
+of	O
+attention	B-NP
+-	I-NP
+deficit	I-NP
+hyperactivity	I-NP
+disorder	I-NP
+and	O
+affective	O
+instability	O
+;	O
+major	O
+depression	B-NP
+with	O
+psychotic	B-NP
+features	O
+;	O
+a	O
+family	O
+history	O
+of	O
+affective	B-NP
+disorder	I-NP
+","	O
+especially	O
+bipolar	B-NP
+disorder	I-NP
+;	O
+and	O
+a	O
+diagnosis	O
+of	O
+bipolar	B-NP
+disorder	I-NP
+.	O
+	
+Further	O
+study	O
+is	O
+needed	O
+to	O
+determine	O
+the	O
+optimal	O
+dosage	O
+and	O
+to	O
+identify	O
+risk	O
+factors	O
+that	O
+increase	O
+individual	O
+vulnerability	O
+to	O
+fluoxetine	O
+induced	O
+mania	B-NP
+in	O
+adolescents	O
+.	O
+	
+Acute	B-NP
+renal	I-NP
+insufficiency	I-NP
+after	O
+high	O
+-	O
+dose	O
+melphalan	O
+in	O
+patients	O
+with	O
+primary	B-NP
+systemic	I-NP
+amyloidosis	I-NP
+during	O
+stem	O
+cell	O
+transplantation	O
+.	O
+	
+BACKGROUND	O
+:	O
+Patients	O
+with	O
+primary	B-NP
+systemic	I-NP
+amyloidosis	I-NP
+(	O
+AL	B-NP
+)	O
+have	O
+a	O
+poor	O
+prognosis	O
+.	O
+	
+Median	O
+survival	O
+time	O
+from	O
+standard	O
+treatments	O
+is	O
+only	O
+17	O
+months	O
+.	O
+	
+High	O
+-	O
+dose	O
+intravenous	O
+melphalan	O
+followed	O
+by	O
+peripheral	O
+blood	O
+stem	O
+cell	O
+transplant	O
+(	O
+PBSCT	O
+)	O
+appears	O
+to	O
+be	O
+the	O
+most	O
+promising	O
+therapy	O
+","	O
+but	O
+treatment	O
+mortality	O
+can	O
+be	O
+high	O
+.	O
+	
+The	O
+authors	O
+have	O
+noted	O
+the	O
+development	O
+of	O
+acute	B-NP
+renal	I-NP
+insufficiency	I-NP
+immediately	O
+after	O
+melphalan	O
+conditioning	O
+.	O
+	
+This	O
+study	O
+was	O
+undertaken	O
+to	O
+further	O
+examine	O
+its	O
+risk	O
+factors	O
+and	O
+impact	O
+on	O
+posttransplant	O
+mortality	O
+.	O
+	
+METHODS	O
+:	O
+Consecutive	O
+AL	B-NP
+patients	O
+who	O
+underwent	O
+PBSCT	O
+were	O
+studied	O
+retrospectively	O
+.	O
+	
+Acute	B-NP
+renal	I-NP
+insufficiency	I-NP
+(	O
+ARI	B-NP
+)	O
+after	O
+high	O
+-	O
+dose	O
+melphalan	O
+was	O
+defined	O
+by	O
+a	O
+minimum	O
+increase	O
+of	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+dL	O
+(	O
+44	O
+micromol	O
+/	O
+L	O
+)	O
+in	O
+the	O
+serum	O
+creatinine	O
+level	O
+that	O
+is	O
+greater	O
+than	O
+50	O
+%	O
+of	O
+baseline	O
+immediately	O
+after	O
+conditioning	O
+.	O
+	
+Urine	O
+sediment	O
+score	O
+was	O
+the	O
+sum	O
+of	O
+the	O
+individual	O
+types	O
+of	O
+sediment	O
+identified	O
+on	O
+urine	O
+microscopy	O
+.	O
+	
+RESULTS	O
+:	O
+Of	O
+the	O
+80	O
+patients	O
+studied	O
+","	O
+ARI	B-NP
+developed	O
+in	O
+18	O
+.	O
+8	O
+%	O
+of	O
+the	O
+patients	O
+after	O
+high	O
+-	O
+dose	O
+melphalan	O
+.	O
+	
+Univariate	O
+analysis	O
+identified	O
+age	O
+","	O
+hypoalbuminemia	B-NP
+","	O
+heavy	O
+proteinuria	B-NP
+","	O
+diuretic	O
+use	O
+","	O
+and	O
+urine	O
+sediment	O
+score	O
+(	O
+>	O
+3	O
+)	O
+as	O
+risk	O
+factors	O
+.	O
+	
+Age	O
+and	O
+urine	O
+sediment	O
+score	O
+remained	O
+independently	O
+significant	O
+risk	O
+factors	O
+in	O
+the	O
+multivariate	O
+analysis	O
+.	O
+	
+Patients	O
+who	O
+had	O
+ARI	B-NP
+after	O
+high	O
+-	O
+dose	O
+melphalan	O
+underwent	O
+dialysis	O
+more	O
+often	O
+(	O
+P	O
+=	O
+0	O
+.	O
+7	O
+)	O
+","	O
+and	O
+had	O
+a	O
+worse	O
+1	O
+-	O
+year	O
+survival	O
+(	O
+P	O
+=	O
+0	O
+.	O
+3	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+The	O
+timing	O
+of	O
+renal	B-NP
+injury	I-NP
+strongly	O
+suggests	O
+melphalan	O
+as	O
+the	O
+causative	O
+agent	O
+.	O
+	
+Ongoing	O
+tubular	B-NP
+injury	I-NP
+may	O
+be	O
+a	O
+prerequisite	O
+for	O
+renal	B-NP
+injury	I-NP
+by	O
+melphalan	O
+as	O
+evidenced	O
+by	O
+the	O
+active	O
+urinary	O
+sediment	O
+.	O
+	
+Development	O
+of	O
+ARI	B-NP
+adversely	O
+affected	O
+the	O
+outcome	O
+after	O
+PBSCT	O
+.	O
+	
+Effective	O
+preventive	O
+measures	O
+may	O
+help	O
+decrease	O
+the	O
+treatment	O
+mortality	O
+of	O
+PBSCT	O
+in	O
+AL	B-NP
+patients	O
+.	O
+	
+Focal	O
+cerebral	B-NP
+ischemia	I-NP
+in	O
+rats	O
+:	O
+effect	O
+of	O
+phenylephrine	O
+-	O
+induced	O
+hypertension	B-NP
+during	O
+reperfusion	O
+.	O
+	
+After	O
+180	O
+min	O
+of	O
+temporary	O
+middle	B-NP
+cerebral	I-NP
+artery	I-NP
+occlusion	I-NP
+in	O
+spontaneously	O
+hypertensive	B-NP
+rats	O
+","	O
+the	O
+effect	O
+of	O
+phenylephrine	O
+-	O
+induced	O
+hypertension	B-NP
+on	O
+ischemic	B-NP
+brain	I-NP
+injury	I-NP
+and	O
+blood	O
+-	O
+brain	O
+barrier	O
+permeability	O
+was	O
+determined	O
+.	O
+	
+Blood	O
+pressure	O
+was	O
+manipulated	O
+by	O
+one	O
+of	O
+the	O
+following	O
+schedules	O
+during	O
+120	O
+min	O
+of	O
+reperfusion	O
+:	O
+Control	O
+","	O
+normotensive	O
+reperfusion	O
+;	O
+90	O
+/	O
+hypertension	B-NP
+(	O
+90	O
+/	O
+HTN	B-NP
+)	O
+","	O
+blood	O
+pressure	O
+was	O
+increased	O
+by	O
+35	O
+mm	O
+Hg	O
+during	O
+the	O
+initial	O
+90	O
+min	O
+of	O
+reperfusion	O
+only	O
+;	O
+15	O
+/	O
+hypertension	B-NP
+(	O
+15	O
+/	O
+HTN	B-NP
+)	O
+","	O
+normotensive	O
+reperfusion	O
+for	O
+30	O
+min	O
+followed	O
+by	O
+15	O
+min	O
+of	O
+hypertension	B-NP
+and	O
+75	O
+min	O
+of	O
+normotension	O
+.	O
+	
+Part	O
+A	O
+","	O
+for	O
+eight	O
+rats	O
+in	O
+each	O
+group	O
+brain	B-NP
+injury	I-NP
+was	O
+evaluated	O
+by	O
+staining	O
+tissue	O
+using	O
+2	O
+","	O
+3	O
+","	O
+5	O
+-	O
+triphenyltetrazolium	O
+chloride	O
+and	O
+edema	B-NP
+was	O
+evaluated	O
+by	O
+microgravimetry	O
+.	O
+	
+Part	O
+B	O
+","	O
+for	O
+eight	O
+different	O
+rats	O
+in	O
+each	O
+group	O
+blood	O
+-	O
+brain	O
+barrier	O
+permeability	O
+was	O
+evaluated	O
+by	O
+measuring	O
+the	O
+amount	O
+and	O
+extent	O
+of	O
+extravasation	O
+of	O
+Evans	O
+Blue	O
+dye	O
+.	O
+	
+Brain	B-NP
+injury	I-NP
+(	O
+percentage	O
+of	O
+the	O
+ischemic	B-NP
+hemisphere	I-NP
+)	O
+was	O
+less	O
+in	O
+the	O
+15	O
+/	O
+HTN	B-NP
+group	O
+(	O
+16	O
++	O
+/	O
+-	O
+6	O
+","	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+)	O
+versus	O
+the	O
+90	O
+/	O
+HTN	B-NP
+group	O
+(	O
+30	O
++	O
+/	O
+-	O
+6	O
+)	O
+","	O
+which	O
+was	O
+in	O
+turn	O
+less	O
+than	O
+the	O
+control	O
+group	O
+(	O
+42	O
++	O
+/	O
+-	O
+5	O
+)	O
+.	O
+	
+Specific	O
+gravity	O
+was	O
+greater	O
+in	O
+the	O
+15	O
+/	O
+HTN	B-NP
+group	O
+(	O
+1	O
+.	O
+43	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+)	O
+versus	O
+the	O
+90	O
+/	O
+HTN	B-NP
+(	O
+1	O
+.	O
+36	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+)	O
+and	O
+control	O
+(	O
+1	O
+.	O
+37	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+)	O
+groups	O
+.	O
+	
+Evans	O
+Blue	O
+(	O
+mug	O
+g	O
+-	O
+1	O
+of	O
+brain	O
+tissue	O
+)	O
+was	O
+greater	O
+in	O
+the	O
+90	O
+/	O
+HTN	B-NP
+group	O
+(	O
+24	O
+.	O
+4	O
++	O
+/	O
+-	O
+6	O
+.	O
+0	O
+)	O
+versus	O
+the	O
+control	O
+group	O
+(	O
+12	O
+.	O
+3	O
++	O
+/	O
+-	O
+4	O
+.	O
+1	O
+)	O
+","	O
+which	O
+was	O
+in	O
+turn	O
+greater	O
+than	O
+the	O
+15	O
+/	O
+HTN	B-NP
+group	O
+(	O
+7	O
+.	O
+3	O
++	O
+/	O
+-	O
+3	O
+.	O
+2	O
+)	O
+.	O
+	
+This	O
+study	O
+supports	O
+a	O
+hypothesis	O
+that	O
+during	O
+reperfusion	O
+","	O
+a	O
+short	O
+interval	O
+of	O
+hypertension	B-NP
+decreases	O
+brain	B-NP
+injury	I-NP
+and	O
+edema	B-NP
+;	O
+and	O
+that	O
+sustained	O
+hypertension	B-NP
+increases	O
+the	O
+risk	O
+of	O
+vasogenic	B-NP
+edema	I-NP
+.	O
+	
+People	O
+aged	O
+over	O
+75	O
+in	O
+atrial	B-NP
+fibrillation	I-NP
+on	O
+warfarin	O
+:	O
+the	O
+rate	O
+of	O
+major	O
+hemorrhage	B-NP
+and	O
+stroke	B-NP
+in	O
+more	O
+than	O
+500	O
+patient	O
+-	O
+years	O
+of	O
+follow	O
+-	O
+up	O
+.	O
+	
+OBJECTIVES	O
+:	O
+To	O
+determine	O
+the	O
+incidence	O
+of	O
+major	O
+hemorrhage	B-NP
+and	O
+stroke	B-NP
+in	O
+people	O
+aged	O
+76	O
+and	O
+older	O
+with	O
+atrial	B-NP
+fibrillation	I-NP
+on	O
+adjusted	O
+-	O
+dose	O
+warfarin	O
+who	O
+had	O
+been	O
+recently	O
+been	O
+admitted	O
+to	O
+hospital	O
+.	O
+	
+DESIGN	O
+:	O
+A	O
+retrospective	O
+observational	O
+cohort	O
+study	O
+.	O
+	
+SETTING	O
+:	O
+A	O
+major	O
+healthcare	O
+network	O
+involving	O
+four	O
+tertiary	O
+hospitals	O
+.	O
+	
+PARTICIPANTS	O
+:	O
+Two	O
+hundred	O
+thirty	O
+-	O
+five	O
+patients	O
+aged	O
+76	O
+and	O
+older	O
+admitted	O
+to	O
+a	O
+major	O
+healthcare	O
+network	O
+between	O
+July	O
+1	O
+","	O
+2001	O
+","	O
+and	O
+June	O
+30	O
+","	O
+2002	O
+","	O
+with	O
+atrial	B-NP
+fibrillation	I-NP
+on	O
+warfarin	O
+were	O
+enrolled	O
+.	O
+	
+MEASUREMENTS	O
+:	O
+Information	O
+regarding	O
+major	O
+bleeding	B-NP
+episodes	O
+","	O
+strokes	B-NP
+","	O
+and	O
+warfarin	O
+use	O
+was	O
+obtained	O
+from	O
+patients	O
+","	O
+relatives	O
+","	O
+primary	O
+physicians	O
+","	O
+and	O
+medical	O
+records	O
+.	O
+	
+RESULTS	O
+:	O
+Two	O
+hundred	O
+twenty	O
+-	O
+eight	O
+patients	O
+(	O
+42	O
+%	O
+men	O
+)	O
+with	O
+a	O
+mean	O
+age	O
+of	O
+81	O
+.	O
+1	O
+(	O
+range	O
+76	O
+-	O
+94	O
+)	O
+were	O
+included	O
+in	O
+the	O
+analysis	O
+.	O
+	
+Total	O
+follow	O
+-	O
+up	O
+on	O
+warfarin	O
+was	O
+530	O
+years	O
+(	O
+mean	O
+28	O
+months	O
+)	O
+.	O
+	
+There	O
+were	O
+53	O
+major	O
+hemorrhages	B-NP
+","	O
+for	O
+an	O
+annual	O
+rate	O
+of	O
+10	O
+.	O
+0	O
+%	O
+","	O
+including	O
+24	O
+(	O
+45	O
+.	O
+3	O
+%	O
+)	O
+life	O
+-	O
+threatening	O
+and	O
+five	O
+(	O
+9	O
+.	O
+4	O
+%	O
+)	O
+fatal	O
+bleeds	O
+.	O
+	
+The	O
+annual	O
+stroke	B-NP
+rate	O
+after	O
+initiation	O
+of	O
+warfarin	O
+was	O
+2	O
+.	O
+6	O
+%	O
+.	O
+	
+CONCLUSION	O
+:	O
+The	O
+rate	O
+of	O
+major	O
+hemorrhage	B-NP
+was	O
+high	O
+in	O
+this	O
+old	O
+","	O
+frail	O
+group	O
+","	O
+but	O
+excluding	O
+fatalities	O
+","	O
+resulted	O
+in	O
+no	O
+long	O
+-	O
+term	O
+sequelae	O
+","	O
+and	O
+the	O
+stroke	B-NP
+rate	O
+on	O
+warfarin	O
+was	O
+low	O
+","	O
+demonstrating	O
+how	O
+effective	O
+warfarin	O
+treatment	O
+is	O
+.	O
+	
+Safety	O
+of	O
+celecoxib	O
+in	O
+patients	O
+with	O
+adverse	O
+skin	B-NP
+reactions	I-NP
+to	O
+acetaminophen	O
+(	O
+paracetamol	O
+)	O
+and	O
+nimesulide	O
+associated	O
+or	O
+not	O
+with	O
+common	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+.	O
+	
+BACKGROUND	O
+:	O
+Acetaminophen	O
+(	O
+paracetamol	O
+-	O
+-	O
+P	O
+)	O
+and	O
+Nimesulide	O
+(	O
+N	O
+)	O
+are	O
+widely	O
+used	O
+analgesic	O
+-	O
+antipyretic	O
+/	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+.	O
+	
+The	O
+rate	O
+of	O
+adverse	O
+hypersensitivity	B-NP
+reactions	O
+to	O
+these	O
+agents	O
+is	O
+generally	O
+low	O
+.	O
+	
+On	O
+the	O
+contrary	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+(	O
+NSAIDs	O
+)	O
+are	O
+commonly	O
+involved	O
+in	O
+such	O
+reactions	O
+.	O
+	
+Celecoxib	O
+(	O
+CE	O
+)	O
+is	O
+a	O
+novel	O
+drug	O
+","	O
+with	O
+high	O
+selectivity	O
+and	O
+affinity	O
+for	O
+COX	O
+-	O
+2	O
+enzyme	O
+.	O
+	
+OBJECTIVE	O
+:	O
+We	O
+evaluated	O
+the	O
+tolerability	O
+of	O
+CE	O
+in	O
+a	O
+group	O
+of	O
+patients	O
+with	O
+documented	O
+history	O
+of	O
+adverse	O
+cutaneous	B-NP
+reactions	I-NP
+to	O
+P	O
+and	O
+N	O
+associated	O
+or	O
+not	O
+to	O
+classic	O
+NSAIDs	O
+.	O
+	
+METHODS	O
+:	O
+We	O
+studied	O
+9	O
+patients	O
+with	O
+hypersensitivity	B-NP
+to	O
+P	O
+and	O
+N	O
+with	O
+or	O
+without	O
+associated	O
+reactions	O
+to	O
+classic	O
+NSAIDs	O
+.	O
+	
+The	O
+diagnosis	O
+of	O
+P	O
+and	O
+N	O
+-	O
+induced	O
+skin	B-NP
+reactions	I-NP
+was	O
+based	O
+in	O
+vivo	O
+challenge	O
+.	O
+	
+The	O
+placebo	O
+was	O
+blindly	O
+administered	O
+at	O
+the	O
+beginning	O
+of	O
+each	O
+challenge	O
+.	O
+	
+After	O
+three	O
+days	O
+","	O
+a	O
+cumulative	O
+dosage	O
+of	O
+200	O
+mg	O
+of	O
+CE	O
+in	O
+refracted	O
+doses	O
+were	O
+given	O
+.	O
+	
+After	O
+2	O
+-	O
+3	O
+days	O
+","	O
+a	O
+single	O
+dose	O
+of	O
+200	O
+mg	O
+was	O
+administered	O
+.	O
+	
+All	O
+patients	O
+were	O
+observed	O
+for	O
+6	O
+hours	O
+after	O
+each	O
+challenge	O
+","	O
+and	O
+controlled	O
+again	O
+after	O
+24	O
+hours	O
+to	O
+exclude	O
+delayed	O
+reactions	O
+.	O
+	
+The	O
+challenge	O
+was	O
+considered	O
+positive	O
+if	O
+one	O
+or	O
+more	O
+of	O
+the	O
+following	O
+appeared	O
+:	O
+erythema	B-NP
+","	O
+rush	O
+or	O
+urticaria	B-NP
+-	O
+angioedema	B-NP
+.	O
+	
+RESULTS	O
+:	O
+No	O
+reaction	O
+was	O
+observed	O
+with	O
+placebo	O
+and	O
+eight	O
+patients	O
+(	O
+88	O
+.	O
+8	O
+%	O
+)	O
+tolerated	O
+CE	O
+.	O
+	
+Only	O
+one	O
+patient	O
+developed	O
+a	O
+moderate	O
+angioedema	B-NP
+of	O
+the	O
+lips	O
+.	O
+	
+CONCLUSION	O
+:	O
+Only	O
+one	O
+hypersensitivity	B-NP
+reaction	O
+to	O
+CE	O
+was	O
+documented	O
+among	O
+9	O
+P	O
+and	O
+N	O
+-	O
+highly	O
+NSAIDs	O
+intolerant	O
+patients	O
+.	O
+	
+Thus	O
+","	O
+we	O
+conclude	O
+that	O
+CE	O
+is	O
+a	O
+reasonably	O
+safe	O
+alternative	O
+to	O
+be	O
+used	O
+in	O
+subjects	O
+who	O
+do	O
+not	O
+tolerate	O
+P	O
+and	O
+N	O
+.	O
+	
+Case	O
+-	O
+control	O
+study	O
+of	O
+regular	O
+analgesic	O
+and	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+use	O
+and	O
+end	B-NP
+-	I-NP
+stage	I-NP
+renal	I-NP
+disease	I-NP
+.	O
+	
+BACKGROUND	O
+:	O
+Studies	O
+on	O
+the	O
+association	O
+between	O
+the	O
+long	O
+-	O
+term	O
+use	O
+of	O
+aspirin	O
+and	O
+other	O
+analgesic	O
+and	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+(	O
+NSAIDs	O
+)	O
+and	O
+end	B-NP
+-	I-NP
+stage	I-NP
+renal	I-NP
+disease	I-NP
+(	O
+ESRD	B-NP
+)	O
+have	O
+given	O
+conflicting	O
+results	O
+.	O
+	
+In	O
+order	O
+to	O
+examine	O
+this	O
+association	O
+","	O
+a	O
+case	O
+-	O
+control	O
+study	O
+with	O
+incident	O
+cases	O
+of	O
+ESRD	B-NP
+was	O
+carried	O
+out	O
+.	O
+	
+METHODS	O
+:	O
+The	O
+cases	O
+were	O
+all	O
+patients	O
+entering	O
+the	O
+local	O
+dialysis	O
+program	O
+because	O
+of	O
+ESRD	B-NP
+in	O
+the	O
+study	O
+area	O
+between	O
+June	O
+1	O
+","	O
+1995	O
+and	O
+November	O
+30	O
+","	O
+1997	O
+.	O
+	
+They	O
+were	O
+classified	O
+according	O
+to	O
+the	O
+underlying	O
+disease	O
+","	O
+which	O
+had	O
+presumably	O
+led	O
+them	O
+to	O
+ESRD	B-NP
+.	O
+	
+Controls	O
+were	O
+patients	O
+admitted	O
+to	O
+the	O
+same	O
+hospitals	O
+from	O
+where	O
+the	O
+cases	O
+arose	O
+","	O
+also	O
+matched	O
+by	O
+age	O
+and	O
+sex	O
+.	O
+	
+Odds	O
+ratios	O
+were	O
+calculated	O
+using	O
+a	O
+conditional	O
+logistic	O
+model	O
+","	O
+including	O
+potential	O
+confounding	O
+factors	O
+","	O
+both	O
+for	O
+the	O
+whole	O
+study	O
+population	O
+and	O
+for	O
+the	O
+various	O
+underlying	O
+diseases	O
+.	O
+	
+RESULTS	O
+:	O
+Five	O
+hundred	O
+and	O
+eighty	O
+-	O
+three	O
+cases	O
+and	O
+1190	O
+controls	O
+were	O
+included	O
+in	O
+the	O
+analysis	O
+.	O
+	
+Long	O
+-	O
+term	O
+use	O
+of	O
+any	O
+analgesic	O
+was	O
+associated	O
+with	O
+an	O
+overall	O
+odds	O
+ratio	O
+of	O
+1	O
+.	O
+22	O
+(	O
+95	O
+%	O
+CI	O
+","	O
+0	O
+.	O
+89	O
+-	O
+1	O
+.	O
+66	O
+)	O
+.	O
+	
+For	O
+specific	O
+groups	O
+of	O
+drugs	O
+","	O
+the	O
+risks	O
+were	O
+1	O
+.	O
+56	O
+(	O
+1	O
+.	O
+5	O
+-	O
+2	O
+.	O
+30	O
+)	O
+for	O
+aspirin	O
+","	O
+1	O
+.	O
+3	O
+(	O
+0	O
+.	O
+60	O
+-	O
+1	O
+.	O
+76	O
+)	O
+for	O
+pyrazolones	O
+","	O
+0	O
+.	O
+80	O
+(	O
+0	O
+.	O
+39	O
+-	O
+1	O
+.	O
+63	O
+)	O
+for	O
+paracetamol	O
+","	O
+and	O
+0	O
+.	O
+94	O
+(	O
+0	O
+.	O
+57	O
+-	O
+1	O
+.	O
+56	O
+)	O
+for	O
+nonaspirin	O
+NSAIDs	O
+.	O
+	
+The	O
+risk	O
+of	O
+ESRD	B-NP
+associated	O
+with	O
+aspirin	O
+was	O
+related	O
+to	O
+the	O
+cumulated	O
+dose	O
+and	O
+duration	O
+of	O
+use	O
+","	O
+and	O
+it	O
+was	O
+particularly	O
+high	O
+among	O
+the	O
+subset	O
+of	O
+patients	O
+with	O
+vascular	O
+nephropathy	B-NP
+as	O
+underlying	O
+disease	O
+[	O
+2	O
+.	O
+35	O
+(	O
+1	O
+.	O
+17	O
+-	O
+4	O
+.	O
+72	O
+)	O
+]	O
+.	O
+	
+CONCLUSION	O
+:	O
+Our	O
+data	O
+indicate	O
+that	O
+long	O
+-	O
+term	O
+use	O
+of	O
+nonaspirin	O
+analgesic	O
+drugs	O
+and	O
+NSAIDs	O
+is	O
+not	O
+associated	O
+with	O
+an	O
+increased	O
+risk	O
+of	O
+ESRD	B-NP
+.	O
+	
+However	O
+","	O
+the	O
+chronic	O
+use	O
+of	O
+aspirin	O
+may	O
+increase	O
+the	O
+risk	O
+of	O
+ESRD	B-NP
+.	O
+	
+Two	O
+cases	O
+of	O
+amisulpride	O
+overdose	B-NP
+:	O
+a	O
+cause	O
+for	O
+prolonged	B-NP
+QT	I-NP
+syndrome	I-NP
+.	O
+	
+Two	O
+cases	O
+of	O
+deliberate	O
+self	O
+-	O
+poisoning	B-NP
+with	O
+5	O
+g	O
+and	O
+3	O
+.	O
+6	O
+g	O
+of	O
+amisulpride	O
+","	O
+respectively	O
+","	O
+are	O
+reported	O
+.	O
+	
+In	O
+both	O
+cases	O
+","	O
+QT	B-NP
+prolongation	I-NP
+and	O
+hypocalcaemia	B-NP
+were	O
+noted	O
+.	O
+	
+The	O
+QT	B-NP
+prolongation	I-NP
+appeared	O
+to	O
+respond	O
+to	O
+administration	O
+of	O
+i	O
+.	O
+v	O
+.	O
+calcium	O
+gluconate	O
+.	O
+	
+Growth	O
+-	O
+associated	O
+protein	O
+43	O
+expression	O
+in	O
+hippocampal	O
+molecular	O
+layer	O
+of	O
+chronic	O
+epileptic	B-NP
+rats	O
+treated	O
+with	O
+cycloheximide	O
+.	O
+	
+PURPOSE	O
+:	O
+GAP43	O
+has	O
+been	O
+thought	O
+to	O
+be	O
+linked	O
+with	O
+mossy	O
+fiber	O
+sprouting	O
+(	O
+MFS	O
+)	O
+in	O
+various	O
+experimental	O
+models	O
+of	O
+epilepsy	B-NP
+.	O
+	
+To	O
+investigate	O
+how	O
+GAP43	O
+expression	O
+(	O
+GAP43	O
+-	O
+ir	O
+)	O
+correlates	O
+with	O
+MFS	O
+","	O
+we	O
+assessed	O
+the	O
+intensity	O
+(	O
+densitometry	O
+)	O
+and	O
+extension	O
+(	O
+width	O
+)	O
+of	O
+GAP43	O
+-	O
+ir	O
+in	O
+the	O
+inner	O
+molecular	O
+layer	O
+of	O
+the	O
+dentate	O
+gyrus	O
+(	O
+IML	O
+)	O
+of	O
+rats	O
+subject	O
+to	O
+status	B-NP
+epilepticus	I-NP
+induced	O
+by	O
+pilocarpine	O
+(	O
+Pilo	O
+)	O
+","	O
+previously	O
+injected	O
+or	O
+not	O
+with	O
+cycloheximide	O
+(	O
+CHX	O
+)	O
+","	O
+which	O
+has	O
+been	O
+shown	O
+to	O
+inhibit	O
+MFS	O
+.	O
+	
+METHODS	O
+:	O
+CHX	O
+was	O
+injected	O
+before	O
+the	O
+Pilo	O
+injection	O
+in	O
+adult	O
+Wistar	O
+rats	O
+.	O
+	
+The	O
+Pilo	O
+group	O
+was	O
+injected	O
+with	O
+the	O
+same	O
+drugs	O
+","	O
+except	O
+for	O
+CHX	O
+.	O
+	
+Animals	O
+were	O
+killed	O
+between	O
+30	O
+and	O
+60	O
+days	O
+later	O
+","	O
+and	O
+brain	O
+sections	O
+were	O
+processed	O
+for	O
+GAP43	O
+immunohistochemistry	O
+.	O
+	
+RESULTS	O
+:	O
+Densitometry	O
+showed	O
+no	O
+significant	O
+difference	O
+regarding	O
+GAP43	O
+-	O
+ir	O
+in	O
+the	O
+IML	O
+between	O
+Pilo	O
+","	O
+CHX	O
++	O
+Pilo	O
+","	O
+and	O
+control	O
+groups	O
+.	O
+	
+However	O
+","	O
+the	O
+results	O
+of	O
+the	O
+width	O
+of	O
+the	O
+GAP43	O
+-	O
+ir	O
+band	O
+in	O
+the	O
+IML	O
+showed	O
+that	O
+CHX	O
++	O
+Pilo	O
+and	O
+control	O
+animals	O
+had	O
+a	O
+significantly	O
+larger	O
+band	O
+(	O
+p	O
+=	O
+0	O
+.	O
+3	O
+)	O
+as	O
+compared	O
+with	O
+that	O
+in	O
+the	O
+Pilo	O
+group	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Our	O
+current	O
+finding	O
+that	O
+animals	O
+in	O
+the	O
+CHX	O
++	O
+Pilo	O
+group	O
+have	O
+a	O
+GAP43	O
+-	O
+ir	O
+band	O
+in	O
+the	O
+IML	O
+","	O
+similar	O
+to	O
+that	O
+of	O
+controls	O
+","	O
+reinforces	O
+prior	O
+data	O
+on	O
+the	O
+blockade	O
+of	O
+MFS	O
+in	O
+these	O
+animals	O
+.	O
+	
+The	O
+change	O
+in	O
+GAP43	O
+-	O
+ir	O
+present	O
+in	O
+Pilo	O
+-	O
+treated	O
+animals	O
+was	O
+a	O
+thinning	O
+of	O
+the	O
+band	O
+to	O
+a	O
+very	O
+narrow	O
+layer	O
+just	O
+above	O
+the	O
+granule	O
+cell	O
+layer	O
+that	O
+is	O
+likely	O
+to	O
+be	O
+associated	O
+with	O
+the	O
+loss	O
+of	O
+hilar	O
+cell	O
+projections	O
+that	O
+express	O
+GAP	O
+-	O
+43	O
+.	O
+	
+Nicotine	O
+antagonizes	O
+caffeine	O
+-	O
+but	O
+not	O
+pentylenetetrazole	O
+-	O
+induced	O
+anxiogenic	O
+effect	O
+in	O
+mice	O
+.	O
+	
+RATIONALE	O
+:	O
+Nicotine	O
+and	O
+caffeine	O
+are	O
+widely	O
+consumed	O
+licit	O
+psychoactive	O
+drugs	O
+worldwide	O
+.	O
+	
+Epidemiological	O
+studies	O
+showed	O
+that	O
+they	O
+were	O
+generally	O
+used	O
+concurrently	O
+.	O
+	
+Although	O
+some	O
+studies	O
+in	O
+experimental	O
+animals	O
+indicate	O
+clear	O
+pharmacological	O
+interactions	O
+between	O
+them	O
+","	O
+no	O
+studies	O
+have	O
+shown	O
+a	O
+specific	O
+interaction	O
+on	O
+anxiety	B-NP
+responses	O
+.	O
+	
+OBJECTIVES	O
+:	O
+The	O
+present	O
+study	O
+investigates	O
+the	O
+effects	O
+of	O
+nicotine	O
+on	O
+anxiety	B-NP
+induced	O
+by	O
+caffeine	O
+and	O
+another	O
+anxiogenic	O
+drug	O
+","	O
+pentylenetetrazole	O
+","	O
+in	O
+mice	O
+.	O
+	
+The	O
+elevated	O
+plus	O
+-	O
+maze	O
+(	O
+EPM	O
+)	O
+test	O
+was	O
+used	O
+to	O
+evaluate	O
+the	O
+effects	O
+of	O
+drugs	O
+on	O
+anxiety	B-NP
+.	O
+	
+METHODS	O
+:	O
+Adult	O
+male	O
+Swiss	O
+Webster	O
+mice	O
+(	O
+25	O
+-	O
+32	O
+g	O
+)	O
+were	O
+given	O
+nicotine	O
+(	O
+0	O
+.	O
+5	O
+-	O
+0	O
+.	O
+25	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+or	O
+saline	O
+10	O
+min	O
+before	O
+caffeine	O
+(	O
+70	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+or	O
+pentylenetetrazole	O
+(	O
+15	O
+and	O
+30	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+injections	O
+.	O
+	
+After	O
+15	O
+min	O
+","	O
+mice	O
+were	O
+evaluated	O
+for	O
+their	O
+open	O
+-	O
+and	O
+closed	O
+-	O
+arm	O
+time	O
+and	O
+entries	O
+on	O
+the	O
+EPM	O
+for	O
+a	O
+10	O
+-	O
+min	O
+session	O
+.	O
+	
+Locomotor	O
+activity	O
+was	O
+recorded	O
+for	O
+individual	O
+groups	O
+by	O
+using	O
+the	O
+same	O
+treatment	O
+protocol	O
+with	O
+the	O
+EPM	O
+test	O
+.	O
+	
+RESULTS	O
+:	O
+Nicotine	O
+(	O
+0	O
+.	O
+5	O
+-	O
+0	O
+.	O
+25	O
+mg	O
+/	O
+kg	O
+)	O
+itself	O
+did	O
+not	O
+produce	O
+any	O
+significant	O
+effect	O
+in	O
+the	O
+EPM	O
+test	O
+","	O
+whereas	O
+caffeine	O
+(	O
+70	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+pentylenetetrazole	O
+(	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+produced	O
+an	O
+anxiogenic	O
+effect	O
+","	O
+apparent	O
+with	O
+decreases	O
+in	O
+open	O
+-	O
+arm	O
+time	O
+and	O
+entry	O
+.	O
+	
+Nicotine	O
+(	O
+0	O
+.	O
+25	O
+mg	O
+/	O
+kg	O
+)	O
+pretreatment	O
+blocked	O
+the	O
+caffeine	O
+-	O
+but	O
+not	O
+pentylenetetrazole	O
+-	O
+induced	O
+anxiety	B-NP
+.	O
+	
+Administration	O
+of	O
+each	O
+drug	O
+and	O
+their	O
+combinations	O
+did	O
+not	O
+produce	O
+any	O
+effect	O
+on	O
+locomotor	O
+activity	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Our	O
+results	O
+suggest	O
+that	O
+the	O
+antagonistic	O
+effect	O
+of	O
+nicotine	O
+on	O
+caffeine	O
+-	O
+induced	O
+anxiety	B-NP
+is	O
+specific	O
+to	O
+caffeine	O
+","	O
+instead	O
+of	O
+a	O
+non	O
+-	O
+specific	O
+anxiolytic	O
+effect	O
+.	O
+	
+Thus	O
+","	O
+it	O
+may	O
+extend	O
+the	O
+current	O
+findings	O
+on	O
+the	O
+interaction	O
+between	O
+nicotine	O
+and	O
+caffeine	O
+.	O
+	
+Long	O
+term	O
+hormone	O
+therapy	O
+for	O
+perimenopausal	O
+and	O
+postmenopausal	O
+women	O
+.	O
+	
+BACKGROUND	O
+:	O
+Hormone	O
+therapy	O
+(	O
+HT	O
+)	O
+is	O
+widely	O
+used	O
+for	O
+controlling	O
+menopausal	B-NP
+symptoms	I-NP
+.	O
+	
+It	O
+has	O
+also	O
+been	O
+used	O
+for	O
+the	O
+management	O
+and	O
+prevention	O
+of	O
+cardiovascular	B-NP
+disease	I-NP
+","	O
+osteoporosis	B-NP
+and	O
+dementia	B-NP
+in	O
+older	O
+women	O
+but	O
+the	O
+evidence	O
+supporting	O
+its	O
+use	O
+for	O
+these	O
+indications	O
+is	O
+largely	O
+observational	O
+.	O
+	
+OBJECTIVES	O
+:	O
+To	O
+assess	O
+the	O
+effect	O
+of	O
+long	O
+-	O
+term	O
+HT	O
+on	O
+mortality	O
+","	O
+heart	B-NP
+disease	I-NP
+","	O
+venous	B-NP
+thromboembolism	I-NP
+","	O
+stroke	B-NP
+","	O
+transient	B-NP
+ischaemic	I-NP
+attacks	I-NP
+","	O
+breast	B-NP
+cancer	I-NP
+","	O
+colorectal	B-NP
+cancer	I-NP
+","	O
+ovarian	B-NP
+cancer	I-NP
+","	O
+endometrial	B-NP
+cancer	I-NP
+","	O
+gallbladder	B-NP
+disease	I-NP
+","	O
+cognitive	O
+function	O
+","	O
+dementia	B-NP
+","	O
+fractures	B-NP
+and	O
+quality	O
+of	O
+life	O
+.	O
+	
+SEARCH	O
+STRATEGY	O
+:	O
+We	O
+searched	O
+the	O
+following	O
+databases	O
+up	O
+to	O
+November	O
+2004	O
+:	O
+the	O
+Cochrane	O
+Menstrual	O
+Disorders	O
+and	O
+Subfertility	O
+Group	O
+Trials	O
+Register	O
+","	O
+Cochrane	O
+Central	O
+Register	O
+of	O
+Controlled	O
+Trials	O
+(	O
+CENTRAL	O
+)	O
+","	O
+MEDLINE	O
+","	O
+EMBASE	O
+","	O
+Biological	O
+Abstracts	O
+.	O
+	
+Relevant	O
+non	O
+-	O
+indexed	O
+journals	O
+and	O
+conference	O
+abstracts	O
+were	O
+also	O
+searched	O
+.	O
+	
+SELECTION	O
+CRITERIA	O
+:	O
+Randomised	O
+double	O
+-	O
+blind	O
+trials	O
+of	O
+HT	O
+(	O
+oestrogens	O
+with	O
+or	O
+without	O
+progestogens	O
+)	O
+versus	O
+placebo	O
+","	O
+taken	O
+for	O
+at	O
+least	O
+one	O
+year	O
+by	O
+perimenopausal	O
+or	O
+postmenopausal	O
+women	O
+.	O
+	
+DATA	O
+COLLECTION	O
+AND	O
+ANALYSIS	O
+:	O
+Fifteen	O
+RCTs	O
+were	O
+included	O
+.	O
+	
+Trials	O
+were	O
+assessed	O
+for	O
+quality	O
+and	O
+two	O
+review	O
+authors	O
+extracted	O
+data	O
+independently	O
+.	O
+	
+They	O
+calculated	O
+risk	O
+ratios	O
+for	O
+dichotomous	O
+outcomes	O
+and	O
+weighted	O
+mean	O
+differences	O
+for	O
+continuous	O
+outcomes	O
+.	O
+	
+Clinical	O
+heterogeneity	O
+precluded	O
+meta	O
+-	O
+analysis	O
+for	O
+most	O
+outcomes	O
+.	O
+	
+MAIN	O
+RESULTS	O
+:	O
+All	O
+the	O
+statistically	O
+significant	O
+results	O
+were	O
+derived	O
+from	O
+the	O
+two	O
+biggest	O
+trials	O
+.	O
+	
+In	O
+relatively	O
+healthy	O
+women	O
+","	O
+combined	O
+continuous	O
+HT	O
+significantly	O
+increased	O
+the	O
+risk	O
+of	O
+venous	B-NP
+thromboembolism	I-NP
+or	O
+coronary	O
+event	O
+(	O
+after	O
+one	O
+year	O
+'	O
+s	O
+use	O
+)	O
+","	O
+stroke	B-NP
+(	O
+after	O
+3	O
+years	O
+)	O
+","	O
+breast	B-NP
+cancer	I-NP
+(	O
+after	O
+5	O
+years	O
+)	O
+and	O
+gallbladder	B-NP
+disease	I-NP
+.	O
+	
+Long	O
+-	O
+term	O
+oestrogen	O
+-	O
+only	O
+HT	O
+also	O
+significantly	O
+increased	O
+the	O
+risk	O
+of	O
+stroke	B-NP
+and	O
+gallbladder	B-NP
+disease	I-NP
+.	O
+	
+Overall	O
+","	O
+the	O
+only	O
+statistically	O
+significant	O
+benefits	O
+of	O
+HT	O
+were	O
+a	O
+decreased	O
+incidence	O
+of	O
+fractures	B-NP
+and	O
+colon	B-NP
+cancer	I-NP
+with	O
+long	O
+-	O
+term	O
+use	O
+.	O
+	
+Among	O
+relatively	O
+healthy	O
+women	O
+over	O
+65	O
+years	O
+taking	O
+continuous	O
+combined	O
+HT	O
+","	O
+there	O
+was	O
+a	O
+statistically	O
+significant	O
+increase	O
+in	O
+the	O
+incidence	O
+of	O
+dementia	B-NP
+.	O
+	
+Among	O
+women	O
+with	O
+cardiovascular	B-NP
+disease	I-NP
+","	O
+long	O
+-	O
+term	O
+use	O
+of	O
+combined	O
+continuous	O
+HT	O
+significantly	O
+increased	O
+the	O
+risk	O
+of	O
+venous	B-NP
+thromboembolism	I-NP
+.	O
+	
+No	O
+trials	O
+focussed	O
+specifically	O
+on	O
+younger	O
+women	O
+.	O
+	
+However	O
+","	O
+one	O
+trial	O
+analysed	O
+subgroups	O
+of	O
+2839	O
+relatively	O
+healthy	O
+50	O
+to	O
+59	O
+year	O
+-	O
+old	O
+women	O
+taking	O
+combined	O
+continuous	O
+HT	O
+and	O
+1637	O
+taking	O
+oestrogen	O
+-	O
+only	O
+HT	O
+","	O
+versus	O
+similar	O
+-	O
+sized	O
+placebo	O
+groups	O
+.	O
+	
+The	O
+only	O
+significantly	O
+increased	O
+risk	O
+reported	O
+was	O
+for	O
+venous	B-NP
+thromboembolism	I-NP
+in	O
+women	O
+taking	O
+combined	O
+continuous	O
+HT	O
+;	O
+their	O
+absolute	O
+risk	O
+remained	O
+very	O
+low	O
+.	O
+	
+AUTHORS	O
+'	O
+CONCLUSIONS	O
+:	O
+HT	O
+is	O
+not	O
+indicated	O
+for	O
+the	O
+routine	O
+management	O
+of	O
+chronic	B-NP
+disease	I-NP
+.	O
+	
+We	O
+need	O
+more	O
+evidence	O
+on	O
+the	O
+safety	O
+of	O
+HT	O
+for	O
+menopausal	O
+symptom	O
+control	O
+","	O
+though	O
+short	O
+-	O
+term	O
+use	O
+appears	O
+to	O
+be	O
+relatively	O
+safe	O
+for	O
+healthy	O
+younger	O
+women	O
+.	O
+	
+Drug	B-NP
+-	I-NP
+induced	I-NP
+liver	I-NP
+injury	I-NP
+:	O
+an	O
+analysis	O
+of	O
+461	O
+incidences	O
+submitted	O
+to	O
+the	O
+Spanish	O
+registry	O
+over	O
+a	O
+10	O
+-	O
+year	O
+period	O
+.	O
+	
+BACKGROUND	O
+&	O
+AIMS	O
+:	O
+Progress	O
+in	O
+the	O
+understanding	O
+of	O
+susceptibility	O
+factors	O
+to	O
+drug	B-NP
+-	I-NP
+induced	I-NP
+liver	I-NP
+injury	I-NP
+(	O
+DILI	B-NP
+)	O
+and	O
+outcome	O
+predictability	O
+are	O
+hampered	O
+by	O
+the	O
+lack	O
+of	O
+systematic	O
+programs	O
+to	O
+detect	O
+bona	O
+fide	O
+cases	O
+.	O
+	
+METHODS	O
+:	O
+A	O
+cooperative	O
+network	O
+was	O
+created	O
+in	O
+1994	O
+in	O
+Spain	O
+to	O
+identify	O
+all	O
+suspicions	O
+of	O
+DILI	B-NP
+following	O
+a	O
+prospective	O
+structured	O
+report	O
+form	O
+.	O
+	
+The	O
+liver	B-NP
+damage	I-NP
+was	O
+characterized	O
+according	O
+to	O
+hepatocellular	O
+","	O
+cholestatic	B-NP
+","	O
+and	O
+mixed	O
+laboratory	O
+criteria	O
+and	O
+to	O
+histologic	O
+criteria	O
+when	O
+available	O
+.	O
+	
+Further	O
+evaluation	O
+of	O
+causality	O
+assessment	O
+was	O
+centrally	O
+performed	O
+.	O
+	
+RESULTS	O
+:	O
+Since	O
+April	O
+1994	O
+to	O
+August	O
+2004	O
+","	O
+461	O
+out	O
+of	O
+570	O
+submitted	O
+cases	O
+","	O
+involving	O
+505	O
+drugs	O
+","	O
+were	O
+deemed	O
+to	O
+be	O
+related	O
+to	O
+DILI	B-NP
+.	O
+	
+The	O
+antiinfective	O
+group	O
+of	O
+drugs	O
+was	O
+the	O
+more	O
+frequently	O
+incriminated	O
+","	O
+amoxicillin	O
+-	O
+clavulanate	O
+accounting	O
+for	O
+the	O
+12	O
+.	O
+8	O
+%	O
+of	O
+the	O
+whole	O
+series	O
+.	O
+	
+The	O
+hepatocellular	O
+pattern	O
+of	O
+damage	O
+was	O
+the	O
+most	O
+common	O
+(	O
+58	O
+%	O
+)	O
+","	O
+was	O
+inversely	O
+correlated	O
+with	O
+age	O
+(	O
+P	O
+<	O
+.	O
+1	O
+)	O
+","	O
+and	O
+had	O
+the	O
+worst	O
+outcome	O
+(	O
+Cox	O
+regression	O
+","	O
+P	O
+<	O
+.	O
+34	O
+)	O
+.	O
+	
+Indeed	O
+","	O
+the	O
+incidence	O
+of	O
+liver	O
+transplantation	O
+and	O
+death	O
+in	O
+this	O
+group	O
+was	O
+11	O
+.	O
+7	O
+%	O
+if	O
+patients	O
+had	O
+jaundice	B-NP
+at	O
+presentation	O
+","	O
+whereas	O
+the	O
+corresponding	O
+figure	O
+was	O
+3	O
+.	O
+8	O
+%	O
+in	O
+nonjaundiced	O
+patients	O
+(	O
+P	O
+<	O
+.	O
+4	O
+)	O
+.	O
+	
+Factors	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+fulminant	B-NP
+hepatic	I-NP
+failure	I-NP
+were	O
+female	O
+sex	O
+(	O
+OR	O
+=	O
+25	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+4	O
+.	O
+1	O
+-	O
+151	O
+;	O
+P	O
+<	O
+.	O
+1	O
+)	O
+","	O
+hepatocellular	O
+damage	O
+(	O
+OR	O
+=	O
+7	O
+.	O
+9	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+1	O
+.	O
+6	O
+-	O
+37	O
+;	O
+P	O
+<	O
+.	O
+9	O
+)	O
+","	O
+and	O
+higher	O
+baseline	O
+plasma	O
+bilirubin	O
+value	O
+(	O
+OR	O
+=	O
+1	O
+.	O
+15	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+1	O
+.	O
+9	O
+-	O
+1	O
+.	O
+22	O
+;	O
+P	O
+<	O
+.	O
+1	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Patients	O
+with	O
+drug	O
+-	O
+induced	O
+hepatocellular	O
+jaundice	B-NP
+have	O
+11	O
+.	O
+7	O
+%	O
+chance	O
+of	O
+progressing	O
+to	O
+death	O
+or	O
+transplantation	O
+.	O
+	
+Amoxicillin	O
+-	O
+clavulanate	O
+stands	O
+out	O
+as	O
+the	O
+most	O
+common	O
+drug	O
+related	O
+to	O
+DILI	B-NP
+.	O
+	
+Morphological	O
+evaluation	O
+of	O
+the	O
+effect	O
+of	O
+d	O
+-	O
+ribose	O
+on	O
+adriamycin	O
+-	O
+evoked	O
+cardiotoxicity	B-NP
+in	O
+rats	O
+.	O
+	
+The	O
+influence	O
+of	O
+d	O
+-	O
+ribose	O
+on	O
+adriamycin	O
+-	O
+induced	O
+myocardiopathy	B-NP
+in	O
+rats	O
+was	O
+studied	O
+.	O
+	
+Adriamycin	O
+in	O
+the	O
+cumulative	O
+dose	O
+of	O
+25	O
+mg	O
+/	O
+kg	O
+evoked	O
+fully	O
+developed	O
+cardiac	B-NP
+toxicity	I-NP
+.	O
+	
+D	O
+-	O
+ribose	O
+in	O
+the	O
+multiple	O
+doses	O
+of	O
+200	O
+mg	O
+/	O
+kg	O
+did	O
+not	O
+influence	O
+ADR	O
+cardiotoxicity	B-NP
+.	O
+	
+In	O
+vivo	O
+evidences	O
+suggesting	O
+the	O
+role	O
+of	O
+oxidative	O
+stress	O
+in	O
+pathogenesis	O
+of	O
+vancomycin	O
+-	O
+induced	O
+nephrotoxicity	B-NP
+:	O
+protection	O
+by	O
+erdosteine	O
+.	O
+	
+The	O
+aims	O
+of	O
+this	O
+study	O
+were	O
+to	O
+examine	O
+vancomycin	O
+(	O
+VCM	O
+)	O
+-	O
+induced	O
+oxidative	O
+stress	O
+that	O
+promotes	O
+production	O
+of	O
+reactive	O
+oxygen	O
+species	O
+(	O
+ROS	O
+)	O
+and	O
+to	O
+investigate	O
+the	O
+role	O
+of	O
+erdosteine	O
+","	O
+an	O
+expectorant	O
+agent	O
+","	O
+which	O
+has	O
+also	O
+antioxidant	O
+properties	O
+","	O
+on	O
+kidney	O
+tissue	O
+against	O
+the	O
+possible	O
+VCM	O
+-	O
+induced	O
+renal	B-NP
+impairment	I-NP
+in	O
+rats	O
+.	O
+	
+Rats	O
+were	O
+divided	O
+into	O
+three	O
+groups	O
+:	O
+sham	O
+","	O
+VCM	O
+and	O
+VCM	O
+plus	O
+erdosteine	O
+.	O
+	
+VCM	O
+was	O
+administrated	O
+intraperitoneally	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+with	O
+200mgkg	O
+(	O
+-	O
+1	O
+)	O
+twice	O
+daily	O
+for	O
+7	O
+days	O
+.	O
+	
+Erdosteine	O
+was	O
+administered	O
+orally	O
+.	O
+	
+VCM	O
+administration	O
+to	O
+control	O
+rats	O
+significantly	O
+increased	O
+renal	O
+malondialdehyde	O
+(	O
+MDA	O
+)	O
+and	O
+urinary	O
+N	O
+-	O
+acetyl	O
+-	O
+beta	O
+-	O
+d	O
+-	O
+glucosaminidase	O
+(	O
+NAG	O
+","	O
+a	O
+marker	O
+of	O
+renal	B-NP
+tubular	I-NP
+injury	I-NP
+)	O
+excretion	O
+but	O
+decreased	O
+superoxide	O
+dismutase	O
+(	O
+SOD	O
+)	O
+and	O
+catalase	O
+(	O
+CAT	O
+)	O
+activities	O
+.	O
+	
+Erdosteine	O
+administration	O
+with	O
+VCM	O
+injections	O
+caused	O
+significantly	O
+decreased	O
+renal	O
+MDA	O
+and	O
+urinary	O
+NAG	O
+excretion	O
+","	O
+and	O
+increased	O
+SOD	O
+activity	O
+","	O
+but	O
+not	O
+CAT	O
+activity	O
+in	O
+renal	O
+tissue	O
+when	O
+compared	O
+with	O
+VCM	O
+alone	O
+.	O
+	
+Erdosteine	O
+showed	O
+histopathological	O
+protection	O
+against	O
+VCM	O
+-	O
+induced	O
+nephrotoxicity	B-NP
+.	O
+	
+There	O
+were	O
+a	O
+significant	O
+dilatation	O
+of	O
+tubular	O
+lumens	O
+","	O
+extensive	O
+epithelial	O
+cell	O
+vacuolization	O
+","	O
+atrophy	B-NP
+","	O
+desquamation	B-NP
+","	O
+and	O
+necrosis	B-NP
+in	O
+VCM	O
+-	O
+treated	O
+rats	O
+more	O
+than	O
+those	O
+of	O
+the	O
+control	O
+and	O
+the	O
+erdosteine	O
+groups	O
+.	O
+	
+Erdosteine	O
+caused	O
+a	O
+marked	O
+reduction	O
+in	O
+the	O
+extent	O
+of	O
+tubular	O
+damage	O
+.	O
+	
+It	O
+is	O
+concluded	O
+that	O
+oxidative	O
+tubular	O
+damage	O
+plays	O
+an	O
+important	O
+role	O
+in	O
+the	O
+VCM	O
+-	O
+induced	O
+nephrotoxicity	B-NP
+and	O
+the	O
+modulation	O
+of	O
+oxidative	O
+stress	O
+with	O
+erdosteine	O
+reduces	O
+the	O
+VCM	O
+-	O
+induced	O
+kidney	B-NP
+damage	I-NP
+both	O
+at	O
+the	O
+biochemical	O
+and	O
+histological	O
+levels	O
+.	O
+	
+Gemfibrozil	O
+-	O
+lovastatin	O
+therapy	O
+for	O
+primary	O
+hyperlipoproteinemias	B-NP
+.	O
+	
+The	O
+specific	O
+aim	O
+of	O
+this	O
+retrospective	O
+","	O
+observational	O
+study	O
+was	O
+to	O
+assess	O
+safety	O
+and	O
+efficacy	O
+of	O
+long	O
+-	O
+term	O
+(	O
+21	O
+months	O
+/	O
+patient	O
+)	O
+","	O
+open	O
+-	O
+label	O
+","	O
+gemfibrozil	O
+-	O
+lovastatin	O
+treatment	O
+in	O
+80	O
+patients	O
+with	O
+primary	O
+mixed	O
+hyperlipidemia	B-NP
+(	O
+68	O
+%	O
+of	O
+whom	O
+had	O
+atherosclerotic	B-NP
+vascular	I-NP
+disease	I-NP
+)	O
+.	O
+	
+Because	O
+ideal	O
+lipid	O
+targets	O
+were	O
+not	O
+reached	O
+(	O
+low	O
+-	O
+density	O
+lipoprotein	O
+(	O
+LDL	O
+)	O
+cholesterol	O
+less	O
+than	O
+130	O
+mg	O
+/	O
+dl	O
+","	O
+high	O
+-	O
+density	O
+lipoprotein	O
+(	O
+HDL	O
+)	O
+cholesterol	O
+greater	O
+than	O
+35	O
+mg	O
+/	O
+dl	O
+","	O
+or	O
+total	O
+cholesterol	O
+/	O
+HDL	O
+cholesterol	O
+less	O
+than	O
+4	O
+.	O
+5	O
+mg	O
+/	O
+dl	O
+)	O
+with	O
+diet	O
+plus	O
+a	O
+single	O
+drug	O
+","	O
+gemfibrozil	O
+(	O
+1	O
+.	O
+2	O
+g	O
+/	O
+day	O
+)	O
+-	O
+lovastatin	O
+(	O
+primarily	O
+20	O
+or	O
+40	O
+mg	O
+)	O
+treatment	O
+was	O
+given	O
+.	O
+	
+Follow	O
+-	O
+up	O
+visits	O
+were	O
+scheduled	O
+with	O
+2	O
+-	O
+drug	O
+therapy	O
+every	O
+6	O
+to	O
+8	O
+weeks	O
+","	O
+an	O
+average	O
+of	O
+10	O
+.	O
+3	O
+visits	O
+per	O
+patient	O
+","	O
+with	O
+741	O
+batteries	O
+of	O
+6	O
+liver	O
+function	O
+tests	O
+and	O
+714	O
+creatine	O
+phosphokinase	O
+levels	O
+measured	O
+.	O
+	
+Only	O
+1	O
+of	O
+the	O
+4	O
+","	O
+446	O
+liver	O
+function	O
+tests	O
+(	O
+0	O
+.	O
+2	O
+%	O
+)	O
+","	O
+a	O
+gamma	O
+glutamyl	O
+transferase	O
+","	O
+was	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+3	O
+times	O
+the	O
+upper	O
+normal	O
+limit	O
+.	O
+	
+Of	O
+the	O
+714	O
+creatine	O
+phosphokinase	O
+levels	O
+","	O
+9	O
+%	O
+were	O
+high	O
+;	O
+only	O
+1	O
+(	O
+0	O
+.	O
+1	O
+%	O
+)	O
+was	O
+greater	O
+than	O
+or	O
+equal	O
+to	O
+3	O
+times	O
+the	O
+upper	O
+normal	O
+limit	O
+.	O
+	
+With	O
+2	O
+-	O
+drug	O
+therapy	O
+","	O
+mean	O
+total	O
+cholesterol	O
+decreased	O
+22	O
+%	O
+from	O
+255	O
+to	O
+200	O
+mg	O
+/	O
+dl	O
+","	O
+triglyceride	O
+levels	O
+decreased	O
+35	O
+%	O
+from	O
+236	O
+to	O
+154	O
+mg	O
+/	O
+dl	O
+","	O
+LDL	O
+cholesterol	O
+decreased	O
+26	O
+%	O
+from	O
+176	O
+to	O
+131	O
+mg	O
+/	O
+dl	O
+","	O
+and	O
+the	O
+total	O
+cholesterol	O
+/	O
+HDL	O
+cholesterol	O
+ratio	O
+decreased	O
+24	O
+%	O
+from	O
+7	O
+.	O
+1	O
+to	O
+5	O
+.	O
+4	O
+","	O
+all	O
+p	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+0	O
+.	O
+1	O
+.	O
+	
+Myositis	B-NP
+","	O
+attributable	O
+to	O
+the	O
+drug	O
+combination	O
+and	O
+symptomatic	O
+enough	O
+to	O
+discontinue	O
+it	O
+","	O
+occurred	O
+in	O
+3	O
+%	O
+of	O
+patients	O
+","	O
+and	O
+in	O
+1	O
+%	O
+with	O
+concurrent	O
+high	O
+creatine	O
+phosphokinase	O
+(	O
+769	O
+U	O
+/	O
+liter	O
+)	O
+;	O
+no	O
+patients	O
+had	O
+rhabdomyolysis	B-NP
+or	O
+myoglobinuria	B-NP
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+	
+Does	O
+domperidone	O
+potentiate	O
+mirtazapine	O
+-	O
+associated	O
+restless	B-NP
+legs	I-NP
+syndrome	I-NP
+?	O
+	
+There	O
+is	O
+now	O
+evidence	O
+to	O
+suggest	O
+a	O
+central	O
+role	O
+for	O
+the	O
+dopaminergic	O
+system	O
+in	O
+restless	B-NP
+legs	I-NP
+syndrome	I-NP
+(	O
+RLS	B-NP
+)	O
+.	O
+	
+For	O
+example	O
+","	O
+the	O
+symptoms	O
+of	O
+RLS	B-NP
+can	O
+be	O
+dramatically	O
+improved	O
+by	O
+levodopa	O
+and	O
+dopamine	O
+agonists	O
+","	O
+whereas	O
+central	O
+dopamine	O
+D2	O
+receptor	O
+antagonists	O
+can	O
+induce	O
+or	O
+aggravate	O
+RLS	B-NP
+symptoms	O
+.	O
+	
+To	O
+our	O
+knowledge	O
+","	O
+there	O
+is	O
+no	O
+previous	O
+report	O
+regarding	O
+whether	O
+domperidone	O
+","	O
+a	O
+peripheral	O
+dopamine	O
+D2	O
+receptor	O
+antagonist	O
+","	O
+can	O
+also	O
+induce	O
+or	O
+aggravate	O
+symptoms	O
+of	O
+RLS	B-NP
+.	O
+	
+Mirtazapine	O
+","	O
+the	O
+first	O
+noradrenergic	O
+and	O
+specific	O
+serotonergic	O
+antidepressant	O
+(	O
+NaSSA	O
+)	O
+","	O
+has	O
+been	O
+associated	O
+with	O
+RLS	B-NP
+in	O
+several	O
+recent	O
+publications	O
+.	O
+	
+The	O
+authors	O
+report	O
+here	O
+a	O
+depressed	O
+patient	O
+comorbid	O
+with	O
+postprandial	B-NP
+dyspepsia	I-NP
+who	O
+developed	O
+RLS	B-NP
+after	O
+mirtazapine	O
+had	O
+been	O
+added	O
+to	O
+his	O
+domperidone	O
+therapy	O
+.	O
+	
+Our	O
+patient	O
+started	O
+to	O
+have	O
+symptoms	O
+of	O
+RLS	B-NP
+only	O
+after	O
+he	O
+had	O
+been	O
+treated	O
+with	O
+mirtazapine	O
+","	O
+and	O
+his	O
+RLS	B-NP
+symptoms	O
+resolved	O
+completely	O
+upon	O
+discontinuation	O
+of	O
+his	O
+mirtazapine	O
+.	O
+	
+Such	O
+a	O
+temporal	O
+relationship	O
+between	O
+the	O
+use	O
+of	O
+mirtazapine	O
+and	O
+the	O
+symptoms	O
+of	O
+RLS	B-NP
+in	O
+our	O
+patient	O
+did	O
+not	O
+support	O
+a	O
+potentiating	O
+effect	O
+of	O
+domperione	O
+on	O
+mirtazapine	O
+-	O
+associated	O
+RLS	B-NP
+.	O
+	
+However	O
+","	O
+physicians	O
+should	O
+be	O
+aware	O
+of	O
+the	O
+possibility	O
+that	O
+mirtazapine	O
+can	O
+be	O
+associated	O
+with	O
+RLS	B-NP
+in	O
+some	O
+individuals	O
+","	O
+especially	O
+those	O
+receiving	O
+concomitant	O
+dopamine	O
+D2	O
+receptor	O
+antagonists	O
+.	O
+	
+Antiandrogenic	O
+therapy	O
+can	O
+cause	O
+coronary	B-NP
+arterial	I-NP
+disease	I-NP
+.	O
+	
+AIM	O
+:	O
+To	O
+study	O
+the	O
+change	O
+of	O
+lipid	O
+metabolism	O
+by	O
+antiandrogen	O
+therapy	O
+in	O
+patients	O
+with	O
+prostate	B-NP
+cancer	I-NP
+.	O
+	
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+We	O
+studied	O
+with	O
+a	O
+2	O
+.	O
+5	O
+years	O
+follow	O
+-	O
+up	O
+the	O
+changes	O
+in	O
+plasma	O
+cholesterols	O
+(	O
+C	O
+)	O
+","	O
+triglycerides	O
+(	O
+TG	O
+)	O
+","	O
+lipoproteins	O
+(	O
+LP	O
+)	O
+","	O
+and	O
+apolipoproteins	O
+(	O
+Apo	O
+)	O
+B	O
+-	O
+100	O
+","	O
+A	O
+-	O
+I	O
+","	O
+and	O
+A	O
+-	O
+II	O
+pro	O
+fi	O
+les	O
+in	O
+24	O
+patients	O
+of	O
+mean	O
+age	O
+60	O
+years	O
+with	O
+low	O
+risk	O
+prostate	B-NP
+cancer	I-NP
+(	O
+stage	O
+:	O
+T1cN0M0	O
+","	O
+Gleason	O
+score	O
+:	O
+2	O
+-	O
+5	O
+)	O
+during	O
+treatment	O
+with	O
+cyproterone	O
+acetate	O
+(	O
+CPA	O
+)	O
+without	O
+surgical	O
+management	O
+or	O
+radiation	O
+therapy	O
+.	O
+	
+RESULTS	O
+:	O
+Significant	O
+decreases	O
+of	O
+HDL	O
+-	O
+C	O
+","	O
+Apo	O
+A	O
+-	O
+I	O
+and	O
+Apo	O
+A	O
+-	O
+II	O
+and	O
+an	O
+increase	O
+of	O
+triglyceride	O
+levels	O
+in	O
+VLDL	O
+were	O
+induced	O
+by	O
+CPA	O
+.	O
+	
+After	O
+a	O
+period	O
+of	O
+2	O
+.	O
+5	O
+years	O
+on	O
+CPA	O
+treatment	O
+","	O
+four	O
+patients	O
+out	O
+of	O
+twenty	O
+-	O
+four	O
+were	O
+found	O
+to	O
+be	O
+affected	O
+by	O
+coronary	B-NP
+heart	I-NP
+disease	I-NP
+.	O
+	
+CONCLUSIONS	O
+:	O
+Ischaemic	O
+coronary	B-NP
+arteriosclerosis	I-NP
+with	O
+an	O
+incidence	O
+rate	O
+of	O
+16	O
+.	O
+6	O
+%	O
+as	O
+caused	O
+by	O
+prolonged	O
+CPA	O
+therapy	O
+is	O
+mediated	O
+through	O
+changes	O
+in	O
+HDL	O
+cholesterol	O
+","	O
+Apo	O
+A	O
+-	O
+I	O
+and	O
+Apo	O
+A	O
+-	O
+II	O
+pro	O
+fi	O
+les	O
+","	O
+other	O
+than	O
+the	O
+well	O
+-	O
+known	O
+hyperglyceridemic	B-NP
+effect	I-NP
+caused	O
+by	O
+estrogen	O
+.	O
+	
+5	O
+-	O
+Fluorouracil	O
+cardiotoxicity	B-NP
+induced	O
+by	O
+alpha	O
+-	O
+fluoro	O
+-	O
+beta	O
+-	O
+alanine	O
+.	O
+	
+Cardiotoxicity	B-NP
+is	O
+a	O
+rare	O
+complication	O
+occurring	O
+during	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+treatment	O
+for	O
+malignancies	B-NP
+.	O
+	
+We	O
+herein	O
+report	O
+the	O
+case	O
+of	O
+a	O
+70	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+5	O
+-	O
+FU	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+","	O
+in	O
+whom	O
+a	O
+high	O
+serum	O
+level	O
+of	O
+alpha	O
+-	O
+fluoro	O
+-	O
+beta	O
+-	O
+alanine	O
+(	O
+FBAL	O
+)	O
+was	O
+observed	O
+.	O
+	
+The	O
+patient	O
+","	O
+who	O
+had	O
+unresectable	O
+colon	B-NP
+cancer	I-NP
+metastases	O
+to	O
+the	O
+liver	O
+and	O
+lung	O
+","	O
+was	O
+referred	O
+to	O
+us	O
+for	O
+chemotherapy	O
+from	O
+an	O
+affiliated	O
+hospital	O
+;	O
+he	O
+had	O
+no	O
+cardiac	O
+history	O
+.	O
+	
+After	O
+admission	O
+","	O
+the	O
+patient	O
+received	O
+a	O
+continuous	O
+intravenous	O
+infusion	O
+of	O
+5	O
+-	O
+FU	O
+(	O
+1000	O
+mg	O
+/	O
+day	O
+)	O
+","	O
+during	O
+which	O
+precordial	B-NP
+pain	I-NP
+with	O
+right	B-NP
+bundle	I-NP
+branch	I-NP
+block	I-NP
+occurred	O
+concomitantly	O
+with	O
+a	O
+high	O
+serum	O
+FBAL	O
+concentration	O
+of	O
+1955	O
+ng	O
+/	O
+ml	O
+.	O
+	
+Both	O
+the	O
+precordial	B-NP
+pain	I-NP
+and	O
+the	O
+electrocardiographic	O
+changes	O
+disappeared	O
+spontaneously	O
+after	O
+the	O
+discontinuation	O
+of	O
+5	O
+-	O
+FU	O
+.	O
+	
+As	O
+the	O
+precordial	B-NP
+pain	I-NP
+in	O
+this	O
+patient	O
+was	O
+considered	O
+to	O
+have	O
+been	O
+due	O
+to	O
+5	O
+-	O
+FU	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+","	O
+the	O
+administration	O
+of	O
+5	O
+-	O
+FU	O
+was	O
+abandoned	O
+.	O
+	
+Instead	O
+","	O
+oral	O
+administration	O
+of	O
+S	O
+-	O
+1	O
+(	O
+a	O
+derivative	O
+of	O
+5	O
+-	O
+FU	O
+)	O
+","	O
+at	O
+200	O
+mg	O
+/	O
+day	O
+twice	O
+a	O
+week	O
+","	O
+was	O
+instituted	O
+","	O
+because	O
+S	O
+-	O
+1	O
+has	O
+a	O
+strong	O
+inhibitory	O
+effect	O
+on	O
+dihydropyrimidine	O
+dehydrogenase	O
+","	O
+which	O
+catalyzes	O
+the	O
+degradative	O
+of	O
+5	O
+-	O
+FU	O
+into	O
+FBAL	O
+.	O
+	
+The	O
+serum	O
+FBAL	O
+concentration	O
+subsequently	O
+decreased	O
+to	O
+352	O
+ng	O
+/	O
+ml	O
+","	O
+the	O
+same	O
+as	O
+the	O
+value	O
+measured	O
+on	O
+the	O
+first	O
+day	O
+of	O
+S	O
+-	O
+1	O
+administration	O
+.	O
+	
+Thereafter	O
+","	O
+no	O
+cardiac	B-NP
+symptoms	I-NP
+were	O
+observed	O
+.	O
+	
+The	O
+patient	O
+achieved	O
+a	O
+partial	O
+response	O
+6	O
+months	O
+after	O
+the	O
+initiation	O
+of	O
+the	O
+S	O
+-	O
+1	O
+treatment	O
+.	O
+	
+The	O
+experience	O
+of	O
+this	O
+case	O
+","	O
+together	O
+with	O
+a	O
+review	O
+of	O
+the	O
+literature	O
+","	O
+suggests	O
+that	O
+FBAL	O
+is	O
+related	O
+to	O
+5	O
+-	O
+FU	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+.	O
+	
+S	O
+-	O
+1	O
+may	O
+be	O
+administered	O
+safely	O
+to	O
+patients	O
+with	O
+5	O
+-	O
+FU	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+.	O
+	
+Hepatocellular	B-NP
+carcinoma	I-NP
+in	O
+Fanconi	B-NP
+'	I-NP
+s	I-NP
+anemia	I-NP
+treated	O
+with	O
+androgen	O
+and	O
+corticosteroid	O
+.	O
+	
+The	O
+case	O
+of	O
+an	O
+11	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+is	O
+reported	O
+who	O
+was	O
+known	O
+to	O
+have	O
+Fanconi	B-NP
+'	I-NP
+s	I-NP
+anemia	I-NP
+for	O
+3	O
+years	O
+and	O
+was	O
+treated	O
+with	O
+androgens	O
+","	O
+corticosteroids	O
+and	O
+transfusions	O
+.	O
+	
+Two	O
+weeks	O
+before	O
+his	O
+death	O
+he	O
+was	O
+readmitted	O
+because	O
+of	O
+aplastic	O
+crisis	O
+with	O
+septicemia	B-NP
+and	O
+marked	O
+abnormalities	O
+in	O
+liver	O
+function	O
+and	O
+died	O
+of	O
+hemorrhagic	B-NP
+bronchopneumonia	I-NP
+.	O
+	
+At	O
+autopsy	O
+peliosis	B-NP
+and	O
+multiple	O
+hepatic	B-NP
+tumors	I-NP
+were	O
+found	O
+which	O
+histologically	O
+proved	O
+to	O
+be	O
+well	O
+-	O
+differentiated	O
+hepatocellular	B-NP
+carcinoma	I-NP
+.	O
+	
+This	O
+case	O
+contributes	O
+to	O
+the	O
+previous	O
+observations	O
+that	O
+non	O
+-	O
+metastasizing	O
+hepatic	B-NP
+neoplasms	I-NP
+and	O
+peliosis	B-NP
+can	O
+develop	O
+in	O
+patients	O
+with	O
+androgen	O
+-	O
+and	O
+corticosteroid	O
+-	O
+treated	O
+Fanconi	B-NP
+'	I-NP
+s	I-NP
+anemia	I-NP
+.	O
+	
+The	O
+influence	O
+of	O
+the	O
+time	O
+interval	O
+between	O
+monoHER	O
+and	O
+doxorubicin	O
+administration	O
+on	O
+the	O
+protection	O
+against	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+in	O
+mice	O
+.	O
+	
+PURPOSE	O
+:	O
+Despite	O
+its	O
+well	O
+-	O
+known	O
+cardiotoxicity	B-NP
+","	O
+the	O
+anthracyclin	O
+doxorubicin	O
+(	O
+DOX	O
+)	O
+continues	O
+to	O
+be	O
+an	O
+effective	O
+and	O
+widely	O
+used	O
+chemotherapeutic	O
+agent	O
+.	O
+	
+DOX	O
+-	O
+induced	O
+cardiac	B-NP
+damage	I-NP
+presumably	O
+results	O
+from	O
+the	O
+formation	O
+of	O
+free	O
+radicals	O
+by	O
+DOX	O
+.	O
+	
+Reactive	O
+oxygen	O
+species	O
+particularly	O
+affect	O
+the	O
+cardiac	O
+myocytes	O
+because	O
+these	O
+cells	O
+seem	O
+to	O
+have	O
+a	O
+relatively	O
+poor	O
+antioxidant	O
+defense	O
+system	O
+.	O
+	
+The	O
+semisynthetic	O
+flavonoid	O
+monohydroxyethylrutoside	O
+(	O
+monoHER	O
+)	O
+showed	O
+cardioprotection	O
+against	O
+DOX	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+through	O
+its	O
+radical	O
+scavenging	O
+and	O
+iron	O
+chelating	O
+properties	O
+.	O
+	
+Because	O
+of	O
+the	O
+relatively	O
+short	O
+final	O
+half	O
+-	O
+life	O
+of	O
+monoHER	O
+(	O
+about	O
+30	O
+min	O
+)	O
+","	O
+it	O
+is	O
+expected	O
+that	O
+the	O
+time	O
+interval	O
+between	O
+monoHER	O
+and	O
+DOX	O
+might	O
+be	O
+of	O
+influence	O
+on	O
+the	O
+cardioprotective	O
+effect	O
+of	O
+monoHER	O
+.	O
+	
+Therefore	O
+","	O
+the	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+investigate	O
+this	O
+possible	O
+effect	O
+.	O
+	
+METHODS	O
+:	O
+Six	O
+groups	O
+of	O
+6	O
+BALB	O
+/	O
+c	O
+mice	O
+were	O
+treated	O
+with	O
+saline	O
+","	O
+DOX	O
+alone	O
+or	O
+DOX	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+preceded	O
+by	O
+monoHER	O
+(	O
+500	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+with	O
+an	O
+interval	O
+of	O
+10	O
+","	O
+30	O
+","	O
+60	O
+or	O
+120	O
+min	O
+.	O
+	
+After	O
+a	O
+6	O
+-	O
+week	O
+treatment	O
+period	O
+and	O
+additional	O
+observation	O
+for	O
+2	O
+weeks	O
+","	O
+the	O
+mice	O
+were	O
+sacrificed	O
+.	O
+	
+Their	O
+cardiac	O
+tissues	O
+were	O
+processed	O
+for	O
+light	O
+microscopy	O
+","	O
+after	O
+which	O
+cardiomyocyte	B-NP
+damage	I-NP
+was	O
+evaluated	O
+according	O
+to	O
+Billingham	O
+(	O
+in	O
+Cancer	B-NP
+Treat	O
+Rep	O
+62	O
+(	O
+6	O
+)	O
+:	O
+865	O
+-	O
+872	O
+","	O
+1978	O
+)	O
+.	O
+	
+Microscopic	O
+evaluation	O
+revealed	O
+that	O
+treatment	O
+with	O
+DOX	O
+alone	O
+induced	O
+significant	O
+cardiac	B-NP
+damage	I-NP
+in	O
+comparison	O
+to	O
+the	O
+saline	O
+control	O
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+number	O
+of	O
+damaged	O
+cardiomyocytes	O
+was	O
+9	O
+.	O
+6	O
+-	O
+fold	O
+(	O
+95	O
+%	O
+CI	O
+4	O
+.	O
+4	O
+-	O
+21	O
+.	O
+0	O
+)	O
+higher	O
+in	O
+mice	O
+treated	O
+with	O
+DOX	O
+alone	O
+than	O
+that	O
+in	O
+animals	O
+of	O
+the	O
+control	O
+group	O
+.	O
+	
+The	O
+ratio	O
+of	O
+aberrant	O
+cardiomyocytes	O
+in	O
+mice	O
+treated	O
+with	O
+DOX	O
+preceded	O
+by	O
+monoHER	O
+and	O
+those	O
+in	O
+mice	O
+treated	O
+with	O
+saline	O
+ranged	O
+from	O
+1	O
+.	O
+6	O
+to	O
+2	O
+.	O
+8	O
+(	O
+mean	O
+2	O
+.	O
+2	O
+","	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+2	O
+-	O
+4	O
+.	O
+1	O
+","	O
+P	O
+=	O
+0	O
+.	O
+19	O
+)	O
+.	O
+	
+The	O
+mean	O
+protective	O
+effect	O
+by	O
+adding	O
+monoHER	O
+before	O
+DOX	O
+led	O
+to	O
+a	O
+significant	O
+4	O
+.	O
+4	O
+-	O
+fold	O
+reduction	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+","	O
+95	O
+%	O
+CI	O
+2	O
+.	O
+3	O
+-	O
+8	O
+.	O
+2	O
+)	O
+of	O
+abnormal	O
+cardiomyocytes	O
+.	O
+	
+This	O
+protective	O
+effect	O
+did	O
+not	O
+depend	O
+on	O
+the	O
+time	O
+interval	O
+between	O
+monoHER	O
+and	O
+DOX	O
+administration	O
+(	O
+P	O
+=	O
+0	O
+.	O
+345	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+The	O
+results	O
+indicate	O
+that	O
+in	O
+an	O
+outpatient	O
+clinical	O
+setting	O
+monoHER	O
+may	O
+be	O
+administered	O
+shortly	O
+before	O
+DOX	O
+.	O
+	
+Clinical	O
+evaluation	O
+of	O
+adverse	O
+effects	O
+during	O
+bepridil	O
+administration	O
+for	O
+atrial	B-NP
+fibrillation	I-NP
+and	I-NP
+flutter	I-NP
+.	O
+	
+BACKGROUND	O
+:	O
+Bepridil	O
+hydrochloride	O
+(	O
+Bpd	O
+)	O
+has	O
+attracted	O
+attention	O
+as	O
+an	O
+effective	O
+drug	O
+for	O
+atrial	B-NP
+fibrillation	I-NP
+(	O
+AF	B-NP
+)	O
+and	O
+atrial	B-NP
+flutter	I-NP
+(	O
+AFL	B-NP
+)	O
+.	O
+	
+However	O
+","	O
+serious	O
+adverse	O
+effects	O
+","	O
+including	O
+torsade	B-NP
+de	I-NP
+pointes	I-NP
+(	O
+Tdp	B-NP
+)	O
+","	O
+have	O
+been	O
+reported	O
+.	O
+	
+METHODS	O
+AND	O
+RESULTS	O
+:	O
+Adverse	O
+effects	O
+of	O
+Bpd	O
+requiring	O
+discontinuation	O
+of	O
+treatment	O
+were	O
+evaluated	O
+.	O
+	
+Bpd	O
+was	O
+administered	O
+to	O
+459	O
+patients	O
+(	O
+361	O
+males	O
+","	O
+63	O
++	O
+/	O
+-	O
+12	O
+years	O
+old	O
+)	O
+comprising	O
+378	O
+AF	B-NP
+and	O
+81	O
+AFL	B-NP
+cases	O
+.	O
+	
+Mean	O
+left	O
+ventricular	O
+ejection	O
+fraction	O
+and	O
+atrial	O
+dimension	O
+(	O
+LAD	O
+)	O
+were	O
+66	O
++	O
+/	O
+-	O
+11	O
+%	O
+and	O
+40	O
++	O
+/	O
+-	O
+6	O
+mm	O
+","	O
+respectively	O
+.	O
+	
+Adverse	O
+effects	O
+were	O
+observed	O
+in	O
+19	O
+patients	O
+(	O
+4	O
+%	O
+)	O
+during	O
+an	O
+average	O
+follow	O
+-	O
+up	O
+of	O
+20	O
+months	O
+.	O
+	
+There	O
+was	O
+marked	O
+QT	B-NP
+prolongation	I-NP
+greater	O
+than	O
+0	O
+.	O
+55	O
+s	O
+in	O
+13	O
+patients	O
+","	O
+bradycardia	B-NP
+less	O
+than	O
+40	O
+beats	O
+/	O
+min	O
+in	O
+6	O
+patients	O
+","	O
+dizziness	B-NP
+and	O
+general	O
+fatigue	B-NP
+in	O
+1	O
+patient	O
+each	O
+.	O
+	
+In	O
+4	O
+of	O
+13	O
+patients	O
+with	O
+QT	B-NP
+prolongation	I-NP
+","	O
+Tdp	B-NP
+occurred	O
+.	O
+	
+The	O
+major	O
+triggering	O
+factors	O
+of	O
+Tdp	B-NP
+were	O
+hypokalemia	B-NP
+and	O
+sudden	O
+decrease	O
+in	O
+heart	O
+rate	O
+.	O
+	
+There	O
+were	O
+no	O
+differences	O
+in	O
+the	O
+clinical	O
+backgrounds	O
+of	O
+the	O
+patients	O
+with	O
+and	O
+without	O
+Tdp	B-NP
+other	O
+than	O
+LAD	O
+and	O
+age	O
+","	O
+which	O
+were	O
+larger	O
+and	O
+older	O
+in	O
+the	O
+patients	O
+with	O
+Tdp	B-NP
+.	O
+	
+CONCLUSION	O
+:	O
+Careful	O
+observation	O
+of	O
+serum	O
+potassium	O
+concentration	O
+and	O
+the	O
+ECG	O
+should	O
+always	O
+be	O
+done	O
+during	O
+Bpd	O
+administration	O
+","	O
+particularly	O
+in	O
+elderly	O
+patients	O
+.	O
+	
+Enhanced	O
+isoproterenol	O
+-	O
+induced	O
+cardiac	B-NP
+hypertrophy	I-NP
+in	O
+transgenic	O
+rats	O
+with	O
+low	O
+brain	O
+angiotensinogen	O
+.	O
+	
+We	O
+have	O
+previously	O
+shown	O
+that	O
+a	O
+permanent	O
+deficiency	O
+in	O
+the	O
+brain	O
+renin	O
+-	O
+angiotensin	O
+system	O
+(	O
+RAS	O
+)	O
+may	O
+increase	O
+the	O
+sensitivity	O
+of	O
+the	O
+baroreflex	O
+control	O
+of	O
+heart	O
+rate	O
+.	O
+	
+In	O
+this	O
+study	O
+we	O
+aimed	O
+at	O
+studying	O
+the	O
+involvement	O
+of	O
+the	O
+brain	O
+RAS	O
+in	O
+the	O
+cardiac	O
+reactivity	O
+to	O
+the	O
+beta	O
+-	O
+adrenoceptor	O
+(	O
+beta	O
+-	O
+AR	O
+)	O
+agonist	O
+isoproterenol	O
+(	O
+Iso	O
+)	O
+.	O
+	
+Transgenic	O
+rats	O
+with	O
+low	O
+brain	O
+angiotensinogen	O
+(	O
+TGR	O
+)	O
+were	O
+used	O
+.	O
+	
+In	O
+isolated	O
+hearts	O
+","	O
+Iso	O
+induced	O
+a	O
+significantly	O
+greater	O
+increase	O
+in	O
+left	O
+ventricular	O
+(	O
+LV	O
+)	O
+pressure	O
+and	O
+maximal	O
+contraction	O
+(	O
++	O
+dP	O
+/	O
+dt	O
+(	O
+max	O
+)	O
+)	O
+in	O
+the	O
+TGR	O
+than	O
+in	O
+the	O
+Sprague	O
+-	O
+Dawley	O
+(	O
+SD	O
+)	O
+rats	O
+.	O
+	
+LV	B-NP
+hypertrophy	I-NP
+induced	O
+by	O
+Iso	O
+treatment	O
+was	O
+significantly	O
+higher	O
+in	O
+TGR	O
+than	O
+in	O
+SD	O
+rats	O
+(	O
+in	O
+g	O
+LV	O
+wt	O
+/	O
+100	O
+g	O
+body	O
+wt	O
+","	O
+0	O
+.	O
+28	O
++	O
+/	O
+-	O
+0	O
+.	O
+4	O
+vs	O
+.	O
+0	O
+.	O
+24	O
++	O
+/	O
+-	O
+0	O
+.	O
+4	O
+","	O
+respectively	O
+)	O
+.	O
+	
+The	O
+greater	O
+LV	B-NP
+hypertrophy	I-NP
+in	O
+TGR	O
+rats	O
+was	O
+associated	O
+with	O
+more	O
+pronounced	O
+downregulation	O
+of	O
+beta	O
+-	O
+AR	O
+and	O
+upregulation	O
+of	O
+LV	O
+beta	O
+-	O
+AR	O
+kinase	O
+-	O
+1	O
+mRNA	O
+levels	O
+compared	O
+with	O
+those	O
+in	O
+SD	O
+rats	O
+.	O
+	
+The	O
+decrease	O
+in	O
+the	O
+heart	O
+rate	O
+(	O
+HR	O
+)	O
+induced	O
+by	O
+the	O
+beta	O
+-	O
+AR	O
+antagonist	O
+metoprolol	O
+in	O
+conscious	O
+rats	O
+was	O
+significantly	O
+attenuated	O
+in	O
+TGR	O
+compared	O
+with	O
+SD	O
+rats	O
+(	O
+-	O
+9	O
+.	O
+9	O
++	O
+/	O
+-	O
+1	O
+.	O
+7	O
+%	O
+vs	O
+.	O
+-	O
+18	O
+.	O
+1	O
++	O
+/	O
+-	O
+1	O
+.	O
+5	O
+%	O
+)	O
+","	O
+whereas	O
+the	O
+effect	O
+of	O
+parasympathetic	O
+blockade	O
+by	O
+atropine	O
+on	O
+HR	O
+was	O
+similar	O
+in	O
+both	O
+strains	O
+.	O
+	
+These	O
+results	O
+indicate	O
+that	O
+TGR	O
+are	O
+more	O
+sensitive	O
+to	O
+beta	O
+-	O
+AR	O
+agonist	O
+-	O
+induced	O
+cardiac	B-NP
+inotropic	I-NP
+response	O
+and	O
+hypertrophy	B-NP
+","	O
+possibly	O
+due	O
+to	O
+chronically	O
+low	O
+sympathetic	O
+outflow	O
+directed	O
+to	O
+the	O
+heart	O
+.	O
+	
+Drug	O
+-	O
+induced	O
+long	B-NP
+QT	I-NP
+syndrome	I-NP
+in	O
+injection	O
+drug	O
+users	O
+receiving	O
+methadone	O
+:	O
+high	O
+frequency	O
+in	O
+hospitalized	O
+patients	O
+and	O
+risk	O
+factors	O
+.	O
+	
+BACKGROUND	O
+:	O
+Drug	O
+-	O
+induced	O
+long	B-NP
+QT	I-NP
+syndrome	I-NP
+is	O
+a	O
+serious	O
+adverse	O
+drug	O
+reaction	O
+.	O
+	
+Methadone	O
+prolongs	O
+the	O
+QT	O
+interval	O
+in	O
+vitro	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+.	O
+	
+In	O
+the	O
+inpatient	O
+setting	O
+","	O
+the	O
+frequency	O
+of	O
+QT	B-NP
+interval	I-NP
+prolongation	I-NP
+with	O
+methadone	O
+treatment	O
+","	O
+its	O
+dose	O
+dependence	O
+","	O
+and	O
+the	O
+importance	O
+of	O
+cofactors	O
+such	O
+as	O
+drug	O
+-	O
+drug	O
+interactions	O
+remain	O
+unknown	O
+.	O
+	
+METHODS	O
+:	O
+We	O
+performed	O
+a	O
+systematic	O
+","	O
+retrospective	O
+study	O
+comparing	O
+active	O
+or	O
+former	O
+intravenous	O
+drug	O
+users	O
+receiving	O
+methadone	O
+and	O
+those	O
+not	O
+receiving	O
+methadone	O
+among	O
+all	O
+patients	O
+hospitalized	O
+over	O
+a	O
+5	O
+-	O
+year	O
+period	O
+in	O
+a	O
+tertiary	O
+care	O
+hospital	O
+.	O
+	
+A	O
+total	O
+of	O
+167	O
+patients	O
+receiving	O
+methadone	O
+fulfilled	O
+the	O
+inclusion	O
+criteria	O
+and	O
+were	O
+compared	O
+with	O
+a	O
+control	O
+group	O
+of	O
+80	O
+injection	O
+drug	O
+users	O
+not	O
+receiving	O
+methadone	O
+.	O
+	
+In	O
+addition	O
+to	O
+methadone	O
+dose	O
+","	O
+15	O
+demographic	O
+","	O
+biological	O
+","	O
+and	O
+pharmacological	O
+variables	O
+were	O
+considered	O
+as	O
+potential	O
+risk	O
+factors	O
+for	O
+QT	B-NP
+prolongation	I-NP
+.	O
+	
+RESULTS	O
+:	O
+Among	O
+167	O
+methadone	O
+maintenance	O
+patients	O
+","	O
+the	O
+prevalence	O
+of	O
+QTc	O
+prolongation	O
+to	O
+0	O
+.	O
+50	O
+second	O
+(	O
+(	O
+1	O
+/	O
+2	O
+)	O
+)	O
+or	O
+longer	O
+was	O
+16	O
+.	O
+2	O
+%	O
+compared	O
+with	O
+0	O
+%	O
+in	O
+80	O
+control	O
+subjects	O
+.	O
+	
+Six	O
+patients	O
+(	O
+3	O
+.	O
+6	O
+%	O
+)	O
+in	O
+the	O
+methadone	O
+group	O
+presented	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+.	O
+	
+QTc	O
+length	O
+was	O
+weakly	O
+but	O
+significantly	O
+associated	O
+with	O
+methadone	O
+daily	O
+dose	O
+(	O
+Spearman	O
+rank	O
+correlation	O
+coefficient	O
+","	O
+0	O
+.	O
+20	O
+;	O
+P	O
+<	O
+.	O
+1	O
+)	O
+.	O
+	
+Multivariate	O
+regression	O
+analysis	O
+allowed	O
+attribution	O
+of	O
+31	O
+.	O
+8	O
+%	O
+of	O
+QTc	O
+variability	O
+to	O
+methadone	O
+dose	O
+","	O
+cytochrome	O
+P	O
+-	O
+450	O
+3A4	O
+drug	O
+-	O
+drug	O
+interactions	O
+","	O
+hypokalemia	B-NP
+","	O
+and	O
+altered	O
+liver	O
+function	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+QT	B-NP
+interval	I-NP
+prolongation	I-NP
+in	O
+methadone	O
+maintenance	O
+patients	O
+hospitalized	O
+in	O
+a	O
+tertiary	O
+care	O
+center	O
+is	O
+a	O
+frequent	O
+finding	O
+.	O
+	
+Methadone	O
+dose	O
+","	O
+presence	O
+of	O
+cytochrome	O
+P	O
+-	O
+450	O
+3A4	O
+inhibitors	O
+","	O
+potassium	O
+level	O
+","	O
+and	O
+liver	O
+function	O
+contribute	O
+to	O
+QT	B-NP
+prolongation	I-NP
+.	O
+	
+Long	B-NP
+QT	I-NP
+syndrome	I-NP
+can	O
+occur	O
+with	O
+low	O
+doses	O
+of	O
+methadone	O
+.	O
+	
+Mechanisms	O
+of	O
+hypertension	B-NP
+induced	O
+by	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+deficiency	O
+:	O
+focus	O
+on	O
+venous	O
+function	O
+.	O
+	
+Loss	O
+of	O
+endothelial	O
+cell	O
+-	O
+derived	O
+nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+in	O
+hypertension	B-NP
+is	O
+a	O
+hallmark	O
+of	O
+arterial	B-NP
+dysfunction	I-NP
+.	O
+	
+Experimental	O
+hypertension	B-NP
+created	O
+by	O
+the	O
+removal	O
+of	O
+NO	O
+","	O
+however	O
+","	O
+involves	O
+mechanisms	O
+in	O
+addition	O
+to	O
+decreased	O
+arterial	O
+vasodilator	O
+activity	O
+.	O
+	
+These	O
+include	O
+augmented	O
+endothelin	O
+-	O
+1	O
+(	O
+ET	O
+-	O
+1	O
+)	O
+release	O
+","	O
+increased	O
+sympathetic	O
+nervous	O
+system	O
+activity	O
+","	O
+and	O
+elevated	O
+tissue	O
+oxidative	O
+stress	O
+.	O
+	
+We	O
+hypothesized	O
+that	O
+increased	O
+venous	O
+smooth	O
+muscle	O
+(	O
+venomotor	O
+)	O
+tone	O
+plays	O
+a	O
+role	O
+in	O
+Nomega	O
+-	O
+nitro	O
+-	O
+L	O
+-	O
+arginine	O
+(	O
+LNNA	O
+)	O
+hypertension	B-NP
+through	O
+these	O
+mechanisms	O
+.	O
+	
+Rats	O
+were	O
+treated	O
+with	O
+the	O
+NO	O
+synthase	O
+inhibitor	O
+LNNA	O
+(	O
+0	O
+.	O
+5	O
+g	O
+/	O
+L	O
+in	O
+drinking	O
+water	O
+)	O
+for	O
+2	O
+weeks	O
+.	O
+	
+Mean	O
+arterial	O
+pressure	O
+of	O
+conscious	O
+rats	O
+was	O
+119	O
++	O
+/	O
+-	O
+2	O
+mm	O
+Hg	O
+in	O
+control	O
+and	O
+194	O
++	O
+/	O
+-	O
+5	O
+mm	O
+Hg	O
+in	O
+LNNA	O
+rats	O
+(	O
+P	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+Carotid	O
+arteries	O
+and	O
+vena	O
+cava	O
+were	O
+removed	O
+for	O
+measurement	O
+of	O
+isometric	O
+contraction	O
+.	O
+	
+Maximal	O
+contraction	O
+to	O
+norepinephrine	O
+was	O
+modestly	O
+reduced	O
+in	O
+arteries	O
+from	O
+LNNA	O
+compared	O
+with	O
+control	O
+rats	O
+whereas	O
+the	O
+maximum	O
+contraction	O
+to	O
+ET	O
+-	O
+1	O
+was	O
+significantly	O
+reduced	O
+(	O
+54	O
+%	O
+control	O
+)	O
+.	O
+	
+Maximum	O
+contraction	O
+of	O
+vena	O
+cava	O
+to	O
+norepinephrine	O
+(	O
+37	O
+%	O
+control	O
+)	O
+also	O
+was	O
+reduced	O
+but	O
+no	O
+change	O
+in	O
+response	O
+to	O
+ET	O
+-	O
+1	O
+was	O
+observed	O
+.	O
+	
+Mean	O
+circulatory	O
+filling	O
+pressure	O
+","	O
+an	O
+in	O
+vivo	O
+measure	O
+of	O
+venomotor	O
+tone	O
+","	O
+was	O
+not	O
+elevated	O
+in	O
+LNNA	O
+hypertension	B-NP
+at	O
+1	O
+or	O
+2	O
+weeks	O
+after	O
+LNNA	O
+.	O
+	
+The	O
+superoxide	O
+scavenger	O
+tempol	O
+(	O
+30	O
+","	O
+100	O
+","	O
+and	O
+300	O
+micromol	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+","	O
+IV	O
+)	O
+did	O
+not	O
+change	O
+arterial	O
+pressure	O
+in	O
+control	O
+rats	O
+but	O
+caused	O
+a	O
+dose	O
+-	O
+dependent	O
+decrease	O
+in	O
+LNNA	O
+rats	O
+(	O
+-	O
+18	O
++	O
+/	O
+-	O
+8	O
+","	O
+-	O
+26	O
++	O
+/	O
+-	O
+15	O
+","	O
+and	O
+-	O
+54	O
++	O
+/	O
+-	O
+11	O
+mm	O
+Hg	O
+)	O
+.	O
+	
+Similarly	O
+","	O
+ganglionic	O
+blockade	O
+with	O
+hexamethonium	O
+caused	O
+a	O
+significantly	O
+greater	O
+fall	O
+in	O
+LNNA	O
+hypertensive	B-NP
+rats	O
+(	O
+76	O
++	O
+/	O
+-	O
+9	O
+mm	O
+Hg	O
+)	O
+compared	O
+with	O
+control	O
+rats	O
+(	O
+35	O
++	O
+/	O
+-	O
+10	O
+mm	O
+Hg	O
+)	O
+.	O
+	
+Carotid	O
+arteries	O
+","	O
+vena	O
+cava	O
+","	O
+and	O
+sympathetic	O
+ganglia	O
+from	O
+LNNA	O
+rats	O
+had	O
+higher	O
+basal	O
+levels	O
+of	O
+superoxide	O
+compared	O
+with	O
+those	O
+from	O
+control	O
+rats	O
+.	O
+	
+These	O
+data	O
+suggest	O
+that	O
+while	O
+NO	O
+deficiency	O
+increases	O
+oxidative	O
+stress	O
+and	O
+sympathetic	O
+activity	O
+in	O
+both	O
+arterial	O
+and	O
+venous	O
+vessels	O
+","	O
+the	O
+impact	O
+on	O
+veins	O
+does	O
+not	O
+make	O
+a	O
+major	O
+contribution	O
+to	O
+this	O
+form	O
+of	O
+hypertension	B-NP
+.	O
+	
+Association	O
+of	O
+DRD2	O
+polymorphisms	O
+and	O
+chlorpromazine	O
+-	O
+induced	O
+extrapyramidal	B-NP
+syndrome	I-NP
+in	O
+Chinese	O
+schizophrenic	B-NP
+patients	O
+.	O
+	
+AIM	O
+:	O
+Extrapyramidal	B-NP
+syndrome	I-NP
+(	O
+EPS	B-NP
+)	O
+is	O
+most	O
+commonly	O
+affected	O
+by	O
+typical	O
+antipsychotic	O
+drugs	O
+that	O
+have	O
+a	O
+high	O
+affinity	O
+with	O
+the	O
+D2	O
+receptor	O
+.	O
+	
+Recently	O
+","	O
+many	O
+research	O
+groups	O
+have	O
+reported	O
+on	O
+the	O
+positive	O
+relationship	O
+between	O
+the	O
+genetic	O
+variations	O
+in	O
+the	O
+DRD2	O
+gene	O
+and	O
+the	O
+therapeutic	O
+response	O
+in	O
+schizophrenia	B-NP
+patients	O
+as	O
+a	O
+result	O
+of	O
+the	O
+role	O
+of	O
+variations	O
+in	O
+the	O
+receptor	O
+in	O
+modulating	O
+receptor	O
+expression	O
+.	O
+	
+In	O
+this	O
+study	O
+","	O
+we	O
+evaluate	O
+the	O
+role	O
+DRD2	O
+plays	O
+in	O
+chlorpromazine	O
+-	O
+induced	O
+EPS	B-NP
+in	O
+schizophrenic	B-NP
+patients	O
+.	O
+	
+METHODS	O
+:	O
+We	O
+identified	O
+seven	O
+SNP	O
+(	O
+single	O
+nucleotide	O
+polymorphism	O
+)	O
+(	O
+-	O
+141Cins	O
+>	O
+del	O
+","	O
+TaqIB	O
+","	O
+TaqID	O
+","	O
+Ser311Cys	O
+","	O
+rs6275	O
+","	O
+rs6277	O
+and	O
+TaqIA	O
+)	O
+in	O
+the	O
+DRD2	O
+gene	O
+in	O
+146	O
+schizophrenic	B-NP
+inpatients	O
+(	O
+59	O
+with	O
+EPS	B-NP
+and	O
+87	O
+without	O
+EPS	B-NP
+according	O
+to	O
+the	O
+Simpson	O
+-	O
+Angus	O
+Scale	O
+)	O
+treated	O
+with	O
+chlorpromazine	O
+after	O
+8	O
+weeks	O
+.	O
+	
+The	O
+alleles	O
+of	O
+all	O
+loci	O
+were	O
+determined	O
+by	O
+PCR	O
+(	O
+polymerase	O
+chain	O
+reaction	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+Polymorphisms	O
+TaqID	O
+","	O
+Ser311Cys	O
+and	O
+rs6277	O
+were	O
+not	O
+polymorphic	O
+in	O
+the	O
+population	O
+recruited	O
+in	O
+the	O
+present	O
+study	O
+.	O
+	
+No	O
+statistical	O
+significance	O
+was	O
+found	O
+in	O
+the	O
+allele	O
+distribution	O
+of	O
+-	O
+141Cins	O
+>	O
+del	O
+","	O
+TaqIB	O
+","	O
+rs6275	O
+and	O
+TaqIA	O
+or	O
+in	O
+the	O
+estimated	O
+haplotypes	O
+(	O
+constituted	O
+by	O
+TaqIB	O
+","	O
+rs6275	O
+and	O
+TaqIA	O
+)	O
+in	O
+linkage	O
+disequilibrium	O
+between	O
+the	O
+two	O
+groups	O
+.	O
+	
+CONCLUSION	O
+:	O
+Our	O
+results	O
+did	O
+not	O
+lend	O
+strong	O
+support	O
+to	O
+the	O
+view	O
+that	O
+the	O
+genetic	O
+variation	O
+of	O
+the	O
+DRD2	O
+gene	O
+plays	O
+a	O
+major	O
+role	O
+in	O
+the	O
+individually	O
+variable	O
+adverse	O
+effect	O
+induced	O
+by	O
+chlorpromazine	O
+","	O
+at	O
+least	O
+in	O
+Chinese	O
+patients	O
+with	O
+schizophrenia	B-NP
+.	O
+	
+Our	O
+results	O
+confirmed	O
+a	O
+previous	O
+study	O
+on	O
+the	O
+relationship	O
+between	O
+DRD2	O
+and	O
+EPS	B-NP
+in	O
+Caucasians	O
+.	O
+	
+Physical	O
+training	O
+decreases	O
+susceptibility	O
+to	O
+subsequent	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B-NP
+in	O
+the	O
+rat	O
+.	O
+	
+Regular	O
+motor	O
+activity	O
+has	O
+many	O
+benefits	O
+for	O
+mental	O
+and	O
+physical	O
+condition	O
+but	O
+its	O
+implications	O
+for	O
+epilepsy	B-NP
+are	O
+still	O
+controversial	O
+.	O
+	
+In	O
+order	O
+to	O
+elucidate	O
+this	O
+problem	O
+","	O
+we	O
+have	O
+studied	O
+the	O
+effect	O
+of	O
+long	O
+-	O
+term	O
+physical	O
+activity	O
+on	O
+susceptibility	O
+to	O
+subsequent	O
+seizures	B-NP
+.	O
+	
+Male	O
+Wistar	O
+rats	O
+were	O
+subjected	O
+to	O
+repeated	O
+training	O
+sessions	O
+in	O
+a	O
+treadmill	O
+and	O
+swimming	O
+pool	O
+.	O
+	
+Thereafter	O
+","	O
+seizures	B-NP
+were	O
+induced	O
+by	O
+pilocarpine	O
+injections	O
+in	O
+trained	O
+and	O
+non	O
+-	O
+trained	O
+control	O
+groups	O
+.	O
+	
+During	O
+the	O
+acute	O
+period	O
+of	O
+status	B-NP
+epilepticus	I-NP
+","	O
+we	O
+measured	O
+:	O
+(	O
+1	O
+)	O
+the	O
+latency	O
+of	O
+the	O
+first	O
+motor	O
+sign	O
+","	O
+(	O
+2	O
+)	O
+the	O
+intensity	O
+of	O
+seizures	B-NP
+","	O
+(	O
+3	O
+)	O
+the	O
+time	O
+when	O
+it	O
+occurred	O
+within	O
+the	O
+6	O
+-	O
+h	O
+observation	O
+period	O
+","	O
+and	O
+(	O
+4	O
+)	O
+the	O
+time	O
+when	O
+the	O
+acute	O
+period	O
+ended	O
+.	O
+	
+All	O
+these	O
+behavioral	O
+parameters	O
+showed	O
+statistically	O
+significant	O
+changes	O
+suggesting	O
+that	O
+regular	O
+physical	O
+exercises	O
+decrease	O
+susceptibility	O
+to	O
+subsequently	O
+induced	O
+seizures	B-NP
+and	O
+ameliorate	O
+the	O
+course	O
+of	O
+experimentally	O
+induced	O
+status	B-NP
+epilepticus	I-NP
+.	O
+	
+Tonic	O
+dopaminergic	O
+stimulation	O
+impairs	B-NP
+associative	I-NP
+learning	I-NP
+in	O
+healthy	O
+subjects	O
+.	O
+	
+Endogenous	O
+dopamine	O
+plays	O
+a	O
+central	O
+role	O
+in	O
+salience	O
+coding	O
+during	O
+associative	O
+learning	O
+.	O
+	
+Administration	O
+of	O
+the	O
+dopamine	O
+precursor	O
+levodopa	O
+enhances	O
+learning	O
+in	O
+healthy	O
+subjects	O
+and	O
+stroke	B-NP
+patients	O
+.	O
+	
+Because	O
+levodopa	O
+increases	O
+both	O
+phasic	O
+and	O
+tonic	O
+dopaminergic	O
+neurotransmission	O
+","	O
+the	O
+critical	O
+mechanism	O
+mediating	O
+the	O
+enhancement	O
+of	O
+learning	O
+is	O
+unresolved	O
+.	O
+	
+We	O
+here	O
+probed	O
+how	O
+selective	O
+tonic	O
+dopaminergic	O
+stimulation	O
+affects	O
+associative	O
+learning	O
+.	O
+	
+Forty	O
+healthy	O
+subjects	O
+were	O
+trained	O
+in	O
+a	O
+novel	O
+vocabulary	O
+of	O
+45	O
+concrete	O
+nouns	O
+over	O
+the	O
+course	O
+of	O
+5	O
+consecutive	O
+training	O
+days	O
+in	O
+a	O
+prospective	O
+","	O
+randomized	O
+","	O
+double	O
+-	O
+blind	O
+","	O
+placebo	O
+-	O
+controlled	O
+design	O
+.	O
+	
+Subjects	O
+received	O
+the	O
+tonically	O
+stimulating	O
+dopamine	O
+-	O
+receptor	O
+agonist	O
+pergolide	O
+(	O
+0	O
+.	O
+1	O
+mg	O
+)	O
+vs	O
+placebo	O
+120	O
+min	O
+before	O
+training	O
+on	O
+each	O
+training	O
+day	O
+.	O
+	
+The	O
+dopamine	O
+agonist	O
+significantly	O
+impaired	B-NP
+novel	I-NP
+word	I-NP
+learning	I-NP
+compared	O
+to	O
+placebo	O
+.	O
+	
+This	O
+learning	O
+decrement	O
+persisted	O
+up	O
+to	O
+the	O
+last	O
+follow	O
+-	O
+up	O
+4	O
+weeks	O
+post	O
+-	O
+training	O
+.	O
+	
+Subjects	O
+treated	O
+with	O
+pergolide	O
+also	O
+showed	O
+restricted	O
+emotional	O
+responses	O
+compared	O
+to	O
+the	O
+PLACEBO	O
+group	O
+.	O
+	
+The	O
+extent	O
+of	O
+'	O
+flattened	O
+'	O
+affect	O
+with	O
+pergolide	O
+was	O
+related	O
+to	O
+the	O
+degree	O
+of	O
+learning	O
+inhibition	O
+.	O
+	
+These	O
+findings	O
+suggest	O
+that	O
+tonic	O
+occupation	O
+of	O
+dopamine	O
+receptors	O
+impairs	O
+learning	O
+by	O
+competition	O
+with	O
+phasic	O
+dopamine	O
+signals	O
+.	O
+	
+Thus	O
+","	O
+phasic	O
+signaling	O
+seems	O
+to	O
+be	O
+the	O
+critical	O
+mechanism	O
+by	O
+which	O
+dopamine	O
+enhances	O
+associative	O
+learning	O
+in	O
+healthy	O
+subjects	O
+and	O
+stroke	B-NP
+patients	O
+.	O
+	
+Minocycline	O
+-	O
+induced	O
+vasculitis	B-NP
+fulfilling	O
+the	O
+criteria	O
+of	O
+polyarteritis	B-NP
+nodosa	I-NP
+.	O
+	
+A	O
+47	O
+-	O
+year	O
+-	O
+old	O
+man	O
+who	O
+had	O
+been	O
+taking	O
+minocycline	O
+for	O
+palmoplantar	B-NP
+pustulosis	I-NP
+developed	O
+fever	B-NP
+","	O
+myalgias	B-NP
+","	O
+polyneuropathy	B-NP
+","	O
+and	O
+testicular	B-NP
+pain	I-NP
+","	O
+with	O
+elevated	O
+C	O
+-	O
+reactive	O
+protein	O
+(	O
+CRP	O
+)	O
+.	O
+	
+Neither	O
+myeloperoxidase	O
+-	O
+nor	O
+proteinase	O
+-	O
+3	O
+-	O
+antineutrophil	O
+cytoplasmic	O
+antibody	O
+was	O
+positive	O
+.	O
+	
+These	O
+manifestations	O
+met	O
+the	O
+American	O
+College	O
+of	O
+Rheumatology	O
+1990	O
+criteria	O
+for	O
+the	O
+classification	O
+of	O
+polyarteritis	B-NP
+nodosa	I-NP
+.	O
+	
+Stopping	O
+minocycline	O
+led	O
+to	O
+amelioration	O
+of	O
+symptoms	O
+and	O
+normalization	O
+of	O
+CRP	O
+level	O
+.	O
+	
+To	O
+our	O
+knowledge	O
+","	O
+this	O
+is	O
+the	O
+second	O
+case	O
+of	O
+minocycline	O
+-	O
+induced	O
+vasculitis	B-NP
+satisfying	O
+the	O
+criteria	O
+.	O
+	
+Differential	O
+diagnosis	O
+for	O
+drug	O
+-	O
+induced	O
+disease	O
+is	O
+invaluable	O
+even	O
+for	O
+patients	O
+with	O
+classical	O
+polyarteritis	B-NP
+nodosa	I-NP
+.	O
+	
+Intramuscular	O
+hepatitis	B-NP
+B	I-NP
+immune	O
+globulin	O
+combined	O
+with	O
+lamivudine	O
+in	O
+prevention	O
+of	O
+hepatitis	B-NP
+B	I-NP
+recurrence	O
+after	O
+liver	O
+transplantation	O
+.	O
+	
+BACKGROUND	O
+:	O
+Combined	O
+hepatitis	B-NP
+B	I-NP
+immune	O
+globulin	O
+(	O
+HBIg	O
+)	O
+and	O
+lamivudine	O
+in	O
+prophylaxis	O
+of	O
+the	O
+recurrence	O
+of	O
+hepatitis	B-NP
+B	I-NP
+after	O
+liver	O
+transplantation	O
+has	O
+significantly	O
+improved	O
+the	O
+survival	O
+of	O
+HBsAg	O
+positive	O
+patients	O
+.	O
+	
+This	O
+study	O
+was	O
+undertaken	O
+to	O
+evaluate	O
+the	O
+outcomes	O
+of	O
+liver	O
+transplantation	O
+for	O
+patients	O
+with	O
+hepatitis	B-NP
+B	I-NP
+virus	O
+(	O
+HBV	O
+)	O
+.	O
+	
+METHODS	O
+:	O
+A	O
+retrospective	O
+chart	O
+analysis	O
+and	O
+a	O
+review	O
+of	O
+the	O
+organ	O
+transplant	O
+database	O
+identified	O
+51	O
+patients	O
+(	O
+43	O
+men	O
+and	O
+8	O
+women	O
+)	O
+transplanted	O
+for	O
+benign	O
+HBV	O
+-	O
+related	O
+cirrhotic	B-NP
+diseases	I-NP
+between	O
+June	O
+2002	O
+and	O
+December	O
+2004	O
+who	O
+had	O
+survived	O
+more	O
+than	O
+3	O
+months	O
+.	O
+	
+HBIg	O
+was	O
+administered	O
+intravenously	O
+during	O
+the	O
+first	O
+week	O
+and	O
+intramuscularly	O
+thereafter	O
+.	O
+	
+RESULTS	O
+:	O
+At	O
+a	O
+median	O
+follow	O
+-	O
+up	O
+of	O
+14	O
+.	O
+1	O
+months	O
+","	O
+the	O
+overall	O
+recurrence	O
+rate	O
+in	O
+the	O
+51	O
+patients	O
+was	O
+3	O
+.	O
+9	O
+%	O
+(	O
+2	O
+/	O
+51	O
+)	O
+.	O
+	
+The	O
+overall	O
+patient	O
+survival	O
+was	O
+88	O
+.	O
+3	O
+%	O
+","	O
+and	O
+82	O
+.	O
+4	O
+%	O
+after	O
+1	O
+and	O
+2	O
+years	O
+","	O
+respectively	O
+.	O
+	
+A	O
+daily	O
+oral	O
+dose	O
+of	O
+100	O
+mg	O
+lamivudine	O
+for	O
+2	O
+weeks	O
+before	O
+transplantation	O
+for	O
+10	O
+patients	O
+enabled	O
+57	O
+.	O
+1	O
+%	O
+(	O
+4	O
+/	O
+7	O
+)	O
+and	O
+62	O
+.	O
+5	O
+%	O
+(	O
+5	O
+/	O
+8	O
+)	O
+of	O
+HBV	O
+-	O
+DNA	O
+and	O
+HBeAg	O
+positive	O
+patients	O
+respectively	O
+to	O
+convert	O
+to	O
+be	O
+negative	O
+.	O
+	
+Intramuscular	O
+HBIg	O
+was	O
+well	O
+tolerated	O
+in	O
+all	O
+patients	O
+.	O
+	
+CONCLUSION	O
+:	O
+Lamivudine	O
+combined	O
+with	O
+intramuscular	O
+HBIg	O
+can	O
+effectively	O
+prevent	O
+allograft	O
+from	O
+the	O
+recurrence	O
+of	O
+HBV	O
+after	O
+liver	O
+transplantation	O
+.	O
+	
+Anticonvulsant	O
+effect	O
+of	O
+eslicarbazepine	O
+acetate	O
+(	O
+BIA	O
+2	O
+-	O
+93	O
+)	O
+on	O
+seizures	B-NP
+induced	O
+by	O
+microperfusion	O
+of	O
+picrotoxin	O
+in	O
+the	O
+hippocampus	O
+of	O
+freely	O
+moving	O
+rats	O
+.	O
+	
+Eslicarbazepine	O
+acetate	O
+(	O
+BIA	O
+2	O
+-	O
+93	O
+","	O
+S	O
+-	O
+(	O
+-	O
+)	O
+-	O
+10	O
+-	O
+acetoxy	O
+-	O
+10	O
+","	O
+11	O
+-	O
+dihydro	O
+-	O
+5H	O
+-	O
+dibenzo	O
+/	O
+b	O
+","	O
+f	O
+/	O
+azepine	O
+-	O
+5	O
+-	O
+carboxamide	O
+)	O
+is	O
+a	O
+novel	O
+antiepileptic	O
+drug	O
+","	O
+now	O
+in	O
+Phase	O
+III	O
+clinical	O
+trials	O
+","	O
+designed	O
+with	O
+the	O
+aim	O
+of	O
+improving	O
+efficacy	O
+and	O
+safety	O
+in	O
+comparison	O
+with	O
+the	O
+structurally	O
+related	O
+drugs	O
+carbamazepine	O
+(	O
+CBZ	O
+)	O
+and	O
+oxcarbazepine	O
+(	O
+OXC	O
+)	O
+.	O
+	
+We	O
+have	O
+studied	O
+the	O
+effects	O
+of	O
+oral	O
+treatment	O
+with	O
+eslicarbazepine	O
+acetate	O
+on	O
+a	O
+whole	O
+-	O
+animal	O
+model	O
+in	O
+which	O
+partial	O
+seizures	B-NP
+can	O
+be	O
+elicited	O
+repeatedly	O
+on	O
+different	O
+days	O
+without	O
+changes	O
+in	O
+threshold	O
+or	O
+seizure	B-NP
+patterns	O
+.	O
+	
+In	O
+the	O
+animals	O
+treated	O
+with	O
+threshold	O
+doses	O
+of	O
+picrotoxin	O
+","	O
+the	O
+average	O
+number	O
+of	O
+seizures	B-NP
+was	O
+2	O
+.	O
+3	O
++	O
+/	O
+-	O
+1	O
+.	O
+2	O
+","	O
+and	O
+average	O
+seizure	B-NP
+duration	O
+was	O
+39	O
+.	O
+5	O
++	O
+/	O
+-	O
+8	O
+.	O
+4s	O
+.	O
+	
+Pre	O
+-	O
+treatment	O
+with	O
+a	O
+dose	O
+of	O
+30	O
+mg	O
+/	O
+kg	O
+2h	O
+before	O
+picrotoxin	O
+microperfusion	O
+prevented	O
+seizures	B-NP
+in	O
+the	O
+75	O
+%	O
+of	O
+the	O
+rats	O
+.	O
+	
+Lower	O
+doses	O
+(	O
+3	O
+and	O
+10mg	O
+/	O
+kg	O
+)	O
+did	O
+not	O
+suppress	O
+seizures	B-NP
+","	O
+however	O
+","	O
+after	O
+administration	O
+of	O
+10mg	O
+/	O
+kg	O
+","	O
+significant	O
+reductions	O
+in	O
+seizures	B-NP
+duration	O
+(	O
+24	O
+.	O
+3	O
++	O
+/	O
+-	O
+6	O
+.	O
+8s	O
+)	O
+and	O
+seizure	B-NP
+number	O
+(	O
+1	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+34	O
+)	O
+were	O
+found	O
+.	O
+	
+No	O
+adverse	O
+effects	O
+of	O
+eslicarbazepine	O
+acetate	O
+were	O
+observed	O
+in	O
+the	O
+behavioral	O
+/	O
+EEG	O
+patterns	O
+studied	O
+","	O
+including	O
+sleep	O
+/	O
+wakefulness	O
+cycle	O
+","	O
+at	O
+the	O
+doses	O
+studied	O
+.	O
+	
+Acute	B-NP
+renal	I-NP
+failure	I-NP
+associated	O
+with	O
+prolonged	O
+intake	O
+of	O
+slimming	O
+pills	O
+containing	O
+anthraquinones	O
+.	O
+	
+Chinese	O
+herbal	O
+medicine	O
+preparations	O
+are	O
+widely	O
+available	O
+and	O
+often	O
+regarded	O
+by	O
+the	O
+public	O
+as	O
+natural	O
+and	O
+safe	O
+remedies	O
+for	O
+a	O
+variety	O
+of	O
+medical	O
+conditions	O
+.	O
+	
+Nephropathy	B-NP
+caused	O
+by	O
+Chinese	O
+herbs	O
+has	O
+previously	O
+been	O
+reported	O
+","	O
+usually	O
+involving	O
+the	O
+use	O
+of	O
+aristolochic	O
+acids	O
+.	O
+	
+We	O
+report	O
+a	O
+23	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+who	O
+developed	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+following	O
+prolonged	O
+use	O
+of	O
+a	O
+proprietary	O
+Chinese	O
+herbal	O
+slimming	O
+pill	O
+that	O
+contained	O
+anthraquinone	O
+derivatives	O
+","	O
+extracted	O
+from	O
+Rhizoma	O
+Rhei	O
+(	O
+rhubarb	O
+)	O
+.	O
+	
+The	O
+renal	B-NP
+injury	I-NP
+was	O
+probably	O
+aggravated	O
+by	O
+the	O
+concomitant	O
+intake	O
+of	O
+a	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drug	O
+","	O
+diclofenac	O
+.	O
+	
+Renal	O
+pathology	O
+was	O
+that	O
+of	O
+hypocellular	O
+interstitial	O
+fibrosis	B-NP
+.	O
+	
+Spontaneous	O
+renal	O
+recovery	O
+occurred	O
+upon	O
+cessation	O
+of	O
+the	O
+slimming	O
+pills	O
+","	O
+but	O
+mild	O
+interstitial	O
+fibrosis	B-NP
+and	O
+tubular	O
+atrophy	B-NP
+was	O
+still	O
+evident	O
+histologically	O
+4	O
+months	O
+later	O
+.	O
+	
+Although	O
+a	O
+causal	O
+relationship	O
+between	O
+the	O
+use	O
+of	O
+an	O
+anthraquinone	O
+-	O
+containing	O
+herbal	O
+agent	O
+and	O
+renal	B-NP
+injury	I-NP
+remains	O
+to	O
+be	O
+proven	O
+","	O
+phytotherapy	O
+-	O
+associated	O
+interstitial	O
+nephropathy	B-NP
+should	O
+be	O
+considered	O
+in	O
+patients	O
+who	O
+present	O
+with	O
+unexplained	O
+renal	B-NP
+failure	I-NP
+.	O
+	
+Chloroacetaldehyde	O
+as	O
+a	O
+sulfhydryl	O
+reagent	O
+:	O
+the	O
+role	O
+of	O
+critical	O
+thiol	O
+groups	O
+in	O
+ifosfamide	O
+nephropathy	B-NP
+.	O
+	
+Chloroacetaldehyde	O
+(	O
+CAA	O
+)	O
+is	O
+a	O
+metabolite	O
+of	O
+the	O
+alkylating	O
+agent	O
+ifosfamide	O
+(	O
+IFO	O
+)	O
+and	O
+putatively	O
+responsible	O
+for	O
+renal	B-NP
+damage	I-NP
+following	O
+anti	O
+-	O
+tumor	B-NP
+therapy	O
+with	O
+IFO	O
+.	O
+	
+Depletion	O
+of	O
+sulfhydryl	O
+(	O
+SH	O
+)	O
+groups	O
+has	O
+been	O
+reported	O
+from	O
+cell	O
+culture	O
+","	O
+animal	O
+and	O
+clinical	O
+studies	O
+.	O
+	
+In	O
+this	O
+work	O
+the	O
+effect	O
+of	O
+CAA	O
+on	O
+human	O
+proximal	O
+tubule	O
+cells	O
+in	O
+primary	O
+culture	O
+(	O
+hRPTEC	O
+)	O
+was	O
+investigated	O
+.	O
+	
+Toxicity	B-NP
+of	O
+CAA	O
+was	O
+determined	O
+by	O
+protein	O
+content	O
+","	O
+cell	O
+number	O
+","	O
+LDH	O
+release	O
+","	O
+trypan	O
+blue	O
+exclusion	O
+assay	O
+and	O
+caspase	O
+-	O
+3	O
+activity	O
+.	O
+	
+Free	O
+thiols	O
+were	O
+measured	O
+by	O
+the	O
+method	O
+of	O
+Ellman	O
+.	O
+	
+CAA	O
+reduced	O
+hRPTEC	O
+cell	O
+number	O
+and	O
+protein	O
+","	O
+induced	O
+a	O
+loss	O
+in	O
+free	O
+intracellular	O
+thiols	O
+and	O
+an	O
+increase	O
+in	O
+necrosis	B-NP
+markers	O
+.	O
+	
+CAA	O
+but	O
+not	O
+acrolein	O
+inhibited	O
+the	O
+cysteine	O
+proteases	O
+caspase	O
+-	O
+3	O
+","	O
+caspase	O
+-	O
+8	O
+and	O
+cathepsin	O
+B	O
+.	O
+	
+Caspase	O
+activation	O
+by	O
+cisplatin	O
+was	O
+inhibited	O
+by	O
+CAA	O
+.	O
+	
+In	O
+cells	O
+stained	O
+with	O
+fluorescent	O
+dyes	O
+targeting	O
+lysosomes	O
+","	O
+CAA	O
+induced	O
+an	O
+increase	O
+in	O
+lysosomal	O
+size	O
+and	O
+lysosomal	O
+leakage	O
+.	O
+	
+The	O
+effects	O
+of	O
+CAA	O
+on	O
+cysteine	O
+protease	O
+activities	O
+and	O
+thiols	O
+could	O
+be	O
+reproduced	O
+in	O
+cell	O
+lysate	O
+.	O
+	
+Acidification	O
+","	O
+which	O
+slowed	O
+the	O
+reaction	O
+of	O
+CAA	O
+with	O
+thiol	O
+donors	O
+","	O
+could	O
+also	O
+attenuate	O
+effects	O
+of	O
+CAA	O
+on	O
+necrosis	B-NP
+markers	O
+","	O
+thiol	O
+depletion	O
+and	O
+cysteine	O
+protease	O
+inhibition	O
+in	O
+living	O
+cells	O
+.	O
+	
+Thus	O
+","	O
+CAA	O
+directly	O
+reacts	O
+with	O
+cellular	O
+protein	O
+and	O
+non	O
+-	O
+protein	O
+thiols	O
+","	O
+mediating	O
+its	O
+toxicity	B-NP
+on	O
+hRPTEC	O
+.	O
+	
+This	O
+effect	O
+can	O
+be	O
+reduced	O
+by	O
+acidification	O
+.	O
+	
+Therefore	O
+","	O
+urinary	O
+acidification	O
+could	O
+be	O
+an	O
+option	O
+to	O
+prevent	O
+IFO	O
+nephropathy	B-NP
+in	O
+patients	O
+.	O
+	
+Stereological	O
+methods	O
+reveal	O
+the	O
+robust	O
+size	O
+and	O
+stability	O
+of	O
+ectopic	O
+hilar	O
+granule	O
+cells	O
+after	O
+pilocarpine	O
+-	O
+induced	O
+status	B-NP
+epilepticus	I-NP
+in	O
+the	O
+adult	O
+rat	O
+.	O
+	
+Following	O
+status	B-NP
+epilepticus	I-NP
+in	O
+the	O
+rat	O
+","	O
+dentate	O
+granule	O
+cell	O
+neurogenesis	O
+increases	O
+greatly	O
+","	O
+and	O
+many	O
+of	O
+the	O
+new	O
+neurons	O
+appear	O
+to	O
+develop	O
+ectopically	O
+","	O
+in	O
+the	O
+hilar	O
+region	O
+of	O
+the	O
+hippocampal	O
+formation	O
+.	O
+	
+It	O
+has	O
+been	O
+suggested	O
+that	O
+the	O
+ectopic	O
+hilar	O
+granule	O
+cells	O
+could	O
+contribute	O
+to	O
+the	O
+spontaneous	O
+seizures	B-NP
+that	O
+ultimately	O
+develop	O
+after	O
+status	B-NP
+epilepticus	I-NP
+.	O
+	
+However	O
+","	O
+the	O
+population	O
+has	O
+never	O
+been	O
+quantified	O
+","	O
+so	O
+it	O
+is	O
+unclear	O
+whether	O
+it	O
+is	O
+substantial	O
+enough	O
+to	O
+have	O
+a	O
+strong	O
+influence	O
+on	O
+epileptogenesis	O
+.	O
+	
+To	O
+quantify	O
+this	O
+population	O
+","	O
+the	O
+total	O
+number	O
+of	O
+ectopic	O
+hilar	O
+granule	O
+cells	O
+was	O
+estimated	O
+using	O
+unbiased	O
+stereology	O
+at	O
+different	O
+times	O
+after	O
+pilocarpine	O
+-	O
+induced	O
+status	B-NP
+epilepticus	I-NP
+.	O
+	
+The	O
+number	O
+of	O
+hilar	O
+neurons	O
+immunoreactive	O
+for	O
+Prox	O
+-	O
+1	O
+","	O
+a	O
+granule	O
+-	O
+cell	O
+-	O
+specific	O
+marker	O
+","	O
+was	O
+estimated	O
+using	O
+the	O
+optical	O
+fractionator	O
+method	O
+.	O
+	
+The	O
+results	O
+indicate	O
+that	O
+the	O
+size	O
+of	O
+the	O
+hilar	O
+ectopic	O
+granule	O
+cell	O
+population	O
+after	O
+status	B-NP
+epilepticus	I-NP
+is	O
+substantial	O
+","	O
+and	O
+stable	O
+over	O
+time	O
+.	O
+	
+Interestingly	O
+","	O
+the	O
+size	O
+of	O
+the	O
+population	O
+appears	O
+to	O
+be	O
+correlated	O
+with	O
+the	O
+frequency	O
+of	O
+behavioral	O
+seizures	B-NP
+","	O
+because	O
+animals	O
+with	O
+more	O
+ectopic	O
+granule	O
+cells	O
+in	O
+the	O
+hilus	O
+have	O
+more	O
+frequent	O
+behavioral	O
+seizures	B-NP
+.	O
+	
+The	O
+hilar	O
+ectopic	O
+granule	O
+cell	O
+population	O
+does	O
+not	O
+appear	O
+to	O
+vary	O
+systematically	O
+across	O
+the	O
+septotemporal	O
+axis	O
+","	O
+although	O
+it	O
+is	O
+associated	O
+with	O
+an	O
+increase	O
+in	O
+volume	O
+of	O
+the	O
+hilus	O
+.	O
+	
+The	O
+results	O
+provide	O
+new	O
+insight	O
+into	O
+the	O
+potential	O
+role	O
+of	O
+ectopic	O
+hilar	O
+granule	O
+cells	O
+in	O
+the	O
+pilocarpine	O
+model	O
+of	O
+temporal	B-NP
+lobe	I-NP
+epilepsy	I-NP
+.	O
+	
+A	O
+prospective	O
+","	O
+open	O
+-	O
+label	O
+trial	O
+of	O
+galantamine	O
+in	O
+autistic	B-NP
+disorder	I-NP
+.	O
+	
+OBJECTIVE	O
+:	O
+Post	O
+-	O
+mortem	O
+studies	O
+have	O
+reported	O
+abnormalities	O
+of	O
+the	O
+cholinergic	O
+system	O
+in	O
+autism	B-NP
+.	O
+	
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+assess	O
+the	O
+use	O
+of	O
+galantamine	O
+","	O
+an	O
+acetylcholinesterase	O
+inhibitor	O
+and	O
+nicotinic	O
+receptor	O
+modulator	O
+","	O
+in	O
+the	O
+treatment	O
+of	O
+interfering	O
+behaviors	O
+in	O
+children	O
+with	O
+autism	B-NP
+.	O
+	
+METHODS	O
+:	O
+Thirteen	O
+medication	O
+-	O
+free	O
+children	O
+with	O
+autism	B-NP
+(	O
+mean	O
+age	O
+","	O
+8	O
+.	O
+8	O
++	O
+/	O
+-	O
+3	O
+.	O
+5	O
+years	O
+)	O
+participated	O
+in	O
+a	O
+12	O
+-	O
+week	O
+","	O
+open	O
+-	O
+label	O
+trial	O
+of	O
+galantamine	O
+.	O
+	
+Patients	O
+were	O
+rated	O
+monthly	O
+by	O
+parents	O
+on	O
+the	O
+Aberrant	O
+Behavior	O
+Checklist	O
+(	O
+ABC	O
+)	O
+and	O
+the	O
+Conners	O
+'	O
+Parent	O
+Rating	O
+Scale	O
+-	O
+Revised	O
+","	O
+and	O
+by	O
+a	O
+physician	O
+using	O
+the	O
+Children	O
+'	O
+s	O
+Psychiatric	O
+Rating	O
+Scale	O
+and	O
+the	O
+Clinical	O
+Global	O
+Impressions	O
+scale	O
+.	O
+	
+RESULTS	O
+:	O
+Patients	O
+showed	O
+a	O
+significant	O
+reduction	O
+in	O
+parent	O
+-	O
+rated	O
+irritability	B-NP
+and	O
+social	O
+withdrawal	O
+on	O
+the	O
+ABC	O
+as	O
+well	O
+as	O
+significant	O
+improvements	O
+in	O
+emotional	O
+lability	O
+and	O
+inattention	O
+on	O
+the	O
+Conners	O
+'	O
+Parent	O
+Rating	O
+Scale	O
+-	O
+-	O
+Revised	O
+.	O
+	
+Similarly	O
+","	O
+clinician	O
+ratings	O
+showed	O
+reductions	O
+in	O
+the	O
+anger	O
+subscale	O
+of	O
+the	O
+Children	O
+'	O
+s	O
+Psychiatric	O
+Rating	O
+Scale	O
+.	O
+	
+Eight	O
+of	O
+13	O
+participants	O
+were	O
+rated	O
+as	O
+responders	O
+on	O
+the	O
+basis	O
+of	O
+their	O
+improvement	O
+scores	O
+on	O
+the	O
+Clinical	O
+Global	O
+Impressions	O
+scale	O
+.	O
+	
+Overall	O
+","	O
+galantamine	O
+was	O
+well	O
+-	O
+tolerated	O
+","	O
+with	O
+no	O
+significant	O
+adverse	O
+effects	O
+apart	O
+from	O
+headaches	B-NP
+in	O
+one	O
+patient	O
+.	O
+	
+CONCLUSION	O
+:	O
+In	O
+this	O
+open	O
+trial	O
+","	O
+galantamine	O
+was	O
+well	O
+-	O
+tolerated	O
+and	O
+appeared	O
+to	O
+be	O
+beneficial	O
+for	O
+the	O
+treatment	O
+of	O
+interfering	O
+behaviors	O
+in	O
+children	O
+with	O
+autism	B-NP
+","	O
+particularly	O
+aggression	B-NP
+","	O
+behavioral	B-NP
+dyscontrol	I-NP
+","	O
+and	O
+inattention	B-NP
+.	O
+	
+Further	O
+controlled	O
+trials	O
+are	O
+warranted	O
+.	O
+	
+Randomized	O
+comparison	O
+of	O
+olanzapine	O
+versus	O
+risperidone	O
+for	O
+the	O
+treatment	O
+of	O
+first	O
+-	O
+episode	O
+schizophrenia	B-NP
+:	O
+4	O
+-	O
+month	O
+outcomes	O
+.	O
+	
+OBJECTIVE	O
+:	O
+The	O
+authors	O
+compared	O
+4	O
+-	O
+month	O
+treatment	O
+outcomes	O
+for	O
+olanzapine	O
+versus	O
+risperidone	O
+in	O
+patients	O
+with	O
+first	O
+-	O
+episode	O
+schizophrenia	B-NP
+spectrum	O
+disorders	O
+.	O
+	
+METHOD	O
+:	O
+One	O
+hundred	O
+twelve	O
+subjects	O
+(	O
+70	O
+%	O
+male	O
+;	O
+mean	O
+age	O
+=	O
+23	O
+.	O
+3	O
+years	O
+[	O
+SD	O
+=	O
+5	O
+.	O
+1	O
+]	O
+)	O
+with	O
+first	O
+-	O
+episode	O
+schizophrenia	B-NP
+(	O
+75	O
+%	O
+)	O
+","	O
+schizophreniform	B-NP
+disorder	I-NP
+(	O
+17	O
+%	O
+)	O
+","	O
+or	O
+schizoaffective	B-NP
+disorder	I-NP
+(	O
+8	O
+%	O
+)	O
+were	O
+randomly	O
+assigned	O
+to	O
+treatment	O
+with	O
+olanzapine	O
+(	O
+2	O
+.	O
+5	O
+-	O
+20	O
+mg	O
+/	O
+day	O
+)	O
+or	O
+risperidone	O
+(	O
+1	O
+-	O
+6	O
+mg	O
+/	O
+day	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+Response	O
+rates	O
+did	O
+not	O
+significantly	O
+differ	O
+between	O
+olanzapine	O
+(	O
+43	O
+.	O
+7	O
+%	O
+","	O
+95	O
+%	O
+CI	O
+=	O
+28	O
+.	O
+8	O
+%	O
+-	O
+58	O
+.	O
+6	O
+%	O
+)	O
+and	O
+risperidone	O
+(	O
+54	O
+.	O
+3	O
+%	O
+","	O
+95	O
+%	O
+CI	O
+=	O
+39	O
+.	O
+9	O
+%	O
+-	O
+68	O
+.	O
+7	O
+%	O
+)	O
+.	O
+	
+Among	O
+those	O
+responding	O
+to	O
+treatment	O
+","	O
+more	O
+subjects	O
+in	O
+the	O
+olanzapine	O
+group	O
+(	O
+40	O
+.	O
+9	O
+%	O
+","	O
+95	O
+%	O
+CI	O
+=	O
+16	O
+.	O
+8	O
+%	O
+-	O
+65	O
+.	O
+0	O
+%	O
+)	O
+than	O
+in	O
+the	O
+risperidone	O
+group	O
+(	O
+18	O
+.	O
+9	O
+%	O
+","	O
+95	O
+%	O
+CI	O
+=	O
+0	O
+%	O
+-	O
+39	O
+.	O
+2	O
+%	O
+)	O
+had	O
+subsequent	O
+ratings	O
+not	O
+meeting	O
+response	O
+criteria	O
+.	O
+	
+Negative	O
+symptom	O
+outcomes	O
+and	O
+measures	O
+of	O
+parkinsonism	B-NP
+and	O
+akathisia	B-NP
+did	O
+not	O
+differ	O
+between	O
+medications	O
+.	O
+	
+Extrapyramidal	B-NP
+symptom	I-NP
+severity	O
+scores	O
+were	O
+1	O
+.	O
+4	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+1	O
+.	O
+2	O
+-	O
+1	O
+.	O
+6	O
+)	O
+with	O
+risperidone	O
+and	O
+1	O
+.	O
+2	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+1	O
+.	O
+0	O
+-	O
+1	O
+.	O
+4	O
+)	O
+with	O
+olanzapine	O
+.	O
+	
+Significantly	O
+more	O
+weight	B-NP
+gain	I-NP
+occurred	O
+with	O
+olanzapine	O
+than	O
+with	O
+risperidone	O
+:	O
+the	O
+increase	O
+in	O
+weight	O
+at	O
+4	O
+months	O
+relative	O
+to	O
+baseline	O
+weight	O
+was	O
+17	O
+.	O
+3	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+14	O
+.	O
+2	O
+%	O
+-	O
+20	O
+.	O
+5	O
+%	O
+)	O
+with	O
+olanzapine	O
+and	O
+11	O
+.	O
+3	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+8	O
+.	O
+4	O
+%	O
+-	O
+14	O
+.	O
+3	O
+%	O
+)	O
+with	O
+risperidone	O
+.	O
+	
+Body	O
+mass	O
+index	O
+at	O
+baseline	O
+and	O
+at	O
+4	O
+months	O
+was	O
+24	O
+.	O
+3	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+22	O
+.	O
+8	O
+-	O
+25	O
+.	O
+7	O
+)	O
+versus	O
+28	O
+.	O
+2	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+26	O
+.	O
+7	O
+-	O
+29	O
+.	O
+7	O
+)	O
+with	O
+olanzapine	O
+and	O
+23	O
+.	O
+9	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+22	O
+.	O
+5	O
+-	O
+25	O
+.	O
+3	O
+)	O
+versus	O
+26	O
+.	O
+7	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+25	O
+.	O
+2	O
+-	O
+28	O
+.	O
+2	O
+)	O
+with	O
+risperidone	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Clinical	O
+outcomes	O
+with	O
+risperidone	O
+were	O
+equal	O
+to	O
+those	O
+with	O
+olanzapine	O
+","	O
+and	O
+response	O
+may	O
+be	O
+more	O
+stable	O
+.	O
+	
+Olanzapine	O
+may	O
+have	O
+an	O
+advantage	O
+for	O
+motor	O
+side	O
+effects	O
+.	O
+	
+Both	O
+medications	O
+caused	O
+substantial	O
+rapid	O
+weight	B-NP
+gain	I-NP
+","	O
+but	O
+weight	B-NP
+gain	I-NP
+was	O
+greater	O
+with	O
+olanzapine	O
+.	O
+	
+Early	O
+paracentral	O
+visual	B-NP
+field	I-NP
+loss	I-NP
+in	O
+patients	O
+taking	O
+hydroxychloroquine	O
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+review	O
+the	O
+natural	O
+history	O
+and	O
+ocular	O
+and	O
+systemic	O
+adverse	O
+effects	O
+of	O
+patients	O
+taking	O
+hydroxychloroquine	O
+sulfate	O
+who	O
+attended	O
+an	O
+ophthalmic	O
+screening	O
+program	O
+.	O
+	
+DESIGN	O
+:	O
+Retrospective	O
+study	O
+.	O
+	
+RESULTS	O
+:	O
+Records	O
+of	O
+262	O
+patients	O
+who	O
+were	O
+taking	O
+hydroxychloroquine	O
+and	O
+screened	O
+in	O
+the	O
+Department	O
+of	O
+Ophthalmology	O
+were	O
+reviewed	O
+.	O
+	
+Of	O
+the	O
+262	O
+patients	O
+","	O
+14	O
+(	O
+18	O
+%	O
+)	O
+of	O
+76	O
+who	O
+had	O
+stopped	O
+treatment	O
+at	O
+the	O
+time	O
+of	O
+the	O
+study	O
+experienced	O
+documented	O
+adverse	O
+effects	O
+.	O
+	
+Systemic	O
+adverse	O
+effects	O
+occurred	O
+in	O
+8	O
+patients	O
+(	O
+10	O
+.	O
+5	O
+%	O
+)	O
+and	O
+ocular	O
+adverse	O
+effects	O
+","	O
+in	O
+5	O
+(	O
+6	O
+.	O
+5	O
+%	O
+)	O
+.	O
+	
+Thirty	O
+-	O
+five	O
+patients	O
+(	O
+13	O
+.	O
+4	O
+%	O
+)	O
+had	O
+visual	B-NP
+field	I-NP
+abnormalities	I-NP
+","	O
+which	O
+were	O
+attributed	O
+to	O
+hydroxychloroquine	O
+treatment	O
+in	O
+4	O
+patients	O
+(	O
+1	O
+.	O
+5	O
+%	O
+)	O
+.	O
+	
+Three	O
+of	O
+the	O
+4	O
+patients	O
+were	O
+taking	O
+less	O
+than	O
+6	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+and	O
+all	O
+patients	O
+had	O
+normal	O
+renal	O
+and	O
+liver	O
+function	O
+test	O
+results	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+current	O
+study	O
+used	O
+a	O
+protocol	O
+of	O
+visual	O
+acuity	O
+and	O
+color	O
+vision	O
+assessment	O
+","	O
+funduscopy	O
+","	O
+and	O
+Humphrey	O
+10	O
+-	O
+2	O
+visual	O
+field	O
+testing	O
+and	O
+shows	O
+that	O
+visual	B-NP
+field	I-NP
+defects	I-NP
+appeared	O
+before	O
+any	O
+corresponding	O
+changes	O
+in	O
+any	O
+other	O
+tested	O
+clinical	O
+parameters	O
+;	O
+the	O
+defects	O
+were	O
+reproducible	O
+and	O
+the	O
+test	O
+parameters	O
+were	O
+reliable	O
+.	O
+	
+Patients	O
+taking	O
+hydroxychloroquine	O
+can	O
+demonstrate	O
+a	O
+toxic	O
+reaction	O
+in	O
+the	O
+retina	O
+despite	O
+the	O
+absence	O
+of	O
+known	O
+risk	O
+factors	O
+.	O
+	
+Screening	O
+","	O
+including	O
+Humphrey	O
+10	O
+-	O
+2	O
+visual	O
+field	O
+assessment	O
+","	O
+is	O
+recommended	O
+2	O
+years	O
+after	O
+the	O
+initial	O
+baseline	O
+and	O
+yearly	O
+thereafter	O
+.	O
+	
+Peri	O
+-	O
+operative	O
+atrioventricular	B-NP
+block	I-NP
+as	O
+a	O
+result	O
+of	O
+chemotherapy	O
+with	O
+epirubicin	O
+and	O
+paclitaxel	O
+.	O
+	
+A	O
+47	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+presented	O
+for	O
+mastectomy	O
+and	O
+immediate	O
+latissimus	O
+dorsi	O
+flap	O
+reconstruction	O
+having	O
+been	O
+diagnosed	O
+with	O
+carcinoma	B-NP
+of	I-NP
+the	I-NP
+breast	I-NP
+6	O
+months	O
+previously	O
+.	O
+	
+In	O
+the	O
+preceding	O
+months	O
+she	O
+had	O
+received	O
+neo	O
+-	O
+adjuvant	O
+chemotherapy	O
+with	O
+epirubicin	O
+","	O
+paclitaxel	O
+(	O
+Taxol	O
+)	O
+and	O
+cyclophosphamide	O
+.	O
+	
+This	O
+had	O
+been	O
+apparently	O
+uncomplicated	O
+and	O
+she	O
+had	O
+maintained	O
+a	O
+remarkably	O
+high	O
+level	O
+of	O
+physical	O
+activity	O
+.	O
+	
+She	O
+was	O
+found	O
+to	O
+be	O
+bradycardic	B-NP
+at	O
+pre	O
+-	O
+operative	O
+assessment	O
+but	O
+had	O
+no	O
+cardiac	O
+symptoms	O
+.	O
+	
+Second	O
+degree	O
+Mobitz	O
+type	O
+II	O
+atrioventricular	B-NP
+block	I-NP
+was	O
+diagnosed	O
+on	O
+electrocardiogram	O
+","	O
+and	O
+temporary	O
+transvenous	O
+ventricular	O
+pacing	O
+instituted	O
+in	O
+the	O
+peri	O
+-	O
+operative	O
+period	O
+.	O
+	
+We	O
+discuss	O
+how	O
+evidence	O
+-	O
+based	O
+guidelines	O
+would	O
+not	O
+have	O
+been	O
+helpful	O
+in	O
+this	O
+case	O
+","	O
+and	O
+how	O
+chemotherapy	O
+can	O
+exhibit	O
+substantial	O
+cardiotoxicity	B-NP
+that	O
+may	O
+develop	O
+over	O
+many	O
+years	O
+.	O
+	
+We	O
+suggest	O
+that	O
+patients	O
+who	O
+have	O
+received	O
+chemotherapy	O
+at	O
+any	O
+time	O
+should	O
+have	O
+a	O
+pre	O
+-	O
+operative	O
+electrocardiogram	O
+even	O
+if	O
+they	O
+are	O
+asymptomatic	O
+.	O
+	
+Risks	O
+and	O
+benefits	O
+of	O
+COX	O
+-	O
+2	O
+inhibitors	O
+vs	O
+non	O
+-	O
+selective	O
+NSAIDs	O
+:	O
+does	O
+their	O
+cardiovascular	O
+risk	O
+exceed	O
+their	O
+gastrointestinal	O
+benefit	O
+?	O
+	
+A	O
+retrospective	O
+cohort	O
+study	O
+.	O
+	
+OBJECTIVES	O
+:	O
+The	O
+risk	O
+of	O
+acute	B-NP
+myocardial	I-NP
+infarction	I-NP
+(	O
+AMI	B-NP
+)	O
+with	O
+COX	O
+-	O
+2	O
+inhibitors	O
+may	O
+offset	O
+their	O
+gastrointestinal	O
+(	O
+GI	O
+)	O
+benefit	O
+compared	O
+with	O
+non	O
+-	O
+selective	O
+(	O
+NS	O
+)	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+(	O
+NSAIDs	O
+)	O
+.	O
+	
+We	O
+aimed	O
+to	O
+compare	O
+the	O
+risks	O
+of	O
+hospitalization	O
+for	O
+AMI	B-NP
+and	O
+GI	B-NP
+bleeding	I-NP
+among	O
+elderly	O
+patients	O
+using	O
+COX	O
+-	O
+2	O
+inhibitors	O
+","	O
+NS	O
+-	O
+NSAIDs	O
+and	O
+acetaminophen	O
+.	O
+	
+METHODS	O
+:	O
+We	O
+conducted	O
+a	O
+retrospective	O
+cohort	O
+study	O
+using	O
+administrative	O
+data	O
+of	O
+patients	O
+>	O
+or	O
+=	O
+65	O
+years	O
+of	O
+age	O
+who	O
+filled	O
+a	O
+prescription	O
+for	O
+NSAID	O
+or	O
+acetaminophen	O
+during	O
+1999	O
+-	O
+2002	O
+.	O
+	
+Outcomes	O
+were	O
+compared	O
+using	O
+Cox	O
+regression	O
+models	O
+with	O
+time	O
+-	O
+dependent	O
+exposures	O
+.	O
+	
+RESULTS	O
+:	O
+Person	O
+-	O
+years	O
+of	O
+exposure	O
+among	O
+non	O
+-	O
+users	O
+of	O
+aspirin	O
+were	O
+:	O
+75	O
+","	O
+761	O
+to	O
+acetaminophen	O
+","	O
+42	O
+","	O
+671	O
+to	O
+rofecoxib	O
+65	O
+","	O
+860	O
+to	O
+celecoxib	O
+","	O
+and	O
+37	O
+","	O
+495	O
+to	O
+NS	O
+-	O
+NSAIDs	O
+.	O
+	
+Among	O
+users	O
+of	O
+aspirin	O
+","	O
+they	O
+were	O
+:	O
+14	O
+","	O
+671	O
+to	O
+rofecoxib	O
+","	O
+22	O
+","	O
+875	O
+to	O
+celecoxib	O
+","	O
+9	O
+","	O
+832	O
+to	O
+NS	O
+-	O
+NSAIDs	O
+and	O
+38	O
+","	O
+48	O
+to	O
+acetaminophen	O
+.	O
+	
+Among	O
+non	O
+-	O
+users	O
+of	O
+aspirin	O
+","	O
+the	O
+adjusted	O
+hazard	O
+ratios	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+)	O
+of	O
+hospitalization	O
+for	O
+AMI	B-NP
+/	O
+GI	O
+vs	O
+the	O
+acetaminophen	O
+(	O
+with	O
+no	O
+aspirin	O
+)	O
+group	O
+were	O
+:	O
+rofecoxib	O
+1	O
+.	O
+27	O
+(	O
+1	O
+.	O
+13	O
+","	O
+1	O
+.	O
+42	O
+)	O
+","	O
+celecoxib	O
+0	O
+.	O
+93	O
+(	O
+0	O
+.	O
+83	O
+","	O
+1	O
+.	O
+3	O
+)	O
+","	O
+naproxen	O
+1	O
+.	O
+59	O
+(	O
+1	O
+.	O
+31	O
+","	O
+1	O
+.	O
+93	O
+)	O
+","	O
+diclofenac	O
+1	O
+.	O
+17	O
+(	O
+0	O
+.	O
+99	O
+","	O
+1	O
+.	O
+38	O
+)	O
+and	O
+ibuprofen	O
+1	O
+.	O
+5	O
+(	O
+0	O
+.	O
+74	O
+","	O
+1	O
+.	O
+51	O
+)	O
+.	O
+	
+Among	O
+users	O
+of	O
+aspirin	O
+","	O
+they	O
+were	O
+:	O
+rofecoxib	O
+1	O
+.	O
+73	O
+(	O
+1	O
+.	O
+52	O
+","	O
+1	O
+.	O
+98	O
+)	O
+","	O
+celecoxib	O
+1	O
+.	O
+34	O
+(	O
+1	O
+.	O
+19	O
+","	O
+1	O
+.	O
+52	O
+)	O
+","	O
+ibuprofen	O
+1	O
+.	O
+51	O
+(	O
+0	O
+.	O
+95	O
+","	O
+2	O
+.	O
+41	O
+)	O
+","	O
+diclofenac	O
+1	O
+.	O
+69	O
+(	O
+1	O
+.	O
+35	O
+","	O
+2	O
+.	O
+10	O
+)	O
+","	O
+naproxen	O
+1	O
+.	O
+35	O
+(	O
+0	O
+.	O
+97	O
+","	O
+1	O
+.	O
+88	O
+)	O
+and	O
+acetaminophen	O
+1	O
+.	O
+29	O
+(	O
+1	O
+.	O
+17	O
+","	O
+1	O
+.	O
+42	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+Among	O
+non	O
+-	O
+users	O
+of	O
+aspirin	O
+","	O
+naproxen	O
+seemed	O
+to	O
+carry	O
+the	O
+highest	O
+risk	O
+for	O
+AMI	B-NP
+/	O
+GI	B-NP
+bleeding	I-NP
+.	O
+	
+The	O
+AMI	B-NP
+/	O
+GI	O
+toxicity	B-NP
+of	O
+celecoxib	O
+was	O
+similar	O
+to	O
+that	O
+of	O
+acetaminophen	O
+and	O
+seemed	O
+to	O
+be	O
+better	O
+than	O
+those	O
+of	O
+rofecoxib	O
+and	O
+NS	O
+-	O
+NSAIDs	O
+.	O
+	
+Among	O
+users	O
+of	O
+aspirin	O
+","	O
+both	O
+celecoxib	O
+and	O
+naproxen	O
+seemed	O
+to	O
+be	O
+the	O
+least	O
+toxic	O
+.	O
+	
+Quinine	O
+-	O
+induced	O
+arrhythmia	B-NP
+in	O
+a	O
+patient	O
+with	O
+severe	B-NP
+malaria	I-NP
+.	O
+	
+It	O
+was	O
+reported	O
+that	O
+there	O
+was	O
+a	O
+case	O
+of	O
+severe	B-NP
+malaria	I-NP
+patient	O
+with	O
+jaundice	B-NP
+who	O
+presented	O
+with	O
+arrhythmia	B-NP
+(	O
+premature	B-NP
+ventricular	I-NP
+contraction	I-NP
+)	O
+while	O
+getting	O
+quinine	O
+infusion	O
+was	O
+reported	O
+.	O
+	
+A	O
+man	O
+","	O
+25	O
+years	O
+old	O
+","	O
+was	O
+admitted	O
+to	O
+hospital	O
+with	O
+high	O
+fever	B-NP
+","	O
+chill	B-NP
+","	O
+vomiting	B-NP
+","	O
+jaundice	B-NP
+.	O
+	
+The	O
+patient	O
+was	O
+fully	O
+conscious	O
+","	O
+blood	O
+pressure	O
+120	O
+/	O
+80	O
+mmHg	O
+","	O
+pulse	O
+rate	O
+100	O
+x	O
+/	O
+minute	O
+","	O
+regular	O
+.	O
+	
+On	O
+admission	O
+","	O
+laboratory	O
+examination	O
+showed	O
+Plasmodium	O
+falciparum	O
+(	O
++	O
++	O
++	O
++	O
+)	O
+","	O
+total	O
+bilirubin	O
+8	O
+.	O
+25	O
+mg	O
+/	O
+dL	O
+","	O
+conjugated	O
+bilirubin	O
+4	O
+.	O
+36	O
+mg	O
+/	O
+dL	O
+","	O
+unconjugated	O
+bilirubin	O
+3	O
+.	O
+89	O
+mg	O
+/	O
+dL	O
+","	O
+potassium	O
+3	O
+.	O
+52	O
+meq	O
+/	O
+L	O
+Patient	O
+was	O
+diagnosed	O
+as	O
+severe	B-NP
+malaria	I-NP
+with	O
+jaundice	B-NP
+and	O
+got	O
+quinine	O
+infusion	O
+in	O
+dextrose	O
+5	O
+%	O
+500	O
+mg	O
+/	O
+8	O
+hour	O
+.	O
+	
+On	O
+the	O
+second	O
+day	O
+the	O
+patient	O
+had	O
+vomitus	B-NP
+","	O
+diarrhea	B-NP
+","	O
+tinnitus	B-NP
+","	O
+loss	B-NP
+of	I-NP
+hearing	I-NP
+.	O
+	
+After	O
+30	O
+hours	O
+of	O
+quinine	O
+infusion	O
+the	O
+patient	O
+felt	O
+palpitation	B-NP
+and	O
+electrocardiography	O
+(	O
+ECG	O
+)	O
+recording	O
+showed	O
+premature	B-NP
+ventricular	I-NP
+contraction	I-NP
+(	O
+PVC	B-NP
+)	O
+>	O
+5	O
+x	O
+/	O
+minute	O
+","	O
+trigemini	O
+","	O
+constant	O
+type	O
+-	O
+-	O
+sinoatrial	B-NP
+block	I-NP
+","	O
+positive	O
+U	O
+wave	O
+.	O
+	
+He	O
+was	O
+treated	O
+with	O
+lidocaine	O
+50	O
+mg	O
+intravenously	O
+followed	O
+by	O
+infusion	O
+1500	O
+mg	O
+in	O
+dextrose	O
+5	O
+%	O
+/	O
+24	O
+hour	O
+and	O
+potassium	O
+aspartate	O
+tablet	O
+.	O
+	
+Quinine	O
+infusion	O
+was	O
+discontinued	O
+and	O
+changed	O
+with	O
+sulfate	O
+quinine	O
+tablets	O
+.	O
+	
+Three	O
+hours	O
+later	O
+the	O
+patient	O
+felt	O
+better	O
+","	O
+the	O
+frequency	O
+of	O
+PVC	B-NP
+reduced	O
+to	O
+4	O
+-	O
+5	O
+x	O
+/	O
+minute	O
+and	O
+on	O
+the	O
+third	O
+day	O
+ECG	O
+was	O
+normal	O
+","	O
+potassium	O
+level	O
+was	O
+3	O
+.	O
+34	O
+meq	O
+/	O
+L	O
+.	O
+	
+He	O
+was	O
+discharged	O
+on	O
+7th	O
+day	O
+in	O
+good	O
+condition	O
+.	O
+	
+Quinine	O
+","	O
+like	O
+quinidine	O
+","	O
+is	O
+a	O
+chincona	O
+alkaloid	O
+that	O
+has	O
+anti	O
+-	O
+arrhythmic	B-NP
+property	O
+","	O
+although	O
+it	O
+also	O
+pro	O
+-	O
+arrhythmic	B-NP
+that	O
+can	O
+cause	O
+various	O
+arrhythmias	B-NP
+","	O
+including	O
+severe	O
+arrhythmia	B-NP
+such	O
+as	O
+multiple	O
+PVC	B-NP
+.	O
+	
+Administration	O
+of	O
+parenteral	O
+quinine	O
+must	O
+be	O
+done	O
+carefully	O
+and	O
+with	O
+good	O
+observation	O
+because	O
+of	O
+its	O
+pro	O
+-	O
+arrhythmic	B-NP
+effect	O
+","	O
+especially	O
+in	O
+older	O
+patients	O
+who	O
+have	O
+heart	B-NP
+diseases	I-NP
+or	O
+patients	O
+with	O
+electrolyte	B-NP
+disorder	I-NP
+(	O
+hypokalemia	B-NP
+)	O
+which	O
+frequently	O
+occurs	O
+due	O
+to	O
+vomiting	B-NP
+and	O
+or	O
+diarrhea	B-NP
+in	O
+malaria	B-NP
+cases	O
+.	O
+	
+Penicillamine	O
+-	O
+related	O
+lichenoid	B-NP
+dermatitis	I-NP
+and	O
+utility	O
+of	O
+zinc	O
+acetate	O
+in	O
+a	O
+Wilson	B-NP
+disease	I-NP
+patient	O
+with	O
+hepatic	O
+presentation	O
+","	O
+anxiety	B-NP
+and	O
+SPECT	O
+abnormalities	O
+.	O
+	
+Wilson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+is	O
+an	O
+autosomal	O
+recessive	O
+disorder	O
+of	O
+hepatic	O
+copper	O
+metabolism	O
+with	O
+consequent	O
+copper	O
+accumulation	O
+and	O
+toxicity	B-NP
+in	O
+many	O
+tissues	O
+and	O
+consequent	O
+hepatic	B-NP
+","	I-NP
+neurologic	I-NP
+and	I-NP
+psychiatric	I-NP
+disorders	I-NP
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+Wilson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+with	O
+chronic	B-NP
+liver	I-NP
+disease	I-NP
+;	O
+moreover	O
+","	O
+in	O
+our	O
+patient	O
+","	O
+presenting	O
+also	O
+with	O
+high	O
+levels	O
+of	O
+state	O
+anxiety	B-NP
+without	O
+depression	B-NP
+","	O
+99mTc	O
+-	O
+ECD	O
+-	O
+SPECT	O
+showed	O
+cortical	O
+hypoperfusion	O
+in	O
+frontal	O
+lobes	O
+","	O
+more	O
+marked	O
+on	O
+the	O
+left	O
+frontal	O
+lobe	O
+.	O
+	
+During	O
+the	O
+follow	O
+-	O
+up	O
+of	O
+our	O
+patient	O
+","	O
+penicillamine	O
+was	O
+interrupted	O
+after	O
+the	O
+appearance	O
+of	O
+a	O
+lichenoid	B-NP
+dermatitis	I-NP
+","	O
+and	O
+zinc	O
+acetate	O
+permitted	O
+to	O
+continue	O
+the	O
+successful	O
+treatment	O
+of	O
+the	O
+patient	O
+without	O
+side	O
+-	O
+effects	O
+.	O
+	
+In	O
+our	O
+case	O
+the	O
+therapy	O
+with	O
+zinc	O
+acetate	O
+represented	O
+an	O
+effective	O
+treatment	O
+for	O
+a	O
+Wilson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+patient	O
+in	O
+which	O
+penicillamine	O
+-	O
+related	O
+side	O
+effects	O
+appeared	O
+.	O
+	
+The	O
+safety	O
+of	O
+the	O
+zinc	O
+acetate	O
+allowed	O
+us	O
+to	O
+avoid	O
+other	O
+potentially	O
+toxic	O
+chelating	O
+drugs	O
+;	O
+this	O
+observation	O
+is	O
+in	O
+line	O
+with	O
+the	O
+growing	O
+evidence	O
+on	O
+the	O
+efficacy	O
+of	O
+the	O
+drug	O
+in	O
+the	O
+treatment	O
+of	O
+Wilson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+Since	O
+most	O
+of	O
+Wilson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+penicillamine	O
+-	O
+treated	O
+patients	O
+do	O
+not	O
+seem	O
+to	O
+develop	O
+this	O
+skin	B-NP
+lesion	I-NP
+","	O
+it	O
+could	O
+be	O
+conceivable	O
+that	O
+a	O
+specific	O
+genetic	O
+factor	O
+is	O
+involved	O
+in	O
+drug	O
+response	O
+.	O
+	
+Further	O
+studies	O
+are	O
+needed	O
+for	O
+a	O
+better	O
+clarification	O
+of	O
+Wilson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+therapy	O
+","	O
+and	O
+in	O
+particular	O
+to	O
+differentiate	O
+specific	O
+therapies	O
+for	O
+different	O
+Wilson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+phenotypes	O
+.	O
+	
+A	O
+dramatic	O
+drop	B-NP
+in	I-NP
+blood	I-NP
+pressure	I-NP
+following	O
+prehospital	O
+GTN	O
+administration	O
+.	O
+	
+A	O
+male	O
+in	O
+his	O
+sixties	O
+with	O
+no	O
+history	O
+of	O
+cardiac	O
+chest	B-NP
+pain	I-NP
+awoke	O
+with	O
+chest	B-NP
+pain	I-NP
+following	O
+an	O
+afternoon	O
+sleep	O
+.	O
+	
+The	O
+patient	O
+did	O
+not	O
+self	O
+medicate	O
+.	O
+	
+The	O
+patient	O
+'	O
+s	O
+observations	O
+were	O
+within	O
+normal	O
+limits	O
+","	O
+he	O
+was	O
+administered	O
+oxygen	O
+via	O
+a	O
+face	O
+mask	O
+and	O
+glyceryl	O
+trinitrate	O
+(	O
+GTN	O
+)	O
+.	O
+	
+Several	O
+minutes	O
+after	O
+the	O
+GTN	O
+the	O
+patient	O
+experienced	O
+a	O
+sudden	O
+drop	B-NP
+in	I-NP
+blood	I-NP
+pressure	I-NP
+and	O
+heart	O
+rate	O
+","	O
+this	O
+was	O
+rectified	O
+by	O
+atropine	O
+sulphate	O
+and	O
+a	O
+fluid	O
+challenge	O
+.	O
+	
+There	O
+was	O
+no	O
+further	O
+deterioration	O
+in	O
+the	O
+patient	O
+'	O
+s	O
+condition	O
+during	O
+transport	O
+to	O
+hospital	O
+.	O
+	
+There	O
+are	O
+very	O
+few	O
+documented	O
+case	O
+like	O
+this	O
+in	O
+the	O
+prehospital	O
+scientific	O
+literature	O
+.	O
+	
+The	O
+cause	O
+appears	O
+to	O
+be	O
+the	O
+Bezold	O
+-	O
+Jarish	O
+reflex	O
+","	O
+stimulation	O
+of	O
+the	O
+ventricular	O
+walls	O
+which	O
+in	O
+turn	O
+decreases	O
+sympathetic	O
+outflow	O
+from	O
+the	O
+vasomotor	O
+centre	O
+.	O
+	
+Prehospital	O
+care	O
+providers	O
+who	O
+are	O
+managing	O
+any	O
+patient	O
+with	O
+a	O
+syncopal	B-NP
+episode	I-NP
+that	O
+fails	O
+to	O
+recover	O
+within	O
+a	O
+reasonable	O
+time	O
+frame	O
+should	O
+consider	O
+the	O
+Bezold	O
+-	O
+Jarisch	O
+reflex	O
+as	O
+the	O
+cause	O
+and	O
+manage	O
+the	O
+patient	O
+accordingly	O
+.	O
+	
+Chronic	O
+lesion	O
+of	O
+rostral	O
+ventrolateral	O
+medulla	O
+in	O
+spontaneously	O
+hypertensive	B-NP
+rats	O
+.	O
+	
+We	O
+studied	O
+the	O
+effects	O
+of	O
+chronic	O
+selective	O
+neuronal	O
+lesion	O
+of	O
+rostral	O
+ventrolateral	O
+medulla	O
+on	O
+mean	O
+arterial	O
+pressure	O
+","	O
+heart	O
+rate	O
+","	O
+and	O
+neurogenic	O
+tone	O
+in	O
+conscious	O
+","	O
+unrestrained	O
+spontaneously	O
+hypertensive	B-NP
+rats	O
+.	O
+	
+The	O
+lesions	O
+were	O
+placed	O
+via	O
+bilateral	O
+microinjections	O
+of	O
+30	O
+nmol	O
+/	O
+200	O
+nl	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartic	O
+acid	O
+.	O
+	
+The	O
+restimulation	O
+of	O
+this	O
+area	O
+with	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartic	O
+acid	O
+15	O
+days	O
+postlesion	O
+failed	O
+to	O
+produce	O
+a	O
+pressor	O
+response	O
+.	O
+	
+One	O
+day	O
+postlesion	O
+","	O
+the	O
+resting	O
+mean	O
+arterial	O
+pressure	O
+was	O
+significantly	O
+decreased	O
+in	O
+lesioned	O
+rats	O
+when	O
+compared	O
+with	O
+sham	O
+rats	O
+(	O
+100	O
++	O
+/	O
+-	O
+7	O
+versus	O
+173	O
++	O
+/	O
+-	O
+4	O
+mm	O
+Hg	O
+","	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+Fifteen	O
+days	O
+later	O
+","	O
+the	O
+lesioned	O
+group	O
+still	O
+showed	O
+values	O
+significantly	O
+lower	O
+than	O
+the	O
+sham	O
+group	O
+(	O
+150	O
++	O
+/	O
+-	O
+6	O
+versus	O
+167	O
++	O
+/	O
+-	O
+5	O
+mm	O
+Hg	O
+","	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+No	O
+significant	O
+heart	O
+rate	O
+differences	O
+were	O
+observed	O
+between	O
+the	O
+sham	O
+and	O
+lesioned	O
+groups	O
+.	O
+	
+The	O
+ganglionic	O
+blocker	O
+trimethaphan	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+i	O
+.	O
+v	O
+.	O
+)	O
+caused	O
+similar	O
+reductions	O
+in	O
+mean	O
+arterial	O
+pressure	O
+in	O
+both	O
+lesioned	O
+and	O
+sham	O
+groups	O
+.	O
+	
+The	O
+trimethaphan	O
+-	O
+induced	O
+hypotension	B-NP
+was	O
+accompanied	O
+by	O
+a	O
+significant	O
+bradycardia	B-NP
+in	O
+lesioned	O
+rats	O
+(	O
+-	O
+32	O
++	O
+/	O
+-	O
+13	O
+beats	O
+per	O
+minute	O
+)	O
+but	O
+a	O
+tachycardia	B-NP
+in	O
+sham	O
+rats	O
+(	O
++	O
+33	O
++	O
+/	O
+-	O
+12	O
+beats	O
+per	O
+minute	O
+)	O
+1	O
+day	O
+postlesion	O
+.	O
+	
+Therefore	O
+","	O
+rostral	O
+ventrolateral	O
+medulla	O
+neurons	O
+appear	O
+to	O
+play	O
+a	O
+significant	O
+role	O
+in	O
+maintaining	O
+hypertension	B-NP
+in	O
+conscious	O
+spontaneously	O
+hypertensive	B-NP
+rats	O
+.	O
+	
+Spinal	O
+or	O
+suprabulbar	O
+structures	O
+could	O
+be	O
+responsible	O
+for	O
+the	O
+gradual	O
+recovery	O
+of	O
+the	O
+hypertension	B-NP
+in	O
+the	O
+lesioned	O
+rats	O
+.	O
+	
+Acute	B-NP
+encephalopathy	I-NP
+and	O
+cerebral	B-NP
+vasospasm	I-NP
+after	O
+multiagent	O
+chemotherapy	O
+including	O
+PEG	O
+-	O
+asparaginase	O
+and	O
+intrathecal	O
+cytarabine	O
+for	O
+the	O
+treatment	O
+of	O
+acute	B-NP
+lymphoblastic	I-NP
+leukemia	I-NP
+.	O
+	
+A	O
+7	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+with	O
+an	O
+unusual	O
+reaction	O
+to	O
+induction	O
+chemotherapy	O
+for	O
+precursor	O
+B	O
+-	O
+cell	O
+acute	B-NP
+lymphoblastic	I-NP
+leukemia	I-NP
+(	O
+ALL	B-NP
+)	O
+is	O
+described	O
+.	O
+	
+The	O
+patient	O
+developed	O
+acute	B-NP
+encephalopathy	I-NP
+evidenced	O
+by	O
+behavioral	O
+changes	O
+","	O
+aphasia	B-NP
+","	O
+incontinence	B-NP
+","	O
+visual	B-NP
+hallucinations	I-NP
+","	O
+and	O
+right	O
+-	O
+sided	O
+weakness	B-NP
+with	O
+diffuse	O
+cerebral	B-NP
+vasospasm	I-NP
+on	O
+magnetic	O
+resonance	O
+angiography	O
+after	O
+the	O
+administration	O
+of	O
+intrathecal	O
+cytarabine	O
+.	O
+	
+Vincristine	O
+","	O
+dexamethasone	O
+","	O
+and	O
+polyethylene	O
+glycol	O
+-	O
+asparaginase	O
+were	O
+also	O
+administered	O
+before	O
+the	O
+episode	O
+as	O
+part	O
+of	O
+induction	O
+therapy	O
+.	O
+	
+Neurologic	O
+status	O
+returned	O
+to	O
+baseline	O
+within	O
+10	O
+days	O
+of	O
+the	O
+acute	O
+event	O
+","	O
+and	O
+magnetic	O
+resonance	O
+angiography	O
+findings	O
+returned	O
+to	O
+normal	O
+4	O
+months	O
+later	O
+.	O
+	
+Comparison	O
+of	O
+valsartan	O
+/	O
+hydrochlorothiazide	O
+combination	O
+therapy	O
+at	O
+doses	O
+up	O
+to	O
+320	O
+/	O
+25	O
+mg	O
+versus	O
+monotherapy	O
+:	O
+a	O
+double	O
+-	O
+blind	O
+","	O
+placebo	O
+-	O
+controlled	O
+study	O
+followed	O
+by	O
+long	O
+-	O
+term	O
+combination	O
+therapy	O
+in	O
+hypertensive	B-NP
+adults	O
+.	O
+	
+BACKGROUND	O
+:	O
+One	O
+third	O
+of	O
+patients	O
+treated	O
+for	O
+hypertension	B-NP
+attain	O
+adequate	O
+blood	O
+pressure	O
+(	O
+BP	O
+)	O
+control	O
+","	O
+and	O
+multidrug	O
+regimens	O
+are	O
+often	O
+required	O
+.	O
+	
+Given	O
+the	O
+lifelong	O
+nature	O
+of	O
+hypertension	B-NP
+","	O
+there	O
+is	O
+a	O
+need	O
+to	O
+evaluate	O
+the	O
+long	O
+-	O
+term	O
+efficacy	O
+and	O
+tolerability	O
+of	O
+higher	O
+doses	O
+of	O
+combination	O
+anti	O
+-	O
+hypertensive	B-NP
+therapies	O
+.	O
+	
+OBJECTIVE	O
+:	O
+This	O
+study	O
+investigated	O
+the	O
+efficacy	O
+and	O
+tolerability	O
+of	O
+valsartan	O
+(	O
+VAL	O
+)	O
+or	O
+hydrochlorothiazide	O
+(	O
+HCTZ	O
+)	O
+-	O
+monotherapy	O
+and	O
+higher	O
+-	O
+dose	O
+combinations	O
+in	O
+patients	O
+with	O
+essential	B-NP
+hypertension	I-NP
+.	O
+	
+METHODS	O
+:	O
+The	O
+first	O
+part	O
+of	O
+this	O
+study	O
+was	O
+an	O
+8	O
+-	O
+week	O
+","	O
+multicenter	O
+","	O
+randomized	O
+","	O
+double	O
+-	O
+blind	O
+","	O
+placebo	O
+controlled	O
+","	O
+parallel	O
+-	O
+group	O
+trial	O
+.	O
+	
+Patients	O
+with	O
+essential	B-NP
+hypertension	I-NP
+(	O
+mean	O
+sitting	O
+diastolic	O
+BP	O
+[	O
+MSDBP	O
+]	O
+","	O
+>	O
+or	O
+=	O
+95	O
+mm	O
+Hg	O
+and	O
+<	O
+110	O
+mm	O
+Hg	O
+)	O
+were	O
+randomized	O
+to	O
+1	O
+of	O
+8	O
+treatment	O
+groups	O
+:	O
+VAL	O
+160	O
+or	O
+320	O
+mg	O
+;	O
+HCTZ	O
+12	O
+.	O
+5	O
+or	O
+25	O
+mg	O
+;	O
+VAL	O
+/	O
+HCTZ	O
+160	O
+/	O
+12	O
+.	O
+5	O
+","	O
+320	O
+/	O
+12	O
+.	O
+5	O
+","	O
+or	O
+320	O
+/	O
+25	O
+mg	O
+;	O
+or	O
+placebo	O
+.	O
+	
+Mean	O
+changes	O
+in	O
+MSDBP	O
+and	O
+mean	O
+sitting	O
+systolic	O
+BP	O
+(	O
+MSSBP	O
+)	O
+were	O
+analyzed	O
+at	O
+the	O
+8	O
+-	O
+week	O
+core	O
+study	O
+end	O
+point	O
+.	O
+	
+VAL	O
+/	O
+HCTZ	O
+320	O
+/	O
+12	O
+.	O
+5	O
+and	O
+320	O
+/	O
+25	O
+mg	O
+were	O
+further	O
+investigated	O
+in	O
+a	O
+54	O
+-	O
+week	O
+","	O
+open	O
+-	O
+label	O
+extension	O
+.	O
+	
+Response	O
+was	O
+defined	O
+as	O
+MSDBP	O
+<	O
+90	O
+mm	O
+Hg	O
+or	O
+a	O
+>	O
+or	O
+=	O
+10	O
+mm	O
+Hg	O
+decrease	O
+compared	O
+to	O
+baseline	O
+.	O
+	
+Control	O
+was	O
+defined	O
+as	O
+MSDBP	O
+<	O
+90	O
+mm	O
+Hg	O
+compared	O
+with	O
+baseline	O
+.	O
+	
+Tolerability	O
+was	O
+assessed	O
+by	O
+monitoring	O
+adverse	O
+events	O
+at	O
+randomization	O
+and	O
+all	O
+subsequent	O
+study	O
+visits	O
+and	O
+regular	O
+evaluation	O
+of	O
+hematology	O
+and	O
+blood	O
+chemistry	O
+.	O
+	
+RESULTS	O
+:	O
+A	O
+total	O
+of	O
+1346	O
+patients	O
+were	O
+randomized	O
+into	O
+the	O
+8	O
+-	O
+week	O
+core	O
+study	O
+(	O
+734	O
+men	O
+","	O
+612	O
+women	O
+;	O
+924	O
+white	O
+","	O
+291	O
+black	O
+","	O
+23	O
+Asian	O
+","	O
+108	O
+other	O
+;	O
+mean	O
+age	O
+","	O
+52	O
+.	O
+7	O
+years	O
+;	O
+mean	O
+weight	O
+","	O
+92	O
+.	O
+6	O
+kg	O
+)	O
+.	O
+	
+All	O
+active	O
+treatments	O
+were	O
+associated	O
+with	O
+significantly	O
+reduced	O
+MSSBP	O
+and	O
+MSDBP	O
+during	O
+the	O
+core	O
+8	O
+-	O
+week	O
+study	O
+","	O
+with	O
+each	O
+monotherapy	O
+significantly	O
+contributing	O
+to	O
+the	O
+overall	O
+effect	O
+of	O
+combination	O
+therapy	O
+(	O
+VAL	O
+and	O
+HCTZ	O
+","	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Each	O
+combination	O
+was	O
+associated	O
+with	O
+significantly	O
+greater	O
+reductions	O
+in	O
+MSSBP	O
+and	O
+MSDBP	O
+compared	O
+with	O
+the	O
+monotherapies	O
+and	O
+placebo	O
+(	O
+all	O
+","	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+The	O
+mean	O
+reduction	O
+in	O
+MSSBP	O
+/	O
+MSDBP	O
+with	O
+VAL	O
+/	O
+HCTZ	O
+320	O
+/	O
+25	O
+mg	O
+was	O
+24	O
+.	O
+7	O
+/	O
+16	O
+.	O
+6	O
+mm	O
+Hg	O
+","	O
+compared	O
+with	O
+5	O
+.	O
+9	O
+/	O
+7	O
+.	O
+0	O
+mm	O
+Hg	O
+with	O
+placebo	O
+.	O
+	
+The	O
+reduction	O
+in	O
+MSSBP	O
+was	O
+significantly	O
+greater	O
+with	O
+VAL	O
+/	O
+HCTZ	O
+320	O
+/	O
+25	O
+mg	O
+compared	O
+with	O
+VAL	O
+/	O
+HCTZ	O
+160	O
+/	O
+12	O
+.	O
+5	O
+mg	O
+(	O
+P	O
+<	O
+0	O
+.	O
+2	O
+)	O
+.	O
+	
+Rates	O
+of	O
+response	O
+and	O
+BP	O
+control	O
+were	O
+significantly	O
+higher	O
+in	O
+the	O
+groups	O
+that	O
+received	O
+combination	O
+treatment	O
+compared	O
+with	O
+those	O
+that	O
+received	O
+monotherapy	O
+.	O
+	
+The	O
+incidence	O
+of	O
+hypokalemia	B-NP
+was	O
+lower	O
+with	O
+VAL	O
+/	O
+HCTZ	O
+combinations	O
+(	O
+1	O
+.	O
+8	O
+%	O
+-	O
+6	O
+.	O
+1	O
+%	O
+)	O
+than	O
+with	O
+HCTZ	O
+monotherapies	O
+(	O
+7	O
+.	O
+1	O
+%	O
+-	O
+13	O
+.	O
+3	O
+%	O
+)	O
+.	O
+	
+The	O
+majority	O
+of	O
+adverse	O
+events	O
+in	O
+the	O
+core	O
+study	O
+were	O
+of	O
+mild	O
+to	O
+moderate	O
+severity	O
+.	O
+	
+The	O
+efficacy	O
+and	O
+tolerability	O
+of	O
+VAL	O
+/	O
+HCTZ	O
+combinations	O
+were	O
+maintained	O
+during	O
+the	O
+extension	O
+(	O
+797	O
+patients	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+In	O
+this	O
+study	O
+population	O
+","	O
+combination	O
+therapies	O
+with	O
+VAL	O
+/	O
+HCTZ	O
+were	O
+associated	O
+with	O
+significantly	O
+greater	O
+BP	O
+reductions	O
+compared	O
+with	O
+either	O
+monotherapy	O
+","	O
+were	O
+well	O
+tolerated	O
+","	O
+and	O
+were	O
+associated	O
+with	O
+less	O
+hypokalemia	B-NP
+than	O
+HCTZ	O
+alone	O
+.	O
+	
+Succimer	O
+chelation	O
+improves	O
+learning	O
+","	O
+attention	O
+","	O
+and	O
+arousal	O
+regulation	O
+in	O
+lead	O
+-	O
+exposed	O
+rats	O
+but	O
+produces	O
+lasting	O
+cognitive	B-NP
+impairment	I-NP
+in	O
+the	O
+absence	O
+of	O
+lead	O
+exposure	O
+.	O
+	
+BACKGROUND	O
+:	O
+There	O
+is	O
+growing	O
+pressure	O
+for	O
+clinicians	O
+to	O
+prescribe	O
+chelation	O
+therapy	O
+at	O
+only	O
+slightly	O
+elevated	O
+blood	O
+lead	O
+levels	O
+.	O
+	
+However	O
+","	O
+very	O
+few	O
+studies	O
+have	O
+evaluated	O
+whether	O
+chelation	O
+improves	O
+cognitive	O
+outcomes	O
+in	O
+Pb	O
+-	O
+exposed	O
+children	O
+","	O
+or	O
+whether	O
+these	O
+agents	O
+have	O
+adverse	O
+effects	O
+that	O
+may	O
+affect	O
+brain	O
+development	O
+in	O
+the	O
+absence	O
+of	O
+Pb	O
+exposure	O
+.	O
+	
+OBJECTIVES	O
+:	O
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+answer	O
+these	O
+questions	O
+","	O
+using	O
+a	O
+rodent	O
+model	O
+of	O
+early	O
+childhood	O
+Pb	O
+exposure	O
+and	O
+treatment	O
+with	O
+succimer	O
+","	O
+a	O
+widely	O
+used	O
+chelating	O
+agent	O
+for	O
+the	O
+treatment	O
+of	O
+Pb	B-NP
+poisoning	I-NP
+.	O
+	
+RESULTS	O
+:	O
+Pb	O
+exposure	O
+produced	O
+lasting	O
+impairments	B-NP
+in	I-NP
+learning	I-NP
+","	I-NP
+attention	I-NP
+","	I-NP
+inhibitory	I-NP
+control	I-NP
+","	I-NP
+and	I-NP
+arousal	I-NP
+regulation	I-NP
+","	O
+paralleling	O
+the	O
+areas	O
+of	O
+dysfunction	O
+seen	O
+in	O
+Pb	O
+-	O
+exposed	O
+children	O
+.	O
+	
+Succimer	O
+treatment	O
+of	O
+the	O
+Pb	O
+-	O
+exposed	O
+rats	O
+significantly	O
+improved	O
+learning	O
+","	O
+attention	O
+","	O
+and	O
+arousal	O
+regulation	O
+","	O
+although	O
+the	O
+efficacy	O
+of	O
+the	O
+treatment	O
+varied	O
+as	O
+a	O
+function	O
+of	O
+the	O
+Pb	O
+exposure	O
+level	O
+and	O
+the	O
+specific	O
+functional	O
+deficit	O
+.	O
+	
+In	O
+contrast	O
+","	O
+succimer	O
+treatment	O
+of	O
+rats	O
+not	O
+previously	O
+exposed	O
+to	O
+Pb	O
+produced	O
+lasting	O
+and	O
+pervasive	O
+cognitive	B-NP
+and	I-NP
+affective	I-NP
+dysfunction	I-NP
+comparable	O
+in	O
+magnitude	O
+to	O
+that	O
+produced	O
+by	O
+the	O
+higher	O
+Pb	O
+exposure	O
+regimen	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+These	O
+are	O
+the	O
+first	O
+data	O
+","	O
+to	O
+our	O
+knowledge	O
+","	O
+to	O
+show	O
+that	O
+treatment	O
+with	O
+any	O
+chelating	O
+agent	O
+can	O
+alleviate	O
+cognitive	B-NP
+deficits	I-NP
+due	O
+to	O
+Pb	O
+exposure	O
+.	O
+	
+These	O
+findings	O
+suggest	O
+that	O
+it	O
+may	O
+be	O
+possible	O
+to	O
+identify	O
+a	O
+succimer	O
+treatment	O
+protocol	O
+that	O
+improves	O
+cognitive	O
+outcomes	O
+in	O
+Pb	O
+-	O
+exposed	O
+children	O
+.	O
+	
+However	O
+","	O
+they	O
+also	O
+suggest	O
+that	O
+succimer	O
+treatment	O
+should	O
+be	O
+strongly	O
+discouraged	O
+for	O
+children	O
+who	O
+do	O
+not	O
+have	O
+elevated	O
+tissue	O
+levels	O
+of	O
+Pb	O
+or	O
+other	O
+heavy	O
+metals	O
+.	O
+	
+Caffeine	O
+challenge	O
+test	O
+in	O
+panic	B-NP
+disorder	I-NP
+and	O
+depression	B-NP
+with	O
+panic	B-NP
+attacks	I-NP
+.	O
+	
+Our	O
+aim	O
+was	O
+to	O
+observe	O
+if	O
+patients	O
+with	O
+panic	B-NP
+disorder	I-NP
+(	O
+PD	B-NP
+)	O
+and	O
+patients	O
+with	O
+major	B-NP
+depression	I-NP
+with	O
+panic	B-NP
+attacks	I-NP
+(	O
+MDP	B-NP
+)	O
+(	O
+Diagnostic	O
+and	O
+Statistical	O
+Manual	O
+of	O
+Mental	B-NP
+Disorders	I-NP
+","	O
+Fourth	O
+Edition	O
+criteria	O
+)	O
+respond	O
+in	O
+a	O
+similar	O
+way	O
+to	O
+the	O
+induction	O
+of	O
+panic	B-NP
+attacks	I-NP
+by	O
+an	O
+oral	O
+caffeine	O
+challenge	O
+test	O
+.	O
+	
+We	O
+randomly	O
+selected	O
+29	O
+patients	O
+with	O
+PD	B-NP
+","	O
+27	O
+with	O
+MDP	B-NP
+","	O
+25	O
+with	O
+major	B-NP
+depression	I-NP
+without	O
+panic	B-NP
+attacks	I-NP
+(	O
+MD	B-NP
+)	O
+","	O
+and	O
+28	O
+healthy	O
+volunteers	O
+.	O
+	
+The	O
+patients	O
+had	O
+no	O
+psychotropic	O
+drug	O
+for	O
+at	O
+least	O
+a	O
+4	O
+-	O
+week	O
+period	O
+.	O
+	
+In	O
+a	O
+randomized	O
+double	O
+-	O
+blind	O
+experiment	O
+performed	O
+in	O
+2	O
+occasions	O
+7	O
+days	O
+apart	O
+","	O
+480	O
+mg	O
+caffeine	O
+and	O
+a	O
+caffeine	O
+-	O
+free	O
+(	O
+placebo	O
+)	O
+solution	O
+were	O
+administered	O
+in	O
+a	O
+coffee	O
+form	O
+and	O
+anxiety	B-NP
+scales	O
+were	O
+applied	O
+before	O
+and	O
+after	O
+each	O
+test	O
+.	O
+	
+A	O
+total	O
+of	O
+58	O
+.	O
+6	O
+%	O
+(	O
+n	O
+=	O
+17	O
+)	O
+of	O
+patients	O
+with	O
+PD	B-NP
+","	O
+44	O
+.	O
+4	O
+%	O
+(	O
+n	O
+=	O
+12	O
+)	O
+of	O
+patients	O
+with	O
+MDP	B-NP
+","	O
+12	O
+.	O
+0	O
+%	O
+(	O
+n	O
+=	O
+3	O
+)	O
+of	O
+patients	O
+with	O
+MD	B-NP
+","	O
+and	O
+7	O
+.	O
+1	O
+%	O
+(	O
+n	O
+=	O
+2	O
+)	O
+of	O
+control	O
+subjects	O
+had	O
+a	O
+panic	B-NP
+attack	I-NP
+after	O
+the	O
+480	O
+-	O
+mg	O
+caffeine	O
+challenge	O
+test	O
+(	O
+chi	O
+(	O
+2	O
+)	O
+(	O
+3	O
+)	O
+=	O
+16	O
+.	O
+22	O
+","	O
+P	O
+=	O
+.	O
+1	O
+)	O
+.	O
+	
+The	O
+patients	O
+with	O
+PD	B-NP
+and	O
+MDP	B-NP
+were	O
+more	O
+sensitive	O
+to	O
+caffeine	O
+than	O
+were	O
+patients	O
+with	O
+MD	B-NP
+and	O
+healthy	O
+volunteers	O
+.	O
+	
+No	O
+panic	B-NP
+attack	I-NP
+was	O
+observed	O
+after	O
+the	O
+caffeine	O
+-	O
+free	O
+solution	O
+intake	O
+.	O
+	
+The	O
+patients	O
+with	O
+MD	B-NP
+had	O
+a	O
+lower	O
+heart	O
+rate	O
+response	O
+to	O
+the	O
+test	O
+than	O
+all	O
+the	O
+other	O
+groups	O
+(	O
+2	O
+-	O
+way	O
+analysis	O
+of	O
+variance	O
+","	O
+group	O
+by	O
+time	O
+interaction	O
+with	O
+Greenhouse	O
+-	O
+Geisser	O
+correction	O
+:	O
+F	O
+(	O
+3	O
+","	O
+762	O
+)	O
+=	O
+2	O
+.	O
+85	O
+","	O
+P	O
+=	O
+.	O
+26	O
+)	O
+.	O
+	
+Our	O
+data	O
+suggest	O
+that	O
+there	O
+is	O
+an	O
+association	O
+between	O
+panic	B-NP
+attacks	I-NP
+","	O
+no	O
+matter	O
+if	O
+associated	O
+with	O
+PD	B-NP
+or	O
+MDP	B-NP
+","	O
+and	O
+hyperreactivity	O
+to	O
+an	O
+oral	O
+caffeine	O
+challenge	O
+test	O
+.	O
+	
+Mitral	O
+annuloplasty	O
+as	O
+a	O
+ventricular	O
+restoration	O
+method	O
+for	O
+the	O
+failing	B-NP
+left	I-NP
+ventricle	I-NP
+:	O
+a	O
+pilot	O
+study	O
+.	O
+	
+BACKGROUND	O
+AND	O
+AIM	O
+OF	O
+THE	O
+STUDY	O
+:	O
+Undersized	O
+mitral	O
+annuloplasty	O
+(	O
+MAP	O
+)	O
+is	O
+effective	O
+in	O
+patients	O
+with	O
+dilated	B-NP
+cardiomyopathy	I-NP
+and	O
+functional	O
+mitral	B-NP
+regurgitation	I-NP
+(	O
+MR	B-NP
+)	O
+since	O
+","	O
+as	O
+well	O
+as	O
+addressing	O
+the	O
+MR	B-NP
+","	O
+the	O
+MAP	O
+may	O
+also	O
+reshape	O
+the	O
+dilated	O
+left	O
+ventricular	O
+(	O
+LV	O
+)	O
+base	O
+.	O
+	
+However	O
+","	O
+the	O
+direct	O
+benefits	O
+of	O
+this	O
+possible	O
+reshaping	O
+on	O
+LV	O
+function	O
+in	O
+the	O
+absence	O
+of	O
+underlying	O
+MR	B-NP
+remain	O
+incompletely	O
+understood	O
+.	O
+	
+The	O
+study	O
+aim	O
+was	O
+to	O
+identify	O
+these	O
+benefits	O
+in	O
+a	O
+canine	O
+model	O
+of	O
+acute	O
+heart	B-NP
+failure	I-NP
+.	O
+	
+METHODS	O
+:	O
+Six	O
+dogs	O
+underwent	O
+MAP	O
+with	O
+a	O
+prosthetic	O
+band	O
+on	O
+the	O
+posterior	O
+mitral	O
+annulus	O
+","	O
+using	O
+four	O
+mattress	O
+sutures	O
+.	O
+	
+The	O
+sutures	O
+were	O
+passed	O
+individually	O
+through	O
+four	O
+tourniquets	O
+and	O
+exteriorized	O
+untied	O
+via	O
+the	O
+left	O
+atriotomy	O
+.	O
+	
+Sonomicrometry	O
+crystals	O
+were	O
+implanted	O
+around	O
+the	O
+mitral	O
+annulus	O
+and	O
+left	O
+ventricle	O
+to	O
+measure	O
+geometry	O
+and	O
+regional	O
+function	O
+.	O
+	
+Acute	O
+heart	B-NP
+failure	I-NP
+was	O
+induced	O
+by	O
+propranolol	O
+and	O
+volume	O
+loading	O
+after	O
+weaning	O
+from	O
+cardiopulmonary	O
+bypass	O
+;	O
+an	O
+absence	O
+of	O
+MR	B-NP
+was	O
+confirmed	O
+by	O
+echocardiography	O
+.	O
+	
+MAP	O
+was	O
+accomplished	O
+by	O
+cinching	O
+the	O
+tourniquets	O
+.	O
+	
+Data	O
+were	O
+acquired	O
+at	O
+baseline	O
+","	O
+after	O
+induction	O
+of	O
+acute	O
+heart	B-NP
+failure	I-NP
+","	O
+and	O
+after	O
+MAP	O
+.	O
+	
+RESULTS	O
+:	O
+MAP	O
+decreased	O
+mitral	O
+annular	O
+dimensions	O
+in	O
+both	O
+commissure	O
+-	O
+commissure	O
+and	O
+septal	O
+-	O
+lateral	O
+directions	O
+.	O
+	
+Concomitantly	O
+","	O
+the	O
+diastolic	O
+diameter	O
+of	O
+the	O
+LV	O
+base	O
+and	O
+LV	O
+sphericity	O
+decreased	O
+(	O
+i	O
+.	O
+e	O
+.	O
+","	O
+improved	O
+)	O
+from	O
+37	O
+.	O
+4	O
++	O
+/	O
+-	O
+9	O
+.	O
+3	O
+to	O
+35	O
+.	O
+9	O
++	O
+/	O
+-	O
+10	O
+mm	O
+(	O
+p	O
+=	O
+0	O
+.	O
+63	O
+)	O
+","	O
+and	O
+from	O
+67	O
+.	O
+9	O
++	O
+/	O
+-	O
+18	O
+.	O
+6	O
+%	O
+to	O
+65	O
+.	O
+3	O
++	O
+/	O
+-	O
+18	O
+.	O
+9	O
+%	O
+(	O
+p	O
+=	O
+0	O
+.	O
+16	O
+)	O
+","	O
+respectively	O
+.	O
+	
+Decreases	O
+were	O
+evident	O
+in	O
+both	O
+LV	O
+end	O
+-	O
+diastolic	O
+pressure	O
+(	O
+from	O
+17	O
++	O
+/	O
+-	O
+7	O
+to	O
+15	O
++	O
+/	O
+-	O
+6	O
+mmHg	O
+","	O
+p	O
+=	O
+0	O
+.	O
+480	O
+and	O
+Tau	O
+(	O
+from	O
+48	O
++	O
+/	O
+-	O
+8	O
+to	O
+45	O
++	O
+/	O
+-	O
+8	O
+ms	O
+","	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+","	O
+while	O
+fractional	O
+shortening	O
+at	O
+the	O
+LV	O
+base	O
+increased	O
+from	O
+7	O
+.	O
+7	O
++	O
+/	O
+-	O
+4	O
+.	O
+5	O
+%	O
+to	O
+9	O
+.	O
+4	O
++	O
+/	O
+-	O
+4	O
+.	O
+5	O
+%	O
+(	O
+p	O
+=	O
+0	O
+.	O
+45	O
+)	O
+.	O
+	
+After	O
+MAP	O
+","	O
+increases	O
+were	O
+identified	O
+in	O
+both	O
+cardiac	O
+output	O
+(	O
+from	O
+1	O
+.	O
+54	O
++	O
+/	O
+-	O
+0	O
+.	O
+57	O
+to	O
+1	O
+.	O
+65	O
++	O
+/	O
+-	O
+0	O
+.	O
+57	O
+1	O
+/	O
+min	O
+)	O
+and	O
+Emax	O
+(	O
+from	O
+1	O
+.	O
+86	O
++	O
+/	O
+-	O
+0	O
+.	O
+9	O
+to	O
+2	O
+.	O
+41	O
++	O
+/	O
+-	O
+1	O
+.	O
+31	O
+mmHg	O
+/	O
+ml	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+The	O
+data	O
+acquired	O
+suggest	O
+that	O
+isolated	O
+MAP	O
+may	O
+have	O
+certain	O
+benefits	O
+on	O
+LV	O
+dimension	O
+/	O
+function	O
+in	O
+acute	O
+heart	B-NP
+failure	I-NP
+","	O
+even	O
+in	O
+the	O
+absence	O
+of	O
+MR	B-NP
+.	O
+	
+However	O
+","	O
+further	O
+investigations	O
+are	O
+warranted	O
+in	O
+a	O
+model	O
+of	O
+chronic	O
+heart	B-NP
+failure	I-NP
+.	O
+	
+Piperacillin	O
+/	O
+tazobactam	O
+-	O
+induced	O
+seizure	B-NP
+rapidly	O
+reversed	O
+by	O
+high	O
+flux	O
+hemodialysis	O
+in	O
+a	O
+patient	O
+on	O
+peritoneal	O
+dialysis	O
+.	O
+	
+Despite	O
+popular	O
+use	O
+of	O
+piperacillin	O
+","	O
+the	O
+dire	O
+neurotoxicity	B-NP
+associated	O
+with	O
+piperacillin	O
+still	O
+goes	O
+unrecognized	O
+","	O
+leading	O
+to	O
+a	O
+delay	O
+in	O
+appropriate	O
+management	O
+.	O
+	
+We	O
+report	O
+a	O
+57	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+end	B-NP
+-	I-NP
+stage	I-NP
+renal	I-NP
+disease	I-NP
+receiving	O
+continuous	O
+ambulatory	O
+peritoneal	O
+dialysis	O
+(	O
+CAPD	O
+)	O
+","	O
+who	O
+developed	O
+slurred	O
+speech	O
+","	O
+tremor	B-NP
+","	O
+bizarre	O
+behavior	O
+","	O
+progressive	O
+mental	O
+confusion	B-NP
+","	O
+and	O
+2	O
+episodes	O
+of	O
+generalized	O
+tonic	B-NP
+-	I-NP
+clonic	I-NP
+seizure	I-NP
+(	O
+GTCS	B-NP
+)	O
+after	O
+5	O
+doses	O
+of	O
+piperacillin	O
+/	O
+tazobactam	O
+(	O
+2	O
+g	O
+/	O
+250	O
+mg	O
+)	O
+were	O
+given	O
+for	O
+bronchiectasis	B-NP
+with	O
+secondary	B-NP
+infection	I-NP
+.	O
+	
+The	O
+laboratory	O
+data	O
+revealed	O
+normal	O
+plasma	O
+electrolyte	O
+and	O
+ammonia	O
+levels	O
+but	O
+leukocytosis	B-NP
+.	O
+	
+Neurologic	O
+examinations	O
+showed	O
+dysarthria	B-NP
+and	O
+bilateral	O
+Babinski	O
+sign	O
+.	O
+	
+Computed	O
+tomography	O
+of	O
+brain	O
+and	O
+electroencephalogram	O
+were	O
+unremarkable	O
+.	O
+	
+Despite	O
+the	O
+use	O
+of	O
+antiepileptic	O
+agents	O
+","	O
+another	O
+GTCS	B-NP
+episode	O
+recurred	O
+after	O
+the	O
+sixth	O
+dose	O
+of	O
+piperacillin	O
+/	O
+tazobactam	O
+.	O
+	
+Brain	O
+magnetic	O
+resonance	O
+imaging	O
+did	O
+not	O
+demonstrate	O
+acute	O
+infarction	B-NP
+and	O
+organic	B-NP
+brain	I-NP
+lesions	I-NP
+.	O
+	
+Initiation	O
+of	O
+high	O
+-	O
+flux	O
+hemodialysis	O
+rapidly	O
+reversed	O
+the	O
+neurologic	O
+symptoms	O
+within	O
+4	O
+hours	O
+.	O
+	
+Piperacillin	O
+-	O
+induced	O
+encephalopathy	B-NP
+should	O
+be	O
+considered	O
+in	O
+any	O
+uremic	B-NP
+patients	O
+with	O
+unexplained	O
+neurological	O
+manifestations	O
+.	O
+	
+CAPD	O
+is	O
+inefficient	O
+in	O
+removing	O
+piperacillin	O
+","	O
+whereas	O
+hemodialysis	O
+can	O
+rapidly	O
+terminate	O
+the	O
+piperacillin	O
+-	O
+induced	O
+encephalopathy	B-NP
+.	O
+	
+Frequency	O
+of	O
+transient	O
+ipsilateral	O
+vocal	B-NP
+cord	I-NP
+paralysis	I-NP
+in	O
+patients	O
+undergoing	O
+carotid	O
+endarterectomy	O
+under	O
+local	O
+anesthesia	O
+.	O
+	
+BACKGROUND	O
+:	O
+Especially	O
+because	O
+of	O
+improvements	O
+in	O
+clinical	O
+neurologic	O
+monitoring	O
+","	O
+carotid	O
+endarterectomy	O
+done	O
+under	O
+local	O
+anesthesia	O
+has	O
+become	O
+the	O
+technique	O
+of	O
+choice	O
+in	O
+several	O
+centers	O
+.	O
+	
+Temporary	O
+ipsilateral	O
+vocal	B-NP
+nerve	I-NP
+palsies	I-NP
+due	O
+to	O
+local	O
+anesthetics	O
+have	O
+been	O
+described	O
+","	O
+however	O
+.	O
+	
+Such	O
+complications	O
+are	O
+most	O
+important	O
+in	O
+situations	O
+where	O
+there	O
+is	O
+a	O
+pre	O
+-	O
+existing	O
+contralateral	O
+paralysis	B-NP
+.	O
+	
+We	O
+therefore	O
+examined	O
+the	O
+effect	O
+of	O
+local	O
+anesthesia	O
+on	O
+vocal	O
+cord	O
+function	O
+to	O
+better	O
+understand	O
+its	O
+possible	O
+consequences	O
+.	O
+	
+METHODS	O
+:	O
+This	O
+prospective	O
+study	O
+included	O
+28	O
+patients	O
+undergoing	O
+carotid	O
+endarterectomy	O
+under	O
+local	O
+anesthesia	O
+.	O
+	
+Vocal	O
+cord	O
+function	O
+was	O
+evaluated	O
+before	O
+","	O
+during	O
+","	O
+and	O
+after	O
+surgery	O
+(	O
+postoperative	O
+day	O
+1	O
+)	O
+using	O
+flexible	O
+laryngoscopy	O
+.	O
+	
+Anesthesia	O
+was	O
+performed	O
+by	O
+injecting	O
+20	O
+to	O
+40	O
+mL	O
+of	O
+a	O
+mixture	O
+of	O
+long	O
+-	O
+acting	O
+(	O
+ropivacaine	O
+)	O
+and	O
+short	O
+-	O
+acting	O
+(	O
+prilocaine	O
+)	O
+anesthetic	O
+.	O
+	
+RESULTS	O
+:	O
+All	O
+patients	O
+had	O
+normal	O
+vocal	O
+cord	O
+function	O
+preoperatively	O
+.	O
+	
+Twelve	O
+patients	O
+(	O
+43	O
+%	O
+)	O
+were	O
+found	O
+to	O
+have	O
+intraoperative	O
+ipsilateral	O
+vocal	B-NP
+cord	I-NP
+paralysis	I-NP
+.	O
+	
+It	O
+resolved	O
+in	O
+all	O
+cases	O
+<	O
+or	O
+=	O
+24	O
+hours	O
+.	O
+	
+There	O
+were	O
+no	O
+significant	O
+differences	O
+in	O
+operating	O
+time	O
+or	O
+volume	O
+or	O
+frequency	O
+of	O
+anesthetic	O
+administration	O
+in	O
+patients	O
+with	O
+temporary	O
+vocal	B-NP
+cord	I-NP
+paralysis	I-NP
+compared	O
+with	O
+those	O
+without	O
+.	O
+	
+CONCLUSION	O
+:	O
+Local	O
+anesthesia	O
+led	O
+to	O
+temporary	O
+ipsilateral	O
+vocal	B-NP
+cord	I-NP
+paralysis	I-NP
+in	O
+almost	O
+half	O
+of	O
+these	O
+patients	O
+.	O
+	
+Because	O
+pre	O
+-	O
+existing	O
+paralysis	B-NP
+is	O
+of	O
+a	O
+relevant	O
+frequency	O
+(	O
+up	O
+to	O
+3	O
+%	O
+)	O
+","	O
+a	O
+preoperative	O
+evaluation	O
+of	O
+vocal	O
+cord	O
+function	O
+before	O
+carotid	O
+endarterectomy	O
+under	O
+local	O
+anesthesia	O
+is	O
+recommended	O
+to	O
+avoid	O
+intraoperative	O
+bilateral	O
+paralysis	B-NP
+.	O
+	
+In	O
+patients	O
+with	O
+preoperative	O
+contralateral	O
+vocal	B-NP
+cord	I-NP
+paralysis	I-NP
+","	O
+surgery	O
+under	O
+general	O
+anesthesia	O
+should	O
+be	O
+considered	O
+.	O
+	
+Impaired	B-NP
+fear	I-NP
+recognition	I-NP
+in	O
+regular	O
+recreational	O
+cocaine	O
+users	O
+.	O
+	
+INTRODUCTION	O
+:	O
+The	O
+ability	O
+to	O
+read	O
+facial	O
+expressions	O
+is	O
+essential	O
+for	O
+normal	O
+human	O
+social	O
+interaction	O
+.	O
+	
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+conduct	O
+the	O
+first	O
+investigation	O
+of	O
+facial	O
+expression	O
+recognition	O
+performance	O
+in	O
+recreational	O
+cocaine	O
+users	O
+.	O
+	
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+Three	O
+groups	O
+","	O
+comprised	O
+of	O
+21	O
+cocaine	O
+naive	O
+participants	O
+(	O
+CN	O
+)	O
+","	O
+30	O
+occasional	O
+cocaine	O
+(	O
+OC	O
+)	O
+","	O
+and	O
+48	O
+regular	O
+recreational	O
+cocaine	O
+(	O
+RC	O
+)	O
+users	O
+","	O
+were	O
+compared	O
+.	O
+	
+An	O
+emotional	O
+facial	O
+expression	O
+(	O
+EFE	O
+)	O
+task	O
+consisting	O
+of	O
+a	O
+male	O
+and	O
+female	O
+face	O
+expressing	O
+six	O
+basic	O
+emotions	O
+(	O
+happiness	O
+","	O
+surprise	O
+","	O
+sadness	O
+","	O
+anger	O
+","	O
+fear	O
+","	O
+and	O
+disgust	O
+)	O
+was	O
+administered	O
+.	O
+	
+Mean	O
+percent	O
+accuracy	O
+and	O
+latencies	O
+for	O
+correct	O
+responses	O
+across	O
+eight	O
+presentations	O
+of	O
+each	O
+basic	O
+emotion	O
+were	O
+derived	O
+.	O
+	
+Participants	O
+were	O
+also	O
+assessed	O
+with	O
+the	O
+"	O
+Eyes	O
+task	O
+"	O
+to	O
+investigate	O
+their	O
+ability	O
+to	O
+recognize	O
+more	O
+complex	O
+emotional	O
+states	O
+and	O
+the	O
+Symptom	O
+CheckList	O
+-	O
+90	O
+-	O
+Revised	O
+to	O
+measure	O
+psychopathology	O
+.	O
+	
+RESULTS	O
+:	O
+There	O
+were	O
+no	O
+group	O
+differences	O
+in	O
+psychopathology	O
+or	O
+"	O
+eyes	O
+task	O
+"	O
+performance	O
+","	O
+but	O
+the	O
+RC	O
+group	O
+","	O
+who	O
+otherwise	O
+had	O
+similar	O
+illicit	O
+substance	O
+use	O
+histories	O
+to	O
+the	O
+OC	O
+group	O
+","	O
+exhibited	O
+impaired	B-NP
+fear	I-NP
+recognition	I-NP
+accuracy	O
+compared	O
+to	O
+the	O
+OC	O
+and	O
+CN	O
+groups	O
+.	O
+	
+The	O
+RC	O
+group	O
+also	O
+correctly	O
+identified	O
+anger	O
+","	O
+fear	O
+","	O
+happiness	O
+","	O
+and	O
+surprise	O
+","	O
+more	O
+slowly	O
+than	O
+CN	O
+","	O
+but	O
+not	O
+OC	O
+participants	O
+.	O
+	
+The	O
+OC	O
+group	O
+was	O
+slower	O
+than	O
+CN	O
+when	O
+correctly	O
+identifying	O
+disgust	O
+.	O
+	
+The	O
+selective	O
+deficit	B-NP
+in	I-NP
+fear	I-NP
+recognition	I-NP
+accuracy	O
+manifested	O
+by	O
+the	O
+RC	O
+group	O
+cannot	O
+be	O
+explained	O
+by	O
+the	O
+subacute	O
+effects	O
+of	O
+cocaine	O
+","	O
+or	O
+ecstasy	O
+","	O
+because	O
+recent	O
+and	O
+less	O
+recent	O
+users	O
+of	O
+these	O
+drugs	O
+within	O
+this	O
+group	O
+were	O
+similarly	O
+impaired	O
+.	O
+	
+Possible	O
+parallels	O
+between	O
+RC	O
+users	O
+and	O
+psychopaths	B-NP
+with	O
+respect	O
+to	O
+impaired	B-NP
+fear	I-NP
+recognition	I-NP
+","	O
+amygdala	B-NP
+dysfunction	I-NP
+","	O
+and	O
+etiology	O
+are	O
+discussed	O
+.	O
+	
+Damage	B-NP
+of	I-NP
+substantia	I-NP
+nigra	I-NP
+pars	I-NP
+reticulata	I-NP
+during	O
+pilocarpine	O
+-	O
+induced	O
+status	B-NP
+epilepticus	I-NP
+in	O
+the	O
+rat	O
+:	O
+immunohistochemical	O
+study	O
+of	O
+neurons	O
+","	O
+astrocytes	O
+and	O
+serum	O
+-	O
+protein	O
+extravasation	O
+.	O
+	
+The	O
+substantia	O
+nigra	O
+has	O
+a	O
+gating	O
+function	O
+controlling	O
+the	O
+spread	O
+of	O
+epileptic	B-NP
+seizure	I-NP
+activity	O
+.	O
+	
+Additionally	O
+","	O
+in	O
+models	O
+of	O
+prolonged	B-NP
+status	I-NP
+epilepticus	I-NP
+the	O
+pars	O
+reticulata	O
+of	O
+substantia	O
+nigra	O
+(	O
+SNR	O
+)	O
+suffers	O
+from	O
+a	O
+massive	O
+lesion	O
+which	O
+may	O
+arise	O
+from	O
+a	O
+massive	O
+metabolic	B-NP
+derangement	I-NP
+and	O
+hyperexcitation	O
+developing	O
+in	O
+the	O
+activated	O
+SNR	O
+.	O
+	
+In	O
+this	O
+study	O
+","	O
+status	B-NP
+epilepticus	I-NP
+was	O
+induced	O
+by	O
+systemic	O
+injection	O
+of	O
+pilocarpine	O
+in	O
+rats	O
+.	O
+	
+The	O
+neuropathology	O
+of	O
+SNR	O
+was	O
+investigated	O
+using	O
+immunohistochemical	O
+techniques	O
+with	O
+the	O
+major	O
+emphasis	O
+on	O
+the	O
+time	O
+-	O
+course	O
+of	O
+changes	O
+in	O
+neurons	O
+and	O
+astrocytes	O
+.	O
+	
+Animals	O
+surviving	O
+20	O
+","	O
+30	O
+","	O
+40	O
+","	O
+60	O
+min	O
+","	O
+2	O
+","	O
+3	O
+","	O
+6	O
+hours	O
+","	O
+1	O
+","	O
+2	O
+","	O
+and	O
+3	O
+days	O
+after	O
+induction	O
+of	O
+status	B-NP
+epilepticus	I-NP
+were	O
+perfusion	O
+-	O
+fixed	O
+","	O
+and	O
+brains	O
+processed	O
+for	O
+immunohistochemical	O
+staining	O
+of	O
+SNR	O
+.	O
+	
+Nissl	O
+-	O
+staining	O
+and	O
+antibodies	O
+against	O
+the	O
+neuron	O
+-	O
+specific	O
+calcium	O
+-	O
+binding	O
+protein	O
+","	O
+parvalbumin	O
+","	O
+served	O
+to	O
+detect	O
+neuronal	B-NP
+damage	I-NP
+in	O
+SNR	O
+.	O
+	
+Antibodies	O
+against	O
+the	O
+astroglia	O
+-	O
+specific	O
+cytoskeletal	O
+protein	O
+","	O
+glial	O
+fibrillary	O
+acidic	O
+protein	O
+(	O
+GFAP	O
+)	O
+","	O
+and	O
+against	O
+the	O
+glial	O
+calcium	O
+-	O
+binding	O
+protein	O
+","	O
+S	O
+-	O
+100	O
+protein	O
+","	O
+were	O
+used	O
+to	O
+assess	O
+the	O
+status	O
+of	O
+astrocytes	O
+.	O
+	
+Immunohistochemical	O
+staining	O
+for	O
+serum	O
+-	O
+albumin	O
+and	O
+immunoglobulins	O
+in	O
+brain	O
+tissue	O
+was	O
+taken	O
+as	O
+indicator	O
+of	O
+blood	O
+-	O
+brain	O
+barrier	O
+disturbances	O
+and	O
+vasogenic	B-NP
+edema	I-NP
+formation	O
+.	O
+	
+Immunohistochemical	O
+staining	O
+indicated	O
+loss	O
+of	O
+GFAP	O
+-	O
+staining	O
+already	O
+at	O
+30	O
+min	O
+after	O
+induction	O
+of	O
+seizures	B-NP
+in	O
+an	O
+oval	O
+focus	O
+situated	O
+in	O
+the	O
+center	O
+of	O
+SNR	O
+while	O
+sparing	O
+medial	O
+and	O
+lateral	O
+aspects	O
+.	O
+	
+At	O
+1	O
+h	O
+there	O
+was	O
+additional	O
+vacuolation	O
+in	O
+S	O
+-	O
+100	O
+protein	O
+staining	O
+.	O
+	
+By	O
+2	O
+hours	O
+","	O
+parvalbumin	O
+-	O
+staining	O
+changed	O
+in	O
+the	O
+central	O
+SNR	O
+indicating	O
+neuronal	B-NP
+damage	I-NP
+","	O
+and	O
+Nissl	O
+-	O
+staining	O
+visualized	O
+some	O
+neuronal	O
+distortion	O
+.	O
+	
+Staining	O
+for	O
+serum	O
+-	O
+proteins	O
+occurred	O
+in	O
+a	O
+patchy	O
+manner	O
+throughout	O
+the	O
+forebrain	O
+during	O
+the	O
+first	O
+hours	O
+.	O
+	
+By	O
+6	O
+h	O
+","	O
+vasogenic	B-NP
+edema	I-NP
+covered	O
+the	O
+lesioned	B-NP
+SNR	I-NP
+.	O
+	
+By	O
+24	O
+h	O
+","	O
+glial	O
+and	O
+neuronal	O
+markers	O
+indicated	O
+a	O
+massive	O
+lesion	O
+in	O
+the	O
+center	O
+of	O
+SNR	O
+.	O
+	
+By	O
+48	O
+-	O
+72	O
+h	O
+","	O
+astrocytes	O
+surrounding	O
+the	O
+lesion	O
+increased	O
+in	O
+size	O
+","	O
+and	O
+polymorphic	O
+phagocytotic	O
+cells	O
+invaded	O
+the	O
+damaged	O
+area	O
+.	O
+	
+In	O
+a	O
+further	O
+group	O
+of	O
+animals	O
+surviving	O
+1	O
+to	O
+5	O
+days	O
+","	O
+conventional	O
+paraffin	O
+-	O
+sections	O
+confirmed	O
+the	O
+neuronal	O
+and	O
+glial	O
+damage	B-NP
+of	I-NP
+SNR	I-NP
+.	O
+	
+Additional	O
+pathology	O
+of	O
+similar	O
+quality	O
+was	O
+found	O
+in	O
+the	O
+globus	O
+pallidus	O
+.	O
+	
+Since	O
+astrocytes	O
+were	O
+always	O
+damaged	O
+in	O
+parallel	O
+with	O
+neurons	O
+in	O
+SNR	O
+it	O
+is	O
+proposed	O
+that	O
+the	O
+anatomical	O
+and	O
+functional	O
+interrelationship	O
+between	O
+neurons	O
+and	O
+astrocytes	O
+is	O
+particularly	O
+tight	O
+in	O
+SNR	O
+.	O
+	
+Both	O
+cell	O
+elements	O
+may	O
+suffer	O
+in	O
+common	O
+from	O
+metabolic	O
+disturbance	O
+and	O
+neurotransmitter	B-NP
+dysfunction	I-NP
+as	O
+occur	O
+during	O
+massive	O
+status	B-NP
+epilepticus	I-NP
+.	O
+	
+Neuroprotective	O
+effects	O
+of	O
+melatonin	O
+upon	O
+the	O
+offspring	O
+cerebellar	O
+cortex	O
+in	O
+the	O
+rat	O
+model	O
+of	O
+BCNU	O
+-	O
+induced	O
+cortical	B-NP
+dysplasia	I-NP
+.	O
+	
+Cortical	B-NP
+dysplasia	I-NP
+is	O
+a	O
+malformation	O
+characterized	O
+by	O
+defects	O
+in	O
+proliferation	O
+","	O
+migration	O
+and	O
+maturation	O
+.	O
+	
+This	O
+study	O
+was	O
+designed	O
+to	O
+evaluate	O
+the	O
+alterations	O
+in	O
+offspring	O
+rat	O
+cerebellum	O
+induced	O
+by	O
+maternal	O
+exposure	O
+to	O
+carmustine	O
+-	O
+[	O
+1	O
+","	O
+3	O
+-	O
+bis	O
+(	O
+2	O
+-	O
+chloroethyl	O
+)	O
+-	O
+1	O
+-	O
+nitrosoure	O
+]	O
+(	O
+BCNU	O
+)	O
+and	O
+to	O
+investigate	O
+the	O
+effects	O
+of	O
+exogenous	O
+melatonin	O
+upon	O
+cerebellar	O
+BCNU	O
+-	O
+induced	O
+cortical	B-NP
+dysplasia	I-NP
+","	O
+using	O
+histological	O
+and	O
+biochemical	O
+analyses	O
+.	O
+	
+Pregnant	O
+Wistar	O
+rats	O
+were	O
+assigned	O
+to	O
+five	O
+groups	O
+:	O
+intact	O
+-	O
+control	O
+","	O
+saline	O
+-	O
+control	O
+","	O
+melatonin	O
+-	O
+treated	O
+","	O
+BCNU	O
+-	O
+exposed	O
+and	O
+BCNU	O
+-	O
+exposed	O
+plus	O
+melatonin	O
+.	O
+	
+Rats	O
+were	O
+exposed	O
+to	O
+BCNU	O
+on	O
+embryonic	O
+day	O
+15	O
+and	O
+melatonin	O
+was	O
+given	O
+until	O
+delivery	O
+.	O
+	
+Immuno	O
+/	O
+histochemistry	O
+and	O
+electron	O
+microscopy	O
+were	O
+carried	O
+out	O
+on	O
+the	O
+offspring	O
+cerebellum	O
+","	O
+and	O
+levels	O
+of	O
+malondialdehyde	O
+and	O
+superoxide	O
+dismutase	O
+were	O
+determined	O
+.	O
+	
+Histopathologically	O
+","	O
+typical	O
+findings	O
+were	O
+observed	O
+in	O
+the	O
+cerebella	O
+from	O
+the	O
+control	O
+groups	O
+","	O
+but	O
+the	O
+findings	O
+consistent	O
+with	O
+early	O
+embryonic	O
+development	O
+were	O
+noted	O
+in	O
+BCNU	O
+-	O
+exposed	O
+cortical	B-NP
+dysplasia	I-NP
+group	O
+.	O
+	
+There	O
+was	O
+a	O
+marked	O
+increase	O
+in	O
+the	O
+number	O
+of	O
+TUNEL	O
+positive	O
+cells	O
+and	O
+nestin	O
+positive	O
+cells	O
+in	O
+BCNU	O
+-	O
+exposed	O
+group	O
+","	O
+but	O
+a	O
+decreased	O
+immunoreactivity	O
+to	O
+glial	O
+fibrillary	O
+acidic	O
+protein	O
+","	O
+synaptophysin	O
+and	O
+transforming	O
+growth	O
+factor	O
+beta1	O
+was	O
+observed	O
+","	O
+indicating	O
+a	O
+delayed	O
+maturation	O
+","	O
+and	O
+melatonin	O
+significantly	O
+reversed	O
+these	O
+changes	O
+.	O
+	
+Malondialdehyde	O
+level	O
+in	O
+BCNU	O
+-	O
+exposed	O
+group	O
+was	O
+higher	O
+than	O
+those	O
+in	O
+control	O
+groups	O
+and	O
+melatonin	O
+decreased	O
+malondialdehyde	O
+levels	O
+in	O
+BCNU	O
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+","	O
+while	O
+there	O
+were	O
+no	O
+significant	O
+differences	O
+in	O
+the	O
+superoxide	O
+dismutase	O
+levels	O
+between	O
+these	O
+groups	O
+.	O
+	
+These	O
+data	O
+suggest	O
+that	O
+exposure	O
+of	O
+animals	O
+to	O
+BCNU	O
+during	O
+pregnancy	O
+leads	O
+to	O
+delayed	O
+maturation	O
+of	O
+offspring	O
+cerebellum	O
+and	O
+melatonin	O
+protects	O
+the	O
+cerebellum	O
+against	O
+the	O
+effects	O
+of	O
+BCNU	O
+.	O
+	
+Reduced	O
+cardiotoxicity	B-NP
+of	O
+doxorubicin	O
+given	O
+in	O
+the	O
+form	O
+of	O
+N	O
+-	O
+(	O
+2	O
+-	O
+hydroxypropyl	O
+)	O
+methacrylamide	O
+conjugates	O
+:	O
+and	O
+experimental	O
+study	O
+in	O
+the	O
+rat	O
+.	O
+	
+A	O
+rat	O
+model	O
+was	O
+used	O
+to	O
+evaluate	O
+the	O
+general	O
+acute	O
+toxicity	B-NP
+and	O
+the	O
+late	O
+cardiotoxicity	B-NP
+of	O
+4	O
+mg	O
+/	O
+kg	O
+doxorubicin	O
+(	O
+DOX	O
+)	O
+given	O
+either	O
+as	O
+free	O
+drug	O
+or	O
+in	O
+the	O
+form	O
+of	O
+three	O
+N	O
+-	O
+(	O
+2	O
+-	O
+hydroxypropyl	O
+)	O
+methacrylamide	O
+(	O
+HPMA	O
+)	O
+copolymer	O
+conjugates	O
+.	O
+	
+In	O
+these	O
+HPMA	O
+copolymers	O
+","	O
+DOX	O
+was	O
+covalently	O
+bound	O
+via	O
+peptide	O
+linkages	O
+that	O
+were	O
+either	O
+non	O
+-	O
+biodegradable	O
+(	O
+Gly	O
+-	O
+Gly	O
+)	O
+or	O
+degradable	O
+by	O
+lysosomal	O
+proteinases	O
+(	O
+Gly	O
+-	O
+Phe	O
+-	O
+Leu	O
+-	O
+Gly	O
+)	O
+.	O
+	
+In	O
+addition	O
+","	O
+one	O
+biodegradable	O
+conjugate	O
+containing	O
+galactosamine	O
+was	O
+used	O
+;	O
+this	O
+residue	O
+was	O
+targeted	O
+to	O
+the	O
+liver	O
+.	O
+	
+Over	O
+the	O
+first	O
+3	O
+weeks	O
+after	O
+the	O
+i	O
+.	O
+v	O
+.	O
+administration	O
+of	O
+free	O
+and	O
+polymer	O
+-	O
+bound	O
+DOX	O
+","	O
+all	O
+animals	O
+showed	O
+a	O
+transient	O
+reduction	O
+in	O
+body	O
+weight	O
+.	O
+	
+However	O
+","	O
+the	O
+maximal	O
+reduction	O
+in	O
+body	O
+weight	O
+seen	O
+in	O
+animals	O
+that	O
+received	O
+polymer	O
+-	O
+bound	O
+DOX	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+significantly	O
+lower	O
+than	O
+that	O
+observed	O
+in	O
+those	O
+that	O
+received	O
+free	O
+DOX	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+)	O
+or	O
+a	O
+mixture	O
+of	O
+the	O
+unmodified	O
+parent	O
+HPMA	O
+copolymer	O
+and	O
+free	O
+DOX	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+;	O
+P	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Throughout	O
+the	O
+study	O
+(	O
+20	O
+weeks	O
+)	O
+","	O
+deaths	O
+related	O
+to	O
+cardiotoxicity	B-NP
+were	O
+observed	O
+only	O
+in	O
+animals	O
+that	O
+received	O
+either	O
+free	O
+DOX	O
+or	O
+the	O
+mixture	O
+of	O
+HPMA	O
+copolymer	O
+and	O
+free	O
+DOX	O
+;	O
+in	O
+these	O
+cases	O
+","	O
+histological	O
+investigations	O
+revealed	O
+marked	O
+changes	O
+in	O
+the	O
+heart	O
+that	O
+were	O
+consistent	O
+with	O
+DOX	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+.	O
+	
+Sequential	O
+measurements	O
+of	O
+cardiac	O
+output	O
+in	O
+surviving	O
+animals	O
+that	O
+received	O
+either	O
+free	O
+DOX	O
+or	O
+the	O
+mixture	O
+of	O
+HPMA	O
+copolymer	O
+and	O
+free	O
+DOX	O
+showed	O
+a	O
+reduction	O
+of	O
+approximately	O
+30	O
+%	O
+in	O
+function	O
+beginning	O
+at	O
+the	O
+4th	O
+week	O
+after	O
+drug	O
+administration	O
+.	O
+	
+The	O
+heart	O
+rate	O
+in	O
+these	O
+animals	O
+was	O
+approximately	O
+12	O
+%	O
+lower	O
+than	O
+that	O
+measured	O
+in	O
+age	O
+-	O
+matched	O
+control	O
+rats	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+Animals	O
+that	O
+were	O
+given	O
+the	O
+HPMA	O
+copolymer	O
+conjugates	O
+containing	O
+DOX	O
+exhibited	O
+no	O
+significant	O
+change	O
+in	O
+cardiac	O
+output	O
+throughout	O
+the	O
+study	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+In	O
+addition	O
+","	O
+no	O
+significant	O
+histological	O
+change	O
+was	O
+observed	O
+in	O
+the	O
+heart	O
+of	O
+animals	O
+that	O
+received	O
+DOX	O
+in	O
+the	O
+form	O
+of	O
+HPMA	O
+copolymer	O
+conjugates	O
+and	O
+were	O
+killed	O
+at	O
+the	O
+end	O
+of	O
+the	O
+study	O
+.	O
+	
+However	O
+","	O
+these	O
+animals	O
+had	O
+shown	O
+a	O
+significant	O
+increase	O
+in	O
+heart	O
+rate	O
+beginning	O
+at	O
+8	O
+weeks	O
+after	O
+drug	O
+administration	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+400	O
+WORDS	O
+)	O
+	
+Corneal	B-NP
+ulcers	I-NP
+associated	O
+with	O
+aerosolized	O
+crack	O
+cocaine	O
+use	O
+.	O
+	
+PURPOSE	O
+:	O
+We	O
+report	O
+4	O
+cases	O
+of	O
+corneal	B-NP
+ulcers	I-NP
+associated	O
+with	O
+drug	B-NP
+abuse	I-NP
+.	O
+	
+The	O
+pathogenesis	O
+of	O
+these	O
+ulcers	B-NP
+and	O
+management	O
+of	O
+these	O
+patients	O
+are	O
+also	O
+reviewed	O
+.	O
+	
+METHODS	O
+:	O
+Review	O
+of	O
+all	O
+cases	O
+of	O
+corneal	B-NP
+ulcers	I-NP
+associated	O
+with	O
+drug	B-NP
+abuse	I-NP
+seen	O
+at	O
+our	O
+institution	O
+from	O
+July	O
+2006	O
+to	O
+December	O
+2006	O
+.	O
+	
+RESULTS	O
+:	O
+Four	O
+patients	O
+with	O
+corneal	B-NP
+ulcers	I-NP
+associated	O
+with	O
+crack	O
+cocaine	O
+use	O
+were	O
+reviewed	O
+.	O
+	
+All	O
+corneal	B-NP
+ulcers	I-NP
+were	O
+cultured	O
+","	O
+and	O
+the	O
+patients	O
+were	O
+admitted	O
+to	O
+the	O
+hospital	O
+for	O
+intensive	O
+topical	O
+antibiotic	O
+treatment	O
+.	O
+	
+Each	O
+patient	O
+received	O
+comprehensive	O
+health	O
+care	O
+","	O
+including	O
+medical	O
+and	O
+substance	B-NP
+abuse	I-NP
+consultations	O
+.	O
+	
+Streptococcal	O
+organisms	O
+were	O
+found	O
+in	O
+3	O
+cases	O
+and	O
+Capnocytophaga	O
+and	O
+Brevibacterium	O
+casei	O
+in	O
+1	O
+patient	O
+.	O
+	
+The	O
+infections	B-NP
+responded	O
+to	O
+antibiotic	O
+treatment	O
+.	O
+	
+Two	O
+patients	O
+needed	O
+a	O
+lateral	O
+tarsorrhaphy	O
+for	O
+persistent	O
+epithelial	B-NP
+defects	I-NP
+.	O
+	
+CONCLUSIONS	O
+:	O
+Aerosolized	O
+crack	O
+cocaine	O
+use	O
+can	O
+be	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+corneal	B-NP
+ulcers	I-NP
+.	O
+	
+Drug	B-NP
+abuse	I-NP
+provides	O
+additional	O
+challenges	O
+for	O
+management	O
+.	O
+	
+Not	O
+only	O
+treatment	O
+of	O
+their	O
+infections	B-NP
+but	O
+also	O
+the	O
+overall	O
+poor	O
+health	O
+of	O
+the	O
+patients	O
+and	O
+increased	O
+risk	O
+of	O
+noncompliance	O
+need	O
+to	O
+be	O
+addressed	O
+.	O
+	
+Comprehensive	O
+care	O
+may	O
+provide	O
+the	O
+patient	O
+the	O
+opportunity	O
+to	O
+discontinue	O
+their	O
+substance	B-NP
+abuse	I-NP
+","	O
+improve	O
+their	O
+overall	O
+health	O
+","	O
+and	O
+prevent	O
+future	O
+corneal	O
+complications	O
+.	O
+	
+Topical	O
+0	O
+.	O
+25	O
+%	O
+capsaicin	O
+in	O
+chronic	O
+post	B-NP
+-	I-NP
+herpetic	I-NP
+neuralgia	I-NP
+:	O
+efficacy	O
+","	O
+predictors	O
+of	O
+response	O
+and	O
+long	O
+-	O
+term	O
+course	O
+.	O
+	
+In	O
+order	O
+to	O
+evaluate	O
+the	O
+efficacy	O
+","	O
+time	O
+-	O
+course	O
+of	O
+action	O
+and	O
+predictors	O
+of	O
+response	O
+to	O
+topical	O
+capsaicin	O
+","	O
+39	O
+patients	O
+with	O
+chronic	O
+post	B-NP
+-	I-NP
+herpetic	I-NP
+neuralgia	I-NP
+(	O
+PHN	B-NP
+)	O
+","	O
+median	O
+duration	O
+24	O
+months	O
+","	O
+were	O
+treated	O
+with	O
+0	O
+.	O
+25	O
+%	O
+capsaicin	O
+cream	O
+for	O
+8	O
+weeks	O
+.	O
+	
+During	O
+therapy	O
+the	O
+patients	O
+rated	O
+their	O
+pain	B-NP
+on	O
+a	O
+visual	O
+analogue	O
+scale	O
+(	O
+VAS	O
+)	O
+and	O
+a	O
+verbal	O
+outcome	O
+scale	O
+.	O
+	
+A	O
+follow	O
+-	O
+up	O
+investigation	O
+was	O
+performed	O
+10	O
+-	O
+12	O
+months	O
+after	O
+study	O
+onset	O
+on	O
+the	O
+patients	O
+who	O
+had	O
+improved	O
+.	O
+	
+Nineteen	O
+patients	O
+(	O
+48	O
+.	O
+7	O
+%	O
+)	O
+substantially	O
+improved	O
+after	O
+the	O
+8	O
+-	O
+week	O
+trial	O
+;	O
+5	O
+(	O
+12	O
+.	O
+8	O
+%	O
+)	O
+discontinued	O
+therapy	O
+due	O
+to	O
+side	O
+-	O
+effects	O
+such	O
+as	O
+intolerable	O
+capsaicin	O
+-	O
+induced	O
+burning	O
+sensations	O
+(	O
+4	O
+)	O
+or	O
+mastitis	B-NP
+(	O
+1	O
+)	O
+;	O
+15	O
+(	O
+38	O
+.	O
+5	O
+%	O
+)	O
+reported	O
+no	O
+benefit	O
+.	O
+	
+The	O
+decrease	O
+in	O
+VAS	O
+ratings	O
+was	O
+significant	O
+after	O
+2	O
+weeks	O
+of	O
+continuous	O
+application	O
+.	O
+	
+Of	O
+the	O
+responders	O
+72	O
+.	O
+2	O
+%	O
+were	O
+still	O
+improved	O
+at	O
+the	O
+follow	O
+-	O
+up	O
+;	O
+only	O
+one	O
+-	O
+third	O
+of	O
+them	O
+had	O
+continued	O
+application	O
+irregularly	O
+.	O
+	
+Treatment	O
+effect	O
+was	O
+not	O
+dependent	O
+on	O
+patient	O
+'	O
+s	O
+age	O
+","	O
+duration	O
+or	O
+localization	O
+of	O
+PHN	B-NP
+(	O
+trigeminal	O
+involvement	O
+was	O
+excluded	O
+)	O
+","	O
+sensory	B-NP
+disturbance	I-NP
+or	O
+pain	B-NP
+character	O
+.	O
+	
+Treatment	O
+response	O
+was	O
+not	O
+correlated	O
+with	O
+the	O
+incidence	O
+","	O
+time	O
+-	O
+course	O
+or	O
+severity	O
+of	O
+capsaicin	O
+-	O
+induced	O
+burning	O
+.	O
+	
+If	O
+confirmed	O
+in	O
+controlled	O
+trials	O
+","	O
+the	O
+long	O
+-	O
+term	O
+results	O
+of	O
+this	O
+open	O
+","	O
+non	O
+-	O
+randomized	O
+study	O
+might	O
+indicate	O
+that	O
+the	O
+analgesic	O
+effect	O
+of	O
+capsaicin	O
+in	O
+PHN	B-NP
+is	O
+mediated	O
+by	O
+both	O
+interference	O
+with	O
+neuropeptide	O
+metabolism	O
+and	O
+morphological	O
+changes	O
+(	O
+perhaps	O
+degeneration	O
+)	O
+of	O
+nociceptive	O
+afferents	O
+.	O
+	
+Myo	O
+-	O
+inositol	O
+-	O
+1	O
+-	O
+phosphate	O
+(	O
+MIP	O
+)	O
+synthase	O
+inhibition	O
+:	O
+in	O
+-	O
+vivo	O
+study	O
+in	O
+rats	O
+.	O
+	
+Lithium	O
+and	O
+valproate	O
+are	O
+the	O
+prototypic	O
+mood	O
+stabilizers	O
+and	O
+have	O
+diverse	O
+structures	O
+and	O
+targets	O
+.	O
+	
+Both	O
+drugs	O
+influence	O
+inositol	O
+metabolism	O
+.	O
+	
+Lithium	O
+inhibits	O
+IMPase	O
+and	O
+valproate	O
+inhibits	O
+MIP	O
+synthase	O
+.	O
+	
+This	O
+study	O
+shows	O
+that	O
+MIP	O
+synthase	O
+inhibition	O
+does	O
+not	O
+replicate	O
+or	O
+augment	O
+the	O
+effects	O
+of	O
+lithium	O
+in	O
+the	O
+inositol	O
+sensitive	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B-NP
+model	O
+.	O
+	
+This	O
+lack	O
+of	O
+effects	O
+may	O
+stem	O
+from	O
+the	O
+low	O
+contribution	O
+of	O
+de	O
+-	O
+novo	O
+synthesis	O
+to	O
+cellular	O
+inositol	O
+supply	O
+or	O
+to	O
+the	O
+inhibition	O
+of	O
+the	O
+de	O
+-	O
+novo	O
+synthesis	O
+by	O
+lithium	O
+itself	O
+.	O
+	
+Non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+-	O
+associated	O
+acute	O
+interstitial	B-NP
+nephritis	I-NP
+with	O
+granular	O
+tubular	O
+basement	O
+membrane	O
+deposits	O
+.	O
+	
+Acute	B-NP
+tubulo	I-NP
+-	I-NP
+interstitial	I-NP
+nephritis	I-NP
+(	O
+ATIN	B-NP
+)	O
+is	O
+an	O
+important	O
+cause	O
+of	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+resulting	O
+from	O
+a	O
+variety	O
+of	O
+insults	O
+","	O
+including	O
+immune	O
+complex	O
+-	O
+mediated	O
+tubulo	B-NP
+-	I-NP
+interstitial	I-NP
+injury	I-NP
+","	O
+but	O
+drugs	O
+such	O
+as	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+(	O
+NSAIDs	O
+)	O
+are	O
+a	O
+far	O
+more	O
+frequent	O
+cause	O
+.	O
+	
+Overall	O
+","	O
+as	O
+an	O
+entity	O
+","	O
+ATIN	B-NP
+remains	O
+under	O
+-	O
+diagnosed	O
+","	O
+as	O
+symptoms	O
+resolve	O
+spontaneously	O
+if	O
+the	O
+medication	O
+is	O
+stopped	O
+.	O
+	
+We	O
+report	O
+on	O
+a	O
+14	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+who	O
+developed	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+2	O
+weeks	O
+after	O
+aortic	O
+valve	O
+surgery	O
+.	O
+	
+He	O
+was	O
+put	O
+on	O
+aspirin	O
+following	O
+surgery	O
+and	O
+took	O
+ibuprofen	O
+for	O
+fever	B-NP
+for	O
+nearly	O
+a	O
+week	O
+prior	O
+to	O
+presentation	O
+.	O
+	
+He	O
+then	O
+presented	O
+to	O
+the	O
+emergency	O
+department	O
+feeling	O
+quite	O
+ill	O
+and	O
+was	O
+found	O
+to	O
+have	O
+a	O
+blood	O
+urea	O
+nitrogen	O
+(	O
+BUN	O
+)	O
+concentration	O
+of	O
+of	O
+147	O
+mg	O
+/	O
+dl	O
+","	O
+creatinine	O
+of	O
+15	O
+.	O
+3	O
+mg	O
+/	O
+dl	O
+and	O
+serum	O
+potassium	O
+of	O
+8	O
+.	O
+7	O
+mEq	O
+/	O
+l	O
+.	O
+	
+Dialysis	O
+was	O
+immediately	O
+initiated	O
+.	O
+	
+A	O
+kidney	O
+biopsy	O
+showed	O
+inflammatory	O
+infiltrate	O
+consistent	O
+with	O
+ATIN	B-NP
+.	O
+	
+However	O
+","	O
+in	O
+the	O
+tubular	O
+basement	O
+membrane	O
+(	O
+TBM	O
+)	O
+","	O
+very	O
+intense	O
+granular	O
+deposits	O
+of	O
+polyclonal	O
+IgG	O
+and	O
+C3	O
+were	O
+noted	O
+.	O
+	
+He	O
+needed	O
+dialysis	O
+for	O
+2	O
+weeks	O
+and	O
+was	O
+treated	O
+successfully	O
+with	O
+steroids	O
+for	O
+6	O
+months	O
+.	O
+	
+His	O
+renal	O
+recovery	O
+and	O
+disappearance	O
+of	O
+proteinuria	B-NP
+took	O
+a	O
+year	O
+.	O
+	
+In	O
+conclusion	O
+","	O
+this	O
+is	O
+a	O
+first	O
+report	O
+of	O
+NSAIDs	O
+-	O
+associated	O
+ATIN	B-NP
+","	O
+showing	O
+deposits	O
+of	O
+granular	O
+immune	O
+complex	O
+present	O
+only	O
+in	O
+the	O
+TBM	O
+and	O
+not	O
+in	O
+the	O
+glomeruli	O
+.	O
+	
+Rifampicin	O
+-	O
+associated	O
+segmental	O
+necrotizing	O
+glomerulonephritis	B-NP
+in	O
+staphylococcal	B-NP
+endocarditis	I-NP
+.	O
+	
+Segmental	O
+necrotising	O
+glomerulonephritis	B-NP
+has	O
+been	O
+reported	O
+as	O
+complication	O
+of	O
+rifampicin	O
+therapy	O
+in	O
+patients	O
+receiving	O
+treatment	O
+for	O
+tuberculosis	B-NP
+.	O
+	
+Changing	O
+epidemiology	O
+of	O
+infections	B-NP
+such	O
+as	O
+infective	B-NP
+endocarditis	I-NP
+(	O
+IE	B-NP
+)	O
+has	O
+led	O
+to	O
+an	O
+increase	O
+in	O
+the	O
+use	O
+of	O
+rifampicin	O
+for	O
+Staphylococcal	B-NP
+infections	I-NP
+.	O
+	
+We	O
+describe	O
+a	O
+case	O
+of	O
+a	O
+patient	O
+with	O
+Staphylococcal	B-NP
+IE	I-NP
+who	O
+developed	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+secondary	O
+to	O
+a	O
+segmental	O
+necrotising	O
+glomerulonephritis	B-NP
+while	O
+being	O
+treated	O
+with	O
+rifampicin	O
+","	O
+and	O
+review	O
+the	O
+literature	O
+regarding	O
+this	O
+complication	O
+of	O
+rifampicin	O
+therapy	O
+.	O
+	
+Rate	O
+of	O
+YMDD	O
+motif	O
+mutants	O
+in	O
+lamivudine	O
+-	O
+untreated	O
+Iranian	O
+patients	O
+with	O
+chronic	B-NP
+hepatitis	I-NP
+B	I-NP
+virus	I-NP
+infection	I-NP
+.	O
+	
+BACKGROUND	O
+:	O
+Lamivudine	O
+is	O
+used	O
+for	O
+the	O
+treatment	O
+of	O
+chronic	B-NP
+hepatitis	I-NP
+B	I-NP
+patients	O
+.	O
+	
+Recent	O
+studies	O
+show	O
+that	O
+the	O
+YMDD	O
+motif	O
+mutants	O
+(	O
+resistant	O
+hepatitis	B-NP
+B	I-NP
+virus	O
+)	O
+occur	O
+as	O
+natural	O
+genome	O
+variability	O
+in	O
+lamivudine	O
+-	O
+untreated	O
+chronic	B-NP
+hepatitis	I-NP
+B	I-NP
+patients	O
+.	O
+	
+In	O
+this	O
+study	O
+we	O
+aimed	O
+to	O
+determine	O
+the	O
+rate	O
+of	O
+YMDD	O
+motif	O
+mutants	O
+in	O
+lamivudine	O
+-	O
+untreated	O
+chronic	B-NP
+hepatitis	I-NP
+B	I-NP
+patients	O
+in	O
+Iran	O
+.	O
+	
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+A	O
+total	O
+of	O
+77	O
+chronic	B-NP
+hepatitis	I-NP
+B	I-NP
+patients	O
+who	O
+had	O
+not	O
+been	O
+treated	O
+with	O
+lamivudine	O
+were	O
+included	O
+in	O
+the	O
+study	O
+.	O
+	
+Serum	O
+samples	O
+from	O
+patients	O
+were	O
+tested	O
+by	O
+polymerase	O
+chain	O
+reaction	O
+-	O
+restriction	O
+fragment	O
+length	O
+polymorphism	O
+(	O
+PCR	O
+-	O
+RFLP	O
+)	O
+for	O
+detection	O
+of	O
+YMDD	O
+motif	O
+mutants	O
+.	O
+	
+All	O
+patients	O
+were	O
+also	O
+tested	O
+for	O
+liver	O
+enzymes	O
+","	O
+anti	O
+-	O
+HCV	O
+","	O
+HBeAg	O
+","	O
+and	O
+anti	O
+-	O
+HBe	O
+.	O
+	
+RESULTS	O
+:	O
+Of	O
+the	O
+77	O
+patients	O
+enrolled	O
+in	O
+the	O
+study	O
+","	O
+73	O
+%	O
+were	O
+male	O
+and	O
+27	O
+%	O
+were	O
+female	O
+.	O
+	
+Mean	O
+ALT	O
+and	O
+AST	O
+levels	O
+were	O
+124	O
+.	O
+4	O
++	O
+/	O
+-	O
+73	O
+.	O
+4	O
+and	O
+103	O
+.	O
+1	O
++	O
+/	O
+-	O
+81	O
+IU	O
+/	O
+l	O
+","	O
+respectively	O
+.	O
+	
+HBeAg	O
+was	O
+positive	O
+in	O
+40	O
+%	O
+and	O
+anti	O
+-	O
+HBe	O
+in	O
+60	O
+%	O
+of	O
+the	O
+patients	O
+.	O
+	
+Anti	O
+-	O
+HCV	O
+was	O
+negative	O
+in	O
+all	O
+of	O
+them	O
+.	O
+	
+YMDD	O
+motif	O
+mutants	O
+were	O
+not	O
+detected	O
+in	O
+any	O
+of	O
+the	O
+patients	O
+despite	O
+the	O
+liver	O
+enzyme	O
+levels	O
+and	O
+the	O
+presence	O
+of	O
+HBeAg	O
+or	O
+anti	O
+-	O
+HBe	O
+.	O
+	
+CONCLUSION	O
+:	O
+Although	O
+the	O
+natural	O
+occurrence	O
+of	O
+YMDD	O
+motif	O
+mutants	O
+in	O
+lamivudine	O
+-	O
+untreated	O
+patients	O
+with	O
+chronic	B-NP
+hepatitis	I-NP
+B	I-NP
+has	O
+been	O
+reported	O
+","	O
+these	O
+mutants	O
+were	O
+not	O
+detected	O
+in	O
+Iranian	O
+lamivudine	O
+-	O
+untreated	O
+chronic	B-NP
+hepatitis	I-NP
+B	I-NP
+patients	O
+.	O
+	
+Branch	O
+retinal	B-NP
+vein	I-NP
+occlusion	I-NP
+and	O
+fluoxetine	O
+.	O
+	
+A	O
+case	O
+of	O
+branch	O
+retinal	B-NP
+vein	I-NP
+occlusion	I-NP
+associated	O
+with	O
+fluoxetine	O
+-	O
+induced	O
+secondary	O
+hypertension	B-NP
+is	O
+described	O
+.	O
+	
+Although	O
+an	O
+infrequent	O
+complication	O
+of	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitor	O
+therapy	O
+","	O
+it	O
+is	O
+important	O
+that	O
+ophthalmologists	O
+are	O
+aware	O
+that	O
+these	O
+agents	O
+can	O
+cause	O
+hypertension	B-NP
+because	O
+this	O
+class	O
+of	O
+drugs	O
+is	O
+widely	O
+prescribed	O
+.	O
+	
+The	O
+differential	O
+effects	O
+of	O
+bupivacaine	O
+and	O
+lidocaine	O
+on	O
+prostaglandin	O
+E2	O
+release	O
+","	O
+cyclooxygenase	O
+gene	O
+expression	O
+and	O
+pain	B-NP
+in	O
+a	O
+clinical	O
+pain	B-NP
+model	O
+.	O
+	
+BACKGROUND	O
+:	O
+In	O
+addition	O
+to	O
+blocking	O
+nociceptive	O
+input	O
+from	O
+surgical	O
+sites	O
+","	O
+long	O
+-	O
+acting	O
+local	O
+anesthetics	O
+might	O
+directly	O
+modulate	O
+inflammation	B-NP
+.	O
+	
+In	O
+the	O
+present	O
+study	O
+","	O
+we	O
+describe	O
+the	O
+proinflammatory	O
+effects	O
+of	O
+bupivacaine	O
+on	O
+local	O
+prostaglandin	O
+E2	O
+(	O
+PGE2	O
+)	O
+production	O
+and	O
+cyclooxygenase	O
+(	O
+COX	O
+)	O
+gene	O
+expression	O
+that	O
+increases	O
+postoperative	B-NP
+pain	I-NP
+in	O
+human	O
+subjects	O
+.	O
+	
+METHODS	O
+:	O
+Subjects	O
+(	O
+n	O
+=	O
+114	O
+)	O
+undergoing	O
+extraction	O
+of	O
+impacted	O
+third	O
+molars	O
+received	O
+either	O
+2	O
+%	O
+lidocaine	O
+or	O
+0	O
+.	O
+5	O
+%	O
+bupivacaine	O
+before	O
+surgery	O
+and	O
+either	O
+rofecoxib	O
+50	O
+mg	O
+or	O
+placebo	O
+orally	O
+90	O
+min	O
+before	O
+surgery	O
+and	O
+for	O
+the	O
+following	O
+48	O
+h	O
+.	O
+	
+Oral	O
+mucosal	O
+biopsies	O
+were	O
+taken	O
+before	O
+surgery	O
+and	O
+48	O
+h	O
+after	O
+surgery	O
+.	O
+	
+After	O
+extraction	O
+","	O
+a	O
+microdialysis	O
+probe	O
+was	O
+placed	O
+at	O
+the	O
+surgical	O
+site	O
+for	O
+PGE2	O
+and	O
+thromboxane	O
+B2	O
+(	O
+TXB2	O
+)	O
+measurements	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+bupivacaine	O
+/	O
+rofecoxib	O
+group	O
+reported	O
+significantly	O
+less	O
+pain	B-NP
+","	O
+as	O
+assessed	O
+by	O
+a	O
+visual	O
+analog	O
+scale	O
+","	O
+compared	O
+with	O
+the	O
+other	O
+three	O
+treatment	O
+groups	O
+over	O
+the	O
+first	O
+4	O
+h	O
+.	O
+	
+However	O
+","	O
+the	O
+bupivacaine	O
+/	O
+placebo	O
+group	O
+reported	O
+significantly	O
+more	O
+pain	B-NP
+at	O
+24	O
+h	O
+and	O
+PGE2	O
+levels	O
+during	O
+the	O
+first	O
+4	O
+h	O
+were	O
+significantly	O
+higher	O
+than	O
+the	O
+other	O
+three	O
+treatment	O
+groups	O
+.	O
+	
+Moreover	O
+","	O
+bupivacaine	O
+significantly	O
+increased	O
+COX	O
+-	O
+2	O
+gene	O
+expression	O
+at	O
+48	O
+h	O
+as	O
+compared	O
+with	O
+the	O
+lidocaine	O
+/	O
+placebo	O
+group	O
+.	O
+	
+Thromboxane	O
+levels	O
+were	O
+not	O
+significantly	O
+affected	O
+by	O
+any	O
+of	O
+the	O
+treatments	O
+","	O
+indicating	O
+that	O
+the	O
+effects	O
+seen	O
+were	O
+attributable	O
+to	O
+inhibition	O
+of	O
+COX	O
+-	O
+2	O
+","	O
+but	O
+not	O
+COX	O
+-	O
+1	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+These	O
+results	O
+suggest	O
+that	O
+bupivacaine	O
+stimulates	O
+COX	O
+-	O
+2	O
+gene	O
+expression	O
+after	O
+tissue	B-NP
+injury	I-NP
+","	O
+which	O
+is	O
+associated	O
+with	O
+higher	O
+PGE2	O
+production	O
+and	O
+pain	B-NP
+after	O
+the	O
+local	O
+anesthetic	O
+effect	O
+dissipates	O
+.	O
+	
+p75NTR	O
+expression	O
+in	O
+rat	O
+urinary	O
+bladder	O
+sensory	O
+neurons	O
+and	O
+spinal	O
+cord	O
+with	O
+cyclophosphamide	O
+-	O
+induced	O
+cystitis	B-NP
+.	O
+	
+A	O
+role	O
+for	O
+nerve	O
+growth	O
+factor	O
+(	O
+NGF	O
+)	O
+in	O
+contributing	O
+to	O
+increased	O
+voiding	O
+frequency	O
+and	O
+altered	O
+sensation	O
+from	O
+the	O
+urinary	O
+bladder	O
+has	O
+been	O
+suggested	O
+.	O
+	
+Previous	O
+studies	O
+have	O
+examined	O
+the	O
+expression	O
+and	O
+regulation	O
+of	O
+tyrosine	O
+kinase	O
+receptors	O
+(	O
+Trks	O
+)	O
+in	O
+micturition	O
+reflexes	O
+with	O
+urinary	B-NP
+bladder	I-NP
+inflammation	I-NP
+.	O
+	
+The	O
+present	O
+studies	O
+examine	O
+the	O
+expression	O
+and	O
+regulation	O
+of	O
+another	O
+receptor	O
+known	O
+to	O
+bind	O
+NGF	O
+","	O
+p75	O
+(	O
+NTR	O
+)	O
+","	O
+after	O
+various	O
+durations	O
+of	O
+bladder	B-NP
+inflammation	I-NP
+induced	O
+by	O
+cyclophosphamide	O
+(	O
+CYP	O
+)	O
+.	O
+	
+CYP	O
+-	O
+induced	O
+cystitis	B-NP
+increased	O
+(	O
+P	O
+<	O
+or	O
+=	O
+0	O
+.	O
+1	O
+)	O
+p75	O
+(	O
+NTR	O
+)	O
+expression	O
+in	O
+the	O
+superficial	O
+lateral	O
+and	O
+medial	O
+dorsal	O
+horn	O
+in	O
+L1	O
+-	O
+L2	O
+and	O
+L6	O
+-	O
+S1	O
+spinal	O
+segments	O
+.	O
+	
+The	O
+number	O
+of	O
+p75	O
+(	O
+NTR	O
+)	O
+-	O
+immunoreactive	O
+(	O
+-	O
+IR	O
+)	O
+cells	O
+in	O
+the	O
+lumbosacral	O
+dorsal	O
+root	O
+ganglia	O
+(	O
+DRG	O
+)	O
+also	O
+increased	O
+(	O
+P	O
+<	O
+or	O
+=	O
+0	O
+.	O
+5	O
+)	O
+with	O
+CYP	O
+-	O
+induced	O
+cystitis	B-NP
+(	O
+acute	O
+","	O
+intermediate	O
+","	O
+and	O
+chronic	O
+)	O
+.	O
+	
+Quantitative	O
+","	O
+real	O
+-	O
+time	O
+polymerase	O
+chain	O
+reaction	O
+also	O
+demonstrated	O
+significant	O
+increases	O
+(	O
+P	O
+<	O
+or	O
+=	O
+0	O
+.	O
+1	O
+)	O
+in	O
+p75	O
+(	O
+NTR	O
+)	O
+mRNA	O
+in	O
+DRG	O
+with	O
+intermediate	O
+and	O
+chronic	O
+CYP	O
+-	O
+induced	O
+cystitis	B-NP
+.	O
+	
+Retrograde	O
+dye	O
+-	O
+tracing	O
+techniques	O
+with	O
+Fastblue	O
+were	O
+used	O
+to	O
+identify	O
+presumptive	O
+bladder	O
+afferent	O
+cells	O
+in	O
+the	O
+lumbosacral	O
+DRG	O
+.	O
+	
+In	O
+bladder	O
+afferent	O
+cells	O
+in	O
+DRG	O
+","	O
+p75	O
+(	O
+NTR	O
+)	O
+-	O
+IR	O
+was	O
+also	O
+increased	O
+(	O
+P	O
+<	O
+or	O
+=	O
+0	O
+.	O
+1	O
+)	O
+with	O
+cystitis	B-NP
+.	O
+	
+In	O
+addition	O
+to	O
+increases	O
+in	O
+p75	O
+(	O
+NTR	O
+)	O
+-	O
+IR	O
+in	O
+DRG	O
+cell	O
+bodies	O
+","	O
+increases	O
+(	O
+P	O
+<	O
+or	O
+=	O
+0	O
+.	O
+1	O
+)	O
+in	O
+pericellular	O
+(	O
+encircling	O
+DRG	O
+cells	O
+)	O
+p75	O
+(	O
+NTR	O
+)	O
+-	O
+IR	O
+in	O
+DRG	O
+also	O
+increased	O
+.	O
+	
+Confocal	O
+analyses	O
+demonstrated	O
+that	O
+pericellular	O
+p75	O
+(	O
+NTR	O
+)	O
+-	O
+IR	O
+was	O
+not	O
+colocalized	O
+with	O
+the	O
+glial	O
+marker	O
+","	O
+glial	O
+fibrillary	O
+acidic	O
+protein	O
+(	O
+GFAP	O
+)	O
+.	O
+	
+These	O
+studies	O
+demonstrate	O
+that	O
+p75	O
+(	O
+NTR	O
+)	O
+expression	O
+in	O
+micturition	O
+reflexes	O
+is	O
+present	O
+constitutively	O
+and	O
+modified	O
+by	O
+bladder	B-NP
+inflammation	I-NP
+.	O
+	
+The	O
+functional	O
+significance	O
+of	O
+p75	O
+(	O
+NTR	O
+)	O
+expression	O
+in	O
+micturition	O
+reflexes	O
+remains	O
+to	O
+be	O
+determined	O
+.	O
+	
+Azathioprine	O
+-	O
+induced	O
+suicidal	O
+erythrocyte	O
+death	O
+.	O
+	
+BACKGROUND	O
+:	O
+Azathioprine	O
+is	O
+widely	O
+used	O
+as	O
+an	O
+immunosuppressive	O
+drug	O
+.	O
+	
+The	O
+side	O
+effects	O
+of	O
+azathioprine	O
+include	O
+anemia	B-NP
+","	O
+which	O
+has	O
+been	O
+attributed	O
+to	O
+bone	O
+marrow	O
+suppression	O
+.	O
+	
+Alternatively	O
+","	O
+anemia	B-NP
+could	O
+result	O
+from	O
+accelerated	O
+suicidal	O
+erythrocyte	O
+death	O
+or	O
+eryptosis	O
+","	O
+which	O
+is	O
+characterized	O
+by	O
+exposure	O
+of	O
+phosphatidylserine	O
+(	O
+PS	O
+)	O
+at	O
+the	O
+erythrocyte	O
+surface	O
+and	O
+by	O
+cell	O
+shrinkage	O
+.	O
+	
+METHODS	O
+:	O
+The	O
+present	O
+experiments	O
+explored	O
+whether	O
+azathioprine	O
+influences	O
+eryptosis	O
+.	O
+	
+According	O
+to	O
+annexin	O
+V	O
+binding	O
+","	O
+erythrocytes	O
+from	O
+patients	O
+indeed	O
+showed	O
+a	O
+significant	O
+increase	O
+of	O
+PS	O
+exposure	O
+within	O
+1	O
+week	O
+of	O
+treatment	O
+with	O
+azathioprine	O
+.	O
+	
+In	O
+a	O
+second	O
+series	O
+","	O
+cytosolic	O
+Ca2	O
++	O
+activity	O
+(	O
+Fluo3	O
+fluorescence	O
+)	O
+","	O
+cell	O
+volume	O
+(	O
+forward	O
+scatter	O
+)	O
+","	O
+and	O
+PS	O
+-	O
+exposure	O
+(	O
+annexin	O
+V	O
+binding	O
+)	O
+were	O
+determined	O
+by	O
+FACS	O
+analysis	O
+in	O
+erythrocytes	O
+from	O
+healthy	O
+volunteers	O
+.	O
+	
+RESULTS	O
+:	O
+Exposure	O
+to	O
+azathioprine	O
+(	O
+>	O
+or	O
+=	O
+2	O
+microg	O
+/	O
+mL	O
+)	O
+for	O
+48	O
+hours	O
+increased	O
+cytosolic	O
+Ca2	O
++	O
+activity	O
+and	O
+annexin	O
+V	O
+binding	O
+and	O
+decreased	O
+forward	O
+scatter	O
+.	O
+	
+The	O
+effect	O
+of	O
+azathioprine	O
+on	O
+both	O
+annexin	O
+V	O
+binding	O
+and	O
+forward	O
+scatter	O
+was	O
+significantly	O
+blunted	O
+in	O
+the	O
+nominal	O
+absence	O
+of	O
+extracellular	O
+Ca2	O
++	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Azathioprine	O
+triggers	O
+suicidal	O
+erythrocyte	O
+death	O
+","	O
+an	O
+effect	O
+presumably	O
+contributing	O
+to	O
+azathioprine	O
+-	O
+induced	O
+anemia	B-NP
+.	O
+	
+Levetiracetam	O
+as	O
+an	O
+adjunct	O
+to	O
+phenobarbital	O
+treatment	O
+in	O
+cats	O
+with	O
+suspected	O
+idiopathic	B-NP
+epilepsy	I-NP
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+assess	O
+pharmacokinetics	O
+","	O
+efficacy	O
+","	O
+and	O
+tolerability	O
+of	O
+oral	O
+levetiracetam	O
+administered	O
+as	O
+an	O
+adjunct	O
+to	O
+phenobarbital	O
+treatment	O
+in	O
+cats	O
+with	O
+poorly	O
+controlled	O
+suspected	O
+idiopathic	B-NP
+epilepsy	I-NP
+.	O
+	
+DESIGN	O
+-	O
+Open	O
+-	O
+label	O
+","	O
+noncomparative	O
+clinical	O
+trial	O
+.	O
+	
+ANIMALS	O
+:	O
+12	O
+cats	O
+suspected	O
+to	O
+have	O
+idiopathic	B-NP
+epilepsy	I-NP
+that	O
+was	O
+poorly	O
+controlled	O
+with	O
+phenobarbital	O
+or	O
+that	O
+had	O
+unacceptable	O
+adverse	O
+effects	O
+when	O
+treated	O
+with	O
+phenobarbital	O
+.	O
+	
+PROCEDURES	O
+:	O
+Cats	O
+were	O
+treated	O
+with	O
+levetiracetam	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+[	O
+9	O
+.	O
+1	O
+mg	O
+/	O
+lb	O
+]	O
+","	O
+PO	O
+","	O
+q	O
+8	O
+h	O
+)	O
+.	O
+	
+After	O
+a	O
+minimum	O
+of	O
+1	O
+week	O
+of	O
+treatment	O
+","	O
+serum	O
+levetiracetam	O
+concentrations	O
+were	O
+measured	O
+before	O
+and	O
+2	O
+","	O
+4	O
+","	O
+and	O
+6	O
+hours	O
+after	O
+drug	O
+administration	O
+","	O
+and	O
+maximum	O
+and	O
+minimum	O
+serum	O
+concentrations	O
+and	O
+elimination	O
+half	O
+-	O
+life	O
+were	O
+calculated	O
+.	O
+	
+Seizure	B-NP
+frequencies	O
+before	O
+and	O
+after	O
+initiation	O
+of	O
+levetiracetam	O
+treatment	O
+were	O
+compared	O
+","	O
+and	O
+adverse	O
+effects	O
+were	O
+recorded	O
+.	O
+	
+RESULTS	O
+:	O
+Median	O
+maximum	O
+serum	O
+levetiracetam	O
+concentration	O
+was	O
+25	O
+.	O
+5	O
+microg	O
+/	O
+mL	O
+","	O
+median	O
+minimum	O
+serum	O
+levetiracetam	O
+concentration	O
+was	O
+8	O
+.	O
+3	O
+microg	O
+/	O
+mL	O
+","	O
+and	O
+median	O
+elimination	O
+half	O
+-	O
+life	O
+was	O
+2	O
+.	O
+9	O
+hours	O
+.	O
+	
+Median	O
+seizure	B-NP
+frequency	O
+prior	O
+to	O
+treatment	O
+with	O
+levetiracetam	O
+(	O
+2	O
+.	O
+1	O
+seizures	B-NP
+/	O
+mo	O
+)	O
+was	O
+significantly	O
+higher	O
+than	O
+median	O
+seizure	B-NP
+frequency	O
+after	O
+initiation	O
+of	O
+levetiracetam	O
+treatment	O
+(	O
+0	O
+.	O
+42	O
+seizures	B-NP
+/	O
+mo	O
+)	O
+","	O
+and	O
+7	O
+of	O
+10	O
+cats	O
+were	O
+classified	O
+as	O
+having	O
+responded	O
+to	O
+levetiracetam	O
+treatment	O
+(	O
+ie	O
+","	O
+reduction	O
+in	O
+seizure	B-NP
+frequency	O
+of	O
+>	O
+or	O
+=	O
+50	O
+%	O
+)	O
+.	O
+	
+Two	O
+cats	O
+had	O
+transient	O
+lethargy	B-NP
+and	O
+inappetence	B-NP
+.	O
+	
+CONCLUSIONS	O
+AND	O
+CLINICAL	O
+RELEVANCE	O
+:	O
+Results	O
+suggested	O
+that	O
+levetiracetam	O
+is	O
+well	O
+tolerated	O
+in	O
+cats	O
+and	O
+may	O
+be	O
+useful	O
+as	O
+an	O
+adjunct	O
+to	O
+phenobarbital	O
+treatment	O
+in	O
+cats	O
+with	O
+idiopathic	B-NP
+epilepsy	I-NP
+.	O
+	
+Serotonin	O
+reuptake	O
+inhibitors	O
+","	O
+paranoia	B-NP
+","	O
+and	O
+the	O
+ventral	O
+basal	O
+ganglia	O
+.	O
+	
+Antidepressants	O
+have	O
+previously	O
+been	O
+associated	O
+with	O
+paranoid	B-NP
+reactions	O
+in	O
+psychiatric	O
+patients	O
+.	O
+	
+Five	O
+cases	O
+of	O
+paranoid	B-NP
+exacerbation	O
+with	O
+the	O
+serotonin	O
+reuptake	O
+inhibitors	O
+fluoxetine	O
+and	O
+amitriptyline	O
+are	O
+reported	O
+here	O
+.	O
+	
+Elements	O
+common	O
+to	O
+these	O
+cases	O
+included	O
+a	O
+history	O
+of	O
+paranoid	B-NP
+symptomatology	O
+and	O
+the	O
+concomitant	O
+occurrence	O
+of	O
+depressive	B-NP
+and	I-NP
+psychotic	I-NP
+symptoms	I-NP
+.	O
+	
+Complicated	O
+depressive	B-NP
+disorders	I-NP
+(	O
+including	O
+atypicality	O
+of	O
+course	O
+and	O
+symptomatology	O
+","	O
+chronicity	O
+","	O
+psychosis	B-NP
+","	O
+bipolarity	O
+","	O
+and	O
+secondary	O
+onset	O
+in	O
+the	O
+course	O
+of	O
+a	O
+primary	O
+psychosis	B-NP
+)	O
+may	O
+present	O
+particular	O
+vulnerability	O
+to	O
+paranoid	B-NP
+exacerbations	O
+associated	O
+with	O
+serotonin	O
+reuptake	O
+inhibitors	O
+.	O
+	
+Although	O
+the	O
+pharmacology	O
+and	O
+neurobiology	O
+of	O
+paranoia	B-NP
+remain	O
+cryptic	O
+","	O
+several	O
+mechanisms	O
+","	O
+including	O
+5HT3	O
+receptor	O
+-	O
+mediated	O
+dopamine	O
+release	O
+","	O
+beta	O
+-	O
+noradrenergic	O
+receptor	O
+downregulation	O
+","	O
+or	O
+GABAB	O
+receptor	O
+upregulation	O
+acting	O
+in	O
+the	O
+vicinity	O
+of	O
+the	O
+ventral	O
+basal	O
+ganglia	O
+(	O
+possibly	O
+in	O
+lateral	O
+orbitofrontal	O
+or	O
+anterior	O
+cingulate	O
+circuits	O
+)	O
+","	O
+might	O
+apply	O
+to	O
+this	O
+phenomenon	O
+.	O
+	
+These	O
+cases	O
+call	O
+attention	O
+to	O
+possible	O
+paranoid	B-NP
+exacerbations	O
+with	O
+serotonin	O
+reuptake	O
+blockers	O
+in	O
+select	O
+patients	O
+and	O
+raise	O
+neurobiological	O
+considerations	O
+regarding	O
+paranoia	B-NP
+.	O
+	
+Clinical	O
+comparison	O
+of	O
+cardiorespiratory	O
+effects	O
+during	O
+unilateral	O
+and	O
+conventional	O
+spinal	O
+anaesthesia	O
+.	O
+	
+BACKGROUND	O
+:	O
+Spinal	O
+anaesthesia	O
+is	O
+widely	O
+employed	O
+in	O
+clinical	O
+practice	O
+but	O
+has	O
+the	O
+main	O
+drawback	O
+of	O
+post	O
+-	O
+spinal	O
+block	O
+hypotension	B-NP
+.	O
+	
+Efforts	O
+must	O
+therefore	O
+continue	O
+to	O
+be	O
+made	O
+to	O
+obviate	O
+this	O
+setback	O
+OBJECTIVE	O
+:	O
+To	O
+evaluate	O
+the	O
+cardiovascular	O
+and	O
+respiratory	O
+changes	O
+during	O
+unilateral	O
+and	O
+conventional	O
+spinal	O
+anaesthesia	O
+.	O
+	
+METHODS	O
+:	O
+With	O
+ethical	O
+approval	O
+","	O
+we	O
+studied	O
+74	O
+American	O
+Society	O
+of	O
+Anesthesiologists	O
+(	O
+ASA	O
+)	O
+","	O
+physical	O
+status	O
+class	O
+1	O
+and	O
+2	O
+patients	O
+scheduled	O
+for	O
+elective	O
+unilateral	O
+lower	O
+limb	O
+surgery	O
+.	O
+	
+Patients	O
+were	O
+randomly	O
+allocated	O
+into	O
+one	O
+of	O
+two	O
+groups	O
+:	O
+lateral	O
+and	O
+conventional	O
+spinal	O
+anaesthesia	O
+groups	O
+.	O
+	
+In	O
+the	O
+lateral	O
+position	O
+with	O
+operative	O
+side	O
+down	O
+","	O
+patients	O
+recived	O
+10	O
+mg	O
+(	O
+2mls	O
+)	O
+of	O
+0	O
+.	O
+5	O
+%	O
+hyperbaric	O
+bupivacaine	O
+through	O
+a	O
+25	O
+-	O
+gauge	O
+spinal	O
+needle	O
+.	O
+	
+Patients	O
+in	O
+the	O
+unilateral	O
+group	O
+were	O
+maintained	O
+in	O
+the	O
+lateral	O
+position	O
+for	O
+15	O
+minutes	O
+following	O
+spinal	O
+injection	O
+while	O
+those	O
+in	O
+the	O
+conventional	O
+group	O
+were	O
+turned	O
+supine	O
+immediately	O
+after	O
+injection	O
+.	O
+	
+Blood	O
+pressure	O
+","	O
+heart	O
+rate	O
+","	O
+respiratory	O
+rate	O
+and	O
+oxygen	O
+saturation	O
+were	O
+monitored	O
+over	O
+1	O
+hour	O
+.	O
+	
+RESULTS	O
+:	O
+Three	O
+patients	O
+(	O
+8	O
+.	O
+1	O
+%	O
+)	O
+in	O
+the	O
+unilateral	O
+group	O
+and	O
+5	O
+(	O
+13	O
+.	O
+5	O
+%	O
+)	O
+in	O
+the	O
+conventional	O
+group	O
+developed	O
+hypotension	B-NP
+","	O
+P	O
+=	O
+0	O
+.	O
+71	O
+.	O
+	
+Four	O
+(	O
+10	O
+.	O
+8	O
+%	O
+)	O
+patients	O
+in	O
+the	O
+conventional	O
+group	O
+and	O
+1	O
+(	O
+2	O
+.	O
+7	O
+%	O
+)	O
+in	O
+the	O
+unilateral	O
+group	O
+","	O
+P	O
+=	O
+0	O
+.	O
+17	O
+required	O
+epinephrine	O
+infusion	O
+to	O
+treat	O
+hypotension	B-NP
+.	O
+	
+Patients	O
+in	O
+the	O
+conventional	O
+group	O
+had	O
+statistically	O
+significant	O
+greater	O
+fall	O
+in	O
+the	O
+systolic	O
+blood	O
+pressures	O
+at	O
+15	O
+","	O
+30	O
+and	O
+45	O
+minutes	O
+when	O
+compared	O
+to	O
+the	O
+baseline	O
+(	O
+P	O
+=	O
+0	O
+.	O
+3	O
+","	O
+0	O
+.	O
+1	O
+and	O
+0	O
+.	O
+4	O
+)	O
+.	O
+	
+The	O
+mean	O
+respiratory	O
+rate	O
+and	O
+oxygen	O
+saturations	O
+in	O
+the	O
+two	O
+groups	O
+were	O
+similar	O
+.	O
+	
+CONCLUSION	O
+:	O
+Compared	O
+to	O
+conventional	O
+spinal	O
+anaesthesia	O
+","	O
+unilateral	O
+spinal	O
+anaesthesia	O
+was	O
+associated	O
+with	O
+fewer	O
+cardiovascular	O
+perturbations	O
+.	O
+	
+Also	O
+","	O
+the	O
+type	O
+of	O
+spinal	O
+block	O
+instituted	O
+affected	O
+neither	O
+the	O
+respiratory	O
+rate	O
+nor	O
+the	O
+arterial	O
+oxygen	O
+saturation	O
+.	O
+	
+Spectrum	O
+of	O
+adverse	O
+events	O
+after	O
+generic	O
+HAART	O
+in	O
+southern	O
+Indian	O
+HIV	B-NP
+-	I-NP
+infected	I-NP
+patients	O
+.	O
+	
+To	O
+determine	O
+the	O
+incidence	O
+of	O
+clinically	O
+significant	O
+adverse	O
+events	O
+after	O
+long	O
+-	O
+term	O
+","	O
+fixed	O
+-	O
+dose	O
+","	O
+generic	O
+highly	O
+active	O
+antiretroviral	O
+therapy	O
+(	O
+HAART	O
+)	O
+use	O
+among	O
+HIV	B-NP
+-	I-NP
+infected	I-NP
+individuals	O
+in	O
+South	O
+India	O
+","	O
+we	O
+examined	O
+the	O
+experiences	O
+of	O
+3154	O
+HIV	B-NP
+-	I-NP
+infected	I-NP
+individuals	O
+who	O
+received	O
+a	O
+minimum	O
+of	O
+3	O
+months	O
+of	O
+generic	O
+HAART	O
+between	O
+February	O
+1996	O
+and	O
+December	O
+2006	O
+at	O
+a	O
+tertiary	O
+HIV	O
+care	O
+referral	O
+center	O
+in	O
+South	O
+India	O
+.	O
+	
+The	O
+most	O
+common	O
+regimens	O
+were	O
+3TC	O
++	O
+d4T	O
++	O
+nevirapine	O
+(	O
+NVP	O
+)	O
+(	O
+54	O
+.	O
+8	O
+%	O
+)	O
+","	O
+zidovudine	O
+(	O
+AZT	O
+)	O
++	O
+3TC	O
++	O
+NVP	O
+(	O
+14	O
+.	O
+5	O
+%	O
+)	O
+","	O
+3TC	O
++	O
+d4T	O
++	O
+efavirenz	O
+(	O
+EFV	O
+)	O
+(	O
+20	O
+.	O
+1	O
+%	O
+)	O
+","	O
+and	O
+AZT	O
++	O
+3TC	O
++	O
+EFV	O
+(	O
+5	O
+.	O
+4	O
+%	O
+)	O
+.	O
+	
+The	O
+most	O
+common	O
+adverse	O
+events	O
+and	O
+median	O
+CD4	O
+at	O
+time	O
+of	O
+event	O
+were	O
+rash	B-NP
+(	O
+15	O
+.	O
+2	O
+%	O
+;	O
+CD4	O
+","	O
+285	O
+cells	O
+/	O
+microL	O
+)	O
+and	O
+peripheral	B-NP
+neuropathy	I-NP
+(	O
+9	O
+.	O
+0	O
+%	O
+and	O
+348	O
+cells	O
+/	O
+microL	O
+)	O
+.	O
+	
+Clinically	O
+significant	O
+anemia	B-NP
+(	O
+hemoglobin	O
+<	O
+7	O
+g	O
+/	O
+dL	O
+)	O
+was	O
+observed	O
+in	O
+5	O
+.	O
+4	O
+%	O
+of	O
+patients	O
+(	O
+CD4	O
+","	O
+165	O
+cells	O
+/	O
+microL	O
+)	O
+and	O
+hepatitis	B-NP
+(	O
+clinical	O
+jaundice	B-NP
+with	O
+alanine	O
+aminotransferase	O
+>	O
+5	O
+times	O
+upper	O
+limits	O
+of	O
+normal	O
+)	O
+in	O
+3	O
+.	O
+5	O
+%	O
+of	O
+patients	O
+(	O
+CD4	O
+","	O
+260	O
+cells	O
+/	O
+microL	O
+)	O
+.	O
+	
+Women	O
+were	O
+significantly	O
+more	O
+likely	O
+to	O
+experience	O
+lactic	B-NP
+acidosis	I-NP
+","	O
+while	O
+men	O
+were	O
+significantly	O
+more	O
+likely	O
+to	O
+experience	O
+immune	B-NP
+reconstitution	I-NP
+syndrome	I-NP
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+Among	O
+the	O
+patients	O
+with	O
+1	O
+year	O
+of	O
+follow	O
+-	O
+up	O
+","	O
+NVP	O
+therapy	O
+was	O
+significantly	O
+associated	O
+with	O
+developing	O
+rash	B-NP
+and	O
+d4T	O
+therapy	O
+with	O
+developing	O
+peripheral	B-NP
+neuropathy	I-NP
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+Anemia	B-NP
+and	O
+hepatitis	B-NP
+often	O
+occur	O
+within	O
+12	O
+weeks	O
+of	O
+initiating	O
+generic	O
+HAART	O
+.	O
+	
+Frequent	O
+and	O
+early	O
+monitoring	O
+for	O
+these	O
+toxicities	B-NP
+is	O
+warranted	O
+in	O
+developing	O
+countries	O
+where	O
+generic	O
+HAART	O
+is	O
+increasingly	O
+available	O
+.	O
+	
+Thalidomide	O
+and	O
+sensory	B-NP
+neurotoxicity	I-NP
+:	O
+a	O
+neurophysiological	O
+study	O
+.	O
+	
+BACKGROUND	O
+:	O
+Recent	O
+studies	O
+confirmed	O
+a	O
+high	O
+incidence	O
+of	O
+sensory	B-NP
+axonal	I-NP
+neuropathy	I-NP
+in	O
+patients	O
+treated	O
+with	O
+different	O
+doses	O
+of	O
+thalidomide	O
+.	O
+	
+The	O
+study	O
+'	O
+s	O
+aims	O
+were	O
+to	O
+measure	O
+variations	O
+in	O
+sural	O
+nerve	O
+sensory	O
+action	O
+potential	O
+(	O
+SAP	O
+)	O
+amplitude	O
+in	O
+patients	O
+with	O
+refractory	O
+cutaneous	B-NP
+lupus	I-NP
+erythematosus	I-NP
+(	O
+CLE	B-NP
+)	O
+treated	O
+with	O
+thalidomide	O
+and	O
+use	O
+these	O
+findings	O
+to	O
+identify	O
+the	O
+neurotoxic	B-NP
+potential	O
+of	O
+thalidomide	O
+and	O
+the	O
+recovery	O
+capacity	O
+of	O
+sensory	O
+fibres	O
+after	O
+discontinuation	O
+of	O
+treatment	O
+.	O
+	
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+Clinical	O
+and	O
+electrophysiological	O
+data	O
+in	O
+12	O
+female	O
+patients	O
+with	O
+CLE	B-NP
+during	O
+treatment	O
+with	O
+thalidomide	O
+and	O
+up	O
+to	O
+47	O
+months	O
+after	O
+discontinuation	O
+of	O
+treatment	O
+were	O
+analysed	O
+.	O
+	
+Sural	O
+nerve	O
+SAP	O
+amplitude	O
+reduction	O
+>	O
+or	O
+=	O
+40	O
+%	O
+was	O
+the	O
+criteria	O
+for	O
+discontinuing	O
+therapy	O
+.	O
+	
+RESULTS	O
+:	O
+During	O
+treatment	O
+","	O
+11	O
+patients	O
+showed	O
+a	O
+reduction	O
+in	O
+sural	O
+nerve	O
+SAP	O
+amplitude	O
+compared	O
+to	O
+baseline	O
+values	O
+(	O
+9	O
+with	O
+a	O
+reduction	O
+>	O
+or	O
+=	O
+50	O
+%	O
+and	O
+2	O
+<	O
+50	O
+%	O
+)	O
+.	O
+	
+One	O
+patient	O
+showed	O
+no	O
+changes	O
+in	O
+SAP	O
+amplitude	O
+.	O
+	
+Five	O
+patients	O
+complained	O
+of	O
+paresthesias	B-NP
+and	O
+leg	O
+cramps	B-NP
+.	O
+	
+After	O
+thalidomide	O
+treatment	O
+","	O
+sural	O
+SAP	O
+amplitude	O
+recovered	O
+in	O
+3	O
+patients	O
+.	O
+	
+At	O
+detection	O
+of	O
+reduction	O
+in	O
+sural	O
+nerve	O
+SAP	O
+amplitude	O
+","	O
+the	O
+median	O
+thalidomide	O
+cumulative	O
+dose	O
+was	O
+21	O
+.	O
+4	O
+g	O
+.	O
+	
+The	O
+threshold	O
+neurotoxic	B-NP
+dosage	O
+is	O
+lower	O
+than	O
+previously	O
+reported	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Sural	O
+nerve	O
+SAP	O
+amplitude	O
+reduction	O
+is	O
+a	O
+reliable	O
+and	O
+sensitive	O
+marker	O
+of	O
+degeneration	O
+and	O
+recovery	O
+of	O
+sensory	O
+fibres	O
+.	O
+	
+This	O
+electrophysiological	O
+parameter	O
+provides	O
+information	O
+about	O
+subclinical	O
+neurotoxic	B-NP
+potential	O
+of	O
+thalidomide	O
+but	O
+is	O
+not	O
+helpful	O
+in	O
+predicting	O
+the	O
+appearance	O
+of	O
+sensory	O
+symptoms	O
+.	O
+	
+Five	O
+cases	O
+of	O
+encephalitis	B-NP
+during	O
+treatment	O
+of	O
+loiasis	B-NP
+with	O
+diethylcarbamazine	O
+.	O
+	
+Five	O
+cases	O
+of	O
+encephalitis	B-NP
+following	O
+treatment	O
+with	O
+diethylcarbamazine	O
+(	O
+DEC	O
+)	O
+were	O
+observed	O
+in	O
+Congolese	O
+patients	O
+with	O
+Loa	O
+loa	O
+filariasis	B-NP
+.	O
+	
+Two	O
+cases	O
+had	O
+a	O
+fatal	O
+outcome	O
+and	O
+one	O
+resulted	O
+in	O
+severe	O
+sequelae	O
+.	O
+	
+The	O
+notable	O
+fact	O
+was	O
+that	O
+this	O
+complication	O
+occurred	O
+in	O
+three	O
+patients	O
+hospitalized	O
+before	O
+treatment	O
+began	O
+","	O
+with	O
+whom	O
+particularly	O
+strict	O
+therapeutic	O
+precautions	O
+were	O
+taken	O
+","	O
+i	O
+.	O
+e	O
+.	O
+","	O
+initial	O
+dose	O
+less	O
+than	O
+10	O
+mg	O
+of	O
+DEC	O
+","	O
+very	O
+gradual	O
+dose	O
+increases	O
+","	O
+and	O
+associated	O
+anti	O
+-	O
+allergic	O
+treatment	O
+.	O
+	
+This	O
+type	O
+of	O
+drug	O
+-	O
+induced	O
+complication	O
+may	O
+not	O
+be	O
+that	O
+uncommon	O
+in	O
+highly	O
+endemic	O
+regions	O
+.	O
+	
+It	O
+occurs	O
+primarily	O
+","	O
+but	O
+not	O
+exclusively	O
+","	O
+in	O
+subjects	O
+presenting	O
+with	O
+a	O
+high	O
+microfilarial	O
+load	O
+.	O
+	
+The	O
+relationship	O
+between	O
+the	O
+occurrence	O
+of	O
+encephalitis	B-NP
+and	O
+the	O
+decrease	O
+in	O
+microfilaremia	B-NP
+is	O
+evident	O
+.	O
+	
+The	O
+pathophysiological	O
+mechanisms	O
+are	O
+discussed	O
+in	O
+the	O
+light	O
+of	O
+these	O
+observations	O
+and	O
+the	O
+few	O
+other	O
+comments	O
+on	O
+this	O
+subject	O
+published	O
+in	O
+the	O
+literature	O
+.	O
+	
+Amiodarone	O
+-	O
+related	O
+pulmonary	B-NP
+mass	I-NP
+and	O
+unique	O
+membranous	B-NP
+glomerulonephritis	I-NP
+in	O
+a	O
+patient	O
+with	O
+valvular	B-NP
+heart	I-NP
+disease	I-NP
+:	O
+Diagnostic	O
+pitfall	O
+and	O
+new	O
+findings	O
+.	O
+	
+Amiodarone	O
+is	O
+an	O
+anti	O
+-	O
+arrhythmic	B-NP
+drug	O
+for	O
+life	O
+-	O
+threatening	O
+tachycardia	B-NP
+","	O
+but	O
+various	O
+adverse	O
+effects	O
+have	O
+been	O
+reported	O
+.	O
+	
+Reported	O
+herein	O
+is	O
+an	O
+autopsy	O
+case	O
+of	O
+valvular	B-NP
+heart	I-NP
+disease	I-NP
+","	O
+in	O
+a	O
+patient	O
+who	O
+developed	O
+a	O
+lung	B-NP
+mass	I-NP
+(	O
+1	O
+.	O
+5	O
+cm	O
+in	O
+diameter	O
+)	O
+and	O
+proteinuria	B-NP
+(	O
+2	O
+.	O
+76	O
+g	O
+/	O
+day	O
+)	O
+after	O
+treatment	O
+with	O
+amiodarone	O
+for	O
+a	O
+long	O
+time	O
+.	O
+	
+The	O
+lung	B-NP
+mass	I-NP
+was	O
+highly	O
+suspected	O
+to	O
+be	O
+lung	B-NP
+cancer	I-NP
+on	O
+CT	O
+and	O
+positron	O
+emission	O
+tomography	O
+","	O
+but	O
+histologically	O
+the	O
+lesion	O
+was	O
+composed	O
+of	O
+lymphoplasmacytic	O
+infiltrates	O
+in	O
+alveolar	O
+walls	O
+and	O
+intra	O
+-	O
+alveolar	O
+accumulation	O
+of	O
+foamy	O
+macrophages	O
+containing	O
+characteristic	O
+myelinoid	O
+bodies	O
+","	O
+indicating	O
+that	O
+it	O
+was	O
+an	O
+amiodarone	O
+-	O
+related	O
+lesion	O
+.	O
+	
+In	O
+addition	O
+","	O
+the	O
+lung	O
+tissue	O
+had	O
+unevenly	O
+distributed	O
+hemosiderin	B-NP
+deposition	O
+","	O
+and	O
+abnormally	O
+tortuous	O
+capillaries	O
+were	O
+seen	O
+in	O
+the	O
+mass	O
+and	O
+in	O
+heavily	O
+hemosiderotic	B-NP
+lung	O
+portions	O
+outside	O
+the	O
+mass	O
+.	O
+	
+In	O
+the	O
+kidneys	O
+","	O
+glomeruli	O
+had	O
+membrane	O
+spikes	O
+","	O
+prominent	O
+swelling	O
+of	O
+podocytes	O
+and	O
+subepithelial	O
+deposits	O
+","	O
+which	O
+were	O
+sometimes	O
+large	O
+and	O
+hump	O
+-	O
+like	O
+.	O
+	
+Autoimmune	B-NP
+diseases	I-NP
+","	O
+viral	B-NP
+hepatitis	I-NP
+","	O
+malignant	O
+neoplasms	B-NP
+or	O
+other	O
+diseases	O
+with	O
+a	O
+known	O
+relationship	O
+to	O
+membranous	B-NP
+glomerulonephritis	I-NP
+were	O
+not	O
+found	O
+.	O
+	
+The	O
+present	O
+case	O
+highlights	O
+the	O
+possibility	O
+that	O
+differential	O
+diagnosis	O
+between	O
+an	O
+amiodarone	O
+-	O
+related	O
+pulmonary	B-NP
+lesion	I-NP
+and	O
+a	O
+neoplasm	B-NP
+can	O
+be	O
+very	O
+difficult	O
+radiologically	O
+","	O
+and	O
+suggests	O
+that	O
+membranous	B-NP
+glomerulonephritis	I-NP
+might	O
+be	O
+another	O
+possible	O
+complication	O
+of	O
+amiodarone	O
+treatment	O
+.	O
+	
+Risk	O
+of	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+associated	O
+with	O
+initial	O
+sulphonylurea	O
+treatment	O
+of	O
+patients	O
+with	O
+type	B-NP
+2	I-NP
+diabetes	I-NP
+:	O
+a	O
+matched	O
+case	O
+-	O
+control	O
+study	O
+.	O
+	
+AIMS	O
+:	O
+This	O
+study	O
+sought	O
+to	O
+assess	O
+the	O
+risk	O
+of	O
+developing	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+(	O
+CAD	B-NP
+)	O
+associated	O
+with	O
+initial	O
+treatment	O
+of	O
+type	B-NP
+2	I-NP
+diabetes	I-NP
+with	O
+different	O
+sulphonylureas	O
+.	O
+	
+METHODS	O
+:	O
+In	O
+type	B-NP
+2	I-NP
+diabetic	I-NP
+patients	O
+","	O
+cases	O
+who	O
+developed	O
+CAD	B-NP
+were	O
+compared	O
+retrospectively	O
+with	O
+controls	O
+that	O
+did	O
+not	O
+.	O
+	
+The	O
+20	O
+-	O
+year	O
+risk	O
+of	O
+CAD	B-NP
+at	O
+diagnosis	O
+of	O
+diabetes	B-NP
+","	O
+using	O
+the	O
+UKPDS	O
+risk	O
+engine	O
+","	O
+was	O
+used	O
+to	O
+match	O
+cases	O
+with	O
+controls	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+76	O
+cases	O
+of	O
+CAD	B-NP
+were	O
+compared	O
+with	O
+152	O
+controls	O
+.	O
+	
+The	O
+hazard	O
+of	O
+developing	O
+CAD	B-NP
+(	O
+95	O
+%	O
+CI	O
+)	O
+associated	O
+with	O
+initial	O
+treatment	O
+increased	O
+by	O
+2	O
+.	O
+4	O
+-	O
+fold	O
+(	O
+1	O
+.	O
+3	O
+-	O
+4	O
+.	O
+3	O
+","	O
+P	O
+=	O
+0	O
+.	O
+4	O
+)	O
+with	O
+glibenclamide	O
+;	O
+2	O
+-	O
+fold	O
+(	O
+0	O
+.	O
+9	O
+-	O
+4	O
+.	O
+6	O
+","	O
+P	O
+=	O
+0	O
+.	O
+99	O
+)	O
+with	O
+glipizide	O
+;	O
+2	O
+.	O
+9	O
+-	O
+fold	O
+(	O
+1	O
+.	O
+6	O
+-	O
+5	O
+.	O
+1	O
+","	O
+P	O
+=	O
+0	O
+.	O
+0	O
+)	O
+with	O
+either	O
+","	O
+and	O
+was	O
+unchanged	O
+with	O
+metformin	O
+.	O
+	
+The	O
+hazard	O
+decreased	O
+0	O
+.	O
+3	O
+-	O
+fold	O
+(	O
+0	O
+.	O
+7	O
+-	O
+1	O
+.	O
+7	O
+","	O
+P	O
+=	O
+0	O
+.	O
+385	O
+)	O
+with	O
+glimepiride	O
+","	O
+0	O
+.	O
+4	O
+-	O
+fold	O
+(	O
+0	O
+.	O
+7	O
+-	O
+1	O
+.	O
+3	O
+","	O
+P	O
+=	O
+0	O
+.	O
+192	O
+)	O
+with	O
+gliclazide	O
+","	O
+and	O
+0	O
+.	O
+4	O
+-	O
+fold	O
+(	O
+0	O
+.	O
+7	O
+-	O
+1	O
+.	O
+1	O
+","	O
+P	O
+=	O
+0	O
+.	O
+9	O
+)	O
+with	O
+either	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Initiating	O
+treatment	O
+of	O
+type	B-NP
+2	I-NP
+diabetes	I-NP
+with	O
+glibenclamide	O
+or	O
+glipizide	O
+is	O
+associated	O
+with	O
+increased	O
+risk	O
+of	O
+CAD	B-NP
+in	O
+comparison	O
+to	O
+gliclazide	O
+or	O
+glimepiride	O
+.	O
+	
+If	O
+confirmed	O
+","	O
+this	O
+may	O
+be	O
+important	O
+because	O
+most	O
+Indian	O
+patients	O
+receive	O
+the	O
+cheaper	O
+older	O
+sulphonylureas	O
+","	O
+and	O
+present	O
+guidelines	O
+do	O
+not	O
+distinguish	O
+between	O
+individual	O
+agents	O
+.	O
+	
+Reduced	O
+progression	O
+of	O
+adriamycin	O
+nephropathy	B-NP
+in	O
+spontaneously	O
+hypertensive	B-NP
+rats	O
+treated	O
+by	O
+losartan	O
+.	O
+	
+BACKGROUND	O
+:	O
+The	O
+aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+antihypertensive	O
+effects	O
+of	O
+angiotensin	O
+II	O
+type	O
+-	O
+1	O
+receptor	O
+blocker	O
+","	O
+losartan	O
+","	O
+and	O
+its	O
+potential	O
+in	O
+slowing	O
+down	O
+renal	B-NP
+disease	I-NP
+progression	O
+in	O
+spontaneously	O
+hypertensive	B-NP
+rats	O
+(	O
+SHR	O
+)	O
+with	O
+adriamycin	O
+(	O
+ADR	O
+)	O
+nephropathy	B-NP
+.	O
+	
+METHODS	O
+:	O
+Six	O
+-	O
+month	O
+-	O
+old	O
+female	O
+SHR	O
+were	O
+randomly	O
+selected	O
+in	O
+six	O
+groups	O
+.	O
+	
+Two	O
+control	O
+groups	O
+(	O
+SH	O
+(	O
+6	O
+)	O
+","	O
+SH	O
+(	O
+12	O
+)	O
+)	O
+received	O
+vehicle	O
+.	O
+	
+Groups	O
+ADR	O
+(	O
+6	O
+)	O
+","	O
+ADR	O
++	O
+LOS	O
+(	O
+6	O
+)	O
+and	O
+ADR	O
+(	O
+12	O
+)	O
+","	O
+and	O
+ADR	O
++	O
+LOS	O
+(	O
+12	O
+)	O
+received	O
+ADR	O
+(	O
+2	O
+mg	O
+/	O
+kg	O
+/	O
+b	O
+.	O
+w	O
+.	O
+i	O
+.	O
+v	O
+.	O
+)	O
+twice	O
+in	O
+a	O
+3	O
+-	O
+week	O
+interval	O
+.	O
+	
+Group	O
+ADR	O
++	O
+LOS	O
+(	O
+6	O
+)	O
+received	O
+losartan	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+/	O
+b	O
+.	O
+w	O
+.	O
+/	O
+day	O
+by	O
+gavages	O
+)	O
+for	O
+6	O
+weeks	O
+and	O
+group	O
+ADR	O
++	O
+LOS	O
+(	O
+12	O
+)	O
+for	O
+12	O
+weeks	O
+after	O
+second	O
+injection	O
+of	O
+ADR	O
+.	O
+	
+Animals	O
+were	O
+killed	O
+after	O
+6	O
+or	O
+12	O
+weeks	O
+","	O
+respectively	O
+.	O
+	
+Haemodynamic	O
+measurements	O
+were	O
+performed	O
+on	O
+anaesthetized	O
+animals	O
+","	O
+blood	O
+and	O
+urine	O
+samples	O
+were	O
+taken	O
+for	O
+biochemical	O
+analysis	O
+and	O
+the	O
+left	O
+kidney	O
+was	O
+processed	O
+for	O
+morphological	O
+studies	O
+.	O
+	
+RESULTS	O
+:	O
+Short	O
+-	O
+term	O
+losartan	O
+treatment	O
+","	O
+besides	O
+antihypertensive	O
+effect	O
+","	O
+improved	O
+glomerular	O
+filtration	O
+rate	O
+and	O
+ameliorated	O
+glomerulosclerosis	B-NP
+resulting	O
+in	O
+decreased	O
+proteinuria	B-NP
+.	O
+	
+Prolonged	O
+treatment	O
+with	O
+losartan	O
+showed	O
+further	O
+reduction	O
+of	O
+glomerulosclerosis	B-NP
+associated	O
+with	O
+reduced	O
+progression	O
+of	O
+tubular	O
+atrophy	B-NP
+and	O
+interstitial	B-NP
+fibrosis	I-NP
+","	O
+thus	O
+preventing	O
+heavy	O
+proteinuria	B-NP
+and	O
+chronic	B-NP
+renal	I-NP
+failure	I-NP
+.	O
+	
+Losartan	O
+reduced	O
+uraemia	B-NP
+and	O
+increased	O
+urea	O
+clearance	O
+in	O
+advanced	O
+ADR	O
+nephropathy	B-NP
+in	O
+SHR	O
+.	O
+	
+Histological	O
+examination	O
+showed	O
+that	O
+losartan	O
+could	O
+prevent	O
+tubular	O
+atrophy	B-NP
+","	O
+interstitial	O
+infiltration	O
+and	O
+fibrosis	B-NP
+in	O
+ADR	O
+nephropathy	B-NP
+.	O
+	
+CONCLUSION	O
+:	O
+Losartan	O
+reduces	O
+the	O
+rate	O
+of	O
+progression	O
+of	O
+ADR	O
+-	O
+induced	O
+focal	B-NP
+segmental	I-NP
+glomerulosclerosis	I-NP
+to	O
+end	B-NP
+-	I-NP
+stage	I-NP
+renal	I-NP
+disease	I-NP
+in	O
+SHR	O
+.	O
+	
+The	O
+risks	O
+of	O
+aprotinin	O
+and	O
+tranexamic	O
+acid	O
+in	O
+cardiac	O
+surgery	O
+:	O
+a	O
+one	O
+-	O
+year	O
+follow	O
+-	O
+up	O
+of	O
+1188	O
+consecutive	O
+patients	O
+.	O
+	
+BACKGROUND	O
+:	O
+Our	O
+aim	O
+was	O
+to	O
+investigate	O
+postoperative	O
+complications	O
+and	O
+mortality	O
+after	O
+administration	O
+of	O
+aprotinin	O
+compared	O
+to	O
+tranexamic	O
+acid	O
+in	O
+an	O
+unselected	O
+","	O
+consecutive	O
+cohort	O
+.	O
+	
+METHODS	O
+:	O
+Perioperative	O
+data	O
+from	O
+consecutive	O
+cardiac	O
+surgery	O
+patients	O
+were	O
+prospectively	O
+collected	O
+between	O
+September	O
+2005	O
+and	O
+June	O
+2006	O
+in	O
+a	O
+university	O
+-	O
+affiliated	O
+clinic	O
+(	O
+n	O
+=	O
+1188	O
+)	O
+.	O
+	
+During	O
+the	O
+first	O
+5	O
+mo	O
+","	O
+596	O
+patients	O
+received	O
+aprotinin	O
+(	O
+Group	O
+A	O
+)	O
+;	O
+in	O
+the	O
+next	O
+5	O
+mo	O
+","	O
+592	O
+patients	O
+were	O
+treated	O
+with	O
+tranexamic	O
+acid	O
+(	O
+Group	O
+T	O
+)	O
+.	O
+	
+Except	O
+for	O
+antifibrinolytic	O
+therapy	O
+","	O
+the	O
+anesthetic	O
+and	O
+surgical	O
+protocols	O
+remained	O
+unchanged	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+pre	O
+-	O
+and	O
+intraoperative	O
+variables	O
+were	O
+comparable	O
+between	O
+the	O
+treatment	O
+groups	O
+.	O
+	
+Postoperatively	O
+","	O
+a	O
+significantly	O
+higher	O
+incidence	O
+of	O
+seizures	B-NP
+was	O
+found	O
+in	O
+Group	O
+T	O
+(	O
+4	O
+.	O
+6	O
+%	O
+vs	O
+1	O
+.	O
+2	O
+%	O
+","	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+This	O
+difference	O
+was	O
+also	O
+significant	O
+in	O
+the	O
+primary	O
+valve	O
+surgery	O
+and	O
+the	O
+high	O
+risk	O
+surgery	O
+subgroups	O
+(	O
+7	O
+.	O
+9	O
+%	O
+vs	O
+1	O
+.	O
+2	O
+%	O
+","	O
+P	O
+=	O
+0	O
+.	O
+3	O
+;	O
+7	O
+.	O
+3	O
+%	O
+vs	O
+2	O
+.	O
+4	O
+%	O
+","	O
+P	O
+=	O
+0	O
+.	O
+35	O
+","	O
+respectively	O
+)	O
+.	O
+	
+Persistent	O
+atrial	O
+fibrillation	O
+(	O
+7	O
+.	O
+9	O
+%	O
+vs	O
+2	O
+.	O
+3	O
+%	O
+","	O
+P	O
+=	O
+0	O
+.	O
+20	O
+)	O
+and	O
+renal	B-NP
+failure	I-NP
+(	O
+9	O
+.	O
+7	O
+%	O
+vs	O
+1	O
+.	O
+7	O
+%	O
+","	O
+P	O
+=	O
+0	O
+.	O
+2	O
+)	O
+were	O
+also	O
+more	O
+common	O
+in	O
+Group	O
+T	O
+","	O
+in	O
+the	O
+primary	O
+valve	O
+surgery	O
+subgroup	O
+.	O
+	
+On	O
+the	O
+contrary	O
+","	O
+among	O
+primary	O
+coronary	O
+artery	O
+bypass	O
+surgery	O
+patients	O
+","	O
+there	O
+were	O
+more	O
+acute	O
+myocardial	B-NP
+infarctions	I-NP
+and	O
+renal	B-NP
+dysfunction	I-NP
+in	O
+Group	O
+A	O
+(	O
+5	O
+.	O
+8	O
+%	O
+vs	O
+2	O
+.	O
+0	O
+%	O
+","	O
+P	O
+=	O
+0	O
+.	O
+27	O
+;	O
+22	O
+.	O
+5	O
+%	O
+vs	O
+15	O
+.	O
+2	O
+%	O
+","	O
+P	O
+=	O
+0	O
+.	O
+36	O
+","	O
+respectively	O
+)	O
+.	O
+	
+The	O
+1	O
+-	O
+yr	O
+mortality	O
+was	O
+significantly	O
+higher	O
+after	O
+aprotinin	O
+treatment	O
+in	O
+the	O
+high	O
+risk	O
+surgery	O
+group	O
+(	O
+17	O
+.	O
+7	O
+%	O
+vs	O
+9	O
+.	O
+8	O
+%	O
+","	O
+P	O
+=	O
+0	O
+.	O
+34	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+Both	O
+antifibrinolytic	O
+drugs	O
+bear	O
+the	O
+risk	O
+of	O
+adverse	O
+outcome	O
+depending	O
+on	O
+the	O
+type	O
+of	O
+cardiac	O
+surgery	O
+.	O
+	
+Administration	O
+of	O
+aprotinin	O
+should	O
+be	O
+avoided	O
+in	O
+coronary	O
+artery	O
+bypass	O
+graft	O
+and	O
+high	O
+risk	O
+patients	O
+","	O
+whereas	O
+administration	O
+of	O
+tranexamic	O
+acid	O
+is	O
+not	O
+recommended	O
+in	O
+valve	O
+surgery	O
+.	O
+	
+Delirium	B-NP
+in	O
+an	O
+elderly	O
+woman	O
+possibly	O
+associated	O
+with	O
+administration	O
+of	O
+misoprostol	O
+.	O
+	
+Misoprostol	O
+has	O
+been	O
+associated	O
+with	O
+adverse	O
+reactions	O
+","	O
+including	O
+gastrointestinal	O
+symptoms	O
+","	O
+gynecologic	O
+problems	O
+","	O
+and	O
+headache	B-NP
+.	O
+	
+Changes	O
+in	O
+mental	O
+status	O
+","	O
+however	O
+","	O
+have	O
+not	O
+been	O
+reported	O
+.	O
+	
+We	O
+present	O
+a	O
+case	O
+in	O
+which	O
+an	O
+89	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+in	O
+a	O
+long	O
+-	O
+term	O
+care	O
+facility	O
+became	O
+confused	O
+after	O
+the	O
+initiation	O
+of	O
+misoprostol	O
+therapy	O
+.	O
+	
+The	O
+patient	O
+'	O
+s	O
+change	O
+in	O
+mental	O
+status	O
+was	O
+first	O
+reported	O
+nine	O
+days	O
+after	O
+the	O
+initiation	O
+of	O
+therapy	O
+.	O
+	
+Her	O
+delirium	B-NP
+significantly	O
+improved	O
+after	O
+misoprostol	O
+was	O
+discontinued	O
+and	O
+her	O
+mental	O
+status	O
+returned	O
+to	O
+normal	O
+within	O
+a	O
+week	O
+.	O
+	
+Because	O
+no	O
+other	O
+factors	O
+related	O
+to	O
+this	O
+patient	O
+changed	O
+significantly	O
+","	O
+the	O
+delirium	B-NP
+experienced	O
+by	O
+this	O
+patient	O
+possibly	O
+resulted	O
+from	O
+misoprostol	O
+therapy	O
+.	O
+	
+The	O
+biological	O
+properties	O
+of	O
+the	O
+optical	O
+isomers	O
+of	O
+propranolol	O
+and	O
+their	O
+effects	O
+on	O
+cardiac	B-NP
+arrhythmias	I-NP
+.	O
+	
+1	O
+.	O
+	
+The	O
+optical	O
+isomers	O
+of	O
+propranolol	O
+have	O
+been	O
+compared	O
+for	O
+their	O
+beta	O
+-	O
+blocking	O
+and	O
+antiarrhythmic	O
+activities	O
+.	O
+2	O
+.	O
+	
+In	O
+blocking	O
+the	O
+positive	O
+inotropic	O
+and	O
+chronotropic	O
+responses	O
+to	O
+isoprenaline	O
+","	O
+(	O
++	O
+)	O
+-	O
+propranolol	O
+had	O
+less	O
+than	O
+one	O
+hundredth	O
+the	O
+potency	O
+of	O
+(	O
+-	O
+)	O
+-	O
+propranolol	O
+.	O
+	
+At	O
+dose	O
+levels	O
+of	O
+(	O
++	O
+)	O
+-	O
+propranolol	O
+which	O
+attenuated	O
+the	O
+responses	O
+to	O
+isoprenaline	O
+","	O
+there	O
+was	O
+a	O
+significant	O
+prolongation	O
+of	O
+the	O
+PR	O
+interval	O
+of	O
+the	O
+electrocardiogram	O
+.	O
+3	O
+.	O
+	
+The	O
+metabolic	O
+responses	O
+to	O
+isoprenaline	O
+in	O
+dogs	O
+(	O
+an	O
+increase	O
+in	O
+circulating	O
+glucose	O
+","	O
+lactate	O
+and	O
+free	O
+fatty	O
+acids	O
+)	O
+were	O
+all	O
+blocked	O
+by	O
+(	O
+-	O
+)	O
+-	O
+propranolol	O
+.	O
+	
+(	O
++	O
+)	O
+-	O
+Propranolol	O
+had	O
+no	O
+effect	O
+on	O
+fatty	O
+acid	O
+mobilization	O
+but	O
+significantly	O
+reduced	O
+the	O
+increments	O
+in	O
+both	O
+lactate	O
+and	O
+glucose	O
+.	O
+4	O
+.	O
+	
+Both	O
+isomers	O
+of	O
+propranolol	O
+possessed	O
+similar	O
+depressant	O
+potency	O
+on	O
+isolated	O
+atrial	O
+muscle	O
+taken	O
+from	O
+guinea	O
+-	O
+pigs	O
+.	O
+5	O
+.	O
+	
+The	O
+isomers	O
+of	O
+propranolol	O
+exhibited	O
+similar	O
+local	O
+anaesthetic	O
+potencies	O
+on	O
+an	O
+isolated	O
+frog	O
+nerve	O
+preparation	O
+at	O
+a	O
+level	O
+approximately	O
+three	O
+times	O
+that	O
+of	O
+procaine	O
+.	O
+	
+The	O
+racemic	O
+compound	O
+was	O
+significantly	O
+less	O
+potent	O
+than	O
+either	O
+isomer	O
+.	O
+6	O
+.	O
+	
+Both	O
+isomers	O
+of	O
+propranolol	O
+were	O
+capable	O
+of	O
+preventing	O
+adrenaline	O
+-	O
+induced	O
+cardiac	B-NP
+arrhythmias	I-NP
+in	O
+cats	O
+anaesthetized	O
+with	O
+halothane	O
+","	O
+but	O
+the	O
+mean	O
+dose	O
+of	O
+(	O
+-	O
+)	O
+-	O
+propranolol	O
+was	O
+0	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+whereas	O
+that	O
+of	O
+(	O
++	O
+)	O
+-	O
+propranolol	O
+was	O
+4	O
+.	O
+2	O
++	O
+/	O
+-	O
+1	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+.	O
+	
+At	O
+the	O
+effective	O
+dose	O
+level	O
+of	O
+(	O
++	O
+)	O
+-	O
+propranolol	O
+there	O
+was	O
+a	O
+significant	O
+prolongation	O
+of	O
+the	O
+PR	O
+interval	O
+of	O
+the	O
+electrocardiogram	O
+.	O
+	
+Blockade	O
+of	O
+arrhythmias	B-NP
+with	O
+both	O
+isomers	O
+was	O
+surmountable	O
+by	O
+increasing	O
+the	O
+dose	O
+of	O
+adrenaline	O
+.	O
+7	O
+.	O
+	
+Both	O
+isomers	O
+of	O
+propranolol	O
+were	O
+also	O
+capable	O
+of	O
+reversing	O
+ventricular	B-NP
+tachycardia	I-NP
+caused	O
+by	O
+ouabain	O
+in	O
+anaesthetized	O
+cats	O
+and	O
+dogs	O
+.	O
+	
+The	O
+dose	O
+of	O
+(	O
+-	O
+)	O
+-	O
+propranolol	O
+was	O
+significantly	O
+smaller	O
+than	O
+that	O
+of	O
+(	O
++	O
+)	O
+-	O
+propranolol	O
+in	O
+both	O
+species	O
+but	O
+much	O
+higher	O
+than	O
+that	O
+required	O
+to	O
+produce	O
+evidence	O
+of	O
+beta	O
+-	O
+blockade	O
+.	O
+8	O
+.	O
+	
+The	O
+implications	O
+of	O
+these	O
+results	O
+are	O
+discussed	O
+.	O
+	
+Topotecan	O
+in	O
+combination	O
+with	O
+radiotherapy	O
+in	O
+unresectable	O
+glioblastoma	B-NP
+:	O
+a	O
+phase	O
+2	O
+study	O
+.	O
+	
+Improving	O
+glioblastoma	B-NP
+multiforme	I-NP
+(	O
+GBM	B-NP
+)	O
+treatment	O
+with	O
+radio	O
+-	O
+chemotherapy	O
+remains	O
+a	O
+challenge	O
+.	O
+	
+Topotecan	O
+is	O
+an	O
+attractive	O
+option	O
+as	O
+it	O
+exhibits	O
+growth	O
+inhibition	O
+of	O
+human	O
+glioma	B-NP
+as	O
+well	O
+as	O
+brain	O
+penetration	O
+.	O
+	
+The	O
+present	O
+study	O
+assessed	O
+the	O
+combination	O
+of	O
+radiotherapy	O
+(	O
+60	O
+Gy	O
+/	O
+30	O
+fractions	O
+/	O
+40	O
+days	O
+)	O
+and	O
+topotecan	O
+(	O
+0	O
+.	O
+9	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+/	O
+day	O
+on	O
+days	O
+1	O
+-	O
+5	O
+on	O
+weeks	O
+1	O
+","	O
+3	O
+and	O
+5	O
+)	O
+in	O
+50	O
+adults	O
+with	O
+histologically	O
+proven	O
+and	O
+untreated	O
+GBM	B-NP
+.	O
+	
+The	O
+incidence	O
+of	O
+non	O
+-	O
+hematological	O
+toxicities	B-NP
+was	O
+low	O
+and	O
+grade	O
+3	O
+-	O
+4	O
+hematological	O
+toxicities	B-NP
+were	O
+reported	O
+in	O
+20	O
+patients	O
+(	O
+mainly	O
+lymphopenia	B-NP
+and	O
+neutropenia	B-NP
+)	O
+.	O
+	
+Partial	O
+response	O
+and	O
+stabilization	O
+rates	O
+were	O
+2	O
+%	O
+and	O
+32	O
+%	O
+","	O
+respectively	O
+","	O
+with	O
+an	O
+overall	O
+time	O
+to	O
+progression	O
+of	O
+12	O
+weeks	O
+.	O
+	
+One	O
+-	O
+year	O
+overall	O
+survival	O
+(	O
+OS	O
+)	O
+rate	O
+was	O
+42	O
+%	O
+","	O
+with	O
+a	O
+median	O
+OS	O
+of	O
+40	O
+weeks	O
+.	O
+	
+Topotecan	O
+in	O
+combination	O
+with	O
+radiotherapy	O
+was	O
+well	O
+tolerated	O
+.	O
+	
+However	O
+","	O
+while	O
+response	O
+and	O
+stabilization	O
+concerned	O
+one	O
+-	O
+third	O
+of	O
+the	O
+patients	O
+","	O
+the	O
+study	O
+did	O
+not	O
+show	O
+increased	O
+benefits	O
+in	O
+terms	O
+of	O
+survival	O
+in	O
+patients	O
+with	O
+unresectable	O
+GBM	B-NP
+.	O
+	
+Long	O
+-	O
+term	O
+lithium	O
+therapy	O
+leading	O
+to	O
+hyperparathyroidism	B-NP
+:	O
+a	O
+case	O
+report	O
+.	O
+	
+PURPOSE	O
+:	O
+This	O
+paper	O
+reviews	O
+the	O
+effect	O
+of	O
+chronic	O
+lithium	O
+therapy	O
+on	O
+serum	O
+calcium	O
+level	O
+and	O
+parathyroid	O
+glands	O
+","	O
+its	O
+pathogenesis	O
+","	O
+and	O
+treatment	O
+options	O
+.	O
+	
+We	O
+examined	O
+the	O
+case	O
+of	O
+a	O
+lithium	O
+-	O
+treated	O
+patient	O
+who	O
+had	O
+recurrent	O
+hypercalcemia	B-NP
+to	O
+better	O
+understand	O
+the	O
+disease	O
+process	O
+.	O
+	
+CONCLUSION	O
+:	O
+Primary	B-NP
+hyperparathyroidism	I-NP
+is	O
+a	O
+rare	O
+but	O
+potentially	O
+life	O
+-	O
+threatening	O
+side	O
+effect	O
+of	O
+long	O
+-	O
+term	O
+lithium	O
+therapy	O
+.	O
+	
+Careful	O
+patient	O
+selection	O
+and	O
+long	O
+-	O
+term	O
+follow	O
+-	O
+up	O
+can	O
+reduce	O
+morbidity	O
+.	O
+	
+PRACTICAL	O
+IMPLICATIONS	O
+:	O
+As	O
+much	O
+as	O
+15	O
+%	O
+of	O
+lithium	O
+-	O
+treated	O
+patients	O
+become	O
+hypercalcemic	B-NP
+.	O
+	
+By	O
+routinely	O
+monitoring	O
+serum	O
+calcium	O
+levels	O
+","	O
+healthcare	O
+providers	O
+can	O
+improve	O
+the	O
+quality	O
+of	O
+life	O
+of	O
+this	O
+patient	O
+group	O
+.	O
+	
+Comparison	O
+of	O
+laryngeal	O
+mask	O
+with	O
+endotracheal	O
+tube	O
+for	O
+anesthesia	O
+in	O
+endoscopic	O
+sinus	O
+surgery	O
+.	O
+	
+BACKGROUND	O
+:	O
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+compare	O
+surgical	O
+conditions	O
+","	O
+including	O
+the	O
+amount	O
+of	O
+intraoperative	O
+bleeding	B-NP
+as	O
+well	O
+as	O
+intraoperative	O
+blood	O
+pressure	O
+","	O
+during	O
+functional	O
+endoscopic	O
+sinus	O
+surgery	O
+(	O
+FESS	O
+)	O
+using	O
+flexible	O
+reinforced	O
+laryngeal	O
+mask	O
+airway	O
+(	O
+FRLMA	O
+)	O
+versus	O
+endotracheal	O
+tube	O
+(	O
+ETT	O
+)	O
+in	O
+maintaining	O
+controlled	O
+hypotension	B-NP
+anesthesia	O
+induced	O
+by	O
+propofol	O
+-	O
+remifentanil	O
+total	O
+i	O
+.	O
+v	O
+.	O
+anesthesia	O
+(	O
+TIVA	O
+)	O
+.	O
+	
+METHODS	O
+:	O
+Sixty	O
+normotensive	O
+American	O
+Society	O
+of	O
+Anesthesiologists	O
+I	O
+-	O
+II	O
+adult	O
+patients	O
+undergoing	O
+FESS	O
+under	O
+controlled	O
+hypotension	B-NP
+anesthesia	O
+caused	O
+by	O
+propofol	O
+-	O
+remifentanil	O
+-	O
+TIVA	O
+were	O
+randomly	O
+assigned	O
+into	O
+two	O
+groups	O
+:	O
+group	O
+I	O
+","	O
+FRLMA	O
+;	O
+group	O
+II	O
+","	O
+ETT	O
+.	O
+	
+Hemorrhage	B-NP
+was	O
+measured	O
+and	O
+the	O
+visibility	O
+of	O
+the	O
+operative	O
+field	O
+was	O
+evaluated	O
+according	O
+to	O
+a	O
+six	O
+-	O
+point	O
+scale	O
+.	O
+	
+RESULTS	O
+:	O
+Controlled	O
+hypotension	B-NP
+was	O
+achieved	O
+within	O
+a	O
+shorter	O
+period	O
+using	O
+laryngeal	O
+mask	O
+using	O
+lower	O
+rates	O
+of	O
+remifentanil	O
+infusion	O
+and	O
+lower	O
+total	O
+dose	O
+of	O
+remifentanil	O
+.	O
+	
+CONCLUSION	O
+:	O
+In	O
+summary	O
+","	O
+our	O
+results	O
+indicate	O
+that	O
+airway	O
+management	O
+using	O
+FRLMA	O
+during	O
+controlled	O
+hypotension	B-NP
+anesthesia	O
+provided	O
+better	O
+surgical	O
+conditions	O
+in	O
+terms	O
+of	O
+quality	O
+of	O
+operative	O
+field	O
+and	O
+blood	O
+loss	O
+and	O
+allowed	O
+for	O
+convenient	O
+induced	O
+hypotension	B-NP
+with	O
+low	O
+doses	O
+of	O
+remifentanil	O
+during	O
+TIVA	O
+in	O
+patients	O
+undergoing	O
+FESS	O
+.	O
+	
+Nonalcoholic	B-NP
+fatty	I-NP
+liver	I-NP
+disease	I-NP
+during	O
+valproate	O
+therapy	O
+.	O
+	
+Valproic	O
+acid	O
+(	O
+VPA	O
+)	O
+is	O
+effective	O
+for	O
+the	O
+treatment	O
+of	O
+many	O
+types	O
+of	O
+epilepsy	B-NP
+","	O
+but	O
+its	O
+use	O
+can	O
+be	O
+associated	O
+with	O
+an	O
+increase	O
+in	O
+body	O
+weight	O
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+nonalcoholic	B-NP
+fatty	I-NP
+liver	I-NP
+disease	I-NP
+(	O
+NAFLD	B-NP
+)	O
+arising	O
+in	O
+a	O
+child	O
+who	O
+developed	O
+obesity	B-NP
+during	O
+VPA	O
+treatment	O
+.	O
+	
+Laboratory	O
+data	O
+revealed	O
+hyperinsulinemia	B-NP
+with	O
+insulin	B-NP
+resistance	I-NP
+.	O
+	
+After	O
+the	O
+withdrawal	O
+of	O
+VPA	O
+therapy	O
+","	O
+our	O
+patient	O
+showed	O
+a	O
+significant	O
+weight	B-NP
+loss	I-NP
+","	O
+a	O
+decrease	O
+of	O
+body	O
+mass	O
+index	O
+","	O
+and	O
+normalization	O
+of	O
+metabolic	O
+and	O
+endocrine	O
+parameters	O
+;	O
+moreover	O
+","	O
+ultrasound	O
+measurements	O
+showed	O
+a	O
+complete	O
+normalization	O
+.	O
+	
+The	O
+present	O
+case	O
+suggests	O
+that	O
+obesity	B-NP
+","	O
+hyperinsulinemia	B-NP
+","	O
+insulin	B-NP
+resistance	I-NP
+","	O
+and	O
+long	O
+-	O
+term	O
+treatment	O
+with	O
+VPA	O
+may	O
+be	O
+all	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+NAFLD	B-NP
+;	O
+this	O
+side	O
+effect	O
+is	O
+reversible	O
+after	O
+VPA	O
+withdrawal	O
+.	O
+	
+Carbimazole	O
+induced	O
+ANCA	B-NP
+positive	I-NP
+vasculitis	I-NP
+.	O
+	
+Anti	O
+-	O
+thyroid	O
+drugs	O
+","	O
+like	O
+carbimazole	O
+and	O
+propylthiouracil	O
+(	O
+PTU	O
+)	O
+are	O
+commonly	O
+prescribed	O
+for	O
+the	O
+treatment	O
+of	O
+hyperthyroidism	B-NP
+.	O
+	
+One	O
+should	O
+be	O
+aware	O
+of	O
+the	O
+side	O
+effects	O
+of	O
+antithyroid	O
+medications	O
+.	O
+	
+Antineutrophil	B-NP
+cytoplasmic	I-NP
+antibody	I-NP
+(	I-NP
+ANCA	I-NP
+)	I-NP
+-	I-NP
+-	I-NP
+associated	I-NP
+vasculitis	I-NP
+is	O
+a	O
+potentially	O
+life	O
+-	O
+threatening	O
+adverse	O
+effect	O
+of	O
+antithyroidmedications	O
+.	O
+	
+We	O
+report	O
+a	O
+patient	O
+with	O
+Graves	B-NP
+'	I-NP
+disease	I-NP
+who	O
+developed	O
+ANCA	O
+positive	O
+carbimazole	O
+induced	O
+vasculitis	B-NP
+.	O
+	
+The	O
+episode	O
+was	O
+characterized	O
+by	O
+a	O
+vasculitic	B-NP
+skin	B-NP
+rash	I-NP
+associated	O
+with	O
+large	O
+joint	O
+arthritis	B-NP
+","	O
+pyrexia	B-NP
+and	O
+parotiditis	B-NP
+but	O
+no	O
+renal	O
+or	O
+pulmonary	O
+involvement	O
+.	O
+	
+He	O
+was	O
+referred	O
+to	O
+us	O
+for	O
+neurological	O
+evaluation	O
+because	O
+he	O
+had	O
+difficulty	O
+in	O
+getting	O
+up	O
+from	O
+squatting	O
+position	O
+and	O
+was	O
+suspected	O
+to	O
+have	O
+myositis	B-NP
+.	O
+	
+Carbimazole	O
+and	O
+methimazole	O
+have	O
+a	O
+lower	O
+incidence	O
+of	O
+reported	O
+ANCA	O
+positive	O
+side	O
+effects	O
+than	O
+PUT	O
+.	O
+	
+To	O
+the	O
+best	O
+of	O
+our	O
+knowledge	O
+this	O
+is	O
+the	O
+first	O
+ANCA	O
+positive	O
+carbimazole	O
+induced	O
+vasculitis	B-NP
+case	O
+reported	O
+from	O
+India	O
+.	O
+	
+Aspirin	O
+for	O
+the	O
+primary	O
+prevention	O
+of	O
+cardiovascular	O
+events	O
+:	O
+an	O
+update	O
+of	O
+the	O
+evidence	O
+for	O
+the	O
+U	O
+.	O
+S	O
+.	O
+	
+Preventive	O
+Services	O
+Task	O
+Force	O
+.	O
+	
+BACKGROUND	O
+:	O
+Coronary	B-NP
+heart	I-NP
+disease	I-NP
+and	O
+cerebrovascular	B-NP
+disease	I-NP
+are	O
+leading	O
+causes	O
+of	O
+death	O
+in	O
+the	O
+United	O
+States	O
+.	O
+	
+In	O
+2002	O
+","	O
+the	O
+U	O
+.	O
+S	O
+.	O
+	
+Preventive	O
+Services	O
+Task	O
+Force	O
+(	O
+USPSTF	O
+)	O
+strongly	O
+recommended	O
+that	O
+clinicians	O
+discuss	O
+aspirin	O
+with	O
+adults	O
+who	O
+are	O
+at	O
+increased	O
+risk	O
+for	O
+coronary	B-NP
+heart	I-NP
+disease	I-NP
+.	O
+	
+PURPOSE	O
+:	O
+To	O
+determine	O
+the	O
+benefits	O
+and	O
+harms	O
+of	O
+taking	O
+aspirin	O
+for	O
+the	O
+primary	O
+prevention	O
+of	O
+myocardial	B-NP
+infarctions	I-NP
+","	O
+strokes	B-NP
+","	O
+and	O
+death	O
+.	O
+	
+DATA	O
+SOURCES	O
+:	O
+MEDLINE	O
+and	O
+Cochrane	O
+Library	O
+(	O
+search	O
+dates	O
+","	O
+1	O
+January	O
+2001	O
+to	O
+28	O
+August	O
+2008	O
+)	O
+","	O
+recent	O
+systematic	O
+reviews	O
+","	O
+reference	O
+lists	O
+of	O
+retrieved	O
+articles	O
+","	O
+and	O
+suggestions	O
+from	O
+experts	O
+.	O
+	
+STUDY	O
+SELECTION	O
+:	O
+English	O
+-	O
+language	O
+randomized	O
+","	O
+controlled	O
+trials	O
+(	O
+RCTs	O
+)	O
+;	O
+case	O
+-	O
+control	O
+studies	O
+;	O
+meta	O
+-	O
+analyses	O
+;	O
+and	O
+systematic	O
+reviews	O
+of	O
+aspirin	O
+versus	O
+control	O
+for	O
+the	O
+primary	O
+prevention	O
+of	O
+cardiovascular	B-NP
+disease	I-NP
+(	O
+CVD	B-NP
+)	O
+were	O
+selected	O
+to	O
+answer	O
+the	O
+following	O
+questions	O
+:	O
+Does	O
+aspirin	O
+decrease	O
+coronary	O
+heart	O
+events	O
+","	O
+strokes	B-NP
+","	O
+death	O
+from	O
+coronary	O
+heart	O
+events	O
+or	O
+stroke	B-NP
+","	O
+or	O
+all	O
+-	O
+cause	O
+mortality	O
+in	O
+adults	O
+without	O
+known	O
+CVD	B-NP
+?	O
+	
+Does	O
+aspirin	O
+increase	O
+gastrointestinal	B-NP
+bleeding	I-NP
+or	O
+hemorrhagic	B-NP
+strokes	I-NP
+?	O
+	
+DATA	O
+EXTRACTION	O
+:	O
+All	O
+studies	O
+were	O
+reviewed	O
+","	O
+abstracted	O
+","	O
+and	O
+rated	O
+for	O
+quality	O
+by	O
+using	O
+predefined	O
+USPSTF	O
+criteria	O
+.	O
+	
+DATA	O
+SYNTHESIS	O
+:	O
+New	O
+evidence	O
+from	O
+1	O
+good	O
+-	O
+quality	O
+RCT	O
+","	O
+1	O
+good	O
+-	O
+quality	O
+meta	O
+-	O
+analysis	O
+","	O
+and	O
+2	O
+fair	O
+-	O
+quality	O
+subanalyses	O
+of	O
+RCTs	O
+demonstrates	O
+that	O
+aspirin	O
+use	O
+reduces	O
+the	O
+number	O
+of	O
+CVD	B-NP
+events	O
+in	O
+patients	O
+without	O
+known	O
+CVD	B-NP
+.	O
+	
+Men	O
+in	O
+these	O
+studies	O
+experienced	O
+fewer	O
+myocardial	B-NP
+infarctions	I-NP
+and	O
+women	O
+experienced	O
+fewer	O
+ischemic	O
+strokes	B-NP
+.	O
+	
+Aspirin	O
+does	O
+not	O
+seem	O
+to	O
+affect	O
+CVD	B-NP
+mortality	O
+or	O
+all	O
+-	O
+cause	O
+mortality	O
+in	O
+either	O
+men	O
+or	O
+women	O
+.	O
+	
+The	O
+use	O
+of	O
+aspirin	O
+for	O
+primary	O
+prevention	O
+increases	O
+the	O
+risk	O
+for	O
+major	O
+bleeding	B-NP
+events	O
+","	O
+primarily	O
+gastrointestinal	B-NP
+bleeding	I-NP
+events	O
+","	O
+in	O
+both	O
+men	O
+and	O
+women	O
+.	O
+	
+Men	O
+have	O
+an	O
+increased	O
+risk	O
+for	O
+hemorrhagic	B-NP
+strokes	I-NP
+with	O
+aspirin	O
+use	O
+.	O
+	
+A	O
+new	O
+RCT	O
+and	O
+meta	O
+-	O
+analysis	O
+suggest	O
+that	O
+the	O
+risk	O
+for	O
+hemorrhagic	B-NP
+strokes	I-NP
+in	O
+women	O
+is	O
+not	O
+statistically	O
+significantly	O
+increased	O
+.	O
+	
+LIMITATIONS	O
+:	O
+New	O
+evidence	O
+on	O
+aspirin	O
+for	O
+the	O
+primary	O
+prevention	O
+of	O
+CVD	B-NP
+is	O
+limited	O
+.	O
+	
+The	O
+dose	O
+of	O
+aspirin	O
+used	O
+in	O
+the	O
+RCTs	O
+varied	O
+","	O
+which	O
+prevented	O
+the	O
+estimation	O
+of	O
+the	O
+most	O
+appropriate	O
+dose	O
+for	O
+primary	O
+prevention	O
+.	O
+	
+Several	O
+of	O
+the	O
+RCTs	O
+were	O
+conducted	O
+within	O
+populations	O
+of	O
+health	O
+professionals	O
+","	O
+which	O
+potentially	O
+limits	O
+generalizability	O
+.	O
+	
+CONCLUSION	O
+:	O
+Aspirin	O
+reduces	O
+the	O
+risk	O
+for	O
+myocardial	B-NP
+infarction	I-NP
+in	O
+men	O
+and	O
+strokes	B-NP
+in	O
+women	O
+.	O
+	
+Aspirin	O
+use	O
+increases	O
+the	O
+risk	O
+for	O
+serious	O
+bleeding	B-NP
+events	O
+.	O
+	
+Reducing	O
+harm	O
+associated	O
+with	O
+anticoagulation	O
+:	O
+practical	O
+considerations	O
+of	O
+argatroban	O
+therapy	O
+in	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+.	O
+	
+Argatroban	O
+is	O
+a	O
+hepatically	O
+metabolized	O
+","	O
+direct	O
+thrombin	O
+inhibitor	O
+used	O
+for	O
+prophylaxis	O
+or	O
+treatment	O
+of	O
+thrombosis	B-NP
+in	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+(	O
+HIT	B-NP
+)	O
+and	O
+for	O
+patients	O
+with	O
+or	O
+at	O
+risk	O
+of	O
+HIT	B-NP
+undergoing	O
+percutaneous	O
+coronary	O
+intervention	O
+(	O
+PCI	O
+)	O
+.	O
+	
+The	O
+objective	O
+of	O
+this	O
+review	O
+is	O
+to	O
+summarize	O
+practical	O
+considerations	O
+of	O
+argatroban	O
+therapy	O
+in	O
+HIT	B-NP
+.	O
+	
+The	O
+US	O
+FDA	O
+-	O
+recommended	O
+argatroban	O
+dose	O
+in	O
+HIT	B-NP
+is	O
+2	O
+microg	O
+/	O
+kg	O
+/	O
+min	O
+(	O
+reduced	O
+in	O
+patients	O
+with	O
+hepatic	B-NP
+impairment	I-NP
+and	O
+in	O
+paediatric	O
+patients	O
+)	O
+","	O
+adjusted	O
+to	O
+achieve	O
+activated	O
+partial	O
+thromboplastin	O
+times	O
+(	O
+aPTTs	O
+)	O
+1	O
+.	O
+5	O
+-	O
+3	O
+times	O
+baseline	O
+(	O
+not	O
+>	O
+100	O
+seconds	O
+)	O
+.	O
+	
+Contemporary	O
+experiences	O
+indicate	O
+that	O
+reduced	O
+doses	O
+are	O
+also	O
+needed	O
+in	O
+patients	O
+with	O
+conditions	O
+associated	O
+with	O
+hepatic	O
+hypoperfusion	O
+","	O
+e	O
+.	O
+g	O
+.	O
+heart	B-NP
+failure	I-NP
+","	O
+yet	O
+are	O
+unnecessary	O
+for	O
+renal	B-NP
+dysfunction	I-NP
+","	O
+adult	O
+age	O
+","	O
+sex	O
+","	O
+race	O
+/	O
+ethnicity	O
+or	O
+obesity	B-NP
+.	O
+	
+Argatroban	O
+0	O
+.	O
+5	O
+-	O
+1	O
+.	O
+2	O
+microg	O
+/	O
+kg	O
+/	O
+min	O
+typically	O
+supports	O
+therapeutic	O
+aPTTs	O
+.	O
+	
+The	O
+FDA	O
+-	O
+recommended	O
+dose	O
+during	O
+PCI	O
+is	O
+25	O
+microg	O
+/	O
+kg	O
+/	O
+min	O
+(	O
+350	O
+microg	O
+/	O
+kg	O
+initial	O
+bolus	O
+)	O
+","	O
+adjusted	O
+to	O
+achieve	O
+activated	O
+clotting	O
+times	O
+(	O
+ACTs	O
+)	O
+of	O
+300	O
+-	O
+450	O
+sec	O
+.	O
+	
+For	O
+PCI	O
+","	O
+argatroban	O
+has	O
+not	O
+been	O
+investigated	O
+in	O
+hepatically	O
+impaired	O
+patients	O
+;	O
+dose	O
+adjustment	O
+is	O
+unnecessary	O
+for	O
+adult	O
+age	O
+","	O
+sex	O
+","	O
+race	O
+/	O
+ethnicity	O
+or	O
+obesity	B-NP
+","	O
+and	O
+lesser	O
+doses	O
+may	O
+be	O
+adequate	O
+with	O
+concurrent	O
+glycoprotein	O
+IIb	O
+/	O
+IIIa	O
+inhibition	O
+.	O
+	
+Argatroban	O
+prolongs	O
+the	O
+International	O
+Normalized	O
+Ratio	O
+","	O
+and	O
+published	O
+approaches	O
+for	O
+monitoring	O
+the	O
+argatroban	O
+-	O
+to	O
+-	O
+warfarin	O
+transition	O
+should	O
+be	O
+followed	O
+.	O
+	
+Major	O
+bleeding	B-NP
+with	O
+argatroban	O
+is	O
+0	O
+-	O
+10	O
+%	O
+in	O
+the	O
+non	O
+-	O
+interventional	O
+setting	O
+and	O
+0	O
+-	O
+5	O
+.	O
+8	O
+%	O
+periprocedurally	O
+.	O
+	
+Argatroban	O
+has	O
+no	O
+specific	O
+antidote	O
+","	O
+and	O
+if	O
+excessive	O
+anticoagulation	O
+occurs	O
+","	O
+argatroban	O
+infusion	O
+should	O
+be	O
+stopped	O
+or	O
+reduced	O
+.	O
+	
+Improved	O
+familiarity	O
+of	O
+healthcare	O
+professionals	O
+with	O
+argatroban	O
+therapy	O
+in	O
+HIT	B-NP
+","	O
+including	O
+in	O
+special	O
+populations	O
+and	O
+during	O
+PCI	O
+","	O
+may	O
+facilitate	O
+reduction	O
+of	O
+harm	O
+associated	O
+with	O
+HIT	B-NP
+(	O
+e	O
+.	O
+g	O
+.	O
+fewer	O
+thromboses	O
+)	O
+or	O
+its	O
+treatment	O
+(	O
+e	O
+.	O
+g	O
+.	O
+fewer	O
+argatroban	O
+medication	O
+errors	O
+)	O
+.	O
+	
+Rhabdomyolysis	B-NP
+and	O
+brain	O
+ischemic	B-NP
+stroke	I-NP
+in	O
+a	O
+heroin	O
+-	O
+dependent	O
+male	O
+under	O
+methadone	O
+maintenance	O
+therapy	O
+.	O
+	
+OBJECTIVE	O
+:	O
+There	O
+are	O
+several	O
+complications	O
+associated	O
+with	O
+heroin	B-NP
+abuse	I-NP
+","	O
+some	O
+of	O
+which	O
+are	O
+life	O
+-	O
+threatening	O
+.	O
+	
+Methadone	O
+may	O
+aggravate	O
+this	O
+problem	O
+.	O
+	
+METHOD	O
+:	O
+A	O
+clinical	O
+case	O
+description	O
+.	O
+	
+RESULTS	O
+:	O
+A	O
+33	O
+-	O
+year	O
+-	O
+old	O
+man	O
+presented	O
+with	O
+rhabdomyolysis	B-NP
+and	O
+cerebral	O
+ischemic	B-NP
+stroke	I-NP
+after	O
+intravenous	O
+heroin	O
+.	O
+	
+He	O
+had	O
+used	O
+heroin	O
+since	O
+age	O
+20	O
+","	O
+and	O
+had	O
+used	O
+150	O
+mg	O
+methadone	O
+daily	O
+for	O
+6	O
+months	O
+.	O
+	
+He	O
+was	O
+found	O
+unconsciousness	B-NP
+at	O
+home	O
+and	O
+was	O
+sent	O
+to	O
+our	O
+hospital	O
+.	O
+	
+In	O
+the	O
+ER	O
+","	O
+his	O
+opiate	O
+level	O
+was	O
+4497	O
+ng	O
+/	O
+ml	O
+.	O
+	
+In	O
+the	O
+ICU	O
+","	O
+we	O
+found	O
+rhabdomyolysis	B-NP
+","	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+and	O
+acute	O
+respiratory	B-NP
+failure	I-NP
+.	O
+	
+After	O
+transfer	O
+to	O
+an	O
+internal	O
+ward	O
+","	O
+we	O
+noted	O
+aphasia	B-NP
+and	O
+weakness	B-NP
+of	O
+his	O
+left	O
+limbs	O
+.	O
+	
+After	O
+MRI	O
+","	O
+we	O
+found	O
+cerebral	B-NP
+ischemic	I-NP
+infarction	I-NP
+.	O
+	
+CONCLUSION	O
+:	O
+Those	O
+using	O
+methadone	O
+and	O
+heroin	O
+simultaneously	O
+may	O
+increase	O
+risk	O
+of	O
+rhabdomyolysis	B-NP
+and	O
+ischemic	B-NP
+stroke	I-NP
+.	O
+	
+Patients	O
+under	O
+methadone	O
+maintenance	O
+therapy	O
+should	O
+be	O
+warned	O
+regarding	O
+these	O
+serious	O
+adverse	O
+events	O
+.	O
+	
+Hypotheses	O
+of	O
+heroin	O
+-	O
+related	O
+rhabdomyolysis	B-NP
+and	O
+stroke	B-NP
+in	O
+heroin	O
+abusers	O
+are	O
+discussed	O
+.	O
+	
+Increased	O
+vulnerability	O
+to	O
+6	O
+-	O
+hydroxydopamine	O
+lesion	O
+and	O
+reduced	O
+development	O
+of	O
+dyskinesias	B-NP
+in	O
+mice	O
+lacking	O
+CB1	O
+cannabinoid	O
+receptors	O
+.	O
+	
+Motor	O
+impairment	O
+","	O
+dopamine	O
+(	O
+DA	O
+)	O
+neuronal	O
+activity	O
+and	O
+proenkephalin	O
+(	O
+PENK	O
+)	O
+gene	O
+expression	O
+in	O
+the	O
+caudate	O
+-	O
+putamen	O
+(	O
+CPu	O
+)	O
+were	O
+measured	O
+in	O
+6	O
+-	O
+OHDA	O
+-	O
+lesioned	O
+and	O
+treated	O
+(	O
+L	O
+-	O
+DOPA	O
++	O
+benserazide	O
+)	O
+CB1	O
+KO	O
+and	O
+WT	O
+mice	O
+.	O
+	
+A	O
+lesion	O
+induced	O
+by	O
+6	O
+-	O
+OHDA	O
+produced	O
+more	O
+severe	O
+motor	O
+deterioration	O
+in	O
+CB1	O
+KO	O
+mice	O
+accompanied	O
+by	O
+more	O
+loss	O
+of	O
+DA	O
+neurons	O
+and	O
+increased	O
+PENK	O
+gene	O
+expression	O
+in	O
+the	O
+CPu	O
+.	O
+	
+Oxidative	O
+/	O
+nitrosative	O
+and	O
+neuroinflammatory	O
+parameters	O
+were	O
+estimated	O
+in	O
+the	O
+CPu	O
+and	O
+cingulate	O
+cortex	O
+(	O
+Cg	O
+)	O
+.	O
+	
+CB1	O
+KO	O
+mice	O
+exhibited	O
+higher	O
+MDA	O
+levels	O
+and	O
+iNOS	O
+protein	O
+expression	O
+in	O
+the	O
+CPu	O
+and	O
+Cg	O
+compared	O
+to	O
+WT	O
+mice	O
+.	O
+	
+Treatment	O
+with	O
+L	O
+-	O
+DOPA	O
++	O
+benserazide	O
+(	O
+12	O
+weeks	O
+)	O
+resulted	O
+in	O
+less	O
+severe	O
+dyskinesias	B-NP
+in	O
+CB1	O
+KO	O
+than	O
+in	O
+WT	O
+mice	O
+.	O
+	
+The	O
+results	O
+revealed	O
+that	O
+the	O
+lack	O
+of	O
+cannabinoid	O
+CB1	O
+receptors	O
+increased	O
+the	O
+severity	O
+of	O
+motor	O
+impairment	O
+and	O
+DA	O
+lesion	O
+","	O
+and	O
+reduced	O
+L	O
+-	O
+DOPA	O
+-	O
+induced	O
+dyskinesias	B-NP
+.	O
+	
+These	O
+results	O
+suggest	O
+that	O
+activation	O
+of	O
+CB1	O
+receptors	O
+offers	O
+neuroprotection	O
+against	O
+dopaminergic	O
+lesion	O
+and	O
+the	O
+development	O
+of	O
+L	O
+-	O
+DOPA	O
+-	O
+induced	O
+dyskinesias	B-NP
+.	O
+	
+Hepatocellular	O
+oxidant	O
+stress	O
+following	O
+intestinal	O
+ischemia	B-NP
+-	O
+reperfusion	B-NP
+injury	I-NP
+.	O
+	
+Reperfusion	O
+of	O
+ischemic	B-NP
+intestine	O
+results	O
+in	O
+acute	O
+liver	B-NP
+dysfunction	I-NP
+characterized	O
+by	O
+hepatocellular	O
+enzyme	O
+release	O
+into	O
+plasma	O
+","	O
+reduction	O
+in	O
+bile	O
+flow	O
+rate	O
+","	O
+and	O
+neutrophil	O
+sequestration	O
+within	O
+the	O
+liver	O
+.	O
+	
+The	O
+pathophysiology	O
+underlying	O
+this	O
+acute	O
+hepatic	B-NP
+injury	I-NP
+is	O
+unknown	O
+.	O
+	
+This	O
+study	O
+was	O
+undertaken	O
+to	O
+determine	O
+whether	O
+oxidants	O
+are	O
+associated	O
+with	O
+the	O
+hepatic	B-NP
+injury	I-NP
+and	O
+to	O
+determine	O
+the	O
+relative	O
+value	O
+of	O
+several	O
+indirect	O
+methods	O
+of	O
+assessing	O
+oxidant	O
+exposure	O
+in	O
+vivo	O
+.	O
+	
+Rats	O
+were	O
+subjected	O
+to	O
+a	O
+standardized	O
+intestinal	O
+ischemia	B-NP
+-	O
+reperfusion	B-NP
+injury	I-NP
+.	O
+	
+Hepatic	O
+tissue	O
+was	O
+assayed	O
+for	O
+lipid	O
+peroxidation	O
+products	O
+and	O
+oxidized	O
+and	O
+reduced	O
+glutathione	O
+.	O
+	
+There	O
+was	O
+no	O
+change	O
+in	O
+hepatic	O
+tissue	O
+total	O
+glutathione	O
+following	O
+intestinal	O
+ischemia	B-NP
+-	O
+reperfusion	B-NP
+injury	I-NP
+.	O
+	
+Oxidized	O
+glutathione	O
+(	O
+GSSG	O
+)	O
+increased	O
+significantly	O
+following	O
+30	O
+and	O
+60	O
+min	O
+of	O
+reperfusion	O
+.	O
+	
+There	O
+was	O
+no	O
+increase	O
+in	O
+any	O
+of	O
+the	O
+products	O
+of	O
+lipid	O
+peroxidation	O
+associated	O
+with	O
+this	O
+injury	O
+.	O
+	
+An	O
+increase	O
+in	O
+GSSG	O
+within	O
+hepatic	O
+tissue	O
+during	O
+intestinal	O
+reperfusion	O
+suggests	O
+exposure	O
+of	O
+hepatocytes	O
+to	O
+an	O
+oxidant	O
+stress	O
+.	O
+	
+The	O
+lack	O
+of	O
+a	O
+significant	O
+increase	O
+in	O
+products	O
+of	O
+lipid	O
+peroxidation	O
+suggests	O
+that	O
+the	O
+oxidant	O
+stress	O
+is	O
+of	O
+insufficient	O
+magnitude	O
+to	O
+result	O
+in	O
+irreversible	O
+injury	O
+to	O
+hepatocyte	O
+cell	O
+membranes	O
+.	O
+	
+These	O
+data	O
+also	O
+suggest	O
+that	O
+the	O
+measurement	O
+of	O
+tissue	O
+GSSG	O
+may	O
+be	O
+a	O
+more	O
+sensitive	O
+indicator	O
+of	O
+oxidant	O
+stress	O
+than	O
+measurement	O
+of	O
+products	O
+of	O
+lipid	O
+peroxidation	O
+.	O
+	
+Animal	O
+model	O
+of	O
+mania	B-NP
+induced	O
+by	O
+ouabain	O
+:	O
+Evidence	O
+of	O
+oxidative	O
+stress	O
+in	O
+submitochondrial	O
+particles	O
+of	O
+the	O
+rat	O
+brain	O
+.	O
+	
+The	O
+intracerebroventricular	O
+(	O
+ICV	O
+)	O
+administration	O
+of	O
+ouabain	O
+(	O
+a	O
+Na	O
+(	O
++	O
+)	O
+/	O
+K	O
+(	O
++	O
+)	O
+-	O
+ATPase	O
+inhibitor	O
+)	O
+in	O
+rats	O
+has	O
+been	O
+suggested	O
+to	O
+mimic	O
+some	O
+symptoms	O
+of	O
+human	O
+bipolar	B-NP
+mania	I-NP
+.	O
+	
+Clinical	O
+studies	O
+have	O
+shown	O
+that	O
+bipolar	B-NP
+disorder	I-NP
+may	O
+be	O
+related	O
+to	O
+mitochondrial	B-NP
+dysfunction	I-NP
+.	O
+	
+Herein	O
+","	O
+we	O
+investigated	O
+the	O
+behavioral	O
+and	O
+biochemical	O
+effects	O
+induced	O
+by	O
+the	O
+ICV	O
+administration	O
+of	O
+ouabain	O
+in	O
+rats	O
+.	O
+	
+To	O
+achieve	O
+this	O
+aim	O
+","	O
+the	O
+effects	O
+of	O
+ouabain	O
+injection	O
+immediately	O
+after	O
+and	O
+7	O
+days	O
+following	O
+a	O
+single	O
+ICV	O
+administration	O
+(	O
+at	O
+concentrations	O
+of	O
+10	O
+(	O
+-	O
+2	O
+)	O
+and	O
+10	O
+(	O
+-	O
+3	O
+)	O
+M	O
+)	O
+on	O
+locomotion	O
+was	O
+measured	O
+using	O
+the	O
+open	O
+-	O
+field	O
+test	O
+.	O
+	
+Additionally	O
+","	O
+thiobarbituric	O
+acid	O
+reactive	O
+substances	O
+(	O
+TBARSs	O
+)	O
+and	O
+superoxide	O
+production	O
+were	O
+measured	O
+in	O
+submitochondrial	O
+particles	O
+of	O
+the	O
+prefrontal	O
+cortex	O
+","	O
+hippocampus	O
+","	O
+striatum	O
+and	O
+amygdala	O
+.	O
+	
+Our	O
+findings	O
+demonstrated	O
+that	O
+ouabain	O
+at	O
+10	O
+(	O
+-	O
+2	O
+)	O
+and	O
+10	O
+(	O
+-	O
+3	O
+)	O
+M	O
+induced	O
+hyperlocomotion	B-NP
+in	O
+rats	O
+","	O
+and	O
+this	O
+response	O
+remained	O
+up	O
+to	O
+7	O
+days	O
+following	O
+a	O
+single	O
+ICV	O
+injection	O
+.	O
+	
+In	O
+addition	O
+","	O
+we	O
+observed	O
+that	O
+the	O
+persistent	O
+increase	O
+in	O
+the	O
+rat	O
+spontaneous	O
+locomotion	O
+is	O
+associated	O
+with	O
+increased	O
+TBARS	O
+levels	O
+and	O
+superoxide	O
+generation	O
+in	O
+submitochondrial	O
+particles	O
+in	O
+the	O
+prefrontal	O
+cortex	O
+","	O
+striatum	O
+and	O
+amygdala	O
+.	O
+	
+In	O
+conclusion	O
+","	O
+ouabain	O
+-	O
+induced	O
+mania	B-NP
+-	O
+like	O
+behavior	O
+may	O
+provide	O
+a	O
+useful	O
+animal	O
+model	O
+to	O
+test	O
+the	O
+hypothesis	O
+of	O
+the	O
+involvement	O
+of	O
+oxidative	O
+stress	O
+in	O
+bipolar	B-NP
+disorder	I-NP
+.	O
+	
+Intraoperative	O
+dialysis	O
+during	O
+liver	O
+transplantation	O
+with	O
+citrate	O
+dialysate	O
+.	O
+	
+Liver	O
+transplantation	O
+for	O
+acutely	O
+ill	O
+patients	O
+with	O
+fulminant	B-NP
+liver	I-NP
+failure	I-NP
+carries	O
+high	O
+intraoperative	O
+and	O
+immediate	O
+postoperative	O
+risks	O
+.	O
+	
+These	O
+are	O
+increased	O
+with	O
+the	O
+presence	O
+of	O
+concomitant	O
+acute	B-NP
+kidney	I-NP
+injury	I-NP
+(	O
+AKI	B-NP
+)	O
+and	O
+intraoperative	O
+dialysis	O
+is	O
+sometimes	O
+required	O
+to	O
+allow	O
+the	O
+transplant	O
+to	O
+proceed	O
+.	O
+	
+The	O
+derangements	O
+in	O
+the	O
+procoagulant	O
+and	O
+anticoagulant	O
+pathways	O
+during	O
+fulminant	B-NP
+liver	I-NP
+failure	I-NP
+can	O
+lead	O
+to	O
+difficulties	O
+with	O
+anticoagulation	O
+during	O
+dialysis	O
+","	O
+especially	O
+when	O
+continued	O
+in	O
+the	O
+operating	O
+room	O
+.	O
+	
+Systemic	O
+anticoagulation	O
+is	O
+unsafe	O
+and	O
+regional	O
+citrate	O
+anticoagulation	O
+in	O
+the	O
+absence	O
+of	O
+a	O
+functional	O
+liver	O
+carries	O
+the	O
+risk	O
+of	O
+citrate	O
+toxicity	B-NP
+.	O
+	
+Citrate	O
+dialysate	O
+","	O
+a	O
+new	O
+dialysate	O
+with	O
+citric	O
+acid	O
+can	O
+be	O
+used	O
+for	O
+anticoagulation	O
+in	O
+patients	O
+who	O
+cannot	O
+tolerate	O
+heparin	O
+or	O
+regional	O
+citrate	O
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+a	O
+40	O
+-	O
+year	O
+-	O
+old	O
+female	O
+with	O
+acetaminophen	O
+-	O
+induced	O
+fulminant	B-NP
+liver	I-NP
+failure	I-NP
+with	O
+associated	O
+AKI	B-NP
+who	O
+underwent	O
+intraoperative	O
+dialytic	O
+support	O
+during	O
+liver	O
+transplantation	O
+anticoagulated	O
+with	O
+citrate	O
+dialysate	O
+during	O
+the	O
+entire	O
+procedure	O
+.	O
+	
+The	O
+patient	O
+tolerated	O
+the	O
+procedure	O
+well	O
+without	O
+any	O
+signs	O
+of	O
+citrate	O
+toxicity	B-NP
+and	O
+maintained	O
+adequate	O
+anticoagulation	O
+for	O
+patency	O
+of	O
+the	O
+dialysis	O
+circuit	O
+.	O
+	
+Citrate	O
+dialysate	O
+is	O
+a	O
+safe	O
+alternative	O
+for	O
+intradialytic	O
+support	O
+of	O
+liver	O
+transplantation	O
+in	O
+fulminant	B-NP
+liver	I-NP
+failure	I-NP
+.	O
+	
+Delirium	B-NP
+in	O
+a	O
+patient	O
+with	O
+toxic	O
+flecainide	O
+plasma	O
+concentrations	O
+:	O
+the	O
+role	O
+of	O
+a	O
+pharmacokinetic	O
+drug	O
+interaction	O
+with	O
+paroxetine	O
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+describe	O
+a	O
+case	O
+of	O
+flecainide	O
+-	O
+induced	O
+delirium	B-NP
+associated	O
+with	O
+a	O
+pharmacokinetic	O
+drug	O
+interaction	O
+with	O
+paroxetine	O
+.	O
+	
+CASE	O
+SUMMARY	O
+:	O
+A	O
+69	O
+-	O
+year	O
+-	O
+old	O
+white	O
+female	O
+presented	O
+to	O
+the	O
+emergency	O
+department	O
+with	O
+a	O
+history	O
+of	O
+confusion	B-NP
+and	O
+paranoia	B-NP
+over	O
+the	O
+past	O
+several	O
+days	O
+.	O
+	
+On	O
+admission	O
+the	O
+patient	O
+was	O
+taking	O
+carvedilol	O
+12	O
+mg	O
+twice	O
+daily	O
+","	O
+warfarin	O
+2	O
+mg	O
+/	O
+day	O
+","	O
+folic	O
+acid	O
+1	O
+mg	O
+/	O
+day	O
+","	O
+levothyroxine	O
+100	O
+microg	O
+/	O
+day	O
+","	O
+pantoprazole	O
+40	O
+mg	O
+/	O
+day	O
+","	O
+paroxetine	O
+40	O
+mg	O
+/	O
+day	O
+","	O
+and	O
+flecainide	O
+100	O
+mg	O
+twice	O
+daily	O
+.	O
+	
+Flecainide	O
+had	O
+been	O
+started	O
+2	O
+weeks	O
+prior	O
+for	O
+atrial	B-NP
+fibrillation	I-NP
+.	O
+	
+Laboratory	O
+test	O
+findings	O
+on	O
+admission	O
+were	O
+notable	O
+only	O
+for	O
+a	O
+flecainide	O
+plasma	O
+concentration	O
+of	O
+1360	O
+microg	O
+/	O
+L	O
+(	O
+reference	O
+range	O
+200	O
+-	O
+1000	O
+)	O
+.	O
+	
+A	O
+metabolic	O
+drug	O
+interaction	O
+between	O
+flecainide	O
+and	O
+paroxetine	O
+","	O
+which	O
+the	O
+patient	O
+had	O
+been	O
+taking	O
+for	O
+more	O
+than	O
+5	O
+years	O
+","	O
+was	O
+considered	O
+.	O
+	
+Paroxetine	O
+was	O
+discontinued	O
+and	O
+the	O
+dose	O
+of	O
+flecainide	O
+was	O
+reduced	O
+to	O
+50	O
+mg	O
+twice	O
+daily	O
+.	O
+	
+Her	O
+delirium	B-NP
+resolved	O
+3	O
+days	O
+later	O
+.	O
+	
+DISCUSSION	O
+:	O
+Flecainide	O
+and	O
+pharmacologically	O
+similar	O
+agents	O
+that	O
+interact	O
+with	O
+sodium	O
+channels	O
+may	O
+cause	O
+delirium	B-NP
+in	O
+susceptible	O
+patients	O
+.	O
+	
+A	O
+MEDLINE	O
+search	O
+(	O
+1966	O
+-	O
+January	O
+2009	O
+)	O
+revealed	O
+one	O
+in	O
+vivo	O
+pharmacokinetic	O
+study	O
+on	O
+the	O
+interaction	O
+between	O
+flecainide	O
+","	O
+a	O
+CYP2D6	O
+substrate	O
+","	O
+and	O
+paroxetine	O
+","	O
+a	O
+CYP2D6	O
+inhibitor	O
+","	O
+as	O
+well	O
+as	O
+3	O
+case	O
+reports	O
+of	O
+flecainide	O
+-	O
+induced	O
+delirium	B-NP
+.	O
+	
+According	O
+to	O
+the	O
+Naranjo	O
+probability	O
+scale	O
+","	O
+flecainide	O
+was	O
+the	O
+probable	O
+cause	O
+of	O
+the	O
+patient	O
+'	O
+s	O
+delirium	B-NP
+;	O
+the	O
+Horn	O
+Drug	O
+Interaction	O
+Probability	O
+Scale	O
+indicates	O
+a	O
+possible	O
+pharmacokinetic	O
+drug	O
+interaction	O
+between	O
+flecainide	O
+and	O
+paroxetine	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Supratherapeutic	O
+flecainide	O
+plasma	O
+concentrations	O
+may	O
+cause	O
+delirium	B-NP
+.	O
+	
+Because	O
+toxicity	B-NP
+may	O
+occur	O
+when	O
+flecainide	O
+is	O
+prescribed	O
+with	O
+paroxetine	O
+and	O
+other	O
+potent	O
+CYP2D6	O
+inhibitors	O
+","	O
+flecainide	O
+plasma	O
+concentrations	O
+should	O
+be	O
+monitored	O
+closely	O
+with	O
+commencement	O
+of	O
+CYP2D6	O
+inhibitors	O
+.	O
+	
+Efficacy	O
+of	O
+everolimus	O
+(	O
+RAD001	O
+)	O
+in	O
+patients	O
+with	O
+advanced	O
+NSCLC	B-NP
+previously	O
+treated	O
+with	O
+chemotherapy	O
+alone	O
+or	O
+with	O
+chemotherapy	O
+and	O
+EGFR	O
+inhibitors	O
+.	O
+	
+BACKGROUND	O
+:	O
+Treatment	O
+options	O
+are	O
+scarce	O
+in	O
+pretreated	O
+advanced	O
+non	B-NP
+-	I-NP
+small	I-NP
+-	I-NP
+cell	I-NP
+lung	I-NP
+cancer	I-NP
+(	O
+NSCLC	B-NP
+)	O
+patients	O
+.	O
+	
+RAD001	O
+","	O
+an	O
+oral	O
+inhibitor	O
+of	O
+the	O
+mammalian	O
+target	O
+of	O
+rapamycin	O
+(	O
+mTOR	O
+)	O
+","	O
+has	O
+shown	O
+phase	O
+I	O
+efficacy	O
+in	O
+NSCLC	B-NP
+.	O
+	
+METHODS	O
+:	O
+Stage	O
+IIIb	O
+or	O
+IV	O
+NSCLC	B-NP
+patients	O
+","	O
+with	O
+two	O
+or	O
+fewer	O
+prior	O
+chemotherapy	O
+regimens	O
+","	O
+one	O
+platinum	O
+based	O
+(	O
+stratum	O
+1	O
+)	O
+or	O
+both	O
+chemotherapy	O
+and	O
+epidermal	O
+growth	O
+factor	O
+receptor	O
+tyrosine	O
+kinase	O
+inhibitors	O
+(	O
+stratum	O
+2	O
+)	O
+","	O
+received	O
+RAD001	O
+10	O
+mg	O
+/	O
+day	O
+until	O
+progression	O
+or	O
+unacceptable	O
+toxicity	B-NP
+.	O
+	
+Primary	O
+objective	O
+was	O
+overall	O
+response	O
+rate	O
+(	O
+ORR	O
+)	O
+.	O
+	
+Analyses	O
+of	O
+markers	O
+associated	O
+with	O
+the	O
+mTOR	O
+pathway	O
+were	O
+carried	O
+out	O
+on	O
+archival	O
+tumor	B-NP
+from	O
+a	O
+subgroup	O
+using	O
+immunohistochemistry	O
+(	O
+IHC	O
+)	O
+and	O
+direct	O
+mutation	O
+sequencing	O
+.	O
+	
+RESULTS	O
+:	O
+Eighty	O
+-	O
+five	O
+patients	O
+were	O
+enrolled	O
+","	O
+42	O
+in	O
+stratum	O
+1	O
+and	O
+43	O
+in	O
+stratum	O
+.	O
+	
+ORR	O
+was	O
+4	O
+.	O
+7	O
+%	O
+(	O
+7	O
+.	O
+1	O
+%	O
+stratum	O
+1	O
+;	O
+2	O
+.	O
+3	O
+%	O
+stratum	O
+2	O
+)	O
+.	O
+	
+Overall	O
+disease	O
+control	O
+rate	O
+was	O
+47	O
+.	O
+1	O
+%	O
+.	O
+	
+Median	O
+progression	O
+-	O
+free	O
+survivals	O
+(	O
+PFSs	O
+)	O
+were	O
+2	O
+.	O
+6	O
+(	O
+stratum	O
+1	O
+)	O
+and	O
+2	O
+.	O
+7	O
+months	O
+(	O
+stratum	O
+2	O
+)	O
+.	O
+	
+Common	O
+>	O
+or	O
+=	O
+grade	O
+3	O
+events	O
+were	O
+fatigue	B-NP
+","	O
+dyspnea	B-NP
+","	O
+stomatitis	B-NP
+","	O
+anemia	B-NP
+","	O
+and	O
+thrombocytopenia	B-NP
+.	O
+	
+Pneumonitis	B-NP
+","	O
+probably	O
+or	O
+possibly	O
+related	O
+","	O
+mainly	O
+grade	O
+1	O
+/	O
+2	O
+","	O
+occurred	O
+in	O
+25	O
+%	O
+.	O
+	
+Cox	O
+regression	O
+analysis	O
+of	O
+IHC	O
+scores	O
+found	O
+that	O
+only	O
+phospho	O
+AKT	O
+(	O
+pAKT	O
+)	O
+was	O
+a	O
+significant	O
+independent	O
+predictor	O
+of	O
+worse	O
+PFS	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+RAD001	O
+10	O
+mg	O
+/	O
+day	O
+was	O
+well	O
+tolerated	O
+","	O
+showing	O
+modest	O
+clinical	O
+activity	O
+in	O
+pretreated	O
+NSCLC	B-NP
+.	O
+	
+Evaluation	O
+of	O
+RAD001	O
+plus	O
+standard	O
+therapy	O
+for	O
+metastatic	O
+NSCLC	B-NP
+continues	O
+.	O
+	
+Posttransplant	O
+anemia	B-NP
+:	O
+the	O
+role	O
+of	O
+sirolimus	O
+.	O
+	
+Posttransplant	O
+anemia	B-NP
+is	O
+a	O
+common	O
+problem	O
+that	O
+may	O
+hinder	O
+patients	O
+'	O
+quality	O
+of	O
+life	O
+.	O
+	
+It	O
+occurs	O
+in	O
+12	O
+to	O
+76	O
+%	O
+of	O
+patients	O
+","	O
+and	O
+is	O
+most	O
+common	O
+in	O
+the	O
+immediate	O
+posttransplant	O
+period	O
+.	O
+	
+A	O
+variety	O
+of	O
+factors	O
+have	O
+been	O
+identified	O
+that	O
+increase	O
+the	O
+risk	O
+of	O
+posttransplant	O
+anemia	B-NP
+","	O
+of	O
+which	O
+the	O
+level	O
+of	O
+renal	O
+function	O
+is	O
+most	O
+important	O
+.	O
+	
+Sirolimus	O
+","	O
+a	O
+mammalian	O
+target	O
+of	O
+rapamycin	O
+inhibitor	O
+","	O
+has	O
+been	O
+implicated	O
+as	O
+playing	O
+a	O
+special	O
+role	O
+in	O
+posttransplant	O
+anemia	B-NP
+.	O
+	
+This	O
+review	O
+considers	O
+anemia	B-NP
+associated	O
+with	O
+sirolimus	O
+","	O
+including	O
+its	O
+presentation	O
+","	O
+mechanisms	O
+","	O
+and	O
+management	O
+.	O
+	
+Coronary	O
+computerized	O
+tomography	O
+angiography	O
+for	O
+rapid	O
+discharge	O
+of	O
+low	O
+-	O
+risk	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B-NP
+pain	I-NP
+.	O
+	
+BACKGROUND	O
+:	O
+Most	O
+patients	O
+presenting	O
+to	O
+emergency	O
+departments	O
+(	O
+EDs	O
+)	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B-NP
+pain	I-NP
+are	O
+admitted	O
+for	O
+at	O
+least	O
+12	O
+hours	O
+and	O
+receive	O
+a	O
+"	O
+rule	O
+out	O
+acute	B
+coronary	I
+syndrome	I
+"	O
+protocol	O
+","	O
+often	O
+with	O
+noninvasive	O
+testing	O
+prior	O
+to	O
+discharge	O
+.	O
+	
+In	O
+patients	O
+without	O
+cocaine	O
+use	O
+","	O
+coronary	O
+computerized	O
+tomography	O
+angiography	O
+(	O
+CTA	O
+)	O
+has	O
+been	O
+shown	O
+to	O
+be	O
+useful	O
+for	O
+identifying	O
+a	O
+group	O
+of	O
+patients	O
+at	O
+low	O
+risk	O
+for	O
+cardiac	O
+events	O
+who	O
+can	O
+be	O
+safely	O
+discharged	O
+.	O
+	
+It	O
+is	O
+unclear	O
+whether	O
+a	O
+coronary	O
+CTA	O
+strategy	O
+would	O
+be	O
+efficacious	O
+in	O
+cocaine	O
+-	O
+associated	O
+chest	B-NP
+pain	I-NP
+","	O
+as	O
+coronary	B-NP
+vasospasm	I-NP
+may	O
+account	O
+for	O
+some	O
+of	O
+the	O
+ischemia	B-NP
+.	O
+	
+We	O
+studied	O
+whether	O
+a	O
+negative	O
+coronary	O
+CTA	O
+in	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B-NP
+pain	I-NP
+could	O
+identify	O
+a	O
+subset	O
+safe	O
+for	O
+discharge	O
+.	O
+	
+METHODS	O
+:	O
+We	O
+prospectively	O
+evaluated	O
+the	O
+safety	O
+of	O
+coronary	O
+CTA	O
+for	O
+low	O
+-	O
+risk	O
+patients	O
+who	O
+presented	O
+to	O
+the	O
+ED	O
+with	O
+cocaineassociated	O
+chest	B-NP
+pain	I-NP
+(	O
+self	O
+-	O
+reported	O
+or	O
+positive	O
+urine	O
+test	O
+)	O
+.	O
+	
+Consecutive	O
+patients	O
+received	O
+either	O
+immediate	O
+coronary	O
+CTA	O
+in	O
+the	O
+ED	O
+(	O
+without	O
+serial	O
+markers	O
+)	O
+or	O
+underwent	O
+coronary	O
+CTA	O
+after	O
+a	O
+brief	O
+observation	O
+period	O
+with	O
+serial	O
+cardiac	O
+marker	O
+measurements	O
+.	O
+	
+Patients	O
+with	O
+negative	O
+coronary	O
+CTA	O
+(	O
+maximal	O
+stenosis	B-NP
+less	O
+than	O
+50	O
+%	O
+)	O
+were	O
+discharged	O
+.	O
+	
+The	O
+main	O
+outcome	O
+was	O
+30	O
+-	O
+day	O
+cardiovascular	O
+death	O
+or	O
+myocardial	B-NP
+infarction	I-NP
+.	O
+	
+RESULTS	O
+:	O
+A	O
+total	O
+of	O
+59	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+chest	B-NP
+pain	I-NP
+were	O
+evaluated	O
+.	O
+	
+Patients	O
+had	O
+a	O
+mean	O
+age	O
+of	O
+45	O
+.	O
+6	O
++	O
+/	O
+-	O
+6	O
+.	O
+6	O
+yrs	O
+and	O
+were	O
+86	O
+%	O
+black	O
+","	O
+66	O
+%	O
+male	O
+.	O
+	
+Seventy	O
+-	O
+nine	O
+percent	O
+had	O
+a	O
+normal	O
+or	O
+nonspecific	O
+ECG	O
+and	O
+85	O
+%	O
+had	O
+a	O
+TIMI	O
+score	O
+<	O
+2	O
+.	O
+	
+Twenty	O
+patients	O
+received	O
+coronary	O
+CTA	O
+immediately	O
+in	O
+the	O
+ED	O
+","	O
+18	O
+of	O
+whom	O
+were	O
+discharged	O
+following	O
+CTA	O
+(	O
+90	O
+%	O
+)	O
+.	O
+	
+Thirty	O
+-	O
+nine	O
+received	O
+coronary	O
+CTA	O
+after	O
+a	O
+brief	O
+observation	O
+period	O
+","	O
+with	O
+37	O
+discharged	O
+home	O
+following	O
+CTA	O
+(	O
+95	O
+%	O
+)	O
+.	O
+	
+Six	O
+patients	O
+had	O
+coronary	B-NP
+stenosis	I-NP
+>	O
+or	O
+=	O
+50	O
+%	O
+.	O
+	
+During	O
+the	O
+30	O
+-	O
+day	O
+follow	O
+-	O
+up	O
+period	O
+","	O
+no	O
+patients	O
+died	O
+of	O
+a	O
+cardiovascular	O
+event	O
+(	O
+0	O
+%	O
+;	O
+95	O
+%	O
+CI	O
+","	O
+0	O
+-	O
+6	O
+.	O
+1	O
+%	O
+)	O
+and	O
+no	O
+patient	O
+sustained	O
+a	O
+nonfatal	O
+myocardial	B-NP
+infarction	I-NP
+(	O
+0	O
+%	O
+;	O
+95	O
+%	O
+CI	O
+","	O
+0	O
+-	O
+6	O
+.	O
+1	O
+%	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Although	O
+cocaine	O
+-	O
+associated	O
+myocardial	B-NP
+ischemia	I-NP
+can	O
+result	O
+from	O
+coronary	O
+vasoconstriction	O
+","	O
+patients	O
+with	O
+cocaine	O
+associated	O
+chest	B-NP
+pain	I-NP
+","	O
+a	O
+non	O
+-	O
+ischemic	B-NP
+ECG	O
+","	O
+and	O
+a	O
+TIMI	O
+risk	O
+score	O
+<	O
+2	O
+may	O
+be	O
+safely	O
+discharged	O
+from	O
+the	O
+ED	O
+after	O
+a	O
+negative	O
+coronary	O
+CTA	O
+with	O
+a	O
+low	O
+risk	O
+of	O
+30	O
+-	O
+day	O
+adverse	O
+events	O
+.	O
+	
+Bilateral	O
+haemorrhagic	B-NP
+infarction	I-NP
+of	I-NP
+the	I-NP
+globus	I-NP
+pallidus	I-NP
+after	O
+cocaine	O
+and	O
+alcohol	O
+intoxication	O
+.	O
+	
+Cocaine	O
+is	O
+a	O
+risk	O
+factor	O
+for	O
+both	O
+ischemic	B-NP
+and	I-NP
+haemorrhagic	I-NP
+stroke	I-NP
+.	O
+	
+We	O
+present	O
+the	O
+case	O
+of	O
+a	O
+31	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+bilateral	O
+ischemia	B-NP
+of	I-NP
+the	I-NP
+globus	I-NP
+pallidus	I-NP
+after	O
+excessive	O
+alcohol	O
+and	O
+intranasal	O
+cocaine	O
+use	O
+.	O
+	
+Drug	O
+-	O
+related	O
+globus	B-NP
+pallidus	I-NP
+infarctions	I-NP
+are	O
+most	O
+often	O
+associated	O
+with	O
+heroin	O
+.	O
+	
+Bilateral	O
+basal	B-NP
+ganglia	I-NP
+infarcts	I-NP
+after	O
+the	O
+use	O
+of	O
+cocaine	O
+","	O
+without	O
+concurrent	O
+heroin	O
+use	O
+","	O
+have	O
+never	O
+been	O
+reported	O
+.	O
+	
+In	O
+our	O
+patient	O
+","	O
+transient	O
+cardiac	B-NP
+arrhythmia	I-NP
+or	O
+respiratory	B-NP
+dysfunction	I-NP
+related	O
+to	O
+cocaine	O
+and	O
+/	O
+or	O
+ethanol	O
+use	O
+were	O
+the	O
+most	O
+likely	O
+causes	O
+of	O
+cerebral	B-NP
+hypoperfusion	I-NP
+.	O
+	
+Late	O
+fulminant	O
+posterior	B-NP
+reversible	I-NP
+encephalopathy	I-NP
+syndrome	I-NP
+after	O
+liver	O
+transplant	O
+.	O
+	
+OBJECTIVES	O
+:	O
+Posterior	B-NP
+leukoencephalopathy	I-NP
+due	O
+to	O
+calcineurin	O
+-	O
+inhibitor	O
+-	O
+related	O
+neurotoxicity	B-NP
+is	O
+a	O
+rare	O
+but	O
+severe	O
+complication	O
+that	O
+results	O
+from	O
+treatment	O
+with	O
+immunosuppressive	O
+agents	O
+(	O
+primarily	O
+those	O
+administered	O
+after	O
+a	O
+liver	O
+or	O
+kidney	O
+transplant	O
+)	O
+.	O
+	
+The	O
+pathophysiologic	O
+mechanisms	O
+of	O
+that	O
+disorder	O
+remain	O
+unknown	O
+.	O
+	
+CASE	O
+:	O
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+46	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+who	O
+received	O
+a	O
+liver	O
+transplant	O
+in	O
+our	O
+center	O
+as	O
+treatment	O
+for	O
+alcoholic	B-NP
+cirrhosis	I-NP
+and	O
+in	O
+whom	O
+either	O
+a	O
+fulminant	O
+course	O
+of	O
+posterior	B-NP
+leukoencephalopathy	I-NP
+or	O
+posterior	B-NP
+reversible	I-NP
+encephalopathy	I-NP
+syndrome	I-NP
+developed	O
+110	O
+days	O
+after	O
+transplant	O
+.	O
+	
+After	O
+an	O
+initially	O
+uneventful	O
+course	O
+after	O
+the	O
+transplant	O
+","	O
+the	O
+patient	O
+rapidly	O
+fell	O
+into	O
+deep	O
+coma	O
+.	O
+	
+RESULTS	O
+:	O
+Cerebral	O
+MRI	O
+scan	O
+showed	O
+typical	O
+signs	O
+of	O
+enhancement	O
+in	O
+the	O
+pontine	O
+and	O
+posterior	O
+regions	O
+.	O
+	
+Switching	O
+the	O
+immunosuppressive	O
+regimen	O
+from	O
+tacrolimus	O
+to	O
+cyclosporine	O
+did	O
+not	O
+improve	O
+the	O
+clinical	O
+situation	O
+.	O
+	
+The	O
+termination	O
+of	O
+treatment	O
+with	O
+any	O
+calcineurin	O
+inhibitor	O
+resulted	O
+in	O
+a	O
+complete	O
+resolution	O
+of	O
+that	O
+complication	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Posterior	B-NP
+reversible	I-NP
+encephalopathy	I-NP
+syndrome	I-NP
+after	O
+liver	O
+transplant	O
+is	O
+rare	O
+.	O
+	
+We	O
+recommend	O
+a	O
+complete	O
+cessation	O
+of	O
+any	O
+calcineurin	O
+inhibitor	O
+rather	O
+than	O
+a	O
+dose	O
+reduction	O
+.	O
+	
+Prolonged	O
+hypothermia	B-NP
+as	O
+a	O
+bridge	O
+to	O
+recovery	O
+for	O
+cerebral	B-NP
+edema	I-NP
+and	O
+intracranial	B-NP
+hypertension	I-NP
+associated	O
+with	O
+fulminant	B-NP
+hepatic	I-NP
+failure	I-NP
+.	O
+	
+BACKGROUND	O
+:	O
+To	O
+review	O
+evidence	O
+-	O
+based	O
+treatment	O
+options	O
+in	O
+patients	O
+with	O
+cerebral	B-NP
+edema	I-NP
+complicating	O
+fulminant	B-NP
+hepatic	I-NP
+failure	I-NP
+(	O
+FHF	B-NP
+)	O
+and	O
+discuss	O
+the	O
+potential	O
+applications	O
+of	O
+hypothermia	B-NP
+.	O
+	
+METHOD	O
+:	O
+Case	O
+-	O
+based	O
+observations	O
+from	O
+a	O
+medical	O
+intensive	O
+care	O
+unit	O
+(	O
+MICU	O
+)	O
+in	O
+a	O
+tertiary	O
+care	O
+facility	O
+in	O
+a	O
+27	O
+-	O
+year	O
+-	O
+old	O
+female	O
+with	O
+FHF	B-NP
+from	O
+acetaminophen	O
+and	O
+resultant	O
+cerebral	B-NP
+edema	I-NP
+.	O
+	
+RESULTS	O
+:	O
+Our	O
+patient	O
+was	O
+admitted	O
+to	O
+the	O
+MICU	O
+after	O
+being	O
+found	O
+unresponsive	O
+with	O
+presumed	O
+toxicity	B-NP
+from	O
+acetaminophen	O
+which	O
+was	O
+ingested	O
+over	O
+a	O
+2	O
+-	O
+day	O
+period	O
+.	O
+	
+The	O
+patient	O
+had	O
+depressed	O
+of	O
+mental	O
+status	O
+lasting	O
+at	O
+least	O
+24	O
+h	O
+prior	O
+to	O
+admission	O
+.	O
+	
+Initial	O
+evaluation	O
+confirmed	O
+FHF	B-NP
+from	O
+acetaminophen	O
+and	O
+cerebral	B-NP
+edema	I-NP
+.	O
+	
+The	O
+patient	O
+was	O
+treated	O
+with	O
+hyperosmolar	O
+therapy	O
+","	O
+hyperventilation	B-NP
+","	O
+sedation	O
+","	O
+and	O
+chemical	O
+paralysis	B-NP
+.	O
+	
+Her	O
+intracranial	O
+pressure	O
+remained	O
+elevated	O
+despite	O
+maximal	O
+medical	O
+therapy	O
+.	O
+	
+We	O
+then	O
+initiated	O
+therapeutic	O
+hypothermia	B-NP
+which	O
+was	O
+continued	O
+for	O
+5	O
+days	O
+.	O
+	
+At	O
+re	O
+-	O
+warming	O
+","	O
+patient	O
+had	O
+resolution	O
+of	O
+her	O
+cerebral	B-NP
+edema	I-NP
+and	O
+intracranial	B-NP
+hypertension	I-NP
+.	O
+	
+At	O
+discharge	O
+","	O
+she	O
+had	O
+complete	O
+recovery	O
+of	O
+neurological	O
+and	O
+hepatic	O
+functions	O
+.	O
+	
+CONCLUSION	O
+:	O
+In	O
+patients	O
+with	O
+FHF	B-NP
+and	O
+cerebral	B-NP
+edema	I-NP
+from	O
+acetaminophen	O
+overdose	B-NP
+","	O
+prolonged	O
+therapeutic	O
+hypothermia	B-NP
+could	O
+potentially	O
+be	O
+used	O
+as	O
+a	O
+life	O
+saving	O
+therapy	O
+and	O
+a	O
+bridge	O
+to	O
+hepatic	O
+and	O
+neurological	O
+recovery	O
+.	O
+	
+A	O
+clinical	O
+trial	O
+of	O
+hypothermia	B-NP
+in	O
+patients	O
+with	O
+this	O
+condition	O
+is	O
+warranted	O
+.	O
+	
+Binasal	B-NP
+visual	I-NP
+field	I-NP
+defects	I-NP
+are	O
+not	O
+specific	O
+to	O
+vigabatrin	O
+.	O
+	
+This	O
+study	O
+investigated	O
+the	O
+visual	B-NP
+defects	I-NP
+associated	O
+with	O
+the	O
+antiepileptic	O
+drug	O
+vigabatrin	O
+(	O
+VGB	O
+)	O
+.	O
+	
+Two	O
+hundred	O
+four	O
+people	O
+with	O
+epilepsy	B-NP
+were	O
+grouped	O
+on	O
+the	O
+basis	O
+of	O
+antiepileptic	O
+drug	O
+therapy	O
+(	O
+current	O
+","	O
+previous	O
+","	O
+or	O
+no	O
+exposure	O
+to	O
+VGB	O
+)	O
+.	O
+	
+Groups	O
+were	O
+matched	O
+with	O
+respect	O
+to	O
+age	O
+","	O
+gender	O
+","	O
+and	O
+seizure	B-NP
+frequency	O
+.	O
+	
+All	O
+patients	O
+underwent	O
+objective	O
+assessment	O
+of	O
+electrophysiological	O
+function	O
+(	O
+wide	O
+-	O
+field	O
+multifocal	O
+electroretinography	O
+)	O
+and	O
+conventional	O
+visual	O
+field	O
+testing	O
+(	O
+static	O
+perimetry	O
+)	O
+.	O
+	
+Bilateral	O
+visual	O
+field	O
+constriction	O
+was	O
+observed	O
+in	O
+59	O
+%	O
+of	O
+patients	O
+currently	O
+taking	O
+VGB	O
+","	O
+43	O
+%	O
+of	O
+patients	O
+who	O
+previously	O
+took	O
+VGB	O
+","	O
+and	O
+24	O
+%	O
+of	O
+patients	O
+with	O
+no	O
+exposure	O
+to	O
+VGB	O
+.	O
+	
+Assessment	O
+of	O
+retinal	O
+function	O
+revealed	O
+abnormal	O
+responses	O
+in	O
+48	O
+%	O
+of	O
+current	O
+VGB	O
+users	O
+and	O
+22	O
+%	O
+of	O
+prior	O
+VGB	O
+users	O
+","	O
+but	O
+in	O
+none	O
+of	O
+the	O
+patients	O
+without	O
+previous	O
+exposure	O
+to	O
+VGB	O
+.	O
+	
+Bilateral	B-NP
+visual	I-NP
+field	I-NP
+abnormalities	I-NP
+are	O
+common	O
+in	O
+the	O
+treated	O
+epilepsy	B-NP
+population	O
+","	O
+irrespective	O
+of	O
+drug	O
+history	O
+.	O
+	
+Assessment	O
+by	O
+conventional	O
+static	O
+perimetry	O
+may	O
+neither	O
+be	O
+sufficiently	O
+sensitive	O
+nor	O
+specific	O
+to	O
+reliably	O
+identify	O
+retinal	B-NP
+toxicity	I-NP
+associated	O
+with	O
+VGB	O
+.	O
+	
+Smoking	O
+of	O
+crack	O
+cocaine	O
+as	O
+a	O
+risk	O
+factor	O
+for	O
+HIV	B-NP
+infection	I-NP
+among	O
+people	O
+who	O
+use	O
+injection	O
+drugs	O
+.	O
+	
+BACKGROUND	O
+:	O
+Little	O
+is	O
+known	O
+about	O
+the	O
+possible	O
+role	O
+that	O
+smoking	O
+crack	O
+cocaine	O
+has	O
+on	O
+the	O
+incidence	O
+of	O
+HIV	B-NP
+infection	I-NP
+.	O
+	
+Given	O
+the	O
+increasing	O
+use	O
+of	O
+crack	O
+cocaine	O
+","	O
+we	O
+sought	O
+to	O
+examine	O
+whether	O
+use	O
+of	O
+this	O
+illicit	O
+drug	O
+has	O
+become	O
+a	O
+risk	O
+factor	O
+for	O
+HIV	B-NP
+infection	I-NP
+.	O
+	
+METHODS	O
+:	O
+We	O
+included	O
+data	O
+from	O
+people	O
+participating	O
+in	O
+the	O
+Vancouver	O
+Injection	O
+Drug	O
+Users	O
+Study	O
+who	O
+reported	O
+injecting	O
+illicit	O
+drugs	O
+at	O
+least	O
+once	O
+in	O
+the	O
+month	O
+before	O
+enrolment	O
+","	O
+lived	O
+in	O
+the	O
+greater	O
+Vancouver	O
+area	O
+","	O
+were	O
+HIV	O
+-	O
+negative	O
+at	O
+enrolment	O
+and	O
+completed	O
+at	O
+least	O
+1	O
+follow	O
+-	O
+up	O
+study	O
+visit	O
+.	O
+	
+To	O
+determine	O
+whether	O
+the	O
+risk	O
+of	O
+HIV	B-NP
+seroconversion	I-NP
+among	O
+daily	O
+smokers	O
+of	O
+crack	O
+cocaine	O
+changed	O
+over	O
+time	O
+","	O
+we	O
+used	O
+Cox	O
+proportional	O
+hazards	O
+regression	O
+and	O
+divided	O
+the	O
+study	O
+into	O
+3	O
+periods	O
+:	O
+May	O
+1	O
+","	O
+1996	O
+-	O
+Nov	O
+.	O
+	
+30	O
+","	O
+1999	O
+(	O
+period	O
+1	O
+)	O
+","	O
+Dec	O
+.	O
+	
+1	O
+","	O
+1999	O
+-	O
+Nov	O
+.	O
+	
+30	O
+","	O
+2002	O
+(	O
+period	O
+2	O
+)	O
+","	O
+and	O
+Dec	O
+.	O
+	
+1	O
+","	O
+2002	O
+-	O
+Dec	O
+.	O
+	
+30	O
+","	O
+2005	O
+(	O
+period	O
+3	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+Overall	O
+","	O
+1048	O
+eligible	O
+injection	O
+drug	O
+users	O
+were	O
+included	O
+in	O
+our	O
+study	O
+.	O
+	
+Of	O
+these	O
+","	O
+137	O
+acquired	O
+HIV	B-NP
+infection	I-NP
+during	O
+follow	O
+-	O
+up	O
+.	O
+	
+The	O
+mean	O
+proportion	O
+of	O
+participants	O
+who	O
+reported	O
+daily	O
+smoking	O
+of	O
+crack	O
+cocaine	O
+increased	O
+from	O
+11	O
+.	O
+6	O
+%	O
+in	O
+period	O
+1	O
+to	O
+39	O
+.	O
+7	O
+%	O
+in	O
+period	O
+3	O
+.	O
+	
+After	O
+adjusting	O
+for	O
+potential	O
+confounders	O
+","	O
+we	O
+found	O
+that	O
+the	O
+risk	O
+of	O
+HIV	B-NP
+seroconversion	I-NP
+among	O
+participants	O
+who	O
+were	O
+daily	O
+smokers	O
+of	O
+crack	O
+cocaine	O
+increased	O
+over	O
+time	O
+(	O
+period	O
+1	O
+:	O
+hazard	O
+ratio	O
+[	O
+HR	O
+]	O
+1	O
+.	O
+3	O
+","	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+0	O
+.	O
+57	O
+-	O
+1	O
+.	O
+85	O
+;	O
+period	O
+2	O
+:	O
+HR	O
+1	O
+.	O
+68	O
+","	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+1	O
+-	O
+2	O
+.	O
+80	O
+;	O
+and	O
+period	O
+3	O
+:	O
+HR	O
+2	O
+.	O
+74	O
+","	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+6	O
+-	O
+7	O
+.	O
+11	O
+)	O
+.	O
+	
+INTERPRETATION	O
+:	O
+Smoking	O
+of	O
+crack	O
+cocaine	O
+was	O
+found	O
+to	O
+be	O
+an	O
+independent	O
+risk	O
+factor	O
+for	O
+HIV	B-NP
+seroconversion	I-NP
+among	O
+people	O
+who	O
+were	O
+injection	O
+drug	O
+users	O
+.	O
+	
+This	O
+finding	O
+points	O
+to	O
+the	O
+urgent	O
+need	O
+for	O
+evidence	O
+-	O
+based	O
+public	O
+health	O
+initiatives	O
+targeted	O
+at	O
+people	O
+who	O
+smoke	O
+crack	O
+cocaine	O
+.	O
+	
+Fluoxetine	O
+improves	O
+the	O
+memory	B-NP
+deficits	I-NP
+caused	O
+by	O
+the	O
+chemotherapy	O
+agent	O
+5	O
+-	O
+fluorouracil	O
+.	O
+	
+Cancer	B-NP
+patients	O
+who	O
+have	O
+been	O
+treated	O
+with	O
+systemic	O
+adjuvant	O
+chemotherapy	O
+have	O
+described	O
+experiencing	O
+deteriorations	O
+in	O
+cognition	O
+.	O
+	
+A	O
+widely	O
+used	O
+chemotherapeutic	O
+agent	O
+","	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+","	O
+readily	O
+crosses	O
+the	O
+blood	O
+-	O
+brain	O
+barrier	O
+and	O
+so	O
+could	O
+have	O
+a	O
+direct	O
+effect	O
+on	O
+brain	O
+function	O
+.	O
+	
+In	O
+particular	O
+this	O
+anti	O
+mitotic	O
+drug	O
+could	O
+reduce	O
+cell	O
+proliferation	O
+in	O
+the	O
+neurogenic	O
+regions	O
+of	O
+the	O
+adult	O
+brain	O
+.	O
+	
+In	O
+contrast	O
+reports	O
+indicate	O
+that	O
+hippocampal	O
+dependent	O
+neurogenesis	O
+and	O
+cognition	O
+are	O
+enhanced	O
+by	O
+the	O
+SSRI	O
+antidepressant	O
+Fluoxetine	O
+.	O
+	
+In	O
+this	O
+investigation	O
+the	O
+behavioural	O
+effects	O
+of	O
+chronic	O
+(	O
+two	O
+week	O
+)	O
+treatment	O
+with	O
+5	O
+-	O
+FU	O
+and	O
+(	O
+three	O
+weeks	O
+)	O
+with	O
+Fluoxetine	O
+either	O
+separately	O
+or	O
+in	O
+combination	O
+with	O
+5	O
+-	O
+FU	O
+were	O
+tested	O
+on	O
+adult	O
+Lister	O
+hooded	O
+rats	O
+.	O
+	
+Behavioural	O
+effects	O
+were	O
+tested	O
+using	O
+a	O
+context	O
+dependent	O
+conditioned	O
+emotional	O
+response	O
+test	O
+(	O
+CER	O
+)	O
+which	O
+showed	O
+that	O
+animals	O
+treated	O
+with	O
+5	O
+-	O
+FU	O
+had	O
+a	O
+significant	O
+reduction	O
+in	O
+freezing	O
+time	O
+compared	O
+to	O
+controls	O
+.	O
+	
+A	O
+separate	O
+group	O
+of	O
+animals	O
+was	O
+tested	O
+using	O
+a	O
+hippocampal	O
+dependent	O
+spatial	O
+working	O
+memory	O
+test	O
+","	O
+the	O
+object	O
+location	O
+recognition	O
+test	O
+(	O
+OLR	O
+)	O
+.	O
+	
+Animals	O
+treated	O
+only	O
+with	O
+5	O
+-	O
+FU	O
+showed	O
+significant	O
+deficits	O
+in	O
+their	O
+ability	O
+to	O
+carry	O
+out	O
+the	O
+OLR	O
+task	O
+but	O
+co	O
+administration	O
+of	O
+Fluoxetine	O
+improved	O
+their	O
+performance	O
+.	O
+	
+5	O
+-	O
+FU	O
+chemotherapy	O
+caused	O
+a	O
+significant	O
+reduction	O
+in	O
+the	O
+number	O
+of	O
+proliferating	O
+cells	O
+in	O
+the	O
+sub	O
+granular	O
+zone	O
+of	O
+the	O
+dentate	O
+gyrus	O
+compared	O
+to	O
+controls	O
+.	O
+	
+This	O
+reduction	O
+was	O
+eliminated	O
+when	O
+Fluoxetine	O
+was	O
+co	O
+administered	O
+with	O
+5	O
+-	O
+FU	O
+.	O
+	
+Fluoxetine	O
+on	O
+its	O
+own	O
+had	O
+no	O
+effect	O
+on	O
+proliferating	O
+cell	O
+number	O
+or	O
+behaviour	O
+.	O
+	
+These	O
+findings	O
+suggest	O
+that	O
+5	O
+-	O
+FU	O
+can	O
+negatively	O
+affect	O
+both	O
+cell	O
+proliferation	O
+and	O
+hippocampal	O
+dependent	O
+working	O
+memory	O
+and	O
+that	O
+these	O
+deficits	O
+can	O
+be	O
+reversed	O
+by	O
+the	O
+simultaneous	O
+administration	O
+of	O
+the	O
+antidepressant	O
+Fluoxetine	O
+.	O
+	
+Liver	O
+-	O
+specific	O
+ablation	O
+of	O
+integrin	O
+-	O
+linked	O
+kinase	O
+in	O
+mice	O
+results	O
+in	O
+enhanced	O
+and	O
+prolonged	O
+cell	O
+proliferation	O
+and	O
+hepatomegaly	B-NP
+after	O
+phenobarbital	O
+administration	O
+.	O
+	
+We	O
+have	O
+recently	O
+demonstrated	O
+that	O
+disruption	O
+of	O
+extracellular	O
+matrix	O
+(	O
+ECM	O
+)	O
+/	O
+integrin	O
+signaling	O
+via	O
+elimination	O
+of	O
+integrin	O
+-	O
+linked	O
+kinase	O
+(	O
+ILK	O
+)	O
+in	O
+hepatocytes	O
+interferes	O
+with	O
+signals	O
+leading	O
+to	O
+termination	O
+of	O
+liver	O
+regeneration	O
+.	O
+	
+This	O
+study	O
+investigates	O
+the	O
+role	O
+of	O
+ILK	O
+in	O
+liver	O
+enlargement	O
+induced	O
+by	O
+phenobarbital	O
+(	O
+PB	O
+)	O
+.	O
+	
+Wild	O
+-	O
+type	O
+(	O
+WT	O
+)	O
+and	O
+ILK	O
+:	O
+liver	O
+-	O
+/	O
+-	O
+mice	O
+were	O
+given	O
+PB	O
+(	O
+0	O
+.	O
+1	O
+%	O
+in	O
+drinking	O
+water	O
+)	O
+for	O
+10	O
+days	O
+.	O
+	
+Livers	O
+were	O
+harvested	O
+on	O
+2	O
+","	O
+5	O
+","	O
+and	O
+10	O
+days	O
+during	O
+PB	O
+administration	O
+.	O
+	
+In	O
+the	O
+hepatocyte	O
+-	O
+specific	O
+ILK	O
+/	O
+liver	O
+-	O
+/	O
+-	O
+mice	O
+","	O
+the	O
+liver	O
+:	O
+body	O
+weight	O
+ratio	O
+was	O
+more	O
+than	O
+double	O
+as	O
+compared	O
+to	O
+0	O
+h	O
+at	O
+day	O
+2	O
+(	O
+2	O
+.	O
+5	O
+times	O
+)	O
+","	O
+while	O
+at	O
+days	O
+5	O
+and	O
+10	O
+","	O
+it	O
+was	O
+enlarged	O
+three	O
+times	O
+.	O
+	
+In	O
+the	O
+WT	O
+mice	O
+","	O
+the	O
+increase	O
+was	O
+as	O
+expected	O
+from	O
+previous	O
+literature	O
+(	O
+1	O
+.	O
+8	O
+times	O
+)	O
+and	O
+seems	O
+to	O
+have	O
+leveled	O
+off	O
+after	O
+day	O
+2	O
+.	O
+	
+There	O
+were	O
+slightly	O
+increased	O
+proliferating	O
+cell	O
+nuclear	O
+antigen	O
+-	O
+positive	O
+cells	O
+in	O
+the	O
+ILK	O
+/	O
+liver	O
+-	O
+/	O
+-	O
+animals	O
+at	O
+day	O
+2	O
+as	O
+compared	O
+to	O
+WT	O
+after	O
+PB	O
+administration	O
+.	O
+	
+In	O
+the	O
+WT	O
+animals	O
+","	O
+the	O
+proliferative	O
+response	O
+had	O
+come	O
+back	O
+to	O
+normal	O
+by	O
+days	O
+5	O
+and	O
+10	O
+.	O
+	
+Hepatocytes	O
+of	O
+the	O
+ILK	O
+/	O
+liver	O
+-	O
+/	O
+-	O
+mice	O
+continued	O
+to	O
+proliferate	O
+up	O
+until	O
+day	O
+10	O
+.	O
+	
+ILK	O
+/	O
+liver	O
+-	O
+/	O
+-	O
+mice	O
+also	O
+showed	O
+increased	O
+expression	O
+of	O
+key	O
+genes	O
+involved	O
+in	O
+hepatocyte	O
+proliferation	O
+at	O
+different	O
+time	O
+points	O
+during	O
+PB	O
+administration	O
+.	O
+	
+In	O
+summary	O
+","	O
+ECM	O
+proteins	O
+communicate	O
+with	O
+the	O
+signaling	O
+machinery	O
+of	O
+dividing	O
+cells	O
+via	O
+ILK	O
+to	O
+regulate	O
+hepatocyte	O
+proliferation	O
+and	O
+termination	O
+of	O
+the	O
+proliferative	O
+response	O
+.	O
+	
+Lack	O
+of	O
+ILK	O
+in	O
+the	O
+hepatocytes	O
+imparts	O
+prolonged	O
+proliferative	O
+response	O
+not	O
+only	O
+to	O
+stimuli	O
+related	O
+to	O
+liver	O
+regeneration	O
+but	O
+also	O
+to	O
+xenobiotic	O
+chemical	O
+mitogens	O
+","	O
+such	O
+as	O
+PB	O
+.	O
+	
+Decreased	O
+Expression	O
+of	O
+Na	O
+/	O
+K	O
+-	O
+ATPase	O
+","	O
+NHE3	O
+","	O
+NBC1	O
+","	O
+AQP1	O
+and	O
+OAT	O
+in	O
+Gentamicin	O
+-	O
+induced	O
+Nephropathy	B-NP
+.	O
+	
+The	O
+present	O
+study	O
+was	O
+aimed	O
+to	O
+determine	O
+whether	O
+there	O
+is	O
+an	O
+altered	O
+regulation	O
+of	O
+tubular	O
+transporters	O
+in	O
+gentamicin	O
+-	O
+induced	O
+nephropathy	B-NP
+.	O
+	
+Sprague	O
+-	O
+Dawley	O
+male	O
+rats	O
+(	O
+200	O
+~	O
+250	O
+g	O
+)	O
+were	O
+subcutaneously	O
+injected	O
+with	O
+gentamicin	O
+(	O
+100	O
+mg	O
+/	O
+kg	O
+per	O
+day	O
+)	O
+for	O
+7	O
+days	O
+","	O
+and	O
+the	O
+expression	O
+of	O
+tubular	O
+transporters	O
+was	O
+determined	O
+by	O
+immunoblotting	O
+and	O
+immunohistochemistry	O
+.	O
+	
+The	O
+mRNA	O
+and	O
+protein	O
+expression	O
+of	O
+OAT	O
+was	O
+also	O
+determined	O
+.	O
+	
+Gentamicin	O
+-	O
+treated	O
+rats	O
+exhibited	O
+significantly	O
+decreased	O
+creatinine	O
+clearance	O
+along	O
+with	O
+increased	O
+plasma	O
+creatinine	O
+levels	O
+.	O
+	
+Accordingly	O
+","	O
+the	O
+fractional	O
+excretion	O
+of	O
+sodium	O
+increased	O
+.	O
+	
+Urine	O
+volume	O
+was	O
+increased	O
+","	O
+while	O
+urine	O
+osmolality	O
+and	O
+free	O
+water	O
+reabsorption	O
+were	O
+decreased	O
+.	O
+	
+Immunoblotting	O
+and	O
+immunohistochemistry	O
+revealed	O
+decreased	O
+expression	O
+of	O
+Na	O
+(	O
++	O
+)	O
+/	O
+K	O
+(	O
++	O
+)	O
+-	O
+ATPase	O
+","	O
+NHE3	O
+","	O
+NBC1	O
+","	O
+and	O
+AQP1	O
+in	O
+the	O
+kidney	O
+of	O
+gentamicin	O
+-	O
+treated	O
+rats	O
+.	O
+	
+The	O
+expression	O
+of	O
+OAT1	O
+and	O
+OAT3	O
+was	O
+also	O
+decreased	O
+.	O
+	
+Gentamicin	O
+-	O
+induced	O
+nephropathy	B-NP
+may	O
+at	O
+least	O
+in	O
+part	O
+be	O
+causally	O
+related	O
+with	O
+a	O
+decreased	O
+expression	O
+of	O
+Na	O
+(	O
++	O
+)	O
+/	O
+K	O
+(	O
++	O
+)	O
+-	O
+ATPase	O
+","	O
+NHE3	O
+","	O
+NBC1	O
+","	O
+AQP1	O
+and	O
+OAT	O
+.	O
+	
+Acute	B-NP
+renal	I-NP
+failure	I-NP
+after	O
+high	O
+-	O
+dose	O
+methotrexate	O
+therapy	O
+in	O
+a	O
+patient	O
+with	O
+ileostomy	O
+.	O
+	
+High	O
+-	O
+dose	O
+methotrexate	O
+(	O
+HD	O
+-	O
+MTX	O
+)	O
+is	O
+an	O
+important	O
+treatment	O
+for	O
+Burkitt	B-NP
+lymphoma	I-NP
+","	O
+but	O
+can	O
+cause	O
+hepatic	B-NP
+and	I-NP
+renal	I-NP
+toxicity	I-NP
+when	O
+its	O
+clearance	O
+is	O
+delayed	O
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+after	O
+HD	O
+-	O
+MTX	O
+therapy	O
+in	O
+a	O
+patient	O
+with	O
+ileostomy	O
+","	O
+The	O
+patient	O
+was	O
+a	O
+3	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+who	O
+had	O
+received	O
+a	O
+living	O
+-	O
+related	O
+liver	O
+transplantation	O
+for	O
+congenital	O
+biliary	B-NP
+atresia	I-NP
+.	O
+	
+At	O
+day	O
+833	O
+after	O
+the	O
+transplantation	O
+","	O
+he	O
+was	O
+diagnosed	O
+with	O
+PTLD	B-NP
+(	O
+post	B-NP
+-	I-NP
+transplantation	I-NP
+lymphoproliferative	I-NP
+disorder	I-NP
+","	O
+Burkitt	B-NP
+-	I-NP
+type	I-NP
+malignant	I-NP
+lymphoma	I-NP
+)	O
+.	O
+	
+During	O
+induction	O
+therapy	O
+","	O
+he	O
+suffered	O
+ileal	O
+perforation	O
+and	O
+ileostomy	O
+was	O
+performed	O
+.	O
+	
+Subsequent	O
+HD	O
+-	O
+MTX	O
+therapy	O
+caused	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+that	O
+required	O
+continuous	O
+hemodialysis	O
+.	O
+	
+We	O
+supposed	O
+that	O
+intravascular	O
+hypovolemia	B-NP
+due	O
+to	O
+substantial	O
+drainage	O
+from	O
+the	O
+ileostoma	O
+caused	O
+acute	B-NP
+prerenal	I-NP
+failure	I-NP
+.	O
+	
+After	O
+recovery	O
+of	O
+his	O
+renal	O
+function	O
+","	O
+we	O
+could	O
+safely	O
+treat	O
+the	O
+patient	O
+with	O
+HD	O
+-	O
+MTX	O
+therapy	O
+by	O
+controlling	O
+drainage	O
+from	O
+ileostoma	O
+with	O
+total	O
+parenteral	O
+nutrition	O
+.	O
+	
+Longitudinal	O
+association	O
+of	O
+alcohol	O
+use	O
+with	O
+HIV	B-NP
+disease	I-NP
+progression	O
+and	O
+psychological	O
+health	O
+of	O
+women	O
+with	O
+HIV	O
+.	O
+	
+We	O
+evaluated	O
+the	O
+association	O
+of	O
+alcohol	O
+consumption	O
+and	O
+depression	B-NP
+","	O
+and	O
+their	O
+effects	O
+on	O
+HIV	B-NP
+disease	I-NP
+progression	O
+among	O
+women	O
+with	O
+HIV	O
+.	O
+	
+The	O
+study	O
+included	O
+871	O
+women	O
+with	O
+HIV	O
+who	O
+were	O
+recruited	O
+from	O
+1993	O
+-	O
+1995	O
+in	O
+four	O
+US	O
+cities	O
+.	O
+	
+The	O
+participants	O
+had	O
+physical	O
+examination	O
+","	O
+medical	O
+record	O
+extraction	O
+","	O
+and	O
+venipuncture	O
+","	O
+CD4	O
++	O
+T	O
+-	O
+cell	O
+counts	O
+determination	O
+","	O
+measurement	O
+of	O
+depression	B-NP
+symptoms	O
+(	O
+using	O
+the	O
+self	O
+-	O
+report	O
+Center	O
+for	O
+Epidemiological	O
+Studies	O
+-	O
+Depression	B-NP
+Scale	O
+)	O
+","	O
+and	O
+alcohol	O
+use	O
+assessment	O
+at	O
+enrollment	O
+","	O
+and	O
+semiannually	O
+until	O
+March	O
+2000	O
+.	O
+	
+Multilevel	O
+random	O
+coefficient	O
+ordinal	O
+models	O
+as	O
+well	O
+as	O
+multilevel	O
+models	O
+with	O
+joint	O
+responses	O
+were	O
+used	O
+in	O
+the	O
+analysis	O
+.	O
+	
+There	O
+was	O
+no	O
+significant	O
+association	O
+between	O
+level	O
+of	O
+alcohol	O
+use	O
+and	O
+CD4	O
++	O
+T	O
+-	O
+cell	O
+counts	O
+.	O
+	
+When	O
+participants	O
+were	O
+stratified	O
+by	O
+antiretroviral	O
+therapy	O
+(	O
+ART	O
+)	O
+use	O
+","	O
+the	O
+association	O
+between	O
+alcohol	O
+and	O
+CD4	O
++	O
+T	O
+-	O
+cell	O
+did	O
+not	O
+reach	O
+statistical	O
+significance	O
+.	O
+	
+The	O
+association	O
+between	O
+alcohol	O
+consumption	O
+and	O
+depression	B-NP
+was	O
+significant	O
+(	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Depression	B-NP
+had	O
+a	O
+significant	O
+negative	O
+effect	O
+on	O
+CD4	O
++	O
+T	O
+-	O
+cell	O
+counts	O
+over	O
+time	O
+regardless	O
+of	O
+ART	O
+use	O
+.	O
+	
+Our	O
+findings	O
+suggest	O
+that	O
+alcohol	O
+consumption	O
+has	O
+a	O
+direct	O
+association	O
+with	O
+depression	B-NP
+.	O
+	
+Moreover	O
+","	O
+depression	B-NP
+is	O
+associated	O
+with	O
+HIV	B-NP
+disease	I-NP
+progression	O
+.	O
+	
+Our	O
+findings	O
+have	O
+implications	O
+for	O
+the	O
+provision	O
+of	O
+alcohol	O
+use	O
+interventions	O
+and	O
+psychological	O
+resources	O
+to	O
+improve	O
+the	O
+health	O
+of	O
+women	O
+with	O
+HIV	O
+.	O
+	
+Chemokine	O
+CCL2	O
+and	O
+its	O
+receptor	O
+CCR2	O
+are	O
+increased	O
+in	O
+the	O
+hippocampus	O
+following	O
+pilocarpine	O
+-	O
+induced	O
+status	B-NP
+epilepticus	I-NP
+.	O
+	
+BACKGROUND	O
+:	O
+Neuroinflammation	B-NP
+occurs	O
+after	O
+seizures	B-NP
+and	O
+is	O
+implicated	O
+in	O
+epileptogenesis	O
+.	O
+	
+CCR2	O
+is	O
+a	O
+chemokine	O
+receptor	O
+for	O
+CCL2	O
+and	O
+their	O
+interaction	O
+mediates	O
+monocyte	O
+infiltration	O
+in	O
+the	O
+neuroinflammatory	B-NP
+cascade	O
+triggered	O
+in	O
+different	O
+brain	O
+pathologies	O
+.	O
+	
+In	O
+this	O
+work	O
+CCR2	O
+and	O
+CCL2	O
+expression	O
+were	O
+examined	O
+following	O
+status	B-NP
+epilepticus	I-NP
+(	O
+SE	B-NP
+)	O
+induced	O
+by	O
+pilocarpine	O
+injection	O
+.	O
+	
+METHODS	O
+:	O
+SE	B-NP
+was	O
+induced	O
+by	O
+pilocarpine	O
+injection	O
+.	O
+	
+Control	O
+rats	O
+were	O
+injected	O
+with	O
+saline	O
+instead	O
+of	O
+pilocarpine	O
+.	O
+	
+Five	O
+days	O
+after	O
+SE	B-NP
+","	O
+CCR2	O
+staining	O
+in	O
+neurons	O
+and	O
+glial	O
+cells	O
+was	O
+examined	O
+using	O
+imunohistochemical	O
+analyses	O
+.	O
+	
+The	O
+number	O
+of	O
+CCR2	O
+positive	O
+cells	O
+was	O
+determined	O
+using	O
+stereology	O
+probes	O
+in	O
+the	O
+hippocampus	O
+.	O
+	
+CCL2	O
+expression	O
+in	O
+the	O
+hippocampus	O
+was	O
+examined	O
+by	O
+molecular	O
+assay	O
+.	O
+	
+RESULTS	O
+:	O
+Increased	O
+CCR2	O
+was	O
+observed	O
+in	O
+the	O
+hippocampus	O
+after	O
+SE	B-NP
+.	O
+	
+Seizures	B-NP
+also	O
+resulted	O
+in	O
+alterations	O
+to	O
+the	O
+cell	O
+types	O
+expressing	O
+CCR2	O
+.	O
+	
+Increased	O
+numbers	O
+of	O
+neurons	O
+that	O
+expressed	O
+CCR2	O
+was	O
+observed	O
+following	O
+SE	B-NP
+.	O
+	
+Microglial	O
+cells	O
+were	O
+more	O
+closely	O
+apposed	O
+to	O
+the	O
+CCR2	O
+-	O
+labeled	O
+cells	O
+in	O
+SE	B-NP
+rats	O
+.	O
+	
+In	O
+addition	O
+","	O
+rats	O
+that	O
+experienced	O
+SE	B-NP
+exhibited	O
+CCR2	O
+-	O
+labeling	O
+in	O
+populations	O
+of	O
+hypertrophied	B-NP
+astrocytes	O
+","	O
+especially	O
+in	O
+CA1	O
+and	O
+dentate	O
+gyrus	O
+.	O
+	
+These	O
+CCR2	O
++	O
+astroctytes	O
+were	O
+not	O
+observed	O
+in	O
+control	O
+rats	O
+.	O
+	
+Examination	O
+of	O
+CCL2	O
+expression	O
+showed	O
+that	O
+it	O
+was	O
+elevated	O
+in	O
+the	O
+hippocampus	O
+following	O
+SE	B-NP
+.	O
+	
+CONCLUSION	O
+:	O
+The	O
+data	O
+show	O
+that	O
+CCR2	O
+and	O
+CCL2	O
+are	O
+up	O
+-	O
+regulated	O
+in	O
+the	O
+hippocampus	O
+after	O
+pilocarpine	O
+-	O
+induced	O
+SE	B-NP
+.	O
+	
+Seizures	B-NP
+also	O
+result	O
+in	O
+changes	O
+to	O
+CCR2	O
+receptor	O
+expression	O
+in	O
+neurons	O
+and	O
+astrocytes	O
+.	O
+	
+These	O
+changes	O
+might	O
+be	O
+involved	O
+in	O
+detrimental	O
+neuroplasticity	O
+and	O
+neuroinflammatory	B-NP
+changes	O
+that	O
+occur	O
+following	O
+seizures	B-NP
+.	O
+	
+Metallothionein	O
+induction	O
+reduces	O
+caspase	O
+-	O
+3	O
+activity	O
+and	O
+TNFalpha	O
+levels	O
+with	O
+preservation	O
+of	O
+cognitive	O
+function	O
+and	O
+intact	O
+hippocampal	O
+neurons	O
+in	O
+carmustine	O
+-	O
+treated	O
+rats	O
+.	O
+	
+Hippocampal	O
+integrity	O
+is	O
+essential	O
+for	O
+cognitive	O
+functions	O
+.	O
+	
+On	O
+the	O
+other	O
+hand	O
+","	O
+induction	O
+of	O
+metallothionein	O
+(	O
+MT	O
+)	O
+by	O
+ZnSO	O
+(	O
+4	O
+)	O
+and	O
+its	O
+role	O
+in	O
+neuroprotection	O
+has	O
+been	O
+documented	O
+.	O
+	
+The	O
+present	O
+study	O
+aimed	O
+to	O
+explore	O
+the	O
+effect	O
+of	O
+MT	O
+induction	O
+on	O
+carmustine	O
+(	O
+BCNU	O
+)	O
+-	O
+induced	O
+hippocampal	O
+cognitive	B-NP
+dysfunction	I-NP
+in	O
+rats	O
+.	O
+	
+A	O
+total	O
+of	O
+60	O
+male	O
+Wistar	O
+albino	O
+rats	O
+were	O
+randomly	O
+divided	O
+into	O
+four	O
+groups	O
+(	O
+15	O
+/	O
+group	O
+)	O
+:	O
+The	O
+control	O
+group	O
+injected	O
+with	O
+single	O
+doses	O
+of	O
+normal	O
+saline	O
+(	O
+i	O
+.	O
+c	O
+.	O
+v	O
+)	O
+followed	O
+24	O
+h	O
+later	O
+by	O
+BCNU	O
+solvent	O
+(	O
+i	O
+.	O
+v	O
+)	O
+.	O
+	
+The	O
+second	O
+group	O
+administered	O
+ZnSO	O
+(	O
+4	O
+)	O
+(	O
+0	O
+.	O
+1	O
+micromol	O
+/	O
+10	O
+microl	O
+normal	O
+saline	O
+","	O
+i	O
+.	O
+c	O
+.	O
+v	O
+","	O
+once	O
+)	O
+then	O
+BCNU	O
+solvent	O
+(	O
+i	O
+.	O
+v	O
+)	O
+after	O
+24	O
+h	O
+.	O
+	
+Third	O
+group	O
+received	O
+BCNU	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+v	O
+","	O
+once	O
+)	O
+24	O
+h	O
+after	O
+injection	O
+with	O
+normal	O
+saline	O
+(	O
+i	O
+.	O
+c	O
+.	O
+v	O
+)	O
+.	O
+	
+Fourth	O
+group	O
+received	O
+a	O
+single	O
+dose	O
+of	O
+ZnSO	O
+(	O
+4	O
+)	O
+(	O
+0	O
+.	O
+1	O
+micromol	O
+/	O
+10	O
+microl	O
+normal	O
+saline	O
+","	O
+i	O
+.	O
+c	O
+.	O
+v	O
+)	O
+then	O
+BCNU	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+v	O
+","	O
+once	O
+)	O
+after	O
+24	O
+h	O
+.	O
+	
+The	O
+obtained	O
+data	O
+revealed	O
+that	O
+BCNU	O
+administration	O
+resulted	O
+in	O
+deterioration	B-NP
+of	I-NP
+learning	I-NP
+and	I-NP
+short	I-NP
+-	I-NP
+term	I-NP
+memory	I-NP
+(	O
+STM	O
+)	O
+","	O
+as	O
+measured	O
+by	O
+using	O
+radial	O
+arm	O
+water	O
+maze	O
+","	O
+accompanied	O
+with	O
+decreased	O
+hippocampal	O
+glutathione	O
+reductase	O
+(	O
+GR	O
+)	O
+activity	O
+and	O
+reduced	O
+glutathione	O
+(	O
+GSH	O
+)	O
+content	O
+.	O
+	
+Also	O
+","	O
+BCNU	O
+administration	O
+increased	O
+serum	O
+tumor	B-NP
+necrosis	B-NP
+factor	O
+-	O
+alpha	O
+(	O
+TNFalpha	O
+)	O
+","	O
+hippocampal	O
+MT	O
+and	O
+malondialdehyde	O
+(	O
+MDA	O
+)	O
+contents	O
+as	O
+well	O
+as	O
+caspase	O
+-	O
+3	O
+activity	O
+in	O
+addition	O
+to	O
+histological	O
+alterations	O
+.	O
+	
+ZnSO	O
+(	O
+4	O
+)	O
+pretreatment	O
+counteracted	O
+BCNU	O
+-	O
+induced	O
+inhibition	O
+of	O
+GR	O
+and	O
+depletion	O
+of	O
+GSH	O
+and	O
+resulted	O
+in	O
+significant	O
+reduction	O
+in	O
+the	O
+levels	O
+of	O
+MDA	O
+and	O
+TNFalpha	O
+as	O
+well	O
+as	O
+the	O
+activity	O
+of	O
+caspase	O
+-	O
+3	O
+.	O
+	
+The	O
+histological	O
+features	O
+were	O
+improved	O
+in	O
+hippocampus	O
+of	O
+rats	O
+treated	O
+with	O
+ZnSO	O
+(	O
+4	O
+)	O
++	O
+BCNU	O
+compared	O
+to	O
+only	O
+BCNU	O
+-	O
+treated	O
+animals	O
+.	O
+	
+In	O
+conclusion	O
+","	O
+MT	O
+induction	O
+halts	O
+BCNU	O
+-	O
+induced	O
+hippocampal	O
+toxicity	B-NP
+as	O
+it	O
+prevented	O
+GR	O
+inhibition	O
+and	O
+GSH	O
+depletion	O
+and	O
+counteracted	O
+the	O
+increased	O
+levels	O
+of	O
+TNFalpha	O
+","	O
+MDA	O
+and	O
+caspase	O
+-	O
+3	O
+activity	O
+with	O
+subsequent	O
+preservation	O
+of	O
+cognition	O
+.	O
+	
+Fatal	O
+carbamazepine	O
+induced	O
+fulminant	B-NP
+eosinophilic	I-NP
+(	O
+hypersensitivity	B-NP
+)	O
+myocarditis	B-NP
+:	O
+emphasis	O
+on	O
+anatomical	O
+and	O
+histological	O
+characteristics	O
+","	O
+mechanisms	O
+and	O
+genetics	O
+of	O
+drug	B-NP
+hypersensitivity	I-NP
+and	O
+differential	O
+diagnosis	O
+.	O
+	
+The	O
+most	O
+severe	O
+adverse	O
+reactions	O
+to	O
+carbamazepine	O
+have	O
+been	O
+observed	O
+in	O
+the	O
+haemopoietic	O
+system	O
+","	O
+the	O
+liver	O
+and	O
+the	O
+cardiovascular	O
+system	O
+.	O
+	
+A	O
+frequently	O
+fatal	O
+","	O
+although	O
+exceptionally	O
+rare	O
+side	O
+effect	O
+of	O
+carbamazepine	O
+is	O
+necrotizing	O
+eosinophilic	O
+(	O
+hypersensitivity	B-NP
+)	O
+myocarditis	B-NP
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+hypersensitivity	B-NP
+myocarditis	B-NP
+secondary	O
+to	O
+administration	O
+of	O
+carbamazepine	O
+.	O
+	
+Acute	O
+hypersensitivity	B-NP
+myocarditis	B-NP
+was	O
+not	O
+suspected	O
+clinically	O
+","	O
+and	O
+the	O
+diagnosis	O
+was	O
+made	O
+post	O
+-	O
+mortem	O
+.	O
+	
+Histology	O
+revealed	O
+diffuse	O
+infiltration	O
+of	O
+the	O
+myocardium	O
+by	O
+eosinophils	O
+and	O
+lymphocytes	O
+with	O
+myocyte	O
+damage	O
+.	O
+	
+Clinically	O
+","	O
+death	O
+was	O
+due	O
+to	O
+cardiogenic	B-NP
+shock	I-NP
+.	O
+	
+To	O
+best	O
+of	O
+our	O
+knowledge	O
+this	O
+is	O
+the	O
+second	O
+case	O
+of	O
+fatal	O
+carbamazepine	O
+induced	O
+myocarditis	B-NP
+reported	O
+in	O
+English	O
+literature	O
+.	O
+	
+Neuropsychiatric	O
+behaviors	O
+in	O
+the	O
+MPTP	O
+marmoset	O
+model	O
+of	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+OBJECTIVES	O
+:	O
+Neuropsychiatric	O
+symptoms	O
+are	O
+increasingly	O
+recognised	O
+as	O
+a	O
+significant	O
+problem	O
+in	O
+patients	O
+with	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+(	O
+PD	B-NP
+)	O
+.	O
+	
+These	O
+symptoms	O
+may	O
+be	O
+due	O
+to	O
+'	O
+sensitisation	O
+'	O
+following	O
+repeated	O
+levodopa	O
+treatment	O
+or	O
+a	O
+direct	O
+effect	O
+of	O
+dopamine	O
+on	O
+the	O
+disease	O
+state	O
+.	O
+	
+The	O
+levodopa	O
+-	O
+treated	O
+MPTP	O
+-	O
+lesioned	O
+marmoset	O
+was	O
+used	O
+as	O
+a	O
+model	O
+of	O
+neuropsychiatric	B-NP
+symptoms	I-NP
+in	O
+PD	B-NP
+patients	O
+.	O
+	
+Here	O
+we	O
+compare	O
+the	O
+time	O
+course	O
+of	O
+levodopa	O
+-	O
+induced	O
+motor	O
+fluctuations	O
+and	O
+neuropsychiatric	B-NP
+-	I-NP
+like	I-NP
+behaviors	I-NP
+to	O
+determine	O
+the	O
+relationship	O
+between	O
+duration	O
+of	O
+treatment	O
+and	O
+onset	O
+of	O
+symptoms	O
+.	O
+	
+METHODS	O
+:	O
+Marmosets	O
+were	O
+administered	O
+1	O
+-	O
+methyl	O
+-	O
+4	O
+-	O
+phenyl	O
+-	O
+1	O
+","	O
+2	O
+","	O
+3	O
+","	O
+6	O
+-	O
+tetrahydropyridine	O
+(	O
+2	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+s	O
+.	O
+c	O
+.	O
+)	O
+for	O
+five	O
+days	O
+","	O
+resulting	O
+in	O
+stable	O
+parkinsonism	B-NP
+.	O
+	
+Levodopa	O
+(	O
+15	O
+mg	O
+/	O
+kg	O
+and	O
+benserazide	O
+","	O
+3	O
+.	O
+75	O
+mg	O
+/	O
+kg	O
+)	O
+p	O
+.	O
+o	O
+.	O
+	
+b	O
+.	O
+i	O
+.	O
+d	O
+","	O
+was	O
+administered	O
+for	O
+30	O
+days	O
+.	O
+	
+Animals	O
+were	O
+evaluated	O
+for	O
+parkinsonian	B-NP
+disability	I-NP
+","	O
+dyskinesia	B-NP
+and	O
+on	O
+-	O
+time	O
+(	O
+motor	O
+fluctuations	O
+)	O
+and	O
+neuropsychiatric	B-NP
+-	I-NP
+like	I-NP
+behaviors	I-NP
+on	O
+Day	O
+0	O
+(	O
+prior	O
+to	O
+levodopa	O
+)	O
+and	O
+on	O
+Days	O
+1	O
+","	O
+7	O
+","	O
+13	O
+","	O
+27	O
+and	O
+30	O
+of	O
+treatment	O
+using	O
+post	O
+hoc	O
+DVD	O
+analysis	O
+by	O
+a	O
+trained	O
+rater	O
+","	O
+blind	O
+to	O
+the	O
+treatment	O
+day	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+neuropsychiatric	B-NP
+-	I-NP
+like	I-NP
+behavior	I-NP
+rating	O
+scale	O
+demonstrated	O
+high	O
+interrater	O
+reliability	O
+between	O
+three	O
+trained	O
+raters	O
+of	O
+differing	O
+professional	O
+backgrounds	O
+.	O
+	
+As	O
+anticipated	O
+","	O
+animals	O
+exhibited	O
+a	O
+progressive	O
+increase	O
+in	O
+levodopa	O
+-	O
+induced	O
+motor	O
+fluctuations	O
+","	O
+dyskinesia	B-NP
+and	O
+wearing	O
+-	O
+off	O
+","	O
+that	O
+correlated	O
+with	O
+the	O
+duration	O
+of	O
+levodopa	O
+therapy	O
+.	O
+	
+In	O
+contrast	O
+","	O
+levodopa	O
+-	O
+induced	O
+neuropsychiatric	B-NP
+-	I-NP
+like	I-NP
+behaviors	I-NP
+were	O
+present	O
+on	O
+Day	O
+1	O
+of	O
+levodopa	O
+treatment	O
+and	O
+their	O
+severity	O
+did	O
+not	O
+correlate	O
+with	O
+duration	O
+of	O
+treatment	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+data	O
+suggest	O
+that	O
+neuropsychiatric	B-NP
+disorders	I-NP
+in	O
+PD	B-NP
+are	O
+more	O
+likely	O
+an	O
+interaction	O
+between	O
+levodopa	O
+and	O
+the	O
+disease	O
+state	O
+than	O
+a	O
+consequence	O
+of	O
+sensitisation	O
+to	O
+repeated	O
+dopaminergic	O
+therapy	O
+.	O
+	
+Contrast	O
+medium	O
+nephrotoxicity	B-NP
+after	O
+renal	O
+artery	O
+and	O
+coronary	O
+angioplasty	O
+.	O
+	
+BACKGROUND	O
+:	O
+Renal	B-NP
+dysfunction	I-NP
+induced	O
+by	O
+iodinated	O
+contrast	O
+medium	O
+(	O
+CM	O
+)	O
+administration	O
+can	O
+minimize	O
+the	O
+benefit	O
+of	O
+the	O
+interventional	O
+procedure	O
+in	O
+patients	O
+undergoing	O
+renal	O
+angioplasty	O
+(	O
+PTRA	O
+)	O
+.	O
+	
+PURPOSE	O
+:	O
+To	O
+compare	O
+the	O
+susceptibility	O
+to	O
+nephrotoxic	B-NP
+effect	O
+of	O
+CM	O
+in	O
+patients	O
+undergoing	O
+PTRA	O
+with	O
+that	O
+of	O
+patients	O
+submitted	O
+to	O
+percutaneous	O
+coronary	O
+intervention	O
+(	O
+PCI	O
+)	O
+.	O
+	
+MATERIAL	O
+AND	O
+METHODS	O
+:	O
+A	O
+total	O
+of	O
+33	O
+patients	O
+successfully	O
+treated	O
+with	O
+PTRA	O
+(	O
+PTRA	O
+group	O
+","	O
+mean	O
+age	O
+70	O
++	O
+/	O
+-	O
+12	O
+years	O
+","	O
+23	O
+female	O
+","	O
+basal	O
+creatinine	O
+1	O
+.	O
+46	O
++	O
+/	O
+-	O
+0	O
+.	O
+79	O
+","	O
+range	O
+0	O
+.	O
+7	O
+-	O
+4	O
+.	O
+9	O
+mg	O
+/	O
+dl	O
+)	O
+were	O
+compared	O
+with	O
+33	O
+patients	O
+undergoing	O
+successful	O
+PCI	O
+(	O
+PCI	O
+group	O
+)	O
+","	O
+matched	O
+for	O
+basal	O
+creatinine	O
+(	O
+1	O
+.	O
+44	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+","	O
+range	O
+0	O
+.	O
+7	O
+-	O
+3	O
+.	O
+4	O
+mg	O
+/	O
+dl	O
+)	O
+","	O
+gender	O
+","	O
+and	O
+age	O
+.	O
+	
+In	O
+both	O
+groups	O
+postprocedural	O
+(	O
+48	O
+h	O
+)	O
+serum	O
+creatinine	O
+was	O
+measured	O
+.	O
+	
+RESULTS	O
+:	O
+Postprocedural	O
+creatinine	O
+level	O
+decreased	O
+nonsignificantly	O
+in	O
+the	O
+PTRA	O
+group	O
+(	O
+1	O
+.	O
+46	O
++	O
+/	O
+-	O
+0	O
+.	O
+8	O
+vs	O
+.	O
+1	O
+.	O
+34	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+dl	O
+","	O
+P	O
+=	O
+NS	O
+)	O
+and	O
+increased	O
+significantly	O
+in	O
+the	O
+PCI	O
+group	O
+(	O
+1	O
+.	O
+44	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+vs	O
+.	O
+1	O
+.	O
+57	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+mg	O
+/	O
+dl	O
+","	O
+P	O
+<	O
+0	O
+.	O
+2	O
+)	O
+.	O
+	
+Changes	O
+in	O
+serum	O
+creatinine	O
+after	O
+intervention	O
+(	O
+after	O
+-	O
+before	O
+)	O
+were	O
+significantly	O
+different	O
+between	O
+the	O
+PTRA	O
+and	O
+PCI	O
+groups	O
+(	O
+-	O
+0	O
+.	O
+12	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+vs	O
+.	O
+0	O
+.	O
+13	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+","	O
+P	O
+=	O
+0	O
+.	O
+14	O
+)	O
+.	O
+	
+This	O
+difference	O
+was	O
+not	O
+related	O
+to	O
+either	O
+a	O
+different	O
+clinical	O
+risk	O
+profile	O
+or	O
+to	O
+the	O
+volume	O
+of	O
+CM	O
+administered	O
+.	O
+	
+CONCLUSION	O
+:	O
+In	O
+this	O
+preliminary	O
+study	O
+patients	O
+submitted	O
+to	O
+PTRA	O
+showed	O
+a	O
+lower	O
+susceptibility	O
+to	O
+renal	B-NP
+damage	I-NP
+induced	O
+by	O
+CM	O
+administration	O
+than	O
+PCI	O
+patients	O
+.	O
+	
+The	O
+effectiveness	O
+of	O
+PTRA	O
+on	O
+renal	O
+function	O
+seems	O
+to	O
+be	O
+barely	O
+influenced	O
+by	O
+CM	O
+toxicity	B-NP
+.	O
+	
+Diphenhydramine	O
+prevents	O
+the	O
+haemodynamic	O
+changes	O
+of	O
+cimetidine	O
+in	O
+ICU	O
+patients	O
+.	O
+	
+Cimetidine	O
+","	O
+a	O
+histamine	O
+2	O
+(	O
+H2	O
+)	O
+antagonist	O
+","	O
+produces	O
+a	O
+decrease	O
+in	O
+arterial	O
+pressure	O
+due	O
+to	O
+vasodilatation	O
+","	O
+especially	O
+in	O
+critically	O
+ill	O
+patients	O
+.	O
+	
+This	O
+may	O
+be	O
+because	O
+cimetidine	O
+acts	O
+as	O
+a	O
+histamine	O
+agonist	O
+.	O
+	
+We	O
+","	O
+therefore	O
+","	O
+investigated	O
+the	O
+effects	O
+of	O
+the	O
+histamine	O
+1	O
+(	O
+H1	O
+)	O
+receptor	O
+antagonist	O
+","	O
+diphenhydramine	O
+","	O
+on	O
+the	O
+haemodynamic	O
+changes	O
+observed	O
+after	O
+cimetidine	O
+in	O
+ICU	O
+patients	O
+.	O
+	
+Each	O
+patient	O
+was	O
+studied	O
+on	O
+two	O
+separate	O
+days	O
+.	O
+	
+In	O
+a	O
+random	O
+fashion	O
+","	O
+they	O
+received	O
+cimetidine	O
+200	O
+mg	O
+iv	O
+on	O
+one	O
+day	O
+","	O
+and	O
+on	O
+the	O
+other	O
+","	O
+a	O
+pretreatment	O
+of	O
+diphenhydramine	O
+40	O
+mg	O
+iv	O
+with	O
+cimetidine	O
+200	O
+mg	O
+iv	O
+.	O
+	
+In	O
+the	O
+non	O
+-	O
+pretreatment	O
+group	O
+","	O
+mean	O
+arterial	O
+pressure	O
+(	O
+MAP	O
+)	O
+decreased	O
+from	O
+107	O
+.	O
+4	O
++	O
+/	O
+-	O
+8	O
+.	O
+4	O
+mmHg	O
+to	O
+86	O
+.	O
+7	O
++	O
+/	O
+-	O
+11	O
+.	O
+4	O
+mmHg	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+two	O
+minutes	O
+after	O
+cimetidine	O
+.	O
+	
+Also	O
+","	O
+systemic	O
+vascular	O
+resistance	O
+(	O
+SVR	O
+)	O
+decreased	O
+during	O
+the	O
+eight	O
+-	O
+minute	O
+observation	O
+period	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+In	O
+contrast	O
+","	O
+in	O
+the	O
+pretreatment	O
+group	O
+","	O
+little	O
+haemodynamic	O
+change	O
+was	O
+seen	O
+.	O
+	
+We	O
+conclude	O
+that	O
+an	O
+H1	O
+antagonist	O
+may	O
+be	O
+useful	O
+in	O
+preventing	O
+hypotension	B-NP
+caused	O
+by	O
+iv	O
+cimetidine	O
+","	O
+since	O
+the	O
+vasodilating	O
+activity	O
+of	O
+cimetidine	O
+is	O
+mediated	O
+","	O
+in	O
+part	O
+","	O
+through	O
+the	O
+H1	O
+receptor	O
+.	O
+	
+Medical	O
+and	O
+psychiatric	O
+outcomes	O
+for	O
+patients	O
+transplanted	O
+for	O
+acetaminophen	O
+-	O
+induced	O
+acute	B-NP
+liver	I-NP
+failure	I-NP
+:	O
+a	O
+case	O
+-	O
+control	O
+study	O
+.	O
+	
+BACKGROUND	O
+:	O
+Acetaminophen	O
+-	O
+induced	O
+hepatotoxicity	B-NP
+is	O
+the	O
+most	O
+common	O
+cause	O
+of	O
+acute	B-NP
+liver	I-NP
+failure	I-NP
+(	O
+ALF	B-NP
+)	O
+in	O
+the	O
+UK	O
+.	O
+	
+Patients	O
+often	O
+consume	O
+the	O
+drug	O
+with	O
+suicidal	O
+intent	O
+or	O
+with	O
+a	O
+background	O
+of	O
+substance	O
+dependence	O
+.	O
+	
+AIMS	O
+AND	O
+METHODS	O
+:	O
+We	O
+compared	O
+the	O
+severity	O
+of	O
+pretransplant	O
+illness	O
+","	O
+psychiatric	O
+co	O
+-	O
+morbidity	O
+","	O
+medical	O
+and	O
+psychosocial	O
+outcomes	O
+of	O
+all	O
+patients	O
+who	O
+had	O
+undergone	O
+liver	O
+transplantation	O
+(	O
+LT	O
+)	O
+emergently	O
+between	O
+1999	O
+-	O
+2004	O
+for	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B-NP
+(	O
+n	O
+=	O
+36	O
+)	O
+with	O
+age	O
+-	O
+and	O
+sex	O
+-	O
+matched	O
+patients	O
+undergoing	O
+emergent	O
+LT	O
+for	O
+non	O
+-	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B-NP
+(	O
+n	O
+=	O
+35	O
+)	O
+and	O
+elective	O
+LT	O
+for	O
+chronic	B-NP
+liver	I-NP
+disease	I-NP
+(	O
+CLD	B-NP
+","	O
+n	O
+=	O
+34	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+Acetaminophen	O
+-	O
+induced	O
+ALF	B-NP
+patients	O
+undergoing	O
+LT	O
+had	O
+a	O
+greater	O
+severity	O
+of	O
+pre	O
+-	O
+LT	O
+illness	O
+reflected	O
+by	O
+higher	O
+Acute	O
+Physiology	O
+and	O
+Chronic	O
+Health	O
+Evaluation	O
+II	O
+scores	O
+and	O
+requirement	O
+for	O
+organ	O
+support	O
+compared	O
+with	O
+the	O
+other	O
+two	O
+groups	O
+.	O
+	
+Twenty	O
+(	O
+56	O
+%	O
+)	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B-NP
+patients	O
+had	O
+a	O
+formal	O
+psychiatric	O
+diagnosis	O
+before	O
+LT	O
+(	O
+non	O
+-	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B-NP
+=	O
+0	O
+/	O
+35	O
+","	O
+CLD	B-NP
+=	O
+2	O
+/	O
+34	O
+;	O
+P	O
+<	O
+0	O
+.	O
+1	O
+for	O
+all	O
+)	O
+and	O
+nine	O
+(	O
+25	O
+%	O
+)	O
+had	O
+a	O
+previous	O
+suicide	O
+attempt	O
+.	O
+	
+During	O
+follow	O
+-	O
+up	O
+(	O
+median	O
+5	O
+years	O
+)	O
+","	O
+there	O
+were	O
+no	O
+significant	O
+differences	O
+in	O
+rejection	O
+(	O
+acute	O
+and	O
+chronic	O
+)	O
+","	O
+graft	O
+failure	O
+or	O
+survival	O
+between	O
+the	O
+groups	O
+(	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B-NP
+1	O
+year	O
+87	O
+%	O
+","	O
+5	O
+years	O
+75	O
+%	O
+;	O
+non	O
+-	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B-NP
+88	O
+%	O
+","	O
+78	O
+%	O
+;	O
+CLD	B-NP
+93	O
+%	O
+","	O
+82	O
+%	O
+:	O
+P	O
+>	O
+0	O
+.	O
+6	O
+log	O
+rank	O
+)	O
+.	O
+	
+Two	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B-NP
+patients	O
+reattempted	O
+suicide	O
+post	O
+-	O
+LT	O
+(	O
+one	O
+died	O
+8	O
+years	O
+post	O
+-	O
+LT	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Despite	O
+a	O
+high	O
+prevalence	O
+of	O
+psychiatric	O
+disturbance	O
+","	O
+outcomes	O
+for	O
+patients	O
+transplanted	O
+emergently	O
+for	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B-NP
+were	O
+comparable	O
+to	O
+those	O
+transplanted	O
+for	O
+non	O
+-	O
+acetaminophen	O
+-	O
+induced	O
+ALF	B-NP
+and	O
+electively	O
+for	O
+CLD	B-NP
+.	O
+	
+Multidisciplinary	O
+approaches	O
+with	O
+long	O
+-	O
+term	O
+psychiatric	O
+follow	O
+-	O
+up	O
+may	O
+contribute	O
+to	O
+low	O
+post	O
+-	O
+transplant	O
+suicide	O
+rates	O
+seen	O
+and	O
+low	O
+rates	O
+of	O
+graft	O
+loss	O
+because	O
+of	O
+non	O
+-	O
+compliance	O
+.	O
+	
+Antithrombotic	O
+drug	O
+use	O
+","	O
+cerebral	B-NP
+microbleeds	I-NP
+","	O
+and	O
+intracerebral	B-NP
+hemorrhage	I-NP
+:	O
+a	O
+systematic	O
+review	O
+of	O
+published	O
+and	O
+unpublished	O
+studies	O
+.	O
+	
+BACKGROUND	O
+AND	O
+PURPOSE	O
+:	O
+Cerebral	B-NP
+microbleeds	I-NP
+(	O
+MB	B-NP
+)	O
+are	O
+potential	O
+risk	O
+factors	O
+for	O
+intracerebral	B-NP
+hemorrhage	I-NP
+(	O
+ICH	B-NP
+)	O
+","	O
+but	O
+it	O
+is	O
+unclear	O
+if	O
+they	O
+are	O
+a	O
+contraindication	O
+to	O
+using	O
+antithrombotic	O
+drugs	O
+.	O
+	
+Insights	O
+could	O
+be	O
+gained	O
+by	O
+pooling	O
+data	O
+on	O
+MB	B-NP
+frequency	O
+stratified	O
+by	O
+antithrombotic	O
+use	O
+in	O
+cohorts	O
+with	O
+ICH	B-NP
+and	O
+ischemic	B-NP
+stroke	I-NP
+(	O
+IS	B-NP
+)	O
+/	O
+transient	B-NP
+ischemic	I-NP
+attack	I-NP
+(	O
+TIA	B-NP
+)	O
+.	O
+	
+METHODS	O
+:	O
+We	O
+performed	O
+a	O
+systematic	O
+review	O
+of	O
+published	O
+and	O
+unpublished	O
+data	O
+from	O
+cohorts	O
+with	O
+stroke	B-NP
+or	O
+TIA	B-NP
+to	O
+compare	O
+the	O
+presence	O
+of	O
+MB	B-NP
+in	O
+:	O
+(	O
+1	O
+)	O
+antithrombotic	O
+users	O
+vs	O
+nonantithrombotic	O
+users	O
+with	O
+ICH	B-NP
+;	O
+(	O
+2	O
+)	O
+antithrombotic	O
+users	O
+vs	O
+nonusers	O
+with	O
+IS	B-NP
+/	O
+TIA	B-NP
+;	O
+and	O
+(	O
+3	O
+)	O
+ICH	B-NP
+vs	O
+ischemic	B-NP
+events	O
+stratified	O
+by	O
+antithrombotic	O
+use	O
+.	O
+	
+We	O
+also	O
+analyzed	O
+published	O
+and	O
+unpublished	O
+follow	O
+-	O
+up	O
+data	O
+to	O
+determine	O
+the	O
+risk	O
+of	O
+ICH	B-NP
+in	O
+antithrombotic	O
+users	O
+with	O
+MB	B-NP
+.	O
+	
+RESULTS	O
+:	O
+In	O
+a	O
+pooled	O
+analysis	O
+of	O
+1460	O
+ICH	B-NP
+and	O
+3817	O
+IS	B-NP
+/	O
+TIA	B-NP
+","	O
+MB	B-NP
+were	O
+more	O
+frequent	O
+in	O
+ICH	B-NP
+vs	O
+IS	B-NP
+/	O
+TIA	B-NP
+in	O
+all	O
+treatment	O
+groups	O
+","	O
+but	O
+the	O
+excess	O
+increased	O
+from	O
+2	O
+.	O
+8	O
+(	O
+odds	O
+ratio	O
+;	O
+range	O
+","	O
+2	O
+.	O
+3	O
+-	O
+3	O
+.	O
+5	O
+)	O
+in	O
+nonantithrombotic	O
+users	O
+to	O
+5	O
+.	O
+7	O
+(	O
+range	O
+","	O
+3	O
+.	O
+4	O
+-	O
+9	O
+.	O
+7	O
+)	O
+in	O
+antiplatelet	O
+users	O
+and	O
+8	O
+.	O
+0	O
+(	O
+range	O
+","	O
+3	O
+.	O
+5	O
+-	O
+17	O
+.	O
+8	O
+)	O
+in	O
+warfarin	O
+users	O
+(	O
+P	O
+difference	O
+=	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+There	O
+was	O
+also	O
+an	O
+excess	O
+of	O
+MB	B-NP
+in	O
+warfarin	O
+users	O
+vs	O
+nonusers	O
+with	O
+ICH	B-NP
+(	O
+OR	O
+","	O
+2	O
+.	O
+7	O
+;	O
+95	O
+%	O
+CI	O
+","	O
+1	O
+.	O
+6	O
+-	O
+4	O
+.	O
+4	O
+;	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+but	O
+none	O
+in	O
+warfarin	O
+users	O
+with	O
+IS	B-NP
+/	O
+TIA	B-NP
+(	O
+OR	O
+","	O
+1	O
+.	O
+3	O
+;	O
+95	O
+%	O
+CI	O
+","	O
+0	O
+.	O
+9	O
+-	O
+1	O
+.	O
+7	O
+;	O
+P	O
+=	O
+0	O
+.	O
+33	O
+;	O
+P	O
+difference	O
+=	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+There	O
+was	O
+a	O
+smaller	O
+excess	O
+of	O
+MB	B-NP
+in	O
+antiplatelet	O
+users	O
+vs	O
+nonusers	O
+with	O
+ICH	B-NP
+(	O
+OR	O
+","	O
+1	O
+.	O
+7	O
+;	O
+95	O
+%	O
+CI	O
+","	O
+1	O
+.	O
+3	O
+-	O
+2	O
+.	O
+3	O
+;	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+","	O
+but	O
+findings	O
+were	O
+similar	O
+for	O
+antiplatelet	O
+users	O
+with	O
+IS	B-NP
+/	O
+TIA	B-NP
+(	O
+OR	O
+","	O
+1	O
+.	O
+4	O
+;	O
+95	O
+%	O
+CI	O
+","	O
+1	O
+.	O
+2	O
+-	O
+1	O
+.	O
+7	O
+;	O
+P	O
+<	O
+0	O
+.	O
+1	O
+;	O
+P	O
+difference	O
+=	O
+0	O
+.	O
+25	O
+)	O
+.	O
+	
+In	O
+pooled	O
+follow	O
+-	O
+up	O
+data	O
+for	O
+768	O
+antithrombotic	O
+users	O
+","	O
+presence	O
+of	O
+MB	B-NP
+at	O
+baseline	O
+was	O
+associated	O
+with	O
+a	O
+substantially	O
+increased	O
+risk	O
+of	O
+subsequent	O
+ICH	B-NP
+(	O
+OR	O
+","	O
+12	O
+.	O
+1	O
+;	O
+95	O
+%	O
+CI	O
+","	O
+3	O
+.	O
+4	O
+-	O
+42	O
+.	O
+5	O
+;	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+excess	O
+of	O
+MB	B-NP
+in	O
+warfarin	O
+users	O
+with	O
+ICH	B-NP
+compared	O
+to	O
+other	O
+groups	O
+suggests	O
+that	O
+MB	B-NP
+increase	O
+the	O
+risk	O
+of	O
+warfarin	O
+-	O
+associated	O
+ICH	B-NP
+.	O
+	
+Limited	O
+prospective	O
+data	O
+corroborate	O
+these	O
+findings	O
+","	O
+but	O
+larger	O
+prospective	O
+studies	O
+are	O
+urgently	O
+required	O
+.	O
+	
+Studies	O
+of	O
+synergy	O
+between	O
+morphine	O
+and	O
+a	O
+novel	O
+sodium	O
+channel	O
+blocker	O
+","	O
+CNSB002	O
+","	O
+in	O
+rat	O
+models	O
+of	O
+inflammatory	O
+and	O
+neuropathic	B-NP
+pain	I-NP
+.	O
+	
+OBJECTIVE	O
+:	O
+This	O
+study	O
+determined	O
+the	O
+antihyperalgesic	O
+effect	O
+of	O
+CNSB002	O
+","	O
+a	O
+sodium	O
+channel	O
+blocker	O
+with	O
+antioxidant	O
+properties	O
+given	O
+alone	O
+and	O
+in	O
+combinations	O
+with	O
+morphine	O
+in	O
+rat	O
+models	O
+of	O
+inflammatory	O
+and	O
+neuropathic	B-NP
+pain	I-NP
+.	O
+	
+DESIGN	O
+:	O
+Dose	O
+response	O
+curves	O
+for	O
+nonsedating	O
+doses	O
+of	O
+morphine	O
+and	O
+CNSB002	O
+given	O
+intraperitoneally	O
+alone	O
+and	O
+together	O
+in	O
+combinations	O
+were	O
+constructed	O
+for	O
+antihyperalgesic	O
+effect	O
+using	O
+paw	O
+withdrawal	O
+from	O
+noxious	O
+heat	O
+in	O
+two	O
+rat	O
+pain	B-NP
+models	O
+:	O
+carrageenan	O
+-	O
+induced	O
+paw	O
+inflammation	B-NP
+and	O
+streptozotocin	O
+(	O
+STZ	O
+)	O
+-	O
+induced	O
+diabetic	B-NP
+neuropathy	I-NP
+.	O
+	
+RESULTS	O
+:	O
+The	O
+maximum	O
+nonsedating	O
+doses	O
+were	O
+:	O
+morphine	O
+","	O
+3	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+;	O
+CNSB002	O
+10	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+;	O
+5	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+CNSB002	O
+with	O
+morphine	O
+3	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+in	O
+combination	O
+.	O
+	
+The	O
+doses	O
+calculated	O
+to	O
+cause	O
+50	O
+%	O
+reversal	O
+of	O
+hyperalgesia	B-NP
+(	O
+ED50	O
+)	O
+were	O
+7	O
+.	O
+54	O
+(	O
+1	O
+.	O
+81	O
+)	O
+and	O
+4	O
+.	O
+83	O
+(	O
+1	O
+.	O
+54	O
+)	O
+in	O
+the	O
+carrageenan	O
+model	O
+and	O
+44	O
+.	O
+18	O
+(	O
+1	O
+.	O
+37	O
+)	O
+and	O
+9	O
+.	O
+14	O
+(	O
+1	O
+.	O
+24	O
+)	O
+in	O
+the	O
+STZ	O
+-	O
+induced	O
+neuropathy	B-NP
+model	O
+for	O
+CNSB002	O
+and	O
+morphine	O
+","	O
+respectively	O
+(	O
+mg	O
+/	O
+kg	O
+;	O
+mean	O
+","	O
+SEM	O
+)	O
+.	O
+	
+These	O
+values	O
+were	O
+greater	O
+than	O
+the	O
+maximum	O
+nonsedating	O
+doses	O
+.	O
+	
+The	O
+ED50	O
+values	O
+for	O
+morphine	O
+when	O
+given	O
+in	O
+combination	O
+with	O
+CNSB002	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+were	O
+less	O
+than	O
+the	O
+maximum	O
+nonsedating	O
+dose	O
+:	O
+0	O
+.	O
+56	O
+(	O
+1	O
+.	O
+55	O
+)	O
+in	O
+the	O
+carrageenan	O
+model	O
+and	O
+1	O
+.	O
+37	O
+(	O
+1	O
+.	O
+23	O
+)	O
+in	O
+the	O
+neuropathy	B-NP
+model	O
+(	O
+mg	O
+/	O
+kg	O
+;	O
+mean	O
+","	O
+SEM	O
+)	O
+.	O
+	
+The	O
+antinociception	O
+after	O
+morphine	O
+(	O
+3	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+increased	O
+by	O
+co	O
+-	O
+administration	O
+with	O
+CNSB002	O
+from	O
+28	O
+.	O
+0	O
+and	O
+31	O
+.	O
+7	O
+%	O
+to	O
+114	O
+.	O
+6	O
+and	O
+56	O
+.	O
+9	O
+%	O
+reversal	O
+of	O
+hyperalgesia	B-NP
+in	O
+the	O
+inflammatory	O
+and	O
+neuropathic	B-NP
+models	O
+","	O
+respectively	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+;	O
+one	O
+-	O
+way	O
+analysis	O
+of	O
+variance	O
+-	O
+significantly	O
+greater	O
+than	O
+either	O
+drug	O
+given	O
+alone	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+maximum	O
+antihyperalgesic	O
+effect	O
+achievable	O
+with	O
+nonsedating	O
+doses	O
+of	O
+morphine	O
+may	O
+be	O
+increased	O
+significantly	O
+when	O
+the	O
+drug	O
+is	O
+used	O
+in	O
+combination	O
+with	O
+CNSB002	O
+.	O
+	
+Heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+:	O
+a	O
+practical	O
+review	O
+.	O
+	
+Heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+(	O
+HIT	B-NP
+)	O
+remains	O
+under	O
+-	O
+recognized	O
+despite	O
+its	O
+potentially	O
+devastating	O
+outcomes	O
+.	O
+	
+It	O
+begins	O
+when	O
+heparin	O
+exposure	O
+stimulates	O
+the	O
+formation	O
+of	O
+heparin	O
+-	O
+platelet	O
+factor	O
+4	O
+antibodies	O
+","	O
+which	O
+in	O
+turn	O
+triggers	O
+the	O
+release	O
+of	O
+procoagulant	O
+platelet	O
+particles	O
+.	O
+	
+Thrombosis	B-NP
+and	O
+thrombocytopenia	B-NP
+that	O
+follow	O
+comprise	O
+the	O
+2	O
+hallmark	O
+traits	O
+of	O
+HIT	B-NP
+","	O
+with	O
+the	O
+former	O
+largely	O
+responsible	O
+for	O
+significant	O
+vascular	O
+complications	O
+.	O
+	
+The	O
+prevalence	O
+of	O
+HIT	B-NP
+varies	O
+among	O
+several	O
+subgroups	O
+","	O
+with	O
+greater	O
+incidence	O
+in	O
+surgical	O
+as	O
+compared	O
+with	O
+medical	O
+populations	O
+.	O
+	
+HIT	B-NP
+must	O
+be	O
+acknowledged	O
+for	O
+its	O
+intense	O
+predilection	O
+for	O
+thrombosis	B-NP
+and	O
+suspected	O
+whenever	O
+thrombosis	B-NP
+occurs	O
+after	O
+heparin	O
+exposure	O
+.	O
+	
+Early	O
+recognition	O
+that	O
+incorporates	O
+the	O
+clinical	O
+and	O
+serologic	O
+clues	O
+is	O
+paramount	O
+to	O
+timely	O
+institution	O
+of	O
+treatment	O
+","	O
+as	O
+its	O
+delay	O
+may	O
+result	O
+in	O
+catastrophic	O
+outcomes	O
+.	O
+	
+The	O
+treatment	O
+of	O
+HIT	B-NP
+mandates	O
+an	O
+immediate	O
+cessation	O
+of	O
+all	O
+heparin	O
+exposure	O
+and	O
+the	O
+institution	O
+of	O
+an	O
+antithrombotic	O
+therapy	O
+","	O
+most	O
+commonly	O
+using	O
+a	O
+direct	O
+thrombin	O
+inhibitor	O
+.	O
+	
+Current	O
+"	O
+diagnostic	O
+"	O
+tests	O
+","	O
+which	O
+primarily	O
+include	O
+functional	O
+and	O
+antigenic	O
+assays	O
+","	O
+have	O
+more	O
+of	O
+a	O
+confirmatory	O
+than	O
+diagnostic	O
+role	O
+in	O
+the	O
+management	O
+of	O
+HIT	B-NP
+.	O
+	
+Special	O
+attention	O
+must	O
+be	O
+paid	O
+to	O
+cardiac	O
+patients	O
+who	O
+are	O
+often	O
+exposed	O
+to	O
+heparin	O
+multiple	O
+times	O
+during	O
+their	O
+course	O
+of	O
+treatment	O
+.	O
+	
+Direct	O
+thrombin	O
+inhibitors	O
+are	O
+appropriate	O
+","	O
+evidence	O
+-	O
+based	O
+alternatives	O
+to	O
+heparin	O
+in	O
+patients	O
+with	O
+a	O
+history	O
+of	O
+HIT	B-NP
+","	O
+who	O
+need	O
+to	O
+undergo	O
+percutaneous	O
+coronary	O
+intervention	O
+.	O
+	
+As	O
+heparin	O
+remains	O
+one	O
+of	O
+the	O
+most	O
+frequently	O
+used	O
+medications	O
+today	O
+with	O
+potential	O
+for	O
+HIT	B-NP
+with	O
+every	O
+heparin	O
+exposure	O
+","	O
+a	O
+close	O
+vigilance	O
+of	O
+platelet	O
+counts	O
+must	O
+be	O
+practiced	O
+whenever	O
+heparin	O
+is	O
+initiated	O
+.	O
+	
+Abductor	O
+paralysis	B-NP
+after	O
+botox	O
+injection	O
+for	O
+adductor	B-NP
+spasmodic	I-NP
+dysphonia	I-NP
+.	O
+	
+OBJECTIVES	O
+/	O
+HYPOTHESIS	O
+:	O
+Botulinum	O
+toxin	O
+(	O
+Botox	O
+)	O
+injections	O
+into	O
+the	O
+thyroarytenoid	O
+muscles	O
+are	O
+the	O
+current	O
+standard	O
+of	O
+care	O
+for	O
+adductor	B-NP
+spasmodic	I-NP
+dysphonia	I-NP
+(	O
+ADSD	B-NP
+)	O
+.	O
+	
+Reported	O
+adverse	O
+effects	O
+include	O
+a	O
+period	O
+of	O
+breathiness	O
+","	O
+throat	B-NP
+pain	I-NP
+","	O
+and	O
+difficulty	O
+with	O
+swallowing	O
+liquids	O
+.	O
+	
+Here	O
+we	O
+report	O
+multiple	O
+cases	O
+of	O
+bilateral	O
+abductor	O
+paralysis	B-NP
+following	O
+Botox	O
+injections	O
+for	O
+ADSD	B-NP
+","	O
+a	O
+complication	O
+previously	O
+unreported	O
+.	O
+	
+STUDY	O
+DESIGN	O
+:	O
+Retrospective	O
+case	O
+series	O
+.	O
+	
+METHODS	O
+:	O
+Patients	O
+that	O
+received	O
+Botox	O
+injections	O
+for	O
+spasmodic	B-NP
+dysphonia	I-NP
+between	O
+January	O
+2000	O
+and	O
+October	O
+2009	O
+were	O
+evaluated	O
+.	O
+	
+Patients	O
+with	O
+ADSD	B-NP
+were	O
+identified	O
+.	O
+	
+The	O
+number	O
+of	O
+treatments	O
+received	O
+and	O
+adverse	O
+effects	O
+were	O
+noted	O
+.	O
+	
+For	O
+patients	O
+with	O
+bilateral	O
+abductor	O
+paralysis	B-NP
+","	O
+age	O
+","	O
+sex	O
+","	O
+paralytic	O
+Botox	O
+dose	O
+","	O
+prior	O
+Botox	O
+dose	O
+","	O
+and	O
+course	O
+following	O
+paralysis	B-NP
+were	O
+noted	O
+.	O
+	
+RESULTS	O
+:	O
+From	O
+a	O
+database	O
+of	O
+452	O
+patients	O
+receiving	O
+Botox	O
+","	O
+352	O
+patients	O
+had	O
+been	O
+diagnosed	O
+with	O
+ADSD	B-NP
+.	O
+	
+Of	O
+these	O
+352	O
+patients	O
+","	O
+eight	O
+patients	O
+suffered	O
+bilateral	O
+abductor	O
+paralysis	B-NP
+","	O
+and	O
+two	O
+suffered	O
+this	O
+complication	O
+twice	O
+.	O
+	
+All	O
+affected	O
+patients	O
+were	O
+females	O
+over	O
+the	O
+age	O
+of	O
+50	O
+years	O
+.	O
+	
+Most	O
+patients	O
+had	O
+received	O
+treatments	O
+prior	O
+to	O
+abductor	O
+paralysis	B-NP
+and	O
+continued	O
+receiving	O
+after	O
+paralysis	B-NP
+.	O
+	
+Seven	O
+patients	O
+recovered	O
+after	O
+a	O
+brief	O
+period	O
+of	O
+activity	O
+restrictions	O
+","	O
+and	O
+one	O
+underwent	O
+a	O
+tracheotomy	O
+.	O
+	
+The	O
+incidence	O
+of	O
+abductor	O
+paralysis	B-NP
+after	O
+Botox	O
+injection	O
+for	O
+ADSD	B-NP
+was	O
+0	O
+.	O
+34	O
+%	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Bilateral	O
+abductor	O
+paralysis	B-NP
+is	O
+a	O
+rare	O
+complication	O
+of	O
+Botox	O
+injections	O
+for	O
+ADSD	B-NP
+","	O
+causing	O
+difficulty	O
+with	O
+breathing	O
+upon	O
+exertion	O
+.	O
+	
+The	O
+likely	O
+mechanism	O
+of	O
+paralysis	B-NP
+is	O
+diffusion	O
+of	O
+Botox	O
+around	O
+the	O
+muscular	O
+process	O
+of	O
+the	O
+arytenoid	O
+to	O
+the	O
+posterior	O
+cricoarytenoid	O
+muscles	O
+.	O
+	
+The	O
+paralysis	B-NP
+is	O
+temporary	O
+","	O
+and	O
+watchful	O
+waiting	O
+with	O
+restriction	O
+of	O
+activity	O
+is	O
+the	O
+recommended	O
+management	O
+.	O
+	
+Mitochondrial	B-NP
+impairment	I-NP
+contributes	O
+to	O
+cocaine	O
+-	O
+induced	O
+cardiac	B-NP
+dysfunction	I-NP
+:	O
+Prevention	O
+by	O
+the	O
+targeted	O
+antioxidant	O
+MitoQ	O
+.	O
+	
+The	O
+goal	O
+of	O
+this	O
+study	O
+was	O
+to	O
+assess	O
+mitochondrial	O
+function	O
+and	O
+ROS	O
+production	O
+in	O
+an	O
+experimental	O
+model	O
+of	O
+cocaine	O
+-	O
+induced	O
+cardiac	B-NP
+dysfunction	I-NP
+.	O
+	
+We	O
+hypothesized	O
+that	O
+cocaine	B-NP
+abuse	I-NP
+may	O
+lead	O
+to	O
+altered	O
+mitochondrial	O
+function	O
+that	O
+in	O
+turn	O
+may	O
+cause	O
+left	B-NP
+ventricular	I-NP
+dysfunction	I-NP
+.	O
+	
+Seven	O
+days	O
+of	O
+cocaine	O
+administration	O
+to	O
+rats	O
+led	O
+to	O
+an	O
+increased	O
+oxygen	O
+consumption	O
+detected	O
+in	O
+cardiac	O
+fibers	O
+","	O
+specifically	O
+through	O
+complex	O
+I	O
+and	O
+complex	O
+III	O
+.	O
+	
+ROS	O
+levels	O
+were	O
+increased	O
+","	O
+specifically	O
+in	O
+interfibrillar	O
+mitochondria	O
+.	O
+	
+In	O
+parallel	O
+there	O
+was	O
+a	O
+decrease	O
+in	O
+ATP	O
+synthesis	O
+","	O
+whereas	O
+no	O
+difference	O
+was	O
+observed	O
+in	O
+subsarcolemmal	O
+mitochondria	O
+.	O
+	
+This	O
+uncoupling	O
+effect	O
+on	O
+oxidative	O
+phosphorylation	O
+was	O
+not	O
+detectable	O
+after	O
+short	O
+-	O
+term	O
+exposure	O
+to	O
+cocaine	O
+","	O
+suggesting	O
+that	O
+these	O
+mitochondrial	B-NP
+abnormalities	I-NP
+were	O
+a	O
+late	O
+rather	O
+than	O
+a	O
+primary	O
+event	O
+in	O
+the	O
+pathological	O
+response	O
+to	O
+cocaine	O
+.	O
+	
+MitoQ	O
+","	O
+a	O
+mitochondrial	O
+-	O
+targeted	O
+antioxidant	O
+","	O
+was	O
+shown	O
+to	O
+completely	O
+prevent	O
+these	O
+mitochondrial	B-NP
+abnormalities	I-NP
+as	O
+well	O
+as	O
+cardiac	B-NP
+dysfunction	I-NP
+characterized	O
+here	O
+by	O
+a	O
+diastolic	B-NP
+dysfunction	I-NP
+studied	O
+with	O
+a	O
+conductance	O
+catheter	O
+to	O
+obtain	O
+pressure	O
+-	O
+volume	O
+data	O
+.	O
+	
+Taken	O
+together	O
+","	O
+these	O
+results	O
+extend	O
+previous	O
+studies	O
+and	O
+demonstrate	O
+that	O
+cocaine	O
+-	O
+induced	O
+cardiac	B-NP
+dysfunction	I-NP
+may	O
+be	O
+due	O
+to	O
+a	O
+mitochondrial	B-NP
+defect	I-NP
+.	O
+	
+Trimethoprim	O
+-	O
+induced	O
+immune	O
+hemolytic	B-NP
+anemia	I-NP
+in	O
+a	O
+pediatric	O
+oncology	O
+patient	O
+presenting	O
+as	O
+an	O
+acute	O
+hemolytic	O
+transfusion	O
+reaction	O
+.	O
+	
+A	O
+10	O
+-	O
+year	O
+-	O
+old	O
+male	O
+with	O
+acute	B-NP
+leukemia	I-NP
+presented	O
+with	O
+post	O
+-	O
+chemotherapy	O
+anemia	B-NP
+.	O
+	
+During	O
+red	O
+cell	O
+transfusion	O
+","	O
+he	O
+developed	O
+hemoglobinuria	B-NP
+.	O
+	
+Transfusion	O
+reaction	O
+workup	O
+was	O
+negative	O
+.	O
+	
+Drug	O
+-	O
+induced	O
+immune	O
+hemolytic	B-NP
+anemia	I-NP
+was	O
+suspected	O
+because	O
+of	O
+positive	O
+direct	O
+antiglobulin	O
+test	O
+","	O
+negative	O
+eluate	O
+","	O
+and	O
+microspherocytes	O
+on	O
+smear	O
+pre	O
+-	O
+and	O
+post	O
+-	O
+transfusion	O
+.	O
+	
+Drug	O
+studies	O
+using	O
+the	O
+indirect	O
+antiglobulin	O
+test	O
+were	O
+strongly	O
+positive	O
+with	O
+trimethoprim	O
+and	O
+trimethoprim	O
+-	O
+sulfamethoxazole	O
+but	O
+negative	O
+with	O
+sulfamethoxazole	O
+.	O
+	
+The	O
+patient	O
+recovered	O
+after	O
+discontinuing	O
+the	O
+drug	O
+","	O
+with	O
+no	O
+recurrence	O
+in	O
+2	O
+years	O
+.	O
+	
+Other	O
+causes	O
+of	O
+anemia	B-NP
+should	O
+be	O
+considered	O
+in	O
+patients	O
+with	O
+worse	O
+-	O
+than	O
+-	O
+expected	O
+anemia	B-NP
+after	O
+chemotherapy	O
+.	O
+	
+Furthermore	O
+","	O
+hemolysis	B-NP
+during	O
+transfusion	O
+is	O
+not	O
+always	O
+a	O
+transfusion	O
+reaction	O
+.	O
+	
+Verapamil	O
+stimulation	O
+test	O
+in	O
+hyperprolactinemia	B-NP
+:	O
+loss	O
+of	O
+prolactin	O
+response	O
+in	O
+anatomic	O
+or	O
+functional	O
+stalk	O
+effect	O
+.	O
+	
+AIM	O
+:	O
+Verapamil	O
+stimulation	O
+test	O
+was	O
+previously	O
+investigated	O
+as	O
+a	O
+tool	O
+for	O
+differential	O
+diagnosis	O
+of	O
+hyperprolactinemia	B-NP
+","	O
+but	O
+with	O
+conflicting	O
+results	O
+.	O
+	
+Macroprolactinemia	B-NP
+was	O
+never	O
+considered	O
+in	O
+those	O
+previous	O
+studies	O
+.	O
+	
+Here	O
+","	O
+we	O
+aimed	O
+to	O
+re	O
+-	O
+investigate	O
+the	O
+diagnostic	O
+value	O
+of	O
+verapamil	O
+in	O
+a	O
+population	O
+who	O
+were	O
+all	O
+screened	O
+for	O
+macroprolactinemia	B-NP
+.	O
+	
+Prolactin	O
+responses	O
+to	O
+verapamil	O
+in	O
+65	O
+female	O
+patients	O
+(	O
+age	O
+:	O
+29	O
+.	O
+9	O
++	O
+/	O
+-	O
+8	O
+.	O
+1	O
+years	O
+)	O
+with	O
+hyperprolactinemia	B-NP
+were	O
+tested	O
+in	O
+a	O
+descriptive	O
+","	O
+matched	O
+case	O
+-	O
+control	O
+study	O
+.	O
+	
+METHODS	O
+:	O
+Verapamil	O
+80	O
+mg	O
+","	O
+p	O
+.	O
+o	O
+.	O
+was	O
+administered	O
+","	O
+and	O
+then	O
+PRL	O
+levels	O
+were	O
+measured	O
+at	O
+8th	O
+and	O
+16th	O
+hours	O
+","	O
+by	O
+immunometric	O
+chemiluminescence	O
+.	O
+	
+Verapamil	O
+responsiveness	O
+was	O
+determined	O
+by	O
+peak	O
+percent	O
+change	O
+in	O
+basal	O
+prolactin	O
+levels	O
+(	O
+PRL	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+Verapamil	O
+significantly	O
+increased	O
+PRL	O
+levels	O
+in	O
+healthy	O
+controls	O
+(	O
+N	O
+.	O
+8	O
+","	O
+PRL	O
+:	O
+183	O
+%	O
+)	O
+","	O
+macroprolactinoma	B-NP
+(	O
+N	O
+.	O
+8	O
+","	O
+PRL	O
+:	O
+7	O
+%	O
+)	O
+","	O
+microprolactinoma	B-NP
+(	O
+N	O
+.	O
+19	O
+","	O
+PRL	O
+:	O
+21	O
+%	O
+)	O
+","	O
+macroprolactinemia	B-NP
+(	O
+N	O
+.	O
+23	O
+","	O
+PRL	O
+:	O
+126	O
+%	O
+)	O
+","	O
+but	O
+not	O
+in	O
+pseudoprolactinoma	B-NP
+(	O
+N	O
+.	O
+8	O
+","	O
+PRL	O
+:	O
+0	O
+.	O
+8	O
+%	O
+)	O
+","	O
+and	O
+risperidone	O
+-	O
+induced	O
+hyperprolactinemia	B-NP
+(	O
+N	O
+.	O
+7	O
+","	O
+PRL	O
+:	O
+3	O
+%	O
+)	O
+.	O
+	
+ROC	O
+curve	O
+analysis	O
+revealed	O
+that	O
+unresponsiveness	O
+to	O
+verapamil	O
+defined	O
+as	O
+PRL	O
+<	O
+7	O
+%	O
+","	O
+discriminated	O
+anatomical	O
+or	O
+functional	O
+stalk	O
+effect	O
+(	O
+sensitivity	O
+:	O
+74	O
+%	O
+","	O
+specificity	O
+:	O
+73	O
+%	O
+","	O
+AUC	O
+:	O
+0	O
+.	O
+855	O
++	O
+/	O
+-	O
+0	O
+.	O
+4	O
+","	O
+P	O
+<	O
+0	O
+.	O
+1	O
+","	O
+CI	O
+:	O
+0	O
+.	O
+768	O
+-	O
+0	O
+.	O
+942	O
+)	O
+associated	O
+with	O
+pseudoprolactinoma	B-NP
+or	O
+risperidone	O
+-	O
+induced	O
+hyperprolactinemia	B-NP
+","	O
+respectively	O
+.	O
+	
+CONCLUSION	O
+:	O
+Verapamil	O
+responsiveness	O
+is	O
+not	O
+a	O
+reliable	O
+finding	O
+for	O
+the	O
+differential	O
+diagnosis	O
+of	O
+hyperprolactinemia	B-NP
+.	O
+	
+However	O
+","	O
+verapamil	O
+unresponsiveness	O
+discriminates	O
+stalk	O
+effect	O
+(	O
+i	O
+.	O
+e	O
+.	O
+","	O
+anatomically	O
+or	O
+functionally	O
+inhibited	O
+dopaminergic	O
+tonus	O
+)	O
+from	O
+other	O
+causes	O
+of	O
+hyperprolactinemia	B-NP
+with	O
+varying	O
+degrees	O
+of	O
+responsiveness	O
+.	O
+	
+Blockade	O
+of	O
+endothelial	O
+-	O
+mesenchymal	O
+transition	O
+by	O
+a	O
+Smad3	O
+inhibitor	O
+delays	O
+the	O
+early	O
+development	O
+of	O
+streptozotocin	O
+-	O
+induced	O
+diabetic	B-NP
+nephropathy	I-NP
+.	O
+	
+OBJECTIVE	O
+:	O
+A	O
+multicenter	O
+","	O
+controlled	O
+trial	O
+showed	O
+that	O
+early	O
+blockade	O
+of	O
+the	O
+renin	O
+-	O
+angiotensin	O
+system	O
+in	O
+patients	O
+with	O
+type	B-NP
+1	I-NP
+diabetes	I-NP
+and	O
+normoalbuminuria	O
+did	O
+not	O
+retard	O
+the	O
+progression	O
+of	O
+nephropathy	B-NP
+","	O
+suggesting	O
+that	O
+other	O
+mechanism	O
+(	O
+s	O
+)	O
+are	O
+involved	O
+in	O
+the	O
+pathogenesis	O
+of	O
+early	O
+diabetic	B-NP
+nephropathy	I-NP
+(	O
+diabetic	B-NP
+nephropathy	I-NP
+)	O
+.	O
+	
+We	O
+have	O
+previously	O
+demonstrated	O
+that	O
+endothelial	O
+-	O
+mesenchymal	O
+-	O
+transition	O
+(	O
+EndoMT	O
+)	O
+contributes	O
+to	O
+the	O
+early	O
+development	O
+of	O
+renal	O
+interstitial	O
+fibrosis	B-NP
+independently	O
+of	O
+microalbuminuria	O
+in	O
+mice	O
+with	O
+streptozotocin	O
+(	O
+STZ	O
+)	O
+-	O
+induced	O
+diabetes	B-NP
+.	O
+	
+In	O
+the	O
+present	O
+study	O
+","	O
+we	O
+hypothesized	O
+that	O
+blocking	O
+EndoMT	O
+reduces	O
+the	O
+early	O
+development	O
+of	O
+diabetic	B-NP
+nephropathy	I-NP
+.	O
+	
+RESEARCH	O
+DESIGN	O
+AND	O
+METHODS	O
+:	O
+EndoMT	O
+was	O
+induced	O
+in	O
+a	O
+mouse	O
+pancreatic	O
+microvascular	O
+endothelial	O
+cell	O
+line	O
+(	O
+MMEC	O
+)	O
+in	O
+the	O
+presence	O
+of	O
+advanced	O
+glycation	O
+end	O
+products	O
+(	O
+AGEs	O
+)	O
+and	O
+in	O
+the	O
+endothelial	O
+lineage	O
+-	O
+traceble	O
+mouse	O
+line	O
+Tie2	O
+-	O
+Cre	O
+;	O
+Loxp	O
+-	O
+EGFP	O
+by	O
+administration	O
+of	O
+AGEs	O
+","	O
+with	O
+nonglycated	O
+mouse	O
+albumin	O
+serving	O
+as	O
+a	O
+control	O
+.	O
+	
+Phosphorylated	O
+Smad3	O
+was	O
+detected	O
+by	O
+immunoprecipitation	O
+/	O
+Western	O
+blotting	O
+and	O
+confocal	O
+microscopy	O
+.	O
+	
+Blocking	O
+studies	O
+using	O
+receptor	O
+for	O
+AGE	O
+siRNA	O
+and	O
+a	O
+specific	O
+inhibitor	O
+of	O
+Smad3	O
+(	O
+SIS3	O
+)	O
+were	O
+performed	O
+in	O
+MMECs	O
+and	O
+in	O
+STZ	O
+-	O
+induced	O
+diabetic	B-NP
+nephropathy	I-NP
+in	O
+Tie2	O
+-	O
+Cre	O
+;	O
+Loxp	O
+-	O
+EGFP	O
+mice	O
+.	O
+	
+RESULTS	O
+:	O
+Confocal	O
+microscopy	O
+and	O
+real	O
+-	O
+time	O
+PCR	O
+demonstrated	O
+that	O
+AGEs	O
+induced	O
+EndoMT	O
+in	O
+MMECs	O
+and	O
+in	O
+Tie2	O
+-	O
+Cre	O
+;	O
+Loxp	O
+-	O
+EGFP	O
+mice	O
+.	O
+	
+Immunoprecipitation	O
+/	O
+Western	O
+blotting	O
+showed	O
+that	O
+Smad3	O
+was	O
+activated	O
+by	O
+AGEs	O
+but	O
+was	O
+inhibited	O
+by	O
+SIS3	O
+in	O
+MMECs	O
+and	O
+in	O
+STZ	O
+-	O
+induced	O
+diabetic	B-NP
+nephropathy	I-NP
+.	O
+	
+Confocal	O
+microscopy	O
+and	O
+real	O
+-	O
+time	O
+PCR	O
+further	O
+demonstrated	O
+that	O
+SIS3	O
+abrogated	O
+EndoMT	O
+","	O
+reduced	O
+renal	O
+fibrosis	B-NP
+","	O
+and	O
+retarded	O
+progression	O
+of	O
+nephropathy	B-NP
+.	O
+	
+CONCLUSIONS	O
+:	O
+EndoMT	O
+is	O
+a	O
+novel	O
+pathway	O
+leading	O
+to	O
+early	O
+development	O
+of	O
+diabetic	B-NP
+nephropathy	I-NP
+.	O
+	
+Blockade	O
+of	O
+EndoMT	O
+by	O
+SIS3	O
+may	O
+provide	O
+a	O
+new	O
+strategy	O
+to	O
+retard	O
+the	O
+progression	O
+of	O
+diabetic	B-NP
+nephropathy	I-NP
+and	O
+other	O
+diabetes	B-NP
+complications	I-NP
+.	O
+	
+Cytostatic	O
+and	O
+anti	O
+-	O
+angiogenic	O
+effects	O
+of	O
+temsirolimus	O
+in	O
+refractory	O
+mantle	B-NP
+cell	I-NP
+lymphoma	I-NP
+.	O
+	
+Mantle	B-NP
+cell	I-NP
+lymphoma	I-NP
+(	O
+MCL	B-NP
+)	O
+is	O
+a	O
+rare	O
+and	O
+aggressive	O
+type	O
+of	O
+B	B-NP
+-	I-NP
+cell	I-NP
+non	I-NP
+-	I-NP
+Hodgkin	I-NP
+'	I-NP
+s	I-NP
+lymphoma	I-NP
+.	O
+	
+Patients	O
+become	O
+progressively	O
+refractory	O
+to	O
+conventional	O
+chemotherapy	O
+","	O
+and	O
+their	O
+prognosis	O
+is	O
+poor	O
+.	O
+	
+However	O
+","	O
+a	O
+38	O
+%	O
+remission	O
+rate	O
+has	O
+been	O
+recently	O
+reported	O
+in	O
+refractory	O
+MCL	B-NP
+treated	O
+with	O
+temsirolimus	O
+","	O
+a	O
+mTOR	O
+inhibitor	O
+.	O
+Here	O
+we	O
+had	O
+the	O
+opportunity	O
+to	O
+study	O
+a	O
+case	O
+of	O
+refractory	O
+MCL	B-NP
+who	O
+had	O
+tumor	B-NP
+regression	O
+two	O
+months	O
+after	O
+temsirolimus	O
+treatment	O
+","	O
+and	O
+a	O
+progression	O
+-	O
+free	O
+survival	O
+of	O
+10	O
+months	O
+.	O
+	
+In	O
+this	O
+case	O
+","	O
+lymph	O
+node	O
+biopsies	O
+were	O
+performed	O
+before	O
+and	O
+six	O
+months	O
+after	O
+temsirolimus	O
+therapy	O
+.	O
+	
+Comparison	O
+of	O
+the	O
+two	O
+biopsies	O
+showed	O
+that	O
+temsirolimus	O
+inhibited	O
+tumor	B-NP
+cell	O
+proliferation	O
+through	O
+cell	O
+cycle	O
+arrest	O
+","	O
+but	O
+did	O
+not	O
+induce	O
+any	O
+change	O
+in	O
+the	O
+number	O
+of	O
+apoptotic	O
+tumor	B-NP
+cells	O
+.	O
+	
+Apart	O
+from	O
+this	O
+cytostatic	O
+effect	O
+","	O
+temsirolimus	O
+had	O
+an	O
+antiangiogenic	O
+effect	O
+with	O
+decrease	O
+of	O
+tumor	B-NP
+microvessel	O
+density	O
+and	O
+of	O
+VEGF	O
+expression	O
+.	O
+	
+Moreover	O
+","	O
+numerous	O
+patchy	O
+","	O
+well	O
+-	O
+limited	O
+fibrotic	O
+areas	O
+","	O
+compatible	O
+with	O
+post	O
+-	O
+necrotic	B-NP
+tissue	O
+repair	O
+","	O
+were	O
+found	O
+after	O
+6	O
+-	O
+month	O
+temsirolimus	O
+therapy	O
+.	O
+	
+Thus	O
+","	O
+temsirolimus	O
+reduced	O
+tumor	B-NP
+burden	O
+through	O
+associated	O
+cytostatic	O
+and	O
+anti	O
+-	O
+angiogenic	O
+effects	O
+.	O
+This	O
+dual	O
+effect	O
+of	O
+temsirolimus	O
+on	O
+tumor	B-NP
+tissue	O
+could	O
+contribute	O
+to	O
+its	O
+recently	O
+reported	O
+efficiency	O
+in	O
+refractory	O
+MCL	B-NP
+resistant	O
+to	O
+conventional	O
+chemotherapy	O
+.	O
+	
+Acute	B-NP
+renal	I-NP
+failure	I-NP
+due	O
+to	O
+rifampicin	O
+.	O
+	
+A	O
+23	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+with	O
+bacteriologically	O
+proven	O
+pulmonary	B-NP
+tuberculosis	I-NP
+was	O
+treated	O
+with	O
+the	O
+various	O
+regimens	O
+of	O
+antituberculosis	O
+drugs	O
+for	O
+nearly	O
+15	O
+months	O
+.	O
+	
+Rifampicin	O
+was	O
+administered	O
+thrice	O
+as	O
+one	O
+of	O
+the	O
+3	O
+-	O
+4	O
+drug	O
+regimen	O
+and	O
+each	O
+time	O
+he	O
+developed	O
+untoward	O
+side	O
+effects	O
+like	O
+nausea	B-NP
+","	O
+vomiting	B-NP
+and	O
+fever	B-NP
+with	O
+chills	O
+and	O
+rigors	O
+.	O
+	
+The	O
+last	O
+such	O
+episode	O
+was	O
+of	O
+acute	O
+renal	O
+failure	O
+at	O
+which	O
+stage	O
+the	O
+patient	O
+was	O
+seen	O
+by	O
+the	O
+authors	O
+of	O
+this	O
+report	O
+.	O
+	
+The	O
+patient	O
+","	O
+however	O
+","	O
+made	O
+a	O
+full	O
+recovery	O
+.	O
+	
+Syncope	B-NP
+caused	O
+by	O
+hyperkalemia	B-NP
+during	O
+use	O
+of	O
+a	O
+combined	O
+therapy	O
+with	O
+the	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitor	O
+and	O
+spironolactone	O
+.	O
+	
+A	O
+76	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+a	O
+history	O
+of	O
+coronary	O
+artery	O
+bypass	O
+grafting	O
+and	O
+prior	O
+myocardial	B-NP
+infarction	I-NP
+was	O
+transferred	O
+to	O
+the	O
+emergency	O
+room	O
+with	O
+loss	B-NP
+of	I-NP
+consciousness	I-NP
+due	O
+to	O
+marked	O
+bradycardia	B-NP
+caused	O
+by	O
+hyperkalemia	B-NP
+.	O
+	
+The	O
+concentration	O
+of	O
+serum	O
+potassium	O
+was	O
+high	O
+","	O
+and	O
+normal	O
+sinus	O
+rhythm	O
+was	O
+restored	O
+after	O
+correction	O
+of	O
+the	O
+serum	O
+potassium	O
+level	O
+.	O
+	
+The	O
+cause	O
+of	O
+hyperkalemia	B-NP
+was	O
+considered	O
+to	O
+be	O
+several	O
+doses	O
+of	O
+spiranolactone	O
+","	O
+an	O
+aldosterone	O
+antagonist	O
+","	O
+in	O
+addition	O
+to	O
+the	O
+long	O
+-	O
+term	O
+intake	O
+of	O
+ramipril	O
+","	O
+an	O
+ACE	O
+inhibitor	O
+.	O
+	
+This	O
+case	O
+is	O
+a	O
+good	O
+example	O
+of	O
+electrolyte	O
+imbalance	O
+causing	O
+acute	O
+life	O
+-	O
+threatening	O
+cardiac	O
+events	O
+.	O
+	
+Clinicians	O
+should	O
+be	O
+alert	O
+to	O
+the	O
+possibility	O
+of	O
+hyperkalemia	B-NP
+","	O
+especially	O
+in	O
+elderly	O
+patients	O
+using	O
+ACE	O
+/	O
+ARB	O
+in	O
+combination	O
+with	O
+potassium	O
+sparing	O
+agents	O
+and	O
+who	O
+have	O
+mild	O
+renal	B-NP
+disturbance	I-NP
+.	O
+	
+Diffuse	O
+skeletal	O
+pain	B-NP
+after	O
+administration	O
+of	O
+alendronate	O
+.	O
+	
+BACKGROUND	O
+:	O
+Osteoporosis	B-NP
+is	O
+caused	O
+by	O
+bone	O
+resorption	O
+in	O
+excess	O
+of	O
+bone	O
+formation	O
+","	O
+and	O
+bisphosphonates	O
+","	O
+are	O
+used	O
+to	O
+inhibit	O
+bone	O
+resorption	O
+.	O
+	
+Alendronate	O
+","	O
+a	O
+biphosphonate	O
+","	O
+is	O
+effective	O
+for	O
+both	O
+the	O
+treatment	O
+and	O
+prevention	O
+of	O
+osteoporosis	B-NP
+in	O
+postmenopausal	O
+women	O
+.	O
+	
+Side	O
+effects	O
+are	O
+relatively	O
+few	O
+and	O
+prominently	O
+gastrointestinal	O
+.	O
+	
+Musculoskeletal	B-NP
+pain	I-NP
+may	O
+be	O
+an	O
+important	O
+side	O
+effect	O
+in	O
+these	O
+patients	O
+.	O
+	
+We	O
+presented	O
+a	O
+patient	O
+admitted	O
+to	O
+our	O
+out	O
+-	O
+patient	O
+clinic	O
+with	O
+diffuse	O
+skeletal	O
+pain	B-NP
+after	O
+three	O
+consecutive	O
+administration	O
+of	O
+alendronate	O
+.	O
+	
+CONCLUSION	O
+:	O
+We	O
+conclude	O
+that	O
+patients	O
+with	O
+osteoporosis	B-NP
+can	O
+report	O
+pain	B-NP
+","	O
+and	O
+bisphosphonate	O
+-	O
+related	O
+pain	B-NP
+should	O
+also	O
+be	O
+considered	O
+before	O
+ascribing	O
+this	O
+complaint	O
+to	O
+osteoporosis	B-NP
+.	O
+	
+Cerebrospinal	O
+fluid	O
+penetration	O
+of	O
+high	O
+-	O
+dose	O
+daptomycin	O
+in	O
+suspected	O
+Staphylococcus	O
+aureus	O
+meningitis	B-NP
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+methicillin	O
+-	O
+sensitive	O
+Staphylococcus	O
+aureus	O
+(	O
+MSSA	O
+)	O
+bacteremia	B-NP
+with	O
+suspected	O
+MSSA	O
+meningitis	B-NP
+treated	O
+with	O
+high	O
+-	O
+dose	O
+daptomycin	O
+assessed	O
+with	O
+concurrent	O
+serum	O
+and	O
+cerebrospinal	O
+fluid	O
+(	O
+CSF	O
+)	O
+concentrations	O
+.	O
+	
+CASE	O
+SUMMARY	O
+:	O
+A	O
+54	O
+-	O
+year	O
+-	O
+old	O
+male	O
+presented	O
+to	O
+the	O
+emergency	O
+department	O
+with	O
+generalized	O
+weakness	B-NP
+and	O
+presumed	O
+health	O
+-	O
+care	O
+-	O
+associated	O
+pneumonia	B-NP
+shown	O
+on	O
+chest	O
+radiograph	O
+.	O
+	
+Treatment	O
+was	O
+empirically	O
+initiated	O
+with	O
+vancomycin	O
+","	O
+levofloxacin	O
+","	O
+and	O
+piperacillin	O
+/	O
+tazobactam	O
+.	O
+	
+Blood	O
+cultures	O
+revealed	O
+S	O
+.	O
+aureus	O
+susceptible	O
+to	O
+oxacillin	O
+.	O
+	
+Empiric	O
+antibiotic	O
+treatment	O
+was	O
+narrowed	O
+to	O
+nafcillin	O
+on	O
+day	O
+4	O
+.	O
+	
+On	O
+day	O
+8	O
+","	O
+the	O
+patient	O
+developed	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+(	O
+serum	O
+creatinine	O
+1	O
+.	O
+9	O
+mg	O
+/	O
+dL	O
+","	O
+increased	O
+from	O
+1	O
+.	O
+2	O
+mg	O
+/	O
+dL	O
+the	O
+previous	O
+day	O
+and	O
+0	O
+.	O
+8	O
+mg	O
+/	O
+dL	O
+on	O
+admission	O
+)	O
+.	O
+	
+The	O
+patient	O
+'	O
+s	O
+Glasgow	O
+Coma	O
+Score	O
+was	O
+3	O
+","	O
+with	O
+normal	O
+findings	O
+shown	O
+on	O
+computed	O
+tomography	O
+scan	O
+of	O
+the	O
+head	O
+72	O
+hours	O
+following	O
+an	O
+episode	O
+of	O
+cardiac	B-NP
+arrest	I-NP
+on	O
+day	O
+10	O
+.	O
+	
+The	O
+patient	O
+experienced	O
+relapsing	O
+MSSA	O
+bacteremia	B-NP
+on	O
+day	O
+9	O
+","	O
+increasing	O
+the	O
+suspicion	O
+for	O
+a	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+infection	B-NP
+.	O
+	
+Nafcillin	O
+was	O
+discontinued	O
+and	O
+daptomycin	O
+9	O
+mg	O
+/	O
+kg	O
+daily	O
+was	O
+initiated	O
+for	O
+suspected	O
+meningitis	B-NP
+and	O
+was	O
+continued	O
+until	O
+the	O
+patient	O
+'	O
+s	O
+death	O
+on	O
+day	O
+16	O
+.	O
+	
+Daptomycin	O
+serum	O
+and	O
+CSF	O
+trough	O
+concentrations	O
+were	O
+11	O
+.	O
+21	O
+ug	O
+/	O
+mL	O
+and	O
+0	O
+.	O
+52	O
+ug	O
+/	O
+mL	O
+","	O
+respectively	O
+","	O
+prior	O
+to	O
+the	O
+third	O
+dose	O
+.	O
+	
+Lumbar	O
+puncture	O
+results	O
+were	O
+inconclusive	O
+and	O
+no	O
+further	O
+blood	O
+cultures	O
+were	O
+positive	O
+for	O
+MSSA	O
+.	O
+	
+Creatine	O
+kinase	O
+levels	O
+were	O
+normal	O
+prior	O
+to	O
+daptomycin	O
+therapy	O
+and	O
+were	O
+not	O
+reassessed	O
+.	O
+	
+DISCUSSION	O
+:	O
+Daptomycin	O
+was	O
+initiated	O
+in	O
+our	O
+patient	O
+secondary	O
+to	O
+possible	O
+nafcillin	O
+-	O
+induced	O
+acute	O
+interstitial	B-NP
+nephritis	I-NP
+and	O
+relapsing	O
+bacteremia	B-NP
+.	O
+	
+At	O
+a	O
+dose	O
+of	O
+9	O
+mg	O
+/	O
+kg	O
+","	O
+resultant	O
+penetration	O
+of	O
+5	O
+%	O
+was	O
+higher	O
+than	O
+in	O
+previous	O
+reports	O
+","	O
+more	O
+consistent	O
+with	O
+inflamed	O
+meninges	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+High	O
+-	O
+dose	O
+daptomycin	O
+may	O
+be	O
+an	O
+alternative	O
+option	O
+for	O
+MSSA	O
+bacteremia	B-NP
+with	O
+or	O
+without	O
+a	O
+CNS	O
+source	O
+in	O
+patients	O
+who	O
+have	O
+failed	O
+or	O
+cannot	O
+tolerate	O
+standard	O
+therapy	O
+.	O
+	
+Further	O
+clinical	O
+evaluation	O
+in	O
+patients	O
+with	O
+confirmed	O
+meningitis	B-NP
+is	O
+warranted	O
+.	O
+	
+The	O
+role	O
+of	O
+nitric	O
+oxide	O
+in	O
+convulsions	B-NP
+induced	O
+by	O
+lindane	O
+in	O
+rats	O
+.	O
+	
+Lindane	O
+is	O
+an	O
+organochloride	O
+pesticide	O
+and	O
+scabicide	O
+.	O
+	
+It	O
+evokes	O
+convulsions	B-NP
+mainly	O
+trough	O
+the	O
+blockage	O
+of	O
+GABA	O
+(	O
+A	O
+)	O
+receptors	O
+.	O
+	
+Nitric	O
+oxide	O
+(	O
+NO	O
+)	O
+","	O
+gaseous	O
+neurotransmitter	O
+","	O
+has	O
+contradictor	O
+role	O
+in	O
+epileptogenesis	O
+due	O
+to	O
+opposite	O
+effects	O
+of	O
+L	O
+-	O
+arginine	O
+","	O
+precursor	O
+of	O
+NO	O
+syntheses	O
+(	O
+NOS	O
+)	O
+","	O
+and	O
+L	O
+-	O
+NAME	O
+(	O
+NOS	O
+inhibitor	O
+)	O
+observed	O
+in	O
+different	O
+epilepsy	B-NP
+models	O
+.	O
+	
+The	O
+aim	O
+of	O
+the	O
+current	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+effects	O
+of	O
+NO	O
+on	O
+the	O
+behavioral	O
+and	O
+EEG	O
+characteristics	O
+of	O
+lindane	O
+-	O
+induced	O
+epilepsy	B-NP
+in	O
+male	O
+Wistar	O
+albino	O
+rats	O
+.	O
+	
+The	O
+administration	O
+of	O
+L	O
+-	O
+arginine	O
+(	O
+600	O
+","	O
+800	O
+and	O
+1000	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+p	O
+.	O
+)	O
+in	O
+dose	O
+-	O
+dependent	O
+manner	O
+significantly	O
+increased	O
+convulsion	B-NP
+incidence	O
+and	O
+severity	O
+and	O
+shortened	O
+latency	O
+time	O
+to	O
+first	O
+convulsion	B-NP
+elicited	O
+by	O
+lower	O
+lindane	O
+dose	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+	
+On	O
+the	O
+contrary	O
+","	O
+pretreatment	O
+with	O
+L	O
+-	O
+NAME	O
+(	O
+500	O
+","	O
+700	O
+and	O
+900	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+p	O
+.	O
+)	O
+decreased	O
+convulsion	B-NP
+incidence	O
+and	O
+severity	O
+and	O
+prolonged	O
+latency	O
+time	O
+to	O
+convulsion	B-NP
+following	O
+injection	O
+with	O
+a	O
+convulsive	B-NP
+dose	O
+of	O
+lindane	O
+(	O
+8	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+	
+EEG	O
+analyses	O
+showed	O
+increase	O
+of	O
+number	O
+and	O
+duration	O
+of	O
+ictal	O
+periods	O
+in	O
+EEG	O
+of	O
+rats	O
+receiving	O
+l	O
+-	O
+arginine	O
+prior	O
+to	O
+lindane	O
+and	O
+decrease	O
+of	O
+this	O
+number	O
+in	O
+rats	O
+pretreated	O
+with	O
+L	O
+-	O
+NAME	O
+.	O
+	
+These	O
+results	O
+support	O
+the	O
+conclusion	O
+that	O
+NO	O
+plays	O
+a	O
+role	O
+of	O
+endogenous	O
+convulsant	O
+in	O
+rat	O
+model	O
+of	O
+lindane	O
+seizures	B-NP
+.	O
+	
+Severe	O
+polyneuropathy	B-NP
+and	O
+motor	O
+loss	O
+after	O
+intrathecal	O
+thiotepa	O
+combination	O
+chemotherapy	O
+:	O
+description	O
+of	O
+two	O
+cases	O
+.	O
+	
+Two	O
+cases	O
+of	O
+severe	O
+delayed	O
+neurologic	B-NP
+toxicity	I-NP
+related	O
+to	O
+the	O
+administration	O
+of	O
+intrathecal	O
+(	O
+IT	O
+)	O
+combination	O
+chemotherapy	O
+including	O
+thiotepa	O
+(	O
+TSPA	O
+)	O
+are	O
+presented	O
+.	O
+	
+Both	O
+cases	O
+developed	O
+axonal	B-NP
+neuropathy	I-NP
+with	O
+motor	O
+predominance	O
+in	O
+the	O
+lower	O
+extremities	O
+1	O
+and	O
+6	O
+months	O
+after	O
+IT	O
+chemotherapy	O
+was	O
+administered	O
+.	O
+	
+Neurologic	B-NP
+toxicities	I-NP
+have	O
+been	O
+described	O
+with	O
+IT	O
+-	O
+methotrexate	O
+","	O
+IT	O
+-	O
+cytosine	O
+arabinoside	O
+and	O
+IT	O
+-	O
+TSPA	O
+.	O
+	
+To	O
+our	O
+knowledge	O
+","	O
+however	O
+","	O
+axonal	B-NP
+neuropathy	I-NP
+following	O
+administration	O
+of	O
+these	O
+three	O
+agents	O
+has	O
+not	O
+been	O
+previously	O
+described	O
+.	O
+	
+In	O
+spite	O
+of	O
+the	O
+fact	O
+that	O
+TSPA	O
+is	O
+a	O
+useful	O
+IT	O
+agent	O
+","	O
+its	O
+combination	O
+with	O
+MTX	O
+","	O
+ara	O
+-	O
+C	O
+and	O
+radiotherapy	O
+could	O
+cause	O
+severe	O
+neurotoxicity	B-NP
+.	O
+	
+This	O
+unexpected	O
+complication	O
+indicates	O
+the	O
+need	O
+for	O
+further	O
+toxicology	O
+research	O
+on	O
+IT	O
+-	O
+TSPA	O
+.	O
+	
+Effects	O
+of	O
+cromakalim	O
+and	O
+pinacidil	O
+on	O
+large	O
+epicardial	O
+and	O
+small	O
+coronary	O
+arteries	O
+in	O
+conscious	O
+dogs	O
+.	O
+	
+The	O
+effects	O
+of	O
+i	O
+.	O
+v	O
+.	O
+bolus	O
+administration	O
+of	O
+cromakalim	O
+(	O
+1	O
+-	O
+10	O
+micrograms	O
+/	O
+kg	O
+)	O
+and	O
+pinacidil	O
+(	O
+3	O
+-	O
+100	O
+micrograms	O
+/	O
+kg	O
+)	O
+on	O
+large	O
+(	O
+circumflex	O
+artery	O
+)	O
+and	O
+small	O
+coronary	O
+arteries	O
+and	O
+on	O
+systemic	O
+hemodynamics	O
+were	O
+investigated	O
+in	O
+chronically	O
+instrumented	O
+conscious	O
+dogs	O
+and	O
+compared	O
+to	O
+those	O
+of	O
+nitroglycerin	O
+(	O
+0	O
+.	O
+3	O
+-	O
+10	O
+micrograms	O
+/	O
+kg	O
+)	O
+.	O
+	
+Nitroglycerin	O
+","	O
+up	O
+to	O
+0	O
+.	O
+3	O
+micrograms	O
+/	O
+kg	O
+","	O
+selectively	O
+increased	O
+circumflex	O
+artery	O
+diameter	O
+(	O
+CxAD	O
+)	O
+without	O
+simultaneously	O
+affecting	O
+any	O
+other	O
+cardiac	O
+or	O
+systemic	O
+hemodynamic	O
+parameter	O
+.	O
+	
+In	O
+contrast	O
+","	O
+cromakalim	O
+and	O
+pinacidil	O
+at	O
+all	O
+doses	O
+and	O
+nitroglycerin	O
+at	O
+doses	O
+higher	O
+than	O
+0	O
+.	O
+3	O
+micrograms	O
+/	O
+kg	O
+simultaneously	O
+and	O
+dose	O
+-	O
+dependently	O
+increased	O
+CxAD	O
+","	O
+coronary	O
+blood	O
+flow	O
+and	O
+heart	O
+rate	O
+and	O
+decreased	O
+coronary	O
+vascular	O
+resistance	O
+and	O
+aortic	O
+pressure	O
+.	O
+	
+Cromakalim	O
+was	O
+approximately	O
+8	O
+-	O
+to	O
+9	O
+.	O
+5	O
+-	O
+fold	O
+more	O
+potent	O
+than	O
+pinacidil	O
+in	O
+increasing	O
+CxAD	O
+.	O
+	
+Vasodilation	O
+of	O
+large	O
+and	O
+small	O
+coronary	O
+vessels	O
+and	O
+hypotension	B-NP
+induced	O
+by	O
+cromakalim	O
+and	O
+pinacidil	O
+were	O
+not	O
+affected	O
+by	O
+prior	O
+combined	O
+beta	O
+adrenergic	O
+and	O
+muscarinic	O
+receptors	O
+blockade	O
+but	O
+drug	O
+-	O
+induced	O
+tachycardia	B-NP
+was	O
+abolished	O
+.	O
+	
+When	O
+circumflex	O
+artery	O
+blood	O
+flow	O
+was	O
+maintained	O
+constant	O
+","	O
+the	O
+increases	O
+in	O
+CxAD	O
+induced	O
+by	O
+cromakalim	O
+(	O
+10	O
+micrograms	O
+/	O
+kg	O
+)	O
+","	O
+pinacidil	O
+(	O
+30	O
+micrograms	O
+/	O
+kg	O
+)	O
+and	O
+nitroglycerin	O
+(	O
+10	O
+micrograms	O
+/	O
+kg	O
+)	O
+were	O
+reduced	O
+by	O
+68	O
++	O
+/	O
+-	O
+7	O
+","	O
+54	O
++	O
+/	O
+-	O
+9	O
+and	O
+1	O
++	O
+/	O
+-	O
+1	O
+%	O
+","	O
+respectively	O
+.	O
+	
+Thus	O
+","	O
+whereas	O
+nitroglycerin	O
+preferentially	O
+and	O
+flow	O
+-	O
+independently	O
+dilates	O
+large	O
+coronary	O
+arteries	O
+","	O
+cromakalim	O
+and	O
+pinacidil	O
+dilate	O
+both	O
+large	O
+and	O
+small	O
+coronary	O
+arteries	O
+and	O
+this	O
+effect	O
+is	O
+not	O
+dependent	O
+upon	O
+the	O
+simultaneous	O
+beta	O
+adrenoceptors	O
+-	O
+mediated	O
+rise	O
+in	O
+myocardial	O
+metabolic	O
+demand	O
+.	O
+	
+Finally	O
+","	O
+two	O
+mechanisms	O
+at	O
+least	O
+","	O
+direct	O
+vasodilation	O
+and	O
+flow	O
+dependency	O
+","	O
+are	O
+involved	O
+in	O
+the	O
+cromakalim	O
+-	O
+and	O
+pinacidil	O
+-	O
+induced	O
+increase	O
+in	O
+CxAD	O
+.	O
+	
+Mefenamic	O
+acid	O
+-	O
+induced	O
+neutropenia	B-NP
+and	O
+renal	B-NP
+failure	I-NP
+in	O
+elderly	O
+females	O
+with	O
+hypothyroidism	B-NP
+.	O
+	
+We	O
+report	O
+mefenamic	O
+acid	O
+-	O
+induced	O
+non	O
+-	O
+oliguric	O
+renal	B-NP
+failure	I-NP
+and	O
+severe	O
+neutropenia	B-NP
+occurring	O
+simultaneously	O
+in	O
+two	O
+elderly	O
+females	O
+.	O
+	
+The	O
+neutropenia	B-NP
+was	O
+due	O
+to	O
+maturation	O
+arrest	O
+of	O
+the	O
+myeloid	O
+series	O
+in	O
+one	O
+patient	O
+.	O
+	
+Both	O
+patients	O
+were	O
+also	O
+hypothyroid	B-NP
+","	O
+but	O
+it	O
+is	O
+not	O
+clear	O
+whether	O
+this	O
+was	O
+a	O
+predisposing	O
+factor	O
+to	O
+the	O
+development	O
+of	O
+these	O
+adverse	O
+reactions	O
+.	O
+	
+However	O
+","	O
+it	O
+would	O
+seem	O
+prudent	O
+not	O
+to	O
+use	O
+mefenamic	O
+acid	O
+in	O
+hypothyroid	B-NP
+patients	O
+until	O
+the	O
+hypothyroidism	B-NP
+has	O
+been	O
+corrected	O
+.	O
+	
+Etiology	O
+of	O
+hypercalcemia	B-NP
+in	O
+hemodialysis	O
+patients	O
+on	O
+calcium	O
+carbonate	O
+therapy	O
+.	O
+	
+Fourteen	O
+of	O
+39	O
+dialysis	O
+patients	O
+(	O
+36	O
+%	O
+)	O
+became	O
+hypercalcemic	B-NP
+after	O
+switching	O
+to	O
+calcium	O
+carbonate	O
+as	O
+their	O
+principal	O
+phosphate	O
+binder	O
+.	O
+	
+In	O
+order	O
+to	O
+identify	O
+risk	O
+factors	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+hypercalcemia	B-NP
+","	O
+indirect	O
+parameters	O
+of	O
+intestinal	O
+calcium	O
+reabsorption	O
+and	O
+bone	O
+turnover	O
+rate	O
+in	O
+these	O
+14	O
+patients	O
+were	O
+compared	O
+with	O
+results	O
+in	O
+14	O
+eucalcemic	O
+patients	O
+matched	O
+for	O
+age	O
+","	O
+sex	O
+","	O
+length	O
+of	O
+time	O
+on	O
+dialysis	O
+","	O
+and	O
+etiology	O
+of	O
+renal	B-NP
+disease	I-NP
+.	O
+	
+In	O
+addition	O
+to	O
+experiencing	O
+hypercalcemic	B-NP
+episodes	O
+with	O
+peak	O
+calcium	O
+values	O
+of	O
+2	O
+.	O
+7	O
+to	O
+3	O
+.	O
+8	O
+mmol	O
+/	O
+L	O
+(	O
+10	O
+.	O
+7	O
+to	O
+15	O
+.	O
+0	O
+mg	O
+/	O
+dL	O
+)	O
+","	O
+patients	O
+in	O
+the	O
+hypercalcemic	B-NP
+group	O
+exhibited	O
+a	O
+significant	O
+increase	O
+in	O
+the	O
+mean	O
+calcium	O
+concentration	O
+obtained	O
+during	O
+6	O
+months	O
+before	O
+the	O
+switch	O
+","	O
+compared	O
+with	O
+the	O
+mean	O
+value	O
+obtained	O
+during	O
+the	O
+7	O
+months	O
+of	O
+observation	O
+after	O
+the	O
+switch	O
+(	O
+2	O
+.	O
+4	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+to	O
+2	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+mmol	O
+/	O
+L	O
+[	O
+9	O
+.	O
+7	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+to	O
+10	O
+.	O
+2	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+mg	O
+/	O
+dL	O
+]	O
+","	O
+P	O
+=	O
+0	O
+.	O
+6	O
+)	O
+.	O
+	
+In	O
+contrast	O
+","	O
+eucalcemic	O
+patients	O
+exhibited	O
+no	O
+change	O
+in	O
+mean	O
+calcium	O
+values	O
+over	O
+the	O
+same	O
+time	O
+period	O
+(	O
+2	O
+.	O
+3	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+to	O
+2	O
+.	O
+3	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+mmol	O
+/	O
+L	O
+[	O
+9	O
+.	O
+2	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+to	O
+9	O
+.	O
+2	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+mg	O
+/	O
+dL	O
+]	O
+)	O
+.	O
+	
+CaCO3	O
+dosage	O
+","	O
+calculated	O
+dietary	O
+calcium	O
+intake	O
+","	O
+and	O
+circulating	O
+levels	O
+of	O
+vitamin	O
+D	O
+metabolites	O
+were	O
+similar	O
+in	O
+both	O
+groups	O
+.	O
+	
+Physical	O
+activity	O
+index	O
+and	O
+predialysis	O
+serum	O
+bicarbonate	O
+levels	O
+also	O
+were	O
+similar	O
+in	O
+both	O
+groups	O
+.	O
+	
+However	O
+","	O
+there	O
+was	O
+a	O
+significant	O
+difference	O
+in	O
+parameters	O
+reflecting	O
+bone	O
+turnover	O
+rates	O
+between	O
+groups	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+	
+Late	O
+-	O
+onset	O
+scleroderma	B-NP
+renal	I-NP
+crisis	I-NP
+induced	O
+by	O
+tacrolimus	O
+and	O
+prednisolone	O
+:	O
+a	O
+case	O
+report	O
+.	O
+	
+Scleroderma	B-NP
+renal	I-NP
+crisis	I-NP
+(	O
+SRC	B-NP
+)	O
+is	O
+a	O
+rare	O
+complication	O
+of	O
+systemic	B-NP
+sclerosis	I-NP
+(	O
+SSc	B-NP
+)	O
+but	O
+can	O
+be	O
+severe	O
+enough	O
+to	O
+require	O
+temporary	O
+or	O
+permanent	O
+renal	O
+replacement	O
+therapy	O
+.	O
+	
+Moderate	O
+to	O
+high	O
+dose	O
+corticosteroid	O
+use	O
+is	O
+recognized	O
+as	O
+a	O
+major	O
+risk	O
+factor	O
+for	O
+SRC	B-NP
+.	O
+	
+Furthermore	O
+","	O
+there	O
+have	O
+been	O
+reports	O
+of	O
+thrombotic	B-NP
+microangiopathy	I-NP
+precipitated	O
+by	O
+cyclosporine	O
+in	O
+patients	O
+with	O
+SSc	B-NP
+.	O
+	
+In	O
+this	O
+article	O
+","	O
+we	O
+report	O
+a	O
+patient	O
+with	O
+SRC	B-NP
+induced	O
+by	O
+tacrolimus	O
+and	O
+corticosteroids	O
+.	O
+	
+The	O
+aim	O
+of	O
+this	O
+work	O
+is	O
+to	O
+call	O
+attention	O
+to	O
+the	O
+risk	O
+of	O
+tacrolimus	O
+use	O
+in	O
+patients	O
+with	O
+SSc	B-NP
+.	O
+	
+Methyldopa	O
+-	O
+induced	O
+hemolytic	B-NP
+anemia	I-NP
+in	O
+a	O
+15	O
+year	O
+old	O
+presenting	O
+as	O
+near	O
+-	O
+syncope	B-NP
+.	O
+	
+Methyldopa	O
+is	O
+an	O
+antihypertensive	O
+medication	O
+which	O
+is	O
+available	O
+generically	O
+and	O
+under	O
+the	O
+trade	O
+name	O
+Aldomet	O
+that	O
+is	O
+widely	O
+prescribed	O
+in	O
+the	O
+adult	O
+population	O
+and	O
+infrequently	O
+used	O
+in	O
+children	O
+.	O
+	
+Methyldopa	O
+causes	O
+an	O
+autoimmune	B-NP
+hemolytic	I-NP
+anemia	I-NP
+in	O
+a	O
+small	O
+percentage	O
+of	O
+patients	O
+who	O
+take	O
+the	O
+drug	O
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+methyldopa	O
+-	O
+induced	O
+hemolytic	B-NP
+anemia	I-NP
+in	O
+a	O
+15	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+who	O
+presented	O
+to	O
+the	O
+emergency	B-NP
+department	I-NP
+with	O
+near	O
+-	O
+syncope	B-NP
+.	O
+	
+The	O
+boy	O
+had	O
+been	O
+treated	O
+with	O
+intravenous	O
+methyldopa	O
+during	O
+a	O
+trauma	B-NP
+admission	O
+seven	O
+weeks	O
+prior	O
+to	O
+presentation	O
+.	O
+	
+Evaluation	O
+revealed	O
+a	O
+hemoglobin	O
+of	O
+three	O
+grams	O
+","	O
+3	O
++	O
+Coombs	O
+'	O
+test	O
+with	O
+polyspecific	O
+anti	O
+-	O
+human	O
+globulin	O
+and	O
+monospecific	O
+IgG	O
+reagents	O
+","	O
+and	O
+a	O
+warm	O
+reacting	O
+autoantibody	O
+.	O
+	
+Transfusion	O
+and	O
+corticosteroid	O
+therapy	O
+resulted	O
+in	O
+a	O
+complete	O
+recovery	O
+of	O
+the	O
+patient	O
+.	O
+	
+Emergency	O
+physicians	O
+treating	O
+children	O
+must	O
+be	O
+aware	O
+of	O
+this	O
+syndrome	O
+in	O
+order	O
+to	O
+diagnose	O
+and	O
+treat	O
+it	O
+correctly	O
+.	O
+	
+A	O
+brief	O
+review	O
+of	O
+autoimmune	O
+and	O
+drug	O
+-	O
+induced	O
+hemolytic	B-NP
+anemias	I-NP
+is	O
+provided	O
+.	O
+	
+The	O
+risk	O
+and	O
+associated	O
+factors	O
+of	O
+methamphetamine	O
+psychosis	B-NP
+in	O
+methamphetamine	O
+-	O
+dependent	O
+patients	O
+in	O
+Malaysia	O
+.	O
+	
+OBJECTIVE	O
+:	O
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+risk	O
+of	O
+lifetime	O
+and	O
+current	O
+methamphetamine	O
+-	O
+induced	O
+psychosis	B-NP
+in	O
+patients	O
+with	O
+methamphetamine	O
+dependence	O
+.	O
+	
+The	O
+association	O
+between	O
+psychiatric	O
+co	O
+-	O
+morbidity	O
+and	O
+methamphetamine	O
+-	O
+induced	O
+psychosis	B-NP
+was	O
+also	O
+studied	O
+.	O
+	
+METHODS	O
+:	O
+This	O
+was	O
+a	O
+cross	O
+-	O
+sectional	O
+study	O
+conducted	O
+concurrently	O
+at	O
+a	O
+teaching	O
+hospital	O
+and	O
+a	O
+drug	O
+rehabilitation	O
+center	O
+in	O
+Malaysia	O
+.	O
+	
+Patients	O
+with	O
+the	O
+diagnosis	O
+of	O
+methamphetamine	O
+based	O
+on	O
+DSM	O
+-	O
+IV	O
+were	O
+interviewed	O
+using	O
+the	O
+Mini	O
+International	O
+Neuropsychiatric	O
+Interview	O
+(	O
+M	O
+.	O
+I	O
+.	O
+N	O
+.	O
+I	O
+.	O
+)	O
+for	O
+methamphetamine	O
+-	O
+induced	O
+psychosis	B-NP
+and	O
+other	O
+Axis	O
+I	O
+psychiatric	B-NP
+disorders	I-NP
+.	O
+	
+The	O
+information	O
+on	O
+sociodemographic	O
+background	O
+and	O
+drug	O
+use	O
+history	O
+was	O
+obtained	O
+from	O
+interview	O
+or	O
+medical	O
+records	O
+.	O
+	
+RESULTS	O
+:	O
+Of	O
+292	O
+subjects	O
+","	O
+47	O
+.	O
+9	O
+%	O
+of	O
+the	O
+subjects	O
+had	O
+a	O
+past	O
+history	O
+of	O
+psychotic	B-NP
+symptoms	I-NP
+and	O
+13	O
+.	O
+0	O
+%	O
+of	O
+the	O
+patients	O
+were	O
+having	O
+current	O
+psychotic	B-NP
+symptoms	I-NP
+.	O
+	
+Co	O
+-	O
+morbid	O
+major	O
+depressive	B-NP
+disorder	I-NP
+(	O
+OR	O
+=	O
+7	O
+.	O
+18	O
+","	O
+95	O
+CI	O
+=	O
+2	O
+.	O
+612	O
+-	O
+19	O
+.	O
+708	O
+)	O
+","	O
+bipolar	B-NP
+disorder	I-NP
+(	O
+OR	O
+=	O
+13	O
+.	O
+807	O
+","	O
+95	O
+CI	O
+=	O
+5	O
+.	O
+194	O
+-	O
+36	O
+.	O
+706	O
+)	O
+","	O
+antisocial	B-NP
+personality	I-NP
+disorder	I-NP
+(	O
+OR	O
+=	O
+12	O
+.	O
+619	O
+","	O
+95	O
+CI	O
+=	O
+6	O
+.	O
+702	O
+-	O
+23	O
+.	O
+759	O
+)	O
+and	O
+heavy	O
+methamphetamine	O
+uses	O
+were	O
+significantly	O
+associated	O
+with	O
+lifetime	O
+methamphetamine	O
+-	O
+induced	O
+psychosis	B-NP
+after	O
+adjusted	O
+for	O
+other	O
+factors	O
+.	O
+	
+Major	B-NP
+depressive	I-NP
+disorder	I-NP
+(	O
+OR	O
+=	O
+2	O
+.	O
+870	O
+","	O
+CI	O
+=	O
+1	O
+.	O
+154	O
+-	O
+7	O
+.	O
+142	O
+)	O
+and	O
+antisocial	B-NP
+personality	I-NP
+disorder	I-NP
+(	O
+OR	O
+=	O
+3	O
+.	O
+299	O
+","	O
+95	O
+CI	O
+=	O
+1	O
+.	O
+375	O
+-	O
+7	O
+.	O
+914	O
+)	O
+were	O
+the	O
+only	O
+factors	O
+associated	O
+with	O
+current	O
+psychosis	B-NP
+.	O
+	
+CONCLUSION	O
+:	O
+There	O
+was	O
+a	O
+high	O
+risk	O
+of	O
+psychosis	B-NP
+in	O
+patients	O
+with	O
+methamphetamine	O
+dependence	O
+.	O
+	
+It	O
+was	O
+associated	O
+with	O
+co	O
+-	O
+morbid	O
+affective	B-NP
+disorder	I-NP
+","	O
+antisocial	B-NP
+personality	I-NP
+","	O
+and	O
+heavy	O
+methamphetamine	O
+use	O
+.	O
+	
+It	O
+is	O
+recommended	O
+that	O
+all	O
+cases	O
+of	O
+methamphetamine	O
+dependence	O
+should	O
+be	O
+screened	O
+for	O
+psychotic	B-NP
+symptoms	I-NP
+.	O
+	
+Cerebellar	O
+sensory	O
+processing	O
+alterations	O
+impact	O
+motor	O
+cortical	O
+plasticity	O
+in	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+:	O
+clues	O
+from	O
+dyskinetic	B-NP
+patients	O
+.	O
+	
+The	O
+plasticity	O
+of	O
+primary	O
+motor	O
+cortex	O
+(	O
+M1	O
+)	O
+in	O
+patients	O
+with	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+(	O
+PD	B-NP
+)	O
+and	O
+levodopa	O
+-	O
+induced	O
+dyskinesias	B-NP
+(	O
+LIDs	B-NP
+)	O
+is	O
+severely	O
+impaired	O
+.	O
+	
+We	O
+recently	O
+reported	O
+in	O
+young	O
+healthy	O
+subjects	O
+that	O
+inhibitory	O
+cerebellar	O
+stimulation	O
+enhanced	O
+the	O
+sensorimotor	O
+plasticity	O
+of	O
+M1	O
+that	O
+was	O
+induced	O
+by	O
+paired	O
+associative	O
+stimulation	O
+(	O
+PAS	O
+)	O
+.	O
+	
+This	O
+study	O
+demonstrates	O
+that	O
+the	O
+deficient	O
+sensorimotor	O
+M1	O
+plasticity	O
+in	O
+16	O
+patients	O
+with	O
+LIDs	B-NP
+could	O
+be	O
+reinstated	O
+by	O
+a	O
+single	O
+session	O
+of	O
+real	O
+inhibitory	O
+cerebellar	O
+stimulation	O
+but	O
+not	O
+sham	O
+stimulation	O
+.	O
+	
+This	O
+was	O
+evident	O
+only	O
+when	O
+a	O
+sensory	O
+component	O
+was	O
+involved	O
+in	O
+the	O
+induction	O
+of	O
+plasticity	O
+","	O
+indicating	O
+that	O
+cerebellar	O
+sensory	O
+processing	O
+function	O
+is	O
+involved	O
+in	O
+the	O
+resurgence	O
+of	O
+M1	O
+plasticity	O
+.	O
+	
+The	O
+benefit	O
+of	O
+inhibitory	O
+cerebellar	O
+stimulation	O
+on	O
+LIDs	B-NP
+is	O
+known	O
+.	O
+	
+To	O
+explore	O
+whether	O
+this	O
+benefit	O
+is	O
+linked	O
+to	O
+the	O
+restoration	O
+of	O
+sensorimotor	O
+plasticity	O
+of	O
+M1	O
+","	O
+we	O
+conducted	O
+an	O
+additional	O
+study	O
+looking	O
+at	O
+changes	O
+in	O
+LIDs	B-NP
+and	O
+PAS	O
+-	O
+induced	O
+plasticity	O
+after	O
+10	O
+sessions	O
+of	O
+either	O
+bilateral	O
+","	O
+real	O
+inhibitory	O
+cerebellar	O
+stimulation	O
+or	O
+sham	O
+stimulation	O
+.	O
+	
+Only	O
+real	O
+and	O
+not	O
+sham	O
+stimulation	O
+had	O
+an	O
+antidyskinetic	O
+effect	O
+and	O
+it	O
+was	O
+paralleled	O
+by	O
+a	O
+resurgence	O
+in	O
+the	O
+sensorimotor	O
+plasticity	O
+of	O
+M1	O
+.	O
+	
+These	O
+results	O
+suggest	O
+that	O
+alterations	O
+in	O
+cerebellar	O
+sensory	O
+processing	O
+function	O
+","	O
+occurring	O
+secondary	O
+to	O
+abnormal	O
+basal	O
+ganglia	O
+signals	O
+reaching	O
+it	O
+","	O
+may	O
+be	O
+an	O
+important	O
+element	O
+contributing	O
+to	O
+the	O
+maladaptive	O
+sensorimotor	O
+plasticity	O
+of	O
+M1	O
+and	O
+the	O
+emergence	O
+of	O
+abnormal	B-NP
+involuntary	I-NP
+movements	I-NP
+.	O
+	
+The	O
+long	O
+-	O
+term	O
+safety	O
+of	O
+danazol	O
+in	O
+women	O
+with	O
+hereditary	B-NP
+angioedema	I-NP
+.	O
+	
+Although	O
+the	O
+short	O
+-	O
+term	O
+safety	O
+(	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+6	O
+months	O
+)	O
+of	O
+danazol	O
+has	O
+been	O
+established	O
+in	O
+a	O
+variety	O
+of	O
+settings	O
+","	O
+no	O
+information	O
+exists	O
+as	O
+to	O
+its	O
+long	O
+-	O
+term	O
+safety	O
+.	O
+	
+We	O
+therefore	O
+investigated	O
+the	O
+long	O
+-	O
+term	O
+safety	O
+of	O
+danazol	O
+by	O
+performing	O
+a	O
+retrospective	O
+chart	O
+review	O
+of	O
+60	O
+female	O
+patients	O
+with	O
+hereditary	B-NP
+angioedema	I-NP
+treated	O
+with	O
+danazol	O
+for	O
+a	O
+continuous	O
+period	O
+of	O
+6	O
+months	O
+or	O
+longer	O
+.	O
+	
+The	O
+mean	O
+age	O
+of	O
+the	O
+patients	O
+was	O
+35	O
+.	O
+2	O
+years	O
+and	O
+the	O
+mean	O
+duration	O
+of	O
+therapy	O
+was	O
+59	O
+.	O
+7	O
+months	O
+.	O
+	
+Virtually	O
+all	O
+patients	O
+experienced	O
+one	O
+or	O
+more	O
+adverse	O
+reactions	O
+.	O
+	
+Menstrual	B-NP
+abnormalities	I-NP
+(	O
+79	O
+%	O
+)	O
+","	O
+weight	B-NP
+gain	I-NP
+(	O
+60	O
+%	O
+)	O
+","	O
+muscle	B-NP
+cramps	I-NP
+/	O
+myalgias	B-NP
+(	O
+40	O
+%	O
+)	O
+","	O
+and	O
+transaminase	O
+elevations	O
+(	O
+40	O
+%	O
+)	O
+were	O
+the	O
+most	O
+common	O
+adverse	O
+reactions	O
+.	O
+	
+The	O
+drug	O
+was	O
+discontinued	O
+due	O
+to	O
+adverse	O
+reactions	O
+in	O
+8	O
+patients	O
+.	O
+	
+No	O
+patient	O
+has	O
+died	O
+or	O
+suffered	O
+any	O
+apparent	O
+long	O
+-	O
+term	O
+sequelae	O
+that	O
+were	O
+directly	O
+attributable	O
+to	O
+the	O
+drug	O
+.	O
+	
+We	O
+conclude	O
+that	O
+","	O
+despite	O
+a	O
+relatively	O
+high	O
+incidence	O
+of	O
+adverse	O
+reactions	O
+","	O
+danazol	O
+has	O
+proven	O
+to	O
+be	O
+remarkably	O
+safe	O
+over	O
+the	O
+long	O
+-	O
+term	O
+in	O
+this	O
+group	O
+of	O
+patients	O
+.	O
+	
+The	O
+function	O
+of	O
+P2X3	O
+receptor	O
+and	O
+NK1	O
+receptor	O
+antagonists	O
+on	O
+cyclophosphamide	O
+-	O
+induced	O
+cystitis	B-NP
+in	O
+rats	O
+.	O
+	
+PURPOSE	O
+:	O
+The	O
+purpose	O
+of	O
+the	O
+study	O
+is	O
+to	O
+explore	O
+the	O
+function	O
+of	O
+P2X3	O
+and	O
+NK1	O
+receptors	O
+antagonists	O
+on	O
+cyclophosphamide	O
+(	O
+CYP	O
+)	O
+-	O
+induced	O
+cystitis	B-NP
+in	O
+rats	O
+.	O
+	
+METHODS	O
+:	O
+Sixty	O
+female	O
+Sprague	O
+-	O
+Dawley	O
+(	O
+SD	O
+)	O
+rats	O
+were	O
+randomly	O
+divided	O
+into	O
+three	O
+groups	O
+.	O
+	
+The	O
+rats	O
+in	O
+the	O
+control	O
+group	O
+were	O
+intraperitoneally	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+injected	O
+with	O
+0	O
+.	O
+9	O
+%	O
+saline	O
+(	O
+4	O
+ml	O
+/	O
+kg	O
+)	O
+;	O
+the	O
+rats	O
+in	O
+the	O
+model	O
+group	O
+were	O
+i	O
+.	O
+p	O
+.	O
+injected	O
+with	O
+CYP	O
+(	O
+150	O
+mg	O
+/	O
+kg	O
+)	O
+;	O
+and	O
+the	O
+rats	O
+in	O
+the	O
+intervention	O
+group	O
+were	O
+i	O
+.	O
+p	O
+.	O
+injected	O
+with	O
+CYP	O
+with	O
+subsequently	O
+perfusion	O
+of	O
+bladder	O
+with	O
+P2X3	O
+and	O
+NK1	O
+receptors	O
+'	O
+antagonists	O
+","	O
+Suramin	O
+and	O
+GR	O
+82334	O
+.	O
+	
+Spontaneous	O
+pain	B-NP
+behaviors	O
+following	O
+the	O
+administration	O
+of	O
+CYP	O
+were	O
+observed	O
+.	O
+	
+Urodynamic	O
+parameters	O
+","	O
+bladder	O
+pressure	O
+-	O
+volume	O
+curve	O
+","	O
+maximum	O
+voiding	O
+pressure	O
+(	O
+MVP	O
+)	O
+","	O
+and	O
+maximum	O
+cystometric	O
+capacity	O
+(	O
+MCC	O
+)	O
+","	O
+were	O
+recorded	O
+.	O
+	
+Pathological	O
+changes	O
+in	O
+bladder	O
+tissue	O
+were	O
+observed	O
+.	O
+	
+Immunofluorescence	O
+was	O
+used	O
+to	O
+detect	O
+the	O
+expression	O
+of	O
+P2X3	O
+and	O
+NK1	O
+receptors	O
+in	O
+bladder	O
+.	O
+	
+RESULTS	O
+:	O
+Cyclophosphamide	O
+treatment	O
+increased	O
+the	O
+spontaneous	O
+pain	B-NP
+behaviors	O
+scores	O
+.	O
+	
+The	O
+incidence	O
+of	O
+bladder	O
+instability	O
+during	O
+urine	O
+storage	O
+period	O
+of	O
+model	O
+group	O
+was	O
+significantly	O
+higher	O
+than	O
+intervention	O
+group	O
+(	O
+X	O
+(	O
+2	O
+)	O
+=	O
+7	O
+.	O
+619	O
+","	O
+P	O
+=	O
+0	O
+.	O
+7	O
+)	O
+and	O
+control	O
+group	O
+(	O
+X	O
+(	O
+2	O
+)	O
+=	O
+13	O
+.	O
+755	O
+","	O
+P	O
+=	O
+0	O
+.	O
+0	O
+)	O
+.	O
+	
+MCC	O
+in	O
+the	O
+model	O
+group	O
+was	O
+lower	O
+than	O
+the	O
+control	O
+and	O
+intervention	O
+groups	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Histological	O
+changes	O
+evident	O
+in	O
+model	O
+and	O
+intervention	O
+groups	O
+rats	O
+'	O
+bladder	O
+included	O
+edema	B-NP
+","	O
+vasodilation	O
+","	O
+and	O
+infiltration	O
+of	O
+inflammatory	O
+cells	O
+.	O
+	
+In	O
+model	O
+group	O
+","	O
+the	O
+expression	O
+of	O
+P2X3	O
+receptor	O
+increased	O
+in	O
+urothelium	O
+and	O
+suburothelium	O
+","	O
+and	O
+NK1	O
+receptor	O
+increased	O
+in	O
+suburothelium	O
+","	O
+while	O
+the	O
+expression	O
+of	O
+them	O
+in	O
+intervention	O
+group	O
+was	O
+lower	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+In	O
+CYP	O
+-	O
+induced	O
+cystitis	B-NP
+","	O
+the	O
+expression	O
+of	O
+P2X3	O
+and	O
+NK1	O
+receptors	O
+increased	O
+in	O
+urothelium	O
+and	O
+/	O
+or	O
+suburothelium	O
+.	O
+	
+Perfusion	O
+of	O
+bladder	O
+with	O
+P2X3	O
+and	O
+NK1	O
+receptors	O
+antagonists	O
+ameliorated	O
+the	O
+bladder	O
+function	O
+.	O
+	
+Patient	O
+tolerance	O
+study	O
+of	O
+topical	O
+chlorhexidine	O
+diphosphanilate	O
+:	O
+a	O
+new	O
+topical	O
+agent	O
+for	O
+burns	B-NP
+.	O
+	
+Effective	O
+topical	O
+antimicrobial	O
+agents	O
+decrease	O
+infection	B-NP
+and	O
+mortality	O
+in	O
+burn	B-NP
+patients	O
+.	O
+	
+Chlorhexidine	O
+phosphanilate	O
+(	O
+CHP	O
+)	O
+","	O
+a	O
+new	O
+broad	O
+-	O
+spectrum	O
+antimicrobial	O
+agent	O
+","	O
+has	O
+been	O
+evaluated	O
+as	O
+a	O
+topical	O
+burn	B-NP
+wound	O
+dressing	O
+in	O
+cream	O
+form	O
+","	O
+but	O
+preliminary	O
+clinical	O
+trials	O
+reported	O
+that	O
+it	O
+was	O
+painful	O
+upon	O
+application	O
+.	O
+	
+This	O
+study	O
+compared	O
+various	O
+concentrations	O
+of	O
+CHP	O
+to	O
+determine	O
+if	O
+a	O
+tolerable	O
+concentration	O
+could	O
+be	O
+identified	O
+with	O
+retention	O
+of	O
+antimicrobial	O
+efficacy	O
+.	O
+	
+Twenty	O
+-	O
+nine	O
+burn	B-NP
+patients	O
+","	O
+each	O
+with	O
+two	O
+similar	O
+burns	B-NP
+which	O
+could	O
+be	O
+separately	O
+treated	O
+","	O
+were	O
+given	O
+pairs	O
+of	O
+treatments	O
+at	O
+successive	O
+12	O
+-	O
+h	O
+intervals	O
+over	O
+a	O
+3	O
+-	O
+day	O
+period	O
+.	O
+	
+One	O
+burn	B-NP
+site	O
+was	O
+treated	O
+with	O
+each	O
+of	O
+four	O
+different	O
+CHP	O
+concentrations	O
+","	O
+from	O
+0	O
+.	O
+25	O
+per	O
+cent	O
+to	O
+2	O
+per	O
+cent	O
+","	O
+their	O
+vehicle	O
+","	O
+and	O
+1	O
+per	O
+cent	O
+silver	O
+sulphadiazine	O
+(	O
+AgSD	O
+)	O
+cream	O
+","	O
+an	O
+antimicrobial	O
+agent	O
+frequently	O
+used	O
+for	O
+topical	O
+treatment	O
+of	O
+burn	B-NP
+wounds	O
+.	O
+	
+The	O
+other	O
+site	O
+was	O
+always	O
+treated	O
+with	O
+AgSD	O
+cream	O
+.	O
+	
+There	O
+was	O
+a	O
+direct	O
+relationship	O
+between	O
+CHP	O
+concentration	O
+and	O
+patients	O
+'	O
+ratings	O
+of	O
+pain	B-NP
+on	O
+an	O
+analogue	O
+scale	O
+.	O
+	
+The	O
+0	O
+.	O
+25	O
+per	O
+cent	O
+CHP	O
+cream	O
+was	O
+closest	O
+to	O
+AgSD	O
+in	O
+pain	B-NP
+tolerance	O
+;	O
+however	O
+","	O
+none	O
+of	O
+the	O
+treatments	O
+differed	O
+statistically	O
+from	O
+AgSD	O
+or	O
+from	O
+each	O
+other	O
+.	O
+	
+In	O
+addition	O
+","	O
+ease	O
+of	O
+application	O
+of	O
+CHP	O
+creams	O
+was	O
+less	O
+satisfactory	O
+than	O
+that	O
+of	O
+AgSD	O
+.	O
+	
+It	O
+was	O
+concluded	O
+that	O
+formulations	O
+at	O
+or	O
+below	O
+0	O
+.	O
+5	O
+per	O
+cent	O
+CHP	O
+may	O
+prove	O
+acceptable	O
+for	O
+wound	O
+care	O
+","	O
+but	O
+the	O
+vehicle	O
+system	O
+needs	O
+pharmaceutical	O
+improvement	O
+to	O
+render	O
+it	O
+more	O
+tolerable	O
+and	O
+easier	O
+to	O
+use	O
+.	O
+	
+Acute	O
+hepatitis	B-NP
+associated	O
+with	O
+clopidogrel	O
+:	O
+a	O
+case	O
+report	O
+and	O
+review	O
+of	O
+the	O
+literature	O
+.	O
+	
+Drug	O
+-	O
+induced	O
+hepatotoxicity	B-NP
+is	O
+a	O
+common	O
+cause	O
+of	O
+acute	O
+hepatitis	B-NP
+","	O
+and	O
+the	O
+recognition	O
+of	O
+the	O
+responsible	O
+drug	O
+may	O
+be	O
+difficult	O
+.	O
+	
+We	O
+describe	O
+a	O
+case	O
+of	O
+clopidogrel	O
+-	O
+related	O
+acute	O
+hepatitis	B-NP
+.	O
+	
+The	O
+diagnosis	O
+is	O
+strongly	O
+suggested	O
+by	O
+an	O
+accurate	O
+medical	O
+history	O
+and	O
+liver	O
+biopsy	O
+.	O
+	
+Reports	O
+about	O
+cases	O
+of	O
+hepatotoxicity	B-NP
+due	O
+to	O
+clopidogrel	O
+are	O
+increasing	O
+in	O
+the	O
+last	O
+few	O
+years	O
+","	O
+after	O
+the	O
+increased	O
+use	O
+of	O
+this	O
+drug	O
+.	O
+	
+In	O
+conclusion	O
+","	O
+we	O
+believe	O
+that	O
+physicians	O
+should	O
+carefully	O
+consider	O
+the	O
+risk	O
+of	O
+drug	O
+-	O
+induced	O
+hepatic	B-NP
+injury	I-NP
+when	O
+clopidogrel	O
+is	O
+prescribed	O
+.	O
+	
+Bortezomib	O
+and	O
+dexamethasone	O
+as	O
+salvage	O
+therapy	O
+in	O
+patients	O
+with	O
+relapsed	O
+/	O
+refractory	O
+multiple	B-NP
+myeloma	I-NP
+:	O
+analysis	O
+of	O
+long	O
+-	O
+term	O
+clinical	O
+outcomes	O
+.	O
+	
+Bortezomib	O
+(	O
+bort	O
+)	O
+-	O
+dexamethasone	O
+(	O
+dex	O
+)	O
+is	O
+an	O
+effective	O
+therapy	O
+for	O
+relapsed	O
+/	O
+refractory	O
+(	O
+R	O
+/	O
+R	O
+)	O
+multiple	B-NP
+myeloma	I-NP
+(	O
+MM	B-NP
+)	O
+.	O
+	
+This	O
+retrospective	O
+study	O
+investigated	O
+the	O
+combination	O
+of	O
+bort	O
+(	O
+1	O
+.	O
+3	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+on	O
+days	O
+1	O
+","	O
+4	O
+","	O
+8	O
+","	O
+and	O
+11	O
+every	O
+3	O
+weeks	O
+)	O
+and	O
+dex	O
+(	O
+20	O
+mg	O
+on	O
+the	O
+day	O
+of	O
+and	O
+the	O
+day	O
+after	O
+bort	O
+)	O
+as	O
+salvage	O
+treatment	O
+in	O
+85	O
+patients	O
+with	O
+R	O
+/	O
+R	O
+MM	B-NP
+after	O
+prior	O
+autologous	O
+stem	O
+cell	O
+transplantation	O
+or	O
+conventional	O
+chemotherapy	O
+.	O
+	
+The	O
+median	O
+number	O
+of	O
+prior	O
+lines	O
+of	O
+therapy	O
+was	O
+2	O
+.	O
+	
+Eighty	O
+-	O
+seven	O
+percent	O
+of	O
+the	O
+patients	O
+had	O
+received	O
+immunomodulatory	O
+drugs	O
+included	O
+in	O
+some	O
+line	O
+of	O
+therapy	O
+before	O
+bort	O
+-	O
+dex	O
+.	O
+	
+The	O
+median	O
+number	O
+of	O
+bort	O
+-	O
+dex	O
+cycles	O
+was	O
+6	O
+","	O
+up	O
+to	O
+a	O
+maximum	O
+of	O
+12	O
+cycles	O
+.	O
+	
+On	O
+an	O
+intention	O
+-	O
+to	O
+-	O
+treat	O
+basis	O
+","	O
+55	O
+%	O
+of	O
+the	O
+patients	O
+achieved	O
+at	O
+least	O
+partial	O
+response	O
+","	O
+including	O
+19	O
+%	O
+CR	O
+and	O
+35	O
+%	O
+achieved	O
+at	O
+least	O
+very	O
+good	O
+partial	O
+response	O
+.	O
+	
+Median	O
+durations	O
+of	O
+response	O
+","	O
+time	O
+to	O
+next	O
+therapy	O
+and	O
+treatment	O
+-	O
+free	O
+interval	O
+were	O
+8	O
+","	O
+11	O
+.	O
+2	O
+","	O
+and	O
+5	O
+.	O
+1	O
+months	O
+","	O
+respectively	O
+.	O
+	
+The	O
+most	O
+relevant	O
+adverse	O
+event	O
+was	O
+peripheral	B-NP
+neuropathy	I-NP
+","	O
+which	O
+occurred	O
+in	O
+78	O
+%	O
+of	O
+the	O
+patients	O
+(	O
+grade	O
+II	O
+","	O
+38	O
+%	O
+;	O
+grade	O
+III	O
+","	O
+21	O
+%	O
+)	O
+and	O
+led	O
+to	O
+treatment	O
+discontinuation	O
+in	O
+6	O
+%	O
+.	O
+	
+With	O
+a	O
+median	O
+follow	O
+up	O
+of	O
+22	O
+months	O
+","	O
+median	O
+time	O
+to	O
+progression	O
+","	O
+progression	O
+-	O
+free	O
+survival	O
+(	O
+PFS	O
+)	O
+and	O
+overall	O
+survival	O
+(	O
+OS	O
+)	O
+were	O
+8	O
+.	O
+9	O
+","	O
+8	O
+.	O
+7	O
+","	O
+and	O
+22	O
+months	O
+","	O
+respectively	O
+.	O
+	
+Prolonged	O
+PFS	O
+and	O
+OS	O
+were	O
+observed	O
+in	O
+patients	O
+achieving	O
+CR	O
+and	O
+receiving	O
+bort	O
+-	O
+dex	O
+a	O
+single	O
+line	O
+of	O
+prior	O
+therapy	O
+.	O
+	
+Bort	O
+-	O
+dex	O
+was	O
+an	O
+effective	O
+salvage	O
+treatment	O
+for	O
+MM	B-NP
+patients	O
+","	O
+particularly	O
+for	O
+those	O
+in	O
+first	O
+relapse	O
+.	O
+	
+Pubertal	O
+exposure	O
+to	O
+Bisphenol	O
+A	O
+increases	O
+anxiety	B-NP
+-	O
+like	O
+behavior	O
+and	O
+decreases	O
+acetylcholinesterase	O
+activity	O
+of	O
+hippocampus	O
+in	O
+adult	O
+male	O
+mice	O
+.	O
+	
+The	O
+negative	O
+effects	O
+of	O
+Bisphenol	O
+A	O
+(	O
+BPA	O
+)	O
+on	O
+neurodevelopment	O
+and	O
+behaviors	O
+have	O
+been	O
+well	O
+established	O
+.	O
+	
+Acetylcholinesterase	O
+(	O
+AChE	O
+)	O
+is	O
+a	O
+regulatory	O
+enzyme	O
+which	O
+is	O
+involved	O
+in	O
+anxiety	B-NP
+-	O
+like	O
+behavior	O
+.	O
+	
+This	O
+study	O
+investigated	O
+behavioral	O
+phenotypes	O
+and	O
+AChE	O
+activity	O
+in	O
+male	O
+mice	O
+following	O
+BPA	O
+exposure	O
+during	O
+puberty	O
+.	O
+	
+On	O
+postnatal	O
+day	O
+(	O
+PND	O
+)	O
+35	O
+","	O
+male	O
+mice	O
+were	O
+exposed	O
+to	O
+50mg	O
+BPA	O
+/	O
+kg	O
+diet	O
+per	O
+day	O
+for	O
+a	O
+period	O
+of	O
+35	O
+days	O
+.	O
+	
+On	O
+PND71	O
+","	O
+a	O
+behavioral	O
+assay	O
+was	O
+performed	O
+using	O
+the	O
+elevated	O
+plus	O
+maze	O
+(	O
+EPM	O
+)	O
+and	O
+the	O
+light	O
+/	O
+dark	O
+test	O
+.	O
+	
+In	O
+addition	O
+","	O
+AChE	O
+activity	O
+was	O
+measured	O
+in	O
+the	O
+prefrontal	O
+cortex	O
+","	O
+hypothalamus	O
+","	O
+cerebellum	O
+and	O
+hippocampus	O
+.	O
+	
+Results	O
+from	O
+our	O
+behavioral	O
+phenotyping	O
+indicated	O
+that	O
+anxiety	B-NP
+-	O
+like	O
+behavior	O
+was	O
+increased	O
+in	O
+mice	O
+exposed	O
+to	O
+BPA	O
+.	O
+	
+AChE	O
+activity	O
+was	O
+significantly	O
+decreased	O
+in	O
+the	O
+hippocampus	O
+of	O
+mice	O
+with	O
+BPA	O
+compared	O
+to	O
+control	O
+mice	O
+","	O
+whereas	O
+no	O
+difference	O
+was	O
+found	O
+in	O
+the	O
+prefrontal	O
+cortex	O
+","	O
+hypothalamus	O
+and	O
+cerebellum	O
+.	O
+	
+Our	O
+findings	O
+showed	O
+that	O
+pubertal	O
+BPA	O
+exposure	O
+increased	O
+anxiety	B-NP
+-	O
+like	O
+behavior	O
+","	O
+which	O
+may	O
+be	O
+associated	O
+with	O
+decreased	O
+AChE	O
+activity	O
+of	O
+the	O
+hippocampus	O
+in	O
+adult	O
+male	O
+mice	O
+.	O
+	
+Further	O
+studies	O
+are	O
+necessary	O
+to	O
+investigate	O
+the	O
+cholinergic	O
+signaling	O
+of	O
+the	O
+hippocampus	O
+in	O
+PBE	O
+induced	O
+anxiety	B-NP
+-	O
+like	O
+behaviors	O
+.	O
+	
+Biochemical	O
+effects	O
+of	O
+Solidago	O
+virgaurea	O
+extract	O
+on	O
+experimental	O
+cardiotoxicity	B-NP
+.	O
+	
+Cardiovascular	B-NP
+diseases	I-NP
+(	O
+CVDs	B-NP
+)	O
+are	O
+the	O
+major	O
+health	O
+problem	O
+of	O
+advanced	O
+as	O
+well	O
+as	O
+developing	O
+countries	O
+of	O
+the	O
+world	O
+.	O
+	
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+protective	O
+effect	O
+of	O
+the	O
+Solidago	O
+virgaurea	O
+extract	O
+on	O
+isoproterenol	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+in	O
+rats	O
+.	O
+	
+The	O
+subcutaneous	O
+injection	O
+of	O
+isoproterenol	O
+(	O
+30	O
+mg	O
+/	O
+kg	O
+)	O
+into	O
+rats	O
+twice	O
+at	O
+an	O
+interval	O
+of	O
+24	O
+h	O
+","	O
+for	O
+two	O
+consecutive	O
+days	O
+","	O
+led	O
+to	O
+a	O
+significant	O
+increase	O
+in	O
+serum	O
+lactate	O
+dehydrogenase	O
+","	O
+creatine	O
+phosphokinase	O
+","	O
+alanine	O
+transaminase	O
+","	O
+aspartate	O
+transaminase	O
+","	O
+and	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+activities	O
+","	O
+total	O
+cholesterol	O
+","	O
+triglycerides	O
+","	O
+free	O
+serum	O
+fatty	O
+acid	O
+","	O
+cardiac	O
+tissue	O
+malondialdehyde	O
+(	O
+MDA	O
+)	O
+","	O
+and	O
+nitric	O
+oxide	O
+levels	O
+and	O
+a	O
+significant	O
+decrease	O
+in	O
+levels	O
+of	O
+glutathione	O
+and	O
+superoxide	O
+dismutase	O
+in	O
+cardiac	O
+tissue	O
+as	O
+compared	O
+to	O
+the	O
+normal	O
+control	O
+group	O
+(	O
+P	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+Pretreatment	O
+with	O
+S	O
+.	O
+virgaurea	O
+extract	O
+for	O
+5	O
+weeks	O
+at	O
+a	O
+dose	O
+of	O
+250	O
+mg	O
+/	O
+kg	O
+followed	O
+by	O
+isoproterenol	O
+injection	O
+significantly	O
+prevented	O
+the	O
+observed	O
+alterations	O
+.	O
+	
+Captopril	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+","	O
+given	O
+orally	O
+)	O
+","	O
+an	O
+inhibitor	O
+of	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+used	O
+as	O
+a	O
+standard	O
+cardioprotective	O
+drug	O
+","	O
+was	O
+used	O
+as	O
+a	O
+positive	O
+control	O
+in	O
+this	O
+study	O
+.	O
+	
+The	O
+data	O
+of	O
+the	O
+present	O
+study	O
+suggest	O
+that	O
+S	O
+.	O
+virgaurea	O
+extract	O
+exerts	O
+its	O
+protective	O
+effect	O
+by	O
+decreasing	O
+MDA	O
+level	O
+and	O
+increasing	O
+the	O
+antioxidant	O
+status	O
+in	O
+isoproterenol	O
+-	O
+treated	O
+rats	O
+.	O
+	
+The	O
+study	O
+emphasizes	O
+the	O
+beneficial	O
+action	O
+of	O
+S	O
+.	O
+virgaurea	O
+extract	O
+as	O
+a	O
+cardioprotective	O
+agent	O
+.	O
+	
+"	O
+Real	O
+-	O
+world	O
+"	O
+data	O
+on	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+lenalidomide	O
+and	O
+dexamethasone	O
+in	O
+patients	O
+with	O
+relapsed	O
+/	O
+refractory	O
+multiple	B-NP
+myeloma	I-NP
+who	O
+were	O
+treated	O
+according	O
+to	O
+the	O
+standard	O
+clinical	O
+practice	O
+:	O
+a	O
+study	O
+of	O
+the	O
+Greek	O
+Myeloma	B-NP
+Study	O
+Group	O
+.	O
+	
+Lenalidomide	O
+and	O
+dexamethasone	O
+(	O
+RD	O
+)	O
+is	O
+a	O
+standard	O
+of	O
+care	O
+for	O
+relapsed	O
+/	O
+refractory	O
+multiple	B-NP
+myeloma	I-NP
+(	O
+RRMM	B-NP
+)	O
+","	O
+but	O
+there	O
+is	O
+limited	O
+published	O
+data	O
+on	O
+its	O
+efficacy	O
+and	O
+safety	O
+in	O
+the	O
+"	O
+real	O
+world	O
+"	O
+(	O
+RW	O
+)	O
+","	O
+according	O
+to	O
+the	O
+International	O
+Society	O
+of	O
+Pharmacoeconomics	O
+and	O
+Outcomes	O
+Research	O
+definition	O
+.	O
+	
+We	O
+studied	O
+212	O
+RRMM	B-NP
+patients	O
+who	O
+received	O
+RD	O
+in	O
+RW	O
+.	O
+	
+Objective	O
+response	O
+(	O
+>	O
+PR	O
+(	O
+partial	O
+response	O
+)	O
+)	O
+rate	O
+was	O
+77	O
+.	O
+4	O
+%	O
+(	O
+complete	O
+response	O
+(	O
+CR	O
+)	O
+","	O
+20	O
+.	O
+2	O
+%	O
+)	O
+.	O
+	
+Median	O
+time	O
+to	O
+first	O
+and	O
+best	O
+response	O
+was	O
+2	O
+and	O
+5	O
+months	O
+","	O
+respectively	O
+.	O
+	
+Median	O
+time	O
+to	O
+CR	O
+when	O
+RD	O
+was	O
+given	O
+as	O
+2nd	O
+or	O
+>	O
+2	O
+(	O
+nd	O
+)	O
+-	O
+line	O
+treatment	O
+at	O
+4	O
+and	O
+11	O
+months	O
+","	O
+respectively	O
+.	O
+	
+Quality	O
+of	O
+response	O
+was	O
+independent	O
+of	O
+previous	O
+lines	O
+of	O
+therapies	O
+or	O
+previous	O
+exposure	O
+to	O
+thalidomide	O
+or	O
+bortezomib	O
+.	O
+	
+Median	O
+duration	O
+of	O
+response	O
+was	O
+34	O
+.	O
+4	O
+months	O
+","	O
+and	O
+it	O
+was	O
+higher	O
+in	O
+patients	O
+who	O
+received	O
+RD	O
+until	O
+progression	O
+(	O
+not	O
+reached	O
+versus	O
+19	O
+months	O
+","	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Improvement	O
+of	O
+humoral	O
+immunity	O
+occurred	O
+in	O
+60	O
+%	O
+of	O
+responders	O
+(	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+and	O
+in	O
+the	O
+majority	O
+of	O
+patients	O
+who	O
+achieved	O
+stable	O
+disease	O
+.	O
+	
+Adverse	O
+events	O
+were	O
+reported	O
+in	O
+68	O
+.	O
+9	O
+%	O
+of	O
+patients	O
+(	O
+myelosuppression	B-NP
+in	O
+49	O
+.	O
+4	O
+%	O
+)	O
+and	O
+12	O
+.	O
+7	O
+%	O
+of	O
+patients	O
+needed	O
+hospitalization	O
+.	O
+	
+Peripheral	B-NP
+neuropathy	I-NP
+was	O
+observed	O
+only	O
+in	O
+2	O
+.	O
+5	O
+%	O
+of	O
+patients	O
+and	O
+deep	B-NP
+vein	I-NP
+thrombosis	I-NP
+in	O
+5	O
+.	O
+7	O
+%	O
+.	O
+	
+Dose	O
+reductions	O
+were	O
+needed	O
+in	O
+31	O
+%	O
+of	O
+patients	O
+and	O
+permanent	O
+discontinuation	O
+in	O
+38	O
+.	O
+9	O
+%	O
+.	O
+	
+Median	O
+time	O
+to	O
+treatment	O
+discontinuation	O
+was	O
+16	O
+.	O
+8	O
+months	O
+.	O
+	
+Performance	O
+status	O
+(	O
+PS	O
+)	O
+and	O
+initial	O
+lenalidomide	O
+dose	O
+predicted	O
+for	O
+treatment	O
+discontinuation	O
+.	O
+	
+Extra	O
+-	O
+medullary	O
+relapses	O
+occurred	O
+in	O
+3	O
+.	O
+8	O
+%	O
+of	O
+patients	O
+.	O
+	
+Our	O
+study	O
+confirms	O
+that	O
+RD	O
+is	O
+effective	O
+and	O
+safe	O
+in	O
+RRMM	B-NP
+in	O
+the	O
+RW	O
+;	O
+it	O
+produces	O
+durable	O
+responses	O
+especially	O
+in	O
+patients	O
+who	O
+continue	O
+on	O
+treatment	O
+till	O
+progression	O
+and	O
+improves	O
+humoral	O
+immunity	O
+even	O
+in	O
+patients	O
+with	O
+stable	O
+disease	O
+.	O
+	
+The	O
+cytogenetic	O
+action	O
+of	O
+ifosfamide	O
+","	O
+mesna	O
+","	O
+and	O
+their	O
+combination	O
+on	O
+peripheral	O
+rabbit	O
+lymphocytes	O
+:	O
+an	O
+in	O
+vivo	O
+/	O
+in	O
+vitro	O
+cytogenetic	O
+study	O
+.	O
+	
+Ifosfamide	O
+(	O
+IFO	O
+)	O
+is	O
+an	O
+alkylating	O
+nitrogen	O
+mustard	O
+","	O
+administrated	O
+as	O
+an	O
+antineoplasmic	O
+agent	O
+.	O
+	
+It	O
+is	O
+characterized	O
+by	O
+its	O
+intense	O
+urotoxic	O
+action	O
+","	O
+leading	O
+to	O
+hemorrhagic	B-NP
+cystitis	I-NP
+.	O
+	
+This	O
+side	O
+effect	O
+of	O
+IFO	O
+raises	O
+the	O
+requirement	O
+for	O
+the	O
+co	O
+-	O
+administration	O
+with	O
+sodium	O
+2	O
+-	O
+sulfanylethanesulfonate	O
+(	O
+Mesna	O
+)	O
+aiming	O
+to	O
+avoid	O
+or	O
+minimize	O
+this	O
+effect	O
+.	O
+	
+IFO	O
+and	O
+Mesna	O
+were	O
+administrated	O
+separately	O
+on	O
+rabbit	O
+'	O
+s	O
+lymphocytes	O
+in	O
+vivo	O
+","	O
+which	O
+were	O
+later	O
+developed	O
+in	O
+vitro	O
+.	O
+	
+Cytogenetic	O
+markers	O
+for	O
+sister	O
+chromatid	O
+exchanges	O
+(	O
+SCEs	O
+)	O
+","	O
+proliferation	O
+rate	O
+index	O
+(	O
+PRI	O
+)	O
+and	O
+Mitotic	O
+Index	O
+were	O
+recorded	O
+.	O
+	
+Mesna	O
+'	O
+s	O
+action	O
+","	O
+in	O
+conjunction	O
+with	O
+IFO	O
+reduces	O
+the	O
+frequency	O
+of	O
+SCEs	O
+","	O
+in	O
+comparison	O
+with	O
+the	O
+SCEs	O
+recordings	O
+obtained	O
+when	O
+IFO	O
+is	O
+administered	O
+alone	O
+.	O
+	
+In	O
+addition	O
+to	O
+this	O
+","	O
+when	O
+high	O
+concentrations	O
+of	O
+Mesna	O
+were	O
+administered	O
+alone	O
+significant	O
+reductions	O
+of	O
+the	O
+PRI	O
+were	O
+noted	O
+","	O
+than	O
+with	O
+IFO	O
+acting	O
+at	O
+the	O
+same	O
+concentration	O
+on	O
+the	O
+lymphocytes	O
+.	O
+	
+Mesna	O
+significantly	O
+reduces	O
+IFO	O
+'	O
+s	O
+genotoxicity	B-NP
+","	O
+while	O
+when	O
+administered	O
+in	O
+high	O
+concentrations	O
+it	O
+acts	O
+in	O
+an	O
+inhibitory	O
+fashion	O
+on	O
+the	O
+cytostatic	O
+action	O
+of	O
+the	O
+drug	O
+.	O
+	
+Risk	O
+factors	O
+and	O
+predictors	O
+of	O
+levodopa	O
+-	O
+induced	O
+dyskinesia	B-NP
+among	O
+multiethnic	O
+Malaysians	O
+with	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+Chronic	O
+pulsatile	O
+levodopa	O
+therapy	O
+for	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+(	O
+PD	B-NP
+)	O
+leads	O
+to	O
+the	O
+development	O
+of	O
+motor	O
+fluctuations	O
+and	O
+dyskinesia	B-NP
+.	O
+	
+We	O
+studied	O
+the	O
+prevalence	O
+and	O
+predictors	O
+of	O
+levodopa	O
+-	O
+induced	O
+dyskinesia	B-NP
+among	O
+multiethnic	O
+Malaysian	O
+patients	O
+with	O
+PD	B-NP
+.	O
+	
+METHODS	O
+:	O
+This	O
+is	O
+a	O
+cross	O
+-	O
+sectional	O
+study	O
+involving	O
+95	O
+patients	O
+with	O
+PD	B-NP
+on	O
+uninterrupted	O
+levodopa	O
+therapy	O
+for	O
+at	O
+least	O
+6	O
+months	O
+.	O
+	
+The	O
+instrument	O
+used	O
+was	O
+the	O
+UPDRS	O
+questionnaires	O
+.	O
+	
+The	O
+predictors	O
+of	O
+dyskinesia	B-NP
+were	O
+determined	O
+using	O
+multivariate	O
+logistic	O
+regression	O
+analysis	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+mean	O
+age	O
+was	O
+65	O
+.	O
+6	O
++	O
+8	O
+.	O
+5	O
+years	O
+.	O
+	
+The	O
+mean	O
+onset	O
+age	O
+was	O
+58	O
+.	O
+5	O
++	O
+9	O
+.	O
+8	O
+years	O
+.	O
+	
+The	O
+median	O
+disease	O
+duration	O
+was	O
+6	O
+(	O
+7	O
+)	O
+years	O
+.	O
+	
+Dyskinesia	B-NP
+was	O
+present	O
+in	O
+44	O
+%	O
+(	O
+n	O
+=	O
+42	O
+)	O
+with	O
+median	O
+levodopa	O
+therapy	O
+of	O
+3	O
+years	O
+.	O
+	
+There	O
+were	O
+64	O
+.	O
+3	O
+%	O
+Chinese	O
+","	O
+31	O
+%	O
+Malays	O
+","	O
+and	O
+3	O
+.	O
+7	O
+%	O
+Indians	O
+and	O
+other	O
+ethnic	O
+groups	O
+.	O
+	
+Eighty	O
+-	O
+one	O
+percent	O
+of	O
+patients	O
+with	O
+dyskinesia	B-NP
+had	O
+clinical	O
+fluctuations	O
+.	O
+	
+Patients	O
+with	O
+dyskinesia	B-NP
+had	O
+lower	O
+onset	O
+age	O
+(	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+","	O
+longer	O
+duration	O
+of	O
+levodopa	O
+therapy	O
+(	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+","	O
+longer	O
+disease	O
+duration	O
+(	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+","	O
+higher	O
+total	O
+daily	O
+levodopa	O
+dose	O
+(	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+","	O
+and	O
+higher	O
+total	O
+UPDRS	O
+scores	O
+(	O
+p	O
+=	O
+0	O
+.	O
+5	O
+)	O
+than	O
+patients	O
+without	O
+dyskinesia	B-NP
+.	O
+	
+The	O
+three	O
+significant	O
+predictors	O
+of	O
+dyskinesia	B-NP
+were	O
+duration	O
+of	O
+levodopa	O
+therapy	O
+","	O
+onset	O
+age	O
+","	O
+and	O
+total	O
+daily	O
+levodopa	O
+dose	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+prevalence	O
+of	O
+levodopa	O
+-	O
+induced	O
+dyskinesia	B-NP
+in	O
+our	O
+patients	O
+was	O
+44	O
+%	O
+.	O
+	
+The	O
+most	O
+significant	O
+predictors	O
+were	O
+duration	O
+of	O
+levodopa	O
+therapy	O
+","	O
+total	O
+daily	O
+levodopa	O
+dose	O
+","	O
+and	O
+onset	O
+age	O
+.	O
+	
+Dose	O
+-	O
+dependent	O
+neurotoxicity	B-NP
+of	O
+high	O
+-	O
+dose	O
+busulfan	O
+in	O
+children	O
+:	O
+a	O
+clinical	O
+and	O
+pharmacological	O
+study	O
+.	O
+	
+Busulfan	O
+is	O
+known	O
+to	O
+be	O
+neurotoxic	B-NP
+in	O
+animals	O
+and	O
+humans	O
+","	O
+but	O
+its	O
+acute	O
+neurotoxicity	B-NP
+remains	O
+poorly	O
+characterized	O
+in	O
+children	O
+.	O
+	
+We	O
+report	O
+here	O
+a	O
+retrospective	O
+study	O
+of	O
+123	O
+children	O
+(	O
+median	O
+age	O
+","	O
+6	O
+.	O
+5	O
+years	O
+)	O
+receiving	O
+high	O
+-	O
+dose	O
+busulfan	O
+in	O
+combined	O
+chemotherapy	O
+before	O
+bone	O
+marrow	O
+transplantation	O
+for	O
+malignant	O
+solid	O
+tumors	B-NP
+","	O
+brain	B-NP
+tumors	I-NP
+excluded	O
+.	O
+	
+Busulfan	O
+was	O
+given	O
+p	O
+.	O
+o	O
+.	O
+","	O
+every	O
+6	O
+hours	O
+for	O
+16	O
+doses	O
+over	O
+4	O
+days	O
+.	O
+	
+Two	O
+total	O
+doses	O
+were	O
+consecutively	O
+used	O
+:	O
+16	O
+mg	O
+/	O
+kg	O
+","	O
+then	O
+600	O
+mg	O
+/	O
+m2	O
+.	O
+	
+The	O
+dose	O
+calculation	O
+on	O
+the	O
+basis	O
+of	O
+body	O
+surface	O
+area	O
+results	O
+in	O
+higher	O
+doses	O
+in	O
+young	O
+children	O
+than	O
+in	O
+older	O
+patients	O
+(	O
+16	O
+to	O
+28	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+	
+Ninety	O
+-	O
+six	O
+patients	O
+were	O
+not	O
+given	O
+anticonvulsive	O
+prophylaxis	O
+;	O
+7	O
+(	O
+7	O
+.	O
+5	O
+%	O
+)	O
+developed	O
+seizures	B-NP
+during	O
+the	O
+4	O
+days	O
+of	O
+the	O
+busulfan	O
+course	O
+or	O
+within	O
+24	O
+h	O
+after	O
+the	O
+last	O
+dosing	O
+.	O
+	
+When	O
+the	O
+total	O
+busulfan	O
+dose	O
+was	O
+taken	O
+into	O
+account	O
+","	O
+there	O
+was	O
+a	O
+significant	O
+difference	O
+in	O
+terms	O
+of	O
+neurotoxicity	B-NP
+incidence	O
+among	O
+patients	O
+under	O
+16	O
+mg	O
+/	O
+kg	O
+(	O
+1	O
+of	O
+57	O
+","	O
+1	O
+.	O
+7	O
+%	O
+)	O
+and	O
+patients	O
+under	O
+600	O
+mg	O
+/	O
+m2	O
+(	O
+6	O
+of	O
+39	O
+","	O
+15	O
+.	O
+4	O
+%	O
+)	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+2	O
+)	O
+.	O
+	
+Twenty	O
+-	O
+seven	O
+patients	O
+were	O
+given	O
+a	O
+600	O
+-	O
+mg	O
+/	O
+m2	O
+busulfan	O
+total	O
+dose	O
+with	O
+continuous	O
+i	O
+.	O
+v	O
+.	O
+infusion	O
+of	O
+clonazepam	O
+;	O
+none	O
+had	O
+any	O
+neurological	B-NP
+symptoms	I-NP
+.	O
+	
+Busulfan	O
+levels	O
+were	O
+measured	O
+by	O
+a	O
+gas	O
+chromatographic	O
+-	O
+mass	O
+spectrometry	O
+assay	O
+in	O
+the	O
+plasma	O
+and	O
+cerebrospinal	O
+fluid	O
+of	O
+9	O
+children	O
+without	O
+central	B-NP
+nervous	I-NP
+system	I-NP
+disease	I-NP
+under	O
+600	O
+mg	O
+/	O
+m2	O
+busulfan	O
+with	O
+clonazepam	O
+:	O
+busulfan	O
+cerebrospinal	O
+fluid	O
+:	O
+plasma	O
+ratio	O
+was	O
+1	O
+.	O
+39	O
+.	O
+	
+This	O
+was	O
+significantly	O
+different	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+2	O
+)	O
+from	O
+the	O
+cerebrospinal	O
+fluid	O
+:	O
+plasma	O
+ratio	O
+previously	O
+defined	O
+in	O
+children	O
+receiving	O
+a	O
+16	O
+-	O
+mg	O
+/	O
+kg	O
+total	O
+dose	O
+of	O
+busulfan	O
+.	O
+	
+This	O
+study	O
+shows	O
+that	O
+busulfan	O
+neurotoxicity	B-NP
+is	O
+dose	O
+-	O
+dependent	O
+in	O
+children	O
+and	O
+efficiently	O
+prevented	O
+by	O
+clonazepam	O
+.	O
+	
+A	O
+busulfan	O
+dose	O
+calculated	O
+on	O
+the	O
+basis	O
+of	O
+body	O
+surface	O
+area	O
+","	O
+resulting	O
+in	O
+higher	O
+doses	O
+in	O
+young	O
+children	O
+","	O
+was	O
+followed	O
+by	O
+increased	O
+neurotoxicity	B-NP
+","	O
+close	O
+to	O
+neurotoxicity	B-NP
+incidence	O
+observed	O
+in	O
+adults	O
+.	O
+	
+Since	O
+plasma	O
+pharmacokinetic	O
+studies	O
+showed	O
+a	O
+faster	O
+busulfan	O
+clearance	O
+in	O
+children	O
+than	O
+in	O
+adults	O
+","	O
+this	O
+new	O
+dose	O
+may	O
+approximate	O
+more	O
+closely	O
+the	O
+adult	O
+systemic	O
+exposure	O
+obtained	O
+after	O
+the	O
+usual	O
+16	O
+-	O
+mg	O
+/	O
+kg	O
+total	O
+dose	O
+","	O
+with	O
+potential	O
+inferences	O
+in	O
+terms	O
+of	O
+anticancer	O
+or	O
+myeloablative	O
+effects	O
+.	O
+	
+The	O
+busulfan	O
+dose	O
+in	O
+children	O
+and	O
+infants	O
+undergoing	O
+bone	O
+marrow	O
+transplantation	O
+should	O
+be	O
+reconsidered	O
+on	O
+the	O
+basis	O
+of	O
+pharmacokinetic	O
+studies	O
+.	O
+	
+An	O
+unexpected	O
+diagnosis	O
+in	O
+a	O
+renal	O
+-	O
+transplant	O
+patient	O
+with	O
+proteinuria	B-NP
+treated	O
+with	O
+everolimus	O
+:	O
+AL	B-NP
+amyloidosis	B-NP
+.	O
+	
+Proteinuria	B-NP
+is	O
+an	O
+expected	O
+complication	O
+in	O
+transplant	O
+patients	O
+treated	O
+with	O
+mammalian	O
+target	O
+of	O
+rapamycin	O
+inhibitors	O
+(	O
+mTOR	O
+-	O
+i	O
+)	O
+.	O
+	
+However	O
+","	O
+clinical	O
+suspicion	O
+should	O
+always	O
+be	O
+supported	O
+by	O
+histological	O
+evidence	O
+in	O
+order	O
+to	O
+investigate	O
+potential	O
+alternate	O
+diagnoses	O
+such	O
+as	O
+acute	O
+or	O
+chronic	O
+rejection	O
+","	O
+interstitial	O
+fibrosis	B-NP
+and	O
+tubular	O
+atrophy	B-NP
+","	O
+or	O
+recurrent	O
+or	O
+de	O
+novo	O
+glomerulopathy	B-NP
+.	O
+	
+In	O
+this	O
+case	O
+we	O
+report	O
+the	O
+unexpected	O
+diagnosis	O
+of	O
+amyloidosis	B-NP
+in	O
+a	O
+renal	O
+-	O
+transplant	O
+patient	O
+with	O
+pre	O
+-	O
+transplant	O
+monoclonal	O
+gammapathy	O
+of	O
+undetermined	O
+significance	O
+who	O
+developed	O
+proteinuria	B-NP
+after	O
+conversion	O
+from	O
+tacrolimus	O
+to	O
+everolimus	O
+.	O
+	
+Long	O
+-	O
+term	O
+oral	O
+galactose	O
+treatment	O
+prevents	O
+cognitive	B-NP
+deficits	I-NP
+in	O
+male	O
+Wistar	O
+rats	O
+treated	O
+intracerebroventricularly	O
+with	O
+streptozotocin	O
+.	O
+	
+Basic	O
+and	O
+clinical	O
+research	O
+has	O
+demonstrated	O
+that	O
+dementia	B-NP
+of	O
+sporadic	O
+Alzheimer	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+(	O
+sAD	O
+)	O
+type	O
+is	O
+associated	O
+with	O
+dysfunction	O
+of	O
+the	O
+insulin	O
+-	O
+receptor	O
+(	O
+IR	O
+)	O
+system	O
+followed	O
+by	O
+decreased	O
+glucose	O
+transport	O
+via	O
+glucose	O
+transporter	O
+GLUT4	O
+and	O
+decreased	O
+glucose	O
+metabolism	O
+in	O
+brain	O
+cells	O
+.	O
+	
+An	O
+alternative	O
+source	O
+of	O
+energy	O
+is	O
+d	O
+-	O
+galactose	O
+(	O
+the	O
+C	O
+-	O
+4	O
+-	O
+epimer	O
+of	O
+d	O
+-	O
+glucose	O
+)	O
+which	O
+is	O
+transported	O
+into	O
+the	O
+brain	O
+by	O
+insulin	O
+-	O
+independent	O
+GLUT3	O
+transporter	O
+where	O
+it	O
+might	O
+be	O
+metabolized	O
+to	O
+glucose	O
+via	O
+the	O
+Leloir	O
+pathway	O
+.	O
+	
+Exclusively	O
+parenteral	O
+daily	O
+injections	O
+of	O
+galactose	O
+induce	O
+memory	B-NP
+deterioration	I-NP
+in	O
+rodents	O
+and	O
+are	O
+used	O
+to	O
+generate	O
+animal	O
+aging	O
+model	O
+","	O
+but	O
+the	O
+effects	O
+of	O
+oral	O
+galactose	O
+treatment	O
+on	O
+cognitive	O
+functions	O
+have	O
+never	O
+been	O
+tested	O
+.	O
+	
+We	O
+have	O
+investigated	O
+the	O
+effects	O
+of	O
+continuous	O
+daily	O
+oral	O
+galactose	O
+(	O
+200	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+)	O
+treatment	O
+on	O
+cognitive	B-NP
+deficits	I-NP
+in	O
+streptozotocin	O
+-	O
+induced	O
+(	O
+STZ	O
+-	O
+icv	O
+)	O
+rat	O
+model	O
+of	O
+sAD	O
+","	O
+tested	O
+by	O
+Morris	O
+Water	O
+Maze	O
+and	O
+Passive	O
+Avoidance	O
+test	O
+","	O
+respectively	O
+.	O
+	
+One	O
+month	O
+of	O
+oral	O
+galactose	O
+treatment	O
+initiated	O
+immediately	O
+after	O
+the	O
+STZ	O
+-	O
+icv	O
+administration	O
+","	O
+successfully	O
+prevented	O
+development	O
+of	O
+the	O
+STZ	O
+-	O
+icv	O
+-	O
+induced	O
+cognitive	B-NP
+deficits	I-NP
+.	O
+	
+Beneficial	O
+effect	O
+of	O
+oral	O
+galactose	O
+was	O
+independent	O
+of	O
+the	O
+rat	O
+age	O
+and	O
+of	O
+the	O
+galactose	O
+dose	O
+ranging	O
+from	O
+100	O
+to	O
+300	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+.	O
+	
+Additionally	O
+","	O
+oral	O
+galactose	O
+administration	O
+led	O
+to	O
+the	O
+appearance	O
+of	O
+galactose	O
+in	O
+the	O
+blood	O
+.	O
+	
+The	O
+increase	O
+of	O
+galactose	O
+concentration	O
+in	O
+the	O
+cerebrospinal	O
+fluid	O
+was	O
+several	O
+times	O
+lower	O
+after	O
+oral	O
+than	O
+after	O
+parenteral	O
+administration	O
+of	O
+the	O
+same	O
+galactose	O
+dose	O
+.	O
+	
+Oral	O
+galactose	O
+exposure	O
+might	O
+have	O
+beneficial	O
+effects	O
+on	O
+learning	O
+and	O
+memory	O
+ability	O
+and	O
+could	O
+be	O
+worth	O
+investigating	O
+for	O
+improvement	O
+of	O
+cognitive	B-NP
+deficits	I-NP
+associated	O
+with	O
+glucose	B-NP
+hypometabolism	I-NP
+in	O
+AD	B-NP
+.	O
+	
+An	O
+investigation	O
+of	O
+the	O
+pattern	O
+of	O
+kidney	B-NP
+injury	I-NP
+in	O
+HIV	O
+-	O
+positive	O
+persons	O
+exposed	O
+to	O
+tenofovir	O
+disoproxil	O
+fumarate	O
+:	O
+an	O
+examination	O
+of	O
+a	O
+large	O
+population	O
+database	O
+(	O
+MHRA	O
+database	O
+)	O
+.	O
+	
+The	O
+potential	O
+for	O
+tenofovir	O
+to	O
+cause	O
+a	O
+range	O
+of	O
+kidney	O
+syndromes	O
+has	O
+been	O
+established	O
+from	O
+mechanistic	O
+and	O
+randomised	O
+clinical	O
+trials	O
+.	O
+	
+However	O
+","	O
+the	O
+exact	O
+pattern	O
+of	O
+kidney	O
+involvement	O
+is	O
+still	O
+uncertain	O
+.	O
+	
+We	O
+undertook	O
+a	O
+descriptive	O
+analysis	O
+of	O
+Yellow	O
+Card	O
+records	O
+of	O
+407	O
+HIV	O
+-	O
+positive	O
+persons	O
+taking	O
+tenofovir	O
+disoproxil	O
+fumarate	O
+(	O
+TDF	O
+)	O
+as	O
+part	O
+of	O
+their	O
+antiretroviral	O
+therapy	O
+regimen	O
+and	O
+submitted	O
+to	O
+the	O
+Medicines	O
+and	O
+Healthcare	O
+Products	O
+Regulatory	O
+Agency	O
+(	O
+MHRA	O
+)	O
+with	O
+suspected	O
+kidney	O
+adverse	O
+effects	O
+.	O
+	
+Reports	O
+that	O
+satisfy	O
+defined	O
+criteria	O
+were	O
+classified	O
+as	O
+acute	B-NP
+kidney	I-NP
+injury	I-NP
+","	O
+kidney	B-NP
+tubular	I-NP
+dysfunction	I-NP
+and	O
+Fanconi	B-NP
+syndrome	I-NP
+.	O
+	
+Of	O
+the	O
+407	O
+Yellow	O
+Card	O
+records	O
+analysed	O
+","	O
+106	O
+satisfied	O
+criteria	O
+for	O
+TDF	O
+-	O
+related	O
+kidney	B-NP
+disease	I-NP
+","	O
+of	O
+which	O
+53	O
+(	O
+50	O
+%	O
+)	O
+had	O
+features	O
+of	O
+kidney	B-NP
+tubular	I-NP
+dysfunction	I-NP
+","	O
+35	O
+(	O
+33	O
+%	O
+)	O
+were	O
+found	O
+to	O
+have	O
+features	O
+of	O
+glomerular	B-NP
+dysfunction	I-NP
+and	O
+18	O
+(	O
+17	O
+%	O
+)	O
+had	O
+Fanconi	B-NP
+syndrome	I-NP
+.	O
+	
+The	O
+median	O
+TDF	O
+exposure	O
+was	O
+316	O
+days	O
+(	O
+interquartile	O
+range	O
+120	O
+-	O
+740	O
+)	O
+.	O
+	
+The	O
+incidence	O
+of	O
+hospitalisation	O
+for	O
+TDF	O
+kidney	O
+adverse	O
+effects	O
+was	O
+high	O
+","	O
+particularly	O
+amongst	O
+patients	O
+with	O
+features	O
+of	O
+Fanconi	B-NP
+syndrome	I-NP
+.	O
+	
+The	O
+pattern	O
+of	O
+kidney	O
+syndromes	O
+in	O
+this	O
+population	O
+series	O
+mirrors	O
+that	O
+reported	O
+in	O
+randomised	O
+clinical	O
+trials	O
+.	O
+	
+Cessation	O
+of	O
+TDF	O
+was	O
+associated	O
+with	O
+complete	O
+restoration	O
+of	O
+kidney	O
+function	O
+in	O
+up	O
+half	O
+of	O
+the	O
+patients	O
+in	O
+this	O
+report	O
+.	O
+	
+Incidence	O
+of	O
+postoperative	B-NP
+delirium	I-NP
+is	O
+high	O
+even	O
+in	O
+a	O
+population	O
+without	O
+known	O
+risk	O
+factors	O
+.	O
+	
+PURPOSE	O
+:	O
+Postoperative	B-NP
+delirium	I-NP
+is	O
+a	O
+recognized	O
+complication	O
+in	O
+populations	O
+at	O
+risk	O
+.	O
+	
+The	O
+aim	O
+of	O
+this	O
+study	O
+is	O
+to	O
+assess	O
+the	O
+prevalence	O
+of	O
+early	O
+postoperative	B-NP
+delirium	I-NP
+in	O
+a	O
+population	O
+without	O
+known	O
+risk	O
+factors	O
+admitted	O
+to	O
+the	O
+ICU	O
+for	O
+postoperative	O
+monitoring	O
+after	O
+elective	O
+major	O
+surgery	O
+.	O
+	
+The	O
+secondary	O
+outcome	O
+investigated	O
+is	O
+to	O
+identify	O
+eventual	O
+independent	O
+risk	O
+factors	O
+among	O
+demographic	O
+data	O
+and	O
+anesthetic	O
+drugs	O
+used	O
+.	O
+	
+METHODS	O
+:	O
+An	O
+observational	O
+","	O
+prospective	O
+study	O
+was	O
+conducted	O
+on	O
+a	O
+consecutive	O
+cohort	O
+of	O
+patients	O
+admitted	O
+to	O
+our	O
+ICU	O
+within	O
+and	O
+for	O
+at	O
+least	O
+24	O
+h	O
+after	O
+major	O
+surgical	O
+procedures	O
+.	O
+	
+Exclusion	O
+criteria	O
+were	O
+any	O
+preexisting	O
+predisposing	O
+factor	O
+for	O
+delirium	B-NP
+or	O
+other	O
+potentially	O
+confounding	O
+neurological	B-NP
+dysfunctions	I-NP
+.	O
+	
+Patients	O
+were	O
+assessed	O
+daily	O
+using	O
+the	O
+confusion	B-NP
+assessment	O
+method	O
+for	O
+the	O
+ICU	O
+scale	O
+for	O
+3	O
+days	O
+after	O
+the	O
+surgical	O
+procedure	O
+.	O
+	
+Early	O
+postoperative	B-NP
+delirium	I-NP
+incidence	O
+risk	O
+factors	O
+were	O
+then	O
+assessed	O
+through	O
+three	O
+different	O
+multiple	O
+regression	O
+models	O
+.	O
+	
+RESULTS	O
+:	O
+According	O
+to	O
+the	O
+confusion	O
+assessment	O
+method	O
+for	O
+the	O
+ICU	O
+scale	O
+","	O
+28	O
+%	O
+of	O
+patients	O
+were	O
+diagnosed	O
+with	O
+early	O
+postoperative	B-NP
+delirium	I-NP
+.	O
+	
+The	O
+use	O
+of	O
+thiopentone	O
+was	O
+significantly	O
+associated	O
+with	O
+an	O
+eight	O
+-	O
+fold	O
+-	O
+higher	O
+risk	O
+for	O
+delirium	B-NP
+compared	O
+to	O
+propofol	O
+(	O
+57	O
+.	O
+1	O
+%	O
+vs	O
+.	O
+7	O
+.	O
+1	O
+%	O
+","	O
+RR	O
+=	O
+8	O
+.	O
+0	O
+","	O
+X2	O
+=	O
+4	O
+.	O
+256	O
+;	O
+df	O
+=	O
+1	O
+;	O
+0	O
+.	O
+5	O
+<	O
+p	O
+<	O
+0	O
+.	O
+2	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+In	O
+this	O
+study	O
+early	O
+postoperative	B-NP
+delirium	I-NP
+was	O
+found	O
+to	O
+be	O
+a	O
+very	O
+common	O
+complication	O
+after	O
+major	O
+surgery	O
+","	O
+even	O
+in	O
+a	O
+population	O
+without	O
+known	O
+risk	O
+factors	O
+.	O
+	
+Thiopentone	O
+was	O
+independently	O
+associated	O
+with	O
+an	O
+increase	O
+in	O
+its	O
+relative	O
+risk	O
+.	O
+	
+A	O
+single	O
+neurotoxic	B-NP
+dose	O
+of	O
+methamphetamine	O
+induces	O
+a	O
+long	O
+-	O
+lasting	O
+depressive	B-NP
+-	O
+like	O
+behaviour	O
+in	O
+mice	O
+.	O
+	
+Methamphetamine	O
+(	O
+METH	O
+)	O
+triggers	O
+a	O
+disruption	O
+of	O
+the	O
+monoaminergic	O
+system	O
+and	O
+METH	O
+abuse	O
+leads	O
+to	O
+negative	O
+emotional	O
+states	O
+including	O
+depressive	B-NP
+symptoms	I-NP
+during	O
+drug	O
+withdrawal	O
+.	O
+	
+However	O
+","	O
+it	O
+is	O
+currently	O
+unknown	O
+if	O
+the	O
+acute	O
+toxic	O
+dosage	O
+of	O
+METH	O
+also	O
+causes	O
+a	O
+long	O
+-	O
+lasting	O
+depressive	B-NP
+phenotype	O
+and	O
+persistent	O
+monoaminergic	O
+deficits	O
+.	O
+	
+Thus	O
+","	O
+we	O
+now	O
+assessed	O
+the	O
+depressive	B-NP
+-	O
+like	O
+behaviour	O
+in	O
+mice	O
+at	O
+early	O
+and	O
+long	O
+-	O
+term	O
+periods	O
+following	O
+a	O
+single	O
+high	O
+METH	O
+dose	O
+(	O
+30	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+	
+METH	O
+did	O
+not	O
+alter	O
+the	O
+motor	O
+function	O
+and	O
+procedural	O
+memory	O
+of	O
+mice	O
+as	O
+assessed	O
+by	O
+swimming	O
+speed	O
+and	O
+escape	O
+latency	O
+to	O
+find	O
+the	O
+platform	O
+in	O
+a	O
+cued	O
+version	O
+of	O
+the	O
+water	O
+maze	O
+task	O
+.	O
+	
+However	O
+","	O
+METH	O
+significantly	O
+increased	O
+the	O
+immobility	O
+time	O
+in	O
+the	O
+tail	O
+suspension	O
+test	O
+at	O
+3	O
+and	O
+49	O
+days	O
+post	O
+-	O
+administration	O
+.	O
+	
+This	O
+depressive	B-NP
+-	O
+like	O
+profile	O
+induced	O
+by	O
+METH	O
+was	O
+accompanied	O
+by	O
+a	O
+marked	O
+depletion	O
+of	O
+frontostriatal	O
+dopaminergic	O
+and	O
+serotonergic	O
+neurotransmission	O
+","	O
+indicated	O
+by	O
+a	O
+reduction	O
+in	O
+the	O
+levels	O
+of	O
+dopamine	O
+","	O
+DOPAC	O
+and	O
+HVA	O
+","	O
+tyrosine	O
+hydroxylase	O
+and	O
+serotonin	O
+","	O
+observed	O
+at	O
+both	O
+3	O
+and	O
+49	O
+days	O
+post	O
+-	O
+administration	O
+.	O
+	
+In	O
+parallel	O
+","	O
+another	O
+neurochemical	O
+feature	O
+of	O
+depression	B-NP
+-	O
+-	O
+astroglial	O
+dysfunction	O
+-	O
+-	O
+was	O
+unaffected	O
+in	O
+the	O
+cortex	O
+and	O
+the	O
+striatal	O
+levels	O
+of	O
+the	O
+astrocytic	O
+protein	O
+marker	O
+","	O
+glial	O
+fibrillary	O
+acidic	O
+protein	O
+","	O
+were	O
+only	O
+transiently	O
+increased	O
+at	O
+3	O
+days	O
+.	O
+	
+These	O
+findings	O
+demonstrate	O
+for	O
+the	O
+first	O
+time	O
+that	O
+a	O
+single	O
+high	O
+dose	O
+of	O
+METH	O
+induces	O
+long	O
+-	O
+lasting	O
+depressive	B-NP
+-	O
+like	O
+behaviour	O
+in	O
+mice	O
+associated	O
+with	O
+a	O
+persistent	O
+disruption	O
+of	O
+frontostriatal	O
+dopaminergic	O
+and	O
+serotonergic	O
+homoeostasis	O
+.	O
+	
+Linezolid	O
+-	O
+induced	O
+optic	B-NP
+neuropathy	I-NP
+.	O
+	
+Many	O
+systemic	O
+antimicrobials	O
+have	O
+been	O
+implicated	O
+to	O
+cause	O
+ocular	O
+adverse	O
+effects	O
+.	O
+	
+This	O
+is	O
+especially	O
+relevant	O
+in	O
+multidrug	O
+therapy	O
+where	O
+more	O
+than	O
+one	O
+drug	O
+can	O
+cause	O
+a	O
+similar	O
+ocular	O
+adverse	O
+effect	O
+.	O
+	
+We	O
+describe	O
+a	O
+case	O
+of	O
+progressive	O
+loss	B-NP
+of	I-NP
+vision	I-NP
+associated	O
+with	O
+linezolid	O
+therapy	O
+.	O
+	
+A	O
+45	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+who	O
+was	O
+on	O
+treatment	O
+with	O
+multiple	O
+second	O
+-	O
+line	O
+anti	O
+-	O
+tuberculous	O
+drugs	O
+including	O
+linezolid	O
+and	O
+ethambutol	O
+for	O
+extensively	B-NP
+drug	I-NP
+-	I-NP
+resistant	I-NP
+tuberculosis	I-NP
+(	O
+XDR	B-NP
+-	I-NP
+TB	I-NP
+)	O
+presented	O
+to	O
+us	O
+with	O
+painless	O
+progressive	O
+loss	B-NP
+of	I-NP
+vision	I-NP
+in	O
+both	O
+eyes	O
+.	O
+	
+Color	O
+vision	O
+was	O
+defective	O
+and	O
+fundus	O
+examination	O
+revealed	O
+optic	B-NP
+disc	I-NP
+edema	I-NP
+in	O
+both	O
+eyes	O
+.	O
+	
+Ethambutol	O
+-	O
+induced	O
+toxic	B-NP
+optic	I-NP
+neuropathy	I-NP
+was	O
+suspected	O
+and	O
+tablet	O
+ethambutol	O
+was	O
+withdrawn	O
+.	O
+	
+Deterioration	B-NP
+of	I-NP
+vision	I-NP
+occurred	O
+despite	O
+withdrawal	O
+of	O
+ethambutol	O
+.	O
+	
+Discontinuation	O
+of	O
+linezolid	O
+resulted	O
+in	O
+marked	O
+improvement	O
+of	O
+vision	O
+.	O
+	
+Our	O
+report	O
+emphasizes	O
+the	O
+need	O
+for	O
+monitoring	O
+of	O
+visual	O
+function	O
+in	O
+patients	O
+on	O
+long	O
+-	O
+term	O
+linezolid	O
+treatment	O
+.	O
+	
+Resuscitation	O
+with	O
+lipid	O
+","	O
+epinephrine	O
+","	O
+or	O
+both	O
+in	O
+levobupivacaine	O
+-	O
+induced	O
+cardiac	B-NP
+toxicity	I-NP
+in	O
+newborn	O
+piglets	O
+.	O
+	
+BACKGROUND	O
+:	O
+The	O
+optimal	O
+dosing	O
+regimens	O
+of	O
+lipid	O
+emulsion	O
+","	O
+epinephrine	O
+","	O
+or	O
+both	O
+are	O
+not	O
+yet	O
+determined	O
+in	O
+neonates	O
+in	O
+cases	O
+of	O
+local	O
+anaesthetic	O
+systemic	O
+toxicity	B-NP
+(	O
+LAST	O
+)	O
+.	O
+	
+METHODS	O
+:	O
+Newborn	O
+piglets	O
+received	O
+levobupivacaine	O
+until	O
+cardiovascular	B-NP
+collapse	I-NP
+occurred	O
+.	O
+	
+Standard	O
+cardiopulmonary	O
+resuscitation	O
+was	O
+started	O
+and	O
+electrocardiogram	O
+(	O
+ECG	O
+)	O
+was	O
+monitored	O
+for	O
+ventricular	B-NP
+tachycardia	I-NP
+","	O
+fibrillation	B-NP
+","	O
+or	O
+QRS	O
+prolongation	O
+.	O
+	
+Piglets	O
+were	O
+then	O
+randomly	O
+allocated	O
+to	O
+four	O
+groups	O
+:	O
+control	O
+(	O
+saline	O
+)	O
+","	O
+Intralipid	O
+(	O
+)	O
+alone	O
+","	O
+epinephrine	O
+alone	O
+","	O
+or	O
+a	O
+combination	O
+of	O
+Intralipd	O
+plus	O
+epinephrine	O
+.	O
+	
+Resuscitation	O
+continued	O
+for	O
+30	O
+min	O
+or	O
+until	O
+there	O
+was	O
+a	O
+return	O
+of	O
+spontaneous	O
+circulation	O
+(	O
+ROSC	O
+)	O
+accompanied	O
+by	O
+a	O
+mean	O
+arterial	O
+pressure	O
+at	O
+or	O
+superior	O
+to	O
+the	O
+baseline	O
+pressure	O
+and	O
+normal	O
+sinus	O
+rhythm	O
+for	O
+a	O
+period	O
+of	O
+30	O
+min	O
+.	O
+	
+RESULTS	O
+:	O
+ROSC	O
+was	O
+achieved	O
+in	O
+only	O
+one	O
+of	O
+the	O
+control	O
+piglets	O
+compared	O
+with	O
+most	O
+of	O
+the	O
+treated	O
+piglets	O
+.	O
+	
+Mortality	O
+was	O
+not	O
+significantly	O
+different	O
+between	O
+the	O
+three	O
+treatment	O
+groups	O
+","	O
+but	O
+was	O
+significantly	O
+lower	O
+in	O
+all	O
+the	O
+treatment	O
+groups	O
+compared	O
+with	O
+control	O
+.	O
+	
+The	O
+number	O
+of	O
+ECG	O
+abnormalities	O
+was	O
+zero	O
+in	O
+the	O
+Intralipid	O
+only	O
+group	O
+","	O
+but	O
+14	O
+and	O
+17	O
+","	O
+respectively	O
+","	O
+in	O
+the	O
+epinephrine	O
+and	O
+epinephrine	O
+plus	O
+lipid	O
+groups	O
+(	O
+P	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Lipid	O
+emulsion	O
+with	O
+or	O
+without	O
+epinephrine	O
+","	O
+or	O
+epinephrine	O
+alone	O
+were	O
+equally	O
+effective	O
+in	O
+achieving	O
+a	O
+return	O
+to	O
+spontaneous	O
+circulation	O
+in	O
+this	O
+model	O
+of	O
+LAST	O
+.	O
+	
+Epinephrine	O
+alone	O
+or	O
+in	O
+combination	O
+with	O
+lipid	O
+was	O
+associated	O
+with	O
+an	O
+increased	O
+number	O
+of	O
+ECG	O
+abnormalities	O
+compared	O
+with	O
+lipid	O
+emulsion	O
+alone	O
+.	O
+	
+Incidence	O
+of	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+type	I-NP
+II	I-NP
+and	O
+postoperative	O
+recovery	O
+of	O
+platelet	O
+count	O
+in	O
+liver	O
+graft	O
+recipients	O
+:	O
+a	O
+retrospective	O
+cohort	O
+analysis	O
+.	O
+	
+BACKGROUND	O
+:	O
+Thrombocytopenia	B-NP
+in	O
+patients	O
+with	O
+end	B-NP
+-	I-NP
+stage	I-NP
+liver	I-NP
+disease	I-NP
+is	O
+a	O
+common	O
+disorder	O
+caused	O
+mainly	O
+by	O
+portal	B-NP
+hypertension	I-NP
+","	O
+low	O
+levels	O
+of	O
+thrombopoetin	O
+","	O
+and	O
+endotoxemia	B-NP
+.	O
+	
+The	O
+impact	O
+of	O
+immune	O
+-	O
+mediated	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+type	I-NP
+II	I-NP
+(	O
+HIT	B-NP
+type	I-NP
+II	I-NP
+)	O
+as	O
+a	O
+cause	O
+of	O
+thrombocytopenia	B-NP
+after	O
+liver	O
+transplantation	O
+is	O
+not	O
+yet	O
+understood	O
+","	O
+with	O
+few	O
+literature	O
+citations	O
+reporting	O
+contradictory	O
+results	O
+.	O
+	
+The	O
+aim	O
+of	O
+our	O
+study	O
+was	O
+to	O
+demonstrate	O
+the	O
+perioperative	O
+course	O
+of	O
+thrombocytopenia	B-NP
+after	O
+liver	O
+transplantation	O
+and	O
+determine	O
+the	O
+occurrence	O
+of	O
+clinical	O
+HIT	B-NP
+type	I-NP
+II	I-NP
+.	O
+	
+METHOD	O
+:	O
+We	O
+retrospectively	O
+evaluated	O
+the	O
+medical	O
+records	O
+of	O
+205	O
+consecutive	O
+adult	O
+patients	O
+who	O
+underwent	O
+full	O
+-	O
+size	O
+liver	O
+transplantation	O
+between	O
+January	O
+2006	O
+and	O
+December	O
+2010	O
+due	O
+to	O
+end	B-NP
+-	I-NP
+stage	I-NP
+or	I-NP
+malignant	I-NP
+liver	I-NP
+disease	I-NP
+.	O
+	
+Preoperative	O
+platelet	O
+count	O
+","	O
+postoperative	O
+course	O
+of	O
+platelets	O
+","	O
+and	O
+clinical	O
+signs	O
+of	O
+HIT	B-NP
+type	I-NP
+II	I-NP
+were	O
+analyzed	O
+.	O
+	
+RESULTS	O
+:	O
+A	O
+total	O
+of	O
+155	O
+(	O
+75	O
+.	O
+6	O
+%	O
+)	O
+of	O
+205	O
+patients	O
+had	O
+thrombocytopenia	B-NP
+before	O
+transplantation	O
+","	O
+significantly	O
+influenced	O
+by	O
+Model	O
+of	O
+End	B-NP
+-	I-NP
+Stage	I-NP
+Liver	I-NP
+Disease	I-NP
+score	O
+and	O
+liver	B-NP
+cirrhosis	I-NP
+.	O
+	
+The	O
+platelet	O
+count	O
+exceeded	O
+100	O
+","	O
+0	O
+/	O
+uL	O
+in	O
+most	O
+of	O
+the	O
+patients	O
+(	O
+n	O
+=	O
+193	O
+)	O
+at	O
+a	O
+medium	O
+of	O
+7	O
+d	O
+.	O
+	
+Regarding	O
+HIT	B-NP
+II	I-NP
+","	O
+there	O
+were	O
+four	O
+(	O
+1	O
+.	O
+95	O
+%	O
+)	O
+patients	O
+with	O
+a	O
+background	O
+of	O
+HIT	B-NP
+type	I-NP
+II	I-NP
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+incidence	O
+of	O
+HIT	B-NP
+in	O
+patients	O
+with	O
+end	B-NP
+-	I-NP
+stage	I-NP
+hepatic	I-NP
+failure	I-NP
+is	O
+","	O
+with	O
+about	O
+1	O
+.	O
+95	O
+%	O
+","	O
+rare	O
+.	O
+	
+For	O
+further	O
+reduction	O
+of	O
+HIT	B-NP
+type	I-NP
+II	I-NP
+","	O
+the	O
+use	O
+of	O
+intravenous	O
+heparin	O
+should	O
+be	O
+avoided	O
+and	O
+the	O
+prophylactic	O
+anticoagulation	O
+should	O
+be	O
+performed	O
+with	O
+low	O
+-	O
+molecular	O
+-	O
+weight	O
+heparin	O
+after	O
+normalization	O
+of	O
+platelet	O
+count	O
+.	O
+	
+Takotsubo	B-NP
+syndrome	I-NP
+(	O
+or	O
+apical	B-NP
+ballooning	I-NP
+syndrome	I-NP
+)	O
+secondary	O
+to	O
+Zolmitriptan	O
+.	O
+	
+Takotsubo	B-NP
+syndrome	I-NP
+(	O
+TS	B-NP
+)	O
+","	O
+also	O
+known	O
+as	O
+broken	B-NP
+heart	I-NP
+syndrome	I-NP
+","	O
+is	O
+characterized	O
+by	O
+left	O
+ventricle	O
+apical	O
+ballooning	O
+with	O
+elevated	O
+cardiac	O
+biomarkers	O
+and	O
+electrocardiographic	O
+changes	O
+suggestive	O
+of	O
+an	O
+acute	B-NP
+coronary	I-NP
+syndrome	I-NP
+(	O
+ie	O
+","	O
+ST	O
+-	O
+segment	O
+elevation	O
+","	O
+T	O
+wave	O
+inversions	O
+","	O
+and	O
+pathologic	O
+Q	O
+waves	O
+)	O
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+54	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+medical	O
+history	O
+of	O
+mitral	B-NP
+valve	I-NP
+prolapse	I-NP
+and	O
+migraines	B-NP
+","	O
+who	O
+was	O
+admitted	O
+to	O
+the	O
+hospital	O
+for	O
+substernal	O
+chest	B-NP
+pain	I-NP
+and	O
+electrocardiogram	O
+demonstrated	O
+1	O
+/	O
+2	O
+mm	O
+ST	O
+-	O
+segment	O
+elevation	O
+in	O
+leads	O
+II	O
+","	O
+III	O
+","	O
+aVF	O
+","	O
+V5	O
+","	O
+and	O
+V6	O
+and	O
+positive	O
+troponin	O
+I	O
+.	O
+	
+Emergent	O
+coronary	O
+angiogram	O
+revealed	O
+normal	O
+coronary	O
+arteries	O
+with	O
+moderately	O
+reduced	O
+left	O
+ventricular	O
+ejection	O
+fraction	O
+with	O
+wall	O
+motion	O
+abnormalities	O
+consistent	O
+with	O
+TS	B-NP
+.	O
+	
+Detailed	O
+history	O
+obtained	O
+retrospectively	O
+revealed	O
+that	O
+the	O
+patient	O
+took	O
+zolmitriptan	O
+sparingly	O
+only	O
+when	O
+she	O
+had	O
+migraines	B-NP
+.	O
+	
+But	O
+before	O
+this	O
+event	O
+","	O
+she	O
+was	O
+taking	O
+zolmitriptan	O
+2	O
+-	O
+3	O
+times	O
+daily	O
+for	O
+several	O
+days	O
+because	O
+of	O
+a	O
+persistent	O
+migraine	B-NP
+headache	I-NP
+.	O
+	
+She	O
+otherwise	O
+reported	O
+that	O
+she	O
+is	O
+quite	O
+active	O
+","	O
+rides	O
+horses	O
+","	O
+and	O
+does	O
+show	O
+jumping	O
+without	O
+any	O
+limitations	O
+in	O
+her	O
+physical	O
+activity	O
+.	O
+	
+There	O
+was	O
+no	O
+evidence	O
+of	O
+any	O
+recent	O
+stress	O
+or	O
+status	B-NP
+migrainosus	I-NP
+.	O
+	
+Extensive	O
+literature	O
+search	O
+revealed	O
+multiple	O
+cases	O
+of	O
+coronary	B-NP
+artery	I-NP
+vasospasm	I-NP
+secondary	O
+to	O
+zolmitriptan	O
+","	O
+but	O
+none	O
+of	O
+the	O
+cases	O
+were	O
+associated	O
+with	O
+TS	B-NP
+.	O
+	
+Depression	B-NP
+","	O
+impulsiveness	B-NP
+","	O
+sleep	O
+","	O
+and	O
+memory	O
+in	O
+past	O
+and	O
+present	O
+polydrug	O
+users	O
+of	O
+3	O
+","	O
+4	O
+-	O
+methylenedioxymethamphetamine	O
+(	O
+MDMA	O
+","	O
+ecstasy	O
+)	O
+.	O
+	
+RATIONALE	O
+:	O
+Ecstasy	O
+(	O
+3	O
+","	O
+4	O
+-	O
+methylenedioxymethamphetamine	O
+","	O
+MDMA	O
+)	O
+is	O
+a	O
+worldwide	O
+recreational	O
+drug	O
+of	O
+abuse	O
+.	O
+	
+Unfortunately	O
+","	O
+the	O
+results	O
+from	O
+human	O
+research	O
+investigating	O
+its	O
+psychological	O
+effects	O
+have	O
+been	O
+inconsistent	O
+.	O
+	
+OBJECTIVES	O
+:	O
+The	O
+present	O
+study	O
+aimed	O
+to	O
+be	O
+the	O
+largest	O
+to	O
+date	O
+in	O
+sample	O
+size	O
+and	O
+5HT	O
+-	O
+related	O
+behaviors	O
+;	O
+the	O
+first	O
+to	O
+compare	O
+present	O
+ecstasy	O
+users	O
+with	O
+past	O
+users	O
+after	O
+an	O
+abstinence	O
+of	O
+4	O
+or	O
+more	O
+years	O
+","	O
+and	O
+the	O
+first	O
+to	O
+include	O
+robust	O
+controls	O
+for	O
+other	O
+recreational	O
+substances	O
+.	O
+	
+METHODS	O
+:	O
+A	O
+sample	O
+of	O
+997	O
+participants	O
+(	O
+52	O
+%	O
+male	O
+)	O
+was	O
+recruited	O
+to	O
+four	O
+control	O
+groups	O
+(	O
+non	O
+-	O
+drug	O
+(	O
+ND	O
+)	O
+","	O
+alcohol	O
+/	O
+nicotine	O
+(	O
+AN	O
+)	O
+","	O
+cannabis	O
+/	O
+alcohol	O
+/	O
+nicotine	O
+(	O
+CAN	O
+)	O
+","	O
+non	O
+-	O
+ecstasy	O
+polydrug	O
+(	O
+PD	O
+)	O
+)	O
+","	O
+and	O
+two	O
+ecstasy	O
+polydrug	O
+groups	O
+(	O
+present	O
+(	O
+MDMA	O
+)	O
+and	O
+past	O
+users	O
+(	O
+EX	O
+-	O
+MDMA	O
+)	O
+.	O
+	
+Participants	O
+completed	O
+a	O
+drug	O
+history	O
+questionnaire	O
+","	O
+Beck	O
+Depression	B-NP
+Inventory	O
+","	O
+Barratt	O
+Impulsiveness	B-NP
+Scale	O
+","	O
+Pittsburgh	O
+Sleep	O
+Quality	O
+Index	O
+","	O
+and	O
+Wechsler	O
+Memory	O
+Scale	O
+-	O
+Revised	O
+which	O
+","	O
+in	O
+total	O
+","	O
+provided	O
+13	O
+psychometric	O
+measures	O
+.	O
+	
+RESULTS	O
+:	O
+While	O
+the	O
+CAN	O
+and	O
+PD	O
+groups	O
+tended	O
+to	O
+record	O
+greater	O
+deficits	O
+than	O
+the	O
+non	O
+-	O
+drug	O
+controls	O
+","	O
+the	O
+MDMA	O
+and	O
+EX	O
+-	O
+MDMA	O
+groups	O
+recorded	O
+greater	O
+deficits	O
+than	O
+all	O
+the	O
+control	O
+groups	O
+on	O
+ten	O
+of	O
+the	O
+13	O
+psychometric	O
+measures	O
+.	O
+	
+Strikingly	O
+","	O
+despite	O
+prolonged	O
+abstinence	O
+(	O
+mean	O
+","	O
+4	O
+.	O
+98	O
+;	O
+range	O
+","	O
+4	O
+-	O
+9	O
+years	O
+)	O
+","	O
+past	O
+ecstasy	O
+users	O
+showed	O
+few	O
+signs	O
+of	O
+recovery	O
+.	O
+	
+Compared	O
+with	O
+present	O
+ecstasy	O
+users	O
+","	O
+the	O
+past	O
+users	O
+showed	O
+no	O
+change	O
+for	O
+ten	O
+measures	O
+","	O
+increased	O
+impairment	O
+for	O
+two	O
+measures	O
+","	O
+and	O
+improvement	O
+on	O
+just	O
+one	O
+measure	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Given	O
+this	O
+record	O
+of	O
+impaired	B-NP
+memory	I-NP
+and	O
+clinically	O
+significant	O
+levels	O
+of	O
+depression	B-NP
+","	O
+impulsiveness	B-NP
+","	O
+and	O
+sleep	B-NP
+disturbance	I-NP
+","	O
+the	O
+prognosis	O
+for	O
+the	O
+current	O
+generation	O
+of	O
+ecstasy	O
+users	O
+is	O
+a	O
+major	O
+cause	O
+for	O
+concern	O
+.	O
+	
+Association	O
+of	O
+common	O
+genetic	O
+variants	O
+of	O
+HOMER1	O
+gene	O
+with	O
+levodopa	O
+adverse	O
+effects	O
+in	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+patients	O
+.	O
+	
+Levodopa	O
+is	O
+the	O
+most	O
+effective	O
+symptomatic	O
+therapy	O
+for	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+","	O
+but	O
+its	O
+chronic	O
+use	O
+could	O
+lead	O
+to	O
+chronic	O
+adverse	O
+outcomes	O
+","	O
+such	O
+as	O
+motor	O
+fluctuations	O
+","	O
+dyskinesia	B-NP
+and	O
+visual	B-NP
+hallucinations	I-NP
+.	O
+	
+HOMER1	O
+is	O
+a	O
+protein	O
+with	O
+pivotal	O
+function	O
+in	O
+glutamate	O
+transmission	O
+","	O
+which	O
+has	O
+been	O
+related	O
+to	O
+the	O
+pathogenesis	O
+of	O
+these	O
+complications	O
+.	O
+	
+This	O
+study	O
+investigates	O
+whether	O
+polymorphisms	O
+in	O
+the	O
+HOMER1	O
+gene	O
+promoter	O
+region	O
+are	O
+associated	O
+with	O
+the	O
+occurrence	O
+of	O
+the	O
+chronic	O
+complications	O
+of	O
+levodopa	O
+therapy	O
+.	O
+	
+A	O
+total	O
+of	O
+205	O
+patients	O
+with	O
+idiopathic	B-NP
+Parkinson	I-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+were	O
+investigated	O
+.	O
+	
+Patients	O
+were	O
+genotyped	O
+for	O
+rs4704559	O
+","	O
+rs10942891	O
+and	O
+rs4704560	O
+by	O
+allelic	O
+discrimination	O
+with	O
+Taqman	O
+assays	O
+.	O
+	
+The	O
+rs4704559	O
+G	O
+allele	O
+was	O
+associated	O
+with	O
+a	O
+lower	O
+prevalence	O
+of	O
+dyskinesia	B-NP
+(	O
+prevalence	O
+ratio	O
+(	O
+PR	O
+)	O
+=	O
+0	O
+.	O
+615	O
+","	O
+95	O
+%	O
+confidence	O
+interval	O
+(	O
+CI	O
+)	O
+0	O
+.	O
+426	O
+-	O
+0	O
+.	O
+887	O
+","	O
+P	O
+=	O
+0	O
+.	O
+9	O
+)	O
+and	O
+visual	B-NP
+hallucinations	I-NP
+(	O
+PR	O
+=	O
+0	O
+.	O
+515	O
+","	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+295	O
+-	O
+0	O
+.	O
+899	O
+","	O
+P	O
+=	O
+0	O
+.	O
+20	O
+)	O
+.	O
+	
+Our	O
+data	O
+suggest	O
+that	O
+HOMER1	O
+rs4704559	O
+G	O
+allele	O
+has	O
+a	O
+protective	O
+role	O
+for	O
+the	O
+development	O
+of	O
+levodopa	O
+adverse	O
+effects	O
+.	O
+	
+Crocin	O
+improves	O
+lipid	O
+dysregulation	O
+in	O
+subacute	O
+diazinon	O
+exposure	O
+through	O
+ERK1	O
+/	O
+2	O
+pathway	O
+in	O
+rat	O
+liver	O
+.	O
+	
+INTRODUCTION	O
+:	O
+Diazinon	O
+Yis	O
+one	O
+of	O
+the	O
+most	O
+broadly	O
+used	O
+organophosphorus	O
+insecticides	O
+in	O
+agriculture	O
+.	O
+	
+It	O
+has	O
+been	O
+shown	O
+that	O
+exposure	O
+to	O
+diazinon	O
+may	O
+interfere	O
+with	O
+lipid	O
+metabolism	O
+.	O
+	
+Moreover	O
+","	O
+the	O
+hypolipidemic	O
+effect	O
+of	O
+crocin	O
+has	O
+been	O
+established	O
+.	O
+	
+Earlier	O
+studies	O
+revealed	O
+the	O
+major	O
+role	O
+of	O
+Extracellular	O
+signal	O
+-	O
+regulated	O
+kinase	O
+(	O
+ERK	O
+)	O
+pathways	O
+in	O
+low	O
+-	O
+density	O
+lipoprotein	O
+receptor	O
+(	O
+LDLr	O
+)	O
+expression	O
+.	O
+	
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+evaluate	O
+changes	O
+in	O
+the	O
+regulation	O
+of	O
+lipid	O
+metabolism	O
+","	O
+ERK	O
+and	O
+LDLr	O
+expression	O
+in	O
+the	O
+liver	O
+of	O
+rats	O
+exposed	O
+to	O
+subacute	O
+diazinon	O
+.	O
+	
+Furthermore	O
+ameliorating	O
+effect	O
+of	O
+crocin	O
+on	O
+diazinon	O
+induced	O
+disturbed	O
+cholesterol	O
+homeostasis	O
+was	O
+studied	O
+.	O
+	
+METHODS	O
+:	O
+24	O
+Rats	O
+were	O
+divided	O
+into	O
+4	O
+groups	O
+and	O
+received	O
+following	O
+treatments	O
+for	O
+4	O
+weeks	O
+;	O
+Corn	O
+oil	O
+(	O
+control	O
+)	O
+","	O
+diazinon	O
+(	O
+15mg	O
+/	O
+kg	O
+per	O
+day	O
+","	O
+orally	O
+)	O
+and	O
+crocin	O
+(	O
+12	O
+.	O
+5	O
+and	O
+25mg	O
+/	O
+kg	O
+per	O
+day	O
+","	O
+intraperitoneally	O
+)	O
+in	O
+combination	O
+with	O
+diazinon	O
+(	O
+15	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+	
+The	O
+levels	O
+of	O
+cholesterol	O
+","	O
+triglyceride	O
+and	O
+LDL	O
+in	O
+blood	O
+of	O
+rats	O
+were	O
+analyzed	O
+.	O
+	
+Moreover	O
+mRNA	O
+levels	O
+of	O
+LDLr	O
+and	O
+ERK1	O
+/	O
+2	O
+as	O
+well	O
+as	O
+protein	O
+levels	O
+of	O
+total	O
+and	O
+activated	O
+forms	O
+of	O
+ERK1	O
+/	O
+2	O
+in	O
+rat	O
+liver	O
+were	O
+evaluated	O
+by	O
+Western	O
+blotting	O
+and	O
+quantitative	O
+real	O
+time	O
+polymerase	O
+chain	O
+reaction	O
+analysis	O
+.	O
+	
+RESULTS	O
+:	O
+Our	O
+data	O
+showed	O
+that	O
+subacute	O
+exposure	O
+to	O
+diazinon	O
+significantly	O
+increased	O
+concentrations	O
+of	O
+cholesterol	O
+","	O
+triglyceride	O
+and	O
+LDL	O
+.	O
+	
+Moreover	O
+diazinon	O
+decreased	O
+ERK1	O
+/	O
+2	O
+protein	O
+phosphorylation	O
+and	O
+LDLr	O
+transcript	O
+.	O
+	
+Crocin	O
+reduced	O
+inhibition	O
+of	O
+ERK	O
+activation	O
+and	O
+diazinon	O
+-	O
+induced	O
+hyperlipemia	B-NP
+and	O
+increased	O
+levels	O
+of	O
+LDLr	O
+transcript	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Crocin	O
+may	O
+be	O
+considered	O
+as	O
+a	O
+novel	O
+protective	O
+agent	O
+in	O
+diazinon	O
+-	O
+induced	O
+hyperlipemia	B-NP
+through	O
+modulating	O
+of	O
+ERK	O
+pathway	O
+and	O
+increase	O
+of	O
+LDLr	O
+expression	O
+.	O
+	
+GEM	O
+-	O
+P	O
+chemotherapy	O
+is	O
+active	O
+in	O
+the	O
+treatment	O
+of	O
+relapsed	O
+Hodgkin	B-NP
+lymphoma	I-NP
+.	O
+	
+Hodgkin	B-NP
+lymphoma	I-NP
+(	O
+HL	B-NP
+)	O
+is	O
+a	O
+relatively	O
+chemosensitive	O
+malignancy	B-NP
+.	O
+	
+However	O
+","	O
+for	O
+those	O
+who	O
+relapse	O
+","	O
+high	O
+-	O
+dose	O
+chemotherapy	O
+with	O
+autologous	O
+stem	O
+cell	O
+transplant	O
+is	O
+the	O
+treatment	O
+of	O
+choice	O
+which	O
+relies	O
+on	O
+adequate	O
+disease	O
+control	O
+with	O
+salvage	O
+chemotherapy	O
+.	O
+	
+Regimens	O
+commonly	O
+used	O
+often	O
+require	O
+inpatient	O
+administration	O
+and	O
+can	O
+be	O
+difficult	O
+to	O
+deliver	O
+due	O
+to	O
+toxicity	B-NP
+.	O
+	
+Gemcitabine	O
+and	O
+cisplatin	O
+have	O
+activity	O
+in	O
+HL	B-NP
+","	O
+non	O
+-	O
+overlapping	O
+toxicity	B-NP
+with	O
+first	O
+-	O
+line	O
+chemotherapeutics	O
+","	O
+and	O
+may	O
+be	O
+delivered	O
+in	O
+an	O
+outpatient	O
+setting	O
+.	O
+	
+In	O
+this	O
+retrospective	O
+single	O
+-	O
+centre	O
+analysis	O
+","	O
+patients	O
+with	O
+relapsed	O
+or	O
+refractory	O
+HL	B-NP
+treated	O
+with	O
+gemcitabine	O
+1	O
+","	O
+0	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+day	O
+(	O
+D	O
+)	O
+1	O
+","	O
+D8	O
+and	O
+D15	O
+;	O
+methylprednisolone	O
+1	O
+","	O
+0	O
+mg	O
+D1	O
+-	O
+5	O
+;	O
+and	O
+cisplatin	O
+100	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+D15	O
+","	O
+every	O
+28	O
+days	O
+(	O
+GEM	O
+-	O
+P	O
+)	O
+were	O
+included	O
+.	O
+	
+Demographic	O
+","	O
+survival	O
+","	O
+response	O
+and	O
+toxicity	B-NP
+data	O
+were	O
+recorded	O
+.	O
+	
+Forty	O
+-	O
+one	O
+eligible	O
+patients	O
+were	O
+identified	O
+:	O
+median	O
+age	O
+27	O
+.	O
+	
+One	O
+hundred	O
+and	O
+twenty	O
+-	O
+two	O
+cycles	O
+of	O
+GEM	O
+-	O
+P	O
+were	O
+administered	O
+in	O
+total	O
+(	O
+median	O
+3	O
+cycles	O
+;	O
+range	O
+1	O
+-	O
+6	O
+)	O
+.	O
+	
+Twenty	O
+of	O
+41	O
+(	O
+48	O
+%	O
+)	O
+patients	O
+received	O
+GEM	O
+-	O
+P	O
+as	O
+second	O
+-	O
+line	O
+treatment	O
+and	O
+11	O
+/	O
+41	O
+(	O
+27	O
+%	O
+)	O
+as	O
+third	O
+-	O
+line	O
+therapy	O
+.	O
+	
+Overall	O
+response	O
+rate	O
+(	O
+ORR	O
+)	O
+to	O
+GEM	O
+-	O
+P	O
+in	O
+the	O
+entire	O
+cohort	O
+was	O
+80	O
+%	O
+(	O
+complete	O
+response	O
+(	O
+CR	O
+)	O
+37	O
+%	O
+","	O
+partial	O
+response	O
+44	O
+%	O
+)	O
+with	O
+14	O
+/	O
+15	O
+CR	O
+confirmed	O
+as	O
+a	O
+metabolic	O
+CR	O
+on	O
+PET	O
+and	O
+ORR	O
+of	O
+85	O
+%	O
+in	O
+the	O
+20	O
+second	O
+-	O
+line	O
+patients	O
+.	O
+	
+The	O
+most	O
+common	O
+grade	O
+3	O
+/	O
+4	O
+toxicities	B-NP
+were	O
+haematological	O
+:	O
+neutropenia	B-NP
+54	O
+%	O
+and	O
+thrombocytopenia	B-NP
+51	O
+%	O
+.	O
+	
+Median	O
+follow	O
+-	O
+up	O
+from	O
+the	O
+start	O
+of	O
+GEM	O
+-	O
+P	O
+was	O
+4	O
+.	O
+5	O
+years	O
+.	O
+	
+Following	O
+GEM	O
+-	O
+P	O
+","	O
+5	O
+-	O
+year	O
+progression	O
+-	O
+free	O
+survival	O
+was	O
+46	O
+%	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+(	O
+CI	O
+)	O
+","	O
+30	O
+-	O
+62	O
+%	O
+)	O
+and	O
+5	O
+-	O
+year	O
+overall	O
+survival	O
+was	O
+59	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+","	O
+43	O
+-	O
+74	O
+%	O
+)	O
+.	O
+	
+Fourteen	O
+of	O
+41	O
+patients	O
+proceeded	O
+directly	O
+to	O
+autologous	O
+transplant	O
+.	O
+	
+GEM	O
+-	O
+P	O
+is	O
+a	O
+salvage	O
+chemotherapy	O
+with	O
+relatively	O
+high	O
+response	O
+rates	O
+","	O
+leading	O
+to	O
+successful	O
+transplantation	O
+in	O
+appropriate	O
+patients	O
+","	O
+in	O
+the	O
+treatment	O
+of	O
+relapsed	O
+or	O
+refractory	O
+HL	B-NP
+.	O
+	
+Basal	O
+functioning	O
+of	O
+the	O
+hypothalamic	O
+-	O
+pituitary	O
+-	O
+adrenal	O
+(	O
+HPA	O
+)	O
+axis	O
+and	O
+psychological	O
+distress	O
+in	O
+recreational	O
+ecstasy	O
+polydrug	O
+users	O
+.	O
+	
+RATIONALE	O
+:	O
+Ecstasy	O
+(	O
+MDMA	O
+)	O
+is	O
+a	O
+psychostimulant	O
+drug	O
+which	O
+is	O
+increasingly	O
+associated	O
+with	O
+psychobiological	B-NP
+dysfunction	I-NP
+.	O
+	
+While	O
+some	O
+recent	O
+studies	O
+suggest	O
+acute	O
+changes	O
+in	O
+neuroendocrine	O
+function	O
+","	O
+less	O
+is	O
+known	O
+about	O
+long	O
+-	O
+term	O
+changes	O
+in	O
+HPA	O
+functionality	O
+in	O
+recreational	O
+users	O
+.	O
+	
+OBJECTIVES	O
+:	O
+The	O
+current	O
+study	O
+is	O
+the	O
+first	O
+to	O
+explore	O
+the	O
+effects	O
+of	O
+ecstasy	O
+-	O
+polydrug	O
+use	O
+on	O
+psychological	O
+distress	O
+and	O
+basal	O
+functioning	O
+of	O
+the	O
+HPA	O
+axis	O
+through	O
+assessing	O
+the	O
+secretion	O
+of	O
+cortisol	O
+across	O
+the	O
+diurnal	O
+period	O
+.	O
+	
+METHOD	O
+:	O
+Seventy	O
+-	O
+six	O
+participants	O
+(	O
+21	O
+nonusers	O
+","	O
+29	O
+light	O
+ecstasy	O
+-	O
+polydrug	O
+users	O
+","	O
+26	O
+heavy	O
+ecstasy	O
+-	O
+polydrug	O
+users	O
+)	O
+completed	O
+a	O
+substance	O
+use	O
+inventory	O
+and	O
+measures	O
+of	O
+psychological	O
+distress	O
+at	O
+baseline	O
+","	O
+then	O
+two	O
+consecutive	O
+days	O
+of	O
+cortisol	O
+sampling	O
+(	O
+on	O
+awakening	O
+","	O
+30	O
+min	O
+post	O
+awakening	O
+","	O
+between	O
+1400	O
+and	O
+1600	O
+hours	O
+and	O
+pre	O
+bedtime	O
+)	O
+.	O
+	
+On	O
+day	O
+2	O
+","	O
+participants	O
+also	O
+attended	O
+the	O
+laboratory	O
+to	O
+complete	O
+a	O
+20	O
+-	O
+min	O
+multitasking	O
+stressor	O
+.	O
+	
+RESULTS	O
+:	O
+Both	O
+user	O
+groups	O
+exhibited	O
+significantly	O
+greater	O
+levels	O
+of	O
+anxiety	B-NP
+and	O
+depression	B-NP
+than	O
+nonusers	O
+.	O
+	
+On	O
+day	O
+1	O
+","	O
+all	O
+participants	O
+exhibited	O
+a	O
+typical	O
+cortisol	O
+profile	O
+","	O
+though	O
+light	O
+users	O
+had	O
+significantly	O
+elevated	O
+levels	O
+pre	O
+-	O
+bed	O
+.	O
+	
+On	O
+day	O
+2	O
+","	O
+heavy	O
+users	O
+demonstrated	O
+elevated	O
+levels	O
+upon	O
+awakening	O
+and	O
+all	O
+ecstasy	O
+-	O
+polydrug	O
+users	O
+demonstrated	O
+elevated	O
+pre	O
+-	O
+bed	O
+levels	O
+compared	O
+to	O
+non	O
+-	O
+users	O
+.	O
+	
+Significant	O
+between	O
+group	O
+differences	O
+were	O
+also	O
+observed	O
+in	O
+afternoon	O
+cortisol	O
+levels	O
+and	O
+in	O
+overall	O
+cortisol	O
+secretion	O
+across	O
+the	O
+day	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+increases	O
+in	O
+anxiety	B-NP
+and	O
+depression	B-NP
+are	O
+in	O
+line	O
+with	O
+previous	O
+observations	O
+in	O
+recreational	O
+ecstasy	O
+-	O
+polydrug	O
+users	O
+.	O
+	
+Dysregulated	O
+diurnal	O
+cortisol	O
+may	O
+be	O
+indicative	O
+of	O
+inappropriate	O
+anticipation	O
+of	O
+forthcoming	O
+demands	O
+and	O
+hypersecretion	O
+may	O
+lead	O
+to	O
+the	O
+increased	O
+psychological	O
+and	O
+physical	O
+morbidity	O
+associated	O
+with	O
+heavy	O
+recreational	O
+use	O
+of	O
+ecstasy	O
+.	O
+	
+Ifosfamide	O
+related	O
+encephalopathy	B-NP
+:	O
+the	O
+need	O
+for	O
+a	O
+timely	O
+EEG	O
+evaluation	O
+.	O
+	
+BACKGROUND	O
+:	O
+Ifosfamide	O
+is	O
+an	O
+alkylating	O
+agent	O
+useful	O
+in	O
+the	O
+treatment	O
+of	O
+a	O
+wide	O
+range	O
+of	O
+cancers	B-NP
+including	O
+sarcomas	B-NP
+","	O
+lymphoma	B-NP
+","	O
+gynecologic	B-NP
+and	I-NP
+testicular	I-NP
+cancers	I-NP
+.	O
+	
+Encephalopathy	B-NP
+has	O
+been	O
+reported	O
+in	O
+10	O
+-	O
+40	O
+%	O
+of	O
+patients	O
+receiving	O
+high	O
+-	O
+dose	O
+IV	O
+ifosfamide	O
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+highlight	O
+the	O
+role	O
+of	O
+electroencephalogram	O
+(	O
+EEG	O
+)	O
+in	O
+the	O
+early	O
+detection	O
+and	O
+management	O
+of	O
+ifosfamide	O
+related	O
+encephalopathy	B-NP
+.	O
+	
+METHODS	O
+:	O
+Retrospective	O
+chart	O
+review	O
+including	O
+clinical	O
+data	O
+and	O
+EEG	O
+recordings	O
+was	O
+done	O
+on	O
+five	O
+patients	O
+","	O
+admitted	O
+to	O
+MD	O
+Anderson	O
+Cancer	B-NP
+Center	O
+between	O
+years	O
+2009	O
+and	O
+2012	O
+","	O
+who	O
+developed	O
+ifosfamide	O
+related	O
+acute	O
+encephalopathy	B-NP
+.	O
+	
+RESULTS	O
+:	O
+All	O
+five	O
+patients	O
+experienced	O
+symptoms	O
+of	O
+encephalopathy	B-NP
+soon	O
+after	O
+(	O
+within	O
+12	O
+h	O
+-	O
+2	O
+days	O
+)	O
+receiving	O
+ifosfamide	O
+.	O
+	
+Two	O
+patients	O
+developed	O
+generalized	O
+convulsions	B-NP
+while	O
+one	O
+patient	O
+developed	O
+continuous	O
+non	B-NP
+-	I-NP
+convulsive	I-NP
+status	I-NP
+epilepticus	I-NP
+(	O
+NCSE	B-NP
+)	O
+that	O
+required	O
+ICU	O
+admission	O
+and	O
+intubation	O
+.	O
+	
+Initial	O
+EEG	O
+showed	O
+epileptiform	O
+discharges	O
+in	O
+three	O
+patients	O
+;	O
+run	O
+of	O
+triphasic	O
+waves	O
+in	O
+one	O
+patient	O
+and	O
+moderate	O
+degree	O
+diffuse	O
+generalized	O
+slowing	O
+.	O
+	
+Mixed	O
+pattern	O
+with	O
+the	O
+presence	O
+of	O
+both	O
+sharps	O
+and	O
+triphasic	O
+waves	O
+were	O
+also	O
+noted	O
+.	O
+	
+Repeat	O
+EEGs	O
+within	O
+24	O
+_	O
+h	O
+of	O
+symptom	O
+onset	O
+showed	O
+marked	O
+improvement	O
+that	O
+was	O
+correlated	O
+with	O
+clinical	O
+improvement	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Severity	O
+of	O
+ifosfamide	O
+related	O
+encephalopathy	B-NP
+correlates	O
+with	O
+EEG	O
+changes	O
+.	O
+	
+We	O
+suggest	O
+a	O
+timely	O
+EEG	O
+evaluation	O
+for	O
+patients	O
+receiving	O
+ifosfamide	O
+who	O
+develop	O
+features	O
+of	O
+encephalopathy	B-NP
+.	O
+	
+Incidence	O
+of	O
+contrast	O
+-	O
+induced	O
+nephropathy	B-NP
+in	O
+hospitalised	O
+patients	O
+with	O
+cancer	B-NP
+.	O
+	
+OBJECTIVES	O
+:	O
+To	O
+determine	O
+the	O
+frequency	O
+of	O
+and	O
+possible	O
+factors	O
+related	O
+to	O
+contrast	O
+-	O
+induced	O
+nephropathy	B-NP
+(	O
+CIN	O
+)	O
+in	O
+hospitalised	O
+patients	O
+with	O
+cancer	B-NP
+.	O
+	
+METHODS	O
+:	O
+Ninety	O
+adult	O
+patients	O
+were	O
+enrolled	O
+.	O
+	
+Patients	O
+with	O
+risk	O
+factors	O
+for	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+were	O
+excluded	O
+.	O
+	
+Blood	O
+samples	O
+were	O
+examined	O
+the	O
+day	O
+before	O
+contrast	O
+-	O
+enhanced	O
+computed	O
+tomography	O
+(	O
+CT	O
+)	O
+and	O
+serially	O
+for	O
+3	O
+days	O
+thereafter	O
+.	O
+	
+CIN	O
+was	O
+defined	O
+as	O
+an	O
+increase	O
+in	O
+serum	O
+creatinine	O
+(	O
+Cr	O
+)	O
+of	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+dl	O
+or	O
+more	O
+","	O
+or	O
+elevation	O
+of	O
+Cr	O
+to	O
+25	O
+%	O
+over	O
+baseline	O
+.	O
+	
+Relationships	O
+between	O
+CIN	O
+and	O
+possible	O
+risk	O
+factors	O
+were	O
+investigated	O
+.	O
+	
+RESULTS	O
+:	O
+CIN	O
+was	O
+detected	O
+in	O
+18	O
+/	O
+90	O
+(	O
+20	O
+%	O
+)	O
+patients	O
+.	O
+	
+CIN	O
+developed	O
+in	O
+25	O
+.	O
+5	O
+%	O
+patients	O
+who	O
+underwent	O
+chemotherapy	O
+and	O
+in	O
+11	O
+%	O
+patients	O
+who	O
+did	O
+not	O
+(	O
+P	O
+=	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+CIN	O
+more	O
+frequently	O
+developed	O
+in	O
+patients	O
+who	O
+had	O
+undergone	O
+CT	O
+within	O
+45	O
+days	O
+after	O
+the	O
+last	O
+chemotherapy	O
+(	O
+P	O
+=	O
+0	O
+.	O
+5	O
+)	O
+;	O
+it	O
+was	O
+also	O
+an	O
+independent	O
+risk	O
+factor	O
+(	O
+P	O
+=	O
+0	O
+.	O
+17	O
+)	O
+.	O
+	
+CIN	O
+was	O
+significantly	O
+more	O
+after	O
+treatment	O
+with	O
+bevacizumab	O
+/	O
+irinotecan	O
+(	O
+P	O
+=	O
+0	O
+.	O
+21	O
+)	O
+and	O
+in	O
+patients	O
+with	O
+hypertension	B-NP
+(	O
+P	O
+=	O
+0	O
+.	O
+44	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+incidence	O
+of	O
+CIN	O
+after	O
+CT	O
+in	O
+hospitalised	O
+oncological	O
+patients	O
+was	O
+20	O
+%	O
+.	O
+	
+CIN	O
+developed	O
+4	O
+.	O
+5	O
+-	O
+times	O
+more	O
+frequently	O
+in	O
+patients	O
+with	O
+cancer	B-NP
+who	O
+had	O
+undergone	O
+recent	O
+chemotherapy	O
+.	O
+	
+Hypertension	B-NP
+and	O
+the	O
+combination	O
+of	O
+bevacizumab	O
+/	O
+irinotecan	O
+may	O
+be	O
+additional	O
+risk	O
+factors	O
+for	O
+CIN	O
+development	O
+.	O
+	
+KEY	O
+POINTS	O
+:	O
+.	O
+	
+Contrast	O
+-	O
+induced	O
+nephropathy	B-NP
+(	O
+CIN	O
+)	O
+is	O
+a	O
+concern	O
+for	O
+oncological	O
+patients	O
+undergoing	O
+CT	O
+.	O
+	
+.	O
+CIN	O
+occurs	O
+more	O
+often	O
+when	O
+CT	O
+is	O
+performed	O
+<	O
+45	O
+days	O
+after	O
+chemotherapy	O
+.	O
+	
+.	O
+Hypertension	B-NP
+and	O
+treatment	O
+with	O
+bevacizumab	O
+appear	O
+to	O
+be	O
+additional	O
+risk	O
+factors	O
+.	O
+	
+Syndrome	B-NP
+of	I-NP
+inappropriate	I-NP
+antidiuretic	I-NP
+hormone	I-NP
+secretion	O
+associated	O
+with	O
+desvenlafaxine	O
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+report	O
+a	O
+case	O
+of	O
+syndrome	B-NP
+of	I-NP
+inappropriate	I-NP
+anti	I-NP
+-	I-NP
+diuretic	I-NP
+hormone	I-NP
+(	O
+SIADH	B-NP
+)	O
+secretion	O
+associated	O
+with	O
+desvenlafaxine	O
+.	O
+	
+CASE	O
+SUMMARY	O
+:	O
+A	O
+57	O
+-	O
+year	O
+old	O
+female	O
+with	O
+hyponatraemia	B-NP
+.	O
+	
+Her	O
+medications	O
+included	O
+desvenlafaxine	O
+","	O
+and	O
+symptoms	O
+included	O
+nausea	B-NP
+","	O
+anxiety	B-NP
+and	O
+confusion	B-NP
+.	O
+	
+The	O
+serum	O
+sodium	O
+at	O
+this	O
+time	O
+was	O
+120	O
+mmol	O
+/	O
+L	O
+","	O
+serum	O
+osmolality	O
+was	O
+263	O
+mosmol	O
+/	O
+kg	O
+","	O
+urine	O
+osmolality	O
+410	O
+mosmol	O
+/	O
+kg	O
+and	O
+urine	O
+sodium	O
+63	O
+mmol	O
+/	O
+L	O
+","	O
+consistent	O
+with	O
+a	O
+diagnosis	O
+of	O
+SIADH	B-NP
+.	O
+	
+Desvenlafaxine	O
+was	O
+ceased	O
+and	O
+fluid	O
+restriction	O
+implemented	O
+.	O
+	
+After	O
+4	O
+days	O
+the	O
+sodium	O
+increased	O
+to	O
+128	O
+mmol	O
+/	O
+L	O
+and	O
+fluid	O
+restriction	O
+was	O
+relaxed	O
+.	O
+	
+During	O
+her	O
+further	O
+3	O
+weeks	O
+inpatient	O
+admission	O
+the	O
+serum	O
+sodium	O
+ranged	O
+from	O
+134	O
+to	O
+137	O
+mmol	O
+/	O
+L	O
+during	O
+treatment	O
+with	O
+mirtazapine	O
+.	O
+	
+DISCUSSION	O
+:	O
+SIADH	B-NP
+has	O
+been	O
+widely	O
+reported	O
+with	O
+a	O
+range	O
+of	O
+antidepressants	O
+.	O
+	
+This	O
+case	O
+report	O
+suggests	O
+that	O
+desvenlafaxine	O
+might	O
+cause	O
+clinically	O
+significant	O
+hyponatremia	B-NP
+.	O
+	
+CONCLUSIONS	O
+:	O
+Clinicians	O
+should	O
+be	O
+aware	O
+of	O
+the	O
+potential	O
+for	O
+antidepressants	O
+to	O
+cause	O
+hyponatremia	B-NP
+","	O
+and	O
+take	O
+appropriate	O
+corrective	O
+action	O
+where	O
+necessary	O
+.	O
+	
+Oxidative	O
+stress	O
+on	O
+cardiotoxicity	B-NP
+after	O
+treatment	O
+with	O
+single	O
+and	O
+multiple	O
+doses	O
+of	O
+doxorubicin	O
+.	O
+	
+The	O
+mechanism	O
+of	O
+doxorubicin	O
+(	O
+DOX	O
+)	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+remains	O
+controversial	O
+.	O
+	
+Wistar	O
+rats	O
+(	O
+n	O
+=	O
+66	O
+)	O
+received	O
+DOX	O
+injections	O
+intraperitoneally	O
+and	O
+were	O
+randomly	O
+assigned	O
+to	O
+2	O
+experimental	O
+protocols	O
+:	O
+(	O
+1	O
+)	O
+rats	O
+were	O
+killed	O
+before	O
+(	O
+-	O
+24	O
+h	O
+","	O
+n	O
+=	O
+8	O
+)	O
+and	O
+24	O
+h	O
+after	O
+(	O
++	O
+24	O
+h	O
+","	O
+n	O
+=	O
+8	O
+)	O
+a	O
+single	O
+dose	O
+of	O
+DOX	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+)	O
+to	O
+determine	O
+the	O
+DOX	O
+acute	O
+effect	O
+and	O
+(	O
+2	O
+)	O
+rats	O
+(	O
+n	O
+=	O
+58	O
+)	O
+received	O
+4	O
+injections	O
+of	O
+DOX	O
+(	O
+4	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+/	O
+week	O
+)	O
+and	O
+were	O
+killed	O
+before	O
+the	O
+first	O
+injection	O
+(	O
+M0	O
+)	O
+and	O
+1	O
+week	O
+after	O
+each	O
+injection	O
+(	O
+M1	O
+","	O
+M2	O
+","	O
+M3	O
+","	O
+and	O
+M4	O
+)	O
+to	O
+determine	O
+the	O
+chronological	O
+effects	O
+.	O
+	
+Animals	O
+used	O
+at	O
+M0	O
+(	O
+n	O
+=	O
+8	O
+)	O
+were	O
+also	O
+used	O
+at	O
+moment	O
+-	O
+24	O
+h	O
+of	O
+acute	O
+study	O
+.	O
+	
+Cardiac	O
+total	O
+antioxidant	O
+performance	O
+(	O
+TAP	O
+)	O
+","	O
+DNA	O
+damage	O
+","	O
+and	O
+morphology	O
+analyses	O
+were	O
+carried	O
+out	O
+at	O
+each	O
+time	O
+point	O
+.	O
+	
+Single	O
+dose	O
+of	O
+DOX	O
+was	O
+associated	O
+with	O
+increased	O
+cardiac	B-NP
+disarrangement	I-NP
+","	O
+necrosis	B-NP
+","	O
+and	O
+DNA	O
+damage	O
+(	O
+strand	O
+breaks	O
+(	O
+SBs	O
+)	O
+and	O
+oxidized	O
+pyrimidines	O
+)	O
+and	O
+decreased	O
+TAP	O
+.	O
+	
+The	O
+chronological	O
+study	O
+showed	O
+an	O
+effect	O
+of	O
+a	O
+cumulative	O
+dose	O
+on	O
+body	O
+weight	O
+(	O
+R	O
+=	O
+-	O
+0	O
+.	O
+99	O
+","	O
+p	O
+=	O
+0	O
+.	O
+11	O
+)	O
+","	O
+necrosis	B-NP
+(	O
+R	O
+=	O
+1	O
+.	O
+0	O
+","	O
+p	O
+=	O
+0	O
+.	O
+4	O
+)	O
+","	O
+TAP	O
+(	O
+R	O
+=	O
+0	O
+.	O
+95	O
+","	O
+p	O
+=	O
+0	O
+.	O
+49	O
+)	O
+","	O
+and	O
+DNA	O
+SBs	O
+(	O
+R	O
+=	O
+-	O
+0	O
+.	O
+95	O
+","	O
+p	O
+=	O
+0	O
+.	O
+49	O
+)	O
+.	O
+	
+DNA	O
+SBs	O
+damage	O
+was	O
+negatively	O
+associated	O
+with	O
+TAP	O
+(	O
+R	O
+=	O
+-	O
+0	O
+.	O
+98	O
+","	O
+p	O
+=	O
+0	O
+.	O
+18	O
+)	O
+","	O
+and	O
+necrosis	B-NP
+(	O
+R	O
+=	O
+-	O
+0	O
+.	O
+97	O
+","	O
+p	O
+=	O
+0	O
+.	O
+27	O
+)	O
+.	O
+	
+Our	O
+results	O
+suggest	O
+that	O
+oxidative	O
+damage	O
+is	O
+associated	O
+with	O
+acute	O
+cardiotoxicity	B-NP
+induced	O
+by	O
+a	O
+single	O
+dose	O
+of	O
+DOX	O
+only	O
+.	O
+	
+Increased	O
+resistance	O
+to	O
+the	O
+oxidative	O
+stress	O
+is	O
+plausible	O
+for	O
+the	O
+multiple	O
+dose	O
+of	O
+DOX	O
+.	O
+	
+Thus	O
+","	O
+different	O
+mechanisms	O
+may	O
+be	O
+involved	O
+in	O
+acute	O
+toxicity	B-NP
+versus	O
+chronic	O
+toxicity	B-NP
+.	O
+	
+Tacrolimus	O
+-	O
+related	O
+seizure	B-NP
+after	O
+pediatric	O
+liver	O
+transplantation	O
+-	O
+-	O
+a	O
+single	O
+-	O
+center	O
+experience	O
+.	O
+	
+To	O
+identify	O
+the	O
+risk	O
+factors	O
+for	O
+new	O
+-	O
+onset	O
+seizures	B-NP
+after	O
+pediatric	O
+LT	O
+and	O
+to	O
+assess	O
+their	O
+clinical	O
+implications	O
+and	O
+long	O
+-	O
+term	O
+prognosis	O
+.	O
+	
+The	O
+clinical	O
+and	O
+laboratory	O
+data	O
+of	O
+27	O
+consecutive	O
+children	O
+who	O
+underwent	O
+LT	O
+from	O
+January	O
+2007	O
+to	O
+December	O
+2010	O
+in	O
+our	O
+center	O
+were	O
+analyzed	O
+retrospectively	O
+.	O
+	
+Patients	O
+were	O
+divided	O
+into	O
+seizures	B-NP
+group	O
+and	O
+a	O
+non	O
+-	O
+seizures	B-NP
+group	O
+.	O
+	
+Pre	O
+-	O
+operative	O
+","	O
+intra	O
+-	O
+operative	O
+","	O
+and	O
+post	O
+-	O
+operative	O
+data	O
+were	O
+collected	O
+.	O
+	
+Seizures	B-NP
+occurred	O
+in	O
+four	O
+children	O
+","	O
+an	O
+incidence	O
+of	O
+14	O
+.	O
+8	O
+%	O
+.	O
+	
+All	O
+exhibited	O
+generalized	O
+tonic	B-NP
+-	I-NP
+clonic	I-NP
+seizures	I-NP
+within	O
+the	O
+first	O
+two	O
+wk	O
+after	O
+LT	O
+.	O
+	
+Univariate	O
+analysis	O
+showed	O
+that	O
+the	O
+risk	O
+factors	O
+associated	O
+with	O
+seizures	B-NP
+after	O
+pediatric	O
+LT	O
+included	O
+gender	O
+","	O
+pediatric	O
+end	B-NP
+-	I-NP
+stage	I-NP
+liver	I-NP
+disease	I-NP
+score	O
+before	O
+surgery	O
+","	O
+Child	O
+-	O
+Pugh	O
+score	O
+before	O
+surgery	O
+","	O
+serum	O
+total	O
+bilirubin	O
+after	O
+surgery	O
+","	O
+and	O
+trough	O
+TAC	O
+level	O
+.	O
+	
+Multivariate	O
+analysis	O
+showed	O
+that	O
+trough	O
+TAC	O
+level	O
+was	O
+the	O
+only	O
+independent	O
+risk	O
+factor	O
+associated	O
+with	O
+the	O
+seizures	B-NP
+.	O
+	
+All	O
+children	O
+who	O
+experienced	O
+seizures	B-NP
+survived	O
+with	O
+good	O
+graft	O
+function	O
+and	O
+remained	O
+seizure	B-NP
+-	O
+free	O
+without	O
+anti	O
+-	O
+epileptic	B-NP
+drugs	O
+over	O
+a	O
+mean	O
+follow	O
+-	O
+up	O
+period	O
+of	O
+33	O
+.	O
+7	O
++	O
+14	O
+.	O
+6	O
+months	O
+.	O
+	
+High	O
+trough	O
+TAC	O
+level	O
+was	O
+the	O
+predominant	O
+factor	O
+that	O
+contributed	O
+to	O
+seizures	B-NP
+in	O
+the	O
+early	O
+post	O
+-	O
+operative	O
+period	O
+after	O
+pediatric	O
+LT	O
+.	O
+	
+High	O
+PELD	O
+and	O
+Child	O
+-	O
+Pugh	O
+scores	O
+before	O
+LT	O
+and	O
+high	O
+post	O
+-	O
+operative	O
+serum	O
+Tbil	O
+may	O
+be	O
+contributory	O
+risk	O
+factors	O
+for	O
+TAC	O
+-	O
+related	O
+seizures	B-NP
+.	O
+	
+The	O
+flavonoid	O
+apigenin	O
+delays	O
+forgetting	O
+of	O
+passive	O
+avoidance	O
+conditioning	O
+in	O
+rats	O
+.	O
+	
+The	O
+present	O
+experiments	O
+were	O
+performed	O
+to	O
+study	O
+the	O
+effect	O
+of	O
+the	O
+flavonoid	O
+apigenin	O
+(	O
+20	O
+mg	O
+/	O
+kg	O
+intraperitoneally	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+","	O
+1	O
+h	O
+before	O
+acquisition	O
+)	O
+","	O
+on	O
+24	O
+h	O
+retention	O
+performance	O
+and	O
+forgetting	O
+of	O
+a	O
+step	O
+-	O
+through	O
+passive	O
+avoidance	O
+task	O
+","	O
+in	O
+young	O
+male	O
+Wistar	O
+rats	O
+.	O
+	
+There	O
+were	O
+no	O
+differences	O
+between	O
+saline	O
+-	O
+and	O
+apigenin	O
+-	O
+treated	O
+groups	O
+in	O
+the	O
+24	O
+h	O
+retention	O
+trial	O
+.	O
+	
+Furthermore	O
+","	O
+apigenin	O
+did	O
+not	O
+prevent	O
+the	O
+amnesia	B-NP
+induced	O
+by	O
+scopolamine	O
+(	O
+1mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+p	O
+.	O
+","	O
+30	O
+min	O
+before	O
+the	O
+acquisition	O
+)	O
+.	O
+	
+The	O
+saline	O
+-	O
+and	O
+apigenin	O
+-	O
+treated	O
+rats	O
+that	O
+did	O
+not	O
+step	O
+through	O
+into	O
+the	O
+dark	O
+compartment	O
+during	O
+the	O
+cut	O
+-	O
+off	O
+time	O
+(	O
+540	O
+s	O
+)	O
+were	O
+retested	O
+weekly	O
+for	O
+up	O
+to	O
+eight	O
+weeks	O
+.	O
+	
+In	O
+the	O
+saline	O
+treated	O
+group	O
+","	O
+the	O
+first	O
+significant	O
+decline	O
+in	O
+passive	O
+avoidance	O
+response	O
+was	O
+observed	O
+at	O
+four	O
+weeks	O
+","	O
+and	O
+complete	O
+memory	B-NP
+loss	I-NP
+was	O
+found	O
+five	O
+weeks	O
+after	O
+the	O
+acquisition	O
+of	O
+the	O
+passive	O
+avoidance	O
+task	O
+.	O
+	
+At	O
+the	O
+end	O
+of	O
+the	O
+experimental	O
+period	O
+","	O
+60	O
+%	O
+of	O
+the	O
+animals	O
+treated	O
+with	O
+apigenin	O
+still	O
+did	O
+not	O
+step	O
+through	O
+.	O
+	
+These	O
+data	O
+suggest	O
+that	O
+1	O
+)	O
+apigenin	O
+delays	O
+the	O
+long	O
+-	O
+term	O
+forgetting	O
+but	O
+did	O
+not	O
+modulate	O
+the	O
+24	O
+h	O
+retention	O
+of	O
+fear	O
+memory	O
+and	O
+2	O
+)	O
+the	O
+obtained	O
+beneficial	O
+effect	O
+of	O
+apigenin	O
+on	O
+the	O
+passive	O
+avoidance	O
+conditioning	O
+is	O
+mediated	O
+by	O
+mechanisms	O
+that	O
+do	O
+not	O
+implicate	O
+its	O
+action	O
+on	O
+the	O
+muscarinic	O
+cholinergic	O
+system	O
+.	O
+	
+Histamine	O
+antagonists	O
+and	O
+d	O
+-	O
+tubocurarine	O
+-	O
+induced	O
+hypotension	B-NP
+in	O
+cardiac	O
+surgical	O
+patients	O
+.	O
+	
+Hemodynamic	O
+effects	O
+and	O
+histamine	O
+release	O
+by	O
+bolus	O
+injection	O
+of	O
+0	O
+.	O
+35	O
+mg	O
+/	O
+kg	O
+of	O
+d	O
+-	O
+tubocurarine	O
+were	O
+studied	O
+in	O
+24	O
+patients	O
+.	O
+	
+H1	O
+-	O
+and	O
+H2	O
+-	O
+histamine	O
+antagonists	O
+or	O
+placebo	O
+were	O
+given	O
+before	O
+dosing	O
+with	O
+d	O
+-	O
+tubocurarine	O
+in	O
+a	O
+randomized	O
+double	O
+-	O
+blind	O
+fashion	O
+to	O
+four	O
+groups	O
+:	O
+group	O
+1	O
+-	O
+-	O
+placebo	O
+;	O
+group	O
+2	O
+-	O
+-	O
+cimetidine	O
+","	O
+4	O
+mg	O
+/	O
+kg	O
+","	O
+plus	O
+placebo	O
+;	O
+group	O
+3	O
+-	O
+-	O
+chlorpheniramine	O
+","	O
+0	O
+.	O
+1	O
+mg	O
+/	O
+kg	O
+","	O
+plus	O
+placebo	O
+;	O
+and	O
+group	O
+4	O
+-	O
+-	O
+cimetidine	O
+plus	O
+chlorpheniramine	O
+.	O
+	
+Histamine	O
+release	O
+occurred	O
+in	O
+most	O
+patients	O
+","	O
+the	O
+highest	O
+level	O
+2	O
+minutes	O
+after	O
+d	O
+-	O
+tubocurarine	O
+dosing	O
+.	O
+	
+Group	O
+1	O
+had	O
+a	O
+moderate	O
+negative	O
+correlation	O
+between	O
+plasma	O
+histamine	O
+change	O
+and	O
+systemic	O
+vascular	O
+resistance	O
+(	O
+r	O
+=	O
+0	O
+.	O
+58	O
+;	O
+P	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+not	O
+present	O
+in	O
+group	O
+4	O
+.	O
+	
+Prior	O
+dosing	O
+with	O
+antagonists	O
+partially	O
+prevented	O
+the	O
+fall	O
+in	O
+systemic	O
+vascular	O
+resistance	O
+.	O
+	
+These	O
+data	O
+demonstrate	O
+that	O
+the	O
+hemodynamic	O
+changes	O
+associated	O
+with	O
+d	O
+-	O
+tubocurarine	O
+dosing	O
+are	O
+only	O
+partially	O
+explained	O
+by	O
+histamine	O
+release	O
+.	O
+	
+Thus	O
+prior	O
+dosing	O
+with	O
+H1	O
+-	O
+and	O
+H2	O
+-	O
+antagonists	O
+provides	O
+only	O
+partial	O
+protection	O
+.	O
+	
+Cholecystokinin	O
+-	O
+octapeptide	O
+restored	O
+morphine	O
+-	O
+induced	O
+hippocampal	O
+long	O
+-	O
+term	O
+potentiation	O
+impairment	O
+in	O
+rats	O
+.	O
+	
+Cholecystokinin	O
+-	O
+octapeptide	O
+(	O
+CCK	O
+-	O
+8	O
+)	O
+","	O
+which	O
+is	O
+a	O
+typical	O
+brain	O
+-	O
+gut	O
+peptide	O
+","	O
+exerts	O
+a	O
+wide	O
+range	O
+of	O
+biological	O
+activities	O
+on	O
+the	O
+central	O
+nervous	O
+system	O
+.	O
+	
+We	O
+have	O
+previously	O
+reported	O
+that	O
+CCK	O
+-	O
+8	O
+significantly	O
+alleviated	O
+morphine	O
+-	O
+induced	O
+amnesia	B-NP
+and	O
+reversed	O
+spine	O
+density	O
+decreases	O
+in	O
+the	O
+CA1	O
+region	O
+of	O
+the	O
+hippocampus	O
+in	O
+morphine	O
+-	O
+treated	O
+animals	O
+.	O
+	
+Here	O
+","	O
+we	O
+investigated	O
+the	O
+effects	O
+of	O
+CCK	O
+-	O
+8	O
+on	O
+long	O
+-	O
+term	O
+potentiation	O
+(	O
+LTP	O
+)	O
+in	O
+the	O
+lateral	O
+perforant	O
+path	O
+(	O
+LPP	O
+)	O
+-	O
+granule	O
+cell	O
+synapse	O
+of	O
+rat	O
+dentate	O
+gyrus	O
+(	O
+DG	O
+)	O
+in	O
+acute	O
+saline	O
+or	O
+morphine	O
+-	O
+treated	O
+rats	O
+.	O
+	
+Population	O
+spikes	O
+(	O
+PS	O
+)	O
+","	O
+which	O
+were	O
+evoked	O
+by	O
+stimulation	O
+of	O
+the	O
+LPP	O
+","	O
+were	O
+recorded	O
+in	O
+the	O
+DG	O
+region	O
+.	O
+	
+Acute	O
+morphine	O
+(	O
+30mg	O
+/	O
+kg	O
+","	O
+s	O
+.	O
+c	O
+.	O
+)	O
+treatment	O
+significantly	O
+attenuated	O
+hippocampal	O
+LTP	O
+and	O
+CCK	O
+-	O
+8	O
+(	O
+1ug	O
+","	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+restored	O
+the	O
+amplitude	O
+of	O
+PS	O
+that	O
+was	O
+attenuated	O
+by	O
+morphine	O
+injection	O
+.	O
+	
+Furthermore	O
+","	O
+microinjection	O
+of	O
+CCK	O
+-	O
+8	O
+(	O
+0	O
+.	O
+1	O
+and	O
+1ug	O
+","	O
+i	O
+.	O
+c	O
+.	O
+v	O
+.	O
+)	O
+also	O
+significantly	O
+augmented	O
+hippocampal	O
+LTP	O
+in	O
+saline	O
+-	O
+treated	O
+(	O
+1ml	O
+/	O
+kg	O
+","	O
+s	O
+.	O
+c	O
+.	O
+)	O
+rats	O
+.	O
+	
+Pre	O
+-	O
+treatment	O
+of	O
+the	O
+CCK2	O
+receptor	O
+antagonist	O
+L	O
+-	O
+365	O
+","	O
+260	O
+(	O
+10ug	O
+","	O
+i	O
+.	O
+c	O
+.	O
+v	O
+)	O
+reversed	O
+the	O
+effects	O
+of	O
+CCK	O
+-	O
+8	O
+","	O
+but	O
+the	O
+CCK1	O
+receptor	O
+antagonist	O
+L	O
+-	O
+364	O
+","	O
+718	O
+(	O
+10ug	O
+","	O
+i	O
+.	O
+c	O
+.	O
+v	O
+)	O
+did	O
+not	O
+.	O
+	
+The	O
+present	O
+results	O
+demonstrate	O
+that	O
+CCK	O
+-	O
+8	O
+attenuates	O
+the	O
+effect	O
+of	O
+morphine	O
+on	O
+hippocampal	O
+LTP	O
+through	O
+CCK2	O
+receptors	O
+and	O
+suggest	O
+an	O
+ameliorative	O
+function	O
+of	O
+CCK	O
+-	O
+8	O
+on	O
+morphine	O
+-	O
+induced	O
+memory	B-NP
+impairment	I-NP
+.	O
+	
+Glial	O
+activation	O
+and	O
+post	O
+-	O
+synaptic	O
+neurotoxicity	B-NP
+:	O
+the	O
+key	O
+events	O
+in	O
+Streptozotocin	O
+(	O
+ICV	O
+)	O
+induced	O
+memory	B-NP
+impairment	I-NP
+in	O
+rats	O
+.	O
+	
+In	O
+the	O
+present	O
+study	O
+the	O
+role	O
+of	O
+glial	O
+activation	O
+and	O
+post	O
+synaptic	O
+toxicity	B-NP
+in	O
+ICV	O
+Streptozotocin	O
+(	O
+STZ	O
+)	O
+induced	O
+memory	B-NP
+impaired	I-NP
+rats	O
+was	O
+explored	O
+.	O
+	
+In	O
+experiment	O
+set	O
+up	O
+1	O
+:	O
+Memory	B-NP
+deficit	I-NP
+was	O
+found	O
+in	O
+Morris	O
+water	O
+maze	O
+test	O
+on	O
+14	O
+-	O
+16	O
+days	O
+after	O
+STZ	O
+(	O
+ICV	O
+;	O
+3mg	O
+/	O
+Kg	O
+)	O
+administration	O
+.	O
+	
+STZ	O
+causes	O
+increased	O
+expression	O
+of	O
+GFAP	O
+","	O
+CD11b	O
+and	O
+TNF	O
+-	O
+a	O
+indicating	O
+glial	O
+activation	O
+and	O
+neuroinflammation	B-NP
+.	O
+	
+STZ	O
+also	O
+significantly	O
+increased	O
+the	O
+level	O
+of	O
+ROS	O
+","	O
+nitrite	O
+","	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+and	O
+reduced	O
+the	O
+mitochondrial	O
+activity	O
+in	O
+synaptosomal	O
+preparation	O
+illustrating	O
+free	O
+radical	O
+generation	O
+and	O
+excitotoxicity	B-NP
+.	O
+	
+Increased	O
+expression	O
+and	O
+activity	O
+of	O
+Caspase	O
+-	O
+3	O
+was	O
+also	O
+observed	O
+in	O
+STZ	O
+treated	O
+rat	O
+which	O
+specify	O
+apoptotic	O
+cell	O
+death	O
+in	O
+hippocampus	O
+and	O
+cortex	O
+.	O
+	
+STZ	O
+treatment	O
+showed	O
+decrease	O
+expression	O
+of	O
+post	O
+synaptic	O
+markers	O
+CaMKIIa	O
+and	O
+PSD	O
+-	O
+95	O
+","	O
+while	O
+","	O
+expression	O
+of	O
+pre	O
+synaptic	O
+markers	O
+(	O
+synaptophysin	O
+and	O
+SNAP	O
+-	O
+25	O
+)	O
+remains	O
+unaltered	O
+indicating	O
+selective	O
+post	O
+synaptic	O
+neurotoxicity	B-NP
+.	O
+	
+Oral	O
+treatment	O
+with	O
+Memantine	O
+(	O
+10mg	O
+/	O
+kg	O
+)	O
+and	O
+Ibuprofen	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+daily	O
+for	O
+13	O
+days	O
+attenuated	O
+STZ	O
+induced	O
+glial	O
+activation	O
+","	O
+apoptotic	O
+cell	O
+death	O
+and	O
+post	O
+synaptic	O
+neurotoxicity	B-NP
+in	O
+rat	O
+brain	O
+.	O
+	
+Further	O
+","	O
+in	O
+experiment	O
+set	O
+up	O
+2	O
+:	O
+where	O
+memory	O
+function	O
+was	O
+not	O
+affected	O
+i	O
+.	O
+e	O
+.	O
+7	O
+-	O
+9	O
+days	O
+after	O
+STZ	O
+treatment	O
+.	O
+	
+The	O
+level	O
+of	O
+GFAP	O
+","	O
+CD11b	O
+","	O
+TNF	O
+-	O
+a	O
+","	O
+ROS	O
+and	O
+nitrite	O
+levels	O
+were	O
+increased	O
+.	O
+	
+On	O
+the	O
+other	O
+hand	O
+","	O
+apoptotic	O
+marker	O
+","	O
+synaptic	O
+markers	O
+","	O
+mitochondrial	O
+activity	O
+and	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+levels	O
+remained	O
+unaffected	O
+.	O
+	
+Collective	O
+data	O
+indicates	O
+that	O
+neuroinflammatory	B-NP
+process	O
+and	O
+oxidative	O
+stress	O
+occurs	O
+earlier	O
+to	O
+apoptosis	O
+and	O
+does	O
+not	O
+affect	O
+memory	O
+function	O
+.	O
+	
+Present	O
+study	O
+clearly	O
+suggests	O
+that	O
+glial	O
+activation	O
+and	O
+post	O
+synaptic	O
+neurotoxicity	B-NP
+are	O
+the	O
+key	O
+factors	O
+in	O
+STZ	O
+induced	O
+memory	B-NP
+impairment	I-NP
+and	O
+neuronal	O
+cell	O
+death	O
+.	O
+	
+Comparison	O
+of	O
+effects	O
+of	O
+isotonic	O
+sodium	O
+chloride	O
+with	O
+diltiazem	O
+in	O
+prevention	O
+of	O
+contrast	O
+-	O
+induced	O
+nephropathy	B-NP
+.	O
+	
+INTRODUCTION	O
+AND	O
+OBJECTIVE	O
+:	O
+Contrast	O
+-	O
+induced	O
+nephropathy	B-NP
+(	O
+CIN	O
+)	O
+significantly	O
+increases	O
+the	O
+morbidity	O
+and	O
+mortality	O
+of	O
+patients	O
+.	O
+	
+The	O
+aim	O
+of	O
+this	O
+study	O
+is	O
+to	O
+investigate	O
+and	O
+compare	O
+the	O
+protective	O
+effects	O
+of	O
+isotonic	O
+sodium	O
+chloride	O
+with	O
+sodium	O
+bicarbonate	O
+infusion	O
+and	O
+isotonic	O
+sodium	O
+chloride	O
+infusion	O
+with	O
+diltiazem	O
+","	O
+a	O
+calcium	O
+channel	O
+blocker	O
+","	O
+in	O
+preventing	O
+CIN	O
+.	O
+	
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+Our	O
+study	O
+included	O
+patients	O
+who	O
+were	O
+administered	O
+30	O
+-	O
+60	O
+mL	O
+of	O
+iodinated	O
+contrast	O
+agent	O
+for	O
+percutaneous	O
+coronary	O
+angiography	O
+(	O
+PCAG	O
+)	O
+","	O
+all	O
+with	O
+creatinine	O
+values	O
+between	O
+1	O
+.	O
+1	O
+and	O
+3	O
+.	O
+1	O
+mg	O
+/	O
+dL	O
+.	O
+	
+Patients	O
+were	O
+divided	O
+into	O
+three	O
+groups	O
+and	O
+each	O
+group	O
+had	O
+20	O
+patients	O
+.	O
+	
+The	O
+first	O
+group	O
+of	O
+patients	O
+was	O
+administered	O
+isotonic	O
+sodium	O
+chloride	O
+;	O
+the	O
+second	O
+group	O
+was	O
+administered	O
+a	O
+solution	O
+that	O
+of	O
+5	O
+%	O
+dextrose	O
+and	O
+sodium	O
+bicarbonate	O
+","	O
+while	O
+the	O
+third	O
+group	O
+was	O
+administered	O
+isotonic	O
+sodium	O
+chloride	O
+before	O
+and	O
+after	O
+the	O
+contrast	O
+injection	O
+.	O
+	
+The	O
+third	O
+group	O
+received	O
+an	O
+additional	O
+injection	O
+of	O
+diltiazem	O
+the	O
+day	O
+before	O
+and	O
+first	O
+2	O
+days	O
+after	O
+the	O
+contrast	O
+injection	O
+.	O
+	
+All	O
+of	O
+the	O
+patients	O
+'	O
+plasma	O
+blood	O
+urea	O
+nitrogen	O
+(	O
+BUN	O
+)	O
+and	O
+creatinine	O
+levels	O
+were	O
+measured	O
+on	O
+the	O
+second	O
+and	O
+seventh	O
+day	O
+after	O
+the	O
+administration	O
+of	O
+intravenous	O
+contrast	O
+material	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+basal	O
+creatinine	O
+levels	O
+were	O
+similar	O
+for	O
+all	O
+three	O
+groups	O
+(	O
+p	O
+>	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+Among	O
+a	O
+total	O
+of	O
+60	O
+patients	O
+included	O
+in	O
+the	O
+study	O
+","	O
+16	O
+patients	O
+developed	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+(	O
+ARF	B-NP
+)	O
+on	O
+the	O
+second	O
+day	O
+after	O
+contrast	O
+material	O
+was	O
+injected	O
+(	O
+26	O
+.	O
+6	O
+%	O
+)	O
+.	O
+	
+The	O
+number	O
+of	O
+patients	O
+who	O
+developed	O
+ARF	B-NP
+on	O
+the	O
+second	O
+day	O
+after	O
+the	O
+injection	O
+in	O
+the	O
+first	O
+group	O
+was	O
+five	O
+(	O
+25	O
+%	O
+)	O
+","	O
+in	O
+the	O
+second	O
+group	O
+was	O
+six	O
+(	O
+30	O
+%	O
+)	O
+and	O
+the	O
+third	O
+group	O
+was	O
+five	O
+(	O
+25	O
+%	O
+)	O
+(	O
+p	O
+>	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+There	O
+was	O
+no	O
+significant	O
+difference	O
+between	O
+isotonic	O
+sodium	O
+chloride	O
+","	O
+sodium	O
+bicarbonate	O
+and	O
+isotonic	O
+sodium	O
+chloride	O
+with	O
+diltiazem	O
+application	O
+in	O
+prevention	O
+of	O
+CIN	O
+.	O
+	
+Neurocognitive	O
+and	O
+neuroradiologic	O
+central	O
+nervous	O
+system	O
+late	O
+effects	O
+in	O
+children	O
+treated	O
+on	O
+Pediatric	O
+Oncology	O
+Group	O
+(	O
+POG	O
+)	O
+P9605	O
+(	O
+standard	O
+risk	O
+)	O
+and	O
+P9201	O
+(	O
+lesser	O
+risk	O
+)	O
+acute	B-NP
+lymphoblastic	I-NP
+leukemia	I-NP
+protocols	O
+(	O
+ACCL0131	O
+)	O
+:	O
+a	O
+methotrexate	O
+consequence	O
+?	O
+	
+A	O
+report	O
+from	O
+the	O
+Children	O
+'	O
+s	O
+Oncology	O
+Group	O
+.	O
+	
+Concerns	O
+about	O
+long	O
+-	O
+term	O
+methotrexate	O
+(	O
+MTX	O
+)	O
+neurotoxicity	B-NP
+in	O
+the	O
+1990s	O
+led	O
+to	O
+modifications	O
+in	O
+intrathecal	O
+(	O
+IT	O
+)	O
+therapy	O
+","	O
+leucovorin	O
+rescue	O
+","	O
+and	O
+frequency	O
+of	O
+systemic	O
+MTX	O
+administration	O
+in	O
+children	O
+with	O
+acute	B-NP
+lymphoblastic	I-NP
+leukemia	I-NP
+.	O
+	
+In	O
+this	O
+study	O
+","	O
+neurocognitive	O
+outcomes	O
+and	O
+neuroradiologic	O
+evidence	O
+of	O
+leukoencephalopathy	B-NP
+were	O
+compared	O
+in	O
+children	O
+treated	O
+with	O
+intense	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+-	O
+directed	O
+therapy	O
+(	O
+P9605	O
+)	O
+versus	O
+those	O
+receiving	O
+fewer	O
+CNS	O
+-	O
+directed	O
+treatment	O
+days	O
+during	O
+intensive	O
+consolidation	O
+(	O
+P9201	O
+)	O
+.	O
+	
+A	O
+total	O
+of	O
+66	O
+children	O
+from	O
+16	O
+Pediatric	O
+Oncology	O
+Group	O
+institutions	O
+with	O
+"	O
+standard	O
+-	O
+risk	O
+"	O
+acute	B-NP
+lymphoblastic	I-NP
+leukemia	I-NP
+","	O
+1	O
+.	O
+0	O
+to	O
+9	O
+.	O
+99	O
+years	O
+at	O
+diagnosis	O
+","	O
+without	O
+evidence	O
+of	O
+CNS	O
+leukemia	B-NP
+at	O
+diagnosis	O
+were	O
+enrolled	O
+on	O
+ACCL0131	O
+:	O
+28	O
+from	O
+P9201	O
+and	O
+38	O
+from	O
+P9605	O
+.	O
+	
+Magnetic	O
+resonance	O
+imaging	O
+scans	O
+and	O
+standard	O
+neuropsychological	O
+tests	O
+were	O
+performed	O
+>	O
+2	O
+.	O
+6	O
+years	O
+after	O
+the	O
+end	O
+of	O
+treatment	O
+.	O
+	
+Significantly	O
+more	O
+P9605	O
+patients	O
+developed	O
+leukoencephalopathy	B-NP
+compared	O
+with	O
+P9201	O
+patients	O
+(	O
+68	O
+%	O
+","	O
+95	O
+%	O
+confidence	O
+interval	O
+49	O
+%	O
+-	O
+83	O
+%	O
+vs	O
+.	O
+22	O
+%	O
+","	O
+95	O
+%	O
+confidence	O
+interval	O
+5	O
+%	O
+-	O
+44	O
+%	O
+;	O
+P	O
+=	O
+0	O
+.	O
+1	O
+)	O
+identified	O
+as	O
+late	O
+as	O
+7	O
+.	O
+7	O
+years	O
+after	O
+the	O
+end	O
+of	O
+treatment	O
+.	O
+	
+Overall	O
+","	O
+40	O
+%	O
+of	O
+patients	O
+scored	O
+<	O
+85	O
+on	O
+either	O
+Verbal	O
+or	O
+Performance	O
+IQ	O
+.	O
+	
+Children	O
+on	O
+both	O
+studies	O
+had	O
+significant	O
+attention	B-NP
+problems	I-NP
+","	O
+but	O
+P9605	O
+children	O
+scored	O
+below	O
+average	O
+on	O
+more	O
+neurocognitive	O
+measures	O
+than	O
+those	O
+treated	O
+on	O
+P9201	O
+(	O
+82	O
+%	O
+","	O
+14	O
+/	O
+17	O
+measures	O
+vs	O
+.	O
+24	O
+%	O
+","	O
+4	O
+/	O
+17	O
+measures	O
+)	O
+.	O
+	
+This	O
+supports	O
+ongoing	O
+concerns	O
+about	O
+intensive	O
+MTX	O
+exposure	O
+as	O
+a	O
+major	O
+contributor	O
+to	O
+CNS	O
+late	O
+effects	O
+.	O
+	
+Tranexamic	O
+acid	O
+overdosage	O
+-	O
+induced	O
+generalized	O
+seizure	B-NP
+in	O
+renal	B-NP
+failure	I-NP
+.	O
+	
+We	O
+report	O
+a	O
+45	O
+-	O
+year	O
+-	O
+old	O
+lady	O
+with	O
+chronic	B-NP
+kidney	I-NP
+disease	I-NP
+stage	O
+4	O
+due	O
+to	O
+chronic	O
+tubulointerstial	B-NP
+disease	I-NP
+.	O
+	
+She	O
+was	O
+admitted	O
+to	O
+our	O
+center	O
+for	O
+severe	O
+anemia	B-NP
+due	O
+to	O
+menorrhagia	B-NP
+and	O
+deterioration	B-NP
+of	I-NP
+renal	I-NP
+function	I-NP
+.	O
+	
+She	O
+was	O
+infused	O
+three	O
+units	O
+of	O
+packed	O
+cells	O
+during	O
+a	O
+session	O
+of	O
+hemodialysis	O
+.	O
+	
+Tranexamic	O
+acid	O
+(	O
+TNA	O
+)	O
+1	O
+g	O
+8	O
+-	O
+hourly	O
+was	O
+administered	O
+to	O
+her	O
+to	O
+control	O
+bleeding	B-NP
+per	O
+vaginum	O
+.	O
+	
+Two	O
+hours	O
+after	O
+the	O
+sixth	O
+dose	O
+of	O
+TNA	O
+","	O
+she	O
+had	O
+an	O
+episode	O
+of	O
+generalized	O
+tonic	B-NP
+clonic	I-NP
+convulsions	I-NP
+.	O
+	
+TNA	O
+was	O
+discontinued	O
+.	O
+	
+Investigations	O
+of	O
+the	O
+patient	O
+revealed	O
+no	O
+biochemical	O
+or	O
+structural	O
+central	O
+nervous	B-NP
+system	I-NP
+abnormalities	I-NP
+that	O
+could	O
+have	O
+provoked	O
+the	O
+convulsions	B-NP
+.	O
+	
+She	O
+did	O
+not	O
+require	O
+any	O
+further	O
+dialytic	O
+support	O
+.	O
+	
+She	O
+had	O
+no	O
+further	O
+episodes	O
+of	O
+convulsion	B-NP
+till	O
+dis	O
+-	O
+charge	O
+and	O
+during	O
+the	O
+two	O
+months	O
+of	O
+follow	O
+-	O
+up	O
+.	O
+	
+Thus	O
+","	O
+the	O
+precipitating	O
+cause	O
+of	O
+convulsions	B-NP
+was	O
+believed	O
+to	O
+be	O
+an	O
+overdose	B-NP
+of	O
+TNA	O
+.	O
+	
+Pre	O
+-	O
+treatment	O
+of	O
+bupivacaine	O
+-	O
+induced	O
+cardiovascular	B-NP
+depression	I-NP
+using	O
+different	O
+lipid	O
+formulations	O
+of	O
+propofol	O
+.	O
+	
+BACKGROUND	O
+:	O
+Pre	O
+-	O
+treatment	O
+with	O
+lipid	O
+emulsions	O
+has	O
+been	O
+shown	O
+to	O
+increase	O
+lethal	O
+doses	O
+of	O
+bupivacaine	O
+","	O
+and	O
+the	O
+lipid	O
+content	O
+of	O
+propofol	O
+may	O
+alleviate	O
+bupivacaine	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+.	O
+	
+The	O
+aim	O
+of	O
+this	O
+study	O
+is	O
+to	O
+investigate	O
+the	O
+effects	O
+of	O
+propofol	O
+in	O
+intralipid	O
+or	O
+medialipid	O
+emulsions	O
+on	O
+bupivacaine	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+.	O
+	
+METHODS	O
+:	O
+Rats	O
+were	O
+anaesthetised	O
+with	O
+ketamine	O
+and	O
+were	O
+given	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+/	O
+min	O
+propofol	O
+in	O
+intralipid	O
+(	O
+Group	O
+P	O
+)	O
+","	O
+propofol	O
+in	O
+medialipid	O
+(	O
+Group	O
+L	O
+)	O
+","	O
+or	O
+saline	O
+(	O
+Group	O
+C	O
+)	O
+over	O
+20	O
+min	O
+.	O
+	
+Thereafter	O
+","	O
+2	O
+mg	O
+/	O
+kg	O
+/	O
+min	O
+bupivacaine	O
+0	O
+.	O
+5	O
+%	O
+was	O
+infused	O
+.	O
+	
+We	O
+recorded	O
+time	O
+to	O
+first	O
+dysrhythmia	B-NP
+occurrence	O
+","	O
+respective	O
+times	O
+to	O
+25	O
+%	O
+and	O
+50	O
+%	O
+reduction	O
+of	O
+the	O
+heart	O
+rate	O
+(	O
+HR	O
+)	O
+and	O
+mean	O
+arterial	O
+pressure	O
+","	O
+and	O
+time	O
+to	O
+asystole	B-NP
+and	O
+total	O
+amount	O
+of	O
+bupivacaine	O
+consumption	O
+.	O
+	
+Blood	O
+and	O
+tissue	O
+samples	O
+were	O
+collected	O
+following	O
+asystole	B-NP
+.	O
+	
+RESULTS	O
+:	O
+The	O
+time	O
+to	O
+first	O
+dysrhythmia	B-NP
+occurrence	O
+","	O
+time	O
+to	O
+25	O
+%	O
+and	O
+50	O
+%	O
+reductions	O
+in	O
+HR	O
+","	O
+and	O
+time	O
+to	O
+asystole	B-NP
+were	O
+longer	O
+in	O
+Group	O
+P	O
+than	O
+the	O
+other	O
+groups	O
+.	O
+	
+The	O
+cumulative	O
+bupivacaine	O
+dose	O
+given	O
+at	O
+those	O
+time	O
+points	O
+was	O
+higher	O
+in	O
+Group	O
+P	O
+.	O
+Plasma	O
+bupivacaine	O
+levels	O
+were	O
+significantly	O
+lower	O
+in	O
+Group	O
+P	O
+than	O
+in	O
+Group	O
+C	O
+.	O
+Bupivacaine	O
+levels	O
+in	O
+the	O
+brain	O
+and	O
+heart	O
+were	O
+significantly	O
+lower	O
+in	O
+Group	O
+P	O
+and	O
+Group	O
+L	O
+than	O
+in	O
+Group	O
+C	O
+.	O
+	
+CONCLUSION	O
+:	O
+We	O
+conclude	O
+that	O
+pre	O
+-	O
+treatment	O
+with	O
+propofol	O
+in	O
+intralipid	O
+","	O
+compared	O
+with	O
+propofol	O
+in	O
+medialipid	O
+or	O
+saline	O
+","	O
+delayed	O
+the	O
+onset	O
+of	O
+bupivacaine	O
+-	O
+induced	O
+cardiotoxic	B-NP
+effects	O
+as	O
+well	O
+as	O
+reduced	O
+plasma	O
+bupivacaine	O
+levels	O
+.	O
+	
+Further	O
+studies	O
+are	O
+needed	O
+to	O
+explore	O
+tissue	O
+bupivacaine	O
+levels	O
+of	O
+propofol	O
+in	O
+medialipid	O
+and	O
+adapt	O
+these	O
+results	O
+to	O
+clinical	O
+practice	O
+.	O
+	
+Drug	B-NP
+-	I-NP
+Induced	I-NP
+Acute	I-NP
+Liver	I-NP
+Injury	I-NP
+Within	O
+12	O
+Hours	O
+After	O
+Fluvastatin	O
+Therapy	O
+.	O
+	
+Although	O
+statins	O
+are	O
+generally	O
+well	O
+-	O
+tolerated	O
+drugs	O
+","	O
+recent	O
+cases	O
+of	O
+drug	B-NP
+-	I-NP
+induced	I-NP
+liver	I-NP
+injury	I-NP
+associated	O
+with	O
+their	O
+use	O
+have	O
+been	O
+reported	O
+.	O
+	
+A	O
+52	O
+-	O
+year	O
+-	O
+old	O
+Chinese	O
+man	O
+reported	O
+with	O
+liver	B-NP
+damage	I-NP
+","	O
+which	O
+appeared	O
+12	O
+hours	O
+after	O
+beginning	O
+treatment	O
+with	O
+fluvastatin	O
+.	O
+	
+Patient	O
+presented	O
+with	O
+complaints	O
+of	O
+increasing	O
+nausea	B-NP
+","	O
+anorexia	B-NP
+","	O
+and	O
+upper	O
+abdominal	B-NP
+pain	I-NP
+.	O
+	
+His	O
+laboratory	O
+values	O
+showed	O
+elevated	O
+creatine	O
+kinase	O
+and	O
+transaminases	O
+.	O
+	
+Testing	O
+for	O
+autoantibodies	O
+was	O
+also	O
+negative	O
+.	O
+	
+The	O
+liver	O
+biochemistries	O
+eventually	O
+normalized	O
+within	O
+3	O
+weeks	O
+of	O
+stopping	O
+the	O
+fluvastatin	O
+.	O
+	
+Therefore	O
+","	O
+when	O
+prescribing	O
+statins	O
+","	O
+the	O
+possibility	O
+of	O
+hepatic	B-NP
+damage	I-NP
+should	O
+be	O
+taken	O
+into	O
+account	O
+.	O
+	
+Fluconazole	O
+associated	O
+agranulocytosis	B-NP
+and	O
+thrombocytopenia	B-NP
+.	O
+	
+CASE	O
+:	O
+We	O
+describe	O
+a	O
+second	O
+case	O
+of	O
+fluconazole	O
+associated	O
+agranulocytosis	B-NP
+with	O
+thrombocytopenia	B-NP
+and	O
+recovery	O
+upon	O
+discontinuation	O
+of	O
+therapy	O
+.	O
+	
+The	O
+patient	O
+began	O
+to	O
+have	O
+changes	O
+in	O
+white	O
+blood	O
+cells	O
+and	O
+platelets	O
+within	O
+48	O
+h	O
+of	O
+administration	O
+of	O
+fluconazole	O
+and	O
+began	O
+to	O
+recover	O
+with	O
+48	O
+h	O
+of	O
+discontinuation	O
+.	O
+	
+This	O
+case	O
+highlights	O
+that	O
+drug	O
+-	O
+induced	O
+blood	B-NP
+dyscrasias	I-NP
+can	O
+occur	O
+unexpectedly	O
+as	O
+a	O
+result	O
+of	O
+treatment	O
+with	O
+a	O
+commonly	O
+used	O
+drug	O
+thought	O
+to	O
+be	O
+"	O
+safe	O
+"	O
+.	O
+	
+CONCLUSION	O
+:	O
+According	O
+to	O
+Naranjo	O
+'	O
+s	O
+algorithm	O
+the	O
+likelihood	O
+that	O
+our	O
+patient	O
+'	O
+s	O
+agranulocytosis	B-NP
+and	O
+thrombocytopenia	B-NP
+occurred	O
+as	O
+a	O
+result	O
+of	O
+therapy	O
+with	O
+fluconazole	O
+is	O
+probable	O
+","	O
+with	O
+a	O
+total	O
+of	O
+six	O
+points	O
+.	O
+	
+We	O
+feel	O
+that	O
+the	O
+weight	O
+of	O
+the	O
+overall	O
+evidence	O
+of	O
+this	O
+evidence	O
+is	O
+strong	O
+.	O
+	
+In	O
+particular	O
+the	O
+temporal	O
+relationship	O
+of	O
+bone	B-NP
+marrow	I-NP
+suppression	I-NP
+to	O
+the	O
+initiation	O
+of	O
+fluconazole	O
+and	O
+the	O
+abatement	O
+of	O
+symptoms	O
+that	O
+rapidly	O
+reversed	O
+immediately	O
+following	O
+discontinuation	O
+.	O
+	
+Two	O
+-	O
+dimensional	O
+speckle	O
+tracking	O
+echocardiography	O
+combined	O
+with	O
+high	O
+-	O
+sensitive	O
+cardiac	O
+troponin	O
+T	O
+in	O
+early	O
+detection	O
+and	O
+prediction	O
+of	O
+cardiotoxicity	B-NP
+during	O
+epirubicine	O
+-	O
+based	O
+chemotherapy	O
+.	O
+	
+AIMS	O
+:	O
+To	O
+investigate	O
+whether	O
+alterations	O
+of	O
+myocardial	B-NP
+strain	I-NP
+and	O
+high	O
+-	O
+sensitive	O
+cardiac	O
+troponin	O
+T	O
+(	O
+cTnT	O
+)	O
+could	O
+predict	O
+future	O
+cardiac	B-NP
+dysfunction	I-NP
+in	O
+patients	O
+after	O
+epirubicin	O
+exposure	O
+.	O
+	
+METHODS	O
+:	O
+Seventy	O
+-	O
+five	O
+patients	O
+with	O
+non	B-NP
+-	I-NP
+Hodgkin	I-NP
+lymphoma	I-NP
+treated	O
+with	O
+epirubicin	O
+were	O
+studied	O
+.	O
+	
+Blood	O
+collection	O
+and	O
+echocardiography	O
+were	O
+performed	O
+at	O
+baseline	O
+","	O
+1	O
+day	O
+after	O
+the	O
+third	O
+cycle	O
+","	O
+and	O
+1	O
+day	O
+after	O
+completion	O
+of	O
+chemotherapy	O
+.	O
+	
+Patients	O
+were	O
+studied	O
+using	O
+echocardiography	O
+during	O
+follow	O
+-	O
+up	O
+.	O
+	
+Global	O
+longitudinal	O
+(	O
+GLS	O
+)	O
+","	O
+circumferential	O
+(	O
+GCS	O
+)	O
+","	O
+and	O
+radial	O
+strain	O
+(	O
+GRS	O
+)	O
+were	O
+calculated	O
+using	O
+speckle	O
+tracking	O
+echocardiography	O
+.	O
+	
+Left	O
+ventricular	O
+ejection	O
+fraction	O
+was	O
+analysed	O
+by	O
+real	O
+-	O
+time	O
+3D	O
+echocardiography	O
+.	O
+	
+Cardiotoxicity	B-NP
+was	O
+defined	O
+as	O
+a	O
+reduction	O
+of	O
+the	O
+LVEF	O
+of	O
+>	O
+5	O
+%	O
+to	O
+<	O
+55	O
+%	O
+with	O
+symptoms	O
+of	O
+heart	B-NP
+failure	I-NP
+or	O
+an	O
+asymptomatic	O
+reduction	O
+of	O
+the	O
+LVEF	O
+of	O
+>	O
+10	O
+%	O
+to	O
+<	O
+55	O
+%	O
+.	O
+	
+RESULTS	O
+:	O
+Fourteen	O
+patients	O
+(	O
+18	O
+.	O
+67	O
+%	O
+)	O
+developed	O
+cardiotoxicity	B-NP
+after	O
+treatment	O
+.	O
+	
+GLS	O
+(	O
+-	O
+18	O
+.	O
+48	O
++	O
+1	O
+.	O
+72	O
+%	O
+vs	O
+.	O
+-	O
+15	O
+.	O
+96	O
++	O
+1	O
+.	O
+6	O
+%	O
+)	O
+","	O
+GCS	O
+(	O
+-	O
+20	O
+.	O
+93	O
++	O
+2	O
+.	O
+86	O
+%	O
+vs	O
+.	O
+-	O
+19	O
+.	O
+20	O
++	O
+3	O
+.	O
+21	O
+%	O
+)	O
+","	O
+and	O
+GRS	O
+(	O
+39	O
+.	O
+23	O
++	O
+6	O
+.	O
+44	O
+%	O
+vs	O
+.	O
+34	O
+.	O
+98	O
++	O
+6	O
+.	O
+2	O
+%	O
+)	O
+were	O
+markedly	O
+reduced	O
+and	O
+cTnT	O
+was	O
+elevated	O
+from	O
+0	O
+.	O
+10	O
++	O
+0	O
+.	O
+20	O
+to	O
+0	O
+.	O
+73	O
++	O
+0	O
+.	O
+38	O
+ng	O
+/	O
+mL	O
+(	O
+P	O
+all	O
+<	O
+0	O
+.	O
+1	O
+)	O
+at	O
+the	O
+completion	O
+of	O
+chemotherapy	O
+compared	O
+with	O
+baseline	O
+values	O
+.	O
+	
+A	O
+>	O
+15	O
+.	O
+9	O
+%	O
+decrease	O
+in	O
+GLS	O
+[	O
+sensitivity	O
+","	O
+86	O
+%	O
+;	O
+specificity	O
+","	O
+75	O
+%	O
+;	O
+area	O
+under	O
+the	O
+curve	O
+(	O
+AUC	O
+)	O
+=	O
+0	O
+.	O
+815	O
+;	O
+P	O
+=	O
+0	O
+.	O
+1	O
+]	O
+and	O
+a	O
+>	O
+0	O
+.	O
+4	O
+ng	O
+/	O
+mL	O
+elevation	O
+in	O
+cTnT	O
+(	O
+sensitivity	O
+","	O
+79	O
+%	O
+;	O
+specificity	O
+","	O
+64	O
+%	O
+;	O
+AUC	O
+=	O
+0	O
+.	O
+757	O
+;	O
+P	O
+=	O
+0	O
+.	O
+5	O
+)	O
+from	O
+baseline	O
+to	O
+the	O
+third	O
+cycle	O
+of	O
+chemotherapy	O
+predicted	O
+later	O
+cardiotoxicity	B-NP
+.	O
+	
+The	O
+decrease	O
+in	O
+GLS	O
+remained	O
+the	O
+only	O
+independent	O
+predictor	O
+of	O
+cardiotoxicity	B-NP
+(	O
+P	O
+=	O
+0	O
+.	O
+0	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+GLS	O
+combined	O
+with	O
+cTnT	O
+may	O
+provide	O
+a	O
+reliable	O
+and	O
+non	O
+-	O
+invasive	O
+method	O
+to	O
+predict	O
+cardiac	B-NP
+dysfunction	I-NP
+in	O
+patients	O
+receiving	O
+anthracycline	O
+-	O
+based	O
+chemotherapy	O
+.	O
+	
+Prevention	O
+of	O
+etomidate	O
+-	O
+induced	O
+myoclonus	B-NP
+:	O
+which	O
+is	O
+superior	O
+:	O
+Fentanyl	O
+","	O
+midazolam	O
+","	O
+or	O
+a	O
+combination	O
+?	O
+	
+A	O
+Retrospective	O
+comparative	O
+study	O
+.	O
+	
+BACKGROUND	O
+:	O
+In	O
+this	O
+retrospective	O
+comparative	O
+study	O
+","	O
+we	O
+aimed	O
+to	O
+compare	O
+the	O
+effectiveness	O
+of	O
+fentanyl	O
+","	O
+midazolam	O
+","	O
+and	O
+a	O
+combination	O
+of	O
+fentanyl	O
+and	O
+midazolam	O
+to	O
+prevent	O
+etomidate	O
+-	O
+induced	O
+myoclonus	B-NP
+.	O
+	
+MATERIAL	O
+AND	O
+METHODS	O
+:	O
+This	O
+study	O
+was	O
+performed	O
+based	O
+on	O
+anesthesia	O
+records	O
+.	O
+	
+Depending	O
+on	O
+the	O
+drugs	O
+that	O
+would	O
+be	O
+given	O
+before	O
+the	O
+induction	O
+of	O
+anesthesia	O
+with	O
+etomidate	O
+","	O
+the	O
+patients	O
+were	O
+separated	O
+into	O
+4	O
+groups	O
+:	O
+no	O
+pretreatment	O
+(	O
+Group	O
+NP	O
+)	O
+","	O
+fentanyl	O
+1	O
+ug	O
+.	O
+kg	O
+-	O
+1	O
+(	O
+Group	O
+F	O
+)	O
+","	O
+midazolam	O
+0	O
+.	O
+3	O
+mg	O
+.	O
+kg	O
+-	O
+1	O
+(	O
+Group	O
+M	O
+)	O
+","	O
+and	O
+midazolam	O
+0	O
+.	O
+15	O
+mg	O
+.	O
+kg	O
+-	O
+1	O
++	O
+fentanyl	O
+0	O
+.	O
+5	O
+ug	O
+.	O
+kg	O
+-	O
+1	O
+(	O
+Group	O
+FM	O
+)	O
+.	O
+	
+Patients	O
+who	O
+received	O
+the	O
+same	O
+anesthetic	O
+procedure	O
+were	O
+selected	O
+:	O
+2	O
+minutes	O
+after	O
+intravenous	O
+injections	O
+of	O
+the	O
+pretreatment	O
+drugs	O
+","	O
+anesthesia	O
+is	O
+induced	O
+with	O
+0	O
+.	O
+3	O
+mg	O
+.	O
+kg	O
+-	O
+1	O
+etomidate	O
+injected	O
+intravenously	O
+over	O
+a	O
+period	O
+of	O
+20	O
+-	O
+30	O
+seconds	O
+.	O
+	
+Myoclonic	B-NP
+movements	I-NP
+are	O
+evaluated	O
+","	O
+which	O
+were	O
+observed	O
+and	O
+graded	O
+according	O
+to	O
+clinical	O
+severity	O
+during	O
+the	O
+2	O
+minutes	O
+after	O
+etomidate	O
+injection	O
+.	O
+	
+The	O
+severity	O
+of	O
+pain	B-NP
+due	O
+to	O
+etomidate	O
+injection	O
+","	O
+mean	O
+arterial	O
+pressure	O
+","	O
+heart	O
+rate	O
+","	O
+and	O
+adverse	O
+effects	O
+were	O
+also	O
+evaluated	O
+.	O
+	
+RESULTS	O
+:	O
+Study	O
+results	O
+showed	O
+that	O
+myoclonus	B-NP
+incidence	O
+was	O
+85	O
+%	O
+","	O
+40	O
+%	O
+","	O
+70	O
+%	O
+","	O
+and	O
+25	O
+%	O
+in	O
+Group	O
+NP	O
+","	O
+Group	O
+F	O
+","	O
+Group	O
+M	O
+","	O
+and	O
+Group	O
+FM	O
+","	O
+respectively	O
+","	O
+and	O
+were	O
+significantly	O
+lower	O
+in	O
+Group	O
+F	O
+and	O
+Group	O
+FM	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+We	O
+conclude	O
+that	O
+pretreatment	O
+with	O
+fentanyl	O
+or	O
+combination	O
+of	O
+fentanyl	O
+and	O
+midazolam	O
+was	O
+effective	O
+in	O
+preventing	O
+etomidate	O
+-	O
+induced	O
+myoclonus	B-NP
+.	O
+	
+Convulsant	O
+effect	O
+of	O
+lindane	O
+and	O
+regional	O
+brain	O
+concentration	O
+of	O
+GABA	O
+and	O
+dopamine	O
+.	O
+	
+Lindane	O
+(	O
+gamma	O
+-	O
+hexachlorocyclohexane	O
+)	O
+is	O
+an	O
+organochlorine	O
+insecticide	O
+with	O
+known	O
+neurotoxic	B-NP
+effects	O
+.	O
+	
+Its	O
+mechanism	O
+of	O
+action	O
+is	O
+not	O
+well	O
+understood	O
+although	O
+it	O
+has	O
+been	O
+proposed	O
+that	O
+lindane	O
+acts	O
+as	O
+a	O
+non	O
+-	O
+competitive	O
+antagonist	O
+at	O
+the	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+(	O
+GABA	O
+)	O
+-	O
+A	O
+receptor	O
+.	O
+	
+We	O
+studied	O
+the	O
+effect	O
+of	O
+lindane	O
+(	O
+150	O
+mg	O
+/	O
+kg	O
+)	O
+on	O
+the	O
+GABAergic	O
+and	O
+dopaminergic	O
+systems	O
+by	O
+measuring	O
+the	O
+concentration	O
+of	O
+GABA	O
+","	O
+dopamine	O
+and	O
+its	O
+metabolites	O
+in	O
+7	O
+brain	O
+areas	O
+at	O
+the	O
+onset	O
+of	O
+seizures	B-NP
+.	O
+	
+All	O
+animals	O
+suffered	O
+tonic	O
+convulsions	B-NP
+at	O
+18	O
+.	O
+3	O
++	O
+/	O
+-	O
+1	O
+.	O
+4	O
+min	O
+after	O
+lindane	O
+administration	O
+.	O
+	
+The	O
+concentration	O
+of	O
+GABA	O
+was	O
+only	O
+slightly	O
+but	O
+significantly	O
+decreased	O
+in	O
+the	O
+colliculi	O
+without	O
+modifications	O
+in	O
+the	O
+other	O
+areas	O
+.	O
+	
+The	O
+concentration	O
+of	O
+dopamine	O
+was	O
+increased	O
+in	O
+the	O
+mesencephalon	O
+and	O
+that	O
+of	O
+its	O
+metabolite	O
+DOPAC	O
+was	O
+also	O
+increased	O
+in	O
+the	O
+mesencephalon	O
+and	O
+the	O
+striatum	O
+.	O
+	
+Cholestatic	B-NP
+presentation	O
+of	O
+yellow	O
+phosphorus	O
+poisoning	B-NP
+.	O
+	
+Yellow	O
+phosphorus	O
+","	O
+a	O
+component	O
+of	O
+certain	O
+pesticide	O
+pastes	O
+and	O
+fireworks	O
+","	O
+is	O
+well	O
+known	O
+to	O
+cause	O
+hepatotoxicity	B-NP
+.	O
+	
+Poisoning	B-NP
+with	O
+yellow	O
+phosphorus	O
+classically	O
+manifests	O
+with	O
+acute	B-NP
+hepatitis	I-NP
+leading	O
+to	O
+acute	B-NP
+liver	I-NP
+failure	I-NP
+which	O
+may	O
+need	O
+liver	O
+transplantation	O
+.	O
+	
+We	O
+present	O
+a	O
+case	O
+of	O
+yellow	O
+phosphorus	O
+poisoning	B-NP
+in	O
+which	O
+a	O
+patient	O
+presented	O
+with	O
+florid	O
+clinical	O
+features	O
+of	O
+cholestasis	B-NP
+highlighting	O
+the	O
+fact	O
+that	O
+cholestasis	B-NP
+can	O
+rarely	O
+be	O
+a	O
+presenting	O
+feature	O
+of	O
+yellow	O
+phosphorus	O
+hepatotoxicity	B-NP
+.	O
+	
+Vasovagal	B-NP
+syncope	I-NP
+and	O
+severe	O
+bradycardia	B-NP
+following	O
+intranasal	O
+dexmedetomidine	O
+for	O
+pediatric	O
+procedural	O
+sedation	O
+.	O
+	
+We	O
+report	O
+syncope	B-NP
+and	O
+bradycardia	B-NP
+in	O
+an	O
+11	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+following	O
+administration	O
+of	O
+intranasal	O
+dexmedetomidine	O
+for	O
+sedation	O
+for	O
+a	O
+voiding	O
+cystourethrogram	O
+.	O
+	
+Following	O
+successful	O
+completion	O
+of	O
+VCUG	O
+and	O
+a	O
+60	O
+-	O
+min	O
+recovery	O
+period	O
+","	O
+the	O
+patient	O
+'	O
+s	O
+level	O
+of	O
+consciousness	O
+and	O
+vital	O
+signs	O
+returned	O
+to	O
+presedation	O
+levels	O
+.	O
+	
+Upon	O
+leaving	O
+the	O
+sedation	O
+area	O
+","	O
+the	O
+patient	O
+collapsed	O
+","	O
+with	O
+no	O
+apparent	O
+inciting	O
+event	O
+.	O
+	
+The	O
+patient	O
+quickly	O
+regained	O
+consciousness	O
+and	O
+no	O
+injury	O
+occurred	O
+.	O
+	
+The	O
+primary	O
+abnormality	O
+found	O
+was	O
+persistent	O
+bradycardia	B-NP
+","	O
+and	O
+she	O
+was	O
+admitted	O
+to	O
+the	O
+hospital	O
+for	O
+telemetric	O
+observation	O
+.	O
+	
+The	O
+bradycardia	B-NP
+lasted	O
+~	O
+2	O
+h	O
+","	O
+and	O
+further	O
+cardiac	O
+workup	O
+revealed	O
+no	O
+underlying	O
+abnormality	O
+.	O
+	
+Unanticipated	O
+and	O
+previously	O
+unreported	O
+outcomes	O
+may	O
+be	O
+witnessed	O
+as	O
+we	O
+expand	O
+the	O
+use	O
+of	O
+certain	O
+sedatives	O
+to	O
+alternative	O
+routes	O
+of	O
+administration	O
+.	O
+	
+Paradoxical	O
+severe	O
+agitation	B-NP
+induced	O
+by	O
+add	O
+-	O
+on	O
+high	O
+-	O
+doses	O
+quetiapine	O
+in	O
+schizo	B-NP
+-	I-NP
+affective	I-NP
+disorder	I-NP
+.	O
+	
+We	O
+report	O
+the	O
+case	O
+of	O
+a	O
+35	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+suffering	O
+from	O
+schizo	B-NP
+-	I-NP
+affective	I-NP
+disorder	I-NP
+since	O
+the	O
+age	O
+of	O
+19	O
+years	O
+","	O
+treated	O
+by	O
+a	O
+combination	O
+of	O
+first	O
+-	O
+generation	O
+antipsychotics	O
+","	O
+zuclopenthixol	O
+(	O
+100	O
+mg	O
+/	O
+day	O
+)	O
+and	O
+lithium	O
+(	O
+1200	O
+mg	O
+/	O
+day	O
+)	O
+(	O
+serum	O
+lithium	O
+=	O
+0	O
+.	O
+85	O
+mEq	O
+/	O
+l	O
+)	O
+.	O
+	
+This	O
+patient	O
+had	O
+no	O
+associated	O
+personality	B-NP
+disorder	I-NP
+(	O
+particularly	O
+no	O
+antisocial	B-NP
+disorder	I-NP
+)	O
+and	O
+no	O
+substance	B-NP
+abuse	I-NP
+disorder	I-NP
+.	O
+	
+Within	O
+the	O
+48	O
+h	O
+following	O
+the	O
+gradual	O
+introduction	O
+of	O
+quetiapine	O
+(	O
+up	O
+to	O
+600	O
+mg	O
+/	O
+day	O
+)	O
+","	O
+the	O
+patient	O
+presented	O
+severe	O
+agitation	B-NP
+without	O
+an	O
+environmental	O
+explanation	O
+","	O
+contrasting	O
+with	O
+the	O
+absence	O
+of	O
+a	O
+history	O
+of	O
+aggressiveness	B-NP
+or	O
+personality	B-NP
+disorder	I-NP
+.	O
+	
+The	O
+diagnoses	O
+of	O
+manic	B-NP
+shift	O
+and	O
+akathisia	B-NP
+were	O
+dismissed	O
+.	O
+	
+The	O
+withdrawal	O
+and	O
+the	O
+gradual	O
+reintroduction	O
+of	O
+quetiapine	O
+2	O
+weeks	O
+later	O
+","	O
+which	O
+led	O
+to	O
+another	O
+severe	O
+agitation	B-NP
+","	O
+enabled	O
+us	O
+to	O
+attribute	O
+the	O
+agitation	B-NP
+specifically	O
+to	O
+quetiapine	O
+.	O
+	
+Antioxidant	O
+effects	O
+of	O
+bovine	O
+lactoferrin	O
+on	O
+dexamethasone	O
+-	O
+induced	O
+hypertension	B-NP
+in	O
+rat	O
+.	O
+	
+Dexamethasone	O
+-	O
+(	O
+Dex	O
+-	O
+)	O
+induced	O
+hypertension	B-NP
+is	O
+associated	O
+with	O
+enhanced	O
+oxidative	O
+stress	O
+.	O
+	
+Lactoferrin	O
+(	O
+LF	O
+)	O
+is	O
+an	O
+iron	O
+-	O
+binding	O
+glycoprotein	O
+with	O
+antihypertensive	O
+properties	O
+.	O
+	
+In	O
+this	O
+study	O
+","	O
+we	O
+investigated	O
+the	O
+effect	O
+of	O
+chronic	O
+administration	O
+of	O
+LF	O
+on	O
+oxidative	O
+stress	O
+and	O
+hypertension	B-NP
+upon	O
+Dex	O
+administration	O
+.	O
+	
+Male	O
+Wistar	O
+rats	O
+were	O
+treated	O
+by	O
+Dex	O
+(	O
+30	O
+u	O
+g	O
+/	O
+kg	O
+/	O
+day	O
+subcutaneously	O
+)	O
+or	O
+saline	O
+for	O
+14	O
+days	O
+.	O
+	
+Oral	O
+bovine	O
+LF	O
+(	O
+30	O
+","	O
+100	O
+","	O
+300	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+given	O
+from	O
+day	O
+8	O
+to	O
+14	O
+in	O
+a	O
+reversal	O
+study	O
+.	O
+	
+In	O
+a	O
+prevention	O
+study	O
+","	O
+rats	O
+received	O
+4	O
+days	O
+of	O
+LF	O
+treatment	O
+followed	O
+by	O
+Dex	O
+and	O
+continued	O
+during	O
+the	O
+test	O
+period	O
+.	O
+	
+Systolic	O
+blood	O
+pressure	O
+(	O
+SBP	O
+)	O
+was	O
+measured	O
+using	O
+tail	O
+-	O
+cuff	O
+method	O
+.	O
+	
+Thymus	O
+weight	O
+was	O
+used	O
+as	O
+a	O
+marker	O
+of	O
+glucocorticoid	O
+activity	O
+.	O
+	
+Plasma	O
+hydrogen	O
+peroxide	O
+(	O
+H2O2	O
+)	O
+concentration	O
+and	O
+ferric	O
+reducing	O
+antioxidant	O
+power	O
+(	O
+FRAP	O
+)	O
+value	O
+were	O
+determined	O
+.	O
+	
+Dexamethasone	O
+significantly	O
+increased	O
+SBP	O
+and	O
+plasma	O
+H2O2	O
+level	O
+and	O
+decreased	O
+thymus	O
+and	O
+body	O
+weights	O
+.	O
+	
+LF	O
+lowered	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+and	O
+dose	O
+dependently	O
+prevented	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+Dex	O
+-	O
+induced	O
+hypertension	B-NP
+.	O
+	
+LF	O
+prevented	O
+body	O
+weight	B-NP
+loss	I-NP
+and	O
+significantly	O
+reduced	O
+the	O
+elevated	O
+plasma	O
+H2O2	O
+and	O
+increased	O
+FRAP	O
+values	O
+.	O
+	
+Chronic	O
+administration	O
+of	O
+LF	O
+strongly	O
+reduced	O
+the	O
+blood	O
+pressure	O
+and	O
+production	O
+of	O
+ROS	O
+and	O
+improved	O
+antioxidant	O
+capacity	O
+in	O
+Dex	O
+-	O
+induced	O
+hypertension	B-NP
+","	O
+suggesting	O
+the	O
+role	O
+of	O
+inhibition	O
+of	O
+oxidative	O
+stress	O
+as	O
+another	O
+mechanism	O
+of	O
+antihypertensive	O
+action	O
+of	O
+LF	O
+.	O
+	
+The	O
+association	O
+between	O
+tranexamic	O
+acid	O
+and	O
+convulsive	B-NP
+seizures	B-NP
+after	O
+cardiac	O
+surgery	O
+:	O
+a	O
+multivariate	O
+analysis	O
+in	O
+11	O
+529	O
+patients	O
+.	O
+	
+Because	O
+of	O
+a	O
+lack	O
+of	O
+contemporary	O
+data	O
+regarding	O
+seizures	B-NP
+after	O
+cardiac	O
+surgery	O
+","	O
+we	O
+undertook	O
+a	O
+retrospective	O
+analysis	O
+of	O
+prospectively	O
+collected	O
+data	O
+from	O
+11	O
+529	O
+patients	O
+in	O
+whom	O
+cardiopulmonary	O
+bypass	O
+was	O
+used	O
+from	O
+January	O
+2004	O
+to	O
+December	O
+2010	O
+.	O
+	
+A	O
+convulsive	B-NP
+seizure	B-NP
+was	O
+defined	O
+as	O
+a	O
+transient	O
+episode	O
+of	O
+disturbed	O
+brain	O
+function	O
+characterised	O
+by	O
+abnormal	B-NP
+involuntary	I-NP
+motor	I-NP
+movements	I-NP
+.	O
+	
+Multivariate	O
+regression	O
+analysis	O
+was	O
+performed	O
+to	O
+identify	O
+independent	O
+predictors	O
+of	O
+postoperative	O
+seizures	B-NP
+.	O
+	
+A	O
+total	O
+of	O
+100	O
+(	O
+0	O
+.	O
+9	O
+%	O
+)	O
+patients	O
+developed	O
+postoperative	O
+convulsive	B-NP
+seizures	B-NP
+.	O
+	
+Generalised	B-NP
+and	I-NP
+focal	I-NP
+seizures	I-NP
+were	O
+identified	O
+in	O
+68	O
+and	O
+32	O
+patients	O
+","	O
+respectively	O
+.	O
+	
+The	O
+median	O
+(	O
+IQR	O
+[	O
+range	O
+]	O
+)	O
+time	O
+after	O
+surgery	O
+when	O
+the	O
+seizure	B-NP
+occurred	O
+was	O
+7	O
+(	O
+6	O
+-	O
+12	O
+[	O
+1	O
+-	O
+216	O
+]	O
+)	O
+h	O
+and	O
+8	O
+(	O
+6	O
+-	O
+11	O
+[	O
+4	O
+-	O
+18	O
+]	O
+)	O
+h	O
+","	O
+respectively	O
+.	O
+	
+Epileptiform	O
+findings	O
+on	O
+electroencephalography	O
+were	O
+seen	O
+in	O
+19	O
+patients	O
+.	O
+	
+Independent	O
+predictors	O
+of	O
+postoperative	O
+seizures	B-NP
+included	O
+age	O
+","	O
+female	O
+sex	O
+","	O
+redo	O
+cardiac	O
+surgery	O
+","	O
+calcification	O
+of	O
+ascending	O
+aorta	O
+","	O
+congestive	B-NP
+heart	I-NP
+failure	I-NP
+","	O
+deep	O
+hypothermic	B-NP
+circulatory	O
+arrest	O
+","	O
+duration	O
+of	O
+aortic	O
+cross	O
+-	O
+clamp	O
+and	O
+tranexamic	O
+acid	O
+.	O
+	
+When	O
+tested	O
+in	O
+a	O
+multivariate	O
+regression	O
+analysis	O
+","	O
+tranexamic	O
+acid	O
+was	O
+a	O
+strong	O
+independent	O
+predictor	O
+of	O
+seizures	B-NP
+(	O
+OR	O
+14	O
+.	O
+3	O
+","	O
+95	O
+%	O
+CI	O
+5	O
+.	O
+5	O
+-	O
+36	O
+.	O
+7	O
+;	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Patients	O
+with	O
+convulsive	B-NP
+seizures	B-NP
+had	O
+2	O
+.	O
+5	O
+times	O
+higher	O
+in	O
+-	O
+hospital	O
+mortality	O
+rates	O
+and	O
+twice	O
+the	O
+length	O
+of	O
+hospital	O
+stay	O
+compared	O
+with	O
+patients	O
+without	O
+convulsive	B-NP
+seizures	B-NP
+.	O
+	
+Mean	O
+(	O
+IQR	O
+[	O
+range	O
+]	O
+)	O
+length	O
+of	O
+stay	O
+in	O
+the	O
+intensive	O
+care	O
+unit	O
+was	O
+115	O
+(	O
+49	O
+-	O
+228	O
+[	O
+32	O
+-	O
+481	O
+]	O
+)	O
+h	O
+in	O
+patients	O
+with	O
+convulsive	B-NP
+seizures	B-NP
+compared	O
+with	O
+26	O
+(	O
+22	O
+-	O
+69	O
+[	O
+14	O
+-	O
+1080	O
+]	O
+)	O
+h	O
+in	O
+patients	O
+without	O
+seizures	B-NP
+(	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Convulsive	B-NP
+seizures	B-NP
+are	O
+a	O
+serious	O
+postoperative	B-NP
+complication	I-NP
+after	O
+cardiac	O
+surgery	O
+.	O
+	
+As	O
+tranexamic	O
+acid	O
+is	O
+the	O
+only	O
+modifiable	O
+factor	O
+","	O
+its	O
+administration	O
+","	O
+particularly	O
+in	O
+doses	O
+exceeding	O
+80	O
+mg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+","	O
+should	O
+be	O
+weighed	O
+against	O
+the	O
+risk	O
+of	O
+postoperative	O
+seizures	B-NP
+.	O
+	
+Dysfunctional	B-NP
+overnight	I-NP
+memory	I-NP
+consolidation	O
+in	O
+ecstasy	O
+users	O
+.	O
+	
+Sleep	O
+plays	O
+an	O
+important	O
+role	O
+in	O
+the	O
+consolidation	O
+and	O
+integration	O
+of	O
+memory	O
+in	O
+a	O
+process	O
+called	O
+overnight	O
+memory	O
+consolidation	O
+.	O
+	
+Previous	O
+studies	O
+indicate	O
+that	O
+ecstasy	O
+users	O
+have	O
+marked	O
+and	O
+persistent	O
+neurocognitive	O
+and	O
+sleep	B-NP
+-	I-NP
+related	I-NP
+impairments	I-NP
+.	O
+	
+We	O
+extend	O
+past	O
+research	O
+by	O
+examining	O
+overnight	O
+memory	O
+consolidation	O
+among	O
+regular	O
+ecstasy	O
+users	O
+(	O
+n	O
+=	O
+12	O
+)	O
+and	O
+drug	O
+naive	O
+healthy	O
+controls	O
+(	O
+n	O
+=	O
+26	O
+)	O
+.	O
+	
+Memory	O
+recall	O
+of	O
+word	O
+pairs	O
+was	O
+evaluated	O
+before	O
+and	O
+after	O
+a	O
+period	O
+of	O
+sleep	O
+","	O
+with	O
+and	O
+without	O
+interference	O
+prior	O
+to	O
+testing	O
+.	O
+	
+In	O
+addition	O
+","	O
+we	O
+assessed	O
+neurocognitive	O
+performances	O
+across	O
+tasks	O
+of	O
+learning	O
+","	O
+memory	O
+and	O
+executive	O
+functioning	O
+.	O
+	
+Ecstasy	O
+users	O
+demonstrated	O
+impaired	B-NP
+overnight	I-NP
+memory	I-NP
+consolidation	O
+","	O
+a	O
+finding	O
+that	O
+was	O
+more	O
+pronounced	O
+following	O
+associative	O
+interference	O
+.	O
+	
+Additionally	O
+","	O
+ecstasy	O
+users	O
+demonstrated	O
+impairments	O
+on	O
+tasks	O
+recruiting	O
+frontostriatal	O
+and	O
+hippocampal	O
+neural	O
+circuitry	O
+","	O
+in	O
+the	O
+domains	O
+of	O
+proactive	O
+interference	O
+memory	O
+","	O
+long	O
+-	O
+term	O
+memory	O
+","	O
+encoding	O
+","	O
+working	O
+memory	O
+and	O
+complex	O
+planning	O
+.	O
+	
+We	O
+suggest	O
+that	O
+ecstasy	O
+-	O
+associated	O
+dysfunction	O
+in	O
+fronto	O
+-	O
+temporal	O
+circuitry	O
+may	O
+underlie	O
+overnight	O
+consolidation	O
+memory	B-NP
+impairments	I-NP
+in	O
+regular	O
+ecstasy	O
+users	O
+.	O
+	
+Normoammonemic	O
+encephalopathy	B-NP
+:	O
+solely	O
+valproate	O
+induced	O
+or	O
+multiple	O
+mechanisms	O
+?	O
+	
+A	O
+77	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+presented	O
+with	O
+subacute	O
+onset	O
+progressive	O
+confusion	B-NP
+","	O
+aggression	B-NP
+","	O
+auditory	B-NP
+hallucinations	I-NP
+and	O
+delusions	B-NP
+.	O
+	
+In	O
+the	O
+preceding	O
+months	O
+","	O
+the	O
+patient	O
+had	O
+a	O
+number	O
+of	O
+admissions	O
+with	O
+transient	O
+unilateral	O
+hemiparesis	B-NP
+with	O
+facial	O
+droop	O
+","	O
+and	O
+had	O
+been	O
+started	O
+on	O
+valproate	O
+for	O
+presumed	O
+hemiplegic	B-NP
+migraine	I-NP
+.	O
+	
+Valproate	O
+was	O
+withdrawn	O
+soon	O
+after	O
+admission	O
+and	O
+her	O
+cognitive	O
+abilities	O
+have	O
+gradually	O
+improved	O
+over	O
+3	O
+months	O
+of	O
+follow	O
+-	O
+up	O
+.	O
+	
+Valproate	O
+levels	O
+taken	O
+prior	O
+to	O
+withdrawal	O
+were	O
+subtherapeutic	O
+and	O
+the	O
+patient	O
+was	O
+normoammonaemic	O
+.	O
+	
+EEG	O
+undertaken	O
+during	O
+inpatient	O
+stay	O
+showed	O
+changes	O
+consistent	O
+with	O
+encephalopathy	B-NP
+","	O
+and	O
+low	O
+titre	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+receptor	O
+antibodies	O
+were	O
+present	O
+in	O
+this	O
+patient	O
+.	O
+	
+The	O
+possible	O
+aetiologies	O
+of	O
+valproate	O
+-	O
+induced	O
+encephalopathy	B-NP
+and	O
+NMDA	O
+receptor	O
+-	O
+associated	O
+encephalitis	B-NP
+present	O
+a	O
+diagnostic	O
+dilemma	O
+.	O
+	
+We	O
+present	O
+a	O
+putative	O
+combinatorial	O
+hypothesis	O
+to	O
+explain	O
+this	O
+patient	O
+'	O
+s	O
+symptoms	O
+.	O
+	
+Cerebellar	B-NP
+and	I-NP
+oculomotor	I-NP
+dysfunction	I-NP
+induced	O
+by	O
+rapid	O
+infusion	O
+of	O
+pethidine	O
+.	O
+	
+Pethidine	O
+is	O
+an	O
+opioid	O
+that	O
+gains	O
+its	O
+popularity	O
+for	O
+the	O
+effective	O
+pain	B-NP
+control	O
+through	O
+acting	O
+on	O
+the	O
+opioid	O
+-	O
+receptors	O
+.	O
+	
+However	O
+","	O
+rapid	O
+pain	B-NP
+relief	O
+sometimes	O
+brings	O
+about	O
+unfavourable	O
+side	O
+effects	O
+that	O
+largely	O
+limit	O
+its	O
+clinical	O
+utility	O
+.	O
+	
+Common	O
+side	O
+effects	O
+include	O
+nausea	B-NP
+","	O
+vomiting	B-NP
+and	O
+hypotension	B-NP
+.	O
+	
+In	O
+patients	O
+with	O
+impaired	B-NP
+renal	I-NP
+and	I-NP
+liver	I-NP
+function	I-NP
+","	O
+and	O
+those	O
+who	O
+need	O
+long	O
+-	O
+term	O
+pain	B-NP
+control	O
+","	O
+pethidine	O
+may	O
+cause	O
+excitatory	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+effects	O
+through	O
+its	O
+neurotoxic	B-NP
+metabolite	O
+","	O
+norpethidine	O
+","	O
+resulting	O
+in	O
+irritability	B-NP
+and	O
+seizure	B-NP
+attack	O
+.	O
+	
+On	O
+the	O
+contrary	O
+","	O
+though	O
+not	O
+clinically	O
+apparent	O
+","	O
+pethidine	O
+potentially	O
+causes	O
+inhibitory	O
+impacts	O
+on	O
+the	O
+CNS	O
+and	O
+impairs	O
+normal	O
+cerebellar	O
+and	O
+oculomotor	O
+function	O
+in	O
+the	O
+short	O
+term	O
+.	O
+	
+In	O
+this	O
+case	O
+report	O
+","	O
+we	O
+highlight	O
+opioid	O
+'	O
+s	O
+inhibitory	O
+side	O
+effects	O
+on	O
+the	O
+cerebellar	O
+structure	O
+that	O
+causes	O
+dysmetria	B-NP
+","	O
+dysarthria	B-NP
+","	O
+reduced	O
+smooth	O
+pursuit	O
+gain	O
+and	O
+decreased	O
+saccadic	O
+velocity	O
+.	O
+	
+Baboon	B-NP
+syndrome	I-NP
+induced	O
+by	O
+ketoconazole	O
+.	O
+	
+A	O
+27	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+presented	O
+with	O
+a	O
+maculopapular	B-NP
+eruption	I-NP
+on	O
+the	O
+flexural	O
+areas	O
+and	O
+buttocks	O
+after	O
+using	O
+oral	O
+ketoconazole	O
+.	O
+	
+The	O
+patient	O
+was	O
+diagnosed	O
+with	O
+drug	O
+-	O
+induced	O
+baboon	B-NP
+syndrome	I-NP
+based	O
+on	O
+his	O
+history	O
+","	O
+which	O
+included	O
+prior	O
+sensitivity	O
+to	O
+topical	O
+ketoconazole	O
+","	O
+a	O
+physical	O
+examination	O
+","	O
+and	O
+histopathological	O
+findings	O
+.	O
+	
+Baboon	B-NP
+syndrome	I-NP
+is	O
+a	O
+drug	O
+-	O
+or	O
+contact	O
+allergen	O
+-	O
+related	O
+maculopapular	B-NP
+eruption	I-NP
+that	O
+typically	O
+involves	O
+the	O
+flexural	O
+and	O
+gluteal	O
+areas	O
+.	O
+	
+To	O
+the	O
+best	O
+of	O
+our	O
+knowledge	O
+","	O
+this	O
+is	O
+the	O
+first	O
+reported	O
+case	O
+of	O
+ketoconazole	O
+-	O
+induced	O
+baboon	B-NP
+syndrome	I-NP
+in	O
+the	O
+English	O
+literature	O
+.	O
+	
+A	O
+Case	O
+of	O
+Sudden	B-NP
+Cardiac	I-NP
+Death	I-NP
+due	O
+to	O
+Pilsicainide	O
+-	O
+Induced	O
+Torsades	B-NP
+de	I-NP
+Pointes	I-NP
+.	O
+	
+An	O
+84	O
+-	O
+year	O
+-	O
+old	O
+male	O
+received	O
+oral	O
+pilsicainide	O
+","	O
+a	O
+pure	O
+sodium	O
+channel	O
+blocker	O
+with	O
+slow	O
+recovery	O
+kinetics	O
+","	O
+to	O
+convert	O
+his	O
+paroxysmal	O
+atrial	B-NP
+fibrillation	I-NP
+to	O
+a	O
+sinus	O
+rhythm	O
+;	O
+the	O
+patient	O
+developed	O
+sudden	B-NP
+cardiac	I-NP
+death	I-NP
+two	O
+days	O
+later	O
+.	O
+	
+The	O
+Holter	O
+electrocardiogram	O
+","	O
+which	O
+was	O
+worn	O
+by	O
+chance	O
+","	O
+revealed	O
+torsade	B-NP
+de	I-NP
+pointes	I-NP
+with	O
+gradually	O
+prolonged	O
+QT	O
+intervals	O
+.	O
+	
+This	O
+drug	O
+is	O
+rapidly	O
+absorbed	O
+from	O
+the	O
+gastrointestinal	O
+tract	O
+","	O
+and	O
+most	O
+of	O
+it	O
+is	O
+excreted	O
+from	O
+the	O
+kidney	O
+.	O
+	
+Although	O
+the	O
+patient	O
+'	O
+s	O
+renal	O
+function	O
+was	O
+not	O
+highly	O
+impaired	O
+and	O
+the	O
+dose	O
+of	O
+pilsicainide	O
+was	O
+low	O
+","	O
+the	O
+plasma	O
+concentration	O
+of	O
+pilsicainide	O
+may	O
+have	O
+been	O
+high	O
+","	O
+which	O
+can	O
+produce	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+in	O
+the	O
+octogenarian	O
+.	O
+	
+Although	O
+the	O
+oral	O
+administration	O
+of	O
+class	O
+IC	O
+drugs	O
+","	O
+including	O
+pilsicainide	O
+","	O
+is	O
+effective	O
+to	O
+terminate	O
+atrial	B-NP
+fibrillation	I-NP
+","	O
+careful	O
+consideration	O
+must	O
+be	O
+taken	O
+before	O
+giving	O
+these	O
+drugs	O
+to	O
+octogenarians	O
+.	O
+	
+All	O
+-	O
+trans	O
+retinoic	O
+acid	O
+-	O
+induced	O
+inflammatory	O
+myositis	B-NP
+in	O
+a	O
+patient	O
+with	O
+acute	B-NP
+promyelocytic	I-NP
+leukemia	I-NP
+.	O
+	
+All	O
+-	O
+trans	O
+retinoic	O
+acid	O
+(	O
+ATRA	O
+)	O
+","	O
+a	O
+component	O
+of	O
+standard	O
+therapy	O
+for	O
+acute	B-NP
+promyelocytic	I-NP
+leukemia	I-NP
+(	O
+APL	B-NP
+)	O
+","	O
+is	O
+associated	O
+with	O
+potentially	O
+serious	O
+but	O
+treatable	O
+adverse	O
+effects	O
+involving	O
+numerous	O
+organ	O
+systems	O
+","	O
+including	O
+rare	O
+skeletal	O
+muscle	O
+involvement	O
+.	O
+	
+Only	O
+a	O
+handful	O
+of	O
+cases	O
+of	O
+ATRA	O
+-	O
+induced	O
+myositis	B-NP
+in	O
+children	O
+have	O
+been	O
+reported	O
+","	O
+and	O
+none	O
+in	O
+the	O
+radiology	O
+literature	O
+.	O
+	
+We	O
+present	O
+such	O
+a	O
+case	O
+in	O
+a	O
+15	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+with	O
+APL	B-NP
+","	O
+where	O
+recognition	O
+of	O
+imaging	O
+findings	O
+played	O
+a	O
+crucial	O
+role	O
+in	O
+making	O
+the	O
+diagnosis	O
+and	O
+facilitated	O
+prompt	O
+","	O
+effective	O
+treatment	O
+.	O
+	
+Tolerability	O
+of	O
+lomustine	O
+in	O
+combination	O
+with	O
+cyclophosphamide	O
+in	O
+dogs	O
+with	O
+lymphoma	B-NP
+.	O
+	
+This	O
+retrospective	O
+study	O
+describes	O
+toxicity	B-NP
+associated	O
+with	O
+a	O
+protocol	O
+of	O
+lomustine	O
+(	O
+CCNU	O
+)	O
+and	O
+cyclophosphamide	O
+(	O
+CTX	O
+)	O
+in	O
+dogs	O
+with	O
+lymphoma	B-NP
+.	O
+	
+CCNU	O
+was	O
+administered	O
+per	O
+os	O
+(	O
+PO	O
+)	O
+at	O
+a	O
+targeted	O
+dosage	O
+of	O
+60	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+body	O
+surface	O
+area	O
+on	O
+day	O
+0	O
+","	O
+CTX	O
+was	O
+administered	O
+PO	O
+at	O
+a	O
+targeted	O
+dosage	O
+of	O
+250	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+divided	O
+over	O
+days	O
+0	O
+through	O
+4	O
+","	O
+and	O
+all	O
+dogs	O
+received	O
+prophylactic	O
+antibiotics	O
+.	O
+	
+Ninety	O
+treatments	O
+were	O
+given	O
+to	O
+the	O
+57	O
+dogs	O
+included	O
+in	O
+the	O
+study	O
+.	O
+	
+Neutropenia	B-NP
+was	O
+the	O
+principal	O
+toxic	O
+effect	O
+","	O
+and	O
+the	O
+overall	O
+frequency	O
+of	O
+grade	O
+4	O
+neutropenia	B-NP
+after	O
+the	O
+first	O
+treatment	O
+of	O
+CCNU	O
+/	O
+CTX	O
+was	O
+30	O
+%	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+","	O
+19	O
+-	O
+43	O
+%	O
+)	O
+.	O
+	
+The	O
+mean	O
+body	O
+weight	O
+of	O
+dogs	O
+with	O
+grade	O
+4	O
+neutropenia	B-NP
+(	O
+19	O
+.	O
+7	O
+kg	O
++	O
+13	O
+.	O
+4	O
+kg	O
+)	O
+was	O
+significantly	O
+less	O
+than	O
+the	O
+mean	O
+body	O
+weight	O
+of	O
+dogs	O
+that	O
+did	O
+not	O
+develop	O
+grade	O
+4	O
+neutropenia	B-NP
+(	O
+31	O
+.	O
+7	O
+kg	O
++	O
+12	O
+.	O
+4	O
+kg	O
+;	O
+P	O
+=	O
+.	O
+5	O
+)	O
+.	O
+	
+One	O
+dog	O
+(	O
+3	O
+%	O
+)	O
+developed	O
+hematologic	O
+changes	O
+suggestive	O
+of	O
+hepatotoxicity	B-NP
+.	O
+	
+No	O
+dogs	O
+had	O
+evidence	O
+of	O
+either	O
+renal	B-NP
+toxicity	I-NP
+or	O
+hemorrhagic	B-NP
+cystitis	I-NP
+.	O
+	
+Adverse	O
+gastrointestinal	O
+effects	O
+were	O
+uncommon	O
+.	O
+	
+On	O
+the	O
+basis	O
+of	O
+the	O
+findings	O
+reported	O
+herein	O
+","	O
+a	O
+dose	O
+of	O
+60	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+of	O
+CCNU	O
+combined	O
+with	O
+250	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+of	O
+CTX	O
+(	O
+divided	O
+over	O
+5	O
+days	O
+)	O
+q	O
+4	O
+wk	O
+is	O
+tolerable	O
+in	O
+tumor	B-NP
+-	O
+bearing	O
+dogs	O
+.	O
+	
+Nelarabine	O
+neurotoxicity	B-NP
+with	O
+concurrent	O
+intrathecal	O
+chemotherapy	O
+:	O
+Case	O
+report	O
+and	O
+review	O
+of	O
+literature	O
+.	O
+	
+Severe	O
+nelarabine	O
+neurotoxicity	B-NP
+in	O
+a	O
+patient	O
+who	O
+received	O
+concurrent	O
+intrathecal	O
+(	O
+IT	O
+)	O
+chemotherapy	O
+is	O
+reported	O
+.	O
+	
+A	O
+37	O
+-	O
+year	O
+-	O
+old	O
+Caucasian	O
+woman	O
+with	O
+a	O
+history	O
+of	O
+T	B-NP
+-	I-NP
+cell	I-NP
+lymphoblastic	I-NP
+lymphoma	I-NP
+was	O
+admitted	O
+for	O
+relapsed	O
+disease	O
+.	O
+	
+She	O
+was	O
+originally	O
+treated	O
+with	O
+induction	O
+chemotherapy	O
+followed	O
+by	O
+an	O
+autologous	O
+transplant	O
+.	O
+	
+She	O
+developed	O
+relapsed	O
+disease	O
+10	O
+months	O
+later	O
+with	O
+leukemic	B-NP
+involvement	O
+.	O
+	
+She	O
+was	O
+re	O
+-	O
+induced	O
+with	O
+nelarabine	O
+1500	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+on	O
+days	O
+1	O
+","	O
+3	O
+","	O
+and	O
+5	O
+with	O
+1	O
+dose	O
+of	O
+IT	O
+cytarabine	O
+100	O
+mg	O
+on	O
+day	O
+2	O
+as	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+prophylaxis	O
+.	O
+	
+At	O
+the	O
+time	O
+of	O
+treatment	O
+","	O
+she	O
+was	O
+on	O
+continuous	O
+renal	O
+replacement	O
+therapy	O
+due	O
+to	O
+sequelae	O
+of	O
+tumor	B-NP
+lysis	I-NP
+syndrome	I-NP
+(	O
+TLS	B-NP
+)	O
+.	O
+	
+She	O
+tolerated	O
+therapy	O
+well	O
+","	O
+entered	O
+a	O
+complete	O
+remission	O
+","	O
+and	O
+recovered	O
+her	O
+renal	O
+function	O
+.	O
+	
+She	O
+received	O
+a	O
+second	O
+cycle	O
+of	O
+nelarabine	O
+without	O
+additional	O
+IT	O
+prophylaxis	O
+one	O
+month	O
+later	O
+.	O
+	
+A	O
+week	O
+after	O
+this	O
+second	O
+cycle	O
+","	O
+she	O
+noted	O
+numbness	O
+in	O
+her	O
+lower	O
+extremities	O
+.	O
+	
+Predominantly	O
+sensory	O
+","	O
+though	O
+also	O
+motor	O
+and	O
+autonomic	O
+","	O
+peripheral	B-NP
+neuropathy	I-NP
+started	O
+in	O
+her	O
+feet	O
+","	O
+ascended	O
+proximally	O
+to	O
+the	O
+mid	O
+-	O
+thoracic	O
+region	O
+","	O
+and	O
+eventually	O
+included	O
+her	O
+distal	O
+upper	O
+extremities	O
+.	O
+	
+A	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+of	O
+her	O
+spine	O
+demonstrated	O
+changes	O
+from	O
+C2	O
+to	O
+C6	O
+consistent	O
+with	O
+subacute	O
+combined	O
+degeneration	O
+.	O
+	
+Nelarabine	O
+was	O
+felt	O
+to	O
+be	O
+the	O
+cause	O
+of	O
+her	O
+symptoms	O
+.	O
+	
+Her	O
+neuropathy	B-NP
+stabilized	O
+and	O
+showed	O
+slight	O
+improvement	O
+and	O
+ultimately	O
+received	O
+an	O
+unrelated	O
+","	O
+reduced	O
+-	O
+intensity	O
+allogeneic	O
+transplant	O
+while	O
+in	O
+complete	O
+remission	O
+","	O
+but	O
+relapsed	O
+disease	O
+10	O
+weeks	O
+later	O
+.	O
+	
+She	O
+is	O
+currently	O
+being	O
+treated	O
+with	O
+best	O
+supportive	O
+care	O
+.	O
+	
+To	O
+our	O
+knowledge	O
+","	O
+this	O
+is	O
+the	O
+first	O
+published	O
+case	O
+report	O
+of	O
+severe	O
+neurotoxicity	B-NP
+caused	O
+by	O
+nelarabine	O
+in	O
+a	O
+patient	O
+who	O
+received	O
+concurrent	O
+IT	O
+chemotherapy	O
+.	O
+	
+Valproate	O
+-	O
+induced	O
+hyperammonemic	B-NP
+encephalopathy	B-NP
+in	O
+a	O
+renal	O
+transplanted	O
+patient	O
+.	O
+	
+Neurological	B-NP
+complications	I-NP
+after	O
+renal	O
+transplantation	O
+constitute	O
+an	O
+important	O
+cause	O
+of	O
+morbidity	O
+and	O
+mortality	O
+.	O
+	
+Their	O
+differential	O
+diagnosis	O
+is	O
+difficult	O
+and	O
+essential	O
+for	O
+subsequent	O
+patient	O
+'	O
+s	O
+management	O
+.	O
+	
+Valproate	O
+-	O
+induced	O
+hyperammonemic	B-NP
+encephalopathy	B-NP
+is	O
+an	O
+uncommon	O
+but	O
+serious	O
+effect	O
+of	O
+valproate	O
+treatment	O
+.	O
+	
+Here	O
+","	O
+we	O
+describe	O
+the	O
+case	O
+of	O
+a	O
+15	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+who	O
+was	O
+on	O
+a	O
+long	O
+-	O
+term	O
+therapy	O
+with	O
+valproate	O
+due	O
+to	O
+epilepsy	B-NP
+and	O
+revealed	O
+impaired	B-NP
+consciousness	I-NP
+with	O
+hyperammonemia	B-NP
+12	O
+days	O
+after	O
+renal	O
+transplantation	O
+.	O
+	
+After	O
+withdraw	O
+of	O
+valproate	O
+","	O
+patients	O
+'	O
+symptoms	O
+resolved	O
+within	O
+24	O
+h	O
+.	O
+	
+Clinicians	O
+should	O
+increase	O
+their	O
+awareness	O
+for	O
+potential	O
+complication	O
+of	O
+valproate	O
+","	O
+especially	O
+in	O
+transplanted	O
+patients	O
+.	O
+	
+Necrotising	B-NP
+fasciitis	I-NP
+after	O
+bortezomib	O
+and	O
+dexamethasone	O
+-	O
+containing	O
+regimen	O
+in	O
+an	O
+elderly	O
+patient	O
+of	O
+Waldenstrom	B-NP
+macroglobulinaemia	I-NP
+.	O
+	
+Bortezomib	O
+and	O
+high	O
+-	O
+dose	O
+dexamethasone	O
+-	O
+containing	O
+regimens	O
+are	O
+considered	O
+to	O
+be	O
+generally	O
+tolerable	O
+with	O
+few	O
+severe	O
+bacterial	B-NP
+infections	I-NP
+in	O
+patients	O
+with	O
+B	O
+-	O
+cell	O
+malignancies	B-NP
+.	O
+	
+However	O
+","	O
+information	O
+is	O
+limited	O
+concerning	O
+the	O
+safety	O
+of	O
+the	O
+regimen	O
+in	O
+elderly	O
+patients	O
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+a	O
+76	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+Waldenstrom	B-NP
+macroglobulinaemia	I-NP
+who	O
+suffered	O
+necrotising	B-NP
+fasciitis	I-NP
+without	O
+neutropenia	B-NP
+after	O
+the	O
+combination	O
+treatment	O
+with	O
+bortezomib	O
+","	O
+high	O
+-	O
+dose	O
+dexamethasone	O
+and	O
+rituximab	O
+.	O
+	
+Despite	O
+immediate	O
+intravenous	O
+antimicrobial	O
+therapy	O
+","	O
+he	O
+succumbed	O
+23	O
+h	O
+after	O
+the	O
+onset	O
+.	O
+	
+Physicians	O
+should	O
+recognise	O
+the	O
+possibility	O
+of	O
+fatal	O
+bacterial	B-NP
+infections	I-NP
+related	O
+to	O
+bortezomib	O
+plus	O
+high	O
+-	O
+dose	O
+dexamethasone	O
+in	O
+elderly	O
+patients	O
+","	O
+and	O
+we	O
+believe	O
+this	O
+case	O
+warrants	O
+further	O
+investigation	O
+.	O
+	
+An	O
+integrated	O
+characterization	O
+of	O
+serological	O
+","	O
+pathological	O
+","	O
+and	O
+functional	O
+events	O
+in	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+.	O
+	
+Many	O
+efficacious	O
+cancer	B-NP
+treatments	O
+cause	O
+significant	O
+cardiac	O
+morbidity	O
+","	O
+yet	O
+biomarkers	O
+or	O
+functional	O
+indices	O
+of	O
+early	O
+damage	O
+","	O
+which	O
+would	O
+allow	O
+monitoring	O
+and	O
+intervention	O
+","	O
+are	O
+lacking	O
+.	O
+	
+In	O
+this	O
+study	O
+","	O
+we	O
+have	O
+utilized	O
+a	O
+rat	O
+model	O
+of	O
+progressive	O
+doxorubicin	O
+(	O
+DOX	O
+)	O
+-	O
+induced	O
+cardiomyopathy	B-NP
+","	O
+applying	O
+multiple	O
+approaches	O
+","	O
+including	O
+cardiac	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+","	O
+to	O
+provide	O
+the	O
+most	O
+comprehensive	O
+characterization	O
+to	O
+date	O
+of	O
+the	O
+timecourse	O
+of	O
+serological	O
+","	O
+pathological	O
+","	O
+and	O
+functional	O
+events	O
+underlying	O
+this	O
+toxicity	B-NP
+.	O
+	
+Hannover	O
+Wistar	O
+rats	O
+were	O
+dosed	O
+with	O
+1	O
+.	O
+25	O
+mg	O
+/	O
+kg	O
+DOX	O
+weekly	O
+for	O
+8	O
+weeks	O
+followed	O
+by	O
+a	O
+4	O
+week	O
+off	O
+-	O
+dosing	O
+"	O
+recovery	O
+"	O
+period	O
+.	O
+	
+Electron	O
+microscopy	O
+of	O
+the	O
+myocardium	O
+revealed	O
+subcellular	B-NP
+degeneration	I-NP
+and	O
+marked	O
+mitochondrial	O
+changes	O
+after	O
+a	O
+single	O
+dose	O
+.	O
+	
+Histopathological	O
+analysis	O
+revealed	O
+progressive	O
+cardiomyocyte	B-NP
+degeneration	I-NP
+","	O
+hypertrophy	B-NP
+/	O
+cytomegaly	O
+","	O
+and	O
+extensive	O
+vacuolation	O
+after	O
+two	O
+doses	O
+.	O
+	
+Extensive	O
+replacement	O
+fibrosis	B-NP
+(	O
+quantified	O
+by	O
+Sirius	O
+red	O
+staining	O
+)	O
+developed	O
+during	O
+the	O
+off	O
+-	O
+dosing	O
+period	O
+.	O
+	
+Functional	O
+indices	O
+assessed	O
+by	O
+cardiac	O
+MRI	O
+(	O
+including	O
+left	O
+ventricular	O
+ejection	O
+fraction	O
+(	O
+LVEF	O
+)	O
+","	O
+cardiac	O
+output	O
+","	O
+and	O
+E	O
+/	O
+A	O
+ratio	O
+)	O
+declined	O
+progressively	O
+","	O
+reaching	O
+statistical	O
+significance	O
+after	O
+two	O
+doses	O
+and	O
+culminating	O
+in	O
+"	O
+clinical	O
+"	O
+LV	B-NP
+dysfunction	I-NP
+by	O
+12	O
+weeks	O
+.	O
+	
+Significant	O
+increases	O
+in	O
+peak	O
+myocardial	O
+contrast	O
+enhancement	O
+and	O
+serological	O
+cardiac	O
+troponin	O
+I	O
+(	O
+cTnI	O
+)	O
+emerged	O
+after	O
+eight	O
+doses	O
+","	O
+importantly	O
+preceding	O
+the	O
+LVEF	O
+decline	O
+to	O
+<	O
+50	O
+%	O
+.	O
+	
+Troponin	O
+I	O
+levels	O
+positively	O
+correlated	O
+with	O
+delayed	O
+and	O
+peak	O
+gadolinium	O
+contrast	O
+enhancement	O
+","	O
+histopathological	O
+grading	O
+","	O
+and	O
+diastolic	B-NP
+dysfunction	I-NP
+.	O
+	
+In	O
+summary	O
+","	O
+subcellular	O
+cardiomyocyte	B-NP
+degeneration	I-NP
+was	O
+the	O
+earliest	O
+marker	O
+","	O
+followed	O
+by	O
+progressive	O
+functional	O
+decline	O
+and	O
+histopathological	O
+manifestations	O
+.	O
+	
+Myocardial	O
+contrast	O
+enhancement	O
+and	O
+elevations	O
+in	O
+cTnI	O
+occurred	O
+later	O
+.	O
+	
+However	O
+","	O
+all	O
+indices	O
+predated	O
+"	O
+clinical	O
+"	O
+LV	B-NP
+dysfunction	I-NP
+and	O
+thus	O
+warrant	O
+further	O
+evaluation	O
+as	O
+predictive	O
+biomarkers	O
+.	O
+	
+Intradermal	O
+glutamate	O
+and	O
+capsaicin	O
+injections	O
+:	O
+intra	O
+-	O
+and	O
+interindividual	O
+variability	O
+of	O
+provoked	O
+hyperalgesia	B-NP
+and	O
+allodynia	B-NP
+.	O
+	
+Intradermal	O
+injections	O
+of	O
+glutamate	O
+and	O
+capsaicin	O
+are	O
+attractive	O
+to	O
+use	O
+in	O
+human	O
+experimental	O
+pain	B-NP
+models	O
+because	O
+hyperalgesia	B-NP
+and	O
+allodynia	B-NP
+mimic	O
+isolated	O
+aspects	O
+of	O
+clinical	O
+pain	B-NP
+disorders	I-NP
+.	O
+	
+The	O
+aim	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+reproducibility	O
+of	O
+these	O
+models	O
+.	O
+	
+Twenty	O
+healthy	O
+male	O
+volunteers	O
+(	O
+mean	O
+age	O
+24	O
+years	O
+;	O
+range	O
+18	O
+-	O
+38	O
+years	O
+)	O
+received	O
+intradermal	O
+injections	O
+of	O
+glutamate	O
+and	O
+capsaicin	O
+in	O
+the	O
+volar	O
+forearm	O
+.	O
+	
+Magnitudes	O
+of	O
+secondary	O
+pinprick	O
+hyperalgesia	B-NP
+and	O
+brush	O
+-	O
+evoked	O
+allodynia	B-NP
+were	O
+investigated	O
+using	O
+von	O
+Frey	O
+filaments	O
+(	O
+gauges	O
+10	O
+","	O
+15	O
+","	O
+60	O
+and	O
+100	O
+g	O
+)	O
+and	O
+brush	O
+strokes	O
+.	O
+	
+Areas	O
+of	O
+secondary	B-NP
+hyperalgesia	I-NP
+and	O
+allodynia	B-NP
+were	O
+quantified	O
+immediately	O
+after	O
+injection	O
+and	O
+after	O
+15	O
+","	O
+30	O
+and	O
+60	O
+min	O
+.	O
+	
+Two	O
+identical	O
+experiments	O
+separated	O
+by	O
+at	O
+least	O
+7	O
+days	O
+were	O
+performed	O
+.	O
+	
+Reproducibility	O
+across	O
+and	O
+within	O
+volunteers	O
+(	O
+inter	O
+-	O
+and	O
+intra	O
+-	O
+individual	O
+variation	O
+","	O
+respectively	O
+)	O
+was	O
+assessed	O
+using	O
+intraclass	O
+correlation	O
+coefficient	O
+(	O
+ICC	O
+)	O
+and	O
+coefficient	O
+of	O
+variation	O
+(	O
+CV	O
+)	O
+.	O
+	
+Secondary	O
+pinprick	O
+hyperalgesia	B-NP
+was	O
+observed	O
+as	O
+a	O
+marked	O
+increase	O
+in	O
+the	O
+visual	O
+analogue	O
+scale	O
+(	O
+VAS	O
+)	O
+response	O
+to	O
+von	O
+Frey	O
+gauges	O
+60	O
+and	O
+100	O
+g	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+after	O
+glutamate	O
+injection	O
+.	O
+	
+For	O
+capsaicin	O
+","	O
+secondary	O
+pinprick	O
+hyperalgesia	B-NP
+was	O
+detected	O
+with	O
+all	O
+von	O
+Frey	O
+gauges	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Glutamate	O
+evoked	O
+reproducible	O
+VAS	O
+response	O
+to	O
+all	O
+von	O
+Frey	O
+gauges	O
+(	O
+ICC	O
+>	O
+0	O
+.	O
+60	O
+)	O
+and	O
+brush	O
+strokes	O
+(	O
+ICC	O
+>	O
+0	O
+.	O
+83	O
+)	O
+.	O
+	
+Capsaicin	O
+injection	O
+was	O
+reproducible	O
+for	O
+secondary	B-NP
+hyperalgesia	I-NP
+(	O
+ICC	O
+>	O
+0	O
+.	O
+70	O
+)	O
+and	O
+allodynia	B-NP
+(	O
+ICC	O
+>	O
+0	O
+.	O
+71	O
+)	O
+.	O
+	
+Intra	O
+-	O
+individual	O
+variability	O
+was	O
+generally	O
+lower	O
+for	O
+the	O
+VAS	O
+response	O
+to	O
+von	O
+Frey	O
+and	O
+brush	O
+compared	O
+with	O
+areas	O
+of	O
+secondary	B-NP
+hyperalgesia	I-NP
+and	O
+allodynia	B-NP
+.	O
+	
+In	O
+conclusion	O
+","	O
+glutamate	O
+and	O
+capsaicin	O
+yield	O
+reproducible	O
+hyperalgesic	B-NP
+and	O
+allodynic	B-NP
+responses	O
+","	O
+and	O
+the	O
+present	O
+model	O
+is	O
+well	O
+suited	O
+for	O
+basic	O
+research	O
+","	O
+as	O
+well	O
+as	O
+for	O
+assessing	O
+the	O
+modulation	O
+of	O
+central	O
+phenomena	O
+.	O
+	
+Ocular	O
+-	O
+specific	O
+ER	O
+stress	O
+reduction	O
+rescues	O
+glaucoma	B-NP
+in	O
+murine	O
+glucocorticoid	O
+-	O
+induced	O
+glaucoma	B-NP
+.	O
+	
+Administration	O
+of	O
+glucocorticoids	O
+induces	O
+ocular	B-NP
+hypertension	I-NP
+in	O
+some	O
+patients	O
+.	O
+	
+If	O
+untreated	O
+","	O
+these	O
+patients	O
+can	O
+develop	O
+a	O
+secondary	O
+glaucoma	B-NP
+that	O
+resembles	O
+primary	B-NP
+open	I-NP
+-	I-NP
+angle	I-NP
+glaucoma	I-NP
+(	O
+POAG	B-NP
+)	O
+.	O
+	
+The	O
+underlying	O
+pathology	O
+of	O
+glucocorticoid	O
+-	O
+induced	O
+glaucoma	B-NP
+is	O
+not	O
+fully	O
+understood	O
+","	O
+due	O
+in	O
+part	O
+to	O
+lack	O
+of	O
+an	O
+appropriate	O
+animal	O
+model	O
+.	O
+	
+Here	O
+","	O
+we	O
+developed	O
+a	O
+murine	O
+model	O
+of	O
+glucocorticoid	O
+-	O
+induced	O
+glaucoma	B-NP
+that	O
+exhibits	O
+glaucoma	B-NP
+features	O
+that	O
+are	O
+observed	O
+in	O
+patients	O
+.	O
+	
+Treatment	O
+of	O
+WT	O
+mice	O
+with	O
+topical	O
+ocular	O
+0	O
+.	O
+1	O
+%	O
+dexamethasone	O
+led	O
+to	O
+elevation	O
+of	O
+intraocular	O
+pressure	O
+(	O
+IOP	O
+)	O
+","	O
+functional	O
+and	O
+structural	O
+loss	O
+of	O
+retinal	B-NP
+ganglion	I-NP
+cells	O
+","	O
+and	O
+axonal	B-NP
+degeneration	I-NP
+","	O
+resembling	O
+glucocorticoid	O
+-	O
+induced	O
+glaucoma	B-NP
+in	O
+human	O
+patients	O
+.	O
+	
+Furthermore	O
+","	O
+dexamethasone	O
+-	O
+induced	O
+ocular	B-NP
+hypertension	I-NP
+was	O
+associated	O
+with	O
+chronic	O
+ER	O
+stress	O
+of	O
+the	O
+trabecular	O
+meshwork	O
+(	O
+TM	O
+)	O
+.	O
+	
+Similar	O
+to	O
+patients	O
+","	O
+withdrawal	O
+of	O
+dexamethasone	O
+treatment	O
+reduced	O
+elevated	O
+IOP	O
+and	O
+ER	O
+stress	O
+in	O
+this	O
+animal	O
+model	O
+.	O
+	
+Dexamethasone	O
+induced	O
+the	O
+transcriptional	O
+factor	O
+CHOP	O
+","	O
+a	O
+marker	O
+for	O
+chronic	O
+ER	O
+stress	O
+","	O
+in	O
+the	O
+anterior	O
+segment	O
+tissues	O
+","	O
+and	O
+Chop	O
+deletion	O
+reduced	O
+ER	O
+stress	O
+in	O
+these	O
+tissues	O
+and	O
+prevented	O
+dexamethasone	O
+-	O
+induced	O
+ocular	B-NP
+hypertension	I-NP
+.	O
+	
+Furthermore	O
+","	O
+reduction	O
+of	O
+ER	O
+stress	O
+in	O
+the	O
+TM	O
+with	O
+sodium	O
+4	O
+-	O
+phenylbutyrate	O
+prevented	O
+dexamethasone	O
+-	O
+induced	O
+ocular	B-NP
+hypertension	I-NP
+in	O
+WT	O
+mice	O
+.	O
+	
+Our	O
+data	O
+indicate	O
+that	O
+ER	O
+stress	O
+contributes	O
+to	O
+glucocorticoid	O
+-	O
+induced	O
+ocular	B-NP
+hypertension	I-NP
+and	O
+suggest	O
+that	O
+reducing	O
+ER	O
+stress	O
+has	O
+potential	O
+as	O
+a	O
+therapeutic	O
+strategy	O
+for	O
+treating	O
+glucocorticoid	O
+-	O
+induced	O
+glaucoma	B-NP
+.	O
+	
+Effects	O
+of	O
+ginsenosides	O
+on	O
+opioid	O
+-	O
+induced	O
+hyperalgesia	B-NP
+in	O
+mice	O
+.	O
+	
+Opioid	O
+-	O
+induced	O
+hyperalgesia	B-NP
+(	O
+OIH	B-NP
+)	O
+is	O
+characterized	O
+by	O
+nociceptive	O
+sensitization	O
+caused	O
+by	O
+the	O
+cessation	O
+of	O
+chronic	O
+opioid	O
+use	O
+.	O
+	
+OIH	B-NP
+can	O
+limit	O
+the	O
+clinical	O
+use	O
+of	O
+opioid	O
+analgesics	O
+and	O
+complicate	O
+withdrawal	O
+from	O
+opioid	B-NP
+addiction	I-NP
+.	O
+	
+In	O
+this	O
+study	O
+","	O
+we	O
+investigated	O
+the	O
+effects	O
+of	O
+Re	O
+","	O
+Rg1	O
+","	O
+and	O
+Rb1	O
+ginsenosides	O
+","	O
+the	O
+bioactive	O
+components	O
+of	O
+ginseng	O
+","	O
+on	O
+OIH	B-NP
+.	O
+	
+OIH	B-NP
+was	O
+achieved	O
+in	O
+mice	O
+after	O
+subcutaneous	O
+administration	O
+of	O
+morphine	O
+for	O
+7	O
+consecutive	O
+days	O
+three	O
+times	O
+per	O
+day	O
+.	O
+	
+During	O
+withdrawal	O
+(	O
+days	O
+8	O
+and	O
+9	O
+)	O
+","	O
+these	O
+mice	O
+were	O
+administered	O
+Re	O
+","	O
+Rg1	O
+","	O
+or	O
+Rb1	O
+intragastrically	O
+two	O
+times	O
+per	O
+day	O
+.	O
+	
+On	O
+the	O
+test	O
+day	O
+(	O
+day	O
+10	O
+)	O
+","	O
+mice	O
+were	O
+subjected	O
+to	O
+the	O
+thermal	O
+sensitivity	O
+test	O
+and	O
+the	O
+acetic	O
+acid	O
+-	O
+induced	O
+writhing	O
+test	O
+.	O
+	
+Re	O
+(	O
+300	O
+mg	O
+/	O
+kg	O
+)	O
+inhibited	O
+OIH	B-NP
+in	O
+both	O
+the	O
+thermal	O
+sensitivity	O
+test	O
+and	O
+the	O
+acetic	O
+acid	O
+-	O
+induced	O
+writhing	O
+test	O
+.	O
+	
+However	O
+","	O
+the	O
+Rg1	O
+and	O
+Rb1	O
+ginsenosides	O
+failed	O
+to	O
+prevent	O
+OIH	B-NP
+in	O
+either	O
+test	O
+.	O
+	
+Furthermore	O
+","	O
+Rg1	O
+showed	O
+a	O
+tendency	O
+to	O
+aggravate	O
+OIH	B-NP
+in	O
+the	O
+acetic	O
+acid	O
+-	O
+induced	O
+writhing	O
+test	O
+.	O
+	
+Our	O
+data	O
+suggested	O
+that	O
+the	O
+ginsenoside	O
+Re	O
+","	O
+but	O
+not	O
+Rg1	O
+or	O
+Rb1	O
+","	O
+may	O
+contribute	O
+toward	O
+reversal	O
+of	O
+OIH	B-NP
+.	O
+	
+A	O
+comparison	O
+of	O
+severe	O
+hemodynamic	O
+disturbances	O
+between	O
+dexmedetomidine	O
+and	O
+propofol	O
+for	O
+sedation	O
+in	O
+neurocritical	O
+care	O
+patients	O
+.	O
+	
+OBJECTIVE	O
+:	O
+Dexmedetomidine	O
+and	O
+propofol	O
+are	O
+commonly	O
+used	O
+sedatives	O
+in	O
+neurocritical	O
+care	O
+as	O
+they	O
+allow	O
+for	O
+frequent	O
+neurologic	O
+examinations	O
+.	O
+	
+However	O
+","	O
+both	O
+agents	O
+are	O
+associated	O
+with	O
+significant	O
+hemodynamic	O
+side	O
+effects	O
+.	O
+	
+The	O
+primary	O
+objective	O
+of	O
+this	O
+study	O
+is	O
+to	O
+compare	O
+the	O
+prevalence	O
+of	O
+severe	O
+hemodynamic	O
+effects	O
+in	O
+neurocritical	O
+care	O
+patients	O
+receiving	O
+dexmedetomidine	O
+and	O
+propofol	O
+.	O
+	
+DESIGN	O
+:	O
+Multicenter	O
+","	O
+retrospective	O
+","	O
+propensity	O
+-	O
+matched	O
+cohort	O
+study	O
+.	O
+	
+SETTING	O
+:	O
+Neurocritical	O
+care	O
+units	O
+at	O
+two	O
+academic	O
+medical	O
+centers	O
+with	O
+dedicated	O
+neurocritical	O
+care	O
+teams	O
+and	O
+board	O
+-	O
+certified	O
+neurointensivists	O
+.	O
+	
+PATIENTS	O
+:	O
+Neurocritical	O
+care	O
+patients	O
+admitted	O
+between	O
+July	O
+2009	O
+and	O
+September	O
+2012	O
+were	O
+evaluated	O
+and	O
+then	O
+matched	O
+1	O
+:	O
+1	O
+based	O
+on	O
+propensity	O
+scoring	O
+of	O
+baseline	O
+characteristics	O
+.	O
+	
+INTERVENTIONS	O
+:	O
+Continuous	O
+sedation	O
+with	O
+dexmedetomidine	O
+or	O
+propofol	O
+.	O
+	
+MEASUREMENTS	O
+AND	O
+MAIN	O
+RESULTS	O
+:	O
+A	O
+total	O
+of	O
+342	O
+patients	O
+(	O
+105	O
+dexmedetomidine	O
+and	O
+237	O
+propofol	O
+)	O
+were	O
+included	O
+in	O
+the	O
+analysis	O
+","	O
+with	O
+190	O
+matched	O
+(	O
+95	O
+in	O
+each	O
+group	O
+)	O
+by	O
+propensity	O
+score	O
+.	O
+	
+The	O
+primary	O
+outcome	O
+of	O
+this	O
+study	O
+was	O
+a	O
+composite	O
+of	O
+severe	O
+hypotension	B-NP
+(	O
+mean	O
+arterial	O
+pressure	O
+<	O
+60	O
+mm	O
+Hg	O
+)	O
+and	O
+bradycardia	B-NP
+(	O
+heart	O
+rate	O
+<	O
+50	O
+beats	O
+/	O
+min	O
+)	O
+during	O
+sedative	O
+infusion	O
+.	O
+	
+No	O
+difference	O
+in	O
+the	O
+primary	O
+composite	O
+outcome	O
+in	O
+both	O
+the	O
+unmatched	O
+(	O
+30	O
+%	O
+vs	O
+30	O
+%	O
+","	O
+p	O
+=	O
+0	O
+.	O
+94	O
+)	O
+or	O
+matched	O
+cohorts	O
+(	O
+28	O
+%	O
+vs	O
+34	O
+%	O
+","	O
+p	O
+=	O
+0	O
+.	O
+35	O
+)	O
+could	O
+be	O
+found	O
+.	O
+	
+When	O
+analyzed	O
+separately	O
+","	O
+no	O
+differences	O
+could	O
+be	O
+found	O
+in	O
+the	O
+prevalence	O
+of	O
+severe	O
+hypotension	B-NP
+or	O
+bradycardia	B-NP
+in	O
+either	O
+the	O
+unmatched	O
+or	O
+matched	O
+cohorts	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Severe	O
+hypotension	B-NP
+and	O
+bradycardia	B-NP
+occur	O
+at	O
+similar	O
+prevalence	O
+in	O
+neurocritical	O
+care	O
+patients	O
+who	O
+receive	O
+dexmedetomidine	O
+or	O
+propofol	O
+.	O
+	
+Providers	O
+should	O
+similarly	O
+consider	O
+the	O
+likelihood	O
+of	O
+hypotension	B-NP
+or	O
+bradycardia	B-NP
+before	O
+starting	O
+either	O
+sedative	O
+.	O
+	
+Hydroxytyrosol	O
+ameliorates	O
+oxidative	O
+stress	O
+and	O
+mitochondrial	B-NP
+dysfunction	I-NP
+in	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+in	O
+rats	O
+with	O
+breast	B-NP
+cancer	I-NP
+.	O
+	
+Oxidative	O
+stress	O
+is	O
+involved	O
+in	O
+several	O
+processes	O
+including	O
+cancer	B-NP
+","	O
+aging	O
+and	O
+cardiovascular	B-NP
+disease	I-NP
+","	O
+and	O
+has	O
+been	O
+shown	O
+to	O
+potentiate	O
+the	O
+therapeutic	O
+effect	O
+of	O
+drugs	O
+such	O
+as	O
+doxorubicin	O
+.	O
+	
+Doxorubicin	O
+causes	O
+significant	O
+cardiotoxicity	B-NP
+characterized	O
+by	O
+marked	O
+increases	O
+in	O
+oxidative	O
+stress	O
+and	O
+mitochondrial	B-NP
+dysfunction	I-NP
+.	O
+	
+Herein	O
+","	O
+we	O
+investigate	O
+whether	O
+doxorubicin	O
+-	O
+associated	O
+chronic	O
+cardiac	B-NP
+toxicity	I-NP
+can	O
+be	O
+ameliorated	O
+with	O
+the	O
+antioxidant	O
+hydroxytyrosol	O
+in	O
+rats	O
+with	O
+breast	B-NP
+cancer	I-NP
+.	O
+	
+Thirty	O
+-	O
+six	O
+rats	O
+bearing	O
+breast	B-NP
+tumors	I-NP
+induced	O
+chemically	O
+were	O
+divided	O
+into	O
+4	O
+groups	O
+:	O
+control	O
+","	O
+hydroxytyrosol	O
+(	O
+0	O
+.	O
+5mg	O
+/	O
+kg	O
+","	O
+5days	O
+/	O
+week	O
+)	O
+","	O
+doxorubicin	O
+(	O
+1mg	O
+/	O
+kg	O
+/	O
+week	O
+)	O
+","	O
+and	O
+doxorubicin	O
+plus	O
+hydroxytyrosol	O
+.	O
+	
+Cardiac	B-NP
+disturbances	I-NP
+at	O
+the	O
+cellular	O
+and	O
+mitochondrial	O
+level	O
+","	O
+mitochondrial	O
+electron	O
+transport	O
+chain	O
+complexes	O
+I	O
+-	O
+IV	O
+and	O
+apoptosis	O
+-	O
+inducing	O
+factor	O
+","	O
+and	O
+oxidative	O
+stress	O
+markers	O
+have	O
+been	O
+analyzed	O
+.	O
+	
+Hydroxytyrosol	O
+improved	O
+the	O
+cardiac	B-NP
+disturbances	I-NP
+enhanced	O
+by	O
+doxorubicin	O
+by	O
+significantly	O
+reducing	O
+the	O
+percentage	O
+of	O
+altered	O
+mitochondria	O
+and	O
+oxidative	O
+damage	O
+.	O
+	
+These	O
+results	O
+suggest	O
+that	O
+hydroxytyrosol	O
+improve	O
+the	O
+mitochondrial	O
+electron	O
+transport	O
+chain	O
+.	O
+	
+This	O
+study	O
+demonstrates	O
+that	O
+hydroxytyrosol	O
+protect	O
+rat	O
+heart	B-NP
+damage	I-NP
+provoked	O
+by	O
+doxorubicin	O
+decreasing	O
+oxidative	O
+damage	O
+and	O
+mitochondrial	O
+alterations	O
+.	O
+	
+Amiodarone	O
+-	O
+induced	O
+myxoedema	B-NP
+coma	I-NP
+.	O
+	
+A	O
+62	O
+-	O
+year	O
+-	O
+old	O
+man	O
+was	O
+found	O
+to	O
+have	O
+bradycardia	B-NP
+","	O
+hypothermia	B-NP
+and	O
+respiratory	B-NP
+failure	I-NP
+3	O
+weeks	O
+after	O
+initiation	O
+of	O
+amiodarone	O
+therapy	O
+for	O
+atrial	B-NP
+fibrillation	I-NP
+.	O
+	
+Thyroid	O
+-	O
+stimulating	O
+hormone	O
+was	O
+found	O
+to	O
+be	O
+168	O
+uIU	O
+/	O
+mL	O
+(	O
+nl	O
+.	O
+0	O
+.	O
+3	O
+-	O
+5	O
+uIU	O
+/	O
+mL	O
+)	O
+and	O
+free	O
+thyroxine	O
+(	O
+FT4	O
+)	O
+was	O
+<	O
+0	O
+.	O
+2	O
+ng	O
+/	O
+dL	O
+(	O
+nl	O
+.	O
+0	O
+.	O
+8	O
+-	O
+1	O
+.	O
+8	O
+ng	O
+/	O
+dL	O
+)	O
+.	O
+	
+He	O
+received	O
+intravenous	O
+fluids	O
+","	O
+vasopressor	O
+therapy	O
+and	O
+stress	O
+dose	O
+steroids	O
+;	O
+he	O
+was	O
+intubated	O
+and	O
+admitted	O
+to	O
+the	O
+intensive	O
+care	O
+unit	O
+.	O
+	
+He	O
+received	O
+500	O
+ug	O
+of	O
+intravenous	O
+levothyroxine	O
+in	O
+the	O
+first	O
+18	O
+h	O
+of	O
+therapy	O
+","	O
+and	O
+150	O
+ug	O
+intravenous	O
+daily	O
+thereafter	O
+.	O
+	
+Haemodynamic	O
+improvement	O
+","	O
+along	O
+with	O
+complete	O
+recovery	O
+of	O
+mental	O
+status	O
+","	O
+occurred	O
+after	O
+48	O
+h	O
+.	O
+	
+Twelve	O
+hours	O
+after	O
+the	O
+initiation	O
+of	O
+therapy	O
+","	O
+FT4	O
+was	O
+0	O
+.	O
+96	O
+ng	O
+/	O
+dL	O
+.	O
+	
+The	O
+patient	O
+was	O
+maintained	O
+on	O
+levothyroxine	O
+175	O
+(	O
+g	O
+POorally	O
+daily	O
+.	O
+	
+A	O
+thyroid	O
+ultrasound	O
+showed	O
+diffuse	O
+heterogeneity	O
+.	O
+	
+The	O
+24	O
+hour	O
+excretion	O
+of	O
+iodine	O
+was	O
+3657	O
+(	O
+mcg	O
+(	O
+25	O
+-	O
+756	O
+(	O
+mcg	O
+)	O
+.	O
+	
+The	O
+only	O
+two	O
+cases	O
+of	O
+amiodarone	O
+-	O
+induced	O
+myxoedema	B-NP
+coma	I-NP
+in	O
+the	O
+literature	O
+report	O
+patient	O
+death	O
+despite	O
+supportive	O
+therapy	O
+and	O
+thyroid	O
+hormone	O
+replacement	O
+.	O
+	
+This	O
+case	O
+represents	O
+the	O
+most	O
+thoroughly	O
+investigated	O
+case	O
+of	O
+amiodarone	O
+-	O
+induced	O
+myxoedema	B-NP
+coma	I-NP
+with	O
+a	O
+history	O
+significant	O
+for	O
+subclinical	O
+thyroid	B-NP
+disease	I-NP
+.	O
+	
+Use	O
+of	O
+argatroban	O
+and	O
+catheter	O
+-	O
+directed	O
+thrombolysis	B-NP
+with	O
+alteplase	O
+in	O
+an	O
+oncology	O
+patient	O
+with	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+with	O
+thrombosis	B-NP
+.	O
+	
+PURPOSE	O
+:	O
+The	O
+case	O
+of	O
+an	O
+oncology	O
+patient	O
+who	O
+developed	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+with	O
+thrombosis	B-NP
+(	O
+HITT	B-NP
+)	O
+and	O
+was	O
+treated	O
+with	O
+argatroban	O
+plus	O
+catheter	O
+-	O
+directed	O
+thrombolysis	B-NP
+(	O
+CDT	O
+)	O
+with	O
+alteplase	O
+is	O
+presented	O
+.	O
+	
+SUMMARY	O
+:	O
+A	O
+63	O
+-	O
+year	O
+-	O
+old	O
+Caucasian	O
+man	O
+with	O
+renal	O
+amyloidosis	B-NP
+undergoing	O
+peripheral	O
+blood	O
+stem	O
+cell	O
+collection	O
+for	O
+an	O
+autologous	O
+stem	O
+cell	O
+transplant	O
+developed	O
+extensive	O
+bilateral	O
+upper	B-NP
+-	I-NP
+extremity	I-NP
+deep	I-NP
+venous	I-NP
+thrombosis	I-NP
+(	O
+DVT	B-NP
+)	O
+and	O
+pulmonary	B-NP
+embolism	I-NP
+secondary	O
+to	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+.	O
+	
+A	O
+continuous	O
+i	O
+.	O
+v	O
+.	O
+infusion	O
+of	O
+argatroban	O
+was	O
+initiated	O
+","	O
+and	O
+the	O
+patient	O
+was	O
+managed	O
+on	O
+the	O
+general	O
+medical	O
+floor	O
+.	O
+	
+After	O
+one	O
+week	O
+of	O
+therapy	O
+","	O
+he	O
+was	O
+transferred	O
+to	O
+the	O
+intensive	O
+care	O
+unit	O
+with	O
+cardiopulmonary	O
+compromise	O
+related	O
+to	O
+superior	B-NP
+vena	I-NP
+cava	I-NP
+(	I-NP
+SVC	I-NP
+)	I-NP
+syndrome	I-NP
+.	O
+	
+A	O
+percutaneous	O
+mechanical	O
+thrombectomy	O
+and	O
+CDT	O
+with	O
+alteplase	O
+were	O
+attempted	O
+","	O
+but	O
+the	O
+procedure	O
+was	O
+aborted	O
+due	O
+to	O
+epistaxis	B-NP
+.	O
+	
+The	O
+epistaxis	B-NP
+resolved	O
+the	O
+next	O
+day	O
+","	O
+and	O
+the	O
+patient	O
+was	O
+restarted	O
+on	O
+argatroban	O
+.	O
+	
+A	O
+second	O
+percutaneous	O
+mechanical	O
+thrombectomy	O
+was	O
+performed	O
+six	O
+days	O
+later	O
+and	O
+resulted	O
+in	O
+partial	O
+revascularization	O
+of	O
+the	O
+SVC	O
+and	O
+central	O
+veins	O
+.	O
+	
+Postthrombectomy	O
+continuous	O
+CDT	O
+with	O
+alteplase	O
+was	O
+commenced	O
+while	O
+argatroban	O
+was	O
+withheld	O
+","	O
+and	O
+complete	O
+patency	O
+of	O
+the	O
+SVC	O
+and	O
+central	O
+veins	O
+was	O
+achieved	O
+after	O
+three	O
+days	O
+of	O
+therapy	O
+.	O
+	
+Alteplase	O
+was	O
+discontinued	O
+","	O
+and	O
+the	O
+patient	O
+was	O
+reinitiated	O
+on	O
+argatroban	O
+;	O
+ultimately	O
+","	O
+he	O
+was	O
+transitioned	O
+to	O
+warfarin	O
+for	O
+long	O
+-	O
+term	O
+anticoagulation	O
+.	O
+	
+Although	O
+the	O
+patient	O
+recovered	O
+","	O
+he	O
+experienced	O
+permanent	O
+vision	B-NP
+and	I-NP
+hearing	I-NP
+loss	I-NP
+","	O
+as	O
+well	O
+as	O
+end	B-NP
+-	I-NP
+stage	I-NP
+renal	I-NP
+disease	I-NP
+.	O
+	
+CONCLUSION	O
+:	O
+A	O
+63	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+renal	O
+amyloidosis	B-NP
+and	O
+SVC	B-NP
+syndrome	I-NP
+secondary	O
+to	O
+HITT	B-NP
+was	O
+successfully	O
+treated	O
+with	O
+argatroban	O
+and	O
+CDT	O
+with	O
+alteplase	O
+.	O
+	
+Effects	O
+of	O
+dehydroepiandrosterone	O
+in	O
+amphetamine	O
+-	O
+induced	O
+schizophrenia	B-NP
+models	O
+in	O
+mice	O
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+examine	O
+the	O
+effects	O
+of	O
+dehydroepiandrosterone	O
+(	O
+DHEA	O
+)	O
+on	O
+animal	O
+models	O
+of	O
+schizophrenia	B-NP
+.	O
+	
+METHODS	O
+:	O
+Seventy	O
+Swiss	O
+albino	O
+female	O
+mice	O
+(	O
+25	O
+-	O
+35	O
+g	O
+)	O
+were	O
+divided	O
+into	O
+4	O
+groups	O
+:	O
+amphetamine	O
+-	O
+free	O
+(	O
+control	O
+)	O
+","	O
+amphetamine	O
+","	O
+50	O
+","	O
+and	O
+100	O
+mg	O
+/	O
+kg	O
+DHEA	O
+.	O
+	
+The	O
+DHEA	O
+was	O
+administered	O
+intraperitoneally	O
+(	O
+ip	O
+)	O
+for	O
+5	O
+days	O
+.	O
+	
+Amphetamine	O
+(	O
+3	O
+mg	O
+/	O
+kg	O
+ip	O
+)	O
+induced	O
+hyper	B-NP
+locomotion	O
+","	O
+apomorphine	O
+(	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+subcutaneously	O
+[	O
+sc	O
+]	O
+)	O
+induced	O
+climbing	O
+","	O
+and	O
+haloperidol	O
+(	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+sc	O
+)	O
+induced	O
+catalepsy	B-NP
+tests	O
+were	O
+used	O
+as	O
+animal	O
+models	O
+of	O
+schizophrenia	B-NP
+.	O
+	
+The	O
+study	O
+was	O
+conducted	O
+at	O
+the	O
+Animal	O
+Experiment	O
+Laboratories	O
+","	O
+Department	O
+of	O
+Pharmacology	O
+","	O
+Medical	O
+School	O
+","	O
+Eskisehir	O
+Osmangazi	O
+University	O
+","	O
+Eskisehir	O
+","	O
+Turkey	O
+between	O
+March	O
+and	O
+May	O
+2012	O
+.	O
+	
+Statistical	O
+analysis	O
+was	O
+carried	O
+out	O
+using	O
+Kruskal	O
+-	O
+Wallis	O
+test	O
+for	O
+hyper	B-NP
+locomotion	O
+","	O
+and	O
+one	O
+-	O
+way	O
+ANOVA	O
+for	O
+climbing	O
+and	O
+catalepsy	B-NP
+tests	O
+.	O
+	
+RESULTS	O
+:	O
+In	O
+the	O
+amphetamine	O
+-	O
+induced	O
+locomotion	O
+test	O
+","	O
+there	O
+were	O
+significant	O
+increases	O
+in	O
+all	O
+movements	O
+compared	O
+with	O
+the	O
+amphetamine	O
+-	O
+free	O
+group	O
+.	O
+	
+Both	O
+DHEA	O
+50	O
+mg	O
+/	O
+kg	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+","	O
+and	O
+100	O
+mg	O
+/	O
+kg	O
+(	O
+p	O
+<	O
+0	O
+.	O
+1	O
+)	O
+significantly	O
+decreased	O
+all	O
+movements	O
+compared	O
+with	O
+the	O
+amphetamine	O
+-	O
+induced	O
+locomotion	O
+group	O
+.	O
+	
+There	O
+was	O
+a	O
+significant	O
+difference	O
+between	O
+groups	O
+in	O
+the	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B-NP
+test	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+There	O
+was	O
+no	O
+significant	O
+difference	O
+between	O
+groups	O
+in	O
+terms	O
+of	O
+total	O
+climbing	O
+time	O
+in	O
+the	O
+apomorphine	O
+-	O
+induced	O
+climbing	O
+test	O
+(	O
+p	O
+>	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+We	O
+observed	O
+that	O
+DHEA	O
+reduced	O
+locomotor	O
+activity	O
+and	O
+increased	O
+catalepsy	B-NP
+at	O
+both	O
+doses	O
+","	O
+while	O
+it	O
+had	O
+no	O
+effect	O
+on	O
+climbing	O
+behavior	O
+.	O
+	
+We	O
+suggest	O
+that	O
+DHEA	O
+displays	O
+typical	O
+neuroleptic	O
+-	O
+like	O
+effects	O
+","	O
+and	O
+may	O
+be	O
+used	O
+in	O
+the	O
+treatment	O
+of	O
+schizophrenia	B-NP
+.	O
+	
+Availability	O
+of	O
+human	O
+induced	O
+pluripotent	O
+stem	O
+cell	O
+-	O
+derived	O
+cardiomyocytes	O
+in	O
+assessment	O
+of	O
+drug	O
+potential	O
+for	O
+QT	B-NP
+prolongation	I-NP
+.	O
+	
+Field	O
+potential	O
+duration	O
+(	O
+FPD	O
+)	O
+in	O
+human	O
+-	O
+induced	O
+pluripotent	O
+stem	O
+cell	O
+-	O
+derived	O
+cardiomyocytes	O
+(	O
+hiPS	O
+-	O
+CMs	O
+)	O
+","	O
+which	O
+can	O
+express	O
+QT	O
+interval	O
+in	O
+an	O
+electrocardiogram	O
+","	O
+is	O
+reported	O
+to	O
+be	O
+a	O
+useful	O
+tool	O
+to	O
+predict	O
+K	O
+(	O
++	O
+)	O
+channel	O
+and	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+channel	O
+blocker	O
+effects	O
+on	O
+QT	O
+interval	O
+.	O
+	
+However	O
+","	O
+there	O
+is	O
+no	O
+report	O
+showing	O
+that	O
+this	O
+technique	O
+can	O
+be	O
+used	O
+to	O
+predict	O
+multichannel	O
+blocker	O
+potential	O
+for	O
+QT	B-NP
+prolongation	I-NP
+.	O
+	
+The	O
+aim	O
+of	O
+this	O
+study	O
+is	O
+to	O
+show	O
+that	O
+FPD	O
+from	O
+MEA	O
+(	O
+Multielectrode	O
+array	O
+)	O
+of	O
+hiPS	O
+-	O
+CMs	O
+can	O
+detect	O
+QT	B-NP
+prolongation	I-NP
+induced	O
+by	O
+multichannel	O
+blockers	O
+.	O
+	
+hiPS	O
+-	O
+CMs	O
+were	O
+seeded	O
+onto	O
+MEA	O
+and	O
+FPD	O
+was	O
+measured	O
+for	O
+2min	O
+every	O
+10min	O
+for	O
+30min	O
+after	O
+drug	O
+exposure	O
+for	O
+the	O
+vehicle	O
+and	O
+each	O
+drug	O
+concentration	O
+.	O
+	
+IKr	O
+and	O
+IKs	O
+blockers	O
+concentration	O
+-	O
+dependently	O
+prolonged	O
+corrected	O
+FPD	O
+(	O
+FPDc	O
+)	O
+","	O
+whereas	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+channel	O
+blockers	O
+concentration	O
+-	O
+dependently	O
+shortened	O
+FPDc	O
+.	O
+	
+Also	O
+","	O
+the	O
+multichannel	O
+blockers	O
+Amiodarone	O
+","	O
+Paroxetine	O
+","	O
+Terfenadine	O
+and	O
+Citalopram	O
+prolonged	O
+FPDc	O
+in	O
+a	O
+concentration	O
+dependent	O
+manner	O
+.	O
+	
+Finally	O
+","	O
+the	O
+IKr	O
+blockers	O
+","	O
+Terfenadine	O
+and	O
+Citalopram	O
+","	O
+which	O
+are	O
+reported	O
+to	O
+cause	O
+Torsade	B-NP
+de	I-NP
+Pointes	I-NP
+(	O
+TdP	B-NP
+)	O
+in	O
+clinical	O
+practice	O
+","	O
+produced	O
+early	O
+afterdepolarization	O
+(	O
+EAD	O
+)	O
+.	O
+	
+hiPS	O
+-	O
+CMs	O
+using	O
+MEA	O
+system	O
+and	O
+FPDc	O
+can	O
+predict	O
+the	O
+effects	O
+of	O
+drug	O
+candidates	O
+on	O
+QT	O
+interval	O
+.	O
+	
+This	O
+study	O
+also	O
+shows	O
+that	O
+this	O
+assay	O
+can	O
+help	O
+detect	O
+EAD	O
+for	O
+drugs	O
+with	O
+TdP	B-NP
+potential	O
+.	O
+	
+Dermal	O
+developmental	O
+toxicity	B-NP
+of	O
+N	O
+-	O
+phenylimide	O
+herbicides	O
+in	O
+rats	O
+.	O
+	
+BACKGROUND	O
+:	O
+S	O
+-	O
+53482	O
+and	O
+S	O
+-	O
+23121	O
+are	O
+N	O
+-	O
+phenylimide	O
+herbicides	O
+and	O
+produced	O
+embryolethality	B-NP
+","	O
+teratogenicity	B-NP
+(	O
+mainly	O
+ventricular	B-NP
+septal	I-NP
+defects	I-NP
+and	O
+wavy	O
+ribs	O
+)	O
+","	O
+and	O
+growth	B-NP
+retardation	I-NP
+in	O
+rats	O
+in	O
+conventional	O
+oral	O
+developmental	O
+toxicity	B-NP
+studies	O
+.	O
+	
+Our	O
+objective	O
+in	O
+this	O
+study	O
+was	O
+to	O
+investigate	O
+whether	O
+the	O
+compounds	O
+induce	O
+developmental	O
+toxicity	B-NP
+via	O
+the	O
+dermal	O
+route	O
+","	O
+which	O
+is	O
+more	O
+relevant	O
+to	O
+occupational	O
+exposure	O
+","	O
+hence	O
+better	O
+addressing	O
+human	O
+health	O
+risks	O
+.	O
+	
+METHODS	O
+:	O
+S	O
+-	O
+53482	O
+was	O
+administered	O
+dermally	O
+to	O
+rats	O
+at	O
+30	O
+","	O
+100	O
+","	O
+and	O
+300	O
+mg	O
+/	O
+kg	O
+during	O
+organogenesis	O
+","	O
+and	O
+S	O
+-	O
+23121	O
+was	O
+administered	O
+at	O
+200	O
+","	O
+400	O
+","	O
+and	O
+800	O
+mg	O
+/	O
+kg	O
+(	O
+the	O
+maximum	O
+applicable	O
+dose	O
+level	O
+)	O
+.	O
+	
+Fetuses	O
+were	O
+obtained	O
+by	O
+a	O
+Cesarean	O
+section	O
+and	O
+examined	O
+for	O
+external	O
+","	O
+visceral	O
+","	O
+and	O
+skeletal	O
+alterations	O
+.	O
+	
+RESULTS	O
+:	O
+Dermal	O
+exposure	O
+of	O
+rats	O
+to	O
+S	O
+-	O
+53482	O
+at	O
+300	O
+mg	O
+/	O
+kg	O
+produced	O
+patterns	O
+of	O
+developmental	O
+toxicity	B-NP
+similar	O
+to	O
+those	O
+resulting	O
+from	O
+oral	O
+exposure	O
+.	O
+	
+Toxicity	B-NP
+included	O
+embryolethality	B-NP
+","	O
+teratogenicity	B-NP
+","	O
+and	O
+growth	B-NP
+retardation	I-NP
+.	O
+	
+Dermal	O
+administration	O
+of	O
+S	O
+-	O
+23121	O
+at	O
+800	O
+mg	O
+/	O
+kg	O
+resulted	O
+in	O
+an	O
+increased	O
+incidence	O
+of	O
+embryonic	B-NP
+death	I-NP
+and	O
+ventricular	B-NP
+septal	I-NP
+defect	I-NP
+","	O
+but	O
+retarded	O
+fetal	O
+growth	O
+was	O
+not	O
+observed	O
+as	O
+it	O
+was	O
+following	O
+oral	O
+exposure	O
+to	O
+S	O
+-	O
+23121	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Based	O
+on	O
+the	O
+results	O
+","	O
+S	O
+-	O
+53482	O
+and	O
+S	O
+-	O
+23121	O
+were	O
+teratogenic	B-NP
+when	O
+administered	O
+dermally	O
+to	O
+pregnant	O
+rats	O
+as	O
+were	O
+the	O
+compounds	O
+administered	O
+orally	O
+.	O
+	
+Thus	O
+","	O
+investigation	O
+of	O
+the	O
+mechanism	O
+and	O
+its	O
+human	O
+relevancy	O
+become	O
+more	O
+important	O
+.	O
+	
+Rates	O
+of	O
+Renal	B-NP
+Toxicity	I-NP
+in	O
+Cancer	B-NP
+Patients	O
+Receiving	O
+Cisplatin	O
+With	O
+and	O
+Without	O
+Mannitol	O
+.	O
+	
+BACKGROUND	O
+:	O
+Cisplatin	O
+is	O
+a	O
+widely	O
+used	O
+antineoplastic	O
+.	O
+	
+One	O
+of	O
+the	O
+major	O
+complications	O
+of	O
+cisplatin	O
+use	O
+is	O
+dose	O
+-	O
+limiting	O
+nephrotoxicity	B-NP
+.	O
+	
+There	O
+are	O
+many	O
+strategies	O
+to	O
+prevent	O
+this	O
+toxicity	B-NP
+","	O
+including	O
+the	O
+use	O
+of	O
+mannitol	O
+as	O
+a	O
+nephroprotectant	O
+in	O
+combination	O
+with	O
+hydration	O
+.	O
+	
+OBJECTIVE	O
+:	O
+We	O
+aimed	O
+to	O
+evaluate	O
+the	O
+rates	O
+of	O
+cisplatin	O
+-	O
+induced	O
+nephrotoxicity	B-NP
+in	O
+cancer	B-NP
+patients	O
+receiving	O
+single	O
+-	O
+agent	O
+cisplatin	O
+with	O
+and	O
+without	O
+mannitol	O
+.	O
+	
+METHODS	O
+:	O
+This	O
+single	O
+-	O
+center	O
+retrospective	O
+analysis	O
+was	O
+a	O
+quasi	O
+experiment	O
+created	O
+by	O
+the	O
+national	O
+mannitol	O
+shortage	O
+.	O
+	
+Data	O
+were	O
+collected	O
+on	O
+adult	O
+cancer	B-NP
+patients	O
+receiving	O
+single	O
+-	O
+agent	O
+cisplatin	O
+as	O
+an	O
+outpatient	O
+from	O
+January	O
+2011	O
+to	O
+September	O
+2012	O
+.	O
+	
+The	O
+primary	O
+outcome	O
+was	O
+acute	B-NP
+kidney	I-NP
+injury	I-NP
+(	O
+AKI	B-NP
+)	O
+.	O
+	
+RESULTS	O
+:	O
+We	O
+evaluated	O
+143	O
+patients	O
+who	O
+received	O
+single	O
+-	O
+agent	O
+cisplatin	O
+;	O
+97	O
+.	O
+2	O
+%	O
+of	O
+patients	O
+had	O
+head	B-NP
+and	I-NP
+neck	I-NP
+cancer	I-NP
+as	O
+their	O
+primary	O
+malignancy	B-NP
+.	O
+	
+Patients	O
+who	O
+did	O
+not	O
+receive	O
+mannitol	O
+were	O
+more	O
+likely	O
+to	O
+develop	O
+nephrotoxicity	B-NP
+:	O
+odds	O
+ratio	O
+[	O
+OR	O
+]	O
+=	O
+2	O
+.	O
+646	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+1	O
+.	O
+8	O
+","	O
+6	O
+.	O
+944	O
+;	O
+P	O
+=	O
+0	O
+.	O
+48	O
+)	O
+.	O
+	
+Patients	O
+who	O
+received	O
+the	O
+100	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+dosing	O
+and	O
+patients	O
+who	O
+had	O
+a	O
+history	O
+of	O
+hypertension	B-NP
+also	O
+had	O
+a	O
+higher	O
+likelihood	O
+of	O
+developing	O
+nephrotoxicity	B-NP
+:	O
+OR	O
+=	O
+11	O
+.	O
+494	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+4	O
+.	O
+149	O
+","	O
+32	O
+.	O
+258	O
+;	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+and	O
+OR	O
+=	O
+3	O
+.	O
+219	O
+(	O
+95	O
+%	O
+CI	O
+=	O
+1	O
+.	O
+228	O
+","	O
+8	O
+.	O
+439	O
+;	O
+P	O
+=	O
+0	O
+.	O
+17	O
+)	O
+","	O
+respectively	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+When	O
+limited	O
+quantities	O
+of	O
+mannitol	O
+are	O
+available	O
+","	O
+it	O
+should	O
+preferentially	O
+be	O
+given	O
+to	O
+patients	O
+at	O
+particularly	O
+high	O
+risk	O
+of	O
+nephrotoxicity	B-NP
+.	O
+	
+Our	O
+analysis	O
+suggests	O
+that	O
+those	O
+patients	O
+receiving	O
+the	O
+dosing	O
+schedule	O
+of	O
+100	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+cisplatin	O
+every	O
+3	O
+weeks	O
+and	O
+those	O
+with	O
+hypertension	B-NP
+are	O
+at	O
+the	O
+greatest	O
+risk	O
+of	O
+nephrotoxicity	B-NP
+and	O
+would	O
+benefit	O
+from	O
+the	O
+addition	O
+of	O
+mannitol	O
+.	O
+	
+Metformin	O
+protects	O
+against	O
+seizures	B-NP
+","	O
+learning	B-NP
+and	I-NP
+memory	I-NP
+impairments	I-NP
+and	O
+oxidative	O
+damage	O
+induced	O
+by	O
+pentylenetetrazole	O
+-	O
+induced	O
+kindling	O
+in	O
+mice	O
+.	O
+	
+Cognitive	B-NP
+impairment	I-NP
+","	O
+the	O
+most	O
+common	O
+and	O
+severe	O
+comorbidity	O
+of	O
+epilepsy	B-NP
+","	O
+greatly	O
+diminishes	O
+the	O
+quality	O
+of	O
+life	O
+.	O
+	
+However	O
+","	O
+current	O
+therapeutic	O
+interventions	O
+for	O
+epilepsy	B-NP
+can	O
+also	O
+cause	O
+untoward	O
+cognitive	O
+effects	O
+.	O
+	
+Thus	O
+","	O
+there	O
+is	O
+an	O
+urgent	O
+need	O
+for	O
+new	O
+kinds	O
+of	O
+agents	O
+targeting	O
+both	O
+seizures	B-NP
+and	O
+cognition	B-NP
+deficits	I-NP
+.	O
+	
+Oxidative	O
+stress	O
+is	O
+considered	O
+to	O
+play	O
+an	O
+important	O
+role	O
+in	O
+epileptogenesis	O
+and	O
+cognitive	B-NP
+deficits	I-NP
+","	O
+and	O
+antioxidants	O
+have	O
+a	O
+putative	O
+antiepileptic	O
+potential	O
+.	O
+	
+Metformin	O
+","	O
+the	O
+most	O
+commonly	O
+prescribed	O
+antidiabetic	O
+oral	O
+drug	O
+","	O
+has	O
+antioxidant	O
+properties	O
+.	O
+	
+This	O
+study	O
+was	O
+designed	O
+to	O
+evaluate	O
+the	O
+ameliorative	O
+effects	O
+of	O
+metformin	O
+on	O
+seizures	B-NP
+","	O
+cognitive	B-NP
+impairment	I-NP
+and	O
+brain	O
+oxidative	O
+stress	O
+markers	O
+observed	O
+in	O
+pentylenetetrazole	O
+-	O
+induced	O
+kindling	O
+animals	O
+.	O
+	
+Male	O
+C57BL	O
+/	O
+6	O
+mice	O
+were	O
+administered	O
+with	O
+subconvulsive	O
+dose	O
+of	O
+pentylenetetrazole	O
+(	O
+37	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+p	O
+.	O
+)	O
+every	O
+other	O
+day	O
+for	O
+14	O
+injections	O
+.	O
+	
+Metformin	O
+was	O
+injected	O
+intraperitoneally	O
+in	O
+dose	O
+of	O
+200mg	O
+/	O
+kg	O
+along	O
+with	O
+alternate	O
+-	O
+day	O
+PTZ	O
+.	O
+	
+We	O
+found	O
+that	O
+metformin	O
+suppressed	O
+the	O
+progression	O
+of	O
+kindling	O
+","	O
+ameliorated	O
+the	O
+cognitive	B-NP
+impairment	I-NP
+and	O
+decreased	O
+brain	O
+oxidative	O
+stress	O
+.	O
+	
+Thus	O
+the	O
+present	O
+study	O
+concluded	O
+that	O
+metformin	O
+may	O
+be	O
+a	O
+potential	O
+agent	O
+for	O
+the	O
+treatment	O
+of	O
+epilepsy	B-NP
+as	O
+well	O
+as	O
+a	O
+protective	O
+medicine	O
+against	O
+cognitive	B-NP
+impairment	I-NP
+induced	O
+by	O
+seizures	B-NP
+.	O
+	
+P53	O
+inhibition	O
+exacerbates	O
+late	O
+-	O
+stage	O
+anthracycline	O
+cardiotoxicity	B-NP
+.	O
+	
+AIMS	O
+:	O
+Doxorubicin	O
+(	O
+DOX	O
+)	O
+is	O
+an	O
+effective	O
+anti	O
+-	O
+cancer	B-NP
+therapeutic	O
+","	O
+but	O
+is	O
+associated	O
+with	O
+both	O
+acute	O
+and	O
+late	O
+-	O
+stage	O
+cardiotoxicity	B-NP
+.	O
+	
+Children	O
+are	O
+particularly	O
+sensitive	O
+to	O
+DOX	O
+-	O
+induced	O
+heart	B-NP
+failure	I-NP
+.	O
+	
+Here	O
+","	O
+the	O
+impact	O
+of	O
+p53	O
+inhibition	O
+on	O
+acute	O
+vs	O
+.	O
+late	O
+-	O
+stage	O
+DOX	O
+cardiotoxicity	B-NP
+was	O
+examined	O
+in	O
+a	O
+juvenile	O
+model	O
+.	O
+	
+METHODS	O
+AND	O
+RESULTS	O
+:	O
+Two	O
+-	O
+week	O
+-	O
+old	O
+MHC	O
+-	O
+CB7	O
+mice	O
+(	O
+which	O
+express	O
+dominant	O
+-	O
+interfering	O
+p53	O
+in	O
+cardiomyocytes	O
+)	O
+and	O
+their	O
+non	O
+-	O
+transgenic	O
+(	O
+NON	O
+-	O
+TXG	O
+)	O
+littermates	O
+received	O
+weekly	O
+DOX	O
+injections	O
+for	O
+5	O
+weeks	O
+(	O
+25	O
+mg	O
+/	O
+kg	O
+cumulative	O
+dose	O
+)	O
+.	O
+	
+One	O
+week	O
+after	O
+the	O
+last	O
+DOX	O
+treatment	O
+(	O
+acute	O
+stage	O
+)	O
+","	O
+MHC	O
+-	O
+CB7	O
+mice	O
+exhibited	O
+improved	O
+cardiac	O
+function	O
+and	O
+lower	O
+levels	O
+of	O
+cardiomyocyte	O
+apoptosis	O
+when	O
+compared	O
+with	O
+the	O
+NON	O
+-	O
+TXG	O
+mice	O
+.	O
+	
+Surprisingly	O
+","	O
+by	O
+13	O
+weeks	O
+following	O
+the	O
+last	O
+DOX	O
+treatment	O
+(	O
+late	O
+stage	O
+)	O
+","	O
+MHC	O
+-	O
+CB7	O
+exhibited	O
+a	O
+progressive	O
+decrease	O
+in	O
+cardiac	O
+function	O
+and	O
+higher	O
+rates	O
+of	O
+cardiomyocyte	O
+apoptosis	O
+when	O
+compared	O
+with	O
+NON	O
+-	O
+TXG	O
+mice	O
+.	O
+	
+p53	O
+inhibition	O
+blocked	O
+transient	O
+DOX	O
+-	O
+induced	O
+STAT3	O
+activation	O
+in	O
+MHC	O
+-	O
+CB7	O
+mice	O
+","	O
+which	O
+was	O
+associated	O
+with	O
+enhanced	O
+induction	O
+of	O
+the	O
+DNA	O
+repair	O
+proteins	O
+Ku70	O
+and	O
+Ku80	O
+.	O
+	
+Mice	O
+with	O
+cardiomyocyte	O
+-	O
+restricted	O
+deletion	O
+of	O
+STAT3	O
+exhibited	O
+worse	O
+cardiac	O
+function	O
+","	O
+higher	O
+levels	O
+of	O
+cardiomyocyte	O
+apoptosis	O
+","	O
+and	O
+a	O
+greater	O
+induction	O
+of	O
+Ku70	O
+and	O
+Ku80	O
+in	O
+response	O
+to	O
+DOX	O
+treatment	O
+during	O
+the	O
+acute	O
+stage	O
+when	O
+compared	O
+with	O
+control	O
+animals	O
+.	O
+	
+CONCLUSION	O
+:	O
+These	O
+data	O
+support	O
+a	O
+model	O
+wherein	O
+a	O
+p53	O
+-	O
+dependent	O
+cardioprotective	O
+pathway	O
+","	O
+mediated	O
+via	O
+STAT3	O
+activation	O
+","	O
+mitigates	O
+DOX	O
+-	O
+induced	O
+myocardial	O
+stress	O
+during	O
+drug	O
+delivery	O
+.	O
+	
+Furthermore	O
+","	O
+these	O
+data	O
+suggest	O
+an	O
+explanation	O
+as	O
+to	O
+how	O
+p53	O
+inhibition	O
+can	O
+result	O
+in	O
+cardioprotection	O
+during	O
+drug	O
+treatment	O
+and	O
+","	O
+paradoxically	O
+","	O
+enhanced	O
+cardiotoxicity	B-NP
+long	O
+after	O
+the	O
+cessation	O
+of	O
+drug	O
+treatment	O
+.	O
+	
+Metronidazole	O
+-	O
+induced	O
+encephalopathy	B-NP
+:	O
+an	O
+uncommon	O
+scenario	O
+.	O
+	
+Metronidazole	O
+can	O
+produce	O
+neurological	O
+complications	O
+although	O
+it	O
+is	O
+not	O
+a	O
+common	O
+scenario	O
+.	O
+	
+We	O
+present	O
+a	O
+case	O
+where	O
+a	O
+patient	O
+developed	O
+features	O
+of	O
+encephalopathy	B-NP
+following	O
+prolonged	O
+metronidazole	O
+intake	O
+.	O
+	
+Magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+brain	O
+showed	O
+abnormal	O
+signal	O
+intensity	O
+involving	O
+both	O
+dentate	O
+nuclei	O
+of	O
+cerebellum	O
+and	O
+splenium	O
+of	O
+corpus	O
+callosum	O
+.	O
+	
+The	O
+diagnosis	O
+of	O
+metronidazole	O
+toxicity	B-NP
+was	O
+made	O
+by	O
+the	O
+MRI	O
+findings	O
+and	O
+supported	O
+clinically	O
+.	O
+	
+Aconitine	O
+-	O
+induced	O
+Ca2	O
++	O
+overload	O
+causes	O
+arrhythmia	B-NP
+and	O
+triggers	O
+apoptosis	O
+through	O
+p38	O
+MAPK	O
+signaling	O
+pathway	O
+in	O
+rats	O
+.	O
+	
+Aconitine	O
+is	O
+a	O
+major	O
+bioactive	O
+diterpenoid	O
+alkaloid	O
+with	O
+high	O
+content	O
+derived	O
+from	O
+herbal	O
+aconitum	O
+plants	O
+.	O
+	
+Emerging	O
+evidence	O
+indicates	O
+that	O
+voltage	O
+-	O
+dependent	O
+Na	O
+(	O
++	O
+)	O
+channels	O
+have	O
+pivotal	O
+roles	O
+in	O
+the	O
+cardiotoxicity	B-NP
+of	O
+aconitine	O
+.	O
+	
+However	O
+","	O
+no	O
+reports	O
+are	O
+available	O
+on	O
+the	O
+role	O
+of	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+in	O
+aconitine	O
+poisoning	B-NP
+.	O
+	
+In	O
+this	O
+study	O
+","	O
+we	O
+explored	O
+the	O
+importance	O
+of	O
+pathological	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+signaling	O
+in	O
+aconitine	O
+poisoning	B-NP
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+.	O
+	
+We	O
+found	O
+that	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+overload	O
+lead	O
+to	O
+accelerated	O
+beating	O
+rhythm	O
+in	O
+adult	O
+rat	O
+ventricular	O
+myocytes	O
+and	O
+caused	O
+arrhythmia	B-NP
+in	O
+conscious	O
+freely	O
+moving	O
+rats	O
+.	O
+	
+To	O
+investigate	O
+effects	O
+of	O
+aconitine	O
+on	O
+myocardial	B-NP
+injury	I-NP
+","	O
+we	O
+performed	O
+cytotoxicity	B-NP
+assay	O
+in	O
+neonatal	O
+rat	O
+ventricular	O
+myocytes	O
+(	O
+NRVMs	O
+)	O
+","	O
+as	O
+well	O
+as	O
+measured	O
+lactate	O
+dehydrogenase	O
+level	O
+in	O
+the	O
+culture	O
+medium	O
+of	O
+NRVMs	O
+and	O
+activities	O
+of	O
+serum	O
+cardiac	O
+enzymes	O
+in	O
+rats	O
+.	O
+	
+The	O
+results	O
+showed	O
+that	O
+aconitine	O
+resulted	O
+in	O
+myocardial	B-NP
+injury	I-NP
+and	O
+reduced	O
+NRVMs	O
+viability	O
+dose	O
+-	O
+dependently	O
+.	O
+	
+To	O
+confirm	O
+the	O
+pro	O
+-	O
+apoptotic	O
+effects	O
+","	O
+we	O
+performed	O
+flow	O
+cytometric	O
+detection	O
+","	O
+cardiac	O
+histology	O
+","	O
+transmission	O
+electron	O
+microscopy	O
+and	O
+terminal	O
+deoxynucleotidyl	O
+transferase	O
+-	O
+mediated	O
+dUTP	O
+-	O
+biotin	O
+nick	O
+end	O
+labeling	O
+assay	O
+.	O
+	
+The	O
+results	O
+showed	O
+that	O
+aconitine	O
+stimulated	O
+apoptosis	O
+time	O
+-	O
+dependently	O
+.	O
+	
+The	O
+expression	O
+analysis	O
+of	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+handling	O
+proteins	O
+demonstrated	O
+that	O
+aconitine	O
+promoted	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+overload	O
+through	O
+the	O
+expression	O
+regulation	O
+of	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+handling	O
+proteins	O
+.	O
+	
+The	O
+expression	O
+analysis	O
+of	O
+apoptosis	O
+-	O
+related	O
+proteins	O
+revealed	O
+that	O
+pro	O
+-	O
+apoptotic	O
+protein	O
+expression	O
+was	O
+upregulated	O
+","	O
+and	O
+anti	O
+-	O
+apoptotic	O
+protein	O
+BCL	O
+-	O
+2	O
+expression	O
+was	O
+downregulated	O
+.	O
+	
+Furthermore	O
+","	O
+increased	O
+phosphorylation	O
+of	O
+MAPK	O
+family	O
+members	O
+","	O
+especially	O
+the	O
+P	O
+-	O
+P38	O
+/	O
+P38	O
+ratio	O
+was	O
+found	O
+in	O
+cardiac	O
+tissues	O
+.	O
+	
+Hence	O
+","	O
+our	O
+results	O
+suggest	O
+that	O
+aconitine	O
+significantly	O
+aggravates	O
+Ca	O
+(	O
+2	O
++	O
+)	O
+overload	O
+and	O
+causes	O
+arrhythmia	B-NP
+and	O
+finally	O
+promotes	O
+apoptotic	O
+development	O
+via	O
+phosphorylation	O
+of	O
+P38	O
+mitogen	O
+-	O
+activated	O
+protein	O
+kinase	O
+.	O
+	
+Chronic	O
+treatment	O
+with	O
+metformin	O
+suppresses	O
+toll	O
+-	O
+like	O
+receptor	O
+4	O
+signaling	O
+and	O
+attenuates	O
+left	B-NP
+ventricular	I-NP
+dysfunction	I-NP
+following	O
+myocardial	B-NP
+infarction	I-NP
+.	O
+	
+Acute	O
+treatment	O
+with	O
+metformin	O
+has	O
+a	O
+protective	O
+effect	O
+in	O
+myocardial	B-NP
+infarction	I-NP
+by	O
+suppression	O
+of	O
+inflammatory	O
+responses	O
+due	O
+to	O
+activation	O
+of	O
+AMP	O
+-	O
+activated	O
+protein	O
+kinase	O
+(	O
+AMPK	O
+)	O
+.	O
+	
+In	O
+the	O
+present	O
+study	O
+","	O
+the	O
+effect	O
+of	O
+chronic	O
+pre	O
+-	O
+treatment	O
+with	O
+metformin	O
+on	O
+cardiac	B-NP
+dysfunction	I-NP
+and	O
+toll	O
+-	O
+like	O
+receptor	O
+4	O
+(	O
+TLR4	O
+)	O
+activities	O
+following	O
+myocardial	B-NP
+infarction	I-NP
+and	O
+their	O
+relation	O
+with	O
+AMPK	O
+were	O
+assessed	O
+.	O
+	
+Male	O
+Wistar	O
+rats	O
+were	O
+randomly	O
+assigned	O
+to	O
+one	O
+of	O
+5	O
+groups	O
+(	O
+n	O
+=	O
+6	O
+)	O
+:	O
+normal	O
+control	O
+and	O
+groups	O
+were	O
+injected	O
+isoproterenol	O
+after	O
+chronic	O
+pre	O
+-	O
+treatment	O
+with	O
+0	O
+","	O
+25	O
+","	O
+50	O
+","	O
+or	O
+100mg	O
+/	O
+kg	O
+of	O
+metformin	O
+twice	O
+daily	O
+for	O
+14	O
+days	O
+.	O
+	
+Isoproterenol	O
+(	O
+100mg	O
+/	O
+kg	O
+)	O
+was	O
+injected	O
+subcutaneously	O
+on	O
+the	O
+13th	O
+and	O
+14th	O
+days	O
+to	O
+induce	O
+acute	B-NP
+myocardial	I-NP
+infarction	I-NP
+.	O
+	
+Isoproterenol	O
+alone	O
+decreased	O
+left	O
+ventricular	O
+systolic	O
+pressure	O
+and	O
+myocardial	O
+contractility	O
+indexed	O
+as	O
+LVdp	O
+/	O
+dtmax	O
+and	O
+LVdp	O
+/	O
+dtmin	O
+.	O
+	
+The	O
+left	B-NP
+ventricular	I-NP
+dysfunction	I-NP
+was	O
+significantly	O
+lower	O
+in	O
+the	O
+groups	O
+treated	O
+with	O
+25	O
+and	O
+50mg	O
+/	O
+kg	O
+of	O
+metformin	O
+.	O
+	
+Metfromin	O
+markedly	O
+lowered	O
+isoproterenol	O
+-	O
+induced	O
+elevation	O
+in	O
+the	O
+levels	O
+of	O
+TLR4	O
+mRNA	O
+","	O
+myeloid	O
+differentiation	O
+protein	O
+88	O
+(	O
+MyD88	O
+)	O
+","	O
+tumor	B-NP
+necrosis	B-NP
+factor	O
+-	O
+alpha	O
+(	O
+TNF	O
+-	O
+a	O
+)	O
+","	O
+and	O
+interleukin	O
+6	O
+(	O
+IL	O
+-	O
+6	O
+)	O
+in	O
+the	O
+heart	O
+tissues	O
+.	O
+	
+Similar	O
+changes	O
+were	O
+also	O
+seen	O
+in	O
+the	O
+serum	O
+levels	O
+of	O
+TNF	O
+-	O
+a	O
+and	O
+IL	O
+-	O
+6	O
+.	O
+	
+However	O
+","	O
+the	O
+lower	O
+doses	O
+of	O
+25	O
+and	O
+50mg	O
+/	O
+kg	O
+were	O
+more	O
+effective	O
+than	O
+100mg	O
+/	O
+kg	O
+.	O
+	
+Phosphorylated	O
+AMPKa	O
+(	O
+p	O
+-	O
+AMPK	O
+)	O
+in	O
+the	O
+myocardium	O
+was	O
+significantly	O
+elevated	O
+by	O
+25mg	O
+/	O
+kg	O
+of	O
+metformin	O
+","	O
+slightly	O
+by	O
+50mg	O
+/	O
+kg	O
+","	O
+but	O
+not	O
+by	O
+100mg	O
+/	O
+kg	O
+.	O
+	
+Chronic	O
+pre	O
+-	O
+treatment	O
+with	O
+metformin	O
+reduces	O
+post	O
+-	O
+myocardial	B-NP
+infarction	I-NP
+cardiac	O
+dysfunction	O
+and	O
+suppresses	O
+inflammatory	O
+responses	O
+","	O
+possibly	O
+through	O
+inhibition	O
+of	O
+TLR4	O
+activities	O
+.	O
+	
+This	O
+mechanism	O
+can	O
+be	O
+considered	O
+as	O
+a	O
+target	O
+to	O
+protect	O
+infarcted	O
+myocardium	O
+.	O
+	
+Unusual	O
+complications	O
+of	O
+antithyroid	O
+drug	O
+therapy	O
+:	O
+four	O
+case	O
+reports	O
+and	O
+review	O
+of	O
+literature	O
+.	O
+	
+Two	O
+cases	O
+of	O
+propylthiouracil	O
+-	O
+associated	O
+acute	O
+hepatitis	B-NP
+","	O
+one	O
+case	O
+of	O
+fatal	O
+methimazole	O
+-	O
+associated	O
+hepatocellular	B-NP
+necrosis	I-NP
+and	O
+one	O
+case	O
+of	O
+propylthiouracil	O
+-	O
+associated	O
+lupus	B-NP
+-	I-NP
+like	I-NP
+syndrome	I-NP
+are	O
+described	O
+.	O
+	
+The	O
+literature	O
+related	O
+to	O
+antithyroid	O
+drug	O
+side	O
+effects	O
+and	O
+the	O
+mechanisms	O
+for	O
+their	O
+occurrence	O
+are	O
+reviewed	O
+and	O
+the	O
+efficacy	O
+and	O
+complications	O
+of	O
+thyroidectomy	O
+and	O
+radioiodine	O
+compared	O
+to	O
+those	O
+of	O
+antithyroid	O
+drugs	O
+.	O
+	
+It	O
+is	O
+concluded	O
+that	O
+in	O
+most	O
+circumstances	O
+131I	O
+is	O
+the	O
+therapy	O
+of	O
+choice	O
+for	O
+hyperthyroidism	B-NP
+.	O
+	
+Neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+induced	O
+by	O
+combination	O
+therapy	O
+with	O
+tetrabenazine	O
+and	O
+tiapride	O
+in	O
+a	O
+Japanese	O
+patient	O
+with	O
+Huntington	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+at	O
+the	O
+terminal	O
+stage	O
+of	O
+recurrent	O
+breast	B-NP
+cancer	I-NP
+.	O
+	
+We	O
+herein	O
+describe	O
+the	O
+case	O
+of	O
+an	O
+81	O
+-	O
+year	O
+-	O
+old	O
+Japanese	O
+woman	O
+with	O
+neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+that	O
+occurred	O
+36	O
+days	O
+after	O
+the	O
+initiation	O
+of	O
+combination	O
+therapy	O
+with	O
+tiapride	O
+(	O
+75	O
+mg	O
+/	O
+day	O
+)	O
+and	O
+tetrabenazine	O
+(	O
+12	O
+.	O
+5	O
+mg	O
+/	O
+day	O
+)	O
+for	O
+Huntington	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+The	O
+patient	O
+had	O
+been	O
+treated	O
+with	O
+tiapride	O
+or	O
+tetrabenazine	O
+alone	O
+without	O
+any	O
+adverse	O
+effects	O
+before	O
+the	O
+administration	O
+of	O
+the	O
+combination	O
+therapy	O
+.	O
+	
+She	O
+also	O
+had	O
+advanced	O
+breast	B-NP
+cancer	I-NP
+when	O
+the	O
+combination	O
+therapy	O
+was	O
+initiated	O
+.	O
+	
+To	O
+the	O
+best	O
+of	O
+our	O
+knowledge	O
+","	O
+the	O
+occurrence	O
+of	O
+neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+due	O
+to	O
+combination	O
+therapy	O
+with	O
+tetrabenazine	O
+and	O
+tiapride	O
+has	O
+not	O
+been	O
+previously	O
+reported	O
+.	O
+	
+Tetrabenazine	O
+should	O
+be	O
+administered	O
+very	O
+carefully	O
+in	O
+combination	O
+with	O
+other	O
+neuroleptic	O
+drugs	O
+","	O
+particularly	O
+in	O
+patients	O
+with	O
+a	O
+worsening	O
+general	O
+condition	O
+.	O
+	
+A	O
+metoprolol	O
+-	O
+terbinafine	O
+combination	O
+induced	O
+bradycardia	B-NP
+.	O
+	
+To	O
+report	O
+a	O
+sinus	B-NP
+bradycardia	I-NP
+induced	O
+by	O
+metoprolol	O
+and	O
+terbinafine	O
+drug	O
+-	O
+drug	O
+interaction	O
+and	O
+its	O
+management	O
+.	O
+	
+A	O
+63	O
+year	O
+-	O
+old	O
+Caucasian	O
+man	O
+on	O
+metoprolol	O
+200	O
+mg	O
+/	O
+day	O
+for	O
+stable	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+was	O
+prescribed	O
+a	O
+90	O
+-	O
+day	O
+course	O
+of	O
+oral	O
+terbinafine	O
+250	O
+mg	O
+/	O
+day	O
+for	O
+onychomycosis	B-NP
+.	O
+	
+On	O
+the	O
+49th	O
+day	O
+of	O
+terbinafine	O
+therapy	O
+","	O
+he	O
+was	O
+brought	O
+to	O
+the	O
+emergency	O
+room	O
+for	O
+a	O
+decrease	O
+of	O
+his	O
+global	O
+health	O
+status	O
+","	O
+confusion	B-NP
+and	O
+falls	O
+.	O
+	
+The	O
+electrocardiogram	O
+revealed	O
+a	O
+37	O
+beats	O
+/	O
+min	O
+sinus	B-NP
+bradycardia	I-NP
+.	O
+	
+A	O
+score	O
+of	O
+7	O
+on	O
+the	O
+Naranjo	O
+adverse	B-NP
+drug	I-NP
+reaction	I-NP
+probability	O
+scale	O
+indicates	O
+a	O
+probable	O
+relationship	O
+between	O
+the	O
+patient	O
+'	O
+s	O
+sinus	B-NP
+bradycardia	I-NP
+and	O
+the	O
+drug	O
+interaction	O
+between	O
+metoprolol	O
+and	O
+terbinafine	O
+.	O
+	
+The	O
+heart	O
+rate	O
+ameliorated	O
+first	O
+with	O
+a	O
+decrease	O
+in	O
+the	O
+dose	O
+of	O
+metoprolol	O
+.	O
+	
+It	O
+was	O
+subsequently	O
+changed	O
+to	O
+bisoprolol	O
+and	O
+the	O
+heart	O
+rate	O
+remained	O
+normal	O
+.	O
+	
+By	O
+inhibiting	O
+the	O
+cytochrome	O
+P450	O
+2D6	O
+","	O
+terbinafine	O
+had	O
+decreased	O
+metoprolol	O
+'	O
+s	O
+clearance	O
+","	O
+leading	O
+in	O
+metoprolol	O
+accumulation	O
+which	O
+has	O
+resulted	O
+in	O
+clinically	O
+significant	O
+sinus	B-NP
+bradycardia	I-NP
+.	O
+	
+Optochiasmatic	O
+and	O
+peripheral	B-NP
+neuropathy	I-NP
+due	O
+to	O
+ethambutol	O
+overtreatment	O
+.	O
+	
+Ethambutol	O
+is	O
+known	O
+to	O
+cause	O
+optic	B-NP
+neuropathy	I-NP
+and	O
+","	O
+more	O
+rarely	O
+","	O
+axonal	O
+polyneuropathy	B-NP
+.	O
+	
+We	O
+characterize	O
+the	O
+clinical	O
+","	O
+neurophysiological	O
+","	O
+and	O
+neuroimaging	O
+findings	O
+in	O
+a	O
+72	O
+-	O
+year	O
+-	O
+old	O
+man	O
+who	O
+developed	O
+visual	B-NP
+loss	I-NP
+and	O
+paresthesias	B-NP
+after	O
+11	O
+weeks	O
+of	O
+exposure	O
+to	O
+a	O
+supratherapeutic	O
+dose	O
+of	O
+ethambutol	O
+.	O
+	
+This	O
+case	O
+demonstrates	O
+the	O
+selective	O
+vulnerability	O
+of	O
+the	O
+anterior	O
+visual	O
+pathways	O
+and	O
+peripheral	O
+nerves	O
+to	O
+ethambutol	O
+toxicity	B-NP
+.	O
+	
+Testosterone	O
+ameliorates	O
+streptozotocin	O
+-	O
+induced	O
+memory	B-NP
+impairment	I-NP
+in	O
+male	O
+rats	O
+.	O
+	
+AIM	O
+:	O
+To	O
+study	O
+the	O
+effects	O
+of	O
+testosterone	O
+on	O
+streptozotocin	O
+(	O
+STZ	O
+)	O
+-	O
+induced	O
+memory	B-NP
+impairment	I-NP
+in	O
+male	O
+rats	O
+.	O
+	
+METHODS	O
+:	O
+Adult	O
+male	O
+Wistar	O
+rats	O
+were	O
+intracerebroventricularly	O
+(	O
+icv	O
+)	O
+infused	O
+with	O
+STZ	O
+(	O
+750	O
+ug	O
+)	O
+on	O
+d	O
+1	O
+and	O
+d	O
+3	O
+","	O
+and	O
+a	O
+passive	O
+avoidance	O
+task	O
+was	O
+assessed	O
+2	O
+weeks	O
+after	O
+the	O
+first	O
+injection	O
+of	O
+STZ	O
+.	O
+	
+Castration	O
+surgery	O
+was	O
+performed	O
+in	O
+another	O
+group	O
+of	O
+rats	O
+","	O
+and	O
+the	O
+passive	O
+avoidance	O
+task	O
+was	O
+assessed	O
+4	O
+weeks	O
+after	O
+the	O
+operation	O
+.	O
+	
+Testosterone	O
+(	O
+1	O
+mg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+d	O
+(	O
+-	O
+1	O
+)	O
+","	O
+sc	O
+)	O
+","	O
+the	O
+androgen	O
+receptor	O
+antagonist	O
+flutamide	O
+(	O
+10	O
+mg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+d	O
+(	O
+-	O
+1	O
+)	O
+","	O
+ip	O
+)	O
+","	O
+the	O
+estrogen	O
+receptor	O
+antagonist	O
+tamoxifen	O
+(	O
+1	O
+mg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+d	O
+(	O
+-	O
+1	O
+)	O
+","	O
+ip	O
+)	O
+or	O
+the	O
+aromatase	O
+inhibitor	O
+letrozole	O
+(	O
+4	O
+mg	O
+.	O
+kg	O
+(	O
+-	O
+1	O
+)	O
+.	O
+d	O
+(	O
+-	O
+1	O
+)	O
+","	O
+ip	O
+)	O
+were	O
+administered	O
+for	O
+6	O
+d	O
+after	O
+the	O
+first	O
+injection	O
+of	O
+STZ	O
+.	O
+	
+RESULTS	O
+:	O
+STZ	O
+administration	O
+and	O
+castration	O
+markedly	O
+decreased	O
+both	O
+STL1	O
+(	O
+the	O
+short	O
+memory	O
+)	O
+and	O
+STL2	O
+(	O
+the	O
+long	O
+memory	O
+)	O
+in	O
+passive	O
+avoidance	O
+tests	O
+.	O
+	
+Testosterone	O
+replacement	O
+almost	O
+restored	O
+the	O
+STL1	O
+and	O
+STL2	O
+in	O
+castrated	O
+rats	O
+","	O
+and	O
+significantly	O
+prolonged	O
+the	O
+STL1	O
+and	O
+STL2	O
+in	O
+STZ	O
+-	O
+treated	O
+rats	O
+.	O
+	
+Administration	O
+of	O
+flutamide	O
+","	O
+letrozole	O
+or	O
+tamoxifen	O
+significantly	O
+impaired	B-NP
+the	I-NP
+memory	I-NP
+in	O
+intact	O
+rats	O
+","	O
+and	O
+significantly	O
+attenuated	O
+the	O
+testosterone	O
+replacement	O
+in	O
+improving	O
+STZ	O
+-	O
+and	O
+castration	O
+-	O
+induced	O
+memory	B-NP
+impairment	I-NP
+.	O
+	
+CONCLUSION	O
+:	O
+Testosterone	O
+administration	O
+ameliorates	O
+STZ	O
+-	O
+and	O
+castration	O
+-	O
+induced	O
+memory	B-NP
+impairment	I-NP
+in	O
+male	O
+Wistar	O
+rats	O
+.	O
+	
+Behavioral	O
+and	O
+neurochemical	O
+studies	O
+in	O
+mice	O
+pretreated	O
+with	O
+garcinielliptone	O
+FC	O
+in	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B-NP
+.	O
+	
+Garcinielliptone	O
+FC	O
+(	O
+GFC	O
+)	O
+isolated	O
+from	O
+hexanic	O
+fraction	O
+seed	O
+extract	O
+of	O
+species	O
+Platonia	O
+insignis	O
+Mart	O
+.	O
+	
+It	O
+is	O
+widely	O
+used	O
+in	O
+folk	O
+medicine	O
+to	O
+treat	O
+skin	B-NP
+diseases	I-NP
+in	O
+both	O
+humans	O
+and	O
+animals	O
+as	O
+well	O
+as	O
+the	O
+seed	O
+decoction	O
+has	O
+been	O
+used	O
+to	O
+treat	O
+diarrheas	B-NP
+and	O
+inflammatory	B-NP
+diseases	I-NP
+.	O
+	
+However	O
+","	O
+there	O
+is	O
+no	O
+research	O
+on	O
+GFC	O
+effects	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+of	O
+rodents	O
+.	O
+	
+The	O
+present	O
+study	O
+aimed	O
+to	O
+evaluate	O
+the	O
+GFC	O
+effects	O
+at	O
+doses	O
+of	O
+25	O
+","	O
+50	O
+or	O
+75	O
+mg	O
+/	O
+kg	O
+on	O
+seizure	B-NP
+parameters	O
+to	O
+determine	O
+their	O
+anticonvulsant	O
+activity	O
+and	O
+its	O
+effects	O
+on	O
+amino	O
+acid	O
+(	O
+r	O
+-	O
+aminobutyric	O
+acid	O
+(	O
+GABA	O
+)	O
+","	O
+glutamine	O
+","	O
+aspartate	O
+and	O
+glutathione	O
+)	O
+levels	O
+as	O
+well	O
+as	O
+on	O
+acetylcholinesterase	O
+(	O
+AChE	O
+)	O
+activity	O
+in	O
+mice	O
+hippocampus	O
+after	O
+seizures	B-NP
+.	O
+	
+GFC	O
+produced	O
+an	O
+increased	O
+latency	O
+to	O
+first	O
+seizure	B-NP
+","	O
+at	O
+doses	O
+25mg	O
+/	O
+kg	O
+(	O
+20	O
+.	O
+12	O
++	O
+2	O
+.	O
+20	O
+min	O
+)	O
+","	O
+50mg	O
+/	O
+kg	O
+(	O
+20	O
+.	O
+95	O
++	O
+2	O
+.	O
+21	O
+min	O
+)	O
+or	O
+75	O
+mg	O
+/	O
+kg	O
+(	O
+23	O
+.	O
+43	O
++	O
+1	O
+.	O
+99	O
+min	O
+)	O
+when	O
+compared	O
+with	O
+seized	O
+mice	O
+.	O
+	
+In	O
+addition	O
+","	O
+GABA	O
+content	O
+of	O
+mice	O
+hippocampus	O
+treated	O
+with	O
+GFC75	O
+plus	O
+P400	O
+showed	O
+an	O
+increase	O
+of	O
+46	O
+.	O
+90	O
+%	O
+when	O
+compared	O
+with	O
+seized	O
+mice	O
+.	O
+	
+In	O
+aspartate	O
+","	O
+glutamine	O
+and	O
+glutamate	O
+levels	O
+detected	O
+a	O
+decrease	O
+of	O
+5	O
+.	O
+21	O
+%	O
+","	O
+13	O
+.	O
+55	O
+%	O
+and	O
+21	O
+.	O
+80	O
+%	O
+","	O
+respectively	O
+in	O
+mice	O
+hippocampus	O
+treated	O
+with	O
+GFC75	O
+plus	O
+P400	O
+when	O
+compared	O
+with	O
+seized	O
+mice	O
+.	O
+	
+Hippocampus	O
+mice	O
+treated	O
+with	O
+GFC75	O
+plus	O
+P400	O
+showed	O
+an	O
+increase	O
+in	O
+AChE	O
+activity	O
+(	O
+63	O
+.	O
+30	O
+%	O
+)	O
+when	O
+compared	O
+with	O
+seized	O
+mice	O
+.	O
+	
+The	O
+results	O
+indicate	O
+that	O
+GFC	O
+can	O
+exert	O
+anticonvulsant	O
+activity	O
+and	O
+reduce	O
+the	O
+frequency	O
+of	O
+installation	O
+of	O
+pilocarpine	O
+-	O
+induced	O
+status	B-NP
+epilepticus	I-NP
+","	O
+as	O
+demonstrated	O
+by	O
+increase	O
+in	O
+latency	O
+to	O
+first	O
+seizure	B-NP
+and	O
+decrease	O
+in	O
+mortality	O
+rate	O
+of	O
+animals	O
+.	O
+	
+In	O
+conclusion	O
+","	O
+our	O
+data	O
+suggest	O
+that	O
+GFC	O
+may	O
+influence	O
+in	O
+epileptogenesis	O
+and	O
+promote	O
+anticonvulsant	O
+actions	O
+in	O
+pilocarpine	O
+model	O
+by	O
+modulating	O
+the	O
+GABA	O
+and	O
+glutamate	O
+contents	O
+and	O
+of	O
+AChE	O
+activity	O
+in	O
+seized	O
+mice	O
+hippocampus	O
+.	O
+	
+This	O
+compound	O
+may	O
+be	O
+useful	O
+to	O
+produce	O
+neuronal	O
+protection	O
+and	O
+it	O
+can	O
+be	O
+considered	O
+as	O
+an	O
+anticonvulsant	O
+agent	O
+.	O
+	
+Standard	O
+operating	O
+procedures	O
+for	O
+antibiotic	O
+therapy	O
+and	O
+the	O
+occurrence	O
+of	O
+acute	B-NP
+kidney	I-NP
+injury	I-NP
+:	O
+a	O
+prospective	O
+","	O
+clinical	O
+","	O
+non	O
+-	O
+interventional	O
+","	O
+observational	O
+study	O
+.	O
+	
+INTRODUCTION	O
+:	O
+Acute	B-NP
+kidney	I-NP
+injury	I-NP
+(	O
+AKI	B-NP
+)	O
+occurs	O
+in	O
+7	O
+%	O
+of	O
+hospitalized	O
+and	O
+66	O
+%	O
+of	O
+Intensive	O
+Care	O
+Unit	O
+(	O
+ICU	O
+)	O
+patients	O
+.	O
+	
+It	O
+increases	O
+mortality	O
+","	O
+hospital	O
+length	O
+of	O
+stay	O
+","	O
+and	O
+costs	O
+.	O
+	
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+investigate	O
+","	O
+whether	O
+there	O
+is	O
+an	O
+association	O
+between	O
+adherence	O
+to	O
+guidelines	O
+(	O
+standard	O
+operating	O
+procedures	O
+(	O
+SOP	O
+)	O
+)	O
+for	O
+potentially	O
+nephrotoxic	B-NP
+antibiotics	O
+and	O
+the	O
+occurrence	O
+of	O
+AKI	B-NP
+.	O
+	
+METHODS	O
+:	O
+This	O
+study	O
+was	O
+carried	O
+out	O
+as	O
+a	O
+prospective	O
+","	O
+clinical	O
+","	O
+non	O
+-	O
+interventional	O
+","	O
+observational	O
+study	O
+.	O
+	
+Data	O
+collection	O
+was	O
+performed	O
+over	O
+a	O
+total	O
+of	O
+170	O
+days	O
+in	O
+three	O
+ICUs	O
+at	O
+Charite	O
+-	O
+Universitaetsmedizin	O
+Berlin	O
+.	O
+	
+A	O
+total	O
+of	O
+675	O
+patients	O
+were	O
+included	O
+;	O
+163	O
+of	O
+these	O
+had	O
+therapy	O
+with	O
+vancomycin	O
+","	O
+gentamicin	O
+","	O
+or	O
+tobramycin	O
+;	O
+were	O
+>	O
+18	O
+years	O
+;	O
+and	O
+treated	O
+in	O
+the	O
+ICU	O
+for	O
+>	O
+24	O
+hours	O
+.	O
+	
+Patients	O
+with	O
+an	O
+adherence	O
+to	O
+SOP	O
+>	O
+70	O
+%	O
+were	O
+classified	O
+into	O
+the	O
+high	O
+adherence	O
+group	O
+(	O
+HAG	O
+)	O
+and	O
+patients	O
+with	O
+an	O
+adherence	O
+of	O
+<	O
+70	O
+%	O
+into	O
+the	O
+low	O
+adherence	O
+group	O
+(	O
+LAG	O
+)	O
+.	O
+	
+AKI	B-NP
+was	O
+defined	O
+according	O
+to	O
+RIFLE	O
+criteria	O
+.	O
+	
+Adherence	O
+to	O
+SOPs	O
+was	O
+evaluated	O
+by	O
+retrospective	O
+expert	O
+audit	O
+.	O
+	
+Development	O
+of	O
+AKI	B-NP
+was	O
+compared	O
+between	O
+groups	O
+with	O
+exact	O
+Chi2	O
+-	O
+test	O
+and	O
+multivariate	O
+logistic	O
+regression	O
+analysis	O
+(	O
+two	O
+-	O
+sided	O
+P	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+LAG	O
+consisted	O
+of	O
+75	O
+patients	O
+(	O
+46	O
+%	O
+)	O
+versus	O
+88	O
+HAG	O
+patients	O
+(	O
+54	O
+%	O
+)	O
+.	O
+	
+AKI	B-NP
+occurred	O
+significantly	O
+more	O
+often	O
+in	O
+LAG	O
+with	O
+36	O
+%	O
+versus	O
+21	O
+%	O
+in	O
+HAG	O
+(	O
+P	O
+=	O
+0	O
+.	O
+35	O
+)	O
+.	O
+	
+Basic	O
+characteristics	O
+were	O
+comparable	O
+","	O
+except	O
+an	O
+increased	O
+rate	O
+of	O
+soft	O
+tissue	O
+infections	B-NP
+in	O
+LAG	O
+.	O
+	
+Multivariate	O
+analysis	O
+revealed	O
+an	O
+odds	O
+ratio	O
+of	O
+2	O
+.	O
+5	O
+-	O
+fold	O
+for	O
+LAG	O
+to	O
+develop	O
+AKI	B-NP
+compared	O
+with	O
+HAG	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+1	O
+.	O
+195	O
+to	O
+5	O
+.	O
+124	O
+","	O
+P	O
+=	O
+0	O
+.	O
+39	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+Low	O
+adherence	O
+to	O
+SOPs	O
+for	O
+potentially	O
+nephrotoxic	B-NP
+antibiotics	O
+was	O
+associated	O
+with	O
+a	O
+higher	O
+occurrence	O
+of	O
+AKI	B-NP
+.	O
+	
+TRIAL	O
+REGISTRATION	O
+:	O
+Current	O
+Controlled	O
+Trials	O
+ISRCTN54598675	O
+.	O
+	
+Registered	O
+17	O
+August	O
+2007	O
+.	O
+	
+Rhabdomyolysis	B-NP
+in	O
+a	O
+hepatitis	B-NP
+C	I-NP
+virus	I-NP
+infected	I-NP
+patient	O
+treated	O
+with	O
+telaprevir	O
+and	O
+simvastatin	O
+.	O
+	
+A	O
+46	O
+-	O
+year	O
+old	O
+man	O
+with	O
+a	O
+chronic	O
+hepatitis	B-NP
+C	I-NP
+virus	I-NP
+infection	I-NP
+received	O
+triple	O
+therapy	O
+with	O
+ribavirin	O
+","	O
+pegylated	O
+interferon	O
+and	O
+telaprevir	O
+.	O
+	
+The	O
+patient	O
+also	O
+received	O
+simvastatin	O
+.	O
+	
+One	O
+month	O
+after	O
+starting	O
+the	O
+antiviral	O
+therapy	O
+","	O
+the	O
+patient	O
+was	O
+admitted	O
+to	O
+the	O
+hospital	O
+because	O
+he	O
+developed	O
+rhabdomyolysis	B-NP
+.	O
+	
+At	O
+admission	O
+simvastatin	O
+and	O
+all	O
+antiviral	O
+drugs	O
+were	O
+discontinued	O
+because	O
+toxicity	B-NP
+due	O
+to	O
+a	O
+drug	O
+-	O
+drug	O
+interaction	O
+was	O
+suspected	O
+.	O
+	
+The	O
+creatine	O
+kinase	O
+peaked	O
+at	O
+62	O
+","	O
+246	O
+IU	O
+/	O
+L	O
+and	O
+the	O
+patient	O
+was	O
+treated	O
+with	O
+intravenous	O
+normal	O
+saline	O
+.	O
+	
+The	O
+patient	O
+'	O
+s	O
+renal	O
+function	O
+remained	O
+unaffected	O
+.	O
+	
+Fourteen	O
+days	O
+after	O
+hospitalization	O
+","	O
+creatine	O
+kinase	O
+level	O
+had	O
+returned	O
+to	O
+230	O
+IU	O
+/	O
+L	O
+and	O
+the	O
+patient	O
+was	O
+discharged	O
+.	O
+	
+Telaprevir	O
+was	O
+considered	O
+the	O
+probable	O
+causative	O
+agent	O
+of	O
+an	O
+interaction	O
+with	O
+simvastatin	O
+according	O
+to	O
+the	O
+Drug	O
+Interaction	O
+Probability	O
+Scale	O
+.	O
+	
+The	O
+interaction	O
+is	O
+due	O
+to	O
+inhibition	O
+of	O
+CYP3A4	O
+-	O
+mediated	O
+simvastatin	O
+clearance	O
+.	O
+	
+Simvastatin	O
+plasma	O
+concentration	O
+increased	O
+30	O
+times	O
+in	O
+this	O
+patient	O
+and	O
+statin	O
+induced	O
+muscle	B-NP
+toxicity	I-NP
+is	O
+related	O
+to	O
+the	O
+concentration	O
+of	O
+the	O
+statin	O
+in	O
+blood	O
+.	O
+	
+In	O
+conclusion	O
+","	O
+with	O
+this	O
+case	O
+we	O
+illustrate	O
+that	O
+telaprevir	O
+as	O
+well	O
+as	O
+statins	O
+are	O
+susceptible	O
+to	O
+clinical	O
+relevant	O
+drug	O
+-	O
+drug	O
+interactions	O
+.	O
+	
+Combination	O
+of	O
+bortezomib	O
+","	O
+thalidomide	O
+","	O
+and	O
+dexamethasone	O
+(	O
+VTD	O
+)	O
+as	O
+a	O
+consolidation	O
+therapy	O
+after	O
+autologous	O
+stem	O
+cell	O
+transplantation	O
+for	O
+symptomatic	O
+multiple	B-NP
+myeloma	I-NP
+in	O
+Japanese	O
+patients	O
+.	O
+	
+Consolidation	O
+therapy	O
+for	O
+patients	O
+with	O
+multiple	B-NP
+myeloma	I-NP
+(	O
+MM	B-NP
+)	O
+has	O
+been	O
+widely	O
+adopted	O
+to	O
+improve	O
+treatment	O
+response	O
+following	O
+autologous	O
+stem	O
+cell	O
+transplantation	O
+.	O
+	
+In	O
+this	O
+study	O
+","	O
+we	O
+retrospectively	O
+analyzed	O
+the	O
+safety	O
+and	O
+efficacy	O
+of	O
+combination	O
+regimen	O
+of	O
+bortezomib	O
+","	O
+thalidomide	O
+","	O
+and	O
+dexamethasone	O
+(	O
+VTD	O
+)	O
+as	O
+consolidation	O
+therapy	O
+in	O
+24	O
+Japanese	O
+patients	O
+with	O
+newly	O
+diagnosed	O
+MM	B-NP
+.	O
+	
+VTD	O
+consisted	O
+of	O
+bortezomib	O
+at	O
+a	O
+dose	O
+of	O
+1	O
+.	O
+3	O
+mg	O
+/	O
+m	O
+(	O
+2	O
+)	O
+and	O
+dexamethasone	O
+at	O
+a	O
+dose	O
+of	O
+40	O
+mg	O
+/	O
+day	O
+on	O
+days	O
+1	O
+","	O
+8	O
+","	O
+15	O
+","	O
+and	O
+22	O
+of	O
+a	O
+35	O
+-	O
+day	O
+cycle	O
+","	O
+with	O
+daily	O
+oral	O
+thalidomide	O
+at	O
+a	O
+dose	O
+of	O
+100	O
+mg	O
+/	O
+day	O
+.	O
+	
+Grade	O
+3	O
+-	O
+4	O
+neutropenia	B-NP
+and	O
+thrombocytopenia	B-NP
+were	O
+documented	O
+in	O
+four	O
+and	O
+three	O
+patients	O
+(	O
+17	O
+and	O
+13	O
+%	O
+)	O
+","	O
+respectively	O
+","	O
+but	O
+drug	O
+dose	O
+reduction	O
+due	O
+to	O
+cytopenia	B-NP
+was	O
+not	O
+required	O
+in	O
+any	O
+case	O
+.	O
+	
+Peripheral	B-NP
+neuropathy	I-NP
+was	O
+common	O
+(	O
+63	O
+%	O
+)	O
+","	O
+but	O
+severe	O
+grade	O
+3	O
+-	O
+4	O
+peripheral	B-NP
+neuropathy	I-NP
+was	O
+not	O
+observed	O
+.	O
+	
+Very	O
+good	O
+partial	O
+response	O
+or	O
+better	O
+response	O
+(	O
+>	O
+VGPR	O
+)	O
+rates	O
+before	O
+and	O
+after	O
+consolidation	O
+therapy	O
+were	O
+54	O
+and	O
+79	O
+%	O
+","	O
+respectively	O
+.	O
+	
+Patients	O
+had	O
+a	O
+significant	O
+probability	O
+of	O
+improving	O
+from	O
+<	O
+VGPR	O
+before	O
+consolidation	O
+therapy	O
+to	O
+>	O
+VGPR	O
+after	O
+consolidation	O
+therapy	O
+(	O
+p	O
+=	O
+0	O
+.	O
+41	O
+)	O
+.	O
+	
+The	O
+VTD	O
+regimen	O
+may	O
+be	O
+safe	O
+and	O
+effective	O
+as	O
+a	O
+consolidation	O
+therapy	O
+in	O
+the	O
+treatment	O
+of	O
+MM	O
+in	O
+Japanese	O
+population	O
+.	O
+	
+Conversion	O
+to	O
+sirolimus	O
+ameliorates	O
+cyclosporine	O
+-	O
+induced	O
+nephropathy	B-NP
+in	O
+the	O
+rat	O
+:	O
+focus	O
+on	O
+serum	O
+","	O
+urine	O
+","	O
+gene	O
+","	O
+and	O
+protein	O
+renal	O
+expression	O
+biomarkers	O
+.	O
+	
+Protocols	O
+of	O
+conversion	O
+from	O
+cyclosporin	O
+A	O
+(	O
+CsA	O
+)	O
+to	O
+sirolimus	O
+(	O
+SRL	O
+)	O
+have	O
+been	O
+widely	O
+used	O
+in	O
+immunotherapy	O
+after	O
+transplantation	O
+to	O
+prevent	O
+CsA	O
+-	O
+induced	O
+nephropathy	B-NP
+","	O
+but	O
+the	O
+molecular	O
+mechanisms	O
+underlying	O
+these	O
+protocols	O
+remain	O
+nuclear	O
+.	O
+	
+This	O
+study	O
+aimed	O
+to	O
+identify	O
+the	O
+molecular	O
+pathways	O
+and	O
+putative	O
+biomarkers	O
+of	O
+CsA	O
+-	O
+to	O
+-	O
+SRL	O
+conversion	O
+in	O
+a	O
+rat	O
+model	O
+.	O
+	
+Four	O
+animal	O
+groups	O
+(	O
+n	O
+=	O
+6	O
+)	O
+were	O
+tested	O
+during	O
+9	O
+weeks	O
+:	O
+control	O
+","	O
+CsA	O
+","	O
+SRL	O
+","	O
+and	O
+conversion	O
+(	O
+CsA	O
+for	O
+3	O
+weeks	O
+followed	O
+by	O
+SRL	O
+for	O
+6	O
+weeks	O
+)	O
+.	O
+	
+Classical	O
+and	O
+emergent	O
+serum	O
+","	O
+urinary	O
+","	O
+and	O
+kidney	O
+tissue	O
+(	O
+gene	O
+and	O
+protein	O
+expression	O
+)	O
+markers	O
+were	O
+assessed	O
+.	O
+	
+Renal	B-NP
+lesions	I-NP
+were	O
+analyzed	O
+in	O
+hematoxylin	O
+and	O
+eosin	O
+","	O
+periodic	O
+acid	O
+-	O
+Schiff	O
+","	O
+and	O
+Masson	O
+'	O
+s	O
+trichrome	O
+stains	O
+.	O
+	
+SRL	O
+-	O
+treated	O
+rats	O
+presented	O
+proteinuria	B-NP
+and	O
+NGAL	O
+(	O
+serum	O
+and	O
+urinary	O
+)	O
+as	O
+the	O
+best	O
+markers	O
+of	O
+renal	B-NP
+impairment	I-NP
+.	O
+	
+Short	O
+CsA	O
+treatment	O
+presented	O
+slight	O
+or	O
+even	O
+absent	O
+kidney	B-NP
+lesions	I-NP
+and	O
+TGF	O
+-	O
+b	O
+","	O
+NF	O
+-	O
+kb	O
+","	O
+mTOR	O
+","	O
+PCNA	O
+","	O
+TP53	O
+","	O
+KIM	O
+-	O
+1	O
+","	O
+and	O
+CTGF	O
+as	O
+relevant	O
+gene	O
+and	O
+protein	O
+changes	O
+.	O
+	
+Prolonged	O
+CsA	O
+exposure	O
+aggravated	O
+renal	B-NP
+damage	I-NP
+","	O
+without	O
+clear	O
+changes	O
+on	O
+the	O
+traditional	O
+markers	O
+","	O
+but	O
+with	O
+changes	O
+in	O
+serums	O
+TGF	O
+-	O
+b	O
+and	O
+IL	O
+-	O
+7	O
+","	O
+TBARs	O
+clearance	O
+","	O
+and	O
+kidney	O
+TGF	O
+-	O
+b	O
+and	O
+mTOR	O
+.	O
+	
+Conversion	O
+to	O
+SRL	O
+prevented	O
+CsA	O
+-	O
+induced	O
+renal	B-NP
+damage	I-NP
+evolution	O
+(	O
+absent	O
+/	O
+mild	O
+grade	O
+lesions	O
+)	O
+","	O
+while	O
+NGAL	O
+(	O
+serum	O
+versus	O
+urine	O
+)	O
+seems	O
+to	O
+be	O
+a	O
+feasible	O
+biomarker	O
+of	O
+CsA	O
+replacement	O
+to	O
+SRL	O
+.	O
+	
+Kinin	O
+B2	O
+receptor	O
+deletion	O
+and	O
+blockage	O
+ameliorates	O
+cisplatin	O
+-	O
+induced	O
+acute	B-NP
+renal	I-NP
+injury	I-NP
+.	O
+	
+Cisplatin	O
+treatment	O
+has	O
+been	O
+adopted	O
+in	O
+some	O
+chemotherapies	O
+;	O
+however	O
+","	O
+this	O
+drug	O
+can	O
+induce	O
+acute	B-NP
+kidney	I-NP
+injury	I-NP
+due	O
+its	O
+ability	O
+to	O
+negatively	O
+affect	O
+renal	O
+function	O
+","	O
+augment	O
+serum	O
+levels	O
+of	O
+creatinine	O
+and	O
+urea	O
+","	O
+increase	O
+the	O
+acute	B-NP
+tubular	I-NP
+necrosis	I-NP
+score	O
+and	O
+up	O
+-	O
+regulate	O
+cytokines	O
+(	O
+e	O
+.	O
+g	O
+.	O
+","	O
+IL	O
+-	O
+1b	O
+and	O
+TNF	O
+-	O
+a	O
+)	O
+.	O
+	
+The	O
+kinin	O
+B2	O
+receptor	O
+has	O
+been	O
+associated	O
+with	O
+the	O
+inflammation	B-NP
+process	O
+","	O
+as	O
+well	O
+as	O
+the	O
+regulation	O
+of	O
+cytokine	O
+expression	O
+","	O
+and	O
+its	O
+deletion	O
+resulted	O
+in	O
+an	O
+improvement	O
+in	O
+the	O
+diabetic	B-NP
+nephropathy	I-NP
+status	O
+.	O
+	
+To	O
+examine	O
+the	O
+role	O
+of	O
+the	O
+kinin	O
+B2	O
+receptor	O
+in	O
+cisplatin	O
+-	O
+induced	O
+acute	B-NP
+kidney	I-NP
+injury	I-NP
+","	O
+kinin	O
+B2	O
+receptor	O
+knockout	O
+mice	O
+were	O
+challenged	O
+with	O
+cisplatin	O
+.	O
+	
+Additionally	O
+","	O
+WT	O
+mice	O
+were	O
+treated	O
+with	O
+a	O
+B2	O
+receptor	O
+antagonist	O
+after	O
+cisplatin	O
+administration	O
+.	O
+	
+B2	O
+receptor	O
+-	O
+deficient	O
+mice	O
+were	O
+less	O
+sensitive	O
+to	O
+this	O
+drug	O
+than	O
+the	O
+WT	O
+mice	O
+","	O
+as	O
+shown	O
+by	O
+reduced	O
+weight	B-NP
+loss	I-NP
+","	O
+better	O
+preservation	O
+of	O
+kidney	O
+function	O
+","	O
+down	O
+regulation	O
+of	O
+inflammatory	O
+cytokines	O
+and	O
+less	O
+acute	B-NP
+tubular	I-NP
+necrosis	I-NP
+.	O
+	
+Moreover	O
+","	O
+treatment	O
+with	O
+the	O
+kinin	O
+B2	O
+receptor	O
+antagonist	O
+effectively	O
+reduced	O
+the	O
+levels	O
+of	O
+serum	O
+creatinine	O
+and	O
+blood	O
+urea	O
+after	O
+cisplatin	O
+administration	O
+.	O
+	
+Thus	O
+","	O
+our	O
+data	O
+suggest	O
+that	O
+the	O
+kinin	O
+B2	O
+receptor	O
+is	O
+involved	O
+in	O
+cisplatin	O
+-	O
+induced	O
+acute	B-NP
+kidney	I-NP
+injury	I-NP
+by	O
+mediating	O
+the	O
+necrotic	B-NP
+process	O
+and	O
+the	O
+expression	O
+of	O
+inflammatory	O
+cytokines	O
+","	O
+thus	O
+resulting	O
+in	O
+declined	O
+renal	O
+function	O
+.	O
+	
+These	O
+results	O
+highlight	O
+the	O
+kinin	O
+B2	O
+receptor	O
+antagonist	O
+treatment	O
+in	O
+amelioration	O
+of	O
+nephrotoxicity	B-NP
+induced	O
+by	O
+cisplatin	O
+therapy	O
+.	O
+	
+Safety	O
+and	O
+efficacy	O
+of	O
+fluocinolone	O
+acetonide	O
+intravitreal	O
+implant	O
+(	O
+0	O
+.	O
+59	O
+mg	O
+)	O
+in	O
+birdshot	B-NP
+retinochoroidopathy	I-NP
+.	O
+	
+PURPOSE	O
+:	O
+To	O
+report	O
+the	O
+treatment	O
+outcomes	O
+of	O
+the	O
+fluocinolone	O
+acetonide	O
+intravitreal	O
+implant	O
+(	O
+0	O
+.	O
+59	O
+mg	O
+)	O
+in	O
+patients	O
+with	O
+birdshot	B-NP
+retinochoroidopathy	I-NP
+whose	O
+disease	O
+is	O
+refractory	O
+or	O
+intolerant	O
+to	O
+conventional	O
+immunomodulatory	O
+therapy	O
+.	O
+	
+METHODS	O
+:	O
+A	O
+retrospective	O
+case	O
+series	O
+involving	O
+11	O
+birdshot	B-NP
+retinochoroidopathy	I-NP
+patients	O
+(	O
+11	O
+eyes	O
+)	O
+.	O
+	
+Eleven	O
+patients	O
+(	O
+11	O
+eyes	O
+)	O
+underwent	O
+surgery	O
+for	O
+fluocinolone	O
+acetonide	O
+implant	O
+(	O
+0	O
+.	O
+59	O
+mg	O
+)	O
+.	O
+	
+Treatment	O
+outcomes	O
+of	O
+interest	O
+were	O
+noted	O
+at	O
+baseline	O
+","	O
+before	O
+fluocinolone	O
+acetonide	O
+implant	O
+","	O
+and	O
+then	O
+at	O
+6	O
+months	O
+","	O
+1	O
+year	O
+","	O
+2	O
+years	O
+","	O
+3	O
+years	O
+","	O
+and	O
+beyond	O
+3	O
+years	O
+.	O
+	
+Disease	O
+activity	O
+markers	O
+","	O
+including	O
+signs	O
+of	O
+ocular	O
+inflammation	B-NP
+","	O
+evidence	O
+of	O
+retinal	B-NP
+vasculitis	I-NP
+","	O
+Swedish	O
+interactive	O
+threshold	O
+algorithm	O
+-	O
+short	O
+wavelength	O
+automated	O
+perimetry	O
+Humphrey	O
+visual	O
+field	O
+analysis	O
+","	O
+electroretinographic	O
+parameters	O
+","	O
+and	O
+optical	O
+coherence	O
+tomography	O
+were	O
+recorded	O
+.	O
+	
+Data	O
+on	O
+occurrence	O
+of	O
+cataract	B-NP
+and	O
+raised	B-NP
+intraocular	I-NP
+pressure	I-NP
+were	O
+collected	O
+in	O
+all	O
+eyes	O
+.	O
+	
+RESULTS	O
+:	O
+Intraocular	O
+inflammation	B-NP
+was	O
+present	O
+in	O
+54	O
+.	O
+5	O
+","	O
+9	O
+.	O
+9	O
+","	O
+11	O
+.	O
+1	O
+","	O
+and	O
+0	O
+%	O
+of	O
+patients	O
+at	O
+baseline	O
+","	O
+6	O
+months	O
+","	O
+1	O
+year	O
+","	O
+2	O
+years	O
+","	O
+3	O
+years	O
+","	O
+and	O
+beyond	O
+3	O
+years	O
+after	O
+receiving	O
+the	O
+implant	O
+","	O
+respectively	O
+.	O
+	
+Active	O
+vasculitis	B-NP
+was	O
+noted	O
+in	O
+36	O
+.	O
+3	O
+%	O
+patients	O
+at	O
+baseline	O
+and	O
+0	O
+%	O
+at	O
+3	O
+years	O
+of	O
+follow	O
+-	O
+up	O
+.	O
+	
+More	O
+than	O
+20	O
+%	O
+(	O
+47	O
+.	O
+61	O
+-	O
+67	O
+.	O
+2	O
+%	O
+)	O
+reduction	O
+in	O
+central	O
+retinal	O
+thickness	O
+was	O
+noted	O
+in	O
+all	O
+patients	O
+with	O
+cystoid	B-NP
+macular	I-NP
+edema	I-NP
+at	O
+6	O
+months	O
+","	O
+1	O
+year	O
+","	O
+2	O
+years	O
+","	O
+and	O
+3	O
+years	O
+postimplant	O
+.	O
+	
+At	O
+baseline	O
+","	O
+54	O
+.	O
+5	O
+%	O
+patients	O
+were	O
+on	O
+immunomodulatory	O
+agents	O
+.	O
+	
+This	O
+percentage	O
+decreased	O
+to	O
+45	O
+.	O
+45	O
+","	O
+44	O
+.	O
+4	O
+","	O
+and	O
+14	O
+.	O
+28	O
+%	O
+at	O
+1	O
+year	O
+","	O
+2	O
+years	O
+","	O
+and	O
+3	O
+years	O
+postimplant	O
+","	O
+respectively	O
+.	O
+	
+Adverse	O
+events	O
+included	O
+increased	B-NP
+intraocular	I-NP
+pressure	I-NP
+(	O
+54	O
+.	O
+5	O
+%	O
+)	O
+and	O
+cataract	B-NP
+formation	O
+(	O
+100	O
+%	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+The	O
+data	O
+suggest	O
+that	O
+fluocinolone	O
+acetonide	O
+implant	O
+(	O
+0	O
+.	O
+59	O
+mg	O
+)	O
+helps	O
+to	O
+control	O
+inflammation	B-NP
+in	O
+otherwise	O
+treatment	O
+-	O
+refractory	O
+cases	O
+of	O
+birdshot	B-NP
+retinochoroidopathy	I-NP
+.	O
+	
+It	O
+is	O
+associated	O
+with	O
+significant	O
+side	O
+effects	O
+of	O
+cataract	B-NP
+and	O
+ocular	B-NP
+hypertension	I-NP
+requiring	O
+treatment	O
+.	O
+	
+Optimal	O
+precurarizing	O
+dose	O
+of	O
+rocuronium	O
+to	O
+decrease	O
+fasciculation	B-NP
+and	O
+myalgia	B-NP
+following	O
+succinylcholine	O
+administration	O
+.	O
+	
+BACKGROUND	O
+:	O
+Succinylcholine	O
+commonly	O
+produces	O
+frequent	O
+adverse	O
+effects	O
+","	O
+including	O
+muscle	B-NP
+fasciculation	I-NP
+and	O
+myalgia	B-NP
+.	O
+	
+The	O
+current	O
+study	O
+identified	O
+the	O
+optimal	O
+dose	O
+of	O
+rocuronium	O
+to	O
+prevent	O
+succinylcholine	O
+-	O
+induced	O
+fasciculation	B-NP
+and	O
+myalgia	B-NP
+and	O
+evaluated	O
+the	O
+influence	O
+of	O
+rocuronium	O
+on	O
+the	O
+speed	O
+of	O
+onset	O
+produced	O
+by	O
+succinylcholine	O
+.	O
+	
+METHODS	O
+:	O
+This	O
+randomized	O
+","	O
+double	O
+-	O
+blinded	O
+study	O
+was	O
+conducted	O
+in	O
+100	O
+patients	O
+randomly	O
+allocated	O
+into	O
+five	O
+groups	O
+of	O
+20	O
+patients	O
+each	O
+.	O
+	
+Patients	O
+were	O
+randomized	O
+to	O
+receive	O
+0	O
+.	O
+2	O
+","	O
+0	O
+.	O
+3	O
+","	O
+0	O
+.	O
+4	O
+","	O
+0	O
+.	O
+5	O
+and	O
+0	O
+.	O
+6	O
+mg	O
+/	O
+kg	O
+rocuronium	O
+as	O
+a	O
+precurarizing	O
+dose	O
+.	O
+	
+Neuromuscular	O
+monitoring	O
+after	O
+each	O
+precurarizing	O
+dose	O
+was	O
+recorded	O
+from	O
+the	O
+adductor	O
+pollicis	O
+muscle	O
+using	O
+acceleromyography	O
+with	O
+train	O
+-	O
+of	O
+-	O
+four	O
+stimulation	O
+of	O
+the	O
+ulnar	O
+nerve	O
+.	O
+	
+All	O
+patients	O
+received	O
+succinylcholine	O
+1	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+at	O
+2	O
+minutes	O
+after	O
+the	O
+precurarization	O
+","	O
+and	O
+were	O
+assessed	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+fasciculations	B-NP
+","	O
+while	O
+myalgia	B-NP
+was	O
+assessed	O
+at	O
+24	O
+hours	O
+after	O
+surgery	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+incidence	O
+and	O
+severity	O
+of	O
+visible	O
+muscle	B-NP
+fasciculation	I-NP
+was	O
+significantly	O
+less	O
+with	O
+increasing	O
+the	O
+amount	O
+of	O
+precurarizing	O
+dose	O
+of	O
+rocuronium	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Those	O
+of	O
+myalgia	B-NP
+tend	O
+to	O
+decrease	O
+according	O
+to	O
+increasing	O
+the	O
+amount	O
+of	O
+precurarizing	O
+dose	O
+of	O
+rocuronium	O
+","	O
+but	O
+there	O
+was	O
+no	O
+significance	O
+(	O
+P	O
+=	O
+0	O
+.	O
+72	O
+)	O
+.	O
+	
+The	O
+onset	O
+time	O
+of	O
+succinylcholine	O
+was	O
+significantly	O
+longer	O
+with	O
+increasing	O
+the	O
+amount	O
+of	O
+precurarizing	O
+dose	O
+of	O
+rocuronium	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Precurarization	O
+with	O
+0	O
+.	O
+4	O
+mg	O
+/	O
+kg	O
+rocuronium	O
+was	O
+the	O
+optimal	O
+dose	O
+considering	O
+the	O
+reduction	O
+in	O
+the	O
+incidence	O
+and	O
+severity	O
+of	O
+fasciculation	B-NP
+and	O
+myalgia	B-NP
+with	O
+acceptable	O
+onset	O
+time	O
+","	O
+and	O
+the	O
+safe	O
+and	O
+effective	O
+precurarization	O
+.	O
+	
+Absence	O
+of	O
+PKC	O
+-	O
+alpha	O
+attenuates	O
+lithium	O
+-	O
+induced	O
+nephrogenic	B-NP
+diabetes	I-NP
+insipidus	I-NP
+.	O
+	
+Lithium	O
+","	O
+an	O
+effective	O
+antipsychotic	O
+","	O
+induces	O
+nephrogenic	B-NP
+diabetes	I-NP
+insipidus	I-NP
+(	O
+NDI	B-NP
+)	O
+in	O
+40	O
+%	O
+of	O
+patients	O
+.	O
+	
+The	O
+decreased	O
+capacity	O
+to	O
+concentrate	O
+urine	O
+is	O
+likely	O
+due	O
+to	O
+lithium	O
+acutely	O
+disrupting	O
+the	O
+cAMP	O
+pathway	O
+and	O
+chronically	O
+reducing	O
+urea	O
+transporter	O
+(	O
+UT	O
+-	O
+A1	O
+)	O
+and	O
+water	O
+channel	O
+(	O
+AQP2	O
+)	O
+expression	O
+in	O
+the	O
+inner	O
+medulla	O
+.	O
+	
+Targeting	O
+an	O
+alternative	O
+signaling	O
+pathway	O
+","	O
+such	O
+as	O
+PKC	O
+-	O
+mediated	O
+signaling	O
+","	O
+may	O
+be	O
+an	O
+effective	O
+method	O
+of	O
+treating	O
+lithium	O
+-	O
+induced	O
+polyuria	B-NP
+.	O
+	
+PKC	O
+-	O
+alpha	O
+null	O
+mice	O
+(	O
+PKCa	O
+KO	O
+)	O
+and	O
+strain	O
+-	O
+matched	O
+wild	O
+type	O
+(	O
+WT	O
+)	O
+controls	O
+were	O
+treated	O
+with	O
+lithium	O
+for	O
+0	O
+","	O
+3	O
+or	O
+5	O
+days	O
+.	O
+	
+WT	O
+mice	O
+had	O
+increased	O
+urine	O
+output	O
+and	O
+lowered	O
+urine	O
+osmolality	O
+after	O
+3	O
+and	O
+5	O
+days	O
+of	O
+treatment	O
+whereas	O
+PKCa	O
+KO	O
+mice	O
+had	O
+no	O
+change	O
+in	O
+urine	O
+output	O
+or	O
+concentration	O
+.	O
+	
+Western	O
+blot	O
+analysis	O
+revealed	O
+that	O
+AQP2	O
+expression	O
+in	O
+medullary	O
+tissues	O
+was	O
+lowered	O
+after	O
+3	O
+and	O
+5	O
+days	O
+in	O
+WT	O
+mice	O
+;	O
+however	O
+","	O
+AQP2	O
+was	O
+unchanged	O
+in	O
+PKCa	O
+KO	O
+.	O
+	
+Similar	O
+results	O
+were	O
+observed	O
+with	O
+UT	O
+-	O
+A1	O
+expression	O
+.	O
+	
+Animals	O
+were	O
+also	O
+treated	O
+with	O
+lithium	O
+for	O
+6	O
+weeks	O
+.	O
+	
+Lithium	O
+-	O
+treated	O
+WT	O
+mice	O
+had	O
+19	O
+-	O
+fold	O
+increased	O
+urine	O
+output	O
+whereas	O
+treated	O
+PKCa	O
+KO	O
+animals	O
+had	O
+a	O
+4	O
+-	O
+fold	O
+increase	O
+in	O
+output	O
+.	O
+	
+AQP2	O
+and	O
+UT	O
+-	O
+A1	O
+expression	O
+was	O
+lowered	O
+in	O
+6	O
+week	O
+lithium	O
+-	O
+treated	O
+WT	O
+animals	O
+whereas	O
+in	O
+treated	O
+PKCa	O
+KO	O
+mice	O
+","	O
+AQP2	O
+was	O
+only	O
+reduced	O
+by	O
+2	O
+-	O
+fold	O
+and	O
+UT	O
+-	O
+A1	O
+expression	O
+was	O
+unaffected	O
+.	O
+	
+Urinary	O
+sodium	O
+","	O
+potassium	O
+and	O
+calcium	O
+were	O
+elevated	O
+in	O
+lithium	O
+-	O
+fed	O
+WT	O
+but	O
+not	O
+in	O
+lithium	O
+-	O
+fed	O
+PKCa	O
+KO	O
+mice	O
+.	O
+	
+Our	O
+data	O
+show	O
+that	O
+ablation	O
+of	O
+PKCa	O
+preserves	O
+AQP2	O
+and	O
+UT	O
+-	O
+A1	O
+protein	O
+expression	O
+and	O
+localization	O
+in	O
+lithium	O
+-	O
+induced	O
+NDI	B-NP
+","	O
+and	O
+prevents	O
+the	O
+development	O
+of	O
+the	O
+severe	O
+polyuria	B-NP
+associated	O
+with	O
+lithium	O
+therapy	O
+.	O
+	
+Is	O
+Dysguesia	B-NP
+Going	O
+to	O
+be	O
+a	O
+Rare	O
+or	O
+a	O
+Common	O
+Side	O
+-	O
+effect	O
+of	O
+Amlodipine	O
+?	O
+	
+A	O
+very	O
+rare	O
+side	O
+-	O
+effect	O
+of	O
+amlodipine	O
+is	O
+dysguesia	B-NP
+.	O
+	
+A	O
+review	O
+of	O
+the	O
+literature	O
+produced	O
+only	O
+one	O
+case	O
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+about	O
+a	O
+female	O
+with	O
+essential	O
+hypertension	B-NP
+on	O
+drug	O
+treatment	O
+with	O
+amlodipine	O
+developed	O
+loss	B-NP
+of	I-NP
+taste	I-NP
+sensation	I-NP
+.	O
+	
+Condition	O
+moderately	O
+improved	O
+on	O
+stoppage	O
+of	O
+the	O
+drug	O
+for	O
+25	O
+days	O
+.	O
+	
+We	O
+conclude	O
+that	O
+amlodipine	O
+can	O
+cause	O
+dysguesia	B-NP
+.	O
+	
+Here	O
+","	O
+we	O
+describe	O
+the	O
+clinical	O
+presentation	O
+and	O
+review	O
+the	O
+relevant	O
+literature	O
+on	O
+amlodipine	O
+and	O
+dysguesia	B-NP
+.	O
+	
+Rhabdomyolysis	B-NP
+in	O
+association	O
+with	O
+simvastatin	O
+and	O
+dosage	O
+increment	O
+in	O
+clarithromycin	O
+.	O
+	
+Clarithromycin	O
+is	O
+the	O
+most	O
+documented	O
+cytochrome	O
+P450	O
+3A4	O
+(	O
+CYP3A4	O
+)	O
+inhibitor	O
+to	O
+cause	O
+an	O
+adverse	O
+interaction	O
+with	O
+simvastatin	O
+.	O
+	
+This	O
+particular	O
+case	O
+is	O
+of	O
+interest	O
+as	O
+rhabdomyolysis	B-NP
+only	O
+occurred	O
+after	O
+an	O
+increase	O
+in	O
+the	O
+dose	O
+of	O
+clarithromycin	O
+.	O
+	
+The	O
+patient	O
+developed	O
+raised	O
+cardiac	O
+biomarkers	O
+without	O
+any	O
+obvious	O
+cardiac	O
+issues	O
+","	O
+a	O
+phenomenon	O
+that	O
+has	O
+been	O
+linked	O
+to	O
+rhabdomyolysis	B-NP
+previously	O
+.	O
+	
+To	O
+date	O
+","	O
+there	O
+has	O
+been	O
+no	O
+reported	O
+effect	O
+of	O
+rhabdomyolysis	B-NP
+on	O
+the	O
+structure	O
+and	O
+function	O
+of	O
+cardiac	O
+muscle	O
+.	O
+	
+Clinicians	O
+need	O
+to	O
+be	O
+aware	O
+of	O
+prescribing	O
+concomitant	O
+medications	O
+that	O
+increase	O
+the	O
+risk	O
+of	O
+myopathy	B-NP
+or	O
+inhibit	O
+the	O
+CYP3A4	O
+enzyme	O
+.	O
+	
+Our	O
+case	O
+suggests	O
+that	O
+troponin	O
+elevation	O
+could	O
+be	O
+associated	O
+with	O
+statin	O
+induced	O
+rhabdomyolysis	B-NP
+","	O
+which	O
+may	O
+warrant	O
+further	O
+studies	O
+.	O
+	
+Characterization	O
+of	O
+a	O
+novel	O
+BCHE	O
+"	O
+silent	O
+"	O
+allele	O
+:	O
+point	O
+mutation	O
+(	O
+p	O
+.	O
+Val204Asp	O
+)	O
+causes	O
+loss	O
+of	O
+activity	O
+and	O
+prolonged	O
+apnea	B-NP
+with	O
+suxamethonium	O
+.	O
+	
+Butyrylcholinesterase	B-NP
+deficiency	I-NP
+is	O
+characterized	O
+by	O
+prolonged	O
+apnea	B-NP
+after	O
+the	O
+use	O
+of	O
+muscle	O
+relaxants	O
+(	O
+suxamethonium	O
+or	O
+mivacurium	O
+)	O
+in	O
+patients	O
+who	O
+have	O
+mutations	O
+in	O
+the	O
+BCHE	O
+gene	O
+.	O
+	
+Here	O
+","	O
+we	O
+report	O
+a	O
+case	O
+of	O
+prolonged	O
+neuromuscular	O
+block	O
+after	O
+administration	O
+of	O
+suxamethonium	O
+leading	O
+to	O
+the	O
+discovery	O
+of	O
+a	O
+novel	O
+BCHE	O
+variant	O
+(	O
+c	O
+.	O
+695T	O
+>	O
+A	O
+","	O
+p	O
+.	O
+Val204Asp	O
+)	O
+.	O
+	
+Inhibition	O
+studies	O
+","	O
+kinetic	O
+analysis	O
+and	O
+molecular	O
+dynamics	O
+were	O
+undertaken	O
+to	O
+understand	O
+how	O
+this	O
+mutation	O
+disrupts	O
+the	O
+catalytic	O
+triad	O
+and	O
+determines	O
+a	O
+"	O
+silent	O
+"	O
+phenotype	O
+.	O
+	
+Low	O
+activity	O
+of	O
+patient	O
+plasma	O
+butyrylcholinesterase	O
+with	O
+butyrylthiocholine	O
+(	O
+BTC	O
+)	O
+and	O
+benzoylcholine	O
+","	O
+and	O
+values	O
+of	O
+dibucaine	O
+and	O
+fluoride	O
+numbers	O
+fit	O
+with	O
+heterozygous	O
+atypical	O
+silent	O
+genotype	O
+.	O
+	
+Electrophoretic	O
+analysis	O
+of	O
+plasma	O
+BChE	O
+of	O
+the	O
+proband	O
+and	O
+his	O
+mother	O
+showed	O
+that	O
+patient	O
+has	O
+a	O
+reduced	O
+amount	O
+of	O
+tetrameric	O
+enzyme	O
+in	O
+plasma	O
+and	O
+that	O
+minor	O
+fast	O
+-	O
+moving	O
+BChE	O
+components	O
+:	O
+monomer	O
+","	O
+dimer	O
+","	O
+and	O
+monomer	O
+-	O
+albumin	O
+conjugate	O
+are	O
+missing	O
+.	O
+	
+Kinetic	O
+analysis	O
+showed	O
+that	O
+the	O
+p	O
+.	O
+Val204Asp	O
+/	O
+p	O
+.	O
+Asp70Gly	O
+-	O
+p	O
+.	O
+Ala539Thr	O
+BChE	O
+displays	O
+a	O
+pure	O
+Michaelian	O
+behavior	O
+with	O
+BTC	O
+as	O
+the	O
+substrate	O
+.	O
+	
+Both	O
+catalytic	O
+parameters	O
+Km	O
+=	O
+265	O
+uM	O
+for	O
+BTC	O
+","	O
+two	O
+times	O
+higher	O
+than	O
+that	O
+of	O
+the	O
+atypical	O
+enzyme	O
+","	O
+and	O
+a	O
+low	O
+Vmax	O
+are	O
+consistent	O
+with	O
+the	O
+absence	O
+of	O
+activity	O
+against	O
+suxamethonium	O
+.	O
+	
+Molecular	O
+dynamic	O
+(	O
+MD	O
+)	O
+simulations	O
+showed	O
+that	O
+the	O
+overall	O
+effect	O
+of	O
+the	O
+mutation	O
+p	O
+.	O
+Val204Asp	O
+is	O
+disruption	O
+of	O
+hydrogen	O
+bonding	O
+between	O
+Gln223	O
+and	O
+Glu441	O
+","	O
+leading	O
+Ser198	O
+and	O
+His438	O
+to	O
+move	O
+away	O
+from	O
+each	O
+other	O
+with	O
+subsequent	O
+disruption	O
+of	O
+the	O
+catalytic	O
+triad	O
+functionality	O
+regardless	O
+of	O
+the	O
+type	O
+of	O
+substrate	O
+.	O
+	
+MD	O
+also	O
+showed	O
+that	O
+the	O
+enzyme	O
+volume	O
+is	O
+increased	O
+","	O
+suggesting	O
+a	O
+pre	O
+-	O
+denaturation	O
+state	O
+.	O
+	
+This	O
+fits	O
+with	O
+the	O
+reduced	O
+concentration	O
+of	O
+p	O
+.	O
+Ala204Asp	O
+/	O
+p	O
+.	O
+Asp70Gly	O
+-	O
+p	O
+.	O
+Ala539Thr	O
+tetrameric	O
+enzyme	O
+in	O
+the	O
+plasma	O
+and	O
+non	O
+-	O
+detectable	O
+fast	O
+moving	O
+-	O
+bands	O
+on	O
+electrophoresis	O
+gels	O
+.	O
+	
+Delayed	O
+anemia	B-NP
+after	O
+treatment	O
+with	O
+injectable	O
+artesunate	O
+in	O
+the	O
+Democratic	O
+Republic	O
+of	O
+the	O
+Congo	O
+:	O
+a	O
+manageable	O
+issue	O
+.	O
+	
+Cases	O
+of	O
+delayed	O
+hemolytic	B-NP
+anemia	I-NP
+have	O
+been	O
+described	O
+after	O
+treatment	O
+with	O
+injectable	O
+artesunate	O
+","	O
+the	O
+current	O
+World	O
+Health	O
+Organization	O
+(	O
+WHO	O
+)	O
+-	O
+recommended	O
+first	O
+-	O
+line	O
+drug	O
+for	O
+the	O
+treatment	O
+of	O
+severe	O
+malaria	B-NP
+.	O
+	
+A	O
+total	O
+of	O
+350	O
+patients	O
+(	O
+215	O
+[	O
+61	O
+.	O
+4	O
+%	O
+]	O
+<	O
+5	O
+years	O
+of	O
+age	O
+and	O
+135	O
+[	O
+38	O
+.	O
+6	O
+%	O
+]	O
+>	O
+5	O
+years	O
+of	O
+age	O
+)	O
+were	O
+followed	O
+-	O
+up	O
+after	O
+treatment	O
+with	O
+injectable	O
+artesunate	O
+for	O
+severe	O
+malaria	B-NP
+in	O
+hospitals	O
+and	O
+health	O
+centers	O
+of	O
+the	O
+Democratic	O
+Republic	O
+of	O
+the	O
+Congo	O
+.	O
+	
+Complete	O
+series	O
+of	O
+hemoglobin	O
+(	O
+Hb	O
+)	O
+measurements	O
+were	O
+available	O
+for	O
+201	O
+patients	O
+.	O
+	
+A	O
+decrease	O
+in	O
+Hb	O
+levels	O
+between	O
+2	O
+and	O
+5	O
+g	O
+/	O
+dL	O
+was	O
+detected	O
+in	O
+23	O
+(	O
+11	O
+.	O
+4	O
+%	O
+)	O
+patients	O
+during	O
+the	O
+follow	O
+-	O
+up	O
+period	O
+.	O
+	
+For	O
+five	O
+patients	O
+","	O
+Hb	O
+levels	O
+decreased	O
+below	O
+5	O
+g	O
+/	O
+dL	O
+during	O
+at	O
+least	O
+one	O
+follow	O
+-	O
+up	O
+visit	O
+.	O
+	
+All	O
+cases	O
+of	O
+delayed	O
+anemia	B-NP
+were	O
+clinically	O
+manageable	O
+and	O
+resolved	O
+within	O
+one	O
+month	O
+.	O
+	
+Regulation	O
+of	O
+signal	O
+transducer	O
+and	O
+activator	O
+of	O
+transcription	O
+3	O
+and	O
+apoptotic	O
+pathways	O
+by	O
+betaine	O
+attenuates	O
+isoproterenol	O
+-	O
+induced	O
+acute	O
+myocardial	B-NP
+injury	I-NP
+in	O
+rats	O
+.	O
+	
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+investigate	O
+the	O
+cardioprotective	O
+effects	O
+of	O
+betaine	O
+on	O
+acute	O
+myocardial	B-NP
+ischemia	I-NP
+induced	O
+experimentally	O
+in	O
+rats	O
+focusing	O
+on	O
+regulation	O
+of	O
+signal	O
+transducer	O
+and	O
+activator	O
+of	O
+transcription	O
+3	O
+(	O
+STAT3	O
+)	O
+and	O
+apoptotic	O
+pathways	O
+as	O
+the	O
+potential	O
+mechanism	O
+underlying	O
+the	O
+drug	O
+effect	O
+.	O
+	
+Male	O
+Sprague	O
+Dawley	O
+rats	O
+were	O
+treated	O
+with	O
+betaine	O
+(	O
+100	O
+","	O
+200	O
+","	O
+and	O
+400	O
+mg	O
+/	O
+kg	O
+)	O
+orally	O
+for	O
+40	O
+days	O
+.	O
+	
+Acute	O
+myocardial	B-NP
+ischemic	I-NP
+injury	I-NP
+was	O
+induced	O
+in	O
+rats	O
+by	O
+subcutaneous	O
+injection	O
+of	O
+isoproterenol	O
+(	O
+85	O
+mg	O
+/	O
+kg	O
+)	O
+","	O
+for	O
+two	O
+consecutive	O
+days	O
+.	O
+	
+Serum	O
+cardiac	O
+marker	O
+enzyme	O
+","	O
+histopathological	O
+variables	O
+and	O
+expression	O
+of	O
+protein	O
+levels	O
+were	O
+analyzed	O
+.	O
+	
+Oral	O
+administration	O
+of	O
+betaine	O
+(	O
+200	O
+and	O
+400	O
+mg	O
+/	O
+kg	O
+)	O
+significantly	O
+reduced	O
+the	O
+level	O
+of	O
+cardiac	O
+marker	O
+enzyme	O
+in	O
+the	O
+serum	O
+and	O
+prevented	O
+left	O
+ventricular	B-NP
+remodeling	I-NP
+.	O
+	
+Western	O
+blot	O
+analysis	O
+showed	O
+that	O
+isoproterenol	O
+-	O
+induced	O
+phosphorylation	O
+of	O
+STAT3	O
+was	O
+maintained	O
+or	O
+further	O
+enhanced	O
+by	O
+betaine	O
+treatment	O
+in	O
+myocardium	O
+.	O
+	
+Furthermore	O
+","	O
+betaine	O
+(	O
+200	O
+and	O
+400	O
+mg	O
+/	O
+kg	O
+)	O
+treatment	O
+increased	O
+the	O
+ventricular	O
+expression	O
+of	O
+Bcl	O
+-	O
+2	O
+and	O
+reduced	O
+the	O
+level	O
+of	O
+Bax	O
+","	O
+therefore	O
+causing	O
+a	O
+significant	O
+increase	O
+in	O
+the	O
+ratio	O
+of	O
+Bcl	O
+-	O
+2	O
+/	O
+Bax	O
+.	O
+	
+The	O
+protective	O
+role	O
+of	O
+betaine	O
+on	O
+myocardial	B-NP
+damage	I-NP
+was	O
+further	O
+confirmed	O
+by	O
+histopathological	O
+examination	O
+.	O
+	
+In	O
+summary	O
+","	O
+our	O
+results	O
+showed	O
+that	O
+betaine	O
+pretreatment	O
+attenuated	O
+isoproterenol	O
+-	O
+induced	O
+acute	O
+myocardial	B-NP
+ischemia	I-NP
+via	O
+the	O
+regulation	O
+of	O
+STAT3	O
+and	O
+apoptotic	O
+pathways	O
+.	O
+	
+Quetiapine	O
+-	O
+induced	O
+neutropenia	B-NP
+in	O
+a	O
+bipolar	B-NP
+patient	O
+with	O
+hepatocellular	B-NP
+carcinoma	I-NP
+.	O
+	
+OBJECTIVE	O
+:	O
+Quetiapine	O
+is	O
+a	O
+dibenzothiazepine	O
+derivative	O
+","	O
+similar	O
+to	O
+clozapine	O
+","	O
+which	O
+has	O
+the	O
+highest	O
+risk	O
+of	O
+causing	O
+blood	B-NP
+dyscrasias	I-NP
+","	O
+especially	O
+neutropenia	B-NP
+.	O
+	
+There	O
+are	O
+some	O
+case	O
+reports	O
+about	O
+this	O
+side	O
+effect	O
+of	O
+quetiapine	O
+","	O
+but	O
+possible	O
+risk	O
+factors	O
+are	O
+seldom	O
+discussed	O
+and	O
+identified	O
+.	O
+	
+A	O
+case	O
+of	O
+a	O
+patient	O
+with	O
+hepatocellular	B-NP
+carcinoma	I-NP
+that	O
+developed	O
+neutropenia	B-NP
+after	O
+treatment	O
+with	O
+quetiapine	O
+is	O
+described	O
+here	O
+.	O
+	
+CASE	O
+REPORT	O
+:	O
+A	O
+62	O
+-	O
+year	O
+-	O
+old	O
+Taiwanese	O
+widow	O
+with	O
+bipolar	B-NP
+disorder	I-NP
+was	O
+diagnosed	O
+with	O
+hepatocellular	B-NP
+carcinoma	I-NP
+at	O
+age	O
+60	O
+.	O
+	
+She	O
+developed	O
+leucopenia	B-NP
+after	O
+being	O
+treated	O
+with	O
+quetiapine	O
+.	O
+	
+After	O
+quetiapine	O
+was	O
+discontinued	O
+","	O
+her	O
+white	O
+blood	O
+cell	O
+count	O
+returned	O
+to	O
+normal	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Although	O
+neutropenia	B-NP
+is	O
+not	O
+a	O
+common	O
+side	O
+effect	O
+of	O
+quetiapine	O
+","	O
+physicians	O
+should	O
+be	O
+cautious	O
+about	O
+its	O
+presentation	O
+and	O
+associated	O
+risk	O
+factors	O
+.	O
+	
+Hepatic	B-NP
+dysfunction	I-NP
+may	O
+be	O
+one	O
+of	O
+the	O
+possible	O
+risk	O
+factors	O
+","	O
+and	O
+concomitant	O
+fever	B-NP
+may	O
+be	O
+a	O
+diagnostic	O
+marker	O
+for	O
+adverse	O
+reaction	O
+to	O
+quetiapine	O
+.	O
+	
+Lateral	O
+antebrachial	O
+cutaneous	O
+neuropathy	B-NP
+after	O
+steroid	O
+injection	O
+at	O
+lateral	O
+epicondyle	O
+.	O
+	
+BACKGROUND	O
+AND	O
+OBJECTIVES	O
+:	O
+This	O
+report	O
+aimed	O
+to	O
+present	O
+a	O
+case	O
+of	O
+lateral	O
+antebrachial	O
+cutaneous	O
+neuropathy	B-NP
+(	O
+LACNP	O
+)	O
+that	O
+occurred	O
+after	O
+a	O
+steroid	O
+injection	O
+in	O
+the	O
+lateral	O
+epicondyle	O
+to	O
+treat	O
+lateral	B-NP
+epicondylitis	I-NP
+in	O
+a	O
+40	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+.	O
+	
+MATERIAL	O
+AND	O
+METHOD	O
+:	O
+A	O
+40	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+presented	O
+with	O
+decreased	O
+sensation	O
+and	O
+paresthesia	B-NP
+over	O
+her	O
+right	O
+lateral	O
+forearm	O
+;	O
+the	O
+paresthesia	B-NP
+had	O
+occurred	O
+after	O
+a	O
+steroid	O
+injection	O
+in	O
+the	O
+right	O
+lateral	O
+epicondyle	O
+3	O
+months	O
+before	O
+.	O
+	
+Her	O
+sensation	O
+of	O
+light	O
+touch	O
+and	O
+pain	B-NP
+was	O
+diminished	O
+over	O
+the	O
+lateral	O
+side	O
+of	O
+the	O
+right	O
+forearm	O
+and	O
+wrist	O
+area	O
+.	O
+	
+RESULTS	O
+:	O
+The	O
+sensory	O
+action	O
+potential	O
+amplitude	O
+of	O
+the	O
+right	O
+lateral	O
+antebrachial	O
+cutaneous	O
+nerve	O
+(	O
+LACN	O
+)	O
+(	O
+6	O
+.	O
+2	O
+uV	O
+)	O
+was	O
+lower	O
+than	O
+that	O
+of	O
+the	O
+left	O
+(	O
+13	O
+.	O
+1	O
+uV	O
+)	O
+.	O
+	
+The	O
+difference	O
+of	O
+amplitude	O
+between	O
+both	O
+sides	O
+was	O
+significant	O
+because	O
+there	O
+was	O
+more	O
+than	O
+a	O
+50	O
+%	O
+reduction	O
+.	O
+	
+She	O
+was	O
+diagnosed	O
+with	O
+right	O
+LACNP	O
+(	O
+mainly	O
+axonal	O
+involvement	O
+)	O
+on	O
+the	O
+basis	O
+of	O
+the	O
+clinical	O
+manifestation	O
+and	O
+the	O
+electrodiagnostic	O
+findings	O
+.	O
+	
+Her	O
+symptoms	O
+improved	O
+through	O
+physical	O
+therapy	O
+but	O
+persisted	O
+to	O
+some	O
+degree	O
+.	O
+	
+CONCLUSION	O
+:	O
+This	O
+report	O
+describes	O
+the	O
+case	O
+of	O
+a	O
+woman	O
+with	O
+LACNP	O
+that	O
+developed	O
+after	O
+a	O
+steroid	O
+injection	O
+for	O
+the	O
+treatment	O
+of	O
+lateral	B-NP
+epicondylitis	I-NP
+.	O
+	
+An	O
+electrodiagnostic	O
+study	O
+","	O
+including	O
+a	O
+nerve	O
+conduction	O
+study	O
+of	O
+the	O
+LACN	O
+","	O
+was	O
+helpful	O
+to	O
+diagnose	O
+right	O
+LACNP	O
+and	O
+to	O
+find	O
+the	O
+passage	O
+of	O
+the	O
+LACN	O
+on	O
+the	O
+lateral	O
+epicondyle	O
+.	O
+	
+Curcumin	O
+prevents	O
+maleate	O
+-	O
+induced	O
+nephrotoxicity	B-NP
+:	O
+relation	O
+to	O
+hemodynamic	O
+alterations	O
+","	O
+oxidative	O
+stress	O
+","	O
+mitochondrial	O
+oxygen	O
+consumption	O
+and	O
+activity	O
+of	O
+respiratory	O
+complex	O
+I	O
+.	O
+	
+The	O
+potential	O
+protective	O
+effect	O
+of	O
+the	O
+dietary	O
+antioxidant	O
+curcumin	O
+(	O
+120	O
+mg	O
+/	O
+Kg	O
+/	O
+day	O
+for	O
+6	O
+days	O
+)	O
+against	O
+the	O
+renal	B-NP
+injury	I-NP
+induced	O
+by	O
+maleate	O
+was	O
+evaluated	O
+.	O
+	
+Tubular	O
+proteinuria	B-NP
+and	O
+oxidative	O
+stress	O
+were	O
+induced	O
+by	O
+a	O
+single	O
+injection	O
+of	O
+maleate	O
+(	O
+400	O
+mg	O
+/	O
+kg	O
+)	O
+in	O
+rats	O
+.	O
+	
+Maleate	O
+-	O
+induced	O
+renal	B-NP
+injury	I-NP
+included	O
+increase	O
+in	O
+renal	O
+vascular	O
+resistance	O
+and	O
+in	O
+the	O
+urinary	O
+excretion	O
+of	O
+total	O
+protein	O
+","	O
+glucose	O
+","	O
+sodium	O
+","	O
+neutrophil	O
+gelatinase	O
+-	O
+associated	O
+lipocalin	O
+(	O
+NGAL	O
+)	O
+and	O
+N	O
+-	O
+acetyl	O
+b	O
+-	O
+D	O
+-	O
+glucosaminidase	O
+(	O
+NAG	O
+)	O
+","	O
+upregulation	O
+of	O
+kidney	B-NP
+injury	I-NP
+molecule	O
+(	O
+KIM	O
+)	O
+-	O
+1	O
+","	O
+decrease	O
+in	O
+renal	O
+blood	O
+flow	O
+and	O
+claudin	O
+-	O
+2	O
+expression	O
+besides	O
+of	O
+necrosis	B-NP
+and	O
+apoptosis	O
+of	O
+tubular	O
+cells	O
+on	O
+24	O
+h	O
+.	O
+	
+Oxidative	O
+stress	O
+was	O
+determined	O
+by	O
+measuring	O
+the	O
+oxidation	O
+of	O
+lipids	O
+and	O
+proteins	O
+and	O
+diminution	O
+in	O
+renal	O
+Nrf2	O
+levels	O
+.	O
+	
+Studies	O
+were	O
+also	O
+conducted	O
+in	O
+renal	O
+epithelial	O
+LLC	O
+-	O
+PK1	O
+cells	O
+and	O
+in	O
+mitochondria	O
+isolated	O
+from	O
+kidneys	O
+of	O
+all	O
+the	O
+experimental	O
+groups	O
+.	O
+	
+Maleate	O
+induced	O
+cell	O
+damage	O
+and	O
+reactive	O
+oxygen	O
+species	O
+(	O
+ROS	O
+)	O
+production	O
+in	O
+LLC	O
+-	O
+PK1	O
+cells	O
+in	O
+culture	O
+.	O
+	
+In	O
+addition	O
+","	O
+maleate	O
+treatment	O
+reduced	O
+oxygen	O
+consumption	O
+in	O
+ADP	O
+-	O
+stimulated	O
+mitochondria	O
+and	O
+diminished	O
+respiratory	O
+control	O
+index	O
+when	O
+using	O
+malate	O
+/	O
+glutamate	O
+as	O
+substrate	O
+.	O
+	
+The	O
+activities	O
+of	O
+both	O
+complex	O
+I	O
+and	O
+aconitase	O
+were	O
+also	O
+diminished	O
+.	O
+	
+All	O
+the	O
+above	O
+-	O
+described	O
+alterations	O
+were	O
+prevented	O
+by	O
+curcumin	O
+.	O
+	
+It	O
+is	O
+concluded	O
+that	O
+curcumin	O
+is	O
+able	O
+to	O
+attenuate	O
+in	O
+vivo	O
+maleate	O
+-	O
+induced	O
+nephropathy	B-NP
+and	O
+in	O
+vitro	O
+cell	O
+damage	O
+.	O
+	
+The	O
+in	O
+vivo	O
+protection	O
+was	O
+associated	O
+to	O
+the	O
+prevention	O
+of	O
+oxidative	O
+stress	O
+and	O
+preservation	O
+of	O
+mitochondrial	O
+oxygen	O
+consumption	O
+and	O
+activity	O
+of	O
+respiratory	O
+complex	O
+I	O
+","	O
+and	O
+the	O
+in	O
+vitro	O
+protection	O
+was	O
+associated	O
+to	O
+the	O
+prevention	O
+of	O
+ROS	O
+production	O
+.	O
+	
+Anticonvulsant	O
+actions	O
+of	O
+MK	O
+-	O
+801	O
+on	O
+the	O
+lithium	O
+-	O
+pilocarpine	O
+model	O
+of	O
+status	B-NP
+epilepticus	I-NP
+in	O
+rats	O
+.	O
+	
+MK	O
+-	O
+801	O
+","	O
+a	O
+noncompetitive	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+(	O
+NMDA	O
+)	O
+receptor	O
+antagonist	O
+","	O
+was	O
+tested	O
+for	O
+anticonvulsant	O
+effects	O
+in	O
+rats	O
+using	O
+two	O
+seizure	B-NP
+models	O
+","	O
+coadministration	O
+of	O
+lithium	O
+and	O
+pilocarpine	O
+and	O
+administration	O
+of	O
+a	O
+high	O
+dose	O
+of	O
+pilocarpine	O
+alone	O
+.	O
+	
+Three	O
+major	O
+results	O
+are	O
+reported	O
+.	O
+	
+First	O
+","	O
+pretreatment	O
+with	O
+MK	O
+-	O
+801	O
+produced	O
+an	O
+effective	O
+and	O
+dose	O
+-	O
+dependent	O
+anticonvulsant	O
+action	O
+with	O
+the	O
+lithium	O
+-	O
+pilocarpine	O
+model	O
+but	O
+not	O
+with	O
+rats	O
+treated	O
+with	O
+pilocarpine	O
+alone	O
+","	O
+suggesting	O
+that	O
+different	O
+biochemical	O
+mechanisms	O
+control	O
+seizures	B-NP
+in	O
+these	O
+two	O
+models	O
+.	O
+	
+Second	O
+","	O
+the	O
+anticonvulsant	O
+effect	O
+of	O
+MK	O
+-	O
+801	O
+in	O
+the	O
+lithium	O
+-	O
+pilocarpine	O
+model	O
+only	O
+occurred	O
+after	O
+initial	O
+periods	O
+of	O
+seizure	B-NP
+activity	O
+.	O
+	
+This	O
+observation	O
+is	O
+suggested	O
+to	O
+be	O
+an	O
+in	O
+vivo	O
+demonstration	O
+of	O
+the	O
+conclusion	O
+derived	O
+from	O
+in	O
+vitro	O
+experiments	O
+that	O
+MK	O
+-	O
+801	O
+binding	O
+requires	O
+agonist	O
+-	O
+induced	O
+opening	O
+of	O
+the	O
+channel	O
+sites	O
+of	O
+the	O
+NMDA	O
+receptor	O
+.	O
+	
+Third	O
+","	O
+although	O
+it	O
+is	O
+relatively	O
+easy	O
+to	O
+block	O
+seizures	B-NP
+induced	O
+by	O
+lithium	O
+and	O
+pilocarpine	O
+by	O
+administration	O
+of	O
+anticonvulsants	O
+prior	O
+to	O
+pilocarpine	O
+","	O
+it	O
+is	O
+more	O
+difficult	O
+to	O
+terminate	O
+ongoing	O
+status	B-NP
+epilepticus	I-NP
+and	O
+block	O
+the	O
+lethality	O
+of	O
+the	O
+seizures	B-NP
+.	O
+	
+Administration	O
+of	O
+MK	O
+-	O
+801	O
+30	O
+or	O
+60	O
+min	O
+after	O
+pilocarpine	O
+","	O
+i	O
+.	O
+e	O
+.	O
+","	O
+during	O
+status	B-NP
+epilepticus	I-NP
+","	O
+gradually	O
+reduced	O
+electrical	O
+and	O
+behavioral	O
+seizure	B-NP
+activity	O
+and	O
+greatly	O
+enhanced	O
+the	O
+survival	O
+rate	O
+.	O
+	
+These	O
+results	O
+suggest	O
+that	O
+activation	O
+of	O
+NMDA	O
+receptors	O
+plays	O
+an	O
+important	O
+role	O
+in	O
+status	B-NP
+epilepticus	I-NP
+and	O
+brain	B-NP
+damage	I-NP
+in	O
+the	O
+lithium	O
+-	O
+pilocarpine	O
+model	O
+.	O
+	
+This	O
+was	O
+further	O
+supported	O
+by	O
+results	O
+showing	O
+that	O
+nonconvulsive	O
+doses	O
+of	O
+NMDA	O
+and	O
+pilocarpine	O
+were	O
+synergistic	O
+","	O
+resulting	O
+in	O
+status	B-NP
+epilepticus	I-NP
+and	O
+subsequent	O
+mortality	O
+.	O
+	
+Continuous	O
+infusion	O
+tobramycin	O
+combined	O
+with	O
+carbenicillin	O
+for	O
+infections	B-NP
+in	O
+cancer	B-NP
+patients	O
+.	O
+	
+The	O
+cure	O
+rate	O
+of	O
+infections	B-NP
+in	O
+cancer	B-NP
+patients	O
+is	O
+adversely	O
+affected	O
+by	O
+neutropenia	B-NP
+(	O
+less	O
+than	O
+1	O
+","	O
+0	O
+/	O
+mm3	O
+)	O
+.	O
+	
+In	O
+particular	O
+","	O
+patients	O
+with	O
+severe	O
+neutropenia	B-NP
+(	O
+less	O
+than	O
+100	O
+/	O
+mm3	O
+)	O
+have	O
+shown	O
+a	O
+poor	O
+response	O
+to	O
+antibiotics	O
+.	O
+	
+To	O
+overcome	O
+the	O
+adverse	O
+effects	O
+of	O
+neutropenia	B-NP
+","	O
+tobramycin	O
+was	O
+given	O
+by	O
+continuous	O
+infusion	O
+and	O
+combined	O
+with	O
+intermittent	O
+carbenicillin	O
+.	O
+	
+Tobramycin	O
+was	O
+given	O
+to	O
+a	O
+total	O
+daily	O
+dose	O
+of	O
+300	O
+mg	O
+/	O
+m2	O
+and	O
+carbenicillin	O
+was	O
+given	O
+at	O
+a	O
+dose	O
+of	O
+5	O
+gm	O
+every	O
+four	O
+hours	O
+.	O
+	
+There	O
+were	O
+125	O
+infectious	O
+episodes	O
+in	O
+116	O
+cancer	B-NP
+patients	O
+receiving	O
+myelosuppressive	O
+chemotherapy	O
+.	O
+	
+The	O
+overall	O
+cure	O
+rate	O
+was	O
+70	O
+%	O
+.	O
+	
+Pneumonia	B-NP
+was	O
+the	O
+most	O
+common	O
+infection	B-NP
+and	O
+61	O
+%	O
+of	O
+59	O
+episodes	O
+were	O
+cured	O
+.	O
+	
+Gram	O
+-	O
+negative	O
+bacilli	O
+were	O
+the	O
+most	O
+common	O
+causative	O
+organisms	O
+and	O
+69	O
+%	O
+of	O
+these	O
+infections	B-NP
+were	O
+cured	O
+.	O
+	
+The	O
+most	O
+common	O
+pathogen	O
+was	O
+Klebsiella	O
+pneumoniae	B-NP
+and	O
+this	O
+","	O
+together	O
+with	O
+Escherichia	O
+coli	O
+and	O
+Pseudomonas	O
+aeruginosa	O
+","	O
+accounted	O
+for	O
+74	O
+%	O
+of	O
+all	O
+gram	B-NP
+-	I-NP
+negative	I-NP
+bacillary	I-NP
+infections	I-NP
+.	O
+	
+Response	O
+was	O
+not	O
+influenced	O
+by	O
+the	O
+initial	O
+neutrophil	O
+count	O
+","	O
+with	O
+a	O
+62	O
+%	O
+cure	O
+rate	O
+for	O
+39	O
+episodes	O
+associated	O
+with	O
+severe	O
+neutropenia	B-NP
+.	O
+	
+However	O
+","	O
+failure	O
+of	O
+the	O
+neutrophil	O
+count	O
+to	O
+increase	O
+during	O
+therapy	O
+adversely	O
+affected	O
+response	O
+.	O
+	
+Azotemia	B-NP
+was	O
+the	O
+major	O
+side	O
+effect	O
+recognized	O
+","	O
+and	O
+it	O
+occurred	O
+in	O
+11	O
+%	O
+of	O
+episodes	O
+.	O
+	
+Major	O
+azotemia	B-NP
+(	O
+serum	O
+creatinine	O
+greater	O
+than	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+dl	O
+or	O
+BUN	O
+greater	O
+than	O
+50	O
+mg	O
+/	O
+dl	O
+)	O
+occurred	O
+in	O
+only	O
+2	O
+%	O
+.	O
+	
+Azotemia	B-NP
+was	O
+not	O
+related	O
+to	O
+duration	O
+of	O
+therapy	O
+or	O
+serum	O
+tobramycin	O
+concentration	O
+.	O
+	
+This	O
+antibiotic	O
+regimen	O
+showed	O
+both	O
+therapeutic	O
+efficacy	O
+and	O
+acceptable	O
+renal	B-NP
+toxicity	I-NP
+for	O
+these	O
+patients	O
+.	O
+	
+Incidence	O
+of	O
+solid	O
+tumours	B-NP
+among	O
+pesticide	O
+applicators	O
+exposed	O
+to	O
+the	O
+organophosphate	O
+insecticide	O
+diazinon	O
+in	O
+the	O
+Agricultural	O
+Health	O
+Study	O
+:	O
+an	O
+updated	O
+analysis	O
+.	O
+	
+OBJECTIVE	O
+:	O
+Diazinon	O
+","	O
+a	O
+common	O
+organophosphate	O
+insecticide	O
+with	O
+genotoxic	O
+properties	O
+","	O
+was	O
+previously	O
+associated	O
+with	O
+lung	B-NP
+cancer	I-NP
+in	O
+the	O
+Agricultural	O
+Health	O
+Study	O
+(	O
+AHS	O
+)	O
+cohort	O
+","	O
+but	O
+few	O
+other	O
+epidemiological	O
+studies	O
+have	O
+examined	O
+diazinon	O
+-	O
+associated	O
+cancer	B-NP
+risk	O
+.	O
+	
+We	O
+used	O
+updated	O
+diazinon	O
+exposure	O
+and	O
+cancer	B-NP
+incidence	O
+information	O
+to	O
+evaluate	O
+solid	O
+tumour	B-NP
+risk	O
+in	O
+the	O
+AHS	O
+.	O
+	
+METHODS	O
+:	O
+Male	O
+pesticide	O
+applicators	O
+in	O
+Iowa	O
+and	O
+North	O
+Carolina	O
+reported	O
+lifetime	O
+diazinon	O
+use	O
+at	O
+enrolment	O
+(	O
+1993	O
+-	O
+1997	O
+)	O
+and	O
+follow	O
+-	O
+up	O
+(	O
+1998	O
+-	O
+2005	O
+)	O
+;	O
+cancer	B-NP
+incidence	O
+was	O
+assessed	O
+through	O
+2010	O
+(	O
+North	O
+Carolina	O
+)	O
+/	O
+2011	O
+(	O
+Iowa	O
+)	O
+.	O
+	
+Among	O
+applicators	O
+with	O
+usage	O
+information	O
+sufficient	O
+to	O
+evaluate	O
+exposure	O
+-	O
+response	O
+patterns	O
+","	O
+we	O
+used	O
+Poisson	O
+regression	O
+to	O
+estimate	O
+adjusted	O
+rate	O
+ratios	O
+(	O
+RRs	O
+)	O
+and	O
+95	O
+%	O
+CI	O
+for	O
+cancer	B-NP
+sites	O
+with	O
+>	O
+10	O
+exposed	O
+cases	O
+for	O
+both	O
+lifetime	O
+(	O
+LT	O
+)	O
+exposure	O
+days	O
+and	O
+intensity	O
+-	O
+weighted	O
+(	O
+IW	O
+)	O
+lifetime	O
+exposure	O
+days	O
+(	O
+accounting	O
+for	O
+factors	O
+impacting	O
+exposure	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+We	O
+observed	O
+elevated	O
+lung	B-NP
+cancer	I-NP
+risks	O
+(	O
+N	O
+=	O
+283	O
+)	O
+among	O
+applicators	O
+with	O
+the	O
+greatest	O
+number	O
+of	O
+LT	O
+(	O
+RR	O
+=	O
+1	O
+.	O
+60	O
+;	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+11	O
+to	O
+2	O
+.	O
+31	O
+;	O
+Ptrend	O
+=	O
+0	O
+.	O
+2	O
+)	O
+and	O
+IW	O
+days	O
+of	O
+diazinon	O
+use	O
+(	O
+RR	O
+=	O
+1	O
+.	O
+41	O
+;	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+98	O
+to	O
+2	O
+.	O
+4	O
+;	O
+Ptrend	O
+=	O
+0	O
+.	O
+8	O
+)	O
+.	O
+	
+Kidney	B-NP
+cancer	I-NP
+(	O
+N	O
+=	O
+94	O
+)	O
+risks	O
+were	O
+non	O
+-	O
+significantly	O
+elevated	O
+(	O
+RRLT	O
+days	O
+=	O
+1	O
+.	O
+77	O
+;	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+90	O
+to	O
+3	O
+.	O
+51	O
+;	O
+Ptrend	O
+=	O
+0	O
+.	O
+9	O
+;	O
+RRIW	O
+days	O
+1	O
+.	O
+37	O
+;	O
+95	O
+%	O
+CI	O
+0	O
+.	O
+64	O
+to	O
+2	O
+.	O
+92	O
+;	O
+Ptrend	O
+=	O
+0	O
+.	O
+50	O
+)	O
+","	O
+as	O
+were	O
+risks	O
+for	O
+aggressive	O
+prostate	B-NP
+cancer	I-NP
+(	O
+N	O
+=	O
+656	O
+)	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Our	O
+updated	O
+evaluation	O
+of	O
+diazinon	O
+provides	O
+additional	O
+evidence	O
+of	O
+an	O
+association	O
+with	O
+lung	B-NP
+cancer	I-NP
+risk	O
+.	O
+	
+Newly	O
+identified	O
+links	O
+to	O
+kidney	B-NP
+cancer	I-NP
+and	O
+associations	O
+with	O
+aggressive	O
+prostate	B-NP
+cancer	I-NP
+require	O
+further	O
+evaluation	O
+.	O
+	
+Associations	O
+of	O
+Ozone	O
+and	O
+PM2	O
+.	O
+5	O
+Concentrations	O
+With	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+Disease	I-NP
+Among	O
+Participants	O
+in	O
+the	O
+Agricultural	O
+Health	O
+Study	O
+.	O
+	
+OBJECTIVE	O
+:	O
+This	O
+study	O
+describes	O
+associations	O
+of	O
+ozone	O
+and	O
+fine	O
+particulate	O
+matter	O
+with	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+observed	O
+among	O
+farmers	O
+in	O
+North	O
+Carolina	O
+and	O
+Iowa	O
+.	O
+	
+METHODS	O
+:	O
+We	O
+used	O
+logistic	O
+regression	O
+to	O
+determine	O
+the	O
+associations	O
+of	O
+these	O
+pollutants	O
+with	O
+self	O
+-	O
+reported	O
+","	O
+doctor	O
+-	O
+diagnosed	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+Daily	O
+predicted	O
+pollutant	O
+concentrations	O
+were	O
+used	O
+to	O
+derive	O
+surrogates	O
+of	O
+long	O
+-	O
+term	O
+exposure	O
+and	O
+link	O
+them	O
+to	O
+study	O
+participants	O
+'	O
+geocoded	O
+addresses	O
+.	O
+	
+RESULTS	O
+:	O
+We	O
+observed	O
+positive	O
+associations	O
+of	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+with	O
+ozone	O
+(	O
+odds	O
+ratio	O
+=	O
+1	O
+.	O
+39	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+0	O
+.	O
+98	O
+to	O
+1	O
+.	O
+98	O
+)	O
+and	O
+fine	O
+particulate	O
+matter	O
+(	O
+odds	O
+ratio	O
+=	O
+1	O
+.	O
+34	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+0	O
+.	O
+93	O
+to	O
+1	O
+.	O
+93	O
+)	O
+in	O
+North	O
+Carolina	O
+but	O
+not	O
+in	O
+Iowa	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+The	O
+plausibility	O
+of	O
+an	O
+effect	O
+of	O
+ambient	O
+concentrations	O
+of	O
+these	O
+pollutants	O
+on	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+risk	O
+is	O
+supported	O
+by	O
+experimental	O
+data	O
+demonstrating	O
+damage	O
+to	O
+dopaminergic	O
+neurons	O
+at	O
+relevant	O
+concentrations	O
+.	O
+	
+Additional	O
+studies	O
+are	O
+needed	O
+to	O
+address	O
+uncertainties	O
+related	O
+to	O
+confounding	O
+and	O
+to	O
+examine	O
+temporal	O
+aspects	O
+of	O
+the	O
+associations	O
+we	O
+observed	O
+.	O
+	
+Low	O
+functional	O
+programming	O
+of	O
+renal	O
+AT2R	O
+mediates	O
+the	O
+developmental	O
+origin	O
+of	O
+glomerulosclerosis	B-NP
+in	O
+adult	O
+offspring	O
+induced	O
+by	O
+prenatal	O
+caffeine	O
+exposure	O
+.	O
+	
+UNASSIGNED	O
+:	O
+Our	O
+previous	O
+study	O
+has	O
+indicated	O
+that	O
+prenatal	O
+caffeine	O
+exposure	O
+(	O
+PCE	O
+)	O
+could	O
+induce	O
+intrauterine	B-NP
+growth	I-NP
+retardation	I-NP
+(	O
+IUGR	B-NP
+)	O
+of	O
+offspring	O
+.	O
+	
+Recent	O
+research	O
+suggested	O
+that	O
+IUGR	B-NP
+is	O
+a	O
+risk	O
+factor	O
+for	O
+glomerulosclerosis	B-NP
+.	O
+	
+However	O
+","	O
+whether	O
+PCE	O
+could	O
+induce	O
+glomerulosclerosis	B-NP
+and	O
+its	O
+underlying	O
+mechanisms	O
+remain	O
+unknown	O
+.	O
+	
+This	O
+study	O
+aimed	O
+to	O
+demonstrate	O
+the	O
+induction	O
+to	O
+glomerulosclerosis	B-NP
+in	O
+adult	O
+offspring	O
+by	O
+PCE	O
+and	O
+its	O
+intrauterine	O
+programming	O
+mechanisms	O
+.	O
+	
+A	O
+rat	O
+model	O
+of	O
+IUGR	B-NP
+was	O
+established	O
+by	O
+PCE	O
+","	O
+male	O
+fetuses	O
+and	O
+adult	O
+offspring	O
+at	O
+the	O
+age	O
+of	O
+postnatal	O
+week	O
+24	O
+were	O
+euthanized	O
+.	O
+	
+The	O
+results	O
+revealed	O
+that	O
+the	O
+adult	O
+offspring	O
+kidneys	O
+in	O
+the	O
+PCE	O
+group	O
+exhibited	O
+glomerulosclerosis	B-NP
+as	O
+well	O
+as	O
+interstitial	B-NP
+fibrosis	I-NP
+","	O
+accompanied	O
+by	O
+elevated	O
+levels	O
+of	O
+serum	O
+creatinine	O
+and	O
+urine	O
+protein	O
+.	O
+	
+Renal	O
+angiotensin	O
+II	O
+receptor	O
+type	O
+2	O
+(	O
+AT2R	O
+)	O
+gene	O
+expression	O
+in	O
+adult	O
+offspring	O
+was	O
+reduced	O
+by	O
+PCE	O
+","	O
+whereas	O
+the	O
+renal	O
+angiotensin	O
+II	O
+receptor	O
+type	O
+1a	O
+(	O
+AT1aR	O
+)	O
+/	O
+AT2R	O
+expression	O
+ratio	O
+was	O
+increased	O
+.	O
+	
+The	O
+fetal	O
+kidneys	O
+in	O
+the	O
+PCE	O
+group	O
+displayed	O
+an	O
+enlarged	O
+Bowman	O
+'	O
+s	O
+space	O
+and	O
+a	O
+shrunken	O
+glomerular	O
+tuft	O
+","	O
+accompanied	O
+by	O
+a	O
+reduced	O
+cortex	O
+width	O
+and	O
+an	O
+increase	O
+in	O
+the	O
+nephrogenic	O
+zone	O
+/	O
+cortical	O
+zone	O
+ratio	O
+.	O
+	
+Observation	O
+by	O
+electronic	O
+microscope	O
+revealed	O
+structural	O
+damage	O
+of	O
+podocytes	O
+;	O
+the	O
+reduced	O
+expression	O
+level	O
+of	O
+podocyte	O
+marker	O
+genes	O
+","	O
+nephrin	O
+and	O
+podocin	O
+","	O
+was	O
+also	O
+detected	O
+by	O
+q	O
+-	O
+PCR	O
+.	O
+	
+Moreover	O
+","	O
+AT2R	O
+gene	O
+and	O
+protein	O
+expressions	O
+in	O
+fetal	O
+kidneys	O
+were	O
+inhibited	O
+by	O
+PCE	O
+","	O
+associated	O
+with	O
+the	O
+repression	O
+of	O
+the	O
+gene	O
+expression	O
+of	O
+glial	O
+-	O
+cell	O
+-	O
+line	O
+-	O
+derived	O
+neurotrophic	O
+factor	O
+(	O
+GDNF	O
+)	O
+/	O
+tyrosine	O
+kinase	O
+receptor	O
+(	O
+c	O
+-	O
+Ret	O
+)	O
+signaling	O
+pathway	O
+.	O
+	
+These	O
+results	O
+demonstrated	O
+that	O
+PCE	O
+could	O
+induce	O
+dysplasia	B-NP
+of	I-NP
+fetal	I-NP
+kidneys	I-NP
+as	O
+well	O
+as	O
+glomerulosclerosis	B-NP
+of	O
+adult	O
+offspring	O
+","	O
+and	O
+the	O
+low	O
+functional	O
+programming	O
+of	O
+renal	O
+AT2R	O
+might	O
+mediate	O
+the	O
+developmental	O
+origin	O
+of	O
+adult	O
+glomerulosclerosis	B-NP
+.	O
+	
+1	O
+","	O
+3	O
+-	O
+Butadiene	O
+","	O
+CML	B-NP
+and	O
+the	O
+t	O
+(	O
+9	O
+:	O
+22	O
+)	O
+translocation	O
+:	O
+A	O
+reality	O
+check	O
+.	O
+	
+UNASSIGNED	O
+:	O
+Epidemiological	O
+studies	O
+of	O
+1	O
+","	O
+3	O
+-	O
+butadiene	O
+have	O
+suggest	O
+that	O
+exposures	O
+to	O
+humans	O
+are	O
+associated	O
+with	O
+chronic	B-NP
+myeloid	I-NP
+leukemia	I-NP
+(	O
+CML	B-NP
+)	O
+.	O
+	
+CML	B-NP
+has	O
+a	O
+well	O
+-	O
+documented	O
+association	O
+with	O
+ionizing	O
+radiation	O
+","	O
+but	O
+reports	O
+of	O
+associations	O
+with	O
+chemical	O
+exposures	O
+have	O
+been	O
+questioned	O
+.	O
+	
+Ionizing	O
+radiation	O
+is	O
+capable	O
+of	O
+inducing	O
+the	O
+requisite	O
+CML	B-NP
+-	O
+associated	O
+t	O
+(	O
+9	O
+:	O
+22	O
+)	O
+translocation	O
+(	O
+Philadelphia	B-NP
+chromosome	I-NP
+)	O
+in	O
+appropriate	O
+cells	O
+in	O
+vitro	O
+but	O
+","	O
+thus	O
+far	O
+","	O
+chemicals	O
+have	O
+not	O
+shown	O
+this	O
+capacity	O
+.	O
+	
+We	O
+have	O
+proposed	O
+that	O
+1	O
+","	O
+3	O
+-	O
+butadiene	O
+metabolites	O
+be	O
+so	O
+tested	O
+as	O
+a	O
+reality	O
+check	O
+on	O
+the	O
+epidemiological	O
+reports	O
+.	O
+	
+In	O
+order	O
+to	O
+conduct	O
+reliable	O
+testing	O
+in	O
+this	O
+regard	O
+","	O
+it	O
+is	O
+essential	O
+that	O
+a	O
+positive	O
+control	O
+for	O
+induction	O
+be	O
+available	O
+.	O
+	
+We	O
+have	O
+used	O
+ionizing	O
+radiation	O
+to	O
+develop	O
+such	O
+a	O
+control	O
+.	O
+	
+Results	O
+described	O
+here	O
+demonstrate	O
+that	O
+this	O
+agent	O
+does	O
+in	O
+fact	O
+induce	O
+pathogenic	O
+t	O
+(	O
+9	O
+:	O
+22	O
+)	O
+translocations	O
+in	O
+a	O
+human	O
+myeloid	O
+cell	O
+line	O
+in	O
+vitro	O
+","	O
+but	O
+does	O
+so	O
+at	O
+low	O
+frequencies	O
+.	O
+	
+Conditions	O
+that	O
+will	O
+be	O
+required	O
+for	O
+studies	O
+of	O
+1	O
+","	O
+3	O
+-	O
+butadiene	O
+are	O
+discussed	O
+.	O
+	
+Cancer	B-NP
+incidence	O
+and	O
+metolachlor	O
+use	O
+in	O
+the	O
+Agricultural	O
+Health	O
+Study	O
+:	O
+An	O
+update	O
+.	O
+	
+UNASSIGNED	O
+:	O
+Metolachlor	O
+","	O
+a	O
+widely	O
+used	O
+herbicide	O
+","	O
+is	O
+classified	O
+as	O
+a	O
+Group	O
+C	O
+carcinogen	O
+by	O
+the	O
+U	O
+.	O
+S	O
+.	O
+	
+Environmental	O
+Protection	O
+Agency	O
+based	O
+on	O
+increased	O
+liver	B-NP
+neoplasms	I-NP
+in	O
+female	O
+rats	O
+.	O
+	
+Epidemiologic	O
+studies	O
+of	O
+the	O
+health	O
+effects	O
+of	O
+metolachlor	O
+have	O
+been	O
+limited	O
+.	O
+	
+The	O
+Agricultural	O
+Health	O
+Study	O
+(	O
+AHS	O
+)	O
+is	O
+a	O
+prospective	O
+cohort	O
+study	O
+including	O
+licensed	O
+private	O
+and	O
+commercial	O
+pesticide	O
+applicators	O
+in	O
+Iowa	O
+and	O
+North	O
+Carolina	O
+enrolled	O
+1993	O
+-	O
+1997	O
+.	O
+	
+We	O
+evaluated	O
+cancer	B-NP
+incidence	O
+through	O
+2010	O
+/	O
+2011	O
+(	O
+NC	O
+/	O
+IA	O
+)	O
+for	O
+49	O
+","	O
+616	O
+applicators	O
+","	O
+53	O
+%	O
+of	O
+whom	O
+reported	O
+ever	O
+using	O
+metolachlor	O
+.	O
+	
+We	O
+used	O
+Poisson	O
+regression	O
+to	O
+evaluate	O
+relations	O
+between	O
+two	O
+metrics	O
+of	O
+metolachlor	O
+use	O
+(	O
+lifetime	O
+days	O
+","	O
+intensity	O
+-	O
+weighted	O
+lifetime	O
+days	O
+)	O
+and	O
+cancer	B-NP
+incidence	O
+.	O
+	
+We	O
+saw	O
+no	O
+association	O
+between	O
+metolachlor	O
+use	O
+and	O
+incidence	O
+of	O
+all	O
+cancers	B-NP
+combined	O
+(	O
+n	O
+=	O
+5	O
+","	O
+701	O
+with	O
+a	O
+5	O
+-	O
+year	O
+lag	O
+)	O
+or	O
+most	O
+site	O
+-	O
+specific	O
+cancers	B-NP
+.	O
+	
+For	O
+liver	B-NP
+cancer	I-NP
+","	O
+in	O
+analyses	O
+restricted	O
+to	O
+exposed	O
+workers	O
+","	O
+elevations	O
+observed	O
+at	O
+higher	O
+categories	O
+of	O
+use	O
+were	O
+not	O
+statistically	O
+significant	O
+.	O
+	
+However	O
+","	O
+trends	O
+for	O
+both	O
+lifetime	O
+and	O
+intensity	O
+-	O
+weighted	O
+lifetime	O
+days	O
+of	O
+metolachor	O
+use	O
+were	O
+positive	O
+and	O
+statistically	O
+significant	O
+with	O
+an	O
+unexposed	O
+reference	O
+group	O
+.	O
+	
+A	O
+similar	O
+pattern	O
+was	O
+observed	O
+for	O
+follicular	B-NP
+cell	I-NP
+lymphoma	I-NP
+","	O
+but	O
+no	O
+other	O
+lymphoma	B-NP
+subtypes	O
+.	O
+	
+An	O
+earlier	O
+suggestion	O
+of	O
+increased	O
+lung	B-NP
+cancer	I-NP
+risk	O
+at	O
+high	O
+levels	O
+of	O
+metolachlor	O
+use	O
+in	O
+this	O
+cohort	O
+was	O
+not	O
+confirmed	O
+in	O
+this	O
+update	O
+.	O
+	
+This	O
+suggestion	O
+of	O
+an	O
+association	O
+between	O
+metolachlor	O
+and	O
+liver	B-NP
+cancer	I-NP
+among	O
+pesticide	O
+applicators	O
+is	O
+a	O
+novel	O
+finding	O
+and	O
+echoes	O
+observation	O
+of	O
+increased	O
+liver	B-NP
+neoplasms	I-NP
+in	O
+some	O
+animal	O
+studies	O
+.	O
+	
+However	O
+","	O
+our	O
+findings	O
+for	O
+both	O
+liver	B-NP
+cancer	I-NP
+and	O
+follicular	O
+cell	O
+lymphoma	B-NP
+warrant	O
+follow	O
+-	O
+up	O
+to	O
+better	O
+differentiate	O
+effects	O
+of	O
+metolachlor	O
+use	O
+from	O
+other	O
+factors	O
+.	O
+	
+Mechanisms	O
+Underlying	O
+Latent	O
+Disease	O
+Risk	O
+Associated	O
+with	O
+Early	O
+-	O
+Life	O
+Arsenic	O
+Exposure	O
+:	O
+Current	O
+Research	O
+Trends	O
+and	O
+Scientific	O
+Gaps	O
+.	O
+	
+BACKGROUND	O
+:	O
+Millions	O
+of	O
+individuals	O
+worldwide	O
+","	O
+particularly	O
+those	O
+living	O
+in	O
+rural	O
+and	O
+developing	O
+areas	O
+","	O
+are	O
+exposed	O
+to	O
+harmful	O
+levels	O
+of	O
+inorganic	O
+arsenic	O
+(	O
+iAs	O
+)	O
+in	O
+their	O
+drinking	O
+water	O
+.	O
+	
+Inorganic	O
+As	O
+exposure	O
+during	O
+key	O
+developmental	O
+periods	O
+is	O
+associated	O
+with	O
+a	O
+variety	O
+of	O
+adverse	O
+health	O
+effects	O
+including	O
+those	O
+that	O
+are	O
+evident	O
+in	O
+adulthood	O
+.	O
+	
+There	O
+is	O
+considerable	O
+interest	O
+in	O
+identifying	O
+the	O
+molecular	O
+mechanisms	O
+that	O
+relate	O
+early	O
+-	O
+life	O
+iAs	O
+exposure	O
+to	O
+the	O
+development	O
+of	O
+these	O
+latent	O
+diseases	O
+","	O
+particularly	O
+in	O
+relationship	O
+to	O
+cancer	B-NP
+.	O
+	
+OBJECTIVES	O
+:	O
+This	O
+work	O
+summarizes	O
+research	O
+on	O
+the	O
+molecular	O
+mechanisms	O
+that	O
+underlie	O
+the	O
+increased	O
+risk	O
+of	O
+cancer	B-NP
+development	O
+in	O
+adulthood	O
+that	O
+is	O
+associated	O
+with	O
+early	O
+-	O
+life	O
+iAs	O
+exposure	O
+.	O
+	
+DISCUSSION	O
+:	O
+Epigenetic	O
+reprogramming	O
+that	O
+imparts	O
+functional	O
+changes	O
+in	O
+gene	O
+expression	O
+","	O
+the	O
+development	O
+of	O
+cancer	B-NP
+stem	O
+cells	O
+","	O
+and	O
+immunomodulation	O
+are	O
+plausible	O
+underlying	O
+mechanisms	O
+by	O
+which	O
+early	O
+-	O
+life	O
+iAs	O
+exposure	O
+elicits	O
+latent	O
+carcinogenic	O
+effects	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Evidence	O
+is	O
+mounting	O
+that	O
+relates	O
+early	O
+-	O
+life	O
+iAs	O
+exposure	O
+and	O
+cancer	B-NP
+development	O
+later	O
+in	O
+life	O
+.	O
+	
+Future	O
+research	O
+should	O
+include	O
+animal	O
+studies	O
+that	O
+address	O
+mechanistic	O
+hypotheses	O
+and	O
+studies	O
+of	O
+human	O
+populations	O
+that	O
+integrate	O
+early	O
+-	O
+life	O
+exposure	O
+","	O
+molecular	O
+alterations	O
+","	O
+and	O
+latent	O
+disease	O
+outcomes	O
+.	O
+	
+Nifedipine	O
+induced	O
+bradycardia	B-NP
+in	O
+a	O
+patient	O
+with	O
+autonomic	B-NP
+neuropathy	I-NP
+.	O
+	
+An	O
+80	O
+year	O
+old	O
+diabetic	B-NP
+male	O
+with	O
+evidence	O
+of	O
+peripheral	B-NP
+and	I-NP
+autonomic	I-NP
+neuropathy	I-NP
+was	O
+admitted	O
+with	O
+chest	B-NP
+pain	I-NP
+.	O
+	
+He	O
+was	O
+found	O
+to	O
+have	O
+atrial	B-NP
+flutter	I-NP
+at	O
+a	O
+ventricular	O
+rate	O
+of	O
+70	O
+/	O
+min	O
+which	O
+slowed	O
+down	O
+to	O
+30	O
+-	O
+40	O
+/	O
+min	O
+when	O
+nifedipine	O
+(	O
+60	O
+mg	O
+)	O
+in	O
+3	O
+divided	O
+doses	O
+","	O
+during	O
+which	O
+he	O
+was	O
+paced	O
+at	O
+a	O
+rate	O
+of	O
+70	O
+/	O
+min	O
+.	O
+	
+This	O
+is	O
+inconsistent	O
+with	O
+the	O
+well	O
+-	O
+established	O
+finding	O
+that	O
+nifedipine	O
+induces	O
+tachycardia	B-NP
+in	O
+normally	O
+innervated	O
+hearts	O
+.	O
+	
+However	O
+","	O
+in	O
+hearts	O
+deprived	O
+of	O
+compensatory	O
+sympathetic	O
+drive	O
+","	O
+it	O
+may	O
+lead	O
+to	O
+bradycardia	B-NP
+.	O
+	
+The	O
+effect	O
+of	O
+haloperidol	O
+in	O
+cocaine	O
+and	O
+amphetamine	O
+intoxication	O
+.	O
+	
+The	O
+effectiveness	O
+of	O
+haloperidol	O
+pretreatment	O
+in	O
+preventing	O
+the	O
+toxic	O
+effects	O
+of	O
+high	O
+doses	O
+of	O
+amphetamine	O
+and	O
+cocaine	O
+was	O
+studied	O
+in	O
+rats	O
+.	O
+	
+In	O
+this	O
+model	O
+","	O
+toxic	O
+effects	O
+were	O
+induced	O
+by	O
+intraperitoneal	O
+(	O
+i	O
+.	O
+p	O
+.	O
+)	O
+injection	O
+of	O
+amphetamine	O
+75	O
+mg	O
+/	O
+kg	O
+(	O
+100	O
+%	O
+death	O
+rate	O
+)	O
+or	O
+cocaine	O
+70	O
+mg	O
+/	O
+kg	O
+(	O
+82	O
+%	O
+death	O
+rate	O
+)	O
+.	O
+	
+Haloperidol	O
+failed	O
+to	O
+prevent	O
+amphetamine	O
+-	O
+induced	O
+seizures	B-NP
+","	O
+but	O
+did	O
+lower	O
+the	O
+mortality	O
+rate	O
+at	O
+most	O
+doses	O
+tested	O
+.	O
+	
+Haloperidol	O
+decreased	O
+the	O
+incidence	O
+of	O
+cocaine	O
+-	O
+induced	O
+seizures	B-NP
+at	O
+the	O
+two	O
+highest	O
+doses	O
+","	O
+but	O
+the	O
+lowering	O
+of	O
+the	O
+mortality	O
+rate	O
+did	O
+not	O
+reach	O
+statistical	O
+significance	O
+at	O
+any	O
+dose	O
+.	O
+	
+These	O
+data	O
+suggest	O
+a	O
+protective	O
+role	O
+for	O
+the	O
+central	O
+dopamine	O
+blocker	O
+haloperidol	O
+against	O
+death	O
+from	O
+high	O
+-	O
+dose	O
+amphetamine	O
+exposure	O
+without	O
+reducing	O
+the	O
+incidence	O
+of	O
+seizures	B-NP
+.	O
+	
+In	O
+contrast	O
+","	O
+haloperidol	O
+demonstrated	O
+an	O
+ability	O
+to	O
+reduce	O
+cocaine	O
+-	O
+induced	O
+seizures	B-NP
+without	O
+significantly	O
+reducing	O
+mortality	O
+.	O
+	
+Autoradiographic	O
+evidence	O
+of	O
+estrogen	O
+binding	O
+sites	O
+in	O
+nuclei	O
+of	O
+diethylstilbesterol	O
+induced	O
+hamster	O
+renal	B-NP
+carcinomas	I-NP
+.	O
+	
+Estrogen	O
+binding	O
+sites	O
+were	O
+demonstrated	O
+by	O
+autoradiography	O
+in	O
+one	O
+transplantable	O
+and	O
+five	O
+primary	O
+diethylstilbesterol	O
+induced	O
+renal	B-NP
+carcinomas	I-NP
+in	O
+three	O
+hamsters	O
+.	O
+	
+Radiolabelling	O
+","	O
+following	O
+the	O
+in	O
+vivo	O
+injection	O
+of	O
+3H	O
+-	O
+17	O
+beta	O
+estradiol	O
+","	O
+was	O
+increased	O
+only	O
+over	O
+the	O
+nuclei	O
+of	O
+tumor	B-NP
+cells	O
+;	O
+stereologic	O
+analysis	O
+revealed	O
+a	O
+4	O
+.	O
+5	O
+-	O
+to	O
+6	O
+.	O
+7	O
+-	O
+times	O
+higher	O
+concentration	O
+of	O
+reduced	O
+silver	O
+grains	O
+over	O
+nuclei	O
+than	O
+cytoplasm	O
+of	O
+these	O
+cells	O
+.	O
+	
+Despite	O
+rapid	O
+tubular	O
+excretion	O
+of	O
+estradiol	O
+which	O
+peaked	O
+in	O
+less	O
+than	O
+1	O
+h	O
+","	O
+the	O
+normal	O
+cells	O
+did	O
+not	O
+appear	O
+to	O
+bind	O
+the	O
+ligand	O
+.	O
+	
+This	O
+is	O
+the	O
+first	O
+published	O
+report	O
+documenting	O
+the	O
+preferential	O
+in	O
+vivo	O
+binding	O
+of	O
+estrogen	O
+to	O
+nuclei	O
+of	O
+cells	O
+in	O
+estrogen	O
+induced	O
+hamster	O
+renal	B-NP
+carcinomas	I-NP
+.	O
+	
+Bradycardia	B-NP
+due	O
+to	O
+biperiden	O
+.	O
+	
+In	O
+a	O
+38	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+suffering	O
+from	O
+a	O
+severe	O
+postzosteric	B-NP
+trigeminal	B-NP
+neuralgia	I-NP
+","	O
+intravenous	O
+application	O
+of	O
+10	O
+mg	O
+biperiden	O
+lactate	O
+led	O
+to	O
+a	O
+long	O
+-	O
+lasting	O
+paradoxical	O
+reaction	O
+characterized	O
+by	O
+considerable	O
+bradycardia	B-NP
+","	O
+dysarthria	B-NP
+","	O
+and	O
+dysphagia	B-NP
+.	O
+	
+The	O
+heart	O
+rate	O
+was	O
+back	O
+to	O
+normal	O
+within	O
+12	O
+hours	O
+upon	O
+administration	O
+of	O
+orciprenaline	O
+under	O
+cardiac	O
+monitoring	O
+in	O
+an	O
+intensive	O
+care	O
+unit	O
+.	O
+	
+Bradycardia	B-NP
+induced	O
+by	O
+biperiden	O
+is	O
+attributed	O
+to	O
+the	O
+speed	O
+of	O
+injection	O
+and	O
+to	O
+a	O
+dose	O
+-	O
+related	O
+dual	O
+effect	O
+of	O
+atropine	O
+-	O
+like	O
+drugs	O
+on	O
+muscarine	O
+receptors	O
+.	O
+	
+Deliberate	O
+hypotension	B-NP
+induced	O
+by	O
+labetalol	O
+with	O
+halothane	O
+","	O
+enflurane	O
+or	O
+isoflurane	O
+for	O
+middle	O
+-	O
+ear	O
+surgery	O
+.	O
+	
+The	O
+feasibility	O
+of	O
+using	O
+labetalol	O
+","	O
+an	O
+alpha	O
+-	O
+and	O
+beta	O
+-	O
+adrenergic	O
+blocking	O
+agent	O
+","	O
+as	O
+a	O
+hypotensive	B-NP
+agent	O
+in	O
+combination	O
+with	O
+inhalation	O
+anaesthetics	O
+(	O
+halothane	O
+","	O
+enflurane	O
+or	O
+isoflurane	O
+)	O
+was	O
+studied	O
+in	O
+23	O
+adult	O
+patients	O
+undergoing	O
+middle	O
+-	O
+ear	O
+surgery	O
+.	O
+	
+The	O
+mean	O
+arterial	O
+pressure	O
+was	O
+decreased	O
+from	O
+86	O
++	O
+/	O
+-	O
+5	O
+(	O
+s	O
+.	O
+e	O
+.	O
+mean	O
+)	O
+mmHg	O
+to	O
+52	O
++	O
+/	O
+-	O
+1	O
+mmHg	O
+(	O
+11	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+to	O
+6	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+kPa	O
+)	O
+for	O
+98	O
++	O
+/	O
+-	O
+10	O
+min	O
+in	O
+the	O
+halothane	O
+(	O
+H	O
+)	O
+group	O
+","	O
+from	O
+79	O
++	O
+/	O
+-	O
+5	O
+to	O
+53	O
++	O
+/	O
+-	O
+1	O
+mmHg	O
+(	O
+10	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+to	O
+7	O
+.	O
+1	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+kPa	O
+)	O
+for	O
+129	O
++	O
+/	O
+-	O
+11	O
+min	O
+in	O
+the	O
+enflurane	O
+(	O
+E	O
+)	O
+group	O
+","	O
+and	O
+from	O
+80	O
++	O
+/	O
+-	O
+4	O
+to	O
+49	O
++	O
+/	O
+-	O
+1	O
+mmHg	O
+(	O
+10	O
+.	O
+7	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+to	O
+6	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+kPa	O
+)	O
+for	O
+135	O
++	O
+/	O
+-	O
+15	O
+min	O
+in	O
+the	O
+isoflurane	O
+(	O
+I	O
+)	O
+group	O
+.	O
+	
+The	O
+mean	O
+H	O
+concentration	O
+during	O
+hypotension	B-NP
+in	O
+the	O
+inspiratory	O
+gas	O
+was	O
+0	O
+.	O
+7	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+vol	O
+%	O
+","	O
+the	O
+mean	O
+E	O
+concentration	O
+1	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+2	O
+vol	O
+%	O
+","	O
+and	O
+the	O
+mean	O
+I	O
+concentration	O
+1	O
+.	O
+0	O
++	O
+/	O
+-	O
+0	O
+.	O
+1	O
+vol	O
+%	O
+.	O
+	
+In	O
+addition	O
+","	O
+the	O
+patients	O
+received	O
+fentanyl	O
+and	O
+d	O
+-	O
+tubocurarine	O
+.	O
+	
+The	O
+initial	O
+dose	O
+of	O
+labetalol	O
+for	O
+lowering	O
+blood	O
+pressure	O
+was	O
+similar	O
+","	O
+0	O
+.	O
+52	O
+-	O
+0	O
+.	O
+59	O
+mg	O
+/	O
+kg	O
+","	O
+in	O
+all	O
+the	O
+groups	O
+.	O
+	
+During	O
+hypotension	B-NP
+","	O
+the	O
+heart	O
+rate	O
+was	O
+stable	O
+without	O
+tachy	B-NP
+-	I-NP
+or	I-NP
+bradycardia	I-NP
+.	O
+	
+The	O
+operating	O
+conditions	O
+regarding	O
+bleeding	B-NP
+were	O
+estimated	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+manner	O
+","	O
+and	O
+did	O
+not	O
+differ	O
+significantly	O
+between	O
+the	O
+groups	O
+.	O
+	
+During	O
+hypotension	B-NP
+","	O
+the	O
+serum	O
+creatinine	O
+concentration	O
+rose	O
+significantly	O
+in	O
+all	O
+groups	O
+from	O
+the	O
+values	O
+before	O
+hypotension	B-NP
+and	O
+returned	O
+postoperatively	O
+to	O
+the	O
+initial	O
+level	O
+in	O
+the	O
+other	O
+groups	O
+","	O
+except	O
+the	O
+isoflurane	O
+group	O
+.	O
+	
+After	O
+hypotension	B-NP
+there	O
+was	O
+no	O
+rebound	O
+phenomenon	O
+in	O
+either	O
+blood	O
+pressure	O
+or	O
+heart	O
+rate	O
+.	O
+	
+These	O
+results	O
+indicate	O
+that	O
+labetalol	O
+induces	O
+easily	O
+adjustable	O
+hypotension	B-NP
+without	O
+compensatory	O
+tachycardia	B-NP
+and	O
+rebound	O
+hypertension	B-NP
+.	O
+	
+Convulsion	B-NP
+following	O
+intravenous	O
+fluorescein	O
+angiography	O
+.	O
+	
+Tonic	B-NP
+-	I-NP
+clonic	I-NP
+seizures	I-NP
+followed	O
+intravenous	O
+fluorescein	O
+injection	O
+for	O
+fundus	O
+angiography	O
+in	O
+a	O
+47	O
+-	O
+year	O
+-	O
+old	O
+male	O
+.	O
+	
+Despite	O
+precautions	O
+this	O
+adverse	O
+reaction	O
+recurred	O
+on	O
+re	O
+-	O
+exposure	O
+to	O
+intravenous	O
+fluorescein	O
+.	O
+	
+Pharmacology	O
+of	O
+ACC	O
+-	O
+9653	O
+(	O
+phenytoin	O
+prodrug	O
+)	O
+.	O
+	
+ACC	O
+-	O
+9653	O
+","	O
+the	O
+disodium	O
+phosphate	O
+ester	O
+of	O
+3	O
+-	O
+hydroxymethyl	O
+-	O
+5	O
+","	O
+5	O
+-	O
+diphenylhydantoin	O
+","	O
+is	O
+a	O
+prodrug	O
+of	O
+phenytoin	O
+with	O
+advantageous	O
+physicochemical	O
+properties	O
+.	O
+	
+ACC	O
+-	O
+9653	O
+is	O
+rapidly	O
+converted	O
+enzymatically	O
+to	O
+phenytoin	O
+in	O
+vivo	O
+.	O
+	
+ACC	O
+-	O
+9653	O
+and	O
+phenytoin	O
+sodium	O
+have	O
+equivalent	O
+anticonvulsant	O
+activity	O
+against	O
+seizures	B-NP
+induced	O
+by	O
+maximal	O
+electroshock	O
+(	O
+MES	O
+)	O
+in	O
+mice	O
+following	O
+i	O
+.	O
+p	O
+.	O
+","	O
+oral	O
+","	O
+or	O
+i	O
+.	O
+v	O
+.	O
+administration	O
+.	O
+	
+The	O
+ED50	O
+doses	O
+were	O
+16	O
+mg	O
+/	O
+kg	O
+for	O
+i	O
+.	O
+v	O
+.	O
+ACC	O
+-	O
+9653	O
+and	O
+8	O
+mg	O
+/	O
+kg	O
+for	O
+i	O
+.	O
+v	O
+.	O
+phenytoin	O
+sodium	O
+.	O
+	
+ACC	O
+-	O
+9653	O
+and	O
+phenytoin	O
+sodium	O
+have	O
+similar	O
+antiarrhythmic	O
+activity	O
+against	O
+ouabain	O
+-	O
+induced	O
+ventricular	B-NP
+tachycardia	I-NP
+in	O
+anesthetized	O
+dogs	O
+.	O
+	
+The	O
+total	O
+doses	O
+of	O
+ACC	O
+-	O
+9653	O
+or	O
+phenytoin	O
+sodium	O
+necessary	O
+to	O
+convert	O
+the	O
+arrhythmia	B-NP
+to	O
+a	O
+normal	O
+sinus	O
+rhythm	O
+were	O
+24	O
++	O
+/	O
+-	O
+6	O
+and	O
+14	O
++	O
+/	O
+-	O
+3	O
+mg	O
+/	O
+kg	O
+","	O
+respectively	O
+.	O
+	
+Only	O
+phenytoin	O
+sodium	O
+displayed	O
+in	O
+vitro	O
+antiarrhythmic	O
+activity	O
+against	O
+strophanthidin	O
+-	O
+induced	O
+arrhythmias	B-NP
+in	O
+guinea	O
+pig	O
+right	O
+atria	O
+.	O
+	
+In	O
+anesthetized	O
+dogs	O
+","	O
+a	O
+high	O
+dose	O
+of	O
+ACC	O
+-	O
+9653	O
+(	O
+31	O
+mg	O
+/	O
+kg	O
+)	O
+was	O
+infused	O
+over	O
+15	O
+","	O
+20	O
+","	O
+and	O
+30	O
+min	O
+and	O
+the	O
+responses	O
+were	O
+compared	O
+to	O
+an	O
+equimolar	O
+dose	O
+of	O
+phenytoin	O
+sodium	O
+(	O
+21	O
+mg	O
+/	O
+kg	O
+)	O
+.	O
+	
+The	O
+ACC	O
+-	O
+9653	O
+and	O
+phenytoin	O
+sodium	O
+treatments	O
+produced	O
+similar	O
+marked	O
+reductions	O
+in	O
+diastolic	O
+blood	O
+pressure	O
+and	O
+contractile	O
+force	O
+(	O
+LVdP	O
+/	O
+dt	O
+)	O
+.	O
+	
+The	O
+maximum	O
+effects	O
+of	O
+each	O
+treatment	O
+occurred	O
+at	O
+the	O
+time	O
+of	O
+maximum	O
+phenytoin	O
+sodium	O
+levels	O
+.	O
+	
+Acute	O
+toxicity	B-NP
+studies	O
+of	O
+ACC	O
+-	O
+9653	O
+and	O
+phenytoin	O
+sodium	O
+were	O
+carried	O
+out	O
+in	O
+mice	O
+","	O
+rats	O
+","	O
+rabbits	O
+","	O
+and	O
+dogs	O
+by	O
+i	O
+.	O
+v	O
+.	O
+","	O
+i	O
+.	O
+m	O
+.	O
+","	O
+and	O
+i	O
+.	O
+p	O
+.	O
+routes	O
+of	O
+administration	O
+.	O
+	
+The	O
+systemic	O
+toxic	O
+signs	O
+of	O
+both	O
+agents	O
+were	O
+similar	O
+and	O
+occurred	O
+at	O
+approximately	O
+equivalent	O
+doses	O
+.	O
+	
+Importantly	O
+","	O
+the	O
+local	O
+irritation	O
+of	O
+ACC	O
+-	O
+9653	O
+was	O
+markedly	O
+less	O
+than	O
+phenytoin	O
+sodium	O
+following	O
+i	O
+.	O
+m	O
+.	O
+administration	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+	
+Tachyphylaxis	O
+to	O
+systemic	O
+but	O
+not	O
+to	O
+airway	O
+responses	O
+during	O
+prolonged	O
+therapy	O
+with	O
+high	O
+dose	O
+inhaled	O
+salbutamol	O
+in	O
+asthmatics	B-NP
+.	O
+	
+High	O
+doses	O
+of	O
+inhaled	O
+salbutamol	O
+produce	O
+substantial	O
+improvements	O
+in	O
+airway	O
+response	O
+in	O
+patients	O
+with	O
+asthma	B-NP
+","	O
+and	O
+are	O
+associated	O
+with	O
+dose	O
+-	O
+dependent	O
+systemic	O
+beta	O
+-	O
+adrenoceptor	O
+responses	O
+.	O
+	
+The	O
+purpose	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+investigate	O
+whether	O
+tachyphylaxis	O
+occurs	O
+during	O
+prolonged	O
+treatment	O
+with	O
+high	O
+dose	O
+inhaled	O
+salbutamol	O
+.	O
+	
+Twelve	O
+asthmatic	B-NP
+patients	O
+(	O
+FEV1	O
+","	O
+81	O
++	O
+/	O
+-	O
+4	O
+%	O
+predicted	O
+)	O
+","	O
+requiring	O
+only	O
+occasional	O
+inhaled	O
+beta	O
+-	O
+agonists	O
+as	O
+their	O
+sole	O
+therapy	O
+","	O
+were	O
+given	O
+a	O
+14	O
+-	O
+day	O
+treatment	O
+with	O
+high	O
+dose	O
+inhaled	O
+salbutamol	O
+(	O
+HDS	O
+)	O
+","	O
+4	O
+","	O
+0	O
+micrograms	O
+daily	O
+","	O
+low	O
+dose	O
+inhaled	O
+salbutamol	O
+(	O
+LDS	O
+)	O
+","	O
+800	O
+micrograms	O
+daily	O
+","	O
+or	O
+placebo	O
+(	O
+PI	O
+)	O
+by	O
+metered	O
+-	O
+dose	O
+inhaler	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+","	O
+randomized	O
+crossover	O
+design	O
+.	O
+	
+During	O
+the	O
+14	O
+-	O
+day	O
+run	O
+-	O
+in	O
+and	O
+during	O
+washout	O
+periods	O
+","	O
+inhaled	O
+beta	O
+-	O
+agonists	O
+were	O
+withheld	O
+and	O
+ipratropium	O
+bromide	O
+was	O
+substituted	O
+for	O
+rescue	O
+purposes	O
+.	O
+	
+At	O
+the	O
+end	O
+of	O
+each	O
+14	O
+-	O
+day	O
+treatment	O
+","	O
+a	O
+dose	O
+-	O
+response	O
+curve	O
+(	O
+DRC	O
+)	O
+was	O
+performed	O
+","	O
+and	O
+airway	O
+(	O
+FEV1	O
+","	O
+FEF25	O
+-	O
+75	O
+)	O
+chronotropic	O
+(	O
+HR	O
+)	O
+","	O
+tremor	B-NP
+","	O
+and	O
+metabolic	O
+(	O
+K	O
+","	O
+Glu	O
+)	O
+responses	O
+were	O
+measured	O
+at	O
+each	O
+step	O
+(	O
+from	O
+100	O
+to	O
+4	O
+","	O
+0	O
+micrograms	O
+)	O
+.	O
+	
+Treatment	O
+had	O
+no	O
+significant	O
+effect	O
+on	O
+baseline	O
+values	O
+.	O
+	
+There	O
+were	O
+dose	O
+-	O
+dependent	O
+increases	O
+in	O
+FEV1	O
+and	O
+FEF25	O
+-	O
+75	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+and	O
+pretreatment	O
+with	O
+HDS	O
+did	O
+not	O
+displace	O
+the	O
+DRC	O
+to	O
+the	O
+right	O
+.	O
+	
+DRC	O
+for	O
+HR	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+K	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+and	O
+Glu	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+were	O
+attenuated	O
+after	O
+treatment	O
+with	O
+HDS	O
+compared	O
+with	O
+PI	O
+.	O
+	
+There	O
+were	O
+also	O
+differences	O
+between	O
+HDS	O
+and	O
+LDS	O
+for	O
+HR	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+and	O
+Glu	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+responses	O
+.	O
+	
+Frequency	O
+and	O
+severity	O
+of	O
+subjective	O
+adverse	O
+effects	O
+were	O
+also	O
+reduced	O
+after	O
+HDS	O
+:	O
+tremor	B-NP
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+palpitations	B-NP
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+	
+Phenytoin	O
+induced	O
+fatal	O
+hepatic	B-NP
+injury	I-NP
+.	O
+	
+A	O
+61	O
+year	O
+old	O
+female	O
+developed	O
+fatal	O
+hepatic	B-NP
+failure	I-NP
+after	O
+phenytoin	O
+administration	O
+.	O
+	
+A	O
+typical	O
+multisystem	O
+clinical	O
+pattern	O
+precedes	O
+the	O
+manifestations	O
+of	O
+hepatic	B-NP
+injury	I-NP
+.	O
+	
+The	O
+hematologic	O
+","	O
+biochemical	O
+and	O
+pathologic	O
+features	O
+indicate	O
+a	O
+mixed	O
+hepatocellular	B-NP
+damage	I-NP
+due	O
+to	O
+drug	B-NP
+hypersensitivity	I-NP
+.	O
+	
+In	O
+a	O
+patient	O
+receiving	O
+phenytoin	O
+who	O
+presents	O
+a	O
+viral	O
+-	O
+like	O
+illness	O
+","	O
+early	O
+recognition	O
+and	O
+discontinuation	O
+of	O
+the	O
+drug	O
+are	O
+mandatory	O
+.	O
+	
+Treatment	O
+of	O
+lethal	O
+pertussis	O
+vaccine	O
+reaction	O
+with	O
+histamine	O
+H1	O
+antagonists	O
+.	O
+	
+We	O
+studied	O
+mortality	O
+after	O
+pertussis	B-NP
+immunization	O
+in	O
+the	O
+mouse	O
+.	O
+	
+Without	O
+treatment	O
+","	O
+73	O
+of	O
+92	O
+animals	O
+(	O
+80	O
+%	O
+)	O
+died	O
+after	O
+injection	O
+of	O
+bovine	O
+serum	O
+albumin	O
+(	O
+BSA	O
+)	O
+on	O
+day	O
++	O
+7	O
+of	O
+pertussis	B-NP
+immunization	O
+.	O
+	
+After	O
+pretreatment	O
+with	O
+3	O
+mg	O
+of	O
+cyproheptadine	O
+","	O
+2	O
+mg	O
+mianserin	O
+","	O
+or	O
+2	O
+mg	O
+chlorpheniramine	O
+","	O
+only	O
+5	O
+of	O
+105	O
+animals	O
+(	O
+5	O
+%	O
+)	O
+died	O
+after	O
+receiving	O
+BSA	O
+on	O
+day	O
++	O
+7	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Blockade	O
+of	O
+histamine	O
+H1	O
+receptors	O
+may	O
+reduce	O
+mortality	O
+in	O
+pertussis	B-NP
+immunization	O
+-	O
+induced	O
+encephalopathy	B-NP
+in	O
+mice	O
+.	O
+	
+Support	O
+for	O
+adrenaline	O
+-	O
+hypertension	B-NP
+hypothesis	O
+:	O
+18	O
+hour	O
+pressor	O
+effect	O
+after	O
+6	O
+hours	O
+adrenaline	O
+infusion	O
+.	O
+	
+In	O
+a	O
+double	O
+blind	O
+","	O
+crossover	O
+study	O
+6	O
+h	O
+infusions	O
+of	O
+adrenaline	O
+(	O
+15	O
+ng	O
+/	O
+kg	O
+/	O
+min	O
+;	O
+1	O
+ng	O
+=	O
+5	O
+.	O
+458	O
+pmol	O
+)	O
+","	O
+noradrenaline	O
+(	O
+30	O
+ng	O
+/	O
+kg	O
+/	O
+min	O
+;	O
+1	O
+ng	O
+=	O
+5	O
+.	O
+911	O
+pmol	O
+)	O
+","	O
+and	O
+a	O
+5	O
+%	O
+dextrose	O
+solution	O
+(	O
+5	O
+.	O
+4	O
+ml	O
+/	O
+h	O
+)	O
+","	O
+were	O
+given	O
+to	O
+ten	O
+healthy	O
+volunteers	O
+in	O
+random	O
+order	O
+2	O
+weeks	O
+apart	O
+.	O
+	
+By	O
+means	O
+of	O
+intra	O
+-	O
+arterial	O
+ambulatory	O
+monitoring	O
+the	O
+haemodynamic	O
+effects	O
+were	O
+followed	O
+for	O
+18	O
+h	O
+after	O
+the	O
+infusions	O
+were	O
+stopped	O
+.	O
+	
+Adrenaline	O
+","	O
+but	O
+not	O
+noradrenaline	O
+","	O
+caused	O
+a	O
+delayed	O
+and	O
+protracted	O
+pressor	O
+effect	O
+.	O
+	
+Over	O
+the	O
+total	O
+postinfusion	O
+period	O
+systolic	O
+and	O
+diastolic	O
+arterial	O
+pressure	O
+were	O
+6	O
+(	O
+SEM	O
+2	O
+)	O
+%	O
+and	O
+7	O
+(	O
+2	O
+)	O
+%	O
+","	O
+respectively	O
+","	O
+higher	O
+than	O
+after	O
+dextrose	O
+infusion	O
+(	O
+ANOVA	O
+","	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Thus	O
+","	O
+"	O
+stress	O
+"	O
+levels	O
+of	O
+adrenaline	O
+(	O
+230	O
+pg	O
+/	O
+ml	O
+)	O
+for	O
+6	O
+h	O
+cause	O
+a	O
+delayed	O
+and	O
+protracted	O
+pressor	O
+effect	O
+.	O
+	
+These	O
+findings	O
+are	O
+strong	O
+support	O
+for	O
+the	O
+adrenaline	O
+-	O
+hypertension	B-NP
+hypothesis	O
+in	O
+man	O
+.	O
+	
+Effect	O
+of	O
+alkylxanthines	O
+on	O
+gentamicin	O
+-	O
+induced	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+in	O
+the	O
+rat	O
+.	O
+	
+Adenosine	O
+antagonists	O
+have	O
+been	O
+previously	O
+shown	O
+to	O
+be	O
+of	O
+benefit	O
+in	O
+some	O
+ischaemic	B-NP
+and	O
+nephrotoxic	B-NP
+models	O
+of	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+(	O
+ARF	B-NP
+)	O
+.	O
+	
+In	O
+the	O
+present	O
+study	O
+","	O
+the	O
+effects	O
+of	O
+three	O
+alkylxanthines	O
+with	O
+different	O
+potencies	O
+as	O
+adenosine	O
+antagonists	O
+8	O
+-	O
+phenyltheophylline	O
+","	O
+theophylline	O
+and	O
+enprofylline	O
+","	O
+were	O
+examined	O
+in	O
+rats	O
+developing	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+after	O
+4	O
+daily	O
+injections	O
+of	O
+gentamicin	O
+(	O
+200	O
+mg	O
+kg	O
+-	O
+1	O
+)	O
+.	O
+	
+Renal	O
+function	O
+was	O
+assessed	O
+by	O
+biochemical	O
+(	O
+plasma	O
+urea	O
+and	O
+creatinine	O
+)	O
+","	O
+functional	O
+(	O
+urine	O
+analysis	O
+and	O
+[	O
+3H	O
+]	O
+inulin	O
+and	O
+[	O
+14C	O
+]	O
+p	O
+-	O
+aminohippuric	O
+acid	O
+clearances	O
+)	O
+and	O
+morphological	O
+(	O
+degree	O
+of	O
+necrosis	B-NP
+)	O
+indices	O
+.	O
+	
+The	O
+various	O
+drug	O
+treatments	O
+produced	O
+improvements	O
+in	O
+some	O
+","	O
+but	O
+not	O
+all	O
+","	O
+measurements	O
+of	O
+renal	O
+function	O
+.	O
+	
+However	O
+","	O
+any	O
+improvement	O
+produced	O
+by	O
+drug	O
+treatment	O
+was	O
+largely	O
+a	O
+result	O
+of	O
+a	O
+beneficial	O
+effect	O
+exerted	O
+by	O
+its	O
+vehicle	O
+(	O
+polyethylene	O
+glycol	O
+and	O
+NaOH	O
+)	O
+.	O
+	
+The	O
+lack	O
+of	O
+any	O
+consistent	O
+protective	O
+effect	O
+noted	O
+with	O
+the	O
+alkylxanthines	O
+tested	O
+in	O
+the	O
+present	O
+study	O
+indicates	O
+that	O
+adenosine	O
+plays	O
+little	O
+","	O
+if	O
+any	O
+","	O
+pathophysiological	O
+role	O
+in	O
+gentamicin	O
+-	O
+induced	O
+ARF	B-NP
+.	O
+	
+Adverse	O
+ocular	O
+reactions	O
+possibly	O
+associated	O
+with	O
+isotretinoin	O
+.	O
+	
+A	O
+total	O
+of	O
+261	O
+adverse	O
+ocular	O
+reactions	O
+occurred	O
+in	O
+237	O
+patients	O
+who	O
+received	O
+isotretinoin	O
+","	O
+a	O
+commonly	O
+used	O
+drug	O
+in	O
+the	O
+treatment	O
+of	O
+severe	O
+cystic	O
+acne	B-NP
+.	O
+	
+Blepharoconjunctivitis	B-NP
+","	O
+subjective	O
+complaints	O
+of	O
+dry	B-NP
+eyes	I-NP
+","	O
+blurred	B-NP
+vision	I-NP
+","	O
+contact	O
+lens	O
+intolerance	O
+","	O
+and	O
+photodermatitis	B-NP
+are	O
+reversible	O
+side	O
+effects	O
+.	O
+	
+More	O
+serious	O
+ocular	O
+adverse	O
+reactions	O
+include	O
+papilledema	B-NP
+","	O
+pseudotumor	B-NP
+cerebri	I-NP
+","	O
+and	O
+white	O
+or	O
+gray	O
+subepithelial	O
+corneal	B-NP
+opacities	I-NP
+;	O
+all	O
+of	O
+these	O
+are	O
+reversible	O
+if	O
+the	O
+drug	O
+is	O
+discontinued	O
+.	O
+	
+Reported	O
+cases	O
+of	O
+decreased	O
+dark	O
+adaptation	O
+are	O
+under	O
+investigation	O
+.	O
+	
+Isotretinoin	O
+is	O
+contraindicated	O
+in	O
+pregnancy	O
+because	O
+of	O
+the	O
+many	O
+reported	O
+congenital	B-NP
+abnormalities	I-NP
+after	O
+maternal	O
+use	O
+(	O
+including	O
+microphthalmos	B-NP
+","	O
+orbital	O
+hypertelorism	B-NP
+","	O
+and	O
+optic	B-NP
+nerve	I-NP
+hypoplasia	I-NP
+)	O
+.	O
+	
+Procaterol	O
+and	O
+terbutaline	O
+in	O
+bronchial	B-NP
+asthma	I-NP
+.	O
+	
+A	O
+double	O
+-	O
+blind	O
+","	O
+placebo	O
+-	O
+controlled	O
+","	O
+cross	O
+-	O
+over	O
+study	O
+.	O
+	
+Procaterol	O
+","	O
+a	O
+new	O
+beta	O
+-	O
+2	O
+adrenoceptor	O
+stimulant	O
+","	O
+was	O
+studied	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+","	O
+placebo	O
+-	O
+controlled	O
+","	O
+cross	O
+-	O
+over	O
+trial	O
+in	O
+patients	O
+with	O
+bronchial	B-NP
+asthma	I-NP
+.	O
+	
+Oral	O
+procaterol	O
+50	O
+micrograms	O
+b	O
+.	O
+d	O
+.	O
+","	O
+procaterol	O
+100	O
+micrograms	O
+b	O
+.	O
+d	O
+.	O
+","	O
+and	O
+terbutaline	O
+5	O
+mg	O
+t	O
+.	O
+i	O
+.	O
+d	O
+.	O
+","	O
+were	O
+compared	O
+when	O
+given	O
+randomly	O
+in	O
+1	O
+-	O
+week	O
+treatment	O
+periods	O
+.	O
+	
+The	O
+best	O
+clinical	O
+effect	O
+was	O
+found	O
+with	O
+terbutaline	O
+.	O
+	
+Both	O
+anti	O
+-	O
+asthmatic	B-NP
+and	O
+tremorgenic	B-NP
+effects	O
+of	O
+procaterol	O
+were	O
+dose	O
+-	O
+related	O
+.	O
+	
+Procaterol	O
+appeared	O
+effective	O
+in	O
+the	O
+doses	O
+tested	O
+","	O
+and	O
+a	O
+twice	O
+daily	O
+regimen	O
+would	O
+appear	O
+to	O
+be	O
+suitable	O
+with	O
+this	O
+drug	O
+.	O
+	
+Subacute	O
+effects	O
+of	O
+propranolol	O
+and	O
+B	O
+24	O
+/	O
+76	O
+on	O
+isoproterenol	O
+-	O
+induced	O
+rat	O
+heart	B-NP
+hypertrophy	I-NP
+in	O
+correlation	O
+with	O
+blood	O
+pressure	O
+.	O
+	
+We	O
+compared	O
+the	O
+potential	O
+beta	O
+-	O
+receptor	O
+blocker	O
+","	O
+B	O
+24	O
+/	O
+76	O
+i	O
+.	O
+e	O
+.	O
+1	O
+-	O
+(	O
+2	O
+","	O
+4	O
+-	O
+dichlorophenoxy	O
+)	O
+-	O
+3	O
+[	O
+2	O
+-	O
+3	O
+","	O
+4	O
+-	O
+dimethoxyphenyl	O
+)	O
+ethanolamino	O
+]	O
+-	O
+prop	O
+an	O
+-	O
+2	O
+-	O
+ol	O
+","	O
+which	O
+is	O
+characterized	O
+by	O
+beta	O
+1	O
+-	O
+adrenoceptor	O
+blocking	O
+and	O
+beta	O
+2	O
+-	O
+adrenoceptor	O
+stimulating	O
+properties	O
+with	O
+propranolol	O
+.	O
+	
+The	O
+studies	O
+were	O
+performed	O
+using	O
+an	O
+experimental	O
+model	O
+of	O
+isoproterenol	O
+-	O
+induced	O
+heart	B-NP
+hypertrophy	I-NP
+in	O
+rats	O
+.	O
+	
+A	O
+correlation	O
+of	O
+the	O
+blood	O
+pressure	O
+was	O
+neither	O
+found	O
+in	O
+the	O
+development	O
+nor	O
+in	O
+the	O
+attempt	O
+to	O
+suppress	O
+the	O
+development	O
+of	O
+heart	B-NP
+hypertrophy	I-NP
+with	O
+the	O
+two	O
+beta	O
+-	O
+receptor	O
+blockers	O
+.	O
+	
+Both	O
+beta	O
+-	O
+blockers	O
+influenced	O
+the	O
+development	O
+of	O
+hypertrophy	B-NP
+to	O
+a	O
+different	O
+","	O
+but	O
+not	O
+reproducible	O
+extent	O
+.	O
+	
+It	O
+was	O
+possible	O
+to	O
+suppress	O
+the	O
+increased	O
+ornithine	O
+decarboxylase	O
+activity	O
+with	O
+both	O
+beta	O
+-	O
+blockers	O
+in	O
+hypertrophied	B-NP
+hearts	I-NP
+","	O
+but	O
+there	O
+was	O
+no	O
+effect	O
+on	O
+the	O
+heart	O
+mass	O
+.	O
+	
+Neither	O
+propranolol	O
+nor	O
+B	O
+24	O
+/	O
+76	O
+could	O
+stop	O
+the	O
+changes	O
+in	O
+the	O
+characteristic	O
+myosin	O
+isoenzyme	O
+pattern	O
+of	O
+the	O
+hypertrophied	B-NP
+rat	O
+heart	O
+.	O
+	
+Thus	O
+","	O
+the	O
+investigations	O
+did	O
+not	O
+provide	O
+any	O
+evidence	O
+that	O
+the	O
+beta	O
+-	O
+receptor	O
+blockers	O
+propranolol	O
+and	O
+B	O
+24	O
+/	O
+76	O
+have	O
+the	O
+potency	O
+to	O
+prevent	O
+isoproterenol	O
+from	O
+producing	O
+heart	B-NP
+hypertrophy	I-NP
+.	O
+	
+Increased	O
+anxiogenic	O
+effects	O
+of	O
+caffeine	O
+in	O
+panic	B-NP
+disorders	I-NP
+.	O
+	
+The	O
+effects	O
+of	O
+oral	O
+administration	O
+of	O
+caffeine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+on	O
+behavioral	O
+ratings	O
+","	O
+somatic	O
+symptoms	O
+","	O
+blood	O
+pressure	O
+and	O
+plasma	O
+levels	O
+of	O
+3	O
+-	O
+methoxy	O
+-	O
+4	O
+-	O
+hydroxyphenethyleneglycol	O
+(	O
+MHPG	O
+)	O
+and	O
+cortisol	O
+were	O
+determined	O
+in	O
+17	O
+healthy	O
+subjects	O
+and	O
+21	O
+patients	O
+meeting	O
+DSM	O
+-	O
+III	O
+criteria	O
+for	O
+agoraphobia	B-NP
+with	O
+panic	B-NP
+attacks	I-NP
+or	O
+panic	B-NP
+disorder	I-NP
+.	O
+	
+Caffeine	O
+produced	O
+significantly	O
+greater	O
+increases	O
+in	O
+subject	O
+-	O
+rated	O
+anxiety	B-NP
+","	O
+nervousness	O
+","	O
+fear	O
+","	O
+nausea	B-NP
+","	O
+palpitations	B-NP
+","	O
+restlessness	B-NP
+","	O
+and	O
+tremors	B-NP
+in	O
+the	O
+patients	O
+compared	O
+with	O
+healthy	O
+subjects	O
+.	O
+	
+In	O
+the	O
+patients	O
+","	O
+but	O
+not	O
+the	O
+healthy	O
+subjects	O
+","	O
+these	O
+symptoms	O
+were	O
+significantly	O
+correlated	O
+with	O
+plasma	O
+caffeine	O
+levels	O
+.	O
+	
+Seventy	O
+-	O
+one	O
+percent	O
+of	O
+the	O
+patients	O
+reported	O
+that	O
+the	O
+behavioral	O
+effects	O
+of	O
+caffeine	O
+were	O
+similar	O
+to	O
+those	O
+experienced	O
+during	O
+panic	B-NP
+attacks	I-NP
+.	O
+	
+Caffeine	O
+did	O
+not	O
+alter	O
+plasma	O
+MHPG	O
+levels	O
+in	O
+either	O
+the	O
+healthy	O
+subjects	O
+or	O
+patients	O
+.	O
+	
+Caffeine	O
+increased	O
+plasma	O
+cortisol	O
+levels	O
+equally	O
+in	O
+the	O
+patient	O
+and	O
+healthy	O
+groups	O
+.	O
+	
+Because	O
+caffeine	O
+is	O
+an	O
+adenosine	O
+receptor	O
+antagonist	O
+","	O
+these	O
+results	O
+suggest	O
+that	O
+some	O
+panic	B-NP
+disorder	I-NP
+patients	O
+may	O
+have	O
+abnormalities	B-NP
+in	I-NP
+neuronal	I-NP
+systems	I-NP
+involving	O
+adenosine	O
+.	O
+	
+Patients	O
+with	O
+anxiety	B-NP
+disorders	I-NP
+may	O
+benefit	O
+by	O
+avoiding	O
+caffeine	O
+-	O
+containing	O
+foods	O
+and	O
+beverages	O
+.	O
+	
+Comparison	O
+of	O
+the	O
+effect	O
+of	O
+oxitropium	O
+bromide	O
+and	O
+of	O
+slow	O
+-	O
+release	O
+theophylline	O
+on	O
+nocturnal	O
+asthma	B-NP
+.	O
+	
+The	O
+effects	O
+of	O
+a	O
+new	O
+inhaled	O
+antimuscarinic	O
+drug	O
+","	O
+oxitropium	O
+bromide	O
+","	O
+and	O
+of	O
+a	O
+slow	O
+-	O
+release	O
+theophylline	O
+preparation	O
+upon	O
+nocturnal	O
+asthma	B-NP
+were	O
+compared	O
+in	O
+a	O
+placebo	O
+-	O
+controlled	O
+double	O
+-	O
+blind	O
+study	O
+.	O
+	
+Two	O
+samples	O
+were	O
+studied	O
+:	O
+12	O
+patients	O
+received	O
+oxitropium	O
+at	O
+600	O
+micrograms	O
+(	O
+6	O
+subjects	O
+)	O
+or	O
+at	O
+400	O
+micrograms	O
+t	O
+.	O
+i	O
+.	O
+d	O
+.	O
+	
+(	O
+6	O
+subjects	O
+)	O
+whereas	O
+11	O
+received	O
+theophylline	O
+at	O
+300	O
+mg	O
+b	O
+.	O
+i	O
+.	O
+d	O
+.	O
+	
+Morning	O
+dipping	O
+","	O
+assessed	O
+by	O
+the	O
+fall	O
+in	O
+peak	O
+flow	O
+overnight	O
+","	O
+was	O
+significantly	O
+reduced	O
+in	O
+the	O
+periods	O
+when	O
+either	O
+active	O
+drug	O
+was	O
+taken	O
+","	O
+whereas	O
+no	O
+difference	O
+was	O
+noticed	O
+during	O
+the	O
+placebo	O
+administration	O
+.	O
+	
+No	O
+significant	O
+difference	O
+was	O
+noticed	O
+between	O
+results	O
+obtained	O
+with	O
+either	O
+active	O
+drug	O
+","	O
+as	O
+well	O
+as	O
+with	O
+either	O
+dosage	O
+of	O
+oxitropium	O
+.	O
+	
+No	O
+subject	O
+reported	O
+side	O
+effects	O
+of	O
+oxitropium	O
+","	O
+as	O
+compared	O
+to	O
+three	O
+subjects	O
+reporting	O
+nausea	B-NP
+","	O
+vomiting	B-NP
+and	O
+tremors	B-NP
+after	O
+theophylline	O
+.	O
+	
+Oxitropium	O
+proves	O
+to	O
+be	O
+a	O
+valuable	O
+alternative	O
+to	O
+theophylline	O
+in	O
+nocturnal	O
+asthma	B-NP
+","	O
+since	O
+it	O
+is	O
+equally	O
+potent	O
+","	O
+safer	O
+and	O
+does	O
+not	O
+require	O
+the	O
+titration	O
+of	O
+dosage	O
+.	O
+	
+Penicillin	O
+anaphylaxis	B-NP
+.	O
+	
+A	O
+case	O
+of	O
+oral	O
+penicillin	O
+anaphylaxis	B-NP
+is	O
+described	O
+","	O
+and	O
+the	O
+terminology	O
+","	O
+occurrence	O
+","	O
+clinical	O
+manifestations	O
+","	O
+pathogenesis	O
+","	O
+prevention	O
+","	O
+and	O
+treatment	O
+of	O
+anaphylaxis	B-NP
+are	O
+reviewed	O
+.	O
+	
+Emergency	O
+physicians	O
+should	O
+be	O
+aware	O
+of	O
+oral	O
+penicillin	O
+anaphylaxis	B-NP
+in	O
+order	O
+to	O
+prevent	O
+its	O
+occurrence	O
+by	O
+prescribing	O
+the	O
+antibiotic	O
+judiciously	O
+and	O
+knowledgeably	O
+and	O
+to	O
+offer	O
+optimal	O
+medical	O
+therapy	O
+once	O
+this	O
+life	O
+-	O
+threatening	O
+reaction	O
+has	O
+begun	O
+.	O
+	
+Reversible	O
+valproic	O
+acid	O
+-	O
+induced	O
+dementia	B-NP
+:	O
+a	O
+case	O
+report	O
+.	O
+	
+Reversible	O
+valproic	O
+acid	O
+-	O
+induced	O
+dementia	B-NP
+was	O
+documented	O
+in	O
+a	O
+21	O
+-	O
+year	O
+-	O
+old	O
+man	O
+with	O
+epilepsy	B-NP
+who	O
+had	O
+a	O
+3	O
+-	O
+year	O
+history	O
+of	O
+insidious	O
+progressive	O
+decline	O
+in	O
+global	O
+cognitive	O
+abilities	O
+documented	O
+by	O
+serial	O
+neuropsychological	O
+studies	O
+.	O
+	
+Repeat	O
+neuropsychological	O
+testing	O
+7	O
+weeks	O
+after	O
+discontinuation	O
+of	O
+the	O
+drug	O
+revealed	O
+dramatic	O
+improvement	O
+in	O
+IQ	O
+","	O
+memory	O
+","	O
+naming	O
+","	O
+and	O
+other	O
+tasks	O
+commensurate	O
+with	O
+clinical	O
+recovery	O
+in	O
+his	O
+intellectual	O
+capacity	O
+.	O
+	
+Possible	O
+pathophysiological	O
+mechanisms	O
+which	O
+may	O
+have	O
+been	O
+operative	O
+in	O
+this	O
+case	O
+include	O
+:	O
+a	O
+direct	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+toxic	O
+effect	O
+of	O
+valproic	O
+acid	O
+;	O
+a	O
+paradoxical	O
+epileptogenic	O
+effect	O
+secondary	O
+to	O
+the	O
+drug	O
+;	O
+and	O
+an	O
+indirect	O
+CNS	O
+toxic	O
+effect	O
+mediated	O
+through	O
+valproic	O
+acid	O
+-	O
+induced	O
+hyperammonemia	B-NP
+.	O
+	
+Reversal	O
+of	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B-NP
+of	O
+passive	O
+avoidance	O
+by	O
+pre	O
+-	O
+and	O
+post	O
+-	O
+training	O
+naloxone	O
+.	O
+	
+In	O
+a	O
+series	O
+of	O
+five	O
+experiments	O
+","	O
+the	O
+modulating	O
+role	O
+of	O
+naloxone	O
+on	O
+a	O
+scopolamine	O
+-	O
+induced	O
+retention	B-NP
+deficit	I-NP
+in	O
+a	O
+passive	O
+avoidance	O
+paradigm	O
+was	O
+investigated	O
+in	O
+mice	O
+.	O
+	
+Scopolamine	O
+","	O
+but	O
+not	O
+methyl	O
+scopolamine	O
+(	O
+1	O
+and	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+","	O
+induced	O
+an	O
+amnesia	B-NP
+as	O
+measured	O
+by	O
+latency	O
+and	O
+duration	O
+parameters	O
+.	O
+	
+Naloxone	O
+(	O
+0	O
+.	O
+3	O
+","	O
+1	O
+","	O
+3	O
+","	O
+and	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+injected	O
+prior	O
+to	O
+training	O
+attenuated	O
+the	O
+retention	B-NP
+deficit	I-NP
+with	O
+a	O
+peak	O
+of	O
+activity	O
+at	O
+3	O
+mg	O
+/	O
+kg	O
+.	O
+	
+The	O
+effect	O
+of	O
+naloxone	O
+could	O
+be	O
+antagonized	O
+with	O
+morphine	O
+(	O
+1	O
+","	O
+3	O
+","	O
+and	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+","	O
+demonstrating	O
+the	O
+opioid	O
+specificity	O
+of	O
+the	O
+naloxone	O
+effect	O
+.	O
+	
+Post	O
+-	O
+training	O
+administration	O
+of	O
+naloxone	O
+(	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+as	O
+a	O
+single	O
+or	O
+as	O
+a	O
+split	O
+dose	O
+also	O
+attenuated	O
+the	O
+scopolamine	O
+-	O
+induced	O
+amnesia	B-NP
+.	O
+	
+Control	O
+experiments	O
+indicated	O
+that	O
+neither	O
+an	O
+increase	O
+in	O
+pain	B-NP
+sensitivity	O
+(	O
+pre	O
+-	O
+training	O
+naloxone	O
+)	O
+nor	O
+an	O
+induced	O
+aversive	O
+state	O
+(	O
+post	O
+-	O
+training	O
+naloxone	O
+)	O
+appear	O
+to	O
+be	O
+responsible	O
+for	O
+the	O
+influence	O
+of	O
+naloxone	O
+on	O
+the	O
+scopolamine	O
+-	O
+induced	O
+retention	B-NP
+deficit	I-NP
+.	O
+	
+These	O
+results	O
+extend	O
+previous	O
+findings	O
+implicating	O
+a	O
+cholinergic	O
+-	O
+opioid	O
+interaction	O
+in	O
+memory	O
+processes	O
+.	O
+	
+A	O
+possible	O
+mechanism	O
+for	O
+this	O
+interaction	O
+involving	O
+the	O
+septo	O
+-	O
+hippocampal	O
+cholinergic	O
+pathway	O
+is	O
+discussed	O
+.	O
+	
+Electron	O
+microscopic	O
+investigations	O
+of	O
+the	O
+cyclophosphamide	O
+-	O
+induced	O
+lesions	B-NP
+of	I-NP
+the	I-NP
+urinary	I-NP
+bladder	I-NP
+of	O
+the	O
+rat	O
+and	O
+their	O
+prevention	O
+by	O
+mesna	O
+.	O
+	
+Fully	O
+developed	O
+cyclophosphamide	O
+-	O
+induced	O
+cystitis	B-NP
+is	O
+characterized	O
+by	O
+nearly	O
+complete	O
+detachment	O
+of	O
+the	O
+urothelium	O
+","	O
+severe	O
+submucosal	O
+edema	B-NP
+owing	O
+to	O
+damage	O
+to	O
+the	O
+microvascular	O
+bed	O
+and	O
+focal	O
+muscle	O
+necroses	B-NP
+.	O
+	
+The	O
+initial	O
+response	O
+to	O
+the	O
+primary	O
+attack	O
+by	O
+the	O
+cyclophosphamide	O
+metabolites	O
+seems	O
+to	O
+be	O
+fragmentation	O
+of	O
+the	O
+luminal	O
+membrane	O
+.	O
+	
+This	O
+damages	O
+the	O
+cellular	O
+barrier	O
+against	O
+the	O
+hypertonic	O
+urine	O
+.	O
+	
+Subsequent	O
+breaks	O
+in	O
+the	O
+lateral	O
+cell	O
+membranes	O
+of	O
+the	O
+superficial	O
+cells	O
+and	O
+in	O
+all	O
+the	O
+plasma	O
+membranes	O
+of	O
+the	O
+intermediate	O
+and	O
+basal	O
+cells	O
+","	O
+intercellular	O
+and	O
+intracellular	O
+edema	B-NP
+and	O
+disintegration	O
+of	O
+the	O
+desmosomes	O
+and	O
+hemidesmosomes	O
+lead	O
+to	O
+progressive	O
+degeneration	O
+and	O
+detachment	O
+of	O
+the	O
+epithelial	O
+cells	O
+with	O
+exposure	O
+and	O
+splitting	O
+of	O
+the	O
+basal	O
+membrane	O
+.	O
+	
+The	O
+morphological	O
+changes	O
+of	O
+the	O
+endothelial	O
+cells	O
+","	O
+which	O
+become	O
+more	O
+pronounced	O
+in	O
+the	O
+later	O
+stages	O
+of	O
+the	O
+experiment	O
+","	O
+the	O
+involvement	O
+of	O
+blood	O
+vessels	O
+regardless	O
+of	O
+their	O
+diameter	O
+and	O
+the	O
+location	O
+-	O
+dependent	O
+extent	O
+of	O
+the	O
+damage	O
+indicate	O
+a	O
+direct	O
+type	O
+of	O
+damage	O
+which	O
+is	O
+preceded	O
+by	O
+a	O
+mediator	O
+-	O
+induced	O
+increase	O
+in	O
+permeability	O
+","	O
+the	O
+morphological	O
+correlate	O
+of	O
+which	O
+is	O
+the	O
+formation	O
+of	O
+gaps	O
+in	O
+the	O
+interendothelial	O
+cell	O
+connections	O
+on	O
+the	O
+venules	O
+.	O
+	
+These	O
+changes	O
+can	O
+be	O
+effectively	O
+prevented	O
+by	O
+mesna	O
+.	O
+	
+The	O
+only	O
+sign	O
+of	O
+a	O
+possible	O
+involvement	O
+is	O
+the	O
+increase	O
+in	O
+the	O
+number	O
+of	O
+specific	O
+granules	O
+with	O
+a	O
+presumed	O
+lysosomal	O
+function	O
+in	O
+the	O
+superficial	O
+cells	O
+.	O
+	
+Increase	O
+in	O
+intragastric	O
+pressure	O
+during	O
+suxamethonium	O
+-	O
+induced	O
+muscle	B-NP
+fasciculations	I-NP
+in	O
+children	O
+:	O
+inhibition	O
+by	O
+alfentanil	O
+.	O
+	
+Changes	O
+in	O
+intragastric	O
+pressure	O
+after	O
+the	O
+administration	O
+of	O
+suxamethonium	O
+1	O
+.	O
+5	O
+mg	O
+kg	O
+-	O
+1	O
+i	O
+.	O
+v	O
+.	O
+were	O
+studied	O
+in	O
+32	O
+children	O
+(	O
+mean	O
+age	O
+6	O
+.	O
+9	O
+yr	O
+)	O
+pretreated	O
+with	O
+either	O
+physiological	O
+saline	O
+or	O
+alfentanil	O
+50	O
+micrograms	O
+kg	O
+-	O
+1	O
+.	O
+	
+Anaesthesia	O
+was	O
+induced	O
+with	O
+thiopentone	O
+5	O
+mg	O
+kg	O
+-	O
+1	O
+.	O
+	
+The	O
+incidence	O
+and	O
+intensity	O
+of	O
+muscle	B-NP
+fasciculations	I-NP
+caused	O
+by	O
+suxamethonium	O
+were	O
+significantly	O
+greater	O
+in	O
+the	O
+control	O
+than	O
+in	O
+the	O
+alfentanil	O
+group	O
+.	O
+	
+The	O
+intragastric	O
+pressure	O
+during	O
+muscle	B-NP
+fasciculations	I-NP
+was	O
+significantly	O
+higher	O
+in	O
+the	O
+control	O
+group	O
+(	O
+16	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+(	O
+SEM	O
+)	O
+cm	O
+H2O	O
+)	O
+than	O
+in	O
+the	O
+alfentanil	O
+group	O
+(	O
+7	O
+.	O
+7	O
++	O
+/	O
+-	O
+1	O
+.	O
+5	O
+(	O
+SEM	O
+)	O
+cm	O
+H2O	O
+)	O
+.	O
+	
+The	O
+increase	O
+in	O
+intragastric	O
+pressure	O
+was	O
+directly	O
+related	O
+to	O
+the	O
+intensity	O
+of	O
+muscle	B-NP
+fasciculations	I-NP
+(	O
+regression	O
+line	O
+:	O
+y	O
+=	O
+0	O
+.	O
+5	O
++	O
+4	O
+.	O
+78x	O
+with	O
+r	O
+of	O
+0	O
+.	O
+78	O
+)	O
+.	O
+	
+It	O
+is	O
+concluded	O
+that	O
+intragastric	O
+pressure	O
+increases	O
+significantly	O
+during	O
+muscle	B-NP
+fasciculations	I-NP
+caused	O
+by	O
+suxamethonium	O
+in	O
+healthy	O
+children	O
+.	O
+	
+Alfentanil	O
+50	O
+micrograms	O
+kg	O
+-	O
+1	O
+effectively	O
+inhibits	O
+the	O
+incidence	O
+and	O
+intensity	O
+of	O
+suxamethonium	O
+-	O
+induced	O
+muscle	B-NP
+fasciculations	I-NP
+;	O
+moreover	O
+","	O
+intragastric	O
+pressure	O
+remains	O
+at	O
+its	O
+control	O
+value	O
+.	O
+	
+Acute	O
+insulin	O
+treatment	O
+normalizes	O
+the	O
+resistance	O
+to	O
+the	O
+cardiotoxic	B-NP
+effect	O
+of	O
+isoproterenol	O
+in	O
+streptozotocin	O
+diabetic	B-NP
+rats	O
+.	O
+	
+A	O
+morphometric	O
+study	O
+of	O
+isoproterenol	O
+induced	O
+myocardial	O
+fibrosis	B-NP
+.	O
+	
+The	O
+acute	O
+effect	O
+of	O
+insulin	O
+treatment	O
+on	O
+the	O
+earlier	O
+reported	O
+protective	O
+effect	O
+of	O
+streptozotocin	O
+diabetes	B-NP
+against	O
+the	O
+cardiotoxic	B-NP
+effect	O
+of	O
+high	O
+doses	O
+of	O
+isoproterenol	O
+(	O
+ISO	O
+)	O
+was	O
+investigated	O
+in	O
+rats	O
+.	O
+	
+Thirty	O
+to	O
+135	O
+min	O
+after	O
+the	O
+injection	O
+of	O
+crystalline	O
+insulin	O
+","	O
+ISO	O
+was	O
+given	O
+subcutaneously	O
+and	O
+when	O
+ISO	O
+induced	O
+fibrosis	B-NP
+in	O
+the	O
+myocardium	O
+was	O
+morphometrically	O
+analyzed	O
+7	O
+days	O
+later	O
+","	O
+a	O
+highly	O
+significant	O
+correlation	O
+(	O
+r	O
+=	O
+0	O
+.	O
+83	O
+","	O
+2	O
+p	O
+=	O
+0	O
+.	O
+6	O
+)	O
+to	O
+the	O
+slope	O
+of	O
+the	O
+fall	O
+in	O
+blood	O
+glucose	O
+after	O
+insulin	O
+treatment	O
+appeared	O
+.	O
+	
+The	O
+myocardial	O
+content	O
+of	O
+catecholamines	O
+was	O
+estimated	O
+in	O
+these	O
+8	O
+day	O
+diabetic	B-NP
+rats	O
+.	O
+	
+The	O
+norepinephrine	O
+content	O
+was	O
+significantly	O
+increased	O
+while	O
+epinephrine	O
+remained	O
+unchanged	O
+.	O
+	
+An	O
+enhanced	O
+sympathetic	O
+nervous	O
+system	O
+activity	O
+with	O
+a	O
+consequent	O
+down	O
+regulation	O
+of	O
+the	O
+myocardial	O
+beta	O
+-	O
+adrenergic	O
+receptors	O
+could	O
+","	O
+therefore	O
+","	O
+explain	O
+this	O
+catecholamine	O
+resistance	O
+.	O
+	
+The	O
+rapid	O
+reversion	O
+after	O
+insulin	O
+treatment	O
+excludes	O
+the	O
+possibility	O
+that	O
+streptozotocin	O
+in	O
+itself	O
+causes	O
+the	O
+ISO	O
+resistance	O
+and	O
+points	O
+towards	O
+a	O
+direct	O
+insulin	O
+effect	O
+on	O
+myocardial	O
+catecholamine	O
+sensitivity	O
+in	O
+diabetic	B-NP
+rats	O
+.	O
+	
+The	O
+phenomenon	O
+described	O
+might	O
+elucidate	O
+pathogenetic	O
+mechanisms	O
+behind	O
+toxic	O
+myocardial	O
+cell	O
+degeneration	O
+and	O
+may	O
+possibly	O
+have	O
+relevance	O
+for	O
+acute	O
+cardiovascular	O
+complications	O
+in	O
+diabetic	B-NP
+patients	O
+.	O
+	
+Differential	O
+effects	O
+of	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+on	O
+seizures	B-NP
+produced	O
+by	O
+pilocarpine	O
+in	O
+rats	O
+.	O
+	
+The	O
+muscarinic	O
+cholinergic	O
+agonist	O
+pilocarpine	O
+induces	O
+in	O
+rats	O
+seizures	B-NP
+and	O
+status	B-NP
+epilepticus	I-NP
+followed	O
+by	O
+widespread	O
+damage	O
+to	O
+the	O
+forebrain	O
+.	O
+	
+The	O
+present	O
+study	O
+was	O
+designed	O
+to	O
+investigate	O
+the	O
+effect	O
+of	O
+5	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+","	O
+sodium	O
+salicylate	O
+","	O
+phenylbutazone	O
+","	O
+indomethacin	O
+","	O
+ibuprofen	O
+and	O
+mefenamic	O
+acid	O
+","	O
+on	O
+seizures	B-NP
+produced	O
+by	O
+pilocarpine	O
+.	O
+	
+Pretreatment	O
+of	O
+rats	O
+with	O
+sodium	O
+salicylate	O
+","	O
+ED50	O
+103	O
+mg	O
+/	O
+kg	O
+(	O
+60	O
+-	O
+174	O
+)	O
+","	O
+and	O
+phenylbutazone	O
+","	O
+59	O
+mg	O
+/	O
+kg	O
+(	O
+50	O
+-	O
+70	O
+)	O
+converted	O
+the	O
+non	O
+-	O
+convulsant	O
+dose	O
+of	O
+pilocarpine	O
+","	O
+200	O
+mg	O
+/	O
+kg	O
+","	O
+to	O
+a	O
+convulsant	O
+one	O
+.	O
+	
+Indomethacin	O
+","	O
+1	O
+-	O
+10	O
+mg	O
+/	O
+kg	O
+","	O
+and	O
+ibuprofen	O
+","	O
+10	O
+-	O
+100	O
+mg	O
+/	O
+kg	O
+","	O
+failed	O
+to	O
+modulate	O
+seizures	B-NP
+produced	O
+by	O
+pilocarpine	O
+.	O
+	
+Mefenamic	O
+acid	O
+","	O
+26	O
+(	O
+22	O
+-	O
+30	O
+)	O
+mg	O
+/	O
+kg	O
+","	O
+prevented	O
+seizures	B-NP
+and	O
+protected	O
+rats	O
+from	O
+seizure	B-NP
+-	O
+related	O
+brain	B-NP
+damage	I-NP
+induced	O
+by	O
+pilocarpine	O
+","	O
+380	O
+mg	O
+/	O
+kg	O
+.	O
+	
+These	O
+results	O
+indicate	O
+that	O
+non	O
+-	O
+steroidal	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+differentially	O
+modulate	O
+the	O
+threshold	O
+for	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B-NP
+.	O
+	
+Acute	B-NP
+neurologic	I-NP
+dysfunction	I-NP
+after	O
+high	O
+-	O
+dose	O
+etoposide	O
+therapy	O
+for	O
+malignant	B-NP
+glioma	I-NP
+.	O
+	
+Etoposide	O
+(	O
+VP	O
+-	O
+16	O
+-	O
+213	O
+)	O
+has	O
+been	O
+used	O
+in	O
+the	O
+treatment	O
+of	O
+many	O
+solid	O
+tumors	B-NP
+and	O
+hematologic	B-NP
+malignancies	I-NP
+.	O
+	
+When	O
+used	O
+in	O
+high	O
+doses	O
+and	O
+in	O
+conjunction	O
+with	O
+autologous	O
+bone	O
+marrow	O
+transplantation	O
+","	O
+this	O
+agent	O
+has	O
+activity	O
+against	O
+several	O
+treatment	O
+-	O
+resistant	O
+cancers	B-NP
+including	O
+malignant	B-NP
+glioma	I-NP
+.	O
+	
+In	O
+six	O
+of	O
+eight	O
+patients	O
+(	O
+75	O
+%	O
+)	O
+who	O
+we	O
+treated	O
+for	O
+recurrent	O
+or	O
+resistant	O
+glioma	B-NP
+","	O
+sudden	O
+severe	O
+neurologic	B-NP
+deterioration	I-NP
+occurred	O
+.	O
+	
+This	O
+developed	O
+a	O
+median	O
+of	O
+9	O
+days	O
+after	O
+initiation	O
+of	O
+high	O
+-	O
+dose	O
+etoposide	O
+therapy	O
+.	O
+	
+Significant	O
+clinical	O
+manifestations	O
+have	O
+included	O
+confusion	B-NP
+","	O
+papilledema	B-NP
+","	O
+somnolence	B-NP
+","	O
+exacerbation	O
+of	O
+motor	B-NP
+deficits	I-NP
+","	O
+and	O
+sharp	O
+increase	O
+in	O
+seizure	B-NP
+activity	O
+.	O
+	
+These	O
+abnormalities	O
+resolved	O
+rapidly	O
+after	O
+initiation	O
+of	O
+high	O
+-	O
+dose	O
+intravenous	O
+dexamethasone	O
+therapy	O
+.	O
+	
+In	O
+all	O
+patients	O
+","	O
+computerized	O
+tomographic	O
+(	O
+CT	O
+)	O
+brain	O
+scans	O
+demonstrated	O
+stability	O
+in	O
+tumor	B-NP
+size	O
+and	O
+peritumor	O
+edema	B-NP
+when	O
+compared	O
+with	O
+pretransplant	O
+scans	O
+.	O
+	
+This	O
+complication	O
+appears	O
+to	O
+represent	O
+a	O
+significant	O
+new	O
+toxicity	B-NP
+of	O
+high	O
+-	O
+dose	O
+etoposide	O
+therapy	O
+for	O
+malignant	B-NP
+glioma	I-NP
+.	O
+	
+Progressive	O
+bile	B-NP
+duct	I-NP
+injury	I-NP
+after	O
+thiabendazole	O
+administration	O
+.	O
+	
+A	O
+27	O
+-	O
+yr	O
+-	O
+old	O
+man	O
+developed	O
+jaundice	B-NP
+2	O
+wk	O
+after	O
+exposure	O
+to	O
+thiabendazole	O
+.	O
+	
+Cholestasis	B-NP
+persisted	O
+for	O
+3	O
+yr	O
+","	O
+at	O
+which	O
+time	O
+a	O
+liver	O
+transplant	O
+was	O
+performed	O
+.	O
+	
+Two	O
+liver	O
+biopsy	O
+specimens	O
+and	O
+the	O
+hepatectomy	O
+specimen	O
+were	O
+remarkable	O
+for	O
+almost	O
+complete	O
+disappearance	O
+of	O
+interlobular	O
+bile	O
+ducts	O
+.	O
+	
+Prominent	O
+fibrosis	B-NP
+and	O
+hepatocellular	O
+regeneration	O
+were	O
+also	O
+present	O
+;	O
+however	O
+","	O
+the	O
+lobular	O
+architecture	O
+was	O
+preserved	O
+.	O
+	
+This	O
+case	O
+represents	O
+an	O
+example	O
+of	O
+"	O
+idiosyncratic	O
+"	O
+drug	B-NP
+-	I-NP
+induced	I-NP
+liver	I-NP
+damage	I-NP
+in	O
+which	O
+the	O
+primary	O
+target	O
+of	O
+injury	O
+is	O
+the	O
+bile	O
+duct	O
+.	O
+	
+An	O
+autoimmune	O
+pathogenesis	O
+of	O
+the	O
+bile	B-NP
+duct	I-NP
+destruction	I-NP
+is	O
+suggested	O
+.	O
+	
+Differential	O
+effects	O
+of	O
+1	O
+","	O
+4	O
+-	O
+dihydropyridine	O
+calcium	O
+channel	O
+blockers	O
+:	O
+therapeutic	O
+implications	O
+.	O
+	
+Increasing	O
+recognition	O
+of	O
+the	O
+importance	O
+of	O
+calcium	O
+in	O
+the	O
+pathogenesis	O
+of	O
+cardiovascular	B-NP
+disease	I-NP
+has	O
+stimulated	O
+research	O
+into	O
+the	O
+use	O
+of	O
+calcium	O
+channel	O
+blocking	O
+agents	O
+for	O
+treatment	O
+of	O
+a	O
+variety	O
+of	O
+cardiovascular	B-NP
+diseases	I-NP
+.	O
+	
+The	O
+favorable	O
+efficacy	O
+and	O
+tolerability	O
+profiles	O
+of	O
+these	O
+agents	O
+make	O
+them	O
+attractive	O
+therapeutic	O
+modalities	O
+.	O
+	
+Clinical	O
+applications	O
+of	O
+calcium	O
+channel	O
+blockers	O
+parallel	O
+their	O
+tissue	O
+selectivity	O
+.	O
+	
+In	O
+contrast	O
+to	O
+verapamil	O
+and	O
+diltiazem	O
+","	O
+which	O
+are	O
+roughly	O
+equipotent	O
+in	O
+their	O
+actions	O
+on	O
+the	O
+heart	O
+and	O
+vascular	O
+smooth	O
+muscle	O
+","	O
+the	O
+dihydropyridine	O
+calcium	O
+channel	O
+blockers	O
+are	O
+a	O
+group	O
+of	O
+potent	O
+peripheral	O
+vasodilator	O
+agents	O
+that	O
+exert	O
+minimal	O
+electrophysiologic	O
+effects	O
+on	O
+cardiac	O
+nodal	O
+or	O
+conduction	O
+tissue	O
+.	O
+	
+As	O
+the	O
+first	O
+dihydropyridine	O
+available	O
+for	O
+use	O
+in	O
+the	O
+United	O
+States	O
+","	O
+nifedipine	O
+controls	O
+angina	B-NP
+and	O
+hypertension	B-NP
+with	O
+minimal	O
+depression	O
+of	O
+cardiac	O
+function	O
+.	O
+	
+Additional	O
+members	O
+of	O
+this	O
+group	O
+of	O
+calcium	O
+channel	O
+blockers	O
+have	O
+been	O
+studied	O
+for	O
+a	O
+variety	O
+of	O
+indications	O
+for	O
+which	O
+they	O
+may	O
+offer	O
+advantages	O
+over	O
+current	O
+therapy	O
+.	O
+	
+Once	O
+or	O
+twice	O
+daily	O
+dosage	O
+possible	O
+with	O
+nitrendipine	O
+and	O
+nisoldipine	O
+offers	O
+a	O
+convenient	O
+administration	O
+schedule	O
+","	O
+which	O
+encourages	O
+patient	O
+compliance	O
+in	O
+long	O
+-	O
+term	O
+therapy	O
+of	O
+hypertension	B-NP
+.	O
+	
+The	O
+coronary	O
+vasodilating	O
+properties	O
+of	O
+nisoldipine	O
+have	O
+led	O
+to	O
+the	O
+investigation	O
+of	O
+this	O
+agent	O
+for	O
+use	O
+in	O
+angina	B-NP
+.	O
+	
+Selectivity	O
+for	O
+the	O
+cerebrovascular	O
+bed	O
+makes	O
+nimodipine	O
+potentially	O
+useful	O
+in	O
+the	O
+treatment	O
+of	O
+subarachnoid	B-NP
+hemorrhage	I-NP
+","	O
+migraine	B-NP
+headache	I-NP
+","	O
+dementia	B-NP
+","	O
+and	O
+stroke	B-NP
+.	O
+	
+In	O
+general	O
+","	O
+the	O
+dihydropyridine	O
+calcium	O
+channel	O
+blockers	O
+are	O
+usually	O
+well	O
+tolerated	O
+","	O
+with	O
+headache	B-NP
+","	O
+facial	O
+flushing	B-NP
+","	O
+palpitations	B-NP
+","	O
+edema	B-NP
+","	O
+nausea	B-NP
+","	O
+anorexia	B-NP
+","	O
+and	O
+dizziness	B-NP
+being	O
+the	O
+more	O
+common	O
+adverse	O
+effects	O
+.	O
+	
+The	O
+enhancement	O
+of	O
+aminonucleoside	O
+nephrosis	B-NP
+by	O
+the	O
+co	O
+-	O
+administration	O
+of	O
+protamine	O
+.	O
+	
+An	O
+experimental	O
+model	O
+of	O
+focal	B-NP
+segmental	I-NP
+glomerular	I-NP
+sclerosis	I-NP
+(	O
+FSGS	B-NP
+)	O
+was	O
+developed	O
+in	O
+rats	O
+by	O
+the	O
+combined	O
+administration	O
+of	O
+puromycin	O
+-	O
+aminonucleoside	O
+(	O
+AMNS	O
+)	O
+and	O
+protamine	O
+sulfate	O
+(	O
+PS	O
+)	O
+.	O
+	
+Male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+","	O
+uninephrectomized	O
+three	O
+weeks	O
+before	O
+","	O
+received	O
+daily	O
+injections	O
+of	O
+subcutaneous	O
+AMNS	O
+(	O
+1	O
+mg	O
+/	O
+100	O
+g	O
+body	O
+wt	O
+)	O
+and	O
+intravenous	O
+PS	O
+(	O
+2	O
+separated	O
+doses	O
+of	O
+2	O
+.	O
+5	O
+mg	O
+/	O
+100	O
+g	O
+body	O
+wt	O
+)	O
+for	O
+four	O
+days	O
+.	O
+	
+The	O
+series	O
+of	O
+injections	O
+were	O
+repeated	O
+another	O
+three	O
+times	O
+at	O
+10	O
+day	O
+intervals	O
+.	O
+	
+The	O
+animals	O
+were	O
+sacrificed	O
+on	O
+days	O
+24	O
+","	O
+52	O
+","	O
+and	O
+80	O
+.	O
+	
+They	O
+developed	O
+nephrotic	B-NP
+syndrome	I-NP
+and	O
+finally	O
+renal	B-NP
+failure	I-NP
+.	O
+	
+The	O
+time	O
+-	O
+course	O
+curve	O
+of	O
+creatinine	O
+clearance	O
+dropped	O
+and	O
+showed	O
+significant	O
+difference	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+from	O
+that	O
+of	O
+each	O
+control	O
+group	O
+","	O
+such	O
+as	O
+","	O
+AMNS	O
+alone	O
+","	O
+PS	O
+alone	O
+or	O
+saline	O
+injected	O
+.	O
+	
+Their	O
+glomeruli	O
+showed	O
+changes	O
+of	O
+progressive	O
+FSGS	B-NP
+.	O
+	
+The	O
+ultrastructural	O
+studies	O
+in	O
+the	O
+initial	O
+stage	O
+revealed	O
+significant	O
+lack	O
+of	O
+particles	O
+of	O
+perfused	O
+ruthenium	O
+red	O
+on	O
+the	O
+lamina	O
+rara	O
+externa	O
+and	O
+marked	O
+changes	O
+in	O
+epithelial	O
+cell	O
+cytoplasm	O
+.	O
+	
+Therefore	O
+","	O
+it	O
+is	O
+suggested	O
+that	O
+the	O
+administration	O
+of	O
+PS	O
+enhances	O
+the	O
+toxicity	B-NP
+of	O
+AMNS	O
+on	O
+the	O
+glomerulus	O
+and	O
+readily	O
+produces	O
+progressive	O
+FSGS	B-NP
+in	O
+rats	O
+resulting	O
+in	O
+the	O
+end	B-NP
+-	I-NP
+stage	I-NP
+renal	I-NP
+disease	I-NP
+.	O
+	
+Theophylline	O
+neurotoxicity	B-NP
+in	O
+pregnant	O
+rats	O
+.	O
+	
+The	O
+purpose	O
+of	O
+this	O
+investigation	O
+was	O
+to	O
+determine	O
+whether	O
+the	O
+neurotoxicity	B-NP
+of	O
+theophylline	O
+is	O
+altered	O
+in	O
+advanced	O
+pregnancy	O
+.	O
+	
+Sprague	O
+-	O
+Dawley	O
+rats	O
+that	O
+were	O
+20	O
+days	O
+pregnant	O
+and	O
+nonpregnant	O
+rats	O
+of	O
+the	O
+same	O
+age	O
+and	O
+strain	O
+received	O
+infusions	O
+of	O
+aminophylline	O
+until	O
+onset	O
+of	O
+maximal	O
+seizures	B-NP
+which	O
+occurred	O
+after	O
+28	O
+and	O
+30	O
+minutes	O
+respectively	O
+.	O
+	
+Theophylline	O
+concentrations	O
+at	O
+this	O
+endpoint	O
+in	O
+serum	O
+(	O
+total	O
+)	O
+and	O
+CSF	O
+were	O
+similar	O
+but	O
+serum	O
+(	O
+free	O
+)	O
+and	O
+brain	O
+concentrations	O
+were	O
+slightly	O
+different	O
+in	O
+pregnant	O
+rats	O
+.	O
+	
+Theophylline	O
+serum	O
+protein	O
+binding	O
+determined	O
+by	O
+equilibrium	O
+dialysis	O
+was	O
+lower	O
+in	O
+pregnant	O
+rats	O
+.	O
+	
+Fetal	O
+serum	O
+concentrations	O
+at	O
+onset	O
+of	O
+seizures	B-NP
+in	O
+the	O
+mother	O
+were	O
+similar	O
+to	O
+maternal	O
+brain	O
+and	O
+CSF	O
+concentrations	O
+and	O
+correlated	O
+significantly	O
+with	O
+the	O
+former	O
+.	O
+	
+It	O
+is	O
+concluded	O
+that	O
+advanced	O
+pregnancy	O
+has	O
+a	O
+negligible	O
+effect	O
+on	O
+the	O
+neurotoxic	B-NP
+response	O
+to	O
+theophylline	O
+in	O
+rats	O
+.	O
+	
+Hyperkalemia	B-NP
+induced	O
+by	O
+indomethacin	O
+and	O
+naproxen	O
+and	O
+reversed	O
+by	O
+fludrocortisone	O
+.	O
+	
+We	O
+have	O
+described	O
+a	O
+patient	O
+with	O
+severe	O
+rheumatoid	B-NP
+arthritis	I-NP
+and	O
+a	O
+history	O
+of	O
+mefenamic	O
+acid	O
+nephropathy	B-NP
+in	O
+whom	O
+hyperkalemia	B-NP
+and	O
+inappropriate	O
+hypoaldosteronism	B-NP
+were	O
+caused	O
+by	O
+both	O
+indomethacin	O
+and	O
+naproxen	O
+","	O
+without	O
+major	O
+decline	O
+in	O
+renal	O
+function	O
+.	O
+	
+It	O
+is	O
+likely	O
+that	O
+preexisting	O
+renal	B-NP
+disease	I-NP
+predisposed	O
+this	O
+patient	O
+to	O
+type	B-NP
+IV	I-NP
+renal	I-NP
+tubular	I-NP
+acidosis	I-NP
+with	O
+prostaglandin	O
+synthetase	O
+inhibitors	O
+.	O
+	
+Because	O
+he	O
+was	O
+unable	O
+to	O
+discontinue	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+drug	O
+therapy	O
+","	O
+fludrocortisone	O
+was	O
+added	O
+","	O
+correcting	O
+the	O
+hyperkalemia	B-NP
+and	O
+allowing	O
+indomethacin	O
+therapy	O
+to	O
+be	O
+continued	O
+safely	O
+.	O
+	
+Hypotension	B-NP
+as	O
+a	O
+manifestation	O
+of	O
+cardiotoxicity	B-NP
+in	O
+three	O
+patients	O
+receiving	O
+cisplatin	O
+and	O
+5	O
+-	O
+fluorouracil	O
+.	O
+	
+Cardiac	O
+symptoms	O
+","	O
+including	O
+hypotension	B-NP
+","	O
+developed	O
+in	O
+three	O
+patients	O
+with	O
+advanced	O
+colorectal	B-NP
+carcinoma	I-NP
+while	O
+being	O
+treated	O
+with	O
+cisplatin	O
+(	O
+CDDP	O
+)	O
+and	O
+5	O
+-	O
+fluorouracil	O
+(	O
+5	O
+-	O
+FU	O
+)	O
+.	O
+	
+In	O
+two	O
+patients	O
+","	O
+hypotension	B-NP
+was	O
+associated	O
+with	O
+severe	O
+left	B-NP
+ventricular	I-NP
+dysfunction	I-NP
+.	O
+	
+All	O
+three	O
+patients	O
+required	O
+therapy	O
+discontinuation	O
+.	O
+	
+Cardiac	O
+enzymes	O
+remained	O
+normal	O
+despite	O
+transient	O
+electrocardiographic	O
+(	O
+EKG	O
+)	O
+changes	O
+.	O
+	
+The	O
+presentation	O
+and	O
+cardiac	O
+evaluation	O
+(	O
+hemodynamic	O
+","	O
+echocardiographic	O
+","	O
+and	O
+scintigraphic	O
+)	O
+of	O
+these	O
+patients	O
+suggest	O
+new	O
+manifestations	O
+of	O
+5	O
+-	O
+FU	O
+cardiotoxicity	B-NP
+that	O
+may	O
+be	O
+influenced	O
+by	O
+CDDP	O
+.	O
+	
+The	O
+possible	O
+pathophysiologic	O
+mechanisms	O
+are	O
+discussed	O
+.	O
+	
+Fatal	O
+aplastic	B-NP
+anemia	I-NP
+in	O
+a	O
+patient	O
+treated	O
+with	O
+carbamazepine	O
+.	O
+	
+A	O
+case	O
+of	O
+fatal	O
+aplastic	B-NP
+anemia	I-NP
+due	O
+to	O
+carbamazepine	O
+treatment	O
+in	O
+an	O
+epileptic	B-NP
+woman	O
+is	O
+reported	O
+.	O
+	
+Despite	O
+concerns	O
+of	O
+fatal	O
+bone	B-NP
+marrow	I-NP
+toxicity	I-NP
+due	O
+to	O
+carbamazepine	O
+","	O
+this	O
+is	O
+only	O
+the	O
+fourth	O
+documented	O
+and	O
+published	O
+report	O
+.	O
+	
+Carbamazepine	O
+is	O
+a	O
+safe	O
+drug	O
+","	O
+but	O
+physicians	O
+and	O
+patients	O
+should	O
+be	O
+aware	O
+of	O
+the	O
+exceedingly	O
+rare	O
+but	O
+potentially	O
+fatal	O
+side	O
+effects	O
+","	O
+better	O
+prevented	O
+by	O
+clinical	O
+than	O
+by	O
+laboratory	O
+monitoring	O
+.	O
+	
+Participation	O
+of	O
+a	O
+bulbospinal	O
+serotonergic	O
+pathway	O
+in	O
+the	O
+rat	O
+brain	O
+in	O
+clonidine	O
+-	O
+induced	O
+hypotension	B-NP
+and	O
+bradycardia	B-NP
+.	O
+	
+The	O
+effects	O
+of	O
+microinjection	O
+of	O
+clonidine	O
+(	O
+1	O
+-	O
+10	O
+micrograms	O
+in	O
+1	O
+microliter	O
+)	O
+into	O
+a	O
+region	O
+adjacent	O
+to	O
+the	O
+ventrolateral	O
+surface	O
+of	O
+the	O
+medulla	O
+oblongata	O
+on	O
+cardiovascular	O
+function	O
+were	O
+assessed	O
+in	O
+urethane	O
+-	O
+anesthetized	O
+rats	O
+.	O
+	
+Intramedullary	O
+administration	O
+of	O
+clonidine	O
+","	O
+but	O
+not	O
+saline	O
+vehicle	O
+","	O
+caused	O
+a	O
+dose	O
+-	O
+dependent	O
+decrease	O
+in	O
+both	O
+the	O
+mean	O
+arterial	O
+pressure	O
+and	O
+the	O
+heart	O
+rate	O
+.	O
+	
+The	O
+clonidine	O
+-	O
+induced	O
+hypotension	B-NP
+was	O
+antagonized	O
+by	O
+prior	O
+spinal	O
+transection	O
+","	O
+but	O
+not	O
+bilateral	O
+vagotomy	O
+.	O
+	
+On	O
+the	O
+other	O
+hand	O
+","	O
+the	O
+clonidine	O
+-	O
+induced	O
+bradycardia	B-NP
+was	O
+antagonized	O
+by	O
+prior	O
+bilateral	O
+vagotomy	O
+","	O
+but	O
+not	O
+spinal	O
+transection	O
+.	O
+	
+Furthermore	O
+","	O
+selective	O
+destruction	O
+of	O
+the	O
+spinal	O
+5	O
+-	O
+HT	O
+nerves	O
+","	O
+produced	O
+by	O
+bilateral	O
+spinal	O
+injection	O
+of	O
+5	O
+","	O
+7	O
+-	O
+dihydroxytryptamine	O
+","	O
+reduced	O
+the	O
+magnitude	O
+of	O
+the	O
+vasodepressor	O
+or	O
+the	O
+bradycardiac	B-NP
+responses	O
+to	O
+clonidine	O
+microinjected	O
+into	O
+the	O
+area	O
+near	O
+the	O
+ventrolateral	O
+surface	O
+of	O
+the	O
+medulla	O
+oblongata	O
+in	O
+rats	O
+.	O
+	
+The	O
+data	O
+indicate	O
+that	O
+a	O
+bulbospinal	O
+serotonergic	O
+pathway	O
+is	O
+involved	O
+in	O
+development	O
+of	O
+clonidine	O
+-	O
+induced	O
+hypotension	B-NP
+and	O
+bradycardia	B-NP
+.	O
+	
+The	O
+induced	O
+hypotension	B-NP
+is	O
+brought	O
+about	O
+by	O
+a	O
+decrease	O
+in	O
+sympathetic	O
+efferent	O
+activity	O
+","	O
+whereas	O
+the	O
+induced	O
+bradycardia	B-NP
+was	O
+due	O
+to	O
+an	O
+increase	O
+in	O
+vagal	O
+efferent	O
+activity	O
+.	O
+	
+Hypertension	B-NP
+in	O
+neuroblastoma	B-NP
+induced	O
+by	O
+imipramine	O
+.	O
+	
+Hypertension	B-NP
+is	O
+a	O
+well	O
+-	O
+known	O
+finding	O
+in	O
+some	O
+patients	O
+with	O
+neuroblastoma	B-NP
+.	O
+	
+However	O
+","	O
+it	O
+has	O
+not	O
+previously	O
+been	O
+described	O
+in	O
+association	O
+with	O
+the	O
+use	O
+of	O
+Imipramine	O
+.	O
+	
+We	O
+report	O
+the	O
+occurrence	O
+of	O
+severe	O
+hypertension	B-NP
+(	O
+blood	O
+pressure	O
+190	O
+/	O
+160	O
+)	O
+in	O
+a	O
+4	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+with	O
+neuroblastoma	B-NP
+who	O
+was	O
+given	O
+Imipramine	O
+to	O
+control	O
+a	O
+behavior	B-NP
+disorder	I-NP
+.	O
+	
+It	O
+was	O
+determined	O
+later	O
+that	O
+this	O
+patient	O
+'	O
+s	O
+tumor	B-NP
+was	O
+recurring	O
+at	O
+the	O
+time	O
+of	O
+her	O
+hypertensive	B-NP
+episode	O
+.	O
+	
+Since	O
+she	O
+had	O
+no	O
+blood	O
+pressure	O
+elevation	O
+at	O
+initial	O
+diagnosis	O
+and	O
+none	O
+following	O
+discontinuation	O
+of	O
+the	O
+Imipramine	O
+(	O
+when	O
+she	O
+was	O
+in	O
+florid	O
+relapse	O
+)	O
+","	O
+we	O
+believe	O
+that	O
+this	O
+drug	O
+rather	O
+than	O
+her	O
+underlying	O
+disease	O
+alone	O
+caused	O
+her	O
+hypertension	B-NP
+.	O
+	
+The	O
+mechanism	O
+for	O
+this	O
+reaction	O
+is	O
+believed	O
+to	O
+be	O
+increased	O
+levels	O
+of	O
+vasoactive	O
+catecholamines	O
+due	O
+to	O
+interference	O
+of	O
+their	O
+physiologic	O
+inactivation	O
+by	O
+Imipramine	O
+.	O
+	
+From	O
+this	O
+experience	O
+","	O
+we	O
+urge	O
+extreme	O
+caution	O
+in	O
+the	O
+use	O
+of	O
+tricyclic	O
+antidepressants	O
+in	O
+children	O
+with	O
+active	O
+neuroblastoma	B-NP
+.	O
+	
+Rechallenge	O
+of	O
+patients	O
+who	O
+developed	O
+oral	B-NP
+candidiasis	I-NP
+or	O
+hoarseness	B-NP
+with	O
+beclomethasone	O
+dipropionate	O
+.	O
+	
+Of	O
+158	O
+asthmatic	B-NP
+patients	O
+who	O
+were	O
+placed	O
+on	O
+inhaled	O
+beclomethasone	O
+","	O
+15	O
+(	O
+9	O
+.	O
+5	O
+%	O
+)	O
+developed	O
+either	O
+hoarseness	B-NP
+(	O
+8	O
+)	O
+","	O
+oral	O
+thrush	B-NP
+(	O
+6	O
+)	O
+","	O
+or	O
+both	O
+(	O
+1	O
+)	O
+.	O
+	
+When	O
+their	O
+adverse	O
+reactions	O
+subsided	O
+","	O
+seven	O
+of	O
+these	O
+15	O
+patients	O
+were	O
+rechallenged	O
+with	O
+inhaled	O
+beclomethasone	O
+.	O
+	
+These	O
+included	O
+five	O
+cases	O
+who	O
+developed	O
+hoarseness	B-NP
+and	O
+three	O
+who	O
+developed	O
+Candidiasis	B-NP
+.	O
+	
+One	O
+patient	O
+had	O
+both	O
+.	O
+	
+Oral	O
+thrush	B-NP
+did	O
+not	O
+recur	O
+","	O
+but	O
+60	O
+%	O
+(	O
+3	O
+/	O
+5	O
+)	O
+of	O
+patients	O
+with	O
+hoarseness	B-NP
+had	O
+recurrence	O
+.	O
+	
+We	O
+conclude	O
+that	O
+patients	O
+may	O
+be	O
+restarted	O
+on	O
+inhaled	O
+beclomethasone	O
+when	O
+clinically	O
+indicated	O
+;	O
+however	O
+","	O
+because	O
+of	O
+the	O
+high	O
+recurrence	O
+rate	O
+","	O
+patients	O
+who	O
+develop	O
+hoarseness	B-NP
+should	O
+not	O
+be	O
+re	O
+-	O
+challenged	O
+.	O
+	
+Concomitant	O
+use	O
+of	O
+oral	O
+prednisone	O
+and	O
+topical	O
+beclomethasone	O
+may	O
+increase	O
+the	O
+risk	O
+of	O
+developing	O
+hoarseness	B-NP
+or	O
+candidiasis	B-NP
+.	O
+	
+Cyclophosphamide	O
+cardiotoxicity	B-NP
+:	O
+an	O
+analysis	O
+of	O
+dosing	O
+as	O
+a	O
+risk	O
+factor	O
+.	O
+	
+Patients	O
+who	O
+undergo	O
+bone	O
+marrow	O
+transplantation	O
+are	O
+generally	O
+immunosuppressed	O
+with	O
+a	O
+dose	O
+of	O
+cyclophosphamide	O
+(	O
+CYA	O
+)	O
+which	O
+is	O
+usually	O
+calculated	O
+based	O
+on	O
+the	O
+patient	O
+'	O
+s	O
+weight	O
+.	O
+	
+At	O
+these	O
+high	O
+doses	O
+of	O
+CYA	O
+","	O
+serious	O
+cardiotoxicity	B-NP
+may	O
+occur	O
+","	O
+but	O
+definitive	O
+risk	O
+factors	O
+for	O
+the	O
+development	O
+of	O
+such	O
+cardiotoxicity	B-NP
+have	O
+not	O
+been	O
+described	O
+.	O
+	
+Since	O
+chemotherapeutic	O
+agent	O
+toxicity	B-NP
+generally	O
+correlates	O
+with	O
+dose	O
+per	O
+body	O
+surface	O
+area	O
+","	O
+we	O
+retrospectively	O
+calculated	O
+the	O
+dose	O
+of	O
+CYA	O
+in	O
+patients	O
+transplanted	O
+at	O
+our	O
+institution	O
+to	O
+determine	O
+whether	O
+the	O
+incidence	O
+of	O
+CYA	O
+cardiotoxicity	B-NP
+correlated	O
+with	O
+the	O
+dose	O
+per	O
+body	O
+surface	O
+area	O
+.	O
+	
+Eighty	O
+patients	O
+who	O
+were	O
+to	O
+receive	O
+CYA	O
+50	O
+mg	O
+/	O
+kg	O
+/	O
+d	O
+for	O
+four	O
+days	O
+as	O
+preparation	O
+for	O
+marrow	O
+grafting	O
+underwent	O
+a	O
+total	O
+of	O
+84	O
+transplants	O
+for	O
+aplastic	B-NP
+anemia	I-NP
+","	O
+Wiskott	B-NP
+-	I-NP
+Aldrich	I-NP
+syndrome	I-NP
+","	O
+or	O
+severe	B-NP
+combined	I-NP
+immunodeficiency	I-NP
+syndrome	I-NP
+.	O
+	
+Fourteen	O
+of	O
+84	O
+(	O
+17	O
+%	O
+)	O
+patients	O
+had	O
+symptoms	O
+and	O
+signs	O
+consistent	O
+with	O
+CYA	O
+cardiotoxicity	B-NP
+within	O
+ten	O
+days	O
+of	O
+receiving	O
+1	O
+to	O
+4	O
+doses	O
+of	O
+CYA	O
+.	O
+	
+Six	O
+of	O
+the	O
+14	O
+patients	O
+died	O
+with	O
+congestive	B-NP
+heart	I-NP
+failure	I-NP
+.	O
+	
+The	O
+dose	O
+of	O
+CYA	O
+per	O
+body	O
+surface	O
+area	O
+was	O
+calculated	O
+for	O
+all	O
+patients	O
+and	O
+the	O
+patients	O
+were	O
+divided	O
+into	O
+two	O
+groups	O
+based	O
+on	O
+daily	O
+CYA	O
+dose	O
+:	O
+Group	O
+1	O
+","	O
+CYA	O
+less	O
+than	O
+or	O
+equal	O
+to	O
+1	O
+.	O
+55	O
+g	O
+/	O
+m2	O
+/	O
+d	O
+;	O
+Group	O
+2	O
+","	O
+CYA	O
+greater	O
+than	O
+1	O
+.	O
+55	O
+g	O
+/	O
+m2	O
+/	O
+d	O
+.	O
+	
+Cardiotoxicity	B-NP
+that	O
+was	O
+thought	O
+to	O
+be	O
+related	O
+to	O
+CYA	O
+occurred	O
+in	O
+1	O
+/	O
+32	O
+(	O
+3	O
+%	O
+)	O
+of	O
+patients	O
+in	O
+Group	O
+1	O
+and	O
+in	O
+13	O
+/	O
+52	O
+(	O
+25	O
+%	O
+)	O
+patients	O
+in	O
+Group	O
+2	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+25	O
+)	O
+.	O
+	
+Congestive	B-NP
+heart	I-NP
+failure	I-NP
+caused	O
+or	O
+contributed	O
+to	O
+death	O
+in	O
+0	O
+/	O
+32	O
+patients	O
+in	O
+Group	O
+1	O
+v	O
+6	O
+/	O
+52	O
+(	O
+12	O
+%	O
+)	O
+of	O
+patients	O
+in	O
+Group	O
+2	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+25	O
+)	O
+.	O
+	
+There	O
+was	O
+no	O
+difference	O
+in	O
+the	O
+rate	O
+of	O
+engraftment	O
+of	O
+evaluable	O
+patients	O
+in	O
+the	O
+two	O
+groups	O
+(	O
+P	O
+greater	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+We	O
+conclude	O
+that	O
+the	O
+CYA	O
+cardiotoxicity	B-NP
+correlates	O
+with	O
+CYA	O
+dosage	O
+as	O
+calculated	O
+by	O
+body	O
+surface	O
+area	O
+","	O
+and	O
+that	O
+patients	O
+with	O
+aplastic	B-NP
+anemia	I-NP
+and	O
+immunodeficiencies	B-NP
+can	O
+be	O
+effectively	O
+prepared	O
+for	O
+bone	O
+marrow	O
+grafting	O
+at	O
+a	O
+CYA	O
+dose	O
+of	O
+1	O
+.	O
+55	O
+g	O
+/	O
+m2	O
+/	O
+d	O
+for	O
+four	O
+days	O
+with	O
+a	O
+lower	O
+incidence	O
+of	O
+cardiotoxicity	B-NP
+than	O
+patients	O
+whose	O
+CYA	O
+dosage	O
+is	O
+calculated	O
+based	O
+on	O
+weight	O
+.	O
+	
+This	O
+study	O
+reaffirms	O
+the	O
+principle	O
+that	O
+drug	O
+toxicity	B-NP
+correlates	O
+with	O
+dose	O
+per	O
+body	O
+surface	O
+area	O
+.	O
+	
+Studies	O
+of	O
+risk	O
+factors	O
+for	O
+aminoglycoside	O
+nephrotoxicity	B-NP
+.	O
+	
+The	O
+epidemiology	O
+of	O
+aminoglycoside	O
+-	O
+induced	O
+nephrotoxicity	B-NP
+is	O
+not	O
+fully	O
+understood	O
+.	O
+	
+Experimental	O
+studies	O
+in	O
+healthy	O
+human	O
+volunteers	O
+indicate	O
+aminoglycosides	O
+cause	O
+proximal	O
+tubular	O
+damage	O
+in	O
+most	O
+patients	O
+","	O
+but	O
+rarely	O
+","	O
+if	O
+ever	O
+","	O
+cause	O
+glomerular	B-NP
+or	I-NP
+tubular	I-NP
+dysfunction	I-NP
+.	O
+	
+Clinical	O
+trials	O
+of	O
+aminoglycosides	O
+in	O
+seriously	O
+ill	O
+patients	O
+indicate	O
+that	O
+the	O
+relative	O
+risk	O
+for	O
+developing	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+during	O
+therapy	O
+ranges	O
+from	O
+8	O
+to	O
+10	O
+and	O
+that	O
+the	O
+attributable	O
+risk	O
+is	O
+70	O
+%	O
+to	O
+80	O
+%	O
+.	O
+	
+Further	O
+analysis	O
+of	O
+these	O
+data	O
+suggests	O
+that	O
+the	O
+duration	O
+of	O
+therapy	O
+","	O
+plasma	O
+aminoglycoside	O
+levels	O
+","	O
+liver	B-NP
+disease	I-NP
+","	O
+advanced	O
+age	O
+","	O
+high	O
+initial	O
+estimated	O
+creatinine	O
+clearance	O
+and	O
+","	O
+possibly	O
+","	O
+female	O
+gender	O
+all	O
+increase	O
+the	O
+risk	O
+for	O
+nephrotoxicity	B-NP
+.	O
+	
+Other	O
+causes	O
+of	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+","	O
+such	O
+as	O
+shock	B-NP
+","	O
+appear	O
+to	O
+have	O
+an	O
+additive	O
+effect	O
+.	O
+	
+Predictive	O
+models	O
+have	O
+been	O
+developed	O
+from	O
+these	O
+analyses	O
+that	O
+should	O
+be	O
+useful	O
+for	O
+identifying	O
+patients	O
+at	O
+high	O
+risk	O
+.	O
+	
+These	O
+models	O
+may	O
+also	O
+be	O
+useful	O
+in	O
+developing	O
+insights	O
+into	O
+the	O
+pathophysiology	O
+of	O
+aminoglycoside	O
+-	O
+induced	O
+nephrotoxicity	B-NP
+.	O
+	
+Central	O
+action	O
+of	O
+narcotic	O
+analgesics	O
+.	O
+	
+Part	O
+IV	O
+.	O
+	
+Noradrenergic	O
+influences	O
+on	O
+the	O
+activity	O
+of	O
+analgesics	O
+in	O
+rats	O
+.	O
+	
+The	O
+effect	O
+of	O
+clonidine	O
+","	O
+naphazoline	O
+and	O
+xylometazoline	O
+on	O
+analgesia	O
+induced	O
+by	O
+morphine	O
+","	O
+codeine	O
+","	O
+fentanyl	O
+and	O
+pentazocine	O
+","	O
+and	O
+on	O
+cataleptic	B-NP
+effect	O
+of	O
+morphine	O
+","	O
+codine	O
+and	O
+fentanyl	O
+was	O
+studied	O
+in	O
+rats	O
+.	O
+	
+The	O
+biochemical	O
+assays	O
+on	O
+the	O
+influence	O
+of	O
+four	O
+analgesics	O
+on	O
+the	O
+brain	O
+concentration	O
+and	O
+turnover	O
+of	O
+noradrenaline	O
+(	O
+NA	O
+)	O
+were	O
+also	O
+performed	O
+.	O
+	
+It	O
+was	O
+found	O
+that	O
+three	O
+drugs	O
+stimulating	O
+central	O
+NA	O
+receptors	O
+failed	O
+to	O
+affect	O
+the	O
+analgesic	O
+ED50	O
+of	O
+all	O
+antinociceptive	O
+agents	O
+and	O
+they	O
+enhanced	O
+catalepsy	B-NP
+induced	O
+by	O
+morphine	O
+and	O
+fentanyl	O
+.	O
+	
+Codeine	O
+catalepsy	B-NP
+was	O
+increased	O
+by	O
+clonidine	O
+and	O
+decreased	O
+by	O
+naphazoline	O
+and	O
+xylometazoline	O
+.	O
+	
+The	O
+brain	O
+concentration	O
+of	O
+NA	O
+was	O
+not	O
+changed	O
+by	O
+morphine	O
+and	O
+fentanyl	O
+","	O
+but	O
+one	O
+of	O
+the	O
+doses	O
+of	O
+codeine	O
+(	O
+45	O
+mg	O
+/	O
+kg	O
+)	O
+slightly	O
+enhanced	O
+it	O
+.	O
+	
+Pentazocine	O
+dose	O
+-	O
+dependently	O
+decreased	O
+the	O
+brain	O
+level	O
+of	O
+NA	O
+.	O
+	
+The	O
+rate	O
+of	O
+NA	O
+turnover	O
+was	O
+not	O
+altered	O
+by	O
+analgesics	O
+except	O
+for	O
+the	O
+higher	O
+dose	O
+of	O
+fentanyl	O
+(	O
+0	O
+.	O
+2	O
+mg	O
+/	O
+kg	O
+)	O
+following	O
+which	O
+the	O
+disappearance	O
+of	O
+NA	O
+from	O
+the	O
+brain	O
+was	O
+diminished	O
+.	O
+	
+The	O
+results	O
+are	O
+discussed	O
+in	O
+the	O
+light	O
+of	O
+various	O
+and	O
+non	O
+-	O
+uniform	O
+data	O
+from	O
+the	O
+literature	O
+.	O
+	
+It	O
+is	O
+suggested	O
+that	O
+in	O
+rats	O
+the	O
+brain	O
+NA	O
+plays	O
+a	O
+less	O
+important	O
+function	O
+than	O
+the	O
+other	O
+monoamines	O
+in	O
+the	O
+behavioural	O
+activity	O
+of	O
+potent	O
+analgesics	O
+.	O
+	
+Flurothyl	O
+seizure	B-NP
+thresholds	O
+in	O
+mice	O
+treated	O
+neonatally	O
+with	O
+a	O
+single	O
+injection	O
+of	O
+monosodium	O
+glutamate	O
+(	O
+MSG	O
+)	O
+:	O
+evaluation	O
+of	O
+experimental	O
+parameters	O
+in	O
+flurothyl	O
+seizure	B-NP
+testing	O
+.	O
+	
+Monosodium	O
+glutamate	O
+(	O
+MSG	O
+)	O
+administration	O
+to	O
+neonatal	O
+rodents	O
+produces	O
+convulsions	B-NP
+and	O
+results	O
+in	O
+numerous	O
+biochemical	O
+and	O
+behavioral	O
+deficits	O
+.	O
+	
+These	O
+studies	O
+were	O
+undertaken	O
+to	O
+determine	O
+if	O
+neonatal	O
+administration	O
+of	O
+MSG	O
+produced	O
+permanent	O
+alterations	O
+in	O
+seizure	B-NP
+susceptibility	O
+","	O
+since	O
+previous	O
+investigations	O
+were	O
+inconclusive	O
+.	O
+	
+A	O
+flurothyl	O
+ether	O
+seizure	B-NP
+screening	O
+technique	O
+was	O
+used	O
+to	O
+evaluate	O
+seizure	B-NP
+susceptibility	O
+in	O
+adult	O
+mice	O
+that	O
+received	O
+neonatal	O
+injections	O
+of	O
+MSG	O
+(	O
+4	O
+mg	O
+/	O
+g	O
+and	O
+1	O
+mg	O
+/	O
+g	O
+)	O
+.	O
+	
+MSG	O
+treatment	O
+resulted	O
+in	O
+significant	O
+reductions	O
+in	O
+whole	O
+brain	O
+weight	O
+but	O
+did	O
+not	O
+alter	O
+seizure	B-NP
+threshold	O
+.	O
+	
+A	O
+naloxone	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+challenge	O
+was	O
+also	O
+ineffective	O
+in	O
+altering	O
+the	O
+seizure	B-NP
+thresholds	O
+of	O
+either	O
+control	O
+of	O
+MSG	O
+-	O
+treated	O
+mice	O
+.	O
+	
+Flurothyl	O
+ether	O
+produced	O
+hypothermia	B-NP
+which	O
+was	O
+correlated	O
+with	O
+the	O
+duration	O
+of	O
+flurothyl	O
+exposure	O
+;	O
+however	O
+","	O
+the	O
+relationship	O
+of	O
+hypothermia	B-NP
+to	O
+seizure	B-NP
+induction	O
+was	O
+unclear	O
+.	O
+	
+Flurothyl	O
+seizure	B-NP
+testing	O
+proved	O
+to	O
+be	O
+a	O
+rapid	O
+and	O
+reliable	O
+technique	O
+with	O
+which	O
+to	O
+evaluate	O
+seizure	B-NP
+susceptibility	O
+.	O
+	
+Susceptibility	O
+to	O
+seizures	B-NP
+produced	O
+by	O
+pilocarpine	O
+in	O
+rats	O
+after	O
+microinjection	O
+of	O
+isoniazid	O
+or	O
+gamma	O
+-	O
+vinyl	O
+-	O
+GABA	O
+into	O
+the	O
+substantia	O
+nigra	O
+.	O
+	
+Pilocarpine	O
+","	O
+given	O
+intraperitoneally	O
+to	O
+rats	O
+","	O
+reproduces	O
+the	O
+neuropathological	O
+sequelae	O
+of	O
+temporal	B-NP
+lobe	I-NP
+epilepsy	I-NP
+and	O
+provides	O
+a	O
+relevant	O
+animal	O
+model	O
+for	O
+studying	O
+mechanisms	O
+of	O
+buildup	O
+of	O
+convulsive	B-NP
+activity	O
+and	O
+pathways	O
+operative	O
+in	O
+the	O
+generalization	O
+and	O
+propagation	O
+of	O
+seizures	B-NP
+within	O
+the	O
+forebrain	O
+.	O
+	
+In	O
+the	O
+present	O
+study	O
+","	O
+the	O
+effects	O
+of	O
+manipulating	O
+the	O
+activity	O
+of	O
+the	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+(	O
+GABA	O
+)	O
+-	O
+mediated	O
+synaptic	O
+inhibition	O
+within	O
+the	O
+substantia	O
+nigra	O
+on	O
+seizures	B-NP
+produced	O
+by	O
+pilocarpine	O
+in	O
+rats	O
+","	O
+were	O
+investigated	O
+.	O
+	
+In	O
+animals	O
+pretreated	O
+with	O
+microinjections	O
+of	O
+isoniazid	O
+","	O
+150	O
+micrograms	O
+","	O
+an	O
+inhibitor	O
+of	O
+activity	O
+of	O
+the	O
+GABA	O
+-	O
+synthesizing	O
+enzyme	O
+","	O
+L	O
+-	O
+glutamic	O
+acid	O
+decarboxylase	O
+","	O
+into	O
+the	O
+substantia	O
+nigra	O
+pars	O
+reticulata	O
+(	O
+SNR	O
+)	O
+","	O
+bilaterally	O
+","	O
+non	O
+-	O
+convulsant	O
+doses	O
+of	O
+pilocarpine	O
+","	O
+100	O
+and	O
+200	O
+mg	O
+/	O
+kg	O
+","	O
+resulted	O
+in	O
+severe	O
+motor	O
+limbic	O
+seizures	B-NP
+and	O
+status	B-NP
+epilepticus	I-NP
+.	O
+	
+Electroencephalographic	O
+and	O
+behavioral	O
+monitoring	O
+revealed	O
+a	O
+profound	O
+reduction	O
+of	O
+the	O
+threshold	O
+for	O
+pilocarpine	O
+-	O
+induced	O
+convulsions	B-NP
+.	O
+	
+Morphological	O
+analysis	O
+of	O
+frontal	O
+forebrain	O
+sections	O
+with	O
+light	O
+microscopy	O
+revealed	O
+seizure	B-NP
+-	O
+related	O
+damage	O
+to	O
+the	O
+hippocampal	O
+formation	O
+","	O
+thalamus	O
+","	O
+amygdala	O
+","	O
+olfactory	O
+cortex	O
+","	O
+substantia	O
+nigra	O
+and	O
+neocortex	O
+","	O
+which	O
+is	O
+typically	O
+observed	O
+with	O
+pilocarpine	O
+in	O
+doses	O
+exceeding	O
+350	O
+mg	O
+/	O
+kg	O
+.	O
+	
+Bilateral	O
+intrastriatal	O
+injections	O
+of	O
+isoniazid	O
+did	O
+not	O
+augment	O
+seizures	B-NP
+produced	O
+by	O
+pilocarpine	O
+","	O
+200	O
+mg	O
+/	O
+kg	O
+.	O
+	
+Application	O
+of	O
+an	O
+irreversible	O
+inhibitor	O
+of	O
+GABA	O
+transaminase	O
+","	O
+gamma	O
+-	O
+vinyl	O
+-	O
+GABA	O
+(	O
+D	O
+","	O
+L	O
+-	O
+4	O
+-	O
+amino	O
+-	O
+hex	O
+-	O
+5	O
+-	O
+enoic	O
+acid	O
+)	O
+","	O
+5	O
+micrograms	O
+","	O
+into	O
+the	O
+SNR	O
+","	O
+bilaterally	O
+","	O
+suppressed	O
+the	O
+appearance	O
+of	O
+electrographic	O
+and	O
+behavioral	O
+seizures	B-NP
+produced	O
+by	O
+pilocarpine	O
+","	O
+380	O
+mg	O
+/	O
+kg	O
+.	O
+	
+This	O
+treatment	O
+was	O
+also	O
+sufficient	O
+to	O
+protect	O
+animals	O
+from	O
+the	O
+occurrence	O
+of	O
+brain	B-NP
+damage	I-NP
+.	O
+	
+Microinjections	O
+of	O
+gamma	O
+-	O
+vinyl	O
+-	O
+GABA	O
+","	O
+5	O
+micrograms	O
+","	O
+into	O
+the	O
+dorsal	O
+striatum	O
+","	O
+bilaterally	O
+","	O
+failed	O
+to	O
+prevent	O
+the	O
+development	O
+of	O
+convulsions	B-NP
+produced	O
+by	O
+pilocarpine	O
+","	O
+380	O
+mg	O
+/	O
+kg	O
+.	O
+	
+The	O
+results	O
+demonstrate	O
+that	O
+the	O
+threshold	O
+for	O
+pilocarpine	O
+-	O
+induced	O
+seizures	B-NP
+in	O
+rats	O
+is	O
+subjected	O
+to	O
+the	O
+regulation	O
+of	O
+the	O
+GABA	O
+-	O
+mediated	O
+synaptic	O
+inhibition	O
+within	O
+the	O
+substantia	O
+nigra	O
+.	O
+	
+Human	O
+and	O
+canine	O
+ventricular	O
+vasoactive	O
+intestinal	O
+polypeptide	O
+:	O
+decrease	O
+with	O
+heart	B-NP
+failure	I-NP
+.	O
+	
+Vasoactive	O
+intestinal	O
+polypeptide	O
+(	O
+VIP	O
+)	O
+is	O
+a	O
+systemic	O
+and	O
+coronary	O
+vasodilator	O
+that	O
+may	O
+have	O
+positive	O
+inotropic	O
+properties	O
+.	O
+	
+Myocardial	O
+levels	O
+of	O
+VIP	O
+were	O
+assayed	O
+before	O
+and	O
+after	O
+the	O
+development	O
+of	O
+heart	B-NP
+failure	I-NP
+in	O
+two	O
+canine	O
+models	O
+.	O
+	
+In	O
+the	O
+first	O
+","	O
+cobalt	O
+cardiomyopathy	B-NP
+was	O
+induced	O
+in	O
+eight	O
+dogs	O
+;	O
+VIP	O
+(	O
+by	O
+radioimmunoassay	O
+)	O
+decreased	O
+from	O
+35	O
++	O
+/	O
+-	O
+11	O
+pg	O
+/	O
+mg	O
+protein	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+)	O
+to	O
+5	O
++	O
+/	O
+-	O
+4	O
+pg	O
+/	O
+mg	O
+protein	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+In	O
+six	O
+dogs	O
+with	O
+doxorubicin	O
+-	O
+induced	O
+heart	B-NP
+failure	I-NP
+","	O
+VIP	O
+decreased	O
+from	O
+31	O
++	O
+/	O
+-	O
+7	O
+to	O
+11	O
++	O
+/	O
+-	O
+4	O
+pg	O
+/	O
+mg	O
+protein	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+In	O
+addition	O
+","	O
+VIP	O
+content	O
+of	O
+left	O
+ventricular	O
+muscle	O
+of	O
+resected	O
+failing	O
+hearts	O
+in	O
+10	O
+patients	O
+receiving	O
+a	O
+heart	O
+transplant	O
+was	O
+compared	O
+with	O
+the	O
+papillary	O
+muscles	O
+in	O
+14	O
+patients	O
+(	O
+five	O
+with	O
+rheumatic	B-NP
+disease	I-NP
+","	O
+nine	O
+with	O
+myxomatous	B-NP
+degeneration	I-NP
+)	O
+receiving	O
+mitral	O
+valve	O
+prostheses	O
+.	O
+	
+The	O
+lowest	O
+myocardial	O
+VIP	O
+concentration	O
+was	O
+found	O
+in	O
+the	O
+hearts	O
+of	O
+patients	O
+with	O
+coronary	B-NP
+disease	I-NP
+(	O
+one	O
+patient	O
+receiving	O
+a	O
+transplant	O
+and	O
+three	O
+receiving	O
+mitral	O
+prostheses	O
+)	O
+(	O
+6	O
+.	O
+3	O
++	O
+/	O
+-	O
+1	O
+.	O
+9	O
+pg	O
+/	O
+mg	O
+protein	O
+)	O
+.	O
+	
+The	O
+other	O
+patients	O
+undergoing	O
+transplantation	O
+had	O
+an	O
+average	O
+ejection	O
+fraction	O
+of	O
+17	O
+%	O
++	O
+/	O
+-	O
+6	O
+%	O
+and	O
+a	O
+VIP	O
+level	O
+of	O
+8	O
+.	O
+8	O
++	O
+/	O
+-	O
+3	O
+.	O
+9	O
+pg	O
+/	O
+mg	O
+protein	O
+.	O
+	
+The	O
+hearts	O
+without	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+(	O
+average	O
+ejection	O
+fraction	O
+of	O
+this	O
+group	O
+62	O
+%	O
++	O
+/	O
+-	O
+10	O
+%	O
+)	O
+had	O
+a	O
+VIP	O
+concentration	O
+of	O
+14	O
+.	O
+1	O
++	O
+/	O
+-	O
+7	O
+.	O
+9	O
+pg	O
+/	O
+mg	O
+protein	O
+","	O
+and	O
+this	O
+was	O
+greater	O
+than	O
+in	O
+hearts	O
+of	O
+the	O
+patients	O
+with	O
+coronary	B-NP
+disease	I-NP
+and	O
+the	O
+hearts	O
+of	O
+patients	O
+receiving	O
+a	O
+transplant	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+Myocardial	O
+catecholamines	O
+were	O
+also	O
+determined	O
+in	O
+14	O
+subjects	O
+;	O
+a	O
+weak	O
+correlation	O
+(	O
+r	O
+=	O
+0	O
+.	O
+57	O
+","	O
+P	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+between	O
+the	O
+tissue	O
+concentrations	O
+of	O
+VIP	O
+and	O
+norepinephrine	O
+was	O
+noted	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+	
+Non	O
+-	O
+invasive	O
+detection	O
+of	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+by	O
+body	O
+surface	O
+electrocardiographic	O
+mapping	O
+after	O
+dipyridamole	O
+infusion	O
+.	O
+	
+Electrocardiographic	O
+changes	O
+after	O
+dipyridamole	O
+infusion	O
+(	O
+0	O
+.	O
+568	O
+mg	O
+/	O
+kg	O
+/	O
+4	O
+min	O
+)	O
+were	O
+studied	O
+in	O
+41	O
+patients	O
+with	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+and	O
+compared	O
+with	O
+those	O
+after	O
+submaximal	O
+treadmill	O
+exercise	O
+by	O
+use	O
+of	O
+the	O
+body	O
+surface	O
+mapping	O
+technique	O
+.	O
+	
+Patients	O
+were	O
+divided	O
+into	O
+three	O
+groups	O
+;	O
+19	O
+patients	O
+without	O
+myocardial	B-NP
+infarction	I-NP
+(	O
+non	O
+-	O
+MI	B-NP
+group	O
+)	O
+","	O
+14	O
+with	O
+anterior	B-NP
+infarction	I-NP
+(	O
+ANT	B-NP
+-	I-NP
+MI	I-NP
+)	O
+and	O
+eight	O
+with	O
+inferior	B-NP
+infarction	I-NP
+(	O
+INF	B-NP
+-	I-NP
+MI	I-NP
+)	O
+.	O
+	
+Eighty	O
+-	O
+seven	O
+unipolar	O
+electrocardiograms	O
+(	O
+ECGs	O
+)	O
+distributed	O
+over	O
+the	O
+entire	O
+thoracic	O
+surface	O
+were	O
+simultaneously	O
+recorded	O
+.	O
+	
+After	O
+dipyridamole	O
+","	O
+ischemic	B-NP
+ST	O
+-	O
+segment	O
+depression	B-NP
+(	O
+0	O
+.	O
+5	O
+mV	O
+or	O
+more	O
+)	O
+was	O
+observed	O
+in	O
+84	O
+%	O
+of	O
+the	O
+non	O
+-	O
+MI	B-NP
+group	O
+","	O
+29	O
+%	O
+of	O
+the	O
+ANT	B-NP
+-	I-NP
+MI	I-NP
+group	O
+","	O
+63	O
+%	O
+of	O
+the	O
+INF	B-NP
+-	I-NP
+MI	I-NP
+group	O
+and	O
+61	O
+%	O
+of	O
+the	O
+total	O
+population	O
+.	O
+	
+Exercise	O
+-	O
+induced	O
+ST	O
+depression	B-NP
+was	O
+observed	O
+in	O
+84	O
+%	O
+of	O
+the	O
+non	O
+-	O
+MI	B-NP
+group	O
+","	O
+43	O
+%	O
+of	O
+the	O
+ANT	B-NP
+-	I-NP
+MI	I-NP
+group	O
+","	O
+38	O
+%	O
+of	O
+the	O
+INF	B-NP
+-	I-NP
+MI	I-NP
+group	O
+and	O
+61	O
+%	O
+of	O
+the	O
+total	O
+.	O
+	
+For	O
+individual	O
+patients	O
+","	O
+there	O
+were	O
+no	O
+obvious	O
+differences	O
+between	O
+the	O
+body	O
+surface	O
+distribution	O
+of	O
+ST	O
+depression	B-NP
+in	O
+both	O
+tests	O
+.	O
+	
+The	O
+increase	O
+in	O
+pressure	O
+rate	O
+product	O
+after	O
+dipyridamole	O
+was	O
+significantly	O
+less	O
+than	O
+that	O
+during	O
+the	O
+treadmill	O
+exercise	O
+.	O
+	
+The	O
+data	O
+suggest	O
+that	O
+the	O
+dipyridamole	O
+-	O
+induced	O
+myocardial	B-NP
+ischemia	I-NP
+is	O
+caused	O
+by	O
+the	O
+inhomogenous	O
+distribution	O
+of	O
+myocardial	O
+blood	O
+flow	O
+.	O
+	
+We	O
+conclude	O
+that	O
+the	O
+dipyridamole	O
+ECG	O
+test	O
+is	O
+as	O
+useful	O
+as	O
+the	O
+exercise	O
+ECG	O
+test	O
+for	O
+the	O
+assessment	O
+of	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+.	O
+	
+Bradycardia	B-NP
+after	O
+high	O
+-	O
+dose	O
+intravenous	O
+methylprednisolone	O
+therapy	O
+.	O
+	
+In	O
+5	O
+consecutive	O
+patients	O
+with	O
+rheumatoid	B-NP
+arthritis	I-NP
+who	O
+received	O
+intravenous	O
+high	O
+-	O
+dose	O
+methylprednisolone	O
+(	O
+MP	O
+)	O
+therapy	O
+(	O
+1	O
+g	O
+daily	O
+for	O
+2	O
+or	O
+3	O
+consecutive	O
+days	O
+)	O
+","	O
+a	O
+decline	O
+in	O
+pulse	O
+rate	O
+was	O
+observed	O
+","	O
+most	O
+pronounced	O
+on	O
+day	O
+4	O
+.	O
+	
+In	O
+one	O
+of	O
+the	O
+5	O
+patients	O
+the	O
+bradycardia	B-NP
+was	O
+associated	O
+with	O
+complaints	O
+of	O
+substernal	O
+pressure	O
+.	O
+	
+Reversal	O
+to	O
+normal	O
+heart	O
+rate	O
+was	O
+found	O
+on	O
+day	O
+7	O
+.	O
+	
+Electrocardiographic	O
+registrations	O
+showed	O
+sinus	B-NP
+bradycardia	I-NP
+in	O
+all	O
+cases	O
+.	O
+	
+No	O
+significant	O
+changes	O
+in	O
+plasma	O
+concentrations	O
+of	O
+electrolytes	O
+were	O
+found	O
+.	O
+	
+Careful	O
+observation	O
+of	O
+patients	O
+receiving	O
+high	O
+-	O
+dose	O
+MP	O
+is	O
+recommended	O
+.	O
+	
+High	O
+-	O
+dose	O
+MP	O
+may	O
+be	O
+contraindicated	O
+in	O
+patients	O
+with	O
+known	O
+heart	B-NP
+disease	I-NP
+.	O
+	
+Two	O
+cases	O
+of	O
+downbeat	B-NP
+nystagmus	I-NP
+and	O
+oscillopsia	B-NP
+associated	O
+with	O
+carbamazepine	O
+.	O
+	
+Downbeat	B-NP
+nystagmus	I-NP
+is	O
+often	O
+associated	O
+with	O
+structural	O
+lesions	O
+at	O
+the	O
+craniocervical	O
+junction	O
+","	O
+but	O
+has	O
+occasionally	O
+been	O
+reported	O
+as	O
+a	O
+manifestation	O
+of	O
+metabolic	O
+imbalance	O
+or	O
+drug	O
+intoxication	O
+.	O
+	
+We	O
+recorded	O
+the	O
+eye	O
+movements	O
+of	O
+two	O
+patients	O
+with	O
+reversible	O
+downbeat	B-NP
+nystagmus	I-NP
+related	O
+to	O
+carbamazepine	O
+therapy	O
+.	O
+	
+The	O
+nystagmus	B-NP
+of	O
+both	O
+patients	O
+resolved	O
+after	O
+reduction	O
+of	O
+the	O
+serum	O
+carbamazepine	O
+levels	O
+.	O
+	
+Neuroradiologic	O
+investigations	O
+including	O
+magnetic	O
+resonance	O
+imaging	O
+scans	O
+in	O
+both	O
+patients	O
+showed	O
+no	O
+evidence	O
+of	O
+intracranial	O
+abnormality	O
+.	O
+	
+In	O
+patients	O
+with	O
+downbeat	B-NP
+nystagmus	I-NP
+who	O
+are	O
+taking	O
+anticonvulsant	O
+medications	O
+","	O
+consideration	O
+should	O
+be	O
+given	O
+to	O
+reduction	O
+in	O
+dose	O
+before	O
+further	O
+investigation	O
+is	O
+undertaken	O
+.	O
+	
+Improvement	O
+by	O
+denopamine	O
+(	O
+TA	O
+-	O
+64	O
+)	O
+of	O
+pentobarbital	O
+-	O
+induced	O
+cardiac	B-NP
+failure	I-NP
+in	O
+the	O
+dog	O
+heart	O
+-	O
+lung	O
+preparation	O
+.	O
+	
+The	O
+efficacy	O
+of	O
+denopamine	O
+","	O
+an	O
+orally	O
+active	O
+beta	O
+1	O
+-	O
+adrenoceptor	O
+agonist	O
+","	O
+in	O
+improving	O
+cardiac	B-NP
+failure	I-NP
+was	O
+assessed	O
+in	O
+dog	O
+heart	O
+-	O
+lung	O
+preparations	O
+.	O
+	
+Cardiac	O
+functions	O
+depressed	O
+by	O
+pentobarbital	O
+(	O
+118	O
++	O
+/	O
+-	O
+28	O
+mg	O
+;	O
+mean	O
+value	O
++	O
+/	O
+-	O
+SD	O
+)	O
+such	O
+that	O
+cardiac	O
+output	O
+and	O
+maximum	O
+rate	O
+of	O
+rise	O
+of	O
+left	O
+ventricular	O
+pressure	O
+(	O
+LV	O
+dP	O
+/	O
+dt	O
+max	O
+)	O
+had	O
+been	O
+reduced	O
+by	O
+about	O
+35	O
+%	O
+and	O
+26	O
+%	O
+of	O
+the	O
+respective	O
+controls	O
+were	O
+improved	O
+by	O
+denopamine	O
+(	O
+10	O
+-	O
+300	O
+micrograms	O
+)	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+.	O
+	
+With	O
+100	O
+micrograms	O
+denopamine	O
+","	O
+almost	O
+complete	O
+restoration	O
+of	O
+cardiac	O
+performance	O
+was	O
+attained	O
+","	O
+associated	O
+with	O
+a	O
+slight	O
+increase	O
+in	O
+heart	O
+rate	O
+.	O
+	
+No	O
+arrhythmias	B-NP
+were	O
+induced	O
+by	O
+these	O
+doses	O
+of	O
+denopamine	O
+.	O
+	
+The	O
+results	O
+warrant	O
+clinical	O
+trials	O
+of	O
+denopamine	O
+in	O
+the	O
+treatment	O
+of	O
+cardiac	B-NP
+failure	I-NP
+.	O
+	
+Clonazepam	O
+monotherapy	O
+for	O
+epilepsy	B-NP
+in	O
+childhood	O
+.	O
+	
+Sixty	O
+patients	O
+(	O
+age	O
+-	O
+range	O
+one	O
+month	O
+to	O
+14	O
+years	O
+)	O
+with	O
+other	O
+types	O
+of	O
+epilepsy	B-NP
+than	O
+infantile	B-NP
+spasms	I-NP
+were	O
+treated	O
+with	O
+clonazepam	O
+.	O
+	
+Disappearance	O
+of	O
+seizures	B-NP
+and	O
+normalization	O
+of	O
+abnormal	O
+EEG	O
+with	O
+disappearance	O
+of	O
+seizures	B-NP
+were	O
+recognized	O
+in	O
+77	O
+%	O
+and	O
+50	O
+%	O
+","	O
+respectively	O
+.	O
+	
+Seizures	B-NP
+disappeared	O
+in	O
+71	O
+%	O
+of	O
+the	O
+patients	O
+with	O
+generalized	O
+seizures	B-NP
+and	O
+89	O
+%	O
+of	O
+partial	O
+seizures	B-NP
+.	O
+	
+Improvement	O
+of	O
+abnormal	O
+EEG	O
+was	O
+noticed	O
+in	O
+76	O
+%	O
+of	O
+diffuse	O
+paroxysms	O
+and	O
+in	O
+67	O
+%	O
+of	O
+focal	O
+paroxysms	O
+.	O
+	
+In	O
+excellent	O
+cases	O
+","	O
+mean	O
+effective	O
+dosages	O
+were	O
+0	O
+.	O
+86	O
++	O
+/	O
+-	O
+0	O
+.	O
+21	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+in	O
+infants	O
+and	O
+0	O
+.	O
+57	O
++	O
+/	O
+-	O
+0	O
+.	O
+22	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+in	O
+schoolchildren	O
+","	O
+this	O
+difference	O
+was	O
+statistically	O
+significant	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+The	O
+incidence	O
+of	O
+side	O
+effects	O
+such	O
+as	O
+drowsiness	B-NP
+and	O
+ataxia	B-NP
+was	O
+only	O
+5	O
+%	O
+.	O
+	
+Postmarketing	O
+study	O
+of	O
+timolol	O
+-	O
+hydrochlorothiazide	O
+antihypertensive	O
+therapy	O
+.	O
+	
+A	O
+postmarketing	O
+surveillance	O
+study	O
+was	O
+conducted	O
+to	O
+determine	O
+the	O
+safety	O
+and	O
+efficacy	O
+of	O
+a	O
+fixed	O
+-	O
+ratio	O
+combination	O
+containing	O
+10	O
+mg	O
+of	O
+timolol	O
+maleate	O
+and	O
+25	O
+mg	O
+of	O
+hydrochlorothiazide	O
+","	O
+administered	O
+twice	O
+daily	O
+for	O
+one	O
+month	O
+to	O
+hypertensive	B-NP
+patients	O
+.	O
+	
+Data	O
+on	O
+9	O
+","	O
+37	O
+patients	O
+were	O
+collected	O
+by	O
+1	O
+","	O
+455	O
+participating	O
+physicians	O
+.	O
+	
+Mean	O
+systolic	O
+blood	O
+pressure	O
+decreased	O
+25	O
+mmHg	O
+and	O
+mean	O
+diastolic	O
+blood	O
+pressure	O
+declined	O
+15	O
+mmHg	O
+after	O
+one	O
+month	O
+of	O
+timolol	O
+-	O
+hydrochlorothiazide	O
+therapy	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+1	O
+","	O
+both	O
+comparisons	O
+)	O
+.	O
+	
+Age	O
+","	O
+race	O
+","	O
+and	O
+sex	O
+appeared	O
+to	O
+have	O
+no	O
+influence	O
+on	O
+the	O
+decrease	O
+in	O
+blood	O
+pressure	O
+.	O
+	
+The	O
+antihypertensive	O
+effect	O
+of	O
+the	O
+drug	O
+was	O
+greater	O
+in	O
+patients	O
+with	O
+more	O
+severe	O
+hypertension	B-NP
+.	O
+	
+Overall	O
+","	O
+1	O
+","	O
+453	O
+patients	O
+experienced	O
+a	O
+total	O
+of	O
+2	O
+","	O
+658	O
+adverse	O
+events	O
+","	O
+the	O
+most	O
+common	O
+being	O
+fatigue	B-NP
+","	O
+dizziness	B-NP
+","	O
+and	O
+weakness	B-NP
+.	O
+	
+Treatment	O
+in	O
+590	O
+patients	O
+was	O
+discontinued	O
+because	O
+of	O
+adverse	O
+events	O
+.	O
+	
+Salicylate	O
+nephropathy	B-NP
+in	O
+the	O
+Gunn	O
+rat	O
+:	O
+potential	O
+role	O
+of	O
+prostaglandins	O
+.	O
+	
+We	O
+examined	O
+the	O
+potential	O
+role	O
+of	O
+prostaglandins	O
+in	O
+the	O
+development	O
+of	O
+analgesic	O
+nephropathy	B-NP
+in	O
+the	O
+Gunn	O
+strain	O
+of	O
+rat	O
+.	O
+	
+The	O
+homozygous	O
+Gunn	O
+rats	O
+have	O
+unconjugated	O
+hyperbilirubinemia	B-NP
+due	O
+to	O
+the	O
+absence	O
+of	O
+glucuronyl	O
+transferase	O
+","	O
+leading	O
+to	O
+marked	O
+bilirubin	O
+deposition	O
+in	O
+renal	O
+medulla	O
+and	O
+papilla	O
+.	O
+	
+These	O
+rats	O
+are	O
+also	O
+highly	O
+susceptible	O
+to	O
+develop	O
+papillary	B-NP
+necrosis	I-NP
+with	O
+analgesic	O
+administration	O
+.	O
+	
+We	O
+used	O
+homozygous	O
+(	O
+jj	O
+)	O
+and	O
+phenotypically	O
+normal	O
+heterozygous	O
+(	O
+jJ	O
+)	O
+animals	O
+.	O
+	
+Four	O
+groups	O
+of	O
+rats	O
+(	O
+n	O
+=	O
+7	O
+)	O
+were	O
+studied	O
+:	O
+jj	O
+and	O
+jJ	O
+rats	O
+treated	O
+either	O
+with	O
+aspirin	O
+300	O
+mg	O
+/	O
+kg	O
+every	O
+other	O
+day	O
+or	O
+sham	O
+-	O
+treated	O
+.	O
+	
+After	O
+one	O
+week	O
+","	O
+slices	O
+of	O
+cortex	O
+","	O
+outer	O
+and	O
+inner	O
+medulla	O
+from	O
+one	O
+kidney	O
+were	O
+incubated	O
+in	O
+buffer	O
+and	O
+prostaglandin	O
+synthesis	O
+was	O
+determined	O
+by	O
+radioimmunoassay	O
+.	O
+	
+The	O
+other	O
+kidney	O
+was	O
+examined	O
+histologically	O
+.	O
+	
+A	O
+marked	O
+corticomedullary	O
+gradient	O
+of	O
+prostaglandin	O
+synthesis	O
+was	O
+observed	O
+in	O
+all	O
+groups	O
+.	O
+	
+PGE2	O
+synthesis	O
+was	O
+significantly	O
+higher	O
+in	O
+outer	O
+medulla	O
+","	O
+but	O
+not	O
+cortex	O
+or	O
+inner	O
+medulla	O
+","	O
+of	O
+jj	O
+(	O
+38	O
++	O
+/	O
+-	O
+6	O
+ng	O
+/	O
+mg	O
+prot	O
+)	O
+than	O
+jJ	O
+rats	O
+(	O
+15	O
++	O
+/	O
+-	O
+3	O
+)	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+Aspirin	O
+treatment	O
+reduced	O
+PGE2	O
+synthesis	O
+in	O
+all	O
+regions	O
+","	O
+but	O
+outer	O
+medullary	O
+PGE2	O
+remained	O
+higher	O
+in	O
+jj	O
+(	O
+18	O
++	O
+/	O
+-	O
+3	O
+)	O
+than	O
+jJ	O
+rats	O
+(	O
+9	O
++	O
+/	O
+-	O
+2	O
+)	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+PGF2	O
+alpha	O
+was	O
+also	O
+significantly	O
+higher	O
+in	O
+the	O
+outer	O
+medulla	O
+of	O
+jj	O
+rats	O
+with	O
+and	O
+without	O
+aspirin	O
+administration	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+The	O
+changes	O
+in	O
+renal	O
+prostaglandin	O
+synthesis	O
+were	O
+accompanied	O
+by	O
+evidence	O
+of	O
+renal	B-NP
+damage	I-NP
+in	O
+aspirin	O
+-	O
+treated	O
+jj	O
+but	O
+not	O
+jJ	O
+rats	O
+as	O
+evidenced	O
+by	O
+:	O
+increased	O
+incidence	O
+and	O
+severity	O
+of	O
+hematuria	B-NP
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+;	O
+increased	O
+serum	O
+creatinine	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+;	O
+and	O
+increase	O
+in	O
+outer	O
+medullary	O
+histopathologic	O
+lesions	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+compared	O
+to	O
+either	O
+sham	O
+-	O
+treated	O
+jj	O
+or	O
+aspirin	O
+-	O
+treated	O
+jJ	O
+)	O
+.	O
+	
+These	O
+results	O
+suggest	O
+that	O
+enhanced	O
+prostaglandin	O
+synthesis	O
+contributes	O
+to	O
+maintenance	O
+of	O
+renal	O
+function	O
+and	O
+morphological	O
+integrity	O
+","	O
+and	O
+that	O
+inhibition	O
+of	O
+prostaglandin	O
+synthesis	O
+may	O
+lead	O
+to	O
+pathological	B-NP
+renal	I-NP
+medullary	I-NP
+lesions	I-NP
+and	O
+deterioration	B-NP
+of	I-NP
+renal	I-NP
+function	I-NP
+.	O
+	
+Prophylactic	O
+lidocaine	O
+in	O
+the	O
+early	O
+phase	O
+of	O
+suspected	O
+myocardial	B-NP
+infarction	I-NP
+.	O
+	
+Four	O
+hundred	O
+two	O
+patients	O
+with	O
+suspected	O
+myocardial	B-NP
+infarction	I-NP
+seen	O
+within	O
+6	O
+hours	O
+of	O
+the	O
+onset	O
+of	O
+symptoms	O
+entered	O
+a	O
+double	O
+-	O
+blind	O
+randomized	O
+trial	O
+of	O
+lidocaine	O
+vs	O
+placebo	O
+.	O
+	
+During	O
+the	O
+1	O
+hour	O
+after	O
+administration	O
+of	O
+the	O
+drug	O
+the	O
+incidence	O
+of	O
+ventricular	B-NP
+fibrillation	I-NP
+or	O
+sustained	O
+ventricular	B-NP
+tachycardia	I-NP
+among	O
+the	O
+204	O
+patients	O
+with	O
+acute	O
+myocardial	B-NP
+infarction	I-NP
+was	O
+low	O
+","	O
+1	O
+.	O
+5	O
+%	O
+.	O
+	
+Lidocaine	O
+","	O
+given	O
+in	O
+a	O
+300	O
+mg	O
+dose	O
+intramuscularly	O
+followed	O
+by	O
+100	O
+mg	O
+intravenously	O
+","	O
+did	O
+not	O
+prevent	O
+sustained	O
+ventricular	B-NP
+tachycardia	I-NP
+","	O
+although	O
+there	O
+was	O
+a	O
+significant	O
+reduction	O
+in	O
+the	O
+number	O
+of	O
+patients	O
+with	O
+warning	O
+arrhythmias	B-NP
+between	O
+15	O
+and	O
+45	O
+minutes	O
+after	O
+the	O
+administration	O
+of	O
+lidocaine	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+The	O
+average	O
+plasma	O
+lidocaine	O
+level	O
+10	O
+minutes	O
+after	O
+administration	O
+for	O
+patients	O
+without	O
+a	O
+myocardial	B-NP
+infarction	I-NP
+was	O
+significantly	O
+higher	O
+than	O
+that	O
+for	O
+patients	O
+with	O
+an	O
+acute	O
+infarction	B-NP
+.	O
+	
+The	O
+mean	O
+plasma	O
+lidocaine	O
+level	O
+of	O
+patients	O
+on	O
+beta	O
+-	O
+blocking	O
+agents	O
+was	O
+no	O
+different	O
+from	O
+that	O
+in	O
+patients	O
+not	O
+on	O
+beta	O
+blocking	O
+agents	O
+.	O
+	
+During	O
+the	O
+1	O
+-	O
+hour	O
+study	O
+period	O
+","	O
+the	O
+incidence	O
+of	O
+central	O
+nervous	O
+system	O
+side	O
+effects	O
+was	O
+significantly	O
+greater	O
+in	O
+the	O
+lidocaine	O
+group	O
+","	O
+hypotension	B-NP
+occurred	O
+in	O
+11	O
+patients	O
+","	O
+nine	O
+of	O
+whom	O
+had	O
+received	O
+lidocaine	O
+","	O
+and	O
+four	O
+patients	O
+died	O
+from	O
+asystole	B-NP
+","	O
+three	O
+of	O
+whom	O
+had	O
+had	O
+lidocaine	O
+.	O
+	
+We	O
+cannot	O
+advocate	O
+the	O
+administration	O
+of	O
+lidocaine	O
+prophylactically	O
+in	O
+the	O
+early	O
+hours	O
+of	O
+suspected	O
+myocardial	B-NP
+infarction	I-NP
+.	O
+	
+Evidence	O
+for	O
+a	O
+cholinergic	O
+role	O
+in	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B-NP
+.	O
+	
+Experiments	O
+in	O
+mice	O
+tested	O
+previous	O
+evidence	O
+that	O
+activation	O
+of	O
+cholinergic	O
+systems	O
+promotes	O
+catalepsy	B-NP
+and	O
+that	O
+cholinergic	O
+mechanisms	O
+need	O
+to	O
+be	O
+intact	O
+for	O
+full	O
+expression	O
+of	O
+neuroleptic	O
+-	O
+induced	O
+catalepsy	B-NP
+.	O
+	
+Large	O
+doses	O
+of	O
+the	O
+cholinomimetic	O
+","	O
+pilocarpine	O
+","	O
+could	O
+induce	O
+catalepsy	B-NP
+when	O
+peripheral	O
+cholinergic	O
+receptors	O
+were	O
+blocked	O
+.	O
+	
+Low	O
+doses	O
+of	O
+pilocarpine	O
+caused	O
+a	O
+pronounced	O
+enhancement	O
+of	O
+the	O
+catalepsy	B-NP
+that	O
+was	O
+induced	O
+by	O
+the	O
+dopaminergic	O
+blocker	O
+","	O
+haloperidol	O
+.	O
+	
+A	O
+muscarinic	O
+receptor	O
+blocker	O
+","	O
+atropine	O
+","	O
+disrupted	O
+haloperidol	O
+-	O
+induced	O
+catalepsy	B-NP
+.	O
+	
+Intracranial	O
+injection	O
+of	O
+an	O
+acetylcholine	O
+-	O
+synthesis	O
+inhibitor	O
+","	O
+hemicholinium	O
+","	O
+prevented	O
+the	O
+catalepsy	B-NP
+that	O
+is	O
+usually	O
+induced	O
+by	O
+haloperidol	O
+.	O
+	
+These	O
+findings	O
+suggest	O
+the	O
+hypothesis	O
+that	O
+the	O
+catalepsy	B-NP
+that	O
+is	O
+produced	O
+by	O
+neuroleptics	O
+such	O
+as	O
+haloperidol	O
+is	O
+actually	O
+mediated	O
+by	O
+intrinsic	O
+central	O
+cholinergic	O
+systems	O
+.	O
+	
+Alternatively	O
+","	O
+activation	O
+of	O
+central	O
+cholinergic	O
+systems	O
+could	O
+promote	O
+catalepsy	B-NP
+by	O
+suppression	O
+of	O
+dopaminergic	O
+systems	O
+.	O
+	
+Cardiovascular	B-NP
+dysfunction	I-NP
+and	O
+hypersensitivity	B-NP
+to	O
+sodium	O
+pentobarbital	O
+induced	O
+by	O
+chronic	O
+barium	O
+chloride	O
+ingestion	O
+.	O
+	
+Barium	O
+-	O
+supplemented	O
+Long	O
+-	O
+Evans	O
+hooded	O
+rats	O
+were	O
+characterized	O
+by	O
+a	O
+persistent	O
+hypertension	B-NP
+that	O
+was	O
+evident	O
+after	O
+1	O
+month	O
+of	O
+barium	O
+(	O
+100	O
+micrograms	O
+/	O
+ml	O
+mineral	O
+fortified	O
+water	O
+)	O
+treatment	O
+.	O
+	
+Analysis	O
+of	O
+in	O
+vivo	O
+myocardial	O
+excitability	O
+","	O
+contractility	O
+","	O
+and	O
+metabolic	O
+characteristics	O
+at	O
+16	O
+months	O
+revealed	O
+other	O
+significant	O
+barium	O
+-	O
+induced	O
+disturbances	B-NP
+within	I-NP
+the	I-NP
+cardiovascular	I-NP
+system	I-NP
+.	O
+	
+The	O
+most	O
+distinctive	O
+aspect	O
+of	O
+the	O
+barium	O
+effect	O
+was	O
+a	O
+demonstrated	O
+hypersensitivity	B-NP
+of	O
+the	O
+cardiovascular	O
+system	O
+to	O
+sodium	O
+pentobarbital	O
+.	O
+	
+Under	O
+barbiturate	O
+anesthesia	O
+","	O
+virtually	O
+all	O
+of	O
+the	O
+myocardial	O
+contractile	O
+indices	O
+were	O
+depressed	O
+significantly	O
+in	O
+barium	O
+-	O
+exposed	O
+rats	O
+relative	O
+to	O
+the	O
+corresponding	O
+control	O
+-	O
+fed	O
+rats	O
+.	O
+	
+The	O
+lack	O
+of	O
+a	O
+similar	O
+response	O
+to	O
+ketamine	O
+and	O
+xylazine	O
+anesthesia	O
+revealed	O
+that	O
+the	O
+cardiovascular	O
+actions	O
+of	O
+sodium	O
+pentobarbital	O
+in	O
+barium	O
+-	O
+treated	O
+rats	O
+were	O
+linked	O
+specifically	O
+to	O
+this	O
+anesthetic	O
+","	O
+and	O
+were	O
+not	O
+representative	O
+of	O
+a	O
+generalized	O
+anesthetic	O
+response	O
+.	O
+	
+Other	O
+myocardial	O
+pathophysiologic	O
+and	O
+metabolic	O
+changes	O
+induced	O
+by	O
+barium	O
+were	O
+manifest	O
+","	O
+irrespective	O
+of	O
+the	O
+anesthetic	O
+employed	O
+.	O
+	
+The	O
+contractile	O
+element	O
+shortening	O
+velocity	O
+of	O
+the	O
+cardiac	O
+muscle	O
+fibers	O
+was	O
+significantly	O
+slower	O
+in	O
+both	O
+groups	O
+of	O
+barium	O
+-	O
+treated	O
+rats	O
+relative	O
+to	O
+the	O
+control	O
+groups	O
+","	O
+irrespective	O
+of	O
+the	O
+anesthetic	O
+regimen	O
+.	O
+	
+Similarly	O
+","	O
+significant	O
+disturbances	O
+in	O
+myocardial	O
+energy	O
+metabolism	O
+were	O
+detected	O
+in	O
+the	O
+barium	O
+-	O
+exposed	O
+rats	O
+which	O
+were	O
+consistent	O
+with	O
+the	O
+reduced	O
+contractile	O
+element	O
+shortening	O
+velocity	O
+.	O
+	
+In	O
+addition	O
+","	O
+the	O
+excitability	O
+of	O
+the	O
+cardiac	O
+conduction	O
+system	O
+was	O
+depressed	O
+preferentially	O
+in	O
+the	O
+atrioventricular	O
+nodal	O
+region	O
+of	O
+hearts	O
+from	O
+barium	O
+-	O
+exposed	O
+rats	O
+.	O
+	
+Overall	O
+","	O
+the	O
+altered	O
+cardiac	O
+contractility	O
+and	O
+excitability	O
+characteristics	O
+","	O
+the	O
+myocardial	O
+metabolic	B-NP
+disturbances	I-NP
+","	O
+and	O
+the	O
+hypersensitivity	B-NP
+of	O
+the	O
+cardiovascular	O
+system	O
+to	O
+sodium	O
+pentobarbital	O
+suggest	O
+the	O
+existence	O
+of	O
+a	O
+heretofore	O
+undescribed	O
+cardiomyopathic	B-NP
+disorder	I-NP
+induced	O
+by	O
+chronic	O
+barium	O
+exposure	O
+.	O
+	
+These	O
+experimental	O
+findings	O
+represent	O
+the	O
+first	O
+indication	O
+that	O
+life	O
+-	O
+long	O
+barium	O
+ingestion	O
+may	O
+have	O
+significant	O
+adverse	O
+effects	O
+on	O
+the	O
+mammalian	O
+cardiovascular	O
+system	O
+.	O
+	
+Propranolol	O
+antagonism	O
+of	O
+phenylpropanolamine	O
+-	O
+induced	O
+hypertension	B-NP
+.	O
+	
+Phenylpropanolamine	O
+(	O
+PPA	O
+)	O
+overdose	B-NP
+can	O
+cause	O
+severe	O
+hypertension	B-NP
+","	O
+intracerebral	B-NP
+hemorrhage	I-NP
+","	O
+and	O
+death	O
+.	O
+	
+We	O
+studied	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+propranolol	O
+in	O
+the	O
+treatment	O
+of	O
+PPA	O
+-	O
+induced	O
+hypertension	B-NP
+.	O
+	
+Subjects	O
+received	O
+propranolol	O
+either	O
+by	O
+mouth	O
+for	O
+48	O
+hours	O
+before	O
+PPA	O
+or	O
+as	O
+a	O
+rapid	O
+intravenous	O
+infusion	O
+after	O
+PPA	O
+.	O
+	
+PPA	O
+","	O
+75	O
+mg	O
+alone	O
+","	O
+increased	O
+blood	O
+pressure	O
+(	O
+31	O
++	O
+/	O
+-	O
+14	O
+mm	O
+Hg	O
+systolic	O
+","	O
+20	O
++	O
+/	O
+-	O
+5	O
+mm	O
+Hg	O
+diastolic	O
+)	O
+","	O
+and	O
+propranolol	O
+pretreatment	O
+antagonized	O
+this	O
+increase	O
+(	O
+12	O
++	O
+/	O
+-	O
+10	O
+mm	O
+Hg	O
+systolic	O
+","	O
+10	O
++	O
+/	O
+-	O
+7	O
+mm	O
+Hg	O
+diastolic	O
+)	O
+.	O
+	
+Intravenous	O
+propranolol	O
+after	O
+PPA	O
+also	O
+decreased	O
+blood	O
+pressure	O
+.	O
+	
+Left	O
+ventricular	O
+function	O
+(	O
+assessed	O
+by	O
+echocardiography	O
+)	O
+showed	O
+that	O
+PPA	O
+increased	O
+the	O
+stroke	B-NP
+volume	O
+30	O
+%	O
+(	O
+from	O
+62	O
+.	O
+5	O
++	O
+/	O
+-	O
+20	O
+.	O
+9	O
+to	O
+80	O
+.	O
+8	O
++	O
+/	O
+-	O
+22	O
+.	O
+4	O
+ml	O
+)	O
+","	O
+the	O
+ejection	O
+fraction	O
+9	O
+%	O
+(	O
+from	O
+64	O
+%	O
++	O
+/	O
+-	O
+10	O
+%	O
+to	O
+70	O
+%	O
++	O
+/	O
+-	O
+7	O
+%	O
+)	O
+","	O
+and	O
+cardiac	O
+output	O
+14	O
+%	O
+(	O
+from	O
+3	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+to	O
+4	O
+.	O
+1	O
++	O
+/	O
+-	O
+1	O
+.	O
+0	O
+L	O
+/	O
+min	O
+)	O
+.	O
+	
+Intravenous	O
+propranolol	O
+reversed	O
+these	O
+effects	O
+.	O
+	
+Systemic	O
+vascular	O
+resistance	O
+was	O
+increased	O
+by	O
+PPA	O
+28	O
+%	O
+(	O
+from	O
+1710	O
++	O
+/	O
+-	O
+200	O
+to	O
+2190	O
++	O
+/	O
+-	O
+700	O
+dyne	O
+X	O
+sec	O
+/	O
+cm5	O
+)	O
+and	O
+was	O
+further	O
+increased	O
+by	O
+propranolol	O
+22	O
+%	O
+(	O
+to	O
+2660	O
++	O
+/	O
+-	O
+1200	O
+dyne	O
+X	O
+sec	O
+/	O
+cm5	O
+)	O
+.	O
+	
+We	O
+conclude	O
+that	O
+PPA	O
+increases	O
+blood	O
+pressure	O
+by	O
+increasing	O
+systemic	O
+vascular	O
+resistance	O
+and	O
+cardiac	O
+output	O
+","	O
+and	O
+that	O
+propranolol	O
+antagonizes	O
+this	O
+increase	O
+by	O
+reversing	O
+the	O
+effect	O
+of	O
+PPA	O
+on	O
+cardiac	O
+output	O
+.	O
+	
+That	O
+propranolol	O
+antagonizes	O
+the	O
+pressor	O
+effect	O
+of	O
+PPA	O
+is	O
+in	O
+contrast	O
+to	O
+the	O
+interaction	O
+in	O
+which	O
+propranolol	O
+enhances	O
+the	O
+pressor	O
+effect	O
+of	O
+norepinephrine	O
+.	O
+	
+This	O
+is	O
+probably	O
+because	O
+PPA	O
+has	O
+less	O
+beta	O
+2	O
+activity	O
+than	O
+does	O
+norepinephrine	O
+.	O
+	
+Mesangial	O
+function	O
+and	O
+glomerular	B-NP
+sclerosis	I-NP
+in	O
+rats	O
+with	O
+aminonucleoside	O
+nephrosis	B-NP
+.	O
+	
+The	O
+possible	O
+relationship	O
+between	O
+mesangial	B-NP
+dysfunction	I-NP
+and	O
+development	O
+of	O
+glomerular	B-NP
+sclerosis	I-NP
+was	O
+studied	O
+in	O
+the	O
+puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+)	O
+model	O
+.	O
+	
+Five	O
+male	O
+Wistar	O
+rats	O
+received	O
+repeated	O
+subcutaneous	O
+PAN	O
+injections	O
+;	O
+five	O
+controls	O
+received	O
+saline	O
+only	O
+.	O
+	
+After	O
+4	O
+weeks	O
+the	O
+PAN	O
+rats	O
+were	O
+severely	O
+proteinuric	B-NP
+(	O
+190	O
++	O
+/	O
+-	O
+80	O
+mg	O
+/	O
+24	O
+hr	O
+)	O
+","	O
+and	O
+all	O
+rats	O
+were	O
+given	O
+colloidal	O
+carbon	O
+(	O
+CC	O
+)	O
+intravenously	O
+.	O
+	
+At	O
+5	O
+months	O
+glomerular	B-NP
+sclerosis	I-NP
+was	O
+found	O
+in	O
+7	O
+.	O
+6	O
++	O
+/	O
+-	O
+3	O
+.	O
+4	O
+%	O
+of	O
+the	O
+glomeruli	O
+of	O
+PAN	O
+rats	O
+;	O
+glomeruli	O
+of	O
+the	O
+controls	O
+were	O
+normal	O
+.	O
+	
+Glomeruli	O
+of	O
+PAN	O
+rats	O
+contained	O
+significantly	O
+more	O
+CC	O
+than	O
+glomeruli	O
+of	O
+controls	O
+.	O
+	
+Glomeruli	O
+with	O
+sclerosis	B-NP
+contained	O
+significantly	O
+more	O
+CC	O
+than	O
+non	O
+-	O
+sclerotic	O
+glomeruli	O
+in	O
+the	O
+same	O
+kidneys	O
+.	O
+	
+CC	O
+was	O
+preferentially	O
+localized	O
+within	O
+the	O
+sclerotic	O
+areas	O
+of	O
+the	O
+affected	O
+glomeruli	O
+.	O
+	
+Since	O
+mesangial	O
+CC	O
+clearance	O
+from	O
+the	O
+mesangium	O
+did	O
+not	O
+change	O
+during	O
+chronic	O
+PAN	O
+treatment	O
+","	O
+we	O
+conclude	O
+that	O
+this	O
+preferential	O
+CC	O
+localization	O
+within	O
+the	O
+lesions	O
+is	O
+caused	O
+by	O
+an	O
+increased	O
+CC	O
+uptake	O
+shortly	O
+after	O
+injection	O
+in	O
+apparent	O
+vulnerable	O
+areas	O
+where	O
+sclerosis	B-NP
+will	O
+develop	O
+subsequently	O
+.	O
+	
+Cluster	O
+analysis	O
+showed	O
+a	O
+random	O
+distribution	O
+of	O
+lesions	O
+in	O
+the	O
+PAN	O
+glomeruli	O
+in	O
+concordance	O
+with	O
+the	O
+random	O
+localization	O
+of	O
+mesangial	O
+areas	O
+with	O
+dysfunction	O
+in	O
+this	O
+model	O
+.	O
+	
+Similar	O
+to	O
+the	O
+remnant	O
+kidney	O
+model	O
+in	O
+PAN	O
+nephrosis	B-NP
+the	O
+development	O
+of	O
+glomerular	B-NP
+sclerosis	I-NP
+may	O
+be	O
+related	O
+to	O
+"	O
+mesangial	O
+overloading	O
+.	O
+"	O
+	
+Relationship	O
+between	O
+nicotine	O
+-	O
+induced	O
+seizures	B-NP
+and	O
+hippocampal	O
+nicotinic	O
+receptors	O
+.	O
+	
+A	O
+controversy	O
+has	O
+existed	O
+for	O
+several	O
+years	O
+concerning	O
+the	O
+physiological	O
+relevance	O
+of	O
+the	O
+nicotinic	O
+receptor	O
+measured	O
+by	O
+alpha	O
+-	O
+bungarotoxin	O
+binding	O
+.	O
+	
+Using	O
+mice	O
+derived	O
+from	O
+a	O
+classical	O
+F2	O
+and	O
+backcross	O
+genetic	O
+design	O
+","	O
+a	O
+relationship	O
+between	O
+nicotine	O
+-	O
+induced	O
+seizures	B-NP
+and	O
+alpha	O
+-	O
+bungarotoxin	O
+nicotinic	O
+receptor	O
+concentration	O
+was	O
+found	O
+.	O
+	
+Mice	O
+sensitive	O
+to	O
+the	O
+convulsant	O
+effects	O
+of	O
+nicotine	O
+had	O
+greater	O
+alpha	O
+-	O
+bungarotoxin	O
+binding	O
+in	O
+the	O
+hippocampus	O
+than	O
+seizure	B-NP
+insensitive	O
+mice	O
+.	O
+	
+The	O
+binding	O
+sites	O
+from	O
+seizure	B-NP
+sensitive	O
+and	O
+resistant	O
+mice	O
+were	O
+equally	O
+affected	O
+by	O
+treatment	O
+with	O
+dithiothreitol	O
+","	O
+trypsin	O
+or	O
+heat	O
+.	O
+	
+Thus	O
+it	O
+appears	O
+that	O
+the	O
+difference	O
+between	O
+seizure	B-NP
+sensitive	O
+and	O
+insensitive	O
+animals	O
+may	O
+be	O
+due	O
+to	O
+a	O
+difference	O
+in	O
+hippocampal	O
+nicotinic	O
+receptor	O
+concentration	O
+as	O
+measured	O
+with	O
+alpha	O
+-	O
+bungarotoxin	O
+binding	O
+.	O
+	
+The	O
+role	O
+of	O
+p	O
+-	O
+aminophenol	O
+in	O
+acetaminophen	O
+-	O
+induced	O
+nephrotoxicity	B-NP
+:	O
+effect	O
+of	O
+bis	O
+(	O
+p	O
+-	O
+nitrophenyl	O
+)	O
+phosphate	O
+on	O
+acetaminophen	O
+and	O
+p	O
+-	O
+aminophenol	O
+nephrotoxicity	B-NP
+and	O
+metabolism	O
+in	O
+Fischer	O
+344	O
+rats	O
+.	O
+	
+Acetaminophen	O
+(	O
+APAP	O
+)	O
+produces	O
+proximal	O
+tubular	B-NP
+necrosis	I-NP
+in	O
+Fischer	O
+344	O
+(	O
+F344	O
+)	O
+rats	O
+.	O
+	
+Recently	O
+","	O
+p	O
+-	O
+aminophenol	O
+(	O
+PAP	O
+)	O
+","	O
+a	O
+known	O
+potent	O
+nephrotoxicant	O
+","	O
+was	O
+identified	O
+as	O
+a	O
+metabolite	O
+of	O
+APAP	O
+in	O
+F344	O
+rats	O
+.	O
+	
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+if	O
+PAP	O
+formation	O
+is	O
+a	O
+requisite	O
+step	O
+in	O
+APAP	O
+-	O
+induced	O
+nephrotoxicity	B-NP
+.	O
+	
+Therefore	O
+","	O
+the	O
+effect	O
+of	O
+bis	O
+(	O
+p	O
+-	O
+nitrophenyl	O
+)	O
+phosphate	O
+(	O
+BNPP	O
+)	O
+","	O
+an	O
+acylamidase	O
+inhibitor	O
+","	O
+on	O
+APAP	O
+and	O
+PAP	O
+nephrotoxicity	B-NP
+and	O
+metabolism	O
+was	O
+determined	O
+.	O
+	
+BNPP	O
+(	O
+1	O
+to	O
+8	O
+mM	O
+)	O
+reduced	O
+APAP	O
+deacetylation	O
+and	O
+covalent	O
+binding	O
+in	O
+F344	O
+renal	O
+cortical	O
+homogenates	O
+in	O
+a	O
+concentration	O
+-	O
+dependent	O
+manner	O
+.	O
+	
+Pretreatment	O
+of	O
+animals	O
+with	O
+BNPP	O
+prior	O
+to	O
+APAP	O
+or	O
+PAP	O
+administration	O
+resulted	O
+in	O
+marked	O
+reduction	O
+of	O
+APAP	O
+(	O
+900	O
+mg	O
+/	O
+kg	O
+)	O
+nephrotoxicity	B-NP
+but	O
+not	O
+PAP	O
+nephrotoxicity	B-NP
+.	O
+	
+This	O
+result	O
+was	O
+not	O
+due	O
+to	O
+altered	O
+disposition	O
+of	O
+either	O
+APAP	O
+or	O
+acetylated	O
+metabolites	O
+in	O
+plasma	O
+or	O
+renal	O
+cortical	O
+and	O
+hepatic	O
+tissue	O
+.	O
+	
+Rather	O
+","	O
+BNPP	O
+pretreatment	O
+reduced	O
+the	O
+fraction	O
+of	O
+APAP	O
+excreted	O
+as	O
+PAP	O
+by	O
+64	O
+and	O
+75	O
+%	O
+after	O
+APAP	O
+doses	O
+of	O
+750	O
+and	O
+900	O
+mg	O
+/	O
+kg	O
+.	O
+	
+BNPP	O
+did	O
+not	O
+alter	O
+the	O
+excretion	O
+of	O
+APAP	O
+or	O
+any	O
+of	O
+its	O
+non	O
+-	O
+deacetylated	O
+metabolites	O
+nor	O
+did	O
+BNPP	O
+alter	O
+excretion	O
+of	O
+PAP	O
+or	O
+its	O
+metabolites	O
+after	O
+PAP	O
+doses	O
+of	O
+150	O
+and	O
+300	O
+mg	O
+/	O
+kg	O
+.	O
+	
+Therefore	O
+","	O
+the	O
+BNPP	O
+-	O
+induced	O
+reduction	O
+in	O
+APAP	O
+-	O
+induced	O
+nephrotoxicity	B-NP
+appears	O
+to	O
+be	O
+due	O
+to	O
+inhibition	O
+of	O
+APAP	O
+deacetylation	O
+.	O
+	
+It	O
+is	O
+concluded	O
+that	O
+PAP	O
+formation	O
+","	O
+in	O
+vivo	O
+","	O
+accounts	O
+","	O
+at	O
+least	O
+in	O
+part	O
+","	O
+for	O
+APAP	O
+-	O
+induced	O
+renal	B-NP
+tubular	I-NP
+necrosis	I-NP
+.	O
+	
+Morphine	O
+-	O
+induced	O
+seizures	B-NP
+in	O
+newborn	O
+infants	O
+.	O
+	
+Two	O
+neonates	O
+suffered	O
+from	O
+generalized	O
+seizures	B-NP
+during	O
+the	O
+course	O
+of	O
+intravenous	O
+morphine	O
+sulfate	O
+for	O
+post	O
+-	O
+operative	O
+analgesia	O
+.	O
+	
+They	O
+received	O
+morphine	O
+in	O
+doses	O
+of	O
+32	O
+micrograms	O
+/	O
+kg	O
+/	O
+hr	O
+and	O
+40	O
+micrograms	O
+/	O
+kg	O
+/	O
+hr	O
+larger	O
+than	O
+a	O
+group	O
+of	O
+10	O
+neonates	O
+who	O
+received	O
+6	O
+-	O
+24	O
+micrograms	O
+/	O
+kg	O
+/	O
+hr	O
+and	O
+had	O
+no	O
+seizures	B-NP
+.	O
+	
+Plasma	O
+concentrations	O
+of	O
+morphine	O
+in	O
+these	O
+neonates	O
+was	O
+excessive	O
+(	O
+60	O
+and	O
+90	O
+mg	O
+/	O
+ml	O
+)	O
+.	O
+	
+Other	O
+known	O
+reasons	O
+for	O
+seizures	B-NP
+were	O
+ruled	O
+out	O
+and	O
+the	O
+convulsions	B-NP
+stopped	O
+a	O
+few	O
+hours	O
+after	O
+cessation	O
+of	O
+morphine	O
+and	O
+did	O
+not	O
+reoccur	O
+in	O
+the	O
+subsequent	O
+8	O
+months	O
+.	O
+	
+It	O
+is	O
+suggested	O
+that	O
+post	O
+-	O
+operative	O
+intravenous	O
+morphine	O
+should	O
+not	O
+exceed	O
+20	O
+micrograms	O
+/	O
+kg	O
+/	O
+ml	O
+in	O
+neonates	O
+.	O
+	
+Indomethacin	O
+induced	O
+hypotension	B-NP
+in	O
+sodium	O
+and	O
+volume	O
+depleted	O
+rats	O
+.	O
+	
+After	O
+a	O
+single	O
+oral	O
+dose	O
+of	O
+4	O
+mg	O
+/	O
+kg	O
+indomethacin	O
+(	O
+IDM	O
+)	O
+to	O
+sodium	O
+and	O
+volume	O
+depleted	O
+rats	O
+plasma	O
+renin	O
+activity	O
+(	O
+PRA	O
+)	O
+and	O
+systolic	O
+blood	O
+pressure	O
+fell	O
+significantly	O
+within	O
+four	O
+hours	O
+.	O
+	
+In	O
+sodium	O
+repleted	O
+animals	O
+indomethacin	O
+did	O
+not	O
+change	O
+systolic	O
+blood	O
+pressure	O
+(	O
+BP	O
+)	O
+although	O
+plasma	O
+renin	O
+activity	O
+was	O
+decreased	O
+.	O
+	
+Thus	O
+","	O
+indomethacin	O
+by	O
+inhibition	O
+of	O
+prostaglandin	O
+synthesis	O
+may	O
+diminish	O
+the	O
+blood	O
+pressure	O
+maintaining	O
+effect	O
+of	O
+the	O
+stimulated	O
+renin	O
+-	O
+angiotensin	O
+system	O
+in	O
+sodium	O
+and	O
+volume	O
+depletion	O
+.	O
+	
+On	O
+the	O
+antiarrhythmic	O
+activity	O
+of	O
+one	O
+N	O
+-	O
+substituted	O
+piperazine	O
+derivative	O
+of	O
+trans	O
+-	O
+2	O
+-	O
+amino	O
+-	O
+3	O
+-	O
+hydroxy	O
+-	O
+1	O
+","	O
+2	O
+","	O
+3	O
+","	O
+4	O
+-	O
+tetrahydroanaphthalene	O
+.	O
+	
+The	O
+antiarrhythmic	O
+activity	O
+of	O
+the	O
+compound	O
+N	O
+-	O
+(	O
+trans	O
+-	O
+3	O
+-	O
+hydroxy	O
+-	O
+1	O
+","	O
+2	O
+","	O
+3	O
+","	O
+4	O
+-	O
+tetrahydro	O
+-	O
+2	O
+-	O
+naphthyl	O
+)	O
+-	O
+N	O
+-	O
+(	O
+3	O
+-	O
+oxo	O
+-	O
+3	O
+-	O
+phenyl	O
+-	O
+2	O
+-	O
+methylpropyl	O
+)	O
+-	O
+piperazine	O
+hydrochloride	O
+","	O
+referred	O
+to	O
+as	O
+P11	O
+","	O
+is	O
+studied	O
+on	O
+anaesthesized	O
+cats	O
+and	O
+Wistar	O
+albino	O
+rats	O
+","	O
+as	O
+well	O
+as	O
+on	O
+non	O
+-	O
+anaesthesized	O
+rabbits	O
+.	O
+	
+Four	O
+types	O
+of	O
+experimental	O
+arrhythmia	B-NP
+are	O
+used	O
+-	O
+-	O
+with	O
+BaCl2	O
+","	O
+with	O
+chloroform	O
+-	O
+adrenaline	O
+","	O
+with	O
+strophantine	O
+G	O
+and	O
+with	O
+aconitine	O
+.	O
+	
+The	O
+compound	O
+P11	O
+is	O
+introduced	O
+in	O
+doses	O
+of	O
+0	O
+.	O
+25	O
+and	O
+0	O
+.	O
+50	O
+mg	O
+/	O
+kg	O
+intravenously	O
+and	O
+10	O
+mg	O
+/	O
+kg	O
+orally	O
+.	O
+	
+The	O
+compound	O
+manifests	O
+antiarrhythmic	O
+activity	O
+in	O
+all	O
+models	O
+of	O
+experimental	O
+arrhythmia	B-NP
+used	O
+","	O
+causing	O
+greatest	O
+inhibition	O
+on	O
+the	O
+arrhythmia	B-NP
+induced	O
+by	O
+chloroform	O
+-	O
+adrenaline	O
+(	O
+in	O
+90	O
+per	O
+cent	O
+)	O
+and	O
+with	O
+BaCl2	O
+(	O
+in	O
+84	O
+per	O
+cent	O
+)	O
+.	O
+	
+The	O
+results	O
+obtained	O
+are	O
+associated	O
+with	O
+the	O
+beta	O
+-	O
+adrenoblocking	O
+and	O
+with	O
+the	O
+membrane	O
+-	O
+stabilizing	O
+action	O
+of	O
+the	O
+compound	O
+.	O
+	
+Recurrent	O
+subarachnoid	B-NP
+hemorrhage	I-NP
+associated	O
+with	O
+aminocaproic	O
+acid	O
+therapy	O
+and	O
+acute	B-NP
+renal	I-NP
+artery	I-NP
+thrombosis	I-NP
+.	O
+	
+Case	O
+report	O
+.	O
+	
+Epsilon	O
+aminocaproic	O
+acid	O
+(	O
+EACA	O
+)	O
+has	O
+been	O
+used	O
+to	O
+prevent	O
+rebleeding	O
+in	O
+patients	O
+with	O
+subarachnoid	B-NP
+hemorrhage	I-NP
+(	O
+SAH	B-NP
+)	O
+.	O
+	
+Although	O
+this	O
+agent	O
+does	O
+decrease	O
+the	O
+frequency	O
+of	O
+rebleeding	O
+","	O
+several	O
+reports	O
+have	O
+described	O
+thrombotic	B-NP
+complications	O
+of	O
+EACA	O
+therapy	O
+.	O
+	
+These	O
+complications	O
+have	O
+included	O
+clinical	O
+deterioration	O
+and	O
+intracranial	B-NP
+vascular	I-NP
+thrombosis	I-NP
+in	O
+patients	O
+with	O
+SAH	B-NP
+","	O
+arteriolar	O
+and	O
+capillary	O
+fibrin	O
+thrombi	B-NP
+in	O
+patients	O
+with	O
+fibrinolytic	O
+syndromes	O
+treated	O
+with	O
+EACA	O
+","	O
+or	O
+other	O
+thromboembolic	B-NP
+phenomena	I-NP
+.	O
+	
+Since	O
+intravascular	O
+fibrin	O
+thrombi	B-NP
+are	O
+often	O
+observed	O
+in	O
+patients	O
+with	O
+fibrinolytic	O
+disorders	O
+","	O
+EACA	O
+should	O
+not	O
+be	O
+implicated	O
+in	O
+the	O
+pathogenesis	O
+of	O
+fibrin	O
+thrombi	B-NP
+in	O
+patients	O
+with	O
+disseminated	B-NP
+intravascular	I-NP
+coagulation	I-NP
+or	O
+other	O
+"	O
+consumption	B
+coagulopathies	I
+.	O
+"	O
+This	O
+report	O
+describes	O
+subtotal	O
+infarction	B-NP
+of	O
+the	O
+kidney	O
+due	O
+to	O
+thrombosis	B-NP
+of	I-NP
+a	I-NP
+normal	I-NP
+renal	I-NP
+artery	I-NP
+.	O
+	
+This	O
+occlusion	O
+occurred	O
+after	O
+EACA	O
+therapy	O
+in	O
+a	O
+patient	O
+with	O
+SAH	B-NP
+and	O
+histopathological	O
+documentation	O
+of	O
+recurrent	O
+SAH	B-NP
+.	O
+	
+The	O
+corresponding	O
+clinical	O
+event	O
+was	O
+characterized	O
+by	O
+marked	O
+hypertension	B-NP
+and	O
+abrupt	O
+neurological	O
+deterioration	O
+.	O
+	
+Effect	O
+of	O
+vincristine	O
+sulfate	O
+on	O
+Pseudomonas	B-NP
+infections	I-NP
+in	O
+monkeys	O
+.	O
+	
+In	O
+rhesus	O
+monkeys	O
+","	O
+intravenous	O
+challenge	O
+with	O
+0	O
+.	O
+6	O
+x	O
+10	O
+(	O
+10	O
+)	O
+to	O
+2	O
+.	O
+2	O
+x	O
+10	O
+(	O
+10	O
+)	O
+Pseudomonas	O
+aeruginosa	O
+organisms	O
+caused	O
+acute	O
+illness	O
+of	O
+4	O
+to	O
+5	O
+days	O
+'	O
+duration	O
+with	O
+spontaneous	O
+recovery	O
+in	O
+13	O
+of	O
+15	O
+monkeys	O
+;	O
+blood	O
+cultures	O
+became	O
+negative	O
+3	O
+to	O
+17	O
+days	O
+after	O
+challenge	O
+.	O
+	
+Leukocytosis	B-NP
+was	O
+observed	O
+in	O
+all	O
+monkeys	O
+.	O
+	
+Intravenous	O
+or	O
+intratracheal	O
+inoculation	O
+of	O
+2	O
+.	O
+0	O
+to	O
+2	O
+.	O
+5	O
+mg	O
+of	O
+vincristine	O
+sulfate	O
+was	O
+followed	O
+by	O
+leukopenia	B-NP
+in	O
+4	O
+to	O
+5	O
+days	O
+.	O
+	
+Intravenous	O
+inoculation	O
+of	O
+4	O
+.	O
+2	O
+x	O
+10	O
+(	O
+10	O
+)	O
+to	O
+7	O
+.	O
+8	O
+x	O
+10	O
+(	O
+10	O
+)	O
+pyocin	O
+type	O
+6	O
+Pseudomonas	O
+organisms	O
+in	O
+monkeys	O
+given	O
+vincristine	O
+sulfate	O
+4	O
+days	O
+previously	O
+resulted	O
+in	O
+fatal	O
+infection	B-NP
+in	O
+11	O
+of	O
+14	O
+monkeys	O
+","	O
+whereas	O
+none	O
+of	O
+four	O
+receiving	O
+Pseudomonas	O
+alone	O
+died	O
+.	O
+	
+These	O
+studies	O
+suggest	O
+that	O
+an	O
+antimetabolite	O
+-	O
+induced	O
+leukopenia	B-NP
+predisposes	O
+to	O
+severe	O
+Pseudomonas	O
+sepsis	B-NP
+and	O
+that	O
+such	O
+monkeys	O
+may	O
+serve	O
+as	O
+a	O
+biological	O
+model	O
+for	O
+study	O
+of	O
+comparative	O
+efficacy	O
+of	O
+antimicrobial	O
+agents	O
+.	O
+	
+Modification	O
+by	O
+propranolol	O
+of	O
+cardiovascular	O
+effects	O
+of	O
+induced	O
+hypoglycaemia	B-NP
+.	O
+	
+The	O
+cardiovascular	O
+effects	O
+of	O
+hypoglycaemia	B-NP
+","	O
+with	O
+and	O
+without	O
+beta	O
+-	O
+blockade	O
+","	O
+were	O
+compared	O
+in	O
+fourteen	O
+healthy	O
+men	O
+.	O
+	
+Eight	O
+received	O
+insulin	O
+alone	O
+","	O
+and	O
+eight	O
+","	O
+including	O
+two	O
+of	O
+the	O
+original	O
+insulin	O
+-	O
+only	O
+group	O
+","	O
+were	O
+given	O
+propranolol	O
+and	O
+insulin	O
+.	O
+	
+In	O
+the	O
+insulin	O
+-	O
+group	O
+the	O
+period	O
+of	O
+hypoglycaemia	B-NP
+was	O
+associated	O
+with	O
+an	O
+increase	O
+in	O
+heart	O
+-	O
+rate	O
+and	O
+a	O
+fall	O
+in	O
+diastolic	O
+blood	O
+-	O
+pressure	O
+.	O
+	
+In	O
+the	O
+propranolol	O
+-	O
+insulin	O
+group	O
+there	O
+was	O
+a	O
+significant	O
+fall	O
+in	O
+heart	O
+-	O
+rate	O
+in	O
+most	O
+subjects	O
+and	O
+an	O
+increase	O
+in	O
+diastolic	O
+pressure	O
+.	O
+	
+Typical	O
+S	O
+-	O
+T	O
+/	O
+T	O
+changes	O
+occurred	O
+in	O
+the	O
+insulin	O
+-	O
+group	O
+but	O
+in	O
+none	O
+of	O
+the	O
+propranolol	O
+-	O
+insulin	O
+group	O
+.	O
+	
+Hypertension	B-NP
+in	O
+diabetics	B-NP
+prone	O
+to	O
+hypoglycaemia	B-NP
+attacks	O
+should	O
+not	O
+be	O
+treated	O
+with	O
+beta	O
+-	O
+blockers	O
+because	O
+these	O
+drugs	O
+may	O
+cause	O
+a	O
+sharp	O
+rise	O
+in	O
+blood	O
+-	O
+pressure	O
+in	O
+such	O
+patients	O
+.	O
+	
+Long	O
+-	O
+term	O
+propranolol	O
+therapy	O
+in	O
+pregnancy	O
+:	O
+maternal	O
+and	O
+fetal	O
+outcome	O
+.	O
+	
+Propranolol	O
+","	O
+a	O
+beta	O
+-	O
+adrenergic	O
+blocking	O
+agent	O
+","	O
+has	O
+found	O
+an	O
+important	O
+position	O
+in	O
+the	O
+practice	O
+of	O
+medicine	O
+.	O
+	
+Its	O
+use	O
+in	O
+pregnancy	O
+","	O
+however	O
+","	O
+is	O
+an	O
+open	O
+question	O
+as	O
+a	O
+number	O
+of	O
+detrimental	O
+side	O
+effects	O
+have	O
+been	O
+reported	O
+in	O
+the	O
+fetus	O
+and	O
+neonate	O
+.	O
+	
+Ten	O
+patients	O
+and	O
+12	O
+pregnancies	O
+are	O
+reported	O
+where	O
+chronic	O
+propranolol	O
+has	O
+been	O
+administered	O
+.	O
+	
+Five	O
+patients	O
+with	O
+serial	O
+pregnancies	O
+with	O
+and	O
+without	O
+propranolol	O
+therapy	O
+are	O
+also	O
+examined	O
+.	O
+	
+Maternal	O
+","	O
+fetal	O
+","	O
+and	O
+neonatal	O
+complications	O
+are	O
+examined	O
+.	O
+	
+An	O
+attempt	O
+is	O
+made	O
+to	O
+differentiate	O
+drug	O
+-	O
+related	O
+complications	O
+from	O
+maternal	O
+disease	O
+-	O
+-	O
+related	O
+complications	O
+.	O
+	
+We	O
+conclude	O
+that	O
+previously	O
+reported	O
+hypoglycemia	B-NP
+","	O
+hyperbilirubinemia	B-NP
+","	O
+polycythemia	B-NP
+","	O
+neonatal	B-NP
+apnea	I-NP
+","	O
+and	O
+bradycardia	B-NP
+are	O
+not	O
+invariable	O
+and	O
+cannot	O
+be	O
+statistically	O
+correlated	O
+with	O
+chronic	O
+propranolol	O
+therapy	O
+.	O
+	
+Growth	B-NP
+retardation	I-NP
+","	O
+however	O
+","	O
+appears	O
+to	O
+be	O
+significant	O
+in	O
+both	O
+of	O
+our	O
+series	O
+.	O
+	
+Central	O
+excitatory	O
+actions	O
+of	O
+flurazepam	O
+.	O
+	
+Toxic	O
+actions	O
+of	O
+flurazepam	O
+(	O
+FZP	O
+)	O
+were	O
+studied	O
+in	O
+cats	O
+","	O
+mice	O
+and	O
+rats	O
+.	O
+	
+High	O
+doses	O
+caused	O
+an	O
+apparent	O
+central	O
+excitation	O
+","	O
+most	O
+clearly	O
+seen	O
+as	O
+clonic	O
+convulsions	B-NP
+","	O
+superimposed	O
+on	O
+general	O
+depression	B-NP
+.	O
+	
+Following	O
+a	O
+lethal	O
+dose	O
+","	O
+death	O
+was	O
+always	O
+associated	O
+with	O
+convulsions	B-NP
+.	O
+	
+Comparing	O
+the	O
+relative	O
+sensitivity	O
+to	O
+central	O
+depression	B-NP
+and	O
+excitation	O
+revealed	O
+that	O
+rats	O
+were	O
+least	O
+likely	O
+to	O
+have	O
+convulsions	B-NP
+at	O
+doses	O
+that	O
+did	O
+not	O
+first	O
+cause	O
+loss	B-NP
+of	I-NP
+consciousness	I-NP
+","	O
+while	O
+cats	O
+most	O
+clearly	O
+showed	O
+marked	O
+central	O
+excitatory	O
+actions	O
+.	O
+	
+Signs	O
+of	O
+FZP	O
+toxocity	B-NP
+in	O
+cats	O
+included	O
+excessive	O
+salivation	B-NP
+","	O
+extreme	O
+apprehensive	O
+behavior	O
+","	O
+retching	O
+","	O
+muscle	B-NP
+tremors	I-NP
+and	O
+convulsions	B-NP
+.	O
+	
+An	O
+interaction	O
+between	O
+FZP	O
+and	O
+pentylenetetrazol	O
+(	O
+PTZ	O
+)	O
+was	O
+shown	O
+by	O
+pretreating	O
+mice	O
+with	O
+FZP	O
+before	O
+PTZ	O
+challenge	O
+.	O
+	
+As	O
+a	O
+function	O
+of	O
+dose	O
+","	O
+FZP	O
+first	O
+protected	O
+against	O
+convulsions	B-NP
+and	O
+death	O
+.	O
+	
+At	O
+higher	O
+doses	O
+","	O
+however	O
+","	O
+convulsions	B-NP
+again	O
+emerged	O
+.	O
+	
+These	O
+doses	O
+of	O
+FZP	O
+were	O
+lower	O
+than	O
+those	O
+that	O
+would	O
+alone	O
+cause	O
+convulsions	B-NP
+.	O
+	
+These	O
+results	O
+may	O
+be	O
+relevant	O
+to	O
+the	O
+use	O
+of	O
+FZP	O
+in	O
+clinical	O
+situations	O
+in	O
+which	O
+there	O
+is	O
+increased	O
+neural	O
+excitability	O
+","	O
+such	O
+as	O
+epilepsy	B-NP
+or	O
+sedative	O
+-	O
+hypnotic	O
+drug	O
+withdrawal	O
+.	O
+	
+Use	O
+of	O
+propranolol	O
+in	O
+the	O
+treatment	O
+of	O
+idiopathic	B-NP
+orthostatic	I-NP
+hypotension	I-NP
+.	O
+	
+Five	O
+patients	O
+with	O
+idiopathic	B-NP
+orthostatic	I-NP
+hypotension	I-NP
+who	O
+had	O
+physiologic	O
+and	O
+biochemical	O
+evidence	O
+of	O
+severe	O
+autonomic	O
+dysfunction	O
+were	O
+included	O
+in	O
+the	O
+study	O
+.	O
+	
+They	O
+all	O
+exhibited	O
+markedly	O
+reduced	O
+plasma	O
+catecholamines	O
+and	O
+plasma	O
+renin	O
+activity	O
+in	O
+both	O
+recumbent	O
+and	O
+upright	O
+positions	O
+and	O
+had	O
+marked	O
+hypersensitivity	B-NP
+to	O
+the	O
+pressor	O
+effects	O
+of	O
+infused	O
+norepinephrine	O
+.	O
+	
+Treatment	O
+with	O
+propanolol	O
+administered	O
+intravenously	O
+(	O
+1	O
+-	O
+5	O
+mg	O
+)	O
+produced	O
+increases	O
+in	O
+supine	O
+and	O
+upright	O
+blood	O
+pressure	O
+in	O
+4	O
+of	O
+the	O
+5	O
+individuals	O
+with	O
+rises	O
+ranging	O
+from	O
+11	O
+/	O
+6	O
+to	O
+22	O
+/	O
+11	O
+mmHg	O
+.	O
+	
+Chronic	O
+oral	O
+administration	O
+of	O
+propranolol	O
+(	O
+40	O
+-	O
+160	O
+mg	O
+/	O
+day	O
+)	O
+also	O
+elevated	O
+the	O
+blood	O
+pressures	O
+of	O
+these	O
+individuals	O
+with	O
+increases	O
+in	O
+the	O
+order	O
+of	O
+20	O
+-	O
+35	O
+/	O
+15	O
+-	O
+25	O
+mmg	O
+being	O
+observed	O
+.	O
+	
+In	O
+1	O
+patient	O
+","	O
+marked	O
+hypertension	B-NP
+was	O
+induced	O
+by	O
+propranolol	O
+and	O
+the	O
+drug	O
+had	O
+to	O
+be	O
+withdrawn	O
+.	O
+	
+It	O
+otherwise	O
+was	O
+well	O
+tolerated	O
+and	O
+no	O
+important	O
+side	O
+effects	O
+were	O
+observed	O
+.	O
+	
+Treatment	O
+has	O
+been	O
+continued	O
+in	O
+3	O
+individuals	O
+for	O
+6	O
+-	O
+13	O
+months	O
+with	O
+persistence	O
+of	O
+the	O
+pressor	O
+effect	O
+","	O
+although	O
+there	O
+appears	O
+to	O
+have	O
+been	O
+some	O
+decrease	O
+in	O
+the	O
+degree	O
+of	O
+response	O
+with	O
+time	O
+.	O
+	
+Hemodynamic	O
+measurements	O
+in	O
+1	O
+of	O
+the	O
+patients	O
+demonstrated	O
+an	O
+increase	O
+in	O
+total	O
+peripheral	O
+resistance	O
+and	O
+essentially	O
+no	O
+change	O
+in	O
+cardiac	O
+output	O
+following	O
+propranolol	O
+therapy	O
+.	O
+	
+The	O
+studies	O
+suggest	O
+that	O
+propranolol	O
+is	O
+a	O
+useful	O
+drug	O
+in	O
+selected	O
+patients	O
+with	O
+severe	O
+idiopathic	B-NP
+orthostatic	I-NP
+hypotension	I-NP
+.	O
+	
+Total	O
+intravenous	O
+anesthesia	O
+with	O
+etomidate	O
+.	O
+	
+III	O
+.	O
+	
+Some	O
+observations	O
+in	O
+adults	O
+.	O
+	
+An	O
+investigation	O
+was	O
+undertaken	O
+to	O
+determine	O
+the	O
+dosage	O
+of	O
+etomidate	O
+required	O
+to	O
+maintain	O
+sleep	O
+in	O
+adults	O
+undergoing	O
+surgery	O
+under	O
+regional	O
+local	O
+anesthesia	O
+.	O
+	
+Premedication	O
+of	O
+diazepam	O
+10	O
+mg	O
+and	O
+atropine	O
+0	O
+.	O
+5	O
+mg	O
+was	O
+given	O
+","	O
+and	O
+sleep	O
+was	O
+induced	O
+and	O
+maintained	O
+by	O
+intermittent	O
+intravenous	O
+injections	O
+of	O
+etomidate	O
+0	O
+.	O
+1	O
+/	O
+mg	O
+/	O
+kg	O
+","	O
+given	O
+whenever	O
+the	O
+patient	O
+would	O
+open	O
+his	O
+eyes	O
+on	O
+request	O
+.	O
+	
+A	O
+mean	O
+overall	O
+dose	O
+of	O
+etomidate	O
+17	O
+.	O
+4	O
+microgram	O
+/	O
+kg	O
+/	O
+min	O
+.	O
+was	O
+required	O
+to	O
+maintain	O
+sleep	O
+","	O
+but	O
+great	O
+individual	O
+variation	O
+occurred	O
+","	O
+with	O
+older	O
+patients	O
+requiring	O
+less	O
+drug	O
+.	O
+	
+The	O
+investigation	O
+was	O
+discontinued	O
+after	O
+18	O
+patients	O
+because	O
+of	O
+the	O
+frequency	O
+and	O
+intensity	O
+of	O
+side	O
+-	O
+effects	O
+","	O
+particularly	O
+pain	B-NP
+and	O
+myoclonia	B-NP
+","	O
+which	O
+caused	O
+the	O
+technique	O
+to	O
+be	O
+abandoned	O
+in	O
+two	O
+cases	O
+.	O
+	
+It	O
+is	O
+considered	O
+unlikely	O
+that	O
+etomidate	O
+will	O
+prove	O
+to	O
+be	O
+the	O
+hypnotic	O
+of	O
+choice	O
+for	O
+a	O
+totally	O
+intravenous	O
+anesthetic	O
+technique	O
+in	O
+adults	O
+because	O
+of	O
+the	O
+high	O
+incidence	O
+of	O
+myoclonia	B-NP
+after	O
+prolonged	O
+administration	O
+.	O
+	
+In	O
+several	O
+patients	O
+uncontrollable	O
+muscle	O
+movements	O
+persisted	O
+for	O
+many	O
+minutes	O
+after	O
+complete	O
+recovery	O
+of	O
+consciousness	O
+.	O
+	
+Evidence	O
+for	O
+cardiac	O
+beta	O
+2	O
+-	O
+adrenoceptors	O
+in	O
+man	O
+.	O
+	
+We	O
+compared	O
+the	O
+effects	O
+of	O
+single	O
+doses	O
+of	O
+50	O
+mg	O
+atenolol	O
+(	O
+cardioselective	O
+)	O
+","	O
+40	O
+mg	O
+propranolol	O
+(	O
+nonselective	O
+)	O
+","	O
+and	O
+placebo	O
+on	O
+both	O
+exercise	O
+-	O
+and	O
+isoproterenol	O
+-	O
+induced	O
+tachycardia	B-NP
+in	O
+two	O
+experiments	O
+involving	O
+nine	O
+normal	O
+subjects	O
+.	O
+	
+Maximal	O
+exercise	O
+heart	O
+rate	O
+was	O
+reduced	O
+from	O
+187	O
++	O
+/	O
+-	O
+4	O
+(	O
+SEM	O
+)	O
+after	O
+placebo	O
+to	O
+146	O
++	O
+/	O
+-	O
+7	O
+bpm	O
+after	O
+atenolol	O
+and	O
+138	O
++	O
+/	O
+-	O
+6	O
+bpm	O
+after	O
+propranolol	O
+","	O
+but	O
+there	O
+were	O
+no	O
+differences	O
+between	O
+the	O
+drugs	O
+.	O
+	
+The	O
+effects	O
+on	O
+isoproterenol	O
+tachycardia	B-NP
+were	O
+determined	O
+before	O
+and	O
+after	O
+atropine	O
+(	O
+0	O
+.	O
+4	O
+mg	O
+/	O
+kg	O
+IV	O
+)	O
+.	O
+	
+Isoproterenol	O
+sensitivity	O
+was	O
+determined	O
+as	O
+the	O
+intravenous	O
+dose	O
+that	O
+increased	O
+heart	O
+rate	O
+by	O
+25	O
+bpm	O
+(	O
+CD25	O
+)	O
+and	O
+this	O
+was	O
+increased	O
+from	O
+1	O
+.	O
+8	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+micrograms	O
+after	O
+placebo	O
+to	O
+38	O
+.	O
+9	O
++	O
+/	O
+-	O
+8	O
+.	O
+3	O
+micrograms	O
+after	O
+propranolol	O
+and	O
+8	O
+.	O
+3	O
++	O
+/	O
+-	O
+1	O
+.	O
+7	O
+micrograms	O
+after	O
+atenolol	O
+.	O
+	
+The	O
+difference	O
+in	O
+the	O
+effects	O
+of	O
+the	O
+two	O
+was	O
+significant	O
+.	O
+	
+After	O
+atropine	O
+the	O
+CD25	O
+was	O
+unchanged	O
+after	O
+placebo	O
+(	O
+2	O
+.	O
+3	O
++	O
+/	O
+-	O
+0	O
+.	O
+3	O
+micrograms	O
+)	O
+and	O
+atenolol	O
+(	O
+7	O
+.	O
+7	O
++	O
+/	O
+-	O
+1	O
+.	O
+3	O
+micrograms	O
+)	O
+;	O
+it	O
+was	O
+reduced	O
+after	O
+propranolol	O
+(	O
+24	O
+.	O
+8	O
++	O
+/	O
+-	O
+5	O
+.	O
+0	O
+micrograms	O
+)	O
+","	O
+but	O
+remained	O
+different	O
+from	O
+atenolol	O
+.	O
+	
+This	O
+change	O
+with	O
+propranolol	O
+sensitivity	O
+was	O
+calculated	O
+as	O
+the	O
+apparent	O
+Ka	O
+","	O
+this	O
+was	O
+unchanged	O
+by	O
+atropine	O
+(	O
+11	O
+.	O
+7	O
++	O
+/	O
+-	O
+2	O
+.	O
+1	O
+and	O
+10	O
+.	O
+1	O
++	O
+/	O
+-	O
+2	O
+.	O
+5	O
+ml	O
+/	O
+ng	O
+)	O
+.	O
+	
+These	O
+data	O
+are	O
+consistent	O
+with	O
+the	O
+hypothesis	O
+that	O
+exercise	O
+-	O
+induced	O
+tachycardia	B-NP
+results	O
+largely	O
+from	O
+beta	O
+1	O
+-	O
+receptor	O
+activation	O
+that	O
+is	O
+blocked	O
+by	O
+both	O
+cardioselective	O
+and	O
+nonselective	O
+drugs	O
+","	O
+whereas	O
+isoproterenol	O
+activates	O
+both	O
+beta	O
+1	O
+-	O
+and	O
+beta	O
+2	O
+-	O
+receptors	O
+so	O
+that	O
+after	O
+cardioselective	O
+blockade	O
+there	O
+remains	O
+a	O
+beta	O
+2	O
+-	O
+component	O
+that	O
+can	O
+be	O
+blocked	O
+with	O
+a	O
+nonselective	O
+drug	O
+.	O
+	
+While	O
+there	O
+appear	O
+to	O
+be	O
+beta	O
+2	O
+-	O
+receptors	O
+in	O
+the	O
+human	O
+heart	O
+","	O
+their	O
+physiologic	O
+or	O
+pathologic	O
+roles	O
+remain	O
+to	O
+be	O
+defined	O
+.	O
+	
+Hormones	O
+and	O
+risk	O
+of	O
+breast	B-NP
+cancer	I-NP
+.	O
+	
+This	O
+paper	O
+reports	O
+the	O
+results	O
+of	O
+a	O
+study	O
+of	O
+50	O
+menopausal	O
+women	O
+receiving	O
+hormonal	O
+replacement	O
+therapy	O
+.	O
+	
+The	O
+majority	O
+(	O
+29	O
+)	O
+had	O
+surgical	O
+menopause	O
+;	O
+their	O
+mean	O
+age	O
+was	O
+45	O
+.	O
+7	O
+years	O
+.	O
+	
+It	O
+was	O
+hypothesized	O
+that	O
+progestins	O
+could	O
+equilibrate	O
+the	O
+effects	O
+of	O
+the	O
+estrogenic	O
+stimulation	O
+on	O
+the	O
+mammary	O
+and	O
+endometrial	O
+target	O
+tissues	O
+of	O
+women	O
+on	O
+hormonal	O
+replacement	O
+therapy	O
+.	O
+	
+The	O
+treatment	O
+schedule	O
+consisted	O
+of	O
+conjugated	O
+estrogens	O
+(	O
+Premarin	O
+)	O
+1	O
+.	O
+25	O
+mg	O
+/	O
+day	O
+for	O
+21	O
+days	O
+and	O
+Medroxyprogesterone	O
+acetate	O
+10	O
+mg	O
+/	O
+day	O
+for	O
+10	O
+days	O
+in	O
+each	O
+month	O
+.	O
+	
+The	O
+mean	O
+treatment	O
+period	O
+was	O
+18	O
+months	O
+.	O
+	
+During	O
+the	O
+follow	O
+-	O
+up	O
+period	O
+","	O
+attention	O
+was	O
+paid	O
+to	O
+breast	O
+modifications	O
+as	O
+evidenced	O
+by	O
+symptomatology	O
+","	O
+physical	O
+examination	O
+","	O
+and	O
+plate	O
+thermography	O
+.	O
+	
+Mastodynia	B-NP
+was	O
+reported	O
+by	O
+21	O
+patients	O
+","	O
+and	O
+physical	O
+examination	O
+revealed	O
+a	O
+light	O
+increase	O
+in	O
+breast	O
+firmness	O
+in	O
+12	O
+women	O
+and	O
+a	O
+moderate	O
+increase	O
+in	O
+breast	O
+nodularity	O
+in	O
+2	O
+women	O
+.	O
+	
+Themography	O
+confirmed	O
+the	O
+existence	O
+of	O
+an	O
+excessive	O
+breast	O
+stimulation	O
+in	O
+1	O
+women	O
+who	O
+complained	O
+of	O
+moderate	O
+mastodynia	B-NP
+and	O
+in	O
+5	O
+of	O
+the	O
+7	O
+women	O
+who	O
+complained	O
+of	O
+severe	O
+mastodynia	B-NP
+.	O
+	
+Normalization	O
+was	O
+obtained	O
+by	O
+halving	O
+the	O
+estrogen	O
+dose	O
+.	O
+	
+These	O
+results	O
+suggest	O
+that	O
+hormonal	O
+replacement	O
+therapy	O
+can	O
+be	O
+safely	O
+prescribed	O
+if	O
+the	O
+following	O
+criteria	O
+are	O
+satisfied	O
+:	O
+1	O
+)	O
+preliminary	O
+evaluation	O
+of	O
+patients	O
+from	O
+a	O
+clinical	O
+","	O
+metabolic	O
+","	O
+cytologic	O
+","	O
+and	O
+mammographic	O
+perspective	O
+;	O
+2	O
+)	O
+cyclic	O
+treatment	O
+schedule	O
+","	O
+with	O
+a	O
+progestative	O
+phase	O
+of	O
+10	O
+days	O
+;	O
+and	O
+3	O
+)	O
+periodic	O
+complete	O
+follow	O
+-	O
+up	O
+","	O
+with	O
+accurate	O
+thermographic	O
+evaluation	O
+of	O
+the	O
+breast	O
+target	O
+tissues	O
+.	O
+	
+Early	O
+infections	B-NP
+in	O
+kidney	O
+","	O
+heart	O
+","	O
+and	O
+liver	O
+transplant	O
+recipients	O
+on	O
+cyclosporine	O
+.	O
+	
+Eighty	O
+-	O
+one	O
+renal	O
+","	O
+seventeen	O
+heart	O
+","	O
+and	O
+twenty	O
+-	O
+four	O
+liver	O
+transplant	O
+patients	O
+were	O
+followed	O
+for	O
+infection	B-NP
+.	O
+	
+Seventeen	O
+renal	O
+patients	O
+received	O
+azathioprine	O
+(	O
+Aza	O
+)	O
+and	O
+prednisone	O
+as	O
+part	O
+of	O
+a	O
+randomized	O
+trial	O
+of	O
+immunosuppression	O
+with	O
+21	O
+cyclosporine	O
+-	O
+and	O
+-	O
+prednisone	O
+-	O
+treated	O
+renal	O
+transplant	O
+patients	O
+.	O
+	
+All	O
+others	O
+received	O
+cyclosporine	O
+and	O
+prednisone	O
+.	O
+	
+The	O
+randomized	O
+Aza	O
+patients	O
+had	O
+more	O
+overall	O
+infections	B-NP
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+and	O
+more	O
+nonviral	O
+infections	B-NP
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+2	O
+)	O
+than	O
+the	O
+randomized	O
+cyclosporine	O
+patients	O
+.	O
+	
+Heart	O
+and	O
+liver	O
+patients	O
+had	O
+more	O
+infections	B-NP
+than	O
+cyclosporine	O
+renal	O
+patients	O
+but	O
+fewer	O
+infections	B-NP
+than	O
+the	O
+Aza	O
+renal	O
+patients	O
+.	O
+	
+There	O
+were	O
+no	O
+infectious	O
+deaths	O
+in	O
+renal	O
+transplant	O
+patients	O
+on	O
+cyclosporine	O
+or	O
+Aza	O
+","	O
+but	O
+infection	B-NP
+played	O
+a	O
+major	O
+role	O
+in	O
+3	O
+out	O
+of	O
+6	O
+cardiac	O
+transplant	O
+deaths	O
+and	O
+in	O
+8	O
+out	O
+of	O
+9	O
+liver	O
+transplant	O
+deaths	O
+.	O
+	
+Renal	O
+patients	O
+on	O
+cyclosporine	O
+had	O
+the	O
+fewest	O
+bacteremias	B-NP
+.	O
+	
+Analysis	O
+of	O
+site	O
+of	O
+infection	B-NP
+showed	O
+a	O
+preponderance	O
+of	O
+abdominal	B-NP
+infections	I-NP
+in	O
+liver	O
+patients	O
+","	O
+intrathoracic	O
+infections	B-NP
+in	O
+heart	O
+patients	O
+","	O
+and	O
+urinary	B-NP
+tract	I-NP
+infections	I-NP
+in	O
+renal	O
+patients	O
+.	O
+	
+Pulmonary	O
+infections	B-NP
+were	O
+less	O
+common	O
+in	O
+cyclosporine	O
+-	O
+treated	O
+renal	O
+patients	O
+than	O
+in	O
+Aza	O
+-	O
+treated	O
+patients	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+Aza	O
+patients	O
+had	O
+significantly	O
+more	O
+staphylococcal	B-NP
+infections	I-NP
+than	O
+all	O
+other	O
+transplant	O
+groups	O
+(	O
+P	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+","	O
+and	O
+systemic	O
+fungal	B-NP
+infections	I-NP
+occurred	O
+only	O
+in	O
+the	O
+liver	O
+transplant	O
+group	O
+.	O
+	
+Cytomegalovirus	O
+(	O
+CMV	O
+)	O
+shedding	O
+or	O
+serological	O
+rises	O
+in	O
+antibody	O
+titer	O
+","	O
+or	O
+both	O
+occurred	O
+in	O
+78	O
+%	O
+of	O
+cyclosporine	O
+patients	O
+and	O
+76	O
+%	O
+of	O
+Aza	O
+patients	O
+.	O
+	
+Of	O
+the	O
+cyclosporine	O
+patients	O
+","	O
+15	O
+%	O
+had	O
+symptoms	O
+related	O
+to	O
+CMV	B-NP
+infection	I-NP
+.	O
+	
+Serological	O
+evidence	O
+for	O
+Epstein	B-NP
+Barr	I-NP
+Virus	I-NP
+infection	I-NP
+was	O
+found	O
+in	O
+20	O
+%	O
+of	O
+65	O
+cyclosporine	O
+patients	O
+studied	O
+.	O
+	
+Three	O
+had	O
+associated	O
+symptoms	O
+","	O
+and	O
+one	O
+developed	O
+a	O
+lymphoma	B-NP
+.	O
+	
+Structure	O
+-	O
+activity	O
+and	O
+dose	O
+-	O
+effect	O
+relationships	O
+of	O
+the	O
+antagonism	O
+of	O
+picrotoxin	O
+-	O
+induced	O
+seizures	B-NP
+by	O
+cholecystokinin	O
+","	O
+fragments	O
+and	O
+analogues	O
+of	O
+cholecystokinin	O
+in	O
+mice	O
+.	O
+	
+Intraperitoneal	O
+administration	O
+of	O
+cholecystokinin	O
+octapeptide	O
+sulphate	O
+ester	O
+(	O
+CCK	O
+-	O
+8	O
+-	O
+SE	O
+)	O
+and	O
+nonsulphated	O
+cholecystokinin	O
+octapeptide	O
+(	O
+CCK	O
+-	O
+8	O
+-	O
+NS	O
+)	O
+enhanced	O
+the	O
+latency	O
+of	O
+seizures	B-NP
+induced	O
+by	O
+picrotoxin	O
+in	O
+mice	O
+.	O
+	
+Experiments	O
+with	O
+N	O
+-	O
+and	O
+C	O
+-	O
+terminal	O
+fragments	O
+revealed	O
+that	O
+the	O
+C	O
+-	O
+terminal	O
+tetrapeptide	O
+(	O
+CCK	O
+-	O
+5	O
+-	O
+8	O
+)	O
+was	O
+the	O
+active	O
+centre	O
+of	O
+the	O
+CCK	O
+octapeptide	O
+molecule	O
+.	O
+	
+The	O
+analogues	O
+CCK	O
+-	O
+8	O
+-	O
+SE	O
+and	O
+CCK	O
+-	O
+8	O
+-	O
+NS	O
+(	O
+dose	O
+range	O
+0	O
+.	O
+2	O
+-	O
+6	O
+.	O
+4	O
+mumol	O
+/	O
+kg	O
+)	O
+and	O
+caerulein	O
+dose	O
+range	O
+0	O
+.	O
+1	O
+-	O
+0	O
+.	O
+8	O
+mumol	O
+/	O
+kg	O
+)	O
+showed	O
+bell	O
+-	O
+shaped	O
+dose	O
+-	O
+effect	O
+curves	O
+","	O
+with	O
+the	O
+greatest	O
+maximum	O
+inhibition	O
+for	O
+CCK	O
+-	O
+8	O
+-	O
+NS	O
+.	O
+	
+The	O
+peptide	O
+CCK	O
+-	O
+5	O
+-	O
+8	O
+had	O
+weak	O
+anticonvulsant	O
+activity	O
+in	O
+comparison	O
+to	O
+the	O
+octapeptides	O
+","	O
+3	O
+.	O
+2	O
+mumol	O
+/	O
+kg	O
+and	O
+larger	O
+doses	O
+of	O
+the	O
+reference	O
+drug	O
+","	O
+diazepam	O
+","	O
+totally	O
+prevented	O
+picrotoxin	O
+-	O
+induced	O
+seizures	B-NP
+and	O
+mortality	O
+.	O
+	
+The	O
+maximum	O
+effect	O
+of	O
+the	O
+peptides	O
+tested	O
+was	O
+less	O
+than	O
+that	O
+of	O
+diazepam	O
+.	O
+	
+Experiments	O
+with	O
+analogues	O
+and	O
+derivatives	O
+of	O
+CCK	O
+-	O
+5	O
+-	O
+8	O
+demonstrated	O
+that	O
+the	O
+effectiveness	O
+of	O
+the	O
+beta	O
+-	O
+alanyl	O
+derivatives	O
+of	O
+CCK	O
+-	O
+5	O
+-	O
+8	O
+were	O
+enhanced	O
+and	O
+that	O
+they	O
+were	O
+equipotent	O
+with	O
+CCK	O
+-	O
+8	O
+-	O
+SE	O
+.	O
+	
+Of	O
+the	O
+CCK	O
+-	O
+2	O
+-	O
+8	O
+analogues	O
+","	O
+Ser	O
+(	O
+SO3H	O
+)	O
+7	O
+-	O
+Ac	O
+-	O
+CCK	O
+-	O
+2	O
+-	O
+8	O
+-	O
+SE	O
+and	O
+Thr	O
+(	O
+SO3H	O
+)	O
+7	O
+-	O
+Ac	O
+-	O
+CCK	O
+-	O
+2	O
+-	O
+8	O
+-	O
+SE	O
+and	O
+Hyp	O
+(	O
+SO3H	O
+)	O
+-	O
+Ac	O
+-	O
+CCK	O
+-	O
+2	O
+-	O
+8	O
+-	O
+SE	O
+were	O
+slightly	O
+more	O
+active	O
+than	O
+CCK	O
+-	O
+8	O
+-	O
+SE	O
+.	O
+	
+Vasopressin	O
+as	O
+a	O
+possible	O
+contributor	O
+to	O
+hypertension	B-NP
+.	O
+	
+The	O
+role	O
+of	O
+vasopressin	O
+as	O
+a	O
+pressor	O
+agent	O
+to	O
+the	O
+hypertensive	B-NP
+process	O
+was	O
+examined	O
+.	O
+	
+Vasopressin	O
+plays	O
+a	O
+major	O
+role	O
+in	O
+the	O
+pathogenesis	O
+of	O
+DOCA	O
+-	O
+salt	O
+hypertension	B-NP
+","	O
+since	O
+the	O
+elevation	O
+of	O
+blood	O
+pressure	O
+was	O
+not	O
+substantial	O
+in	O
+the	O
+rats	O
+with	O
+lithium	O
+-	O
+treated	O
+diabetes	B-NP
+insipidus	I-NP
+after	O
+DOCA	O
+-	O
+salt	O
+treatment	O
+.	O
+	
+Administration	O
+of	O
+DDAVP	O
+which	O
+has	O
+antidiuretic	O
+action	O
+but	O
+minimal	O
+vasopressor	O
+effect	O
+failed	O
+to	O
+increase	O
+blood	O
+pressure	O
+to	O
+the	O
+levels	O
+observed	O
+after	O
+administration	O
+of	O
+AVP	O
+.	O
+	
+Furthermore	O
+","	O
+the	O
+pressor	O
+action	O
+of	O
+vasopressin	O
+appears	O
+to	O
+be	O
+important	O
+in	O
+the	O
+development	O
+of	O
+this	O
+model	O
+of	O
+hypertension	B-NP
+","	O
+since	O
+the	O
+enhanced	O
+pressor	O
+responsiveness	O
+to	O
+the	O
+hormone	O
+was	O
+observed	O
+in	O
+the	O
+initial	O
+stage	O
+of	O
+hypertension	B-NP
+.	O
+	
+Increased	O
+secretion	O
+of	O
+vasopressin	O
+from	O
+neurohypophysis	O
+also	O
+promotes	O
+the	O
+function	O
+of	O
+the	O
+hormone	O
+as	O
+a	O
+pathogenetic	O
+factor	O
+in	O
+hypertension	B-NP
+.	O
+	
+An	O
+unproportional	O
+release	O
+of	O
+vasopressin	O
+compared	O
+to	O
+plasma	O
+osmolality	O
+may	O
+be	O
+induced	O
+by	O
+the	O
+absence	O
+of	O
+an	O
+adjusting	O
+control	O
+of	O
+angiotensin	O
+II	O
+forming	O
+and	O
+receptor	O
+binding	O
+capacity	O
+for	O
+sodium	O
+balance	O
+in	O
+the	O
+brain	O
+.	O
+	
+However	O
+","	O
+the	O
+role	O
+of	O
+vasopressin	O
+remains	O
+to	O
+be	O
+determined	O
+in	O
+human	O
+essential	O
+hypertension	B-NP
+.	O
+	
+Toxic	B-NP
+hepatitis	I-NP
+induced	O
+by	O
+disulfiram	O
+in	O
+a	O
+non	O
+-	O
+alcoholic	O
+.	O
+	
+A	O
+reversible	O
+toxic	B-NP
+liver	I-NP
+damage	I-NP
+was	O
+observed	O
+in	O
+a	O
+non	O
+-	O
+alcoholic	O
+woman	O
+treated	O
+with	O
+disulfiram	O
+.	O
+	
+The	O
+causative	O
+relationship	O
+was	O
+proven	O
+by	O
+challenge	O
+.	O
+	
+Atrial	B-NP
+thrombosis	I-NP
+involving	O
+the	O
+heart	O
+of	O
+F	O
+-	O
+344	O
+rats	O
+ingesting	O
+quinacrine	O
+hydrochloride	O
+.	O
+	
+Quinacrine	O
+hydrochloride	O
+is	O
+toxic	O
+for	O
+the	O
+heart	O
+of	O
+F	O
+-	O
+344	O
+rats	O
+.	O
+	
+Rats	O
+treated	O
+with	O
+500	O
+ppm	O
+quinacrine	O
+hydrochloride	O
+in	O
+the	O
+diet	O
+all	O
+developed	O
+a	O
+high	O
+incidence	O
+of	O
+left	O
+atrial	B-NP
+thrombosis	I-NP
+.	O
+	
+The	O
+lesion	O
+was	O
+associated	O
+with	O
+cardiac	B-NP
+hypertrophy	I-NP
+and	O
+dilatation	O
+and	O
+focal	O
+myocardial	B-NP
+degeneration	I-NP
+.	O
+	
+Rats	O
+died	O
+from	O
+cardiac	B-NP
+hypertrophy	I-NP
+with	O
+severe	O
+acute	O
+and	O
+chronic	O
+congestion	O
+of	O
+the	O
+lungs	O
+","	O
+liver	O
+","	O
+and	O
+other	O
+organs	O
+.	O
+	
+Seventy	O
+percent	O
+of	O
+rats	O
+given	O
+250	O
+ppm	O
+quinacrine	O
+hydrochloride	O
+and	O
+1	O
+","	O
+0	O
+ppm	O
+sodium	O
+nitrite	O
+simultaneously	O
+in	O
+the	O
+diet	O
+had	O
+thrombosis	B-NP
+of	O
+the	O
+atria	O
+of	O
+the	O
+heart	O
+","	O
+while	O
+untreated	O
+control	O
+rats	O
+in	O
+this	O
+laboratory	O
+did	O
+not	O
+have	O
+atrial	B-NP
+thrombosis	I-NP
+.	O
+	
+Sodium	O
+nitrite	O
+in	O
+combination	O
+with	O
+quinacrine	O
+hydrochloride	O
+appeared	O
+to	O
+have	O
+no	O
+additional	O
+effect	O
+.	O
+	
+Alternating	B-NP
+sinus	I-NP
+rhythm	I-NP
+and	O
+intermittent	O
+sinoatrial	B-NP
+block	I-NP
+induced	O
+by	O
+propranolol	O
+.	O
+	
+Alternating	B-NP
+sinus	I-NP
+rhythm	I-NP
+and	O
+intermittent	O
+sinoatrial	B-NP
+(	I-NP
+S	I-NP
+-	I-NP
+A	I-NP
+)	I-NP
+block	I-NP
+was	O
+observed	O
+in	O
+a	O
+57	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+","	O
+under	O
+treatment	O
+for	O
+angina	B-NP
+with	O
+80	O
+mg	O
+propranolol	O
+daily	O
+.	O
+	
+The	O
+electrocardiogram	O
+showed	O
+alternation	O
+of	O
+long	O
+and	O
+short	O
+P	O
+-	O
+P	O
+intervals	O
+and	O
+occasional	O
+pauses	O
+.	O
+	
+These	O
+pauses	O
+were	O
+always	O
+preceded	O
+by	O
+the	O
+short	O
+P	O
+-	O
+P	O
+intervals	O
+and	O
+were	O
+usually	O
+followed	O
+by	O
+one	O
+or	O
+two	O
+P	O
+-	O
+P	O
+intervals	O
+of	O
+0	O
+.	O
+92	O
+-	O
+0	O
+.	O
+95	O
+s	O
+representing	O
+the	O
+basic	O
+sinus	O
+cycle	O
+.	O
+	
+Following	O
+these	O
+basic	O
+sinus	O
+cycles	O
+","	O
+alternating	B-NP
+rhythm	I-NP
+started	O
+with	O
+the	O
+longer	O
+P	O
+-	O
+P	O
+interval	O
+.	O
+	
+The	O
+long	O
+P	O
+-	O
+P	O
+intervals	O
+ranged	O
+between	O
+1	O
+.	O
+4	O
+-	O
+1	O
+.	O
+12	O
+s	O
+and	O
+the	O
+short	O
+P	O
+-	O
+P	O
+intervals	O
+between	O
+0	O
+.	O
+80	O
+-	O
+0	O
+.	O
+84	O
+s	O
+","	O
+respectively	O
+.	O
+	
+The	O
+duration	O
+of	O
+the	O
+pauses	O
+were	O
+equal	O
+or	O
+almost	O
+equal	O
+to	O
+one	O
+short	O
+plus	O
+one	O
+long	O
+P	O
+-	O
+P	O
+interval	O
+or	O
+to	O
+twice	O
+the	O
+basic	O
+sinus	O
+cycle	O
+.	O
+	
+In	O
+one	O
+recording	O
+a	O
+short	O
+period	O
+of	O
+regular	O
+sinus	O
+rhythm	O
+with	O
+intermittent	O
+2	O
+/	O
+1	O
+S	B-NP
+-	I-NP
+A	I-NP
+block	I-NP
+was	O
+observed	O
+.	O
+	
+This	O
+short	O
+period	O
+of	O
+sinus	O
+rhythm	O
+was	O
+interrupted	O
+by	O
+sudden	O
+prolongation	O
+of	O
+the	O
+P	O
+-	O
+P	O
+interval	O
+starting	O
+the	O
+alternative	O
+rhythm	O
+.	O
+	
+There	O
+were	O
+small	O
+changes	O
+in	O
+the	O
+shape	O
+of	O
+the	O
+P	O
+waves	O
+and	O
+P	O
+-	O
+R	O
+intervals	O
+.	O
+	
+S	O
+-	O
+A	O
+conduction	O
+through	O
+two	O
+pathways	O
+","	O
+the	O
+first	O
+with	O
+2	O
+/	O
+1	O
+block	O
+the	O
+second	O
+having	O
+0	O
+.	O
+12	O
+-	O
+0	O
+.	O
+14	O
+s	O
+longer	O
+conduction	O
+time	O
+and	O
+with	O
+occasional	O
+2	O
+/	O
+1	O
+block	O
+was	O
+proposed	O
+for	O
+the	O
+explanation	O
+of	O
+the	O
+alternating	O
+P	O
+-	O
+P	O
+interval	O
+and	O
+other	O
+electrocardiographic	O
+features	O
+seen	O
+.	O
+	
+Atropine	O
+1	O
+mg	O
+given	O
+intravenously	O
+resulted	O
+in	O
+shortening	O
+of	O
+all	O
+P	O
+-	O
+P	O
+intervals	O
+without	O
+changing	O
+the	O
+rhythm	O
+.	O
+	
+The	O
+abnormal	O
+rhythm	O
+disappeared	O
+with	O
+the	O
+withdrawal	O
+of	O
+propranolol	O
+and	O
+when	O
+the	O
+drug	O
+was	O
+restarted	O
+a	O
+2	O
+/	O
+1	O
+S	B-NP
+-	I-NP
+A	I-NP
+block	I-NP
+was	O
+seen	O
+.	O
+	
+This	O
+was	O
+accepted	O
+as	O
+evidence	O
+for	O
+propranolol	O
+being	O
+the	O
+cause	O
+of	O
+this	O
+conduction	B-NP
+disorder	I-NP
+.	O
+	
+Antitumor	O
+effect	O
+","	O
+cardiotoxicity	B-NP
+","	O
+and	O
+nephrotoxicity	B-NP
+of	O
+doxorubicin	O
+in	O
+the	O
+IgM	O
+solid	O
+immunocytoma	B-NP
+-	O
+bearing	O
+LOU	O
+/	O
+M	O
+/	O
+WSL	O
+rat	O
+.	O
+	
+Antitumor	O
+activity	O
+","	O
+cardiotoxicity	B-NP
+","	O
+and	O
+nephrotoxicity	B-NP
+induced	O
+by	O
+doxorubicin	O
+were	O
+studied	O
+in	O
+LOU	O
+/	O
+M	O
+/	O
+WSL	O
+inbred	O
+rats	O
+each	O
+bearing	O
+a	O
+transplantable	O
+solid	O
+IgM	O
+immunocytoma	B-NP
+.	O
+	
+Animals	O
+with	O
+a	O
+tumor	B-NP
+(	O
+diameter	O
+","	O
+15	O
+.	O
+8	O
++	O
+/	O
+-	O
+3	O
+.	O
+3	O
+mm	O
+)	O
+were	O
+treated	O
+with	O
+iv	O
+injections	O
+of	O
+doxorubicin	O
+on	O
+5	O
+consecutive	O
+days	O
+","	O
+followed	O
+by	O
+1	O
+weekly	O
+injection	O
+for	O
+7	O
+weeks	O
+(	O
+dose	O
+range	O
+","	O
+0	O
+.	O
+15	O
+-	O
+4	O
+.	O
+0	O
+mg	O
+/	O
+kg	O
+body	O
+wt	O
+)	O
+.	O
+	
+Tumor	B-NP
+regression	O
+was	O
+observed	O
+with	O
+0	O
+.	O
+5	O
+mg	O
+doxorubicin	O
+/	O
+kg	O
+.	O
+	
+Complete	O
+disappearance	O
+of	O
+the	O
+tumor	B-NP
+was	O
+induced	O
+with	O
+1	O
+.	O
+0	O
+mg	O
+doxorubicin	O
+/	O
+kg	O
+.	O
+	
+Histologic	O
+evidence	O
+of	O
+cardiotoxicity	B-NP
+scored	O
+as	O
+grade	O
+III	O
+was	O
+only	O
+observed	O
+at	O
+a	O
+dose	O
+of	O
+1	O
+.	O
+0	O
+mg	O
+doxorubicin	O
+/	O
+kg	O
+.	O
+	
+Light	O
+microscopic	O
+evidence	O
+of	O
+renal	B-NP
+damage	I-NP
+was	O
+seen	O
+above	O
+a	O
+dose	O
+of	O
+0	O
+.	O
+5	O
+mg	O
+doxorubicin	O
+/	O
+kg	O
+","	O
+which	O
+resulted	O
+in	O
+albuminuria	B-NP
+and	O
+very	O
+low	O
+serum	O
+albumin	O
+levels	O
+.	O
+	
+In	O
+the	O
+group	O
+that	O
+received	O
+1	O
+.	O
+0	O
+mg	O
+doxorubicin	O
+/	O
+kg	O
+","	O
+the	O
+serum	O
+albumin	O
+level	O
+decreased	O
+from	O
+33	O
+.	O
+6	O
++	O
+/	O
+-	O
+4	O
+.	O
+1	O
+to	O
+1	O
+.	O
+5	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+g	O
+/	O
+liter	O
+.	O
+	
+Ascites	B-NP
+and	O
+hydrothorax	B-NP
+were	O
+observed	O
+simultaneously	O
+.	O
+	
+The	O
+same	O
+experiments	O
+were	O
+performed	O
+with	O
+non	O
+-	O
+tumor	B-NP
+-	O
+bearing	O
+rats	O
+","	O
+in	O
+which	O
+no	O
+major	O
+differences	O
+were	O
+observed	O
+.	O
+	
+In	O
+conclusion	O
+","	O
+antitumor	O
+activity	O
+","	O
+cardiotoxicity	B-NP
+","	O
+and	O
+nephrotoxicity	B-NP
+were	O
+studied	O
+simultaneously	O
+in	O
+the	O
+same	O
+LOU	O
+/	O
+M	O
+/	O
+WSL	O
+rat	O
+.	O
+	
+Albuminuria	B-NP
+due	O
+to	O
+renal	B-NP
+damage	I-NP
+led	O
+to	O
+extremely	O
+low	O
+serum	O
+albumin	O
+levels	O
+","	O
+so	O
+ascites	B-NP
+and	O
+hydrothorax	B-NP
+were	O
+not	O
+necessarily	O
+a	O
+consequence	O
+of	O
+the	O
+observed	O
+cardiomyopathy	B-NP
+.	O
+	
+Intraoperative	O
+bradycardia	B-NP
+and	O
+hypotension	B-NP
+associated	O
+with	O
+timolol	O
+and	O
+pilocarpine	O
+eye	O
+drops	O
+.	O
+	
+A	O
+69	O
+-	O
+yr	O
+-	O
+old	O
+man	O
+","	O
+who	O
+was	O
+concurrently	O
+being	O
+treated	O
+with	O
+pilocarpine	O
+nitrate	O
+and	O
+timolol	O
+maleate	O
+eye	O
+drops	O
+","	O
+developed	O
+a	O
+bradycardia	B-NP
+and	O
+became	O
+hypotensive	B-NP
+during	O
+halothane	O
+anaesthesia	O
+.	O
+	
+Both	O
+timolol	O
+and	O
+pilocarpine	O
+were	O
+subsequently	O
+identified	O
+in	O
+a	O
+24	O
+-	O
+h	O
+collection	O
+of	O
+urine	O
+.	O
+	
+Timolol	O
+(	O
+but	O
+not	O
+pilocarpine	O
+)	O
+was	O
+detected	O
+in	O
+a	O
+sample	O
+of	O
+plasma	O
+removed	O
+during	O
+surgery	O
+;	O
+the	O
+plasma	O
+concentration	O
+of	O
+timolol	O
+(	O
+2	O
+.	O
+6	O
+ng	O
+ml	O
+-	O
+1	O
+)	O
+was	O
+consistent	O
+with	O
+partial	O
+beta	O
+-	O
+adrenoceptor	O
+blockade	O
+.	O
+	
+It	O
+is	O
+postulated	O
+that	O
+this	O
+action	O
+may	O
+have	O
+been	O
+enhanced	O
+during	O
+halothane	O
+anaesthesia	O
+with	O
+resultant	O
+bradycardia	B-NP
+and	O
+hypotension	B-NP
+.	O
+	
+Pilocarpine	O
+may	O
+have	O
+had	O
+a	O
+contributory	O
+effect	O
+.	O
+	
+Succinylcholine	O
+apnoea	B-NP
+:	O
+attempted	O
+reversal	O
+with	O
+anticholinesterases	O
+.	O
+	
+Anticholinesterases	O
+were	O
+administered	O
+in	O
+an	O
+attempt	O
+to	O
+antagonize	O
+prolonged	O
+neuromuscular	B-NP
+blockade	I-NP
+following	O
+the	O
+administration	O
+of	O
+succinylcholine	O
+in	O
+a	O
+patient	O
+later	O
+found	O
+to	O
+be	O
+homozygous	O
+for	O
+atypical	O
+plasma	O
+cholinesterase	O
+.	O
+	
+Edrophonium	O
+10	O
+mg	O
+","	O
+given	O
+74	O
+min	O
+after	O
+succinylcholine	O
+","	O
+when	O
+train	O
+-	O
+of	O
+-	O
+four	O
+stimulation	O
+was	O
+characteristic	O
+of	O
+phase	O
+II	O
+block	O
+","	O
+produced	O
+partial	O
+antagonism	O
+which	O
+was	O
+not	O
+sustained	O
+.	O
+	
+Repeated	O
+doses	O
+of	O
+edrophonium	O
+to	O
+70	O
+mg	O
+and	O
+neostigmine	O
+to	O
+2	O
+.	O
+5	O
+mg	O
+did	O
+not	O
+antagonize	O
+or	O
+augment	O
+the	O
+block	O
+.	O
+	
+Spontaneous	O
+respiration	O
+recommenced	O
+200	O
+min	O
+after	O
+succinylcholine	O
+administration	O
+.	O
+	
+It	O
+is	O
+concluded	O
+that	O
+anticholinesterases	O
+are	O
+only	O
+partially	O
+effective	O
+in	O
+restoring	O
+neuromuscular	O
+function	O
+in	O
+succinylcholine	O
+apnoea	B-NP
+despite	O
+muscle	O
+twitch	O
+activity	O
+typical	O
+of	O
+phase	O
+II	O
+block	O
+.	O
+	
+Effect	O
+of	O
+doxorubicin	O
+on	O
+[	O
+omega	O
+-	O
+I	O
+-	O
+131	O
+]	O
+heptadecanoic	O
+acid	O
+myocardial	O
+scintigraphy	O
+and	O
+echocardiography	O
+in	O
+dogs	O
+.	O
+	
+The	O
+effects	O
+of	O
+serial	O
+treatment	O
+with	O
+doxorubicin	O
+on	O
+dynamic	O
+myocardial	O
+scintigraphy	O
+with	O
+[	O
+omega	O
+-	O
+I	O
+-	O
+131	O
+]	O
+heptadecanoic	O
+acid	O
+(	O
+I	O
+-	O
+131	O
+HA	O
+)	O
+","	O
+and	O
+on	O
+global	O
+left	O
+-	O
+ventricular	O
+function	O
+determined	O
+echocardiographically	O
+","	O
+were	O
+studied	O
+in	O
+a	O
+group	O
+of	O
+nine	O
+mongrel	O
+dogs	O
+.	O
+	
+Total	O
+extractable	O
+myocardial	O
+lipid	O
+was	O
+compared	O
+postmortem	O
+between	O
+a	O
+group	O
+of	O
+control	O
+dogs	O
+and	O
+doxorubicin	O
+-	O
+treated	O
+dogs	O
+.	O
+	
+A	O
+significant	O
+and	O
+then	O
+progressive	O
+fall	O
+in	O
+global	O
+LV	O
+function	O
+was	O
+observed	O
+at	O
+a	O
+cumulative	O
+doxorubicin	O
+dose	O
+of	O
+4	O
+mg	O
+/	O
+kg	O
+.	O
+	
+A	O
+significant	O
+increase	O
+in	O
+the	O
+myocardial	O
+t1	O
+/	O
+2	O
+of	O
+the	O
+I	O
+-	O
+131	O
+HA	O
+was	O
+observed	O
+only	O
+at	O
+a	O
+higher	O
+cumulative	O
+dose	O
+","	O
+10	O
+mg	O
+/	O
+kg	O
+.	O
+	
+No	O
+significant	O
+alteration	O
+in	O
+total	O
+extractable	O
+myocardial	O
+lipids	O
+was	O
+observed	O
+between	O
+control	O
+dogs	O
+and	O
+those	O
+treated	O
+with	O
+doxorubicin	O
+.	O
+	
+Our	O
+findings	O
+suggest	O
+that	O
+the	O
+changes	O
+leading	O
+to	O
+an	O
+alteration	O
+of	O
+myocardial	O
+dynamic	O
+imaging	O
+with	O
+I	O
+-	O
+131	O
+HA	O
+are	O
+not	O
+the	O
+initiating	O
+factor	O
+in	O
+doxorubicin	O
+cardiotoxicity	B-NP
+.	O
+	
+Hemodynamics	O
+and	O
+myocardial	O
+metabolism	O
+under	O
+deliberate	O
+hypotension	B-NP
+.	O
+	
+An	O
+experimental	O
+study	O
+in	O
+dogs	O
+.	O
+	
+Coronary	O
+blood	O
+flow	O
+","	O
+cardiac	O
+work	O
+and	O
+metabolism	O
+were	O
+studied	O
+in	O
+dogs	O
+under	O
+sodium	O
+nitroprusside	O
+(	O
+SNP	O
+)	O
+and	O
+trimetaphan	O
+(	O
+TMP	O
+)	O
+deliberate	O
+hypotension	B-NP
+(	O
+20	O
+%	O
+and	O
+40	O
+%	O
+mean	O
+pressure	O
+decrease	O
+from	O
+baseline	O
+)	O
+.	O
+	
+Regarding	O
+the	O
+effects	O
+of	O
+drug	O
+-	O
+induced	O
+hypotension	B-NP
+on	O
+coronary	O
+blood	O
+flow	O
+","	O
+aortic	O
+and	O
+coronary	O
+sinus	O
+metabolic	O
+data	O
+(	O
+pH	O
+","	O
+pO2	O
+","	O
+pCO2	O
+)	O
+we	O
+could	O
+confirm	O
+that	O
+nitroprusside	O
+hypotension	B-NP
+could	O
+be	O
+safely	O
+used	O
+to	O
+30	O
+%	O
+mean	O
+blood	O
+pressure	O
+decrease	O
+from	O
+control	O
+","	O
+trimetaphan	O
+hypotension	B-NP
+to	O
+20	O
+%	O
+mean	O
+blood	O
+pressure	O
+decrease	O
+.	O
+	
+Cardiac	O
+work	O
+was	O
+significantly	O
+reduced	O
+during	O
+SNP	O
+hypotension	B-NP
+.	O
+	
+Myocardial	O
+O2	O
+consumption	O
+and	O
+O2	O
+availability	O
+were	O
+directly	O
+dependent	O
+on	O
+the	O
+coronary	O
+perfusion	O
+.	O
+	
+Careful	O
+invasive	O
+monitoring	O
+of	O
+the	O
+blood	O
+pressure	O
+","	O
+blood	O
+gases	O
+and	O
+of	O
+the	O
+ECG	O
+ST	O
+-	O
+T	O
+segment	O
+is	O
+mandatory	O
+.	O
+	
+Evidence	O
+for	O
+a	O
+selective	O
+brain	O
+noradrenergic	O
+involvement	O
+in	O
+the	O
+locomotor	O
+stimulant	O
+effects	O
+of	O
+amphetamine	O
+in	O
+the	O
+rat	O
+.	O
+	
+Male	O
+rats	O
+received	O
+the	O
+noradrenaline	O
+neurotoxin	O
+DSP4	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+)	O
+7	O
+days	O
+prior	O
+to	O
+injection	O
+of	O
+D	O
+-	O
+amphetamine	O
+(	O
+10	O
+or	O
+40	O
+mumol	O
+/	O
+kg	O
+i	O
+.	O
+p	O
+.	O
+)	O
+.	O
+	
+The	O
+hyperactivity	B-NP
+induced	O
+by	O
+D	O
+-	O
+amphetamine	O
+(	O
+10	O
+mumol	O
+/	O
+kg	O
+)	O
+was	O
+significantly	O
+reduced	O
+by	O
+DSP4	O
+pretreatment	O
+.	O
+	
+However	O
+","	O
+the	O
+increased	O
+rearings	O
+and	O
+the	O
+amphetamine	O
+-	O
+induced	O
+stereotypies	B-NP
+were	O
+not	O
+blocked	O
+by	O
+pretreatment	O
+with	O
+DSP4	O
+.	O
+	
+The	O
+reduction	O
+of	O
+amphetamine	O
+hyperactivity	B-NP
+induced	O
+by	O
+DSP4	O
+was	O
+blocked	O
+by	O
+pretreatment	O
+with	O
+the	O
+noradrenaline	O
+-	O
+uptake	O
+blocking	O
+agent	O
+","	O
+desipramine	O
+","	O
+which	O
+prevents	O
+the	O
+neurotoxic	B-NP
+action	O
+of	O
+DSP4	O
+.	O
+	
+The	O
+present	O
+results	O
+suggest	O
+a	O
+selective	O
+involvement	O
+of	O
+central	O
+noradrenergic	O
+neurones	O
+in	O
+the	O
+locomotor	O
+stimulant	O
+effect	O
+of	O
+amphetamine	O
+in	O
+the	O
+rat	O
+.	O
+	
+Accelerated	B-NP
+junctional	I-NP
+rhythms	I-NP
+during	O
+oral	O
+verapamil	O
+therapy	O
+.	O
+	
+This	O
+study	O
+examined	O
+the	O
+frequency	O
+of	O
+atrioventricular	O
+(	O
+AV	O
+)	O
+dissociation	O
+and	O
+accelerated	B-NP
+junctional	I-NP
+rhythms	I-NP
+in	O
+59	O
+patients	O
+receiving	O
+oral	O
+verapamil	O
+.	O
+	
+Accelerated	B-NP
+junctional	I-NP
+rhythms	I-NP
+and	O
+AV	O
+dissociation	O
+were	O
+frequent	O
+in	O
+patients	O
+with	O
+supraventricular	B-NP
+tachyarrhythmias	I-NP
+","	O
+particularly	O
+AV	O
+nodal	O
+reentry	O
+.	O
+	
+Verapamil	O
+administration	O
+to	O
+these	O
+patients	O
+led	O
+to	O
+an	O
+asymptomatic	O
+increase	O
+in	O
+activity	O
+of	O
+these	O
+junctional	O
+pacemakers	O
+.	O
+	
+In	O
+patients	O
+with	O
+various	O
+chest	B-NP
+pain	I-NP
+syndromes	O
+","	O
+verapamil	O
+neither	O
+increased	O
+the	O
+frequency	O
+of	O
+junctional	O
+rhythms	O
+nor	O
+suppressed	O
+their	O
+role	O
+as	O
+escape	O
+rhythms	O
+under	O
+physiologically	O
+appropriate	O
+circumstances	O
+.	O
+	
+Interstrain	O
+variation	O
+in	O
+acute	O
+toxic	O
+response	O
+to	O
+caffeine	O
+among	O
+inbred	O
+mice	O
+.	O
+	
+Acute	O
+toxic	O
+dosage	O
+-	O
+dependent	O
+behavioral	O
+effects	O
+of	O
+caffeine	O
+were	O
+compared	O
+in	O
+adult	O
+males	O
+from	O
+seven	O
+inbred	O
+mouse	O
+strains	O
+(	O
+A	O
+/	O
+J	O
+","	O
+BALB	O
+/	O
+cJ	O
+","	O
+CBA	O
+/	O
+J	O
+","	O
+C3H	O
+/	O
+HeJ	O
+","	O
+C57BL	O
+/	O
+6J	O
+","	O
+DBA	O
+/	O
+2J	O
+","	O
+SWR	O
+/	O
+J	O
+)	O
+.	O
+	
+C57BL	O
+/	O
+6J	O
+","	O
+chosen	O
+as	O
+a	O
+"	O
+prototypic	O
+"	O
+mouse	O
+strain	O
+","	O
+was	O
+used	O
+to	O
+determine	O
+behavioral	O
+responses	O
+to	O
+a	O
+broad	O
+range	O
+(	O
+5	O
+-	O
+500	O
+mg	O
+/	O
+kg	O
+)	O
+of	O
+caffeine	O
+doses	O
+.	O
+	
+Five	O
+phenotypic	O
+characteristics	O
+-	O
+-	O
+locomotor	O
+activity	O
+","	O
+righting	O
+ability	O
+","	O
+clonic	B-NP
+seizure	I-NP
+induction	O
+","	O
+stress	O
+-	O
+induced	O
+lethality	O
+","	O
+death	O
+without	O
+external	O
+stress	O
+-	O
+-	O
+were	O
+scored	O
+at	O
+various	O
+caffeine	O
+doses	O
+in	O
+drug	O
+-	O
+naive	O
+animals	O
+under	O
+empirically	O
+optimized	O
+","	O
+rigidly	O
+constant	O
+experimental	O
+conditions	O
+.	O
+	
+Mice	O
+(	O
+n	O
+=	O
+12	O
+for	O
+each	O
+point	O
+)	O
+received	O
+single	O
+IP	O
+injections	O
+of	O
+a	O
+fixed	O
+volume	O
+/	O
+g	O
+body	O
+weight	O
+of	O
+physiological	O
+saline	O
+carrier	O
+with	O
+or	O
+without	O
+caffeine	O
+in	O
+doses	O
+ranging	O
+from	O
+125	O
+-	O
+500	O
+mg	O
+/	O
+kg	O
+.	O
+	
+Loss	O
+of	O
+righting	O
+ability	O
+was	O
+scored	O
+at	O
+1	O
+","	O
+3	O
+","	O
+5	O
+min	O
+post	O
+dosing	O
+and	O
+at	O
+5	O
+min	O
+intervals	O
+thereafter	O
+for	O
+20	O
+min	O
+.	O
+	
+In	O
+the	O
+same	O
+animals	O
+the	O
+occurrence	O
+of	O
+clonic	B-NP
+seizures	I-NP
+was	O
+scored	O
+as	O
+to	O
+time	O
+of	O
+onset	O
+and	O
+severity	O
+for	O
+20	O
+min	O
+after	O
+drug	O
+administration	O
+.	O
+	
+When	O
+these	O
+proceeded	O
+to	O
+tonic	B-NP
+seizures	I-NP
+","	O
+death	O
+occurred	O
+in	O
+less	O
+than	O
+20	O
+min	O
+.	O
+	
+Animals	O
+surviving	O
+for	O
+20	O
+min	O
+were	O
+immediately	O
+stressed	O
+by	O
+a	O
+swim	O
+test	O
+in	O
+25	O
+degrees	O
+C	O
+water	O
+","	O
+and	O
+death	O
+-	O
+producing	O
+tonic	B-NP
+seizures	I-NP
+were	O
+scored	O
+for	O
+2	O
+min	O
+.	O
+	
+In	O
+other	O
+animals	O
+locomotor	O
+activity	O
+was	O
+measured	O
+15	O
+or	O
+60	O
+min	O
+after	O
+caffeine	O
+administration	O
+.	O
+	
+By	O
+any	O
+single	O
+behavioral	O
+criterion	O
+or	O
+a	O
+combination	O
+of	O
+these	O
+criteria	O
+","	O
+marked	O
+differences	O
+in	O
+response	O
+to	O
+toxic	O
+caffeine	O
+doses	O
+were	O
+observed	O
+between	O
+strains	O
+.	O
+	
+These	O
+results	O
+indicate	O
+that	O
+behavioral	O
+toxicity	B-NP
+testing	O
+of	O
+alkylxanthines	O
+in	O
+a	O
+single	O
+mouse	O
+strain	O
+may	O
+be	O
+misleading	O
+and	O
+suggest	O
+that	O
+toxic	O
+responses	O
+of	O
+the	O
+central	O
+nervous	O
+system	O
+to	O
+this	O
+class	O
+of	O
+compounds	O
+are	O
+genetically	O
+influenced	O
+in	O
+mammals	O
+.	O
+	
+Treatment	O
+of	O
+ovarian	B-NP
+cancer	I-NP
+with	O
+a	O
+combination	O
+of	O
+cis	O
+-	O
+platinum	O
+","	O
+adriamycin	O
+","	O
+cyclophosphamide	O
+and	O
+hexamethylmelamine	O
+.	O
+	
+During	O
+the	O
+last	O
+2	O
+1	O
+/	O
+2	O
+years	O
+","	O
+38	O
+patients	O
+with	O
+ovarian	B-NP
+cancer	I-NP
+were	O
+treated	O
+with	O
+a	O
+combination	O
+of	O
+cisplatinum	O
+(	O
+CPDD	O
+)	O
+","	O
+50	O
+mg	O
+/	O
+m2	O
+","	O
+adriamycin	O
+","	O
+30	O
+mg	O
+/	O
+m2	O
+","	O
+cyclophosphamide	O
+","	O
+300	O
+mg	O
+/	O
+m2	O
+","	O
+on	O
+day	O
+1	O
+;	O
+and	O
+hexamethylmelamine	O
+(	O
+HMM	O
+)	O
+","	O
+6	O
+mg	O
+/	O
+kg	O
+daily	O
+","	O
+for	O
+14	O
+days	O
+.	O
+	
+Each	O
+course	O
+was	O
+repeated	O
+monthly	O
+.	O
+	
+2	O
+patients	O
+had	O
+stage	O
+II	O
+","	O
+14	O
+stage	O
+III	O
+and	O
+22	O
+stage	O
+IV	O
+disease	O
+.	O
+	
+14	O
+of	O
+the	O
+38	O
+patients	O
+were	O
+previously	O
+treated	O
+with	O
+chemotherapy	O
+","	O
+1	O
+with	O
+radiation	O
+","	O
+6	O
+with	O
+both	O
+chemotherapy	O
+and	O
+radiation	O
+","	O
+and	O
+17	O
+did	O
+not	O
+have	O
+any	O
+treatment	O
+before	O
+CPDD	O
+combination	O
+.	O
+	
+31	O
+of	O
+the	O
+38	O
+cases	O
+(	O
+81	O
+.	O
+5	O
+%	O
+)	O
+demonstrated	O
+objective	O
+responses	O
+lasting	O
+for	O
+2	O
+months	O
+or	O
+more	O
+.	O
+	
+These	O
+responses	O
+were	O
+partial	O
+in	O
+19	O
+and	O
+complete	O
+in	O
+12	O
+cases	O
+.	O
+	
+Hematologic	B-NP
+toxicity	I-NP
+was	O
+moderate	O
+and	O
+with	O
+reversible	O
+anemia	B-NP
+developing	O
+in	O
+71	O
+%	O
+of	O
+patients	O
+.	O
+	
+Gastrointestinal	O
+side	O
+effects	O
+from	O
+CPDD	O
+were	O
+universal	O
+.	O
+	
+HMM	O
+gastrointestinal	B-NP
+toxicity	I-NP
+necessitated	O
+discontinuation	O
+of	O
+the	O
+drug	O
+in	O
+5	O
+patients	O
+.	O
+	
+Severe	O
+nephrotoxicity	B-NP
+was	O
+observed	O
+in	O
+2	O
+patients	O
+but	O
+was	O
+reversible	O
+.	O
+	
+There	O
+were	O
+no	O
+drug	O
+-	O
+related	O
+deaths	O
+.	O
+	
+Nontraumatic	O
+dissecting	B-NP
+aneurysm	I-NP
+of	O
+the	O
+basilar	O
+artery	O
+.	O
+	
+A	O
+case	O
+of	O
+nontraumatic	O
+dissecting	B-NP
+aneurysm	I-NP
+of	O
+the	O
+basilar	O
+artery	O
+in	O
+association	O
+with	O
+hypertension	B-NP
+","	O
+smoke	O
+","	O
+and	O
+oral	O
+contraceptives	O
+is	O
+reported	O
+in	O
+a	O
+young	O
+female	O
+patient	O
+with	O
+a	O
+locked	B-NP
+-	I-NP
+in	I-NP
+syndrome	I-NP
+.	O
+	
+A	O
+method	O
+for	O
+the	O
+measurement	O
+of	O
+tremor	B-NP
+","	O
+and	O
+a	O
+comparison	O
+of	O
+the	O
+effects	O
+of	O
+tocolytic	O
+beta	O
+-	O
+mimetics	O
+.	O
+	
+A	O
+method	O
+permitting	O
+measurement	O
+of	O
+finger	O
+tremor	B-NP
+as	O
+a	O
+displacement	O
+-	O
+time	O
+curve	O
+is	O
+described	O
+","	O
+using	O
+a	O
+test	O
+system	O
+with	O
+simple	O
+amplitude	O
+calibration	O
+.	O
+	
+The	O
+coordinates	O
+of	O
+the	O
+inversion	O
+points	O
+of	O
+the	O
+displacement	O
+-	O
+time	O
+curves	O
+were	O
+transferred	O
+through	O
+graphical	O
+input	O
+equipment	O
+to	O
+punched	O
+tape	O
+.	O
+	
+By	O
+means	O
+of	O
+a	O
+computer	O
+program	O
+","	O
+periods	O
+and	O
+amplitudes	O
+of	O
+tremor	B-NP
+oscillations	O
+were	O
+calculated	O
+and	O
+classified	O
+.	O
+	
+The	O
+event	O
+frequency	O
+for	O
+each	O
+class	O
+of	O
+periods	O
+and	O
+amplitudes	O
+was	O
+determined	O
+.	O
+	
+The	O
+actions	O
+of	O
+fenoterol	O
+-	O
+hydrobromide	O
+","	O
+ritodrin	O
+-	O
+HCl	O
+and	O
+placebo	O
+given	O
+to	O
+10	O
+healthy	O
+subjects	O
+by	O
+intravenous	O
+infusion	O
+in	O
+a	O
+double	O
+-	O
+blind	O
+crossover	O
+study	O
+were	O
+tested	O
+by	O
+this	O
+method	O
+.	O
+	
+At	O
+therapeutic	O
+doses	O
+both	O
+substances	O
+raised	O
+the	O
+mean	O
+tremor	B-NP
+amplitude	O
+to	O
+about	O
+three	O
+times	O
+the	O
+control	O
+level	O
+.	O
+	
+At	O
+the	O
+same	O
+time	O
+","	O
+the	O
+mean	O
+period	O
+within	O
+each	O
+class	O
+of	O
+amplitudes	O
+shortened	O
+by	O
+10	O
+-	O
+-	O
+20	O
+ms	O
+","	O
+whereas	O
+the	O
+mean	O
+periods	O
+calculated	O
+from	O
+all	O
+oscillations	O
+together	O
+did	O
+not	O
+change	O
+significantly	O
+.	O
+	
+After	O
+the	O
+end	O
+of	O
+fenoterol	O
+-	O
+hydrobromide	O
+infusion	O
+","	O
+tremor	B-NP
+amplitudes	O
+decreased	O
+significantly	O
+faster	O
+than	O
+those	O
+following	O
+ritodrin	O
+-	O
+HCl	O
+infusion	O
+.	O
+	
+Propylthiouracil	O
+-	O
+induced	O
+hepatic	B-NP
+damage	I-NP
+.	O
+	
+Two	O
+cases	O
+of	O
+propylthiouracil	O
+-	O
+induced	O
+liver	B-NP
+damage	I-NP
+have	O
+been	O
+observed	O
+.	O
+	
+The	O
+first	O
+case	O
+is	O
+of	O
+an	O
+acute	O
+type	O
+of	O
+damage	O
+","	O
+proven	O
+by	O
+rechallenge	O
+;	O
+the	O
+second	O
+presents	O
+a	O
+clinical	O
+and	O
+histologic	O
+picture	O
+resembling	O
+chronic	B-NP
+active	I-NP
+hepatitis	I-NP
+","	O
+with	O
+spontaneous	O
+remission	O
+.	O
+	
+Studies	O
+on	O
+the	O
+bradycardia	B-NP
+induced	O
+by	O
+bepridil	O
+.	O
+	
+Bepridil	O
+","	O
+a	O
+novel	O
+active	O
+compound	O
+for	O
+prophylactic	O
+treatment	O
+of	O
+anginal	B-NP
+attacks	I-NP
+","	O
+induced	O
+persistent	O
+bradycardia	B-NP
+and	O
+a	O
+non	O
+-	O
+specific	O
+anti	O
+-	O
+tachycardial	B-NP
+effect	O
+","	O
+the	O
+mechanisms	O
+of	O
+which	O
+were	O
+investigated	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+.	O
+	
+In	O
+vitro	O
+perfusion	O
+of	O
+bepridil	O
+in	O
+the	O
+life	O
+-	O
+support	O
+medium	O
+for	O
+isolated	O
+sino	O
+-	O
+atrial	O
+tissue	O
+from	O
+rabbit	O
+heart	O
+","	O
+caused	O
+a	O
+reduction	O
+in	O
+action	O
+potential	O
+(	O
+AP	O
+)	O
+spike	O
+frequency	O
+(	O
+recorded	O
+by	O
+KCl	O
+microelectrodes	O
+)	O
+starting	O
+at	O
+doses	O
+of	O
+5	O
+X	O
+10	O
+(	O
+-	O
+6	O
+)	O
+M	O
+.	O
+	
+This	O
+effect	O
+was	O
+dose	O
+-	O
+dependent	O
+up	O
+to	O
+concentrations	O
+of	O
+5	O
+X	O
+10	O
+(	O
+-	O
+5	O
+)	O
+M	O
+","	O
+whereupon	O
+blockade	O
+of	O
+sinus	O
+activity	O
+set	O
+in	O
+.	O
+	
+Bepridil	O
+at	O
+a	O
+dose	O
+of	O
+5	O
+X	O
+10	O
+(	O
+-	O
+6	O
+)	O
+M	O
+","	O
+induced	O
+a	O
+concomitant	O
+reduction	O
+in	O
+AP	O
+amplitude	O
+(	O
+falling	O
+from	O
+71	O
++	O
+/	O
+-	O
+8	O
+mV	O
+to	O
+47	O
++	O
+/	O
+-	O
+6	O
+mV	O
+)	O
+","	O
+maximum	O
+systolic	O
+depolarization	O
+velocity	O
+(	O
+phase	O
+0	O
+)	O
+which	O
+fell	O
+from	O
+1	O
+.	O
+85	O
++	O
+/	O
+-	O
+0	O
+.	O
+35	O
+V	O
+/	O
+s	O
+to	O
+0	O
+.	O
+84	O
++	O
+/	O
+-	O
+0	O
+.	O
+28	O
+V	O
+/	O
+s	O
+","	O
+together	O
+with	O
+maximum	O
+diastolic	O
+depolarization	O
+velocity	O
+(	O
+phase	O
+4	O
+)	O
+which	O
+fell	O
+from	O
+38	O
++	O
+/	O
+-	O
+3	O
+mV	O
+/	O
+s	O
+to	O
+24	O
++	O
+/	O
+-	O
+5	O
+mV	O
+/	O
+s	O
+.	O
+	
+In	O
+vivo	O
+injection	O
+of	O
+bepridil	O
+at	O
+a	O
+dose	O
+of	O
+5	O
+mg	O
+/	O
+kg	O
+(	O
+i	O
+.	O
+v	O
+.	O
+)	O
+into	O
+6	O
+anaesthetized	O
+dogs	O
+which	O
+had	O
+undergone	O
+ablation	O
+of	O
+all	O
+the	O
+extrinsic	O
+cardiac	O
+afferent	O
+nerve	O
+supply	O
+","	O
+together	O
+with	O
+a	O
+bilateral	O
+medullo	O
+-	O
+adrenalectomy	O
+","	O
+caused	O
+a	O
+marked	O
+reduction	O
+in	O
+heart	O
+rate	O
+which	O
+fell	O
+from	O
+98	O
+.	O
+7	O
++	O
+/	O
+-	O
+4	O
+.	O
+2	O
+beats	O
+/	O
+min	O
+to	O
+76	O
++	O
+/	O
+-	O
+5	O
+.	O
+3	O
+beats	O
+/	O
+min	O
+sustained	O
+for	O
+more	O
+than	O
+45	O
+min	O
+.	O
+	
+It	O
+is	O
+concluded	O
+that	O
+bepridil	O
+reduces	O
+heart	O
+rate	O
+by	O
+acting	O
+directly	O
+on	O
+the	O
+sinus	O
+node	O
+.	O
+	
+This	O
+effect	O
+","	O
+which	O
+results	O
+in	O
+a	O
+flattening	O
+of	O
+the	O
+phase	O
+0	O
+and	O
+phase	O
+4	O
+slope	O
+","	O
+together	O
+with	O
+a	O
+longer	O
+AP	O
+duration	O
+","	O
+may	O
+be	O
+due	O
+to	O
+an	O
+increase	O
+in	O
+the	O
+time	O
+constants	O
+of	O
+slow	O
+inward	O
+ionic	O
+currents	O
+(	O
+already	O
+demonstrated	O
+elsewhere	O
+)	O
+","	O
+but	O
+also	O
+to	O
+an	O
+increased	O
+time	O
+constant	O
+for	O
+deactivation	O
+of	O
+the	O
+outward	O
+potassium	O
+current	O
+(	O
+Ip	O
+)	O
+.	O
+	
+Hepatitis	B-NP
+and	O
+renal	B-NP
+tubular	I-NP
+acidosis	I-NP
+after	O
+anesthesia	O
+with	O
+methoxyflurane	O
+.	O
+	
+A	O
+69	O
+-	O
+year	O
+-	O
+old	O
+man	O
+operated	O
+for	O
+acute	B-NP
+cholecystitis	I-NP
+under	O
+methoxyflurane	O
+anesthesia	O
+developed	O
+postoperatively	O
+a	O
+hepatic	B-NP
+insufficiency	I-NP
+syndrome	I-NP
+and	O
+renal	B-NP
+tubular	I-NP
+acidosis	I-NP
+.	O
+	
+Massive	O
+bleeding	B-NP
+appeared	O
+during	O
+surgery	O
+which	O
+lasted	O
+for	O
+six	O
+hours	O
+.	O
+	
+Postoperative	O
+evolution	O
+under	O
+supportive	O
+therapy	O
+was	O
+favourable	O
+.	O
+	
+Complete	O
+recovery	O
+was	O
+confirmed	O
+by	O
+repeated	O
+controls	O
+performed	O
+over	O
+a	O
+period	O
+of	O
+one	O
+year	O
+after	O
+surgery	O
+.	O
+	
+Pituitary	O
+response	O
+to	O
+luteinizing	O
+hormone	O
+-	O
+releasing	O
+hormone	O
+during	O
+haloperidol	O
+-	O
+induced	O
+hyperprolactinemia	B-NP
+.	O
+	
+The	O
+effects	O
+of	O
+a	O
+6	O
+-	O
+hour	O
+infusion	O
+with	O
+haloperidol	O
+on	O
+serum	O
+prolactin	O
+and	O
+luteinizing	O
+hormone	O
+(	O
+LH	O
+)	O
+levels	O
+was	O
+studied	O
+in	O
+a	O
+group	O
+of	O
+male	O
+subjects	O
+.	O
+	
+Five	O
+hours	O
+after	O
+starting	O
+the	O
+infusions	O
+","	O
+a	O
+study	O
+of	O
+the	O
+pituitary	O
+responses	O
+to	O
+LH	O
+-	O
+releasing	O
+hormone	O
+(	O
+LH	O
+-	O
+RH	O
+)	O
+was	O
+carried	O
+out	O
+.	O
+	
+Control	O
+patients	O
+received	O
+infusions	O
+of	O
+0	O
+.	O
+9	O
+%	O
+NaCl	O
+solution	O
+.	O
+	
+During	O
+the	O
+course	O
+of	O
+haloperidol	O
+infusions	O
+","	O
+significant	O
+hyperprolactinemia	B-NP
+was	O
+found	O
+","	O
+together	O
+with	O
+an	O
+abolished	O
+pituitary	O
+response	O
+to	O
+LH	O
+-	O
+RH	O
+","	O
+as	O
+compared	O
+with	O
+responses	O
+of	O
+control	O
+subjects	O
+.	O
+	
+Antirifampicin	O
+antibodies	O
+in	O
+acute	O
+rifampicin	O
+-	O
+associated	O
+renal	B-NP
+failure	I-NP
+.	O
+	
+5	O
+patients	O
+with	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+(	O
+3	O
+with	O
+thrombopenia	B-NP
+and	O
+hemolysis	B-NP
+)	O
+induced	O
+by	O
+the	O
+reintroduction	O
+of	O
+rifampicin	O
+are	O
+described	O
+.	O
+	
+No	O
+correlation	O
+was	O
+found	O
+between	O
+the	O
+severity	O
+of	O
+clinical	O
+manifestations	O
+and	O
+the	O
+total	O
+dose	O
+taken	O
+by	O
+the	O
+patients	O
+.	O
+	
+In	O
+all	O
+but	O
+1	O
+patient	O
+","	O
+antirifampicin	O
+antibodies	O
+were	O
+detected	O
+.	O
+	
+Antibodies	O
+suggested	O
+to	O
+be	O
+of	O
+the	O
+IgM	O
+class	O
+were	O
+detected	O
+in	O
+all	O
+3	O
+patients	O
+with	O
+hematological	B-NP
+disorders	I-NP
+.	O
+	
+The	O
+pattern	O
+of	O
+non	O
+-	O
+specific	O
+acute	B-NP
+tubular	I-NP
+necrosis	I-NP
+found	O
+in	O
+the	O
+2	O
+biopsied	O
+patients	O
+","	O
+indistinguishable	O
+from	O
+that	O
+of	O
+ischemic	O
+origin	O
+","	O
+raised	O
+the	O
+possibility	O
+of	O
+a	O
+vascular	O
+-	O
+mediated	O
+damage	O
+.	O
+	
+In	O
+3	O
+patients	O
+","	O
+the	O
+possibility	O
+of	O
+a	O
+triggering	O
+immunoallergic	O
+mechanism	O
+is	O
+discussed	O
+.	O
+	
+Cardiovascular	O
+effects	O
+of	O
+hypotension	B-NP
+induced	O
+by	O
+adenosine	O
+triphosphate	O
+and	O
+sodium	O
+nitroprusside	O
+on	O
+dogs	O
+with	O
+denervated	O
+hearts	O
+.	O
+	
+Adenosine	O
+triphosphate	O
+(	O
+ATP	O
+)	O
+and	O
+sodium	O
+nitroprusside	O
+(	O
+SNP	O
+)	O
+are	O
+administered	O
+to	O
+patients	O
+to	O
+induce	O
+and	O
+control	O
+hypotension	B-NP
+during	O
+anesthesia	O
+.	O
+	
+SNP	O
+is	O
+authorized	O
+for	O
+clinical	O
+use	O
+in	O
+USA	O
+and	O
+UK	O
+","	O
+and	O
+ATP	O
+is	O
+clinically	O
+used	O
+in	O
+other	O
+countries	O
+such	O
+as	O
+Japan	O
+.	O
+	
+We	O
+investigated	O
+how	O
+these	O
+two	O
+drugs	O
+act	O
+on	O
+the	O
+cardiovascular	O
+systems	O
+of	O
+20	O
+dogs	O
+whose	O
+hearts	O
+had	O
+been	O
+denervated	O
+by	O
+a	O
+procedure	O
+we	O
+had	O
+devised	O
+.	O
+	
+ATP	O
+(	O
+10	O
+dogs	O
+)	O
+or	O
+SNP	O
+(	O
+10	O
+dogs	O
+)	O
+was	O
+administered	O
+to	O
+reduce	O
+mean	O
+arterial	O
+pressure	O
+by	O
+30	O
+%	O
+to	O
+70	O
+%	O
+of	O
+control	O
+.	O
+	
+Before	O
+","	O
+during	O
+and	O
+after	O
+induced	O
+hypotension	B-NP
+","	O
+we	O
+measured	O
+major	O
+cardiovascular	O
+parameters	O
+.	O
+	
+Hypotension	B-NP
+induced	O
+by	O
+ATP	O
+was	O
+accompanied	O
+by	O
+significant	O
+decreases	O
+in	O
+mean	O
+pulmonary	O
+arterial	O
+pressure	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+central	O
+venous	O
+pressure	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+left	O
+ventricular	O
+end	O
+-	O
+diastolic	O
+pressure	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+total	O
+peripheral	O
+resistance	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+rate	O
+pressure	O
+product	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+total	O
+body	O
+oxygen	O
+consumption	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+","	O
+and	O
+heart	O
+rate	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+;	O
+all	O
+these	O
+variables	O
+returned	O
+normal	O
+within	O
+30	O
+min	O
+after	O
+ATP	O
+was	O
+stopped	O
+.	O
+	
+Cardiac	O
+output	O
+did	O
+not	O
+change	O
+.	O
+	
+During	O
+hypotension	B-NP
+produced	O
+by	O
+SNP	O
+similar	O
+decreases	O
+were	O
+observed	O
+in	O
+mean	O
+pulmonary	O
+arterial	O
+pressure	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+central	O
+venous	O
+pressure	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+left	O
+ventricular	O
+end	O
+-	O
+diastolic	O
+pressure	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+total	O
+peripheral	O
+resistance	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+rate	O
+pressure	O
+product	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+","	O
+and	O
+oxygen	O
+content	O
+difference	O
+between	O
+arterial	O
+and	O
+mixed	O
+venous	O
+blood	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+","	O
+while	O
+heart	O
+rate	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+1	O
+)	O
+and	O
+cardiac	O
+output	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+were	O
+increased	O
+.	O
+	
+Recoveries	O
+of	O
+heart	O
+rate	O
+and	O
+left	O
+ventricular	O
+end	O
+-	O
+diastolic	O
+pressure	O
+were	O
+not	O
+shown	O
+within	O
+60	O
+min	O
+after	O
+SNP	O
+had	O
+been	O
+stopped	O
+.	O
+	
+Both	O
+ATP	O
+and	O
+SNP	O
+should	O
+act	O
+on	O
+the	O
+pacemaker	O
+tissue	O
+of	O
+the	O
+heart	O
+.	O
+	
+Comparative	O
+study	O
+:	O
+Endografine	O
+(	O
+diatrizoate	O
+)	O
+","	O
+Vasurix	O
+polyvidone	O
+(	O
+acetrizoate	O
+)	O
+","	O
+Dimer	O
+-	O
+X	O
+(	O
+iocarmate	O
+)	O
+and	O
+Hexabrix	O
+(	O
+ioxaglate	O
+)	O
+in	O
+hysterosalpingography	O
+.	O
+	
+Side	O
+effects	O
+of	O
+hysterosalpingography	O
+with	O
+Dimer	O
+-	O
+X	O
+","	O
+Hexabrix	O
+","	O
+Vasurix	O
+polyvidone	O
+and	O
+Endografine	O
+in	O
+142	O
+consecutive	O
+patients	O
+","	O
+receiving	O
+one	O
+of	O
+the	O
+four	O
+tested	O
+media	O
+were	O
+evaluated	O
+from	O
+replies	O
+to	O
+postal	O
+questionnaires	O
+.	O
+	
+The	O
+Dimer	O
+-	O
+X	O
+group	O
+had	O
+a	O
+higher	O
+incidence	O
+of	O
+nausea	B-NP
+and	O
+dizziness	B-NP
+.	O
+	
+The	O
+Endografine	O
+group	O
+had	O
+a	O
+higher	O
+incidence	O
+of	O
+abdominal	B-NP
+pain	I-NP
+.	O
+	
+These	O
+differences	O
+occur	O
+especially	O
+in	O
+the	O
+age	O
+groups	O
+under	O
+30	O
+years	O
+.	O
+	
+Hexabrix	O
+and	O
+Vasurix	O
+polyvidone	O
+are	O
+considered	O
+the	O
+best	O
+contrast	O
+media	O
+for	O
+hysterosalpingography	O
+and	O
+perhaps	O
+because	O
+of	O
+its	O
+low	O
+toxicity	B-NP
+Hexabrix	O
+should	O
+be	O
+preferred	O
+.	O
+	
+Post	O
+-	O
+suxamethonium	O
+pains	B-NP
+in	O
+Nigerian	O
+surgical	O
+patients	O
+.	O
+	
+Contrary	O
+to	O
+an	O
+earlier	O
+report	O
+by	O
+Coxon	O
+","	O
+scoline	O
+pain	B-NP
+occurs	O
+in	O
+African	O
+negroes	O
+.	O
+	
+Its	O
+incidence	O
+was	O
+determined	O
+in	O
+a	O
+prospective	O
+study	O
+involving	O
+a	O
+total	O
+of	O
+100	O
+Nigerian	O
+patients	O
+(	O
+50	O
+out	O
+-	O
+patients	O
+and	O
+50	O
+in	O
+-	O
+patients	O
+)	O
+.	O
+	
+About	O
+62	O
+%	O
+of	O
+the	O
+out	O
+-	O
+patients	O
+developed	O
+scoline	O
+pain	B-NP
+as	O
+compared	O
+with	O
+about	O
+26	O
+%	O
+among	O
+the	O
+in	O
+-	O
+patients	O
+.	O
+	
+The	O
+abolition	O
+of	O
+muscle	O
+fasciculations	B-NP
+(	O
+by	O
+0	O
+.	O
+075mg	O
+/	O
+kg	O
+dose	O
+of	O
+Fazadinium	O
+)	O
+did	O
+not	O
+influence	O
+the	O
+occurrence	O
+of	O
+scoline	O
+pain	B-NP
+.	O
+	
+Neither	O
+the	O
+type	O
+of	O
+induction	O
+agent	O
+(	O
+Althesin	O
+or	O
+Thiopentone	O
+)	O
+nor	O
+the	O
+salt	O
+preparation	O
+of	O
+suxamethonium	O
+used	O
+(	O
+chloride	O
+or	O
+bromide	O
+)	O
+","	O
+affected	O
+the	O
+incidence	O
+of	O
+scoline	O
+pain	B-NP
+.	O
+	
+Invasive	O
+carcinoma	B-NP
+of	I-NP
+the	I-NP
+renal	I-NP
+pelvis	I-NP
+following	O
+cyclophosphamide	O
+therapy	O
+for	O
+nonmalignant	O
+disease	O
+.	O
+	
+A	O
+47	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+right	O
+hydroureteronephrosis	B-NP
+due	O
+to	O
+ureterovesical	O
+junction	O
+obstruction	O
+had	O
+gross	O
+hematuria	B-NP
+after	O
+being	O
+treated	O
+for	O
+five	O
+years	O
+wtih	O
+cyclophosphamide	O
+for	O
+cerebral	B-NP
+vasculitis	I-NP
+.	O
+	
+A	O
+right	O
+nephroureterectomy	O
+was	O
+required	O
+for	O
+control	O
+of	O
+bleeding	B-NP
+.	O
+	
+The	O
+pathology	O
+specimen	O
+contained	O
+clinically	O
+occult	O
+invasive	O
+carcinoma	B-NP
+of	I-NP
+the	I-NP
+renal	I-NP
+pelvis	I-NP
+.	O
+	
+Although	O
+the	O
+ability	O
+of	O
+cyclophosphamide	O
+to	O
+cause	O
+hemorrhagic	B-NP
+cystitis	I-NP
+and	O
+urine	O
+cytologic	O
+abnormalities	O
+indistinguishable	O
+from	O
+high	O
+grade	O
+carcinoma	B-NP
+is	O
+well	O
+known	O
+","	O
+it	O
+is	O
+less	O
+widely	O
+appreciated	O
+that	O
+it	O
+is	O
+also	O
+associated	O
+with	O
+carcinoma	B-NP
+of	I-NP
+the	I-NP
+urinary	I-NP
+tract	I-NP
+.	O
+	
+Twenty	O
+carcinomas	B-NP
+of	I-NP
+the	I-NP
+urinary	I-NP
+bladder	I-NP
+and	O
+one	O
+carcinoma	B-NP
+of	I-NP
+the	I-NP
+prostate	I-NP
+have	O
+been	O
+reported	O
+in	O
+association	O
+with	O
+its	O
+use	O
+.	O
+	
+The	O
+present	O
+case	O
+is	O
+the	O
+first	O
+carcinoma	B-NP
+of	I-NP
+the	I-NP
+renal	I-NP
+pelvis	I-NP
+reported	O
+in	O
+association	O
+with	O
+cyclophosphamide	O
+treatment	O
+.	O
+	
+It	O
+is	O
+the	O
+third	O
+urinary	B-NP
+tract	I-NP
+cancer	I-NP
+reported	O
+in	O
+association	O
+with	O
+cyclophosphamide	O
+treatment	O
+for	O
+nonmalignant	O
+disease	O
+.	O
+	
+The	O
+association	O
+of	O
+the	O
+tumor	B-NP
+with	O
+preexisting	O
+hydroureteronephrosis	B-NP
+suggests	O
+that	O
+stasis	O
+prolonged	O
+and	O
+intensified	O
+exposure	O
+of	O
+upper	O
+urinary	O
+tract	O
+epithelium	O
+to	O
+cyclophosphamide	O
+.	O
+	
+Patients	O
+who	O
+are	O
+candidates	O
+for	O
+long	O
+-	O
+term	O
+cyclophosphamide	O
+treatment	O
+should	O
+be	O
+routinely	O
+evaluated	O
+for	O
+obstructive	B-NP
+uropathy	I-NP
+.	O
+	
+Medial	O
+changes	O
+in	O
+arterial	O
+spasm	B-NP
+induced	O
+by	O
+L	O
+-	O
+norepinephrine	O
+.	O
+	
+In	O
+normal	O
+rats	O
+","	O
+the	O
+media	O
+of	O
+small	O
+arteries	O
+(	O
+0	O
+.	O
+4	O
+-	O
+-	O
+0	O
+.	O
+2	O
+mm	O
+in	O
+diameter	O
+)	O
+previously	O
+was	O
+shown	O
+to	O
+contain	O
+intracellular	O
+vacuoles	O
+","	O
+identified	O
+ultrastructurally	O
+as	O
+herniations	O
+of	O
+one	O
+smooth	O
+muscle	O
+cell	O
+into	O
+another	O
+.	O
+	
+The	O
+hypothesis	O
+that	O
+intense	O
+vasoconstriction	O
+would	O
+increase	O
+the	O
+number	O
+of	O
+such	O
+vacuoles	O
+has	O
+been	O
+tested	O
+.	O
+	
+In	O
+the	O
+media	O
+of	O
+the	O
+saphenous	O
+artery	O
+and	O
+its	O
+distal	O
+branch	O
+","	O
+vasoconstriction	O
+induced	O
+by	O
+L	O
+-	O
+norepinephrine	O
+produced	O
+many	O
+cell	O
+-	O
+to	O
+-	O
+cell	O
+hernias	B-NP
+within	O
+15	O
+minutes	O
+.	O
+	
+At	O
+1	O
+day	O
+their	O
+number	O
+was	O
+reduced	O
+to	O
+about	O
+1	O
+/	O
+10	O
+of	O
+the	O
+original	O
+number	O
+.	O
+	
+By	O
+7	O
+days	O
+the	O
+vessel	O
+was	O
+almost	O
+restored	O
+to	O
+normal	O
+.	O
+	
+Triple	O
+stimulation	O
+over	O
+1	O
+day	O
+induced	O
+more	O
+severe	O
+changes	O
+in	O
+the	O
+media	O
+.	O
+	
+These	O
+findings	O
+suggest	O
+that	O
+smooth	O
+muscle	O
+cells	O
+are	O
+susceptible	O
+to	O
+damage	O
+in	O
+the	O
+course	O
+of	O
+their	O
+specific	O
+function	O
+.	O
+	
+The	O
+experimental	O
+data	O
+are	O
+discussed	O
+in	O
+relation	O
+to	O
+medial	O
+changes	O
+observed	O
+in	O
+other	O
+instances	O
+of	O
+arterial	O
+spasm	B-NP
+.	O
+	
+Endothelial	O
+changes	O
+that	O
+developed	O
+in	O
+the	O
+same	O
+experimental	O
+model	O
+were	O
+described	O
+in	O
+a	O
+previous	O
+paper	O
+.	O
+	
+Bilateral	O
+retinal	B-NP
+artery	I-NP
+and	I-NP
+choriocapillaris	I-NP
+occlusion	I-NP
+following	O
+the	O
+injection	O
+of	O
+long	O
+-	O
+acting	O
+corticosteroid	O
+suspensions	O
+in	O
+combination	O
+with	O
+other	O
+drugs	O
+:	O
+I	O
+.	O
+	
+Clinical	O
+studies	O
+.	O
+	
+Two	O
+well	O
+-	O
+documented	O
+cases	O
+of	O
+bilateral	O
+retinal	B-NP
+artery	I-NP
+and	I-NP
+choriocapillaris	I-NP
+occlusions	I-NP
+with	O
+blindness	B-NP
+following	O
+head	O
+and	O
+neck	O
+soft	O
+-	O
+tissue	O
+injection	O
+with	O
+methylprednisolone	O
+acetate	O
+in	O
+combination	O
+with	O
+lidocaine	O
+","	O
+epinephrine	O
+","	O
+or	O
+penicillin	O
+are	O
+reported	O
+.	O
+	
+One	O
+case	O
+had	O
+only	O
+a	O
+unilateral	O
+injection	O
+.	O
+	
+The	O
+acute	O
+observations	O
+included	O
+hazy	O
+sensorium	O
+","	O
+superior	O
+gaze	O
+palsy	B-NP
+","	O
+pupillary	B-NP
+abnormalities	I-NP
+","	O
+and	O
+conjunctival	O
+hemorrhages	B-NP
+with	O
+edema	B-NP
+.	O
+	
+Follow	O
+-	O
+up	O
+changes	O
+showed	O
+marked	O
+visual	B-NP
+loss	I-NP
+","	O
+constricted	O
+visual	O
+fields	O
+","	O
+optic	O
+nerve	O
+pallor	O
+","	O
+vascular	O
+attenuation	O
+","	O
+and	O
+chorioretinal	B-NP
+atrophy	I-NP
+.	O
+	
+The	O
+literature	O
+is	O
+reviewed	O
+","	O
+and	O
+possible	O
+causes	O
+are	O
+discussed	O
+.	O
+	
+Abnormalities	O
+of	O
+the	O
+pupil	O
+and	O
+visual	O
+-	O
+evoked	O
+potential	O
+in	O
+quinine	O
+amblyopia	B-NP
+.	O
+	
+Total	O
+blindness	B-NP
+with	O
+a	O
+transient	O
+tonic	B-NP
+pupillary	I-NP
+response	O
+","	O
+denervation	O
+supersensitivity	O
+","	O
+and	O
+abnormal	O
+visual	O
+-	O
+evoked	O
+potentials	O
+developed	O
+in	O
+a	O
+54	O
+-	O
+year	O
+-	O
+old	O
+man	O
+after	O
+the	O
+use	O
+of	O
+quinine	O
+sulfate	O
+for	O
+leg	B-NP
+cramps	I-NP
+.	O
+	
+He	O
+later	O
+recovered	O
+normal	O
+visual	O
+acuity	O
+.	O
+	
+A	O
+transient	O
+tonic	B-NP
+pupillary	I-NP
+response	O
+","	O
+denervation	O
+supersensitivity	O
+","	O
+and	O
+abnormal	O
+visual	O
+-	O
+evoked	O
+potentials	O
+in	O
+quinine	O
+toxicity	B-NP
+","	O
+to	O
+our	O
+knowledge	O
+","	O
+have	O
+not	O
+been	O
+previously	O
+reported	O
+.	O
+	
+Suxamethonium	O
+-	O
+induced	O
+jaw	B-NP
+stiffness	I-NP
+and	O
+myalgia	B-NP
+associated	O
+with	O
+atypical	O
+cholinesterase	O
+:	O
+case	O
+report	O
+.	O
+	
+An	O
+11	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+was	O
+given	O
+halothane	O
+","	O
+nitrous	O
+oxide	O
+and	O
+oxygen	O
+","	O
+pancuronium	O
+0	O
+.	O
+4	O
+mg	O
+and	O
+suxamethonium	O
+100	O
+mg	O
+for	O
+induction	O
+of	O
+anaesthesia	O
+.	O
+	
+In	O
+response	O
+to	O
+this	O
+a	O
+marked	O
+jaw	B-NP
+stiffness	I-NP
+occurred	O
+which	O
+lasted	O
+for	O
+two	O
+minutes	O
+and	O
+the	O
+anaesthesia	O
+were	O
+terminated	O
+.	O
+	
+Four	O
+hours	O
+of	O
+apnoea	B-NP
+ensued	O
+and	O
+he	O
+suffered	O
+generalized	O
+severe	O
+myalgia	B-NP
+lasting	O
+for	O
+one	O
+week	O
+.	O
+	
+He	O
+was	O
+found	O
+to	O
+have	O
+atypical	O
+plasma	O
+cholinesterase	O
+with	O
+a	O
+dibucaine	O
+number	O
+of	O
+12	O
+","	O
+indicating	O
+homozygocity	O
+.	O
+	
+This	O
+was	O
+verified	O
+by	O
+study	O
+of	O
+the	O
+family	O
+.	O
+	
+The	O
+case	O
+shows	O
+that	O
+prolonged	B-NP
+jaw	I-NP
+rigidity	I-NP
+and	O
+myalgia	B-NP
+may	O
+occur	O
+after	O
+suxamethonium	O
+in	O
+patients	O
+with	O
+atypical	O
+cholinesterase	O
+despite	O
+pretreatment	O
+with	O
+pancuronium	O
+.	O
+	
+Indomethacin	O
+-	O
+induced	O
+hyperkalemia	B-NP
+in	O
+three	O
+patients	O
+with	O
+gouty	B-NP
+arthritis	I-NP
+.	O
+	
+We	O
+describe	O
+three	O
+patients	O
+in	O
+whom	O
+severe	O
+","	O
+life	O
+-	O
+threatening	O
+hyperkalemia	B-NP
+and	O
+renal	B-NP
+insufficiency	I-NP
+developed	O
+after	O
+treatment	O
+of	O
+acute	O
+gouty	B-NP
+arthritis	I-NP
+with	O
+indomethacin	O
+.	O
+	
+This	O
+complication	O
+may	O
+result	O
+from	O
+an	O
+inhibition	O
+of	O
+prostaglandin	O
+synthesis	O
+and	O
+consequent	O
+hyporeninemic	B-NP
+hypoaidosteronism	I-NP
+.	O
+	
+Careful	O
+attention	O
+to	O
+renal	O
+function	O
+and	O
+potassium	O
+balance	O
+in	O
+patients	O
+receiving	O
+indomethacin	O
+or	O
+other	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+agents	O
+","	O
+particularly	O
+in	O
+those	O
+patients	O
+with	O
+diabetes	B-NP
+mellitus	I-NP
+or	O
+preexisting	O
+renal	B-NP
+disease	I-NP
+","	O
+will	O
+help	O
+prevent	O
+this	O
+potentially	O
+serious	O
+complication	O
+.	O
+	
+Etomidate	O
+:	O
+a	O
+foreshortened	O
+clinical	O
+trial	O
+.	O
+	
+A	O
+clinical	O
+evaluation	O
+of	O
+etomidate	O
+for	O
+outpatient	O
+cystoscopy	O
+was	O
+embarked	O
+upon	O
+.	O
+	
+Unpremedicated	O
+patients	O
+were	O
+given	O
+fentanyl	O
+1	O
+microgram	O
+/	O
+kg	O
+followed	O
+by	O
+etomidate	O
+0	O
+.	O
+3	O
+mg	O
+/	O
+kg	O
+.	O
+	
+Anaesthesia	O
+was	O
+maintained	O
+with	O
+intermittent	O
+etomidate	O
+in	O
+2	O
+-	O
+4	O
+mg	O
+doses	O
+.	O
+	
+Patients	O
+were	O
+interviewed	O
+personally	O
+later	O
+the	O
+same	O
+day	O
+","	O
+and	O
+by	O
+questionnaire	O
+three	O
+to	O
+four	O
+weeks	O
+later	O
+.	O
+	
+The	O
+trial	O
+was	O
+discontinued	O
+after	O
+20	O
+cases	O
+because	O
+of	O
+an	O
+unacceptable	O
+incidence	O
+of	O
+side	O
+effects	O
+.	O
+	
+Venous	O
+pain	B-NP
+occurred	O
+in	O
+68	O
+%	O
+of	O
+patients	O
+and	O
+50	O
+%	O
+had	O
+redness	O
+","	O
+pain	B-NP
+or	O
+swelling	B-NP
+related	O
+to	O
+the	O
+injection	O
+site	O
+","	O
+in	O
+some	O
+cases	O
+lasting	O
+up	O
+to	O
+three	O
+weeks	O
+after	O
+anaesthesia	O
+.	O
+	
+Skeletal	O
+movements	O
+occurred	O
+in	O
+50	O
+%	O
+of	O
+patients	O
+;	O
+30	O
+%	O
+experienced	O
+respiratory	B-NP
+upset	I-NP
+","	O
+one	O
+sufficiently	O
+severe	O
+to	O
+necessitate	O
+abandoning	O
+the	O
+technique	O
+.	O
+	
+Nausea	B-NP
+and	O
+vomiting	B-NP
+occurred	O
+in	O
+40	O
+%	O
+and	O
+25	O
+%	O
+had	O
+disturbing	O
+emergence	O
+psychoses	B-NP
+.	O
+	
+Levodopa	O
+-	O
+induced	O
+dyskinesias	B-NP
+are	O
+improved	O
+by	O
+fluoxetine	O
+.	O
+	
+We	O
+evaluated	O
+the	O
+severity	O
+of	O
+motor	B-NP
+disability	I-NP
+and	O
+dyskinesias	B-NP
+in	O
+seven	O
+levodopa	O
+-	O
+responsive	O
+patients	O
+with	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+after	O
+an	O
+acute	O
+challenge	O
+with	O
+the	O
+mixed	O
+dopamine	O
+agonist	O
+","	O
+apomorphine	O
+","	O
+before	O
+and	O
+after	O
+the	O
+administration	O
+of	O
+fluoxetine	O
+(	O
+20	O
+mg	O
+twice	O
+per	O
+day	O
+)	O
+for	O
+11	O
++	O
+/	O
+-	O
+1	O
+days	O
+.	O
+	
+After	O
+fluoxetine	O
+treatment	O
+","	O
+there	O
+was	O
+a	O
+significant	O
+47	O
+%	O
+improvement	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+of	O
+apomorphine	O
+-	O
+induced	O
+dyskinesias	B-NP
+without	O
+modification	O
+of	O
+parkinsonian	B-NP
+motor	B-NP
+disability	I-NP
+.	O
+	
+The	O
+dyskinesias	B-NP
+were	O
+reduced	O
+predominantly	O
+in	O
+the	O
+lower	O
+limbs	O
+during	O
+the	O
+onset	O
+and	O
+disappearance	O
+of	O
+dystonic	B-NP
+dyskinesias	I-NP
+(	O
+onset	O
+-	O
+and	O
+end	O
+-	O
+of	O
+-	O
+dose	O
+dyskinesias	B-NP
+)	O
+and	O
+in	O
+the	O
+upper	O
+limbs	O
+during	O
+choreic	B-NP
+mid	I-NP
+-	I-NP
+dose	I-NP
+dyskinesias	I-NP
+.	O
+	
+The	O
+results	O
+suggest	O
+that	O
+increased	O
+brain	O
+serotoninergic	O
+transmission	O
+with	O
+fluoxetine	O
+may	O
+reduce	O
+levodopa	O
+-	O
+or	O
+dopamine	O
+agonist	O
+-	O
+induced	O
+dyskinesias	B-NP
+without	O
+aggravating	O
+parkinsonian	B-NP
+motor	B-NP
+disability	I-NP
+.	O
+	
+A	O
+large	O
+population	O
+-	O
+based	O
+follow	O
+-	O
+up	O
+study	O
+of	O
+trimethoprim	O
+-	O
+sulfamethoxazole	O
+","	O
+trimethoprim	O
+","	O
+and	O
+cephalexin	O
+for	O
+uncommon	O
+serious	O
+drug	B-NP
+toxicity	I-NP
+.	O
+	
+We	O
+conducted	O
+a	O
+population	O
+-	O
+based	O
+45	O
+-	O
+day	O
+follow	O
+-	O
+up	O
+study	O
+of	O
+232	O
+","	O
+390	O
+people	O
+who	O
+were	O
+prescribed	O
+trimethoprim	O
+-	O
+sulfamethoxazole	O
+(	O
+TMP	O
+-	O
+SMZ	O
+)	O
+","	O
+266	O
+","	O
+951	O
+prescribed	O
+trimethoprim	O
+alone	O
+","	O
+and	O
+196	O
+","	O
+397	O
+prescribed	O
+cephalexin	O
+","	O
+to	O
+estimate	O
+the	O
+risk	O
+of	O
+serious	O
+liver	B-NP
+","	I-NP
+blood	I-NP
+","	I-NP
+skin	I-NP
+","	I-NP
+and	I-NP
+renal	I-NP
+disorders	I-NP
+resulting	O
+in	O
+referral	O
+or	O
+hospitalization	O
+associated	O
+with	O
+these	O
+drugs	O
+.	O
+	
+The	O
+results	O
+were	O
+based	O
+on	O
+information	O
+recorded	O
+on	O
+office	O
+computers	O
+by	O
+selected	O
+general	O
+practitioners	O
+in	O
+the	O
+United	O
+Kingdom	O
+","	O
+together	O
+with	O
+a	O
+review	O
+of	O
+clinical	O
+records	O
+.	O
+	
+The	O
+risk	O
+of	O
+clinically	O
+important	O
+idiopathic	O
+liver	B-NP
+disease	I-NP
+was	O
+similar	O
+for	O
+persons	O
+prescribed	O
+TMP	O
+-	O
+SMZ	O
+(	O
+5	O
+.	O
+2	O
+/	O
+100	O
+","	O
+0	O
+)	O
+and	O
+those	O
+prescribed	O
+trimethoprim	O
+alone	O
+(	O
+3	O
+.	O
+8	O
+/	O
+100	O
+","	O
+0	O
+)	O
+.	O
+	
+The	O
+risk	O
+for	O
+those	O
+prescribed	O
+cephalexin	O
+was	O
+somewhat	O
+lower	O
+(	O
+2	O
+.	O
+0	O
+/	O
+100	O
+","	O
+0	O
+)	O
+.	O
+	
+Only	O
+five	O
+patients	O
+experienced	O
+blood	O
+disorders	O
+","	O
+one	O
+of	O
+whom	O
+was	O
+exposed	O
+to	O
+TMP	O
+-	O
+SMZ	O
+;	O
+of	O
+seven	O
+with	O
+erythema	B-NP
+multiforme	I-NP
+and	O
+Stevens	B-NP
+-	I-NP
+Johnson	I-NP
+syndrome	I-NP
+","	O
+four	O
+were	O
+exposed	O
+to	O
+TMP	O
+-	O
+SMZ	O
+.	O
+	
+The	O
+one	O
+case	O
+of	O
+toxic	B-NP
+epidermal	I-NP
+necrolysis	I-NP
+occurred	O
+in	O
+a	O
+patient	O
+who	O
+took	O
+cephalexin	O
+.	O
+	
+Finally	O
+","	O
+only	O
+five	O
+cases	O
+of	O
+acute	O
+parenchymal	O
+renal	B-NP
+disease	I-NP
+occurred	O
+","	O
+none	O
+likely	O
+to	O
+be	O
+caused	O
+by	O
+a	O
+study	O
+drug	O
+.	O
+	
+We	O
+conclude	O
+that	O
+the	O
+risk	O
+of	O
+the	O
+serious	O
+diseases	O
+studied	O
+is	O
+small	O
+for	O
+the	O
+three	O
+agents	O
+","	O
+and	O
+compares	O
+reasonably	O
+with	O
+the	O
+risk	O
+for	O
+many	O
+other	O
+antibiotics	O
+.	O
+	
+Clinical	O
+safety	O
+of	O
+lidocaine	O
+in	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+myocardial	B-NP
+infarction	I-NP
+.	O
+	
+STUDY	O
+OBJECTIVE	O
+:	O
+To	O
+evaluate	O
+the	O
+safety	O
+of	O
+lidocaine	O
+in	O
+the	O
+setting	O
+of	O
+cocaine	O
+-	O
+induced	O
+myocardial	B-NP
+infarction	I-NP
+(	O
+MI	B-NP
+)	O
+.	O
+	
+DESIGN	O
+:	O
+A	O
+retrospective	O
+","	O
+multicenter	O
+study	O
+.	O
+	
+SETTING	O
+:	O
+Twenty	O
+-	O
+nine	O
+university	O
+","	O
+university	O
+-	O
+affiliated	O
+","	O
+or	O
+community	O
+hospitals	O
+during	O
+a	O
+6	O
+-	O
+year	O
+period	O
+(	O
+total	O
+of	O
+117	O
+cumulative	O
+hospital	O
+-	O
+years	O
+)	O
+.	O
+	
+PARTICIPANTS	O
+:	O
+Patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+MI	B-NP
+who	O
+received	O
+lidocaine	O
+in	O
+the	O
+emergency	O
+department	O
+.	O
+	
+RESULTS	O
+:	O
+Of	O
+29	O
+patients	O
+who	O
+received	O
+lidocaine	O
+in	O
+the	O
+setting	O
+of	O
+cocaine	O
+-	O
+associated	O
+MI	B-NP
+","	O
+no	O
+patient	O
+died	O
+;	O
+exhibited	O
+bradydysrhythmias	B-NP
+","	O
+ventricular	B-NP
+tachycardia	I-NP
+","	O
+or	O
+ventricular	B-NP
+fibrillation	I-NP
+;	O
+or	O
+experienced	O
+seizures	B-NP
+after	O
+administration	O
+of	O
+lidocaine	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+","	O
+0	O
+%	O
+to	O
+11	O
+%	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+Despite	O
+theoretical	O
+concerns	O
+that	O
+lidocaine	O
+may	O
+enhance	O
+cocaine	O
+toxicity	B-NP
+","	O
+the	O
+use	O
+of	O
+lidocaine	O
+in	O
+patients	O
+with	O
+cocaine	O
+-	O
+associated	O
+MI	B-NP
+was	O
+not	O
+associated	O
+with	O
+significant	O
+cardiovascular	B-NP
+or	I-NP
+central	I-NP
+nervous	I-NP
+system	I-NP
+toxicity	I-NP
+.	O
+	
+Experimental	O
+progressive	O
+muscular	B-NP
+dystrophy	I-NP
+and	O
+its	O
+treatment	O
+with	O
+high	O
+doses	O
+anabolizing	O
+agents	O
+.	O
+	
+We	O
+are	O
+still	O
+a	O
+long	O
+way	O
+from	O
+discovering	O
+an	O
+unequivocal	O
+pathogenetic	O
+interpretation	O
+of	O
+progressive	O
+muscular	B-NP
+dystrophy	I-NP
+in	O
+man	O
+.	O
+	
+Noteworthy	O
+efforts	O
+have	O
+been	O
+made	O
+in	O
+the	O
+experimental	O
+field	O
+;	O
+a	O
+recessive	O
+autosomic	O
+form	O
+found	O
+in	O
+the	O
+mouse	O
+seems	O
+to	O
+bear	O
+the	O
+closest	O
+resemblance	O
+to	O
+the	O
+human	O
+form	O
+from	O
+the	O
+genetic	O
+point	O
+of	O
+view	O
+.	O
+	
+Myopathy	B-NP
+due	O
+to	O
+lack	O
+of	O
+vitamin	O
+E	O
+and	O
+myopathy	B-NP
+induced	O
+by	O
+certain	O
+viruses	O
+have	O
+much	O
+in	O
+common	O
+anatomically	O
+and	O
+pathologically	O
+with	O
+the	O
+human	O
+form	O
+.	O
+	
+The	O
+authors	O
+induced	O
+myodystrophy	B-NP
+in	O
+the	O
+rat	O
+by	O
+giving	O
+it	O
+a	O
+diet	O
+lacking	O
+in	O
+vitamin	O
+E	O
+.	O
+	
+The	O
+pharmacological	O
+characteristics	O
+of	O
+vitamin	O
+E	O
+and	O
+the	O
+degenerative	O
+changes	O
+brought	O
+about	O
+by	O
+its	O
+deficiency	O
+","	O
+especially	O
+in	O
+the	O
+muscles	O
+","	O
+are	O
+illustrated	O
+.	O
+	
+It	O
+is	O
+thus	O
+confirmed	O
+that	O
+the	O
+histological	O
+characteristics	O
+of	O
+myopathic	B-NP
+rat	O
+muscle	O
+induced	O
+experimentally	O
+are	O
+extraordinarily	O
+similar	O
+to	O
+those	O
+of	O
+human	O
+myopathy	B-NP
+as	O
+confirmed	O
+during	O
+biopsies	O
+performed	O
+at	O
+the	O
+Orthopaedic	O
+Traumatological	O
+Centre	O
+","	O
+Florence	O
+.	O
+	
+The	O
+encouraging	O
+results	O
+obtained	O
+in	O
+various	O
+authoratative	O
+departments	O
+in	O
+myopathic	B-NP
+patients	O
+by	O
+using	O
+anabolizing	O
+steroids	O
+have	O
+encouraged	O
+the	O
+authors	O
+to	O
+investigate	O
+the	O
+beneficial	O
+effects	O
+of	O
+one	O
+anabolizing	O
+agent	O
+(	O
+Dianabol	O
+","	O
+CIBA	O
+)	O
+at	O
+high	O
+doses	O
+in	O
+rats	O
+rendered	O
+myopathic	B-NP
+by	O
+a	O
+diet	O
+deficient	O
+in	O
+vitamin	O
+E	O
+.	O
+	
+In	O
+this	O
+way	O
+they	O
+obtained	O
+appreciable	O
+changes	O
+in	O
+body	O
+weight	O
+(	O
+increased	O
+from	O
+50	O
+to	O
+70	O
+g	O
+after	O
+forty	O
+days	O
+at	O
+a	O
+dose	O
+of	O
+5	O
+mg	O
+per	O
+day	O
+of	O
+anabolizing	O
+agent	O
+)	O
+","	O
+but	O
+most	O
+of	O
+all	O
+they	O
+found	O
+histological	O
+changes	O
+due	O
+to	O
+"	O
+regenerative	O
+"	O
+changes	O
+in	O
+the	O
+muscle	O
+tissue	O
+","	O
+which	O
+however	O
+maintained	O
+its	O
+myopathic	B-NP
+characteristics	O
+in	O
+the	O
+control	O
+animals	O
+that	O
+were	O
+not	O
+treated	O
+with	O
+the	O
+anabolizing	O
+agent	O
+.	O
+	
+The	O
+authors	O
+conclude	O
+by	O
+affirming	O
+the	O
+undoubted	O
+efficacy	O
+of	O
+the	O
+anabolizing	O
+steroids	O
+in	O
+experimental	O
+myopathic	B-NP
+disease	I-NP
+","	O
+but	O
+they	O
+have	O
+reservations	O
+as	O
+to	O
+the	O
+transfer	O
+of	O
+the	O
+results	O
+into	O
+the	O
+human	O
+field	O
+","	O
+where	O
+high	O
+dosage	O
+cannot	O
+be	O
+carried	O
+out	O
+continuously	O
+because	O
+of	O
+the	O
+effects	O
+of	O
+the	O
+drug	O
+on	O
+virility	O
+;	O
+because	O
+the	O
+tissue	O
+injury	O
+too	O
+often	O
+occurs	O
+at	O
+an	O
+irreversible	O
+stage	O
+vis	O
+-	O
+a	O
+-	O
+vis	O
+the	O
+"	O
+regeneration	O
+"	O
+of	O
+the	O
+muscle	O
+tissue	O
+;	O
+and	O
+finally	O
+because	O
+the	O
+dystrophic	O
+injurious	O
+agent	O
+is	O
+certainly	O
+not	O
+the	O
+lack	O
+of	O
+vitamin	O
+E	O
+but	O
+something	O
+as	O
+yet	O
+unknown	O
+.	O
+	
+Paclitaxel	O
+3	O
+-	O
+hour	O
+infusion	O
+given	O
+alone	O
+and	O
+combined	O
+with	O
+carboplatin	O
+:	O
+preliminary	O
+results	O
+of	O
+dose	O
+-	O
+escalation	O
+trials	O
+.	O
+	
+Paclitaxel	O
+(	O
+Taxol	O
+;	O
+Bristol	O
+-	O
+Myers	O
+Squibb	O
+Company	O
+","	O
+Princeton	O
+","	O
+NJ	O
+)	O
+by	O
+3	O
+-	O
+hour	O
+infusion	O
+was	O
+combined	O
+with	O
+carboplatin	O
+in	O
+a	O
+phase	O
+I	O
+/	O
+II	O
+study	O
+directed	O
+to	O
+patients	O
+with	O
+non	B-NP
+-	I-NP
+small	I-NP
+cell	I-NP
+lung	I-NP
+cancer	I-NP
+.	O
+	
+Carboplatin	O
+was	O
+given	O
+at	O
+a	O
+fixed	O
+target	O
+area	O
+under	O
+the	O
+concentration	O
+-	O
+time	O
+curve	O
+of	O
+6	O
+.	O
+0	O
+by	O
+the	O
+Calvert	O
+formula	O
+","	O
+whereas	O
+paclitaxel	O
+was	O
+escalated	O
+in	O
+patient	O
+cohorts	O
+from	O
+150	O
+mg	O
+/	O
+m2	O
+(	O
+dose	O
+level	O
+I	O
+)	O
+to	O
+175	O
+","	O
+200	O
+","	O
+225	O
+","	O
+and	O
+250	O
+mg	O
+/	O
+m2	O
+.	O
+	
+The	O
+225	O
+mg	O
+/	O
+m2	O
+level	O
+was	O
+expanded	O
+for	O
+the	O
+phase	O
+II	O
+study	O
+since	O
+the	O
+highest	O
+level	O
+achieved	O
+(	O
+250	O
+mg	O
+/	O
+m2	O
+)	O
+required	O
+modification	O
+because	O
+of	O
+nonhematologic	O
+toxicities	B-NP
+(	O
+arthralgia	B-NP
+and	O
+sensory	B-NP
+neuropathy	I-NP
+)	O
+.	O
+	
+Therapeutic	O
+effects	O
+were	O
+noted	O
+at	O
+all	O
+dose	O
+levels	O
+","	O
+with	O
+objective	O
+responses	O
+in	O
+17	O
+(	O
+two	O
+complete	O
+and	O
+15	O
+partial	O
+regressions	O
+)	O
+of	O
+41	O
+previously	O
+untreated	O
+patients	O
+.	O
+	
+Toxicities	B-NP
+were	O
+compared	O
+with	O
+a	O
+cohort	O
+of	O
+patients	O
+in	O
+a	O
+phase	O
+I	O
+trial	O
+of	O
+paclitaxel	O
+alone	O
+at	O
+identical	O
+dose	O
+levels	O
+.	O
+	
+Carboplatin	O
+did	O
+not	O
+appear	O
+to	O
+add	O
+to	O
+the	O
+hematologic	B-NP
+toxicities	I-NP
+observed	O
+","	O
+and	O
+the	O
+paclitaxel	O
+/	O
+carboplatin	O
+combination	O
+could	O
+be	O
+dosed	O
+every	O
+3	O
+weeks	O
+.	O
+	
+The	O
+dose	O
+-	O
+dependent	O
+effect	O
+of	O
+misoprostol	O
+on	O
+indomethacin	O
+-	O
+induced	O
+renal	B-NP
+dysfunction	I-NP
+in	O
+well	O
+compensated	O
+cirrhosis	B-NP
+.	O
+	
+Misoprostol	O
+(	O
+200	O
+micrograms	O
+)	O
+has	O
+been	O
+shown	O
+to	O
+acutely	O
+counteract	O
+the	O
+indomethacin	O
+-	O
+induced	O
+renal	B-NP
+dysfunction	I-NP
+in	O
+well	O
+compensated	O
+cirrhotic	B-NP
+patients	O
+.	O
+	
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+if	O
+the	O
+prophylactic	O
+value	O
+of	O
+misoprostol	O
+was	O
+dose	O
+-	O
+dependent	O
+.	O
+	
+Parameters	O
+of	O
+renal	O
+hemodynamics	O
+and	O
+tubular	O
+sodium	O
+and	O
+water	O
+handling	O
+were	O
+assessed	O
+by	O
+clearance	O
+techniques	O
+in	O
+26	O
+well	O
+compensated	O
+cirrhotic	B-NP
+patients	O
+before	O
+and	O
+after	O
+an	O
+oral	O
+combination	O
+of	O
+50	O
+mg	O
+of	O
+indomethacin	O
+and	O
+various	O
+doses	O
+of	O
+misoprostol	O
+.	O
+	
+The	O
+200	O
+-	O
+micrograms	O
+dose	O
+was	O
+able	O
+to	O
+totally	O
+abolish	O
+the	O
+deleterious	O
+renal	O
+effects	O
+of	O
+indomethacin	O
+","	O
+whereas	O
+the	O
+800	O
+-	O
+micrograms	O
+dose	O
+resulted	O
+in	O
+significant	O
+worsening	O
+of	O
+renal	O
+hemodynamics	O
+and	O
+sodium	O
+retention	O
+.	O
+	
+These	O
+changes	O
+were	O
+maximal	O
+in	O
+the	O
+hour	O
+immediately	O
+after	O
+medications	O
+and	O
+slowly	O
+returned	O
+toward	O
+base	O
+-	O
+line	O
+levels	O
+thereafter	O
+.	O
+	
+These	O
+results	O
+suggest	O
+that	O
+the	O
+renal	O
+protective	O
+effects	O
+of	O
+misoprostol	O
+is	O
+dose	O
+-	O
+dependent	O
+.	O
+	
+However	O
+","	O
+until	O
+this	O
+apparent	O
+ability	O
+of	O
+200	O
+micrograms	O
+of	O
+misoprostol	O
+to	O
+prevent	O
+the	O
+adverse	O
+effects	O
+of	O
+indomethacin	O
+on	O
+renal	O
+function	O
+is	O
+confirmed	O
+with	O
+chronic	O
+frequent	O
+dosing	O
+","	O
+it	O
+would	O
+be	O
+prudent	O
+to	O
+avoid	O
+nonsteroidal	O
+anti	O
+-	O
+inflammatory	O
+therapy	O
+in	O
+patients	O
+with	O
+cirrhosis	B-NP
+.	O
+	
+Increased	O
+frequency	O
+and	O
+severity	O
+of	O
+angio	B-NP
+-	I-NP
+oedema	I-NP
+related	O
+to	O
+long	O
+-	O
+term	O
+therapy	O
+with	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+inhibitor	O
+in	O
+two	O
+patients	O
+.	O
+	
+Adverse	O
+reactions	O
+to	O
+drugs	O
+are	O
+well	O
+recognized	O
+as	O
+a	O
+cause	O
+of	O
+acute	O
+or	O
+chronic	O
+urticaria	B-NP
+","	O
+and	O
+angio	B-NP
+-	I-NP
+oedema	I-NP
+.	O
+	
+Angiotensin	O
+-	O
+converting	O
+enzyme	O
+(	O
+ACE	O
+)	O
+inhibitors	O
+","	O
+used	O
+to	O
+treat	O
+hypertension	B-NP
+and	O
+congestive	B-NP
+heart	I-NP
+failure	I-NP
+","	O
+were	O
+introduced	O
+in	O
+Europe	O
+in	O
+the	O
+middle	O
+of	O
+the	O
+eighties	O
+","	O
+and	O
+the	O
+use	O
+of	O
+these	O
+drugs	O
+has	O
+increased	O
+progressively	O
+.	O
+	
+Soon	O
+after	O
+the	O
+introduction	O
+of	O
+ACE	O
+inhibitors	O
+","	O
+acute	O
+bouts	O
+of	O
+angio	B-NP
+-	I-NP
+oedema	I-NP
+were	O
+reported	O
+in	O
+association	O
+with	O
+the	O
+use	O
+of	O
+these	O
+drugs	O
+.	O
+	
+We	O
+wish	O
+to	O
+draw	O
+attention	O
+to	O
+the	O
+possibility	O
+of	O
+adverse	O
+reactions	O
+to	O
+ACE	O
+inhibitors	O
+after	O
+long	O
+-	O
+term	O
+use	O
+and	O
+in	O
+patients	O
+with	O
+pre	O
+-	O
+existing	O
+angio	B-NP
+-	I-NP
+oedema	I-NP
+.	O
+	
+Myoclonus	B-NP
+associated	O
+with	O
+lorazepam	O
+therapy	O
+in	O
+very	O
+-	O
+low	O
+-	O
+birth	O
+-	O
+weight	O
+infants	O
+.	O
+	
+Lorazepam	O
+is	O
+being	O
+used	O
+with	O
+increasing	O
+frequency	O
+as	O
+a	O
+sedative	O
+in	O
+the	O
+newborn	O
+and	O
+the	O
+young	O
+infant	O
+.	O
+	
+Concern	O
+has	O
+been	O
+raised	O
+with	O
+regard	O
+to	O
+the	O
+safety	O
+of	O
+lorazepam	O
+in	O
+this	O
+age	O
+group	O
+","	O
+especially	O
+in	O
+very	O
+-	O
+low	O
+-	O
+birth	O
+-	O
+weight	O
+(	O
+VLBW	O
+;	O
+<	O
+1	O
+","	O
+500	O
+g	O
+)	O
+infants	O
+.	O
+	
+Three	O
+young	O
+infants	O
+","	O
+all	O
+of	O
+birth	O
+weight	O
+<	O
+1	O
+","	O
+500	O
+g	O
+","	O
+experienced	O
+myoclonus	B-NP
+following	O
+the	O
+intravenous	O
+administration	O
+of	O
+lorazepam	O
+.	O
+	
+The	O
+potential	O
+neurotoxic	B-NP
+effects	O
+of	O
+the	O
+drug	O
+(	O
+and	O
+its	O
+vehicle	O
+)	O
+in	O
+this	O
+population	O
+are	O
+discussed	O
+.	O
+	
+Injectable	O
+lorazepam	O
+should	O
+be	O
+used	O
+with	O
+caution	O
+in	O
+VLBW	O
+infants	O
+.	O
+	
+Transvenous	O
+right	O
+ventricular	O
+pacing	O
+during	O
+cardiopulmonary	O
+resuscitation	O
+of	O
+pediatric	O
+patients	O
+with	O
+acute	O
+cardiomyopathy	B-NP
+.	O
+	
+We	O
+describe	O
+the	O
+cardiopulmonary	O
+resuscitation	O
+efforts	O
+on	O
+five	O
+patients	O
+who	O
+presented	O
+in	O
+acute	O
+circulatory	B-NP
+failure	I-NP
+from	O
+myocardial	B-NP
+dysfunction	I-NP
+.	O
+	
+Three	O
+patients	O
+had	O
+acute	O
+viral	O
+myocarditis	B-NP
+","	O
+one	O
+had	O
+a	O
+carbamazepine	O
+-	O
+induced	O
+acute	O
+eosinophilic	B-NP
+myocarditis	I-NP
+","	O
+and	O
+one	O
+had	O
+cardiac	O
+hemosiderosis	O
+resulting	O
+in	O
+acute	O
+cardiogenic	B-NP
+shock	I-NP
+.	O
+	
+All	O
+patients	O
+were	O
+continuously	O
+monitored	O
+with	O
+central	O
+venous	O
+and	O
+arterial	O
+catheters	O
+in	O
+addition	O
+to	O
+routine	O
+noninvasive	O
+monitoring	O
+.	O
+	
+An	O
+introducer	O
+sheath	O
+","	O
+a	O
+pacemaker	O
+","	O
+and	O
+sterile	O
+pacing	O
+wires	O
+were	O
+made	O
+readily	O
+available	O
+for	O
+the	O
+patients	O
+","	O
+should	O
+the	O
+need	O
+arise	O
+to	O
+terminate	O
+resistant	O
+cardiac	O
+dysrhythmias	B-NP
+.	O
+	
+All	O
+patients	O
+developed	O
+cardiocirculatory	O
+arrest	O
+associated	O
+with	O
+extreme	O
+hypotension	B-NP
+and	O
+dysrhythmias	B-NP
+within	O
+the	O
+first	O
+48	O
+hours	O
+of	O
+their	O
+admission	O
+to	O
+the	O
+pediatric	O
+intensive	O
+care	O
+unit	O
+(	O
+PICU	O
+)	O
+.	O
+	
+Right	O
+ventricular	O
+pacemaker	O
+wires	O
+were	O
+inserted	O
+in	O
+all	O
+of	O
+them	O
+during	O
+cardiopulmonary	O
+resuscitation	O
+(	O
+CPR	O
+)	O
+.	O
+	
+In	O
+four	O
+patients	O
+","	O
+cardiac	O
+pacing	O
+was	O
+used	O
+","	O
+resulting	O
+in	O
+a	O
+temporary	O
+captured	O
+rhythm	O
+and	O
+restoration	O
+of	O
+their	O
+cardiac	O
+output	O
+.	O
+	
+These	O
+patients	O
+had	O
+a	O
+second	O
+event	O
+of	O
+cardiac	B-NP
+arrest	I-NP
+","	O
+resulting	O
+in	O
+death	O
+","	O
+within	O
+10	O
+to	O
+60	O
+minutes	O
+.	O
+	
+In	O
+one	O
+patient	O
+","	O
+cardiac	O
+pacing	O
+was	O
+not	O
+used	O
+","	O
+because	O
+he	O
+converted	O
+to	O
+normal	O
+sinus	O
+rhythm	O
+by	O
+electrical	O
+defibrillation	O
+within	O
+three	O
+minutes	O
+of	O
+initiating	O
+CPR	O
+.	O
+	
+We	O
+conclude	O
+that	O
+cardiac	O
+pacing	O
+during	O
+resuscitative	O
+efforts	O
+in	O
+pediatric	O
+patients	O
+suffering	O
+from	O
+acute	O
+myocardial	B-NP
+dysfunction	I-NP
+may	O
+not	O
+have	O
+long	O
+-	O
+term	O
+value	O
+in	O
+and	O
+of	O
+itself	O
+;	O
+however	O
+","	O
+if	O
+temporary	O
+hemodynamic	O
+stability	O
+is	O
+achieved	O
+by	O
+this	O
+procedure	O
+","	O
+it	O
+may	O
+provide	O
+additional	O
+time	O
+needed	O
+to	O
+institute	O
+other	O
+therapeutic	O
+modalities	O
+.	O
+	
+Efficacy	O
+and	O
+safety	O
+of	O
+granisetron	O
+","	O
+a	O
+selective	O
+5	O
+-	O
+hydroxytryptamine	O
+-	O
+3	O
+receptor	O
+antagonist	O
+","	O
+in	O
+the	O
+prevention	O
+of	O
+nausea	B-NP
+and	O
+vomiting	B-NP
+induced	O
+by	O
+high	O
+-	O
+dose	O
+cisplatin	O
+.	O
+	
+PURPOSE	O
+:	O
+To	O
+assess	O
+the	O
+antiemetic	O
+effects	O
+and	O
+safety	O
+profile	O
+of	O
+four	O
+different	O
+doses	O
+of	O
+granisetron	O
+(	O
+Kytril	O
+;	O
+SmithKline	O
+Beecham	O
+Pharmaceuticals	O
+","	O
+Philadelphia	O
+","	O
+PA	O
+)	O
+when	O
+administered	O
+as	O
+a	O
+single	O
+intravenous	O
+(	O
+IV	O
+)	O
+dose	O
+for	O
+prophylaxis	O
+of	O
+cisplatin	O
+-	O
+induced	O
+nausea	B-NP
+and	O
+vomiting	B-NP
+.	O
+	
+PATIENTS	O
+AND	O
+METHODS	O
+:	O
+One	O
+hundred	O
+eighty	O
+-	O
+four	O
+chemotherapy	O
+-	O
+naive	O
+patients	O
+receiving	O
+high	O
+-	O
+dose	O
+cisplatin	O
+(	O
+81	O
+to	O
+120	O
+mg	O
+/	O
+m2	O
+)	O
+were	O
+randomized	O
+to	O
+receive	O
+one	O
+of	O
+four	O
+granisetron	O
+doses	O
+(	O
+5	O
+","	O
+10	O
+","	O
+20	O
+","	O
+or	O
+40	O
+micrograms	O
+/	O
+kg	O
+)	O
+administered	O
+before	O
+chemotherapy	O
+.	O
+	
+Patients	O
+were	O
+observed	O
+on	O
+an	O
+inpatient	O
+basis	O
+for	O
+18	O
+to	O
+24	O
+hours	O
+","	O
+and	O
+vital	O
+signs	O
+","	O
+nausea	B-NP
+","	O
+vomiting	B-NP
+","	O
+retching	O
+","	O
+and	O
+appetite	O
+were	O
+assessed	O
+.	O
+	
+Safety	O
+analyses	O
+included	O
+incidence	O
+of	O
+adverse	O
+experiences	O
+and	O
+laboratory	O
+parameter	O
+changes	O
+.	O
+	
+RESULTS	O
+:	O
+After	O
+granisetron	O
+doses	O
+of	O
+5	O
+","	O
+10	O
+","	O
+20	O
+","	O
+and	O
+40	O
+micrograms	O
+/	O
+kg	O
+","	O
+a	O
+major	O
+response	O
+(	O
+<	O
+or	O
+=	O
+two	O
+vomiting	B-NP
+or	O
+retching	O
+episodes	O
+","	O
+and	O
+no	O
+antiemetic	O
+rescue	O
+)	O
+was	O
+recorded	O
+in	O
+23	O
+%	O
+","	O
+57	O
+%	O
+","	O
+58	O
+%	O
+","	O
+and	O
+60	O
+%	O
+of	O
+patients	O
+","	O
+respectively	O
+","	O
+and	O
+a	O
+complete	O
+response	O
+(	O
+no	O
+vomiting	B-NP
+or	O
+retching	O
+","	O
+and	O
+no	O
+antiemetic	O
+rescue	O
+)	O
+in	O
+18	O
+%	O
+","	O
+41	O
+%	O
+","	O
+40	O
+%	O
+","	O
+and	O
+47	O
+%	O
+of	O
+patients	O
+","	O
+respectively	O
+.	O
+	
+There	O
+was	O
+a	O
+statistically	O
+longer	O
+time	O
+to	O
+first	O
+episode	O
+of	O
+nausea	B-NP
+(	O
+P	O
+=	O
+.	O
+15	O
+)	O
+and	O
+vomiting	B-NP
+(	O
+P	O
+=	O
+.	O
+1	O
+)	O
+","	O
+and	O
+fewer	O
+patients	O
+were	O
+administered	O
+additional	O
+antiemetic	O
+medication	O
+in	O
+the	O
+10	O
+-	O
+micrograms	O
+/	O
+kg	O
+dosing	O
+groups	O
+than	O
+in	O
+the	O
+5	O
+-	O
+micrograms	O
+/	O
+kg	O
+dosing	O
+group	O
+.	O
+	
+As	O
+granisetron	O
+dose	O
+increased	O
+","	O
+appetite	O
+return	O
+increased	O
+(	O
+P	O
+=	O
+.	O
+40	O
+)	O
+.	O
+	
+Headache	B-NP
+was	O
+the	O
+most	O
+frequently	O
+reported	O
+adverse	O
+event	O
+(	O
+20	O
+%	O
+)	O
+.	O
+	
+CONCLUSION	O
+:	O
+A	O
+single	O
+10	O
+-	O
+","	O
+20	O
+-	O
+","	O
+or	O
+40	O
+-	O
+micrograms	O
+/	O
+kg	O
+dose	O
+of	O
+granisetron	O
+was	O
+effective	O
+in	O
+controlling	O
+vomiting	B-NP
+in	O
+57	O
+%	O
+to	O
+60	O
+%	O
+of	O
+patients	O
+who	O
+received	O
+cisplatin	O
+at	O
+doses	O
+greater	O
+than	O
+81	O
+mg	O
+/	O
+m2	O
+and	O
+totally	O
+prevented	O
+vomiting	B-NP
+in	O
+40	O
+%	O
+to	O
+47	O
+%	O
+of	O
+patients	O
+.	O
+	
+There	O
+were	O
+no	O
+statistically	O
+significant	O
+differences	O
+in	O
+efficacy	O
+between	O
+the	O
+10	O
+-	O
+micrograms	O
+/	O
+kg	O
+dose	O
+and	O
+the	O
+20	O
+-	O
+and	O
+40	O
+-	O
+micrograms	O
+/	O
+kg	O
+doses	O
+.	O
+	
+Granisetron	O
+was	O
+well	O
+tolerated	O
+at	O
+all	O
+doses	O
+.	O
+	
+Adverse	O
+interaction	O
+between	O
+clonidine	O
+and	O
+verapamil	O
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+report	O
+two	O
+cases	O
+of	O
+a	O
+possible	O
+adverse	O
+interaction	O
+between	O
+clonidine	O
+and	O
+verapamil	O
+resulting	O
+in	O
+atrioventricular	B-NP
+(	I-NP
+AV	I-NP
+)	I-NP
+block	I-NP
+in	O
+both	O
+patients	O
+and	O
+severe	O
+hypotension	B-NP
+in	O
+one	O
+patient	O
+.	O
+	
+CASE	O
+SUMMARIES	O
+:	O
+A	O
+54	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+hyperaldosteronism	B-NP
+was	O
+treated	O
+with	O
+verapamil	O
+480	O
+mg	O
+/	O
+d	O
+and	O
+spironolactone	O
+100	O
+mg	O
+/	O
+d	O
+.	O
+	
+After	O
+the	O
+addition	O
+of	O
+a	O
+minimal	O
+dose	O
+of	O
+clonidine	O
+(	O
+0	O
+.	O
+15	O
+mg	O
+bid	O
+)	O
+","	O
+she	O
+developed	O
+complete	O
+AV	B-NP
+block	I-NP
+and	O
+severe	O
+hypotension	B-NP
+","	O
+which	O
+resolved	O
+upon	O
+cessation	O
+of	O
+all	O
+medications	O
+.	O
+	
+A	O
+65	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+was	O
+treated	O
+with	O
+extended	O
+-	O
+release	O
+verapamil	O
+240	O
+mg	O
+/	O
+d	O
+.	O
+	
+After	O
+the	O
+addition	O
+of	O
+clonidine	O
+0	O
+.	O
+15	O
+mg	O
+bid	O
+she	O
+developed	O
+complete	O
+AV	B-NP
+block	I-NP
+","	O
+which	O
+resolved	O
+after	O
+all	O
+therapy	O
+was	O
+stopped	O
+.	O
+	
+DISCUSSION	O
+:	O
+An	O
+adverse	O
+interaction	O
+between	O
+clonidine	O
+and	O
+verapamil	O
+has	O
+not	O
+been	O
+reported	O
+previously	O
+.	O
+	
+We	O
+describe	O
+two	O
+such	O
+cases	O
+and	O
+discuss	O
+the	O
+various	O
+mechanisms	O
+that	O
+might	O
+cause	O
+such	O
+an	O
+interaction	O
+.	O
+	
+Clinicians	O
+should	O
+be	O
+acquainted	O
+with	O
+this	O
+possibly	O
+fatal	O
+interaction	O
+between	O
+two	O
+commonly	O
+used	O
+antihypertensive	O
+drugs	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+Caution	O
+is	O
+recommended	O
+in	O
+combining	O
+clonidine	O
+and	O
+verapamil	O
+therapy	O
+","	O
+even	O
+in	O
+patients	O
+who	O
+do	O
+not	O
+have	O
+sinus	O
+or	O
+AV	O
+node	O
+dysfunction	O
+.	O
+	
+The	O
+two	O
+drugs	O
+may	O
+act	O
+synergistically	O
+on	O
+both	O
+the	O
+AV	O
+node	O
+and	O
+the	O
+peripheral	O
+circulation	O
+.	O
+	
+Pharmacological	O
+studies	O
+on	O
+a	O
+new	O
+dihydrothienopyridine	O
+calcium	O
+antagonist	O
+","	O
+S	O
+-	O
+312	O
+-	O
+d	O
+.	O
+	
+5th	O
+communication	O
+:	O
+anticonvulsant	O
+effects	O
+in	O
+mice	O
+.	O
+	
+S	O
+-	O
+312	O
+","	O
+S	O
+-	O
+312	O
+-	O
+d	O
+","	O
+but	O
+not	O
+S	O
+-	O
+312	O
+-	O
+l	O
+","	O
+L	O
+-	O
+type	O
+calcium	O
+channel	O
+antagonists	O
+","	O
+showed	O
+anticonvulsant	O
+effects	O
+on	O
+the	O
+audiogenic	B-NP
+tonic	I-NP
+convulsions	I-NP
+in	O
+DBA	O
+/	O
+2	O
+mice	O
+;	O
+and	O
+their	O
+ED50	O
+values	O
+were	O
+18	O
+.	O
+4	O
+(	O
+12	O
+.	O
+8	O
+-	O
+27	O
+.	O
+1	O
+)	O
+mg	O
+/	O
+kg	O
+","	O
+p	O
+.	O
+o	O
+.	O
+and	O
+15	O
+.	O
+0	O
+(	O
+10	O
+.	O
+2	O
+-	O
+23	O
+.	O
+7	O
+)	O
+mg	O
+/	O
+kg	O
+","	O
+p	O
+.	O
+o	O
+.	O
+","	O
+respectively	O
+","	O
+while	O
+that	O
+of	O
+flunarizine	O
+was	O
+34	O
+.	O
+0	O
+(	O
+26	O
+.	O
+0	O
+-	O
+44	O
+.	O
+8	O
+)	O
+mg	O
+/	O
+kg	O
+","	O
+p	O
+.	O
+o	O
+.	O
+	
+Although	O
+moderate	O
+anticonvulsant	O
+effects	O
+of	O
+S	O
+-	O
+312	O
+-	O
+d	O
+in	O
+higher	O
+doses	O
+were	O
+observed	O
+against	O
+the	O
+clonic	O
+convulsions	B-NP
+induced	O
+by	O
+pentylenetetrazole	O
+(	O
+85	O
+mg	O
+/	O
+kg	O
+","	O
+s	O
+.	O
+c	O
+.	O
+)	O
+or	O
+bemegride	O
+(	O
+40	O
+mg	O
+/	O
+kg	O
+","	O
+s	O
+.	O
+c	O
+.	O
+)	O
+","	O
+no	O
+effects	O
+were	O
+observed	O
+in	O
+convulsions	B-NP
+induced	O
+by	O
+N	O
+-	O
+methyl	O
+-	O
+D	O
+-	O
+aspartate	O
+","	O
+picrotoxin	O
+","	O
+or	O
+electroshock	O
+in	O
+Slc	O
+:	O
+ddY	O
+mice	O
+.	O
+	
+S	O
+-	O
+312	O
+-	O
+d	O
+may	O
+be	O
+useful	O
+in	O
+the	O
+therapy	O
+of	O
+certain	O
+types	O
+of	O
+human	O
+epilepsy	B-NP
+.	O
+	
+Transmural	O
+myocardial	B-NP
+infarction	I-NP
+with	O
+sumatriptan	O
+.	O
+	
+For	O
+sumatriptan	O
+","	O
+tightness	O
+in	O
+the	O
+chest	O
+caused	O
+by	O
+an	O
+unknown	O
+mechanism	O
+has	O
+been	O
+reported	O
+in	O
+3	O
+-	O
+5	O
+%	O
+of	O
+users	O
+.	O
+	
+We	O
+describe	O
+a	O
+47	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+an	O
+acute	O
+myocardial	B-NP
+infarction	I-NP
+after	O
+administration	O
+of	O
+sumatriptan	O
+6	O
+mg	O
+subcutaneously	O
+for	O
+cluster	B-NP
+headache	I-NP
+.	O
+	
+The	O
+patient	O
+had	O
+no	O
+history	O
+of	O
+underlying	O
+ischaemic	B-NP
+heart	I-NP
+disease	I-NP
+or	O
+Prinzmetal	B-NP
+'	I-NP
+s	I-NP
+angina	I-NP
+.	O
+	
+She	O
+recovered	O
+without	O
+complications	O
+.	O
+	
+Flumazenil	O
+induces	O
+seizures	B-NP
+and	O
+death	O
+in	O
+mixed	O
+cocaine	O
+-	O
+diazepam	O
+intoxications	O
+.	O
+	
+STUDY	O
+HYPOTHESIS	O
+:	O
+Administration	O
+of	O
+the	O
+benzodiazepine	O
+antagonist	O
+flumazenil	O
+may	O
+unmask	O
+seizures	B-NP
+in	O
+mixed	O
+cocaine	O
+-	O
+benzodiazepine	O
+intoxication	O
+.	O
+	
+DESIGN	O
+:	O
+Male	O
+Sprague	O
+-	O
+Dawley	O
+rats	O
+received	O
+100	O
+mg	O
+/	O
+kg	O
+cocaine	O
+IP	O
+alone	O
+","	O
+5	O
+mg	O
+/	O
+kg	O
+diazepam	O
+alone	O
+","	O
+or	O
+a	O
+combination	O
+of	O
+diazepam	O
+and	O
+cocaine	O
+.	O
+	
+Three	O
+minutes	O
+later	O
+","	O
+groups	O
+were	O
+challenged	O
+with	O
+vehicle	O
+or	O
+flumazenil	O
+5	O
+or	O
+10	O
+mg	O
+/	O
+kg	O
+IP	O
+.	O
+	
+Animal	O
+behavior	O
+","	O
+seizures	B-NP
+(	O
+time	O
+to	O
+and	O
+incidence	O
+)	O
+","	O
+death	O
+(	O
+time	O
+to	O
+and	O
+incidence	O
+)	O
+","	O
+and	O
+cortical	O
+EEG	O
+tracings	O
+were	O
+recorded	O
+.	O
+	
+INTERVENTIONS	O
+:	O
+Administration	O
+of	O
+flumazenil	O
+to	O
+animals	O
+after	O
+they	O
+had	O
+received	O
+a	O
+combination	O
+dose	O
+of	O
+cocaine	O
+and	O
+diazepam	O
+.	O
+	
+RESULTS	O
+:	O
+In	O
+group	O
+1	O
+","	O
+animals	O
+received	O
+cocaine	O
+followed	O
+by	O
+vehicle	O
+.	O
+	
+This	O
+resulted	O
+in	O
+100	O
+%	O
+developing	O
+seizures	B-NP
+and	O
+death	O
+.	O
+	
+Group	O
+2	O
+received	O
+diazepam	O
+alone	O
+followed	O
+by	O
+vehicle	O
+.	O
+	
+Animals	O
+became	O
+somnolent	O
+and	O
+none	O
+died	O
+.	O
+	
+Group	O
+3	O
+received	O
+diazepam	O
+followed	O
+by	O
+5	O
+mg	O
+/	O
+kg	O
+flumazenil	O
+.	O
+	
+Animals	O
+became	O
+somnolent	O
+after	O
+diazepam	O
+and	O
+then	O
+active	O
+after	O
+flumazenil	O
+administration	O
+.	O
+	
+In	O
+group	O
+4	O
+","	O
+a	O
+combination	O
+of	O
+cocaine	O
+and	O
+diazepam	O
+was	O
+administered	O
+simultaneously	O
+.	O
+	
+This	O
+resulted	O
+in	O
+no	O
+overt	O
+or	O
+EEG	O
+-	O
+detectable	O
+seizures	B-NP
+and	O
+a	O
+50	O
+%	O
+incidence	O
+of	O
+death	O
+.	O
+	
+Group	O
+5	O
+received	O
+a	O
+similar	O
+combination	O
+of	O
+cocaine	O
+and	O
+diazepam	O
+","	O
+followed	O
+later	O
+by	O
+5	O
+mg	O
+/	O
+kg	O
+flumazenil	O
+.	O
+	
+This	O
+resulted	O
+in	O
+an	O
+increased	O
+incidence	O
+of	O
+seizures	B-NP
+","	O
+90	O
+%	O
+(	O
+P	O
+<	O
+.	O
+1	O
+)	O
+","	O
+and	O
+death	O
+","	O
+100	O
+%	O
+(	O
+P	O
+<	O
+or	O
+=	O
+.	O
+1	O
+)	O
+","	O
+compared	O
+with	O
+group	O
+4	O
+.	O
+	
+Group	O
+6	O
+received	O
+cocaine	O
+and	O
+diazepam	O
+followed	O
+by	O
+10	O
+mg	O
+/	O
+kg	O
+flumazenil	O
+.	O
+	
+This	O
+also	O
+resulted	O
+in	O
+an	O
+increased	O
+incidence	O
+of	O
+seizures	B-NP
+","	O
+90	O
+%	O
+(	O
+P	O
+<	O
+or	O
+=	O
+.	O
+1	O
+)	O
+","	O
+and	O
+death	O
+","	O
+90	O
+%	O
+(	O
+P	O
+<	O
+or	O
+=	O
+.	O
+5	O
+)	O
+","	O
+compared	O
+with	O
+group	O
+4	O
+.	O
+	
+CONCLUSION	O
+:	O
+Flumazenil	O
+can	O
+unmask	O
+seizures	B-NP
+and	O
+increase	O
+the	O
+incidence	O
+of	O
+death	O
+in	O
+a	O
+model	O
+of	O
+combined	O
+cocaine	O
+-	O
+diazepam	O
+intoxications	O
+.	O
+	
+Mechanisms	O
+for	O
+protective	O
+effects	O
+of	O
+free	O
+radical	O
+scavengers	O
+on	O
+gentamicin	O
+-	O
+mediated	O
+nephropathy	B-NP
+in	O
+rats	O
+.	O
+	
+Studies	O
+were	O
+performed	O
+to	O
+examine	O
+the	O
+mechanisms	O
+for	O
+the	O
+protective	O
+effects	O
+of	O
+free	O
+radical	O
+scavengers	O
+on	O
+gentamicin	O
+(	O
+GM	O
+)	O
+-	O
+mediated	O
+nephropathy	B-NP
+.	O
+	
+Administration	O
+of	O
+GM	O
+at	O
+40	O
+mg	O
+/	O
+kg	O
+sc	O
+for	O
+13	O
+days	O
+to	O
+rats	O
+induced	O
+a	O
+significant	O
+reduction	O
+in	O
+renal	O
+blood	O
+flow	O
+(	O
+RBF	O
+)	O
+and	O
+inulin	O
+clearance	O
+(	O
+CIn	O
+)	O
+as	O
+well	O
+as	O
+marked	O
+tubular	B-NP
+damage	I-NP
+.	O
+	
+A	O
+significant	O
+reduction	O
+in	O
+urinary	O
+guanosine	O
+3	O
+'	O
+","	O
+5	O
+'	O
+-	O
+cyclic	O
+monophosphate	O
+(	O
+cGMP	O
+)	O
+excretion	O
+and	O
+a	O
+significant	O
+increase	O
+in	O
+renal	O
+cortical	O
+renin	O
+and	O
+endothelin	O
+-	O
+1	O
+contents	O
+were	O
+also	O
+observed	O
+in	O
+GM	O
+-	O
+mediated	O
+nephropathy	B-NP
+.	O
+	
+Superoxide	O
+dismutase	O
+(	O
+SOD	O
+)	O
+or	O
+dimethylthiourea	O
+(	O
+DMTU	O
+)	O
+significantly	O
+lessened	O
+the	O
+GM	O
+-	O
+induced	O
+decrement	O
+in	O
+CIn	O
+.	O
+	
+The	O
+SOD	O
+-	O
+induced	O
+increase	O
+in	O
+glomerular	O
+filtration	O
+rate	O
+was	O
+associated	O
+with	O
+a	O
+marked	O
+improvement	O
+in	O
+RBF	O
+","	O
+an	O
+increase	O
+in	O
+urinary	O
+cGMP	O
+excretion	O
+","	O
+and	O
+a	O
+decrease	O
+in	O
+renal	O
+renin	O
+and	O
+endothelin	O
+-	O
+1	O
+content	O
+.	O
+	
+SOD	O
+did	O
+not	O
+attenuate	O
+the	O
+tubular	B-NP
+damage	I-NP
+.	O
+	
+In	O
+contrast	O
+","	O
+DMTU	O
+significantly	O
+reduced	O
+the	O
+tubular	B-NP
+damage	I-NP
+and	O
+lipid	O
+peroxidation	O
+","	O
+but	O
+it	O
+did	O
+not	O
+affect	O
+renal	O
+hemodynamics	O
+and	O
+vasoactive	O
+substances	O
+.	O
+	
+Neither	O
+SOD	O
+nor	O
+DMTU	O
+affected	O
+the	O
+renal	O
+cortical	O
+GM	O
+content	O
+in	O
+GM	O
+-	O
+treated	O
+rats	O
+.	O
+	
+These	O
+results	O
+suggest	O
+that	O
+1	O
+)	O
+both	O
+SOD	O
+and	O
+DMTU	O
+have	O
+protective	O
+effects	O
+on	O
+GM	O
+-	O
+mediated	O
+nephropathy	B-NP
+","	O
+2	O
+)	O
+the	O
+mechanisms	O
+for	O
+the	O
+protective	O
+effects	O
+differ	O
+for	O
+SOD	O
+and	O
+DMTU	O
+","	O
+and	O
+3	O
+)	O
+superoxide	O
+anions	O
+play	O
+a	O
+critical	O
+role	O
+in	O
+GM	O
+-	O
+induced	O
+renal	O
+vasoconstriction	O
+.	O
+	
+Cephalothin	O
+-	O
+induced	O
+immune	O
+hemolytic	B-NP
+anemia	I-NP
+.	O
+	
+A	O
+patient	O
+with	O
+renal	B-NP
+disease	I-NP
+developed	O
+Coombs	O
+-	O
+positive	O
+hemolytic	B-NP
+anemia	I-NP
+while	O
+receiving	O
+cephalothin	O
+therapy	O
+.	O
+	
+An	O
+anti	O
+-	O
+cephalothin	O
+IgG	O
+antibody	O
+was	O
+detected	O
+in	O
+the	O
+patient	O
+'	O
+s	O
+serum	O
+and	O
+in	O
+the	O
+eluates	O
+from	O
+her	O
+erythrocytes	O
+.	O
+	
+In	O
+addition	O
+","	O
+nonimmunologic	O
+binding	O
+of	O
+normal	O
+and	O
+patient	O
+'	O
+s	O
+serum	O
+proteins	O
+to	O
+her	O
+own	O
+and	O
+cephalothin	O
+-	O
+coated	O
+normal	O
+red	O
+cells	O
+was	O
+demonstrated	O
+.	O
+	
+Skin	O
+tests	O
+and	O
+in	O
+vitro	O
+lymphocyte	O
+stimulation	O
+revealed	O
+that	O
+the	O
+patient	O
+was	O
+sensitized	O
+to	O
+cephalothin	O
+and	O
+also	O
+to	O
+ampicillin	O
+.	O
+	
+Careful	O
+investigation	O
+of	O
+drug	O
+-	O
+induced	O
+hemolytic	B-NP
+anemias	I-NP
+reveals	O
+the	O
+complexity	O
+of	O
+the	O
+immune	O
+mechanisms	O
+involved	O
+.	O
+	
+Assessment	O
+of	O
+cardiomyocyte	O
+DNA	O
+synthesis	O
+during	O
+hypertrophy	B-NP
+in	O
+adult	O
+mice	O
+.	O
+	
+The	O
+ability	O
+of	O
+cardiomyocytes	O
+to	O
+synthesize	O
+DNA	O
+in	O
+response	O
+to	O
+experimentally	O
+induced	O
+cardiac	B-NP
+hypertrophy	I-NP
+was	O
+assessed	O
+in	O
+adult	O
+mice	O
+.	O
+	
+Isoproterenol	O
+delivered	O
+by	O
+osmotic	O
+minipump	O
+implantation	O
+in	O
+adult	O
+C3Heb	O
+/	O
+FeJ	O
+mice	O
+resulted	O
+in	O
+a	O
+46	O
+%	O
+increase	O
+in	O
+heart	O
+weight	O
+and	O
+a	O
+19	O
+.	O
+3	O
+%	O
+increase	O
+in	O
+cardiomyocyte	O
+area	O
+.	O
+	
+No	O
+DNA	O
+synthesis	O
+","	O
+as	O
+assessed	O
+by	O
+autoradiographic	O
+analysis	O
+of	O
+isolated	O
+cardiomyocytes	O
+","	O
+was	O
+observed	O
+in	O
+control	O
+or	O
+hypertrophic	B-NP
+hearts	I-NP
+.	O
+	
+A	O
+survey	O
+of	O
+15	O
+independent	O
+inbred	O
+strains	O
+of	O
+mice	O
+revealed	O
+that	O
+ventricular	O
+cardiomyocyte	O
+nuclear	O
+number	O
+ranged	O
+from	O
+3	O
+to	O
+13	O
+%	O
+mononucleate	O
+","	O
+suggesting	O
+that	O
+cardiomyocyte	O
+terminal	O
+differentiation	O
+is	O
+influenced	O
+directly	O
+or	O
+indirectly	O
+by	O
+genetic	O
+background	O
+.	O
+	
+To	O
+determine	O
+whether	O
+the	O
+capacity	O
+for	O
+reactive	O
+DNA	O
+synthesis	O
+was	O
+also	O
+subject	O
+to	O
+genetic	O
+regulation	O
+","	O
+cardiac	B-NP
+hypertrophy	I-NP
+was	O
+induced	O
+in	O
+the	O
+strains	O
+of	O
+mice	O
+comprising	O
+the	O
+extremes	O
+of	O
+the	O
+nuclear	O
+number	O
+survey	O
+.	O
+	
+These	O
+data	O
+indicate	O
+that	O
+adult	O
+mouse	O
+atrial	O
+and	O
+ventricular	O
+cardiomyocytes	O
+do	O
+not	O
+synthesize	O
+DNA	O
+in	O
+response	O
+to	O
+isoproterenol	O
+-	O
+induced	O
+cardiac	B-NP
+hypertrophy	I-NP
+.	O
+	
+Central	O
+cardiovascular	O
+effects	O
+of	O
+AVP	O
+and	O
+ANP	O
+in	O
+normotensive	O
+and	O
+spontaneously	O
+hypertensive	B-NP
+rats	O
+.	O
+	
+The	O
+purpose	O
+of	O
+the	O
+present	O
+study	O
+was	O
+to	O
+compare	O
+influence	O
+of	O
+central	O
+arginine	O
+vasopressin	O
+(	O
+AVP	O
+)	O
+and	O
+of	O
+atrial	O
+natriuretic	O
+peptide	O
+(	O
+ANP	O
+)	O
+on	O
+control	O
+of	O
+arterial	O
+blood	O
+pressure	O
+(	O
+MAP	O
+)	O
+and	O
+heart	O
+rate	O
+(	O
+HR	O
+)	O
+in	O
+normotensive	O
+(	O
+WKY	O
+)	O
+and	O
+spontaneously	O
+hypertensive	B-NP
+(	O
+SHR	O
+)	O
+rats	O
+.	O
+	
+Three	O
+series	O
+of	O
+experiments	O
+were	O
+performed	O
+on	O
+30	O
+WKY	O
+and	O
+30	O
+SHR	O
+","	O
+chronically	O
+instrumented	O
+with	O
+guide	O
+tubes	O
+in	O
+the	O
+lateral	O
+ventricle	O
+(	O
+LV	O
+)	O
+and	O
+arterial	O
+and	O
+venous	O
+catheters	O
+.	O
+	
+MAP	O
+and	O
+HR	O
+were	O
+monitored	O
+before	O
+and	O
+after	O
+i	O
+.	O
+v	O
+.	O
+injections	O
+of	O
+either	O
+vehicle	O
+or	O
+1	O
+","	O
+10	O
+and	O
+50	O
+ng	O
+of	O
+AVP	O
+and	O
+25	O
+","	O
+125	O
+and	O
+500	O
+ng	O
+of	O
+ANP	O
+.	O
+	
+Sensitivity	O
+of	O
+cardiac	O
+component	O
+of	O
+baroreflex	O
+(	O
+CCB	O
+)	O
+","	O
+expressed	O
+as	O
+a	O
+slope	O
+of	O
+the	O
+regression	O
+line	O
+was	O
+determined	O
+from	O
+relationships	O
+between	O
+systolic	O
+arterial	O
+pressure	O
+(	O
+SAP	O
+)	O
+and	O
+HR	O
+period	O
+(	O
+HRp	O
+)	O
+during	O
+phenylephrine	O
+(	O
+Phe	O
+)	O
+-	O
+induced	O
+hypertension	B-NP
+and	O
+sodium	O
+nitroprusside	O
+(	O
+SN	O
+)	O
+-	O
+induced	O
+hypotension	B-NP
+.	O
+	
+CCB	O
+was	O
+measured	O
+before	O
+and	O
+after	O
+administration	O
+of	O
+either	O
+vehicle	O
+","	O
+AVP	O
+","	O
+ANP	O
+","	O
+or	O
+both	O
+peptides	O
+together	O
+.	O
+	
+Increases	O
+of	O
+MAP	O
+occurred	O
+after	O
+LV	O
+administration	O
+of	O
+1	O
+","	O
+10	O
+and	O
+50	O
+ng	O
+of	O
+AVP	O
+in	O
+WKY	O
+and	O
+of	O
+10	O
+and	O
+50	O
+ng	O
+in	O
+SHR	O
+.	O
+	
+ANP	O
+did	O
+not	O
+cause	O
+significant	O
+changes	O
+in	O
+MAP	O
+in	O
+both	O
+strains	O
+as	O
+compared	O
+to	O
+vehicle	O
+","	O
+but	O
+it	O
+abolished	O
+AVP	O
+-	O
+induced	O
+MAP	O
+increase	O
+in	O
+WKY	O
+and	O
+SHR	O
+.	O
+	
+CCB	O
+was	O
+reduced	O
+in	O
+WKY	O
+and	O
+SHR	O
+after	O
+LV	O
+administration	O
+of	O
+AVP	O
+during	O
+SN	O
+-	O
+induced	O
+hypotension	B-NP
+.	O
+	
+In	O
+SHR	O
+but	O
+not	O
+in	O
+WKY	O
+administration	O
+of	O
+ANP	O
+","	O
+AVP	O
+and	O
+ANP	O
++	O
+AVP	O
+decreased	O
+CCB	O
+during	O
+Phe	O
+-	O
+induced	O
+MAP	O
+elevation	O
+.	O
+	
+The	O
+results	O
+indicate	O
+that	O
+centrally	O
+applied	O
+AVP	O
+and	O
+ANP	O
+exert	O
+differential	O
+effects	O
+on	O
+blood	O
+pressure	O
+and	O
+baroreflex	O
+control	O
+of	O
+heart	O
+rate	O
+in	O
+WKY	O
+and	O
+SHR	O
+and	O
+suggest	O
+interaction	O
+of	O
+these	O
+two	O
+peptides	O
+in	O
+blood	O
+pressure	O
+regulation	O
+at	O
+the	O
+level	O
+of	O
+central	O
+nervous	O
+system	O
+.	O
+	
+Cutaneous	O
+exposure	O
+to	O
+warfarin	O
+-	O
+like	O
+anticoagulant	O
+causing	O
+an	O
+intracerebral	B-NP
+hemorrhage	I-NP
+:	O
+a	O
+case	O
+report	O
+.	O
+	
+A	O
+case	O
+of	O
+intercerebral	O
+hematoma	B-NP
+due	O
+to	O
+warfarin	O
+-	O
+induced	O
+coagulopathy	B-NP
+is	O
+presented	O
+.	O
+	
+The	O
+39	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+had	O
+spread	O
+a	O
+warfarin	O
+-	O
+type	O
+rat	O
+poison	O
+around	O
+her	O
+house	O
+weekly	O
+using	O
+her	O
+bare	O
+hands	O
+","	O
+with	O
+no	O
+washing	O
+post	O
+application	O
+.	O
+	
+Percutaneous	O
+absorption	O
+of	O
+warfarin	O
+causing	O
+coagulopathy	B-NP
+","	O
+reported	O
+three	O
+times	O
+in	O
+the	O
+past	O
+","	O
+is	O
+a	O
+significant	O
+risk	O
+if	O
+protective	O
+measures	O
+","	O
+such	O
+as	O
+gloves	O
+","	O
+are	O
+not	O
+used	O
+.	O
+	
+An	O
+adverse	O
+drug	O
+interaction	O
+with	O
+piroxicam	O
+","	O
+which	O
+she	O
+took	O
+occasionally	O
+","	O
+may	O
+have	O
+exacerbated	O
+the	O
+coagulopathy	B-NP
+.	O
+	
+Pediatric	O
+heart	O
+transplantation	O
+without	O
+chronic	O
+maintenance	O
+steroids	O
+.	O
+	
+From	O
+1986	O
+to	O
+February	O
+1993	O
+","	O
+40	O
+children	O
+aged	O
+2	O
+months	O
+to	O
+18	O
+years	O
+(	O
+average	O
+age	O
+10	O
+.	O
+4	O
++	O
+/	O
+-	O
+5	O
+.	O
+8	O
+years	O
+)	O
+underwent	O
+heart	O
+transplantation	O
+.	O
+	
+Indications	O
+for	O
+transplantation	O
+were	O
+idiopathic	B-NP
+cardiomyopathy	I-NP
+(	O
+52	O
+%	O
+)	O
+","	O
+congenital	B-NP
+heart	I-NP
+disease	I-NP
+(	O
+35	O
+%	O
+)	O
+with	O
+and	O
+without	O
+prior	O
+repair	O
+(	O
+71	O
+%	O
+and	O
+29	O
+%	O
+","	O
+respectively	O
+)	O
+","	O
+hypertrophic	B-NP
+cardiomyopathy	I-NP
+(	O
+5	O
+%	O
+)	O
+","	O
+valvular	B-NP
+heart	I-NP
+disease	I-NP
+(	O
+3	O
+%	O
+)	O
+","	O
+and	O
+doxorubicin	O
+cardiomyopathy	B-NP
+(	O
+5	O
+%	O
+)	O
+.	O
+	
+Patients	O
+were	O
+managed	O
+with	O
+cyclosporine	O
+and	O
+azathioprine	O
+.	O
+	
+No	O
+prophylaxis	O
+with	O
+antilymphocyte	O
+globulin	O
+was	O
+used	O
+.	O
+	
+Steroids	O
+were	O
+given	O
+to	O
+39	O
+%	O
+of	O
+patients	O
+for	O
+refractory	O
+rejection	O
+","	O
+but	O
+weaning	O
+was	O
+always	O
+attempted	O
+and	O
+generally	O
+successful	O
+(	O
+64	O
+%	O
+)	O
+.	O
+	
+Five	O
+patients	O
+(	O
+14	O
+%	O
+)	O
+received	O
+maintenance	O
+steroids	O
+.	O
+	
+Four	O
+patients	O
+died	O
+in	O
+the	O
+perioperative	O
+period	O
+and	O
+one	O
+died	O
+4	O
+months	O
+later	O
+.	O
+	
+There	O
+have	O
+been	O
+no	O
+deaths	O
+related	O
+to	O
+rejection	O
+or	O
+infection	B-NP
+.	O
+	
+Average	O
+follow	O
+-	O
+up	O
+was	O
+36	O
++	O
+/	O
+-	O
+19	O
+months	O
+(	O
+range	O
+1	O
+to	O
+65	O
+months	O
+)	O
+.	O
+	
+Cumulative	O
+survival	O
+is	O
+88	O
+%	O
+at	O
+5	O
+years	O
+.	O
+	
+In	O
+patients	O
+less	O
+than	O
+7	O
+years	O
+of	O
+age	O
+","	O
+rejection	O
+was	O
+monitored	O
+noninvasively	O
+.	O
+	
+In	O
+the	O
+first	O
+postoperative	O
+month	O
+","	O
+89	O
+%	O
+of	O
+patients	O
+were	O
+treated	O
+for	O
+rejection	O
+.	O
+	
+Freedom	O
+from	O
+serious	O
+infections	B-NP
+was	O
+83	O
+%	O
+at	O
+1	O
+month	O
+and	O
+65	O
+%	O
+at	O
+1	O
+year	O
+.	O
+	
+Cytomegalovirus	B-NP
+infections	I-NP
+were	O
+treated	O
+successfully	O
+with	O
+ganciclovir	O
+in	O
+11	O
+patients	O
+.	O
+	
+No	O
+impairment	O
+of	O
+growth	O
+was	O
+observed	O
+in	O
+children	O
+who	O
+underwent	O
+transplantation	O
+compared	O
+with	O
+a	O
+control	O
+population	O
+.	O
+	
+Twenty	O
+-	O
+one	O
+patients	O
+(	O
+60	O
+%	O
+)	O
+have	O
+undergone	O
+annual	O
+catheterizations	O
+and	O
+no	O
+sign	O
+of	O
+graft	O
+atherosclerosis	B-NP
+has	O
+been	O
+observed	O
+.	O
+	
+Seizures	B-NP
+occurred	O
+in	O
+five	O
+patients	O
+(	O
+14	O
+%	O
+)	O
+and	O
+hypertension	B-NP
+was	O
+treated	O
+in	O
+10	O
+patients	O
+(	O
+28	O
+%	O
+)	O
+.	O
+	
+No	O
+patient	O
+was	O
+disabled	O
+and	O
+no	O
+lymphoproliferative	B-NP
+disorder	I-NP
+was	O
+observed	O
+.	O
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+	
+Delirium	B-NP
+during	O
+fluoxetine	O
+treatment	O
+.	O
+	
+A	O
+case	O
+report	O
+.	O
+	
+The	O
+correlation	O
+between	O
+high	O
+serum	O
+tricyclic	O
+antidepressant	O
+concentrations	O
+and	O
+central	O
+nervous	O
+system	O
+side	O
+effects	O
+has	O
+been	O
+well	O
+established	O
+.	O
+	
+Only	O
+a	O
+few	O
+reports	O
+exist	O
+","	O
+however	O
+","	O
+on	O
+the	O
+relationship	O
+between	O
+the	O
+serum	O
+concentrations	O
+of	O
+selective	O
+serotonin	O
+reuptake	O
+inhibitors	O
+(	O
+SSRIs	O
+)	O
+and	O
+their	O
+toxic	O
+effects	O
+.	O
+	
+In	O
+some	O
+cases	O
+","	O
+a	O
+high	O
+serum	O
+concentration	O
+of	O
+citalopram	O
+(	O
+>	O
+600	O
+nmol	O
+/	O
+L	O
+)	O
+in	O
+elderly	O
+patients	O
+has	O
+been	O
+associated	O
+with	O
+increased	O
+somnolence	B-NP
+and	O
+movement	B-NP
+difficulties	I-NP
+.	O
+	
+Widespread	O
+cognitive	B-NP
+disorders	I-NP
+","	O
+such	O
+as	O
+delirium	B-NP
+","	O
+have	O
+not	O
+been	O
+previously	O
+linked	O
+with	O
+high	O
+blood	O
+levels	O
+of	O
+SSRIs	O
+.	O
+	
+In	O
+this	O
+report	O
+","	O
+we	O
+describe	O
+a	O
+patient	O
+with	O
+acute	O
+hyperkinetic	B-NP
+delirium	B-NP
+connected	O
+with	O
+a	O
+high	O
+serum	O
+total	O
+fluoxetine	O
+(	O
+fluoxetine	O
+plus	O
+desmethylfluoxetine	O
+)	O
+concentration	O
+.	O
+	
+Pulmonary	B-NP
+edema	I-NP
+and	O
+shock	B-NP
+after	O
+high	O
+-	O
+dose	O
+aracytine	O
+-	O
+C	O
+for	O
+lymphoma	B-NP
+;	O
+possible	O
+role	O
+of	O
+TNF	O
+-	O
+alpha	O
+and	O
+PAF	O
+.	O
+	
+Four	O
+out	O
+of	O
+23	O
+consecutive	O
+patients	O
+treated	O
+with	O
+high	O
+-	O
+dose	O
+Ara	O
+-	O
+C	O
+for	O
+lymphomas	B-NP
+in	O
+our	O
+institution	O
+developed	O
+a	O
+strikingly	O
+similar	O
+syndrome	O
+during	O
+the	O
+perfusion	O
+.	O
+	
+It	O
+was	O
+characterized	O
+by	O
+the	O
+onset	O
+of	O
+fever	B-NP
+","	O
+diarrhea	B-NP
+","	O
+shock	B-NP
+","	O
+pulmonary	B-NP
+edema	I-NP
+","	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+","	O
+metabolic	B-NP
+acidosis	I-NP
+","	O
+weight	B-NP
+gain	I-NP
+and	O
+leukocytosis	B-NP
+.	O
+	
+Thorough	O
+bacteriological	O
+screening	O
+failed	O
+to	O
+provide	O
+evidence	O
+of	O
+infection	B-NP
+.	O
+	
+Sequential	O
+biological	O
+assays	O
+of	O
+IL	O
+-	O
+1	O
+","	O
+IL	O
+-	O
+2	O
+","	O
+TNF	O
+and	O
+PAF	O
+were	O
+performed	O
+during	O
+Ara	O
+-	O
+C	O
+infusion	O
+to	O
+ten	O
+patients	O
+","	O
+including	O
+the	O
+four	O
+who	O
+developed	O
+the	O
+syndrome	O
+.	O
+	
+TNF	O
+and	O
+PAF	O
+activity	O
+was	O
+found	O
+in	O
+the	O
+serum	O
+of	O
+respectively	O
+two	O
+and	O
+four	O
+of	O
+the	O
+cases	O
+","	O
+but	O
+not	O
+in	O
+the	O
+six	O
+controls	O
+.	O
+	
+As	O
+TNF	O
+and	O
+PAF	O
+are	O
+thought	O
+to	O
+be	O
+involved	O
+in	O
+the	O
+development	O
+of	O
+septic	O
+shock	B-NP
+and	O
+adult	B-NP
+respiratory	I-NP
+distress	I-NP
+syndrome	I-NP
+","	O
+we	O
+hypothesize	O
+that	O
+high	O
+-	O
+dose	O
+Ara	O
+-	O
+C	O
+may	O
+be	O
+associated	O
+with	O
+cytokine	O
+release	O
+.	O
+	
+Protective	O
+effect	O
+of	O
+clentiazem	O
+against	O
+epinephrine	O
+-	O
+induced	O
+cardiac	B-NP
+injury	I-NP
+in	O
+rats	O
+.	O
+	
+We	O
+investigated	O
+the	O
+effects	O
+of	O
+clentiazem	O
+","	O
+a	O
+1	O
+","	O
+5	O
+-	O
+benzothiazepine	O
+calcium	O
+antagonist	O
+","	O
+on	O
+epinephrine	O
+-	O
+induced	O
+cardiomyopathy	B-NP
+in	O
+rats	O
+.	O
+	
+With	O
+2	O
+-	O
+week	O
+chronic	O
+epinephrine	O
+infusion	O
+","	O
+16	O
+of	O
+30	O
+rats	O
+died	O
+within	O
+4	O
+days	O
+","	O
+and	O
+severe	O
+ischemic	B-NP
+lesions	I-NP
+and	O
+fibrosis	B-NP
+of	O
+the	O
+left	O
+ventricles	O
+were	O
+observed	O
+.	O
+	
+In	O
+epinephrine	O
+-	O
+treated	O
+rats	O
+","	O
+left	O
+atrial	O
+and	O
+left	O
+ventricular	O
+papillary	O
+muscle	O
+contractile	O
+responses	O
+to	O
+isoproterenol	O
+were	O
+reduced	O
+","	O
+but	O
+responses	O
+to	O
+calcium	O
+were	O
+normal	O
+or	O
+enhanced	O
+compared	O
+to	O
+controls	O
+.	O
+	
+Left	O
+ventricular	O
+alpha	O
+and	O
+beta	O
+adrenoceptor	O
+densities	O
+were	O
+also	O
+reduced	O
+compared	O
+to	O
+controls	O
+.	O
+	
+Treatment	O
+with	O
+clentiazem	O
+prevented	O
+epinephrine	O
+-	O
+induced	O
+death	O
+(	O
+P	O
+<	O
+.	O
+5	O
+)	O
+","	O
+and	O
+attenuated	O
+the	O
+ventricular	O
+ischemic	B-NP
+lesions	I-NP
+and	O
+fibrosis	B-NP
+","	O
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+.	O
+	
+Left	O
+atrial	O
+and	O
+left	O
+ventricular	O
+papillary	O
+muscle	O
+contractile	O
+responses	O
+to	O
+isoproterenol	O
+were	O
+reduced	O
+compared	O
+to	O
+controls	O
+in	O
+groups	O
+treated	O
+with	O
+clentiazem	O
+alone	O
+","	O
+but	O
+combined	O
+with	O
+epinephrine	O
+","	O
+clentiazem	O
+restored	O
+left	O
+atrial	O
+responses	O
+and	O
+enhanced	O
+left	O
+ventricular	O
+papillary	O
+responses	O
+to	O
+isoproterenol	O
+.	O
+	
+On	O
+the	O
+other	O
+hand	O
+clentiazem	O
+did	O
+not	O
+prevent	O
+epinephrine	O
+-	O
+induced	O
+down	O
+-	O
+regulation	O
+of	O
+alpha	O
+and	O
+beta	O
+adrenoceptors	O
+.	O
+	
+Interestingly	O
+","	O
+clentiazem	O
+","	O
+infused	O
+alone	O
+","	O
+resulted	O
+in	O
+decreased	O
+adrenergic	O
+receptor	O
+densities	O
+in	O
+the	O
+left	O
+ventricle	O
+.	O
+	
+Clentiazem	O
+also	O
+did	O
+not	O
+prevent	O
+the	O
+enhanced	O
+responses	O
+to	O
+calcium	O
+seen	O
+in	O
+the	O
+epinephrine	O
+-	O
+treated	O
+animals	O
+","	O
+although	O
+the	O
+high	O
+dose	O
+of	O
+clentiazem	O
+partially	O
+attenuated	O
+the	O
+maximal	O
+response	O
+to	O
+calcium	O
+compared	O
+to	O
+epinephrine	O
+-	O
+treated	O
+animals	O
+.	O
+	
+In	O
+conclusion	O
+","	O
+clentiazem	O
+attenuated	O
+epinephrine	O
+-	O
+induced	O
+cardiac	B-NP
+injury	I-NP
+","	O
+possibly	O
+through	O
+its	O
+effect	O
+on	O
+the	O
+adrenergic	O
+pathway	O
+.	O
+	
+Kaliuretic	O
+effect	O
+of	O
+L	O
+-	O
+dopa	O
+treatment	O
+in	O
+parkinsonian	B-NP
+patients	O
+.	O
+	
+Hypokalemia	B-NP
+","	O
+sometimes	O
+severe	O
+","	O
+was	O
+observed	O
+in	O
+some	O
+L	O
+-	O
+dopa	O
+-	O
+treated	O
+parkinsonian	B-NP
+patients	O
+.	O
+	
+The	O
+influence	O
+of	O
+L	O
+-	O
+dopa	O
+on	O
+the	O
+renal	O
+excretion	O
+of	O
+potassium	O
+was	O
+studied	O
+in	O
+3	O
+patients	O
+with	O
+hypokalemia	B-NP
+and	O
+in	O
+5	O
+normokalemic	O
+patients	O
+by	O
+determination	O
+of	O
+renal	O
+plasma	O
+flow	O
+","	O
+glomerular	O
+filtration	O
+rate	O
+","	O
+plasma	O
+concentration	O
+of	O
+potassium	O
+and	O
+sodium	O
+as	O
+well	O
+as	O
+urinary	O
+excretion	O
+of	O
+potassium	O
+","	O
+sodium	O
+and	O
+aldosterone	O
+.	O
+	
+L	O
+-	O
+Dopa	O
+intake	O
+was	O
+found	O
+to	O
+cause	O
+an	O
+increased	O
+excretion	O
+of	O
+potassium	O
+","	O
+and	O
+sometimes	O
+also	O
+of	O
+sodium	O
+","	O
+in	O
+the	O
+hypokalemic	O
+but	O
+not	O
+in	O
+the	O
+normokalemic	O
+patients	O
+.	O
+	
+This	O
+effect	O
+on	O
+the	O
+renal	O
+function	O
+could	O
+be	O
+prohibited	O
+by	O
+the	O
+administration	O
+of	O
+a	O
+peripheral	O
+dopa	O
+decarbodylase	O
+inhibitor	O
+.	O
+	
+It	O
+is	O
+not	O
+known	O
+why	O
+this	O
+effect	O
+occurred	O
+in	O
+some	O
+individuals	O
+but	O
+not	O
+in	O
+others	O
+","	O
+but	O
+our	O
+results	O
+indicate	O
+a	O
+correlation	O
+between	O
+aldosterone	O
+production	O
+and	O
+this	O
+renal	O
+effect	O
+of	O
+L	O
+-	O
+dopa	O
+.	O
+	
+Cocaine	O
+induced	O
+myocardial	B-NP
+ischemia	I-NP
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+myocardial	B-NP
+ischemia	I-NP
+induced	O
+by	O
+cocaine	O
+.	O
+	
+The	O
+ischemia	B-NP
+probably	O
+induced	O
+by	O
+coronary	B-NP
+artery	I-NP
+spasm	I-NP
+was	O
+reversed	O
+by	O
+nitroglycerin	O
+and	O
+calcium	O
+blocking	O
+agents	O
+.	O
+	
+Doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+monitored	O
+by	O
+ECG	O
+in	O
+freely	O
+moving	O
+mice	O
+.	O
+	
+A	O
+new	O
+model	O
+to	O
+test	O
+potential	O
+protectors	O
+.	O
+	
+In	O
+laboratory	O
+animals	O
+","	O
+histology	O
+is	O
+most	O
+commonly	O
+used	O
+to	O
+study	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+.	O
+	
+However	O
+","	O
+for	O
+monitoring	O
+during	O
+treatment	O
+","	O
+large	O
+numbers	O
+of	O
+animals	O
+are	O
+needed	O
+.	O
+	
+Recently	O
+we	O
+developed	O
+a	O
+new	O
+method	O
+to	O
+measure	O
+ECG	O
+values	O
+in	O
+freely	O
+moving	O
+mice	O
+by	O
+telemetry	O
+.	O
+	
+With	O
+this	O
+model	O
+we	O
+investigated	O
+the	O
+effect	O
+of	O
+chronic	O
+doxorubicin	O
+administration	O
+on	O
+the	O
+ECG	O
+of	O
+freely	O
+moving	O
+BALB	O
+/	O
+c	O
+mice	O
+and	O
+the	O
+efficacy	O
+of	O
+ICRF	O
+-	O
+187	O
+as	O
+a	O
+protective	O
+agent	O
+.	O
+	
+The	O
+ST	O
+interval	O
+significantly	O
+widened	O
+from	O
+15	O
+.	O
+0	O
++	O
+/	O
+-	O
+1	O
+.	O
+5	O
+to	O
+56	O
+.	O
+8	O
++	O
+/	O
+-	O
+11	O
+.	O
+8	O
+ms	O
+in	O
+week	O
+10	O
+(	O
+7	O
+weekly	O
+doses	O
+of	O
+4	O
+mg	O
+/	O
+kg	O
+doxorubicin	O
+given	O
+i	O
+.	O
+v	O
+.	O
+plus	O
+3	O
+weeks	O
+of	O
+observation	O
+)	O
+.	O
+	
+The	O
+ECG	O
+of	O
+the	O
+control	O
+animals	O
+did	O
+not	O
+change	O
+during	O
+the	O
+entire	O
+study	O
+.	O
+	
+After	O
+sacrifice	O
+the	O
+hearts	O
+of	O
+doxorubicin	O
+-	O
+treated	O
+animals	O
+were	O
+enlarged	O
+and	O
+the	O
+atria	O
+were	O
+hypertrophic	B-NP
+.	O
+	
+As	O
+this	O
+schedule	O
+exerted	O
+more	O
+toxicity	B-NP
+than	O
+needed	O
+to	O
+investigate	O
+protective	O
+agents	O
+","	O
+the	O
+protection	O
+of	O
+ICRF	O
+-	O
+187	O
+was	O
+determined	O
+using	O
+a	O
+dose	O
+schedule	O
+with	O
+lower	O
+general	O
+toxicity	B-NP
+(	O
+6	O
+weekly	O
+doses	O
+of	O
+4	O
+mg	O
+/	O
+kg	O
+doxorubicin	O
+given	O
+i	O
+.	O
+v	O
+.	O
+plus	O
+2	O
+weeks	O
+of	O
+observation	O
+)	O
+.	O
+	
+On	O
+this	O
+schedule	O
+","	O
+the	O
+animals	O
+'	O
+hearts	O
+appeared	O
+normal	O
+after	O
+sacrifice	O
+and	O
+ICRF	O
+-	O
+187	O
+(	O
+50	O
+mg	O
+/	O
+kg	O
+given	O
+i	O
+.	O
+p	O
+.	O
+1	O
+h	O
+before	O
+doxorubicin	O
+)	O
+provided	O
+almost	O
+full	O
+protection	O
+.	O
+	
+These	O
+data	O
+were	O
+confirmed	O
+by	O
+histology	O
+.	O
+	
+The	O
+results	O
+indicate	O
+that	O
+this	O
+new	O
+model	O
+is	O
+very	O
+sensitive	O
+and	O
+enables	O
+monitoring	O
+of	O
+the	O
+development	O
+of	O
+cardiotoxicity	B-NP
+with	O
+time	O
+.	O
+	
+These	O
+findings	O
+result	O
+in	O
+a	O
+model	O
+that	O
+allows	O
+the	O
+testing	O
+of	O
+protectors	O
+against	O
+doxorubicin	O
+-	O
+induced	O
+cardiotoxicity	B-NP
+as	O
+demonstrated	O
+by	O
+the	O
+protection	O
+provided	O
+by	O
+ICRF	O
+-	O
+187	O
+.	O
+	
+Epinephrine	O
+dysrhythmogenicity	O
+is	O
+not	O
+enhanced	O
+by	O
+subtoxic	O
+bupivacaine	O
+in	O
+dogs	O
+.	O
+	
+Since	O
+bupivacaine	O
+and	O
+epinephrine	O
+may	O
+both	O
+precipitate	O
+dysrhythmias	B-NP
+","	O
+circulating	O
+bupivacaine	O
+during	O
+regional	O
+anesthesia	O
+could	O
+potentiate	O
+dysrhythmogenic	O
+effects	O
+of	O
+epinephrine	O
+.	O
+	
+We	O
+therefore	O
+examined	O
+whether	O
+bupivacaine	O
+alters	O
+the	O
+dysrhythmogenicity	O
+of	O
+subsequent	O
+administration	O
+of	O
+epinephrine	O
+in	O
+conscious	O
+","	O
+healthy	O
+dogs	O
+and	O
+in	O
+anesthetized	O
+dogs	O
+with	O
+myocardial	B-NP
+infarction	I-NP
+.	O
+	
+Forty	O
+-	O
+one	O
+conscious	O
+dogs	O
+received	O
+10	O
+micrograms	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+epinephrine	O
+.	O
+	
+Seventeen	O
+animals	O
+responded	O
+with	O
+ventricular	B-NP
+tachycardia	I-NP
+(	O
+VT	B-NP
+)	O
+within	O
+3	O
+min	O
+.	O
+	
+After	O
+3	O
+h	O
+","	O
+these	O
+responders	O
+randomly	O
+received	O
+1	O
+or	O
+2	O
+mg	O
+/	O
+kg	O
+bupivacaine	O
+or	O
+saline	O
+over	O
+5	O
+min	O
+","	O
+followed	O
+by	O
+10	O
+micrograms	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+epinephrine	O
+.	O
+	
+In	O
+the	O
+bupivacaine	O
+groups	O
+","	O
+epinephrine	O
+caused	O
+fewer	O
+prodysrhythmic	O
+effects	O
+than	O
+without	O
+bupivacaine	O
+.	O
+	
+VT	B-NP
+appeared	O
+in	O
+fewer	O
+dogs	O
+and	O
+at	O
+a	O
+later	O
+time	O
+","	O
+and	O
+there	O
+were	O
+more	O
+sinoatrial	O
+beats	O
+and	O
+less	O
+ectopies	O
+.	O
+	
+Epinephrine	O
+shortened	O
+QT	O
+less	O
+after	O
+bupivacaine	O
+than	O
+in	O
+control	O
+animals	O
+.	O
+	
+One	O
+day	O
+after	O
+experimental	O
+myocardial	B-NP
+infarction	I-NP
+","	O
+six	O
+additional	O
+halothane	O
+-	O
+anesthetized	O
+dogs	O
+received	O
+4	O
+micrograms	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+epinephrine	O
+until	O
+VT	B-NP
+appeared	O
+.	O
+	
+After	O
+45	O
+min	O
+","	O
+1	O
+mg	O
+/	O
+kg	O
+bupivacaine	O
+was	O
+injected	O
+over	O
+5	O
+min	O
+","	O
+again	O
+followed	O
+by	O
+4	O
+micrograms	O
+.	O
+kg	O
+-	O
+1	O
+.	O
+min	O
+-	O
+1	O
+epinephrine	O
+.	O
+	
+In	O
+these	O
+dogs	O
+","	O
+the	O
+prodysrhythmic	O
+response	O
+to	O
+epinephrine	O
+was	O
+also	O
+mitigated	O
+by	O
+preceding	O
+bupivacaine	O
+.	O
+	
+Bupivacaine	O
+antagonizes	O
+epinephrine	O
+dysrhythmogenicity	O
+in	O
+conscious	O
+dogs	O
+susceptible	O
+to	O
+VT	B-NP
+and	O
+in	O
+anesthetized	O
+dogs	O
+with	O
+spontaneous	O
+postinfarct	O
+dysrhythmias	B-NP
+.	O
+	
+There	O
+is	O
+no	O
+evidence	O
+that	O
+systemic	O
+subtoxic	O
+bupivacaine	O
+administration	O
+enhances	O
+the	O
+dysrhythmogenicity	O
+of	O
+subsequent	O
+epinephrine	O
+.	O
+	
+Milk	B-NP
+-	I-NP
+alkali	I-NP
+syndrome	I-NP
+induced	O
+by	O
+1	O
+","	O
+25	O
+(	O
+OH	O
+)	O
+2D	O
+in	O
+a	O
+patient	O
+with	O
+hypoparathyroidism	B-NP
+.	O
+	
+Milk	B-NP
+-	I-NP
+alkali	I-NP
+syndrome	I-NP
+was	O
+first	O
+described	O
+70	O
+years	O
+ago	O
+in	O
+the	O
+context	O
+of	O
+the	O
+treatment	O
+of	O
+peptic	B-NP
+ulcer	I-NP
+disease	I-NP
+with	O
+large	O
+amounts	O
+of	O
+calcium	O
+and	O
+alkali	O
+.	O
+	
+Although	O
+with	O
+current	O
+ulcer	B-NP
+therapy	O
+(	O
+H	O
+-	O
+2	O
+blockers	O
+","	O
+omeprazole	O
+","	O
+and	O
+sucralfate	O
+)	O
+","	O
+the	O
+frequency	O
+of	O
+milk	B-NP
+-	I-NP
+alkali	I-NP
+syndrome	I-NP
+has	O
+decreased	O
+significantly	O
+","	O
+the	O
+classic	O
+triad	O
+of	O
+hypercalcemia	B-NP
+","	O
+alkalosis	B-NP
+","	O
+and	O
+renal	B-NP
+impairment	I-NP
+remains	O
+the	O
+hallmark	O
+of	O
+the	O
+syndrome	O
+.	O
+	
+Milk	B-NP
+-	I-NP
+alkali	I-NP
+syndrome	I-NP
+can	O
+present	O
+serious	O
+and	O
+occasionally	O
+life	O
+-	O
+threatening	O
+illness	O
+unless	O
+diagnosed	O
+and	O
+treated	O
+appropriately	O
+.	O
+	
+This	O
+article	O
+presents	O
+a	O
+patient	O
+with	O
+hypoparathyroidism	B-NP
+who	O
+was	O
+treated	O
+with	O
+calcium	O
+carbonate	O
+and	O
+calcitriol	O
+resulting	O
+in	O
+two	O
+admissions	O
+to	O
+the	O
+hospital	O
+for	O
+milk	B-NP
+-	I-NP
+alkali	I-NP
+syndrome	I-NP
+.	O
+	
+The	O
+patient	O
+was	O
+successfully	O
+treated	O
+with	O
+intravenous	O
+pamidronate	O
+on	O
+his	O
+first	O
+admission	O
+and	O
+with	O
+hydrocortisone	O
+on	O
+the	O
+second	O
+.	O
+	
+This	O
+illustrates	O
+intravenous	O
+pamidronate	O
+as	O
+a	O
+valuable	O
+therapeutic	O
+tool	O
+when	O
+milk	B-NP
+-	I-NP
+alkali	I-NP
+syndrome	I-NP
+presents	O
+as	O
+hypercalcemic	B-NP
+emergency	I-NP
+.	O
+	
+Famotidine	O
+-	O
+associated	O
+delirium	B-NP
+.	O
+	
+A	O
+series	O
+of	O
+six	O
+cases	O
+.	O
+	
+Famotidine	O
+is	O
+a	O
+histamine	O
+H2	O
+-	O
+receptor	O
+antagonist	O
+used	O
+in	O
+inpatient	O
+settings	O
+for	O
+prevention	O
+of	O
+stress	O
+ulcers	B-NP
+and	O
+is	O
+showing	O
+increasing	O
+popularity	O
+because	O
+of	O
+its	O
+low	O
+cost	O
+.	O
+	
+Although	O
+all	O
+of	O
+the	O
+currently	O
+available	O
+H2	O
+-	O
+receptor	O
+antagonists	O
+have	O
+shown	O
+the	O
+propensity	O
+to	O
+cause	O
+delirium	B-NP
+","	O
+only	O
+two	O
+previously	O
+reported	O
+cases	O
+have	O
+been	O
+associated	O
+with	O
+famotidine	O
+.	O
+	
+The	O
+authors	O
+report	O
+on	O
+six	O
+cases	O
+of	O
+famotidine	O
+-	O
+associated	O
+delirium	B-NP
+in	O
+hospitalized	O
+patients	O
+who	O
+cleared	O
+completely	O
+upon	O
+removal	O
+of	O
+famotidine	O
+.	O
+	
+The	O
+pharmacokinetics	O
+of	O
+famotidine	O
+are	O
+reviewed	O
+","	O
+with	O
+no	O
+change	O
+in	O
+its	O
+metabolism	O
+in	O
+the	O
+elderly	O
+population	O
+seen	O
+.	O
+	
+The	O
+implications	O
+of	O
+using	O
+famotidine	O
+in	O
+elderly	O
+persons	O
+are	O
+discussed	O
+.	O
+	
+Encephalopathy	B-NP
+during	O
+amitriptyline	O
+therapy	O
+:	O
+are	O
+neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+and	O
+serotonin	B-NP
+syndrome	I-NP
+spectrum	O
+disorders	O
+?	O
+	
+This	O
+report	O
+describes	O
+a	O
+case	O
+of	O
+encephalopathy	B-NP
+developed	O
+in	O
+the	O
+course	O
+of	O
+amitriptyline	O
+therapy	O
+","	O
+during	O
+a	O
+remission	O
+of	O
+unipolar	B-NP
+depression	I-NP
+.	O
+	
+This	O
+patient	O
+could	O
+have	O
+been	O
+diagnosed	O
+as	O
+having	O
+either	O
+neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+(	O
+NMS	B-NP
+)	O
+or	O
+serotonin	B-NP
+syndrome	I-NP
+(	O
+SS	B-NP
+)	O
+.	O
+	
+The	O
+major	O
+determinant	O
+of	O
+the	O
+symptoms	O
+may	O
+have	O
+been	O
+dopamine	O
+/	O
+serotonin	O
+imbalance	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+.	O
+	
+The	O
+NMS	B-NP
+-	O
+like	O
+encephalopathy	B-NP
+that	O
+develops	O
+in	O
+association	O
+with	O
+the	O
+use	O
+of	O
+antidepressants	O
+indicates	O
+that	O
+NMS	B-NP
+and	O
+SS	B-NP
+are	O
+spectrum	O
+disorders	O
+induced	O
+by	O
+drugs	O
+with	O
+both	O
+antidopaminergic	O
+and	O
+serotonergic	O
+effects	O
+.	O
+	
+Genetic	O
+separation	O
+of	O
+tumor	B-NP
+growth	O
+and	O
+hemorrhagic	B-NP
+phenotypes	O
+in	O
+an	O
+estrogen	O
+-	O
+induced	O
+tumor	B-NP
+.	O
+	
+Chronic	O
+administration	O
+of	O
+estrogen	O
+to	O
+the	O
+Fischer	O
+344	O
+(	O
+F344	O
+)	O
+rat	O
+induces	O
+growth	O
+of	O
+large	O
+","	O
+hemorrhagic	B-NP
+pituitary	B-NP
+tumors	I-NP
+.	O
+	
+Ten	O
+weeks	O
+of	O
+diethylstilbestrol	O
+(	O
+DES	O
+)	O
+treatment	O
+caused	O
+female	O
+F344	O
+rat	O
+pituitaries	O
+to	O
+grow	O
+to	O
+an	O
+average	O
+of	O
+109	O
+.	O
+2	O
++	O
+/	O
+-	O
+6	O
+.	O
+3	O
+mg	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SE	O
+)	O
+versus	O
+11	O
+.	O
+3	O
++	O
+/	O
+-	O
+1	O
+.	O
+4	O
+mg	O
+for	O
+untreated	O
+rats	O
+","	O
+and	O
+to	O
+become	O
+highly	O
+hemorrhagic	B-NP
+.	O
+	
+The	O
+same	O
+DES	O
+treatment	O
+produced	O
+no	O
+significant	O
+growth	O
+(	O
+8	O
+.	O
+9	O
++	O
+/	O
+-	O
+0	O
+.	O
+5	O
+mg	O
+for	O
+treated	O
+females	O
+versus	O
+8	O
+.	O
+7	O
++	O
+/	O
+-	O
+1	O
+.	O
+1	O
+for	O
+untreated	O
+females	O
+)	O
+or	O
+morphological	O
+changes	O
+in	O
+Brown	O
+Norway	O
+(	O
+BN	O
+)	O
+rat	O
+pituitaries	O
+.	O
+	
+An	O
+F1	O
+hybrid	O
+of	O
+F344	O
+and	O
+BN	O
+exhibited	O
+significant	O
+pituitary	O
+growth	O
+after	O
+10	O
+weeks	O
+of	O
+DES	O
+treatment	O
+with	O
+an	O
+average	O
+mass	O
+of	O
+26	O
+.	O
+3	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+mg	O
+compared	O
+with	O
+8	O
+.	O
+6	O
++	O
+/	O
+-	O
+0	O
+.	O
+9	O
+mg	O
+for	O
+untreated	O
+rats	O
+.	O
+	
+Surprisingly	O
+","	O
+the	O
+F1	O
+hybrid	O
+tumors	B-NP
+were	O
+not	O
+hemorrhagic	B-NP
+and	O
+had	O
+hemoglobin	O
+content	O
+and	O
+outward	O
+appearance	O
+identical	O
+to	O
+that	O
+of	O
+BN	O
+.	O
+	
+Expression	O
+of	O
+both	O
+growth	O
+and	O
+morphological	O
+changes	O
+is	O
+due	O
+to	O
+multiple	O
+genes	O
+.	O
+	
+However	O
+","	O
+while	O
+DES	O
+-	O
+induced	O
+pituitary	O
+growth	O
+exhibited	O
+quantitative	O
+","	O
+additive	O
+inheritance	O
+","	O
+the	O
+hemorrhagic	B-NP
+phenotype	O
+exhibited	O
+recessive	O
+","	O
+epistatic	O
+inheritance	O
+.	O
+	
+Only	O
+5	O
+of	O
+the	O
+160	O
+F2	O
+pituitaries	O
+exhibited	O
+the	O
+hemorrhagic	B-NP
+phenotype	O
+;	O
+36	O
+of	O
+the	O
+160	O
+F2	O
+pituitaries	O
+were	O
+in	O
+the	O
+F344	O
+range	O
+of	O
+mass	O
+","	O
+but	O
+31	O
+of	O
+these	O
+were	O
+not	O
+hemorrhagic	B-NP
+","	O
+indicating	O
+that	O
+the	O
+hemorrhagic	B-NP
+phenotype	O
+is	O
+not	O
+merely	O
+a	O
+consequence	O
+of	O
+extensive	O
+growth	O
+.	O
+	
+The	O
+hemorrhagic	B-NP
+F2	O
+pituitaries	O
+were	O
+all	O
+among	O
+the	O
+most	O
+massive	O
+","	O
+indicating	O
+that	O
+some	O
+of	O
+the	O
+genes	O
+regulate	O
+both	O
+phenotypes	O
+.	O
+	
+Increased	O
+expression	O
+of	O
+neuronal	O
+nitric	O
+oxide	O
+synthase	O
+in	O
+bladder	O
+afferent	O
+pathways	O
+following	O
+chronic	O
+bladder	B-NP
+irritation	I-NP
+.	O
+	
+Immunocytochemical	O
+techniques	O
+were	O
+used	O
+to	O
+examine	O
+alterations	O
+in	O
+the	O
+expression	O
+of	O
+neuronal	O
+nitric	O
+oxide	O
+synthase	O
+(	O
+NOS	O
+)	O
+in	O
+bladder	O
+pathways	O
+following	O
+acute	O
+and	O
+chronic	O
+irritation	B-NP
+of	I-NP
+the	I-NP
+urinary	I-NP
+tract	I-NP
+of	O
+the	O
+rat	O
+.	O
+	
+Chemical	O
+cystitis	B-NP
+was	O
+induced	O
+by	O
+cyclophosphamide	O
+(	O
+CYP	O
+)	O
+which	O
+is	O
+metabolized	O
+to	O
+acrolein	O
+","	O
+an	O
+irritant	O
+eliminated	O
+in	O
+the	O
+urine	O
+.	O
+	
+Injection	O
+of	O
+CYP	O
+(	O
+n	O
+=	O
+10	O
+","	O
+75	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+p	O
+.	O
+)	O
+2	O
+hours	O
+prior	O
+to	O
+perfusion	O
+(	O
+acute	O
+treatment	O
+)	O
+of	O
+the	O
+animals	O
+increased	O
+Fos	O
+-	O
+immunoreactivity	O
+(	O
+IR	O
+)	O
+in	O
+neurons	O
+in	O
+the	O
+dorsal	O
+commissure	O
+","	O
+dorsal	O
+horn	O
+","	O
+and	O
+autonomic	O
+regions	O
+of	O
+spinal	O
+segments	O
+(	O
+L1	O
+-	O
+L2	O
+and	O
+L6	O
+-	O
+S1	O
+)	O
+which	O
+receive	O
+afferent	O
+inputs	O
+from	O
+the	O
+bladder	O
+","	O
+urethra	O
+","	O
+and	O
+ureter	O
+.	O
+	
+Fos	O
+-	O
+IR	O
+in	O
+the	O
+spinal	O
+cord	O
+was	O
+not	O
+changed	O
+in	O
+rats	O
+receiving	O
+chronic	O
+CYP	O
+treatment	O
+(	O
+n	O
+=	O
+15	O
+","	O
+75	O
+mg	O
+/	O
+kg	O
+","	O
+i	O
+.	O
+p	O
+.	O
+","	O
+every	O
+3rd	O
+day	O
+for	O
+2	O
+weeks	O
+)	O
+.	O
+	
+In	O
+control	O
+animals	O
+and	O
+in	O
+animals	O
+treated	O
+acutely	O
+with	O
+CYP	O
+","	O
+only	O
+small	O
+numbers	O
+of	O
+NOS	O
+-	O
+IR	O
+cells	O
+(	O
+0	O
+.	O
+5	O
+-	O
+0	O
+.	O
+7	O
+cell	O
+profiles	O
+/	O
+sections	O
+)	O
+were	O
+detected	O
+in	O
+the	O
+L6	O
+-	O
+S1	O
+dorsal	O
+root	O
+ganglia	O
+(	O
+DRG	O
+)	O
+.	O
+	
+Chronic	O
+CYP	O
+administration	O
+significantly	O
+(	O
+P	O
+<	O
+or	O
+=	O
+.	O
+2	O
+)	O
+increased	O
+bladder	O
+weight	O
+by	O
+60	O
+%	O
+and	O
+increased	O
+(	O
+7	O
+-	O
+to	O
+11	O
+-	O
+fold	O
+)	O
+the	O
+numbers	O
+of	O
+NOS	O
+-	O
+immunoreactive	O
+(	O
+IR	O
+)	O
+afferent	O
+neurons	O
+in	O
+the	O
+L6	O
+-	O
+S1	O
+DRG	O
+.	O
+	
+A	O
+small	O
+increase	O
+(	O
+1	O
+.	O
+5	O
+-	O
+fold	O
+)	O
+also	O
+occurred	O
+in	O
+the	O
+L1	O
+DRG	O
+","	O
+but	O
+no	O
+change	O
+was	O
+detected	O
+in	O
+the	O
+L2	O
+and	O
+L5	O
+DRG	O
+.	O
+	
+Bladder	O
+afferent	O
+cells	O
+in	O
+the	O
+L6	O
+-	O
+S1	O
+DRG	O
+labeled	O
+by	O
+Fluorogold	O
+(	O
+40	O
+microliters	O
+)	O
+injected	O
+into	O
+the	O
+bladder	O
+wall	O
+did	O
+not	O
+exhibit	O
+NOS	O
+-	O
+IR	O
+in	O
+control	O
+animals	O
+;	O
+however	O
+","	O
+following	O
+chronic	O
+CYP	O
+administration	O
+","	O
+a	O
+significant	O
+percentage	O
+of	O
+bladder	O
+afferent	O
+neurons	O
+were	O
+NOS	O
+-	O
+IR	O
+:	O
+L6	O
+(	O
+19	O
+.	O
+8	O
++	O
+/	O
+-	O
+4	O
+.	O
+6	O
+%	O
+)	O
+and	O
+S1	O
+(	O
+25	O
+.	O
+3	O
++	O
+/	O
+-	O
+2	O
+.	O
+9	O
+%	O
+)	O
+.	O
+	
+These	O
+results	O
+indicate	O
+that	O
+neuronal	O
+gene	O
+expression	O
+in	O
+visceral	O
+sensory	O
+pathways	O
+can	O
+be	O
+upregulated	O
+by	O
+chemical	O
+irritation	O
+of	O
+afferent	O
+receptors	O
+in	O
+the	O
+urinary	O
+tract	O
+and	O
+/	O
+or	O
+that	O
+pathological	O
+changes	O
+in	O
+the	O
+urinary	O
+tract	O
+can	O
+initiate	O
+chemical	O
+signals	O
+that	O
+alter	O
+the	O
+chemical	O
+properties	O
+of	O
+visceral	O
+afferent	O
+neurons	O
+.	O
+	
+Effects	O
+of	O
+a	O
+new	O
+calcium	O
+antagonist	O
+","	O
+CD	O
+-	O
+832	O
+","	O
+on	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B-NP
+ischemia	I-NP
+in	O
+dogs	O
+with	O
+partial	O
+coronary	B-NP
+stenosis	I-NP
+.	O
+	
+Effects	O
+of	O
+CD	O
+-	O
+832	O
+on	O
+isoproterenol	O
+(	O
+ISO	O
+)	O
+-	O
+induced	O
+myocardial	B-NP
+ischemia	I-NP
+were	O
+studied	O
+in	O
+dogs	O
+with	O
+partial	O
+coronary	B-NP
+stenosis	I-NP
+of	O
+the	O
+left	O
+circumflex	O
+coronary	O
+artery	O
+and	O
+findings	O
+were	O
+compared	O
+with	O
+those	O
+for	O
+nifedipine	O
+or	O
+diltiazem	O
+.	O
+	
+In	O
+the	O
+presence	O
+of	O
+coronary	B-NP
+artery	I-NP
+stenosis	I-NP
+","	O
+3	O
+-	O
+min	O
+periods	O
+of	O
+intracoronary	O
+ISO	O
+infusion	O
+(	O
+10	O
+ng	O
+/	O
+kg	O
+/	O
+min	O
+)	O
+increased	O
+heart	O
+rate	O
+and	O
+maximal	O
+rate	O
+of	O
+left	O
+ventricular	O
+pressure	O
+rise	O
+","	O
+which	O
+resulted	O
+in	O
+a	O
+decrease	O
+in	O
+percentage	O
+segmental	O
+shortening	O
+and	O
+ST	O
+-	O
+segment	O
+elevation	O
+of	O
+the	O
+epicardial	O
+electrocardiogram	O
+.	O
+	
+After	O
+the	O
+control	O
+ISO	O
+infusion	O
+with	O
+stenosis	B-NP
+was	O
+performed	O
+","	O
+equihypotensive	O
+doses	O
+of	O
+CD	O
+-	O
+832	O
+(	O
+3	O
+and	O
+10	O
+micrograms	O
+/	O
+kg	O
+/	O
+min	O
+","	O
+n	O
+=	O
+7	O
+)	O
+","	O
+nifedipine	O
+(	O
+1	O
+and	O
+3	O
+micrograms	O
+/	O
+kg	O
+/	O
+min	O
+","	O
+n	O
+=	O
+9	O
+)	O
+or	O
+diltiazem	O
+(	O
+10	O
+and	O
+30	O
+micrograms	O
+/	O
+kg	O
+/	O
+min	O
+","	O
+n	O
+=	O
+7	O
+)	O
+were	O
+infused	O
+5	O
+min	O
+before	O
+and	O
+during	O
+the	O
+second	O
+and	O
+third	O
+ISO	O
+infusion	O
+.	O
+	
+Both	O
+CD	O
+-	O
+832	O
+and	O
+diltiazem	O
+","	O
+but	O
+not	O
+nifedipine	O
+","	O
+significantly	O
+reduced	O
+the	O
+increase	O
+in	O
+heart	O
+rate	O
+induced	O
+by	O
+ISO	O
+infusion	O
+.	O
+	
+In	O
+contrast	O
+to	O
+nifedipine	O
+","	O
+CD	O
+-	O
+832	O
+(	O
+10	O
+micrograms	O
+/	O
+kg	O
+/	O
+min	O
+)	O
+prevented	O
+the	O
+decrease	O
+in	O
+percentage	O
+segmental	O
+shortening	O
+from	O
+32	O
++	O
+/	O
+-	O
+12	O
+%	O
+to	O
+115	O
++	O
+/	O
+-	O
+26	O
+%	O
+of	O
+the	O
+control	O
+value	O
+(	O
+P	O
+<	O
+.	O
+1	O
+)	O
+and	O
+ST	O
+-	O
+segment	O
+elevation	O
+from	O
+5	O
+.	O
+6	O
++	O
+/	O
+-	O
+1	O
+.	O
+0	O
+mV	O
+to	O
+1	O
+.	O
+6	O
++	O
+/	O
+-	O
+1	O
+.	O
+3	O
+mV	O
+(	O
+P	O
+<	O
+.	O
+1	O
+)	O
+at	O
+3	O
+min	O
+after	O
+ISO	O
+infusion	O
+with	O
+stenosis	B-NP
+.	O
+	
+Diltiazem	O
+(	O
+30	O
+micrograms	O
+/	O
+kg	O
+/	O
+min	O
+)	O
+also	O
+prevented	O
+the	O
+decrease	O
+in	O
+percentage	O
+segmental	O
+shortening	O
+from	O
+34	O
++	O
+/	O
+-	O
+14	O
+%	O
+to	O
+63	O
++	O
+/	O
+-	O
+18	O
+%	O
+of	O
+the	O
+control	O
+value	O
+(	O
+P	O
+<	O
+.	O
+5	O
+)	O
+and	O
+ST	O
+-	O
+segment	O
+elevation	O
+from	O
+4	O
+.	O
+7	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+mV	O
+to	O
+2	O
+.	O
+1	O
++	O
+/	O
+-	O
+0	O
+.	O
+7	O
+mV	O
+(	O
+P	O
+<	O
+.	O
+1	O
+)	O
+at	O
+3	O
+min	O
+after	O
+ISO	O
+infusion	O
+with	O
+stenosis	B-NP
+.	O
+	
+These	O
+data	O
+show	O
+that	O
+CD	O
+-	O
+832	O
+improves	O
+myocardial	B-NP
+ischemia	I-NP
+during	O
+ISO	O
+infusion	O
+with	O
+stenosis	B-NP
+and	O
+suggest	O
+that	O
+the	O
+negative	O
+chronotropic	O
+property	O
+of	O
+CD	O
+-	O
+832	O
+plays	O
+a	O
+major	O
+role	O
+in	O
+the	O
+beneficial	O
+effects	O
+of	O
+CD	O
+-	O
+832	O
+.	O
+	
+The	O
+effect	O
+of	O
+recombinant	O
+human	O
+insulin	O
+-	O
+like	O
+growth	O
+factor	O
+-	O
+I	O
+on	O
+chronic	O
+puromycin	O
+aminonucleoside	O
+nephropathy	B-NP
+in	O
+rats	O
+.	O
+	
+We	O
+recently	O
+demonstrated	O
+that	O
+recombinant	O
+hGH	O
+exacerbates	O
+renal	O
+functional	O
+and	O
+structural	O
+injury	O
+in	O
+chronic	O
+puromycin	O
+aminonucleoside	O
+(	O
+PAN	O
+)	O
+nephropathy	B-NP
+","	O
+an	O
+experimental	O
+model	O
+of	O
+glomerular	B-NP
+disease	I-NP
+.	O
+	
+Therefore	O
+","	O
+we	O
+examined	O
+whether	O
+recombinant	O
+human	O
+(	O
+rh	O
+)	O
+IGF	O
+-	O
+I	O
+is	O
+a	O
+safer	O
+alternative	O
+for	O
+the	O
+treatment	O
+of	O
+growth	B-NP
+failure	I-NP
+in	O
+rats	O
+with	O
+chronic	O
+PAN	O
+nephropathy	B-NP
+.	O
+	
+The	O
+glomerulopathy	B-NP
+was	O
+induced	O
+by	O
+seven	O
+serial	O
+injections	O
+of	O
+PAN	O
+over	O
+12	O
+wk	O
+.	O
+	
+Experimental	O
+animals	O
+(	O
+n	O
+=	O
+6	O
+)	O
+received	O
+rhIGF	O
+-	O
+I	O
+","	O
+400	O
+micrograms	O
+/	O
+d	O
+","	O
+whereas	O
+control	O
+rats	O
+(	O
+n	O
+=	O
+6	O
+)	O
+received	O
+the	O
+vehicle	O
+.	O
+	
+rhIGF	O
+-	O
+I	O
+improved	O
+weight	O
+gain	O
+by	O
+14	O
+%	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+","	O
+without	O
+altering	O
+hematocrit	O
+or	O
+blood	O
+pressure	O
+in	O
+rats	O
+with	O
+renal	B-NP
+disease	I-NP
+.	O
+	
+Urinary	O
+protein	O
+excretion	O
+was	O
+unaltered	O
+by	O
+rhIGF	O
+-	O
+I	O
+treatment	O
+in	O
+rats	O
+with	O
+chronic	O
+PAN	O
+nephropathy	B-NP
+.	O
+	
+After	O
+12	O
+wk	O
+","	O
+the	O
+inulin	O
+clearance	O
+was	O
+higher	O
+in	O
+rhIGF	O
+-	O
+I	O
+-	O
+treated	O
+rats	O
+","	O
+0	O
+.	O
+48	O
++	O
+/	O
+-	O
+0	O
+.	O
+8	O
+versus	O
+0	O
+.	O
+24	O
++	O
+/	O
+-	O
+0	O
+.	O
+6	O
+mL	O
+/	O
+min	O
+/	O
+100	O
+g	O
+of	O
+body	O
+weight	O
+in	O
+untreated	O
+PAN	O
+nephropathy	B-NP
+animals	O
+","	O
+p	O
+<	O
+0	O
+.	O
+5	O
+.	O
+	
+The	O
+improvement	O
+in	O
+GFR	O
+was	O
+not	O
+associated	O
+with	O
+enhanced	O
+glomerular	B-NP
+hypertrophy	I-NP
+or	O
+increased	O
+segmental	O
+glomerulosclerosis	B-NP
+","	O
+tubulointerstitial	B-NP
+injury	I-NP
+","	O
+or	O
+renal	O
+cortical	O
+malondialdehyde	O
+content	O
+.	O
+	
+In	O
+rats	O
+with	O
+PAN	O
+nephropathy	B-NP
+","	O
+administration	O
+of	O
+rhIGF	O
+-	O
+I	O
+increased	O
+IGF	O
+-	O
+I	O
+and	O
+GH	O
+receptor	O
+gene	O
+expression	O
+","	O
+without	O
+altering	O
+the	O
+steady	O
+state	O
+level	O
+of	O
+IGF	O
+-	O
+I	O
+receptor	O
+mRNA	O
+.	O
+	
+In	O
+normal	O
+rats	O
+with	O
+intact	O
+kidneys	O
+","	O
+rhIGF	O
+-	O
+I	O
+administration	O
+(	O
+n	O
+=	O
+4	O
+)	O
+did	O
+not	O
+alter	O
+weight	O
+gain	O
+","	O
+blood	O
+pressure	O
+","	O
+proteinuria	B-NP
+","	O
+GFR	O
+","	O
+glomerular	O
+planar	O
+area	O
+","	O
+renal	O
+cortical	O
+malondialdehyde	O
+content	O
+","	O
+or	O
+glomerular	O
+or	O
+tubulointerstitial	B-NP
+damage	I-NP
+","	O
+compared	O
+with	O
+untreated	O
+animals	O
+(	O
+n	O
+=	O
+4	O
+)	O
+.	O
+	
+rhIGF	O
+-	O
+I	O
+treatment	O
+reduced	O
+the	O
+steady	O
+state	O
+renal	O
+IGF	O
+-	O
+I	O
+mRNA	O
+level	O
+but	O
+did	O
+not	O
+modify	O
+gene	O
+expression	O
+of	O
+the	O
+IGF	O
+-	O
+I	O
+or	O
+GH	O
+receptors	O
+.	O
+	
+We	O
+conclude	O
+that	O
+:	O
+1	O
+)	O
+administration	O
+of	O
+rhIGF	O
+-	O
+I	O
+improves	O
+growth	O
+and	O
+GFR	O
+in	O
+rats	O
+with	O
+chronic	O
+PAN	O
+nephropathy	B-NP
+and	O
+2	O
+)	O
+unlike	O
+rhGH	O
+","	O
+long	O
+-	O
+term	O
+use	O
+of	O
+rhIGF	O
+-	O
+I	O
+does	O
+not	O
+worsen	O
+renal	O
+functional	O
+and	O
+structural	O
+injury	O
+in	O
+this	O
+disease	O
+model	O
+.	O
+	
+Nefiracetam	O
+(	O
+DM	O
+-	O
+9384	O
+)	O
+reverses	O
+apomorphine	O
+-	O
+induced	O
+amnesia	B-NP
+of	O
+a	O
+passive	O
+avoidance	O
+response	O
+:	O
+delayed	O
+emergence	O
+of	O
+the	O
+memory	O
+retention	O
+effects	O
+.	O
+	
+Nefiracetam	O
+is	O
+a	O
+novel	O
+pyrrolidone	O
+derivative	O
+which	O
+attenuates	O
+scopolamine	O
+-	O
+induced	O
+learning	B-NP
+and	I-NP
+post	I-NP
+-	I-NP
+training	I-NP
+consolidation	I-NP
+deficits	I-NP
+.	O
+	
+Given	O
+that	O
+apomorphine	O
+inhibits	O
+passive	O
+avoidance	O
+retention	O
+when	O
+given	O
+during	O
+training	O
+or	O
+in	O
+a	O
+defined	O
+10	O
+-	O
+12h	O
+post	O
+-	O
+training	O
+period	O
+","	O
+we	O
+evaluated	O
+the	O
+ability	O
+of	O
+nefiracetam	O
+to	O
+attenuate	O
+amnesia	B-NP
+induced	O
+by	O
+dopaminergic	O
+agonism	O
+.	O
+	
+A	O
+step	O
+-	O
+down	O
+passive	O
+avoidance	O
+paradigm	O
+was	O
+employed	O
+and	O
+nefiracetam	O
+(	O
+3	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+apomorphine	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+were	O
+given	O
+alone	O
+or	O
+in	O
+combination	O
+during	O
+training	O
+and	O
+at	O
+the	O
+10	O
+-	O
+12h	O
+post	O
+-	O
+training	O
+period	O
+of	O
+consolidation	O
+.	O
+	
+Co	O
+-	O
+administration	O
+of	O
+nefiracetam	O
+and	O
+apomorphine	O
+during	O
+training	O
+or	O
+10h	O
+thereafter	O
+produced	O
+no	O
+significant	O
+anti	O
+-	O
+amnesic	O
+effect	O
+.	O
+	
+However	O
+","	O
+administration	O
+of	O
+nefiracetam	O
+during	O
+training	O
+completely	O
+reversed	O
+the	O
+amnesia	B-NP
+induced	O
+by	O
+apomorphine	O
+at	O
+the	O
+10h	O
+post	O
+-	O
+training	O
+time	O
+and	O
+the	O
+converse	O
+was	O
+also	O
+TRUE	O
+.	O
+	
+These	O
+effects	O
+were	O
+not	O
+mediated	O
+by	O
+a	O
+dopaminergic	O
+mechanism	O
+as	O
+nefiracetam	O
+","	O
+at	O
+millimolar	O
+concentrations	O
+","	O
+failed	O
+to	O
+displace	O
+either	O
+[	O
+3H	O
+]	O
+SCH	O
+23390	O
+or	O
+[	O
+3H	O
+]	O
+spiperone	O
+binding	O
+from	O
+D1	O
+or	O
+D2	O
+dopamine	O
+receptor	O
+subtypes	O
+","	O
+respectively	O
+.	O
+	
+It	O
+is	O
+suggested	O
+that	O
+nefiracetam	O
+augments	O
+molecular	O
+processes	O
+in	O
+the	O
+early	O
+stages	O
+of	O
+events	O
+which	O
+ultimately	O
+lead	O
+to	O
+consolidation	O
+of	O
+memory	O
+.	O
+	
+Phenytoin	O
+encephalopathy	B-NP
+as	O
+probable	O
+idiosyncratic	O
+reaction	O
+:	O
+case	O
+report	O
+.	O
+	
+A	O
+case	O
+of	O
+phenytoin	O
+(	O
+DPH	O
+)	O
+encephalopathy	B-NP
+with	O
+increasing	O
+seizures	B-NP
+and	O
+EEG	O
+and	O
+mental	O
+changes	O
+is	O
+described	O
+.	O
+	
+Despite	O
+adequate	O
+oral	O
+dosage	O
+of	O
+DPH	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+/	O
+daily	O
+)	O
+the	O
+plasma	O
+level	O
+was	O
+very	O
+low	O
+(	O
+2	O
+.	O
+8	O
+microgramg	O
+/	O
+ml	O
+)	O
+.	O
+	
+The	O
+encephalopathy	B-NP
+was	O
+probably	O
+an	O
+idiosyncratic	O
+and	O
+not	O
+toxic	O
+or	O
+allergic	O
+reaction	O
+.	O
+	
+In	O
+fact	O
+the	O
+concentration	O
+of	O
+free	O
+DPH	O
+was	O
+normal	O
+","	O
+the	O
+patient	O
+presented	O
+a	O
+retarded	O
+morbilliform	O
+rash	B-NP
+during	O
+DPH	O
+treatment	O
+","	O
+the	O
+protidogram	O
+was	O
+normal	O
+","	O
+and	O
+an	O
+intradermic	O
+DPH	O
+injection	O
+had	O
+no	O
+local	O
+effect	O
+.	O
+	
+The	O
+authors	O
+conclude	O
+that	O
+in	O
+a	O
+patient	O
+starting	O
+DPH	O
+treatment	O
+an	O
+unexpected	O
+increase	O
+in	O
+seizures	B-NP
+","	O
+with	O
+EEG	O
+and	O
+mental	O
+changes	O
+occurring	O
+simultaneously	O
+","	O
+should	O
+alert	O
+the	O
+physician	O
+to	O
+the	O
+possible	O
+need	O
+for	O
+eliminating	O
+DPH	O
+from	O
+the	O
+therapeutic	O
+regimen	O
+","	O
+even	O
+if	O
+plasma	O
+concentrations	O
+are	O
+low	O
+.	O
+	
+Prevention	O
+and	O
+treatment	O
+of	O
+endometrial	B-NP
+disease	I-NP
+in	O
+climacteric	O
+women	O
+receiving	O
+oestrogen	O
+therapy	O
+.	O
+	
+The	O
+treatment	O
+regimens	O
+are	O
+described	O
+in	O
+74	O
+patients	O
+with	O
+endometrial	B-NP
+disease	I-NP
+among	O
+850	O
+climacteric	O
+women	O
+receiving	O
+oestrogen	O
+therapy	O
+.	O
+	
+Cystic	O
+hyperplasia	B-NP
+was	O
+associated	O
+with	O
+unopposed	O
+oestrogen	O
+therapy	O
+without	O
+progestagen	O
+.	O
+	
+Two	O
+courses	O
+of	O
+21	O
+days	O
+of	O
+5	O
+mg	O
+norethisterone	O
+daily	O
+caused	O
+reversion	O
+to	O
+normal	O
+in	O
+all	O
+57	O
+cases	O
+of	O
+cystic	O
+hyperplasia	B-NP
+and	O
+6	O
+of	O
+the	O
+8	O
+cases	O
+of	O
+atypical	O
+hyperplasia	B-NP
+.	O
+	
+4	O
+cases	O
+of	O
+endometrial	B-NP
+carcinoma	I-NP
+referred	O
+from	O
+elsewhere	O
+demonstrated	O
+the	O
+problems	O
+of	O
+inappropriate	O
+and	O
+unsupervised	O
+unopposed	O
+oestrogen	O
+therapy	O
+and	O
+the	O
+difficulty	O
+in	O
+distinguishing	O
+severe	O
+hyperplasia	B-NP
+from	O
+malignancy	B-NP
+.	O
+	
+Cyclical	O
+low	O
+-	O
+dose	O
+oestrogen	O
+therapy	O
+with	O
+7	O
+-	O
+-	O
+13	O
+days	O
+of	O
+progestagen	O
+does	O
+not	O
+seem	O
+to	O
+increase	O
+the	O
+risk	O
+of	O
+endometrial	B-NP
+hyperplasia	I-NP
+or	O
+carcinoma	B-NP
+.	O
+	
+Effects	O
+of	O
+exercise	O
+on	O
+the	O
+severity	O
+of	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B-NP
+infarction	I-NP
+.	O
+	
+The	O
+effect	O
+of	O
+exercise	O
+on	O
+the	O
+severity	O
+of	O
+isoproterenol	O
+-	O
+induced	O
+myocardial	B-NP
+infarction	I-NP
+was	O
+studied	O
+in	O
+male	O
+rats	O
+.	O
+	
+Ninety	O
+-	O
+three	O
+rats	O
+were	O
+randomly	O
+divided	O
+into	O
+three	O
+groups	O
+.	O
+	
+The	O
+exercise	O
+-	O
+isoproterenol	O
+(	O
+E	O
+-	O
+1	O
+)	O
+and	O
+exercise	O
+control	O
+(	O
+EC	O
+)	O
+groups	O
+exercised	O
+daily	O
+for	O
+thirty	O
+days	O
+on	O
+a	O
+treadmill	O
+at	O
+1	O
+mph	O
+","	O
+2	O
+%	O
+grade	O
+while	O
+animals	O
+of	O
+the	O
+sedentary	O
+-	O
+isoproterenol	O
+(	O
+S	O
+-	O
+I	O
+)	O
+group	O
+remained	O
+sedentary	O
+.	O
+	
+Eight	O
+animals	O
+were	O
+assigned	O
+to	O
+the	O
+sedentary	O
+control	O
+(	O
+SC	O
+)	O
+group	O
+which	O
+remained	O
+sedentary	O
+throughout	O
+the	O
+experimental	O
+period	O
+.	O
+	
+Forty	O
+-	O
+eight	O
+hours	O
+after	O
+the	O
+final	O
+exercise	O
+period	O
+","	O
+S	O
+-	O
+I	O
+and	O
+E	O
+-	O
+I	O
+animals	O
+received	O
+a	O
+single	O
+subcutaneous	O
+injection	O
+of	O
+isoproterenol	O
+(	O
+250	O
+mg	O
+/	O
+kg	O
+body	O
+weight	O
+)	O
+.	O
+	
+Animals	O
+of	O
+the	O
+S	O
+-	O
+I	O
+group	O
+exhibited	O
+significantly	O
+(	O
+Pp	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+greater	O
+mortality	O
+from	O
+the	O
+effects	O
+of	O
+isoproterenol	O
+than	O
+animals	O
+of	O
+the	O
+E	O
+-	O
+I	O
+group	O
+.	O
+	
+Serum	O
+CPK	O
+activity	O
+for	O
+E	O
+-	O
+I	O
+animals	O
+was	O
+significantly	O
+(	O
+p	O
+less	O
+than	O
+0	O
+.	O
+5	O
+)	O
+greater	O
+than	O
+for	O
+animals	O
+in	O
+the	O
+S	O
+-	O
+I	O
+and	O
+EC	O
+groups	O
+twenty	O
+hours	O
+following	O
+isoproterenol	O
+injection	O
+.	O
+	
+No	O
+statistically	O
+significant	O
+differences	O
+were	O
+observed	O
+between	O
+the	O
+two	O
+isoproterenol	O
+treated	O
+groups	O
+for	O
+severity	O
+of	O
+the	O
+induced	O
+lesions	O
+","	O
+changes	O
+in	O
+heart	O
+weight	O
+","	O
+or	O
+heart	O
+weight	O
+to	O
+body	O
+weight	O
+ratios	O
+.	O
+	
+The	O
+results	O
+indicated	O
+that	O
+exercise	O
+reduced	O
+the	O
+mortality	O
+associated	O
+with	O
+the	O
+effects	O
+of	O
+large	O
+dosages	O
+of	O
+isoproterenol	O
+but	O
+had	O
+little	O
+on	O
+the	O
+severity	O
+of	O
+the	O
+infarction	B-NP
+.	O
+	
+Human	O
+corticotropin	O
+-	O
+releasing	O
+hormone	O
+and	O
+thyrotropin	O
+-	O
+releasing	O
+hormone	O
+modulate	O
+the	O
+hypercapnic	B-NP
+ventilatory	O
+response	O
+in	O
+humans	O
+.	O
+	
+Human	O
+corticotropin	O
+-	O
+releasing	O
+hormone	O
+(	O
+hCRH	O
+)	O
+and	O
+thyrotropin	O
+-	O
+releasing	O
+hormone	O
+(	O
+TRH	O
+)	O
+are	O
+known	O
+to	O
+stimulate	O
+ventilation	O
+after	O
+i	O
+.	O
+v	O
+.	O
+administration	O
+in	O
+humans	O
+.	O
+	
+In	O
+a	O
+placebo	O
+-	O
+controlled	O
+","	O
+single	O
+-	O
+blind	O
+study	O
+we	O
+aimed	O
+to	O
+clarify	O
+if	O
+both	O
+peptides	O
+act	O
+by	O
+altering	O
+central	O
+chemosensitivity	O
+.	O
+	
+Two	O
+subsequent	O
+CO2	O
+-	O
+rebreathing	O
+tests	O
+were	O
+performed	O
+in	O
+healthy	O
+young	O
+volunteers	O
+.	O
+	
+During	O
+the	O
+first	O
+test	O
+0	O
+.	O
+9	O
+%	O
+NaCl	O
+was	O
+given	O
+i	O
+.	O
+v	O
+.	O
+;	O
+during	O
+the	O
+second	O
+test	O
+200	O
+micrograms	O
+of	O
+hCRH	O
+(	O
+n	O
+=	O
+12	O
+)	O
+or	O
+400	O
+micrograms	O
+of	O
+TRH	O
+(	O
+n	O
+=	O
+6	O
+)	O
+was	O
+administered	O
+i	O
+.	O
+v	O
+.	O
+Nine	O
+subjects	O
+received	O
+0	O
+.	O
+9	O
+%	O
+NaCl	O
+i	O
+.	O
+v	O
+.	O
+during	O
+both	O
+rebreathing	O
+manoeuvres	O
+.	O
+	
+The	O
+CO2	O
+-	O
+response	O
+curves	O
+for	O
+the	O
+two	O
+tests	O
+were	O
+compared	O
+within	O
+the	O
+same	O
+subject	O
+.	O
+	
+In	O
+the	O
+hCRH	O
+group	O
+a	O
+marked	O
+parallel	O
+shift	O
+of	O
+the	O
+CO2	O
+-	O
+response	O
+curve	O
+to	O
+the	O
+left	O
+was	O
+observed	O
+after	O
+hCRH	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+.	O
+	
+The	O
+same	O
+effect	O
+occurred	O
+following	O
+TRH	O
+but	O
+was	O
+less	O
+striking	O
+(	O
+P	O
+=	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+hCRH	O
+and	O
+TRH	O
+caused	O
+a	O
+reduction	O
+in	O
+the	O
+CO2	O
+threshold	O
+.	O
+	
+The	O
+CO2	O
+-	O
+response	O
+curves	O
+in	O
+the	O
+control	O
+group	O
+were	O
+nearly	O
+identical	O
+.	O
+	
+The	O
+results	O
+indicate	O
+an	O
+additive	O
+effect	O
+of	O
+both	O
+releasing	O
+hormones	O
+on	O
+the	O
+hypercapnic	B-NP
+ventilatory	O
+response	O
+in	O
+humans	O
+","	O
+presumably	O
+independent	O
+of	O
+central	O
+chemosensitivity	O
+.	O
+	
+Lamivudine	O
+is	O
+effective	O
+in	O
+suppressing	O
+hepatitis	B-NP
+B	I-NP
+virus	O
+DNA	O
+in	O
+Chinese	O
+hepatitis	O
+B	O
+surface	O
+antigen	O
+carriers	O
+:	O
+a	O
+placebo	O
+-	O
+controlled	O
+trial	O
+.	O
+	
+Lamivudine	O
+is	O
+a	O
+novel	O
+2	O
+'	O
+","	O
+3	O
+'	O
+-	O
+dideoxy	O
+cytosine	O
+analogue	O
+that	O
+has	O
+potent	O
+inhibitory	O
+effects	O
+on	O
+hepatitis	B-NP
+B	I-NP
+virus	O
+replication	O
+in	O
+vitro	O
+and	O
+in	O
+vivo	O
+.	O
+	
+We	O
+performed	O
+a	O
+single	O
+-	O
+blind	O
+","	O
+placebo	O
+-	O
+controlled	O
+study	O
+to	O
+assess	O
+its	O
+effectiveness	O
+and	O
+safety	O
+in	O
+Chinese	O
+hepatitis	O
+B	O
+surface	O
+antigen	O
+(	O
+HBsAg	O
+)	O
+carriers	O
+.	O
+	
+Forty	O
+-	O
+two	O
+Chinese	O
+HBsAg	O
+carriers	O
+were	O
+randomized	O
+to	O
+receive	O
+placebo	O
+(	O
+6	O
+patients	O
+)	O
+or	O
+lamivudine	O
+orally	O
+in	O
+dosages	O
+of	O
+25	O
+mg	O
+","	O
+100	O
+mg	O
+","	O
+or	O
+300	O
+mg	O
+daily	O
+(	O
+12	O
+patients	O
+for	O
+each	O
+dosage	O
+)	O
+.	O
+	
+The	O
+drug	O
+was	O
+given	O
+for	O
+4	O
+weeks	O
+.	O
+	
+The	O
+patients	O
+were	O
+closely	O
+monitored	O
+clinically	O
+","	O
+biochemically	O
+","	O
+and	O
+serologically	O
+up	O
+to	O
+4	O
+weeks	O
+after	O
+drug	O
+treatment	O
+.	O
+	
+All	O
+36	O
+patients	O
+receiving	O
+lamivudine	O
+had	O
+a	O
+decrease	O
+in	O
+hepatitis	B-NP
+B	I-NP
+virus	O
+(	O
+HBV	O
+)	O
+DNA	O
+values	O
+of	O
+>	O
+90	O
+%	O
+(	O
+P	O
+<	O
+.	O
+1	O
+compared	O
+with	O
+placebo	O
+)	O
+.	O
+	
+Although	O
+25	O
+mg	O
+of	O
+lamivudine	O
+was	O
+slightly	O
+less	O
+effective	O
+than	O
+100	O
+mg	O
+(	O
+P	O
+=	O
+.	O
+11	O
+)	O
+and	O
+300	O
+mg	O
+(	O
+P	O
+=	O
+.	O
+5	O
+)	O
+","	O
+it	O
+still	O
+induced	O
+94	O
+%	O
+suppression	O
+of	O
+HBV	O
+DNA	O
+after	O
+the	O
+fourth	O
+week	O
+of	O
+therapy	O
+.	O
+	
+HBV	O
+DNA	O
+values	O
+returned	O
+to	O
+pretreatment	O
+levels	O
+within	O
+4	O
+weeks	O
+of	O
+cessation	O
+of	O
+therapy	O
+.	O
+	
+There	O
+was	O
+no	O
+change	O
+in	O
+the	O
+hepatitis	B-NP
+B	I-NP
+e	O
+antigen	O
+status	O
+or	O
+in	O
+aminotransferase	O
+levels	O
+.	O
+	
+No	O
+serious	O
+adverse	O
+events	O
+were	O
+observed	O
+.	O
+	
+In	O
+conclusion	O
+","	O
+a	O
+4	O
+-	O
+week	O
+course	O
+of	O
+lamivudine	O
+was	O
+safe	O
+and	O
+effective	O
+in	O
+suppression	O
+of	O
+HBV	O
+DNA	O
+in	O
+Chinese	O
+HBsAg	O
+carriers	O
+.	O
+	
+The	O
+suppression	O
+was	O
+>	O
+90	O
+%	O
+but	O
+reversible	O
+.	O
+	
+Studies	O
+with	O
+long	O
+-	O
+term	O
+lamivudine	O
+administration	O
+should	O
+be	O
+performed	O
+to	O
+determine	O
+if	O
+prolonged	O
+suppression	O
+of	O
+HBV	O
+DNA	O
+can	O
+be	O
+achieved	O
+.	O
+	
+Population	O
+-	O
+based	O
+study	O
+of	O
+risk	O
+of	O
+venous	B-NP
+thromboembolism	I-NP
+associated	O
+with	O
+various	O
+oral	O
+contraceptives	O
+.	O
+	
+BACKGROUND	O
+:	O
+Four	O
+studies	O
+published	O
+since	O
+December	O
+","	O
+1995	O
+","	O
+reported	O
+that	O
+the	O
+incidence	O
+of	O
+venous	B-NP
+thromboembolism	I-NP
+(	O
+VTE	B-NP
+)	O
+was	O
+higher	O
+in	O
+women	O
+who	O
+used	O
+oral	O
+contraceptives	O
+(	O
+OCs	O
+)	O
+containing	O
+the	O
+third	O
+-	O
+generation	O
+progestagens	O
+gestodene	O
+or	O
+desogestrel	O
+than	O
+in	O
+users	O
+of	O
+OCs	O
+containing	O
+second	O
+-	O
+generation	O
+progestagens	O
+.	O
+	
+However	O
+","	O
+confounding	O
+and	O
+bias	O
+in	O
+the	O
+design	O
+of	O
+these	O
+studies	O
+may	O
+have	O
+affected	O
+the	O
+findings	O
+.	O
+	
+The	O
+aim	O
+of	O
+our	O
+study	O
+was	O
+to	O
+re	O
+-	O
+examine	O
+the	O
+association	O
+between	O
+risk	O
+of	O
+VTE	B-NP
+and	O
+OC	O
+use	O
+with	O
+a	O
+different	O
+study	O
+design	O
+and	O
+analysis	O
+to	O
+avoid	O
+some	O
+of	O
+the	O
+bias	O
+and	O
+confounding	O
+of	O
+the	O
+earlier	O
+studies	O
+.	O
+	
+METHODS	O
+:	O
+We	O
+used	O
+computer	O
+records	O
+of	O
+patients	O
+from	O
+143	O
+general	O
+practices	O
+in	O
+the	O
+UK	O
+.	O
+	
+The	O
+study	O
+was	O
+based	O
+on	O
+the	O
+medical	O
+records	O
+of	O
+about	O
+540	O
+","	O
+0	O
+women	O
+born	O
+between	O
+1941	O
+and	O
+1981	O
+.	O
+	
+All	O
+women	O
+who	O
+had	O
+a	O
+recorded	O
+diagnosis	O
+of	O
+deep	B-NP
+-	I-NP
+vein	I-NP
+thrombosis	I-NP
+","	O
+venous	B-NP
+thrombosis	I-NP
+not	O
+otherwise	O
+specified	O
+","	O
+or	O
+pulmonary	O
+embolus	O
+during	O
+the	O
+study	O
+period	O
+","	O
+and	O
+who	O
+had	O
+been	O
+treated	O
+with	O
+an	O
+anticoagulant	O
+were	O
+identified	O
+as	O
+potential	O
+cases	O
+of	O
+VTE	B-NP
+.	O
+	
+We	O
+did	O
+a	O
+cohort	O
+analysis	O
+to	O
+estimate	O
+and	O
+compare	O
+incidence	O
+of	O
+VTE	B-NP
+in	O
+users	O
+of	O
+the	O
+main	O
+OC	O
+preparations	O
+","	O
+and	O
+a	O
+nested	O
+case	O
+-	O
+control	O
+study	O
+to	O
+calculate	O
+the	O
+odds	O
+ratios	O
+of	O
+VTE	B-NP
+associated	O
+with	O
+use	O
+of	O
+different	O
+types	O
+of	O
+OC	O
+","	O
+after	O
+adjustment	O
+for	O
+potential	O
+confounding	O
+factors	O
+.	O
+	
+In	O
+the	O
+case	O
+-	O
+control	O
+study	O
+","	O
+we	O
+matched	O
+cases	O
+to	O
+controls	O
+by	O
+exact	O
+year	O
+of	O
+birth	O
+","	O
+practice	O
+","	O
+and	O
+current	O
+use	O
+of	O
+OCs	O
+.	O
+	
+We	O
+used	O
+a	O
+multiple	O
+logistic	O
+regression	O
+model	O
+that	O
+included	O
+body	O
+-	O
+mass	O
+index	O
+","	O
+number	O
+of	O
+cycles	O
+","	O
+change	O
+in	O
+type	O
+of	O
+OC	O
+prescribed	O
+within	O
+3	O
+months	O
+of	O
+the	O
+event	O
+","	O
+previous	O
+pregnancy	O
+","	O
+and	O
+concurrent	O
+disease	O
+.	O
+	
+FINDINGS	O
+:	O
+85	O
+women	O
+met	O
+the	O
+inclusion	O
+criteria	O
+for	O
+VTE	B-NP
+","	O
+two	O
+of	O
+whom	O
+were	O
+users	O
+of	O
+progestagen	O
+-	O
+only	O
+OCs	O
+.	O
+	
+Of	O
+the	O
+83	O
+cases	O
+of	O
+VTE	B-NP
+associated	O
+with	O
+use	O
+of	O
+combined	O
+OCs	O
+","	O
+43	O
+were	O
+recorded	O
+as	O
+deep	B-NP
+-	I-NP
+vein	I-NP
+thrombosis	I-NP
+","	O
+35	O
+as	O
+pulmonary	O
+thrombosis	B-NP
+","	O
+and	O
+five	O
+as	O
+venous	B-NP
+thrombosis	I-NP
+not	O
+otherwise	O
+specified	O
+.	O
+	
+The	O
+crude	O
+rate	O
+of	O
+VTE	B-NP
+per	O
+10	O
+","	O
+0	O
+woman	O
+-	O
+years	O
+was	O
+4	O
+.	O
+10	O
+in	O
+current	O
+users	O
+of	O
+any	O
+OC	O
+","	O
+3	O
+.	O
+10	O
+in	O
+users	O
+of	O
+second	O
+-	O
+generation	O
+OCs	O
+","	O
+and	O
+4	O
+.	O
+96	O
+in	O
+users	O
+of	O
+third	O
+-	O
+generation	O
+preparations	O
+.	O
+	
+After	O
+adjustment	O
+for	O
+age	O
+","	O
+the	O
+rate	O
+ratio	O
+of	O
+VTE	B-NP
+in	O
+users	O
+of	O
+third	O
+-	O
+generation	O
+relative	O
+to	O
+second	O
+-	O
+generation	O
+OCs	O
+was	O
+1	O
+.	O
+68	O
+(	O
+95	O
+%	O
+CI	O
+1	O
+.	O
+4	O
+-	O
+2	O
+.	O
+75	O
+)	O
+.	O
+	
+Logistic	O
+regression	O
+showed	O
+no	O
+significant	O
+difference	O
+in	O
+the	O
+risk	O
+of	O
+VTE	B-NP
+between	O
+users	O
+of	O
+third	O
+-	O
+generation	O
+and	O
+second	O
+-	O
+generation	O
+OCs	O
+.	O
+	
+Among	O
+users	O
+of	O
+third	O
+-	O
+generation	O
+progestagens	O
+","	O
+the	O
+risk	O
+of	O
+VTE	B-NP
+was	O
+higher	O
+in	O
+users	O
+of	O
+desogestrel	O
+with	O
+20	O
+g	O
+ethinyloestradiol	O
+than	O
+in	O
+users	O
+of	O
+gestodene	O
+or	O
+desogestrel	O
+with	O
+30	O
+g	O
+ethinyloestradiol	O
+.	O
+	
+With	O
+all	O
+second	O
+-	O
+generation	O
+OCs	O
+as	O
+the	O
+reference	O
+","	O
+the	O
+odds	O
+ratios	O
+for	O
+VTE	B-NP
+were	O
+3	O
+.	O
+49	O
+(	O
+1	O
+.	O
+21	O
+-	O
+10	O
+.	O
+12	O
+)	O
+for	O
+desogestrel	O
+plus	O
+20	O
+g	O
+ethinyloestradiol	O
+and	O
+1	O
+.	O
+18	O
+(	O
+0	O
+.	O
+66	O
+-	O
+2	O
+.	O
+17	O
+)	O
+for	O
+the	O
+other	O
+third	O
+-	O
+generation	O
+progestagens	O
+.	O
+	
+INTERPRETATION	O
+:	O
+The	O
+previously	O
+reported	O
+increase	O
+in	O
+odds	O
+ratio	O
+associated	O
+with	O
+third	O
+-	O
+generation	O
+OCs	O
+when	O
+compared	O
+with	O
+second	O
+-	O
+generation	O
+products	O
+is	O
+likely	O
+to	O
+have	O
+been	O
+the	O
+result	O
+of	O
+residual	O
+confounding	O
+by	O
+age	O
+.	O
+	
+The	O
+increased	O
+odds	O
+ratio	O
+associated	O
+with	O
+products	O
+containing	O
+20	O
+micrograms	O
+ethinyloestradiol	O
+and	O
+desogestrel	O
+compared	O
+with	O
+the	O
+30	O
+micrograms	O
+product	O
+is	O
+biologically	O
+implausible	O
+","	O
+and	O
+is	O
+likely	O
+to	O
+be	O
+the	O
+result	O
+of	O
+preferential	O
+prescribing	O
+and	O
+","	O
+thus	O
+","	O
+confounding	O
+.	O
+	
+MK	O
+-	O
+801	O
+augments	O
+pilocarpine	O
+-	O
+induced	O
+electrographic	O
+seizure	B-NP
+but	O
+protects	O
+against	O
+brain	B-NP
+damage	I-NP
+in	O
+rats	O
+.	O
+	
+1	O
+.	O
+	
+The	O
+authors	O
+examined	O
+the	O
+anticonvulsant	O
+effects	O
+of	O
+MK	O
+-	O
+801	O
+on	O
+the	O
+pilocarpine	O
+-	O
+induced	O
+seizure	B-NP
+model	O
+.	O
+	
+Intraperitoneal	O
+injection	O
+of	O
+pilocarpine	O
+(	O
+400	O
+mg	O
+/	O
+kg	O
+)	O
+induced	O
+tonic	B-NP
+and	I-NP
+clonic	I-NP
+seizure	I-NP
+.	O
+	
+Scopolamine	O
+(	O
+10	O
+mg	O
+/	O
+kg	O
+)	O
+and	O
+pentobarbital	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+prevented	O
+development	O
+of	O
+pilocarpine	O
+-	O
+induced	O
+behavioral	O
+seizure	B-NP
+but	O
+MK	O
+-	O
+801	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+/	O
+kg	O
+)	O
+did	O
+not	O
+.	O
+	
+2	O
+.	O
+	
+An	O
+electrical	O
+seizure	B-NP
+measured	O
+with	O
+hippocampal	O
+EEG	O
+appeared	O
+in	O
+the	O
+pilocarpine	O
+-	O
+treated	O
+group	O
+.	O
+	
+Scopolamine	O
+and	O
+pentobarbital	O
+blocked	O
+the	O
+pilocarpine	O
+-	O
+induced	O
+electrographic	O
+seizure	B-NP
+","	O
+MK	O
+-	O
+801	O
+treatment	O
+augmented	O
+the	O
+electrographic	O
+seizure	B-NP
+induced	O
+by	O
+pilocarpine	O
+.	O
+	
+3	O
+.	O
+	
+Brain	B-NP
+damage	I-NP
+was	O
+assessed	O
+by	O
+examining	O
+the	O
+hippocampus	O
+microscopically	O
+.	O
+	
+Pilocarpine	O
+produced	O
+neuronal	B-NP
+death	I-NP
+in	O
+the	O
+hippocampus	O
+","	O
+which	O
+showed	O
+pyknotic	O
+changes	O
+.	O
+	
+Pentobarbital	O
+","	O
+scopolamine	O
+and	O
+MK	O
+-	O
+801	O
+protected	O
+the	O
+brain	B-NP
+damage	I-NP
+by	O
+pilocarpine	O
+","	O
+though	O
+in	O
+the	O
+MK	O
+-	O
+801	O
+-	O
+treated	O
+group	O
+","	O
+the	O
+pyramidal	O
+cells	O
+of	O
+hippocampus	O
+appeared	O
+darker	O
+than	O
+normal	O
+.	O
+	
+In	O
+all	O
+treatments	O
+","	O
+granule	O
+cells	O
+of	O
+the	O
+dentate	O
+gyrus	O
+were	O
+not	O
+affected	O
+.	O
+	
+4	O
+.	O
+	
+These	O
+results	O
+indicate	O
+that	O
+status	B-NP
+epilepticus	I-NP
+induced	O
+by	O
+pilocarpine	O
+is	O
+initiated	O
+by	O
+cholinergic	O
+overstimulation	O
+and	O
+propagated	O
+by	O
+glutamatergic	O
+transmission	O
+","	O
+the	O
+elevation	O
+of	O
+which	O
+may	O
+cause	O
+brain	B-NP
+damage	I-NP
+through	O
+an	O
+excitatory	O
+NMDA	O
+receptor	O
+-	O
+mediated	O
+mechanism	O
+.	O
+	
+Paclitaxel	O
+","	O
+5	O
+-	O
+fluorouracil	O
+","	O
+and	O
+folinic	O
+acid	O
+in	O
+metastatic	O
+breast	B-NP
+cancer	I-NP
+:	O
+BRE	O
+-	O
+26	O
+","	O
+a	O
+phase	O
+II	O
+trial	O
+.	O
+	
+5	O
+-	O
+Fluorouracil	O
+plus	O
+folinic	O
+acid	O
+and	O
+paclitaxel	O
+(	O
+Taxol	O
+;	O
+Bristol	O
+-	O
+Myers	O
+Squibb	O
+Company	O
+","	O
+Princeton	O
+","	O
+NJ	O
+)	O
+are	O
+effective	O
+salvage	O
+therapies	O
+for	O
+metastatic	O
+breast	B-NP
+cancer	I-NP
+patients	O
+.	O
+	
+Paclitaxel	O
+and	O
+5	O
+-	O
+fluorouracil	O
+have	O
+additive	O
+cytotoxicity	B-NP
+in	O
+MCF	O
+-	O
+7	O
+cell	O
+lines	O
+.	O
+	
+We	O
+performed	O
+a	O
+phase	O
+II	O
+trial	O
+of	O
+paclitaxel	O
+175	O
+mg	O
+/	O
+m2	O
+over	O
+3	O
+hours	O
+on	O
+day	O
+I	O
+followed	O
+by	O
+folinic	O
+acid	O
+300	O
+mg	O
+over	O
+1	O
+hour	O
+before	O
+5	O
+-	O
+fluorouracil	O
+350	O
+mg	O
+/	O
+m2	O
+on	O
+days	O
+1	O
+to	O
+3	O
+every	O
+28	O
+days	O
+(	O
+TFL	O
+)	O
+in	O
+women	O
+with	O
+metastatic	O
+breast	B-NP
+cancer	I-NP
+.	O
+	
+Analysis	O
+is	O
+reported	O
+on	O
+37	O
+patients	O
+with	O
+a	O
+minimum	O
+of	O
+6	O
+months	O
+follow	O
+-	O
+up	O
+who	O
+received	O
+a	O
+total	O
+of	O
+192	O
+cycles	O
+of	O
+TFL	O
+:	O
+nine	O
+cycles	O
+(	O
+5	O
+%	O
+)	O
+were	O
+associated	O
+with	O
+grade	O
+3	O
+/	O
+4	O
+neutropenia	B-NP
+requiring	O
+hospitalization	O
+;	O
+seven	O
+(	O
+4	O
+%	O
+)	O
+cycles	O
+in	O
+two	O
+patients	O
+required	O
+granulocyte	O
+colony	O
+-	O
+stimulating	O
+factor	O
+due	O
+to	O
+neutropenia	B-NP
+;	O
+no	O
+patient	O
+required	O
+platelet	O
+transfusions	O
+.	O
+	
+Grade	O
+3	O
+/	O
+4	O
+nonhematologic	O
+toxicities	B-NP
+were	O
+uncommon	O
+.	O
+	
+Among	O
+the	O
+34	O
+patients	O
+evaluable	O
+for	O
+response	O
+","	O
+there	O
+were	O
+three	O
+complete	O
+responses	O
+(	O
+9	O
+%	O
+)	O
+and	O
+18	O
+partial	O
+responses	O
+(	O
+53	O
+%	O
+)	O
+for	O
+an	O
+overall	O
+response	O
+rate	O
+of	O
+62	O
+%	O
+.	O
+	
+Of	O
+the	O
+19	O
+evaluable	O
+patients	O
+with	O
+prior	O
+doxorubicin	O
+exposure	O
+","	O
+11	O
+(	O
+58	O
+%	O
+)	O
+responded	O
+compared	O
+with	O
+nine	O
+of	O
+15	O
+(	O
+60	O
+%	O
+)	O
+without	O
+prior	O
+doxorubicin	O
+.	O
+	
+Plasma	O
+paclitaxel	O
+concentrations	O
+were	O
+measured	O
+at	O
+the	O
+completion	O
+of	O
+paclitaxel	O
+infusion	O
+and	O
+at	O
+24	O
+hours	O
+in	O
+19	O
+patients	O
+.	O
+	
+TFL	O
+is	O
+an	O
+active	O
+","	O
+well	O
+-	O
+tolerated	O
+regimen	O
+in	O
+metastatic	O
+breast	B-NP
+cancer	I-NP
+.	O
+	
+Efficacy	O
+and	O
+proarrhythmia	B-NP
+with	O
+the	O
+use	O
+of	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+for	O
+sustained	O
+ventricular	B-NP
+tachyarrhythmias	I-NP
+.	O
+	
+This	O
+study	O
+prospectively	O
+evaluated	O
+the	O
+clinical	O
+efficacy	O
+","	O
+the	O
+incidence	O
+of	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+","	O
+and	O
+the	O
+presumable	O
+risk	O
+factors	O
+for	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+in	O
+patients	O
+treated	O
+with	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+for	O
+sustained	O
+ventricular	B-NP
+tachyarrhythmias	I-NP
+.	O
+	
+Eighty	O
+-	O
+one	O
+consecutive	O
+patients	O
+(	O
+54	O
+with	O
+coronary	B-NP
+artery	I-NP
+disease	I-NP
+","	O
+and	O
+20	O
+with	O
+dilated	B-NP
+cardiomyopathy	I-NP
+)	O
+with	O
+inducible	O
+sustained	O
+ventricular	B-NP
+tachycardia	I-NP
+or	O
+ventricular	B-NP
+fibrillation	I-NP
+received	O
+oral	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+to	O
+prevent	O
+induction	O
+of	O
+the	O
+ventricular	B-NP
+tachyarrhythmia	I-NP
+.	O
+	
+During	O
+oral	O
+loading	O
+with	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+","	O
+continuous	O
+electrocardiographic	O
+(	O
+ECG	O
+)	O
+monitoring	O
+was	O
+performed	O
+.	O
+	
+Those	O
+patients	O
+in	O
+whom	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+prevented	O
+induction	O
+of	O
+ventricular	B-NP
+tachycardia	I-NP
+or	O
+ventricular	B-NP
+fibrillation	I-NP
+were	O
+discharged	O
+with	O
+the	O
+drug	O
+and	O
+followed	O
+up	O
+on	O
+an	O
+outpatient	O
+basis	O
+for	O
+21	O
++	O
+/	O
+-	O
+18	O
+months	O
+.	O
+	
+Induction	O
+of	O
+the	O
+ventricular	B-NP
+tachyarrhythmia	I-NP
+was	O
+prevented	O
+by	O
+oral	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+in	O
+35	O
+(	O
+43	O
+%	O
+)	O
+patients	O
+;	O
+the	O
+ventricular	B-NP
+tachyarrhythmia	I-NP
+remained	O
+inducible	O
+in	O
+40	O
+(	O
+49	O
+%	O
+)	O
+patients	O
+;	O
+and	O
+two	O
+(	O
+2	O
+.	O
+5	O
+%	O
+)	O
+patients	O
+did	O
+not	O
+tolerate	O
+even	O
+40	O
+mg	O
+of	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+once	O
+daily	O
+.	O
+	
+Four	O
+(	O
+5	O
+%	O
+)	O
+patients	O
+had	O
+from	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+during	O
+the	O
+initial	O
+oral	O
+treatment	O
+with	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+.	O
+	
+Neither	O
+ECG	O
+[	O
+sinus	O
+-	O
+cycle	O
+length	O
+(	O
+SCL	O
+)	O
+","	O
+QT	O
+or	O
+QTc	O
+interval	O
+","	O
+or	O
+U	O
+wave	O
+]	O
+nor	O
+clinical	O
+parameters	O
+identified	O
+patients	O
+at	O
+risk	O
+for	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+.	O
+	
+However	O
+","	O
+the	O
+oral	O
+dose	O
+of	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+was	O
+significantly	O
+lower	O
+in	O
+patients	O
+with	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+(	O
+200	O
++	O
+/	O
+-	O
+46	O
+vs	O
+.	O
+328	O
++	O
+/	O
+-	O
+53	O
+mg	O
+/	O
+day	O
+;	O
+p	O
+=	O
+0	O
+.	O
+17	O
+)	O
+.	O
+	
+Risk	O
+factors	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+were	O
+the	O
+appearance	O
+of	O
+an	O
+U	O
+wave	O
+(	O
+p	O
+=	O
+0	O
+.	O
+49	O
+)	O
+","	O
+female	O
+gender	O
+(	O
+p	O
+=	O
+0	O
+.	O
+15	O
+)	O
+","	O
+and	O
+significant	O
+dose	O
+-	O
+corrected	O
+changes	O
+of	O
+SCL	O
+","	O
+QT	O
+interval	O
+","	O
+and	O
+QTc	O
+interval	O
+(	O
+p	O
+<	O
+0	O
+.	O
+5	O
+)	O
+.	O
+	
+During	O
+follow	O
+-	O
+up	O
+","	O
+seven	O
+(	O
+20	O
+%	O
+)	O
+patients	O
+had	O
+a	O
+nonfatal	O
+ventricular	B-NP
+tachycardia	I-NP
+recurrence	O
+","	O
+and	O
+two	O
+(	O
+6	O
+%	O
+)	O
+patients	O
+died	O
+suddenly	O
+.	O
+	
+One	O
+female	O
+patient	O
+with	O
+stable	O
+cardiac	B-NP
+disease	I-NP
+had	O
+recurrent	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+after	O
+2	O
+years	O
+of	O
+successful	O
+treatment	O
+with	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+.	O
+	
+Torsades	B-NP
+de	I-NP
+pointes	I-NP
+occurred	O
+early	O
+during	O
+treatment	O
+even	O
+with	O
+low	O
+doses	O
+of	O
+oral	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+.	O
+	
+Pronounced	O
+changes	O
+in	O
+the	O
+surface	O
+ECG	O
+(	O
+cycle	O
+length	O
+","	O
+QT	O
+","	O
+and	O
+QTc	O
+)	O
+in	O
+relation	O
+to	O
+the	O
+dose	O
+of	O
+oral	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+might	O
+identify	O
+a	O
+subgroup	O
+of	O
+patients	O
+with	O
+an	O
+increased	O
+risk	O
+for	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+.	O
+	
+Other	O
+ECG	O
+parameters	O
+before	O
+the	O
+application	O
+of	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+did	O
+not	O
+identify	O
+patients	O
+at	O
+increased	O
+risk	O
+for	O
+torsades	B-NP
+de	I-NP
+pointes	I-NP
+.	O
+	
+Recurrence	O
+rates	O
+of	O
+ventricular	B-NP
+tachyarrhythmias	I-NP
+are	O
+high	O
+despite	O
+complete	O
+suppression	O
+of	O
+the	O
+arrhythmia	B-NP
+during	O
+programmed	O
+stimulation	O
+.	O
+	
+Therefore	O
+programmed	O
+electrical	O
+stimulation	O
+in	O
+the	O
+case	O
+of	O
+d	O
+","	O
+l	O
+-	O
+sotalol	O
+seems	O
+to	O
+be	O
+of	O
+limited	O
+prognostic	O
+value	O
+.	O
+	
+Chronic	O
+hyperprolactinemia	B-NP
+and	O
+changes	O
+in	O
+dopamine	O
+neurons	O
+.	O
+	
+The	O
+tuberoinfundibular	O
+dopaminergic	O
+(	O
+TIDA	O
+)	O
+system	O
+is	O
+known	O
+to	O
+inhibit	O
+prolactin	O
+(	O
+PRL	O
+)	O
+secretion	O
+.	O
+	
+In	O
+young	O
+animals	O
+this	O
+system	O
+responds	O
+to	O
+acute	O
+elevations	O
+in	O
+serum	O
+PRL	O
+by	O
+increasing	O
+its	O
+activity	O
+.	O
+	
+However	O
+","	O
+this	O
+responsiveness	O
+is	O
+lost	O
+in	O
+aging	O
+rats	O
+with	O
+chronically	O
+high	O
+serum	O
+PRL	O
+levels	O
+.	O
+	
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+induce	O
+hyperprolactinemia	B-NP
+in	O
+rats	O
+for	O
+extended	O
+periods	O
+of	O
+time	O
+and	O
+examine	O
+its	O
+effects	O
+on	O
+dopaminergic	O
+systems	O
+in	O
+the	O
+brain	O
+.	O
+	
+Hyperprolactinemia	B-NP
+was	O
+induced	O
+by	O
+treatment	O
+with	O
+haloperidol	O
+","	O
+a	O
+dopamine	O
+receptor	O
+antagonist	O
+","	O
+and	O
+Palkovits	O
+'	O
+microdissection	O
+technique	O
+in	O
+combination	O
+with	O
+high	O
+-	O
+performance	O
+liquid	O
+chromatography	O
+was	O
+used	O
+to	O
+measure	O
+neurotransmitter	O
+concentrations	O
+in	O
+several	O
+areas	O
+of	O
+the	O
+brain	O
+.	O
+	
+After	O
+6	O
+months	O
+of	O
+hyperprolactinemia	B-NP
+","	O
+dopamine	O
+(	O
+DA	O
+)	O
+concentrations	O
+in	O
+the	O
+median	O
+eminence	O
+(	O
+ME	O
+)	O
+increased	O
+by	O
+84	O
+%	O
+over	O
+the	O
+control	O
+group	O
+.	O
+	
+Nine	O
+months	O
+of	O
+hyperprolactinemia	B-NP
+produced	O
+a	O
+50	O
+%	O
+increase	O
+in	O
+DA	O
+concentrations	O
+in	O
+the	O
+ME	O
+over	O
+the	O
+control	O
+group	O
+.	O
+	
+However	O
+","	O
+DA	O
+response	O
+was	O
+lost	O
+if	O
+a	O
+9	O
+-	O
+month	O
+long	O
+haloperidol	O
+-	O
+induced	O
+hyperprolactinemia	B-NP
+was	O
+followed	O
+by	O
+a	O
+1	O
+1	O
+/	O
+2	O
+month	O
+-	O
+long	O
+extremely	O
+high	O
+increase	O
+in	O
+serum	O
+PRL	O
+levels	O
+produced	O
+by	O
+implantation	O
+of	O
+MMQ	O
+cells	O
+under	O
+the	O
+kidney	O
+capsule	O
+.	O
+	
+There	O
+was	O
+no	O
+change	O
+in	O
+the	O
+levels	O
+of	O
+DA	O
+","	O
+norepinephrine	O
+(	O
+NE	O
+)	O
+","	O
+serotonin	O
+(	O
+5	O
+-	O
+HT	O
+)	O
+","	O
+or	O
+their	O
+metabolites	O
+in	O
+the	O
+arcuate	O
+nucleus	O
+(	O
+AN	O
+)	O
+","	O
+medial	O
+preoptic	O
+area	O
+(	O
+MPA	O
+)	O
+","	O
+caudate	O
+putamen	O
+(	O
+CP	O
+)	O
+","	O
+substantia	O
+nigra	O
+(	O
+SN	O
+)	O
+","	O
+and	O
+zona	O
+incerta	O
+(	O
+ZI	O
+)	O
+","	O
+except	O
+for	O
+a	O
+decrease	O
+in	O
+5	O
+-	O
+hydroxyindoleacetic	O
+acid	O
+(	O
+5	O
+-	O
+HIAA	O
+)	O
+in	O
+the	O
+AN	O
+after	O
+6	O
+-	O
+months	O
+of	O
+hyperprolactinemia	B-NP
+and	O
+an	O
+increase	O
+in	O
+DA	O
+concentrations	O
+in	O
+the	O
+AN	O
+after	O
+9	O
+-	O
+months	O
+of	O
+hyperprolactinemia	B-NP
+.	O
+	
+These	O
+results	O
+demonstrate	O
+that	O
+hyperprolactinemia	B-NP
+specifically	O
+affects	O
+TIDA	O
+neurons	O
+and	O
+these	O
+effects	O
+vary	O
+","	O
+depending	O
+on	O
+the	O
+duration	O
+and	O
+intensity	O
+of	O
+hyperprolactinemia	B-NP
+.	O
+	
+The	O
+age	O
+-	O
+related	O
+decrease	O
+in	O
+hypothalamic	O
+dopamine	O
+function	O
+may	O
+be	O
+associated	O
+with	O
+increases	O
+in	O
+PRL	O
+secretion	O
+.	O
+	
+Treatment	O
+-	O
+related	O
+disseminated	O
+necrotizing	O
+leukoencephalopathy	B-NP
+with	O
+characteristic	O
+contrast	O
+enhancement	O
+of	O
+the	O
+white	O
+matter	O
+.	O
+	
+This	O
+report	O
+describes	O
+unique	O
+contrast	O
+enhancement	O
+of	O
+the	O
+white	O
+matter	O
+on	O
+T1	O
+-	O
+weighted	O
+magnetic	O
+resonance	O
+images	O
+of	O
+two	O
+patients	O
+with	O
+disseminated	O
+necrotizing	O
+leukoencephalopathy	B-NP
+","	O
+which	O
+developed	O
+from	O
+acute	B-NP
+lymphoblastic	I-NP
+leukemia	I-NP
+treated	O
+with	O
+high	O
+-	O
+dose	O
+methotrexate	O
+.	O
+	
+In	O
+both	O
+patients	O
+","	O
+the	O
+enhancement	O
+was	O
+more	O
+pronounced	O
+near	O
+the	O
+base	O
+of	O
+the	O
+brain	O
+than	O
+at	O
+the	O
+vertex	O
+.	O
+	
+Necropsy	O
+of	O
+the	O
+first	O
+case	O
+revealed	O
+loss	B-NP
+of	I-NP
+myelination	I-NP
+and	O
+necrosis	B-NP
+of	O
+the	O
+white	O
+matter	O
+.	O
+	
+Possible	O
+mechanisms	O
+causing	O
+such	O
+a	O
+leukoencephalopathy	B-NP
+are	O
+discussed	O
+.	O
+	
+Thrombotic	B-NP
+complications	O
+in	O
+acute	B-NP
+promyelocytic	I-NP
+leukemia	I-NP
+during	O
+all	O
+-	O
+trans	O
+-	O
+retinoic	O
+acid	O
+therapy	O
+.	O
+	
+A	O
+case	O
+of	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+","	O
+due	O
+to	O
+occlusion	B-NP
+of	I-NP
+renal	I-NP
+vessels	I-NP
+in	O
+a	O
+patient	O
+with	O
+acute	B-NP
+promyelocytic	I-NP
+leukemia	I-NP
+(	O
+APL	B-NP
+)	O
+treated	O
+with	O
+all	O
+-	O
+trans	O
+-	O
+retinoic	O
+acid	O
+(	O
+ATRA	O
+)	O
+and	O
+tranexamic	O
+acid	O
+has	O
+been	O
+described	O
+recently	O
+.	O
+	
+We	O
+report	O
+a	O
+case	O
+of	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+in	O
+an	O
+APL	B-NP
+patient	O
+treated	O
+with	O
+ATRA	O
+alone	O
+.	O
+	
+This	O
+case	O
+further	O
+supports	O
+the	O
+concern	O
+about	O
+thromboembolic	B-NP
+complications	O
+associated	O
+with	O
+ATRA	O
+therapy	O
+in	O
+APL	B-NP
+patients	O
+.	O
+	
+The	O
+patients	O
+","	O
+a	O
+43	O
+-	O
+year	O
+-	O
+old	O
+man	O
+","	O
+presented	O
+all	O
+the	O
+signs	O
+and	O
+symptoms	O
+of	O
+APL	B-NP
+and	O
+was	O
+included	O
+in	O
+a	O
+treatment	O
+protocol	O
+with	O
+ATRA	O
+.	O
+	
+After	O
+10	O
+days	O
+of	O
+treatment	O
+","	O
+he	O
+developed	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+that	O
+was	O
+completely	O
+reversible	O
+after	O
+complete	O
+remission	O
+of	O
+APL	B-NP
+was	O
+achieved	O
+and	O
+therapy	O
+discontinued	O
+.	O
+	
+We	O
+conclude	O
+that	O
+ATRA	O
+is	O
+a	O
+valid	O
+therapeutic	O
+choice	O
+for	O
+patients	O
+with	O
+APL	B-NP
+","	O
+although	O
+the	O
+procoagulant	O
+tendency	O
+is	O
+not	O
+completely	O
+corrected	O
+.	O
+	
+Thrombotic	B-NP
+events	O
+","	O
+however	O
+","	O
+could	O
+be	O
+avoided	O
+by	O
+using	O
+low	O
+-	O
+dose	O
+heparin	O
+.	O
+	
+Pupillary	O
+changes	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+stimulant	O
+-	O
+induced	O
+mania	B-NP
+:	O
+a	O
+case	O
+report	O
+.	O
+	
+A	O
+30	O
+-	O
+year	O
+-	O
+old	O
+cocaine	O
+-	O
+dependent	O
+man	O
+who	O
+was	O
+a	O
+subject	O
+in	O
+a	O
+study	O
+evaluating	O
+the	O
+anticraving	O
+efficacy	O
+of	O
+the	O
+stimulant	O
+medication	O
+diethylpropion	O
+(	O
+DEP	O
+)	O
+became	O
+manic	B-NP
+during	O
+his	O
+second	O
+week	O
+on	O
+the	O
+study	O
+drug	O
+.	O
+	
+Pupillometric	O
+changes	O
+while	O
+on	O
+DEP	O
+","	O
+especially	O
+changes	O
+in	O
+the	O
+total	O
+power	O
+of	O
+pupillary	B-NP
+oscillation	I-NP
+","	O
+were	O
+dramatically	O
+different	O
+than	O
+those	O
+observed	O
+in	O
+the	O
+eight	O
+other	O
+study	O
+subjects	O
+who	O
+did	O
+not	O
+become	O
+manic	B-NP
+.	O
+	
+The	O
+large	O
+changes	O
+in	O
+total	O
+power	O
+of	O
+pupillary	B-NP
+oscillation	I-NP
+occurred	O
+a	O
+few	O
+days	O
+before	O
+the	O
+patient	O
+became	O
+fully	O
+manic	B-NP
+.	O
+	
+Such	O
+medication	O
+-	O
+associated	O
+changes	O
+in	O
+the	O
+total	O
+power	O
+of	O
+pupillary	B-NP
+oscillation	I-NP
+might	O
+be	O
+of	O
+utility	O
+in	O
+identifying	O
+persons	O
+at	O
+risk	O
+for	O
+manic	B-NP
+-	O
+like	O
+adverse	O
+effects	O
+during	O
+the	O
+medical	O
+use	O
+of	O
+psychomotor	O
+stimulants	O
+or	O
+sympathomimetic	O
+agents	O
+.	O
+	
+Fetal	O
+risks	O
+due	O
+to	O
+warfarin	O
+therapy	O
+during	O
+pregnancy	O
+.	O
+	
+Two	O
+mothers	O
+with	O
+heart	O
+valve	O
+prosthesis	O
+were	O
+treated	O
+with	O
+warfarin	O
+during	O
+pregnancy	O
+.	O
+	
+In	O
+the	O
+first	O
+case	O
+a	O
+caesarean	O
+section	O
+was	O
+done	O
+one	O
+week	O
+after	O
+replacement	O
+of	O
+warfarin	O
+with	O
+heparin	O
+.	O
+	
+The	O
+baby	O
+died	O
+of	O
+cerebral	B-NP
+and	I-NP
+pulmonary	I-NP
+hemorrhage	I-NP
+.	O
+	
+The	O
+second	O
+mother	O
+had	O
+a	O
+male	O
+infant	O
+by	O
+caesarean	O
+section	O
+.	O
+	
+The	O
+baby	O
+showed	O
+warfarin	O
+-	O
+induced	O
+embryopathy	B-NP
+with	O
+nasal	B-NP
+hypoplasia	I-NP
+and	O
+stippled	B-NP
+epiphyses	I-NP
+(	O
+chondrodysplasia	B-NP
+punctata	I-NP
+)	O
+.	O
+	
+Nasal	B-NP
+hypoplasia	I-NP
+with	O
+or	O
+without	O
+stippled	B-NP
+epiphyses	I-NP
+has	O
+now	O
+been	O
+reported	O
+in	O
+11	O
+infants	O
+born	O
+to	O
+mothers	O
+treated	O
+with	O
+warfarin	O
+during	O
+the	O
+first	O
+trimester	O
+","	O
+and	O
+a	O
+causal	O
+association	O
+is	O
+probable	O
+.	O
+	
+In	O
+view	O
+of	O
+the	O
+risks	O
+to	O
+both	O
+mother	O
+and	O
+fetus	O
+in	O
+women	O
+with	O
+prosthetic	O
+cardiac	O
+valves	O
+it	O
+is	O
+recommended	O
+that	O
+therapeutic	O
+abortion	O
+be	O
+advised	O
+as	O
+the	O
+first	O
+alternative	O
+.	O
+	
+The	O
+negative	O
+mucosal	O
+potential	O
+:	O
+separating	O
+central	O
+and	O
+peripheral	O
+effects	O
+of	O
+NSAIDs	O
+in	O
+man	O
+.	O
+	
+OBJECTIVE	O
+:	O
+We	O
+wanted	O
+to	O
+test	O
+whether	O
+assessment	O
+of	O
+both	O
+a	O
+central	O
+pain	B-NP
+-	O
+related	O
+signal	O
+(	O
+chemo	O
+-	O
+somatosensory	O
+evoked	O
+potential	O
+","	O
+CSSEP	O
+)	O
+and	O
+a	O
+concomitantly	O
+recorded	O
+peripheral	O
+signal	O
+(	O
+negative	O
+mucosal	O
+potential	O
+","	O
+NMP	O
+)	O
+allows	O
+for	O
+separation	O
+of	O
+central	O
+and	O
+peripheral	O
+effects	O
+of	O
+NSAIDs	O
+.	O
+	
+For	O
+this	O
+purpose	O
+","	O
+experimental	O
+conditions	O
+were	O
+created	O
+in	O
+which	O
+NSAIDs	O
+had	O
+previously	O
+been	O
+observed	O
+to	O
+produce	O
+effects	O
+on	O
+phasic	O
+and	O
+tonic	O
+pain	B-NP
+by	O
+either	O
+central	O
+or	O
+peripheral	O
+mechanisms	O
+.	O
+	
+METHODS	O
+:	O
+According	O
+to	O
+a	O
+double	O
+-	O
+blind	O
+","	O
+randomised	O
+","	O
+controlled	O
+","	O
+threefold	O
+cross	O
+-	O
+over	O
+design	O
+","	O
+18	O
+healthy	O
+subjects	O
+(	O
+11	O
+males	O
+","	O
+7	O
+females	O
+;	O
+mean	O
+age	O
+26	O
+years	O
+)	O
+received	O
+either	O
+placebo	O
+","	O
+400	O
+mg	O
+ibuprofen	O
+","	O
+or	O
+800	O
+mg	O
+ibuprofen	O
+.	O
+	
+Phasic	O
+pain	B-NP
+was	O
+applied	O
+by	O
+means	O
+of	O
+short	O
+pulses	O
+of	O
+CO2	O
+to	O
+the	O
+nasal	O
+mucosa	O
+(	O
+stimulus	O
+duration	O
+500	O
+ms	O
+","	O
+interval	O
+approximately	O
+60	O
+s	O
+)	O
+","	O
+and	O
+tonic	O
+pain	B-NP
+was	O
+induced	O
+in	O
+the	O
+nasal	O
+cavity	O
+by	O
+means	O
+of	O
+dry	O
+air	O
+of	O
+controlled	O
+temperature	O
+","	O
+humidity	O
+and	O
+flow	O
+rate	O
+(	O
+22	O
+degrees	O
+C	O
+","	O
+0	O
+%	O
+relative	O
+humidity	O
+","	O
+145	O
+ml	O
+.	O
+s	O
+-	O
+1	O
+)	O
+.	O
+	
+Both	O
+CSSEPs	O
+as	O
+central	O
+and	O
+NMPs	O
+as	O
+peripheral	O
+correlates	O
+of	O
+pain	B-NP
+were	O
+obtained	O
+in	O
+response	O
+to	O
+the	O
+CO2	O
+stimuli	O
+.	O
+	
+Additionally	O
+","	O
+the	O
+subjects	O
+rated	O
+the	O
+intensity	O
+of	O
+both	O
+phasic	O
+and	O
+tonic	O
+pain	B-NP
+by	O
+means	O
+of	O
+visual	O
+analogue	O
+scales	O
+.	O
+	
+RESULTS	O
+:	O
+As	O
+described	O
+earlier	O
+","	O
+administration	O
+of	O
+ibuprofen	O
+was	O
+followed	O
+by	O
+a	O
+decrease	O
+in	O
+tonic	O
+pain	B-NP
+but	O
+-	O
+relative	O
+to	O
+placebo	O
+-	O
+an	O
+increase	O
+in	O
+correlates	O
+of	O
+phasic	O
+pain	B-NP
+","	O
+indicating	O
+a	O
+specific	O
+effect	O
+of	O
+ibuprofen	O
+on	O
+the	O
+interaction	O
+between	O
+the	O
+pain	B-NP
+stimuli	O
+under	O
+these	O
+special	O
+experimental	O
+conditions	O
+.	O
+	
+Based	O
+on	O
+the	O
+similar	O
+behaviour	O
+of	O
+CSSEP	O
+and	O
+NMP	O
+","	O
+it	O
+was	O
+concluded	O
+that	O
+the	O
+pharmacological	O
+process	O
+underlying	O
+this	O
+phenomenon	O
+was	O
+localised	O
+in	O
+the	O
+periphery	O
+.	O
+	
+By	O
+means	O
+of	O
+the	O
+simultaneous	O
+recording	O
+of	O
+interrelated	O
+peripheral	O
+and	O
+central	O
+electrophysiologic	O
+correlates	O
+of	O
+nociception	O
+","	O
+it	O
+was	O
+possible	O
+to	O
+separate	O
+central	O
+and	O
+peripheral	O
+effects	O
+of	O
+an	O
+NSAID	O
+.	O
+	
+The	O
+major	O
+advantage	O
+of	O
+this	O
+pain	B-NP
+model	O
+is	O
+the	O
+possibility	O
+of	O
+obtaining	O
+peripheral	O
+pain	B-NP
+-	O
+related	O
+activity	O
+directly	O
+using	O
+a	O
+non	O
+-	O
+invasive	O
+technique	O
+in	O
+humans	O
+.	O
+	
+Effect	O
+of	O
+D	O
+-	O
+Glucarates	O
+on	O
+basic	O
+antibiotic	O
+-	O
+induced	O
+renal	B-NP
+damage	I-NP
+in	O
+rats	O
+.	O
+	
+Dehydrated	B-NP
+rats	O
+regularly	O
+develop	O
+acute	B-NP
+renal	I-NP
+failure	I-NP
+following	O
+single	O
+injection	O
+of	O
+aminoglycoside	O
+antibiotics	O
+combined	O
+with	O
+dextran	O
+or	O
+of	O
+antibiotics	O
+only	O
+.	O
+	
+Oral	O
+administration	O
+of	O
+2	O
+","	O
+5	O
+-	O
+di	O
+-	O
+O	O
+-	O
+acetyl	O
+-	O
+D	O
+-	O
+glucaro	O
+-	O
+1	O
+","	O
+4	O
+-	O
+6	O
+","	O
+3	O
+-	O
+dilactone	O
+protected	O
+rats	O
+against	O
+renal	B-NP
+failure	I-NP
+induced	O
+by	O
+kanamycin	O
+-	O
+dextran	O
+.	O
+	
+The	O
+protective	O
+effect	O
+was	O
+prevalent	O
+among	O
+D	O
+-	O
+glucarates	O
+","	O
+and	O
+also	O
+to	O
+other	O
+saccharic	O
+acid	O
+","	O
+hexauronic	O
+acids	O
+and	O
+hexaaldonic	O
+acids	O
+","	O
+although	O
+to	O
+a	O
+lesser	O
+degree	O
+","	O
+but	O
+not	O
+to	O
+a	O
+hexaaldose	O
+","	O
+sugar	O
+alcohols	O
+","	O
+substances	O
+inthe	O
+TCA	O
+cycle	O
+and	O
+other	O
+acidic	O
+compounds	O
+.	O
+	
+D	O
+-	O
+Glucarates	O
+were	O
+effective	O
+against	O
+renal	B-NP
+damage	I-NP
+induced	O
+by	O
+peptide	O
+antibiotics	O
+as	O
+well	O
+as	O
+various	O
+aminoglycoside	O
+antibitocis	O
+.	O
+	
+Dose	O
+-	O
+responses	O
+were	O
+observed	O
+in	O
+the	O
+protective	O
+effect	O
+of	O
+D	O
+-	O
+Glucarates	O
+.	O
+	
+With	O
+a	O
+D	O
+-	O
+glucarate	O
+of	O
+a	O
+fixed	O
+size	O
+of	O
+dose	O
+","	O
+approximately	O
+the	O
+same	O
+degree	O
+of	O
+protection	O
+was	O
+obtained	O
+against	O
+renal	B-NP
+damages	I-NP
+induced	O
+by	O
+different	O
+basic	O
+antibiotics	O
+despite	O
+large	O
+disparities	O
+in	O
+administration	O
+doses	O
+of	O
+different	O
+antibiotics	O
+.	O
+	
+D	O
+-	O
+Glucarates	O
+had	O
+the	O
+ability	O
+to	O
+prevent	O
+renal	B-NP
+damage	I-NP
+but	O
+not	O
+to	O
+cure	O
+it	O
+.	O
+	
+Rats	O
+excreted	O
+acidic	O
+urine	O
+when	O
+they	O
+were	O
+spared	O
+from	O
+renal	B-NP
+lesions	I-NP
+by	O
+monosaccharides	O
+.	O
+	
+The	O
+reduction	O
+effect	O
+of	O
+D	O
+-	O
+glucarates	O
+against	O
+nephrotoxicity	B-NP
+of	O
+basic	O
+antibiotics	O
+was	O
+discussed	O
+.	O
+	
+Acute	O
+severe	O
+depression	B-NP
+following	O
+peri	O
+-	O
+operative	O
+ondansetron	O
+.	O
+	
+A	O
+41	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+a	O
+strong	O
+history	O
+of	O
+postoperative	B-NP
+nausea	I-NP
+and	I-NP
+vomiting	I-NP
+presented	O
+for	O
+abdominal	O
+hysterectomy	O
+3	O
+months	O
+after	O
+a	O
+previous	O
+anaesthetic	O
+where	O
+ondansetron	O
+prophylaxis	O
+had	O
+been	O
+used	O
+.	O
+	
+She	O
+had	O
+developed	O
+a	O
+severe	O
+acute	O
+major	B-NP
+depression	I-NP
+disorder	I-NP
+almost	O
+immediately	O
+thereafter	O
+","	O
+possibly	O
+related	O
+to	O
+the	O
+use	O
+of	O
+a	O
+serotonin	O
+antagonist	O
+.	O
+	
+Nine	O
+years	O
+before	O
+she	O
+had	O
+experienced	O
+a	O
+self	O
+-	O
+limited	O
+puerperal	O
+depressive	B-NP
+episode	I-NP
+.	O
+	
+Anaesthesia	O
+with	O
+a	O
+propofol	O
+infusion	O
+and	O
+avoidance	O
+of	O
+serotonin	O
+antagonists	O
+provided	O
+a	O
+nausea	B-NP
+-	O
+free	O
+postoperative	O
+course	O
+without	O
+exacerbation	O
+of	O
+the	O
+depression	B-NP
+disorder	I-NP
+.	O
+	
+Hypertensive	B-NP
+response	O
+during	O
+dobutamine	O
+stress	O
+echocardiography	O
+.	O
+	
+Among	O
+3	O
+","	O
+129	O
+dobutamine	O
+stress	O
+echocardiographic	O
+studies	O
+","	O
+a	O
+hypertensive	B-NP
+response	O
+","	O
+defined	O
+as	O
+systolic	O
+blood	O
+pressure	O
+(	O
+BP	O
+)	O
+>	O
+or	O
+=	O
+220	O
+mm	O
+Hg	O
+and	O
+/	O
+or	O
+diastolic	O
+BP	O
+>	O
+or	O
+=	O
+110	O
+mm	O
+Hg	O
+","	O
+occurred	O
+in	O
+30	O
+patients	O
+(	O
+1	O
+%	O
+)	O
+.	O
+	
+Patients	O
+with	O
+this	O
+response	O
+more	O
+often	O
+had	O
+a	O
+history	O
+of	O
+hypertension	B-NP
+and	O
+had	O
+higher	O
+resting	O
+systolic	O
+and	O
+diastolic	O
+BP	O
+before	O
+dobutamine	O
+infusion	O
+.	O
+	
+Continuously	O
+nebulized	O
+albuterol	O
+in	O
+severe	O
+exacerbations	O
+of	O
+asthma	B-NP
+in	O
+adults	O
+:	O
+a	O
+case	O
+-	O
+controlled	O
+study	O
+.	O
+	
+A	O
+retrospective	O
+","	O
+case	O
+-	O
+controlled	O
+analysis	O
+comparing	O
+patients	O
+admitted	O
+to	O
+a	O
+medical	O
+intensive	O
+care	O
+unit	O
+with	O
+severe	O
+exacerbations	O
+of	O
+asthma	B-NP
+who	O
+received	O
+continuously	O
+nebulized	O
+albuterol	O
+(	O
+CNA	O
+)	O
+versus	O
+intermittent	O
+albuterol	O
+(	O
+INA	O
+)	O
+treatments	O
+is	O
+reported	O
+.	O
+	
+Forty	O
+matched	O
+pairs	O
+of	O
+patients	O
+with	O
+asthma	B-NP
+are	O
+compared	O
+.	O
+	
+CNA	O
+was	O
+administered	O
+for	O
+a	O
+mean	O
+of	O
+11	O
++	O
+/	O
+-	O
+10	O
+hr	O
+.	O
+	
+The	O
+incidence	O
+of	O
+cardiac	B-NP
+dysrhythmias	I-NP
+was	O
+similar	O
+between	O
+groups	O
+.	O
+	
+Symptomatic	O
+hypokalemia	B-NP
+did	O
+not	O
+occur	O
+.	O
+	
+CNA	O
+patients	O
+had	O
+higher	O
+heart	O
+rates	O
+during	O
+treatment	O
+","	O
+which	O
+may	O
+reflect	O
+severity	O
+of	O
+illness	O
+.	O
+	
+The	O
+incidence	O
+of	O
+intubation	O
+was	O
+similar	O
+.	O
+	
+We	O
+conclude	O
+that	O
+CNA	O
+and	O
+INA	O
+demonstrated	O
+similar	O
+profiles	O
+with	O
+regard	O
+to	O
+safety	O
+","	O
+morbidity	O
+","	O
+and	O
+mortality	O
+.	O
+	
+Paraplegia	B-NP
+following	O
+intrathecal	O
+methotrexate	O
+:	O
+report	O
+of	O
+a	O
+case	O
+and	O
+review	O
+of	O
+the	O
+literature	O
+.	O
+	
+A	O
+patient	O
+who	O
+developed	O
+paraplegia	B-NP
+following	O
+the	O
+intrathecal	O
+instillation	O
+of	O
+methotrexate	O
+is	O
+discribed	O
+.	O
+	
+The	O
+ten	O
+previously	O
+reported	O
+cases	O
+of	O
+this	O
+unusual	O
+complication	O
+are	O
+reviewed	O
+.	O
+	
+The	O
+following	O
+factors	O
+appear	O
+to	O
+predispose	O
+to	O
+the	O
+development	O
+of	O
+this	O
+complication	O
+:	O
+abnormal	O
+cerebrospinal	O
+dynamics	O
+related	O
+to	O
+the	O
+presence	O
+of	O
+central	B-NP
+nervous	I-NP
+system	I-NP
+leukemia	I-NP
+","	O
+and	O
+epidural	O
+cerebrospinal	O
+leakage	O
+;	O
+elevated	O
+cerebrospinal	O
+fluid	O
+methothexate	O
+concentration	O
+related	O
+to	O
+abnormal	O
+cerebrospinal	O
+fluid	O
+dynamics	O
+and	O
+to	O
+inappropriately	O
+high	O
+methotrexate	O
+doses	O
+based	O
+on	O
+body	O
+surface	O
+area	O
+calculations	O
+in	O
+older	O
+children	O
+and	O
+adults	O
+;	O
+the	O
+presence	O
+of	O
+neurotoxic	B-NP
+preservatives	O
+in	O
+commercially	O
+available	O
+methotrexate	O
+preparations	O
+and	O
+diluents	O
+;	O
+and	O
+the	O
+use	O
+of	O
+methotrexate	O
+diluents	O
+of	O
+unphysiologic	O
+pH	O
+","	O
+ionic	O
+content	O
+and	O
+osmolarity	O
+.	O
+	
+The	O
+role	O
+of	O
+methotrexate	O
+contaminants	O
+","	O
+local	O
+folate	B-NP
+deficiency	I-NP
+","	O
+and	O
+cranial	O
+irradiation	O
+in	O
+the	O
+pathogenesis	O
+of	O
+intrathecal	O
+methotrexate	O
+toxicity	B-NP
+is	O
+unclear	O
+.	O
+	
+The	O
+incidence	O
+of	O
+neurotoxicity	B-NP
+may	O
+be	O
+reduced	O
+by	O
+employing	O
+lower	O
+doses	O
+of	O
+methotrexate	O
+in	O
+the	O
+presence	O
+of	O
+central	B-NP
+nervous	I-NP
+system	I-NP
+leukemia	I-NP
+","	O
+in	O
+older	O
+children	O
+and	O
+adults	O
+","	O
+and	O
+in	O
+the	O
+presence	O
+of	O
+epidural	O
+leakage	O
+.	O
+	
+Only	O
+preservative	O
+-	O
+free	O
+methotrexate	O
+in	O
+Elliott	O
+'	O
+s	O
+B	O
+Solution	O
+at	O
+a	O
+concentration	O
+of	O
+not	O
+more	O
+than	O
+1	O
+mg	O
+/	O
+ml	O
+should	O
+be	O
+used	O
+for	O
+intrathecal	O
+administration	O
+.	O
+	
+Periodic	O
+monitoring	O
+of	O
+cerebruspinal	O
+fluid	O
+methotrexate	O
+levels	O
+may	O
+be	O
+predictive	O
+of	O
+the	O
+development	O
+of	O
+serious	O
+neurotoxicity	B-NP
+.	O
+	
+Hyperosmolar	B-NP
+nonketotic	I-NP
+coma	I-NP
+precipitated	O
+by	O
+lithium	O
+-	O
+induced	O
+nephrogenic	B-NP
+diabetes	I-NP
+insipidus	I-NP
+.	O
+	
+A	O
+45	O
+-	O
+year	O
+-	O
+old	O
+man	O
+","	O
+with	O
+a	O
+10	O
+-	O
+year	O
+history	O
+of	O
+manic	B-NP
+depression	I-NP
+treated	O
+with	O
+lithium	O
+","	O
+was	O
+admitted	O
+with	O
+hyperosmolar	B-NP
+","	I-NP
+nonketotic	I-NP
+coma	I-NP
+.	O
+	
+He	O
+gave	O
+a	O
+five	O
+-	O
+year	O
+history	O
+of	O
+polyuria	B-NP
+and	O
+polydipsia	B-NP
+","	O
+during	O
+which	O
+time	O
+urinalysis	O
+had	O
+been	O
+negative	O
+for	O
+glucose	O
+.	O
+	
+After	O
+recovery	O
+from	O
+hyperglycaemia	B-NP
+","	O
+he	O
+remained	O
+polyuric	B-NP
+despite	O
+normal	O
+blood	O
+glucose	O
+concentrations	O
+;	O
+water	O
+deprivation	O
+testing	O
+indicated	O
+nephrogenic	B-NP
+diabetes	I-NP
+insipidus	I-NP
+","	O
+likely	O
+to	O
+be	O
+lithium	O
+-	O
+induced	O
+.	O
+	
+We	O
+hypothesize	O
+that	O
+when	O
+this	O
+man	O
+developed	O
+type	B-NP
+2	I-NP
+diabetes	I-NP
+","	O
+chronic	O
+polyuria	B-NP
+due	O
+to	O
+nephrogenic	B-NP
+diabetes	I-NP
+insipidus	I-NP
+was	O
+sufficient	O
+to	O
+precipitate	O
+hyperosmolar	O
+dehydration	B-NP
+.	O
+	
+Effects	O
+of	O
+the	O
+intracoronary	O
+infusion	O
+of	O
+cocaine	O
+on	O
+left	O
+ventricular	O
+systolic	O
+and	O
+diastolic	O
+function	O
+in	O
+humans	O
+.	O
+	
+BACKGROUND	O
+:	O
+In	O
+dogs	O
+","	O
+a	O
+large	O
+amount	O
+of	O
+intravenous	O
+cocaine	O
+causes	O
+a	O
+profound	O
+deterioration	B-NP
+of	I-NP
+left	I-NP
+ventricular	I-NP
+(	I-NP
+LV	I-NP
+)	I-NP
+systolic	I-NP
+function	I-NP
+and	O
+an	O
+increase	O
+in	O
+LV	O
+end	O
+-	O
+diastolic	O
+pressure	O
+.	O
+	
+This	O
+study	O
+was	O
+done	O
+to	O
+assess	O
+the	O
+influence	O
+of	O
+a	O
+high	O
+intracoronary	O
+cocaine	O
+concentration	O
+on	O
+LV	O
+systolic	O
+and	O
+diastolic	O
+function	O
+in	O
+humans	O
+.	O
+	
+METHODS	O
+AND	O
+RESULTS	O
+:	O
+In	O
+20	O
+patients	O
+(	O
+14	O
+men	O
+and	O
+6	O
+women	O
+aged	O
+39	O
+to	O
+72	O
+years	O
+)	O
+referred	O
+for	O
+cardiac	O
+catheterization	O
+for	O
+the	O
+evaluation	O
+of	O
+chest	B-NP
+pain	I-NP
+","	O
+we	O
+measured	O
+heart	O
+rate	O
+","	O
+systemic	O
+arterial	O
+pressure	O
+","	O
+LV	O
+pressure	O
+and	O
+its	O
+first	O
+derivative	O
+(	O
+dP	O
+/	O
+dt	O
+)	O
+","	O
+and	O
+LV	O
+volumes	O
+and	O
+ejection	O
+fraction	O
+before	O
+and	O
+during	O
+the	O
+final	O
+2	O
+to	O
+3	O
+minutes	O
+of	O
+a	O
+15	O
+-	O
+minute	O
+intracoronary	O
+infusion	O
+of	O
+saline	O
+(	O
+n	O
+=	O
+10	O
+","	O
+control	O
+subjects	O
+)	O
+or	O
+cocaine	O
+hydrochloride	O
+1	O
+mg	O
+/	O
+min	O
+(	O
+n	O
+=	O
+10	O
+)	O
+.	O
+	
+No	O
+variable	O
+changed	O
+with	O
+saline	O
+.	O
+	
+With	O
+cocaine	O
+","	O
+the	O
+drug	O
+concentration	O
+in	O
+blood	O
+obtained	O
+from	O
+the	O
+coronary	O
+sinus	O
+was	O
+3	O
+.	O
+0	O
++	O
+/	O
+-	O
+0	O
+.	O
+4	O
+(	O
+mean	O
++	O
+/	O
+-	O
+SD	O
+)	O
+mg	O
+/	O
+L	O
+","	O
+similar	O
+in	O
+magnitude	O
+to	O
+the	O
+blood	O
+cocaine	O
+concentration	O
+reported	O
+in	O
+abusers	O
+dying	O
+of	O
+cocaine	O
+intoxication	O
+.	O
+	
+Cocaine	O
+induced	O
+no	O
+significant	O
+change	O
+in	O
+heart	O
+rate	O
+","	O
+LV	O
+dP	O
+/	O
+dt	O
+(	O
+positive	O
+or	O
+negative	O
+)	O
+","	O
+or	O
+LV	O
+end	O
+-	O
+diastolic	O
+volume	O
+","	O
+but	O
+it	O
+caused	O
+an	O
+increase	O
+in	O
+systolic	O
+and	O
+mean	O
+arterial	O
+pressures	O
+","	O
+LV	O
+end	O
+-	O
+diastolic	O
+pressure	O
+","	O
+and	O
+LV	O
+end	O
+-	O
+systolic	O
+volume	O
+","	O
+as	O
+well	O
+as	O
+a	O
+decrease	O
+in	O
+LV	O
+ejection	O
+fraction	O
+.	O
+	
+CONCLUSIONS	O
+:	O
+In	O
+humans	O
+","	O
+the	O
+intracoronary	O
+infusion	O
+of	O
+cocaine	O
+sufficient	O
+in	O
+amount	O
+to	O
+achieve	O
+a	O
+high	O
+drug	O
+concentration	O
+in	O
+coronary	O
+sinus	O
+blood	O
+causes	O
+a	O
+deterioration	B-NP
+of	I-NP
+LV	I-NP
+systolic	I-NP
+and	I-NP
+diastolic	I-NP
+performance	I-NP
+.	O
+	
+Ascending	O
+dose	O
+tolerance	O
+study	O
+of	O
+intramuscular	O
+carbetocin	O
+administered	O
+after	O
+normal	O
+vaginal	O
+birth	O
+.	O
+	
+OBJECTIVE	O
+:	O
+To	O
+determine	O
+the	O
+maximum	O
+tolerated	O
+dose	O
+(	O
+MTD	O
+)	O
+of	O
+carbetocin	O
+(	O
+a	O
+long	O
+-	O
+acting	O
+synthetic	O
+analogue	O
+of	O
+oxytocin	O
+)	O
+","	O
+when	O
+administered	O
+immediately	O
+after	O
+vaginal	O
+delivery	O
+at	O
+term	O
+.	O
+	
+MATERIALS	O
+AND	O
+METHODS	O
+:	O
+Carbetocin	O
+was	O
+given	O
+as	O
+an	O
+intramuscular	O
+injection	O
+immediately	O
+after	O
+the	O
+birth	O
+of	O
+the	O
+infant	O
+in	O
+45	O
+healthy	O
+women	O
+with	O
+normal	O
+singleton	O
+pregnancies	O
+who	O
+delivered	O
+vaginally	O
+at	O
+term	O
+.	O
+	
+Dosage	O
+groups	O
+of	O
+15	O
+","	O
+30	O
+","	O
+50	O
+","	O
+75	O
+","	O
+100	O
+","	O
+125	O
+","	O
+150	O
+","	O
+175	O
+or	O
+200	O
+microg	O
+carbetocin	O
+were	O
+assigned	O
+to	O
+blocks	O
+of	O
+three	O
+women	O
+according	O
+to	O
+the	O
+continual	O
+reassessment	O
+method	O
+(	O
+CRM	O
+)	O
+.	O
+	
+RESULTS	O
+:	O
+All	O
+dosage	O
+groups	O
+consisted	O
+of	O
+three	O
+women	O
+","	O
+except	O
+those	O
+with	O
+100	O
+microg	O
+(	O
+n	O
+=	O
+6	O
+)	O
+and	O
+200	O
+microg	O
+(	O
+n	O
+=	O
+18	O
+)	O
+.	O
+	
+Recorded	O
+were	O
+dose	O
+-	O
+limiting	O
+adverse	O
+events	O
+:	O
+hyper	B-NP
+-	I-NP
+or	I-NP
+hypotension	I-NP
+(	O
+three	O
+)	O
+","	O
+severe	O
+abdominal	B-NP
+pain	I-NP
+(	O
+0	O
+)	O
+","	O
+vomiting	B-NP
+(	O
+0	O
+)	O
+and	O
+retained	B-NP
+placenta	I-NP
+(	O
+four	O
+)	O
+.	O
+	
+Serious	O
+adverse	O
+events	O
+occurred	O
+in	O
+seven	O
+women	O
+:	O
+six	O
+cases	O
+with	O
+blood	B-NP
+loss	I-NP
+>	O
+or	O
+=	O
+1000	O
+ml	O
+","	O
+four	O
+cases	O
+of	O
+manual	O
+placenta	O
+removal	O
+","	O
+five	O
+cases	O
+of	O
+additional	O
+oxytocics	O
+administration	O
+and	O
+five	O
+cases	O
+of	O
+blood	O
+transfusion	O
+.	O
+	
+Maximum	O
+blood	B-NP
+loss	I-NP
+was	O
+greatest	O
+at	O
+the	O
+upper	O
+and	O
+lower	O
+dose	O
+levels	O
+","	O
+and	O
+lowest	O
+in	O
+the	O
+70	O
+-	O
+125	O
+microg	O
+dose	O
+range	O
+.	O
+	
+Four	O
+out	O
+of	O
+six	O
+cases	O
+with	O
+blood	B-NP
+loss	I-NP
+>	O
+or	O
+=	O
+1000	O
+ml	O
+occurred	O
+in	O
+the	O
+200	O
+microg	O
+group	O
+.	O
+	
+The	O
+majority	O
+of	O
+additional	O
+administration	O
+of	O
+oxytocics	O
+(	O
+4	O
+/	O
+5	O
+)	O
+and	O
+blood	O
+transfusion	O
+(	O
+3	O
+/	O
+5	O
+)	O
+occurred	O
+in	O
+the	O
+dose	O
+groups	O
+of	O
+200	O
+microg	O
+.	O
+	
+All	O
+retained	O
+placentae	O
+were	O
+found	O
+in	O
+the	O
+group	O
+of	O
+200	O
+microg	O
+.	O
+	
+CONCLUSION	O
+:	O
+The	O
+MTD	O
+was	O
+calculated	O
+to	O
+be	O
+at	O
+200	O
+microg	O
+carbetocin	O
+.	O
+	
+Heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+","	O
+paradoxical	O
+thromboembolism	B-NP
+","	O
+and	O
+other	O
+side	O
+effects	O
+of	O
+heparin	O
+therapy	O
+.	O
+	
+Although	O
+several	O
+new	O
+anticoagulant	O
+drugs	O
+are	O
+in	O
+development	O
+","	O
+heparin	O
+remains	O
+the	O
+drug	O
+of	O
+choice	O
+for	O
+most	O
+anticoagulation	O
+needs	O
+.	O
+	
+The	O
+clinical	O
+effects	O
+of	O
+heparin	O
+are	O
+meritorious	O
+","	O
+but	O
+side	O
+effects	O
+do	O
+exist	O
+.	O
+	
+Important	O
+untoward	O
+effects	O
+of	O
+heparin	O
+therapy	O
+including	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	B-NP
+","	O
+heparin	O
+-	O
+associated	O
+osteoporosis	B-NP
+","	O
+eosinophilia	B-NP
+","	O
+skin	B-NP
+reactions	I-NP
+","	O
+allergic	B-NP
+reactions	I-NP
+other	O
+than	O
+thrombocytopenia	B-NP
+and	O
+alopecia	B-NP
+will	O
+be	O
+discussed	O
+in	O
+this	O
+article	O
+.	O
+	
+Nonopaque	O
+crystal	O
+deposition	O
+causing	O
+ureteric	B-NP
+obstruction	I-NP
+in	O
+patients	O
+with	O
+HIV	O
+undergoing	O
+indinavir	O
+therapy	O
+.	O
+	
+OBJECTIVE	O
+:	O
+We	O
+describe	O
+the	O
+unique	O
+CT	O
+features	O
+of	O
+ureteric	B-NP
+calculi	I-NP
+in	O
+six	O
+HIV	B-NP
+-	I-NP
+infected	I-NP
+patients	O
+receiving	O
+indinavir	O
+","	O
+the	O
+most	O
+commonly	O
+used	O
+HIV	O
+protease	O
+inhibitor	O
+","	O
+which	O
+is	O
+associated	O
+with	O
+an	O
+increased	O
+incidence	O
+of	O
+urolithiasis	B-NP
+.	O
+	
+CONCLUSION	O
+:	O
+Ureteric	B-NP
+obstruction	I-NP
+caused	O
+by	O
+precipitated	O
+indinavir	O
+crystals	O
+may	O
+be	O
+difficult	O
+to	O
+diagnose	O
+with	O
+unenhanced	O
+CT	O
+.	O
+	
+The	O
+calculi	O
+are	O
+not	O
+opaque	O
+","	O
+and	O
+secondary	O
+signs	O
+of	O
+obstruction	O
+may	O
+be	O
+absent	O
+or	O
+minimal	O
+and	O
+should	O
+be	O
+sought	O
+carefully	O
+.	O
+	
+Images	O
+may	O
+need	O
+to	O
+be	O
+obtained	O
+using	O
+i	O
+.	O
+v	O
+.	O
+contrast	O
+material	O
+to	O
+enable	O
+diagnosis	O
+of	O
+ureteric	B-NP
+stones	I-NP
+or	I-NP
+obstruction	I-NP
+in	O
+patients	O
+with	O
+HIV	B-NP
+infection	I-NP
+who	O
+receive	O
+indinavir	O
+therapy	O
+.	O
+	
+Ischemic	B-NP
+colitis	I-NP
+and	O
+sumatriptan	O
+use	O
+.	O
+	
+Sumatriptan	O
+succinate	O
+","	O
+a	O
+serotonin	O
+-	O
+1	O
+(	O
+5	O
+-	O
+hydroxytryptamine	O
+-	O
+1	O
+)	O
+receptor	O
+agonist	O
+","	O
+is	O
+an	O
+antimigraine	O
+drug	O
+that	O
+is	O
+reported	O
+to	O
+act	O
+by	O
+selectively	O
+constricting	O
+intracranial	O
+arteries	O
+.	O
+	
+Recently	O
+","	O
+vasopressor	O
+responses	O
+that	O
+are	O
+distinct	O
+from	O
+the	O
+cranial	O
+circulation	O
+have	O
+been	O
+demonstrated	O
+to	O
+occur	O
+in	O
+the	O
+systemic	O
+","	O
+pulmonary	O
+","	O
+and	O
+coronary	O
+circulations	O
+.	O
+	
+Cases	O
+have	O
+been	O
+published	O
+of	O
+coronary	B-NP
+vasospasm	I-NP
+","	O
+myocardial	B-NP
+ischemia	I-NP
+","	O
+and	O
+myocardial	B-NP
+infarction	I-NP
+occurring	O
+after	O
+sumatriptan	O
+use	O
+.	O
+	
+We	O
+report	O
+on	O
+the	O
+development	O
+of	O
+8	O
+serious	O
+cases	O
+of	O
+ischemic	B-NP
+colitis	I-NP
+in	O
+patients	O
+with	O
+migraine	B-NP
+treated	O
+with	O
+sumatriptan	O
+.	O
+	
+Pallidotomy	O
+with	O
+the	O
+gamma	O
+knife	O
+:	O
+a	O
+positive	O
+experience	O
+.	O
+	
+51	O
+patients	O
+with	O
+medically	O
+refractory	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+underwent	O
+stereotactic	O
+posteromedial	O
+pallidotomy	O
+between	O
+August	O
+1993	O
+and	O
+February	O
+1997	O
+for	O
+treatment	O
+of	O
+bradykinesia	B-NP
+","	O
+rigidity	B-NP
+","	O
+and	O
+L	O
+-	O
+DOPA	O
+-	O
+induced	O
+dyskinesias	B-NP
+.	O
+	
+In	O
+29	O
+patients	O
+","	O
+the	O
+pallidotomies	O
+were	O
+performed	O
+with	O
+the	O
+Leksell	O
+Gamma	O
+Knife	O
+and	O
+in	O
+22	O
+they	O
+were	O
+performed	O
+with	O
+the	O
+standard	O
+radiofrequency	O
+(	O
+RF	O
+)	O
+method	O
+.	O
+	
+Clinical	O
+assessment	O
+as	O
+well	O
+as	O
+blinded	O
+ratings	O
+of	O
+Unified	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+Disease	I-NP
+Rating	O
+Scale	O
+(	O
+UPDRS	O
+)	O
+scores	O
+were	O
+carried	O
+out	O
+pre	O
+-	O
+and	O
+postoperatively	O
+.	O
+	
+Mean	O
+follow	O
+-	O
+up	O
+time	O
+is	O
+20	O
+.	O
+6	O
+months	O
+(	O
+range	O
+6	O
+-	O
+48	O
+)	O
+and	O
+all	O
+except	O
+4	O
+patients	O
+have	O
+been	O
+followed	O
+more	O
+than	O
+one	O
+year	O
+.	O
+	
+85	O
+percent	O
+of	O
+patients	O
+with	O
+dyskinesias	B-NP
+were	O
+relieved	O
+of	O
+symptoms	O
+","	O
+regardless	O
+of	O
+whether	O
+the	O
+pallidotomies	O
+were	O
+performed	O
+with	O
+the	O
+Gamma	O
+Knife	O
+or	O
+radiofrequency	O
+methods	O
+.	O
+	
+About	O
+2	O
+/	O
+3	O
+of	O
+the	O
+patients	O
+in	O
+both	O
+Gamma	O
+Knife	O
+and	O
+radiofrequency	O
+groups	O
+showed	O
+improvements	O
+in	O
+bradykinesia	B-NP
+and	O
+rigidity	B-NP
+","	O
+although	O
+when	O
+considered	O
+as	O
+a	O
+group	O
+neither	O
+the	O
+Gamma	O
+Knife	O
+nor	O
+the	O
+radiofrequency	O
+group	O
+showed	O
+statistically	O
+significant	O
+improvements	O
+in	O
+UPDRS	O
+scores	O
+.	O
+	
+One	O
+patient	O
+in	O
+the	O
+Gamma	O
+Knife	O
+group	O
+(	O
+3	O
+.	O
+4	O
+%	O
+)	O
+developed	O
+a	O
+homonymous	B-NP
+hemianopsia	I-NP
+9	O
+months	O
+following	O
+treatment	O
+and	O
+5	O
+patients	O
+(	O
+27	O
+.	O
+7	O
+%	O
+)	O
+in	O
+the	O
+radiofrequency	O
+group	O
+became	O
+transiently	O
+confused	O
+postoperatively	O
+.	O
+	
+No	O
+other	O
+complications	O
+were	O
+seen	O
+.	O
+	
+Gamma	O
+Knife	O
+pallidotomy	O
+is	O
+as	O
+effective	O
+as	O
+radiofrequency	O
+pallidotomy	O
+in	O
+controlling	O
+certain	O
+of	O
+the	O
+symptoms	O
+of	O
+Parkinson	B-NP
+'	I-NP
+s	I-NP
+disease	I-NP
+.	O
+	
+It	O
+may	O
+be	O
+the	O
+only	O
+practical	O
+technique	O
+available	O
+in	O
+certain	O
+patients	O
+","	O
+such	O
+as	O
+those	O
+who	O
+take	O
+anticoagulants	O
+","	O
+have	O
+bleeding	B-NP
+diatheses	O
+or	O
+serious	O
+systemic	O
+medical	O
+illnesses	O
+.	O
+	
+It	O
+is	O
+a	O
+viable	O
+option	O
+for	O
+other	O
+patients	O
+as	O
+well	O
+.	O
+	
+Centrally	O
+mediated	O
+cardiovascular	O
+effects	O
+of	O
+intracisternal	O
+application	O
+of	O
+carbachol	O
+in	O
+anesthetized	O
+rats	O
+.	O
+	
+The	O
+pressor	O
+response	O
+to	O
+the	O
+intracisternal	O
+(	O
+i	O
+.	O
+c	O
+.	O
+)	O
+injection	O
+of	O
+carbachol	O
+(	O
+1	O
+mug	O
+)	O
+in	O
+anesthetized	O
+rats	O
+was	O
+analyzed	O
+.	O
+	
+This	O
+response	O
+was	O
+significantly	O
+reduced	O
+by	O
+the	O
+intravenous	O
+(	O
+i	O
+.	O
+v	O
+.	O
+)	O
+injection	O
+of	O
+guanethidine	O
+(	O
+5	O
+mg	O
+)	O
+","	O
+hexamethonium	O
+(	O
+10	O
+mg	O
+)	O
+or	O
+phentolamine	O
+(	O
+5	O
+mg	O
+)	O
+","	O
+and	O
+conversely	O
+","	O
+potentiated	O
+by	O
+i	O
+.	O
+v	O
+.	O
+desmethylimipramine	O
+(	O
+0	O
+.	O
+3	O
+mg	O
+)	O
+","	O
+while	O
+propranolol	O
+(	O
+0	O
+.	O
+5	O
+mg	O
+)	O
+i	O
+.	O
+v	O
+.	O
+selectively	O
+inhibited	O
+the	O
+enlargement	B-NP
+of	I-NP
+pulse	I-NP
+pressure	I-NP
+and	O
+the	O
+tachycardia	B-NP
+following	O
+i	O
+.	O
+c	O
+.	O
+carbachol	O
+(	O
+1	O
+mug	O
+)	O
+.	O
+	
+On	O
+the	O
+other	O
+hand	O
+","	O
+the	O
+pressor	O
+response	O
+to	O
+i	O
+.	O
+c	O
+.	O
+carbachol	O
+(	O
+1	O
+mug	O
+)	O
+was	O
+almost	O
+completely	O
+blocked	O
+by	O
+i	O
+.	O
+c	O
+.	O
+atropine	O
+(	O
+3	O
+mug	O
+)	O
+or	O
+hexamethonium	O
+(	O
+500	O
+mug	O
+)	O
+","	O
+and	O
+significantly	O
+reduced	O
+by	O
+i	O
+.	O
+c	O
+.	O
+chlorpromazine	O
+(	O
+50	O
+mug	O
+)	O
+but	O
+significantly	O
+potentiated	O
+by	O
+i	O
+.	O
+c	O
+.	O
+desmethylimipramine	O
+(	O
+30	O
+mug	O
+)	O
+.	O
+	
+The	O
+pressor	O
+response	O
+to	O
+i	O
+.	O
+c	O
+.	O
+carbachol	O
+(	O
+1	O
+mug	O
+)	O
+remained	O
+unchanged	O
+after	O
+sectioning	O
+of	O
+the	O
+bilateral	O
+cervical	O
+vagal	O
+nerves	O
+but	O
+disappeared	O
+after	O
+sectioning	O
+of	O
+the	O
+spinal	O
+cord	O
+(	O
+C7	O
+-	O
+C8	O
+)	O
+.	O
+	
+From	O
+the	O
+above	O
+result	O
+it	O
+is	O
+suggested	O
+that	O
+the	O
+pressor	O
+response	O
+to	O
+i	O
+.	O
+c	O
+.	O
+carbachol	O
+ortral	O
+and	O
+peripheral	O
+adrenergic	O
+mechanisms	O
+","	O
+and	O
+that	O
+the	O
+sympathetic	O
+trunk	O
+is	O
+the	O
+main	O
+pathway	O
+.	O
+	
+Neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+and	O
+methylphenidate	O
+.	O
+	
+A	O
+1	O
+-	O
+year	O
+-	O
+old	O
+female	O
+presented	O
+with	O
+neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+probably	O
+caused	O
+by	O
+methylphenidate	O
+.	O
+	
+She	O
+had	O
+defects	O
+in	O
+the	O
+supratentorial	O
+brain	O
+including	O
+the	O
+basal	O
+ganglia	O
+and	O
+the	O
+striatum	O
+(	O
+multicystic	B-NP
+encephalomalacia	I-NP
+)	O
+due	O
+to	O
+severe	O
+perinatal	O
+hypoxic	B-NP
+-	I-NP
+ischemic	I-NP
+encephalopathy	I-NP
+","	O
+which	O
+was	O
+considered	O
+to	O
+be	O
+a	O
+possible	O
+predisposing	O
+factor	O
+causing	O
+neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+.	O
+	
+A	O
+dopaminergic	O
+blockade	O
+mechanism	O
+generally	O
+is	O
+accepted	O
+as	O
+the	O
+pathogenesis	O
+of	O
+this	O
+syndrome	O
+.	O
+	
+However	O
+","	O
+methylphenidate	O
+is	O
+a	O
+dopamine	O
+agonist	O
+via	O
+the	O
+inhibition	O
+of	O
+uptake	O
+of	O
+dopamine	O
+","	O
+and	O
+therefore	O
+dopaminergic	O
+systems	O
+in	O
+the	O
+brainstem	O
+(	O
+mainly	O
+the	O
+midbrain	O
+)	O
+and	O
+the	O
+spinal	O
+cord	O
+were	O
+unlikely	O
+to	O
+participate	O
+in	O
+the	O
+onset	O
+of	O
+this	O
+syndrome	O
+.	O
+	
+A	O
+relative	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+-	O
+ergic	O
+deficiency	O
+might	O
+occur	O
+because	O
+diazepam	O
+","	O
+a	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+-	O
+mimetic	O
+agent	O
+","	O
+was	O
+strikingly	O
+effective	O
+.	O
+	
+This	O
+is	O
+the	O
+first	O
+reported	O
+patient	O
+with	O
+neuroleptic	B-NP
+malignant	I-NP
+syndrome	I-NP
+probably	O
+caused	O
+by	O
+methylphenidate	O
+.	O
+	
+Differential	O
+effects	O
+of	O
+17alpha	O
+-	O
+ethinylestradiol	O
+on	O
+the	O
+neutral	O
+and	O
+acidic	O
+pathways	O
+of	O
+bile	O
+salt	O
+synthesis	O
+in	O
+the	O
+rat	O
+.	O
+	
+Effects	O
+of	O
+17alpha	O
+-	O
+ethinylestradiol	O
+(	O
+EE	O
+)	O
+on	O
+the	O
+neutral	O
+and	O
+acidic	O
+biosynthetic	O
+pathways	O
+of	O
+bile	O
+salt	O
+(	O
+BS	O
+)	O
+synthesis	O
+were	O
+evaluated	O
+in	O
+rats	O
+with	O
+an	O
+intact	O
+enterohepatic	O
+circulation	O
+and	O
+in	O
+rats	O
+with	O
+long	O
+-	O
+term	O
+bile	O
+diversion	O
+to	O
+induce	O
+BS	O
+synthesis	O
+.	O
+	
+For	O
+this	O
+purpose	O
+","	O
+bile	O
+salt	O
+pool	O
+composition	O
+","	O
+synthesis	O
+of	O
+individual	O
+BS	O
+in	O
+vivo	O
+","	O
+hepatic	O
+activities	O
+","	O
+and	O
+expression	O
+levels	O
+of	O
+cholesterol	O
+7alpha	O
+-	O
+hydroxylase	O
+(	O
+CYP7A	O
+)	O
+","	O
+and	O
+sterol	O
+27	O
+-	O
+hydroxylase	O
+(	O
+CYP27	O
+)	O
+","	O
+as	O
+well	O
+as	O
+of	O
+other	O
+enzymes	O
+involved	O
+in	O
+BS	O
+synthesis	O
+","	O
+were	O
+analyzed	O
+in	O
+rats	O
+treated	O
+with	O
+EE	O
+(	O
+5	O
+mg	O
+/	O
+kg	O
+","	O
+3	O
+days	O
+)	O
+or	O
+its	O
+vehicle	O
+.	O
+	
+BS	O
+pool	O
+size	O
+was	O
+decreased	O
+by	O
+27	O
+%	O
+but	O
+total	O
+BS	O
+synthesis	O
+was	O
+not	O
+affected	O
+by	O
+EE	O
+in	O
+intact	O
+rats	O
+.	O
+	
+Synthesis	O
+of	O
+cholate	O
+was	O
+reduced	O
+by	O
+68	O
+%	O
+in	O
+EE	O
+-	O
+treated	O
+rats	O
+","	O
+while	O
+that	O
+of	O
+chenodeoxycholate	O
+was	O
+increased	O
+by	O
+60	O
+%	O
+.	O
+	
+The	O
+recently	O
+identified	O
+Delta22	O
+-	O
+isomer	O
+of	O
+beta	O
+-	O
+muricholate	O
+contributed	O
+for	O
+5	O
+.	O
+4	O
+%	O
+and	O
+18	O
+.	O
+3	O
+%	O
+(	O
+P	O
+<	O
+0	O
+.	O
+1	O
+)	O
+to	O
+the	O
+pool	O
+in	O
+control	O
+and	O
+EE	O
+-	O
+treated	O
+rats	O
+","	O
+respectively	O
+","	O
+but	O
+could	O
+not	O
+be	O
+detected	O
+in	O
+bile	O
+after	O
+exhaustion	O
+of	O
+the	O
+pool	O
+.	O
+	
+A	O
+clear	O
+reduction	O
+of	O
+BS	O
+synthesis	O
+was	O
+found	O
+in	O
+bile	O
+-	O
+diverted	O
+rats	O
+treated	O
+with	O
+EE	O
+","	O
+yet	O
+biliary	O
+BS	O
+composition	O
+was	O
+only	O
+minimally	O
+affected	O
+.	O
+	
+Activity	O
+of	O
+CYP7A	O
+was	O
+decreased	O
+by	O
+EE	O
+in	O
+both	O
+intact	O
+and	O
+bile	O
+-	O
+diverted	O
+rats	O
+","	O
+whereas	O
+the	O
+activity	O
+of	O
+the	O
+CYP27	O
+was	O
+not	O
+affected	O
+.	O
+	
+Hepatic	O
+mRNA	O
+levels	O
+of	O
+CYP7A	O
+were	O
+significantly	O
+reduced	O
+by	O
+EE	O
+in	O
+bile	O
+-	O
+diverted	O
+rats	O
+only	O
+;	O
+CYP27	O
+mRNA	O
+levels	O
+were	O
+not	O
+affected	O
+by	O
+EE	O
+.	O
+	
+In	O
+addition	O
+","	O
+mRNA	O
+levels	O
+of	O
+sterol	O
+12alpha	O
+-	O
+hydroxylase	O
+and	O
+lithocholate	O
+6beta	O
+-	O
+hydroxylase	O
+were	O
+increased	O
+by	O
+bile	O
+diversion	O
+and	O
+suppressed	O
+by	O
+EE	O
+.	O
+	
+This	O
+study	O
+shows	O
+that	O
+17alpha	O
+-	O
+ethinylestradiol	O
+(	O
+EE	O
+)	O
+-	O
+induced	O
+intrahepatic	B-NP
+cholestasis	I-NP
+in	O
+rats	O
+is	O
+associated	O
+with	O
+selective	O
+inhibition	O
+of	O
+the	O
+neutral	O
+pathway	O
+of	O
+bile	O
+salt	O
+(	O
+BS	O
+)	O
+synthesis	O
+.	O
+	
+Simultaneous	O
+impairment	O
+of	O
+other	O
+enzymes	O
+in	O
+the	O
+BS	O
+biosynthetic	O
+pathways	O
+may	O
+contribute	O
+to	O
+overall	O
+effects	O
+of	O
+EE	O
+on	O
+BS	O
+synthesis	O
+.	O
+	
+Glibenclamide	O
+-	O
+sensitive	O
+hypotension	B-NP
+produced	O
+by	O
+helodermin	O
+assessed	O
+in	O
+the	O
+rat	O
+.	O
+	
+The	O
+effects	O
+of	O
+helodermin	O
+","	O
+a	O
+basic	O
+35	O
+-	O
+amino	O
+acid	O
+peptide	O
+isolated	O
+from	O
+the	O
+venom	O
+of	O
+a	O
+lizard	O
+salivary	O
+gland	O
+","	O
+on	O
+arterial	O
+blood	O
+pressure	O
+and	O
+heart	O
+rate	O
+were	O
+examined	O
+in	O
+the	O
+rat	O
+","	O
+focusing	O
+on	O
+the	O
+possibility	O
+that	O
+activation	O
+of	O
+ATP	O
+sensitive	O
+K	O
++	O
+(	O
+K	O
+(	O
+ATP	O
+)	O
+)	O
+channels	O
+is	O
+involved	O
+in	O
+the	O
+responses	O
+.	O
+	
+The	O
+results	O
+were	O
+also	O
+compared	O
+with	O
+those	O
+of	O
+vasoactive	O
+intestinal	O
+polypeptide	O
+(	O
+VIP	O
+)	O
+.	O
+	
+Helodermin	O
+produced	O
+hypotension	B-NP
+in	O
+a	O
+dose	O
+-	O
+dependent	O
+manner	O
+with	O
+approximately	O
+similar	O
+potency	O
+and	O
+duration	O
+to	O
+VIP	O
+.	O
+	
+Hypotension	B-NP
+induced	O
+by	O
+both	O
+peptides	O
+was	O
+significantly	O
+attenuated	O
+by	O
+glibenclamide	O
+","	O
+which	O
+abolished	O
+a	O
+levcromakalim	O
+-	O
+produced	O
+decrease	O
+in	O
+arterial	O
+blood	O
+pressure	O
+.	O
+	
+Oxyhemoglobin	O
+did	O
+not	O
+affect	O
+helodermin	O
+-	O
+induced	O
+hypotension	B-NP
+","	O
+whereas	O
+it	O
+shortened	O
+the	O
+duration	O
+of	O
+acetylcholine	O
+(	O
+ACh	O
+)	O
+-	O
+produced	O
+hypotension	B-NP
+.	O
+	
+These	O
+findings	O
+suggest	O
+that	O
+helodermin	O
+-	O
+produced	O
+hypotension	B-NP
+is	O
+partly	O
+attributable	O
+to	O
+the	O
+activation	O
+of	O
+glibenclamide	O
+-	O
+sensitive	O
+K	O
++	O
+channels	O
+(	O
+K	O
+(	O
+ATP	O
+)	O
+channels	O
+)	O
+","	O
+which	O
+presumably	O
+exist	O
+on	O
+arterial	O
+smooth	O
+muscle	O
+cells	O
+.	O
+	
+EDRF	O
+(	O
+endothelium	O
+-	O
+derived	O
+relaxing	O
+factor	O
+)	O
+/	O
+nitric	O
+oxide	O
+does	O
+not	O
+seem	O
+to	O
+play	O
+an	O
+important	O
+role	O
+in	O
+the	O
+peptide	O
+-	O
+produced	O
+hypotension	B-NP
+.	O
+	
+Long	O
+-	O
+term	O
+efficacy	O
+and	O
+adverse	O
+event	O
+of	O
+nifedipine	O
+sustained	O
+-	O
+release	O
+tablets	O
+for	O
+cyclosporin	O
+A	O
+-	O
+induced	O
+hypertension	B-NP
+in	O
+patients	O
+with	O
+psoriasis	B-NP
+.	O
+	
+Thirteen	O
+psoriatic	B-NP
+patients	O
+with	O
+hypertension	B-NP
+during	O
+the	O
+course	O
+of	O
+cyclosporin	O
+A	O
+therapy	O
+were	O
+treated	O
+for	O
+25	O
+months	O
+with	O
+a	O
+calcium	O
+channel	O
+blocker	O
+","	O
+sustained	O
+-	O
+release	O
+nifedipine	O
+","	O
+to	O
+study	O
+the	O
+clinical	O
+antihypertensive	O
+effects	O
+and	O
+adverse	O
+events	O
+during	O
+treatment	O
+with	O
+both	O
+drugs	O
+.	O
+	
+Seven	O
+of	O
+the	O
+13	O
+patients	O
+had	O
+exhibited	O
+a	O
+subclinical	O
+hypertensive	B-NP
+state	O
+before	O
+cyclosporin	O
+A	O
+therapy	O
+.	O
+	
+Both	O
+systolic	O
+and	O
+diastolic	O
+blood	O
+pressures	O
+of	O
+these	O
+13	O
+patients	O
+were	O
+decreased	O
+significantly	O
+after	O
+4	O
+weeks	O
+of	O
+nifedipine	O
+therapy	O
+","	O
+and	O
+blood	O
+pressure	O
+was	O
+maintained	O
+within	O
+the	O
+normal	O
+range	O
+thereafter	O
+for	O
+25	O
+months	O
+.	O
+	
+The	O
+adverse	O
+events	O
+during	O
+combined	O
+therapy	O
+with	O
+cyclosporin	O
+A	O
+and	O
+nifedipine	O
+included	O
+an	O
+increase	O
+in	O
+blood	O
+urea	O
+nitrogen	O
+levels	O
+in	O
+9	O
+of	O
+the	O
+13	O
+patients	O
+and	O
+development	O
+of	O
+gingival	B-NP
+hyperplasia	I-NP
+in	O
+2	O
+of	O
+the	O
+13	O
+patients	O
+.	O
+	
+Our	O
+findings	O
+indicate	O
+that	O
+sustained	O
+-	O
+release	O
+nifedipine	O
+is	O
+useful	O
+for	O
+hypertensive	B-NP
+psoriatic	B-NP
+patients	O
+under	O
+long	O
+-	O
+term	O
+treatment	O
+with	O
+cyclosporin	O
+A	O
+","	O
+but	O
+that	O
+these	O
+patients	O
+should	O
+be	O
+monitored	O
+for	O
+gingival	B-NP
+hyperplasia	I-NP
+.	O
\ No newline at end of file
diff --git a/helper/tokenized_txt.py b/helper/tokenized_txt.py
new file mode 100644
index 0000000..6c9512d
--- /dev/null
+++ b/helper/tokenized_txt.py
@@ -0,0 +1,26 @@
+
+def tokenize(data):
+    import csv
+    """
+    tokenize .tsv labeled data
+    remove labels and tokenize sentences with whitespace and write them to .txt file
+    
+    E.g.
+    Torsade de pointes ventricular tachycardia during low dose intermittent dobutamine treatment
+     in a patient with dilated cardiomyopathy and congestive heart failure .
+    """
+
+    with open(data,'r') as f:
+        tokens = []
+        r = csv.reader(f, delimiter='\t', quotechar=None)
+        lines = list(r)
+
+        for line in lines:
+            if len(line) > 0:
+                print(line[0])
+                tokens.append(line[0])
+
+        f = open('tokenized_test.txt','w')
+        for token in tokens:
+            f.write(token + ' ')
+
diff --git a/huner/.DS_Store b/huner/.DS_Store
new file mode 100644
index 0000000..2bbaac9
Binary files /dev/null and b/huner/.DS_Store differ
diff --git a/huner/Dockerfile b/huner/Dockerfile
new file mode 100644
index 0000000..c894076
--- /dev/null
+++ b/huner/Dockerfile
@@ -0,0 +1,61 @@
+FROM ubuntu:18.04
+
+
+# Install build-essential, git, wget, python-dev, pip, BLAS + LAPACK and other dependencies
+RUN apt-get update && apt-get install -y \
+build-essential \
+gfortran \
+git \
+wget \
+liblapack-dev \
+libopenblas-dev \
+python-dev \
+python-pip \
+python-nose \
+python-numpy \
+python-scipy \
+python3-dev \
+python3-pip \
+python3-nose \
+python3-numpy \
+python3-scipy \
+default-jre \
+default-jdk \
+curl 
+
+# Set locale to get file encodings right
+RUN apt-get install -y locales
+RUN locale-gen en_US.UTF-8
+ENV LANG en_US.UTF-8
+ENV LANGUAGE en_US:en
+ENV LC_ALL en_US.UTF-8
+
+ENV workdir /usr/src/myapp
+RUN mkdir -p $workdir
+WORKDIR $workdir
+
+RUN curl -o $workdir/apache-opennlp-1.8.4-bin.tar.xz https://archive.apache.org/dist/opennlp/opennlp-1.8.4/apache-opennlp-1.8.4-bin.tar.gz
+RUN tar xzf apache-opennlp-1.8.4-bin.tar.xz
+RUN rm apache-opennlp-1.8.4-bin.tar.xz
+RUN mv apache-opennlp-1.8.4/ /usr/bin/
+
+ENV OPENNLP /usr/bin/apache-opennlp-1.8.4
+
+RUN mkdir -p $OPENNLP/models
+RUN curl -o $OPENNLP/models/en-sent.bin http://opennlp.sourceforge.net/models-1.5/en-sent.bin
+RUN curl -o $OPENNLP/models/en-token.bin http://opennlp.sourceforge.net/models-1.5/en-token.bin
+RUN curl -o $OPENNLP/models/en-pos-maxent.bin http://opennlp.sourceforge.net/models-1.5/en-pos-maxent.bin
+
+
+# Install bleeding-edge Theano
+RUN pip install --upgrade pip
+RUN pip install --upgrade six
+RUN pip install --upgrade --no-deps git+git://github.com/Theano/Theano.git
+RUN pip install joblib gunicorn flask pexpect
+
+RUN pip3 install pexpect tqdm lxml beautifulsoup4
+
+
+
+EXPOSE 5000:5000
+
diff --git a/huner/README.md b/huner/README.md
new file mode 100644
index 0000000..50cc2b6
--- /dev/null
+++ b/huner/README.md
@@ -0,0 +1,82 @@
+# HUNER
+HUNER is a state-of-the-art NER model for biomedical entities. It comes with models for genes/proteins, chemicals, diseases, species and cell lines.
+
+The code is based on the great LSTM-CRF NER tagger implementation [glample/tagger](https://github.com/glample/tagger) by Guillaume Lample.
+
+## Content
+| Section | Description |
+|-|-|
+| [Installation](#installation) | How to install HUNER |
+| [Usage](#usage) | How to use HUNER |
+| [Models](#models) | Available pretrained models |
+| [Corpora](#corpora) | The HUNER Corpora |
+
+
+# Installation
+1. [Install docker](https://docs.docker.com/install/)
+1. Clone this repository to `$dir`
+1. Download the pretrained model you want to use from [here](https://drive.google.com/drive/folders/1Y6vdSymGN5QEeEITPF2zZj4qUcoDWvXf), place it into `$dir/models/$model_name` and untar it using `tar xzf $model_name`
+
+# Usage
+
+# Tagging
+To tokenize, sentence split and tag a file INPUT.TXT:
+
+1. Start the HUNER server from `$dir` using `./start_server $model_name`. The model must reside in the directory `$dir/models/$model_name`.
+1. Tag text with `python client.py INPUT.TXT OUTPUT.CONLL --name $model_name`.
+
+the output will then be written to OUTPUT.CONLL in the conll2003 format.
+
+
+The options for `client.py` are:
+* `--asume_tokenized`: The input is already pre-tokenized and the tokens are separated by whitespace
+* `--assume_sentence_splitted`: The input is already split into sentences and each line of the input contains one sentence
+
+## Fine-tuning on a new corpus
+The steps to fine-tune a base-model `$base_model` (e.g. `gene_all`) on a new corpus `$corpus` are:
+
+
+1. Copy the chosen base-model to a new directory, because the weight files will be updated during fine-tuning:
+```bash
+cp $dir/models/$base_model $dir/models/$fine_tuned_model
+```
+2. Convert your corpus to conll format and split it into `train`, `dev` and `test` portions. If you don't want to use either dev or test data you can just provide the training data as `dev` or `test`. Note however, that without dev data, results will probably suffer, because early-stopping can't be performed.
+3. Fine-tune the model:
+```bash
+./train.sh $fine_tuned_model $corpus_train $corpus_dev $corpus_test
+```
+After successful training, `$fine_tuned_model` will contain the fine-tuned model and can be used exactly like the models provided by us.
+
+## Retraining a base-model from scratch (without fine-tuning)
+To train a model from scratch without initializing it from a base-model, proceed as follows:
+1. Convert your corpus to conll format and split it into `train`, `dev` and `test` portions. If you don't want to use either dev or test data you can just provide the training data as `dev` or `test`. Note however, that without dev data, results will probably suffer, because early-stopping can't be performed.
+2. Train the model:
+```bash
+./train_no_finetune.sh $corpus_train $corpus_dev $corpus_test
+```
+After sucessful training, the model can be found in a newly created directory in `models/`. The directory name reflects the chosen hyper-parameters and usually reads like `tag_scheme=iob,lower=False,zeros=False,char_dim=25...`.
+
+
+
+# Models
+| Model | Test sets P / R / F1 (%) | CRAFT P / R / F1 (%) |
+|   -   |       -      |    -     |
+| [cellline_all](https://drive.google.com/open?id=1aqtenziAHmxEHeaHf8JGdTkRe21ovjts) | 65.09 / 67.69 / 66.08 | - |
+| [chemical_all](https://drive.google.com/open?id=1lEXPKiMZ0x3y51epBIS2kWHG3cNxnN4r) | 83.34 / 80.26 / 81.71 | 53.56 / 35.85 / 42.95 |
+| [disease_all](https://drive.google.com/open?id=12vdtSi3hg_htCXXROKkPV4jaDO3ep8OY) | 75.01 / 77.71 / 76.20 | - |
+| [gene_all](https://drive.google.com/open?id=1xdMkeA5HynmrAe4Ky2QwJAqCjP3pp2EO) | 75.01 / 79.16 / 76.81 | 59.67 / 65.98 / 62.66 |
+| [species_all](https://drive.google.com/open?id=1JO6JuG2gz7W3C_44dJ0gmCozKKFsAEo6) | 85.37 / 79.98 / 82.59| 98.51 / 73.83 / 84.40 |
+
+# Corpora
+For details and instructions on the HUNER corpora please refer to https://github.com/hu-ner/huner/tree/master/ner_scripts and the corresponding readme.
+
+# Citation
+Please use the following bibtex entry:
+```
+@article{weber2019huner,
+  title={HUNER: Improving Biomedical NER with Pretraining},
+  author={Weber, Leon and M{\"u}nchmeyer, Jannes and Rockt{\"a}schel, Tim and Habibi, Maryam and Leser, Ulf},
+  journal={Bioinformatics},
+  year={2019}
+}
+```
diff --git a/huner/client.py b/huner/client.py
new file mode 100644
index 0000000..7a02827
--- /dev/null
+++ b/huner/client.py
@@ -0,0 +1,142 @@
+import json
+import sys
+import subprocess
+import argparse
+import requests
+
+
+def get_port(name: str):
+    info = subprocess.run(["docker", "inspect", name], stdout=subprocess.PIPE).stdout
+    info = json.loads(info)
+    return info[0]['NetworkSettings']['Ports']['5000/tcp'][0]['HostPort']
+
+
+
+def has_entity(sent):
+    has_ent = False 
+    for tok, tag in sent:
+        if tag != "O":
+            has_ent = True
+    return has_ent
+
+class HUNERTagger:
+    def __init__(self, names=None):
+        self.names = names or ["huner"]
+        self.ports = [get_port(name) for name in self.names]
+
+    def merge_entities(self, results):
+        new_results = []
+        for sent in results:
+            new_sent = []
+            curr_ent = []
+            curr_name = None
+            for tok, tag in sent:
+                if "/" in tag:
+                    name, tag = tag.split("/")
+                if tag[0] in {"B", "O"} and len(curr_ent) > 0:
+                    new_sent.append([" ".join(curr_ent), curr_name])
+                    curr_ent = []
+                    curr_name = None
+
+                if tag[0] in {"B", "I"}:
+                    curr_ent.append(tok)
+                    curr_name = name
+                else:
+                    new_sent.append([tok, tag])
+
+            if len(curr_ent) > 0:
+                new_sent.append([" ".join(curr_ent), curr_name])
+            new_results.append(new_sent)
+
+        return new_results
+
+    def merge_names(self, results):
+        merged = results[0]
+        for sent in merged:
+            for i, (tok, tag) in enumerate(sent):
+                if tag[0] in {"B", "I"}:
+                    sent[i][1] = self.names[0] + "/" + tag
+
+
+        for result, name in zip(results[1:], self.names[1:]):
+            for merged_sent, other_sent in zip(merged, result):
+                in_ent = False
+                ent_begin = None
+                ent_end = None
+                for i, (tok, tag) in enumerate(other_sent):
+                    if tag.startswith("B"):
+                        in_ent = True
+                        ent_begin = i
+                    elif tag in {"B", "O"}:
+                        if in_ent:
+                            ent_end = i
+                            
+                            if not has_entity(merged_sent[ent_begin:ent_end]):
+                                for j, (_, tag) in enumerate(other_sent[ent_begin:ent_end]):
+                                    merged_sent[j][1] = name + '/' + tag
+                    
+                    if tag == 'O':
+                        in_ent = False
+
+                if in_ent:
+                    ent_end = i+1
+                    
+                    if not has_entity(merged_sent[ent_begin:ent_end]):
+                        for j, (_, tag) in enumerate(other_sent[ent_begin:ent_end]):
+                            merged_sent[j][1] = name + '/' + tag
+
+                                
+        return merged
+
+    def tag(self, text, split_sentences=True, tokenize=True, merge_names=False, merge_entities=False):
+        data = {'text': text, 'split_sentences': split_sentences, 'tokenize': tokenize}
+        results = []
+        for name, port in zip(self.names, self.ports):
+            response = requests.post(f"http://localhost:{port}/tag", json=data)
+            results.append(response.json())
+        if merge_names:
+            results = self.merge_names(results)
+
+        if merge_entities:
+            results = self.merge_entities(results)
+        return results
+
+if __name__ == '__main__':
+    parser = argparse.ArgumentParser()
+    parser.add_argument("input")
+    parser.add_argument("output")
+    parser.add_argument("--name", required=True)
+    parser.add_argument("--assume_sentence_splitted", action='store_true')
+    parser.add_argument("--assume_tokenized", action='store_true')
+    parser.add_argument("--batchsize", type=int, default=256) 
+    args = parser.parse_args()
+
+    tagger = HUNERTagger(names=[args.name])
+    split_sentences = not args.assume_sentence_splitted and not args.assume_tokenized
+
+    with open(args.input) as f_in, open(args.output, 'w') as f_out:
+        buff = []
+        c = 0
+        for line in f_in:
+            if args.assume_tokenized:
+                line = [line.split()]
+            elif args.assume_sentence_splitted:
+                line = [line]
+            else:
+                line = [line]
+            c += 1
+            buff += line
+            if c % args.batchsize == 0:
+                tagged_line = tagger.tag(buff, split_sentences=split_sentences, tokenize=not args.assume_tokenized)[0]
+                for sentence in tagged_line:
+                    for tok, tag in sentence:
+                        f_out.write(f"{tok}\tPOS\t{tag}\n")
+                    f_out.write("\n")
+                buff = []
+        if buff:
+            tagged_line = tagger.tag(buff, split_sentences=split_sentences, tokenize=not args.assume_tokenized)[0]
+            for sentence in tagged_line:
+                for tok, tag in sentence:
+                    f_out.write(f"{tok}\tPOS\t{tag}\n")
+                f_out.write("\n")
+
diff --git a/huner/conll_to_huner.py b/huner/conll_to_huner.py
new file mode 100755
index 0000000..c857ef7
--- /dev/null
+++ b/huner/conll_to_huner.py
@@ -0,0 +1,21 @@
+import argparse
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input")
+args = parser.parse_args()
+
+f = open(args.input, 'r')
+
+last = False
+for line in f:
+    line = line.strip()
+    if 'DOCSTART' in line:
+        continue
+    if not line:
+        if not last:
+            print()
+            last = True
+    else:
+        print(line.split()[-3] + " ", end="")
+        last = False
+
diff --git a/huner/evaluation/conlleval b/huner/evaluation/conlleval
new file mode 100755
index 0000000..70e4ad2
--- /dev/null
+++ b/huner/evaluation/conlleval
@@ -0,0 +1,315 @@
+#!/usr/bin/perl -w
+# conlleval: evaluate result of processing CoNLL-2000 shared task
+# usage:     conlleval [-l] [-r] [-d delimiterTag] [-o oTag] < file
+#            README: http://cnts.uia.ac.be/conll2000/chunking/output.html
+# options:   l: generate LaTeX output for tables like in
+#               http://cnts.uia.ac.be/conll2003/ner/example.tex
+#            r: accept raw result tags (without B- and I- prefix;
+#                                       assumes one word per chunk)
+#            d: alternative delimiter tag (default is single space)
+#            o: alternative outside tag (default is O)
+# note:      the file should contain lines with items separated
+#            by $delimiter characters (default space). The final
+#            two items should contain the correct tag and the 
+#            guessed tag in that order. Sentences should be
+#            separated from each other by empty lines or lines
+#            with $boundary fields (default -X-).
+# url:       http://lcg-www.uia.ac.be/conll2000/chunking/
+# started:   1998-09-25
+# version:   2004-01-26
+# author:    Erik Tjong Kim Sang <erikt@uia.ua.ac.be>
+
+use strict;
+
+my $false = 0;
+my $true = 42;
+
+my $boundary = "-X-";     # sentence boundary
+my $correct;              # current corpus chunk tag (I,O,B)
+my $correctChunk = 0;     # number of correctly identified chunks
+my $correctTags = 0;      # number of correct chunk tags
+my $correctType;          # type of current corpus chunk tag (NP,VP,etc.)
+my $delimiter = " ";      # field delimiter
+my $FB1 = 0.0;            # FB1 score (Van Rijsbergen 1979)
+my $firstItem;            # first feature (for sentence boundary checks)
+my $foundCorrect = 0;     # number of chunks in corpus
+my $foundGuessed = 0;     # number of identified chunks
+my $guessed;              # current guessed chunk tag
+my $guessedType;          # type of current guessed chunk tag
+my $i;                    # miscellaneous counter
+my $inCorrect = $false;   # currently processed chunk is correct until now
+my $lastCorrect = "O";    # previous chunk tag in corpus
+my $latex = 0;            # generate LaTeX formatted output
+my $lastCorrectType = ""; # type of previously identified chunk tag
+my $lastGuessed = "O";    # previously identified chunk tag
+my $lastGuessedType = ""; # type of previous chunk tag in corpus
+my $lastType;             # temporary storage for detecting duplicates
+my $line;                 # line
+my $nbrOfFeatures = -1;   # number of features per line
+my $precision = 0.0;      # precision score
+my $oTag = "O";           # outside tag, default O
+my $raw = 0;              # raw input: add B to every token
+my $recall = 0.0;         # recall score
+my $tokenCounter = 0;     # token counter (ignores sentence breaks)
+
+my %correctChunk = ();    # number of correctly identified chunks per type
+my %foundCorrect = ();    # number of chunks in corpus per type
+my %foundGuessed = ();    # number of identified chunks per type
+
+my @features;             # features on line
+my @sortedTypes;          # sorted list of chunk type names
+
+# sanity check
+while (@ARGV and $ARGV[0] =~ /^-/) {
+   if ($ARGV[0] eq "-l") { $latex = 1; shift(@ARGV); }
+   elsif ($ARGV[0] eq "-r") { $raw = 1; shift(@ARGV); }
+   elsif ($ARGV[0] eq "-d") { 
+      shift(@ARGV); 
+      if (not defined $ARGV[0]) { 
+         die "conlleval: -d requires delimiter character"; 
+      }
+      $delimiter = shift(@ARGV);
+   } elsif ($ARGV[0] eq "-o") {
+      shift(@ARGV);
+      if (not defined $ARGV[0]) {
+         die "conlleval: -o requires delimiter character";
+      }
+      $oTag = shift(@ARGV);
+   } else { die "conlleval: unknown argument $ARGV[0]\n"; }
+}
+if (@ARGV) { die "conlleval: unexpected command line argument\n"; }
+# process input
+while (<STDIN>) {
+   chomp($line = $_);
+   @features = split(/$delimiter/,$line);
+   if ($nbrOfFeatures < 0) { $nbrOfFeatures = $#features; }
+   elsif ($nbrOfFeatures != $#features and @features != 0) {
+      printf STDERR "unexpected number of features: %d (%d)\n",
+         $#features+1,$nbrOfFeatures+1;
+      exit(1);
+   }
+   if (@features == 0 or 
+       $features[0] eq $boundary) { @features = ($boundary,"O","O"); }
+   if (@features < 2) { 
+      die "conlleval: unexpected number of features in line $line\n"; 
+   }
+   if ($raw) {
+      if ($features[$#features] eq $oTag) { $features[$#features] = "O"; } 
+      if ($features[$#features-1] eq $oTag) { $features[$#features-1] = "O"; } 
+      if ($features[$#features] ne "O") { 
+         $features[$#features] = "B-$features[$#features]";
+      }
+      if ($features[$#features-1] ne "O") { 
+         $features[$#features-1] = "B-$features[$#features-1]";
+      }
+   }
+   # 20040126 ET code which allows hyphens in the types
+   if ($features[$#features] =~ /^([^-]*)-(.*)$/) {
+      $guessed = $1;
+      $guessedType = $2;
+   } else { 
+      $guessed = $features[$#features]; 
+      $guessedType = ""; 
+   }
+   pop(@features);
+   if ($features[$#features] =~ /^([^-]*)-(.*)$/) {
+      $correct = $1;
+      $correctType = $2;
+   } else { 
+      $correct = $features[$#features]; 
+      $correctType = ""; 
+   }
+   pop(@features);
+#  ($guessed,$guessedType) = split(/-/,pop(@features));
+#  ($correct,$correctType) = split(/-/,pop(@features));
+   $guessedType = $guessedType ? $guessedType : "";
+   $correctType = $correctType ? $correctType : "";
+   $firstItem = shift(@features);
+
+   # 1999-06-26 sentence breaks should always be counted as out of chunk
+   if ( $firstItem eq $boundary ) { $guessed = "O"; }
+
+   if ($inCorrect) {
+      if ( &endOfChunk($lastCorrect,$correct,$lastCorrectType,$correctType) and
+           &endOfChunk($lastGuessed,$guessed,$lastGuessedType,$guessedType) and
+           $lastGuessedType eq $lastCorrectType) {
+         $inCorrect=$false;
+         $correctChunk++;
+         $correctChunk{$lastCorrectType} = $correctChunk{$lastCorrectType} ?
+             $correctChunk{$lastCorrectType}+1 : 1;
+      } elsif ( 
+           &endOfChunk($lastCorrect,$correct,$lastCorrectType,$correctType) != 
+           &endOfChunk($lastGuessed,$guessed,$lastGuessedType,$guessedType) or
+           $guessedType ne $correctType ) {
+         $inCorrect=$false; 
+      }
+   }
+
+   if ( &startOfChunk($lastCorrect,$correct,$lastCorrectType,$correctType) and 
+        &startOfChunk($lastGuessed,$guessed,$lastGuessedType,$guessedType) and
+        $guessedType eq $correctType) { $inCorrect = $true; }
+
+   if ( &startOfChunk($lastCorrect,$correct,$lastCorrectType,$correctType) ) {
+      $foundCorrect++; 
+      $foundCorrect{$correctType} = $foundCorrect{$correctType} ?
+          $foundCorrect{$correctType}+1 : 1;
+   }
+   if ( &startOfChunk($lastGuessed,$guessed,$lastGuessedType,$guessedType) ) {
+      $foundGuessed++; 
+      $foundGuessed{$guessedType} = $foundGuessed{$guessedType} ?
+          $foundGuessed{$guessedType}+1 : 1;
+   }
+   if ( $firstItem ne $boundary ) { 
+      if ( $correct eq $guessed and $guessedType eq $correctType ) { 
+         $correctTags++; 
+      }
+      $tokenCounter++; 
+   }
+
+   $lastGuessed = $guessed;
+   $lastCorrect = $correct;
+   $lastGuessedType = $guessedType;
+   $lastCorrectType = $correctType;
+}
+if ($inCorrect) { 
+   $correctChunk++;
+   $correctChunk{$lastCorrectType} = $correctChunk{$lastCorrectType} ?
+       $correctChunk{$lastCorrectType}+1 : 1;
+}
+
+if (not $latex) {
+   # compute overall precision, recall and FB1 (default values are 0.0)
+   $precision = 100*$correctChunk/$foundGuessed if ($foundGuessed > 0);
+   $recall = 100*$correctChunk/$foundCorrect if ($foundCorrect > 0);
+   $FB1 = 2*$precision*$recall/($precision+$recall)
+      if ($precision+$recall > 0);
+   
+   # print overall performance
+   printf "processed $tokenCounter tokens with $foundCorrect phrases; ";
+   printf "found: $foundGuessed phrases; correct: $correctChunk.\n";
+   if ($tokenCounter>0) {
+      printf "accuracy: %6.2f%%; ",100*$correctTags/$tokenCounter;
+      printf "precision: %6.2f%%; ",$precision;
+      printf "recall: %6.2f%%; ",$recall;
+      printf "FB1: %6.2f\n",$FB1;
+   }
+}
+
+# sort chunk type names
+undef($lastType);
+@sortedTypes = ();
+foreach $i (sort (keys %foundCorrect,keys %foundGuessed)) {
+   if (not($lastType) or $lastType ne $i) { 
+      push(@sortedTypes,($i));
+   }
+   $lastType = $i;
+}
+# print performance per chunk type
+if (not $latex) {
+   for $i (@sortedTypes) {
+      $correctChunk{$i} = $correctChunk{$i} ? $correctChunk{$i} : 0;
+      if (not($foundGuessed{$i})) { $foundGuessed{$i} = 0; $precision = 0.0; }
+      else { $precision = 100*$correctChunk{$i}/$foundGuessed{$i}; }
+      if (not($foundCorrect{$i})) { $recall = 0.0; }
+      else { $recall = 100*$correctChunk{$i}/$foundCorrect{$i}; }
+      if ($precision+$recall == 0.0) { $FB1 = 0.0; }
+      else { $FB1 = 2*$precision*$recall/($precision+$recall); }
+      printf "%17s: ",$i;
+      printf "precision: %6.2f%%; ",$precision;
+      printf "recall: %6.2f%%; ",$recall;
+      printf "FB1: %6.2f  %d\n",$FB1,$foundGuessed{$i};
+   }
+} else {
+   print "        & Precision &  Recall  & F\$_{\\beta=1} \\\\\\hline";
+   for $i (@sortedTypes) {
+      $correctChunk{$i} = $correctChunk{$i} ? $correctChunk{$i} : 0;
+      if (not($foundGuessed{$i})) { $precision = 0.0; }
+      else { $precision = 100*$correctChunk{$i}/$foundGuessed{$i}; }
+      if (not($foundCorrect{$i})) { $recall = 0.0; }
+      else { $recall = 100*$correctChunk{$i}/$foundCorrect{$i}; }
+      if ($precision+$recall == 0.0) { $FB1 = 0.0; }
+      else { $FB1 = 2*$precision*$recall/($precision+$recall); }
+      printf "\n%-7s &  %6.2f\\%% & %6.2f\\%% & %6.2f \\\\",
+             $i,$precision,$recall,$FB1;
+   }
+   print "\\hline\n";
+   $precision = 0.0;
+   $recall = 0;
+   $FB1 = 0.0;
+   $precision = 100*$correctChunk/$foundGuessed if ($foundGuessed > 0);
+   $recall = 100*$correctChunk/$foundCorrect if ($foundCorrect > 0);
+   $FB1 = 2*$precision*$recall/($precision+$recall)
+      if ($precision+$recall > 0);
+   printf "Overall &  %6.2f\\%% & %6.2f\\%% & %6.2f \\\\\\hline\n",
+          $precision,$recall,$FB1;
+}
+
+exit 0;
+
+# endOfChunk: checks if a chunk ended between the previous and current word
+# arguments:  previous and current chunk tags, previous and current types
+# note:       this code is capable of handling other chunk representations
+#             than the default CoNLL-2000 ones, see EACL'99 paper of Tjong
+#             Kim Sang and Veenstra http://xxx.lanl.gov/abs/cs.CL/9907006
+
+sub endOfChunk {
+   my $prevTag = shift(@_);
+   my $tag = shift(@_);
+   my $prevType = shift(@_);
+   my $type = shift(@_);
+   my $chunkEnd = $false;
+
+   if ( $prevTag eq "B" and $tag eq "B" ) { $chunkEnd = $true; }
+   if ( $prevTag eq "B" and $tag eq "O" ) { $chunkEnd = $true; }
+   if ( $prevTag eq "I" and $tag eq "B" ) { $chunkEnd = $true; }
+   if ( $prevTag eq "I" and $tag eq "O" ) { $chunkEnd = $true; }
+
+   if ( $prevTag eq "E" and $tag eq "E" ) { $chunkEnd = $true; }
+   if ( $prevTag eq "E" and $tag eq "I" ) { $chunkEnd = $true; }
+   if ( $prevTag eq "E" and $tag eq "O" ) { $chunkEnd = $true; }
+   if ( $prevTag eq "I" and $tag eq "O" ) { $chunkEnd = $true; }
+
+   if ($prevTag ne "O" and $prevTag ne "." and $prevType ne $type) { 
+      $chunkEnd = $true; 
+   }
+
+   # corrected 1998-12-22: these chunks are assumed to have length 1
+   if ( $prevTag eq "]" ) { $chunkEnd = $true; }
+   if ( $prevTag eq "[" ) { $chunkEnd = $true; }
+
+   return($chunkEnd);   
+}
+
+# startOfChunk: checks if a chunk started between the previous and current word
+# arguments:    previous and current chunk tags, previous and current types
+# note:         this code is capable of handling other chunk representations
+#               than the default CoNLL-2000 ones, see EACL'99 paper of Tjong
+#               Kim Sang and Veenstra http://xxx.lanl.gov/abs/cs.CL/9907006
+
+sub startOfChunk {
+   my $prevTag = shift(@_);
+   my $tag = shift(@_);
+   my $prevType = shift(@_);
+   my $type = shift(@_);
+   my $chunkStart = $false;
+
+   if ( $prevTag eq "B" and $tag eq "B" ) { $chunkStart = $true; }
+   if ( $prevTag eq "I" and $tag eq "B" ) { $chunkStart = $true; }
+   if ( $prevTag eq "O" and $tag eq "B" ) { $chunkStart = $true; }
+   if ( $prevTag eq "O" and $tag eq "I" ) { $chunkStart = $true; }
+
+   if ( $prevTag eq "E" and $tag eq "E" ) { $chunkStart = $true; }
+   if ( $prevTag eq "E" and $tag eq "I" ) { $chunkStart = $true; }
+   if ( $prevTag eq "O" and $tag eq "E" ) { $chunkStart = $true; }
+   if ( $prevTag eq "O" and $tag eq "I" ) { $chunkStart = $true; }
+
+   if ($tag ne "O" and $tag ne "." and $prevType ne $type) { 
+      $chunkStart = $true; 
+   }
+
+   # corrected 1998-12-22: these chunks are assumed to have length 1
+   if ( $tag eq "[" ) { $chunkStart = $true; }
+   if ( $tag eq "]" ) { $chunkStart = $true; }
+
+   return($chunkStart);   
+}
diff --git a/huner/loader.py b/huner/loader.py
new file mode 100644
index 0000000..7d537d9
--- /dev/null
+++ b/huner/loader.py
@@ -0,0 +1,191 @@
+import os
+import re
+import codecs
+from utils import create_dico, create_mapping, zero_digits
+from utils import iob2, iob_iobes
+
+
+def load_sentences(path, lower, zeros):
+    """
+    Load sentences. A line must contain at least a word and its tag.
+    Sentences are separated by empty lines.
+    """
+    sentences = []
+    sentence = []
+    for line in codecs.open(path, 'r', 'utf8'):
+        line = zero_digits(line.rstrip()) if zeros else line.rstrip()
+        if not line:
+            if len(sentence) > 0:
+                if 'DOCSTART' not in sentence[0][0]:
+                    sentences.append(sentence)
+                sentence = []
+        else:
+            word = line.split()
+            assert len(word) >= 2
+            sentence.append(word)
+    if len(sentence) > 0:
+        if 'DOCSTART' not in sentence[0][0]:
+            sentences.append(sentence)
+    return sentences
+
+
+def update_tag_scheme(sentences, tag_scheme):
+    """
+    Check and update sentences tagging scheme to IOB2.
+    Only IOB1 and IOB2 schemes are accepted.
+    """
+    for i, s in enumerate(sentences):
+        tags = [w[-1] for w in s]
+        # Check that tags are given in the IOB format
+        if not iob2(tags):
+            s_str = '\n'.join(' '.join(w) for w in s)
+            raise Exception('Sentences should be given in IOB format! ' +
+                            'Please check sentence %i:\n%s' % (i, s_str))
+        if tag_scheme == 'iob':
+            # If format was IOB1, we convert to IOB2
+            for word, new_tag in zip(s, tags):
+                word[-1] = new_tag
+        elif tag_scheme == 'iobes':
+            new_tags = iob_iobes(tags)
+            for word, new_tag in zip(s, new_tags):
+                word[-1] = new_tag
+        else:
+            raise Exception('Unknown tagging scheme!')
+
+
+def word_mapping(sentences, lower):
+    """
+    Create a dictionary and a mapping of words, sorted by frequency.
+    """
+    words = [[x[0].lower() if lower else x[0] for x in s] for s in sentences]
+    dico = create_dico(words)
+    dico['<UNK>'] = 10000000
+    word_to_id, id_to_word = create_mapping(dico)
+    print "Found %i unique words (%i in total)" % (
+        len(dico), sum(len(x) for x in words)
+    )
+    return dico, word_to_id, id_to_word
+
+
+def char_mapping(sentences):
+    """
+    Create a dictionary and mapping of characters, sorted by frequency.
+    """
+    chars = ["".join([w[0] for w in s]) for s in sentences]
+    dico = create_dico(chars)
+    char_to_id, id_to_char = create_mapping(dico)
+    print "Found %i unique characters" % len(dico)
+    return dico, char_to_id, id_to_char
+
+
+def tag_mapping(sentences):
+    """
+    Create a dictionary and a mapping of tags, sorted by frequency.
+    """
+    tags = [[word[-1] for word in s] for s in sentences]
+    dico = create_dico(tags)
+    tag_to_id, id_to_tag = create_mapping(dico)
+    print "Found %i unique named entity tags" % len(dico)
+    return dico, tag_to_id, id_to_tag
+
+
+def cap_feature(s):
+    """
+    Capitalization feature:
+    0 = low caps
+    1 = all caps
+    2 = first letter caps
+    3 = one capital (not first letter)
+    """
+    if s.lower() == s:
+        return 0
+    elif s.upper() == s:
+        return 1
+    elif s[0].upper() == s[0]:
+        return 2
+    else:
+        return 3
+
+
+def prepare_sentence(str_words, word_to_id, char_to_id, lower=False):
+    """
+    Prepare a sentence for evaluation.
+    """
+    def f(x): return x.lower() if lower else x
+    words = [word_to_id[f(w) if f(w) in word_to_id else '<UNK>']
+             for w in str_words]
+    chars = [[char_to_id[c] for c in w if c in char_to_id]
+             for w in str_words]
+    caps = [cap_feature(w) for w in str_words]
+    return {
+        'str_words': str_words,
+        'words': words,
+        'chars': chars,
+        'caps': caps
+    }
+
+
+def prepare_dataset(sentences, word_to_id, char_to_id, tag_to_id, lower=False):
+    """
+    Prepare the dataset. Return a list of lists of dictionaries containing:
+        - word indexes
+        - word char indexes
+        - tag indexes
+    """
+    def f(x): return x.lower() if lower else x
+    data = []
+    prob_chars = set()
+    for s in sentences:
+        str_words = [w[0] for w in s]
+        words = [word_to_id[f(w) if f(w) in word_to_id else '<UNK>']
+                 for w in str_words]
+        # Skip characters that are not in the training set
+        chars = [[char_to_id[c] if c in char_to_id else char_to_id[','] for c in w]
+                 for w in str_words]
+        caps = [cap_feature(w) for w in str_words]
+        tags = [tag_to_id[w[-1]] for w in s]
+        data.append({
+            'str_words': str_words,
+            'words': words,
+            'chars': chars,
+            'caps': caps,
+            'tags': tags,
+        })
+    return data
+
+
+def augment_with_pretrained(dictionary, ext_emb_path, words):
+    """
+    Augment the dictionary with words that have a pretrained embedding.
+    If `words` is None, we add every word that has a pretrained embedding
+    to the dictionary, otherwise, we only add the words that are given by
+    `words` (typically the words in the development and test sets.)
+    """
+    print 'Loading pretrained embeddings from %s...' % ext_emb_path
+    assert os.path.isfile(ext_emb_path)
+
+    # Load pretrained embeddings from file
+    pretrained = set([
+        line.rstrip().split()[0].strip()
+        for line in codecs.open(ext_emb_path, 'r', 'utf-8')
+        if len(ext_emb_path) > 0
+    ])
+
+    # We either add every word in the pretrained file,
+    # or only words given in the `words` list to which
+    # we can assign a pretrained embedding
+    if words is None:
+        for word in pretrained:
+            if word not in dictionary:
+                dictionary[word] = 0
+    else:
+        for word in words:
+            if any(x in pretrained for x in [
+                word,
+                word.lower(),
+                re.sub('\d', '0', word.lower())
+            ]) and word not in dictionary:
+                dictionary[word] = 0
+
+    word_to_id, id_to_word = create_mapping(dictionary)
+    return dictionary, word_to_id, id_to_word
diff --git a/huner/model.py b/huner/model.py
new file mode 100644
index 0000000..ae87492
--- /dev/null
+++ b/huner/model.py
@@ -0,0 +1,399 @@
+import os
+import re
+import numpy as np
+import scipy.io
+import theano
+import theano.tensor as T
+import codecs
+import cPickle
+import joblib
+
+from utils import shared, set_values, get_name
+from nn import HiddenLayer, EmbeddingLayer, DropoutLayer, LSTM, forward
+from optimization import Optimization
+
+
+class Model(object):
+    """
+    Network architecture.
+    """
+    def __init__(self, parameters=None, models_path=None, model_path=None):
+        """
+        Initialize the model. We either provide the parameters and a path where
+        we store the models, or the location of a trained model.
+        """
+        if model_path is None:
+            assert parameters and models_path
+            # Create a name based on the parameters
+            self.parameters = parameters
+            self.name = get_name(parameters)
+            # Model location
+            model_path = os.path.join(models_path, self.name)
+            self.model_path = model_path
+            self.parameters_path = os.path.join(model_path, 'parameters.pkl')
+            self.mappings_path = os.path.join(model_path, 'mappings.pkl')
+            # Create directory for the model if it does not exist
+            if not os.path.exists(self.model_path):
+                os.makedirs(self.model_path)
+            # Save the parameters to disk
+            with open(self.parameters_path, 'wb') as f:
+                cPickle.dump(parameters, f)
+        else:
+            assert parameters is None and models_path is None
+            # Model location
+            self.model_path = model_path
+            self.parameters_path = os.path.join(model_path, 'parameters.pkl')
+            self.mappings_path = os.path.join(model_path, 'mappings.pkl')
+            # Load the parameters and the mappings from disk
+            with open(self.parameters_path, 'rb') as f:
+                self.parameters = cPickle.load(f)
+            self.reload_mappings()
+        self.components = {}
+
+    def save_mappings(self, id_to_word, id_to_char, id_to_tag):
+        """
+        We need to save the mappings if we want to use the model later.
+        """
+        self.id_to_word = id_to_word
+        self.id_to_char = id_to_char
+        self.id_to_tag = id_to_tag
+        with open(self.mappings_path, 'wb') as f:
+            mappings = {
+                'id_to_word': self.id_to_word,
+                'id_to_char': self.id_to_char,
+                'id_to_tag': self.id_to_tag,
+            }
+            cPickle.dump(mappings, f)
+
+    def reload_mappings(self):
+        """
+        Load mappings from disk.
+        """
+        with open(self.mappings_path, 'rb') as f:
+            mappings = cPickle.load(f)
+        self.id_to_word = mappings['id_to_word']
+        self.id_to_char = mappings['id_to_char']
+        self.id_to_tag = mappings['id_to_tag']
+
+    def add_component(self, param):
+        """
+        Add a new parameter to the network.
+        """
+        if param.name in self.components:
+            raise Exception('The network already has a parameter "%s"!'
+                            % param.name)
+        self.components[param.name] = param
+
+    def save(self):
+        """
+        Write components values to disk.
+        """
+        for name, param in self.components.items():
+            param_path = os.path.join(self.model_path, "%s.mat" % name)
+            if hasattr(param, 'params'):
+                param_values = {p.name: p.get_value() for p in param.params}
+            else:
+                param_values = {name: param.get_value()}
+            joblib.dump(param_values, param_path)
+
+    def reload(self):
+        """
+        Load components values from disk.
+        """
+        for name, param in self.components.items():
+            param_path = os.path.join(self.model_path, "%s.mat" % name)
+            param_values = joblib.load(param_path)
+            if hasattr(param, 'params'):
+                for p in param.params:
+                    set_values(p.name, p, param_values[p.name])
+            else:
+                set_values(name, param, param_values[name])
+
+    def build(self,
+              dropout,
+              char_dim,
+              char_lstm_dim,
+              char_bidirect,
+              word_dim,
+              word_lstm_dim,
+              word_bidirect,
+              lr_method,
+              pre_emb,
+              crf,
+              cap_dim,
+              training=True,
+              **kwargs
+              ):
+        """
+        Build the network.
+        """
+        # Training parameters
+        n_words = len(self.id_to_word)
+        n_chars = len(self.id_to_char)
+        n_tags = len(self.id_to_tag)
+
+        # Number of capitalization features
+        if cap_dim:
+            n_cap = 4
+
+        # Network variables
+        is_train = T.iscalar('is_train')
+        word_ids = T.ivector(name='word_ids')
+        char_for_ids = T.imatrix(name='char_for_ids')
+        char_rev_ids = T.imatrix(name='char_rev_ids')
+        char_pos_ids = T.ivector(name='char_pos_ids')
+        tag_ids = T.ivector(name='tag_ids')
+        if cap_dim:
+            cap_ids = T.ivector(name='cap_ids')
+
+        # Sentence length
+        s_len = (word_ids if word_dim else char_pos_ids).shape[0]
+
+        # Final input (all word features)
+        input_dim = 0
+        inputs = []
+
+        #
+        # Word inputs
+        #
+        if word_dim:
+            input_dim += word_dim
+            word_layer = EmbeddingLayer(n_words, word_dim, name='word_layer')
+            word_input = word_layer.link(word_ids)
+            inputs.append(word_input)
+            # Initialize with pretrained embeddings
+            if pre_emb and training:
+                new_weights = word_layer.embeddings.get_value()
+                print 'Loading pretrained embeddings from %s...' % pre_emb
+                pretrained = {}
+                emb_invalid = 0
+                for i, line in enumerate(codecs.open(pre_emb, 'r', 'utf-8')):
+                    line = line.rstrip().split()
+                    if len(line) == word_dim + 1:
+                        pretrained[line[0]] = np.array(
+                            [float(x) for x in line[1:]]
+                        ).astype(np.float32)
+                    else:
+                        emb_invalid += 1
+                if emb_invalid > 0:
+                    print 'WARNING: %i invalid lines' % emb_invalid
+                c_found = 0
+                c_lower = 0
+                c_zeros = 0
+                # Lookup table initialization
+                for i in xrange(n_words):
+                    word = self.id_to_word[i]
+                    if word in pretrained:
+                        new_weights[i] = pretrained[word]
+                        c_found += 1
+                    elif word.lower() in pretrained:
+                        new_weights[i] = pretrained[word.lower()]
+                        c_lower += 1
+                    elif re.sub('\d', '0', word.lower()) in pretrained:
+                        new_weights[i] = pretrained[
+                            re.sub('\d', '0', word.lower())
+                        ]
+                        c_zeros += 1
+                word_layer.embeddings.set_value(new_weights)
+                print 'Loaded %i pretrained embeddings.' % len(pretrained)
+                print ('%i / %i (%.4f%%) words have been initialized with '
+                       'pretrained embeddings.') % (
+                            c_found + c_lower + c_zeros, n_words,
+                            100. * (c_found + c_lower + c_zeros) / n_words
+                      )
+                print ('%i found directly, %i after lowercasing, '
+                       '%i after lowercasing + zero.') % (
+                          c_found, c_lower, c_zeros
+                      )
+
+        #
+        # Chars inputs
+        #
+        if char_dim:
+            input_dim += char_lstm_dim
+            char_layer = EmbeddingLayer(n_chars, char_dim, name='char_layer')
+
+            char_lstm_for = LSTM(char_dim, char_lstm_dim, with_batch=True,
+                                 name='char_lstm_for')
+            char_lstm_rev = LSTM(char_dim, char_lstm_dim, with_batch=True,
+                                 name='char_lstm_rev')
+
+            char_lstm_for.link(char_layer.link(char_for_ids))
+            char_lstm_rev.link(char_layer.link(char_rev_ids))
+
+            char_for_output = char_lstm_for.h.dimshuffle((1, 0, 2))[
+                T.arange(s_len), char_pos_ids
+            ]
+            char_rev_output = char_lstm_rev.h.dimshuffle((1, 0, 2))[
+                T.arange(s_len), char_pos_ids
+            ]
+
+            inputs.append(char_for_output)
+            if char_bidirect:
+                inputs.append(char_rev_output)
+                input_dim += char_lstm_dim
+
+        #
+        # Capitalization feature
+        #
+        if cap_dim:
+            input_dim += cap_dim
+            cap_layer = EmbeddingLayer(n_cap, cap_dim, name='cap_layer')
+            inputs.append(cap_layer.link(cap_ids))
+
+        # Prepare final input
+        if len(inputs) != 1:
+            inputs = T.concatenate(inputs, axis=1)
+
+        #
+        # Dropout on final input
+        #
+        if dropout:
+            dropout_layer = DropoutLayer(p=dropout)
+            input_train = dropout_layer.link(inputs)
+            input_test = (1 - dropout) * inputs
+            inputs = T.switch(T.neq(is_train, 0), input_train, input_test)
+
+        # LSTM for words
+        word_lstm_for = LSTM(input_dim, word_lstm_dim, with_batch=False,
+                             name='word_lstm_for')
+        word_lstm_rev = LSTM(input_dim, word_lstm_dim, with_batch=False,
+                             name='word_lstm_rev')
+        word_lstm_for.link(inputs)
+        word_lstm_rev.link(inputs[::-1, :])
+        word_for_output = word_lstm_for.h
+        word_rev_output = word_lstm_rev.h[::-1, :]
+        if word_bidirect:
+            final_output = T.concatenate(
+                [word_for_output, word_rev_output],
+                axis=1
+            )
+            tanh_layer = HiddenLayer(2 * word_lstm_dim, word_lstm_dim,
+                                     name='tanh_layer', activation='tanh')
+            final_output = tanh_layer.link(final_output)
+        else:
+            final_output = word_for_output
+
+        # Sentence to Named Entity tags - Score
+        final_layer = HiddenLayer(word_lstm_dim, n_tags, name='final_layer',
+                                  activation=(None if crf else 'softmax'))
+        tags_scores = final_layer.link(final_output)
+
+        # No CRF
+        if not crf:
+            cost = T.nnet.categorical_crossentropy(tags_scores, tag_ids).mean()
+        # CRF
+        else:
+            transitions = shared((n_tags + 2, n_tags + 2), 'transitions')
+
+            small = -1000
+            b_s = np.array([[small] * n_tags + [0, small]]).astype(np.float32)
+            e_s = np.array([[small] * n_tags + [small, 0]]).astype(np.float32)
+            observations = T.concatenate(
+                [tags_scores, small * T.ones((s_len, 2))],
+                axis=1
+            )
+            observations = T.concatenate(
+                [b_s, observations, e_s],
+                axis=0
+            )
+
+            # Score from tags
+            real_path_score = tags_scores[T.arange(s_len), tag_ids].sum()
+
+            # Score from transitions
+            b_id = theano.shared(value=np.array([n_tags], dtype=np.int32))
+            e_id = theano.shared(value=np.array([n_tags + 1], dtype=np.int32))
+            padded_tags_ids = T.concatenate([b_id, tag_ids, e_id], axis=0)
+            real_path_score += transitions[
+                padded_tags_ids[T.arange(s_len + 1)],
+                padded_tags_ids[T.arange(s_len + 1) + 1]
+            ].sum()
+
+            all_paths_scores = forward(observations, transitions)
+            cost = - (real_path_score - all_paths_scores)
+
+        # Network parameters
+        params = []
+        if word_dim:
+            self.add_component(word_layer)
+            params.extend(word_layer.params)
+        if char_dim:
+            self.add_component(char_layer)
+            self.add_component(char_lstm_for)
+            params.extend(char_layer.params)
+            params.extend(char_lstm_for.params)
+            if char_bidirect:
+                self.add_component(char_lstm_rev)
+                params.extend(char_lstm_rev.params)
+        self.add_component(word_lstm_for)
+        params.extend(word_lstm_for.params)
+        if word_bidirect:
+            self.add_component(word_lstm_rev)
+            params.extend(word_lstm_rev.params)
+        if cap_dim:
+            self.add_component(cap_layer)
+            params.extend(cap_layer.params)
+        self.add_component(final_layer)
+        params.extend(final_layer.params)
+        if crf:
+            self.add_component(transitions)
+            params.append(transitions)
+        if word_bidirect:
+            self.add_component(tanh_layer)
+            params.extend(tanh_layer.params)
+
+        # Prepare train and eval inputs
+        eval_inputs = []
+        if word_dim:
+            eval_inputs.append(word_ids)
+        if char_dim:
+            eval_inputs.append(char_for_ids)
+            if char_bidirect:
+                eval_inputs.append(char_rev_ids)
+            eval_inputs.append(char_pos_ids)
+        if cap_dim:
+            eval_inputs.append(cap_ids)
+        train_inputs = eval_inputs + [tag_ids]
+
+        # Parse optimization method parameters
+        if "-" in lr_method:
+            lr_method_name = lr_method[:lr_method.find('-')]
+            lr_method_parameters = {}
+            for x in lr_method[lr_method.find('-') + 1:].split('-'):
+                split = x.split('_')
+                assert len(split) == 2
+                lr_method_parameters[split[0]] = float(split[1])
+        else:
+            lr_method_name = lr_method
+            lr_method_parameters = {}
+
+        # Compile training function
+        print 'Compiling...'
+        if training:
+            updates = Optimization(clip=5.).get_updates(lr_method_name, cost, params, **lr_method_parameters)
+            f_train = theano.function(
+                inputs=train_inputs,
+                outputs=cost,
+                updates=updates,
+                givens=({is_train: np.cast['int32'](1)} if dropout else {})
+            )
+        else:
+            f_train = None
+
+        # Compile evaluation function
+        if not crf:
+            f_eval = theano.function(
+                inputs=eval_inputs,
+                outputs=tags_scores,
+                givens=({is_train: np.cast['int32'](0)} if dropout else {})
+            )
+        else:
+            f_eval = theano.function(
+                inputs=eval_inputs,
+                outputs=forward(observations, transitions, viterbi=True,
+                                return_alpha=False, return_best_sequence=True),
+                givens=({is_train: np.cast['int32'](0)} if dropout else {})
+            )
+
+        return f_train, f_eval
diff --git a/huner/models/.gitkeep b/huner/models/.gitkeep
new file mode 100644
index 0000000..e69de29
diff --git a/huner/ner_scripts/README.md b/huner/ner_scripts/README.md
new file mode 100644
index 0000000..d638c76
--- /dev/null
+++ b/huner/ner_scripts/README.md
@@ -0,0 +1,42 @@
+# The HUNER corpora
+
+This collection of scripts obtains 35 BioNER corpora and converts them into the common IOB format with POS tags. The corpora are split into training, development and test set in the ratio 6:1:3.
+
+The corpora cover five domains, which are:
++ Cell lines
++ Chemicals
++ Diseases
++ Genes/Proteins
++ Species
+
+As some of the corpora contain multiple of these entity types, they appear in the output multiple times.
+
+## Requirements
+The scripts run on `python3` and require version 3.5 or newer. Install python requirements with `pip install -r requirments.txt`.
+
+For syntactic analysis the scripts depend on Apache OpenNLP. Please download and install it following the instructions at <https://opennlp.apache.org/>.
+Please download the following models and put them in a `models/` subdirectory of your OpenNLP installation.
+```
+en-pos-maxent.bin
+en-sent.bin
+en-token.bin
+```
+
+## Usage
+To obtain the corpora run:
+```
+python3 download_files.py
+```
+Please ensure, that the process finishes without any errors. You'll be instructed to download the CDR corpus manually, as it is password protected.
+
+To convert and split the corpora please run:
+```
+OPENNLP=path/to/opennlp ./convert_corpora.sh
+```
+Please be aware that this will take a couple of days, as the syntactic analysis of hugh corpora are computationally expensive.
+
+If you are an experienced unix user and have a multi-core machine with at least 32GB of memory available, you can also use:
+```
+OPENNLP=path/to/opennlp ./convert_corpora_parallel.sh
+```
+This will run all conversions in parallel, reducing the runtime to less than a day. Please be aware that due to concurrency issues, some conversion tasks may fail. Those have to be restarted manually, together with the downstream processing.
diff --git a/huner/ner_scripts/convert_corpora.sh b/huner/ner_scripts/convert_corpora.sh
new file mode 100755
index 0000000..89d61b3
--- /dev/null
+++ b/huner/ner_scripts/convert_corpora.sh
@@ -0,0 +1,173 @@
+#!/bin/sh
+
+DATA_DIR=data
+DISEASE_DIR=converted/disease
+GENE_DIR=converted/gene
+SPECIES_DIR=converted/species
+CELLLINE_DIR=converted/cellline
+CHEMICAL_DIR=converted/chemical
+PATCH_DIR=patches
+SCRIPT_DIR=scripts
+
+mkdir -p $DISEASE_DIR
+mkdir -p $GENE_DIR
+mkdir -p $SPECIES_DIR
+mkdir -p $CELLLINE_DIR
+mkdir -p $CHEMICAL_DIR
+
+docker pull huner/huner:master;
+
+
+
+# Arizona disease
+# echo "Converting Arizona"
+# docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/arizona_disease_to_conll.py $DATA_DIR/arizona.txt $DISEASE_DIR/arizona.conll
+
+# BioCreative 2 GeneMentions
+echo "Converting BC2GM"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/bc2gm_gene_to_conll.py $DATA_DIR/bc2gm/train/train.in $DATA_DIR/bc2gm/train/GENE.eval $GENE_DIR/bc2gm1.conll"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/bc2gm_gene_to_conll.py $DATA_DIR/bc2gm/test/test.in $DATA_DIR/bc2gm/test/GENE.eval $GENE_DIR/bc2gm2.conll"
+cat $GENE_DIR/bc2gm1.conll $GENE_DIR/bc2gm2.conll > $GENE_DIR/bc2gm.conll
+rm $GENE_DIR/bc2gm1.conll
+rm $GENE_DIR/bc2gm2.conll
+
+## BioInfer
+echo "Converting BioInfer"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/bioinfer_to_conll.py $DATA_DIR/bioinfer.xml $GENE_DIR/bioinfer.conll"
+
+# Biosemantics
+echo "Converting Biosemantics"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/biosemantics_to_conll.py $DATA_DIR/biosemantics M,I,Y,D,B,C,F,R,G,MOA $CHEMICAL_DIR/biosemantics.conll"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/biosemantics_to_conll.py $DATA_DIR/biosemantics Disease $DISEASE_DIR/biosemantics.conll"
+
+# CDR
+echo "Converting CDR"
+patch $DATA_DIR/CDR_Data/CDR.Corpus.v010516/CDR_TrainingSet.BioC.xml patches/CDR_TrainingSet.BioC.xml.patch -o $DATA_DIR/CDR_Data/CDR.Corpus.v010516/CDR_TrainingSet.BioC.xml.patched
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/cdr_to_conll.py $DATA_DIR/CDR_Data/CDR.Corpus.v010516/CDR_DevelopmentSet.BioC.xml $DISEASE_DIR/cdr1.conll Disease"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/cdr_to_conll.py $DATA_DIR/CDR_Data/CDR.Corpus.v010516/CDR_DevelopmentSet.BioC.xml $CHEMICAL_DIR/cdr1.conll Chemical"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/cdr_to_conll.py $DATA_DIR/CDR_Data/CDR.Corpus.v010516/CDR_TestSet.BioC.xml $DISEASE_DIR/cdr2.conll Disease"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/cdr_to_conll.py $DATA_DIR/CDR_Data/CDR.Corpus.v010516/CDR_TestSet.BioC.xml $CHEMICAL_DIR/cdr2.conll Chemical"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/cdr_to_conll.py $DATA_DIR/CDR_Data/CDR.Corpus.v010516/CDR_TrainingSet.BioC.xml.patched $DISEASE_DIR/cdr3.conll Disease"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/cdr_to_conll.py $DATA_DIR/CDR_Data/CDR.Corpus.v010516/CDR_TrainingSet.BioC.xml.patched $CHEMICAL_DIR/cdr3.conll Chemical"
+cat $DISEASE_DIR/cdr1.conll $DISEASE_DIR/cdr2.conll $DISEASE_DIR/cdr3.conll > $DISEASE_DIR/cdr.conll
+rm $DISEASE_DIR/cdr1.conll $DISEASE_DIR/cdr2.conll $DISEASE_DIR/cdr3.conll
+cat $CHEMICAL_DIR/cdr1.conll $CHEMICAL_DIR/cdr2.conll $CHEMICAL_DIR/cdr3.conll > $CHEMICAL_DIR/cdr.conll
+rm $CHEMICAL_DIR/cdr1.conll $CHEMICAL_DIR/cdr2.conll $CHEMICAL_DIR/cdr3.conll
+
+# CellFinder
+echo "Converting Cellfinder"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/cellfinder_to_conll.py $DATA_DIR/cellfinder CellLine $CELLLINE_DIR/cellfinder.conll"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/cellfinder_to_conll.py $DATA_DIR/cellfinder Species $SPECIES_DIR/cellfinder.conll"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/cellfinder_to_conll.py $DATA_DIR/cellfinder GeneProtein $GENE_DIR/cellfinder.conll"
+
+# CEMP
+echo "Converting CEMP"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/gpro_gene_to_conll.py $DATA_DIR/cemp_train.txt $DATA_DIR/cemp_train.ann $CHEMICAL_DIR/cemp1.conll"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/gpro_gene_to_conll.py $DATA_DIR/cemp_val.txt $DATA_DIR/cemp_val.ann $CHEMICAL_DIR/cemp2.conll"
+cat $CHEMICAL_DIR/cemp1.conll $CHEMICAL_DIR/cemp2.conll > $CHEMICAL_DIR/cemp.conll
+rm $CHEMICAL_DIR/cemp1.conll $CHEMICAL_DIR/cemp2.conll
+
+# CHEBI
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/chebi_to_conll.py $DATA_DIR/chebi $CHEMICAL_DIR/chebi.conll"
+
+# CHEMDNER
+echo "Converting CHEMDNER"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/gpro_gene_to_conll.py $DATA_DIR/chemdner_test.txt $DATA_DIR/chemdner_test.ann $CHEMICAL_DIR/chemdner1.conll"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/gpro_gene_to_conll.py $DATA_DIR/chemdner_train.txt $DATA_DIR/chemdner_train.ann $CHEMICAL_DIR/chemdner2.conll"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/gpro_gene_to_conll.py $DATA_DIR/chemdner_val.txt $DATA_DIR/chemdner_val.ann $CHEMICAL_DIR/chemdner3.conll"
+cat $CHEMICAL_DIR/chemdner1.conll $CHEMICAL_DIR/chemdner2.conll $CHEMICAL_DIR/chemdner3.conll > $CHEMICAL_DIR/chemdner.conll
+rm $CHEMICAL_DIR/chemdner1.conll $CHEMICAL_DIR/chemdner2.conll $CHEMICAL_DIR/chemdner3.conll
+
+# CLL
+echo "Converting CLL"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/cll_cell_lines_to_conll.py $DATA_DIR/cll/* $CELLLINE_DIR/cll.conll"
+
+# DECA
+echo "Converting DECA"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/deca_genes_to_conll.py $DATA_DIR/deca $GENE_DIR/deca.conll"
+
+# FSU
+echo "Converting FSU"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/fsu_gene_to_conll.py $DATA_DIR/fsu/Genes_cytorec,$DATA_DIR/fsu/Genes_genetag1,$DATA_DIR/fsu/Genes_genetag2,$DATA_DIR/fsu/Genes_LLL_Aimed,$DATA_DIR/fsu/Genes_PIR,$DATA_DIR/fsu/Genes_x45_shuffled,$DATA_DIR/fsu/Proteins_0,$DATA_DIR/fsu/Proteins0_shuffled,$DATA_DIR/fsu/Proteins_5,$DATA_DIR/fsu/Proteins_ecoli,$DATA_DIR/fsu/Proteins_KIR $GENE_DIR/fsu.conll"
+
+# GELLUS
+echo "Converting GELLUS"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/gellus_to_conll.py $DATA_DIR/gellus/* $CELLLINE_DIR/gellus.conll"
+sed -i 's/Cell-line-name/NP/' $CELLLINE_DIR/gellus.conll
+
+# GPRO
+echo "Converting GPRO"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/gpro_gene_to_conll.py $DATA_DIR/gpro/chemdner_patents_development_text.txt $DATA_DIR/gpro/chemdner_gpro_gold_standard_development.tsv $GENE_DIR/gpro1.conll"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/gpro_gene_to_conll.py $DATA_DIR/gpro/chemdner_patents_train_text.txt $DATA_DIR/gpro/chemdner_gpro_gold_standard_train_v02.tsv $GENE_DIR/gpro2.conll"
+cat $GENE_DIR/gpro1.conll $GENE_DIR/gpro2.conll > $GENE_DIR/gpro.conll
+rm $GENE_DIR/gpro1.conll $GENE_DIR/gpro2.conll
+
+# IEPA
+echo "Converting IEPA"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/iepa_gene_to_conll.py $DATA_DIR/iepa.xml $GENE_DIR/iepa.conll"
+
+# JNLPBA
+echo "Converting JNLPBA"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/jnlpba_to_conll.py $DATA_DIR/jnlpba/Genia4ERtask2.iob2 cell_line $CELLLINE_DIR/jnlpba.conll"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/jnlpba_to_conll.py $DATA_DIR/jnlpba/Genia4ERtask2.iob2 protein $GENE_DIR/jnlpba.conll"
+
+# Linneaus
+echo "Converting Linneaus"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/linneaus_species_to_conll.py $DATA_DIR/linneaus $SPECIES_DIR/linneaus.conll"
+
+# Loctext
+echo "Converting Loctext"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/loctext_gene_to_conll.py $DATA_DIR/LocText uniprot,go $GENE_DIR/loctext.conll"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/loctext_gene_to_conll.py $DATA_DIR/LocText taxonomy $SPECIES_DIR/loctext.conll"
+
+# miRNA
+echo "Converting miRNA"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/mirna_to_conll.py $DATA_DIR/miRNA_test.xml Genes/Proteins $GENE_DIR/miRNA1.conll"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/mirna_to_conll.py $DATA_DIR/miRNA_train.xml Genes/Proteins $GENE_DIR/miRNA2.conll"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/mirna_to_conll.py $DATA_DIR/miRNA_test.xml Species $SPECIES_DIR/miRNA1.conll"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/mirna_to_conll.py $DATA_DIR/miRNA_train.xml Species $SPECIES_DIR/miRNA2.conll"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/mirna_to_conll.py $DATA_DIR/miRNA_test.xml Diseases $DISEASE_DIR/miRNA1.conll"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/mirna_to_conll.py $DATA_DIR/miRNA_train.xml Diseases $DISEASE_DIR/miRNA2.conll"
+cat $GENE_DIR/miRNA1.conll $GENE_DIR/miRNA2.conll > $GENE_DIR/miRNA.conll
+rm $GENE_DIR/miRNA1.conll $GENE_DIR/miRNA2.conll
+cat $SPECIES_DIR/miRNA1.conll $SPECIES_DIR/miRNA2.conll > $SPECIES_DIR/miRNA.conll
+rm $SPECIES_DIR/miRNA1.conll $SPECIES_DIR/miRNA2.conll
+cat $DISEASE_DIR/miRNA1.conll $DISEASE_DIR/miRNA2.conll > $DISEASE_DIR/miRNA.conll
+rm $DISEASE_DIR/miRNA1.conll $DISEASE_DIR/miRNA2.conll
+
+# NCBI
+echo "Converting NCBI"
+patch $DATA_DIR/ncbi/NCBItrainset_corpus.txt $PATCH_DIR/NCBItrainset_corpus.patch -o $DATA_DIR/ncbi/NCBItrainset_corpus.txt.patched
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/ncbi_diseases_to_conll.py $DATA_DIR/ncbi/NCBIdevelopset_corpus.txt $DISEASE_DIR/ncbi1.conll"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/ncbi_diseases_to_conll.py $DATA_DIR/ncbi/NCBItrainset_corpus.txt.patched $DISEASE_DIR/ncbi2.conll"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/ncbi_diseases_to_conll.py $DATA_DIR/ncbi/NCBItestset_corpus.txt $DISEASE_DIR/ncbi3.conll"
+cat $DISEASE_DIR/ncbi1.conll $DISEASE_DIR/ncbi2.conll $DISEASE_DIR/ncbi3.conll > $DISEASE_DIR/ncbi.conll
+rm $DISEASE_DIR/ncbi1.conll $DISEASE_DIR/ncbi2.conll $DISEASE_DIR/ncbi3.conll
+
+# Osiris
+echo "Converting Osiris"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/osiris_gene_to_conll.py $DATA_DIR/osiris ge $GENE_DIR/osiris.conll"
+
+# S800
+echo "Converting S800"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/S800_species_to_conll.py $DATA_DIR/s800 $SPECIES_DIR/s800.conll"
+
+# SCAI Chemicals
+echo "Converting SCAI Chemicals"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/scai_to_conll.py $DATA_DIR/scai_chemicals.conll $CHEMICAL_DIR/scai_chemicals.conll"
+
+# SCAI Diseases
+echo "Converting SCAI Diseases"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/scai_to_conll.py $DATA_DIR/scai_diseases.conll $DISEASE_DIR/scai_diseases.conll"
+
+# Variome
+echo "Converting Variome"
+patch $DATA_DIR/variome.xml $PATCH_DIR/variome.patch -o $DATA_DIR/variome.xml.patched
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/variome_to_conll.py $DATA_DIR/variome.xml.patched $GENE_DIR/variome.conll gene"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/variome_to_conll.py $DATA_DIR/variome.xml.patched $DISEASE_DIR/variome.conll Disorder,disease"
+docker run -t -i --volume ${PWD}:/usr/ner_scripts huner/huner:master /bin/bash -c "cd /usr/ner_scripts; python3 $SCRIPT_DIR/variome_to_conll.py $DATA_DIR/variome.xml.patched $SPECIES_DIR/variome.conll Living_Beings"
+
+echo "Splitting corpora"
+./split_corpora.sh
+
+echo "Finished!"
diff --git a/huner/ner_scripts/convert_corpora_parallel.sh b/huner/ner_scripts/convert_corpora_parallel.sh
new file mode 100755
index 0000000..5e7a27d
--- /dev/null
+++ b/huner/ner_scripts/convert_corpora_parallel.sh
@@ -0,0 +1,150 @@
+#!/bin/sh
+
+DATA_DIR=data
+DISEASE_DIR=converted/disease
+GENE_DIR=converted/gene
+SPECIES_DIR=converted/species
+CELLLINE_DIR=converted/cellline
+CHEMICAL_DIR=converted/chemical
+PATCH_DIR=patches
+SCRIPT_DIR=scripts
+
+mkdir -p $DISEASE_DIR
+mkdir -p $GENE_DIR
+mkdir -p $SPECIES_DIR
+mkdir -p $CELLLINE_DIR
+mkdir -p $CHEMICAL_DIR
+
+patch $DATA_DIR/CDR_Data/CDR_Data/CDR.Corpus.v010516/CDR_TrainingSet.BioC.xml patches/CDR_TrainingSet.BioC.xml.patch -o $DATA_DIR/CDR_Data/CDR_Data/CDR.Corpus.v010516/CDR_TrainingSet.BioC.xml.patched
+patch $DATA_DIR/ncbi/NCBItrainset_corpus.txt $PATCH_DIR/NCBItrainset_corpus.patch -o $DATA_DIR/ncbi/NCBItrainset_corpus.txt.patched
+patch $DATA_DIR/variome.xml $PATCH_DIR/variome.patch -o $DATA_DIR/variome.xml.patched
+
+echo "Starting conversion processing"
+
+# Arizona disease
+python3 $SCRIPT_DIR/arizona_disease_to_conll.py $DATA_DIR/arizona.txt $DISEASE_DIR/arizona.conll &
+
+# BioCreative 2 GeneMentions
+python3 $SCRIPT_DIR/bc2gm_gene_to_conll.py $DATA_DIR/bc2gm/train/train.in $DATA_DIR/bc2gm/train/GENE.eval $GENE_DIR/bc2gm1.conll &
+python3 $SCRIPT_DIR/bc2gm_gene_to_conll.py $DATA_DIR/bc2gm/test/test.in $DATA_DIR/bc2gm/test/GENE.eval $GENE_DIR/bc2gm2.conll &
+
+# BioInfer
+python3 $SCRIPT_DIR/bioinfer_to_conll.py $DATA_DIR/bioinfer.xml $GENE_DIR/bioinfer.conll &
+
+# Biosemantics
+python3 $SCRIPT_DIR/biosemantics_to_conll.py $DATA_DIR/biosemantics M,I,Y,D,B,C,F,R,G,MOA $CHEMICAL_DIR/biosemantics.conll &
+python3 $SCRIPT_DIR/biosemantics_to_conll.py $DATA_DIR/biosemantics Disease $DISEASE_DIR/biosemantics.conll &
+
+# CDR
+python3 $SCRIPT_DIR/cdr_to_conll.py $DATA_DIR/CDR_Data/CDR_Data/CDR.Corpus.v010516/CDR_DevelopmentSet.BioC.xml $DISEASE_DIR/cdr1.conll Disease &
+python3 $SCRIPT_DIR/cdr_to_conll.py $DATA_DIR/CDR_Data/CDR_Data/CDR.Corpus.v010516/CDR_DevelopmentSet.BioC.xml $CHEMICAL_DIR/cdr1.conll Chemical &
+python3 $SCRIPT_DIR/cdr_to_conll.py $DATA_DIR/CDR_Data/CDR_Data/CDR.Corpus.v010516/CDR_TestSet.BioC.xml $DISEASE_DIR/cdr2.conll Disease &
+python3 $SCRIPT_DIR/cdr_to_conll.py $DATA_DIR/CDR_Data/CDR_Data/CDR.Corpus.v010516/CDR_TestSet.BioC.xml $CHEMICAL_DIR/cdr2.conll Chemical &
+python3 $SCRIPT_DIR/cdr_to_conll.py $DATA_DIR/CDR_Data/CDR_Data/CDR.Corpus.v010516/CDR_TrainingSet.BioC.xml.patched $DISEASE_DIR/cdr3.conll Disease &
+python3 $SCRIPT_DIR/cdr_to_conll.py $DATA_DIR/CDR_Data/CDR_Data/CDR.Corpus.v010516/CDR_TrainingSet.BioC.xml.patched $CHEMICAL_DIR/cdr3.conll Chemical &
+
+# CellFinder
+python3 $SCRIPT_DIR/cellfinder_to_conll.py $DATA_DIR/cellfinder CellLine $CELLLINE_DIR/cellfinder.conll &
+python3 $SCRIPT_DIR/cellfinder_to_conll.py $DATA_DIR/cellfinder Species $SPECIES_DIR/cellfinder.conll &
+python3 $SCRIPT_DIR/cellfinder_to_conll.py $DATA_DIR/cellfinder GeneProtein $GENE_DIR/cellfinder.conll &
+
+# CEMP
+python3 $SCRIPT_DIR/gpro_gene_to_conll.py $DATA_DIR/cemp_train.txt $DATA_DIR/cemp_train.ann $CHEMICAL_DIR/cemp1.conll &
+python3 $SCRIPT_DIR/gpro_gene_to_conll.py $DATA_DIR/cemp_val.txt $DATA_DIR/cemp_val.ann $CHEMICAL_DIR/cemp2.conll &
+
+# CHEBI
+python3 $SCRIPT_DIR/chebi_to_conll.py $DATA_DIR/chebi $CHEMICAL_DIR/chebi.conll &
+
+# CHEMDNER
+python3 $SCRIPT_DIR/gpro_gene_to_conll.py $DATA_DIR/chemdner_test.txt $DATA_DIR/chemdner_test.ann $CHEMICAL_DIR/chemdner1.conll &
+python3 $SCRIPT_DIR/gpro_gene_to_conll.py $DATA_DIR/chemdner_train.txt $DATA_DIR/chemdner_train.ann $CHEMICAL_DIR/chemdner2.conll &
+python3 $SCRIPT_DIR/gpro_gene_to_conll.py $DATA_DIR/chemdner_val.txt $DATA_DIR/chemdner_val.ann $CHEMICAL_DIR/chemdner3.conll &
+
+# CLL
+python3 $SCRIPT_DIR/cll_cell_lines_to_conll.py "$DATA_DIR/cll/*" $CELLLINE_DIR/cll.conll &
+
+# DECA
+python3 $SCRIPT_DIR/deca_genes_to_conll.py $DATA_DIR/deca $GENE_DIR/deca.conll &
+
+# FSU
+python3 $SCRIPT_DIR/fsu_gene_to_conll.py $DATA_DIR/fsu/Genes_cytorec,$DATA_DIR/fsu/Genes_genetag1,$DATA_DIR/fsu/Genes_genetag2,$DATA_DIR/fsu/Genes_LLL_Aimed,$DATA_DIR/fsu/Genes_PIR,$DATA_DIR/fsu/Genes_x45_shuffled,$DATA_DIR/fsu/Proteins_0,$DATA_DIR/fsu/Proteins0_shuffled,$DATA_DIR/fsu/Proteins_5,$DATA_DIR/fsu/Proteins_ecoli,$DATA_DIR/fsu/Proteins_KIR $GENE_DIR/fsu.conll &
+
+# GELLUS
+python3 $SCRIPT_DIR/gellus_to_conll.py "$DATA_DIR/gellus/*" $CELLLINE_DIR/gellus.conll &
+
+# GPRO
+python3 $SCRIPT_DIR/gpro_gene_to_conll.py $DATA_DIR/gpro/chemdner_patents_development_text.txt $DATA_DIR/gpro/chemdner_gpro_gold_standard_development.tsv $GENE_DIR/gpro1.conll &
+python3 $SCRIPT_DIR/gpro_gene_to_conll.py $DATA_DIR/gpro/chemdner_patents_train_text.txt $DATA_DIR/gpro/chemdner_gpro_gold_standard_train_v02.tsv $GENE_DIR/gpro2.conll &
+
+# IEPA
+python3 $SCRIPT_DIR/iepa_gene_to_conll.py $DATA_DIR/iepa.xml $GENE_DIR/iepa.conll &
+
+# JNLPBA
+python3 $SCRIPT_DIR/jnlpba_to_conll.py $DATA_DIR/jnlpba/Genia4ERtask2.iob2 cell_line $CELLLINE_DIR/jnlpba.conll &
+python3 $SCRIPT_DIR/jnlpba_to_conll.py $DATA_DIR/jnlpba/Genia4ERtask2.iob2 protein $GENE_DIR/jnlpba.conll &
+
+# Linneaus
+python3 $SCRIPT_DIR/linneaus_species_to_conll.py $DATA_DIR/linneaus $SPECIES_DIR/linneaus.conll &
+
+# Loctext
+python3 $SCRIPT_DIR/loctext_gene_to_conll.py $DATA_DIR/LocText uniprot,go $GENE_DIR/loctext.conll &
+python3 $SCRIPT_DIR/loctext_gene_to_conll.py $DATA_DIR/LocText taxonomy $SPECIES_DIR/loctext.conll &
+
+# miRNA
+python3 $SCRIPT_DIR/mirna_to_conll.py $DATA_DIR/miRNA_test.xml Genes/Proteins $GENE_DIR/miRNA1.conll &
+python3 $SCRIPT_DIR/mirna_to_conll.py $DATA_DIR/miRNA_train.xml Genes/Proteins $GENE_DIR/miRNA2.conll &
+python3 $SCRIPT_DIR/mirna_to_conll.py $DATA_DIR/miRNA_test.xml Species $SPECIES_DIR/miRNA1.conll &
+python3 $SCRIPT_DIR/mirna_to_conll.py $DATA_DIR/miRNA_train.xml Species $SPECIES_DIR/miRNA2.conll &
+python3 $SCRIPT_DIR/mirna_to_conll.py $DATA_DIR/miRNA_test.xml Diseases $DISEASE_DIR/miRNA1.conll &
+python3 $SCRIPT_DIR/mirna_to_conll.py $DATA_DIR/miRNA_train.xml Diseases $DISEASE_DIR/miRNA2.conll &
+
+# NCBI
+python3 $SCRIPT_DIR/ncbi_diseases_to_conll.py $DATA_DIR/ncbi/NCBIdevelopset_corpus.txt $DISEASE_DIR/ncbi1.conll &
+python3 $SCRIPT_DIR/ncbi_diseases_to_conll.py $DATA_DIR/ncbi/NCBItrainset_corpus.txt.patched $DISEASE_DIR/ncbi2.conll &
+python3 $SCRIPT_DIR/ncbi_diseases_to_conll.py $DATA_DIR/ncbi/NCBItestset_corpus.txt $DISEASE_DIR/ncbi3.conll &
+
+# Osiris
+python3 $SCRIPT_DIR/osiris_gene_to_conll.py $DATA_DIR/osiris ge $GENE_DIR/osiris.conll &
+
+# S800
+python3 $SCRIPT_DIR/S800_species_to_conll.py "$DATA_DIR/s800" "$SPECIES_DIR/s800.conll" &
+
+# SCAI Chemicals
+python3 $SCRIPT_DIR/scai_to_conll.py "$DATA_DIR/scai_chemicals.conll" "$CHEMICAL_DIR/scai_chemicals.conll" &
+
+# SCAI Diseases
+python3 $SCRIPT_DIR/scai_to_conll.py "$DATA_DIR/scai_diseases.conll" "$DISEASE_DIR/scai_diseases.conll" &
+
+# Variome
+python3 $SCRIPT_DIR/variome_to_conll.py "$DATA_DIR/variome.xml.patched" "$GENE_DIR/variome.conll" gene &
+python3 $SCRIPT_DIR/variome_to_conll.py "$DATA_DIR/variome.xml.patched" "$DISEASE_DIR/variome.conll" Disorder,disease &
+python3 $SCRIPT_DIR/variome_to_conll.py "$DATA_DIR/variome.xml.patched" "$SPECIES_DIR/variome.conll" Living_Beings &
+
+wait
+
+cat $DISEASE_DIR/cdr1.conll $DISEASE_DIR/cdr2.conll $DISEASE_DIR/cdr3.conll > $DISEASE_DIR/cdr.conll
+rm $DISEASE_DIR/cdr1.conll $DISEASE_DIR/cdr2.conll $DISEASE_DIR/cdr3.conll
+cat $CHEMICAL_DIR/cdr1.conll $CHEMICAL_DIR/cdr2.conll $CHEMICAL_DIR/cdr3.conll > $CHEMICAL_DIR/cdr.conll
+rm $CHEMICAL_DIR/cdr1.conll $CHEMICAL_DIR/cdr2.conll $CHEMICAL_DIR/cdr3.conll
+cat $CHEMICAL_DIR/cemp1.conll $CHEMICAL_DIR/cemp2.conll > $CHEMICAL_DIR/cemp.conll
+rm $CHEMICAL_DIR/cemp1.conll $CHEMICAL_DIR/cemp2.conll
+cat $CHEMICAL_DIR/chemdner1.conll $CHEMICAL_DIR/chemdner2.conll $CHEMICAL_DIR/chemdner3.conll > $CHEMICAL_DIR/chemdner.conll
+rm $CHEMICAL_DIR/chemdner1.conll $CHEMICAL_DIR/chemdner2.conll $CHEMICAL_DIR/chemdner3.conll
+cat $GENE_DIR/gpro1.conll $GENE_DIR/gpro2.conll > $GENE_DIR/gpro.conll
+rm $GENE_DIR/gpro1.conll $GENE_DIR/gpro2.conll
+cat $DISEASE_DIR/ncbi1.conll $DISEASE_DIR/ncbi2.conll $DISEASE_DIR/ncbi3.conll > $DISEASE_DIR/ncbi.conll
+rm $DISEASE_DIR/ncbi1.conll $DISEASE_DIR/ncbi2.conll $DISEASE_DIR/ncbi3.conll
+cat $GENE_DIR/miRNA1.conll $GENE_DIR/miRNA2.conll > $GENE_DIR/miRNA.conll
+rm $GENE_DIR/miRNA1.conll $GENE_DIR/miRNA2.conll
+cat $SPECIES_DIR/miRNA1.conll $SPECIES_DIR/miRNA2.conll > $SPECIES_DIR/miRNA.conll
+rm $SPECIES_DIR/miRNA1.conll $SPECIES_DIR/miRNA2.conll
+cat $DISEASE_DIR/miRNA1.conll $DISEASE_DIR/miRNA2.conll > $DISEASE_DIR/miRNA.conll
+rm $DISEASE_DIR/miRNA1.conll $DISEASE_DIR/miRNA2.conll
+cat $GENE_DIR/bc2gm1.conll $GENE_DIR/bc2gm2.conll > $GENE_DIR/bc2gm.conll
+rm $GENE_DIR/bc2gm1.conll $GENE_DIR/bc2gm2.conll
+sed -i 's/Cell-line-name/NP/' $CELLLINE_DIR/gellus.conll
+
+echo "Splitting corpora"
+./split_corpora.sh
+
+echo "Finished!"
diff --git a/huner/ner_scripts/convert_craft.sh b/huner/ner_scripts/convert_craft.sh
new file mode 100755
index 0000000..7e22ba9
--- /dev/null
+++ b/huner/ner_scripts/convert_craft.sh
@@ -0,0 +1,17 @@
+#!/bin/sh
+
+# Craft corpus can be obtained from http://sourceforge.net/projects/bionlp-corpora/files/CRAFT/v2.0/craft-2.0.tar.gz/download
+
+CRAFT_DIR=$1
+
+python scripts/craft_to_conll.py $CRAFT_DIR chebi craft_chemicals_tmp.conll
+awk '{print (NF ? $2"\t"$3"\t"$4 : $0)}' craft_chemicals_tmp.conll > craft_chemicals.conll
+rm craft_chemicals_tmp.conll
+
+python scripts/craft_to_conll.py $CRAFT_DIR entrezgene,pr craft_genes_tmp.conll
+awk '{print (NF ? $2"\t"$3"\t"$4 : $0)}' craft_genes_tmp.conll > craft_genes.conll
+rm craft_genes_tmp.conll
+
+python scripts/craft_to_conll.py $CRAFT_DIR ncbitaxon craft_species_tmp.conll
+awk '{print (NF ? $2"\t"$3"\t"$4 : $0)}' craft_species_tmp.conll > craft_species.conll
+rm craft_species_tmp.conll
diff --git a/huner/ner_scripts/download_files.py b/huner/ner_scripts/download_files.py
new file mode 100644
index 0000000..fb73b18
--- /dev/null
+++ b/huner/ner_scripts/download_files.py
@@ -0,0 +1,352 @@
+#!/usr/bin/env python3
+from glob import glob
+import gzip
+import os
+import shutil
+import tarfile
+import zipfile
+import requests
+import rarfile
+import shlex
+import subprocess
+
+if __name__ == '__main__':
+    parent_dir = os.path.dirname(os.path.realpath(__file__))
+    data_dir = os.path.join(parent_dir, 'data')
+    os.makedirs(data_dir, exist_ok=True)
+
+
+    def file_exists(fname):
+        return os.path.isfile(os.path.join(data_dir, fname))
+
+
+    def is_missing(fnames):
+        for fname in fnames:
+            if not file_exists(fname):
+                print(fname + " is missing. Downloading...")
+                return True
+        return False
+
+
+    def is_empty(dirname):
+        dirpath = os.path.join(data_dir, dirname)
+        empty = (not os.path.isdir(dirpath)) or len(os.listdir(dirpath)) == 0
+        if empty:
+            print(dirname + " is missing. Downloading...")
+            return True
+        else:
+            return False
+
+
+    #BioInfer
+    if is_missing(['bioinfer.xml']):
+        with open('bioinfer.zip', 'wb') as f:
+            resp = requests.get('http://mars.cs.utu.fi/BioInfer/files/BioInfer_corpus_1.1.1.zip')
+            f.write(resp.content)
+
+        with zipfile.ZipFile('bioinfer.zip') as f:
+            f.extractall()
+
+        shutil.move('BioInfer_corpus_1.1.1.xml', os.path.join(data_dir, 'bioinfer.xml'))
+        os.remove('bioinfer.zip')
+
+    # Biosemantics
+    if is_empty("biosemantics"):
+        with open('Patent_Corpus.rar', 'wb') as f:
+            resp = requests.get('http://biosemantics.org/PatentCorpus/Patent_Corpus.rar')
+            f.write(resp.content)
+        
+        with rarfile.RarFile("Patent_Corpus.rar") as f:
+            f.extractall()
+            shutil.move(os.path.join("Patent_Corpus/Full_set"), os.path.join(data_dir, "biosemantics"))
+            os.remove("Patent_Corpus.rar")
+            shutil.rmtree("Patent_Corpus")
+
+    # CellFinder
+    if is_empty('cellfinder'):
+        with open('cellfinder.tar.gz', 'wb') as f:
+            resp = requests.get("https://www.informatik.hu-berlin.de/de/forschung/gebiete/wbi/resources/cellfinder/cellfinder1_brat.tar.gz")
+            f.write(resp.content)
+
+        path = os.path.join(data_dir, 'cellfinder')
+        os.makedirs(path)
+        with tarfile.open("cellfinder.tar.gz") as f:
+            f.extractall(path)
+        os.remove("cellfinder.tar.gz")
+
+    # CHEMDNER Patents
+    if is_missing(['cemp_train.txt', 'cemp_train.ann',
+                   'cemp_val.txt', 'cemp_val.ann']):
+        with open('cemp_train.tar.gz', 'wb') as fp:
+            resp = requests.get('https://biocreative.bioinformatics.udel.edu/media/store/files/2015/cemp_training_set.tar.gz')
+            fp.write(resp.content)
+        with open('cemp_val.tar.gz', 'wb') as fp:
+            resp = requests.get('https://biocreative.bioinformatics.udel.edu/media/store/files/2015/cemp_development_set_v03.tar.gz')
+            fp.write(resp.content)
+
+        with tarfile.open('cemp_train.tar.gz') as f:
+            f.extractall()
+        os.remove('cemp_train.tar.gz')
+
+        with tarfile.open('cemp_val.tar.gz') as f:
+            f.extractall()
+        os.remove('cemp_val.tar.gz')
+
+        shutil.move(os.path.join('cemp_training_set', 'chemdner_patents_train_text.txt'),
+                    os.path.join(data_dir, 'cemp_train.txt'))
+        shutil.move(os.path.join('cemp_training_set', 'chemdner_cemp_gold_standard_train.tsv'),
+                    os.path.join(data_dir, 'cemp_train.ann'))
+
+        shutil.move(os.path.join('cemp_development_set_v03', 'chemdner_patents_development_text.txt'),
+                    os.path.join(data_dir, 'cemp_val.txt'))
+        shutil.move(os.path.join('cemp_development_set_v03', 'chemdner_cemp_gold_standard_development_v03.tsv'),
+                    os.path.join(data_dir, 'cemp_val.ann'))
+
+        shutil.rmtree('cemp_training_set')
+        shutil.rmtree('cemp_development_set_v03')
+
+    # CHEBI
+    if is_empty('chebi'):
+        cmd = 'cvs -z3 -d:pserver:anonymous@a.cvs.sourceforge.net:/cvsroot/chebi co -P chapati'
+        cmd = shlex.split(cmd)
+        subprocess.run(cmd)
+        with tarfile.open(os.path.join('chapati', 'patentsGoldStandard', 'PatentAnnotations_GoldStandard.tgz')) as f:
+            f.extractall()
+            shutil.move('scrapbook', os.path.join(data_dir, 'chebi'))
+        shutil.rmtree('chapati')
+
+
+    # CHEMDNER
+    if is_missing(['chemdner_train.txt', 'chemdner_train.ann',
+                   'chemdner_val.txt', 'chemdner_val.ann',
+                   'chemdner_test.txt', 'chemdner_test.ann'
+                   ]):
+
+        with open('chemdner.tar.gz', 'wb') as fp:
+            resp = requests.get('https://biocreative.bioinformatics.udel.edu/media/store/files/2014/chemdner_corpus.tar.gz')
+            fp.write(resp.content)
+
+        with tarfile.open('chemdner.tar.gz') as f:
+            f.extractall()
+        shutil.move(os.path.join('chemdner_corpus', 'training.abstracts.txt'),
+                    os.path.join(data_dir, 'chemdner_train.txt'))
+        shutil.move(os.path.join('chemdner_corpus', 'training.annotations.txt'),
+                    os.path.join(data_dir, 'chemdner_train.ann'))
+        shutil.move(os.path.join('chemdner_corpus', 'development.abstracts.txt'),
+                    os.path.join(data_dir, 'chemdner_val.txt'))
+        shutil.move(os.path.join('chemdner_corpus', 'development.annotations.txt'),
+                    os.path.join(data_dir, 'chemdner_val.ann'))
+        shutil.move(os.path.join('chemdner_corpus', 'evaluation.abstracts.txt'),
+                    os.path.join(data_dir, 'chemdner_test.txt'))
+        shutil.move(os.path.join('chemdner_corpus', 'evaluation.annotations.txt'),
+                    os.path.join(data_dir, 'chemdner_test.ann'))
+        shutil.rmtree('chemdner_corpus')
+        os.remove('chemdner.tar.gz')
+
+    # CLL
+    if is_empty('cll'):
+        with open('cll.tar.gz', 'wb') as fp:
+            resp = requests.get('http://bionlp-www.utu.fi/cell-lines/CLL_corpus.tar.gz')
+            fp.write(resp.content)
+
+        with tarfile.open('cll.tar.gz') as f:
+            f.extractall()
+        shutil.move(os.path.join('CLL-1.0.2', 'conll'),
+                    os.path.join(data_dir, 'cll'))
+        os.remove('cll.tar.gz')
+        shutil.rmtree('CLL-1.0.2')
+
+    # Gellus
+    if is_empty('gellus'):
+        with open('gellus.tar.gz', 'wb') as fp:
+            resp = requests.get('http://bionlp-www.utu.fi/cell-lines/Gellus_corpus.tar.gz')
+            fp.write(resp.content)
+
+        with tarfile.open('gellus.tar.gz') as f:
+            f.extractall()
+        shutil.move(os.path.join(parent_dir,'GELLUS-1.0.3','conll','all'),
+                    os.path.join(data_dir, 'gellus'))
+        os.remove('gellus.tar.gz')
+        shutil.rmtree('GELLUS-1.0.3')
+
+    # DECA
+    if is_empty('deca'):
+        with open('deca.tar.gz', 'wb') as fp:
+            resp = requests.get('http://www.nactem.ac.uk/deca/species_corpus_0.2.tar.gz')
+            fp.write(resp.content)
+
+        with tarfile.open('deca.tar.gz') as f:
+            f.extractall()
+        shutil.move('species_corpus_0.2', os.path.join(data_dir, 'deca'))
+        os.remove('deca.tar.gz')
+
+    # FSU-PRGE
+    if is_empty('fsu'):
+        with open('fsu.tar.gz', 'wb') as fp:
+            resp = requests.get('https://julielab.de/downloads/resources/fsu_prge_release_v1_0.tgz')
+            fp.write(resp.content)
+
+        with tarfile.open('fsu.tar.gz') as f:
+            f.extractall()
+        shutil.move('fsu-prge-release-v1.0', os.path.join(data_dir, 'fsu'))
+        os.remove('fsu.tar.gz')
+
+    # GPRO
+    if is_empty('gpro'):
+        with open('gpro_train.tar.gz', 'wb') as fp:
+            resp = requests.get('https://biocreative.bioinformatics.udel.edu/media/store/files/2015/gpro_training_set_v02.tar.gz')
+            fp.write(resp.content)
+
+        with open('gpro_val.tar.gz', 'wb') as fp:
+            resp = requests.get('https://biocreative.bioinformatics.udel.edu/media/store/files/2015/gpro_development_set.tar_.gz')
+            fp.write(resp.content)
+
+        with tarfile.open('gpro_train.tar.gz') as f:
+            f.extractall()
+
+        with tarfile.open('gpro_val.tar.gz') as f:
+            f.extractall()
+
+        corpus_dir = os.path.join(data_dir, 'gpro')
+        os.makedirs(corpus_dir, exist_ok=True)
+
+        for fname in glob(os.path.join('gpro_training_set_v02', '*')) + glob(os.path.join('gpro_development_set', '*')):
+            shutil.move(fname,corpus_dir)
+
+        os.remove('gpro_train.tar.gz')
+        os.remove('gpro_val.tar.gz')
+        shutil.rmtree('gpro_training_set_v02')
+        shutil.rmtree('gpro_development_set')
+
+    # IEPA
+    if is_missing(['iepa.xml']):
+        with open('iepa.zip', 'wb') as fp:
+            resp = requests.get('http://corpora.informatik.hu-berlin.de/corpora/brat2bioc/iepa_bioc.xml.zip')
+            fp.write(resp.content)
+        with zipfile.ZipFile('iepa.zip') as f:
+            f.extractall()
+        shutil.move('iepa_bioc.xml', os.path.join(data_dir, 'iepa.xml'))
+        os.remove('iepa.zip')
+
+    # JNLPBA
+    if is_empty('jnlpba'):
+        with open('genia_train.tar.gz', 'wb') as fp:
+            resp = requests.get('http://www.nactem.ac.uk/GENIA/current/Shared-tasks/JNLPBA/Train/Genia4ERtraining.tar.gz')
+            fp.write(resp.content)
+        with open('genia_test.tar.gz', 'wb') as fp:
+            resp = requests.get('http://www.nactem.ac.uk/GENIA/current/Shared-tasks/JNLPBA/Evaluation/Genia4ERtest.tar.gz')
+            fp.write(resp.content)
+        with tarfile.open('genia_train.tar.gz') as f:
+            f.extractall(os.path.join(data_dir, 'jnlpba'))
+        with tarfile.open('genia_test.tar.gz') as f:
+            f.extractall(os.path.join(data_dir, 'jnlpba'))
+        os.remove('genia_train.tar.gz')
+        os.remove('genia_test.tar.gz')
+
+    # Linneaus
+    if is_empty('linneaus'):
+        with open('linneaus.tar.gz', 'wb') as fp:
+            resp = requests.get('https://sourceforge.net/projects/linnaeus/files/Corpora/manual-corpus-species-1.0.tar.gz/download')
+            fp.write(resp.content)
+        with tarfile.open('linneaus.tar.gz') as f:
+            f.extractall()
+        shutil.move('manual-corpus-species-1.0',
+                    os.path.join(data_dir, 'linneaus'))
+        os.remove('linneaus.tar.gz')
+
+    # miRNA
+    if is_missing(['miRNA_test.xml', 'miRNA_train.xml']):
+        with open(os.path.join(data_dir, 'miRNA_test.xml'), 'wb') as fp:
+            resp = requests.get('https://www.scai.fraunhofer.de/content/dam/scai/de/downloads/bioinformatik/miRNA/miRNA-Test-Corpus.xml')
+            fp.write(resp.content)
+        with open(os.path.join(data_dir, 'miRNA_train.xml'), 'wb') as fp:
+            resp = requests.get('https://www.scai.fraunhofer.de/content/dam/scai/de/downloads/bioinformatik/miRNA/miRNA-Train-Corpus.xml')
+            fp.write(resp.content)
+
+    # NCBI
+    if is_empty('ncbi'):
+        with open('ncbi_train.zip', 'wb') as fp:
+            resp = requests.get('https://www.ncbi.nlm.nih.gov/CBBresearch/Dogan/DISEASE/NCBItrainset_corpus.zip')
+            fp.write(resp.content)
+        with open('ncbi_val.zip', 'wb') as fp:
+            resp = requests.get('https://www.ncbi.nlm.nih.gov/CBBresearch/Dogan/DISEASE/NCBIdevelopset_corpus.zip')
+            fp.write(resp.content)
+        with open('ncbi_test.zip', 'wb') as fp:
+            resp = requests.get('https://www.ncbi.nlm.nih.gov/CBBresearch/Dogan/DISEASE/NCBItestset_corpus.zip')
+            fp.write(resp.content)
+        with zipfile.ZipFile('ncbi_train.zip') as f:
+            f.extractall(os.path.join(data_dir, 'ncbi'))
+        with zipfile.ZipFile('ncbi_val.zip') as f:
+            f.extractall(os.path.join(data_dir, 'ncbi'))
+        with zipfile.ZipFile('ncbi_test.zip') as f:
+            f.extractall(os.path.join(data_dir, 'ncbi'))
+        os.remove('ncbi_train.zip')
+        os.remove('ncbi_val.zip')
+        os.remove('ncbi_test.zip')
+
+    # Osiris
+    if is_empty('osiris'):
+        with open('osiris.tar', 'wb') as fp:
+            resp = requests.get('http://ibi.imim.es/OSIRIScorpusv02.tar')
+            fp.write(resp.content)
+        with tarfile.open('osiris.tar') as f:
+            f.extractall()
+        shutil.move('OSIRIScorpusv02',
+                    os.path.join(data_dir, 'osiris'))
+        os.remove('osiris.tar')
+
+    # S800
+    if is_empty('s800'):
+        with open('s800.tar.gz', 'wb') as fp:
+            resp = requests.get('https://species.jensenlab.org/files/S800-1.0.tar.gz')
+            fp.write(resp.content)
+        with tarfile.open('s800.tar.gz') as f:
+            f.extractall(os.path.join(data_dir, 's800'))
+        os.remove('s800.tar.gz')
+
+    # SCAI Chemicals
+    if is_missing(['scai_chemicals.conll']):
+        with open('scai_chemicals.gz', 'wb') as fp:
+            resp = requests.get('https://www.scai.fraunhofer.de/content/dam/scai/de/downloads/bioinformatik/Corpora-for-Chemical-Entity-Recognition/chemicals-test-corpus-27-04-2009-v3_iob.gz')
+            fp.write(resp.content)
+        with gzip.open('scai_chemicals.gz') as f_in, open(os.path.join(data_dir, 'scai_chemicals.conll'), 'wb') as f_out:
+            f_out.write(f_in.read())
+        os.remove('scai_chemicals.gz')
+
+    # SCAI Diseases
+    if is_missing(['scai_diseases.conll']):
+        with open(os.path.join(data_dir, 'scai_diseases.conll'), 'wb') as fp:
+            resp = requests.get('https://www.scai.fraunhofer.de/content/dam/scai/de/downloads/bioinformatik/Disease-ae-corpus.iob')
+            fp.write(resp.content)
+
+    # Variome
+    if is_missing(['variome.xml']):
+        with open('variome.zip', 'wb') as fp:
+            resp = requests.get('http://corpora.informatik.hu-berlin.de/corpora/brat2bioc/hvp_bioc.xml.zip')
+            fp.write(resp.content)
+        with zipfile.ZipFile('variome.zip') as f:
+            f.extractall()
+        shutil.move('hvp_bioc.xml', os.path.join(data_dir, 'variome.xml'))
+        os.remove('variome.zip')
+
+    # LocText
+    if is_empty('LocText'):
+        with open('loctext.tar.gz', 'wb') as fp:
+            resp = requests.get('http://pubannotation.org/projects/LocText/annotations.tgz')
+            fp.write(resp.content)
+        with tarfile.open('loctext.tar.gz') as f:
+            f.extractall()
+        shutil.move('LocText', os.path.join(data_dir))
+        os.remove('loctext.tar.gz')
+
+
+    # CDR
+    if is_empty('CDR_Data'):
+        raise ValueError("Please download the data from https://biocreative.bioinformatics.udel.edu/tasks/biocreative-v/track-3-cdr/ and move the extracted directory to data/ ...")
+
+    # Biocreative
+    if is_empty('bc2gm/train') or is_empty('bc2gm/test'):
+        raise ValueError("Please download the train and test data for the GM subtask from https://biocreative.bioinformatics.udel.edu/resources/corpora/biocreative-ii-corpus/ and place the directories named 'train' and 'test' into data/bc2gm ...")
+
+
+    print("Success! All corpora should now be available.")
diff --git a/huner/ner_scripts/patches/CDR_TrainingSet.BioC.xml.patch b/huner/ner_scripts/patches/CDR_TrainingSet.BioC.xml.patch
new file mode 100644
index 0000000..0f7eb64
--- /dev/null
+++ b/huner/ner_scripts/patches/CDR_TrainingSet.BioC.xml.patch
@@ -0,0 +1,11 @@
+--- CDR_TrainingSet.BioC.xml	2018-01-25 15:16:31.810076292 +0100
++++ CDR_TrainingSet.BioC.xml.patched	2018-01-25 15:38:10.129154694 +0100
+@@ -53450,7 +53450,7 @@
+ <infon key="type">Disease</infon>
+ <infon key="CompositeRole">IndividualMention</infon>
+ <infon key="MESH">D009436</infon>
+-<location offset='946' length='20' />
++<location offset='948' length='20' />
+ <text>midline (MD) defects</text>
+ </annotation>
+ <annotation id='13'>
diff --git a/huner/ner_scripts/patches/NCBItrainset_corpus.patch b/huner/ner_scripts/patches/NCBItrainset_corpus.patch
new file mode 100644
index 0000000..06e811a
--- /dev/null
+++ b/huner/ner_scripts/patches/NCBItrainset_corpus.patch
@@ -0,0 +1,4 @@
+3249c3249
+< 10923035	711	761	generalized epilepsy and febrile seizures   plus  	SpecificDisease	D004829+D003294
+---
+> 10923035	711	761	generalized epilepsy and febrile seizures " plus "	SpecificDisease	D004829+D003294
diff --git a/huner/ner_scripts/patches/variome.patch b/huner/ner_scripts/patches/variome.patch
new file mode 100644
index 0000000..f8bb137
--- /dev/null
+++ b/huner/ner_scripts/patches/variome.patch
@@ -0,0 +1,154 @@
+--- hvp_bioc.xml	2018-02-15 11:40:46.329577280 +0100
++++ hvp_bioc_patched.xml	2018-02-21 11:04:59.569344797 +0100
+@@ -517,7 +517,7 @@
+ ** IGNORE LINE **
+ Introduction
+ 
+-Colorectal cancer (CRC) is one of the common malignancies in industrialized countries. Lynch syndrome, a highly penetrant disorder that confers predisposition to cancer of the colorectum, endometrium and other extra-colonic sites [1], is caused by germline mutations in DNA Mismatch Repair genes (MMR). Including sporadic forms, defective MMR underlies ∼12–15% of CRC [2]. MMR plays critical roles in the maintenance of genomic stability in both prokaryotes and eukaryotes [3]. The study of model organisms has yielded great insights into the mechanisms through which MMR prevents cancer [1],[3],[4],[5],[6],[7],[8]. Briefly, there are nine mammalian MMR genes (MLH1, MLH3, PMS1-2, MSH2-6). The mammalian E coli MutS homologues (MSH) directly contact DNA, scanning along the genomic DNA for mismatches analogous to a “sliding clamp�? until they encounter a base-pair containing a mismatch [9],[10]. MSH2-MSH6 primarily recognizes single-base substitutions and 1 base-pair insertion-deletion loop (IDL) mutations, while MSH2-MSH3 recognizes 1–4 base-pair insertion-deletion mutations [1],[3].The IDL repair deficiency is commonly referred to as Microsatellite Instability (MSI). The MSH proteins interact with multiple proteins including the mammalian E coli MutL homologues (MLH) and yeast post-meiotic segregation (PMS) homologue proteins (which have significant amino acid identify and structural similarity to the MLH proteins), as well as RPA, EXO1, RFC, HMGB1, POLDC and other proteins [1],[8],[11],[12]. MLH1-PMS2 is the primary MutL complex that interacts with both MSH2/6 and MSH3 complexes. MLH1–MLH3 is less well characterized, but is believed to participate in IDL repair [13],[14], DNA damage response [13], and possibly single-base point mutation repair (SBR)[15]. MLH1-PMS1 exists in mammalian cells but currently has no clearly defined roles in processes related to cancer prevention [16],[17].
++Colorectal cancer (CRC) is one of the common malignancies in industrialized countries. Lynch syndrome, a highly penetrant disorder that confers predisposition to cancer of the colorectum, endometrium and other extra-colonic sites [1], is caused by germline mutations in DNA Mismatch Repair genes (MMR). Including sporadic forms, defective MMR underlies ∼12–15% of CRC [2]. MMR plays critical roles in the maintenance of genomic stability in both prokaryotes and eukaryotes [3]. The study of model organisms has yielded great insights into the mechanisms through which MMR prevents cancer [1],[3],[4],[5],[6],[7],[8]. Briefly, there are nine mammalian MMR genes (MLH1, MLH3, PMS1-2, MSH2-6). The mammalian E coli MutS homologues (MSH) directly contact DNA, scanning along the genomic DNA for mismatches analogous to a “sliding clamp? until they encounter a base-pair containing a mismatch [9],[10]. MSH2-MSH6 primarily recognizes single-base substitutions and 1 base-pair insertion-deletion loop (IDL) mutations, while MSH2-MSH3 recognizes 1–4 base-pair insertion-deletion mutations [1],[3].The IDL repair deficiency is commonly referred to as Microsatellite Instability (MSI). The MSH proteins interact with multiple proteins including the mammalian E coli MutL homologues (MLH) and yeast post-meiotic segregation (PMS) homologue proteins (which have significant amino acid identify and structural similarity to the MLH proteins), as well as RPA, EXO1, RFC, HMGB1, POLDC and other proteins [1],[8],[11],[12]. MLH1-PMS2 is the primary MutL complex that interacts with both MSH2/6 and MSH3 complexes. MLH1–MLH3 is less well characterized, but is believed to participate in IDL repair [13],[14], DNA damage response [13], and possibly single-base point mutation repair (SBR)[15]. MLH1-PMS1 exists in mammalian cells but currently has no clearly defined roles in processes related to cancer prevention [16],[17].
+ 
+ To study the precise mechanisms through which MMR suppresses carcinogenesis in vivo, we and others [16],[18],[19],[20],[21],[22],[23],[24] previously developed several mouse models carrying mutations in different MMR genes. Mlh1−/− and Msh2−/− mice develop early onset GI epithelial cancers, lymphomas and other types of cancer. Pms2−/− mice develop lymphomas, but not GI epithelial cancers. Mlh3−/− mice develop GI and extra-GI tumors, have decreased survival when compared with Wt mice, but with later onset than Mlh1−/− [13]. Mlh3−/−;Pms2−/− mice have increased cancer incidence, resistance to apoptosis and MSI [13]. However, the precise mechanisms in which Mlh3 and Pms2 participate to suppress GI epithelial tumorigenesis and progression remain poorly characterized.
+ 
+@@ -865,7 +865,7 @@
+ 
+ Tle6-like and TLE6D Enhance Cell Proliferation, Colony Formation, and Cell Migration.
+ 
+-(A) HCT116 Cell proliferation MTT assay. (B) Representative picture of plates of colony formation assay on MEFs transfected with vector, TLE6D, and Tle6-like. (C) Plot of number of colonies from colony formation assay. (D) In Vitro Cell Mobility Assay. “Wound�? was generated by razor blade, clearing the adherent cells on the right side of the slides. Black lines indicate the edge of the “wound�?. Representative pictures from HCT116 cells transfected with vector, TLE6D, and Tle6-like are shown.
++(A) HCT116 Cell proliferation MTT assay. (B) Representative picture of plates of colony formation assay on MEFs transfected with vector, TLE6D, and Tle6-like. (C) Plot of number of colonies from colony formation assay. (D) In Vitro Cell Mobility Assay. “Wound? was generated by razor blade, clearing the adherent cells on the right side of the slides. Black lines indicate the edge of the “wound?. Representative pictures from HCT116 cells transfected with vector, TLE6D, and Tle6-like are shown.
+ 
+ </text><annotation id="T29"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="317" length="5"></location><text>RUNX3</text></annotation><annotation id="T28"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2556" length="5"></location><text>TLE6D</text></annotation><annotation id="T27"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="141" length="5"></location><text>TLE6D</text></annotation><annotation id="T26"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2567" length="9"></location><text>Tle6-like</text></annotation><annotation id="T25"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="54" length="5"></location><text>TLE6D</text></annotation><annotation id="T24"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="307" length="5"></location><text>TLE6D</text></annotation><annotation id="T23"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="151" length="5"></location><text>RUNX3</text></annotation><annotation id="T22"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1210" length="5"></location><text>TLE6D</text></annotation><annotation id="T21"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1196" length="9"></location><text>Tle6-like</text></annotation><annotation id="T20"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1180" length="5"></location><text>TLE6D</text></annotation><annotation id="T38"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2324" length="5"></location><text>TLE6D</text></annotation><annotation id="T37"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2314" length="6"></location><text>Tle6sh</text></annotation><annotation id="T39"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="113" length="7"></location><text>cancers</text></annotation><annotation id="T34"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1875" length="9"></location><text>Tle6-like</text></annotation><annotation id="T33"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2051" length="9"></location><text>Tle6-like</text></annotation><annotation id="T36"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2346" length="5"></location><text>TLE6D</text></annotation><annotation id="T35"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2332" length="9"></location><text>Tle6-like</text></annotation><annotation id="T30"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="431" length="5"></location><text>RUNX3</text></annotation><annotation id="T32"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2064" length="5"></location><text>TLE6D</text></annotation><annotation id="T31"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="2291" length="5"></location><text>tumor</text></annotation><annotation id="T6"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="995" length="4"></location><text>mice</text></annotation><annotation id="T7"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="992" length="2"></location><text>MA</text></annotation><annotation id="T49"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="815" length="9"></location><text>Tle6-like</text></annotation><annotation id="T4"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1042" length="9"></location><text>Tle6-like</text></annotation><annotation id="T5"><infon key="file">ann</infon><infon key="type">Phenomena</infon><location offset="940" length="34"></location><text>increased number of adenocarcinoma</text></annotation><annotation id="T48"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="699" length="5"></location><text>RUNX3</text></annotation><annotation id="T8"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="980" length="3"></location><text>Apc</text></annotation><annotation id="T9"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="983" length="5"></location><text>1638N</text></annotation><annotation id="T43"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="102" length="10"></location><text>colorectal</text></annotation><annotation id="T42"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="64" length="5"></location><text>RUNX3</text></annotation><annotation id="T41"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="102" length="18"></location><text>colorectal cancers</text></annotation><annotation id="T40"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2884" length="5"></location><text>TLE6D</text></annotation><annotation id="T47"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="758" length="5"></location><text>TLE6D</text></annotation><annotation id="T46"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="532" length="5"></location><text>TLE6D</text></annotation><annotation id="T45"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="523" length="5"></location><text>RUNX3</text></annotation><annotation id="T44"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="440" length="5"></location><text>TLE6D</text></annotation><annotation id="T50"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="829" length="5"></location><text>TLE6D</text></annotation><annotation id="T1"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="258" length="6"></location><text>normal</text></annotation><annotation id="T3"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="1095" length="5"></location><text>tumor</text></annotation><annotation id="T2"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1167" length="9"></location><text>Tle6-like</text></annotation><annotation id="T10"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="960" length="14"></location><text>adenocarcinoma</text></annotation><annotation id="T11"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="928" length="4"></location><text>mice</text></annotation><annotation id="T12"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="265" length="15"></location><text>adjacent mucosa</text></annotation><annotation id="T13"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1811" length="5"></location><text>TLE6D</text></annotation><annotation id="T14"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1801" length="9"></location><text>Tle6-like</text></annotation><annotation id="T52"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="909" length="2"></location><text>GI</text></annotation><annotation id="T15"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1888" length="5"></location><text>TLE6D</text></annotation><annotation id="T51"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2895" length="9"></location><text>Tle6-like</text></annotation><annotation id="T16"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1469" length="4"></location><text>TLE6</text></annotation><annotation id="T54"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="924" length="3"></location><text>MPA</text></annotation><annotation id="T17"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1459" length="9"></location><text>Tle6-like</text></annotation><annotation id="T53"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="912" length="6"></location><text>tumors</text></annotation><annotation id="T18"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1585" length="5"></location><text>TLE6D</text></annotation><annotation id="T19"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1572" length="9"></location><text>Tle6-like</text></annotation><relation id="R8"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T5" role="Arg1"></node><node refid="T10" role="Arg2"></node></relation><relation id="R9"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T43" role="Arg1"></node><node refid="T39" role="Arg2"></node></relation><relation id="R6"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T12" role="Arg1"></node><node refid="T1" role="Arg2"></node></relation><relation id="R7"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T11" role="Arg1"></node><node refid="T53" role="Arg2"></node></relation><relation id="R4"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T6" role="Arg1"></node><node refid="T7" role="Arg2"></node></relation><relation id="R5"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T52" role="Arg1"></node><node refid="T53" role="Arg2"></node></relation><relation id="R2"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T11" role="Arg1"></node><node refid="T54" role="Arg2"></node></relation><relation id="R3"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T5" role="Arg1"></node><node refid="T11" role="Arg2"></node></relation><relation id="R1"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T6" role="Arg1"></node><node refid="T9" role="Arg2"></node></relation><relation id="R10"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T8" role="Arg1"></node><node refid="T9" role="Arg2"></node></relation></passage></document><document><id>2438340-04-Results-p03</id><passage><offset>0</offset><text>** IGNORE LINE **
+ ** IGNORE LINE **
+@@ -897,7 +897,7 @@
+ 
+ (A) Large-scale sequencing of breast and colon cancers identified 189 CAN genes as reported by Sjoblom et al. [7]. Candidate hypermethylated genes were identified via expression microarray analysis as described in the text. The cell lines used in the analyses were the breast cancer lines MCF7, MDA-MB-231, MDA-MB-468, and T-47D; and the colon cancer lines SW480, RKO, HCT116, Caco-2, Colo320, and HT-29. Filters were used as discussed in the text. Genes without promoter CpG islands were excluded.
+ 
+-(B) Frequency of promoter methylation in the 36 CAN genes that are subject to hypermethylation. x-Axis denotes percent methylation. Methylation status was determined in the six colorectal cancer cell lines and in the 15 breast cancer lines described in the text (four lines used for microarray analysis plus 11 “Discovery Phase�? breast cancer lines).
++(B) Frequency of promoter methylation in the 36 CAN genes that are subject to hypermethylation. x-Axis denotes percent methylation. Methylation status was determined in the six colorectal cancer cell lines and in the 15 breast cancer lines described in the text (four lines used for microarray analysis plus 11 “Discovery Phase? breast cancer lines).
+ 
+ We next analyzed in the laboratory, using MSP [23] and RT-PCR, the DNA methylation and expression status of the above 56 genes, including the response of the latter to treatment of cells with DAC, in four breast cancer cell lines (MCF7, MDA-MB-231, MDA-MB-468, and T-47D) and six colorectal cancer (CRC) cell lines (SW480, RKO, HCT116, Caco-2, Colo320, and HT-29). Importantly, we also focused, additionally, on the exact 11 breast cancer lines used in the large-scale sequence analysis reported by Sjoblom et al. to identify the CAN genes (HCC38, HCC1954, HCC1008, HCC1143, HCC1187, HCC1395, HCC1937, HCC2218, HCC2157, Hs578T, and HCC1599). Thirty-six of the genes were found to be hypermethylated in the original breast and colon cancer cell lines in which they were identified as candidates and in the 11 breast cancer lines in which the original CAN gene mutations were found (Figure 1B, Table 1). RT-PCR analysis demonstrated markedly reduced or no expression accompanying this hypermethylated state and re-expression after DAC treatment (examples in Figures 2 and 3 and summarized in Table S1).
+ 
+@@ -974,7 +974,7 @@
+ 
+ One of the main hopes of comprehensively cataloging cancer mutations is that doing so may provide novel biomarkers and knowledge of genes involved in key pathways in oncogenesis. To this end, we first determined whether cancer-specific methylation of the common target genes would correlate in any way with tumor stage or grade. We determined this, first, by directly analyzing the methylation state of breast cancers of varying stages (1–4) and grades (1–3). We found that SYNE1 and COL7A1 are preferentially methylated in advanced tumors and PTPRD, SYNE1, and EVL are preferentially hypermethylated in high-grade tumors (Figure 9). For example, in stage 1 and 2 tumors, SYNE1 is silenced 8% (1/12) of the time whereas in stage 3 and 4 tumors, the frequency of silencing is 50% (6/12). This is consistent with a role during tumor progression or during initiation of tumors predestined to evolve aggressive clinical behavior.
+ 
+-Hypermethylation of Selected “Common Target�? Genes Predict for Poor Clinical Prognosis
++Hypermethylation of Selected “Common Target? Genes Predict for Poor Clinical Prognosis
+ 
+ Hypermethylation of selected common target genes by grade and stage in primary breast tumors. The first graph shows the frequency of methylation of at least one of the three genes listed in low- versus high-grade breast tumors. The second (SYNE1) and third (COL7A1) graphs show the frequency of methylation of the indicated genes in different stages of breast cancer. p-Values are adjusted using the Holm method.
+ 
+@@ -1147,7 +1147,7 @@
+ </text><annotation id="T6"><infon key="file">ann</infon><infon key="type">age</infon><location offset="680" length="5"></location><text>young</text></annotation><annotation id="T7"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="523" length="8"></location><text>patients</text></annotation><annotation id="T4"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="995" length="8"></location><text>carriers</text></annotation><annotation id="T5"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="864" length="14"></location><text>Lynch syndrome</text></annotation><annotation id="T27"><infon key="file">ann</infon><infon key="type">Disorder</infon><location offset="745" length="23"></location><text>positive family history</text></annotation><annotation id="T8"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="814" length="5"></location><text>cases</text></annotation><annotation id="T26"><infon key="file">ann</infon><infon key="type">size</infon><location offset="341" length="2"></location><text>15</text></annotation><annotation id="T9"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="353" length="14"></location><text>family members</text></annotation><annotation id="T25"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="122" length="19"></location><text>Germ line mutations</text></annotation><annotation id="T24"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="244" length="12"></location><text>malignancies</text></annotation><annotation id="T23"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="230" length="9"></location><text>carcinoma</text></annotation><annotation id="T22"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="219" length="10"></location><text>colorectal</text></annotation><annotation id="T21"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="287" length="4"></location><text>Case</text></annotation><annotation id="T20"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="1105" length="6"></location><text>family</text></annotation><annotation id="T1"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="482" length="14"></location><text>tumor syndrome</text></annotation><annotation id="T3"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="329" length="6"></location><text>family</text></annotation><annotation id="T2"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="344" length="8"></location><text>affected</text></annotation><annotation id="T10"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="555" length="14"></location><text>family members</text></annotation><annotation id="T11"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="206" length="8"></location><text>carriers</text></annotation><annotation id="T12"><infon key="file">ann</infon><infon key="type">Disorder</infon><location offset="704" length="34"></location><text>multiple tumors in multiple organs</text></annotation><annotation id="T13"><infon key="file">ann</infon><infon key="type">Concepts_Ideas</infon><location offset="471" length="10"></location><text>hereditary</text></annotation><annotation id="T14"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="145" length="21"></location><text>mismatch repair genes</text></annotation><annotation id="T15"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="54" length="14"></location><text>Lynch syndrome</text></annotation><annotation id="T16"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="314" length="14"></location><text>Lynch syndrome</text></annotation><annotation id="T17"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="176" length="14"></location><text>Lynch syndrome</text></annotation><annotation id="T18"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="713" length="6"></location><text>tumors</text></annotation><annotation id="T19"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="754" length="6"></location><text>family</text></annotation><relation id="R8"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T9" role="Arg1"></node><node refid="T26" role="Arg2"></node></relation><relation id="R9"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T3" role="Arg1"></node><node refid="T16" role="Arg2"></node></relation><relation id="R6"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T9" role="Arg1"></node><node refid="T2" role="Arg2"></node></relation><relation id="R7"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T9" role="Arg1"></node><node refid="T16" role="Arg2"></node></relation><relation id="R4"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T22" role="Arg1"></node><node refid="T24" role="Arg2"></node></relation><relation id="R5"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T22" role="Arg1"></node><node refid="T23" role="Arg2"></node></relation><relation id="R2"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T12" role="Arg1"></node><node refid="T18" role="Arg2"></node></relation><relation id="R3"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T14" role="Arg1"></node><node refid="T25" role="Arg2"></node></relation><relation id="R1"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T27" role="Arg1"></node><node refid="T19" role="Arg2"></node></relation><relation id="R11"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T17" role="Arg1"></node><node refid="T25" role="Arg2"></node></relation><relation id="R10"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T13" role="Arg1"></node><node refid="T1" role="Arg2"></node></relation></passage></document><document><id>2429944-04-Results-p08</id><passage><offset>0</offset><text>** IGNORE LINE **
+ ** IGNORE LINE **
+ ** IGNORE LINE **
+-Decreased Expression of Selected “Common Target�? Genes Predict for Poor Clinical Prognosis
++Decreased Expression of Selected “Common Target? Genes Predict for Poor Clinical Prognosis
+ 
+ Box-plots showing decreased expression of candidate genes correlate with unfavorable clinical features. The y-axis represents normalized expression. Shaded boxes represent the interquartile range (25th–75th percentile). Whiskers represent the 10th–90th percentile. The bars denote the median.
+ 
+@@ -1394,7 +1394,7 @@
+ </text><annotation id="T6"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2489" length="17"></location><text>liability classes</text></annotation><annotation id="T7"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="1682" length="4"></location><text>SNPs</text></annotation><annotation id="T4"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2326" length="17"></location><text>liability classes</text></annotation><annotation id="T10"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="758" length="6"></location><text>family</text></annotation><annotation id="T5"><infon key="file">ann</infon><infon key="type">size</infon><location offset="1679" length="2"></location><text>18</text></annotation><annotation id="T11"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="152" length="8"></location><text>families</text></annotation><annotation id="T8"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2663" length="17"></location><text>liability classes</text></annotation><annotation id="T9"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2538" length="4"></location><text>MLH1</text></annotation><annotation id="T1"><infon key="file">ann</infon><infon key="type">size</infon><location offset="1013" length="17"></location><text>1256 of the 10053</text></annotation><annotation id="T3"><infon key="file">ann</infon><infon key="type">size</infon><location offset="1688" length="5"></location><text>0.21%</text></annotation><annotation id="T2"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="1031" length="4"></location><text>SNPs</text></annotation><relation id="R2"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T2" role="Arg1"></node><node refid="T1" role="Arg2"></node></relation><relation id="R3"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T7" role="Arg1"></node><node refid="T5" role="Arg2"></node></relation><relation id="R1"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T7" role="Arg1"></node><node refid="T3" role="Arg2"></node></relation></passage></document><document><id>2429944-05-Discussion-p02</id><passage><offset>0</offset><text>** IGNORE LINE **
+ ** IGNORE LINE **
+ ** IGNORE LINE **
+-Second, our results suggest that tumors may be less biologically heterogeneous with respect to denoting key tumor suppressor pathway disruptions when consideration is given to both genetic and epigenetic changes. To our knowledge, this study represents the most comprehensive analysis of genes targeted by both mutation and hypermethylation. Prior to the present study, only a small number of genes had been found to be frequently affected by both mutations and promoter hypermethylation. Most of these genes were the initial classic tumor suppressor genes where the epigenetic event was first defined as meaningfully functional. These genes are closely linked to cancer initiation and include those for which germ-line mutations occur, such as VHL, BRCA1, and STK11 in familial forms of renal, breast, and colon cancer, respectively [10,52,53]. These tumor suppressors are frequently hypermethylated in sporadic forms of the corresponding tumor types [54–56]. Furthermore, methylation-associated silencing can act as a “second genetic hit�? in these genes in tumors from individuals harboring germline mutations, resulting in functional LOH [57]. Our current findings now indicate that, particularly for tumor suppressor genes with a low incidence of mutations, it may be the rule rather than the exception that epigenetic inactivation is a more frequent event than genetic disruption. Tumor suppressors that are important for tumorigenesis may, then, often be targeted by multiple methods of functional inactivation.
++Second, our results suggest that tumors may be less biologically heterogeneous with respect to denoting key tumor suppressor pathway disruptions when consideration is given to both genetic and epigenetic changes. To our knowledge, this study represents the most comprehensive analysis of genes targeted by both mutation and hypermethylation. Prior to the present study, only a small number of genes had been found to be frequently affected by both mutations and promoter hypermethylation. Most of these genes were the initial classic tumor suppressor genes where the epigenetic event was first defined as meaningfully functional. These genes are closely linked to cancer initiation and include those for which germ-line mutations occur, such as VHL, BRCA1, and STK11 in familial forms of renal, breast, and colon cancer, respectively [10,52,53]. These tumor suppressors are frequently hypermethylated in sporadic forms of the corresponding tumor types [54–56]. Furthermore, methylation-associated silencing can act as a “second genetic hit? in these genes in tumors from individuals harboring germline mutations, resulting in functional LOH [57]. Our current findings now indicate that, particularly for tumor suppressor genes with a low incidence of mutations, it may be the rule rather than the exception that epigenetic inactivation is a more frequent event than genetic disruption. Tumor suppressors that are important for tumorigenesis may, then, often be targeted by multiple methods of functional inactivation.
+ 
+ A third important conclusion is that there may be more similarity among individual breast and colon tumors than is apparent from analysis of the mutational spectrum only, and, therefore, any comparison of biological changes between tumors may need to account for epigenetic effects in addition to genetic ones. Clearly, the same tumor suppressor genes in different cancers may undergo different modes of inactivation. This scenario is analogous to the situation that is observed for oncogenes such as MYC. In hematopoietic malignancies, aberrant activation of MYC results frequently from translocations whereas the gene is more often subject to amplifications and mutations in solid tumors [58,59]. The processes underlying these differences are fundamentally important for understanding cancer and are worthy of future study.
+ 
+@@ -2028,13 +2028,13 @@
+ 
+ Cancer is one of the developed world's biggest killers—over half a million Americans die of cancer each year, for instance. As a result, there is great interest in understanding the genetic and environmental causes of cancer in order to improve cancer prevention, diagnosis, and treatment.
+ 
+-Cancer begins when cells begin to multiply out of control. DNA is the sequence of coded instructions—genes—for how to build and maintain the body. Certain “tumor suppressor�? genes, for instance, help to prevent cancer by preventing tumors from developing, but changes that alter the DNA code sequence—mutations—can profoundly affect how a gene works. Modern techniques of genetic analysis have identified genes such as tumor suppressors that, when mutated, are linked to the development of certain cancers.
++Cancer begins when cells begin to multiply out of control. DNA is the sequence of coded instructions—genes—for how to build and maintain the body. Certain “tumor suppressor? genes, for instance, help to prevent cancer by preventing tumors from developing, but changes that alter the DNA code sequence—mutations—can profoundly affect how a gene works. Modern techniques of genetic analysis have identified genes such as tumor suppressors that, when mutated, are linked to the development of certain cancers.
+ 
+ Why Was This Study Done?
+ 
+-However, in recent years, it has become increasingly apparent that mutations are neither necessary nor sufficient to explain every case of cancer. This has led researchers to look at so-called epigenetic factors, which also alter how a gene works without altering its DNA sequence. An example of this is “methylation,�? which prevents a gene from being expressed—deactivates it—by a chemical tag. Methylation of genes is part of the normal functioning of DNA, but abnormal methylation has been linked with cancer, aging, and some rare birth abnormalities.
++However, in recent years, it has become increasingly apparent that mutations are neither necessary nor sufficient to explain every case of cancer. This has led researchers to look at so-called epigenetic factors, which also alter how a gene works without altering its DNA sequence. An example of this is “methylation,? which prevents a gene from being expressed—deactivates it—by a chemical tag. Methylation of genes is part of the normal functioning of DNA, but abnormal methylation has been linked with cancer, aging, and some rare birth abnormalities.
+ 
+-Previous analysis of DNA from breast and colon cancer cells had revealed 189 “candidate cancer genes�?—mutated genes that were linked to the development of breast and colon cancer. However, it was not clear how those mutations gave rise to cancer, and individual mutations were present in only 5% to 15% of specific tumors. The authors of this study wanted to know whether epigenetic factors such as methylation contributed to causing the cancers.
++Previous analysis of DNA from breast and colon cancer cells had revealed 189 “candidate cancer genes?—mutated genes that were linked to the development of breast and colon cancer. However, it was not clear how those mutations gave rise to cancer, and individual mutations were present in only 5% to 15% of specific tumors. The authors of this study wanted to know whether epigenetic factors such as methylation contributed to causing the cancers.
+ 
+ What Did the Researchers Do and Find?
+ 
+@@ -2072,7 +2072,7 @@
+ 
+ We next examined whether decreased expression of the genes undergoing cancer-specific silencing correlated with the key clinical characteristics noted in Figure 10. The finding of decreased expression levels of seven genes is associated with unfavorable clinical characteristics in either breast, colon cancer, or both. Importantly, these genes included the four genes, SYNE 1, COL7A1, PTPRD, and EVL, for which, in the studies described in Figure 9, we found relationships between stage and grade in the studies from our own tumor samples at Johns Hopkins Hospital. Figures 11–13 show plots of normalized expression values for selected genes across multiple tumors with the indicated characteristics. Importantly, decreased expression of five of the six genes predicted for decreased disease-free or overall survival in these cancers as well as other poor prognosis features such as high grade (Figure 10). These relationships are highlighted by the fact that, when we also analyzed a number of CAN genes that we directly determined to not have altered methylation expression levels in breast or colon cancers (including GGA1, PTPN14, ABCB8, OTOF, SIX4, SLCO1B3, and HIST1H1B), the clinical endpoints we mentioned above were not associated with decreased expression of any of these genes.
+ 
+-Decreased Expression of Hypermethylated “Common Target�? Genes Predict for Poor Clinical Prognosis
++Decreased Expression of Hypermethylated “Common Target? Genes Predict for Poor Clinical Prognosis
+ 
+ Summary of results from analysis of expression microarray data. p-Values from representative analyses for specific genes are shown. Blue indicates that a decrease in expression of the indicated gene is significantly associated with the following: overall survival or disease-specific survival less than 5 y, metastasis versus primary tumor, and/or increased grade or invasiveness. The p-value was calculated using the Student's t-test with adjustment for multiple testing as described previously [21].
+ 
+@@ -2164,7 +2164,7 @@
+ ** IGNORE LINE **
+ In Vitro Cell Mobility Assay
+ 
+-The monolayer “wounding assay�? was used to demonstrate the in vitro cell migration. Human colon cancer HCT116 cells stably expressing corresponding plasmids were plated on glass microscopy slides and cultured to confluence. A “wound�? was generated by scratching the slide with a razor blade, clearing a portion of adherent cells on the slide. Photo documentation was taken at day 4 and the migration of cells from the cut edge of the monolayer into the clear portion of the slides was assessed. Two independently-derived stable cell lines for each plasmid were used in this assay.
++The monolayer “wounding assay? was used to demonstrate the in vitro cell migration. Human colon cancer HCT116 cells stably expressing corresponding plasmids were plated on glass microscopy slides and cultured to confluence. A “wound? was generated by scratching the slide with a razor blade, clearing a portion of adherent cells on the slide. Photo documentation was taken at day 4 and the migration of cells from the cut edge of the monolayer into the clear portion of the slides was assessed. Two independently-derived stable cell lines for each plasmid were used in this assay.
+ 
+ Antibodies, Immunoprecipitation, and Immunoblotting
+ 
+@@ -2633,7 +2633,7 @@
+ 
+ Author Summary
+ 
+-Inherited mutations in the genes BRCA1 and BRCA2 increase risk of breast cancer and contribute to a proportion of breast cancer families. However, more than half of the reported sequence alterations in BRCA1 and BRCA2 are currently of unknown clinical significance. We analysed gene expression in lymphoblastoid cell lines derived from blood of patients with sequence alterations in BRCA1 and BRCA2 and compared these to lymphoblastoid cells from familial breast cancer patients without such alterations. We then classified these lymphoblastoid cells based on their gene profiles. We found that BRCA1 and BRCA2 samples were more similar to each other than to familial breast cancer patients without BRCA1/2 mutations, and that the type of sequence change in BRCA1 and BRCA2 (missense or truncating) influenced gene expression. We included in the study ten familial breast cancer samples, which carried sequence changes in BRCA1 or BRCA2, that are believed to be of little clinical significance. Interestingly these samples were distinct from other familial breast cancer cases without any sequence alteration in BRCA1 or BRCA2, indicating that further work needs to be performed to determine the possible association of these “low clinical significance�? sequence changes with a low to moderate risk of cancer.
++Inherited mutations in the genes BRCA1 and BRCA2 increase risk of breast cancer and contribute to a proportion of breast cancer families. However, more than half of the reported sequence alterations in BRCA1 and BRCA2 are currently of unknown clinical significance. We analysed gene expression in lymphoblastoid cell lines derived from blood of patients with sequence alterations in BRCA1 and BRCA2 and compared these to lymphoblastoid cells from familial breast cancer patients without such alterations. We then classified these lymphoblastoid cells based on their gene profiles. We found that BRCA1 and BRCA2 samples were more similar to each other than to familial breast cancer patients without BRCA1/2 mutations, and that the type of sequence change in BRCA1 and BRCA2 (missense or truncating) influenced gene expression. We included in the study ten familial breast cancer samples, which carried sequence changes in BRCA1 or BRCA2, that are believed to be of little clinical significance. Interestingly these samples were distinct from other familial breast cancer cases without any sequence alteration in BRCA1 or BRCA2, indicating that further work needs to be performed to determine the possible association of these “low clinical significance? sequence changes with a low to moderate risk of cancer.
+ 
+ </text><annotation id="T29"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="1130" length="8"></location><text>carriers</text></annotation><annotation id="T28"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="745" length="5"></location><text>BRCAX</text></annotation><annotation id="T27"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="871" length="8"></location><text>mutation</text></annotation><annotation id="T26"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="3210" length="16"></location><text>sequence changes</text></annotation><annotation id="T25"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="993" length="5"></location><text>BRCAX</text></annotation><annotation id="T24"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="2292" length="5"></location><text>blood</text></annotation><annotation id="T23"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="551" length="8"></location><text>affected</text></annotation><annotation id="T22"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="507" length="9"></location><text>mutations</text></annotation><annotation id="T21"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="518" length="5"></location><text>BRCAX</text></annotation><annotation id="T20"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="501" length="5"></location><text>BRCA2</text></annotation><annotation id="T38"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="776" length="7"></location><text>BRCA1/2</text></annotation><annotation id="T37"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="784" length="17"></location><text>sequence variants</text></annotation><annotation id="T39"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1042" length="5"></location><text>BRCAX</text></annotation><annotation id="T34"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="1493" length="7"></location><text>samples</text></annotation><annotation id="T33"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="711" length="5"></location><text>BRCAX</text></annotation><annotation id="T36"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="855" length="5"></location><text>BRCA1</text></annotation><annotation id="T35"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="865" length="5"></location><text>BRCA2</text></annotation><annotation id="T30"><infon key="file">ann</infon><infon key="type">size</infon><location offset="742" length="2"></location><text>10</text></annotation><annotation id="T32"><infon key="file">ann</infon><infon key="type">size</infon><location offset="708" length="2"></location><text>27</text></annotation><annotation id="T31"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="2486" length="20"></location><text>lymphoblastoid cells</text></annotation><annotation id="T49"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1113" length="7"></location><text>BRCA1/2</text></annotation><annotation id="T48"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="1121" length="8"></location><text>mutation</text></annotation><annotation id="T100"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="717" length="11"></location><text>individuals</text></annotation><annotation id="T43"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="1360" length="8"></location><text>missense</text></annotation><annotation id="T42"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2134" length="20"></location><text>sequence alterations</text></annotation><annotation id="T102"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="999" length="11"></location><text>individuals</text></annotation><annotation id="T41"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="226" length="8"></location><text>missense</text></annotation><annotation id="T101"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="751" length="11"></location><text>individuals</text></annotation><annotation id="T40"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="949" length="17"></location><text>missense mutation</text></annotation><annotation id="T47"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="967" length="8"></location><text>carriers</text></annotation><annotation id="T46"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="880" length="8"></location><text>carriers</text></annotation><annotation id="T45"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="1369" length="8"></location><text>carriers</text></annotation><annotation id="T44"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="1616" length="8"></location><text>carriers</text></annotation><annotation id="T109"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="524" length="5"></location><text>cases</text></annotation><annotation id="T107"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="448" length="5"></location><text>cases</text></annotation><annotation id="T108"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2714" length="5"></location><text>BRCA1</text></annotation><annotation id="T105"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="1048" length="11"></location><text>individuals</text></annotation><annotation id="T106"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2724" length="5"></location><text>BRCA2</text></annotation><annotation id="T103"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2647" length="25"></location><text>without BRCA1/2 mutations</text></annotation><annotation id="T104"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2655" length="7"></location><text>BRCA1/2</text></annotation><annotation id="T50"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1178" length="5"></location><text>BRCA1</text></annotation><annotation id="T59"><infon key="file">ann</infon><infon key="type">Concepts_Ideas</infon><location offset="2615" length="8"></location><text>familial</text></annotation><annotation id="T52"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1487" length="5"></location><text>BRCAX</text></annotation><annotation id="T51"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1185" length="5"></location><text>BRCA2</text></annotation><annotation id="T54"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2561" length="5"></location><text>BRCA2</text></annotation><annotation id="T110"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="3027" length="5"></location><text>cases</text></annotation><annotation id="T53"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2551" length="5"></location><text>BRCA1</text></annotation><annotation id="T56"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="2412" length="6"></location><text>breast</text></annotation><annotation id="T55"><infon key="file">ann</infon><infon key="type">Concepts_Ideas</infon><location offset="2403" length="8"></location><text>familial</text></annotation><annotation id="T58"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2567" length="7"></location><text>samples</text></annotation><annotation id="T57"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="2624" length="6"></location><text>breast</text></annotation><annotation id="T75"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3068" length="5"></location><text>BRCA1</text></annotation><annotation id="T76"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3077" length="5"></location><text>BRCA2</text></annotation><annotation id="T73"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="3258" length="6"></location><text>cancer</text></annotation><annotation id="T74"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="560" length="5"></location><text>women</text></annotation><annotation id="T79"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="2412" length="13"></location><text>breast cancer</text></annotation><annotation id="T77"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="2821" length="13"></location><text>breast cancer</text></annotation><annotation id="T78"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="3013" length="13"></location><text>breast cancer</text></annotation><annotation id="T72"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1599" length="7"></location><text>BRCA1/2</text></annotation><annotation id="T71"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="1607" length="8"></location><text>mutation</text></annotation><annotation id="T70"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2168" length="5"></location><text>BRCA2</text></annotation><annotation id="T62"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2339" length="5"></location><text>BRCA1</text></annotation><annotation id="T63"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="1835" length="6"></location><text>cancer</text></annotation><annotation id="T64"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="1966" length="9"></location><text>mutations</text></annotation><annotation id="T65"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1989" length="5"></location><text>BRCA1</text></annotation><annotation id="T66"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1999" length="5"></location><text>BRCA2</text></annotation><annotation id="T67"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="2022" length="6"></location><text>breast</text></annotation><annotation id="T68"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="2070" length="6"></location><text>breast</text></annotation><annotation id="T69"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2158" length="5"></location><text>BRCA1</text></annotation><annotation id="T61"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2349" length="5"></location><text>BRCA2</text></annotation><annotation id="T60"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2315" length="20"></location><text>sequence alterations</text></annotation><annotation id="T99"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2638" length="8"></location><text>patients</text></annotation><annotation id="T97"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2301" length="8"></location><text>patients</text></annotation><annotation id="T98"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2426" length="8"></location><text>patients</text></annotation><annotation id="T95"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="2070" length="13"></location><text>breast cancer</text></annotation><annotation id="T96"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="2022" length="13"></location><text>breast cancer</text></annotation><annotation id="T6"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="353" length="5"></location><text>BRCA1</text></annotation><annotation id="T7"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="586" length="7"></location><text>ovarian</text></annotation><annotation id="T4"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="379" length="32"></location><text>truncating and missense mutation</text></annotation><annotation id="T5"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="362" length="5"></location><text>BRCA2</text></annotation><annotation id="T8"><infon key="file">ann</infon><infon key="type">gender</infon><location offset="560" length="5"></location><text>women</text></annotation><annotation id="T9"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2084" length="8"></location><text>families</text></annotation><annotation id="T94"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="434" length="13"></location><text>breast cancer</text></annotation><annotation id="T93"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2835" length="7"></location><text>samples</text></annotation><annotation id="T92"><infon key="file">ann</infon><infon key="type">Concepts_Ideas</infon><location offset="2812" length="8"></location><text>familial</text></annotation><annotation id="T91"><infon key="file">ann</infon><infon key="type">size</infon><location offset="2808" length="3"></location><text>ten</text></annotation><annotation id="T90"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2731" length="22"></location><text>missense or truncating</text></annotation><annotation id="T88"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="2821" length="6"></location><text>breast</text></annotation><annotation id="T89"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2878" length="5"></location><text>BRCA1</text></annotation><annotation id="T84"><infon key="file">ann</infon><infon key="type">Concepts_Ideas</infon><location offset="3004" length="8"></location><text>familial</text></annotation><annotation id="T85"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2971" length="7"></location><text>samples</text></annotation><annotation id="T86"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2858" length="16"></location><text>sequence changes</text></annotation><annotation id="T87"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2887" length="5"></location><text>BRCA2</text></annotation><annotation id="T1"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="492" length="5"></location><text>BRCA1</text></annotation><annotation id="T3"><infon key="file">ann</infon><infon key="type">Concepts_Ideas</infon><location offset="425" length="8"></location><text>familial</text></annotation><annotation id="T2"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="434" length="6"></location><text>breast</text></annotation><annotation id="T10"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="594" length="8"></location><text>families</text></annotation><annotation id="T11"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="694" length="8"></location><text>carriers</text></annotation><annotation id="T12"><infon key="file">ann</infon><infon key="type">size</infon><location offset="685" length="2"></location><text>22</text></annotation><annotation id="T13"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="688" length="5"></location><text>BRCA2</text></annotation><annotation id="T14"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="669" length="5"></location><text>BRCA1</text></annotation><annotation id="T15"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="579" length="6"></location><text>breast</text></annotation><annotation id="T81"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="247" length="7"></location><text>disease</text></annotation><annotation id="T16"><infon key="file">ann</infon><infon key="type">size</infon><location offset="666" length="2"></location><text>23</text></annotation><annotation id="T80"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="2624" length="13"></location><text>breast cancer</text></annotation><annotation id="T17"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="732" length="6"></location><text>subset</text></annotation><annotation id="T83"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="3013" length="6"></location><text>breast</text></annotation><annotation id="T18"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="675" length="8"></location><text>carriers</text></annotation><annotation id="T82"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="460" length="7"></location><text>disease</text></annotation><annotation id="T19"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="412" length="8"></location><text>carriers</text></annotation><relation id="R19"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T74" role="Arg1"></node><node refid="T8" role="Arg2"></node></relation><relation id="R17"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T101" role="Arg1"></node><node refid="T28" role="Arg2"></node></relation><relation id="R18"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T19" role="Arg1"></node><node refid="T4" role="Arg2"></node></relation><relation id="R15"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T109" role="Arg1"></node><node refid="T21" role="Arg2"></node></relation><relation id="R16"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T56" role="Arg1"></node><node refid="T79" role="Arg2"></node></relation><relation id="R13"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T106" role="Arg1"></node><node refid="T90" role="Arg2"></node></relation><relation id="R14"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T110" role="Arg1"></node><node refid="T78" role="Arg2"></node></relation><relation id="R11"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T88" role="Arg1"></node><node refid="T77" role="Arg2"></node></relation><relation id="R40"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T70" role="Arg1"></node><node refid="T42" role="Arg2"></node></relation><relation id="R12"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T11" role="Arg1"></node><node refid="T12" role="Arg2"></node></relation><relation id="R41"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T44" role="Arg1"></node><node refid="T71" role="Arg2"></node></relation><relation id="R10"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T55" role="Arg1"></node><node refid="T79" role="Arg2"></node></relation><relation id="R45"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T20" role="Arg1"></node><node refid="T22" role="Arg2"></node></relation><relation id="R8"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T87" role="Arg1"></node><node refid="T86" role="Arg2"></node></relation><relation id="R44"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T45" role="Arg1"></node><node refid="T43" role="Arg2"></node></relation><relation id="R9"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T47" role="Arg1"></node><node refid="T40" role="Arg2"></node></relation><relation id="R43"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T99" role="Arg1"></node><node refid="T80" role="Arg2"></node></relation><relation id="R6"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T36" role="Arg1"></node><node refid="T27" role="Arg2"></node></relation><relation id="R42"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T34" role="Arg1"></node><node refid="T52" role="Arg2"></node></relation><relation id="R7"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T98" role="Arg1"></node><node refid="T79" role="Arg2"></node></relation><relation id="R4"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T57" role="Arg1"></node><node refid="T80" role="Arg2"></node></relation><relation id="R49"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T3" role="Arg1"></node><node refid="T94" role="Arg2"></node></relation><relation id="R48"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T2" role="Arg1"></node><node refid="T94" role="Arg2"></node></relation><relation id="R5"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T92" role="Arg1"></node><node refid="T77" role="Arg2"></node></relation><relation id="R2"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T100" role="Arg1"></node><node refid="T33" role="Arg2"></node></relation><relation id="R47"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T65" role="Arg1"></node><node refid="T64" role="Arg2"></node></relation><relation id="R3"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T83" role="Arg1"></node><node refid="T78" role="Arg2"></node></relation><relation id="R46"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T5" role="Arg1"></node><node refid="T4" role="Arg2"></node></relation><relation id="R1"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T108" role="Arg1"></node><node refid="T90" role="Arg2"></node></relation><relation id="R50"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T66" role="Arg1"></node><node refid="T64" role="Arg2"></node></relation><relation id="R51"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T38" role="Arg1"></node><node refid="T37" role="Arg2"></node></relation><relation id="R52"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T101" role="Arg1"></node><node refid="T37" role="Arg2"></node></relation><relation id="R54"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T72" role="Arg1"></node><node refid="T71" role="Arg2"></node></relation><relation id="R53"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T99" role="Arg1"></node><node refid="T103" role="Arg2"></node></relation><relation id="R56"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T107" role="Arg1"></node><node refid="T94" role="Arg2"></node></relation><relation id="R55"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T35" role="Arg1"></node><node refid="T27" role="Arg2"></node></relation><relation id="R58"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T59" role="Arg1"></node><node refid="T80" role="Arg2"></node></relation><relation id="R57"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T101" role="Arg1"></node><node refid="T30" role="Arg2"></node></relation><relation id="R59"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T104" role="Arg1"></node><node refid="T103" role="Arg2"></node></relation><relation id="R60"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T49" role="Arg1"></node><node refid="T48" role="Arg2"></node></relation><relation id="R27"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T97" role="Arg1"></node><node refid="T60" role="Arg2"></node></relation><relation id="R26"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T67" role="Arg1"></node><node refid="T96" role="Arg2"></node></relation><relation id="R25"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T68" role="Arg1"></node><node refid="T95" role="Arg2"></node></relation><relation id="R24"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T93" role="Arg1"></node><node refid="T86" role="Arg2"></node></relation><relation id="R23"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T61" role="Arg1"></node><node refid="T60" role="Arg2"></node></relation><relation id="R22"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T1" role="Arg1"></node><node refid="T22" role="Arg2"></node></relation><relation id="R21"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T74" role="Arg1"></node><node refid="T23" role="Arg2"></node></relation><relation id="R20"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T18" role="Arg1"></node><node refid="T16" role="Arg2"></node></relation><relation id="R29"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T9" role="Arg1"></node><node refid="T95" role="Arg2"></node></relation><relation id="R28"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T93" role="Arg1"></node><node refid="T91" role="Arg2"></node></relation><relation id="R30"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T62" role="Arg1"></node><node refid="T60" role="Arg2"></node></relation><relation id="R36"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T102" role="Arg1"></node><node refid="T25" role="Arg2"></node></relation><relation id="R35"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T89" role="Arg1"></node><node refid="T86" role="Arg2"></node></relation><relation id="R38"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T29" role="Arg1"></node><node refid="T48" role="Arg2"></node></relation><relation id="R37"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T105" role="Arg1"></node><node refid="T39" role="Arg2"></node></relation><relation id="R32"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T93" role="Arg1"></node><node refid="T77" role="Arg2"></node></relation><relation id="R31"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T84" role="Arg1"></node><node refid="T78" role="Arg2"></node></relation><relation id="R34"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T69" role="Arg1"></node><node refid="T42" role="Arg2"></node></relation><relation id="R33"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T100" role="Arg1"></node><node refid="T32" role="Arg2"></node></relation><relation id="R39"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T6" role="Arg1"></node><node refid="T4" role="Arg2"></node></relation></passage></document><document><id>1619718-03-Materials-and-methods-p01</id><passage><offset>0</offset><text>** IGNORE LINE **
+ ** IGNORE LINE **
+@@ -2974,7 +2974,7 @@
+ 
+ Concomitant Analysis of Genetic and Methylation Events
+ 
+-We next compared the genetic and epigenetic status of the 18 genes directly in the 11 “Discovery Phase�? breast cancer lines in which the mutations for CAN genes were documented by Sjoblom et al. (Figure 7) [7]. Several observations are apparent. First, genes that are mutated in colon cancer but not in breast may instead be hypermethylated in breast cancer and vice versa. Furthermore, while the breast cancer mutations for a given gene are usually found in only one line, hypermethylation of most of the genes occurs in multiple lines for both breast and colon cancers (Figure 7A and 7B).
++We next compared the genetic and epigenetic status of the 18 genes directly in the 11 “Discovery Phase? breast cancer lines in which the mutations for CAN genes were documented by Sjoblom et al. (Figure 7) [7]. Several observations are apparent. First, genes that are mutated in colon cancer but not in breast may instead be hypermethylated in breast cancer and vice versa. Furthermore, while the breast cancer mutations for a given gene are usually found in only one line, hypermethylation of most of the genes occurs in multiple lines for both breast and colon cancers (Figure 7A and 7B).
+ 
+ Concomitant Mapping of Mutation and Methylation of CAN Genes in Human Breast and Colon Cancers
+ 
+@@ -3087,7 +3087,7 @@
+ 
+ Spectrum of Apc Mutations in MA and MPA Mice Tumors
+ 
+-In vitro studies have alternatively suggested that Mlh3 participates in either IDL repair [13] or SBR [15]. To understand the role of Mlh3 in these processes, we used the wild type Apc allele as a tumor-associated in vivo reporter gene to analyze the mutation spectrum from MA GI tumors. A total of 49 tumors from MA mice and 28 tumors from Apc1638N littermates were analyzed for Apc truncation mutations by IVTT analysis. Truncated Apc products were detected in 27 of 49 (55%) MA tumors while only 9 of 28 (32%) were found in Apc1638N tumors. The current observed incidence of Apc somatic mutations of Apc1638N tumors is in agreement with the previous results (7 of 22, 32%) [36], hence for better understanding of mutational differences between the two strains, this and the previous data for Apc1638N tumors were combined and used for further comparisons. This 23% increase in somatic Apc mutations in MA mice was significant (P&lt;0.0048; Fisher exact test) and was attributable to increased small insertion/deletion frameshift mutations (62.5%) vs. Apc1638N (33.3%) mice (P&lt;0.001; Fisher exact test; Figure 2B and Tables 1 and 2). MA mice had one recurrent insertion/deletion mutation “hotspot�? also observed in Mlh1;Apc1638N mice (amino acid 1464) (Figure 2A). Furthermore, examination of the sequences surrounding each Apc mutation site in MA tumors showed that, unlike in other mismatch repair deficient tumors such as Mlh1−/−;Apc1638N or Msh6−/−;Msh3−/−;Apc1638N [32],[33], about 40% of frameshift mutations occurred at non-repetitive sequences within the Apc coding region. These data are consistent with a primary in vivo role for Mlh3 in DNA repair of small insertion/deletion mutations in GI epithelial cells.
++In vitro studies have alternatively suggested that Mlh3 participates in either IDL repair [13] or SBR [15]. To understand the role of Mlh3 in these processes, we used the wild type Apc allele as a tumor-associated in vivo reporter gene to analyze the mutation spectrum from MA GI tumors. A total of 49 tumors from MA mice and 28 tumors from Apc1638N littermates were analyzed for Apc truncation mutations by IVTT analysis. Truncated Apc products were detected in 27 of 49 (55%) MA tumors while only 9 of 28 (32%) were found in Apc1638N tumors. The current observed incidence of Apc somatic mutations of Apc1638N tumors is in agreement with the previous results (7 of 22, 32%) [36], hence for better understanding of mutational differences between the two strains, this and the previous data for Apc1638N tumors were combined and used for further comparisons. This 23% increase in somatic Apc mutations in MA mice was significant (P&lt;0.0048; Fisher exact test) and was attributable to increased small insertion/deletion frameshift mutations (62.5%) vs. Apc1638N (33.3%) mice (P&lt;0.001; Fisher exact test; Figure 2B and Tables 1 and 2). MA mice had one recurrent insertion/deletion mutation “hotspot? also observed in Mlh1;Apc1638N mice (amino acid 1464) (Figure 2A). Furthermore, examination of the sequences surrounding each Apc mutation site in MA tumors showed that, unlike in other mismatch repair deficient tumors such as Mlh1−/−;Apc1638N or Msh6−/−;Msh3−/−;Apc1638N [32],[33], about 40% of frameshift mutations occurred at non-repetitive sequences within the Apc coding region. These data are consistent with a primary in vivo role for Mlh3 in DNA repair of small insertion/deletion mutations in GI epithelial cells.
+ 
+ </text><annotation id="T114"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="3487" length="3"></location><text>−/−</text></annotation><annotation id="T115"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3475" length="4"></location><text>Msh6</text></annotation><annotation id="T116"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="114" length="5"></location><text>Tumor</text></annotation><annotation id="T117"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3670" length="4"></location><text>Mlh3</text></annotation><annotation id="T118"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="233" length="6"></location><text>tumors</text></annotation><annotation id="T119"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="3730" length="19"></location><text>GI epithelial cells</text></annotation><annotation id="T29"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="886" length="21"></location><text>Mismatch Repair genes</text></annotation><annotation id="T28"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="942" length="18"></location><text>adenomatous polyps</text></annotation><annotation id="T27"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="438" length="2"></location><text>MA</text></annotation><annotation id="T26"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="925" length="16"></location><text>small intestinal</text></annotation><annotation id="T25"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3483" length="4"></location><text>Msh3</text></annotation><annotation id="T24"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3250" length="3"></location><text>Apc</text></annotation><annotation id="T120"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="1545" length="2"></location><text>MA</text></annotation><annotation id="T23"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3245" length="4"></location><text>Mlh1</text></annotation><annotation id="T22"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="1479" length="4"></location><text>mice</text></annotation><annotation id="T122"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="1489" length="4"></location><text>mice</text></annotation><annotation id="T21"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="3265" length="15"></location><text>amino acid 1464</text></annotation><annotation id="T121"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="69" length="4"></location><text>Pms2</text></annotation><annotation id="T20"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3354" length="3"></location><text>Apc</text></annotation><annotation id="T124"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3463" length="3"></location><text>Apc</text></annotation><annotation id="T123"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="78" length="3"></location><text>Apc</text></annotation><annotation id="T127"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="334" length="2"></location><text>GI</text></annotation><annotation id="T128"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3455" length="4"></location><text>Mlh1</text></annotation><annotation id="T125"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="245" length="3"></location><text>Apc</text></annotation><annotation id="T126"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="3459" length="3"></location><text>−/−</text></annotation><annotation id="T129"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2464" length="3"></location><text>Apc</text></annotation><annotation id="T38"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="207" length="2"></location><text>MA</text></annotation><annotation id="T37"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="3440" length="6"></location><text>tumors</text></annotation><annotation id="T39"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="3524" length="20"></location><text>frameshift mutations</text></annotation><annotation id="T131"><infon key="file">ann</infon><infon key="type">size</infon><location offset="2504" length="3"></location><text>55%</text></annotation><annotation id="T34"><infon key="file">ann</infon><infon key="type">age</infon><location offset="525" length="3"></location><text>9.5</text></annotation><annotation id="T130"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2512" length="6"></location><text>tumors</text></annotation><annotation id="T33"><infon key="file">ann</infon><infon key="type">age</infon><location offset="533" length="11"></location><text>10.5 months</text></annotation><annotation id="T36"><infon key="file">ann</infon><infon key="type">size</infon><location offset="378" length="3"></location><text>65%</text></annotation><annotation id="T35"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3593" length="3"></location><text>Apc</text></annotation><annotation id="T135"><infon key="file">ann</infon><infon key="type">size</infon><location offset="2357" length="2"></location><text>28</text></annotation><annotation id="T30"><infon key="file">ann</infon><infon key="type">size</infon><location offset="447" length="3"></location><text>70%</text></annotation><annotation id="T134"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2411" length="3"></location><text>Apc</text></annotation><annotation id="T133"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2415" length="20"></location><text>truncation mutations</text></annotation><annotation id="T32"><infon key="file">ann</infon><infon key="type">size</infon><location offset="455" length="3"></location><text>30%</text></annotation><annotation id="T132"><infon key="file">ann</infon><infon key="type">size</infon><location offset="2494" length="8"></location><text>27 of 49</text></annotation><annotation id="T31"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3491" length="3"></location><text>Apc</text></annotation><annotation id="T49"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="807" length="3"></location><text>MPA</text></annotation><annotation id="T48"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2558" length="3"></location><text>Apc</text></annotation><annotation id="T100"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="1953" length="3"></location><text>−/−</text></annotation><annotation id="T43"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="1071" length="14"></location><text>adenocarcinoma</text></annotation><annotation id="T42"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="811" length="4"></location><text>mice</text></annotation><annotation id="T102"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="1960" length="5"></location><text>1638N</text></annotation><annotation id="T41"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="970" length="5"></location><text>mouse</text></annotation><annotation id="T101"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1957" length="3"></location><text>Apc</text></annotation><annotation id="T40"><infon key="file">ann</infon><infon key="type">size</infon><location offset="386" length="3"></location><text>35%</text></annotation><annotation id="T47"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="976" length="7"></location><text>duodena</text></annotation><annotation id="T46"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="2567" length="6"></location><text>tumors</text></annotation><annotation id="T45"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="1062" length="8"></location><text>jejeunal</text></annotation><annotation id="T44"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2561" length="5"></location><text>1638N</text></annotation><annotation id="T109"><infon key="file">ann</infon><infon key="type">size</infon><location offset="2539" length="3"></location><text>32%</text></annotation><annotation id="T107"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1782" length="4"></location><text>Pms2</text></annotation><annotation id="T108"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="2512" length="6"></location><text>tumors</text></annotation><annotation id="T105"><infon key="file">ann</infon><infon key="type">size</infon><location offset="3517" length="3"></location><text>40%</text></annotation><annotation id="T106"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="1818" length="2"></location><text>GI</text></annotation><annotation id="T103"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="1966" length="4"></location><text>mice</text></annotation><annotation id="T104"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="1994" length="9"></location><text>Mutations</text></annotation><annotation id="T50"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="1443" length="9"></location><text>mutations</text></annotation><annotation id="T59"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2609" length="3"></location><text>Apc</text></annotation><annotation id="T113"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="3479" length="3"></location><text>−/−</text></annotation><annotation id="T52"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="1260" length="5"></location><text>Tumor</text></annotation><annotation id="T112"><infon key="file">ann</infon><infon key="type">size</infon><location offset="2530" length="7"></location><text>9 of 28</text></annotation><annotation id="T51"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="966" length="3"></location><text>MPA</text></annotation><annotation id="T111"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2454" length="9"></location><text>Truncated</text></annotation><annotation id="T54"><infon key="file">ann</infon><infon key="type">size</infon><location offset="2693" length="7"></location><text>7 of 22</text></annotation><annotation id="T110"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2567" length="6"></location><text>tumors</text></annotation><annotation id="T53"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="441" length="4"></location><text>mice</text></annotation><annotation id="T56"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2643" length="6"></location><text>tumors</text></annotation><annotation id="T55"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="2643" length="6"></location><text>tumors</text></annotation><annotation id="T58"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2637" length="5"></location><text>1638N</text></annotation><annotation id="T57"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2634" length="3"></location><text>Apc</text></annotation><annotation id="T75"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2165" length="4"></location><text>Mlh3</text></annotation><annotation id="T76"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2212" length="3"></location><text>Apc</text></annotation><annotation id="T73"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1777" length="4"></location><text>Mlh3</text></annotation><annotation id="T74"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1729" length="3"></location><text>Apc</text></annotation><annotation id="T79"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="2308" length="2"></location><text>GI</text></annotation><annotation id="T77"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="2023" length="6"></location><text>Tumors</text></annotation><annotation id="T78"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2082" length="4"></location><text>Mlh3</text></annotation><annotation id="T159"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="691" length="5"></location><text>tumor</text></annotation><annotation id="T158"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="662" length="4"></location><text>Mlh3</text></annotation><annotation id="T161"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="688" length="2"></location><text>GI</text></annotation><annotation id="T162"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2305" length="2"></location><text>MA</text></annotation><annotation id="T163"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="716" length="5"></location><text>tumor</text></annotation><annotation id="T164"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2375" length="5"></location><text>1638N</text></annotation><annotation id="T165"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="769" length="5"></location><text>tumor</text></annotation><annotation id="T166"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2372" length="3"></location><text>Apc</text></annotation><annotation id="T167"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="874" length="3"></location><text>Apc</text></annotation><annotation id="T72"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="1658" length="5"></location><text>1638N</text></annotation><annotation id="T71"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="1664" length="4"></location><text>mice</text></annotation><annotation id="T70"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="1649" length="2"></location><text>MA</text></annotation><annotation id="T160"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="1475" length="3"></location><text>MPA</text></annotation><annotation id="T62"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="1732" length="5"></location><text>1638N</text></annotation><annotation id="T63"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="1548" length="4"></location><text>mice</text></annotation><annotation id="T64"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="2835" length="6"></location><text>tumors</text></annotation><annotation id="T65"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2829" length="5"></location><text>1638N</text></annotation><annotation id="T66"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1533" length="3"></location><text>Apc</text></annotation><annotation id="T67"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1655" length="3"></location><text>Apc</text></annotation><annotation id="T68"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2826" length="3"></location><text>Apc</text></annotation><annotation id="T69"><infon key="file">ann</infon><infon key="type">size</infon><location offset="2702" length="3"></location><text>32%</text></annotation><annotation id="T61"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="1536" length="5"></location><text>1638N</text></annotation><annotation id="T60"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2613" length="17"></location><text>somatic mutations</text></annotation><annotation id="T99"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1949" length="4"></location><text>Mlh1</text></annotation><annotation id="T97"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="1094" length="3"></location><text>MPA</text></annotation><annotation id="T98"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="515" length="8"></location><text>affected</text></annotation><annotation id="T95"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="3164" length="2"></location><text>MA</text></annotation><annotation id="T96"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="1821" length="5"></location><text>tumor</text></annotation><annotation id="T137"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="2360" length="6"></location><text>tumors</text></annotation><annotation id="T136"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2381" length="11"></location><text>littermates</text></annotation><annotation id="T139"><infon key="file">ann</infon><infon key="type">size</infon><location offset="2330" length="2"></location><text>49</text></annotation><annotation id="T138"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="2333" length="6"></location><text>tumors</text></annotation><annotation id="T143"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="63" length="4"></location><text>Mlh3</text></annotation><annotation id="T6"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3082" length="3"></location><text>Apc</text></annotation><annotation id="T144"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="337" length="8"></location><text>adenomas</text></annotation><annotation id="T7"><infon key="file">ann</infon><infon key="type">Concepts_Ideas</infon><location offset="223" length="16"></location><text>&gt;50% more tumors</text></annotation><annotation id="T145"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="1485" length="3"></location><text>MPA</text></annotation><annotation id="T4"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2936" length="2"></location><text>MA</text></annotation><annotation id="T146"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2333" length="6"></location><text>tumors</text></annotation><annotation id="T5"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="3085" length="5"></location><text>1638N</text></annotation><annotation id="T140"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="1628" length="15"></location><text>adenocarcinomas</text></annotation><annotation id="T141"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="1901" length="3"></location><text>MPA</text></annotation><annotation id="T8"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="254" length="4"></location><text>mice</text></annotation><annotation id="T142"><infon key="file">ann</infon><infon key="type">Concepts_Ideas</infon><location offset="1512" length="16"></location><text>shorter survival</text></annotation><annotation id="T9"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="248" length="5"></location><text>1638N</text></annotation><annotation id="T94"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1990" length="3"></location><text>Apc</text></annotation><annotation id="T93"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2007" length="2"></location><text>MA</text></annotation><annotation id="T92"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="1098" length="5"></location><text>mouse</text></annotation><annotation id="T91"><infon key="file">ann</infon><infon key="type">size</infon><location offset="3176" length="3"></location><text>one</text></annotation><annotation id="T90"><infon key="file">ann</infon><infon key="type">Disorder</infon><location offset="3414" length="25"></location><text>mismatch repair deficient</text></annotation><annotation id="T88"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="3475" length="24"></location><text>Msh6−/−;Msh3−/−;Apc1638N</text></annotation><annotation id="T89"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="3378" length="6"></location><text>tumors</text></annotation><annotation id="T84"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="3259" length="4"></location><text>mice</text></annotation><annotation id="T85"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="3245" length="13"></location><text>Mlh1;Apc1638N</text></annotation><annotation id="T86"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="3375" length="2"></location><text>MA</text></annotation><annotation id="T87"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="3455" length="16"></location><text>Mlh1−/−;Apc1638N</text></annotation><annotation id="T1"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2835" length="6"></location><text>tumors</text></annotation><annotation id="T149"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="349" length="10"></location><text>carcinomas</text></annotation><annotation id="T148"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2348" length="4"></location><text>mice</text></annotation><annotation id="T3"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2919" length="3"></location><text>Apc</text></annotation><annotation id="T147"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2360" length="6"></location><text>tumors</text></annotation><annotation id="T2"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2911" length="21"></location><text>somatic Apc mutations</text></annotation><annotation id="T156"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="1905" length="4"></location><text>mice</text></annotation><annotation id="T157"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2018" length="4"></location><text>Mice</text></annotation><annotation id="T154"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2014" length="3"></location><text>MPA</text></annotation><annotation id="T155"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="590" length="6"></location><text>cancer</text></annotation><annotation id="T10"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="372" length="4"></location><text>mice</text></annotation><annotation id="T152"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="363" length="3"></location><text>Apc</text></annotation><annotation id="T11"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="210" length="4"></location><text>mice</text></annotation><annotation id="T153"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="581" length="8"></location><text>extra-GI</text></annotation><annotation id="T12"><infon key="file">ann</infon><infon key="type">age</infon><location offset="188" length="17"></location><text>9.5 months of age</text></annotation><annotation id="T150"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2345" length="2"></location><text>MA</text></annotation><annotation id="T13"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="366" length="5"></location><text>1638N</text></annotation><annotation id="T151"><infon key="file">ann</infon><infon key="type">body-part</infon><location offset="1122" length="6"></location><text>glands</text></annotation><annotation id="T14"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="3099" length="4"></location><text>mice</text></annotation><annotation id="T15"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="82" length="9"></location><text>Mutations</text></annotation><annotation id="T81"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="2311" length="6"></location><text>tumors</text></annotation><annotation id="T16"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="3190" length="27"></location><text>insertion/deletion mutation</text></annotation><annotation id="T80"><infon key="file">ann</infon><infon key="type">disease</infon><location offset="2228" length="5"></location><text>tumor</text></annotation><annotation id="T17"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1438" length="4"></location><text>Pms2</text></annotation><annotation id="T83"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2509" length="2"></location><text>MA</text></annotation><annotation id="T18"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="3167" length="4"></location><text>mice</text></annotation><annotation id="T82"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2939" length="4"></location><text>mice</text></annotation><annotation id="T19"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1429" length="4"></location><text>Mlh3</text></annotation><relation id="R81"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T31" role="Arg1"></node><node refid="T88" role="Arg2"></node></relation><relation id="R80"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T41" role="Arg1"></node><node refid="T28" role="Arg2"></node></relation><relation id="R85"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T128" role="Arg1"></node><node refid="T126" role="Arg2"></node></relation><relation id="R19"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T37" role="Arg1"></node><node refid="T88" role="Arg2"></node></relation><relation id="R84"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T31" role="Arg1"></node><node refid="T88" role="Arg2"></node></relation><relation id="R83"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T11" role="Arg1"></node><node refid="T38" role="Arg2"></node></relation><relation id="R17"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T125" role="Arg1"></node><node refid="T9" role="Arg2"></node></relation><relation id="R82"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T157" role="Arg1"></node><node refid="T77" role="Arg2"></node></relation><relation id="R18"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T136" role="Arg1"></node><node refid="T137" role="Arg2"></node></relation><relation id="R15"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T37" role="Arg1"></node><node refid="T87" role="Arg2"></node></relation><relation id="R16"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T79" role="Arg1"></node><node refid="T81" role="Arg2"></node></relation><relation id="R13"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T89" role="Arg1"></node><node refid="T86" role="Arg2"></node></relation><relation id="R14"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T142" role="Arg1"></node><node refid="T122" role="Arg2"></node></relation><relation id="R11"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T90" role="Arg1"></node><node refid="T37" role="Arg2"></node></relation><relation id="R12"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T53" role="Arg1"></node><node refid="T144" role="Arg2"></node></relation><relation id="R10"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T82" role="Arg1"></node><node refid="T2" role="Arg2"></node></relation><relation id="R88"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T88" role="Arg1"></node><node refid="T114" role="Arg2"></node></relation><relation id="R89"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T148" role="Arg1"></node><node refid="T138" role="Arg2"></node></relation><relation id="R86"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T115" role="Arg1"></node><node refid="T88" role="Arg2"></node></relation><relation id="R87"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T88" role="Arg1"></node><node refid="T113" role="Arg2"></node></relation><relation id="R90"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T23" role="Arg1"></node><node refid="T85" role="Arg2"></node></relation><relation id="R92"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T124" role="Arg1"></node><node refid="T87" role="Arg2"></node></relation><relation id="R91"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T25" role="Arg1"></node><node refid="T114" role="Arg2"></node></relation><relation id="R94"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T101" role="Arg1"></node><node refid="T102" role="Arg2"></node></relation><relation id="R93"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T24" role="Arg1"></node><node refid="T85" role="Arg2"></node></relation><relation id="R96"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T115" role="Arg1"></node><node refid="T113" role="Arg2"></node></relation><relation id="R95"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T110" role="Arg1"></node><node refid="T112" role="Arg2"></node></relation><relation id="R97"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T92" role="Arg1"></node><node refid="T43" role="Arg2"></node></relation><relation id="R98"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T130" role="Arg1"></node><node refid="T111" role="Arg2"></node></relation><relation id="R99"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T99" role="Arg1"></node><node refid="T100" role="Arg2"></node></relation><relation id="R63"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T71" role="Arg1"></node><node refid="T72" role="Arg2"></node></relation><relation id="R62"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T146" role="Arg1"></node><node refid="T139" role="Arg2"></node></relation><relation id="R61"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T7" role="Arg1"></node><node refid="T11" role="Arg2"></node></relation><relation id="R60"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T10" role="Arg1"></node><node refid="T149" role="Arg2"></node></relation><relation id="R100"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T46" role="Arg1"></node><node refid="T44" role="Arg2"></node></relation><relation id="R68"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T103" role="Arg1"></node><node refid="T102" role="Arg2"></node></relation><relation id="R69"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T53" role="Arg1"></node><node refid="T27" role="Arg2"></node></relation><relation id="R66"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T156" role="Arg1"></node><node refid="T141" role="Arg2"></node></relation><relation id="R67"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T25" role="Arg1"></node><node refid="T88" role="Arg2"></node></relation><relation id="R64"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T10" role="Arg1"></node><node refid="T36" role="Arg2"></node></relation><relation id="R65"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T106" role="Arg1"></node><node refid="T96" role="Arg2"></node></relation><relation id="R72"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T74" role="Arg1"></node><node refid="T62" role="Arg2"></node></relation><relation id="R71"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T11" role="Arg1"></node><node refid="T118" role="Arg2"></node></relation><relation id="R74"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T47" role="Arg1"></node><node refid="T28" role="Arg2"></node></relation><relation id="R73"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T157" role="Arg1"></node><node refid="T154" role="Arg2"></node></relation><relation id="R70"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T103" role="Arg1"></node><node refid="T100" role="Arg2"></node></relation><relation id="R109"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T18" role="Arg1"></node><node refid="T95" role="Arg2"></node></relation><relation id="R107"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T3" role="Arg1"></node><node refid="T2" role="Arg2"></node></relation><relation id="R108"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T153" role="Arg1"></node><node refid="T155" role="Arg2"></node></relation><relation id="R105"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T127" role="Arg1"></node><node refid="T144" role="Arg2"></node></relation><relation id="R106"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T6" role="Arg1"></node><node refid="T5" role="Arg2"></node></relation><relation id="R103"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T130" role="Arg1"></node><node refid="T108" role="Arg2"></node></relation><relation id="R104"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T84" role="Arg1"></node><node refid="T85" role="Arg2"></node></relation><relation id="R101"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T147" role="Arg1"></node><node refid="T137" role="Arg2"></node></relation><relation id="R102"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T129" role="Arg1"></node><node refid="T111" role="Arg2"></node></relation><relation id="R111"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T24" role="Arg1"></node><node refid="T85" role="Arg2"></node></relation><relation id="R110"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T68" role="Arg1"></node><node refid="T65" role="Arg2"></node></relation><relation id="R79"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T157" role="Arg1"></node><node refid="T104" role="Arg2"></node></relation><relation id="R75"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T130" role="Arg1"></node><node refid="T132" role="Arg2"></node></relation><relation id="R76"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T122" role="Arg1"></node><node refid="T145" role="Arg2"></node></relation><relation id="R77"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T81" role="Arg1"></node><node refid="T162" role="Arg2"></node></relation><relation id="R78"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T136" role="Arg1"></node><node refid="T164" role="Arg2"></node></relation><relation id="R113"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T14" role="Arg1"></node><node refid="T5" role="Arg2"></node></relation><relation id="R112"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T12" role="Arg1"></node><node refid="T11" role="Arg2"></node></relation><relation id="R115"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T7" role="Arg1"></node><node refid="T118" role="Arg2"></node></relation><relation id="R114"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T146" role="Arg1"></node><node refid="T138" role="Arg2"></node></relation><relation id="R117"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T152" role="Arg1"></node><node refid="T13" role="Arg2"></node></relation><relation id="R116"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T121" role="Arg1"></node><node refid="T15" role="Arg2"></node></relation><relation id="R119"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T82" role="Arg1"></node><node refid="T4" role="Arg2"></node></relation><relation id="R118"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T1" role="Arg1"></node><node refid="T65" role="Arg2"></node></relation><relation id="R40"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T147" role="Arg1"></node><node refid="T135" role="Arg2"></node></relation><relation id="R41"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T63" role="Arg1"></node><node refid="T120" role="Arg2"></node></relation><relation id="R45"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T56" role="Arg1"></node><node refid="T58" role="Arg2"></node></relation><relation id="R8"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T134" role="Arg1"></node><node refid="T133" role="Arg2"></node></relation><relation id="R44"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T56" role="Arg1"></node><node refid="T55" role="Arg2"></node></relation><relation id="R9"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T56" role="Arg1"></node><node refid="T54" role="Arg2"></node></relation><relation id="R43"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T48" role="Arg1"></node><node refid="T44" role="Arg2"></node></relation><relation id="R6"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T59" role="Arg1"></node><node refid="T60" role="Arg2"></node></relation><relation id="R42"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T161" role="Arg1"></node><node refid="T159" role="Arg2"></node></relation><relation id="R7"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T42" role="Arg1"></node><node refid="T49" role="Arg2"></node></relation><relation id="R4"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T41" role="Arg1"></node><node refid="T51" role="Arg2"></node></relation><relation id="R49"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T63" role="Arg1"></node><node refid="T61" role="Arg2"></node></relation><relation id="R48"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T87" role="Arg1"></node><node refid="T126" role="Arg2"></node></relation><relation id="R5"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T130" role="Arg1"></node><node refid="T131" role="Arg2"></node></relation><relation id="R47"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T124" role="Arg1"></node><node refid="T87" role="Arg2"></node></relation><relation id="R2"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T66" role="Arg1"></node><node refid="T61" role="Arg2"></node></relation><relation id="R46"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T110" role="Arg1"></node><node refid="T46" role="Arg2"></node></relation><relation id="R3"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T17" role="Arg1"></node><node refid="T50" role="Arg2"></node></relation><relation id="R120"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T19" role="Arg1"></node><node refid="T50" role="Arg2"></node></relation><relation id="R1"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T166" role="Arg1"></node><node refid="T164" role="Arg2"></node></relation><relation id="R50"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T92" role="Arg1"></node><node refid="T97" role="Arg2"></node></relation><relation id="R51"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T128" role="Arg1"></node><node refid="T87" role="Arg2"></node></relation><relation id="R52"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T137" role="Arg1"></node><node refid="T164" role="Arg2"></node></relation><relation id="R54"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T10" role="Arg1"></node><node refid="T144" role="Arg2"></node></relation><relation id="R53"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T143" role="Arg1"></node><node refid="T15" role="Arg2"></node></relation><relation id="R56"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T148" role="Arg1"></node><node refid="T150" role="Arg2"></node></relation><relation id="R55"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T123" role="Arg1"></node><node refid="T15" role="Arg2"></node></relation><relation id="R58"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T10" role="Arg1"></node><node refid="T13" role="Arg2"></node></relation><relation id="R57"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T10" role="Arg1"></node><node refid="T40" role="Arg2"></node></relation><relation id="R59"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T67" role="Arg1"></node><node refid="T72" role="Arg2"></node></relation><relation id="R27"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T39" role="Arg1"></node><node refid="T105" role="Arg2"></node></relation><relation id="R26"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T110" role="Arg1"></node><node refid="T111" role="Arg2"></node></relation><relation id="R25"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T53" role="Arg1"></node><node refid="T30" role="Arg2"></node></relation><relation id="R24"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T53" role="Arg1"></node><node refid="T32" role="Arg2"></node></relation><relation id="R23"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T16" role="Arg1"></node><node refid="T91" role="Arg2"></node></relation><relation id="R22"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T110" role="Arg1"></node><node refid="T109" role="Arg2"></node></relation><relation id="R21"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T56" role="Arg1"></node><node refid="T60" role="Arg2"></node></relation><relation id="R20"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T26" role="Arg1"></node><node refid="T28" role="Arg2"></node></relation><relation id="R29"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T22" role="Arg1"></node><node refid="T160" role="Arg2"></node></relation><relation id="R28"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T57" role="Arg1"></node><node refid="T58" role="Arg2"></node></relation><relation id="R30"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T138" role="Arg1"></node><node refid="T150" role="Arg2"></node></relation><relation id="R36"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T157" role="Arg1"></node><node refid="T93" role="Arg2"></node></relation><relation id="R35"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T71" role="Arg1"></node><node refid="T70" role="Arg2"></node></relation><relation id="R38"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T8" role="Arg1"></node><node refid="T9" role="Arg2"></node></relation><relation id="R37"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T56" role="Arg1"></node><node refid="T69" role="Arg2"></node></relation><relation id="R32"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T53" role="Arg1"></node><node refid="T149" role="Arg2"></node></relation><relation id="R31"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T1" role="Arg1"></node><node refid="T64" role="Arg2"></node></relation><relation id="R34"><infon key="relation type">relatedTo</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T45" role="Arg1"></node><node refid="T43" role="Arg2"></node></relation><relation id="R33"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T108" role="Arg1"></node><node refid="T83" role="Arg2"></node></relation><relation id="R39"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T94" role="Arg1"></node><node refid="T104" role="Arg2"></node></relation></passage></document><document><id>2526421-05-DISCUSSION-p03</id><passage><offset>0</offset><text>** IGNORE LINE **
+ ** IGNORE LINE **
+@@ -3137,7 +3137,7 @@
+ ** IGNORE LINE **
+ Introduction
+ 
+-Approximately 7% of breast cancer cases occur in women with a strong family history of the disease [1]. Mutations in BRCA1 and BRCA2 account for a considerable proportion of these familial breast cancer cases, with the average cumulative risk in BRCA1 and BRCA2 mutation carriers by age 70 years estimated at 65% and 45%, respectively [2]. The Breast Cancer Information Core (BIC) database (http://research.nhgri.nih.gov/bic/) currently has more than 1400 and 1800 unique sequence variants listed in the BRCA1 and BRCA2 genes, respectively. These include frameshift, nonsense, missense, splice site alterations and polymorphisms. Greater than a third of the BRCA1 and greater than half of the BRCA2 unique variants are “unclassified variants�? without compelling evidence of pathogenicity or functional significance. The majority of unclassified variants recorded in the BIC database are predicted missense changes (more than 400 BRCA1 and 800 BRCA2). However other variants which may be categorised as unclassified variants are in-frame deletions or duplications, variants that may disrupt splicing, or variants in the 3′UTR that may affect RNA stability (www.kconfab.org). BRCA1/2 unclassified variants represent a problem in the clinical setting as it is not known which variants are associated with the high risk of disease reported for classical truncating mutations.
++Approximately 7% of breast cancer cases occur in women with a strong family history of the disease [1]. Mutations in BRCA1 and BRCA2 account for a considerable proportion of these familial breast cancer cases, with the average cumulative risk in BRCA1 and BRCA2 mutation carriers by age 70 years estimated at 65% and 45%, respectively [2]. The Breast Cancer Information Core (BIC) database (http://research.nhgri.nih.gov/bic/) currently has more than 1400 and 1800 unique sequence variants listed in the BRCA1 and BRCA2 genes, respectively. These include frameshift, nonsense, missense, splice site alterations and polymorphisms. Greater than a third of the BRCA1 and greater than half of the BRCA2 unique variants are “unclassified variants? without compelling evidence of pathogenicity or functional significance. The majority of unclassified variants recorded in the BIC database are predicted missense changes (more than 400 BRCA1 and 800 BRCA2). However other variants which may be categorised as unclassified variants are in-frame deletions or duplications, variants that may disrupt splicing, or variants in the 3′UTR that may affect RNA stability (www.kconfab.org). BRCA1/2 unclassified variants represent a problem in the clinical setting as it is not known which variants are associated with the high risk of disease reported for classical truncating mutations.
+ 
+ Several functional assays may be used to determine the significance of unclassified variants, including transcription activation and complementation assays [3]–[9], but a disadvantage of biochemical assays is that they rely on the functions of specific domains of the protein, require specialized laboratory skills, and are time–consuming to perform. Other methods for classifying variants include the analysis of clinical and histopathological data [10], loss of heterozygosity analysis [11] and bioinformatic analysis to predict the effect of the amino acid change on structure and multiple sequence alignment strategies [12]; [13]–[15]. Integrated evaluation of unclassified variants which combines several approaches, such as the analysis of co-segregation of the mutation with disease, co-occurrence of the variant with a deleterious mutation, sequence conservation of the amino acid change, severity of amino acid change, tumor loss of heterozygosity, and tumor histopathology classification, provides a quantitative tool for the classification of variants [16]–[22]. This multifactorial method was developed to classify such rare unclassified variants into two categories, variants with features of classical high-risk mutations (termed pathogenic), and variants that do not have the features of a high-risk mutation (termed neutral or low clinical significance (LCS)). While the availability of appropriate biospecimens (e.g. number of families and tumors) for inclusion in likelihood prediction is a major factor determining the classification of any single variant, another major caveat of the multifactorial approach is that it is not appropriate for the evaluation of possible moderate or low risk variants, since it uses high-risk mutations as reference for the underlying assumptions [16],[19],[20]. Therefore, the current multifactorial method cannot exclude the possibility that rare variants classified to be of low clinical significance may be associated with a moderate or low risk of cancer.
+ 
+@@ -3189,7 +3189,7 @@
+ 
+ Determination of −1 bp frameshift mutation rates of TGFBR2 exon 3 and ACVR2 exon 10 in human cells
+ 
+-The mutation rate was defined as the probability of a cell undergoing a mutation in its lifetime and expressed per cell per generation. We used a “method of the mean�? developed by Luria and Delbruck [28] to estimate mutation rate. The “method of the mean�? is moment-based, whereby the mutation rate is estimated as a function of the sample mean of the number of mutants. The formula used in the computation is r̂ = μN ln(μNC), where r̂ is the mean number of mutants in a culture, C is the number of parallel cultures, μ is the mutation rate, and N is the number of cells at risk of undergoing a mutation, which Luria–Delbruck assumed to be equal to the final number of cells in a culture. Three parallel cultures were used, and r̂ was estimated as the mean of the number of mutants across the three cultures. The total number of cells N was based on averaging across cultures. The formula listed above was used to calculate mutation rates of the M2 cell population (full mutants) using data from flow cytometry analysis at each time point between day 14 and day 35. Single mutation rates were then calculated by combining and averaging time-specific mutation rates to minimize the variance of the estimate as previously described [25]. Data were expressed as mean±the standard errors of mean (SEM).
++The mutation rate was defined as the probability of a cell undergoing a mutation in its lifetime and expressed per cell per generation. We used a “method of the mean? developed by Luria and Delbruck [28] to estimate mutation rate. The “method of the mean? is moment-based, whereby the mutation rate is estimated as a function of the sample mean of the number of mutants. The formula used in the computation is r̂ = μN ln(μNC), where r̂ is the mean number of mutants in a culture, C is the number of parallel cultures, μ is the mutation rate, and N is the number of cells at risk of undergoing a mutation, which Luria–Delbruck assumed to be equal to the final number of cells in a culture. Three parallel cultures were used, and r̂ was estimated as the mean of the number of mutants across the three cultures. The total number of cells N was based on averaging across cultures. The formula listed above was used to calculate mutation rates of the M2 cell population (full mutants) using data from flow cytometry analysis at each time point between day 14 and day 35. Single mutation rates were then calculated by combining and averaging time-specific mutation rates to minimize the variance of the estimate as previously described [25]. Data were expressed as mean±the standard errors of mean (SEM).
+ 
+ </text><annotation id="T1"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="2092" length="11"></location><text>populations</text></annotation><annotation id="T3"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1637" length="6"></location><text>TGFBR2</text></annotation><annotation id="T2"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1731" length="5"></location><text>ACVR2</text></annotation><annotation id="T6"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="1132" length="11"></location><text>populations</text></annotation><annotation id="T7"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2052" length="5"></location><text>ACVR2</text></annotation><annotation id="T4"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="1496" length="11"></location><text>populations</text></annotation><annotation id="T5"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="147" length="6"></location><text>TGFBR2</text></annotation><annotation id="T10"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="172" length="5"></location><text>ACVR2</text></annotation><annotation id="T11"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2359" length="6"></location><text>TGFBR2</text></annotation><annotation id="T12"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2278" length="6"></location><text>TGFBR2</text></annotation><annotation id="T8"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2041" length="6"></location><text>TGFBR2</text></annotation><annotation id="T13"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2377" length="5"></location><text>ACVR2</text></annotation><annotation id="T14"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2324" length="25"></location><text>−1 bp frameshift mutation</text></annotation><annotation id="T9"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="158" length="6"></location><text>TGFBR2</text></annotation><annotation id="T15"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="185" length="5"></location><text>ACVR2</text></annotation><annotation id="T16"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2289" length="5"></location><text>ACVR2</text></annotation><relation id="R2"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T11" role="Arg1"></node><node refid="T14" role="Arg2"></node></relation><relation id="R1"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T13" role="Arg1"></node><node refid="T14" role="Arg2"></node></relation></passage></document><document><id>1334229-04-Results-p02</id><passage><offset>0</offset><text>With respect to the localisation in the colorectal tract, tumours of the rectosigmoid and rectum more frequently harboured truncating APC mutations when compared to colon tumours (P = 0.001), as shown in table 3. Rectosigmoid and rectal tumours have a relatively higher frequency of K-ras mutations in codons 12 and 13 when compared to colon tumours (P = 0.05) (Table 3). Nine per cent of tumours showed hMLH1 deficiency, as determined by immunohistochemistry (Figure 2). Tumours lacking hMLH1 expression occur almost exclusively in the proximal colon (P &lt; 0.001) and relatively more frequently show poor differentiation or are undifferentiated (P &lt; 0.001) when compared to tumours with hMLH1 expression (Table 3).
+ 
+@@ -4166,7 +4166,7 @@
+ ** IGNORE LINE **
+ Frameshift mutation at coding microsatellites of TGFBR2 exon 3 and ACVR2 exon 10 in different human MMR deficient backgrounds.
+ 
+-Cells from the M1 and/or M2 populations of hMLH1−/− TGFBR2 OF or ACVR2 OF cells, hMSH6−/− TGFBR2 OF or ACVR2 OF cells, and hMSH3−/− TGFBR2 OF cells were sorted and cultured. DNA from each cell line was amplified by PCR, sub-cloned and all single cell clones were individually sequenced to assess for frameshift mutation of the coding microsatellites of TGFBR2 exon 3 and ACVR2 exon 10. Sequence analysis of DNA clones from hMLH1 and hMSH6 deficiencies revealed mostly 1 bp deletion at microsatellites (A9 for TGFBR2 or A7 for ACVR2), shifting the EGFP gene into the reading frame and leading to its expression (A). Note that M2 clones from hMLH1−/− TGFBR2 OF cells revealed 100% A9/T9 microsatellite sequences, termed a “full mutant�? whereas M1 clones revealed a mixture of A10/T10 and A9/T9 microsatellite sequences, which suggests the presence of an A10/T9 heteroduplex, termed an “intermediate mutant�? (B).
++Cells from the M1 and/or M2 populations of hMLH1−/− TGFBR2 OF or ACVR2 OF cells, hMSH6−/− TGFBR2 OF or ACVR2 OF cells, and hMSH3−/− TGFBR2 OF cells were sorted and cultured. DNA from each cell line was amplified by PCR, sub-cloned and all single cell clones were individually sequenced to assess for frameshift mutation of the coding microsatellites of TGFBR2 exon 3 and ACVR2 exon 10. Sequence analysis of DNA clones from hMLH1 and hMSH6 deficiencies revealed mostly 1 bp deletion at microsatellites (A9 for TGFBR2 or A7 for ACVR2), shifting the EGFP gene into the reading frame and leading to its expression (A). Note that M2 clones from hMLH1−/− TGFBR2 OF cells revealed 100% A9/T9 microsatellite sequences, termed a “full mutant? whereas M1 clones revealed a mixture of A10/T10 and A9/T9 microsatellite sequences, which suggests the presence of an A10/T9 heteroduplex, termed an “intermediate mutant? (B).
+ 
+ To determine the nature of the mutations observed in the M1 population, we analyzed pooled cells as well as single cell clones. In pooled samples, unlike fully mutant sequences observed in the M2 populations, M1 population sequences often revealed two overlapping sequences, suggestive of heteroduplexes (A9/T10 in TGFBR2 and A7/T8 in ACVR2) (Fig. 5B). Single cell clones revealed the presence of both WT and −1 bp frameshift mutants (Fig. 5B), consistent with heteroduplexes that weakly drive EGFP expression.
+ 
+@@ -4174,7 +4174,7 @@
+ 
+ The frameshift mutation rates at the coding microsatellites of TGFBR2 exon 3 and ACVR2 exon 10 are dependent on the MMR background
+ 
+-The M2 population (full mutants) was used to calculate the mutation rates at microsatellites of TGFBR2 exon 3 and ACVR2 exon 10 by the “method of the mean�? [28] (Table 1). A single mutation rate was calculated by taking a weighted average of the mutation rates at the different time points, the weights of which were chosen to minimize the variance of the estimate as previously described [25]. As predicted, the mutation rate at the microsatellite of TGFBR2 in the hMLH1−/− background was highest: 5.91×10−4±1.26×10−4. Mutation at the A10 microsatellite of TGFBR2 is ∼3 times more frequent than mutation at the A8 microsatellite of ACVR2 in hMLH1 deficiency (P&lt;0.01). In addition, mutation at the microsatellite of TGFBR2 is ∼4 times higher than mutation at the microsatellite of ACVR2 in hMSH6 deficiency. Furthermore, mutations at the microsatellites of TGFBR2 and ACVR2 are ∼11–15 times higher in hMLH1 deficiency than in hMSH6 deficiency (P&lt;0.01). Mutation rates from hMSH3−/− and MMR-proficient cell lines were not calculated due to a lack of net fluorescent M2 populations. These data confirm that hMLH1 deficiency allows a higher susceptibility for mutation at the coding microsatellites of TGFBR2 exon 3 and ACVR2 exon 10 than hMSH6 and hMSH3 deficiencies, and that TGFBR2 exon 3 has a higher susceptibility to mutation at its coding microsatellite over ACVR2 exon 10 in both hMLH1 and hMSH6 deficiencies.
++The M2 population (full mutants) was used to calculate the mutation rates at microsatellites of TGFBR2 exon 3 and ACVR2 exon 10 by the “method of the mean? [28] (Table 1). A single mutation rate was calculated by taking a weighted average of the mutation rates at the different time points, the weights of which were chosen to minimize the variance of the estimate as previously described [25]. As predicted, the mutation rate at the microsatellite of TGFBR2 in the hMLH1−/− background was highest: 5.91×10−4±1.26×10−4. Mutation at the A10 microsatellite of TGFBR2 is ∼3 times more frequent than mutation at the A8 microsatellite of ACVR2 in hMLH1 deficiency (P&lt;0.01). In addition, mutation at the microsatellite of TGFBR2 is ∼4 times higher than mutation at the microsatellite of ACVR2 in hMSH6 deficiency. Furthermore, mutations at the microsatellites of TGFBR2 and ACVR2 are ∼11–15 times higher in hMLH1 deficiency than in hMSH6 deficiency (P&lt;0.01). Mutation rates from hMSH3−/− and MMR-proficient cell lines were not calculated due to a lack of net fluorescent M2 populations. These data confirm that hMLH1 deficiency allows a higher susceptibility for mutation at the coding microsatellites of TGFBR2 exon 3 and ACVR2 exon 10 than hMSH6 and hMSH3 deficiencies, and that TGFBR2 exon 3 has a higher susceptibility to mutation at its coding microsatellite over ACVR2 exon 10 in both hMLH1 and hMSH6 deficiencies.
+ 
+ </text><annotation id="T73"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="1830" length="3"></location><text>−/−</text></annotation><annotation id="T29"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3529" length="5"></location><text>ACVR2</text></annotation><annotation id="T28"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1428" length="5"></location><text>ACVR2</text></annotation><annotation id="T27"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3441" length="6"></location><text>TGFBR2</text></annotation><annotation id="T26"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="103" length="6"></location><text>TGFBR2</text></annotation><annotation id="T25"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2618" length="6"></location><text>TGFBR2</text></annotation><annotation id="T24"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3365" length="6"></location><text>TGFBR2</text></annotation><annotation id="T23"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3383" length="5"></location><text>ACVR2</text></annotation><annotation id="T22"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2947" length="5"></location><text>ACVR2</text></annotation><annotation id="T72"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="1843" length="3"></location><text>−/−</text></annotation><annotation id="T21"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="2637" length="3"></location><text>−/−</text></annotation><annotation id="T71"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1891" length="6"></location><text>TGFBR2</text></annotation><annotation id="T20"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2799" length="5"></location><text>ACVR2</text></annotation><annotation id="T70"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="1820" length="3"></location><text>−/−</text></annotation><annotation id="T62"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1825" length="5"></location><text>hMSH6</text></annotation><annotation id="T63"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="247" length="5"></location><text>ACVR2</text></annotation><annotation id="T64"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1838" length="5"></location><text>hMSH3</text></annotation><annotation id="T65"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1976" length="5"></location><text>ACVR2</text></annotation><annotation id="T66"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2000" length="5"></location><text>hMSH6</text></annotation><annotation id="T67"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2012" length="5"></location><text>hMSH3</text></annotation><annotation id="T68"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="827" length="3"></location><text>−/−</text></annotation><annotation id="T69"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2956" length="5"></location><text>hMSH6</text></annotation><annotation id="T38"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1637" length="5"></location><text>hMLH1</text></annotation><annotation id="T37"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="272" length="6"></location><text>TGFBR2</text></annotation><annotation id="T39"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="268" length="3"></location><text>−/−</text></annotation><annotation id="T34"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="1289" length="11"></location><text>populations</text></annotation><annotation id="T33"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="210" length="11"></location><text>populations</text></annotation><annotation id="T36"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2632" length="5"></location><text>hMLH1</text></annotation><annotation id="T35"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1993" length="5"></location><text>hMLH1</text></annotation><annotation id="T30"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="3144" length="3"></location><text>−/−</text></annotation><annotation id="T61"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="831" length="6"></location><text>TGFBR2</text></annotation><annotation id="T32"><infon key="file">ann</infon><infon key="type">cohort-patient</infon><location offset="3234" length="11"></location><text>populations</text></annotation><annotation id="T60"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="615" length="5"></location><text>hMSH6</text></annotation><annotation id="T31"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1760" length="5"></location><text>ACVR2</text></annotation><annotation id="T6"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3561" length="5"></location><text>hMSH6</text></annotation><annotation id="T7"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3412" length="5"></location><text>hMSH3</text></annotation><annotation id="T49"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="234" length="6"></location><text>TGFBR2</text></annotation><annotation id="T4"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2882" length="6"></location><text>TGFBR2</text></annotation><annotation id="T5"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2724" length="6"></location><text>TGFBR2</text></annotation><annotation id="T48"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2115" length="5"></location><text>ACVR2</text></annotation><annotation id="T8"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3402" length="5"></location><text>hMSH6</text></annotation><annotation id="T9"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3139" length="5"></location><text>hMSH3</text></annotation><annotation id="T43"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2262" length="6"></location><text>TGFBR2</text></annotation><annotation id="T42"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3067" length="5"></location><text>hMLH1</text></annotation><annotation id="T41"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2808" length="5"></location><text>hMLH1</text></annotation><annotation id="T40"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1815" length="5"></location><text>hMLH1</text></annotation><annotation id="T47"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="154" length="3"></location><text>MMR</text></annotation><annotation id="T46"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2097" length="6"></location><text>TGFBR2</text></annotation><annotation id="T45"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2150" length="3"></location><text>MMR</text></annotation><annotation id="T44"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="2280" length="5"></location><text>ACVR2</text></annotation><annotation id="T50"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="121" length="5"></location><text>ACVR2</text></annotation><annotation id="T1"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3152" length="3"></location><text>MMR</text></annotation><annotation id="T3"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3023" length="6"></location><text>TGFBR2</text></annotation><annotation id="T2"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3034" length="5"></location><text>ACVR2</text></annotation><annotation id="T59"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="305" length="5"></location><text>hMSH3</text></annotation><annotation id="T10"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3092" length="5"></location><text>hMSH6</text></annotation><annotation id="T11"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="553" length="5"></location><text>ACVR2</text></annotation><annotation id="T12"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1408" length="6"></location><text>TGFBR2</text></annotation><annotation id="T13"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="691" length="6"></location><text>TGFBR2</text></annotation><annotation id="T14"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="708" length="5"></location><text>ACVR2</text></annotation><annotation id="T52"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="225" length="5"></location><text>hMLH1</text></annotation><annotation id="T15"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1797" length="3"></location><text>MMR</text></annotation><annotation id="T51"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="230" length="3"></location><text>−/−</text></annotation><annotation id="T16"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="285" length="5"></location><text>ACVR2</text></annotation><annotation id="T54"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="605" length="5"></location><text>hMLH1</text></annotation><annotation id="T17"><infon key="file">ann</infon><infon key="type">mutation</infon><location offset="310" length="3"></location><text>−/−</text></annotation><annotation id="T53"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="822" length="5"></location><text>hMLH1</text></annotation><annotation id="T18"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="314" length="6"></location><text>TGFBR2</text></annotation><annotation id="T56"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3271" length="5"></location><text>hMLH1</text></annotation><annotation id="T19"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="535" length="6"></location><text>TGFBR2</text></annotation><annotation id="T55"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="1742" length="6"></location><text>TGFBR2</text></annotation><annotation id="T58"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="263" length="5"></location><text>hMSH6</text></annotation><annotation id="T57"><infon key="file">ann</infon><infon key="type">gene</infon><location offset="3551" length="5"></location><text>hMLH1</text></annotation><relation id="R8"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T40" role="Arg1"></node><node refid="T70" role="Arg2"></node></relation><relation id="R9"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T53" role="Arg1"></node><node refid="T68" role="Arg2"></node></relation><relation id="R6"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T58" role="Arg1"></node><node refid="T39" role="Arg2"></node></relation><relation id="R7"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T59" role="Arg1"></node><node refid="T17" role="Arg2"></node></relation><relation id="R4"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T52" role="Arg1"></node><node refid="T51" role="Arg2"></node></relation><relation id="R5"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T62" role="Arg1"></node><node refid="T73" role="Arg2"></node></relation><relation id="R2"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T36" role="Arg1"></node><node refid="T21" role="Arg2"></node></relation><relation id="R3"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T9" role="Arg1"></node><node refid="T30" role="Arg2"></node></relation><relation id="R1"><infon key="relation type">has</infon><infon key="file">ann</infon><infon key="type">Relation</infon><node refid="T64" role="Arg1"></node><node refid="T72" role="Arg2"></node></relation></passage></document><document><id>1619718-05-Discussion-p02</id><passage><offset>0</offset><text>** IGNORE LINE **
+ ** IGNORE LINE **
diff --git a/huner/ner_scripts/requirements.txt b/huner/ner_scripts/requirements.txt
new file mode 100644
index 0000000..503d5a7
--- /dev/null
+++ b/huner/ner_scripts/requirements.txt
@@ -0,0 +1,5 @@
+pexpect
+tqdm
+lxml
+beautifulsoup4
+rarfile
\ No newline at end of file
diff --git a/huner/ner_scripts/scripts/.opennlp_wrapper.py.swp b/huner/ner_scripts/scripts/.opennlp_wrapper.py.swp
new file mode 100644
index 0000000..8e10a18
Binary files /dev/null and b/huner/ner_scripts/scripts/.opennlp_wrapper.py.swp differ
diff --git a/huner/ner_scripts/scripts/S800_species_to_conll.py b/huner/ner_scripts/scripts/S800_species_to_conll.py
new file mode 100644
index 0000000..00cc6c7
--- /dev/null
+++ b/huner/ner_scripts/scripts/S800_species_to_conll.py
@@ -0,0 +1,59 @@
+import argparse
+import utils
+import os
+from opennlp_wrapper import SentenceSplitter
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input_dir")
+parser.add_argument("output")
+args = parser.parse_args()
+
+opennlp_path = os.environ['OPENNLP']
+sentence_splitter = SentenceSplitter(opennlp_path, 'en-sent.bin')
+
+sentences = []
+entities = []
+document_ids = []
+
+files = set(os.listdir(os.path.join(args.input_dir, 'abstracts')))
+
+with open(os.path.join(args.input_dir, 'S800.tsv'), 'r') as f_in:
+    last_doc = ''
+    tmp_sentences = []
+    tmp_entities = []
+
+    for line in f_in:
+        if not line:
+            continue
+        line = line.split('\t')
+        if line[1].split(':')[0] != last_doc:
+            sentences += tmp_sentences
+            entities += tmp_entities
+            document_ids += [last_doc.split(':')[0]] * len(tmp_sentences)
+            last_doc = line[1].split(':')[0]
+            with open(os.path.join(args.input_dir, 'abstracts', last_doc + '.txt'), 'r') as doc:
+                files.remove(last_doc + '.txt')
+                tmp_sentences = sentence_splitter.split(doc.read())
+                tmp_entities = [[] for _ in tmp_sentences]
+        id, start, end = sentence_splitter.map_offsets(int(line[2]), int(line[3])+1)
+        while len(tmp_sentences[id])<end:
+            tmp_sentences = sentence_splitter.merge_sentences(id)
+            tmp_entities[id] += tmp_entities[id+1]
+            del tmp_entities[id+1]
+            id, start, end = sentence_splitter.map_offsets(int(line[2]), int(line[3])+1)
+        assert tmp_sentences[id][start:end] == line[4].strip()
+        tmp_entities[id] += [(start, end)]
+    sentences += tmp_sentences
+    entities += tmp_entities
+    document_ids += [last_doc.split(':')[0]] * len(tmp_sentences)
+
+for file in files:
+    with open(os.path.join(args.input_dir, 'abstracts', file), 'r') as doc:
+        tmp_sentences = sentence_splitter.split(doc.read())
+        tmp_entities = [[] for _ in tmp_sentences]
+        sentences += tmp_sentences
+        entities += tmp_entities
+        document_ids += [file.strip('.txt')] * len(tmp_sentences)
+
+with open(args.output, 'w') as f_out:
+    utils.write_to_conll(sentences, entities, document_ids, f_out)
diff --git a/huner/ner_scripts/scripts/__pycache__/opennlp_wrapper.cpython-36.pyc b/huner/ner_scripts/scripts/__pycache__/opennlp_wrapper.cpython-36.pyc
new file mode 100644
index 0000000..790fa70
Binary files /dev/null and b/huner/ner_scripts/scripts/__pycache__/opennlp_wrapper.cpython-36.pyc differ
diff --git a/huner/ner_scripts/scripts/arizona_disease_to_conll.py b/huner/ner_scripts/scripts/arizona_disease_to_conll.py
new file mode 100644
index 0000000..1db32db
--- /dev/null
+++ b/huner/ner_scripts/scripts/arizona_disease_to_conll.py
@@ -0,0 +1,45 @@
+# Arizona disease is excluded from the automatic conversion and splitting process, due to its overlap with NCBI disease.
+# Simultaneous evaluation on both corpora could lead to skewed results.
+# The conversion script is still given, in case evaluation on this corpus is still intended.
+
+import argparse
+import utils
+from collections import defaultdict
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input")
+parser.add_argument("output")
+args = parser.parse_args()
+
+sentences = {}
+sentence_ids_in_order = []
+entities_per_sentence = defaultdict(list)
+document_ids = []
+
+with open(args.input, encoding='latin1') as f_in, open(args.output, 'w') as f_out:
+    next(f_in)
+    for line in f_in:
+        document_id = line.split('\t')[0]
+        pmid = line.split('\t')[1]
+        sentence_no = line.split('\t')[2]
+
+        sentence_id = pmid + '.' + sentence_no
+        if not len(sentence_ids_in_order) or sentence_ids_in_order[-1] != sentence_id:
+            sentence_ids_in_order.append(sentence_id)
+            document_ids.append(document_id)
+        sentence = line.split('\t')[3]
+
+        assert sentence_id not in sentences or sentences[sentence_id] == sentence
+        sentences[sentence_id] = sentence
+
+        try:
+            start_point = int(line.split('\t')[4]) - 1
+            end_point = int(line.split('\t')[5])
+        except ValueError:  # no annotation
+            continue
+
+        entities_per_sentence[sentence_id].append((start_point, end_point))
+
+    sentences = [sentences[s_id] for s_id in sentence_ids_in_order]
+    entities = [utils.merge_overlapping_entities(entities_per_sentence[s_id]) for s_id in sentence_ids_in_order]
+    utils.write_to_conll(sentences, entities, document_ids, f_out)
diff --git a/huner/ner_scripts/scripts/bc2gm_disease_to_conll.py b/huner/ner_scripts/scripts/bc2gm_disease_to_conll.py
new file mode 100644
index 0000000..c739d69
--- /dev/null
+++ b/huner/ner_scripts/scripts/bc2gm_disease_to_conll.py
@@ -0,0 +1,53 @@
+import argparse
+import utils
+from collections import defaultdict
+
+parser = argparse.ArgumentParser()
+parser.add_argument("sentences")
+parser.add_argument("tags")
+parser.add_argument("output")
+args = parser.parse_args()
+
+sentences = {}
+sentence_ids_in_order = []
+entities_per_sentence = defaultdict(list)
+document_ids = []
+
+with open(args.sentences) as f_in:
+    for line in f_in:
+        sentence_id = line.split()[0]
+        document_ids.append(sentence_id)
+
+        if not len(sentence_ids_in_order) or sentence_ids_in_order[-1] != sentence_id:
+            sentence_ids_in_order.append(sentence_id)
+        sentence = " ".join(line.split()[1:])
+
+        assert sentence_id not in sentences or sentences[sentence_id] == sentence
+        sentences[sentence_id] = sentence
+
+with open(args.tags) as f_in:
+    for line in f_in:
+        split = line.split('|')
+        sentence_id = split[0]
+        sentence = sentences[sentence_id]
+        start_idx, end_idx = [int(i) for i in split[1].split()]
+        entity = split[2].strip()
+
+        non_whitespaces_chars = 0
+        new_start_idx = None
+        new_end_idx = None
+        for i, char in enumerate(sentence):
+            if char != ' ':
+                non_whitespaces_chars += 1
+            if new_start_idx is None and non_whitespaces_chars == start_idx+1:
+                new_start_idx = i
+            if non_whitespaces_chars == end_idx+1:
+                new_end_idx = i+1
+                break
+        entities_per_sentence[sentence_id].append((new_start_idx, new_end_idx))
+
+
+with open(args.output, 'w') as f_out:
+    sentences = [sentences[s_id] for s_id in sentence_ids_in_order]
+    entities = [utils.merge_overlapping_entities(entities_per_sentence[s_id]) for s_id in sentence_ids_in_order]
+    utils.write_to_conll(sentences, entities, document_ids, f_out)
diff --git a/huner/ner_scripts/scripts/bc2gm_gene_to_conll.py b/huner/ner_scripts/scripts/bc2gm_gene_to_conll.py
new file mode 100644
index 0000000..c739d69
--- /dev/null
+++ b/huner/ner_scripts/scripts/bc2gm_gene_to_conll.py
@@ -0,0 +1,53 @@
+import argparse
+import utils
+from collections import defaultdict
+
+parser = argparse.ArgumentParser()
+parser.add_argument("sentences")
+parser.add_argument("tags")
+parser.add_argument("output")
+args = parser.parse_args()
+
+sentences = {}
+sentence_ids_in_order = []
+entities_per_sentence = defaultdict(list)
+document_ids = []
+
+with open(args.sentences) as f_in:
+    for line in f_in:
+        sentence_id = line.split()[0]
+        document_ids.append(sentence_id)
+
+        if not len(sentence_ids_in_order) or sentence_ids_in_order[-1] != sentence_id:
+            sentence_ids_in_order.append(sentence_id)
+        sentence = " ".join(line.split()[1:])
+
+        assert sentence_id not in sentences or sentences[sentence_id] == sentence
+        sentences[sentence_id] = sentence
+
+with open(args.tags) as f_in:
+    for line in f_in:
+        split = line.split('|')
+        sentence_id = split[0]
+        sentence = sentences[sentence_id]
+        start_idx, end_idx = [int(i) for i in split[1].split()]
+        entity = split[2].strip()
+
+        non_whitespaces_chars = 0
+        new_start_idx = None
+        new_end_idx = None
+        for i, char in enumerate(sentence):
+            if char != ' ':
+                non_whitespaces_chars += 1
+            if new_start_idx is None and non_whitespaces_chars == start_idx+1:
+                new_start_idx = i
+            if non_whitespaces_chars == end_idx+1:
+                new_end_idx = i+1
+                break
+        entities_per_sentence[sentence_id].append((new_start_idx, new_end_idx))
+
+
+with open(args.output, 'w') as f_out:
+    sentences = [sentences[s_id] for s_id in sentence_ids_in_order]
+    entities = [utils.merge_overlapping_entities(entities_per_sentence[s_id]) for s_id in sentence_ids_in_order]
+    utils.write_to_conll(sentences, entities, document_ids, f_out)
diff --git a/huner/ner_scripts/scripts/bioinfer_to_conll.py b/huner/ner_scripts/scripts/bioinfer_to_conll.py
new file mode 100644
index 0000000..9091dab
--- /dev/null
+++ b/huner/ner_scripts/scripts/bioinfer_to_conll.py
@@ -0,0 +1,70 @@
+import argparse
+import utils
+from collections import defaultdict
+from lxml import etree
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input")
+parser.add_argument("output")
+args = parser.parse_args()
+
+sentences = {}
+sentence_ids_in_order = []
+entities_per_sentence = defaultdict(list)
+token_ids_per_sentence = {}
+
+with open(args.input) as f_in:
+    tree = etree.parse(f_in)
+    sentence_elems = tree.xpath('//sentence')
+    for sentence in sentence_elems:
+        sentence_id = sentence.attrib['id']
+        sentence_ids_in_order.append(sentence_id)
+        token_ids = []
+        token_offsets = []
+        sentence_text = ""
+
+        all_entity_token_ids = []
+        entities = (sentence.xpath(".//entity[@type='Individual_protein']") +
+                    sentence.xpath(".//entity[@type='Gene/protein/RNA']") +
+                    sentence.xpath(".//entity[@type='Gene']") +
+                    sentence.xpath(".//entity[@type='Protein_family_or_group']") +
+                    sentence.xpath(".//entity[@type='Protein_complex']") +
+                    sentence.xpath(".//entity[@type='DNA_family_or_group']"))
+        for entity in entities:
+            valid_entity = True
+            entity_token_ids = set()
+            for subtoken in entity.xpath('.//nestedsubtoken'):
+                token_id = '.'.join(subtoken.attrib['id'].split('.')[1:3])
+                entity_token_ids.add(token_id)
+
+            if valid_entity:
+                all_entity_token_ids.append(entity_token_ids)
+
+        for token in sentence.xpath('.//token'):
+            token_text = ''.join(token.xpath('.//subtoken/@text'))
+            token_id = '.'.join(token.attrib['id'].split('.')[1:])
+            token_ids.append(token_id)
+            token_offsets.append(len(sentence_text)+1)
+            sentence_text += ' ' + token_text
+
+        assert sentence_id not in sentences or sentences[sentence_id] == sentence_text
+        sentences[sentence_id] = sentence_text
+
+        for entity_token_ids in all_entity_token_ids:
+            entity_start = None
+            for token_idx, (token_id, token_offset) in enumerate(zip(token_ids, token_offsets)):
+                if token_id in entity_token_ids:
+                    if entity_start is None:
+                        entity_start = token_offset
+                else:
+                    if entity_start is not None:
+                        entities_per_sentence[sentence_id].append((entity_start, token_offset - 1))
+                        entity_start = None
+
+
+with open(args.output, 'w') as f_out:
+    sentences = [sentences[s_id] for s_id in sentence_ids_in_order]
+    entities = [utils.merge_overlapping_entities(entities_per_sentence[s_id]) for s_id in sentence_ids_in_order]
+    def tokenizer(sentence):
+        return sentence.split()
+    utils.write_to_conll(sentences, entities, [str(x) for x in range(0, len(sentence_ids_in_order))], f_out, tokenizer=tokenizer)
diff --git a/huner/ner_scripts/scripts/biosemantics_diseases_to_conll.py b/huner/ner_scripts/scripts/biosemantics_diseases_to_conll.py
new file mode 100644
index 0000000..32a39fd
--- /dev/null
+++ b/huner/ner_scripts/scripts/biosemantics_diseases_to_conll.py
@@ -0,0 +1,61 @@
+import argparse
+import os
+from tqdm import tqdm
+
+import utils
+from opennlp_wrapper import SentenceSplitter
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input_dir")
+parser.add_argument("types")
+parser.add_argument("output")
+args = parser.parse_args()
+
+types = args.types.split(',')
+
+opennlp_path = os.environ['OPENNLP']
+sentence_splitter = SentenceSplitter(opennlp_path, 'en-sent.bin')
+
+dirs = [file for file in os.listdir(args.input_dir) if os.path.isdir(os.path.join(args.input_dir, file))]
+files = []
+for directory in dirs:
+    files += [os.path.join(directory, file) for file in os.listdir(os.path.join(args.input_dir, directory)) if file[-4:]=='.ann']
+
+sentences = []
+entities = []
+document_ids = []
+
+for file in tqdm(files):
+    with open(os.path.join(args.input_dir, file), 'r') as f_ann:
+        with open(os.path.join(args.input_dir, file[:-4]+'.txt'), 'r') as f_txt:
+            document_id = os.path.basename(file).split('_')[0]
+            text = f_txt.read()
+            tmp_sentences = sentence_splitter.split(text)
+            tmp_entities = [[] for _ in tmp_sentences]
+            for line in f_ann:
+                if line[-1] == '\n':
+                    line = line[:-1]
+                if not line:
+                    continue
+                line = line.split('\t')
+                mid = line[1].split()
+                line = [line[0], mid[0], mid[1], mid[-1], line[2]]
+                if line[1] not in types:
+                    continue
+                o_start = int(line[2])
+                o_end = int(line[3])
+                id, start, end = sentence_splitter.map_offsets(o_start, o_end)
+                while (len(tmp_sentences[id]) < end):
+                    tmp_sentences = sentence_splitter.merge_sentences(id)
+                    tmp_entities[id] += tmp_entities[id + 1]
+                    del tmp_entities[id + 1]
+                    id, start, end = sentence_splitter.map_offsets(o_start, o_end)
+                assert tmp_sentences[id][start:end] == text[o_start:o_end].replace('\n', ' ')
+                assert tmp_sentences[id][start:end] == line[4]
+                tmp_entities[id] += [(start, end)]
+            sentences += tmp_sentences
+            document_ids += [document_id] * len(tmp_sentences)
+            entities += tmp_entities
+
+with open(args.output, 'w') as f_out:
+    utils.write_to_conll(sentences, entities, document_ids, f_out)
diff --git a/huner/ner_scripts/scripts/biosemantics_to_conll.py b/huner/ner_scripts/scripts/biosemantics_to_conll.py
new file mode 100644
index 0000000..dbc89d2
--- /dev/null
+++ b/huner/ner_scripts/scripts/biosemantics_to_conll.py
@@ -0,0 +1,69 @@
+import argparse
+import os
+from tqdm import tqdm
+
+import utils
+from opennlp_wrapper import SentenceSplitter
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input_dir")
+parser.add_argument("types")
+parser.add_argument("output")
+args = parser.parse_args()
+
+types = args.types.split(',')
+
+opennlp_path = os.environ['OPENNLP']
+sentence_splitter = SentenceSplitter(opennlp_path, 'en-sent.bin')
+
+dirs = [file for file in os.listdir(args.input_dir) if os.path.isdir(os.path.join(args.input_dir, file))]
+files = []
+for directory in dirs:
+    files += [os.path.join(directory, file) for file in os.listdir(os.path.join(args.input_dir, directory)) if
+              file[-4:] == '.ann']
+
+sentences = []
+entities = []
+document_ids = []
+
+for file in tqdm(files):
+    file_is_dirty = False
+    with open(os.path.join(args.input_dir, file), 'r') as f_ann:
+        with open(os.path.join(args.input_dir, file[:-4] + '.txt'), 'r') as f_txt:
+            document_id = os.path.basename(file).split('_')[0]
+            text = f_txt.read()
+            tmp_sentences = sentence_splitter.split(text)
+            tmp_entities = [[] for _ in tmp_sentences]
+            for line in f_ann:
+                if line[-1] == '\n':
+                    line = line[:-1]
+                if not line:
+                    continue
+                line = line.split('\t')
+                mid = line[1].split()
+                line = [line[0], mid[0], mid[1], mid[-1], line[2]]
+                if line[1] not in types:
+                    continue
+                o_start = int(line[2])
+                o_end = int(line[3])
+                id, start, end = sentence_splitter.map_offsets(o_start, o_end)
+                while len(tmp_sentences[id]) < end:
+                    tmp_sentences = sentence_splitter.merge_sentences(id)
+                    tmp_entities[id] += tmp_entities[id + 1]
+                    del tmp_entities[id + 1]
+                    id, start, end = sentence_splitter.map_offsets(o_start, o_end)
+
+                if (tmp_sentences[id][start:end] != text[o_start:o_end].replace('\n', ' ') or
+                        tmp_sentences[id][start:end] != line[4]):
+                    file_is_dirty = True
+                    break
+                else:
+                    tmp_entities[id] += [(start, end)]
+
+            if not file_is_dirty:
+                sentences += tmp_sentences
+                entities += tmp_entities
+                document_ids += [document_id] * len(tmp_sentences)
+
+with open(args.output, 'w') as f_out:
+    utils.write_to_conll(sentences, entities, document_ids, f_out)
diff --git a/huner/ner_scripts/scripts/cdr_to_conll.py b/huner/ner_scripts/scripts/cdr_to_conll.py
new file mode 100644
index 0000000..889c606
--- /dev/null
+++ b/huner/ner_scripts/scripts/cdr_to_conll.py
@@ -0,0 +1,21 @@
+import argparse
+
+import extractors
+import utils
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input")
+parser.add_argument("output")
+parser.add_argument("type")
+args = parser.parse_args()
+
+
+all_sentences = []
+all_entities = []
+
+with open(args.input, 'r') as f_in:
+    type = args.type[0].upper() + args.type[1:]
+    sentences, entities, document_ids = extractors.extract_from_biocreative(f_in, type, split_sentences=True)
+
+with open(args.output, 'w') as f_out:
+    utils.write_to_conll(sentences, entities, document_ids, f_out)
diff --git a/huner/ner_scripts/scripts/cellfinder_to_conll.py b/huner/ner_scripts/scripts/cellfinder_to_conll.py
new file mode 100644
index 0000000..67ffbd4
--- /dev/null
+++ b/huner/ner_scripts/scripts/cellfinder_to_conll.py
@@ -0,0 +1,48 @@
+import argparse
+import utils
+import os
+from opennlp_wrapper import SentenceSplitter
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input_dir")
+parser.add_argument("type")
+parser.add_argument("output")
+args = parser.parse_args()
+
+opennlp_path = os.environ['OPENNLP']
+sentence_splitter = SentenceSplitter(opennlp_path, 'en-sent.bin')
+
+sentences = []
+entities = []
+document_ids = []
+
+ann_files = [file for file in os.listdir(args.input_dir) if file[-4:]=='.ann']
+
+for ann_file in ann_files:
+    txt_file = ann_file[:-4] + '.txt'
+    with open(os.path.join(args.input_dir, ann_file)) as f_ann:
+        with open(os.path.join(args.input_dir, txt_file)) as f_txt:
+            document_id = os.path.basename(txt_file).strip('.txt')
+            tmp_sentences = sentence_splitter.split(f_txt.read())
+            tmp_entities = [[] for _ in tmp_sentences]
+            for line in f_ann:
+                if not line:
+                    continue
+                line = line.split('\t')
+                line = [line[0]] + line[1].split() + [line[2]]
+                if line[1] != args.type:
+                    continue
+                id, start, end = sentence_splitter.map_offsets(int(line[2]), int(line[3]))
+                while len(tmp_sentences[id]) < end:
+                    tmp_sentences = sentence_splitter.merge_sentences(id)
+                    tmp_entities[id] += tmp_entities[id + 1]
+                    del tmp_entities[id + 1]
+                    id, start, end = sentence_splitter.map_offsets(int(line[2]), int(line[3]))
+                assert tmp_sentences[id][start:end] == line[4].strip()
+                tmp_entities[id] += [(start, end)]
+    sentences += tmp_sentences
+    document_ids += [document_id] * len(tmp_sentences)
+    entities += tmp_entities
+
+with open(args.output, 'w') as f_out:
+    utils.write_to_conll(sentences, entities, document_ids, f_out)
diff --git a/huner/ner_scripts/scripts/chebi_to_conll.py b/huner/ner_scripts/scripts/chebi_to_conll.py
new file mode 100644
index 0000000..5cd6486
--- /dev/null
+++ b/huner/ner_scripts/scripts/chebi_to_conll.py
@@ -0,0 +1,100 @@
+import argparse
+from glob import glob
+from tqdm import tqdm
+
+import os
+from bs4 import BeautifulSoup
+
+import utils
+from opennlp_wrapper import SentenceSplitter
+
+
+def is_named_entity(entity):
+    try:
+        return entity['type'] in {
+            'CHEMICAL',
+            'FORMULA',
+            'LIGAND',
+            'CM',
+            'CLASS'
+        }
+
+    except KeyError:
+        return False
+
+
+def extract_sentence_info(sentence):
+    """
+    :param sentence:
+    :return:
+    """
+    sentence_text = []
+    sentence_entities = []
+
+    def helper(entity):
+        if hasattr(entity, "children"):
+            if is_named_entity(entity):
+                # Hack around immutable strings + scoping mechanisms
+                # (see https://stackoverflow.com/questions/5218895/python-nested-functions-variable-scoping)
+                text = "".join(sentence_text)
+                entity_start = len(text)
+                sentence_text.append(entity.get_text())
+                entity_end = len(text) + len(entity.get_text())
+                sentence_entities.append((entity_start, entity_end))
+            else:
+                for child in entity.children:
+                    helper(child)
+        else:
+            sentence_text.append(entity)
+
+    for child in sentence.children:
+        helper(child)
+
+    return "".join(sentence_text), sentence_entities
+
+
+if __name__ == '__main__':
+    parser = argparse.ArgumentParser()
+    parser.add_argument("input")
+    parser.add_argument("output")
+    args = parser.parse_args()
+
+    opennlp_path = os.environ['OPENNLP']
+    sentence_splitter = SentenceSplitter(opennlp_path, 'en-sent.bin')
+
+    all_sentences = []
+    all_entities = []
+    documents = glob(os.path.join(args.input, '**', '*.xml'))
+    document_ids = []
+    for document in tqdm(documents):
+        with open(document, 'r') as f_in:
+            soup = BeautifulSoup(f_in, 'lxml')
+            for paragraph in soup.find_all('snippet'):
+                if len(paragraph.text.strip()) == 0:
+                    continue
+                # each (new-line-separated) sentence seems to be valid html
+                # so we extract the source, split at newline and parse again
+                source = "".join(str(elem) for elem in paragraph.children)
+                sentences = source.split('\n')
+                for sentence in sentences:
+                    document_id = os.path.basename(os.path.dirname(document))
+                    sentence_bs = BeautifulSoup(sentence, 'lxml')
+                    sentence_text, sentence_entities = extract_sentence_info(sentence_bs)
+                    tmp_sentences = sentence_splitter.split(sentence_text)
+                    tmp_entities = [[] for _ in tmp_sentences]
+                    for entity in sentence_entities:
+                        org_start = entity[0]
+                        org_end = entity[1]
+                        id, start, end = sentence_splitter.map_offsets(org_start, org_end)
+                        while len(tmp_sentences[id]) < end:
+                            tmp_sentences = sentence_splitter.merge_sentences(id)
+                            tmp_entities[id] += tmp_entities[id + 1]
+                            del tmp_entities[id + 1]
+                            id, start, end = sentence_splitter.map_offsets(org_start, org_end)
+                        tmp_entities[id] += [(start, end)]
+                    all_sentences += tmp_sentences
+                    all_entities += tmp_entities
+                    document_ids += [document_id] * len(tmp_sentences)
+
+    with open(args.output, 'w') as f_out:
+        utils.write_to_conll(all_sentences, all_entities, document_ids, f_out)
diff --git a/huner/ner_scripts/scripts/cll_cell_lines_to_conll.py b/huner/ner_scripts/scripts/cll_cell_lines_to_conll.py
new file mode 100644
index 0000000..9532a26
--- /dev/null
+++ b/huner/ner_scripts/scripts/cll_cell_lines_to_conll.py
@@ -0,0 +1,40 @@
+import argparse
+import os
+from glob import glob
+
+from opennlp_wrapper import OpenNLP
+
+opennlp_path = os.environ['OPENNLP']
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input_dir")
+parser.add_argument("output")
+args = parser.parse_args()
+
+pos_tagger = OpenNLP(opennlp_path, 'POSTagger', 'en-pos-maxent.bin')
+input_files = glob(args.input_dir)
+if os.path.exists(args.output):
+    os.remove(args.output)
+
+for fname in input_files:
+    with open(fname, 'r') as f_in:
+        with open(args.output, 'a') as f_out:
+            document_id = os.path.basename(fname).strip('.conll')
+            tokens = []
+            entities = []
+            for line in f_in:
+                line = line.strip()
+                if not line:
+                    pos_tags = pos_tagger.parse(' '.join(tokens)).decode().split()
+                    for pos_tag, token, entity in zip(pos_tags, tokens, entities):
+                        f_out.write(document_id + ' ' + token + ' ' + pos_tag.split('_')[-1] + ' ' + entity + '\n')
+                    f_out.write('\n')
+                    tokens = []
+                    entities = []
+                else:
+                    parts = line.split()
+                    tokens += [parts[1].strip()]
+                    entity = parts[0].strip()
+                    if len(entity) == 4:
+                        entity = entity[:-2] + 'NP'
+                    entities += [entity]
diff --git a/huner/ner_scripts/scripts/craft_to_conll.py b/huner/ner_scripts/scripts/craft_to_conll.py
new file mode 100644
index 0000000..d90974e
--- /dev/null
+++ b/huner/ner_scripts/scripts/craft_to_conll.py
@@ -0,0 +1,66 @@
+import argparse
+import os
+from tqdm import tqdm
+from lxml import etree
+
+import utils
+from opennlp_wrapper import SentenceSplitter
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input_dir")
+parser.add_argument("types")
+parser.add_argument("output")
+args = parser.parse_args()
+
+types = args.types.split(',')
+
+opennlp_path = os.environ['OPENNLP']
+sentence_splitter = SentenceSplitter(opennlp_path, 'en-sent.bin')
+
+files = []
+
+files = [os.path.join(args.input_dir, 'xml', 'TYPE', file) for file in
+         os.listdir(os.path.join(args.input_dir, 'xml', types[0])) if file[-4:] == '.xml']
+
+sentences = []
+entities = []
+document_ids = []
+
+for file in tqdm(files):
+    txt_path = os.path.join(args.input_dir, 'articles', 'txt', os.path.basename(file)[:12])
+    annotations = []
+    for t in types:
+        f_ann = open(file.replace('TYPE', t), 'r')
+        ann_tree = etree.parse(f_ann)
+        annotations += ann_tree.xpath('//annotation')
+    with open(txt_path, 'r') as f_txt:
+        document_id = os.path.basename(file).split('.')[0]
+        text = f_txt.read()
+        tmp_sentences = sentence_splitter.split(text)
+        tmp_entities = [[] for _ in tmp_sentences]
+        for ann in annotations:
+            span = ann.xpath('span')[0]
+            entity = ann.xpath('spannedText')[0].text
+            o_start = int(span.get('start'))
+            o_end = int(span.get('end'))
+            id, start, end = sentence_splitter.map_offsets(o_start, o_end)
+            while len(tmp_sentences[id]) < end:
+                tmp_sentences = sentence_splitter.merge_sentences(id)
+                tmp_entities[id] += tmp_entities[id + 1]
+                del tmp_entities[id + 1]
+                id, start, end = sentence_splitter.map_offsets(o_start, o_end)
+
+            if (tmp_sentences[id][start:end] != text[o_start:o_end].replace('\n', ' ') or
+                    tmp_sentences[id][start:end] != entity):
+                if entity.find('...') == -1:
+                    print(f'Encountered error in file {file} for entity {entity}')
+                    break
+            else:
+                tmp_entities[id] += [(start, end)]
+
+        sentences += tmp_sentences
+        entities += tmp_entities
+        document_ids += [document_id] * len(tmp_sentences)
+
+with open(args.output, 'w') as f_out:
+    utils.write_to_conll(sentences, entities, document_ids, f_out)
diff --git a/huner/ner_scripts/scripts/deca_genes_to_conll.py b/huner/ner_scripts/scripts/deca_genes_to_conll.py
new file mode 100644
index 0000000..64735ac
--- /dev/null
+++ b/huner/ner_scripts/scripts/deca_genes_to_conll.py
@@ -0,0 +1,64 @@
+import argparse
+import utils
+import os
+from opennlp_wrapper import SentenceSplitter
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input_dir")
+parser.add_argument("output")
+args = parser.parse_args()
+
+opennlp_path = os.environ['OPENNLP']
+sentence_splitter = SentenceSplitter(opennlp_path, 'en-sent.bin')
+
+sentences = []
+entities = []
+document_ids = []
+
+files = set(os.listdir(os.path.join(args.input_dir, 'text')))
+files = set(fname for fname in files if not fname.startswith('.'))
+
+with open(os.path.join(args.input_dir, 'gold.txt'), 'r') as f_in:
+    last_doc = ''
+    tmp_sentences = []
+    tmp_entities = []
+    for line in f_in:
+        if not line:
+            continue
+        line = line.split('\t')
+        if line[0] != last_doc:
+            document_id = os.path.basename(last_doc).strip('.txt')
+            sentences += tmp_sentences
+            entities += tmp_entities
+            document_ids += [document_id] * len(tmp_sentences)
+            last_doc = line[0]
+            with open(os.path.join(args.input_dir, 'text', last_doc), 'r') as doc:
+                files.remove(last_doc)
+                tmp_sentences = sentence_splitter.split(doc.read())
+                tmp_entities = [[] for _ in tmp_sentences]
+        id, start, end = sentence_splitter.map_offsets(int(line[1]), int(line[2]))
+        while len(tmp_sentences[id])<end:
+            tmp_sentences = sentence_splitter.merge_sentences(id)
+            tmp_entities[id] += tmp_entities[id+1]
+            del tmp_entities[id+1]
+            id, start, end = sentence_splitter.map_offsets(int(line[1]), int(line[2]))
+        assert tmp_sentences[id][start:end] == line[3]
+        tmp_entities[id] += [(start, end)]
+
+    document_id = os.path.basename(last_doc).strip('.txt')
+    sentences += tmp_sentences
+    entities += tmp_entities
+    document_ids += [document_id] * len(tmp_sentences)
+
+
+for file in files:
+    with open(os.path.join(args.input_dir, 'text', file), 'r') as doc:
+        tmp_sentences = sentence_splitter.split(doc.read())
+        tmp_entities = [[] for _ in tmp_sentences]
+        sentences += tmp_sentences
+        entities += tmp_entities
+        document_ids += [os.path.basename(file).strip('.txt')] * len(tmp_sentences)
+
+
+with open(args.output, 'w') as f_out:
+    utils.write_to_conll(sentences, entities, document_ids, f_out)
diff --git a/huner/ner_scripts/scripts/extractors.py b/huner/ner_scripts/scripts/extractors.py
new file mode 100644
index 0000000..f6c65a0
--- /dev/null
+++ b/huner/ner_scripts/scripts/extractors.py
@@ -0,0 +1,77 @@
+import os
+from lxml import etree
+from tqdm import tqdm
+
+from opennlp_wrapper import SentenceSplitter
+
+
+opennlp_path = os.environ['OPENNLP']
+
+
+def extract_from_biocreative(f, annotation_type, split_sentences=False) :
+    sentence_splitter = SentenceSplitter(opennlp_path, 'en-sent.bin')
+    tree = etree.parse(f)
+    sentences = []
+    entities = []
+    document_ids = []
+    documents = tree.xpath('.//document')
+
+    for document in tqdm(documents):
+        document_id = document.xpath('./id')[0].text
+        passages = document.xpath('passage')
+        uses_passage_offset = len(passages) > 1
+
+        for passage in document.xpath('passage'):
+            text = passage.xpath('text/text()')[0]
+
+            if not split_sentences:
+                tmp_sentences = text.split('\n')
+            else:
+                tmp_sentences = sentence_splitter.split(text)
+            tmp_entities = [[] for _ in tmp_sentences]
+
+            for annotation in passage.xpath('.//annotation'):
+                # skip non-contiguous entities
+                if len(annotation.xpath('.//location')) > 1:
+                    continue
+
+                is_entity = False
+
+                for infon in annotation.xpath('.//infon'):
+                    # Check if multiple types are given as a list
+                    if type(annotation_type)==type(""):
+                        is_entity |= ((infon.get('key') == 'type') & (infon.text == annotation_type))
+                    else:
+                        is_entity |= ((infon.get('key') == 'type') & (infon.text in annotation_type))
+                if not is_entity:
+                    continue
+                offset = int(annotation.xpath('.//location')[0].get('offset'))
+                if uses_passage_offset:
+                    offset -= int(passage.xpath('./offset/text()')[0])
+                length = int(annotation.xpath('.//location')[0].get('length'))
+                if not split_sentences:
+                    sentence_idx = 0
+                    while offset > len(tmp_sentences[sentence_idx]):
+                        offset -= len(tmp_sentences[sentence_idx])+1
+                        sentence_idx += 1
+                    end = offset + length
+                else:
+                    o_end = offset + length
+                    o_offset = offset
+                    sentence_idx, offset, end = sentence_splitter.map_offsets(o_offset, o_end)
+                    while (len(tmp_sentences[sentence_idx])<end):
+                        tmp_sentences = sentence_splitter.merge_sentences(sentence_idx)
+                        tmp_entities[sentence_idx] += tmp_entities[sentence_idx+1]
+                        del tmp_entities[sentence_idx+1]
+                        sentence_idx, offset, end = sentence_splitter.map_offsets(o_offset, o_end)
+                annotated_entity = tmp_sentences[sentence_idx][offset:end]
+                true_entity = annotation.xpath('.//text')[0].text
+                assert annotated_entity.lower() == true_entity.lower()
+
+                tmp_entities[sentence_idx] += [(offset, end)]
+
+            document_ids += [document_id] * len(tmp_sentences)
+            sentences += tmp_sentences
+            entities += tmp_entities
+
+    return sentences, entities, document_ids
diff --git a/huner/ner_scripts/scripts/fsu_gene_to_conll.py b/huner/ner_scripts/scripts/fsu_gene_to_conll.py
new file mode 100644
index 0000000..36e115d
--- /dev/null
+++ b/huner/ner_scripts/scripts/fsu_gene_to_conll.py
@@ -0,0 +1,65 @@
+import argparse
+import os
+from lxml import etree
+
+import utils
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input_dirs")
+parser.add_argument("output")
+args = parser.parse_args()
+
+sentences = []
+entities = []
+document_ids = []
+
+for dir in args.input_dirs.split(','):
+    docs = [file for file in os.listdir(os.path.join(dir, 'mmax')) if os.path.isdir(os.path.join(dir, 'mmax', file))]
+    for doc in docs:
+        try:
+            word_f = open(os.path.join(dir, 'mmax', doc, 'Basedata', 'Basedata.xml'), 'r')
+            sentence_f = open(os.path.join(dir, 'mmax', doc, 'Markables', 'sentence.xml'), 'r')
+            protein_f = open(os.path.join(dir, 'mmax', doc, 'Markables', 'proteins.xml'), 'r')
+            id_f = open(os.path.join(dir, 'mmax', doc, 'Basedata.uri'), 'r')
+            document_id = id_f.read().strip()
+            word_tree = etree.parse(word_f)
+            sentence_tree = etree.parse(sentence_f).getroot()
+            protein_tree = etree.parse(protein_f).getroot()
+        except:
+            print('Skipped invalid XML')
+            continue
+        word_to_id = {}
+        words = []
+        for i, token in enumerate(word_tree.xpath('.//word')):
+            words += [token.text]
+            word_to_id[token.get('id')] = i
+        word_pos = [(0,0) for _ in words]
+        pre_sentences = []
+        for sentence in sentence_tree:
+            pre_sentences += [(int(sentence.get('id').split('_')[-1]), sentence.get('span'))]
+        pre_sentences.sort()
+        tmp_sentences = []
+        for j, sentence in enumerate(pre_sentences):
+            tmp_sentence = []
+            akt_pos = 0
+            start = word_to_id[sentence[1].split('..')[0]]
+            end = word_to_id[sentence[1].split('..')[1]]
+            for i in range(start, end+1):
+                tmp_sentence += [words[i]]
+                word_pos[i] = (j, akt_pos)
+                akt_pos += len(words[i])+1
+            tmp_sentences += [tmp_sentence]
+        tmp_entities = [[] for _ in tmp_sentences]
+        for protein in protein_tree:
+            try:
+                start = word_to_id[protein.get('span').split('..')[0]]
+                end = word_to_id[protein.get('span').split('..')[-1]]
+                tmp_entities[word_pos[start][0]] += [(word_pos[start][1], word_pos[end][1]+len(words[end]))]
+            except:
+                print('Skipped multipart entity')
+        sentences += tmp_sentences
+        entities += tmp_entities
+        document_ids += [document_id] * len(tmp_sentences)
+
+with open(args.output, 'w') as f_out:
+    utils.write_to_conll([' '.join(x) for x in sentences], entities, document_ids, f_out, tokenizer=lambda x:x.split(' '))
diff --git a/huner/ner_scripts/scripts/gellus_to_conll.py b/huner/ner_scripts/scripts/gellus_to_conll.py
new file mode 100644
index 0000000..65d60ef
--- /dev/null
+++ b/huner/ner_scripts/scripts/gellus_to_conll.py
@@ -0,0 +1,41 @@
+import argparse
+import os
+from glob import glob
+
+from opennlp_wrapper import OpenNLP
+
+opennlp_path = os.environ['OPENNLP']
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input_dir")
+parser.add_argument("output")
+args = parser.parse_args()
+
+pos_tagger = OpenNLP(opennlp_path, 'POSTagger', 'en-pos-maxent.bin')
+
+if os.path.exists(args.output):
+    os.remove(args.output)
+
+files = glob(args.input_dir)
+for fname in files:
+    with open(fname, 'r') as f_in:
+        with open(args.output, 'a') as f_out:
+            document_id = os.path.basename(fname).strip('.conll')
+            tokens = []
+            entities = []
+            for line in f_in:
+                line = line.strip()
+                if not line:
+                    pos_tags = pos_tagger.parse(' '.join(tokens)).decode().split()
+                    for pos_tag, token, entity in zip(pos_tags, tokens, entities):
+                        f_out.write(document_id + ' ' + token + ' ' + pos_tag.split('_')[-1] + ' ' + entity + '\n')
+                    f_out.write('\n')
+                    tokens = []
+                    entities = []
+                else:
+                    parts = line.split()
+                    tokens += [parts[0].strip()]
+                    entity = parts[1].strip()
+                    if len(entity) == 4:
+                        entity = entity[:-2] + 'NP'
+                    entities += [entity]
diff --git a/huner/ner_scripts/scripts/genia_to_conll.py b/huner/ner_scripts/scripts/genia_to_conll.py
new file mode 100644
index 0000000..d2043f9
--- /dev/null
+++ b/huner/ner_scripts/scripts/genia_to_conll.py
@@ -0,0 +1,66 @@
+import argparse
+
+from bs4 import BeautifulSoup
+from tqdm import tqdm
+
+import utils
+
+
+def is_named_entity(entity):
+    try:
+        return entity['sem'] in {
+            'G#protein_molecule',
+            'G#protein_family_or_group'
+        }
+
+    except KeyError:
+        return False
+
+
+def extract_sentence_info(sentence):
+    """
+    :param sentence:
+    :return:
+    """
+    sentence_text = []
+    sentence_entities = []
+
+    def helper(entity):
+        if hasattr(entity, "children"):
+            if is_named_entity(entity):
+                # Hack around immutable strings + scoping mechanisms
+                # (see https://stackoverflow.com/questions/5218895/python-nested-functions-variable-scoping)
+                text = "".join(sentence_text)
+                entity_start = len(text)
+                sentence_text.append(entity.get_text())
+                entity_end = len(text) + len(entity.get_text())
+                sentence_entities.append((entity_start, entity_end))
+            else:
+                for child in entity.children:
+                    helper(child)
+        else:
+            sentence_text.append(entity)
+
+    for child in sentence.children:
+        helper(child)
+
+    return "".join(sentence_text), sentence_entities
+
+if __name__ == '__main__':
+    parser = argparse.ArgumentParser()
+    parser.add_argument("input")
+    parser.add_argument("output")
+    args = parser.parse_args()
+
+    all_sentences = []
+    all_entities = []
+
+    with open(args.input, 'r') as f_in:
+        soup = BeautifulSoup(f_in, 'lxml')
+        for sentence in tqdm(soup.find_all('sentence')):
+            sentence_text, sentence_entities = extract_sentence_info(sentence)
+            all_sentences.append(sentence_text)
+            all_entities.append(sentence_entities)
+
+    with open(args.output, 'w') as f_out:
+        utils.write_to_conll(all_sentences, all_entities, f_out)
diff --git a/huner/ner_scripts/scripts/gpro_gene_to_conll.py b/huner/ner_scripts/scripts/gpro_gene_to_conll.py
new file mode 100644
index 0000000..615e479
--- /dev/null
+++ b/huner/ner_scripts/scripts/gpro_gene_to_conll.py
@@ -0,0 +1,74 @@
+import argparse
+
+from tqdm import tqdm
+
+import utils
+import os
+from opennlp_wrapper import SentenceSplitter
+
+parser = argparse.ArgumentParser()
+parser.add_argument("text")
+parser.add_argument("annotations")
+parser.add_argument("output")
+args = parser.parse_args()
+
+opennlp_path = os.environ['OPENNLP']
+sentence_splitter = SentenceSplitter(opennlp_path, 'en-sent.bin')
+
+sentences = []
+entities = []
+document_ids = []
+
+with open(args.text, 'r') as f_text:
+    with open(args.annotations, 'r') as f_annotations:
+        texts = {}
+        for line in f_text:
+            if not line:
+                continue
+            parts = line.split('\t')
+            texts[parts[0]] = (parts[1], parts[2])
+        last_doc = ''
+        tmp_sentences = []
+        tmp_entities = []
+        for line in tqdm(f_annotations):
+            if not line:
+                continue
+            line = line.split('\t')
+            if line[0] != last_doc:
+                sentences += tmp_sentences
+                entities += tmp_entities
+                document_ids += [last_doc] * len(tmp_sentences)
+                if last_doc:
+                    del texts[last_doc]
+                last_doc = line[0]
+                tmp_sentences = sentence_splitter.split(texts[line[0]][1])
+                tmp_sentences += [texts[line[0]][0]]
+                tmp_entities = [[] for _ in tmp_sentences]
+            if line[1] == 'T':
+                tmp_entities[-1] += [(int(line[2]), int(line[3]))]
+                assert tmp_sentences[-1][int(line[2]):int(line[3])] == line[4]
+            else:
+                id, start, end = sentence_splitter.map_offsets(int(line[2]), int(line[3]))
+                while (len(tmp_sentences[id])<end):
+                    tmp_sentences = sentence_splitter.merge_sentences(id)
+                    tmp_entities[id] += tmp_entities[id+1]
+                    del tmp_entities[id+1]
+                    id, start, end = sentence_splitter.map_offsets(int(line[2]), int(line[3]))
+                assert tmp_sentences[id][start:end] == line[4]
+                tmp_entities[id] += [(start, end)]
+        sentences.append(tmp_sentences[-1])
+        sentences += tmp_sentences[:-1]
+        entities.append(tmp_entities[-1])
+        entities += tmp_entities[:-1]
+        document_ids += [last_doc] * len(tmp_sentences)
+
+    for document_id, text in texts.items():
+        tmp_sentences = [text[0]]
+        tmp_sentences += sentence_splitter.split(text[1])
+        tmp_entities = [[] for _ in tmp_sentences]
+        sentences += tmp_sentences
+        entities += tmp_entities
+        document_ids += [document_id] * len(tmp_sentences)
+
+with open(args.output, 'w') as f_out:
+    utils.write_to_conll(sentences, entities, document_ids, f_out)
diff --git a/huner/ner_scripts/scripts/hprd50_gene_to_conll.py b/huner/ner_scripts/scripts/hprd50_gene_to_conll.py
new file mode 100644
index 0000000..ea80aca
--- /dev/null
+++ b/huner/ner_scripts/scripts/hprd50_gene_to_conll.py
@@ -0,0 +1,37 @@
+import argparse
+import utils
+from lxml import etree
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input")
+parser.add_argument("output")
+args = parser.parse_args()
+
+sentences = []
+entities = []
+
+with open(args.input, 'r') as f_in:
+    tree = etree.parse(f_in)
+    for document in tree.xpath('.//document'):
+        assert len(document.xpath('passage/text')) == 1
+        text = document.xpath('passage/text')[0].text
+        tmp_sentences = text.split('\n')
+        tmp_entities = [[] for x in tmp_sentences]
+        for annotation in document.xpath('.//annotation'):
+            prot = False
+            for infon in annotation.xpath('.//infon'):
+                prot |= ((infon.get('key') == 'type') & (infon.text[0:2] == 'pm'))
+            if not prot:
+                continue
+            offset = int(annotation.xpath('.//location')[0].get('offset'))
+            length = int(annotation.xpath('.//location')[0].get('length'))
+            i = 0
+            while offset > len(tmp_sentences[i]):
+                offset -= len(tmp_sentences[i])+1
+                i += 1
+            tmp_entities[i] += [(offset, offset+length)]
+        sentences += tmp_sentences
+        entities += tmp_entities
+
+with open(args.output, 'w') as f_out:
+    utils.write_to_conll(sentences, entities, f_out)
diff --git a/huner/ner_scripts/scripts/iepa_gene_to_conll.py b/huner/ner_scripts/scripts/iepa_gene_to_conll.py
new file mode 100644
index 0000000..1044e0f
--- /dev/null
+++ b/huner/ner_scripts/scripts/iepa_gene_to_conll.py
@@ -0,0 +1,16 @@
+import argparse
+
+import extractors
+import utils
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input")
+parser.add_argument("output")
+args = parser.parse_args()
+
+
+with open(args.input, 'r') as f_in:
+    sentences, entities, document_ids = extractors.extract_from_biocreative(f_in, 'Protein')
+
+with open(args.output, 'w') as f_out:
+    utils.write_to_conll(sentences, entities, document_ids, f_out)
diff --git a/huner/ner_scripts/scripts/jnlpba_to_conll.py b/huner/ner_scripts/scripts/jnlpba_to_conll.py
new file mode 100644
index 0000000..0207038
--- /dev/null
+++ b/huner/ner_scripts/scripts/jnlpba_to_conll.py
@@ -0,0 +1,42 @@
+import argparse
+import os
+from opennlp_wrapper import OpenNLP
+
+opennlp_path = os.environ['OPENNLP']
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input")
+parser.add_argument("types")
+parser.add_argument("output")
+args = parser.parse_args()
+
+types = args.types.split(',')
+
+pos_tagger = OpenNLP(opennlp_path, 'POSTagger', 'en-pos-maxent.bin')
+
+with open(args.input, 'r') as f_in:
+    with open(args.output, 'w') as f_out:
+        tokens = []
+        entities = []
+        for line in f_in:
+            line = line.strip()
+            if line[:3] == '###':
+                document_id = line.split(':')[-1]
+                f_in.__next__()
+                continue
+            if not line:
+                pos_tags = pos_tagger.parse(' '.join(tokens)).decode().split()
+                for pos_tag, token, entity in zip(pos_tags, tokens, entities):
+                    f_out.write(document_id + ' ' + token + ' ' + pos_tag.split('_')[-1] + ' ' + entity + '\n')
+                f_out.write('\n')
+                tokens = []
+                entities = []
+            else:
+                parts = line.split()
+                tokens += [parts[0].strip()]
+                entity = parts[1].strip()
+                if entity[2:] in types:
+                    entity = entity[:2]+'NP'
+                else:
+                    entity = 'O'
+                entities += [entity]
diff --git a/huner/ner_scripts/scripts/linneaus_species_to_conll.py b/huner/ner_scripts/scripts/linneaus_species_to_conll.py
new file mode 100644
index 0000000..a5cd433
--- /dev/null
+++ b/huner/ner_scripts/scripts/linneaus_species_to_conll.py
@@ -0,0 +1,59 @@
+import argparse
+import utils
+import os
+from opennlp_wrapper import SentenceSplitter
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input_dir")
+parser.add_argument("output")
+args = parser.parse_args()
+
+opennlp_path = os.environ['OPENNLP']
+sentence_splitter = SentenceSplitter(opennlp_path, 'en-sent.bin')
+
+sentences = []
+entities = []
+document_ids = []
+
+files = set(os.listdir(os.path.join(args.input_dir, 'txt')))
+
+with open(os.path.join(args.input_dir, 'filtered_tags.tsv'), 'r') as f_in:
+    next(f_in)
+    last_doc = ''
+    tmp_sentences = []
+    tmp_entities = []
+    for line in f_in:
+        if not line:
+            continue
+        line = line.split('\t')
+        if line[1] != last_doc:
+            document_ids += [last_doc] * len(tmp_sentences)
+            sentences += tmp_sentences
+            entities += tmp_entities
+            last_doc = line[1]
+            with open(os.path.join(args.input_dir, 'txt', last_doc + '.txt'), 'r') as doc:
+                files.remove(last_doc + '.txt')
+                tmp_sentences = sentence_splitter.split(doc.read())
+                tmp_entities = [[] for _ in tmp_sentences]
+        id, start, end = sentence_splitter.map_offsets(int(line[2]), int(line[3]))
+        while len(tmp_sentences[id])<end:
+            tmp_sentences = sentence_splitter.merge_sentences(id)
+            tmp_entities[id] += tmp_entities[id+1]
+            del tmp_entities[id+1]
+            id, start, end = sentence_splitter.map_offsets(int(line[2]), int(line[3]))
+        assert tmp_sentences[id][start:end] == line[4]
+        tmp_entities[id] += [(start, end)]
+    document_ids += [last_doc] * len(tmp_sentences)
+    sentences += tmp_sentences
+    entities += tmp_entities
+
+for file in files:
+    with open(os.path.join(args.input_dir, 'txt', file), 'r') as doc:
+        tmp_sentences = sentence_splitter.split(doc.read())
+        tmp_entities = [[] for _ in tmp_sentences]
+        sentences += tmp_sentences
+        entities += tmp_entities
+        document_ids += [file.strip('.txt')] * len(tmp_sentences)
+
+with open(args.output, 'w') as f_out:
+    utils.write_to_conll(sentences, entities, document_ids, f_out)
diff --git a/huner/ner_scripts/scripts/loctext_gene_to_conll.py b/huner/ner_scripts/scripts/loctext_gene_to_conll.py
new file mode 100644
index 0000000..f1aaca2
--- /dev/null
+++ b/huner/ner_scripts/scripts/loctext_gene_to_conll.py
@@ -0,0 +1,50 @@
+import argparse
+import os
+import json
+from opennlp_wrapper import SentenceSplitter
+import tqdm
+
+import utils
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input_dir")
+parser.add_argument("types")
+parser.add_argument("output")
+args = parser.parse_args()
+
+sentences = []
+entities = []
+document_ids = []
+types = args.types.split(',')
+
+opennlp_path = os.environ['OPENNLP']
+sentence_splitter = SentenceSplitter(opennlp_path, 'en-sent.bin')
+
+files = [file for file in os.listdir(args.input_dir) if file[-5:]=='.json']
+
+for file in tqdm.tqdm(files):
+    document_id = os.path.basename(file).strip('.json')
+    with open(os.path.join(args.input_dir, file), 'r') as f_in:
+        data = json.load(f_in)
+        tmp_sentences = sentence_splitter.split(data['text'])
+        tmp_entities = [[] for _ in tmp_sentences]
+        if 'denotations' in data.keys():
+            for ann in data['denotations']:
+                o_start = ann['span']['begin']
+                o_end = ann['span']['end']
+                if not ann['obj'].split(':')[0] in types:
+                    continue
+                id, start, end = sentence_splitter.map_offsets(o_start, o_end)
+                while (len(tmp_sentences[id]) < end):
+                    tmp_sentences = sentence_splitter.merge_sentences(id)
+                    tmp_entities[id] += tmp_entities[id + 1]
+                    del tmp_entities[id + 1]
+                    id, start, end = sentence_splitter.map_offsets(o_start, o_end)
+                assert tmp_sentences[id][start:end] == data['text'][o_start:o_end]
+                tmp_entities[id] += [(start, end)]
+        sentences += tmp_sentences
+        document_ids += [document_id] * len(tmp_sentences)
+        entities += tmp_entities
+
+with open(args.output, 'w') as f_out:
+    utils.write_to_conll(sentences, entities, document_ids, f_out)
diff --git a/huner/ner_scripts/scripts/mirna_to_conll.py b/huner/ner_scripts/scripts/mirna_to_conll.py
new file mode 100644
index 0000000..846640c
--- /dev/null
+++ b/huner/ner_scripts/scripts/mirna_to_conll.py
@@ -0,0 +1,33 @@
+import argparse
+import utils
+from lxml import etree
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input")
+parser.add_argument("types")
+parser.add_argument("output")
+args = parser.parse_args()
+
+sentences = []
+entities = []
+document_ids = []
+types = args.types.split(',')
+
+with open(args.input) as f_in:
+    tree = etree.parse(f_in)
+    for document in tree.xpath('.//document'):
+        sentence_elems = document.xpath('.//sentence')
+        for sentence in sentence_elems:
+            sentences += [sentence.get('text')]
+            document_ids += [document.get('id')]
+            entities += [[]]
+
+            for entity in sentence.xpath(".//entity"):
+                if not entity.get('type') in types:
+                    continue
+                char_offset = entity.get('charOffset').split('-')
+                entities[-1] += [(int(char_offset[0]), int(char_offset[1]))]
+
+
+with open(args.output, 'w') as f_out:
+    utils.write_to_conll(sentences, entities, document_ids, f_out)
diff --git a/huner/ner_scripts/scripts/ncbi_diseases_to_conll.py b/huner/ner_scripts/scripts/ncbi_diseases_to_conll.py
new file mode 100644
index 0000000..ea2c2f5
--- /dev/null
+++ b/huner/ner_scripts/scripts/ncbi_diseases_to_conll.py
@@ -0,0 +1,61 @@
+import argparse
+import os
+
+import utils
+from opennlp_wrapper import SentenceSplitter
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input")
+parser.add_argument("output")
+args = parser.parse_args()
+
+opennlp_path = os.environ['OPENNLP']
+sentence_splitter = SentenceSplitter(opennlp_path, 'en-sent.bin')
+
+sentences = []
+entities = []
+document_ids = []
+
+with open(args.input, 'r') as f_in:
+    c = 1
+    text = ''
+    tmp_sentences = []
+    tmp_entities = []
+    document_id = ''
+    for line in f_in:
+        line = line.strip()
+        if not line:
+            sentences += tmp_sentences
+            entities += tmp_entities
+            document_ids += [document_id] * len(tmp_sentences)
+            c=1
+            continue
+        if c==1:
+            text = line.split('|')[2] + ' '
+            document_id = line.split('|')[0]
+        elif c==2:
+            text += line.split('|')[2]
+            tmp_sentences = sentence_splitter.split(text)
+            tmp_entities = [[] for _ in tmp_sentences]
+        else:
+            line = line.split('\t')
+            o_start = int(line[1])
+            o_end = int(line[2])
+            id, start, end = sentence_splitter.map_offsets(o_start, o_end)
+            while len(tmp_sentences[id]) < end:
+                tmp_sentences = sentence_splitter.merge_sentences(id)
+                tmp_entities[id] += tmp_entities[id + 1]
+                del tmp_entities[id + 1]
+                id, start, end = sentence_splitter.map_offsets(o_start, o_end)
+            assert tmp_sentences[id][start:end] == text[o_start:o_end]
+            assert tmp_sentences[id][start:end] == line[3]
+            tmp_entities[id] += [(start, end)]
+        c += 1
+
+    if c != 1:
+        sentences += tmp_sentences
+        entities += tmp_entities
+        document_ids += [document_id] * len(tmp_sentences)
+
+with open(args.output, 'w') as f_out:
+    utils.write_to_conll(sentences, entities, document_ids, f_out)
diff --git a/huner/ner_scripts/scripts/opennlp_wrapper.py b/huner/ner_scripts/scripts/opennlp_wrapper.py
new file mode 100644
index 0000000..dd3f1ad
--- /dev/null
+++ b/huner/ner_scripts/scripts/opennlp_wrapper.py
@@ -0,0 +1,102 @@
+import pexpect
+from subprocess import Popen, PIPE
+
+
+class OpenNLP():
+    def __init__(self, path, tool, model):
+        '''
+            Initializes OpenNLP
+            :params
+                path: Absolute path to the opennlp folder
+                tool:OpenNLP tool (Eg: ChunkerME, TokenizerME)
+                model: model file name
+        '''
+        opennlp = path + '/bin/opennlp'
+        model_path = path + '/models/' + model
+        cmd = '%s %s %s' % (opennlp, tool, model_path)
+
+        # Spawn the chunker process
+        self.process = pexpect.spawn(cmd)
+        self.process.setecho(False)
+        self.process.expect('done')
+        self.process.expect('\r\n')
+
+    def parse(self, text):
+        # clear any pending output
+        try:
+            self.process.read_nonblocking(2048, 0)
+        except:
+            pass
+
+        self.process.sendline(text)
+        self.process.waitnoecho()  # remove this if not working
+        timeout = 5 + len(text) / 20.0
+
+        self.process.expect('\r\n', timeout)
+        results = self.process.before
+        if len(text) != 0:
+            while len(results) == 0:
+                self.process.expect('\r\n', timeout)
+                results = self.process.before
+
+        # Remove this if block if required.
+        # This is added to address invalid input format for ChunkerME
+        if b'Invalid' in results:
+            try:
+                self.process.readline()
+            except:
+                pass
+            return False
+        return results
+
+
+class SentenceSplitter():
+    def __init__(self, path, model):
+        opennlp = path + '/bin/opennlp'
+        model_path = path + '/models/' + model
+        self.cmd = [opennlp, 'SentenceDetector', model_path]
+        self.sentences = []
+        self.sentence_offsets = []
+        self.text = None
+
+    def split(self, text):
+        self.text = text
+        p = Popen(self.cmd, stdin=PIPE, stdout=PIPE, stderr=PIPE)
+        result, err = p.communicate(text.encode('utf-8'))
+        result = result.decode('utf-8')
+        self.sentences = result.split('\n')
+        self.calc_offsets()
+        return self.sentences
+
+    def calc_offsets(self):
+        self.sentence_offsets = []
+        akt_pos = 0
+        for sentence in self.sentences:
+            if sentence:
+                akt_pos = self.text.find(sentence[0], akt_pos)
+                self.sentence_offsets += [akt_pos]
+                akt_pos += len(sentence)
+            else:
+                self.sentence_offsets += [akt_pos]
+
+    def map_offsets(self, start, end):
+        minp = 0
+        maxp = len(self.sentence_offsets)
+        while (maxp-minp!=1):
+            m = (maxp+minp)//2
+            if self.sentence_offsets[m] > start:
+                maxp = m
+            else:
+                minp = m
+        sentence_id = minp
+        new_start = start - self.sentence_offsets[minp]
+        new_end = end - self.sentence_offsets[minp]
+        return sentence_id, new_start, new_end
+
+    def merge_sentences(self, id):
+        # Merges sentences id and id+1
+        spaces = self.sentence_offsets[id+1]-self.sentence_offsets[id]-len(self.sentences[id])
+        self.sentences[id] += ' ' * spaces + self.sentences[id+1]
+        del self.sentences[id+1]
+        del self.sentence_offsets[id+1]
+        return self.sentences
diff --git a/huner/ner_scripts/scripts/osiris_gene_to_conll.py b/huner/ner_scripts/scripts/osiris_gene_to_conll.py
new file mode 100644
index 0000000..6b29fd2
--- /dev/null
+++ b/huner/ner_scripts/scripts/osiris_gene_to_conll.py
@@ -0,0 +1,51 @@
+import argparse
+import os
+from lxml import etree
+from opennlp_wrapper import SentenceSplitter
+import tqdm
+
+import utils
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input_dir")
+parser.add_argument("types")
+parser.add_argument("output")
+args = parser.parse_args()
+
+types = args.types.split(',')
+
+sentences = []
+entities = []
+document_ids = []
+
+opennlp_path = os.environ['OPENNLP']
+sentence_splitter = SentenceSplitter(opennlp_path, 'en-sent.bin')
+
+files = [file for file in os.listdir(args.input_dir) if file[-4:]=='.ann']
+
+for file in tqdm.tqdm(files):
+    with open(os.path.join(args.input_dir, file), 'r') as f_ann:
+        with open(os.path.join(args.input_dir, file[:-4]), 'r') as f_txt:
+            text = f_txt.read()
+            document_id = text.split('\n\n')[0]
+            tmp_sentences = sentence_splitter.split(text)
+            tmp_entities = [[] for _ in tmp_sentences]
+            tree = etree.parse(f_ann)
+            for annotation in tree.xpath(".//Annotation"):
+                if not annotation.get('type') in types:
+                    continue
+                o_start, o_end = [int(x) for x in annotation.get('span').split('..')]
+                id, start, end = sentence_splitter.map_offsets(o_start, o_end)
+                while (len(tmp_sentences[id]) < end):
+                    tmp_sentences = sentence_splitter.merge_sentences(id)
+                    tmp_entities[id] += tmp_entities[id + 1]
+                    del tmp_entities[id + 1]
+                    id, start, end = sentence_splitter.map_offsets(o_start, o_end)
+                assert tmp_sentences[id][start:end] == text[o_start:o_end]
+                tmp_entities[id] += [(start, end)]
+            sentences += tmp_sentences[1:]
+            entities += tmp_entities[1:]
+            document_ids += [document_id] * (len(tmp_sentences) - 1)
+
+with open(args.output, 'w') as f_out:
+    utils.write_to_conll(sentences, entities, document_ids, f_out)
diff --git a/huner/ner_scripts/scripts/scai_to_conll.py b/huner/ner_scripts/scripts/scai_to_conll.py
new file mode 100644
index 0000000..adfbe2f
--- /dev/null
+++ b/huner/ner_scripts/scripts/scai_to_conll.py
@@ -0,0 +1,44 @@
+import argparse
+import os
+from opennlp_wrapper import OpenNLP, SentenceSplitter
+
+opennlp_path = os.environ['OPENNLP']
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input")
+parser.add_argument("output")
+args = parser.parse_args()
+
+pos_tagger = OpenNLP(opennlp_path, 'POSTagger', 'en-pos-maxent.bin')
+sentence_splitter = SentenceSplitter(opennlp_path, 'en-sent.bin')
+
+with open(args.input, 'r', encoding='iso-8859-1') as f_in:
+    with open(args.output, 'w') as f_out:
+        tokens = []
+        entities = []
+        for line in f_in:
+            line = line.strip()
+            if not line:
+                continue
+            if line[:3]=='###':
+                i = 0
+                for sentence in sentence_splitter.split(' '.join(tokens)):
+                    sentence_start = i
+                    length = 0
+                    while length < len(sentence):
+                        length += len(tokens[i])+1
+                        i+=1
+                    pos_tags = [x.split('_')[-1] for x in pos_tagger.parse(' '.join(tokens[sentence_start:i])).decode().split()]
+                    for pos_tag, token, entity in zip(pos_tags, tokens[sentence_start:i], entities[sentence_start:i]):
+                        f_out.write(document_id + ' ' + token + ' ' + pos_tag.split('_')[-1] + ' ' + entity + '\n')
+                    f_out.write('\n')
+                tokens = []
+                entities = []
+                document_id = line.strip('#').strip()
+            else:
+                parts = line.split('|')
+                tokens += [parts[0].split('\t')[0].strip()]
+                entity = parts[1].strip()
+                if len(entity)>1:
+                    entity = entity[:2]+'NP'
+                entities += [entity]
diff --git a/huner/ner_scripts/scripts/split_corpora.py b/huner/ner_scripts/scripts/split_corpora.py
new file mode 100644
index 0000000..8219af3
--- /dev/null
+++ b/huner/ner_scripts/scripts/split_corpora.py
@@ -0,0 +1,69 @@
+import argparse
+from collections import defaultdict
+
+parser = argparse.ArgumentParser()
+parser.add_argument("file")
+parser.add_argument("splits")
+args = parser.parse_args()
+
+
+def write_file(f_out, sentences):
+    for sentence in sentences:
+        for line in sentence.split('\n'):
+            f_out.write(' '.join(line.split()[1:]))
+            f_out.write('\n')
+        f_out.write('\n')
+
+train_ids = set()
+test_ids = set()
+dev_ids = set()
+
+with open(args.splits + '.train', 'r') as f_in:
+    for line in f_in:
+        train_ids.add(line.strip())
+
+with open(args.splits + '.test', 'r') as f_in:
+    for line in f_in:
+        test_ids.add(line.strip())
+
+with open(args.splits + '.dev', 'r') as f_in:
+    for line in f_in:
+        dev_ids.add(line.strip())
+
+train_ids = sorted(train_ids)
+test_ids = sorted(test_ids)
+dev_ids = sorted(dev_ids)
+
+with open(args.file, 'r') as f_in:
+    text = f_in.read()
+    sentences = [x.strip() for x in text.split('\n\n') if x.split()]
+    sentences_per_doc = defaultdict(list)
+    for sentence in sentences:
+        doc_id = sentence.split()[0]
+        sentences_per_doc[doc_id].append(sentence)
+
+    train = []
+    test = []
+    dev = []
+
+    for doc_id in train_ids:
+        if len(sentences_per_doc[doc_id]) > 0:
+            train += ["0 -DOCSTART- X X O"] # add dummy id as first column will be removed
+            train += sentences_per_doc[doc_id]
+
+    for doc_id in test_ids:
+        if len(sentences_per_doc[doc_id]) > 0:
+            test += ["0 -DOCSTART- X X O"]
+            test += sentences_per_doc[doc_id]
+
+    for doc_id in dev_ids:
+        if len(sentences_per_doc[doc_id]) > 0:
+            dev += ["0 -DOCSTART- X X O"]
+            dev += sentences_per_doc[doc_id]
+
+    with open(args.file+'.train', 'w') as f_out:
+        write_file(f_out, train)
+    with open(args.file+'.dev', 'w') as f_out:
+        write_file(f_out, dev)
+    with open(args.file+'.test', 'w') as f_out:
+        write_file(f_out, test)
diff --git a/huner/ner_scripts/scripts/utils.py b/huner/ner_scripts/scripts/utils.py
new file mode 100644
index 0000000..dcf1dee
--- /dev/null
+++ b/huner/ner_scripts/scripts/utils.py
@@ -0,0 +1,87 @@
+from itertools import combinations
+from opennlp_wrapper import OpenNLP
+import os
+from tqdm import tqdm
+
+
+def overlap(entity1, entity2):
+    return range(max(entity1[0], entity2[0]), min(entity1[1], entity2[1]))
+
+
+def merge_overlapping_entities(entities):
+    entities = list(entities)
+
+    entity_set_stable = False
+    while not entity_set_stable:
+        for e1, e2 in combinations(entities, 2):
+            if overlap(e1, e2):
+                merged_entity = (min(e1[0], e2[0]), max(e1[1], e2[1]))
+                entities.remove(e1)
+                entities.remove(e2)
+                entities.append(merged_entity)
+                break
+        else:
+            entity_set_stable = True
+
+    return entities
+
+
+def compute_token_char_offsets(tokens, sentence):
+    start_idx = 0
+    end_idx = 0
+
+    indices = []
+    for token in tokens:
+        start_idx = end_idx
+        while not sentence[start_idx].strip():
+            start_idx += 1
+        end_idx = start_idx + len(token)
+
+        #if token != sentence[start_idx:end_idx]:
+        #    import IPython;IPython.embed()
+
+        assert token == sentence[start_idx:end_idx]
+
+        indices.append((start_idx, end_idx))
+
+    return indices
+
+
+def write_to_conll(sentences, entities_per_sentence, document_ids,
+                   output_file, tokenizer=None):
+    opennlp_path = os.environ['OPENNLP']
+    if tokenizer is None:
+        opennlp_tokenizer = OpenNLP(opennlp_path, 'TokenizerME', 'en-token.bin')
+        def tokenizer(sentence):
+            return opennlp_tokenizer.parse(sentence).decode().split()
+
+    pos_tagger = OpenNLP(opennlp_path, 'POSTagger', 'en-pos-maxent.bin')
+
+    for sentence, entities, document_id in tqdm(list(zip(sentences, entities_per_sentence, document_ids))):
+        if len(sentence) == 0:
+            continue
+
+        tokens = [token for token in tokenizer(sentence)]
+        entities = [range(*e) for e in entities]
+        in_entity = False
+
+        token_char_offsets = compute_token_char_offsets([token for token in tokens], sentence)
+        pos_tags = pos_tagger.parse(' '.join(tokens)).decode()
+
+        for (start_idx, end_idx), token_pos in zip(token_char_offsets, pos_tags.split()):
+            token = '_'.join(token_pos.split('_')[:-1])
+            pos_tag = token_pos.split('_')[-1]
+            for entity in entities:
+                if start_idx in entity:
+                    if in_entity != entity:
+                        tag = 'B-NP'
+                        in_entity = entity
+                    else:
+                        tag = 'I-NP'
+                    break
+            else:
+                tag = 'O'
+                in_entity = False
+
+            output_file.write(document_id+' '+token+' '+pos_tag+' '+tag+'\n')
+        output_file.write('\n')
diff --git a/huner/ner_scripts/scripts/variome_to_conll.py b/huner/ner_scripts/scripts/variome_to_conll.py
new file mode 100644
index 0000000..274384d
--- /dev/null
+++ b/huner/ner_scripts/scripts/variome_to_conll.py
@@ -0,0 +1,23 @@
+### NEEDS PATCHED INPUT FILE ###
+
+import argparse
+
+import extractors
+import utils
+
+parser = argparse.ArgumentParser()
+parser.add_argument("input")
+parser.add_argument("output")
+parser.add_argument("type")
+args = parser.parse_args()
+
+
+all_sentences = []
+all_entities = []
+types = args.type.split(',')
+
+with open(args.input, 'r') as f_in:
+    sentences, entities, document_ids = extractors.extract_from_biocreative(f_in, types, split_sentences=True)
+
+with open(args.output, 'w') as f_out:
+    utils.write_to_conll(sentences, entities, document_ids, f_out)
diff --git a/huner/ner_scripts/show_corpus_stats.sh b/huner/ner_scripts/show_corpus_stats.sh
new file mode 100755
index 0000000..49245dd
--- /dev/null
+++ b/huner/ner_scripts/show_corpus_stats.sh
@@ -0,0 +1,6 @@
+echo 'Blank lines';
+grep -cvP '\S' $CORPUS.conll.*;
+echo 'B-NP tokens';
+grep -c B-NP $CORPUS.conll.*;
+echo 'Lines';
+wc -l $CORPUS.conll.*;
diff --git a/huner/ner_scripts/split_corpora.sh b/huner/ner_scripts/split_corpora.sh
new file mode 100755
index 0000000..8e5ac4e
--- /dev/null
+++ b/huner/ner_scripts/split_corpora.sh
@@ -0,0 +1,53 @@
+#!/bin/sh
+
+if [ -z "$1" ] 
+then
+    base_dir="."
+else
+    base_dir="$1"
+fi
+
+DISEASE_DIR="$base_dir"/converted/disease
+GENE_DIR="$base_dir"/converted/gene
+SPECIES_DIR="$base_dir"/converted/species
+CELLLINE_DIR="$base_dir"/converted/cellline
+CHEMICAL_DIR="$base_dir"/converted/chemical
+SPLIT_DIR=splits
+SCRIPT_DIR=scripts
+
+python3 $SCRIPT_DIR/split_corpora.py $GENE_DIR/osiris.conll $SPLIT_DIR/osiris
+python3 $SCRIPT_DIR/split_corpora.py $GENE_DIR/bc2gm.conll $SPLIT_DIR/bc2gm
+python3 $SCRIPT_DIR/split_corpora.py $GENE_DIR/bioinfer.conll $SPLIT_DIR/bioinfer
+python3 $SCRIPT_DIR/split_corpora.py $GENE_DIR/loctext.conll $SPLIT_DIR/loctext
+python3 $SCRIPT_DIR/split_corpora.py $GENE_DIR/cellfinder.conll $SPLIT_DIR/cellfinder_protein
+python3 $SCRIPT_DIR/split_corpora.py $GENE_DIR/variome.conll $SPLIT_DIR/variome_gene
+python3 $SCRIPT_DIR/split_corpora.py $GENE_DIR/iepa.conll $SPLIT_DIR/iepa
+python3 $SCRIPT_DIR/split_corpora.py $GENE_DIR/jnlpba.conll $SPLIT_DIR/genia
+python3 $SCRIPT_DIR/split_corpora.py $GENE_DIR/deca.conll $SPLIT_DIR/deca
+python3 $SCRIPT_DIR/split_corpora.py $GENE_DIR/fsu.conll $SPLIT_DIR/fsu
+python3 $SCRIPT_DIR/split_corpora.py $GENE_DIR/gpro.conll $SPLIT_DIR/gpro
+python3 $SCRIPT_DIR/split_corpora.py $GENE_DIR/miRNA.conll $SPLIT_DIR/miRNA
+python3 $SCRIPT_DIR/split_corpora.py $DISEASE_DIR/scai_diseases.conll $SPLIT_DIR/scai_disease
+python3 $SCRIPT_DIR/split_corpora.py $DISEASE_DIR/ncbi.conll $SPLIT_DIR/ncbi
+python3 $SCRIPT_DIR/split_corpora.py $DISEASE_DIR/cdr.conll $SPLIT_DIR/CDRDisease
+python3 $SCRIPT_DIR/split_corpora.py $DISEASE_DIR/biosemantics.conll $SPLIT_DIR/bios
+python3 $SCRIPT_DIR/split_corpora.py $DISEASE_DIR/variome.conll $SPLIT_DIR/variome_disease
+# python3 $SCRIPT_DIR/split_corpora.py $DISEASE_DIR/arizona.conll $SPLIT_DIR/arizona
+python3 $SCRIPT_DIR/split_corpora.py $DISEASE_DIR/miRNA.conll $SPLIT_DIR/miRNA
+python3 $SCRIPT_DIR/split_corpora.py $CELLLINE_DIR/cellfinder.conll $SPLIT_DIR/cellfinder_cellline
+python3 $SCRIPT_DIR/split_corpora.py $CELLLINE_DIR/cll.conll $SPLIT_DIR/cll
+python3 $SCRIPT_DIR/split_corpora.py $CELLLINE_DIR/gellus.conll $SPLIT_DIR/gellus
+python3 $SCRIPT_DIR/split_corpora.py $CELLLINE_DIR/jnlpba.conll $SPLIT_DIR/genia
+python3 $SCRIPT_DIR/split_corpora.py $SPECIES_DIR/cellfinder.conll $SPLIT_DIR/cellfinder_species
+python3 $SCRIPT_DIR/split_corpora.py $SPECIES_DIR/variome.conll $SPLIT_DIR/variome_species
+python3 $SCRIPT_DIR/split_corpora.py $SPECIES_DIR/s800.conll $SPLIT_DIR/s800
+python3 $SCRIPT_DIR/split_corpora.py $SPECIES_DIR/linneaus.conll $SPLIT_DIR/linneaus
+python3 $SCRIPT_DIR/split_corpora.py $SPECIES_DIR/loctext.conll $SPLIT_DIR/loctext
+python3 $SCRIPT_DIR/split_corpora.py $SPECIES_DIR/miRNA.conll $SPLIT_DIR/miRNA
+python3 $SCRIPT_DIR/split_corpora.py $CHEMICAL_DIR/cdr.conll $SPLIT_DIR/CDRChem
+python3 $SCRIPT_DIR/split_corpora.py $CHEMICAL_DIR/cemp.conll $SPLIT_DIR/cemp
+python3 $SCRIPT_DIR/split_corpora.py $CHEMICAL_DIR/chebi.conll $SPLIT_DIR/chebi
+python3 $SCRIPT_DIR/split_corpora.py $CHEMICAL_DIR/chemdner.conll $SPLIT_DIR/chemdner
+python3 $SCRIPT_DIR/split_corpora.py $CHEMICAL_DIR/biosemantics.conll $SPLIT_DIR/bios
+python3 $SCRIPT_DIR/split_corpora.py $CHEMICAL_DIR/scai_chemicals.conll $SPLIT_DIR/scai_chemicals
+
diff --git a/huner/ner_scripts/splits/CDRChem.dev b/huner/ner_scripts/splits/CDRChem.dev
new file mode 100644
index 0000000..14c02e6
--- /dev/null
+++ b/huner/ner_scripts/splits/CDRChem.dev
@@ -0,0 +1,150 @@
+
+10328196
+10354657
+10565806
+10692744
+1079693
+10840460
+11009181
+11022397
+11058428
+11230490
+11302406
+11337188
+11752998
+11827497
+11858397
+11860495
+11861791
+11900788
+12013711
+12091028
+1255900
+12600698
+12691807
+12734532
+12760988
+12852481
+1415380
+14648024
+15096016
+15266362
+15686794
+15897593
+1595783
+16225977
+16600756
+1687392
+17049862
+1711760
+17923537
+18201582
+18483878
+18513945
+19203554
+19274460
+19719056
+19893084
+20394767
+2055425
+20635749
+2257294
+22836123
+23433219
+2343592
+23535177
+23666265
+23846525
+23864035
+23871786
+23872883
+23892921
+23949582
+23952588
+24040781
+24067251
+24068571
+24072398
+24088636
+24091473
+24100055
+24100257
+24114426
+24126708
+24132704
+24158386
+24190587
+24209900
+24220752
+24234943
+24275640
+24283660
+24284476
+24309294
+24333387
+24341598
+24345882
+24434397
+24438483
+24451297
+24459006
+24464946
+24535067
+24554916
+24571687
+24582773
+24587916
+24588023
+24595967
+24614773
+2569282
+2576810
+2594614
+2598570
+2840807
+2886572
+28952
+3084782
+3120485
+3183120
+3411101
+3461217
+3934126
+3952818
+3973521
+430165
+439781
+48362
+6153967
+6308526
+6402369
+6454943
+6496797
+6615052
+6732043
+6817363
+7053705
+7161250
+7197363
+7421734
+7437994
+7565311
+7650771
+7710775
+7803371
+7843916
+803783
+804391
+8045270
+8278214
+8475949
+8480959
+8494478
+85485
+8617710
+8701013
+8841157
+8988571
+9061311
+9067481
+9630698
diff --git a/huner/ner_scripts/splits/CDRChem.test b/huner/ner_scripts/splits/CDRChem.test
new file mode 100644
index 0000000..7d7f534
--- /dev/null
+++ b/huner/ner_scripts/splits/CDRChem.test
@@ -0,0 +1,451 @@
+
+10087562
+10219427
+10327032
+10390729
+10401555
+10427794
+10462057
+10510854
+10672628
+10677406
+10713017
+10726030
+10764869
+10770468
+10933650
+10939760
+10960401
+10975596
+10985896
+10986547
+11026989
+11105626
+11135381
+1117341
+11176729
+11229942
+11299446
+11366874
+11380496
+11385188
+11395263
+11401944
+11423811
+11425091
+11439380
+11474137
+1158089
+11708428
+11745287
+11799346
+11835460
+11915580
+11936424
+11988250
+12051122
+12059909
+12119460
+12165618
+12359538
+12372954
+12452552
+12487093
+12498738
+12523489
+12535818
+12559315
+12644816
+12677626
+12678199
+12699527
+12752472
+1280054
+1280707
+12828076
+12865514
+1289188
+12912689
+12948256
+12950111
+1359137
+1360900
+1361574
+1395192
+1420650
+1423336
+1424076
+1449452
+1451544
+14616590
+146391
+14748761
+15018178
+15094729
+15096374
+1522360
+15229250
+15265979
+15276093
+15282950
+15321332
+15366550
+15482540
+1556529
+15605432
+15609701
+15614572
+15625689
+15627798
+15630069
+1563460
+1564030
+15696449
+15815446
+15817013
+15859361
+15882284
+15953230
+15987266
+15991002
+16034922
+16083708
+16092435
+16112787
+1615846
+16309808
+16323982
+16369751
+1655018
+16565833
+16723784
+16731636
+16801510
+16810074
+16867246
+16876986
+16880771
+16906379
+16911931
+16920333
+17028363
+17035713
+17042797
+17069550
+17151160
+17159032
+17223814
+17255138
+17297207
+17346443
+17351238
+1735570
+17356399
+17379047
+17384765
+17445520
+17484470
+17496739
+17543491
+17554526
+1756784
+17572393
+1760851
+17721298
+1779253
+17828434
+17879100
+17879217
+17954033
+18025637
+18165598
+18189308
+18340638
+18341442
+1837756
+18399341
+18422462
+18450790
+1858969
+18801087
+18945509
+18987260
+19020118
+1905439
+19108278
+19139825
+19154241
+19178808
+19184102
+19263707
+19293073
+19338378
+19392810
+19419794
+1943082
+19447152
+19515070
+19531695
+19549709
+19553912
+19655282
+19681452
+19715529
+19728177
+19815465
+19841052
+19914299
+19920070
+19967075
+20009434
+20024739
+20034406
+20046642
+20129423
+20169779
+20192893
+2021990
+20408947
+20431083
+20447294
+20495512
+20513036
+20566328
+20589632
+20595935
+20682692
+20828385
+2083961
+20859899
+20927253
+20959502
+21195121
+2131034
+2173761
+2217015
+2239937
+2320485
+2358093
+2383364
+2400986
+24055495
+2429800
+2453942
+24641119
+24653743
+24658375
+24659727
+24664478
+24665854
+24671324
+24675088
+24684312
+24691439
+24709919
+24717468
+24727461
+24729111
+24733133
+24739405
+24742750
+24753331
+24778426
+24802403
+24812279
+24816962
+24840785
+24842192
+2484903
+24881749
+24894748
+24897009
+24902786
+24911645
+24923469
+24927617
+24928523
+24971338
+24975837
+24999722
+25006369
+25006961
+25031906
+25041770
+25054547
+25071004
+25080425
+25084821
+25096313
+25119790
+2553470
+256433
+25907210
+25951420
+25986755
+26002693
+26033014
+26115410
+2614930
+2625524
+2650911
+2710809
+2718706
+2765447
+2767010
+2782734
+2818777
+2884595
+2904523
+2907577
+2931989
+2933998
+2974281
+2983630
+3074291
+3083835
+3084231
+3088653
+3109094
+3125850
+3155884
+3191389
+3289726
+3297909
+3323259
+3323599
+3339945
+3375885
+3383127
+3409843
+3423103
+3439580
+3475563
+3533179
+3538855
+35781
+3685052
+3708328
+3711722
+3746148
+3798047
+3812624
+3831029
+3832950
+3833372
+3864191
+3895875
+3925479
+3975902
+3987172
+3990093
+4010471
+4082192
+4082466
+44072
+448423
+4631913
+48835
+573555
+6106951
+611664
+612112
+6299641
+6305660
+6310832
+6316193
+6321816
+6453500
+6517710
+6529939
+6585590
+6615679
+6627074
+6631522
+6673474
+6687006
+6695685
+6728873
+6806735
+6884395
+689020
+6893265
+6985297
+6985498
+7018927
+7121659
+7147232
+7173007
+7176945
+7248895
+7315949
+733189
+7369302
+7378868
+7411769
+7457821
+7477981
+7479194
+7492040
+753803
+7644931
+7661171
+7671401
+7727612
+7739955
+7931490
+7949506
+7967231
+8096565
+8135424
+8160791
+816141
+8184922
+8188982
+8308951
+8312343
+8312983
+8318674
+8392553
+851038
+8511251
+8603459
+8659767
+8667442
+8748050
+8755612
+8808730
+8819482
+8825380
+8829135
+891494
+89511
+895432
+8957205
+8985298
+8996419
+9061777
+9071336
+9125676
+9128918
+9132810
+9158667
+9197951
+920167
+9272404
+931801
+9323412
+9382023
+9428298
+946593
+9538487
+9570197
+9578276
+9646784
+9725303
+9759693
+9782254
+978847
+9831002
+9869655
+9881641
+9889429
diff --git a/huner/ner_scripts/splits/CDRChem.train b/huner/ner_scripts/splits/CDRChem.train
new file mode 100644
index 0000000..82d4ee6
--- /dev/null
+++ b/huner/ner_scripts/splits/CDRChem.train
@@ -0,0 +1,900 @@
+
+10027919
+10074612
+10091616
+10091617
+1009330
+10193204
+10193809
+10225068
+10342929
+10365197
+10406016
+10411803
+10414674
+10457883
+10520387
+10523326
+10524660
+10526274
+10533019
+10539815
+10579464
+10669626
+10683478
+10704919
+10706004
+10721819
+10728962
+10737864
+10739826
+10743446
+10743694
+10791295
+10807237
+10835440
+1085609
+10901305
+10910842
+11007689
+11027904
+11027905
+11063349
+11077455
+11078231
+11079278
+11099450
+11135224
+11147747
+11166519
+11185967
+11195262
+11198499
+11206082
+11208990
+11226639
+11243580
+11245434
+11250767
+11256525
+11263551
+11271907
+11279304
+11282081
+11284996
+1130930
+11334364
+11379838
+11391224
+1141447
+11419773
+11426838
+11431197
+11467664
+1147734
+11524350
+11532387
+11569530
+11573852
+11581460
+11583940
+11587867
+11642480
+11672959
+11679859
+11694026
+11704023
+11705128
+11706060
+11745184
+11752354
+11773892
+11807648
+11838826
+11847945
+11860278
+11868798
+11875660
+11890511
+11897407
+11912119
+11928786
+11961407
+11999899
+12041669
+12042105
+12063090
+12084448
+12090760
+12093990
+12101159
+12109865
+12139551
+12180796
+12198388
+12202650
+12231232
+12369736
+12443032
+12448656
+12452237
+12464714
+12481039
+12483326
+12523465
+12536034
+12549952
+12571256
+12574103
+12584269
+12589964
+12596116
+12615818
+12617329
+12627929
+12639165
+12653683
+12684739
+12695819
+12707296
+12716030
+12739036
+12745515
+12757899
+12789195
+12820454
+12842176
+12851669
+1286498
+12905102
+12907309
+12907924
+12911170
+12921865
+1300436
+133615
+1355091
+137340
+1378968
+1420741
+1423339
+1428568
+1436384
+1445986
+14513889
+14568327
+14596845
+14633084
+14657095
+14659530
+1468485
+14698717
+14704468
+14736955
+14742097
+14745746
+14765563
+14975762
+14976857
+14982270
+15009014
+15036754
+15042318
+1504402
+15075188
+150790
+15120741
+15130900
+15145918
+15188772
+15233872
+15266215
+1527456
+15275829
+15276120
+15278670
+15325671
+15338796
+1535072
+1545575
+15458908
+1549199
+15515654
+15517007
+15531665
+15565293
+15572383
+15579441
+15580403
+15602202
+15632880
+15638391
+1564236
+15649445
+15673851
+15737522
+15764424
+15804801
+15811908
+15814210
+15858223
+15859940
+15863244
+15867025
+15893386
+15899738
+1592014
+15930398
+15957009
+15974569
+15985056
+16005948
+16006300
+1601297
+16047871
+1610717
+16116131
+16132524
+16157917
+16160878
+1616457
+16167916
+16174948
+16181582
+16192988
+16274958
+1628552
+16298782
+16330293
+16330766
+16337777
+1636026
+16364460
+1639466
+16403073
+16418614
+16428221
+16428827
+16471092
+16563323
+16574712
+16574713
+16584858
+16586083
+16596970
+16629641
+16634859
+1664218
+16680561
+16710500
+16720068
+16725121
+16740173
+16755009
+16787750
+16820346
+16826348
+16844102
+16858720
+16867021
+16904497
+16938416
+16960342
+1700207
+17019386
+17020434
+17042884
+17042910
+17074608
+17111419
+17147461
+17175308
+17194457
+1720453
+17241657
+17241784
+17242861
+17244258
+17261653
+17263743
+17285209
+1728522
+1728915
+1732369
+1732442
+17343925
+17344330
+17344566
+17366349
+17400887
+17437408
+17439425
+17466854
+17490790
+17490864
+17491223
+1749407
+17511042
+17532790
+17562951
+17574447
+17600377
+17608141
+17612891
+17615423
+17639754
+17682013
+17702969
+17786501
+17854040
+1786266
+17879945
+17919553
+17931375
+17943461
+17965424
+17975693
+18004067
+18006530
+18020536
+18023325
+18081909
+18083142
+18086064
+18161408
+18162529
+18177388
+18182964
+18186898
+18208574
+18217897
+18221780
+18239197
+18261172
+18308784
+18329269
+1833784
+18343374
+1835291
+18356633
+18363626
+18405372
+18410508
+18417364
+18439803
+18441470
+18442015
+18464113
+1848636
+18503483
+18541230
+18544179
+18560792
+18589141
+18619688
+18627295
+18631865
+18657397
+1867351
+18674790
+18703024
+18726058
+18752389
+18754075
+18768591
+18791946
+18808529
+18809400
+18821488
+188339
+18951540
+1899352
+18996674
+18997632
+19037603
+19058010
+19058474
+19105845
+19135948
+19139001
+1919871
+19211690
+19234905
+19269743
+1928887
+19289093
+19299179
+19300240
+19300402
+19308880
+19319147
+19346865
+19356053
+19356307
+19370593
+19387625
+19445921
+19473225
+19581773
+19631624
+19642243
+19657887
+19674115
+1967484
+19692487
+1969772
+19707748
+19721134
+19729346
+19759529
+19761039
+19767176
+19803309
+19820426
+19843802
+1987816
+19884587
+19889778
+19917396
+19923525
+1992636
+19940105
+19944333
+19944736
+19957053
+19996135
+20003049
+2004
+2004015
+20042557
+20067456
+20080419
+20080983
+20084309
+2008831
+20098969
+20103708
+20164825
+20195852
+20196116
+2021202
+2024540
+20304337
+20331935
+20466178
+20470218
+20477932
+20510337
+2051906
+20520283
+20528871
+20533999
+2054792
+20552622
+20558148
+20588063
+20619828
+20621845
+20633755
+20667451
+20683499
+20698227
+2070391
+20705401
+2071257
+20722491
+20727411
+20735774
+20880751
+20882060
+2096243
+20973483
+21029050
+21294084
+21418164
+220563
+2220369
+2224762
+2234245
+2265898
+2266990
+2273650
+227508
+230316
+2304736
+2312209
+2320800
+2322844
+2334179
+2334618
+2339463
+234669
+2348231
+2355241
+2375138
+2385256
+2396046
+2422478
+2425813
+2435991
+2440413
+2445283
+2466960
+2476560
+2484011
+2505783
+2515254
+2522601
+2528969
+2533791
+2549018
+2557556
+2559236
+2564649
+2572625
+2578334
+26094
+2611118
+2632720
+2670794
+2673163
+2696505
+2709684
+2716967
+2722224
+2750819
+2790457
+2802551
+2819587
+2826064
+2870085
+2887062
+2893236
+2894433
+2894766
+2907585
+2917114
+2924746
+2950248
+2951327
+2980315
+3001299
+3015327
+3015567
+3031535
+3057041
+3070035
+3076126
+3088349
+3101906
+3107448
+3108839
+3115150
+3123611
+3125768
+3131282
+3137399
+3173179
+3173180
+3187073
+3192036
+3220106
+322550
+326460
+3300918
+3311455
+3341566
+3358181
+3371379
+33969
+3403780
+3409645
+3412544
+3413271
+3425586
+3431591
+343678
+3437726
+347884
+3496378
+3503576
+3535719
+354896
+3560095
+3560096
+3564823
+3615541
+3629586
+3653576
+3670965
+3676049
+3686155
+3693336
+3703509
+3708922
+3714122
+3719553
+3732088
+3750012
+3762968
+3769769
+3780697
+3780814
+3780846
+3782049
+3800626
+3827439
+3828020
+384871
+3856631
+3865016
+3950060
+3961813
+3962737
+3969369
+3970039
+3985451
+3997294
+4008111
+4027862
+4038130
+4069770
+4071154
+4090988
+424937
+435349
+458486
+4812392
+567256
+591536
+603022
+6103707
+6111982
+6115999
+6118280
+6127992
+6133211
+6150641
+6203452
+6203632
+6209318
+6216862
+6229975
+625456
+6286738
+6287825
+6292680
+6293644
+6308277
+6323692
+6381653
+6386793
+6387529
+6415512
+6433367
+6436733
+6466532
+6503301
+6504332
+6518066
+6534871
+6538499
+6540303
+663266
+6634932
+6637851
+6640832
+6666578
+6674249
+6692345
+6695415
+6699841
+6727060
+6728084
+6747681
+6769133
+6773726
+6794356
+6861444
+6888657
+6892185
+6942642
+7007443
+7053303
+7059267
+7066357
+7072798
+7083920
+7088431
+7102237
+7189975
+7199841
+7234705
+7248170
+7263204
+7265370
+7269015
+7282516
+7292072
+7337133
+7352670
+7416947
+7420681
+7423039
+7444978
+7449470
+7453952
+7468724
+7504976
+7516729
+7542793
+7582165
+7596955
+7604176
+761833
+7619765
+7628595
+7647582
+7651879
+7707116
+7724492
+7752389
+7785794
+7791169
+7802851
+783197
+7834920
+7858459
+7862923
+7880714
+7881871
+7890216
+7905523
+7910951
+7919560
+7930386
+7977601
+7988234
+8012887
+8073369
+8092427
+809711
+8106150
+8111719
+8170551
+8231633
+8251368
+8267029
+8268147
+8302922
+8305357
+8319760
+8372922
+8384253
+8386779
+8387218
+839274
+8410052
+8410199
+84204
+8421099
+8423889
+8424298
+8437969
+8441146
+8473723
+8492347
+8514073
+8546130
+8558192
+8586822
+8590259
+8595686
+8599504
+8600333
+8607407
+8638206
+8638876
+8643966
+8643971
+8643973
+8649546
+8665051
+8669433
+8677458
+8682684
+8686832
+8690168
+869641
+8701950
+871943
+873132
+8739323
+8741744
+8742498
+8752018
+8766220
+8800187
+8829025
+88336
+8854309
+8864707
+8888541
+891050
+8911359
+8919272
+8953972
+8955532
+8958188
+8996652
+9022662
+9034419
+9041081
+9088814
+9098464
+9100294
+9105126
+9121607
+9154656
+9165568
+9195768
+9199746
+9201797
+9205462
+9209318
+921394
+9214597
+9226773
+9228650
+9245658
+9249847
+9270571
+9284778
+9293063
+9305828
+9321531
+9326871
+9334596
+9351491
+9390208
+9401499
+9406968
+9431903
+9495837
+950631
+9514561
+9522143
+9522152
+9523805
+9523850
+9545159
+9564988
+9579567
+9587734
+9625142
+9636837
+9653867
+9660111
+9669632
+9672273
+9672936
+9698967
+9721172
+9727773
+9746003
+9754849
+9758264
+9766615
+9799166
+9812111
+982002
+983936
+9848575
+9855119
+9862868
+9867728
+9869257
+9875685
+9915601
+9931093
+9952311
diff --git a/huner/ner_scripts/splits/CDRDisease.dev b/huner/ner_scripts/splits/CDRDisease.dev
new file mode 100644
index 0000000..14c02e6
--- /dev/null
+++ b/huner/ner_scripts/splits/CDRDisease.dev
@@ -0,0 +1,150 @@
+
+10328196
+10354657
+10565806
+10692744
+1079693
+10840460
+11009181
+11022397
+11058428
+11230490
+11302406
+11337188
+11752998
+11827497
+11858397
+11860495
+11861791
+11900788
+12013711
+12091028
+1255900
+12600698
+12691807
+12734532
+12760988
+12852481
+1415380
+14648024
+15096016
+15266362
+15686794
+15897593
+1595783
+16225977
+16600756
+1687392
+17049862
+1711760
+17923537
+18201582
+18483878
+18513945
+19203554
+19274460
+19719056
+19893084
+20394767
+2055425
+20635749
+2257294
+22836123
+23433219
+2343592
+23535177
+23666265
+23846525
+23864035
+23871786
+23872883
+23892921
+23949582
+23952588
+24040781
+24067251
+24068571
+24072398
+24088636
+24091473
+24100055
+24100257
+24114426
+24126708
+24132704
+24158386
+24190587
+24209900
+24220752
+24234943
+24275640
+24283660
+24284476
+24309294
+24333387
+24341598
+24345882
+24434397
+24438483
+24451297
+24459006
+24464946
+24535067
+24554916
+24571687
+24582773
+24587916
+24588023
+24595967
+24614773
+2569282
+2576810
+2594614
+2598570
+2840807
+2886572
+28952
+3084782
+3120485
+3183120
+3411101
+3461217
+3934126
+3952818
+3973521
+430165
+439781
+48362
+6153967
+6308526
+6402369
+6454943
+6496797
+6615052
+6732043
+6817363
+7053705
+7161250
+7197363
+7421734
+7437994
+7565311
+7650771
+7710775
+7803371
+7843916
+803783
+804391
+8045270
+8278214
+8475949
+8480959
+8494478
+85485
+8617710
+8701013
+8841157
+8988571
+9061311
+9067481
+9630698
diff --git a/huner/ner_scripts/splits/CDRDisease.test b/huner/ner_scripts/splits/CDRDisease.test
new file mode 100644
index 0000000..7d7f534
--- /dev/null
+++ b/huner/ner_scripts/splits/CDRDisease.test
@@ -0,0 +1,451 @@
+
+10087562
+10219427
+10327032
+10390729
+10401555
+10427794
+10462057
+10510854
+10672628
+10677406
+10713017
+10726030
+10764869
+10770468
+10933650
+10939760
+10960401
+10975596
+10985896
+10986547
+11026989
+11105626
+11135381
+1117341
+11176729
+11229942
+11299446
+11366874
+11380496
+11385188
+11395263
+11401944
+11423811
+11425091
+11439380
+11474137
+1158089
+11708428
+11745287
+11799346
+11835460
+11915580
+11936424
+11988250
+12051122
+12059909
+12119460
+12165618
+12359538
+12372954
+12452552
+12487093
+12498738
+12523489
+12535818
+12559315
+12644816
+12677626
+12678199
+12699527
+12752472
+1280054
+1280707
+12828076
+12865514
+1289188
+12912689
+12948256
+12950111
+1359137
+1360900
+1361574
+1395192
+1420650
+1423336
+1424076
+1449452
+1451544
+14616590
+146391
+14748761
+15018178
+15094729
+15096374
+1522360
+15229250
+15265979
+15276093
+15282950
+15321332
+15366550
+15482540
+1556529
+15605432
+15609701
+15614572
+15625689
+15627798
+15630069
+1563460
+1564030
+15696449
+15815446
+15817013
+15859361
+15882284
+15953230
+15987266
+15991002
+16034922
+16083708
+16092435
+16112787
+1615846
+16309808
+16323982
+16369751
+1655018
+16565833
+16723784
+16731636
+16801510
+16810074
+16867246
+16876986
+16880771
+16906379
+16911931
+16920333
+17028363
+17035713
+17042797
+17069550
+17151160
+17159032
+17223814
+17255138
+17297207
+17346443
+17351238
+1735570
+17356399
+17379047
+17384765
+17445520
+17484470
+17496739
+17543491
+17554526
+1756784
+17572393
+1760851
+17721298
+1779253
+17828434
+17879100
+17879217
+17954033
+18025637
+18165598
+18189308
+18340638
+18341442
+1837756
+18399341
+18422462
+18450790
+1858969
+18801087
+18945509
+18987260
+19020118
+1905439
+19108278
+19139825
+19154241
+19178808
+19184102
+19263707
+19293073
+19338378
+19392810
+19419794
+1943082
+19447152
+19515070
+19531695
+19549709
+19553912
+19655282
+19681452
+19715529
+19728177
+19815465
+19841052
+19914299
+19920070
+19967075
+20009434
+20024739
+20034406
+20046642
+20129423
+20169779
+20192893
+2021990
+20408947
+20431083
+20447294
+20495512
+20513036
+20566328
+20589632
+20595935
+20682692
+20828385
+2083961
+20859899
+20927253
+20959502
+21195121
+2131034
+2173761
+2217015
+2239937
+2320485
+2358093
+2383364
+2400986
+24055495
+2429800
+2453942
+24641119
+24653743
+24658375
+24659727
+24664478
+24665854
+24671324
+24675088
+24684312
+24691439
+24709919
+24717468
+24727461
+24729111
+24733133
+24739405
+24742750
+24753331
+24778426
+24802403
+24812279
+24816962
+24840785
+24842192
+2484903
+24881749
+24894748
+24897009
+24902786
+24911645
+24923469
+24927617
+24928523
+24971338
+24975837
+24999722
+25006369
+25006961
+25031906
+25041770
+25054547
+25071004
+25080425
+25084821
+25096313
+25119790
+2553470
+256433
+25907210
+25951420
+25986755
+26002693
+26033014
+26115410
+2614930
+2625524
+2650911
+2710809
+2718706
+2765447
+2767010
+2782734
+2818777
+2884595
+2904523
+2907577
+2931989
+2933998
+2974281
+2983630
+3074291
+3083835
+3084231
+3088653
+3109094
+3125850
+3155884
+3191389
+3289726
+3297909
+3323259
+3323599
+3339945
+3375885
+3383127
+3409843
+3423103
+3439580
+3475563
+3533179
+3538855
+35781
+3685052
+3708328
+3711722
+3746148
+3798047
+3812624
+3831029
+3832950
+3833372
+3864191
+3895875
+3925479
+3975902
+3987172
+3990093
+4010471
+4082192
+4082466
+44072
+448423
+4631913
+48835
+573555
+6106951
+611664
+612112
+6299641
+6305660
+6310832
+6316193
+6321816
+6453500
+6517710
+6529939
+6585590
+6615679
+6627074
+6631522
+6673474
+6687006
+6695685
+6728873
+6806735
+6884395
+689020
+6893265
+6985297
+6985498
+7018927
+7121659
+7147232
+7173007
+7176945
+7248895
+7315949
+733189
+7369302
+7378868
+7411769
+7457821
+7477981
+7479194
+7492040
+753803
+7644931
+7661171
+7671401
+7727612
+7739955
+7931490
+7949506
+7967231
+8096565
+8135424
+8160791
+816141
+8184922
+8188982
+8308951
+8312343
+8312983
+8318674
+8392553
+851038
+8511251
+8603459
+8659767
+8667442
+8748050
+8755612
+8808730
+8819482
+8825380
+8829135
+891494
+89511
+895432
+8957205
+8985298
+8996419
+9061777
+9071336
+9125676
+9128918
+9132810
+9158667
+9197951
+920167
+9272404
+931801
+9323412
+9382023
+9428298
+946593
+9538487
+9570197
+9578276
+9646784
+9725303
+9759693
+9782254
+978847
+9831002
+9869655
+9881641
+9889429
diff --git a/huner/ner_scripts/splits/CDRDisease.train b/huner/ner_scripts/splits/CDRDisease.train
new file mode 100644
index 0000000..82d4ee6
--- /dev/null
+++ b/huner/ner_scripts/splits/CDRDisease.train
@@ -0,0 +1,900 @@
+
+10027919
+10074612
+10091616
+10091617
+1009330
+10193204
+10193809
+10225068
+10342929
+10365197
+10406016
+10411803
+10414674
+10457883
+10520387
+10523326
+10524660
+10526274
+10533019
+10539815
+10579464
+10669626
+10683478
+10704919
+10706004
+10721819
+10728962
+10737864
+10739826
+10743446
+10743694
+10791295
+10807237
+10835440
+1085609
+10901305
+10910842
+11007689
+11027904
+11027905
+11063349
+11077455
+11078231
+11079278
+11099450
+11135224
+11147747
+11166519
+11185967
+11195262
+11198499
+11206082
+11208990
+11226639
+11243580
+11245434
+11250767
+11256525
+11263551
+11271907
+11279304
+11282081
+11284996
+1130930
+11334364
+11379838
+11391224
+1141447
+11419773
+11426838
+11431197
+11467664
+1147734
+11524350
+11532387
+11569530
+11573852
+11581460
+11583940
+11587867
+11642480
+11672959
+11679859
+11694026
+11704023
+11705128
+11706060
+11745184
+11752354
+11773892
+11807648
+11838826
+11847945
+11860278
+11868798
+11875660
+11890511
+11897407
+11912119
+11928786
+11961407
+11999899
+12041669
+12042105
+12063090
+12084448
+12090760
+12093990
+12101159
+12109865
+12139551
+12180796
+12198388
+12202650
+12231232
+12369736
+12443032
+12448656
+12452237
+12464714
+12481039
+12483326
+12523465
+12536034
+12549952
+12571256
+12574103
+12584269
+12589964
+12596116
+12615818
+12617329
+12627929
+12639165
+12653683
+12684739
+12695819
+12707296
+12716030
+12739036
+12745515
+12757899
+12789195
+12820454
+12842176
+12851669
+1286498
+12905102
+12907309
+12907924
+12911170
+12921865
+1300436
+133615
+1355091
+137340
+1378968
+1420741
+1423339
+1428568
+1436384
+1445986
+14513889
+14568327
+14596845
+14633084
+14657095
+14659530
+1468485
+14698717
+14704468
+14736955
+14742097
+14745746
+14765563
+14975762
+14976857
+14982270
+15009014
+15036754
+15042318
+1504402
+15075188
+150790
+15120741
+15130900
+15145918
+15188772
+15233872
+15266215
+1527456
+15275829
+15276120
+15278670
+15325671
+15338796
+1535072
+1545575
+15458908
+1549199
+15515654
+15517007
+15531665
+15565293
+15572383
+15579441
+15580403
+15602202
+15632880
+15638391
+1564236
+15649445
+15673851
+15737522
+15764424
+15804801
+15811908
+15814210
+15858223
+15859940
+15863244
+15867025
+15893386
+15899738
+1592014
+15930398
+15957009
+15974569
+15985056
+16005948
+16006300
+1601297
+16047871
+1610717
+16116131
+16132524
+16157917
+16160878
+1616457
+16167916
+16174948
+16181582
+16192988
+16274958
+1628552
+16298782
+16330293
+16330766
+16337777
+1636026
+16364460
+1639466
+16403073
+16418614
+16428221
+16428827
+16471092
+16563323
+16574712
+16574713
+16584858
+16586083
+16596970
+16629641
+16634859
+1664218
+16680561
+16710500
+16720068
+16725121
+16740173
+16755009
+16787750
+16820346
+16826348
+16844102
+16858720
+16867021
+16904497
+16938416
+16960342
+1700207
+17019386
+17020434
+17042884
+17042910
+17074608
+17111419
+17147461
+17175308
+17194457
+1720453
+17241657
+17241784
+17242861
+17244258
+17261653
+17263743
+17285209
+1728522
+1728915
+1732369
+1732442
+17343925
+17344330
+17344566
+17366349
+17400887
+17437408
+17439425
+17466854
+17490790
+17490864
+17491223
+1749407
+17511042
+17532790
+17562951
+17574447
+17600377
+17608141
+17612891
+17615423
+17639754
+17682013
+17702969
+17786501
+17854040
+1786266
+17879945
+17919553
+17931375
+17943461
+17965424
+17975693
+18004067
+18006530
+18020536
+18023325
+18081909
+18083142
+18086064
+18161408
+18162529
+18177388
+18182964
+18186898
+18208574
+18217897
+18221780
+18239197
+18261172
+18308784
+18329269
+1833784
+18343374
+1835291
+18356633
+18363626
+18405372
+18410508
+18417364
+18439803
+18441470
+18442015
+18464113
+1848636
+18503483
+18541230
+18544179
+18560792
+18589141
+18619688
+18627295
+18631865
+18657397
+1867351
+18674790
+18703024
+18726058
+18752389
+18754075
+18768591
+18791946
+18808529
+18809400
+18821488
+188339
+18951540
+1899352
+18996674
+18997632
+19037603
+19058010
+19058474
+19105845
+19135948
+19139001
+1919871
+19211690
+19234905
+19269743
+1928887
+19289093
+19299179
+19300240
+19300402
+19308880
+19319147
+19346865
+19356053
+19356307
+19370593
+19387625
+19445921
+19473225
+19581773
+19631624
+19642243
+19657887
+19674115
+1967484
+19692487
+1969772
+19707748
+19721134
+19729346
+19759529
+19761039
+19767176
+19803309
+19820426
+19843802
+1987816
+19884587
+19889778
+19917396
+19923525
+1992636
+19940105
+19944333
+19944736
+19957053
+19996135
+20003049
+2004
+2004015
+20042557
+20067456
+20080419
+20080983
+20084309
+2008831
+20098969
+20103708
+20164825
+20195852
+20196116
+2021202
+2024540
+20304337
+20331935
+20466178
+20470218
+20477932
+20510337
+2051906
+20520283
+20528871
+20533999
+2054792
+20552622
+20558148
+20588063
+20619828
+20621845
+20633755
+20667451
+20683499
+20698227
+2070391
+20705401
+2071257
+20722491
+20727411
+20735774
+20880751
+20882060
+2096243
+20973483
+21029050
+21294084
+21418164
+220563
+2220369
+2224762
+2234245
+2265898
+2266990
+2273650
+227508
+230316
+2304736
+2312209
+2320800
+2322844
+2334179
+2334618
+2339463
+234669
+2348231
+2355241
+2375138
+2385256
+2396046
+2422478
+2425813
+2435991
+2440413
+2445283
+2466960
+2476560
+2484011
+2505783
+2515254
+2522601
+2528969
+2533791
+2549018
+2557556
+2559236
+2564649
+2572625
+2578334
+26094
+2611118
+2632720
+2670794
+2673163
+2696505
+2709684
+2716967
+2722224
+2750819
+2790457
+2802551
+2819587
+2826064
+2870085
+2887062
+2893236
+2894433
+2894766
+2907585
+2917114
+2924746
+2950248
+2951327
+2980315
+3001299
+3015327
+3015567
+3031535
+3057041
+3070035
+3076126
+3088349
+3101906
+3107448
+3108839
+3115150
+3123611
+3125768
+3131282
+3137399
+3173179
+3173180
+3187073
+3192036
+3220106
+322550
+326460
+3300918
+3311455
+3341566
+3358181
+3371379
+33969
+3403780
+3409645
+3412544
+3413271
+3425586
+3431591
+343678
+3437726
+347884
+3496378
+3503576
+3535719
+354896
+3560095
+3560096
+3564823
+3615541
+3629586
+3653576
+3670965
+3676049
+3686155
+3693336
+3703509
+3708922
+3714122
+3719553
+3732088
+3750012
+3762968
+3769769
+3780697
+3780814
+3780846
+3782049
+3800626
+3827439
+3828020
+384871
+3856631
+3865016
+3950060
+3961813
+3962737
+3969369
+3970039
+3985451
+3997294
+4008111
+4027862
+4038130
+4069770
+4071154
+4090988
+424937
+435349
+458486
+4812392
+567256
+591536
+603022
+6103707
+6111982
+6115999
+6118280
+6127992
+6133211
+6150641
+6203452
+6203632
+6209318
+6216862
+6229975
+625456
+6286738
+6287825
+6292680
+6293644
+6308277
+6323692
+6381653
+6386793
+6387529
+6415512
+6433367
+6436733
+6466532
+6503301
+6504332
+6518066
+6534871
+6538499
+6540303
+663266
+6634932
+6637851
+6640832
+6666578
+6674249
+6692345
+6695415
+6699841
+6727060
+6728084
+6747681
+6769133
+6773726
+6794356
+6861444
+6888657
+6892185
+6942642
+7007443
+7053303
+7059267
+7066357
+7072798
+7083920
+7088431
+7102237
+7189975
+7199841
+7234705
+7248170
+7263204
+7265370
+7269015
+7282516
+7292072
+7337133
+7352670
+7416947
+7420681
+7423039
+7444978
+7449470
+7453952
+7468724
+7504976
+7516729
+7542793
+7582165
+7596955
+7604176
+761833
+7619765
+7628595
+7647582
+7651879
+7707116
+7724492
+7752389
+7785794
+7791169
+7802851
+783197
+7834920
+7858459
+7862923
+7880714
+7881871
+7890216
+7905523
+7910951
+7919560
+7930386
+7977601
+7988234
+8012887
+8073369
+8092427
+809711
+8106150
+8111719
+8170551
+8231633
+8251368
+8267029
+8268147
+8302922
+8305357
+8319760
+8372922
+8384253
+8386779
+8387218
+839274
+8410052
+8410199
+84204
+8421099
+8423889
+8424298
+8437969
+8441146
+8473723
+8492347
+8514073
+8546130
+8558192
+8586822
+8590259
+8595686
+8599504
+8600333
+8607407
+8638206
+8638876
+8643966
+8643971
+8643973
+8649546
+8665051
+8669433
+8677458
+8682684
+8686832
+8690168
+869641
+8701950
+871943
+873132
+8739323
+8741744
+8742498
+8752018
+8766220
+8800187
+8829025
+88336
+8854309
+8864707
+8888541
+891050
+8911359
+8919272
+8953972
+8955532
+8958188
+8996652
+9022662
+9034419
+9041081
+9088814
+9098464
+9100294
+9105126
+9121607
+9154656
+9165568
+9195768
+9199746
+9201797
+9205462
+9209318
+921394
+9214597
+9226773
+9228650
+9245658
+9249847
+9270571
+9284778
+9293063
+9305828
+9321531
+9326871
+9334596
+9351491
+9390208
+9401499
+9406968
+9431903
+9495837
+950631
+9514561
+9522143
+9522152
+9523805
+9523850
+9545159
+9564988
+9579567
+9587734
+9625142
+9636837
+9653867
+9660111
+9669632
+9672273
+9672936
+9698967
+9721172
+9727773
+9746003
+9754849
+9758264
+9766615
+9799166
+9812111
+982002
+983936
+9848575
+9855119
+9862868
+9867728
+9869257
+9875685
+9915601
+9931093
+9952311
diff --git a/huner/ner_scripts/splits/arizona.dev b/huner/ner_scripts/splits/arizona.dev
new file mode 100644
index 0000000..5d4493f
--- /dev/null
+++ b/huner/ner_scripts/splits/arizona.dev
@@ -0,0 +1,284 @@
+
+1695
+1696
+1697
+1698
+1699
+1700
+1701
+1702
+1703
+1704
+1705
+1706
+1707
+1708
+1709
+1710
+1711
+1712
+1713
+1714
+1715
+1716
+1717
+1718
+1719
+1720
+1721
+1722
+1723
+1724
+1725
+1726
+1727
+1728
+1729
+1730
+1731
+1732
+1733
+1734
+1735
+1736
+1737
+1738
+1739
+1740
+1741
+1742
+1743
+1744
+1745
+1746
+1747
+1748
+1749
+1750
+1751
+1752
+1753
+1754
+1755
+1756
+1757
+1758
+1759
+1760
+1761
+1762
+1763
+1764
+1765
+1766
+1767
+1768
+1769
+1770
+1771
+1772
+1773
+1774
+1775
+1776
+1777
+1778
+1779
+1780
+1781
+1782
+1783
+1784
+1785
+1786
+1787
+1788
+1789
+1790
+1791
+1792
+1793
+1794
+1795
+1796
+1797
+1798
+1799
+1800
+1801
+1802
+1803
+1804
+1805
+1806
+1807
+1808
+1809
+1810
+1811
+1812
+1813
+1814
+1815
+1816
+1817
+1818
+1819
+1820
+1821
+1822
+1823
+1824
+1825
+1826
+1827
+1828
+1829
+1830
+1831
+1832
+1833
+1834
+1835
+1836
+1837
+1838
+1839
+1840
+1841
+1842
+1843
+1844
+1845
+1846
+1847
+1848
+1849
+1850
+1851
+1852
+1853
+1854
+1855
+1856
+1857
+1858
+1859
+1860
+1861
+1862
+1863
+1864
+1865
+1866
+1867
+1868
+1869
+1870
+1871
+1872
+1873
+1874
+1875
+1876
+1877
+1878
+1879
+1880
+1881
+1882
+1883
+1884
+1885
+1886
+1887
+1888
+1889
+1890
+1891
+1892
+1893
+1894
+1895
+1896
+1897
+1898
+1899
+1900
+1901
+1902
+1903
+1904
+1905
+1906
+1907
+1908
+1909
+1910
+1911
+1912
+1913
+1914
+1915
+1916
+1917
+1918
+1919
+1920
+1921
+1922
+1923
+1924
+1925
+1926
+1927
+1928
+1929
+1930
+1931
+1932
+1933
+1934
+1935
+1936
+1937
+1938
+1939
+1940
+1941
+1942
+1943
+1944
+1945
+1946
+1947
+1948
+1949
+1950
+1951
+1952
+1953
+1954
+1955
+1956
+1957
+1958
+1959
+1960
+1961
+1962
+1963
+1964
+1965
+1966
+1967
+1968
+1969
+1970
+1971
+1972
+1973
+1974
+1975
+1976
+1977
diff --git a/huner/ner_scripts/splits/arizona.test b/huner/ner_scripts/splits/arizona.test
new file mode 100644
index 0000000..28dfd2b
--- /dev/null
+++ b/huner/ner_scripts/splits/arizona.test
@@ -0,0 +1,849 @@
+
+1978
+1979
+1980
+1981
+1982
+1983
+1984
+1985
+1986
+1987
+1988
+1989
+1990
+1991
+1992
+1993
+1994
+1995
+1996
+1997
+1998
+1999
+2000
+2001
+2002
+2003
+2004
+2005
+2006
+2007
+2008
+2009
+2010
+2011
+2012
+2013
+2014
+2015
+2016
+2017
+2018
+2019
+2020
+2021
+2022
+2023
+2024
+2025
+2026
+2027
+2028
+2029
+2030
+2031
+2032
+2033
+2034
+2035
+2036
+2037
+2038
+2039
+2040
+2041
+2042
+2043
+2044
+2045
+2046
+2047
+2048
+2049
+2050
+2051
+2052
+2053
+2054
+2055
+2056
+2057
+2058
+2059
+2060
+2061
+2062
+2063
+2064
+2065
+2066
+2067
+2068
+2069
+2070
+2071
+2072
+2073
+2074
+2075
+2076
+2077
+2078
+2079
+2080
+2081
+2082
+2083
+2084
+2085
+2086
+2087
+2088
+2089
+2090
+2091
+2092
+2093
+2094
+2095
+2096
+2097
+2098
+2099
+2100
+2101
+2102
+2103
+2104
+2105
+2106
+2107
+2108
+2109
+2110
+2111
+2112
+2113
+2114
+2115
+2116
+2117
+2118
+2119
+2120
+2121
+2122
+2123
+2124
+2125
+2126
+2127
+2128
+2129
+2130
+2131
+2132
+2133
+2134
+2135
+2136
+2137
+2138
+2139
+2140
+2141
+2142
+2143
+2144
+2145
+2146
+2147
+2148
+2149
+2150
+2151
+2152
+2153
+2154
+2155
+2156
+2157
+2158
+2159
+2160
+2161
+2162
+2163
+2164
+2165
+2166
+2167
+2168
+2169
+2170
+2171
+2172
+2173
+2174
+2175
+2176
+2177
+2178
+2179
+2180
+2181
+2182
+2183
+2184
+2185
+2186
+2187
+2188
+2189
+2190
+2191
+2192
+2193
+2194
+2195
+2196
+2197
+2198
+2199
+2200
+2201
+2202
+2203
+2204
+2205
+2206
+2207
+2208
+2209
+2210
+2211
+2212
+2213
+2214
+2215
+2216
+2217
+2218
+2219
+2220
+2221
+2222
+2223
+2224
+2225
+2226
+2227
+2228
+2229
+2230
+2231
+2232
+2233
+2234
+2235
+2236
+2237
+2238
+2239
+2240
+2241
+2242
+2243
+2244
+2245
+2246
+2247
+2248
+2249
+2250
+2251
+2252
+2253
+2254
+2255
+2256
+2257
+2258
+2259
+2260
+2261
+2262
+2263
+2264
+2265
+2266
+2267
+2268
+2269
+2270
+2271
+2272
+2273
+2274
+2275
+2276
+2277
+2278
+2279
+2280
+2281
+2282
+2283
+2284
+2285
+2286
+2287
+2288
+2289
+2290
+2291
+2292
+2293
+2294
+2295
+2296
+2297
+2298
+2299
+2300
+2301
+2302
+2303
+2304
+2305
+2306
+2307
+2308
+2309
+2310
+2311
+2312
+2313
+2314
+2315
+2316
+2317
+2318
+2319
+2320
+2321
+2322
+2323
+2324
+2325
+2326
+2327
+2328
+2329
+2330
+2331
+2332
+2333
+2334
+2335
+2336
+2337
+2338
+2339
+2340
+2341
+2342
+2343
+2344
+2345
+2346
+2347
+2348
+2349
+2350
+2351
+2352
+2353
+2354
+2355
+2356
+2357
+2358
+2359
+2360
+2361
+2362
+2363
+2364
+2365
+2366
+2367
+2368
+2369
+2370
+2371
+2372
+2373
+2374
+2375
+2376
+2377
+2378
+2379
+2380
+2381
+2382
+2383
+2384
+2385
+2386
+2387
+2388
+2389
+2390
+2391
+2392
+2393
+2394
+2395
+2396
+2397
+2398
+2399
+2400
+2401
+2402
+2403
+2404
+2405
+2406
+2407
+2408
+2409
+2410
+2411
+2412
+2413
+2414
+2415
+2416
+2417
+2418
+2419
+2420
+2421
+2422
+2423
+2424
+2425
+2426
+2427
+2428
+2429
+2430
+2431
+2432
+2433
+2434
+2435
+2436
+2437
+2438
+2439
+2440
+2441
+2442
+2443
+2444
+2445
+2446
+2447
+2448
+2449
+2450
+2451
+2452
+2453
+2454
+2455
+2456
+2457
+2458
+2459
+2460
+2461
+2462
+2463
+2464
+2465
+2466
+2467
+2468
+2469
+2470
+2471
+2472
+2473
+2474
+2475
+2476
+2477
+2478
+2479
+2480
+2481
+2482
+2483
+2484
+2485
+2486
+2487
+2488
+2489
+2490
+2491
+2492
+2493
+2494
+2495
+2496
+2497
+2498
+2499
+2500
+2501
+2502
+2503
+2504
+2505
+2506
+2507
+2508
+2509
+2510
+2511
+2512
+2513
+2514
+2515
+2516
+2517
+2518
+2519
+2520
+2521
+2522
+2523
+2524
+2525
+2526
+2527
+2528
+2529
+2530
+2531
+2532
+2533
+2534
+2535
+2536
+2537
+2538
+2539
+2540
+2541
+2542
+2543
+2544
+2545
+2546
+2547
+2548
+2549
+2550
+2551
+2552
+2553
+2554
+2555
+2556
+2557
+2558
+2559
+2560
+2561
+2562
+2563
+2564
+2565
+2566
+2567
+2568
+2569
+2570
+2571
+2572
+2573
+2574
+2575
+2576
+2577
+2578
+2579
+2580
+2581
+2582
+2583
+2584
+2585
+2586
+2587
+2588
+2589
+2590
+2591
+2592
+2593
+2594
+2595
+2596
+2597
+2598
+2599
+2600
+2601
+2602
+2603
+2604
+2605
+2606
+2607
+2608
+2609
+2610
+2611
+2612
+2613
+2614
+2615
+2616
+2617
+2618
+2619
+2620
+2621
+2622
+2623
+2624
+2625
+2626
+2627
+2628
+2629
+2630
+2631
+2632
+2633
+2634
+2635
+2636
+2637
+2638
+2639
+2640
+2641
+2642
+2643
+2644
+2645
+2646
+2647
+2648
+2649
+2650
+2651
+2652
+2653
+2654
+2655
+2656
+2657
+2658
+2659
+2660
+2661
+2662
+2663
+2664
+2665
+2666
+2667
+2668
+2669
+2670
+2671
+2672
+2673
+2674
+2675
+2676
+2677
+2678
+2679
+2680
+2681
+2682
+2683
+2684
+2685
+2686
+2687
+2688
+2689
+2690
+2691
+2692
+2693
+2694
+2695
+2696
+2697
+2698
+2699
+2700
+2701
+2702
+2703
+2704
+2705
+2706
+2707
+2708
+2709
+2710
+2711
+2712
+2713
+2714
+2715
+2716
+2717
+2718
+2719
+2720
+2721
+2722
+2723
+2724
+2725
+2726
+2727
+2728
+2729
+2730
+2731
+2732
+2733
+2734
+2735
+2736
+2737
+2738
+2739
+2740
+2741
+2742
+2743
+2744
+2745
+2746
+2747
+2748
+2749
+2750
+2751
+2752
+2753
+2754
+2755
+2756
+2757
+2758
+2759
+2760
+2761
+2762
+2763
+2764
+2765
+2766
+2767
+2768
+2769
+2770
+2771
+2772
+2773
+2774
+2775
+2776
+2777
+2778
+2779
+2780
+2781
+2782
+2783
+2784
+2785
+2786
+2787
+2788
+2789
+2790
+2791
+2792
+2793
+2794
+2795
+2796
+2797
+2798
+2799
+2800
+2801
+2802
+2803
+2804
+2805
+2806
+2807
+2808
+2809
+2810
+2811
+2812
+2813
+2814
+2815
+2816
+2817
+2818
+2819
+2820
+2821
+2822
+2823
+2824
+2825
diff --git a/huner/ner_scripts/splits/arizona.train b/huner/ner_scripts/splits/arizona.train
new file mode 100644
index 0000000..a7020f1
--- /dev/null
+++ b/huner/ner_scripts/splits/arizona.train
@@ -0,0 +1,1696 @@
+
+0
+1
+10
+100
+1000
+1001
+1002
+1003
+1004
+1005
+1006
+1007
+1008
+1009
+101
+1010
+1011
+1012
+1013
+1014
+1015
+1016
+1017
+1018
+1019
+102
+1020
+1021
+1022
+1023
+1024
+1025
+1026
+1027
+1028
+1029
+103
+1030
+1031
+1032
+1033
+1034
+1035
+1036
+1037
+1038
+1039
+104
+1040
+1041
+1042
+1043
+1044
+1045
+1046
+1047
+1048
+1049
+105
+1050
+1051
+1052
+1053
+1054
+1055
+1056
+1057
+1058
+1059
+106
+1060
+1061
+1062
+1063
+1064
+1065
+1066
+1067
+1068
+1069
+107
+1070
+1071
+1072
+1073
+1074
+1075
+1076
+1077
+1078
+1079
+108
+1080
+1081
+1082
+1083
+1084
+1085
+1086
+1087
+1088
+1089
+109
+1090
+1091
+1092
+1093
+1094
+1095
+1096
+1097
+1098
+1099
+11
+110
+1100
+1101
+1102
+1103
+1104
+1105
+1106
+1107
+1108
+1109
+111
+1110
+1111
+1112
+1113
+1114
+1115
+1116
+1117
+1118
+1119
+112
+1120
+1121
+1122
+1123
+1124
+1125
+1126
+1127
+1128
+1129
+113
+1130
+1131
+1132
+1133
+1134
+1135
+1136
+1137
+1138
+1139
+114
+1140
+1141
+1142
+1143
+1144
+1145
+1146
+1147
+1148
+1149
+115
+1150
+1151
+1152
+1153
+1154
+1155
+1156
+1157
+1158
+1159
+116
+1160
+1161
+1162
+1163
+1164
+1165
+1166
+1167
+1168
+1169
+117
+1170
+1171
+1172
+1173
+1174
+1175
+1176
+1177
+1178
+1179
+118
+1180
+1181
+1182
+1183
+1184
+1185
+1186
+1187
+1188
+1189
+119
+1190
+1191
+1192
+1193
+1194
+1195
+1196
+1197
+1198
+1199
+12
+120
+1200
+1201
+1202
+1203
+1204
+1205
+1206
+1207
+1208
+1209
+121
+1210
+1211
+1212
+1213
+1214
+1215
+1216
+1217
+1218
+1219
+122
+1220
+1221
+1222
+1223
+1224
+1225
+1226
+1227
+1228
+1229
+123
+1230
+1231
+1232
+1233
+1234
+1235
+1236
+1237
+1238
+1239
+124
+1240
+1241
+1242
+1243
+1244
+1245
+1246
+1247
+1248
+1249
+125
+1250
+1251
+1252
+1253
+1254
+1255
+1256
+1257
+1258
+1259
+126
+1260
+1261
+1262
+1263
+1264
+1265
+1266
+1267
+1268
+1269
+127
+1270
+1271
+1272
+1273
+1274
+1275
+1276
+1277
+1278
+1279
+128
+1280
+1281
+1282
+1283
+1284
+1285
+1286
+1287
+1288
+1289
+129
+1290
+1291
+1292
+1293
+1294
+1295
+1296
+1297
+1298
+1299
+13
+130
+1300
+1301
+1302
+1303
+1304
+1305
+1306
+1307
+1308
+1309
+131
+1310
+1311
+1312
+1313
+1314
+1315
+1316
+1317
+1318
+1319
+132
+1320
+1321
+1322
+1323
+1324
+1325
+1326
+1327
+1328
+1329
+133
+1330
+1331
+1332
+1333
+1334
+1335
+1336
+1337
+1338
+1339
+134
+1340
+1341
+1342
+1343
+1344
+1345
+1346
+1347
+1348
+1349
+135
+1350
+1351
+1352
+1353
+1354
+1355
+1356
+1357
+1358
+1359
+136
+1360
+1361
+1362
+1363
+1364
+1365
+1366
+1367
+1368
+1369
+137
+1370
+1371
+1372
+1373
+1374
+1375
+1376
+1377
+1378
+1379
+138
+1380
+1381
+1382
+1383
+1384
+1385
+1386
+1387
+1388
+1389
+139
+1390
+1391
+1392
+1393
+1394
+1395
+1396
+1397
+1398
+1399
+14
+140
+1400
+1401
+1402
+1403
+1404
+1405
+1406
+1407
+1408
+1409
+141
+1410
+1411
+1412
+1413
+1414
+1415
+1416
+1417
+1418
+1419
+142
+1420
+1421
+1422
+1423
+1424
+1425
+1426
+1427
+1428
+1429
+143
+1430
+1431
+1432
+1433
+1434
+1435
+1436
+1437
+1438
+1439
+144
+1440
+1441
+1442
+1443
+1444
+1445
+1446
+1447
+1448
+1449
+145
+1450
+1451
+1452
+1453
+1454
+1455
+1456
+1457
+1458
+1459
+146
+1460
+1461
+1462
+1463
+1464
+1465
+1466
+1467
+1468
+1469
+147
+1470
+1471
+1472
+1473
+1474
+1475
+1476
+1477
+1478
+1479
+148
+1480
+1481
+1482
+1483
+1484
+1485
+1486
+1487
+1488
+1489
+149
+1490
+1491
+1492
+1493
+1494
+1495
+1496
+1497
+1498
+1499
+15
+150
+1500
+1501
+1502
+1503
+1504
+1505
+1506
+1507
+1508
+1509
+151
+1510
+1511
+1512
+1513
+1514
+1515
+1516
+1517
+1518
+1519
+152
+1520
+1521
+1522
+1523
+1524
+1525
+1526
+1527
+1528
+1529
+153
+1530
+1531
+1532
+1533
+1534
+1535
+1536
+1537
+1538
+1539
+154
+1540
+1541
+1542
+1543
+1544
+1545
+1546
+1547
+1548
+1549
+155
+1550
+1551
+1552
+1553
+1554
+1555
+1556
+1557
+1558
+1559
+156
+1560
+1561
+1562
+1563
+1564
+1565
+1566
+1567
+1568
+1569
+157
+1570
+1571
+1572
+1573
+1574
+1575
+1576
+1577
+1578
+1579
+158
+1580
+1581
+1582
+1583
+1584
+1585
+1586
+1587
+1588
+1589
+159
+1590
+1591
+1592
+1593
+1594
+1595
+1596
+1597
+1598
+1599
+16
+160
+1600
+1601
+1602
+1603
+1604
+1605
+1606
+1607
+1608
+1609
+161
+1610
+1611
+1612
+1613
+1614
+1615
+1616
+1617
+1618
+1619
+162
+1620
+1621
+1622
+1623
+1624
+1625
+1626
+1627
+1628
+1629
+163
+1630
+1631
+1632
+1633
+1634
+1635
+1636
+1637
+1638
+1639
+164
+1640
+1641
+1642
+1643
+1644
+1645
+1646
+1647
+1648
+1649
+165
+1650
+1651
+1652
+1653
+1654
+1655
+1656
+1657
+1658
+1659
+166
+1660
+1661
+1662
+1663
+1664
+1665
+1666
+1667
+1668
+1669
+167
+1670
+1671
+1672
+1673
+1674
+1675
+1676
+1677
+1678
+1679
+168
+1680
+1681
+1682
+1683
+1684
+1685
+1686
+1687
+1688
+1689
+169
+1690
+1691
+1692
+1693
+1694
+17
+170
+171
+172
+173
+174
+175
+176
+177
+178
+179
+18
+180
+181
+182
+183
+184
+185
+186
+187
+188
+189
+19
+190
+191
+192
+193
+194
+195
+196
+197
+198
+199
+2
+20
+200
+201
+202
+203
+204
+205
+206
+207
+208
+209
+21
+210
+211
+212
+213
+214
+215
+216
+217
+218
+219
+22
+220
+221
+222
+223
+224
+225
+226
+227
+228
+229
+23
+230
+231
+232
+233
+234
+235
+236
+237
+238
+239
+24
+240
+241
+242
+243
+244
+245
+246
+247
+248
+249
+25
+250
+251
+252
+253
+254
+255
+256
+257
+258
+259
+26
+260
+261
+262
+263
+264
+265
+266
+267
+268
+269
+27
+270
+271
+272
+273
+274
+275
+276
+277
+278
+279
+28
+280
+281
+282
+283
+284
+285
+286
+287
+288
+289
+29
+290
+291
+292
+293
+294
+295
+296
+297
+298
+299
+3
+30
+300
+301
+302
+303
+304
+305
+306
+307
+308
+309
+31
+310
+311
+312
+313
+314
+315
+316
+317
+318
+319
+32
+320
+321
+322
+323
+324
+325
+326
+327
+328
+329
+33
+330
+331
+332
+333
+334
+335
+336
+337
+338
+339
+34
+340
+341
+342
+343
+344
+345
+346
+347
+348
+349
+35
+350
+351
+352
+353
+354
+355
+356
+357
+358
+359
+36
+360
+361
+362
+363
+364
+365
+366
+367
+368
+369
+37
+370
+371
+372
+373
+374
+375
+376
+377
+378
+379
+38
+380
+381
+382
+383
+384
+385
+386
+387
+388
+389
+39
+390
+391
+392
+393
+394
+395
+396
+397
+398
+399
+4
+40
+400
+401
+402
+403
+404
+405
+406
+407
+408
+409
+41
+410
+411
+412
+413
+414
+415
+416
+417
+418
+419
+42
+420
+421
+422
+423
+424
+425
+426
+427
+428
+429
+43
+430
+431
+432
+433
+434
+435
+436
+437
+438
+439
+44
+440
+441
+442
+443
+444
+445
+446
+447
+448
+449
+45
+450
+451
+452
+453
+454
+455
+456
+457
+458
+459
+46
+460
+461
+462
+463
+464
+465
+466
+467
+468
+469
+47
+470
+471
+472
+473
+474
+475
+476
+477
+478
+479
+48
+480
+481
+482
+483
+484
+485
+486
+487
+488
+489
+49
+490
+491
+492
+493
+494
+495
+496
+497
+498
+499
+5
+50
+500
+501
+502
+503
+504
+505
+506
+507
+508
+509
+51
+510
+511
+512
+513
+514
+515
+516
+517
+518
+519
+52
+520
+521
+522
+523
+524
+525
+526
+527
+528
+529
+53
+530
+531
+532
+533
+534
+535
+536
+537
+538
+539
+54
+540
+541
+542
+543
+544
+545
+546
+547
+548
+549
+55
+550
+551
+552
+553
+554
+555
+556
+557
+558
+559
+56
+560
+561
+562
+563
+564
+565
+566
+567
+568
+569
+57
+570
+571
+572
+573
+574
+575
+576
+577
+578
+579
+58
+580
+581
+582
+583
+584
+585
+586
+587
+588
+589
+59
+590
+591
+592
+593
+594
+595
+596
+597
+598
+599
+6
+60
+600
+601
+602
+603
+604
+605
+606
+607
+608
+609
+61
+610
+611
+612
+613
+614
+615
+616
+617
+618
+619
+62
+620
+621
+622
+623
+624
+625
+626
+627
+628
+629
+63
+630
+631
+632
+633
+634
+635
+636
+637
+638
+639
+64
+640
+641
+642
+643
+644
+645
+646
+647
+648
+649
+65
+650
+651
+652
+653
+654
+655
+656
+657
+658
+659
+66
+660
+661
+662
+663
+664
+665
+666
+667
+668
+669
+67
+670
+671
+672
+673
+674
+675
+676
+677
+678
+679
+68
+680
+681
+682
+683
+684
+685
+686
+687
+688
+689
+69
+690
+691
+692
+693
+694
+695
+696
+697
+698
+699
+7
+70
+700
+701
+702
+703
+704
+705
+706
+707
+708
+709
+71
+710
+711
+712
+713
+714
+715
+716
+717
+718
+719
+72
+720
+721
+722
+723
+724
+725
+726
+727
+728
+729
+73
+730
+731
+732
+733
+734
+735
+736
+737
+738
+739
+74
+740
+741
+742
+743
+744
+745
+746
+747
+748
+749
+75
+750
+751
+752
+753
+754
+755
+756
+757
+758
+759
+76
+760
+761
+762
+763
+764
+765
+766
+767
+768
+769
+77
+770
+771
+772
+773
+774
+775
+776
+777
+778
+779
+78
+780
+781
+782
+783
+784
+785
+786
+787
+788
+789
+79
+790
+791
+792
+793
+794
+795
+796
+797
+798
+799
+8
+80
+800
+801
+802
+803
+804
+805
+806
+807
+808
+809
+81
+810
+811
+812
+813
+814
+815
+816
+817
+818
+819
+82
+820
+821
+822
+823
+824
+825
+826
+827
+828
+829
+83
+830
+831
+832
+833
+834
+835
+836
+837
+838
+839
+84
+840
+841
+842
+843
+844
+845
+846
+847
+848
+849
+85
+850
+851
+852
+853
+854
+855
+856
+857
+858
+859
+86
+860
+861
+862
+863
+864
+865
+866
+867
+868
+869
+87
+870
+871
+872
+873
+874
+875
+876
+877
+878
+879
+88
+880
+881
+882
+883
+884
+885
+886
+887
+888
+889
+89
+890
+891
+892
+893
+894
+895
+896
+897
+898
+899
+9
+90
+900
+901
+902
+903
+904
+905
+906
+907
+908
+909
+91
+910
+911
+912
+913
+914
+915
+916
+917
+918
+919
+92
+920
+921
+922
+923
+924
+925
+926
+927
+928
+929
+93
+930
+931
+932
+933
+934
+935
+936
+937
+938
+939
+94
+940
+941
+942
+943
+944
+945
+946
+947
+948
+949
+95
+950
+951
+952
+953
+954
+955
+956
+957
+958
+959
+96
+960
+961
+962
+963
+964
+965
+966
+967
+968
+969
+97
+970
+971
+972
+973
+974
+975
+976
+977
+978
+979
+98
+980
+981
+982
+983
+984
+985
+986
+987
+988
+989
+99
+990
+991
+992
+993
+994
+995
+996
+997
+998
+999
diff --git a/huner/ner_scripts/splits/bc2gm.conll.dev b/huner/ner_scripts/splits/bc2gm.conll.dev
new file mode 100644
index 0000000..748d2d2
--- /dev/null
+++ b/huner/ner_scripts/splits/bc2gm.conll.dev
@@ -0,0 +1,2000 @@
+P08000497A0179
+P09510398A1138
+P06972501A0615
+P08654435A0540
+P11208814A0673
+P08690118A0845
+P01771593A1152
+BC2GM041250465
+P02474356A0559
+P09144195A1051
+BC2GM051190318
+P00381783T0000
+P08105994T0000
+BC2GM008296773
+P10878398A0542
+P07652575A0435
+BC2GM064737481
+P06880604A0167
+P08955111A0989
+P06245672T0000
+P09777600A0000
+P08552095A0686
+P00837811A0675
+BC2GM058549376
+P07393976A0000
+BC2GM072699759
+P08383492A1205
+P01713213A0488
+P08611280A0820
+P08636428A1363
+P08270580A0155
+P01851386T0092
+P02530470A0604
+BC2GM022364640
+BC2GM041206962
+P11356835A0000
+BC2GM044994896
+P01664192A1577
+BC2GM097577617
+BC2GM014519920
+P08615025A1214
+P09300697A0000
+P03733563A0820
+P09765466A0231
+P09362499A0000
+P11139974A0762
+BC2GM078893266
+P03251210A0981
+P08428907A0653
+P11557127A0991
+P11274184A1068
+P01720843A1506
+BC2GM019793109
+P00417301T0001
+P09486890A0234
+BC2GM019245307
+P09642227A0000
+P09528770A1379
+P08555597A0808
+P08576262A0160
+P05389125T0000
+P09452444A0450
+P08414410A0270
+BC2GM020828058
+BC2GM005729141
+P10651805T0000
+P01918073A0150
+P07814405A1170
+BC2GM064435872
+P03198436T0000
+P07987924A0670
+P07937656A0182
+BC2GM003154305
+BC2GM031365198
+P02024816A0521
+P08213235A1024
+P11016014A0181
+P09549179A0774
+P09580563A0331
+BC2GM004847396
+P02534067A0316
+P07983744A0920
+P03755623A1233
+BC2GM053556516
+BC2GM027946341
+P01098592A0567
+P09267439A0000
+P07902583A0545
+P09623830A0000
+P07512258A0441
+BC2GM080639482
+P01027644T0001
+P01627830A0000
+BC2GM063564891
+P10931524A0313
+P07475793T0000
+BC2GM097865195
+BC2GM054717309
+BC2GM055252448
+P10567581A0119
+P08088513A0419
+P05274128T0001
+P06653755A0192
+P07365183A0000
+BC2GM016319405
+P08682317A0900
+P06876006A0930
+P04787472T0001
+P09234717A0000
+BC2GM085843951
+BC2GM095336401
+P02781495T0001
+BC2GM036044830
+BC2GM056370942
+P03977603A0326
+P08020702A0000
+BC2GM050190565
+P09882303T0000
+P08000074A0162
+BC2GM059240976
+P08124956T0000
+P09175858A1449
+P09291098T0000
+BC2GM020044790
+P09242499A0505
+P01281771T0000
+BC2GM071926370
+P09545638A0330b
+BC2GM027030914
+P06555107A1227
+BC2GM084871019
+BC2GM016713440
+P10938556A0248
+P02904322A0002
+P08293412T0000
+P08425050A0898
+P00985276A0000
+P05274526T0000
+P09808366A0828
+P03769224A0000
+BC2GM002201420
+BC2GM058928163
+P06362239T0001
+P09003462A0792
+P01995951A0000
+P04387103T0000
+BC2GM014569562
+P07966580A0518
+P07814321A0850
+P08776735A0000
+BC2GM087049151
+P06330082A0329
+P07931490A0237
+P10598101A0000
+P09203585A0660
+BC2GM035693756
+P11172944A0826
+P08639561T0000
+P09016566A0655
+P11046146A1202
+P10870043A0621
+P01782424A0278
+P09765411A0991
+P11371343A0125
+BC2GM024460635
+P11402674T0000
+P08703959A0659
+P10611353A0458
+P01280807A0575
+P08986228A0000
+P01788002T0001
+P08144668A0802
+P07565712A0286
+BC2GM074572349
+P09878437A0967
+P08616743T0000
+P08980413A0500
+BC2GM023576851
+P10848605T0000
+BC2GM036805670
+BC2GM009829131
+P11178696A0301
+P10727511A0294
+P07891713T0000
+P09579602A1720
+P11281201T0000
+P01695322A0000
+P11090762A0527
+P10798607A1359
+P04718233T0000
+P08025074A0000
+P10071212A0399
+P11069791A0226
+BC2GM088550314
+P09568549A0188
+BC2GM020276784
+BC2GM011866603
+BC2GM056771328
+P11353774A0255
+BC2GM029691403
+P06503885A0342
+P02417023T0001
+P08940132A1120
+P07926789A0960
+P08163546A1230
+P05884183T0001
+BC2GM081194969
+BC2GM035615525
+P08082215A0230
+P02551886A0332
+BC2GM063338768
+P05379901T0000
+P03017225A0706
+P03898382A0000
+P02838319A0527
+P08719697A0221
+P09694514A0000
+BC2GM027529733
+P01276105A0313
+P09268387A0293
+P09192998A0356
+P09514272A0482
+P11291552A0156
+P09250554A0402
+P10843810A0802
+P09522979T0000
+P09533030T0000
+P11789216T0001
+BC2GM084597422
+P11094066A0505
+P08323294T0000
+BC2GM081586375
+P01740121A0136
+BC2GM041916498
+P08309953A0776
+P04579436T0000
+BC2GM054086435
+P01339373T0000
+P01551568A1476
+P06978566A0197
+P09082335A0730
+BC2GM016884667
+BC2GM042062377
+P08071982T0000
+P01478672A0795
+BC2GM002038023
+P09675154A0690
+P09723896A0000
+P07704689T0000
+P08816483A0869
+P04990556T0000
+P08223613A0105
+P09904139T0000
+BC2GM049393382
+P10681562A0263
+P01422265A0263
+P03346210A0000
+P10706736A1091
+P10304090T0000
+P08985122A0501
+BC2GM019727288
+P08746981A0154
+P06095774T0001
+BC2GM039082460
+P08195216A1022
+P09055221A0288
+BC2GM086974168
+P03119485A0476
+P09945838T0000
+P11028944A1020
+P02889352A0000
+P01628904A0386
+P10611225A1127
+BC2GM046571166
+P08760889A0170
+P01168956A0552
+P08618882A0343
+BC2GM037219569
+P02704579A1078
+P07822329A0773
+P05276380T0000
+P11003641A0811
+P03493240T0000
+P09249039A0124
+P02340595A0124
+BC2GM085703128
+P08387508A0551
+P02024625A0202
+P07575947T0000
+P01544928A1252
+P03403313A0298
+BC2GM092675349
+P02725495A0929
+P10904191A0000
+P03570455A0433
+P07629103T0000
+P08224260A1248
+BC2GM065118476
+P01560774A0885
+P05303700T0066
+BC2GM022760333
+BC2GM071659744
+P11454703A0000
+BC2GM042126877
+BC2GM090376124
+BC2GM047739640
+P08798643T0000
+P06304771A1284
+P09560390A0771
+P01939878A0765
+P01653173A0619
+P03046931A0247
+P08004442A0265
+P09223479A1193
+BC2GM026076995
+BC2GM068686527
+BC2GM009645672
+P10008261T0000
+BC2GM027655679
+P09774403A0107
+BC2GM030008462
+P00008997A0472
+P01748292A0000
+P10837126A1004
+BC2GM032982135
+BC2GM007092490
+P07913080A0564
+P07691837A1359
+P01537334A0507
+P09813098A0521
+P01854339A0221
+P03243027T0000
+P10715322A0000
+P03237446A0377
+BC2GM091067876
+BC2GM044764990
+BC2GM049036740
+BC2GM025926172
+P07642538A0138
+BC2GM080578931
+P08817323A0714
+P03553439A0404
+P02078080T0040
+P11295523A0218
+P00342623A0228
+BC2GM035149396
+BC2GM025499244
+P07706307A0914
+BC2GM017211898
+P02331361A0268
+BC2GM016704905
+P10586107A0160
+P08132541A0000
+BC2GM039216973
+P00759400T0000
+P03883052T0001
+P10838139A1447
+P09171389A0549
+P01829060A0649
+P09049306A0830
+P09999742T0000
+P07665948A0591
+P10778740A1493
+BC2GM079274366
+P08390747A0586
+P06794480A0785
+P09413375A1486
+P10817754T0000
+P08836740A1025
+P11469926T0000
+P02423533A1314
+P09324922T0065
+P07534285A0155
+BC2GM040715083
+P03746508A0390
+P02745666A0000
+P11413148A0573
+P09465783A0449
+P10965905A1618
+P11259503A0212
+P08973630A0923
+P06615403A0718
+P10606245A0906
+P10797586A0402
+P01769919A0393
+BC2GM008157990
+P09183145T0001
+BC2GM062642302
+BC2GM032150077
+P09731705A2126
+P11572388A0000
+BC2GM073006220
+P02774808A0194
+BC2GM094374885
+P02784507A0000
+BC2GM008542019
+P10939030A0986
+P03069980T0000
+P08428750T0000
+BC2GM045771943
+P11334124A0903
+P08656672A0678
+BC2GM001536665
+P02188168A0000
+P09020169A0552
+P09857265A0669
+P09428787A0138
+P02148799A0000
+BC2GM065749452
+P09132057A0559
+P11137551A0437
+BC2GM081449509
+P03417668A1233
+BC2GM063086995
+P01436261A0145
+P09707498A0262
+P08028671A0687
+BC2GM044089781
+P02146266A0000
+P09148903A1715
+BC2GM081686289
+BC2GM053000072
+P02153683A1579
+P09687511A1091
+P10721704X0000
+BC2GM056600805
+BC2GM015309588
+P02600306A0140
+P07897696A0000
+P08086450A0467
+P11740806X0810
+BC2GM090142421
+P07802655T0000
+BC2GM059966403
+P10690866A0783
+P07905453A0281
+P00136175A1137
+BC2GM040893145
+P09398332A0732
+P09278450A1338
+BC2GM038029406
+P07747462A0332
+P08619866A0000
+P08663392A0215
+P07816630A1333
+P11350165A1606
+P02739739T0000
+BC2GM004578175
+P08276851A0347
+P11067928A0532
+P08751635A0135
+P09101910A0394
+BC2GM060403286
+P00519173A0126
+P06707357A0180
+P08033490A0875
+P08745669A0000
+P05066316T0001
+P02555418A0973
+BC2GM017612777
+P02748188A0091
+P11235335T0000
+BC2GM027121414
+P01735447A0271
+P07980669A0373
+P02598745A0251
+BC2GM067111314
+P06517816A0388
+P02167321T0000
+P02185140A0000
+BC2GM013088712
+BC2GM075767585
+P01314953A1266
+BC2GM097406919
+BC2GM053977202
+P11583428A0191
+P09578042A0363
+P01649173A0160
+P02636920T0001
+P07937108A0325
+BC2GM007444164
+P09642238A1285
+P10618645A0750
+P10918572A0794
+P07831799T0000
+P07775428A0172
+BC2GM081056774
+P01394200A0592
+BC2GM065203942
+P10677297A0933
+P08325639A0129
+BC2GM084813234
+BC2GM003538479
+P07513703T0000
+P04013604A0412
+P08807408A0524
+P08942999T0000
+P01272816A0000
+BC2GM050480913
+P11331604A0267
+P06466804A0686
+P01626430A1112
+P08801403T0001
+P01379150A0996
+P01408474A0531
+P09353343T0000
+BC2GM045193318
+P06723849A0197
+P02198289A0436
+P11576158A1371
+P11176098A0342
+P08363332A0365
+P09582331A0506
+P09150595A0225
+P06382374A0206
+P00868903A0000
+P11095248A0423
+BC2GM095421849
+BC2GM032669155
+P07659746A1464
+P08976253A0637
+P09029713A1120
+P05253274T0001
+P06173860A0000
+P11243494A0833
+P11058008A0159
+P01716629A0000
+P03026915A1024
+P11282394A0841
+P08188290A0544
+P07687745T0000
+P08973527A0000
+BC2GM085081988
+P07311881T0000
+P02648396A1033
+P09829836A0000
+P07945134A0079
+P10455087A1400
+BC2GM013965440
+BC2GM058884519
+P02196450A0870
+P08035499A0941
+P08516308A0669
+P02123466A0272
+BC2GM003230275
+P09005273A1558
+P02303158T0000
+P01619642A0131
+P03592297A0138
+P02390538A0000
+P02325208A0209
+P01922739A0336
+P09386074A0694
+P04032716A0299
+P08132667T0000
+BC2GM020722431
+BC2GM027223397
+P11566948A1217
+BC2GM027886760
+BC2GM051341452
+P09189783A0000
+P02518691A0251
+P08986770A0268
+P01628806A1347
+P09811730A1396
+P11555516A0639
+P10926776A0731
+P08943032A0000
+P11034933A0389
+BC2GM085794657
+P07685263A0503
+P09786197A0322
+BC2GM014151852
+P03325081A0524
+P03427474A0853
+P03659994A0150
+P11118062A1691
+BC2GM027315963
+P10391277A0000
+P02237431A0000
+P02213566A0000
+BC2GM033697921
+P09365201A2018
+P05552149T0000
+P02648396A0565
+P10055173T0000
+BC2GM058154023
+P02601707A0986
+P09218775A1229
+P03243920A0591
+BC2GM044965167
+P11160683A1220
+P09599724A0193
+P07693967A0905
+P10722969A0510
+BC2GM033411321
+P06714298X0000
+P09892017A2151
+P02548683T0001
+P00503336A0285
+P03534581A0976
+P10766493T0000
+P07610324A0319
+P03537721A0876
+P10085383A1367
+P10855690A0870
+P03381039A0364
+P08413291A1473
+P05718994T0000
+P08505605A0461
+BC2GM095257968
+BC2GM015257023
+P08488700A0283
+P00484177A0242
+P01083375T0000
+BC2GM033228661
+P11438838A0788
+BC2GM028886679
+BC2GM005102149
+P10586626A0607
+BC2GM032387601
+P03776779A0238
+P08978690A0262
+BC2GM003435732
+P10695685T0000
+P08204348T0000
+BC2GM047029029
+P11439343A0785
+P10580071A0436
+P00060529A0695
+P08887674A0920
+P07840643A1006
+P11156789A1669
+P01848300A0910
+BC2GM024043854
+BC2GM081059742
+P01327758A0000
+P09442031A0586
+BC2GM066933865
+BC2GM073356328
+P01992742A0000
+P08282749A1474
+P08172653A1589
+P10681588A0899b
+BC2GM091594657
+P01569945A0529
+P10758489A0206
+P03233862T0000
+P08400240A0166
+P00600943T0001
+P09200029A0211
+P06700231A0259
+BC2GM052108285
+BC2GM082234251
+P09321930A0567
+P07538818A0197
+P03023859A0000
+P09625762A0426
+P01697683T0000
+P08588852A0236
+BC2GM069666252
+P11058120A0256
+P01774062A0257
+BC2GM088020091
+P08300605A0671
+P07890599A0132
+P08034742A0307
+BC2GM086254445
+P09802206A1058
+P03698251T0000
+P07873631A0114
+P11404312A0660
+P09862481A0000
+BC2GM016668855
+P08497269A0999
+BC2GM052077853
+P03709191A0125
+BC2GM034834811
+P01718983A1640
+P11064829T0058
+P03697971A0311
+P10815807A1271
+P02729666A0267
+BC2GM027266609
+BC2GM043140660
+P11278286A1083
+BC2GM081816003
+P10731926A0775
+P09371698A1254
+BC2GM036910658
+BC2GM059590650
+BC2GM032675979
+P06884450A0234
+P02257899T0000
+P06794666A0208
+P09829843A0119
+P11408099A0518
+P10629035A0827
+BC2GM097372131
+P10732669A0510
+P10506160A0297
+BC2GM096226765
+P11251252A0494
+P09065690A0463
+P00635143T0001
+P08273122A0708
+P09453689A0000
+P06252883A0100
+P02278474A0000
+P07806492A1162
+P09539421A0970
+P07106323A0560
+BC2GM036783364
+P11080796A0883
+BC2GM043523673
+P04316696T0001
+P08397123T0000
+P10748125A0000
+P09770378A0641
+P10908478A0717
+P00722298A0619
+P01867069A0000
+P07979827A0722
+BC2GM060485652
+BC2GM050121577
+BC2GM031712129
+BC2GM082790827
+P01740330A0329
+P07483857A0350
+P08429019A0735
+P06439135A0250
+BC2GM067853242
+P02950216A0084
+P01970560A1024
+BC2GM051172236
+P08294459A0446
+P02994253A0482
+P08530342T0000
+BC2GM018717311
+P06807149A0222
+P09502720T0000
+P01629768A0131
+P11210401A0000
+P09744095A1016
+BC2GM051932987
+P10564495A0444
+BC2GM027887044
+P08591700A0972
+P01310899A0339
+BC2GM078652752
+P09151837A0723
+P09798068A0290
+BC2GM006670958
+BC2GM034110005
+P10603349A1667
+P10395199A0792
+P10668701A1311
+P02115572A1323
+P07875595A0910
+BC2GM068485408
+P09146027A0809
+P11267679A0102
+P09312087A0000
+P01740437A0851
+P03253219T0000
+BC2GM024107686
+P00167544A0067
+P11046153A1052
+BC2GM037286587
+BC2GM070224595
+BC2GM033913312
+P06209403A0562
+BC2GM002670368
+BC2GM043040465
+P01649318A1222
+P04032268A0358
+P11264176A0181
+P01641628A0869
+P11323716A0413
+BC2GM018593064
+P03382310A0903
+P04661961T0001
+BC2GM069042705
+P00842406A0771
+P08139543A1520
+BC2GM091683569
+P01634308A0191
+BC2GM086696613
+P08971835A1057
+P03013841A0207
+BC2GM075404725
+P09801156A0220
+P11027289A0000
+BC2GM010976531
+P03626129T0001
+BC2GM067585100
+P06993660A0000
+BC2GM056032445
+P11012680A1020
+P10872851A0714
+P01330077A0000
+P08645219A1377
+P11468958A0122
+P11159081A1155
+P09171363A0149
+P09397261A0940
+P09209406A1021
+P06658586T0001
+P08756636T0000
+P09485308A1165
+BC2GM044349472
+P02517008A0481
+BC2GM007331951
+P00358945A0225
+P10931960A0630
+BC2GM082270855
+P08546707T0000
+P03811852A0109
+BC2GM059417476
+BC2GM090212976
+P02958233A0123
+P03687078T0001
+BC2GM043328446
+P00488534A0308
+P07601828A0095
+P06381438A1280
+P09328476A0068
+P00764737X0000
+P08660998A0851
+P08279098T0001
+BC2GM024357509
+BC2GM039939591
+P11182520A0889
+P11146961T0000
+P09843572A0944
+BC2GM017071077
+P02125153A0410
+P01527020A0511
+P10791819A0771
+BC2GM072697080
+P10658588A0304
+BC2GM014230016
+P08918810A0967
+P01657594A0472
+P11251083T0000
+BC2GM066160627
+P08160387T0000
+P03118631A0140
+P07263374T0000
+BC2GM097338310
+P07488291A0934
+P09751114A0967
+BC2GM043347947
+P01003819A0498
+P11256962A0233
+P09208930T0000
+P09964171T0000
+P08200528A0970
+P05982700T0000
+BC2GM057834406
+BC2GM027749985
+BC2GM086681787
+P09731354A0963
+P10702926T0089
+P09964770T0000
+P02206858A0000
+P07774807A0405
+P09325135A0737
+BC2GM097463042
+P11287654A0150
+P01265443A0159
+P09271417A1011
+BC2GM093832681
+P09268631A0316
+P08294865A0236
+BC2GM090670157
+P10741850A0452
+P07713936A0393
+BC2GM025094237
+P00073344A0367
+P02664229A0138
+P07608268A0194
+P08894826A0228
+P11207216A0719
+P05172320T0001
+P02076816T0000
+P07844155A0327
+P04043489A0648
+P11012680A0676
+P08114710A0137
+P05797287T0069
+BC2GM065990339
+P09922856A0459
+P03732252A0556
+BC2GM092963902
+P06286191T0000
+P02576405A0223
+BC2GM006556353
+P00917721A0484
+P08485317A0000
+BC2GM023966802
+P07251564A0569
+P02241742A0766
+P09867159A1444
+P09508511A0588
+P10573781A0631
+BC2GM027443624
+BC2GM035313252
+P00968181A0264
+P11266227A0295
+P03045725A0872
+P07557091A0314
+P01849675A0167
+P09556861A1018
+BC2GM084033136
+P07675449A0848
+P09001667A0312
+BC2GM047781166
+BC2GM031270698
+P08756609A0498
+P10873286X0000
+P04034666T0000
+P11566961A0472
+BC2GM047234366
+P08710377A0577
+P02233729A1065
+P09150566A0316
+P02300577A0852
+P08849834A0000
+BC2GM053225720
+P07418498A0217
+P02744123A0237
+P06962492A0612
+P01616475A0756
+P01839414T0000
+P08395014A1364
+P09138076A1099
+BC2GM037195225
+P01808829A0510
+P10744749T0000
+BC2GM085649644
+P02399053A1032
+BC2GM027260839
+P00959656A0250
+BC2GM067096168
+P02821340A0434
+P01658741A1047
+BC2GM068076074
+P01948783A0000
+BC2GM007721864
+BC2GM002038787
+P06153936A0784
+P00541752A1032
+P08106245A0325
+P08185288A0106
+P07508140A0448
+P03873141A0304
+P10516072A0146
+P01762917A0615
+P07814388A0662
+P06336045A0261a
+P01636714A0845
+P05152314T0001
+P01967130A0645
+P10801244A0578
+BC2GM052871586
+P02532032A0385
+P10576545A0926
+P08103379A0577
+BC2GM008233762
+P10571474A0571
+P09573374A0687
+BC2GM066800010
+P06494215A0248
+P04027182T0000
+P09421507A0000
+P01551910A0313
+P09743233A0526
+BC2GM081733719
+BC2GM042134341
+P01328197A0985
+BC2GM088319331
+P09421521T0000
+P01916405A0242
+P10743608A1154
+P11070078A1153
+P02733690T0000
+P03418727A0992
+P08439597A0000
+P07961958T0000
+P08756433A0282
+P02479635A0659
+P09822602A0237
+BC2GM087236793
+BC2GM078821043
+BC2GM086866960
+BC2GM047245566
+P02209811T0000
+P03645733T0001
+P09444316A0388
+P07527168A0524
+P11278440A0095
+BC2GM072992671
+P09218459A0000
+P03608916A0790
+P10918599A0071
+P03976323A0821
+BC2GM011126259
+P09085842A0181
+P08188978A0822
+P09108279A0431
+P09046013A0000
+P04039307A0613
+P08257754A0711
+BC2GM063705940
+P07799939A0628
+P05203499T0001
+P01725547A0354
+P07824726A0454
+P09304123A0079
+BC2GM098640095
+P08223592A0424
+P02332018A0538
+P10568275A0679
+P05733952T0001
+P08014919A0530
+BC2GM098491104
+P01513213A0231
+P07529504A0000
+P11223153A0533
+BC2GM048845063
+BC2GM023214186
+BC2GM000692061
+BC2GM035523240
+P01817497A0715
+P02506390T0001
+P07844425A0289
+P02190122A0633
+P09999256T0000
+P07918128A0000
+P01785749A0695
+P09265642A0668
+P10479492A0000
+P01249198A1097
+P08935991A0844
+P01842498A0000
+BC2GM054001196
+P09367288A0115
+P10915728A0216
+P10490065T0000
+P09765285A0998
+P10630471T0000
+P00406585T0001
+BC2GM074053029
+P01287197A0761
+P10932679A0049
+BC2GM091017201
+P02691998A0672
+P08660892A1044
+BC2GM005086687
+BC2GM049662793
+BC2GM055940365
+P11038366A1417
+P06630319A0244
+P07786820A0284
+P08660733X0000
+BC2GM082631911
+P08083998A1723a
+P07160491A0547
+P05758469T0001
+P02236060A1671
+P08545502A0914
+P00580106T0000
+P02099622A1046
+BC2GM095399332
+P07296303A0418
+BC2GM088510048
+BC2GM053114631
+P06487290A0000
+P11160732A1199
+P08020702A0137
+P01833637A0531
+P10899128A0661
+BC2GM026606071
+P00337102T0058
+P00917572T0001
+P10580438A0508
+P01097100A0217
+P07514295A0000
+BC2GM086734097
+BC2GM027314864
+BC2GM087160593
+P08878044A1390
+BC2GM060037556
+P06872800T0000
+P08575754T0000
+P09405536A0777
+P01324385A0329
+P11337859A0651
+BC2GM096331447
+BC2GM075740515
+BC2GM077833737
+P07745696A0932
+P08566747A0756
+P09642764A0469
+P02312470A0774
+P07450031A0691
+BC2GM004099886
+BC2GM026014073
+P00875778T0000
+P11027289A0321
+BC2GM083915598
+BC2GM031508417
+P10796486A0817
+BC2GM013433125
+BC2GM013283171
+P11207609A0994
+P03628713A0961
+BC2GM009334391
+BC2GM000854272
+P10642524A0156
+P07205967T0000
+BC2GM095899932
+P00346829X0000
+BC2GM084436440
+P08040391T0000
+P01584812T0000
+BC2GM032311862
+P09219526A0383
+P09042078A0202
+BC2GM074489263
+P01128985A0000
+P06493655A0415
+BC2GM000554364
+BC2GM094094269
+P00594617A0192
+P08264579A1209
+P09632785A0000
+P07896846T0000
+P03882029A0000
+BC2GM044606080
+P03765552A0582
+P07372928A0105
+P11454239A0478
+P02910989T0000
+BC2GM063679270
+BC2GM018506059
+P11396685A0477
+P07568865A0305
+BC2GM041191299
+P09482107A0551
+P07789809A1246
+P09653641A0471
+P11071651A1308
+P07693132A0100
+P08321741A0396
+P01771593A1232
+P09234677A0770
+P01727494A0000
+P08861963T0000
+BC2GM033838267
+P00665053A0276
+P00521732T0000
+P00183063A0300
+P08543173A0314
+P10906317A0351
+P03781000A0101
+BC2GM076159056
+P09765261A0000
+P08396713A0305
+P09573884A0392
+P10620010A1155
+BC2GM099053917
+P08946668A0077
+P01396601A0986
+P07149303T0000
+P03802195A0481
+P02199311A0620
+BC2GM068280141
+BC2GM099912787
+BC2GM051140215
+P10713083A0560
+P10934310A0698
+P05388567T0000
+BC2GM091705287
+P07908827A1200
+BC2GM046827862
+P01770651T0001
+P02284573A0943
+BC2GM004377989
+P09039744T0000
+BC2GM019432575
+P07282552A0990
+P10940553A0912
+P08668190A1364
+P02324104A0151
+P02979426T0000
+BC2GM065497063
+BC2GM075043873
+P02164588A0266
+P09311835A0147
+P02033062A1169
+P11126806A0206
+BC2GM017819030
+BC2GM060767735
+P01899409T0000a
+P09346935A0927
+P08031424T0000
+P02259334A0205
+P07494293A0585
+BC2GM065119340
+BC2GM054468941
+P04371279T0000
+P02157067A0610
+BC2GM089085833
+BC2GM089791646
+P02833049A1041
+P03465957A1008
+BC2GM082132977
+P11348318A0940
+P08201758A0125
+P07969116A0196
+BC2GM095560139
+BC2GM036149639
+P01349705T0000
+P04364369T0000
+P09875541A0210
+P11180255A0776
+P10575231A0355
+BC2GM052383687
+BC2GM028011707
+P01201977T0000
+P09199292A0536
+P08014377A1277
+BC2GM091790699
+P06395804A0382
+P02154602A0092
+BC2GM037814296
+P07140493A1045
+P09864689A1408
+P09064868T0001
+P02324104A0516
+P10607900T0000
+P02757862T0000
+P04583791T0000
+P01849509T0000
+P01333047A0404
+P09154827A0158
+BC2GM052215077
+P07062036A0072
+P08868954A0648
+P10752450A0288
+P09004987T0001
+P08995659A0563
+P08676495A0129
+P06372563T0000
+P02373810A1118
+P01618027A1108
+P04837183T0000
+P08234166A0425
+BC2GM025094273
+P01512654A0503
+BC2GM092341620
+P11480555A0928
+P01709486A0000
+P09427627A0802
+P08627649A0734
+BC2GM026829531
+P01954355A0997
+BC2GM005882702
+P01349837T0000
+P08500524A0424
+BC2GM052496419
+BC2GM036499922
+P04468264T0053
+P06825641A0076
+BC2GM097944036
+P02894741A0000
+P09187371A0450
+P01724982A0237
+P00512215A0000
+P07507458A0250
+P01869565A1254
+P09225686A0683
+P08931991A1026
+P03322829A0952
+BC2GM009595830
+P02055484A0538
+P09976626T0000
+P02839488A1314
+P11490862A0141
+P09354684A1158
+BC2GM089535838
+P08159174A0581
+P02045809A0331
+BC2GM009438252
+P10620335A0749
+BC2GM099369048
+P11528500A0571
+P08622030A0667
+P09587549T0001
+BC2GM028289615
+P04377328T0027
+P02361008T0000
+BC2GM092196424
+BC2GM007219216
+BC2GM005310044
+BC2GM029322086
+P09230216T0000
+P08240170A0000
+BC2GM002546611
+P08430095A0161
+BC2GM068318843
+P10972990A1518
+P09891092A1000
+BC2GM086236532
+BC2GM069019076
+P09099743A0585
+P10788476A0891
+BC2GM090485804
+P00846559A0000
+P06113443T0000
+P10671519A0641
+P09512416A0460
+P01493864A0619
+P08817324A1070
+P01895358A0000
+P11382948A0793
+P08001136T0000
+P09227099A0106
+P02536096A0327
+P08006773A0836
+P03159903A0352
+P07590525A0811
+P07869913A1076
+P08654946A0986
+BC2GM030067070
+P06674977A1181
+P02028125A0101
+P08887659A0753
+P10607899A0605
+P03770143A1209
+BC2GM097376485
+P09642238A0532
+P11459962A0785
+P08264664A0128
+P08797362T0037
+P09328833A0588
+P01370446A0818
+BC2GM009718351
+P10942599A1298
+BC2GM000577306
+BC2GM064715787
+P01409581A0206
+P08383287A0611
+P11113823A0197
+P00242427T0001
+BC2GM061130955
+BC2GM055588958
+BC2GM084745915
+P11479501A0744
+BC2GM060450171
+P09882499A0231
+P11016850A0423
+BC2GM039075173
+BC2GM047756282
+P06244732T0000
+BC2GM074932175
+P02657883T0001
+P08360180A1041
+P08787110A0981
+BC2GM019437752
+BC2GM021905510
+P02458080T0000
+P08449978A0000
+P07593896A1053
+P01620129A0417
+P03398433T0001
+P01380062A0097
+BC2GM022818569
+BC2GM009237641
+P07935577A0305
+P07943556A0694
+P08738510A0254
+P02475506A0878
+P08662936A0428
+P11422757A0737
+P01918010A0000
+P11221845A0800
+P10906176A0000
+BC2GM028481632
+P09564917A0900
+P09780002A0996
+P08449133A0578
+BC2GM073109990
+P01623900A0670
+P01942033T0000
+BC2GM067886213
+P06671065A0000
+P10660676A0000
+P07476971A0381
+BC2GM013098163
+P04101003T0001
+P10454568A0815
+P02034655T0000
+P10211329A0457
+P01840608A0823
+P00996364X0000
+BC2GM096832130
+P02688772T0000
+BC2GM005153590
+P09712859A1110
+P09368014A0740
+P07592721A0827
+P02143186A1306
+P10964833A1696
+P07598106A0709
+P08082292T0000
+P02470955A0101
+P09056761A0000
+P07165767T0000
+BC2GM015227811
+BC2GM083262968
+P11583621A0301
+BC2GM035406397
+P08020962A1226
+P00839378A0649
+BC2GM008520158
+BC2GM006291661
+P08643759A0338
+P11480490A0443
+P08955306A0224
+BC2GM013174234
+P10892823A1040
+P10563605A0773
+P00222827A0000
+P04878680T0000
+BC2GM082753569
+P01925092A0304
+P11006283A1180
+P09272108A1295a
+P00757244A0000
+P11389085A1032
+BC2GM010412536
+P08654983A0000
+BC2GM055762789
+P07760819A0731
+P02727909A0383
+P02201905A1004
+P10032581T0000
+P04021281T0001
+P06328504A0161
+P07542577A0438
+BC2GM023099486
+P03199043A0248
+P11524015A0937
+P01893195A0000
+P11469701A0377
+P09987634A1265
+P00602622A0362
+P10863048A0000
+P09920930A0521
+P09371622A0779
+P10907971T0000
+P11502778A0941
+P08661119A0085
+P08610272A0265
+P08246987A0260
+P11842728X0001
+P03439248A0000
+P01354506T0000
+P01640778A0485
+BC2GM098160022
+P09263010T0000
+P01324406A1250
+BC2GM042018281
+P11238105A0959
+P11450776T0000
+P10792583A0000
+P09489670A1157
+BC2GM040473941
+P10756225A1464
+BC2GM013825160
+P08854459A0000
+P01798407A1011
+BC2GM022449738
+BC2GM049324626
+BC2GM045448639
+BC2GM082757224
+P00137671A0896
+P09371431T0000
+BC2GM040023769
+P09193072A0199
+P09864335A1226
+BC2GM049820346
+P09108038A1128
+P10825000A1245
+P01779299A0000
+BC2GM067379320
+BC2GM092358374
+P10669751T0000
+P08018361A0636
+BC2GM090622796
+P10721704A1155
+P01332964A0247
+P08990168A0688
+P07476701A0654
+P07730328A0000
+P09582953A1097
+BC2GM037522432
+P11535532A0189
+P03759731A0992
+P07565113A0000
+P00172199A0270
+P01936213T0000
+BC2GM008125101
+P11037823A1134
+BC2GM069268475
+P08307564A0233
+P09153010A0499
+P08626325A0543
+P11007949A1395
+P08647822T0000
+P10046849T0000
+P10687366A0000
+P09112589A0078
+P01731979A1408
+P09753241A0524
+P09574799A1072
+BC2GM037203130
+P07064662A0222
+P08602169A0484
+P07580058A0000
+P11327858A0087
+P09096234T0000
+BC2GM026991147
+P08347677A0308
+P01738653T0014
+P08173814A0132
+P07854324A0742
+P08457205A0240
+BC2GM098621694
+BC2GM062392652
+P07876210A0751
+P07309562T0000
+P11568988A0960
+P08993393T0000
+P08369887A0781
+P08324792T0000
+BC2GM037830517
+BC2GM033021196
+P05359464T0000
+P08601806A0875
+P02967915A0968
+P08666102A0820
+BC2GM078528949
+BC2GM092355993
+P09360953A1057
+BC2GM008918503
+BC2GM070175350
+BC2GM073538623
+BC2GM006621209
+BC2GM053866508
+BC2GM073138597
+P00891370A0000
+P01317376A0981
+BC2GM035763240
+BC2GM023802177
+BC2GM096583756
+P02907308T0001
+BC2GM054621405
+P09322872A0745
+P07933095A0000
+P07499252A0150
+P03296254A0556
+P02489895T0001
+P08824201A0270
+P09884275T0000
+BC2GM041284002
+P02705296A0231
+P03625762A0308
+BC2GM096599542
+P10585480A0157
+P08265955T0000
+P08710504A0995
+P07887226A0858
+P08428952A0399
+BC2GM040122571
+P07800505T0000
+P08543595A1093
+P02175908A0805
+P11447490A0598
+P03109147T0127
+BC2GM018910839
+BC2GM094853535
+BC2GM005295111
+P07871721A0392
+BC2GM063881420
+P09443978A0262
+P07194905A0332
+P09786949A0114
+P08962614A0000
+P02623038A0632
+P06719057A0181
+P07825888A0715
+BC2GM012674132
+P06516977T0000
+BC2GM034715588
+BC2GM071895729
+BC2GM047782308
+BC2GM025934950
+P09226345A0436
+BC2GM079386869
+P08839832A1220
+BC2GM065453807
+P10708243A0000
+P03928357A0340
+BC2GM014331768
+P03595418A0688
+P02920591A0251
+P09376626A0737
+P11139336A0257
+BC2GM073047126
+P01735447A0833
+P09537295T0000
+P10935880A1049
+P09488725T0000
+P07474617A1035
+P07385543T0001
+P08232304A1166
+P10836542A0363
+BC2GM091426108
+P06479362A0680
+P09227799A0254
+P02714852T0000
+P11127250A1111
+P07945330A0103
+P01499616A0136
+BC2GM048186198
+BC2GM060833693
+P09640162A0242
+P09786926A0095
+P09024805A0905b
+P09389137A0763
+P11356853A0554
+P08721999A0432
+P08044794A0000
+P03785212A0091
+P02816251A0397
+P10727413A1244
+P11241332A0393
+P06981991A0756
+P10215803T0000
+BC2GM032797223
+BC2GM021649255
+P09168218A0216
+P04041346T0000
+P04088233A0309
+P01705541A0273
+P09704296T0000
+P02473198A0613
+BC2GM041796235
+P08418183A0000
+P04753286T0000
+P09115265A1160
+BC2GM020447854
+P03413681A0659
+P03009826A0201
+P09484781A1233
+P11207261A1421
+P02175433A0575
+P08955928A0390
+P07796935A0284
+P09584180A0701
+BC2GM075752604
+P01371413A0742
+BC2GM046628798
+P01309593A1092
+P02930623A0404
+BC2GM079614007
+P00956364A0138
+P10943891A1062
+BC2GM068399734
+P02928376A0312
+BC2GM051669825
+BC2GM016145858
+BC2GM085265641
+P11161816A0851
+BC2GM094951467
+P01726211A0502
+P08871635A0000
+BC2GM071576712
+BC2GM044501927
+P11282395A0530
+P04843031T0000
+P02837575A0979
+P03553149A0299
+BC2GM042620717
+P06803634A0810
+P01400396A1265
+P07751848A0222
+P01304809T0001
+BC2GM052825552
+P08454858A0285
+P11407289A1507
+P10429946A0473
+P08614403A0557
+P10934640A1114
+P07761420A0909
+P04189158T0000
+P10451209A0000
+BC2GM029724458
+P08089834A0561
+BC2GM094712703
+BC2GM033552450
+P09408796A0648
+BC2GM044203528
+P03287597T0000
+BC2GM026130174
+BC2GM053719721
+P11024047A0626
+P07737118A0317
+P09515924A0553
+P07490766T0000
+BC2GM097623388
+P09729481A1177
+P01050144A0297
+BC2GM069080186
+P08497248A0000
+BC2GM032337812
+P07589069A1245
+P11029704A0378
+BC2GM080784888
+P08419376A0357
+P09892736A0343
+P07476975A0492
+P04656185T0000
+P07626469A1341
+P00234206T0000
+P07891708A1192
+P07829097A0000
+BC2GM055859383
+P04164669T0000
+P10669736A0903
+BC2GM042846376
+P02666034A1520
+P11029262T0000
+P08603921A1346
+P07859665A0498
+P07654712A0774
+P02403035A0621
+BC2GM021539597
+P11071852A0297
+BC2GM029944945
+BC2GM047438255
+P09447979A1430
+BC2GM035114288
+P03117046T0000
+P09372451T0000
+BC2GM017641405
+BC2GM080548139
+P07811964A1252
+P11139148A0421
+P11371417A0744
+P07819225A1094
+P07791783A0000
+P07759529A0288
+BC2GM082796346
+BC2GM064134481
+P09799086A0725
+P06309969T0055
+P04948325T0000
+P07546293A0968
+P09658769A0058
+BC2GM062859122
+BC2GM076394317
+P07473169A0133
+P08386319A1229
+P02093888A0293
+P09362473A1540
+P09990507A0000
+P01850096A0662
+BC2GM049868543
+BC2GM081350038
+P08440720A1404
+P07749461A0632
+BC2GM053590893
+P08262054A0565
+P11245986T0000
+P09515858A0000
+BC2GM007988676
+P01869968A0000
+P07871721A0000
+P10471383A0229
+P11722993A0276
+P09388201A1027
+P11559564A0459
+BC2GM074417017
+P11169113A0555
+BC2GM017902303
+BC2GM093697629
+BC2GM000522836
+P09872337A0000
+BC2GM013735127
+P11285235A0466
+P03541263A0368
+BC2GM039571849
+P07790719A0098
+P03052327A1474
+P11069223A0593
+P08742385A0211
+P03687148T0187
+P07852400A0519
+BC2GM080497809
+P04976988T0000
+P07554541A0587
+P02034655A1224
+P04021305A0530
+P11116148A0741
+BC2GM064660212
+BC2GM036047624
+P08016189A0741
+BC2GM025977756
+BC2GM012758546
+P11069788A0531
+P07991582A1023b
+BC2GM026838513
+P09144165A1275
+P09694897T0000
+BC2GM049476497
+BC2GM068884936
+BC2GM070141070
+BC2GM068876712
+P07278578T0001
+BC2GM030135043
+BC2GM033367187
+P07595221A0733
+BC2GM003230260
+BC2GM099666829
+BC2GM008652234
+P01923167A0000
+P06361318A0440
+BC2GM010869565
+P02657883A0000
+P08106325A0000
+P02351297A0000
+P05353667T0000
+P07456774A0448
+P01316125A0382
+P11313398A0687
+P09234713A0754
+P07084198T0000
+P08901635A0000
+BC2GM032391800
+P01639092A0776
+P08131545A0158
+P03117147A1059
+P07559524A0000
+P01099693T0000
+P01717833T0000
+BC2GM029530491
+P01764899A0399
+P09230307A0329
+P01898113A0265
+P08898365A0274
+P02545357A0000
+P07894359T0000
+P02399053A0153
+P11027294A0483
+P03615763A0170
+BC2GM050151466
+P08391748A0452
+P10589562A1208
+BC2GM029191037
+P11112700T0000
+P01581965A0388
+P02468795A1086
+P08610328A0228
+P08065901A0997
+P08291761A0416
+BC2GM012798293
+P02462305A1071
+P06376227A0217
+P07862141A1412
+P08063108A0109
+P06685177T0000
+P09152656A0149
+P04028871A0133
+BC2GM094275796
+P02419588A0284
+BC2GM043493383
+P02484714T0000
+BC2GM056889976
+P00806295A0193
+P11274184A0000
+P09706565A1072
+P09430461A0742
+P10729155A0653
+BC2GM099206103
+P08106313A1492
+P08776792A0626
+P09498553A0702
+BC2GM042452037
+P05769307T0000
+BC2GM071420231
+P09924675A0412
+P02180935A0535
+BC2GM004666359
+BC2GM048998172
+BC2GM097629610
+P01697611A0738
+P07783822A0000
+P10467004A0116
+P11116131A0863
+P02276891T0000
+P03894482A0549
+BC2GM020166073
+P02967915A0000
+P01840513A1019
+P09142146A0887
+P07768836A1126
+P01292230A0283
+P11274368A0469
+P08756597A0854
+BC2GM074670492
+BC2GM042845952
+P09032233T0000
+P07026328A0369
+P11063252A0437
+P07851758A0330
+BC2GM022119208
+P08660866A0504
+BC2GM035223840
+P11301189A1396
+P09312028A0975
+P02322535A0658
+P09380707A0714
+P08006101A1142
+P03450438A0446
+P01327967A0668
+P08207795A0409
+P06065507T0000
+BC2GM043951008
+P09869528T0000
+BC2GM049276320
+P06138015T0114
+BC2GM035651086
+P11471231A0964
+P11180688A0000
+P03354341A0177
+P03552363A0568
+P09609342A0000
+P09622055A0207
+P09005836A0977
+BC2GM027774736
+P09111863A0743
+P03720966A1043
+P04506738T0000
+P11566874T0000
+P09230986A0000
+P03827071T0040
+BC2GM015656322
+BC2GM036247814
+BC2GM014990106
+P08778265A0422
+P10940562T0000
+P02293664A0946
+BC2GM069151821
+P08566756A0752
+P09504514T0000
+P07568116A0902
+P07782302A0479
+P08902988A0258
+P01707800A0354
+BC2GM011254040
+P08970979A1246
+P08472750A0999
+P06072512T0000
+P06113084T0000
+BC2GM021103469
+P03744168T0001
+P01459451A0478
+P07592790A1457
+BC2GM062223441
+P09694034A0713
+P03912247A0282
+BC2GM034214374
+P08412120A0839
+BC2GM043724689
+P08770896A1121
+P00575231A0422
+P03625688A0372
+P07853476A0159
+P08355696A0236
+P06459831T0001
+P01546522A0000
+P09168511A0640
+BC2GM091685564
+P06096863T0000
+P03154072A0862
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/bc2gm.conll.test b/huner/ner_scripts/splits/bc2gm.conll.test
new file mode 100644
index 0000000..a94ca02
--- /dev/null
+++ b/huner/ner_scripts/splits/bc2gm.conll.test
@@ -0,0 +1,6000 @@
+P04013576A0981
+P08647086A0720
+P06388818A0000
+P01125117A0183
+BC2GM082775110
+BC2GM083857019
+P00168176A0000
+BC2GM042151214
+P09049304A1193
+BC2GM076693165
+P08970352A0880
+P09488713A0886
+BC2GM046346737
+P11145563A0202
+P09551938A0318
+P03413890T0001
+P09453537A0863
+P00823087A0608
+BC2GM088125251
+P07935468T0000
+P09893262A1272
+BC2GM031995468
+BC2GM016976027
+P11035037A0183
+P07237560A1038
+P01694009A0112
+BC2GM051120604
+P08510924A0490
+P09739401A0000
+P01644831A0824
+P08855804A1528
+BC2GM022578153
+P03001705T0000
+BC2GM016290576
+P03507689A0000
+BC2GM044014286
+P01373374A0735
+BC2GM051369049
+P01536575A1213
+P10962593A0580
+P08868660A0087
+BC2GM096120426
+P06715792A0295
+P03981952T0000
+BC2GM084495640
+P07528028A1192
+BC2GM055948186
+BC2GM023848611
+BC2GM066811191
+P03972185A0137
+P08543275A0130
+BC2GM048840420
+BC2GM090513544
+P02036066A0000
+P05826818T0098
+BC2GM037370433
+P08918918T0000
+BC2GM028280868
+P05068271T0000
+P09098899A0435
+BC2GM049997228
+P08769409A0114
+P11000521A0588
+P03175942A0706
+BC2GM042419868
+P08625900T0000
+BC2GM055754960
+BC2GM091114680
+BC2GM026304956
+P10630630A0614
+P08552096A0151
+BC2GM012490279
+P03772471A1054
+P09596638T0000
+P08387507A1015
+P09121774A0611
+P10612505A1317
+P09726988A0275
+P03066208A0310
+P01332589A0666
+P05110049T0001
+P02173399A0333
+BC2GM068857149
+P09278454A1261
+P09259052A0568
+P06316623A0188
+P08552643A0261
+P04040083A0000
+P09788739A1096
+BC2GM033802791
+BC2GM088461338
+P09263856A0563
+P09418871A0620
+P08849569A0615
+BC2GM037708472
+P10692433A0000
+P02420432A1060
+P09545638A1181
+P04138224T0095
+P00063680T0000
+P10566862A0000
+BC2GM027254558
+P02708288A0621
+BC2GM088701024
+P02283378A0385
+P08224907A0000
+P09469415A1337
+P08622070A0889
+BC2GM063388732
+P02196565T0000
+P10737366A0280
+P11328699A0000
+P07797346T0000
+P02473156A0000
+BC2GM017296599
+P03073091A0338
+BC2GM006513676
+P08281153A0543
+P11278390A0632
+P09647240A0000
+P07856102A1616
+BC2GM012836491
+BC2GM033301301
+P02269426A0428
+P08895579A0583
+P06402859A0000
+P07629196A0274
+BC2GM034696553
+P01309593A0095
+P00767155T0001
+BC2GM003819880
+P08367487A1014
+BC2GM092059167
+BC2GM073386715
+P05083872T0000
+P09735366A1180
+P07596697A0971
+BC2GM072974603
+P01739439A0257
+P07758459A1277
+P08668201A1059
+P08299896A0880
+P02438637T0000
+P02335713A0905
+P10834707A1533
+BC2GM085716701
+P11525486A0350
+P01498607A0000
+P07564004A0292
+P01828248A0189
+P07474124A1360
+P07514301A0000
+P10825200T0000
+P09343426A0456
+BC2GM014829301
+P09570107A0355
+P01542565A0220
+P07565688T0000
+P02852894T0000
+P07236351A0812
+P09269879A0266
+P08519862T0001
+P08203260A1204
+P11456259A0142
+P09153348A0647
+P01565882A0737
+P07680120A1008
+P08608447A0806
+P02748595A0492
+BC2GM006491686
+P08300601A0745
+BC2GM015573126
+P08628260A0895
+BC2GM069540508
+BC2GM043187885
+P10915780A1063
+P01626440A0449
+P01331060A0768
+P02139891A0532
+P10925207A0634
+P02549343A1008
+BC2GM057519691
+P08816482A0234
+P00892353A0686
+P09455695A0762
+P03478354A0436
+P10940413A1153
+P04552263T0000
+P01326557T0000
+BC2GM043554799
+P02669199A0000
+P06401749T0000
+P00524451A0136
+P10566630A0371
+BC2GM083628661
+P07297576A0454
+P03629974A1468
+P08808939A0000
+P08655555A0772
+P00024600A0522
+P01246210A0648
+P08504928T0000
+BC2GM019598575
+P11384880A0719
+BC2GM069560811
+BC2GM080424073
+P11897950A0617
+P03508698A0535
+BC2GM094806221
+P08661007T0000
+P02707909A0209
+BC2GM002649706
+BC2GM039284976
+P01191964A0000
+P01958368A0556
+BC2GM066121491
+P07791769A0826
+BC2GM097784903
+P08794326A0405
+P08972182A0000
+BC2GM081353874
+P09316937A0133
+P01748067A0000
+P08474438A0000
+P01473196A1016
+BC2GM086069469
+P10720434A0291
+P09665503A0526
+P09423310A0251
+P10950398T0100
+P03789052A0527
+P08035505A0586
+BC2GM069852295
+P08413223A0847
+P11489597A0379
+P08892859A0563
+P08264650A0925
+P08828142A0000
+P08454591A1322
+P09663062A0175
+P07538173A0307
+P07205120T0000
+P02451872A0391
+BC2GM040204368
+P00630713T0000
+P11519466A0196
+P06254973A1757
+P08712799A0123
+BC2GM094472638
+P09767687T0000
+P09204570A0110
+P03147912A0422
+BC2GM049622274
+P01083321X0000
+P08012448T0000
+P02060052A0954
+BC2GM098872814
+P09551096A0108
+P02965149A0727
+BC2GM040128143
+P10627518A0544
+P08013457A0342
+BC2GM098014583
+P11181531A0464
+BC2GM077951036
+P10619062T0000
+P11198053T0000
+P10938105A0000
+BC2GM022041209
+BC2GM087148691
+P08005230A0222
+P06452461A0930
+P03537711A0181
+P09006910A0000
+BC2GM069129077
+P02173405A0270
+P09335298A1227
+P06694380A1483
+P11569900A0660
+P09498553T0000
+BC2GM090366403
+P02778237A0585
+P02846640A0643
+P01473234A1001
+P02120833A0000
+P10731411A0958
+P06810070A0502
+BC2GM040414744
+P01299489A0788
+P09193080A0904
+P10601280A0674
+BC2GM071046961
+P01968224A0119
+P08887661A0138
+P06495195A0536
+P11369453A1083
+P11113201A1114
+BC2GM070776704
+P01321336A0731
+P02162049A0291
+P09032258A0395
+P02165181A0299
+P09190202A0166
+P08798700A0134
+P07674649A0508
+P06453290A0000
+BC2GM083586381
+P03382772A0319
+P08229102A0768
+P09394650A0121
+P10628748A0746
+P09299696A1074
+P02153977A0364
+P00425547A0000
+P09858571T0000
+P08119149A0000
+P08702644A0499
+BC2GM081530471
+P10710985T0000
+P07665187A0208
+P01295373A0651
+BC2GM023306376
+P09354757A1444
+P11305129T0000
+P09480929T0000
+BC2GM034391394
+P09235618A0000
+BC2GM027269907
+P11194101A0532
+P09084227A0833
+P00659962T0000
+P07658777A0400
+P10940557A1687
+P07820057A0000
+P08755898A0339
+BC2GM081297373
+BC2GM058126747
+P09041123A0195
+BC2GM055283849
+BC2GM023833000
+P06090369A0000
+P11048832A0271
+BC2GM084139818
+P00921032T0000
+P09162092A0675
+P01661369A0825
+BC2GM032772191
+BC2GM091775961
+BC2GM001304367
+P04017295A0139
+P08756332A0000
+P09710131A0374
+P10692167A0364
+BC2GM061017656
+P09519830A0282
+P02631566A0151
+P10981094A0779
+P07730337A1439
+P07999363A0000
+P07597030A0260
+P08901135A1132
+P08749394A0874
+BC2GM064638906
+P03218714A0000
+P02525044A1026
+P06842629A0446
+BC2GM079202513
+P03035218T0000
+P02938185A0223
+P11838102T0001
+P02196311A1034
+P11401611A1703
+P10597222A1371
+P08223576A1261
+P08252976A0467
+P11255423A0211
+P08403245A1234
+P11210401A0544
+BC2GM096137044
+BC2GM085419447
+P03612316A0102
+P10349084T0000
+P02393895A0918
+P07972012A0956
+P07960796A0154
+BC2GM038777318
+P02511069A0532
+P08615012A0627
+P08051074A0000
+BC2GM091282092
+BC2GM004773918
+P09633274A0000
+P02196176A0749
+BC2GM051322057
+P03616174A1069
+BC2GM043142143
+P09200498T0000
+BC2GM013984753
+BC2GM034827451
+P09074508A0397
+P10826861A0000
+BC2GM012154477
+BC2GM029952373
+P06625058A0666
+P08775674A0000
+P04039525A0475
+BC2GM066396358
+P02708353A1452
+P01452584T0000
+P10804379T0001
+P07559478A0389
+P11350812A0829
+P09146071T0001
+P01371272A1167
+P09271496T0000
+P06308536T0001
+BC2GM063455036
+P09159111A0437
+BC2GM010615307
+P03780371A0792
+P08972182A0527
+BC2GM038859248
+P08520646A0000
+P06527872T0000
+P08222618A0000
+P00510341T0036
+P09447994A0000
+BC2GM065802628
+BC2GM066788416
+P02631887A0000
+P01467828A0542
+BC2GM057189560
+BC2GM004792351
+BC2GM097074870
+P02773930T0000
+BC2GM037412150
+P07410037A0752
+BC2GM005929354
+BC2GM003906024
+BC2GM086842152
+P07565775A1265
+BC2GM073564937
+P08850585A0602
+P03783160A0285
+P01284032A0213
+P07741255A0194
+P07191804A0000
+BC2GM052708788
+P09920982A0253
+P11554566A0668
+P02348408A0126
+BC2GM092481573
+P11408338A1686
+P10527180A0869
+P06092048A1111
+BC2GM030618899
+P08206848A0296
+P03676174A0730
+P08790387A0299
+P11534900A0000
+P08999414A0819
+P05933228T0000
+P11172944A0548
+P03692331A0000
+P09290571A0420
+P09891049A0761
+BC2GM068294994
+P02879951T0000
+P06098719A0369
+P01901859A0000
+P09715384A0235
+BC2GM012757246
+BC2GM058190767
+BC2GM090984958
+P09147420T0000
+P08662499A0484
+P09238860A0175
+P08722568A1001
+P00702773A0327
+P09811718A0979a
+P07500386A0870
+BC2GM000562167
+P02053289A0701
+P09849722A0797
+P07651398A0803
+BC2GM099480245
+P09726201T0000
+P01765266A0000
+P09396722A0185
+P08065310A1144
+BC2GM075844356
+P05796272T0000
+P10715602A0149
+P05060388T0000
+P06835914A0192
+BC2GM056723131
+P10779329T0000
+BC2GM072261734
+P11495920A0504
+BC2GM030876064
+BC2GM042679394
+P07880449A0091
+P03578948A0448
+P11385840A1684
+BC2GM075394719
+P10574992A0901
+BC2GM055275814
+BC2GM067272025
+P11335710A0320
+BC2GM085880360
+P01742606A0000
+P09058002T0000
+P07495120A0260
+BC2GM045487899
+P02708353A1080
+P08912232A0260
+BC2GM033321471
+P10748204A0238
+P06584416A0157
+BC2GM078490707
+P01656235A0946
+P03473379A0183
+P09000108A0330
+BC2GM015500367
+BC2GM054764143
+BC2GM078339197
+P10944466A0451
+BC2GM001873364
+P00726581T0122
+P02291628A0264
+P04085589A0264b
+P10851267A0000
+P02670457T0000
+BC2GM040702474
+P01427034A0440
+P08154182A0955
+BC2GM085260486
+P09165035A0842
+P01869907A2146
+P07648338A0815
+P06755986A0382
+P00879829A0564
+P08762472A0000
+P07498727A0724
+P08458660A0855
+BC2GM088515251
+BC2GM095236565
+P01636339A0200
+P08642285A1548
+P01627828A0475
+BC2GM012129841
+P09057840A0946
+P07841230T0000
+P08167396A0154
+P00265964A0562
+P01383695A0100
+P09641167A1359
+P11039780A0770
+P11222387A1497
+P07565049A1032
+P01596007A0908
+P01927421A0181
+P07984261A0536
+P09813110A0982
+BC2GM065355579
+P09230384A0725
+P09598894A0732
+BC2GM021758062
+BC2GM083051633
+P08239164A0551
+P08598051T0000
+P10725382A0398
+P09876794T0000
+P09032304T0000
+P06691304A0284
+P02939260A1553
+BC2GM014548790
+P11306845A0168
+P04082267A0720
+BC2GM018310054
+P08456879A0000
+P09417928A0980
+P08550461A0284
+P09472608A0253
+P11297866A0484
+P07537362A1112
+BC2GM066994310
+P01279696A0862
+BC2GM068782112
+BC2GM048362726
+P08891346A1217
+P07988731A0002
+P07184795A0517
+BC2GM047204097
+BC2GM048469729
+BC2GM039494188
+P09487130A0383
+P11113546A0728
+P08833653A0783
+P11029467T0000
+P07579023A0214
+P03997467A0000
+P08510320A0000
+P06895559A0000
+P03004739A0753
+P09157337A0545
+BC2GM039351888
+P09149929A0750
+P07679836A0387
+BC2GM072200502
+P01988041A0281
+P02020082A0356
+P08634423A0498
+BC2GM074751408
+BC2GM069327394
+BC2GM096903917
+P09858883A1106
+P09750540A0000
+BC2GM061536305
+BC2GM011130797
+BC2GM054158346
+P09395456A0424
+BC2GM023938146
+BC2GM064479626
+P03042778A0643
+P10619169A0411
+BC2GM085041109
+P07730337T0000
+P09705352A0879
+P10839593A0000
+P04828587T0000
+P11545594A1556
+P09763470A0000
+P01378526A0535
+P11239529A0981
+P10694210A0385
+P11462024A0306
+P08228805A0540
+P11309077A0953
+BC2GM021392794
+P05162342T0001
+BC2GM071251330
+P08662193A0404
+P09685346A0419
+P07563994A0488
+P07478523A0551
+P05463837T0023
+P03186270T0001
+P10951579A1238
+BC2GM092881858
+P09246343T0000
+P08521717A0126
+P02760922A0000
+P09484463T0000
+P09843577A0000
+P03684517A0462
+P10687855T0000
+P08622698T0000
+P01386210A0293
+BC2GM057651504
+P02832744A0403
+P10932329A0597
+BC2GM050974186
+BC2GM011080889
+P10667597A0668
+P08057356A1824
+P02679804A2000
+P09155015A0140
+BC2GM046719637
+P09650275T0000
+P03002501A1327
+P09366628T0000
+P08621542A0535
+BC2GM006849123
+P02916764A0253
+P03714473A0496
+P02147422A0000
+P09353328A0736
+P11321187A0355
+BC2GM034493633
+P05471866T0000
+BC2GM056033085
+P02328328A0419
+P09895323T0000
+P02627159A0899
+P00964758T0001
+P03060953A0481
+P03360667A0000
+P02045524A0000
+P08636211A0983
+P06070072T0052
+BC2GM071079182
+P07848358A0254
+BC2GM010251771
+P09389492A0520
+P03200844A1211
+BC2GM015636298
+P08552095A0758
+P08934533A0784
+BC2GM025770197
+P07660712A0118
+P11390581A1203
+P11403719A1257
+P09478921A0126
+BC2GM029534167
+P01505488A0231
+P08626785A0674
+P00478714T0000
+P09373140A0000
+P07857762A0611
+BC2GM046935375
+P02511207A0282
+BC2GM000222745
+P07922709T0000
+P03582982A0000
+P03987818A0440
+P03678269A0633
+P09883639A0000
+P03335651A0000
+P10830395A0408
+BC2GM002989216
+BC2GM050909815
+P02515953A0459
+P07846153A0403
+BC2GM029595476
+P10955313A0000
+BC2GM078212435
+P06310553T0000
+BC2GM018207544
+BC2GM006571611
+P06341661T0001
+P06694778A0000
+P10867199A0230
+P11308877A0213
+P10564474T0000
+P08139031A1168
+BC2GM010769407
+BC2GM041090140
+P01703632T0000
+P11342479A0430
+BC2GM089807452
+P02473693A0174
+P08617311A0979
+P09612775A0726
+P09228202A0581
+P04654249T0000
+P10567538A1028
+P08412665A0000
+P08964172A0221
+P03138190A0347
+BC2GM078700363
+P07910946A0323
+P10119827T0000
+BC2GM037647258
+P10756020A0571
+P09310836A1019
+P03227288A0542
+BC2GM035550761
+P02981457A0368
+BC2GM061836675
+P01688841A0430
+P09294422A1223
+P07935375A1197
+P03109954A0945
+P07791760A0424
+P11524815A0753
+P09601516A0695
+P02017159A0646
+BC2GM020674763
+P07537736A0453
+P11441952A0414
+P07592723A0814
+BC2GM028574302
+P03746107A0192
+BC2GM010665846
+BC2GM051746475
+BC2GM073202656
+BC2GM098968246
+BC2GM086442334
+BC2GM053427855
+P09832518A0615
+P08549859A1604
+P06520418A0325
+P03473253A0000
+BC2GM017504057
+P10855796A1160
+BC2GM080092738
+P11279086A1350
+P09252397A0081
+P09407031A0557
+BC2GM026914728
+P08843419A1290
+P11264182A0000
+P02789062A0000
+P10563836A1234
+BC2GM071734326
+P08180129A1256
+P03395009A1750
+P05025918T0000
+P11196199T0000
+P07385933A0085
+P11094075A0257
+P08072547A0690
+P07852037A0548
+P07971282A0000
+P07543684A1027
+P09417082A0127
+P01321277A0664
+P09571563A0000
+P00967223T0059
+P08793029A0246
+BC2GM090157482
+BC2GM084901055
+P07888788A1010
+BC2GM084642529
+P01389573A1071
+P10684097A0175
+BC2GM064636435
+BC2GM050646541
+P01462786T0000
+P03186091T0000
+P10882163A1077
+P10648489A1117
+P11391793A0856
+P10699354A0557
+P07841663A0685
+BC2GM011711443
+BC2GM040382030
+BC2GM000748612
+P07415340A0280
+P07783641A0591
+BC2GM038818397
+BC2GM052791430
+P08294511A0639
+P07828824A0307
+BC2GM040951364
+P08163498A0789
+P09611016A0652
+P11018264A0397
+P03167060A0000
+BC2GM042376349
+P02149487A0348
+P11121118T0000
+P08638435A0522
+P02137704A0000
+P09618164A0709
+BC2GM039715012
+P00811852T0001
+P09165039A1372
+P01738936A0292
+BC2GM002520653
+P04115870T0000
+BC2GM026200487
+P08900164A0188
+P08572616A0000
+BC2GM069669537
+BC2GM001825459
+BC2GM061354086
+P11207282A0729
+P10793143A1533
+P10052371A0171
+P10589711A1228
+P01350780A0184
+BC2GM053348868
+P09089093A0373
+BC2GM023118027
+BC2GM056745249
+P10769144A0000
+P03337024A0000
+BC2GM063132076
+BC2GM034677761
+P01906509A0072
+P10945781A0412
+P02675492A0806
+P07865888A1309
+P09343222A0415
+BC2GM074492181
+P08810278A0682
+P09789025A0149
+P08530418A1182
+P08816759A0000
+BC2GM079042018
+P07916588A0471
+P08642313A0770
+P09028308A0590
+BC2GM053682759
+P05919308T0001
+P11265853A0000
+P10822117A1386
+P03911702A0530
+P09075739A0827
+BC2GM071825291
+P07666414A0614
+P02205970A0684
+P06369355A0834
+P06767648A0734
+P08300625A1352
+BC2GM035652683
+P11134822A0629
+P02605679A0306
+P06816609A0639
+P02542194A1496
+BC2GM041377318
+BC2GM068305355
+P08396749A1112b
+P09312032A0165
+P07715922A0188
+P05045351T0000
+P08887661A1061
+P01651918A0000
+BC2GM072047092
+BC2GM021400038
+P01918070A0281
+P10910908A0767
+P09774484T0000
+P08552670T0000
+P06385474T0001
+BC2GM013779301
+P07806532A0659
+P00039271T0000
+P09418882A0760
+P02825139A0661
+BC2GM055940358
+BC2GM011712856
+P09234723A0846
+P09545332A0137
+P07735590A0990
+P09143465A0838
+P08551577A0000
+P02957125A0601
+BC2GM084023430
+P08816438A0316
+P02308496A0000
+BC2GM006151148
+BC2GM058293960
+P02595451T0000
+BC2GM001302183
+BC2GM080154101
+BC2GM083801874
+P00681571T0028
+P08133502T0105
+P03312514A0756
+BC2GM081464048
+P01138330A0204
+P01316903A0296
+P02997622A0916
+BC2GM013273874
+P07784061A0894
+P00130573T0054
+P05627251T0000
+P10780883T0000
+P03276924A0090
+P01334428A1102
+P04093211A0560
+BC2GM031182945
+P06749072A0116
+P01885613A1298
+P08774732A0271
+P08893779A0229
+P06895663A0810
+P11058119A0957
+BC2GM083962510
+P10874044A0647
+P08055939A0707
+P03023970A0922
+P00415543A0320
+P04281856T0001
+P08929563T0000
+P09373651A0255
+BC2GM009941081
+P06772370A0342
+P07916689A0312
+P03753022A0000
+P09233809A0815
+P09819377A1209
+P01871135A0295
+P07202525A0200
+BC2GM097549804
+P07937112A0220
+P11160688A1726
+BC2GM070908421
+P02388685A0577
+BC2GM027306792
+BC2GM018246985
+P06259220A0464
+P09475724T0000
+P08684522A0415
+BC2GM046604998
+P07395750A0294
+BC2GM079564376
+P11149472A1257
+P02809651A0492
+P06435565A0648
+P08669676A1644
+P01566576A0605
+P08209423T0000
+P08246984A0923
+P10585480A0265
+BC2GM091144220
+P11474642A1451
+BC2GM062537861
+BC2GM034228721
+P10587460A0302
+P09163332A0275
+BC2GM050804040
+P07958898A1050
+P01808049A0262
+P07226440T0000
+P06627569T0001
+P02443028A0695
+BC2GM022542601
+P02351239A0693
+BC2GM043975609
+P01392012A0228
+P07897359A0354
+BC2GM055691020
+P08939891A0285
+P02004521A0266
+P03712050T0000
+P07937132A0819
+P11045607A0239
+P11039341A0180
+P01763106A0070
+BC2GM040125018
+P00668122A0414
+P01653238A1062
+P03371894A0355
+P06473252A1073
+P08973917T0000
+P07105635A0412
+BC2GM004649890
+BC2GM044977015
+BC2GM041669085
+P01544918A1240
+BC2GM056337043
+P03933784A0420
+P00879329A0176
+P00227393T0000
+P07853524A1944
+BC2GM078123829
+P02592543A0106
+BC2GM036804417
+P07306839T0001
+P11197328T0000
+P08921865A1293
+P08132574A0831
+P10891093A0000
+P10228795A0842
+P11200568A0830
+BC2GM046996485
+BC2GM031753625
+P01518833A0397
+BC2GM037547379
+P06155967A1132
+P03031602A1001
+P09989334A0964
+P08230452A0551
+P10885750A0236
+P00439716T0001
+P10747879A0607
+P10704338A0354
+P02026147A0000
+P07579704A0085
+P10623804A0808
+P00703932A0000
+BC2GM022719960
+BC2GM066127781
+P10085697T0000
+P00962222A0633
+P09506990T0000
+P09829916T0000
+P11062047A1208
+P08754840A0793
+P06704467A0539
+P02689439A0000
+BC2GM028364416
+P11127200A1024
+P01700272A0838
+P02493644A0588
+P06753902A0437
+P07745726A0960
+BC2GM074970735
+BC2GM006926838
+P07659757A0191
+P07440085T0061
+P10989777A1286
+P01190251A0335
+P00528144T0000
+BC2GM020792074
+P11123054T0000
+P03929610A0268
+P07954891T0000
+P03020001A0781
+P11399064T0000
+P08506317A0000
+BC2GM081881949
+BC2GM044414750
+BC2GM030750070
+P10974541A0389
+P09467707T0000
+P03540591A0330
+P02081463A0110
+P08164302A0547
+P10865940A0000
+P10675610A0279
+P05394352T0000
+P07607213A0140
+P11023832A1038
+P11408774X0893
+BC2GM080942212
+BC2GM086116473
+P01044338A0240
+BC2GM032189532
+P09517646A0149
+BC2GM063663214
+P07541589A0652
+P01771959A0442
+BC2GM035498745
+P03540853A0652
+P06513456T0001
+P10218357A0486
+P08668209A0406
+BC2GM048306473
+BC2GM015964287
+P10788320A1034
+P01468625A1080
+BC2GM083943524
+P01482912A0617
+P08628681A0364
+BC2GM030584049
+P05859016T0000
+P01860846A0663
+P01454819A0000
+P09118196A0281
+BC2GM058267325
+P06350092A0916
+P10721698A1195
+P11075929A1657
+P09575217A0000
+BC2GM018630607
+BC2GM096229187
+P06795832A0148
+BC2GM010453739
+P01708098A0922
+P10861906A1479
+BC2GM071468863
+P04084607A0663
+BC2GM070296233
+P01429724A0664
+P04418687T0000
+P09173733A0404
+BC2GM033317667
+BC2GM074024777
+P03436529A1066
+P10678968A1096
+BC2GM040090407
+BC2GM060645160
+P11414754X1099
+P09579789A0974
+P10579331A1225
+BC2GM041921266
+P00477794T0000
+P09397723T0001
+P08538382A1012
+P10648020A0151
+P08878045A0606
+BC2GM072060480
+P01725622A0292
+P09651394A0440
+BC2GM015848639
+P10874151A0000
+BC2GM006899273
+BC2GM025748861
+P02880841A0313
+BC2GM064087768
+P09149825A0151
+BC2GM075427191
+P01723962A0165
+P03024343A0372
+P05497793T0000
+BC2GM036041110
+BC2GM098002058
+P07768898A0492
+P10712599A0349
+P09655248A0000
+P10766556T0000
+BC2GM006411333
+P08208540A0000
+P02714525A0529
+BC2GM040580909
+P03378994T0000
+BC2GM085535477
+P10423193A1309
+P02620085A0656
+P04999086T0001
+P02181760A0311
+P11372959A1447
+BC2GM077359774
+BC2GM071264087
+P01000378T0000
+P07705627A1107
+BC2GM072420137
+P03935375A0414
+BC2GM023165643
+P02115111T0000
+P02103140A1088
+BC2GM070947450
+P02281118A1191
+BC2GM044104855
+P08139543A0427
+P11163932A0000
+BC2GM038486910
+P09531549A0658
+P01852438A0928
+P02575174A0229
+BC2GM031982996
+BC2GM050904596
+BC2GM049338650
+BC2GM026620474
+P04067540A0413
+BC2GM070791643
+BC2GM052589330
+P08308008A0201
+P01241437A0152
+P02176021T0000
+P08763953A0805
+P01388160A1102
+P09479498A0000
+BC2GM018705374
+BC2GM006738398
+BC2GM015090389
+P02740347A0644
+BC2GM023252709
+P01048968A0152
+P11404010A0235
+P08034486A0579
+BC2GM023056895
+P11101008A0649
+P09528768A0000
+P01098179A0167
+BC2GM018490469
+BC2GM015232187
+BC2GM098004575
+P09704927A0479
+BC2GM071783264
+P09279889A1124
+P10567589A1268
+P07499421A0237
+P07659515T0000
+P01993656A1860
+P08093616T0000
+P09233811A0072
+BC2GM046917309
+P08648665A0956
+P10872831A0000
+P07509472A1320
+BC2GM010227811
+BC2GM059603247
+BC2GM026944266
+P01310879A0000
+P09837913A0000
+P04014861A0000
+P08816498A0000
+P02680843A0724
+P11123701A0442
+P02378945A0487
+P00876722T0000
+BC2GM071742493
+P02241892A0681
+P03123310A0000
+P03067505A0688
+P02383693A0301
+BC2GM042108030
+P06467241A0000
+BC2GM050726449
+P02116537A1237
+P11170476A1546
+P08244034T0000
+BC2GM047223393
+P08764015A0284
+P03536682A0572
+P08884757A0653
+BC2GM054191583
+BC2GM032251939
+P06342141A0226
+BC2GM019597390
+BC2GM055081476
+P01358592A0752
+P11710233T0000
+P07622060A0967
+P05806615T0001
+P00227610A1593
+P09088416A0000
+P09706643A0206
+P07933101A0131
+P10820904A0000
+P09353343A0919
+P10647177A0599
+P09553686A0000
+P04239041T0045
+BC2GM084376040
+BC2GM023122487
+P11168422A0248
+P08535537A0000
+P09751114A1987
+P07813786A0641
+BC2GM041631891
+P02083230A0938
+BC2GM064373042
+P10835732A0911
+P06290899T0000
+P10640701T0000
+P04034220A0205
+P09749988A0000
+P08722011A0103
+BC2GM010446827
+P09020172A0964
+P02571924A0000
+P03143048A1091
+P06327292A0846
+BC2GM030261099
+P01557217A0272
+BC2GM020418673
+BC2GM025874563
+P00599601A0260
+BC2GM016116401
+BC2GM008312798
+P02333749A0411
+P08012566A0254
+P10838399A0525
+P00465829T0000
+P02519327T0001
+P01765095A0680
+BC2GM046362536
+P05742879T0000
+P10987301A0332
+P11279385A3917
+P08676266A0838
+P07742024A0121
+BC2GM068703036
+P11372882A1143
+P09238860A1974
+P08838144A0107
+BC2GM030553104
+BC2GM087773567
+P01532914A0067
+P08746605A0377
+P02504603T0000
+BC2GM024036486
+P10903733A0540
+P07516469A1025
+BC2GM098226809
+BC2GM023083522
+P02281948A0245
+P05049711T0000
+P10610716A1127
+P11525102A0970
+P08550470A1021
+P08252067A0917
+BC2GM081655876
+P06692631A0129
+P11023074A1105
+P05020660T0000
+P06234369T0000
+P07519481A1275
+P01321280A0494
+P10722661A0146
+P06467797A0233
+BC2GM089434490
+P08958137A0534
+P11432776A0421
+BC2GM003035581
+BC2GM067383084
+P06969638A0180
+P08114745A0953
+P09003410A0000
+BC2GM059483475
+BC2GM071845732
+P10602419A1253
+P07623825T0000
+P07829554A0257
+P01386897A0000
+P08387519A0000
+BC2GM008813180
+P07499848A0409
+P07282444A0075
+P07933116A0412
+P08469831T0001
+P08702517A0000
+P10604945A0731
+P02361812A1110
+BC2GM087025767
+P11030476A0685
+P02029468A0296
+BC2GM052715311
+P09150595T0000
+BC2GM097038641
+P07699632A0715
+P08648408A0792
+BC2GM024641386
+P07979810A0340
+P10034615T0000
+BC2GM034704877
+BC2GM013614335
+BC2GM067512942
+P08222384A0455
+P02113699A0372
+BC2GM041444754
+P08312243A0177
+P06709310A0000
+BC2GM028126771
+P09426068A0826
+P11034392A1072
+P06324089A0453
+BC2GM084941902
+P10802909A0478
+BC2GM049307951
+P08707516A0194
+P09359844A0674
+P02107073A0584
+P06203843A0757
+P02281330A0556
+P03597218A0901
+P08943354A0295
+P10779313A1842
+P09878256A0000
+P11553704A0674
+BC2GM025278730
+P03199436A1060
+BC2GM070003542
+BC2GM080820769
+P05890093T0000
+P09605137A0677
+P08195186A0000
+P07552974A0217
+P06545651A0346
+P01779769A0000
+BC2GM063198333
+P09468515A0621
+P01690812A0000
+BC2GM067523581
+BC2GM075459951
+P02169887A0360
+P09414074A0827
+P08612852A0553
+P02384265A0947
+P09421511A0827
+P10480937A0000
+BC2GM055980217
+P02911540A0478
+BC2GM045059476
+P02913368A1037
+P09707577A1047
+P02182240A0355
+P08668210A0000
+P08828152A1825
+P11685284X0000
+BC2GM084727485
+P07916327A0250
+BC2GM093717157
+BC2GM061400791
+P07639703A1703
+P08719832A0397
+P08101843A0151
+P10962738A0000
+P00676416A0320
+P07530502A0974
+P11295760A1374
+P08410042T0000
+P11274109A0129
+BC2GM065349890
+BC2GM080679474
+P06997203A0325
+P02637597A0362
+BC2GM015841458
+P07114083A0153
+P06208477A0000
+P05749438T0001
+P09121476T0000
+P08595012A0817
+P02483438A0498
+P07483285A0322
+P09117345A0945
+P09096958A0000
+BC2GM070522560
+BC2GM097326747
+BC2GM073091634
+P11092809A0823
+P11133830A0174
+P07973397T0001
+P08898866A0458
+BC2GM023843160
+BC2GM063318762
+P10942587A0981
+P08178490A0879
+P10648211A0000
+BC2GM025777984
+P02473619A0202
+BC2GM005819408
+P09834521A0000
+P04123217T0000
+P01934378A1219
+P02148508A1478
+P09760243A0970
+P03332022A1094
+P06524761A0596
+P01974550A0362
+P09383156A0691
+BC2GM040902360
+P08039422A0000
+BC2GM043315404
+P03984683A0000
+P03346157A0000
+P08960827A1169
+BC2GM000478841
+P02142240A0506
+P07642538A0744
+P08352268A0000
+P02454976A0944
+P09463964A0243
+P11085600A0123
+P08628251A1455
+P09474001A0825
+BC2GM044076816
+BC2GM031456280
+P09873291A0620
+P11124902X1337
+P08625924A0411
+P11274357A0724
+P08322117A1019
+P05210791T0001
+P08626667A1517
+P09820611T0000
+BC2GM011253634
+P00497494A0112
+P06957633T0001
+P07973364A0325
+BC2GM023937291
+P10606272A1241
+P07263745T0000
+BC2GM000019979
+P09568445T0000
+P09817131A0296
+P08119995A0814
+P09172812A0660
+P02567030A0482
+P07862162A0408
+P06309020A0473
+P07592467A0000
+BC2GM039889670
+P09858599A0392
+P01524549A0241
+P09865775A0162
+P08547205A1060
+P08945479T0000
+P11133741A0617
+P11036786A0628
+P03830255A0074
+BC2GM078789356
+P07582592A0545
+P06242113T0001
+P09925372A0458
+P02089054A0121
+P10647633A1685
+P03443144A0409
+BC2GM084448237
+P06295429A0412
+P06594105A0560
+P11910344A1119
+P02850967T0000
+P02935638A0000
+BC2GM007772947
+P00381505X0000
+BC2GM027280090
+BC2GM045795328
+P09092580A1354
+P10841601T0000
+P11469970A0873
+P10713161A0985
+P03183103A0000
+P00336354A0543
+P11486476A0147
+P02229282A0454
+P03017996A0731
+BC2GM051932313
+BC2GM085006579
+P05858571T0000
+P09045636A0789
+P09537651A0366
+P08631934A0000
+P09422727A0196
+BC2GM009468247
+P11145717A0936
+P09565584A0770
+BC2GM096642340
+P11416737T0000
+BC2GM061835240
+P11532856A1175
+P09985302T0000
+P07181985A0107
+BC2GM003488368
+P01185956A0722
+P11282395A1073
+BC2GM062141275
+BC2GM014101305
+P11341405A1154
+P01172917T0000
+P09944066T0073
+P08739209A0700
+P01694280A0000
+BC2GM085517047
+P11017876A0787
+BC2GM096609252
+P08151787A0355
+BC2GM001534399
+P02283873A0308
+BC2GM062117187
+P09594299A0468
+P03704087A0394
+P01744039A0511
+P10824958A1109
+P09499031A0000
+P09515921A1662
+P00693987T0001
+P03061301A1409
+P01747972T0000
+P07739542A1419
+P08090767A0000
+P09545312A1197
+P10652093A0139
+P06324121A0256
+P09197241A0770
+BC2GM041323158
+P07748502A0794
+P01585014A0000
+P11296288A1107
+BC2GM041774560
+P01428490A0671
+P02919832A0144
+P09099702A0692
+BC2GM026261296
+BC2GM099775528
+P11044097A0422
+BC2GM059554638
+P11071974A0155
+P11160738A1414
+P02113174A0064
+P09223042A0000
+P11278870A0123
+P01513114A1133
+P08631760A0609
+P08301702A1083
+BC2GM049617857
+P03040403A0155
+P01421145A1190
+P10578528A0730
+P09892642A0172
+P02833101T0000
+P01363166T0001
+P03110746A0146
+P07752886A0595
+P07945937A0358
+P10646820T0000
+P02052544A0641
+BC2GM051136020
+P08035517A0753
+P11354975A0850
+P08357834A0285
+BC2GM091989431
+BC2GM035321349
+P11484578A1132
+P03970191A0275
+P07887859A0998
+P08661104A0687
+P08961873T0000
+P11424992A0712
+P08084592A0145
+P08733123A0951
+BC2GM017792516
+P08386637A1220
+P10653359A1297
+P06101359T0000
+P02148291A0173
+BC2GM074570108
+P01648530A0000
+P08199204A0746
+BC2GM010201696
+P10612773A1210
+P10683244X2359
+P01495069A0392
+BC2GM037653411
+BC2GM050337073
+BC2GM031882943
+P01427457A0000
+P08585957A0101
+BC2GM000227172
+P08213747A0000
+BC2GM052697029
+P08887652A0341
+P11517190T0000
+P03963860A0137
+P09209312A0968
+P11177686A0243
+P01649318A0734
+P10982391A0425
+BC2GM065796546
+P04015988T0000
+P09776293A0777
+P11137296A0923
+P03571135T0000
+P09065170A0853
+P09440166A0857
+P09667482A0978
+P07450388A0406
+P02011924A0729
+BC2GM091155868
+P09168879A0219
+P09703213A0280
+BC2GM019838730
+P02166825A0198
+P10811908A0938
+P07295033A0513
+P09372950A1283
+P11223199A0751
+BC2GM066584690
+P08417117A0592
+P09564860A2315
+P07432288A0218
+BC2GM011323900
+P02283378T0000
+P08820642A0173
+P11121043A0074
+P09442024A0236
+BC2GM082413558
+P01470741T0062
+BC2GM062323081
+BC2GM072711375
+P05967610T0000
+BC2GM023227858
+P01784589A0000
+P05120197T0000
+P07972237A0665
+P06278424A0145
+P01406703A1435
+P08355063A0456
+P08534848A0188b
+P01928923A0000
+BC2GM020497918
+BC2GM037222335
+BC2GM012924248
+BC2GM043027311
+BC2GM039204419
+BC2GM065338169
+P10854699A0424
+P08856077T0000
+BC2GM039057912
+BC2GM058205876
+P01406677A0000
+P09808155A0813
+BC2GM049796840
+BC2GM039408846
+BC2GM061879889
+BC2GM041957406
+BC2GM014430266
+BC2GM031428839
+P02575567T0001
+BC2GM031373959
+P11389085A0290
+P07964918A0000
+P02906027A1156
+P08237112A0553
+P02458234T0000
+P02736482A0550
+BC2GM062583466
+BC2GM087329770
+P02204625A1130
+BC2GM028406999
+P06281759A1086
+BC2GM016475600
+P01429836A0457
+BC2GM071557168
+BC2GM046228270
+P07901121T0000
+P02072238T0000
+P11244733A0782
+P01101272T0000
+P04533208T0083
+P08754777A1214
+P08126096A0478
+BC2GM034605250
+BC2GM025315374
+P01549129A0356
+BC2GM016838790
+P08127950A0000
+BC2GM030292353
+P09025122A0374
+P00336547A0000
+BC2GM096046498
+P09151806A1125
+P01925092A0000
+BC2GM095732578
+P09645961A1158
+P08057762A0878
+P02557350A0632
+P08219227A0830
+P02160502A0471
+P05789870T0001
+P00574222T0000
+P10693246A0252
+BC2GM089976750
+BC2GM096040259
+BC2GM041801302
+BC2GM053199516
+P01652755A1492
+P01711041A0962
+P09285789A0712
+P09448574A0964
+BC2GM040811399
+P03115087A0515
+P07892353A0667
+BC2GM017190400
+P08643633A1187
+P11191208A0000
+BC2GM008458026
+P08771787T0000
+P09585253A1147
+BC2GM048779386
+P09683576A0542
+P02083546A0000
+BC2GM065065002
+BC2GM007356608
+P02126504A0602
+P06468694A0441
+P00927633T0001
+BC2GM084985682
+P07413806T0000
+BC2GM003267548
+BC2GM042842840
+P08451187A0267
+P09573187T0000
+P03300118A0392
+BC2GM038940991
+P06505014A1192
+BC2GM000816999
+P01460772T0001
+P11316127A0485
+P01408137A0974
+P07623821T0000
+BC2GM032722941
+BC2GM090808688
+P07776979A0702
+P11101847A0159
+BC2GM008491090
+P01141114A0188
+P07615634A0535
+BC2GM021026668
+P01496784A0939
+P08629348A0237
+P01331516A0103
+BC2GM064518776
+P02482293A1518
+P00155973A0387
+P00330364A0132
+P11106667A1061
+BC2GM068073142
+P08325883A0368
+P07799948A0777
+P04437406T0000
+P11333263A0240
+P04037809A0964
+P08129955A0572
+BC2GM082123096
+P11214177A1125
+P05172970T0001
+BC2GM011752487
+P11542677A0411
+P01731933T0000a
+BC2GM014952112
+BC2GM035226570
+BC2GM024789471
+BC2GM046888921
+P11162666A0442
+P02505087A1037
+P11355668T0000
+BC2GM076892506
+P06241980A0855
+P07560137T0000
+P02118612A0629
+P08600048T0000
+P08267658A0391
+P02442837A0060
+P07588603A1054
+P04214345T0000
+P03403412A0000
+P04760826T0000
+BC2GM057520621
+BC2GM098970669
+P09630245A0903
+P07933107A0991
+P09741391A0581
+P09427627T0000
+P07606548T0000
+P02800417A0332
+BC2GM026086766
+BC2GM004721098
+P08432137A0000
+BC2GM020757047
+BC2GM078674905
+P01840607A0294
+P08813900A1088
+P10562495A0188
+P08626667A1372
+BC2GM063898512
+P07698727A0386
+BC2GM019152487
+P09341192T0000
+P06218005A0948
+BC2GM011836972
+P01447139A0208
+P01131946T0001
+P08304301A0331
+P09570030T0000
+P07816808A1102
+BC2GM069598999
+P08497280T0000
+P00219565A0172
+P02002051A0276
+BC2GM092456996
+P01486836A0774
+P08306356A0000
+P09525105A0298
+P02017271A0502
+BC2GM016014528
+P02844767A1022
+P01374398A0951
+BC2GM057631357
+BC2GM021306881
+P01577819A0709
+P02307067A1348
+BC2GM075721646
+P08178446A1160
+P09366517A0835
+BC2GM083916737
+P00903772A0359
+P06931124A0109
+P06648156T0034
+P01824713A0964
+P11218739A0811
+P09737921T0000
+BC2GM014963504
+P11110040A0000
+P07933066T0000
+P08748033A0874
+P07835826A0195
+BC2GM084852812
+P09611877A0455
+P10762254A0954
+P09506439A2179
+BC2GM082618683
+P07959760A0763
+BC2GM048973712
+BC2GM010682095
+P07791768A0930
+P10799879T0000
+P11007954A0170
+BC2GM014138510
+P08804012A0662
+P10120952T0000
+P02034669A0293
+P10674484A0633
+P01856021A0577
+BC2GM029006862
+P10860131A0847
+P08044800A0550
+P10730763A1491
+P07633444T0000
+P11278563A0917
+P00340692T0033
+P11401105T0000
+P07192722A0682
+P09335298A2129
+P07519447T0000
+P01400217T0000
+BC2GM055024591
+P08649773A1374
+P06882578A0464
+P08138364T0000
+P10134977T0000
+BC2GM034162528
+P00636526T0033
+P11237038A0889
+P07677715A1076
+BC2GM049586226
+BC2GM086016998
+BC2GM088125306
+P11139605A0811
+BC2GM016575957
+P10839547A0978
+P03384033A0155
+P07264787A0351
+P08617800A0150
+P01923985A0111
+BC2GM005461741
+P08847723A2351
+P09547349A0000
+P02021630A1104
+P09582343A0000
+P08806693A0584
+BC2GM000030196
+BC2GM082788210
+P08106369A0000
+P03913522A0000
+BC2GM022311934
+P09635276A1608
+P09199286A0086
+P09866068A1058
+P09891061A0373
+P10754312A0798
+BC2GM071296895
+BC2GM003645917
+BC2GM038872278
+P04308979T0000
+P05781385T0000
+P08675608T0000
+P08922391A0304
+P09517989A0476
+P02236064A1178
+P01853796T0000
+P11239184A1340
+P02510242A0313
+P09813093A0624
+P08550476A0610
+BC2GM017992906
+BC2GM058534127
+P01419945A1386
+P11137296A1216
+P02437895A0000
+P03814493T0000
+BC2GM023719948
+P00133214T0064
+P07672822T0000
+P02883963A0000
+BC2GM097555294
+P10683072T0000
+P10684967A0000
+P03582149T0001
+BC2GM096342624
+P08995681A0518
+BC2GM080722657
+BC2GM037682924
+P07406527A0212
+P11051370A1906
+P06341139A0213
+BC2GM076697045
+P09561616A0142
+BC2GM069899033
+P02877124A0000
+BC2GM084258366
+P02236022A0000
+P08260635A0926
+P09781874A1061
+BC2GM085541430
+P08093642A0600
+P08702845A0000
+P07647570A0713
+P00664320T0000
+P09234720A1015
+P10920906A0759
+P09638485A0111
+BC2GM005683824
+BC2GM084802462
+P01999459A0795
+P10653693A0429
+P08769566A0000
+P01956491A0095
+BC2GM008286757
+BC2GM062434933
+P07079595A0848
+P08065324A0458
+P11268887A1174
+P03335444A0000
+P02225687A0546
+P11564871A1184
+P08566751A0788
+P09420219A0284
+P11518868A0559
+P08325720A0840
+P08386280T0000
+BC2GM053865645
+BC2GM049485558
+P07725980T0022
+BC2GM016763749
+BC2GM066547944
+P02446871A1021
+P03443573A0329
+BC2GM019520345
+P09447973A0168
+BC2GM079864843
+P00601401A0181
+P03965012A0163
+BC2GM087746443
+P06185014A0642
+P08421897A0000
+P09037032T0000
+P06760394T0001
+P06615053A0202
+P02182618A0168
+BC2GM096155639
+P09536901A0362
+BC2GM064814479
+P09680994A0169
+P07471210A0384
+P11075678A0298
+P08887678A0000
+P00807356T0001
+P02423773T0001
+BC2GM078153532
+BC2GM066457601
+BC2GM051756783
+P10999301A0000
+P01721884A0962
+BC2GM069162607
+P11309389A0273
+P00008171T0000
+BC2GM014585915
+BC2GM038217943
+BC2GM074827794
+P09094671A1192
+P11327698A0191
+P00898500A0246
+P03293844T0000
+P11150114T0000
+BC2GM043540576
+P01004298A0744
+P07612557A0635
+P08747078T0000
+P08952796A0743
+P08565330A1783
+P02323517A0557
+P10805747A0633
+BC2GM046561038
+P03207975A0709
+P11128312A1238
+P08900296A0000
+BC2GM086563474
+P03443566A0675
+P09869400A0203
+BC2GM048166276
+P11382701A0688
+P09108207A0306
+P11194147A1496
+P04752455T0000
+P09105530A0000
+P09088737T0000
+P08458849A0364
+P08569680A0636
+BC2GM075516743
+P08187177A0405
+P02751080A0176
+P01895384A0746
+P01863887A0174
+P03459385T0000
+BC2GM009205276
+P08394464A1080
+P02685461A0380
+P07721422A0241
+P07567830A0072
+P10952828A2638
+P11134033A0000
+P01429836A1205
+P09651321A0000
+P03826871A0000
+P09029104A0226
+P08649373T0000
+P07455042A0457
+P11302072A0508
+P02311544A0086
+P11230534A0688
+P04727344T0000
+P11463359A0167
+BC2GM081998478
+P07949205A0286
+P08516324A0000
+P07894021A1130
+P08647264T0000
+P08933640A0000
+P10600171A1066
+P07738026A0216
+BC2GM078178539
+P02789217A1323
+P03713187A0691
+P02831398A0346
+P08760776A1559
+P08892755A0186
+BC2GM034359599
+P09950394A0336
+P09171038A0219
+P10947274A0839
+BC2GM063257384
+P09753769A0362
+BC2GM060829915
+P09176837A0211
+P09733493A0493
+P03296212A0603
+P07534306A0444
+BC2GM044079043
+P00131739T0001
+P07867604A1777
+P10744974T0000
+P09135066A0653
+BC2GM010723108
+P10749849A0000
+BC2GM036305978
+P11106428A0635
+P07677836A1356
+P10973385A1423
+P09059039A0850
+P10527106A0384
+P09573244A0523
+BC2GM004899991
+BC2GM058726742
+BC2GM055577023
+BC2GM041118324
+P07208984A0000
+BC2GM056857198
+P10641688A0341
+P03383897A0189
+P10801860A0000
+P00725257A0452
+P07274042A0249
+P09987961A0093
+P09395470A0294
+P00913623A0242
+P10713155A0151
+P07870305A1015
+BC2GM095725237
+P09490676A0800
+P10645921A1320
+P11105717A0123
+P02691811A0355
+P03757294A0414
+P01420579A0292
+P02830282A0155
+P10772856X1492
+P08617237A0489
+P08998115A0114
+P09665720A0325
+P07545510A0735
+P03494649A0472
+BC2GM067301071
+P04495034T0000
+P07474772A0274
+P08486035T0000
+P03185322A1305
+BC2GM070795322
+BC2GM033054784
+P02157764A1115
+P07910716A0359
+BC2GM036083685
+P08877103A0081
+BC2GM047855598
+P01765407A0866
+P09393875A0873
+P10865838A0000
+BC2GM076012440
+BC2GM040518813
+P01943184A1050
+P06950004T0047
+P08657157A0000
+P02958204A0175
+P03863561A0405
+P02793216A0876
+P09368026A0000
+P07498791A0680
+P06953957A0503
+BC2GM059988355
+P03066131A0000
+P00304806A0760
+P09713584A1193
+P01464329T0000
+P09653182A1298
+P09638342T0000
+P09139910A1572
+P09032275A1133
+P08091655A0000
+BC2GM006399626
+P07528772A1539
+P08496185A0484
+BC2GM022006150
+P08422975A1205
+P01300914A1066
+P00384744T0000
+P06290859A0426
+P02919483A0091
+P07865787A1086
+P08675821A0657
+P02529378A0536
+P02008982A0463
+P03484075T0001
+P09560430A0000
+P03027661A0000
+P07860208A0000
+P04640155T0045
+P06230499A0128
+BC2GM093786389
+BC2GM048518411
+BC2GM075900069
+P06426493A0331
+P10567582A1334
+P07791776T0000
+P08864219A0178
+P11040101A1180
+P09673037A0358
+BC2GM041364730
+P11251697T0000
+P00822611A0467
+P10653733A0596
+P09043534A1600
+P08079268T0028
+P07623807A0162
+P08624445A0257
+BC2GM052108283
+P08078473A1107
+P11274179A0610
+BC2GM080178845
+P10951848A0230
+P09458030A0192
+BC2GM027361300
+P08015672A1282
+P09817601T0000
+P09528858A0205
+BC2GM044737613
+BC2GM079948235
+P09973607A0254
+P01619114A0383
+P06848729A0000
+BC2GM035901068
+BC2GM008088904
+P09767593A0130
+P09576915A0269
+BC2GM047130607
+P07829519A1251
+BC2GM074194450
+P10758726T0000
+P08760286A0696
+P09682897A0218
+P09892422A1096
+P08678959A0640
+BC2GM065804496
+P05553261T0000
+P07084617A0204
+P06051644T0000
+P08370119A0642
+P07675445A0463
+BC2GM003829554
+P09588228A0370
+BC2GM090178909
+P09090054A0186
+BC2GM000099421
+P00885562A0281
+P07903670A1202
+BC2GM066695616
+BC2GM006001053
+P08484891A0000
+P09151152A0174
+BC2GM090237633
+BC2GM096199881
+P08217862A1336
+P11118712A1296
+BC2GM084799105
+P11319098A0164
+P09492038A0352
+P08542026A0792
+P08978996A0000
+P07844201T0000
+P10629938A1352
+P02868446A0184
+P11069307A0546
+BC2GM008948246
+P11403173A0192
+P09092675A0283
+BC2GM012126360
+P06237518A0117
+BC2GM017027776
+P06330478A0304
+P02341669A0000
+BC2GM082165105
+P09861099A1011
+P09506959T0000
+BC2GM077691653
+P03178161A0000
+P08535138A0857
+P02592640A0466
+P11156484A0223
+P10884978A0633
+BC2GM055876986
+P08633855A1064
+P09797189A0559
+P01012640T0001
+P02522297A0000
+BC2GM029605480
+P01655126T0000
+P10802669A1434
+P05787318T0000
+BC2GM032017565
+P09488491A0000
+P10805738A0799
+P04543036T0001
+P11369106A0428
+P07888306A1659
+BC2GM003098775
+P05177935T0001
+P09215891A0000
+P05782943T0001
+P01884998A1135
+P09583592A0263
+P11524823X0001
+P02526165X0000
+P08265602T0000
+P10193950A0478
+P09402029A1632
+P09430668A0172a
+P03403480A0299
+BC2GM068691299
+P09626662A1076
+BC2GM022742805
+BC2GM064815025
+BC2GM040848172
+P10601344A1653
+P08621420A1166
+BC2GM083941161
+BC2GM077069782
+P09324988X0000
+P08306834A0866
+BC2GM085827097
+BC2GM053146893
+P11312120A1311
+P03743702A0158
+BC2GM032430456
+P03738919A0000
+P11181995A1093
+P07429009T0121
+BC2GM030060311
+BC2GM089330500
+P08952965A1182
+P11108720A1130
+P10647817T0000
+P08283531A0700
+P11160096A1067
+P09165004A1700
+P08664462A1404
+P01248124A0281
+BC2GM033388156
+P07636187A0585
+BC2GM032512561
+P10732669A1336
+P08732665A0000
+P01124944A0830
+BC2GM096526830
+P09267431A0000
+P07978229T0000
+BC2GM049289655
+P08148463A0000
+BC2GM025711637
+P03375184A0000
+P06835516A0000
+BC2GM091903894
+P02971710A0734
+P02001033A1907
+P11359827T0000
+BC2GM022584300
+P09130718A0497
+P11266558A1470
+P01309244A0798
+P08575618A1138
+P08709831A0599
+P01985920T0000
+P02282815T0000
+BC2GM036761066
+P06849842T0000
+P01651232A0152
+P11140472A0497
+P09351823A0414
+P10834781A0693
+P00361059T0000
+P07658262A0944
+P01569015A0120
+P09806546A1270
+BC2GM034608401
+P01469047A1606
+P01443748A1190
+P09420671A1190
+BC2GM020095584
+P10564231A0315
+P02592961A0327
+BC2GM070700185
+P11437660A1219
+P11254134A0648
+P03062370A0000
+P01420223T0000
+P00635194A0093
+P08103935T0000
+P11096662T0000
+BC2GM039440214
+P09018122A1389
+P09504423A0114
+P02386485A0554
+P08717391A0466
+P08091669A0828
+P02521674T0000
+BC2GM023032582
+P06527379T0044
+P03457330A0271
+BC2GM045195775
+P06972443A0375
+P01658468A0123
+P03185540T0000
+P10684941A0722
+BC2GM029220064
+P01225339A0590
+BC2GM022819615
+P08675769A0158
+P09965234T0000
+BC2GM025821174
+BC2GM024341758
+P11796977T0000
+P02590097A0093
+BC2GM004210078
+P07237123T0000
+P07891685A1051
+P03982288T0000
+BC2GM047579187
+P01810154A0491
+P07252346A0223
+P05501347T0001
+BC2GM049023434
+P01147436T0000
+P09199413A0518
+P00267764A0651
+P07951874A0320
+P09649537A0000
+P02124710A0193
+P10625438A1429
+P07539119A0985
+BC2GM020677635
+BC2GM032656820
+P09418861A0623
+P02684159A0870
+P02164604A0399
+P09257651T0000
+P02065022A0747
+P07562775A0596
+BC2GM064809845
+P03198525A0164
+BC2GM066107969
+P09396823T0000
+BC2GM024886173
+P10054976T0000
+P09157100A0583
+P07191972A0391
+BC2GM093619245
+P09449018T0000
+BC2GM079539609
+P06173032T0000
+P09407090T0000
+P04002131A0506
+P09084176A0601
+BC2GM038900690
+P08921667A0294
+BC2GM016146952
+P01019207A0232
+P09185183A0089
+P11251951A0000
+BC2GM056432965
+P07941739A0000
+BC2GM005272522
+P09495771A0379
+BC2GM073475138
+BC2GM003632823
+P02006558A0000
+P07629123A0885
+BC2GM055969816
+BC2GM036804385
+P10184191T0045
+BC2GM012170235
+P09243505A1194
+P11175333A0336
+P03401060A0000
+BC2GM092925197
+BC2GM067565355
+P01316903A1040
+P10750524A0724
+BC2GM003302721
+BC2GM083277547
+P01441120T0000
+P08886845A1274
+P07829057T0000
+P02542612A0530
+P11443999A0573
+P01113908A0475
+P09321406T0000
+P11143384A0267
+P08321227A0854
+P01333053A0110
+P04325736T0001
+P07282943A0097
+P10965905T0000
+P06152844T0000
+P03022129A0842
+P11470914A0305
+BC2GM027981774
+P10890911A0470
+P10619353T0000
+P08388543A1263
+P01989561A0100
+BC2GM032584152
+BC2GM090921453
+P11306463A0383
+BC2GM031127519
+P08020965A0465
+P08601283A0875
+P08844577A0000
+P09180687A0096
+P00663166A0000
+BC2GM023767363
+BC2GM080507984
+P09845043A0000
+P11088635A0200
+P00173860A0475
+BC2GM033082377
+P09294471A1198
+BC2GM037968390
+P06864837T0000
+P07419485A0158
+P02246803A0692
+P09815948A1065
+P08808924A0326
+P03138449A0759
+BC2GM020608832
+P06441624A0263
+P11530684A0667
+P11430976X0000
+BC2GM048416316
+P11391531A1157
+P02597549A0964
+BC2GM013080012
+P11566996A1391
+P02206789A0002
+BC2GM022050616
+P07180901A0539
+BC2GM094263980
+P07375864A0431
+BC2GM076163727
+P03004364A0775
+P01435698A0000
+P00639410T0000
+P11108523A0326
+BC2GM031146030
+P09170159A0721
+BC2GM067333955
+P08989025A0359
+P09017443A0734
+P09460171T0000
+P02647403A0000
+P06946314T0000
+P11028131A1374
+BC2GM058702886
+P08692892A0330
+P09325273A1240
+P02010912A0366
+P08649425A0373
+P07806820A0091
+P11283010A0701
+P08844712A0000
+P10710499A0000
+P01337142A2043
+P04676734T0000
+P11387940A0647
+P03486405A0341
+BC2GM053648425
+P07563072A0773
+P08035833A1556
+P09971806A1585
+P01874752A0948
+P10787804T0000
+BC2GM062143954
+P02982332T0001
+BC2GM048760172
+P10861086A0904
+P08820324A1699
+P07898178A0849
+P09415711A1348
+BC2GM033019840
+P10725433A0543
+P01850893A0286
+P01978857A0504
+P08481004A0321
+BC2GM017837173
+P11004369A0000
+P07618280A0550
+BC2GM052866692
+P09881692A0094
+BC2GM011520579
+BC2GM022884107
+P10925159A1353
+P08816460A1769
+BC2GM019371061
+P07668043A0277
+P02358975A0709
+P08979828A1561
+P01398071A0526
+BC2GM014834356
+P10767560A0105
+P03536864A0000
+BC2GM088666537
+P01459447A0484
+P02159470A1432
+P00627129A0944
+BC2GM056080482
+BC2GM064277567
+P09343982A0890
+BC2GM025336946
+P01707659A0458
+BC2GM031587452
+P11528253X1211
+P07742917T0001
+P11416012T0000
+BC2GM078543266
+BC2GM042698596
+BC2GM071297366
+P11380370A0000
+P09377374A0000
+P07789275A0325
+P09006555A0738
+P02488148A1156
+BC2GM028814476
+P09038166A0818
+P01538403A1058
+P09222057A0176
+BC2GM055311228
+BC2GM017164841
+BC2GM020087373
+P02299543A0317
+P01084413A0271
+BC2GM045793760
+P08576179A0126
+P11278819A0565
+P09881666A0535
+P03379058A0188
+P01140184A0342
+P00715753A0241
+P04024685A0650
+P09469833A0533
+BC2GM065739819
+P08932385T0000
+P08509430A0372
+P08188603A0230
+P01901946A0243
+P11325195A0661
+P02456827A0899
+P02166040A0385
+P08524241A0212
+P11227182A1475
+P11410679A0000
+P10568744A0728
+BC2GM047597727
+BC2GM057633611
+BC2GM055737184
+P06443714T0001
+P09765277A0000
+BC2GM096245457
+P04826272T0074
+P01655713A0294
+P07516466A1054
+BC2GM009256073
+BC2GM042327107
+P11311464A0362
+P04088733T0001
+P01875922A0770
+P09886850A0145
+P01352113A0231
+P07863992A0908
+P09601007A0223
+P01178153A0056
+BC2GM067442667
+P07678695A0604
+P05284310T0000
+BC2GM094635943
+P09235998A0788
+P11160902A0962
+P10764970A1009
+BC2GM078763746
+P01899846A0862
+P00464387A1185
+P08445792A0469
+P11313946A0449
+P08703010A0905
+P08804389A0893
+P09176340A1194
+P11554727A0890
+P09130595A0478
+P10727247A0461
+BC2GM011268636
+P09827724A1362
+P10679065A0711
+P08809680T0000
+P07636984A1349
+P02159559A0779
+P07476164A1602
+BC2GM090911628
+P11278290A1220
+P03964489A1195
+P01492463T0001
+P10739408A0896
+BC2GM043004762
+P10483945A0641
+P09524250A0767
+P07548425A0000
+BC2GM096261608
+P03036415T0000
+P08869358A0121
+P01329039A0239
+P10931950A0869
+P07116298A1079
+P11369066A1210
+P03014515T0000
+P09388198A1396
+BC2GM040034463
+P07836218A0128
+P09096229T0000
+P11007949A1607
+P09028089A0183
+P02371273A0144
+P07959015A0478
+P01509798A0520
+P10614857A0584
+BC2GM092424481
+P10628755A0000
+P01504178T0000
+P07695629A0489
+BC2GM028564481
+BC2GM021675012
+P09343433A0360
+P07935383A0108
+P01579537A0000
+P01982061A0615
+P06807659T0001
+BC2GM082066284
+BC2GM066299877
+BC2GM084151426
+P02403634A0788
+P08794547A1403
+P01913955A0177
+BC2GM038291943
+P09396796A1173
+BC2GM031921056
+BC2GM086105729
+BC2GM093464345
+P09628375A0700
+P02405589A0000
+BC2GM008619056
+P08663120T0000
+P11413310A0148
+P11131634A0955
+P08285710A0634
+P09417108A0000
+P11248463A0187
+P02411513A0667
+P09214274T0001
+P07990136A1124
+BC2GM018016290
+BC2GM051960304
+BC2GM092131835
+P10815410A0000
+P08303233A0313
+P06977605T0000
+BC2GM097330592
+P07559524A0741
+P03448035T0000
+BC2GM033441009
+P05642051T0000
+P00030937A0119
+P08863824A0509
+P00827364A0000
+P11358958A0878
+P09118704A0771
+P07678051A1303
+P11154491A0322
+P09042755T0000
+P07590657A0624
+P08600028A1129
+P03384272A0145
+P11873003X0000
+BC2GM020401171
+P06391496T0000
+P08377199A1432
+P08666241A0930
+P10799576A0196
+P09111367A1098
+P11400644A0435
+BC2GM088223982
+P01545818A0696
+P09582267A0326
+BC2GM032924091
+BC2GM080095863
+BC2GM026151864
+P09650299A0000
+P09735286A0599
+P09725651A0077
+P02547778A0786
+P01425921A1286
+BC2GM026075633
+BC2GM044595672
+P09799237A0624
+P00627202T0000
+P08713933A0606
+BC2GM005593098
+BC2GM073047103
+P03911965A0513
+BC2GM003445386
+BC2GM092679978
+BC2GM070120777
+P07666538A0000
+P09423123A0000
+P00748978T0000
+P07997174A0936
+P11220857T0000
+P01057137A0192
+P10699684A0661
+BC2GM055133205
+P09929088A0000
+P11311687A0231
+P09813259A1097
+P01901950T0000
+P09294422A1376
+P07693708A0000
+P03228785A1047
+P02481429T0000
+BC2GM020915741
+P02270096T0000
+P02863492A0544
+P11496617A0301
+P09130700A0676
+P02195715T0000
+P07530549A0956
+P08634290A0000
+P10653550A1120
+P08766781A0322
+BC2GM045159577
+P08691106A0733
+P10650104X0284
+P10633499A1306
+P01779433A0694
+P08810323A0735
+BC2GM098918087
+P06319072A0711
+P09593302A1165
+BC2GM014908370
+P07217523A0364
+P06286443A0498
+P02732341A0000
+P10862289A0289
+BC2GM063546497
+BC2GM070010580
+BC2GM092286757
+BC2GM067263204
+BC2GM076965048
+P03335398A0568
+P01720555A1087
+P03618039A0126
+P07579695A0693
+BC2GM012794802
+BC2GM059456391
+P09931391A0944
+BC2GM088354300
+P03559232T0000
+P07707544T0000
+P08498570A1118
+P00303189A0247
+P08437521A0000
+P07784870A0119
+BC2GM003073174
+P11318608A1155
+P06089575A0464
+BC2GM076852913
+P07770033A0978
+BC2GM028852576
+P07413242A0000
+P01206896T0001
+P07630934A0343
+P07879204T0000
+P01973384A0206
+P09710589A1111
+P09178752A0574
+P03940818T0000
+P09657003T0000
+P08847403T0000
+BC2GM010221833
+P01075075T0038
+P04598670T0000
+P09461594A0000
+P09100202A0000
+BC2GM068917661
+P07937127A0645
+P07915144A0000
+P08396657A0452
+P06876317T0033
+P09188094A0934
+BC2GM049887251
+P02174861A0736
+BC2GM011249269
+BC2GM048180696
+P07640422A0649
+P08441869A0334
+BC2GM049762234
+BC2GM077944631
+P09459685T0001
+P10683244A1860
+P00565314A0293
+BC2GM012988556
+P03632739T0000
+P06340703A0324
+BC2GM043513819
+P05410590T0000
+BC2GM095821650
+P10567533A0818
+BC2GM096315697
+P08511994A0000
+P03195167A0104
+P08691962T0000
+P06099656T0000
+P09892662A0334
+P01123658A0000
+BC2GM056512837
+P10991648T0000
+P07488247T0000
+BC2GM023194685
+P11241356T0000
+BC2GM028948784
+P02901763A0977
+P11108151A0560
+P09123055T0000
+P02265055A0417
+P05174753T0001
+BC2GM083493191
+BC2GM038644966
+P08846775A0110
+P08643578A0000
+BC2GM028463998
+P08842143A0000
+P08762021A0156
+P09341158A0167
+BC2GM098314451
+P11592532A0188
+P00621626T0000
+P01692962A0980
+P08468320A0941
+P08194139A0498
+BC2GM075408371
+P09442172A0908
+BC2GM069784959
+P07784942T0001
+BC2GM086763772
+BC2GM078051387
+P02724227T0000
+P07501016T0000
+P09849961A0387
+BC2GM093787356
+BC2GM054416322
+P02443924A0083
+P01970926A0000
+P03721666A0000
+P06785113A0337
+P07202919A0142
+P04001413A0093
+BC2GM020549068
+BC2GM069591323
+BC2GM010596597
+P02899792T0000
+BC2GM087369574
+P03015611A0331
+P00583004A0445
+BC2GM072127832
+P03463537T0001
+BC2GM026662709
+P07844142A0640
+P08474464A0348
+P01872856A0277
+P07588777A1524
+P08125319A1085
+BC2GM061275857
+P06373855A0000
+P10651805A1600
+P08254738A0428
+P08513025A0000
+P07601078A1003
+P11345445A0533
+P01304515A0178
+BC2GM063573521
+BC2GM090917188
+P08630583A1056
+BC2GM068752767
+BC2GM089678817
+P11087141A0977
+P09140474T0000
+P07919540A0240
+P07466831A0714
+P07369458A0606
+BC2GM069379364
+P08473967T0000
+P06744024A0000
+P03545955A0751
+P08420230A0544
+BC2GM077706962
+P10801330A1714
+BC2GM039293973
+P08281634A1801
+P01328854T0000
+P03701640A1178
+BC2GM088776852
+BC2GM095367875
+P00066874T0000
+P11509673A0574
+P09986796A1761
+P01542565T0000
+P03485064A0135
+P09367426A1354
+BC2GM004658722
+BC2GM029087061
+P08973917A0632
+P11223256A1212
+P02262439A0508
+BC2GM005118324
+P07559488A0440
+P11448051A0093
+P11406277A0598
+P07385920A0189
+P02110148A0423
+P03953361A0000
+P02964329A0000
+P02061333A1359
+P03679407A0556
+P08798610A0843
+P06582285A0222
+P07941750A0344
+P08406419A0155
+BC2GM031784532
+P03007281A0905
+P11576776T0081
+BC2GM023547323
+P08509333A0843
+BC2GM067535519
+P08301841A0000
+P02252891T0000
+P07413144T0018
+BC2GM049247911
+P11179400T0000
+P07969132A0268
+P07588240A0000
+BC2GM001234519
+BC2GM082412019
+P09751458A0845
+P09446616A0780
+BC2GM046993980
+BC2GM035984243
+P11035867A0000
+P09126622A0466
+P10972980A0295
+P03083441T0000
+BC2GM060824736
+P01511231A0085
+BC2GM083274778
+P10208865A1246
+P07565713A0634
+P01903404A0688
+P00033873T0001
+P02963517A0453
+P11042199A0572
+BC2GM013081581
+P07469692A0000
+P03522105A1011
+P02511150T0025
+P02139473A1603
+P09863624A2301
+BC2GM083699993
+BC2GM035316486
+BC2GM087506083
+P04429269T0000
+P09138492A0806
+P02712450A0989
+P07822161A1172
+P05732641T0001
+P00100791A0425
+BC2GM022069821
+P07758246A0469
+P11139469A0402
+P03788231A0802
+P11263664A1085
+P00768220X0000
+P08421823A1041
+P09528766A0915
+P09790771A0956
+P09738087A0583
+P02489032A0000
+P11849796A0452
+P10945010T0001
+P09995897T0000
+BC2GM086417938
+P03863231A0530
+P08306959A0278
+P03543485A0069
+P09813207A0434
+P07034479A1050
+P07862154A0340
+P11528127A1402
+P01674177T0001
+P08144852A0000
+P07651141A0265
+BC2GM004900930
+P01740448A1735
+P02508306A0528
+P08188606A1034
+P04291759T0048
+P09311796A0218
+BC2GM057071865
+P02843694T0001
+BC2GM024519999
+BC2GM017085693
+BC2GM036721419
+P07298259T0000
+BC2GM039462814
+P02298741A0809
+P08415637A0000
+BC2GM092052838
+P02145268A0746
+BC2GM093591586
+P08156332T0000
+P07627317A1502
+P01447189A1546
+P09488466A0695
+P08030243A1011
+BC2GM015590289
+P09296251A0163
+P07075024A0540
+P01637758A0532
+P03679756A0830
+P00606849T0000
+BC2GM098476170
+P03666957A0219
+P07431059A0000
+P10972688A1272
+P11230889A1151
+P06404842A0127
+P07699845A0537
+P06181216A0070
+P09315633A0333
+BC2GM033281770
+BC2GM088202512
+P11181548A0214
+BC2GM009453021
+P09642214A0244
+P06501086A0165
+P08291233A0000
+P03652083A0720
+BC2GM030532264
+P00409927A0570
+P08057421A1583
+BC2GM063896502
+BC2GM049920668
+P07752644A1031
+P11228700T0000
+P09478976T0000
+P09533109A0449
+P10781611A1023
+P11518505A0107
+P10729221A0798
+P08178572A1118
+BC2GM089636250
+P09806858T0000
+P11422200A0000
+P01947449A0191
+P02566613T0000
+P04488271T0001
+P00954819A1041
+P10805286A0914
+BC2GM001917913
+BC2GM014733001
+BC2GM063968223
+BC2GM005484781
+P10858355A0920
+P04973523T0000
+BC2GM096057654
+BC2GM024331581
+BC2GM054625415
+P08140847X0001
+P01363080A0710
+P02162754A0801
+P07453919A0000
+P01846489A1119
+P02179188A1223
+P09704006A0224
+P01477021A0394
+BC2GM049482687
+BC2GM009169433
+P00083846T0000
+P08589735A0577
+P00704675A0199
+BC2GM035995772
+P09192842A0988
+P10001541T0000
+BC2GM082256131
+P09388271A1243
+P01921463T0000
+P03312033A0501
+BC2GM054235351
+BC2GM051328807
+P10972894A0488
+P09524229A0000
+P08108099T0000
+P10825294A0473
+P04385060T0000
+P11277913T0000
+P07112654A0388
+P11040219A0548
+P10873158A0000
+P11279207A0904
+P11215622A0949
+P10905349A0329
+P03861687A0000
+P09447963A0223
+P03878585A0507
+P00420460A0291
+P11125363A0525
+P09940132T0000
+P07651424A0487
+P07190869A0316
+P10756100A0457
+BC2GM038586241
+BC2GM085223521
+P02116071A0000
+P03090237A0202
+P07511496A1511
+P10604246A0523
+P07528667A0834
+P08585994A0567
+BC2GM006761039
+P11353392A1127
+P01252223A0347
+P09036529A0343
+P09844106A0835
+P01752441A0000
+P04164595T0020
+P01982190T0001
+P07323063A0000
+BC2GM084592604
+P09328824A0000
+P07217329A0000
+BC2GM012849815
+P07377378A0143
+P11211936A1490
+P07708488A0151
+BC2GM055184868
+P01157191A0536
+BC2GM097617253
+BC2GM030304217
+P10871379A0261
+P06325415A0757
+P08237171A0000
+P10724436A0085
+P09393966A0190
+P07225540A0193
+P08530105A0308
+BC2GM073939713
+P06897114A0240
+P07607342A0703
+P06808529A0167
+P09913308T0000
+BC2GM073834099
+P09806857A0854
+P07682842A0294
+P09267306A0381
+P09692965A0904
+P05357390T0001
+P05135168T0000
+P09656414A0220
+P09891085A0815
+P01324404A0813
+P09230384A1056
+P08388496A1117
+BC2GM047731031
+P07038189A2301
+BC2GM011847629
+P09525598A0325
+P10590368X0000
+P08663172A0311
+P02163382A0169
+BC2GM056965108
+P07018810A0002
+P07730795A0104
+BC2GM042434185
+P02123820A0000
+P07651424A0743
+P08589315A1029
+P11433024A0260
+P08881036A0351
+BC2GM007199944
+P08400928A0318
+P08139542T0000
+P02817724A0075
+P01348504A0757
+BC2GM089485975
+P11006331A0319
+BC2GM013162443
+P00383169A0000
+P02966671A0151
+P09529721A0000
+P11314046A0000
+P10771709A0291
+BC2GM024261949
+P00842522T0000
+P00930947A0629
+P08070654A0574
+BC2GM025329435
+P09473040A1303a
+P10838531A0675
+P06460889A0111
+P08605324A0434
+P07859301A0325
+P07681147A1420
+P09832505A0903
+P10031854T0000
+P10742216A0555
+P06321505A0401
+BC2GM012934099
+P09420239A1937
+P01324639T0000
+P09405195A0320
+P07037479T0000
+P07988945T0000
+P04947347T0000
+P11145563A0303
+BC2GM082618608
+P01380825A0622
+P02531203A0241
+P06521999A0677
+BC2GM025052466
+P08621448A0862
+P11188971A0000
+BC2GM054816469
+P03038643A1374
+P09933848A1008
+P02830265A0341
+P05368978T0000
+BC2GM084929620
+BC2GM018485716
+P09427544A0000
+P02242222T0000
+BC2GM016890014
+P04051521T0001
+P11764062A0000
+P07898589T0000
+P10861906A0999
+P10750020A0843
+P11006284T0000
+P08223823T0000
+P11367523A2624
+P01970801A0925
+P01193458T0001
+P11162936A2727
+P09002648A0202
+P08878037A0000
+P06278544T0027
+BC2GM088054752
+P11016737A0275
+BC2GM059462976
+BC2GM047717064
+P02343033A0000
+P01791363A0208
+P11278461A0637
+BC2GM080121917
+P11000250A0200
+BC2GM099591467
+P07779812A0000
+BC2GM013239156
+P07081327A0546
+P07714758A1193
+P02969316A0002
+BC2GM021272736
+P08955402A0288
+P08138180A0593
+P10633075A1111
+P08770920A1220
+P09348226A0852
+P01048020T0000
+P01898164A0839
+P09689919A1192
+P08331067T0000
+BC2GM003946244
+BC2GM024780744
+BC2GM081973466
+P07490770A0267
+BC2GM031955724
+BC2GM060497618
+P03763241A0446
+P02502960A0762
+P10782640A0444
+P00713525A0268
+P08741280A0374
+P08923258A0353
+P06095372A0435
+P02995999A0000
+P05719746T0001
+BC2GM067873375
+BC2GM088957012
+P00417166T0000
+P08383214A0389
+P01656675A0236
+BC2GM007186546
+P08824805A0832
+P09202147A0866
+P02004705A0686
+P02559630A0270
+BC2GM035284828
+P03516189A0406
+P04925617T0000
+BC2GM099607997
+P02789062A1420
+P07880650A0493
+P09420252A0092
+BC2GM055057838
+P02958660A1094
+P09464525T0000
+P07663160A0287
+P00701144T0000
+BC2GM021603045
+BC2GM052103407
+P01529530T0000
+P11117263A0570
+P07917016A0581
+P07509624T0000
+BC2GM011317190
+BC2GM042227725
+P07283110A0000
+P10585417A1412
+P02895472A0178
+P02752303A0000
+BC2GM059007743
+P09840822A0462
+BC2GM042797974
+P08614403A0989
+BC2GM068997634
+P02007045A0092
+P09164856A0980
+BC2GM071733083
+P02686980A0000
+P03688301A0129
+P03668736A0177
+BC2GM070673792
+P09181130A1067
+P00792847A0000
+P02713994A0482
+P02512010A0801
+P03014593A0681
+P08350061A0209
+P05822499T0034
+P08413215A0327
+P01675154T0000
+P08088818A1053
+BC2GM068306112
+BC2GM011270186
+P11428487T0000
+BC2GM054534012
+P08759870A1128
+BC2GM075306454
+P08542027A1471
+BC2GM012664119
+BC2GM052977122
+P11849417A0900
+P08892755A0981
+P11315633A0920
+P01408090A0572
+P02455821A0099
+P04909355T0000
+P07576178A0000
+BC2GM081183440
+P08289831A0290
+P06671385A0856
+P10593950A1113
+P02828926A1870
+P00985110T0001
+BC2GM031297991
+P03466730A0210
+P07743515A0223
+P08533472A0777
+BC2GM021733424
+P07487067A0592
+P09727046A0000
+P07936640A0900
+P01313894A1179
+BC2GM094732618
+P01398098A0770
+P07857163A0551
+BC2GM048059334
+P10033973T0000
+P09305592A0000
+P09238850A0785
+P08813766A0605
+BC2GM092243053
+P03651330T0000
+P08417330A0149
+P01922734T0000
+BC2GM035428099
+P07609372A0261
+BC2GM002567582
+P02586513A0622
+P11403663A0359
+P08524292A1022
+P01264640T0028
+P11902068T0000
+BC2GM076181563
+P08454591A0692
+P08524294A0652
+P00657551T0000
+BC2GM030739462
+P08139542A1229
+P03417104A0536
+P01429624A0328
+P08922385A0622
+BC2GM083917947
+P02705556A1049
+P07964458A0179
+P07629150A0155
+P01385462A0151
+BC2GM040314258
+P08058326A0463
+P08495786A0085
+P09029956T0000
+P08223425T0000
+P02403926A0307
+BC2GM030329937
+P02668691A0570
+P02646007T0000
+P10850849A0730
+P08471796A1654
+P00851286A0375
+P09716095T0000
+P07073520A0153
+P02132636A0188
+P08232412A1342
+P02846852A1459
+BC2GM004690060
+P07964814T0000
+BC2GM091917178
+BC2GM045332665
+P09398598A0256
+P09753775A0734
+P09686344T0000
+P06830033A0661
+P02607766A0000
+BC2GM065051600
+P10781990A0455
+BC2GM007741669
+P08286035A0587
+BC2GM076134275
+P07653094A0169
+BC2GM027384741
+P07016141A0238
+P09704857T0000
+P09622121A0525
+P07692668A0326
+P01992953A0247
+P09483596A0626
+P11255252A0961
+P06318078T0000
+BC2GM010522848
+P09819430A0000
+P10760950A1133
+P07816619A0000
+BC2GM068106933
+P06310608A0749
+P07909936A0672
+P02875224A1059
+BC2GM023331710
+P11311980A1049
+BC2GM097805959
+P06277159T0033
+P04041307A0614
+P01360294A0000
+P08253386A0800
+P06497671T0001
+P02326946T0000
+P04801663T0049
+P08062824A0626
+P07615541T0000
+P08993393A0498
+BC2GM061897910
+P11020375A0134
+P07479004A0421
+P10855793A1418
+BC2GM068822744
+P10907348A0508
+P09808441A0320
+BC2GM016530751
+P01903841A1449
+P01047895T0001
+P11331589A0113
+P10938102A1359
+P02176209A0954
+P11055786A0306
+BC2GM035122268
+P09518808T0000
+P09582635A0523
+P11032677A0230
+P02305014A0226
+P04970131T0001
+P10790390X0000
+P06370553A0444
+P10958698A0280
+BC2GM028611908
+P09920775A0075
+P04321861T0001
+P08825633A0304
+P08508774A0242
+P05938720T0000
+P01855255T0000
+P09365431A0314
+P07225300A0968
+P00755245A0000
+P00445720A0263
+P09369453A0273
+P03057259A0514
+P01339773A0778
+P09482902A0942
+BC2GM007318409
+BC2GM013622004
+BC2GM080956637
+P05372511T0105
+P09244282A1371
+P09578570A0200
+BC2GM004383808
+P00463973A0000
+P02142486A0367
+P11050084A0000
+P01431380A0244
+BC2GM044384474
+P10584138T0001
+P11278855A0205
+P03219107A0212
+P01009739T0001
+P02995967T0000
+P08906139A2935
+BC2GM005826415
+BC2GM089431747
+P02223652A0939
+P09020138A0833
+P07124743A1223
+P08057833A0573
+P06281786A1222
+P05154132T0000
+P01309815A0972
+P01782669A0496
+BC2GM062721233
+P06362602T0001
+BC2GM019547641
+P09786926A1372
+P09252879A0470
+P03280807A0000
+P09685021A0127
+P11050084A0888
+BC2GM069896778
+P02229068A0156
+P01708774A0203
+BC2GM028996943
+BC2GM029915444
+BC2GM049751751
+P10864989A0484
+P00646193T0000
+P11530829A0000
+BC2GM073846842
+P07524265T0000
+P09237695A0000
+P03326381A0423
+P03069046A0126
+P08421687A0397
+P07758167A1488
+P09131139T0000
+BC2GM036865431
+P11142380A0389
+P08441411A1260
+BC2GM028707148
+P09891707A0000
+P07540773A0576
+P07862141A0317
+P07683131A0885
+P09528987A1348
+P07463294A1216
+P10826946A1198
+BC2GM052594867
+P06212776A0000
+BC2GM032114855
+BC2GM090403592
+P09224811A0000
+BC2GM047470331
+P01331292A1425
+BC2GM089517365
+P07755914A0000
+BC2GM069603149
+BC2GM026059945
+P09651367T0000
+P09155024A0955
+P01812102A0101
+P00495097A0663
+P01449301A0710
+P08441394A1297
+P00941050T0000
+P11522584A0882
+P08975713A0454
+BC2GM099382056
+P01357190A0726
+P09079817A0928
+P11045180A1892
+BC2GM000160086
+P09849421A0332
+P06093354A0000
+BC2GM059940131
+BC2GM011982866
+P10869076A1384
+BC2GM061963337
+P09889306A0321
+P08383850A0206
+BC2GM035479139
+P02985812A0984
+P10831972A1091
+P00745775A0170
+P00564943A0444
+P06240448A0652
+BC2GM035976811
+P07623844A0639
+P08299725A0724
+P08230418A0812
+P06216125A0470
+P03150015T0001
+BC2GM003162436
+P11145590A0217
+P08922344A1539
+P08522530A1342
+P09271394A0558
+BC2GM070690502
+BC2GM036866383
+P01694525A0000
+P08622675A0587
+BC2GM083865368
+P02934891A0845
+P02603374A0383
+P00240518A0000
+P01437562A0462
+BC2GM092754644
+BC2GM071933956
+P01119658A0000
+P01423738A0639
+P03220077A0274
+P04040858A0000
+BC2GM024464549
+P07999066A0238
+BC2GM004396508
+P10564593A0428
+P07560662A0496
+BC2GM007792943
+BC2GM096383167
+P09030688A0435
+P03021050A0501
+BC2GM077505350
+P08750173A0000
+BC2GM010924622
+P04488232T0001
+P09372924A0758
+P11003471A1149
+P08995652A0812
+P09154797A0777
+P02391344T0000
+P09160881A0491
+P08524272T0000
+BC2GM030100060
+P09029159A0000
+BC2GM075850023
+BC2GM011015031
+P10779508A0897
+P04226360T0001
+P10894816A0836
+P08808275A1193
+P02133731A1572
+BC2GM085429283
+BC2GM071199911
+BC2GM058606403
+P01531214A0885
+P09015757T0000
+P11393463A0274
+P00868301A0043
+P09244100A0194
+BC2GM016387762
+P10582831T0000
+BC2GM080802212
+P09545638A0836
+P08201352A0239
+P07327097A0647
+BC2GM034262338
+P04039109A0139
+P05839844T0000
+P08299896A0626
+BC2GM078287872
+P09560221A0282
+P01379032A0495
+P07109788A0333
+BC2GM019562705
+P07806507A0121
+P09154795A0628
+P08550425A1401
+P08597108A0642
+P00622556A0111
+P08747343A0790
+P02220304A0501
+P07270991A0149
+P10853778A0316
+BC2GM011301969
+P11121490A0000
+P11094066A1194
+BC2GM025350751
+P10616948A0998
+P04487835T0001
+P11469737A1791
+P02585492A1005
+P07706287A0698
+P08450015A0175
+P11062257A0977
+BC2GM075887001
+P01871971A0836
+P07499401A0444
+P03964855A0254
+P07828852A0153
+P10781423A0993
+P06935514A0000
+P09736715A0729
+P11478627A0573
+BC2GM041011754
+P10852485A0477
+P08223875A0711
+BC2GM003734508
+P11152070A0573
+P11129515A0000
+P01398068A0948
+BC2GM084639431
+P08873159A0791
+P11562870A0892
+P03651840A0266
+P10725017A0673
+P10628971A0824
+P02148508A0374
+P11522431A0673
+P03038891A0935
+P09177857A0000
+P00958550T0001
+BC2GM095197069
+P08332495A0408
+P09169420A0000
+P11152521A0181
+BC2GM097589583
+BC2GM075443045
+BC2GM026957766
+P10810083A1283
+P09790771A1032
+P07876210A0275
+BC2GM023811799
+BC2GM031585190
+P11095981A0254
+P04082592T0000
+BC2GM014154951
+P10733581A1391
+P09446600A0260
+P07798271A0330
+P03016883A0000
+P07670943A0308
+P08289339A0527
+P08291620A0372
+BC2GM044117466
+P09227332A1798
+BC2GM073223559
+BC2GM040147994
+P03025606T0000
+P11340516A0509
+BC2GM007746647
+P02598034A0000
+P08621453A0815
+P11336211A0132
+BC2GM056384922
+P02030910A0000
+P01873999A0000
+P04544704T0001
+P09463380A1050
+BC2GM078540680
+P02264601A0000
+P02307848T0042
+P11555669A0983
+P04757217T0000
+P09765394A1590
+BC2GM018887080
+P03223123T0001
+P09369451A0693
+P08570615T0000
+BC2GM050682340
+P07075438T0000
+P01432453T0000
+P03830147A0000
+P09645576A0148
+P07298523T0000
+BC2GM023106158
+P08034708A0000
+BC2GM095548936
+P07748493A1045
+BC2GM047037521
+BC2GM023971804
+P07607197A1048
+BC2GM003985442
+P09524222A1113
+P08463485T0000
+P08115744A0846
+BC2GM091729767
+P09877417A0704
+P07636408T0000
+P01865010A0000
+P04350410T0000
+P04088936T0001
+P01265887T0001
+P08700531A1420
+P02971603A0883
+P09456312A1064
+BC2GM011710885
+P07984088A0592
+BC2GM040336555
+P11180027A1306
+BC2GM079052068
+P08675395A0751
+P07592946A0997
+P05942953T0049
+P11106216A0918
+P10958673A0142
+BC2GM051391908
+P01325386A0766
+P00637637T0000
+P10753553T0000
+BC2GM037509935
+P00931089T0001
+P11238916A0838
+P03779205A0459
+P10694511A0570
+P00097989A0106
+P10866677A1839
+BC2GM026058529
+P07702378A0668
+P02119530T0000
+BC2GM087511042
+P08576042A0765
+P03360948A0477
+P03049570A1242
+P01682509A0539
+P01552052A0139
+P08429019A2022
+BC2GM018877680
+P06111283T0032
+P07862533A0000
+P01752792A0000
+P09338414A0430
+P09613946A0194
+BC2GM002651672
+P08505075A0236
+BC2GM012196374
+P09911328T0000
+P10881275T0000
+P02123877A1452
+P02805945A0000
+P01398140A0488
+P10611320A0816
+P01991521A0481
+P10882850A0000
+BC2GM005891745
+P03209019A0662
+P03610663A0201
+P07949137A0000
+P10371097A0963
+BC2GM075161698
+P08381121A0773
+P08649425T0000
+P07888156A0169
+BC2GM009914955
+BC2GM098731910
+BC2GM097574601
+P11787322X0001
+P09335608T0000
+P02125016A0145
+P02793620A0214
+P07575438A1409
+P09301350A0946
+P07766885A0405
+P08822208A1364
+BC2GM020223301
+P11786945A0958
+BC2GM070088556
+P06096380A0662
+P09681822A0520
+P11266194A0743
+BC2GM056914428
+P11074210A0623
+P08647086T0000
+P01451771A0619
+P07113365A0737
+BC2GM025716724
+P09238850A2042
+P02792430A0000
+BC2GM020742355
+P08631817T0000
+P02862656T0000
+P03555318T0000
+P09028998A0143
+P07967360A1048
+P10729151A1160
+P08496848A0692
+P02473907A1338
+P08331728A0686
+P08528796A1470
+P02162467A0311
+P11370174A0447
+P02172672T0001
+P08648665A1320
+P02069873X0000
+P08269424A0339
+P08300527T0000
+BC2GM089767540
+P09423968A0039
+P09050849A1459
+P01688972A0803
+P07916729T0000
+P01658356T0000
+P10749166A0991
+P07249895A0177
+P01413984A0737
+P02012097T0000
+P11031773A0174
+P08967963A1735
+BC2GM054122511
+P00589073A0000
+BC2GM037459381
+P10576177A0308
+P03896991T0000
+P08647451A0663
+BC2GM051237837
+P01036714A0072
+BC2GM049290595
+P00261981A0434
+P07653812T0000
+BC2GM006956250
+BC2GM087933545
+P10591990A0178
+P04114211T0000
+BC2GM055613257
+BC2GM043720007
+P09420234A0654
+P11554566A0833
+P07569640A0539
+P00331128A0000
+P10657658A0165
+P02073222A0269
+P01917943A0621b
+BC2GM086570767
+P11498795A0716
+P07491305A0102
+P11152344A0416
+P08356792T0000
+P01400401A0065
+P07277222A1391
+P07563090A0124
+P11051364A0890
+P08508861A0294
+P03575656A0120
+BC2GM003994836
+P03377891A0652
+P08862522A0690
+P09006936T0000
+BC2GM001365084
+P01459921A0000
+P02810911A0372
+P06217859T0000
+P07835273A0411
+P08625987A1086
+BC2GM057332311
+BC2GM081384324
+P03133250A0000
+P11012671A0576
+P03420466A0000
+P07944542T0000
+BC2GM005821288
+P03097643A1357
+P09111004A0732
+P02485188A0415
+P11287555A1057
+P11505407A0461
+P11560509T0000
+P07949137A0532
+P07622521A0418
+P09504553T0000
+BC2GM002489529
+BC2GM097830096
+BC2GM035217555
+P03172863T0000
+P02590391A0442
+P08620889A0771
+P01480183A0000
+P06588306A0076
+P10764574A0718
+BC2GM042573806
+BC2GM055154765
+P09794795A0183
+P09414319A1442
+P10767251A1046
+P09061698A0177
+P02113901A0000
+P11533340A1285
+P10706513A0843
+P08881542T0000
+P02234345A0215
+P06856669A1004
+P05133723T0000
+BC2GM044153984
+BC2GM010367775
+BC2GM083218556
+BC2GM020542705
+P07927267T0000
+P09804779A0000
+P11024182A0781
+P08620856A1172
+BC2GM017907484
+P09652742A0455
+BC2GM079928665
+P09620873A1710
+P07702808A0427
+BC2GM013293084
+P02062116A0688
+BC2GM072306591
+P03504971A0000
+P09314554A0149
+P11148042A1258
+P01542730A1982
+P08106398A1003
+P09079638A0883
+P09328349A1679
+P07746397A0233
+P06198241A0209
+P08959062A0372
+P06084279A0218
+P10987280A0604
+BC2GM021740420
+P08721526A0000
+P09556573A1062
+BC2GM019410354
+P01012904A0333
+P08528479A0000
+P09575187A1558
+P08300463A0581
+BC2GM065583903
+P02459309T0000
+P09258439A1001
+P04970918T0069
+P09695194T0000
+P11560992A1184
+P02507815A0000
+P07853488T0000
+P11341405A0146
+P10825293T0000
+P08903339A0264
+BC2GM057358124
+P09822661T0073
+P01403222A0391
+P09336455A0000
+P09126487A1399
+P08064351A1020
+BC2GM036498049
+P06750608A1442
+BC2GM005749359
+P11007961A0930
+BC2GM006599822
+P08974103A0451
+P02012789A0051
+P08795304T0000
+P09287352A0930
+P00836637A0000
+BC2GM063229471
+P00476572A0139
+BC2GM000796681
+P07876194T0000
+P02577867T0000
+BC2GM048811705
+P09032267A0850
+P07776882A0000
+P07143347T0000
+P11054011A1685
+P08910373A0315
+P01862027A0212
+P09714109A0000
+P07107287A1083
+BC2GM099320794
+P05124707T0001
+P02655381A0000
+BC2GM057965554
+P08625806A0263
+P02902844A1219
+P07500597A0212
+BC2GM099940943
+BC2GM026322966
+P08628681A0821
+BC2GM069951819
+BC2GM064060868
+P08665853A0228
+P08583846A0121
+P01156631A0658
+P11427611A0000
+BC2GM085078611
+P07482069A0606
+P11384225A0634
+P02249872A1051
+P09653745A0180
+P09335298A0529
+BC2GM058610750
+P11038042A0948
+P09547311A1394
+BC2GM079526142
+BC2GM022332450
+P01644821A1259
+P08896804A0000
+P09356645A0672
+BC2GM067117543
+BC2GM067919498
+P00219533T0001
+P09631366A0951
+BC2GM037366873
+BC2GM030264277
+P01652515A0379
+P11125872A0133
+P10733880X1783
+P07580782T0000
+P07969115A0000
+P07221179A0156
+P09368097T0000
+P09268578A0225
+P02998043A1199
+P11102367A1170
+P07557446T0000
+P09364440A2206
+BC2GM038333674
+BC2GM068132374
+P08466864A0878
+P11015197A0310
+BC2GM017938095
+BC2GM051315195
+P10766246A0000
+P10594130A0652
+P08190633A0273
+P02233680A1115
+P01934378T0000
+P00614915T0001
+BC2GM079384236
+P07540607A0709
+P07801180A0197
+P11233643A0000
+P09701895A0119
+P10903495A0533
+P09023197T0000
+P11287579A1084
+P07610735A1471
+P08040336A0435
+P10743719A0223
+P01792580A0198
+BC2GM080581742
+P02590869A0743
+P08530107A1003
+P08416952A0956
+BC2GM015513463
+P09081389A1088
+P03601533T0001
+P11278713A1054
+BC2GM067919797
+P09417493A0823
+P10958688A0265
+P08764136A0000
+P11138009A1032
+P11145887A1393
+P09151376A0000
+P01487144A0505
+P02195715A0143
+BC2GM085145891
+P01844982A0324
+BC2GM004396231
+P09819507A0000
+P11030066A0142
+P09282985A0961
+BC2GM049397374
+P09447962A0452
+P01279374A0396
+P07203410T0000
+P07490079T0000
+P08007954A0374
+P03875231A0627
+P02209237A0239
+BC2GM057936039
+P09275164A0000
+BC2GM003408029
+P01518926T0000
+BC2GM089869328
+P10650939A0789
+BC2GM088911039
+P07851643A1365
+P11709890T0000
+P08631685A0000
+P08395004A0558
+P00474064A0205
+P10644753A0725
+P09368057A1083
+BC2GM025882502
+P11062068T0000
+P08139577T0000
+P01945430A0660
+P02762006A0071
+P08927169A0178
+P08102364A0000
+P02509123A0371
+BC2GM047053837
+P00114144A0189
+P07914507A1029
+P08806491A0542
+BC2GM033925563
+P07521601A0000
+BC2GM060812049
+BC2GM076272520
+P02320008A0651
+BC2GM065388195
+BC2GM077588119
+P08595627A1513
+P07932095A0000
+P07559430A0909
+P07791763T0000
+BC2GM051097875
+BC2GM059704173
+P01312005A0600
+BC2GM005174218
+P07765118A0967
+P07760790A0327
+P05595036T0001
+P02290216T0001
+BC2GM022393515
+P09062130A0116
+P02131902A0000
+P11435428A0000
+P03421425A0878
+BC2GM064675128
+BC2GM044133796
+P07651131A1407
+BC2GM004225569
+P09596536A0219
+P05774062T0000
+P08683108A1501
+P10905352A0000
+P09592219A0652
+P07597488T0000
+P07797583A0222
+P06726257A1179
+P09882489A0451
+P09530251A0766
+BC2GM016356336
+P09819110A0703
+P03746896A0890
+P09325278A0458
+BC2GM093309915
+BC2GM081931379
+P08769132A0000
+P10835485A0941
+P09409774A0214
+P03931797A0134
+P07494306A0240
+BC2GM067166518
+P02518645T0001
+BC2GM040451160
+P08391534A0828
+P05496619T0000
+P09084174A0667
+P08673026T0000
+P10913172A0442
+BC2GM069558891
+P01890989A1392
+P08370275A0290
+P03776438A0000
+P07489502A0000
+BC2GM005308134
+P09557682A0490
+P09004304A0000
+P05364951T0001
+P07706299A0563
+P09006902A0370
+P07588633A0362
+P01906111A1295
+P01186344A0303
+P03171279A0158
+BC2GM098133751
+P00975540T0000
+P08419333A0126
+BC2GM071898501
+BC2GM048773311
+P00716366T0001
+P09529216A0644
+BC2GM078276040
+BC2GM079579959
+P08294906A1315
+P02985820A1287
+BC2GM088286294
+BC2GM064870034
+P01567649A0139
+BC2GM004901699
+P07739520A1250
+P09882348A0611
+BC2GM094724499
+P01588963A1153
+BC2GM035996110
+P07516337A1119
+P10900269A0396
+P09025549A0000
+P08798782A0976
+P09038192A0846
+BC2GM020911940
+BC2GM044080615
+P10760109A1050
+BC2GM053252394
+P08975532T0001
+P01474990A0000
+BC2GM032527280
+P09581775A0185
+P02960012A0838
+P10688663A0207
+P10913276A0684
+P02890200T0001
+P04992478T0000
+BC2GM011390376
+P08610582A0150
+BC2GM032470094
+P08750190A0000
+BC2GM060582381
+BC2GM036409328
+P01692837A0390
+P11687083A0218
+P02925568A0460
+BC2GM083470342
+P04407649T0000
+P09784245T0000
+P08045834A0783
+P03178626A0137
+BC2GM033817811
+P10671554A0492
+BC2GM015678949
+P10846069T0000
+P10794936A0241
+P09111340A0240
+BC2GM099407743
+P09823561T0001
+BC2GM069407837
+BC2GM005391893
+P09091125A0161
+P11340048A0432
+P08655497A0000
+BC2GM076429520
+P09770686A0484
+BC2GM034188692
+P08921387A1182
+P03371806A0000
+P10585808A0000
+BC2GM048437284
+P10671224A0254
+P05417431T0001
+P02575959A0643
+P11042204A0186
+BC2GM084752921
+BC2GM050148188
+BC2GM070361623
+P09817190A0074
+P02190134A0572
+BC2GM018048012
+P08051151A0347
+BC2GM023199646
+P08768377A1387
+BC2GM085015084
+P09420275A1111
+BC2GM084593857
+P00733067A0188
+P01625527A0000
+P09171235A0851
+P08261398A0838
+BC2GM037435242
+P06298014A0647
+P01905199A0210
+BC2GM003217917
+P05837169T0001
+P07828600A0095
+P08225657A0000
+P07136524A0180
+BC2GM033154318
+BC2GM058412492
+P03317796A0853
+BC2GM004581999
+P01654349A0327
+P08586643A0951
+P10770041A0731
+BC2GM073208468
+P09094093A0578
+P04803629T0001
+P10961046A0342
+BC2GM047630047
+P08166402A0631
+P10805390A0340
+BC2GM072421473
+BC2GM069147613
+P06713200A0630
+P01782982A0155
+P08727992A0570
+P07906265A0897
+P11231287A0158
+P01454518A0336
+P06593862T0001
+P08054281A0731
+P00741476A0000
+P09733815T0000
+P08497280A1397
+P08585324A0467
+BC2GM070276124
+P09773981A0415b
+BC2GM023793226
+P09012636A0723
+BC2GM099658397
+P09642042A0646
+P00331936T0000
+P04613073T0001
+BC2GM034695488
+BC2GM018703043
+P09917391A0380
+P11246887A0000
+P02813404T0000
+P04394290T0000
+P07720572A0701
+BC2GM018602202
+P01727488A1146
+P10785294A0720
+P01448932T0000
+P10684660A1266
+P10857215A0000
+P09716183A1036
+P07926748A0383
+BC2GM010069099
+P05892712T0034
+BC2GM037434431
+P11000266T0000
+P07172690A0547
+BC2GM066604493
+P07607233A0186
+P09211913A0000
+P02792270A1220
+BC2GM044150575
+P08289793A1226
+P02005547A0121
+P08776748T0000
+BC2GM000570200
+P09268638A0332
+P09545293A0590
+P09436657A0303
+P10727426A1280
+P06328485A0277
+P11687352A0215
+P09286115T0000
+P02527365T0000
+P09739913A0194
+P11103601T0025
+P09535892A0000
+P08876167A0322
+P11449014A0000
+P07559510A0000
+P11872359A0000
+P07106534A0160
+P02826717A0179
+P08455623A0630
+BC2GM016660026
+P02811378A0250
+P07563090A0624
+BC2GM014858349
+P08263933T0000
+P03923976T0001
+P09965909T0000
+P08636031A1413
+P04063732A0509
+P01202616A0466
+P10673426A0168
+P10885731A0915
+P00594466T0001
+P09524259A0301
+P09880327A0322
+BC2GM056924608
+BC2GM002647660
+P02307848A0347
+BC2GM063598630
+P02162754A0339
+P07559650A0558
+BC2GM086837323
+P07501458A0578
+BC2GM038397641
+P09891061A1240
+BC2GM000828997
+BC2GM015782693
+P10891286A0000
+P09368026A0435
+BC2GM040660386
+BC2GM053748645
+P08144470A0711
+BC2GM028930096
+BC2GM013781370
+P11416393A0000
+P09774450A0000
+BC2GM088697037
+BC2GM047020001
+P08125337A0940
+BC2GM083452156
+P08851434A0383
+P11108616A0000
+P09395525A0395
+P00352569A0000
+P10598316A1534
+BC2GM052334866
+BC2GM077438111
+P00929418T0001
+P07595857A0521
+P07644503A0729
+BC2GM050603433
+P03420266A0000
+P08723352A0084
+P09237862A0782
+BC2GM085654782
+P08915508A0000
+P01851527T0000
+BC2GM034218044
+P09827993A0000
+P01857326A0160
+P08093450A0688
+BC2GM028962502
+P04025179A0955
+P07935472A0790
+P07966602A0130
+P09988767A1496
+P00321261A0104
+P10564479A0384
+P09371626A1345
+P02934778A0702
+BC2GM076960951
+P02092131T0000
+P02574052A0910
+P09528784A0000
+P08756556A0406
+P03799323A0501
+BC2GM009739613
+P09725292A1473
+P03673881A0000
+P07681539A0000
+BC2GM020995115
+P09218775A0000
+P08226956A1397
+BC2GM010137266
+BC2GM090258989
+P11431348A0000
+P08663127A0697
+BC2GM050016393
+P09774444A0351
+P09473755A0318
+P08794869A0274
+P08730470A0000
+P01429714A0730
+P01587267A1144
+BC2GM087481968
+P08107167A0222
+P09278494A0762
+P09606924T0000
+P07376165T0001
+P09599664A0881
+P10780518A1270
+P09111309A0674
+P09754571A1257
+BC2GM066438188
+BC2GM059465323
+P01903841A0125
+P03487348A0000
+P01378431A0202
+P08704240A1111
+P09032259A0972
+P02873593A0581
+P08917696A0485
+P08848052A0733
+P03449358T0001
+P05792911T0000
+BC2GM031611293
+P07500953A0305
+P11084556T0000
+P02997777A0609
+P03331933T0048
+P11415958A0000
+P08499916A0000
+P06384983T0000
+BC2GM084651011
+P09042269A1007
+P07815811A1487b
+P09541636T0000
+P08986214A0000
+BC2GM030303279
+BC2GM053432792
+P10913094A0424
+BC2GM098818949
+BC2GM030055087
+BC2GM069768430
+P09515924A0104
+BC2GM007595336
+P07221354T0000
+P09065463A1012
+BC2GM021493197
+BC2GM024081433
+P01769189A0000
+P09169475A0772
+P01512941A0000
+P07568026A0622
+P02019572A0000
+P11007777A0813
+P01441818T0001
+P09671313A0334
+P10811079A1277
+P03407676A0585
+P06097027A0000
+P09573378A0761
+P10002245T0000
+BC2GM098791019
+P11011139A0000
+P11071789T0000
+P08249390A0111
+P01899209A0883
+P11391303A1023
+P07650958A0123
+P08650818A0000
+P00540707A0255
+P08776901A0000
+P09099702A0000
+P02528730A1073
+P02767733A0690
+P08824798A0761
+P11112790A0989
+P11773921A0397
+P09737453A0557
+P03146017A0983
+P10696007A1325
+BC2GM052040080
+P09819038A0448
+BC2GM009567777
+P01372456A0426
+BC2GM040359047
+P02306539T0000
+P02315472A0583
+P10550571A0000
+BC2GM032519240
+P08300611A0341
+BC2GM094961159
+P01814182A0000
+P01615493A0975
+P05890351T0001
+P02123029A0478
+P01285807A0365
+P10655164A0546
+P01658356A1369
+BC2GM094617831
+BC2GM014061737
+P09961682T0000
+P09447962A1027
+P08530432A0093
+P03184267A0000
+P01174873T0000
+P07676587T0000
+P08204426T0001
+P07596287A0183
+P09050689A0685
+P03871445T0000
+P07711730A0000
+P10775038A0142
+BC2GM018332132
+P01765375A0290
+P06986168A0304
+P02047597A0149
+P00871237A0601
+P11327292A0190
+BC2GM056070197
+P05525652T0064
+P02348225A0192
+P11350175A0173
+BC2GM096948473
+P02632904A0619
+P02595451A1136
+P11312584X1846
+P09763470A1756
+P02123293A0227
+BC2GM023763281
+BC2GM081648973
+P08075070A1632
+BC2GM082079771
+P08692885A0663
+P03258069A0000
+BC2GM017195618
+P09601921A0000
+P02848842A0643
+P07565720A0256
+BC2GM030760863
+P10572866A0481
+P07739382A0457
+P02549036A0000
+P06858449A0335
+BC2GM022444174
+BC2GM016623296
+P11150439A0701
+P10775623A0120
+P07878029A0721
+P09722043A2070
+P06816053A0849
+BC2GM048894159
+BC2GM011438021
+P07592439A0000
+P11723500X0000
+P10848993A0000
+P09421516A1516
+P07567979A1266
+P07913926A0878
+BC2GM022531495
+P02767166A0368
+P01776715A0489
+P09232593A0946
+BC2GM088211733
+P04176625T0000
+BC2GM072719765
+BC2GM015438826
+P03818866A0116
+P09499254A1309
+P11207216A0296
+BC2GM067940878
+P07886610A0000
+BC2GM027086451
+BC2GM031481247
+BC2GM058404635
+P09583208A0171
+BC2GM089563862
+P08153146A0327
+P08412620A0688
+BC2GM022481867
+P07436459A0245
+BC2GM095436717
+P09315651T0000
+BC2GM010707671
+P06588501T0059
+BC2GM003643024
+BC2GM050923022
+BC2GM063827916
+P00989973A0000
+P00665214A0374
+BC2GM049472280
+P09667795A0000
+P08977235A0588
+P11357063A0138
+P09029091A0881
+P11266615A0258
+P09168892A1016
+P10747782A0390
+P06726257T0000
+BC2GM050680877
+BC2GM012221483
+P02645431A1562
+BC2GM056273356
+P11063169T0000
+BC2GM025168893
+P11383860A0661
+BC2GM053940831
+P03292076A0820
+P11502738A1457
+BC2GM098953976
+P06136374A0151
+P05466177T0001
+P08595878A0201
+BC2GM081593003
+P08749393A0783
+P10928179A0101
+P01548756A1102
+P06754662T0001
+P09947191T0000
+P10861086A0259
+P09080250A0212
+P03036933A0774
+P08839832A0729
+P08604338A0885
+P08972211A0059
+BC2GM011499496
+P08918934A0424
+BC2GM096590375
+P07535768A1076
+P08393143A1281
+BC2GM006714669
+P07521009A0377
+P07663998T0000
+P08894144A1173
+P01310154A0879
+P02506740A0742
+BC2GM067993736
+P11152451A0529
+P01280413T0001
+P00150066A0554
+P08896280A0860
+P01993181T0000
+BC2GM018615629
+P06656249T0000
+P10591976A0317
+P01878489A0959
+P03025655T0000
+P08499376A0000
+P09226113A0857
+BC2GM054126156
+P09583823A0238
+P00264240A1843
+P05621339T0001
+BC2GM029364330
+P10556263A1035
+BC2GM051724994
+P11157879A0192
+P07748848A0263
+P08818718A1229
+BC2GM037686534
+P06815368A0203
+P10673335X0782
+P10132730T0000
+P10891399A1185
+P02217741T0001
+BC2GM087589281
+P01399206A0375
+P00863773T0000
+P09050849A0000
+P11138231T0000
+P07542764A0497
+BC2GM066302060
+BC2GM032903217
+BC2GM094089829
+P08226776A0990
+BC2GM037059835
+P11256845A0340
+P09379301A2036
+P08417349A1633
+BC2GM067397943
+P09301114A0573
+P02761008X0000
+P01678392A0648
+BC2GM000667374
+P10561251A0000
+P10551848A0000
+P09068989T0000
+P11432112A0000
+P08460918A0252
+BC2GM015319491
+BC2GM059332523
+BC2GM000462914
+P11202434T0000
+BC2GM084545112
+P03780248A0274
+P07753796A0743
+P03334950A0000
+P08413186A1199
+P09400613A1209
+BC2GM030561421
+P11086872A0000
+P08754852A0960
+P08664667A0093
+BC2GM014747695
+P10611228A1388
+P09655916A0415
+P04311951T0001
+P02685565A0165
+BC2GM004916804
+BC2GM020495057
+BC2GM032501279
+P02580830A1131
+P06781728A0690
+P11084649A0497
+P01791754T0000
+P11495833T0000
+P07588608A1687
+P01398073A0986
+P02834478A0000
+P09412079T0001
+BC2GM080374905
+P09693134A0782
+P08726247A0175
+P09229420A0158
+P10828751A2258
+P07490278A0799
+P02349998A0297
+BC2GM017503197
+P08192451A0885
+P09780336A0771
+P08443339A1374
+BC2GM003959017
+P07184774T0000
+BC2GM086777586
+P09229595A0618
+BC2GM071999397
+P10402467T0000
+P07789396A0504
+P08508778A0112
+P04733391T0000
+P11113179A1020
+P09582306T0000
+P06740919A0162
+P08457291A0170
+BC2GM005475872
+BC2GM074709129
+BC2GM086467089
+P02744490A0894
+P11431472A0540
+BC2GM034609463
+P09294139A0729
+BC2GM080331933
+P09795341A0806
+P03607109A0370
+P02692881A0354
+BC2GM000534680
+P05763287T0063
+P08632779A0351
+P07642544A0868
+P11145571A0788
+P10607566A0880
+BC2GM067528741
+P00201881A0487
+P02247069A0261
+P08980522A0280
+P01211754A0192
+BC2GM024059771
+P07564210A0557
+P07565797A0116
+P09696819A0450
+P10896008A0531
+BC2GM094704292
+P02987220A0472
+P08589358A0235
+P07808210A1510
+P04621188T0000
+P08974135A0052
+BC2GM039101947
+P07917540A0000
+BC2GM096497535
+BC2GM079563549
+P08647091A0592
+P07878040A0505
+P09211934A0722
+BC2GM004875958
+P02016769A0720
+BC2GM072766443
+BC2GM026812413
+P04941419T0000
+P07826412T0112
+P04315233T0128
+P02856622T0001
+P08276865A1188
+P09323366A0299
+P09712898T0000
+P08220494A0231
+P10692374A1873
+P08522511A1250
+BC2GM094104412
+P10041728T0000
+P08598449A0784
+P08780339A0142
+BC2GM091513023
+P01662794A0640
+P09618475A0747
+P08595414A0000
+BC2GM004874774
+P08566754A0783
+BC2GM026246927
+P00113657A0628
+BC2GM004527593
+P08078416A0581
+P06972179A0556
+P07644127A0000
+P09193077A0000
+P08955136A0606
+BC2GM047538840
+BC2GM061678141
+P10679922A1110
+P03257146A1037
+P09185183T0000
+BC2GM058485418
+P00055040A0000
+BC2GM000487648
+P10918164A0878
+P11139473A0696
+P01360180A1568
+P08923460A0565
+P03722016A0797
+P06858640A0262
+BC2GM041159775
+BC2GM028962331
+P08065366A0918
+P11368914T0071
+P03476002A0148
+BC2GM071696836
+P10938102T0000
+P09920903A1045
+P02187871T0000
+P01298173A0153
+P09011744A0790
+BC2GM002830287
+P03180595A1040
+P03440780A0779
+P11108720A0124
+BC2GM005914798
+P08097666A1135
+P07948129A0297
+P09987176A0260
+P11438666A0555
+P01922082A0149
+P03556834T0000
+BC2GM078534924
+P07434431A0203
+BC2GM008579133
+P09212063A0425
+P09799362A1463
+P09208214A0572
+P06349364A1051
+P09770241A0000
+BC2GM051338650
+P11279038A0194
+P03027905A0632
+P03749226A0506
+P02330041A0335
+P01844017A0410
+BC2GM017509191
+P10918572A1547
+BC2GM055697926
+P10628971A1165
+P08702936A0984
+P03795488A0487
+BC2GM013042173
+P09784192A1027
+P09535835A0279
+P09852005A1287
+BC2GM020106641
+P01682484A0680
+P09294452A2107
+BC2GM057409363
+P07663138A0835
+P01547957A1083
+P02194972T0000
+P02991060A0465
+P08380736A0895
+P00920381T0000
+P10823630A1124
+P06473219T0000
+BC2GM076746345
+P09763446A0000
+BC2GM011526436
+P11278310A1516
+BC2GM005335832
+P07655505A0527
+P08917435A0481
+P08253387A0801
+P02554310A0419
+P10637230A0332
+P02371517A0747
+P11331596A0710
+P07798217T0095
+P10585311A0494
+P05000171T0000
+P04031488A1091
+P08919289A0402
+P00583522T0001
+P09121774T0000
+BC2GM035459552
+P02783181A0000
+BC2GM089582706
+P01448107A0361
+P08686381A0527
+P08148756A0358
+P07537267A2094
+P11298326A0677
+BC2GM014046465
+P07116962A0299
+BC2GM046530898
+P10809233A0606
+P10965830A0305
+P08407784A0850
+P09143328A1002
+P03132498A0730
+P09464248A0289
+BC2GM046642250
+P09813041A1122
+P09832436T0000
+P09846033A0488
+P03041046A0127
+BC2GM088022090
+P08065368A0839
+P01145884T0028
+P09051656A0390
+BC2GM091752131
+P09776360A1781
+P07798217T0000
+P02892762A0296
+P08688556A0242
+P08104189A1168
+P05750950T0001
+P02154474A1504
+P02038784A0317
+P08163528T0000
+BC2GM043473136
+P04820791T0001
+P01882240A0526
+P08892757T0000
+P07601445A0207
+P09995847T0000
+P01370281A0461
+BC2GM003613157
+BC2GM025160880
+P06891051A0587
+BC2GM028865518
+BC2GM013853953
+P01374392A0341
+BC2GM011289618
+P07428037A0989
+BC2GM082967002
+P08525186A0288
+BC2GM043891105
+P10666238A1322
+P10869465A1054
+P02814182A1211
+P07960608A0228
+P10568728A1445
+P03351478A0371
+BC2GM061319668
+P01907941A0275
+P01662609A0398
+BC2GM074517332
+BC2GM079255764
+P09393717A1517
+P09188699A1388
+BC2GM013877363
+BC2GM049346947
+P09827878A0091
+P09362480A0452
+P00656008T0000
+P00010943A0733
+BC2GM076572185
+BC2GM083937971
+P09813635A0678
+P09346938A1680
+P09251843A0189
+BC2GM059318256
+P06175691T0000
+BC2GM064306495
+P06662623A0124
+P09278445T0000
+BC2GM028069237
+BC2GM015350935
+P11801459T0000
+P08803845A0665
+P04852635T0000
+P09544991A0750
+P01656220T0000
+P08194753A0157
+P08112870A0484
+BC2GM063978181
+P09148929A0372
+P03292082A0486
+P09666103A0496
+BC2GM057597725
+P10713083A0170
+P07571953T0000
+P09529649A0307
+P11314373T0000
+P08524036A0747
+P10102000A1206
+P00119339A0400
+P07604047A0704
+P07693975T0000
+BC2GM089468953
+P08707846A2308
+P08082440A0339a
+BC2GM044661165
+BC2GM032479556
+P09290207A0731
+P08187085A0086
+P01823520A0183
+P08798635A0870
+BC2GM087975149
+P11268459A0167
+P06828396A0095
+P01762053A0557
+P11459794A1172
+P11157334A1107
+P11341828A0744
+P07959953A0423
+P01522699A0092
+P09579808A0000
+P08576546A0975
+P09797456A0000
+P09423856A1098
+P09590294A0453
+P00915090A0536
+BC2GM004666921
+P11160656A0000
+P10679649A0311
+P01310178A0876
+BC2GM021619038
+BC2GM092572255
+P02088781A0653
+P01228258A0000
+P09387999A1053
+P03629973A0240
+P03586925T0001
+P01626631A0557
+P00911590T0000
+P11585856A0285
+P11187016T0000
+P09819421A0000
+P09868412A1628
+P10679781A1183
+P10959676A0200
+P09169127A0371
+P08459012T0000
+P06141764A0339
+P08917270A0229
+P11821098A0269
+P01176905A0094
+P06938948T0001
+P07745685A1442
+P11003669A0000
+P08187088A0530
+P02839716A0673
+P11278583A0873
+P00947327A0000
+P06198532A0982
+P11292335A0852
+BC2GM024572595
+BC2GM060268532
+P08552670A0665
+P11274368A0818
+P03001084A0406
+P11368787A0180
+P07780148A1153
+BC2GM060814876
+P02702849A0418
+P02022188A0112
+P02110145T0000
+P02813369A0390
+P01842867A0696
+P01531632A0000
+BC2GM073122143
+BC2GM045006907
+P09649501A0358
+P07865895A0896
+P06454625A0000
+P08798420A0207
+P07963540A0795
+P11158456A0223
+P09061697T0000
+P05536803T0001
+P11413641A0373
+P02550682A0411
+P07542698A0137
+BC2GM091983873
+BC2GM065898705
+BC2GM067657042
+BC2GM060307457
+BC2GM046025995
+P07985305T0001
+P09128730A0000
+BC2GM032693967
+P07397066T0000
+P10622576A0552
+BC2GM089850642
+P00074758T0000
+BC2GM092872868
+P11181564A0733
+BC2GM047517578
+BC2GM071413005
+P09577365A0747
+P10821836A0842
+BC2GM044964847
+BC2GM015891432
+P02968055A0984
+P09031639A0474
+P08413186A0077
+P07293327T0001
+P09396402A0264
+P08154171A0649
+P09418872A0417
+BC2GM068680235
+P08394019A0695
+BC2GM045792980
+P11029700A0295
+P07526609A0736
+P07505349A0702
+P05901778T0000
+P02849759A0865
+P08069427T0000
+P07963782A0000
+BC2GM002401623
+BC2GM036087490
+BC2GM087357752
+P02477373A0930
+P09454719A0181
+P08740416A0919
+BC2GM033901476
+BC2GM051860407
+BC2GM026047963
+P07977648A0880
+P02481230A1258
+P08264591A1190
+P09480831A0272
+BC2GM066240715
+P03139750A0000
+P00729003A1182
+P09447917A0000
+BC2GM099460087
+P11552724A0527
+P07823919A1422
+P04145244T0000
+P09442080A0856
+BC2GM050815443
+P02427812A0865
+BC2GM051891413
+BC2GM089723467
+P09424012A1774
+P11347201X0001
+P06258699T0000
+P10857215A0806
+P03874921A0862
+BC2GM033756854
+BC2GM093097670
+P10637149A0806
+P09824021A1263
+BC2GM037692816
+BC2GM073635511
+BC2GM011492237
+BC2GM090935032
+P02918474A0817
+P09314570A0153
+BC2GM095844038
+P01122015A0467
+BC2GM027491434
+P01939906A0233
+P08246984A0512
+P03668396A0171
+P00992316A0178
+BC2GM007788205
+P01279197T0000
+P11570820T0000
+P00411465A0142
+P01333317A1008
+P09419415A0236
+P02243093A0000
+BC2GM053136580
+P09396437A0878
+P07678006A0472
+P08805824A1155
+P08831364A1252
+P02496090A0252
+P01325221A0870
+P07653892A0306
+P09167421A0234
+P00112627A0542
+BC2GM087530510
+P03682805A0375
+P08100765A0361
+BC2GM050589731
+BC2GM013941232
+P08518797T0000
+P08794363A0259
+P07525843A0859
+P09505135A0182
+P08496475T0000
+BC2GM027554175
+P11789206A1182
+P10782989A0575
+P00481612A1121
+BC2GM083150371
+P10758289A0141
+BC2GM050874395
+P09553040A0651
+P08049521T0000
+P01923628T0001
+P06354594A0114
+P02970640A0341
+P06823837A0562
+P10850719A0680
+P04794218T0001
+BC2GM069902375
+BC2GM016797236
+P02398897A0000
+P08816052A0238
+BC2GM041430420
+P07682842A0771
+P03282813A0794
+BC2GM071513043
+P02519679T0000
+P09328476A0374
+P01512259A0867
+P00736376A0371
+P02868848A0167
+P02115115A1053
+P07995910A0119
+P06795119T0000
+P04546974T0000
+P08438584T0000
+P08670556A0425
+P01901664T0064
+BC2GM053139054
+P02820128A1670
+P07824657A1456
+P02289639A0989
+P09073582A0444
+P10983857A0923
+P09417870A0105
+P10963735A0651
+P11376687A0344
+P08355857A1293
+P09531559A1153
+BC2GM079401550
+P08876701A0177
+P06287737A0477
+P07744763A0514
+P11127955X0001
+P09049198A0289
+P08823646A1012
+P03040023A0113
+P03278829A0082
+P03628532A0000
+P09065768A0862
+BC2GM091384124
+P07590268A0740
+P08196618A0473
+P11361338A0093
+P08605705A0676
+BC2GM023754004
+P11037759T0000
+P01970984A0668
+P08914388A1645
+P01103390A0149
+P11014821T0000
+BC2GM042145005
+P08167555A0972
+BC2GM004529705
+P09150728A0596
+P10997904A1258
+BC2GM087006265
+BC2GM025829397
+BC2GM022846280
+P07761091A0294
+P09668063A0274
+P09396427A1488
+BC2GM035007740
+P09538156A0130
+P00628990A0000
+P09528758T0000
+P02693593A0866
+P01396583A0204
+P08844448A0000
+P09724654A0761
+BC2GM067195317
+P11282029A0075
+P08524267A1022
+P09838122A0489
+P08288606A0240
+P07693672A0259
+P11125411A0857
+P02869125A0120
+P01649539T0000
+P08435885A0787
+P01871033A0434
+P01630454A0635
+BC2GM093691513
+BC2GM070747884
+P08792217A1407
+P01093845A0208
+P04539552T0001
+BC2GM060854323
+P09079915T0000
+BC2GM097083223
+P09115247A2069
+P10954564A1262
+BC2GM043181941
+P00294502T0001
+P09665720A1145
+P09015799T0000
+BC2GM010408815
+P08663141T0000
+P08939966A0816
+BC2GM071024994
+P02217307T0000
+P06837312A0000
+P01469042A0355
+P07784199A0000
+P07491791A0263
+BC2GM035650199
+BC2GM034699530
+P11240600A0523
+P03192799T0000
+P08672242A0517
+BC2GM044659370
+BC2GM059008483
+P06246254A0676
+BC2GM020487228
+P08394862A0565
+P07927838A0000
+P11368363A1103
+P08872671A0573
+BC2GM023722122
+P02370571A0663
+P08023662T0000
+P07844555A0406
+P09694869A0932
+P10972990A0966
+P01425653T0000
+P06684624A0736
+BC2GM012342232
+BC2GM006702465
+P04679807T0000
+P11152963A0000
+BC2GM057108840
+P03840480T0000
+P07969954T0000
+P11406642A0792
+BC2GM000772761
+P10710742T0000
+BC2GM011018907
+P09761711A0000
+P03021088A0135
+P08139539A0446
+P08971721A1314
+BC2GM056026890
+BC2GM095387001
+P01551176A0000
+P01328884T0000
+P08022212A0071
+P09389669A1009
+P07704456A1014
+P09798100A0705
+P07871755A0521
+P08083963A0795
+P01639724A0452
+P07874060A0810
+P09918715A1158
+BC2GM052748917
+P09664033A1204
+P02700977A0444
+BC2GM055386745
+P09819440A0783
+P11279108T0000
+P01339125A0153
+P09223667A0139
+P01130531A0224
+P11408604A1440
+P03366720A1335
+P10392914A0000
+BC2GM005317665
+BC2GM093048431
+P04056218A0463
+P10644357A0935
+P08049401A0428
+P04179445T0036
+P00970320A0000
+BC2GM042831244
+P06740373A0891
+P09755199A0559
+P07280654A0000
+BC2GM009533483
+P03479897A0961
+P07876191A0808
+P05359130T0086
+P02906249A1195
+P11071924A0588
+P10724483A0540
+BC2GM069360294
+P06468565A0000
+P08917449A0000
+BC2GM095870614
+BC2GM084526121
+BC2GM083696051
+BC2GM080153743
+P09390125A0379
+P06764669T0001
+BC2GM074781397
+P10601606A0152
+P08663326A0000
+P07262239T0000
+P08083011A0584
+P02993630A1190
+P09749533A0764
+P01738470A0441
+P08055941A1264
+BC2GM065562233
+P03078268A0529
+P04081425T0016
+P02044975A0380
+P08913974A0533
+P08922384A0466
+P11463834A0606
+P11095248A1523
+P09514962A0841
+P04066274A0265
+BC2GM024417394
+BC2GM078923542
+P09927589T0000
+BC2GM097604426
+P05947377T0001
+BC2GM022402970
+P05718386T0001
+P09581872A0000
+BC2GM097874818
+P09840934A0435
+P03143485A0366
+P03680791A0230
+BC2GM004333942
+P09573202A0900
+P10723723A0781
+P06272844A0000
+P03610674T0000
+P06781339A0501
+BC2GM009570936
+P07579164A0409
+P00431832T0001
+P01206772T0000
+P00232354A0286
+P11303890A0996
+P11238882A0157
+P07235355A0462
+P11302704T0000
+BC2GM093769700
+BC2GM019113426
+P11161793A1033
+BC2GM036637526
+BC2GM094112642
+BC2GM068467868
+BC2GM004818954
+BC2GM052310515
+BC2GM080763421
+P09144770A0906
+P09261178T0000
+P08825636T0000
+P06610347A0581
+P01933614A0406
+P08567717T0000
+BC2GM022720719
+P03110119A0267
+P10773667A0351
+P11134351A1405
+P01714452A0559
+P09808216A0000
+BC2GM081841697
+P03931293A0437
+P06361318A1127
+P07328000T0000
+P09476520A1326
+P00149899T0001
+P07396545A0217
+BC2GM029072102
+BC2GM083317663
+P11179689A0000
+P01644814A0068
+P00863184T0043
+P10823837A1213
+BC2GM002497068
+P09354644A0124
+P02307371A0263
+P11371160A0193
+P09369482A0690
+P02368931A0587
+P09790768A0621
+BC2GM026399698
+P06193351A1010
+P01960974A0000
+P03935117T0000
+P06316347A0852
+BC2GM049034176
+P03050147A1520
+P02876899A0568
+P00029953T0045
+P00725752T0001
+BC2GM030583614
+P09712644T0000
+P09988682T0033
+BC2GM007416400
+P04050821A0531
+BC2GM011571896
+P07835214A0603
+P01662884A1029
+BC2GM026591982
+P03296019T0000
+BC2GM013192574
+P01618243T0000
+P09643153T0000
+P06634712A0557
+BC2GM027526688
+P08505495A0253
+P08021175A0486
+BC2GM019584475
+P11211759A0165
+P08075421A0621a
+BC2GM016410750
+P09426239A0386
+P09135772T0000
+P02056553T0000
+P07623814A1040
+P10757983A0733
+P02779752A0776
+P08206991A0466
+P07925097A1205
+BC2GM065683949
+BC2GM019191435
+P10992299A0745
+BC2GM027793192
+P11374051A0437
+BC2GM059503308
+P02879906A0000
+P09071308A0376
+P10745563A0409
+P08935931A0787
+P09717835A0941
+P09148770A0977
+P11054341A0599
+P08632009A1067
+P06506074A0456
+BC2GM060492967
+P08778700A0476
+P02220102A0271
+BC2GM075340756
+BC2GM057093148
+P07596287A1724
+P08331064A0440
+BC2GM034468940
+P09771555A0499
+P03037334A0932
+P11486032A1261
+P08794339A1162
+P06307099A1005
+BC2GM065423133
+BC2GM064837210
+P10704196A1051
+BC2GM052408999
+BC2GM097108682
+P09698457A0778
+P08938420A0862
+BC2GM083448203
+BC2GM064007116
+P02162835A0989
+P07516597A1017
+P01418834A0987
+BC2GM022663100
+P10701534A0164
+P02799892A0154
+P01569344A0404
+P10205099A0377
+BC2GM046472114
+P07647303T0000
+P11251104A0526
+P11179668A0869
+P08575609A0526
+P08816453A0000
+BC2GM088220160
+BC2GM072477958
+P09858714A1171
+P04085589A0264a
+P00516545T0001
+BC2GM077560209
+P10395911A0288
+P08823187A1020
+P02115121A0000
+BC2GM003040896
+BC2GM050066357
+P08574414A1037
+P03956647A1063
+P10805729A0987
+P10779508T0000
+P02861067A0000
+P02849100A0441
+P09882303A1984
+P11015200A0156
+P08043523A0000
+P08626290T0000
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/bc2gm.conll.train b/huner/ner_scripts/splits/bc2gm.conll.train
new file mode 100644
index 0000000..80dfee6
--- /dev/null
+++ b/huner/ner_scripts/splits/bc2gm.conll.train
@@ -0,0 +1,12000 @@
+BC2GM019414766
+P10191090A0000
+P10375640A0153
+P10450815A0180
+P10498717A1048
+P10358083A0263
+P10430886A0838
+P10487217A0735
+P11860876A0409
+P11793172A0545
+P10026211A0136
+P10384129A0000
+P11824701A0894
+P10544037A0617
+P10488148A1267
+P11836046A0549
+P10072205A0167
+P10374632A0818
+P11815644A0081
+BC2GM014590821
+P10540553A0980
+P10359664A0579
+P10543270A1054
+BC2GM050688193
+P10474898A0629
+P10394919A1058
+P10331875A0523
+P11669281A0653
+P10400593A1084
+P11836303A0518
+P11843252A0907
+P08081293A0078
+P11737056A0680
+BC2GM095955751
+P10448902A0921
+P10409741A0382
+P10330146A0730
+P11775180A0379
+P10194225A1132
+P10551879T0000
+P11859943A0150
+P11911552A0776
+P10521447A1190
+P10748164A1284
+P11724510T0000
+P08435794A0658
+P09990060A0803
+BC2GM019659042
+BC2GM081844353
+P09186056A0514
+P10321158T0000
+P10209031A0832
+P10510295A0606
+P10393910A0705
+P10243927A0000
+P10473623A0081
+P10066790A0497
+P10079173A0000
+P10510379A0105
+P10359575A0317
+P10375718A0000
+P11912677A0281
+P10501936T0000
+P10078876A0000
+P10378989A0000
+BC2GM075862192
+P10407269A0000a
+BC2GM001191968
+P00411465A0417
+BC2GM076616336
+P10498706A1219
+P10219091A0246
+P10698937T0000
+P09468509A0463
+P10082570A0440
+P10502434A0604
+P08628284A0181
+P10194230A0817
+P10377438A0647
+BC2GM018687842
+P10492127A0914
+P08506384A0146
+P05101997T0040
+P10430583A0000
+P10531342A1111
+P10096469T0000
+P10484818A0292
+P11800586A1090
+BC2GM005932533
+P10232078A0552
+P10358138A0672
+P10556046A0328
+P11595840A0000
+P10021333A0674
+P08106512A0522
+P10488147A1176
+P11882054A1250
+P10471721A0141
+P10231026A0253
+P11599079A1040
+P10403839A0140
+P11790897T0000
+P10319320A1022
+P11715079A1016
+P10075415A1178
+P11804100A0365b
+BC2GM035505674
+P01316459A0311
+BC2GM063365941
+P02591993A0000
+P01406630A0545
+P11705093A2016
+P10672899A0078
+P10190324A0000
+P10405635A0374
+BC2GM015390020
+P01710985A0315
+P10376991A0977
+P10411140A0499
+BC2GM006272677
+P11893403A0252
+P10458914A0674
+P10511554T0000
+BC2GM037553498
+P10438627A0885
+P10181397A0641
+P10375107A1138
+P10092847A0455
+P10353073A0118
+P10478848A0331
+P11800878T0000
+P10362652A1456
+P10196127A1059
+P08798641A0400
+P11587514A0758
+P11697760A0000
+P10518956A1212
+P10366722T0000
+P10209119A0076
+P10024498A0783
+P10379942T0000
+P11710685A0994a
+P10541432A0185
+P10087213A0878
+P10340883A1266
+P10491187T0000
+P11709561T0000
+P11840365A0949
+P10898795A0527
+P09192769T0000
+P10430580A0000
+P10350638A0000
+P11875695A0718
+P10541550A0487
+P10556089A0901
+P11736792A0204
+P10070158A0573
+P10452306A0502
+P10318859A0535
+P10426450A1458
+P11678437A0000
+P10231454A0731
+P10477583A0000b
+P10318918A0824
+P11595170A0582
+P10091594A0284
+P10487921A0132
+BC2GM018263888
+P01545787A0345
+P10460171A0842
+P11822790A0907
+P10532354A1374
+P11846187A0894
+P10489680A0927
+P10499357A0439
+P10517675A0809
+P10712618A0181
+BC2GM005637228
+BC2GM088793769
+P10454540A0392
+P10488148T0000
+P11806132A0253
+P09136080A1469
+P10517666A1069
+P10364523A0826
+P11776922A0830
+P10078734A0480
+BC2GM002856642
+P10454561A0594
+P10373507A0680
+P10209021A0212
+P11728771A0187
+P10496388A1956b
+P10094701A0000
+P10072774A0537
+P08662928A1153
+P11853943A0122
+P07565736A2134
+P10087993A0782
+P10225279A0450
+P05161399T0025
+P10364319A0109
+BC2GM026767504
+P10467403A0000
+BC2GM013271145
+P10199539A1353
+P11500377A0518
+P11824801A0661
+P10090535A1194
+P10523674A0000
+P10224257A0079
+P10334888A0960
+P10196248A0482
+P11744953A0878
+P10101198A0632
+P02590278A0540
+P10333526A0459
+P10026784A0929
+P10453371A0640
+P10318900A0637
+P10196318T0000
+P09473317X2131
+P10438924T0000
+P10037576T0000
+P10490816A0000
+P10400794T0000
+P10428294A0227
+P08183915A0000
+P09129147A0644
+P11732417A0571
+P10085120A0000
+P10385384A0654
+P10531360A0958
+P10406465A0589
+P11893767A0356
+P01833185A0547
+P10358080A1114
+P10395378A1198
+P10369625A0942
+P11862350T0000
+P09858619A0356
+P09317131A0000
+P10026824A0309
+P10490955T0000
+P10541865A1301
+P10212426A1067
+P10366559A0605
+P10487753A0788
+BC2GM030124031
+P10331646A0595
+P09317131A1332
+P11160280A1275
+P10529198A0068
+P11599840A0813
+P10523319A0209
+BC2GM088433679
+P11589779T0000
+P10392669A0935
+P11881923A1256
+BC2GM065421759
+P10411139A0887
+P10221820A0902
+P11303027A0954
+P11726413A1756
+P10392903A0889
+P10049775T0000
+P10202006A1266
+P10446998A0955
+P10322629A0198
+P11596104A0614
+P10460015A0465
+P10326221A0531
+P08946166A0568
+P11730182A0984
+P10446998A0375
+P10477597A0126
+P10203611T0000
+P10318806A0918
+P10512699T0000
+P10097932A0915
+P10413607A0085
+P10196597A0510
+P10449072A0560
+P08455611A0000
+P10082585A0512
+P10476970A0542
+P10453006A0000
+P10320480A0451
+P10556044A0913
+P10233885A0899
+P09451016A1037
+P10553551A0000
+P10320177A0487
+BC2GM009964186
+P10390538T0000
+P11597936A0570
+P08970984A0765
+P10506143A0610
+P10347220A1477
+BC2GM014918843
+P08382139A1111
+P10493580A1126
+P10562418A0238
+P11723511A0780
+P10430944A1298
+BC2GM017582406
+P10536369A1280
+P10488088T0000
+P10518937A0572
+P10495573A0365
+P10085505A1184
+P10209759T0000
+BC2GM006324019
+BC2GM020863784
+P10482565A0469
+P10220275A0694
+P10496388A1956a
+P11587980A1039
+P11680835A0756
+P10051400A0000
+P10231862A1117
+P11791571T0000
+P10085605A0239
+P10393422A0476
+P10330396A0387
+P11036939A2149
+P10096573A0207
+P10543727A0282
+P10413662A0193
+P10027498A0536
+P10090943A1976
+P11913427A0290
+P11826141T0000
+P10082554T0000
+P11866130A0419
+BC2GM086763162
+P11737900A0700
+P10516026A0270
+P10049742T0000
+P10670681A0952
+P10077533A0976
+BC2GM090138510
+P10488875A0000
+P11708032A0183
+P11885053A1897
+P11908529A0553
+P10355085A1119
+P10095062A0558
+P10187842A1155
+P11737158A1517
+BC2GM034088457
+P01426109A1837
+P10391903T0000
+P01426635A0496
+BC2GM043332798
+P10406843A1265
+P10029917A0366
+P10359014A1077
+P11899479A0122
+P10037004A0000
+P10449899A0881
+P10478275A1230
+P10391246A0756
+P11708431A0904
+P10092132A0285
+P10395283A0960
+P11685047A0301
+P10497199A0559
+P10380878A0542
+P10453006A0478
+P10406122T0000
+P10512882A0137
+P10098601A1320
+P10022867A1069b
+P10080436T0000
+P10428811A0628
+P10207092A0924
+P10101744A0917
+P10534402A0659
+P10503812A1450
+P11679441A0429
+P11787720A1313
+P10467004A0683
+P10369775A0178
+P08692924A0328
+P10454570A0846
+P11804100A0365a
+P10376065A0881
+P04798293T0029
+P10556145A1034
+P11708362A0889
+P11005831A0242
+P11586096A0699
+P10407269A0000b
+P10406954A0715
+P10423156A0265
+P10458905A0000
+P10153759A0360
+P10037774A0366
+P11810685A0147
+P10086544A0504
+P10090125A0750
+P10205933A0699
+P11718197A1282
+P10488087A0340
+P10383764A1809
+BC2GM005330146
+P10748054T0048
+P10466825T0000
+P10232872A0081
+P11730262A0874
+P10225945A0436
+P10417703A1326
+P10026275A0549
+P08505312A0285
+P10452991A0331
+P10463057A0534
+P10367240A1354
+P10228561A0539
+P11890354A0000
+P10367385A0000
+P10551816A0162
+P11783457A0000
+P11887803A1455
+P10556595A0391
+P10198056A0000
+P10358079A0391
+P09806830X1174
+P10428811A1067
+P10357751A0866
+P10452951A0000
+P10076007A0656
+P11904017A0000
+P10502434A0367
+P10342829A1370
+P10022210A0620
+P11881268A0000
+P10445161A1565
+P01348684A0000
+P11764226A0798
+P11876937A0261
+P11726262A0692
+P10224513A0240
+P10532805A0792
+P11708761A1388
+P10518956A0137
+P10561460A0615
+P10393197A0543
+P11897888A0590
+P10094314A0935
+P10068040A0136
+P10370778A0000
+P10319327A1237
+P10231581A1125
+P11861092A0730
+BC2GM011894137
+BC2GM010461186
+P10430883A0000
+P11895024A1054
+P10215485A0837
+P10022880A0000
+P10344736A0796
+P11595813A0633
+P11707977A0750
+P08709637A1471
+P10428862A0834
+P10102136A0220
+P10102136A0646
+P06778645A0000
+P09223506T0000
+P10217683A0509
+P10226029A0905
+P10542274A1376
+P10430421T0000
+P10588946A0432
+P10419521A0136
+P10208893A0839
+P10366503A1506
+P11863811A0259
+P09032250A0257
+P10445506A0073
+P10333529A0277
+P10553959A0812
+P10330159A1258
+P09343210A1112
+P08944755A0211
+P10212284A0000
+P10364076A0429
+P10095059A1003
+P11816779A0343
+P10066815T0000
+P10074921A1169
+P10025506A0079
+P10366446A0893
+P01851756A0743
+BC2GM029775114
+P10207049A1001
+P10099247A1051
+P11782218A0349
+P10328351A0443
+P10194769A0146
+P10375694T0000
+P10517672A1417
+P10409730A0597
+P10464185T0000
+P11677839A0876
+P10475972A0269
+BC2GM010073598
+BC2GM008918951
+P09794414T0000
+P10544089A1208
+P11600314A0000
+P10477545T0000
+P10393251T0000
+BC2GM026003128
+P10496553A1004
+BC2GM075861735
+P10228157T0000
+P10417331A1008
+P07659529A0135
+P03125420A0421
+P10463242A0316
+P10454533A0859
+P10195425T0000
+P10485353T0000
+P07862168A0000
+P10229668A0190
+P10207049A0693
+P10358031A0303
+P10561153A0225
+P10392900A1020
+P10496284A0115
+P10073947A1110
+BC2GM056590088
+P10349443A0358
+P10502402A0533
+P10094396A0000
+P10372627A0530
+P10022867A1069a
+P11727209A0502
+BC2GM002743419
+P08441379A0912
+P10087993A1352
+P11771979A1141
+P10518502T0000
+P10490822A1167
+P10052878A0135
+P01309587A0715
+P10557008T0000
+P09376325A0167
+P10229084A0000
+P10394116T0000
+P10549354A1782
+P10323463T0000b
+P11693461A1649
+P10367646A0569
+P01986254A0452
+P10353880A0257
+P10400757A0000
+P01827203A0136
+P11584328A0532
+P10402022A0432
+P11785827A0986
+P11828186A0239
+BC2GM038738146
+P10403690A0000
+P11736254A0000
+P11802601A0107
+P10348859A0292
+P10216052A1682
+P11669476A0346
+P10233946A0000
+P10501969A1329
+P10518496A0952
+P09846482A0441
+P10051488A1293
+P10187864A1372
+P10342511A0909
+P03600633A1069
+P10358075A0984
+P10375638A0859
+P11791853A0532
+P09990060A0937
+P10364314A0919
+P10101159A0742
+P10501034A0839
+BC2GM012913597
+P10332733A0000
+BC2GM075291885
+P10490609A0413
+P08985415A1096
+P11684665A0000
+P10098744A0630
+P10036191A0000
+P10459809A1262
+P10077188A1172
+P10446206A0000
+P07605990A1110
+P11775301A0797
+P11768467A0000
+P10549912A0136
+P01695378A1406
+P10483124T0000
+P10400032A0304
+BC2GM091451815
+P10206698A2041
+P10376874A0759
+P10441506A0098
+BC2GM029039601
+P10049357A0608
+P10068834A0713
+P10224244T0000
+P11726574A1304
+BC2GM081756425
+P11723928A0294
+P10617613A1192
+P10457075A1198
+P11704380A1608
+BC2GM054841165
+P10187798A1098
+P10411139A1344
+P10086725A0000
+P10343189A0911
+P09572990A0630
+P11743360A2491
+P10521796A0872
+P10215594A1728
+P10350484A0346
+P10373029A0204
+P10025506A1078
+P01968061A0371
+P10037460A0221
+P10523520A0986
+P10068446A0124
+P10521450A0437
+P10527158T0000
+P08122364A0954
+P11590364A1056
+P07935451T0000
+P10455143T0000
+P11642687T0000
+P10561095A2141
+P10326856T0000
+P10542260A0832
+P10407184A0149
+P10403575A1401
+P11686378A0326
+P10503540A0602
+P10523663A0404
+P10370675A0649
+BC2GM020185752
+P11605598A0785
+P10555079A0254
+P11800119A0814
+P10560014A0000
+P11915436A0491
+P11726068A0539
+P01346534T0000
+P11895184A0000
+P10281637A0000
+P11777632A1678
+P10490639A0000
+BC2GM080507424
+P10339566A0602
+P11885737A1713
+P10069815A0285
+BC2GM043173941
+BC2GM041662908
+BC2GM035707050
+P10523647A1001
+P10212332T0000
+BC2GM089252708
+P10477583A0000a
+P10205176A0000
+P03044592A1061
+P10364425A0610
+P01744042A1355
+P10441449X1212
+P10363517A0401
+P10103002A0705
+P10548434A1549
+P10447593A0144
+P10396343A0754
+P10320579A1831
+P10497874A0925
+P10533066A1197
+P11716441A0585
+P07686619A0704
+BC2GM073260953
+P10446998T0000
+P11886473A0796
+P09920882A0287
+P10454550A0960
+P10091619A0104
+P10323863A0852
+P10540915A0697
+P11500512A0000
+P10516878T0000
+P11578685A0077
+P11899489A0119
+P10429184A0000
+P11858635A0896
+BC2GM024708623
+P10442493A0815
+P10487759A0630
+P10422468A0524
+P10071761A2374
+P10438924A1009
+P10518561A0885
+P10521509A0000
+P10425094A1006
+P10036181A0603
+P01406630A0965
+P10380800A0194
+P11844812A0915
+P10065176A0657
+P11836303A1191
+P02163347A0472
+P11732088A0471
+BC2GM088713745
+BC2GM093016277
+P11687869A0000
+P10556063A0092
+P10073899A0740
+P10192134A1088
+BC2GM065096427
+BC2GM092790663
+P10523647A0000
+P10757975A0509
+P11595176T0000
+P11602353A0770
+P09932288A0378
+P09139721A0183
+P10195690A0000
+P10022858A0985
+P10085088A0918
+P10413604A0063
+P10231513T0000
+P10231485A0342
+P10557308A0000
+P10080875A0772
+P10022925A0870
+P11675912A0131
+P11766747A0000
+BC2GM004506929
+P10487953A0765
+P11884014A0665
+P10446131A0132
+P11706668A0000
+P11600467A1436
+P10439040A0658
+P10381377T0000
+P11579100T0000
+P09279813A1389
+P10487762A0252
+P10215811A0635
+P10361038A0281
+P08455611A0154
+P10385395A0000
+P10206152A1024
+P10216161A1530
+BC2GM019293265
+P10521544T0000
+P10551788A0229
+P11781615A0000
+P10407985A0574
+P10550574A1038
+P11741259A1233
+P11845547A0449
+P11580301A1161
+P10323463T0000a
+P10531334A0525
+P10194451A0000
+P08662928T0000
+P11279217A0273
+P10026146A0680
+P10436016A0337
+P08756617A1204
+P10478844A1604
+P10347203A0832
+P10390158A1150
+P03182802A0278
+P10216052A0105
+P10218200A0534
+P10379942A0956
+P10406462A1127
+P10455183A0930
+P10542281A2021
+BC2GM057764341
+BC2GM051178458
+P10087549A0720
+P11769229A0357
+P11822811A0319
+P11834476A1187
+P07738856A0174
+P10198003A1505
+P07592676A0466
+P10224758A0202
+BC2GM064017613
+P07814403A0433
+P10446149A0809
+P10527426A0521
+P10027904A0768
+P10395908A0236
+P11859400A0229
+P11691585T0000
+P10050883A0967
+P11902781A0550
+P10521447A0606
+P10220364A0087
+P10502402A0129
+P11760796A0698
+BC2GM043622260
+P10068674A0644
+P10403839A1459
+P10359673A0000
+P10074903A0915
+P09837933T0000
+P10687862A1980
+P08183915T0000
+P10516011A0471
+P10215850A0754
+P10540292A1179
+P10223338A1601
+P10440923A0684
+P10497262A0000
+P10202006A0546
+BC2GM075049436
+P10559320A0080
+P10492169A0939
+P11816458A0319
+P10223498A0479
+P10211919A0846
+P11676899A0704
+BC2GM067017397
+P10400785A0912
+P10556751A0758
+BC2GM074512746
+P11596838A1357
+P10226838A1011
+P10527475A0643
+P11860097A1695
+P10557072A1218
+P10526670A1828
+BC2GM024845152
+P10228009A0600
+P10438540A1185
+BC2GM054094309
+P10551796T0000
+P10464310A0218
+P08530384A0559
+P11852907A0871
+P10543949A0686
+BC2GM002300410
+P10051488A1610
+P10428759A0743
+P11851941A0372
+BC2GM035315423
+P10026784A0331
+P10393251A0283
+P10556028A0292
+BC2GM045755791
+P11844591A0329
+P11761601A0133
+P11704829A0312
+P11580173A0181
+P10430980A0465
+P10488129T0058
+BC2GM045303279
+P10029337A0406
+BC2GM083535249
+P10441483A0454
+P10409699A0292
+P11600365A0471
+P10429740A0000
+P10545248A0567
+P10233147A0218
+BC2GM041496183
+P10022978A1261
+P10359603A0430
+BC2GM049191503
+P10073940A0335
+P10385915A1341
+P10435595A0203
+P10221467T0000
+P10524258A0286
+P10544088A0308
+P10369926A0251
+P09341193A0362
+P10207090A0801
+P11687180A3209
+P10322022A0263
+P10229668A0560
+P10228155A1293
+P10559303A0000
+P11778044A0000
+P10392903A0000
+P10414451A0093
+P11792586A0290
+P10542237A0357
+P11847580T0000
+P10542249A0415
+BC2GM079897140
+P11787746A0374
+P10318806A0476
+BC2GM081421874
+P11898018T0000
+P10438941A1197
+P11600252A0795
+P10425445T0000
+P10329586A0414
+P10470220A1011
+P10458907A0543
+P08621451A0552
+P10308312A0203
+P10379547A0000
+BC2GM000365921
+P11778804A0179
+P10082573A1015
+P10562456T0000
+P07635572A1153
+P10427654A0000
+P10224289T0000
+P09837914A0844
+P08683106A0374
+P11687517A1619
+P10319955A0941
+P10024383T0000
+BC2GM079234722
+P10095061A0592
+P11858256A0102
+P09115242A0934
+P07822333A0376
+P10376446A0000
+P10444597A0586
+P10022875A1265
+P10513756A0584
+P10029860A0605
+P10496161A0503
+P10542277A0000
+P10557072A0418
+P10383966A0000
+P10516738A0925
+P10471696A0734
+P10209119A0594
+P09710582A0535
+P11900770T0000
+P10502216A0289
+P10487744T0000
+P10498616A0157
+P10364523T0000
+P08419318A1695
+P10376877A0611
+P10197763A0580
+P11589568A0744
+P10224293A2021
+P10207041A0065
+P08383323A0000
+P10548722A0099
+P10205176A0704
+P10223338A2186
+BC2GM033128498
+P11811825A0972
+P11606538A1002
+BC2GM007417930
+BC2GM056813896
+P10428091A0322
+BC2GM090401322
+P10364163A0092
+P11577094A1226
+P10367460A0191
+P10532805A1084
+P10084294A0219
+P10342829A0236
+P11593394A0000
+BC2GM033438467
+P11909404A0000
+P11804081A0552
+P10471746A1102
+P10234698A0728
+P11865218A0069
+P10359663A0425
+P10400760A0663
+P10491213A0263
+P10215608A0161
+BC2GM033539828
+P10430890A1059
+P09057648A0422
+P10497117A0358
+P02049617A0504
+P10347839A0434
+P10232600T0000
+BC2GM048938799
+P10068637A1320
+P11787041A0167
+BC2GM009274132
+P10536369A0662
+P11882054A0568
+P10469656T0000
+P11711701A0602
+P10388670A1976
+P08332492A0145
+P11604152A0526
+BC2GM058996965
+P10377345A0740
+P10398286A0678
+P11907691A0214
+P10350027A0942
+P11802580A0000
+P10101198A0946
+P10400712A0000
+P10545281A0836
+P10226074A0637
+P10092856A0798
+P10487307A0768
+P10438607A0330
+P10518561A0261
+P10542269A0000
+P10327051A0688
+P10531342A0348
+P10333481A1102
+P10037681A0494
+P10512699A0364
+P10499121A0542
+P11830544A0335
+P11846167A0000
+P10469174A0678
+P10396793A0815
+P10479025A0528
+P10413676A1193
+P10501656A1415
+P10271171A0458
+P10097120T0000
+P10409656A1016
+P11369759A0605
+P10090943A1426
+P10021350A0093
+P10373523A0924
+P11867388A0502
+P10395920A1424
+P07636179A0000
+P10051030A1080
+P10329736A0681
+P10394900A1166
+P10397257A1142
+P11874637A0212
+P10540015A0664
+P10422342A0535
+P10473589A0189
+P10329736A1106
+P11683558A0446
+P11730712A0416
+P07665567A0495
+P10548622A0906
+P10063739A0601
+P10555285A1065
+P09234696A0238
+P09209372A0345
+P03182872A1122
+P10536125A0093
+P11738404A0120
+P10366503A0812
+P10369757A0000
+P11691585A1174
+P10529354A0375
+P10446833T0000
+P07059567T0055
+BC2GM076533289
+P11639485A0478
+P10482516A1158
+P10556033A0000
+P10514493A0199
+P10467465T0000
+P10438950A0580
+P10392710A1000
+P10323225A0244
+P10472836A0189
+P11917882A0326
+P10350454A0000
+P10513922A1237
+P10504332A0701
+P10409749T0000
+P11773168A0915
+P11835109A0000
+P10229682A1151
+P10464302A1109b
+P10534402A0126
+P11744290T0045
+P10318806A0000
+P10446912A0883
+P08504932A0123
+P11921126A1196
+P10082137A0262
+P10065684A0916
+P10713175A1399
+P10211422T0000
+P10037378A0176
+P10429946A0988
+P10074425A0729
+P11791292A0193
+P10473598A0691
+P10200473A0171
+P10454557A0975
+P10364202A0646
+P10330168A0135
+P10022921A0608
+P08011009T0057
+P10490843A0159
+BC2GM056160161
+P10502522A0000
+P10475610A1289
+P11858548A0241
+P11890438A0838
+P11763176A0918
+P10551867A0350
+P07579328A1345
+P10448285A1035
+P11278488T0000
+P10329574A1733
+P11912261A0284
+BC2GM018128647
+BC2GM003056399
+P10487040A0453
+P11804510A0730
+P11791585A0287
+P10544113A0293
+P11726022A0909
+P09712915A0672
+P10074282A0236
+P10491133A0365
+BC2GM084077526
+P11597185A0477
+P10026229A0950
+P10534048A0297
+P08157663A0882
+P10214610A0900
+P11811743A0800
+P08219072A0287
+P10364159A0813
+P09949178A0264
+P10396343T0000
+P10554946A0082
+P11831512A0468
+P10479382A1098
+P10523640A0367
+BC2GM082122625
+P11740571A0114
+P10407184A0520
+P10329135A1326
+BC2GM073729839
+P09209438A0994
+P07579328A0653
+P11842037A0327
+P10085140A1004
+P10466306A0000
+P10355910A0369
+P11677363A0775
+P02213128A0209
+P10561546A0000
+P10501965A0879
+P10471743A0000
+P10355536A0172
+P11716043A0380
+P10534691A0542
+BC2GM044941923
+P10490662A0431
+P11917061A0922
+BC2GM050074470
+P10509768A1118
+P10369965A0000
+P10347197A0502
+P10422291A0572
+P10497800A0000
+P10464291A0597
+P11703464A0560
+P10102627A0217
+P10235265A0197
+P10359663A1280
+P10413676A0595
+P10212278A0387
+P11742432A0798
+P09234727A0770
+P10542281A0382
+BC2GM035682880
+P11723675A1022
+P11837409A0584
+P10196316A0715
+P10446910A0147
+P10559364A0846
+P10455189A0104
+P11706949T0000
+P10409755A1846
+P10556029A0852
+P10409724A1021
+P10198061A0339
+P11825801A1212
+P07706273T0000
+P09278441A0163
+P10210952A0261
+P10526670A0236
+BC2GM033482973
+P10090146T0000
+P10218109T0000
+P10471587A0239
+P10207115A0389
+P07657162A1412
+P10192638T0000
+P10380659A0545
+P10438593A0000
+P10536788A0931
+P10026784A2166
+P10197985A0145
+P10393201A0654
+P10485470A0242
+BC2GM078078489
+P10195697A0456
+P11870646A0668
+P02034676A0267
+P10342536A0954
+P10460172A0823
+BC2GM001006298
+P10071806A0377
+BC2GM040930805
+P11920896A0298
+P10482620A1009
+P10545192T0000
+P10406459A0000
+P02083253A1512
+P10326654A0351
+P10406047A1244
+P08443122A0657
+P10400712A0577
+P11786248A1162
+P10171173A0955
+P10448095A0865
+P10406464A0687
+P11695481A0310
+P11692004A1200
+P11860723A0182
+P10426878A0367
+P10395827A1297
+P08642282A1009
+P10022850A0929
+P11777575A0363
+P10486210A0126
+P10212969A0470
+P10419006A0378
+P10360839A1338
+P10080901A0271
+P10477748A1076
+P11741554T0000
+BC2GM090825486
+P10358080T0000
+BC2GM094941573
+P10146207A0223
+P10455189A0427
+P10192432A0214
+P10448036A0748
+P10490835T0000
+P10331276A0298
+P11888183A0541
+P10100605A0392
+P10525413A1408
+BC2GM011031439
+BC2GM091665948
+P10359792A0610
+P10512857A0000
+P11882747A0354
+P10325413A1211
+BC2GM099329110
+P11898797A0124
+P10369418A0644
+P10066798A0391
+P10477620A0580
+P10559324A0716
+P10489822T0000
+BC2GM039407902
+P10207087A0956
+P10330134A0765
+P10196266A0000
+P10493575T0000
+P10468585A0980
+P08065331A0279
+P03510185A0187
+P10531446A0203
+P10381570A1355
+P10224293A0000
+BC2GM014618195
+P11883763A1062
+P07873876A1035
+P10194762A0648
+P10413676A0000
+P10490826T0000
+P10549354A2371
+P11819326A0000
+P10423292A0782
+P11710685A0994b
+P01531086A0127
+P10524258T0000
+P02822081A1034
+P09371612A1964
+P11689217T0000
+P11765448A0588
+P10399136A0389
+P11703558A0000
+P10392266A0111
+P10381257A0000
+BC2GM065607488
+P10482516T0000
+P10074135T0000
+P10360454A0916
+P10360947A1113
+P10049359A1073
+P10444813A0448
+P10543730A0000
+P10026211A0543
+BC2GM026532994
+BC2GM033988822
+P10336495A0547
+P11833863A0987
+P10099576A0666
+P10380890A0619
+P10533066A0758
+P11883682A0162
+P10505694A0739
+P10455183A0530
+P05570175X0000
+P10329566A0610
+P11686239A0464
+P10347144A0516
+P10535715A0268
+P10068418A1194
+P10557072A0127
+P11755894A0466
+P10362652A0350
+P10523634A1404
+P10064604A0824
+P10508522A1598
+P10490604A0601
+P02144290A1444
+P10074520T0000
+P10025050A1052
+P10103057A0251
+P10521345A0202
+P10339552A0361
+P10468033T0000
+P10049912T0000
+P10024882A0541
+P10521443A0486
+P10376873A0706
+P11803325A0868
+P10201468A0297
+P10559207A0207
+P10022032A0000
+P10398682A0365
+P10477599T0000
+P10488337T0000
+P10505694A0000
+P10071205A0833
+P10340447A0424
+P10493203T0000
+P10453721A0445
+P10341219A0481
+P10469140A0336
+P10488148A0111
+P10365883A1355
+P10454557A0000
+P10447597A1004
+P10490662A0819
+BC2GM075375859
+P10487760A0336
+P10543728A0358
+P10391075A0000
+P11726164A0215
+P10498616A1280
+P11743612A1179
+P10433970A0279
+P10329625A0715
+P10400757A1498
+P10484695A0791
+P02943562T0000
+P11376946A0000
+P09305870A0894
+P07616569A0168
+P02310496X0000
+BC2GM077245777
+P03263357A0112
+BC2GM067367771
+P07891708A0690
+P07651734A0961
+BC2GM068839310
+BC2GM040624059
+BC2GM046184202
+P09220158A0537
+P08284227A0336
+P09765388T0000
+BC2GM030881541
+P08937989A1365
+BC2GM081134768
+P02631505A0382
+P00703350A0418
+P01607223A0000
+P02027839A0250
+P07838156A0789
+P09013760A0000
+P09459835A0297
+P10585453A1029
+P08336012A0632
+P08336543A0243
+P07125064T0000
+P11592315A0325
+P01392358A0389
+P09566918A1115
+P02094221A0247
+BC2GM055197158
+P07219297T0000
+P10529246A0362
+P11445008A0816
+P09210012A0000
+P10652324A0177
+P10823961A0664
+P02115889A0436
+BC2GM088454426
+P11134033A0639
+P09463560A0124
+P07136569A0000
+P09058250A0128
+P00808266T0000
+P03249840A0411
+BC2GM062680443
+P08605326A0772
+BC2GM028090853
+P10411160T0000
+BC2GM068116027
+P02870249T0000
+BC2GM090043718
+BC2GM031957537
+P05472485T0000
+BC2GM094642532
+P04039667T0000
+P02167784A0109
+P11393791A1153
+BC2GM068734803
+P09882593A0996
+BC2GM084966023
+P03755673A0054
+P09288848A0780
+P07298209A0291
+P01569584A0672
+P02383771A0544
+BC2GM024386015
+P10727433T0000
+P08194549A0000
+P08563483A0094
+P01808602A0000
+P03306340A0537
+P09454735A1782
+BC2GM052716394
+P11294895A0292
+BC2GM070216905
+P07436702A0156
+BC2GM040960284
+BC2GM006980122
+P08470021A0195
+P08626612A1040
+P01298398A0461
+BC2GM039069187
+BC2GM051430553
+BC2GM070556783
+P07667195A0146
+P09731513A1090
+P06362143A0565
+P03678372A0170
+BC2GM009017382
+P01404401A0740
+P09747651A0000
+P02080902A0183
+P10871412A0369
+P02599995A1031
+P09317830T0000
+BC2GM008847096
+P02843495A0544
+BC2GM082714483
+BC2GM022687280
+BC2GM021508246
+BC2GM055477804
+BC2GM018717750
+BC2GM076247276
+P09678837A0736
+BC2GM052715986
+P10714985A1057
+P04073848T0000
+P02818122A0000
+P07959734A0194
+P02183467A0668
+BC2GM079025954
+P02796216A0063
+P11094072A1234
+P00753237A0000
+P08702633A0164
+P09352127A0953
+BC2GM044796005
+P10623758A0947
+BC2GM051722169
+BC2GM046544917
+P10785880A0947
+P01719684A0494
+P06345840A0348
+P08468475A1280
+P08007835A0538
+BC2GM018532054
+BC2GM058638697
+BC2GM025900425
+P06851280A0144
+P08938418A0099
+P11838058A0084
+P10850329A0248
+BC2GM030782524
+P08664229T0000
+P03908196T0000
+BC2GM076151355
+P05908762T0031
+BC2GM039160075
+P09276882A0479
+P11167019A1249
+P11156303A1098
+BC2GM085686844
+P08623554A1058
+P11517190A0352
+P03234790T0001
+P08574583A0658
+P03120334A0893
+P09340641T0001
+BC2GM044336863
+BC2GM093642275
+P07670504A0834
+P03820222A0203
+BC2GM092138955
+BC2GM057451821
+P10893243T0000
+P06189698A0246
+P07885999A0000
+BC2GM009597017
+P03212551T0001
+P07599449A0445
+BC2GM039068445
+P07126067T0000
+P09703816A0139
+P10940892A0573
+P08554540A1480
+BC2GM077752729
+P08703005A0645
+P02998016A0527
+P10047970T0013
+P08440688A1509
+P11429702A0917
+P00129659T0000
+P10991383A0289
+BC2GM044291180
+BC2GM008214727
+P06085839A0721
+P01339815A1545
+P00987649T0001
+P01347944A0964
+BC2GM066832835
+P10850942A0989
+P09643546A0436
+BC2GM076238232
+P05340801T0000
+P01235347T0001
+BC2GM094364440
+BC2GM056788126
+P08408963A0048
+BC2GM051214920
+P09852752A0950
+P00872442T0000
+P07888828A0765
+P04048245A0331
+P08207232A0503
+P08415712A1153
+P04810131T0000
+P09303437A0875
+BC2GM084163116
+P09164543A0219
+P11552058A0833
+P03073091A0449
+P04515631T0000
+P08657150A1049
+P08247005A0584
+BC2GM030293079
+BC2GM038263382
+P09499048A1003
+P08618864A0754
+P06259220A0000
+P06735247A0803
+P09303635A0000
+P10592791T0001
+P01896777T0000
+BC2GM055239754
+P08094927A0311
+P09722508A0953
+P02874078A0252
+P01402647A0114
+BC2GM037804373
+P07739544A0364
+P08435755A1078
+P01901405A0694
+P11250196A0455
+P08654200A0274
+P09225682A0579
+BC2GM007864175
+BC2GM091799459
+P11435688A0262
+P09792630A1127
+BC2GM089615963
+P04040307A0145
+P08095875T0000
+P01347664A1026
+P07760841A0647
+P04025178A0126
+P10908822A0519
+P10722063A0328
+BC2GM074447065
+P02844797A1225
+P08995054A0618
+P01377962A1012
+BC2GM050389722
+P11212249A0993
+BC2GM092152216
+P11198385A0000
+P04653144T0000
+P09182281A0197
+BC2GM038917907
+P08492164T0000
+BC2GM055437471
+P08276336A0371
+BC2GM028935369
+P11302566A1318
+P08615183T0000
+P07651386A0925
+P03967144T0001
+P09315632A1137
+P06200300A0409
+P02149570T0000
+P10897973T0001
+P08496157A0000
+P01774822A0289
+BC2GM029565037
+P07935997A0000
+P09893913A0656
+P10919971A0606
+BC2GM009734777
+P08182041A1067
+P11042197A0386
+P03697798T0001
+P03275873A0379
+P08196624A0593
+P02836623A1094
+P08762172A0178
+P00313766A0666
+BC2GM067850977
+P09482902A0423
+P00064414A1098
+P08385337A0282
+P08086453T0000
+P03612648A0085
+P04510102T0000
+BC2GM034205084
+P03979084A1019
+P01669611A0142
+BC2GM085416989
+P01316461A1083
+P09575143A1189
+P03091849A0000
+BC2GM066303688
+P10620777A1399
+P08193147A0831
+P11278594A0618
+P02272095A0832
+P06911559T0000
+P09620606A0000
+P02025515A0979
+BC2GM071680095
+BC2GM006829575
+P09726979T0000
+P08388600A0000
+P09200811T0000
+P02830214A0000
+P10647859A0000
+P02418701A0000
+BC2GM047650925
+P07630687A0010
+P08969495A0256
+P09582327A0295
+BC2GM083779200
+P08375651T0000
+P07779811A0901
+P08223554A0574
+P11122588A0549
+P01961996A0522
+P06962634A0190
+P01380716A0174
+P07762431A0356
+BC2GM026487710
+P01552662A0398
+BC2GM064062109
+BC2GM065297737
+BC2GM068080836
+P11224226A0000
+P10744749A0315
+P03700952A0273
+BC2GM004675076
+BC2GM087325432
+P08816443A1674
+P08900190A0430
+P11580757A0304
+BC2GM097338238
+P08824585A0260
+P01408219A0670
+P01931966A0490
+P07476963A0000
+P08662980A0762
+P10591633A0138
+P10592791A0370
+P10627834A0178
+BC2GM025050820
+P03622423A0000
+P01443745T0000
+BC2GM000816003
+P03862898A0563
+P08439597A0176
+P01692135A0783
+P11574088A1687
+P08663000A0000
+P08824800A0808
+BC2GM071692892
+P09067577A0307
+BC2GM091139291
+P10932527A0947
+BC2GM061416577
+P07783064A0452
+P08419338A0273
+P03688202A0377
+BC2GM046405419
+BC2GM069267647
+P08972232A0365
+P10652362A0933
+P00193587T0000
+P01360180A0513
+P08366034A0637
+P01557411A1282
+P08898336A0268
+P00222102A0227
+P11014215A1092
+P11063742A0000
+P08384309A0000
+BC2GM094180317
+P01357528A0084
+BC2GM091292121
+BC2GM096793174
+P08046923A0000
+P09241092A1108
+BC2GM020300405
+P08683108A0965
+P09114972A1366
+P11007509A1271
+BC2GM072257563
+BC2GM028014715
+P11214354A1104
+P10619254A1055
+P09241232A0653
+P09858531A1017
+BC2GM050378714
+BC2GM037320701
+P08350398A1616
+BC2GM042242435
+BC2GM081102567
+P08643578A0532
+BC2GM070631455
+P06687953T0000
+P06738410T0000
+BC2GM031056055
+P08455629A0335
+BC2GM038464760
+P02035805T0000
+P06319040A1627
+P08041362T0000
+P06434572A0157
+BC2GM090808370
+P02757033A0905
+P01673220A0578
+P03114995T0000
+P08682868A0738
+P01316680A0643
+BC2GM003525859
+P09346935A0459
+P02022188A1463
+P02123467A0811
+BC2GM036204067
+BC2GM024075956
+BC2GM030960650
+P06795900A0000
+BC2GM082875858
+BC2GM060654368
+BC2GM078904500
+BC2GM038768942
+P08632463A1508
+P09848653A0597
+P08555446A0000
+P10684646A0224
+BC2GM034370454
+P10903877A0879
+P08051059A1000
+P01690728A1166
+P02834843A0000
+P02711167A0818
+P04460692T0000
+P09046186A0189
+P08750702A0183
+P08639742T0000
+P08584026A0115
+P07530502T0000
+BC2GM022693469
+P08496184A0772
+P08575614A0264
+P09776360A0620
+P11102458A0000
+P10646863A0838
+P10892300A0268
+BC2GM012402149
+BC2GM087839527
+P02145268A1454
+P03622571A0208
+P11210839A0282
+P08878019A0357
+P01457695T0000a
+BC2GM046011623
+P02394718A0130
+BC2GM024610990
+BC2GM071336386
+P07937954A0612
+P10693314A0521
+P10634007A0202
+P08298129T0000
+P07681513A0000
+P09212059A1356
+P06300836A0285
+P09210478A0000
+P11243980A0510
+BC2GM095342382
+BC2GM084311645
+P11564893A1068
+P01190120A0832
+BC2GM025047286
+P08806817A0244
+BC2GM072049758
+P02885517T0000
+P08843411A0801
+P08858211A0694
+BC2GM016378782
+BC2GM083717359
+P10861909A0502
+BC2GM082852129
+P09467900A0701
+P10865422A0138
+P06328272A0705
+P07107462A0202
+P11046148A0716
+P10781541A1063
+BC2GM062590002
+P03430221A1236
+P07935415T0000
+BC2GM005581370
+P07813466A0074
+BC2GM052190930
+BC2GM054696358
+BC2GM020389288
+BC2GM061319895
+P08091665T0000
+P08628302A0683
+P08589358A0841
+P09704569T0000
+P09218599A0184
+P09822690A0000
+P11179664T0000
+P09225998A0000
+BC2GM057310449
+BC2GM079983245
+BC2GM084759712
+P00450367T0000
+P08683983A0785
+BC2GM083462824
+P01320255A0795
+BC2GM039225135
+BC2GM077712374
+P08761169T0000
+BC2GM051838944
+P04746559T0053
+P02409297A0984
+P02486634A0632
+BC2GM099774461
+P02209243A0237
+BC2GM042361998
+BC2GM095315156
+BC2GM075650650
+P07905413A0585
+P09598205A0430
+P08218056A0000
+P09795130A0742
+BC2GM072444628
+P10845522A0000
+BC2GM064897549
+BC2GM048672886
+P03052641A0204
+P08096066A0623
+P01358758A0000
+BC2GM074709603
+P08621719A0568
+P08558187A0403
+P09521909A0081
+P01321337A0318
+P03499822A0182
+P07379334A0503
+P01999035A0383
+BC2GM005019655
+P09346953A0000
+BC2GM005485785
+P06795654A0434
+P02165589A0888
+P09774641A0824
+P09753730A0881
+P09389198A0363
+P04084896A0569
+BC2GM090582830
+BC2GM044230142
+BC2GM044831438
+P08139562A0404
+P09736239A0436
+P02761540A0873
+P08226777A0936
+BC2GM077180939
+BC2GM084450992
+P08538702A0214
+P10955913A0827
+P09050861A0903
+P10897233A1057
+P07191183A0505
+P09837824A0419
+BC2GM057123623
+P11059777A0813
+BC2GM002436660
+BC2GM033866755
+P11430042A0000
+P09333231T0018
+P11158295A0158
+P08979089A1197
+P09005609A0299
+P10997863A0753
+P08075421A0621b
+P00877857A0763
+P01339468A0272
+P09292499A0887
+P10600171A1432
+P09211981A0526
+P11285329A0682
+BC2GM016645087
+P07386864T0000
+P09058373A1620
+BC2GM093130778
+BC2GM061863069
+P07583190A0306
+P02983316A0310
+BC2GM040688881
+P11145562A0468
+BC2GM091736061
+P08199878T0000
+P11191365A0682
+P09668098A0868
+P01383690A1023
+P07478514A0237
+P07094905A0644
+P03259437A0140
+P09153795A0298
+P07965152A0764
+P03777398A0156
+P09452421A1042
+P08409284A0262
+BC2GM011718257
+P03930549A0209
+P02324104A1195
+P06796300A0759
+P08125258A0142
+P11090172A0612
+P09147420A0623
+P08552092A1678
+P10999369A0192
+P03658866A0081
+P08088022A1417
+P06531286A0382
+P07980440A0138
+P09428799A0897
+P01448917A0775
+P09334264A0540
+BC2GM093377717
+BC2GM018952146
+P08505340T0000
+BC2GM012491320
+P01588315A0356
+P08626809A0729
+P00755869A0216
+P06786756T0000
+BC2GM036083760
+P06959130A0996
+P06818113A0384
+P01331086T0000
+P07707531A0550
+P00970488A0105
+P08913387A1010
+P11297419A0894
+BC2GM073658017
+BC2GM083424933
+BC2GM071527942
+BC2GM016009074
+BC2GM041356222
+P11194183A0866
+P07330073T0000
+P01679068A0000
+P08374753A0335
+BC2GM071545303
+BC2GM083230779
+P07730273A1309
+P02994336A0864
+P09445488A0230
+P06873504T0000
+P01358190A0654
+BC2GM081450728
+P04778129T0000
+BC2GM074423927
+P11793614A0000
+P09604052A0166
+P07753027A0240
+BC2GM080799996
+P07854130A1387
+P03714348A0833
+P03911052A0909
+P03999219A0463
+P06084810A0169
+P10767091A0133
+P07852361A0868
+P07509450A0705
+P09000632A2341
+P09606633A0523
+P00015731A0090
+BC2GM044172582
+P08663219A0246
+P09765754A1727
+BC2GM043498135
+P03998813A0406
+P08130942A0051
+P09419421A0385
+P10866689A0295
+BC2GM038447358
+P11241166A0677
+BC2GM011632979
+P08491383A0154
+P01396592A1113
+P10648619A0000
+P09148935A0805
+BC2GM047781094
+P10624787A0432
+P11500571A0976
+BC2GM092393835
+P07847036A0353
+P08649372A0755
+BC2GM097292555
+BC2GM029344954
+BC2GM023883518
+P04246054T0028
+BC2GM065395717
+BC2GM089738543
+BC2GM068132437
+P02164585A0814
+P02713310T0000
+BC2GM080041758
+P09478971A1896
+BC2GM087902003
+BC2GM061492332
+BC2GM074262156
+P09638650A0169
+P10574982A1075
+P09914500A0000
+P08763207A0402
+P09003617A0000
+BC2GM072003693
+BC2GM038644769
+P00473229T0000
+BC2GM029330776
+P00975314T0001
+P11283256A0258
+P11108839A0401
+P08296434A1141
+P01418542A0000
+P03041802A0975
+P08806817A0716
+P09591221A0137
+P03019505A0390
+P07729427A0942
+P08382300A0341
+BC2GM070291312
+P03998071T0000
+P07535593A0714
+P07256543A0814
+P09733794A1323
+P09040011A1316
+BC2GM031759031
+BC2GM001799055
+BC2GM095014015
+P09045919A1250
+P07999604A0139
+P10814989T0000
+P09633630A0740
+P11288208A0712
+P08710371A0000
+P10675154T0000
+P09914518A1217
+BC2GM064262659
+BC2GM095166166
+P10864271A0504
+BC2GM080831833
+BC2GM047324484
+P02417669A0218
+BC2GM048352135
+P07125238T0000
+P10660304A0522
+BC2GM010215483
+P09418905A1396
+P00808898A0000
+BC2GM031697099
+P06413492A0990
+P07202224A0452
+P09314306A0571
+BC2GM003460926
+P07369183T0000
+P00369683T0000
+P08344248A0910
+P08702543A0000
+P11198424T0000
+BC2GM076157697
+P02574551T0000
+P01647813A0512
+P09842517A0497
+P01371863A0000
+P06108610A0518
+P09658405A0000
+P09577395A0000
+BC2GM017308812
+BC2GM054501592
+P00094639A0313
+BC2GM026679979
+P01968043A0908
+P08221251A0239
+BC2GM019146982
+BC2GM004455813
+P06444119A0340
+P08794547A0648
+P02347407A0217
+P00027967A0207
+P02252953A0300
+BC2GM093309719
+BC2GM045265175
+P00701462A0722
+P06318322A0350
+P00755671A0485
+P08995614T0000
+P08182056A0695
+P07609037A0775
+P02141425A0175
+BC2GM030669575
+P01675424A0991
+P09280747A0195
+P11377975A0898
+P08459465A0257
+P08461981A0882
+BC2GM060862443
+BC2GM074751014
+BC2GM093459907
+P11358962A0344
+P08245456A0501
+BC2GM052850929
+P08682155A0902
+P03561622A0659
+P11350957A0457
+P08255758A0000
+P01296815A0059
+P01910505A0000
+P03929486A0309
+P08661101A0396
+P11049241A0659
+P11560992A0651
+P07214230T0000
+P07278104T0001
+P09080517A0215
+P08073505T0000
+BC2GM087011590
+P09584194A0000
+P09286981A0147
+BC2GM018608003
+P03549045A0878
+P11311480A0079
+P09665361T0000
+P11371115A0962
+P01549118A0000
+P07413781A0169
+P07894761A0000
+BC2GM060572853
+BC2GM048987709
+P01657969A1420
+P09147788A0458
+P11160307A0394
+P02033038A0309
+P08854844A0637
+BC2GM037134844
+P02591969A0961
+BC2GM053778229
+BC2GM097964351
+P09373155T0000
+BC2GM025395318
+P00029555A0861
+P11238884A0892
+P10656802A1724
+P09551182A0212
+P07137927A0000
+P08871567A0629
+P08534217A0402
+BC2GM056719795
+BC2GM094026101
+BC2GM036717390
+BC2GM065785628
+P08896795A0166
+BC2GM070056586
+BC2GM003935200
+BC2GM042317082
+P00728718T0000
+P10984122A0911
+BC2GM094133140
+P09628821A1194
+P11278610A0902
+P10009565T0000
+P09627598A0384
+P05794247T0000
+P11024036A0984
+P02229072A1012
+P08649424A0000
+P02573303A0000
+BC2GM021068289
+BC2GM024681168
+BC2GM041800456
+BC2GM058654225
+P01562659A0676
+P11428283A0228
+BC2GM091875448
+BC2GM070333070
+P09795170A0774
+P03890486A0000
+BC2GM020893421
+P08858463A0853
+BC2GM097798916
+P11044097T0000
+P02423533A1790
+P11584107T0000
+P01907265A0670
+BC2GM037544012
+BC2GM008819696
+P07829102T0000
+P09420220A0070
+BC2GM006873780
+P09660838A0920
+P09835615A0574
+P01267446A0210
+P08617243A0336
+BC2GM038704123
+P01698772A0238
+BC2GM007283823
+BC2GM027354703
+P03966687A0000
+P09360956A0840
+P07862092A0302
+BC2GM024346106
+P09353296A0510
+BC2GM044292594
+P09368100A1354
+BC2GM081507457
+P08386279A1621
+P00909114A0000
+P09713996T0000
+P09343432A0209
+P07992027A0485
+BC2GM016210640
+P02555703T0000
+BC2GM089906052
+P10885708T0000
+P03343730A0486
+P09959737T0000
+BC2GM032887840
+P08727192A0000
+P09001828A0222
+P05847772T0001
+P08289341A1202
+P10738139A0681
+P07877308A1175
+P08837503A0392
+P03712106A0000
+P01682542A0690
+P03974790A0053
+P01157614T0000
+BC2GM096535156
+P06948398A0523
+P09921179T0001
+P08812490A1509
+P08189533A0919
+P00743335T0001
+P07865786A0457
+P09710591A0981
+P07780738A0091
+P02833012A0428
+P02487898A0315
+P08526620A1344
+BC2GM024208708
+P09315631A1064
+P10756007A1512
+P11308851A0333
+P11464997A0566
+P01516829A0113
+P03011793A0582
+P02530413A0195
+P01545806T0000
+P01262596T0000
+P10907971A0806
+P11387351A0092
+P07678006A0901
+P02256678A1224
+BC2GM033846356
+P09819288A0578
+P10958698A0485
+BC2GM063584171
+BC2GM019111306
+P07268828A0000
+P09104816A0610
+P07418829A0191
+P03577670A0236
+P03285764A0675
+BC2GM066316127
+P03688676A0487
+P07929560T0000
+P09285715A1257
+P07235317T0000
+BC2GM015870833
+P08531669A0950
+P08807288T0000
+P09581834A2578
+P02360336A0574
+P11542780A0086
+P09200530A0411
+P09371431A1172
+P01313846A0850
+P09701609A0116
+P01883992A0922
+P00821833A0000
+BC2GM025023094
+P11069011A0224
+P09632709A0464
+BC2GM045948715
+P09467955A0468
+P02405393T0000
+BC2GM036507029
+P08201932A0355
+P09767504A1371
+P07845672A0368
+BC2GM037203350
+P03142875A0366
+P07865917A0191
+P07656588A0101
+BC2GM075340311
+P07600111A0000
+BC2GM016026210
+P11390663A1400
+P03877298A0718
+BC2GM009893203
+P09006051A1162
+BC2GM056659741
+P11513180A1257
+P11278848A1316
+P09781871A0404
+P07603726T0000
+P02002511A0637
+P01964989A0145
+BC2GM093469461
+P09748261A0000
+BC2GM028602474
+BC2GM013088114
+BC2GM014045933
+P07467975A0316
+P02143961A0400
+BC2GM054770517
+P10606515A0389
+P03359860A0000
+BC2GM055829583
+P00168431T0000
+P05414186T0001
+P10653697A0133
+P11387950X0001
+BC2GM066025610
+BC2GM072307565
+P10683244A0939
+BC2GM014162917
+P11368901A0327
+P08458906A0827
+BC2GM090355952
+BC2GM031364553
+P10958456A0529
+P09150774A0616
+P09192786T0000
+BC2GM004118493
+P08914532A0598
+BC2GM002848058
+P01326329A0703
+P09159183A0119
+P01976638A1135
+P06731302A0930
+P03065610A0375
+P06270347A0740
+P04369884T0000
+P02650663A0178
+P03280807A1447
+P11399834T0000
+P10899142A0000
+BC2GM006832917
+P03075154T0000
+P10918059A0569
+P08639837A0268
+BC2GM050006872
+BC2GM016568777
+P06670732A0000
+P07737944A0000
+P09121454A1328
+BC2GM032149031
+BC2GM038288477
+P07768848A1880
+P08643682A0268
+BC2GM097801700
+P00928529T0001
+P07744954A0418
+BC2GM049146071
+P08529662A0507
+P00641395A0441
+P01423454A0309
+BC2GM027382651
+BC2GM067715676
+P01977585A0222
+P02484994T0001
+P10895417A0000
+BC2GM080452134
+BC2GM090086707
+BC2GM057164114
+P07935395A0094
+P10788480T0000
+P08316240A1068
+P11024026A0133
+BC2GM064685099
+BC2GM093402905
+P08522511A1578
+BC2GM023906400
+P10895417A0669
+BC2GM003763223
+P07666523T0000
+BC2GM005600450
+P11029656A0640
+BC2GM067799557
+BC2GM099522196
+P09354349A0338
+P11177538A0655
+BC2GM060173727
+P01558942A1369
+BC2GM040040983
+P06209499A0682
+P07761434A1084
+P11223257A0404
+BC2GM093930415
+P09765271A1108
+BC2GM064850672
+P06539738T0000
+P11254864T0000
+BC2GM024410649
+BC2GM093150217
+P07537851A0000
+P02479823A0727
+P09990315A0205
+BC2GM039343812
+P01646487A0874
+P08449986A0455
+P09153319A0844
+BC2GM043010172
+BC2GM080426712
+P09800187A0100
+P09790767A0372
+BC2GM007835217
+BC2GM092581148
+BC2GM058805467
+P09652736A1205
+P03528748A0414
+P09383188A0654
+P11167111A0957
+P08981371A2049b
+P02787430A0124
+P08125949A1162
+P10587461A0341
+BC2GM053331936
+BC2GM043735377
+P09705564T0000
+BC2GM064662484
+BC2GM024601560
+P08723883A0823
+P11221845A0295
+BC2GM013473921
+P08853893A0158
+P09083345A0851
+P09426907A0391
+BC2GM014615834
+P08781119A0723
+P06486932A0000
+P09504906A0099
+BC2GM094415622
+BC2GM014978613
+P09371731A0627
+BC2GM075271187
+BC2GM029012322
+P09523478A0572
+P09586285A0551
+BC2GM043242186
+BC2GM083193914
+P11053263A0200
+P07934666A0158
+BC2GM004233255
+BC2GM094778247
+BC2GM061570261
+BC2GM062170558
+BC2GM069431845
+BC2GM095437250
+P02296509A0997
+P06692517T0000
+P07559640A1230
+P01919831T0000
+BC2GM008631262
+P03039177A0503
+P07214665A0000
+P11160896A0713
+BC2GM006783722
+BC2GM048333023
+P11029458A0000
+P04262268T0001
+BC2GM016049892
+P09989339A0968
+P03407843T0000
+P07666415A0000
+P11910310A0279
+P08987225A0675
+P07797077A0842
+P09223122A0774
+P03060846T0000
+P08564588A1318
+P04824747T0000
+P09736697A1107
+P09372908A1068
+BC2GM075603170
+P03305875T0000
+P06184276T0001
+P02310350A0221
+P11003807A0303
+BC2GM000665827
+P07927130A0625
+P06407348A0516
+BC2GM066800893
+P08204403A0000
+P10688660A0992
+P07629122A0323
+P09265534A0455
+P08891341A0724
+BC2GM039052742
+P07571766A0122
+P08866485A0125
+BC2GM059714682
+P01316125A0176
+P06627123A0000
+BC2GM043104937
+P01710766A0349
+P09520398A0124
+P08003700T0000
+P00479222A0682
+P01927845A0107
+P02355920A0681
+P01581577A1186
+P01178637T0001
+P00725336T0000
+P08106087A0139
+P03001110A0546
+P10773458A0000
+P02158927A0000
+P01711048T0000
+P11469853A1053
+P00803867A0315
+P08195217A0799
+BC2GM033643051
+P05684081T0001
+P07918494A1163
+P11275986A0091
+BC2GM021360319
+P11309677A0000
+P01278251A0000
+BC2GM078070574
+P11297514A0218
+BC2GM091638425
+BC2GM063812072
+P07835273A0000
+BC2GM035842115
+P11552058A0235
+P09090050A0419
+P07519463A0000
+P00339289T0049
+P09729481A0000
+P08555076A0333
+P10861080A0433
+P08918464A0225
+P01318739A0410
+P07517544A0515
+P05316745T0000
+P11038118A0000
+P08320120A0361
+BC2GM060672103
+P04152725T0001
+BC2GM043526079
+P07828584A0681
+BC2GM063757924
+BC2GM082800985
+BC2GM067677787
+BC2GM057671926
+P08249319A0578
+P02236276T0000
+BC2GM046574139
+P09178269A0107
+P09840928A0884
+P09477316A0140
+P07784197A0827
+BC2GM079551353
+P00597715A0256
+P04071063A0863
+P07249497A0688
+P04196986T0000
+P02266679A0740
+P00910823A0196
+P10564472A0853
+P11223164A0000
+P09915798A1077
+BC2GM017736340
+P02457922A0991
+P09313755A0816
+BC2GM001964645
+BC2GM001929746
+P08289783A0000
+BC2GM095746583
+P09436989A1011
+P10699896A0455
+P11059786T0000
+P02476664A0563
+P09434160A2078
+P03653226A0833
+BC2GM043298820
+P02201770A0188
+BC2GM094775430
+BC2GM003517703
+P09425038A0752
+P03062370A0384
+BC2GM053826454
+BC2GM057810743
+BC2GM071924862
+BC2GM092761606
+BC2GM048911038
+P09268652A0116
+P09294161A1103
+P02115118A0565
+P07505798A0000
+BC2GM066838338
+BC2GM043491752
+P09494078A1362
+P08476854A0097
+P09199932A1357
+P09115279A0345
+P11108548A0710
+BC2GM024171427
+P03673640A0533
+BC2GM021445348
+P07440430A1074
+P07533880T0000
+P00956554A0414
+P03320875A2090
+P09487841A0132
+P09046384A0403
+BC2GM005667784
+P08914522A0118
+BC2GM021860677
+P07692366A0000
+P09491074A0104
+P07698219A0551
+P08149484A1551
+P07579683A0660
+P07064923T0000
+BC2GM002025862
+BC2GM093817406
+P11221845A1713
+P08676858A0309
+P07951410A1332
+BC2GM008093196
+BC2GM063604617
+P09710621A0598
+P07762504A0648
+BC2GM008972334
+P08709251A0000
+P08471241T0000
+P11198289T0000
+P01242636A0678
+P08657918A0360
+P08356792A1275
+P00550399A0615
+P07689154A0168
+BC2GM051293681
+P02574193A0663
+P02174105A1232
+P04377003A0000
+P08209051T0000
+BC2GM027460732
+P01329039A0951
+BC2GM038571179
+P03001645A0785
+P10617126A1005
+BC2GM081842707
+P08411276A0302
+P09700644T0000
+P08996730A1146
+P01009841T0001
+P01679749A1171
+P11092770A0238
+P09122198A0478
+P06946693T0000
+P02333239T0000
+P07984105A1509
+P07579695A0336
+P08183552T0000
+BC2GM002757226
+BC2GM077489528
+P01597170A0000
+P09931435A0357
+BC2GM087700709
+P07007181T0000
+P09823775A1122
+P11325944A0511
+BC2GM086259287
+BC2GM018375556
+P00633909A0000
+P08270985A0590
+P11416260A0000
+P09778191A0000
+P06321770A1353
+BC2GM025848591
+P02330110A1085
+P07068493A0414
+P09162097A1258
+P03937481T0001
+P08585324A0823
+P05132558T0000
+BC2GM075735017
+P02725513A0617
+P07858986A0310
+P09393771A1659
+P10628490T0000
+P10756007A0575
+P09643548A0000
+P11902738A0185
+P00101300A0257
+P09476399A0141
+BC2GM005052505
+BC2GM004472936
+P02735364A1330
+P02497340A0989
+P08289784A0381
+BC2GM066692058
+P07926774A0652
+P10801482A0968
+P00918965A0728
+P02002051T0000
+P11073954A0337
+P11181516A0119
+P08807245A0843
+P01633816A0667
+BC2GM049661443
+BC2GM074649255
+P09187277A0118
+BC2GM019812857
+P09510189A0192
+P09632637A0361
+BC2GM074209039
+P08044802A0462
+P05544291T0031
+P05567721T0000
+P07494303A0000
+P02543621A0788
+P06801778T0001
+BC2GM018447830
+BC2GM003020957
+BC2GM044619064
+P08361755A0734
+P07929165T0000
+P11552922A0361
+P02800435A0000
+P10681588A0899a
+P00096241A0087
+P11236056A0374
+P00938594A0149
+BC2GM053457298
+P02393001A0324
+P08365944A1537
+P09829836A0815
+BC2GM052914680
+P11469853A0702
+BC2GM041191504
+P07823951A1100
+P07183576A0157
+P09509226A1235
+P09753774A2246
+BC2GM021289219
+P06412385A0356
+P01699944A1538
+P09555046A1617
+BC2GM011718637
+P09754571A0169
+P02138707A0198
+BC2GM042404259
+P10793991A0569
+BC2GM058204459
+P07184375T0001
+P11193666A1269
+P07957243A1316
+P07835088A0238
+P06963337T0000
+P08278480T0002
+P09389982A1383
+BC2GM023238812
+P08337841A0612
+P00450760T0001
+BC2GM077538777
+P08664347A0923
+P11263622A0683
+P08630548A0000
+P09263094A0799
+P08626529A0000
+P08635771A0000
+P08299568A1401
+BC2GM034609623
+P01999999T0001
+P09893060A0767
+P09121452A0538
+P01634464A0163
+P08684742A0000
+P03563604A1075
+BC2GM037400518
+P03488532A0235
+P09293006A1412
+BC2GM075235574
+P07720710A0861
+P09243267A0401
+BC2GM006558727
+BC2GM065655704
+BC2GM092988766
+BC2GM087746529
+P09821978A1255
+P01589576A0170
+P07748952A1329
+P01760166A0963
+BC2GM066642984
+BC2GM012511616
+BC2GM049012897
+P02647918A0588
+BC2GM005798555
+P08879080A0265
+BC2GM061416403
+P09172641A0181
+P07752223A0960
+P09199328T0000
+P03937294A0404
+P07824464A0169
+P08947028A0992
+P03352947T0001
+BC2GM064716554
+BC2GM091780091
+BC2GM024592460
+P08985115A1571
+P04143528A0394
+P04066194A0163
+P08002857A1070
+P03080793T0000
+BC2GM063772047
+BC2GM090334902
+P08836032T0000
+BC2GM033997623
+P09469933A1060
+BC2GM097255960
+P09307312A0172
+BC2GM040694019
+P03249792A0241
+P07697294A0329
+P01328681A0348
+BC2GM046830258
+BC2GM059243006
+P09685226A0000
+P10828319A0342
+P09813063T0000
+BC2GM008441714
+P09115395A0478
+P11083358A1071
+BC2GM011299853
+BC2GM045351753
+P01483771A1335
+P08309957A0000
+P09705324A1602
+BC2GM016633318
+P09974642T0000
+P09726991T0000
+P06541019A0555
+P09487590A0657
+P08626610A0931
+P11113692A0169
+P01580738T0001
+P02756878A0075
+P09187637A1199
+BC2GM060988781
+P09660823A0934
+P08408841A0281
+P06772612A0000
+BC2GM057201448
+P10870391T0034
+P11435578A2231
+P03791645A1124
+P08698756A1240
+P09436706A0168
+BC2GM003679439
+P01930470A0337
+P07347728T0000
+P09420275A0682
+P09172312T0000
+P10681679A0220
+P08895522T0000
+P11572467A0658
+P08969777A0771
+P04782788T0001
+P01888896A0505
+P09001245A0187
+BC2GM008866104
+BC2GM034787231
+P07511444T0000
+P05128149T0001
+BC2GM055423276
+P01734020A1318
+BC2GM056569042
+P09247645A0000
+BC2GM004444068
+P03591464A0840a
+BC2GM031044079
+P00139624A0318
+P08781144A1520
+BC2GM033539277
+BC2GM063432144
+P06279309A0000
+BC2GM087023573
+P09636119T0000
+P07936650A0656
+P00932817A0499
+P09832504A0596
+P11241672T0000
+P11554469A1386
+P09671791T0000
+BC2GM099614397
+BC2GM031563114
+P07954475A0714
+P05959588T0000
+P07182523A0462
+P08460346A0350
+P08514757A1100
+P08289593A1404
+P01569102A0708
+BC2GM069537069
+P11036938A1162
+P08218230A1920
+P11118440T0000
+BC2GM046577623
+P02143186A0867
+P08576131A0151
+P08666238T0000
+P07565776A0612
+P09174049A1788
+P08592713T0001
+BC2GM018078380
+P07592711T0000
+P04784432T0001
+P07375836T0000
+P09077108A0458
+P11523446A0523
+P02763467A0903
+BC2GM067531031
+P09826778A0943
+BC2GM042911073
+BC2GM011436488
+BC2GM060554389
+P10751398A1135
+P08816792A0000
+P08411024T0000
+P10763827A1158
+P03761523A0000
+P00216939T0001
+P08621661A1035
+P02454390T0000
+P09677405A0856
+P02102831A1282
+BC2GM032327372
+BC2GM033197644
+P09168083A0987
+P07707523A0704
+P07902532A1655
+BC2GM022663710
+P07806651A0097
+P08597177T0000
+P09609720A0357
+BC2GM007906275
+P05362866T0000
+BC2GM031419699
+P08231816A1473
+P06609166A0209
+P09353255A0159
+BC2GM070573613
+P08142875A0877
+P09856732A0114
+BC2GM024364656
+BC2GM009539472
+P01406688A0898
+P06880563A0516
+BC2GM023639868
+P07790271A1185
+P03023067A0779
+P10797125A0000
+P06121577A0280
+BC2GM049097167
+P09402088A2250
+BC2GM009988175
+P03499657A0000
+P04014833A0400
+P02376023A0307
+P11727073A0842
+BC2GM057418939
+P08896402A0587
+P08005412A0608
+BC2GM084554864
+BC2GM086764035
+P02547706A0928
+P03048024A0418
+P05322747T0034
+P11274563T0000
+P09810087A0379
+P10819327T0000
+P06542918A1131
+P08986692A0306
+P07260389A0221
+P06777229A0243
+P08356944A0589
+P08382778A0891
+P07531321A0369
+BC2GM001711845
+P09091010A1003
+P01885006A0995
+P10597317A1156
+P00737422A0832
+P01847665A1079
+BC2GM092320331
+P04445874T0001
+P07623838A1112
+P07740490T0000
+BC2GM077346848
+BC2GM097835170
+P01884435A0088
+P11018028A0263
+P04086403A1016
+P08024139A0393
+P01217450A0295
+P00932738A0116
+P09178491A0262
+BC2GM025563582
+P11324516A0159
+P08496601A1153
+BC2GM014203936
+BC2GM045577252
+P02973304A0000
+P08955159A0000
+P09561560A0579
+P07507187T0000
+P06147504A0086
+P09971822A1542
+BC2GM088118556
+BC2GM031143223
+BC2GM044423776
+BC2GM082814800
+P09197342T0000
+P02629109A0000
+BC2GM020930043
+P07519606A1269
+BC2GM031584591
+P08897721A0000
+P09169853A0000
+P06675047A0000
+BC2GM064583998
+P04624863T0001
+BC2GM015002604
+P11166478T0000
+P11444762A0373
+P09819440A0000
+BC2GM020598843
+P02462047A0208
+BC2GM044561188
+P10679015A0216
+P08554069A0743
+BC2GM090707363
+P02204621T0000
+BC2GM054437021
+BC2GM022946300
+P09381950A0209
+P07565723A0200
+P08933487A0325
+P01915580A0889
+P09230129A0039
+P11462004A1500
+P06138313A0948
+P09743720A0268
+BC2GM086432214
+P09635149A1148
+P07683375A0000
+P09521913A0400
+P00050628A0202
+P08761480A0331
+P09638793A1446
+P03059171A1232
+P06503329A0588
+P09346925A0660
+P07932943A0113
+P09278475A0465
+BC2GM025661360
+P11196191A1789
+BC2GM079950529
+P08399970T0000
+P01634400A1101
+P07308849A0817
+P09400738A1046
+P09073074T0000
+BC2GM058248998
+BC2GM095220597
+P03543936A0000
+P09443972A1145
+BC2GM087282034
+P05672903T0001
+P10773351A0672
+P08864061A0000
+P09627285A0554
+P09713996A0262
+P01808186A0984
+P10805823A1920
+P03436119A0000
+BC2GM047557108
+P09805977A0143
+P03137346A0319
+P07582316A0696
+BC2GM003905153
+P10574929A0583
+P08626529A0799
+P01158512T0000
+P11533238A1137
+P01765269A0308
+P04102280T0000
+P01904546A0671
+P09846927A0227
+BC2GM016588295
+P09862496A0187
+BC2GM076278508
+P04645078T0001
+P10908364A0000
+P11785085X0001
+P02889495A0000
+P09618150A1464
+BC2GM095888580
+P01961213A0150
+P02482511A0860
+BC2GM018838269
+P01845899A0000
+P07891638T0000
+P08401614A0187
+P07935418A0447
+P11121118A0075
+P07771745A0442
+P10843716A0406
+BC2GM005608882
+BC2GM036174332
+BC2GM076347404
+P02775136A1151
+BC2GM001896188
+P02902615A0000
+BC2GM005581340
+BC2GM092640548
+P10652102A0620
+P02237431A0833
+P10698974A0951
+P10833486A0598
+BC2GM076657224
+P07669351A1278
+P01331501A0397
+BC2GM021696117
+P03780704A0573
+P11156413T0000
+BC2GM038727625
+BC2GM005993806
+P08552042A1497
+BC2GM026702973
+P01389585A0825
+P01825027T0000
+P10602516A0182
+P08151787T0000
+BC2GM074622354
+P09060676A1634
+P08827783A0499
+P10928337A0590
+P10644414T0000
+BC2GM079407274
+P02095150T0000
+BC2GM017291390
+BC2GM043977767
+P10672433A0199
+P07958911A0500
+P09828137A0000
+BC2GM053931795
+P05095988T0001
+P09358837T0000
+BC2GM021380457
+P09718372T0000
+BC2GM075119828
+P01583819A0377
+P08112601T0000
+P04796997T0000
+BC2GM006948843
+P07759525A0417
+P01870194A0302
+BC2GM085276860
+BC2GM011075999
+P03987857A0733
+P09278441A1160
+P06807149T0000
+BC2GM018411684
+P11888867A0000
+P09020856A0560
+P09248639A0152
+BC2GM060051589
+P01130186A0568
+P02436005A0707
+P00232456T0000
+P11358801A1046
+BC2GM037537411
+P10780018A0539
+P02831796A0000
+P00221725A0523
+P03563399A0534
+P09799793T0000
+BC2GM077806960
+P10613874A0663
+P07149047A0260
+P09015543A0210
+P08553580A0102
+BC2GM018605587
+P08395010T0000
+BC2GM075521296
+BC2GM044742819
+P02254418A0641
+P01375913A0484
+P09867855T0000
+P09595496A0000
+BC2GM071814520
+BC2GM039354270
+BC2GM079045353
+P04423347T0001
+P09605934A0801
+P09918720A0998
+BC2GM057610190
+P07942076A0497
+BC2GM095923750
+P07592658A0309
+P00465681A0000
+P06868345A0000
+BC2GM080157820
+P03451761A0215
+BC2GM019331308
+P03214709A0559
+P08409593A0357
+P09249070A0989
+BC2GM064633844
+P06208024A0168
+P07767011A0689
+BC2GM081961422
+P09872326A0566
+P03200488A0439
+P00427715A0000
+P02223773A0000
+P07964162A0941
+BC2GM015535578
+P09407642A0305
+BC2GM002487539
+P10022905A0446
+BC2GM098824982
+P00038408T0000
+P09084621A2567
+P02247924A0078
+BC2GM005777371
+P11259593A1094
+BC2GM078755837
+P05123884T0000
+BC2GM091158051
+P08777374A1471
+P06674374T0000
+P10763823A0824
+P07659085A1520
+P07929238A0734
+BC2GM094127714
+P01830928A0361
+BC2GM062280963
+BC2GM042560945
+P08417331A0745
+BC2GM092558649
+BC2GM022278881
+P09165039A0728
+BC2GM076789342
+P09525891T0000
+BC2GM033998537
+BC2GM073514147
+BC2GM054051105
+BC2GM077245988
+BC2GM058847965
+BC2GM010930693
+P09108029A0399
+BC2GM043530454
+P01671675A0905
+P09171468T0000
+P02711601A0601
+P03029111A0155
+P08490002A0620
+P10706475A0644
+P09549398A1463
+P03023887A0470
+P06524202A0167
+P02333545A0313
+BC2GM091278857
+BC2GM029787145
+P09132061A0828
+P02247081A0223
+BC2GM072933790
+P02336338A0931
+BC2GM050984092
+BC2GM026423593
+BC2GM091220407
+P09387333T0001
+P03885983A0254
+BC2GM037081508
+P02941237A0160
+P10574913A1108
+P08523031A0737
+BC2GM045876412
+P03545955A1378
+P09372968A0532
+P09067577A0721
+BC2GM061631132
+BC2GM076704194
+P10641037A1371
+BC2GM008190369
+BC2GM013416504
+BC2GM022592779
+P10687945A0000
+P03568311A0273
+P11438654A1237
+P08268912A0657
+P09236118A1455
+P02569411A0151
+P02989637A0671
+BC2GM052299815
+P01497582A0593
+P01518396T0000
+BC2GM015726285
+P04049799A0466
+P07758837A1118
+BC2GM080339050
+BC2GM077681760
+P11098420A0175
+P11374866X0914
+BC2GM064612390
+BC2GM043009268
+P08262067A1608
+P08522175A0306
+P09936001T0000
+BC2GM083405439
+P03513989A1149
+P00710217T0001
+P08978817A0620
+P01537845A0571
+P09358045A0000
+BC2GM027522433
+P09792439T0000
+P01624425A0907
+P08702756A0000
+P11311909A0938
+P10564593A1618
+P00578648T0048
+P05572662T0000
+P11371160A0854
+P10608053A0923
+BC2GM070643698
+P08194970A0000
+P10612805A0716
+P05101762T0000
+P11085267A0562
+P09536028A0945
+P09028942A0000
+BC2GM060649336
+P09271393A1333
+P01756539A0354
+P11289149A0658
+P09224655T0000
+P08651853T0000
+P06600533T0000
+P09858094A0583
+P01284828T0001
+P08703908A1814
+P07551787A0917
+P01846491A0459
+BC2GM065617223
+P07436794A0148
+P08120019A1500
+P11158310A0993
+P11221836A0981
+P03690262A0428
+P04018444A0000
+P08534367A0984
+P08838585A0968
+P03717936A0252
+P07824325A0714
+P09710599A0310
+P01191955A0077
+P01597272A0077
+BC2GM097445371
+P08336698T0000
+BC2GM095896930
+BC2GM004656785
+P11243777A0000
+BC2GM021307129
+BC2GM092923041
+P08523545T0000
+P02666568A0000
+BC2GM066241550
+P08157009A0264
+BC2GM048391096
+P06309855T0000
+P01837842A1410
+P09856397A0099
+P01380076A0165
+BC2GM096331297
+P08343961A0000
+P11465844T0000
+P08708984T0000
+P11280799A1025
+P09312025A0373
+P09368190A1053
+BC2GM045969390
+BC2GM068345268
+P10690725A1037
+BC2GM098192106
+BC2GM069143937
+P10567430A0785
+BC2GM048575101
+P06840803A0397
+P07638517A0000
+P09621372A0369
+BC2GM096399526
+BC2GM056776703
+P08055939A0159
+BC2GM045993010
+BC2GM015550026
+P01653238A1715
+P02543679A1291
+P01147502T0000
+P01347476T0000
+P10873388A0623
+P07565740T0000
+BC2GM005933281
+P01971191A1271
+P00686836A0000
+P02590540A0741
+BC2GM000843512
+P08994968A0926
+P10810745A0677
+P09242551A0653
+BC2GM001205480
+BC2GM022908464
+P07706291T0000
+P01954835A0000
+P09584194A1305
+P09537378A1227
+P03550444T0000
+P10786742A0670
+P08643557A0259
+P11158326A1032
+P07533527A0128
+P08626698A0989
+P01678287A1308
+BC2GM093522380
+BC2GM097779504
+BC2GM072704944
+P06809586T0000
+P11254752A1875
+P08890537A0355
+P04758799T0000
+P10688661A0237
+BC2GM054430010
+P11626110T0000
+BC2GM046112338
+P09820205A0000
+P07590744A0829
+P11325391A0498
+P07249660T0000
+P08509419A0785
+P04075061A0355
+P11435578A0760
+P11543317A0203
+BC2GM028646260
+P04172166T0000
+P08216115A0158
+P02547706T0001
+P05028628T0001
+BC2GM068931709
+P03728230A0104
+BC2GM045173873
+P07623840A0352
+P10704285A0536
+P01909027A0922
+BC2GM064382331
+P02705072A0464
+P07667097A0267
+P02740955A0333
+P02555177A0488
+P11387208T0000
+P07565688A0797
+P08639521A1032
+BC2GM057243625
+P08943934A0604
+P07413441T0070
+P09171081T0000
+P10563212A0514
+P01861034A0798
+P09346238T0000
+P01626372T0000
+P02200736A1003
+P07914700A0000
+P07597804A1007
+P03601275A0601
+P08626313A1037
+P09368419A0628
+P09333026A0397
+P08808707A0631
+P09811695A1146
+P03076124A0496
+P08144037A0000
+P00626014T0001
+BC2GM088377969
+P02702566A0000
+P01985920A0156
+P06816123A0526
+P07973825A0445
+P07520098A0211
+P11340080A0096
+P08063836A0904
+BC2GM083904809
+BC2GM097601782
+P03111946A0309
+BC2GM096844246
+P00696680A0000
+BC2GM085074416
+P11352663A0138
+P11113822A0999
+P07276210T0000
+P10810294A0730
+P08268718A0676
+P08300611T0000
+P02483210A0000
+P11879108A0719
+BC2GM035632930
+P07628456A0000
+P02609112A0000
+P11437439A0201
+P09639074A0707
+BC2GM049324176
+P08798762A1279
+P07771671T0000
+P02131666A0483
+P09759691A1051
+P02831556A0173
+BC2GM045403692
+P11318608A0669
+P07743472A0181
+P08626596A0000
+P08993836A0699
+P08189498T0000
+BC2GM094246030
+P10812294X0000
+P07968409A0123
+P01035457A0623
+P09804779A1163
+P02987777A0000
+P08276900A0543
+P02894689A0000
+BC2GM077161229
+P08444344A0000
+P08627667A0132
+BC2GM043707576
+P09601940A0280
+P09334475A0327
+P10739671A0136
+P08309975A0662
+P08139928T0000
+P10586115A0477
+P02176152A0896
+P10713176A0885
+P03568311A1361
+P07529516A0474
+P09858588A1046
+BC2GM098375429
+P10741947T0000
+BC2GM018871077
+BC2GM005714480
+P10871842A0988
+BC2GM084179136
+P06994049T0001
+P09291098A0452
+BC2GM073017347
+BC2GM034072679
+P03904004A1577
+P11220166A0616
+P09582953A0000
+P08922390A2076
+P09583201A0759
+P08683983A1163
+P09488486A0906
+BC2GM038386703
+P03946125T0000
+P07857344A0591
+BC2GM085890702
+P09001313A0000
+BC2GM055422231
+P11413277A1121
+BC2GM086028884
+P11279324A0710
+BC2GM007032064
+P10749932A0000
+P07883168A0090
+P09984526T0000
+P08212571A0971
+P08760889A0531
+P08835969A0000
+BC2GM051590745
+P04038702A0768
+BC2GM053665808
+P11406007A0292
+P01885915A0000
+P09431812A0576
+P04791420T0000
+P01956285A0000
+P10601335A0892
+BC2GM058761763
+P01424674A0000
+P11310937A0548
+BC2GM006085106
+P01846206A0665
+P03015953T0000
+P10963735A0193
+P11126353A0582
+P06298720A0893
+P02853922A0596
+P05460466T0001
+P03072580A0455
+P03659603A0797
+P01107226A0808
+P04021431A0000
+BC2GM003163464
+P01577056A0178
+P08576131A0685
+P05005311T0000
+P09917389A1239
+BC2GM064369940
+P03183127A0068
+P02122454A1042
+P01739956A0638
+BC2GM019595321
+BC2GM089028538
+BC2GM050762362
+P11070007A0136
+BC2GM056576430
+P08496599A0310
+P07590268A0350
+BC2GM066700172
+BC2GM014145288
+P02489753A0581
+P02511430A0000
+BC2GM039680603
+P08058948A0810
+P00199012T0000
+P09369450A1358
+P03146784A0158
+BC2GM009197562
+P07474140A1036
+P00696858A0000
+P03006066A0653
+P07253335T0000
+P09032254A0724
+P09431828A1472
+P09867253A0229
+P09084621A0374
+P08561897A0604
+P08677443A0238
+P10866323A0666
+P07592485A0734
+P00837262A0000
+P04512496T0000
+P07982964A1017
+P06096246T0000
+P10441243A0443
+P09046090T0000
+P03887769A0093
+P09552469A0225
+P10684304A1242
+BC2GM075112019
+P03227568T0001
+BC2GM051098108
+BC2GM027072594
+P05893495T0001
+BC2GM075182696
+P07495726A1189
+P09861365A0000
+P10019841T0000
+P01116466A0185
+P08816459A0090
+P00926272A0000
+BC2GM047671701
+BC2GM045967019
+P08833153A0628
+P02861238T0000
+P07569075A0585
+P03517388A0763
+P06790572A0330
+P10932196A0359
+BC2GM015437343
+P11380837A1505
+P04392584T0000
+BC2GM062865451
+P09061697A0629
+P11216247T0000
+P08072547A1009
+P01256410T0001
+P10856491A0178
+P10597232A0000
+P01476376T0000
+BC2GM036882521
+BC2GM001688677
+P09153319A1332
+P01625131A0452
+P10773951A0000
+P09880029A0703
+P07929431A0949
+BC2GM022798605
+P04446923T0001
+BC2GM085879791
+P08517737A0889
+BC2GM009275309
+BC2GM045854489
+P07676655A0214
+P08937112A0561
+P00430247A1073
+BC2GM066131450
+BC2GM031886187
+P09570133A0474
+P03330711T0000
+P04787716T0000
+P11434084A0508
+P09317757T0000
+P08036004A0292
+BC2GM049951633
+P11520436A0705
+P01324172A0880
+P00866577A0579
+P08523566A1106
+P08390120A0785
+P02406570A0466
+BC2GM090587249
+BC2GM063124230
+P08848013A1469
+P03404334T0000
+P10896859A0000
+P02496109A0754
+P09952425A0893
+BC2GM020478123
+BC2GM075378170
+BC2GM095082528
+BC2GM044020511
+P09076336A0281
+BC2GM086175633
+P02790009A0375
+BC2GM089015386
+P08812490A0000
+P09710641A0000
+BC2GM030828493
+P08188258A0000
+P07881077A0195
+BC2GM037899934
+P07869721A0000
+P01158838A0438
+P03368701A0113
+P04069756T0025
+BC2GM033742253
+P09171239A1118
+P03828500T0001
+P00473249T0000
+P09010223A0667
+P00479246T0000
+P03108171A0088
+P07666966A0207
+P10777586A1022
+P08621384A0935
+P08334304A0473
+P01996312A0454
+BC2GM090038156
+P11433018A0756
+P09770415A0139
+P02143023A0729
+P03837609T0000
+BC2GM063549189
+P08798443A0660
+P07742550A0407
+P09206968A0000
+P01087288T0000
+P09189896A0611
+BC2GM053683599
+BC2GM091634210
+P11295470A0954
+BC2GM023518208
+BC2GM066695661
+P02535460A1443
+BC2GM082522645
+BC2GM017399394
+P07588750T0061
+P06074640T0001
+BC2GM012909505
+BC2GM053097733
+P07871891A0227
+P08723883A1684
+P09781761A0384
+BC2GM040272991
+P09365272T0000
+P09990507A0763
+P09018133A0244
+P09195923A0125
+P09777477A0000
+P09115365A0000
+P09053835A0865
+P07890680A1193
+P09188863A0954
+P09628890A0455
+BC2GM084248034
+P05807222T0052
+P01736844T0000
+P09027506T0000
+BC2GM074465218
+P02113455A0207
+P07906616A0191
+P01545792A0492
+P01691184A0995
+BC2GM090228241
+BC2GM053041112
+P02179052A1044
+P07541912A0485
+BC2GM034354079
+BC2GM070595219
+P11513121T0000
+P07892076A0578
+P09309457A0680
+P11207288A0897
+P02156828A0164
+P10612918A0318
+P09878542A1151
+P09787323A0000
+BC2GM081453931
+P10727515A1202
+P07565104A0084
+P00780639X0000
+P00304310A0000
+P07538122A0800
+BC2GM015638731
+BC2GM061646727
+P09858581A0183
+P01759282A0000
+P09748669A0414
+P01783088A1136
+BC2GM056619320
+BC2GM051472026
+P09536440A0000
+P06162419A0118
+P09206230A0000
+P08626539T0000
+BC2GM099313539
+P09778006A0718
+BC2GM017403809
+BC2GM053532690
+BC2GM003309537
+P09268298T0000
+P02861144A0242
+P03133360A1215
+BC2GM057515981
+P08317092A0304
+P07902532A0312
+P09510582A0157
+P10654032A1133
+P08876167A0717
+BC2GM084419683
+P09239635A0477
+P02231162T0000
+P07916689A1407
+P02895754A0000
+BC2GM001871340
+P01730412T0000
+P09621893A0000
+P01961747A0000
+P06152670T0000
+BC2GM025369087
+P10872827A0000
+P06411659A0264
+P01523111A0769
+P01554334A0000
+P10433729A1559
+P09242375A1313
+P02765001A0105
+P06300662T0000
+BC2GM039969653
+P07274505A0660
+P02406992A0192
+P02228615A0974
+P07267675A0000
+P08760872A0696
+BC2GM051143447
+P06251469A0830
+BC2GM083693291
+BC2GM060353149
+P08666398T0000
+P01630455A0448
+P06098828A0352
+BC2GM014167322
+P08209772A0167
+BC2GM018313543
+P02209540A1362
+P02597484A0624
+P10747987A0658
+P02514498A0000
+P08937981A0840
+P01986241A0117
+P07004236A0741
+P09565606A0520
+P09678579A0768
+P01675637T0033
+P07528325A0165
+P10848848A0413
+P00771729X0000
+P09897032T0000
+P07572582A0000
+P09049313A0116
+P07799925A0526
+BC2GM033668177
+BC2GM083885285
+BC2GM090980905
+P09341182A0605
+BC2GM096003316
+P11353770A0085
+P10932527T0000
+P09799634A0161
+P08720407A1386
+P10657238A0541
+P01774063A0161
+P08269439X0000
+BC2GM065517718
+BC2GM002326238
+P09689047A0253
+BC2GM093300665
+P07080496A0097
+BC2GM014406229
+P06516847A0393
+BC2GM092362540
+BC2GM088490970
+P08662852A1297
+P08072352A0567
+P09393706A1171
+P07636648A1229
+P07320153T0000
+P11486399A0000
+P00616575A0000
+P02151229A0000
+P09328343A0181
+P09045805A0945
+BC2GM017879501
+BC2GM089291687
+P08421910A0599
+P02923687A0218
+P11408591A0000
+P02967496A0182
+P01695314T0000
+BC2GM092831891
+P06667015A0832
+BC2GM090610024
+BC2GM040656099
+P07543592A0624
+P08837746A0951
+P09335267A0142
+BC2GM098593892
+P06319071A0173
+P07455521A0414
+BC2GM009991407
+BC2GM074912352
+P04026903A0512
+P09511724A0483
+P00825571T0031
+P11112438X0847
+P08927841A0053
+P07592072A0217
+BC2GM084096579
+P00369397A0280
+BC2GM055315258
+P08818436A0557
+P09466267A1192
+BC2GM032522078
+P02591078A0000
+P10742114A0486
+P08562688A0968
+P09009208A0337
+P04247472T0001
+P01194673A0652
+BC2GM011109464
+BC2GM064390333
+P05594277T0051
+P11152081A0413
+P07546794A0100
+P08702826A0870
+P11117826A0788
+P04638365T0001
+P09636708A0460
+BC2GM053725258
+BC2GM089407597
+P03857577A0413
+P06805504A0629
+P02779752A0000
+P08392623A1374
+P08276732A0799
+P09670943T0000
+P01824944A0988
+P07525548A1380
+P08794601A0000
+BC2GM013674517
+P08237578A0253
+P08790288A0068
+P11185475T0034
+P06869215A0347
+BC2GM063998013
+P03602261A0238
+P01170143A0247
+P08390831A0143
+BC2GM084536918
+BC2GM026213346
+P08849778A0598
+P09003311A0478
+P09833740A1112
+P11441974A0320
+P09241232A1154
+P08771781A1103
+P08816461A0892
+P08649403A0963
+BC2GM072208661
+BC2GM039739428
+P11123089A0362
+P08443341A0384
+P07523363A0440
+BC2GM073857956
+P06367414A0000
+P08948440A0628
+P02164637A0515
+BC2GM062065726
+P09000589A0000
+P10564484A0859
+P08597596A0135
+P09819411A0897
+P02778873A0761
+BC2GM018326303
+P02119946T0000
+BC2GM096950581
+P06658445A0140
+BC2GM057856601
+P10976413A0514
+P01532229A1264
+BC2GM034256968
+P09916786A0811
+P03308909A0485
+P05309471T0000
+P07740487A0167
+P10748672A0130
+P10715325A0834
+P07728201A0660
+P04967824T0000
+P02014928T0000
+P05806936T0000
+P07988559A0836
+BC2GM065027203
+BC2GM052576426
+P09701821A1108
+P09837913A0419
+P08839498A0507
+P08196607A0280
+P02315151T0020
+P02572777T0000
+P10992983T0000
+P07522163T0000
+P08094464A2014
+P11203702A1307
+P10642531A2322
+P06109017A0000
+P08231398A0802
+P04004168A0000
+BC2GM012559118
+P07862150A0429
+BC2GM080568509
+P11390650A0562
+P06880650A0316
+P08139001A1235
+P11411961A0735
+P03335127A0176
+BC2GM037741487
+P11189314A1000
+P09400613A0594
+BC2GM085157618
+BC2GM005451560
+BC2GM091911719
+P08915559A0366
+P08649427A0689
+P07862108A0987
+P03542945T0000
+P08647086A0622
+BC2GM004628180
+P08000427A0000
+P10704283A0649a
+BC2GM093193565
+P01459885A0705
+P03691316A0560
+P06854957T0066
+P09305755A0540
+P06957125T0000
+P08702936A0168
+P11522658A0870
+BC2GM053054541
+BC2GM057069955
+P09642200A0956
+P09345495A0000
+BC2GM075057659
+P07640309A0000
+P01734283A0817
+P10779352T0000
+BC2GM021097776
+P07061350A0042
+P08521780A0485
+P00619948A0000
+P08360112T0036
+P05065548T0075
+P03018491A0840
+P09633879A0246
+P08408825A0000
+P10868488A0921
+P08916960A1331
+BC2GM008563458
+BC2GM005568941
+P07983715A0996
+BC2GM029716691
+P08072547T0000
+P11072388T0000
+P01992459A0000
+P01559209T0000
+BC2GM013299082
+P11179956A1818
+P02717133T0001
+BC2GM007116849
+P09072361A0357
+BC2GM045785731
+P10677214A1045
+P06151518A0000
+P01717718A1255
+P11345435A0199
+BC2GM086602241
+P11264177T0000
+P09770493A0499
+P08035498A0833
+P08552093A0657
+P08580671A0137
+BC2GM090241856
+BC2GM069413294
+P11029045A0000
+BC2GM085413059
+BC2GM079199097
+P03774111T0000
+P10762348A0269
+P07341346A0174
+P06131038A0000
+BC2GM039075708
+P07559233A0534
+P02859434T0000
+P02317413A0364
+BC2GM081228563
+P05441564T0001
+P09463991T0000
+P06310457A0000
+P07472582A0993
+P00013683A0210
+P09358055A0590
+BC2GM019076970
+P08430095A0913
+BC2GM024564253
+P09880103A0387
+BC2GM048329227
+BC2GM042469418
+P02131652A0883
+P06833047A0000
+P07916326A0000
+P10928477A0764
+BC2GM011910286
+P02898752A0683
+P06320380T0001
+P10896859A0838
+P11012568A0192
+P01458170A0155
+P01630569A0605
+BC2GM038169511
+P07547220A0229
+BC2GM066709301
+BC2GM052592239
+P07888623A0721
+P11280495A1330
+P06296833A0000
+P08126096A1071
+P02818260T0000
+P01897515A0348
+P11176290T0000
+P07731686A0000
+P01338867A0503
+BC2GM009218919
+P07401318A0823
+P08504933A0000
+BC2GM077229462
+P09514260A1083
+P08202546A1206
+P03805090A0645
+P01398104A0834
+P08067013T0001
+P10860827A0399
+BC2GM007462529
+P08873063A0493
+BC2GM070035080
+P02024252A0000
+P09414287A0637
+BC2GM011442958
+P01916168A0969
+P01702426A0196
+P09005273A0322
+P09024097A0000
+P02300759A0000
+P05034373T0000
+BC2GM038794623
+BC2GM021235622
+P08361761A0174
+P07935491A0495
+P07372433A0000
+P07496184T0001
+BC2GM086709432
+P08970991A0747
+P11539522A0612
+P04562038T0001
+P01171020A0711
+P09271397A1596
+P01539996A0588
+BC2GM063528560
+BC2GM012984521
+P08332033T0000
+P08314922A0941
+BC2GM048598667
+BC2GM075197573
+P00001606T0076
+P09474648A0298
+P02274509A0623
+BC2GM097982255
+P01765386A0305
+P11416012A1982
+P09658403A1207
+BC2GM089348837
+P01506705A0282
+P09236224A0939
+BC2GM047640437
+BC2GM048797879
+BC2GM046344700
+BC2GM070645862
+P09826434T0000
+P03597269A0409
+P08816472T0000
+P10691972T0000
+BC2GM080881152
+P10756032A0599
+P02838246A0225
+P09498769A0095
+P09610755A1731
+BC2GM027119323
+BC2GM095526870
+BC2GM014345579
+P07557387A0241
+P11031366T0001
+P09199322T0000
+P01542686A0000
+BC2GM096905196
+P06672094A0390
+P09717887A0239
+P08910567A2269
+P11266540A0328
+P06602580A0664
+BC2GM002874950
+P07872788A1717
+P03276246A0037
+P01253191T0000
+BC2GM083080586
+P07776711A0295
+BC2GM098647724
+P01982061T0000
+P08002564A0249
+P03192950A0566
+BC2GM089489545
+P09452444A0000
+P09353304A0732
+BC2GM089490423
+P07113897A0285
+P09480843A0848
+P10622574A0000
+P08719156A0953
+BC2GM017175901
+BC2GM057130541
+P06984225A0367
+P09915118T0000
+P08170400T0000
+P02179815A0582
+P00857024A0888
+P07518426A0000
+P10936920A0105
+P00219674A0000
+P11197288A0855
+P09550591A0454
+BC2GM037342398
+P06161823A0129
+P11570735A1097
+P06685004A0000
+P11428435A0446
+BC2GM001213287
+P09344650A0967
+P10933154A1118
+BC2GM034824731
+P08396261A0388
+P09450932A0142
+P02574016A0428
+BC2GM000026289
+P07542616A0486
+P02731611A0134
+P10729220A1569
+BC2GM058292678
+P02111015A0574
+BC2GM060722870
+P09233809A0381
+P07635140A0172
+P06167806A0000
+P09205677A0577
+BC2GM018123689
+P06319740A1331
+P10493876A0000
+P09121433A0463
+P03627720A0196
+BC2GM036750141
+BC2GM020852658
+P09197408A0126
+P02809831A0799
+P05145925T0000
+P08453101A0128
+P08707424A0709
+P02390989A0745
+BC2GM077166085
+BC2GM027258079
+P08208540A1114
+BC2GM057809152
+P08550467A0863
+BC2GM033411061
+BC2GM005575827
+P07744846A1006
+BC2GM094893147
+BC2GM054881964
+P09417941A1287
+P08264582A0750
+P09625807A0000
+P07559555A0557
+BC2GM003241979
+P08675026A0420
+P08661114A0564
+P07899581A0000
+P10786671A0182
+BC2GM024533099
+P11056007A0224
+BC2GM087199820
+P09259320A0830
+P08491124A0517
+P10485585A0175
+P11082587X0000
+BC2GM079069555
+P09473483A0953
+BC2GM072333569
+BC2GM084800882
+BC2GM035600571
+P06224974A0833
+P08049885T0000
+P02182323A0121
+P08264583A0520
+BC2GM070226026
+P02766508A0421
+P01330975T0000
+P09507032A1144
+P08649372A0501
+P03776080A0400
+P00239014A0000
+P02899177A0605
+P09425676A0000
+P10970048A0352
+P10708424A0800
+BC2GM083638339
+P00198510T0000
+P07908187T0000
+P11207269A0745
+P06120429T0000
+BC2GM062596008
+P04061342A0512
+P07237817T0000
+BC2GM012120254
+P11309678A0489
+P09390183A1027
+BC2GM022628668
+P07296997A0125
+BC2GM064070437
+BC2GM018288795
+BC2GM083615175
+P11278400A0668
+BC2GM065459831
+P10873387A0816
+P01464606A0344
+P07516866A0000
+P00429893A0000
+P07508082A0821
+P00118044A0000
+P01844878A0000
+P01403391T0000
+P09234743A0475
+BC2GM090380328
+P10722737A1726
+P04086993T0000
+P09691037A0355
+P10857751A0304
+P07673128A0989
+P07190627T0000
+BC2GM071536994
+BC2GM008162838
+P11145743A0170
+P02844767A0191
+P11014197A0339
+P11285054A0781
+BC2GM083269522
+P03841627T0001
+P01990254A0791
+BC2GM083471063
+P11108374A1466
+P09023378A0959
+P11132790A0609
+BC2GM043897639
+P02354381A0207
+BC2GM057244424
+P09847371A0000
+P09807755A0146
+P10888570A0678
+P07487363A0447
+P02153243A0965
+P08593813A0967
+P00985279A0493
+P11391303A0807
+P09294262A0885
+P08451331T0000
+P08229330A0000
+P02814820A0967
+P09422351A0000
+P09242506A1033
+P09792627A0441
+BC2GM009462696
+P07405701T0000
+P04140567T0001
+BC2GM090248535
+P04213917T0001
+BC2GM096521893
+P08361754A0733
+P07958920A1157
+P05692759T0001
+P07761216T0000
+P00211881A0602
+BC2GM070651049
+BC2GM097347861
+P08899719A0318
+BC2GM077216151
+BC2GM078039869
+P02247072A0794
+P07864652A0753
+BC2GM007000776
+P09171969A1165
+P10850997A1016
+BC2GM028177619
+P07999982A0086
+P03072021A0696
+P08294386A0000
+P02121371T0000
+P07784079A1018
+P08829393A0083
+P07890485A0827
+BC2GM091451478
+P06966678A0523
+P11210988T0000
+P07135112T0000
+P02423850A0292
+P06784123T0000
+BC2GM078278195
+P00569989A0239
+BC2GM059925570
+P03880838T0000
+P08497259A0452
+BC2GM023060026
+P11286833A0959
+P02078570A0287
+P02621983T0001
+P08840506A0544
+P09115357A0073
+P08637006A0000
+P01281472T0000
+BC2GM078861237
+P07345217A0000
+P11059786A0682
+P08343216A0883
+P10665308T0001
+P09446815A1021
+P08707825A0063
+P00111174A0351
+P01628201A0824
+BC2GM046451066
+P07494274A1015
+P08534855A0000
+BC2GM052870770
+P06890935T0001
+BC2GM083427683
+P11007968A0255
+P03396437A0321
+P00022143T0000
+BC2GM056577777
+BC2GM084696826
+BC2GM034787245
+P00506649T0000
+P07508441A0487
+P09182990A0245
+BC2GM011563299
+P08916960A0350
+P09545638T0000
+BC2GM074564112
+BC2GM028392901
+P08371713T0000
+P00618078A0367
+P11118438A0411
+BC2GM084178776
+P01446828A1088
+BC2GM034941243
+P08277632A0997
+P02761537A0168
+P00437749A0242
+P01384165A0000
+BC2GM022990188
+P09006007A0997
+BC2GM063249278
+P00557559A0170
+P07078263T0000
+P03246999A0483
+BC2GM039524689
+P00815369X0000
+P09488725A0904
+P04075021T0000
+P08816507A1125
+P11114924A0808
+P10649449A0413
+P01310935T0000
+P11114718A0349
+P00456424A0000
+BC2GM021612626
+P08587075T0000
+P11404016A1922
+P02196565A0606
+P09914156A1496
+P04919613T0001
+P01968156T0000
+P09111314A1243
+P11569800T0000
+BC2GM083564005
+BC2GM030428855
+P11565747A1020
+BC2GM062242948
+P10829973T0000
+P08429020A0495
+P00493818A0422
+P06092588T0000
+P07809410A0606
+P09822685A0596
+P07528746A1049
+P02195025T0000
+P02335521T0000
+P02840034A1266
+P02776471A0235
+P03484894A0782
+P01909960A0134
+P01208811T0001
+BC2GM050319569
+BC2GM057017444
+P09792682A0713
+BC2GM013302577
+P03344586T0000
+BC2GM084663535
+P01586901A0000
+P07636962A1288
+BC2GM098250324
+P01939899A2043
+P02154686A0185
+P06535384A1115
+P07657705A1181
+P09426143A1358
+BC2GM029041456
+P08538052A0000
+P02203672A1542
+P10651076T0000
+P07559639A0996
+P10871045A1221
+P10671606A0884
+P02649811T0000
+P03115787A0633
+BC2GM094871087
+P02102823A0492
+P09538258A0200
+P08601284A0000
+BC2GM007028303
+P07262625A0000
+P07832779A0719
+BC2GM085373279
+BC2GM050673543
+P08902847A1946
+BC2GM084353628
+P11427329A1077
+P03311954A0000
+P08868473A1287
+P08293992A0432
+P07598303A1728
+P06916588A0304
+P07126413A0000
+P06928974T0000
+P07836228A1052
+P02907533A0362
+BC2GM046169713
+BC2GM027073602
+P11297545A0948
+P07782087A0559
+P07957106A0471
+P02776823A0000
+P01797459A0103
+P01714358A0990
+P09235424A1200
+P02284393A0751
+P02809722A0926
+P00316723A0558
+BC2GM072405160
+BC2GM099647804
+P07953785A0648
+P00100540T0000
+P08530345A0880
+BC2GM039301722
+BC2GM085408195
+P07753030A0173
+P09366456A0234
+BC2GM085810143
+BC2GM009500252
+BC2GM053451054
+BC2GM011104369
+P00084275T0063
+P08980536A1196
+P07612174A1064
+P07601827A0778
+BC2GM068674132
+P11098217A0674
+P03684378A0653
+P07499394A0187
+P03370815T0000
+P05456002T0000
+BC2GM081105938
+P08550460A0374
+P09271400A0475
+P01525966T0000
+P09524122A0336
+BC2GM023248039
+P11504709A0981
+P07696450A0271
+P10380232A0000
+P02046202A0625
+BC2GM022697096
+P02123295A0645
+BC2GM051884914
+P09524267A1023
+BC2GM081600105
+P07859777A0000
+P06674516A0350
+BC2GM053572973
+P07687541A0992
+BC2GM040683768
+BC2GM026141578
+P09774662A0958
+P01892680A0907
+P02473718A0000
+P01932650A0435
+P01751255A0529
+P08355062A0000
+P08952483A0207
+P09694599A1355
+BC2GM035382344
+P05087496T0000
+P09151925A0479
+P01309910A0428
+BC2GM029508007
+P06130348T0000
+P10657899A0685
+P10770065A0264
+P02312689A0360
+P09343208A1405
+P10662614A0972
+P08438584A0524
+BC2GM076094656
+P02070227T0000
+BC2GM019927220
+P08896590T0000
+P10901133A0381
+P03977577T0000
+P10664876A0000
+P09693306T0000
+BC2GM095835528
+P11263664T0000
+P02137458A1129
+P11282761A0531
+BC2GM033262537
+P07021505A0510
+P07873831T0000
+P08955189A1198
+P09843412A0130
+BC2GM015170864
+P10393969A0000
+BC2GM058284658
+BC2GM014357227
+P02949170A0184
+P09712898A0911
+P01396432A0388
+P03274204A0642
+P04524081T0000
+P09889202T0000
+P08639310A0548
+P09824158A1336
+P07975882T0000
+P09297698A0933
+P03010281A0220
+P03000457A1554
+BC2GM072883448
+P09778197A0415
+P09398267A0440
+P00414575T0000
+P10682570A0453
+P09337861T0000
+P02541882A0251
+BC2GM069498013
+P07891709A1542
+P07969135A0913
+P09676349A0000
+P08182171A0000
+P01742879A0471
+P08088777A0754
+P09679750A0304
+P09630245A0102
+P09244430A0693
+P05734847T0000
+P01726631T0001
+P11359907A0099
+BC2GM046384493
+P09162097A0776
+BC2GM076369923
+P01364100A0377
+P11034547A1355
+P11257870A0000
+P03112028A0404
+P08576245A0000
+BC2GM095153900
+P07626806A1098
+P08847138A0609
+P09651375T0000
+P10598101A0754
+P03887085A0000
+BC2GM013625410
+P02532210A0000
+BC2GM048243610
+P07994021A1223
+BC2GM019284772
+P08083220A0988
+P07789342A1352
+BC2GM045860738
+BC2GM075993463
+BC2GM045550408
+BC2GM081970159
+P03065141A0448
+P01138215T0001
+P05718500T0001
+P01757341A0591
+P09671579A1168
+BC2GM018362321
+BC2GM011727188
+P07096587A0267
+BC2GM030855437
+BC2GM094780513
+P02204029A0184
+P09037064A0183
+P07595374A1215
+P03179496T0000
+BC2GM052999233
+P09300698A1219
+P04580044T0047
+P08637717A1231
+P11368911T0000
+P09632734A0943
+BC2GM085332953
+BC2GM037104240
+P01485648A0000
+P08152800A0357
+P08355539A0133
+P10240361T0000
+P09258606A0822
+P06373409A1163
+P07748952A0462
+P07834582A0115
+P07780525A0495
+P02353453A1249
+P01171935A0313
+P09000049A1341
+BC2GM057796202
+P01333125A0000
+P11008420A0580
+P00196255A0000
+P11161455A1286
+P07349416A0337
+P11323419T0000
+P09903722T0000
+P01846803A0688
+P08145646T0000
+P11025367A1009
+P01544854A0699
+BC2GM064857683
+P09418040T0000
+BC2GM008087680
+P00847967T0000
+P08877818A0184
+P11423991A1393
+P09204566T0000
+P06658029A0086
+P01653918A0286
+BC2GM012663791
+P10187317T0000
+P03146150T0000
+BC2GM006351577
+P03491190A0233
+P08056474A0438
+BC2GM030625500
+P08040468A0303
+P06728580A0291
+P08245125A0822
+BC2GM011862984
+P07835710T0000
+P10906999T0000
+P02356823A0063
+P08349499A1169
+P01901443A0297
+P03940426A0618
+P08421295A0365
+P11410563A0363
+BC2GM022540559
+P09388199A0948
+BC2GM066102549
+BC2GM084547844
+BC2GM020659515
+P07809128T0000
+BC2GM000493215
+P06720371T0000
+P03928678T0000
+P11213342A0492
+P11259347A0000
+P10871615A0368
+BC2GM044494195
+P09545323T0000
+P11418662A0917
+BC2GM078517067
+P09326317A0372
+BC2GM032835553
+P03023679A0624
+P11818675X0897
+BC2GM013684936
+P08282576A0297
+P02154599A0382
+P08283292A0779
+P08427501A0221
+BC2GM035405200
+BC2GM001805382
+P07967725A0262
+P10644760A0956
+BC2GM092921833
+P11494391A0579
+P04079738A0677
+P03888621A0185
+P02572928T0000
+BC2GM024324906
+P11536063A0178
+BC2GM013429399
+BC2GM066038185
+P09287036A0457
+P01549465A0122
+P02204810A1080
+BC2GM068897228
+BC2GM098204946
+P01895370A0199
+P03746906A0000
+BC2GM027366629
+P08515776A0971
+P10675331A0600
+P08001792A0284
+P10599727A1567
+P09235073A0000
+P01518849A0165
+P02492111A0670
+P03992022A0330
+P11160732A0464
+P00465223A0373
+BC2GM045716820
+P04335965T0000
+BC2GM090642348
+P06314312A0359
+BC2GM090857419
+P01963438T0000
+P01396444A0934
+P08195233A0147
+P01741249A0177
+P07654740A0563
+P09649265A1575
+P07926775A0895
+P01895555T0001
+P07791771A0183
+P00445259T0000
+P02568930T0000
+BC2GM001245991
+P01653236A0895
+P02236002A0958
+P09022040A0263
+BC2GM047460616
+P09949312A0524
+BC2GM037150480
+P03664038A0000
+P11092886A0341
+P03559287T0000
+P08316209A0000
+P08632015A1226
+P04563045T0000
+BC2GM040092989
+P09599102A1191
+P01916632A0431
+P08376397A0788
+P09576230T0000
+P11350982A0560
+P07140060T0000
+P09882451A0195
+P11471077A0382
+BC2GM064960643
+BC2GM019494722
+P07499242A0898
+P07651340A0286
+BC2GM019485774
+BC2GM038250262
+BC2GM095049284
+BC2GM062202050
+P00986800A0325
+P07575416A0000
+P01777841A0744
+P09111331A0119
+P07935094A0516
+P03064524A0160
+P03034956A0666
+BC2GM078938959
+P07745693A0914
+BC2GM052216512
+P01939131A0871
+P07457931A0655
+P09602124A0127
+P09651383A0967
+P09130720A0417
+P11413319A0000
+P06314276T0000
+P02026461A0760
+BC2GM040737294
+P01911767T0000
+P01468625A0282
+P11070056A0704
+P09121424A0296
+P09333168A0310
+BC2GM096394711
+P07567980T0000
+P06732946A0281
+P02566680A0820
+P09435789A0961a
+P07891720A0818
+P09917064T0000
+P11204897A0797
+BC2GM071919705
+P01870428A0677
+P11178765A0642
+P06340643A0598
+P10805739A0343
+BC2GM055384901
+BC2GM007915861
+P02030910A1070
+P07926739A0766
+P11133927T0000
+P07511444A0728
+P06671925T0000
+BC2GM059522936
+BC2GM010895648
+BC2GM051997462
+BC2GM039151408
+P08636124A0410
+BC2GM074834235
+BC2GM008564407
+P02188096A0955
+P08668124A0744
+P08626540A1007
+BC2GM073396210
+BC2GM044963002
+P09427627A0930
+P07563076A0766
+BC2GM070904413
+P01209618A0409
+BC2GM008679879
+P08627354A0000
+BC2GM011821006
+BC2GM056629834
+P08105727A0099
+P04086657T0000
+BC2GM032259254
+P06657559A0489
+P07883193A0000
+P02093033T0001
+P00061478T0000
+P05413428T0000
+BC2GM029325311
+P11333268A1521
+P02989786A0328
+P08220621T0000
+P04428981T0000
+P07007591A0324
+BC2GM046385397
+P07969181A0313
+P00926604A0504
+P02562787A0637
+P02174974A0000
+P01621584A0183
+BC2GM023474684
+P10894149T0000
+P06308607A0375
+P09566871A0343
+P08497273T0000
+P09605930A1428
+P11328853A0644
+BC2GM006482394
+P09617765A0174
+P09271417A0585
+P03672532A1111
+P07496400A0525
+P08529630A0840
+P03881260A0000
+P08649389A0000
+P07916003A0688
+P09426595T0000
+P03286611A1198
+BC2GM087141217
+P08997490A1127
+P11092850A1023
+P07959952A1446
+P00617815A0215
+P09931118A1072
+BC2GM036392527
+P09581552A1323
+BC2GM017589231
+P01010638A0161
+P07668009A0172
+P11288930A0000
+P02300541A0000
+P00593119T0001
+P11398899A1183
+P09034337A0251
+P08549706T0000
+P01850127A0000
+P02826127A0709
+P07487908A0230
+BC2GM092705100
+BC2GM030204205
+BC2GM012329811
+P03119227A0079
+P04942414T0000
+P09806516A1212
+BC2GM076028870
+P08631797A0982
+BC2GM086450359
+BC2GM040056717
+P07247059A0775
+P07626378T0000
+P08218230A1505
+P09236656A0124
+P08959117A0708
+P10652800A0984
+P08632015A0879
+P04730467T0000
+P09058373A0670
+P08428940A1763
+P09308234A0225
+BC2GM014433955
+P07174122A0000
+P11131321T0000
+P10850453A1292
+BC2GM039883635
+P06054411T0000
+P03743683A0000
+P01080374A0709
+P02552316A0526
+P08290421A0165
+P08288622A0725
+P07745726A1496
+P06809474A1156
+BC2GM027985903
+P10775585A0754
+P08160905A0217
+P11897449A0566
+P09780228A0613
+P04482661T0001
+P02404451A1532
+BC2GM025908037
+P07553942A0810
+BC2GM023807131
+P01930660T0000
+BC2GM033841968
+P11379106A0372
+BC2GM052769911
+BC2GM090842010
+BC2GM046615396
+BC2GM061934161
+P10747053A1102
+P01646753A0336
+P09650180A1130
+P11355576A1125
+BC2GM066378322
+P10650938T0000
+P02146495A0706
+P03228518A0339
+BC2GM055880563
+P07763727A1035
+P09021684A1418
+P06223586A0000
+P03229917A0099
+P07713421A1435a
+P09769209A0100
+P07559563A0282
+P09079878A0000
+P07495059T0078
+P01736093A0731
+P11562278A0169
+P01702426A1006
+P03181276A0422
+P01812690A0475
+P03015628A1078
+P05091970T0000
+BC2GM064815808
+P08045431A0894
+P06093363A0612
+P11472696A0387
+BC2GM040397014
+BC2GM062891050
+BC2GM053475151
+P02959089T0000
+P07528531A0904
+P11486141A0424
+BC2GM062932226
+P09503526A0614
+P10791251A0110
+P09353247A0922
+BC2GM038829305
+P08463320A1219
+P07780719A0477
+P09802902A0225
+P11038317A0000
+P07743697A0703
+P00041512T0067
+P10967361A0000
+P10464250A0275
+BC2GM077422273
+BC2GM068727128
+P07991437A1032
+P09924987A0000
+P06667868T0001
+P08394255A0000
+P08189174A0148
+P08958720A1204
+P09675896A0959
+BC2GM030879551
+P03865743A0859
+P08371936T0000
+P11313342A0224
+BC2GM041365584
+P08005438A1185
+P03403826T0000
+P06686454A0585
+BC2GM076683276
+P02872786A0147
+P09079902A0713
+P08567847A1005
+BC2GM067289380
+BC2GM009022291
+P03838797A0903
+BC2GM051345201
+BC2GM080710806
+P09857038A1374
+P09269900A1035
+BC2GM038525158
+P08382303T0000
+P11158236A0000
+P09140079A2528
+P10684265T0000
+P01697928A1214
+BC2GM072286442
+P01767592A0682
+P10669319A1722
+P11292844A0081
+P09154822T0000
+P02332798A0725
+P07818416A0895
+P10893258T0000
+P07784078A1064
+BC2GM000360337
+P06821147A0468
+P01577740A1111
+P03759330A0713
+BC2GM064553826
+P07944461A0321
+BC2GM091583660
+BC2GM046535575
+P08541793A0796
+BC2GM022740779
+P09411459A0729
+P02694731A0241
+P01309894A0807
+P01702972A0613
+P10662614A0000
+BC2GM028667009
+BC2GM093098525
+P07616563A0532
+P09359887A1168
+P09089653A1112
+P03013477A0000
+P11264561A0167
+P11435560A1322
+P02865502T0000
+BC2GM042983371
+P08442384T0000
+P08621628A1233
+P04511139T0001
+P11256944A1144
+BC2GM085800935
+P07926749A0471
+P09144958A0047
+P01350932A1123
+P02474204A0105
+P02511898A0000
+BC2GM031800406
+P11441311X0001
+P08798512A1197
+BC2GM019804740
+P05529283T0000
+P02452313A0114
+P10905349A0609
+BC2GM002325093
+P10400774A0240
+P08590465A0773
+P09514156A1147
+P08420995A0499
+BC2GM069191701
+P09314487T0000
+P00993176A0066
+P08124912A0456
+P04890336T0001
+P07749088A0119
+P11152283A0223
+P09343433A0000
+P00627039T0000
+P11282433T0000
+P02176232T0001
+BC2GM070173071
+P01340470A0000
+BC2GM096544601
+BC2GM041156819
+P09748286A0000
+P08144631A0000
+BC2GM031237575
+BC2GM078836227
+P09050847A0180
+P11241215A0566
+P03995513T0000
+P02068085A1273
+P01505516A0928
+P02170687A0000
+P01909621A0119
+P01541577A0000
+P10125354T0000
+P09045842T0000
+BC2GM025767093
+BC2GM053837168
+P11124024A1098
+P03526279T0000
+P07394364A0738
+BC2GM027891273
+P09057841T0000
+P08929089A0231
+P08325504A0226
+BC2GM036723867
+P08035796A0890
+P08521414A1384
+P03194410A0771
+P09549632A1189
+P11532556A0000
+P01553407T0000
+P01526658A0454
+P11042703A0875
+P07977239A1283
+BC2GM049401430
+P08070654A0000
+P03005231A0649
+P09632734A0081
+P07509053A0139
+P09852109A1475
+P08784787A0383
+BC2GM090002876
+P09488486A0000
+BC2GM027879674
+P01421390T0000
+P08492290A0306
+P10946303A0000
+P04704186T0000
+BC2GM024652235
+P02268461A0224
+P03981421A0246
+BC2GM064119241
+P08931388A0806
+P11003653A0198
+BC2GM030350925
+P08386318A1102
+P05792868T0000
+BC2GM021800196
+P09636358A0000
+P09813254A0000
+P09407026A0426
+P04884060T0000
+P03933232T0000
+BC2GM014851186
+P01282638A0934
+P09676419A0158
+P09710614T0000
+BC2GM064361080
+P08314163T0000
+P01551910A0978
+P02870720A0188
+BC2GM087367998
+P02347655A0193
+P02543734A0414
+P08076937A0851
+P06035001T0000
+P06606043A0598
+P05552642T0000
+P07594047T0000
+P06306342A1156
+BC2GM090387828
+BC2GM065187167
+BC2GM061773962
+P08584035A0740
+P01861188A0000
+P06698047A0445
+BC2GM015089402
+BC2GM066297688
+BC2GM058306655
+P09834070A0793
+P01649835A0822
+P09566731A0458
+P01690703A0285
+P01837787T0000
+BC2GM038824735
+P09178494A1123
+P07493327A0507
+BC2GM019813491
+BC2GM087769438
+P09311810A0814
+BC2GM098689605
+BC2GM083059835
+BC2GM049234843
+P08100057A0577
+P09528950A0716
+P09246585T0000
+P11559366T0000
+P07623821A0649
+P09252406A0511
+P06492188A0615
+BC2GM006294233
+P05425195T0001
+P09060623A0961
+P07068496A0000
+P11416650T0000
+P03171221A0531
+P00921911A0159
+P08157674T0000
+BC2GM011606685
+BC2GM056849108
+P02431314A0834
+P02614668A0971
+P06864955T0000
+P11451447A0205
+P01532796A0107
+P08995410A0000
+P06599282T0001
+P07555373A0000
+P03404495A0172
+P08191910A0228
+P09650789A0185
+P11283014A0921
+P01952827A0215
+P09671464A0316
+P07474085A0932
+P09003001A1909
+BC2GM034839336
+P07687541A0200
+P06817410A0982
+P10570996A1213
+P06291369A0000
+BC2GM094013655
+P11517269A0472
+P02072798A0330
+BC2GM026543710
+P11027027A0061
+P09837715A0581
+P08134115A1161
+P09465035A1032
+P07588628A0318
+BC2GM073035412
+P09756895A0322
+P07744776A0617
+P01395755A1023
+BC2GM032241035
+P03717475A0208
+BC2GM020267089
+P07864709A0324
+BC2GM070526429
+P11352423A0084
+P01647656A0000
+P10982076A0000
+P02703925A0359
+BC2GM006641909
+P08652081A1953
+P08649389A0692
+P09548481A0000
+P01168607A0672
+P01353478T0000
+P08858268A1307
+P09475898T0000
+BC2GM055943127
+P08573083A0645
+P02405818A0550
+P08267667A0748
+BC2GM054522727
+P06994035T0001
+BC2GM062196323
+BC2GM094469292
+P08702728A1325
+P07679390A0721
+P11311153T0000
+P10724519A1185
+P00535520A0239
+P10773455A1268
+P05305671T0000
+P07414817T0001
+P09160361A0858
+P02708288A0139
+P08642693T0000
+BC2GM009398467
+BC2GM028887515
+P03930894T0000
+P08675763A0788
+BC2GM081669747
+P02349942A0287
+P10913276A0510
+P09093867T0000
+BC2GM054844326
+P09524222A0769
+P02475717A0565
+P09333026A0851
+P10594239A0614
+P08649440T0000
+P10640683A0670
+P07628438T0000
+P01904154A0164
+P11460035A0548
+P02135343A0131
+P09294453A0949
+P11179687A1118
+BC2GM079747386
+P09751061A0000
+P08428952A1957
+P08507921A1021
+P01840711A0000
+P09257887A0457
+P03309892A0637
+P00240016T0033
+BC2GM019020336
+BC2GM011718278
+P08251622A0000
+P10666253A1291
+P07559356T0000
+BC2GM002404692
+P08395654T0000
+P02138915A1060
+P01924920A0115
+P06948868A0082
+P01285009A0000
+P11054565A0654
+P09090592A0175
+BC2GM058058644
+P07154928T0001
+P09725854A1060
+P00933251T0000
+BC2GM097462810
+BC2GM058564521
+BC2GM063929508
+P09990057T0000
+P11278604A0300
+BC2GM057222507
+P09543227A0815
+BC2GM066166532
+P02645276T0088
+BC2GM092441762
+P02878100A0674
+P09154621A1475
+P02324102A1157
+P08069481A0736
+P07483276A0139
+P09234736A0999
+P07408970A0706
+P01389362T0000
+P09473040A1303b
+P09177169A0935
+P11314428A0651
+P08839911A0716
+P09501169A0000
+P09845662A0085
+P02550118A0610
+P08666404A0311
+BC2GM052318281
+P00890028A0507
+BC2GM044672439
+BC2GM017310347
+P10043466T0000
+P10379899A0446
+BC2GM001987154
+P10954525A1161
+P09767575A0657
+P09202669A1530
+P10702389A1148
+P02638964A0372
+BC2GM069139164
+P08647802A0000
+P06254403A0000
+BC2GM038488756
+BC2GM060681176
+BC2GM054393816
+P00712117A0521
+P10681520A0525
+P01679124A1368
+P01533760T0000
+P07593266A1174
+P07494314A1287
+P06374418A0877
+BC2GM069806610
+P11509266A0955
+BC2GM034659182
+P04839176T0001
+P02476030A0000
+P09649069A0490
+P03097509A0654
+P09915860A0000
+P09374541A0277
+P09727045A0817
+P11030744A0763
+BC2GM078941863
+P07981143A0633
+P07859739T0000
+P07537851A0891
+BC2GM058610366
+P09162084A0956
+P08334989A0070
+P00234264A0164
+P06503132A0784
+P08869825A0000
+BC2GM085576147
+P04863895T0000
+P09182707A0254
+P07636962A1883b
+P07565731A1629
+BC2GM066024326
+BC2GM083166259
+P07297978A0570
+P11306511A1476
+P09169475A0272
+BC2GM089987435
+BC2GM084502835
+BC2GM000288103
+P08076631A0000
+P02253663A0687
+BC2GM005288788
+P02713520T0000
+P09371657A0165
+BC2GM074705876
+P11157784A0141
+P06714354A0194
+BC2GM087826956
+BC2GM070888113
+P09011745T0000
+P05740389T0001
+P01552457T0000
+P10778757A0000
+BC2GM083712853
+P05850652T0001
+BC2GM070372119
+P05437405T0000
+P11266184A0000
+P02357537A0451
+P07068493A0636
+BC2GM057387777
+P01937989A0383
+P03264299A0679
+P10933728A1398
+P07380615A0478
+BC2GM001246752
+P09407031A0974
+P11093745A0563
+P10592824A1157
+P00054900A0226
+BC2GM052219408
+BC2GM026443605
+BC2GM098365261
+P08706368A1024
+BC2GM068389238
+P08282501A0358
+P01297332T0000
+P02444507A0240
+P02758382A0478
+P11235817A0000
+BC2GM086752058
+P06807192A0312
+P09277472A1070
+P09079650A0136
+P01334518T0000
+BC2GM003392848
+P11522658A0086
+BC2GM053477208
+P09931216A0566
+P09592208A0470
+P10601410A0977
+P09712919A0307
+BC2GM094973350
+BC2GM074597498
+BC2GM012136507
+P00872922A0204
+BC2GM052850405
+P08643513A0361
+P11529914T0000
+P08812490A0542
+P08083999A0501
+P07772036A1000
+BC2GM090231645
+P09755478A0366
+P02717349A0311
+BC2GM034622067
+BC2GM034402560
+P04001490T0001
+P08891474A0667
+P09508119A0498
+BC2GM003946891
+BC2GM057075557
+P09929811A0000
+P10934073A1433
+P01992953T0000
+BC2GM052917492
+P09168134A0858
+P06184487A1485
+BC2GM085924161
+P08093616A1214
+P07919540A1119
+P11053009A0000
+P09763522A2545
+P05412122T0000
+P02829183A0117
+BC2GM088537216
+P02292272T0000
+P08898916A0791
+BC2GM007719127
+P09370276A0781
+P11752821A1365
+P09442072A0716
+P01420177A1065
+P08253387A1291
+P07916983A0623
+P01708771A1215
+BC2GM095055828
+P07959011A0379a
+BC2GM070319467
+P05356107T0001
+BC2GM036738213
+P09756687A0981
+P08150970A0434
+P11573891A0525
+P11872570T0000
+P05689427T0052
+P09710599T0000
+P11246679A0000
+P03423732A0341
+P11254713A1029
+P02163394T0000
+P11572377T0000
+P02536160A0518
+P07704730T0000
+BC2GM076945603
+P11340085A0211
+P01093847A0000
+P08177143T0000
+P09935377T0108
+P03114829T0000
+P08449943A0225
+P08621714A0361
+BC2GM017195942
+BC2GM056444302
+P00833472A0907
+P09199626A0613
+P01657415A0837
+BC2GM088326389
+P08647884A0547
+P08383526A0591
+P02651487A0000
+P09362105X0422
+BC2GM031317365
+P03319646T0000
+BC2GM088483359
+BC2GM095573888
+P09890778T0000
+P10777499A0883
+P06333433A0000
+P01082726A0248
+P10684534A0634
+P07534297A0141
+P07918097T0000
+P09077076A0219
+P11053370A0708
+P01563343A0548
+P10998679A0500
+P10791901A0609
+P07639106A0678
+P01374331A0636
+BC2GM070662634
+P09468386A0594
+P09519828A0809
+P10767338T0000
+BC2GM009473053
+P09763421A1199
+P07983712A0914
+P10671520T0000
+P09058378A1134
+P01849734A1063
+BC2GM030320745
+P04729063T0000
+P08621017A1186
+BC2GM029694123
+BC2GM097325580
+P07192369T0000
+P10520800A0307
+BC2GM007950303
+P09030581A0990
+P08835393A2829
+P09279379A0310
+P03149774A0173
+P10666222A0330
+BC2GM020218379
+P02971957A0287
+P09961326T0000
+BC2GM064144639
+P10910073A0876
+P08999882T0000
+BC2GM011637972
+P07490742A0636
+P04712626T0000
+P03848527T0020
+P11390684A1170
+BC2GM043410270
+P08289783A1476
+P08953340A0000
+P08662617A2051
+BC2GM062962431
+P07714608A1252
+P07937147A0205
+BC2GM011344570
+P04103248T0000
+BC2GM057027725
+P08255022A0827
+BC2GM099236530
+BC2GM072370465
+P01832197T0001
+P08082286A0748
+P01407286A0427
+P08822399A0518
+P10799595A1454
+P11243336A0000
+P09094315A0541
+BC2GM095731252
+BC2GM014013049
+BC2GM096403627
+P08257666A0662
+P03050147A0896
+P02523800A1178
+BC2GM085583133
+P09135928A0912
+P11134508A0317
+P08094464A0869
+BC2GM018871936
+P06388189T0001
+P09502720A0214
+P11433014A0683
+P03406054A0351
+P09952378A0529
+BC2GM096620128
+P09735368A0636
+BC2GM088368088
+P10938135A0259
+P01420363T0000
+P02123875A0223
+P07607537A0954
+P09043768A0139
+BC2GM036908769
+P08833653A0304
+P03935797A0183
+P09368058A0969
+BC2GM043837371
+P09443973A1028
+P08205827A0940
+P02562825A0413
+P11251276A0793
+BC2GM065023987
+P07416204A0437
+BC2GM077013458
+BC2GM043725941
+BC2GM044052355
+P09047344A0000
+P08783180A0000
+P08902214A1486
+BC2GM019377317
+BC2GM094661498
+P02248732A1113
+BC2GM097088873
+P07565031A0454
+P07673154A0688
+BC2GM080383743
+P08988257A1256
+P03377864A0000
+P02361575T0000
+P10560997A1072
+BC2GM033982048
+BC2GM020687268
+P03810361A0576
+P09438427T0000
+BC2GM079994389
+BC2GM009701774
+P02691557A0273
+BC2GM047934950
+BC2GM085712382
+P08065327A0000
+BC2GM063579260
+P09053309A1103
+P08119907A0000
+P06802500T0001
+P09249710A0331
+P10972990A0526
+P01733358A0240
+P05693605T0001
+P06782869A0263
+BC2GM091988881
+BC2GM090889601
+P06689413A0174
+P11344530A0320
+P07665477A0901
+P02162103A0000
+P02208762A0228
+BC2GM095985725
+P02733116T0000
+P08716757T0001
+BC2GM051225435
+P00453780A0430
+P09218520A0075
+P10683259A0774
+BC2GM025679566
+BC2GM082082186
+P08049444A0351
+P07748451A0343
+P00451192A0248
+BC2GM096019104
+BC2GM004737779
+BC2GM079066948
+P11404019A0532
+P07877619A1284
+BC2GM033123409
+P11419938T0000
+P01718043A0384
+P06394228T0073
+BC2GM015085481
+P02566613A0831
+P01396572A0320
+BC2GM050125975
+P07702327T0000
+P11384229A1669
+P07355527A0467
+BC2GM071034942
+BC2GM073528534
+P09780228A0122
+P09215525A0581
+P09884232A0286
+P02115122A0562
+P11157763T0000
+P02227438A0492
+BC2GM010561492
+BC2GM045159719
+P03428084A0430
+P11162576A0213
+P09367676A1115
+BC2GM026460390
+P02246362T0000
+P09199348A0156
+BC2GM067787787
+P08349104A0450
+BC2GM009844506
+P06659982A0231
+BC2GM024210872
+P01715975A0885
+P03275867A0187
+BC2GM027811998
+P08532516A0000
+P08814651A0000
+BC2GM078881982
+BC2GM095302327
+P02093741A0211
+P11075944A0691
+P07337609A0531
+BC2GM056359594
+P09805052A0119
+BC2GM012008422
+P08097732A0000
+P08895997A0336
+P10713176A0422
+P11425877A1026
+P01643943A0300
+P08891345A0684
+BC2GM037323939
+P08070393A0631
+P08872162A0884
+BC2GM025927345
+P07606587A0266
+P09118664A1734
+P07504712A0843
+BC2GM082621888
+P01456888A0074
+P00935526A0000
+BC2GM083864266
+P00747722A0486
+P09334330A0252
+P07969136A0273
+P01286732A0572
+P11378898A0164
+BC2GM046724705
+P03537721A0491
+BC2GM075504151
+P04941951T0000
+P02378615A0807
+P09443948A0000
+BC2GM033547721
+P02934889A0558
+P09718671A0000
+BC2GM018712064
+P09843378A0187
+P03978045A0857
+BC2GM047215943
+P07651398T0000
+P09826658A0691
+P01722319A0849
+P11044105A0616
+P01446132A0328
+P07559355A0066
+P03027779A0000
+P10733591A0146
+P09199970A1101
+BC2GM039968036
+P08299181A1148
+P09920539A0272
+P04600603T0001
+BC2GM034973771
+P11099377T0000
+P08278548A0597
+P09506962A1000
+P06654047A0694
+P08376796A0172
+P07518578A0000
+P09882334A0822
+P02324104A0929
+P09103382T0000
+BC2GM031634103
+P02406570A0898
+P11356214A0794
+P09710615T0000
+P03390074A0000
+BC2GM021219162
+P11278671T0000
+P08668158A0765
+P00947834X0000
+P06482665A0735
+P07581364A0500
+BC2GM087115294
+BC2GM019801606
+BC2GM038764825
+P09235995A0339
+P05760665T0000
+P01601869A1389
+P10663558T0000
+P10962564A0883
+P07387242A0236
+P06336045A0261b
+P11313946T0000
+P07846942A0717
+P08825556A0522
+P06702643A0000
+P10864641A1400
+P08641705A0986
+P10702241A0357
+P00476020T0000
+P09459241A0707
+P09086268A0611
+BC2GM052999467
+P08552387A0000
+P02355765A0220
+P01328681A0149
+P04019066A0000
+BC2GM037252566
+P04627477T0001
+BC2GM055659274
+BC2GM013148295
+P11560992A0000
+P08349104A0000
+P04544430T0001
+P09590540A0513
+P08248688A0726
+P06073427T0001
+P07445971A0241
+P10856805T0000
+P03988001A0227
+P09259328A0440
+P09512550T0000
+P10660604A0748
+P06755468A0180
+P07688112A0274
+P01301171A0979
+P02291144A0493
+P02164604A1574
+BC2GM052166427
+P09290571A0799
+P09428389A1805
+BC2GM083759997
+P08601616A0726
+BC2GM093919585
+P03373755T0001
+P08119958A0273
+P02766745T0000
+P07195615A0087
+P02403926A0000
+P07478525A1177
+P09522297A0744
+P08175031A0566
+P08245461A0700
+P08262041A0727
+P10982825A0363
+P11043469A0440
+P01983026A0483
+P09622121T0000
+BC2GM074348497
+P07831829A1324
+P08164661A0414
+P09738693T0000
+P08731155A0499
+P09409821T0000
+P00056837A0000
+P08836172A1382
+P08509051A0316
+BC2GM024114351
+P08550462A0815
+P10611235A1927
+P11168588T0000
+BC2GM082960134
+P07158726T0001
+P02586485A0511
+P09366517A1828
+BC2GM068206281
+BC2GM068969050
+P08645214A1052
+BC2GM002155163
+P07753837A0724
+P11509615T0000
+P08637711A1121
+P01762914A1218
+P08880405A1170
+BC2GM049538260
+P07823953A0777
+P02353875A0800
+P09586832A0229
+P03829848T0001
+P05949971T0000
+P07528772A0616
+P09668096A0806
+P11097079A0525
+P07449221A0086
+P07259325A0394
+P02794828A0214
+P11466227A1665
+P10748113A0187
+BC2GM001477367
+P09186507A0882
+BC2GM095945527
+P08007975A0000
+P06829082A0187
+BC2GM091999980
+BC2GM045048834
+P07169630A0983
+P11241243A0693
+P09471984A0000
+P00587791T0054
+P09837920A0222
+P07508954A0000
+P07859238A1150
+BC2GM079935127
+P09886602A0000
+P07576307A1654
+P07521285A1109
+P10704410T0000
+BC2GM078874950
+P08719155A0105
+P09115989A0993
+BC2GM084544513
+P11311563A0423
+P02017414A0307
+P01631229T0000
+P02870851A0349
+P01259027A0416
+P09060444A0557
+P01982997A1104
+P01674817T0000
+P01974876A1051
+BC2GM088538156
+P01327280A0000
+P07752454A0341
+P02667259A0331
+P00779272T0001
+P09858745A2033
+P03315359A0732
+P02424743A0280
+P10585440A0204
+BC2GM065577575
+P06328002A0000
+P02250919A0404
+P09813203T0000
+P01502157A0000
+P00722652A0118
+P03109147A0000
+P07935471A0613
+BC2GM067463780
+P08196616A1112
+P09193671A0347
+P06369954T0000
+P05930797T0000
+BC2GM057454173
+BC2GM001207192
+P11141003T0000
+BC2GM007200523
+P10448440T0020
+P01428513A0440
+BC2GM068744925
+P11000203A0752
+P11016724A0536
+BC2GM080063852
+P01652372A0153
+BC2GM019777256
+BC2GM018365165
+P07462481A0422
+BC2GM010424307
+P02826729A0790
+P11543154T0000
+P01767899A0136
+P01754381A0000
+P07053251A0666
+BC2GM008228861
+P01081904A0198
+P09755199A0373
+P09994942T0000
+P09436795A0350
+P08763311A0189
+P10708769A0433
+P02969819A0814
+P02160622A0000
+BC2GM021160807
+P08621719A0000
+BC2GM076681368
+P08464056A0510
+P09601510A0215
+P01499213A0185
+P07179412A1131
+BC2GM034355012
+BC2GM052598708
+BC2GM060603409
+P08977235A0134
+P01694014A0716
+BC2GM087479423
+P03746053A0670
+BC2GM025371189
+P08710371A0499
+P07755884A0000
+P10841593A0780
+P00210220X0000
+BC2GM033814986
+P11123912A0306
+P03110801A0532
+P10999205A0607
+P07646439A0535
+P01088654T0001
+P11084334A0590
+P02294048A0881
+BC2GM021744852
+P08923469A1391
+P09603345A1257
+P00354315T0000
+BC2GM062047431
+P08668158A1252
+P11078726X0000
+P08649386A1032
+P07935379A0347
+BC2GM061513457
+P11560292A0557
+P02537485A0841
+BC2GM066867028
+BC2GM055232950
+P09339900A0939
+P02498322A0226
+P09888711A0781
+BC2GM070901707
+P07664278A0135
+P07871757A0846
+P08416977A0892
+BC2GM084277240
+P09619631A0344
+P06685643A0179
+P06607427A0000
+P00052597T0000
+BC2GM029173033
+P01093055T0000
+P03344812A0924
+P00401521A0138
+P08617800A0675
+BC2GM014548210
+P01787085A0331
+P08597636A0000
+P01984665T0000
+P03956695A0617
+P08920499A0164
+BC2GM005703373
+BC2GM058781724
+BC2GM070838857
+P02107548A0727
+P08230445A0000
+P07871754A0857
+P10688646A0535
+P01732033A0000
+P00580151A0706
+P05909034T0000
+P02374886A0305
+P01650524A0837
+P08824884A0000
+P11132195A0000
+P06542372A0159
+P07916685A0455
+BC2GM060551138
+P11311550A0253
+P06223586A0460
+P07951410A0647
+P08189533A0203
+P06048505T0000
+P07614762A0224
+P08901658A0498
+P10852221A0422
+P01890362A0305
+P08098228A0625
+P07937965T0000
+P10895851A0696
+BC2GM001695842
+P01549123A0480
+P06238540A0798
+P02480419A0735
+P01748194A0767
+P01473207A0582
+P01431809T0000
+P03073192T0000
+BC2GM077208182
+P01334493A0289
+P00012653T0045
+BC2GM003261420
+P09562398A0848
+BC2GM064768852
+BC2GM053409406
+P04055593A0523
+P09004504A0000
+P07629113A0726
+P09879766A0402
+BC2GM021723092
+P08145770A1078
+P09420269A0000
+P01660925T0000
+P08497190T0079
+BC2GM008773952
+P07753796A0625
+BC2GM036119481
+P11221845A1370
+P01975428A0151
+P11349796A0950
+P07854324A0281
+BC2GM065029145
+P07888156T0000
+P06886948A0750
+P08274774A0958
+P00619782A0058
+P06700469T0000
+P02329840A0383
+BC2GM049574231
+P08986190A0927
+P10839470A1148
+P08999857A0801
+BC2GM013864172
+P06355483A0134
+P02747653A0910
+P02674141A1202
+P02521217A1035
+P10590092A0124
+P07696878A0222
+BC2GM075272247
+P11473254A0000
+P08445299T0000
+P00984209A0614
+BC2GM053210179
+P07604783A0952
+P00602702A0309
+BC2GM017562219
+P01480183A1689
+P05799686T0001
+P09882321A0948
+BC2GM034033075
+BC2GM065840723
+P09566876A0000
+P07936650A1752
+BC2GM045174565
+P01918010A1730
+BC2GM002134546
+P01756195A1117
+P11105716A0782
+P01608239T0001
+P09650299A1334
+P09121430A1075
+BC2GM030336153
+P11484028T0000
+P07876300A0994
+P03577670A0102
+P09790986A0689
+BC2GM032107617
+BC2GM093377314
+P01377764A0309
+P11028131T0000
+P09013499A0198
+BC2GM079186021
+P07592710T0000
+BC2GM054295560
+BC2GM019564620
+P08970951A0823
+BC2GM069744943
+BC2GM042107668
+P01496348A0000
+P08561607A1443
+P10930526A0174
+P05170106T0034
+P06546392A0542
+BC2GM012939166
+P08676858A1084
+P04021437A0000
+BC2GM047468980
+BC2GM025704157
+P10572130A1623
+P09792714A1408
+P09773975A1873
+P04289156T0000
+P01730747A0205
+P07798207A0759
+P00592887T0000
+P10572087A0326
+P11169149A0097
+P10643313A0345
+BC2GM018805771
+P02674327A0493
+P09914525A0890
+P07742363A0135
+BC2GM096535818
+P09159160A0000
+P02833517A0467
+P09614065A0966
+P02538450A0000
+P02054754A0919
+P03004982A0199
+P02045366A1149
+BC2GM096119161
+P03192724A0000
+P01808136T0000
+P08954725A1175
+BC2GM059750371
+P03190914A0149
+P00640584A0250
+P10602507A0652
+P11126275A1068
+P02474110A1039
+P09837945A0820
+P09230894A0422
+P07616802A0315
+P09420251A1363
+P02773507A0750
+P02674671A0601
+P07049690T0000
+P09724763T0000
+P09854034A0536
+BC2GM099821771
+P08601490A0659
+P10393192A0792
+BC2GM044293029
+BC2GM022014688
+P09891009T0000
+P09541280A0404
+P07596283A0396
+P03668003T0000
+BC2GM073487820
+P08918885A0811
+P11041308A0156
+BC2GM012462768
+BC2GM018110366
+P08985109A1285
+BC2GM045058559
+P10727433A0560
+P08373274A0546
+P07658471A0000
+P07354367A0162
+P00513284A1255
+P10613843A0107
+P06762321T0000
+BC2GM084904030
+P01766999A0000
+P09238467A0763
+P04039439A0842
+P06784123A0286
+P10684069A0508
+P06238704T0001
+P08000112T0000
+P11062705A0658
+P09102113A0739
+P02496100T0000
+BC2GM086255271
+P02844767A0596
+P08085782A0164
+P03693543A0405
+P10947840A0762
+P03046655A0000
+BC2GM000008491
+P07601121A0153
+P01279352A0473
+P08227129T0000
+P10733591A0533
+P02642976A1474
+P09858713A1174
+P01431602A0229
+P01845885A1003
+P08756712A0227
+P07507207A0991
+P05114515T0000
+BC2GM072636195
+P07044842A2062
+P03035658A0355
+BC2GM081703119
+BC2GM030904098
+P01420363A0818
+BC2GM021744548
+P09331864A0230
+P11319880A1108
+P09010223A1850
+P08832146A0959
+P09560325A1285
+P11226752A0750
+P07948921A0051
+BC2GM044027057
+BC2GM097718440
+P09742129A0491
+BC2GM077073177
+P01740682A0703
+P00163384A0000
+BC2GM042374200
+BC2GM045278199
+P11073163A0131
+P08226780A0160
+P07693975A1418
+P10625721T0101
+BC2GM002241638
+P02674679A1237
+P08504707A0376
+P09871353A0174
+P11561623A0897
+P02129338A0568
+P11314030A1264
+P09325322A1293
+P06287231A0914
+P09931252A1055
+P11375392T0000
+BC2GM049336360
+P09139694A0789
+P10909973A1508
+P01331057A0000
+P03208493A0849
+P08752714A0000
+BC2GM062639747
+P01857143A0351
+P03685073A0200
+BC2GM084522196
+BC2GM053739384
+P09852068A0150b
+P08532967A0364
+P09653648A0445
+P01594554A0845
+P03036817A0213
+P10891441A0871
+BC2GM098358600
+BC2GM065082565
+P07745311A0264
+P08476087A0814
+P05693602T0001
+BC2GM056636695
+P03981640A0168
+BC2GM066216653
+BC2GM081673758
+P02631743A0275
+P00619305A0759
+P07240343A0000
+BC2GM058597920
+P08403804A0754
+P07672821A0763
+P00951909X0001
+BC2GM087473233
+P01894696A0301
+P01717925A0477
+P08175188A0685
+P08606267A0740
+P10852953A0000
+BC2GM020782530
+P07266969A0246
+P03925712A0229
+P09736697A0783
+P08922390A0361
+P02605182A0936
+BC2GM080486141
+P08726024A0532
+P01627106A0320
+P09288916T0000
+P02124433A0235
+P06992600A0405
+P10684286A0386
+P06858805A0314
+BC2GM015182129
+P06131378A0818
+P08994832A0782
+P04704137T0001
+P09168623A0614
+P07949551A0000
+P09475378A1449
+P08289342A0931
+P01723619A0766
+P11473261A0587
+P03696899T0001
+P01460054A0478
+P08432696A1117
+P01541556A1040
+P08740416A0239
+P02261254A0168
+P02689439A0402
+BC2GM077439334
+BC2GM074265935
+P11133986A0350
+P11573771T0000
+P01772201T0001
+P10967531A1025
+P09713990T0000
+P01339773A0000
+P09371455A0000
+P08918456A0455
+BC2GM083303978
+P09308738A1216
+P07988731A1301
+BC2GM056468201
+BC2GM070993491
+P01852603A0000
+P09514159A0562
+P08548291A1059
+BC2GM012710435
+BC2GM094584922
+BC2GM046414753
+P07326596A0061
+BC2GM050874939
+P01847464A0856
+P05722341T0000
+P03765731A0918
+P10752807A1598
+P08396120A0690
+BC2GM009448248
+P07678242A0473
+BC2GM004777845
+P07449253A0411
+BC2GM068581710
+BC2GM011914168
+P07534286A0842
+P02795923A0000
+BC2GM073745691
+BC2GM007582543
+P11450490A0565
+BC2GM066466622
+P08654972A0000
+BC2GM076461759
+P10799863T0000
+BC2GM074968808
+P11157035A1405
+P07592771A0258
+P03398714A0594
+BC2GM086205722
+BC2GM063781276
+P02273690T0001
+P07935472A0276
+P07655184A0852
+P10965135A1207
+P01792914T0000
+P06948493T0026
+P01398074A1081
+P09822825A0141
+P09614106T0000
+P01547942A0120
+P08470895A1617
+P10669594A0969
+P07260987A0336
+P01681075A0429
+P10940562A0379
+BC2GM059055199
+P05322558T0000
+P00710372A0302
+P06482179A0497
+P04026972T0000
+P08169201A0291
+P01009451A0728
+BC2GM069590110
+P02781567A0544
+P07586403A0765
+P08849208A1022
+P07147622T0000
+BC2GM060909713
+P01938178T0000
+P00564032A0724
+BC2GM005627247
+P02396415T0001
+P09389666A0538
+P09099745A1446
+BC2GM075883505
+P09525888A1482
+P04005190A1288
+P03936828T0000
+P01735721A0185
+BC2GM011471991
+P03922116A0197
+BC2GM059747347
+P09035307A0000
+P01804671A1001
+BC2GM077137738
+P08089184A0825
+BC2GM045996206
+P02044950A0258
+P08906056A1290
+P02254749A0133
+P09092493A0861
+P11435517A0396
+P01776306A0572
+BC2GM019360660
+P08085609A0384
+P10698516T0000
+P07577904A0141
+BC2GM028713807
+P09088371T0000
+P02919530A0000
+BC2GM048576585
+P03628794A0648
+P08415643A0555
+P01568960A1129
+BC2GM062031104
+P11361338A0447
+BC2GM051429391
+BC2GM012807345
+P09324878A0952
+P11158337A0000
+P09620273A0189
+P08037338A0000
+P02740627A0137
+P03891766A1473
+BC2GM035066986
+BC2GM059623461
+P08367388T0035
+P09030781A0734
+P08884273A1413
+P11287623A0286
+BC2GM013674707
+BC2GM047129964
+BC2GM076520533
+P08728040T0000
+BC2GM086765060
+P09887544A0000
+BC2GM037564004
+P03420324A0178
+P09916809A0405
+P02617623A0740
+P07567300T0000
+P11548027A0163
+P11481625A0202
+P10601290A0742
+P08823709A0220
+P01851876A0129
+P09092636A0802
+BC2GM047251992
+P07720709A0755
+P11368363A0129
+P09516472A0292
+P01573270A0000
+BC2GM088003576
+P10688639A1310
+BC2GM010467864
+P11150315A0844
+P06411659A0793
+P09002672A0439
+P07620491T0000
+P03332848A0000
+P11073539A0866
+P09435806T0001
+BC2GM033468681
+BC2GM008859713
+BC2GM046461652
+BC2GM035990949
+BC2GM084137425
+P01687050T0000
+P09374082A0504
+P10851745A0624
+P03914875T0001
+BC2GM072960583
+P09656485A0351
+BC2GM004292158
+P09385169T0000
+P08069298A0492
+P08099443A0359
+P09267542A0126
+BC2GM007629398
+P09691031A1050
+P00159600A0871
+BC2GM009260448
+P09572965A1235
+BC2GM073366663
+P08823260A1161
+P04911925T0001
+P05833022T0001
+P04428800T0001
+P03709627A0247
+P10781109T0000
+P10690702A0065
+P11023853A0188
+P08445655A1009
+BC2GM070051606
+P08937631A1223
+P08754834A1097
+BC2GM065749861
+P01845829A0158
+P10629176A0887
+P09765394A0000
+P07517869A0411
+BC2GM051993138
+BC2GM052141177
+P11289135A0975
+P10706887A0281
+P11157774A0789
+P09203586A1197
+P02144610A1306
+P03703493A0654
+BC2GM086588725
+P02765214A0486
+P09048617A0648
+P11574105A0727
+BC2GM045721161
+BC2GM070037858
+P08242861A0368
+P09506983A0304
+P09006022A0252
+P10669633A0391
+P08828152A1238
+P11235777A0878
+BC2GM062157969
+BC2GM062176134
+BC2GM023485577
+BC2GM014113607
+P01650557T0000
+P10866886A1277
+P02761492A0124
+P06782612A0142
+BC2GM050477465
+BC2GM026306487
+P10688666A1010
+P09753774A1642
+BC2GM028226886
+P08062833A0000
+BC2GM026154054
+P06214605A0123
+BC2GM092290359
+P08319907A0754
+P08873063A0875
+P01588270A1029
+P07539314T0000
+BC2GM066012770
+P09949160A0600
+P09327881T0000
+P08144615A0533
+BC2GM048317669
+P02630543A0210
+P11516890A0236
+P11072155A0764
+P01582500A0178
+P00499588T0000
+BC2GM052316852
+P09811730T0000
+P11237598A0962
+P10900129A0138
+P02677002A0205
+P09190940A0127
+P09256973A0455
+P08794348A1067
+P05299993T0000
+P08389074A1227
+BC2GM034750890
+P08555498A0427
+BC2GM000293986
+P11054539A0114
+P11069999A1602
+BC2GM017449722
+P07107773A0000
+P08543810A0000
+P02233626T0000
+P07737508A0649
+P02677429A0366
+P11062274T0000
+BC2GM025063596
+P01864821A0000
+P00970839A0118
+P05683363T0001
+BC2GM047847482
+BC2GM022729580
+BC2GM047662900
+P11128925A0000
+P02079811A0407
+P09083563A0971
+P02557217A0000
+BC2GM067091384
+P02927391A0238
+P03750700T0001
+BC2GM072980050
+BC2GM059504332
+P08378082A1031
+P09637689A0150
+P01582413A0759
+BC2GM099003482
+P09786404A0541
+P09419680A1112
+P00105401A0635
+BC2GM016180513
+P10711674A0000
+P08461946A0386
+P07592946A0261
+P02909528A1081
+P10908317A1459
+P07816617A0763
+P06751455A0117
+P08456378A0134
+P11013079A0927
+P08143667A0222
+P05500957T0001
+P09844921A0000
+P01372802A1481
+P01881595A0476
+P02243386A0113
+P04305850T0000
+BC2GM098934435
+BC2GM014257511
+BC2GM081653847
+BC2GM046485760
+P09858593A0334
+P08090571T0001
+P10678144A0509
+BC2GM030793511
+P02897651A0000
+P02649445A0412
+P07876192A0443
+BC2GM059696646
+P07777518A0483
+P04039439A0000
+P07916577A0190
+P11572467T0000
+P09734808A0000
+BC2GM088652504
+P10747099A0507
+P10514808T0000
+P11197549A0748
+BC2GM041201611
+BC2GM047096684
+P04759722T0000
+P07721878A1163
+BC2GM062761406
+P02642466T0000
+BC2GM020320741
+P03972038A0000
+P07474078A0838
+P06027841T0000
+P10656154A0722
+BC2GM017445898
+P09432752A0109
+P07472736A0278
+P08626777A0537
+BC2GM010655694
+BC2GM017739498
+P07644466A0578
+P11179272T0000
+P08605931A0777
+P02547079A0910
+P08763925A0588
+P01433524A0788
+P09003463A0198
+P01460054A0968
+P09201980A0910
+P11073218A0800
+P01378052A0594
+BC2GM008130653
+P09763446A1234
+BC2GM018406143
+BC2GM009609268
+P03720615A0434
+BC2GM000136143
+P09519757A0482
+P02809116A0237
+BC2GM027002069
+P11148589A1124
+P07592647T0000
+BC2GM063547892
+BC2GM014111333
+BC2GM040722108
+BC2GM026311034
+P08770981A0328
+P08386592A0089
+BC2GM002932224
+P06683807A0160
+P06591992A0569
+P08840997A0765
+P07836471A0375
+P08288633A0144
+P08925545T0001
+P04632967T0000
+BC2GM010819774
+P09079904A0995
+P07542616A0313
+BC2GM095085610
+P08206867A0874
+P09933641A0241
+P03001054A0703
+BC2GM038012165
+P02815229A0139
+BC2GM020803257
+P11034547A0674
+P09701616A0108
+BC2GM055784735
+P08620003T0000
+P09857197A0289
+P07218008T0000
+P09613574A0905
+P08768374A0765
+P09261155A0833
+P08276762T0000
+P08382296A0766
+P07786821A2292
+P07061263A0293
+P08789441A0339
+P09785114A1026
+P10840001A0188
+BC2GM088289193
+P06705456A0346
+BC2GM002667802
+P10871347A0477
+P04646045T0001
+P08034682T0000
+P09326727T0000
+P11273995A1148
+P09721798A1734
+P09157760A0000
+P10993787A0369
+BC2GM056335260
+BC2GM038107026
+P08239586T0000
+P07436187A0147
+P01712296A0157
+P08524284A0309
+P08595658A0961
+P08164680A1086
+P02789180A0407
+P11208017A0070
+P09194250A0708
+P11127161T0000
+BC2GM040216592
+P09724772A0840
+P08531373A0470
+P07896088A0720
+P08670910A0156
+P02793753A0354
+P03001086A0587
+BC2GM045767472
+BC2GM081733082
+P02287860T0001
+P02940334A0141
+P01450815A0337
+P10918596A0000
+P03352439T0000
+BC2GM065471552
+BC2GM087637002
+P09551972A1033
+P08936640A0105
+P03499608A1054
+P08208540A0417
+P01832019A0265
+P09438165A0405
+P01316900A0000
+P10644760A0000
+P08617216A0584
+BC2GM000627922
+P02464097T0000
+P00767161A0837
+P08149484A0151
+BC2GM046248491
+P07750217T0000
+P10575642T0000
+P04764049T0001
+BC2GM050518839
+P09596542A0542
+P09064659A1055
+P05879595T0094
+BC2GM093006252
+P04002667A0181
+BC2GM083214428
+BC2GM031494591
+P11117523A0650
+P07510635A0479
+P08491383A1291
+P08413239A0490
+P10585311A1542
+P01438287T0000
+P09098066A0119
+P09743128A0969
+P11543662A0562
+P10602502A0422
+P08649393A0000
+BC2GM097504248
+P08114702A0000
+P09628419A0812
+P09642276A0881
+P09427844A0739
+BC2GM039377977
+P09225151T0000
+BC2GM018711708
+BC2GM097056879
+BC2GM017257591
+P08395004A0141
+P09186430A0341
+BC2GM080904323
+BC2GM007100869
+P00386251A0899
+P01480470A0323
+P07655509T0000
+BC2GM037344526
+P09220177A0564
+P11222720A1699
+BC2GM088026149
+P02041088A1053
+BC2GM053284567
+P08988913A0821
+P02894789A0954
+P08853303A0431
+BC2GM053959497
+P03137105A0146
+P11276426A0501
+P07914192A0844
+P08964067A0188
+P08891131A0000
+BC2GM002297931
+BC2GM026295270
+P09735371A0227
+P07044389T0000
+P08501030A0456
+P01556068A0000
+P09348931T0000
+P07652066A0677
+P01433502A1163
+P02277319A0211
+P11094073A0000
+P10593939A0747
+BC2GM006418171
+P10703633A0747
+P01285554T0000
+BC2GM080933132
+P06568939A0000
+P07913891A0174
+P11121434A0915
+BC2GM078586075
+P09688264A1029
+P01565093A0179
+BC2GM040760692
+P02023421A0343
+BC2GM057768867
+P03034570A0943
+P06322183A1070
+P08455598A0000
+P01833716A0990
+P00759049A0185
+BC2GM043101437
+P03270085A0382
+P09806516A1689
+P11172610A0508
+P03267732A0788
+P11220306A1753
+P07599653A0898
+P11559821A1315
+P10555964A0778
+P08278929A0866
+BC2GM051957137
+P11384576A1132
+P02711145T0000
+P07739566A1076
+BC2GM071151906
+P09920896A1230
+P10938102A0265
+BC2GM088996203
+P09515031A1020
+P01696715T0074
+BC2GM080141188
+P05502054T0000
+P09486531A0638
+P03799790A0146
+BC2GM008474326
+BC2GM036342195
+P08604338A0198
+P09434185A0902
+P10625494A1059
+P04036838A0918
+P11560990A0272
+P07557424A0124
+P11395469A1373
+P08676454A0731
+P07624119A0528
+P07836390A1152
+BC2GM072515083
+P09918715A0304
+P11274149A0625
+P09022632T0000
+P08628255A0932
+P10867496T0001
+BC2GM085352639
+BC2GM021589926
+P02209605A0510
+BC2GM033557862
+P09544991A0483
+P10679065A1217
+P02154885A0153
+BC2GM027725550
+P07880442A0236
+P09223647T0000
+P01467088T0075
+P09441746A0546
+P08322823A0839
+P08396749A1112a
+P08355697A0000
+BC2GM062155957
+P07340196T0001
+BC2GM084539216
+P06415299A0233
+P03023682A0271
+P10781604A0827
+P07532278A0833
+P07835886A0894
+P03763836T0001
+P11129724A0904
+P08630542A1421
+P08869763A0378
+P03806696A0000
+P08230452A1489
+P00221136A0984
+P02124710A1624
+BC2GM004672850
+P09759865A0673
+BC2GM063927738
+BC2GM055611171
+BC2GM083528781
+P08825087A0213
+P06579152A1061
+P01711041A0348
+P03871298A0217
+P06185493A0468
+BC2GM082670974
+P08896473A0282
+P07789971A0758
+BC2GM068470337
+P08950144A0172
+P01376319T0000
+P09703021A0000
+P08445729A0657
+P09650403A0868
+BC2GM021990815
+P08172905A0000
+BC2GM012197912
+P07501700A0000
+P08555753A0591
+P10903837A1208
+P11169080T0000
+BC2GM036212227
+P07708058A0178
+BC2GM099964294
+BC2GM032297282
+P11195401A1030
+P01448806A0135
+BC2GM066529343
+P08172598A0237
+P08253777A0301
+P10903843A0447
+BC2GM064656341
+P07635312A0692
+BC2GM011193274
+P09596738T0000
+P09323612A0374
+BC2GM060083809
+P07538068A1094
+P11121397A0587
+P03781948T0000
+P08345191A1140
+BC2GM095754088
+P02480959A0470
+P09121432A0000
+P09620955A0370
+P10938109A1361
+P10938113A0388
+BC2GM051853385
+BC2GM074994659
+P08179827T0000
+P01734570T0000
+P09917555T0001
+P07168531T0001
+P09328341A1449
+BC2GM061410736
+P09272108A1295b
+BC2GM080113467
+BC2GM017555562
+P08510647A1347
+BC2GM075120339
+P10649738A0953
+P00980255T0000
+BC2GM092239807
+P09079928A0525
+P00555495T0000
+P00534613A0000
+P11556809A2085
+P01372900A0448
+BC2GM023484942
+P01702361A0621
+P08011166A0207
+P09382498A0618
+P00485615A0935
+BC2GM015899967
+P01547787A0548
+P00115974A0576
+P02077560T0000
+BC2GM040338006
+P04139943T0001
+P03256150A1866
+BC2GM021031743
+P08264631A0746
+BC2GM011957341
+BC2GM057600455
+P01742341A0499
+P08290278A0374
+P10584704A0913
+BC2GM015846745
+P08940298A0962
+BC2GM009503758
+P09445488A1169
+BC2GM032286416
+P11409425A0000
+P02229541T0000
+BC2GM003670421
+P06287212A1352
+BC2GM039253941
+BC2GM028241887
+BC2GM087723838
+P07961957A1565
+BC2GM044666504
+P11335116A1099
+P09917387T0000
+P09372287A0296
+P03110692A0156
+P06507629A0717
+BC2GM058599775
+P11238402A0191
+P00918556A0000
+P03768208A0879
+P01244236A1122
+P07663963A1588
+P08151790A0354
+BC2GM059254999
+BC2GM056030212
+P01656221A1319
+P02233715A0914
+BC2GM084116601
+BC2GM054689635
+P08690198A0346
+P09566871T0000
+P09858572A0000
+P10564939A0981
+P06468632A0135
+P09305944A0621
+P03065621T0000
+BC2GM075805410
+P02392511T0000
+P07622058A0411
+P02651448A0000
+P07477245A0625
+P02902927A0145
+P07461848A0230
+P10765095A0308
+BC2GM022806510
+P09216017A0621
+P09562558T0000
+P01972379T0042
+P03104245A0402
+BC2GM087385719
+P03920700A0491
+P07132408A0387
+P11525640A0560
+BC2GM007534249
+P02219751A0517
+P02076620T0000
+BC2GM005711983
+P02644735A0427
+BC2GM076143207
+P05474466T0001
+BC2GM034854345
+P01830114A1587
+P01963419A0501
+P10908462A3159
+P01535242A0557
+P08192795T0000
+P08108413A0964
+P08825639A0827
+P00117748T0000
+P09738010A0305
+P03818467A0180
+P09254678A0106
+P07642633T0000
+BC2GM094523699
+P01662807A1182
+P10827885T0059
+P10965135A0735
+P03264886A0000
+BC2GM041907191
+P08486705A0181
+P01895393A0745
+P09881692A1109
+BC2GM072322164
+P02528329A0000
+P10853850A1103
+P08670853A0000
+BC2GM081030617
+P09430661A0796
+P07547510A0261
+P03319621A0707
+BC2GM086512279
+P09582350A0165
+BC2GM026833170
+P11580941A0815
+P01722479A0302
+BC2GM006557709
+BC2GM019723956
+P08371650T0000
+BC2GM052291844
+P09171239A2146
+P05075857T0000
+BC2GM071451741
+BC2GM053319803
+P11016954A0438
+P09632217A0477
+P09550919A0365
+P01899287A0726
+P07972831A0563
+P08383129A0776
+P10772977A0222
+P02270834A0123
+BC2GM000132505
+BC2GM083794730
+P06856306T0000
+BC2GM056216898
+P08474456A1041
+P08642313T0000
+P11137367A0297
+P07475733T0000
+P09053973A1252
+P00818380A0239
+P08334158A0660
+P02355293A0749
+P02458699A0650
+P09858577A1186
+P11260662X0000
+P01766876A0000
+P06822645T0039
+P08816504T0000
+P03446332A0831
+P01939199A0588
+P03104914T0000
+BC2GM067535411
+P07490156A0647
+P11350038A0459
+BC2GM042959881
+P08441423A0145
+P00224013A0661
+P09891046A0269
+P00838152A0863
+P08643111A0855
+P09305631A0770
+P11238947A0636
+P07798134T0000
+P03371139A0829
+BC2GM083212050
+P01457380A0000
+BC2GM075933403
+P02874635T0000
+P02538720A0582
+BC2GM036933937
+P04039744A0141
+BC2GM038038322
+BC2GM096376764
+P07830112A0532
+P09582953A1670
+P00378492A0475
+P11073870A0375
+P01878755A0496
+BC2GM067694313
+BC2GM057268278
+P08532536A0925
+P08584074A0000
+BC2GM092245108
+P01826043A0431
+P11197926A0000
+P01418494T0000
+P07896291A0693
+BC2GM057663917
+P09618481T0000
+P08808756A0587
+P11116084A0000
+P02394707A0789
+P11094091A0000
+P02154467A0709
+P06158844A0000
+BC2GM021489980
+BC2GM010471023
+BC2GM059205443
+BC2GM067269145
+P09925372A1063
+P02342477A1292
+P11312326A0169
+BC2GM097016872
+P07565775T0000
+P11166863A0167
+P02038326A0538
+P02024791A0582
+P07988730A0220
+P08413260A1437
+BC2GM091781458
+P06798609A0000
+P07274482A0000
+P11069897A1112
+P08798443A1218
+P02076620A0548
+P08654390A0000
+BC2GM088340339
+P08622596A0189
+P01241588A1470
+BC2GM003857556
+P02552143A0748
+P10795098A0253
+P08153130T0000
+P08435755A0938
+P09820621A0067
+BC2GM076417003
+P09223880A1147
+P11094087T0000
+BC2GM058378997
+BC2GM035173306
+P11238586A0000
+BC2GM029984247
+P01703335T0000
+P06711642A0093
+P11313961A1323
+P07966565A0901
+P06671047A1124
+P02500432A1416
+P09367676A0275
+P10013227T0000
+P02685331A0523
+P02981840A0907
+P10362897A0545
+P03761122T0000
+P08516301A0080
+BC2GM052567540
+P11081962T0000
+BC2GM036162857
+P03137601A0212
+P10713453A0172
+P06883385A0509
+P07065206A0398
+P06891270A0000
+P02091890A0614
+BC2GM011974374
+BC2GM076888648
+P09852136A0507
+P01545792A0000
+P09139910A0350
+P08608126A0811
+P11155096A0222
+P08618433A0000
+P09199353A1924
+P06482318A0117
+P07956578A0851
+P09416898A1798
+P07863047A0229
+P03008094A0697
+P02656257A0000
+P01247475A0000
+P08291886T0024
+P03824908A0116
+P09712297T0000
+P07565685A0420
+P09639558A0957
+P02044785A0000
+BC2GM021762963
+BC2GM032718257
+BC2GM080439811
+P08464924A0243
+P07487811A0000
+P08112526A0443
+BC2GM023376128
+P09570952A0000
+P01674242A0358
+P09714109A0785
+P09445056A0215
+P01990266A0678
+P09721207A0637
+P04813394T0000
+P09371596T0000
+P09572428A0526
+P02246447A0460
+P11114521A0282
+P09535908A0321
+P08439564A0883
+P07547500A0066
+P08992115A0199
+BC2GM083666450
+P10913304A0894
+P07936635A1134
+P11230145A0732
+P11479104A0446
+P03835413A0616
+BC2GM074224073
+BC2GM035992425
+P03600705T0000
+P03261005A0216
+BC2GM091667751
+P02310300A0298
+P08566773A1023
+P03923828A1031
+BC2GM062801890
+BC2GM095278451
+P08226794A0501
+P10903440A0515
+P11356853A0873
+BC2GM065743412
+P03939317A0352
+BC2GM020664774
+BC2GM063458894
+P02882893A0301
+BC2GM012661651
+P02307850A1197
+BC2GM087578129
+P07509811A1357
+P01674817A0862
+BC2GM057843919
+P09765372A0669
+BC2GM040553763
+P03025862A0860
+P03427613A0659
+P01443047A0773
+P08430087A0467
+P02155017A1106
+P07312707T0000
+BC2GM080360058
+P09119112A1350
+P08644734A0404
+P03605895A0888
+BC2GM039478548
+P10665798A0598
+BC2GM076347015
+P00799988A0554
+P02167467T0000
+P01603088A1121
+P11167778T0000
+P02721169A0171
+P09006935A0590
+P08669274T0000
+BC2GM014301582
+P09649426A0636
+P07438482A0145
+P10982143A0346
+P00874942T0000
+P10918943T0000
+P08405433A0000
+P11027274A1682
+P03592297A0679
+BC2GM030870711
+BC2GM026280361
+P06460889A0512
+P08082360A0411
+P11480497T0000
+BC2GM023340483
+P03053713A0752
+P02914422A0409
+P06229542T0045
+BC2GM011323524
+BC2GM053776586
+P10936051T0000
+P01302765A0999
+P10656161A0316
+P01735347A0482
+P08668203A1230
+P08971009A0860
+P01433391A0594
+P11158324A1073
+P10777669A0582
+P08382769A0924
+BC2GM020630421
+P03232410A1467
+P03382855A0368
+P07966873A0693
+P02427797A0199
+P09537295A0951
+P08893822A0560
+P03212929A0000
+P03745833A0258
+P00974901A0080
+P10567524T0000
+P07062269A0798
+P09502627A0705
+P10975465A0134
+P08887674A0630
+BC2GM039116924
+P09649438A0182
+BC2GM091026320
+P01313909A0526
+BC2GM069293246
+P09880513A1013
+P08144497T0000
+P08585639T0000
+P02198259A0685
+BC2GM079167914
+P07969152A0721
+P11207308A0999
+P10872535A0000
+P07511818A0485
+P08387994A0980
+P01406656A1075
+P09747873T0000
+BC2GM082240751
+P10496303A1968
+P01438224A0749
+P11152451A1580
+P08281740A0000
+P08029334T0000
+P07533858A1503
+P08605302A1770
+BC2GM044241169
+BC2GM060734859
+P02556269A0187
+P07596558A0824
+P11411623T0000
+BC2GM002844887
+BC2GM069088909
+P10891266A0421
+P09882303A1413
+P02776742A0000
+P09368419A0000
+BC2GM028146318
+P11188993A0298
+BC2GM079908417
+P08626065A0000
+BC2GM004277618
+BC2GM029654898
+P09244350A0000
+BC2GM022748890
+BC2GM069948018
+P07958446A0000
+P08677678A0258
+P08464056A0000
+BC2GM048997766
+BC2GM007910996
+BC2GM052397745
+BC2GM085771334
+P08432526A0580
+P02307850A0000
+BC2GM084109623
+P11281268A0000
+P08659545A0000
+P04578686T0000
+P07678602A0153
+P01320640A0336
+P01452037A0000
+P09539779A0621
+P11056019A0926
+BC2GM002040357
+P07933076A0211
+P11317256A0361
+BC2GM039881960
+P08808120A0774
+BC2GM088087323
+P07435185A0074
+P04536964T0000
+P10921197A0179
+P09705324A0213
+P08144504T0064
+P08980819A0193
+P11132148A0162
+P11279720A0844
+P11547819A0532
+BC2GM083082153
+P02392032A0657
+P10889399A0243
+P03463543A1613
+P10700262A0000
+BC2GM037103656
+P01582413A0192
+BC2GM004475360
+P08446579A1210
+P07063606T0000
+BC2GM073438143
+P09122215A0335
+P10722509A0392
+P07957106A0875
+BC2GM016841080
+BC2GM057852138
+P09374541T0000
+P01898928A0260
+P10591933A0798
+P07704040A0000
+P03915540A0863
+P08440238T0000
+P07045156A0204
+P07702752A0545
+BC2GM016129428
+P09156883A0294
+P09501093A0071
+P07863619A0098
+P00819176T0001
+BC2GM018080572
+P02802280A0495
+P08885270A0428
+P10660069A0819
+BC2GM097970761
+P02118519A0516
+P07323573A0644
+P03003695A0395
+BC2GM009859517
+P06428116T0000
+BC2GM065134610
+P10734312A0503
+P11168366A0569
+P03268555T0000
+BC2GM045825131
+BC2GM023957927
+P00517890A0468
+P09817373A0000
+P01572549A0000
+BC2GM039797757
+BC2GM043911638
+P08757265A0466
+P08288596A0663
+P09368006A1332
+P01620610A1070
+BC2GM065484905
+P00430889T0001
+P03734641A0203
+P08856132T0000
+BC2GM008128545
+P11292839A0531
+P08533473A0375
+P09540062A0755
+P02777797A0720
+P10001333T0038
+P08276234A0119
+BC2GM051388825
+P08771781A0103
+BC2GM081882075
+BC2GM099337674
+P09351242A0719
+P03280946A0375
+P11227039A0953
+BC2GM010669638
+P06886031A0898
+P10854004A0788
+BC2GM092742899
+P09360993T0000
+P00234626T0036
+BC2GM018866489
+P02307613A0783
+P08169709T0000
+P09486035A0051
+P08913186A0431
+P07794556A0000
+P10833461A0603
+BC2GM040965133
+P11248626T0000
+P00762763A0253
+P06734713T0000
+P08284337A0825
+P08189503A0000
+P02166416A0419
+BC2GM036058953
+P11080796A1277
+P08902548A0144
+P09185645T0000
+P11760398A0553
+P08583846A0807
+BC2GM005501477
+P06142279T0000
+BC2GM089212224
+BC2GM051832821
+P07927711A0698
+P10206959A0368
+P09566882A0693
+P07304905A0336
+P07195880A0621
+BC2GM061191789
+P07941174T0001
+P00644539A0783
+P07550216A0195
+P01906692A0321
+P09499061A0000
+P08993831A0000
+P09882337A0000
+P01333035T0000
+P03001952A0958
+BC2GM064852247
+P07854130T0000
+P09915860A0119
+P11389077A0000
+P09727046A0784
+P08098842A0660
+BC2GM088684177
+P08317094A0778
+BC2GM067510592
+P07386500A0174
+P06763897A0216
+P01634861A1336
+BC2GM036029614
+P07787179A0312
+BC2GM021742629
+P08825554A0000
+P09708565A0000
+P07088195T0019
+BC2GM081897643
+BC2GM021811332
+P11410110A0190
+P08395681A0388
+BC2GM043026651
+P08095698T0000
+P09765285A1763
+BC2GM089809726
+P09938097T0000
+P04088396A0145
+P09927449A0421
+P03065140A0273
+P09225506A0462
+P02330333A0325
+P08048582A0821
+BC2GM070142081
+P08389365A1344
+BC2GM062732556
+P08608448A0353
+BC2GM083575704
+P02148219A0508
+P07715200A0000
+BC2GM050861861
+P09349501A0196
+P02752651A0480
+P07757315A1227
+P07234308A0121
+P07928954A0545
+P07044562T0000
+BC2GM031241503
+BC2GM097598269
+P11357063A1053
+P09934611A1054
+P10784393A0000
+P07377954A0117
+P07782113A0726
+BC2GM076808148
+P04176268T0000
+P02884860A0329
+P05683809T0000
+P09792702A0754
+P08987009A0400
+P08229826A1145
+P08981371A2049a
+P09243385A1314
+BC2GM017323042
+P00385457A0187
+P07957632A0000
+P07677573A0000
+P05027295T0034
+P08094498A0614
+P07746794A0000
+P00590594T0000
+P10662550A0679
+P08355680A0824
+P11050168A1185
+P07576179A0781
+P08298129A0274
+P02520622A0200
+P09784063A0621
+P08845378A0368
+BC2GM041136178
+P03581160A0583
+BC2GM041754029
+BC2GM064970806
+P08413274A0452
+P01579472A1018
+BC2GM042091404
+P09584179A0673
+P11431857A0186
+P08823163T0000
+P02120707A0594
+P10805737T0000
+P11533863A0125
+P01732752A0156
+P06090458A0407
+P09529156A1238
+P01429740A1065
+BC2GM092797387
+P01989999A0000
+P07993559A0233
+P02876820A0841
+P04328746T0073
+P02756731T0001
+BC2GM006852575
+P08190633A0000
+P09716435A1004
+BC2GM048018983
+P09580700A0841
+BC2GM066374194
+P02362803A0608
+BC2GM041137121
+P10852460A0170
+P02565807A1198
+P11161720X1294
+P01543909A0787
+P09122168A1427
+P01400401A0854
+P08015850A1076
+P01116254A0000
+P08041793A0242
+P01064124A0560
+P07543868A0414
+P09553134A0596
+P02549417A0000
+BC2GM048321842
+P09032328A0650
+BC2GM033472267
+P01674369A0417
+BC2GM060341382
+P07134924A0640
+P09098899A0000
+P08561893A0100
+P05021912T0000
+P09971815A2094
+P10642889A0393
+P07525596A0584
+BC2GM029897790
+P00962277T0000
+P00603783A0647
+P02798953A0307
+P11193045A1193
+P11341349T0000
+P01809854A0106
+P06165132A0000
+P07926729A0000
+P07935447A0972
+P09275990A0938
+P02712246T0042
+P09858745A1350
+P02928112T0000
+P02731671A0000
+BC2GM099015286
+P10918948A0110
+BC2GM053163697
+P00756511T0036
+P01648142A1170
+P10801809T0000
+P08927612T0000
+P10706887A1457
+P10997330A0361
+P07836406A0884
+BC2GM003814386
+BC2GM054248395
+P08327488A0839
+P07504171A1214
+BC2GM030020218
+P10950924A0393
+P09053494A0612
+BC2GM014656011
+P08626493A1468
+P01763065A0913
+BC2GM016312848
+P01905517A1076
+P01555556A0565
+BC2GM056227993
+BC2GM087087501
+P07942448A1227
+P08482539A0913
+P06890622A0067
+P04074214A0000
+P11278521A0849
+P06508393T0000
+P08503348A0226
+BC2GM040414983
+P06088722A0171
+P08530369A0099
+P02310261A0115
+P08634357A0527
+P01675763A1389
+P04176249T0001
+P08918885A1087
+P10713239A0988
+P09326263A0410
+P01985924A0554
+BC2GM049845600
+P04753073T0000
+P02212540A0473
+BC2GM012470081
+P03952387A0336
+P01695314A0762
+P03452920T0001
+P09372937T0000
+P08152800A0709
+P00025557A0100
+P11517399A0858
+P06191243T0000
+P01414219A0319
+BC2GM019879007
+BC2GM066006503
+P02845654A0510
+P01657246A0325
+P01783375A1066
+BC2GM058050857
+P01937790A0292
+BC2GM078500347
+BC2GM019974743
+P06319421A0937
+P10807903A0362
+P11435983T0000
+P09135149A0000
+P02966671A0551
+P03340774A0328
+P01538401A1244
+P03649340A1119
+BC2GM048824639
+P08143236A1055
+BC2GM009210929
+P03520729A0381
+P06328012A0549
+P09891046A0554
+P09512559T0000
+P11376134A1506
+P07585246T0000
+P11413760A0000
+BC2GM014160134
+P09089653A0615
+BC2GM051466655
+BC2GM035585393
+P01309860A0559
+P07174046T0000
+P10721717A0676
+P11352671A0492
+BC2GM067441518
+BC2GM089782491
+BC2GM082766404
+P03910310A0666
+BC2GM091307930
+P09331119A0659
+P07558583A0562
+P11063127A0000
+P03168709A0000
+BC2GM032034538
+BC2GM098636877
+P02106287A0478
+P07594592A0755
+P06479976A0386
+P00413854A0958
+BC2GM066509312
+P08383622T0000
+P10694605A1327
+P09243587A0000
+P07811639A0222
+P09539746A0781
+P08756642A0230
+BC2GM029314014
+P01731107A0928
+P00122718A0500
+P02202496T0000
+P09451857T0001
+P11535832A0586
+P09757012A0942
+P09925120A0074
+P11014213A1019
+P01977856A1036
+P09851614A0109
+P08977013A0788
+P08604708A1086
+P06776918T0000
+P09201946A0000
+P08582143A0614
+P11832019A0668
+P08386317T0000
+BC2GM075671967
+P07162146A0000
+P09150334A0559
+BC2GM069671775
+P02462523A0394
+BC2GM029453791
+P01986360A0000
+BC2GM007514824
+P11082185A0415
+P02344529T0000
+P03567017A0000
+P01658375A0854
+BC2GM053041146
+BC2GM055489778
+P06668316A0178
+BC2GM035302143
+BC2GM077718596
+P00574956A0304
+P05308271T0000
+P08333643A0000
+BC2GM093692420
+BC2GM053319236
+P08163183T0000
+BC2GM053438621
+P11435605A0587
+BC2GM094222143
+P11416132A1351
+BC2GM022142685
+P06333878T0000
+P11054970A0282
+P05836483T0000
+BC2GM092988479
+BC2GM012346343
+BC2GM089696492
+P08173693A0390
+P01421609A1067
+BC2GM066639389
+P07935370A0000
+P08083998A1723b
+P10792718T0000
+P09508775A0293
+P11223938X1218
+BC2GM075054681
+P01328219A1397
+BC2GM048702510
+P01587763A0402
+P11451995T0000
+P03441587A0000
+P09111314A0970
+BC2GM079567049
+P01620781A0611
+P09888994A0858
+BC2GM070272053
+P09006914A0812
+P08537388A0825
+P03887769A0584
+BC2GM097216118
+P10568455A0000
+P07592647A0797
+P09575217A0971
+BC2GM022830780
+BC2GM067923861
+P02280777T0000
+BC2GM082328834
+P06327638A0155
+P09900679T0000
+P09636670T0000
+P08647434A1124
+P10717612A0000
+P10575545A0147
+BC2GM089043766
+P11583880T0000
+BC2GM005625314
+P02020314A1290
+P07461226A0958
+P11376007A0584
+P08293993A0948
+P08071356A0232
+P09133122A0656
+P02193033A0195
+P03561036T0000
+P02584969A0119
+P07826625X0000
+P08101134A0376
+P01832152A0902
+BC2GM091971820
+P02807780A0143
+BC2GM095222501
+BC2GM080887068
+P07951235A0277
+P09815578A1245
+P11336698A0075
+P08626437A0332
+P07544357A0808
+P02936284A0357
+P09584165T0000
+P11118619A0835
+BC2GM054387079
+P07518460A0771
+P08107208A0673
+P01237206A0199
+BC2GM076178142
+P08207805A0000
+P01542667A0125
+P03978132A0108
+BC2GM068206225
+P09679066A1352
+BC2GM049209935
+P07219821T0028
+P10872756A1325
+P11380028A0000
+P07592730A0204
+BC2GM015111811
+P02743981A0347
+P07896817A0204
+P09382886A1061
+P11687737A0000
+P01829460A0329
+P07665187A0824
+P00725534A0888
+P08631820A0755
+P11234223A1451
+BC2GM033034738
+P09769910A1700
+P07730336A0606
+P11145562A0000
+P06612373A0000
+P08537403A0336
+P10628748A0344
+P03676054A0865
+BC2GM043951266
+P09705258A0837
+P09662443A0402
+P03615550A1094
+BC2GM028429714
+P02278217A0372
+BC2GM016105671
+P08444184A0245
+BC2GM041870029
+P10712512A0506
+BC2GM012328015
+BC2GM011525777
+BC2GM095655624
+P02303470A0242
+BC2GM005335689
+P02463050A0514
+P11179687A0280
+P09545638A0330a
+P03144705A0859
+P10767553A0100
+P07557276A0526
+BC2GM071848637
+BC2GM054072257
+P11160860A0662
+BC2GM054091501
+P02062933A0738
+P10564280A0140
+P09472038T0000
+P09511760A0221
+P00205074A0000
+P02154599T0000
+P01797467A0000
+P03537686A0099
+P01471602A0362
+BC2GM065946297
+P11029700A0746
+P06394347A1024
+P02185250A0726
+P03340726A1103
+P08910292T0000
+BC2GM037614071
+P08862743A0603
+P07885678A0709
+P07673178A0982
+P08924381T0000
+BC2GM084701019
+P11535014A1157
+P10653400A0000
+P09619777A1583
+P06286549A0000
+P09873060A0901
+BC2GM043376689
+P07907328A1070
+P07935491A1182
+BC2GM020677655
+BC2GM096761437
+P03443609A0000
+P08828857A2423
+P08034741A0000
+BC2GM057684207
+BC2GM015147115
+P02556264A0278
+P07506253A0742
+P00429949A0000
+P09485790T0000
+P02335815A0530
+P03297181A0127
+BC2GM019218967
+P09886843A0339
+P02075876A0408
+P06310159A0000
+BC2GM079348328
+BC2GM065525497
+P06548953T0001
+P11083868A0386
+BC2GM038659549
+P01313715A0461
+P09334331A0910
+BC2GM012711095
+P01721261T0000
+P09490727A1041
+BC2GM010380443
+BC2GM021336202
+P11160929T0000
+P08621664A1430
+P08431100A0108
+P10652228A0759
+BC2GM012464195
+BC2GM002235510
+P02187091A0721
+P07680035A0221
+P08710151A0782
+P07112320A0086
+BC2GM038819274
+P08812106T0000
+P11201250A0849
+P09922230A1482
+P01686909A0299
+P11247663A1447
+BC2GM036373124
+P08387743A0624
+P04975676T0000
+BC2GM018214365
+BC2GM035122816
+BC2GM005098468
+P08034680A0180
+P11428276A0352
+P01516829A0460
+P11595478A1014
+P08524314A0216
+BC2GM027092021
+P07706396T0000
+BC2GM000169441
+P01082833A0000
+P06655634A0195
+P09658104T0000
+P09407036T0000
+P08123787A0554
+P08383217A0357
+P01404612A0303
+P03398823A0459
+P02339447A0162
+P07724452A0344
+P11019257A0159
+P03434347A0358
+P00916099A0000
+P02647918A0423
+BC2GM077515790
+P00506559A0000
+P07642490A0318
+P09024793A1325
+P01947449A1082
+BC2GM052484918
+P11171118A0836
+P07776685A0000
+P10728986A0000
+P07782775A0889
+BC2GM004196044
+P03436877A0950
+P01295500A0366
+P08515619A0184
+P10780764A0722
+P11168446T0000
+BC2GM033682713
+P08352066A0000
+P02200150A1381
+BC2GM003943388
+P11407650A0661
+BC2GM064288538
+P05081814T0000
+P06414990A0057
+P07864652A1901
+P00377466A0188
+P07539119A0291
+P11392772A0182
+BC2GM055710514
+P11223255A1034
+BC2GM089393717
+P08063775T0000
+P01321337A1161
+P07558263T0000
+BC2GM093503103
+P09703276A2346
+BC2GM011797834
+P11418130A0499
+BC2GM059024558
+P10599013A0505
+BC2GM094581342
+P01148868A0284
+P09524273A0205
+P04989251T0000
+P06419251T0000
+P11084022A1178
+P11309373A0783
+P08757943A0876
+P03008405A0532
+P02466665A0202
+P09169593T0000
+BC2GM097492255
+BC2GM066315892
+BC2GM048995612
+P07799931A1232
+P08340400T0000
+BC2GM099774129
+BC2GM088402436
+BC2GM003776641
+P09803081T0000
+P02560415T0012
+BC2GM081729599
+P09372968A0996
+BC2GM032212038
+P02850971A0180
+P06830351A0397
+P07937841A0790
+P08486276A0419
+P06833422T0000
+P09367392A0567
+P05823624T0031
+P09537375A0198
+P07719527T0000
+BC2GM093512186
+P09261200T0001
+BC2GM080360635
+BC2GM054968924
+BC2GM021995713
+P09314537A1600
+P09278758A1636
+P11103792A0755
+P11159363A1251
+BC2GM082011055
+BC2GM045105148
+P02541251A1327
+P09209031A0350
+BC2GM073488635
+P00418341T0000
+P08721989A1012
+P08649428A1227
+P00439618T0001
+BC2GM086019506
+P03395164A0000
+P09325022A0192
+BC2GM074636309
+P02709819A0495
+BC2GM084680436
+P09282911A0277
+BC2GM037965797
+P09261184A0170
+P07828811A0556
+P09565576T0000
+P01709933T0000
+P06748227A0423
+P10882462T0000
+P08733123A0000
+BC2GM039562937
+BC2GM048519833
+P08396667T0000
+P02117799T0000b
+BC2GM091440565
+P07040659A0212
+P03239106A0856
+P01592545A0726
+BC2GM087392570
+P00454780A0340
+BC2GM097368062
+P08812020A0597
+P08380896A0938
+P10331730A0504
+BC2GM038904960
+BC2GM049242982
+P04615828T0001
+P01526690T0000
+P08915051T0000
+P10761263A1108
+P01660486A1756
+P02775333A1137
+BC2GM053394099
+P07981246A0112
+P03721594A0000
+P08602608A1056
+P09481826T0000
+P09557708A1426
+P08245013A0000
+P08783666A0957
+P02546234A1382
+P06437579A0727
+P00988572A0000
+P10666509A0494
+P10787437A1616
+P08453950A0498
+P06838388A0896
+P09079689A0472
+BC2GM064420857
+P05671267T0000
+BC2GM062580234
+P09222115A0545
+P04011338A0620
+P09370307A0093
+P07914192A0211
+P08741206A1551
+P02469451A0239
+P08891337A0614
+BC2GM040073608
+P07774925A0084
+P08731222A0000
+BC2GM035196654
+P11443509A0293
+BC2GM087067391
+P07310206A0154
+P03190481A0292
+P09236441A0639
+BC2GM006903423
+P11120441A1193
+P10938120A1093
+P01284595A0102
+BC2GM088129513
+P02709081T0000
+P11486476A1512
+P08631667A0851
+P08882710A0000
+BC2GM038225935
+P10954913A0152
+P08289357A0724
+P09731704A0000
+P09325284A0469
+BC2GM033055956
+P09071407T0000
+BC2GM082632472
+P07629163A0770
+P11374559A0103
+P08300605A0432
+P11181525T0000
+P02466414A0000
+P08112611A0404
+P02481779A0213
+BC2GM056410850
+P08413209A0159
+P08707840A0753
+BC2GM071553689
+P05960999T0001
+BC2GM027429119
+P08226616A0000
+BC2GM018283736
+P01936348A0155
+BC2GM093465825
+P09925777A1195
+P09108451A0160
+BC2GM079993649
+P10063122T0000
+P09544987A1583
+P11220306A0911
+P08208247T0030
+P02113174A0957
+P07903099A0918
+P02666404A0220
+P08709224T0000
+P08077236A0243
+P01457695T0000b
+P01600531A0483
+P03659805A0404
+P03771670T0058
+BC2GM085698847
+P08997532A0116
+P08867519A0557
+P04295031T0062
+P08630599A0534
+P09814905A0598
+BC2GM057155678
+P07651398A0257
+P11318363A0085
+P02582918A0000
+P11150315A0226
+BC2GM066387134
+P01281322A0604
+P09121435A1183
+P03544858A0374
+P02061282A0447
+BC2GM069895813
+P01923766A0485
+BC2GM015956258
+BC2GM064548155
+P01470243A0871
+P09256973A0673
+BC2GM062194979
+P07592706A1465
+P11512925A0000
+P07721074A0766
+P07964624A0491
+BC2GM029234966
+BC2GM015853606
+P06374369A1112
+BC2GM084095947
+P00239169T0000
+P02419327A0998
+BC2GM060831893
+P01701088A1335
+P11107637X0001
+P03771703A0000
+P07816025A0196
+P10736223A1227
+BC2GM098787807
+P09106057A0000
+P09980944T0000
+P03000489A0822
+BC2GM056277482
+P11500913A1238
+P07588245T0000
+P09154283A0307
+BC2GM085395991
+BC2GM033424223
+BC2GM014735675
+BC2GM068890496
+P10878606A0876
+P03110794A0991
+P08955071T0000
+P01243628A0286
+P07711667A0766
+P09671496A0557
+P03112412A0985
+BC2GM013367918
+P10973151A0883
+P10006319T0000
+P07426604A0397
+P09983871T0000
+P01092248T0000
+P09971776A0838
+BC2GM019190601
+P09000146T0000
+P08264617A0000
+P08255341A0554
+BC2GM094300739
+P01768648A0853
+P05421537T0001
+P01418860A0797
+P02693208A0166
+P08580083A0259
+BC2GM049253682
+P08268833T0000
+BC2GM046785161
+P08204824A0000
+P01612085A0624
+P09823014T0000
+P02575490A1021
+P01881671T0001
+P09006914A1127
+P10891632A0435
+P01297332A0983
+P09647233A0336
+P11356853A0429
+P07731898A0823
+P09254709T0000
+P02752629A0163
+P08231577A1027
+P09139892A1150
+P11451682A0190
+P02174427A1574
+P07651835A0652
+P11074003A0741
+P07569770A0298
+BC2GM053578806
+BC2GM036511457
+P03866085A0795
+P08990194A0000
+P00830568A0000
+P08843412A0543
+P08766049A0000
+BC2GM007134922
+P08096944A0951
+BC2GM025017192
+P09182527A0443
+P08497280A0266
+P06252520T0000
+P00494659A0391
+BC2GM070219691
+BC2GM029899910
+BC2GM068393922
+P01978834A0076
+BC2GM024718949
+P08621730T0000
+BC2GM068628850
+BC2GM042231510
+BC2GM068742708
+P08887643A1167
+P09508377A0863
+P11254504A0766
+P09202859A0091
+P11535140T0000
+P09185586A0000
+BC2GM014357950
+P07567079A0014
+BC2GM038427842
+P08348919T0000
+BC2GM067330469
+P02498652A0460
+P00843232A0100
+BC2GM042721293
+P09580062A0100
+P02258918A0242
+P00740409A0000
+P08905819A0531
+P08861955A0927
+BC2GM083705867
+BC2GM005540562
+P07733075A1200
+P03934667A0124
+P09715278A1079
+P08390665A0000
+P02157882T0000
+BC2GM076657562
+P11416012A2511
+BC2GM067854100
+P07865129A0293
+P06740697A0318
+P08721999A0727
+P08980533A1160
+P10864496A0401
+P08388510A0891
+P09627285A0160
+P00056901A0308
+P02289102A0114
+BC2GM030870274
+P11461595A0000
+P02875967A0377
+P05763347T0000
+P01645905A0341
+P08143198T0001
+P07687320A0526
+P09837714A1068
+P11489597A0561
+P09283828A0484
+BC2GM037013975
+P06607714T0000
+P10934751T0001
+P03572706A0329
+P10552357A1936
+BC2GM072220423
+BC2GM015535650
+BC2GM070374572
+P02906673T0000
+BC2GM022317313
+P10781552A0000
+P03836854T0000
+P07779558T0000
+P09599897A0000
+P05285978T0076
+P11145955A0189
+P00072928T0000
+P01316476A0842
+P01372365A1202
+P00378735A0000
+P09057703A1389
+BC2GM025639631
+BC2GM048198274
+P03134872T0029
+P01848871A0392
+P08536694A0000
+P09882638A0235
+P09851700A0000
+P10961585A0273
+P00390932T0001
+BC2GM041058675
+P06494766A0241
+P08704124A0420
+P03263465T0000
+BC2GM097917359
+P00300314A0132
+BC2GM010985473
+P03352727T0000
+P05488121T0000
+P03114188A0907
+BC2GM084991496
+P11237491A0000
+P06762025A0171
+BC2GM008224119
+P07110999A0160
+BC2GM020275127
+BC2GM046382854
+P07949770T0000
+BC2GM065939725
+P07761467A0666
+P03298134A0000
+P06239545A0649
+P08812012T0000
+P02142993A0176
+P05779953T0000
+P11046517A0619
+P09668108A1017
+P02797877A0475
+P02395868A0322
+P09750325A0000
+P07693372A0115
+P11714429X0000
+BC2GM014171853
+P07530128A0578
+P05994421T0045
+P08116245A0174
+P10856298A0798
+P09671576A0900
+P01674662A0000
+P09819391A1123
+P08959778A0292
+P09388246A0903
+P09282329A0527
+P10604583T0000
+P08533757A0204
+P00669800A0579
+P09112400A1155
+P10980416T0000
+P08934540A0673
+P00509703A0581
+P01551898A1084
+P01377818A0468
+P07548858A0000
+BC2GM067698579
+BC2GM021968476
+P03261223A0644
+P10007469T0000
+P06094591A0000
+P11369410A0949
+P02863747T0000
+BC2GM040436094
+BC2GM063202569
+BC2GM011154838
+BC2GM016725379
+BC2GM035663099
+BC2GM096877178
+P07816049A1157
+BC2GM046023789
+P01985301T0000
+P05819249T0000
+P06294111A1141
+P06743061A0239
+P00034935A0545
+BC2GM006490341
+BC2GM072512934
+P06402480A0373
+P10972990A0196
+P01118293A0150
+P08423831A0523
+BC2GM025327018
+P04113011T0000
+P10650939A1542
+BC2GM062555785
+P09863624A0629
+P09326163A0942
+P01611699A0000
+P07815546A0411
+P02038293A0919
+P01321332A0970
+BC2GM056690514
+P11599797A0732
+P09139737A0000
+P09539721A0599
+P09027346A1957
+P09426958A0110
+P09230945A0089
+BC2GM089290440
+BC2GM076004917
+BC2GM021354805
+P09321657A0439
+P04050771A0474
+P10550139A0191
+P10665949A1131
+BC2GM091675853
+P08643646A0479
+P08172416A0860
+P02780157A0576
+P07911736A1715
+P01605038T0001
+P09405380A0800
+BC2GM041728644
+P09698457A0976
+BC2GM055589568
+BC2GM008024280
+BC2GM048068707
+P08776793A0811
+BC2GM000611082
+P07871718A1132
+BC2GM048607810
+P07888629A0344
+P11089911A1267
+BC2GM081722350
+P10722661A0406
+P09122176A0970
+P07713421A1435b
+BC2GM015287152
+P10709705T0000
+P07929411A0087
+P09880543A0570
+BC2GM019782679
+P09324720A0317
+P01083784T0000
+P00598012A0174
+P11114294A0075
+P09617807A0929
+P11113179A0541
+P11244568A0506
+BC2GM015923347
+BC2GM075371550
+P07501992A0125
+P05124972T0042
+P02022920A0334
+P01549125A0140
+P03779182A0370
+BC2GM068538767
+P03746601A0299
+BC2GM061568897
+P01569581A0482
+P08198524A1134
+BC2GM064739272
+BC2GM050204231
+P03235487A0404
+P11522626A1374
+P10750021A0728
+P09341139A0690
+P10606664A0000
+P10035841T0000
+P00800141X0000
+P00775582T0000
+BC2GM086778872
+P10873386A0000
+P11112417A1126
+P11032599T0000
+P07509449A0000
+BC2GM020770465
+BC2GM036710318
+P03940733A0755
+P08447005T0001
+P11094072A0842
+BC2GM095403151
+BC2GM049635982
+P01840902A1089
+P02176822A0000
+P09708450A0648
+BC2GM096784284
+P09372960A0456
+P10617232A0393
+P05556977T0001
+P08567683A0401
+P07603956A0115
+P09435056A0128
+BC2GM022896971
+P00423649A0259
+P07692754T0000
+P03637037T0000
+P01314457T0000
+P01633435A0743
+P09183406A0637
+P09833610A0626
+P08874631A1133
+P08655555A1368
+P02605160A0000
+P11162278A0629
+P08555168A0390
+P10995751A0093
+P11303638A0559
+P01348508A0313
+P05412687T0000
+P10760169A1142
+P09557678A0140
+P07274428A0000
+P09612351A0386
+P10586074A0129
+P03583001A0111
+P02962859A0276
+BC2GM070452664
+BC2GM002635728
+P08932363A0807
+P02390633T0000
+P03515840A0000
+P10878675A1278
+P02746099A0000
+P03025661A0260
+P07715602A1088
+P08463284A1531
+P03402183A0171
+P09049270A0488
+P11164078A0833
+P03104982A0690
+BC2GM033020504
+P03033283A0837
+P07546256A0000
+P03607961T0001
+P07628451A0114
+P08798648A1816
+P06137028A0624
+BC2GM029365587
+BC2GM035857523
+BC2GM041736875
+P03340548A1018
+BC2GM050069224
+P08124785A0445
+P00030183T0000
+P01874195A0139
+BC2GM077458624
+P09745797A0943
+BC2GM075464288
+BC2GM053864470
+P09119031A1036
+P09639565A0225
+P09950213A1660
+BC2GM037678814
+P07807002A0500
+P06808287T0001
+BC2GM074656896
+P08471629A0816
+BC2GM060157872
+P08001966A0563
+P09441664A0377
+P10835355A0225
+P08289834A0341
+P08973185T0061
+P07293100T0001
+P09345037A0886
+P10860196A0876
+P11145813A0668
+P08824881A0133
+P04323641T0000
+P08420571A1880
+P08144572A0786
+P09466931T0000
+P07890740A0997
+BC2GM078543585
+P06791500A0622
+P10614676A0000
+BC2GM058484539
+P11027267A0752
+P11202705A1112
+BC2GM095454246
+P08241139A0378
+BC2GM030524461
+P10939785A0540
+P07473742A0187
+BC2GM037059732
+BC2GM043225423
+P07723247A1161
+P00139827A0000
+P08139004A0278
+P08101839A0000
+P01869968A0673
+BC2GM054786865
+P01552853A1377
+BC2GM015421655
+P09884747A0477
+P11428897A0318
+BC2GM032976661
+P07723247A0187
+P07649098A0676
+P02319610A1527
+P07565672A0798
+P09154819A0501
+P02015921A0523
+BC2GM065728074
+P09822647A0000
+P01924315A0158
+BC2GM079844918
+BC2GM041776531
+P10443990A0000
+BC2GM056423678
+P01646157A0414
+P03619249A0428
+P07434456A0286
+BC2GM066585108
+P10820829T0000
+P07242929T0001
+P11504545A0393
+BC2GM033997989
+P07754713A0227
+P02676945A0402
+P06199132A0179
+P06012827T0000
+P02999267A0606
+P10406466A0000
+P08770021T0000
+P10760132A1169
+BC2GM082129693
+BC2GM095213644
+P07860646A1363
+P09755191A0553
+P07072635A0000
+P01644796A0374
+P06360426A0501
+P01702432A1296
+P01932695A1155
+P08136383A0359
+P10807900A0933
+P11559789A0314
+P08627688A1520
+BC2GM030209063
+P06074093T0001
+BC2GM019484817
+P01882386A0000
+BC2GM091616739
+P10730292T0000
+P00646023T0058
+BC2GM011480207
+P11376119A0346
+BC2GM076684671
+P07155579T0001
+P06797063A0000
+P03216131A0559
+P08100843A0134
+BC2GM037915116
+P02745280A0276
+P02538656A0172
+P08598359X0000
+P09973351A1522
+P09760341T0000
+P09105042A1497
+P11139567A1440
+BC2GM039227487
+BC2GM077065468
+BC2GM071764861
+P06775834A0000
+P07925022A0285
+P08631908A0224
+P03694102A0000
+P03348382A0785
+P11125151T0000
+P09326246A0567
+P11196340A1046
+P10637337A0545
+P11502758A0869
+BC2GM045923805
+P11462952A1040
+P01751163A0000
+P02906027A0553
+BC2GM010650292
+P11171320A0894
+P08270257A0551
+P03282232A0743
+P03380547A0169
+P09364750T0000
+BC2GM074443347
+P09819216A0220
+P08408194T0000
+P06163433T0000
+P03102289A0786
+P10860752A1601
+P11408575A0000
+P06685536A0502
+P03810867A0305
+P01556111A0241
+P10805286A0233
+P05424220T0001
+P02907533T0000
+P09894962T0000
+BC2GM017483481
+P02138992A0911
+P01090210A0417
+P01241866A0682
+P07760844A0413
+P08538483A0207
+P09409416A0111
+P03283881A0216
+BC2GM070280766
+P04959816T0000
+P11005808A1082
+P07966583A1268
+BC2GM018588140
+P04284435T0000
+P09814637A1214
+BC2GM069174792
+BC2GM077847565
+P06451557A0777
+P08922488A0187
+P09778068A1129
+P09358069T0000
+P07982995A0000
+BC2GM061835883
+P08552045A0973
+P11555669A0464
+P08524260A0835
+P03002786A0143
+P08428722A1123
+BC2GM025980637
+BC2GM038474271
+BC2GM063578385
+P03400694A0245
+P11369700A0616
+BC2GM023962152
+BC2GM097468485
+P10649456A1061
+P08151980T0001
+BC2GM071925716
+P08238626A0248
+P09698512A0296
+P00209664A0836
+P09572511A0148
+P07908012A0678
+BC2GM018782091
+BC2GM095568717
+BC2GM056033881
+P01886043A0380
+P03372422A0558
+P08627719A0784
+P09694725A0500
+P11145566A0000
+P08688190A0000
+P00996272A0397
+P02824334A0972
+P00812183T0000
+P07869937A1142
+BC2GM040176899
+P10920186A0528
+P02461368A0162
+P02565405T0000
+BC2GM074908707
+P00086313A0000
+P11376165T0000
+P00092689A0352
+P00154430A0906
+P02115116A1137
+P08288240A0304
+P09847397A0935
+P10740602A0141
+P06151942A0235
+P10728945A0233
+BC2GM015790797
+P08662789A0673
+BC2GM048642261
+P07896852T0000
+P08387662A0302
+BC2GM051379224
+P10453248A0094
+P08654946A0475
+P09836881A0441
+P09693035T0000
+P01774093T0000
+P11058406A0447
+P07795104T0000
+BC2GM068921814
+P11223131A0000
+BC2GM000687386
+P09192732A1384
+BC2GM079722932
+P09181130A1587a
+P02602150A0993
+P03061301A0624
+BC2GM014660271
+BC2GM025608940
+P02740196A0704
+BC2GM063513672
+P11111051A0051
+P06975206A0279
+P07746937A0100
+BC2GM037303937
+P03319912A0000
+BC2GM058476475
+BC2GM044066999
+P06869986A0000
+P03032143A0218
+P10744026A0000
+P10887921A0718
+P07745008A0892
+P05857301T0000
+P02157141A0923
+P06784123A0771
+P05733953T0001
+P02147223A1047
+P09872832A1262
+P02983331T0000
+P02947866A1416
+P07568118A1267
+P06902722T0000
+P09545146A0884
+BC2GM030635649
+P06810694A0328
+P08544820T0000
+P11894605A1429
+P09717246A0526
+P09988850A0000
+BC2GM029377540
+P03110678A0702
+P09660836A0983
+P03758250A0000
+P08851337A1092
+P08247043T0000
+P09371564A0713
+BC2GM009689602
+P00225352T0000
+BC2GM025928081
+P06795971A0000
+P07676492A1000
+P00577440A0298
+BC2GM080455463
+P09005979A0841
+BC2GM084839351
+P11306101A0000
+P08619910A0000
+P06150069A0422
+P08173532A0000
+BC2GM099918487
+P08702807A0964
+BC2GM032297274
+P09083291A1378
+P06858967A0167
+BC2GM029532307
+P02565683A0841
+P09488441A0615
+BC2GM015098322
+P09364211A0319
+P00513284A0000
+P08592590A0822
+BC2GM066607362
+BC2GM083596704
+BC2GM054680908
+P01713213A0000
+BC2GM049302974
+P11073919A0631
+P03513989A0580
+P03747493A0000
+P11575977A1133
+P07499409A0367
+BC2GM092540760
+BC2GM066650758
+P06364265T0062
+BC2GM031729179
+P10799501A1391
+P09557912A0699
+BC2GM083364353
+BC2GM084397329
+P11220487T0000
+P11406025A0204
+P08184923A0829
+P07174437A0181
+BC2GM091199615
+P03024703A1036
+P09458021A1373
+P08500938A0408
+P03733563A0716
+P01452703A0782
+P06702257T0001
+BC2GM041273228
+BC2GM008085134
+BC2GM057882399
+P11462004A0886
+P11049889A1271
+P07518257A0351
+P09891065A1493
+P09669641A0425
+P01279352A1197
+P09261397A0509
+P01447189T0000
+P01615182A0206
+P01657249A1019
+BC2GM096262172
+P09851988A0085
+P01391001A0583
+P09716179A0974
+P10704975A0479
+P07803809A1852
+P02686985A0811
+P01536153A0574
+P07512552A0270
+P07392519T0001
+BC2GM022478425
+P08446579A0784
+P09971790A0856
+P09132011A0298
+P01309255A1385
+P02895566A0187
+P09421508A0696
+BC2GM010457655
+BC2GM049036959
+P01394655A0615b
+BC2GM059902297
+BC2GM060909038
+BC2GM008677402
+P01811948A0289
+BC2GM020647680
+BC2GM080426101
+P08666383A1252
+P00361340A0529
+P02023097A0000
+P08192140A0209
+P10702285A0855
+P11355615A0766
+P01772341A0852
+P07929559A0000
+BC2GM068660777
+BC2GM010316325
+P10655230A0685
+P06182979A0807
+BC2GM055959438
+P03016301A0605
+P06652293A0353
+BC2GM028349983
+P09079625A0935
+BC2GM023703398
+P02975753A1333
+P09376782A0328
+BC2GM003313671
+P01904437A0000
+P10674395A0262
+BC2GM097227201
+BC2GM087423181
+P01371181A0688
+P01228882A0437
+P07816049A0686
+P08567556A0000
+P09806826A0244
+P09869297A1807
+P07624615A0267
+P02988457A0650
+P10850453A0713
+P08309726A0000
+BC2GM012382882
+P05715613T0000
+P08259650A0640
+BC2GM078411814
+P08551572A0155
+P09165118A0311
+P09001213A1111
+P02326716A0139
+P11132063A0250
+P07094856A0115
+P08552086A0150
+P03697587T0000
+BC2GM085437815
+P08324107A0000
+BC2GM056101330
+P09855111A0905
+P02168640A0268
+P11069075T0000
+BC2GM027249093
+BC2GM080794726
+P09380697T0000
+BC2GM009127817
+P08534848A0188a
+P11313386A0704
+BC2GM029942800
+BC2GM089297892
+P09472616A1004
+P02901498A0354
+P07841663A0845
+BC2GM083254986
+P02647937A0191
+BC2GM061933593
+P08491683A0651
+P09416467A0959
+BC2GM058516621
+BC2GM011333437
+BC2GM023454935
+P03959045A0000
+P00304240A0369
+BC2GM031391098
+P06718064T0001
+P10570262A0000
+P09272138A1153
+P08810040A0955
+P06227570A0523
+BC2GM023797731
+BC2GM033304611
+P02723503T0000
+P07545920A1336
+BC2GM067276643
+P01832152A0000
+P11416879A1589
+P02151229A0921
+P01766666A0788
+P10931927A0655
+P08896272A0000
+P10416558A0000
+P11243306A0961
+P02648646A0216
+BC2GM019247724
+BC2GM059503446
+P00926751A0000
+P07568576A0074
+P11002236A0328
+P08622887A1026
+P06241900A0000
+P08586874T0000
+P11027280A0536
+BC2GM026427859
+P03045117A0936
+P09505733A0246
+P05031074T0001
+BC2GM003255111
+P08111974A1034
+P07759094A0634
+BC2GM001474754
+P09528792A0000
+P01939827A0150
+P09837978T0093
+BC2GM040449829
+BC2GM079046783
+P03396628A0207
+P09495283A0000
+P06434587A0551
+P03104248A0322
+P10805739A0640
+P09124054A1164
+BC2GM010188722
+P11369700A0074
+P04175007T0001
+P08030704A1503
+BC2GM027790254
+P05805644T0001
+P05719031T0000
+P11008139T0000
+BC2GM010484925
+BC2GM093052916
+P10705783A0433
+BC2GM051967353
+P05031659T0000
+P01748630A0125
+P08373972A0335
+P01375224A0152
+P02362161T0000
+P06165551A0793
+P02113015A0295
+BC2GM094515271
+P07097182A0480
+P11561626A0197
+P07831310A0000
+P03459736A0184
+P01647070A0232
+BC2GM027824972
+P08584530A0545
+P03304866T0001
+P00231555T0001
+BC2GM031489380
+BC2GM087801805
+BC2GM013813111
+BC2GM034945904
+P08425221A0000
+BC2GM018845619
+P09640802A0467
+P09469820A0151
+P02902656A0481
+P03079276T0029
+P08319396A0448
+P08429568A0000
+P10531340A1275
+P09451003A0894
+P02126417A0408
+P06919347T0001
+BC2GM025305972
+P01050400T0000
+P10935488A1033
+P05119546T0001
+BC2GM036120565
+P08898893A0202
+BC2GM023685054
+P10608893A0727
+P10748194T0000
+BC2GM064552901
+BC2GM012522981
+P03125422A0202
+P07689501A0420
+BC2GM045455828
+BC2GM098355088
+BC2GM021225439
+P08631822A0677
+BC2GM095563020
+P01398074A0697
+P03264073A0224
+BC2GM078078201
+P03127463A1017
+P02295521A0922
+P07557717A0184
+P02064119A1172
+P00429151T0000
+P09468514A1065
+P08275618A0457
+BC2GM055466114
+P07701266A0808
+P09121430A0132
+P09592168T0000
+P02083199A1175
+P00254537T0000
+P03304015T0000
+P01294345A0591
+P02976332A1277
+BC2GM085283124
+P08030239A0833
+P09234725A1892
+BC2GM069445885
+BC2GM054116094
+P06443550T0000
+P09434979A0790
+BC2GM013076333
+BC2GM048358040
+P07832086A1023
+P09819422A0768
+P10205588A0000
+BC2GM013509506
+P01560021A0379
+BC2GM054451965
+BC2GM072323236
+P02347102A0000
+P01400775A0435
+P08634697A1155
+P01233561T0001
+P06521802A0251
+P10445945T0000
+P00350465T0000
+P08051102A0532
+BC2GM064734705
+BC2GM080428035
+P09741783A0000
+P08879237A0744
+P03980386A0000
+BC2GM017854624
+BC2GM060809395
+P02253274A0000
+P09510925A0389
+BC2GM015383059
+BC2GM056313668
+P07680629T0000
+BC2GM043099285
+P11467349A0452
+BC2GM029733938
+P08706662A1125
+P08089887A0742
+P02903500A0278
+BC2GM068562414
+P08406004A0691
+P08098914A0400
+BC2GM001962189
+BC2GM005500521
+P02999267A0885
+BC2GM033383172
+P02979834T0000
+P11472523A0535
+P01645902A1462
+P02573336A0000
+P04033402A1112
+P11003652A0961
+BC2GM084635327
+BC2GM000680250
+P10752475A1376
+P03039387A0920
+BC2GM009479019
+P07015018A0395
+P10694189A0469
+P03828209T0000
+P01597462A0457
+P02373686T0000
+P08020806A0187
+P00843670T0000
+P07549005A0530
+P01506746A0476
+P02231479A0585
+P07853448A0601
+P07592337A0891
+P10563789A1951
+P09032259A0150
+P11083154A0881
+P07356273T0022
+P11415952A0369
+P06318091A0395
+P06258806A0963
+BC2GM024256148
+BC2GM057171148
+P09354676A1714
+P01374688A0471
+P08484514A1536
+P02796988A0735
+P11920455X1195
+P06225279A0498
+P11151826T0000
+P07119890T0000
+BC2GM098933066
+P09822602A1172
+P07585559A0000
+BC2GM060294420
+P01642060A0471
+BC2GM017429831
+P09927570A0507
+P09733647A1960
+P01378506A0884
+BC2GM052669347
+P08654375A0544
+P09733854A0198
+P01710979T0000
+P04789916T0001
+BC2GM042287909
+P06524727A0601
+P02925013A1112
+BC2GM081193454
+BC2GM065009088
+P00961711T0000
+P03331525T0001
+BC2GM025314354
+P01418272A1072
+P08608222T0000
+P08566751A0455
+P01889753A0441
+P08661613A0691
+P09832436A0738
+P07876134A0348
+P09918096A0520
+P10796465A0373
+P01525153A0359
+BC2GM046036818
+P09255349A0836
+P09649315A0943
+P10995121A0569
+P11559547T0000
+P01864837A1029
+P09006010A0527
+P02502096A0462
+P03860162A0000
+BC2GM033034194
+BC2GM080435021
+P07957085A0207
+BC2GM007281515
+P09323366A0000
+P03989827T0000
+P11411198A0711
+BC2GM092745333
+P00118810T0001
+BC2GM094372415
+P05999607T0001
+P07749461A1022
+BC2GM044399791
+P09931191A0434
+P10799590A0431
+P07704273A0000
+BC2GM073185216
+P08643382A0752
+P02542270A0000
+BC2GM011190047
+P06629370A0252
+P08335710A0338
+P10639585A0157
+P05015678T0000
+P08849778A0226
+BC2GM093351969
+BC2GM096419837
+BC2GM091592742
+BC2GM011003396
+P06684624A0298
+P07898275A0254
+P00105903A0288
+P03366864A0099
+P08021177A0000
+P11031252A0646
+P07657668A0642
+P01279352A0297
+P07575416A1970
+BC2GM001838288
+P10472314A0717
+P06810694A1000
+P03345706A0561
+P09047252A0209
+P04011466T0000
+P08208618A1334
+P08406497A0000
+P08599945T0000
+P07580330A0331
+BC2GM070607110
+BC2GM050501523
+P09467044A0973
+P09038202A1951
+BC2GM061649078
+P03843496A0919
+P10954093A0000
+P02327159T0001
+P09211675A0392
+P07958915A1507
+P09212059A1856
+BC2GM079896671
+BC2GM015327471
+BC2GM004363438
+P01483755A0000
+P08637717A0817
+P08483412A0000
+P06494297A0939
+P09546424A1550
+P10236651T0000
+P07865876A1292
+BC2GM086808769
+BC2GM026908014
+BC2GM062716898
+BC2GM061508124
+P02109544A0000
+P09057325A0177
+P11359568T0000
+P02303874A1643
+BC2GM012717933
+P08118044A0318
+BC2GM057666669
+BC2GM091928685
+BC2GM098793518
+P07835888A0402
+P07574682T0000
+BC2GM009072433
+P02839716A1907
+P07799950A0282
+BC2GM068155086
+P08016102A1238
+P08634420A1784
+P09233772A0136
+BC2GM089338443
+P02339005T0000
+P03035056T0000
+P11513579A0372
+P05093030T0001
+BC2GM072953233
+P01410071T0000
+P09233801A1180
+P08063791A1370
+P09199327A1250
+P08951815A0465
+P02749215A0000
+P07975763A0000
+P07393856A0314
+P08128629A1164
+P09761791A0489
+P07867622X0000
+BC2GM011611657
+P08919986A1262
+P10625683A0091
+P02900760A0073
+P00393598A0198
+P01917943A0621a
+P02135536A0621
+P09592125A0000
+P07592220A0846
+BC2GM021543883
+BC2GM056896938
+BC2GM064988521
+P07618548T0000
+P09331864A0848
+P02492111A0868
+P08276871A1001
+P08825178A0071
+BC2GM060431058
+BC2GM061728098
+P08733881A0343
+P06816442T0001
+BC2GM090751169
+P02349827A0193
+BC2GM092638353
+P10933732A0000
+P01850105A1093
+P09662339A0744
+P10650958A1315
+P02427024X0000
+P09381261A0970
+P07802355T0000
+P07490079A0825
+P09556557A1238
+P03192537A0370
+P08661100A0285
+BC2GM028908281
+P09343398A1193
+BC2GM025636824
+P10597223A0339
+BC2GM006986011
+P11433379A0000
+P02833049A0630
+P00986925A0002
+BC2GM083038361
+BC2GM013413021
+P03066625A0756
+P11569949A2087
+P01615049A0000
+P01321277A0342
+BC2GM038751995
+P08838148A1218
+P08967870A0000
+BC2GM034977775
+P08874399A0277
+P09216936T0000
+BC2GM068009369
+P08014228A0278
+BC2GM034035554
+P09840932A0365
+P08084339A0907
+P08387155A1248
+P02495745T0000
+P09151828A0919
+P03020513T0000
+P08442384A0430
+P09880544A0693
+P02103403A0149
+BC2GM037763094
+P10857262A0186
+BC2GM003912165
+BC2GM067611275
+BC2GM023743832
+P06579147A0060
+BC2GM000555540
+BC2GM069681293
+BC2GM077447825
+BC2GM064070438
+BC2GM014796441
+P11534132A0219
+P01275335A0158
+P08057356A0531
+P07574064A1416
+P07938137A0384
+BC2GM050960720
+P11029459A0000
+P08919907A0763
+BC2GM004512108
+BC2GM017483846
+P01172734T0035
+P08945810T0001
+BC2GM096030020
+P08840501A0345
+BC2GM031723678
+P10841537A0669
+BC2GM069010582
+BC2GM084598125
+P01816655T0000
+P08994825A0000
+P11278286A0456
+P10880702A0966
+BC2GM034042990
+BC2GM043956840
+P10903583T0000
+P02832149A1009
+BC2GM053926612
+P10882213A0163
+BC2GM053499725
+BC2GM021169148
+P09123787A0486
+P03582184A0448
+P11119611A0428
+P06452827T0001
+P08679131T0000
+P11027833A0362
+P08479742A0985
+P06143734T0000
+BC2GM086852055
+P02142921T0000
+P01744119A0757
+BC2GM079148945
+P09037163A1652
+P01348590A0000
+P02437792T0000
+P09686603A0124
+P09722161A3065
+P03615550A0000
+BC2GM063706036
+P00432615A0541
+P08070004A0782
+BC2GM045276080
+BC2GM042332667
+P06541932A0000
+P08025669A0724
+P00142718A0156
+P07956869A0000
+P08657135A1444
+P00555583T0000
+P11438651A1365
+P08051019A0365
+P11238447A0524
+P03126531T0000
+BC2GM049355866
+P06321634A0123
+BC2GM070228927
+P01753317A0879
+P10777217A0536
+P07791764A0357
+P09403059A0209
+P11209814A0243
+P04247966T0000
+P10705380A0629
+P02547611A0318
+BC2GM003556533
+P07862165A0184
+P09077438A0076
+P07700361A0125
+P11325685A1624
+P05727222T0000
+BC2GM087106608
+P02686749A0000
+P08550564T0000
+P08552095A1115
+P05917315T0026
+P09361007A0922
+P03608989A0668
+P09121998A0663
+BC2GM025598452
+P10860846A0480
+P07636337A0687
+BC2GM068846839
+P09572491A1044
+P11441163T0000
+P09503017A1021
+BC2GM008334952
+P11230169A0480
+P09611234A0098
+P08067123A0248
+BC2GM029932858
+P11373277A0812
+P08524235A0695
+BC2GM075167563
+BC2GM069520528
+BC2GM035302816
+P02774271A0000
+P09726987T0000
+BC2GM050323538
+P09650186A1043
+BC2GM032122398
+P09418057A0684
+BC2GM070919106
+P01341119A0450
+P09392979T0000
+P02764797A0182
+BC2GM093550976
+BC2GM047688296
+BC2GM008294222
+BC2GM056219276
+P11238405A0817
+BC2GM011948412
+BC2GM033795205
+P10828022A0877
+BC2GM001618021
+BC2GM068605843
+P07799931A0287
+P09259313A0950
+P07228955A0000
+P06110026T0000
+P02811378A0379
+BC2GM001125172
+BC2GM089958574
+P02158099A0487
+P02850472A0112
+BC2GM002263739
+P09091403T0001
+BC2GM083483260
+P11296442A0565
+P09670034A0340
+P03616237T0001
+BC2GM068517982
+P10617144A0386
+P07488959T0000
+P07685874A0258
+BC2GM046685387
+P02686588A0592
+P11340525A0737
+BC2GM059365097
+BC2GM074262831
+BC2GM050621994
+P09677330A0584
+P08595184A0407
+P01958821T0000
+P10963577T0016
+P05969185T0001
+BC2GM068580780
+P08164684A1266
+P01330309A1134
+BC2GM011826716
+P01786094T0001
+P11407448A0815
+P08717559A0223
+P07540866A1069
+P02123300T0000
+P03387665A0000
+BC2GM068522547
+P07569532T0001
+P09404725A0644
+P00685922A0451
+P02335034A0584
+P11550795A2583
+P09243840A0663
+BC2GM006080494
+BC2GM006559447
+BC2GM086367761
+P09024039A0247
+P08530149A0689
+P02218094A0395
+BC2GM064221348
+P09169852A0235
+BC2GM031470999
+P10687855A1197
+P01384229A0175
+BC2GM081758402
+P02929056T0000
+P09427551A0501
+P09874803A0000
+BC2GM092277877
+P10918612A0000
+BC2GM046884524
+P10764729A1846
+BC2GM043147756
+P03429371A1051
+P11122381A0908
+P09523551A0367
+BC2GM064373015
+P01620118A0470
+P10831972A0744
+P10677214A2842
+BC2GM019751316
+BC2GM060839599
+P04123662T0000
+P11517445A0221
+BC2GM023488977
+P01392277A0000
+P08649405T0000
+P01285358A0396
+BC2GM043953870
+BC2GM012033196
+P10858988A0786
+BC2GM012340535
+BC2GM034421651
+BC2GM032379937
+BC2GM069816957
+P05995140T0001
+BC2GM019141094
+P07518561A0496
+P01698761A1059
+P09211354A0000
+BC2GM081815204
+P07846199A0000
+P07693699A0831
+P01748287T0000
+P11282088A0837
+BC2GM084039328
+P07270163A0684
+P08621659A0189
+P11156618T0000
+P10670358A0143
+P06788388A0000
+P02283148T0000
+P09849965A0000
+P09199167A0942
+P08524229T0000
+BC2GM068082913
+P09085842A1559
+P09147832A0174
+P07735833A1078
+P02234731A0503
+P02372712A0002
+BC2GM062484182
+P09058323A1287
+P08248246A0838
+BC2GM028672992
+P02684585T0001
+P05560428T0001
+P11454004T0000
+P00176742T0000
+P06602600A0582
+BC2GM094703184
+BC2GM030482607
+P01751970A0209
+P11538437A0568
+P08922390A0793
+BC2GM093671894
+P09527921A1178
+BC2GM032810661
+P08226798A1124
+P01781923A0744
+P08288240A1343
+BC2GM062362815
+P00401676A0414
+P01615493A0408
+P03883541A0200
+BC2GM036335955
+BC2GM012456182
+BC2GM005732630
+P07090151A0165
+BC2GM014758643
+BC2GM013705035
+P09759180A0000
+P08484689T0000
+BC2GM095308818
+P09380507A0514
+P11082715X0001
+BC2GM033262913
+BC2GM064298943
+P09300323A1182
+P01923803A0609
+P07559402A0622
+P07583562A1826
+BC2GM023981862
+P08219081A0000
+P11264372T0000
+P08095872A1672
+BC2GM085389685
+BC2GM084355616
+P04038454A0984
+P09705497A0227
+P07790377A0561
+BC2GM034139781
+P06119262T0000
+P01315706A0000
+BC2GM058528014
+P11323411A0505
+P10735272A0649
+BC2GM061129675
+P11511544T0000
+P08281536A0626
+P01671675A0483
+P01588913A0000
+BC2GM003883590
+BC2GM011651930
+P02883871A1075
+P08943928A1137
+BC2GM002734773
+BC2GM049698710
+BC2GM001606938
+P07935626A1249
+BC2GM006588780
+P09060045A0576
+P08622645A1026
+BC2GM053712179
+BC2GM035126404
+P08385581A0126
+BC2GM092609683
+P02149566A0478
+BC2GM062054764
+P01716292A0000
+P08234308T0000
+P09843944A0976
+P07510461A0731
+P07633756A0690
+P07768953T0039
+P01215067A0000
+BC2GM078932858
+P07491111A0221
+P03836853A0204
+P08705056T0000
+P07742363A0941
+P02975680A0000
+P09440616A0422
+P08808927A0417
+P08474439A0877
+P08115744A0462
+BC2GM051904662
+P03751308T0001
+P08413205A0733
+P11360190A0178
+P07068887A0000
+P01588961A0000
+P10571047A1009
+BC2GM062475449
+BC2GM017023323
+P09611229A1664
+P11553091A1472
+P03009366A0438
+P10824485A0393
+BC2GM019910898
+P02936163T0000
+P08519621A0150
+P02634490A0186
+P01617242T0000
+P02825750A0260
+BC2GM024474184
+P02402678A0463
+P11287611A0802
+P11521191A0000
+P06084864T0001
+P11069825A0530
+P02117799T0000a
+BC2GM005504970
+P01119586A0337
+P09218436A0443
+P08734538A0613
+P09618150A0127
+P07076222A0543
+P06863087A0664
+P08258025A1131
+P03123983T0000
+P08302589A1132
+BC2GM007702287
+P08894144A0330
+P01936997A0795
+P06091914A0000
+BC2GM017309998
+P08636149A0220
+P06327039A0743
+P08739260T0000
+P08067607A0568
+P11354406A1373
+BC2GM088152859
+P01997465A0276
+P09119391A0870
+BC2GM038520766
+P05939748T0000
+P08805338A1061
+P03032964T0000
+P09402139A1121
+P09139665A0784
+BC2GM046491009
+P08483479A1056
+BC2GM031220752
+P09582308A1165
+P07957559A1557
+P01710768A1172
+P07705476A0292
+P09429913A0528
+P00565136T0000
+P03537727A0243
+P06165068A0547
+P02200315A0278
+P08223613A0519
+P00832096T0000
+BC2GM039630251
+P07836364A0000
+P06875478A0542
+BC2GM036938050
+BC2GM032192885
+P11110528A0414
+P10694609A0309
+BC2GM021683203
+P02449431A1121
+P07937106A0100
+BC2GM021163962
+BC2GM007167261
+P08122370A0331
+P11094109A0600
+P01352113A0002
+BC2GM013294615
+P00682762T0001
+P02259795A0570
+P03766370A0546
+BC2GM071213428
+BC2GM035614224
+P06429992T0000
+BC2GM055712987
+BC2GM022597499
+P11287578A1311
+P03033283A1415
+P01236224T0001
+BC2GM079219786
+P08443340A0522
+P07576307A0144
+P09391173A0811
+P09360422A0135
+BC2GM035233185
+P04000347A0442
+P08803710A0701
+P00851041A0000
+P07438346A0381
+BC2GM080877738
+BC2GM074130635
+P10846054A0573
+P08278423A0147
+P11605207T0001
+P09556561A0671
+BC2GM033064195
+P09585540A0440
+P11023934A0855
+P07971709A0907
+P11160742A0696
+P08401570A0828
+P11255035A0331
+P08305058T0000
+P07423803T0001
+BC2GM001910152
+P09652737A1244
+P02745444A0391
+BC2GM045767677
+P07829057A1097
+P08437737A0100
+BC2GM001605361
+BC2GM075265710
+P10721726T0000
+P07883754A0993
+P09111059A0327
+BC2GM064778776
+P10658445A0208
+P08164679A0809
+P04139081T0001
+P09666114A0389
+BC2GM088015029
+BC2GM015832871
+P10747890A1096
+BC2GM019234582
+P01827068T0000
+BC2GM032120704
+P11398134A1565
+P08304342A0605
+P09079928A1319
+P00048373A0377
+P08412662A0333
+BC2GM004334399
+P10983979T0000
+P01516427T0000
+P08530503A1004
+P07184598T0001
+P09827446T0001
+P07961545A1314
+BC2GM048156343
+P10645921A0000
+BC2GM042078510
+P08640866A0473
+P08680702A0548
+P09806919A0447
+P09538220A0000
+P07590283A0820
+P08663310A0157
+BC2GM075482500
+BC2GM035733626
+BC2GM062537661
+BC2GM038144373
+P04068663A0452
+BC2GM076326371
+BC2GM060589467
+P09105363A0636
+P09202669A0614
+P07760841A0221
+P04194466T0000
+BC2GM019952339
+P11258906A0743
+P02883327A0413
+P02384389A0854
+P02427869A0939
+BC2GM006359930
+BC2GM089213701
+P03338154T0000
+BC2GM042193332
+P10851089A1248
+P02502602A0323
+BC2GM054038982
+P02545903A0639
+BC2GM067545009
+P10579722T0000
+BC2GM088102124
+P03687313A0000
+P08564488A1359
+P08160054A0224
+P01282014A0275
+P03335923A0257
+P03736081A0465
+P02066246A0258
+P07173729A0000
+BC2GM043550701
+BC2GM004484072
+P09501982A1178
+P02838710A0299
+P00397806T0039
+P09677410A1059
+P03428274A0000
+P01547775A1024
+P11222639A1273
+BC2GM054420057
+P10959838A0153
+P08689520T0000
+P07745684T0000
+P10958271A0365
+P01737789A0800
+BC2GM078238867
+P11603271T0001
+P09524276A0939
+BC2GM043598116
+BC2GM060327510
+P10611242A0541
+P09081392A0174
+P08569684A0000
+P08816452A0936
+P08631958T0000
+P01030985T0090
+BC2GM021857972
+BC2GM092587242
+BC2GM033188821
+BC2GM000980177
+P03785212A1128
+BC2GM035866321
+BC2GM046754199
+P09923245A0482
+P11459960A1109
+P10032519T0000
+BC2GM061606382
+BC2GM079355460
+P03280021A1615
+BC2GM044671212
+BC2GM015901462
+BC2GM051665080
+P05138738T0001
+BC2GM042178518
+P02254282T0000
+BC2GM089298534
+BC2GM088237349
+P08241656A0189
+P08882492A0000
+P01732736A1076
+P11153302A0000
+BC2GM026348883
+P08139914A0554
+P07678593A0708
+P06468673A0358
+P01339391A0000
+BC2GM002706624
+BC2GM097091019
+BC2GM059635373
+P07995173A0585
+BC2GM063796611
+BC2GM026188221
+P09824001A1665
+P02695914T0000
+P09294161A0650
+P03098018A0139
+P10794405A0000
+BC2GM006409741
+BC2GM033980745
+P07512159A0992
+P07720572A1584
+BC2GM024566497
+BC2GM079434119
+P08131746A0140
+P07234974T0000
+BC2GM014236204
+P10727428A0000
+P01245162A0262
+BC2GM096080543
+BC2GM070253288
+P07508250A0537
+BC2GM078538527
+P00450559A0269
+BC2GM076876749
+P02223928T0069
+BC2GM062788125
+P06689513T0001
+P04788701T0001
+P04622430T0000
+P08529654A0589
+BC2GM074690721
+P10704499A0682
+P07504171A0715
+P00553858A0000
+P05992157T0001
+P08909546A0810
+P01318310A0000
+P03280912T0000
+BC2GM081727936
+BC2GM053004410
+BC2GM085878325
+P05363816T0001
+P11381094A0797
+P10699653A0967
+P08583783A0870
+P03635597A0377
+P11313249T0000
+BC2GM018437479
+P08977401A0227
+P09869356A0926
+BC2GM011525523
+P03928442A0463
+P10733569A0364
+P01618256A0521
+P11264375A0000
+BC2GM091521562
+P07654239A0698
+P05798063T0000
+P08697728A1199
+P07814323A0313
+P08923470A0458
+P09731704A1472
+P02000093A0794
+BC2GM087552846
+P09099683A0000
+P01511950T0000
+P02657388A1011
+P09806826A1773
+P01733105A0127
+P07717823A0328
+BC2GM094592158
+P10601747A0482
+P08912807A0411
+BC2GM008418248
+P09211605A0478
+BC2GM060480858
+P06331684A0607
+BC2GM065259412
+BC2GM058529129
+BC2GM088061371
+P10764760T0000
+P00193088A0196
+P09777999A0796
+P01588965A0000
+P06585277A0000
+P08181755A0989
+P09259315A0809
+P09918842A0184
+P01047417T0000
+BC2GM050954712
+P08754802T0000
+BC2GM091202887
+P07565709A0000
+P09661676T0000
+P09712037A0470
+P06443639T0001
+P01975157A0836
+BC2GM006220127
+P07857086A0949
+BC2GM045312914
+P02837763A0259
+P02075876T0001
+BC2GM053757906
+P07961755A0474
+P02400457A0469
+BC2GM032391801
+P11392306T0000
+BC2GM009549697
+P08769568A0949
+P07876562A1646
+P10637238A0291
+P06097285A1077
+BC2GM023469972
+BC2GM089371905
+P09609705A0895
+BC2GM032790692
+P03361653A0459
+P02762198T0001
+P03004982A1094
+P10785668A0000
+P09003001A1593
+P04548483T0001
+BC2GM026278190
+P09860979A0521
+P09658122T0000
+P10736161T0000
+BC2GM018119295
+P07883167A0157
+BC2GM092473600
+P01549346A0000
+P09352016A1110
+P00555492A1034
+BC2GM043977711
+P09223475A0898
+P04263748T0042
+BC2GM028335304
+P07494244A0335
+P07500950A0000
+P07249544A0343
+P10962881A0900
+P08454077A0956
+P09518383A0000
+P07964459A0845
+BC2GM081878560
+P01275541A0405
+P06643612A0000
+P08628254A0665
+P01449183A0795
+P08581174A0472
+P09268661A1405
+P06463429A0414
+P09322738A0510
+P05344097T0000
+BC2GM043141382
+P08063766A0595
+P07896615A0554
+P03908493A0246
+P10950935A0111
+BC2GM051181003
+BC2GM097783604
+P07490083A0000
+BC2GM095551237
+P07243380A0327
+BC2GM046716836
+P11097040A0000
+P09311164A0245
+BC2GM052205120
+P07015262A0396
+BC2GM096363851
+P08565548A0196
+BC2GM080220626
+P11223186A1095
+P01067493A0119
+P09798263T0000
+P08585883A0381
+BC2GM005435651
+P07559347A0000
+BC2GM046486714
+P08793693A0237
+BC2GM098880938
+BC2GM036514946
+P07651400A0335
+P09556566A0174
+P08582633T0000
+P08936128A0611
+P10771528T0036
+P08648726A0713
+P11459304T0078
+P09837907A0857
+BC2GM083514944
+P03710973A0817
+BC2GM076511044
+P02557217A0398
+BC2GM023386484
+BC2GM069147712
+P10702794A1495
+BC2GM090460954
+P11178248A1042
+P09795213A0129
+P03944212A0166
+P07872673A0332
+P11105129T0000
+P09687514A0521
+P05881833T0001
+BC2GM063096861
+BC2GM050442878
+P08021225A0000
+P01372900A1017
+P10723727A0713
+P03904952T0000
+BC2GM017717134
+P00881630A0000
+P10811804A0800
+P10416429A0221
+P09862343A0225
+BC2GM054410700
+P10759693A0201
+P04487920T0001
+BC2GM038724792
+P10658425A1567
+BC2GM048403963
+BC2GM043696971
+P00089778A0000
+P11038366A1322
+BC2GM034171141
+P08661116A0963
+P05810259T0001
+BC2GM042907506
+P08342703A0966
+P02543226A1559
+P09405685A0113
+P08709245A1521
+P09278441A1777
+P09382850A0000
+BC2GM084411684
+P02164585A0416
+P08098882T0001
+BC2GM004241014
+P04068774A1292
+P08910550A0501
+P00150066A0100
+P10811079A0555
+BC2GM057124014
+P07546294A0000
+P07925282A0705
+P03127034A0591
+P05012220T0000
+P07696183A0567
+P01378127A0841
+BC2GM036319950
+BC2GM068583518
+BC2GM082666535
+BC2GM080062282
+P05445187T0000
+P11653491T0000
+BC2GM070558287
+BC2GM091632436
+P08617802A0993
+BC2GM081729559
+P09840943A0144
+P00023348A0601
+BC2GM073086948
+P10880486A0790
+P03985849A0221
+P00623361A0221
+P02270587A0000
+P09714835A0345
+BC2GM029519664
+P10594239T0000
+P09535579A1105
+BC2GM066617414
+P01644751A0590
+BC2GM063825132
+P11459048A0485
+P01758750A0000
+P09228042A0109
+P02743842A0000
+BC2GM051717947
+P09564860A2139
+P01986225A0250
+P07901125A0416
+P11076860A0872
+P11232947A1451
+P08473731A0149
+P00681550A0000
+P09442017A0435
+P01617801A0088
+P05751819T0000
+BC2GM000870973
+P07957158A1532
+P09763607A0521
+P10863352T0001
+P04052919A0205
+P06346427A0000
+BC2GM094423214
+P07983716A1082
+BC2GM015726029
+P02806916A0000
+P09019302A0600
+P11163968A0152
+P10640683A0204
+P01737741A0000
+P03090372A0607
+P11094590A0617
+P08499903A0883
+P02150473T0067
+P02573836A0244
+BC2GM014143125
+BC2GM040611661
+P09111048X0000
+P10955998A1124
+BC2GM016077661
+P09287362A0589
+BC2GM098444070
+BC2GM007804673
+BC2GM070860352
+P07900915A0000
+P08294429A0153
+P10886067A0520
+P07859371A1246
+BC2GM029590199
+P10638607A0000
+BC2GM096939334
+P02677666A0356
+P09363759A0000
+P08618433A1720
+BC2GM053594335
+P07812450A0849
+P02069738A0000
+P09382924A0131
+P01168908A0000
+P09388200A0639
+BC2GM006679416
+P09880512A1251
+P09549783T0000
+P02910496A0583
+P08251506A0503
+P02790009A1052
+P08556707A1390
+P02194273A0913
+P08509335T0000
+P11260468A1179
+P03001353A0146
+P07980468A0298
+BC2GM060444035
+P07795576A0126
+P08680706A0889
+P01684791A0000
+P09438427A0727
+P11138694A0000
+P02105497A1092
+BC2GM017168033
+P02573829T0000
+BC2GM038301816
+P11003805A0443
+P09032248A0239
+P03843676A0381
+P08702556A0000
+BC2GM077096663
+BC2GM043163295
+P08595836T0000
+P11465655A0439
+P01380454A0451
+P08838805T0000
+P01071715A0903
+P01096741X0000
+BC2GM099816783
+P03150296A0594
+BC2GM093413177
+P01900194T0000
+P08280476A0602
+P02648646A0932
+P07799437A0656
+P07609079A0387
+P01548891A0635
+P10572131A0000
+P10602838A0127
+P06812389A0658
+P10917402T0000
+BC2GM080587518
+P02852805A0216
+P10702253A0357
+P02026144A0741
+P02325895T0000b
+P08228997A0866
+P07493627A0882
+P07768824A0167
+P11415633A1253
+BC2GM094952768
+P09804836A0000
+BC2GM092320908
+BC2GM029863453
+P11425076A0364
+P07665172A0000
+P10779508A0452
+P03352254A0203
+P05896996T0001
+P09845856A0560
+P07425838A0182
+BC2GM013836575
+P08475104A0341
+P10764802A1258
+P01314841A0724
+BC2GM085844125
+P01347908T0000
+P07685823A1234
+P09275159T0000
+P08112341A1128
+BC2GM033119151
+BC2GM088008417
+P02674674A1308
+P09521907A0190
+P09541721A0894
+BC2GM094569593
+P10679190A0693
+BC2GM004781079
+P09736770A0351
+P04518624T0000
+P07665605A1127
+P07708497A0000
+P01811243A0000
+BC2GM078878267
+P09012405A0785
+P09380504A1255
+P02293019A0000
+P11212327A1564
+P11083432A0332
+BC2GM015562296
+P08144035A0387
+P08742135A0000
+BC2GM037491850
+P01159822A0353
+BC2GM020209849
+BC2GM041578046
+BC2GM004715465
+P01736651A0104
+P07797476A1001
+P09687498A1173
+P08276854A1894
+P05593469T0001
+P02615078A0283
+P08428965A1868
+BC2GM075780214
+BC2GM062846639
+P02556603A0606
+BC2GM038580862
+BC2GM007239314
+P07610052A1064
+P03166458A1356
+P03591464A0840b
+P09228092A1779
+P08382359A0469
+BC2GM033658965
+P11283168A0738
+P10653693A0903
+P06397009A0204
+P09751166A1460
+BC2GM096424310
+P03261331A0563
+P08990397A1437
+P07624581A0312
+P10613863T0000
+BC2GM074067305
+P10910439A1196
+P09892021A0712
+BC2GM038625120
+P08396913A1379
+P09312025T0000
+BC2GM073340870
+P11432748T0000
+P11106668A0875
+P10749145T0000
+P01864510A0946
+P11014465A0479
+P02052592A0000
+P08838314A0129
+P07607669A1112
+BC2GM036281424
+P03395249A1044
+P08871542A1352
+P02274343A0064
+P07533758A1038
+BC2GM013419270
+BC2GM092826848
+BC2GM016224723
+P01780235A0094
+P01659685T0000
+P08316100A0586
+BC2GM093870796
+P09311568A0595
+BC2GM091720557
+P02703121T0000
+P09771985A0238
+P10938130A0338
+P09535833A0228
+P07637718A0218
+BC2GM047759053
+P09515032A1230
+P09307065A0553
+P06323556A0126
+BC2GM024643868
+BC2GM035562452
+BC2GM014801779
+BC2GM070953330
+BC2GM061043119
+P08995410A1109
+P11416144A1324
+P01371275T0000
+P08248253A1785
+P09077437T0000
+BC2GM086476863
+P01717833A1223
+P11158290A0728
+P08820648A0123
+P11390395A1018
+P01261005A0711
+P08599946A0999
+P07814717A0669
+P01851862A0273
+P11331613A0827
+BC2GM060736050
+P09668119A0496
+P10528035A1102
+P01893927A0704
+P08726024A0244
+P11864173T0000
+P11367523A1684
+P02143768T0000
+P11312108A2853
+P01823524A0238
+P09730413A0642
+P09545353A1071
+BC2GM063051307
+P09050867A0542
+P07887859A0315
+BC2GM066721015
+P06683876A0244
+P01475381T0001
+P02507523A0791
+BC2GM029296962
+BC2GM070067040
+P06709700A0230
+P11100515A0282
+P01617776A0343
+P04921762T0000
+P02204623A0000
+BC2GM085613208
+BC2GM043460200
+P08309912A0306
+P08897663T0000
+P07947930A0499
+BC2GM071774854
+P09724754A0173
+P08085228A0000
+BC2GM075742629
+BC2GM062023800
+P09172414A0000
+BC2GM093724132
+P09003312A0740
+BC2GM028143170
+P08297376A0236
+P07175474A0102
+P07616056A0278
+P11290906T0000
+P09639410A3282
+BC2GM079565746
+BC2GM094631984
+BC2GM042292162
+BC2GM016213373
+P07699632A0522
+P01384040A1043
+P01429768T0000
+P07628389A0145
+BC2GM099213570
+P09448268A0186
+BC2GM008340188
+BC2GM041958370
+P08108343A0000
+BC2GM084714947
+P11112700A1936
+BC2GM015826249
+P08090746A1288
+P01377696A0000
+BC2GM006294419
+BC2GM010800143
+BC2GM066898247
+P03663789A0568
+P02544059A0377
+P00435187T0000
+P08134108A0277
+P08460270A0205
+P02832293T0000
+P07610716A0117
+P11055513A0564
+BC2GM010728052
+P01822581A0533
+P07942722T0000
+P08029001A1020
+P09199318A1147
+P04160980T0000
+P06483863A0000
+P02165589A0000
+BC2GM031239616
+P07935426A0714
+P03584426A0706
+BC2GM031288971
+P05985275T0000
+P09832099A0000
+P08017290A1347
+P08101171A0924
+BC2GM010999620
+P08649841A0956
+BC2GM045293373
+BC2GM022660122
+P02718683A0142
+P01870500A0276
+BC2GM013849593
+P02808232A0681
+P05533214T0001
+BC2GM080743687
+P11150315A1126
+P09435116A0437
+BC2GM031523666
+P08711631A0989
+P08995054A1368
+P08514766A0732
+P08414502A0244
+P07983011A0617
+P08573637A0434
+P08444345A0403
+P09649437A1140
+BC2GM012610098
+P02119626A0471
+BC2GM074332613
+P09629449A0540
+BC2GM003186870
+P10827952A0158
+P05532854T0001
+BC2GM028423664
+P04040339T0001
+P09349967A0653
+P05027799T0000
+P09408516T0000
+BC2GM041546990
+P09203731A0497
+P10628750A0298
+P09982923T0000
+P02473942A1207
+P09265932A0575
+P07846163A0422
+BC2GM073785891
+P08676456A0879
+P10437043A0164
+P10770471T0000
+P10924061A0588
+P08222556T0000
+P08253958A0000
+P08385131A0000
+P09144165A0614
+BC2GM056805115
+P10612044A1180
+P11059492A0376
+P11238375A0617
+P09535082A0537
+P00490336A0181
+P03061383A0000
+P10811804A0000
+P10887912A0740
+P06379363A0415
+P08916928A0950
+P07112471A0639
+P09927193A0107
+P09722766A0706
+P11223246A0359
+P08512728A0991
+P04547933T0000
+P06281891A0399
+P02720966A0455
+P06070204T0025
+P08288554A0295
+P07523710T0000
+BC2GM016375910
+P11376279A0000
+BC2GM035320296
+P11290415A0288
+BC2GM081451242
+BC2GM089665915
+P07263421A0351
+P08207405A0372
+P07474451A0000
+P10784367A0133
+P09927585A0796
+P07959011A0379b
+P11193704A0000
+P02604420A0234
+BC2GM054602912
+BC2GM041461171
+P00416758T0001
+BC2GM059995524
+BC2GM049429395
+P06851327A0000
+P06716977A0136
+P05725509T0000
+P07529124A0119
+P03016506A0611
+P09570944T0000
+P01581409A0398
+BC2GM050531748
+P11410664A0963
+P09101085A0686
+P08835895A1292
+P09398855A0438
+BC2GM030395765
+P10585463A0859
+BC2GM010599540
+BC2GM004561125
+BC2GM042454699
+BC2GM040247589
+P09234690A0242
+BC2GM084160257
+P08139017A1465
+P08660748X0000
+P09442024A0708
+BC2GM074464938
+BC2GM067551044
+P02160955A0899
+P01885752A0198
+BC2GM070953023
+P11090272A1240
+P04282315T0001
+P02474093T0000
+BC2GM001730189
+BC2GM009600842
+P01695116A0078
+P07691885T0000
+P09819414A1103
+BC2GM096432502
+P10918440T0000
+P11227484T0000
+BC2GM011728728
+P09864141A0528
+P07631267T0001
+P11614398T0000
+P09335619A0583
+P10511216A0654
+BC2GM002081221
+P09110176A0890
+P02016053A0752
+P06571587T0000
+BC2GM069051753
+BC2GM049116336
+P09943651T0000
+P08382303A0507
+P01963858T0001
+P11575109A0214
+P10993773A0717
+P07964770A0172
+BC2GM038900990
+P01193770T0000
+P08986812A1214
+BC2GM035589605
+P01156814T0000
+BC2GM097957533
+P10836786A0516
+BC2GM086705446
+P07823964A0922
+P07912123A0711
+BC2GM041894560
+P06713204A0867
+BC2GM029913363
+P11158288T0000
+P05555149T0001
+BC2GM035688360
+P07130335A1081
+P10518822A1037
+P08370119A1521
+P09863720T0000
+BC2GM070189689
+P06433442T0000
+P08569443A0123
+BC2GM072758555
+BC2GM034925448
+P02740874A0957
+BC2GM095698085
+BC2GM013203108
+P11220486A0686
+P10007564T0000
+BC2GM095215988
+P03354295A0157
+P08120029A0864
+P06439114A0677
+P09191052A0850
+P02766330A0779
+P09264466A0947
+P02582240A1009
+BC2GM059162976
+P02061333A0784
+P07898840X0000
+P07738839A0173
+BC2GM058510012
+P06204120T0001
+BC2GM070100199
+P09673436A0898
+BC2GM079186421
+P09463174A0670
+P02408248A0414
+P02386895A0496
+P07774137A0000
+P09087430A1046
+P06233924T0000
+P01826003A0694
+BC2GM029138982
+P02926499A0340
+P09234703A0192
+P08034318A0724
+P09645942A1164
+BC2GM037381460
+P09042911A0626
+BC2GM057439987
+BC2GM076042408
+P08087887A1067
+P01714322A0969
+BC2GM047747635
+BC2GM052174865
+P01886774A0000
+P09513759A0716
+P10872473A2286
+P09311808A0341
+P08343041A0000
+BC2GM067637713
+P09822652A1118
+P08706731A1303
+P10735848A1440
+P10891489A0152
+P02277005A0227
+P02277452A0116
+P00088391A0181
+P03531317A0930
+P08902641A0930
+BC2GM056550890
+P08622668A1155
+P08676383A0518
+P09719636A1134
+P08066094T0000
+P08668142A1048
+P07510724A1208
+BC2GM069862303
+BC2GM019718038
+P09696164A0000
+P00665336A0908
+P10756094A0671
+BC2GM020102507
+BC2GM041269018
+P07862129A1391
+BC2GM076930779
+P08212571A0597
+P06516369T0001
+P02527745A0865
+BC2GM045289936
+P07286057A0159
+P05574818T0000
+P01490493A0416
+BC2GM049085863
+P03628596A0000
+BC2GM077617268
+P08336738A1273
+BC2GM089231665
+BC2GM064092498
+P04058985A0000
+P04032349A0000
+P09233487A1386
+BC2GM070545500
+P00870859A0121
+P08264628A0418
+P02970061A0271
+P10748175A0000
+P03869442A0223
+P00644314T0000
+P08337828A0895
+BC2GM025162060
+P02634872A0000
+P08950352A0525
+P08870266A0651
+P02853799T0001
+BC2GM031305543
+P10059496T0000
+P11226228A0899
+P03921727A0523
+P08501678A0498
+P06973664A0000
+BC2GM048761602
+P01358880A0251
+BC2GM002383342
+P07999995A0000
+P11356716A0372
+P09478976A0718
+BC2GM096526647
+P09885431A0000
+BC2GM050351916
+P02840376A0461
+P08871567A0000
+P11496495A0000
+P01715593A0838
+BC2GM064320390
+P08389453A0193
+P08723365T0000
+P09346621A1181
+P09633171A0321
+P10627532A0739
+P09277629A0268
+BC2GM050193880
+P08790291A1022
+P07295417A0092
+P10683989A0251
+P03178097A0000
+BC2GM077904179
+BC2GM049579036
+P00952734T0000
+P10764150A0000
+BC2GM045681720
+P03064811A0485
+P02257251T0000
+BC2GM069202593
+P02437625A0197
+P08349632A0679
+BC2GM004982621
+BC2GM050802693
+P07038684A1050
+P08113736A0309
+BC2GM006771200
+BC2GM081412271
+BC2GM077618469
+P01601181A0842
+P11223240A0655
+P10775267A0363
+P01504853A0299
+BC2GM001605780
+BC2GM058126841
+P09799362A0507
+BC2GM024271469
+P01409643A0618
+P11540991A0127
+P04056256A0416
+P03329716A0187
+P01359588A0375
+P08614410A0000
+BC2GM069583481
+P03944239A0780
+P07299857A0294
+P01917962A0152
+P11103472A0802
+P11278928A1634
+BC2GM068101333
+BC2GM053494756
+P09187136A0000
+P11283354A0548
+P08924211A0941
+BC2GM041150256
+P08078167A0000
+P10967890A1120
+P09425036A0649
+BC2GM019139361
+P02118525A0737
+P01324404A1208
+P10913304A1180
+P07958865A1152
+P03771749A0465
+P07934331T0037
+P08617238A0334
+P09790499A0545
+P00146327A0147
+P01759052A0786
+P11182746A0872
+P08940134A0705
+BC2GM039707957
+P11195338A0494
+P11067797A1306
+P10587576A0596
+P06234786A0606
+P09715278A1526
+P10669594A0000
+BC2GM019604417
+P07816619A0872
+P03590911T0001
+BC2GM005244368
+BC2GM062908561
+P07234755A0838
+P10828591A0080
+P10853059X0751
+P10585491A0945
+P10628750T0000
+P09170159A0348
+P08011017A0169
+P10374632A0897
+P04615525T0001
+P09371566A1384
+BC2GM051407853
+BC2GM073702043
+BC2GM086731573
+P02761150A0000
+BC2GM058182434
+BC2GM009721363
+P05410641T0000
+P09621062A0810
+P01429596A1669
+BC2GM090412824
+P07607607T0000
+P00676790T0000
+P11054571A0230
+P08212897A0404
+P08176742A0190
+P01731933T0000b
+BC2GM090325124
+P10613816X0000
+BC2GM033647434
+P11123316T0000
+P02026491A0399
+BC2GM009855865
+P09205965A1249
+P07426745A0177
+P09426183A0000
+P09933428A0351
+P09291077T0000
+P01387105A0933
+P11309400T0000
+P07983704A0330
+P07867944A0365
+P08632018A0587
+BC2GM032318705
+BC2GM068927372
+BC2GM038061455
+P01078982A0227
+P09011591A0309
+BC2GM073294653
+BC2GM044146778
+P09797456A0883
+BC2GM007849960
+P08554723A0187
+P02603923A0220
+P01224116A0576
+P01150658A0683
+BC2GM052718596
+BC2GM038054598
+P08510320A1249
+BC2GM007067197
+BC2GM060653717
+P10894886A0375
+P09820163A0565
+P01886368A0000
+BC2GM014250094
+P02772495A0641
+P01863768A0649
+P10596955A1032
+P01862455T0000
+P08657183A0145
+P04679438T0001
+P10964995A2152
+P10684111A1411
+P02555519A0798
+P04551650T0001
+P05492285T0000
+BC2GM049816389
+BC2GM026873451
+BC2GM088426730
+P01545523A0000
+P11465518A0000
+P01810108A0000
+P06826813A0264
+BC2GM090069165
+BC2GM068735966
+P02317554T0000
+P04068969A0300
+P06480542A0000
+P07899634A0000
+BC2GM086750845
+P01398106A0754
+P09060971A0982
+BC2GM037181461
+BC2GM072949997
+BC2GM055178229
+P08555289A0207
+P11250942A0626
+P11160721A0932
+P07141130A0615
+P00483716A0366
+P08006772A0000
+P11024300A1579
+BC2GM063800112
+P07667621T0001
+P02508726A0498
+P02023904A0120
+P07907846A0623
+P03836777T0001
+P07426101A0124
+P08428953A1718
+BC2GM041094338
+P11454190A0000
+P08321199T0000
+P08406352A0172
+BC2GM027029005
+P02024488A0506
+BC2GM071282561
+P01822995T0000
+P02445751A0925
+BC2GM002778880
+P09786932A1042
+P02537441A0231
+P01695098A1116
+P08111035A0098
+P01806314A0322
+P09764741A0092
+BC2GM097306913
+P09801333A0174
+P10973400A0664
+P06669864T0001
+P00715180T0074
+P08878573A1370
+BC2GM082914643
+P08307338A0227
+BC2GM058880615
+P02201901A0229
+P07458171A0086
+P01564653A0307
+P11027724A0335
+P08280925A0261
+BC2GM049936595
+P02820128A1333
+P02145195A0253
+P08529098A0549
+BC2GM057945888
+P07737024A1003
+P07590264A0373
+P09190821A0707
+BC2GM016417962
+P09832511A0269
+P08794254A2957
+P03088643A0000
+P08013348A0143
+P10595315A0344
+BC2GM009033514
+P08798893A0611
+P08887667A0992
+P01876836T0000
+P10706688A0376
+BC2GM093618725
+P00999494A0000
+P08651853A0607
+P03417588T0000
+BC2GM034539107
+P08887647T0000
+P09549660A0782
+P06406060A0000
+P09829843A0819
+P01906166A0119
+P08261398A0392
+P01613640A0158
+P01717994T0000
+P06446048A0356
+P08542746T0000
+P02094257T0000
+P06654686T0001
+P07463465A0297
+P11420612A0303
+BC2GM087596425
+P10594903A0000
+BC2GM042537375
+P08207022T0000
+P09515665T0000
+P07800479A0201
+P00027739T0000
+P09694860A0498
+BC2GM076054604
+BC2GM049160960
+P07949164A0799
+BC2GM062836340
+BC2GM071664936
+BC2GM071889141
+P09042683A0492
+P10721714A1087
+P11271297T0000
+P07622932T0000
+BC2GM093024251
+P10640734A0190
+P09223229A0565
+P09761723A0226
+P09535851A0591
+P02914492A0183
+BC2GM032692465
+BC2GM056206368
+P02641762T0001
+P11062067A0000
+P07652582A0000
+P08666913A0000
+BC2GM043394225
+P08541499A0306
+P05451324T0000
+P02206430A0197
+P09437001A0769
+P06853042A0282
+P07665633A0284
+BC2GM012515903
+P09920930A0959
+P09333018A0000
+P10950415A0866
+P02833021A1185
+P03429306T0000
+P06597709A0596
+P09434160A0767
+P08243476A1177
+P08861963A0375b
+BC2GM036949597
+P08552082A0480
+BC2GM032564148
+P09531538A0983
+BC2GM043507962
+BC2GM095688766
+BC2GM091136434
+P09035612T0000
+P03712153T0000
+P07521916T0000
+P02269281A1276
+P06259389A0000
+BC2GM081450660
+P07600986A0605
+BC2GM037875786
+BC2GM048694992
+BC2GM091817900
+P02577458A0412
+P08324280A0098
+P08245933A0617
+P00188387A0975
+P10669596A0430
+P02348728A1153
+P09553143A0729
+P02334972A0145
+P08392221A0449
+P09008301A0193
+BC2GM079654891
+BC2GM015948167
+BC2GM041444961
+BC2GM092851466
+BC2GM027051573
+BC2GM062867525
+P08157009T0000
+P02318208A0817
+P08989763A0605
+P07608968A0836
+P09060622A1679
+P04062128T0028
+P07821790A1084
+P07890674A0916
+P10053852T0000
+P03559193A0000
+P09205113A0587
+P08707922A0334
+P09748513X1360
+P09789795A0607
+P02142955A0248
+BC2GM089171248
+P09175708A1526
+P02372496A0782
+P09368760A0665
+BC2GM081513417
+P02320999A0606
+P11113199A0800
+P08631944A0663
+P01767060A0000
+P11361493T0000
+P01321336A0000
+P11066245T0000
+P09377355A0362
+P02400070T0000
+BC2GM030169999
+P11058132A0264
+P10983344A0000
+P01714902A0221
+P04070725A0442
+P09724654A1120
+P01545797A0587
+P10729220A0000
+P10878944A0000
+P02144558A1022
+P10635209A0419
+P07793783A0189
+P10000253T0000
+P02689136A1851
+P08053697A0000
+P01316476A1428
+P04766888T0000
+BC2GM031485809
+P08731511A0625
+P08733874A0000
+P01695905A0480
+P02689544A0456
+P08410097A0356
+P07604794A0958
+BC2GM062247998
+P01346262A0377
+P09852136A0174
+BC2GM064911802
+P04871589T0001
+P10704853T0000
+P11457139A0604
+BC2GM086826510
+BC2GM090747273
+P06793764T0001
+P08622893A0000
+P09582326A0151
+P01563635T0000
+BC2GM002607371
+P11069756A2618
+P08234276A0556
+P08048916A0000
+P03355122A0238
+P11397652A0381
+P05902458T0001
+P08065365A0000
+P02251119A0319
+P05394461T0001
+P06712314A0148
+BC2GM095775239
+BC2GM018583333
+P07084814T0000
+P06721188A0200
+BC2GM095042999
+BC2GM065997756
+P09537361A0149
+BC2GM023079382
+P07608649A1429
+P09430730A0374
+P08754827A0231
+P11209100A0069
+BC2GM038812570
+P02590615A0636
+P06805537T0001
+P01761736A0158
+P09771967A1052
+P09670912T0000
+P08065338T0000
+BC2GM051498268
+BC2GM006693980
+BC2GM001533580
+P08067546A0000
+P01021091T0000
+P09136015A0529
+P07978406A0998
+P08321203A0840
+BC2GM066627539
+BC2GM062613921
+P10902348A0566
+BC2GM056870406
+P09315678A0278
+P07565669T0000
+P07846942T0001
+BC2GM058457481
+BC2GM024468009
+BC2GM062872922
+P10044519T0000
+P02986279A0000
+BC2GM083581791
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/bc2gm.dev b/huner/ner_scripts/splits/bc2gm.dev
new file mode 100644
index 0000000..748d2d2
--- /dev/null
+++ b/huner/ner_scripts/splits/bc2gm.dev
@@ -0,0 +1,2000 @@
+P08000497A0179
+P09510398A1138
+P06972501A0615
+P08654435A0540
+P11208814A0673
+P08690118A0845
+P01771593A1152
+BC2GM041250465
+P02474356A0559
+P09144195A1051
+BC2GM051190318
+P00381783T0000
+P08105994T0000
+BC2GM008296773
+P10878398A0542
+P07652575A0435
+BC2GM064737481
+P06880604A0167
+P08955111A0989
+P06245672T0000
+P09777600A0000
+P08552095A0686
+P00837811A0675
+BC2GM058549376
+P07393976A0000
+BC2GM072699759
+P08383492A1205
+P01713213A0488
+P08611280A0820
+P08636428A1363
+P08270580A0155
+P01851386T0092
+P02530470A0604
+BC2GM022364640
+BC2GM041206962
+P11356835A0000
+BC2GM044994896
+P01664192A1577
+BC2GM097577617
+BC2GM014519920
+P08615025A1214
+P09300697A0000
+P03733563A0820
+P09765466A0231
+P09362499A0000
+P11139974A0762
+BC2GM078893266
+P03251210A0981
+P08428907A0653
+P11557127A0991
+P11274184A1068
+P01720843A1506
+BC2GM019793109
+P00417301T0001
+P09486890A0234
+BC2GM019245307
+P09642227A0000
+P09528770A1379
+P08555597A0808
+P08576262A0160
+P05389125T0000
+P09452444A0450
+P08414410A0270
+BC2GM020828058
+BC2GM005729141
+P10651805T0000
+P01918073A0150
+P07814405A1170
+BC2GM064435872
+P03198436T0000
+P07987924A0670
+P07937656A0182
+BC2GM003154305
+BC2GM031365198
+P02024816A0521
+P08213235A1024
+P11016014A0181
+P09549179A0774
+P09580563A0331
+BC2GM004847396
+P02534067A0316
+P07983744A0920
+P03755623A1233
+BC2GM053556516
+BC2GM027946341
+P01098592A0567
+P09267439A0000
+P07902583A0545
+P09623830A0000
+P07512258A0441
+BC2GM080639482
+P01027644T0001
+P01627830A0000
+BC2GM063564891
+P10931524A0313
+P07475793T0000
+BC2GM097865195
+BC2GM054717309
+BC2GM055252448
+P10567581A0119
+P08088513A0419
+P05274128T0001
+P06653755A0192
+P07365183A0000
+BC2GM016319405
+P08682317A0900
+P06876006A0930
+P04787472T0001
+P09234717A0000
+BC2GM085843951
+BC2GM095336401
+P02781495T0001
+BC2GM036044830
+BC2GM056370942
+P03977603A0326
+P08020702A0000
+BC2GM050190565
+P09882303T0000
+P08000074A0162
+BC2GM059240976
+P08124956T0000
+P09175858A1449
+P09291098T0000
+BC2GM020044790
+P09242499A0505
+P01281771T0000
+BC2GM071926370
+P09545638A0330b
+BC2GM027030914
+P06555107A1227
+BC2GM084871019
+BC2GM016713440
+P10938556A0248
+P02904322A0002
+P08293412T0000
+P08425050A0898
+P00985276A0000
+P05274526T0000
+P09808366A0828
+P03769224A0000
+BC2GM002201420
+BC2GM058928163
+P06362239T0001
+P09003462A0792
+P01995951A0000
+P04387103T0000
+BC2GM014569562
+P07966580A0518
+P07814321A0850
+P08776735A0000
+BC2GM087049151
+P06330082A0329
+P07931490A0237
+P10598101A0000
+P09203585A0660
+BC2GM035693756
+P11172944A0826
+P08639561T0000
+P09016566A0655
+P11046146A1202
+P10870043A0621
+P01782424A0278
+P09765411A0991
+P11371343A0125
+BC2GM024460635
+P11402674T0000
+P08703959A0659
+P10611353A0458
+P01280807A0575
+P08986228A0000
+P01788002T0001
+P08144668A0802
+P07565712A0286
+BC2GM074572349
+P09878437A0967
+P08616743T0000
+P08980413A0500
+BC2GM023576851
+P10848605T0000
+BC2GM036805670
+BC2GM009829131
+P11178696A0301
+P10727511A0294
+P07891713T0000
+P09579602A1720
+P11281201T0000
+P01695322A0000
+P11090762A0527
+P10798607A1359
+P04718233T0000
+P08025074A0000
+P10071212A0399
+P11069791A0226
+BC2GM088550314
+P09568549A0188
+BC2GM020276784
+BC2GM011866603
+BC2GM056771328
+P11353774A0255
+BC2GM029691403
+P06503885A0342
+P02417023T0001
+P08940132A1120
+P07926789A0960
+P08163546A1230
+P05884183T0001
+BC2GM081194969
+BC2GM035615525
+P08082215A0230
+P02551886A0332
+BC2GM063338768
+P05379901T0000
+P03017225A0706
+P03898382A0000
+P02838319A0527
+P08719697A0221
+P09694514A0000
+BC2GM027529733
+P01276105A0313
+P09268387A0293
+P09192998A0356
+P09514272A0482
+P11291552A0156
+P09250554A0402
+P10843810A0802
+P09522979T0000
+P09533030T0000
+P11789216T0001
+BC2GM084597422
+P11094066A0505
+P08323294T0000
+BC2GM081586375
+P01740121A0136
+BC2GM041916498
+P08309953A0776
+P04579436T0000
+BC2GM054086435
+P01339373T0000
+P01551568A1476
+P06978566A0197
+P09082335A0730
+BC2GM016884667
+BC2GM042062377
+P08071982T0000
+P01478672A0795
+BC2GM002038023
+P09675154A0690
+P09723896A0000
+P07704689T0000
+P08816483A0869
+P04990556T0000
+P08223613A0105
+P09904139T0000
+BC2GM049393382
+P10681562A0263
+P01422265A0263
+P03346210A0000
+P10706736A1091
+P10304090T0000
+P08985122A0501
+BC2GM019727288
+P08746981A0154
+P06095774T0001
+BC2GM039082460
+P08195216A1022
+P09055221A0288
+BC2GM086974168
+P03119485A0476
+P09945838T0000
+P11028944A1020
+P02889352A0000
+P01628904A0386
+P10611225A1127
+BC2GM046571166
+P08760889A0170
+P01168956A0552
+P08618882A0343
+BC2GM037219569
+P02704579A1078
+P07822329A0773
+P05276380T0000
+P11003641A0811
+P03493240T0000
+P09249039A0124
+P02340595A0124
+BC2GM085703128
+P08387508A0551
+P02024625A0202
+P07575947T0000
+P01544928A1252
+P03403313A0298
+BC2GM092675349
+P02725495A0929
+P10904191A0000
+P03570455A0433
+P07629103T0000
+P08224260A1248
+BC2GM065118476
+P01560774A0885
+P05303700T0066
+BC2GM022760333
+BC2GM071659744
+P11454703A0000
+BC2GM042126877
+BC2GM090376124
+BC2GM047739640
+P08798643T0000
+P06304771A1284
+P09560390A0771
+P01939878A0765
+P01653173A0619
+P03046931A0247
+P08004442A0265
+P09223479A1193
+BC2GM026076995
+BC2GM068686527
+BC2GM009645672
+P10008261T0000
+BC2GM027655679
+P09774403A0107
+BC2GM030008462
+P00008997A0472
+P01748292A0000
+P10837126A1004
+BC2GM032982135
+BC2GM007092490
+P07913080A0564
+P07691837A1359
+P01537334A0507
+P09813098A0521
+P01854339A0221
+P03243027T0000
+P10715322A0000
+P03237446A0377
+BC2GM091067876
+BC2GM044764990
+BC2GM049036740
+BC2GM025926172
+P07642538A0138
+BC2GM080578931
+P08817323A0714
+P03553439A0404
+P02078080T0040
+P11295523A0218
+P00342623A0228
+BC2GM035149396
+BC2GM025499244
+P07706307A0914
+BC2GM017211898
+P02331361A0268
+BC2GM016704905
+P10586107A0160
+P08132541A0000
+BC2GM039216973
+P00759400T0000
+P03883052T0001
+P10838139A1447
+P09171389A0549
+P01829060A0649
+P09049306A0830
+P09999742T0000
+P07665948A0591
+P10778740A1493
+BC2GM079274366
+P08390747A0586
+P06794480A0785
+P09413375A1486
+P10817754T0000
+P08836740A1025
+P11469926T0000
+P02423533A1314
+P09324922T0065
+P07534285A0155
+BC2GM040715083
+P03746508A0390
+P02745666A0000
+P11413148A0573
+P09465783A0449
+P10965905A1618
+P11259503A0212
+P08973630A0923
+P06615403A0718
+P10606245A0906
+P10797586A0402
+P01769919A0393
+BC2GM008157990
+P09183145T0001
+BC2GM062642302
+BC2GM032150077
+P09731705A2126
+P11572388A0000
+BC2GM073006220
+P02774808A0194
+BC2GM094374885
+P02784507A0000
+BC2GM008542019
+P10939030A0986
+P03069980T0000
+P08428750T0000
+BC2GM045771943
+P11334124A0903
+P08656672A0678
+BC2GM001536665
+P02188168A0000
+P09020169A0552
+P09857265A0669
+P09428787A0138
+P02148799A0000
+BC2GM065749452
+P09132057A0559
+P11137551A0437
+BC2GM081449509
+P03417668A1233
+BC2GM063086995
+P01436261A0145
+P09707498A0262
+P08028671A0687
+BC2GM044089781
+P02146266A0000
+P09148903A1715
+BC2GM081686289
+BC2GM053000072
+P02153683A1579
+P09687511A1091
+P10721704X0000
+BC2GM056600805
+BC2GM015309588
+P02600306A0140
+P07897696A0000
+P08086450A0467
+P11740806X0810
+BC2GM090142421
+P07802655T0000
+BC2GM059966403
+P10690866A0783
+P07905453A0281
+P00136175A1137
+BC2GM040893145
+P09398332A0732
+P09278450A1338
+BC2GM038029406
+P07747462A0332
+P08619866A0000
+P08663392A0215
+P07816630A1333
+P11350165A1606
+P02739739T0000
+BC2GM004578175
+P08276851A0347
+P11067928A0532
+P08751635A0135
+P09101910A0394
+BC2GM060403286
+P00519173A0126
+P06707357A0180
+P08033490A0875
+P08745669A0000
+P05066316T0001
+P02555418A0973
+BC2GM017612777
+P02748188A0091
+P11235335T0000
+BC2GM027121414
+P01735447A0271
+P07980669A0373
+P02598745A0251
+BC2GM067111314
+P06517816A0388
+P02167321T0000
+P02185140A0000
+BC2GM013088712
+BC2GM075767585
+P01314953A1266
+BC2GM097406919
+BC2GM053977202
+P11583428A0191
+P09578042A0363
+P01649173A0160
+P02636920T0001
+P07937108A0325
+BC2GM007444164
+P09642238A1285
+P10618645A0750
+P10918572A0794
+P07831799T0000
+P07775428A0172
+BC2GM081056774
+P01394200A0592
+BC2GM065203942
+P10677297A0933
+P08325639A0129
+BC2GM084813234
+BC2GM003538479
+P07513703T0000
+P04013604A0412
+P08807408A0524
+P08942999T0000
+P01272816A0000
+BC2GM050480913
+P11331604A0267
+P06466804A0686
+P01626430A1112
+P08801403T0001
+P01379150A0996
+P01408474A0531
+P09353343T0000
+BC2GM045193318
+P06723849A0197
+P02198289A0436
+P11576158A1371
+P11176098A0342
+P08363332A0365
+P09582331A0506
+P09150595A0225
+P06382374A0206
+P00868903A0000
+P11095248A0423
+BC2GM095421849
+BC2GM032669155
+P07659746A1464
+P08976253A0637
+P09029713A1120
+P05253274T0001
+P06173860A0000
+P11243494A0833
+P11058008A0159
+P01716629A0000
+P03026915A1024
+P11282394A0841
+P08188290A0544
+P07687745T0000
+P08973527A0000
+BC2GM085081988
+P07311881T0000
+P02648396A1033
+P09829836A0000
+P07945134A0079
+P10455087A1400
+BC2GM013965440
+BC2GM058884519
+P02196450A0870
+P08035499A0941
+P08516308A0669
+P02123466A0272
+BC2GM003230275
+P09005273A1558
+P02303158T0000
+P01619642A0131
+P03592297A0138
+P02390538A0000
+P02325208A0209
+P01922739A0336
+P09386074A0694
+P04032716A0299
+P08132667T0000
+BC2GM020722431
+BC2GM027223397
+P11566948A1217
+BC2GM027886760
+BC2GM051341452
+P09189783A0000
+P02518691A0251
+P08986770A0268
+P01628806A1347
+P09811730A1396
+P11555516A0639
+P10926776A0731
+P08943032A0000
+P11034933A0389
+BC2GM085794657
+P07685263A0503
+P09786197A0322
+BC2GM014151852
+P03325081A0524
+P03427474A0853
+P03659994A0150
+P11118062A1691
+BC2GM027315963
+P10391277A0000
+P02237431A0000
+P02213566A0000
+BC2GM033697921
+P09365201A2018
+P05552149T0000
+P02648396A0565
+P10055173T0000
+BC2GM058154023
+P02601707A0986
+P09218775A1229
+P03243920A0591
+BC2GM044965167
+P11160683A1220
+P09599724A0193
+P07693967A0905
+P10722969A0510
+BC2GM033411321
+P06714298X0000
+P09892017A2151
+P02548683T0001
+P00503336A0285
+P03534581A0976
+P10766493T0000
+P07610324A0319
+P03537721A0876
+P10085383A1367
+P10855690A0870
+P03381039A0364
+P08413291A1473
+P05718994T0000
+P08505605A0461
+BC2GM095257968
+BC2GM015257023
+P08488700A0283
+P00484177A0242
+P01083375T0000
+BC2GM033228661
+P11438838A0788
+BC2GM028886679
+BC2GM005102149
+P10586626A0607
+BC2GM032387601
+P03776779A0238
+P08978690A0262
+BC2GM003435732
+P10695685T0000
+P08204348T0000
+BC2GM047029029
+P11439343A0785
+P10580071A0436
+P00060529A0695
+P08887674A0920
+P07840643A1006
+P11156789A1669
+P01848300A0910
+BC2GM024043854
+BC2GM081059742
+P01327758A0000
+P09442031A0586
+BC2GM066933865
+BC2GM073356328
+P01992742A0000
+P08282749A1474
+P08172653A1589
+P10681588A0899b
+BC2GM091594657
+P01569945A0529
+P10758489A0206
+P03233862T0000
+P08400240A0166
+P00600943T0001
+P09200029A0211
+P06700231A0259
+BC2GM052108285
+BC2GM082234251
+P09321930A0567
+P07538818A0197
+P03023859A0000
+P09625762A0426
+P01697683T0000
+P08588852A0236
+BC2GM069666252
+P11058120A0256
+P01774062A0257
+BC2GM088020091
+P08300605A0671
+P07890599A0132
+P08034742A0307
+BC2GM086254445
+P09802206A1058
+P03698251T0000
+P07873631A0114
+P11404312A0660
+P09862481A0000
+BC2GM016668855
+P08497269A0999
+BC2GM052077853
+P03709191A0125
+BC2GM034834811
+P01718983A1640
+P11064829T0058
+P03697971A0311
+P10815807A1271
+P02729666A0267
+BC2GM027266609
+BC2GM043140660
+P11278286A1083
+BC2GM081816003
+P10731926A0775
+P09371698A1254
+BC2GM036910658
+BC2GM059590650
+BC2GM032675979
+P06884450A0234
+P02257899T0000
+P06794666A0208
+P09829843A0119
+P11408099A0518
+P10629035A0827
+BC2GM097372131
+P10732669A0510
+P10506160A0297
+BC2GM096226765
+P11251252A0494
+P09065690A0463
+P00635143T0001
+P08273122A0708
+P09453689A0000
+P06252883A0100
+P02278474A0000
+P07806492A1162
+P09539421A0970
+P07106323A0560
+BC2GM036783364
+P11080796A0883
+BC2GM043523673
+P04316696T0001
+P08397123T0000
+P10748125A0000
+P09770378A0641
+P10908478A0717
+P00722298A0619
+P01867069A0000
+P07979827A0722
+BC2GM060485652
+BC2GM050121577
+BC2GM031712129
+BC2GM082790827
+P01740330A0329
+P07483857A0350
+P08429019A0735
+P06439135A0250
+BC2GM067853242
+P02950216A0084
+P01970560A1024
+BC2GM051172236
+P08294459A0446
+P02994253A0482
+P08530342T0000
+BC2GM018717311
+P06807149A0222
+P09502720T0000
+P01629768A0131
+P11210401A0000
+P09744095A1016
+BC2GM051932987
+P10564495A0444
+BC2GM027887044
+P08591700A0972
+P01310899A0339
+BC2GM078652752
+P09151837A0723
+P09798068A0290
+BC2GM006670958
+BC2GM034110005
+P10603349A1667
+P10395199A0792
+P10668701A1311
+P02115572A1323
+P07875595A0910
+BC2GM068485408
+P09146027A0809
+P11267679A0102
+P09312087A0000
+P01740437A0851
+P03253219T0000
+BC2GM024107686
+P00167544A0067
+P11046153A1052
+BC2GM037286587
+BC2GM070224595
+BC2GM033913312
+P06209403A0562
+BC2GM002670368
+BC2GM043040465
+P01649318A1222
+P04032268A0358
+P11264176A0181
+P01641628A0869
+P11323716A0413
+BC2GM018593064
+P03382310A0903
+P04661961T0001
+BC2GM069042705
+P00842406A0771
+P08139543A1520
+BC2GM091683569
+P01634308A0191
+BC2GM086696613
+P08971835A1057
+P03013841A0207
+BC2GM075404725
+P09801156A0220
+P11027289A0000
+BC2GM010976531
+P03626129T0001
+BC2GM067585100
+P06993660A0000
+BC2GM056032445
+P11012680A1020
+P10872851A0714
+P01330077A0000
+P08645219A1377
+P11468958A0122
+P11159081A1155
+P09171363A0149
+P09397261A0940
+P09209406A1021
+P06658586T0001
+P08756636T0000
+P09485308A1165
+BC2GM044349472
+P02517008A0481
+BC2GM007331951
+P00358945A0225
+P10931960A0630
+BC2GM082270855
+P08546707T0000
+P03811852A0109
+BC2GM059417476
+BC2GM090212976
+P02958233A0123
+P03687078T0001
+BC2GM043328446
+P00488534A0308
+P07601828A0095
+P06381438A1280
+P09328476A0068
+P00764737X0000
+P08660998A0851
+P08279098T0001
+BC2GM024357509
+BC2GM039939591
+P11182520A0889
+P11146961T0000
+P09843572A0944
+BC2GM017071077
+P02125153A0410
+P01527020A0511
+P10791819A0771
+BC2GM072697080
+P10658588A0304
+BC2GM014230016
+P08918810A0967
+P01657594A0472
+P11251083T0000
+BC2GM066160627
+P08160387T0000
+P03118631A0140
+P07263374T0000
+BC2GM097338310
+P07488291A0934
+P09751114A0967
+BC2GM043347947
+P01003819A0498
+P11256962A0233
+P09208930T0000
+P09964171T0000
+P08200528A0970
+P05982700T0000
+BC2GM057834406
+BC2GM027749985
+BC2GM086681787
+P09731354A0963
+P10702926T0089
+P09964770T0000
+P02206858A0000
+P07774807A0405
+P09325135A0737
+BC2GM097463042
+P11287654A0150
+P01265443A0159
+P09271417A1011
+BC2GM093832681
+P09268631A0316
+P08294865A0236
+BC2GM090670157
+P10741850A0452
+P07713936A0393
+BC2GM025094237
+P00073344A0367
+P02664229A0138
+P07608268A0194
+P08894826A0228
+P11207216A0719
+P05172320T0001
+P02076816T0000
+P07844155A0327
+P04043489A0648
+P11012680A0676
+P08114710A0137
+P05797287T0069
+BC2GM065990339
+P09922856A0459
+P03732252A0556
+BC2GM092963902
+P06286191T0000
+P02576405A0223
+BC2GM006556353
+P00917721A0484
+P08485317A0000
+BC2GM023966802
+P07251564A0569
+P02241742A0766
+P09867159A1444
+P09508511A0588
+P10573781A0631
+BC2GM027443624
+BC2GM035313252
+P00968181A0264
+P11266227A0295
+P03045725A0872
+P07557091A0314
+P01849675A0167
+P09556861A1018
+BC2GM084033136
+P07675449A0848
+P09001667A0312
+BC2GM047781166
+BC2GM031270698
+P08756609A0498
+P10873286X0000
+P04034666T0000
+P11566961A0472
+BC2GM047234366
+P08710377A0577
+P02233729A1065
+P09150566A0316
+P02300577A0852
+P08849834A0000
+BC2GM053225720
+P07418498A0217
+P02744123A0237
+P06962492A0612
+P01616475A0756
+P01839414T0000
+P08395014A1364
+P09138076A1099
+BC2GM037195225
+P01808829A0510
+P10744749T0000
+BC2GM085649644
+P02399053A1032
+BC2GM027260839
+P00959656A0250
+BC2GM067096168
+P02821340A0434
+P01658741A1047
+BC2GM068076074
+P01948783A0000
+BC2GM007721864
+BC2GM002038787
+P06153936A0784
+P00541752A1032
+P08106245A0325
+P08185288A0106
+P07508140A0448
+P03873141A0304
+P10516072A0146
+P01762917A0615
+P07814388A0662
+P06336045A0261a
+P01636714A0845
+P05152314T0001
+P01967130A0645
+P10801244A0578
+BC2GM052871586
+P02532032A0385
+P10576545A0926
+P08103379A0577
+BC2GM008233762
+P10571474A0571
+P09573374A0687
+BC2GM066800010
+P06494215A0248
+P04027182T0000
+P09421507A0000
+P01551910A0313
+P09743233A0526
+BC2GM081733719
+BC2GM042134341
+P01328197A0985
+BC2GM088319331
+P09421521T0000
+P01916405A0242
+P10743608A1154
+P11070078A1153
+P02733690T0000
+P03418727A0992
+P08439597A0000
+P07961958T0000
+P08756433A0282
+P02479635A0659
+P09822602A0237
+BC2GM087236793
+BC2GM078821043
+BC2GM086866960
+BC2GM047245566
+P02209811T0000
+P03645733T0001
+P09444316A0388
+P07527168A0524
+P11278440A0095
+BC2GM072992671
+P09218459A0000
+P03608916A0790
+P10918599A0071
+P03976323A0821
+BC2GM011126259
+P09085842A0181
+P08188978A0822
+P09108279A0431
+P09046013A0000
+P04039307A0613
+P08257754A0711
+BC2GM063705940
+P07799939A0628
+P05203499T0001
+P01725547A0354
+P07824726A0454
+P09304123A0079
+BC2GM098640095
+P08223592A0424
+P02332018A0538
+P10568275A0679
+P05733952T0001
+P08014919A0530
+BC2GM098491104
+P01513213A0231
+P07529504A0000
+P11223153A0533
+BC2GM048845063
+BC2GM023214186
+BC2GM000692061
+BC2GM035523240
+P01817497A0715
+P02506390T0001
+P07844425A0289
+P02190122A0633
+P09999256T0000
+P07918128A0000
+P01785749A0695
+P09265642A0668
+P10479492A0000
+P01249198A1097
+P08935991A0844
+P01842498A0000
+BC2GM054001196
+P09367288A0115
+P10915728A0216
+P10490065T0000
+P09765285A0998
+P10630471T0000
+P00406585T0001
+BC2GM074053029
+P01287197A0761
+P10932679A0049
+BC2GM091017201
+P02691998A0672
+P08660892A1044
+BC2GM005086687
+BC2GM049662793
+BC2GM055940365
+P11038366A1417
+P06630319A0244
+P07786820A0284
+P08660733X0000
+BC2GM082631911
+P08083998A1723a
+P07160491A0547
+P05758469T0001
+P02236060A1671
+P08545502A0914
+P00580106T0000
+P02099622A1046
+BC2GM095399332
+P07296303A0418
+BC2GM088510048
+BC2GM053114631
+P06487290A0000
+P11160732A1199
+P08020702A0137
+P01833637A0531
+P10899128A0661
+BC2GM026606071
+P00337102T0058
+P00917572T0001
+P10580438A0508
+P01097100A0217
+P07514295A0000
+BC2GM086734097
+BC2GM027314864
+BC2GM087160593
+P08878044A1390
+BC2GM060037556
+P06872800T0000
+P08575754T0000
+P09405536A0777
+P01324385A0329
+P11337859A0651
+BC2GM096331447
+BC2GM075740515
+BC2GM077833737
+P07745696A0932
+P08566747A0756
+P09642764A0469
+P02312470A0774
+P07450031A0691
+BC2GM004099886
+BC2GM026014073
+P00875778T0000
+P11027289A0321
+BC2GM083915598
+BC2GM031508417
+P10796486A0817
+BC2GM013433125
+BC2GM013283171
+P11207609A0994
+P03628713A0961
+BC2GM009334391
+BC2GM000854272
+P10642524A0156
+P07205967T0000
+BC2GM095899932
+P00346829X0000
+BC2GM084436440
+P08040391T0000
+P01584812T0000
+BC2GM032311862
+P09219526A0383
+P09042078A0202
+BC2GM074489263
+P01128985A0000
+P06493655A0415
+BC2GM000554364
+BC2GM094094269
+P00594617A0192
+P08264579A1209
+P09632785A0000
+P07896846T0000
+P03882029A0000
+BC2GM044606080
+P03765552A0582
+P07372928A0105
+P11454239A0478
+P02910989T0000
+BC2GM063679270
+BC2GM018506059
+P11396685A0477
+P07568865A0305
+BC2GM041191299
+P09482107A0551
+P07789809A1246
+P09653641A0471
+P11071651A1308
+P07693132A0100
+P08321741A0396
+P01771593A1232
+P09234677A0770
+P01727494A0000
+P08861963T0000
+BC2GM033838267
+P00665053A0276
+P00521732T0000
+P00183063A0300
+P08543173A0314
+P10906317A0351
+P03781000A0101
+BC2GM076159056
+P09765261A0000
+P08396713A0305
+P09573884A0392
+P10620010A1155
+BC2GM099053917
+P08946668A0077
+P01396601A0986
+P07149303T0000
+P03802195A0481
+P02199311A0620
+BC2GM068280141
+BC2GM099912787
+BC2GM051140215
+P10713083A0560
+P10934310A0698
+P05388567T0000
+BC2GM091705287
+P07908827A1200
+BC2GM046827862
+P01770651T0001
+P02284573A0943
+BC2GM004377989
+P09039744T0000
+BC2GM019432575
+P07282552A0990
+P10940553A0912
+P08668190A1364
+P02324104A0151
+P02979426T0000
+BC2GM065497063
+BC2GM075043873
+P02164588A0266
+P09311835A0147
+P02033062A1169
+P11126806A0206
+BC2GM017819030
+BC2GM060767735
+P01899409T0000a
+P09346935A0927
+P08031424T0000
+P02259334A0205
+P07494293A0585
+BC2GM065119340
+BC2GM054468941
+P04371279T0000
+P02157067A0610
+BC2GM089085833
+BC2GM089791646
+P02833049A1041
+P03465957A1008
+BC2GM082132977
+P11348318A0940
+P08201758A0125
+P07969116A0196
+BC2GM095560139
+BC2GM036149639
+P01349705T0000
+P04364369T0000
+P09875541A0210
+P11180255A0776
+P10575231A0355
+BC2GM052383687
+BC2GM028011707
+P01201977T0000
+P09199292A0536
+P08014377A1277
+BC2GM091790699
+P06395804A0382
+P02154602A0092
+BC2GM037814296
+P07140493A1045
+P09864689A1408
+P09064868T0001
+P02324104A0516
+P10607900T0000
+P02757862T0000
+P04583791T0000
+P01849509T0000
+P01333047A0404
+P09154827A0158
+BC2GM052215077
+P07062036A0072
+P08868954A0648
+P10752450A0288
+P09004987T0001
+P08995659A0563
+P08676495A0129
+P06372563T0000
+P02373810A1118
+P01618027A1108
+P04837183T0000
+P08234166A0425
+BC2GM025094273
+P01512654A0503
+BC2GM092341620
+P11480555A0928
+P01709486A0000
+P09427627A0802
+P08627649A0734
+BC2GM026829531
+P01954355A0997
+BC2GM005882702
+P01349837T0000
+P08500524A0424
+BC2GM052496419
+BC2GM036499922
+P04468264T0053
+P06825641A0076
+BC2GM097944036
+P02894741A0000
+P09187371A0450
+P01724982A0237
+P00512215A0000
+P07507458A0250
+P01869565A1254
+P09225686A0683
+P08931991A1026
+P03322829A0952
+BC2GM009595830
+P02055484A0538
+P09976626T0000
+P02839488A1314
+P11490862A0141
+P09354684A1158
+BC2GM089535838
+P08159174A0581
+P02045809A0331
+BC2GM009438252
+P10620335A0749
+BC2GM099369048
+P11528500A0571
+P08622030A0667
+P09587549T0001
+BC2GM028289615
+P04377328T0027
+P02361008T0000
+BC2GM092196424
+BC2GM007219216
+BC2GM005310044
+BC2GM029322086
+P09230216T0000
+P08240170A0000
+BC2GM002546611
+P08430095A0161
+BC2GM068318843
+P10972990A1518
+P09891092A1000
+BC2GM086236532
+BC2GM069019076
+P09099743A0585
+P10788476A0891
+BC2GM090485804
+P00846559A0000
+P06113443T0000
+P10671519A0641
+P09512416A0460
+P01493864A0619
+P08817324A1070
+P01895358A0000
+P11382948A0793
+P08001136T0000
+P09227099A0106
+P02536096A0327
+P08006773A0836
+P03159903A0352
+P07590525A0811
+P07869913A1076
+P08654946A0986
+BC2GM030067070
+P06674977A1181
+P02028125A0101
+P08887659A0753
+P10607899A0605
+P03770143A1209
+BC2GM097376485
+P09642238A0532
+P11459962A0785
+P08264664A0128
+P08797362T0037
+P09328833A0588
+P01370446A0818
+BC2GM009718351
+P10942599A1298
+BC2GM000577306
+BC2GM064715787
+P01409581A0206
+P08383287A0611
+P11113823A0197
+P00242427T0001
+BC2GM061130955
+BC2GM055588958
+BC2GM084745915
+P11479501A0744
+BC2GM060450171
+P09882499A0231
+P11016850A0423
+BC2GM039075173
+BC2GM047756282
+P06244732T0000
+BC2GM074932175
+P02657883T0001
+P08360180A1041
+P08787110A0981
+BC2GM019437752
+BC2GM021905510
+P02458080T0000
+P08449978A0000
+P07593896A1053
+P01620129A0417
+P03398433T0001
+P01380062A0097
+BC2GM022818569
+BC2GM009237641
+P07935577A0305
+P07943556A0694
+P08738510A0254
+P02475506A0878
+P08662936A0428
+P11422757A0737
+P01918010A0000
+P11221845A0800
+P10906176A0000
+BC2GM028481632
+P09564917A0900
+P09780002A0996
+P08449133A0578
+BC2GM073109990
+P01623900A0670
+P01942033T0000
+BC2GM067886213
+P06671065A0000
+P10660676A0000
+P07476971A0381
+BC2GM013098163
+P04101003T0001
+P10454568A0815
+P02034655T0000
+P10211329A0457
+P01840608A0823
+P00996364X0000
+BC2GM096832130
+P02688772T0000
+BC2GM005153590
+P09712859A1110
+P09368014A0740
+P07592721A0827
+P02143186A1306
+P10964833A1696
+P07598106A0709
+P08082292T0000
+P02470955A0101
+P09056761A0000
+P07165767T0000
+BC2GM015227811
+BC2GM083262968
+P11583621A0301
+BC2GM035406397
+P08020962A1226
+P00839378A0649
+BC2GM008520158
+BC2GM006291661
+P08643759A0338
+P11480490A0443
+P08955306A0224
+BC2GM013174234
+P10892823A1040
+P10563605A0773
+P00222827A0000
+P04878680T0000
+BC2GM082753569
+P01925092A0304
+P11006283A1180
+P09272108A1295a
+P00757244A0000
+P11389085A1032
+BC2GM010412536
+P08654983A0000
+BC2GM055762789
+P07760819A0731
+P02727909A0383
+P02201905A1004
+P10032581T0000
+P04021281T0001
+P06328504A0161
+P07542577A0438
+BC2GM023099486
+P03199043A0248
+P11524015A0937
+P01893195A0000
+P11469701A0377
+P09987634A1265
+P00602622A0362
+P10863048A0000
+P09920930A0521
+P09371622A0779
+P10907971T0000
+P11502778A0941
+P08661119A0085
+P08610272A0265
+P08246987A0260
+P11842728X0001
+P03439248A0000
+P01354506T0000
+P01640778A0485
+BC2GM098160022
+P09263010T0000
+P01324406A1250
+BC2GM042018281
+P11238105A0959
+P11450776T0000
+P10792583A0000
+P09489670A1157
+BC2GM040473941
+P10756225A1464
+BC2GM013825160
+P08854459A0000
+P01798407A1011
+BC2GM022449738
+BC2GM049324626
+BC2GM045448639
+BC2GM082757224
+P00137671A0896
+P09371431T0000
+BC2GM040023769
+P09193072A0199
+P09864335A1226
+BC2GM049820346
+P09108038A1128
+P10825000A1245
+P01779299A0000
+BC2GM067379320
+BC2GM092358374
+P10669751T0000
+P08018361A0636
+BC2GM090622796
+P10721704A1155
+P01332964A0247
+P08990168A0688
+P07476701A0654
+P07730328A0000
+P09582953A1097
+BC2GM037522432
+P11535532A0189
+P03759731A0992
+P07565113A0000
+P00172199A0270
+P01936213T0000
+BC2GM008125101
+P11037823A1134
+BC2GM069268475
+P08307564A0233
+P09153010A0499
+P08626325A0543
+P11007949A1395
+P08647822T0000
+P10046849T0000
+P10687366A0000
+P09112589A0078
+P01731979A1408
+P09753241A0524
+P09574799A1072
+BC2GM037203130
+P07064662A0222
+P08602169A0484
+P07580058A0000
+P11327858A0087
+P09096234T0000
+BC2GM026991147
+P08347677A0308
+P01738653T0014
+P08173814A0132
+P07854324A0742
+P08457205A0240
+BC2GM098621694
+BC2GM062392652
+P07876210A0751
+P07309562T0000
+P11568988A0960
+P08993393T0000
+P08369887A0781
+P08324792T0000
+BC2GM037830517
+BC2GM033021196
+P05359464T0000
+P08601806A0875
+P02967915A0968
+P08666102A0820
+BC2GM078528949
+BC2GM092355993
+P09360953A1057
+BC2GM008918503
+BC2GM070175350
+BC2GM073538623
+BC2GM006621209
+BC2GM053866508
+BC2GM073138597
+P00891370A0000
+P01317376A0981
+BC2GM035763240
+BC2GM023802177
+BC2GM096583756
+P02907308T0001
+BC2GM054621405
+P09322872A0745
+P07933095A0000
+P07499252A0150
+P03296254A0556
+P02489895T0001
+P08824201A0270
+P09884275T0000
+BC2GM041284002
+P02705296A0231
+P03625762A0308
+BC2GM096599542
+P10585480A0157
+P08265955T0000
+P08710504A0995
+P07887226A0858
+P08428952A0399
+BC2GM040122571
+P07800505T0000
+P08543595A1093
+P02175908A0805
+P11447490A0598
+P03109147T0127
+BC2GM018910839
+BC2GM094853535
+BC2GM005295111
+P07871721A0392
+BC2GM063881420
+P09443978A0262
+P07194905A0332
+P09786949A0114
+P08962614A0000
+P02623038A0632
+P06719057A0181
+P07825888A0715
+BC2GM012674132
+P06516977T0000
+BC2GM034715588
+BC2GM071895729
+BC2GM047782308
+BC2GM025934950
+P09226345A0436
+BC2GM079386869
+P08839832A1220
+BC2GM065453807
+P10708243A0000
+P03928357A0340
+BC2GM014331768
+P03595418A0688
+P02920591A0251
+P09376626A0737
+P11139336A0257
+BC2GM073047126
+P01735447A0833
+P09537295T0000
+P10935880A1049
+P09488725T0000
+P07474617A1035
+P07385543T0001
+P08232304A1166
+P10836542A0363
+BC2GM091426108
+P06479362A0680
+P09227799A0254
+P02714852T0000
+P11127250A1111
+P07945330A0103
+P01499616A0136
+BC2GM048186198
+BC2GM060833693
+P09640162A0242
+P09786926A0095
+P09024805A0905b
+P09389137A0763
+P11356853A0554
+P08721999A0432
+P08044794A0000
+P03785212A0091
+P02816251A0397
+P10727413A1244
+P11241332A0393
+P06981991A0756
+P10215803T0000
+BC2GM032797223
+BC2GM021649255
+P09168218A0216
+P04041346T0000
+P04088233A0309
+P01705541A0273
+P09704296T0000
+P02473198A0613
+BC2GM041796235
+P08418183A0000
+P04753286T0000
+P09115265A1160
+BC2GM020447854
+P03413681A0659
+P03009826A0201
+P09484781A1233
+P11207261A1421
+P02175433A0575
+P08955928A0390
+P07796935A0284
+P09584180A0701
+BC2GM075752604
+P01371413A0742
+BC2GM046628798
+P01309593A1092
+P02930623A0404
+BC2GM079614007
+P00956364A0138
+P10943891A1062
+BC2GM068399734
+P02928376A0312
+BC2GM051669825
+BC2GM016145858
+BC2GM085265641
+P11161816A0851
+BC2GM094951467
+P01726211A0502
+P08871635A0000
+BC2GM071576712
+BC2GM044501927
+P11282395A0530
+P04843031T0000
+P02837575A0979
+P03553149A0299
+BC2GM042620717
+P06803634A0810
+P01400396A1265
+P07751848A0222
+P01304809T0001
+BC2GM052825552
+P08454858A0285
+P11407289A1507
+P10429946A0473
+P08614403A0557
+P10934640A1114
+P07761420A0909
+P04189158T0000
+P10451209A0000
+BC2GM029724458
+P08089834A0561
+BC2GM094712703
+BC2GM033552450
+P09408796A0648
+BC2GM044203528
+P03287597T0000
+BC2GM026130174
+BC2GM053719721
+P11024047A0626
+P07737118A0317
+P09515924A0553
+P07490766T0000
+BC2GM097623388
+P09729481A1177
+P01050144A0297
+BC2GM069080186
+P08497248A0000
+BC2GM032337812
+P07589069A1245
+P11029704A0378
+BC2GM080784888
+P08419376A0357
+P09892736A0343
+P07476975A0492
+P04656185T0000
+P07626469A1341
+P00234206T0000
+P07891708A1192
+P07829097A0000
+BC2GM055859383
+P04164669T0000
+P10669736A0903
+BC2GM042846376
+P02666034A1520
+P11029262T0000
+P08603921A1346
+P07859665A0498
+P07654712A0774
+P02403035A0621
+BC2GM021539597
+P11071852A0297
+BC2GM029944945
+BC2GM047438255
+P09447979A1430
+BC2GM035114288
+P03117046T0000
+P09372451T0000
+BC2GM017641405
+BC2GM080548139
+P07811964A1252
+P11139148A0421
+P11371417A0744
+P07819225A1094
+P07791783A0000
+P07759529A0288
+BC2GM082796346
+BC2GM064134481
+P09799086A0725
+P06309969T0055
+P04948325T0000
+P07546293A0968
+P09658769A0058
+BC2GM062859122
+BC2GM076394317
+P07473169A0133
+P08386319A1229
+P02093888A0293
+P09362473A1540
+P09990507A0000
+P01850096A0662
+BC2GM049868543
+BC2GM081350038
+P08440720A1404
+P07749461A0632
+BC2GM053590893
+P08262054A0565
+P11245986T0000
+P09515858A0000
+BC2GM007988676
+P01869968A0000
+P07871721A0000
+P10471383A0229
+P11722993A0276
+P09388201A1027
+P11559564A0459
+BC2GM074417017
+P11169113A0555
+BC2GM017902303
+BC2GM093697629
+BC2GM000522836
+P09872337A0000
+BC2GM013735127
+P11285235A0466
+P03541263A0368
+BC2GM039571849
+P07790719A0098
+P03052327A1474
+P11069223A0593
+P08742385A0211
+P03687148T0187
+P07852400A0519
+BC2GM080497809
+P04976988T0000
+P07554541A0587
+P02034655A1224
+P04021305A0530
+P11116148A0741
+BC2GM064660212
+BC2GM036047624
+P08016189A0741
+BC2GM025977756
+BC2GM012758546
+P11069788A0531
+P07991582A1023b
+BC2GM026838513
+P09144165A1275
+P09694897T0000
+BC2GM049476497
+BC2GM068884936
+BC2GM070141070
+BC2GM068876712
+P07278578T0001
+BC2GM030135043
+BC2GM033367187
+P07595221A0733
+BC2GM003230260
+BC2GM099666829
+BC2GM008652234
+P01923167A0000
+P06361318A0440
+BC2GM010869565
+P02657883A0000
+P08106325A0000
+P02351297A0000
+P05353667T0000
+P07456774A0448
+P01316125A0382
+P11313398A0687
+P09234713A0754
+P07084198T0000
+P08901635A0000
+BC2GM032391800
+P01639092A0776
+P08131545A0158
+P03117147A1059
+P07559524A0000
+P01099693T0000
+P01717833T0000
+BC2GM029530491
+P01764899A0399
+P09230307A0329
+P01898113A0265
+P08898365A0274
+P02545357A0000
+P07894359T0000
+P02399053A0153
+P11027294A0483
+P03615763A0170
+BC2GM050151466
+P08391748A0452
+P10589562A1208
+BC2GM029191037
+P11112700T0000
+P01581965A0388
+P02468795A1086
+P08610328A0228
+P08065901A0997
+P08291761A0416
+BC2GM012798293
+P02462305A1071
+P06376227A0217
+P07862141A1412
+P08063108A0109
+P06685177T0000
+P09152656A0149
+P04028871A0133
+BC2GM094275796
+P02419588A0284
+BC2GM043493383
+P02484714T0000
+BC2GM056889976
+P00806295A0193
+P11274184A0000
+P09706565A1072
+P09430461A0742
+P10729155A0653
+BC2GM099206103
+P08106313A1492
+P08776792A0626
+P09498553A0702
+BC2GM042452037
+P05769307T0000
+BC2GM071420231
+P09924675A0412
+P02180935A0535
+BC2GM004666359
+BC2GM048998172
+BC2GM097629610
+P01697611A0738
+P07783822A0000
+P10467004A0116
+P11116131A0863
+P02276891T0000
+P03894482A0549
+BC2GM020166073
+P02967915A0000
+P01840513A1019
+P09142146A0887
+P07768836A1126
+P01292230A0283
+P11274368A0469
+P08756597A0854
+BC2GM074670492
+BC2GM042845952
+P09032233T0000
+P07026328A0369
+P11063252A0437
+P07851758A0330
+BC2GM022119208
+P08660866A0504
+BC2GM035223840
+P11301189A1396
+P09312028A0975
+P02322535A0658
+P09380707A0714
+P08006101A1142
+P03450438A0446
+P01327967A0668
+P08207795A0409
+P06065507T0000
+BC2GM043951008
+P09869528T0000
+BC2GM049276320
+P06138015T0114
+BC2GM035651086
+P11471231A0964
+P11180688A0000
+P03354341A0177
+P03552363A0568
+P09609342A0000
+P09622055A0207
+P09005836A0977
+BC2GM027774736
+P09111863A0743
+P03720966A1043
+P04506738T0000
+P11566874T0000
+P09230986A0000
+P03827071T0040
+BC2GM015656322
+BC2GM036247814
+BC2GM014990106
+P08778265A0422
+P10940562T0000
+P02293664A0946
+BC2GM069151821
+P08566756A0752
+P09504514T0000
+P07568116A0902
+P07782302A0479
+P08902988A0258
+P01707800A0354
+BC2GM011254040
+P08970979A1246
+P08472750A0999
+P06072512T0000
+P06113084T0000
+BC2GM021103469
+P03744168T0001
+P01459451A0478
+P07592790A1457
+BC2GM062223441
+P09694034A0713
+P03912247A0282
+BC2GM034214374
+P08412120A0839
+BC2GM043724689
+P08770896A1121
+P00575231A0422
+P03625688A0372
+P07853476A0159
+P08355696A0236
+P06459831T0001
+P01546522A0000
+P09168511A0640
+BC2GM091685564
+P06096863T0000
+P03154072A0862
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/bc2gm.test b/huner/ner_scripts/splits/bc2gm.test
new file mode 100644
index 0000000..a94ca02
--- /dev/null
+++ b/huner/ner_scripts/splits/bc2gm.test
@@ -0,0 +1,6000 @@
+P04013576A0981
+P08647086A0720
+P06388818A0000
+P01125117A0183
+BC2GM082775110
+BC2GM083857019
+P00168176A0000
+BC2GM042151214
+P09049304A1193
+BC2GM076693165
+P08970352A0880
+P09488713A0886
+BC2GM046346737
+P11145563A0202
+P09551938A0318
+P03413890T0001
+P09453537A0863
+P00823087A0608
+BC2GM088125251
+P07935468T0000
+P09893262A1272
+BC2GM031995468
+BC2GM016976027
+P11035037A0183
+P07237560A1038
+P01694009A0112
+BC2GM051120604
+P08510924A0490
+P09739401A0000
+P01644831A0824
+P08855804A1528
+BC2GM022578153
+P03001705T0000
+BC2GM016290576
+P03507689A0000
+BC2GM044014286
+P01373374A0735
+BC2GM051369049
+P01536575A1213
+P10962593A0580
+P08868660A0087
+BC2GM096120426
+P06715792A0295
+P03981952T0000
+BC2GM084495640
+P07528028A1192
+BC2GM055948186
+BC2GM023848611
+BC2GM066811191
+P03972185A0137
+P08543275A0130
+BC2GM048840420
+BC2GM090513544
+P02036066A0000
+P05826818T0098
+BC2GM037370433
+P08918918T0000
+BC2GM028280868
+P05068271T0000
+P09098899A0435
+BC2GM049997228
+P08769409A0114
+P11000521A0588
+P03175942A0706
+BC2GM042419868
+P08625900T0000
+BC2GM055754960
+BC2GM091114680
+BC2GM026304956
+P10630630A0614
+P08552096A0151
+BC2GM012490279
+P03772471A1054
+P09596638T0000
+P08387507A1015
+P09121774A0611
+P10612505A1317
+P09726988A0275
+P03066208A0310
+P01332589A0666
+P05110049T0001
+P02173399A0333
+BC2GM068857149
+P09278454A1261
+P09259052A0568
+P06316623A0188
+P08552643A0261
+P04040083A0000
+P09788739A1096
+BC2GM033802791
+BC2GM088461338
+P09263856A0563
+P09418871A0620
+P08849569A0615
+BC2GM037708472
+P10692433A0000
+P02420432A1060
+P09545638A1181
+P04138224T0095
+P00063680T0000
+P10566862A0000
+BC2GM027254558
+P02708288A0621
+BC2GM088701024
+P02283378A0385
+P08224907A0000
+P09469415A1337
+P08622070A0889
+BC2GM063388732
+P02196565T0000
+P10737366A0280
+P11328699A0000
+P07797346T0000
+P02473156A0000
+BC2GM017296599
+P03073091A0338
+BC2GM006513676
+P08281153A0543
+P11278390A0632
+P09647240A0000
+P07856102A1616
+BC2GM012836491
+BC2GM033301301
+P02269426A0428
+P08895579A0583
+P06402859A0000
+P07629196A0274
+BC2GM034696553
+P01309593A0095
+P00767155T0001
+BC2GM003819880
+P08367487A1014
+BC2GM092059167
+BC2GM073386715
+P05083872T0000
+P09735366A1180
+P07596697A0971
+BC2GM072974603
+P01739439A0257
+P07758459A1277
+P08668201A1059
+P08299896A0880
+P02438637T0000
+P02335713A0905
+P10834707A1533
+BC2GM085716701
+P11525486A0350
+P01498607A0000
+P07564004A0292
+P01828248A0189
+P07474124A1360
+P07514301A0000
+P10825200T0000
+P09343426A0456
+BC2GM014829301
+P09570107A0355
+P01542565A0220
+P07565688T0000
+P02852894T0000
+P07236351A0812
+P09269879A0266
+P08519862T0001
+P08203260A1204
+P11456259A0142
+P09153348A0647
+P01565882A0737
+P07680120A1008
+P08608447A0806
+P02748595A0492
+BC2GM006491686
+P08300601A0745
+BC2GM015573126
+P08628260A0895
+BC2GM069540508
+BC2GM043187885
+P10915780A1063
+P01626440A0449
+P01331060A0768
+P02139891A0532
+P10925207A0634
+P02549343A1008
+BC2GM057519691
+P08816482A0234
+P00892353A0686
+P09455695A0762
+P03478354A0436
+P10940413A1153
+P04552263T0000
+P01326557T0000
+BC2GM043554799
+P02669199A0000
+P06401749T0000
+P00524451A0136
+P10566630A0371
+BC2GM083628661
+P07297576A0454
+P03629974A1468
+P08808939A0000
+P08655555A0772
+P00024600A0522
+P01246210A0648
+P08504928T0000
+BC2GM019598575
+P11384880A0719
+BC2GM069560811
+BC2GM080424073
+P11897950A0617
+P03508698A0535
+BC2GM094806221
+P08661007T0000
+P02707909A0209
+BC2GM002649706
+BC2GM039284976
+P01191964A0000
+P01958368A0556
+BC2GM066121491
+P07791769A0826
+BC2GM097784903
+P08794326A0405
+P08972182A0000
+BC2GM081353874
+P09316937A0133
+P01748067A0000
+P08474438A0000
+P01473196A1016
+BC2GM086069469
+P10720434A0291
+P09665503A0526
+P09423310A0251
+P10950398T0100
+P03789052A0527
+P08035505A0586
+BC2GM069852295
+P08413223A0847
+P11489597A0379
+P08892859A0563
+P08264650A0925
+P08828142A0000
+P08454591A1322
+P09663062A0175
+P07538173A0307
+P07205120T0000
+P02451872A0391
+BC2GM040204368
+P00630713T0000
+P11519466A0196
+P06254973A1757
+P08712799A0123
+BC2GM094472638
+P09767687T0000
+P09204570A0110
+P03147912A0422
+BC2GM049622274
+P01083321X0000
+P08012448T0000
+P02060052A0954
+BC2GM098872814
+P09551096A0108
+P02965149A0727
+BC2GM040128143
+P10627518A0544
+P08013457A0342
+BC2GM098014583
+P11181531A0464
+BC2GM077951036
+P10619062T0000
+P11198053T0000
+P10938105A0000
+BC2GM022041209
+BC2GM087148691
+P08005230A0222
+P06452461A0930
+P03537711A0181
+P09006910A0000
+BC2GM069129077
+P02173405A0270
+P09335298A1227
+P06694380A1483
+P11569900A0660
+P09498553T0000
+BC2GM090366403
+P02778237A0585
+P02846640A0643
+P01473234A1001
+P02120833A0000
+P10731411A0958
+P06810070A0502
+BC2GM040414744
+P01299489A0788
+P09193080A0904
+P10601280A0674
+BC2GM071046961
+P01968224A0119
+P08887661A0138
+P06495195A0536
+P11369453A1083
+P11113201A1114
+BC2GM070776704
+P01321336A0731
+P02162049A0291
+P09032258A0395
+P02165181A0299
+P09190202A0166
+P08798700A0134
+P07674649A0508
+P06453290A0000
+BC2GM083586381
+P03382772A0319
+P08229102A0768
+P09394650A0121
+P10628748A0746
+P09299696A1074
+P02153977A0364
+P00425547A0000
+P09858571T0000
+P08119149A0000
+P08702644A0499
+BC2GM081530471
+P10710985T0000
+P07665187A0208
+P01295373A0651
+BC2GM023306376
+P09354757A1444
+P11305129T0000
+P09480929T0000
+BC2GM034391394
+P09235618A0000
+BC2GM027269907
+P11194101A0532
+P09084227A0833
+P00659962T0000
+P07658777A0400
+P10940557A1687
+P07820057A0000
+P08755898A0339
+BC2GM081297373
+BC2GM058126747
+P09041123A0195
+BC2GM055283849
+BC2GM023833000
+P06090369A0000
+P11048832A0271
+BC2GM084139818
+P00921032T0000
+P09162092A0675
+P01661369A0825
+BC2GM032772191
+BC2GM091775961
+BC2GM001304367
+P04017295A0139
+P08756332A0000
+P09710131A0374
+P10692167A0364
+BC2GM061017656
+P09519830A0282
+P02631566A0151
+P10981094A0779
+P07730337A1439
+P07999363A0000
+P07597030A0260
+P08901135A1132
+P08749394A0874
+BC2GM064638906
+P03218714A0000
+P02525044A1026
+P06842629A0446
+BC2GM079202513
+P03035218T0000
+P02938185A0223
+P11838102T0001
+P02196311A1034
+P11401611A1703
+P10597222A1371
+P08223576A1261
+P08252976A0467
+P11255423A0211
+P08403245A1234
+P11210401A0544
+BC2GM096137044
+BC2GM085419447
+P03612316A0102
+P10349084T0000
+P02393895A0918
+P07972012A0956
+P07960796A0154
+BC2GM038777318
+P02511069A0532
+P08615012A0627
+P08051074A0000
+BC2GM091282092
+BC2GM004773918
+P09633274A0000
+P02196176A0749
+BC2GM051322057
+P03616174A1069
+BC2GM043142143
+P09200498T0000
+BC2GM013984753
+BC2GM034827451
+P09074508A0397
+P10826861A0000
+BC2GM012154477
+BC2GM029952373
+P06625058A0666
+P08775674A0000
+P04039525A0475
+BC2GM066396358
+P02708353A1452
+P01452584T0000
+P10804379T0001
+P07559478A0389
+P11350812A0829
+P09146071T0001
+P01371272A1167
+P09271496T0000
+P06308536T0001
+BC2GM063455036
+P09159111A0437
+BC2GM010615307
+P03780371A0792
+P08972182A0527
+BC2GM038859248
+P08520646A0000
+P06527872T0000
+P08222618A0000
+P00510341T0036
+P09447994A0000
+BC2GM065802628
+BC2GM066788416
+P02631887A0000
+P01467828A0542
+BC2GM057189560
+BC2GM004792351
+BC2GM097074870
+P02773930T0000
+BC2GM037412150
+P07410037A0752
+BC2GM005929354
+BC2GM003906024
+BC2GM086842152
+P07565775A1265
+BC2GM073564937
+P08850585A0602
+P03783160A0285
+P01284032A0213
+P07741255A0194
+P07191804A0000
+BC2GM052708788
+P09920982A0253
+P11554566A0668
+P02348408A0126
+BC2GM092481573
+P11408338A1686
+P10527180A0869
+P06092048A1111
+BC2GM030618899
+P08206848A0296
+P03676174A0730
+P08790387A0299
+P11534900A0000
+P08999414A0819
+P05933228T0000
+P11172944A0548
+P03692331A0000
+P09290571A0420
+P09891049A0761
+BC2GM068294994
+P02879951T0000
+P06098719A0369
+P01901859A0000
+P09715384A0235
+BC2GM012757246
+BC2GM058190767
+BC2GM090984958
+P09147420T0000
+P08662499A0484
+P09238860A0175
+P08722568A1001
+P00702773A0327
+P09811718A0979a
+P07500386A0870
+BC2GM000562167
+P02053289A0701
+P09849722A0797
+P07651398A0803
+BC2GM099480245
+P09726201T0000
+P01765266A0000
+P09396722A0185
+P08065310A1144
+BC2GM075844356
+P05796272T0000
+P10715602A0149
+P05060388T0000
+P06835914A0192
+BC2GM056723131
+P10779329T0000
+BC2GM072261734
+P11495920A0504
+BC2GM030876064
+BC2GM042679394
+P07880449A0091
+P03578948A0448
+P11385840A1684
+BC2GM075394719
+P10574992A0901
+BC2GM055275814
+BC2GM067272025
+P11335710A0320
+BC2GM085880360
+P01742606A0000
+P09058002T0000
+P07495120A0260
+BC2GM045487899
+P02708353A1080
+P08912232A0260
+BC2GM033321471
+P10748204A0238
+P06584416A0157
+BC2GM078490707
+P01656235A0946
+P03473379A0183
+P09000108A0330
+BC2GM015500367
+BC2GM054764143
+BC2GM078339197
+P10944466A0451
+BC2GM001873364
+P00726581T0122
+P02291628A0264
+P04085589A0264b
+P10851267A0000
+P02670457T0000
+BC2GM040702474
+P01427034A0440
+P08154182A0955
+BC2GM085260486
+P09165035A0842
+P01869907A2146
+P07648338A0815
+P06755986A0382
+P00879829A0564
+P08762472A0000
+P07498727A0724
+P08458660A0855
+BC2GM088515251
+BC2GM095236565
+P01636339A0200
+P08642285A1548
+P01627828A0475
+BC2GM012129841
+P09057840A0946
+P07841230T0000
+P08167396A0154
+P00265964A0562
+P01383695A0100
+P09641167A1359
+P11039780A0770
+P11222387A1497
+P07565049A1032
+P01596007A0908
+P01927421A0181
+P07984261A0536
+P09813110A0982
+BC2GM065355579
+P09230384A0725
+P09598894A0732
+BC2GM021758062
+BC2GM083051633
+P08239164A0551
+P08598051T0000
+P10725382A0398
+P09876794T0000
+P09032304T0000
+P06691304A0284
+P02939260A1553
+BC2GM014548790
+P11306845A0168
+P04082267A0720
+BC2GM018310054
+P08456879A0000
+P09417928A0980
+P08550461A0284
+P09472608A0253
+P11297866A0484
+P07537362A1112
+BC2GM066994310
+P01279696A0862
+BC2GM068782112
+BC2GM048362726
+P08891346A1217
+P07988731A0002
+P07184795A0517
+BC2GM047204097
+BC2GM048469729
+BC2GM039494188
+P09487130A0383
+P11113546A0728
+P08833653A0783
+P11029467T0000
+P07579023A0214
+P03997467A0000
+P08510320A0000
+P06895559A0000
+P03004739A0753
+P09157337A0545
+BC2GM039351888
+P09149929A0750
+P07679836A0387
+BC2GM072200502
+P01988041A0281
+P02020082A0356
+P08634423A0498
+BC2GM074751408
+BC2GM069327394
+BC2GM096903917
+P09858883A1106
+P09750540A0000
+BC2GM061536305
+BC2GM011130797
+BC2GM054158346
+P09395456A0424
+BC2GM023938146
+BC2GM064479626
+P03042778A0643
+P10619169A0411
+BC2GM085041109
+P07730337T0000
+P09705352A0879
+P10839593A0000
+P04828587T0000
+P11545594A1556
+P09763470A0000
+P01378526A0535
+P11239529A0981
+P10694210A0385
+P11462024A0306
+P08228805A0540
+P11309077A0953
+BC2GM021392794
+P05162342T0001
+BC2GM071251330
+P08662193A0404
+P09685346A0419
+P07563994A0488
+P07478523A0551
+P05463837T0023
+P03186270T0001
+P10951579A1238
+BC2GM092881858
+P09246343T0000
+P08521717A0126
+P02760922A0000
+P09484463T0000
+P09843577A0000
+P03684517A0462
+P10687855T0000
+P08622698T0000
+P01386210A0293
+BC2GM057651504
+P02832744A0403
+P10932329A0597
+BC2GM050974186
+BC2GM011080889
+P10667597A0668
+P08057356A1824
+P02679804A2000
+P09155015A0140
+BC2GM046719637
+P09650275T0000
+P03002501A1327
+P09366628T0000
+P08621542A0535
+BC2GM006849123
+P02916764A0253
+P03714473A0496
+P02147422A0000
+P09353328A0736
+P11321187A0355
+BC2GM034493633
+P05471866T0000
+BC2GM056033085
+P02328328A0419
+P09895323T0000
+P02627159A0899
+P00964758T0001
+P03060953A0481
+P03360667A0000
+P02045524A0000
+P08636211A0983
+P06070072T0052
+BC2GM071079182
+P07848358A0254
+BC2GM010251771
+P09389492A0520
+P03200844A1211
+BC2GM015636298
+P08552095A0758
+P08934533A0784
+BC2GM025770197
+P07660712A0118
+P11390581A1203
+P11403719A1257
+P09478921A0126
+BC2GM029534167
+P01505488A0231
+P08626785A0674
+P00478714T0000
+P09373140A0000
+P07857762A0611
+BC2GM046935375
+P02511207A0282
+BC2GM000222745
+P07922709T0000
+P03582982A0000
+P03987818A0440
+P03678269A0633
+P09883639A0000
+P03335651A0000
+P10830395A0408
+BC2GM002989216
+BC2GM050909815
+P02515953A0459
+P07846153A0403
+BC2GM029595476
+P10955313A0000
+BC2GM078212435
+P06310553T0000
+BC2GM018207544
+BC2GM006571611
+P06341661T0001
+P06694778A0000
+P10867199A0230
+P11308877A0213
+P10564474T0000
+P08139031A1168
+BC2GM010769407
+BC2GM041090140
+P01703632T0000
+P11342479A0430
+BC2GM089807452
+P02473693A0174
+P08617311A0979
+P09612775A0726
+P09228202A0581
+P04654249T0000
+P10567538A1028
+P08412665A0000
+P08964172A0221
+P03138190A0347
+BC2GM078700363
+P07910946A0323
+P10119827T0000
+BC2GM037647258
+P10756020A0571
+P09310836A1019
+P03227288A0542
+BC2GM035550761
+P02981457A0368
+BC2GM061836675
+P01688841A0430
+P09294422A1223
+P07935375A1197
+P03109954A0945
+P07791760A0424
+P11524815A0753
+P09601516A0695
+P02017159A0646
+BC2GM020674763
+P07537736A0453
+P11441952A0414
+P07592723A0814
+BC2GM028574302
+P03746107A0192
+BC2GM010665846
+BC2GM051746475
+BC2GM073202656
+BC2GM098968246
+BC2GM086442334
+BC2GM053427855
+P09832518A0615
+P08549859A1604
+P06520418A0325
+P03473253A0000
+BC2GM017504057
+P10855796A1160
+BC2GM080092738
+P11279086A1350
+P09252397A0081
+P09407031A0557
+BC2GM026914728
+P08843419A1290
+P11264182A0000
+P02789062A0000
+P10563836A1234
+BC2GM071734326
+P08180129A1256
+P03395009A1750
+P05025918T0000
+P11196199T0000
+P07385933A0085
+P11094075A0257
+P08072547A0690
+P07852037A0548
+P07971282A0000
+P07543684A1027
+P09417082A0127
+P01321277A0664
+P09571563A0000
+P00967223T0059
+P08793029A0246
+BC2GM090157482
+BC2GM084901055
+P07888788A1010
+BC2GM084642529
+P01389573A1071
+P10684097A0175
+BC2GM064636435
+BC2GM050646541
+P01462786T0000
+P03186091T0000
+P10882163A1077
+P10648489A1117
+P11391793A0856
+P10699354A0557
+P07841663A0685
+BC2GM011711443
+BC2GM040382030
+BC2GM000748612
+P07415340A0280
+P07783641A0591
+BC2GM038818397
+BC2GM052791430
+P08294511A0639
+P07828824A0307
+BC2GM040951364
+P08163498A0789
+P09611016A0652
+P11018264A0397
+P03167060A0000
+BC2GM042376349
+P02149487A0348
+P11121118T0000
+P08638435A0522
+P02137704A0000
+P09618164A0709
+BC2GM039715012
+P00811852T0001
+P09165039A1372
+P01738936A0292
+BC2GM002520653
+P04115870T0000
+BC2GM026200487
+P08900164A0188
+P08572616A0000
+BC2GM069669537
+BC2GM001825459
+BC2GM061354086
+P11207282A0729
+P10793143A1533
+P10052371A0171
+P10589711A1228
+P01350780A0184
+BC2GM053348868
+P09089093A0373
+BC2GM023118027
+BC2GM056745249
+P10769144A0000
+P03337024A0000
+BC2GM063132076
+BC2GM034677761
+P01906509A0072
+P10945781A0412
+P02675492A0806
+P07865888A1309
+P09343222A0415
+BC2GM074492181
+P08810278A0682
+P09789025A0149
+P08530418A1182
+P08816759A0000
+BC2GM079042018
+P07916588A0471
+P08642313A0770
+P09028308A0590
+BC2GM053682759
+P05919308T0001
+P11265853A0000
+P10822117A1386
+P03911702A0530
+P09075739A0827
+BC2GM071825291
+P07666414A0614
+P02205970A0684
+P06369355A0834
+P06767648A0734
+P08300625A1352
+BC2GM035652683
+P11134822A0629
+P02605679A0306
+P06816609A0639
+P02542194A1496
+BC2GM041377318
+BC2GM068305355
+P08396749A1112b
+P09312032A0165
+P07715922A0188
+P05045351T0000
+P08887661A1061
+P01651918A0000
+BC2GM072047092
+BC2GM021400038
+P01918070A0281
+P10910908A0767
+P09774484T0000
+P08552670T0000
+P06385474T0001
+BC2GM013779301
+P07806532A0659
+P00039271T0000
+P09418882A0760
+P02825139A0661
+BC2GM055940358
+BC2GM011712856
+P09234723A0846
+P09545332A0137
+P07735590A0990
+P09143465A0838
+P08551577A0000
+P02957125A0601
+BC2GM084023430
+P08816438A0316
+P02308496A0000
+BC2GM006151148
+BC2GM058293960
+P02595451T0000
+BC2GM001302183
+BC2GM080154101
+BC2GM083801874
+P00681571T0028
+P08133502T0105
+P03312514A0756
+BC2GM081464048
+P01138330A0204
+P01316903A0296
+P02997622A0916
+BC2GM013273874
+P07784061A0894
+P00130573T0054
+P05627251T0000
+P10780883T0000
+P03276924A0090
+P01334428A1102
+P04093211A0560
+BC2GM031182945
+P06749072A0116
+P01885613A1298
+P08774732A0271
+P08893779A0229
+P06895663A0810
+P11058119A0957
+BC2GM083962510
+P10874044A0647
+P08055939A0707
+P03023970A0922
+P00415543A0320
+P04281856T0001
+P08929563T0000
+P09373651A0255
+BC2GM009941081
+P06772370A0342
+P07916689A0312
+P03753022A0000
+P09233809A0815
+P09819377A1209
+P01871135A0295
+P07202525A0200
+BC2GM097549804
+P07937112A0220
+P11160688A1726
+BC2GM070908421
+P02388685A0577
+BC2GM027306792
+BC2GM018246985
+P06259220A0464
+P09475724T0000
+P08684522A0415
+BC2GM046604998
+P07395750A0294
+BC2GM079564376
+P11149472A1257
+P02809651A0492
+P06435565A0648
+P08669676A1644
+P01566576A0605
+P08209423T0000
+P08246984A0923
+P10585480A0265
+BC2GM091144220
+P11474642A1451
+BC2GM062537861
+BC2GM034228721
+P10587460A0302
+P09163332A0275
+BC2GM050804040
+P07958898A1050
+P01808049A0262
+P07226440T0000
+P06627569T0001
+P02443028A0695
+BC2GM022542601
+P02351239A0693
+BC2GM043975609
+P01392012A0228
+P07897359A0354
+BC2GM055691020
+P08939891A0285
+P02004521A0266
+P03712050T0000
+P07937132A0819
+P11045607A0239
+P11039341A0180
+P01763106A0070
+BC2GM040125018
+P00668122A0414
+P01653238A1062
+P03371894A0355
+P06473252A1073
+P08973917T0000
+P07105635A0412
+BC2GM004649890
+BC2GM044977015
+BC2GM041669085
+P01544918A1240
+BC2GM056337043
+P03933784A0420
+P00879329A0176
+P00227393T0000
+P07853524A1944
+BC2GM078123829
+P02592543A0106
+BC2GM036804417
+P07306839T0001
+P11197328T0000
+P08921865A1293
+P08132574A0831
+P10891093A0000
+P10228795A0842
+P11200568A0830
+BC2GM046996485
+BC2GM031753625
+P01518833A0397
+BC2GM037547379
+P06155967A1132
+P03031602A1001
+P09989334A0964
+P08230452A0551
+P10885750A0236
+P00439716T0001
+P10747879A0607
+P10704338A0354
+P02026147A0000
+P07579704A0085
+P10623804A0808
+P00703932A0000
+BC2GM022719960
+BC2GM066127781
+P10085697T0000
+P00962222A0633
+P09506990T0000
+P09829916T0000
+P11062047A1208
+P08754840A0793
+P06704467A0539
+P02689439A0000
+BC2GM028364416
+P11127200A1024
+P01700272A0838
+P02493644A0588
+P06753902A0437
+P07745726A0960
+BC2GM074970735
+BC2GM006926838
+P07659757A0191
+P07440085T0061
+P10989777A1286
+P01190251A0335
+P00528144T0000
+BC2GM020792074
+P11123054T0000
+P03929610A0268
+P07954891T0000
+P03020001A0781
+P11399064T0000
+P08506317A0000
+BC2GM081881949
+BC2GM044414750
+BC2GM030750070
+P10974541A0389
+P09467707T0000
+P03540591A0330
+P02081463A0110
+P08164302A0547
+P10865940A0000
+P10675610A0279
+P05394352T0000
+P07607213A0140
+P11023832A1038
+P11408774X0893
+BC2GM080942212
+BC2GM086116473
+P01044338A0240
+BC2GM032189532
+P09517646A0149
+BC2GM063663214
+P07541589A0652
+P01771959A0442
+BC2GM035498745
+P03540853A0652
+P06513456T0001
+P10218357A0486
+P08668209A0406
+BC2GM048306473
+BC2GM015964287
+P10788320A1034
+P01468625A1080
+BC2GM083943524
+P01482912A0617
+P08628681A0364
+BC2GM030584049
+P05859016T0000
+P01860846A0663
+P01454819A0000
+P09118196A0281
+BC2GM058267325
+P06350092A0916
+P10721698A1195
+P11075929A1657
+P09575217A0000
+BC2GM018630607
+BC2GM096229187
+P06795832A0148
+BC2GM010453739
+P01708098A0922
+P10861906A1479
+BC2GM071468863
+P04084607A0663
+BC2GM070296233
+P01429724A0664
+P04418687T0000
+P09173733A0404
+BC2GM033317667
+BC2GM074024777
+P03436529A1066
+P10678968A1096
+BC2GM040090407
+BC2GM060645160
+P11414754X1099
+P09579789A0974
+P10579331A1225
+BC2GM041921266
+P00477794T0000
+P09397723T0001
+P08538382A1012
+P10648020A0151
+P08878045A0606
+BC2GM072060480
+P01725622A0292
+P09651394A0440
+BC2GM015848639
+P10874151A0000
+BC2GM006899273
+BC2GM025748861
+P02880841A0313
+BC2GM064087768
+P09149825A0151
+BC2GM075427191
+P01723962A0165
+P03024343A0372
+P05497793T0000
+BC2GM036041110
+BC2GM098002058
+P07768898A0492
+P10712599A0349
+P09655248A0000
+P10766556T0000
+BC2GM006411333
+P08208540A0000
+P02714525A0529
+BC2GM040580909
+P03378994T0000
+BC2GM085535477
+P10423193A1309
+P02620085A0656
+P04999086T0001
+P02181760A0311
+P11372959A1447
+BC2GM077359774
+BC2GM071264087
+P01000378T0000
+P07705627A1107
+BC2GM072420137
+P03935375A0414
+BC2GM023165643
+P02115111T0000
+P02103140A1088
+BC2GM070947450
+P02281118A1191
+BC2GM044104855
+P08139543A0427
+P11163932A0000
+BC2GM038486910
+P09531549A0658
+P01852438A0928
+P02575174A0229
+BC2GM031982996
+BC2GM050904596
+BC2GM049338650
+BC2GM026620474
+P04067540A0413
+BC2GM070791643
+BC2GM052589330
+P08308008A0201
+P01241437A0152
+P02176021T0000
+P08763953A0805
+P01388160A1102
+P09479498A0000
+BC2GM018705374
+BC2GM006738398
+BC2GM015090389
+P02740347A0644
+BC2GM023252709
+P01048968A0152
+P11404010A0235
+P08034486A0579
+BC2GM023056895
+P11101008A0649
+P09528768A0000
+P01098179A0167
+BC2GM018490469
+BC2GM015232187
+BC2GM098004575
+P09704927A0479
+BC2GM071783264
+P09279889A1124
+P10567589A1268
+P07499421A0237
+P07659515T0000
+P01993656A1860
+P08093616T0000
+P09233811A0072
+BC2GM046917309
+P08648665A0956
+P10872831A0000
+P07509472A1320
+BC2GM010227811
+BC2GM059603247
+BC2GM026944266
+P01310879A0000
+P09837913A0000
+P04014861A0000
+P08816498A0000
+P02680843A0724
+P11123701A0442
+P02378945A0487
+P00876722T0000
+BC2GM071742493
+P02241892A0681
+P03123310A0000
+P03067505A0688
+P02383693A0301
+BC2GM042108030
+P06467241A0000
+BC2GM050726449
+P02116537A1237
+P11170476A1546
+P08244034T0000
+BC2GM047223393
+P08764015A0284
+P03536682A0572
+P08884757A0653
+BC2GM054191583
+BC2GM032251939
+P06342141A0226
+BC2GM019597390
+BC2GM055081476
+P01358592A0752
+P11710233T0000
+P07622060A0967
+P05806615T0001
+P00227610A1593
+P09088416A0000
+P09706643A0206
+P07933101A0131
+P10820904A0000
+P09353343A0919
+P10647177A0599
+P09553686A0000
+P04239041T0045
+BC2GM084376040
+BC2GM023122487
+P11168422A0248
+P08535537A0000
+P09751114A1987
+P07813786A0641
+BC2GM041631891
+P02083230A0938
+BC2GM064373042
+P10835732A0911
+P06290899T0000
+P10640701T0000
+P04034220A0205
+P09749988A0000
+P08722011A0103
+BC2GM010446827
+P09020172A0964
+P02571924A0000
+P03143048A1091
+P06327292A0846
+BC2GM030261099
+P01557217A0272
+BC2GM020418673
+BC2GM025874563
+P00599601A0260
+BC2GM016116401
+BC2GM008312798
+P02333749A0411
+P08012566A0254
+P10838399A0525
+P00465829T0000
+P02519327T0001
+P01765095A0680
+BC2GM046362536
+P05742879T0000
+P10987301A0332
+P11279385A3917
+P08676266A0838
+P07742024A0121
+BC2GM068703036
+P11372882A1143
+P09238860A1974
+P08838144A0107
+BC2GM030553104
+BC2GM087773567
+P01532914A0067
+P08746605A0377
+P02504603T0000
+BC2GM024036486
+P10903733A0540
+P07516469A1025
+BC2GM098226809
+BC2GM023083522
+P02281948A0245
+P05049711T0000
+P10610716A1127
+P11525102A0970
+P08550470A1021
+P08252067A0917
+BC2GM081655876
+P06692631A0129
+P11023074A1105
+P05020660T0000
+P06234369T0000
+P07519481A1275
+P01321280A0494
+P10722661A0146
+P06467797A0233
+BC2GM089434490
+P08958137A0534
+P11432776A0421
+BC2GM003035581
+BC2GM067383084
+P06969638A0180
+P08114745A0953
+P09003410A0000
+BC2GM059483475
+BC2GM071845732
+P10602419A1253
+P07623825T0000
+P07829554A0257
+P01386897A0000
+P08387519A0000
+BC2GM008813180
+P07499848A0409
+P07282444A0075
+P07933116A0412
+P08469831T0001
+P08702517A0000
+P10604945A0731
+P02361812A1110
+BC2GM087025767
+P11030476A0685
+P02029468A0296
+BC2GM052715311
+P09150595T0000
+BC2GM097038641
+P07699632A0715
+P08648408A0792
+BC2GM024641386
+P07979810A0340
+P10034615T0000
+BC2GM034704877
+BC2GM013614335
+BC2GM067512942
+P08222384A0455
+P02113699A0372
+BC2GM041444754
+P08312243A0177
+P06709310A0000
+BC2GM028126771
+P09426068A0826
+P11034392A1072
+P06324089A0453
+BC2GM084941902
+P10802909A0478
+BC2GM049307951
+P08707516A0194
+P09359844A0674
+P02107073A0584
+P06203843A0757
+P02281330A0556
+P03597218A0901
+P08943354A0295
+P10779313A1842
+P09878256A0000
+P11553704A0674
+BC2GM025278730
+P03199436A1060
+BC2GM070003542
+BC2GM080820769
+P05890093T0000
+P09605137A0677
+P08195186A0000
+P07552974A0217
+P06545651A0346
+P01779769A0000
+BC2GM063198333
+P09468515A0621
+P01690812A0000
+BC2GM067523581
+BC2GM075459951
+P02169887A0360
+P09414074A0827
+P08612852A0553
+P02384265A0947
+P09421511A0827
+P10480937A0000
+BC2GM055980217
+P02911540A0478
+BC2GM045059476
+P02913368A1037
+P09707577A1047
+P02182240A0355
+P08668210A0000
+P08828152A1825
+P11685284X0000
+BC2GM084727485
+P07916327A0250
+BC2GM093717157
+BC2GM061400791
+P07639703A1703
+P08719832A0397
+P08101843A0151
+P10962738A0000
+P00676416A0320
+P07530502A0974
+P11295760A1374
+P08410042T0000
+P11274109A0129
+BC2GM065349890
+BC2GM080679474
+P06997203A0325
+P02637597A0362
+BC2GM015841458
+P07114083A0153
+P06208477A0000
+P05749438T0001
+P09121476T0000
+P08595012A0817
+P02483438A0498
+P07483285A0322
+P09117345A0945
+P09096958A0000
+BC2GM070522560
+BC2GM097326747
+BC2GM073091634
+P11092809A0823
+P11133830A0174
+P07973397T0001
+P08898866A0458
+BC2GM023843160
+BC2GM063318762
+P10942587A0981
+P08178490A0879
+P10648211A0000
+BC2GM025777984
+P02473619A0202
+BC2GM005819408
+P09834521A0000
+P04123217T0000
+P01934378A1219
+P02148508A1478
+P09760243A0970
+P03332022A1094
+P06524761A0596
+P01974550A0362
+P09383156A0691
+BC2GM040902360
+P08039422A0000
+BC2GM043315404
+P03984683A0000
+P03346157A0000
+P08960827A1169
+BC2GM000478841
+P02142240A0506
+P07642538A0744
+P08352268A0000
+P02454976A0944
+P09463964A0243
+P11085600A0123
+P08628251A1455
+P09474001A0825
+BC2GM044076816
+BC2GM031456280
+P09873291A0620
+P11124902X1337
+P08625924A0411
+P11274357A0724
+P08322117A1019
+P05210791T0001
+P08626667A1517
+P09820611T0000
+BC2GM011253634
+P00497494A0112
+P06957633T0001
+P07973364A0325
+BC2GM023937291
+P10606272A1241
+P07263745T0000
+BC2GM000019979
+P09568445T0000
+P09817131A0296
+P08119995A0814
+P09172812A0660
+P02567030A0482
+P07862162A0408
+P06309020A0473
+P07592467A0000
+BC2GM039889670
+P09858599A0392
+P01524549A0241
+P09865775A0162
+P08547205A1060
+P08945479T0000
+P11133741A0617
+P11036786A0628
+P03830255A0074
+BC2GM078789356
+P07582592A0545
+P06242113T0001
+P09925372A0458
+P02089054A0121
+P10647633A1685
+P03443144A0409
+BC2GM084448237
+P06295429A0412
+P06594105A0560
+P11910344A1119
+P02850967T0000
+P02935638A0000
+BC2GM007772947
+P00381505X0000
+BC2GM027280090
+BC2GM045795328
+P09092580A1354
+P10841601T0000
+P11469970A0873
+P10713161A0985
+P03183103A0000
+P00336354A0543
+P11486476A0147
+P02229282A0454
+P03017996A0731
+BC2GM051932313
+BC2GM085006579
+P05858571T0000
+P09045636A0789
+P09537651A0366
+P08631934A0000
+P09422727A0196
+BC2GM009468247
+P11145717A0936
+P09565584A0770
+BC2GM096642340
+P11416737T0000
+BC2GM061835240
+P11532856A1175
+P09985302T0000
+P07181985A0107
+BC2GM003488368
+P01185956A0722
+P11282395A1073
+BC2GM062141275
+BC2GM014101305
+P11341405A1154
+P01172917T0000
+P09944066T0073
+P08739209A0700
+P01694280A0000
+BC2GM085517047
+P11017876A0787
+BC2GM096609252
+P08151787A0355
+BC2GM001534399
+P02283873A0308
+BC2GM062117187
+P09594299A0468
+P03704087A0394
+P01744039A0511
+P10824958A1109
+P09499031A0000
+P09515921A1662
+P00693987T0001
+P03061301A1409
+P01747972T0000
+P07739542A1419
+P08090767A0000
+P09545312A1197
+P10652093A0139
+P06324121A0256
+P09197241A0770
+BC2GM041323158
+P07748502A0794
+P01585014A0000
+P11296288A1107
+BC2GM041774560
+P01428490A0671
+P02919832A0144
+P09099702A0692
+BC2GM026261296
+BC2GM099775528
+P11044097A0422
+BC2GM059554638
+P11071974A0155
+P11160738A1414
+P02113174A0064
+P09223042A0000
+P11278870A0123
+P01513114A1133
+P08631760A0609
+P08301702A1083
+BC2GM049617857
+P03040403A0155
+P01421145A1190
+P10578528A0730
+P09892642A0172
+P02833101T0000
+P01363166T0001
+P03110746A0146
+P07752886A0595
+P07945937A0358
+P10646820T0000
+P02052544A0641
+BC2GM051136020
+P08035517A0753
+P11354975A0850
+P08357834A0285
+BC2GM091989431
+BC2GM035321349
+P11484578A1132
+P03970191A0275
+P07887859A0998
+P08661104A0687
+P08961873T0000
+P11424992A0712
+P08084592A0145
+P08733123A0951
+BC2GM017792516
+P08386637A1220
+P10653359A1297
+P06101359T0000
+P02148291A0173
+BC2GM074570108
+P01648530A0000
+P08199204A0746
+BC2GM010201696
+P10612773A1210
+P10683244X2359
+P01495069A0392
+BC2GM037653411
+BC2GM050337073
+BC2GM031882943
+P01427457A0000
+P08585957A0101
+BC2GM000227172
+P08213747A0000
+BC2GM052697029
+P08887652A0341
+P11517190T0000
+P03963860A0137
+P09209312A0968
+P11177686A0243
+P01649318A0734
+P10982391A0425
+BC2GM065796546
+P04015988T0000
+P09776293A0777
+P11137296A0923
+P03571135T0000
+P09065170A0853
+P09440166A0857
+P09667482A0978
+P07450388A0406
+P02011924A0729
+BC2GM091155868
+P09168879A0219
+P09703213A0280
+BC2GM019838730
+P02166825A0198
+P10811908A0938
+P07295033A0513
+P09372950A1283
+P11223199A0751
+BC2GM066584690
+P08417117A0592
+P09564860A2315
+P07432288A0218
+BC2GM011323900
+P02283378T0000
+P08820642A0173
+P11121043A0074
+P09442024A0236
+BC2GM082413558
+P01470741T0062
+BC2GM062323081
+BC2GM072711375
+P05967610T0000
+BC2GM023227858
+P01784589A0000
+P05120197T0000
+P07972237A0665
+P06278424A0145
+P01406703A1435
+P08355063A0456
+P08534848A0188b
+P01928923A0000
+BC2GM020497918
+BC2GM037222335
+BC2GM012924248
+BC2GM043027311
+BC2GM039204419
+BC2GM065338169
+P10854699A0424
+P08856077T0000
+BC2GM039057912
+BC2GM058205876
+P01406677A0000
+P09808155A0813
+BC2GM049796840
+BC2GM039408846
+BC2GM061879889
+BC2GM041957406
+BC2GM014430266
+BC2GM031428839
+P02575567T0001
+BC2GM031373959
+P11389085A0290
+P07964918A0000
+P02906027A1156
+P08237112A0553
+P02458234T0000
+P02736482A0550
+BC2GM062583466
+BC2GM087329770
+P02204625A1130
+BC2GM028406999
+P06281759A1086
+BC2GM016475600
+P01429836A0457
+BC2GM071557168
+BC2GM046228270
+P07901121T0000
+P02072238T0000
+P11244733A0782
+P01101272T0000
+P04533208T0083
+P08754777A1214
+P08126096A0478
+BC2GM034605250
+BC2GM025315374
+P01549129A0356
+BC2GM016838790
+P08127950A0000
+BC2GM030292353
+P09025122A0374
+P00336547A0000
+BC2GM096046498
+P09151806A1125
+P01925092A0000
+BC2GM095732578
+P09645961A1158
+P08057762A0878
+P02557350A0632
+P08219227A0830
+P02160502A0471
+P05789870T0001
+P00574222T0000
+P10693246A0252
+BC2GM089976750
+BC2GM096040259
+BC2GM041801302
+BC2GM053199516
+P01652755A1492
+P01711041A0962
+P09285789A0712
+P09448574A0964
+BC2GM040811399
+P03115087A0515
+P07892353A0667
+BC2GM017190400
+P08643633A1187
+P11191208A0000
+BC2GM008458026
+P08771787T0000
+P09585253A1147
+BC2GM048779386
+P09683576A0542
+P02083546A0000
+BC2GM065065002
+BC2GM007356608
+P02126504A0602
+P06468694A0441
+P00927633T0001
+BC2GM084985682
+P07413806T0000
+BC2GM003267548
+BC2GM042842840
+P08451187A0267
+P09573187T0000
+P03300118A0392
+BC2GM038940991
+P06505014A1192
+BC2GM000816999
+P01460772T0001
+P11316127A0485
+P01408137A0974
+P07623821T0000
+BC2GM032722941
+BC2GM090808688
+P07776979A0702
+P11101847A0159
+BC2GM008491090
+P01141114A0188
+P07615634A0535
+BC2GM021026668
+P01496784A0939
+P08629348A0237
+P01331516A0103
+BC2GM064518776
+P02482293A1518
+P00155973A0387
+P00330364A0132
+P11106667A1061
+BC2GM068073142
+P08325883A0368
+P07799948A0777
+P04437406T0000
+P11333263A0240
+P04037809A0964
+P08129955A0572
+BC2GM082123096
+P11214177A1125
+P05172970T0001
+BC2GM011752487
+P11542677A0411
+P01731933T0000a
+BC2GM014952112
+BC2GM035226570
+BC2GM024789471
+BC2GM046888921
+P11162666A0442
+P02505087A1037
+P11355668T0000
+BC2GM076892506
+P06241980A0855
+P07560137T0000
+P02118612A0629
+P08600048T0000
+P08267658A0391
+P02442837A0060
+P07588603A1054
+P04214345T0000
+P03403412A0000
+P04760826T0000
+BC2GM057520621
+BC2GM098970669
+P09630245A0903
+P07933107A0991
+P09741391A0581
+P09427627T0000
+P07606548T0000
+P02800417A0332
+BC2GM026086766
+BC2GM004721098
+P08432137A0000
+BC2GM020757047
+BC2GM078674905
+P01840607A0294
+P08813900A1088
+P10562495A0188
+P08626667A1372
+BC2GM063898512
+P07698727A0386
+BC2GM019152487
+P09341192T0000
+P06218005A0948
+BC2GM011836972
+P01447139A0208
+P01131946T0001
+P08304301A0331
+P09570030T0000
+P07816808A1102
+BC2GM069598999
+P08497280T0000
+P00219565A0172
+P02002051A0276
+BC2GM092456996
+P01486836A0774
+P08306356A0000
+P09525105A0298
+P02017271A0502
+BC2GM016014528
+P02844767A1022
+P01374398A0951
+BC2GM057631357
+BC2GM021306881
+P01577819A0709
+P02307067A1348
+BC2GM075721646
+P08178446A1160
+P09366517A0835
+BC2GM083916737
+P00903772A0359
+P06931124A0109
+P06648156T0034
+P01824713A0964
+P11218739A0811
+P09737921T0000
+BC2GM014963504
+P11110040A0000
+P07933066T0000
+P08748033A0874
+P07835826A0195
+BC2GM084852812
+P09611877A0455
+P10762254A0954
+P09506439A2179
+BC2GM082618683
+P07959760A0763
+BC2GM048973712
+BC2GM010682095
+P07791768A0930
+P10799879T0000
+P11007954A0170
+BC2GM014138510
+P08804012A0662
+P10120952T0000
+P02034669A0293
+P10674484A0633
+P01856021A0577
+BC2GM029006862
+P10860131A0847
+P08044800A0550
+P10730763A1491
+P07633444T0000
+P11278563A0917
+P00340692T0033
+P11401105T0000
+P07192722A0682
+P09335298A2129
+P07519447T0000
+P01400217T0000
+BC2GM055024591
+P08649773A1374
+P06882578A0464
+P08138364T0000
+P10134977T0000
+BC2GM034162528
+P00636526T0033
+P11237038A0889
+P07677715A1076
+BC2GM049586226
+BC2GM086016998
+BC2GM088125306
+P11139605A0811
+BC2GM016575957
+P10839547A0978
+P03384033A0155
+P07264787A0351
+P08617800A0150
+P01923985A0111
+BC2GM005461741
+P08847723A2351
+P09547349A0000
+P02021630A1104
+P09582343A0000
+P08806693A0584
+BC2GM000030196
+BC2GM082788210
+P08106369A0000
+P03913522A0000
+BC2GM022311934
+P09635276A1608
+P09199286A0086
+P09866068A1058
+P09891061A0373
+P10754312A0798
+BC2GM071296895
+BC2GM003645917
+BC2GM038872278
+P04308979T0000
+P05781385T0000
+P08675608T0000
+P08922391A0304
+P09517989A0476
+P02236064A1178
+P01853796T0000
+P11239184A1340
+P02510242A0313
+P09813093A0624
+P08550476A0610
+BC2GM017992906
+BC2GM058534127
+P01419945A1386
+P11137296A1216
+P02437895A0000
+P03814493T0000
+BC2GM023719948
+P00133214T0064
+P07672822T0000
+P02883963A0000
+BC2GM097555294
+P10683072T0000
+P10684967A0000
+P03582149T0001
+BC2GM096342624
+P08995681A0518
+BC2GM080722657
+BC2GM037682924
+P07406527A0212
+P11051370A1906
+P06341139A0213
+BC2GM076697045
+P09561616A0142
+BC2GM069899033
+P02877124A0000
+BC2GM084258366
+P02236022A0000
+P08260635A0926
+P09781874A1061
+BC2GM085541430
+P08093642A0600
+P08702845A0000
+P07647570A0713
+P00664320T0000
+P09234720A1015
+P10920906A0759
+P09638485A0111
+BC2GM005683824
+BC2GM084802462
+P01999459A0795
+P10653693A0429
+P08769566A0000
+P01956491A0095
+BC2GM008286757
+BC2GM062434933
+P07079595A0848
+P08065324A0458
+P11268887A1174
+P03335444A0000
+P02225687A0546
+P11564871A1184
+P08566751A0788
+P09420219A0284
+P11518868A0559
+P08325720A0840
+P08386280T0000
+BC2GM053865645
+BC2GM049485558
+P07725980T0022
+BC2GM016763749
+BC2GM066547944
+P02446871A1021
+P03443573A0329
+BC2GM019520345
+P09447973A0168
+BC2GM079864843
+P00601401A0181
+P03965012A0163
+BC2GM087746443
+P06185014A0642
+P08421897A0000
+P09037032T0000
+P06760394T0001
+P06615053A0202
+P02182618A0168
+BC2GM096155639
+P09536901A0362
+BC2GM064814479
+P09680994A0169
+P07471210A0384
+P11075678A0298
+P08887678A0000
+P00807356T0001
+P02423773T0001
+BC2GM078153532
+BC2GM066457601
+BC2GM051756783
+P10999301A0000
+P01721884A0962
+BC2GM069162607
+P11309389A0273
+P00008171T0000
+BC2GM014585915
+BC2GM038217943
+BC2GM074827794
+P09094671A1192
+P11327698A0191
+P00898500A0246
+P03293844T0000
+P11150114T0000
+BC2GM043540576
+P01004298A0744
+P07612557A0635
+P08747078T0000
+P08952796A0743
+P08565330A1783
+P02323517A0557
+P10805747A0633
+BC2GM046561038
+P03207975A0709
+P11128312A1238
+P08900296A0000
+BC2GM086563474
+P03443566A0675
+P09869400A0203
+BC2GM048166276
+P11382701A0688
+P09108207A0306
+P11194147A1496
+P04752455T0000
+P09105530A0000
+P09088737T0000
+P08458849A0364
+P08569680A0636
+BC2GM075516743
+P08187177A0405
+P02751080A0176
+P01895384A0746
+P01863887A0174
+P03459385T0000
+BC2GM009205276
+P08394464A1080
+P02685461A0380
+P07721422A0241
+P07567830A0072
+P10952828A2638
+P11134033A0000
+P01429836A1205
+P09651321A0000
+P03826871A0000
+P09029104A0226
+P08649373T0000
+P07455042A0457
+P11302072A0508
+P02311544A0086
+P11230534A0688
+P04727344T0000
+P11463359A0167
+BC2GM081998478
+P07949205A0286
+P08516324A0000
+P07894021A1130
+P08647264T0000
+P08933640A0000
+P10600171A1066
+P07738026A0216
+BC2GM078178539
+P02789217A1323
+P03713187A0691
+P02831398A0346
+P08760776A1559
+P08892755A0186
+BC2GM034359599
+P09950394A0336
+P09171038A0219
+P10947274A0839
+BC2GM063257384
+P09753769A0362
+BC2GM060829915
+P09176837A0211
+P09733493A0493
+P03296212A0603
+P07534306A0444
+BC2GM044079043
+P00131739T0001
+P07867604A1777
+P10744974T0000
+P09135066A0653
+BC2GM010723108
+P10749849A0000
+BC2GM036305978
+P11106428A0635
+P07677836A1356
+P10973385A1423
+P09059039A0850
+P10527106A0384
+P09573244A0523
+BC2GM004899991
+BC2GM058726742
+BC2GM055577023
+BC2GM041118324
+P07208984A0000
+BC2GM056857198
+P10641688A0341
+P03383897A0189
+P10801860A0000
+P00725257A0452
+P07274042A0249
+P09987961A0093
+P09395470A0294
+P00913623A0242
+P10713155A0151
+P07870305A1015
+BC2GM095725237
+P09490676A0800
+P10645921A1320
+P11105717A0123
+P02691811A0355
+P03757294A0414
+P01420579A0292
+P02830282A0155
+P10772856X1492
+P08617237A0489
+P08998115A0114
+P09665720A0325
+P07545510A0735
+P03494649A0472
+BC2GM067301071
+P04495034T0000
+P07474772A0274
+P08486035T0000
+P03185322A1305
+BC2GM070795322
+BC2GM033054784
+P02157764A1115
+P07910716A0359
+BC2GM036083685
+P08877103A0081
+BC2GM047855598
+P01765407A0866
+P09393875A0873
+P10865838A0000
+BC2GM076012440
+BC2GM040518813
+P01943184A1050
+P06950004T0047
+P08657157A0000
+P02958204A0175
+P03863561A0405
+P02793216A0876
+P09368026A0000
+P07498791A0680
+P06953957A0503
+BC2GM059988355
+P03066131A0000
+P00304806A0760
+P09713584A1193
+P01464329T0000
+P09653182A1298
+P09638342T0000
+P09139910A1572
+P09032275A1133
+P08091655A0000
+BC2GM006399626
+P07528772A1539
+P08496185A0484
+BC2GM022006150
+P08422975A1205
+P01300914A1066
+P00384744T0000
+P06290859A0426
+P02919483A0091
+P07865787A1086
+P08675821A0657
+P02529378A0536
+P02008982A0463
+P03484075T0001
+P09560430A0000
+P03027661A0000
+P07860208A0000
+P04640155T0045
+P06230499A0128
+BC2GM093786389
+BC2GM048518411
+BC2GM075900069
+P06426493A0331
+P10567582A1334
+P07791776T0000
+P08864219A0178
+P11040101A1180
+P09673037A0358
+BC2GM041364730
+P11251697T0000
+P00822611A0467
+P10653733A0596
+P09043534A1600
+P08079268T0028
+P07623807A0162
+P08624445A0257
+BC2GM052108283
+P08078473A1107
+P11274179A0610
+BC2GM080178845
+P10951848A0230
+P09458030A0192
+BC2GM027361300
+P08015672A1282
+P09817601T0000
+P09528858A0205
+BC2GM044737613
+BC2GM079948235
+P09973607A0254
+P01619114A0383
+P06848729A0000
+BC2GM035901068
+BC2GM008088904
+P09767593A0130
+P09576915A0269
+BC2GM047130607
+P07829519A1251
+BC2GM074194450
+P10758726T0000
+P08760286A0696
+P09682897A0218
+P09892422A1096
+P08678959A0640
+BC2GM065804496
+P05553261T0000
+P07084617A0204
+P06051644T0000
+P08370119A0642
+P07675445A0463
+BC2GM003829554
+P09588228A0370
+BC2GM090178909
+P09090054A0186
+BC2GM000099421
+P00885562A0281
+P07903670A1202
+BC2GM066695616
+BC2GM006001053
+P08484891A0000
+P09151152A0174
+BC2GM090237633
+BC2GM096199881
+P08217862A1336
+P11118712A1296
+BC2GM084799105
+P11319098A0164
+P09492038A0352
+P08542026A0792
+P08978996A0000
+P07844201T0000
+P10629938A1352
+P02868446A0184
+P11069307A0546
+BC2GM008948246
+P11403173A0192
+P09092675A0283
+BC2GM012126360
+P06237518A0117
+BC2GM017027776
+P06330478A0304
+P02341669A0000
+BC2GM082165105
+P09861099A1011
+P09506959T0000
+BC2GM077691653
+P03178161A0000
+P08535138A0857
+P02592640A0466
+P11156484A0223
+P10884978A0633
+BC2GM055876986
+P08633855A1064
+P09797189A0559
+P01012640T0001
+P02522297A0000
+BC2GM029605480
+P01655126T0000
+P10802669A1434
+P05787318T0000
+BC2GM032017565
+P09488491A0000
+P10805738A0799
+P04543036T0001
+P11369106A0428
+P07888306A1659
+BC2GM003098775
+P05177935T0001
+P09215891A0000
+P05782943T0001
+P01884998A1135
+P09583592A0263
+P11524823X0001
+P02526165X0000
+P08265602T0000
+P10193950A0478
+P09402029A1632
+P09430668A0172a
+P03403480A0299
+BC2GM068691299
+P09626662A1076
+BC2GM022742805
+BC2GM064815025
+BC2GM040848172
+P10601344A1653
+P08621420A1166
+BC2GM083941161
+BC2GM077069782
+P09324988X0000
+P08306834A0866
+BC2GM085827097
+BC2GM053146893
+P11312120A1311
+P03743702A0158
+BC2GM032430456
+P03738919A0000
+P11181995A1093
+P07429009T0121
+BC2GM030060311
+BC2GM089330500
+P08952965A1182
+P11108720A1130
+P10647817T0000
+P08283531A0700
+P11160096A1067
+P09165004A1700
+P08664462A1404
+P01248124A0281
+BC2GM033388156
+P07636187A0585
+BC2GM032512561
+P10732669A1336
+P08732665A0000
+P01124944A0830
+BC2GM096526830
+P09267431A0000
+P07978229T0000
+BC2GM049289655
+P08148463A0000
+BC2GM025711637
+P03375184A0000
+P06835516A0000
+BC2GM091903894
+P02971710A0734
+P02001033A1907
+P11359827T0000
+BC2GM022584300
+P09130718A0497
+P11266558A1470
+P01309244A0798
+P08575618A1138
+P08709831A0599
+P01985920T0000
+P02282815T0000
+BC2GM036761066
+P06849842T0000
+P01651232A0152
+P11140472A0497
+P09351823A0414
+P10834781A0693
+P00361059T0000
+P07658262A0944
+P01569015A0120
+P09806546A1270
+BC2GM034608401
+P01469047A1606
+P01443748A1190
+P09420671A1190
+BC2GM020095584
+P10564231A0315
+P02592961A0327
+BC2GM070700185
+P11437660A1219
+P11254134A0648
+P03062370A0000
+P01420223T0000
+P00635194A0093
+P08103935T0000
+P11096662T0000
+BC2GM039440214
+P09018122A1389
+P09504423A0114
+P02386485A0554
+P08717391A0466
+P08091669A0828
+P02521674T0000
+BC2GM023032582
+P06527379T0044
+P03457330A0271
+BC2GM045195775
+P06972443A0375
+P01658468A0123
+P03185540T0000
+P10684941A0722
+BC2GM029220064
+P01225339A0590
+BC2GM022819615
+P08675769A0158
+P09965234T0000
+BC2GM025821174
+BC2GM024341758
+P11796977T0000
+P02590097A0093
+BC2GM004210078
+P07237123T0000
+P07891685A1051
+P03982288T0000
+BC2GM047579187
+P01810154A0491
+P07252346A0223
+P05501347T0001
+BC2GM049023434
+P01147436T0000
+P09199413A0518
+P00267764A0651
+P07951874A0320
+P09649537A0000
+P02124710A0193
+P10625438A1429
+P07539119A0985
+BC2GM020677635
+BC2GM032656820
+P09418861A0623
+P02684159A0870
+P02164604A0399
+P09257651T0000
+P02065022A0747
+P07562775A0596
+BC2GM064809845
+P03198525A0164
+BC2GM066107969
+P09396823T0000
+BC2GM024886173
+P10054976T0000
+P09157100A0583
+P07191972A0391
+BC2GM093619245
+P09449018T0000
+BC2GM079539609
+P06173032T0000
+P09407090T0000
+P04002131A0506
+P09084176A0601
+BC2GM038900690
+P08921667A0294
+BC2GM016146952
+P01019207A0232
+P09185183A0089
+P11251951A0000
+BC2GM056432965
+P07941739A0000
+BC2GM005272522
+P09495771A0379
+BC2GM073475138
+BC2GM003632823
+P02006558A0000
+P07629123A0885
+BC2GM055969816
+BC2GM036804385
+P10184191T0045
+BC2GM012170235
+P09243505A1194
+P11175333A0336
+P03401060A0000
+BC2GM092925197
+BC2GM067565355
+P01316903A1040
+P10750524A0724
+BC2GM003302721
+BC2GM083277547
+P01441120T0000
+P08886845A1274
+P07829057T0000
+P02542612A0530
+P11443999A0573
+P01113908A0475
+P09321406T0000
+P11143384A0267
+P08321227A0854
+P01333053A0110
+P04325736T0001
+P07282943A0097
+P10965905T0000
+P06152844T0000
+P03022129A0842
+P11470914A0305
+BC2GM027981774
+P10890911A0470
+P10619353T0000
+P08388543A1263
+P01989561A0100
+BC2GM032584152
+BC2GM090921453
+P11306463A0383
+BC2GM031127519
+P08020965A0465
+P08601283A0875
+P08844577A0000
+P09180687A0096
+P00663166A0000
+BC2GM023767363
+BC2GM080507984
+P09845043A0000
+P11088635A0200
+P00173860A0475
+BC2GM033082377
+P09294471A1198
+BC2GM037968390
+P06864837T0000
+P07419485A0158
+P02246803A0692
+P09815948A1065
+P08808924A0326
+P03138449A0759
+BC2GM020608832
+P06441624A0263
+P11530684A0667
+P11430976X0000
+BC2GM048416316
+P11391531A1157
+P02597549A0964
+BC2GM013080012
+P11566996A1391
+P02206789A0002
+BC2GM022050616
+P07180901A0539
+BC2GM094263980
+P07375864A0431
+BC2GM076163727
+P03004364A0775
+P01435698A0000
+P00639410T0000
+P11108523A0326
+BC2GM031146030
+P09170159A0721
+BC2GM067333955
+P08989025A0359
+P09017443A0734
+P09460171T0000
+P02647403A0000
+P06946314T0000
+P11028131A1374
+BC2GM058702886
+P08692892A0330
+P09325273A1240
+P02010912A0366
+P08649425A0373
+P07806820A0091
+P11283010A0701
+P08844712A0000
+P10710499A0000
+P01337142A2043
+P04676734T0000
+P11387940A0647
+P03486405A0341
+BC2GM053648425
+P07563072A0773
+P08035833A1556
+P09971806A1585
+P01874752A0948
+P10787804T0000
+BC2GM062143954
+P02982332T0001
+BC2GM048760172
+P10861086A0904
+P08820324A1699
+P07898178A0849
+P09415711A1348
+BC2GM033019840
+P10725433A0543
+P01850893A0286
+P01978857A0504
+P08481004A0321
+BC2GM017837173
+P11004369A0000
+P07618280A0550
+BC2GM052866692
+P09881692A0094
+BC2GM011520579
+BC2GM022884107
+P10925159A1353
+P08816460A1769
+BC2GM019371061
+P07668043A0277
+P02358975A0709
+P08979828A1561
+P01398071A0526
+BC2GM014834356
+P10767560A0105
+P03536864A0000
+BC2GM088666537
+P01459447A0484
+P02159470A1432
+P00627129A0944
+BC2GM056080482
+BC2GM064277567
+P09343982A0890
+BC2GM025336946
+P01707659A0458
+BC2GM031587452
+P11528253X1211
+P07742917T0001
+P11416012T0000
+BC2GM078543266
+BC2GM042698596
+BC2GM071297366
+P11380370A0000
+P09377374A0000
+P07789275A0325
+P09006555A0738
+P02488148A1156
+BC2GM028814476
+P09038166A0818
+P01538403A1058
+P09222057A0176
+BC2GM055311228
+BC2GM017164841
+BC2GM020087373
+P02299543A0317
+P01084413A0271
+BC2GM045793760
+P08576179A0126
+P11278819A0565
+P09881666A0535
+P03379058A0188
+P01140184A0342
+P00715753A0241
+P04024685A0650
+P09469833A0533
+BC2GM065739819
+P08932385T0000
+P08509430A0372
+P08188603A0230
+P01901946A0243
+P11325195A0661
+P02456827A0899
+P02166040A0385
+P08524241A0212
+P11227182A1475
+P11410679A0000
+P10568744A0728
+BC2GM047597727
+BC2GM057633611
+BC2GM055737184
+P06443714T0001
+P09765277A0000
+BC2GM096245457
+P04826272T0074
+P01655713A0294
+P07516466A1054
+BC2GM009256073
+BC2GM042327107
+P11311464A0362
+P04088733T0001
+P01875922A0770
+P09886850A0145
+P01352113A0231
+P07863992A0908
+P09601007A0223
+P01178153A0056
+BC2GM067442667
+P07678695A0604
+P05284310T0000
+BC2GM094635943
+P09235998A0788
+P11160902A0962
+P10764970A1009
+BC2GM078763746
+P01899846A0862
+P00464387A1185
+P08445792A0469
+P11313946A0449
+P08703010A0905
+P08804389A0893
+P09176340A1194
+P11554727A0890
+P09130595A0478
+P10727247A0461
+BC2GM011268636
+P09827724A1362
+P10679065A0711
+P08809680T0000
+P07636984A1349
+P02159559A0779
+P07476164A1602
+BC2GM090911628
+P11278290A1220
+P03964489A1195
+P01492463T0001
+P10739408A0896
+BC2GM043004762
+P10483945A0641
+P09524250A0767
+P07548425A0000
+BC2GM096261608
+P03036415T0000
+P08869358A0121
+P01329039A0239
+P10931950A0869
+P07116298A1079
+P11369066A1210
+P03014515T0000
+P09388198A1396
+BC2GM040034463
+P07836218A0128
+P09096229T0000
+P11007949A1607
+P09028089A0183
+P02371273A0144
+P07959015A0478
+P01509798A0520
+P10614857A0584
+BC2GM092424481
+P10628755A0000
+P01504178T0000
+P07695629A0489
+BC2GM028564481
+BC2GM021675012
+P09343433A0360
+P07935383A0108
+P01579537A0000
+P01982061A0615
+P06807659T0001
+BC2GM082066284
+BC2GM066299877
+BC2GM084151426
+P02403634A0788
+P08794547A1403
+P01913955A0177
+BC2GM038291943
+P09396796A1173
+BC2GM031921056
+BC2GM086105729
+BC2GM093464345
+P09628375A0700
+P02405589A0000
+BC2GM008619056
+P08663120T0000
+P11413310A0148
+P11131634A0955
+P08285710A0634
+P09417108A0000
+P11248463A0187
+P02411513A0667
+P09214274T0001
+P07990136A1124
+BC2GM018016290
+BC2GM051960304
+BC2GM092131835
+P10815410A0000
+P08303233A0313
+P06977605T0000
+BC2GM097330592
+P07559524A0741
+P03448035T0000
+BC2GM033441009
+P05642051T0000
+P00030937A0119
+P08863824A0509
+P00827364A0000
+P11358958A0878
+P09118704A0771
+P07678051A1303
+P11154491A0322
+P09042755T0000
+P07590657A0624
+P08600028A1129
+P03384272A0145
+P11873003X0000
+BC2GM020401171
+P06391496T0000
+P08377199A1432
+P08666241A0930
+P10799576A0196
+P09111367A1098
+P11400644A0435
+BC2GM088223982
+P01545818A0696
+P09582267A0326
+BC2GM032924091
+BC2GM080095863
+BC2GM026151864
+P09650299A0000
+P09735286A0599
+P09725651A0077
+P02547778A0786
+P01425921A1286
+BC2GM026075633
+BC2GM044595672
+P09799237A0624
+P00627202T0000
+P08713933A0606
+BC2GM005593098
+BC2GM073047103
+P03911965A0513
+BC2GM003445386
+BC2GM092679978
+BC2GM070120777
+P07666538A0000
+P09423123A0000
+P00748978T0000
+P07997174A0936
+P11220857T0000
+P01057137A0192
+P10699684A0661
+BC2GM055133205
+P09929088A0000
+P11311687A0231
+P09813259A1097
+P01901950T0000
+P09294422A1376
+P07693708A0000
+P03228785A1047
+P02481429T0000
+BC2GM020915741
+P02270096T0000
+P02863492A0544
+P11496617A0301
+P09130700A0676
+P02195715T0000
+P07530549A0956
+P08634290A0000
+P10653550A1120
+P08766781A0322
+BC2GM045159577
+P08691106A0733
+P10650104X0284
+P10633499A1306
+P01779433A0694
+P08810323A0735
+BC2GM098918087
+P06319072A0711
+P09593302A1165
+BC2GM014908370
+P07217523A0364
+P06286443A0498
+P02732341A0000
+P10862289A0289
+BC2GM063546497
+BC2GM070010580
+BC2GM092286757
+BC2GM067263204
+BC2GM076965048
+P03335398A0568
+P01720555A1087
+P03618039A0126
+P07579695A0693
+BC2GM012794802
+BC2GM059456391
+P09931391A0944
+BC2GM088354300
+P03559232T0000
+P07707544T0000
+P08498570A1118
+P00303189A0247
+P08437521A0000
+P07784870A0119
+BC2GM003073174
+P11318608A1155
+P06089575A0464
+BC2GM076852913
+P07770033A0978
+BC2GM028852576
+P07413242A0000
+P01206896T0001
+P07630934A0343
+P07879204T0000
+P01973384A0206
+P09710589A1111
+P09178752A0574
+P03940818T0000
+P09657003T0000
+P08847403T0000
+BC2GM010221833
+P01075075T0038
+P04598670T0000
+P09461594A0000
+P09100202A0000
+BC2GM068917661
+P07937127A0645
+P07915144A0000
+P08396657A0452
+P06876317T0033
+P09188094A0934
+BC2GM049887251
+P02174861A0736
+BC2GM011249269
+BC2GM048180696
+P07640422A0649
+P08441869A0334
+BC2GM049762234
+BC2GM077944631
+P09459685T0001
+P10683244A1860
+P00565314A0293
+BC2GM012988556
+P03632739T0000
+P06340703A0324
+BC2GM043513819
+P05410590T0000
+BC2GM095821650
+P10567533A0818
+BC2GM096315697
+P08511994A0000
+P03195167A0104
+P08691962T0000
+P06099656T0000
+P09892662A0334
+P01123658A0000
+BC2GM056512837
+P10991648T0000
+P07488247T0000
+BC2GM023194685
+P11241356T0000
+BC2GM028948784
+P02901763A0977
+P11108151A0560
+P09123055T0000
+P02265055A0417
+P05174753T0001
+BC2GM083493191
+BC2GM038644966
+P08846775A0110
+P08643578A0000
+BC2GM028463998
+P08842143A0000
+P08762021A0156
+P09341158A0167
+BC2GM098314451
+P11592532A0188
+P00621626T0000
+P01692962A0980
+P08468320A0941
+P08194139A0498
+BC2GM075408371
+P09442172A0908
+BC2GM069784959
+P07784942T0001
+BC2GM086763772
+BC2GM078051387
+P02724227T0000
+P07501016T0000
+P09849961A0387
+BC2GM093787356
+BC2GM054416322
+P02443924A0083
+P01970926A0000
+P03721666A0000
+P06785113A0337
+P07202919A0142
+P04001413A0093
+BC2GM020549068
+BC2GM069591323
+BC2GM010596597
+P02899792T0000
+BC2GM087369574
+P03015611A0331
+P00583004A0445
+BC2GM072127832
+P03463537T0001
+BC2GM026662709
+P07844142A0640
+P08474464A0348
+P01872856A0277
+P07588777A1524
+P08125319A1085
+BC2GM061275857
+P06373855A0000
+P10651805A1600
+P08254738A0428
+P08513025A0000
+P07601078A1003
+P11345445A0533
+P01304515A0178
+BC2GM063573521
+BC2GM090917188
+P08630583A1056
+BC2GM068752767
+BC2GM089678817
+P11087141A0977
+P09140474T0000
+P07919540A0240
+P07466831A0714
+P07369458A0606
+BC2GM069379364
+P08473967T0000
+P06744024A0000
+P03545955A0751
+P08420230A0544
+BC2GM077706962
+P10801330A1714
+BC2GM039293973
+P08281634A1801
+P01328854T0000
+P03701640A1178
+BC2GM088776852
+BC2GM095367875
+P00066874T0000
+P11509673A0574
+P09986796A1761
+P01542565T0000
+P03485064A0135
+P09367426A1354
+BC2GM004658722
+BC2GM029087061
+P08973917A0632
+P11223256A1212
+P02262439A0508
+BC2GM005118324
+P07559488A0440
+P11448051A0093
+P11406277A0598
+P07385920A0189
+P02110148A0423
+P03953361A0000
+P02964329A0000
+P02061333A1359
+P03679407A0556
+P08798610A0843
+P06582285A0222
+P07941750A0344
+P08406419A0155
+BC2GM031784532
+P03007281A0905
+P11576776T0081
+BC2GM023547323
+P08509333A0843
+BC2GM067535519
+P08301841A0000
+P02252891T0000
+P07413144T0018
+BC2GM049247911
+P11179400T0000
+P07969132A0268
+P07588240A0000
+BC2GM001234519
+BC2GM082412019
+P09751458A0845
+P09446616A0780
+BC2GM046993980
+BC2GM035984243
+P11035867A0000
+P09126622A0466
+P10972980A0295
+P03083441T0000
+BC2GM060824736
+P01511231A0085
+BC2GM083274778
+P10208865A1246
+P07565713A0634
+P01903404A0688
+P00033873T0001
+P02963517A0453
+P11042199A0572
+BC2GM013081581
+P07469692A0000
+P03522105A1011
+P02511150T0025
+P02139473A1603
+P09863624A2301
+BC2GM083699993
+BC2GM035316486
+BC2GM087506083
+P04429269T0000
+P09138492A0806
+P02712450A0989
+P07822161A1172
+P05732641T0001
+P00100791A0425
+BC2GM022069821
+P07758246A0469
+P11139469A0402
+P03788231A0802
+P11263664A1085
+P00768220X0000
+P08421823A1041
+P09528766A0915
+P09790771A0956
+P09738087A0583
+P02489032A0000
+P11849796A0452
+P10945010T0001
+P09995897T0000
+BC2GM086417938
+P03863231A0530
+P08306959A0278
+P03543485A0069
+P09813207A0434
+P07034479A1050
+P07862154A0340
+P11528127A1402
+P01674177T0001
+P08144852A0000
+P07651141A0265
+BC2GM004900930
+P01740448A1735
+P02508306A0528
+P08188606A1034
+P04291759T0048
+P09311796A0218
+BC2GM057071865
+P02843694T0001
+BC2GM024519999
+BC2GM017085693
+BC2GM036721419
+P07298259T0000
+BC2GM039462814
+P02298741A0809
+P08415637A0000
+BC2GM092052838
+P02145268A0746
+BC2GM093591586
+P08156332T0000
+P07627317A1502
+P01447189A1546
+P09488466A0695
+P08030243A1011
+BC2GM015590289
+P09296251A0163
+P07075024A0540
+P01637758A0532
+P03679756A0830
+P00606849T0000
+BC2GM098476170
+P03666957A0219
+P07431059A0000
+P10972688A1272
+P11230889A1151
+P06404842A0127
+P07699845A0537
+P06181216A0070
+P09315633A0333
+BC2GM033281770
+BC2GM088202512
+P11181548A0214
+BC2GM009453021
+P09642214A0244
+P06501086A0165
+P08291233A0000
+P03652083A0720
+BC2GM030532264
+P00409927A0570
+P08057421A1583
+BC2GM063896502
+BC2GM049920668
+P07752644A1031
+P11228700T0000
+P09478976T0000
+P09533109A0449
+P10781611A1023
+P11518505A0107
+P10729221A0798
+P08178572A1118
+BC2GM089636250
+P09806858T0000
+P11422200A0000
+P01947449A0191
+P02566613T0000
+P04488271T0001
+P00954819A1041
+P10805286A0914
+BC2GM001917913
+BC2GM014733001
+BC2GM063968223
+BC2GM005484781
+P10858355A0920
+P04973523T0000
+BC2GM096057654
+BC2GM024331581
+BC2GM054625415
+P08140847X0001
+P01363080A0710
+P02162754A0801
+P07453919A0000
+P01846489A1119
+P02179188A1223
+P09704006A0224
+P01477021A0394
+BC2GM049482687
+BC2GM009169433
+P00083846T0000
+P08589735A0577
+P00704675A0199
+BC2GM035995772
+P09192842A0988
+P10001541T0000
+BC2GM082256131
+P09388271A1243
+P01921463T0000
+P03312033A0501
+BC2GM054235351
+BC2GM051328807
+P10972894A0488
+P09524229A0000
+P08108099T0000
+P10825294A0473
+P04385060T0000
+P11277913T0000
+P07112654A0388
+P11040219A0548
+P10873158A0000
+P11279207A0904
+P11215622A0949
+P10905349A0329
+P03861687A0000
+P09447963A0223
+P03878585A0507
+P00420460A0291
+P11125363A0525
+P09940132T0000
+P07651424A0487
+P07190869A0316
+P10756100A0457
+BC2GM038586241
+BC2GM085223521
+P02116071A0000
+P03090237A0202
+P07511496A1511
+P10604246A0523
+P07528667A0834
+P08585994A0567
+BC2GM006761039
+P11353392A1127
+P01252223A0347
+P09036529A0343
+P09844106A0835
+P01752441A0000
+P04164595T0020
+P01982190T0001
+P07323063A0000
+BC2GM084592604
+P09328824A0000
+P07217329A0000
+BC2GM012849815
+P07377378A0143
+P11211936A1490
+P07708488A0151
+BC2GM055184868
+P01157191A0536
+BC2GM097617253
+BC2GM030304217
+P10871379A0261
+P06325415A0757
+P08237171A0000
+P10724436A0085
+P09393966A0190
+P07225540A0193
+P08530105A0308
+BC2GM073939713
+P06897114A0240
+P07607342A0703
+P06808529A0167
+P09913308T0000
+BC2GM073834099
+P09806857A0854
+P07682842A0294
+P09267306A0381
+P09692965A0904
+P05357390T0001
+P05135168T0000
+P09656414A0220
+P09891085A0815
+P01324404A0813
+P09230384A1056
+P08388496A1117
+BC2GM047731031
+P07038189A2301
+BC2GM011847629
+P09525598A0325
+P10590368X0000
+P08663172A0311
+P02163382A0169
+BC2GM056965108
+P07018810A0002
+P07730795A0104
+BC2GM042434185
+P02123820A0000
+P07651424A0743
+P08589315A1029
+P11433024A0260
+P08881036A0351
+BC2GM007199944
+P08400928A0318
+P08139542T0000
+P02817724A0075
+P01348504A0757
+BC2GM089485975
+P11006331A0319
+BC2GM013162443
+P00383169A0000
+P02966671A0151
+P09529721A0000
+P11314046A0000
+P10771709A0291
+BC2GM024261949
+P00842522T0000
+P00930947A0629
+P08070654A0574
+BC2GM025329435
+P09473040A1303a
+P10838531A0675
+P06460889A0111
+P08605324A0434
+P07859301A0325
+P07681147A1420
+P09832505A0903
+P10031854T0000
+P10742216A0555
+P06321505A0401
+BC2GM012934099
+P09420239A1937
+P01324639T0000
+P09405195A0320
+P07037479T0000
+P07988945T0000
+P04947347T0000
+P11145563A0303
+BC2GM082618608
+P01380825A0622
+P02531203A0241
+P06521999A0677
+BC2GM025052466
+P08621448A0862
+P11188971A0000
+BC2GM054816469
+P03038643A1374
+P09933848A1008
+P02830265A0341
+P05368978T0000
+BC2GM084929620
+BC2GM018485716
+P09427544A0000
+P02242222T0000
+BC2GM016890014
+P04051521T0001
+P11764062A0000
+P07898589T0000
+P10861906A0999
+P10750020A0843
+P11006284T0000
+P08223823T0000
+P11367523A2624
+P01970801A0925
+P01193458T0001
+P11162936A2727
+P09002648A0202
+P08878037A0000
+P06278544T0027
+BC2GM088054752
+P11016737A0275
+BC2GM059462976
+BC2GM047717064
+P02343033A0000
+P01791363A0208
+P11278461A0637
+BC2GM080121917
+P11000250A0200
+BC2GM099591467
+P07779812A0000
+BC2GM013239156
+P07081327A0546
+P07714758A1193
+P02969316A0002
+BC2GM021272736
+P08955402A0288
+P08138180A0593
+P10633075A1111
+P08770920A1220
+P09348226A0852
+P01048020T0000
+P01898164A0839
+P09689919A1192
+P08331067T0000
+BC2GM003946244
+BC2GM024780744
+BC2GM081973466
+P07490770A0267
+BC2GM031955724
+BC2GM060497618
+P03763241A0446
+P02502960A0762
+P10782640A0444
+P00713525A0268
+P08741280A0374
+P08923258A0353
+P06095372A0435
+P02995999A0000
+P05719746T0001
+BC2GM067873375
+BC2GM088957012
+P00417166T0000
+P08383214A0389
+P01656675A0236
+BC2GM007186546
+P08824805A0832
+P09202147A0866
+P02004705A0686
+P02559630A0270
+BC2GM035284828
+P03516189A0406
+P04925617T0000
+BC2GM099607997
+P02789062A1420
+P07880650A0493
+P09420252A0092
+BC2GM055057838
+P02958660A1094
+P09464525T0000
+P07663160A0287
+P00701144T0000
+BC2GM021603045
+BC2GM052103407
+P01529530T0000
+P11117263A0570
+P07917016A0581
+P07509624T0000
+BC2GM011317190
+BC2GM042227725
+P07283110A0000
+P10585417A1412
+P02895472A0178
+P02752303A0000
+BC2GM059007743
+P09840822A0462
+BC2GM042797974
+P08614403A0989
+BC2GM068997634
+P02007045A0092
+P09164856A0980
+BC2GM071733083
+P02686980A0000
+P03688301A0129
+P03668736A0177
+BC2GM070673792
+P09181130A1067
+P00792847A0000
+P02713994A0482
+P02512010A0801
+P03014593A0681
+P08350061A0209
+P05822499T0034
+P08413215A0327
+P01675154T0000
+P08088818A1053
+BC2GM068306112
+BC2GM011270186
+P11428487T0000
+BC2GM054534012
+P08759870A1128
+BC2GM075306454
+P08542027A1471
+BC2GM012664119
+BC2GM052977122
+P11849417A0900
+P08892755A0981
+P11315633A0920
+P01408090A0572
+P02455821A0099
+P04909355T0000
+P07576178A0000
+BC2GM081183440
+P08289831A0290
+P06671385A0856
+P10593950A1113
+P02828926A1870
+P00985110T0001
+BC2GM031297991
+P03466730A0210
+P07743515A0223
+P08533472A0777
+BC2GM021733424
+P07487067A0592
+P09727046A0000
+P07936640A0900
+P01313894A1179
+BC2GM094732618
+P01398098A0770
+P07857163A0551
+BC2GM048059334
+P10033973T0000
+P09305592A0000
+P09238850A0785
+P08813766A0605
+BC2GM092243053
+P03651330T0000
+P08417330A0149
+P01922734T0000
+BC2GM035428099
+P07609372A0261
+BC2GM002567582
+P02586513A0622
+P11403663A0359
+P08524292A1022
+P01264640T0028
+P11902068T0000
+BC2GM076181563
+P08454591A0692
+P08524294A0652
+P00657551T0000
+BC2GM030739462
+P08139542A1229
+P03417104A0536
+P01429624A0328
+P08922385A0622
+BC2GM083917947
+P02705556A1049
+P07964458A0179
+P07629150A0155
+P01385462A0151
+BC2GM040314258
+P08058326A0463
+P08495786A0085
+P09029956T0000
+P08223425T0000
+P02403926A0307
+BC2GM030329937
+P02668691A0570
+P02646007T0000
+P10850849A0730
+P08471796A1654
+P00851286A0375
+P09716095T0000
+P07073520A0153
+P02132636A0188
+P08232412A1342
+P02846852A1459
+BC2GM004690060
+P07964814T0000
+BC2GM091917178
+BC2GM045332665
+P09398598A0256
+P09753775A0734
+P09686344T0000
+P06830033A0661
+P02607766A0000
+BC2GM065051600
+P10781990A0455
+BC2GM007741669
+P08286035A0587
+BC2GM076134275
+P07653094A0169
+BC2GM027384741
+P07016141A0238
+P09704857T0000
+P09622121A0525
+P07692668A0326
+P01992953A0247
+P09483596A0626
+P11255252A0961
+P06318078T0000
+BC2GM010522848
+P09819430A0000
+P10760950A1133
+P07816619A0000
+BC2GM068106933
+P06310608A0749
+P07909936A0672
+P02875224A1059
+BC2GM023331710
+P11311980A1049
+BC2GM097805959
+P06277159T0033
+P04041307A0614
+P01360294A0000
+P08253386A0800
+P06497671T0001
+P02326946T0000
+P04801663T0049
+P08062824A0626
+P07615541T0000
+P08993393A0498
+BC2GM061897910
+P11020375A0134
+P07479004A0421
+P10855793A1418
+BC2GM068822744
+P10907348A0508
+P09808441A0320
+BC2GM016530751
+P01903841A1449
+P01047895T0001
+P11331589A0113
+P10938102A1359
+P02176209A0954
+P11055786A0306
+BC2GM035122268
+P09518808T0000
+P09582635A0523
+P11032677A0230
+P02305014A0226
+P04970131T0001
+P10790390X0000
+P06370553A0444
+P10958698A0280
+BC2GM028611908
+P09920775A0075
+P04321861T0001
+P08825633A0304
+P08508774A0242
+P05938720T0000
+P01855255T0000
+P09365431A0314
+P07225300A0968
+P00755245A0000
+P00445720A0263
+P09369453A0273
+P03057259A0514
+P01339773A0778
+P09482902A0942
+BC2GM007318409
+BC2GM013622004
+BC2GM080956637
+P05372511T0105
+P09244282A1371
+P09578570A0200
+BC2GM004383808
+P00463973A0000
+P02142486A0367
+P11050084A0000
+P01431380A0244
+BC2GM044384474
+P10584138T0001
+P11278855A0205
+P03219107A0212
+P01009739T0001
+P02995967T0000
+P08906139A2935
+BC2GM005826415
+BC2GM089431747
+P02223652A0939
+P09020138A0833
+P07124743A1223
+P08057833A0573
+P06281786A1222
+P05154132T0000
+P01309815A0972
+P01782669A0496
+BC2GM062721233
+P06362602T0001
+BC2GM019547641
+P09786926A1372
+P09252879A0470
+P03280807A0000
+P09685021A0127
+P11050084A0888
+BC2GM069896778
+P02229068A0156
+P01708774A0203
+BC2GM028996943
+BC2GM029915444
+BC2GM049751751
+P10864989A0484
+P00646193T0000
+P11530829A0000
+BC2GM073846842
+P07524265T0000
+P09237695A0000
+P03326381A0423
+P03069046A0126
+P08421687A0397
+P07758167A1488
+P09131139T0000
+BC2GM036865431
+P11142380A0389
+P08441411A1260
+BC2GM028707148
+P09891707A0000
+P07540773A0576
+P07862141A0317
+P07683131A0885
+P09528987A1348
+P07463294A1216
+P10826946A1198
+BC2GM052594867
+P06212776A0000
+BC2GM032114855
+BC2GM090403592
+P09224811A0000
+BC2GM047470331
+P01331292A1425
+BC2GM089517365
+P07755914A0000
+BC2GM069603149
+BC2GM026059945
+P09651367T0000
+P09155024A0955
+P01812102A0101
+P00495097A0663
+P01449301A0710
+P08441394A1297
+P00941050T0000
+P11522584A0882
+P08975713A0454
+BC2GM099382056
+P01357190A0726
+P09079817A0928
+P11045180A1892
+BC2GM000160086
+P09849421A0332
+P06093354A0000
+BC2GM059940131
+BC2GM011982866
+P10869076A1384
+BC2GM061963337
+P09889306A0321
+P08383850A0206
+BC2GM035479139
+P02985812A0984
+P10831972A1091
+P00745775A0170
+P00564943A0444
+P06240448A0652
+BC2GM035976811
+P07623844A0639
+P08299725A0724
+P08230418A0812
+P06216125A0470
+P03150015T0001
+BC2GM003162436
+P11145590A0217
+P08922344A1539
+P08522530A1342
+P09271394A0558
+BC2GM070690502
+BC2GM036866383
+P01694525A0000
+P08622675A0587
+BC2GM083865368
+P02934891A0845
+P02603374A0383
+P00240518A0000
+P01437562A0462
+BC2GM092754644
+BC2GM071933956
+P01119658A0000
+P01423738A0639
+P03220077A0274
+P04040858A0000
+BC2GM024464549
+P07999066A0238
+BC2GM004396508
+P10564593A0428
+P07560662A0496
+BC2GM007792943
+BC2GM096383167
+P09030688A0435
+P03021050A0501
+BC2GM077505350
+P08750173A0000
+BC2GM010924622
+P04488232T0001
+P09372924A0758
+P11003471A1149
+P08995652A0812
+P09154797A0777
+P02391344T0000
+P09160881A0491
+P08524272T0000
+BC2GM030100060
+P09029159A0000
+BC2GM075850023
+BC2GM011015031
+P10779508A0897
+P04226360T0001
+P10894816A0836
+P08808275A1193
+P02133731A1572
+BC2GM085429283
+BC2GM071199911
+BC2GM058606403
+P01531214A0885
+P09015757T0000
+P11393463A0274
+P00868301A0043
+P09244100A0194
+BC2GM016387762
+P10582831T0000
+BC2GM080802212
+P09545638A0836
+P08201352A0239
+P07327097A0647
+BC2GM034262338
+P04039109A0139
+P05839844T0000
+P08299896A0626
+BC2GM078287872
+P09560221A0282
+P01379032A0495
+P07109788A0333
+BC2GM019562705
+P07806507A0121
+P09154795A0628
+P08550425A1401
+P08597108A0642
+P00622556A0111
+P08747343A0790
+P02220304A0501
+P07270991A0149
+P10853778A0316
+BC2GM011301969
+P11121490A0000
+P11094066A1194
+BC2GM025350751
+P10616948A0998
+P04487835T0001
+P11469737A1791
+P02585492A1005
+P07706287A0698
+P08450015A0175
+P11062257A0977
+BC2GM075887001
+P01871971A0836
+P07499401A0444
+P03964855A0254
+P07828852A0153
+P10781423A0993
+P06935514A0000
+P09736715A0729
+P11478627A0573
+BC2GM041011754
+P10852485A0477
+P08223875A0711
+BC2GM003734508
+P11152070A0573
+P11129515A0000
+P01398068A0948
+BC2GM084639431
+P08873159A0791
+P11562870A0892
+P03651840A0266
+P10725017A0673
+P10628971A0824
+P02148508A0374
+P11522431A0673
+P03038891A0935
+P09177857A0000
+P00958550T0001
+BC2GM095197069
+P08332495A0408
+P09169420A0000
+P11152521A0181
+BC2GM097589583
+BC2GM075443045
+BC2GM026957766
+P10810083A1283
+P09790771A1032
+P07876210A0275
+BC2GM023811799
+BC2GM031585190
+P11095981A0254
+P04082592T0000
+BC2GM014154951
+P10733581A1391
+P09446600A0260
+P07798271A0330
+P03016883A0000
+P07670943A0308
+P08289339A0527
+P08291620A0372
+BC2GM044117466
+P09227332A1798
+BC2GM073223559
+BC2GM040147994
+P03025606T0000
+P11340516A0509
+BC2GM007746647
+P02598034A0000
+P08621453A0815
+P11336211A0132
+BC2GM056384922
+P02030910A0000
+P01873999A0000
+P04544704T0001
+P09463380A1050
+BC2GM078540680
+P02264601A0000
+P02307848T0042
+P11555669A0983
+P04757217T0000
+P09765394A1590
+BC2GM018887080
+P03223123T0001
+P09369451A0693
+P08570615T0000
+BC2GM050682340
+P07075438T0000
+P01432453T0000
+P03830147A0000
+P09645576A0148
+P07298523T0000
+BC2GM023106158
+P08034708A0000
+BC2GM095548936
+P07748493A1045
+BC2GM047037521
+BC2GM023971804
+P07607197A1048
+BC2GM003985442
+P09524222A1113
+P08463485T0000
+P08115744A0846
+BC2GM091729767
+P09877417A0704
+P07636408T0000
+P01865010A0000
+P04350410T0000
+P04088936T0001
+P01265887T0001
+P08700531A1420
+P02971603A0883
+P09456312A1064
+BC2GM011710885
+P07984088A0592
+BC2GM040336555
+P11180027A1306
+BC2GM079052068
+P08675395A0751
+P07592946A0997
+P05942953T0049
+P11106216A0918
+P10958673A0142
+BC2GM051391908
+P01325386A0766
+P00637637T0000
+P10753553T0000
+BC2GM037509935
+P00931089T0001
+P11238916A0838
+P03779205A0459
+P10694511A0570
+P00097989A0106
+P10866677A1839
+BC2GM026058529
+P07702378A0668
+P02119530T0000
+BC2GM087511042
+P08576042A0765
+P03360948A0477
+P03049570A1242
+P01682509A0539
+P01552052A0139
+P08429019A2022
+BC2GM018877680
+P06111283T0032
+P07862533A0000
+P01752792A0000
+P09338414A0430
+P09613946A0194
+BC2GM002651672
+P08505075A0236
+BC2GM012196374
+P09911328T0000
+P10881275T0000
+P02123877A1452
+P02805945A0000
+P01398140A0488
+P10611320A0816
+P01991521A0481
+P10882850A0000
+BC2GM005891745
+P03209019A0662
+P03610663A0201
+P07949137A0000
+P10371097A0963
+BC2GM075161698
+P08381121A0773
+P08649425T0000
+P07888156A0169
+BC2GM009914955
+BC2GM098731910
+BC2GM097574601
+P11787322X0001
+P09335608T0000
+P02125016A0145
+P02793620A0214
+P07575438A1409
+P09301350A0946
+P07766885A0405
+P08822208A1364
+BC2GM020223301
+P11786945A0958
+BC2GM070088556
+P06096380A0662
+P09681822A0520
+P11266194A0743
+BC2GM056914428
+P11074210A0623
+P08647086T0000
+P01451771A0619
+P07113365A0737
+BC2GM025716724
+P09238850A2042
+P02792430A0000
+BC2GM020742355
+P08631817T0000
+P02862656T0000
+P03555318T0000
+P09028998A0143
+P07967360A1048
+P10729151A1160
+P08496848A0692
+P02473907A1338
+P08331728A0686
+P08528796A1470
+P02162467A0311
+P11370174A0447
+P02172672T0001
+P08648665A1320
+P02069873X0000
+P08269424A0339
+P08300527T0000
+BC2GM089767540
+P09423968A0039
+P09050849A1459
+P01688972A0803
+P07916729T0000
+P01658356T0000
+P10749166A0991
+P07249895A0177
+P01413984A0737
+P02012097T0000
+P11031773A0174
+P08967963A1735
+BC2GM054122511
+P00589073A0000
+BC2GM037459381
+P10576177A0308
+P03896991T0000
+P08647451A0663
+BC2GM051237837
+P01036714A0072
+BC2GM049290595
+P00261981A0434
+P07653812T0000
+BC2GM006956250
+BC2GM087933545
+P10591990A0178
+P04114211T0000
+BC2GM055613257
+BC2GM043720007
+P09420234A0654
+P11554566A0833
+P07569640A0539
+P00331128A0000
+P10657658A0165
+P02073222A0269
+P01917943A0621b
+BC2GM086570767
+P11498795A0716
+P07491305A0102
+P11152344A0416
+P08356792T0000
+P01400401A0065
+P07277222A1391
+P07563090A0124
+P11051364A0890
+P08508861A0294
+P03575656A0120
+BC2GM003994836
+P03377891A0652
+P08862522A0690
+P09006936T0000
+BC2GM001365084
+P01459921A0000
+P02810911A0372
+P06217859T0000
+P07835273A0411
+P08625987A1086
+BC2GM057332311
+BC2GM081384324
+P03133250A0000
+P11012671A0576
+P03420466A0000
+P07944542T0000
+BC2GM005821288
+P03097643A1357
+P09111004A0732
+P02485188A0415
+P11287555A1057
+P11505407A0461
+P11560509T0000
+P07949137A0532
+P07622521A0418
+P09504553T0000
+BC2GM002489529
+BC2GM097830096
+BC2GM035217555
+P03172863T0000
+P02590391A0442
+P08620889A0771
+P01480183A0000
+P06588306A0076
+P10764574A0718
+BC2GM042573806
+BC2GM055154765
+P09794795A0183
+P09414319A1442
+P10767251A1046
+P09061698A0177
+P02113901A0000
+P11533340A1285
+P10706513A0843
+P08881542T0000
+P02234345A0215
+P06856669A1004
+P05133723T0000
+BC2GM044153984
+BC2GM010367775
+BC2GM083218556
+BC2GM020542705
+P07927267T0000
+P09804779A0000
+P11024182A0781
+P08620856A1172
+BC2GM017907484
+P09652742A0455
+BC2GM079928665
+P09620873A1710
+P07702808A0427
+BC2GM013293084
+P02062116A0688
+BC2GM072306591
+P03504971A0000
+P09314554A0149
+P11148042A1258
+P01542730A1982
+P08106398A1003
+P09079638A0883
+P09328349A1679
+P07746397A0233
+P06198241A0209
+P08959062A0372
+P06084279A0218
+P10987280A0604
+BC2GM021740420
+P08721526A0000
+P09556573A1062
+BC2GM019410354
+P01012904A0333
+P08528479A0000
+P09575187A1558
+P08300463A0581
+BC2GM065583903
+P02459309T0000
+P09258439A1001
+P04970918T0069
+P09695194T0000
+P11560992A1184
+P02507815A0000
+P07853488T0000
+P11341405A0146
+P10825293T0000
+P08903339A0264
+BC2GM057358124
+P09822661T0073
+P01403222A0391
+P09336455A0000
+P09126487A1399
+P08064351A1020
+BC2GM036498049
+P06750608A1442
+BC2GM005749359
+P11007961A0930
+BC2GM006599822
+P08974103A0451
+P02012789A0051
+P08795304T0000
+P09287352A0930
+P00836637A0000
+BC2GM063229471
+P00476572A0139
+BC2GM000796681
+P07876194T0000
+P02577867T0000
+BC2GM048811705
+P09032267A0850
+P07776882A0000
+P07143347T0000
+P11054011A1685
+P08910373A0315
+P01862027A0212
+P09714109A0000
+P07107287A1083
+BC2GM099320794
+P05124707T0001
+P02655381A0000
+BC2GM057965554
+P08625806A0263
+P02902844A1219
+P07500597A0212
+BC2GM099940943
+BC2GM026322966
+P08628681A0821
+BC2GM069951819
+BC2GM064060868
+P08665853A0228
+P08583846A0121
+P01156631A0658
+P11427611A0000
+BC2GM085078611
+P07482069A0606
+P11384225A0634
+P02249872A1051
+P09653745A0180
+P09335298A0529
+BC2GM058610750
+P11038042A0948
+P09547311A1394
+BC2GM079526142
+BC2GM022332450
+P01644821A1259
+P08896804A0000
+P09356645A0672
+BC2GM067117543
+BC2GM067919498
+P00219533T0001
+P09631366A0951
+BC2GM037366873
+BC2GM030264277
+P01652515A0379
+P11125872A0133
+P10733880X1783
+P07580782T0000
+P07969115A0000
+P07221179A0156
+P09368097T0000
+P09268578A0225
+P02998043A1199
+P11102367A1170
+P07557446T0000
+P09364440A2206
+BC2GM038333674
+BC2GM068132374
+P08466864A0878
+P11015197A0310
+BC2GM017938095
+BC2GM051315195
+P10766246A0000
+P10594130A0652
+P08190633A0273
+P02233680A1115
+P01934378T0000
+P00614915T0001
+BC2GM079384236
+P07540607A0709
+P07801180A0197
+P11233643A0000
+P09701895A0119
+P10903495A0533
+P09023197T0000
+P11287579A1084
+P07610735A1471
+P08040336A0435
+P10743719A0223
+P01792580A0198
+BC2GM080581742
+P02590869A0743
+P08530107A1003
+P08416952A0956
+BC2GM015513463
+P09081389A1088
+P03601533T0001
+P11278713A1054
+BC2GM067919797
+P09417493A0823
+P10958688A0265
+P08764136A0000
+P11138009A1032
+P11145887A1393
+P09151376A0000
+P01487144A0505
+P02195715A0143
+BC2GM085145891
+P01844982A0324
+BC2GM004396231
+P09819507A0000
+P11030066A0142
+P09282985A0961
+BC2GM049397374
+P09447962A0452
+P01279374A0396
+P07203410T0000
+P07490079T0000
+P08007954A0374
+P03875231A0627
+P02209237A0239
+BC2GM057936039
+P09275164A0000
+BC2GM003408029
+P01518926T0000
+BC2GM089869328
+P10650939A0789
+BC2GM088911039
+P07851643A1365
+P11709890T0000
+P08631685A0000
+P08395004A0558
+P00474064A0205
+P10644753A0725
+P09368057A1083
+BC2GM025882502
+P11062068T0000
+P08139577T0000
+P01945430A0660
+P02762006A0071
+P08927169A0178
+P08102364A0000
+P02509123A0371
+BC2GM047053837
+P00114144A0189
+P07914507A1029
+P08806491A0542
+BC2GM033925563
+P07521601A0000
+BC2GM060812049
+BC2GM076272520
+P02320008A0651
+BC2GM065388195
+BC2GM077588119
+P08595627A1513
+P07932095A0000
+P07559430A0909
+P07791763T0000
+BC2GM051097875
+BC2GM059704173
+P01312005A0600
+BC2GM005174218
+P07765118A0967
+P07760790A0327
+P05595036T0001
+P02290216T0001
+BC2GM022393515
+P09062130A0116
+P02131902A0000
+P11435428A0000
+P03421425A0878
+BC2GM064675128
+BC2GM044133796
+P07651131A1407
+BC2GM004225569
+P09596536A0219
+P05774062T0000
+P08683108A1501
+P10905352A0000
+P09592219A0652
+P07597488T0000
+P07797583A0222
+P06726257A1179
+P09882489A0451
+P09530251A0766
+BC2GM016356336
+P09819110A0703
+P03746896A0890
+P09325278A0458
+BC2GM093309915
+BC2GM081931379
+P08769132A0000
+P10835485A0941
+P09409774A0214
+P03931797A0134
+P07494306A0240
+BC2GM067166518
+P02518645T0001
+BC2GM040451160
+P08391534A0828
+P05496619T0000
+P09084174A0667
+P08673026T0000
+P10913172A0442
+BC2GM069558891
+P01890989A1392
+P08370275A0290
+P03776438A0000
+P07489502A0000
+BC2GM005308134
+P09557682A0490
+P09004304A0000
+P05364951T0001
+P07706299A0563
+P09006902A0370
+P07588633A0362
+P01906111A1295
+P01186344A0303
+P03171279A0158
+BC2GM098133751
+P00975540T0000
+P08419333A0126
+BC2GM071898501
+BC2GM048773311
+P00716366T0001
+P09529216A0644
+BC2GM078276040
+BC2GM079579959
+P08294906A1315
+P02985820A1287
+BC2GM088286294
+BC2GM064870034
+P01567649A0139
+BC2GM004901699
+P07739520A1250
+P09882348A0611
+BC2GM094724499
+P01588963A1153
+BC2GM035996110
+P07516337A1119
+P10900269A0396
+P09025549A0000
+P08798782A0976
+P09038192A0846
+BC2GM020911940
+BC2GM044080615
+P10760109A1050
+BC2GM053252394
+P08975532T0001
+P01474990A0000
+BC2GM032527280
+P09581775A0185
+P02960012A0838
+P10688663A0207
+P10913276A0684
+P02890200T0001
+P04992478T0000
+BC2GM011390376
+P08610582A0150
+BC2GM032470094
+P08750190A0000
+BC2GM060582381
+BC2GM036409328
+P01692837A0390
+P11687083A0218
+P02925568A0460
+BC2GM083470342
+P04407649T0000
+P09784245T0000
+P08045834A0783
+P03178626A0137
+BC2GM033817811
+P10671554A0492
+BC2GM015678949
+P10846069T0000
+P10794936A0241
+P09111340A0240
+BC2GM099407743
+P09823561T0001
+BC2GM069407837
+BC2GM005391893
+P09091125A0161
+P11340048A0432
+P08655497A0000
+BC2GM076429520
+P09770686A0484
+BC2GM034188692
+P08921387A1182
+P03371806A0000
+P10585808A0000
+BC2GM048437284
+P10671224A0254
+P05417431T0001
+P02575959A0643
+P11042204A0186
+BC2GM084752921
+BC2GM050148188
+BC2GM070361623
+P09817190A0074
+P02190134A0572
+BC2GM018048012
+P08051151A0347
+BC2GM023199646
+P08768377A1387
+BC2GM085015084
+P09420275A1111
+BC2GM084593857
+P00733067A0188
+P01625527A0000
+P09171235A0851
+P08261398A0838
+BC2GM037435242
+P06298014A0647
+P01905199A0210
+BC2GM003217917
+P05837169T0001
+P07828600A0095
+P08225657A0000
+P07136524A0180
+BC2GM033154318
+BC2GM058412492
+P03317796A0853
+BC2GM004581999
+P01654349A0327
+P08586643A0951
+P10770041A0731
+BC2GM073208468
+P09094093A0578
+P04803629T0001
+P10961046A0342
+BC2GM047630047
+P08166402A0631
+P10805390A0340
+BC2GM072421473
+BC2GM069147613
+P06713200A0630
+P01782982A0155
+P08727992A0570
+P07906265A0897
+P11231287A0158
+P01454518A0336
+P06593862T0001
+P08054281A0731
+P00741476A0000
+P09733815T0000
+P08497280A1397
+P08585324A0467
+BC2GM070276124
+P09773981A0415b
+BC2GM023793226
+P09012636A0723
+BC2GM099658397
+P09642042A0646
+P00331936T0000
+P04613073T0001
+BC2GM034695488
+BC2GM018703043
+P09917391A0380
+P11246887A0000
+P02813404T0000
+P04394290T0000
+P07720572A0701
+BC2GM018602202
+P01727488A1146
+P10785294A0720
+P01448932T0000
+P10684660A1266
+P10857215A0000
+P09716183A1036
+P07926748A0383
+BC2GM010069099
+P05892712T0034
+BC2GM037434431
+P11000266T0000
+P07172690A0547
+BC2GM066604493
+P07607233A0186
+P09211913A0000
+P02792270A1220
+BC2GM044150575
+P08289793A1226
+P02005547A0121
+P08776748T0000
+BC2GM000570200
+P09268638A0332
+P09545293A0590
+P09436657A0303
+P10727426A1280
+P06328485A0277
+P11687352A0215
+P09286115T0000
+P02527365T0000
+P09739913A0194
+P11103601T0025
+P09535892A0000
+P08876167A0322
+P11449014A0000
+P07559510A0000
+P11872359A0000
+P07106534A0160
+P02826717A0179
+P08455623A0630
+BC2GM016660026
+P02811378A0250
+P07563090A0624
+BC2GM014858349
+P08263933T0000
+P03923976T0001
+P09965909T0000
+P08636031A1413
+P04063732A0509
+P01202616A0466
+P10673426A0168
+P10885731A0915
+P00594466T0001
+P09524259A0301
+P09880327A0322
+BC2GM056924608
+BC2GM002647660
+P02307848A0347
+BC2GM063598630
+P02162754A0339
+P07559650A0558
+BC2GM086837323
+P07501458A0578
+BC2GM038397641
+P09891061A1240
+BC2GM000828997
+BC2GM015782693
+P10891286A0000
+P09368026A0435
+BC2GM040660386
+BC2GM053748645
+P08144470A0711
+BC2GM028930096
+BC2GM013781370
+P11416393A0000
+P09774450A0000
+BC2GM088697037
+BC2GM047020001
+P08125337A0940
+BC2GM083452156
+P08851434A0383
+P11108616A0000
+P09395525A0395
+P00352569A0000
+P10598316A1534
+BC2GM052334866
+BC2GM077438111
+P00929418T0001
+P07595857A0521
+P07644503A0729
+BC2GM050603433
+P03420266A0000
+P08723352A0084
+P09237862A0782
+BC2GM085654782
+P08915508A0000
+P01851527T0000
+BC2GM034218044
+P09827993A0000
+P01857326A0160
+P08093450A0688
+BC2GM028962502
+P04025179A0955
+P07935472A0790
+P07966602A0130
+P09988767A1496
+P00321261A0104
+P10564479A0384
+P09371626A1345
+P02934778A0702
+BC2GM076960951
+P02092131T0000
+P02574052A0910
+P09528784A0000
+P08756556A0406
+P03799323A0501
+BC2GM009739613
+P09725292A1473
+P03673881A0000
+P07681539A0000
+BC2GM020995115
+P09218775A0000
+P08226956A1397
+BC2GM010137266
+BC2GM090258989
+P11431348A0000
+P08663127A0697
+BC2GM050016393
+P09774444A0351
+P09473755A0318
+P08794869A0274
+P08730470A0000
+P01429714A0730
+P01587267A1144
+BC2GM087481968
+P08107167A0222
+P09278494A0762
+P09606924T0000
+P07376165T0001
+P09599664A0881
+P10780518A1270
+P09111309A0674
+P09754571A1257
+BC2GM066438188
+BC2GM059465323
+P01903841A0125
+P03487348A0000
+P01378431A0202
+P08704240A1111
+P09032259A0972
+P02873593A0581
+P08917696A0485
+P08848052A0733
+P03449358T0001
+P05792911T0000
+BC2GM031611293
+P07500953A0305
+P11084556T0000
+P02997777A0609
+P03331933T0048
+P11415958A0000
+P08499916A0000
+P06384983T0000
+BC2GM084651011
+P09042269A1007
+P07815811A1487b
+P09541636T0000
+P08986214A0000
+BC2GM030303279
+BC2GM053432792
+P10913094A0424
+BC2GM098818949
+BC2GM030055087
+BC2GM069768430
+P09515924A0104
+BC2GM007595336
+P07221354T0000
+P09065463A1012
+BC2GM021493197
+BC2GM024081433
+P01769189A0000
+P09169475A0772
+P01512941A0000
+P07568026A0622
+P02019572A0000
+P11007777A0813
+P01441818T0001
+P09671313A0334
+P10811079A1277
+P03407676A0585
+P06097027A0000
+P09573378A0761
+P10002245T0000
+BC2GM098791019
+P11011139A0000
+P11071789T0000
+P08249390A0111
+P01899209A0883
+P11391303A1023
+P07650958A0123
+P08650818A0000
+P00540707A0255
+P08776901A0000
+P09099702A0000
+P02528730A1073
+P02767733A0690
+P08824798A0761
+P11112790A0989
+P11773921A0397
+P09737453A0557
+P03146017A0983
+P10696007A1325
+BC2GM052040080
+P09819038A0448
+BC2GM009567777
+P01372456A0426
+BC2GM040359047
+P02306539T0000
+P02315472A0583
+P10550571A0000
+BC2GM032519240
+P08300611A0341
+BC2GM094961159
+P01814182A0000
+P01615493A0975
+P05890351T0001
+P02123029A0478
+P01285807A0365
+P10655164A0546
+P01658356A1369
+BC2GM094617831
+BC2GM014061737
+P09961682T0000
+P09447962A1027
+P08530432A0093
+P03184267A0000
+P01174873T0000
+P07676587T0000
+P08204426T0001
+P07596287A0183
+P09050689A0685
+P03871445T0000
+P07711730A0000
+P10775038A0142
+BC2GM018332132
+P01765375A0290
+P06986168A0304
+P02047597A0149
+P00871237A0601
+P11327292A0190
+BC2GM056070197
+P05525652T0064
+P02348225A0192
+P11350175A0173
+BC2GM096948473
+P02632904A0619
+P02595451A1136
+P11312584X1846
+P09763470A1756
+P02123293A0227
+BC2GM023763281
+BC2GM081648973
+P08075070A1632
+BC2GM082079771
+P08692885A0663
+P03258069A0000
+BC2GM017195618
+P09601921A0000
+P02848842A0643
+P07565720A0256
+BC2GM030760863
+P10572866A0481
+P07739382A0457
+P02549036A0000
+P06858449A0335
+BC2GM022444174
+BC2GM016623296
+P11150439A0701
+P10775623A0120
+P07878029A0721
+P09722043A2070
+P06816053A0849
+BC2GM048894159
+BC2GM011438021
+P07592439A0000
+P11723500X0000
+P10848993A0000
+P09421516A1516
+P07567979A1266
+P07913926A0878
+BC2GM022531495
+P02767166A0368
+P01776715A0489
+P09232593A0946
+BC2GM088211733
+P04176625T0000
+BC2GM072719765
+BC2GM015438826
+P03818866A0116
+P09499254A1309
+P11207216A0296
+BC2GM067940878
+P07886610A0000
+BC2GM027086451
+BC2GM031481247
+BC2GM058404635
+P09583208A0171
+BC2GM089563862
+P08153146A0327
+P08412620A0688
+BC2GM022481867
+P07436459A0245
+BC2GM095436717
+P09315651T0000
+BC2GM010707671
+P06588501T0059
+BC2GM003643024
+BC2GM050923022
+BC2GM063827916
+P00989973A0000
+P00665214A0374
+BC2GM049472280
+P09667795A0000
+P08977235A0588
+P11357063A0138
+P09029091A0881
+P11266615A0258
+P09168892A1016
+P10747782A0390
+P06726257T0000
+BC2GM050680877
+BC2GM012221483
+P02645431A1562
+BC2GM056273356
+P11063169T0000
+BC2GM025168893
+P11383860A0661
+BC2GM053940831
+P03292076A0820
+P11502738A1457
+BC2GM098953976
+P06136374A0151
+P05466177T0001
+P08595878A0201
+BC2GM081593003
+P08749393A0783
+P10928179A0101
+P01548756A1102
+P06754662T0001
+P09947191T0000
+P10861086A0259
+P09080250A0212
+P03036933A0774
+P08839832A0729
+P08604338A0885
+P08972211A0059
+BC2GM011499496
+P08918934A0424
+BC2GM096590375
+P07535768A1076
+P08393143A1281
+BC2GM006714669
+P07521009A0377
+P07663998T0000
+P08894144A1173
+P01310154A0879
+P02506740A0742
+BC2GM067993736
+P11152451A0529
+P01280413T0001
+P00150066A0554
+P08896280A0860
+P01993181T0000
+BC2GM018615629
+P06656249T0000
+P10591976A0317
+P01878489A0959
+P03025655T0000
+P08499376A0000
+P09226113A0857
+BC2GM054126156
+P09583823A0238
+P00264240A1843
+P05621339T0001
+BC2GM029364330
+P10556263A1035
+BC2GM051724994
+P11157879A0192
+P07748848A0263
+P08818718A1229
+BC2GM037686534
+P06815368A0203
+P10673335X0782
+P10132730T0000
+P10891399A1185
+P02217741T0001
+BC2GM087589281
+P01399206A0375
+P00863773T0000
+P09050849A0000
+P11138231T0000
+P07542764A0497
+BC2GM066302060
+BC2GM032903217
+BC2GM094089829
+P08226776A0990
+BC2GM037059835
+P11256845A0340
+P09379301A2036
+P08417349A1633
+BC2GM067397943
+P09301114A0573
+P02761008X0000
+P01678392A0648
+BC2GM000667374
+P10561251A0000
+P10551848A0000
+P09068989T0000
+P11432112A0000
+P08460918A0252
+BC2GM015319491
+BC2GM059332523
+BC2GM000462914
+P11202434T0000
+BC2GM084545112
+P03780248A0274
+P07753796A0743
+P03334950A0000
+P08413186A1199
+P09400613A1209
+BC2GM030561421
+P11086872A0000
+P08754852A0960
+P08664667A0093
+BC2GM014747695
+P10611228A1388
+P09655916A0415
+P04311951T0001
+P02685565A0165
+BC2GM004916804
+BC2GM020495057
+BC2GM032501279
+P02580830A1131
+P06781728A0690
+P11084649A0497
+P01791754T0000
+P11495833T0000
+P07588608A1687
+P01398073A0986
+P02834478A0000
+P09412079T0001
+BC2GM080374905
+P09693134A0782
+P08726247A0175
+P09229420A0158
+P10828751A2258
+P07490278A0799
+P02349998A0297
+BC2GM017503197
+P08192451A0885
+P09780336A0771
+P08443339A1374
+BC2GM003959017
+P07184774T0000
+BC2GM086777586
+P09229595A0618
+BC2GM071999397
+P10402467T0000
+P07789396A0504
+P08508778A0112
+P04733391T0000
+P11113179A1020
+P09582306T0000
+P06740919A0162
+P08457291A0170
+BC2GM005475872
+BC2GM074709129
+BC2GM086467089
+P02744490A0894
+P11431472A0540
+BC2GM034609463
+P09294139A0729
+BC2GM080331933
+P09795341A0806
+P03607109A0370
+P02692881A0354
+BC2GM000534680
+P05763287T0063
+P08632779A0351
+P07642544A0868
+P11145571A0788
+P10607566A0880
+BC2GM067528741
+P00201881A0487
+P02247069A0261
+P08980522A0280
+P01211754A0192
+BC2GM024059771
+P07564210A0557
+P07565797A0116
+P09696819A0450
+P10896008A0531
+BC2GM094704292
+P02987220A0472
+P08589358A0235
+P07808210A1510
+P04621188T0000
+P08974135A0052
+BC2GM039101947
+P07917540A0000
+BC2GM096497535
+BC2GM079563549
+P08647091A0592
+P07878040A0505
+P09211934A0722
+BC2GM004875958
+P02016769A0720
+BC2GM072766443
+BC2GM026812413
+P04941419T0000
+P07826412T0112
+P04315233T0128
+P02856622T0001
+P08276865A1188
+P09323366A0299
+P09712898T0000
+P08220494A0231
+P10692374A1873
+P08522511A1250
+BC2GM094104412
+P10041728T0000
+P08598449A0784
+P08780339A0142
+BC2GM091513023
+P01662794A0640
+P09618475A0747
+P08595414A0000
+BC2GM004874774
+P08566754A0783
+BC2GM026246927
+P00113657A0628
+BC2GM004527593
+P08078416A0581
+P06972179A0556
+P07644127A0000
+P09193077A0000
+P08955136A0606
+BC2GM047538840
+BC2GM061678141
+P10679922A1110
+P03257146A1037
+P09185183T0000
+BC2GM058485418
+P00055040A0000
+BC2GM000487648
+P10918164A0878
+P11139473A0696
+P01360180A1568
+P08923460A0565
+P03722016A0797
+P06858640A0262
+BC2GM041159775
+BC2GM028962331
+P08065366A0918
+P11368914T0071
+P03476002A0148
+BC2GM071696836
+P10938102T0000
+P09920903A1045
+P02187871T0000
+P01298173A0153
+P09011744A0790
+BC2GM002830287
+P03180595A1040
+P03440780A0779
+P11108720A0124
+BC2GM005914798
+P08097666A1135
+P07948129A0297
+P09987176A0260
+P11438666A0555
+P01922082A0149
+P03556834T0000
+BC2GM078534924
+P07434431A0203
+BC2GM008579133
+P09212063A0425
+P09799362A1463
+P09208214A0572
+P06349364A1051
+P09770241A0000
+BC2GM051338650
+P11279038A0194
+P03027905A0632
+P03749226A0506
+P02330041A0335
+P01844017A0410
+BC2GM017509191
+P10918572A1547
+BC2GM055697926
+P10628971A1165
+P08702936A0984
+P03795488A0487
+BC2GM013042173
+P09784192A1027
+P09535835A0279
+P09852005A1287
+BC2GM020106641
+P01682484A0680
+P09294452A2107
+BC2GM057409363
+P07663138A0835
+P01547957A1083
+P02194972T0000
+P02991060A0465
+P08380736A0895
+P00920381T0000
+P10823630A1124
+P06473219T0000
+BC2GM076746345
+P09763446A0000
+BC2GM011526436
+P11278310A1516
+BC2GM005335832
+P07655505A0527
+P08917435A0481
+P08253387A0801
+P02554310A0419
+P10637230A0332
+P02371517A0747
+P11331596A0710
+P07798217T0095
+P10585311A0494
+P05000171T0000
+P04031488A1091
+P08919289A0402
+P00583522T0001
+P09121774T0000
+BC2GM035459552
+P02783181A0000
+BC2GM089582706
+P01448107A0361
+P08686381A0527
+P08148756A0358
+P07537267A2094
+P11298326A0677
+BC2GM014046465
+P07116962A0299
+BC2GM046530898
+P10809233A0606
+P10965830A0305
+P08407784A0850
+P09143328A1002
+P03132498A0730
+P09464248A0289
+BC2GM046642250
+P09813041A1122
+P09832436T0000
+P09846033A0488
+P03041046A0127
+BC2GM088022090
+P08065368A0839
+P01145884T0028
+P09051656A0390
+BC2GM091752131
+P09776360A1781
+P07798217T0000
+P02892762A0296
+P08688556A0242
+P08104189A1168
+P05750950T0001
+P02154474A1504
+P02038784A0317
+P08163528T0000
+BC2GM043473136
+P04820791T0001
+P01882240A0526
+P08892757T0000
+P07601445A0207
+P09995847T0000
+P01370281A0461
+BC2GM003613157
+BC2GM025160880
+P06891051A0587
+BC2GM028865518
+BC2GM013853953
+P01374392A0341
+BC2GM011289618
+P07428037A0989
+BC2GM082967002
+P08525186A0288
+BC2GM043891105
+P10666238A1322
+P10869465A1054
+P02814182A1211
+P07960608A0228
+P10568728A1445
+P03351478A0371
+BC2GM061319668
+P01907941A0275
+P01662609A0398
+BC2GM074517332
+BC2GM079255764
+P09393717A1517
+P09188699A1388
+BC2GM013877363
+BC2GM049346947
+P09827878A0091
+P09362480A0452
+P00656008T0000
+P00010943A0733
+BC2GM076572185
+BC2GM083937971
+P09813635A0678
+P09346938A1680
+P09251843A0189
+BC2GM059318256
+P06175691T0000
+BC2GM064306495
+P06662623A0124
+P09278445T0000
+BC2GM028069237
+BC2GM015350935
+P11801459T0000
+P08803845A0665
+P04852635T0000
+P09544991A0750
+P01656220T0000
+P08194753A0157
+P08112870A0484
+BC2GM063978181
+P09148929A0372
+P03292082A0486
+P09666103A0496
+BC2GM057597725
+P10713083A0170
+P07571953T0000
+P09529649A0307
+P11314373T0000
+P08524036A0747
+P10102000A1206
+P00119339A0400
+P07604047A0704
+P07693975T0000
+BC2GM089468953
+P08707846A2308
+P08082440A0339a
+BC2GM044661165
+BC2GM032479556
+P09290207A0731
+P08187085A0086
+P01823520A0183
+P08798635A0870
+BC2GM087975149
+P11268459A0167
+P06828396A0095
+P01762053A0557
+P11459794A1172
+P11157334A1107
+P11341828A0744
+P07959953A0423
+P01522699A0092
+P09579808A0000
+P08576546A0975
+P09797456A0000
+P09423856A1098
+P09590294A0453
+P00915090A0536
+BC2GM004666921
+P11160656A0000
+P10679649A0311
+P01310178A0876
+BC2GM021619038
+BC2GM092572255
+P02088781A0653
+P01228258A0000
+P09387999A1053
+P03629973A0240
+P03586925T0001
+P01626631A0557
+P00911590T0000
+P11585856A0285
+P11187016T0000
+P09819421A0000
+P09868412A1628
+P10679781A1183
+P10959676A0200
+P09169127A0371
+P08459012T0000
+P06141764A0339
+P08917270A0229
+P11821098A0269
+P01176905A0094
+P06938948T0001
+P07745685A1442
+P11003669A0000
+P08187088A0530
+P02839716A0673
+P11278583A0873
+P00947327A0000
+P06198532A0982
+P11292335A0852
+BC2GM024572595
+BC2GM060268532
+P08552670A0665
+P11274368A0818
+P03001084A0406
+P11368787A0180
+P07780148A1153
+BC2GM060814876
+P02702849A0418
+P02022188A0112
+P02110145T0000
+P02813369A0390
+P01842867A0696
+P01531632A0000
+BC2GM073122143
+BC2GM045006907
+P09649501A0358
+P07865895A0896
+P06454625A0000
+P08798420A0207
+P07963540A0795
+P11158456A0223
+P09061697T0000
+P05536803T0001
+P11413641A0373
+P02550682A0411
+P07542698A0137
+BC2GM091983873
+BC2GM065898705
+BC2GM067657042
+BC2GM060307457
+BC2GM046025995
+P07985305T0001
+P09128730A0000
+BC2GM032693967
+P07397066T0000
+P10622576A0552
+BC2GM089850642
+P00074758T0000
+BC2GM092872868
+P11181564A0733
+BC2GM047517578
+BC2GM071413005
+P09577365A0747
+P10821836A0842
+BC2GM044964847
+BC2GM015891432
+P02968055A0984
+P09031639A0474
+P08413186A0077
+P07293327T0001
+P09396402A0264
+P08154171A0649
+P09418872A0417
+BC2GM068680235
+P08394019A0695
+BC2GM045792980
+P11029700A0295
+P07526609A0736
+P07505349A0702
+P05901778T0000
+P02849759A0865
+P08069427T0000
+P07963782A0000
+BC2GM002401623
+BC2GM036087490
+BC2GM087357752
+P02477373A0930
+P09454719A0181
+P08740416A0919
+BC2GM033901476
+BC2GM051860407
+BC2GM026047963
+P07977648A0880
+P02481230A1258
+P08264591A1190
+P09480831A0272
+BC2GM066240715
+P03139750A0000
+P00729003A1182
+P09447917A0000
+BC2GM099460087
+P11552724A0527
+P07823919A1422
+P04145244T0000
+P09442080A0856
+BC2GM050815443
+P02427812A0865
+BC2GM051891413
+BC2GM089723467
+P09424012A1774
+P11347201X0001
+P06258699T0000
+P10857215A0806
+P03874921A0862
+BC2GM033756854
+BC2GM093097670
+P10637149A0806
+P09824021A1263
+BC2GM037692816
+BC2GM073635511
+BC2GM011492237
+BC2GM090935032
+P02918474A0817
+P09314570A0153
+BC2GM095844038
+P01122015A0467
+BC2GM027491434
+P01939906A0233
+P08246984A0512
+P03668396A0171
+P00992316A0178
+BC2GM007788205
+P01279197T0000
+P11570820T0000
+P00411465A0142
+P01333317A1008
+P09419415A0236
+P02243093A0000
+BC2GM053136580
+P09396437A0878
+P07678006A0472
+P08805824A1155
+P08831364A1252
+P02496090A0252
+P01325221A0870
+P07653892A0306
+P09167421A0234
+P00112627A0542
+BC2GM087530510
+P03682805A0375
+P08100765A0361
+BC2GM050589731
+BC2GM013941232
+P08518797T0000
+P08794363A0259
+P07525843A0859
+P09505135A0182
+P08496475T0000
+BC2GM027554175
+P11789206A1182
+P10782989A0575
+P00481612A1121
+BC2GM083150371
+P10758289A0141
+BC2GM050874395
+P09553040A0651
+P08049521T0000
+P01923628T0001
+P06354594A0114
+P02970640A0341
+P06823837A0562
+P10850719A0680
+P04794218T0001
+BC2GM069902375
+BC2GM016797236
+P02398897A0000
+P08816052A0238
+BC2GM041430420
+P07682842A0771
+P03282813A0794
+BC2GM071513043
+P02519679T0000
+P09328476A0374
+P01512259A0867
+P00736376A0371
+P02868848A0167
+P02115115A1053
+P07995910A0119
+P06795119T0000
+P04546974T0000
+P08438584T0000
+P08670556A0425
+P01901664T0064
+BC2GM053139054
+P02820128A1670
+P07824657A1456
+P02289639A0989
+P09073582A0444
+P10983857A0923
+P09417870A0105
+P10963735A0651
+P11376687A0344
+P08355857A1293
+P09531559A1153
+BC2GM079401550
+P08876701A0177
+P06287737A0477
+P07744763A0514
+P11127955X0001
+P09049198A0289
+P08823646A1012
+P03040023A0113
+P03278829A0082
+P03628532A0000
+P09065768A0862
+BC2GM091384124
+P07590268A0740
+P08196618A0473
+P11361338A0093
+P08605705A0676
+BC2GM023754004
+P11037759T0000
+P01970984A0668
+P08914388A1645
+P01103390A0149
+P11014821T0000
+BC2GM042145005
+P08167555A0972
+BC2GM004529705
+P09150728A0596
+P10997904A1258
+BC2GM087006265
+BC2GM025829397
+BC2GM022846280
+P07761091A0294
+P09668063A0274
+P09396427A1488
+BC2GM035007740
+P09538156A0130
+P00628990A0000
+P09528758T0000
+P02693593A0866
+P01396583A0204
+P08844448A0000
+P09724654A0761
+BC2GM067195317
+P11282029A0075
+P08524267A1022
+P09838122A0489
+P08288606A0240
+P07693672A0259
+P11125411A0857
+P02869125A0120
+P01649539T0000
+P08435885A0787
+P01871033A0434
+P01630454A0635
+BC2GM093691513
+BC2GM070747884
+P08792217A1407
+P01093845A0208
+P04539552T0001
+BC2GM060854323
+P09079915T0000
+BC2GM097083223
+P09115247A2069
+P10954564A1262
+BC2GM043181941
+P00294502T0001
+P09665720A1145
+P09015799T0000
+BC2GM010408815
+P08663141T0000
+P08939966A0816
+BC2GM071024994
+P02217307T0000
+P06837312A0000
+P01469042A0355
+P07784199A0000
+P07491791A0263
+BC2GM035650199
+BC2GM034699530
+P11240600A0523
+P03192799T0000
+P08672242A0517
+BC2GM044659370
+BC2GM059008483
+P06246254A0676
+BC2GM020487228
+P08394862A0565
+P07927838A0000
+P11368363A1103
+P08872671A0573
+BC2GM023722122
+P02370571A0663
+P08023662T0000
+P07844555A0406
+P09694869A0932
+P10972990A0966
+P01425653T0000
+P06684624A0736
+BC2GM012342232
+BC2GM006702465
+P04679807T0000
+P11152963A0000
+BC2GM057108840
+P03840480T0000
+P07969954T0000
+P11406642A0792
+BC2GM000772761
+P10710742T0000
+BC2GM011018907
+P09761711A0000
+P03021088A0135
+P08139539A0446
+P08971721A1314
+BC2GM056026890
+BC2GM095387001
+P01551176A0000
+P01328884T0000
+P08022212A0071
+P09389669A1009
+P07704456A1014
+P09798100A0705
+P07871755A0521
+P08083963A0795
+P01639724A0452
+P07874060A0810
+P09918715A1158
+BC2GM052748917
+P09664033A1204
+P02700977A0444
+BC2GM055386745
+P09819440A0783
+P11279108T0000
+P01339125A0153
+P09223667A0139
+P01130531A0224
+P11408604A1440
+P03366720A1335
+P10392914A0000
+BC2GM005317665
+BC2GM093048431
+P04056218A0463
+P10644357A0935
+P08049401A0428
+P04179445T0036
+P00970320A0000
+BC2GM042831244
+P06740373A0891
+P09755199A0559
+P07280654A0000
+BC2GM009533483
+P03479897A0961
+P07876191A0808
+P05359130T0086
+P02906249A1195
+P11071924A0588
+P10724483A0540
+BC2GM069360294
+P06468565A0000
+P08917449A0000
+BC2GM095870614
+BC2GM084526121
+BC2GM083696051
+BC2GM080153743
+P09390125A0379
+P06764669T0001
+BC2GM074781397
+P10601606A0152
+P08663326A0000
+P07262239T0000
+P08083011A0584
+P02993630A1190
+P09749533A0764
+P01738470A0441
+P08055941A1264
+BC2GM065562233
+P03078268A0529
+P04081425T0016
+P02044975A0380
+P08913974A0533
+P08922384A0466
+P11463834A0606
+P11095248A1523
+P09514962A0841
+P04066274A0265
+BC2GM024417394
+BC2GM078923542
+P09927589T0000
+BC2GM097604426
+P05947377T0001
+BC2GM022402970
+P05718386T0001
+P09581872A0000
+BC2GM097874818
+P09840934A0435
+P03143485A0366
+P03680791A0230
+BC2GM004333942
+P09573202A0900
+P10723723A0781
+P06272844A0000
+P03610674T0000
+P06781339A0501
+BC2GM009570936
+P07579164A0409
+P00431832T0001
+P01206772T0000
+P00232354A0286
+P11303890A0996
+P11238882A0157
+P07235355A0462
+P11302704T0000
+BC2GM093769700
+BC2GM019113426
+P11161793A1033
+BC2GM036637526
+BC2GM094112642
+BC2GM068467868
+BC2GM004818954
+BC2GM052310515
+BC2GM080763421
+P09144770A0906
+P09261178T0000
+P08825636T0000
+P06610347A0581
+P01933614A0406
+P08567717T0000
+BC2GM022720719
+P03110119A0267
+P10773667A0351
+P11134351A1405
+P01714452A0559
+P09808216A0000
+BC2GM081841697
+P03931293A0437
+P06361318A1127
+P07328000T0000
+P09476520A1326
+P00149899T0001
+P07396545A0217
+BC2GM029072102
+BC2GM083317663
+P11179689A0000
+P01644814A0068
+P00863184T0043
+P10823837A1213
+BC2GM002497068
+P09354644A0124
+P02307371A0263
+P11371160A0193
+P09369482A0690
+P02368931A0587
+P09790768A0621
+BC2GM026399698
+P06193351A1010
+P01960974A0000
+P03935117T0000
+P06316347A0852
+BC2GM049034176
+P03050147A1520
+P02876899A0568
+P00029953T0045
+P00725752T0001
+BC2GM030583614
+P09712644T0000
+P09988682T0033
+BC2GM007416400
+P04050821A0531
+BC2GM011571896
+P07835214A0603
+P01662884A1029
+BC2GM026591982
+P03296019T0000
+BC2GM013192574
+P01618243T0000
+P09643153T0000
+P06634712A0557
+BC2GM027526688
+P08505495A0253
+P08021175A0486
+BC2GM019584475
+P11211759A0165
+P08075421A0621a
+BC2GM016410750
+P09426239A0386
+P09135772T0000
+P02056553T0000
+P07623814A1040
+P10757983A0733
+P02779752A0776
+P08206991A0466
+P07925097A1205
+BC2GM065683949
+BC2GM019191435
+P10992299A0745
+BC2GM027793192
+P11374051A0437
+BC2GM059503308
+P02879906A0000
+P09071308A0376
+P10745563A0409
+P08935931A0787
+P09717835A0941
+P09148770A0977
+P11054341A0599
+P08632009A1067
+P06506074A0456
+BC2GM060492967
+P08778700A0476
+P02220102A0271
+BC2GM075340756
+BC2GM057093148
+P07596287A1724
+P08331064A0440
+BC2GM034468940
+P09771555A0499
+P03037334A0932
+P11486032A1261
+P08794339A1162
+P06307099A1005
+BC2GM065423133
+BC2GM064837210
+P10704196A1051
+BC2GM052408999
+BC2GM097108682
+P09698457A0778
+P08938420A0862
+BC2GM083448203
+BC2GM064007116
+P02162835A0989
+P07516597A1017
+P01418834A0987
+BC2GM022663100
+P10701534A0164
+P02799892A0154
+P01569344A0404
+P10205099A0377
+BC2GM046472114
+P07647303T0000
+P11251104A0526
+P11179668A0869
+P08575609A0526
+P08816453A0000
+BC2GM088220160
+BC2GM072477958
+P09858714A1171
+P04085589A0264a
+P00516545T0001
+BC2GM077560209
+P10395911A0288
+P08823187A1020
+P02115121A0000
+BC2GM003040896
+BC2GM050066357
+P08574414A1037
+P03956647A1063
+P10805729A0987
+P10779508T0000
+P02861067A0000
+P02849100A0441
+P09882303A1984
+P11015200A0156
+P08043523A0000
+P08626290T0000
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/bc2gm.train b/huner/ner_scripts/splits/bc2gm.train
new file mode 100644
index 0000000..80dfee6
--- /dev/null
+++ b/huner/ner_scripts/splits/bc2gm.train
@@ -0,0 +1,12000 @@
+BC2GM019414766
+P10191090A0000
+P10375640A0153
+P10450815A0180
+P10498717A1048
+P10358083A0263
+P10430886A0838
+P10487217A0735
+P11860876A0409
+P11793172A0545
+P10026211A0136
+P10384129A0000
+P11824701A0894
+P10544037A0617
+P10488148A1267
+P11836046A0549
+P10072205A0167
+P10374632A0818
+P11815644A0081
+BC2GM014590821
+P10540553A0980
+P10359664A0579
+P10543270A1054
+BC2GM050688193
+P10474898A0629
+P10394919A1058
+P10331875A0523
+P11669281A0653
+P10400593A1084
+P11836303A0518
+P11843252A0907
+P08081293A0078
+P11737056A0680
+BC2GM095955751
+P10448902A0921
+P10409741A0382
+P10330146A0730
+P11775180A0379
+P10194225A1132
+P10551879T0000
+P11859943A0150
+P11911552A0776
+P10521447A1190
+P10748164A1284
+P11724510T0000
+P08435794A0658
+P09990060A0803
+BC2GM019659042
+BC2GM081844353
+P09186056A0514
+P10321158T0000
+P10209031A0832
+P10510295A0606
+P10393910A0705
+P10243927A0000
+P10473623A0081
+P10066790A0497
+P10079173A0000
+P10510379A0105
+P10359575A0317
+P10375718A0000
+P11912677A0281
+P10501936T0000
+P10078876A0000
+P10378989A0000
+BC2GM075862192
+P10407269A0000a
+BC2GM001191968
+P00411465A0417
+BC2GM076616336
+P10498706A1219
+P10219091A0246
+P10698937T0000
+P09468509A0463
+P10082570A0440
+P10502434A0604
+P08628284A0181
+P10194230A0817
+P10377438A0647
+BC2GM018687842
+P10492127A0914
+P08506384A0146
+P05101997T0040
+P10430583A0000
+P10531342A1111
+P10096469T0000
+P10484818A0292
+P11800586A1090
+BC2GM005932533
+P10232078A0552
+P10358138A0672
+P10556046A0328
+P11595840A0000
+P10021333A0674
+P08106512A0522
+P10488147A1176
+P11882054A1250
+P10471721A0141
+P10231026A0253
+P11599079A1040
+P10403839A0140
+P11790897T0000
+P10319320A1022
+P11715079A1016
+P10075415A1178
+P11804100A0365b
+BC2GM035505674
+P01316459A0311
+BC2GM063365941
+P02591993A0000
+P01406630A0545
+P11705093A2016
+P10672899A0078
+P10190324A0000
+P10405635A0374
+BC2GM015390020
+P01710985A0315
+P10376991A0977
+P10411140A0499
+BC2GM006272677
+P11893403A0252
+P10458914A0674
+P10511554T0000
+BC2GM037553498
+P10438627A0885
+P10181397A0641
+P10375107A1138
+P10092847A0455
+P10353073A0118
+P10478848A0331
+P11800878T0000
+P10362652A1456
+P10196127A1059
+P08798641A0400
+P11587514A0758
+P11697760A0000
+P10518956A1212
+P10366722T0000
+P10209119A0076
+P10024498A0783
+P10379942T0000
+P11710685A0994a
+P10541432A0185
+P10087213A0878
+P10340883A1266
+P10491187T0000
+P11709561T0000
+P11840365A0949
+P10898795A0527
+P09192769T0000
+P10430580A0000
+P10350638A0000
+P11875695A0718
+P10541550A0487
+P10556089A0901
+P11736792A0204
+P10070158A0573
+P10452306A0502
+P10318859A0535
+P10426450A1458
+P11678437A0000
+P10231454A0731
+P10477583A0000b
+P10318918A0824
+P11595170A0582
+P10091594A0284
+P10487921A0132
+BC2GM018263888
+P01545787A0345
+P10460171A0842
+P11822790A0907
+P10532354A1374
+P11846187A0894
+P10489680A0927
+P10499357A0439
+P10517675A0809
+P10712618A0181
+BC2GM005637228
+BC2GM088793769
+P10454540A0392
+P10488148T0000
+P11806132A0253
+P09136080A1469
+P10517666A1069
+P10364523A0826
+P11776922A0830
+P10078734A0480
+BC2GM002856642
+P10454561A0594
+P10373507A0680
+P10209021A0212
+P11728771A0187
+P10496388A1956b
+P10094701A0000
+P10072774A0537
+P08662928A1153
+P11853943A0122
+P07565736A2134
+P10087993A0782
+P10225279A0450
+P05161399T0025
+P10364319A0109
+BC2GM026767504
+P10467403A0000
+BC2GM013271145
+P10199539A1353
+P11500377A0518
+P11824801A0661
+P10090535A1194
+P10523674A0000
+P10224257A0079
+P10334888A0960
+P10196248A0482
+P11744953A0878
+P10101198A0632
+P02590278A0540
+P10333526A0459
+P10026784A0929
+P10453371A0640
+P10318900A0637
+P10196318T0000
+P09473317X2131
+P10438924T0000
+P10037576T0000
+P10490816A0000
+P10400794T0000
+P10428294A0227
+P08183915A0000
+P09129147A0644
+P11732417A0571
+P10085120A0000
+P10385384A0654
+P10531360A0958
+P10406465A0589
+P11893767A0356
+P01833185A0547
+P10358080A1114
+P10395378A1198
+P10369625A0942
+P11862350T0000
+P09858619A0356
+P09317131A0000
+P10026824A0309
+P10490955T0000
+P10541865A1301
+P10212426A1067
+P10366559A0605
+P10487753A0788
+BC2GM030124031
+P10331646A0595
+P09317131A1332
+P11160280A1275
+P10529198A0068
+P11599840A0813
+P10523319A0209
+BC2GM088433679
+P11589779T0000
+P10392669A0935
+P11881923A1256
+BC2GM065421759
+P10411139A0887
+P10221820A0902
+P11303027A0954
+P11726413A1756
+P10392903A0889
+P10049775T0000
+P10202006A1266
+P10446998A0955
+P10322629A0198
+P11596104A0614
+P10460015A0465
+P10326221A0531
+P08946166A0568
+P11730182A0984
+P10446998A0375
+P10477597A0126
+P10203611T0000
+P10318806A0918
+P10512699T0000
+P10097932A0915
+P10413607A0085
+P10196597A0510
+P10449072A0560
+P08455611A0000
+P10082585A0512
+P10476970A0542
+P10453006A0000
+P10320480A0451
+P10556044A0913
+P10233885A0899
+P09451016A1037
+P10553551A0000
+P10320177A0487
+BC2GM009964186
+P10390538T0000
+P11597936A0570
+P08970984A0765
+P10506143A0610
+P10347220A1477
+BC2GM014918843
+P08382139A1111
+P10493580A1126
+P10562418A0238
+P11723511A0780
+P10430944A1298
+BC2GM017582406
+P10536369A1280
+P10488088T0000
+P10518937A0572
+P10495573A0365
+P10085505A1184
+P10209759T0000
+BC2GM006324019
+BC2GM020863784
+P10482565A0469
+P10220275A0694
+P10496388A1956a
+P11587980A1039
+P11680835A0756
+P10051400A0000
+P10231862A1117
+P11791571T0000
+P10085605A0239
+P10393422A0476
+P10330396A0387
+P11036939A2149
+P10096573A0207
+P10543727A0282
+P10413662A0193
+P10027498A0536
+P10090943A1976
+P11913427A0290
+P11826141T0000
+P10082554T0000
+P11866130A0419
+BC2GM086763162
+P11737900A0700
+P10516026A0270
+P10049742T0000
+P10670681A0952
+P10077533A0976
+BC2GM090138510
+P10488875A0000
+P11708032A0183
+P11885053A1897
+P11908529A0553
+P10355085A1119
+P10095062A0558
+P10187842A1155
+P11737158A1517
+BC2GM034088457
+P01426109A1837
+P10391903T0000
+P01426635A0496
+BC2GM043332798
+P10406843A1265
+P10029917A0366
+P10359014A1077
+P11899479A0122
+P10037004A0000
+P10449899A0881
+P10478275A1230
+P10391246A0756
+P11708431A0904
+P10092132A0285
+P10395283A0960
+P11685047A0301
+P10497199A0559
+P10380878A0542
+P10453006A0478
+P10406122T0000
+P10512882A0137
+P10098601A1320
+P10022867A1069b
+P10080436T0000
+P10428811A0628
+P10207092A0924
+P10101744A0917
+P10534402A0659
+P10503812A1450
+P11679441A0429
+P11787720A1313
+P10467004A0683
+P10369775A0178
+P08692924A0328
+P10454570A0846
+P11804100A0365a
+P10376065A0881
+P04798293T0029
+P10556145A1034
+P11708362A0889
+P11005831A0242
+P11586096A0699
+P10407269A0000b
+P10406954A0715
+P10423156A0265
+P10458905A0000
+P10153759A0360
+P10037774A0366
+P11810685A0147
+P10086544A0504
+P10090125A0750
+P10205933A0699
+P11718197A1282
+P10488087A0340
+P10383764A1809
+BC2GM005330146
+P10748054T0048
+P10466825T0000
+P10232872A0081
+P11730262A0874
+P10225945A0436
+P10417703A1326
+P10026275A0549
+P08505312A0285
+P10452991A0331
+P10463057A0534
+P10367240A1354
+P10228561A0539
+P11890354A0000
+P10367385A0000
+P10551816A0162
+P11783457A0000
+P11887803A1455
+P10556595A0391
+P10198056A0000
+P10358079A0391
+P09806830X1174
+P10428811A1067
+P10357751A0866
+P10452951A0000
+P10076007A0656
+P11904017A0000
+P10502434A0367
+P10342829A1370
+P10022210A0620
+P11881268A0000
+P10445161A1565
+P01348684A0000
+P11764226A0798
+P11876937A0261
+P11726262A0692
+P10224513A0240
+P10532805A0792
+P11708761A1388
+P10518956A0137
+P10561460A0615
+P10393197A0543
+P11897888A0590
+P10094314A0935
+P10068040A0136
+P10370778A0000
+P10319327A1237
+P10231581A1125
+P11861092A0730
+BC2GM011894137
+BC2GM010461186
+P10430883A0000
+P11895024A1054
+P10215485A0837
+P10022880A0000
+P10344736A0796
+P11595813A0633
+P11707977A0750
+P08709637A1471
+P10428862A0834
+P10102136A0220
+P10102136A0646
+P06778645A0000
+P09223506T0000
+P10217683A0509
+P10226029A0905
+P10542274A1376
+P10430421T0000
+P10588946A0432
+P10419521A0136
+P10208893A0839
+P10366503A1506
+P11863811A0259
+P09032250A0257
+P10445506A0073
+P10333529A0277
+P10553959A0812
+P10330159A1258
+P09343210A1112
+P08944755A0211
+P10212284A0000
+P10364076A0429
+P10095059A1003
+P11816779A0343
+P10066815T0000
+P10074921A1169
+P10025506A0079
+P10366446A0893
+P01851756A0743
+BC2GM029775114
+P10207049A1001
+P10099247A1051
+P11782218A0349
+P10328351A0443
+P10194769A0146
+P10375694T0000
+P10517672A1417
+P10409730A0597
+P10464185T0000
+P11677839A0876
+P10475972A0269
+BC2GM010073598
+BC2GM008918951
+P09794414T0000
+P10544089A1208
+P11600314A0000
+P10477545T0000
+P10393251T0000
+BC2GM026003128
+P10496553A1004
+BC2GM075861735
+P10228157T0000
+P10417331A1008
+P07659529A0135
+P03125420A0421
+P10463242A0316
+P10454533A0859
+P10195425T0000
+P10485353T0000
+P07862168A0000
+P10229668A0190
+P10207049A0693
+P10358031A0303
+P10561153A0225
+P10392900A1020
+P10496284A0115
+P10073947A1110
+BC2GM056590088
+P10349443A0358
+P10502402A0533
+P10094396A0000
+P10372627A0530
+P10022867A1069a
+P11727209A0502
+BC2GM002743419
+P08441379A0912
+P10087993A1352
+P11771979A1141
+P10518502T0000
+P10490822A1167
+P10052878A0135
+P01309587A0715
+P10557008T0000
+P09376325A0167
+P10229084A0000
+P10394116T0000
+P10549354A1782
+P10323463T0000b
+P11693461A1649
+P10367646A0569
+P01986254A0452
+P10353880A0257
+P10400757A0000
+P01827203A0136
+P11584328A0532
+P10402022A0432
+P11785827A0986
+P11828186A0239
+BC2GM038738146
+P10403690A0000
+P11736254A0000
+P11802601A0107
+P10348859A0292
+P10216052A1682
+P11669476A0346
+P10233946A0000
+P10501969A1329
+P10518496A0952
+P09846482A0441
+P10051488A1293
+P10187864A1372
+P10342511A0909
+P03600633A1069
+P10358075A0984
+P10375638A0859
+P11791853A0532
+P09990060A0937
+P10364314A0919
+P10101159A0742
+P10501034A0839
+BC2GM012913597
+P10332733A0000
+BC2GM075291885
+P10490609A0413
+P08985415A1096
+P11684665A0000
+P10098744A0630
+P10036191A0000
+P10459809A1262
+P10077188A1172
+P10446206A0000
+P07605990A1110
+P11775301A0797
+P11768467A0000
+P10549912A0136
+P01695378A1406
+P10483124T0000
+P10400032A0304
+BC2GM091451815
+P10206698A2041
+P10376874A0759
+P10441506A0098
+BC2GM029039601
+P10049357A0608
+P10068834A0713
+P10224244T0000
+P11726574A1304
+BC2GM081756425
+P11723928A0294
+P10617613A1192
+P10457075A1198
+P11704380A1608
+BC2GM054841165
+P10187798A1098
+P10411139A1344
+P10086725A0000
+P10343189A0911
+P09572990A0630
+P11743360A2491
+P10521796A0872
+P10215594A1728
+P10350484A0346
+P10373029A0204
+P10025506A1078
+P01968061A0371
+P10037460A0221
+P10523520A0986
+P10068446A0124
+P10521450A0437
+P10527158T0000
+P08122364A0954
+P11590364A1056
+P07935451T0000
+P10455143T0000
+P11642687T0000
+P10561095A2141
+P10326856T0000
+P10542260A0832
+P10407184A0149
+P10403575A1401
+P11686378A0326
+P10503540A0602
+P10523663A0404
+P10370675A0649
+BC2GM020185752
+P11605598A0785
+P10555079A0254
+P11800119A0814
+P10560014A0000
+P11915436A0491
+P11726068A0539
+P01346534T0000
+P11895184A0000
+P10281637A0000
+P11777632A1678
+P10490639A0000
+BC2GM080507424
+P10339566A0602
+P11885737A1713
+P10069815A0285
+BC2GM043173941
+BC2GM041662908
+BC2GM035707050
+P10523647A1001
+P10212332T0000
+BC2GM089252708
+P10477583A0000a
+P10205176A0000
+P03044592A1061
+P10364425A0610
+P01744042A1355
+P10441449X1212
+P10363517A0401
+P10103002A0705
+P10548434A1549
+P10447593A0144
+P10396343A0754
+P10320579A1831
+P10497874A0925
+P10533066A1197
+P11716441A0585
+P07686619A0704
+BC2GM073260953
+P10446998T0000
+P11886473A0796
+P09920882A0287
+P10454550A0960
+P10091619A0104
+P10323863A0852
+P10540915A0697
+P11500512A0000
+P10516878T0000
+P11578685A0077
+P11899489A0119
+P10429184A0000
+P11858635A0896
+BC2GM024708623
+P10442493A0815
+P10487759A0630
+P10422468A0524
+P10071761A2374
+P10438924A1009
+P10518561A0885
+P10521509A0000
+P10425094A1006
+P10036181A0603
+P01406630A0965
+P10380800A0194
+P11844812A0915
+P10065176A0657
+P11836303A1191
+P02163347A0472
+P11732088A0471
+BC2GM088713745
+BC2GM093016277
+P11687869A0000
+P10556063A0092
+P10073899A0740
+P10192134A1088
+BC2GM065096427
+BC2GM092790663
+P10523647A0000
+P10757975A0509
+P11595176T0000
+P11602353A0770
+P09932288A0378
+P09139721A0183
+P10195690A0000
+P10022858A0985
+P10085088A0918
+P10413604A0063
+P10231513T0000
+P10231485A0342
+P10557308A0000
+P10080875A0772
+P10022925A0870
+P11675912A0131
+P11766747A0000
+BC2GM004506929
+P10487953A0765
+P11884014A0665
+P10446131A0132
+P11706668A0000
+P11600467A1436
+P10439040A0658
+P10381377T0000
+P11579100T0000
+P09279813A1389
+P10487762A0252
+P10215811A0635
+P10361038A0281
+P08455611A0154
+P10385395A0000
+P10206152A1024
+P10216161A1530
+BC2GM019293265
+P10521544T0000
+P10551788A0229
+P11781615A0000
+P10407985A0574
+P10550574A1038
+P11741259A1233
+P11845547A0449
+P11580301A1161
+P10323463T0000a
+P10531334A0525
+P10194451A0000
+P08662928T0000
+P11279217A0273
+P10026146A0680
+P10436016A0337
+P08756617A1204
+P10478844A1604
+P10347203A0832
+P10390158A1150
+P03182802A0278
+P10216052A0105
+P10218200A0534
+P10379942A0956
+P10406462A1127
+P10455183A0930
+P10542281A2021
+BC2GM057764341
+BC2GM051178458
+P10087549A0720
+P11769229A0357
+P11822811A0319
+P11834476A1187
+P07738856A0174
+P10198003A1505
+P07592676A0466
+P10224758A0202
+BC2GM064017613
+P07814403A0433
+P10446149A0809
+P10527426A0521
+P10027904A0768
+P10395908A0236
+P11859400A0229
+P11691585T0000
+P10050883A0967
+P11902781A0550
+P10521447A0606
+P10220364A0087
+P10502402A0129
+P11760796A0698
+BC2GM043622260
+P10068674A0644
+P10403839A1459
+P10359673A0000
+P10074903A0915
+P09837933T0000
+P10687862A1980
+P08183915T0000
+P10516011A0471
+P10215850A0754
+P10540292A1179
+P10223338A1601
+P10440923A0684
+P10497262A0000
+P10202006A0546
+BC2GM075049436
+P10559320A0080
+P10492169A0939
+P11816458A0319
+P10223498A0479
+P10211919A0846
+P11676899A0704
+BC2GM067017397
+P10400785A0912
+P10556751A0758
+BC2GM074512746
+P11596838A1357
+P10226838A1011
+P10527475A0643
+P11860097A1695
+P10557072A1218
+P10526670A1828
+BC2GM024845152
+P10228009A0600
+P10438540A1185
+BC2GM054094309
+P10551796T0000
+P10464310A0218
+P08530384A0559
+P11852907A0871
+P10543949A0686
+BC2GM002300410
+P10051488A1610
+P10428759A0743
+P11851941A0372
+BC2GM035315423
+P10026784A0331
+P10393251A0283
+P10556028A0292
+BC2GM045755791
+P11844591A0329
+P11761601A0133
+P11704829A0312
+P11580173A0181
+P10430980A0465
+P10488129T0058
+BC2GM045303279
+P10029337A0406
+BC2GM083535249
+P10441483A0454
+P10409699A0292
+P11600365A0471
+P10429740A0000
+P10545248A0567
+P10233147A0218
+BC2GM041496183
+P10022978A1261
+P10359603A0430
+BC2GM049191503
+P10073940A0335
+P10385915A1341
+P10435595A0203
+P10221467T0000
+P10524258A0286
+P10544088A0308
+P10369926A0251
+P09341193A0362
+P10207090A0801
+P11687180A3209
+P10322022A0263
+P10229668A0560
+P10228155A1293
+P10559303A0000
+P11778044A0000
+P10392903A0000
+P10414451A0093
+P11792586A0290
+P10542237A0357
+P11847580T0000
+P10542249A0415
+BC2GM079897140
+P11787746A0374
+P10318806A0476
+BC2GM081421874
+P11898018T0000
+P10438941A1197
+P11600252A0795
+P10425445T0000
+P10329586A0414
+P10470220A1011
+P10458907A0543
+P08621451A0552
+P10308312A0203
+P10379547A0000
+BC2GM000365921
+P11778804A0179
+P10082573A1015
+P10562456T0000
+P07635572A1153
+P10427654A0000
+P10224289T0000
+P09837914A0844
+P08683106A0374
+P11687517A1619
+P10319955A0941
+P10024383T0000
+BC2GM079234722
+P10095061A0592
+P11858256A0102
+P09115242A0934
+P07822333A0376
+P10376446A0000
+P10444597A0586
+P10022875A1265
+P10513756A0584
+P10029860A0605
+P10496161A0503
+P10542277A0000
+P10557072A0418
+P10383966A0000
+P10516738A0925
+P10471696A0734
+P10209119A0594
+P09710582A0535
+P11900770T0000
+P10502216A0289
+P10487744T0000
+P10498616A0157
+P10364523T0000
+P08419318A1695
+P10376877A0611
+P10197763A0580
+P11589568A0744
+P10224293A2021
+P10207041A0065
+P08383323A0000
+P10548722A0099
+P10205176A0704
+P10223338A2186
+BC2GM033128498
+P11811825A0972
+P11606538A1002
+BC2GM007417930
+BC2GM056813896
+P10428091A0322
+BC2GM090401322
+P10364163A0092
+P11577094A1226
+P10367460A0191
+P10532805A1084
+P10084294A0219
+P10342829A0236
+P11593394A0000
+BC2GM033438467
+P11909404A0000
+P11804081A0552
+P10471746A1102
+P10234698A0728
+P11865218A0069
+P10359663A0425
+P10400760A0663
+P10491213A0263
+P10215608A0161
+BC2GM033539828
+P10430890A1059
+P09057648A0422
+P10497117A0358
+P02049617A0504
+P10347839A0434
+P10232600T0000
+BC2GM048938799
+P10068637A1320
+P11787041A0167
+BC2GM009274132
+P10536369A0662
+P11882054A0568
+P10469656T0000
+P11711701A0602
+P10388670A1976
+P08332492A0145
+P11604152A0526
+BC2GM058996965
+P10377345A0740
+P10398286A0678
+P11907691A0214
+P10350027A0942
+P11802580A0000
+P10101198A0946
+P10400712A0000
+P10545281A0836
+P10226074A0637
+P10092856A0798
+P10487307A0768
+P10438607A0330
+P10518561A0261
+P10542269A0000
+P10327051A0688
+P10531342A0348
+P10333481A1102
+P10037681A0494
+P10512699A0364
+P10499121A0542
+P11830544A0335
+P11846167A0000
+P10469174A0678
+P10396793A0815
+P10479025A0528
+P10413676A1193
+P10501656A1415
+P10271171A0458
+P10097120T0000
+P10409656A1016
+P11369759A0605
+P10090943A1426
+P10021350A0093
+P10373523A0924
+P11867388A0502
+P10395920A1424
+P07636179A0000
+P10051030A1080
+P10329736A0681
+P10394900A1166
+P10397257A1142
+P11874637A0212
+P10540015A0664
+P10422342A0535
+P10473589A0189
+P10329736A1106
+P11683558A0446
+P11730712A0416
+P07665567A0495
+P10548622A0906
+P10063739A0601
+P10555285A1065
+P09234696A0238
+P09209372A0345
+P03182872A1122
+P10536125A0093
+P11738404A0120
+P10366503A0812
+P10369757A0000
+P11691585A1174
+P10529354A0375
+P10446833T0000
+P07059567T0055
+BC2GM076533289
+P11639485A0478
+P10482516A1158
+P10556033A0000
+P10514493A0199
+P10467465T0000
+P10438950A0580
+P10392710A1000
+P10323225A0244
+P10472836A0189
+P11917882A0326
+P10350454A0000
+P10513922A1237
+P10504332A0701
+P10409749T0000
+P11773168A0915
+P11835109A0000
+P10229682A1151
+P10464302A1109b
+P10534402A0126
+P11744290T0045
+P10318806A0000
+P10446912A0883
+P08504932A0123
+P11921126A1196
+P10082137A0262
+P10065684A0916
+P10713175A1399
+P10211422T0000
+P10037378A0176
+P10429946A0988
+P10074425A0729
+P11791292A0193
+P10473598A0691
+P10200473A0171
+P10454557A0975
+P10364202A0646
+P10330168A0135
+P10022921A0608
+P08011009T0057
+P10490843A0159
+BC2GM056160161
+P10502522A0000
+P10475610A1289
+P11858548A0241
+P11890438A0838
+P11763176A0918
+P10551867A0350
+P07579328A1345
+P10448285A1035
+P11278488T0000
+P10329574A1733
+P11912261A0284
+BC2GM018128647
+BC2GM003056399
+P10487040A0453
+P11804510A0730
+P11791585A0287
+P10544113A0293
+P11726022A0909
+P09712915A0672
+P10074282A0236
+P10491133A0365
+BC2GM084077526
+P11597185A0477
+P10026229A0950
+P10534048A0297
+P08157663A0882
+P10214610A0900
+P11811743A0800
+P08219072A0287
+P10364159A0813
+P09949178A0264
+P10396343T0000
+P10554946A0082
+P11831512A0468
+P10479382A1098
+P10523640A0367
+BC2GM082122625
+P11740571A0114
+P10407184A0520
+P10329135A1326
+BC2GM073729839
+P09209438A0994
+P07579328A0653
+P11842037A0327
+P10085140A1004
+P10466306A0000
+P10355910A0369
+P11677363A0775
+P02213128A0209
+P10561546A0000
+P10501965A0879
+P10471743A0000
+P10355536A0172
+P11716043A0380
+P10534691A0542
+BC2GM044941923
+P10490662A0431
+P11917061A0922
+BC2GM050074470
+P10509768A1118
+P10369965A0000
+P10347197A0502
+P10422291A0572
+P10497800A0000
+P10464291A0597
+P11703464A0560
+P10102627A0217
+P10235265A0197
+P10359663A1280
+P10413676A0595
+P10212278A0387
+P11742432A0798
+P09234727A0770
+P10542281A0382
+BC2GM035682880
+P11723675A1022
+P11837409A0584
+P10196316A0715
+P10446910A0147
+P10559364A0846
+P10455189A0104
+P11706949T0000
+P10409755A1846
+P10556029A0852
+P10409724A1021
+P10198061A0339
+P11825801A1212
+P07706273T0000
+P09278441A0163
+P10210952A0261
+P10526670A0236
+BC2GM033482973
+P10090146T0000
+P10218109T0000
+P10471587A0239
+P10207115A0389
+P07657162A1412
+P10192638T0000
+P10380659A0545
+P10438593A0000
+P10536788A0931
+P10026784A2166
+P10197985A0145
+P10393201A0654
+P10485470A0242
+BC2GM078078489
+P10195697A0456
+P11870646A0668
+P02034676A0267
+P10342536A0954
+P10460172A0823
+BC2GM001006298
+P10071806A0377
+BC2GM040930805
+P11920896A0298
+P10482620A1009
+P10545192T0000
+P10406459A0000
+P02083253A1512
+P10326654A0351
+P10406047A1244
+P08443122A0657
+P10400712A0577
+P11786248A1162
+P10171173A0955
+P10448095A0865
+P10406464A0687
+P11695481A0310
+P11692004A1200
+P11860723A0182
+P10426878A0367
+P10395827A1297
+P08642282A1009
+P10022850A0929
+P11777575A0363
+P10486210A0126
+P10212969A0470
+P10419006A0378
+P10360839A1338
+P10080901A0271
+P10477748A1076
+P11741554T0000
+BC2GM090825486
+P10358080T0000
+BC2GM094941573
+P10146207A0223
+P10455189A0427
+P10192432A0214
+P10448036A0748
+P10490835T0000
+P10331276A0298
+P11888183A0541
+P10100605A0392
+P10525413A1408
+BC2GM011031439
+BC2GM091665948
+P10359792A0610
+P10512857A0000
+P11882747A0354
+P10325413A1211
+BC2GM099329110
+P11898797A0124
+P10369418A0644
+P10066798A0391
+P10477620A0580
+P10559324A0716
+P10489822T0000
+BC2GM039407902
+P10207087A0956
+P10330134A0765
+P10196266A0000
+P10493575T0000
+P10468585A0980
+P08065331A0279
+P03510185A0187
+P10531446A0203
+P10381570A1355
+P10224293A0000
+BC2GM014618195
+P11883763A1062
+P07873876A1035
+P10194762A0648
+P10413676A0000
+P10490826T0000
+P10549354A2371
+P11819326A0000
+P10423292A0782
+P11710685A0994b
+P01531086A0127
+P10524258T0000
+P02822081A1034
+P09371612A1964
+P11689217T0000
+P11765448A0588
+P10399136A0389
+P11703558A0000
+P10392266A0111
+P10381257A0000
+BC2GM065607488
+P10482516T0000
+P10074135T0000
+P10360454A0916
+P10360947A1113
+P10049359A1073
+P10444813A0448
+P10543730A0000
+P10026211A0543
+BC2GM026532994
+BC2GM033988822
+P10336495A0547
+P11833863A0987
+P10099576A0666
+P10380890A0619
+P10533066A0758
+P11883682A0162
+P10505694A0739
+P10455183A0530
+P05570175X0000
+P10329566A0610
+P11686239A0464
+P10347144A0516
+P10535715A0268
+P10068418A1194
+P10557072A0127
+P11755894A0466
+P10362652A0350
+P10523634A1404
+P10064604A0824
+P10508522A1598
+P10490604A0601
+P02144290A1444
+P10074520T0000
+P10025050A1052
+P10103057A0251
+P10521345A0202
+P10339552A0361
+P10468033T0000
+P10049912T0000
+P10024882A0541
+P10521443A0486
+P10376873A0706
+P11803325A0868
+P10201468A0297
+P10559207A0207
+P10022032A0000
+P10398682A0365
+P10477599T0000
+P10488337T0000
+P10505694A0000
+P10071205A0833
+P10340447A0424
+P10493203T0000
+P10453721A0445
+P10341219A0481
+P10469140A0336
+P10488148A0111
+P10365883A1355
+P10454557A0000
+P10447597A1004
+P10490662A0819
+BC2GM075375859
+P10487760A0336
+P10543728A0358
+P10391075A0000
+P11726164A0215
+P10498616A1280
+P11743612A1179
+P10433970A0279
+P10329625A0715
+P10400757A1498
+P10484695A0791
+P02943562T0000
+P11376946A0000
+P09305870A0894
+P07616569A0168
+P02310496X0000
+BC2GM077245777
+P03263357A0112
+BC2GM067367771
+P07891708A0690
+P07651734A0961
+BC2GM068839310
+BC2GM040624059
+BC2GM046184202
+P09220158A0537
+P08284227A0336
+P09765388T0000
+BC2GM030881541
+P08937989A1365
+BC2GM081134768
+P02631505A0382
+P00703350A0418
+P01607223A0000
+P02027839A0250
+P07838156A0789
+P09013760A0000
+P09459835A0297
+P10585453A1029
+P08336012A0632
+P08336543A0243
+P07125064T0000
+P11592315A0325
+P01392358A0389
+P09566918A1115
+P02094221A0247
+BC2GM055197158
+P07219297T0000
+P10529246A0362
+P11445008A0816
+P09210012A0000
+P10652324A0177
+P10823961A0664
+P02115889A0436
+BC2GM088454426
+P11134033A0639
+P09463560A0124
+P07136569A0000
+P09058250A0128
+P00808266T0000
+P03249840A0411
+BC2GM062680443
+P08605326A0772
+BC2GM028090853
+P10411160T0000
+BC2GM068116027
+P02870249T0000
+BC2GM090043718
+BC2GM031957537
+P05472485T0000
+BC2GM094642532
+P04039667T0000
+P02167784A0109
+P11393791A1153
+BC2GM068734803
+P09882593A0996
+BC2GM084966023
+P03755673A0054
+P09288848A0780
+P07298209A0291
+P01569584A0672
+P02383771A0544
+BC2GM024386015
+P10727433T0000
+P08194549A0000
+P08563483A0094
+P01808602A0000
+P03306340A0537
+P09454735A1782
+BC2GM052716394
+P11294895A0292
+BC2GM070216905
+P07436702A0156
+BC2GM040960284
+BC2GM006980122
+P08470021A0195
+P08626612A1040
+P01298398A0461
+BC2GM039069187
+BC2GM051430553
+BC2GM070556783
+P07667195A0146
+P09731513A1090
+P06362143A0565
+P03678372A0170
+BC2GM009017382
+P01404401A0740
+P09747651A0000
+P02080902A0183
+P10871412A0369
+P02599995A1031
+P09317830T0000
+BC2GM008847096
+P02843495A0544
+BC2GM082714483
+BC2GM022687280
+BC2GM021508246
+BC2GM055477804
+BC2GM018717750
+BC2GM076247276
+P09678837A0736
+BC2GM052715986
+P10714985A1057
+P04073848T0000
+P02818122A0000
+P07959734A0194
+P02183467A0668
+BC2GM079025954
+P02796216A0063
+P11094072A1234
+P00753237A0000
+P08702633A0164
+P09352127A0953
+BC2GM044796005
+P10623758A0947
+BC2GM051722169
+BC2GM046544917
+P10785880A0947
+P01719684A0494
+P06345840A0348
+P08468475A1280
+P08007835A0538
+BC2GM018532054
+BC2GM058638697
+BC2GM025900425
+P06851280A0144
+P08938418A0099
+P11838058A0084
+P10850329A0248
+BC2GM030782524
+P08664229T0000
+P03908196T0000
+BC2GM076151355
+P05908762T0031
+BC2GM039160075
+P09276882A0479
+P11167019A1249
+P11156303A1098
+BC2GM085686844
+P08623554A1058
+P11517190A0352
+P03234790T0001
+P08574583A0658
+P03120334A0893
+P09340641T0001
+BC2GM044336863
+BC2GM093642275
+P07670504A0834
+P03820222A0203
+BC2GM092138955
+BC2GM057451821
+P10893243T0000
+P06189698A0246
+P07885999A0000
+BC2GM009597017
+P03212551T0001
+P07599449A0445
+BC2GM039068445
+P07126067T0000
+P09703816A0139
+P10940892A0573
+P08554540A1480
+BC2GM077752729
+P08703005A0645
+P02998016A0527
+P10047970T0013
+P08440688A1509
+P11429702A0917
+P00129659T0000
+P10991383A0289
+BC2GM044291180
+BC2GM008214727
+P06085839A0721
+P01339815A1545
+P00987649T0001
+P01347944A0964
+BC2GM066832835
+P10850942A0989
+P09643546A0436
+BC2GM076238232
+P05340801T0000
+P01235347T0001
+BC2GM094364440
+BC2GM056788126
+P08408963A0048
+BC2GM051214920
+P09852752A0950
+P00872442T0000
+P07888828A0765
+P04048245A0331
+P08207232A0503
+P08415712A1153
+P04810131T0000
+P09303437A0875
+BC2GM084163116
+P09164543A0219
+P11552058A0833
+P03073091A0449
+P04515631T0000
+P08657150A1049
+P08247005A0584
+BC2GM030293079
+BC2GM038263382
+P09499048A1003
+P08618864A0754
+P06259220A0000
+P06735247A0803
+P09303635A0000
+P10592791T0001
+P01896777T0000
+BC2GM055239754
+P08094927A0311
+P09722508A0953
+P02874078A0252
+P01402647A0114
+BC2GM037804373
+P07739544A0364
+P08435755A1078
+P01901405A0694
+P11250196A0455
+P08654200A0274
+P09225682A0579
+BC2GM007864175
+BC2GM091799459
+P11435688A0262
+P09792630A1127
+BC2GM089615963
+P04040307A0145
+P08095875T0000
+P01347664A1026
+P07760841A0647
+P04025178A0126
+P10908822A0519
+P10722063A0328
+BC2GM074447065
+P02844797A1225
+P08995054A0618
+P01377962A1012
+BC2GM050389722
+P11212249A0993
+BC2GM092152216
+P11198385A0000
+P04653144T0000
+P09182281A0197
+BC2GM038917907
+P08492164T0000
+BC2GM055437471
+P08276336A0371
+BC2GM028935369
+P11302566A1318
+P08615183T0000
+P07651386A0925
+P03967144T0001
+P09315632A1137
+P06200300A0409
+P02149570T0000
+P10897973T0001
+P08496157A0000
+P01774822A0289
+BC2GM029565037
+P07935997A0000
+P09893913A0656
+P10919971A0606
+BC2GM009734777
+P08182041A1067
+P11042197A0386
+P03697798T0001
+P03275873A0379
+P08196624A0593
+P02836623A1094
+P08762172A0178
+P00313766A0666
+BC2GM067850977
+P09482902A0423
+P00064414A1098
+P08385337A0282
+P08086453T0000
+P03612648A0085
+P04510102T0000
+BC2GM034205084
+P03979084A1019
+P01669611A0142
+BC2GM085416989
+P01316461A1083
+P09575143A1189
+P03091849A0000
+BC2GM066303688
+P10620777A1399
+P08193147A0831
+P11278594A0618
+P02272095A0832
+P06911559T0000
+P09620606A0000
+P02025515A0979
+BC2GM071680095
+BC2GM006829575
+P09726979T0000
+P08388600A0000
+P09200811T0000
+P02830214A0000
+P10647859A0000
+P02418701A0000
+BC2GM047650925
+P07630687A0010
+P08969495A0256
+P09582327A0295
+BC2GM083779200
+P08375651T0000
+P07779811A0901
+P08223554A0574
+P11122588A0549
+P01961996A0522
+P06962634A0190
+P01380716A0174
+P07762431A0356
+BC2GM026487710
+P01552662A0398
+BC2GM064062109
+BC2GM065297737
+BC2GM068080836
+P11224226A0000
+P10744749A0315
+P03700952A0273
+BC2GM004675076
+BC2GM087325432
+P08816443A1674
+P08900190A0430
+P11580757A0304
+BC2GM097338238
+P08824585A0260
+P01408219A0670
+P01931966A0490
+P07476963A0000
+P08662980A0762
+P10591633A0138
+P10592791A0370
+P10627834A0178
+BC2GM025050820
+P03622423A0000
+P01443745T0000
+BC2GM000816003
+P03862898A0563
+P08439597A0176
+P01692135A0783
+P11574088A1687
+P08663000A0000
+P08824800A0808
+BC2GM071692892
+P09067577A0307
+BC2GM091139291
+P10932527A0947
+BC2GM061416577
+P07783064A0452
+P08419338A0273
+P03688202A0377
+BC2GM046405419
+BC2GM069267647
+P08972232A0365
+P10652362A0933
+P00193587T0000
+P01360180A0513
+P08366034A0637
+P01557411A1282
+P08898336A0268
+P00222102A0227
+P11014215A1092
+P11063742A0000
+P08384309A0000
+BC2GM094180317
+P01357528A0084
+BC2GM091292121
+BC2GM096793174
+P08046923A0000
+P09241092A1108
+BC2GM020300405
+P08683108A0965
+P09114972A1366
+P11007509A1271
+BC2GM072257563
+BC2GM028014715
+P11214354A1104
+P10619254A1055
+P09241232A0653
+P09858531A1017
+BC2GM050378714
+BC2GM037320701
+P08350398A1616
+BC2GM042242435
+BC2GM081102567
+P08643578A0532
+BC2GM070631455
+P06687953T0000
+P06738410T0000
+BC2GM031056055
+P08455629A0335
+BC2GM038464760
+P02035805T0000
+P06319040A1627
+P08041362T0000
+P06434572A0157
+BC2GM090808370
+P02757033A0905
+P01673220A0578
+P03114995T0000
+P08682868A0738
+P01316680A0643
+BC2GM003525859
+P09346935A0459
+P02022188A1463
+P02123467A0811
+BC2GM036204067
+BC2GM024075956
+BC2GM030960650
+P06795900A0000
+BC2GM082875858
+BC2GM060654368
+BC2GM078904500
+BC2GM038768942
+P08632463A1508
+P09848653A0597
+P08555446A0000
+P10684646A0224
+BC2GM034370454
+P10903877A0879
+P08051059A1000
+P01690728A1166
+P02834843A0000
+P02711167A0818
+P04460692T0000
+P09046186A0189
+P08750702A0183
+P08639742T0000
+P08584026A0115
+P07530502T0000
+BC2GM022693469
+P08496184A0772
+P08575614A0264
+P09776360A0620
+P11102458A0000
+P10646863A0838
+P10892300A0268
+BC2GM012402149
+BC2GM087839527
+P02145268A1454
+P03622571A0208
+P11210839A0282
+P08878019A0357
+P01457695T0000a
+BC2GM046011623
+P02394718A0130
+BC2GM024610990
+BC2GM071336386
+P07937954A0612
+P10693314A0521
+P10634007A0202
+P08298129T0000
+P07681513A0000
+P09212059A1356
+P06300836A0285
+P09210478A0000
+P11243980A0510
+BC2GM095342382
+BC2GM084311645
+P11564893A1068
+P01190120A0832
+BC2GM025047286
+P08806817A0244
+BC2GM072049758
+P02885517T0000
+P08843411A0801
+P08858211A0694
+BC2GM016378782
+BC2GM083717359
+P10861909A0502
+BC2GM082852129
+P09467900A0701
+P10865422A0138
+P06328272A0705
+P07107462A0202
+P11046148A0716
+P10781541A1063
+BC2GM062590002
+P03430221A1236
+P07935415T0000
+BC2GM005581370
+P07813466A0074
+BC2GM052190930
+BC2GM054696358
+BC2GM020389288
+BC2GM061319895
+P08091665T0000
+P08628302A0683
+P08589358A0841
+P09704569T0000
+P09218599A0184
+P09822690A0000
+P11179664T0000
+P09225998A0000
+BC2GM057310449
+BC2GM079983245
+BC2GM084759712
+P00450367T0000
+P08683983A0785
+BC2GM083462824
+P01320255A0795
+BC2GM039225135
+BC2GM077712374
+P08761169T0000
+BC2GM051838944
+P04746559T0053
+P02409297A0984
+P02486634A0632
+BC2GM099774461
+P02209243A0237
+BC2GM042361998
+BC2GM095315156
+BC2GM075650650
+P07905413A0585
+P09598205A0430
+P08218056A0000
+P09795130A0742
+BC2GM072444628
+P10845522A0000
+BC2GM064897549
+BC2GM048672886
+P03052641A0204
+P08096066A0623
+P01358758A0000
+BC2GM074709603
+P08621719A0568
+P08558187A0403
+P09521909A0081
+P01321337A0318
+P03499822A0182
+P07379334A0503
+P01999035A0383
+BC2GM005019655
+P09346953A0000
+BC2GM005485785
+P06795654A0434
+P02165589A0888
+P09774641A0824
+P09753730A0881
+P09389198A0363
+P04084896A0569
+BC2GM090582830
+BC2GM044230142
+BC2GM044831438
+P08139562A0404
+P09736239A0436
+P02761540A0873
+P08226777A0936
+BC2GM077180939
+BC2GM084450992
+P08538702A0214
+P10955913A0827
+P09050861A0903
+P10897233A1057
+P07191183A0505
+P09837824A0419
+BC2GM057123623
+P11059777A0813
+BC2GM002436660
+BC2GM033866755
+P11430042A0000
+P09333231T0018
+P11158295A0158
+P08979089A1197
+P09005609A0299
+P10997863A0753
+P08075421A0621b
+P00877857A0763
+P01339468A0272
+P09292499A0887
+P10600171A1432
+P09211981A0526
+P11285329A0682
+BC2GM016645087
+P07386864T0000
+P09058373A1620
+BC2GM093130778
+BC2GM061863069
+P07583190A0306
+P02983316A0310
+BC2GM040688881
+P11145562A0468
+BC2GM091736061
+P08199878T0000
+P11191365A0682
+P09668098A0868
+P01383690A1023
+P07478514A0237
+P07094905A0644
+P03259437A0140
+P09153795A0298
+P07965152A0764
+P03777398A0156
+P09452421A1042
+P08409284A0262
+BC2GM011718257
+P03930549A0209
+P02324104A1195
+P06796300A0759
+P08125258A0142
+P11090172A0612
+P09147420A0623
+P08552092A1678
+P10999369A0192
+P03658866A0081
+P08088022A1417
+P06531286A0382
+P07980440A0138
+P09428799A0897
+P01448917A0775
+P09334264A0540
+BC2GM093377717
+BC2GM018952146
+P08505340T0000
+BC2GM012491320
+P01588315A0356
+P08626809A0729
+P00755869A0216
+P06786756T0000
+BC2GM036083760
+P06959130A0996
+P06818113A0384
+P01331086T0000
+P07707531A0550
+P00970488A0105
+P08913387A1010
+P11297419A0894
+BC2GM073658017
+BC2GM083424933
+BC2GM071527942
+BC2GM016009074
+BC2GM041356222
+P11194183A0866
+P07330073T0000
+P01679068A0000
+P08374753A0335
+BC2GM071545303
+BC2GM083230779
+P07730273A1309
+P02994336A0864
+P09445488A0230
+P06873504T0000
+P01358190A0654
+BC2GM081450728
+P04778129T0000
+BC2GM074423927
+P11793614A0000
+P09604052A0166
+P07753027A0240
+BC2GM080799996
+P07854130A1387
+P03714348A0833
+P03911052A0909
+P03999219A0463
+P06084810A0169
+P10767091A0133
+P07852361A0868
+P07509450A0705
+P09000632A2341
+P09606633A0523
+P00015731A0090
+BC2GM044172582
+P08663219A0246
+P09765754A1727
+BC2GM043498135
+P03998813A0406
+P08130942A0051
+P09419421A0385
+P10866689A0295
+BC2GM038447358
+P11241166A0677
+BC2GM011632979
+P08491383A0154
+P01396592A1113
+P10648619A0000
+P09148935A0805
+BC2GM047781094
+P10624787A0432
+P11500571A0976
+BC2GM092393835
+P07847036A0353
+P08649372A0755
+BC2GM097292555
+BC2GM029344954
+BC2GM023883518
+P04246054T0028
+BC2GM065395717
+BC2GM089738543
+BC2GM068132437
+P02164585A0814
+P02713310T0000
+BC2GM080041758
+P09478971A1896
+BC2GM087902003
+BC2GM061492332
+BC2GM074262156
+P09638650A0169
+P10574982A1075
+P09914500A0000
+P08763207A0402
+P09003617A0000
+BC2GM072003693
+BC2GM038644769
+P00473229T0000
+BC2GM029330776
+P00975314T0001
+P11283256A0258
+P11108839A0401
+P08296434A1141
+P01418542A0000
+P03041802A0975
+P08806817A0716
+P09591221A0137
+P03019505A0390
+P07729427A0942
+P08382300A0341
+BC2GM070291312
+P03998071T0000
+P07535593A0714
+P07256543A0814
+P09733794A1323
+P09040011A1316
+BC2GM031759031
+BC2GM001799055
+BC2GM095014015
+P09045919A1250
+P07999604A0139
+P10814989T0000
+P09633630A0740
+P11288208A0712
+P08710371A0000
+P10675154T0000
+P09914518A1217
+BC2GM064262659
+BC2GM095166166
+P10864271A0504
+BC2GM080831833
+BC2GM047324484
+P02417669A0218
+BC2GM048352135
+P07125238T0000
+P10660304A0522
+BC2GM010215483
+P09418905A1396
+P00808898A0000
+BC2GM031697099
+P06413492A0990
+P07202224A0452
+P09314306A0571
+BC2GM003460926
+P07369183T0000
+P00369683T0000
+P08344248A0910
+P08702543A0000
+P11198424T0000
+BC2GM076157697
+P02574551T0000
+P01647813A0512
+P09842517A0497
+P01371863A0000
+P06108610A0518
+P09658405A0000
+P09577395A0000
+BC2GM017308812
+BC2GM054501592
+P00094639A0313
+BC2GM026679979
+P01968043A0908
+P08221251A0239
+BC2GM019146982
+BC2GM004455813
+P06444119A0340
+P08794547A0648
+P02347407A0217
+P00027967A0207
+P02252953A0300
+BC2GM093309719
+BC2GM045265175
+P00701462A0722
+P06318322A0350
+P00755671A0485
+P08995614T0000
+P08182056A0695
+P07609037A0775
+P02141425A0175
+BC2GM030669575
+P01675424A0991
+P09280747A0195
+P11377975A0898
+P08459465A0257
+P08461981A0882
+BC2GM060862443
+BC2GM074751014
+BC2GM093459907
+P11358962A0344
+P08245456A0501
+BC2GM052850929
+P08682155A0902
+P03561622A0659
+P11350957A0457
+P08255758A0000
+P01296815A0059
+P01910505A0000
+P03929486A0309
+P08661101A0396
+P11049241A0659
+P11560992A0651
+P07214230T0000
+P07278104T0001
+P09080517A0215
+P08073505T0000
+BC2GM087011590
+P09584194A0000
+P09286981A0147
+BC2GM018608003
+P03549045A0878
+P11311480A0079
+P09665361T0000
+P11371115A0962
+P01549118A0000
+P07413781A0169
+P07894761A0000
+BC2GM060572853
+BC2GM048987709
+P01657969A1420
+P09147788A0458
+P11160307A0394
+P02033038A0309
+P08854844A0637
+BC2GM037134844
+P02591969A0961
+BC2GM053778229
+BC2GM097964351
+P09373155T0000
+BC2GM025395318
+P00029555A0861
+P11238884A0892
+P10656802A1724
+P09551182A0212
+P07137927A0000
+P08871567A0629
+P08534217A0402
+BC2GM056719795
+BC2GM094026101
+BC2GM036717390
+BC2GM065785628
+P08896795A0166
+BC2GM070056586
+BC2GM003935200
+BC2GM042317082
+P00728718T0000
+P10984122A0911
+BC2GM094133140
+P09628821A1194
+P11278610A0902
+P10009565T0000
+P09627598A0384
+P05794247T0000
+P11024036A0984
+P02229072A1012
+P08649424A0000
+P02573303A0000
+BC2GM021068289
+BC2GM024681168
+BC2GM041800456
+BC2GM058654225
+P01562659A0676
+P11428283A0228
+BC2GM091875448
+BC2GM070333070
+P09795170A0774
+P03890486A0000
+BC2GM020893421
+P08858463A0853
+BC2GM097798916
+P11044097T0000
+P02423533A1790
+P11584107T0000
+P01907265A0670
+BC2GM037544012
+BC2GM008819696
+P07829102T0000
+P09420220A0070
+BC2GM006873780
+P09660838A0920
+P09835615A0574
+P01267446A0210
+P08617243A0336
+BC2GM038704123
+P01698772A0238
+BC2GM007283823
+BC2GM027354703
+P03966687A0000
+P09360956A0840
+P07862092A0302
+BC2GM024346106
+P09353296A0510
+BC2GM044292594
+P09368100A1354
+BC2GM081507457
+P08386279A1621
+P00909114A0000
+P09713996T0000
+P09343432A0209
+P07992027A0485
+BC2GM016210640
+P02555703T0000
+BC2GM089906052
+P10885708T0000
+P03343730A0486
+P09959737T0000
+BC2GM032887840
+P08727192A0000
+P09001828A0222
+P05847772T0001
+P08289341A1202
+P10738139A0681
+P07877308A1175
+P08837503A0392
+P03712106A0000
+P01682542A0690
+P03974790A0053
+P01157614T0000
+BC2GM096535156
+P06948398A0523
+P09921179T0001
+P08812490A1509
+P08189533A0919
+P00743335T0001
+P07865786A0457
+P09710591A0981
+P07780738A0091
+P02833012A0428
+P02487898A0315
+P08526620A1344
+BC2GM024208708
+P09315631A1064
+P10756007A1512
+P11308851A0333
+P11464997A0566
+P01516829A0113
+P03011793A0582
+P02530413A0195
+P01545806T0000
+P01262596T0000
+P10907971A0806
+P11387351A0092
+P07678006A0901
+P02256678A1224
+BC2GM033846356
+P09819288A0578
+P10958698A0485
+BC2GM063584171
+BC2GM019111306
+P07268828A0000
+P09104816A0610
+P07418829A0191
+P03577670A0236
+P03285764A0675
+BC2GM066316127
+P03688676A0487
+P07929560T0000
+P09285715A1257
+P07235317T0000
+BC2GM015870833
+P08531669A0950
+P08807288T0000
+P09581834A2578
+P02360336A0574
+P11542780A0086
+P09200530A0411
+P09371431A1172
+P01313846A0850
+P09701609A0116
+P01883992A0922
+P00821833A0000
+BC2GM025023094
+P11069011A0224
+P09632709A0464
+BC2GM045948715
+P09467955A0468
+P02405393T0000
+BC2GM036507029
+P08201932A0355
+P09767504A1371
+P07845672A0368
+BC2GM037203350
+P03142875A0366
+P07865917A0191
+P07656588A0101
+BC2GM075340311
+P07600111A0000
+BC2GM016026210
+P11390663A1400
+P03877298A0718
+BC2GM009893203
+P09006051A1162
+BC2GM056659741
+P11513180A1257
+P11278848A1316
+P09781871A0404
+P07603726T0000
+P02002511A0637
+P01964989A0145
+BC2GM093469461
+P09748261A0000
+BC2GM028602474
+BC2GM013088114
+BC2GM014045933
+P07467975A0316
+P02143961A0400
+BC2GM054770517
+P10606515A0389
+P03359860A0000
+BC2GM055829583
+P00168431T0000
+P05414186T0001
+P10653697A0133
+P11387950X0001
+BC2GM066025610
+BC2GM072307565
+P10683244A0939
+BC2GM014162917
+P11368901A0327
+P08458906A0827
+BC2GM090355952
+BC2GM031364553
+P10958456A0529
+P09150774A0616
+P09192786T0000
+BC2GM004118493
+P08914532A0598
+BC2GM002848058
+P01326329A0703
+P09159183A0119
+P01976638A1135
+P06731302A0930
+P03065610A0375
+P06270347A0740
+P04369884T0000
+P02650663A0178
+P03280807A1447
+P11399834T0000
+P10899142A0000
+BC2GM006832917
+P03075154T0000
+P10918059A0569
+P08639837A0268
+BC2GM050006872
+BC2GM016568777
+P06670732A0000
+P07737944A0000
+P09121454A1328
+BC2GM032149031
+BC2GM038288477
+P07768848A1880
+P08643682A0268
+BC2GM097801700
+P00928529T0001
+P07744954A0418
+BC2GM049146071
+P08529662A0507
+P00641395A0441
+P01423454A0309
+BC2GM027382651
+BC2GM067715676
+P01977585A0222
+P02484994T0001
+P10895417A0000
+BC2GM080452134
+BC2GM090086707
+BC2GM057164114
+P07935395A0094
+P10788480T0000
+P08316240A1068
+P11024026A0133
+BC2GM064685099
+BC2GM093402905
+P08522511A1578
+BC2GM023906400
+P10895417A0669
+BC2GM003763223
+P07666523T0000
+BC2GM005600450
+P11029656A0640
+BC2GM067799557
+BC2GM099522196
+P09354349A0338
+P11177538A0655
+BC2GM060173727
+P01558942A1369
+BC2GM040040983
+P06209499A0682
+P07761434A1084
+P11223257A0404
+BC2GM093930415
+P09765271A1108
+BC2GM064850672
+P06539738T0000
+P11254864T0000
+BC2GM024410649
+BC2GM093150217
+P07537851A0000
+P02479823A0727
+P09990315A0205
+BC2GM039343812
+P01646487A0874
+P08449986A0455
+P09153319A0844
+BC2GM043010172
+BC2GM080426712
+P09800187A0100
+P09790767A0372
+BC2GM007835217
+BC2GM092581148
+BC2GM058805467
+P09652736A1205
+P03528748A0414
+P09383188A0654
+P11167111A0957
+P08981371A2049b
+P02787430A0124
+P08125949A1162
+P10587461A0341
+BC2GM053331936
+BC2GM043735377
+P09705564T0000
+BC2GM064662484
+BC2GM024601560
+P08723883A0823
+P11221845A0295
+BC2GM013473921
+P08853893A0158
+P09083345A0851
+P09426907A0391
+BC2GM014615834
+P08781119A0723
+P06486932A0000
+P09504906A0099
+BC2GM094415622
+BC2GM014978613
+P09371731A0627
+BC2GM075271187
+BC2GM029012322
+P09523478A0572
+P09586285A0551
+BC2GM043242186
+BC2GM083193914
+P11053263A0200
+P07934666A0158
+BC2GM004233255
+BC2GM094778247
+BC2GM061570261
+BC2GM062170558
+BC2GM069431845
+BC2GM095437250
+P02296509A0997
+P06692517T0000
+P07559640A1230
+P01919831T0000
+BC2GM008631262
+P03039177A0503
+P07214665A0000
+P11160896A0713
+BC2GM006783722
+BC2GM048333023
+P11029458A0000
+P04262268T0001
+BC2GM016049892
+P09989339A0968
+P03407843T0000
+P07666415A0000
+P11910310A0279
+P08987225A0675
+P07797077A0842
+P09223122A0774
+P03060846T0000
+P08564588A1318
+P04824747T0000
+P09736697A1107
+P09372908A1068
+BC2GM075603170
+P03305875T0000
+P06184276T0001
+P02310350A0221
+P11003807A0303
+BC2GM000665827
+P07927130A0625
+P06407348A0516
+BC2GM066800893
+P08204403A0000
+P10688660A0992
+P07629122A0323
+P09265534A0455
+P08891341A0724
+BC2GM039052742
+P07571766A0122
+P08866485A0125
+BC2GM059714682
+P01316125A0176
+P06627123A0000
+BC2GM043104937
+P01710766A0349
+P09520398A0124
+P08003700T0000
+P00479222A0682
+P01927845A0107
+P02355920A0681
+P01581577A1186
+P01178637T0001
+P00725336T0000
+P08106087A0139
+P03001110A0546
+P10773458A0000
+P02158927A0000
+P01711048T0000
+P11469853A1053
+P00803867A0315
+P08195217A0799
+BC2GM033643051
+P05684081T0001
+P07918494A1163
+P11275986A0091
+BC2GM021360319
+P11309677A0000
+P01278251A0000
+BC2GM078070574
+P11297514A0218
+BC2GM091638425
+BC2GM063812072
+P07835273A0000
+BC2GM035842115
+P11552058A0235
+P09090050A0419
+P07519463A0000
+P00339289T0049
+P09729481A0000
+P08555076A0333
+P10861080A0433
+P08918464A0225
+P01318739A0410
+P07517544A0515
+P05316745T0000
+P11038118A0000
+P08320120A0361
+BC2GM060672103
+P04152725T0001
+BC2GM043526079
+P07828584A0681
+BC2GM063757924
+BC2GM082800985
+BC2GM067677787
+BC2GM057671926
+P08249319A0578
+P02236276T0000
+BC2GM046574139
+P09178269A0107
+P09840928A0884
+P09477316A0140
+P07784197A0827
+BC2GM079551353
+P00597715A0256
+P04071063A0863
+P07249497A0688
+P04196986T0000
+P02266679A0740
+P00910823A0196
+P10564472A0853
+P11223164A0000
+P09915798A1077
+BC2GM017736340
+P02457922A0991
+P09313755A0816
+BC2GM001964645
+BC2GM001929746
+P08289783A0000
+BC2GM095746583
+P09436989A1011
+P10699896A0455
+P11059786T0000
+P02476664A0563
+P09434160A2078
+P03653226A0833
+BC2GM043298820
+P02201770A0188
+BC2GM094775430
+BC2GM003517703
+P09425038A0752
+P03062370A0384
+BC2GM053826454
+BC2GM057810743
+BC2GM071924862
+BC2GM092761606
+BC2GM048911038
+P09268652A0116
+P09294161A1103
+P02115118A0565
+P07505798A0000
+BC2GM066838338
+BC2GM043491752
+P09494078A1362
+P08476854A0097
+P09199932A1357
+P09115279A0345
+P11108548A0710
+BC2GM024171427
+P03673640A0533
+BC2GM021445348
+P07440430A1074
+P07533880T0000
+P00956554A0414
+P03320875A2090
+P09487841A0132
+P09046384A0403
+BC2GM005667784
+P08914522A0118
+BC2GM021860677
+P07692366A0000
+P09491074A0104
+P07698219A0551
+P08149484A1551
+P07579683A0660
+P07064923T0000
+BC2GM002025862
+BC2GM093817406
+P11221845A1713
+P08676858A0309
+P07951410A1332
+BC2GM008093196
+BC2GM063604617
+P09710621A0598
+P07762504A0648
+BC2GM008972334
+P08709251A0000
+P08471241T0000
+P11198289T0000
+P01242636A0678
+P08657918A0360
+P08356792A1275
+P00550399A0615
+P07689154A0168
+BC2GM051293681
+P02574193A0663
+P02174105A1232
+P04377003A0000
+P08209051T0000
+BC2GM027460732
+P01329039A0951
+BC2GM038571179
+P03001645A0785
+P10617126A1005
+BC2GM081842707
+P08411276A0302
+P09700644T0000
+P08996730A1146
+P01009841T0001
+P01679749A1171
+P11092770A0238
+P09122198A0478
+P06946693T0000
+P02333239T0000
+P07984105A1509
+P07579695A0336
+P08183552T0000
+BC2GM002757226
+BC2GM077489528
+P01597170A0000
+P09931435A0357
+BC2GM087700709
+P07007181T0000
+P09823775A1122
+P11325944A0511
+BC2GM086259287
+BC2GM018375556
+P00633909A0000
+P08270985A0590
+P11416260A0000
+P09778191A0000
+P06321770A1353
+BC2GM025848591
+P02330110A1085
+P07068493A0414
+P09162097A1258
+P03937481T0001
+P08585324A0823
+P05132558T0000
+BC2GM075735017
+P02725513A0617
+P07858986A0310
+P09393771A1659
+P10628490T0000
+P10756007A0575
+P09643548A0000
+P11902738A0185
+P00101300A0257
+P09476399A0141
+BC2GM005052505
+BC2GM004472936
+P02735364A1330
+P02497340A0989
+P08289784A0381
+BC2GM066692058
+P07926774A0652
+P10801482A0968
+P00918965A0728
+P02002051T0000
+P11073954A0337
+P11181516A0119
+P08807245A0843
+P01633816A0667
+BC2GM049661443
+BC2GM074649255
+P09187277A0118
+BC2GM019812857
+P09510189A0192
+P09632637A0361
+BC2GM074209039
+P08044802A0462
+P05544291T0031
+P05567721T0000
+P07494303A0000
+P02543621A0788
+P06801778T0001
+BC2GM018447830
+BC2GM003020957
+BC2GM044619064
+P08361755A0734
+P07929165T0000
+P11552922A0361
+P02800435A0000
+P10681588A0899a
+P00096241A0087
+P11236056A0374
+P00938594A0149
+BC2GM053457298
+P02393001A0324
+P08365944A1537
+P09829836A0815
+BC2GM052914680
+P11469853A0702
+BC2GM041191504
+P07823951A1100
+P07183576A0157
+P09509226A1235
+P09753774A2246
+BC2GM021289219
+P06412385A0356
+P01699944A1538
+P09555046A1617
+BC2GM011718637
+P09754571A0169
+P02138707A0198
+BC2GM042404259
+P10793991A0569
+BC2GM058204459
+P07184375T0001
+P11193666A1269
+P07957243A1316
+P07835088A0238
+P06963337T0000
+P08278480T0002
+P09389982A1383
+BC2GM023238812
+P08337841A0612
+P00450760T0001
+BC2GM077538777
+P08664347A0923
+P11263622A0683
+P08630548A0000
+P09263094A0799
+P08626529A0000
+P08635771A0000
+P08299568A1401
+BC2GM034609623
+P01999999T0001
+P09893060A0767
+P09121452A0538
+P01634464A0163
+P08684742A0000
+P03563604A1075
+BC2GM037400518
+P03488532A0235
+P09293006A1412
+BC2GM075235574
+P07720710A0861
+P09243267A0401
+BC2GM006558727
+BC2GM065655704
+BC2GM092988766
+BC2GM087746529
+P09821978A1255
+P01589576A0170
+P07748952A1329
+P01760166A0963
+BC2GM066642984
+BC2GM012511616
+BC2GM049012897
+P02647918A0588
+BC2GM005798555
+P08879080A0265
+BC2GM061416403
+P09172641A0181
+P07752223A0960
+P09199328T0000
+P03937294A0404
+P07824464A0169
+P08947028A0992
+P03352947T0001
+BC2GM064716554
+BC2GM091780091
+BC2GM024592460
+P08985115A1571
+P04143528A0394
+P04066194A0163
+P08002857A1070
+P03080793T0000
+BC2GM063772047
+BC2GM090334902
+P08836032T0000
+BC2GM033997623
+P09469933A1060
+BC2GM097255960
+P09307312A0172
+BC2GM040694019
+P03249792A0241
+P07697294A0329
+P01328681A0348
+BC2GM046830258
+BC2GM059243006
+P09685226A0000
+P10828319A0342
+P09813063T0000
+BC2GM008441714
+P09115395A0478
+P11083358A1071
+BC2GM011299853
+BC2GM045351753
+P01483771A1335
+P08309957A0000
+P09705324A1602
+BC2GM016633318
+P09974642T0000
+P09726991T0000
+P06541019A0555
+P09487590A0657
+P08626610A0931
+P11113692A0169
+P01580738T0001
+P02756878A0075
+P09187637A1199
+BC2GM060988781
+P09660823A0934
+P08408841A0281
+P06772612A0000
+BC2GM057201448
+P10870391T0034
+P11435578A2231
+P03791645A1124
+P08698756A1240
+P09436706A0168
+BC2GM003679439
+P01930470A0337
+P07347728T0000
+P09420275A0682
+P09172312T0000
+P10681679A0220
+P08895522T0000
+P11572467A0658
+P08969777A0771
+P04782788T0001
+P01888896A0505
+P09001245A0187
+BC2GM008866104
+BC2GM034787231
+P07511444T0000
+P05128149T0001
+BC2GM055423276
+P01734020A1318
+BC2GM056569042
+P09247645A0000
+BC2GM004444068
+P03591464A0840a
+BC2GM031044079
+P00139624A0318
+P08781144A1520
+BC2GM033539277
+BC2GM063432144
+P06279309A0000
+BC2GM087023573
+P09636119T0000
+P07936650A0656
+P00932817A0499
+P09832504A0596
+P11241672T0000
+P11554469A1386
+P09671791T0000
+BC2GM099614397
+BC2GM031563114
+P07954475A0714
+P05959588T0000
+P07182523A0462
+P08460346A0350
+P08514757A1100
+P08289593A1404
+P01569102A0708
+BC2GM069537069
+P11036938A1162
+P08218230A1920
+P11118440T0000
+BC2GM046577623
+P02143186A0867
+P08576131A0151
+P08666238T0000
+P07565776A0612
+P09174049A1788
+P08592713T0001
+BC2GM018078380
+P07592711T0000
+P04784432T0001
+P07375836T0000
+P09077108A0458
+P11523446A0523
+P02763467A0903
+BC2GM067531031
+P09826778A0943
+BC2GM042911073
+BC2GM011436488
+BC2GM060554389
+P10751398A1135
+P08816792A0000
+P08411024T0000
+P10763827A1158
+P03761523A0000
+P00216939T0001
+P08621661A1035
+P02454390T0000
+P09677405A0856
+P02102831A1282
+BC2GM032327372
+BC2GM033197644
+P09168083A0987
+P07707523A0704
+P07902532A1655
+BC2GM022663710
+P07806651A0097
+P08597177T0000
+P09609720A0357
+BC2GM007906275
+P05362866T0000
+BC2GM031419699
+P08231816A1473
+P06609166A0209
+P09353255A0159
+BC2GM070573613
+P08142875A0877
+P09856732A0114
+BC2GM024364656
+BC2GM009539472
+P01406688A0898
+P06880563A0516
+BC2GM023639868
+P07790271A1185
+P03023067A0779
+P10797125A0000
+P06121577A0280
+BC2GM049097167
+P09402088A2250
+BC2GM009988175
+P03499657A0000
+P04014833A0400
+P02376023A0307
+P11727073A0842
+BC2GM057418939
+P08896402A0587
+P08005412A0608
+BC2GM084554864
+BC2GM086764035
+P02547706A0928
+P03048024A0418
+P05322747T0034
+P11274563T0000
+P09810087A0379
+P10819327T0000
+P06542918A1131
+P08986692A0306
+P07260389A0221
+P06777229A0243
+P08356944A0589
+P08382778A0891
+P07531321A0369
+BC2GM001711845
+P09091010A1003
+P01885006A0995
+P10597317A1156
+P00737422A0832
+P01847665A1079
+BC2GM092320331
+P04445874T0001
+P07623838A1112
+P07740490T0000
+BC2GM077346848
+BC2GM097835170
+P01884435A0088
+P11018028A0263
+P04086403A1016
+P08024139A0393
+P01217450A0295
+P00932738A0116
+P09178491A0262
+BC2GM025563582
+P11324516A0159
+P08496601A1153
+BC2GM014203936
+BC2GM045577252
+P02973304A0000
+P08955159A0000
+P09561560A0579
+P07507187T0000
+P06147504A0086
+P09971822A1542
+BC2GM088118556
+BC2GM031143223
+BC2GM044423776
+BC2GM082814800
+P09197342T0000
+P02629109A0000
+BC2GM020930043
+P07519606A1269
+BC2GM031584591
+P08897721A0000
+P09169853A0000
+P06675047A0000
+BC2GM064583998
+P04624863T0001
+BC2GM015002604
+P11166478T0000
+P11444762A0373
+P09819440A0000
+BC2GM020598843
+P02462047A0208
+BC2GM044561188
+P10679015A0216
+P08554069A0743
+BC2GM090707363
+P02204621T0000
+BC2GM054437021
+BC2GM022946300
+P09381950A0209
+P07565723A0200
+P08933487A0325
+P01915580A0889
+P09230129A0039
+P11462004A1500
+P06138313A0948
+P09743720A0268
+BC2GM086432214
+P09635149A1148
+P07683375A0000
+P09521913A0400
+P00050628A0202
+P08761480A0331
+P09638793A1446
+P03059171A1232
+P06503329A0588
+P09346925A0660
+P07932943A0113
+P09278475A0465
+BC2GM025661360
+P11196191A1789
+BC2GM079950529
+P08399970T0000
+P01634400A1101
+P07308849A0817
+P09400738A1046
+P09073074T0000
+BC2GM058248998
+BC2GM095220597
+P03543936A0000
+P09443972A1145
+BC2GM087282034
+P05672903T0001
+P10773351A0672
+P08864061A0000
+P09627285A0554
+P09713996A0262
+P01808186A0984
+P10805823A1920
+P03436119A0000
+BC2GM047557108
+P09805977A0143
+P03137346A0319
+P07582316A0696
+BC2GM003905153
+P10574929A0583
+P08626529A0799
+P01158512T0000
+P11533238A1137
+P01765269A0308
+P04102280T0000
+P01904546A0671
+P09846927A0227
+BC2GM016588295
+P09862496A0187
+BC2GM076278508
+P04645078T0001
+P10908364A0000
+P11785085X0001
+P02889495A0000
+P09618150A1464
+BC2GM095888580
+P01961213A0150
+P02482511A0860
+BC2GM018838269
+P01845899A0000
+P07891638T0000
+P08401614A0187
+P07935418A0447
+P11121118A0075
+P07771745A0442
+P10843716A0406
+BC2GM005608882
+BC2GM036174332
+BC2GM076347404
+P02775136A1151
+BC2GM001896188
+P02902615A0000
+BC2GM005581340
+BC2GM092640548
+P10652102A0620
+P02237431A0833
+P10698974A0951
+P10833486A0598
+BC2GM076657224
+P07669351A1278
+P01331501A0397
+BC2GM021696117
+P03780704A0573
+P11156413T0000
+BC2GM038727625
+BC2GM005993806
+P08552042A1497
+BC2GM026702973
+P01389585A0825
+P01825027T0000
+P10602516A0182
+P08151787T0000
+BC2GM074622354
+P09060676A1634
+P08827783A0499
+P10928337A0590
+P10644414T0000
+BC2GM079407274
+P02095150T0000
+BC2GM017291390
+BC2GM043977767
+P10672433A0199
+P07958911A0500
+P09828137A0000
+BC2GM053931795
+P05095988T0001
+P09358837T0000
+BC2GM021380457
+P09718372T0000
+BC2GM075119828
+P01583819A0377
+P08112601T0000
+P04796997T0000
+BC2GM006948843
+P07759525A0417
+P01870194A0302
+BC2GM085276860
+BC2GM011075999
+P03987857A0733
+P09278441A1160
+P06807149T0000
+BC2GM018411684
+P11888867A0000
+P09020856A0560
+P09248639A0152
+BC2GM060051589
+P01130186A0568
+P02436005A0707
+P00232456T0000
+P11358801A1046
+BC2GM037537411
+P10780018A0539
+P02831796A0000
+P00221725A0523
+P03563399A0534
+P09799793T0000
+BC2GM077806960
+P10613874A0663
+P07149047A0260
+P09015543A0210
+P08553580A0102
+BC2GM018605587
+P08395010T0000
+BC2GM075521296
+BC2GM044742819
+P02254418A0641
+P01375913A0484
+P09867855T0000
+P09595496A0000
+BC2GM071814520
+BC2GM039354270
+BC2GM079045353
+P04423347T0001
+P09605934A0801
+P09918720A0998
+BC2GM057610190
+P07942076A0497
+BC2GM095923750
+P07592658A0309
+P00465681A0000
+P06868345A0000
+BC2GM080157820
+P03451761A0215
+BC2GM019331308
+P03214709A0559
+P08409593A0357
+P09249070A0989
+BC2GM064633844
+P06208024A0168
+P07767011A0689
+BC2GM081961422
+P09872326A0566
+P03200488A0439
+P00427715A0000
+P02223773A0000
+P07964162A0941
+BC2GM015535578
+P09407642A0305
+BC2GM002487539
+P10022905A0446
+BC2GM098824982
+P00038408T0000
+P09084621A2567
+P02247924A0078
+BC2GM005777371
+P11259593A1094
+BC2GM078755837
+P05123884T0000
+BC2GM091158051
+P08777374A1471
+P06674374T0000
+P10763823A0824
+P07659085A1520
+P07929238A0734
+BC2GM094127714
+P01830928A0361
+BC2GM062280963
+BC2GM042560945
+P08417331A0745
+BC2GM092558649
+BC2GM022278881
+P09165039A0728
+BC2GM076789342
+P09525891T0000
+BC2GM033998537
+BC2GM073514147
+BC2GM054051105
+BC2GM077245988
+BC2GM058847965
+BC2GM010930693
+P09108029A0399
+BC2GM043530454
+P01671675A0905
+P09171468T0000
+P02711601A0601
+P03029111A0155
+P08490002A0620
+P10706475A0644
+P09549398A1463
+P03023887A0470
+P06524202A0167
+P02333545A0313
+BC2GM091278857
+BC2GM029787145
+P09132061A0828
+P02247081A0223
+BC2GM072933790
+P02336338A0931
+BC2GM050984092
+BC2GM026423593
+BC2GM091220407
+P09387333T0001
+P03885983A0254
+BC2GM037081508
+P02941237A0160
+P10574913A1108
+P08523031A0737
+BC2GM045876412
+P03545955A1378
+P09372968A0532
+P09067577A0721
+BC2GM061631132
+BC2GM076704194
+P10641037A1371
+BC2GM008190369
+BC2GM013416504
+BC2GM022592779
+P10687945A0000
+P03568311A0273
+P11438654A1237
+P08268912A0657
+P09236118A1455
+P02569411A0151
+P02989637A0671
+BC2GM052299815
+P01497582A0593
+P01518396T0000
+BC2GM015726285
+P04049799A0466
+P07758837A1118
+BC2GM080339050
+BC2GM077681760
+P11098420A0175
+P11374866X0914
+BC2GM064612390
+BC2GM043009268
+P08262067A1608
+P08522175A0306
+P09936001T0000
+BC2GM083405439
+P03513989A1149
+P00710217T0001
+P08978817A0620
+P01537845A0571
+P09358045A0000
+BC2GM027522433
+P09792439T0000
+P01624425A0907
+P08702756A0000
+P11311909A0938
+P10564593A1618
+P00578648T0048
+P05572662T0000
+P11371160A0854
+P10608053A0923
+BC2GM070643698
+P08194970A0000
+P10612805A0716
+P05101762T0000
+P11085267A0562
+P09536028A0945
+P09028942A0000
+BC2GM060649336
+P09271393A1333
+P01756539A0354
+P11289149A0658
+P09224655T0000
+P08651853T0000
+P06600533T0000
+P09858094A0583
+P01284828T0001
+P08703908A1814
+P07551787A0917
+P01846491A0459
+BC2GM065617223
+P07436794A0148
+P08120019A1500
+P11158310A0993
+P11221836A0981
+P03690262A0428
+P04018444A0000
+P08534367A0984
+P08838585A0968
+P03717936A0252
+P07824325A0714
+P09710599A0310
+P01191955A0077
+P01597272A0077
+BC2GM097445371
+P08336698T0000
+BC2GM095896930
+BC2GM004656785
+P11243777A0000
+BC2GM021307129
+BC2GM092923041
+P08523545T0000
+P02666568A0000
+BC2GM066241550
+P08157009A0264
+BC2GM048391096
+P06309855T0000
+P01837842A1410
+P09856397A0099
+P01380076A0165
+BC2GM096331297
+P08343961A0000
+P11465844T0000
+P08708984T0000
+P11280799A1025
+P09312025A0373
+P09368190A1053
+BC2GM045969390
+BC2GM068345268
+P10690725A1037
+BC2GM098192106
+BC2GM069143937
+P10567430A0785
+BC2GM048575101
+P06840803A0397
+P07638517A0000
+P09621372A0369
+BC2GM096399526
+BC2GM056776703
+P08055939A0159
+BC2GM045993010
+BC2GM015550026
+P01653238A1715
+P02543679A1291
+P01147502T0000
+P01347476T0000
+P10873388A0623
+P07565740T0000
+BC2GM005933281
+P01971191A1271
+P00686836A0000
+P02590540A0741
+BC2GM000843512
+P08994968A0926
+P10810745A0677
+P09242551A0653
+BC2GM001205480
+BC2GM022908464
+P07706291T0000
+P01954835A0000
+P09584194A1305
+P09537378A1227
+P03550444T0000
+P10786742A0670
+P08643557A0259
+P11158326A1032
+P07533527A0128
+P08626698A0989
+P01678287A1308
+BC2GM093522380
+BC2GM097779504
+BC2GM072704944
+P06809586T0000
+P11254752A1875
+P08890537A0355
+P04758799T0000
+P10688661A0237
+BC2GM054430010
+P11626110T0000
+BC2GM046112338
+P09820205A0000
+P07590744A0829
+P11325391A0498
+P07249660T0000
+P08509419A0785
+P04075061A0355
+P11435578A0760
+P11543317A0203
+BC2GM028646260
+P04172166T0000
+P08216115A0158
+P02547706T0001
+P05028628T0001
+BC2GM068931709
+P03728230A0104
+BC2GM045173873
+P07623840A0352
+P10704285A0536
+P01909027A0922
+BC2GM064382331
+P02705072A0464
+P07667097A0267
+P02740955A0333
+P02555177A0488
+P11387208T0000
+P07565688A0797
+P08639521A1032
+BC2GM057243625
+P08943934A0604
+P07413441T0070
+P09171081T0000
+P10563212A0514
+P01861034A0798
+P09346238T0000
+P01626372T0000
+P02200736A1003
+P07914700A0000
+P07597804A1007
+P03601275A0601
+P08626313A1037
+P09368419A0628
+P09333026A0397
+P08808707A0631
+P09811695A1146
+P03076124A0496
+P08144037A0000
+P00626014T0001
+BC2GM088377969
+P02702566A0000
+P01985920A0156
+P06816123A0526
+P07973825A0445
+P07520098A0211
+P11340080A0096
+P08063836A0904
+BC2GM083904809
+BC2GM097601782
+P03111946A0309
+BC2GM096844246
+P00696680A0000
+BC2GM085074416
+P11352663A0138
+P11113822A0999
+P07276210T0000
+P10810294A0730
+P08268718A0676
+P08300611T0000
+P02483210A0000
+P11879108A0719
+BC2GM035632930
+P07628456A0000
+P02609112A0000
+P11437439A0201
+P09639074A0707
+BC2GM049324176
+P08798762A1279
+P07771671T0000
+P02131666A0483
+P09759691A1051
+P02831556A0173
+BC2GM045403692
+P11318608A0669
+P07743472A0181
+P08626596A0000
+P08993836A0699
+P08189498T0000
+BC2GM094246030
+P10812294X0000
+P07968409A0123
+P01035457A0623
+P09804779A1163
+P02987777A0000
+P08276900A0543
+P02894689A0000
+BC2GM077161229
+P08444344A0000
+P08627667A0132
+BC2GM043707576
+P09601940A0280
+P09334475A0327
+P10739671A0136
+P08309975A0662
+P08139928T0000
+P10586115A0477
+P02176152A0896
+P10713176A0885
+P03568311A1361
+P07529516A0474
+P09858588A1046
+BC2GM098375429
+P10741947T0000
+BC2GM018871077
+BC2GM005714480
+P10871842A0988
+BC2GM084179136
+P06994049T0001
+P09291098A0452
+BC2GM073017347
+BC2GM034072679
+P03904004A1577
+P11220166A0616
+P09582953A0000
+P08922390A2076
+P09583201A0759
+P08683983A1163
+P09488486A0906
+BC2GM038386703
+P03946125T0000
+P07857344A0591
+BC2GM085890702
+P09001313A0000
+BC2GM055422231
+P11413277A1121
+BC2GM086028884
+P11279324A0710
+BC2GM007032064
+P10749932A0000
+P07883168A0090
+P09984526T0000
+P08212571A0971
+P08760889A0531
+P08835969A0000
+BC2GM051590745
+P04038702A0768
+BC2GM053665808
+P11406007A0292
+P01885915A0000
+P09431812A0576
+P04791420T0000
+P01956285A0000
+P10601335A0892
+BC2GM058761763
+P01424674A0000
+P11310937A0548
+BC2GM006085106
+P01846206A0665
+P03015953T0000
+P10963735A0193
+P11126353A0582
+P06298720A0893
+P02853922A0596
+P05460466T0001
+P03072580A0455
+P03659603A0797
+P01107226A0808
+P04021431A0000
+BC2GM003163464
+P01577056A0178
+P08576131A0685
+P05005311T0000
+P09917389A1239
+BC2GM064369940
+P03183127A0068
+P02122454A1042
+P01739956A0638
+BC2GM019595321
+BC2GM089028538
+BC2GM050762362
+P11070007A0136
+BC2GM056576430
+P08496599A0310
+P07590268A0350
+BC2GM066700172
+BC2GM014145288
+P02489753A0581
+P02511430A0000
+BC2GM039680603
+P08058948A0810
+P00199012T0000
+P09369450A1358
+P03146784A0158
+BC2GM009197562
+P07474140A1036
+P00696858A0000
+P03006066A0653
+P07253335T0000
+P09032254A0724
+P09431828A1472
+P09867253A0229
+P09084621A0374
+P08561897A0604
+P08677443A0238
+P10866323A0666
+P07592485A0734
+P00837262A0000
+P04512496T0000
+P07982964A1017
+P06096246T0000
+P10441243A0443
+P09046090T0000
+P03887769A0093
+P09552469A0225
+P10684304A1242
+BC2GM075112019
+P03227568T0001
+BC2GM051098108
+BC2GM027072594
+P05893495T0001
+BC2GM075182696
+P07495726A1189
+P09861365A0000
+P10019841T0000
+P01116466A0185
+P08816459A0090
+P00926272A0000
+BC2GM047671701
+BC2GM045967019
+P08833153A0628
+P02861238T0000
+P07569075A0585
+P03517388A0763
+P06790572A0330
+P10932196A0359
+BC2GM015437343
+P11380837A1505
+P04392584T0000
+BC2GM062865451
+P09061697A0629
+P11216247T0000
+P08072547A1009
+P01256410T0001
+P10856491A0178
+P10597232A0000
+P01476376T0000
+BC2GM036882521
+BC2GM001688677
+P09153319A1332
+P01625131A0452
+P10773951A0000
+P09880029A0703
+P07929431A0949
+BC2GM022798605
+P04446923T0001
+BC2GM085879791
+P08517737A0889
+BC2GM009275309
+BC2GM045854489
+P07676655A0214
+P08937112A0561
+P00430247A1073
+BC2GM066131450
+BC2GM031886187
+P09570133A0474
+P03330711T0000
+P04787716T0000
+P11434084A0508
+P09317757T0000
+P08036004A0292
+BC2GM049951633
+P11520436A0705
+P01324172A0880
+P00866577A0579
+P08523566A1106
+P08390120A0785
+P02406570A0466
+BC2GM090587249
+BC2GM063124230
+P08848013A1469
+P03404334T0000
+P10896859A0000
+P02496109A0754
+P09952425A0893
+BC2GM020478123
+BC2GM075378170
+BC2GM095082528
+BC2GM044020511
+P09076336A0281
+BC2GM086175633
+P02790009A0375
+BC2GM089015386
+P08812490A0000
+P09710641A0000
+BC2GM030828493
+P08188258A0000
+P07881077A0195
+BC2GM037899934
+P07869721A0000
+P01158838A0438
+P03368701A0113
+P04069756T0025
+BC2GM033742253
+P09171239A1118
+P03828500T0001
+P00473249T0000
+P09010223A0667
+P00479246T0000
+P03108171A0088
+P07666966A0207
+P10777586A1022
+P08621384A0935
+P08334304A0473
+P01996312A0454
+BC2GM090038156
+P11433018A0756
+P09770415A0139
+P02143023A0729
+P03837609T0000
+BC2GM063549189
+P08798443A0660
+P07742550A0407
+P09206968A0000
+P01087288T0000
+P09189896A0611
+BC2GM053683599
+BC2GM091634210
+P11295470A0954
+BC2GM023518208
+BC2GM066695661
+P02535460A1443
+BC2GM082522645
+BC2GM017399394
+P07588750T0061
+P06074640T0001
+BC2GM012909505
+BC2GM053097733
+P07871891A0227
+P08723883A1684
+P09781761A0384
+BC2GM040272991
+P09365272T0000
+P09990507A0763
+P09018133A0244
+P09195923A0125
+P09777477A0000
+P09115365A0000
+P09053835A0865
+P07890680A1193
+P09188863A0954
+P09628890A0455
+BC2GM084248034
+P05807222T0052
+P01736844T0000
+P09027506T0000
+BC2GM074465218
+P02113455A0207
+P07906616A0191
+P01545792A0492
+P01691184A0995
+BC2GM090228241
+BC2GM053041112
+P02179052A1044
+P07541912A0485
+BC2GM034354079
+BC2GM070595219
+P11513121T0000
+P07892076A0578
+P09309457A0680
+P11207288A0897
+P02156828A0164
+P10612918A0318
+P09878542A1151
+P09787323A0000
+BC2GM081453931
+P10727515A1202
+P07565104A0084
+P00780639X0000
+P00304310A0000
+P07538122A0800
+BC2GM015638731
+BC2GM061646727
+P09858581A0183
+P01759282A0000
+P09748669A0414
+P01783088A1136
+BC2GM056619320
+BC2GM051472026
+P09536440A0000
+P06162419A0118
+P09206230A0000
+P08626539T0000
+BC2GM099313539
+P09778006A0718
+BC2GM017403809
+BC2GM053532690
+BC2GM003309537
+P09268298T0000
+P02861144A0242
+P03133360A1215
+BC2GM057515981
+P08317092A0304
+P07902532A0312
+P09510582A0157
+P10654032A1133
+P08876167A0717
+BC2GM084419683
+P09239635A0477
+P02231162T0000
+P07916689A1407
+P02895754A0000
+BC2GM001871340
+P01730412T0000
+P09621893A0000
+P01961747A0000
+P06152670T0000
+BC2GM025369087
+P10872827A0000
+P06411659A0264
+P01523111A0769
+P01554334A0000
+P10433729A1559
+P09242375A1313
+P02765001A0105
+P06300662T0000
+BC2GM039969653
+P07274505A0660
+P02406992A0192
+P02228615A0974
+P07267675A0000
+P08760872A0696
+BC2GM051143447
+P06251469A0830
+BC2GM083693291
+BC2GM060353149
+P08666398T0000
+P01630455A0448
+P06098828A0352
+BC2GM014167322
+P08209772A0167
+BC2GM018313543
+P02209540A1362
+P02597484A0624
+P10747987A0658
+P02514498A0000
+P08937981A0840
+P01986241A0117
+P07004236A0741
+P09565606A0520
+P09678579A0768
+P01675637T0033
+P07528325A0165
+P10848848A0413
+P00771729X0000
+P09897032T0000
+P07572582A0000
+P09049313A0116
+P07799925A0526
+BC2GM033668177
+BC2GM083885285
+BC2GM090980905
+P09341182A0605
+BC2GM096003316
+P11353770A0085
+P10932527T0000
+P09799634A0161
+P08720407A1386
+P10657238A0541
+P01774063A0161
+P08269439X0000
+BC2GM065517718
+BC2GM002326238
+P09689047A0253
+BC2GM093300665
+P07080496A0097
+BC2GM014406229
+P06516847A0393
+BC2GM092362540
+BC2GM088490970
+P08662852A1297
+P08072352A0567
+P09393706A1171
+P07636648A1229
+P07320153T0000
+P11486399A0000
+P00616575A0000
+P02151229A0000
+P09328343A0181
+P09045805A0945
+BC2GM017879501
+BC2GM089291687
+P08421910A0599
+P02923687A0218
+P11408591A0000
+P02967496A0182
+P01695314T0000
+BC2GM092831891
+P06667015A0832
+BC2GM090610024
+BC2GM040656099
+P07543592A0624
+P08837746A0951
+P09335267A0142
+BC2GM098593892
+P06319071A0173
+P07455521A0414
+BC2GM009991407
+BC2GM074912352
+P04026903A0512
+P09511724A0483
+P00825571T0031
+P11112438X0847
+P08927841A0053
+P07592072A0217
+BC2GM084096579
+P00369397A0280
+BC2GM055315258
+P08818436A0557
+P09466267A1192
+BC2GM032522078
+P02591078A0000
+P10742114A0486
+P08562688A0968
+P09009208A0337
+P04247472T0001
+P01194673A0652
+BC2GM011109464
+BC2GM064390333
+P05594277T0051
+P11152081A0413
+P07546794A0100
+P08702826A0870
+P11117826A0788
+P04638365T0001
+P09636708A0460
+BC2GM053725258
+BC2GM089407597
+P03857577A0413
+P06805504A0629
+P02779752A0000
+P08392623A1374
+P08276732A0799
+P09670943T0000
+P01824944A0988
+P07525548A1380
+P08794601A0000
+BC2GM013674517
+P08237578A0253
+P08790288A0068
+P11185475T0034
+P06869215A0347
+BC2GM063998013
+P03602261A0238
+P01170143A0247
+P08390831A0143
+BC2GM084536918
+BC2GM026213346
+P08849778A0598
+P09003311A0478
+P09833740A1112
+P11441974A0320
+P09241232A1154
+P08771781A1103
+P08816461A0892
+P08649403A0963
+BC2GM072208661
+BC2GM039739428
+P11123089A0362
+P08443341A0384
+P07523363A0440
+BC2GM073857956
+P06367414A0000
+P08948440A0628
+P02164637A0515
+BC2GM062065726
+P09000589A0000
+P10564484A0859
+P08597596A0135
+P09819411A0897
+P02778873A0761
+BC2GM018326303
+P02119946T0000
+BC2GM096950581
+P06658445A0140
+BC2GM057856601
+P10976413A0514
+P01532229A1264
+BC2GM034256968
+P09916786A0811
+P03308909A0485
+P05309471T0000
+P07740487A0167
+P10748672A0130
+P10715325A0834
+P07728201A0660
+P04967824T0000
+P02014928T0000
+P05806936T0000
+P07988559A0836
+BC2GM065027203
+BC2GM052576426
+P09701821A1108
+P09837913A0419
+P08839498A0507
+P08196607A0280
+P02315151T0020
+P02572777T0000
+P10992983T0000
+P07522163T0000
+P08094464A2014
+P11203702A1307
+P10642531A2322
+P06109017A0000
+P08231398A0802
+P04004168A0000
+BC2GM012559118
+P07862150A0429
+BC2GM080568509
+P11390650A0562
+P06880650A0316
+P08139001A1235
+P11411961A0735
+P03335127A0176
+BC2GM037741487
+P11189314A1000
+P09400613A0594
+BC2GM085157618
+BC2GM005451560
+BC2GM091911719
+P08915559A0366
+P08649427A0689
+P07862108A0987
+P03542945T0000
+P08647086A0622
+BC2GM004628180
+P08000427A0000
+P10704283A0649a
+BC2GM093193565
+P01459885A0705
+P03691316A0560
+P06854957T0066
+P09305755A0540
+P06957125T0000
+P08702936A0168
+P11522658A0870
+BC2GM053054541
+BC2GM057069955
+P09642200A0956
+P09345495A0000
+BC2GM075057659
+P07640309A0000
+P01734283A0817
+P10779352T0000
+BC2GM021097776
+P07061350A0042
+P08521780A0485
+P00619948A0000
+P08360112T0036
+P05065548T0075
+P03018491A0840
+P09633879A0246
+P08408825A0000
+P10868488A0921
+P08916960A1331
+BC2GM008563458
+BC2GM005568941
+P07983715A0996
+BC2GM029716691
+P08072547T0000
+P11072388T0000
+P01992459A0000
+P01559209T0000
+BC2GM013299082
+P11179956A1818
+P02717133T0001
+BC2GM007116849
+P09072361A0357
+BC2GM045785731
+P10677214A1045
+P06151518A0000
+P01717718A1255
+P11345435A0199
+BC2GM086602241
+P11264177T0000
+P09770493A0499
+P08035498A0833
+P08552093A0657
+P08580671A0137
+BC2GM090241856
+BC2GM069413294
+P11029045A0000
+BC2GM085413059
+BC2GM079199097
+P03774111T0000
+P10762348A0269
+P07341346A0174
+P06131038A0000
+BC2GM039075708
+P07559233A0534
+P02859434T0000
+P02317413A0364
+BC2GM081228563
+P05441564T0001
+P09463991T0000
+P06310457A0000
+P07472582A0993
+P00013683A0210
+P09358055A0590
+BC2GM019076970
+P08430095A0913
+BC2GM024564253
+P09880103A0387
+BC2GM048329227
+BC2GM042469418
+P02131652A0883
+P06833047A0000
+P07916326A0000
+P10928477A0764
+BC2GM011910286
+P02898752A0683
+P06320380T0001
+P10896859A0838
+P11012568A0192
+P01458170A0155
+P01630569A0605
+BC2GM038169511
+P07547220A0229
+BC2GM066709301
+BC2GM052592239
+P07888623A0721
+P11280495A1330
+P06296833A0000
+P08126096A1071
+P02818260T0000
+P01897515A0348
+P11176290T0000
+P07731686A0000
+P01338867A0503
+BC2GM009218919
+P07401318A0823
+P08504933A0000
+BC2GM077229462
+P09514260A1083
+P08202546A1206
+P03805090A0645
+P01398104A0834
+P08067013T0001
+P10860827A0399
+BC2GM007462529
+P08873063A0493
+BC2GM070035080
+P02024252A0000
+P09414287A0637
+BC2GM011442958
+P01916168A0969
+P01702426A0196
+P09005273A0322
+P09024097A0000
+P02300759A0000
+P05034373T0000
+BC2GM038794623
+BC2GM021235622
+P08361761A0174
+P07935491A0495
+P07372433A0000
+P07496184T0001
+BC2GM086709432
+P08970991A0747
+P11539522A0612
+P04562038T0001
+P01171020A0711
+P09271397A1596
+P01539996A0588
+BC2GM063528560
+BC2GM012984521
+P08332033T0000
+P08314922A0941
+BC2GM048598667
+BC2GM075197573
+P00001606T0076
+P09474648A0298
+P02274509A0623
+BC2GM097982255
+P01765386A0305
+P11416012A1982
+P09658403A1207
+BC2GM089348837
+P01506705A0282
+P09236224A0939
+BC2GM047640437
+BC2GM048797879
+BC2GM046344700
+BC2GM070645862
+P09826434T0000
+P03597269A0409
+P08816472T0000
+P10691972T0000
+BC2GM080881152
+P10756032A0599
+P02838246A0225
+P09498769A0095
+P09610755A1731
+BC2GM027119323
+BC2GM095526870
+BC2GM014345579
+P07557387A0241
+P11031366T0001
+P09199322T0000
+P01542686A0000
+BC2GM096905196
+P06672094A0390
+P09717887A0239
+P08910567A2269
+P11266540A0328
+P06602580A0664
+BC2GM002874950
+P07872788A1717
+P03276246A0037
+P01253191T0000
+BC2GM083080586
+P07776711A0295
+BC2GM098647724
+P01982061T0000
+P08002564A0249
+P03192950A0566
+BC2GM089489545
+P09452444A0000
+P09353304A0732
+BC2GM089490423
+P07113897A0285
+P09480843A0848
+P10622574A0000
+P08719156A0953
+BC2GM017175901
+BC2GM057130541
+P06984225A0367
+P09915118T0000
+P08170400T0000
+P02179815A0582
+P00857024A0888
+P07518426A0000
+P10936920A0105
+P00219674A0000
+P11197288A0855
+P09550591A0454
+BC2GM037342398
+P06161823A0129
+P11570735A1097
+P06685004A0000
+P11428435A0446
+BC2GM001213287
+P09344650A0967
+P10933154A1118
+BC2GM034824731
+P08396261A0388
+P09450932A0142
+P02574016A0428
+BC2GM000026289
+P07542616A0486
+P02731611A0134
+P10729220A1569
+BC2GM058292678
+P02111015A0574
+BC2GM060722870
+P09233809A0381
+P07635140A0172
+P06167806A0000
+P09205677A0577
+BC2GM018123689
+P06319740A1331
+P10493876A0000
+P09121433A0463
+P03627720A0196
+BC2GM036750141
+BC2GM020852658
+P09197408A0126
+P02809831A0799
+P05145925T0000
+P08453101A0128
+P08707424A0709
+P02390989A0745
+BC2GM077166085
+BC2GM027258079
+P08208540A1114
+BC2GM057809152
+P08550467A0863
+BC2GM033411061
+BC2GM005575827
+P07744846A1006
+BC2GM094893147
+BC2GM054881964
+P09417941A1287
+P08264582A0750
+P09625807A0000
+P07559555A0557
+BC2GM003241979
+P08675026A0420
+P08661114A0564
+P07899581A0000
+P10786671A0182
+BC2GM024533099
+P11056007A0224
+BC2GM087199820
+P09259320A0830
+P08491124A0517
+P10485585A0175
+P11082587X0000
+BC2GM079069555
+P09473483A0953
+BC2GM072333569
+BC2GM084800882
+BC2GM035600571
+P06224974A0833
+P08049885T0000
+P02182323A0121
+P08264583A0520
+BC2GM070226026
+P02766508A0421
+P01330975T0000
+P09507032A1144
+P08649372A0501
+P03776080A0400
+P00239014A0000
+P02899177A0605
+P09425676A0000
+P10970048A0352
+P10708424A0800
+BC2GM083638339
+P00198510T0000
+P07908187T0000
+P11207269A0745
+P06120429T0000
+BC2GM062596008
+P04061342A0512
+P07237817T0000
+BC2GM012120254
+P11309678A0489
+P09390183A1027
+BC2GM022628668
+P07296997A0125
+BC2GM064070437
+BC2GM018288795
+BC2GM083615175
+P11278400A0668
+BC2GM065459831
+P10873387A0816
+P01464606A0344
+P07516866A0000
+P00429893A0000
+P07508082A0821
+P00118044A0000
+P01844878A0000
+P01403391T0000
+P09234743A0475
+BC2GM090380328
+P10722737A1726
+P04086993T0000
+P09691037A0355
+P10857751A0304
+P07673128A0989
+P07190627T0000
+BC2GM071536994
+BC2GM008162838
+P11145743A0170
+P02844767A0191
+P11014197A0339
+P11285054A0781
+BC2GM083269522
+P03841627T0001
+P01990254A0791
+BC2GM083471063
+P11108374A1466
+P09023378A0959
+P11132790A0609
+BC2GM043897639
+P02354381A0207
+BC2GM057244424
+P09847371A0000
+P09807755A0146
+P10888570A0678
+P07487363A0447
+P02153243A0965
+P08593813A0967
+P00985279A0493
+P11391303A0807
+P09294262A0885
+P08451331T0000
+P08229330A0000
+P02814820A0967
+P09422351A0000
+P09242506A1033
+P09792627A0441
+BC2GM009462696
+P07405701T0000
+P04140567T0001
+BC2GM090248535
+P04213917T0001
+BC2GM096521893
+P08361754A0733
+P07958920A1157
+P05692759T0001
+P07761216T0000
+P00211881A0602
+BC2GM070651049
+BC2GM097347861
+P08899719A0318
+BC2GM077216151
+BC2GM078039869
+P02247072A0794
+P07864652A0753
+BC2GM007000776
+P09171969A1165
+P10850997A1016
+BC2GM028177619
+P07999982A0086
+P03072021A0696
+P08294386A0000
+P02121371T0000
+P07784079A1018
+P08829393A0083
+P07890485A0827
+BC2GM091451478
+P06966678A0523
+P11210988T0000
+P07135112T0000
+P02423850A0292
+P06784123T0000
+BC2GM078278195
+P00569989A0239
+BC2GM059925570
+P03880838T0000
+P08497259A0452
+BC2GM023060026
+P11286833A0959
+P02078570A0287
+P02621983T0001
+P08840506A0544
+P09115357A0073
+P08637006A0000
+P01281472T0000
+BC2GM078861237
+P07345217A0000
+P11059786A0682
+P08343216A0883
+P10665308T0001
+P09446815A1021
+P08707825A0063
+P00111174A0351
+P01628201A0824
+BC2GM046451066
+P07494274A1015
+P08534855A0000
+BC2GM052870770
+P06890935T0001
+BC2GM083427683
+P11007968A0255
+P03396437A0321
+P00022143T0000
+BC2GM056577777
+BC2GM084696826
+BC2GM034787245
+P00506649T0000
+P07508441A0487
+P09182990A0245
+BC2GM011563299
+P08916960A0350
+P09545638T0000
+BC2GM074564112
+BC2GM028392901
+P08371713T0000
+P00618078A0367
+P11118438A0411
+BC2GM084178776
+P01446828A1088
+BC2GM034941243
+P08277632A0997
+P02761537A0168
+P00437749A0242
+P01384165A0000
+BC2GM022990188
+P09006007A0997
+BC2GM063249278
+P00557559A0170
+P07078263T0000
+P03246999A0483
+BC2GM039524689
+P00815369X0000
+P09488725A0904
+P04075021T0000
+P08816507A1125
+P11114924A0808
+P10649449A0413
+P01310935T0000
+P11114718A0349
+P00456424A0000
+BC2GM021612626
+P08587075T0000
+P11404016A1922
+P02196565A0606
+P09914156A1496
+P04919613T0001
+P01968156T0000
+P09111314A1243
+P11569800T0000
+BC2GM083564005
+BC2GM030428855
+P11565747A1020
+BC2GM062242948
+P10829973T0000
+P08429020A0495
+P00493818A0422
+P06092588T0000
+P07809410A0606
+P09822685A0596
+P07528746A1049
+P02195025T0000
+P02335521T0000
+P02840034A1266
+P02776471A0235
+P03484894A0782
+P01909960A0134
+P01208811T0001
+BC2GM050319569
+BC2GM057017444
+P09792682A0713
+BC2GM013302577
+P03344586T0000
+BC2GM084663535
+P01586901A0000
+P07636962A1288
+BC2GM098250324
+P01939899A2043
+P02154686A0185
+P06535384A1115
+P07657705A1181
+P09426143A1358
+BC2GM029041456
+P08538052A0000
+P02203672A1542
+P10651076T0000
+P07559639A0996
+P10871045A1221
+P10671606A0884
+P02649811T0000
+P03115787A0633
+BC2GM094871087
+P02102823A0492
+P09538258A0200
+P08601284A0000
+BC2GM007028303
+P07262625A0000
+P07832779A0719
+BC2GM085373279
+BC2GM050673543
+P08902847A1946
+BC2GM084353628
+P11427329A1077
+P03311954A0000
+P08868473A1287
+P08293992A0432
+P07598303A1728
+P06916588A0304
+P07126413A0000
+P06928974T0000
+P07836228A1052
+P02907533A0362
+BC2GM046169713
+BC2GM027073602
+P11297545A0948
+P07782087A0559
+P07957106A0471
+P02776823A0000
+P01797459A0103
+P01714358A0990
+P09235424A1200
+P02284393A0751
+P02809722A0926
+P00316723A0558
+BC2GM072405160
+BC2GM099647804
+P07953785A0648
+P00100540T0000
+P08530345A0880
+BC2GM039301722
+BC2GM085408195
+P07753030A0173
+P09366456A0234
+BC2GM085810143
+BC2GM009500252
+BC2GM053451054
+BC2GM011104369
+P00084275T0063
+P08980536A1196
+P07612174A1064
+P07601827A0778
+BC2GM068674132
+P11098217A0674
+P03684378A0653
+P07499394A0187
+P03370815T0000
+P05456002T0000
+BC2GM081105938
+P08550460A0374
+P09271400A0475
+P01525966T0000
+P09524122A0336
+BC2GM023248039
+P11504709A0981
+P07696450A0271
+P10380232A0000
+P02046202A0625
+BC2GM022697096
+P02123295A0645
+BC2GM051884914
+P09524267A1023
+BC2GM081600105
+P07859777A0000
+P06674516A0350
+BC2GM053572973
+P07687541A0992
+BC2GM040683768
+BC2GM026141578
+P09774662A0958
+P01892680A0907
+P02473718A0000
+P01932650A0435
+P01751255A0529
+P08355062A0000
+P08952483A0207
+P09694599A1355
+BC2GM035382344
+P05087496T0000
+P09151925A0479
+P01309910A0428
+BC2GM029508007
+P06130348T0000
+P10657899A0685
+P10770065A0264
+P02312689A0360
+P09343208A1405
+P10662614A0972
+P08438584A0524
+BC2GM076094656
+P02070227T0000
+BC2GM019927220
+P08896590T0000
+P10901133A0381
+P03977577T0000
+P10664876A0000
+P09693306T0000
+BC2GM095835528
+P11263664T0000
+P02137458A1129
+P11282761A0531
+BC2GM033262537
+P07021505A0510
+P07873831T0000
+P08955189A1198
+P09843412A0130
+BC2GM015170864
+P10393969A0000
+BC2GM058284658
+BC2GM014357227
+P02949170A0184
+P09712898A0911
+P01396432A0388
+P03274204A0642
+P04524081T0000
+P09889202T0000
+P08639310A0548
+P09824158A1336
+P07975882T0000
+P09297698A0933
+P03010281A0220
+P03000457A1554
+BC2GM072883448
+P09778197A0415
+P09398267A0440
+P00414575T0000
+P10682570A0453
+P09337861T0000
+P02541882A0251
+BC2GM069498013
+P07891709A1542
+P07969135A0913
+P09676349A0000
+P08182171A0000
+P01742879A0471
+P08088777A0754
+P09679750A0304
+P09630245A0102
+P09244430A0693
+P05734847T0000
+P01726631T0001
+P11359907A0099
+BC2GM046384493
+P09162097A0776
+BC2GM076369923
+P01364100A0377
+P11034547A1355
+P11257870A0000
+P03112028A0404
+P08576245A0000
+BC2GM095153900
+P07626806A1098
+P08847138A0609
+P09651375T0000
+P10598101A0754
+P03887085A0000
+BC2GM013625410
+P02532210A0000
+BC2GM048243610
+P07994021A1223
+BC2GM019284772
+P08083220A0988
+P07789342A1352
+BC2GM045860738
+BC2GM075993463
+BC2GM045550408
+BC2GM081970159
+P03065141A0448
+P01138215T0001
+P05718500T0001
+P01757341A0591
+P09671579A1168
+BC2GM018362321
+BC2GM011727188
+P07096587A0267
+BC2GM030855437
+BC2GM094780513
+P02204029A0184
+P09037064A0183
+P07595374A1215
+P03179496T0000
+BC2GM052999233
+P09300698A1219
+P04580044T0047
+P08637717A1231
+P11368911T0000
+P09632734A0943
+BC2GM085332953
+BC2GM037104240
+P01485648A0000
+P08152800A0357
+P08355539A0133
+P10240361T0000
+P09258606A0822
+P06373409A1163
+P07748952A0462
+P07834582A0115
+P07780525A0495
+P02353453A1249
+P01171935A0313
+P09000049A1341
+BC2GM057796202
+P01333125A0000
+P11008420A0580
+P00196255A0000
+P11161455A1286
+P07349416A0337
+P11323419T0000
+P09903722T0000
+P01846803A0688
+P08145646T0000
+P11025367A1009
+P01544854A0699
+BC2GM064857683
+P09418040T0000
+BC2GM008087680
+P00847967T0000
+P08877818A0184
+P11423991A1393
+P09204566T0000
+P06658029A0086
+P01653918A0286
+BC2GM012663791
+P10187317T0000
+P03146150T0000
+BC2GM006351577
+P03491190A0233
+P08056474A0438
+BC2GM030625500
+P08040468A0303
+P06728580A0291
+P08245125A0822
+BC2GM011862984
+P07835710T0000
+P10906999T0000
+P02356823A0063
+P08349499A1169
+P01901443A0297
+P03940426A0618
+P08421295A0365
+P11410563A0363
+BC2GM022540559
+P09388199A0948
+BC2GM066102549
+BC2GM084547844
+BC2GM020659515
+P07809128T0000
+BC2GM000493215
+P06720371T0000
+P03928678T0000
+P11213342A0492
+P11259347A0000
+P10871615A0368
+BC2GM044494195
+P09545323T0000
+P11418662A0917
+BC2GM078517067
+P09326317A0372
+BC2GM032835553
+P03023679A0624
+P11818675X0897
+BC2GM013684936
+P08282576A0297
+P02154599A0382
+P08283292A0779
+P08427501A0221
+BC2GM035405200
+BC2GM001805382
+P07967725A0262
+P10644760A0956
+BC2GM092921833
+P11494391A0579
+P04079738A0677
+P03888621A0185
+P02572928T0000
+BC2GM024324906
+P11536063A0178
+BC2GM013429399
+BC2GM066038185
+P09287036A0457
+P01549465A0122
+P02204810A1080
+BC2GM068897228
+BC2GM098204946
+P01895370A0199
+P03746906A0000
+BC2GM027366629
+P08515776A0971
+P10675331A0600
+P08001792A0284
+P10599727A1567
+P09235073A0000
+P01518849A0165
+P02492111A0670
+P03992022A0330
+P11160732A0464
+P00465223A0373
+BC2GM045716820
+P04335965T0000
+BC2GM090642348
+P06314312A0359
+BC2GM090857419
+P01963438T0000
+P01396444A0934
+P08195233A0147
+P01741249A0177
+P07654740A0563
+P09649265A1575
+P07926775A0895
+P01895555T0001
+P07791771A0183
+P00445259T0000
+P02568930T0000
+BC2GM001245991
+P01653236A0895
+P02236002A0958
+P09022040A0263
+BC2GM047460616
+P09949312A0524
+BC2GM037150480
+P03664038A0000
+P11092886A0341
+P03559287T0000
+P08316209A0000
+P08632015A1226
+P04563045T0000
+BC2GM040092989
+P09599102A1191
+P01916632A0431
+P08376397A0788
+P09576230T0000
+P11350982A0560
+P07140060T0000
+P09882451A0195
+P11471077A0382
+BC2GM064960643
+BC2GM019494722
+P07499242A0898
+P07651340A0286
+BC2GM019485774
+BC2GM038250262
+BC2GM095049284
+BC2GM062202050
+P00986800A0325
+P07575416A0000
+P01777841A0744
+P09111331A0119
+P07935094A0516
+P03064524A0160
+P03034956A0666
+BC2GM078938959
+P07745693A0914
+BC2GM052216512
+P01939131A0871
+P07457931A0655
+P09602124A0127
+P09651383A0967
+P09130720A0417
+P11413319A0000
+P06314276T0000
+P02026461A0760
+BC2GM040737294
+P01911767T0000
+P01468625A0282
+P11070056A0704
+P09121424A0296
+P09333168A0310
+BC2GM096394711
+P07567980T0000
+P06732946A0281
+P02566680A0820
+P09435789A0961a
+P07891720A0818
+P09917064T0000
+P11204897A0797
+BC2GM071919705
+P01870428A0677
+P11178765A0642
+P06340643A0598
+P10805739A0343
+BC2GM055384901
+BC2GM007915861
+P02030910A1070
+P07926739A0766
+P11133927T0000
+P07511444A0728
+P06671925T0000
+BC2GM059522936
+BC2GM010895648
+BC2GM051997462
+BC2GM039151408
+P08636124A0410
+BC2GM074834235
+BC2GM008564407
+P02188096A0955
+P08668124A0744
+P08626540A1007
+BC2GM073396210
+BC2GM044963002
+P09427627A0930
+P07563076A0766
+BC2GM070904413
+P01209618A0409
+BC2GM008679879
+P08627354A0000
+BC2GM011821006
+BC2GM056629834
+P08105727A0099
+P04086657T0000
+BC2GM032259254
+P06657559A0489
+P07883193A0000
+P02093033T0001
+P00061478T0000
+P05413428T0000
+BC2GM029325311
+P11333268A1521
+P02989786A0328
+P08220621T0000
+P04428981T0000
+P07007591A0324
+BC2GM046385397
+P07969181A0313
+P00926604A0504
+P02562787A0637
+P02174974A0000
+P01621584A0183
+BC2GM023474684
+P10894149T0000
+P06308607A0375
+P09566871A0343
+P08497273T0000
+P09605930A1428
+P11328853A0644
+BC2GM006482394
+P09617765A0174
+P09271417A0585
+P03672532A1111
+P07496400A0525
+P08529630A0840
+P03881260A0000
+P08649389A0000
+P07916003A0688
+P09426595T0000
+P03286611A1198
+BC2GM087141217
+P08997490A1127
+P11092850A1023
+P07959952A1446
+P00617815A0215
+P09931118A1072
+BC2GM036392527
+P09581552A1323
+BC2GM017589231
+P01010638A0161
+P07668009A0172
+P11288930A0000
+P02300541A0000
+P00593119T0001
+P11398899A1183
+P09034337A0251
+P08549706T0000
+P01850127A0000
+P02826127A0709
+P07487908A0230
+BC2GM092705100
+BC2GM030204205
+BC2GM012329811
+P03119227A0079
+P04942414T0000
+P09806516A1212
+BC2GM076028870
+P08631797A0982
+BC2GM086450359
+BC2GM040056717
+P07247059A0775
+P07626378T0000
+P08218230A1505
+P09236656A0124
+P08959117A0708
+P10652800A0984
+P08632015A0879
+P04730467T0000
+P09058373A0670
+P08428940A1763
+P09308234A0225
+BC2GM014433955
+P07174122A0000
+P11131321T0000
+P10850453A1292
+BC2GM039883635
+P06054411T0000
+P03743683A0000
+P01080374A0709
+P02552316A0526
+P08290421A0165
+P08288622A0725
+P07745726A1496
+P06809474A1156
+BC2GM027985903
+P10775585A0754
+P08160905A0217
+P11897449A0566
+P09780228A0613
+P04482661T0001
+P02404451A1532
+BC2GM025908037
+P07553942A0810
+BC2GM023807131
+P01930660T0000
+BC2GM033841968
+P11379106A0372
+BC2GM052769911
+BC2GM090842010
+BC2GM046615396
+BC2GM061934161
+P10747053A1102
+P01646753A0336
+P09650180A1130
+P11355576A1125
+BC2GM066378322
+P10650938T0000
+P02146495A0706
+P03228518A0339
+BC2GM055880563
+P07763727A1035
+P09021684A1418
+P06223586A0000
+P03229917A0099
+P07713421A1435a
+P09769209A0100
+P07559563A0282
+P09079878A0000
+P07495059T0078
+P01736093A0731
+P11562278A0169
+P01702426A1006
+P03181276A0422
+P01812690A0475
+P03015628A1078
+P05091970T0000
+BC2GM064815808
+P08045431A0894
+P06093363A0612
+P11472696A0387
+BC2GM040397014
+BC2GM062891050
+BC2GM053475151
+P02959089T0000
+P07528531A0904
+P11486141A0424
+BC2GM062932226
+P09503526A0614
+P10791251A0110
+P09353247A0922
+BC2GM038829305
+P08463320A1219
+P07780719A0477
+P09802902A0225
+P11038317A0000
+P07743697A0703
+P00041512T0067
+P10967361A0000
+P10464250A0275
+BC2GM077422273
+BC2GM068727128
+P07991437A1032
+P09924987A0000
+P06667868T0001
+P08394255A0000
+P08189174A0148
+P08958720A1204
+P09675896A0959
+BC2GM030879551
+P03865743A0859
+P08371936T0000
+P11313342A0224
+BC2GM041365584
+P08005438A1185
+P03403826T0000
+P06686454A0585
+BC2GM076683276
+P02872786A0147
+P09079902A0713
+P08567847A1005
+BC2GM067289380
+BC2GM009022291
+P03838797A0903
+BC2GM051345201
+BC2GM080710806
+P09857038A1374
+P09269900A1035
+BC2GM038525158
+P08382303T0000
+P11158236A0000
+P09140079A2528
+P10684265T0000
+P01697928A1214
+BC2GM072286442
+P01767592A0682
+P10669319A1722
+P11292844A0081
+P09154822T0000
+P02332798A0725
+P07818416A0895
+P10893258T0000
+P07784078A1064
+BC2GM000360337
+P06821147A0468
+P01577740A1111
+P03759330A0713
+BC2GM064553826
+P07944461A0321
+BC2GM091583660
+BC2GM046535575
+P08541793A0796
+BC2GM022740779
+P09411459A0729
+P02694731A0241
+P01309894A0807
+P01702972A0613
+P10662614A0000
+BC2GM028667009
+BC2GM093098525
+P07616563A0532
+P09359887A1168
+P09089653A1112
+P03013477A0000
+P11264561A0167
+P11435560A1322
+P02865502T0000
+BC2GM042983371
+P08442384T0000
+P08621628A1233
+P04511139T0001
+P11256944A1144
+BC2GM085800935
+P07926749A0471
+P09144958A0047
+P01350932A1123
+P02474204A0105
+P02511898A0000
+BC2GM031800406
+P11441311X0001
+P08798512A1197
+BC2GM019804740
+P05529283T0000
+P02452313A0114
+P10905349A0609
+BC2GM002325093
+P10400774A0240
+P08590465A0773
+P09514156A1147
+P08420995A0499
+BC2GM069191701
+P09314487T0000
+P00993176A0066
+P08124912A0456
+P04890336T0001
+P07749088A0119
+P11152283A0223
+P09343433A0000
+P00627039T0000
+P11282433T0000
+P02176232T0001
+BC2GM070173071
+P01340470A0000
+BC2GM096544601
+BC2GM041156819
+P09748286A0000
+P08144631A0000
+BC2GM031237575
+BC2GM078836227
+P09050847A0180
+P11241215A0566
+P03995513T0000
+P02068085A1273
+P01505516A0928
+P02170687A0000
+P01909621A0119
+P01541577A0000
+P10125354T0000
+P09045842T0000
+BC2GM025767093
+BC2GM053837168
+P11124024A1098
+P03526279T0000
+P07394364A0738
+BC2GM027891273
+P09057841T0000
+P08929089A0231
+P08325504A0226
+BC2GM036723867
+P08035796A0890
+P08521414A1384
+P03194410A0771
+P09549632A1189
+P11532556A0000
+P01553407T0000
+P01526658A0454
+P11042703A0875
+P07977239A1283
+BC2GM049401430
+P08070654A0000
+P03005231A0649
+P09632734A0081
+P07509053A0139
+P09852109A1475
+P08784787A0383
+BC2GM090002876
+P09488486A0000
+BC2GM027879674
+P01421390T0000
+P08492290A0306
+P10946303A0000
+P04704186T0000
+BC2GM024652235
+P02268461A0224
+P03981421A0246
+BC2GM064119241
+P08931388A0806
+P11003653A0198
+BC2GM030350925
+P08386318A1102
+P05792868T0000
+BC2GM021800196
+P09636358A0000
+P09813254A0000
+P09407026A0426
+P04884060T0000
+P03933232T0000
+BC2GM014851186
+P01282638A0934
+P09676419A0158
+P09710614T0000
+BC2GM064361080
+P08314163T0000
+P01551910A0978
+P02870720A0188
+BC2GM087367998
+P02347655A0193
+P02543734A0414
+P08076937A0851
+P06035001T0000
+P06606043A0598
+P05552642T0000
+P07594047T0000
+P06306342A1156
+BC2GM090387828
+BC2GM065187167
+BC2GM061773962
+P08584035A0740
+P01861188A0000
+P06698047A0445
+BC2GM015089402
+BC2GM066297688
+BC2GM058306655
+P09834070A0793
+P01649835A0822
+P09566731A0458
+P01690703A0285
+P01837787T0000
+BC2GM038824735
+P09178494A1123
+P07493327A0507
+BC2GM019813491
+BC2GM087769438
+P09311810A0814
+BC2GM098689605
+BC2GM083059835
+BC2GM049234843
+P08100057A0577
+P09528950A0716
+P09246585T0000
+P11559366T0000
+P07623821A0649
+P09252406A0511
+P06492188A0615
+BC2GM006294233
+P05425195T0001
+P09060623A0961
+P07068496A0000
+P11416650T0000
+P03171221A0531
+P00921911A0159
+P08157674T0000
+BC2GM011606685
+BC2GM056849108
+P02431314A0834
+P02614668A0971
+P06864955T0000
+P11451447A0205
+P01532796A0107
+P08995410A0000
+P06599282T0001
+P07555373A0000
+P03404495A0172
+P08191910A0228
+P09650789A0185
+P11283014A0921
+P01952827A0215
+P09671464A0316
+P07474085A0932
+P09003001A1909
+BC2GM034839336
+P07687541A0200
+P06817410A0982
+P10570996A1213
+P06291369A0000
+BC2GM094013655
+P11517269A0472
+P02072798A0330
+BC2GM026543710
+P11027027A0061
+P09837715A0581
+P08134115A1161
+P09465035A1032
+P07588628A0318
+BC2GM073035412
+P09756895A0322
+P07744776A0617
+P01395755A1023
+BC2GM032241035
+P03717475A0208
+BC2GM020267089
+P07864709A0324
+BC2GM070526429
+P11352423A0084
+P01647656A0000
+P10982076A0000
+P02703925A0359
+BC2GM006641909
+P08652081A1953
+P08649389A0692
+P09548481A0000
+P01168607A0672
+P01353478T0000
+P08858268A1307
+P09475898T0000
+BC2GM055943127
+P08573083A0645
+P02405818A0550
+P08267667A0748
+BC2GM054522727
+P06994035T0001
+BC2GM062196323
+BC2GM094469292
+P08702728A1325
+P07679390A0721
+P11311153T0000
+P10724519A1185
+P00535520A0239
+P10773455A1268
+P05305671T0000
+P07414817T0001
+P09160361A0858
+P02708288A0139
+P08642693T0000
+BC2GM009398467
+BC2GM028887515
+P03930894T0000
+P08675763A0788
+BC2GM081669747
+P02349942A0287
+P10913276A0510
+P09093867T0000
+BC2GM054844326
+P09524222A0769
+P02475717A0565
+P09333026A0851
+P10594239A0614
+P08649440T0000
+P10640683A0670
+P07628438T0000
+P01904154A0164
+P11460035A0548
+P02135343A0131
+P09294453A0949
+P11179687A1118
+BC2GM079747386
+P09751061A0000
+P08428952A1957
+P08507921A1021
+P01840711A0000
+P09257887A0457
+P03309892A0637
+P00240016T0033
+BC2GM019020336
+BC2GM011718278
+P08251622A0000
+P10666253A1291
+P07559356T0000
+BC2GM002404692
+P08395654T0000
+P02138915A1060
+P01924920A0115
+P06948868A0082
+P01285009A0000
+P11054565A0654
+P09090592A0175
+BC2GM058058644
+P07154928T0001
+P09725854A1060
+P00933251T0000
+BC2GM097462810
+BC2GM058564521
+BC2GM063929508
+P09990057T0000
+P11278604A0300
+BC2GM057222507
+P09543227A0815
+BC2GM066166532
+P02645276T0088
+BC2GM092441762
+P02878100A0674
+P09154621A1475
+P02324102A1157
+P08069481A0736
+P07483276A0139
+P09234736A0999
+P07408970A0706
+P01389362T0000
+P09473040A1303b
+P09177169A0935
+P11314428A0651
+P08839911A0716
+P09501169A0000
+P09845662A0085
+P02550118A0610
+P08666404A0311
+BC2GM052318281
+P00890028A0507
+BC2GM044672439
+BC2GM017310347
+P10043466T0000
+P10379899A0446
+BC2GM001987154
+P10954525A1161
+P09767575A0657
+P09202669A1530
+P10702389A1148
+P02638964A0372
+BC2GM069139164
+P08647802A0000
+P06254403A0000
+BC2GM038488756
+BC2GM060681176
+BC2GM054393816
+P00712117A0521
+P10681520A0525
+P01679124A1368
+P01533760T0000
+P07593266A1174
+P07494314A1287
+P06374418A0877
+BC2GM069806610
+P11509266A0955
+BC2GM034659182
+P04839176T0001
+P02476030A0000
+P09649069A0490
+P03097509A0654
+P09915860A0000
+P09374541A0277
+P09727045A0817
+P11030744A0763
+BC2GM078941863
+P07981143A0633
+P07859739T0000
+P07537851A0891
+BC2GM058610366
+P09162084A0956
+P08334989A0070
+P00234264A0164
+P06503132A0784
+P08869825A0000
+BC2GM085576147
+P04863895T0000
+P09182707A0254
+P07636962A1883b
+P07565731A1629
+BC2GM066024326
+BC2GM083166259
+P07297978A0570
+P11306511A1476
+P09169475A0272
+BC2GM089987435
+BC2GM084502835
+BC2GM000288103
+P08076631A0000
+P02253663A0687
+BC2GM005288788
+P02713520T0000
+P09371657A0165
+BC2GM074705876
+P11157784A0141
+P06714354A0194
+BC2GM087826956
+BC2GM070888113
+P09011745T0000
+P05740389T0001
+P01552457T0000
+P10778757A0000
+BC2GM083712853
+P05850652T0001
+BC2GM070372119
+P05437405T0000
+P11266184A0000
+P02357537A0451
+P07068493A0636
+BC2GM057387777
+P01937989A0383
+P03264299A0679
+P10933728A1398
+P07380615A0478
+BC2GM001246752
+P09407031A0974
+P11093745A0563
+P10592824A1157
+P00054900A0226
+BC2GM052219408
+BC2GM026443605
+BC2GM098365261
+P08706368A1024
+BC2GM068389238
+P08282501A0358
+P01297332T0000
+P02444507A0240
+P02758382A0478
+P11235817A0000
+BC2GM086752058
+P06807192A0312
+P09277472A1070
+P09079650A0136
+P01334518T0000
+BC2GM003392848
+P11522658A0086
+BC2GM053477208
+P09931216A0566
+P09592208A0470
+P10601410A0977
+P09712919A0307
+BC2GM094973350
+BC2GM074597498
+BC2GM012136507
+P00872922A0204
+BC2GM052850405
+P08643513A0361
+P11529914T0000
+P08812490A0542
+P08083999A0501
+P07772036A1000
+BC2GM090231645
+P09755478A0366
+P02717349A0311
+BC2GM034622067
+BC2GM034402560
+P04001490T0001
+P08891474A0667
+P09508119A0498
+BC2GM003946891
+BC2GM057075557
+P09929811A0000
+P10934073A1433
+P01992953T0000
+BC2GM052917492
+P09168134A0858
+P06184487A1485
+BC2GM085924161
+P08093616A1214
+P07919540A1119
+P11053009A0000
+P09763522A2545
+P05412122T0000
+P02829183A0117
+BC2GM088537216
+P02292272T0000
+P08898916A0791
+BC2GM007719127
+P09370276A0781
+P11752821A1365
+P09442072A0716
+P01420177A1065
+P08253387A1291
+P07916983A0623
+P01708771A1215
+BC2GM095055828
+P07959011A0379a
+BC2GM070319467
+P05356107T0001
+BC2GM036738213
+P09756687A0981
+P08150970A0434
+P11573891A0525
+P11872570T0000
+P05689427T0052
+P09710599T0000
+P11246679A0000
+P03423732A0341
+P11254713A1029
+P02163394T0000
+P11572377T0000
+P02536160A0518
+P07704730T0000
+BC2GM076945603
+P11340085A0211
+P01093847A0000
+P08177143T0000
+P09935377T0108
+P03114829T0000
+P08449943A0225
+P08621714A0361
+BC2GM017195942
+BC2GM056444302
+P00833472A0907
+P09199626A0613
+P01657415A0837
+BC2GM088326389
+P08647884A0547
+P08383526A0591
+P02651487A0000
+P09362105X0422
+BC2GM031317365
+P03319646T0000
+BC2GM088483359
+BC2GM095573888
+P09890778T0000
+P10777499A0883
+P06333433A0000
+P01082726A0248
+P10684534A0634
+P07534297A0141
+P07918097T0000
+P09077076A0219
+P11053370A0708
+P01563343A0548
+P10998679A0500
+P10791901A0609
+P07639106A0678
+P01374331A0636
+BC2GM070662634
+P09468386A0594
+P09519828A0809
+P10767338T0000
+BC2GM009473053
+P09763421A1199
+P07983712A0914
+P10671520T0000
+P09058378A1134
+P01849734A1063
+BC2GM030320745
+P04729063T0000
+P08621017A1186
+BC2GM029694123
+BC2GM097325580
+P07192369T0000
+P10520800A0307
+BC2GM007950303
+P09030581A0990
+P08835393A2829
+P09279379A0310
+P03149774A0173
+P10666222A0330
+BC2GM020218379
+P02971957A0287
+P09961326T0000
+BC2GM064144639
+P10910073A0876
+P08999882T0000
+BC2GM011637972
+P07490742A0636
+P04712626T0000
+P03848527T0020
+P11390684A1170
+BC2GM043410270
+P08289783A1476
+P08953340A0000
+P08662617A2051
+BC2GM062962431
+P07714608A1252
+P07937147A0205
+BC2GM011344570
+P04103248T0000
+BC2GM057027725
+P08255022A0827
+BC2GM099236530
+BC2GM072370465
+P01832197T0001
+P08082286A0748
+P01407286A0427
+P08822399A0518
+P10799595A1454
+P11243336A0000
+P09094315A0541
+BC2GM095731252
+BC2GM014013049
+BC2GM096403627
+P08257666A0662
+P03050147A0896
+P02523800A1178
+BC2GM085583133
+P09135928A0912
+P11134508A0317
+P08094464A0869
+BC2GM018871936
+P06388189T0001
+P09502720A0214
+P11433014A0683
+P03406054A0351
+P09952378A0529
+BC2GM096620128
+P09735368A0636
+BC2GM088368088
+P10938135A0259
+P01420363T0000
+P02123875A0223
+P07607537A0954
+P09043768A0139
+BC2GM036908769
+P08833653A0304
+P03935797A0183
+P09368058A0969
+BC2GM043837371
+P09443973A1028
+P08205827A0940
+P02562825A0413
+P11251276A0793
+BC2GM065023987
+P07416204A0437
+BC2GM077013458
+BC2GM043725941
+BC2GM044052355
+P09047344A0000
+P08783180A0000
+P08902214A1486
+BC2GM019377317
+BC2GM094661498
+P02248732A1113
+BC2GM097088873
+P07565031A0454
+P07673154A0688
+BC2GM080383743
+P08988257A1256
+P03377864A0000
+P02361575T0000
+P10560997A1072
+BC2GM033982048
+BC2GM020687268
+P03810361A0576
+P09438427T0000
+BC2GM079994389
+BC2GM009701774
+P02691557A0273
+BC2GM047934950
+BC2GM085712382
+P08065327A0000
+BC2GM063579260
+P09053309A1103
+P08119907A0000
+P06802500T0001
+P09249710A0331
+P10972990A0526
+P01733358A0240
+P05693605T0001
+P06782869A0263
+BC2GM091988881
+BC2GM090889601
+P06689413A0174
+P11344530A0320
+P07665477A0901
+P02162103A0000
+P02208762A0228
+BC2GM095985725
+P02733116T0000
+P08716757T0001
+BC2GM051225435
+P00453780A0430
+P09218520A0075
+P10683259A0774
+BC2GM025679566
+BC2GM082082186
+P08049444A0351
+P07748451A0343
+P00451192A0248
+BC2GM096019104
+BC2GM004737779
+BC2GM079066948
+P11404019A0532
+P07877619A1284
+BC2GM033123409
+P11419938T0000
+P01718043A0384
+P06394228T0073
+BC2GM015085481
+P02566613A0831
+P01396572A0320
+BC2GM050125975
+P07702327T0000
+P11384229A1669
+P07355527A0467
+BC2GM071034942
+BC2GM073528534
+P09780228A0122
+P09215525A0581
+P09884232A0286
+P02115122A0562
+P11157763T0000
+P02227438A0492
+BC2GM010561492
+BC2GM045159719
+P03428084A0430
+P11162576A0213
+P09367676A1115
+BC2GM026460390
+P02246362T0000
+P09199348A0156
+BC2GM067787787
+P08349104A0450
+BC2GM009844506
+P06659982A0231
+BC2GM024210872
+P01715975A0885
+P03275867A0187
+BC2GM027811998
+P08532516A0000
+P08814651A0000
+BC2GM078881982
+BC2GM095302327
+P02093741A0211
+P11075944A0691
+P07337609A0531
+BC2GM056359594
+P09805052A0119
+BC2GM012008422
+P08097732A0000
+P08895997A0336
+P10713176A0422
+P11425877A1026
+P01643943A0300
+P08891345A0684
+BC2GM037323939
+P08070393A0631
+P08872162A0884
+BC2GM025927345
+P07606587A0266
+P09118664A1734
+P07504712A0843
+BC2GM082621888
+P01456888A0074
+P00935526A0000
+BC2GM083864266
+P00747722A0486
+P09334330A0252
+P07969136A0273
+P01286732A0572
+P11378898A0164
+BC2GM046724705
+P03537721A0491
+BC2GM075504151
+P04941951T0000
+P02378615A0807
+P09443948A0000
+BC2GM033547721
+P02934889A0558
+P09718671A0000
+BC2GM018712064
+P09843378A0187
+P03978045A0857
+BC2GM047215943
+P07651398T0000
+P09826658A0691
+P01722319A0849
+P11044105A0616
+P01446132A0328
+P07559355A0066
+P03027779A0000
+P10733591A0146
+P09199970A1101
+BC2GM039968036
+P08299181A1148
+P09920539A0272
+P04600603T0001
+BC2GM034973771
+P11099377T0000
+P08278548A0597
+P09506962A1000
+P06654047A0694
+P08376796A0172
+P07518578A0000
+P09882334A0822
+P02324104A0929
+P09103382T0000
+BC2GM031634103
+P02406570A0898
+P11356214A0794
+P09710615T0000
+P03390074A0000
+BC2GM021219162
+P11278671T0000
+P08668158A0765
+P00947834X0000
+P06482665A0735
+P07581364A0500
+BC2GM087115294
+BC2GM019801606
+BC2GM038764825
+P09235995A0339
+P05760665T0000
+P01601869A1389
+P10663558T0000
+P10962564A0883
+P07387242A0236
+P06336045A0261b
+P11313946T0000
+P07846942A0717
+P08825556A0522
+P06702643A0000
+P10864641A1400
+P08641705A0986
+P10702241A0357
+P00476020T0000
+P09459241A0707
+P09086268A0611
+BC2GM052999467
+P08552387A0000
+P02355765A0220
+P01328681A0149
+P04019066A0000
+BC2GM037252566
+P04627477T0001
+BC2GM055659274
+BC2GM013148295
+P11560992A0000
+P08349104A0000
+P04544430T0001
+P09590540A0513
+P08248688A0726
+P06073427T0001
+P07445971A0241
+P10856805T0000
+P03988001A0227
+P09259328A0440
+P09512550T0000
+P10660604A0748
+P06755468A0180
+P07688112A0274
+P01301171A0979
+P02291144A0493
+P02164604A1574
+BC2GM052166427
+P09290571A0799
+P09428389A1805
+BC2GM083759997
+P08601616A0726
+BC2GM093919585
+P03373755T0001
+P08119958A0273
+P02766745T0000
+P07195615A0087
+P02403926A0000
+P07478525A1177
+P09522297A0744
+P08175031A0566
+P08245461A0700
+P08262041A0727
+P10982825A0363
+P11043469A0440
+P01983026A0483
+P09622121T0000
+BC2GM074348497
+P07831829A1324
+P08164661A0414
+P09738693T0000
+P08731155A0499
+P09409821T0000
+P00056837A0000
+P08836172A1382
+P08509051A0316
+BC2GM024114351
+P08550462A0815
+P10611235A1927
+P11168588T0000
+BC2GM082960134
+P07158726T0001
+P02586485A0511
+P09366517A1828
+BC2GM068206281
+BC2GM068969050
+P08645214A1052
+BC2GM002155163
+P07753837A0724
+P11509615T0000
+P08637711A1121
+P01762914A1218
+P08880405A1170
+BC2GM049538260
+P07823953A0777
+P02353875A0800
+P09586832A0229
+P03829848T0001
+P05949971T0000
+P07528772A0616
+P09668096A0806
+P11097079A0525
+P07449221A0086
+P07259325A0394
+P02794828A0214
+P11466227A1665
+P10748113A0187
+BC2GM001477367
+P09186507A0882
+BC2GM095945527
+P08007975A0000
+P06829082A0187
+BC2GM091999980
+BC2GM045048834
+P07169630A0983
+P11241243A0693
+P09471984A0000
+P00587791T0054
+P09837920A0222
+P07508954A0000
+P07859238A1150
+BC2GM079935127
+P09886602A0000
+P07576307A1654
+P07521285A1109
+P10704410T0000
+BC2GM078874950
+P08719155A0105
+P09115989A0993
+BC2GM084544513
+P11311563A0423
+P02017414A0307
+P01631229T0000
+P02870851A0349
+P01259027A0416
+P09060444A0557
+P01982997A1104
+P01674817T0000
+P01974876A1051
+BC2GM088538156
+P01327280A0000
+P07752454A0341
+P02667259A0331
+P00779272T0001
+P09858745A2033
+P03315359A0732
+P02424743A0280
+P10585440A0204
+BC2GM065577575
+P06328002A0000
+P02250919A0404
+P09813203T0000
+P01502157A0000
+P00722652A0118
+P03109147A0000
+P07935471A0613
+BC2GM067463780
+P08196616A1112
+P09193671A0347
+P06369954T0000
+P05930797T0000
+BC2GM057454173
+BC2GM001207192
+P11141003T0000
+BC2GM007200523
+P10448440T0020
+P01428513A0440
+BC2GM068744925
+P11000203A0752
+P11016724A0536
+BC2GM080063852
+P01652372A0153
+BC2GM019777256
+BC2GM018365165
+P07462481A0422
+BC2GM010424307
+P02826729A0790
+P11543154T0000
+P01767899A0136
+P01754381A0000
+P07053251A0666
+BC2GM008228861
+P01081904A0198
+P09755199A0373
+P09994942T0000
+P09436795A0350
+P08763311A0189
+P10708769A0433
+P02969819A0814
+P02160622A0000
+BC2GM021160807
+P08621719A0000
+BC2GM076681368
+P08464056A0510
+P09601510A0215
+P01499213A0185
+P07179412A1131
+BC2GM034355012
+BC2GM052598708
+BC2GM060603409
+P08977235A0134
+P01694014A0716
+BC2GM087479423
+P03746053A0670
+BC2GM025371189
+P08710371A0499
+P07755884A0000
+P10841593A0780
+P00210220X0000
+BC2GM033814986
+P11123912A0306
+P03110801A0532
+P10999205A0607
+P07646439A0535
+P01088654T0001
+P11084334A0590
+P02294048A0881
+BC2GM021744852
+P08923469A1391
+P09603345A1257
+P00354315T0000
+BC2GM062047431
+P08668158A1252
+P11078726X0000
+P08649386A1032
+P07935379A0347
+BC2GM061513457
+P11560292A0557
+P02537485A0841
+BC2GM066867028
+BC2GM055232950
+P09339900A0939
+P02498322A0226
+P09888711A0781
+BC2GM070901707
+P07664278A0135
+P07871757A0846
+P08416977A0892
+BC2GM084277240
+P09619631A0344
+P06685643A0179
+P06607427A0000
+P00052597T0000
+BC2GM029173033
+P01093055T0000
+P03344812A0924
+P00401521A0138
+P08617800A0675
+BC2GM014548210
+P01787085A0331
+P08597636A0000
+P01984665T0000
+P03956695A0617
+P08920499A0164
+BC2GM005703373
+BC2GM058781724
+BC2GM070838857
+P02107548A0727
+P08230445A0000
+P07871754A0857
+P10688646A0535
+P01732033A0000
+P00580151A0706
+P05909034T0000
+P02374886A0305
+P01650524A0837
+P08824884A0000
+P11132195A0000
+P06542372A0159
+P07916685A0455
+BC2GM060551138
+P11311550A0253
+P06223586A0460
+P07951410A0647
+P08189533A0203
+P06048505T0000
+P07614762A0224
+P08901658A0498
+P10852221A0422
+P01890362A0305
+P08098228A0625
+P07937965T0000
+P10895851A0696
+BC2GM001695842
+P01549123A0480
+P06238540A0798
+P02480419A0735
+P01748194A0767
+P01473207A0582
+P01431809T0000
+P03073192T0000
+BC2GM077208182
+P01334493A0289
+P00012653T0045
+BC2GM003261420
+P09562398A0848
+BC2GM064768852
+BC2GM053409406
+P04055593A0523
+P09004504A0000
+P07629113A0726
+P09879766A0402
+BC2GM021723092
+P08145770A1078
+P09420269A0000
+P01660925T0000
+P08497190T0079
+BC2GM008773952
+P07753796A0625
+BC2GM036119481
+P11221845A1370
+P01975428A0151
+P11349796A0950
+P07854324A0281
+BC2GM065029145
+P07888156T0000
+P06886948A0750
+P08274774A0958
+P00619782A0058
+P06700469T0000
+P02329840A0383
+BC2GM049574231
+P08986190A0927
+P10839470A1148
+P08999857A0801
+BC2GM013864172
+P06355483A0134
+P02747653A0910
+P02674141A1202
+P02521217A1035
+P10590092A0124
+P07696878A0222
+BC2GM075272247
+P11473254A0000
+P08445299T0000
+P00984209A0614
+BC2GM053210179
+P07604783A0952
+P00602702A0309
+BC2GM017562219
+P01480183A1689
+P05799686T0001
+P09882321A0948
+BC2GM034033075
+BC2GM065840723
+P09566876A0000
+P07936650A1752
+BC2GM045174565
+P01918010A1730
+BC2GM002134546
+P01756195A1117
+P11105716A0782
+P01608239T0001
+P09650299A1334
+P09121430A1075
+BC2GM030336153
+P11484028T0000
+P07876300A0994
+P03577670A0102
+P09790986A0689
+BC2GM032107617
+BC2GM093377314
+P01377764A0309
+P11028131T0000
+P09013499A0198
+BC2GM079186021
+P07592710T0000
+BC2GM054295560
+BC2GM019564620
+P08970951A0823
+BC2GM069744943
+BC2GM042107668
+P01496348A0000
+P08561607A1443
+P10930526A0174
+P05170106T0034
+P06546392A0542
+BC2GM012939166
+P08676858A1084
+P04021437A0000
+BC2GM047468980
+BC2GM025704157
+P10572130A1623
+P09792714A1408
+P09773975A1873
+P04289156T0000
+P01730747A0205
+P07798207A0759
+P00592887T0000
+P10572087A0326
+P11169149A0097
+P10643313A0345
+BC2GM018805771
+P02674327A0493
+P09914525A0890
+P07742363A0135
+BC2GM096535818
+P09159160A0000
+P02833517A0467
+P09614065A0966
+P02538450A0000
+P02054754A0919
+P03004982A0199
+P02045366A1149
+BC2GM096119161
+P03192724A0000
+P01808136T0000
+P08954725A1175
+BC2GM059750371
+P03190914A0149
+P00640584A0250
+P10602507A0652
+P11126275A1068
+P02474110A1039
+P09837945A0820
+P09230894A0422
+P07616802A0315
+P09420251A1363
+P02773507A0750
+P02674671A0601
+P07049690T0000
+P09724763T0000
+P09854034A0536
+BC2GM099821771
+P08601490A0659
+P10393192A0792
+BC2GM044293029
+BC2GM022014688
+P09891009T0000
+P09541280A0404
+P07596283A0396
+P03668003T0000
+BC2GM073487820
+P08918885A0811
+P11041308A0156
+BC2GM012462768
+BC2GM018110366
+P08985109A1285
+BC2GM045058559
+P10727433A0560
+P08373274A0546
+P07658471A0000
+P07354367A0162
+P00513284A1255
+P10613843A0107
+P06762321T0000
+BC2GM084904030
+P01766999A0000
+P09238467A0763
+P04039439A0842
+P06784123A0286
+P10684069A0508
+P06238704T0001
+P08000112T0000
+P11062705A0658
+P09102113A0739
+P02496100T0000
+BC2GM086255271
+P02844767A0596
+P08085782A0164
+P03693543A0405
+P10947840A0762
+P03046655A0000
+BC2GM000008491
+P07601121A0153
+P01279352A0473
+P08227129T0000
+P10733591A0533
+P02642976A1474
+P09858713A1174
+P01431602A0229
+P01845885A1003
+P08756712A0227
+P07507207A0991
+P05114515T0000
+BC2GM072636195
+P07044842A2062
+P03035658A0355
+BC2GM081703119
+BC2GM030904098
+P01420363A0818
+BC2GM021744548
+P09331864A0230
+P11319880A1108
+P09010223A1850
+P08832146A0959
+P09560325A1285
+P11226752A0750
+P07948921A0051
+BC2GM044027057
+BC2GM097718440
+P09742129A0491
+BC2GM077073177
+P01740682A0703
+P00163384A0000
+BC2GM042374200
+BC2GM045278199
+P11073163A0131
+P08226780A0160
+P07693975A1418
+P10625721T0101
+BC2GM002241638
+P02674679A1237
+P08504707A0376
+P09871353A0174
+P11561623A0897
+P02129338A0568
+P11314030A1264
+P09325322A1293
+P06287231A0914
+P09931252A1055
+P11375392T0000
+BC2GM049336360
+P09139694A0789
+P10909973A1508
+P01331057A0000
+P03208493A0849
+P08752714A0000
+BC2GM062639747
+P01857143A0351
+P03685073A0200
+BC2GM084522196
+BC2GM053739384
+P09852068A0150b
+P08532967A0364
+P09653648A0445
+P01594554A0845
+P03036817A0213
+P10891441A0871
+BC2GM098358600
+BC2GM065082565
+P07745311A0264
+P08476087A0814
+P05693602T0001
+BC2GM056636695
+P03981640A0168
+BC2GM066216653
+BC2GM081673758
+P02631743A0275
+P00619305A0759
+P07240343A0000
+BC2GM058597920
+P08403804A0754
+P07672821A0763
+P00951909X0001
+BC2GM087473233
+P01894696A0301
+P01717925A0477
+P08175188A0685
+P08606267A0740
+P10852953A0000
+BC2GM020782530
+P07266969A0246
+P03925712A0229
+P09736697A0783
+P08922390A0361
+P02605182A0936
+BC2GM080486141
+P08726024A0532
+P01627106A0320
+P09288916T0000
+P02124433A0235
+P06992600A0405
+P10684286A0386
+P06858805A0314
+BC2GM015182129
+P06131378A0818
+P08994832A0782
+P04704137T0001
+P09168623A0614
+P07949551A0000
+P09475378A1449
+P08289342A0931
+P01723619A0766
+P11473261A0587
+P03696899T0001
+P01460054A0478
+P08432696A1117
+P01541556A1040
+P08740416A0239
+P02261254A0168
+P02689439A0402
+BC2GM077439334
+BC2GM074265935
+P11133986A0350
+P11573771T0000
+P01772201T0001
+P10967531A1025
+P09713990T0000
+P01339773A0000
+P09371455A0000
+P08918456A0455
+BC2GM083303978
+P09308738A1216
+P07988731A1301
+BC2GM056468201
+BC2GM070993491
+P01852603A0000
+P09514159A0562
+P08548291A1059
+BC2GM012710435
+BC2GM094584922
+BC2GM046414753
+P07326596A0061
+BC2GM050874939
+P01847464A0856
+P05722341T0000
+P03765731A0918
+P10752807A1598
+P08396120A0690
+BC2GM009448248
+P07678242A0473
+BC2GM004777845
+P07449253A0411
+BC2GM068581710
+BC2GM011914168
+P07534286A0842
+P02795923A0000
+BC2GM073745691
+BC2GM007582543
+P11450490A0565
+BC2GM066466622
+P08654972A0000
+BC2GM076461759
+P10799863T0000
+BC2GM074968808
+P11157035A1405
+P07592771A0258
+P03398714A0594
+BC2GM086205722
+BC2GM063781276
+P02273690T0001
+P07935472A0276
+P07655184A0852
+P10965135A1207
+P01792914T0000
+P06948493T0026
+P01398074A1081
+P09822825A0141
+P09614106T0000
+P01547942A0120
+P08470895A1617
+P10669594A0969
+P07260987A0336
+P01681075A0429
+P10940562A0379
+BC2GM059055199
+P05322558T0000
+P00710372A0302
+P06482179A0497
+P04026972T0000
+P08169201A0291
+P01009451A0728
+BC2GM069590110
+P02781567A0544
+P07586403A0765
+P08849208A1022
+P07147622T0000
+BC2GM060909713
+P01938178T0000
+P00564032A0724
+BC2GM005627247
+P02396415T0001
+P09389666A0538
+P09099745A1446
+BC2GM075883505
+P09525888A1482
+P04005190A1288
+P03936828T0000
+P01735721A0185
+BC2GM011471991
+P03922116A0197
+BC2GM059747347
+P09035307A0000
+P01804671A1001
+BC2GM077137738
+P08089184A0825
+BC2GM045996206
+P02044950A0258
+P08906056A1290
+P02254749A0133
+P09092493A0861
+P11435517A0396
+P01776306A0572
+BC2GM019360660
+P08085609A0384
+P10698516T0000
+P07577904A0141
+BC2GM028713807
+P09088371T0000
+P02919530A0000
+BC2GM048576585
+P03628794A0648
+P08415643A0555
+P01568960A1129
+BC2GM062031104
+P11361338A0447
+BC2GM051429391
+BC2GM012807345
+P09324878A0952
+P11158337A0000
+P09620273A0189
+P08037338A0000
+P02740627A0137
+P03891766A1473
+BC2GM035066986
+BC2GM059623461
+P08367388T0035
+P09030781A0734
+P08884273A1413
+P11287623A0286
+BC2GM013674707
+BC2GM047129964
+BC2GM076520533
+P08728040T0000
+BC2GM086765060
+P09887544A0000
+BC2GM037564004
+P03420324A0178
+P09916809A0405
+P02617623A0740
+P07567300T0000
+P11548027A0163
+P11481625A0202
+P10601290A0742
+P08823709A0220
+P01851876A0129
+P09092636A0802
+BC2GM047251992
+P07720709A0755
+P11368363A0129
+P09516472A0292
+P01573270A0000
+BC2GM088003576
+P10688639A1310
+BC2GM010467864
+P11150315A0844
+P06411659A0793
+P09002672A0439
+P07620491T0000
+P03332848A0000
+P11073539A0866
+P09435806T0001
+BC2GM033468681
+BC2GM008859713
+BC2GM046461652
+BC2GM035990949
+BC2GM084137425
+P01687050T0000
+P09374082A0504
+P10851745A0624
+P03914875T0001
+BC2GM072960583
+P09656485A0351
+BC2GM004292158
+P09385169T0000
+P08069298A0492
+P08099443A0359
+P09267542A0126
+BC2GM007629398
+P09691031A1050
+P00159600A0871
+BC2GM009260448
+P09572965A1235
+BC2GM073366663
+P08823260A1161
+P04911925T0001
+P05833022T0001
+P04428800T0001
+P03709627A0247
+P10781109T0000
+P10690702A0065
+P11023853A0188
+P08445655A1009
+BC2GM070051606
+P08937631A1223
+P08754834A1097
+BC2GM065749861
+P01845829A0158
+P10629176A0887
+P09765394A0000
+P07517869A0411
+BC2GM051993138
+BC2GM052141177
+P11289135A0975
+P10706887A0281
+P11157774A0789
+P09203586A1197
+P02144610A1306
+P03703493A0654
+BC2GM086588725
+P02765214A0486
+P09048617A0648
+P11574105A0727
+BC2GM045721161
+BC2GM070037858
+P08242861A0368
+P09506983A0304
+P09006022A0252
+P10669633A0391
+P08828152A1238
+P11235777A0878
+BC2GM062157969
+BC2GM062176134
+BC2GM023485577
+BC2GM014113607
+P01650557T0000
+P10866886A1277
+P02761492A0124
+P06782612A0142
+BC2GM050477465
+BC2GM026306487
+P10688666A1010
+P09753774A1642
+BC2GM028226886
+P08062833A0000
+BC2GM026154054
+P06214605A0123
+BC2GM092290359
+P08319907A0754
+P08873063A0875
+P01588270A1029
+P07539314T0000
+BC2GM066012770
+P09949160A0600
+P09327881T0000
+P08144615A0533
+BC2GM048317669
+P02630543A0210
+P11516890A0236
+P11072155A0764
+P01582500A0178
+P00499588T0000
+BC2GM052316852
+P09811730T0000
+P11237598A0962
+P10900129A0138
+P02677002A0205
+P09190940A0127
+P09256973A0455
+P08794348A1067
+P05299993T0000
+P08389074A1227
+BC2GM034750890
+P08555498A0427
+BC2GM000293986
+P11054539A0114
+P11069999A1602
+BC2GM017449722
+P07107773A0000
+P08543810A0000
+P02233626T0000
+P07737508A0649
+P02677429A0366
+P11062274T0000
+BC2GM025063596
+P01864821A0000
+P00970839A0118
+P05683363T0001
+BC2GM047847482
+BC2GM022729580
+BC2GM047662900
+P11128925A0000
+P02079811A0407
+P09083563A0971
+P02557217A0000
+BC2GM067091384
+P02927391A0238
+P03750700T0001
+BC2GM072980050
+BC2GM059504332
+P08378082A1031
+P09637689A0150
+P01582413A0759
+BC2GM099003482
+P09786404A0541
+P09419680A1112
+P00105401A0635
+BC2GM016180513
+P10711674A0000
+P08461946A0386
+P07592946A0261
+P02909528A1081
+P10908317A1459
+P07816617A0763
+P06751455A0117
+P08456378A0134
+P11013079A0927
+P08143667A0222
+P05500957T0001
+P09844921A0000
+P01372802A1481
+P01881595A0476
+P02243386A0113
+P04305850T0000
+BC2GM098934435
+BC2GM014257511
+BC2GM081653847
+BC2GM046485760
+P09858593A0334
+P08090571T0001
+P10678144A0509
+BC2GM030793511
+P02897651A0000
+P02649445A0412
+P07876192A0443
+BC2GM059696646
+P07777518A0483
+P04039439A0000
+P07916577A0190
+P11572467T0000
+P09734808A0000
+BC2GM088652504
+P10747099A0507
+P10514808T0000
+P11197549A0748
+BC2GM041201611
+BC2GM047096684
+P04759722T0000
+P07721878A1163
+BC2GM062761406
+P02642466T0000
+BC2GM020320741
+P03972038A0000
+P07474078A0838
+P06027841T0000
+P10656154A0722
+BC2GM017445898
+P09432752A0109
+P07472736A0278
+P08626777A0537
+BC2GM010655694
+BC2GM017739498
+P07644466A0578
+P11179272T0000
+P08605931A0777
+P02547079A0910
+P08763925A0588
+P01433524A0788
+P09003463A0198
+P01460054A0968
+P09201980A0910
+P11073218A0800
+P01378052A0594
+BC2GM008130653
+P09763446A1234
+BC2GM018406143
+BC2GM009609268
+P03720615A0434
+BC2GM000136143
+P09519757A0482
+P02809116A0237
+BC2GM027002069
+P11148589A1124
+P07592647T0000
+BC2GM063547892
+BC2GM014111333
+BC2GM040722108
+BC2GM026311034
+P08770981A0328
+P08386592A0089
+BC2GM002932224
+P06683807A0160
+P06591992A0569
+P08840997A0765
+P07836471A0375
+P08288633A0144
+P08925545T0001
+P04632967T0000
+BC2GM010819774
+P09079904A0995
+P07542616A0313
+BC2GM095085610
+P08206867A0874
+P09933641A0241
+P03001054A0703
+BC2GM038012165
+P02815229A0139
+BC2GM020803257
+P11034547A0674
+P09701616A0108
+BC2GM055784735
+P08620003T0000
+P09857197A0289
+P07218008T0000
+P09613574A0905
+P08768374A0765
+P09261155A0833
+P08276762T0000
+P08382296A0766
+P07786821A2292
+P07061263A0293
+P08789441A0339
+P09785114A1026
+P10840001A0188
+BC2GM088289193
+P06705456A0346
+BC2GM002667802
+P10871347A0477
+P04646045T0001
+P08034682T0000
+P09326727T0000
+P11273995A1148
+P09721798A1734
+P09157760A0000
+P10993787A0369
+BC2GM056335260
+BC2GM038107026
+P08239586T0000
+P07436187A0147
+P01712296A0157
+P08524284A0309
+P08595658A0961
+P08164680A1086
+P02789180A0407
+P11208017A0070
+P09194250A0708
+P11127161T0000
+BC2GM040216592
+P09724772A0840
+P08531373A0470
+P07896088A0720
+P08670910A0156
+P02793753A0354
+P03001086A0587
+BC2GM045767472
+BC2GM081733082
+P02287860T0001
+P02940334A0141
+P01450815A0337
+P10918596A0000
+P03352439T0000
+BC2GM065471552
+BC2GM087637002
+P09551972A1033
+P08936640A0105
+P03499608A1054
+P08208540A0417
+P01832019A0265
+P09438165A0405
+P01316900A0000
+P10644760A0000
+P08617216A0584
+BC2GM000627922
+P02464097T0000
+P00767161A0837
+P08149484A0151
+BC2GM046248491
+P07750217T0000
+P10575642T0000
+P04764049T0001
+BC2GM050518839
+P09596542A0542
+P09064659A1055
+P05879595T0094
+BC2GM093006252
+P04002667A0181
+BC2GM083214428
+BC2GM031494591
+P11117523A0650
+P07510635A0479
+P08491383A1291
+P08413239A0490
+P10585311A1542
+P01438287T0000
+P09098066A0119
+P09743128A0969
+P11543662A0562
+P10602502A0422
+P08649393A0000
+BC2GM097504248
+P08114702A0000
+P09628419A0812
+P09642276A0881
+P09427844A0739
+BC2GM039377977
+P09225151T0000
+BC2GM018711708
+BC2GM097056879
+BC2GM017257591
+P08395004A0141
+P09186430A0341
+BC2GM080904323
+BC2GM007100869
+P00386251A0899
+P01480470A0323
+P07655509T0000
+BC2GM037344526
+P09220177A0564
+P11222720A1699
+BC2GM088026149
+P02041088A1053
+BC2GM053284567
+P08988913A0821
+P02894789A0954
+P08853303A0431
+BC2GM053959497
+P03137105A0146
+P11276426A0501
+P07914192A0844
+P08964067A0188
+P08891131A0000
+BC2GM002297931
+BC2GM026295270
+P09735371A0227
+P07044389T0000
+P08501030A0456
+P01556068A0000
+P09348931T0000
+P07652066A0677
+P01433502A1163
+P02277319A0211
+P11094073A0000
+P10593939A0747
+BC2GM006418171
+P10703633A0747
+P01285554T0000
+BC2GM080933132
+P06568939A0000
+P07913891A0174
+P11121434A0915
+BC2GM078586075
+P09688264A1029
+P01565093A0179
+BC2GM040760692
+P02023421A0343
+BC2GM057768867
+P03034570A0943
+P06322183A1070
+P08455598A0000
+P01833716A0990
+P00759049A0185
+BC2GM043101437
+P03270085A0382
+P09806516A1689
+P11172610A0508
+P03267732A0788
+P11220306A1753
+P07599653A0898
+P11559821A1315
+P10555964A0778
+P08278929A0866
+BC2GM051957137
+P11384576A1132
+P02711145T0000
+P07739566A1076
+BC2GM071151906
+P09920896A1230
+P10938102A0265
+BC2GM088996203
+P09515031A1020
+P01696715T0074
+BC2GM080141188
+P05502054T0000
+P09486531A0638
+P03799790A0146
+BC2GM008474326
+BC2GM036342195
+P08604338A0198
+P09434185A0902
+P10625494A1059
+P04036838A0918
+P11560990A0272
+P07557424A0124
+P11395469A1373
+P08676454A0731
+P07624119A0528
+P07836390A1152
+BC2GM072515083
+P09918715A0304
+P11274149A0625
+P09022632T0000
+P08628255A0932
+P10867496T0001
+BC2GM085352639
+BC2GM021589926
+P02209605A0510
+BC2GM033557862
+P09544991A0483
+P10679065A1217
+P02154885A0153
+BC2GM027725550
+P07880442A0236
+P09223647T0000
+P01467088T0075
+P09441746A0546
+P08322823A0839
+P08396749A1112a
+P08355697A0000
+BC2GM062155957
+P07340196T0001
+BC2GM084539216
+P06415299A0233
+P03023682A0271
+P10781604A0827
+P07532278A0833
+P07835886A0894
+P03763836T0001
+P11129724A0904
+P08630542A1421
+P08869763A0378
+P03806696A0000
+P08230452A1489
+P00221136A0984
+P02124710A1624
+BC2GM004672850
+P09759865A0673
+BC2GM063927738
+BC2GM055611171
+BC2GM083528781
+P08825087A0213
+P06579152A1061
+P01711041A0348
+P03871298A0217
+P06185493A0468
+BC2GM082670974
+P08896473A0282
+P07789971A0758
+BC2GM068470337
+P08950144A0172
+P01376319T0000
+P09703021A0000
+P08445729A0657
+P09650403A0868
+BC2GM021990815
+P08172905A0000
+BC2GM012197912
+P07501700A0000
+P08555753A0591
+P10903837A1208
+P11169080T0000
+BC2GM036212227
+P07708058A0178
+BC2GM099964294
+BC2GM032297282
+P11195401A1030
+P01448806A0135
+BC2GM066529343
+P08172598A0237
+P08253777A0301
+P10903843A0447
+BC2GM064656341
+P07635312A0692
+BC2GM011193274
+P09596738T0000
+P09323612A0374
+BC2GM060083809
+P07538068A1094
+P11121397A0587
+P03781948T0000
+P08345191A1140
+BC2GM095754088
+P02480959A0470
+P09121432A0000
+P09620955A0370
+P10938109A1361
+P10938113A0388
+BC2GM051853385
+BC2GM074994659
+P08179827T0000
+P01734570T0000
+P09917555T0001
+P07168531T0001
+P09328341A1449
+BC2GM061410736
+P09272108A1295b
+BC2GM080113467
+BC2GM017555562
+P08510647A1347
+BC2GM075120339
+P10649738A0953
+P00980255T0000
+BC2GM092239807
+P09079928A0525
+P00555495T0000
+P00534613A0000
+P11556809A2085
+P01372900A0448
+BC2GM023484942
+P01702361A0621
+P08011166A0207
+P09382498A0618
+P00485615A0935
+BC2GM015899967
+P01547787A0548
+P00115974A0576
+P02077560T0000
+BC2GM040338006
+P04139943T0001
+P03256150A1866
+BC2GM021031743
+P08264631A0746
+BC2GM011957341
+BC2GM057600455
+P01742341A0499
+P08290278A0374
+P10584704A0913
+BC2GM015846745
+P08940298A0962
+BC2GM009503758
+P09445488A1169
+BC2GM032286416
+P11409425A0000
+P02229541T0000
+BC2GM003670421
+P06287212A1352
+BC2GM039253941
+BC2GM028241887
+BC2GM087723838
+P07961957A1565
+BC2GM044666504
+P11335116A1099
+P09917387T0000
+P09372287A0296
+P03110692A0156
+P06507629A0717
+BC2GM058599775
+P11238402A0191
+P00918556A0000
+P03768208A0879
+P01244236A1122
+P07663963A1588
+P08151790A0354
+BC2GM059254999
+BC2GM056030212
+P01656221A1319
+P02233715A0914
+BC2GM084116601
+BC2GM054689635
+P08690198A0346
+P09566871T0000
+P09858572A0000
+P10564939A0981
+P06468632A0135
+P09305944A0621
+P03065621T0000
+BC2GM075805410
+P02392511T0000
+P07622058A0411
+P02651448A0000
+P07477245A0625
+P02902927A0145
+P07461848A0230
+P10765095A0308
+BC2GM022806510
+P09216017A0621
+P09562558T0000
+P01972379T0042
+P03104245A0402
+BC2GM087385719
+P03920700A0491
+P07132408A0387
+P11525640A0560
+BC2GM007534249
+P02219751A0517
+P02076620T0000
+BC2GM005711983
+P02644735A0427
+BC2GM076143207
+P05474466T0001
+BC2GM034854345
+P01830114A1587
+P01963419A0501
+P10908462A3159
+P01535242A0557
+P08192795T0000
+P08108413A0964
+P08825639A0827
+P00117748T0000
+P09738010A0305
+P03818467A0180
+P09254678A0106
+P07642633T0000
+BC2GM094523699
+P01662807A1182
+P10827885T0059
+P10965135A0735
+P03264886A0000
+BC2GM041907191
+P08486705A0181
+P01895393A0745
+P09881692A1109
+BC2GM072322164
+P02528329A0000
+P10853850A1103
+P08670853A0000
+BC2GM081030617
+P09430661A0796
+P07547510A0261
+P03319621A0707
+BC2GM086512279
+P09582350A0165
+BC2GM026833170
+P11580941A0815
+P01722479A0302
+BC2GM006557709
+BC2GM019723956
+P08371650T0000
+BC2GM052291844
+P09171239A2146
+P05075857T0000
+BC2GM071451741
+BC2GM053319803
+P11016954A0438
+P09632217A0477
+P09550919A0365
+P01899287A0726
+P07972831A0563
+P08383129A0776
+P10772977A0222
+P02270834A0123
+BC2GM000132505
+BC2GM083794730
+P06856306T0000
+BC2GM056216898
+P08474456A1041
+P08642313T0000
+P11137367A0297
+P07475733T0000
+P09053973A1252
+P00818380A0239
+P08334158A0660
+P02355293A0749
+P02458699A0650
+P09858577A1186
+P11260662X0000
+P01766876A0000
+P06822645T0039
+P08816504T0000
+P03446332A0831
+P01939199A0588
+P03104914T0000
+BC2GM067535411
+P07490156A0647
+P11350038A0459
+BC2GM042959881
+P08441423A0145
+P00224013A0661
+P09891046A0269
+P00838152A0863
+P08643111A0855
+P09305631A0770
+P11238947A0636
+P07798134T0000
+P03371139A0829
+BC2GM083212050
+P01457380A0000
+BC2GM075933403
+P02874635T0000
+P02538720A0582
+BC2GM036933937
+P04039744A0141
+BC2GM038038322
+BC2GM096376764
+P07830112A0532
+P09582953A1670
+P00378492A0475
+P11073870A0375
+P01878755A0496
+BC2GM067694313
+BC2GM057268278
+P08532536A0925
+P08584074A0000
+BC2GM092245108
+P01826043A0431
+P11197926A0000
+P01418494T0000
+P07896291A0693
+BC2GM057663917
+P09618481T0000
+P08808756A0587
+P11116084A0000
+P02394707A0789
+P11094091A0000
+P02154467A0709
+P06158844A0000
+BC2GM021489980
+BC2GM010471023
+BC2GM059205443
+BC2GM067269145
+P09925372A1063
+P02342477A1292
+P11312326A0169
+BC2GM097016872
+P07565775T0000
+P11166863A0167
+P02038326A0538
+P02024791A0582
+P07988730A0220
+P08413260A1437
+BC2GM091781458
+P06798609A0000
+P07274482A0000
+P11069897A1112
+P08798443A1218
+P02076620A0548
+P08654390A0000
+BC2GM088340339
+P08622596A0189
+P01241588A1470
+BC2GM003857556
+P02552143A0748
+P10795098A0253
+P08153130T0000
+P08435755A0938
+P09820621A0067
+BC2GM076417003
+P09223880A1147
+P11094087T0000
+BC2GM058378997
+BC2GM035173306
+P11238586A0000
+BC2GM029984247
+P01703335T0000
+P06711642A0093
+P11313961A1323
+P07966565A0901
+P06671047A1124
+P02500432A1416
+P09367676A0275
+P10013227T0000
+P02685331A0523
+P02981840A0907
+P10362897A0545
+P03761122T0000
+P08516301A0080
+BC2GM052567540
+P11081962T0000
+BC2GM036162857
+P03137601A0212
+P10713453A0172
+P06883385A0509
+P07065206A0398
+P06891270A0000
+P02091890A0614
+BC2GM011974374
+BC2GM076888648
+P09852136A0507
+P01545792A0000
+P09139910A0350
+P08608126A0811
+P11155096A0222
+P08618433A0000
+P09199353A1924
+P06482318A0117
+P07956578A0851
+P09416898A1798
+P07863047A0229
+P03008094A0697
+P02656257A0000
+P01247475A0000
+P08291886T0024
+P03824908A0116
+P09712297T0000
+P07565685A0420
+P09639558A0957
+P02044785A0000
+BC2GM021762963
+BC2GM032718257
+BC2GM080439811
+P08464924A0243
+P07487811A0000
+P08112526A0443
+BC2GM023376128
+P09570952A0000
+P01674242A0358
+P09714109A0785
+P09445056A0215
+P01990266A0678
+P09721207A0637
+P04813394T0000
+P09371596T0000
+P09572428A0526
+P02246447A0460
+P11114521A0282
+P09535908A0321
+P08439564A0883
+P07547500A0066
+P08992115A0199
+BC2GM083666450
+P10913304A0894
+P07936635A1134
+P11230145A0732
+P11479104A0446
+P03835413A0616
+BC2GM074224073
+BC2GM035992425
+P03600705T0000
+P03261005A0216
+BC2GM091667751
+P02310300A0298
+P08566773A1023
+P03923828A1031
+BC2GM062801890
+BC2GM095278451
+P08226794A0501
+P10903440A0515
+P11356853A0873
+BC2GM065743412
+P03939317A0352
+BC2GM020664774
+BC2GM063458894
+P02882893A0301
+BC2GM012661651
+P02307850A1197
+BC2GM087578129
+P07509811A1357
+P01674817A0862
+BC2GM057843919
+P09765372A0669
+BC2GM040553763
+P03025862A0860
+P03427613A0659
+P01443047A0773
+P08430087A0467
+P02155017A1106
+P07312707T0000
+BC2GM080360058
+P09119112A1350
+P08644734A0404
+P03605895A0888
+BC2GM039478548
+P10665798A0598
+BC2GM076347015
+P00799988A0554
+P02167467T0000
+P01603088A1121
+P11167778T0000
+P02721169A0171
+P09006935A0590
+P08669274T0000
+BC2GM014301582
+P09649426A0636
+P07438482A0145
+P10982143A0346
+P00874942T0000
+P10918943T0000
+P08405433A0000
+P11027274A1682
+P03592297A0679
+BC2GM030870711
+BC2GM026280361
+P06460889A0512
+P08082360A0411
+P11480497T0000
+BC2GM023340483
+P03053713A0752
+P02914422A0409
+P06229542T0045
+BC2GM011323524
+BC2GM053776586
+P10936051T0000
+P01302765A0999
+P10656161A0316
+P01735347A0482
+P08668203A1230
+P08971009A0860
+P01433391A0594
+P11158324A1073
+P10777669A0582
+P08382769A0924
+BC2GM020630421
+P03232410A1467
+P03382855A0368
+P07966873A0693
+P02427797A0199
+P09537295A0951
+P08893822A0560
+P03212929A0000
+P03745833A0258
+P00974901A0080
+P10567524T0000
+P07062269A0798
+P09502627A0705
+P10975465A0134
+P08887674A0630
+BC2GM039116924
+P09649438A0182
+BC2GM091026320
+P01313909A0526
+BC2GM069293246
+P09880513A1013
+P08144497T0000
+P08585639T0000
+P02198259A0685
+BC2GM079167914
+P07969152A0721
+P11207308A0999
+P10872535A0000
+P07511818A0485
+P08387994A0980
+P01406656A1075
+P09747873T0000
+BC2GM082240751
+P10496303A1968
+P01438224A0749
+P11152451A1580
+P08281740A0000
+P08029334T0000
+P07533858A1503
+P08605302A1770
+BC2GM044241169
+BC2GM060734859
+P02556269A0187
+P07596558A0824
+P11411623T0000
+BC2GM002844887
+BC2GM069088909
+P10891266A0421
+P09882303A1413
+P02776742A0000
+P09368419A0000
+BC2GM028146318
+P11188993A0298
+BC2GM079908417
+P08626065A0000
+BC2GM004277618
+BC2GM029654898
+P09244350A0000
+BC2GM022748890
+BC2GM069948018
+P07958446A0000
+P08677678A0258
+P08464056A0000
+BC2GM048997766
+BC2GM007910996
+BC2GM052397745
+BC2GM085771334
+P08432526A0580
+P02307850A0000
+BC2GM084109623
+P11281268A0000
+P08659545A0000
+P04578686T0000
+P07678602A0153
+P01320640A0336
+P01452037A0000
+P09539779A0621
+P11056019A0926
+BC2GM002040357
+P07933076A0211
+P11317256A0361
+BC2GM039881960
+P08808120A0774
+BC2GM088087323
+P07435185A0074
+P04536964T0000
+P10921197A0179
+P09705324A0213
+P08144504T0064
+P08980819A0193
+P11132148A0162
+P11279720A0844
+P11547819A0532
+BC2GM083082153
+P02392032A0657
+P10889399A0243
+P03463543A1613
+P10700262A0000
+BC2GM037103656
+P01582413A0192
+BC2GM004475360
+P08446579A1210
+P07063606T0000
+BC2GM073438143
+P09122215A0335
+P10722509A0392
+P07957106A0875
+BC2GM016841080
+BC2GM057852138
+P09374541T0000
+P01898928A0260
+P10591933A0798
+P07704040A0000
+P03915540A0863
+P08440238T0000
+P07045156A0204
+P07702752A0545
+BC2GM016129428
+P09156883A0294
+P09501093A0071
+P07863619A0098
+P00819176T0001
+BC2GM018080572
+P02802280A0495
+P08885270A0428
+P10660069A0819
+BC2GM097970761
+P02118519A0516
+P07323573A0644
+P03003695A0395
+BC2GM009859517
+P06428116T0000
+BC2GM065134610
+P10734312A0503
+P11168366A0569
+P03268555T0000
+BC2GM045825131
+BC2GM023957927
+P00517890A0468
+P09817373A0000
+P01572549A0000
+BC2GM039797757
+BC2GM043911638
+P08757265A0466
+P08288596A0663
+P09368006A1332
+P01620610A1070
+BC2GM065484905
+P00430889T0001
+P03734641A0203
+P08856132T0000
+BC2GM008128545
+P11292839A0531
+P08533473A0375
+P09540062A0755
+P02777797A0720
+P10001333T0038
+P08276234A0119
+BC2GM051388825
+P08771781A0103
+BC2GM081882075
+BC2GM099337674
+P09351242A0719
+P03280946A0375
+P11227039A0953
+BC2GM010669638
+P06886031A0898
+P10854004A0788
+BC2GM092742899
+P09360993T0000
+P00234626T0036
+BC2GM018866489
+P02307613A0783
+P08169709T0000
+P09486035A0051
+P08913186A0431
+P07794556A0000
+P10833461A0603
+BC2GM040965133
+P11248626T0000
+P00762763A0253
+P06734713T0000
+P08284337A0825
+P08189503A0000
+P02166416A0419
+BC2GM036058953
+P11080796A1277
+P08902548A0144
+P09185645T0000
+P11760398A0553
+P08583846A0807
+BC2GM005501477
+P06142279T0000
+BC2GM089212224
+BC2GM051832821
+P07927711A0698
+P10206959A0368
+P09566882A0693
+P07304905A0336
+P07195880A0621
+BC2GM061191789
+P07941174T0001
+P00644539A0783
+P07550216A0195
+P01906692A0321
+P09499061A0000
+P08993831A0000
+P09882337A0000
+P01333035T0000
+P03001952A0958
+BC2GM064852247
+P07854130T0000
+P09915860A0119
+P11389077A0000
+P09727046A0784
+P08098842A0660
+BC2GM088684177
+P08317094A0778
+BC2GM067510592
+P07386500A0174
+P06763897A0216
+P01634861A1336
+BC2GM036029614
+P07787179A0312
+BC2GM021742629
+P08825554A0000
+P09708565A0000
+P07088195T0019
+BC2GM081897643
+BC2GM021811332
+P11410110A0190
+P08395681A0388
+BC2GM043026651
+P08095698T0000
+P09765285A1763
+BC2GM089809726
+P09938097T0000
+P04088396A0145
+P09927449A0421
+P03065140A0273
+P09225506A0462
+P02330333A0325
+P08048582A0821
+BC2GM070142081
+P08389365A1344
+BC2GM062732556
+P08608448A0353
+BC2GM083575704
+P02148219A0508
+P07715200A0000
+BC2GM050861861
+P09349501A0196
+P02752651A0480
+P07757315A1227
+P07234308A0121
+P07928954A0545
+P07044562T0000
+BC2GM031241503
+BC2GM097598269
+P11357063A1053
+P09934611A1054
+P10784393A0000
+P07377954A0117
+P07782113A0726
+BC2GM076808148
+P04176268T0000
+P02884860A0329
+P05683809T0000
+P09792702A0754
+P08987009A0400
+P08229826A1145
+P08981371A2049a
+P09243385A1314
+BC2GM017323042
+P00385457A0187
+P07957632A0000
+P07677573A0000
+P05027295T0034
+P08094498A0614
+P07746794A0000
+P00590594T0000
+P10662550A0679
+P08355680A0824
+P11050168A1185
+P07576179A0781
+P08298129A0274
+P02520622A0200
+P09784063A0621
+P08845378A0368
+BC2GM041136178
+P03581160A0583
+BC2GM041754029
+BC2GM064970806
+P08413274A0452
+P01579472A1018
+BC2GM042091404
+P09584179A0673
+P11431857A0186
+P08823163T0000
+P02120707A0594
+P10805737T0000
+P11533863A0125
+P01732752A0156
+P06090458A0407
+P09529156A1238
+P01429740A1065
+BC2GM092797387
+P01989999A0000
+P07993559A0233
+P02876820A0841
+P04328746T0073
+P02756731T0001
+BC2GM006852575
+P08190633A0000
+P09716435A1004
+BC2GM048018983
+P09580700A0841
+BC2GM066374194
+P02362803A0608
+BC2GM041137121
+P10852460A0170
+P02565807A1198
+P11161720X1294
+P01543909A0787
+P09122168A1427
+P01400401A0854
+P08015850A1076
+P01116254A0000
+P08041793A0242
+P01064124A0560
+P07543868A0414
+P09553134A0596
+P02549417A0000
+BC2GM048321842
+P09032328A0650
+BC2GM033472267
+P01674369A0417
+BC2GM060341382
+P07134924A0640
+P09098899A0000
+P08561893A0100
+P05021912T0000
+P09971815A2094
+P10642889A0393
+P07525596A0584
+BC2GM029897790
+P00962277T0000
+P00603783A0647
+P02798953A0307
+P11193045A1193
+P11341349T0000
+P01809854A0106
+P06165132A0000
+P07926729A0000
+P07935447A0972
+P09275990A0938
+P02712246T0042
+P09858745A1350
+P02928112T0000
+P02731671A0000
+BC2GM099015286
+P10918948A0110
+BC2GM053163697
+P00756511T0036
+P01648142A1170
+P10801809T0000
+P08927612T0000
+P10706887A1457
+P10997330A0361
+P07836406A0884
+BC2GM003814386
+BC2GM054248395
+P08327488A0839
+P07504171A1214
+BC2GM030020218
+P10950924A0393
+P09053494A0612
+BC2GM014656011
+P08626493A1468
+P01763065A0913
+BC2GM016312848
+P01905517A1076
+P01555556A0565
+BC2GM056227993
+BC2GM087087501
+P07942448A1227
+P08482539A0913
+P06890622A0067
+P04074214A0000
+P11278521A0849
+P06508393T0000
+P08503348A0226
+BC2GM040414983
+P06088722A0171
+P08530369A0099
+P02310261A0115
+P08634357A0527
+P01675763A1389
+P04176249T0001
+P08918885A1087
+P10713239A0988
+P09326263A0410
+P01985924A0554
+BC2GM049845600
+P04753073T0000
+P02212540A0473
+BC2GM012470081
+P03952387A0336
+P01695314A0762
+P03452920T0001
+P09372937T0000
+P08152800A0709
+P00025557A0100
+P11517399A0858
+P06191243T0000
+P01414219A0319
+BC2GM019879007
+BC2GM066006503
+P02845654A0510
+P01657246A0325
+P01783375A1066
+BC2GM058050857
+P01937790A0292
+BC2GM078500347
+BC2GM019974743
+P06319421A0937
+P10807903A0362
+P11435983T0000
+P09135149A0000
+P02966671A0551
+P03340774A0328
+P01538401A1244
+P03649340A1119
+BC2GM048824639
+P08143236A1055
+BC2GM009210929
+P03520729A0381
+P06328012A0549
+P09891046A0554
+P09512559T0000
+P11376134A1506
+P07585246T0000
+P11413760A0000
+BC2GM014160134
+P09089653A0615
+BC2GM051466655
+BC2GM035585393
+P01309860A0559
+P07174046T0000
+P10721717A0676
+P11352671A0492
+BC2GM067441518
+BC2GM089782491
+BC2GM082766404
+P03910310A0666
+BC2GM091307930
+P09331119A0659
+P07558583A0562
+P11063127A0000
+P03168709A0000
+BC2GM032034538
+BC2GM098636877
+P02106287A0478
+P07594592A0755
+P06479976A0386
+P00413854A0958
+BC2GM066509312
+P08383622T0000
+P10694605A1327
+P09243587A0000
+P07811639A0222
+P09539746A0781
+P08756642A0230
+BC2GM029314014
+P01731107A0928
+P00122718A0500
+P02202496T0000
+P09451857T0001
+P11535832A0586
+P09757012A0942
+P09925120A0074
+P11014213A1019
+P01977856A1036
+P09851614A0109
+P08977013A0788
+P08604708A1086
+P06776918T0000
+P09201946A0000
+P08582143A0614
+P11832019A0668
+P08386317T0000
+BC2GM075671967
+P07162146A0000
+P09150334A0559
+BC2GM069671775
+P02462523A0394
+BC2GM029453791
+P01986360A0000
+BC2GM007514824
+P11082185A0415
+P02344529T0000
+P03567017A0000
+P01658375A0854
+BC2GM053041146
+BC2GM055489778
+P06668316A0178
+BC2GM035302143
+BC2GM077718596
+P00574956A0304
+P05308271T0000
+P08333643A0000
+BC2GM093692420
+BC2GM053319236
+P08163183T0000
+BC2GM053438621
+P11435605A0587
+BC2GM094222143
+P11416132A1351
+BC2GM022142685
+P06333878T0000
+P11054970A0282
+P05836483T0000
+BC2GM092988479
+BC2GM012346343
+BC2GM089696492
+P08173693A0390
+P01421609A1067
+BC2GM066639389
+P07935370A0000
+P08083998A1723b
+P10792718T0000
+P09508775A0293
+P11223938X1218
+BC2GM075054681
+P01328219A1397
+BC2GM048702510
+P01587763A0402
+P11451995T0000
+P03441587A0000
+P09111314A0970
+BC2GM079567049
+P01620781A0611
+P09888994A0858
+BC2GM070272053
+P09006914A0812
+P08537388A0825
+P03887769A0584
+BC2GM097216118
+P10568455A0000
+P07592647A0797
+P09575217A0971
+BC2GM022830780
+BC2GM067923861
+P02280777T0000
+BC2GM082328834
+P06327638A0155
+P09900679T0000
+P09636670T0000
+P08647434A1124
+P10717612A0000
+P10575545A0147
+BC2GM089043766
+P11583880T0000
+BC2GM005625314
+P02020314A1290
+P07461226A0958
+P11376007A0584
+P08293993A0948
+P08071356A0232
+P09133122A0656
+P02193033A0195
+P03561036T0000
+P02584969A0119
+P07826625X0000
+P08101134A0376
+P01832152A0902
+BC2GM091971820
+P02807780A0143
+BC2GM095222501
+BC2GM080887068
+P07951235A0277
+P09815578A1245
+P11336698A0075
+P08626437A0332
+P07544357A0808
+P02936284A0357
+P09584165T0000
+P11118619A0835
+BC2GM054387079
+P07518460A0771
+P08107208A0673
+P01237206A0199
+BC2GM076178142
+P08207805A0000
+P01542667A0125
+P03978132A0108
+BC2GM068206225
+P09679066A1352
+BC2GM049209935
+P07219821T0028
+P10872756A1325
+P11380028A0000
+P07592730A0204
+BC2GM015111811
+P02743981A0347
+P07896817A0204
+P09382886A1061
+P11687737A0000
+P01829460A0329
+P07665187A0824
+P00725534A0888
+P08631820A0755
+P11234223A1451
+BC2GM033034738
+P09769910A1700
+P07730336A0606
+P11145562A0000
+P06612373A0000
+P08537403A0336
+P10628748A0344
+P03676054A0865
+BC2GM043951266
+P09705258A0837
+P09662443A0402
+P03615550A1094
+BC2GM028429714
+P02278217A0372
+BC2GM016105671
+P08444184A0245
+BC2GM041870029
+P10712512A0506
+BC2GM012328015
+BC2GM011525777
+BC2GM095655624
+P02303470A0242
+BC2GM005335689
+P02463050A0514
+P11179687A0280
+P09545638A0330a
+P03144705A0859
+P10767553A0100
+P07557276A0526
+BC2GM071848637
+BC2GM054072257
+P11160860A0662
+BC2GM054091501
+P02062933A0738
+P10564280A0140
+P09472038T0000
+P09511760A0221
+P00205074A0000
+P02154599T0000
+P01797467A0000
+P03537686A0099
+P01471602A0362
+BC2GM065946297
+P11029700A0746
+P06394347A1024
+P02185250A0726
+P03340726A1103
+P08910292T0000
+BC2GM037614071
+P08862743A0603
+P07885678A0709
+P07673178A0982
+P08924381T0000
+BC2GM084701019
+P11535014A1157
+P10653400A0000
+P09619777A1583
+P06286549A0000
+P09873060A0901
+BC2GM043376689
+P07907328A1070
+P07935491A1182
+BC2GM020677655
+BC2GM096761437
+P03443609A0000
+P08828857A2423
+P08034741A0000
+BC2GM057684207
+BC2GM015147115
+P02556264A0278
+P07506253A0742
+P00429949A0000
+P09485790T0000
+P02335815A0530
+P03297181A0127
+BC2GM019218967
+P09886843A0339
+P02075876A0408
+P06310159A0000
+BC2GM079348328
+BC2GM065525497
+P06548953T0001
+P11083868A0386
+BC2GM038659549
+P01313715A0461
+P09334331A0910
+BC2GM012711095
+P01721261T0000
+P09490727A1041
+BC2GM010380443
+BC2GM021336202
+P11160929T0000
+P08621664A1430
+P08431100A0108
+P10652228A0759
+BC2GM012464195
+BC2GM002235510
+P02187091A0721
+P07680035A0221
+P08710151A0782
+P07112320A0086
+BC2GM038819274
+P08812106T0000
+P11201250A0849
+P09922230A1482
+P01686909A0299
+P11247663A1447
+BC2GM036373124
+P08387743A0624
+P04975676T0000
+BC2GM018214365
+BC2GM035122816
+BC2GM005098468
+P08034680A0180
+P11428276A0352
+P01516829A0460
+P11595478A1014
+P08524314A0216
+BC2GM027092021
+P07706396T0000
+BC2GM000169441
+P01082833A0000
+P06655634A0195
+P09658104T0000
+P09407036T0000
+P08123787A0554
+P08383217A0357
+P01404612A0303
+P03398823A0459
+P02339447A0162
+P07724452A0344
+P11019257A0159
+P03434347A0358
+P00916099A0000
+P02647918A0423
+BC2GM077515790
+P00506559A0000
+P07642490A0318
+P09024793A1325
+P01947449A1082
+BC2GM052484918
+P11171118A0836
+P07776685A0000
+P10728986A0000
+P07782775A0889
+BC2GM004196044
+P03436877A0950
+P01295500A0366
+P08515619A0184
+P10780764A0722
+P11168446T0000
+BC2GM033682713
+P08352066A0000
+P02200150A1381
+BC2GM003943388
+P11407650A0661
+BC2GM064288538
+P05081814T0000
+P06414990A0057
+P07864652A1901
+P00377466A0188
+P07539119A0291
+P11392772A0182
+BC2GM055710514
+P11223255A1034
+BC2GM089393717
+P08063775T0000
+P01321337A1161
+P07558263T0000
+BC2GM093503103
+P09703276A2346
+BC2GM011797834
+P11418130A0499
+BC2GM059024558
+P10599013A0505
+BC2GM094581342
+P01148868A0284
+P09524273A0205
+P04989251T0000
+P06419251T0000
+P11084022A1178
+P11309373A0783
+P08757943A0876
+P03008405A0532
+P02466665A0202
+P09169593T0000
+BC2GM097492255
+BC2GM066315892
+BC2GM048995612
+P07799931A1232
+P08340400T0000
+BC2GM099774129
+BC2GM088402436
+BC2GM003776641
+P09803081T0000
+P02560415T0012
+BC2GM081729599
+P09372968A0996
+BC2GM032212038
+P02850971A0180
+P06830351A0397
+P07937841A0790
+P08486276A0419
+P06833422T0000
+P09367392A0567
+P05823624T0031
+P09537375A0198
+P07719527T0000
+BC2GM093512186
+P09261200T0001
+BC2GM080360635
+BC2GM054968924
+BC2GM021995713
+P09314537A1600
+P09278758A1636
+P11103792A0755
+P11159363A1251
+BC2GM082011055
+BC2GM045105148
+P02541251A1327
+P09209031A0350
+BC2GM073488635
+P00418341T0000
+P08721989A1012
+P08649428A1227
+P00439618T0001
+BC2GM086019506
+P03395164A0000
+P09325022A0192
+BC2GM074636309
+P02709819A0495
+BC2GM084680436
+P09282911A0277
+BC2GM037965797
+P09261184A0170
+P07828811A0556
+P09565576T0000
+P01709933T0000
+P06748227A0423
+P10882462T0000
+P08733123A0000
+BC2GM039562937
+BC2GM048519833
+P08396667T0000
+P02117799T0000b
+BC2GM091440565
+P07040659A0212
+P03239106A0856
+P01592545A0726
+BC2GM087392570
+P00454780A0340
+BC2GM097368062
+P08812020A0597
+P08380896A0938
+P10331730A0504
+BC2GM038904960
+BC2GM049242982
+P04615828T0001
+P01526690T0000
+P08915051T0000
+P10761263A1108
+P01660486A1756
+P02775333A1137
+BC2GM053394099
+P07981246A0112
+P03721594A0000
+P08602608A1056
+P09481826T0000
+P09557708A1426
+P08245013A0000
+P08783666A0957
+P02546234A1382
+P06437579A0727
+P00988572A0000
+P10666509A0494
+P10787437A1616
+P08453950A0498
+P06838388A0896
+P09079689A0472
+BC2GM064420857
+P05671267T0000
+BC2GM062580234
+P09222115A0545
+P04011338A0620
+P09370307A0093
+P07914192A0211
+P08741206A1551
+P02469451A0239
+P08891337A0614
+BC2GM040073608
+P07774925A0084
+P08731222A0000
+BC2GM035196654
+P11443509A0293
+BC2GM087067391
+P07310206A0154
+P03190481A0292
+P09236441A0639
+BC2GM006903423
+P11120441A1193
+P10938120A1093
+P01284595A0102
+BC2GM088129513
+P02709081T0000
+P11486476A1512
+P08631667A0851
+P08882710A0000
+BC2GM038225935
+P10954913A0152
+P08289357A0724
+P09731704A0000
+P09325284A0469
+BC2GM033055956
+P09071407T0000
+BC2GM082632472
+P07629163A0770
+P11374559A0103
+P08300605A0432
+P11181525T0000
+P02466414A0000
+P08112611A0404
+P02481779A0213
+BC2GM056410850
+P08413209A0159
+P08707840A0753
+BC2GM071553689
+P05960999T0001
+BC2GM027429119
+P08226616A0000
+BC2GM018283736
+P01936348A0155
+BC2GM093465825
+P09925777A1195
+P09108451A0160
+BC2GM079993649
+P10063122T0000
+P09544987A1583
+P11220306A0911
+P08208247T0030
+P02113174A0957
+P07903099A0918
+P02666404A0220
+P08709224T0000
+P08077236A0243
+P01457695T0000b
+P01600531A0483
+P03659805A0404
+P03771670T0058
+BC2GM085698847
+P08997532A0116
+P08867519A0557
+P04295031T0062
+P08630599A0534
+P09814905A0598
+BC2GM057155678
+P07651398A0257
+P11318363A0085
+P02582918A0000
+P11150315A0226
+BC2GM066387134
+P01281322A0604
+P09121435A1183
+P03544858A0374
+P02061282A0447
+BC2GM069895813
+P01923766A0485
+BC2GM015956258
+BC2GM064548155
+P01470243A0871
+P09256973A0673
+BC2GM062194979
+P07592706A1465
+P11512925A0000
+P07721074A0766
+P07964624A0491
+BC2GM029234966
+BC2GM015853606
+P06374369A1112
+BC2GM084095947
+P00239169T0000
+P02419327A0998
+BC2GM060831893
+P01701088A1335
+P11107637X0001
+P03771703A0000
+P07816025A0196
+P10736223A1227
+BC2GM098787807
+P09106057A0000
+P09980944T0000
+P03000489A0822
+BC2GM056277482
+P11500913A1238
+P07588245T0000
+P09154283A0307
+BC2GM085395991
+BC2GM033424223
+BC2GM014735675
+BC2GM068890496
+P10878606A0876
+P03110794A0991
+P08955071T0000
+P01243628A0286
+P07711667A0766
+P09671496A0557
+P03112412A0985
+BC2GM013367918
+P10973151A0883
+P10006319T0000
+P07426604A0397
+P09983871T0000
+P01092248T0000
+P09971776A0838
+BC2GM019190601
+P09000146T0000
+P08264617A0000
+P08255341A0554
+BC2GM094300739
+P01768648A0853
+P05421537T0001
+P01418860A0797
+P02693208A0166
+P08580083A0259
+BC2GM049253682
+P08268833T0000
+BC2GM046785161
+P08204824A0000
+P01612085A0624
+P09823014T0000
+P02575490A1021
+P01881671T0001
+P09006914A1127
+P10891632A0435
+P01297332A0983
+P09647233A0336
+P11356853A0429
+P07731898A0823
+P09254709T0000
+P02752629A0163
+P08231577A1027
+P09139892A1150
+P11451682A0190
+P02174427A1574
+P07651835A0652
+P11074003A0741
+P07569770A0298
+BC2GM053578806
+BC2GM036511457
+P03866085A0795
+P08990194A0000
+P00830568A0000
+P08843412A0543
+P08766049A0000
+BC2GM007134922
+P08096944A0951
+BC2GM025017192
+P09182527A0443
+P08497280A0266
+P06252520T0000
+P00494659A0391
+BC2GM070219691
+BC2GM029899910
+BC2GM068393922
+P01978834A0076
+BC2GM024718949
+P08621730T0000
+BC2GM068628850
+BC2GM042231510
+BC2GM068742708
+P08887643A1167
+P09508377A0863
+P11254504A0766
+P09202859A0091
+P11535140T0000
+P09185586A0000
+BC2GM014357950
+P07567079A0014
+BC2GM038427842
+P08348919T0000
+BC2GM067330469
+P02498652A0460
+P00843232A0100
+BC2GM042721293
+P09580062A0100
+P02258918A0242
+P00740409A0000
+P08905819A0531
+P08861955A0927
+BC2GM083705867
+BC2GM005540562
+P07733075A1200
+P03934667A0124
+P09715278A1079
+P08390665A0000
+P02157882T0000
+BC2GM076657562
+P11416012A2511
+BC2GM067854100
+P07865129A0293
+P06740697A0318
+P08721999A0727
+P08980533A1160
+P10864496A0401
+P08388510A0891
+P09627285A0160
+P00056901A0308
+P02289102A0114
+BC2GM030870274
+P11461595A0000
+P02875967A0377
+P05763347T0000
+P01645905A0341
+P08143198T0001
+P07687320A0526
+P09837714A1068
+P11489597A0561
+P09283828A0484
+BC2GM037013975
+P06607714T0000
+P10934751T0001
+P03572706A0329
+P10552357A1936
+BC2GM072220423
+BC2GM015535650
+BC2GM070374572
+P02906673T0000
+BC2GM022317313
+P10781552A0000
+P03836854T0000
+P07779558T0000
+P09599897A0000
+P05285978T0076
+P11145955A0189
+P00072928T0000
+P01316476A0842
+P01372365A1202
+P00378735A0000
+P09057703A1389
+BC2GM025639631
+BC2GM048198274
+P03134872T0029
+P01848871A0392
+P08536694A0000
+P09882638A0235
+P09851700A0000
+P10961585A0273
+P00390932T0001
+BC2GM041058675
+P06494766A0241
+P08704124A0420
+P03263465T0000
+BC2GM097917359
+P00300314A0132
+BC2GM010985473
+P03352727T0000
+P05488121T0000
+P03114188A0907
+BC2GM084991496
+P11237491A0000
+P06762025A0171
+BC2GM008224119
+P07110999A0160
+BC2GM020275127
+BC2GM046382854
+P07949770T0000
+BC2GM065939725
+P07761467A0666
+P03298134A0000
+P06239545A0649
+P08812012T0000
+P02142993A0176
+P05779953T0000
+P11046517A0619
+P09668108A1017
+P02797877A0475
+P02395868A0322
+P09750325A0000
+P07693372A0115
+P11714429X0000
+BC2GM014171853
+P07530128A0578
+P05994421T0045
+P08116245A0174
+P10856298A0798
+P09671576A0900
+P01674662A0000
+P09819391A1123
+P08959778A0292
+P09388246A0903
+P09282329A0527
+P10604583T0000
+P08533757A0204
+P00669800A0579
+P09112400A1155
+P10980416T0000
+P08934540A0673
+P00509703A0581
+P01551898A1084
+P01377818A0468
+P07548858A0000
+BC2GM067698579
+BC2GM021968476
+P03261223A0644
+P10007469T0000
+P06094591A0000
+P11369410A0949
+P02863747T0000
+BC2GM040436094
+BC2GM063202569
+BC2GM011154838
+BC2GM016725379
+BC2GM035663099
+BC2GM096877178
+P07816049A1157
+BC2GM046023789
+P01985301T0000
+P05819249T0000
+P06294111A1141
+P06743061A0239
+P00034935A0545
+BC2GM006490341
+BC2GM072512934
+P06402480A0373
+P10972990A0196
+P01118293A0150
+P08423831A0523
+BC2GM025327018
+P04113011T0000
+P10650939A1542
+BC2GM062555785
+P09863624A0629
+P09326163A0942
+P01611699A0000
+P07815546A0411
+P02038293A0919
+P01321332A0970
+BC2GM056690514
+P11599797A0732
+P09139737A0000
+P09539721A0599
+P09027346A1957
+P09426958A0110
+P09230945A0089
+BC2GM089290440
+BC2GM076004917
+BC2GM021354805
+P09321657A0439
+P04050771A0474
+P10550139A0191
+P10665949A1131
+BC2GM091675853
+P08643646A0479
+P08172416A0860
+P02780157A0576
+P07911736A1715
+P01605038T0001
+P09405380A0800
+BC2GM041728644
+P09698457A0976
+BC2GM055589568
+BC2GM008024280
+BC2GM048068707
+P08776793A0811
+BC2GM000611082
+P07871718A1132
+BC2GM048607810
+P07888629A0344
+P11089911A1267
+BC2GM081722350
+P10722661A0406
+P09122176A0970
+P07713421A1435b
+BC2GM015287152
+P10709705T0000
+P07929411A0087
+P09880543A0570
+BC2GM019782679
+P09324720A0317
+P01083784T0000
+P00598012A0174
+P11114294A0075
+P09617807A0929
+P11113179A0541
+P11244568A0506
+BC2GM015923347
+BC2GM075371550
+P07501992A0125
+P05124972T0042
+P02022920A0334
+P01549125A0140
+P03779182A0370
+BC2GM068538767
+P03746601A0299
+BC2GM061568897
+P01569581A0482
+P08198524A1134
+BC2GM064739272
+BC2GM050204231
+P03235487A0404
+P11522626A1374
+P10750021A0728
+P09341139A0690
+P10606664A0000
+P10035841T0000
+P00800141X0000
+P00775582T0000
+BC2GM086778872
+P10873386A0000
+P11112417A1126
+P11032599T0000
+P07509449A0000
+BC2GM020770465
+BC2GM036710318
+P03940733A0755
+P08447005T0001
+P11094072A0842
+BC2GM095403151
+BC2GM049635982
+P01840902A1089
+P02176822A0000
+P09708450A0648
+BC2GM096784284
+P09372960A0456
+P10617232A0393
+P05556977T0001
+P08567683A0401
+P07603956A0115
+P09435056A0128
+BC2GM022896971
+P00423649A0259
+P07692754T0000
+P03637037T0000
+P01314457T0000
+P01633435A0743
+P09183406A0637
+P09833610A0626
+P08874631A1133
+P08655555A1368
+P02605160A0000
+P11162278A0629
+P08555168A0390
+P10995751A0093
+P11303638A0559
+P01348508A0313
+P05412687T0000
+P10760169A1142
+P09557678A0140
+P07274428A0000
+P09612351A0386
+P10586074A0129
+P03583001A0111
+P02962859A0276
+BC2GM070452664
+BC2GM002635728
+P08932363A0807
+P02390633T0000
+P03515840A0000
+P10878675A1278
+P02746099A0000
+P03025661A0260
+P07715602A1088
+P08463284A1531
+P03402183A0171
+P09049270A0488
+P11164078A0833
+P03104982A0690
+BC2GM033020504
+P03033283A0837
+P07546256A0000
+P03607961T0001
+P07628451A0114
+P08798648A1816
+P06137028A0624
+BC2GM029365587
+BC2GM035857523
+BC2GM041736875
+P03340548A1018
+BC2GM050069224
+P08124785A0445
+P00030183T0000
+P01874195A0139
+BC2GM077458624
+P09745797A0943
+BC2GM075464288
+BC2GM053864470
+P09119031A1036
+P09639565A0225
+P09950213A1660
+BC2GM037678814
+P07807002A0500
+P06808287T0001
+BC2GM074656896
+P08471629A0816
+BC2GM060157872
+P08001966A0563
+P09441664A0377
+P10835355A0225
+P08289834A0341
+P08973185T0061
+P07293100T0001
+P09345037A0886
+P10860196A0876
+P11145813A0668
+P08824881A0133
+P04323641T0000
+P08420571A1880
+P08144572A0786
+P09466931T0000
+P07890740A0997
+BC2GM078543585
+P06791500A0622
+P10614676A0000
+BC2GM058484539
+P11027267A0752
+P11202705A1112
+BC2GM095454246
+P08241139A0378
+BC2GM030524461
+P10939785A0540
+P07473742A0187
+BC2GM037059732
+BC2GM043225423
+P07723247A1161
+P00139827A0000
+P08139004A0278
+P08101839A0000
+P01869968A0673
+BC2GM054786865
+P01552853A1377
+BC2GM015421655
+P09884747A0477
+P11428897A0318
+BC2GM032976661
+P07723247A0187
+P07649098A0676
+P02319610A1527
+P07565672A0798
+P09154819A0501
+P02015921A0523
+BC2GM065728074
+P09822647A0000
+P01924315A0158
+BC2GM079844918
+BC2GM041776531
+P10443990A0000
+BC2GM056423678
+P01646157A0414
+P03619249A0428
+P07434456A0286
+BC2GM066585108
+P10820829T0000
+P07242929T0001
+P11504545A0393
+BC2GM033997989
+P07754713A0227
+P02676945A0402
+P06199132A0179
+P06012827T0000
+P02999267A0606
+P10406466A0000
+P08770021T0000
+P10760132A1169
+BC2GM082129693
+BC2GM095213644
+P07860646A1363
+P09755191A0553
+P07072635A0000
+P01644796A0374
+P06360426A0501
+P01702432A1296
+P01932695A1155
+P08136383A0359
+P10807900A0933
+P11559789A0314
+P08627688A1520
+BC2GM030209063
+P06074093T0001
+BC2GM019484817
+P01882386A0000
+BC2GM091616739
+P10730292T0000
+P00646023T0058
+BC2GM011480207
+P11376119A0346
+BC2GM076684671
+P07155579T0001
+P06797063A0000
+P03216131A0559
+P08100843A0134
+BC2GM037915116
+P02745280A0276
+P02538656A0172
+P08598359X0000
+P09973351A1522
+P09760341T0000
+P09105042A1497
+P11139567A1440
+BC2GM039227487
+BC2GM077065468
+BC2GM071764861
+P06775834A0000
+P07925022A0285
+P08631908A0224
+P03694102A0000
+P03348382A0785
+P11125151T0000
+P09326246A0567
+P11196340A1046
+P10637337A0545
+P11502758A0869
+BC2GM045923805
+P11462952A1040
+P01751163A0000
+P02906027A0553
+BC2GM010650292
+P11171320A0894
+P08270257A0551
+P03282232A0743
+P03380547A0169
+P09364750T0000
+BC2GM074443347
+P09819216A0220
+P08408194T0000
+P06163433T0000
+P03102289A0786
+P10860752A1601
+P11408575A0000
+P06685536A0502
+P03810867A0305
+P01556111A0241
+P10805286A0233
+P05424220T0001
+P02907533T0000
+P09894962T0000
+BC2GM017483481
+P02138992A0911
+P01090210A0417
+P01241866A0682
+P07760844A0413
+P08538483A0207
+P09409416A0111
+P03283881A0216
+BC2GM070280766
+P04959816T0000
+P11005808A1082
+P07966583A1268
+BC2GM018588140
+P04284435T0000
+P09814637A1214
+BC2GM069174792
+BC2GM077847565
+P06451557A0777
+P08922488A0187
+P09778068A1129
+P09358069T0000
+P07982995A0000
+BC2GM061835883
+P08552045A0973
+P11555669A0464
+P08524260A0835
+P03002786A0143
+P08428722A1123
+BC2GM025980637
+BC2GM038474271
+BC2GM063578385
+P03400694A0245
+P11369700A0616
+BC2GM023962152
+BC2GM097468485
+P10649456A1061
+P08151980T0001
+BC2GM071925716
+P08238626A0248
+P09698512A0296
+P00209664A0836
+P09572511A0148
+P07908012A0678
+BC2GM018782091
+BC2GM095568717
+BC2GM056033881
+P01886043A0380
+P03372422A0558
+P08627719A0784
+P09694725A0500
+P11145566A0000
+P08688190A0000
+P00996272A0397
+P02824334A0972
+P00812183T0000
+P07869937A1142
+BC2GM040176899
+P10920186A0528
+P02461368A0162
+P02565405T0000
+BC2GM074908707
+P00086313A0000
+P11376165T0000
+P00092689A0352
+P00154430A0906
+P02115116A1137
+P08288240A0304
+P09847397A0935
+P10740602A0141
+P06151942A0235
+P10728945A0233
+BC2GM015790797
+P08662789A0673
+BC2GM048642261
+P07896852T0000
+P08387662A0302
+BC2GM051379224
+P10453248A0094
+P08654946A0475
+P09836881A0441
+P09693035T0000
+P01774093T0000
+P11058406A0447
+P07795104T0000
+BC2GM068921814
+P11223131A0000
+BC2GM000687386
+P09192732A1384
+BC2GM079722932
+P09181130A1587a
+P02602150A0993
+P03061301A0624
+BC2GM014660271
+BC2GM025608940
+P02740196A0704
+BC2GM063513672
+P11111051A0051
+P06975206A0279
+P07746937A0100
+BC2GM037303937
+P03319912A0000
+BC2GM058476475
+BC2GM044066999
+P06869986A0000
+P03032143A0218
+P10744026A0000
+P10887921A0718
+P07745008A0892
+P05857301T0000
+P02157141A0923
+P06784123A0771
+P05733953T0001
+P02147223A1047
+P09872832A1262
+P02983331T0000
+P02947866A1416
+P07568118A1267
+P06902722T0000
+P09545146A0884
+BC2GM030635649
+P06810694A0328
+P08544820T0000
+P11894605A1429
+P09717246A0526
+P09988850A0000
+BC2GM029377540
+P03110678A0702
+P09660836A0983
+P03758250A0000
+P08851337A1092
+P08247043T0000
+P09371564A0713
+BC2GM009689602
+P00225352T0000
+BC2GM025928081
+P06795971A0000
+P07676492A1000
+P00577440A0298
+BC2GM080455463
+P09005979A0841
+BC2GM084839351
+P11306101A0000
+P08619910A0000
+P06150069A0422
+P08173532A0000
+BC2GM099918487
+P08702807A0964
+BC2GM032297274
+P09083291A1378
+P06858967A0167
+BC2GM029532307
+P02565683A0841
+P09488441A0615
+BC2GM015098322
+P09364211A0319
+P00513284A0000
+P08592590A0822
+BC2GM066607362
+BC2GM083596704
+BC2GM054680908
+P01713213A0000
+BC2GM049302974
+P11073919A0631
+P03513989A0580
+P03747493A0000
+P11575977A1133
+P07499409A0367
+BC2GM092540760
+BC2GM066650758
+P06364265T0062
+BC2GM031729179
+P10799501A1391
+P09557912A0699
+BC2GM083364353
+BC2GM084397329
+P11220487T0000
+P11406025A0204
+P08184923A0829
+P07174437A0181
+BC2GM091199615
+P03024703A1036
+P09458021A1373
+P08500938A0408
+P03733563A0716
+P01452703A0782
+P06702257T0001
+BC2GM041273228
+BC2GM008085134
+BC2GM057882399
+P11462004A0886
+P11049889A1271
+P07518257A0351
+P09891065A1493
+P09669641A0425
+P01279352A1197
+P09261397A0509
+P01447189T0000
+P01615182A0206
+P01657249A1019
+BC2GM096262172
+P09851988A0085
+P01391001A0583
+P09716179A0974
+P10704975A0479
+P07803809A1852
+P02686985A0811
+P01536153A0574
+P07512552A0270
+P07392519T0001
+BC2GM022478425
+P08446579A0784
+P09971790A0856
+P09132011A0298
+P01309255A1385
+P02895566A0187
+P09421508A0696
+BC2GM010457655
+BC2GM049036959
+P01394655A0615b
+BC2GM059902297
+BC2GM060909038
+BC2GM008677402
+P01811948A0289
+BC2GM020647680
+BC2GM080426101
+P08666383A1252
+P00361340A0529
+P02023097A0000
+P08192140A0209
+P10702285A0855
+P11355615A0766
+P01772341A0852
+P07929559A0000
+BC2GM068660777
+BC2GM010316325
+P10655230A0685
+P06182979A0807
+BC2GM055959438
+P03016301A0605
+P06652293A0353
+BC2GM028349983
+P09079625A0935
+BC2GM023703398
+P02975753A1333
+P09376782A0328
+BC2GM003313671
+P01904437A0000
+P10674395A0262
+BC2GM097227201
+BC2GM087423181
+P01371181A0688
+P01228882A0437
+P07816049A0686
+P08567556A0000
+P09806826A0244
+P09869297A1807
+P07624615A0267
+P02988457A0650
+P10850453A0713
+P08309726A0000
+BC2GM012382882
+P05715613T0000
+P08259650A0640
+BC2GM078411814
+P08551572A0155
+P09165118A0311
+P09001213A1111
+P02326716A0139
+P11132063A0250
+P07094856A0115
+P08552086A0150
+P03697587T0000
+BC2GM085437815
+P08324107A0000
+BC2GM056101330
+P09855111A0905
+P02168640A0268
+P11069075T0000
+BC2GM027249093
+BC2GM080794726
+P09380697T0000
+BC2GM009127817
+P08534848A0188a
+P11313386A0704
+BC2GM029942800
+BC2GM089297892
+P09472616A1004
+P02901498A0354
+P07841663A0845
+BC2GM083254986
+P02647937A0191
+BC2GM061933593
+P08491683A0651
+P09416467A0959
+BC2GM058516621
+BC2GM011333437
+BC2GM023454935
+P03959045A0000
+P00304240A0369
+BC2GM031391098
+P06718064T0001
+P10570262A0000
+P09272138A1153
+P08810040A0955
+P06227570A0523
+BC2GM023797731
+BC2GM033304611
+P02723503T0000
+P07545920A1336
+BC2GM067276643
+P01832152A0000
+P11416879A1589
+P02151229A0921
+P01766666A0788
+P10931927A0655
+P08896272A0000
+P10416558A0000
+P11243306A0961
+P02648646A0216
+BC2GM019247724
+BC2GM059503446
+P00926751A0000
+P07568576A0074
+P11002236A0328
+P08622887A1026
+P06241900A0000
+P08586874T0000
+P11027280A0536
+BC2GM026427859
+P03045117A0936
+P09505733A0246
+P05031074T0001
+BC2GM003255111
+P08111974A1034
+P07759094A0634
+BC2GM001474754
+P09528792A0000
+P01939827A0150
+P09837978T0093
+BC2GM040449829
+BC2GM079046783
+P03396628A0207
+P09495283A0000
+P06434587A0551
+P03104248A0322
+P10805739A0640
+P09124054A1164
+BC2GM010188722
+P11369700A0074
+P04175007T0001
+P08030704A1503
+BC2GM027790254
+P05805644T0001
+P05719031T0000
+P11008139T0000
+BC2GM010484925
+BC2GM093052916
+P10705783A0433
+BC2GM051967353
+P05031659T0000
+P01748630A0125
+P08373972A0335
+P01375224A0152
+P02362161T0000
+P06165551A0793
+P02113015A0295
+BC2GM094515271
+P07097182A0480
+P11561626A0197
+P07831310A0000
+P03459736A0184
+P01647070A0232
+BC2GM027824972
+P08584530A0545
+P03304866T0001
+P00231555T0001
+BC2GM031489380
+BC2GM087801805
+BC2GM013813111
+BC2GM034945904
+P08425221A0000
+BC2GM018845619
+P09640802A0467
+P09469820A0151
+P02902656A0481
+P03079276T0029
+P08319396A0448
+P08429568A0000
+P10531340A1275
+P09451003A0894
+P02126417A0408
+P06919347T0001
+BC2GM025305972
+P01050400T0000
+P10935488A1033
+P05119546T0001
+BC2GM036120565
+P08898893A0202
+BC2GM023685054
+P10608893A0727
+P10748194T0000
+BC2GM064552901
+BC2GM012522981
+P03125422A0202
+P07689501A0420
+BC2GM045455828
+BC2GM098355088
+BC2GM021225439
+P08631822A0677
+BC2GM095563020
+P01398074A0697
+P03264073A0224
+BC2GM078078201
+P03127463A1017
+P02295521A0922
+P07557717A0184
+P02064119A1172
+P00429151T0000
+P09468514A1065
+P08275618A0457
+BC2GM055466114
+P07701266A0808
+P09121430A0132
+P09592168T0000
+P02083199A1175
+P00254537T0000
+P03304015T0000
+P01294345A0591
+P02976332A1277
+BC2GM085283124
+P08030239A0833
+P09234725A1892
+BC2GM069445885
+BC2GM054116094
+P06443550T0000
+P09434979A0790
+BC2GM013076333
+BC2GM048358040
+P07832086A1023
+P09819422A0768
+P10205588A0000
+BC2GM013509506
+P01560021A0379
+BC2GM054451965
+BC2GM072323236
+P02347102A0000
+P01400775A0435
+P08634697A1155
+P01233561T0001
+P06521802A0251
+P10445945T0000
+P00350465T0000
+P08051102A0532
+BC2GM064734705
+BC2GM080428035
+P09741783A0000
+P08879237A0744
+P03980386A0000
+BC2GM017854624
+BC2GM060809395
+P02253274A0000
+P09510925A0389
+BC2GM015383059
+BC2GM056313668
+P07680629T0000
+BC2GM043099285
+P11467349A0452
+BC2GM029733938
+P08706662A1125
+P08089887A0742
+P02903500A0278
+BC2GM068562414
+P08406004A0691
+P08098914A0400
+BC2GM001962189
+BC2GM005500521
+P02999267A0885
+BC2GM033383172
+P02979834T0000
+P11472523A0535
+P01645902A1462
+P02573336A0000
+P04033402A1112
+P11003652A0961
+BC2GM084635327
+BC2GM000680250
+P10752475A1376
+P03039387A0920
+BC2GM009479019
+P07015018A0395
+P10694189A0469
+P03828209T0000
+P01597462A0457
+P02373686T0000
+P08020806A0187
+P00843670T0000
+P07549005A0530
+P01506746A0476
+P02231479A0585
+P07853448A0601
+P07592337A0891
+P10563789A1951
+P09032259A0150
+P11083154A0881
+P07356273T0022
+P11415952A0369
+P06318091A0395
+P06258806A0963
+BC2GM024256148
+BC2GM057171148
+P09354676A1714
+P01374688A0471
+P08484514A1536
+P02796988A0735
+P11920455X1195
+P06225279A0498
+P11151826T0000
+P07119890T0000
+BC2GM098933066
+P09822602A1172
+P07585559A0000
+BC2GM060294420
+P01642060A0471
+BC2GM017429831
+P09927570A0507
+P09733647A1960
+P01378506A0884
+BC2GM052669347
+P08654375A0544
+P09733854A0198
+P01710979T0000
+P04789916T0001
+BC2GM042287909
+P06524727A0601
+P02925013A1112
+BC2GM081193454
+BC2GM065009088
+P00961711T0000
+P03331525T0001
+BC2GM025314354
+P01418272A1072
+P08608222T0000
+P08566751A0455
+P01889753A0441
+P08661613A0691
+P09832436A0738
+P07876134A0348
+P09918096A0520
+P10796465A0373
+P01525153A0359
+BC2GM046036818
+P09255349A0836
+P09649315A0943
+P10995121A0569
+P11559547T0000
+P01864837A1029
+P09006010A0527
+P02502096A0462
+P03860162A0000
+BC2GM033034194
+BC2GM080435021
+P07957085A0207
+BC2GM007281515
+P09323366A0000
+P03989827T0000
+P11411198A0711
+BC2GM092745333
+P00118810T0001
+BC2GM094372415
+P05999607T0001
+P07749461A1022
+BC2GM044399791
+P09931191A0434
+P10799590A0431
+P07704273A0000
+BC2GM073185216
+P08643382A0752
+P02542270A0000
+BC2GM011190047
+P06629370A0252
+P08335710A0338
+P10639585A0157
+P05015678T0000
+P08849778A0226
+BC2GM093351969
+BC2GM096419837
+BC2GM091592742
+BC2GM011003396
+P06684624A0298
+P07898275A0254
+P00105903A0288
+P03366864A0099
+P08021177A0000
+P11031252A0646
+P07657668A0642
+P01279352A0297
+P07575416A1970
+BC2GM001838288
+P10472314A0717
+P06810694A1000
+P03345706A0561
+P09047252A0209
+P04011466T0000
+P08208618A1334
+P08406497A0000
+P08599945T0000
+P07580330A0331
+BC2GM070607110
+BC2GM050501523
+P09467044A0973
+P09038202A1951
+BC2GM061649078
+P03843496A0919
+P10954093A0000
+P02327159T0001
+P09211675A0392
+P07958915A1507
+P09212059A1856
+BC2GM079896671
+BC2GM015327471
+BC2GM004363438
+P01483755A0000
+P08637717A0817
+P08483412A0000
+P06494297A0939
+P09546424A1550
+P10236651T0000
+P07865876A1292
+BC2GM086808769
+BC2GM026908014
+BC2GM062716898
+BC2GM061508124
+P02109544A0000
+P09057325A0177
+P11359568T0000
+P02303874A1643
+BC2GM012717933
+P08118044A0318
+BC2GM057666669
+BC2GM091928685
+BC2GM098793518
+P07835888A0402
+P07574682T0000
+BC2GM009072433
+P02839716A1907
+P07799950A0282
+BC2GM068155086
+P08016102A1238
+P08634420A1784
+P09233772A0136
+BC2GM089338443
+P02339005T0000
+P03035056T0000
+P11513579A0372
+P05093030T0001
+BC2GM072953233
+P01410071T0000
+P09233801A1180
+P08063791A1370
+P09199327A1250
+P08951815A0465
+P02749215A0000
+P07975763A0000
+P07393856A0314
+P08128629A1164
+P09761791A0489
+P07867622X0000
+BC2GM011611657
+P08919986A1262
+P10625683A0091
+P02900760A0073
+P00393598A0198
+P01917943A0621a
+P02135536A0621
+P09592125A0000
+P07592220A0846
+BC2GM021543883
+BC2GM056896938
+BC2GM064988521
+P07618548T0000
+P09331864A0848
+P02492111A0868
+P08276871A1001
+P08825178A0071
+BC2GM060431058
+BC2GM061728098
+P08733881A0343
+P06816442T0001
+BC2GM090751169
+P02349827A0193
+BC2GM092638353
+P10933732A0000
+P01850105A1093
+P09662339A0744
+P10650958A1315
+P02427024X0000
+P09381261A0970
+P07802355T0000
+P07490079A0825
+P09556557A1238
+P03192537A0370
+P08661100A0285
+BC2GM028908281
+P09343398A1193
+BC2GM025636824
+P10597223A0339
+BC2GM006986011
+P11433379A0000
+P02833049A0630
+P00986925A0002
+BC2GM083038361
+BC2GM013413021
+P03066625A0756
+P11569949A2087
+P01615049A0000
+P01321277A0342
+BC2GM038751995
+P08838148A1218
+P08967870A0000
+BC2GM034977775
+P08874399A0277
+P09216936T0000
+BC2GM068009369
+P08014228A0278
+BC2GM034035554
+P09840932A0365
+P08084339A0907
+P08387155A1248
+P02495745T0000
+P09151828A0919
+P03020513T0000
+P08442384A0430
+P09880544A0693
+P02103403A0149
+BC2GM037763094
+P10857262A0186
+BC2GM003912165
+BC2GM067611275
+BC2GM023743832
+P06579147A0060
+BC2GM000555540
+BC2GM069681293
+BC2GM077447825
+BC2GM064070438
+BC2GM014796441
+P11534132A0219
+P01275335A0158
+P08057356A0531
+P07574064A1416
+P07938137A0384
+BC2GM050960720
+P11029459A0000
+P08919907A0763
+BC2GM004512108
+BC2GM017483846
+P01172734T0035
+P08945810T0001
+BC2GM096030020
+P08840501A0345
+BC2GM031723678
+P10841537A0669
+BC2GM069010582
+BC2GM084598125
+P01816655T0000
+P08994825A0000
+P11278286A0456
+P10880702A0966
+BC2GM034042990
+BC2GM043956840
+P10903583T0000
+P02832149A1009
+BC2GM053926612
+P10882213A0163
+BC2GM053499725
+BC2GM021169148
+P09123787A0486
+P03582184A0448
+P11119611A0428
+P06452827T0001
+P08679131T0000
+P11027833A0362
+P08479742A0985
+P06143734T0000
+BC2GM086852055
+P02142921T0000
+P01744119A0757
+BC2GM079148945
+P09037163A1652
+P01348590A0000
+P02437792T0000
+P09686603A0124
+P09722161A3065
+P03615550A0000
+BC2GM063706036
+P00432615A0541
+P08070004A0782
+BC2GM045276080
+BC2GM042332667
+P06541932A0000
+P08025669A0724
+P00142718A0156
+P07956869A0000
+P08657135A1444
+P00555583T0000
+P11438651A1365
+P08051019A0365
+P11238447A0524
+P03126531T0000
+BC2GM049355866
+P06321634A0123
+BC2GM070228927
+P01753317A0879
+P10777217A0536
+P07791764A0357
+P09403059A0209
+P11209814A0243
+P04247966T0000
+P10705380A0629
+P02547611A0318
+BC2GM003556533
+P07862165A0184
+P09077438A0076
+P07700361A0125
+P11325685A1624
+P05727222T0000
+BC2GM087106608
+P02686749A0000
+P08550564T0000
+P08552095A1115
+P05917315T0026
+P09361007A0922
+P03608989A0668
+P09121998A0663
+BC2GM025598452
+P10860846A0480
+P07636337A0687
+BC2GM068846839
+P09572491A1044
+P11441163T0000
+P09503017A1021
+BC2GM008334952
+P11230169A0480
+P09611234A0098
+P08067123A0248
+BC2GM029932858
+P11373277A0812
+P08524235A0695
+BC2GM075167563
+BC2GM069520528
+BC2GM035302816
+P02774271A0000
+P09726987T0000
+BC2GM050323538
+P09650186A1043
+BC2GM032122398
+P09418057A0684
+BC2GM070919106
+P01341119A0450
+P09392979T0000
+P02764797A0182
+BC2GM093550976
+BC2GM047688296
+BC2GM008294222
+BC2GM056219276
+P11238405A0817
+BC2GM011948412
+BC2GM033795205
+P10828022A0877
+BC2GM001618021
+BC2GM068605843
+P07799931A0287
+P09259313A0950
+P07228955A0000
+P06110026T0000
+P02811378A0379
+BC2GM001125172
+BC2GM089958574
+P02158099A0487
+P02850472A0112
+BC2GM002263739
+P09091403T0001
+BC2GM083483260
+P11296442A0565
+P09670034A0340
+P03616237T0001
+BC2GM068517982
+P10617144A0386
+P07488959T0000
+P07685874A0258
+BC2GM046685387
+P02686588A0592
+P11340525A0737
+BC2GM059365097
+BC2GM074262831
+BC2GM050621994
+P09677330A0584
+P08595184A0407
+P01958821T0000
+P10963577T0016
+P05969185T0001
+BC2GM068580780
+P08164684A1266
+P01330309A1134
+BC2GM011826716
+P01786094T0001
+P11407448A0815
+P08717559A0223
+P07540866A1069
+P02123300T0000
+P03387665A0000
+BC2GM068522547
+P07569532T0001
+P09404725A0644
+P00685922A0451
+P02335034A0584
+P11550795A2583
+P09243840A0663
+BC2GM006080494
+BC2GM006559447
+BC2GM086367761
+P09024039A0247
+P08530149A0689
+P02218094A0395
+BC2GM064221348
+P09169852A0235
+BC2GM031470999
+P10687855A1197
+P01384229A0175
+BC2GM081758402
+P02929056T0000
+P09427551A0501
+P09874803A0000
+BC2GM092277877
+P10918612A0000
+BC2GM046884524
+P10764729A1846
+BC2GM043147756
+P03429371A1051
+P11122381A0908
+P09523551A0367
+BC2GM064373015
+P01620118A0470
+P10831972A0744
+P10677214A2842
+BC2GM019751316
+BC2GM060839599
+P04123662T0000
+P11517445A0221
+BC2GM023488977
+P01392277A0000
+P08649405T0000
+P01285358A0396
+BC2GM043953870
+BC2GM012033196
+P10858988A0786
+BC2GM012340535
+BC2GM034421651
+BC2GM032379937
+BC2GM069816957
+P05995140T0001
+BC2GM019141094
+P07518561A0496
+P01698761A1059
+P09211354A0000
+BC2GM081815204
+P07846199A0000
+P07693699A0831
+P01748287T0000
+P11282088A0837
+BC2GM084039328
+P07270163A0684
+P08621659A0189
+P11156618T0000
+P10670358A0143
+P06788388A0000
+P02283148T0000
+P09849965A0000
+P09199167A0942
+P08524229T0000
+BC2GM068082913
+P09085842A1559
+P09147832A0174
+P07735833A1078
+P02234731A0503
+P02372712A0002
+BC2GM062484182
+P09058323A1287
+P08248246A0838
+BC2GM028672992
+P02684585T0001
+P05560428T0001
+P11454004T0000
+P00176742T0000
+P06602600A0582
+BC2GM094703184
+BC2GM030482607
+P01751970A0209
+P11538437A0568
+P08922390A0793
+BC2GM093671894
+P09527921A1178
+BC2GM032810661
+P08226798A1124
+P01781923A0744
+P08288240A1343
+BC2GM062362815
+P00401676A0414
+P01615493A0408
+P03883541A0200
+BC2GM036335955
+BC2GM012456182
+BC2GM005732630
+P07090151A0165
+BC2GM014758643
+BC2GM013705035
+P09759180A0000
+P08484689T0000
+BC2GM095308818
+P09380507A0514
+P11082715X0001
+BC2GM033262913
+BC2GM064298943
+P09300323A1182
+P01923803A0609
+P07559402A0622
+P07583562A1826
+BC2GM023981862
+P08219081A0000
+P11264372T0000
+P08095872A1672
+BC2GM085389685
+BC2GM084355616
+P04038454A0984
+P09705497A0227
+P07790377A0561
+BC2GM034139781
+P06119262T0000
+P01315706A0000
+BC2GM058528014
+P11323411A0505
+P10735272A0649
+BC2GM061129675
+P11511544T0000
+P08281536A0626
+P01671675A0483
+P01588913A0000
+BC2GM003883590
+BC2GM011651930
+P02883871A1075
+P08943928A1137
+BC2GM002734773
+BC2GM049698710
+BC2GM001606938
+P07935626A1249
+BC2GM006588780
+P09060045A0576
+P08622645A1026
+BC2GM053712179
+BC2GM035126404
+P08385581A0126
+BC2GM092609683
+P02149566A0478
+BC2GM062054764
+P01716292A0000
+P08234308T0000
+P09843944A0976
+P07510461A0731
+P07633756A0690
+P07768953T0039
+P01215067A0000
+BC2GM078932858
+P07491111A0221
+P03836853A0204
+P08705056T0000
+P07742363A0941
+P02975680A0000
+P09440616A0422
+P08808927A0417
+P08474439A0877
+P08115744A0462
+BC2GM051904662
+P03751308T0001
+P08413205A0733
+P11360190A0178
+P07068887A0000
+P01588961A0000
+P10571047A1009
+BC2GM062475449
+BC2GM017023323
+P09611229A1664
+P11553091A1472
+P03009366A0438
+P10824485A0393
+BC2GM019910898
+P02936163T0000
+P08519621A0150
+P02634490A0186
+P01617242T0000
+P02825750A0260
+BC2GM024474184
+P02402678A0463
+P11287611A0802
+P11521191A0000
+P06084864T0001
+P11069825A0530
+P02117799T0000a
+BC2GM005504970
+P01119586A0337
+P09218436A0443
+P08734538A0613
+P09618150A0127
+P07076222A0543
+P06863087A0664
+P08258025A1131
+P03123983T0000
+P08302589A1132
+BC2GM007702287
+P08894144A0330
+P01936997A0795
+P06091914A0000
+BC2GM017309998
+P08636149A0220
+P06327039A0743
+P08739260T0000
+P08067607A0568
+P11354406A1373
+BC2GM088152859
+P01997465A0276
+P09119391A0870
+BC2GM038520766
+P05939748T0000
+P08805338A1061
+P03032964T0000
+P09402139A1121
+P09139665A0784
+BC2GM046491009
+P08483479A1056
+BC2GM031220752
+P09582308A1165
+P07957559A1557
+P01710768A1172
+P07705476A0292
+P09429913A0528
+P00565136T0000
+P03537727A0243
+P06165068A0547
+P02200315A0278
+P08223613A0519
+P00832096T0000
+BC2GM039630251
+P07836364A0000
+P06875478A0542
+BC2GM036938050
+BC2GM032192885
+P11110528A0414
+P10694609A0309
+BC2GM021683203
+P02449431A1121
+P07937106A0100
+BC2GM021163962
+BC2GM007167261
+P08122370A0331
+P11094109A0600
+P01352113A0002
+BC2GM013294615
+P00682762T0001
+P02259795A0570
+P03766370A0546
+BC2GM071213428
+BC2GM035614224
+P06429992T0000
+BC2GM055712987
+BC2GM022597499
+P11287578A1311
+P03033283A1415
+P01236224T0001
+BC2GM079219786
+P08443340A0522
+P07576307A0144
+P09391173A0811
+P09360422A0135
+BC2GM035233185
+P04000347A0442
+P08803710A0701
+P00851041A0000
+P07438346A0381
+BC2GM080877738
+BC2GM074130635
+P10846054A0573
+P08278423A0147
+P11605207T0001
+P09556561A0671
+BC2GM033064195
+P09585540A0440
+P11023934A0855
+P07971709A0907
+P11160742A0696
+P08401570A0828
+P11255035A0331
+P08305058T0000
+P07423803T0001
+BC2GM001910152
+P09652737A1244
+P02745444A0391
+BC2GM045767677
+P07829057A1097
+P08437737A0100
+BC2GM001605361
+BC2GM075265710
+P10721726T0000
+P07883754A0993
+P09111059A0327
+BC2GM064778776
+P10658445A0208
+P08164679A0809
+P04139081T0001
+P09666114A0389
+BC2GM088015029
+BC2GM015832871
+P10747890A1096
+BC2GM019234582
+P01827068T0000
+BC2GM032120704
+P11398134A1565
+P08304342A0605
+P09079928A1319
+P00048373A0377
+P08412662A0333
+BC2GM004334399
+P10983979T0000
+P01516427T0000
+P08530503A1004
+P07184598T0001
+P09827446T0001
+P07961545A1314
+BC2GM048156343
+P10645921A0000
+BC2GM042078510
+P08640866A0473
+P08680702A0548
+P09806919A0447
+P09538220A0000
+P07590283A0820
+P08663310A0157
+BC2GM075482500
+BC2GM035733626
+BC2GM062537661
+BC2GM038144373
+P04068663A0452
+BC2GM076326371
+BC2GM060589467
+P09105363A0636
+P09202669A0614
+P07760841A0221
+P04194466T0000
+BC2GM019952339
+P11258906A0743
+P02883327A0413
+P02384389A0854
+P02427869A0939
+BC2GM006359930
+BC2GM089213701
+P03338154T0000
+BC2GM042193332
+P10851089A1248
+P02502602A0323
+BC2GM054038982
+P02545903A0639
+BC2GM067545009
+P10579722T0000
+BC2GM088102124
+P03687313A0000
+P08564488A1359
+P08160054A0224
+P01282014A0275
+P03335923A0257
+P03736081A0465
+P02066246A0258
+P07173729A0000
+BC2GM043550701
+BC2GM004484072
+P09501982A1178
+P02838710A0299
+P00397806T0039
+P09677410A1059
+P03428274A0000
+P01547775A1024
+P11222639A1273
+BC2GM054420057
+P10959838A0153
+P08689520T0000
+P07745684T0000
+P10958271A0365
+P01737789A0800
+BC2GM078238867
+P11603271T0001
+P09524276A0939
+BC2GM043598116
+BC2GM060327510
+P10611242A0541
+P09081392A0174
+P08569684A0000
+P08816452A0936
+P08631958T0000
+P01030985T0090
+BC2GM021857972
+BC2GM092587242
+BC2GM033188821
+BC2GM000980177
+P03785212A1128
+BC2GM035866321
+BC2GM046754199
+P09923245A0482
+P11459960A1109
+P10032519T0000
+BC2GM061606382
+BC2GM079355460
+P03280021A1615
+BC2GM044671212
+BC2GM015901462
+BC2GM051665080
+P05138738T0001
+BC2GM042178518
+P02254282T0000
+BC2GM089298534
+BC2GM088237349
+P08241656A0189
+P08882492A0000
+P01732736A1076
+P11153302A0000
+BC2GM026348883
+P08139914A0554
+P07678593A0708
+P06468673A0358
+P01339391A0000
+BC2GM002706624
+BC2GM097091019
+BC2GM059635373
+P07995173A0585
+BC2GM063796611
+BC2GM026188221
+P09824001A1665
+P02695914T0000
+P09294161A0650
+P03098018A0139
+P10794405A0000
+BC2GM006409741
+BC2GM033980745
+P07512159A0992
+P07720572A1584
+BC2GM024566497
+BC2GM079434119
+P08131746A0140
+P07234974T0000
+BC2GM014236204
+P10727428A0000
+P01245162A0262
+BC2GM096080543
+BC2GM070253288
+P07508250A0537
+BC2GM078538527
+P00450559A0269
+BC2GM076876749
+P02223928T0069
+BC2GM062788125
+P06689513T0001
+P04788701T0001
+P04622430T0000
+P08529654A0589
+BC2GM074690721
+P10704499A0682
+P07504171A0715
+P00553858A0000
+P05992157T0001
+P08909546A0810
+P01318310A0000
+P03280912T0000
+BC2GM081727936
+BC2GM053004410
+BC2GM085878325
+P05363816T0001
+P11381094A0797
+P10699653A0967
+P08583783A0870
+P03635597A0377
+P11313249T0000
+BC2GM018437479
+P08977401A0227
+P09869356A0926
+BC2GM011525523
+P03928442A0463
+P10733569A0364
+P01618256A0521
+P11264375A0000
+BC2GM091521562
+P07654239A0698
+P05798063T0000
+P08697728A1199
+P07814323A0313
+P08923470A0458
+P09731704A1472
+P02000093A0794
+BC2GM087552846
+P09099683A0000
+P01511950T0000
+P02657388A1011
+P09806826A1773
+P01733105A0127
+P07717823A0328
+BC2GM094592158
+P10601747A0482
+P08912807A0411
+BC2GM008418248
+P09211605A0478
+BC2GM060480858
+P06331684A0607
+BC2GM065259412
+BC2GM058529129
+BC2GM088061371
+P10764760T0000
+P00193088A0196
+P09777999A0796
+P01588965A0000
+P06585277A0000
+P08181755A0989
+P09259315A0809
+P09918842A0184
+P01047417T0000
+BC2GM050954712
+P08754802T0000
+BC2GM091202887
+P07565709A0000
+P09661676T0000
+P09712037A0470
+P06443639T0001
+P01975157A0836
+BC2GM006220127
+P07857086A0949
+BC2GM045312914
+P02837763A0259
+P02075876T0001
+BC2GM053757906
+P07961755A0474
+P02400457A0469
+BC2GM032391801
+P11392306T0000
+BC2GM009549697
+P08769568A0949
+P07876562A1646
+P10637238A0291
+P06097285A1077
+BC2GM023469972
+BC2GM089371905
+P09609705A0895
+BC2GM032790692
+P03361653A0459
+P02762198T0001
+P03004982A1094
+P10785668A0000
+P09003001A1593
+P04548483T0001
+BC2GM026278190
+P09860979A0521
+P09658122T0000
+P10736161T0000
+BC2GM018119295
+P07883167A0157
+BC2GM092473600
+P01549346A0000
+P09352016A1110
+P00555492A1034
+BC2GM043977711
+P09223475A0898
+P04263748T0042
+BC2GM028335304
+P07494244A0335
+P07500950A0000
+P07249544A0343
+P10962881A0900
+P08454077A0956
+P09518383A0000
+P07964459A0845
+BC2GM081878560
+P01275541A0405
+P06643612A0000
+P08628254A0665
+P01449183A0795
+P08581174A0472
+P09268661A1405
+P06463429A0414
+P09322738A0510
+P05344097T0000
+BC2GM043141382
+P08063766A0595
+P07896615A0554
+P03908493A0246
+P10950935A0111
+BC2GM051181003
+BC2GM097783604
+P07490083A0000
+BC2GM095551237
+P07243380A0327
+BC2GM046716836
+P11097040A0000
+P09311164A0245
+BC2GM052205120
+P07015262A0396
+BC2GM096363851
+P08565548A0196
+BC2GM080220626
+P11223186A1095
+P01067493A0119
+P09798263T0000
+P08585883A0381
+BC2GM005435651
+P07559347A0000
+BC2GM046486714
+P08793693A0237
+BC2GM098880938
+BC2GM036514946
+P07651400A0335
+P09556566A0174
+P08582633T0000
+P08936128A0611
+P10771528T0036
+P08648726A0713
+P11459304T0078
+P09837907A0857
+BC2GM083514944
+P03710973A0817
+BC2GM076511044
+P02557217A0398
+BC2GM023386484
+BC2GM069147712
+P10702794A1495
+BC2GM090460954
+P11178248A1042
+P09795213A0129
+P03944212A0166
+P07872673A0332
+P11105129T0000
+P09687514A0521
+P05881833T0001
+BC2GM063096861
+BC2GM050442878
+P08021225A0000
+P01372900A1017
+P10723727A0713
+P03904952T0000
+BC2GM017717134
+P00881630A0000
+P10811804A0800
+P10416429A0221
+P09862343A0225
+BC2GM054410700
+P10759693A0201
+P04487920T0001
+BC2GM038724792
+P10658425A1567
+BC2GM048403963
+BC2GM043696971
+P00089778A0000
+P11038366A1322
+BC2GM034171141
+P08661116A0963
+P05810259T0001
+BC2GM042907506
+P08342703A0966
+P02543226A1559
+P09405685A0113
+P08709245A1521
+P09278441A1777
+P09382850A0000
+BC2GM084411684
+P02164585A0416
+P08098882T0001
+BC2GM004241014
+P04068774A1292
+P08910550A0501
+P00150066A0100
+P10811079A0555
+BC2GM057124014
+P07546294A0000
+P07925282A0705
+P03127034A0591
+P05012220T0000
+P07696183A0567
+P01378127A0841
+BC2GM036319950
+BC2GM068583518
+BC2GM082666535
+BC2GM080062282
+P05445187T0000
+P11653491T0000
+BC2GM070558287
+BC2GM091632436
+P08617802A0993
+BC2GM081729559
+P09840943A0144
+P00023348A0601
+BC2GM073086948
+P10880486A0790
+P03985849A0221
+P00623361A0221
+P02270587A0000
+P09714835A0345
+BC2GM029519664
+P10594239T0000
+P09535579A1105
+BC2GM066617414
+P01644751A0590
+BC2GM063825132
+P11459048A0485
+P01758750A0000
+P09228042A0109
+P02743842A0000
+BC2GM051717947
+P09564860A2139
+P01986225A0250
+P07901125A0416
+P11076860A0872
+P11232947A1451
+P08473731A0149
+P00681550A0000
+P09442017A0435
+P01617801A0088
+P05751819T0000
+BC2GM000870973
+P07957158A1532
+P09763607A0521
+P10863352T0001
+P04052919A0205
+P06346427A0000
+BC2GM094423214
+P07983716A1082
+BC2GM015726029
+P02806916A0000
+P09019302A0600
+P11163968A0152
+P10640683A0204
+P01737741A0000
+P03090372A0607
+P11094590A0617
+P08499903A0883
+P02150473T0067
+P02573836A0244
+BC2GM014143125
+BC2GM040611661
+P09111048X0000
+P10955998A1124
+BC2GM016077661
+P09287362A0589
+BC2GM098444070
+BC2GM007804673
+BC2GM070860352
+P07900915A0000
+P08294429A0153
+P10886067A0520
+P07859371A1246
+BC2GM029590199
+P10638607A0000
+BC2GM096939334
+P02677666A0356
+P09363759A0000
+P08618433A1720
+BC2GM053594335
+P07812450A0849
+P02069738A0000
+P09382924A0131
+P01168908A0000
+P09388200A0639
+BC2GM006679416
+P09880512A1251
+P09549783T0000
+P02910496A0583
+P08251506A0503
+P02790009A1052
+P08556707A1390
+P02194273A0913
+P08509335T0000
+P11260468A1179
+P03001353A0146
+P07980468A0298
+BC2GM060444035
+P07795576A0126
+P08680706A0889
+P01684791A0000
+P09438427A0727
+P11138694A0000
+P02105497A1092
+BC2GM017168033
+P02573829T0000
+BC2GM038301816
+P11003805A0443
+P09032248A0239
+P03843676A0381
+P08702556A0000
+BC2GM077096663
+BC2GM043163295
+P08595836T0000
+P11465655A0439
+P01380454A0451
+P08838805T0000
+P01071715A0903
+P01096741X0000
+BC2GM099816783
+P03150296A0594
+BC2GM093413177
+P01900194T0000
+P08280476A0602
+P02648646A0932
+P07799437A0656
+P07609079A0387
+P01548891A0635
+P10572131A0000
+P10602838A0127
+P06812389A0658
+P10917402T0000
+BC2GM080587518
+P02852805A0216
+P10702253A0357
+P02026144A0741
+P02325895T0000b
+P08228997A0866
+P07493627A0882
+P07768824A0167
+P11415633A1253
+BC2GM094952768
+P09804836A0000
+BC2GM092320908
+BC2GM029863453
+P11425076A0364
+P07665172A0000
+P10779508A0452
+P03352254A0203
+P05896996T0001
+P09845856A0560
+P07425838A0182
+BC2GM013836575
+P08475104A0341
+P10764802A1258
+P01314841A0724
+BC2GM085844125
+P01347908T0000
+P07685823A1234
+P09275159T0000
+P08112341A1128
+BC2GM033119151
+BC2GM088008417
+P02674674A1308
+P09521907A0190
+P09541721A0894
+BC2GM094569593
+P10679190A0693
+BC2GM004781079
+P09736770A0351
+P04518624T0000
+P07665605A1127
+P07708497A0000
+P01811243A0000
+BC2GM078878267
+P09012405A0785
+P09380504A1255
+P02293019A0000
+P11212327A1564
+P11083432A0332
+BC2GM015562296
+P08144035A0387
+P08742135A0000
+BC2GM037491850
+P01159822A0353
+BC2GM020209849
+BC2GM041578046
+BC2GM004715465
+P01736651A0104
+P07797476A1001
+P09687498A1173
+P08276854A1894
+P05593469T0001
+P02615078A0283
+P08428965A1868
+BC2GM075780214
+BC2GM062846639
+P02556603A0606
+BC2GM038580862
+BC2GM007239314
+P07610052A1064
+P03166458A1356
+P03591464A0840b
+P09228092A1779
+P08382359A0469
+BC2GM033658965
+P11283168A0738
+P10653693A0903
+P06397009A0204
+P09751166A1460
+BC2GM096424310
+P03261331A0563
+P08990397A1437
+P07624581A0312
+P10613863T0000
+BC2GM074067305
+P10910439A1196
+P09892021A0712
+BC2GM038625120
+P08396913A1379
+P09312025T0000
+BC2GM073340870
+P11432748T0000
+P11106668A0875
+P10749145T0000
+P01864510A0946
+P11014465A0479
+P02052592A0000
+P08838314A0129
+P07607669A1112
+BC2GM036281424
+P03395249A1044
+P08871542A1352
+P02274343A0064
+P07533758A1038
+BC2GM013419270
+BC2GM092826848
+BC2GM016224723
+P01780235A0094
+P01659685T0000
+P08316100A0586
+BC2GM093870796
+P09311568A0595
+BC2GM091720557
+P02703121T0000
+P09771985A0238
+P10938130A0338
+P09535833A0228
+P07637718A0218
+BC2GM047759053
+P09515032A1230
+P09307065A0553
+P06323556A0126
+BC2GM024643868
+BC2GM035562452
+BC2GM014801779
+BC2GM070953330
+BC2GM061043119
+P08995410A1109
+P11416144A1324
+P01371275T0000
+P08248253A1785
+P09077437T0000
+BC2GM086476863
+P01717833A1223
+P11158290A0728
+P08820648A0123
+P11390395A1018
+P01261005A0711
+P08599946A0999
+P07814717A0669
+P01851862A0273
+P11331613A0827
+BC2GM060736050
+P09668119A0496
+P10528035A1102
+P01893927A0704
+P08726024A0244
+P11864173T0000
+P11367523A1684
+P02143768T0000
+P11312108A2853
+P01823524A0238
+P09730413A0642
+P09545353A1071
+BC2GM063051307
+P09050867A0542
+P07887859A0315
+BC2GM066721015
+P06683876A0244
+P01475381T0001
+P02507523A0791
+BC2GM029296962
+BC2GM070067040
+P06709700A0230
+P11100515A0282
+P01617776A0343
+P04921762T0000
+P02204623A0000
+BC2GM085613208
+BC2GM043460200
+P08309912A0306
+P08897663T0000
+P07947930A0499
+BC2GM071774854
+P09724754A0173
+P08085228A0000
+BC2GM075742629
+BC2GM062023800
+P09172414A0000
+BC2GM093724132
+P09003312A0740
+BC2GM028143170
+P08297376A0236
+P07175474A0102
+P07616056A0278
+P11290906T0000
+P09639410A3282
+BC2GM079565746
+BC2GM094631984
+BC2GM042292162
+BC2GM016213373
+P07699632A0522
+P01384040A1043
+P01429768T0000
+P07628389A0145
+BC2GM099213570
+P09448268A0186
+BC2GM008340188
+BC2GM041958370
+P08108343A0000
+BC2GM084714947
+P11112700A1936
+BC2GM015826249
+P08090746A1288
+P01377696A0000
+BC2GM006294419
+BC2GM010800143
+BC2GM066898247
+P03663789A0568
+P02544059A0377
+P00435187T0000
+P08134108A0277
+P08460270A0205
+P02832293T0000
+P07610716A0117
+P11055513A0564
+BC2GM010728052
+P01822581A0533
+P07942722T0000
+P08029001A1020
+P09199318A1147
+P04160980T0000
+P06483863A0000
+P02165589A0000
+BC2GM031239616
+P07935426A0714
+P03584426A0706
+BC2GM031288971
+P05985275T0000
+P09832099A0000
+P08017290A1347
+P08101171A0924
+BC2GM010999620
+P08649841A0956
+BC2GM045293373
+BC2GM022660122
+P02718683A0142
+P01870500A0276
+BC2GM013849593
+P02808232A0681
+P05533214T0001
+BC2GM080743687
+P11150315A1126
+P09435116A0437
+BC2GM031523666
+P08711631A0989
+P08995054A1368
+P08514766A0732
+P08414502A0244
+P07983011A0617
+P08573637A0434
+P08444345A0403
+P09649437A1140
+BC2GM012610098
+P02119626A0471
+BC2GM074332613
+P09629449A0540
+BC2GM003186870
+P10827952A0158
+P05532854T0001
+BC2GM028423664
+P04040339T0001
+P09349967A0653
+P05027799T0000
+P09408516T0000
+BC2GM041546990
+P09203731A0497
+P10628750A0298
+P09982923T0000
+P02473942A1207
+P09265932A0575
+P07846163A0422
+BC2GM073785891
+P08676456A0879
+P10437043A0164
+P10770471T0000
+P10924061A0588
+P08222556T0000
+P08253958A0000
+P08385131A0000
+P09144165A0614
+BC2GM056805115
+P10612044A1180
+P11059492A0376
+P11238375A0617
+P09535082A0537
+P00490336A0181
+P03061383A0000
+P10811804A0000
+P10887912A0740
+P06379363A0415
+P08916928A0950
+P07112471A0639
+P09927193A0107
+P09722766A0706
+P11223246A0359
+P08512728A0991
+P04547933T0000
+P06281891A0399
+P02720966A0455
+P06070204T0025
+P08288554A0295
+P07523710T0000
+BC2GM016375910
+P11376279A0000
+BC2GM035320296
+P11290415A0288
+BC2GM081451242
+BC2GM089665915
+P07263421A0351
+P08207405A0372
+P07474451A0000
+P10784367A0133
+P09927585A0796
+P07959011A0379b
+P11193704A0000
+P02604420A0234
+BC2GM054602912
+BC2GM041461171
+P00416758T0001
+BC2GM059995524
+BC2GM049429395
+P06851327A0000
+P06716977A0136
+P05725509T0000
+P07529124A0119
+P03016506A0611
+P09570944T0000
+P01581409A0398
+BC2GM050531748
+P11410664A0963
+P09101085A0686
+P08835895A1292
+P09398855A0438
+BC2GM030395765
+P10585463A0859
+BC2GM010599540
+BC2GM004561125
+BC2GM042454699
+BC2GM040247589
+P09234690A0242
+BC2GM084160257
+P08139017A1465
+P08660748X0000
+P09442024A0708
+BC2GM074464938
+BC2GM067551044
+P02160955A0899
+P01885752A0198
+BC2GM070953023
+P11090272A1240
+P04282315T0001
+P02474093T0000
+BC2GM001730189
+BC2GM009600842
+P01695116A0078
+P07691885T0000
+P09819414A1103
+BC2GM096432502
+P10918440T0000
+P11227484T0000
+BC2GM011728728
+P09864141A0528
+P07631267T0001
+P11614398T0000
+P09335619A0583
+P10511216A0654
+BC2GM002081221
+P09110176A0890
+P02016053A0752
+P06571587T0000
+BC2GM069051753
+BC2GM049116336
+P09943651T0000
+P08382303A0507
+P01963858T0001
+P11575109A0214
+P10993773A0717
+P07964770A0172
+BC2GM038900990
+P01193770T0000
+P08986812A1214
+BC2GM035589605
+P01156814T0000
+BC2GM097957533
+P10836786A0516
+BC2GM086705446
+P07823964A0922
+P07912123A0711
+BC2GM041894560
+P06713204A0867
+BC2GM029913363
+P11158288T0000
+P05555149T0001
+BC2GM035688360
+P07130335A1081
+P10518822A1037
+P08370119A1521
+P09863720T0000
+BC2GM070189689
+P06433442T0000
+P08569443A0123
+BC2GM072758555
+BC2GM034925448
+P02740874A0957
+BC2GM095698085
+BC2GM013203108
+P11220486A0686
+P10007564T0000
+BC2GM095215988
+P03354295A0157
+P08120029A0864
+P06439114A0677
+P09191052A0850
+P02766330A0779
+P09264466A0947
+P02582240A1009
+BC2GM059162976
+P02061333A0784
+P07898840X0000
+P07738839A0173
+BC2GM058510012
+P06204120T0001
+BC2GM070100199
+P09673436A0898
+BC2GM079186421
+P09463174A0670
+P02408248A0414
+P02386895A0496
+P07774137A0000
+P09087430A1046
+P06233924T0000
+P01826003A0694
+BC2GM029138982
+P02926499A0340
+P09234703A0192
+P08034318A0724
+P09645942A1164
+BC2GM037381460
+P09042911A0626
+BC2GM057439987
+BC2GM076042408
+P08087887A1067
+P01714322A0969
+BC2GM047747635
+BC2GM052174865
+P01886774A0000
+P09513759A0716
+P10872473A2286
+P09311808A0341
+P08343041A0000
+BC2GM067637713
+P09822652A1118
+P08706731A1303
+P10735848A1440
+P10891489A0152
+P02277005A0227
+P02277452A0116
+P00088391A0181
+P03531317A0930
+P08902641A0930
+BC2GM056550890
+P08622668A1155
+P08676383A0518
+P09719636A1134
+P08066094T0000
+P08668142A1048
+P07510724A1208
+BC2GM069862303
+BC2GM019718038
+P09696164A0000
+P00665336A0908
+P10756094A0671
+BC2GM020102507
+BC2GM041269018
+P07862129A1391
+BC2GM076930779
+P08212571A0597
+P06516369T0001
+P02527745A0865
+BC2GM045289936
+P07286057A0159
+P05574818T0000
+P01490493A0416
+BC2GM049085863
+P03628596A0000
+BC2GM077617268
+P08336738A1273
+BC2GM089231665
+BC2GM064092498
+P04058985A0000
+P04032349A0000
+P09233487A1386
+BC2GM070545500
+P00870859A0121
+P08264628A0418
+P02970061A0271
+P10748175A0000
+P03869442A0223
+P00644314T0000
+P08337828A0895
+BC2GM025162060
+P02634872A0000
+P08950352A0525
+P08870266A0651
+P02853799T0001
+BC2GM031305543
+P10059496T0000
+P11226228A0899
+P03921727A0523
+P08501678A0498
+P06973664A0000
+BC2GM048761602
+P01358880A0251
+BC2GM002383342
+P07999995A0000
+P11356716A0372
+P09478976A0718
+BC2GM096526647
+P09885431A0000
+BC2GM050351916
+P02840376A0461
+P08871567A0000
+P11496495A0000
+P01715593A0838
+BC2GM064320390
+P08389453A0193
+P08723365T0000
+P09346621A1181
+P09633171A0321
+P10627532A0739
+P09277629A0268
+BC2GM050193880
+P08790291A1022
+P07295417A0092
+P10683989A0251
+P03178097A0000
+BC2GM077904179
+BC2GM049579036
+P00952734T0000
+P10764150A0000
+BC2GM045681720
+P03064811A0485
+P02257251T0000
+BC2GM069202593
+P02437625A0197
+P08349632A0679
+BC2GM004982621
+BC2GM050802693
+P07038684A1050
+P08113736A0309
+BC2GM006771200
+BC2GM081412271
+BC2GM077618469
+P01601181A0842
+P11223240A0655
+P10775267A0363
+P01504853A0299
+BC2GM001605780
+BC2GM058126841
+P09799362A0507
+BC2GM024271469
+P01409643A0618
+P11540991A0127
+P04056256A0416
+P03329716A0187
+P01359588A0375
+P08614410A0000
+BC2GM069583481
+P03944239A0780
+P07299857A0294
+P01917962A0152
+P11103472A0802
+P11278928A1634
+BC2GM068101333
+BC2GM053494756
+P09187136A0000
+P11283354A0548
+P08924211A0941
+BC2GM041150256
+P08078167A0000
+P10967890A1120
+P09425036A0649
+BC2GM019139361
+P02118525A0737
+P01324404A1208
+P10913304A1180
+P07958865A1152
+P03771749A0465
+P07934331T0037
+P08617238A0334
+P09790499A0545
+P00146327A0147
+P01759052A0786
+P11182746A0872
+P08940134A0705
+BC2GM039707957
+P11195338A0494
+P11067797A1306
+P10587576A0596
+P06234786A0606
+P09715278A1526
+P10669594A0000
+BC2GM019604417
+P07816619A0872
+P03590911T0001
+BC2GM005244368
+BC2GM062908561
+P07234755A0838
+P10828591A0080
+P10853059X0751
+P10585491A0945
+P10628750T0000
+P09170159A0348
+P08011017A0169
+P10374632A0897
+P04615525T0001
+P09371566A1384
+BC2GM051407853
+BC2GM073702043
+BC2GM086731573
+P02761150A0000
+BC2GM058182434
+BC2GM009721363
+P05410641T0000
+P09621062A0810
+P01429596A1669
+BC2GM090412824
+P07607607T0000
+P00676790T0000
+P11054571A0230
+P08212897A0404
+P08176742A0190
+P01731933T0000b
+BC2GM090325124
+P10613816X0000
+BC2GM033647434
+P11123316T0000
+P02026491A0399
+BC2GM009855865
+P09205965A1249
+P07426745A0177
+P09426183A0000
+P09933428A0351
+P09291077T0000
+P01387105A0933
+P11309400T0000
+P07983704A0330
+P07867944A0365
+P08632018A0587
+BC2GM032318705
+BC2GM068927372
+BC2GM038061455
+P01078982A0227
+P09011591A0309
+BC2GM073294653
+BC2GM044146778
+P09797456A0883
+BC2GM007849960
+P08554723A0187
+P02603923A0220
+P01224116A0576
+P01150658A0683
+BC2GM052718596
+BC2GM038054598
+P08510320A1249
+BC2GM007067197
+BC2GM060653717
+P10894886A0375
+P09820163A0565
+P01886368A0000
+BC2GM014250094
+P02772495A0641
+P01863768A0649
+P10596955A1032
+P01862455T0000
+P08657183A0145
+P04679438T0001
+P10964995A2152
+P10684111A1411
+P02555519A0798
+P04551650T0001
+P05492285T0000
+BC2GM049816389
+BC2GM026873451
+BC2GM088426730
+P01545523A0000
+P11465518A0000
+P01810108A0000
+P06826813A0264
+BC2GM090069165
+BC2GM068735966
+P02317554T0000
+P04068969A0300
+P06480542A0000
+P07899634A0000
+BC2GM086750845
+P01398106A0754
+P09060971A0982
+BC2GM037181461
+BC2GM072949997
+BC2GM055178229
+P08555289A0207
+P11250942A0626
+P11160721A0932
+P07141130A0615
+P00483716A0366
+P08006772A0000
+P11024300A1579
+BC2GM063800112
+P07667621T0001
+P02508726A0498
+P02023904A0120
+P07907846A0623
+P03836777T0001
+P07426101A0124
+P08428953A1718
+BC2GM041094338
+P11454190A0000
+P08321199T0000
+P08406352A0172
+BC2GM027029005
+P02024488A0506
+BC2GM071282561
+P01822995T0000
+P02445751A0925
+BC2GM002778880
+P09786932A1042
+P02537441A0231
+P01695098A1116
+P08111035A0098
+P01806314A0322
+P09764741A0092
+BC2GM097306913
+P09801333A0174
+P10973400A0664
+P06669864T0001
+P00715180T0074
+P08878573A1370
+BC2GM082914643
+P08307338A0227
+BC2GM058880615
+P02201901A0229
+P07458171A0086
+P01564653A0307
+P11027724A0335
+P08280925A0261
+BC2GM049936595
+P02820128A1333
+P02145195A0253
+P08529098A0549
+BC2GM057945888
+P07737024A1003
+P07590264A0373
+P09190821A0707
+BC2GM016417962
+P09832511A0269
+P08794254A2957
+P03088643A0000
+P08013348A0143
+P10595315A0344
+BC2GM009033514
+P08798893A0611
+P08887667A0992
+P01876836T0000
+P10706688A0376
+BC2GM093618725
+P00999494A0000
+P08651853A0607
+P03417588T0000
+BC2GM034539107
+P08887647T0000
+P09549660A0782
+P06406060A0000
+P09829843A0819
+P01906166A0119
+P08261398A0392
+P01613640A0158
+P01717994T0000
+P06446048A0356
+P08542746T0000
+P02094257T0000
+P06654686T0001
+P07463465A0297
+P11420612A0303
+BC2GM087596425
+P10594903A0000
+BC2GM042537375
+P08207022T0000
+P09515665T0000
+P07800479A0201
+P00027739T0000
+P09694860A0498
+BC2GM076054604
+BC2GM049160960
+P07949164A0799
+BC2GM062836340
+BC2GM071664936
+BC2GM071889141
+P09042683A0492
+P10721714A1087
+P11271297T0000
+P07622932T0000
+BC2GM093024251
+P10640734A0190
+P09223229A0565
+P09761723A0226
+P09535851A0591
+P02914492A0183
+BC2GM032692465
+BC2GM056206368
+P02641762T0001
+P11062067A0000
+P07652582A0000
+P08666913A0000
+BC2GM043394225
+P08541499A0306
+P05451324T0000
+P02206430A0197
+P09437001A0769
+P06853042A0282
+P07665633A0284
+BC2GM012515903
+P09920930A0959
+P09333018A0000
+P10950415A0866
+P02833021A1185
+P03429306T0000
+P06597709A0596
+P09434160A0767
+P08243476A1177
+P08861963A0375b
+BC2GM036949597
+P08552082A0480
+BC2GM032564148
+P09531538A0983
+BC2GM043507962
+BC2GM095688766
+BC2GM091136434
+P09035612T0000
+P03712153T0000
+P07521916T0000
+P02269281A1276
+P06259389A0000
+BC2GM081450660
+P07600986A0605
+BC2GM037875786
+BC2GM048694992
+BC2GM091817900
+P02577458A0412
+P08324280A0098
+P08245933A0617
+P00188387A0975
+P10669596A0430
+P02348728A1153
+P09553143A0729
+P02334972A0145
+P08392221A0449
+P09008301A0193
+BC2GM079654891
+BC2GM015948167
+BC2GM041444961
+BC2GM092851466
+BC2GM027051573
+BC2GM062867525
+P08157009T0000
+P02318208A0817
+P08989763A0605
+P07608968A0836
+P09060622A1679
+P04062128T0028
+P07821790A1084
+P07890674A0916
+P10053852T0000
+P03559193A0000
+P09205113A0587
+P08707922A0334
+P09748513X1360
+P09789795A0607
+P02142955A0248
+BC2GM089171248
+P09175708A1526
+P02372496A0782
+P09368760A0665
+BC2GM081513417
+P02320999A0606
+P11113199A0800
+P08631944A0663
+P01767060A0000
+P11361493T0000
+P01321336A0000
+P11066245T0000
+P09377355A0362
+P02400070T0000
+BC2GM030169999
+P11058132A0264
+P10983344A0000
+P01714902A0221
+P04070725A0442
+P09724654A1120
+P01545797A0587
+P10729220A0000
+P10878944A0000
+P02144558A1022
+P10635209A0419
+P07793783A0189
+P10000253T0000
+P02689136A1851
+P08053697A0000
+P01316476A1428
+P04766888T0000
+BC2GM031485809
+P08731511A0625
+P08733874A0000
+P01695905A0480
+P02689544A0456
+P08410097A0356
+P07604794A0958
+BC2GM062247998
+P01346262A0377
+P09852136A0174
+BC2GM064911802
+P04871589T0001
+P10704853T0000
+P11457139A0604
+BC2GM086826510
+BC2GM090747273
+P06793764T0001
+P08622893A0000
+P09582326A0151
+P01563635T0000
+BC2GM002607371
+P11069756A2618
+P08234276A0556
+P08048916A0000
+P03355122A0238
+P11397652A0381
+P05902458T0001
+P08065365A0000
+P02251119A0319
+P05394461T0001
+P06712314A0148
+BC2GM095775239
+BC2GM018583333
+P07084814T0000
+P06721188A0200
+BC2GM095042999
+BC2GM065997756
+P09537361A0149
+BC2GM023079382
+P07608649A1429
+P09430730A0374
+P08754827A0231
+P11209100A0069
+BC2GM038812570
+P02590615A0636
+P06805537T0001
+P01761736A0158
+P09771967A1052
+P09670912T0000
+P08065338T0000
+BC2GM051498268
+BC2GM006693980
+BC2GM001533580
+P08067546A0000
+P01021091T0000
+P09136015A0529
+P07978406A0998
+P08321203A0840
+BC2GM066627539
+BC2GM062613921
+P10902348A0566
+BC2GM056870406
+P09315678A0278
+P07565669T0000
+P07846942T0001
+BC2GM058457481
+BC2GM024468009
+BC2GM062872922
+P10044519T0000
+P02986279A0000
+BC2GM083581791
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/bioinfer.dev b/huner/ner_scripts/splits/bioinfer.dev
new file mode 100644
index 0000000..ce86e02
--- /dev/null
+++ b/huner/ner_scripts/splits/bioinfer.dev
@@ -0,0 +1,111 @@
+
+660
+661
+662
+663
+664
+665
+666
+667
+668
+669
+670
+671
+672
+673
+674
+675
+676
+677
+678
+679
+680
+681
+682
+683
+684
+685
+686
+687
+688
+689
+690
+691
+692
+693
+694
+695
+696
+697
+698
+699
+700
+701
+702
+703
+704
+705
+706
+707
+708
+709
+710
+711
+712
+713
+714
+715
+716
+717
+718
+719
+720
+721
+722
+723
+724
+725
+726
+727
+728
+729
+730
+731
+732
+733
+734
+735
+736
+737
+738
+739
+740
+741
+742
+743
+744
+745
+746
+747
+748
+749
+750
+751
+752
+753
+754
+755
+756
+757
+758
+759
+760
+761
+762
+763
+764
+765
+766
+767
+768
+769
diff --git a/huner/ner_scripts/splits/bioinfer.test b/huner/ner_scripts/splits/bioinfer.test
new file mode 100644
index 0000000..e8bbed4
--- /dev/null
+++ b/huner/ner_scripts/splits/bioinfer.test
@@ -0,0 +1,331 @@
+
+1000
+1001
+1002
+1003
+1004
+1005
+1006
+1007
+1008
+1009
+1010
+1011
+1012
+1013
+1014
+1015
+1016
+1017
+1018
+1019
+1020
+1021
+1022
+1023
+1024
+1025
+1026
+1027
+1028
+1029
+1030
+1031
+1032
+1033
+1034
+1035
+1036
+1037
+1038
+1039
+1040
+1041
+1042
+1043
+1044
+1045
+1046
+1047
+1048
+1049
+1050
+1051
+1052
+1053
+1054
+1055
+1056
+1057
+1058
+1059
+1060
+1061
+1062
+1063
+1064
+1065
+1066
+1067
+1068
+1069
+1070
+1071
+1072
+1073
+1074
+1075
+1076
+1077
+1078
+1079
+1080
+1081
+1082
+1083
+1084
+1085
+1086
+1087
+1088
+1089
+1090
+1091
+1092
+1093
+1094
+1095
+1096
+1097
+1098
+1099
+770
+771
+772
+773
+774
+775
+776
+777
+778
+779
+780
+781
+782
+783
+784
+785
+786
+787
+788
+789
+790
+791
+792
+793
+794
+795
+796
+797
+798
+799
+800
+801
+802
+803
+804
+805
+806
+807
+808
+809
+810
+811
+812
+813
+814
+815
+816
+817
+818
+819
+820
+821
+822
+823
+824
+825
+826
+827
+828
+829
+830
+831
+832
+833
+834
+835
+836
+837
+838
+839
+840
+841
+842
+843
+844
+845
+846
+847
+848
+849
+850
+851
+852
+853
+854
+855
+856
+857
+858
+859
+860
+861
+862
+863
+864
+865
+866
+867
+868
+869
+870
+871
+872
+873
+874
+875
+876
+877
+878
+879
+880
+881
+882
+883
+884
+885
+886
+887
+888
+889
+890
+891
+892
+893
+894
+895
+896
+897
+898
+899
+900
+901
+902
+903
+904
+905
+906
+907
+908
+909
+910
+911
+912
+913
+914
+915
+916
+917
+918
+919
+920
+921
+922
+923
+924
+925
+926
+927
+928
+929
+930
+931
+932
+933
+934
+935
+936
+937
+938
+939
+940
+941
+942
+943
+944
+945
+946
+947
+948
+949
+950
+951
+952
+953
+954
+955
+956
+957
+958
+959
+960
+961
+962
+963
+964
+965
+966
+967
+968
+969
+970
+971
+972
+973
+974
+975
+976
+977
+978
+979
+980
+981
+982
+983
+984
+985
+986
+987
+988
+989
+990
+991
+992
+993
+994
+995
+996
+997
+998
+999
diff --git a/huner/ner_scripts/splits/bioinfer.train b/huner/ner_scripts/splits/bioinfer.train
new file mode 100644
index 0000000..59a2a53
--- /dev/null
+++ b/huner/ner_scripts/splits/bioinfer.train
@@ -0,0 +1,661 @@
+
+0
+1
+10
+100
+101
+102
+103
+104
+105
+106
+107
+108
+109
+11
+110
+111
+112
+113
+114
+115
+116
+117
+118
+119
+12
+120
+121
+122
+123
+124
+125
+126
+127
+128
+129
+13
+130
+131
+132
+133
+134
+135
+136
+137
+138
+139
+14
+140
+141
+142
+143
+144
+145
+146
+147
+148
+149
+15
+150
+151
+152
+153
+154
+155
+156
+157
+158
+159
+16
+160
+161
+162
+163
+164
+165
+166
+167
+168
+169
+17
+170
+171
+172
+173
+174
+175
+176
+177
+178
+179
+18
+180
+181
+182
+183
+184
+185
+186
+187
+188
+189
+19
+190
+191
+192
+193
+194
+195
+196
+197
+198
+199
+2
+20
+200
+201
+202
+203
+204
+205
+206
+207
+208
+209
+21
+210
+211
+212
+213
+214
+215
+216
+217
+218
+219
+22
+220
+221
+222
+223
+224
+225
+226
+227
+228
+229
+23
+230
+231
+232
+233
+234
+235
+236
+237
+238
+239
+24
+240
+241
+242
+243
+244
+245
+246
+247
+248
+249
+25
+250
+251
+252
+253
+254
+255
+256
+257
+258
+259
+26
+260
+261
+262
+263
+264
+265
+266
+267
+268
+269
+27
+270
+271
+272
+273
+274
+275
+276
+277
+278
+279
+28
+280
+281
+282
+283
+284
+285
+286
+287
+288
+289
+29
+290
+291
+292
+293
+294
+295
+296
+297
+298
+299
+3
+30
+300
+301
+302
+303
+304
+305
+306
+307
+308
+309
+31
+310
+311
+312
+313
+314
+315
+316
+317
+318
+319
+32
+320
+321
+322
+323
+324
+325
+326
+327
+328
+329
+33
+330
+331
+332
+333
+334
+335
+336
+337
+338
+339
+34
+340
+341
+342
+343
+344
+345
+346
+347
+348
+349
+35
+350
+351
+352
+353
+354
+355
+356
+357
+358
+359
+36
+360
+361
+362
+363
+364
+365
+366
+367
+368
+369
+37
+370
+371
+372
+373
+374
+375
+376
+377
+378
+379
+38
+380
+381
+382
+383
+384
+385
+386
+387
+388
+389
+39
+390
+391
+392
+393
+394
+395
+396
+397
+398
+399
+4
+40
+400
+401
+402
+403
+404
+405
+406
+407
+408
+409
+41
+410
+411
+412
+413
+414
+415
+416
+417
+418
+419
+42
+420
+421
+422
+423
+424
+425
+426
+427
+428
+429
+43
+430
+431
+432
+433
+434
+435
+436
+437
+438
+439
+44
+440
+441
+442
+443
+444
+445
+446
+447
+448
+449
+45
+450
+451
+452
+453
+454
+455
+456
+457
+458
+459
+46
+460
+461
+462
+463
+464
+465
+466
+467
+468
+469
+47
+470
+471
+472
+473
+474
+475
+476
+477
+478
+479
+48
+480
+481
+482
+483
+484
+485
+486
+487
+488
+489
+49
+490
+491
+492
+493
+494
+495
+496
+497
+498
+499
+5
+50
+500
+501
+502
+503
+504
+505
+506
+507
+508
+509
+51
+510
+511
+512
+513
+514
+515
+516
+517
+518
+519
+52
+520
+521
+522
+523
+524
+525
+526
+527
+528
+529
+53
+530
+531
+532
+533
+534
+535
+536
+537
+538
+539
+54
+540
+541
+542
+543
+544
+545
+546
+547
+548
+549
+55
+550
+551
+552
+553
+554
+555
+556
+557
+558
+559
+56
+560
+561
+562
+563
+564
+565
+566
+567
+568
+569
+57
+570
+571
+572
+573
+574
+575
+576
+577
+578
+579
+58
+580
+581
+582
+583
+584
+585
+586
+587
+588
+589
+59
+590
+591
+592
+593
+594
+595
+596
+597
+598
+599
+6
+60
+600
+601
+602
+603
+604
+605
+606
+607
+608
+609
+61
+610
+611
+612
+613
+614
+615
+616
+617
+618
+619
+62
+620
+621
+622
+623
+624
+625
+626
+627
+628
+629
+63
+630
+631
+632
+633
+634
+635
+636
+637
+638
+639
+64
+640
+641
+642
+643
+644
+645
+646
+647
+648
+649
+65
+650
+651
+652
+653
+654
+655
+656
+657
+658
+659
+66
+67
+68
+69
+7
+70
+71
+72
+73
+74
+75
+76
+77
+78
+79
+8
+80
+81
+82
+83
+84
+85
+86
+87
+88
+89
+9
+90
+91
+92
+93
+94
+95
+96
+97
+98
+99
diff --git a/huner/ner_scripts/splits/bios.dev b/huner/ner_scripts/splits/bios.dev
new file mode 100644
index 0000000..f890bcb
--- /dev/null
+++ b/huner/ner_scripts/splits/bios.dev
@@ -0,0 +1,21 @@
+
+EP0525420
+EP1832590
+US20040266788
+US20040266789
+US20100113465
+US4282233
+US4689338
+US4721723
+US4874794
+US4990517
+US5153197
+US5767129
+US7358376
+WO1996019444
+WO2000024718
+WO2001066101
+WO2001077111
+WO2005018625
+WO2009036766
+WO2009126123
diff --git a/huner/ner_scripts/splits/bios.test b/huner/ner_scripts/splits/bios.test
new file mode 100644
index 0000000..532403a
--- /dev/null
+++ b/huner/ner_scripts/splits/bios.test
@@ -0,0 +1,66 @@
+
+EP0854138
+EP1201660
+EP1361212
+EP2050739
+EP2172453
+US20020035136
+US20020198201
+US20030008869
+US20030220373
+US20050124683
+US20050222261
+US20050245543
+US20060122222
+US20060154945
+US20070060589
+US20070179154
+US20070249620
+US20070270434
+US20080176848
+US20080221164
+US20090048258
+US20100105700
+US20100113486
+US4503067
+US4593029
+US4650884
+US4839155
+US4895841
+US4935437
+US5091378
+US5104888
+US5116863
+US5270317
+US5360800
+US5382600
+US5439666
+US5650521
+US5814642
+US5830902
+US6156756
+US6262113
+US6323216
+US6472415
+US6916815
+US7141596
+WO1993020807
+WO1995009631
+WO1996004269
+WO1996011929
+WO2002094811
+WO2003011210
+WO2004022534
+WO2004033455
+WO2005056519
+WO2006004791
+WO2006110516
+WO2007067614
+WO2007067615
+WO2007101213
+WO2008007900
+WO2008098104
+WO2009029592
+WO2009109999
+WO2009133387
+WO2011036127
diff --git a/huner/ner_scripts/splits/bios.train b/huner/ner_scripts/splits/bios.train
new file mode 100644
index 0000000..4960cb8
--- /dev/null
+++ b/huner/ner_scripts/splits/bios.train
@@ -0,0 +1,112 @@
+
+EP1481667
+EP1657241
+EP1757610
+EP1764360
+EP1797878
+EP2128157
+US20010014694
+US20030130506
+US20030134862
+US20040077625
+US20040097566
+US20040192763
+US20040229890
+US20050004369
+US20050107386
+US20050137398
+US20050166270
+US20050228031
+US20050267177
+US20060069101
+US20060106014
+US20070015779
+US20070105909
+US20070105913
+US20070112070
+US20070117761
+US20070155803
+US20080113922
+US20080234237
+US20080255161
+US20080306102
+US20090054413
+US20090062291
+US20090111798
+US20090215743
+US20090215774
+US20100075973
+US4231938
+US4254129
+US4255431
+US4335121
+US4382938
+US4472305
+US4572909
+US4659516
+US4681893
+US4738974
+US4746680
+US4816470
+US4847265
+US4978672
+US5002953
+US5006528
+US5006530
+US5045552
+US5158936
+US5196444
+US5399578
+US5466823
+US5521184
+US5565447
+US5616599
+US5633272
+US5747498
+US5849911
+US5859006
+US5916887
+US6060462
+US6103743
+US6258953
+US6800646
+US6803381
+US7541359
+WO1991009021
+WO1991013082
+WO1995019978
+WO1998022619
+WO2002006274
+WO2002010154
+WO2002026743
+WO2002048169
+WO2002053556
+WO2002072561
+WO2002088140
+WO2003026650
+WO2004000294
+WO2004060872
+WO2004065389
+WO2004089363
+WO2004096781
+WO2005068462
+WO2006024640
+WO2006055708
+WO2006083612
+WO2006116563
+WO2007006547
+WO2007070796
+WO2007081755
+WO2007087066
+WO2007113276
+WO2008071976
+WO2008087654
+WO2008110863
+WO2008129280
+WO2008141385
+WO2009007753
+WO2009015203
+WO2009029625
+WO2009094169
+WO2009152825
+WO2010054968
diff --git a/huner/ner_scripts/splits/cellfinder_cellline.dev b/huner/ner_scripts/splits/cellfinder_cellline.dev
new file mode 100644
index 0000000..34e7005
--- /dev/null
+++ b/huner/ner_scripts/splits/cellfinder_cellline.dev
@@ -0,0 +1,2 @@
+
+17288595
diff --git a/huner/ner_scripts/splits/cellfinder_cellline.test b/huner/ner_scripts/splits/cellfinder_cellline.test
new file mode 100644
index 0000000..17b3e77
--- /dev/null
+++ b/huner/ner_scripts/splits/cellfinder_cellline.test
@@ -0,0 +1,4 @@
+
+16316465
+16672070
+17381551
diff --git a/huner/ner_scripts/splits/cellfinder_cellline.train b/huner/ner_scripts/splits/cellfinder_cellline.train
new file mode 100644
index 0000000..f22b908
--- /dev/null
+++ b/huner/ner_scripts/splits/cellfinder_cellline.train
@@ -0,0 +1,7 @@
+
+15971941
+16623949
+17389645
+17967047
+18162134
+18286199
diff --git a/huner/ner_scripts/splits/cellfinder_protein.dev b/huner/ner_scripts/splits/cellfinder_protein.dev
new file mode 100644
index 0000000..c8c2388
--- /dev/null
+++ b/huner/ner_scripts/splits/cellfinder_protein.dev
@@ -0,0 +1,2 @@
+
+17967047
diff --git a/huner/ner_scripts/splits/cellfinder_protein.test b/huner/ner_scripts/splits/cellfinder_protein.test
new file mode 100644
index 0000000..033c0ca
--- /dev/null
+++ b/huner/ner_scripts/splits/cellfinder_protein.test
@@ -0,0 +1,4 @@
+
+16316465
+16672070
+17288595
diff --git a/huner/ner_scripts/splits/cellfinder_protein.train b/huner/ner_scripts/splits/cellfinder_protein.train
new file mode 100644
index 0000000..d01afcc
--- /dev/null
+++ b/huner/ner_scripts/splits/cellfinder_protein.train
@@ -0,0 +1,7 @@
+
+15971941
+16623949
+17381551
+17389645
+18162134
+18286199
diff --git a/huner/ner_scripts/splits/cellfinder_species.dev b/huner/ner_scripts/splits/cellfinder_species.dev
new file mode 100644
index 0000000..c8c2388
--- /dev/null
+++ b/huner/ner_scripts/splits/cellfinder_species.dev
@@ -0,0 +1,2 @@
+
+17967047
diff --git a/huner/ner_scripts/splits/cellfinder_species.test b/huner/ner_scripts/splits/cellfinder_species.test
new file mode 100644
index 0000000..033c0ca
--- /dev/null
+++ b/huner/ner_scripts/splits/cellfinder_species.test
@@ -0,0 +1,4 @@
+
+16316465
+16672070
+17288595
diff --git a/huner/ner_scripts/splits/cellfinder_species.train b/huner/ner_scripts/splits/cellfinder_species.train
new file mode 100644
index 0000000..d01afcc
--- /dev/null
+++ b/huner/ner_scripts/splits/cellfinder_species.train
@@ -0,0 +1,7 @@
+
+15971941
+16623949
+17381551
+17389645
+18162134
+18286199
diff --git a/huner/ner_scripts/splits/cemp.dev b/huner/ner_scripts/splits/cemp.dev
new file mode 100644
index 0000000..b1b2be5
--- /dev/null
+++ b/huner/ner_scripts/splits/cemp.dev
@@ -0,0 +1,1400 @@
+
+CA2100514C
+CA2154601C
+CA2169831C
+CA2185015C
+CA2185397C
+CA2211389C
+CA2211982C
+CA2224426C
+CA2225822C
+CA2230690C
+CA2263798C
+CA2290220C
+CA2295678C
+CA2298523C
+CA2315835C
+CA2323839C
+CA2336799C
+CA2337988C
+CA2339290C
+CA2341949C
+CA2355102C
+CA2377309C
+CA2379557C
+CA2394717C
+CA2396151C
+CA2397594C
+CA2398539C
+CA2454592C
+CA2456970C
+CA2472449C
+CA2503754A1
+CA2508180C
+CA2529055C
+CA2533117A1
+CA2548379C
+CA2597798A1
+CA2599543A1
+CA2653883A1
+CA2657592A1
+CA2680058A1
+CA2714200A1
+CA2716578A1
+CA2741984A1
+CA2781066C
+CA2820201A1
+CA2837759A1
+CA2843643A1
+CN100579977C
+CN100584851C
+CN100999470B
+CN101007128A
+CN101007811A
+CN101007829A
+CN101011363A
+CN101016324A
+CN101019848B
+CN101020062A
+CN101020700A
+CN101023942A
+CN101024604B
+CN101040860A
+CN101040869A
+CN101041074A
+CN101045149A
+CN101045704A
+CN101049302A
+CN101057969A
+CN101062049A
+CN101062293A
+CN101073581A
+CN101081226A
+CN101088997A
+CN101095815A
+CN101117340A
+CN101129578A
+CN101130556A
+CN101138564A
+CN101195601A
+CN101199567A
+CN101220044A
+CN101224217A
+CN101229126B
+CN101244072A
+CN101244079A
+CN101244087A
+CN101264105B
+CN101269222A
+CN101275135A
+CN101278895A
+CN101278899A
+CN101278964A
+CN101284011A
+CN101293876A
+CN101297669B
+CN101300235A
+CN101301301A
+CN101301305A
+CN101301385B
+CN101307050B
+CN101307063A
+CN101313919B
+CN101314023A
+CN101322689A
+CN101332186A
+CN101332264A
+CN101336921A
+CN101336923A
+CN101341124A
+CN101343299A
+CN101352417A
+CN101352439A
+CN101362736A
+CN101362737A
+CN101362762A
+CN101362763B
+CN101376656A
+CN101386590A
+CN101397330A
+CN101416947A
+CN101422488A
+CN101433633A
+CN101440355A
+CN101468950B
+CN101496791A
+CN101501023A
+CN101502501A
+CN101513530B
+CN101518542A
+CN101519392A
+CN101525391B
+CN101530571A
+CN101531649A
+CN101537003A
+CN101554377A
+CN101570554B
+CN101570560B
+CN101574505A
+CN101574513A
+CN101596198A
+CN101596215A
+CN101601650A
+CN101606903A
+CN101664386B
+CN101693026B
+CN101693038B
+CN101693041A
+CN101693659A
+CN101697969A
+CN101698063B
+CN101700224A
+CN101700241A
+CN101700256A
+CN101700382A
+CN101703469A
+CN101708230B
+CN101717384B
+CN101717397B
+CN101721363A
+CN101723887A
+CN101732232A
+CN101732234A
+CN101732292A
+CN101732645A
+CN101743010A
+CN101744823A
+CN101759684A
+CN101759715A
+CN101766574A
+CN101766643A
+CN101773496A
+CN101780096A
+CN101786975A
+CN101790525A
+CN101792437B
+CN101798558A
+CN101805328A
+CN101809000A
+CN101810605A
+CN101810616A
+CN101817808A
+CN101829053B
+CN101829059B
+CN101856350A
+CN101856374A
+CN101856495A
+CN101863925B
+CN101863936A
+CN101863945A
+CN101870694A
+CN101889975A
+CN101912586A
+CN101919812B
+CN101919824A
+CN101919946B
+CN101921294A
+CN101926830A
+CN101928328A
+CN101932560B
+CN101933894A
+CN101940701A
+CN101941914A
+CN101953792A
+CN101953818A
+CN101961383A
+CN101961489A
+CN101966246A
+CN101978852A
+CN101978978A
+CN101987100A
+CN101991588B
+CN101991591A
+CN102000046B
+CN102010366A
+CN102018706A
+CN102018719A
+CN102018721A
+CN102038752A
+CN102038872A
+CN102068404A
+CN102068684A
+CN102091133A
+CN102114038B
+CN102114165A
+CN102127019A
+CN102127141A
+CN102131805A
+CN102133214A
+CN102133220A
+CN102145008A
+CN102151279A
+CN102172349A
+CN102172355A
+CN102188512A
+CN102188635B
+CN102198109B
+CN102199184A
+CN102228436A
+CN102228458A
+CN102232947A
+CN102240320A
+CN102257133A
+CN102258520B
+CN102283858B
+CN102304087A
+CN102309442A
+CN102327315A
+CN102342930A
+CN102342936A
+CN102349888A
+CN102415988B
+CN102432601A
+CN102452916A
+CN102512380A
+CN102532037A
+CN102532163A
+CN102579354A
+CN102579641A
+CN102584535A
+CN102600074A
+CN102600190A
+CN102614216A
+CN102614232A
+CN102617470A
+CN102626424A
+CN102626441A
+CN102670546A
+CN102675099A
+CN102697740A
+CN102697771A
+CN102716102A
+CN102727509A
+CN102731418A
+CN102743365A
+CN102746220A
+CN102755349A
+CN102764271A
+CN102764277A
+CN102766186A
+CN102772393A
+CN102772412A
+CN102784139A
+CN102784145A
+CN102784164A
+CN102805729A
+CN102805745A
+CN102811743A
+CN102813667A
+CN102871991A
+CN102872084A
+CN102872088A
+CN102895175A
+CN102895669A
+CN102908310A
+CN102911069A
+CN102935071A
+CN102942610A
+CN102949406A
+CN102949574A
+CN102952207A
+CN102961283A
+CN102961785A
+CN102973880A
+CN102973891A
+CN102988470A
+CN102988724A
+CN102993152A
+CN103006656A
+CN103006657A
+CN103006667A
+CN103006675A
+CN103006679A
+CN103012429A
+CN103040754A
+CN103040762A
+CN103041227A
+CN103054861A
+CN103059015A
+CN103059019A
+CN103059042A
+CN103070864A
+CN103070869A
+CN103070876A
+CN103070878A
+CN103070925A
+CN103083274A
+CN103087009A
+CN103099804A
+CN103110586A
+CN103120678A
+CN103142473A
+CN103142474A
+CN103142486A
+CN103142580A
+CN103142597A
+CN103153994A
+CN103157095A
+CN103202804A
+CN103211809A
+CN103222965A
+CN103239449A
+CN103239497A
+CN103242219A
+CN103251581A
+CN103251582A
+CN103265487A
+CN103272070A
+CN103284942A
+CN103284944A
+CN103285023A
+CN103288752A
+CN103301114A
+CN103301377A
+CN103304483A
+CN103304486A
+CN103340312A
+CN103349680A
+CN103355655A
+CN103356522A
+CN103356651A
+CN103360276A
+CN103374014A
+CN103385880A
+CN103385888A
+CN103386013A
+CN103387531A
+CN103393488A
+CN103393680A
+CN103396414A
+CN103420981A
+CN103432105A
+CN103432109A
+CN103462944A
+CN103462961A
+CN103462964A
+CN103463056A
+CN103463066A
+CN103463067A
+CN103476415A
+CN103479522A
+CN103479655A
+CN103479906A
+CN103483272A
+CN103495138A
+CN103505717A
+CN103520101A
+CN103520156A
+CN103520163A
+CN103520232A
+CN103520294A
+CN103536527A
+CN103536583A
+CN103536587A
+CN103536657A
+CN103550288A
+CN103550332A
+CN103565811A
+CN103566083A
+CN103570792A
+CN103585264A
+CN103613574A
+CN103622921A
+CN103622923A
+CN103623151A
+CN103623264A
+CN103638361A
+CN103638493A
+CN103656132A
+CN103656736A
+CN103690939A
+CN103694211A
+CN103717591A
+CN103719313A
+CN103724262A
+CN103724271A
+CN103735689A
+CN103751154A
+CN103751168A
+CN1562004A
+CN1565432A
+CN1565446A
+CN1566094A
+CN1569004A
+CN1569884A
+CN1586474A
+CN1589799A
+CN1594342B
+CN1596888A
+CN1621038A
+CN1623561A
+CN1626072A
+CN1626080A
+CN1631902A
+CN1634046A
+CN1654074A
+CN1669552A
+CN1672684A
+CN1676120A
+CN1679619A
+CN1682733A
+CN1682740A
+CN1726908A
+CN1732918A
+CN1732967A
+CN1733765A
+CN1742745A
+CN1775227A
+CN1799541A
+CN1806808A
+CN1810790A
+CN1820745A
+CN1839125A
+CN1839796A
+CN1850079A
+CN1853675A
+CN1868449A
+CN1872061A
+CN1872068A
+CN1879710A
+CN1879717A
+CN1887285A
+CN1911437A
+CN1923177A
+CN1923798A
+CN1927213A
+CN1927840A
+CN1931329A
+CN1935158A
+CN1935762A
+CN1939330A
+CN1965806A
+CN1966037A
+CN1973871B
+CN1981765A
+CN1994317A
+CN1994998A
+CN201692350U
+CN203354929U
+DE102005008412A1
+DE102006031630A1
+DE102007032661A1
+DE102007032663A1
+EP0644767B3
+EP0804437B1
+EP0902839B1
+EP0941093B1
+EP0944311B1
+EP0944312B1
+EP0969838B2
+EP0972037B1
+EP0979080B9
+EP0988309B1
+EP0994880B1
+EP1001781B1
+EP1039906B1
+EP1052259B1
+EP1089968B1
+EP1107807B1
+EP1119630B1
+EP1127065B1
+EP1175399B1
+EP1190248B1
+EP1218381B1
+EP1239814B1
+EP1239862B1
+EP1242437B1
+EP1280757B1
+EP1301460B1
+EP1303499B1
+EP1303591B1
+EP1325019B1
+EP1343797B1
+EP1351694B1
+EP1365768B1
+EP1383787B1
+EP1411900B1
+EP1414433B1
+EP1434570B1
+EP1472246B1
+EP1482919B1
+EP1498150A1
+EP1501837A1
+EP1536840B1
+EP1538162A2
+EP1542679B1
+EP1545491A1
+EP1551380A1
+EP1572208A2
+EP1585512A1
+EP1591529A2
+EP1596846A2
+EP1623987A1
+EP1632246A2
+EP1663205A1
+EP1677785A1
+EP1684770A1
+EP1712226A2
+EP1712642B1
+EP1721609A2
+EP1753714A2
+EP1763370A1
+EP1776356B1
+EP1786790A1
+EP1786802A1
+EP1793846A1
+EP1802297A2
+EP1802618A1
+EP1807090B9
+EP1834628A1
+EP1837027A1
+EP1854799A1
+EP1897547A1
+EP1909769A2
+EP1909803A2
+EP1928448B1
+EP1955708A1
+EP2014290A2
+EP2019825A1
+EP2036567A2
+EP2044023B1
+EP2063883A2
+EP2094258A1
+EP2097454A2
+EP2100611A1
+EP2116539A1
+EP2120920A2
+EP2170336A1
+EP2181706A2
+EP2229165A1
+EP2257296A1
+EP2265270A1
+EP2285767A2
+EP2307022A1
+EP2308880A1
+EP2343044A1
+EP2349275A1
+EP2352733A1
+EP2364712A1
+EP2385041A1
+EP2389350A1
+EP2394998A1
+EP2419140A2
+EP2424869A1
+EP2427052A1
+EP2437732A1
+EP2440548A1
+EP2471538A1
+EP2477699A1
+EP2520299A1
+EP2536411A2
+EP2544678A2
+EP2545922A1
+EP2549997A2
+EP2564871A1
+EP2571541A2
+EP2581082A1
+EP2582660A1
+EP2595636A2
+EP2596791A1
+EP2604601A1
+EP2606889A1
+EP2619187A1
+EP2630126A1
+EP2632453A1
+EP2651891A1
+EP2654745A1
+EP2661431A2
+EP2668168A1
+EP2688595A2
+EP2694068A1
+EP2697197A1
+EP2701692A1
+EP2729449A1
+EP2730280A1
+EP2730281A1
+EP2747750A2
+EP2749641A1
+EP2769722A1
+EP2780326A1
+EP2780352A1
+US20050014688
+US20050014769
+US20050014806
+US20050014811
+US20050020634
+US20050032759
+US20050049246
+US20050074455
+US20050076916
+US20050250730
+US20050261496
+US20050281749
+US20060008804
+US20060039937
+US20060040873
+US20060052319
+US20060094702
+US20060111235
+US20060128663
+US20060142388
+US20060154898
+US20060160848
+US20060166996
+US20060189538
+US20060217349
+US20060229338
+US20060235027
+US20060235045
+US20060235061
+US20070020230
+US20070053973
+US20070060551
+US20070066564
+US20070066633
+US20070088006
+US20070088024
+US20070112028
+US20070112040
+US20070148197
+US20070149476
+US20070185115
+US20070185137
+US20070213332
+US20070238640
+US20070243192
+US20070259826
+US20070259854
+US20070259857
+US20070259891
+US20070293460
+US20070293473
+US20080004228
+US20080004239
+US20080015189
+US20080027140
+US20080031817
+US20080058267
+US20080085870
+US20080085893
+US20080107707
+US20080107720
+US20080107737
+US20080113015
+US20080119435
+US20080119485
+US20080119530
+US20080125355
+US20080125387
+US20080131370
+US20080132460
+US20080132483
+US20080132507
+US20080139628
+US20080139652
+US20080153914
+US20080161247
+US20080161271
+US20080167327
+US20080170997
+US20080176812
+US20080176888
+US20080176902
+US20080182903
+US20080182907
+US20080187510
+US20080187588
+US20080193381
+US20080194633
+US20080194648
+US20080194663
+US20080194686
+US20080199468
+US20080220056
+US20080221056
+US20080221078
+US20080221105
+US20080221144
+US20080233090
+US20080233158
+US20080234301
+US20080242626
+US20080260702
+US20080260741
+US20080260846
+US20080260850
+US20080260878
+US20080261903
+US20080261907
+US20080261923
+US20080269166
+US20080269189
+US20080269211
+US20080269271
+US20080275018
+US20080280901
+US20080280920
+US20080311184
+US20080311231
+US20080312325
+US20080312333
+US20090011978
+US20090022737
+US20090028824
+US20090041742
+US20090068138
+US20090069305
+US20090069362
+US20090069375
+US20090069376
+US20090082283
+US20090082314
+US20090082324
+US20090082367
+US20090082379
+US20090082405
+US20090088412
+US20090099102
+US20090099124
+US20090099140
+US20090099197
+US20090104230
+US20090104297
+US20090105317
+US20090118685
+US20090136561
+US20090136565
+US20090136573
+US20090148531
+US20090181958
+US20090181975
+US20090186829
+US20090202660
+US20090214465
+US20090214529
+US20090220495
+US20090221625
+US20090221629
+US20090221703
+US20090238879
+US20090239929
+US20090258879
+US20090258882
+US20090270507
+US20090270881
+US20090275525
+US20090275570
+US20090275604
+US20090281169
+US20090305991
+US20100003289
+US20100055067
+US20100055069
+US20100055108
+US20100056475
+US20100056506
+US20100087502
+US20100099649
+US20100104533
+US20100104552
+US20100108059
+US20100120806
+US20100120887
+US20100152121
+US20100152189
+US20100152294
+US20100159030
+US20100166707
+US20100166882
+US20100173967
+US20100184650
+US20100184717
+US20100184765
+US20100210720
+US20100210732
+US20100215635
+US20100215646
+US20100215780
+US20100239641
+US20100239689
+US20100249091
+US20100249093
+US20100256119
+US20100256157
+US20100286143
+US20100286163
+US20100286188
+US20100311595
+US20100311678
+US20100317603
+US20100317651
+US20100317709
+US20100317717
+US20100317727
+US20100317731
+US20110003013
+US20110008328
+US20110009376
+US20110009380
+US20110009381
+US20110009388
+US20110009396
+US20110014197
+US20110014227
+US20110021355
+US20110046076
+US20110052536
+US20110059907
+US20110059918
+US20110059923
+US20110059934
+US20110059940
+US20110065805
+US20110070315
+US20110071115
+US20110071172
+US20110071199
+US20110077283
+US20110091440
+US20110091557
+US20110091560
+US20110104103
+US20110104173
+US20110105470
+US20110105540
+US20110111031
+US20110112047
+US20110112187
+US20110118239
+US20110118255
+US20110118284
+US20110118289
+US20110124612
+US20110124662
+US20110129422
+US20110129437
+US20110129476
+US20110130421
+US20110130444
+US20110160290
+US20110160302
+US20110172286
+US20110172291
+US20110177110
+US20110178470
+US20110189114
+US20110189127
+US20110244032
+US20110245340
+US20110251210
+US20110251243
+US20110256161
+US20110305775
+US20110311461
+US20110311651
+US20110311652
+US20120004167
+US20120004241
+US20120004242
+US20120004276
+US20120010156
+US20120010178
+US20120022001
+US20120022093
+US20120022104
+US20120022110
+US20120022114
+US20120035254
+US20120035256
+US20120041007
+US20120041012
+US20120041071
+US20120053138
+US20120053194
+US20120053200
+US20120058155
+US20120095029
+US20120095060
+US20120095062
+US20120101122
+US20120101131
+US20120101136
+US20120101142
+US20120107303
+US20120107308
+US20120107410
+US20120107417
+US20120108664
+US20120114636
+US20120115851
+US20120115877
+US20120115885
+US20120115896
+US20120121706
+US20120122981
+US20120134991
+US20120136019
+US20120136033
+US20120136048
+US20120156221
+US20120156288
+US20120156312
+US20120195970
+US20120202763
+US20120202791
+US20120202819
+US20120202847
+US20120207846
+US20120207853
+US20120213697
+US20120213713
+US20120214824
+US20120214829
+US20120214860
+US20120214863
+US20120214877
+US20120220610
+US20120225402
+US20120237565
+US20120237568
+US20120263716
+US20120270917
+US20120294940
+US20120308508
+US20120308622
+US20120308642
+US20120309750
+US20120309834
+US20120322776
+US20120328717
+US20130004512
+US20130022651
+US20130022670
+US20130028863
+US20130035754
+US20130052271
+US20130059917
+US20130064794
+US20130065842
+US20130089586
+US20130116219
+US20130158064
+US20130190403
+US20130224281
+US20140141089
+US20140199394
+US6844429
+US6849286
+US6863647
+US6866857
+US6884796
+US6894177
+US6924305
+US6929811
+US6930100
+US6960608
+US6962712
+US6984653
+US6984660
+US7037907
+US7048946
+US7053093
+US7053101
+US7053245
+US7071212
+US7074807
+US7074833
+US7074961
+US7132248
+US7138531
+US7163704
+US7169809
+US7169811
+US7173024
+US7198489
+US7229986
+US7241618
+US7247716
+US7273886
+US7371762
+US7371813
+US7429595
+US7429599
+US7431939
+US7442693
+US7442699
+US7459481
+US7544519
+US7550475
+US7563780
+US7563808
+US7579365
+US7579366
+US7579479
+US7598293
+US7598294
+US7628988
+US7638143
+US7648959
+US7678791
+US7700581
+US7713939
+US7718665
+US7718797
+US7759116
+US7767693
+US7772212
+US7794929
+US7799830
+US7812034
+US7875632
+US7902186
+US7910594
+US7943639
+US7960525
+US8012504
+US8030326
+US8044056
+US8071631
+US8092608
+US8252804
+US8288353
+US8324240
+US8349832
+US8404805
+US8409610
+US8440654
+US8492352
+US8530447
+US8535899
+US8541425
+US8546342
+US8632750
+US8637577
+US8835474
+USRE42164
+WO2001082928A9
+WO2004018482A8
+WO2004112837A8
+WO2005025583A2
+WO2005034956A1
+WO2005047250A1
+WO2005061454A1
+WO2005063230A1
+WO2005067918A1
+WO2005082388A1
+WO2005084709A1
+WO2005089426A3
+WO2005089780A1
+WO2005094805A1
+WO2006000923A3
+WO2006007227A2
+WO2006021657A1
+WO2006032432A3
+WO2006035142A1
+WO2006043532A1
+WO2006050006A3
+WO2006057460A1
+WO2006060535A2
+WO2006065916A1
+WO2006071601A2
+WO2006078925A3
+WO2006081986A1
+WO2006084758A1
+WO2006085562A1
+WO2006086923A1
+WO2006086978A3
+WO2006089689A1
+WO2006090756A1
+WO2006100082A3
+WO2006110119A1
+WO2006112456A1
+WO2006114709A1
+WO2006120573A3
+WO2006121968A3
+WO2006122800A1
+WO2006127503A3
+WO2006129163A1
+WO2006134489A1
+WO2006136823A1
+WO2006137092A1
+WO2007004425A1
+WO2007008045A1
+WO2007010514A3
+WO2007013522A1
+WO2007016476A3
+WO2007018622A3
+WO2007026218A2
+WO2007026240A1
+WO2007038284A1
+WO2007043581A1
+WO2007044698A1
+WO2007048351A1
+WO2007054283A3
+WO2007054296A1
+WO2007059257A8
+WO2007072178A1
+WO2007073687A1
+WO2007079515A1
+WO2007085718A1
+WO2007094605A1
+WO2007101005A3
+WO2007102451A1
+WO2007104719A1
+WO2007115933A1
+WO2007115966A1
+WO2007121883A2
+WO2007128454A1
+WO2007132280A1
+WO2007132807A1
+WO2007139499A1
+WO2007149935A2
+WO2008009077A3
+WO2008009078A2
+WO2008023003A1
+WO2008023446A1
+WO2008026046A1
+WO2008029882A1
+WO2008030584A3
+WO2008038305A3
+WO2008040967A1
+WO2008042240A9
+WO2008050871A1
+WO2008064595A1
+WO2008070609A1
+WO2008082562A3
+WO2008090209A2
+WO2008093763A1
+WO2008095275A1
+WO2008095835A1
+WO2008100422A1
+WO2008104386A2
+WO2008115259A3
+WO2008118164A1
+WO2008120003A1
+WO2008120214A3
+WO2008124927A1
+WO2008129255A1
+WO2008132950A1
+WO2008137446A1
+WO2008142513A2
+WO2008143637A2
+WO2008144223A3
+WO2008149163A3
+WO2008156102A1
+WO2008157191A2
+WO2009005838A3
+WO2009026657A1
+WO2009027736A2
+WO2009028387A1
+WO2009034346A3
+WO2009050506A2
+WO2009070328A1
+WO2009073460A2
+WO2009076512A1
+WO2009077857A3
+WO2009079921A1
+WO2009080778A4
+WO2009088518A1
+WO2009097999A1
+WO2009109071A1
+WO2009112954A3
+WO2009120717A3
+WO2009120826A1
+WO2009126584A1
+WO2009131201A1
+WO2009133387A1
+WO2009142587A1
+WO2009143578A1
+WO2009145357A8
+WO2009146910A8
+WO2009147476A1
+WO2009151910A3
+WO2009152083A1
+WO2010000008A1
+WO2010005520A3
+WO2010011653A1
+WO2010018836A2
+WO2010022725A1
+WO2010023346A1
+WO2010024911A1
+WO2010028116A1
+WO2010032041A3
+WO2010042633A2
+WO2010044686A1
+WO2010045190A1
+WO2010061903A1
+WO2010064047A1
+WO2010069605A3
+WO2010070365A1
+WO2010071885A1
+WO2010082072A1
+WO2010083570A1
+WO2010085352A2
+WO2010093341A1
+WO2010093736A1
+WO2010100650A3
+WO2010102393A1
+WO2010106106A1
+WO2010110689A1
+WO2010112093A1
+WO2010113183A3
+WO2010116926A1
+WO2010117346A3
+WO2010119741A1
+WO2010119875A1
+WO2010123507A1
+WO2010130638A1
+WO2010131718A1
+WO2010138833A1
+WO2010144043A1
+WO2010145207A1
+WO2010151073A2
+WO2011011965A1
+WO2011019348A1
+WO2011024987A1
+WO2011032100A1
+WO2011039367A3
+WO2011041914A1
+WO2011048612A3
+WO2011054947A1
+WO2011057327A1
+WO2011061760A1
+WO2011064559A2
+WO2011075267A1
+WO2011078823A1
+WO2011085544A1
+WO2011095837A1
+WO2011103718A1
+WO2011106599A1
+WO2011119649A3
+WO2011123524A3
+WO2011123691A1
+WO2011123751A3
+WO2011128745A2
+WO2011131975A1
+WO2011143932A1
+WO2011147951A8
+WO2011149841A1
+WO2011151551A1
+WO2011151782A1
+WO2011152751A1
+WO2011156646A3
+WO2012006946A1
+WO2012006958A1
+WO2012008564A1
+WO2012011063A1
+WO2012011129A3
+WO2012026614A1
+WO2012036523A2
+WO2012042951A1
+WO2012047156A1
+WO2012049647A1
+WO2012050465A1
+WO2012064222A1
+WO2012068081A1
+WO2012068535A1
+WO2012080186A1
+WO2012093859A2
+WO2012094313A1
+WO2012100109A2
+WO2012100408A1
+WO2012102555A3
+WO2012104402A1
+WO2012104788A3
+WO2012107532A1
+WO2012111997A2
+WO2012125413A2
+WO2012126231A1
+WO2012128582A3
+WO2012131090A1
+WO2012133489A1
+WO2012134184A2
+WO2012134828A1
+WO2012137227A3
+WO2012143624A2
+WO2012151420A1
+WO2012157587A1
+WO2012158399A1
+WO2012160130A1
+WO2012162536A2
+WO2012166614A2
+WO2012176105A1
+WO2013002439A1
+WO2013005041A1
+WO2013012681A1
+WO2013013308A1
+WO2013019079A3
+WO2013019938A1
+WO2013024427A1
+WO2013025607A1
+WO2013033626A2
+WO2013034098A1
+WO2013036286A2
+WO2013041468A1
+WO2013042139A1
+WO2013044044A2
+WO2013054998A1
+WO2013067769A1
+WO2013068621A1
+WO2013076646A1
+WO2013094676A1
+WO2013096878A1
+WO2013101810A1
+WO2013102234A1
+WO2013107206A1
+WO2013109199A1
+WO2013116753A1
+WO2013147618A1
+WO2013147711A1
+WO2013160222A1
+WO2013161312A1
+WO2013166366A1
+WO2013172339A1
+WO2013173599A1
+WO2013175344A3
+WO2013185635A1
+WO2013187612A1
+WO2013188813A3
+WO2013192367A1
+WO2014000077A1
+WO2014004951A1
+WO2014015830A1
+WO2014016267A1
+WO2014018449A1
+WO2014019468A1
+WO2014022143A1
+WO2014023390A2
+WO2014027017A1
+WO2014033262A1
+WO2014033490A1
+WO2014033560A1
+WO2014036022A1
+WO2014037412A1
+WO2014041708A1
+WO2014048564A8
+WO2014048888A1
+WO2014054980A1
+WO2014056446A1
+WO2014056566A1
+WO2014060375A3
+WO2014060548A1
+WO2014063068A1
+WO2014072220A1
+WO2014078942A1
+WO2014078968A1
+WO2014084401A1
+WO2014085489A1
+WO2014092154A1
+WO2014098092A1
+WO2014108337A1
+WO2014124757A1
+WO2014130894A1
+WO2014140078A1
+WO2014142290A1
+WO2014142780A1
+WO2014143669A1
+WO2014147203A1
+WO2014148216A1
+WO2014157047A1
+WO2014163031A1
diff --git a/huner/ner_scripts/splits/cemp.test b/huner/ner_scripts/splits/cemp.test
new file mode 100644
index 0000000..bab8859
--- /dev/null
+++ b/huner/ner_scripts/splits/cemp.test
@@ -0,0 +1,4201 @@
+
+CA2054762C
+CA2077637C
+CA2092271C
+CA2098849C
+CA2102780C
+CA2106642C
+CA2106819C
+CA2120743C
+CA2142445C
+CA2143752C
+CA2151377C
+CA2163175C
+CA2168921C
+CA2171614C
+CA2173116C
+CA2173876C
+CA2176392C
+CA2176796C
+CA2179955C
+CA2183620C
+CA2188267C
+CA2189221C
+CA2190778C
+CA2191815C
+CA2195370C
+CA2195663C
+CA2201477C
+CA2203885C
+CA2212200C
+CA2213567C
+CA2218553C
+CA2220777C
+CA2224369C
+CA2228060C
+CA2230960C
+CA2232880C
+CA2244512C
+CA2255521C
+CA2257121C
+CA2257579C
+CA2270177C
+CA2270893C
+CA2275686C
+CA2276694C
+CA2282254C
+CA2283464C
+CA2284863C
+CA2288726C
+CA2288983C
+CA2291391C
+CA2291796C
+CA2293714C
+CA2294086C
+CA2299423C
+CA2306214C
+CA2307792C
+CA2308315C
+CA2310659C
+CA2318184C
+CA2320288C
+CA2320430C
+CA2326137C
+CA2330128C
+CA2331471C
+CA2333442C
+CA2346631C
+CA2347117C
+CA2347387C
+CA2347950C
+CA2347981C
+CA2350396C
+CA2350713C
+CA2359708C
+CA2366186C
+CA2373183C
+CA2373634C
+CA2375671C
+CA2379003C
+CA2390563C
+CA2391297C
+CA2406206C
+CA2414241C
+CA2419877C
+CA2421548C
+CA2425556C
+CA2426625C
+CA2441225C
+CA2444244C
+CA2444821C
+CA2448607C
+CA2454699C
+CA2467930C
+CA2516364A1
+CA2525524C
+CA2537747A1
+CA2538729A1
+CA2546853A1
+CA2552694A1
+CA2554386A1
+CA2558043A1
+CA2563793A1
+CA2576022A1
+CA2577676A1
+CA2582949A1
+CA2586384A1
+CA2587247A1
+CA2588990A1
+CA2590334A1
+CA2604392A1
+CA2612595A1
+CA2615127A1
+CA2616222C
+CA2623733A1
+CA2624584A1
+CA2652501C
+CA2659222C
+CA2662732A1
+CA2670440A1
+CA2672190C
+CA2675980A1
+CA2677854A1
+CA2680502A1
+CA2685270C
+CA2687751A1
+CA2691425A1
+CA2700263A1
+CA2723564A1
+CA2725953A1
+CA2730008A1
+CA2742281A1
+CA2746054A1
+CA2761068A1
+CA2764885A1
+CA2777304A1
+CA2780274A1
+CA2782314A1
+CA2796068A1
+CA2797350A1
+CA2799881A1
+CA2816054A1
+CA2834341A1
+CA2835015A1
+CA2852114A1
+CA2853373A1
+CA2853872A1
+CA2856102A1
+CA2856501A1
+CA2856984A1
+CA2857096A1
+CN100579530C
+CN100581544C
+CN100581558C
+CN100582235C
+CN100594024C
+CN100594898C
+CN100998584A
+CN100998603A
+CN101002757A
+CN101002760A
+CN101002768A
+CN101002774A
+CN101002790B
+CN101002897A
+CN101003513A
+CN101006986A
+CN101007018A
+CN101007030A
+CN101007046A
+CN101011084A
+CN101011374A
+CN101011376A
+CN101011439A
+CN101011511A
+CN101015559A
+CN101016265A
+CN101018793A
+CN101019863A
+CN101019888A
+CN101028256A
+CN101028276A
+CN101028510B
+CN101032490A
+CN101032499A
+CN101036678A
+CN101037391A
+CN101039902B
+CN101039914A
+CN101041646B
+CN101045041A
+CN101045060A
+CN101045708A
+CN101049362A
+CN101050179A
+CN101050216B
+CN101054403A
+CN101057899A
+CN101058610A
+CN101060830A
+CN101062118A
+CN101062936A
+CN101062937A
+CN101065375A
+CN101067134A
+CN101069680B
+CN101069695A
+CN101073649A
+CN101073667A
+CN101074227B
+CN101074259A
+CN101076520B
+CN101077341A
+CN101077354A
+CN101081204A
+CN101081208A
+CN101081211A
+CN101084892A
+CN101084906A
+CN101085104A
+CN101085216A
+CN101085354A
+CN101085370A
+CN101091700B
+CN101091705B
+CN101095658A
+CN101095868A
+CN101098867B
+CN101100453A
+CN101103969A
+CN101103992A
+CN101108169A
+CN101112363A
+CN101112364A
+CN101112366A
+CN101116656A
+CN101125855A
+CN101129373A
+CN101129398B
+CN101129858A
+CN101134029A
+CN101134037A
+CN101134769A
+CN101143146A
+CN101143160A
+CN101143165B
+CN101143885A
+CN101147587A
+CN101147732B
+CN101147736A
+CN101164545A
+CN101167777B
+CN101167871B
+CN101185732A
+CN101185758A
+CN101186921A
+CN101190196A
+CN101190914B
+CN101198610B
+CN101199510B
+CN101199514A
+CN101199515B
+CN101199523B
+CN101199526A
+CN101199531A
+CN101199536A
+CN101199544A
+CN101199610A
+CN101199624B
+CN101200446A
+CN101209264B
+CN101210018A
+CN101214218A
+CN101214220A
+CN101214233A
+CN101214247A
+CN101219100A
+CN101219110A
+CN101219113A
+CN101219144A
+CN101222850B
+CN101229294A
+CN101234180A
+CN101235030A
+CN101239038A
+CN101239950B
+CN101244164A
+CN101244253A
+CN101244278A
+CN101245092A
+CN101249062A
+CN101249063A
+CN101249106A
+CN101249161A
+CN101250134B
+CN101252923B
+CN101254172A
+CN101254198A
+CN101255199A
+CN101258156A
+CN101259082A
+CN101259133A
+CN101259214B
+CN101259222B
+CN101260075B
+CN101264063A
+CN101265237A
+CN101268075A
+CN101269006A
+CN101269075A
+CN101269164A
+CN101270163B
+CN101273013A
+CN101273994A
+CN101278902A
+CN101278912A
+CN101278933A
+CN101279979B
+CN101279980B
+CN101283996B
+CN101284071A
+CN101289459A
+CN101289653A
+CN101292952A
+CN101292958A
+CN101292961A
+CN101292974B
+CN101293032A
+CN101293039B
+CN101297869A
+CN101300229A
+CN101301274B
+CN101301278A
+CN101301296A
+CN101301471A
+CN101311171A
+CN101313897A
+CN101313899B
+CN101316839B
+CN101317619A
+CN101317852A
+CN101317899A
+CN101317918A
+CN101318946A
+CN101322747A
+CN101323600A
+CN101326191B
+CN101327212A
+CN101327287A
+CN101328226A
+CN101332203A
+CN101332208A
+CN101332303B
+CN101336897A
+CN101336900A
+CN101336911A
+CN101336916A
+CN101337891B
+CN101342147A
+CN101342174A
+CN101342187B
+CN101347407A
+CN101347446A
+CN101347454A
+CN101348509A
+CN101348514A
+CN101352504B
+CN101356168A
+CN101357165B
+CN101357888B
+CN101361752A
+CN101361951B
+CN101361959B
+CN101362718A
+CN101366722A
+CN101367806B
+CN101367817B
+CN101367822A
+CN101371825A
+CN101371852A
+CN101371857A
+CN101378757B
+CN101380313A
+CN101380320B
+CN101380325A
+CN101380341B
+CN101385707A
+CN101385741A
+CN101385857A
+CN101400353A
+CN101401786B
+CN101401791A
+CN101401794A
+CN101401874A
+CN101402632A
+CN101406457A
+CN101406464A
+CN101406573A
+CN101406637A
+CN101407516A
+CN101411704A
+CN101411719A
+CN101411845B
+CN101416964B
+CN101416984A
+CN101417974A
+CN101418000A
+CN101428000A
+CN101428005A
+CN101428010A
+CN101433544B
+CN101434600A
+CN101439026A
+CN101439032A
+CN101440119A
+CN101445528B
+CN101445541B
+CN101450041B
+CN101461624B
+CN101461800B
+CN101474171B
+CN101474375B
+CN101474412B
+CN101479238A
+CN101480453B
+CN101491529B
+CN101492426B
+CN101492464B
+CN101500562B
+CN101502593A
+CN101502668A
+CN101503437B
+CN101511801A
+CN101513394A
+CN101513399B
+CN101513468A
+CN101513471A
+CN101519375A
+CN101524504A
+CN101525342A
+CN101528229B
+CN101530399B
+CN101530416A
+CN101530426A
+CN101536990A
+CN101536993A
+CN101536997B
+CN101537170A
+CN101537184A
+CN101538191A
+CN101543473A
+CN101543475A
+CN101543501A
+CN101543504A
+CN101543511A
+CN101543600A
+CN101548990B
+CN101550115B
+CN101550139A
+CN101555210A
+CN101555266A
+CN101559050A
+CN101559056A
+CN101559057A
+CN101559063A
+CN101559097A
+CN101564388A
+CN101564396A
+CN101574338A
+CN101574351A
+CN101579308A
+CN101579333A
+CN101579351A
+CN101584662A
+CN101584667A
+CN101584672A
+CN101584741B
+CN101584761B
+CN101590018A
+CN101590025A
+CN101590041A
+CN101590053A
+CN101590078A
+CN101590154A
+CN101591364B
+CN101596236A
+CN101597218A
+CN101601846A
+CN101602707B
+CN101606945A
+CN101606955A
+CN101610764B
+CN101613382B
+CN101628091B
+CN101637444B
+CN101647781B
+CN101647934B
+CN101653421A
+CN101653439B
+CN101653449B
+CN101653452B
+CN101658530B
+CN101658537B
+CN101664493B
+CN101669946A
+CN101669959A
+CN101669962A
+CN101676290A
+CN101684098A
+CN101686985A
+CN101687855A
+CN101693730B
+CN101695497A
+CN101695502A
+CN101696202B
+CN101698016B
+CN101703500A
+CN101703506B
+CN101703569A
+CN101703673A
+CN101708160A
+CN101708186A
+CN101708339A
+CN101712670A
+CN101716214B
+CN101721394A
+CN101721403A
+CN101721405A
+CN101721423B
+CN101721435A
+CN101723903A
+CN101724037A
+CN101724048A
+CN101732301A
+CN101732305B
+CN101732477A
+CN101732597A
+CN101732610B
+CN101732695A
+CN101744769B
+CN101744794A
+CN101757009A
+CN101757077A
+CN101757103A
+CN101757604A
+CN101757624A
+CN101766604A
+CN101766605A
+CN101766606A
+CN101766621A
+CN101766689A
+CN101766821A
+CN101768130A
+CN101768155A
+CN101773489A
+CN101773596A
+CN101780224A
+CN101792788A
+CN101801372A
+CN101804059A
+CN101804067A
+CN101804093A
+CN101810570A
+CN101810571A
+CN101810577B
+CN101810588A
+CN101810599A
+CN101810601A
+CN101810729A
+CN101810850A
+CN101816638A
+CN101816644A
+CN101816660A
+CN101816678A
+CN101817742A
+CN101817833A
+CN101817834A
+CN101822651A
+CN101829127A
+CN101829131A
+CN101829139A
+CN101829200A
+CN101830945A
+CN101831478A
+CN101836960A
+CN101836962A
+CN101837004A
+CN101837010A
+CN101843603A
+CN101843823A
+CN101849928A
+CN101849934A
+CN101850031A
+CN101851250A
+CN101862299A
+CN101862309A
+CN101862628A
+CN101863887B
+CN101863953A
+CN101864367B
+CN101868156A
+CN101869571A
+CN101869578A
+CN101869699A
+CN101874789A
+CN101874797A
+CN101879143A
+CN101879162A
+CN101879173A
+CN101890023A
+CN101890030A
+CN101890035B
+CN101890039A
+CN101892237B
+CN101897699A
+CN101897792A
+CN101898985A
+CN101903348A
+CN101904819A
+CN101912431A
+CN101917995A
+CN101918378A
+CN101919831B
+CN101919832A
+CN101919901B
+CN101920015A
+CN101921238A
+CN101926755A
+CN101926843A
+CN101926927A
+CN101933931A
+CN101940557A
+CN101940560A
+CN101940796A
+CN101947207A
+CN101947214A
+CN101947231A
+CN101947234A
+CN101947267B
+CN101948381A
+CN101948430A
+CN101953856A
+CN101961336A
+CN101961344A
+CN101966184A
+CN101967127A
+CN101967169A
+CN101972226A
+CN101974016A
+CN101977597A
+CN101979025A
+CN101983631A
+CN101985039A
+CN101987166B
+CN101987178A
+CN101991535A
+CN102000070A
+CN102000079B
+CN102008440A
+CN102008462B
+CN102008612A
+CN102008695B
+CN102018677A
+CN102018807A
+CN102020609A
+CN102020623B
+CN102028654A
+CN102028702A
+CN102030809A
+CN102038672A
+CN102038692A
+CN102038808A
+CN102038957B
+CN102048706A
+CN102049051A
+CN102058516B
+CN102058523A
+CN102058556A
+CN102058608A
+CN102066317A
+CN102068442A
+CN102070565A
+CN102078299B
+CN102078319A
+CN102078325A
+CN102079769A
+CN102085187B
+CN102085370A
+CN102091062A
+CN102091067A
+CN102091070A
+CN102091084A
+CN102091273A
+CN102091310A
+CN102100660A
+CN102100665B
+CN102101867A
+CN102106815A
+CN102106936B
+CN102114005A
+CN102114013A
+CN102114016A
+CN102119974B
+CN102125522A
+CN102125571A
+CN102125587A
+CN102127062A
+CN102133210A
+CN102138892A
+CN102138930A
+CN102143761A
+CN102144967B
+CN102144988A
+CN102144991A
+CN102145077A
+CN102145172B
+CN102151245B
+CN102151298A
+CN102161710A
+CN102164887A
+CN102178647A
+CN102178676A
+CN102178894A
+CN102180866A
+CN102186829A
+CN102188373A
+CN102188382A
+CN102188432A
+CN102188692A
+CN102204899A
+CN102204900A
+CN102204915B
+CN102204921A
+CN102206180A
+CN102210669A
+CN102210698A
+CN102229546A
+CN102229558A
+CN102229580A
+CN102232920A
+CN102234250A
+CN102234267A
+CN102234284A
+CN102240283A
+CN102247321A
+CN102247345A
+CN102247347A
+CN102276605B
+CN102302452A
+CN102302468A
+CN102302479A
+CN102302481A
+CN102302482A
+CN102302484A
+CN102304103A
+CN102304104A
+CN102304132A
+CN102311382A
+CN102319221A
+CN102319234A
+CN102321025A
+CN102327235A
+CN102335165A
+CN102335170A
+CN102335179A
+CN102335206A
+CN102335412A
+CN102335462A
+CN102336768A
+CN102349922A
+CN102351934A
+CN102356874A
+CN102357143A
+CN102362868A
+CN102362870A
+CN102362880A
+CN102366560A
+CN102370613A
+CN102379844A
+CN102379878A
+CN102380083A
+CN102382014A
+CN102382036A
+CN102382144A
+CN102391137A
+CN102391263A
+CN102406652A
+CN102423466A
+CN102429911A
+CN102429914A
+CN102440962A
+CN102440969A
+CN102440975A
+CN102440976A
+CN102440982A
+CN102451272A
+CN102451460A
+CN102459588A
+CN102475701A
+CN102488651A
+CN102488658A
+CN102488664A
+CN102488666A
+CN102488678A
+CN102503922A
+CN102512403A
+CN102512443A
+CN102512462A
+CN102512696A
+CN102516213A
+CN102516263A
+CN102525722A
+CN102525957A
+CN102526042A
+CN102526098A
+CN102532099A
+CN102552137A
+CN102552224A
+CN102552226A
+CN102552230A
+CN102552231A
+CN102552250A
+CN102552714A
+CN102579320A
+CN102579325A
+CN102579334A
+CN102579403A
+CN102579462A
+CN102579472A
+CN102579931A
+CN102584683A
+CN102600110A
+CN102600268A
+CN102600288A
+CN102600441A
+CN102603683A
+CN102603753A
+CN102614161A
+CN102614182A
+CN102617437A
+CN102617613A
+CN102617664A
+CN102617672A
+CN102626382A
+CN102626397A
+CN102626399A
+CN102626414A
+CN102631315A
+CN102631340A
+CN102631341A
+CN102633899A
+CN102641280A
+CN102641507A
+CN102643186A
+CN102648909A
+CN102648922A
+CN102649750A
+CN102649773A
+CN102652792A
+CN102653522A
+CN102656179A
+CN102657620A
+CN102657653A
+CN102657654A
+CN102670575A
+CN102670604A
+CN102670625A
+CN102675252A
+CN102688220A
+CN102688225A
+CN102695520A
+CN102697783A
+CN102697795A
+CN102698285A
+CN102698294A
+CN102702033A
+CN102702070A
+CN102702092A
+CN102702582A
+CN102703327A
+CN102712622A
+CN102716098A
+CN102716167A
+CN102716486A
+CN102718693A
+CN102727422A
+CN102727426A
+CN102727459A
+CN102727481A
+CN102727484A
+CN102727811A
+CN102727868A
+CN102731301A
+CN102731365A
+CN102731493A
+CN102731561A
+CN102743335A
+CN102743336A
+CN102743403A
+CN102755295A
+CN102755297A
+CN102757460A
+CN102766109A
+CN102772371A
+CN102772398A
+CN102772733A
+CN102772800A
+CN102784098A
+CN102784108A
+CN102784122A
+CN102784126A
+CN102793729A
+CN102796040A
+CN102796080A
+CN102796100A
+CN102796109A
+CN102796235A
+CN102803263A
+CN102805770A
+CN102807566A
+CN102824337A
+CN102824386A
+CN102824395A
+CN102824630A
+CN102834096A
+CN102836125A
+CN102836140A
+CN102836147A
+CN102846538A
+CN102846540A
+CN102846560A
+CN102846762A
+CN102847175A
+CN102851295A
+CN102861080A
+CN102861096A
+CN102872065A
+CN102872067A
+CN102872106A
+CN102872118A
+CN102872119A
+CN102875564A
+CN102885763A
+CN102885781A
+CN102887904A
+CN102895217A
+CN102895393A
+CN102895494A
+CN102895502A
+CN102895503A
+CN102895509A
+CN102895636A
+CN102898463A
+CN102907671A
+CN102908359A
+CN102911158A
+CN102911180A
+CN102911182A
+CN102920237A
+CN102920651A
+CN102920726A
+CN102920987A
+CN102924322A
+CN102940625A
+CN102940767A
+CN102942551A
+CN102946877A
+CN102947272A
+CN102949366A
+CN102949390A
+CN102973552A
+CN102973572A
+CN102973576A
+CN102973586A
+CN102977101A
+CN102988279A
+CN102988287A
+CN102988293A
+CN102988444A
+CN102992997A
+CN102993095A
+CN103006599A
+CN103006700A
+CN103006718A
+CN103006800A
+CN103007270A
+CN103012397A
+CN103012398A
+CN103027922A
+CN103040743A
+CN103040776A
+CN103040778A
+CN103040779A
+CN103040801A
+CN103040903A
+CN103040917A
+CN103044364A
+CN103044392A
+CN103044439A
+CN103045674A
+CN103054815A
+CN103054817A
+CN103054828A
+CN103054832A
+CN103054841A
+CN103055013A
+CN103058999A
+CN103070918A
+CN103073542A
+CN103083337A
+CN103083389A
+CN103086943A
+CN103086987A
+CN103087021A
+CN103096887A
+CN103099801A
+CN103099814A
+CN103110526A
+CN103110600A
+CN103110603A
+CN103110604A
+CN103110614A
+CN103110623A
+CN103110643A
+CN103110645A
+CN103113295A
+CN103120624A
+CN103126980A
+CN103126984A
+CN103127041A
+CN103127053A
+CN103127062A
+CN103127121A
+CN103127127A
+CN103127149A
+CN103127158A
+CN103127393A
+CN103127525A
+CN103127543A
+CN103130788A
+CN103130795A
+CN103130828A
+CN103142503A
+CN103142512A
+CN103142534A
+CN103142545A
+CN103142547A
+CN103142567A
+CN103142638A
+CN103142641A
+CN103142645A
+CN103142785A
+CN103143019A
+CN103145631A
+CN103145694A
+CN103156817A
+CN103156822A
+CN103156831A
+CN103156835A
+CN103159665A
+CN103159666A
+CN103169661A
+CN103172587A
+CN103172819A
+CN103180322A
+CN103181901A
+CN103181922A
+CN103181943A
+CN103181955A
+CN103182055A
+CN103183709A
+CN103183719A
+CN103189361A
+CN103191049A
+CN103191058A
+CN103191273A
+CN103191284A
+CN103193781A
+CN103202850A
+CN103202858A
+CN103202875A
+CN103211889A
+CN103211972A
+CN103212009A
+CN103214467A
+CN103214489A
+CN103214497A
+CN103222955A
+CN103222982A
+CN103224530A
+CN103228284A
+CN103230365A
+CN103230595A
+CN103239414A
+CN103239666A
+CN103242214A
+CN103242278A
+CN103251569A
+CN103251633A
+CN103254203A
+CN103261189A
+CN103261192A
+CN103263525A
+CN103265538A
+CN103271873A
+CN103271879A
+CN103271923A
+CN103271933A
+CN103271937A
+CN103272042A
+CN103275115A
+CN103284979A
+CN103284983A
+CN103284993A
+CN103285133A
+CN103288800A
+CN103301060A
+CN103301065A
+CN103301069A
+CN103301134A
+CN103301135A
+CN103304609A
+CN103315948A
+CN103315958A
+CN103316003A
+CN103316007A
+CN103316011A
+CN103316018A
+CN103316025A
+CN103316030A
+CN103316343A
+CN103316348A
+CN103319371A
+CN103319496A
+CN103330946A
+CN103333148A
+CN103333163A
+CN103339132A
+CN103349751A
+CN103351285A
+CN103356479A
+CN103356543A
+CN103356547A
+CN103356579A
+CN103356591A
+CN103356592A
+CN103356678A
+CN103356770A
+CN103360294A
+CN103360400A
+CN103360423A
+CN103372002A
+CN103373957A
+CN103374079A
+CN103381143A
+CN103381148A
+CN103381162A
+CN103381167A
+CN103381183A
+CN103381184A
+CN103381194A
+CN103381196A
+CN103384659A
+CN103385850A
+CN103385863A
+CN103385865A
+CN103386036A
+CN103393604A
+CN103393633A
+CN103393658A
+CN103393673A
+CN103393731A
+CN103393751A
+CN103393947A
+CN103396436A
+CN103396557A
+CN103403014A
+CN103404514A
+CN103405418A
+CN103405424A
+CN103405426A
+CN103405571A
+CN103405782A
+CN103408400A
+CN103417470A
+CN103417504A
+CN103417538A
+CN103417764A
+CN103417888A
+CN103429572A
+CN103432083A
+CN103432155A
+CN103432177A
+CN103432181A
+CN103446065A
+CN103446071A
+CN103446079A
+CN103446081A
+CN103446083A
+CN103446094A
+CN103446101A
+CN103446179A
+CN103446468A
+CN103450062A
+CN103450162A
+CN103450173A
+CN103462930A
+CN103463009A
+CN103463012A
+CN103463022A
+CN103463106A
+CN103463112A
+CN103463122A
+CN103463148A
+CN103463154A
+CN103463487A
+CN103467550A
+CN103479568A
+CN103479611A
+CN103479987A
+CN103483187A
+CN103483315A
+CN103494875A
+CN103495174A
+CN103497204A
+CN103505423A
+CN103505430A
+CN103509868A
+CN103520010A
+CN103520086A
+CN103520099A
+CN103520183A
+CN103524533A
+CN103534248A
+CN103536890A
+CN103536925A
+CN103550162A
+CN103550166A
+CN103550182A
+CN103550191A
+CN103550194A
+CN103550233A
+CN103550444A
+CN103554187A
+CN103565750A
+CN103565758A
+CN103565759A
+CN103565787A
+CN103566331A
+CN103570709A
+CN103570720A
+CN103585160A
+CN103585164A
+CN103585196A
+CN103585200A
+CN103585439A
+CN103588673A
+CN103599080A
+CN103601719A
+CN103622973A
+CN103623080A
+CN103623331A
+CN103623421A
+CN103623780A
+CN103626694A
+CN103626764A
+CN103637982A
+CN103637986A
+CN103637987A
+CN103638010A
+CN103638037A
+CN103638041A
+CN103638383A
+CN103638422A
+CN103641807A
+CN103649053A
+CN103649066A
+CN103652703A
+CN103655207A
+CN103655454A
+CN103655463A
+CN103655465A
+CN103655471A
+CN103655493A
+CN103655532A
+CN103655539A
+CN103655540A
+CN103655568A
+CN103655570A
+CN103655585A
+CN103655587A
+CN103655592A
+CN103656611A
+CN103656670A
+CN103664559A
+CN103664777A
+CN103665004A
+CN103665069A
+CN103690777A
+CN103690956A
+CN103690985A
+CN103694133A
+CN103694408A
+CN103703002A
+CN103705454A
+CN103705516A
+CN103705522A
+CN103705523A
+CN103705533A
+CN103705543A
+CN103705888A
+CN103709015A
+CN103709146A
+CN103709154A
+CN103709223A
+CN103720654A
+CN103720672A
+CN103720684A
+CN103720689A
+CN103721103A
+CN103721259A
+CN103724334A
+CN103724445A
+CN103734823A
+CN103735498A
+CN103735500A
+CN103735503A
+CN103735527A
+CN103735537A
+CN103739579A
+CN103739591A
+CN103750606A
+CN103751103A
+CN103751115A
+CN103751116A
+CN103751123A
+CN103751204A
+CN103751237A
+CN103751730A
+CN103755744A
+CN103755771A
+CN103764146A
+CN1294956C
+CN1559409A
+CN1559417A
+CN1561985A
+CN1561991A
+CN1562028A
+CN1562076A
+CN1563069A
+CN1565422A
+CN1565458A
+CN1575813A
+CN1579445A
+CN1580065A
+CN1582913A
+CN1582922A
+CN1590395A
+CN1592620A
+CN1593389A
+CN1593461B
+CN1611500A
+CN1613451A
+CN1615869A
+CN1628664A
+CN1628666A
+CN1628667A
+CN1628688A
+CN1628689A
+CN1634082A
+CN1660126A
+CN1660129A
+CN1666748A
+CN1679521A
+CN1679528A
+CN1679549A
+CN1679572A
+CN1679576A
+CN1679593A
+CN1679594A
+CN1680424A
+CN1682715A
+CN1683369A
+CN1712399B
+CN1720908A
+CN1723880A
+CN1726919A
+CN1727340A
+CN1729979A
+CN1729990A
+CN1729991A
+CN1733704A
+CN1735607B
+CN1739571A
+CN1739573A
+CN1739574A
+CN1742732A
+CN1742737A
+CN1745754A
+CN1752078A
+CN1759844A
+CN1762369A
+CN1762370A
+CN1762374A
+CN1762378A
+CN1763069A
+CN1771971A
+CN1781922A
+CN1785187A
+CN1788719A
+CN1788727A
+CN1792380A
+CN1795865A
+CN1795866A
+CN1795868A
+CN1795928A
+CN1799553A
+CN1810240A
+CN1810803B
+CN1813713A
+CN1813825A
+CN1813973A
+CN1814144A
+CN1817180A
+CN1820781A
+CN1823788A
+CN1823793A
+CN1823842A
+CN1830434A
+CN1836663A
+CN1839837A
+CN1840052A
+CN1840181A
+CN1846677A
+CN1846678A
+CN1846685A
+CN1846686A
+CN1846687A
+CN1846783A
+CN1850044A
+CN1850063A
+CN1853507A
+CN1853623A
+CN1853626B
+CN1853647A
+CN1856485A
+CN1856709A
+CN1857206A
+CN1857220B
+CN1857222B
+CN1857284A
+CN1857309A
+CN1859919A
+CN1861053A
+CN1861082A
+CN1863812A
+CN1864666A
+CN1868452A
+CN1868455A
+CN1870988A
+CN1872072A
+CN1872206A
+CN1872853A
+CN1875967A
+CN1876130A
+CN1879644A
+CN1879737A
+CN1879863B
+CN1883488A
+CN1883671A
+CN1884305A
+CN1887305A
+CN1887859A
+CN1891211A
+CN1895255A
+CN1895365A
+CN1895598B
+CN1899270A
+CN1900094A
+CN1903181A
+CN1903191A
+CN1911207A
+CN1911217A
+CN1911229A
+CN1911236A
+CN1911953A
+CN1915326A
+CN1915335A
+CN1919183A
+CN1919861A
+CN1923209B
+CN1927171A
+CN1927292A
+CN1931130A
+CN1931154A
+CN1931867A
+CN1939535A
+CN1939540A
+CN1939916B
+CN1939919A
+CN1943573A
+CN1943679A
+CN1947701A
+CN1951360A
+CN1951376B
+CN1951896A
+CN1951923A
+CN1951932B
+CN1954855B
+CN1957949A
+CN1965815A
+CN1965840A
+CN1965844A
+CN1969814A
+CN1969826A
+CN1969836A
+CN1969934A
+CN1977861A
+CN1977975A
+CN1981833B
+CN1982306A
+CN1984660A
+CN1984907A
+CN1986826A
+CN1989952A
+CN1989970A
+CN1989971A
+CN1993349A
+CN1993358A
+CN1994295A
+CN200942144Y
+CN201524271U
+CN201625211U
+CN202263198U
+CN2798942Y
+DE102004008375A1
+DE102004027685A1
+DE102004049015A1
+DE102005019549A1
+DE102005023639A1
+DE102005035917A1
+DE102007002073A1
+DE102007059703A1
+DE102008005498A1
+DE102008027868A1
+DE102008034739A1
+DE102009008851A1
+DE102009024133A1
+DE102009049551A1
+DE102010022587A1
+DE102010051391A1
+DE102010056443A1
+DE102011015567A1
+EP0710288B1
+EP0723398B1
+EP0735888B1
+EP0741783B1
+EP0782630B1
+EP0800397B1
+EP0801562B2
+EP0811075B1
+EP0819121B1
+EP0840599B1
+EP0844877B1
+EP0865446B1
+EP0866654B1
+EP0906106B1
+EP0918515B1
+EP0927043B1
+EP0934310B1
+EP0934412B1
+EP0935462B1
+EP0956040B1
+EP0961612B2
+EP0971587B1
+EP0980240B1
+EP0982990B1
+EP0989863B1
+EP0991625B1
+EP1001755B1
+EP1001946B1
+EP1005485B1
+EP1010423B1
+EP1014967B1
+EP1019033B1
+EP1023435B1
+EP1044009B1
+EP1047422B1
+EP1047436B1
+EP1060163B1
+EP1061923B1
+EP1066041B1
+EP1067908B9
+EP1077674B1
+EP1086105B1
+EP1087946B1
+EP1091745B1
+EP1091924B1
+EP1107813B1
+EP1109553B1
+EP1119248B1
+EP1121355B1
+EP1123392B1
+EP1131090B1
+EP1140930B1
+EP1144609B1
+EP1146873B1
+EP1150982B1
+EP1157002B1
+EP1165073B1
+EP1165099B1
+EP1173421B1
+EP1173427B1
+EP1177790B1
+EP1178977B1
+EP1179984B2
+EP1185306B1
+EP1216228B1
+EP1216241B1
+EP1225814B1
+EP1226177B1
+EP1227797B1
+EP1229917B1
+EP1231894B1
+EP1242587B1
+EP1244445B1
+EP1246810B1
+EP1251818B9
+EP1255733B1
+EP1257281B1
+EP1265616B1
+EP1276485B1
+EP1280515B1
+EP1294717B1
+EP1296703B1
+EP1296974B1
+EP1305311B1
+EP1313853B1
+EP1315695B1
+EP1331927B1
+EP1337220A4
+EP1337523B1
+EP1341544B1
+EP1342723B1
+EP1345942B1
+EP1347760B1
+EP1347986B1
+EP1355646B1
+EP1357936B1
+EP1363509B1
+EP1366021B1
+EP1372656B1
+EP1372680B1
+EP1381614B1
+EP1383731B1
+EP1390075B1
+EP1401408A4
+EP1406616B1
+EP1408986B1
+EP1412338B1
+EP1414802B1
+EP1419154B1
+EP1421198A4
+EP1427732B1
+EP1438045B1
+EP1448215B1
+EP1469809B1
+EP1476470B1
+EP1487427A4
+EP1490350B1
+EP1490360B1
+EP1495000A1
+EP1497247A2
+EP1499204A2
+EP1510211A1
+EP1513834B1
+EP1514877A1
+EP1515941A1
+EP1515971A2
+EP1517671A2
+EP1517697A1
+EP1521572B1
+EP1521748A1
+EP1524971A1
+EP1526857A1
+EP1530632A2
+EP1530724B1
+EP1537243A1
+EP1542728A1
+EP1554298A1
+EP1559726A2
+EP1562570A4
+EP1562607A1
+EP1562617B1
+EP1569915A2
+EP1572189A1
+EP1575521A2
+EP1578926A2
+EP1591115A1
+EP1592431A4
+EP1592447B1
+EP1594976A2
+EP1596812A2
+EP1603537A2
+EP1607384A1
+EP1608349A1
+EP1608661A2
+EP1609788A1
+EP1611902A1
+EP1612268A1
+EP1614684B1
+EP1615697A2
+EP1621197A2
+EP1635844A1
+EP1635850B1
+EP1644338A1
+EP1645558A1
+EP1648453A1
+EP1650199A1
+EP1653969A2
+EP1658851A1
+EP1661575A1
+EP1666034A1
+EP1667678B1
+EP1668003A1
+EP1680429A1
+EP1682110A1
+EP1694333A2
+EP1695970A1
+EP1698337A1
+EP1699452A2
+EP1704865A2
+EP1708714A1
+EP1711177B1
+EP1718645A1
+EP1720535B1
+EP1728789A1
+EP1732897A1
+EP1737440A2
+EP1738768A1
+EP1745777A1
+EP1755542A1
+EP1757601A1
+EP1762619A2
+EP1764099A2
+EP1773323A1
+EP1776338A1
+EP1778637B1
+EP1778672A1
+EP1781602A1
+EP1784381A1
+EP1785142A1
+EP1785424A2
+EP1786412A1
+EP1799669A1
+EP1801231B1
+EP1802602A1
+EP1807064B1
+EP1809618A1
+EP1813603A1
+EP1813618A1
+EP1819319A1
+EP1831208A1
+EP1832297A1
+EP1834670A2
+EP1835916B1
+EP1838736A2
+EP1845990B1
+EP1850840A2
+EP1851229A1
+EP1853567A1
+EP1856125A1
+EP1858862A1
+EP1860108A1
+EP1860115A1
+EP1863499A1
+EP1863767A1
+EP1871396A1
+EP1878435A1
+EP1878726A1
+EP1878746A2
+EP1879572B1
+EP1887008A1
+EP1889609A2
+EP1890558B1
+EP1891017A1
+EP1891068A1
+EP1896035A2
+EP1896415A1
+EP1896466A1
+EP1904051A1
+EP1908752A1
+EP1911462A2
+EP1912658A1
+EP1912986A1
+EP1914234A1
+EP1917027A2
+EP1917958A2
+EP1920783A1
+EP1926725A1
+EP1927359A2
+EP1932530A1
+EP1939295A1
+EP1942100A1
+EP1942916A1
+EP1942918A1
+EP1944297A1
+EP1944298A1
+EP1946753A1
+EP1954280A2
+EP1963337B1
+EP1963344A1
+EP1976538B1
+EP1978968A2
+EP1979322A1
+EP1987019A1
+EP1991554A1
+EP1993619A2
+EP1996180B1
+EP2000149A1
+EP2000470A1
+EP2002730A1
+EP2004176A1
+EP2007394A1
+EP2012769A1
+EP2014640A1
+EP2014655A2
+EP2017265A1
+EP2020997A2
+EP2023918B1
+EP2024354B1
+EP2035432B1
+EP2043628A2
+EP2044938A2
+EP2046796A1
+EP2050441A1
+EP2050455A1
+EP2053041A2
+EP2061457A1
+EP2062598A1
+EP2065379A1
+EP2075010A1
+EP2079701A1
+EP2086524A1
+EP2091523A1
+EP2097081A1
+EP2112926A2
+EP2113251A1
+EP2116236A1
+EP2118117A2
+EP2138175A2
+EP2141163A1
+EP2142516A1
+EP2148857A1
+EP2149584A1
+EP2152256A2
+EP2152713A1
+EP2156846A1
+EP2158903A2
+EP2182067A2
+EP2197890A1
+EP2198867A1
+EP2202227A1
+EP2205563A2
+EP2210583A1
+EP2211857A1
+EP2213679A1
+EP2217589A2
+EP2229390A1
+EP2230242A1
+EP2238108A1
+EP2247583A1
+EP2257556A1
+EP2268141A1
+EP2268284A2
+EP2269613A2
+EP2276765A1
+EP2281815A1
+EP2292616A1
+EP2294067A1
+EP2300476A1
+EP2301626A2
+EP2322162A1
+EP2328412A1
+EP2331520A1
+EP2343074A1
+EP2344158A1
+EP2346825A2
+EP2346826A2
+EP2349203A2
+EP2357175A1
+EP2358697A1
+EP2359827A1
+EP2366695A1
+EP2371367A1
+EP2373656A1
+EP2374478A1
+EP2377855A1
+EP2379561A2
+EP2388005A1
+EP2395975A1
+EP2397481A1
+EP2402356A2
+EP2405755A1
+EP2418212A1
+EP2424511A1
+EP2426122A1
+EP2433627A1
+EP2439198A2
+EP2442818A1
+EP2451453A1
+EP2464359A2
+EP2471530A1
+EP2476419A1
+EP2480229A2
+EP2483277A1
+EP2502625A1
+EP2507237A1
+EP2513095A1
+EP2514742A2
+EP2528601A1
+EP2532648A1
+EP2533787A1
+EP2534131A1
+EP2534157A1
+EP2540725A1
+EP2558090A1
+EP2559432A1
+EP2559442A1
+EP2561069A2
+EP2578214A2
+EP2582674A1
+EP2586441A1
+EP2588107A1
+EP2590661A1
+EP2590980A1
+EP2595972A1
+EP2596796A1
+EP2598132A1
+EP2600868A1
+EP2603217A1
+EP2609914A1
+EP2615163A1
+EP2617415A2
+EP2626351A1
+EP2639215A1
+EP2644194A2
+EP2646455A2
+EP2651919A1
+EP2654763A1
+EP2655312A1
+EP2675814A1
+EP2688565A1
+EP2688888A1
+EP2690175A2
+EP2692777A1
+EP2694072A1
+EP2699249A1
+EP2700627A1
+EP2705047A1
+EP2709674A1
+EP2711372A1
+EP2714025A1
+EP2714046A1
+EP2714712A1
+EP2717879A1
+EP2720694A1
+EP2725101A1
+EP2731593A2
+EP2732819A2
+EP2738156A1
+EP2738172A1
+EP2744781A1
+EP2744786A1
+EP2746251A2
+EP2746272A1
+EP2747761A1
+EP2754714A1
+EP2759547A1
+EP2760868A1
+EP2763995A1
+EP2766356A1
+EP2767533A1
+EP2769736A1
+EP2770992A1
+EP2776437A1
+EP2781519A1
+US20050004165
+US20050004177
+US20050004222
+US20050019923
+US20050026980
+US20050026981
+US20050036949
+US20050038019
+US20050038111
+US20050042173
+US20050042215
+US20050054614
+US20050054653
+US20050054683
+US20050059606
+US20050064032
+US20050065107
+US20050065120
+US20050065195
+US20050090481
+US20050095293
+US20050096316
+US20050096392
+US20050096473
+US20050101593
+US20050101632
+US20050101647
+US20050107311
+US20050107455
+US20050112069
+US20050113321
+US20050113357
+US20050118281
+US20050119272
+US20050124537
+US20050124581
+US20050131049
+US20050136127
+US20050143346
+US20050148581
+US20050148607
+US20050152846
+US20050153930
+US20050153975
+US20050154202
+US20050165017
+US20050176756
+US20050176765
+US20050176821
+US20050181042
+US20050192237
+US20050197328
+US20050197375
+US20050208103
+US20050208496
+US20050214360
+US20050215609
+US20050222093
+US20050222413
+US20050227942
+US20050239906
+US20050245471
+US20050245564
+US20050245743
+US20050245750
+US20050255096
+US20050256034
+US20050256122
+US20050272694
+US20050272751
+US20050282786
+US20050288296
+US20050288376
+US20060004030
+US20060018956
+US20060024659
+US20060029689
+US20060073191
+US20060089317
+US20060100175
+US20060100195
+US20060106036
+US20060134228
+US20060148810
+US20060165720
+US20060171984
+US20060173014
+US20060173078
+US20060177499
+US20060182817
+US20060183805
+US20060194847
+US20060194855
+US20060199791
+US20060199795
+US20060205809
+US20060223869
+US20060223990
+US20060246110
+US20060258650
+US20060258733
+US20060264408
+US20060276452
+US20070010473
+US20070027144
+US20070032537
+US20070042006
+US20070042056
+US20070082906
+US20070105894
+US20070116698
+US20070117842
+US20070141579
+US20070160545
+US20070160698
+US20070184058
+US20070203229
+US20070249701
+US20070249713
+US20070249715
+US20070254877
+US20070259014
+US20070265202
+US20070265295
+US20070265353
+US20070270378
+US20070274936
+US20070275887
+US20070275990
+US20070276024
+US20070280972
+US20070281040
+US20070281992
+US20070282017
+US20070297980
+US20080008745
+US20080014248
+US20080014287
+US20080019915
+US20080020030
+US20080020031
+US20080020969
+US20080032982
+US20080038323
+US20080038338
+US20080038358
+US20080038363
+US20080038376
+US20080039500
+US20080039503
+US20080039517
+US20080045525
+US20080050379
+US20080051412
+US20080051452
+US20080051466
+US20080063656
+US20080063661
+US20080064660
+US20080064701
+US20080070826
+US20080070846
+US20080070857
+US20080070858
+US20080070916
+US20080070960
+US20080075692
+US20080075725
+US20080075763
+US20080076738
+US20080076739
+US20080076805
+US20080076823
+US20080085308
+US20080090771
+US20080090784
+US20080095768
+US20080096802
+US20080096843
+US20080096845
+US20080096847
+US20080096878
+US20080096969
+US20080102045
+US20080103112
+US20080103126
+US20080103173
+US20080103197
+US20080103198
+US20080103209
+US20080108559
+US20080108587
+US20080108596
+US20080108616
+US20080108620
+US20080108646
+US20080113953
+US20080113997
+US20080114000
+US20080114025
+US20080138381
+US20080139535
+US20080145314
+US20080145421
+US20080145448
+US20080146522
+US20080146527
+US20080146532
+US20080146533
+US20080146542
+US20080146656
+US20080153766
+US20080153783
+US20080153891
+US20080153893
+US20080153894
+US20080153897
+US20080159984
+US20080171042
+US20080171741
+US20080171765
+US20080188432
+US20080188444
+US20080188445
+US20080188486
+US20080188499
+US20080188540
+US20080194504
+US20080200376
+US20080206159
+US20080206332
+US20080207608
+US20080207675
+US20080207714
+US20080207756
+US20080213324
+US20080213339
+US20080213409
+US20080214509
+US20080214516
+US20080234183
+US20080234195
+US20080234266
+US20080241245
+US20080242704
+US20080242705
+US20080248020
+US20080248035
+US20080248124
+US20080249168
+US20080254035
+US20080254106
+US20080254116
+US20080254146
+US20080255036
+US20080255072
+US20080255166
+US20080255175
+US20080255224
+US20080262284
+US20080274546
+US20080274946
+US20080280846
+US20080286806
+US20080287522
+US20080287549
+US20080292654
+US20080293622
+US20080293700
+US20080293738
+US20080293749
+US20080293801
+US20080300213
+US20080300269
+US20080312160
+US20080312169
+US20080312244
+US20080312248
+US20080312249
+US20080317751
+US20080317756
+US20080317759
+US20080317774
+US20080317869
+US20080319020
+US20080319047
+US20090004206
+US20090004281
+US20090004296
+US20090004299
+US20090005305
+US20090005372
+US20090005399
+US20090005418
+US20090005421
+US20090010929
+US20090010992
+US20090012025
+US20090012048
+US20090012104
+US20090012130
+US20090017145
+US20090018058
+US20090018092
+US20090018103
+US20090030001
+US20090035250
+US20090035267
+US20090035314
+US20090036354
+US20090036540
+US20090043129
+US20090047282
+US20090048179
+US20090048264
+US20090048289
+US20090054360
+US20090054369
+US20090054452
+US20090061008
+US20090062247
+US20090062267
+US20090062270
+US20090062283
+US20090062331
+US20090062385
+US20090068284
+US20090074777
+US20090074870
+US20090074885
+US20090075947
+US20090081309
+US20090081312
+US20090087405
+US20090093418
+US20090093424
+US20090098187
+US20090098191
+US20090098210
+US20090110649
+US20090111865
+US20090111870
+US20090111877
+US20090111893
+US20090118257
+US20090136970
+US20090137482
+US20090149442
+US20090155247
+US20090156546
+US20090163528
+US20090169535
+US20090169595
+US20090170095
+US20090170197
+US20090170812
+US20090176803
+US20090181090
+US20090181110
+US20090182058
+US20090192101
+US20090192108
+US20090197883
+US20090197900
+US20090197909
+US20090197961
+US20090203144
+US20090233909
+US20090234019
+US20090238897
+US20090247549
+US20090247604
+US20090247731
+US20090258015
+US20090258050
+US20090274655
+US20090285849
+US20090285850
+US20090291127
+US20090291917
+US20090291928
+US20090291948
+US20090291975
+US20090298817
+US20090298825
+US20090298884
+US20090306129
+US20090306165
+US20090311225
+US20090312308
+US20090312322
+US20090312357
+US20090318472
+US20090324558
+US20100004194
+US20100004217
+US20100004338
+US20100008931
+US20100008942
+US20100009991
+US20100010019
+US20100016265
+US20100016302
+US20100021506
+US20100021564
+US20100028440
+US20100028456
+US20100029580
+US20100029646
+US20100029655
+US20100029702
+US20100029710
+US20100029765
+US20100029771
+US20100040637
+US20100040662
+US20100041151
+US20100047313
+US20100047372
+US20100048529
+US20100048684
+US20100056583
+US20100056624
+US20100062053
+US20100062972
+US20100062989
+US20100069410
+US20100069412
+US20100069451
+US20100069455
+US20100069482
+US20100074959
+US20100074960
+US20100075891
+US20100075901
+US20100075966
+US20100076046
+US20100076053
+US20100080836
+US20100080851
+US20100080856
+US20100087374
+US20100087384
+US20100087401
+US20100087409
+US20100087459
+US20100092446
+US20100092553
+US20100093738
+US20100093788
+US20100093804
+US20100093827
+US20100098776
+US20100105632
+US20100105642
+US20100113352
+US20100113426
+US20100130623
+US20100135983
+US20100135985
+US20100136024
+US20100136083
+US20100137256
+US20100137260
+US20100137280
+US20100137357
+US20100137367
+US20100137410
+US20100143287
+US20100144597
+US20100144666
+US20100158819
+US20100167980
+US20100168003
+US20100168102
+US20100168224
+US20100168232
+US20100173002
+US20100173862
+US20100173897
+US20100179110
+US20100179170
+US20100179184
+US20100179186
+US20100179200
+US20100179202
+US20100179213
+US20100183665
+US20100183701
+US20100183721
+US20100184830
+US20100184852
+US20100190733
+US20100196449
+US20100196475
+US20100197709
+US20100203017
+US20100203040
+US20100203163
+US20100204234
+US20100204275
+US20100204311
+US20100204339
+US20100209350
+US20100209458
+US20100209479
+US20100209504
+US20100209508
+US20100210605
+US20100210666
+US20100215589
+US20100216764
+US20100216775
+US20100216838
+US20100216853
+US20100216867
+US20100221229
+US20100221345
+US20100222371
+US20100222418
+US20100222424
+US20100222432
+US20100227804
+US20100227904
+US20100233083
+US20100234288
+US20100234381
+US20100234440
+US20100247447
+US20100247583
+US20100247677
+US20100249164
+US20100249224
+US20100254904
+US20100255102
+US20100255109
+US20100256057
+US20100260713
+US20100261662
+US20100266574
+US20100266592
+US20100266657
+US20100266680
+US20100266709
+US20100267740
+US20100267842
+US20100272712
+US20100272775
+US20100272787
+US20100272818
+US20100273733
+US20100273750
+US20100273766
+US20100279965
+US20100279982
+US20100280050
+US20100280069
+US20100280117
+US20100284915
+US20100286106
+US20100286220
+US20100286232
+US20100286241
+US20100286249
+US20100292160
+US20100292189
+US20100303905
+US20100305113
+US20100316624
+US20100316629
+US20100317865
+US20100322993
+US20100323033
+US20100324078
+US20100324088
+US20100330196
+US20100331332
+US20100331384
+US20100331391
+US20110002855
+US20110002914
+US20110002952
+US20110003778
+US20110003892
+US20110020226
+US20110020430
+US20110020457
+US20110021515
+US20110021554
+US20110021567
+US20110021583
+US20110021611
+US20110027214
+US20110027230
+US20110028428
+US20110028484
+US20110028516
+US20110033520
+US20110038908
+US20110038920
+US20110038936
+US20110039927
+US20110045049
+US20110045075
+US20110046207
+US20110046208
+US20110046222
+US20110052722
+US20110052723
+US20110054040
+US20110059074
+US20110059189
+US20110060022
+US20110064721
+US20110064756
+US20110064803
+US20110071203
+US20110071209
+US20110071214
+US20110071221
+US20110071225
+US20110081352
+US20110086006
+US20110086872
+US20110091380
+US20110091392
+US20110092468
+US20110092552
+US20110092553
+US20110092573
+US20110092592
+US20110092599
+US20110098238
+US20110098266
+US20110098267
+US20110098269
+US20110098286
+US20110098333
+US20110110861
+US20110110885
+US20110111005
+US20110117070
+US20110117167
+US20110123577
+US20110123622
+US20110125093
+US20110135622
+US20110135638
+US20110136847
+US20110136884
+US20110136891
+US20110136893
+US20110136912
+US20110142794
+US20110142933
+US20110144003
+US20110144084
+US20110144089
+US20110152206
+US20110152214
+US20110152280
+US20110152294
+US20110152348
+US20110152350
+US20110153302
+US20110158940
+US20110158980
+US20110166191
+US20110171177
+US20110178040
+US20110178046
+US20110178055
+US20110178141
+US20110178154
+US20110178159
+US20110178170
+US20110178177
+US20110183960
+US20110183995
+US20110190316
+US20110190325
+US20110195137
+US20110195974
+US20110195985
+US20110200665
+US20110200677
+US20110201627
+US20110206703
+US20110206743
+US20110207709
+US20110207715
+US20110207719
+US20110207731
+US20110207751
+US20110212186
+US20110212194
+US20110212915
+US20110212917
+US20110212968
+US20110212971
+US20110212990
+US20110217247
+US20110217259
+US20110217371
+US20110223262
+US20110224251
+US20110229418
+US20110229493
+US20110229566
+US20110230486
+US20110230561
+US20110230564
+US20110236344
+US20110237525
+US20110237605
+US20110237659
+US20110243985
+US20110245211
+US20110245253
+US20110257111
+US20110257134
+US20110257215
+US20110262489
+US20110262547
+US20110263920
+US20110268662
+US20110268666
+US20110274739
+US20110275717
+US20110280861
+US20110281927
+US20110281950
+US20110287045
+US20110287067
+US20110288088
+US20110288103
+US20110288159
+US20110293636
+US20110293652
+US20110293708
+US20110300149
+US20110300217
+US20110301099
+US20110301155
+US20110301205
+US20110301233
+US20110306564
+US20110306577
+US20110313036
+US20110313039
+US20110319360
+US20110319392
+US20110319419
+US20110319429
+US20120014912
+US20120015952
+US20120015990
+US20120027707
+US20120027761
+US20120027861
+US20120027871
+US20120029021
+US20120039905
+US20120040917
+US20120040994
+US20120045425
+US20120045465
+US20120045505
+US20120045521
+US20120045522
+US20120045525
+US20120058963
+US20120058992
+US20120058998
+US20120059048
+US20120059054
+US20120070401
+US20120070473
+US20120070489
+US20120071507
+US20120071541
+US20120071542
+US20120076832
+US20120076872
+US20120077843
+US20120077855
+US20120077876
+US20120082623
+US20120082735
+US20120083473
+US20120083474
+US20120083496
+US20120088813
+US20120093738
+US20120093889
+US20120094941
+US20120094991
+US20120095558
+US20120101056
+US20120101067
+US20120101095
+US20120101104
+US20120108543
+US20120122795
+US20120122818
+US20120122859
+US20120122874
+US20120128628
+US20120129849
+US20120132204
+US20120135968
+US20120141590
+US20120142623
+US20120142653
+US20120142679
+US20120142745
+US20120142779
+US20120148519
+US20120148522
+US20120148603
+US20120148661
+US20120148689
+US20120149773
+US20120157416
+US20120157424
+US20120157536
+US20120164122
+US20120165291
+US20120165352
+US20120165369
+US20120165408
+US20120171219
+US20120171309
+US20120172388
+US20120172450
+US20120177691
+US20120177712
+US20120178677
+US20120178704
+US20120178724
+US20120183554
+US20120184530
+US20120184532
+US20120184616
+US20120189569
+US20120189614
+US20120189645
+US20120189678
+US20120189688
+US20120189713
+US20120190692
+US20120190703
+US20120190721
+US20120196830
+US20120196853
+US20120196883
+US20120196920
+US20120201859
+US20120213803
+US20120213832
+US20120225902
+US20120230942
+US20120232038
+US20120244224
+US20120245087
+US20120245112
+US20120245117
+US20120245149
+US20120260922
+US20120272346
+US20120276039
+US20120276196
+US20120276210
+US20120277171
+US20120277179
+US20120277191
+US20120277246
+US20120277249
+US20120277261
+US20120282337
+US20120282359
+US20120283204
+US20120283236
+US20120283239
+US20120283280
+US20120283312
+US20120288487
+US20120289584
+US20120289588
+US20120302491
+US20120302534
+US20120302546
+US20120316177
+US20120321637
+US20130011343
+US20130011422
+US20130011461
+US20130012467
+US20130012519
+US20130012534
+US20130017259
+US20130018014
+US20130018022
+US20130018223
+US20130028956
+US20130035318
+US20130040962
+US20130040997
+US20130065939
+US20130102567
+US20130109752
+US20130165419
+US20130289104
+US20130295078
+US20130315938
+US20130331431
+US20130344166
+US20140018333
+US20140037635
+US6849624
+US6852333
+US6861071
+US6861425
+US6861431
+US6861447
+US6867231
+US6867284
+US6881731
+US6884801
+US6884819
+US6891039
+US6893641
+US6896900
+US6897054
+US6897198
+US6897203
+US6897207
+US6897212
+US6897315
+US6906087
+US6906089
+US6906091
+US6914056
+US6916797
+US6916805
+US6916922
+US6916927
+US6919339
+US6919380
+US6924278
+US6925388
+US6932960
+US6936601
+US6939876
+US6943156
+US6943183
+US6949218
+US6951872
+US6951884
+US6953808
+US6962923
+US6962933
+US6962942
+US6974868
+US6982320
+US6982334
+US6987106
+US6989159
+US6992073
+US6992085
+US6992088
+US6992211
+US6994864
+US6998244
+US6998399
+US6998408
+US7008938
+US7008947
+US7011973
+US7012146
+US7014845
+US7014856
+US7022699
+US7022870
+US7026487
+US7030125
+US7030149
+US7033498
+US7037665
+US7041806
+US7045323
+US7045497
+US7045606
+US7045658
+US7049322
+US7049332
+US7056913
+US7056928
+US7063861
+US7067496
+US7074405
+US7074431
+US7074783
+US7074792
+US7081469
+US7081473
+US7087605
+US7090846
+US7091198
+US7091201
+US7094911
+US7098234
+US7101846
+US7101876
+US7101908
+US7102013
+US7105510
+US7105520
+US7105705
+US7109164
+US7109193
+US7109218
+US7112584
+US7112612
+US7115556
+US7115777
+US7118762
+US7119076
+US7119089
+US7119115
+US7122187
+US7122311
+US7122539
+US7122552
+US7122571
+US7122579
+US7125877
+US7125879
+US7125890
+US7135501
+US7138133
+US7141251
+US7147844
+US7151176
+US7153826
+US7153841
+US7160898
+US7172752
+US7172761
+US7179792
+US7179802
+US7179830
+US7183320
+US7186825
+US7189745
+US7192609
+US7192972
+US7205295
+US7211248
+US7211562
+US7214677
+US7214692
+US7214710
+US7214714
+US7220748
+US7220754
+US7223397
+US7226614
+US7226945
+US7226948
+US7226972
+US7227031
+US7230103
+US7235579
+US7238677
+US7238700
+US7244709
+US7244746
+US7244846
+US7250411
+US7250413
+US7250416
+US7250420
+US7253188
+US7253190
+US7253281
+US7265108
+US7265131
+US7273625
+US7279491
+US7279596
+US7285563
+US7285660
+US7291650
+US7294642
+US7294720
+US7297681
+US7297682
+US7301022
+US7303739
+US7309704
+US7309719
+US7312209
+US7314888
+US7317018
+US7317036
+US7320996
+US7326699
+US7326711
+US7329677
+US7332335
+US7342016
+US7348314
+US7348426
+US7357930
+US7361744
+US7365088
+US7368563
+US7378437
+US7393655
+US7402318
+US7402557
+US7425580
+US7442719
+US7449483
+US7465541
+US7465719
+US7465736
+US7470694
+US7476396
+US7476732
+US7482339
+US7488497
+US7498313
+US7504398
+US7504415
+US7504434
+US7504500
+US7507730
+US7517672
+US7528116
+US7528133
+US7531676
+US7537906
+US7541378
+US7541381
+US7541477
+US7553479
+US7557094
+US7557113
+US7560131
+US7560487
+US7566728
+US7566791
+US7572796
+US7572825
+US7576067
+US7576074
+US7576077
+US7585856
+US7585890
+US7585973
+US7589125
+US7595336
+US7601359
+US7601726
+US7601836
+US7612050
+US7612058
+US7612081
+US7612103
+US7625860
+US7629368
+US7632808
+US7642229
+US7645465
+US7645791
+US7649097
+US7655647
+US7662828
+US7662840
+US7667052
+US7670601
+US7670620
+US7674809
+US7687492
+US7709491
+US7714121
+US7732425
+US7732431
+US7740831
+US7741343
+US7745450
+US7745472
+US7749970
+US7750010
+US7754769
+US7759328
+US7771962
+US7789610
+US7795312
+US7803806
+US7807795
+US7816340
+US7816560
+US7824717
+US7838565
+US7842677
+US7842686
+US7846967
+US7851507
+US7867981
+US7871992
+US7872025
+US7872034
+US7872047
+US7872140
+US7892574
+US7902261
+US7919612
+US7927623
+US7932273
+US7956078
+US7968545
+US7968692
+US7972612
+US7988965
+US7998474
+US7998503
+US8026244
+US8026272
+US8052987
+US8067228
+US8075923
+US8097270
+US8128912
+US8153588
+US8153610
+US8163733
+US8163752
+US8168616
+US8202880
+US8211401
+US8216604
+US8258132
+US8298525
+US8309584
+US8318706
+US8318764
+US8318782
+US8324190
+US8333976
+US8338456
+US8372824
+US8388989
+US8455004
+US8455502
+US8501244
+US8513238
+US8518897
+US8518919
+US8536229
+US8563602
+US8592420
+US8597665
+US8598129
+US8618045
+US8658158
+US8710020
+US8716251
+US8774885
+US8778990
+US8785569
+US8791102
+US8802125
+US8828991
+USRE39862
+USRE40558
+USRE41084
+WO2002069893A3
+WO2003097059A8
+WO2004001072A3
+WO2004009064A8
+WO2004047727A3
+WO2004064760A3
+WO2004076621A3
+WO2004078744A3
+WO2004098500A3
+WO2005012289A1
+WO2005012352A1
+WO2005014580A1
+WO2005014600A1
+WO2005016255A3
+WO2005018556A2
+WO2005019225A1
+WO2005020967A1
+WO2005021739A1
+WO2005026114A1
+WO2005030716A1
+WO2005037270A1
+WO2005040189A1
+WO2005049017A1
+WO2005061492A1
+WO2005067904A1
+WO2005072763A1
+WO2005074983A3
+WO2005082414A3
+WO2005083075A1
+WO2005090332A1
+WO2005094821A1
+WO2005097192A9
+WO2005099686A1
+WO2005100363A8
+WO2005105098A3
+WO2005117920A1
+WO2006000324A3
+WO2006002088A3
+WO2006002119A3
+WO2006004931A3
+WO2006005844A1
+WO2006008649A1
+WO2006008757A3
+WO2006011466A1
+WO2006012603A3
+WO2006016602A1
+WO2006024241A1
+WO2006024863A1
+WO2006027705A3
+WO2006030105A1
+WO2006033422A1
+WO2006035939A1
+WO2006040148A1
+WO2006046492A1
+WO2006051826A1
+WO2006053112A1
+WO2006053120A1
+WO2006053379A1
+WO2006056695A8
+WO2006057011A3
+WO2006057902A2
+WO2006058781A2
+WO2006059637A1
+WO2006060318A2
+WO2006060885A1
+WO2006061340A3
+WO2006061428A2
+WO2006062093A1
+WO2006067466A3
+WO2006067862A1
+WO2006069519A1
+WO2006070202A1
+WO2006074940A2
+WO2006076370B1
+WO2006076844A1
+WO2006077387A3
+WO2006078698A1
+WO2006079478A1
+WO2006079645A1
+WO2006081616A1
+WO2006083204A1
+WO2006085079A2
+WO2006085113A3
+WO2006086888A1
+WO2006089700A1
+WO2006090129A3
+WO2006092490A1
+WO2006092692A1
+WO2006094662A1
+WO2006096780A3
+WO2006101521A3
+WO2006106241A1
+WO2006106423A3
+WO2006106721A1
+WO2006109633A1
+WO2006111424A1
+WO2006111983A3
+WO2006115067A1
+WO2006116157A3
+WO2006116526A8
+WO2006119674A1
+WO2006120557A1
+WO2006122931A1
+WO2006123246A3
+WO2006124684A3
+WO2006126325A1
+WO2006126514A1
+WO2006127941A9
+WO2006128296A1
+WO2006128378A1
+WO2006128735A1
+WO2006129609A1
+WO2006132275A1
+WO2006133391A3
+WO2006133654A1
+WO2006138038A1
+WO2007001010A1
+WO2007001211A3
+WO2007001932A2
+WO2007003554A1
+WO2007004032A1
+WO2007004692A1
+WO2007006707A1
+WO2007009704A3
+WO2007009778A1
+WO2007010337A8
+WO2007010911A1
+WO2007012285A1
+WO2007012479A3
+WO2007012762A1
+WO2007014839A3
+WO2007014895A2
+WO2007015003A3
+WO2007022946A1
+WO2007026104A1
+WO2007026156A1
+WO2007026959A3
+WO2007036131A1
+WO2007037258A1
+WO2007038452A1
+WO2007039463A1
+WO2007039760A3
+WO2007040966A1
+WO2007043606A1
+WO2007050271A3
+WO2007052013A1
+WO2007052124A1
+WO2007052157A3
+WO2007054258A1
+WO2007054623A3
+WO2007054977A3
+WO2007056593A3
+WO2007059154A2
+WO2007060821A1
+WO2007062564A1
+WO2007065023A2
+WO2007067612A1
+WO2007069603A1
+WO2007071598A1
+WO2007074089A1
+WO2007077469A1
+WO2007080362A1
+WO2007080401A8
+WO2007083101A3
+WO2007085557A3
+WO2007086471A1
+WO2007086554A1
+WO2007093624A3
+WO2007094071A1
+WO2007094430A1
+WO2007096251A1
+WO2007097839A3
+WO2007102447A1
+WO2007103468A3
+WO2007106859A3
+WO2007109459A2
+WO2007114326A1
+WO2007115372A1
+WO2007115938A1
+WO2007118711A1
+WO2007124045A2
+WO2007124308A3
+WO2007125293A1
+WO2007129274A9
+WO2007130477A2
+WO2007131329A1
+WO2007132947A1
+WO2007135193A3
+WO2007136250A3
+WO2007136692A2
+WO2007136776A2
+WO2007137792A1
+WO2007139211A1
+WO2007139464A1
+WO2007140588A1
+WO2007141504A1
+WO2007143096A3
+WO2007143423A3
+WO2007144057A3
+WO2007146684A1
+WO2007147834A1
+WO2007149382A3
+WO2007149508A2
+WO2007149929A1
+WO2008001442A1
+WO2008003130A1
+WO2008004117A1
+WO2008006117A2
+WO2008006702A1
+WO2008009927A1
+WO2008010225A2
+WO2008012338A3
+WO2008016674A1
+WO2008016677A2
+WO2008017867A2
+WO2008020491A1
+WO2008020607A1
+WO2008022182A1
+WO2008023005A1
+WO2008023796A1
+WO2008024981A1
+WO2008025539A1
+WO2008026298A1
+WO2008027013A3
+WO2008027812A2
+WO2008028093A1
+WO2008028928A8
+WO2008035358A3
+WO2008035359A3
+WO2008036282A1
+WO2008036843A3
+WO2008041264A1
+WO2008042282A3
+WO2008042892A3
+WO2008043019A1
+WO2008043243A1
+WO2008044691A1
+WO2008045484A1
+WO2008049842A2
+WO2008051080A1
+WO2008054454A3
+WO2008054984A1
+WO2008055629A1
+WO2008059068A3
+WO2008059869A1
+WO2008060448A2
+WO2008064311A2
+WO2008067399A3
+WO2008069262A1
+WO2008070169A2
+WO2008072591A1
+WO2008073684A1
+WO2008073942A3
+WO2008075148A3
+WO2008077650A1
+WO2008079909A1
+WO2008079980A1
+WO2008083634A1
+WO2008084081A2
+WO2008086698A1
+WO2008087177A1
+WO2008088935A2
+WO2008089659A1
+WO2008091170A1
+WO2008091540A2
+WO2008092681A1
+WO2008097317A1
+WO2008099081A3
+WO2008099469A1
+WO2008100463A1
+WO2008101247A2
+WO2008107879A1
+WO2008109007A1
+WO2008109376A1
+WO2008109560A3
+WO2008109991A8
+WO2008112162A3
+WO2008112238A1
+WO2008113469A2
+WO2008113711A1
+WO2008115141A1
+WO2008116161A2
+WO2008117050A1
+WO2008117269A3
+WO2008119711A1
+WO2008119771A3
+WO2008120235A1
+WO2008121328A2
+WO2008121352A2
+WO2008124145A1
+WO2008124878A1
+WO2008124907A3
+WO2008124931A1
+WO2008125424A1
+WO2008125835A1
+WO2008127275A2
+WO2008127996A1
+WO2008129530A1
+WO2008132233A1
+WO2008133132A1
+WO2008134228A1
+WO2008134265A2
+WO2008135239A1
+WO2008135830A1
+WO2008139879A1
+WO2008139952A1
+WO2008139987A1
+WO2008140421A3
+WO2008147562A3
+WO2008148303A1
+WO2008148832A1
+WO2008149140A2
+WO2008153947A2
+WO2008155081A2
+WO2008157404A2
+WO2009000168A1
+WO2009004873A1
+WO2009009132A1
+WO2009011613A1
+WO2009012702A1
+WO2009013444A1
+WO2009016526A3
+WO2009023181A1
+WO2009024825A1
+WO2009025617A1
+WO2009026790A1
+WO2009027766A3
+WO2009030270A1
+WO2009031023A3
+WO2009031195A1
+WO2009034581A1
+WO2009035067A1
+WO2009036955A1
+WO2009037172A1
+WO2009039361A3
+WO2009040512A3
+WO2009040849A1
+WO2009041714A1
+WO2009042138A9
+WO2009042544A1
+WO2009049917A1
+WO2009052191A1
+WO2009053750A2
+WO2009057733A1
+WO2009061569A1
+WO2009062517A1
+WO2009062874A3
+WO2009066009A1
+WO2009066084A1
+WO2009069140A1
+WO2009072625A1
+WO2009075323A1
+WO2009077741A3
+WO2009082346A1
+WO2009083267A2
+WO2009083444A1
+WO2009085226A2
+WO2009086129A1
+WO2009089138A1
+WO2009090656A3
+WO2009091889A1
+WO2009093638A1
+WO2009096377A1
+WO2009097670A1
+WO2009100037A1
+WO2009100890A1
+WO2009101698A1
+WO2009102172A3
+WO2009103427A2
+WO2009109109A1
+WO2009109493A3
+WO2009111574A3
+WO2009113084A1
+WO2009113085A1
+WO2009113435A1
+WO2009113594A1
+WO2009115280A1
+WO2009116636A1
+WO2009116882A1
+WO2009121992A3
+WO2009122748A1
+WO2009122983A1
+WO2009123457A3
+WO2009123575A8
+WO2009126537A1
+WO2009127398A2
+WO2009129491A4
+WO2009129696A1
+WO2009131537A1
+WO2009133127A1
+WO2009133560A1
+WO2009133692A1
+WO2009134718A8
+WO2009138734A2
+WO2009138779A1
+WO2009139181A1
+WO2009139213A1
+WO2009143763A1
+WO2009145814A3
+WO2009147529A1
+WO2009150194A1
+WO2009152735A1
+WO2009152909A1
+WO2009153179A1
+WO2009156092A3
+WO2009158396A1
+WO2010003376A1
+WO2010004525A1
+WO2010005055A1
+WO2010005534A3
+WO2010005725A2
+WO2010005735A3
+WO2010006169A3
+WO2010007318A3
+WO2010008263A1
+WO2010014199A2
+WO2010017827A1
+WO2010019450A3
+WO2010019547A1
+WO2010020762A1
+WO2010027090A1
+WO2010028134A3
+WO2010028174A1
+WO2010028542A1
+WO2010029915A1
+WO2010033495A3
+WO2010033824A1
+WO2010038965A3
+WO2010039174A1
+WO2010039798A3
+WO2010042991A1
+WO2010043010A1
+WO2010043180A1
+WO2010044411A1
+WO2010048264A3
+WO2010053433A1
+WO2010055022A1
+WO2010056320A3
+WO2010058060A1
+WO2010058166A1
+WO2010062260A1
+WO2010064172A3
+WO2010065571A1
+WO2010066901A3
+WO2010068287A8
+WO2010068605A1
+WO2010069073A1
+WO2010070379A1
+WO2010072823A1
+WO2010073721A1
+WO2010074591A1
+WO2010074647A1
+WO2010077839A1
+WO2010079910A2
+WO2010080757A3
+WO2010080817A3
+WO2010083199A1
+WO2010085528A1
+WO2010086129A8
+WO2010087207A1
+WO2010088071A1
+WO2010091241A3
+WO2010092440A1
+WO2010094452A3
+WO2010094837A3
+WO2010096987A1
+WO2010098365A1
+WO2010100050A1
+WO2010100337A1
+WO2010104406A8
+WO2010104563A2
+WO2010109008A1
+WO2010109687A1
+WO2010113225A1
+WO2010113631A1
+WO2010113834A1
+WO2010114319A2
+WO2010117787A3
+WO2010120872A3
+WO2010121175A1
+WO2010121575A1
+WO2010122151A1
+WO2010123766A1
+WO2010124392A1
+WO2010126025A1
+WO2010126034A1
+WO2010126036A1
+WO2010127541A1
+WO2010129321A2
+WO2010132515A1
+WO2010132670A3
+WO2010132873A3
+WO2010134851A1
+WO2010135493A2
+WO2010135527A3
+WO2010138770A2
+WO2010139980A1
+WO2010141427A1
+WO2010142705A1
+WO2010147430A2
+WO2011000309A1
+WO2011001165A3
+WO2011001258A1
+WO2011005645A1
+WO2011007794A1
+WO2011007795A1
+WO2011007865A1
+WO2011009193A8
+WO2011009533A3
+WO2011009695A1
+WO2011013668A1
+WO2011017488A2
+WO2011017809A1
+WO2011022838A1
+WO2011024004A1
+WO2011025932A2
+WO2011027324A1
+WO2011027344A2
+WO2011027888A1
+WO2011028580A1
+WO2011029279A1
+WO2011030868A1
+WO2011031974A1
+WO2011034919A2
+WO2011037433A3
+WO2011038537A1
+WO2011044072A1
+WO2011044504A1
+WO2011046221A1
+WO2011047143A1
+WO2011047466A1
+WO2011056021A2
+WO2011060268A3
+WO2011060553A1
+WO2011067236A2
+WO2011067560A1
+WO2011068171A1
+WO2011076147A1
+WO2011076316A1
+WO2011076878A1
+WO2011077502A1
+WO2011078984A1
+WO2011081937A1
+WO2011083278A1
+WO2011085209A3
+WO2011085216A2
+WO2011085356A2
+WO2011085981A1
+WO2011086575A8
+WO2011089584A1
+WO2011090265A2
+WO2011092290A1
+WO2011092505A1
+WO2011093308A1
+WO2011094352A1
+WO2011095495A1
+WO2011096676A3
+WO2011099872A1
+WO2011101868A4
+WO2011103413A3
+WO2011103510A1
+WO2011105551A1
+WO2011105568A1
+WO2011106334A1
+WO2011107709A1
+WO2011108644A1
+WO2011109341A3
+WO2011112191A1
+WO2011112896A1
+WO2011113284A1
+WO2011113606A1
+WO2011115810A2
+WO2011117668A9
+WO2011120040A2
+WO2011120281A1
+WO2011121434A1
+WO2011125930A1
+WO2011127088A2
+WO2011130787A1
+WO2011130817A1
+WO2011135464A3
+WO2011139079A3
+WO2011140328A1
+WO2011143843A1
+WO2011143864A1
+WO2011149250A3
+WO2011152005A1
+WO2011153382A1
+WO2011155689A3
+WO2011157443A8
+WO2011158388A1
+WO2011159550A3
+WO2011160252A1
+WO2011160684A1
+WO2011161521A1
+WO2012002464A1
+WO2012004207A1
+WO2012007836A1
+WO2012010089A1
+WO2012011174A1
+WO2012012385A2
+WO2012012509A1
+WO2012012886A1
+WO2012013595A1
+WO2012014993A1
+WO2012016408A1
+WO2012016970A1
+WO2012018069A1
+WO2012019106A3
+WO2012019428A8
+WO2012019633A1
+WO2012024284A1
+WO2012026434A1
+WO2012028834A1
+WO2012029456A1
+WO2012029655A1
+WO2012032067A1
+WO2012033261A1
+WO2012036215A1
+WO2012036589A1
+WO2012037060A1
+WO2012039793A1
+WO2012045363A1
+WO2012046825A1
+WO2012047893A2
+WO2012050484A3
+WO2012050695A1
+WO2012052595A1
+WO2012052888A1
+WO2012053768A3
+WO2012055015A1
+WO2012055034A1
+WO2012058976A1
+WO2012064269A1
+WO2012064928A1
+WO2012064981A2
+WO2012067447A2
+WO2012073965A1
+WO2012076190A1
+WO2012076842A1
+WO2012076966A1
+WO2012077133A1
+WO2012077828A1
+WO2012079121A1
+WO2012080703A1
+WO2012080728A1
+WO2012081570A1
+WO2012088044A3
+WO2012091136A1
+WO2012091372A2
+WO2012101064A1
+WO2012102404A1
+WO2012103784A1
+WO2012104874A3
+WO2012108841A1
+WO2012109011A1
+WO2012109100A1
+WO2012110017A1
+WO2012112230A3
+WO2012112462A1
+WO2012116061A1
+WO2012116410A1
+WO2012118462A1
+WO2012123353A1
+WO2012125828A8
+WO2012128501A9
+WO2012129145A8
+WO2012131048A1
+WO2012131142A1
+WO2012137111A1
+WO2012139262A1
+WO2012140298A1
+WO2012142958A1
+WO2012144619A1
+WO2012144892A1
+WO2012145098A1
+WO2012149218A3
+WO2012154807A1
+WO2012157734A1
+WO2012157921A3
+WO2012158552A3
+WO2012158885A1
+WO2012162796A1
+WO2012163236A1
+WO2012166665A2
+WO2012167101A1
+WO2012167600A1
+WO2012169973A1
+WO2012172821A1
+WO2012174229A3
+WO2012174327A1
+WO2012174699A1
+WO2012174926A1
+WO2012176149A1
+WO2012176438A1
+WO2012177565A2
+WO2012177708A1
+WO2013001498A1
+WO2013004116A1
+WO2013004617A1
+WO2013007361A1
+WO2013018685A1
+WO2013020235A1
+WO2013022919A1
+WO2013023856A8
+WO2013024291A2
+WO2013024589A1
+WO2013024898A1
+WO2013026755A1
+WO2013029116A1
+WO2013030512A1
+WO2013035479A1
+WO2013035943A1
+WO2013039947A1
+WO2013049174A1
+WO2013049220A1
+WO2013051024A3
+WO2013051459A1
+WO2013051680A1
+WO2013052019A1
+WO2013052575A1
+WO2013056327A1
+WO2013057337A3
+WO2013059433A3
+WO2013063417A1
+WO2013064445A1
+WO2013065712A1
+WO2013065866A1
+WO2013068967A2
+WO2013068972A1
+WO2013069339A1
+WO2013070116A3
+WO2013071696A1
+WO2013076170A1
+WO2013078413A1
+WO2013078771A1
+WO2013086467A1
+WO2013086980A1
+WO2013090634A1
+WO2013098588A1
+WO2013098675A1
+WO2013100874A1
+WO2013102860A1
+WO2013103155A1
+WO2013106528A1
+WO2013107164A1
+WO2013108263A1
+WO2013108926A1
+WO2013109323A2
+WO2013110309A1
+WO2013111066A3
+WO2013113030A2
+WO2013119794A1
+WO2013121449A1
+WO2013122897A1
+WO2013123618A1
+WO2013124413A1
+WO2013126438A1
+WO2013130775A1
+WO2013131124A1
+WO2013137844A1
+WO2013138312A1
+WO2013139941A1
+WO2013143688A1
+WO2013144085A1
+WO2013145749A1
+WO2013146018A1
+WO2013147072A1
+WO2013148748A1
+WO2013148874A1
+WO2013148912A1
+WO2013149075A1
+WO2013149336A1
+WO2013149996A1
+WO2013150529A2
+WO2013154173A1
+WO2013159064A1
+WO2013159200A1
+WO2013161933A1
+WO2013162054A1
+WO2013162382A1
+WO2013164773A1
+WO2013164838A1
+WO2013166034A1
+WO2013168033A1
+WO2013170142A1
+WO2013170189A1
+WO2013170972A1
+WO2013171729A3
+WO2013173492A1
+WO2013173707A1
+WO2013175231A1
+WO2013176567A1
+WO2013177510A1
+WO2013178816A1
+WO2013179264A4
+WO2013180183A1
+WO2013183718A1
+WO2013184023A1
+WO2013184646A3
+WO2013185209A1
+WO2013185507A1
+WO2013186191A1
+WO2013186493A2
+WO2013186680A1
+WO2013187720A1
+WO2013188829A1
+WO2013189266A1
+WO2013189588A1
+WO2014000033A1
+WO2014001377A1
+WO2014005408A1
+WO2014009219A1
+WO2014009274A1
+WO2014012805A1
+WO2014012942A1
+WO2014013497A1
+WO2014013664A1
+WO2014014814A1
+WO2014014828A1
+WO2014019282A1
+WO2014020031A1
+WO2014021408A1
+WO2014022752A1
+WO2014023063A1
+WO2014025486A1
+WO2014025808A1
+WO2014025890A1
+WO2014027163A2
+WO2014027334A3
+WO2014027658A1
+WO2014028079A1
+WO2014028387A1
+WO2014031515A1
+WO2014033176A1
+WO2014034147A1
+WO2014036608A1
+WO2014036620A1
+WO2014037903A3
+WO2014038653A1
+WO2014039502A1
+WO2014039971A1
+WO2014040087A1
+WO2014041445A3
+WO2014041558A3
+WO2014043685A1
+WO2014047048A1
+WO2014047392A1
+WO2014052640A1
+WO2014054841A1
+WO2014054969A1
+WO2014055768A1
+WO2014056401A1
+WO2014057067A1
+WO2014057435A1
+WO2014060408A1
+WO2014061419A1
+WO2014061826A1
+WO2014062080A1
+WO2014062732A1
+WO2014062852A3
+WO2014063061A1
+WO2014063778A1
+WO2014064258A1
+WO2014065194A1
+WO2014065772A1
+WO2014068095A1
+WO2014068463A3
+WO2014069510A1
+WO2014070214A1
+WO2014071031A1
+WO2014072646A1
+WO2014072673A1
+WO2014073992A1
+WO2014074017A1
+WO2014075392A1
+WO2014075691A1
+WO2014076111A1
+WO2014077712A1
+WO2014078610A1
+WO2014080633A1
+WO2014082254A1
+WO2014083095A1
+WO2014083107A1
+WO2014083171A1
+WO2014084508A1
+WO2014085153A8
+WO2014085526A1
+WO2014086284A1
+WO2014089121A3
+WO2014094353A1
+WO2014100431A1
+WO2014102213A1
+WO2014106473A1
+WO2014106988A1
+WO2014111496A1
+WO2014111839A1
+WO2014116723A1
+WO2014117948A1
+WO2014118677A1
+WO2014121342A1
+WO2014121885A1
+WO2014127149A1
+WO2014128486A1
+WO2014135638A1
+WO2014135674A1
+WO2014138912A1
+WO2014139014A1
+WO2014139978A1
+WO2014140631A1
+WO2014141165A1
+WO2014142291A1
+WO2014143960A1
+WO2014144087A1
+WO2014146492A1
+WO2014146494A1
+WO2014147119A1
+WO2014147246A1
+WO2014149525A1
+WO2014150873A1
+WO2014151180A1
+WO2014151367A1
+WO2014151451A1
+WO2014151620A1
+WO2014152215A1
+WO2014152725A1
+WO2014154747A1
+WO2014154843A1
+WO2014155332A1
+WO2014157437A1
+WO2014160430A1
+WO2014160698A1
+WO2014161836A1
+WO2014162121A1
+WO2014162313A1
+WO2014164667A1
diff --git a/huner/ner_scripts/splits/cemp.train b/huner/ner_scripts/splits/cemp.train
new file mode 100644
index 0000000..021e21c
--- /dev/null
+++ b/huner/ner_scripts/splits/cemp.train
@@ -0,0 +1,8395 @@
+CA2054325C
+CA2073500C
+CA2098842C
+CA2104399C
+CA2110291C
+CA2113023C
+CA2117257C
+CA2119782C
+CA2120731C
+CA2126091C
+CA2129897C
+CA2133439C
+CA2137764C
+CA2144312C
+CA2148253C
+CA2153849C
+CA2155014C
+CA2156289C
+CA2157128C
+CA2157590C
+CA2157792C
+CA2158610C
+CA2161857C
+CA2168021C
+CA2168447C
+CA2173208C
+CA2173839C
+CA2175372C
+CA2176181C
+CA2177961C
+CA2180660C
+CA2182620C
+CA2183549C
+CA2187449C
+CA2202503C
+CA2203237C
+CA2205573C
+CA2207503C
+CA2207804C
+CA2209360C
+CA2210022C
+CA2213842C
+CA2217054C
+CA2217191C
+CA2217479C
+CA2222964C
+CA2224176C
+CA2224269C
+CA2231545C
+CA2232222C
+CA2233620C
+CA2236868C
+CA2240494C
+CA2240721C
+CA2242618C
+CA2243708C
+CA2246760C
+CA2250630C
+CA2250712C
+CA2251949C
+CA2252050C
+CA2252986C
+CA2253130C
+CA2253207C
+CA2254759C
+CA2255804C
+CA2256633C
+CA2257810C
+CA2261923C
+CA2268968C
+CA2270952C
+CA2274314C
+CA2274591C
+CA2276442C
+CA2279063C
+CA2280612C
+CA2281918C
+CA2284774C
+CA2286076C
+CA2288024C
+CA2290893C
+CA2292586C
+CA2292846C
+CA2297198C
+CA2297959C
+CA2298445C
+CA2302445C
+CA2303448C
+CA2303509C
+CA2304704C
+CA2304821C
+CA2306837C
+CA2309256C
+CA2310230C
+CA2311734C
+CA2312990C
+CA2313878C
+CA2314170C
+CA2314326C
+CA2315693C
+CA2316356C
+CA2319836C
+CA2320822C
+CA2321523C
+CA2323536C
+CA2324343C
+CA2326048C
+CA2336628C
+CA2338901C
+CA2339411C
+CA2339630C
+CA2340545C
+CA2340898C
+CA2340921C
+CA2343414C
+CA2344248C
+CA2344652C
+CA2348390C
+CA2348767C
+CA2351617C
+CA2352946C
+CA2353544C
+CA2355712C
+CA2357986C
+CA2360677C
+CA2370201C
+CA2371517C
+CA2382337C
+CA2382631C
+CA2383054C
+CA2386817C
+CA2387351C
+CA2390858C
+CA2393344C
+CA2395016C
+CA2395226C
+CA2395881C
+CA2397593C
+CA2398389C
+CA2399405C
+CA2400737C
+CA2401424C
+CA2403026C
+CA2404688C
+CA2407806C
+CA2410526C
+CA2411818C
+CA2412941C
+CA2413337C
+CA2416512C
+CA2421151C
+CA2426348C
+CA2427261C
+CA2433386C
+CA2434393C
+CA2435672C
+CA2436764C
+CA2437603C
+CA2438270C
+CA2438813C
+CA2441235C
+CA2442151C
+CA2443543C
+CA2455064C
+CA2455659A1
+CA2459033C
+CA2460135C
+CA2464309C
+CA2464777C
+CA2467329A1
+CA2468374C
+CA2471147C
+CA2474904C
+CA2475224C
+CA2492874C
+CA2497725C
+CA2516078C
+CA2526954C
+CA2530543C
+CA2536321A1
+CA2545543A1
+CA2547080A1
+CA2547887C
+CA2548922A1
+CA2553816A1
+CA2554073A1
+CA2555406A1
+CA2558019A1
+CA2558160A1
+CA2562821A1
+CA2567916C
+CA2573472A1
+CA2574060A1
+CA2574518A1
+CA2582262A1
+CA2582559A1
+CA2583392A1
+CA2583658A1
+CA2585967A1
+CA2591917C
+CA2597616A1
+CA2598948A1
+CA2602643C
+CA2603030A1
+CA2603199A1
+CA2604161A1
+CA2604515A1
+CA2611715C
+CA2611917A1
+CA2613911A1
+CA2615112A1
+CA2618638C
+CA2618974A1
+CA2624220A1
+CA2631724C
+CA2633296A1
+CA2635375A1
+CA2635777A1
+CA2641871A1
+CA2644356A1
+CA2647292A1
+CA2658877C
+CA2665501A1
+CA2665717A1
+CA2667039A1
+CA2673097A1
+CA2673510C
+CA2675510A1
+CA2676172A1
+CA2678127A1
+CA2679103A1
+CA2681864A1
+CA2688736A1
+CA2691943A1
+CA2695844A1
+CA2703458A1
+CA2704882A1
+CA2712282A1
+CA2714398A1
+CA2729582A1
+CA2736285A1
+CA2741842A1
+CA2741941A1
+CA2745063A1
+CA2746717A1
+CA2747055C
+CA2749218C
+CA2754058A1
+CA2756796A1
+CA2757759A1
+CA2760779A1
+CA2761656A1
+CA2765919A1
+CA2776971A1
+CA2777406A1
+CA2777816A1
+CA2782946A1
+CA2784015A1
+CA2784807A1
+CA2792669A1
+CA2799390A1
+CA2799416A1
+CA2801535A1
+CA2803880A1
+CA2806362A1
+CA2806647A1
+CA2815792A1
+CA2816104A1
+CA2820236A1
+CA2826892A1
+CA2832310A1
+CA2832958A1
+CA2838659A1
+CA2839244A1
+CA2840746A1
+CA2842015A1
+CA2850955A1
+CA2851516A1
+CA2856646A1
+CA2857374A1
+CA2858025A1
+CA2858257A1
+CA2858571A1
+CN100579521C
+CN100998559A
+CN100998576A
+CN100998579A
+CN100998588A
+CN100999521B
+CN100999539A
+CN101002764A
+CN101002827A
+CN101002973A
+CN101003509A
+CN101003539A
+CN101006984B
+CN101006995A
+CN101006998A
+CN101007087A
+CN101007165A
+CN101007174A
+CN101007809A
+CN101007838A
+CN101010087B
+CN101010102A
+CN101011358A
+CN101011361A
+CN101011362A
+CN101011370A
+CN101011380A
+CN101011383A
+CN101011513A
+CN101011543A
+CN101015524B
+CN101015543A
+CN101015637A
+CN101018775A
+CN101019827A
+CN101019843A
+CN101019844A
+CN101019847A
+CN101019851B
+CN101019856A
+CN101019870A
+CN101019895B
+CN101020059B
+CN101020705A
+CN101023925A
+CN101023944A
+CN101024055A
+CN101027051A
+CN101027059B
+CN101028275A
+CN101028381A
+CN101028417A
+CN101028454A
+CN101032469A
+CN101032473B
+CN101032496A
+CN101036651A
+CN101036654B
+CN101036660A
+CN101036669A
+CN101036722A
+CN101037415A
+CN101040862A
+CN101040905B
+CN101040959A
+CN101040972A
+CN101041079A
+CN101041641A
+CN101041652B
+CN101045048B
+CN101045155A
+CN101045732A
+CN101048149A
+CN101049301A
+CN101050170A
+CN101052384B
+CN101053553B
+CN101053565A
+CN101057855A
+CN101058578A
+CN101062020A
+CN101062030A
+CN101062052A
+CN101062087A
+CN101062194B
+CN101062309A
+CN101066281A
+CN101066956A
+CN101066980A
+CN101067006A
+CN101069729A
+CN101070291A
+CN101070307A
+CN101074249A
+CN101074252B
+CN101077348A
+CN101077862A
+CN101077865A
+CN101081816A
+CN101084868A
+CN101084879A
+CN101084889B
+CN101085075A
+CN101085355A
+CN101087777B
+CN101088497A
+CN101088982A
+CN101091690A
+CN101091709A
+CN101092433A
+CN101095669A
+CN101095675A
+CN101095924A
+CN101099739A
+CN101099744A
+CN101099861A
+CN101102816A
+CN101103985A
+CN101103994A
+CN101104602A
+CN101104864B
+CN101108163A
+CN101108172A
+CN101108173A
+CN101108848A
+CN101108866A
+CN101112396A
+CN101112409A
+CN101117349B
+CN101125125A
+CN101125139A
+CN101125289A
+CN101125837B
+CN101125865A
+CN101129338A
+CN101129350A
+CN101129374A
+CN101129378A
+CN101129388B
+CN101129423A
+CN101129446A
+CN101129501A
+CN101129522A
+CN101129562A
+CN101129948B
+CN101130083B
+CN101134026A
+CN101134039A
+CN101143138B
+CN101143143A
+CN101147752A
+CN101147803B
+CN101148418A
+CN101148437B
+CN101148445A
+CN101152129A
+CN101152144A
+CN101152147B
+CN101152153A
+CN101152163A
+CN101152167B
+CN101152169A
+CN101152172A
+CN101152176B
+CN101152202A
+CN101152205A
+CN101152229A
+CN101156917B
+CN101157689A
+CN101157716B
+CN101161246B
+CN101166732A
+CN101172957B
+CN101175751B
+CN101181388B
+CN101181578B
+CN101185630A
+CN101185868B
+CN101190176A
+CN101190177A
+CN101190190A
+CN101190202A
+CN101190237A
+CN101190917B
+CN101194893A
+CN101194920B
+CN101194940A
+CN101195799A
+CN101199493A
+CN101199527A
+CN101199787B
+CN101199797A
+CN101199855A
+CN101199857B
+CN101204387A
+CN101204388A
+CN101204484A
+CN101204554B
+CN101205205A
+CN101209354B
+CN101210037A
+CN101214255A
+CN101214330B
+CN101214353B
+CN101215297A
+CN101219156A
+CN101219220A
+CN101223139B
+CN101224194B
+CN101224214A
+CN101224265A
+CN101224306B
+CN101225066B
+CN101225070A
+CN101229119A
+CN101229147B
+CN101229150A
+CN101229153A
+CN101229169B
+CN101229172B
+CN101229218A
+CN101229228A
+CN101229278A
+CN101229313B
+CN101230074A
+CN101234090A
+CN101234092A
+CN101234094B
+CN101234107A
+CN101234149B
+CN101234195A
+CN101234203B
+CN101234204A
+CN101234788A
+CN101235048A
+CN101235079A
+CN101235373A
+CN101239045A
+CN101239073A
+CN101239101A
+CN101239918B
+CN101239979A
+CN101244044A
+CN101244046A
+CN101244049A
+CN101244065A
+CN101244075B
+CN101244135A
+CN101244142A
+CN101244187A
+CN101249069B
+CN101249070A
+CN101249088A
+CN101249113A
+CN101249163A
+CN101250182A
+CN101250185B
+CN101254168A
+CN101254170A
+CN101254179A
+CN101254188A
+CN101254246B
+CN101254249B
+CN101254282B
+CN101255179B
+CN101259177A
+CN101259237A
+CN101263145A
+CN101264080A
+CN101264089A
+CN101264329A
+CN101265178A
+CN101265281A
+CN101268050B
+CN101269005A
+CN101269047A
+CN101269053A
+CN101269209A
+CN101269219B
+CN101270052B
+CN101270126A
+CN101273973B
+CN101273986A
+CN101274027B
+CN101274050B
+CN101274054A
+CN101275132B
+CN101278927A
+CN101278976A
+CN101279901B
+CN101283968B
+CN101283969A
+CN101283999A
+CN101284000A
+CN101284005A
+CN101284112B
+CN101284861A
+CN101288666A
+CN101288671A
+CN101288717A
+CN101289455B
+CN101291934B
+CN101292963A
+CN101292969A
+CN101292992A
+CN101293831A
+CN101296707A
+CN101297797A
+CN101298415A
+CN101300014A
+CN101301292A
+CN101301346A
+CN101301477A
+CN101302235B
+CN101302510A
+CN101306133A
+CN101307038A
+CN101307306A
+CN101310710A
+CN101310717B
+CN101310725A
+CN101313895B
+CN101314591B
+CN101314604A
+CN101317819A
+CN101317849A
+CN101317876A
+CN101317927A
+CN101318014A
+CN101318909A
+CN101318965A
+CN101318980A
+CN101322706A
+CN101322717A
+CN101322751A
+CN101327168B
+CN101327192A
+CN101327209A
+CN101327221A
+CN101327238A
+CN101327267A
+CN101328181A
+CN101332177A
+CN101332178A
+CN101332187A
+CN101332188B
+CN101332195A
+CN101332301A
+CN101333218B
+CN101333242A
+CN101336924B
+CN101336927A
+CN101336931B
+CN101336958A
+CN101336960A
+CN101337006A
+CN101337065B
+CN101337067A
+CN101337072B
+CN101337075B
+CN101337987A
+CN101341142A
+CN101342146A
+CN101342156A
+CN101342184B
+CN101342202A
+CN101342240B
+CN101342262A
+CN101342277A
+CN101343078A
+CN101343290A
+CN101347232A
+CN101347455A
+CN101348477A
+CN101348513A
+CN101352418B
+CN101352423B
+CN101352427A
+CN101352428B
+CN101352449A
+CN101352450A
+CN101352503A
+CN101352550A
+CN101353377A
+CN101357116A
+CN101357952B
+CN101361710A
+CN101361731A
+CN101361744A
+CN101361753A
+CN101361907B
+CN101361980A
+CN101366694A
+CN101366705A
+CN101366717B
+CN101366858B
+CN101367819A
+CN101367850B
+CN101370495B
+CN101371820B
+CN101371832B
+CN101371845A
+CN101372491A
+CN101374514A
+CN101375872A
+CN101376658A
+CN101379024B
+CN101380293A
+CN101381320B
+CN101381374B
+CN101381725A
+CN101385714A
+CN101385724A
+CN101385779A
+CN101385833A
+CN101386580A
+CN101386617B
+CN101390848B
+CN101390854A
+CN101390855A
+CN101390864A
+CN101390870A
+CN101390879B
+CN101396348A
+CN101396350A
+CN101396488A
+CN101396560B
+CN101396561A
+CN101396563A
+CN101397300B
+CN101400655A
+CN101401801B
+CN101401806A
+CN101401814B
+CN101401885A
+CN101402650A
+CN101406450A
+CN101406503A
+CN101406674A
+CN101407459A
+CN101407558B
+CN101411701A
+CN101411756A
+CN101411792A
+CN101412707A
+CN101415705A
+CN101416937A
+CN101416939A
+CN101416944A
+CN101416983A
+CN101417133A
+CN101417997A
+CN101422446B
+CN101422458A
+CN101422463A
+CN101422469A
+CN101422484B
+CN101422531B
+CN101426487B
+CN101426495A
+CN101427992A
+CN101427994A
+CN101428030A
+CN101428035A
+CN101429201A
+CN101429216A
+CN101433519A
+CN101433545A
+CN101433550A
+CN101433556A
+CN101433565A
+CN101434570B
+CN101434601A
+CN101439021A
+CN101439039B
+CN101439046B
+CN101439049A
+CN101439091B
+CN101439182A
+CN101444491B
+CN101444492B
+CN101444614B
+CN101461566B
+CN101466683B
+CN101473999B
+CN101474158B
+CN101475458B
+CN101475484B
+CN101475565B
+CN101475615B
+CN101480408B
+CN101485728B
+CN101492461B
+CN101492475B
+CN101492715B
+CN101496813B
+CN101502486A
+CN101502512A
+CN101502516B
+CN101502521A
+CN101502522A
+CN101502569A
+CN101502645A
+CN101503454A
+CN101507718B
+CN101508668A
+CN101513407A
+CN101513411A
+CN101513415A
+CN101513433A
+CN101518509A
+CN101518569B
+CN101519378B
+CN101524340A
+CN101524342A
+CN101524360A
+CN101525319A
+CN101525360A
+CN101525366A
+CN101530386A
+CN101530403A
+CN101530415A
+CN101530419A
+CN101531613B
+CN101536977A
+CN101536995B
+CN101537001A
+CN101537019A
+CN101537148A
+CN101538256A
+CN101538262A
+CN101538272B
+CN101538299A
+CN101543474A
+CN101543496A
+CN101543506A
+CN101543530A
+CN101543540A
+CN101544602A
+CN101547695B
+CN101548949A
+CN101548955B
+CN101548956A
+CN101549039A
+CN101549151A
+CN101550138B
+CN101553234A
+CN101554372B
+CN101554382A
+CN101559214A
+CN101564428A
+CN101565402A
+CN101570539B
+CN101574343B
+CN101574352A
+CN101574394A
+CN101574444A
+CN101574519A
+CN101575315B
+CN101578283A
+CN101579328A
+CN101579353A
+CN101579438A
+CN101579469B
+CN101584661B
+CN101584702B
+CN101585799B
+CN101585841A
+CN101590009A
+CN101590014A
+CN101590026B
+CN101590048A
+CN101590050A
+CN101590061A
+CN101590067A
+CN101590090A
+CN101590150A
+CN101591288A
+CN101591298A
+CN101591316A
+CN101591323A
+CN101591333A
+CN101596190A
+CN101596200A
+CN101596202A
+CN101596245A
+CN101597280A
+CN101601647B
+CN101601666A
+CN101601667A
+CN101601680A
+CN101601681A
+CN101601722A
+CN101601799A
+CN101602737A
+CN101606907A
+CN101606921B
+CN101606929A
+CN101606947A
+CN101606949A
+CN101612170B
+CN101613414B
+CN101618030B
+CN101618082B
+CN101619040B
+CN101623259B
+CN101623502B
+CN101627991A
+CN101628063B
+CN101628115B
+CN101628903B
+CN101632638B
+CN101632642B
+CN101632764B
+CN101632795B
+CN101633671B
+CN101637592B
+CN101638385B
+CN101642461B
+CN101642570B
+CN101647775B
+CN101647794B
+CN101647865B
+CN101648867B
+CN101649004B
+CN101653436A
+CN101654499B
+CN101654529B
+CN101658489B
+CN101658495B
+CN101658528B
+CN101658646B
+CN101669907A
+CN101669908A
+CN101669927B
+CN101669931B
+CN101669941B
+CN101669943A
+CN101669961B
+CN101669989B
+CN101670094A
+CN101675990A
+CN101679456A
+CN101683316A
+CN101683364B
+CN101683486A
+CN101683517A
+CN101684099A
+CN101686981A
+CN101686996A
+CN101687795A
+CN101691372B
+CN101693030A
+CN101693034A
+CN101693711A
+CN101693885A
+CN101695479A
+CN101695488B
+CN101695513A
+CN101696228A
+CN101698103B
+CN101700221A
+CN101703462A
+CN101703479A
+CN101703489B
+CN101703512A
+CN101703514A
+CN101703522A
+CN101703627A
+CN101703649A
+CN101703754A
+CN101708154A
+CN101708164A
+CN101711741B
+CN101711743B
+CN101711763A
+CN101711766A
+CN101712618A
+CN101712655B
+CN101716145A
+CN101716147A
+CN101716152A
+CN101716165A
+CN101716170A
+CN101716171A
+CN101716173A
+CN101716182A
+CN101716219B
+CN101716222A
+CN101721360A
+CN101721382B
+CN101721387A
+CN101721415A
+CN101721478B
+CN101721665A
+CN101721713B
+CN101724033A
+CN101724055A
+CN101732251A
+CN101732256A
+CN101732259A
+CN101732264B
+CN101732297A
+CN101732325A
+CN101732327A
+CN101732332A
+CN101732425A
+CN101732714A
+CN101732727B
+CN101735211B
+CN101743242A
+CN101744763A
+CN101744777A
+CN101744778A
+CN101744781A
+CN101744784A
+CN101744804A
+CN101744828A
+CN101744851A
+CN101744922A
+CN101744976A
+CN101747258A
+CN101747329A
+CN101756895B
+CN101756899A
+CN101756907B
+CN101756913A
+CN101756914B
+CN101756928A
+CN101756931A
+CN101756933A
+CN101756939A
+CN101756946A
+CN101756955A
+CN101756961A
+CN101757024A
+CN101757026A
+CN101757069A
+CN101757182A
+CN101757374A
+CN101757614A
+CN101757623A
+CN101760389A
+CN101766547A
+CN101766608A
+CN101766691A
+CN101766700A
+CN101768097A
+CN101768173A
+CN101768183A
+CN101773463A
+CN101773506A
+CN101773518A
+CN101774993A
+CN101780039A
+CN101780042A
+CN101780101A
+CN101780104A
+CN101780121A
+CN101780183A
+CN101781294A
+CN101785772A
+CN101785774A
+CN101786976A
+CN101786993A
+CN101787029A
+CN101790553B
+CN101791292A
+CN101791293A
+CN101791302B
+CN101792401B
+CN101792443A
+CN101792448B
+CN101792475A
+CN101792477A
+CN101795686A
+CN101797254A
+CN101797258A
+CN101797304A
+CN101797307B
+CN101797374A
+CN101798315B
+CN101801980A
+CN101804025B
+CN101804032A
+CN101804037A
+CN101805330A
+CN101805355A
+CN101805387A
+CN101805412A
+CN101810610A
+CN101810611A
+CN101810615A
+CN101810625A
+CN101810632A
+CN101810668A
+CN101812025A
+CN101812040A
+CN101812063A
+CN101812079B
+CN101812097A
+CN101812102A
+CN101812491A
+CN101816667A
+CN101816668B
+CN101816753A
+CN101817852A
+CN101822663A
+CN101822680A
+CN101822745A
+CN101822810A
+CN101824102A
+CN101829066A
+CN101829074A
+CN101829084A
+CN101829090A
+CN101829140A
+CN101829154A
+CN101829329A
+CN101830935B
+CN101836965A
+CN101837006A
+CN101843625A
+CN101844811A
+CN101845033A
+CN101845069A
+CN101850087A
+CN101851162A
+CN101851237A
+CN101851241B
+CN101851298A
+CN101856116A
+CN101856347A
+CN101856352A
+CN101856356B
+CN101856385A
+CN101857590A
+CN101862337B
+CN101862348A
+CN101862382A
+CN101863823A
+CN101869564A
+CN101869634B
+CN101869708A
+CN101870647A
+CN101871931A
+CN101874761A
+CN101874788A
+CN101874826A
+CN101875686A
+CN101878041A
+CN101879150A
+CN101879217A
+CN101879220A
+CN101884612A
+CN101884621A
+CN101884645A
+CN101884648A
+CN101885676A
+CN101885725A
+CN101890006A
+CN101890036A
+CN101890043A
+CN101890049A
+CN101890075A
+CN101890105A
+CN101891697A
+CN101891705B
+CN101891769A
+CN101892181B
+CN101897666A
+CN101897668A
+CN101897712A
+CN101897713A
+CN101897735A
+CN101897967A
+CN101899006A
+CN101899013B
+CN101899053A
+CN101906085B
+CN101910177A
+CN101912360A
+CN101912361A
+CN101912368A
+CN101912402B
+CN101912405A
+CN101912410A
+CN101912544A
+CN101912554A
+CN101918036A
+CN101919620A
+CN101919815A
+CN101919817B
+CN101919819A
+CN101919840A
+CN101919865A
+CN101919872A
+CN101919936A
+CN101921303A
+CN101926503A
+CN101926765A
+CN101926791A
+CN101926803A
+CN101926817A
+CN101926820A
+CN101926823A
+CN101926825A
+CN101926965A
+CN101933914A
+CN101933919A
+CN101933945A
+CN101933973B
+CN101934115A
+CN101935306A
+CN101939315A
+CN101940549A
+CN101940555A
+CN101940559A
+CN101940618B
+CN101940747A
+CN101940749A
+CN101947220A
+CN101947221A
+CN101947230A
+CN101947235A
+CN101947269B
+CN101952261A
+CN101953775A
+CN101953805A
+CN101953811A
+CN101953859A
+CN101953932A
+CN101955459A
+CN101955976A
+CN101961323A
+CN101961329A
+CN101961378A
+CN101961490A
+CN101966147A
+CN101966154A
+CN101967144A
+CN101970430A
+CN101972243A
+CN101972257A
+CN101972350A
+CN101972412B
+CN101972489A
+CN101973868A
+CN101973938B
+CN101973957A
+CN101977910A
+CN101983684B
+CN101983715A
+CN101984957B
+CN101987101A
+CN101987120B
+CN101987136A
+CN101987180A
+CN101987830A
+CN101987835A
+CN101991556A
+CN101991665B
+CN101991718A
+CN102000023B
+CN102000035A
+CN102000057B
+CN102000069A
+CN102000081A
+CN102000085A
+CN102000088A
+CN102000098A
+CN102000101A
+CN102000153A
+CN102000163A
+CN102002024B
+CN102006868A
+CN102008500A
+CN102008506B
+CN102008522A
+CN102008625A
+CN102008715A
+CN102008727B
+CN102010420A
+CN102010425A
+CN102015678A
+CN102018666A
+CN102018685A
+CN102018694A
+CN102018704A
+CN102018732A
+CN102018735A
+CN102018755B
+CN102020598A
+CN102028666A
+CN102028696A
+CN102030764A
+CN102030765A
+CN102038637A
+CN102038645A
+CN102038650A
+CN102038652A
+CN102038658A
+CN102038659A
+CN102038664A
+CN102038682A
+CN102038685A
+CN102038792A
+CN102040556B
+CN102046202A
+CN102048704A
+CN102048747A
+CN102048780A
+CN102048827A
+CN102048938A
+CN102050759A
+CN102050809A
+CN102056902A
+CN102058547A
+CN102058552B
+CN102058563A
+CN102058581A
+CN102058584B
+CN102058596A
+CN102058620A
+CN102058800A
+CN102060759A
+CN102060875A
+CN102068420A
+CN102068421A
+CN102068487A
+CN102070608A
+CN102070645A
+CN102070670A
+CN102071461B
+CN102076339A
+CN102078312A
+CN102078316A
+CN102078637A
+CN102079700A
+CN102083810A
+CN102085192A
+CN102085211A
+CN102086185A
+CN102088974A
+CN102091059A
+CN102091086A
+CN102091179A
+CN102093308B
+CN102093373A
+CN102093462B
+CN102100667A
+CN102100735A
+CN102101865A
+CN102106813A
+CN102106822A
+CN102106835A
+CN102106842A
+CN102106847A
+CN102106848A
+CN102106850A
+CN102106994A
+CN102107007B
+CN102108372A
+CN102114037A
+CN102114168B
+CN102119929B
+CN102119951A
+CN102120724A
+CN102123991A
+CN102125530A
+CN102125665A
+CN102131503A
+CN102131508A
+CN102133211A
+CN102133395A
+CN102138893A
+CN102138896B
+CN102138910B
+CN102138917A
+CN102139107B
+CN102140126B
+CN102144970B
+CN102144994A
+CN102145110B
+CN102145159B
+CN102145175A
+CN102146081B
+CN102146108A
+CN102146115A
+CN102149671A
+CN102149703A
+CN102151257A
+CN102151263B
+CN102151299A
+CN102153498A
+CN102160863A
+CN102161655A
+CN102166196A
+CN102166209B
+CN102166211A
+CN102172410A
+CN102176916A
+CN102178649A
+CN102178684A
+CN102178691B
+CN102178693A
+CN102178716A
+CN102178846A
+CN102178933A
+CN102188073A
+CN102188368A
+CN102188386A
+CN102188425A
+CN102188426A
+CN102188430A
+CN102188443A
+CN102188718A
+CN102188719A
+CN102190589A
+CN102190656A
+CN102198106A
+CN102198111A
+CN102198113A
+CN102198118A
+CN102198121B
+CN102198166A
+CN102198272A
+CN102199134A
+CN102199163A
+CN102203093A
+CN102204888A
+CN102204905A
+CN102204926A
+CN102205011A
+CN102205094A
+CN102206172A
+CN102206177A
+CN102206213A
+CN102210672A
+CN102210677A
+CN102210784B
+CN102210823A
+CN102212051A
+CN102212069A
+CN102212103A
+CN102215844A
+CN102218065A
+CN102218074A
+CN102218120A
+CN102218133A
+CN102225087A
+CN102225094A
+CN102225133A
+CN102227419A
+CN102228441A
+CN102228445A
+CN102228447A
+CN102228451A
+CN102228454A
+CN102228466A
+CN102228540A
+CN102228676A
+CN102228689A
+CN102232967A
+CN102234249A
+CN102239838A
+CN102240296A
+CN102240319A
+CN102240372A
+CN102240374A
+CN102240403A
+CN102241596A
+CN102247369A
+CN102247382A
+CN102247414A
+CN102247477A
+CN102249936A
+CN102250045A
+CN102250085A
+CN102250144A
+CN102250170A
+CN102256989A
+CN102274203B
+CN102293778B
+CN102302442A
+CN102302453A
+CN102302478A
+CN102302497A
+CN102302502A
+CN102302587A
+CN102302677A
+CN102302783A
+CN102309461A
+CN102309470A
+CN102309476A
+CN102309752A
+CN102309756A
+CN102309761A
+CN102317282A
+CN102319239A
+CN102319272B
+CN102319273A
+CN102319369A
+CN102320989A
+CN102321080A
+CN102321131A
+CN102327214A
+CN102327216A
+CN102327240A
+CN102327275A
+CN102327365A
+CN102327419A
+CN102335128A
+CN102335266A
+CN102335357A
+CN102342330A
+CN102342929A
+CN102342949B
+CN102342951A
+CN102343091A
+CN102344442A
+CN102349543A
+CN102349890A
+CN102349893A
+CN102351852A
+CN102356085A
+CN102357085A
+CN102357088A
+CN102357100A
+CN102357215A
+CN102358742A
+CN102361868A
+CN102366414A
+CN102366422A
+CN102366484A
+CN102370627A
+CN102370639A
+CN102370653A
+CN102370981A
+CN102372701A
+CN102372717A
+CN102378761A
+CN102382073A
+CN102382082B
+CN102382202A
+CN102389396A
+CN102389412B
+CN102389433A
+CN102429870A
+CN102429873A
+CN102429909A
+CN102429913A
+CN102429931A
+CN102440956A
+CN102448495A
+CN102448930A
+CN102451169A
+CN102451350A
+CN102451351A
+CN102475890A
+CN102485222A
+CN102488677A
+CN102497866A
+CN102499909A
+CN102503882A
+CN102503888A
+CN102503954A
+CN102503987A
+CN102512415A
+CN102512446A
+CN102512489A
+CN102516079A
+CN102525891A
+CN102525911A
+CN102525924A
+CN102525968A
+CN102525982A
+CN102525998A
+CN102526036A
+CN102526052A
+CN102526064A
+CN102526080A
+CN102526087A
+CN102526089A
+CN102526099A
+CN102526118A
+CN102526132A
+CN102526738A
+CN102526752A
+CN102532055A
+CN102532092A
+CN102552104A
+CN102552109A
+CN102552132A
+CN102552139A
+CN102552153A
+CN102552181A
+CN102552190A
+CN102552197A
+CN102552203A
+CN102552210B
+CN102552229A
+CN102552247A
+CN102552272A
+CN102552279A
+CN102552280A
+CN102552285A
+CN102552381A
+CN102552389A
+CN102552453A
+CN102552535A
+CN102552642A
+CN102552645A
+CN102552689A
+CN102552848A
+CN102552885A
+CN102557972A
+CN102558045A
+CN102558088A
+CN102558128A
+CN102558142A
+CN102558159A
+CN102558235A
+CN102558261A
+CN102574825A
+CN102579326A
+CN102579392A
+CN102579435A
+CN102579455A
+CN102579469A
+CN102579485A
+CN102579546A
+CN102579926A
+CN102584760A
+CN102584826A
+CN102584871A
+CN102596197A
+CN102600065A
+CN102600100A
+CN102600102A
+CN102600139A
+CN102600159A
+CN102600160A
+CN102600478A
+CN102603861A
+CN102603924A
+CN102614114A
+CN102614184A
+CN102614196A
+CN102614252A
+CN102614292A
+CN102617471A
+CN102617561A
+CN102617573A
+CN102617584A
+CN102617676A
+CN102626386A
+CN102626412A
+CN102627624A
+CN102631388A
+CN102631562A
+CN102633637A
+CN102633849A
+CN102633856A
+CN102641238A
+CN102641266A
+CN102641371A
+CN102648915A
+CN102652736A
+CN102652737A
+CN102652746A
+CN102652750A
+CN102652752A
+CN102659630A
+CN102659687A
+CN102659765A
+CN102665703A
+CN102670490A
+CN102670496A
+CN102670541A
+CN102670548A
+CN102670559A
+CN102670606A
+CN102670645A
+CN102670685A
+CN102670927A
+CN102670972A
+CN102671198A
+CN102675305A
+CN102675330A
+CN102675406A
+CN102675621A
+CN102686569A
+CN102688232A
+CN102688257A
+CN102688370A
+CN102688478A
+CN102690326A
+CN102696481A
+CN102697718A
+CN102697725A
+CN102697753A
+CN102697756A
+CN102697792A
+CN102698243A
+CN102698283A
+CN102702052B
+CN102702134A
+CN102716072A
+CN102716083A
+CN102716085A
+CN102716088A
+CN102716122A
+CN102716134A
+CN102716135A
+CN102716140A
+CN102716197A
+CN102718675A
+CN102718769A
+CN102719397A
+CN102727423A
+CN102727450A
+CN102727455A
+CN102727475A
+CN102727491A
+CN102727505A
+CN102727784A
+CN102727867A
+CN102731380A
+CN102731410A
+CN102731468A
+CN102731492A
+CN102731573A
+CN102731586A
+CN102743351A
+CN102743363A
+CN102743379A
+CN102743387A
+CN102746159A
+CN102746264A
+CN102746278A
+CN102746309A
+CN102755315A
+CN102755317A
+CN102755345A
+CN102757386A
+CN102764259A
+CN102764263A
+CN102766122A
+CN102766180A
+CN102766632A
+CN102772362A
+CN102772378A
+CN102772498A
+CN102775289A
+CN102775389A
+CN102784070A
+CN102784102A
+CN102784149A
+CN102784153A
+CN102784188A
+CN102786394A
+CN102786414A
+CN102786418A
+CN102786570A
+CN102786576A
+CN102793663A
+CN102793775A
+CN102793830A
+CN102793883A
+CN102793930A
+CN102796084A
+CN102796097A
+CN102796645A
+CN102805826A
+CN102811714A
+CN102813112A
+CN102813644A
+CN102813656A
+CN102813669A
+CN102813727A
+CN102813889A
+CN102813892A
+CN102816067A
+CN102816146A
+CN102824316A
+CN102824331A
+CN102824333A
+CN102824340A
+CN102824364A
+CN102824517A
+CN102826982A
+CN102827172A
+CN102836118A
+CN102836138A
+CN102836156A
+CN102838485A
+CN102838617A
+CN102846541A
+CN102846566A
+CN102846587A
+CN102846606A
+CN102846622A
+CN102846629A
+CN102846631A
+CN102846654A
+CN102846659A
+CN102846800A
+CN102846991A
+CN102850335A
+CN102850337A
+CN102850344A
+CN102850345A
+CN102861006A
+CN102861022A
+CN102861039A
+CN102861062A
+CN102861067A
+CN102861075A
+CN102861079A
+CN102861217A
+CN102861339A
+CN102863419A
+CN102871963A
+CN102871983A
+CN102872003A
+CN102872004A
+CN102872028A
+CN102872033A
+CN102872045A
+CN102872071A
+CN102872099A
+CN102872109A
+CN102872121A
+CN102872124A
+CN102872126A
+CN102872136A
+CN102872352A
+CN102875375A
+CN102875472A
+CN102875517A
+CN102875627A
+CN102875630A
+CN102883717A
+CN102885346A
+CN102885807A
+CN102885810A
+CN102885820A
+CN102885822A
+CN102885829A
+CN102885838A
+CN102885853A
+CN102885891A
+CN102886014A
+CN102886041A
+CN102887895A
+CN102895224A
+CN102895236A
+CN102895250A
+CN102895255A
+CN102895308A
+CN102895433A
+CN102895539A
+CN102895623A
+CN102895631A
+CN102895633A
+CN102898377A
+CN102898426A
+CN102898438A
+CN102898641A
+CN102908320A
+CN102908323A
+CN102908343A
+CN102908348A
+CN102908362A
+CN102908525A
+CN102908572A
+CN102908591A
+CN102908597A
+CN102911226A
+CN102911989A
+CN102918047A
+CN102920666A
+CN102920671A
+CN102920689A
+CN102920704A
+CN102920706A
+CN102920947A
+CN102924318A
+CN102924399A
+CN102924426A
+CN102924437A
+CN102924488A
+CN102933237A
+CN102935221A
+CN102940632A
+CN102940634A
+CN102940635A
+CN102949291A
+CN102949338A
+CN102949346A
+CN102949363A
+CN102949400A
+CN102949436A
+CN102949448A
+CN102949694A
+CN102949725A
+CN102952202A
+CN102961250A
+CN102961327A
+CN102961333A
+CN102961344A
+CN102961373A
+CN102961378A
+CN102961380A
+CN102961383A
+CN102961536A
+CN102961744A
+CN102964267A
+CN102964322A
+CN102964386A
+CN102973494A
+CN102973523A
+CN102973528A
+CN102973551A
+CN102973564A
+CN102973571A
+CN102973578A
+CN102973612A
+CN102973662A
+CN102973666A
+CN102973946A
+CN102976974A
+CN102977110A
+CN102977111A
+CN102977146A
+CN102985422A
+CN102986963A
+CN102988286A
+CN102988297A
+CN102988302A
+CN102988326A
+CN102988340A
+CN102988357A
+CN102988369A
+CN102988468A
+CN102988595A
+CN102989003A
+CN102989005A
+CN102993018A
+CN102993150A
+CN102993208A
+CN102993348A
+CN103003234A
+CN103006593A
+CN103006624A
+CN103006633A
+CN103006640A
+CN103006660A
+CN103006663A
+CN103006673A
+CN103007294A
+CN103012231A
+CN103012420A
+CN103025325A
+CN103027846A
+CN103027894A
+CN103027913A
+CN103027914A
+CN103038238A
+CN103040102A
+CN103040795A
+CN103040827A
+CN103040828A
+CN103040835A
+CN103040849A
+CN103040930A
+CN103041168A
+CN103041373A
+CN103041448A
+CN103043635A
+CN103044224A
+CN103044375A
+CN103044446A
+CN103044509A
+CN103054169A
+CN103054795A
+CN103054802A
+CN103054822A
+CN103054829A
+CN103054846A
+CN103054850A
+CN103054853A
+CN103054854A
+CN103054865A
+CN103054874A
+CN103054880A
+CN103054882A
+CN103054972A
+CN103054992A
+CN103058943A
+CN103059160A
+CN103070828A
+CN103070852A
+CN103070935A
+CN103070967A
+CN103073650A
+CN103083235A
+CN103083238A
+CN103083252A
+CN103083262A
+CN103083264A
+CN103083279A
+CN103083289A
+CN103083290A
+CN103083294A
+CN103083299A
+CN103083304A
+CN103083306A
+CN103083327A
+CN103083338A
+CN103086972A
+CN103087024A
+CN103087045A
+CN103087325A
+CN103096908A
+CN103099797A
+CN103099802A
+CN103099812A
+CN103102315A
+CN103108634A
+CN103108882A
+CN103110578A
+CN103110588A
+CN103110599A
+CN103110601A
+CN103110631A
+CN103110638A
+CN103110658A
+CN103113202A
+CN103113355A
+CN103113359A
+CN103118675A
+CN103120664A
+CN103120671A
+CN103120676A
+CN103120680A
+CN103120689A
+CN103120695A
+CN103120703A
+CN103120795A
+CN103120797A
+CN103126987A
+CN103126993A
+CN103127001A
+CN103127006A
+CN103127014A
+CN103127085A
+CN103127107A
+CN103127116A
+CN103127136A
+CN103127146A
+CN103127147A
+CN103127178A
+CN103127308A
+CN103127494A
+CN103127510A
+CN103127512A
+CN103127514A
+CN103130632A
+CN103130730A
+CN103130774A
+CN103130775A
+CN103130791A
+CN103130860A
+CN103142500A
+CN103142524A
+CN103142530A
+CN103142544A
+CN103142552A
+CN103142564A
+CN103142575A
+CN103142591A
+CN103142613A
+CN103142633A
+CN103142992A
+CN103145663A
+CN103145706A
+CN103145794A
+CN103145868A
+CN103153963A
+CN103156821A
+CN103156849A
+CN103156919A
+CN103159748A
+CN103159788A
+CN103168774A
+CN103169673A
+CN103169698A
+CN103169757A
+CN103169793A
+CN103172658A
+CN103181898A
+CN103181907A
+CN103181911A
+CN103181914A
+CN103181946A
+CN103182003A
+CN103182044A
+CN103182083A
+CN103191061A
+CN103191068A
+CN103191080A
+CN103191091A
+CN103191100A
+CN103191102A
+CN103191104A
+CN103191142A
+CN103191184A
+CN103191445A
+CN103193644A
+CN103193659A
+CN103193738A
+CN103193860A
+CN103202317A
+CN103202814A
+CN103202830A
+CN103202849A
+CN103202971A
+CN103202999A
+CN103204897A
+CN103209692A
+CN103209707A
+CN103209977A
+CN103211778A
+CN103211779A
+CN103211784A
+CN103211791A
+CN103212089A
+CN103214370A
+CN103214454A
+CN103214486A
+CN103214547A
+CN103222970A
+CN103223172A
+CN103228274A
+CN103230364A
+CN103230386A
+CN103230407A
+CN103230411A
+CN103230417A
+CN103230601A
+CN103232420A
+CN103239389A
+CN103239425A
+CN103239452A
+CN103239455A
+CN103239463A
+CN103239466A
+CN103239506A
+CN103239600A
+CN103239705A
+CN103239718A
+CN103251599A
+CN103251603A
+CN103251613A
+CN103251637A
+CN103251653A
+CN103251934A
+CN103254155A
+CN103263383A
+CN103263386A
+CN103263407A
+CN103263533A
+CN103263677A
+CN103265517A
+CN103265559A
+CN103265561A
+CN103271877A
+CN103271898A
+CN103271899A
+CN103271912A
+CN103271913A
+CN103271931A
+CN103271940A
+CN103272114A
+CN103272244A
+CN103274987A
+CN103275048A
+CN103275140A
+CN103284043A
+CN103284158A
+CN103284947A
+CN103284954A
+CN103284958A
+CN103284985A
+CN103285002A
+CN103285003A
+CN103285004A
+CN103285044A
+CN103285049A
+CN103285332A
+CN103285381A
+CN103288614A
+CN103288664A
+CN103298816A
+CN103301061A
+CN103301075A
+CN103301081A
+CN103301098A
+CN103301108A
+CN103301140A
+CN103301141A
+CN103301470A
+CN103304552A
+CN103304559A
+CN103304571A
+CN103304580A
+CN103305567A
+CN103313978A
+CN103315287A
+CN103315965A
+CN103315967A
+CN103315970A
+CN103315985A
+CN103316022A
+CN103316026A
+CN103316032A
+CN103316078A
+CN103316350A
+CN103319327A
+CN103319497A
+CN103328441A
+CN103330689A
+CN103330807A
+CN103330812A
+CN103333173A
+CN103333267A
+CN103340834A
+CN103340848A
+CN103340877A
+CN103340954A
+CN103340971A
+CN103342755A
+CN103347527A
+CN103347859A
+CN103349646A
+CN103355665A
+CN103356499A
+CN103356500A
+CN103356507A
+CN103356521A
+CN103356527A
+CN103356542A
+CN103356561A
+CN103356571A
+CN103356573A
+CN103356608A
+CN103356617A
+CN103356635A
+CN103356663A
+CN103356719A
+CN103356872A
+CN103357022A
+CN103360310A
+CN103360370A
+CN103360401A
+CN103360427A
+CN103371924A
+CN103371967A
+CN103371974A
+CN103371983A
+CN103371985A
+CN103371997A
+CN103372021A
+CN103372039A
+CN103380115A
+CN103381175A
+CN103381204A
+CN103382190A
+CN103385859A
+CN103385866A
+CN103385871A
+CN103391780A
+CN103391783A
+CN103393619A
+CN103393645A
+CN103393653A
+CN103393671A
+CN103393686A
+CN103393692A
+CN103393717A
+CN103393762A
+CN103393783A
+CN103394003A
+CN103394086A
+CN103396417A
+CN103405385A
+CN103405387A
+CN103405398A
+CN103405412A
+CN103405440A
+CN103405445A
+CN103405472A
+CN103405492A
+CN103405576A
+CN103405675A
+CN103405739A
+CN103408122A
+CN103408573A
+CN103417467A
+CN103417481A
+CN103417519A
+CN103417529A
+CN103417550A
+CN103417555A
+CN103417600A
+CN103417750A
+CN103417876A
+CN103417937A
+CN103420890A
+CN103420961A
+CN103421002A
+CN103421057A
+CN103421832A
+CN103432068A
+CN103432111A
+CN103432114A
+CN103432125A
+CN103432139A
+CN103432141A
+CN103432151A
+CN103432160A
+CN103432162A
+CN103432223A
+CN103432549A
+CN103432597A
+CN103435514A
+CN103446107A
+CN103446114A
+CN103446171A
+CN103446173A
+CN103446197A
+CN103446282A
+CN103446442A
+CN103446534A
+CN103446577A
+CN103446594A
+CN103450083A
+CN103450133A
+CN103459381A
+CN103462924A
+CN103462952A
+CN103462958A
+CN103462960A
+CN103462993A
+CN103463004A
+CN103463034A
+CN103463038A
+CN103463039A
+CN103463073A
+CN103463089A
+CN103463090A
+CN103463093A
+CN103463094A
+CN103463644A
+CN103467417A
+CN103467448A
+CN103467729A
+CN103476421A
+CN103476432A
+CN103477228A
+CN103479580A
+CN103479615A
+CN103479624A
+CN103479630A
+CN103479645A
+CN103479653A
+CN103479775A
+CN103479785A
+CN103479804A
+CN103479969A
+CN103483194A
+CN103483211A
+CN103483239A
+CN103483487A
+CN103493847A
+CN103494794A
+CN103494798A
+CN103494800A
+CN103494821A
+CN103494826A
+CN103494965A
+CN103494994A
+CN103495070A
+CN103497184A
+CN103497192A
+CN103501789A
+CN103505414A
+CN103505428A
+CN103505437A
+CN103505453A
+CN103505556A
+CN103505730A
+CN103505731A
+CN103505735A
+CN103508943A
+CN103509001A
+CN103509071A
+CN103520110A
+CN103520122A
+CN103520135A
+CN103520152A
+CN103520157A
+CN103520305A
+CN103520493A
+CN103520725A
+CN103520731A
+CN103524573A
+CN103536530A
+CN103536547A
+CN103536553A
+CN103536559A
+CN103536563A
+CN103536569A
+CN103536607A
+CN103536617A
+CN103536688A
+CN103536919A
+CN103536926A
+CN103539659A
+CN103539760A
+CN103539777A
+CN103547164A
+CN103550107A
+CN103550172A
+CN103550230A
+CN103550231A
+CN103553892A
+CN103561747A
+CN103565734A
+CN103565788A
+CN103565832A
+CN103565921A
+CN103566066A
+CN103566068A
+CN103566325A
+CN103570679A
+CN103570780A
+CN103583816A
+CN103583955A
+CN103585116A
+CN103585140A
+CN103585149A
+CN103585159A
+CN103585253A
+CN103588665A
+CN103588739A
+CN103599029A
+CN103599082A
+CN103599089A
+CN103599548A
+CN103601641A
+CN103601707A
+CN103601722A
+CN103601727A
+CN103610646A
+CN103610649A
+CN103610667A
+CN103610668A
+CN103610671A
+CN103610688A
+CN103610816A
+CN103611144A
+CN103611165A
+CN103613490A
+CN103613680A
+CN103622910A
+CN103622924A
+CN103622942A
+CN103622948A
+CN103622951A
+CN103622954A
+CN103622956A
+CN103626769A
+CN103626781A
+CN103626803A
+CN103626824A
+CN103635196A
+CN103636907A
+CN103638008A
+CN103638025A
+CN103638026A
+CN103638042A
+CN103638364A
+CN103641713A
+CN103648495A
+CN103648531A
+CN103649077A
+CN103655486A
+CN103655497A
+CN103655498A
+CN103655500A
+CN103655501A
+CN103655544A
+CN103655600A
+CN103656024A
+CN103656615A
+CN103656685A
+CN103664785A
+CN103664804A
+CN103664893A
+CN103664970A
+CN103664983A
+CN103675152A
+CN103690542A
+CN103690543A
+CN103690547A
+CN103690553A
+CN103690619A
+CN103694252A
+CN103705044A
+CN103705472A
+CN103705478A
+CN103705480A
+CN103705483A
+CN103705490A
+CN103705496A
+CN103705498A
+CN103705499A
+CN103705586A
+CN103705922A
+CN103705927A
+CN103709093A
+CN103709162A
+CN103717592A
+CN103717607A
+CN103720670A
+CN103720675A
+CN103721060A
+CN103732227A
+CN103735473A
+CN103735528A
+CN103735552A
+CN103735565A
+CN103735593A
+CN103736080A
+CN103739549A
+CN103739642A
+CN103751094A
+CN103751095A
+CN103751160A
+CN103751169A
+CN103751176A
+CN103751177A
+CN103751183A
+CN103751185A
+CN103751476A
+CN103751531A
+CN103751788A
+CN103755560A
+CN103755647A
+CN103764659A
+CN1129942B
+CN1366991B
+CN1439375B
+CN1514729B
+CN1545551B
+CN1559389A
+CN1559391A
+CN1559413A
+CN1559414A
+CN1559419A
+CN1559434A
+CN1559612A
+CN1561977A
+CN1561995A
+CN1562026A
+CN1562038A
+CN1562054A
+CN1562310A
+CN1562370A
+CN1565466A
+CN1565471A
+CN1565472A
+CN1566086A
+CN1568944A
+CN1568949A
+CN1568956A
+CN1568965A
+CN1569016A
+CN1569120A
+CN1569841A
+CN1569868A
+CN1579385A
+CN1579386A
+CN1579387A
+CN1579395A
+CN1579396A
+CN1579404A
+CN1580056A
+CN1582937A
+CN1582944A
+CN1583175A
+CN1583753A
+CN1586473A
+CN1586483A
+CN1586484A
+CN1586489A
+CN1589780A
+CN1593401A
+CN1593407A
+CN1593409A
+CN1594311A
+CN1596113B
+CN1596900A
+CN1596907A
+CN1600313A
+CN1602866A
+CN1602873A
+CN1602885A
+CN1602959B
+CN1605335A
+CN1608620A
+CN1609105A
+CN1615851A
+CN1615865A
+CN1615905A
+CN1621039A
+CN1626103A
+CN1628653A
+CN1628854A
+CN1629159A
+CN1631369A
+CN1631373A
+CN1634013A
+CN1634019A
+CN1634034A
+CN1634081A
+CN1634087A
+CN1634088A
+CN1634108A
+CN1634135A
+CN1634885A
+CN1634923A
+CN1636557A
+CN1636568A
+CN1640394A
+CN1647815B
+CN1650851A
+CN1651453A
+CN1657041A
+CN1657049A
+CN1657057A
+CN1658890A
+CN1660105A
+CN1660120A
+CN1660872A
+CN1660885A
+CN1663957A
+CN1666746A
+CN1666749A
+CN1672686A
+CN1679522B
+CN1679525A
+CN1679541A
+CN1679542A
+CN1679616A
+CN1679617A
+CN1680238A
+CN1682701A
+CN1682737B
+CN1682744A
+CN1682745A
+CN1682760A
+CN1682763A
+CN1683385A
+CN1706371B
+CN1718190A
+CN1718244A
+CN1718578A
+CN1723059A
+CN1723890A
+CN1723900A
+CN1723913A
+CN1724521A
+CN1729968A
+CN1729978A
+CN1729995A
+CN1736386A
+CN1736393A
+CN1739492A
+CN1739502A
+CN1739528A
+CN1739531A
+CN1739539A
+CN1739545A
+CN1739572A
+CN1739655B
+CN1739797A
+CN1742853A
+CN1748671A
+CN1748681A
+CN1751690A
+CN1751691A
+CN1754535A
+CN1754556A
+CN1757388A
+CN1759836A
+CN1759838A
+CN1762344A
+CN1762364A
+CN1762368A
+CN1762380A
+CN1763018B
+CN1764432A
+CN1765363A
+CN1765377A
+CN1768742A
+CN1768746A
+CN1771909A
+CN1771925A
+CN1771932A
+CN1771940A
+CN1771987A
+CN1772025A
+CN1772288A
+CN1775224A
+CN1775762A
+CN1781481A
+CN1781488A
+CN1785200A
+CN1785204A
+CN1785253B
+CN1788018B
+CN1788581A
+CN1792247A
+CN1795861A
+CN1795895A
+CN1796375A
+CN1799548A
+CN1799631B
+CN1800198A
+CN1802947A
+CN1802949A
+CN1802950A
+CN1803148A
+CN1806809A
+CN1813674A
+CN1813696A
+CN1813721A
+CN1813722A
+CN1813731A
+CN1813738A
+CN1813740B
+CN1813744A
+CN1813763A
+CN1814080A
+CN1814291A
+CN1814293A
+CN1817153A
+CN1817849A
+CN1820753A
+CN1823734A
+CN1823760A
+CN1823771B
+CN1823805A
+CN1823811A
+CN1823816A
+CN1823822A
+CN1823826A
+CN1823829A
+CN1824041A
+CN1824064B
+CN1824292B
+CN1824657A
+CN1827137B
+CN1830424A
+CN1830425A
+CN1830426A
+CN1830427A
+CN1830445B
+CN1833636A
+CN1833637A
+CN1836657A
+CN1837205A
+CN1839124B
+CN1839813A
+CN1839828A
+CN1839841A
+CN1839854A
+CN1839865A
+CN1839867A
+CN1839968A
+CN1840529A
+CN1840539A
+CN1843373A
+CN1843393A
+CN1846698A
+CN1846708A
+CN1847236B
+CN1850093A
+CN1850094A
+CN1850098A
+CN1850106A
+CN1850116A
+CN1853480A
+CN1853646A
+CN1853714A
+CN1854125A
+CN1857207A
+CN1857212A
+CN1857219A
+CN1857242A
+CN1857244A
+CN1857252A
+CN1857262A
+CN1857266A
+CN1857280A
+CN1857389A
+CN1857456A
+CN1857471A
+CN1857729A
+CN1857733A
+CN1861064A
+CN1861073A
+CN1861085A
+CN1861093A
+CN1861581A
+CN1864673A
+CN1864674A
+CN1864697A
+CN1864732A
+CN1864736A
+CN1865270A
+CN1867331B
+CN1867563A
+CN1868467A
+CN1869080A
+CN1871002A
+CN1872027A
+CN1872028A
+CN1872030A
+CN1872032A
+CN1872045B
+CN1872119A
+CN1872172A
+CN1872838A
+CN1875019A
+CN1875924A
+CN1875938A
+CN1875960A
+CN1875965A
+CN1875971A
+CN1876014A
+CN1876015A
+CN1876065A
+CN1876174A
+CN1879607A
+CN1879634A
+CN1879697A
+CN1879827A
+CN1879882A
+CN1883459A
+CN1883472A
+CN1883496A
+CN1883547A
+CN1883683A
+CN1887255A
+CN1887267A
+CN1887283A
+CN1887876A
+CN1887899A
+CN1891225A
+CN1895239B
+CN1895258A
+CN1895282A
+CN1895398A
+CN1895546B
+CN1903187B
+CN1903193A
+CN1903211A
+CN1903310A
+CN1907291A
+CN1911213A
+CN1911224A
+CN1911242A
+CN1911284A
+CN1911312A
+CN1911326A
+CN1911925A
+CN1915230A
+CN1915232A
+CN1915246A
+CN1919178A
+CN1919192A
+CN1919208A
+CN1923198A
+CN1923219A
+CN1923784B
+CN1923803A
+CN1927174A
+CN1927198A
+CN1927199A
+CN1927215A
+CN1927241A
+CN1927334A
+CN1927351A
+CN1927372A
+CN1927393A
+CN1931131A
+CN1931159B
+CN1931177A
+CN1931355A
+CN1931840A
+CN1932017A
+CN1935129A
+CN1935133A
+CN1935812A
+CN1938282A
+CN1939264A
+CN1939266A
+CN1939290A
+CN1939296B
+CN1939326A
+CN1939489A
+CN1943566A
+CN1943576A
+CN1943581A
+CN1943613A
+CN1944420B
+CN1944442A
+CN1947692A
+CN1947694A
+CN1948248A
+CN1948274B
+CN1951370A
+CN1951375B
+CN1951386A
+CN1954818B
+CN1955163A
+CN1957926A
+CN1957944A
+CN1961869A
+CN1961872A
+CN1964973A
+CN1965807A
+CN1965814A
+CN1965846A
+CN1966525A
+CN1969839A
+CN1969852A
+CN1970559A
+CN1973848A
+CN1973896A
+CN1974545B
+CN1977850A
+CN1977855A
+CN1977859A
+CN1981782A
+CN1985810A
+CN1985830A
+CN1985838A
+CN1985850A
+CN1985956A
+CN1985960A
+CN1988887A
+CN1988904A
+CN1989951A
+CN1989983A
+CN1990003A
+CN1990029A
+CN1990489A
+CN1990494A
+CN1993118B
+CN1993324B
+CN1994289A
+CN1994300A
+CN1994305A
+CN1994307A
+CN1994316A
+CN1995055A
+CN1997394A
+CN200939251Y
+CN201044823Y
+CN201142902Y
+CN201182672Y
+CN201241031Y
+CN201453509U
+CN201469700U
+CN201558397U
+CN201564118U
+CN201586232U
+CN201755322U
+CN202263199U
+CN202314484U
+CN202620297U
+CN202699643U
+CN202761909U
+CN203075251U
+CN203123075U
+CN203436580U
+CN2880081Y
+DE102004009325A1
+DE102004040014A1
+DE102004054426A1
+DE102004060999A1
+DE102005004643A1
+DE102005013622A1
+DE102005041613A1
+DE102006002649A1
+DE102006005221B3
+DE102006006115A1
+DE102006012873A1
+DE102006012875A1
+DE102006028284A1
+DE102006030031A1
+DE102006062566A1
+DE102007021149A1
+DE102007030198A1
+DE102007030370A1
+DE102007032660A1
+DE102007032662A1
+DE102007037018A1
+DE102007044583A1
+DE102007054985A1
+DE102008039254A1
+DE102008054300A1
+DE102009011264A1
+DE102009038634A1
+DE102010004986A1
+DE102010014411A1
+DE102010051776A1
+DE102012022778A1
+DE10352449A1
+DE10360924A1
+DE20321277U1
+DE4393944B4
+EP0708660B1
+EP0754223B1
+EP0759297B1
+EP0776161B2
+EP0793721B1
+EP0808164B1
+EP0813416B1
+EP0814796B1
+EP0823908B1
+EP0833636B1
+EP0841945B1
+EP0869788B1
+EP0871488B1
+EP0873406B1
+EP0876337B1
+EP0876612B1
+EP0881891B1
+EP0890105B1
+EP0907652B1
+EP0923740B1
+EP0931071B1
+EP0949865A4
+EP0956865B1
+EP0957903B1
+EP0958823B1
+EP0959896B1
+EP0966443B1
+EP0969844B1
+EP0970127B1
+EP0970195B1
+EP0975637B1
+EP0980369B1
+EP0983072B2
+EP0991636B1
+EP0994706B1
+EP0998276B1
+EP0998291B2
+EP1003777B1
+EP1008344B1
+EP1016406B1
+EP1019500B1
+EP1021184B1
+EP1024794B1
+EP1024805B1
+EP1042287B1
+EP1042307B1
+EP1044008B1
+EP1045832B1
+EP1049459B1
+EP1049707B1
+EP1054680B1
+EP1054881B1
+EP1063987A4
+EP1065945B1
+EP1068328B1
+EP1069900B1
+EP1075467B1
+EP1076553B1
+EP1077069B1
+EP1078927B1
+EP1079825B1
+EP1086098B1
+EP1100541B1
+EP1104417B1
+EP1105376B1
+EP1107966B1
+EP1112057B1
+EP1117411B1
+EP1121129B1
+EP1124551B1
+EP1133300B1
+EP1140010B1
+EP1140028B1
+EP1140033B1
+EP1143938B1
+EP1144371B1
+EP1152751B1
+EP1162977B1
+EP1163218B1
+EP1165055B1
+EP1165070B1
+EP1171583B1
+EP1173218B1
+EP1173464B1
+EP1177166B1
+EP1178794B1
+EP1178796B1
+EP1178973B1
+EP1181299B1
+EP1183383B1
+EP1186302B1
+EP1187835B1
+EP1187846B1
+EP1189614B1
+EP1189886B1
+EP1196160B1
+EP1196404B1
+EP1202969B1
+EP1206942B1
+EP1212086B1
+EP1214314B1
+EP1214409B1
+EP1218027B1
+EP1220839B1
+EP1221941A4
+EP1227813B1
+EP1233959B1
+EP1234574B1
+EP1235566B1
+EP1237875B1
+EP1237898B1
+EP1239884B1
+EP1248629B1
+EP1251841B1
+EP1251871B1
+EP1253919A4
+EP1254904B1
+EP1254907B1
+EP1255558B1
+EP1259229B1
+EP1259240B1
+EP1261338B1
+EP1263411B1
+EP1265878B1
+EP1268435B1
+EP1274711B1
+EP1278521B1
+EP1280500B1
+EP1280777B1
+EP1284653B1
+EP1284711B1
+EP1289977B1
+EP1291016B1
+EP1292332B1
+EP1293567B1
+EP1294382B1
+EP1296639B1
+EP1296700B1
+EP1307202B1
+EP1309330B1
+EP1311267B1
+EP1311471B1
+EP1311672B1
+EP1313489B1
+EP1313700B1
+EP1317304B1
+EP1320356B2
+EP1320359B1
+EP1322315B1
+EP1328515B1
+EP1330164B1
+EP1337258A4
+EP1337512B1
+EP1339407B1
+EP1345605B1
+EP1345608B1
+EP1345612B1
+EP1345616A4
+EP1349856B1
+EP1355650B1
+EP1357906B1
+EP1363895B1
+EP1363903B1
+EP1365781A4
+EP1366040B1
+EP1367886B1
+EP1368015B1
+EP1368023B1
+EP1370264B1
+EP1370265B1
+EP1370559B1
+EP1370684B1
+EP1372627B1
+EP1372694B1
+EP1373249B1
+EP1377277B1
+EP1377288B1
+EP1377316B1
+EP1379225B1
+EP1379522B1
+EP1383765B1
+EP1385504B1
+EP1385514B1
+EP1385527B1
+EP1385528B1
+EP1389466B1
+EP1390026B1
+EP1390037B1
+EP1390041B1
+EP1392335B1
+EP1397132A4
+EP1406654A4
+EP1408941B1
+EP1408950B1
+EP1409485B1
+EP1409490B1
+EP1411910B1
+EP1411986B1
+EP1431285B1
+EP1434765B1
+EP1448559B1
+EP1450775B1
+EP1451167B1
+EP1453510A4
+EP1454897B1
+EP1467762B1
+EP1469823B1
+EP1474143B1
+EP1476190B1
+EP1477472B1
+EP1478638B1
+EP1482796A4
+EP1485381B1
+EP1487285B9
+EP1487421B1
+EP1490029A4
+EP1490365B1
+EP1493443A1
+EP1494674A1
+EP1494688A4
+EP1496900A2
+EP1499617A1
+EP1500391A1
+EP1501499A1
+EP1501800A1
+EP1505075B1
+EP1506960A1
+EP1507559A1
+EP1507774A1
+EP1509285A2
+EP1511500A2
+EP1511521A1
+EP1513504A1
+EP1515710A1
+EP1515729B1
+EP1518554A1
+EP1519732A1
+EP1519925A1
+EP1521576A1
+EP1524270B1
+EP1524980A1
+EP1525882A1
+EP1526852A1
+EP1529025B1
+EP1530459A2
+EP1531795A1
+EP1532129B1
+EP1532133A1
+EP1536800B1
+EP1537110A2
+EP1539129A1
+EP1539169A2
+EP1539686A1
+EP1539764A1
+EP1541559A1
+EP1542987A1
+EP1545508A1
+EP1546140A2
+EP1549198A2
+EP1549246B1
+EP1549316A1
+EP1555976A2
+EP1556050A1
+EP1558243A2
+EP1558620A1
+EP1558630A2
+EP1559374A1
+EP1561425A1
+EP1562568B1
+EP1567117B1
+EP1567644A2
+EP1569630A4
+EP1569632A1
+EP1570839A1
+EP1570852A2
+EP1572073A2
+EP1572237A1
+EP1572658A1
+EP1575509A2
+EP1578441A2
+EP1578727A2
+EP1578897A2
+EP1581471B1
+EP1581496A2
+EP1581509B1
+EP1581529A1
+EP1583523B1
+EP1583559B1
+EP1589815A2
+EP1592424A1
+EP1593386A1
+EP1593679A1
+EP1596849A1
+EP1596859A1
+EP1597255A1
+EP1598066A1
+EP1599191A2
+EP1599202A1
+EP1600160A1
+EP1603572A4
+EP1605938B1
+EP1605948A1
+EP1612555A1
+EP1613316A1
+EP1613320A1
+EP1613326B1
+EP1614694A1
+EP1615622B1
+EP1615640B1
+EP1616577B1
+EP1623706A2
+EP1626709A1
+EP1627641A1
+EP1631823A2
+EP1633718B1
+EP1638528A2
+EP1641456A2
+EP1641775B1
+EP1643836A1
+EP1646131A1
+EP1646392A2
+EP1647272A1
+EP1648433B1
+EP1652521A1
+EP1658093B1
+EP1658852A1
+EP1660069A2
+EP1660490A1
+EP1661564A1
+EP1664005A1
+EP1670481A1
+EP1670490A1
+EP1674467A1
+EP1674468A1
+EP1675569A1
+EP1675846B1
+EP1682514A1
+EP1682532B1
+EP1683515A2
+EP1684746A1
+EP1685142B1
+EP1686181A2
+EP1689731B1
+EP1690852A1
+EP1694335A4
+EP1695702A2
+EP1697348B1
+EP1699456A1
+EP1700597A1
+EP1700598A1
+EP1702983A2
+EP1704862A1
+EP1706386A1
+EP1708713B1
+EP1711182A1
+EP1711465A1
+EP1713479A1
+EP1713507A2
+EP1714652A2
+EP1716125A1
+EP1718614A1
+EP1719518A1
+EP1720546B1
+EP1722776A2
+EP1723948A1
+EP1725529A1
+EP1726305A1
+EP1726586A1
+EP1728510A2
+EP1729811B1
+EP1730126A1
+EP1731156A1
+EP1733741A2
+EP1735302B1
+EP1735443A2
+EP1740538A2
+EP1741718A2
+EP1745050A1
+EP1745776A1
+EP1749520A1
+EP1749522A2
+EP1750682A2
+EP1754492A1
+EP1754712A2
+EP1755477A2
+EP1756066B1
+EP1762248A1
+EP1764362A1
+EP1765360B1
+EP1768661A1
+EP1772514A2
+EP1776102A1
+EP1781608B1
+EP1782838A1
+EP1784198A2
+EP1788092A1
+EP1789402A1
+EP1791536A1
+EP1791841A1
+EP1804797B1
+EP1809269A1
+EP1809648A2
+EP1817294A1
+EP1818057A1
+EP1828115A2
+EP1828149A1
+EP1828223A2
+EP1829543A1
+EP1830833A2
+EP1831198A1
+EP1832179A1
+EP1832278A1
+EP1833792A1
+EP1838707A1
+EP1842544A2
+EP1842852A1
+EP1843750A1
+EP1847531A1
+EP1849475A1
+EP1852130A1
+EP1853315A1
+EP1853564A1
+EP1855669A1
+EP1856040A2
+EP1857447A1
+EP1858887A1
+EP1861101A2
+EP1861371A1
+EP1863488A2
+EP1864658A1
+EP1864662A1
+EP1864976A1
+EP1866312A1
+EP1868572A2
+EP1870100A1
+EP1870103A2
+EP1871393A2
+EP1873153B1
+EP1874297A1
+EP1874300A2
+EP1878429B1
+EP1881828A1
+EP1886678A1
+EP1889612A2
+EP1890690A2
+EP1893206A2
+EP1898935A2
+EP1898936A1
+EP1902017A1
+EP1902044A1
+EP1904454A2
+EP1905437A1
+EP1911753A1
+EP1913945A2
+EP1915158A1
+EP1915996A1
+EP1931636B1
+EP1935414A2
+EP1951274A1
+EP1951303B1
+EP1951318A1
+EP1954255A1
+EP1957073A2
+EP1957088A1
+EP1958636A1
+EP1961745A1
+EP1961757A1
+EP1961819A2
+EP1962854A2
+EP1963334A1
+EP1967591A2
+EP1968595A2
+EP1970051A1
+EP1971588B1
+EP1971609A1
+EP1973540B1
+EP1976517A1
+EP1977766A1
+EP1979341B1
+EP1981845A2
+EP1982970A1
+EP1985299A1
+EP1986011A2
+EP1986670A2
+EP1991239A1
+EP1991526A1
+EP1994009A1
+EP1996188A1
+EP1998768A2
+EP2001495A2
+EP2002731A1
+EP2004618A1
+EP2005945A2
+EP2005968A9
+EP2011488B1
+EP2013172A1
+EP2018383A1
+EP2018866A1
+EP2020869A1
+EP2022497A1
+EP2026789A2
+EP2027124A1
+EP2027862A1
+EP2030978A1
+EP2035010A1
+EP2037904A1
+EP2041119A1
+EP2044942A1
+EP2046803A1
+EP2048142A2
+EP2052732A1
+EP2055305A1
+EP2060257A1
+EP2061759A1
+EP2062878A1
+EP2066322A2
+EP2068663A1
+EP2068861A2
+EP2069310B1
+EP2069501A2
+EP2078523A1
+EP2079688B1
+EP2079703A1
+EP2091925A1
+EP2091943A2
+EP2094666A1
+EP2094673A1
+EP2097107A2
+EP2099783A1
+EP2100604A1
+EP2100890A1
+EP2107057A1
+EP2108404A1
+EP2110127A1
+EP2111861A1
+EP2114460A2
+EP2116252A1
+EP2117540A1
+EP2119717A1
+EP2123257A2
+EP2124919B1
+EP2127520A1
+EP2127667B1
+EP2128137A1
+EP2134704B1
+EP2141164A1
+EP2143719A1
+EP2143723A1
+EP2148675A1
+EP2148868A1
+EP2155771A1
+EP2160466A1
+EP2164850A2
+EP2167662A2
+EP2172452A1
+EP2177214A1
+EP2179726A2
+EP2180890A1
+EP2183246A2
+EP2184987A1
+EP2185523A2
+EP2193117A1
+EP2199289A1
+EP2201947A2
+EP2211760A1
+EP2211880A1
+EP2222636A2
+EP2222649A2
+EP2222667A2
+EP2226072A1
+EP2233141A1
+EP2234619A2
+EP2234972A1
+EP2235027A1
+EP2236139A1
+EP2237785A2
+EP2241312A1
+EP2241317A1
+EP2251010A1
+EP2251042A2
+EP2253316A1
+EP2253631A1
+EP2254555A2
+EP2255799A1
+EP2256210A1
+EP2257551A2
+EP2258681A2
+EP2259797A2
+EP2263671A1
+EP2265271A1
+EP2266577A1
+EP2268645A1
+EP2269654A2
+EP2269972A1
+EP2270505A1
+EP2271338A1
+EP2275101A1
+EP2279743A2
+EP2280940A1
+EP2285393A1
+EP2286826A2
+EP2289500A1
+EP2292587A1
+EP2295424A1
+EP2295604A2
+EP2297085A2
+EP2297105A1
+EP2298281A1
+EP2298298A2
+EP2300036A1
+EP2301525A1
+EP2305228A1
+EP2305248A1
+EP2305257A1
+EP2306996A1
+EP2308591A1
+EP2311814A1
+EP2311818A1
+EP2319509A1
+EP2322174A2
+EP2323640A2
+EP2323645A1
+EP2324008B1
+EP2325172A1
+EP2326636A2
+EP2328878A1
+EP2335692A1
+EP2335708A1
+EP2340016A2
+EP2343291A1
+EP2343295A1
+EP2343979A1
+EP2346506A1
+EP2348868A1
+EP2349998A2
+EP2358369A1
+EP2359852A1
+EP2363133A1
+EP2363142A1
+EP2363483A2
+EP2364994A1
+EP2365805A1
+EP2367557A1
+EP2368547B1
+EP2368885A1
+EP2370075A1
+EP2370097A1
+EP2370437A1
+EP2376435A2
+EP2377532A1
+EP2379090A1
+EP2389070A1
+EP2393781A1
+EP2397128A1
+EP2397147A1
+EP2399566A1
+EP2400845A1
+EP2403497A1
+EP2407164A1
+EP2409689A1
+EP2409693A2
+EP2411011A1
+EP2413920A1
+EP2419095A2
+EP2419405A1
+EP2419414A1
+EP2419428A1
+EP2422786A1
+EP2425858A2
+EP2428217A1
+EP2431365A1
+EP2437747A1
+EP2438037A1
+EP2440201A1
+EP2442808A2
+EP2442819A2
+EP2446883A1
+EP2450038A1
+EP2452577A1
+EP2453746A1
+EP2453889A1
+EP2455085A2
+EP2456419A1
+EP2461813A1
+EP2461816A1
+EP2462143A1
+EP2464632A1
+EP2467398A1
+EP2470176A1
+EP2470268A1
+EP2474529A1
+EP2478902A1
+EP2480078A1
+EP2480224A1
+EP2480536A2
+EP2481396A2
+EP2486006A1
+EP2486042A1
+EP2487242A1
+EP2488514A1
+EP2489353A1
+EP2491007A1
+EP2492267A1
+EP2493478A1
+EP2494973A1
+EP2497772A1
+EP2501669A2
+EP2507221A1
+EP2508186A1
+EP2509600A1
+EP2510098A1
+EP2512267A1
+EP2515848A1
+EP2516011A1
+EP2516645A1
+EP2519505A1
+EP2519511A1
+EP2520289A1
+EP2523552A1
+EP2523691A1
+EP2527007A1
+EP2527335A1
+EP2527340A1
+EP2529728A1
+EP2532649A1
+EP2532666A1
+EP2540298A1
+EP2543370A1
+EP2548561A1
+EP2548880A2
+EP2550275A1
+EP2552905A1
+EP2552924A1
+EP2554167A1
+EP2554170A1
+EP2555771A1
+EP2556830A1
+EP2560970A1
+EP2563787A1
+EP2566483A1
+EP2576532A1
+EP2578569A1
+EP2582812A1
+EP2582832A1
+EP2585461A1
+EP2586425A1
+EP2588462A1
+EP2589603A1
+EP2590951A1
+EP2591002A2
+EP2594268A1
+EP2594562A2
+EP2598147A1
+EP2601962A1
+EP2603096A1
+EP2603502A1
+EP2609922A1
+EP2615086A1
+EP2616082A2
+EP2617411A1
+EP2620142A1
+EP2621925A1
+EP2625172A1
+EP2629610A1
+EP2632491A2
+EP2633859A1
+EP2635266A1
+EP2635287A1
+EP2641907A1
+EP2643325A1
+EP2646434A1
+EP2647374A1
+EP2649052A1
+EP2650291A1
+EP2653152A1
+EP2653164A1
+EP2658540A1
+EP2659885A1
+EP2659891A1
+EP2660245A1
+EP2662079A1
+EP2663300A1
+EP2665711A1
+EP2668953A1
+EP2671586A1
+EP2674156A1
+EP2674430A1
+EP2681203A1
+EP2681205A1
+EP2681214A1
+EP2682399A1
+EP2683371A1
+EP2683373A1
+EP2683697A1
+EP2683701A1
+EP2683706A1
+EP2684861A2
+EP2685824A1
+EP2688569A1
+EP2688884A1
+EP2689781A1
+EP2690102A1
+EP2691402A1
+EP2694053A2
+EP2694474A1
+EP2694511A1
+EP2697211A1
+EP2698167A2
+EP2699564A1
+EP2700409A1
+EP2703393A1
+EP2704709A1
+EP2708532A1
+EP2709729A1
+EP2711368A1
+EP2714005A1
+EP2714030A1
+EP2714049A1
+EP2714716A1
+EP2717856A2
+EP2717872A1
+EP2719382A1
+EP2722322A2
+EP2725025A1
+EP2726084A1
+EP2726465A1
+EP2729183A1
+EP2729445A1
+EP2730284A1
+EP2730577A1
+EP2734497A1
+EP2736531A2
+EP2736890A1
+EP2737908A1
+EP2739616A1
+EP2740473A1
+EP2740730A1
+EP2742025A1
+EP2742939A1
+EP2744502A2
+EP2745847A1
+EP2747763A1
+EP2749286A1
+EP2751102A1
+EP2753315A1
+EP2753630A1
+EP2754443A1
+EP2755956A1
+EP2755970A1
+EP2759300A2
+EP2760439A2
+EP2760449A1
+EP2760878A1
+EP2763962A1
+EP2764873A1
+EP2766029A1
+EP2766373A1
+EP2772253A1
+EP2772485A1
+EP2772491A1
+EP2773369A1
+EP2773758A2
+EP2774914A1
+EP2776023A1
+EP2776406A2
+EP2777701A1
+EP2780017A1
+EP2783685A1
+EP2783686A1
+EP2784068A1
+EP2785705A1
+EP2785840A1
+EP2786982A1
+US20050004068
+US20050004081
+US20050004172
+US20050009843
+US20050009868
+US20050009925
+US20050013858
+US20050014690
+US20050014730
+US20050020836
+US20050032754
+US20050032820
+US20050032854
+US20050033051
+US20050037077
+US20050037404
+US20050038259
+US20050042202
+US20050042302
+US20050048128
+US20050049202
+US20050049233
+US20050054582
+US20050054617
+US20050059617
+US20050059726
+US20050065165
+US20050065213
+US20050070544
+US20050075332
+US20050075511
+US20050080096
+US20050080104
+US20050085513
+US20050090693
+US20050100902
+US20050107400
+US20050107411
+US20050107428
+US20050107446
+US20050113322
+US20050113370
+US20050119193
+US20050119206
+US20050119224
+US20050123536
+US20050123603
+US20050123627
+US20050123633
+US20050124554
+US20050129621
+US20050129739
+US20050129774
+US20050131051
+US20050131052
+US20050143283
+US20050143419
+US20050152845
+US20050158393
+US20050158724
+US20050158726
+US20050159437
+US20050164988
+US20050166911
+US20050169999
+US20050170384
+US20050171074
+US20050171106
+US20050171151
+US20050171214
+US20050176753
+US20050176813
+US20050180959
+US20050181034
+US20050181506
+US20050182135
+US20050192236
+US20050192259
+US20050196379
+US20050196456
+US20050202019
+US20050208125
+US20050208127
+US20050209169
+US20050215579
+US20050215645
+US20050220819
+US20050220884
+US20050220899
+US20050221395
+US20050222183
+US20050222194
+US20050222211
+US20050228024
+US20050234008
+US20050238737
+US20050244489
+US20050245504
+US20050245507
+US20050245511
+US20050250716
+US20050255529
+US20050256171
+US20050256178
+US20050256208
+US20050256211
+US20050261231
+US20050261333
+US20050261349
+US20050266024
+US20050266075
+US20050282861
+US20060002887
+US20060002966
+US20060004058
+US20060009403
+US20060009426
+US20060009651
+US20060014243
+US20060014825
+US20060019995
+US20060034939
+US20060034951
+US20060035919
+US20060035948
+US20060035977
+US20060040931
+US20060040964
+US20060046992
+US20060051296
+US20060052417
+US20060052440
+US20060052453
+US20060058288
+US20060058345
+US20060058364
+US20060063711
+US20060063839
+US20060069031
+US20060069057
+US20060069067
+US20060074091
+US20060083692
+US20060084702
+US20060088545
+US20060088556
+US20060089353
+US20060094730
+US20060106067
+US20060106074
+US20060111274
+US20060111304
+US20060121010
+US20060121069
+US20060121094
+US20060122191
+US20060128750
+US20060134095
+US20060135769
+US20060140872
+US20060141013
+US20060142184
+US20060142203
+US20060142326
+US20060142571
+US20060148707
+US20060153839
+US20060153939
+US20060154944
+US20060154984
+US20060160878
+US20060165591
+US20060166872
+US20060166892
+US20060167048
+US20060173012
+US20060173059
+US20060177423
+US20060177901
+US20060178426
+US20060183737
+US20060183794
+US20060189631
+US20060189666
+US20060199832
+US20060199978
+US20060210548
+US20060210553
+US20060211651
+US20060211701
+US20060233815
+US20060234940
+US20060234977
+US20060239999
+US20060252766
+US20060257367
+US20060265763
+US20060269613
+US20060270627
+US20060270646
+US20060276460
+US20060287275
+US20060292093
+US20060293242
+US20060293285
+US20060293326
+US20070021414
+US20070021432
+US20070021496
+US20070021506
+US20070026051
+US20070027151
+US20070037882
+US20070059338
+US20070059357
+US20070060619
+US20070072811
+US20070072853
+US20070082908
+US20070093483
+US20070105143
+US20070105840
+US20070116745
+US20070117154
+US20070123510
+US20070128591
+US20070129381
+US20070134308
+US20070134342
+US20070142266
+US20070149492
+US20070161560
+US20070161628
+US20070173537
+US20070191422
+US20070191435
+US20070203141
+US20070218067
+US20070225260
+US20070232636
+US20070232692
+US20070238641
+US20070238728
+US20070238753
+US20070238754
+US20070243268
+US20070244051
+US20070248569
+US20070248620
+US20070248702
+US20070249648
+US20070249726
+US20070253954
+US20070253957
+US20070254867
+US20070258890
+US20070258972
+US20070259849
+US20070259959
+US20070264271
+US20070264290
+US20070265212
+US20070265298
+US20070269522
+US20070269533
+US20070270447
+US20070270488
+US20070270505
+US20070274951
+US20070275919
+US20070275953
+US20070276031
+US20070280908
+US20070280918
+US20070281036
+US20070281903
+US20070281993
+US20070282007
+US20070287677
+US20070287701
+US20070287713
+US20070287724
+US20070287726
+US20070292502
+US20070293433
+US20070293508
+US20070293548
+US20070293578
+US20070293585
+US20070298084
+US20070299032
+US20070299043
+US20070299048
+US20070299083
+US20070299102
+US20080003219
+US20080003232
+US20080003275
+US20080004287
+US20080004338
+US20080004345
+US20080004346
+US20080004347
+US20080008681
+US20080009447
+US20080009518
+US20080009540
+US20080011293
+US20080014283
+US20080015143
+US20080015207
+US20080015240
+US20080015252
+US20080020050
+US20080021021
+US20080021057
+US20080021069
+US20080025986
+US20080026014
+US20080026056
+US20080026086
+US20080026997
+US20080027039
+US20080027048
+US20080027051
+US20080031931
+US20080032925
+US20080032964
+US20080032966
+US20080033011
+US20080038247
+US20080038251
+US20080038268
+US20080038301
+US20080038389
+US20080039410
+US20080039412
+US20080039440
+US20080044390
+US20080044468
+US20080044489
+US20080045485
+US20080050430
+US20080051325
+US20080051330
+US20080051351
+US20080051427
+US20080057025
+US20080057047
+US20080057055
+US20080057074
+US20080057086
+US20080057098
+US20080057112
+US20080057129
+US20080058310
+US20080058383
+US20080058405
+US20080063638
+US20080063709
+US20080064668
+US20080064722
+US20080064753
+US20080064758
+US20080069870
+US20080070850
+US20080070884
+US20080075774
+US20080076766
+US20080081834
+US20080085244
+US20080085279
+US20080085855
+US20080085902
+US20080089861
+US20080090781
+US20080090829
+US20080090872
+US20080090909
+US20080096829
+US20080096838
+US20080096840
+US20080096851
+US20080096913
+US20080096927
+US20080096971
+US20080102038
+US20080102085
+US20080103136
+US20080107652
+US20080107662
+US20080108594
+US20080108608
+US20080108704
+US20080108705
+US20080112888
+US20080112889
+US20080113346
+US20080113955
+US20080114002
+US20080114015
+US20080114044
+US20080114056
+US20080118495
+US20080118556
+US20080118562
+US20080119527
+US20080119549
+US20080124408
+US20080125354
+US20080125358
+US20080125394
+US20080125458
+US20080125470
+US20080125488
+US20080131366
+US20080131503
+US20080132536
+US20080132544
+US20080132552
+US20080132563
+US20080132825
+US20080138400
+US20080139545
+US20080139589
+US20080139614
+US20080145322
+US20080145336
+US20080145456
+US20080146541
+US20080146551
+US20080146556
+US20080152639
+US20080153741
+US20080153781
+US20080153796
+US20080153818
+US20080153910
+US20080159980
+US20080160019
+US20080160022
+US20080160046
+US20080160060
+US20080160083
+US20080161260
+US20080161293
+US20080161328
+US20080161337
+US20080161361
+US20080161393
+US20080161409
+US20080166417
+US20080166730
+US20080167220
+US20080167277
+US20080167279
+US20080167306
+US20080171781
+US20080175811
+US20080175899
+US20080175925
+US20080176923
+US20080176953
+US20080181864
+US20080182780
+US20080182806
+US20080182819
+US20080182827
+US20080182876
+US20080187536
+US20080188435
+US20080188470
+US20080188509
+US20080193488
+US20080193515
+US20080194468
+US20080194492
+US20080194528
+US20080194570
+US20080194580
+US20080194584
+US20080199447
+US20080200432
+US20080200484
+US20080200507
+US20080200512
+US20080200548
+US20080206186
+US20080206203
+US20080206250
+US20080206310
+US20080207496
+US20080207683
+US20080207737
+US20080213234
+US20080213257
+US20080213286
+US20080213407
+US20080214499
+US20080214506
+US20080214530
+US20080214544
+US20080214559
+US20080214563
+US20080214586
+US20080219960
+US20080221018
+US20080221051
+US20080221115
+US20080221121
+US20080221151
+US20080226622
+US20080227698
+US20080227748
+US20080227752
+US20080227786
+US20080233132
+US20080233207
+US20080234283
+US20080234326
+US20080234382
+US20080241133
+US20080241224
+US20080242634
+US20080242645
+US20080247986
+US20080248134
+US20080249040
+US20080249050
+US20080249096
+US20080249105
+US20080249117
+US20080249147
+US20080254010
+US20080254017
+US20080254059
+US20080254101
+US20080254130
+US20080255101
+US20080255179
+US20080260717
+US20080260719
+US20080261865
+US20080261902
+US20080261955
+US20080261963
+US20080261967
+US20080262004
+US20080262009
+US20080262017
+US20080262018
+US20080262028
+US20080262039
+US20080262053
+US20080262055
+US20080262093
+US20080263607
+US20080269146
+US20080269152
+US20080269160
+US20080269222
+US20080269256
+US20080269282
+US20080269307
+US20080269311
+US20080269324
+US20080269334
+US20080269347
+US20080274075
+US20080274998
+US20080275046
+US20080275052
+US20080275076
+US20080275088
+US20080275134
+US20080279764
+US20080279786
+US20080279819
+US20080279855
+US20080280856
+US20080280877
+US20080280887
+US20080280951
+US20080280989
+US20080287364
+US20080287368
+US20080287383
+US20080287417
+US20080287430
+US20080287469
+US20080287478
+US20080292602
+US20080292618
+US20080292681
+US20080292687
+US20080292733
+US20080293698
+US20080293703
+US20080293709
+US20080293721
+US20080293795
+US20080299189
+US20080299204
+US20080300238
+US20080300309
+US20080306079
+US20080306139
+US20080306146
+US20080311180
+US20080311194
+US20080312181
+US20080312206
+US20080312231
+US20080312253
+US20080312319
+US20080312334
+US20080312462
+US20080317822
+US20080317855
+US20080318843
+US20080318904
+US20080318976
+US20080319001
+US20080319222
+US20090004172
+US20090005346
+US20090005352
+US20090005411
+US20090005441
+US20090010867
+US20090011040
+US20090011041
+US20090012014
+US20090012052
+US20090012069
+US20090012089
+US20090012145
+US20090017039
+US20090017104
+US20090017112
+US20090018093
+US20090018155
+US20090018209
+US20090018210
+US20090022732
+US20090022819
+US20090023719
+US20090023728
+US20090023755
+US20090023794
+US20090023798
+US20090023807
+US20090023810
+US20090029932
+US20090035249
+US20090035309
+US20090035357
+US20090036355
+US20090036371
+US20090036430
+US20090036431
+US20090036530
+US20090036541
+US20090041751
+US20090041760
+US20090042874
+US20090042894
+US20090042909
+US20090042954
+US20090042988
+US20090047238
+US20090047321
+US20090047366
+US20090048198
+US20090048235
+US20090048266
+US20090048304
+US20090048313
+US20090048412
+US20090053234
+US20090053285
+US20090053296
+US20090053307
+US20090053336
+US20090054341
+US20090054372
+US20090055941
+US20090060941
+US20090062204
+US20090062216
+US20090062321
+US20090062351
+US20090062391
+US20090068132
+US20090068198
+US20090068264
+US20090069314
+US20090069324
+US20090069339
+US20090069391
+US20090074761
+US20090075900
+US20090075920
+US20090075967
+US20090075992
+US20090076010
+US20090076024
+US20090076027
+US20090076028
+US20090076031
+US20090076051
+US20090076052
+US20090076078
+US20090076097
+US20090076100
+US20090076120
+US20090076131
+US20090076135
+US20090076139
+US20090076144
+US20090076150
+US20090076153
+US20090076170
+US20090081283
+US20090082412
+US20090082436
+US20090082438
+US20090087432
+US20090092573
+US20090092727
+US20090093494
+US20090098108
+US20090099185
+US20090099213
+US20090105171
+US20090105234
+US20090105261
+US20090105264
+US20090105344
+US20090105350
+US20090105537
+US20090110712
+US20090110749
+US20090110756
+US20090111798
+US20090111806
+US20090117072
+US20090117074
+US20090117125
+US20090117163
+US20090117215
+US20090118223
+US20090118224
+US20090118263
+US20090118321
+US20090118350
+US20090124572
+US20090124591
+US20090124657
+US20090124675
+US20090124685
+US20090130062
+US20090130178
+US20090131302
+US20090131410
+US20090131422
+US20090131426
+US20090131457
+US20090131464
+US20090131465
+US20090131481
+US20090131530
+US20090131535
+US20090137504
+US20090137536
+US20090137563
+US20090137575
+US20090137598
+US20090137607
+US20090137660
+US20090143313
+US20090143363
+US20090143424
+US20090143449
+US20090143462
+US20090148459
+US20090149503
+US20090155383
+US20090156601
+US20090156628
+US20090156677
+US20090162363
+US20090163478
+US20090163590
+US20090169511
+US20090169600
+US20090169638
+US20090170814
+US20090170862
+US20090170943
+US20090175795
+US20090176718
+US20090176886
+US20090178148
+US20090181908
+US20090181925
+US20090181939
+US20090181970
+US20090182029
+US20090186853
+US20090186894
+US20090186940
+US20090191144
+US20090192071
+US20090192173
+US20090192183
+US20090192212
+US20090196924
+US20090197853
+US20090197893
+US20090202430
+US20090202601
+US20090203650
+US20090203654
+US20090203664
+US20090203722
+US20090203782
+US20090208425
+US20090208550
+US20090208592
+US20090209507
+US20090209516
+US20090209534
+US20090214555
+US20090215852
+US20090215869
+US20090220528
+US20090220618
+US20090221598
+US20090221648
+US20090221669
+US20090221714
+US20090226431
+US20090226449
+US20090226526
+US20090227511
+US20090227534
+US20090227542
+US20090227561
+US20090227585
+US20090227601
+US20090227654
+US20090233961
+US20090234022
+US20090239875
+US20090239926
+US20090246172
+US20090246189
+US20090246257
+US20090247455
+US20090247558
+US20090247641
+US20090252702
+US20090253685
+US20090253791
+US20090253796
+US20090258870
+US20090258874
+US20090258936
+US20090258951
+US20090263322
+US20090263406
+US20090264497
+US20090264508
+US20090264530
+US20090269404
+US20090270371
+US20090270435
+US20090270496
+US20090274766
+US20090275538
+US20090281061
+US20090281101
+US20090281102
+US20090286775
+US20090286805
+US20090286858
+US20090291934
+US20090291939
+US20090292028
+US20090297644
+US20090298803
+US20090298943
+US20090306026
+US20090306093
+US20090306108
+US20090306178
+US20090311344
+US20090312324
+US20090312390
+US20090312411
+US20090317359
+US20090317487
+US20090318361
+US20090318502
+US20090318532
+US20090318543
+US20090318562
+US20090324668
+US20090324703
+US20090325894
+US20090325900
+US20090325971
+US20090325972
+US20090325991
+US20090326003
+US20090326066
+US20090326067
+US20100003250
+US20100003328
+US20100003340
+US20100003353
+US20100004220
+US20100008935
+US20100008974
+US20100009950
+US20100016276
+US20100016344
+US20100016424
+US20100021415
+US20100021493
+US20100021547
+US20100022449
+US20100022470
+US20100022511
+US20100022581
+US20100022622
+US20100028368
+US20100028400
+US20100029584
+US20100029695
+US20100034901
+US20100035866
+US20100035929
+US20100040599
+US20100041632
+US20100041647
+US20100041695
+US20100041751
+US20100047221
+US20100047362
+US20100048530
+US20100048544
+US20100048722
+US20100056457
+US20100056533
+US20100062039
+US20100062063
+US20100062084
+US20100062998
+US20100063033
+US20100063099
+US20100063109
+US20100063118
+US20100063122
+US20100063132
+US20100068162
+US20100068201
+US20100069331
+US20100069343
+US20100069352
+US20100069395
+US20100069399
+US20100069464
+US20100074850
+US20100074857
+US20100076007
+US20100076036
+US20100076058
+US20100076073
+US20100081625
+US20100081668
+US20100081705
+US20100086556
+US20100086605
+US20100087498
+US20100087547
+US20100092551
+US20100092580
+US20100093725
+US20100093755
+US20100093756
+US20100093852
+US20100098678
+US20100098713
+US20100099640
+US20100099671
+US20100099722
+US20100099745
+US20100104675
+US20100105641
+US20100105735
+US20100105777
+US20100111866
+US20100111888
+US20100113427
+US20100113469
+US20100113479
+US20100113512
+US20100113601
+US20100119472
+US20100119610
+US20100120799
+US20100124554
+US20100125077
+US20100125096
+US20100129353
+US20100129469
+US20100130442
+US20100130449
+US20100130459
+US20100130484
+US20100130490
+US20100130537
+US20100130593
+US20100135952
+US20100135988
+US20100136015
+US20100136107
+US20100136124
+US20100136127
+US20100137259
+US20100137267
+US20100137351
+US20100143295
+US20100143415
+US20100143420
+US20100144684
+US20100144715
+US20100144773
+US20100144786
+US20100144802
+US20100151007
+US20100152125
+US20100152227
+US20100152284
+US20100152303
+US20100158946
+US20100158958
+US20100159011
+US20100160228
+US20100160268
+US20100160269
+US20100160293
+US20100160342
+US20100160397
+US20100168077
+US20100168089
+US20100168248
+US20100169995
+US20100172959
+US20100172981
+US20100172984
+US20100172993
+US20100173008
+US20100173911
+US20100178278
+US20100178305
+US20100178332
+US20100178333
+US20100179163
+US20100179224
+US20100183552
+US20100183579
+US20100183691
+US20100183728
+US20100184724
+US20100184727
+US20100184768
+US20100184804
+US20100189771
+US20100190726
+US20100190743
+US20100190778
+US20100190830
+US20100191040
+US20100191325
+US20100192240
+US20100196286
+US20100196335
+US20100196355
+US20100196358
+US20100196436
+US20100196514
+US20100197564
+US20100197647
+US20100197768
+US20100197790
+US20100203009
+US20100203123
+US20100203166
+US20100204187
+US20100204320
+US20100210518
+US20100210625
+US20100210677
+US20100210709
+US20100210712
+US20100210716
+US20100215579
+US20100215774
+US20100216729
+US20100216736
+US20100216762
+US20100216886
+US20100218266
+US20100221343
+US20100222292
+US20100222296
+US20100222302
+US20100222360
+US20100222437
+US20100226908
+US20100226963
+US20100227839
+US20100227845
+US20100227891
+US20100227896
+US20100233255
+US20100233304
+US20100234313
+US20100234348
+US20100234410
+US20100234450
+US20100239592
+US20100239666
+US20100240603
+US20100240684
+US20100240687
+US20100240738
+US20100240763
+US20100247439
+US20100247659
+US20100247662
+US20100249038
+US20100249086
+US20100249141
+US20100249142
+US20100249222
+US20100254928
+US20100255050
+US20100255064
+US20100255126
+US20100256136
+US20100256161
+US20100256576
+US20100260675
+US20100260825
+US20100260856
+US20100261676
+US20100261681
+US20100261772
+US20100266654
+US20100266676
+US20100267640
+US20100267661
+US20100267706
+US20100269825
+US20100272671
+US20100272762
+US20100272814
+US20100273740
+US20100273783
+US20100273816
+US20100273872
+US20100278759
+US20100278797
+US20100279981
+US20100279996
+US20100284991
+US20100285024
+US20100285030
+US20100285040
+US20100285046
+US20100285087
+US20100285113
+US20100286023
+US20100286032
+US20100286089
+US20100286174
+US20100286207
+US20100286254
+US20100287636
+US20100291043
+US20100291118
+US20100292216
+US20100292229
+US20100292247
+US20100292272
+US20100292290
+US20100292330
+US20100292342
+US20100297015
+US20100297037
+US20100297054
+US20100297221
+US20100297256
+US20100297265
+US20100297269
+US20100298255
+US20100298264
+US20100298274
+US20100298301
+US20100298316
+US20100298376
+US20100298388
+US20100298396
+US20100298406
+US20100298418
+US20100298425
+US20100298431
+US20100303717
+US20100305088
+US20100305119
+US20100305157
+US20100305207
+US20100305500
+US20100310480
+US20100310575
+US20100310622
+US20100310660
+US20100311758
+US20100311796
+US20100311804
+US20100311815
+US20100311825
+US20100311827
+US20100316700
+US20100316708
+US20100316726
+US20100317610
+US20100317666
+US20100319073
+US20100322928
+US20100322979
+US20100323958
+US20100324023
+US20100324117
+US20100330145
+US20100330212
+US20100331247
+US20100331292
+US20100331326
+US20100331345
+US20100331388
+US20100331398
+US20100331536
+US20110002971
+US20110002980
+US20110003818
+US20110003858
+US20110003879
+US20110003882
+US20110008429
+US20110009426
+US20110009429
+US20110009434
+US20110014204
+US20110015136
+US20110015160
+US20110015176
+US20110015186
+US20110015216
+US20110020227
+US20110020455
+US20110020474
+US20110021462
+US20110021507
+US20110021981
+US20110027192
+US20110027340
+US20110027371
+US20110027376
+US20110027387
+US20110030077
+US20110033376
+US20110033406
+US20110033414
+US20110033437
+US20110033438
+US20110033473
+US20110033486
+US20110034409
+US20110034443
+US20110034444
+US20110034461
+US20110034467
+US20110034526
+US20110034532
+US20110034540
+US20110034553
+US20110038862
+US20110038941
+US20110039805
+US20110039815
+US20110039883
+US20110044908
+US20110046184
+US20110046232
+US20110046606
+US20110046982
+US20110052645
+US20110052687
+US20110052708
+US20110053917
+US20110053931
+US20110053952
+US20110053968
+US20110053995
+US20110054012
+US20110059076
+US20110059900
+US20110059921
+US20110059979
+US20110060031
+US20110060049
+US20110064748
+US20110064773
+US20110064830
+US20110065638
+US20110065670
+US20110065689
+US20110065711
+US20110065719
+US20110070287
+US20110070318
+US20110071108
+US20110071118
+US20110071185
+US20110071285
+US20110076230
+US20110076235
+US20110076250
+US20110076258
+US20110076315
+US20110076342
+US20110077222
+US20110081428
+US20110082096
+US20110082124
+US20110082140
+US20110082144
+US20110082197
+US20110082213
+US20110082214
+US20110086800
+US20110086802
+US20110086813
+US20110086834
+US20110086875
+US20110091385
+US20110091415
+US20110092465
+US20110092474
+US20110092495
+US20110092545
+US20110092565
+US20110092581
+US20110097343
+US20110097393
+US20110097403
+US20110097409
+US20110098233
+US20110098241
+US20110098246
+US20110098315
+US20110100371
+US20110104120
+US20110104238
+US20110104257
+US20110104262
+US20110104265
+US20110104272
+US20110104278
+US20110105479
+US20110105504
+US20110105578
+US20110105586
+US20110105588
+US20110111002
+US20110111018
+US20110112043
+US20110112188
+US20110117015
+US20110117175
+US20110117215
+US20110118208
+US20110118268
+US20110118271
+US20110118297
+US20110118359
+US20110123593
+US20110124558
+US20110124600
+US20110124626
+US20110124702
+US20110124725
+US20110129512
+US20110129528
+US20110129530
+US20110129551
+US20110130355
+US20110130378
+US20110130446
+US20110135619
+US20110135722
+US20110135724
+US20110135732
+US20110136758
+US20110136778
+US20110136784
+US20110136832
+US20110136857
+US20110142789
+US20110142797
+US20110142880
+US20110142938
+US20110142948
+US20110144040
+US20110144076
+US20110144168
+US20110144210
+US20110150856
+US20110151000
+US20110152228
+US20110152252
+US20110152328
+US20110152357
+US20110152381
+US20110159045
+US20110159066
+US20110159077
+US20110159078
+US20110159088
+US20110160127
+US20110160132
+US20110160176
+US20110160193
+US20110160203
+US20110160279
+US20110160308
+US20110165092
+US20110165198
+US20110165201
+US20110165269
+US20110166173
+US20110166200
+US20110166212
+US20110166214
+US20110171188
+US20110171239
+US20110171275
+US20110171283
+US20110172193
+US20110172197
+US20110172203
+US20110172251
+US20110172274
+US20110172296
+US20110177097
+US20110177098
+US20110177099
+US20110177161
+US20110178121
+US20110178151
+US20110182822
+US20110182849
+US20110182902
+US20110182912
+US20110182947
+US20110182984
+US20110182997
+US20110183899
+US20110183949
+US20110183956
+US20110183968
+US20110184007
+US20110184025
+US20110184033
+US20110184044
+US20110184057
+US20110189167
+US20110189173
+US20110189199
+US20110189279
+US20110190222
+US20110190234
+US20110190248
+US20110190256
+US20110190274
+US20110190287
+US20110190290
+US20110190293
+US20110190385
+US20110200603
+US20110201496
+US20110201567
+US20110201604
+US20110201678
+US20110206775
+US20110206778
+US20110207693
+US20110207733
+US20110207736
+US20110207772
+US20110207785
+US20110207797
+US20110209248
+US20110212090
+US20110212108
+US20110212170
+US20110212174
+US20110212192
+US20110212888
+US20110212936
+US20110212943
+US20110212947
+US20110212978
+US20110212991
+US20110212996
+US20110212998
+US20110213015
+US20110217239
+US20110217331
+US20110218230
+US20110218234
+US20110218243
+US20110218249
+US20110223247
+US20110224176
+US20110224244
+US20110229423
+US20110229438
+US20110229449
+US20110229485
+US20110229521
+US20110229524
+US20110230490
+US20110230543
+US20110230551
+US20110230555
+US20110236305
+US20110236490
+US20110236494
+US20110237595
+US20110237597
+US20110243914
+US20110245158
+US20110245202
+US20110245207
+US20110245209
+US20110245221
+US20110250142
+US20110250240
+US20110250254
+US20110250257
+US20110250259
+US20110250270
+US20110250297
+US20110251220
+US20110251261
+US20110251283
+US20110256097
+US20110256119
+US20110257110
+US20110257144
+US20110257244
+US20110257270
+US20110262354
+US20110262361
+US20110262449
+US20110262511
+US20110262537
+US20110263532
+US20110263566
+US20110263574
+US20110263581
+US20110263610
+US20110263620
+US20110263621
+US20110263643
+US20110263675
+US20110263676
+US20110263715
+US20110268690
+US20110268803
+US20110268822
+US20110269737
+US20110269741
+US20110269745
+US20110269818
+US20110269819
+US20110274771
+US20110275579
+US20110275596
+US20110275660
+US20110275673
+US20110275694
+US20110280955
+US20110281799
+US20110281887
+US20110281935
+US20110281948
+US20110287008
+US20110287074
+US20110287083
+US20110288033
+US20110288113
+US20110288138
+US20110293526
+US20110293581
+US20110293588
+US20110294746
+US20110294755
+US20110294791
+US20110294793
+US20110294876
+US20110300083
+US20110300164
+US20110301111
+US20110301141
+US20110305642
+US20110305717
+US20110305776
+US20110306559
+US20110306587
+US20110306596
+US20110306616
+US20110306661
+US20110311592
+US20110311618
+US20110312921
+US20110312940
+US20110312959
+US20110313020
+US20110313048
+US20110318411
+US20110318416
+US20110319489
+US20120003220
+US20120003252
+US20120003306
+US20120004200
+US20120004265
+US20120004269
+US20120004272
+US20120004278
+US20120004320
+US20120004636
+US20120009132
+US20120009239
+US20120010227
+US20120010262
+US20120010264
+US20120010287
+US20120015036
+US20120015049
+US20120015906
+US20120015922
+US20120015936
+US20120015950
+US20120021017
+US20120021078
+US20120022011
+US20120022019
+US20120022054
+US20120027811
+US20120028906
+US20120028950
+US20120028985
+US20120029016
+US20120029075
+US20120030779
+US20120034236
+US20120034266
+US20120034304
+US20120035127
+US20120035129
+US20120035139
+US20120035217
+US20120035257
+US20120039867
+US20120039964
+US20120040018
+US20120040025
+US20120041068
+US20120041070
+US20120046230
+US20120046268
+US20120046297
+US20120046300
+US20120046331
+US20120046340
+US20120046366
+US20120052071
+US20120052105
+US20120052136
+US20120053142
+US20120053159
+US20120053171
+US20120058150
+US20120058164
+US20120058171
+US20120058175
+US20120058194
+US20120058200
+US20120064168
+US20120064176
+US20120065147
+US20120065159
+US20120065216
+US20120065247
+US20120065273
+US20120070450
+US20120070483
+US20120071414
+US20120071431
+US20120071475
+US20120071483
+US20120071489
+US20120071505
+US20120071510
+US20120071558
+US20120071562
+US20120076770
+US20120076855
+US20120076859
+US20120076863
+US20120077785
+US20120088737
+US20120088820
+US20120093768
+US20120094944
+US20120095046
+US20120095092
+US20120100107
+US20120100218
+US20120101110
+US20120107255
+US20120107329
+US20120107415
+US20120108650
+US20120108655
+US20120108672
+US20120114602
+US20120114714
+US20120114731
+US20120114768
+US20120115810
+US20120115839
+US20120115857
+US20120115903
+US20120115907
+US20120115926
+US20120115934
+US20120116215
+US20120121582
+US20120121682
+US20120121689
+US20120121697
+US20120122769
+US20120122910
+US20120128744
+US20120128778
+US20120129822
+US20120129837
+US20120129874
+US20120129877
+US20120129943
+US20120129948
+US20120135054
+US20120135094
+US20120141380
+US20120141467
+US20120141603
+US20120142621
+US20120148589
+US20120148646
+US20120149661
+US20120149739
+US20120149745
+US20120149757
+US20120156185
+US20120156211
+US20120156226
+US20120156287
+US20120157450
+US20120157506
+US20120157515
+US20120157518
+US20120164231
+US20120165310
+US20120165313
+US20120171118
+US20120171228
+US20120172392
+US20120172591
+US20120174243
+US20120177623
+US20120177681
+US20120177722
+US20120178792
+US20120178809
+US20120183493
+US20120184494
+US20120184556
+US20120184607
+US20120189684
+US20120190647
+US20120190670
+US20120190737
+US20120191039
+US20120195870
+US20120195920
+US20120196801
+US20120196870
+US20120196879
+US20120201750
+US20120201872
+US20120201901
+US20120202752
+US20120202805
+US20120203050
+US20120203051
+US20120203356
+US20120207834
+US20120208769
+US20120208824
+US20120208846
+US20120208858
+US20120208877
+US20120208889
+US20120213727
+US20120213835
+US20120214832
+US20120214858
+US20120214869
+US20120219527
+US20120219544
+US20120219577
+US20120219594
+US20120219599
+US20120219616
+US20120219619
+US20120220550
+US20120220600
+US20120220632
+US20120225030
+US20120225122
+US20120225134
+US20120225864
+US20120231087
+US20120232042
+US20120232086
+US20120232102
+US20120234721
+US20120237596
+US20120238500
+US20120238513
+US20120238520
+US20120238542
+US20120238547
+US20120238627
+US20120244209
+US20120245139
+US20120245165
+US20120245215
+US20120251516
+US20120251571
+US20120251594
+US20120251626
+US20120252747
+US20120252756
+US20120252774
+US20120252810
+US20120252814
+US20120252830
+US20120252870
+US20120252872
+US20120252904
+US20120253298
+US20120258148
+US20120258958
+US20120258970
+US20120258984
+US20120259000
+US20120259005
+US20120263651
+US20120263653
+US20120263660
+US20120263677
+US20120263730
+US20120263808
+US20120264701
+US20120264724
+US20120264819
+US20120269802
+US20120269866
+US20120270835
+US20120270840
+US20120270849
+US20120270850
+US20120270860
+US20120270870
+US20120270874
+US20120270888
+US20120270895
+US20120271056
+US20120271251
+US20120271275
+US20120277296
+US20120282258
+US20120282350
+US20120283202
+US20120283210
+US20120288486
+US20120289476
+US20120289553
+US20120289581
+US20120289591
+US20120294822
+US20120294930
+US20120295928
+US20120295940
+US20120295961
+US20120301513
+US20120302524
+US20120302528
+US20120302529
+US20120302583
+US20120302593
+US20120308593
+US20120309742
+US20120309749
+US20120315233
+US20120315324
+US20120315343
+US20120316154
+US20120316196
+US20120316225
+US20120321726
+US20120321727
+US20120322718
+US20120322760
+US20120328628
+US20120329806
+US20120329835
+US20130004455
+US20130004519
+US20130004523
+US20130004651
+US20130005676
+US20130005744
+US20130005749
+US20130005785
+US20130011333
+US20130011481
+US20130011486
+US20130011494
+US20130012471
+US20130012497
+US20130012511
+US20130017166
+US20130017203
+US20130018002
+US20130018073
+US20130018102
+US20130022593
+US20130023498
+US20130023512
+US20130023548
+US20130023585
+US20130029935
+US20130029953
+US20130034503
+US20130034536
+US20130034578
+US20130039881
+US20130039953
+US20130040000
+US20130040927
+US20130040939
+US20130041002
+US20130045179
+US20130045250
+US20130045251
+US20130045947
+US20130052155
+US20130052279
+US20130053325
+US20130053334
+US20130053336
+US20130053339
+US20130053354
+US20130053376
+US20130053430
+US20130053449
+US20130058871
+US20130058876
+US20130059007
+US20130059802
+US20130059853
+US20130059871
+US20130059882
+US20130059899
+US20130059907
+US20130064883
+US20130064884
+US20130065853
+US20130065916
+US20130072465
+US20130072478
+US20130072493
+US20130072499
+US20130072509
+US20130072541
+US20130079315
+US20130095095
+US20130095194
+US20130101644
+US20130109755
+US20130123238
+US20130129639
+US20130131621
+US20130136714
+US20130136798
+US20130137727
+US20130143856
+US20130150311
+US20130164258
+US20130171231
+US20130172387
+US20130195890
+US20130236404
+US20130245043
+US20130252933
+US20130266615
+US20130302420
+US20130303482
+US20130309307
+US20130323284
+US20130344028
+US20140010771
+US20140011829
+US20140017337
+US20140051709
+US20140079831
+US20140080875
+US20140093502
+US20140113969
+US20140127278
+US20140142167
+US20140186345
+US20140187601
+US20140271799
+US6838453
+US6838469
+US6844320
+US6844336
+US6846818
+US6846821
+US6849733
+US6852755
+US6855732
+US6855829
+US6858228
+US6858612
+US6858645
+US6858722
+US6858723
+US6858739
+US6861406
+US6864243
+US6864246
+US6867236
+US6869954
+US6869956
+US6869975
+US6870031
+US6872705
+US6872706
+US6881726
+US6884802
+US6887874
+US6887887
+US6890900
+US6890911
+US6890937
+US6890961
+US6894021
+US6894038
+US6894042
+US6894043
+US6894069
+US6897222
+US6900175
+US6900198
+US6900240
+US6903095
+US6903107
+US6903203
+US6906051
+US6906107
+US6911435
+US6911465
+US6916603
+US6916793
+US6916826
+US6916907
+US6919327
+US6919363
+US6927228
+US6927229
+US6930102
+US6933386
+US6936634
+US6939541
+US6939891
+US6942870
+US6942966
+US6943181
+US6943188
+US6943192
+US6943246
+US6946118
+US6946149
+US6946462
+US6946471
+US6949259
+US6949510
+US6949656
+US6951876
+US6953568
+US6953591
+US6953595
+US6955806
+US6958145
+US6960474
+US6962918
+US6962941
+US6964956
+US6964966
+US6964973
+US6967197
+US6974824
+US6977252
+US6977257
+US6977259
+US6982096
+US6982275
+US6984641
+US6984643
+US6984648
+US6987105
+US6987113
+US6987117
+US6987126
+US6989378
+US6992094
+US6994842
+US6994862
+US6994869
+US6995184
+US6998395
+US7001991
+US7002018
+US7005432
+US7005508
+US7008626
+US7008954
+US7008956
+US7015325
+US7018661
+US7018997
+US7018999
+US7019029
+US7022667
+US7022733
+US7025988
+US7026356
+US7026359
+US7030099
+US7030147
+US7033583
+US7034114
+US7040314
+US7041314
+US7041652
+US7041654
+US7041660
+US7041664
+US7041835
+US7045522
+US7045526
+US7045546
+US7045633
+US7049293
+US7053058
+US7053095
+US7053099
+US7053176
+US7053215
+US7056528
+US7056898
+US7056911
+US7056946
+US7060698
+US7060809
+US7060824
+US7064185
+US7064203
+US7064218
+US7067148
+US7070971
+US7071178
+US7071195
+US7074815
+US7074921
+US7078054
+US7078380
+US7078521
+US7078523
+US7081464
+US7083799
+US7084117
+US7084157
+US7084270
+US7087596
+US7087758
+US7091182
+US7091242
+US7094421
+US7094899
+US7101711
+US7101868
+US7101995
+US7105576
+US7105644
+US7109181
+US7109245
+US7109330
+US7112562
+US7112577
+US7115578
+US7115617
+US7115651
+US7122643
+US7129232
+US7129349
+US7132412
+US7132425
+US7132451
+US7135286
+US7135494
+US7138396
+US7138417
+US7138425
+US7144912
+US7144997
+US7148207
+US7148232
+US7148240
+US7148249
+US7148252
+US7153885
+US7153968
+US7157472
+US7157491
+US7160903
+US7160909
+US7161009
+US7163949
+US7166286
+US7166622
+US7166726
+US7169813
+US7169940
+US7172870
+US7173061
+US7173134
+US7176180
+US7176193
+US7176221
+US7179817
+US7183095
+US7183430
+US7186544
+US7186755
+US7186803
+US7186864
+US7189404
+US7189718
+US7192602
+US7192942
+US7192945
+US7192978
+US7195769
+US7196073
+US7196077
+US7196081
+US7196099
+US7196104
+US7196111
+US7196179
+US7199148
+US7202237
+US7202242
+US7202263
+US7202280
+US7205319
+US7205326
+US7205405
+US7205435
+US7208491
+US7208505
+US7208520
+US7211598
+US7214668
+US7214700
+US7214794
+US7214805
+US7217697
+US7217707
+US7217844
+US7220739
+US7220755
+US7223774
+US7226917
+US7229978
+US7229991
+US7230131
+US7235560
+US7235658
+US7240785
+US7241757
+US7241923
+US7244414
+US7244726
+US7247626
+US7247633
+US7252845
+US7252974
+US7253162
+US7253169
+US7256184
+US7256188
+US7256189
+US7256205
+US7259148
+US7259157
+US7259175
+US7268125
+US7268129
+US7268130
+US7271153
+US7271160
+US7271162
+US7271174
+US7273928
+US7276513
+US7279175
+US7279466
+US7279489
+US7282599
+US7285546
+US7285547
+US7288528
+US7291638
+US7294629
+US7297789
+US7307087
+US7312203
+US7312317
+US7320803
+US7320987
+US7321000
+US7326718
+US7332185
+US7335645
+US7335647
+US7335777
+US7338959
+US7341712
+US7341723
+US7341741
+US7341749
+US7342025
+US7342125
+US7344868
+US7345063
+US7345065
+US7348336
+US7348340
+US7351710
+US7351722
+US7354910
+US7354919
+US7354945
+US7358086
+US7358235
+US7361664
+US7361665
+US7364751
+US7364847
+US7371372
+US7371406
+US7371407
+US7375229
+US7378388
+US7378410
+US7384934
+US7384950
+US7387790
+US7390500
+US7390668
+US7390801
+US7393526
+US7393545
+US7393825
+US7393849
+US7393859
+US7396660
+US7396836
+US7399464
+US7399481
+US7402602
+US7402604
+US7407971
+US7414042
+US7416887
+US7419824
+US7419968
+US7422764
+US7423067
+US7425319
+US7432292
+US7432344
+US7432389
+US7438903
+US7439397
+US7442386
+US7449457
+US7449583
+US7452373
+US7452534
+US7452556
+US7453006
+US7459528
+US7459544
+US7465445
+US7465553
+US7465718
+US7468359
+US7473431
+US7479506
+US7485315
+US7495004
+US7495009
+US7495110
+US7495127
+US7498340
+US7501399
+US7501405
+US7501431
+US7510830
+US7511010
+US7511027
+US7514244
+US7514432
+US7517892
+US7521450
+US7521453
+US7524850
+US7524973
+US7531540
+US7531557
+US7531604
+US7534782
+US7538127
+US7541363
+US7544358
+US7544367
+US7550442
+US7557140
+US7560448
+US7560484
+US7560586
+US7563458
+US7566721
+US7572774
+US7572787
+US7575740
+US7576097
+US7579439
+US7582644
+US7582676
+US7588753
+US7589077
+US7589113
+US7591949
+US7592316
+US7595325
+US7598228
+US7601703
+US7615635
+US7622450
+US7622476
+US7625872
+US7629384
+US7629471
+US7634362
+US7635469
+US7635691
+US7635692
+US7635702
+US7642276
+US7642903
+US7645782
+US7645788
+US7648695
+US7649005
+US7649017
+US7652021
+US7659257
+US7662826
+US7666619
+US7666897
+US7671071
+US7678805
+US7678834
+US7683034
+US7683061
+US7683164
+US7687483
+US7687501
+US7691828
+US7691870
+US7691871
+US7691900
+US7696208
+US7696332
+US7696354
+US7700080
+US7700088
+US7700629
+US7700657
+US7700765
+US7709480
+US7718670
+US7718673
+US7718701
+US7727999
+US7728025
+US7732144
+US7732484
+US7745448
+US7763641
+US7767677
+US7767682
+US7772392
+US7776332
+US7776868
+US7781429
+US7781446
+US7786131
+US7786177
+US7799763
+US7799773
+US7799811
+US7799955
+US7807355
+US7807655
+US7809428
+US7811573
+US7812054
+US7812169
+US7816333
+US7820697
+US7820717
+US7820818
+US7825104
+US7825158
+US7829694
+US7833977
+US7834008
+US7834029
+US7838032
+US7838043
+US7838505
+US7838528
+US7858641
+US7858782
+US7863265
+US7863321
+US7867509
+US7871635
+US7871765
+US7872017
+US7875290
+US7880020
+US7888336
+US7893297
+US7897613
+US7902185
+US7902241
+US7906659
+US7919470
+US7928128
+US7928146
+US7932281
+US7943173
+US7943627
+US7947706
+US7951795
+US7951812
+US7960383
+US7960416
+US7968523
+US7968607
+US7972624
+US7994144
+US7994156
+US7994217
+US7994219
+US7998492
+US8008324
+US8012494
+US8012991
+US8017587
+US8017596
+US8021861
+US8022174
+US8034812
+US8044040
+US8048866
+US8053473
+US8063054
+US8067472
+US8071074
+US8076319
+US8080565
+US8093216
+US8093293
+US8097611
+US8106214
+US8114866
+US8119644
+US8119658
+US8124640
+US8143240
+US8143486
+US8148355
+US8148431
+US8163718
+US8168179
+US8178348
+US8178543
+US8182996
+US8183213
+US8188100
+US8198300
+US8207142
+US8207145
+US8211666
+US8212029
+US8231910
+US8246930
+US8246982
+US8252307
+US8252838
+US8263142
+US8263346
+US8263609
+US8268790
+US8277839
+US8287898
+US8309355
+US8318709
+US8318910
+US8324241
+US8329214
+US8329690
+US8338475
+US8338641
+US8343761
+US8349853
+US8362008
+US8377981
+US8383164
+US8383178
+US8388971
+US8389484
+US8398990
+US8404675
+US8404703
+US8440668
+US8445493
+US8461139
+US8464706
+US8476254
+US8476285
+US8481075
+US8486902
+US8487003
+US8492375
+US8497271
+US8501764
+US8518460
+US8518995
+US8524212
+US8535715
+US8541429
+US8546396
+US8552000
+US8552054
+US8563581
+US8575147
+US8580850
+US8609656
+US8617539
+US8623410
+US8633198
+US8642618
+US8658170
+US8658636
+US8658693
+US8673347
+US8673898
+US8680098
+US8680100
+US8686021
+US8691799
+US8691820
+US8697880
+US8729037
+US8742119
+US8747883
+US8748476
+US8753674
+US8759327
+US8759328
+US8765747
+US8779163
+US8790702
+US8791257
+US8796248
+US8802623
+US8808754
+US8809348
+US8821920
+US8822480
+US8822518
+US8828358
+US8829013
+US8835450
+US8846315
+USRE39056
+USRE39061
+USRE39072
+USRE39112
+USRE39591
+USRE39680
+USRE39820
+USRE40851
+USRE40861
+USRE41439
+USRE43879
+USRE44733
+WO2002100330A9
+WO2003053360A3
+WO2003059294A3
+WO2003062392A3
+WO2003072732A3
+WO2003101437A3
+WO2004009590A8
+WO2004022039A3
+WO2004024095A3
+WO2004045490A3
+WO2004071400A3
+WO2004073601A3
+WO2004089333A3
+WO2004091597A3
+WO2004096195A3
+WO2004096197A3
+WO2004105756A3
+WO2004108061A3
+WO2004108682A3
+WO2005000355A1
+WO2005000846A1
+WO2005002587A1
+WO2005004923A1
+WO2005007099A2
+WO2005007153A1
+WO2005007165A1
+WO2005007240A1
+WO2005007646A1
+WO2005011698A1
+WO2005013884A2
+WO2005013946A3
+WO2005013947A3
+WO2005014599A1
+WO2005018528A3
+WO2005020882A2
+WO2005020913A3
+WO2005021012A1
+WO2005023232A2
+WO2005023273A1
+WO2005027661A1
+WO2005027922A1
+WO2005027927A1
+WO2005030198A1
+WO2005030233A1
+WO2005032530A1
+WO2005035534A1
+WO2005036989A1
+WO2005039638A2
+WO2005040045A3
+WO2005042472A3
+WO2005051993A1
+WO2005053679A1
+WO2005055999A1
+WO2005061485A1
+WO2005061549A1
+WO2005063736A1
+WO2005070902A1
+WO2005072720A1
+WO2005077358A1
+WO2005082169A1
+WO2005082459A2
+WO2005082854A1
+WO2005082904A1
+WO2005082924A1
+WO2005084463A1
+WO2005085294A1
+WO2005087224A1
+WO2005089800A1
+WO2005094813A1
+WO2005094854A1
+WO2005095369A1
+WO2005095414A1
+WO2005103054A3
+WO2005105118A1
+WO2005105125A1
+WO2005105998A1
+WO2005108398A1
+WO2005110002A3
+WO2005110451A1
+WO2005110989A1
+WO2005112965A2
+WO2005113002A1
+WO2005113483A2
+WO2005115344A1
+WO2005115377A1
+WO2005115388A1
+WO2005115402A1
+WO2005120435A2
+WO2005121143A1
+WO2005123062A1
+WO2005123651A1
+WO2006000589A8
+WO2006001035A3
+WO2006003013B1
+WO2006003290A2
+WO2006011669A1
+WO2006012504A3
+WO2006013445A3
+WO2006014787A2
+WO2006015590A3
+WO2006017921A1
+WO2006019855A1
+WO2006022543A1
+WO2006023515A3
+WO2006024668A1
+WO2006027987A1
+WO2006028523A3
+WO2006028875A1
+WO2006031556A3
+WO2006033341A1
+WO2006034632A8
+WO2006035291A1
+WO2006040052A1
+WO2006040643A2
+WO2006042249A3
+WO2006042481A1
+WO2006043966A3
+WO2006044503A3
+WO2006044524A1
+WO2006044961A1
+WO2006045865A1
+WO2006046738A1
+WO2006047522A8
+WO2006048248A3
+WO2006048330A1
+WO2006051818A1
+WO2006051937A1
+WO2006051987A1
+WO2006054757A1
+WO2006056877A2
+WO2006057578A3
+WO2006059121A3
+WO2006059507A1
+WO2006060712A3
+WO2006060762A3
+WO2006061712A2
+WO2006061992A1
+WO2006062094A1
+WO2006064228A3
+WO2006064686A1
+WO2006064761A1
+WO2006066846A1
+WO2006067362A1
+WO2006068665A1
+WO2006069740A1
+WO2006072957A1
+WO2006074872A1
+WO2006075226A1
+WO2006075395A1
+WO2006075642A1
+WO2006076317A2
+WO2006077367A1
+WO2006077419A1
+WO2006078056A8
+WO2006080043A3
+WO2006082821A1
+WO2006083005A1
+WO2006085521A1
+WO2006085687A1
+WO2006087229A1
+WO2006088944A1
+WO2006089286A2
+WO2006090613A1
+WO2006090782A1
+WO2006091009A1
+WO2006093217A1
+WO2006093784A2
+WO2006093801A1
+WO2006097323A1
+WO2006098074A1
+WO2006100181A2
+WO2006101818A1
+WO2006102958A1
+WO2006103544A3
+WO2006104141A1
+WO2006104154A1
+WO2006104971A1
+WO2006105063A1
+WO2006105222A3
+WO2006106416A1
+WO2006106914A1
+WO2006107019A1
+WO2006108700A1
+WO2006108709A1
+WO2006113034A1
+WO2006115273A1
+WO2006116630A2
+WO2006117165A3
+WO2006118079A1
+WO2006120696A2
+WO2006120705A2
+WO2006121263A1
+WO2006122661A1
+WO2006124447A2
+WO2006124544A3
+WO2006125048A3
+WO2006126939A8
+WO2006129524A1
+WO2006130588A1
+WO2006131303A3
+WO2006132914A3
+WO2006133104A3
+WO2006134112A1
+WO2006134150A1
+WO2006134279A2
+WO2006135621A2
+WO2006135932A3
+WO2006135973A1
+WO2006137421A1
+WO2006137423A1
+WO2006137469A1
+WO2006137514A1
+WO2006137772A1
+WO2006138428A3
+WO2007000465A1
+WO2007002174A3
+WO2007003594A1
+WO2007004239A1
+WO2007004244A1
+WO2007006549A3
+WO2007007686A1
+WO2007007894A1
+WO2007008119A1
+WO2007009539A2
+WO2007009635A1
+WO2007009690A1
+WO2007009758A3
+WO2007010853A1
+WO2007012254A1
+WO2007013494A1
+WO2007013661A1
+WO2007013694A1
+WO2007013841A1
+WO2007013896A3
+WO2007014970A1
+WO2007015175A2
+WO2007015510A1
+WO2007015528A1
+WO2007017114A1
+WO2007017264A3
+WO2007017678A1
+WO2007019880A1
+WO2007020653A1
+WO2007020917A1
+WO2007022964A3
+WO2007024673A1
+WO2007024814A1
+WO2007025900A1
+WO2007026897A1
+WO2007028030A3
+WO2007028638A1
+WO2007030438A3
+WO2007031338A1
+WO2007031726A1
+WO2007031828A3
+WO2007031833A3
+WO2007033137A1
+WO2007033269A1
+WO2007033400A1
+WO2007035123A1
+WO2007035489A2
+WO2007036363A8
+WO2007037513A1
+WO2007038045A1
+WO2007038785A1
+WO2007039111A2
+WO2007039171A1
+WO2007039563A1
+WO2007039773A1
+WO2007040238A1
+WO2007040436A1
+WO2007042669A2
+WO2007042815A1
+WO2007044085A3
+WO2007044796A3
+WO2007045979A1
+WO2007045989A1
+WO2007046426A1
+WO2007046524A1
+WO2007047626A1
+WO2007048228A1
+WO2007048802A1
+WO2007049642A1
+WO2007049828A1
+WO2007051333A1
+WO2007052295A3
+WO2007052849A1
+WO2007054451A1
+WO2007054573A2
+WO2007055378A1
+WO2007056870A1
+WO2007058338A3
+WO2007059918A1
+WO2007060182A1
+WO2007060484A1
+WO2007060491A3
+WO2007060525A3
+WO2007062678A1
+WO2007062999A3
+WO2007063391A3
+WO2007063839A1
+WO2007064543A1
+WO2007064762A3
+WO2007064914A2
+WO2007066103A1
+WO2007066355A1
+WO2007067416A3
+WO2007068112A1
+WO2007068776A1
+WO2007070504A3
+WO2007070872A1
+WO2007072156A1
+WO2007072169A2
+WO2007075838A2
+WO2007077158A1
+WO2007079199A3
+WO2007079391A3
+WO2007082434A1
+WO2007082666A1
+WO2007082922A2
+WO2007084391A3
+WO2007084857A3
+WO2007087151A2
+WO2007087215A3
+WO2007087395A3
+WO2007088900A1
+WO2007089193A1
+WO2007093600A1
+WO2007094404A1
+WO2007095147A2
+WO2007095561A3
+WO2007095607A1
+WO2007095688A1
+WO2007095784A1
+WO2007095812A1
+WO2007096471A1
+WO2007098828A1
+WO2007099402A3
+WO2007099921A1
+WO2007099981A1
+WO2007099999A1
+WO2007102608A1
+WO2007102703A1
+WO2007104867A3
+WO2007105744A1
+WO2007108434A1
+WO2007108712A1
+WO2007111275A1
+WO2007112914A3
+WO2007113290A1
+WO2007113647A1
+WO2007114124A1
+WO2007114683A1
+WO2007115071A1
+WO2007115261A2
+WO2007115935A1
+WO2007116230A1
+WO2007117398B1
+WO2007118793A1
+WO2007118859A1
+WO2007119116A3
+WO2007120445A1
+WO2007120599A2
+WO2007120768A1
+WO2007121389A3
+WO2007121921A3
+WO2007122401A1
+WO2007123868A2
+WO2007124433A1
+WO2007126126A1
+WO2007128109A1
+WO2007131253A2
+WO2007131424A1
+WO2007133796A3
+WO2007134086A3
+WO2007134819A1
+WO2007134966A1
+WO2007135122A1
+WO2007135134A1
+WO2007136302A2
+WO2007136325A1
+WO2007136696A2
+WO2007139496A1
+WO2007140982A1
+WO2007141764A1
+WO2007141898A1
+WO2007143483A2
+WO2007144084A3
+WO2007144204A1
+WO2007144379A1
+WO2007145365A1
+WO2007147646A1
+WO2007148308A3
+WO2007148711A1
+WO2007150063A2
+WO2008003378A1
+WO2008003855A2
+WO2008006226A1
+WO2008006257A1
+WO2008006589A3
+WO2008008895A1
+WO2008009935A1
+WO2008010472A1
+WO2008010527A1
+WO2008011016A3
+WO2008011392A3
+WO2008011478A2
+WO2008011483A3
+WO2008011980A1
+WO2008014338A3
+WO2008015423A1
+WO2008016665A2
+WO2008018892A2
+WO2008020306A3
+WO2008020489A1
+WO2008020622A1
+WO2008021728A3
+WO2008022771A1
+WO2008023278A8
+WO2008024027A3
+WO2008024304A3
+WO2008025228A1
+WO2008025947A1
+WO2008026729A1
+WO2008026965A1
+WO2008027988A2
+WO2008029294A3
+WO2008030536A2
+WO2008031928A1
+WO2008032041A1
+WO2008033798A3
+WO2008033858A3
+WO2008035757A1
+WO2008036239A2
+WO2008036954A1
+WO2008037716A3
+WO2008038303A2
+WO2008038304A3
+WO2008038394A1
+WO2008040816A1
+WO2008041031A1
+WO2008041236A2
+WO2008043180A1
+WO2008043811A1
+WO2008044729A1
+WO2008046202A1
+WO2008046497A1
+WO2008047853A1
+WO2008049105A3
+WO2008049194A1
+WO2008050200A1
+WO2008050899A1
+WO2008051942A2
+WO2008052072A9
+WO2008053199A1
+WO2008053863A1
+WO2008053909A1
+WO2008056189A1
+WO2008056634A1
+WO2008056657A1
+WO2008057496A3
+WO2008057938A1
+WO2008058897A2
+WO2008059239A1
+WO2008059800A1
+WO2008061399A1
+WO2008061720A3
+WO2008062324A3
+WO2008062424A2
+WO2008062463A2
+WO2008063045A1
+WO2008063772A3
+WO2008064004A2
+WO2008064093A3
+WO2008064337A3
+WO2008064475A1
+WO2008064558A1
+WO2008065123A2
+WO2008065527A3
+WO2008066402A1
+WO2008067527A1
+WO2008067781B1
+WO2008070795A3
+WO2008071665A1
+WO2008071869A3
+WO2008071948A3
+WO2008071964A1
+WO2008072061A1
+WO2008072952A2
+WO2008073961A9
+WO2008074756A1
+WO2008074849A1
+WO2008075466A1
+WO2008076043A1
+WO2008077103A1
+WO2008077130A2
+WO2008078729A1
+WO2008079030A8
+WO2008079257A3
+WO2008080056A3
+WO2008080223A1
+WO2008080369A1
+WO2008080455A1
+WO2008081834A1
+WO2008081901A1
+WO2008081934A1
+WO2008081937A1
+WO2008083107A3
+WO2008083354A1
+WO2008083356A1
+WO2008083442A1
+WO2008084261A1
+WO2008085008A1
+WO2008085921A2
+WO2008086854A1
+WO2008089105A3
+WO2008089201A3
+WO2008090081A1
+WO2008090749A1
+WO2008092465A1
+WO2008092785A1
+WO2008092816A3
+WO2008093075A2
+WO2008093495A1
+WO2008093848A1
+WO2008095366A1
+WO2008096002A1
+WO2008096155A1
+WO2008096769A1
+WO2008097897A9
+WO2008099075A1
+WO2008099804A1
+WO2008099874A1
+WO2008099912A1
+WO2008100560A2
+WO2008100562A3
+WO2008100809A1
+WO2008102128A2
+WO2008103431A2
+WO2008105441A1
+WO2008106731A1
+WO2008106781A1
+WO2008107543A3
+WO2008109286A1
+WO2008110196A1
+WO2008111669A1
+WO2008112241A1
+WO2008112647A3
+WO2008113006A1
+WO2008113134A1
+WO2008113851A3
+WO2008114505A1
+WO2008115118A1
+WO2008117046A1
+WO2008117389A1
+WO2008119042A3
+WO2008120708A1
+WO2008120766A1
+WO2008122100A1
+WO2008122654A2
+WO2008124210A1
+WO2008124323A1
+WO2008128627A3
+WO2008129971A1
+WO2008130261A1
+WO2008131103A2
+WO2008132211A1
+WO2008133157A1
+WO2008133192A1
+WO2008135524A3
+WO2008135743A1
+WO2008135791A8
+WO2008136374A1
+WO2008136378A1
+WO2008138874A1
+WO2008138920A1
+WO2008141239A1
+WO2008141368A1
+WO2008143490A1
+WO2008144602A1
+WO2008146691A1
+WO2008147167A1
+WO2008147697A1
+WO2008148302A1
+WO2008148799A1
+WO2008149138A1
+WO2008149311A1
+WO2008150260A1
+WO2008153426A1
+WO2008153511A1
+WO2008153632A3
+WO2008153767A2
+WO2008153958A2
+WO2008154898A3
+WO2008155132A1
+WO2008156349A3
+WO2009002652A3
+WO2009005613A2
+WO2009005674A3
+WO2009005813A1
+WO2009007441A3
+WO2009007680A3
+WO2009008120A1
+WO2009010416A3
+WO2009010871A2
+WO2009011561A1
+WO2009011787A1
+WO2009011910A3
+WO2009012534A1
+WO2009013348A3
+WO2009013390A1
+WO2009016081A3
+WO2009016084A1
+WO2009016269A1
+WO2009016855A1
+WO2009017664A1
+WO2009019260A3
+WO2009019505A3
+WO2009022104A1
+WO2009022179A2
+WO2009022756A1
+WO2009023179A3
+WO2009024677A3
+WO2009025315A1
+WO2009025326A1
+WO2009025791A3
+WO2009025876A3
+WO2009026326A1
+WO2009027473A1
+WO2009027838A3
+WO2009029618A1
+WO2009031575A1
+WO2009031627A1
+WO2009031709A1
+WO2009032244A1
+WO2009032326A1
+WO2009032972A1
+WO2009033281A1
+WO2009033284A1
+WO2009033505A1
+WO2009033689A1
+WO2009034061A1
+WO2009034433A3
+WO2009034475A3
+WO2009035265A2
+WO2009035473A3
+WO2009035534A3
+WO2009036000A2
+WO2009036754A1
+WO2009036852A1
+WO2009037357A4
+WO2009038057A1
+WO2009038064A1
+WO2009038204A1
+WO2009039362A2
+WO2009040075A1
+WO2009040445A3
+WO2009041566A1
+WO2009041567A1
+WO2009043593A1
+WO2009044153A2
+WO2009044788A1
+WO2009047481A1
+WO2009048603A1
+WO2009048760A3
+WO2009049208A1
+WO2009049362A1
+WO2009049460A1
+WO2009049492A1
+WO2009050199A1
+WO2009050318A1
+WO2009052050A1
+WO2009052072A1
+WO2009052624A9
+WO2009053715A8
+WO2009054423A1
+WO2009054970A1
+WO2009056754A9
+WO2009057795A3
+WO2009058801A1
+WO2009059047A3
+WO2009059452A1
+WO2009060073A1
+WO2009061336A1
+WO2009062082A3
+WO2009062193A2
+WO2009062619A1
+WO2009062662A1
+WO2009063170A1
+WO2009066138A2
+WO2009067081A1
+WO2009067317A2
+WO2009067607A2
+WO2009067703A3
+WO2009068520A2
+WO2009068531A3
+WO2009071990A3
+WO2009073203A1
+WO2009073916A1
+WO2009074835A1
+WO2009077485A3
+WO2009077585A1
+WO2009077990A1
+WO2009078366A1
+WO2009079860A1
+WO2009080432A3
+WO2009080555A3
+WO2009081197A1
+WO2009085584A1
+WO2009085637A1
+WO2009086130A1
+WO2009086705A1
+WO2009087354A2
+WO2009089107A1
+WO2009089534A3
+WO2009090024A1
+WO2009090556A2
+WO2009094845A1
+WO2009096503A1
+WO2009098209A1
+WO2009100107A2
+WO2009100456A2
+WO2009100994A1
+WO2009101199A3
+WO2009102814A2
+WO2009103053A1
+WO2009103953A1
+WO2009105218A3
+WO2009105680A2
+WO2009105936A1
+WO2009106748A3
+WO2009107098A3
+WO2009108118A9
+WO2009108384A2
+WO2009109862A3
+WO2009109986A1
+WO2009110495A1
+WO2009111830A1
+WO2009115547A8
+WO2009116055A1
+WO2009116074A3
+WO2009116509A1
+WO2009117378A3
+WO2009117540A1
+WO2009117710A2
+WO2009118655A2
+WO2009118712A3
+WO2009119858A1
+WO2009119982A2
+WO2009122034A2
+WO2009122148A1
+WO2009123210A1
+WO2009123877A1
+WO2009124252A2
+WO2009124311A1
+WO2009126530A3
+WO2009128395A1
+WO2009129361A2
+WO2009129525A2
+WO2009129532A1
+WO2009130242A1
+WO2009130270A1
+WO2009130326A1
+WO2009131947A2
+WO2009134147A1
+WO2009134637A1
+WO2009135135A3
+WO2009136001A1
+WO2009136176A1
+WO2009137074A1
+WO2009137334A2
+WO2009137660A9
+WO2009138186A3
+WO2009139880A1
+WO2009140078A1
+WO2009140928A1
+WO2009141090A8
+WO2009141571A1
+WO2009143064A2
+WO2009144555A8
+WO2009145299A1
+WO2009145839A1
+WO2009146131A2
+WO2009146310A1
+WO2009148004A1
+WO2009149135A1
+WO2009150137A3
+WO2009150144A1
+WO2009150257A3
+WO2009151094A1
+WO2009151098A1
+WO2009151626A1
+WO2009152087A1
+WO2009152584A1
+WO2009153592A1
+WO2009153791A1
+WO2009154766A1
+WO2009154828A3
+WO2009155475A1
+WO2009155611A9
+WO2009156864A3
+WO2009157880A1
+WO2009158248A2
+WO2010004139A1
+WO2010004433A3
+WO2010004982A1
+WO2010005851A1
+WO2010006129A3
+WO2010006299A1
+WO2010006697A3
+WO2010007248A2
+WO2010008847A3
+WO2010009155A2
+WO2010009775A1
+WO2010010127A1
+WO2010010136A1
+WO2010010797A1
+WO2010011538A1
+WO2010012620A1
+WO2010012811A3
+WO2010012812A1
+WO2010013187A1
+WO2010014889A3
+WO2010015590A1
+WO2010015849A3
+WO2010023390A1
+WO2010024356A1
+WO2010024783A1
+WO2010025073A1
+WO2010025448A3
+WO2010026110A3
+WO2010027094A1
+WO2010027114A1
+WO2010027266A1
+WO2010028130A2
+WO2010029925A1
+WO2010030012A1
+WO2010031801A3
+WO2010032266A9
+WO2010033444A1
+WO2010033958A1
+WO2010034648A1
+WO2010038153A1
+WO2010038803A1
+WO2010038842A1
+WO2010039529A3
+WO2010039997A2
+WO2010040750A1
+WO2010041681A1
+WO2010042212A3
+WO2010042477A1
+WO2010043029A1
+WO2010043550A1
+WO2010043787A1
+WO2010044403A1
+WO2010046388A1
+WO2010047126A1
+WO2010048593A1
+WO2010048731A1
+WO2010049073A1
+WO2010049731A1
+WO2010049841A1
+WO2010049921A1
+WO2010050783A2
+WO2010051683A1
+WO2010053085A1
+WO2010054307A1
+WO2010054758A1
+WO2010055304A3
+WO2010055473A1
+WO2010056633A3
+WO2010056672A2
+WO2010057197A1
+WO2010057804A1
+WO2010058417A1
+WO2010060742A1
+WO2010060968A1
+WO2010061921A1
+WO2010062205A4
+WO2010064252A3
+WO2010064951A1
+WO2010065134A1
+WO2010065801A1
+WO2010067102A1
+WO2010068183A1
+WO2010068815A3
+WO2010069561A1
+WO2010069979A1
+WO2010070076A1
+WO2010070238A1
+WO2010071872A2
+WO2010072166A1
+WO2010072712A1
+WO2010072807A3
+WO2010073104A3
+WO2010073126A3
+WO2010073642A1
+WO2010074088A1
+WO2010077310A2
+WO2010079255A1
+WO2010081387A1
+WO2010081778A1
+WO2010083414A8
+WO2010083444A1
+WO2010084186A1
+WO2010084458A1
+WO2010087521A1
+WO2010091124A2
+WO2010091543A1
+WO2010093787A3
+WO2010094483A1
+WO2010095425A1
+WO2010097373A1
+WO2010097467A1
+WO2010098396A1
+WO2010101302A1
+WO2010103279A1
+WO2010103306A1
+WO2010104571A2
+WO2010106145A1
+WO2010106871A1
+WO2010109434A3
+WO2010110748A1
+WO2010111719A2
+WO2010112091A1
+WO2010113800A1
+WO2010114181A1
+WO2010114471A1
+WO2010115252A1
+WO2010117194A2
+WO2010117727A3
+WO2010118250A3
+WO2010118286A3
+WO2010118298A3
+WO2010118309A3
+WO2010120253A1
+WO2010120875A3
+WO2010120987A1
+WO2010122344A1
+WO2010122456A1
+WO2010123006A1
+WO2010123008A1
+WO2010123018A1
+WO2010123102A1
+WO2010124089A3
+WO2010124601A1
+WO2010127856A1
+WO2010128309A1
+WO2010130178A1
+WO2010131025A1
+WO2010131475A1
+WO2010132440A3
+WO2010132599A1
+WO2010132743A1
+WO2010132959A1
+WO2010133793A1
+WO2010135506A1
+WO2010135714A2
+WO2010137979A8
+WO2010142124A1
+WO2010142985A1
+WO2010145066A1
+WO2010146078A2
+WO2010147068A1
+WO2010147144A1
+WO2010151096A1
+WO2011000811A4
+WO2011003626A1
+WO2011004882A1
+WO2011005295A8
+WO2011006079A3
+WO2011006144A1
+WO2011006536A1
+WO2011008054A2
+WO2011008112A1
+WO2011008947A2
+WO2011011706A2
+WO2011012622A1
+WO2011014008A3
+WO2011014766A2
+WO2011016050A3
+WO2011016395A1
+WO2011016558A1
+WO2011017299A3
+WO2011019124A1
+WO2011024428A1
+WO2011026125A2
+WO2011028794A2
+WO2011030859A1
+WO2011030873A1
+WO2011032169A3
+WO2011033305A1
+WO2011033715A1
+WO2011036303A1
+WO2011036461A1
+WO2011039221A2
+WO2011040613A1
+WO2011042497A1
+WO2011042918A3
+WO2011045934A1
+WO2011046057A1
+WO2011046382A3
+WO2011047636A1
+WO2011049042A1
+WO2011049122A1
+WO2011049213A1
+WO2011050394A1
+WO2011054315A1
+WO2011054820A1
+WO2011055247A1
+WO2011056545A3
+WO2011056549A1
+WO2011057331A1
+WO2011058773A1
+WO2011059121A1
+WO2011059388A1
+WO2011060962A1
+WO2011061303A1
+WO2011063595A1
+WO2011065905A1
+WO2011066006A2
+WO2011067189A3
+WO2011067663A1
+WO2011069335A1
+WO2011069951A1
+WO2011070039A1
+WO2011071057A1
+WO2011071194A1
+WO2011071684A1
+WO2011073160A1
+WO2011073929A1
+WO2011074658A1
+WO2011074695A1
+WO2011074881A2
+WO2011074992A1
+WO2011076363A1
+WO2011076744A1
+WO2011078143A1
+WO2011079767A1
+WO2011081971A2
+WO2011082487A1
+WO2011083853A1
+WO2011084459A1
+WO2011084653A1
+WO2011085155A3
+WO2011085454A1
+WO2011085979A1
+WO2011086507A8
+WO2011086541A1
+WO2011086577A3
+WO2011089168A2
+WO2011089401A1
+WO2011089457A1
+WO2011092293A3
+WO2011093294A1
+WO2011093600A3
+WO2011093664A3
+WO2011094208A2
+WO2011095535A3
+WO2011095579A1
+WO2011098451A1
+WO2011099031A1
+WO2011099764A2
+WO2011101069A3
+WO2011101860A1
+WO2011102407A1
+WO2011102460A1
+WO2011103289A3
+WO2011103345A2
+WO2011106839A1
+WO2011108499A1
+WO2011108690A1
+WO2011109012A1
+WO2011109384A3
+WO2011109767A3
+WO2011111384A1
+WO2011111715A1
+WO2011115819A3
+WO2011119125A1
+WO2011119777A2
+WO2011120886A1
+WO2011121068A1
+WO2011121607A2
+WO2011124093A1
+WO2011126071A1
+WO2011126099A1
+WO2011126385A3
+WO2011128445A1
+WO2011130476A2
+WO2011133687A2
+WO2011135520A1
+WO2011135743A1
+WO2011137155A1
+WO2011138657A1
+WO2011139348A9
+WO2011141004A1
+WO2011143106A1
+WO2011143201A2
+WO2011143721A1
+WO2011144439A1
+WO2011144785A1
+WO2011145909A3
+WO2011146850A1
+WO2011146876A2
+WO2011147199A1
+WO2011148657A1
+WO2011149529A3
+WO2011150288A1
+WO2011150347A2
+WO2011151731A3
+WO2011153192A3
+WO2011154630A1
+WO2011158931A1
+WO2011159634A1
+WO2011160259A1
+WO2011163321A2
+WO2012000519A1
+WO2012003544A1
+WO2012004410A1
+WO2012007493A1
+WO2012007555A3
+WO2012007627A1
+WO2012007632A9
+WO2012008565A1
+WO2012008711A2
+WO2012008908A1
+WO2012009646A1
+WO2012012257A2
+WO2012012305A2
+WO2012013366A3
+WO2012013821A1
+WO2012013967A3
+WO2012014012A1
+WO2012014963A1
+WO2012015677A1
+WO2012016707A2
+WO2012017367A1
+WO2012018145A2
+WO2012018759A3
+WO2012019315A1
+WO2012019430A8
+WO2012020021A9
+WO2012020787A1
+WO2012022776A1
+WO2012023284A1
+WO2012023285A1
+WO2012024282A2
+WO2012025942A1
+WO2012026468A1
+WO2012028340A1
+WO2012029771A1
+WO2012030165A2
+WO2012030894A1
+WO2012030990A1
+WO2012031603A3
+WO2012031941A2
+WO2012035364A1
+WO2012035685A1
+WO2012038785A1
+WO2012040230A1
+WO2012040938A1
+WO2012043481A1
+WO2012045010A1
+WO2012045124A1
+WO2012045195A1
+WO2012047587A2
+WO2012047800A1
+WO2012049555A1
+WO2012050370A3
+WO2012051107A3
+WO2012051296A2
+WO2012051492A3
+WO2012051988A3
+WO2012052169A2
+WO2012052459A1
+WO2012052668A1
+WO2012053003A1
+WO2012054724A1
+WO2012054862A2
+WO2012055884A1
+WO2012059515A1
+WO2012061931A1
+WO2012062210A1
+WO2012066518A1
+WO2012068412A2
+WO2012069432A1
+WO2012071221A2
+WO2012072200A1
+WO2012075849A1
+WO2012076321A1
+WO2012076680A1
+WO2012076916A1
+WO2012077775A1
+WO2012078859A3
+WO2012082997A1
+WO2012085176A1
+WO2012085189A1
+WO2012085481A1
+WO2012087881A1
+WO2012090124A3
+WO2012090204A8
+WO2012090221A1
+WO2012090322A1
+WO2012091010A1
+WO2012092160A3
+WO2012093227A1
+WO2012093383A1
+WO2012094831A1
+WO2012095461A1
+WO2012097052A3
+WO2012098387A1
+WO2012098562A3
+WO2012099452A1
+WO2012101065A3
+WO2012101239A1
+WO2012101440A1
+WO2012102562A3
+WO2012103570A1
+WO2012103806A1
+WO2012104571A1
+WO2012105563A1
+WO2012105708A1
+WO2012105873A1
+WO2012108297A1
+WO2012109976A1
+WO2012110860A1
+WO2012111995A1
+WO2012114285A9
+WO2012115182A1
+WO2012115306A1
+WO2012116577A1
+WO2012117062A1
+WO2012119151A2
+WO2012121178A1
+WO2012122451A3
+WO2012124311A8
+WO2012124738A1
+WO2012127431A1
+WO2012129220A1
+WO2012129473A1
+WO2012130448A1
+WO2012130621A1
+WO2012135064A2
+WO2012135588A3
+WO2012136111A1
+WO2012138988A3
+WO2012139628A1
+WO2012141553A2
+WO2012142029A2
+WO2012142698A1
+WO2012143116A1
+WO2012145678A1
+WO2012145737A1
+WO2012145743A1
+WO2012146194A1
+WO2012146644A1
+WO2012147705A1
+WO2012149667A1
+WO2012150245A1
+WO2012150520A1
+WO2012151058A1
+WO2012151704A1
+WO2012152295A1
+WO2012153302A1
+WO2012154076A1
+WO2012154779A1
+WO2012154956A2
+WO2012155007A1
+WO2012155834A1
+WO2012157239A1
+WO2012158123A1
+WO2012158271A1
+WO2012158517A1
+WO2012158880A3
+WO2012159593A2
+WO2012160392A1
+WO2012161655A1
+WO2012162584A1
+WO2012165914A3
+WO2012168265A1
+WO2012168462A1
+WO2012169571A1
+WO2012169661A1
+WO2012170839A3
+WO2012171125A1
+WO2012171900A1
+WO2012172562A2
+WO2012173217A1
+WO2012174253A1
+WO2012175747A1
+WO2012176842A1
+WO2012177212A1
+WO2012177746A1
+WO2013000855A1
+WO2013000974A1
+WO2013002420A1
+WO2013002428A1
+WO2013003114A8
+WO2013004032A1
+WO2013004332A1
+WO2013004999A1
+WO2013006738A1
+WO2013007765A1
+WO2013008175A1
+WO2013008594A1
+WO2013010018A3
+WO2013010218A1
+WO2013013003A1
+WO2013013826A1
+WO2013016501A1
+WO2013016531A2
+WO2013017071A1
+WO2013018018A1
+WO2013018706A1
+WO2013023982A1
+WO2013024028A1
+WO2013024895A1
+WO2013026118A1
+WO2013028880A1
+WO2013032028A1
+WO2013033061A1
+WO2013033283A1
+WO2013035047A1
+WO2013035423A1
+WO2013036912A3
+WO2013038666A1
+WO2013039202A1
+WO2013040027A1
+WO2013040337A1
+WO2013040863A1
+WO2013040873A1
+WO2013041457A1
+WO2013041859A1
+WO2013042065A4
+WO2013042124A8
+WO2013044596A1
+WO2013045028A1
+WO2013046161A1
+WO2013048787A1
+WO2013050637A1
+WO2013051928A1
+WO2013052010A1
+WO2013053372A1
+WO2013055833A1
+WO2013056046A1
+WO2013056067A1
+WO2013056326A1
+WO2013058751A1
+WO2013059437A1
+WO2013059772A1
+WO2013060304A1
+WO2013060908A1
+WO2013061005A1
+WO2013062402A1
+WO2013062445A1
+WO2013063458A3
+WO2013066181A1
+WO2013066640A1
+WO2013067306A1
+WO2013068966A2
+WO2013070030A1
+WO2013070586A1
+WO2013071203A1
+WO2013075785A1
+WO2013077186A1
+WO2013077433A1
+WO2013077446A1
+WO2013077617A1
+WO2013078123A1
+WO2013078554A1
+WO2013078658A1
+WO2013079211A1
+WO2013079696A1
+WO2013081087A1
+WO2013082541A1
+WO2013082624A3
+WO2013083058A1
+WO2013083552A1
+WO2013083910A3
+WO2013087004A1
+WO2013087083A1
+WO2013087920A1
+WO2013088373A1
+WO2013089986A1
+WO2013093790A1
+WO2013093849A1
+WO2013094489A1
+WO2013095315A1
+WO2013095321A1
+WO2013096689A1
+WO2013097074A8
+WO2013097947A1
+WO2013098320A1
+WO2013098570A1
+WO2013100585A3
+WO2013101983A3
+WO2013102207A1
+WO2013104830A1
+WO2013105092A1
+WO2013106410A3
+WO2013106494A1
+WO2013106824A1
+WO2013106934A1
+WO2013107278A1
+WO2013107413A1
+WO2013108921A1
+WO2013110135A1
+WO2013110198A1
+WO2013110643A1
+WO2013111801A1
+WO2013112878A1
+WO2013114400A3
+WO2013116325A1
+WO2013116562A1
+WO2013121209A1
+WO2013123019A1
+WO2013123996A1
+WO2013124026A8
+WO2013124701A3
+WO2013126550A3
+WO2013126595A1
+WO2013127266A1
+WO2013127828A1
+WO2013128000A1
+WO2013128423A1
+WO2013129879A1
+WO2013132208A1
+WO2013133367A1
+WO2013133450A1
+WO2013134252A1
+WO2013135176A1
+WO2013137009A1
+WO2013138306A1
+WO2013138600A1
+WO2013138612A1
+WO2013138654A1
+WO2013142202A1
+WO2013143466A1
+WO2013146539A1
+WO2013146797A1
+WO2013147117A1
+WO2013148333A1
+WO2013149190A1
+WO2013149987A1
+WO2013150406A3
+WO2013150534A1
+WO2013151699A1
+WO2013152227A1
+WO2013152269A1
+WO2013152298A1
+WO2013154712A1
+WO2013154794A1
+WO2013157021A1
+WO2013157967A1
+WO2013158628A1
+WO2013158874A1
+WO2013158952A1
+WO2013159224A1
+WO2013159412A1
+WO2013160396A1
+WO2013162363A1
+WO2013164337A9
+WO2013164671A1
+WO2013166952A1
+WO2013168011A1
+WO2013168014A1
+WO2013169397A1
+WO2013169577A1
+WO2013171166A1
+WO2013171316A1
+WO2013171473A1
+WO2013172344A1
+WO2013172346A1
+WO2013172714A1
+WO2013173608A1
+WO2013174947A1
+WO2013175215A1
+WO2013175376A3
+WO2013176054A1
+WO2013176503A1
+WO2013179309A1
+WO2013180229A1
+WO2013180271A1
+WO2013181742A1
+WO2013182851A1
+WO2013184732A1
+WO2013185112A8
+WO2013185353A1
+WO2013186138A1
+WO2013186726A3
+WO2013187075A1
+WO2013187088A1
+WO2013187646A1
+WO2013187665A1
+WO2013187755A1
+WO2013187795A1
+WO2013189841A1
+WO2013189910A1
+WO2013190111A1
+WO2013191242A1
+WO2013191984A1
+WO2013192274A3
+WO2013192589A1
+WO2014001356A1
+WO2014002053A1
+WO2014002104A1
+WO2014003808A1
+WO2014005186A1
+WO2014005363A1
+WO2014005720A1
+WO2014006110A1
+WO2014008610A1
+WO2014010528A1
+WO2014011077A3
+WO2014012063A1
+WO2014012360A1
+WO2014013535A1
+WO2014015754A1
+WO2014016381A1
+WO2014016394A1
+WO2014017569A1
+WO2014017659A1
+WO2014017689A1
+WO2014017803A1
+WO2014019268A1
+WO2014019442A1
+WO2014021404A1
+WO2014022636A1
+WO2014022923A1
+WO2014023815A1
+WO2014024056A1
+WO2014025128A1
+WO2014025852A1
+WO2014026329A1
+WO2014026341A1
+WO2014028479A1
+WO2014028585A1
+WO2014029333A1
+WO2014029360A1
+WO2014029726A1
+WO2014029732A1
+WO2014030731A1
+WO2014031465A1
+WO2014032398A1
+WO2014032481A1
+WO2014034798A1
+WO2014035355A1
+WO2014035961A1
+WO2014036595A1
+WO2014037563A1
+WO2014037834A3
+WO2014039960A1
+WO2014041518A1
+WO2014041559A3
+WO2014043163A1
+WO2014043252A3
+WO2014043380A1
+WO2014043618A1
+WO2014044790A1
+WO2014046224A1
+WO2014046472A1
+WO2014047148A1
+WO2014047662A3
+WO2014047780A1
+WO2014048380A1
+WO2014048945A1
+WO2014049044A1
+WO2014053014A1
+WO2014053516A1
+WO2014054421A1
+WO2014054798A1
+WO2014055972A3
+WO2014055977A3
+WO2014056620A1
+WO2014056723A1
+WO2014056897A1
+WO2014057180A1
+WO2014058035A1
+WO2014058079A1
+WO2014058427A1
+WO2014059350A1
+WO2014059383A1
+WO2014059484A1
+WO2014059902A1
+WO2014060138A1
+WO2014060366A1
+WO2014060411A1
+WO2014060464A1
+WO2014061827A1
+WO2014062083A1
+WO2014062658A8
+WO2014063189A1
+WO2014063205A1
+WO2014063441A1
+WO2014063923A1
+WO2014064134A1
+WO2014065275A1
+WO2014065710A1
+WO2014067960A2
+WO2014069426A1
+WO2014071371A1
+WO2014071480A1
+WO2014071863A1
+WO2014072498A1
+WO2014072967A1
+WO2014074584A1
+WO2014074591A1
+WO2014074628A1
+WO2014074795A1
+WO2014074848A1
+WO2014074926A1
+WO2014075309A1
+WO2014075618A1
+WO2014076104A1
+WO2014077358A1
+WO2014077668A1
+WO2014078328A1
+WO2014078578A1
+WO2014078581A1
+WO2014081675A1
+WO2014082230A1
+WO2014082592A1
+WO2014082739A1
+WO2014083071A1
+WO2014084669A1
+WO2014087317A1
+WO2014087778A1
+WO2014088315A1
+WO2014089526A1
+WO2014090168A1
+WO2014090169A1
+WO2014090396A2
+WO2014090875A1
+WO2014091443A1
+WO2014091876A1
+WO2014092006A1
+WO2014092007A1
+WO2014092166A1
+WO2014093074A1
+WO2014093313A1
+WO2014093711A1
+WO2014093773A1
+WO2014094355A1
+WO2014096498A1
+WO2014098512A1
+WO2014099836A1
+WO2014099941A1
+WO2014100022A1
+WO2014100762A1
+WO2014102315A1
+WO2014102417A1
+WO2014102817A1
+WO2014103704A1
+WO2014104272A1
+WO2014104372A1
+WO2014106612A1
+WO2014106763A1
+WO2014107771A1
+WO2014108520A1
+WO2014110259A1
+WO2014110574A1
+WO2014111069A1
+WO2014111584A1
+WO2014111720A1
+WO2014114627A1
+WO2014116973A1
+WO2014118186A1
+WO2014118195A1
+WO2014118226A1
+WO2014118740A1
+WO2014120774A1
+WO2014120885A1
+WO2014122024A1
+WO2014124234A1
+WO2014125277A1
+WO2014127066A1
+WO2014127459A1
+WO2014128465A1
+WO2014128588A1
+WO2014128611A1
+WO2014130638A1
+WO2014130922A1
+WO2014132213A1
+WO2014132215A1
+WO2014134201A1
+WO2014134341A1
+WO2014134380A1
+WO2014135561A1
+WO2014135776A1
+WO2014136116A1
+WO2014137090A1
+WO2014137877A1
+WO2014138085A1
+WO2014138391A1
+WO2014138823A1
+WO2014139150A1
+WO2014139388A1
+WO2014139981A1
+WO2014140065A1
+WO2014140203A1
+WO2014140313A1
+WO2014140797A1
+WO2014142276A1
+WO2014143943A1
+WO2014145118A1
+WO2014146491A1
+WO2014146604A1
+WO2014147610A1
+WO2014148951A1
+WO2014152514A1
+WO2014152843A1
+WO2014154760A1
+WO2014154762A1
+WO2014155056A1
+WO2014157635A1
+WO2014157727A1
+WO2014159937A1
+WO2014162106A1
+WO2014164756A1
+WO2014165057A1
+WO2014165482A1
+WO2014165736A2
+WO2014165786A1
diff --git a/huner/ner_scripts/splits/chebi.dev b/huner/ner_scripts/splits/chebi.dev
new file mode 100644
index 0000000..f3cda4b
--- /dev/null
+++ b/huner/ner_scripts/splits/chebi.dev
@@ -0,0 +1,5 @@
+
+WO2007005470
+WO2007038855
+WO2007038874
+WO2007038995
diff --git a/huner/ner_scripts/splits/chebi.test b/huner/ner_scripts/splits/chebi.test
new file mode 100644
index 0000000..1ecc609
--- /dev/null
+++ b/huner/ner_scripts/splits/chebi.test
@@ -0,0 +1,12 @@
+
+WO2007002913
+WO2007031596
+WO2007035143
+WO2007039057
+WO2007039059
+WO2007041564
+WO2007044001
+WO2007045192
+WO2007045405
+WO2007045867
+WO2007045886
diff --git a/huner/ner_scripts/splits/chebi.train b/huner/ner_scripts/splits/chebi.train
new file mode 100644
index 0000000..b93d372
--- /dev/null
+++ b/huner/ner_scripts/splits/chebi.train
@@ -0,0 +1,24 @@
+
+WO2007000651
+WO2007004952
+WO2007031390
+WO2007031823
+WO2007031904
+WO2007038122
+WO2007038867
+WO2007038869
+WO2007038870
+WO2007038926
+WO2007038943
+WO2007038949
+WO2007039040
+WO2007041240
+WO2007041477
+WO2007041479
+WO2007041481
+WO2007042273
+WO2007045060
+WO2007045478
+WO2007045675
+WO2007046646
+WO2007048709
diff --git a/huner/ner_scripts/splits/chebi_new.dev b/huner/ner_scripts/splits/chebi_new.dev
new file mode 100644
index 0000000..088c7a7
--- /dev/null
+++ b/huner/ner_scripts/splits/chebi_new.dev
@@ -0,0 +1,30 @@
+10245_A
+101555_A
+10230515_A
+10069454_A
+10037325_A
+10092958_A
+10220579_A
+10197958_A
+10192893_A
+10101262_A
+10325611_A
+100603_A
+10027587_A
+10218658_A
+10048572_A
+10348748_A
+10075761_A
+10048567_A
+10219662_A
+10230635_A
+10607880_F
+10379660_F
+10629745_F
+10363800_F
+10536858_F
+11025148_F
+10321028_F
+10451917_F
+10450959_F
+1010599_F
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/chebi_new.test b/huner/ner_scripts/splits/chebi_new.test
new file mode 100644
index 0000000..0029f22
--- /dev/null
+++ b/huner/ner_scripts/splits/chebi_new.test
@@ -0,0 +1,89 @@
+10327614_A
+10030438_A
+10028199_A
+10344562_A
+10344559_A
+10344570_A
+10206430_A
+10320813_A
+10099036_A
+10098958_A
+10028198_A
+10075788_A
+10086989_A
+10027870_A
+10073739_A
+10100848_A
+10193198_A
+10196166_A
+10093966_A
+10048024_A
+10216137_A
+10075742_A
+10211706_A
+1017174_A
+1016232_A
+10350361_A
+10027798_A
+1017184_A
+10224250_A
+10328550_A
+10328555_A
+1003703_A
+10101221_A
+10214695_A
+10188629_A
+10199596_A
+10075107_A
+10198250_A
+10346948_A
+101016_A
+1011939_A
+1020945_A
+10328288_A
+10217534_A
+1025897_A
+10082215_A
+10190490_A
+1009998_A
+10230039_A
+100496_A
+10070780_A
+20117838_A
+10075120_A
+10027801_A
+10184609_A
+10092193_A
+10332870_A
+1028655_A
+10187805_A
+10413892_F
+10422783_F
+10374246_F
+10421766_F
+10408968_F
+10601665_F
+11014275_F
+10576686_F
+10423860_F
+10408272_F
+10219662_F
+10517218_F
+10366768_F
+10209293_F
+10379665_F
+11060896_F
+10457456_F
+10452893_F
+10100848_F
+11809447_F
+10518003_F
+10556516_F
+10365448_F
+1009629_F
+10631313_F
+10101262_F
+10048707_F
+10526188_F
+10563338_F
+10509910_F
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/chebi_new.train b/huner/ner_scripts/splits/chebi_new.train
new file mode 100644
index 0000000..1bb4b55
--- /dev/null
+++ b/huner/ner_scripts/splits/chebi_new.train
@@ -0,0 +1,180 @@
+10344578_A
+1018622_A
+1008820_A
+10199390_A
+10350186_A
+1002932_A
+10189073_A
+10234858_A
+10201831_A
+10077738_A
+10349454_A
+10103229_A
+10334866_A
+103374_A
+10320345_A
+10212124_A
+10052027_A
+1009629_A
+10077434_A
+10096848_A
+10205911_A
+10319113_A
+10048707_A
+10098663_A
+10200331_A
+10217585_A
+1008863_A
+10116_A
+10092191_A
+10037456_A
+10333495_A
+10336579_A
+10085103_A
+10223946_A
+10202961_A
+10048138_A
+10074065_A
+10232931_A
+10099363_A
+10085244_A
+10048141_A
+10109799_A
+1032127_A
+10224157_A
+10080387_A
+10073910_A
+10320809_A
+10211987_A
+10200307_A
+10101144_A
+10049714_A
+10066805_A
+10088651_A
+10086326_A
+10193763_A
+10092192_A
+10198034_A
+10071923_A
+10232625_A
+10075756_A
+1020931_A
+10348036_A
+10064158_A
+10220442_A
+10348037_A
+10088182_A
+10094686_A
+10078838_A
+1011375_A
+10095931_A
+10208753_A
+1028596_A
+10077490_A
+10191284_A
+10200320_A
+10353265_A
+10219966_A
+10335400_A
+1010599_A
+10102460_A
+10188194_A
+10098675_A
+10086325_A
+10052973_A
+10226494_A
+10064560_A
+10098223_A
+10223774_A
+10075791_A
+10349109_A
+10342226_A
+10085152_A
+10029225_A
+10100801_A
+10026165_A
+10336650_A
+10341035_A
+10190971_A
+10096519_A
+1022526_A
+10069359_A
+101233_A
+10027962_A
+1021254_A
+1021287_A
+10201825_A
+10348041_A
+10048179_A
+101268_A
+10336636_A
+10075776_A
+10072406_A
+10209293_A
+10347069_A
+10198245_A
+10075778_A
+10230514_A
+10211016_A
+10321028_A
+1020694_A
+11014261_F
+10631311_F
+11830167_F
+10193198_F
+10320809_F
+10385004_F
+10385976_F
+10574192_F
+10407146_F
+10482447_F
+10404733_F
+10234858_F
+10399297_F
+10597899_F
+10385992_F
+10456320_F
+10075120_F
+10201831_F
+10199390_F
+10622705_F
+10403630_F
+10556681_F
+10611475_F
+10202961_F
+10564776_F
+10217585_F
+10418944_F
+10471084_F
+12878451_F
+10629950_F
+10421447_F
+10230039_F
+10521685_F
+10327614_F
+10515051_F
+10626362_F
+10080387_F
+10511266_F
+10440083_F
+10470363_F
+10456314_F
+10454242_F
+10527378_F
+10414789_F
+10573857_F
+10218658_F
+10350361_F
+10517978_F
+10098223_F
+10544898_F
+10023770_F
+10465418_F
+10420591_F
+10525411_F
+10533279_F
+10598882_F
+10064158_F
+10082215_F
+10462055_F
+11830162_F
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/chemdner.dev b/huner/ner_scripts/splits/chemdner.dev
new file mode 100644
index 0000000..700e30e
--- /dev/null
+++ b/huner/ner_scripts/splits/chemdner.dev
@@ -0,0 +1,1002 @@
+
+21933113
+22079313
+22082827
+22301814
+22301815
+22364642
+22393914
+22439867
+22440717
+22443216
+22451331
+22455790
+22456328
+22495969
+22503097
+22525271
+22525272
+22532499
+22549410
+22564031
+22578098
+22581512
+22614004
+22614014
+22619007
+22626763
+22646532
+22664304
+22691039
+22691108
+22694127
+22697341
+22703447
+22705273
+22712554
+22713803
+22718571
+22719017
+22722774
+22732147
+22766391
+22800435
+22809709
+22813627
+22830954
+22847135
+22850767
+22861486
+22872142
+22878908
+22884111
+22887990
+22899102
+22902308
+22910795
+22923220
+22933435
+22954530
+22954533
+22974972
+22975405
+22977165
+22977167
+22980732
+22981949
+22982479
+22982569
+22983790
+22986947
+22989775
+22990878
+23000445
+23000446
+23007888
+23010670
+23017390
+23017392
+23017398
+23019138
+23022140
+23022600
+23026138
+23027505
+23032079
+23041041
+23041042
+23044094
+23044908
+23044992
+23047462
+23055540
+23060409
+23060411
+23069372
+23072941
+23079545
+23080535
+23084046
+23084047
+23084158
+23085331
+23085334
+23085382
+23085433
+23085436
+23086747
+23089045
+23090760
+23090793
+23091188
+23093023
+23093024
+23104246
+23104248
+23106203
+23108606
+23109114
+23110812
+23111348
+23118028
+23122065
+23122067
+23122070
+23122072
+23122076
+23122079
+23122081
+23122094
+23122099
+23122100
+23122102
+23122111
+23122113
+23122115
+23122120
+23122121
+23122122
+23122126
+23123224
+23123225
+23123249
+23124594
+23126422
+23126495
+23127600
+23129783
+23135241
+23136056
+23136062
+23136071
+23137956
+23141426
+23141427
+23142505
+23142507
+23142547
+23142559
+23142599
+23143037
+23143802
+23143803
+23143892
+23146839
+23148024
+23149118
+23149937
+23150067
+23150999
+23154533
+23157625
+23157627
+23157631
+23157632
+23157634
+23157698
+23159330
+23159360
+23161512
+23161521
+23161581
+23161646
+23161692
+23163337
+23164616
+23164618
+23164619
+23164713
+23164985
+23165154
+23165155
+23165930
+23167767
+23167812
+23168114
+23168115
+23169459
+23169608
+23169609
+23169610
+23171962
+23173549
+23174031
+23174144
+23174340
+23177260
+23178441
+23178593
+23179753
+23179775
+23180790
+23182423
+23184572
+23186033
+23187618
+23188717
+23190031
+23190033
+23190035
+23190093
+23192785
+23193282
+23194408
+23194506
+23194513
+23194514
+23194515
+23194529
+23194532
+23194534
+23194537
+23194541
+23194542
+23194546
+23194548
+23194569
+23195733
+23195751
+23195959
+23197647
+23199366
+23200000
+23200254
+23200255
+23200888
+23200942
+23200943
+23200944
+23201337
+23201371
+23202846
+23202847
+23202848
+23202851
+23202852
+23203941
+23204306
+23205634
+23205668
+23205727
+23205740
+23206272
+23206276
+23207409
+23208787
+23208822
+23209285
+23210463
+23210482
+23211441
+23212047
+23212238
+23212912
+23212963
+23212976
+23215039
+23215051
+23219526
+23219593
+23220489
+23220512
+23220538
+23223499
+23224861
+23225346
+23228341
+23228472
+23229056
+23229057
+23231351
+23234271
+23237384
+23238558
+23238642
+23240979
+23240995
+23244626
+23244629
+23244683
+23245695
+23245699
+23247407
+23247471
+23247545
+23247722
+23249265
+23249276
+23249300
+23249384
+23252846
+23252950
+23253427
+23255101
+23256440
+23256485
+23256525
+23256531
+23256625
+23257735
+23257777
+23258121
+23259487
+23259533
+23259708
+23261051
+23261757
+23262200
+23262201
+23262268
+23262392
+23264019
+23265312
+23265447
+23265448
+23265450
+23265451
+23265454
+23265455
+23265457
+23265460
+23265463
+23265464
+23265465
+23265468
+23265470
+23265471
+23265472
+23265473
+23265474
+23265476
+23265484
+23265489
+23265494
+23265496
+23265532
+23265534
+23265537
+23265539
+23266665
+23266726
+23266733
+23266735
+23267008
+23268441
+23270805
+23270965
+23273895
+23274345
+23274394
+23275571
+23276134
+23276138
+23276150
+23276229
+23276278
+23277288
+23277289
+23277358
+23279930
+23286284
+23287539
+23288051
+23288053
+23288867
+23289528
+23291558
+23291595
+23291608
+23292158
+23292170
+23293300
+23294700
+23295225
+23297162
+23297714
+23297716
+23297736
+23297831
+23297842
+23298236
+23298292
+23300130
+23300254
+23300287
+23301582
+23301592
+23302007
+23303207
+23303314
+23303341
+23303365
+23303469
+23305850
+23305919
+23305994
+23306378
+23307703
+23311668
+23312283
+23314050
+23315277
+23315497
+23317013
+23317099
+23317164
+23317165
+23318354
+23318431
+23318451
+23320732
+23321074
+23321159
+23321957
+23322418
+23323600
+23323640
+23323647
+23323712
+23323808
+23323839
+23325437
+23325562
+23327358
+23327445
+23328624
+23333175
+23333184
+23333907
+23334349
+23334429
+23335030
+23335817
+23337525
+23337529
+23337567
+23337568
+23337596
+23337597
+23337598
+23338044
+23338843
+23340250
+23340252
+23340305
+23343308
+23343346
+23345067
+23345167
+23347043
+23347089
+23348235
+23349485
+23349489
+23349493
+23349496
+23349524
+23349535
+23350690
+23350692
+23351034
+23351043
+23353657
+23353700
+23353701
+23353736
+23353744
+23353747
+23353749
+23353751
+23353753
+23353756
+23354809
+23357170
+23357951
+23358307
+23360676
+23361121
+23361257
+23361264
+23361304
+23361305
+23361313
+23361977
+23363003
+23363038
+23363040
+23364186
+23364315
+23368710
+23369012
+23369048
+23369072
+23369093
+23369932
+23369934
+23369935
+23369988
+23369989
+23370007
+23370194
+23370195
+23370198
+23370266
+23371492
+23372018
+23374506
+23375813
+23376122
+23376217
+23376247
+23376250
+23376258
+23376345
+23376352
+23377618
+23378191
+23379472
+23380374
+23381641
+23382024
+23384772
+23384834
+23385210
+23385213
+23385219
+23385960
+23386413
+23386462
+23387824
+23389615
+23391023
+23391037
+23391095
+23392232
+23392354
+23394067
+23394134
+23397054
+23398572
+23400370
+23402292
+23404092
+23404733
+23404837
+23404894
+23406497
+23406515
+23408261
+23408271
+23408421
+23409710
+23409714
+23409720
+23409722
+23409763
+23411074
+23411077
+23411081
+23411169
+23411180
+23411188
+23411193
+23411197
+23411198
+23411224
+23411227
+23411229
+23414139
+23414209
+23414210
+23414214
+23414235
+23415548
+23416003
+23416004
+23416006
+23416007
+23416040
+23416065
+23416757
+23416796
+23416797
+23419043
+23419812
+23419815
+23419816
+23419872
+23420023
+23421374
+23421432
+23421434
+23422566
+23422569
+23422727
+23423880
+23423904
+23423993
+23426955
+23428794
+23428833
+23429192
+23429263
+23429274
+23430139
+23432010
+23432060
+23432062
+23432065
+23432066
+23432090
+23432093
+23432753
+23434506
+23434663
+23434673
+23435157
+23435158
+23435160
+23435915
+23436315
+23436428
+23436437
+23436442
+23436494
+23437791
+23439478
+23439479
+23439480
+23440512
+23440577
+23440580
+23441017
+23442147
+23442161
+23443513
+23444040
+23444042
+23444043
+23444099
+23444779
+23445219
+23453003
+23453808
+23453838
+23453839
+23453840
+23454112
+23454113
+23454134
+23454150
+23454189
+23454207
+23454269
+23454296
+23454300
+23454306
+23455594
+23455599
+23456815
+23456850
+23458616
+23458618
+23458619
+23458620
+23459107
+23459936
+23462671
+23462672
+23462797
+23463168
+23464522
+23464578
+23466229
+23466230
+23466232
+23466234
+23466330
+23466331
+23466342
+23470217
+23470287
+23471562
+23471665
+23472833
+23472857
+23472952
+23473343
+23474650
+23474753
+23475289
+23475902
+23478148
+23480470
+23482391
+23484901
+23484958
+23485402
+23485474
+23485481
+23487168
+23487175
+23487256
+23489627
+23489628
+23493819
+23493912
+23494230
+23494236
+23495690
+23495693
+23496094
+23499235
+23499926
+23499954
+23500333
+23500491
+23500494
+23505123
+23505224
+23505325
+23506469
+23506537
+23506559
+23507752
+23507976
+23508306
+23511020
+23511945
+23512495
+23512496
+23512499
+23514229
+23514279
+23514973
+23515498
+23517243
+23517910
+23518413
+23521132
+23523950
+23523951
+23523965
+23524316
+23525512
+23525522
+23527529
+23527553
+23527574
+23528740
+23528741
+23528888
+23529900
+23531536
+23531554
+23531555
+23531597
+23532002
+23532057
+23532843
+23532849
+23532918
+23534530
+23534553
+23534615
+23535828
+23536314
+23536316
+23537701
+23537702
+23537746
+23537749
+23538035
+23538162
+23538844
+23539337
+23540443
+23541647
+23541649
+23541668
+23541672
+23541674
+23541721
+23542080
+23542114
+23542166
+23542210
+23542230
+23543426
+23545109
+23546603
+23547762
+23547810
+23547844
+23547872
+23547884
+23547938
+23549679
+23551063
+23553739
+23553772
+23553797
+23557230
+23558432
+23558614
+23558679
+23560944
+23561211
+23561212
+23561214
+23562630
+23562637
+23563104
+23564369
+23565644
+23565654
+23565720
+23565755
+23565759
+23566035
+23566056
+23566058
+23566060
+23567484
+23567490
+23568773
+23569204
+23570232
+23570237
+23570261
+23570284
+23570347
+23570997
+23571664
+23574729
+23575901
+23575940
+23576343
+23576424
+23577636
+23577649
+23577650
+23577695
+23578952
+23578993
+23578994
+23579392
+23579421
+23579429
+23580312
+23580316
+23580332
+23580446
+23580569
+23581750
+23582211
+23582273
+23582326
+23583512
+23583603
+23584743
+23584895
+23584984
+23585309
+23585332
+23585333
+23586669
+23586680
+23586702
+23586737
+23586757
+23588303
+23588308
+23588322
+23590591
+23590723
+23590729
+23591110
+23591115
+23591125
+23591149
+23591959
+23591996
+23591997
+23592428
+23592577
+23594210
+23594301
+23594304
+23594342
+23595593
+23596058
+23596975
+23597402
+23600593
+23601700
+23601990
+23602474
+23603615
+23603634
+23604079
+23606657
+23607293
+23609001
+23610010
+23610039
+23610060
+23610081
+23612689
+23613084
+23614367
+23614395
+23615708
+23617223
+23617275
+23617391
+23617426
+23617429
+23617431
+23618623
+23619284
+23619286
+23620134
+23620214
+23620269
+23621464
+23621524
+23621573
+23622866
+23623904
+23624607
+23624608
+23625804
+23625911
+23625915
+23626400
+23627637
+23627649
+23627670
+23627699
+23627743
+23630301
+23631528
+23631539
+23631561
+23631590
+23631674
+23631736
+23631744
+23631760
+23634707
+23634759
+23636640
+23636685
+23639538
+23639540
+23639541
+23641901
+23642226
+23643631
+23643682
+23643695
+23643733
+23643746
+23643747
+23643751
+23643752
+23643755
+23643756
+23643784
+23643798
+23644193
+23644199
+23644203
+23644205
+23644210
+23644211
+23644213
+23644219
+23644892
+23644914
+23644925
+23646041
diff --git a/huner/ner_scripts/splits/chemdner.test b/huner/ner_scripts/splits/chemdner.test
new file mode 100644
index 0000000..14cf66c
--- /dev/null
+++ b/huner/ner_scripts/splits/chemdner.test
@@ -0,0 +1,3001 @@
+
+21723361
+21838705
+22064666
+22075688
+22082822
+22082826
+22083351
+22150026
+22155887
+22173956
+22231567
+22233192
+22278137
+22284538
+22287617
+22294440
+22301817
+22304229
+22317828
+22320163
+22323477
+22324400
+22324431
+22332833
+22335791
+22340730
+22348279
+22349823
+22349829
+22369145
+22370636
+22370641
+22376270
+22379948
+22391561
+22391568
+22391569
+22400809
+22401743
+22406206
+22417089
+22422627
+22430919
+22439883
+22450748
+22451347
+22473703
+22473789
+22484424
+22491023
+22494023
+22497568
+22497569
+22511564
+22512576
+22512587
+22512662
+22517576
+22521336
+22521499
+22522972
+22532505
+22533633
+22538087
+22546614
+22566066
+22566106
+22566158
+22566187
+22574728
+22574752
+22575576
+22578007
+22580612
+22585533
+22594571
+22607101
+22609536
+22609856
+22610968
+22614005
+22624955
+22625220
+22634112
+22634361
+22646908
+22648665
+22659088
+22659090
+22659408
+22659409
+22665054
+22665061
+22676342
+22677456
+22678081
+22689059
+22690946
+22694056
+22695309
+22695677
+22705074
+22705075
+22705396
+22709946
+22713807
+22713812
+22717325
+22727823
+22728760
+22735770
+22736379
+22744955
+22747593
+22749643
+22749842
+22750078
+22750412
+22752958
+22761049
+22763381
+22766107
+22766390
+22767283
+22770610
+22776507
+22776545
+22776694
+22781580
+22788665
+22796044
+22796105
+22796337
+22797669
+22798247
+22799538
+22801296
+22812659
+22813462
+22817767
+22818713
+22820555
+22820907
+22820932
+22824189
+22824191
+22830980
+22835042
+22848037
+22859661
+22863599
+22867273
+22867529
+22869589
+22871141
+22878862
+22884520
+22884612
+22884720
+22885522
+22885792
+22886720
+22887463
+22887720
+22889206
+22889207
+22890749
+22891925
+22892665
+22893351
+22893354
+22898212
+22898496
+22899726
+22899727
+22899728
+22902307
+22902323
+22902329
+22903142
+22906567
+22906570
+22911949
+22914798
+22917842
+22918703
+22921313
+22921426
+22921427
+22922038
+22922246
+22923492
+22925550
+22926046
+22926699
+22929928
+22930682
+22931530
+22931533
+22931535
+22933107
+22933114
+22933327
+22935067
+22935616
+22936354
+22940465
+22940466
+22940854
+22941424
+22943130
+22944045
+22944068
+22944069
+22944593
+22945792
+22946701
+22949391
+22951946
+22956307
+22956627
+22960442
+22960624
+22961094
+22961427
+22963374
+22963552
+22965296
+22968693
+22969061
+22974400
+22975162
+22975263
+22976768
+22976785
+22976914
+22981808
+22981993
+22982303
+22982445
+22982684
+22982770
+22983144
+22983867
+22986338
+22988818
+22989721
+22991163
+22991447
+22995461
+22995681
+22996137
+22996307
+22997242
+22999652
+22999653
+23000076
+23000916
+23001138
+23002036
+23002089
+23007558
+23007560
+23008503
+23009272
+23009351
+23010104
+23010163
+23010389
+23010392
+23010566
+23014811
+23015541
+23015691
+23016694
+23017387
+23017391
+23017394
+23017395
+23017397
+23017402
+23017408
+23017409
+23017413
+23017415
+23017416
+23017418
+23017421
+23017422
+23017424
+23017673
+23017782
+23020803
+23022015
+23022323
+23023768
+23027385
+23028137
+23030741
+23030812
+23032104
+23032726
+23036451
+23036454
+23038767
+23041078
+23041113
+23041257
+23042693
+23042762
+23043184
+23043462
+23044046
+23044488
+23044709
+23044793
+23044926
+23044938
+23047022
+23047026
+23047321
+23051835
+23051890
+23052036
+23052197
+23053786
+23053787
+23054081
+23055538
+23058474
+23060412
+23061396
+23061466
+23061657
+23063001
+23063003
+23063413
+23063595
+23063671
+23063746
+23063845
+23063874
+23063875
+23063876
+23064031
+23064475
+23064600
+23065140
+23065799
+23066089
+23066091
+23066093
+23066988
+23067059
+23067575
+23068768
+23069375
+23069477
+23074026
+23074081
+23074145
+23075005
+23075165
+23077183
+23079470
+23079670
+23081760
+23082005
+23084793
+23085120
+23085190
+23085367
+23085432
+23085437
+23085546
+23086230
+23086402
+23086461
+23086748
+23086899
+23087260
+23087379
+23089249
+23090210
+23090483
+23090647
+23090712
+23091170
+23092130
+23092679
+23092759
+23092918
+23092949
+23097498
+23098819
+23098820
+23098994
+23099431
+23100158
+23100159
+23101934
+23102509
+23103283
+23103296
+23103298
+23103347
+23103450
+23103562
+23103563
+23103564
+23103565
+23103613
+23103954
+23103983
+23104136
+23104247
+23104378
+23104429
+23104430
+23104969
+23106652
+23108167
+23108216
+23108716
+23108801
+23108927
+23109229
+23109293
+23109429
+23110439
+23111283
+23111828
+23111874
+23115222
+23116145
+23116642
+23116938
+23116965
+23117006
+23117572
+23118328
+23118479
+23122062
+23122063
+23122071
+23122075
+23122078
+23122080
+23122087
+23122091
+23122093
+23122095
+23122096
+23122098
+23122103
+23122109
+23122112
+23122117
+23122119
+23122123
+23122125
+23122133
+23122138
+23122148
+23122150
+23122153
+23122156
+23122158
+23122159
+23122162
+23122164
+23123250
+23123251
+23123253
+23123255
+23123257
+23123298
+23123425
+23123646
+23123677
+23124277
+23125001
+23125180
+23125282
+23125371
+23126604
+23127146
+23127602
+23127818
+23127825
+23127917
+23128353
+23128355
+23129213
+23129525
+23130659
+23130662
+23131042
+23131800
+23134486
+23135544
+23135905
+23137047
+23137955
+23138334
+23139010
+23139061
+23139074
+23139159
+23139348
+23139353
+23139354
+23139355
+23139356
+23140136
+23141189
+23142211
+23142325
+23142425
+23142506
+23142577
+23142634
+23142710
+23142711
+23142712
+23142737
+23142791
+23143040
+23143891
+23143930
+23144004
+23144238
+23145773
+23146663
+23146697
+23146748
+23146754
+23146756
+23147375
+23147390
+23147414
+23147417
+23147420
+23147668
+23147680
+23147807
+23147869
+23148227
+23148911
+23148920
+23148988
+23149809
+23150213
+23150427
+23150485
+23150487
+23150983
+23152001
+23152116
+23152124
+23153455
+23153547
+23153671
+23154302
+23154883
+23155049
+23155064
+23155202
+23157384
+23157624
+23157626
+23157629
+23157633
+23157638
+23159329
+23159501
+23159663
+23159664
+23159708
+23159710
+23159728
+23159884
+23159887
+23159914
+23159985
+23160090
+23160179
+23160270
+23160434
+23160820
+23160931
+23160941
+23161216
+23161368
+23161369
+23161427
+23161470
+23161531
+23161544
+23161550
+23161561
+23161584
+23161651
+23161747
+23161751
+23163352
+23163429
+23163726
+23163768
+23164602
+23164617
+23164673
+23165153
+23165215
+23165312
+23165591
+23165625
+23165754
+23166317
+23166320
+23167621
+23168113
+23169263
+23169689
+23170799
+23170960
+23171137
+23171163
+23172286
+23172657
+23172777
+23174017
+23174265
+23174266
+23174754
+23174758
+23175666
+23177254
+23177257
+23177786
+23177787
+23177789
+23178164
+23178255
+23178380
+23178381
+23178557
+23178652
+23178655
+23178896
+23180160
+23180340
+23180416
+23180651
+23180664
+23180675
+23180678
+23181669
+23182090
+23182463
+23182918
+23182954
+23183423
+23183587
+23183772
+23184152
+23184315
+23184669
+23186244
+23187064
+23187066
+23187687
+23187890
+23188119
+23188828
+23192842
+23192980
+23193181
+23193182
+23193186
+23193255
+23193284
+23194503
+23194508
+23194511
+23194516
+23194519
+23194520
+23194521
+23194523
+23194527
+23194530
+23194536
+23194538
+23194545
+23194547
+23194554
+23194556
+23194558
+23194561
+23194562
+23194565
+23194567
+23194568
+23194824
+23194826
+23194827
+23195331
+23197043
+23197374
+23197648
+23198917
+23199228
+23199882
+23199988
+23199990
+23199991
+23199994
+23200002
+23200243
+23200245
+23200734
+23200736
+23200945
+23201002
+23201310
+23201447
+23201449
+23202249
+23202888
+23204110
+23205533
+23205561
+23205610
+23205707
+23205725
+23206862
+23206991
+23207249
+23207250
+23207251
+23207322
+23207801
+23208951
+23208978
+23209193
+23209194
+23209282
+23210621
+23210706
+23210775
+23210776
+23210778
+23210781
+23210783
+23210787
+23210849
+23210853
+23211008
+23211362
+23211426
+23211442
+23211523
+23211524
+23211868
+23211937
+23212106
+23212108
+23212110
+23212306
+23212442
+23212742
+23212949
+23212989
+23214434
+23214511
+23214931
+23214953
+23215012
+23215021
+23215035
+23215155
+23215439
+23215584
+23218402
+23218602
+23218715
+23218950
+23219002
+23219042
+23219337
+23219342
+23219467
+23219523
+23219524
+23219701
+23219852
+23219857
+23219887
+23220104
+23220105
+23220107
+23220196
+23220294
+23220400
+23220410
+23220490
+23220561
+23220587
+23220590
+23220608
+23220611
+23220742
+23220748
+23220749
+23221600
+23221636
+23222539
+23222639
+23222847
+23223176
+23223191
+23223382
+23223407
+23223414
+23223448
+23223450
+23223497
+23223517
+23223523
+23224299
+23225148
+23225329
+23225776
+23227815
+23227928
+23228175
+23228182
+23228444
+23228695
+23228849
+23229134
+23229135
+23229324
+23229440
+23229509
+23229512
+23229518
+23229954
+23230100
+23230132
+23230213
+23230214
+23230273
+23230450
+23231078
+23231413
+23231492
+23231502
+23231586
+23231808
+23232447
+23233343
+23233534
+23233535
+23234496
+23234568
+23234644
+23237625
+23237706
+23237836
+23237840
+23237841
+23238124
+23238275
+23239137
+23239534
+23239555
+23239592
+23239633
+23239882
+23240691
+23240866
+23240889
+23240892
+23241060
+23241369
+23241370
+23241390
+23242478
+23244065
+23244212
+23244295
+23244296
+23244580
+23244582
+23244684
+23246353
+23246355
+23246435
+23246459
+23246471
+23246516
+23246530
+23246581
+23246619
+23246733
+23246792
+23246863
+23247057
+23247074
+23247176
+23247258
+23248200
+23248975
+23249238
+23249274
+23249752
+23250485
+23250742
+23250746
+23252343
+23252447
+23252515
+23252554
+23252580
+23252711
+23252745
+23252795
+23252880
+23252951
+23252952
+23253128
+23253133
+23253136
+23253172
+23253260
+23254193
+23254340
+23254551
+23255551
+23256441
+23256472
+23256532
+23256622
+23256623
+23256624
+23256725
+23256867
+23257216
+23257237
+23257267
+23257906
+23258195
+23258482
+23259840
+23259841
+23259935
+23260348
+23261424
+23261591
+23261671
+23261673
+23261677
+23261680
+23261716
+23261758
+23261859
+23261865
+23261866
+23261985
+23261990
+23262027
+23262164
+23262269
+23262270
+23262271
+23262278
+23262663
+23263985
+23263988
+23263989
+23264098
+23264447
+23265449
+23265459
+23265461
+23265477
+23265485
+23265490
+23265500
+23265503
+23265513
+23265519
+23265520
+23265530
+23265535
+23265536
+23265540
+23265543
+23265874
+23265875
+23265876
+23265883
+23265885
+23265891
+23265905
+23266123
+23266269
+23266270
+23266271
+23266428
+23266449
+23266450
+23266504
+23266505
+23266567
+23266720
+23266728
+23266730
+23266734
+23267011
+23267661
+23268337
+23268606
+23268742
+23270336
+23270378
+23270514
+23270871
+23270991
+23270994
+23271000
+23271678
+23271732
+23272784
+23273038
+23273052
+23273219
+23273517
+23273521
+23273751
+23273896
+23274058
+23274086
+23274088
+23274302
+23274539
+23274715
+23274766
+23274770
+23274771
+23274777
+23274887
+23274894
+23274908
+23275348
+23275540
+23275570
+23276136
+23276137
+23276209
+23276254
+23276728
+23276752
+23277103
+23278273
+23278282
+23278395
+23279101
+23279839
+23279849
+23279941
+23280515
+23280651
+23280947
+23280986
+23281098
+23281099
+23281267
+23281296
+23281421
+23281423
+23281627
+23281663
+23281812
+23282042
+23282091
+23282222
+23282278
+23282998
+23283976
+23286196
+23286367
+23287076
+23287313
+23287426
+23287738
+23288054
+23288094
+23288142
+23288700
+23288712
+23288946
+23288947
+23289502
+23289665
+23289770
+23289972
+23290487
+23291036
+23291037
+23291046
+23291061
+23291121
+23291240
+23291325
+23291326
+23291333
+23291401
+23291559
+23291560
+23291713
+23292193
+23292249
+23292302
+23292321
+23292791
+23293126
+23293132
+23293133
+23293134
+23293834
+23293839
+23293972
+23294008
+23294220
+23294255
+23294321
+23294333
+23294348
+23294368
+23295222
+23295227
+23295228
+23295712
+23296101
+23296103
+23296256
+23296404
+23296568
+23296984
+23297161
+23297254
+23297412
+23298241
+23298258
+23298261
+23298277
+23298334
+23298616
+23298744
+23298863
+23298867
+23299189
+23299190
+23299435
+23299544
+23299756
+23299757
+23299759
+23300006
+23300078
+23300339
+23301560
+23301766
+23301830
+23301836
+23301848
+23301856
+23301860
+23302584
+23302586
+23302587
+23302593
+23302712
+23303290
+23303709
+23303738
+23303790
+23303916
+23305400
+23305503
+23305534
+23305624
+23305664
+23305921
+23305922
+23305949
+23306025
+23306951
+23307232
+23307557
+23307694
+23307699
+23307788
+23308013
+23311415
+23311608
+23311697
+23311998
+23312278
+23312348
+23312470
+23312472
+23312945
+23313085
+23313243
+23313269
+23313281
+23313337
+23313339
+23313557
+23313610
+23313620
+23313622
+23313623
+23313635
+23313637
+23313663
+23313711
+23313730
+23313795
+23313796
+23314046
+23314047
+23314053
+23314054
+23314071
+23314104
+23314320
+23314800
+23314913
+23315088
+23315275
+23316003
+23316023
+23316685
+23316748
+23316792
+23316943
+23316979
+23317008
+23317031
+23317098
+23317161
+23317339
+23317432
+23317571
+23318433
+23318470
+23318471
+23318553
+23318644
+23318685
+23318728
+23318949
+23319051
+23319075
+23319076
+23319180
+23319288
+23319419
+23319549
+23321024
+23321274
+23321625
+23321687
+23322473
+23322517
+23322906
+23323548
+23323627
+23323717
+23323802
+23323846
+23323861
+23323954
+23324405
+23325361
+23325368
+23325369
+23325491
+23325849
+23327465
+23327600
+23327612
+23327656
+23327669
+23327759
+23327779
+23327841
+23327877
+23327905
+23328125
+23329465
+23329466
+23329698
+23330546
+23330562
+23330711
+23330726
+23330972
+23331020
+23331067
+23331095
+23331245
+23332751
+23333176
+23333573
+23333576
+23333577
+23333583
+23333717
+23333767
+23333790
+23333897
+23333901
+23333998
+23334083
+23334090
+23334329
+23334403
+23334529
+23334753
+23334943
+23335133
+23335392
+23335435
+23335441
+23335626
+23335627
+23336063
+23336064
+23336565
+23336753
+23337516
+23337520
+23337524
+23337530
+23337607
+23339181
+23339339
+23339625
+23339629
+23339682
+23339777
+23339853
+23339855
+23339884
+23339967
+23340199
+23340251
+23340524
+23340650
+23340651
+23340797
+23340887
+23340896
+23340897
+23340918
+23341167
+23341342
+23341452
+23342998
+23343421
+23343596
+23343761
+23343976
+23344039
+23344113
+23344447
+23344553
+23344693
+23344821
+23344822
+23344927
+23344956
+23344961
+23345044
+23345166
+23345168
+23345579
+23346866
+23347038
+23347045
+23347049
+23347071
+23347275
+23347327
+23347396
+23347877
+23347952
+23347953
+23348151
+23348406
+23348408
+23348497
+23348842
+23349208
+23349478
+23349483
+23349488
+23349490
+23350530
+23350706
+23350710
+23350725
+23350737
+23350847
+23350872
+23351005
+23351136
+23351959
+23352144
+23352510
+23352512
+23352690
+23352843
+23352908
+23353004
+23353012
+23353655
+23353656
+23353735
+23353737
+23353742
+23353745
+23353748
+23353754
+23353806
+23353808
+23353902
+23354152
+23354378
+23354393
+23354531
+23354545
+23354695
+23355059
+23355087
+23355347
+23355480
+23355494
+23355539
+23355749
+23356786
+23356789
+23356826
+23356865
+23356880
+23356883
+23357360
+23357402
+23357416
+23357567
+23357977
+23358190
+23358193
+23358194
+23358196
+23359004
+23359358
+23359363
+23360072
+23360104
+23360109
+23360143
+23360215
+23360249
+23360348
+23360369
+23360430
+23360449
+23360537
+23361104
+23361316
+23361653
+23361947
+23362116
+23362121
+23362206
+23362271
+23362274
+23362800
+23362838
+23363020
+23363044
+23363083
+23363244
+23363530
+23368645
+23368743
+23368853
+23368901
+23369094
+23369536
+23370008
+23370290
+23370524
+23371304
+23371415
+23371491
+23371493
+23371806
+23371808
+23371817
+23372041
+23373466
+23373649
+23373650
+23373651
+23373654
+23373751
+23373754
+23373756
+23374337
+23374349
+23374351
+23375059
+23375209
+23375227
+23375796
+23376022
+23376091
+23376120
+23376121
+23376140
+23376161
+23376211
+23376407
+23376438
+23376440
+23376476
+23376478
+23376781
+23376996
+23377117
+23377119
+23377542
+23377699
+23377708
+23377760
+23377859
+23378624
+23378625
+23379481
+23379679
+23379719
+23379995
+23379996
+23380242
+23380376
+23380478
+23380860
+23380918
+23380989
+23381061
+23381223
+23381653
+23381662
+23381692
+23381796
+23381939
+23382074
+23382379
+23382381
+23383712
+23383865
+23383985
+23384061
+23384072
+23384278
+23384287
+23384297
+23384347
+23384447
+23384968
+23385033
+23385091
+23385092
+23385231
+23385876
+23385891
+23385959
+23386200
+23386248
+23386387
+23386394
+23386417
+23386483
+23386596
+23386609
+23386703
+23387414
+23387444
+23387501
+23387511
+23388040
+23389040
+23389043
+23389051
+23389092
+23391154
+23391297
+23391307
+23391363
+23391424
+23391859
+23393214
+23394107
+23394205
+23394402
+23394441
+23394693
+23394702
+23395003
+23395155
+23395163
+23395634
+23395653
+23395667
+23395718
+23395825
+23395899
+23395915
+23395916
+23395978
+23396042
+23396078
+23396090
+23396144
+23396419
+23396446
+23396530
+23397052
+23397053
+23397055
+23397359
+23397419
+23397510
+23397572
+23397585
+23397966
+23398143
+23398172
+23398311
+23398496
+23398503
+23398658
+23398786
+23398844
+23399722
+23399882
+23399949
+23400365
+23400739
+23400747
+23400749
+23400845
+23400899
+23400964
+23401142
+23401166
+23401232
+23401283
+23401304
+23401318
+23401360
+23401373
+23401471
+23401473
+23402278
+23402300
+23402371
+23402432
+23402628
+23402727
+23402744
+23402840
+23402856
+23402857
+23402907
+23402973
+23403015
+23403085
+23403272
+23403471
+23404064
+23404093
+23404300
+23404373
+23404656
+23404680
+23404692
+23405013
+23405965
+23405984
+23405988
+23406025
+23406315
+23406416
+23406484
+23406524
+23406951
+23406954
+23406956
+23407584
+23407783
+23408272
+23409715
+23409718
+23409721
+23409919
+23410043
+23410068
+23410126
+23410129
+23410153
+23410154
+23410161
+23410162
+23410191
+23410221
+23410250
+23410538
+23410587
+23410589
+23410798
+23410960
+23411111
+23411170
+23411171
+23411172
+23411174
+23411176
+23411179
+23411187
+23411190
+23411196
+23411207
+23411218
+23411221
+23411222
+23411225
+23411226
+23411228
+23411237
+23411242
+23411243
+23411246
+23411247
+23411254
+23411256
+23411258
+23411261
+23411262
+23411264
+23411267
+23411276
+23411278
+23411279
+23411282
+23411285
+23411291
+23411292
+23411295
+23411298
+23411302
+23411304
+23411308
+23411309
+23411310
+23411313
+23411319
+23411322
+23411325
+23411328
+23411329
+23411331
+23411332
+23411337
+23411338
+23411339
+23411341
+23411599
+23411834
+23413358
+23414067
+23414099
+23414292
+23414381
+23414431
+23414804
+23414837
+23414838
+23415228
+23415610
+23415892
+23415904
+23416002
+23416005
+23416039
+23416130
+23416144
+23416145
+23416261
+23416647
+23416648
+23416700
+23416701
+23416798
+23416841
+23416882
+23416946
+23416985
+23417424
+23417652
+23417768
+23417894
+23417972
+23418013
+23418022
+23418073
+23418368
+23418678
+23418739
+23418775
+23418898
+23419014
+23419036
+23419055
+23419072
+23419388
+23419389
+23419484
+23419488
+23419536
+23419834
+23420562
+23420583
+23420664
+23420666
+23420692
+23421589
+23421631
+23421805
+23421864
+23421872
+23422337
+23422352
+23422874
+23423383
+23423573
+23423713
+23423714
+23424204
+23424214
+23424216
+23424996
+23425029
+23425114
+23425153
+23425332
+23426224
+23426369
+23426640
+23426869
+23426956
+23427008
+23427019
+23427042
+23427167
+23427187
+23427191
+23427277
+23427814
+23427996
+23428306
+23428346
+23428385
+23428468
+23429041
+23429042
+23429044
+23429061
+23430161
+23430162
+23430974
+23431112
+23431964
+23432059
+23432081
+23432429
+23432591
+23432683
+23433811
+23433938
+23434029
+23434418
+23434419
+23434636
+23434639
+23434640
+23434647
+23434833
+23435124
+23435180
+23435216
+23435353
+23435357
+23435430
+23435613
+23435674
+23435687
+23435847
+23435944
+23435964
+23436245
+23436254
+23436258
+23436264
+23436267
+23436305
+23436492
+23436571
+23436650
+23436656
+23436706
+23436749
+23437929
+23438015
+23438077
+23438471
+23438501
+23438859
+23439233
+23439383
+23439661
+23439872
+23440001
+23440015
+23440581
+23440867
+23440895
+23440918
+23440928
+23440974
+23441007
+23441649
+23441904
+23442787
+23443027
+23443358
+23443488
+23443752
+23443753
+23443810
+23444015
+23444138
+23444282
+23444286
+23444300
+23444334
+23444336
+23444337
+23444774
+23444775
+23444776
+23444913
+23444960
+23444962
+23444963
+23444964
+23445166
+23445346
+23445522
+23445562
+23446434
+23446650
+23448129
+23448165
+23448281
+23448346
+23448403
+23449200
+23449203
+23449501
+23449628
+23450522
+23450708
+23450741
+23450827
+23451853
+23452230
+23452271
+23452431
+23452502
+23452860
+23453305
+23453306
+23453957
+23454002
+23454016
+23454135
+23454144
+23454145
+23454146
+23454149
+23454202
+23454217
+23454288
+23454417
+23454527
+23454528
+23454626
+23454653
+23454828
+23454835
+23454895
+23455039
+23455323
+23455461
+23455597
+23455732
+23456175
+23456256
+23456813
+23456921
+23457020
+23457090
+23457122
+23458149
+23458445
+23458455
+23458473
+23458581
+23458615
+23458967
+23458995
+23459067
+23459109
+23459149
+23459167
+23459442
+23459935
+23460310
+23460363
+23460404
+23460473
+23461378
+23461585
+23461648
+23461679
+23461806
+23462211
+23462233
+23462381
+23462506
+23462569
+23462698
+23462812
+23462886
+23463238
+23463253
+23463696
+23464521
+23464637
+23464650
+23464759
+23464881
+23464929
+23465061
+23465613
+23465614
+23466332
+23466420
+23467004
+23467673
+23468189
+23468458
+23468593
+23469681
+23469757
+23469759
+23469780
+23470011
+23470073
+23470077
+23470196
+23470204
+23470325
+23470776
+23470866
+23471121
+23471352
+23471540
+23471741
+23471964
+23472051
+23472655
+23473032
+23473033
+23473036
+23473268
+23473372
+23473581
+23473803
+23473805
+23474029
+23474171
+23474269
+23474317
+23474318
+23474324
+23474365
+23474589
+23474593
+23474889
+23475068
+23475371
+23475431
+23476712
+23477486
+23477504
+23477570
+23478260
+23478437
+23479060
+23479080
+23479280
+23479391
+23479408
+23479733
+23480170
+23480174
+23480625
+23480726
+23481635
+23481641
+23481648
+23482393
+23482984
+23483103
+23483189
+23484434
+23484493
+23484619
+23484668
+23484861
+23485017
+23485046
+23485401
+23485591
+23485614
+23485653
+23486181
+23486649
+23486920
+23488809
+23488912
+23488982
+23489348
+23489521
+23489620
+23489622
+23490587
+23491640
+23492812
+23493259
+23493372
+23493568
+23493958
+23494186
+23494447
+23494481
+23494524
+23494901
+23494938
+23495085
+23495691
+23495872
+23495999
+23496243
+23496341
+23497872
+23497883
+23497891
+23497903
+23497904
+23498944
+23499293
+23499503
+23499662
+23499735
+23499825
+23499927
+23500059
+23500062
+23500116
+23500380
+23500382
+23500384
+23500386
+23500387
+23500481
+23500490
+23500536
+23500538
+23500544
+23500672
+23500774
+23500779
+23501055
+23501114
+23501490
+23503440
+23503441
+23503457
+23503460
+23503470
+23503611
+23503627
+23503780
+23503967
+23504315
+23504510
+23504628
+23504855
+23504875
+23505206
+23505214
+23505636
+23505965
+23505966
+23506002
+23506120
+23506214
+23506455
+23506492
+23506527
+23506561
+23506783
+23507349
+23507868
+23508266
+23508295
+23508555
+23508685
+23508718
+23508742
+23508744
+23509003
+23509042
+23509611
+23510022
+23510074
+23510370
+23510510
+23510527
+23511023
+23511196
+23511897
+23512318
+23512500
+23512583
+23512910
+23514045
+23514379
+23515291
+23515494
+23515495
+23515584
+23516047
+23516330
+23516963
+23517069
+23517329
+23517413
+23517464
+23517501
+23517732
+23517733
+23517912
+23518229
+23518276
+23518299
+23518319
+23518471
+23519015
+23519077
+23519149
+23519376
+23519470
+23519574
+23519822
+23519881
+23519952
+23520191
+23520265
+23521048
+23521163
+23521174
+23521216
+23521495
+23521722
+23521797
+23522793
+23522835
+23523101
+23523202
+23523368
+23523425
+23523531
+23523547
+23523560
+23523661
+23523830
+23523831
+23523964
+23524100
+23524304
+23524312
+23524313
+23524314
+23524315
+23524663
+23525200
+23525524
+23526644
+23527545
+23527573
+23527578
+23527587
+23527663
+23528295
+23528299
+23528361
+23528610
+23528715
+23528877
+23529014
+23529015
+23529067
+23529381
+23529473
+23529650
+23529672
+23529860
+23529904
+23529932
+23530013
+23530057
+23530530
+23530595
+23530815
+23530834
+23531031
+23531039
+23531416
+23531488
+23532257
+23532331
+23532375
+23532445
+23532633
+23532797
+23532844
+23532932
+23532998
+23532999
+23533219
+23534444
+23534618
+23534703
+23534826
+23534857
+23535146
+23535188
+23535287
+23535329
+23535350
+23535827
+23535883
+23536522
+23536973
+23537166
+23537203
+23537377
+23537388
+23537500
+23537503
+23537574
+23537583
+23537600
+23537601
+23537890
+23538036
+23538115
+23538201
+23538867
+23539296
+23539510
+23539642
+23540648
+23540731
+23540813
+23540839
+23541120
+23541215
+23541371
+23541434
+23541437
+23541671
+23541680
+23541843
+23541893
+23541928
+23541932
+23541982
+23542040
+23542147
+23542439
+23542442
+23542578
+23542609
+23542729
+23542814
+23543012
+23543412
+23543432
+23543601
+23543629
+23543653
+23544460
+23544604
+23544794
+23544891
+23545134
+23545481
+23545560
+23545900
+23546009
+23546396
+23546599
+23546602
+23546614
+23546876
+23547705
+23547729
+23547754
+23547780
+23547794
+23547843
+23548164
+23548202
+23548583
+23548702
+23549262
+23549282
+23549331
+23549423
+23549676
+23549733
+23550942
+23551297
+23551461
+23552261
+23552265
+23552828
+23552832
+23552851
+23552878
+23552907
+23553340
+23553342
+23553601
+23553619
+23553767
+23553997
+23554049
+23554071
+23554095
+23554140
+23554268
+23554275
+23554292
+23554450
+23554507
+23554574
+23556333
+23556340
+23556343
+23556438
+23556444
+23557033
+23557092
+23557591
+23557686
+23557706
+23557746
+23557840
+23557842
+23557932
+23557989
+23557993
+23558202
+23558378
+23558600
+23558678
+23558743
+23559145
+23559483
+23560456
+23560466
+23560542
+23560650
+23560689
+23560747
+23560913
+23561070
+23561073
+23561074
+23561077
+23561078
+23561083
+23561088
+23561099
+23561104
+23561107
+23561108
+23561111
+23561112
+23561126
+23561129
+23561132
+23561144
+23561145
+23561151
+23561153
+23561159
+23561167
+23561168
+23561180
+23561186
+23561193
+23561200
+23561202
+23561205
+23561207
+23561210
+23561215
+23561216
+23561218
+23561221
+23562061
+23562062
+23562164
+23562368
+23562495
+23562497
+23562533
+23562535
+23562611
+23562632
+23562803
+23562928
+23564313
+23564370
+23564651
+23564940
+23566055
+23566057
+23566059
+23566197
+23566650
+23566885
+23567033
+23567036
+23567044
+23567241
+23567243
+23567313
+23567949
+23567950
+23567961
+23567962
+23567998
+23568451
+23568513
+23568542
+23568577
+23568856
+23569205
+23570471
+23570615
+23570748
+23570789
+23570985
+23570999
+23571068
+23571107
+23571427
+23571428
+23571773
+23572393
+23572528
+23573951
+23573972
+23574017
+23574336
+23574520
+23574523
+23575975
+23576019
+23576190
+23576235
+23576432
+23576475
+23578259
+23578341
+23578390
+23578391
+23578393
+23578514
+23578522
+23578608
+23578613
+23578615
+23578616
+23578620
+23578626
+23578628
+23578629
+23578637
+23578638
+23578639
+23578653
+23578654
+23578655
+23578656
+23578658
+23578872
+23578923
+23579166
+23579167
+23579178
+23579428
+23579473
+23580152
+23580372
+23580374
+23580394
+23580445
+23580458
+23580644
+23581456
+23581551
+23581596
+23581848
+23581876
+23581996
+23583259
+23583485
+23583510
+23583511
+23583517
+23583540
+23583635
+23583803
+23583806
+23583883
+23583884
+23583901
+23583931
+23583933
+23584016
+23584355
+23584433
+23584544
+23584554
+23584844
+23585096
+23585278
+23585307
+23585555
+23585769
+23586505
+23586585
+23587021
+23587424
+23587649
+23587769
+23587837
+23587873
+23588092
+23588305
+23588313
+23588391
+23588559
+23588565
+23588836
+23589405
+23589406
+23589407
+23589419
+23589542
+23590116
+23590179
+23590472
+23590522
+23590644
+23591043
+23591113
+23591116
+23591117
+23591579
+23591845
+23592228
+23592595
+23592746
+23594297
+23594303
+23594314
+23594999
+23595053
+23595637
+23595773
+23596326
+23596978
+23597075
+23597080
+23597210
+23597309
+23597444
+23597449
+23597508
+23597791
+23598085
+23598454
+23599007
+23599124
+23600364
+23600402
+23600476
+23600526
+23600654
+23600657
+23600667
+23600682
+23600698
+23600789
+23601082
+23601203
+23601248
+23601384
+23601385
+23601399
+23601401
+23601402
+23601404
+23601411
+23601414
+23601640
+23601708
+23602152
+23602441
+23602987
+23603004
+23603147
+23603194
+23603198
+23603202
+23603294
+23603382
+23603383
+23603429
+23603479
+23603616
+23603689
+23603856
+23603902
+23603917
+23604005
+23604074
+23604141
+23604334
+23604335
+23604336
+23604490
+23604718
+23605691
+23605692
+23605693
+23606373
+23606448
+23606504
+23607283
+23607697
+23607712
+23607891
+23607932
+23607964
+23608020
+23608222
+23608535
+23608635
+23608957
+23609225
+23609350
+23609771
+23609961
+23610058
+23610082
+23611022
+23611117
+23611293
+23611309
+23611476
+23611491
+23611526
+23611691
+23611819
+23611835
+23612420
+23612449
+23612854
+23612971
+23613014
+23613149
+23614400
+23614455
+23614462
+23614709
+23614725
+23615466
+23615512
+23615707
+23616427
+23616470
+23616476
+23617563
+23617585
+23617697
+23617758
+23617821
+23617834
+23617855
+23619605
+23619606
+23619607
+23620211
+23620263
+23620485
+23621148
+23621420
+23621491
+23621521
+23621523
+23621567
+23622243
+23622980
+23623492
+23623548
+23623752
+23623820
+23623839
+23623842
+23623845
+23624115
+23624148
+23624290
+23624292
+23624385
+23624394
+23624670
+23624809
+23624852
+23625175
+23625695
+23625813
+23625817
+23625906
+23625907
+23625908
+23625910
+23625947
+23625967
+23627252
+23627903
+23628345
+23628454
+23628592
+23628620
+23628763
+23628779
+23628896
+23629517
+23629669
+23630169
+23630181
+23630454
+23631374
+23631389
+23631395
+23631402
+23631425
+23631483
+23631496
+23631538
+23631672
+23631841
+23632085
+23632905
+23634642
+23634844
+23635319
+23636129
+23636270
+23636447
+23636901
+23636989
+23637063
+23637074
+23638842
+23639006
+23639103
+23639115
+23639187
+23639190
+23639360
+23639362
+23639434
+23639451
+23639506
+23639539
+23639544
+23639572
+23639586
+23639626
+23639653
+23639801
+23639869
+23639875
+23639947
+23640072
+23640103
+23640180
+23640331
+23640547
+23640662
+23640687
+23640814
+23640846
+23640862
+23640894
+23641914
+23641942
+23642037
+23642079
+23642478
+23643093
+23643094
+23643194
+23643543
+23643544
+23643679
+23643681
+23643699
+23643702
+23643740
+23643743
+23643754
+23643799
+23643845
+23643972
+23644191
+23644197
+23644202
+23644204
+23644657
+23644911
+23644912
+23644980
+23645211
+23645360
+23645536
+23645539
+23645666
+23645677
diff --git a/huner/ner_scripts/splits/chemdner.train b/huner/ner_scripts/splits/chemdner.train
new file mode 100644
index 0000000..5730c97
--- /dev/null
+++ b/huner/ner_scripts/splits/chemdner.train
@@ -0,0 +1,6000 @@
+
+21826085
+22006095
+22056334
+22080034
+22080035
+22080037
+22158333
+22236017
+22236093
+22239172
+22241176
+22258629
+22269904
+22273350
+22275383
+22288603
+22294443
+22301816
+22301818
+22303963
+22304302
+22310169
+22310170
+22312034
+22312035
+22313530
+22317823
+22317825
+22335586
+22342985
+22348222
+22348951
+22349814
+22352409
+22354902
+22360570
+22360797
+22370634
+22370640
+22370645
+22372659
+22372865
+22372916
+22381584
+22385272
+22391562
+22394118
+22397600
+22397675
+22397835
+22400496
+22401597
+22401710
+22404642
+22410775
+22410778
+22420410
+22424051
+22424088
+22424117
+22426233
+22429027
+22430206
+22430207
+22438091
+22438103
+22443683
+22445601
+22447662
+22447684
+22451355
+22455800
+22455986
+22456000
+22465815
+22468693
+22468741
+22469981
+22469988
+22472136
+22475014
+22475036
+22475047
+22480291
+22480349
+22489960
+22491024
+22493952
+22494026
+22497567
+22499272
+22502647
+22507666
+22508482
+22508483
+22510064
+22511240
+22511286
+22511336
+22512590
+22516666
+22519721
+22521210
+22524504
+22531751
+22533550
+22537580
+22543584
+22546615
+22546616
+22548320
+22548348
+22548364
+22551778
+22551786
+22553909
+22554350
+22559719
+22561337
+22563917
+22564439
+22564440
+22564442
+22577127
+22577972
+22579656
+22579759
+22580035
+22580610
+22583008
+22585412
+22585425
+22585450
+22591127
+22591175
+22592975
+22594605
+22607130
+22607769
+22610748
+22610853
+22614018
+22614019
+22616559
+22616577
+22616839
+22616933
+22619070
+22623520
+22625411
+22625416
+22628017
+22628265
+22628292
+22634360
+22638814
+22640571
+22640596
+22640631
+22641218
+22644836
+22648529
+22648611
+22658648
+22659473
+22660443
+22661401
+22664910
+22665062
+22665065
+22669363
+22670797
+22674653
+22677475
+22678994
+22683935
+22687345
+22687520
+22690834
+22693035
+22694738
+22698957
+22703292
+22703341
+22705340
+22707396
+22708546
+22708583
+22708620
+22708639
+22708657
+22708724
+22709945
+22712581
+22712621
+22717740
+22717743
+22718275
+22720714
+22722026
+22722027
+22722028
+22724545
+22725249
+22728231
+22728761
+22732440
+22732441
+22732443
+22733133
+22733134
+22736593
+22736625
+22740094
+22742738
+22743159
+22743996
+22745189
+22749926
+22750050
+22750077
+22750079
+22751286
+22757667
+22760156
+22761031
+22761042
+22765022
+22765159
+22765351
+22766173
+22766394
+22771462
+22776039
+22777357
+22780426
+22780563
+22788542
+22788700
+22788743
+22788802
+22789395
+22790339
+22796110
+22796428
+22796429
+22798246
+22798249
+22799453
+22799569
+22803803
+22804459
+22809021
+22809387
+22812637
+22813628
+22815230
+22815248
+22815312
+22818587
+22820274
+22820275
+22824787
+22824788
+22827445
+22827894
+22830982
+22832075
+22834411
+22835278
+22835502
+22836659
+22836881
+22837389
+22838394
+22840199
+22840229
+22841391
+22841397
+22841916
+22841917
+22842550
+22846225
+22846850
+22849377
+22849656
+22849972
+22851333
+22854821
+22855364
+22856387
+22859660
+22862822
+22862926
+22864622
+22864625
+22864849
+22865292
+22867272
+22867274
+22871218
+22872100
+22872141
+22872606
+22872607
+22874922
+22876784
+22876943
+22876949
+22876950
+22876953
+22876956
+22883213
+22884611
+22885793
+22887768
+22887780
+22889561
+22889582
+22889612
+22889721
+22891663
+22893614
+22898132
+22898566
+22901687
+22902968
+22903169
+22903180
+22905673
+22906569
+22906572
+22906573
+22906800
+22911509
+22914985
+22915370
+22917637
+22918066
+22918489
+22921987
+22922115
+22923473
+22926007
+22926048
+22929022
+22931186
+22931187
+22931212
+22935038
+22935062
+22935104
+22935511
+22935610
+22935770
+22936177
+22936205
+22936348
+22939001
+22939899
+22939943
+22940000
+22940001
+22940283
+22940575
+22940855
+22945305
+22945693
+22948773
+22948775
+22948803
+22949397
+22949511
+22951947
+22951949
+22954283
+22954532
+22955948
+22956413
+22956628
+22956629
+22956630
+22956631
+22956632
+22958332
+22960471
+22961087
+22961093
+22961095
+22961200
+22963367
+22963497
+22963553
+22963554
+22963619
+22964394
+22965581
+22966070
+22966073
+22967140
+22967722
+22968082
+22968089
+22968133
+22972178
+22972179
+22972222
+22972396
+22972752
+22975146
+22975155
+22975406
+22976834
+22977168
+22980124
+22981459
+22981667
+22981668
+22981737
+22981796
+22982007
+22982206
+22982218
+22982248
+22982302
+22982773
+22982776
+22983118
+22983652
+22983831
+22984796
+22985735
+22985736
+22985953
+22986217
+22986456
+22986488
+22987483
+22987605
+22989414
+22989504
+22989703
+22989704
+22989705
+22991192
+22991234
+22991246
+22991293
+22991330
+22991412
+22992330
+22992332
+22992376
+22993196
+22993237
+22995439
+22995584
+22995755
+22995849
+22996261
+22996932
+22997007
+22997060
+22998180
+22998221
+22998240
+22998295
+22999711
+22999913
+23000249
+23000250
+23000251
+23000442
+23000447
+23000449
+23000450
+23000451
+23000507
+23001363
+23001428
+23001627
+23001862
+23002087
+23003213
+23007555
+23007559
+23008095
+23008099
+23008229
+23009741
+23010164
+23010165
+23010360
+23010362
+23010363
+23010565
+23010695
+23010867
+23010870
+23011663
+23011759
+23012257
+23014761
+23016524
+23017385
+23017388
+23017389
+23017393
+23017399
+23017401
+23017404
+23017405
+23017406
+23017407
+23017411
+23017414
+23017417
+23017419
+23017423
+23017425
+23018143
+23019137
+23019139
+23019217
+23019274
+23020239
+23020786
+23020787
+23020788
+23022048
+23022069
+23022271
+23022324
+23022398
+23023024
+23023136
+23023933
+23024176
+23024204
+23025634
+23025922
+23026700
+23027517
+23027804
+23028140
+23030346
+23030680
+23030706
+23030766
+23030793
+23032515
+23033256
+23034931
+23036111
+23036330
+23036350
+23036893
+23038668
+23038768
+23040268
+23041228
+23041232
+23041243
+23041424
+23041510
+23041538
+23041661
+23041725
+23042728
+23042729
+23042730
+23042808
+23042952
+23042953
+23042954
+23043137
+23043183
+23043441
+23044045
+23044047
+23044489
+23046379
+23046389
+23046524
+23046872
+23047001
+23047024
+23047287
+23047828
+23047912
+23048186
+23050902
+23052058
+23052190
+23052191
+23052192
+23052195
+23053666
+23054066
+23055393
+23055445
+23055453
+23055539
+23057615
+23057692
+23058251
+23058997
+23059508
+23059509
+23059538
+23059626
+23059655
+23059794
+23059813
+23060096
+23060276
+23060524
+23061607
+23061622
+23061623
+23061635
+23063002
+23063066
+23063069
+23063411
+23063590
+23063593
+23063623
+23063689
+23063782
+23063927
+23064097
+23064325
+23064722
+23064749
+23065141
+23065531
+23065592
+23065696
+23066090
+23066821
+23066853
+23066870
+23066949
+23066996
+23068419
+23069619
+23069627
+23070981
+23071106
+23071294
+23072367
+23072918
+23073075
+23073171
+23074021
+23074035
+23074088
+23074095
+23074173
+23076553
+23076740
+23076766
+23076840
+23077105
+23078542
+23078954
+23079138
+23079231
+23079287
+23080299
+23080379
+23080539
+23081912
+23081947
+23085085
+23085095
+23085121
+23085122
+23085266
+23085295
+23085330
+23085368
+23085435
+23085495
+23085522
+23085547
+23085979
+23085994
+23086035
+23086037
+23086038
+23086141
+23086182
+23086197
+23086198
+23086703
+23087261
+23089153
+23089211
+23089250
+23089896
+23090968
+23091168
+23091169
+23091189
+23092136
+23092225
+23092237
+23092304
+23092395
+23092723
+23092751
+23092877
+23092880
+23092894
+23092895
+23093494
+23093496
+23093603
+23094599
+23094694
+23094864
+23095167
+23095244
+23095245
+23097024
+23097088
+23097157
+23097213
+23097351
+23098805
+23098818
+23098878
+23098879
+23098993
+23099319
+23099337
+23099339
+23099502
+23099503
+23099645
+23099811
+23100157
+23102508
+23103224
+23103282
+23103297
+23103330
+23103351
+23103426
+23103446
+23103566
+23103568
+23103569
+23103600
+23104244
+23104245
+23104419
+23104432
+23104982
+23106229
+23106482
+23106534
+23106567
+23107818
+23108036
+23108214
+23108727
+23108851
+23108979
+23109068
+23109183
+23109233
+23109258
+23109279
+23109425
+23110414
+23110522
+23110976
+23111282
+23111374
+23111684
+23111753
+23111803
+23111876
+23111877
+23111879
+23111881
+23111883
+23111884
+23111885
+23111886
+23111887
+23111950
+23111981
+23115086
+23115119
+23115221
+23115324
+23115325
+23116112
+23116113
+23116144
+23116643
+23117149
+23117151
+23117207
+23117208
+23117790
+23118018
+23118019
+23118486
+23121767
+23121886
+23121934
+23122060
+23122061
+23122064
+23122066
+23122068
+23122077
+23122085
+23122086
+23122089
+23122092
+23122097
+23122104
+23122105
+23122108
+23122114
+23122116
+23122118
+23122129
+23122134
+23122135
+23122136
+23122137
+23122140
+23122141
+23122142
+23122143
+23122145
+23122147
+23122151
+23122152
+23122154
+23122155
+23122157
+23122160
+23122161
+23122163
+23122165
+23122166
+23122167
+23122168
+23122169
+23122331
+23123188
+23123248
+23123254
+23123331
+23123332
+23123662
+23123664
+23123737
+23123743
+23123771
+23123945
+23124677
+23124905
+23124950
+23125002
+23125070
+23125284
+23126280
+23127499
+23127508
+23127540
+23127567
+23127598
+23127599
+23127601
+23127698
+23127820
+23127826
+23127899
+23127916
+23128829
+23129806
+23130977
+23131177
+23131208
+23131595
+23131797
+23131798
+23132334
+23132629
+23132743
+23132751
+23132773
+23132843
+23132866
+23132909
+23134349
+23134558
+23135547
+23135548
+23135549
+23135892
+23136129
+23137276
+23137796
+23137833
+23137957
+23138112
+23138333
+23138381
+23138972
+23139019
+23139020
+23139351
+23139378
+23139413
+23140132
+23141425
+23142020
+23142073
+23142104
+23142105
+23142112
+23142212
+23142327
+23142538
+23142558
+23142635
+23142699
+23142753
+23142777
+23142789
+23142804
+23142844
+23143036
+23143039
+23143415
+23143619
+23143620
+23143666
+23143674
+23143852
+23143912
+23143926
+23144001
+23145849
+23145944
+23145985
+23146662
+23146664
+23146690
+23146691
+23146692
+23146694
+23146695
+23146698
+23146750
+23146755
+23146758
+23146761
+23146765
+23146766
+23146838
+23146871
+23147004
+23147005
+23147032
+23147033
+23147376
+23147377
+23147415
+23147416
+23147475
+23147567
+23147639
+23147645
+23147692
+23147715
+23147750
+23147837
+23147987
+23149337
+23149657
+23149908
+23149927
+23150210
+23150226
+23150428
+23150491
+23150493
+23150495
+23150659
+23151000
+23151001
+23151002
+23151003
+23151004
+23151250
+23151381
+23151610
+23151611
+23151612
+23152186
+23152189
+23152191
+23152439
+23152449
+23152558
+23153029
+23153054
+23153057
+23153322
+23153456
+23153512
+23153618
+23153668
+23153959
+23154127
+23154194
+23154301
+23154304
+23154582
+23154865
+23155004
+23155052
+23155061
+23155201
+23157419
+23157442
+23157635
+23157637
+23157640
+23159106
+23159331
+23159359
+23159396
+23159397
+23159464
+23159479
+23159502
+23159529
+23159662
+23159666
+23159667
+23159668
+23159669
+23159712
+23159729
+23159732
+23159790
+23159791
+23159885
+23159886
+23159888
+23159894
+23159986
+23160003
+23160089
+23160092
+23160419
+23160480
+23160481
+23160527
+23160529
+23160530
+23160934
+23160940
+23160961
+23160964
+23161062
+23161217
+23161373
+23161424
+23161484
+23161648
+23161664
+23161673
+23161677
+23161731
+23161804
+23161844
+23161866
+23161868
+23161873
+23163395
+23163430
+23163508
+23163696
+23164152
+23164613
+23164615
+23164674
+23164711
+23164921
+23164931
+23164932
+23164984
+23165727
+23165858
+23166012
+23167526
+23167531
+23167566
+23168241
+23168293
+23168915
+23169387
+23169614
+23170792
+23170794
+23170796
+23170798
+23170954
+23170957
+23171045
+23171424
+23171703
+23172038
+23172121
+23172156
+23172229
+23172726
+23172734
+23172744
+23174213
+23174457
+23174517
+23174518
+23174519
+23174539
+23174746
+23174748
+23175103
+23175443
+23175530
+23177255
+23177256
+23177536
+23177784
+23178170
+23178178
+23178179
+23178182
+23178198
+23178221
+23178243
+23178257
+23178279
+23178323
+23178339
+23178632
+23178651
+23178656
+23178681
+23178804
+23178895
+23178949
+23178950
+23179349
+23179350
+23179351
+23179409
+23179765
+23179966
+23180158
+23180341
+23180370
+23180382
+23180449
+23180652
+23180684
+23180691
+23180692
+23180693
+23180762
+23180796
+23180826
+23181488
+23182087
+23182739
+23182766
+23182946
+23183084
+23183177
+23183183
+23183186
+23183374
+23183413
+23183532
+23183543
+23183624
+23183669
+23184149
+23184251
+23184951
+23185042
+23185990
+23186588
+23186623
+23186624
+23187065
+23187874
+23187878
+23188391
+23188714
+23188819
+23189968
+23190030
+23190172
+23190297
+23190339
+23192339
+23192347
+23192350
+23192351
+23192895
+23192981
+23192982
+23193183
+23193260
+23193276
+23194076
+23194156
+23194280
+23194502
+23194504
+23194505
+23194507
+23194510
+23194512
+23194517
+23194518
+23194522
+23194524
+23194525
+23194526
+23194528
+23194531
+23194533
+23194540
+23194543
+23194544
+23194552
+23194555
+23194559
+23194566
+23194750
+23194825
+23194828
+23195329
+23195330
+23195954
+23195960
+23196320
+23196670
+23196805
+23197046
+23197296
+23197323
+23197401
+23197649
+23197771
+23197773
+23198782
+23198810
+23198819
+23198831
+23198958
+23199028
+23199199
+23199223
+23199257
+23199983
+23199984
+23199985
+23199987
+23199989
+23199992
+23199993
+23199996
+23199998
+23199999
+23200004
+23200005
+23200006
+23200246
+23200253
+23200732
+23200735
+23200747
+23200778
+23200887
+23200901
+23201003
+23201051
+23201055
+23201092
+23201124
+23201179
+23201180
+23201223
+23201309
+23201331
+23201370
+23201439
+23201441
+23201442
+23201451
+23201452
+23201622
+23201927
+23202134
+23202250
+23202371
+23202372
+23202442
+23202585
+23202880
+23202986
+23203454
+23203870
+23203920
+23204111
+23204325
+23204443
+23204517
+23205514
+23205567
+23205571
+23205584
+23205763
+23205778
+23206310
+23206503
+23206861
+23206865
+23206867
+23206990
+23207055
+23207056
+23207166
+23207252
+23207323
+23207328
+23207477
+23207679
+23208007
+23208411
+23208609
+23208666
+23208955
+23209189
+23209192
+23210481
+23210485
+23210547
+23210639
+23210662
+23210738
+23210742
+23210774
+23210777
+23210779
+23210780
+23210782
+23210786
+23210788
+23210789
+23210790
+23210850
+23210851
+23210852
+23210854
+23210900
+23211363
+23211364
+23211525
+23211707
+23212103
+23212107
+23212109
+23212787
+23212970
+23212975
+23213044
+23213199
+23214415
+23214423
+23214430
+23214439
+23214714
+23214926
+23214934
+23214973
+23214979
+23214990
+23215007
+23215148
+23215159
+23215238
+23215347
+23215461
+23216107
+23216219
+23216335
+23217961
+23218401
+23218712
+23218713
+23218716
+23218717
+23218718
+23219155
+23219161
+23219324
+23219325
+23219338
+23219339
+23219469
+23219525
+23219590
+23219658
+23219683
+23219696
+23219702
+23219725
+23219778
+23219869
+23219925
+23219934
+23219946
+23219979
+23220002
+23220003
+23220004
+23220035
+23220037
+23220041
+23220145
+23220290
+23220291
+23220293
+23220295
+23220340
+23220412
+23220413
+23220513
+23220514
+23220560
+23220562
+23220586
+23220588
+23220589
+23220609
+23220612
+23220614
+23220616
+23220617
+23220618
+23220635
+23220641
+23220644
+23220646
+23221006
+23221633
+23222689
+23222849
+23223020
+23223023
+23223125
+23223177
+23223234
+23223345
+23223405
+23223445
+23223551
+23223639
+23223641
+23223708
+23223801
+23223802
+23223857
+23224291
+23224775
+23224942
+23225075
+23225241
+23225365
+23225366
+23225536
+23225542
+23225638
+23225671
+23225753
+23225764
+23225770
+23225780
+23227887
+23227961
+23228028
+23228043
+23228193
+23228469
+23228471
+23228475
+23228651
+23228652
+23228696
+23228697
+23228886
+23229055
+23229136
+23229141
+23229510
+23229511
+23229539
+23229552
+23229556
+23229583
+23230131
+23230133
+23230266
+23230274
+23230281
+23230905
+23231350
+23231410
+23231420
+23231439
+23231457
+23231809
+23231967
+23232056
+23232059
+23232060
+23232078
+23232079
+23232123
+23232150
+23232323
+23232333
+23232461
+23232711
+23232866
+23232941
+23233034
+23233197
+23233286
+23233324
+23233454
+23233456
+23233546
+23234246
+23234313
+23234434
+23234537
+23234607
+23234812
+23234855
+23235151
+23235156
+23235158
+23235435
+23235690
+23235742
+23235923
+23237305
+23237450
+23237482
+23237533
+23237546
+23237590
+23237733
+23237828
+23237835
+23237860
+23237939
+23237974
+23238103
+23238121
+23238226
+23238233
+23238235
+23238236
+23238299
+23238352
+23238425
+23238611
+23238657
+23238662
+23238783
+23238784
+23238991
+23239015
+23239045
+23239458
+23239550
+23239587
+23239601
+23239602
+23239629
+23239639
+23239825
+23240655
+23240993
+23241030
+23241059
+23241082
+23241354
+23241831
+23242472
+23243006
+23243659
+23243660
+23244033
+23244162
+23244178
+23244292
+23244521
+23244523
+23244594
+23245188
+23245206
+23245512
+23245513
+23245514
+23245515
+23245516
+23245696
+23245697
+23246428
+23246436
+23246437
+23246460
+23246469
+23246481
+23246531
+23246578
+23246580
+23246611
+23246700
+23246701
+23246732
+23246797
+23246798
+23246865
+23246867
+23247008
+23247009
+23247010
+23247040
+23247048
+23247298
+23247337
+23247504
+23247824
+23248173
+23248191
+23248196
+23248236
+23248329
+23249181
+23249244
+23249338
+23249341
+23249525
+23249538
+23249624
+23249625
+23249626
+23249745
+23249747
+23249751
+23250357
+23250541
+23250802
+23250808
+23250811
+23252421
+23252481
+23252553
+23252610
+23252613
+23252799
+23252823
+23252848
+23253100
+23253127
+23253130
+23253441
+23253856
+23254196
+23254197
+23254198
+23254253
+23254341
+23254573
+23255050
+23255073
+23255236
+23255254
+23255284
+23255384
+23255426
+23255471
+23256442
+23256445
+23256446
+23256474
+23256503
+23256510
+23256609
+23256621
+23256640
+23256643
+23256708
+23256715
+23256716
+23256719
+23256721
+23256722
+23256723
+23256724
+23256769
+23256816
+23256819
+23257178
+23257312
+23257627
+23258430
+23258537
+23258548
+23258565
+23258566
+23258671
+23258708
+23258742
+23258772
+23258773
+23259536
+23259666
+23259731
+23259742
+23259773
+23259819
+23259848
+23259865
+23259866
+23259985
+23260032
+23260346
+23260347
+23260350
+23260352
+23261423
+23261524
+23261526
+23261527
+23261528
+23261588
+23261589
+23261590
+23261643
+23261644
+23261645
+23261646
+23261667
+23261672
+23261676
+23261678
+23261679
+23261705
+23261715
+23261820
+23262028
+23262035
+23262161
+23262162
+23262203
+23262279
+23262390
+23262562
+23263360
+23263362
+23263864
+23263984
+23263987
+23264021
+23264030
+23264448
+23264615
+23265191
+23265282
+23265296
+23265429
+23265452
+23265456
+23265458
+23265462
+23265467
+23265469
+23265483
+23265488
+23265491
+23265492
+23265498
+23265501
+23265502
+23265504
+23265505
+23265506
+23265507
+23265509
+23265510
+23265511
+23265515
+23265516
+23265517
+23265522
+23265523
+23265524
+23265526
+23265528
+23265529
+23265533
+23265542
+23265544
+23265546
+23265660
+23265843
+23265872
+23265873
+23265878
+23265880
+23265884
+23265889
+23265892
+23265893
+23265895
+23265896
+23265899
+23265901
+23265902
+23265903
+23265904
+23266309
+23266310
+23266311
+23266367
+23266447
+23266451
+23266452
+23266453
+23266491
+23266501
+23266502
+23266503
+23266674
+23266719
+23266722
+23266731
+23266732
+23266737
+23266827
+23267695
+23267767
+23267837
+23267840
+23267855
+23267856
+23267857
+23267862
+23268106
+23268549
+23268557
+23268656
+23268927
+23268987
+23269496
+23270282
+23270326
+23270387
+23270527
+23270565
+23270593
+23270704
+23270990
+23270993
+23271001
+23271002
+23271057
+23271679
+23271680
+23271737
+23271742
+23273150
+23273225
+23273260
+23273412
+23273506
+23273978
+23273993
+23273999
+23274087
+23274143
+23274352
+23274353
+23274413
+23274570
+23274698
+23274714
+23274746
+23274767
+23274768
+23274889
+23274893
+23274898
+23274903
+23274907
+23274909
+23274916
+23274917
+23274950
+23275067
+23275110
+23275111
+23275112
+23275113
+23275440
+23275442
+23275471
+23276135
+23276161
+23276627
+23276631
+23276633
+23277104
+23277230
+23278281
+23278314
+23278394
+23278396
+23278398
+23278399
+23278403
+23278633
+23279802
+23279841
+23279844
+23279865
+23279867
+23279886
+23279943
+23280101
+23280488
+23280489
+23280620
+23280672
+23280691
+23280766
+23280809
+23280831
+23280951
+23280958
+23280997
+23281020
+23281044
+23281069
+23281101
+23281179
+23281180
+23281242
+23281275
+23281330
+23281340
+23281578
+23281613
+23281636
+23281657
+23281661
+23281710
+23281847
+23281892
+23281917
+23281937
+23281965
+23282011
+23282017
+23282065
+23282066
+23282083
+23282101
+23282576
+23282999
+23283546
+23284002
+23284082
+23286198
+23286240
+23286606
+23286736
+23286905
+23287045
+23287046
+23287056
+23287389
+23287390
+23287412
+23287538
+23287700
+23287708
+23287710
+23287726
+23287727
+23287728
+23287737
+23288049
+23288052
+23288091
+23288103
+23288144
+23288298
+23288360
+23288505
+23288589
+23288866
+23289403
+23289412
+23289503
+23289585
+23289615
+23289624
+23289646
+23289710
+23289788
+23289802
+23289830
+23289851
+23289872
+23290048
+23290050
+23290051
+23290262
+23290724
+23291030
+23291047
+23291050
+23291051
+23291118
+23291264
+23291323
+23291341
+23291435
+23291503
+23291927
+23292343
+23292655
+23292747
+23292752
+23292753
+23292768
+23292797
+23292798
+23292859
+23292881
+23292985
+23292988
+23293000
+23293001
+23293024
+23293094
+23293106
+23293129
+23293130
+23293875
+23293921
+23293950
+23293962
+23293964
+23293966
+23293970
+23293971
+23294188
+23294277
+23294326
+23294363
+23294378
+23294566
+23294699
+23294895
+23295156
+23295157
+23295223
+23295224
+23295229
+23295323
+23295385
+23295386
+23295582
+23295645
+23295711
+23295732
+23295739
+23295740
+23295826
+23295943
+23295999
+23296019
+23296027
+23296098
+23296100
+23296102
+23296104
+23296105
+23296122
+23296142
+23296156
+23296276
+23296277
+23296368
+23296369
+23296837
+23296902
+23296904
+23296950
+23296979
+23297023
+23297245
+23297250
+23297346
+23297362
+23297676
+23297689
+23297712
+23297713
+23297755
+23297762
+23297817
+23298136
+23298138
+23298139
+23298140
+23298158
+23298322
+23298577
+23298578
+23298612
+23298613
+23298614
+23298622
+23298677
+23298694
+23298698
+23298809
+23298810
+23298862
+23299080
+23299191
+23299192
+23299193
+23299194
+23299647
+23299834
+23299909
+23300000
+23300056
+23300227
+23300338
+23301246
+23301495
+23301655
+23301701
+23301838
+23301853
+23301897
+23301948
+23301955
+23302583
+23302590
+23302592
+23302594
+23303191
+23303198
+23303199
+23303281
+23303441
+23303486
+23303575
+23303698
+23303710
+23303713
+23303717
+23303727
+23303733
+23303785
+23303786
+23305110
+23305127
+23305294
+23305444
+23305465
+23305495
+23305513
+23305550
+23305709
+23305776
+23305777
+23305807
+23305918
+23305993
+23306105
+23306106
+23306171
+23306172
+23306206
+23306788
+23306790
+23306791
+23306944
+23307185
+23307290
+23307548
+23307549
+23307551
+23307587
+23307663
+23307790
+23307927
+23311288
+23311296
+23311400
+23311471
+23311532
+23311695
+23311700
+23311718
+23311754
+23311883
+23311976
+23312279
+23312281
+23312474
+23312946
+23313176
+23313245
+23313270
+23313271
+23313336
+23313338
+23313345
+23313376
+23313377
+23313378
+23313379
+23313380
+23313448
+23313609
+23313621
+23313632
+23313633
+23313638
+23313639
+23313661
+23313712
+23313714
+23313794
+23313797
+23313961
+23313962
+23314045
+23314275
+23314276
+23314277
+23314308
+23314331
+23314757
+23315005
+23315090
+23315091
+23315216
+23315496
+23315522
+23315585
+23315586
+23315598
+23315601
+23315644
+23315683
+23315791
+23315938
+23315996
+23316011
+23316015
+23316021
+23316053
+23316864
+23316913
+23316933
+23316963
+23316964
+23316965
+23316966
+23317100
+23317159
+23317163
+23317370
+23317450
+23317497
+23317498
+23317570
+23317572
+23318226
+23318425
+23318445
+23318455
+23318460
+23318598
+23318645
+23318726
+23318729
+23318730
+23318731
+23318758
+23318833
+23318905
+23319077
+23319078
+23319147
+23319166
+23319584
+23319588
+23319591
+23320385
+23320412
+23320465
+23320521
+23320542
+23320893
+23320931
+23320940
+23321054
+23321216
+23321259
+23321396
+23321560
+23321564
+23321613
+23321677
+23321689
+23321916
+23322164
+23322166
+23322284
+23322347
+23322508
+23322537
+23322558
+23322559
+23322586
+23322587
+23322633
+23322648
+23322676
+23322677
+23322705
+23322709
+23322721
+23322769
+23323519
+23323521
+23323549
+23323677
+23323680
+23323691
+23323746
+23323763
+23323829
+23323854
+23323873
+23323890
+23323975
+23323987
+23324033
+23324400
+23324406
+23324437
+23325046
+23325050
+23325363
+23325370
+23325372
+23325373
+23325374
+23325486
+23325489
+23325492
+23325530
+23325631
+23325700
+23325846
+23325847
+23327103
+23327112
+23327360
+23327491
+23327494
+23327532
+23327533
+23327534
+23327546
+23327557
+23327580
+23327588
+23327668
+23327686
+23327691
+23327722
+23327735
+23327794
+23327832
+23327840
+23327993
+23328072
+23328126
+23328127
+23328252
+23328895
+23329065
+23329125
+23329180
+23329588
+23329685
+23329687
+23330542
+23330549
+23330557
+23330564
+23330613
+23330789
+23330847
+23330848
+23330908
+23330971
+23330984
+23331178
+23331263
+23331539
+23331575
+23331618
+23331669
+23331770
+23331859
+23332347
+23332447
+23332762
+23333093
+23333208
+23333261
+23333305
+23333424
+23333503
+23333575
+23333639
+23333640
+23333641
+23333647
+23333650
+23333716
+23333834
+23333899
+23333900
+23333908
+23334082
+23334176
+23334322
+23334583
+23334800
+23334855
+23334864
+23334979
+23335024
+23335025
+23335034
+23335106
+23335220
+23335243
+23335320
+23335346
+23335398
+23335450
+23335515
+23335561
+23335565
+23335833
+23336337
+23336368
+23336435
+23336441
+23336729
+23337040
+23337041
+23337202
+23337256
+23337257
+23337386
+23337388
+23337397
+23337523
+23337599
+23337600
+23337602
+23337911
+23337925
+23337941
+23338525
+23338536
+23338537
+23338539
+23339036
+23339052
+23339076
+23339480
+23339547
+23339572
+23339577
+23339604
+23339654
+23339663
+23339664
+23339678
+23339742
+23339744
+23339830
+23339966
+23339974
+23340093
+23340113
+23340331
+23340332
+23340333
+23340334
+23340474
+23340494
+23340514
+23340646
+23340653
+23340670
+23340689
+23340858
+23340977
+23340981
+23341143
+23341175
+23341183
+23341191
+23341196
+23341208
+23341212
+23341241
+23341248
+23341258
+23341458
+23343117
+23343172
+23343190
+23343193
+23343200
+23343324
+23343325
+23343474
+23343565
+23343595
+23343598
+23344056
+23344156
+23344429
+23344433
+23344796
+23344820
+23344824
+23344825
+23344855
+23344856
+23344887
+23344974
+23344975
+23344983
+23345125
+23345132
+23345171
+23346856
+23346898
+23346913
+23346994
+23347001
+23347052
+23347151
+23347206
+23347422
+23347547
+23347584
+23347616
+23347683
+23347684
+23347875
+23347937
+23347954
+23348005
+23348055
+23348152
+23348407
+23348409
+23348499
+23348500
+23348501
+23348514
+23348679
+23348754
+23348755
+23349486
+23349494
+23349498
+23349500
+23349501
+23350621
+23350627
+23350730
+23350733
+23350785
+23350797
+23350883
+23350926
+23350945
+23350972
+23350989
+23351040
+23351072
+23351082
+23351096
+23351139
+23351147
+23351169
+23351960
+23351961
+23351962
+23352141
+23352430
+23352465
+23352511
+23352650
+23352748
+23352834
+23352909
+23352910
+23352911
+23352929
+23352980
+23352986
+23353026
+23353027
+23353053
+23353058
+23353081
+23353626
+23353658
+23353659
+23353698
+23353699
+23353733
+23353741
+23353743
+23353805
+23353807
+23353815
+23353816
+23353821
+23353901
+23354070
+23354072
+23354151
+23354391
+23354457
+23354532
+23354536
+23354542
+23354727
+23354728
+23354755
+23355085
+23355141
+23355192
+23355287
+23355456
+23355467
+23355488
+23355489
+23355493
+23355616
+23356207
+23356740
+23356791
+23356859
+23356867
+23356907
+23356946
+23356964
+23356985
+23356987
+23357308
+23357311
+23357312
+23357335
+23357361
+23357362
+23357434
+23357565
+23357626
+23357627
+23357628
+23357629
+23357630
+23357633
+23357976
+23358191
+23358195
+23358236
+23358249
+23358258
+23358500
+23358572
+23359121
+23359135
+23359435
+23359475
+23359520
+23359538
+23359555
+23359587
+23359599
+23360082
+23360118
+23360140
+23360142
+23360180
+23360211
+23360230
+23360232
+23360295
+23360333
+23360361
+23360392
+23360412
+23360443
+23360452
+23360475
+23360513
+23360545
+23360548
+23360549
+23360619
+23360912
+23361062
+23361101
+23361383
+23361398
+23361404
+23361460
+23361517
+23361586
+23361587
+23361846
+23361914
+23362105
+23362135
+23362224
+23362239
+23362240
+23362253
+23362262
+23362923
+23362940
+23362942
+23362960
+23362982
+23363072
+23363299
+23363335
+23363377
+23363397
+23363407
+23363425
+23363574
+23363575
+23363576
+23363577
+23364048
+23364509
+23364612
+23364615
+23364619
+23364814
+23364815
+23364884
+23364886
+23364935
+23365017
+23367873
+23368091
+23368280
+23368510
+23368705
+23368735
+23368753
+23368777
+23368884
+23368902
+23368996
+23369033
+23369206
+23369343
+23369344
+23369537
+23369791
+23369833
+23369933
+23370006
+23370180
+23370306
+23370776
+23370778
+23370795
+23371032
+23371055
+23371303
+23371451
+23371488
+23371489
+23371548
+23371760
+23371763
+23371788
+23371801
+23371805
+23371965
+23373428
+23373444
+23373463
+23373513
+23373530
+23373544
+23373590
+23373613
+23373648
+23373677
+23373696
+23373701
+23373704
+23373724
+23373772
+23373819
+23373869
+23373965
+23374098
+23374864
+23374865
+23374868
+23374869
+23374871
+23374872
+23374873
+23375004
+23375049
+23375228
+23375260
+23375851
+23376007
+23376090
+23376097
+23376110
+23376119
+23376162
+23376242
+23376245
+23376249
+23376353
+23376354
+23376355
+23376356
+23376408
+23376412
+23376437
+23376439
+23376477
+23376546
+23376608
+23376609
+23376610
+23376696
+23376697
+23376712
+23376779
+23376780
+23376802
+23376817
+23376823
+23376975
+23376997
+23377024
+23377100
+23377115
+23377609
+23377617
+23378200
+23378600
+23378608
+23378626
+23378627
+23378820
+23379346
+23379353
+23379362
+23379369
+23379514
+23379686
+23379723
+23379784
+23379795
+23379962
+23380082
+23380243
+23380305
+23380438
+23380477
+23380520
+23380568
+23380916
+23380917
+23381681
+23381727
+23381882
+23381904
+23381905
+23381936
+23381951
+23381968
+23381974
+23382013
+23382105
+23382380
+23382448
+23382458
+23382537
+23383423
+23383594
+23383648
+23383710
+23383723
+23383744
+23383746
+23383750
+23383871
+23384042
+23384309
+23384316
+23384363
+23384387
+23384446
+23384448
+23384967
+23384996
+23384997
+23385032
+23385211
+23385214
+23385325
+23385875
+23386029
+23386058
+23386250
+23386251
+23386368
+23386390
+23386468
+23386597
+23386599
+23386600
+23386616
+23386702
+23386704
+23386779
+23386780
+23387288
+23387306
+23387425
+23387554
+23387796
+23387851
+23387865
+23387901
+23388072
+23388095
+23388705
+23389039
+23389045
+23389090
+23389091
+23389324
+23389625
+23389738
+23389739
+23389756
+23389830
+23389852
+23389862
+23389878
+23389956
+23389991
+23390132
+23390932
+23391096
+23391133
+23391162
+23391207
+23391211
+23391212
+23391254
+23391273
+23391274
+23391280
+23391336
+23391387
+23391389
+23391441
+23391442
+23391443
+23391444
+23391484
+23391485
+23391596
+23391598
+23391631
+23391632
+23391637
+23392120
+23392568
+23392606
+23392755
+23392757
+23393127
+23393163
+23393209
+23393210
+23393213
+23393216
+23393217
+23393218
+23393219
+23393220
+23394218
+23394284
+23394286
+23394309
+23394318
+23394386
+23394392
+23394393
+23394394
+23394432
+23394469
+23394480
+23394542
+23394550
+23394553
+23394555
+23394608
+23394611
+23394701
+23395001
+23395156
+23395165
+23395169
+23395171
+23395172
+23395259
+23395269
+23395652
+23395656
+23395663
+23395665
+23395668
+23395669
+23395689
+23395695
+23395696
+23395717
+23395719
+23395783
+23395804
+23395821
+23395826
+23395914
+23395957
+23395967
+23395981
+23396041
+23396053
+23396094
+23396116
+23396138
+23396185
+23396206
+23396223
+23396400
+23396441
+23396442
+23396488
+23397032
+23397049
+23397584
+23398051
+23398145
+23398173
+23398189
+23398290
+23398356
+23399323
+23399444
+23399639
+23399641
+23399931
+23400048
+23400254
+23400262
+23400270
+23400748
+23400750
+23400782
+23400795
+23400796
+23400848
+23400888
+23400925
+23400943
+23401039
+23401066
+23401084
+23401106
+23401139
+23401140
+23401165
+23401173
+23401211
+23401217
+23401228
+23401244
+23401262
+23401280
+23401281
+23401291
+23401298
+23401303
+23401305
+23401323
+23401324
+23401355
+23401470
+23401472
+23401474
+23401602
+23402211
+23402270
+23402341
+23402364
+23402423
+23402546
+23402549
+23402636
+23402638
+23402647
+23402652
+23402729
+23402735
+23402788
+23402841
+23402846
+23402847
+23402855
+23402859
+23402860
+23402861
+23402862
+23402880
+23402938
+23402971
+23402972
+23403012
+23403014
+23403016
+23403055
+23403058
+23403080
+23403092
+23403184
+23403203
+23403395
+23403537
+23403904
+23404062
+23404198
+23404305
+23404316
+23404443
+23404458
+23404504
+23404505
+23404509
+23404739
+23404750
+23405943
+23406166
+23406277
+23406348
+23406429
+23406460
+23406469
+23406949
+23406955
+23406958
+23407410
+23407452
+23407741
+23407781
+23407893
+23408116
+23408270
+23408434
+23408556
+23408601
+23408642
+23408697
+23408851
+23408858
+23409716
+23409719
+23409765
+23409810
+23409840
+23409842
+23409864
+23409871
+23409925
+23409936
+23409951
+23409952
+23409959
+23410005
+23410038
+23410078
+23410094
+23410105
+23410125
+23410152
+23410155
+23410163
+23410164
+23410166
+23410167
+23410168
+23410169
+23410170
+23410171
+23410172
+23410206
+23410634
+23410745
+23410886
+23411075
+23411076
+23411079
+23411082
+23411168
+23411173
+23411175
+23411177
+23411178
+23411181
+23411182
+23411183
+23411184
+23411185
+23411189
+23411191
+23411192
+23411194
+23411195
+23411199
+23411201
+23411202
+23411204
+23411205
+23411206
+23411208
+23411210
+23411211
+23411212
+23411213
+23411216
+23411217
+23411219
+23411220
+23411223
+23411230
+23411231
+23411232
+23411235
+23411236
+23411238
+23411239
+23411240
+23411241
+23411245
+23411248
+23411250
+23411251
+23411252
+23411253
+23411255
+23411257
+23411259
+23411260
+23411263
+23411265
+23411266
+23411268
+23411269
+23411270
+23411271
+23411272
+23411275
+23411280
+23411281
+23411283
+23411284
+23411286
+23411287
+23411288
+23411289
+23411290
+23411293
+23411294
+23411297
+23411300
+23411303
+23411305
+23411306
+23411307
+23411311
+23411312
+23411314
+23411315
+23411317
+23411318
+23411320
+23411323
+23411327
+23411330
+23411334
+23411335
+23411336
+23411340
+23411342
+23411344
+23411351
+23411352
+23411507
+23412078
+23412112
+23412114
+23412396
+23412751
+23412841
+23412922
+23412992
+23413033
+23413101
+23413803
+23413833
+23414252
+23414340
+23414366
+23414433
+23414527
+23414722
+23414800
+23414802
+23414805
+23414807
+23414808
+23414839
+23414841
+23414844
+23414845
+23415704
+23415714
+23415833
+23415893
+23415902
+23415903
+23416001
+23416011
+23416070
+23416115
+23416131
+23416143
+23416173
+23416178
+23416189
+23416191
+23416192
+23416199
+23416229
+23416262
+23416264
+23416326
+23416409
+23416410
+23416413
+23416650
+23416799
+23416847
+23416930
+23417420
+23417514
+23417717
+23417745
+23417790
+23417870
+23417974
+23418006
+23418011
+23418017
+23418045
+23418059
+23418068
+23418081
+23418087
+23418125
+23418165
+23418168
+23418362
+23418369
+23418674
+23418719
+23418750
+23418783
+23418815
+23418859
+23418880
+23418956
+23418960
+23419007
+23419139
+23419143
+23419237
+23419390
+23419593
+23419638
+23419685
+23419776
+23419783
+23419813
+23419814
+23419950
+23420115
+23420214
+23420400
+23420471
+23420697
+23420700
+23420703
+23420770
+23421331
+23421517
+23421585
+23421616
+23421617
+23421620
+23421648
+23421649
+23421650
+23421714
+23421717
+23421737
+23421743
+23421757
+23421758
+23421779
+23421798
+23421850
+23421877
+23421879
+23421930
+23422033
+23422034
+23422035
+23422073
+23422225
+23422226
+23422227
+23422263
+23422298
+23422733
+23422745
+23422872
+23423243
+23423353
+23423468
+23423570
+23423695
+23423710
+23423711
+23423942
+23423972
+23424012
+23424028
+23424087
+23424203
+23424206
+23424207
+23424208
+23424212
+23424213
+23424217
+23425034
+23425062
+23425125
+23425199
+23425268
+23425273
+23425274
+23425314
+23425339
+23425601
+23425604
+23425605
+23425966
+23425969
+23425970
+23426609
+23426718
+23426858
+23426954
+23426982
+23427007
+23427017
+23427056
+23427063
+23427064
+23427074
+23427076
+23427088
+23427137
+23427148
+23427190
+23427194
+23427338
+23427810
+23427825
+23427850
+23427901
+23428094
+23428109
+23428155
+23428163
+23428212
+23428325
+23428347
+23428368
+23428403
+23428407
+23428645
+23428841
+23428959
+23428960
+23428981
+23429043
+23429184
+23429199
+23429231
+23429282
+23429713
+23429765
+23429889
+23429907
+23429911
+23429912
+23430000
+23430368
+23430408
+23430410
+23430741
+23430747
+23430761
+23432004
+23432007
+23432009
+23432058
+23432061
+23432064
+23432095
+23432124
+23432134
+23432151
+23432203
+23432217
+23432335
+23432336
+23432420
+23432465
+23432579
+23432580
+23432581
+23432582
+23432586
+23432587
+23432590
+23432662
+23432708
+23432912
+23433812
+23434031
+23434193
+23434223
+23434224
+23434226
+23434227
+23434228
+23434322
+23434370
+23434417
+23434422
+23434445
+23434491
+23434641
+23434648
+23434669
+23434829
+23434831
+23434832
+23434929
+23434931
+23434934
+23435179
+23435263
+23435354
+23435356
+23435358
+23435367
+23435428
+23435541
+23435614
+23435615
+23435649
+23435689
+23435910
+23435913
+23435916
+23435942
+23435948
+23436129
+23436259
+23436261
+23436266
+23436293
+23436544
+23436555
+23436709
+23436742
+23436791
+23437766
+23437843
+23437926
+23437977
+23438106
+23438322
+23438375
+23438486
+23438500
+23438503
+23438860
+23438888
+23439033
+23439078
+23439131
+23439223
+23439240
+23439241
+23439561
+23439649
+23439660
+23440054
+23440071
+23440404
+23440664
+23440743
+23440956
+23440959
+23441102
+23441686
+23441753
+23441816
+23441829
+23441843
+23441878
+23441976
+23441977
+23442005
+23442025
+23442151
+23442197
+23442213
+23442788
+23443025
+23443165
+23443405
+23443408
+23443628
+23443757
+23443908
+23443957
+23444144
+23444256
+23444274
+23444284
+23444285
+23444335
+23444386
+23444387
+23444389
+23444428
+23444429
+23444773
+23444782
+23444783
+23444785
+23444833
+23445125
+23445175
+23445189
+23445362
+23445497
+23446230
+23446276
+23447132
+23447427
+23447531
+23447538
+23448196
+23448197
+23448202
+23448247
+23448384
+23448580
+23448620
+23448682
+23448860
+23448861
+23449195
+23449197
+23449198
+23449199
+23449201
+23449204
+23449205
+23449220
+23449223
+23449308
+23449618
+23449888
+23449981
+23450151
+23450164
+23450212
+23450220
+23450304
+23450752
+23450777
+23450806
+23450829
+23451707
+23451758
+23451797
+23451803
+23451823
+23451983
+23452037
+23452042
+23452060
+23452083
+23452147
+23452185
+23452205
+23452219
+23452233
+23452237
+23452243
+23452254
+23452855
+23452857
+23453039
+23453067
+23453068
+23453071
+23453073
+23453303
+23453308
+23453831
+23453986
+23454011
+23454012
+23454052
+23454054
+23454090
+23454133
+23454148
+23454208
+23454297
+23454299
+23454308
+23454309
+23454310
+23454345
+23454513
+23454514
+23454526
+23454529
+23454530
+23454532
+23454648
+23454655
+23454661
+23454672
+23454741
+23454829
+23454831
+23454832
+23454833
+23455056
+23455057
+23455059
+23455229
+23455312
+23455313
+23455314
+23455373
+23455513
+23455592
+23455593
+23455898
+23455995
+23456038
+23456097
+23456248
+23456363
+23456681
+23456735
+23456814
+23456816
+23456892
+23456978
+23457022
+23457058
+23457114
+23457119
+23457123
+23458167
+23458385
+23458420
+23458422
+23458495
+23458573
+23458575
+23458614
+23458617
+23458621
+23458727
+23458730
+23458894
+23458895
+23458897
+23458950
+23458966
+23459146
+23459147
+23459233
+23459473
+23460265
+23460347
+23460383
+23460508
+23460509
+23460644
+23461617
+23461628
+23461650
+23461763
+23461784
+23461801
+23461821
+23461825
+23461841
+23461860
+23461969
+23462104
+23462105
+23462193
+23462194
+23462212
+23462213
+23462281
+23462293
+23462308
+23462379
+23462380
+23462505
+23462526
+23462583
+23462665
+23462666
+23462814
+23463333
+23463334
+23463336
+23463352
+23463609
+23463634
+23463664
+23463732
+23463898
+23464357
+23464520
+23464618
+23464629
+23464667
+23464739
+23464760
+23464789
+23464805
+23464810
+23464829
+23464859
+23464873
+23464990
+23465048
+23465066
+23465072
+23465594
+23465612
+23465865
+23466228
+23466231
+23466235
+23466444
+23466459
+23466460
+23466461
+23466488
+23466500
+23466501
+23466526
+23466565
+23466606
+23466742
+23466874
+23467017
+23467018
+23468099
+23468100
+23468173
+23468310
+23468386
+23468408
+23468426
+23469688
+23469760
+23469781
+23469923
+23469924
+23469927
+23470034
+23470072
+23470076
+23470079
+23470080
+23470104
+23470105
+23470152
+23470166
+23470181
+23470280
+23470359
+23470418
+23470629
+23470692
+23470867
+23470922
+23471029
+23471156
+23471218
+23471440
+23471488
+23471504
+23471539
+23471561
+23471710
+23471769
+23471850
+23471871
+23471969
+23471970
+23472643
+23472709
+23472738
+23472745
+23472803
+23472840
+23472886
+23473024
+23473027
+23473028
+23473030
+23473037
+23473053
+23473066
+23473444
+23473535
+23473568
+23473643
+23473664
+23473679
+23473681
+23473682
+23473801
+23473802
+23473804
+23474013
+23474014
+23474032
+23474169
+23474217
+23474218
+23474267
+23474268
+23474319
+23474320
+23474321
+23474323
+23474356
+23474357
+23474381
+23474382
+23474386
+23474389
+23474441
+23474547
+23474588
+23474645
+23474688
+23474807
+23474845
+23474897
+23474899
+23474903
+23474904
+23474905
+23474955
+23474972
+23475307
+23475368
+23475370
+23475432
+23475433
+23475784
+23475901
+23476936
+23477344
+23477346
+23477372
+23477419
+23477451
+23477455
+23477482
+23477523
+23477619
+23477623
+23477624
+23478338
+23478485
+23478800
+23478802
+23478908
+23479059
+23479079
+23479193
+23479194
+23479318
+23479335
+23479387
+23479388
+23479389
+23479390
+23479392
+23479407
+23479455
+23479726
+23479738
+23480196
+23480235
+23480279
+23480348
+23480446
+23480532
+23480597
+23480643
+23480697
+23480783
+23480798
+23480848
+23480874
+23481139
+23481176
+23481236
+23481256
+23481281
+23481321
+23481590
+23481595
+23481643
+23481644
+23481645
+23481650
+23481651
+23481676
+23481677
+23481678
+23482500
+23483083
+23483201
+23483327
+23483707
+23483712
+23484490
+23484537
+23484546
+23484593
+23484622
+23484633
+23484851
+23484974
+23485065
+23485151
+23485417
+23485440
+23485441
+23485450
+23485559
+23485613
+23485615
+23485616
+23485618
+23485651
+23485652
+23485991
+23486187
+23486447
+23486479
+23486538
+23486542
+23486635
+23487179
+23487486
+23488728
+23488739
+23488748
+23488987
+23489135
+23489301
+23489438
+23489623
+23489624
+23489629
+23489976
+23490078
+23491523
+23491602
+23492810
+23493317
+23493374
+23493449
+23493569
+23493571
+23493576
+23494106
+23494187
+23494232
+23494233
+23494732
+23494763
+23494802
+23494810
+23494831
+23494834
+23494855
+23494861
+23494904
+23494944
+23495001
+23495151
+23495155
+23495161
+23495163
+23495190
+23495205
+23495719
+23495769
+23495771
+23495825
+23495832
+23495911
+23495918
+23496305
+23496349
+23496412
+23496772
+23497227
+23497860
+23497861
+23497862
+23497864
+23497865
+23497866
+23497867
+23497868
+23497870
+23497871
+23497873
+23497875
+23497876
+23497877
+23497878
+23497879
+23497880
+23497881
+23497882
+23497885
+23497887
+23497888
+23497892
+23497894
+23497895
+23497896
+23497898
+23497901
+23497902
+23497905
+23497907
+23497908
+23498899
+23499236
+23499237
+23499423
+23499614
+23499661
+23499663
+23499664
+23499716
+23499717
+23499718
+23499751
+23499758
+23499778
+23499823
+23499856
+23499857
+23499925
+23499945
+23500040
+23500042
+23500058
+23500061
+23500065
+23500115
+23500117
+23500334
+23500335
+23500411
+23500507
+23500537
+23500545
+23500546
+23500547
+23500550
+23500610
+23500659
+23500660
+23500768
+23500769
+23500770
+23500772
+23500775
+23500776
+23500777
+23500778
+23501108
+23501109
+23501111
+23501115
+23503472
+23503588
+23503654
+23503684
+23503701
+23503702
+23503923
+23503927
+23504247
+23504356
+23504441
+23504645
+23504923
+23505043
+23505091
+23505146
+23505344
+23505396
+23506042
+23506052
+23506073
+23506138
+23506209
+23506253
+23506316
+23506497
+23506624
+23506741
+23506842
+23506857
+23507565
+23507573
+23508106
+23508304
+23508556
+23508887
+23508961
+23508963
+23509039
+23509853
+23509904
+23509929
+23509956
+23510192
+23510389
+23510441
+23510462
+23510479
+23511016
+23511018
+23511022
+23511061
+23511088
+23511125
+23511311
+23511348
+23511383
+23511610
+23511711
+23511715
+23511718
+23511783
+23511785
+23511786
+23511973
+23512126
+23512181
+23512337
+23512409
+23512438
+23512501
+23512535
+23512537
+23512538
+23512732
+23512754
+23512787
+23512804
+23512824
+23512927
+23514247
+23514378
+23514442
+23514447
+23514537
+23514599
+23514620
+23514637
+23514730
+23515282
+23515287
+23515497
+23515582
+23515934
+23515940
+23515941
+23516024
+23516041
+23517008
+23517010
+23517028
+23517076
+23517093
+23517126
+23517145
+23517313
+23517340
+23517379
+23517381
+23517437
+23517470
+23517474
+23517479
+23517541
+23517546
+23517558
+23517565
+23517621
+23517636
+23517726
+23517728
+23517729
+23517784
+23518040
+23518155
+23518278
+23518321
+23518472
+23518599
+23518662
+23518857
+23518924
+23519059
+23519110
+23519153
+23519365
+23519392
+23519980
+23520074
+23520132
+23520133
+23520173
+23521014
+23521043
+23521080
+23521110
+23521318
+23521360
+23521433
+23521567
+23522182
+23522564
+23522833
+23522834
+23523142
+23523257
+23523258
+23523372
+23523542
+23523544
+23523545
+23523546
+23523557
+23523606
+23523664
+23523665
+23523780
+23523781
+23523906
+23523949
+23523991
+23524067
+23524112
+23524136
+23524160
+23524188
+23524189
+23524195
+23524228
+23524238
+23524253
+23524254
+23524255
+23524305
+23524567
+23524878
+23524881
+23524983
+23525092
+23525110
+23525112
+23525118
+23525158
+23525167
+23525215
+23525217
+23525221
+23525298
+23525330
+23525463
+23525662
+23525674
+23525786
+23525902
+23526144
+23526157
+23526231
+23526452
+23526571
+23526663
+23526664
+23526674
+23526725
+23526745
+23526814
+23526919
+23527317
+23527551
+23527585
+23527615
+23527619
+23527691
+23528045
+23528109
+23528251
+23528252
+23528296
+23528298
+23528300
+23528363
+23528390
+23528611
+23529548
+23529571
+23529671
+23529793
+23529824
+23529825
+23529829
+23529894
+23529898
+23529905
+23530003
+23530006
+23530011
+23530012
+23530018
+23530019
+23530020
+23530031
+23530033
+23530036
+23530049
+23530552
+23530596
+23530617
+23530626
+23530654
+23530668
+23530747
+23530765
+23530926
+23530959
+23531107
+23531119
+23531154
+23531160
+23531213
+23531217
+23531533
+23531724
+23531865
+23532258
+23532446
+23532634
+23532854
+23532897
+23532940
+23533220
+23534403
+23534411
+23534412
+23534413
+23534440
+23534442
+23534695
+23534827
+23535167
+23535185
+23535186
+23535288
+23535320
+23535321
+23535326
+23535327
+23535334
+23535337
+23535338
+23535348
+23535349
+23535351
+23535360
+23535361
+23535363
+23535364
+23535393
+23535394
+23535516
+23535821
+23535870
+23535915
+23535934
+23536264
+23536271
+23536315
+23536517
+23536518
+23536519
+23536521
+23536582
+23536584
+23536728
+23536974
+23537005
+23537094
+23537133
+23537160
+23537315
+23537321
+23537339
+23537427
+23537575
+23537582
+23537597
+23537598
+23537599
+23537661
+23537700
+23537747
+23537748
+23537889
+23537897
+23537942
+23538319
+23538397
+23538839
+23538843
+23538868
+23538871
+23538998
+23539089
+23539147
+23539351
+23539511
+23539547
+23539641
+23540585
+23540587
+23540609
+23540646
+23540695
+23540698
+23540713
+23540737
+23540754
+23540796
+23540838
+23540906
+23541086
+23541125
+23541399
+23541436
+23541472
+23541514
+23541631
+23541637
+23541646
+23541670
+23541767
+23541768
+23541929
+23541948
+23541949
+23541950
+23542008
+23542039
+23542041
+23542126
+23542239
+23542343
+23542440
+23542441
+23542494
+23542495
+23542513
+23542559
+23542608
+23542652
+23542720
+23542730
+23542815
+23542816
+23542817
+23542819
+23543009
+23543013
+23543014
+23543321
+23543413
+23543460
+23543630
+23543631
+23543632
+23543737
+23543864
+23544432
+23544459
+23544461
+23544463
+23544465
+23544613
+23544615
+23544667
+23544698
+23544715
+23544771
+23545002
+23545108
+23545161
+23545348
+23545456
+23545458
+23545568
+23545706
+23545721
+23545806
+23545846
+23545999
+23546003
+23546004
+23546010
+23546395
+23546397
+23546398
+23546525
+23546600
+23546601
+23546605
+23546867
+23546879
+23547584
+23547652
+23547706
+23547757
+23547776
+23547786
+23548020
+23548025
+23548027
+23548029
+23548055
+23548149
+23548165
+23548584
+23548704
+23548896
+23548897
+23548974
+23549272
+23549285
+23549672
+23549673
+23549985
+23550028
+23550066
+23550656
+23550722
+23550937
+23550966
+23551255
+23551295
+23551329
+23551535
+23551856
+23552101
+23552260
+23552263
+23552264
+23552267
+23552268
+23552269
+23552398
+23552482
+23552830
+23552831
+23552843
+23552852
+23552899
+23552908
+23553331
+23553357
+23553379
+23553497
+23553560
+23553595
+23553632
+23553655
+23553677
+23553679
+23553708
+23553811
+23553887
+23553905
+23553944
+23553961
+23554029
+23554215
+23554335
+23554428
+23554451
+23554463
+23555191
+23556334
+23556338
+23556445
+23556446
+23556447
+23556448
+23556453
+23556998
+23557027
+23557487
+23557601
+23557687
+23557688
+23557832
+23557843
+23557931
+23557933
+23558232
+23558233
+23558236
+23558237
+23558295
+23558297
+23558446
+23558646
+23558682
+23558686
+23558747
+23558950
+23559221
+23559222
+23559258
+23559274
+23559276
+23559436
+23559516
+23559517
+23560391
+23560438
+23560442
+23560447
+23560504
+23560557
+23560571
+23560844
+23560989
+23561071
+23561072
+23561075
+23561076
+23561079
+23561080
+23561081
+23561082
+23561085
+23561089
+23561091
+23561092
+23561093
+23561094
+23561095
+23561096
+23561097
+23561098
+23561100
+23561102
+23561103
+23561106
+23561109
+23561113
+23561114
+23561115
+23561117
+23561118
+23561119
+23561120
+23561121
+23561123
+23561124
+23561125
+23561127
+23561128
+23561130
+23561131
+23561134
+23561135
+23561136
+23561137
+23561138
+23561139
+23561140
+23561141
+23561142
+23561143
+23561146
+23561147
+23561148
+23561150
+23561152
+23561154
+23561155
+23561156
+23561157
+23561158
+23561160
+23561161
+23561163
+23561165
+23561166
+23561169
+23561170
+23561171
+23561172
+23561174
+23561175
+23561176
+23561177
+23561178
+23561179
+23561181
+23561182
+23561183
+23561184
+23561185
+23561187
+23561188
+23561189
+23561190
+23561191
+23561192
+23561194
+23561195
+23561196
+23561197
+23561198
+23561199
+23561203
+23561204
+23561208
+23561209
+23561213
+23561219
+23561220
+23561222
+23561223
+23562056
+23562060
+23562063
+23562072
+23562073
+23562074
+23562075
+23562076
+23562240
+23562245
+23562270
+23562324
+23562365
+23562369
+23562376
+23562496
+23562534
+23562597
+23562633
+23562634
+23562636
+23562706
+23562707
+23562765
+23562910
+23562926
+23562927
+23562995
+23563049
+23563055
+23563178
+23563205
+23563248
+23563271
+23563356
+23563672
+23563730
+23563922
+23564211
+23564329
+23564566
+23564596
+23564642
+23564643
+23564645
+23564646
+23564882
+23564914
+23564917
+23564918
+23564921
+23565060
+23565325
+23565574
+23565585
+23565607
+23565749
+23565753
+23565754
+23565776
+23565822
+23566174
+23566269
+23566299
+23566514
+23566515
+23566520
+23566884
+23566899
+23567022
+23567030
+23567032
+23567034
+23567035
+23567037
+23567038
+23567039
+23567040
+23567041
+23567043
+23567045
+23567046
+23567242
+23567245
+23567269
+23567293
+23567314
+23567316
+23567318
+23567486
+23567861
+23567948
+23567953
+23567954
+23567956
+23567959
+23567963
+23567999
+23568274
+23568429
+23568434
+23568452
+23568455
+23568508
+23568512
+23568554
+23568566
+23568578
+23568579
+23568627
+23569176
+23570266
+23570269
+23570328
+23570394
+23570451
+23570467
+23570469
+23570470
+23570500
+23570514
+23570533
+23570552
+23570561
+23570572
+23570609
+23570612
+23570689
+23570790
+23570839
+23570840
+23570906
+23570913
+23570914
+23570992
+23570993
+23570998
+23571308
+23571414
+23571415
+23571493
+23571495
+23571753
+23571772
+23572241
+23572389
+23572390
+23572392
+23572394
+23572405
+23572407
+23572408
+23572409
+23572424
+23572520
+23573957
+23573970
+23573971
+23573990
+23574008
+23574014
+23574049
+23574259
+23574272
+23574277
+23574308
+23574310
+23574435
+23574519
+23574534
+23574541
+23574807
+23574984
+23575745
+23575765
+23575800
+23576111
+23576174
+23576175
+23576177
+23576194
+23576205
+23576242
+23576269
+23576286
+23576297
+23576306
+23576341
+23576355
+23576378
+23577042
+23577589
+23577599
+23577701
+23577749
+23577871
+23578300
+23578392
+23578583
+23578584
+23578607
+23578610
+23578611
+23578612
+23578614
+23578617
+23578618
+23578619
+23578623
+23578625
+23578627
+23578630
+23578631
+23578632
+23578633
+23578634
+23578635
+23578636
+23578641
+23578642
+23578643
+23578644
+23578647
+23578649
+23578650
+23578651
+23578652
+23578657
+23578688
+23578689
+23578690
+23578763
+23578846
+23578871
+23578968
+23579044
+23579182
+23579333
+23579427
+23579486
+23579487
+23579962
+23580001
+23580027
+23580169
+23580257
+23580375
+23580402
+23580404
+23580421
+23580611
+23580652
+23581295
+23581424
+23581492
+23581964
+23581965
+23581993
+23582019
+23582235
+23582327
+23582330
+23582408
+23582779
+23583009
+23583036
+23583168
+23583169
+23583203
+23583257
+23583258
+23583436
+23583437
+23583454
+23583456
+23583486
+23583493
+23583495
+23583513
+23583556
+23583641
+23583735
+23583736
+23583765
+23583775
+23583787
+23583802
+23583804
+23583882
+23583902
+23583903
+23583910
+23583911
+23583928
+23583929
+23584090
+23584277
+23584282
+23584353
+23584356
+23584358
+23584418
+23584426
+23584427
+23584434
+23584484
+23584530
+23584541
+23584543
+23584545
+23584556
+23584636
+23584857
+23584886
+23584948
+23585019
+23585058
+23585235
+23585274
+23585311
+23585358
+23585380
+23585383
+23585551
+23585770
+23585920
+23586436
+23586441
+23586470
+23586519
+23586638
+23586812
+23586839
+23586848
+23586849
+23586868
+23586925
+23586938
+23586970
+23587048
+23587422
+23587423
+23587425
+23587426
+23587503
+23587526
+23587645
+23587647
+23587648
+23587660
+23587668
+23587849
+23588093
+23588094
+23588096
+23588252
+23588312
+23588316
+23588390
+23588477
+23588558
+23588560
+23588562
+23588563
+23588584
+23588585
+23588681
+23588682
+23588796
+23588997
+23589223
+23589302
+23589329
+23589365
+23589404
+23589408
+23589462
+23589476
+23589499
+23589501
+23589515
+23589624
+23590129
+23590189
+23590193
+23590386
+23590470
+23590471
+23590473
+23590478
+23590563
+23590572
+23590667
+23590689
+23590882
+23590892
+23591044
+23591111
+23591590
+23591660
+23591661
+23591701
+23591777
+23591995
+23592429
+23592516
+23592568
+23592745
+23592747
+23592779
+23592780
+23592781
+23592839
+23592846
+23593923
+23593960
+23594027
+23594047
+23594105
+23594296
+23594299
+23594310
+23594396
+23594687
+23594789
+23595055
+23595057
+23595058
+23595419
+23595510
+23595554
+23595692
+23595911
+23596084
+23596091
+23596124
+23596260
+23596261
+23596325
+23596327
+23596359
+23596972
+23597018
+23597047
+23597051
+23597071
+23597098
+23597099
+23597133
+23597443
+23597445
+23597450
+23597490
+23597506
+23597507
+23597510
+23597511
+23597790
+23597793
+23598043
+23598046
+23598363
+23598364
+23598368
+23598400
+23598442
+23598455
+23598462
+23598904
+23599006
+23599431
+23599433
+23600432
+23600486
+23600612
+23600626
+23600646
+23600648
+23600656
+23600708
+23600717
+23600735
+23600748
+23600754
+23600800
+23600807
+23600865
+23600887
+23600914
+23600925
+23600958
+23601371
+23601382
+23601383
+23601386
+23601387
+23601388
+23601389
+23601390
+23601391
+23601392
+23601393
+23601395
+23601396
+23601397
+23601403
+23601407
+23601409
+23601410
+23601412
+23601413
+23601605
+23601649
+23601709
+23601710
+23601711
+23601753
+23602400
+23602442
+23602515
+23602516
+23602652
+23602732
+23602733
+23602864
+23602891
+23602903
+23602984
+23602985
+23602986
+23602989
+23602997
+23603023
+23603044
+23603045
+23603053
+23603058
+23603059
+23603103
+23603112
+23603145
+23603154
+23603191
+23603192
+23603193
+23603195
+23603200
+23603293
+23603339
+23603380
+23603381
+23603385
+23603477
+23603478
+23603554
+23603635
+23603636
+23603907
+23603918
+23604140
+23604205
+23604390
+23604582
+23604592
+23604717
+23604719
+23604720
+23604721
+23604722
+23604723
+23604819
+23605046
+23605048
+23605050
+23605694
+23605695
+23605905
+23606243
+23606264
+23606278
+23606301
+23606318
+23606334
+23606349
+23606423
+23606438
+23606457
+23606463
+23606503
+23606510
+23606523
+23606533
+23606568
+23606629
+23607484
+23607523
+23607568
+23607578
+23607646
+23607657
+23607669
+23607809
+23607866
+23607869
+23608109
+23608129
+23608189
+23608239
+23608240
+23608241
+23608613
+23608699
+23608700
+23608737
+23608764
+23608896
+23609070
+23609108
+23609109
+23609128
+23609145
+23609238
+23609438
+23609444
+23609445
+23609452
+23609606
+23609769
+23609770
+23609782
+23609940
+23609944
+23609949
+23609963
+23610045
+23610057
+23610077
+23610086
+23610123
+23610558
+23611027
+23611039
+23611120
+23611124
+23611338
+23611475
+23611507
+23611508
+23611538
+23611626
+23611646
+23611733
+23611809
+23612001
+23612242
+23612318
+23612369
+23612419
+23612421
+23612422
+23612423
+23612487
+23612708
+23612709
+23612710
+23612720
+23612967
+23612980
+23613012
+23613080
+23613150
+23613312
+23613425
+23613450
+23613484
+23614368
+23614379
+23614492
+23614566
+23614571
+23614635
+23614643
+23614652
+23614663
+23614728
+23614730
+23614815
+23614827
+23614831
+23614896
+23614904
+23615073
+23615074
+23615124
+23615471
+23615905
+23616190
+23616238
+23616352
+23616376
+23616387
+23616438
+23617226
+23617279
+23617430
+23617439
+23617462
+23617539
+23617615
+23617725
+23617753
+23617807
+23617851
+23618528
+23618624
+23618899
+23618900
+23618901
+23618921
+23619006
+23619018
+23619019
+23619020
+23619028
+23619386
+23619527
+23619567
+23619611
+23619613
+23619817
+23620060
+23620162
+23620199
+23620200
+23620256
+23620266
+23620283
+23620303
+23620436
+23620478
+23620484
+23620487
+23620529
+23620539
+23621317
+23621358
+23621381
+23621493
+23621616
+23621647
+23621689
+23621768
+23621769
+23621813
+23621840
+23621857
+23623416
+23623417
+23623419
+23623491
+23623493
+23623552
+23623556
+23623743
+23623750
+23623751
+23623789
+23623790
+23623795
+23623796
+23623823
+23623838
+23623843
+23623867
+23624029
+23624183
+23624237
+23624240
+23624289
+23624326
+23624352
+23624358
+23624360
+23624376
+23624379
+23624380
+23624383
+23624389
+23624419
+23624422
+23624423
+23624706
+23624810
+23624811
+23624862
+23625160
+23625194
+23625272
+23625273
+23625455
+23625693
+23625731
+23625745
+23625750
+23625769
+23625779
+23625787
+23625792
+23625887
+23625905
+23625909
+23625912
+23625969
+23627254
+23627275
+23627282
+23627311
+23627352
+23627396
+23627414
+23627438
+23627443
+23627597
+23627605
+23627685
+23627717
+23627804
+23627806
+23627834
+23627902
+23628154
+23628332
+23628333
+23628455
+23628456
+23628481
+23628508
+23628509
+23628605
+23628621
+23628674
+23628762
+23628791
+23628829
+23628841
+23629055
+23629515
+23629516
+23629664
+23629675
+23629861
+23629923
+23630043
+23630137
+23631351
+23631427
+23631440
+23631463
+23631490
+23631493
+23631494
+23631498
+23631499
+23631553
+23631732
+23631927
+23632005
+23632006
+23632007
+23632032
+23632081
+23632082
+23632086
+23632099
+23632158
+23632304
+23632309
+23632310
+23632340
+23632448
+23633219
+23633521
+23633529
+23633532
+23633563
+23633618
+23633651
+23633677
+23634668
+23634786
+23634899
+23635005
+23635023
+23635097
+23635829
+23636302
+23636303
+23636446
+23636584
+23636886
+23637306
+23637347
+23637353
+23638621
+23638641
+23638658
+23638683
+23638960
+23638985
+23638991
+23639069
+23639075
+23639096
+23639188
+23639191
+23639192
+23639233
+23639246
+23639248
+23639249
+23639361
+23639363
+23639423
+23639430
+23639431
+23639437
+23639452
+23639537
+23639543
+23639545
+23639627
+23639652
+23639717
+23639738
+23639739
+23639741
+23639798
+23639867
+23639992
+23640034
+23640102
+23640282
+23640283
+23640471
+23640722
+23640863
+23640867
+23640872
+23640884
+23640962
+23641017
+23641685
+23641692
+23641693
+23641695
+23641701
+23641792
+23641955
+23642004
+23642029
+23642033
+23642089
+23642124
+23642262
+23642287
+23642965
+23643483
+23643528
+23643542
+23643664
+23643700
+23643725
+23643730
+23643737
+23643739
+23643744
+23643745
+23643748
+23643792
+23643808
+23643824
+23643828
+23643831
+23643837
+23643839
+23643851
+23643862
+23643883
+23643932
+23643933
+23644192
+23644195
+23644200
+23644201
+23644214
+23644256
+23644411
+23644525
+23644598
+23644652
+23644884
+23645151
+23645248
+23645249
+23645630
+23646355
+23646356
diff --git a/huner/ner_scripts/splits/cll.dev b/huner/ner_scripts/splits/cll.dev
new file mode 100644
index 0000000..5ce2d4b
--- /dev/null
+++ b/huner/ner_scripts/splits/cll.dev
@@ -0,0 +1,22 @@
+
+PMID-19635932
+PMID-19735263
+PMID-19813146
+PMID-19830690
+PMID-19875283
+PMID-19954115
+PMID-19968287
+PMID-20145299
+PMID-20187579
+PMID-20378933
+PMID-20510198
+PMID-20512470
+PMID-20546238
+PMID-20546244
+PMID-20655919
+PMID-21120479
+PMID-21187071
+PMID-21324313
+PMID-21385318
+PMID-21415268
+PMID-2154472
diff --git a/huner/ner_scripts/splits/cll.test b/huner/ner_scripts/splits/cll.test
new file mode 100644
index 0000000..8e60aa0
--- /dev/null
+++ b/huner/ner_scripts/splits/cll.test
@@ -0,0 +1,61 @@
+
+PMID-21556582
+PMID-21635216
+PMID-21896338
+PMID-21951809
+PMID-22134783
+PMID-22166062
+PMID-2284922
+PMID-2481593
+PMID-2502522
+PMID-2585941
+PMID-2819284
+PMID-2883656
+PMID-2924315
+PMID-3002298
+PMID-3182108
+PMID-3297308
+PMID-3839702
+PMID-3841037
+PMID-3876560
+PMID-3917311
+PMID-3930277
+PMID-511204
+PMID-6132476
+PMID-6210375
+PMID-6418813
+PMID-6604701
+PMID-6661740
+PMID-6821557
+PMID-6875516
+PMID-7122454
+PMID-7572991
+PMID-7614530
+PMID-7733922
+PMID-7815389
+PMID-7861622
+PMID-7929220
+PMID-8057447
+PMID-8062221
+PMID-8071372
+PMID-8097969
+PMID-8397593
+PMID-8428798
+PMID-8611478
+PMID-8656685
+PMID-8690298
+PMID-8759870
+PMID-8832573
+PMID-8845302
+PMID-8880099
+PMID-8912897
+PMID-9119746
+PMID-9168941
+PMID-9209447
+PMID-9472102
+PMID-9488691
+PMID-9508371
+PMID-9714552
+PMID-9716011
+PMID-9764578
+PMID-9765589
diff --git a/huner/ner_scripts/splits/cll.train b/huner/ner_scripts/splits/cll.train
new file mode 100644
index 0000000..44d804c
--- /dev/null
+++ b/huner/ner_scripts/splits/cll.train
@@ -0,0 +1,121 @@
+
+PMC-1413994
+PMC-1858713
+PMC-1880850
+PMC-1929068
+PMC-2094660
+PMC-2118273
+PMC-2199329
+PMC-2212536
+PMC-2292795
+PMC-2408657
+PMC-2603006
+PMC-2645429
+PMC-2661890
+PMC-2727490
+PMC-2787531
+PMC-2841583
+PMC-2843654
+PMC-2848976
+PMC-2852526
+PMC-2876068
+PMC-2929338
+PMC-2958529
+PMC-2960324
+PMC-2965212
+PMC-2965384
+PMC-2971155
+PMC-2994709
+PMC-3008728
+PMC-3018404
+PMC-3041769
+PMC-3066204
+PMC-3072406
+PMC-3073946
+PMC-3102737
+PMC-3122064
+PMC-3125305
+PMC-3134876
+PMC-3145754
+PMC-3189939
+PMC-3191362
+PMC-3221660
+PMC-3290594
+PMC-3338386
+PMC-3341393
+PMC-3344255
+PMC-3348545
+PMC-3355137
+PMC-3364240
+PMC-57796
+PMID-10075083
+PMID-10085764
+PMID-10319943
+PMID-10358898
+PMID-10415064
+PMID-10444620
+PMID-10589787
+PMID-10681431
+PMID-10850450
+PMID-10975824
+PMID-11156595
+PMID-11288755
+PMID-11292697
+PMID-11296949
+PMID-11316564
+PMID-11408162
+PMID-11474132
+PMID-11526488
+PMID-11848498
+PMID-11889121
+PMID-12063
+PMID-12511109
+PMID-12778082
+PMID-1327182
+PMID-1339008
+PMID-1379088
+PMID-14555710
+PMID-14667442
+PMID-14692828
+PMID-1480100
+PMID-15035637
+PMID-15234571
+PMID-1527085
+PMID-15325432
+PMID-15357834
+PMID-1540944
+PMID-15469235
+PMID-15528991
+PMID-15905643
+PMID-15927679
+PMID-16018784
+PMID-1612122
+PMID-16230379
+PMID-16309228
+PMID-1663674
+PMID-16741058
+PMID-16814113
+PMID-16856624
+PMID-16939684
+PMID-17077548
+PMID-17094458
+PMID-17094949
+PMID-17169214
+PMID-17207617
+PMID-17215249
+PMID-17249756
+PMID-17350117
+PMID-17506542
+PMID-17611019
+PMID-17618733
+PMID-17973905
+PMID-18299449
+PMID-18319436
+PMID-18374152
+PMID-18383865
+PMID-18398596
+PMID-1841703
+PMID-19165643
+PMID-19282189
+PMID-19360335
+PMID-1959168
diff --git a/huner/ner_scripts/splits/craft.dev b/huner/ner_scripts/splits/craft.dev
new file mode 100644
index 0000000..8ae3790
--- /dev/null
+++ b/huner/ner_scripts/splits/craft.dev
@@ -0,0 +1,7 @@
+15005800
+15917436
+15938754
+16109169
+14611657
+15040800
+15876356
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/craft.test b/huner/ner_scripts/splits/craft.test
new file mode 100644
index 0000000..113ec2a
--- /dev/null
+++ b/huner/ner_scripts/splits/craft.test
@@ -0,0 +1,20 @@
+16221973
+16110338
+15207008
+16255782
+15760270
+17194222
+16670015
+12585968
+17078885
+15314659
+17696610
+16700629
+15314655
+16121256
+15328533
+17425782
+15588329
+16579849
+17590087
+15550985
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/craft.train b/huner/ner_scripts/splits/craft.train
new file mode 100644
index 0000000..b3a6320
--- /dev/null
+++ b/huner/ner_scripts/splits/craft.train
@@ -0,0 +1,40 @@
+15836427
+11532192
+16504143
+17022820
+17002498
+16216087
+17244351
+16462940
+16362077
+16433929
+15630473
+12925238
+16504174
+11597317
+14723793
+16103912
+15819996
+15345036
+11897010
+17608565
+16121255
+15676071
+16279840
+17020410
+17083276
+12079497
+15061865
+15320950
+17447844
+16098226
+14737183
+15492776
+16539743
+16628246
+17069463
+14609438
+16507151
+16870721
+12546709
+15921521
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/deca.conll.dev b/huner/ner_scripts/splits/deca.conll.dev
new file mode 100644
index 0000000..1b88915
--- /dev/null
+++ b/huner/ner_scripts/splits/deca.conll.dev
@@ -0,0 +1,64 @@
+mouse_00001_devtes
+fly_00327_devtes
+mouse_00014_devtes
+1833184
+yeast_00087_devtes
+fly_00345_devtes
+14990717
+yeast_00074_devtes
+9462743
+fly_00346_devtes
+fly_00378_devtes
+yeast_00082_devtes
+9149941
+mouse_00207_devtes
+12101391
+fly_00351_devtes
+9721204
+11152479
+11311562
+mouse_00017_devtes
+mouse_00221_devtes
+mouse_00009_devtes
+mouse_00050_devtes
+15033475
+fly_00420_devtes
+11080599
+mouse_00143_devtes
+mouse_00035_devtes
+yeast_00063_devtes
+yeast_00100_devtes
+10828014
+yeast_00113_devtes
+11997512
+fly_00399_devtes
+12466223
+mouse_00245_devtes
+mouse_00031_devtes
+mouse_00151_devtes
+mouse_00158_devtes
+yeast_00056_devtes
+mouse_00024_devtes
+10619843
+yeast_00067_devtes
+11294830
+fly_00494_devtes
+12140175
+mouse_00103_devtes
+mouse_00094_devtes
+mouse_00072_devtes
+10888605
+yeast_00114_devtes
+10491302
+fly_00437_devtes
+mouse_00226_devtes
+fly_00198_devtes
+mouse_00046_devtes
+fly_00444_devtes
+fly_00385_devtes
+mouse_00090_devtes
+yeast_00089_devtes
+mouse_00063_devtes
+mouse_00028_devtes
+1718282
+9479505
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/deca.conll.test b/huner/ner_scripts/splits/deca.conll.test
new file mode 100644
index 0000000..37e2604
--- /dev/null
+++ b/huner/ner_scripts/splits/deca.conll.test
@@ -0,0 +1,194 @@
+mouse_00173_devtes
+fly_00165_devtes
+9548260
+9047234
+9774969
+mouse_00012_devtes
+9480752
+fly_00382_devtes
+mouse_00114_devtes
+yeast_00132_devtes
+10491763
+fly_00246_devtes
+10553045
+fly_00355_devtes
+fly_00270_devtes
+yeast_00080_devtes
+11955620
+fly_00336_devtes
+8706133
+fly_00151_devtes
+10913346
+11239445
+fly_00163_devtes
+mouse_00112_devtes
+11739631
+mouse_00018_devtes
+fly_00452_devtes
+8333863
+9543345
+fly_00342_devtes
+11196645
+mouse_00111_devtes
+yeast_00115_devtes
+yeast_00078_devtes
+yeast_00068_devtes
+mouse_00053_devtes
+mouse_00168_devtes
+mouse_00186_devtes
+mouse_00052_devtes
+mouse_00079_devtes
+mouse_00108_devtes
+11895476
+10704444
+mouse_00137_devtes
+10531035
+10369880
+9829980
+fly_00343_devtes
+mouse_00066_devtes
+mouse_00153_devtes
+fly_00447_devtes
+11171957
+mouse_00164_devtes
+mouse_00003_devtes
+fly_00162_devtes
+fly_00398_devtes
+fly_00454_devtes
+mouse_00135_devtes
+fly_00409_devtes
+mouse_00225_devtes
+15280356
+mouse_00041_devtes
+12065586
+yeast_00088_devtes
+yeast_00122_devtes
+fly_00068_devtes
+fly_00401_devtes
+mouse_00231_devtes
+mouse_00110_devtes
+mouse_00155_devtes
+mouse_00044_devtes
+fly_00476_devtes
+8606489
+mouse_00228_devtes
+yeast_00111_devtes
+yeast_00093_devtes
+mouse_00232_devtes
+mouse_00048_devtes
+yeast_00133_devtes
+11781389
+mouse_00004_devtes
+12192048
+11062248
+10681536
+fly_00263_devtes
+11172815
+11102511
+mouse_00227_devtes
+mouse_00071_devtes
+fly_00259_devtes
+12728244
+yeast_00008_devtes
+mouse_00016_devtes
+12855678
+fly_00265_devtes
+10831842
+mouse_00218_devtes
+yeast_00116_devtes
+mouse_00064_devtes
+mouse_00161_devtes
+mouse_00213_devtes
+14595443
+mouse_00022_devtes
+yeast_00106_devtes
+mouse_00097_devtes
+mouse_00156_devtes
+11058597
+10092817
+yeast_00110_devtes
+8702627
+yeast_00131_devtes
+11027560
+fly_00366_devtes
+11031099
+mouse_00194_devtes
+mouse_00038_devtes
+mouse_00077_devtes
+fly_00185_devtes
+yeast_00121_devtes
+10747952
+mouse_00205_devtes
+mouse_00243_devtes
+yeast_00070_devtes
+11039935
+mouse_00217_devtes
+9171375
+yeast_00149_devtes
+10944529
+10072769
+yeast_00075_devtes
+11133773
+yeast_00007_devtes
+yeast_00099_devtes
+mouse_00180_devtes
+mouse_00140_devtes
+12446779
+11559747
+15232106
+12093742
+fly_00430_devtes
+fly_00204_devtes
+mouse_00195_devtes
+8537117
+mouse_00167_devtes
+mouse_00193_devtes
+9590290
+yeast_00129_devtes
+11854288
+yeast_00010_devtes
+15130495
+mouse_00202_devtes
+10748049
+10751307
+yeast_00142_devtes
+9843512
+mouse_00100_devtes
+11802771
+mouse_00172_devtes
+yeast_00096_devtes
+mouse_00200_devtes
+mouse_00214_devtes
+mouse_00236_devtes
+10780674
+fly_00490_devtes
+11075807
+14755250
+10534401
+9878755
+mouse_00128_devtes
+11007475
+mouse_00177_devtes
+fly_00099_devtes
+8081366
+11350119
+yeast_00090_devtes
+11698418
+mouse_00249_devtes
+mouse_00074_devtes
+10455115
+14626429
+11054547
+12106695
+11641404
+yeast_00079_devtes
+fly_00381_devtes
+11555636
+mouse_00224_devtes
+mouse_00047_devtes
+mouse_00142_devtes
+fly_00362_devtes
+mouse_00083_devtes
+fly_00164_devtes
+10888872
+mouse_00185_devtes
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/deca.conll.train b/huner/ner_scripts/splits/deca.conll.train
new file mode 100644
index 0000000..879e032
--- /dev/null
+++ b/huner/ner_scripts/splits/deca.conll.train
@@ -0,0 +1,386 @@
+9451016
+yeast_00053_devtes
+mouse_00136_devtes
+10882741
+fly_00459_devtes
+fly_00045_devtes
+yeast_00054_devtes
+yeast_00057_devtes
+10938276
+10692449
+yeast_00130_devtes
+9468509
+fly_00273_devtes
+fly_00040_devtes
+10381257
+mouse_00184_devtes
+11337487
+yeast_00104_devtes
+9932288
+11076957
+14576168
+9721215
+mouse_00181_devtes
+yeast_00072_devtes
+10215850
+yeast_00117_devtes
+mouse_00099_devtes
+11698403
+mouse_00033_devtes
+9129147
+yeast_00124_devtes
+11897791
+10588946
+fly_00255_devtes
+8938450
+fly_00353_devtes
+mouse_00198_devtes
+10936056
+yeast_00107_devtes
+9647693
+yeast_00125_devtes
+11696592
+10747949
+fly_00001_devtes
+11165367
+11410164
+9827804
+yeast_00094_devtes
+10455022
+12801932
+11003675
+yeast_00139_devtes
+fly_00055_devtes
+10729163
+mouse_00127_devtes
+9731181
+10978536
+mouse_00058_devtes
+fly_00429_devtes
+yeast_00150_devtes
+10967136
+12724311
+fly_00171_devtes
+12721283
+yeast_00085_devtes
+10748143
+11027696
+mouse_00059_devtes
+15184369
+10235267
+11891219
+11042359
+10192385
+10623476
+yeast_00112_devtes
+mouse_00113_devtes
+mouse_00144_devtes
+12504082
+10913340
+15122315
+10766186
+fly_00004_devtes
+yeast_00071_devtes
+mouse_00005_devtes
+yeast_00140_devtes
+mouse_00105_devtes
+mouse_00223_devtes
+fly_00271_devtes
+mouse_00175_devtes
+yeast_00145_devtes
+11559748
+fly_00483_devtes
+mouse_00206_devtes
+10072587
+yeast_00003_devtes
+10866201
+10534407
+9694715
+yeast_00092_devtes
+15350218
+12270937
+yeast_00097_devtes
+11342225
+mouse_00165_devtes
+12119107
+mouse_00250_devtes
+mouse_00082_devtes
+12878160
+10954742
+mouse_00183_devtes
+11545741
+mouse_00107_devtes
+mouse_00239_devtes
+12446784
+10949293
+yeast_00144_devtes
+mouse_00034_devtes
+fly_00282_devtes
+mouse_00118_devtes
+mouse_00122_devtes
+9874765
+10409438
+yeast_00102_devtes
+mouse_00139_devtes
+mouse_00145_devtes
+14603251
+fly_00079_devtes
+10534406
+mouse_00124_devtes
+mouse_00125_devtes
+fly_00267_devtes
+mouse_00051_devtes
+mouse_00042_devtes
+fly_00464_devtes
+fly_00431_devtes
+mouse_00222_devtes
+15243141
+fly_00482_devtes
+mouse_00210_devtes
+yeast_00147_devtes
+fly_00317_devtes
+11050005
+mouse_00240_devtes
+10944437
+mouse_00174_devtes
+11152476
+9473517
+9637251
+fly_00313_devtes
+10950930
+mouse_00190_devtes
+fly_00024_devtes
+9426230
+mouse_00179_devtes
+11054569
+fly_00347_devtes
+mouse_00101_devtes
+11034316
+mouse_00160_devtes
+14525983
+fly_00283_devtes
+9234719
+11163187
+10767544
+12862317
+mouse_00171_devtes
+mouse_00235_devtes
+mouse_00141_devtes
+mouse_00020_devtes
+fly_00012_devtes
+12860405
+mouse_00065_devtes
+mouse_00084_devtes
+fly_00092_devtes
+fly_00485_devtes
+mouse_00008_devtes
+yeast_00143_devtes
+11994479
+fly_00244_devtes
+mouse_00246_devtes
+fly_00486_devtes
+fly_00403_devtes
+11278593
+fly_00439_devtes
+10924333
+mouse_00244_devtes
+mouse_00109_devtes
+mouse_00149_devtes
+mouse_00229_devtes
+11980910
+fly_00278_devtes
+10779507
+9223106
+mouse_00089_devtes
+fly_00085_devtes
+mouse_00095_devtes
+fly_00335_devtes
+yeast_00128_devtes
+mouse_00157_devtes
+10197527
+11243782
+mouse_00191_devtes
+fly_00319_devtes
+yeast_00098_devtes
+fly_00042_devtes
+mouse_00039_devtes
+mouse_00015_devtes
+mouse_00159_devtes
+9368056
+10235266
+mouse_00061_devtes
+fly_00367_devtes
+fly_00281_devtes
+11085512
+yeast_00083_devtes
+9482110
+yeast_00127_devtes
+15096576
+yeast_00119_devtes
+mouse_00204_devtes
+mouse_00163_devtes
+mouse_00062_devtes
+mouse_00019_devtes
+mouse_00126_devtes
+9563500
+mouse_00154_devtes
+11063725
+fly_00411_devtes
+11255011
+mouse_00242_devtes
+12027893
+yeast_00146_devtes
+fly_00456_devtes
+11054413
+mouse_00238_devtes
+mouse_00080_devtes
+12504588
+10548550
+12930836
+yeast_00066_devtes
+mouse_00203_devtes
+yeast_00051_devtes
+mouse_00132_devtes
+mouse_00212_devtes
+fly_00208_devtes
+9618483
+yeast_00004_devtes
+10766764
+10607840
+mouse_00196_devtes
+9763455
+mouse_00209_devtes
+11481447
+mouse_00116_devtes
+fly_00293_devtes
+10628838
+9620774
+yeast_00086_devtes
+10022127
+9637683
+mouse_00123_devtes
+yeast_00064_devtes
+mouse_00234_devtes
+mouse_00093_devtes
+mouse_00085_devtes
+11110791
+mouse_00115_devtes
+mouse_00216_devtes
+yeast_00009_devtes
+yeast_00137_devtes
+yeast_00062_devtes
+mouse_00152_devtes
+fly_00161_devtes
+mouse_00076_devtes
+11909966
+11238452
+10625670
+11749039
+yeast_00005_devtes
+mouse_00055_devtes
+yeast_00135_devtes
+mouse_00067_devtes
+9786908
+9647766
+mouse_00121_devtes
+yeast_00108_devtes
+11086001
+10866301
+10882522
+12397388
+15383276
+15064709
+10693807
+mouse_00247_devtes
+fly_00350_devtes
+9315665
+mouse_00166_devtes
+mouse_00007_devtes
+10578051
+fly_00404_devtes
+9892355
+mouse_00230_devtes
+mouse_00182_devtes
+fly_00134_devtes
+mouse_00096_devtes
+fly_00324_devtes
+fly_00349_devtes
+mouse_00233_devtes
+mouse_00060_devtes
+mouse_00192_devtes
+mouse_00098_devtes
+11804589
+mouse_00029_devtes
+mouse_00032_devtes
+mouse_00006_devtes
+10716726
+9748262
+mouse_00078_devtes
+12218053
+8332913
+10967134
+mouse_00104_devtes
+10607832
+mouse_00197_devtes
+yeast_00105_devtes
+10706098
+12489194
+11230181
+10854325
+11750132
+yeast_00059_devtes
+yeast_00120_devtes
+yeast_00141_devtes
+fly_00374_devtes
+yeast_00077_devtes
+mouse_00187_devtes
+11158580
+11597136
+10458166
+mouse_00146_devtes
+9651585
+yeast_00081_devtes
+yeast_00076_devtes
+10799322
+mouse_00199_devtes
+10993894
+yeast_00001_devtes
+yeast_00095_devtes
+10973974
+10967094
+fly_00272_devtes
+10373484
+mouse_00201_devtes
+9651357
+mouse_00073_devtes
+mouse_00147_devtes
+mouse_00102_devtes
+mouse_00056_devtes
+mouse_00057_devtes
+yeast_00084_devtes
+fly_00236_devtes
+9782094
+11084341
+11342227
+mouse_00170_devtes
+10647011
+mouse_00054_devtes
+11095982
+mouse_00069_devtes
+10409432
+mouse_00087_devtes
+mouse_00162_devtes
+11463832
+11081504
+fly_00414_devtes
+12445808
+11056056
+9515818
+mouse_00150_devtes
+yeast_00101_devtes
+yeast_00118_devtes
+11566096
+yeast_00136_devtes
+mouse_00036_devtes
+fly_00182_devtes
+mouse_00013_devtes
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/deca.dev b/huner/ner_scripts/splits/deca.dev
new file mode 100644
index 0000000..1b88915
--- /dev/null
+++ b/huner/ner_scripts/splits/deca.dev
@@ -0,0 +1,64 @@
+mouse_00001_devtes
+fly_00327_devtes
+mouse_00014_devtes
+1833184
+yeast_00087_devtes
+fly_00345_devtes
+14990717
+yeast_00074_devtes
+9462743
+fly_00346_devtes
+fly_00378_devtes
+yeast_00082_devtes
+9149941
+mouse_00207_devtes
+12101391
+fly_00351_devtes
+9721204
+11152479
+11311562
+mouse_00017_devtes
+mouse_00221_devtes
+mouse_00009_devtes
+mouse_00050_devtes
+15033475
+fly_00420_devtes
+11080599
+mouse_00143_devtes
+mouse_00035_devtes
+yeast_00063_devtes
+yeast_00100_devtes
+10828014
+yeast_00113_devtes
+11997512
+fly_00399_devtes
+12466223
+mouse_00245_devtes
+mouse_00031_devtes
+mouse_00151_devtes
+mouse_00158_devtes
+yeast_00056_devtes
+mouse_00024_devtes
+10619843
+yeast_00067_devtes
+11294830
+fly_00494_devtes
+12140175
+mouse_00103_devtes
+mouse_00094_devtes
+mouse_00072_devtes
+10888605
+yeast_00114_devtes
+10491302
+fly_00437_devtes
+mouse_00226_devtes
+fly_00198_devtes
+mouse_00046_devtes
+fly_00444_devtes
+fly_00385_devtes
+mouse_00090_devtes
+yeast_00089_devtes
+mouse_00063_devtes
+mouse_00028_devtes
+1718282
+9479505
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/deca.test b/huner/ner_scripts/splits/deca.test
new file mode 100644
index 0000000..37e2604
--- /dev/null
+++ b/huner/ner_scripts/splits/deca.test
@@ -0,0 +1,194 @@
+mouse_00173_devtes
+fly_00165_devtes
+9548260
+9047234
+9774969
+mouse_00012_devtes
+9480752
+fly_00382_devtes
+mouse_00114_devtes
+yeast_00132_devtes
+10491763
+fly_00246_devtes
+10553045
+fly_00355_devtes
+fly_00270_devtes
+yeast_00080_devtes
+11955620
+fly_00336_devtes
+8706133
+fly_00151_devtes
+10913346
+11239445
+fly_00163_devtes
+mouse_00112_devtes
+11739631
+mouse_00018_devtes
+fly_00452_devtes
+8333863
+9543345
+fly_00342_devtes
+11196645
+mouse_00111_devtes
+yeast_00115_devtes
+yeast_00078_devtes
+yeast_00068_devtes
+mouse_00053_devtes
+mouse_00168_devtes
+mouse_00186_devtes
+mouse_00052_devtes
+mouse_00079_devtes
+mouse_00108_devtes
+11895476
+10704444
+mouse_00137_devtes
+10531035
+10369880
+9829980
+fly_00343_devtes
+mouse_00066_devtes
+mouse_00153_devtes
+fly_00447_devtes
+11171957
+mouse_00164_devtes
+mouse_00003_devtes
+fly_00162_devtes
+fly_00398_devtes
+fly_00454_devtes
+mouse_00135_devtes
+fly_00409_devtes
+mouse_00225_devtes
+15280356
+mouse_00041_devtes
+12065586
+yeast_00088_devtes
+yeast_00122_devtes
+fly_00068_devtes
+fly_00401_devtes
+mouse_00231_devtes
+mouse_00110_devtes
+mouse_00155_devtes
+mouse_00044_devtes
+fly_00476_devtes
+8606489
+mouse_00228_devtes
+yeast_00111_devtes
+yeast_00093_devtes
+mouse_00232_devtes
+mouse_00048_devtes
+yeast_00133_devtes
+11781389
+mouse_00004_devtes
+12192048
+11062248
+10681536
+fly_00263_devtes
+11172815
+11102511
+mouse_00227_devtes
+mouse_00071_devtes
+fly_00259_devtes
+12728244
+yeast_00008_devtes
+mouse_00016_devtes
+12855678
+fly_00265_devtes
+10831842
+mouse_00218_devtes
+yeast_00116_devtes
+mouse_00064_devtes
+mouse_00161_devtes
+mouse_00213_devtes
+14595443
+mouse_00022_devtes
+yeast_00106_devtes
+mouse_00097_devtes
+mouse_00156_devtes
+11058597
+10092817
+yeast_00110_devtes
+8702627
+yeast_00131_devtes
+11027560
+fly_00366_devtes
+11031099
+mouse_00194_devtes
+mouse_00038_devtes
+mouse_00077_devtes
+fly_00185_devtes
+yeast_00121_devtes
+10747952
+mouse_00205_devtes
+mouse_00243_devtes
+yeast_00070_devtes
+11039935
+mouse_00217_devtes
+9171375
+yeast_00149_devtes
+10944529
+10072769
+yeast_00075_devtes
+11133773
+yeast_00007_devtes
+yeast_00099_devtes
+mouse_00180_devtes
+mouse_00140_devtes
+12446779
+11559747
+15232106
+12093742
+fly_00430_devtes
+fly_00204_devtes
+mouse_00195_devtes
+8537117
+mouse_00167_devtes
+mouse_00193_devtes
+9590290
+yeast_00129_devtes
+11854288
+yeast_00010_devtes
+15130495
+mouse_00202_devtes
+10748049
+10751307
+yeast_00142_devtes
+9843512
+mouse_00100_devtes
+11802771
+mouse_00172_devtes
+yeast_00096_devtes
+mouse_00200_devtes
+mouse_00214_devtes
+mouse_00236_devtes
+10780674
+fly_00490_devtes
+11075807
+14755250
+10534401
+9878755
+mouse_00128_devtes
+11007475
+mouse_00177_devtes
+fly_00099_devtes
+8081366
+11350119
+yeast_00090_devtes
+11698418
+mouse_00249_devtes
+mouse_00074_devtes
+10455115
+14626429
+11054547
+12106695
+11641404
+yeast_00079_devtes
+fly_00381_devtes
+11555636
+mouse_00224_devtes
+mouse_00047_devtes
+mouse_00142_devtes
+fly_00362_devtes
+mouse_00083_devtes
+fly_00164_devtes
+10888872
+mouse_00185_devtes
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/deca.train b/huner/ner_scripts/splits/deca.train
new file mode 100644
index 0000000..879e032
--- /dev/null
+++ b/huner/ner_scripts/splits/deca.train
@@ -0,0 +1,386 @@
+9451016
+yeast_00053_devtes
+mouse_00136_devtes
+10882741
+fly_00459_devtes
+fly_00045_devtes
+yeast_00054_devtes
+yeast_00057_devtes
+10938276
+10692449
+yeast_00130_devtes
+9468509
+fly_00273_devtes
+fly_00040_devtes
+10381257
+mouse_00184_devtes
+11337487
+yeast_00104_devtes
+9932288
+11076957
+14576168
+9721215
+mouse_00181_devtes
+yeast_00072_devtes
+10215850
+yeast_00117_devtes
+mouse_00099_devtes
+11698403
+mouse_00033_devtes
+9129147
+yeast_00124_devtes
+11897791
+10588946
+fly_00255_devtes
+8938450
+fly_00353_devtes
+mouse_00198_devtes
+10936056
+yeast_00107_devtes
+9647693
+yeast_00125_devtes
+11696592
+10747949
+fly_00001_devtes
+11165367
+11410164
+9827804
+yeast_00094_devtes
+10455022
+12801932
+11003675
+yeast_00139_devtes
+fly_00055_devtes
+10729163
+mouse_00127_devtes
+9731181
+10978536
+mouse_00058_devtes
+fly_00429_devtes
+yeast_00150_devtes
+10967136
+12724311
+fly_00171_devtes
+12721283
+yeast_00085_devtes
+10748143
+11027696
+mouse_00059_devtes
+15184369
+10235267
+11891219
+11042359
+10192385
+10623476
+yeast_00112_devtes
+mouse_00113_devtes
+mouse_00144_devtes
+12504082
+10913340
+15122315
+10766186
+fly_00004_devtes
+yeast_00071_devtes
+mouse_00005_devtes
+yeast_00140_devtes
+mouse_00105_devtes
+mouse_00223_devtes
+fly_00271_devtes
+mouse_00175_devtes
+yeast_00145_devtes
+11559748
+fly_00483_devtes
+mouse_00206_devtes
+10072587
+yeast_00003_devtes
+10866201
+10534407
+9694715
+yeast_00092_devtes
+15350218
+12270937
+yeast_00097_devtes
+11342225
+mouse_00165_devtes
+12119107
+mouse_00250_devtes
+mouse_00082_devtes
+12878160
+10954742
+mouse_00183_devtes
+11545741
+mouse_00107_devtes
+mouse_00239_devtes
+12446784
+10949293
+yeast_00144_devtes
+mouse_00034_devtes
+fly_00282_devtes
+mouse_00118_devtes
+mouse_00122_devtes
+9874765
+10409438
+yeast_00102_devtes
+mouse_00139_devtes
+mouse_00145_devtes
+14603251
+fly_00079_devtes
+10534406
+mouse_00124_devtes
+mouse_00125_devtes
+fly_00267_devtes
+mouse_00051_devtes
+mouse_00042_devtes
+fly_00464_devtes
+fly_00431_devtes
+mouse_00222_devtes
+15243141
+fly_00482_devtes
+mouse_00210_devtes
+yeast_00147_devtes
+fly_00317_devtes
+11050005
+mouse_00240_devtes
+10944437
+mouse_00174_devtes
+11152476
+9473517
+9637251
+fly_00313_devtes
+10950930
+mouse_00190_devtes
+fly_00024_devtes
+9426230
+mouse_00179_devtes
+11054569
+fly_00347_devtes
+mouse_00101_devtes
+11034316
+mouse_00160_devtes
+14525983
+fly_00283_devtes
+9234719
+11163187
+10767544
+12862317
+mouse_00171_devtes
+mouse_00235_devtes
+mouse_00141_devtes
+mouse_00020_devtes
+fly_00012_devtes
+12860405
+mouse_00065_devtes
+mouse_00084_devtes
+fly_00092_devtes
+fly_00485_devtes
+mouse_00008_devtes
+yeast_00143_devtes
+11994479
+fly_00244_devtes
+mouse_00246_devtes
+fly_00486_devtes
+fly_00403_devtes
+11278593
+fly_00439_devtes
+10924333
+mouse_00244_devtes
+mouse_00109_devtes
+mouse_00149_devtes
+mouse_00229_devtes
+11980910
+fly_00278_devtes
+10779507
+9223106
+mouse_00089_devtes
+fly_00085_devtes
+mouse_00095_devtes
+fly_00335_devtes
+yeast_00128_devtes
+mouse_00157_devtes
+10197527
+11243782
+mouse_00191_devtes
+fly_00319_devtes
+yeast_00098_devtes
+fly_00042_devtes
+mouse_00039_devtes
+mouse_00015_devtes
+mouse_00159_devtes
+9368056
+10235266
+mouse_00061_devtes
+fly_00367_devtes
+fly_00281_devtes
+11085512
+yeast_00083_devtes
+9482110
+yeast_00127_devtes
+15096576
+yeast_00119_devtes
+mouse_00204_devtes
+mouse_00163_devtes
+mouse_00062_devtes
+mouse_00019_devtes
+mouse_00126_devtes
+9563500
+mouse_00154_devtes
+11063725
+fly_00411_devtes
+11255011
+mouse_00242_devtes
+12027893
+yeast_00146_devtes
+fly_00456_devtes
+11054413
+mouse_00238_devtes
+mouse_00080_devtes
+12504588
+10548550
+12930836
+yeast_00066_devtes
+mouse_00203_devtes
+yeast_00051_devtes
+mouse_00132_devtes
+mouse_00212_devtes
+fly_00208_devtes
+9618483
+yeast_00004_devtes
+10766764
+10607840
+mouse_00196_devtes
+9763455
+mouse_00209_devtes
+11481447
+mouse_00116_devtes
+fly_00293_devtes
+10628838
+9620774
+yeast_00086_devtes
+10022127
+9637683
+mouse_00123_devtes
+yeast_00064_devtes
+mouse_00234_devtes
+mouse_00093_devtes
+mouse_00085_devtes
+11110791
+mouse_00115_devtes
+mouse_00216_devtes
+yeast_00009_devtes
+yeast_00137_devtes
+yeast_00062_devtes
+mouse_00152_devtes
+fly_00161_devtes
+mouse_00076_devtes
+11909966
+11238452
+10625670
+11749039
+yeast_00005_devtes
+mouse_00055_devtes
+yeast_00135_devtes
+mouse_00067_devtes
+9786908
+9647766
+mouse_00121_devtes
+yeast_00108_devtes
+11086001
+10866301
+10882522
+12397388
+15383276
+15064709
+10693807
+mouse_00247_devtes
+fly_00350_devtes
+9315665
+mouse_00166_devtes
+mouse_00007_devtes
+10578051
+fly_00404_devtes
+9892355
+mouse_00230_devtes
+mouse_00182_devtes
+fly_00134_devtes
+mouse_00096_devtes
+fly_00324_devtes
+fly_00349_devtes
+mouse_00233_devtes
+mouse_00060_devtes
+mouse_00192_devtes
+mouse_00098_devtes
+11804589
+mouse_00029_devtes
+mouse_00032_devtes
+mouse_00006_devtes
+10716726
+9748262
+mouse_00078_devtes
+12218053
+8332913
+10967134
+mouse_00104_devtes
+10607832
+mouse_00197_devtes
+yeast_00105_devtes
+10706098
+12489194
+11230181
+10854325
+11750132
+yeast_00059_devtes
+yeast_00120_devtes
+yeast_00141_devtes
+fly_00374_devtes
+yeast_00077_devtes
+mouse_00187_devtes
+11158580
+11597136
+10458166
+mouse_00146_devtes
+9651585
+yeast_00081_devtes
+yeast_00076_devtes
+10799322
+mouse_00199_devtes
+10993894
+yeast_00001_devtes
+yeast_00095_devtes
+10973974
+10967094
+fly_00272_devtes
+10373484
+mouse_00201_devtes
+9651357
+mouse_00073_devtes
+mouse_00147_devtes
+mouse_00102_devtes
+mouse_00056_devtes
+mouse_00057_devtes
+yeast_00084_devtes
+fly_00236_devtes
+9782094
+11084341
+11342227
+mouse_00170_devtes
+10647011
+mouse_00054_devtes
+11095982
+mouse_00069_devtes
+10409432
+mouse_00087_devtes
+mouse_00162_devtes
+11463832
+11081504
+fly_00414_devtes
+12445808
+11056056
+9515818
+mouse_00150_devtes
+yeast_00101_devtes
+yeast_00118_devtes
+11566096
+yeast_00136_devtes
+mouse_00036_devtes
+fly_00182_devtes
+mouse_00013_devtes
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/fsu.conll.dev b/huner/ner_scripts/splits/fsu.conll.dev
new file mode 100644
index 0000000..cf2b407
--- /dev/null
+++ b/huner/ner_scripts/splits/fsu.conll.dev
@@ -0,0 +1,330 @@
+11488463
+12141441
+11551215
+11114723
+10881198
+15879703
+12016153
+12673057
+15613280
+12393884
+11641396
+12297098
+11743730
+15215595
+11789762
+12900013
+12183102
+11867536
+10386855
+14614356
+16583313
+16210473
+11007778
+7523145
+10411736
+11470536
+12592707
+16318579
+15961508
+15749028
+11997174
+11781009
+11809823
+1898930
+12101186
+10792815
+10744668
+17587580
+12105219
+9987136
+10926859
+7883171
+10976008
+17675291
+16325183
+12015329
+12060708
+3127379
+10729144
+11873003
+11434463
+10671293
+16564702
+12670940
+10809234
+9683503
+12704196
+11333265
+12126615
+10924517
+10075739
+11086080
+16681467
+14612209
+12547389
+10691110
+11278412
+15225315
+14731280
+1518043
+15838554
+17434987
+10744651
+11722993
+10720944
+15153517
+11868823
+17130561
+10940736
+12379719
+10433729
+11361004
+10555964
+15138264
+17082569
+12393902
+12082086
+12492863
+11303589
+11038188
+12946101
+15618158
+12559906
+11375975
+11134882
+17137555
+11023659
+17640874
+12218090
+10218357
+11956183
+2512576
+12562757
+11793852
+11891665
+10801848
+12140183
+10379899
+11278550
+11587361
+10917982
+8501065
+10852886
+14551259
+10205099
+12050117
+11700562
+11929878
+12297502
+10875271
+16829306
+11859120
+12650457
+12218058
+10995454
+15760680
+12794136
+11096461
+12064592
+12161434
+11598233
+11792123
+11069186
+16282332
+15649902
+15878672
+14622120
+10441243
+14650355
+12374819
+11823470
+9727029
+9234477
+17170464
+17381685
+15985713
+12511422
+12478664
+15310528
+12084819
+16899371
+15513925
+12838448
+12906869
+11021254
+12055595
+14693161
+10799525
+14628103
+12824067
+11331035
+12411321
+12080057
+16765491
+10560997
+12032142
+10864672
+12184921
+12060498
+14581000
+11013304
+11359651
+10811864
+9006059
+12948628
+11707463
+17385066
+15797645
+17158102
+16707463
+17694954
+12954644
+15191745
+12760421
+11988505
+10752835
+10866832
+11901358
+15314042
+12672190
+10816008
+12010552
+12089359
+11842212
+12650940
+16978071
+11999028
+10836749
+12060656
+11726664
+11052813
+11145841
+10074087
+16179013
+14609568
+11785939
+10603362
+14688344
+9422603
+10800598
+11298490
+11950878
+10872823
+15252864
+12870661
+16870466
+11566732
+10686180
+10471383
+10788346
+14519128
+10022905
+11747620
+11061520
+12873803
+10942208
+11100732
+10816131
+10760806
+11438518
+16233813
+12493765
+15044475
+11457489
+9852014
+11376113
+12411432
+11296244
+12426353
+10867000
+11181533
+10934230
+11740806
+15477601
+11911837
+11831386
+15254788
+11860830
+17047292
+10428074
+10806195
+12717106
+15761036
+16672525
+11810296
+12393168
+11747621
+17949365
+10094682
+11243705
+16503147
+10779906
+11580218
+16226501
+12110681
+12606558
+12065583
+12563002
+10505742
+11849417
+10026210
+12112824
+12359436
+10806052
+11570561
+14623738
+12373863
+11021934
+10783262
+15066032
+17264953
+11157961
+15342926
+12799416
+12401780
+15919670
+11554781
+10886368
+11395479
+11923311
+16929347
+15342575
+11368790
+17028280
+15979078
+17559875
+11760398
+11306582
+1938874
+12457460
+10027967
+1527488
+13129615
+13679026
+11926999
+11742001
+12508640
+12198491
+10561251
+11145839
+11748169
+9422764
+11412995
+17185548
+7749980
+12439719
+12356733
+12124628
+10984608
+11032023
+11950392
+10772530
+11721045
+15606615
+11477104
+10094685
+10463184
+15180759
+14756770
+10074428
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/fsu.conll.test b/huner/ner_scripts/splits/fsu.conll.test
new file mode 100644
index 0000000..eea9309
--- /dev/null
+++ b/huner/ner_scripts/splits/fsu.conll.test
@@ -0,0 +1,993 @@
+12107172
+10208865
+11821406
+17376200
+10518822
+17331479
+10479407
+11773921
+11580757
+17046810
+1445207
+14982626
+11290834
+11888290
+10527106
+11148048
+10788508
+10929042
+12858014
+11478396
+10632977
+10601301
+10743660
+11809755
+16458279
+12095414
+12221085
+10805227
+15075204
+11599797
+17316136
+10646643
+10400595
+9696775
+10754314
+12270931
+12942639
+10802239
+11714857
+11815625
+12090913
+11406275
+17339483
+11567029
+11944986
+12061840
+12138086
+11448124
+16545442
+11526079
+17681941
+10406466
+15803059
+15691134
+11896212
+11115104
+11953756
+11712085
+1922387
+12200107
+10516072
+14551329
+15473955
+12145340
+11920156
+11397793
+11259417
+11994151
+9873047
+10097129
+16431125
+11784720
+9922240
+2492118
+14585813
+11207248
+1569009
+11387329
+17097159
+10873786
+16675088
+12297987
+16567866
+12411323
+9464792
+12702545
+11278437
+12077440
+11784131
+10806445
+15781458
+10479404
+17420258
+12101100
+10667797
+15650111
+10975987
+12077706
+14565860
+15851013
+10961952
+15124210
+17519850
+10770767
+12444963
+12011083
+12208494
+11285285
+10708368
+12077248
+11985526
+16440738
+11751917
+11785085
+11073942
+11729309
+11010978
+14717060
+3919317
+9401028
+12297480
+11727264
+16537643
+10899159
+11513144
+12618449
+12483523
+14689281
+10683824
+11846980
+12125072
+11069677
+11978777
+10485585
+15381183
+10727695
+9696771
+10721712
+12212789
+10815997
+17182560
+15248031
+10717352
+16227578
+11738085
+11022047
+11723500
+11032827
+12441142
+11938494
+11470797
+11223948
+10586519
+12446650
+12123454
+10468601
+11390699
+11397878
+11240095
+7494477
+11089975
+12533482
+10982859
+11396990
+12600028
+12856330
+10713460
+10637310
+11854298
+10196125
+11532937
+12086191
+11470772
+12239140
+15120116
+11479134
+10713345
+10601204
+11641397
+11134421
+11466562
+11514509
+10393925
+10623432
+11154405
+11787322
+10550139
+8093697
+12699689
+12198183
+17398095
+15198671
+16241862
+11818523
+12620808
+17713902
+10720441
+15293449
+1329027
+12086470
+12057949
+17017556
+14871302
+1846781
+12160520
+10755408
+16822623
+2997585
+10748552
+12133833
+10506160
+16973241
+12052896
+12037021
+16237016
+11580941
+12963345
+11473265
+10618369
+16624365
+15854555
+10528035
+12192075
+11056395
+8289242
+11022049
+12697152
+11120754
+11237602
+14572508
+12010812
+11439135
+12393171
+11052810
+11684676
+15371877
+10704255
+16978907
+16139357
+16289960
+11035230
+10744645
+16465597
+11418762
+11076872
+16671942
+11282467
+11170888
+10747015
+12409310
+12049201
+10451209
+14617649
+15699037
+11844144
+12111645
+15504367
+11965438
+11548209
+12504121
+10497266
+10674215
+10362897
+12037680
+12100559
+16882169
+12524540
+9271869
+10938793
+16103156
+12210723
+12596048
+10837290
+10206709
+12501174
+17027170
+12744775
+1328224
+10769407
+11161461
+11741957
+14500632
+10709104
+15026176
+16153628
+12493005
+12849706
+10777536
+12119233
+9774442
+11891225
+10613859
+11546807
+10737588
+10620120
+11356143
+11883937
+7704261
+15194195
+12126641
+15368361
+10686096
+11244571
+12242076
+10833331
+10757809
+11553286
+17637225
+12601022
+11888867
+10862610
+12396724
+15207247
+15975820
+12482935
+11737064
+10551805
+11750878
+10600651
+15684739
+11223717
+15025427
+10775603
+15705184
+12409289
+10749681
+11444864
+11179692
+10864922
+10638746
+12062487
+11761714
+15575692
+16187538
+10187858
+11470784
+11796738
+12588519
+10551848
+11690642
+11416004
+10761703
+11788785
+10729625
+10880255
+11399983
+11395449
+17445179
+12649177
+11739466
+11994457
+11444906
+12869989
+10642534
+15379246
+11437344
+10090404
+11825561
+11920455
+11827176
+15803651
+17962451
+11984834
+11479697
+14996803
+10655207
+10944537
+12114499
+15598443
+10644770
+16857169
+11897449
+11152697
+15049811
+12941614
+11497491
+12606287
+11985622
+16128374
+1321115
+10937698
+14986479
+11914737
+15053766
+11583621
+15979891
+11807624
+10369872
+11353725
+10753043
+11787467
+12082095
+15580659
+11448118
+12693801
+12044248
+14573821
+16160843
+14697268
+12585964
+12482858
+10670650
+11823532
+11876708
+15547256
+11912161
+10752558
+12054652
+11356838
+10876090
+14660869
+12062429
+10395199
+11384981
+11787469
+9053439
+12167596
+11440636
+15778373
+12167620
+10873612
+11144295
+12516569
+15778339
+10777712
+9852015
+12890451
+10880227
+14698140
+15207246
+16808796
+11818675
+15153310
+10908112
+11531333
+11742080
+11514624
+11149924
+15212428
+10899166
+11902738
+12010840
+10952944
+14529621
+11160004
+14572467
+15514853
+10438493
+10480937
+12021920
+11883898
+15144571
+11741348
+1326789
+17878237
+10954915
+10411757
+15655823
+10684976
+17455326
+11992404
+10767540
+11139773
+10734050
+11101674
+10843736
+11727073
+16950633
+10464228
+10964484
+11948912
+9497500
+11461926
+14726627
+16423827
+12054582
+11795260
+16213747
+15485810
+7768864
+11208485
+10719247
+16046400
+16672219
+10443990
+12800216
+12401728
+11134135
+15585135
+11896048
+11787847
+10816566
+11437403
+12584323
+16717106
+12138164
+11797095
+11577372
+11969340
+12957669
+11181969
+10551881
+10712517
+16006581
+10393192
+10774747
+17166910
+17156396
+11847269
+16800782
+10777589
+16213154
+11992112
+11278997
+10423193
+12509459
+10781601
+12547700
+12615965
+1575712
+11196700
+10762075
+12200116
+11163076
+16508981
+10841074
+11901424
+10794532
+11196108
+12867478
+11034560
+11967569
+10984492
+17267952
+14964690
+15749710
+10552357
+17092867
+12196012
+10810295
+11023662
+10089131
+10322169
+15616579
+12496348
+15566952
+12417738
+9767589
+10729169
+14769146
+11446592
+15862171
+11297552
+1900507
+12606523
+12050164
+11470801
+12162656
+16438846
+10753311
+8002610
+1544897
+11111049
+16980972
+17070001
+10777493
+10748161
+9234478
+15289321
+11932251
+12391228
+17707376
+10424431
+10996355
+10623829
+11010960
+11212279
+11337197
+9287022
+10848618
+11260213
+11501944
+12368440
+11592315
+10938022
+11467967
+11121055
+14698139
+16003522
+11472112
+11446515
+10691098
+11733582
+12184911
+12218041
+9826699
+10318834
+11753385
+12015308
+9555886
+16203124
+11956185
+10806390
+10441449
+12359356
+11257042
+10437043
+16618968
+12154078
+11177576
+16325497
+11597129
+16582573
+16388920
+12723950
+10493876
+12217688
+12067979
+12909634
+15871661
+12481074
+11994747
+10075935
+10556263
+11912189
+12864862
+16781756
+14567959
+16648635
+10853826
+11586363
+14645248
+15096181
+11313136
+7540694
+8231806
+15804597
+11924557
+17238829
+10529246
+12871401
+10824114
+16806821
+12699619
+12374820
+10666375
+12668644
+16226465
+11359836
+15629928
+8148054
+11719522
+9535080
+11052814
+16530177
+10838667
+12483210
+11179674
+12210795
+10704252
+11839732
+10464187
+17301953
+10416558
+12045490
+12960331
+11169398
+12154120
+11055401
+11374071
+11595478
+11812157
+10666713
+11583428
+12223399
+15665098
+12553867
+10986234
+9894849
+12949161
+11330712
+10654608
+12084720
+15364938
+17349709
+1537790
+11098931
+12081504
+12414651
+11840501
+16620271
+12773564
+12639299
+10843753
+14594816
+9636707
+17493145
+10505738
+10760946
+10049523
+11278501
+11888289
+17425335
+12974468
+10714560
+11160264
+12441141
+8460143
+12788308
+15988019
+15242697
+10965217
+12664264
+16750378
+11576463
+11856758
+15830122
+15242101
+12064938
+10841072
+12016134
+15714591
+11602355
+10511216
+11856887
+12133843
+12559621
+10331730
+10777610
+12608515
+16713539
+11929525
+11788600
+16641112
+12481029
+11022048
+11872359
+10205588
+15987779
+10627506
+11145846
+10731616
+11800371
+15869883
+10809293
+9765287
+12359330
+12149259
+17405810
+10888117
+11928817
+11727258
+10995028
+12391192
+15146989
+12842759
+10644686
+15294958
+2500529
+10650933
+12515039
+11988089
+12536572
+14764684
+14984034
+12213900
+14565861
+16210627
+16723255
+15980341
+11083282
+17928781
+10638706
+15549734
+10913077
+10629188
+11352467
+16978067
+16209565
+10714556
+12857835
+14769145
+15101990
+11799131
+11590544
+11854171
+10525310
+12200141
+11050078
+12416719
+10671297
+10026226
+11860275
+17140415
+10964167
+15469704
+12368812
+16040600
+15223114
+16689656
+11827469
+15388262
+9108277
+12006660
+11815670
+8752328
+12244172
+11299368
+16216871
+17368449
+12808018
+15664650
+12039681
+16099870
+13129950
+10200961
+3114422
+15036241
+10972841
+12104097
+12110693
+16231097
+10629055
+7814326
+12054577
+10475610
+16204540
+16754669
+11145836
+12930526
+17593905
+17316137
+11429164
+11827482
+12096923
+10774739
+10531379
+8547713
+3086839
+12127786
+11787815
+10890180
+10767533
+9774382
+11278918
+14532085
+11226182
+12359428
+10864042
+11063594
+10346902
+11991731
+10802742
+16786149
+10930313
+15077295
+11594795
+1310678
+14983519
+11787938
+16562482
+14551929
+11331269
+11211150
+10972806
+10228795
+11284964
+12967650
+11278317
+11594787
+12813074
+14982625
+12027405
+12367750
+12134158
+10653706
+15140215
+17522365
+10454568
+10846076
+11243704
+12368450
+11836615
+11397877
+10819462
+12391842
+1902213
+14729681
+12538663
+11683586
+11342549
+12100725
+12151636
+12095614
+16487030
+14687581
+14651778
+12019269
+1460045
+11672453
+11418696
+11444905
+15967376
+9139908
+10318773
+12482849
+11904153
+11777003
+10781648
+11298491
+10873451
+11781669
+11814311
+11116209
+11443112
+10837361
+10515909
+10515915
+15609880
+11483596
+10869428
+12368292
+11489845
+16487027
+15912356
+12801995
+15569944
+12200142
+16276440
+11815617
+10390542
+11574907
+10816046
+10913108
+11797931
+10193950
+10887190
+11866033
+11500082
+12672064
+11215376
+15877868
+11992252
+11780382
+16512604
+10874999
+14766582
+11889189
+12208868
+14597230
+12084581
+12594244
+12879269
+15598441
+10777495
+15838788
+15102883
+14767566
+11879108
+17132863
+12729017
+12297112
+12734186
+11838058
+12110845
+2468649
+12200131
+7592487
+11880369
+11054280
+11035787
+12068077
+17954611
+11237435
+7896717
+14718842
+11592532
+1366745
+17367808
+1400361
+11867163
+10819995
+16098201
+16115854
+11023677
+10393969
+17827149
+11080639
+12226108
+10998244
+12160524
+16108732
+11735224
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/fsu.conll.train b/huner/ner_scripts/splits/fsu.conll.train
new file mode 100644
index 0000000..fa2406d
--- /dev/null
+++ b/huner/ner_scripts/splits/fsu.conll.train
@@ -0,0 +1,1984 @@
+10194230
+10092847
+10342536
+10393201
+9915850
+11777632
+11500377
+10542274
+10536788
+11580301
+10207115
+10329574
+10518496
+11595170
+11776922
+10224257
+10026146
+11895184
+10381570
+10488087
+11791585
+10373029
+10051030
+10376065
+10557072
+11743612
+10484818
+10318806
+10394116
+10403839
+10191090
+10487753
+10463057
+10022210
+10548434
+10380232
+11303027
+11773168
+10194225
+11586096
+11337487
+10422291
+10555079
+10082573
+10390538
+10493203
+11862350
+10426450
+10464302
+11895024
+10070158
+10448095
+10541550
+10201468
+10487217
+11785827
+10216052
+10438540
+10468033
+11686239
+10517666
+10393422
+10487040
+10373523
+10445506
+11705093
+11858635
+11881923
+10385915
+11433002
+10471746
+10531360
+10359014
+11691585
+10344736
+11675912
+11861092
+11787746
+11732417
+10370675
+10381377
+10394900
+10540915
+10359575
+11589779
+10358079
+10196316
+11687352
+11593394
+10380659
+10233946
+10394919
+11677363
+10512882
+10502402
+10556751
+10938276
+11802580
+11726574
+10323863
+10187842
+10400757
+10369418
+10692449
+10369926
+11893767
+10395920
+11908529
+10406047
+10347197
+11160280
+11828186
+10446149
+10498706
+10358080
+10497117
+10439040
+10400032
+10435595
+10228157
+10049359
+11596838
+10393197
+10215594
+10194451
+10333529
+11791853
+10523674
+10531342
+10063739
+11800878
+11888183
+10514493
+10363517
+10360947
+10467465
+10103002
+10231581
+10428811
+10190324
+10491187
+10521345
+10478844
+10505694
+10452951
+11679441
+10330159
+10326856
+11156579
+10477583
+10501656
+10441483
+10330396
+10487762
+10485470
+10455189
+10331875
+10281637
+10358031
+10380890
+10385395
+10403690
+10479382
+10406464
+11604152
+11915436
+10430421
+10446912
+11743360
+10336495
+11883682
+10489680
+11730712
+10375107
+10454550
+10491213
+11683558
+11811825
+10037378
+10510379
+11685047
+11913427
+11584328
+10477599
+10220364
+10490609
+10375718
+10440923
+10454557
+10444597
+10429740
+11578685
+11677839
+10320480
+10467403
+10527158
+9837933
+10402022
+11822811
+10087549
+10087993
+10091594
+10447597
+11834476
+10397257
+10560014
+10406459
+10409755
+11639485
+11816779
+10543727
+10209021
+10390158
+10698937
+10066790
+10350484
+10458907
+10460015
+10524258
+10483124
+10347144
+11687180
+11590364
+10223338
+10517675
+10022925
+11687869
+10181397
+10097120
+10438607
+10231485
+10454533
+11846167
+10428091
+10086544
+10398682
+10518937
+10376874
+11902781
+11826141
+10208893
+10207090
+10467004
+11822790
+10353073
+10082554
+10487307
+11669476
+10392266
+10215811
+10411139
+11597185
+10487744
+10553551
+10364159
+10498717
+11824801
+11870646
+10366503
+10428759
+10712618
+10219091
+10339566
+10074282
+10447593
+10214610
+10449899
+10080875
+10146207
+10516878
+10052878
+11737056
+11704380
+10095059
+11761601
+10205176
+11837409
+10391075
+10531446
+10369625
+11806132
+10198061
+10523640
+10554946
+10243927
+10090146
+11587980
+11853943
+10068834
+10409749
+10364076
+10454540
+10085140
+10407985
+10322629
+10455183
+10036191
+10330168
+10493580
+11920896
+10090943
+10068637
+11695481
+10395378
+10411140
+10487759
+10458914
+10444813
+10327051
+10422468
+11887803
+11844591
+10366722
+10225945
+10429184
+11890354
+10339552
+10233147
+10372627
+10406465
+10200473
+10406122
+10026275
+10409724
+10347203
+11863811
+10049775
+10101198
+10466825
+10533066
+11858548
+10366446
+10319320
+10087213
+10051400
+11782218
+10540015
+11595813
+10502216
+10544088
+11738404
+11858256
+10029917
+11800119
+10471743
+10320579
+10448036
+11744290
+11804510
+10318900
+10328351
+10099247
+11736254
+10348859
+11740571
+10206152
+11775180
+10071205
+10347839
+10355085
+10367240
+10478275
+10551788
+10551879
+10487760
+10073947
+10535715
+10226029
+10474898
+11830544
+10430583
+10095062
+10071761
+10369775
+10376873
+11885053
+10196597
+10458905
+10521443
+10021333
+10025050
+11711701
+10037004
+10330134
+11737158
+10460171
+10486210
+11897888
+10529354
+10527475
+11600252
+10469656
+10430580
+10375638
+10215850
+10322022
+10496284
+10501965
+10092856
+10385384
+11708761
+11802601
+10482516
+10425094
+10446998
+10545281
+11768467
+10496161
+11597936
+10082585
+11599840
+10934204
+10323463
+10559207
+10199539
+10099576
+10212969
+10086725
+10376446
+1827203
+10102136
+10532805
+10541865
+10556145
+11726068
+10556029
+11709561
+10534402
+10544089
+11836303
+10357751
+10340447
+11693461
+10320177
+10562418
+10457075
+10544113
+10341219
+11825801
+11728771
+10080901
+10523647
+10487921
+11589568
+10366559
+11596104
+11769229
+10212284
+10497800
+11606538
+1346534
+11778044
+10209119
+10534048
+10096469
+10195425
+10343189
+10518561
+11800586
+10084294
+10076007
+10492127
+11881268
+10065176
+10350027
+10021350
+10101744
+10217683
+10098601
+11783457
+10340883
+10094701
+10228155
+10072774
+10400794
+10379942
+10484695
+10898795
+10090125
+10392914
+10226838
+10376991
+11698403
+10049912
+10448902
+10523319
+10377438
+11904017
+10171173
+10359664
+11786248
+11824701
+10212426
+10085605
+11706949
+10478848
+10027498
+10470220
+10536125
+10559324
+10207041
+10325413
+10536369
+10215608
+10225279
+10549354
+10349443
+10409730
+10097932
+10207092
+11860876
+10329586
+10488088
+10220275
+10430944
+10085120
+11842037
+10542260
+10318918
+10477545
+10359663
+10229668
+10509768
+10209759
+10551796
+10355536
+10548722
+10556063
+10221467
+10417703
+10466306
+10523663
+10068446
+10373507
+10543949
+10498616
+11765448
+10544037
+11723511
+10518502
+10400593
+10526670
+10069815
+10359792
+11580173
+10082570
+10074135
+10391246
+10332733
+10364314
+10485353
+10490639
+11791571
+11912261
+10859308
+10229084
+10413604
+10453721
+11781615
+10464185
+10187864
+10561460
+11599079
+10471696
+11893403
+10517672
+11680835
+10490816
+11845547
+10367460
+1833185
+10350454
+10078734
+10364202
+10504332
+11577094
+10556033
+10068418
+10495573
+11803325
+11804081
+10074520
+10545192
+10413676
+11866130
+10231862
+10196266
+10473623
+10403575
+10559364
+11793172
+10555285
+10194762
+10497262
+10216161
+10367646
+10196248
+10559303
+10438593
+10464291
+10488337
+10413607
+10342511
+10542281
+10080436
+10235265
+10383966
+10442493
+11708362
+10022850
+10436016
+10423292
+10073899
+10446131
+10422342
+10556044
+10355910
+11835109
+10413662
+10491133
+10527426
+11710685
+10384129
+10508522
+10557008
+10102627
+10210952
+10232078
+10022032
+10430886
+11600467
+10228009
+10195697
+10453006
+11890438
+10365883
+10543270
+11884014
+11726022
+10414451
+10501969
+10450815
+11500512
+11684665
+11898797
+11585739
+10096573
+11707977
+11587514
+10713175
+10559320
+10490604
+10503540
+10556028
+11005831
+10496553
+11899479
+10407184
+10198056
+10419006
+10231454
+10026211
+10319955
+10379547
+10476970
+10561153
+11777575
+11804100
+10525413
+10488147
+10036181
+10212278
+10072205
+10205933
+10523634
+10393910
+10452306
+11787041
+10471587
+10211919
+10024882
+10542237
+10490826
+10358075
+10501936
+10022875
+10489822
+10551867
+10550574
+10380878
+10400760
+10218200
+10395827
+10469140
+10499357
+10098744
+10026824
+10347220
+10364319
+10376877
+10473589
+10196318
+10049742
+10419521
+10497874
+10513756
+11836046
+10037774
+11860097
+10198003
+10192638
+11790897
+11741259
+11831512
+10396793
+10024498
+10050883
+10232872
+10323225
+10234698
+10516738
+10085088
+10400712
+11810685
+10203611
+10029860
+10074425
+10407269
+10271171
+11726413
+10326654
+10329135
+11846187
+10308312
+10521447
+10370778
+10438941
+11708431
+10477748
+10037681
+10392900
+10333526
+10438627
+10475972
+10714992
+10521544
+10360454
+10425445
+10218109
+10398286
+10561546
+10022921
+10224289
+10395283
+10228561
+11912677
+10454561
+11763176
+11723675
+10543728
+10078876
+11715079
+10037460
+10391903
+10211422
+10392669
+11642687
+11726262
+11911552
+10493575
+10502434
+11819326
+10192432
+10540292
+10882741
+10094396
+10206698
+11815644
+10545248
+11852907
+10496388
+10187798
+10393251
+10358138
+11704829
+10487953
+11885737
+10473598
+10492169
+10342829
+11874637
+10209031
+10409741
+10226074
+10192134
+10542249
+10441506
+11882747
+11847580
+11907691
+10553959
+11708032
+10479025
+10359603
+10429946
+10026784
+11840365
+10024383
+11278488
+11686378
+10358083
+10194769
+11787720
+10512699
+10049357
+10197985
+10207049
+11775301
+10095061
+10353880
+10468585
+10022880
+10477620
+11917882
+11600314
+10460172
+11921126
+10233885
+10221820
+10383764
+11730182
+10482565
+10748164
+10409656
+10068674
+11760796
+10903325
+10380800
+10153759
+10321158
+11727209
+10399136
+10464310
+10025506
+10092132
+10051488
+10364425
+10471721
+10518956
+10026229
+10400785
+10516011
+11900770
+10426878
+10557308
+10543730
+10490662
+10488148
+11844812
+10438924
+10094314
+10556046
+10374632
+10503812
+10224513
+10064604
+10350638
+11692004
+10561095
+10369965
+10392903
+11595840
+11917061
+10459809
+10490955
+11897791
+11703558
+11706668
+10463242
+11736792
+10360839
+10532354
+11687517
+10748054
+10223498
+11865218
+11697760
+11687737
+10428862
+10231513
+11833863
+10082137
+10377345
+10482620
+10074903
+11689217
+11851941
+11766747
+10364523
+10448285
+10430883
+10073940
+10333481
+10406843
+10534691
+10438950
+11349124
+10094691
+10548622
+10319327
+10367385
+10381257
+10417331
+10497199
+10369757
+11755894
+10521450
+11771979
+10334888
+10027904
+10551816
+10224293
+10202006
+10388670
+11036939
+10224244
+11899489
+10330146
+10065684
+10521796
+10446206
+10556595
+11859400
+11882054
+10329625
+10445161
+11600686
+11742432
+10540553
+10428294
+10531334
+10406954
+10490835
+11791292
+10375640
+10446833
+11579100
+10101159
+11605598
+11764226
+11703464
+10405635
+11883763
+10195690
+10196127
+10409699
+10395908
+10085505
+10490843
+10396343
+10512857
+10542269
+10423156
+10472836
+11860723
+10068040
+11875695
+10022858
+10477597
+11894605
+11876937
+10511554
+11909404
+10452991
+11843252
+10359673
+11816458
+14584942
+10455143
+10103057
+11732088
+10232600
+11726164
+10449072
+11811743
+10215485
+11867388
+10541432
+10207087
+11724510
+10231026
+10488129
+10375694
+11600365
+11792586
+10516026
+10077533
+10224758
+10329736
+10326221
+10488875
+11859943
+10490822
+10523520
+11716043
+10446910
+10029337
+11669281
+11778804
+11678437
+10510295
+10197763
+11602353
+11595176
+10066815
+11898018
+10454570
+10562456
+10075415
+10378989
+1744042
+10090535
+10091619
+10318859
+10430890
+10499121
+10071806
+11718197
+10037576
+10361038
+10529198
+10102000
+10549912
+10453371
+10329566
+10427654
+11744953
+10392710
+10433970
+11886473
+11741554
+10077188
+10022978
+10362652
+10513922
+10502522
+10506143
+10364163
+10022867
+11676899
+10406462
+10066798
+10331276
+10430980
+10687862
+10079173
+10100605
+10542277
+11737900
+10469174
+10212332
+10521509
+11730262
+10331646
+10556089
+10074921
+11716441
+10501034
+11723928
+10229682
+11309652
+11285214
+11795408
+15773991
+16881863
+11836244
+11407111
+11597141
+16024043
+11278906
+10594225
+11698424
+9605119
+10945350
+15135804
+11533230
+1396586
+10671299
+11572857
+10648512
+12901852
+16798779
+10637289
+15036248
+11713982
+16540726
+11680002
+11007056
+12496312
+15598438
+9822625
+15469699
+11790884
+11052816
+12169691
+10692366
+17452927
+11585856
+1836978
+12495080
+12530627
+16169954
+3134591
+15819410
+11208806
+15492870
+11680592
+16343928
+11114248
+15579373
+15996478
+12126648
+10825222
+12930774
+1680916
+16455652
+12359228
+10766860
+11283333
+10052371
+17600048
+16078071
+12857842
+11816009
+12479386
+15220445
+11075930
+17495187
+10768840
+12406748
+17568882
+10930296
+12531696
+10371097
+11741979
+11064201
+10671304
+11251844
+11555653
+9891799
+16260042
+11925441
+10852487
+12362409
+15681655
+15135805
+12813072
+10702265
+10674999
+11547919
+10913073
+11051763
+15231716
+10648098
+15199124
+15110048
+12143056
+11836625
+12351678
+15647926
+11105212
+8946682
+11290784
+9841221
+10531340
+11161269
+10658621
+10433355
+15629932
+10972809
+11390511
+12932582
+16213746
+12499396
+12967642
+15549775
+10779323
+12657290
+11710991
+15879158
+16607637
+12606567
+14751239
+11931557
+10049518
+12016223
+17127808
+16777077
+11302826
+11859088
+11576341
+12050388
+11129656
+11849796
+15975065
+15159391
+3104146
+7966271
+12371681
+1833068
+11044210
+12525632
+11251120
+16326927
+11037881
+10753935
+11818231
+11840773
+1325437
+15653801
+10571676
+10820258
+12393901
+2163341
+9880565
+10564485
+11448122
+12359327
+15631776
+12034027
+12374808
+11864750
+11074787
+10464250
+12849708
+12967644
+11153078
+11526245
+17407096
+11832019
+12519752
+14596817
+8169223
+16680816
+17459655
+11441017
+11297543
+10770210
+10900038
+10756105
+15851489
+15744581
+10768941
+15748978
+12023287
+10799531
+12096904
+14556191
+11244065
+10878124
+17142756
+16734562
+16554930
+17082908
+12149458
+11251884
+10735855
+10753602
+10770741
+10613862
+3106319
+15296756
+7570023
+11279170
+17610203
+8320224
+12615363
+15886715
+10777568
+9846747
+12610214
+17699749
+15183842
+12147251
+12670445
+10220166
+11781834
+14993925
+10760150
+10831800
+12421953
+12226101
+16524739
+11687083
+11405762
+10660889
+11319766
+16144421
+15598655
+12077351
+12631183
+11789206
+12795752
+12359251
+11390449
+10400774
+10767528
+1906867
+11752821
+11527412
+11408283
+1722683
+15355992
+16487070
+11966460
+12392158
+10913114
+10527180
+7679386
+16949074
+11886172
+12031497
+10049515
+10714559
+16221525
+14767868
+10472314
+9748255
+10211329
+11353842
+12547166
+11466284
+11960377
+11821435
+10713673
+15780179
+10781064
+12606047
+12522211
+14635120
+15749024
+15246276
+9792677
+12027407
+11857550
+14652652
+11032397
+11248049
+12758177
+10514496
+10071212
+11470774
+12421026
+12461076
+10933198
+12505196
+11910344
+9670929
+15845919
+15060086
+17361229
+16959267
+10998353
+12034029
+10400599
+11862463
+14557628
+17348688
+16884913
+11836249
+15496550
+10653735
+12161104
+1905664
+12887900
+14592775
+11156551
+12746539
+11955619
+16704299
+11546873
+11705854
+11956105
+11309819
+11972883
+11959571
+17367410
+11353762
+15901830
+14731281
+9324264
+15115907
+12967648
+11714855
+10875629
+11029690
+11986327
+11315634
+16112868
+15276076
+11329262
+11321589
+17092251
+10814528
+11897950
+2496113
+17079270
+11350937
+11692164
+11553611
+1557036
+16077962
+11380493
+17516550
+11778160
+15503221
+16586115
+11223069
+11022796
+17332243
+1569008
+16216875
+15375573
+10781092
+12453469
+16337773
+10508860
+12354228
+11792001
+10742723
+1900494
+10832746
+12899827
+15671246
+12441140
+14679234
+11716065
+16289551
+11798462
+12718525
+12138090
+11672445
+10613694
+16618101
+11274473
+12213191
+10930734
+2111808
+12668783
+9852018
+11916171
+11597003
+12225856
+11259194
+10391277
+12644691
+10830259
+10754235
+14668138
+10520800
+10759557
+16377203
+10910894
+11751814
+10505750
+16051270
+14580941
+10704245
+9658001
+10809280
+12842763
+17586478
+17512708
+11279162
+11875070
+11971879
+10660620
+11983932
+12393185
+10757795
+3036777
+10206993
+12151362
+10497217
+12296995
+11980634
+11931760
+11787814
+10801786
+11287421
+12167609
+10333516
+12450842
+12620189
+10383978
+12620798
+14675435
+11278696
+17143298
+15977061
+12135786
+17520163
+16141329
+10085383
+11938437
+12095985
+15187115
+15126461
+9683469
+11278076
+15325281
+12209014
+11504738
+15016405
+11856366
+10859323
+12027902
+16373435
+12093728
+12075506
+11106509
+10924871
+10550571
+12019563
+11514614
+10828854
+11821098
+11747626
+10677213
+11732910
+15178420
+12070015
+15695932
+1664536
+15138607
+10841080
+11790779
+12027406
+12615335
+11321078
+12235182
+10477718
+15516505
+12899521
+10950949
+12367738
+10496303
+15196029
+11191357
+11035004
+15165819
+11698249
+11377976
+10671569
+12445816
+12474229
+10893425
+11966773
+11483358
+11085997
+15616821
+14689454
+12172575
+11095946
+12963366
+16648306
+10482502
+16893643
+11592592
+10334393
+12951338
+11801662
+12183056
+12382038
+12182844
+12591902
+11229470
+10637279
+11107161
+10483945
+16933036
+11053378
+12694185
+15492278
+14718666
+11136469
+11898002
+12480540
+11778657
+10652340
+15451095
+17385716
+16141522
+11558822
+11193807
+11762872
+17498266
+1969394
+16142438
+11177577
+11011148
+11793614
+12086582
+17720952
+16144521
+11601893
+10937355
+16241859
+10880444
+10794407
+11576342
+12116231
+14623826
+12948487
+11756564
+10395911
+1860836
+10837477
+12581159
+10503549
+14672737
+12029041
+11781319
+11166129
+12210501
+16088344
+12204801
+10805799
+10762614
+12212799
+10843754
+11846562
+15219899
+11697742
+10323866
+12011764
+16930708
+10768758
+15546870
+9651385
+11152573
+14615059
+16491129
+11988330
+12200431
+10785390
+10713102
+10777662
+16938461
+10857755
+10481082
+11764062
+11895916
+10816589
+1435259
+10764711
+14977627
+11668062
+15358414
+10749882
+1304370
+7494476
+11369633
+10880265
+10668397
+1784821
+12121992
+17030865
+11485998
+12095712
+12535070
+17608699
+11927593
+12765942
+10759707
+11576469
+10601028
+11380947
+12058028
+12369628
+17718165
+16814119
+12859856
+1453957
+11701952
+10913096
+10048764
+10853961
+11188688
+12123461
+12207029
+1322798
+12162872
+11150965
+11910310
+11786531
+10715557
+10386866
+8631668
+11791620
+12618911
+10729302
+14645113
+11237432
+17097644
+10744973
+10742712
+12547701
+10913157
+1280226
+16313349
+11683717
+10871327
+12453470
+12389629
+10809956
+12122017
+10876189
+11673429
+15667305
+17556024
+15743952
+12023963
+10744742
+12397057
+16733717
+16603638
+12219026
+10880237
+12035531
+10346978
+15448014
+11027680
+11043495
+9013968
+11073923
+11204787
+12208674
+11926829
+11800374
+17166591
+15760679
+12242079
+11401395
+11069033
+12372421
+14585198
+7642514
+11689695
+12445830
+11177574
+12675795
+10656999
+11751921
+12061839
+15175298
+10402467
+11827967
+10734131
+11104279
+11078185
+8760804
+12228244
+12540637
+15475360
+10600368
+11786945
+11172811
+10805224
+16678201
+15644921
+12008951
+12890448
+11069768
+12043833
+15536520
+12054167
+12122014
+11911953
+11842728
+12897000
+16311596
+10708856
+7797557
+3123701
+12889030
+15986426
+10453248
+12065429
+10681513
+12445308
+12183469
+17559509
+16102971
+10712687
+12008017
+12869629
+10813775
+10525311
+11840488
+11259585
+15489450
+15228543
+17227768
+17123393
+17403058
+16236249
+10820029
+14596814
+11826162
+15655294
+11831556
+11976295
+11737582
+10234829
+10880263
+17151939
+11849540
+11713532
+10720953
+16221990
+10931310
+12082094
+11458008
+11158321
+15805778
+12519208
+16833362
+10801807
+10334384
+12242338
+16981702
+11827972
+15589699
+17236132
+16625003
+10878134
+15198983
+12536240
+15684737
+16700073
+15078877
+12446795
+11257325
+15955463
+1592811
+10674396
+10918068
+17445180
+15452191
+15863281
+11734557
+16716600
+12529443
+12374462
+15544836
+15450129
+14659742
+10699184
+11283302
+10208590
+11792966
+12527202
+10806350
+12460564
+12417715
+12702500
+15242342
+17854304
+10806167
+10762511
+11591708
+17445185
+10975992
+10975996
+11390685
+14640038
+14735319
+10998166
+10781535
+16769147
+12782148
+12629213
+11524459
+12746538
+11602054
+11893753
+12135764
+12081963
+12386808
+11836498
+12890449
+12154091
+11801754
+10913605
+12509515
+11600198
+11440635
+10809742
+11673498
+15225322
+10880230
+16007120
+12107724
+17200871
+11790164
+12151397
+12202460
+11821070
+12957692
+15967374
+11791205
+17052915
+10850706
+12940989
+12694615
+10433361
+10476035
+11859273
+12606394
+10913081
+15050608
+10479400
+11894099
+12783891
+12669426
+10941835
+15279406
+10479492
+12956947
+11840499
+15086570
+10525403
+14769149
+14751865
+10801796
+12207887
+16890899
+16731582
+11923198
+11795295
+11773079
+15940148
+10433809
+10206959
+11714429
+10455087
+10197994
+10860730
+12200112
+16887987
+17317745
+1906926
+17562991
+12029094
+9004507
+17942893
+11529665
+11787853
+12517327
+15090730
+10843756
+12444553
+11438314
+12185535
+11549182
+11278598
+16564157
+10416429
+11395482
+11254692
+11587854
+12748194
+12006491
+11322879
+10642296
+15289616
+17183024
+3919021
+12096920
+15466872
+11796541
+11894222
+16141536
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/fsu.dev b/huner/ner_scripts/splits/fsu.dev
new file mode 100644
index 0000000..cf2b407
--- /dev/null
+++ b/huner/ner_scripts/splits/fsu.dev
@@ -0,0 +1,330 @@
+11488463
+12141441
+11551215
+11114723
+10881198
+15879703
+12016153
+12673057
+15613280
+12393884
+11641396
+12297098
+11743730
+15215595
+11789762
+12900013
+12183102
+11867536
+10386855
+14614356
+16583313
+16210473
+11007778
+7523145
+10411736
+11470536
+12592707
+16318579
+15961508
+15749028
+11997174
+11781009
+11809823
+1898930
+12101186
+10792815
+10744668
+17587580
+12105219
+9987136
+10926859
+7883171
+10976008
+17675291
+16325183
+12015329
+12060708
+3127379
+10729144
+11873003
+11434463
+10671293
+16564702
+12670940
+10809234
+9683503
+12704196
+11333265
+12126615
+10924517
+10075739
+11086080
+16681467
+14612209
+12547389
+10691110
+11278412
+15225315
+14731280
+1518043
+15838554
+17434987
+10744651
+11722993
+10720944
+15153517
+11868823
+17130561
+10940736
+12379719
+10433729
+11361004
+10555964
+15138264
+17082569
+12393902
+12082086
+12492863
+11303589
+11038188
+12946101
+15618158
+12559906
+11375975
+11134882
+17137555
+11023659
+17640874
+12218090
+10218357
+11956183
+2512576
+12562757
+11793852
+11891665
+10801848
+12140183
+10379899
+11278550
+11587361
+10917982
+8501065
+10852886
+14551259
+10205099
+12050117
+11700562
+11929878
+12297502
+10875271
+16829306
+11859120
+12650457
+12218058
+10995454
+15760680
+12794136
+11096461
+12064592
+12161434
+11598233
+11792123
+11069186
+16282332
+15649902
+15878672
+14622120
+10441243
+14650355
+12374819
+11823470
+9727029
+9234477
+17170464
+17381685
+15985713
+12511422
+12478664
+15310528
+12084819
+16899371
+15513925
+12838448
+12906869
+11021254
+12055595
+14693161
+10799525
+14628103
+12824067
+11331035
+12411321
+12080057
+16765491
+10560997
+12032142
+10864672
+12184921
+12060498
+14581000
+11013304
+11359651
+10811864
+9006059
+12948628
+11707463
+17385066
+15797645
+17158102
+16707463
+17694954
+12954644
+15191745
+12760421
+11988505
+10752835
+10866832
+11901358
+15314042
+12672190
+10816008
+12010552
+12089359
+11842212
+12650940
+16978071
+11999028
+10836749
+12060656
+11726664
+11052813
+11145841
+10074087
+16179013
+14609568
+11785939
+10603362
+14688344
+9422603
+10800598
+11298490
+11950878
+10872823
+15252864
+12870661
+16870466
+11566732
+10686180
+10471383
+10788346
+14519128
+10022905
+11747620
+11061520
+12873803
+10942208
+11100732
+10816131
+10760806
+11438518
+16233813
+12493765
+15044475
+11457489
+9852014
+11376113
+12411432
+11296244
+12426353
+10867000
+11181533
+10934230
+11740806
+15477601
+11911837
+11831386
+15254788
+11860830
+17047292
+10428074
+10806195
+12717106
+15761036
+16672525
+11810296
+12393168
+11747621
+17949365
+10094682
+11243705
+16503147
+10779906
+11580218
+16226501
+12110681
+12606558
+12065583
+12563002
+10505742
+11849417
+10026210
+12112824
+12359436
+10806052
+11570561
+14623738
+12373863
+11021934
+10783262
+15066032
+17264953
+11157961
+15342926
+12799416
+12401780
+15919670
+11554781
+10886368
+11395479
+11923311
+16929347
+15342575
+11368790
+17028280
+15979078
+17559875
+11760398
+11306582
+1938874
+12457460
+10027967
+1527488
+13129615
+13679026
+11926999
+11742001
+12508640
+12198491
+10561251
+11145839
+11748169
+9422764
+11412995
+17185548
+7749980
+12439719
+12356733
+12124628
+10984608
+11032023
+11950392
+10772530
+11721045
+15606615
+11477104
+10094685
+10463184
+15180759
+14756770
+10074428
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/fsu.test b/huner/ner_scripts/splits/fsu.test
new file mode 100644
index 0000000..eea9309
--- /dev/null
+++ b/huner/ner_scripts/splits/fsu.test
@@ -0,0 +1,993 @@
+12107172
+10208865
+11821406
+17376200
+10518822
+17331479
+10479407
+11773921
+11580757
+17046810
+1445207
+14982626
+11290834
+11888290
+10527106
+11148048
+10788508
+10929042
+12858014
+11478396
+10632977
+10601301
+10743660
+11809755
+16458279
+12095414
+12221085
+10805227
+15075204
+11599797
+17316136
+10646643
+10400595
+9696775
+10754314
+12270931
+12942639
+10802239
+11714857
+11815625
+12090913
+11406275
+17339483
+11567029
+11944986
+12061840
+12138086
+11448124
+16545442
+11526079
+17681941
+10406466
+15803059
+15691134
+11896212
+11115104
+11953756
+11712085
+1922387
+12200107
+10516072
+14551329
+15473955
+12145340
+11920156
+11397793
+11259417
+11994151
+9873047
+10097129
+16431125
+11784720
+9922240
+2492118
+14585813
+11207248
+1569009
+11387329
+17097159
+10873786
+16675088
+12297987
+16567866
+12411323
+9464792
+12702545
+11278437
+12077440
+11784131
+10806445
+15781458
+10479404
+17420258
+12101100
+10667797
+15650111
+10975987
+12077706
+14565860
+15851013
+10961952
+15124210
+17519850
+10770767
+12444963
+12011083
+12208494
+11285285
+10708368
+12077248
+11985526
+16440738
+11751917
+11785085
+11073942
+11729309
+11010978
+14717060
+3919317
+9401028
+12297480
+11727264
+16537643
+10899159
+11513144
+12618449
+12483523
+14689281
+10683824
+11846980
+12125072
+11069677
+11978777
+10485585
+15381183
+10727695
+9696771
+10721712
+12212789
+10815997
+17182560
+15248031
+10717352
+16227578
+11738085
+11022047
+11723500
+11032827
+12441142
+11938494
+11470797
+11223948
+10586519
+12446650
+12123454
+10468601
+11390699
+11397878
+11240095
+7494477
+11089975
+12533482
+10982859
+11396990
+12600028
+12856330
+10713460
+10637310
+11854298
+10196125
+11532937
+12086191
+11470772
+12239140
+15120116
+11479134
+10713345
+10601204
+11641397
+11134421
+11466562
+11514509
+10393925
+10623432
+11154405
+11787322
+10550139
+8093697
+12699689
+12198183
+17398095
+15198671
+16241862
+11818523
+12620808
+17713902
+10720441
+15293449
+1329027
+12086470
+12057949
+17017556
+14871302
+1846781
+12160520
+10755408
+16822623
+2997585
+10748552
+12133833
+10506160
+16973241
+12052896
+12037021
+16237016
+11580941
+12963345
+11473265
+10618369
+16624365
+15854555
+10528035
+12192075
+11056395
+8289242
+11022049
+12697152
+11120754
+11237602
+14572508
+12010812
+11439135
+12393171
+11052810
+11684676
+15371877
+10704255
+16978907
+16139357
+16289960
+11035230
+10744645
+16465597
+11418762
+11076872
+16671942
+11282467
+11170888
+10747015
+12409310
+12049201
+10451209
+14617649
+15699037
+11844144
+12111645
+15504367
+11965438
+11548209
+12504121
+10497266
+10674215
+10362897
+12037680
+12100559
+16882169
+12524540
+9271869
+10938793
+16103156
+12210723
+12596048
+10837290
+10206709
+12501174
+17027170
+12744775
+1328224
+10769407
+11161461
+11741957
+14500632
+10709104
+15026176
+16153628
+12493005
+12849706
+10777536
+12119233
+9774442
+11891225
+10613859
+11546807
+10737588
+10620120
+11356143
+11883937
+7704261
+15194195
+12126641
+15368361
+10686096
+11244571
+12242076
+10833331
+10757809
+11553286
+17637225
+12601022
+11888867
+10862610
+12396724
+15207247
+15975820
+12482935
+11737064
+10551805
+11750878
+10600651
+15684739
+11223717
+15025427
+10775603
+15705184
+12409289
+10749681
+11444864
+11179692
+10864922
+10638746
+12062487
+11761714
+15575692
+16187538
+10187858
+11470784
+11796738
+12588519
+10551848
+11690642
+11416004
+10761703
+11788785
+10729625
+10880255
+11399983
+11395449
+17445179
+12649177
+11739466
+11994457
+11444906
+12869989
+10642534
+15379246
+11437344
+10090404
+11825561
+11920455
+11827176
+15803651
+17962451
+11984834
+11479697
+14996803
+10655207
+10944537
+12114499
+15598443
+10644770
+16857169
+11897449
+11152697
+15049811
+12941614
+11497491
+12606287
+11985622
+16128374
+1321115
+10937698
+14986479
+11914737
+15053766
+11583621
+15979891
+11807624
+10369872
+11353725
+10753043
+11787467
+12082095
+15580659
+11448118
+12693801
+12044248
+14573821
+16160843
+14697268
+12585964
+12482858
+10670650
+11823532
+11876708
+15547256
+11912161
+10752558
+12054652
+11356838
+10876090
+14660869
+12062429
+10395199
+11384981
+11787469
+9053439
+12167596
+11440636
+15778373
+12167620
+10873612
+11144295
+12516569
+15778339
+10777712
+9852015
+12890451
+10880227
+14698140
+15207246
+16808796
+11818675
+15153310
+10908112
+11531333
+11742080
+11514624
+11149924
+15212428
+10899166
+11902738
+12010840
+10952944
+14529621
+11160004
+14572467
+15514853
+10438493
+10480937
+12021920
+11883898
+15144571
+11741348
+1326789
+17878237
+10954915
+10411757
+15655823
+10684976
+17455326
+11992404
+10767540
+11139773
+10734050
+11101674
+10843736
+11727073
+16950633
+10464228
+10964484
+11948912
+9497500
+11461926
+14726627
+16423827
+12054582
+11795260
+16213747
+15485810
+7768864
+11208485
+10719247
+16046400
+16672219
+10443990
+12800216
+12401728
+11134135
+15585135
+11896048
+11787847
+10816566
+11437403
+12584323
+16717106
+12138164
+11797095
+11577372
+11969340
+12957669
+11181969
+10551881
+10712517
+16006581
+10393192
+10774747
+17166910
+17156396
+11847269
+16800782
+10777589
+16213154
+11992112
+11278997
+10423193
+12509459
+10781601
+12547700
+12615965
+1575712
+11196700
+10762075
+12200116
+11163076
+16508981
+10841074
+11901424
+10794532
+11196108
+12867478
+11034560
+11967569
+10984492
+17267952
+14964690
+15749710
+10552357
+17092867
+12196012
+10810295
+11023662
+10089131
+10322169
+15616579
+12496348
+15566952
+12417738
+9767589
+10729169
+14769146
+11446592
+15862171
+11297552
+1900507
+12606523
+12050164
+11470801
+12162656
+16438846
+10753311
+8002610
+1544897
+11111049
+16980972
+17070001
+10777493
+10748161
+9234478
+15289321
+11932251
+12391228
+17707376
+10424431
+10996355
+10623829
+11010960
+11212279
+11337197
+9287022
+10848618
+11260213
+11501944
+12368440
+11592315
+10938022
+11467967
+11121055
+14698139
+16003522
+11472112
+11446515
+10691098
+11733582
+12184911
+12218041
+9826699
+10318834
+11753385
+12015308
+9555886
+16203124
+11956185
+10806390
+10441449
+12359356
+11257042
+10437043
+16618968
+12154078
+11177576
+16325497
+11597129
+16582573
+16388920
+12723950
+10493876
+12217688
+12067979
+12909634
+15871661
+12481074
+11994747
+10075935
+10556263
+11912189
+12864862
+16781756
+14567959
+16648635
+10853826
+11586363
+14645248
+15096181
+11313136
+7540694
+8231806
+15804597
+11924557
+17238829
+10529246
+12871401
+10824114
+16806821
+12699619
+12374820
+10666375
+12668644
+16226465
+11359836
+15629928
+8148054
+11719522
+9535080
+11052814
+16530177
+10838667
+12483210
+11179674
+12210795
+10704252
+11839732
+10464187
+17301953
+10416558
+12045490
+12960331
+11169398
+12154120
+11055401
+11374071
+11595478
+11812157
+10666713
+11583428
+12223399
+15665098
+12553867
+10986234
+9894849
+12949161
+11330712
+10654608
+12084720
+15364938
+17349709
+1537790
+11098931
+12081504
+12414651
+11840501
+16620271
+12773564
+12639299
+10843753
+14594816
+9636707
+17493145
+10505738
+10760946
+10049523
+11278501
+11888289
+17425335
+12974468
+10714560
+11160264
+12441141
+8460143
+12788308
+15988019
+15242697
+10965217
+12664264
+16750378
+11576463
+11856758
+15830122
+15242101
+12064938
+10841072
+12016134
+15714591
+11602355
+10511216
+11856887
+12133843
+12559621
+10331730
+10777610
+12608515
+16713539
+11929525
+11788600
+16641112
+12481029
+11022048
+11872359
+10205588
+15987779
+10627506
+11145846
+10731616
+11800371
+15869883
+10809293
+9765287
+12359330
+12149259
+17405810
+10888117
+11928817
+11727258
+10995028
+12391192
+15146989
+12842759
+10644686
+15294958
+2500529
+10650933
+12515039
+11988089
+12536572
+14764684
+14984034
+12213900
+14565861
+16210627
+16723255
+15980341
+11083282
+17928781
+10638706
+15549734
+10913077
+10629188
+11352467
+16978067
+16209565
+10714556
+12857835
+14769145
+15101990
+11799131
+11590544
+11854171
+10525310
+12200141
+11050078
+12416719
+10671297
+10026226
+11860275
+17140415
+10964167
+15469704
+12368812
+16040600
+15223114
+16689656
+11827469
+15388262
+9108277
+12006660
+11815670
+8752328
+12244172
+11299368
+16216871
+17368449
+12808018
+15664650
+12039681
+16099870
+13129950
+10200961
+3114422
+15036241
+10972841
+12104097
+12110693
+16231097
+10629055
+7814326
+12054577
+10475610
+16204540
+16754669
+11145836
+12930526
+17593905
+17316137
+11429164
+11827482
+12096923
+10774739
+10531379
+8547713
+3086839
+12127786
+11787815
+10890180
+10767533
+9774382
+11278918
+14532085
+11226182
+12359428
+10864042
+11063594
+10346902
+11991731
+10802742
+16786149
+10930313
+15077295
+11594795
+1310678
+14983519
+11787938
+16562482
+14551929
+11331269
+11211150
+10972806
+10228795
+11284964
+12967650
+11278317
+11594787
+12813074
+14982625
+12027405
+12367750
+12134158
+10653706
+15140215
+17522365
+10454568
+10846076
+11243704
+12368450
+11836615
+11397877
+10819462
+12391842
+1902213
+14729681
+12538663
+11683586
+11342549
+12100725
+12151636
+12095614
+16487030
+14687581
+14651778
+12019269
+1460045
+11672453
+11418696
+11444905
+15967376
+9139908
+10318773
+12482849
+11904153
+11777003
+10781648
+11298491
+10873451
+11781669
+11814311
+11116209
+11443112
+10837361
+10515909
+10515915
+15609880
+11483596
+10869428
+12368292
+11489845
+16487027
+15912356
+12801995
+15569944
+12200142
+16276440
+11815617
+10390542
+11574907
+10816046
+10913108
+11797931
+10193950
+10887190
+11866033
+11500082
+12672064
+11215376
+15877868
+11992252
+11780382
+16512604
+10874999
+14766582
+11889189
+12208868
+14597230
+12084581
+12594244
+12879269
+15598441
+10777495
+15838788
+15102883
+14767566
+11879108
+17132863
+12729017
+12297112
+12734186
+11838058
+12110845
+2468649
+12200131
+7592487
+11880369
+11054280
+11035787
+12068077
+17954611
+11237435
+7896717
+14718842
+11592532
+1366745
+17367808
+1400361
+11867163
+10819995
+16098201
+16115854
+11023677
+10393969
+17827149
+11080639
+12226108
+10998244
+12160524
+16108732
+11735224
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/fsu.train b/huner/ner_scripts/splits/fsu.train
new file mode 100644
index 0000000..fa2406d
--- /dev/null
+++ b/huner/ner_scripts/splits/fsu.train
@@ -0,0 +1,1984 @@
+10194230
+10092847
+10342536
+10393201
+9915850
+11777632
+11500377
+10542274
+10536788
+11580301
+10207115
+10329574
+10518496
+11595170
+11776922
+10224257
+10026146
+11895184
+10381570
+10488087
+11791585
+10373029
+10051030
+10376065
+10557072
+11743612
+10484818
+10318806
+10394116
+10403839
+10191090
+10487753
+10463057
+10022210
+10548434
+10380232
+11303027
+11773168
+10194225
+11586096
+11337487
+10422291
+10555079
+10082573
+10390538
+10493203
+11862350
+10426450
+10464302
+11895024
+10070158
+10448095
+10541550
+10201468
+10487217
+11785827
+10216052
+10438540
+10468033
+11686239
+10517666
+10393422
+10487040
+10373523
+10445506
+11705093
+11858635
+11881923
+10385915
+11433002
+10471746
+10531360
+10359014
+11691585
+10344736
+11675912
+11861092
+11787746
+11732417
+10370675
+10381377
+10394900
+10540915
+10359575
+11589779
+10358079
+10196316
+11687352
+11593394
+10380659
+10233946
+10394919
+11677363
+10512882
+10502402
+10556751
+10938276
+11802580
+11726574
+10323863
+10187842
+10400757
+10369418
+10692449
+10369926
+11893767
+10395920
+11908529
+10406047
+10347197
+11160280
+11828186
+10446149
+10498706
+10358080
+10497117
+10439040
+10400032
+10435595
+10228157
+10049359
+11596838
+10393197
+10215594
+10194451
+10333529
+11791853
+10523674
+10531342
+10063739
+11800878
+11888183
+10514493
+10363517
+10360947
+10467465
+10103002
+10231581
+10428811
+10190324
+10491187
+10521345
+10478844
+10505694
+10452951
+11679441
+10330159
+10326856
+11156579
+10477583
+10501656
+10441483
+10330396
+10487762
+10485470
+10455189
+10331875
+10281637
+10358031
+10380890
+10385395
+10403690
+10479382
+10406464
+11604152
+11915436
+10430421
+10446912
+11743360
+10336495
+11883682
+10489680
+11730712
+10375107
+10454550
+10491213
+11683558
+11811825
+10037378
+10510379
+11685047
+11913427
+11584328
+10477599
+10220364
+10490609
+10375718
+10440923
+10454557
+10444597
+10429740
+11578685
+11677839
+10320480
+10467403
+10527158
+9837933
+10402022
+11822811
+10087549
+10087993
+10091594
+10447597
+11834476
+10397257
+10560014
+10406459
+10409755
+11639485
+11816779
+10543727
+10209021
+10390158
+10698937
+10066790
+10350484
+10458907
+10460015
+10524258
+10483124
+10347144
+11687180
+11590364
+10223338
+10517675
+10022925
+11687869
+10181397
+10097120
+10438607
+10231485
+10454533
+11846167
+10428091
+10086544
+10398682
+10518937
+10376874
+11902781
+11826141
+10208893
+10207090
+10467004
+11822790
+10353073
+10082554
+10487307
+11669476
+10392266
+10215811
+10411139
+11597185
+10487744
+10553551
+10364159
+10498717
+11824801
+11870646
+10366503
+10428759
+10712618
+10219091
+10339566
+10074282
+10447593
+10214610
+10449899
+10080875
+10146207
+10516878
+10052878
+11737056
+11704380
+10095059
+11761601
+10205176
+11837409
+10391075
+10531446
+10369625
+11806132
+10198061
+10523640
+10554946
+10243927
+10090146
+11587980
+11853943
+10068834
+10409749
+10364076
+10454540
+10085140
+10407985
+10322629
+10455183
+10036191
+10330168
+10493580
+11920896
+10090943
+10068637
+11695481
+10395378
+10411140
+10487759
+10458914
+10444813
+10327051
+10422468
+11887803
+11844591
+10366722
+10225945
+10429184
+11890354
+10339552
+10233147
+10372627
+10406465
+10200473
+10406122
+10026275
+10409724
+10347203
+11863811
+10049775
+10101198
+10466825
+10533066
+11858548
+10366446
+10319320
+10087213
+10051400
+11782218
+10540015
+11595813
+10502216
+10544088
+11738404
+11858256
+10029917
+11800119
+10471743
+10320579
+10448036
+11744290
+11804510
+10318900
+10328351
+10099247
+11736254
+10348859
+11740571
+10206152
+11775180
+10071205
+10347839
+10355085
+10367240
+10478275
+10551788
+10551879
+10487760
+10073947
+10535715
+10226029
+10474898
+11830544
+10430583
+10095062
+10071761
+10369775
+10376873
+11885053
+10196597
+10458905
+10521443
+10021333
+10025050
+11711701
+10037004
+10330134
+11737158
+10460171
+10486210
+11897888
+10529354
+10527475
+11600252
+10469656
+10430580
+10375638
+10215850
+10322022
+10496284
+10501965
+10092856
+10385384
+11708761
+11802601
+10482516
+10425094
+10446998
+10545281
+11768467
+10496161
+11597936
+10082585
+11599840
+10934204
+10323463
+10559207
+10199539
+10099576
+10212969
+10086725
+10376446
+1827203
+10102136
+10532805
+10541865
+10556145
+11726068
+10556029
+11709561
+10534402
+10544089
+11836303
+10357751
+10340447
+11693461
+10320177
+10562418
+10457075
+10544113
+10341219
+11825801
+11728771
+10080901
+10523647
+10487921
+11589568
+10366559
+11596104
+11769229
+10212284
+10497800
+11606538
+1346534
+11778044
+10209119
+10534048
+10096469
+10195425
+10343189
+10518561
+11800586
+10084294
+10076007
+10492127
+11881268
+10065176
+10350027
+10021350
+10101744
+10217683
+10098601
+11783457
+10340883
+10094701
+10228155
+10072774
+10400794
+10379942
+10484695
+10898795
+10090125
+10392914
+10226838
+10376991
+11698403
+10049912
+10448902
+10523319
+10377438
+11904017
+10171173
+10359664
+11786248
+11824701
+10212426
+10085605
+11706949
+10478848
+10027498
+10470220
+10536125
+10559324
+10207041
+10325413
+10536369
+10215608
+10225279
+10549354
+10349443
+10409730
+10097932
+10207092
+11860876
+10329586
+10488088
+10220275
+10430944
+10085120
+11842037
+10542260
+10318918
+10477545
+10359663
+10229668
+10509768
+10209759
+10551796
+10355536
+10548722
+10556063
+10221467
+10417703
+10466306
+10523663
+10068446
+10373507
+10543949
+10498616
+11765448
+10544037
+11723511
+10518502
+10400593
+10526670
+10069815
+10359792
+11580173
+10082570
+10074135
+10391246
+10332733
+10364314
+10485353
+10490639
+11791571
+11912261
+10859308
+10229084
+10413604
+10453721
+11781615
+10464185
+10187864
+10561460
+11599079
+10471696
+11893403
+10517672
+11680835
+10490816
+11845547
+10367460
+1833185
+10350454
+10078734
+10364202
+10504332
+11577094
+10556033
+10068418
+10495573
+11803325
+11804081
+10074520
+10545192
+10413676
+11866130
+10231862
+10196266
+10473623
+10403575
+10559364
+11793172
+10555285
+10194762
+10497262
+10216161
+10367646
+10196248
+10559303
+10438593
+10464291
+10488337
+10413607
+10342511
+10542281
+10080436
+10235265
+10383966
+10442493
+11708362
+10022850
+10436016
+10423292
+10073899
+10446131
+10422342
+10556044
+10355910
+11835109
+10413662
+10491133
+10527426
+11710685
+10384129
+10508522
+10557008
+10102627
+10210952
+10232078
+10022032
+10430886
+11600467
+10228009
+10195697
+10453006
+11890438
+10365883
+10543270
+11884014
+11726022
+10414451
+10501969
+10450815
+11500512
+11684665
+11898797
+11585739
+10096573
+11707977
+11587514
+10713175
+10559320
+10490604
+10503540
+10556028
+11005831
+10496553
+11899479
+10407184
+10198056
+10419006
+10231454
+10026211
+10319955
+10379547
+10476970
+10561153
+11777575
+11804100
+10525413
+10488147
+10036181
+10212278
+10072205
+10205933
+10523634
+10393910
+10452306
+11787041
+10471587
+10211919
+10024882
+10542237
+10490826
+10358075
+10501936
+10022875
+10489822
+10551867
+10550574
+10380878
+10400760
+10218200
+10395827
+10469140
+10499357
+10098744
+10026824
+10347220
+10364319
+10376877
+10473589
+10196318
+10049742
+10419521
+10497874
+10513756
+11836046
+10037774
+11860097
+10198003
+10192638
+11790897
+11741259
+11831512
+10396793
+10024498
+10050883
+10232872
+10323225
+10234698
+10516738
+10085088
+10400712
+11810685
+10203611
+10029860
+10074425
+10407269
+10271171
+11726413
+10326654
+10329135
+11846187
+10308312
+10521447
+10370778
+10438941
+11708431
+10477748
+10037681
+10392900
+10333526
+10438627
+10475972
+10714992
+10521544
+10360454
+10425445
+10218109
+10398286
+10561546
+10022921
+10224289
+10395283
+10228561
+11912677
+10454561
+11763176
+11723675
+10543728
+10078876
+11715079
+10037460
+10391903
+10211422
+10392669
+11642687
+11726262
+11911552
+10493575
+10502434
+11819326
+10192432
+10540292
+10882741
+10094396
+10206698
+11815644
+10545248
+11852907
+10496388
+10187798
+10393251
+10358138
+11704829
+10487953
+11885737
+10473598
+10492169
+10342829
+11874637
+10209031
+10409741
+10226074
+10192134
+10542249
+10441506
+11882747
+11847580
+11907691
+10553959
+11708032
+10479025
+10359603
+10429946
+10026784
+11840365
+10024383
+11278488
+11686378
+10358083
+10194769
+11787720
+10512699
+10049357
+10197985
+10207049
+11775301
+10095061
+10353880
+10468585
+10022880
+10477620
+11917882
+11600314
+10460172
+11921126
+10233885
+10221820
+10383764
+11730182
+10482565
+10748164
+10409656
+10068674
+11760796
+10903325
+10380800
+10153759
+10321158
+11727209
+10399136
+10464310
+10025506
+10092132
+10051488
+10364425
+10471721
+10518956
+10026229
+10400785
+10516011
+11900770
+10426878
+10557308
+10543730
+10490662
+10488148
+11844812
+10438924
+10094314
+10556046
+10374632
+10503812
+10224513
+10064604
+10350638
+11692004
+10561095
+10369965
+10392903
+11595840
+11917061
+10459809
+10490955
+11897791
+11703558
+11706668
+10463242
+11736792
+10360839
+10532354
+11687517
+10748054
+10223498
+11865218
+11697760
+11687737
+10428862
+10231513
+11833863
+10082137
+10377345
+10482620
+10074903
+11689217
+11851941
+11766747
+10364523
+10448285
+10430883
+10073940
+10333481
+10406843
+10534691
+10438950
+11349124
+10094691
+10548622
+10319327
+10367385
+10381257
+10417331
+10497199
+10369757
+11755894
+10521450
+11771979
+10334888
+10027904
+10551816
+10224293
+10202006
+10388670
+11036939
+10224244
+11899489
+10330146
+10065684
+10521796
+10446206
+10556595
+11859400
+11882054
+10329625
+10445161
+11600686
+11742432
+10540553
+10428294
+10531334
+10406954
+10490835
+11791292
+10375640
+10446833
+11579100
+10101159
+11605598
+11764226
+11703464
+10405635
+11883763
+10195690
+10196127
+10409699
+10395908
+10085505
+10490843
+10396343
+10512857
+10542269
+10423156
+10472836
+11860723
+10068040
+11875695
+10022858
+10477597
+11894605
+11876937
+10511554
+11909404
+10452991
+11843252
+10359673
+11816458
+14584942
+10455143
+10103057
+11732088
+10232600
+11726164
+10449072
+11811743
+10215485
+11867388
+10541432
+10207087
+11724510
+10231026
+10488129
+10375694
+11600365
+11792586
+10516026
+10077533
+10224758
+10329736
+10326221
+10488875
+11859943
+10490822
+10523520
+11716043
+10446910
+10029337
+11669281
+11778804
+11678437
+10510295
+10197763
+11602353
+11595176
+10066815
+11898018
+10454570
+10562456
+10075415
+10378989
+1744042
+10090535
+10091619
+10318859
+10430890
+10499121
+10071806
+11718197
+10037576
+10361038
+10529198
+10102000
+10549912
+10453371
+10329566
+10427654
+11744953
+10392710
+10433970
+11886473
+11741554
+10077188
+10022978
+10362652
+10513922
+10502522
+10506143
+10364163
+10022867
+11676899
+10406462
+10066798
+10331276
+10430980
+10687862
+10079173
+10100605
+10542277
+11737900
+10469174
+10212332
+10521509
+11730262
+10331646
+10556089
+10074921
+11716441
+10501034
+11723928
+10229682
+11309652
+11285214
+11795408
+15773991
+16881863
+11836244
+11407111
+11597141
+16024043
+11278906
+10594225
+11698424
+9605119
+10945350
+15135804
+11533230
+1396586
+10671299
+11572857
+10648512
+12901852
+16798779
+10637289
+15036248
+11713982
+16540726
+11680002
+11007056
+12496312
+15598438
+9822625
+15469699
+11790884
+11052816
+12169691
+10692366
+17452927
+11585856
+1836978
+12495080
+12530627
+16169954
+3134591
+15819410
+11208806
+15492870
+11680592
+16343928
+11114248
+15579373
+15996478
+12126648
+10825222
+12930774
+1680916
+16455652
+12359228
+10766860
+11283333
+10052371
+17600048
+16078071
+12857842
+11816009
+12479386
+15220445
+11075930
+17495187
+10768840
+12406748
+17568882
+10930296
+12531696
+10371097
+11741979
+11064201
+10671304
+11251844
+11555653
+9891799
+16260042
+11925441
+10852487
+12362409
+15681655
+15135805
+12813072
+10702265
+10674999
+11547919
+10913073
+11051763
+15231716
+10648098
+15199124
+15110048
+12143056
+11836625
+12351678
+15647926
+11105212
+8946682
+11290784
+9841221
+10531340
+11161269
+10658621
+10433355
+15629932
+10972809
+11390511
+12932582
+16213746
+12499396
+12967642
+15549775
+10779323
+12657290
+11710991
+15879158
+16607637
+12606567
+14751239
+11931557
+10049518
+12016223
+17127808
+16777077
+11302826
+11859088
+11576341
+12050388
+11129656
+11849796
+15975065
+15159391
+3104146
+7966271
+12371681
+1833068
+11044210
+12525632
+11251120
+16326927
+11037881
+10753935
+11818231
+11840773
+1325437
+15653801
+10571676
+10820258
+12393901
+2163341
+9880565
+10564485
+11448122
+12359327
+15631776
+12034027
+12374808
+11864750
+11074787
+10464250
+12849708
+12967644
+11153078
+11526245
+17407096
+11832019
+12519752
+14596817
+8169223
+16680816
+17459655
+11441017
+11297543
+10770210
+10900038
+10756105
+15851489
+15744581
+10768941
+15748978
+12023287
+10799531
+12096904
+14556191
+11244065
+10878124
+17142756
+16734562
+16554930
+17082908
+12149458
+11251884
+10735855
+10753602
+10770741
+10613862
+3106319
+15296756
+7570023
+11279170
+17610203
+8320224
+12615363
+15886715
+10777568
+9846747
+12610214
+17699749
+15183842
+12147251
+12670445
+10220166
+11781834
+14993925
+10760150
+10831800
+12421953
+12226101
+16524739
+11687083
+11405762
+10660889
+11319766
+16144421
+15598655
+12077351
+12631183
+11789206
+12795752
+12359251
+11390449
+10400774
+10767528
+1906867
+11752821
+11527412
+11408283
+1722683
+15355992
+16487070
+11966460
+12392158
+10913114
+10527180
+7679386
+16949074
+11886172
+12031497
+10049515
+10714559
+16221525
+14767868
+10472314
+9748255
+10211329
+11353842
+12547166
+11466284
+11960377
+11821435
+10713673
+15780179
+10781064
+12606047
+12522211
+14635120
+15749024
+15246276
+9792677
+12027407
+11857550
+14652652
+11032397
+11248049
+12758177
+10514496
+10071212
+11470774
+12421026
+12461076
+10933198
+12505196
+11910344
+9670929
+15845919
+15060086
+17361229
+16959267
+10998353
+12034029
+10400599
+11862463
+14557628
+17348688
+16884913
+11836249
+15496550
+10653735
+12161104
+1905664
+12887900
+14592775
+11156551
+12746539
+11955619
+16704299
+11546873
+11705854
+11956105
+11309819
+11972883
+11959571
+17367410
+11353762
+15901830
+14731281
+9324264
+15115907
+12967648
+11714855
+10875629
+11029690
+11986327
+11315634
+16112868
+15276076
+11329262
+11321589
+17092251
+10814528
+11897950
+2496113
+17079270
+11350937
+11692164
+11553611
+1557036
+16077962
+11380493
+17516550
+11778160
+15503221
+16586115
+11223069
+11022796
+17332243
+1569008
+16216875
+15375573
+10781092
+12453469
+16337773
+10508860
+12354228
+11792001
+10742723
+1900494
+10832746
+12899827
+15671246
+12441140
+14679234
+11716065
+16289551
+11798462
+12718525
+12138090
+11672445
+10613694
+16618101
+11274473
+12213191
+10930734
+2111808
+12668783
+9852018
+11916171
+11597003
+12225856
+11259194
+10391277
+12644691
+10830259
+10754235
+14668138
+10520800
+10759557
+16377203
+10910894
+11751814
+10505750
+16051270
+14580941
+10704245
+9658001
+10809280
+12842763
+17586478
+17512708
+11279162
+11875070
+11971879
+10660620
+11983932
+12393185
+10757795
+3036777
+10206993
+12151362
+10497217
+12296995
+11980634
+11931760
+11787814
+10801786
+11287421
+12167609
+10333516
+12450842
+12620189
+10383978
+12620798
+14675435
+11278696
+17143298
+15977061
+12135786
+17520163
+16141329
+10085383
+11938437
+12095985
+15187115
+15126461
+9683469
+11278076
+15325281
+12209014
+11504738
+15016405
+11856366
+10859323
+12027902
+16373435
+12093728
+12075506
+11106509
+10924871
+10550571
+12019563
+11514614
+10828854
+11821098
+11747626
+10677213
+11732910
+15178420
+12070015
+15695932
+1664536
+15138607
+10841080
+11790779
+12027406
+12615335
+11321078
+12235182
+10477718
+15516505
+12899521
+10950949
+12367738
+10496303
+15196029
+11191357
+11035004
+15165819
+11698249
+11377976
+10671569
+12445816
+12474229
+10893425
+11966773
+11483358
+11085997
+15616821
+14689454
+12172575
+11095946
+12963366
+16648306
+10482502
+16893643
+11592592
+10334393
+12951338
+11801662
+12183056
+12382038
+12182844
+12591902
+11229470
+10637279
+11107161
+10483945
+16933036
+11053378
+12694185
+15492278
+14718666
+11136469
+11898002
+12480540
+11778657
+10652340
+15451095
+17385716
+16141522
+11558822
+11193807
+11762872
+17498266
+1969394
+16142438
+11177577
+11011148
+11793614
+12086582
+17720952
+16144521
+11601893
+10937355
+16241859
+10880444
+10794407
+11576342
+12116231
+14623826
+12948487
+11756564
+10395911
+1860836
+10837477
+12581159
+10503549
+14672737
+12029041
+11781319
+11166129
+12210501
+16088344
+12204801
+10805799
+10762614
+12212799
+10843754
+11846562
+15219899
+11697742
+10323866
+12011764
+16930708
+10768758
+15546870
+9651385
+11152573
+14615059
+16491129
+11988330
+12200431
+10785390
+10713102
+10777662
+16938461
+10857755
+10481082
+11764062
+11895916
+10816589
+1435259
+10764711
+14977627
+11668062
+15358414
+10749882
+1304370
+7494476
+11369633
+10880265
+10668397
+1784821
+12121992
+17030865
+11485998
+12095712
+12535070
+17608699
+11927593
+12765942
+10759707
+11576469
+10601028
+11380947
+12058028
+12369628
+17718165
+16814119
+12859856
+1453957
+11701952
+10913096
+10048764
+10853961
+11188688
+12123461
+12207029
+1322798
+12162872
+11150965
+11910310
+11786531
+10715557
+10386866
+8631668
+11791620
+12618911
+10729302
+14645113
+11237432
+17097644
+10744973
+10742712
+12547701
+10913157
+1280226
+16313349
+11683717
+10871327
+12453470
+12389629
+10809956
+12122017
+10876189
+11673429
+15667305
+17556024
+15743952
+12023963
+10744742
+12397057
+16733717
+16603638
+12219026
+10880237
+12035531
+10346978
+15448014
+11027680
+11043495
+9013968
+11073923
+11204787
+12208674
+11926829
+11800374
+17166591
+15760679
+12242079
+11401395
+11069033
+12372421
+14585198
+7642514
+11689695
+12445830
+11177574
+12675795
+10656999
+11751921
+12061839
+15175298
+10402467
+11827967
+10734131
+11104279
+11078185
+8760804
+12228244
+12540637
+15475360
+10600368
+11786945
+11172811
+10805224
+16678201
+15644921
+12008951
+12890448
+11069768
+12043833
+15536520
+12054167
+12122014
+11911953
+11842728
+12897000
+16311596
+10708856
+7797557
+3123701
+12889030
+15986426
+10453248
+12065429
+10681513
+12445308
+12183469
+17559509
+16102971
+10712687
+12008017
+12869629
+10813775
+10525311
+11840488
+11259585
+15489450
+15228543
+17227768
+17123393
+17403058
+16236249
+10820029
+14596814
+11826162
+15655294
+11831556
+11976295
+11737582
+10234829
+10880263
+17151939
+11849540
+11713532
+10720953
+16221990
+10931310
+12082094
+11458008
+11158321
+15805778
+12519208
+16833362
+10801807
+10334384
+12242338
+16981702
+11827972
+15589699
+17236132
+16625003
+10878134
+15198983
+12536240
+15684737
+16700073
+15078877
+12446795
+11257325
+15955463
+1592811
+10674396
+10918068
+17445180
+15452191
+15863281
+11734557
+16716600
+12529443
+12374462
+15544836
+15450129
+14659742
+10699184
+11283302
+10208590
+11792966
+12527202
+10806350
+12460564
+12417715
+12702500
+15242342
+17854304
+10806167
+10762511
+11591708
+17445185
+10975992
+10975996
+11390685
+14640038
+14735319
+10998166
+10781535
+16769147
+12782148
+12629213
+11524459
+12746538
+11602054
+11893753
+12135764
+12081963
+12386808
+11836498
+12890449
+12154091
+11801754
+10913605
+12509515
+11600198
+11440635
+10809742
+11673498
+15225322
+10880230
+16007120
+12107724
+17200871
+11790164
+12151397
+12202460
+11821070
+12957692
+15967374
+11791205
+17052915
+10850706
+12940989
+12694615
+10433361
+10476035
+11859273
+12606394
+10913081
+15050608
+10479400
+11894099
+12783891
+12669426
+10941835
+15279406
+10479492
+12956947
+11840499
+15086570
+10525403
+14769149
+14751865
+10801796
+12207887
+16890899
+16731582
+11923198
+11795295
+11773079
+15940148
+10433809
+10206959
+11714429
+10455087
+10197994
+10860730
+12200112
+16887987
+17317745
+1906926
+17562991
+12029094
+9004507
+17942893
+11529665
+11787853
+12517327
+15090730
+10843756
+12444553
+11438314
+12185535
+11549182
+11278598
+16564157
+10416429
+11395482
+11254692
+11587854
+12748194
+12006491
+11322879
+10642296
+15289616
+17183024
+3919021
+12096920
+15466872
+11796541
+11894222
+16141536
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/gellus.dev b/huner/ner_scripts/splits/gellus.dev
new file mode 100644
index 0000000..a66d4bf
--- /dev/null
+++ b/huner/ner_scripts/splits/gellus.dev
@@ -0,0 +1,123 @@
+
+PMID-18451223
+PMID-18455498
+PMID-18469146
+PMID-18499889
+PMID-18502145
+PMID-18505892
+PMID-18537682
+PMID-18554547
+PMID-18559522
+PMID-18564172
+PMID-18565374
+PMID-18566344
+PMID-18578357
+PMID-18581207
+PMID-18600526
+PMID-18646688
+PMID-18657078
+PMID-18662848
+PMID-18667841
+PMID-18669910
+PMID-18670636
+PMID-18671639
+PMID-1869637
+PMID-18709350
+PMID-18717698
+PMID-18761022
+PMID-18761658
+PMID-1877751
+PMID-18789152
+PMID-18814295
+PMID-18824876
+PMID-18826258
+PMID-18829527
+PMID-18835936
+PMID-18841154
+PMID-18852899
+PMID-18922934
+PMID-18942118
+PMID-18945211
+PMID-18953546
+PMID-18953948
+PMID-18979410
+PMID-18980679
+PMID-18995207
+PMID-18996355
+PMID-19000097
+PMID-19050907
+PMID-19075960
+PMID-19080335
+PMID-19082449
+PMID-19091459
+PMID-19098000
+PMID-19101635
+PMID-19109168
+PMID-19118244
+PMID-19139005
+PMID-19148483
+PMID-19152650
+PMID-19163807
+PMID-19164985
+PMID-19208839
+PMID-19219913
+PMID-19223494
+PMID-19232911
+PMID-19236257
+PMID-19240875
+PMID-19269647
+PMID-19278385
+PMID-19292679
+PMID-19295129
+PMID-19318806
+PMID-19323937
+PMID-19338980
+PMID-19347270
+PMID-1934953
+PMID-19351751
+PMID-19351864
+PMID-19360900
+PMID-19369582
+PMID-19372461
+PMID-19380174
+PMID-19389366
+PMID-19406993
+PMID-19416474
+PMID-19422607
+PMID-19444623
+PMID-19446450
+PMID-1945393
+PMID-19471112
+PMID-19481797
+PMID-19489226
+PMID-19509166
+PMID-19514363
+PMID-19528456
+PMID-19540587
+PMID-19542562
+PMID-19556134
+PMID-19570906
+PMID-19574426
+PMID-19575421
+PMID-19576624
+PMID-19594546
+PMID-19595081
+PMID-19605361
+PMID-19620774
+PMID-19622311
+PMID-19622586
+PMID-19623159
+PMID-19625706
+PMID-19632988
+PMID-19636328
+PMID-19637472
+PMID-19637749
+PMID-19648108
+PMID-19654314
+PMID-19679742
+PMID-19695243
+PMID-19700757
+PMID-1970332
+PMID-19706677
+PMID-19717942
+PMID-19721007
diff --git a/huner/ner_scripts/splits/gellus.test b/huner/ner_scripts/splits/gellus.test
new file mode 100644
index 0000000..387a2c2
--- /dev/null
+++ b/huner/ner_scripts/splits/gellus.test
@@ -0,0 +1,364 @@
+
+PMID-19738068
+PMID-19742300
+PMID-19744262
+PMID-19752254
+PMID-19758109
+PMID-19760065
+PMID-19764591
+PMID-19767769
+PMID-19771137
+PMID-19771241
+PMID-19788957
+PMID-19806573
+PMID-19812364
+PMID-198130
+PMID-19843246
+PMID-19917848
+PMID-19919099
+PMID-19922082
+PMID-19953879
+PMID-19956847
+PMID-20006731
+PMID-2003384
+PMID-20061129
+PMID-20112043
+PMID-20116961
+PMID-20124444
+PMID-20129250
+PMID-20143445
+PMID-20157600
+PMID-2028342
+PMID-20345577
+PMID-20346999
+PMID-20353786
+PMID-20379054
+PMID-20385008
+PMID-20392988
+PMID-20433031
+PMID-20448329
+PMID-20460116
+PMID-20525074
+PMID-20549676
+PMID-20554717
+PMID-20562040
+PMID-20563198
+PMID-20564340
+PMID-20565704
+PMID-20570920
+PMID-20597862
+PMID-205979
+PMID-20600540
+PMID-20606040
+PMID-20621240
+PMID-20631994
+PMID-20676141
+PMID-20678472
+PMID-20732829
+PMID-20808831
+PMID-20814749
+PMID-20821256
+PMID-20855870
+PMID-20858762
+PMID-20861187
+PMID-2093149
+PMID-20955597
+PMID-20958264
+PMID-20978192
+PMID-20978953
+PMID-21084727
+PMID-21135106
+PMID-21140139
+PMID-21196269
+PMID-21196400
+PMID-21231550
+PMID-21261822
+PMID-21283795
+PMID-2129802
+PMID-21308684
+PMID-21315571
+PMID-21340684
+PMID-21390189
+PMID-21416173
+PMID-21423801
+PMID-21468425
+PMID-21483806
+PMID-21506108
+PMID-2153347
+PMID-21536653
+PMID-21582121
+PMID-21596785
+PMID-21617625
+PMID-21683672
+PMID-21734284
+PMID-21743150
+PMID-21752900
+PMID-21775419
+PMID-21807601
+PMID-21822531
+PMID-21853499
+PMID-21858812
+PMID-2187437
+PMID-21878661
+PMID-21910784
+PMID-21913457
+PMID-21915357
+PMID-21939640
+PMID-21947854
+PMID-21963494
+PMID-21965773
+PMID-21975934
+PMID-22056386
+PMID-22105864
+PMID-2211345
+PMID-22127321
+PMID-2213113
+PMID-22136381
+PMID-22172720
+PMID-22235331
+PMID-22279574
+PMID-22315407
+PMID-22318232
+PMID-22429855
+PMID-22468084
+PMID-2255190
+PMID-22614711
+PMID-2275272
+PMID-2314900
+PMID-2331105
+PMID-2344835
+PMID-2407842
+PMID-2418866
+PMID-2427928
+PMID-2464672
+PMID-2512762
+PMID-2514403
+PMID-2538232
+PMID-2539554
+PMID-2541348
+PMID-2596160
+PMID-2607031
+PMID-2681013
+PMID-2704697
+PMID-2729721
+PMID-2730023
+PMID-2751363
+PMID-2752538
+PMID-2769204
+PMID-2777242
+PMID-2902221
+PMID-2947053
+PMID-2992384
+PMID-3027568
+PMID-3109978
+PMID-3118962
+PMID-3134031
+PMID-3287150
+PMID-3325878
+PMID-3338202
+PMID-3365266
+PMID-3455408
+PMID-3477575
+PMID-3492269
+PMID-3533793
+PMID-3540090
+PMID-3593589
+PMID-3609040
+PMID-3609047
+PMID-3759367
+PMID-3763732
+PMID-3830071
+PMID-385804
+PMID-3872182
+PMID-3930969
+PMID-3934707
+PMID-3945631
+PMID-3985123
+PMID-3993849
+PMID-4031558
+PMID-4066990
+PMID-424394
+PMID-479303
+PMID-491661
+PMID-5101344
+PMID-521790
+PMID-537829
+PMID-6084300
+PMID-6089351
+PMID-6095116
+PMID-6132379
+PMID-6156133
+PMID-6188401
+PMID-6198387
+PMID-6216020
+PMID-6229539
+PMID-6246863
+PMID-6294124
+PMID-6312919
+PMID-6315590
+PMID-6321955
+PMID-6325250
+PMID-6326669
+PMID-6327760
+PMID-6328275
+PMID-6330210
+PMID-6370602
+PMID-6378935
+PMID-6403470
+PMID-6445577
+PMID-6524192
+PMID-6540195
+PMID-6653557
+PMID-6728933
+PMID-6744243
+PMID-6776697
+PMID-6920468
+PMID-7000775
+PMID-707591
+PMID-7088434
+PMID-7120085
+PMID-7226107
+PMID-7257720
+PMID-73315
+PMID-7420025
+PMID-7474113
+PMID-7474125
+PMID-7475551
+PMID-7504687
+PMID-7505952
+PMID-7511490
+PMID-7515692
+PMID-7541555
+PMID-7543020
+PMID-7543819
+PMID-7566744
+PMID-7566959
+PMID-7585733
+PMID-7586219
+PMID-7624335
+PMID-7654002
+PMID-765945
+PMID-7665251
+PMID-7684185
+PMID-7686447
+PMID-7714663
+PMID-7725754
+PMID-7738772
+PMID-7779866
+PMID-7794272
+PMID-7806663
+PMID-7828172
+PMID-7829228
+PMID-7841024
+PMID-7875243
+PMID-7897308
+PMID-7904970
+PMID-7954458
+PMID-7966592
+PMID-7969665
+PMID-7982854
+PMID-8010976
+PMID-8062825
+PMID-8064416
+PMID-8078269
+PMID-8083968
+PMID-8084600
+PMID-8097963
+PMID-8102531
+PMID-8111717
+PMID-8144214
+PMID-8157709
+PMID-8182638
+PMID-8215620
+PMID-8221565
+PMID-8268781
+PMID-8272146
+PMID-8314345
+PMID-8344624
+PMID-8369040
+PMID-8388511
+PMID-8389297
+PMID-8398065
+PMID-8418304
+PMID-8423986
+PMID-8433010
+PMID-8455978
+PMID-8479750
+PMID-8489886
+PMID-8564850
+PMID-8565523
+PMID-8602617
+PMID-8633524
+PMID-8634981
+PMID-8640445
+PMID-8643685
+PMID-8657764
+PMID-8686754
+PMID-8691230
+PMID-8691350
+PMID-8707513
+PMID-8736173
+PMID-877612
+PMID-8799827
+PMID-8844727
+PMID-8874330
+PMID-8874381
+PMID-8895545
+PMID-8898364
+PMID-8911863
+PMID-8925114
+PMID-8939041
+PMID-8989261
+PMID-899346
+PMID-900085
+PMID-9006118
+PMID-9020068
+PMID-9045885
+PMID-9087293
+PMID-9088383
+PMID-9094635
+PMID-9096095
+PMID-911696
+PMID-9165485
+PMID-9178585
+PMID-9199203
+PMID-9199500
+PMID-9206208
+PMID-9209451
+PMID-9233832
+PMID-9239276
+PMID-9380745
+PMID-9385933
+PMID-9390137
+PMID-9394578
+PMID-9421512
+PMID-9428378
+PMID-9490736
+PMID-950045
+PMID-9503276
+PMID-9562977
+PMID-9633825
+PMID-9635525
+PMID-9641893
+PMID-9648911
+PMID-9663607
+PMID-9669536
+PMID-9671543
+PMID-9679735
+PMID-9695407
+PMID-9727438
+PMID-9728053
+PMID-9744629
+PMID-9754701
+PMID-9770688
+PMID-9776783
+PMID-9778569
+PMID-9804526
+PMID-9840923
+PMID-9843597
+PMID-9852401
+PMID-9864390
+PMID-9891063
+PMID-9891506
+PMID-9924929
+PMID-9931156
diff --git a/huner/ner_scripts/splits/gellus.train b/huner/ner_scripts/splits/gellus.train
new file mode 100644
index 0000000..37479b8
--- /dev/null
+++ b/huner/ner_scripts/splits/gellus.train
@@ -0,0 +1,728 @@
+
+PMC-1044634-sec-01
+PMC-1072800-sec-07
+PMC-1075924-caption-01
+PMC-1097769-caption-08
+PMC-1112599-caption-08
+PMC-1160588-sec-11
+PMC-1168904-sec-12
+PMC-1182367-sec-19
+PMC-1188249-sec-02
+PMC-1200425-caption-05
+PMC-1274342-sec-02
+PMC-1281265-sec-06
+PMC-1281295-caption-02
+PMC-1285065-sec-02
+PMC-137449-sec-08
+PMC-1420288-sec-02
+PMC-1475211-sec-01
+PMC-1519587-sec-01
+PMC-1550851-caption-02
+PMC-1557851-sec-01
+PMC-1592238-sec-23
+PMC-1592597-caption-02
+PMC-1615867-sec-09
+PMC-1635332-sec-23
+PMC-1681490-sec-01
+PMC-1697817-sec-02
+PMC-1698941-caption-09
+PMC-1716863-sec-01
+PMC-1828719-sec-06
+PMC-1852096-sec-05
+PMC-1866506-sec-08
+PMC-1868021-caption-04
+PMC-1868914-caption-03
+PMC-1891110-caption-05
+PMC-1896192-sec-09
+PMC-1925142-sec-12
+PMC-1933192-sec-01
+PMC-194858-caption-04
+PMC-1968612-sec-01
+PMC-1971061-sec-09
+PMC-2024775-sec-01
+PMC-2039847-sec-08
+PMC-2064791-sec-02
+PMC-2074286-sec-01
+PMC-2133064-sec-12
+PMC-2151581-sec-12
+PMC-2171703-sec-06
+PMC-2192393-sec-06
+PMC-2193592-sec-11
+PMC-2211454-sec-18
+PMC-2217075-caption-07
+PMC-2250455-caption-01
+PMC-2255579-caption-01
+PMC-2259298-sec-18
+PMC-2265039-sec-08
+PMC-2267190-sec-04
+PMC-2268729-sec-08
+PMC-2323032-sec-05
+PMC-2330176-sec-05
+PMC-2361780-caption-03
+PMC-2374702-caption-19
+PMC-2374931-sec-01
+PMC-2375120-caption-08
+PMC-2397523-sec-15
+PMC-2412842-sec-03
+PMC-2443159-sec-19
+PMC-2467402-sec-01
+PMC-2474682-caption-05
+PMC-2474864-sec-28
+PMC-2493521-sec-21
+PMC-2495004-sec-11
+PMC-2499988-sec-06
+PMC-2528170-sec-05
+PMC-2535566-caption-18
+PMC-2569084-sec-24
+PMC-2570567-sec-06
+PMC-2570695-caption-09
+PMC-2578989-sec-01
+PMC-2579698-caption-02
+PMC-2596116-sec-09
+PMC-2634619-caption-01
+PMC-2638008-sec-12
+PMC-2644583-sec-04
+PMC-2646243-sec-01
+PMC-2646714-caption-02
+PMC-2648768-caption-01
+PMC-2652060-sec-11
+PMC-2660343-sec-18
+PMC-2660356-caption-07
+PMC-2660904-sec-06
+PMC-2666640-sec-27
+PMC-2672944-sec-14
+PMC-2673029-caption-03
+PMC-2673471-sec-01
+PMC-2677866-sec-12
+PMC-2690976-sec-05
+PMC-2700800-sec-02
+PMC-2701282-sec-04
+PMC-2703643-sec-15
+PMC-2704942-sec-22
+PMC-2707216-sec-06
+PMC-2707607-sec-10
+PMC-2709655-sec-17
+PMC-2710092-sec-01
+PMC-2713402-sec-09
+PMC-2715888-caption-05
+PMC-2719750-sec-10
+PMC-2721088-sec-10
+PMC-2721591-sec-02
+PMC-2724388-sec-01
+PMC-2725788-sec-03
+PMC-2727579-sec-09
+PMC-2727621-caption-02
+PMC-2736529-sec-09
+PMC-2739198-caption-20
+PMC-2739213-sec-17
+PMC-2744784-sec-02
+PMC-2759629-sec-03
+PMC-2767981-sec-02
+PMC-2768028-sec-10
+PMC-2768104-sec-03
+PMC-2769146-sec-05
+PMC-2770848-sec-13
+PMC-2771789-caption-06
+PMC-2774332-sec-09
+PMC-2779440-caption-01
+PMC-2780376-sec-29
+PMC-2782986-sec-02
+PMC-2790131-sec-02
+PMC-2790521-sec-04
+PMC-2792620-sec-33
+PMC-2793023-sec-09
+PMC-2804691-sec-05
+PMC-2811192-caption-03
+PMC-2817706-caption-03
+PMC-2822164-caption-01
+PMC-2823704-sec-12
+PMC-2835514-sec-09
+PMC-2837610-sec-05
+PMC-2840784-sec-02
+PMC-2842303-caption-01
+PMC-2844379-caption-01
+PMC-2845033-sec-09
+PMC-2847972-sec-01
+PMC-2858094-sec-14
+PMC-2858170-sec-04
+PMC-2858731-caption-14
+PMC-2861602-sec-09
+PMC-2875696-sec-02
+PMC-2879834-sec-01
+PMC-2882287-sec-12
+PMC-2883578-sec-04
+PMC-2885393-caption-01
+PMC-2889408-caption-02
+PMC-2892078-sec-02
+PMC-2892437-sec-19
+PMC-2892686-caption-01
+PMC-2894766-caption-01
+PMC-2900753-caption-02
+PMC-2903584-sec-40
+PMC-2908855-caption-01
+PMC-2909993-sec-05
+PMC-2913979-sec-10
+PMC-2917571-sec-20
+PMC-2918592-sec-06
+PMC-2920104-caption-01
+PMC-2922337-sec-10
+PMC-2924302-sec-08
+PMC-2936514-sec-06
+PMC-2938106-sec-02
+PMC-2938375-caption-06
+PMC-2939889-sec-15
+PMC-2941963-sec-01
+PMC-2945143-sec-13
+PMC-2946364-caption-05
+PMC-2946569-sec-02
+PMC-2947726-sec-04
+PMC-2948674-sec-02
+PMC-2949661-caption-02
+PMC-2955004-caption-06
+PMC-2958498-caption-01
+PMC-2958911-caption-05
+PMC-2959025-sec-14
+PMC-2959669-sec-16
+PMC-2959883-sec-06
+PMC-2960999-sec-02
+PMC-2961588-caption-01
+PMC-2968135-sec-03
+PMC-2971783-sec-11
+PMC-2972690-sec-19
+PMC-2979164-sec-17
+PMC-2982831-sec-18
+PMC-2983913-sec-03
+PMC-2984323-caption-02
+PMC-2988921-caption-02
+PMC-2989791-sec-04
+PMC-2992534-sec-07
+PMC-2993105-caption-03
+PMC-2993542-sec-03
+PMC-2994753-caption-05
+PMC-2998423-sec-17
+PMC-3003518-sec-05
+PMC-3003815-caption-03
+PMC-3009312-sec-10
+PMC-3012732-sec-15
+PMC-3013756-sec-09
+PMC-3032248-caption-05
+PMC-3032734-sec-23
+PMC-3039624-sec-11
+PMC-3041749-sec-13
+PMC-3041925-caption-05
+PMC-3042182-caption-05
+PMC-3047434-sec-08
+PMC-3051055-sec-17
+PMC-3052097-caption-01
+PMC-3052613-caption-01
+PMC-3068582-sec-06
+PMC-3072624-caption-03
+PMC-3074639-caption-07
+PMC-3082541-caption-03
+PMC-3086171-sec-12
+PMC-3087566-caption-11
+PMC-3088328-sec-10
+PMC-3089218-caption-02
+PMC-3096661-sec-08
+PMC-3100324-sec-10
+PMC-3100842-sec-07
+PMC-3103976-caption-01
+PMC-3106602-sec-01
+PMC-3106860-sec-04
+PMC-3112138-sec-20
+PMC-3113360-caption-08
+PMC-3113731-sec-31
+PMC-3113832-caption-05
+PMC-3122670-sec-13
+PMC-3124045-caption-01
+PMC-3125269-sec-23
+PMC-3126841-caption-04
+PMC-3131097-caption-02
+PMC-3132469-sec-12
+PMC-3134038-caption-08
+PMC-3134767-sec-08
+PMC-3135183-sec-06
+PMC-3140111-sec-24
+PMC-3141469-caption-02
+PMC-3143519-caption-01
+PMC-3144695-caption-01
+PMC-3150645-caption-02
+PMC-3150795-sec-01
+PMC-3154452-sec-02
+PMC-3155394-sec-04
+PMC-3158436-sec-06
+PMC-3159351-sec-02
+PMC-3159933-sec-12
+PMC-3165302-sec-13
+PMC-3168409-sec-03
+PMC-3168770-caption-05
+PMC-3169771-sec-06
+PMC-3172042-caption-03
+PMC-3173373-caption-02
+PMC-3176744-sec-10
+PMC-3178617-sec-35
+PMC-3180158-sec-09
+PMC-3181428-caption-05
+PMC-3181729-sec-08
+PMC-3191169-sec-14
+PMC-3192753-sec-05
+PMC-3194540-sec-04
+PMC-3195762-caption-11
+PMC-3198795-caption-04
+PMC-3199853-sec-07
+PMC-3202114-sec-05
+PMC-3203455-sec-04
+PMC-3210127-sec-05
+PMC-3212267-sec-05
+PMC-3212698-sec-01
+PMC-3212806-sec-17
+PMC-3213245-sec-16
+PMC-3220010-sec-02
+PMC-3231843-sec-03
+PMC-3234173-sec-08
+PMC-3238981-sec-11
+PMC-3239939-sec-01
+PMC-3242184-sec-02
+PMC-3245051-caption-01
+PMC-3248638-caption-17
+PMC-3248852-sec-15
+PMC-3249382-caption-01
+PMC-3252242-sec-02
+PMC-3252742-sec-08
+PMC-3256136-sec-15
+PMC-3266646-sec-09
+PMC-3267723-sec-02
+PMC-3274927-sec-07
+PMC-3277246-caption-01
+PMC-394315-caption-04
+PMC-464911-sec-25
+PMC-529442-sec-05
+PMC-534790-sec-23
+PMC-59891-sec-03
+PMID-10080451
+PMID-10191918
+PMID-10214859
+PMID-10229326
+PMID-10295626
+PMID-10348440
+PMID-10354550
+PMID-10357269
+PMID-10385711
+PMID-10403689
+PMID-10417401
+PMID-10420526
+PMID-10461060
+PMID-10463077
+PMID-10470095
+PMID-10473104
+PMID-10487573
+PMID-10543260
+PMID-10586954
+PMID-10589785
+PMID-10597602
+PMID-10620704
+PMID-10623751
+PMID-10644902
+PMID-10645002
+PMID-10657950
+PMID-10688644
+PMID-10698499
+PMID-10741713
+PMID-10744669
+PMID-10752531
+PMID-10758166
+PMID-10771470
+PMID-1078780
+PMID-10792950
+PMID-10805736
+PMID-10811911
+PMID-10816661
+PMID-10823148
+PMID-10823420
+PMID-10841092
+PMID-1085358
+PMID-10890377
+PMID-10913166
+PMID-10969782
+PMID-10978248
+PMID-10978899
+PMID-10979970
+PMID-10984714
+PMID-11027431
+PMID-11107120
+PMID-11107747
+PMID-11121230
+PMID-11133803
+PMID-11171752
+PMID-11222727
+PMID-11238633
+PMID-11255762
+PMID-11271930
+PMID-11278466
+PMID-11306510
+PMID-11311231
+PMID-11370224
+PMID-11381168
+PMID-11387198
+PMID-11410793
+PMID-11419822
+PMID-11425277
+PMID-11480035
+PMID-11557773
+PMID-11577003
+PMID-11587364
+PMID-11592301
+PMID-11712346
+PMID-11716301
+PMID-11718104
+PMID-11736312
+PMID-11749071
+PMID-11773437
+PMID-11781057
+PMID-11815955
+PMID-11824472
+PMID-11835401
+PMID-11836604
+PMID-11856141
+PMID-11859873
+PMID-11896602
+PMID-11909360
+PMID-11912515
+PMID-11943784
+PMID-11948691
+PMID-11957196
+PMID-1196405
+PMID-11978547
+PMID-12049815
+PMID-12075162
+PMID-12082607
+PMID-12084351
+PMID-12090046
+PMID-12096842
+PMID-12134045
+PMID-12138191
+PMID-12140030
+PMID-12152164
+PMID-12154044
+PMID-12167423
+PMID-12169574
+PMID-12171358
+PMID-12172105
+PMID-12198766
+PMID-12201487
+PMID-12209602
+PMID-12210482
+PMID-12235242
+PMID-12268797
+PMID-1228728
+PMID-12287551
+PMID-12312519
+PMID-12338811
+PMID-12344153
+PMID-12360110
+PMID-12369594
+PMID-12382229
+PMID-12384438
+PMID-12388106
+PMID-12405260
+PMID-12414659
+PMID-12419822
+PMID-12432255
+PMID-12454816
+PMID-12475948
+PMID-12476350
+PMID-12479523
+PMID-12484699
+PMID-12485499
+PMID-12540483
+PMID-12556444
+PMID-12558942
+PMID-12567143
+PMID-12604762
+PMID-12610665
+PMID-12622417
+PMID-12663827
+PMID-12686753
+PMID-1271119
+PMID-12724285
+PMID-12727857
+PMID-12738672
+PMID-12748830
+PMID-12753707
+PMID-12766067
+PMID-12779350
+PMID-12796408
+PMID-12796817
+PMID-12813373
+PMID-12823209
+PMID-12852503
+PMID-12855648
+PMID-12869564
+PMID-12872134
+PMID-12884381
+PMID-12920663
+PMID-12923331
+PMID-12935890
+PMID-12957491
+PMID-12958070
+PMID-12962723
+PMID-12975002
+PMID-1316705
+PMID-1317293
+PMID-1331932
+PMID-133805
+PMID-1370299
+PMID-1377534
+PMID-1388088
+PMID-1439250
+PMID-14500555
+PMID-14525939
+PMID-14531585
+PMID-14555793
+PMID-14565598
+PMID-14576200
+PMID-14597675
+PMID-14604834
+PMID-14613080
+PMID-14633695
+PMID-14638851
+PMID-14652292
+PMID-14663884
+PMID-14709143
+PMID-14714614
+PMID-14729736
+PMID-14767510
+PMID-1482802
+PMID-14981916
+PMID-14981920
+PMID-14984432
+PMID-15012488
+PMID-15015551
+PMID-15025957
+PMID-15029197
+PMID-15033343
+PMID-15033782
+PMID-15034302
+PMID-15034798
+PMID-15041728
+PMID-1505125
+PMID-15160301
+PMID-1517352
+PMID-15192017
+PMID-15193260
+PMID-15202612
+PMID-15202937
+PMID-15217504
+PMID-15217612
+PMID-15217720
+PMID-15224342
+PMID-15225208
+PMID-15227901
+PMID-15243804
+PMID-15250585
+PMID-15266333
+PMID-15268651
+PMID-15300069
+PMID-15305838
+PMID-1531525
+PMID-15316972
+PMID-15327827
+PMID-15331370
+PMID-15355640
+PMID-15464487
+PMID-15491747
+PMID-15494684
+PMID-15510029
+PMID-15510518
+PMID-15518477
+PMID-15528872
+PMID-1553573
+PMID-15535839
+PMID-15542670
+PMID-15574223
+PMID-15586242
+PMID-15590693
+PMID-15595726
+PMID-15604153
+PMID-15623598
+PMID-15623651
+PMID-15652356
+PMID-15673543
+PMID-15715968
+PMID-15720982
+PMID-15723619
+PMID-15725689
+PMID-15774527
+PMID-15776477
+PMID-15795514
+PMID-15811263
+PMID-15833857
+PMID-15865939
+PMID-15876269
+PMID-15882577
+PMID-15913739
+PMID-15927356
+PMID-15965284
+PMID-15967832
+PMID-15975645
+PMID-16007688
+PMID-16045802
+PMID-16076702
+PMID-16081543
+PMID-16089987
+PMID-16098727
+PMID-16101297
+PMID-16112981
+PMID-16116175
+PMID-16144215
+PMID-16165242
+PMID-16201626
+PMID-16204028
+PMID-16210037
+PMID-16221381
+PMID-16250015
+PMID-16252749
+PMID-16268479
+PMID-1629581
+PMID-16310808
+PMID-16341007
+PMID-16374459
+PMID-1639185
+PMID-16397229
+PMID-16398404
+PMID-16406506
+PMID-16406676
+PMID-16407289
+PMID-16408118
+PMID-16428936
+PMID-16438941
+PMID-16455654
+PMID-16463019
+PMID-16470244
+PMID-16485028
+PMID-16489021
+PMID-16540312
+PMID-16556061
+PMID-16585210
+PMID-16612306
+PMID-16623714
+PMID-16650140
+PMID-16691484
+PMID-1670994
+PMID-16720995
+PMID-16740157
+PMID-1675427
+PMID-16771309
+PMID-16773443
+PMID-16809768
+PMID-16809940
+PMID-1683740
+PMID-16850045
+PMID-16855378
+PMID-16858650
+PMID-16893130
+PMID-16907772
+PMID-16927570
+PMID-16934444
+PMID-16951238
+PMID-16955335
+PMID-16963846
+PMID-16969171
+PMID-16981245
+PMID-17005546
+PMID-17016553
+PMID-17040495
+PMID-17054099
+PMID-17101038
+PMID-17129360
+PMID-17130843
+PMID-17145768
+PMID-17151534
+PMID-17157465
+PMID-17158338
+PMID-17170138
+PMID-17178599
+PMID-17187228
+PMID-17199697
+PMID-17210799
+PMID-17215077
+PMID-17227832
+PMID-17234724
+PMID-17241819
+PMID-17285974
+PMID-17289834
+PMID-17305525
+PMID-17306711
+PMID-17311993
+PMID-17327081
+PMID-17329737
+PMID-17367752
+PMID-17369844
+PMID-17384243
+PMID-17390340
+PMID-17402357
+PMID-17404823
+PMID-17409033
+PMID-17432972
+PMID-17434829
+PMID-17440699
+PMID-17462601
+PMID-17476983
+PMID-17483295
+PMID-17488804
+PMID-17492673
+PMID-17500304
+PMID-17505508
+PMID-17523137
+PMID-17532651
+PMID-17533366
+PMID-17537580
+PMID-17551815
+PMID-17578706
+PMID-17583576
+PMID-17595055
+PMID-17607547
+PMID-17608264
+PMID-17617824
+PMID-17624581
+PMID-17627146
+PMID-17640057
+PMID-17662274
+PMID-17762973
+PMID-17851915
+PMID-17855765
+PMID-17873348
+PMID-17909628
+PMID-17960624
+PMID-17967875
+PMID-17981770
+PMID-18021292
+PMID-1802899
+PMID-1802941
+PMID-18030875
+PMID-18043872
+PMID-18046085
+PMID-18068525
+PMID-18165897
+PMID-18172308
+PMID-18188789
+PMID-18193081
+PMID-18194650
+PMID-18202228
+PMID-1821204
+PMID-18215066
+PMID-18245558
+PMID-18301249
+PMID-18313522
+PMID-18319331
+PMID-18330634
+PMID-1834974
+PMID-18376140
+PMID-18384219
+PMID-18393343
+PMID-18413367
+PMID-18413757
+PMID-18425334
+PMID-18425820
+PMID-18440619
+PMID-18444387
diff --git a/huner/ner_scripts/splits/genia.dev b/huner/ner_scripts/splits/genia.dev
new file mode 100644
index 0000000..9cc8a19
--- /dev/null
+++ b/huner/ner_scripts/splits/genia.dev
@@ -0,0 +1,199 @@
+94179250
+97028169
+97207294
+97269040
+94285936
+97457067
+99279130
+99423690
+95286632
+95301128
+92260664
+98328397
+98087405
+99075977
+91110562
+94249033
+97475199
+98352765
+95367586
+99192743
+96355439
+96195546
+95397944
+97184561
+93228833
+98298224
+95378799
+95362854
+95074854
+98311520
+97226001
+95373165
+91065749
+99101524
+92207144
+96190579
+96144699
+99295929
+97296513
+97188782
+98361309
+93184333
+97152553
+93206138
+98031856
+99006628
+98438501
+95115141
+93079901
+90381807
+95081342
+93303626
+97230366
+96221559
+96029750
+92187059
+99362923
+94216261
+99242637
+99240799
+99329182
+94289707
+97276244
+98018226
+95279435
+95123097
+99286808
+94338593
+97158624
+96421639
+96355009
+96239534
+90376447
+91296379
+95370702
+94119067
+99286016
+91098050
+96063646
+97148606
+99300859
+99307406
+97021709
+97255754
+97383366
+98153997
+97259535
+95365357
+97047764
+99287876
+96001293
+94216500
+98029486
+94025289
+99225548
+90171176
+94118533
+96264685
+98422270
+95145550
+94172207
+91118160
+95072469
+99225553
+91236696
+96198880
+93172387
+99069282
+97407957
+97211823
+96146497
+98343775
+92318928
+96152682
+97378061
+96247643
+92029620
+97113313
+98077369
+97456516
+90244434
+97252236
+94335073
+92135145
+92006162
+99192438
+99244281
+93280143
+98380997
+98038798
+91282927
+96144322
+92165059
+93126354
+97216066
+99005376
+99209754
+98208264
+95280909
+95003681
+98295832
+96180219
+99272418
+95347767
+95365382
+93194904
+98343423
+99192761
+97334241
+95247773
+95161757
+97353026
+94347465
+91349414
+97287044
+98104482
+98104477
+92314696
+94224239
+99120322
+94344126
+96062284
+96278851
+97276784
+99323953
+99170294
+92371447
+90199680
+93145322
+99380601
+99412310
+96268712
+99169183
+94209654
+90285430
+99010726
+95186362
+93228445
+95162017
+97197832
+93194832
+98400938
+97358652
+93260875
+99282941
+96353908
+99149869
+96074843
+97377031
+96303658
+97064186
+95234639
+92215726
+97445683
+94110361
+98309442
+96239524
+99244901
+96096457
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/genia.test b/huner/ner_scripts/splits/genia.test
new file mode 100644
index 0000000..dd755b7
--- /dev/null
+++ b/huner/ner_scripts/splits/genia.test
@@ -0,0 +1,601 @@
+98074940
+99177408
+99197861
+91215472
+90151654
+96373868
+99221887
+96281903
+96210575
+96186742
+99172186
+98282210
+95053891
+95201644
+99155321
+99218532
+92107919
+95138118
+92031293
+99372175
+92052214
+97379437
+97148782
+99344098
+99398660
+96202514
+96387353
+99060915
+91208110
+99252084
+99256996
+94367369
+95197545
+95363073
+99187612
+95221342
+96017239
+95355137
+98322148
+99138796
+96278973
+97115684
+95266275
+99077509
+94243031
+97461470
+96071057
+95236292
+99316282
+98144699
+99223566
+98451426
+95127210
+99244237
+90244394
+99228859
+96374456
+95163578
+99003230
+92213636
+96062305
+96017769
+90140708
+97080592
+98090689
+97289761
+91248763
+95088506
+92193472
+97472344
+99065678
+99103960
+99278386
+97307606
+96201643
+90161003
+98427848
+96320604
+99190497
+95382761
+90158614
+99111421
+97326105
+98438422
+99211588
+95279882
+97184469
+97230346
+96329578
+98012230
+91172250
+97248576
+97067175
+99192765
+91354520
+99156941
+97087515
+99035056
+93264305
+97442480
+98395152
+96140672
+95403468
+95338146
+93087498
+97131617
+93276575
+97449161
+97289591
+99252081
+97228922
+99125803
+98332778
+96226013
+92235212
+95007565
+95012031
+95263289
+97385069
+96413274
+98390872
+95104037
+99148535
+99355592
+99168501
+98395073
+95127261
+92335296
+91017623
+93112057
+96413305
+97233191
+99091640
+98282482
+94240241
+99336784
+98104456
+93224733
+90381353
+97184478
+93266597
+93121695
+97445128
+97332608
+97240797
+96025852
+92144438
+96140436
+95256242
+99182374
+91218850
+98038598
+98043822
+95263486
+99006780
+94026053
+92244343
+97400349
+95403454
+96026328
+99065132
+98051057
+97292307
+97309442
+97031819
+96404971
+98168883
+99092484
+99077977
+92142646
+97150708
+97047122
+98389282
+97456880
+97058563
+99286827
+90382324
+97074532
+99218522
+96369636
+99289427
+90124644
+99126191
+92212930
+99310960
+99335895
+92156261
+96440214
+96322738
+98158921
+91303691
+92362919
+98045094
+99107757
+96144358
+99388640
+91217625
+99003459
+95011022
+98025882
+91172768
+93194883
+98384373
+98062932
+97282709
+94265262
+91016834
+96017245
+98022722
+98295583
+99206664
+96323085
+99315748
+98062995
+99188724
+99083144
+95015835
+95194613
+92291523
+99054659
+97119289
+97186415
+99119105
+90254291
+97222140
+91367666
+97476217
+97261053
+91203899
+97276819
+97384936
+96079922
+96146856
+94338582
+93287269
+97175274
+93281652
+94266606
+98001686
+96295969
+99369970
+97177471
+91092268
+95392577
+93113611
+95014473
+91100449
+91079526
+94375000
+93152894
+98001378
+94289333
+93066282
+92113075
+95047083
+91045897
+98022968
+96141062
+97205502
+97047769
+96007705
+97376853
+90244395
+99138825
+97083501
+99099017
+99161827
+98104455
+99310626
+97274642
+97281244
+99340272
+94184956
+90346297
+95163587
+99201818
+98011518
+99303765
+97303223
+97335975
+96038894
+95368765
+91134976
+91092267
+97098661
+94331553
+96420243
+99286232
+95349600
+99330064
+95010257
+96278836
+91065527
+97057230
+93110357
+96409274
+95374911
+90153985
+93155114
+96025779
+97449280
+96190069
+90287178
+98421365
+98305722
+98439530
+96096469
+99096304
+96089572
+99307057
+97112990
+96358388
+90319091
+97098688
+91034184
+97199262
+99240762
+98426236
+95347379
+97006603
+99352259
+91291720
+97420486
+97342603
+97289747
+95023587
+99008372
+97218076
+98147373
+98282206
+91376384
+99089911
+91043047
+97217364
+96235996
+97000328
+91339573
+95166251
+98362153
+99074319
+98403730
+91174087
+99070073
+99134363
+99427884
+97048062
+99303024
+90205027
+91363265
+94191916
+97450830
+93246027
+96305192
+97154704
+99252090
+98389481
+98104469
+98413772
+99196242
+97445684
+92062170
+97322395
+97180928
+99353321
+96278860
+94140841
+98018275
+92108417
+99113717
+93215800
+95373132
+93072349
+98389801
+98375844
+99233638
+93046624
+97362375
+96178227
+96409256
+97150707
+96379940
+94246743
+96198610
+90311515
+97098712
+99282947
+95016439
+98030536
+94183209
+94190839
+98104459
+99158164
+97296314
+97462740
+93269273
+93329079
+98406066
+94085904
+98417611
+97032774
+98414619
+97218353
+97066958
+99047055
+94267876
+95355456
+96074633
+99376397
+90188846
+99326307
+95052601
+94083530
+97330981
+96069375
+96054968
+93114357
+95151358
+95072277
+95280917
+96437028
+91237114
+97050805
+93309430
+96344715
+99362737
+94119088
+99048705
+93101981
+97228139
+99289426
+93320446
+98013637
+99061637
+95062301
+97334360
+96009559
+97318898
+94051535
+96183254
+99265951
+99023607
+94217708
+96239482
+95229576
+94246160
+99106021
+99007236
+95221892
+95386713
+95184007
+94281746
+93286051
+98014713
+99058080
+90327113
+96201015
+98039716
+97108276
+99101008
+95266282
+98001396
+99225047
+99323946
+96324890
+91175240
+94217690
+97334204
+99137815
+97344875
+95221870
+94209877
+94235006
+98322151
+97239596
+99038200
+99206604
+91164434
+93024468
+95053740
+98101496
+93155082
+99262272
+92366555
+97265687
+91117203
+99288090
+98349401
+98037648
+98384235
+98313295
+93244226
+99172218
+93294310
+97209911
+90351381
+99237607
+95329724
+96285641
+96163492
+95036334
+96200169
+97293200
+98438586
+94361146
+95255485
+93189882
+99090715
+97184542
+91172211
+97353010
+96209427
+99292715
+92077236
+96310948
+90258907
+95187990
+97335966
+96082168
+97333610
+92260679
+96194904
+91048014
+95370270
+97079135
+96203119
+92153263
+92156797
+93280865
+97300635
+92135176
+92042309
+90244306
+93283670
+99386936
+98282481
+92088960
+91187647
+99253956
+96063079
+97289574
+94132650
+94259178
+99190512
+95394020
+97294025
+97081192
+96141969
+95168272
+92392375
+95121921
+98012705
+99214329
+99286816
+98325368
+97253017
+97467112
+93238864
+99008520
+97458236
+97423536
+99192454
+99071844
+96075792
+96181482
+99415939
+97361636
+99357866
+91125342
+93152834
+97166066
+99218427
+91035625
+99294317
+93322080
+99305241
+97011146
+95266250
+96413262
+94267706
+99178629
+99034460
+98079330
+96195006
+95015010
+90292959
+97159684
+97131823
+96128660
+96065933
+99138892
+99145033
+99324612
+95154979
+95199654
+95343554
+92255823
+93202345
+94134077
+99348033
+95261059
+97307577
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/genia.train b/huner/ner_scripts/splits/genia.train
new file mode 100644
index 0000000..a324a8f
--- /dev/null
+++ b/huner/ner_scripts/splits/genia.train
@@ -0,0 +1,1199 @@
+93024383
+95362365
+99145586
+95399778
+99182340
+99045415
+94148994
+99115659
+91266912
+92107162
+95329717
+94344108
+99190650
+99047534
+99182542
+93189564
+99262416
+99189160
+93324366
+99262847
+96102041
+91239569
+97184448
+93105477
+95388524
+96320605
+96278844
+99097447
+99120900
+99047525
+95178839
+98001728
+99333679
+95394907
+97126060
+96264681
+97366676
+98076121
+95363069
+97378046
+95166264
+97461450
+99262230
+92213189
+96293454
+99097434
+91094881
+94331016
+93284506
+97138389
+93153017
+99060916
+99362759
+92186836
+93279468
+90299137
+99187985
+99008545
+93180777
+99097163
+98437269
+99264317
+98378510
+93204975
+95221386
+97353114
+97335974
+92123193
+97025459
+95059073
+94240138
+91190842
+97277320
+96291858
+97353180
+99057540
+99032837
+97210575
+99400649
+99393322
+98418492
+96189099
+99034605
+94167865
+94209308
+96068726
+97281772
+99225313
+98440543
+93012816
+95021266
+99369690
+99228708
+96025857
+94101543
+99135866
+99189164
+99406823
+97378015
+99030136
+95074873
+99078033
+96228299
+90319127
+99182530
+99184529
+98001375
+93183827
+99102381
+95385995
+98241397
+96009612
+97367500
+98383419
+98031743
+95204946
+93278095
+97228330
+99246501
+99174774
+95244883
+95197720
+99218397
+99371288
+93292612
+97070945
+96205972
+97445071
+97209374
+97376857
+96114497
+94339116
+95327953
+97135341
+99170284
+95355848
+92109743
+92366521
+99294118
+94253152
+91364264
+93363253
+96189121
+98209755
+97054651
+99194225
+91092266
+97184601
+92193465
+96355428
+97128814
+93100507
+97056026
+96165503
+91224990
+96009608
+99102590
+93350203
+99369860
+99343400
+96205960
+93041372
+96390735
+95261816
+99285117
+98373989
+97108656
+96264628
+97402252
+99060929
+95190988
+97312374
+99057586
+91266919
+99038208
+99111186
+96141065
+92385366
+98048869
+96099434
+99008506
+97016536
+99356019
+96365473
+97407922
+97375347
+98001571
+97132947
+97269081
+91098724
+96290415
+98341858
+99101510
+99077519
+95298682
+95279790
+92257680
+96074623
+97026428
+99298510
+97387731
+97362321
+90376424
+95129555
+96382512
+93275333
+99239883
+91291757
+99242633
+97189104
+95287902
+92195320
+95325614
+97226013
+97306366
+95011572
+91210272
+99276096
+96085174
+97170874
+98000963
+99200786
+98397262
+94289294
+90360678
+99007753
+93205400
+97005399
+99336788
+98365377
+98019162
+98104462
+96070930
+97118356
+98414302
+99023375
+92103005
+99201482
+96182305
+95124333
+93018835
+91041706
+91101115
+99263020
+93077034
+92378748
+99018025
+99225046
+98380286
+96074632
+97242104
+97444155
+96413288
+93307660
+93030402
+93154317
+97213977
+98400423
+96132964
+98375865
+91246215
+95065655
+96208140
+94179241
+97218151
+90255794
+99067836
+93289270
+99354925
+97077077
+99236832
+97364688
+98090595
+95156575
+96189089
+98101492
+92043714
+98435936
+98406200
+90110496
+95309632
+95014190
+99408727
+95238333
+99049801
+99138988
+91369589
+97184462
+98326600
+96305196
+99296619
+94185011
+99211949
+97115792
+99054996
+98440284
+95337737
+99298193
+93129206
+95190013
+94354848
+98030794
+99098921
+90237240
+99376409
+98012234
+99218312
+97300620
+99015774
+99190753
+93186809
+98405747
+97398336
+99380273
+91319738
+99367411
+94375097
+92408125
+91132035
+97205231
+97196870
+90381363
+93258811
+99248398
+99218482
+91277630
+99210381
+99189777
+94193110
+99361939
+99248162
+96202494
+96186497
+91075236
+96406504
+92112059
+96011839
+91036996
+94347089
+91221358
+95363078
+99057097
+97288734
+95016436
+99343785
+99321124
+99180473
+92060325
+96323103
+97480711
+91292396
+91099657
+99428687
+94088534
+98018399
+97047763
+99285633
+95050523
+99070060
+97460018
+96392389
+98416180
+96009598
+95333264
+98438043
+92185243
+95031992
+96152904
+99303791
+94031267
+97404655
+97127169
+92179751
+93171603
+92013023
+96305203
+95130292
+97167598
+99423672
+94303183
+99353876
+94284067
+95015876
+97083588
+97324097
+96353916
+96091806
+93135830
+95355533
+99262417
+99091536
+92320321
+95386516
+98379695
+98073333
+95001542
+97322372
+97045131
+95369491
+97390710
+94077003
+94149008
+94318550
+94314370
+97138090
+99178889
+94281402
+99308622
+97276226
+92387536
+98380268
+98124483
+98128482
+99023967
+99166942
+95337734
+99244330
+99282915
+94076456
+97349094
+96397528
+91132900
+99115412
+97153026
+93211996
+98022792
+96194562
+95163103
+92052243
+98104475
+99168986
+96431382
+97321386
+98005316
+96186719
+98001085
+92331609
+98019986
+93272960
+99098435
+99059495
+93259462
+99155344
+97205335
+96405332
+95256455
+99016857
+99146379
+98379823
+97236919
+92066454
+96214987
+99221321
+99039380
+97197910
+90158596
+98389427
+99203526
+95257963
+97170849
+97465516
+97462662
+91025498
+91114695
+93346062
+99064961
+95276747
+95152043
+96382503
+99362723
+95363089
+97342767
+95278601
+97358178
+96201628
+98385602
+98282480
+99369911
+90278097
+97330829
+98421396
+93011470
+99369980
+90279052
+98063340
+98416141
+97263535
+92001749
+99049838
+96001288
+94376879
+97025433
+96399059
+91236793
+95104296
+97251018
+99231886
+99394774
+99242525
+96185499
+99410809
+91013631
+98068683
+93061407
+93136418
+92010096
+96133016
+97042487
+95074049
+96003970
+99316341
+95169271
+91361546
+96405269
+98034220
+94327547
+97450986
+92218428
+90206049
+99236847
+98406210
+99408303
+96062038
+96355899
+97180731
+91170801
+97083787
+97140237
+98140255
+99386942
+97025418
+94194029
+99288066
+91187152
+96323172
+93141620
+93262492
+96055286
+99190530
+92051383
+92223210
+97248268
+97415553
+91050279
+99023364
+99384376
+98074810
+98209796
+99258659
+90147621
+92068245
+97362232
+90335211
+99252077
+93233083
+91079577
+99098272
+96107207
+96024587
+98062912
+97353023
+96247664
+91347784
+99262580
+92052179
+95100937
+99135975
+97054663
+92367617
+93157335
+96139448
+99272411
+95372363
+96317173
+95191179
+97261995
+99412333
+99248179
+96194982
+95236293
+97060432
+99055586
+96082382
+99292784
+94280766
+97404663
+96183906
+92127655
+93054486
+91175707
+96397543
+98407711
+95009960
+99074502
+93241941
+95260531
+94202265
+99257180
+94230583
+99240736
+91119580
+96157213
+96038813
+94274683
+96186978
+96184651
+96320558
+98299642
+95399771
+99113747
+91175478
+96190573
+98058835
+99147045
+96239599
+98290745
+91184620
+95394931
+92265660
+99154742
+91219488
+99075480
+98064072
+99147030
+94329809
+99162595
+97342608
+95367587
+97458245
+97119542
+99220021
+90169371
+95014458
+95337142
+97376852
+97031178
+99194238
+97394399
+97103140
+94285937
+97343293
+94230451
+99178617
+98208262
+93321228
+92235036
+96251346
+95235452
+99315834
+99142609
+99374665
+97214626
+99208363
+95369245
+95134788
+96151964
+96226053
+97006605
+96096754
+99214587
+98376488
+93013114
+96437048
+92309248
+99086128
+92294188
+99252177
+96182568
+96288304
+99192735
+98322149
+96063336
+96127450
+97317585
+91028334
+99249555
+99041401
+99223528
+92038993
+99155339
+99248157
+96247660
+98145608
+91173312
+96108879
+96194689
+96072803
+98030550
+93307152
+97360262
+96279126
+93242763
+96136291
+93232271
+96086826
+93041375
+96256807
+96211859
+96055115
+94075814
+96413233
+97182951
+97048170
+96009551
+94181565
+99041167
+92134262
+95193668
+97322371
+98374313
+97162234
+98401161
+91325181
+92164748
+99126331
+95222176
+95107991
+98038749
+97275148
+97361882
+93203219
+93153207
+94290489
+94238904
+98049829
+99008553
+99061768
+97074543
+96102166
+91258741
+90279073
+90317873
+98006327
+99008340
+99357094
+99069401
+94155850
+93152870
+99081619
+96212948
+98421363
+98208270
+91376383
+97134898
+92195648
+97024837
+96016217
+97184463
+98099332
+95056004
+96382507
+97419190
+92408021
+98426244
+93300824
+95248083
+97426442
+99209803
+99102085
+95081587
+97459950
+93024882
+97276939
+94340810
+96226351
+99292717
+94242719
+97234588
+95110287
+92378895
+99077502
+99255395
+97429889
+95116336
+92176633
+95222739
+98391735
+96094166
+99252157
+99138943
+97132074
+99161866
+99388007
+94313679
+96029754
+98353227
+91351285
+96136023
+95202809
+98056814
+97288306
+98133462
+94169380
+91124866
+97175006
+97272160
+96338163
+96134911
+99249588
+99074403
+99223488
+95238477
+97184665
+96214919
+94330935
+98373923
+96224113
+99244898
+94107268
+90247097
+95197524
+99030293
+99261844
+97338567
+98339383
+90242285
+94166578
+96070929
+93300929
+96049646
+95280913
+99200936
+94350980
+93224719
+93315684
+94358417
+94358411
+95336453
+99137801
+96032864
+97024832
+99406845
+99115544
+99021680
+99218525
+97454876
+96191817
+97069862
+98451425
+96413292
+97234679
+99175125
+97132051
+99201425
+94365323
+91366165
+97315348
+96147310
+99379868
+94327655
+94151007
+97284012
+96046572
+96427516
+99217587
+96000378
+92230800
+97332417
+99357809
+96347533
+99078032
+91079583
+99370197
+99169427
+93314685
+90220600
+95151640
+93268332
+95036290
+97069908
+92176657
+99025966
+97225991
+91037456
+97277292
+97468093
+96114389
+97469932
+94183204
+93056505
+93246644
+99401563
+99080869
+97171572
+92107586
+97459703
+99032541
+94278430
+97275156
+92020218
+92156807
+96289501
+96272884
+97088634
+95287633
+95269137
+96190675
+99415908
+99286230
+92049367
+99282926
+98375886
+96278909
+95166259
+97344237
+98281217
+97249714
+94238882
+99207658
+96354999
+99107758
+99260407
+92251244
+99243471
+98322350
+95365343
+97051821
+97423557
+99014176
+96195539
+97166081
+97315062
+97167569
+96202516
+97051521
+98391028
+97126580
+96228347
+94202312
+93020778
+92366509
+98391036
+98005040
+97451158
+94202306
+99248183
+96320521
+93065212
+97196961
+97081063
+99292681
+97314059
+96279111
+96388957
+96279101
+91296472
+91159628
+95077537
+99305240
+97377998
+98000233
+91067681
+99023506
+90298081
+98080700
+99256982
+99254099
+90375934
+97268616
+94151327
+96329553
+93129248
+95152321
+96356325
+99139903
+92317168
+96173754
+91292530
+98089072
+95308691
+97265379
+97047773
+93141262
+99244916
+96315681
+98395103
+94110342
+96357043
+96125073
+98028550
+93315600
+98003050
+96389043
+94209322
+99192449
+99288085
+97199263
+95145523
+92118719
+99049827
+96215633
+98089069
+95195208
+90191722
+95311627
+95059037
+97025698
+93209552
+99310627
+97298895
+99180171
+91184714
+96068922
+94200898
+97132479
+93085167
+98438540
+95001805
+92020850
+97379649
+96215235
+94110603
+97422566
+98430664
+97128276
+97277252
+97219997
+93150054
+94217726
+90173249
+94312466
+91049522
+90302010
+96330347
+97311087
+99328623
+99382334
+94314962
+99419787
+90337320
+92311659
+96176764
+99360752
+99353322
+97195004
+95340873
+97423508
+97289567
+99200773
+98451423
+99203164
+99285507
+91237803
+90317911
+97289433
+93252936
+93253031
+97176699
+99150505
+94327512
+99323972
+90290483
+95091657
+92147648
+93043110
+97153085
+97410435
+98455033
+99121740
+97223498
+99315311
+96030053
+90277507
+95391995
+99410810
+99409030
+95032566
+97304524
+96230713
+94259822
+99192785
+92318932
+99115672
+92269839
+97362594
+96262594
+96216725
+98353313
+96216453
+97460074
+93266777
+99415656
+98455230
+99247345
+97379394
+92013087
+95364954
+97278840
+97066996
+99073952
+98230439
+93204999
+98375837
+98168578
+91264362
+96184185
+95363941
+98024176
+97182946
+96322726
+94120719
+98438583
+92022337
+97362276
+97155934
+95316714
+96184791
+99216457
+96189110
+92052106
+95329723
+99296093
+97276922
+99176388
+96035700
+96341625
+97355572
+90208323
+97436422
+97113352
+96223984
+98363633
+96320762
+95197681
+97061522
+99010987
+91175694
+99192430
+96202489
+93123257
+96184802
+95403403
+98378528
+99141282
+97248400
+99223160
+90368794
+98400847
+95152420
+92224250
+96091353
+95110353
+94187105
+99175479
+99377310
+99301235
+96247631
+95236467
+97131727
+99166958
+95332324
+96239496
+91355651
+96126094
+92368408
+99229667
+98104470
+96338485
+96141087
+99357867
+99087711
+96324400
+96079009
+90293687
+91204058
+96062272
+94129004
+99008517
+98042055
+93216805
+96183228
+91321794
+97107281
+94254835
+99118181
+98374270
+93186822
+93180775
+97276992
+93224755
+94341725
+91293101
+97263762
+95003956
+93124567
+91237800
+95173590
+96247530
+97017504
+94375892
+92407982
+95053781
+99364624
+97277179
+95000924
+99242545
+94214477
+96224055
+97025427
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/gpro.dev b/huner/ner_scripts/splits/gpro.dev
new file mode 100644
index 0000000..b1b2be5
--- /dev/null
+++ b/huner/ner_scripts/splits/gpro.dev
@@ -0,0 +1,1400 @@
+
+CA2100514C
+CA2154601C
+CA2169831C
+CA2185015C
+CA2185397C
+CA2211389C
+CA2211982C
+CA2224426C
+CA2225822C
+CA2230690C
+CA2263798C
+CA2290220C
+CA2295678C
+CA2298523C
+CA2315835C
+CA2323839C
+CA2336799C
+CA2337988C
+CA2339290C
+CA2341949C
+CA2355102C
+CA2377309C
+CA2379557C
+CA2394717C
+CA2396151C
+CA2397594C
+CA2398539C
+CA2454592C
+CA2456970C
+CA2472449C
+CA2503754A1
+CA2508180C
+CA2529055C
+CA2533117A1
+CA2548379C
+CA2597798A1
+CA2599543A1
+CA2653883A1
+CA2657592A1
+CA2680058A1
+CA2714200A1
+CA2716578A1
+CA2741984A1
+CA2781066C
+CA2820201A1
+CA2837759A1
+CA2843643A1
+CN100579977C
+CN100584851C
+CN100999470B
+CN101007128A
+CN101007811A
+CN101007829A
+CN101011363A
+CN101016324A
+CN101019848B
+CN101020062A
+CN101020700A
+CN101023942A
+CN101024604B
+CN101040860A
+CN101040869A
+CN101041074A
+CN101045149A
+CN101045704A
+CN101049302A
+CN101057969A
+CN101062049A
+CN101062293A
+CN101073581A
+CN101081226A
+CN101088997A
+CN101095815A
+CN101117340A
+CN101129578A
+CN101130556A
+CN101138564A
+CN101195601A
+CN101199567A
+CN101220044A
+CN101224217A
+CN101229126B
+CN101244072A
+CN101244079A
+CN101244087A
+CN101264105B
+CN101269222A
+CN101275135A
+CN101278895A
+CN101278899A
+CN101278964A
+CN101284011A
+CN101293876A
+CN101297669B
+CN101300235A
+CN101301301A
+CN101301305A
+CN101301385B
+CN101307050B
+CN101307063A
+CN101313919B
+CN101314023A
+CN101322689A
+CN101332186A
+CN101332264A
+CN101336921A
+CN101336923A
+CN101341124A
+CN101343299A
+CN101352417A
+CN101352439A
+CN101362736A
+CN101362737A
+CN101362762A
+CN101362763B
+CN101376656A
+CN101386590A
+CN101397330A
+CN101416947A
+CN101422488A
+CN101433633A
+CN101440355A
+CN101468950B
+CN101496791A
+CN101501023A
+CN101502501A
+CN101513530B
+CN101518542A
+CN101519392A
+CN101525391B
+CN101530571A
+CN101531649A
+CN101537003A
+CN101554377A
+CN101570554B
+CN101570560B
+CN101574505A
+CN101574513A
+CN101596198A
+CN101596215A
+CN101601650A
+CN101606903A
+CN101664386B
+CN101693026B
+CN101693038B
+CN101693041A
+CN101693659A
+CN101697969A
+CN101698063B
+CN101700224A
+CN101700241A
+CN101700256A
+CN101700382A
+CN101703469A
+CN101708230B
+CN101717384B
+CN101717397B
+CN101721363A
+CN101723887A
+CN101732232A
+CN101732234A
+CN101732292A
+CN101732645A
+CN101743010A
+CN101744823A
+CN101759684A
+CN101759715A
+CN101766574A
+CN101766643A
+CN101773496A
+CN101780096A
+CN101786975A
+CN101790525A
+CN101792437B
+CN101798558A
+CN101805328A
+CN101809000A
+CN101810605A
+CN101810616A
+CN101817808A
+CN101829053B
+CN101829059B
+CN101856350A
+CN101856374A
+CN101856495A
+CN101863925B
+CN101863936A
+CN101863945A
+CN101870694A
+CN101889975A
+CN101912586A
+CN101919812B
+CN101919824A
+CN101919946B
+CN101921294A
+CN101926830A
+CN101928328A
+CN101932560B
+CN101933894A
+CN101940701A
+CN101941914A
+CN101953792A
+CN101953818A
+CN101961383A
+CN101961489A
+CN101966246A
+CN101978852A
+CN101978978A
+CN101987100A
+CN101991588B
+CN101991591A
+CN102000046B
+CN102010366A
+CN102018706A
+CN102018719A
+CN102018721A
+CN102038752A
+CN102038872A
+CN102068404A
+CN102068684A
+CN102091133A
+CN102114038B
+CN102114165A
+CN102127019A
+CN102127141A
+CN102131805A
+CN102133214A
+CN102133220A
+CN102145008A
+CN102151279A
+CN102172349A
+CN102172355A
+CN102188512A
+CN102188635B
+CN102198109B
+CN102199184A
+CN102228436A
+CN102228458A
+CN102232947A
+CN102240320A
+CN102257133A
+CN102258520B
+CN102283858B
+CN102304087A
+CN102309442A
+CN102327315A
+CN102342930A
+CN102342936A
+CN102349888A
+CN102415988B
+CN102432601A
+CN102452916A
+CN102512380A
+CN102532037A
+CN102532163A
+CN102579354A
+CN102579641A
+CN102584535A
+CN102600074A
+CN102600190A
+CN102614216A
+CN102614232A
+CN102617470A
+CN102626424A
+CN102626441A
+CN102670546A
+CN102675099A
+CN102697740A
+CN102697771A
+CN102716102A
+CN102727509A
+CN102731418A
+CN102743365A
+CN102746220A
+CN102755349A
+CN102764271A
+CN102764277A
+CN102766186A
+CN102772393A
+CN102772412A
+CN102784139A
+CN102784145A
+CN102784164A
+CN102805729A
+CN102805745A
+CN102811743A
+CN102813667A
+CN102871991A
+CN102872084A
+CN102872088A
+CN102895175A
+CN102895669A
+CN102908310A
+CN102911069A
+CN102935071A
+CN102942610A
+CN102949406A
+CN102949574A
+CN102952207A
+CN102961283A
+CN102961785A
+CN102973880A
+CN102973891A
+CN102988470A
+CN102988724A
+CN102993152A
+CN103006656A
+CN103006657A
+CN103006667A
+CN103006675A
+CN103006679A
+CN103012429A
+CN103040754A
+CN103040762A
+CN103041227A
+CN103054861A
+CN103059015A
+CN103059019A
+CN103059042A
+CN103070864A
+CN103070869A
+CN103070876A
+CN103070878A
+CN103070925A
+CN103083274A
+CN103087009A
+CN103099804A
+CN103110586A
+CN103120678A
+CN103142473A
+CN103142474A
+CN103142486A
+CN103142580A
+CN103142597A
+CN103153994A
+CN103157095A
+CN103202804A
+CN103211809A
+CN103222965A
+CN103239449A
+CN103239497A
+CN103242219A
+CN103251581A
+CN103251582A
+CN103265487A
+CN103272070A
+CN103284942A
+CN103284944A
+CN103285023A
+CN103288752A
+CN103301114A
+CN103301377A
+CN103304483A
+CN103304486A
+CN103340312A
+CN103349680A
+CN103355655A
+CN103356522A
+CN103356651A
+CN103360276A
+CN103374014A
+CN103385880A
+CN103385888A
+CN103386013A
+CN103387531A
+CN103393488A
+CN103393680A
+CN103396414A
+CN103420981A
+CN103432105A
+CN103432109A
+CN103462944A
+CN103462961A
+CN103462964A
+CN103463056A
+CN103463066A
+CN103463067A
+CN103476415A
+CN103479522A
+CN103479655A
+CN103479906A
+CN103483272A
+CN103495138A
+CN103505717A
+CN103520101A
+CN103520156A
+CN103520163A
+CN103520232A
+CN103520294A
+CN103536527A
+CN103536583A
+CN103536587A
+CN103536657A
+CN103550288A
+CN103550332A
+CN103565811A
+CN103566083A
+CN103570792A
+CN103585264A
+CN103613574A
+CN103622921A
+CN103622923A
+CN103623151A
+CN103623264A
+CN103638361A
+CN103638493A
+CN103656132A
+CN103656736A
+CN103690939A
+CN103694211A
+CN103717591A
+CN103719313A
+CN103724262A
+CN103724271A
+CN103735689A
+CN103751154A
+CN103751168A
+CN1562004A
+CN1565432A
+CN1565446A
+CN1566094A
+CN1569004A
+CN1569884A
+CN1586474A
+CN1589799A
+CN1594342B
+CN1596888A
+CN1621038A
+CN1623561A
+CN1626072A
+CN1626080A
+CN1631902A
+CN1634046A
+CN1654074A
+CN1669552A
+CN1672684A
+CN1676120A
+CN1679619A
+CN1682733A
+CN1682740A
+CN1726908A
+CN1732918A
+CN1732967A
+CN1733765A
+CN1742745A
+CN1775227A
+CN1799541A
+CN1806808A
+CN1810790A
+CN1820745A
+CN1839125A
+CN1839796A
+CN1850079A
+CN1853675A
+CN1868449A
+CN1872061A
+CN1872068A
+CN1879710A
+CN1879717A
+CN1887285A
+CN1911437A
+CN1923177A
+CN1923798A
+CN1927213A
+CN1927840A
+CN1931329A
+CN1935158A
+CN1935762A
+CN1939330A
+CN1965806A
+CN1966037A
+CN1973871B
+CN1981765A
+CN1994317A
+CN1994998A
+CN201692350U
+CN203354929U
+DE102005008412A1
+DE102006031630A1
+DE102007032661A1
+DE102007032663A1
+EP0644767B3
+EP0804437B1
+EP0902839B1
+EP0941093B1
+EP0944311B1
+EP0944312B1
+EP0969838B2
+EP0972037B1
+EP0979080B9
+EP0988309B1
+EP0994880B1
+EP1001781B1
+EP1039906B1
+EP1052259B1
+EP1089968B1
+EP1107807B1
+EP1119630B1
+EP1127065B1
+EP1175399B1
+EP1190248B1
+EP1218381B1
+EP1239814B1
+EP1239862B1
+EP1242437B1
+EP1280757B1
+EP1301460B1
+EP1303499B1
+EP1303591B1
+EP1325019B1
+EP1343797B1
+EP1351694B1
+EP1365768B1
+EP1383787B1
+EP1411900B1
+EP1414433B1
+EP1434570B1
+EP1472246B1
+EP1482919B1
+EP1498150A1
+EP1501837A1
+EP1536840B1
+EP1538162A2
+EP1542679B1
+EP1545491A1
+EP1551380A1
+EP1572208A2
+EP1585512A1
+EP1591529A2
+EP1596846A2
+EP1623987A1
+EP1632246A2
+EP1663205A1
+EP1677785A1
+EP1684770A1
+EP1712226A2
+EP1712642B1
+EP1721609A2
+EP1753714A2
+EP1763370A1
+EP1776356B1
+EP1786790A1
+EP1786802A1
+EP1793846A1
+EP1802297A2
+EP1802618A1
+EP1807090B9
+EP1834628A1
+EP1837027A1
+EP1854799A1
+EP1897547A1
+EP1909769A2
+EP1909803A2
+EP1928448B1
+EP1955708A1
+EP2014290A2
+EP2019825A1
+EP2036567A2
+EP2044023B1
+EP2063883A2
+EP2094258A1
+EP2097454A2
+EP2100611A1
+EP2116539A1
+EP2120920A2
+EP2170336A1
+EP2181706A2
+EP2229165A1
+EP2257296A1
+EP2265270A1
+EP2285767A2
+EP2307022A1
+EP2308880A1
+EP2343044A1
+EP2349275A1
+EP2352733A1
+EP2364712A1
+EP2385041A1
+EP2389350A1
+EP2394998A1
+EP2419140A2
+EP2424869A1
+EP2427052A1
+EP2437732A1
+EP2440548A1
+EP2471538A1
+EP2477699A1
+EP2520299A1
+EP2536411A2
+EP2544678A2
+EP2545922A1
+EP2549997A2
+EP2564871A1
+EP2571541A2
+EP2581082A1
+EP2582660A1
+EP2595636A2
+EP2596791A1
+EP2604601A1
+EP2606889A1
+EP2619187A1
+EP2630126A1
+EP2632453A1
+EP2651891A1
+EP2654745A1
+EP2661431A2
+EP2668168A1
+EP2688595A2
+EP2694068A1
+EP2697197A1
+EP2701692A1
+EP2729449A1
+EP2730280A1
+EP2730281A1
+EP2747750A2
+EP2749641A1
+EP2769722A1
+EP2780326A1
+EP2780352A1
+US20050014688
+US20050014769
+US20050014806
+US20050014811
+US20050020634
+US20050032759
+US20050049246
+US20050074455
+US20050076916
+US20050250730
+US20050261496
+US20050281749
+US20060008804
+US20060039937
+US20060040873
+US20060052319
+US20060094702
+US20060111235
+US20060128663
+US20060142388
+US20060154898
+US20060160848
+US20060166996
+US20060189538
+US20060217349
+US20060229338
+US20060235027
+US20060235045
+US20060235061
+US20070020230
+US20070053973
+US20070060551
+US20070066564
+US20070066633
+US20070088006
+US20070088024
+US20070112028
+US20070112040
+US20070148197
+US20070149476
+US20070185115
+US20070185137
+US20070213332
+US20070238640
+US20070243192
+US20070259826
+US20070259854
+US20070259857
+US20070259891
+US20070293460
+US20070293473
+US20080004228
+US20080004239
+US20080015189
+US20080027140
+US20080031817
+US20080058267
+US20080085870
+US20080085893
+US20080107707
+US20080107720
+US20080107737
+US20080113015
+US20080119435
+US20080119485
+US20080119530
+US20080125355
+US20080125387
+US20080131370
+US20080132460
+US20080132483
+US20080132507
+US20080139628
+US20080139652
+US20080153914
+US20080161247
+US20080161271
+US20080167327
+US20080170997
+US20080176812
+US20080176888
+US20080176902
+US20080182903
+US20080182907
+US20080187510
+US20080187588
+US20080193381
+US20080194633
+US20080194648
+US20080194663
+US20080194686
+US20080199468
+US20080220056
+US20080221056
+US20080221078
+US20080221105
+US20080221144
+US20080233090
+US20080233158
+US20080234301
+US20080242626
+US20080260702
+US20080260741
+US20080260846
+US20080260850
+US20080260878
+US20080261903
+US20080261907
+US20080261923
+US20080269166
+US20080269189
+US20080269211
+US20080269271
+US20080275018
+US20080280901
+US20080280920
+US20080311184
+US20080311231
+US20080312325
+US20080312333
+US20090011978
+US20090022737
+US20090028824
+US20090041742
+US20090068138
+US20090069305
+US20090069362
+US20090069375
+US20090069376
+US20090082283
+US20090082314
+US20090082324
+US20090082367
+US20090082379
+US20090082405
+US20090088412
+US20090099102
+US20090099124
+US20090099140
+US20090099197
+US20090104230
+US20090104297
+US20090105317
+US20090118685
+US20090136561
+US20090136565
+US20090136573
+US20090148531
+US20090181958
+US20090181975
+US20090186829
+US20090202660
+US20090214465
+US20090214529
+US20090220495
+US20090221625
+US20090221629
+US20090221703
+US20090238879
+US20090239929
+US20090258879
+US20090258882
+US20090270507
+US20090270881
+US20090275525
+US20090275570
+US20090275604
+US20090281169
+US20090305991
+US20100003289
+US20100055067
+US20100055069
+US20100055108
+US20100056475
+US20100056506
+US20100087502
+US20100099649
+US20100104533
+US20100104552
+US20100108059
+US20100120806
+US20100120887
+US20100152121
+US20100152189
+US20100152294
+US20100159030
+US20100166707
+US20100166882
+US20100173967
+US20100184650
+US20100184717
+US20100184765
+US20100210720
+US20100210732
+US20100215635
+US20100215646
+US20100215780
+US20100239641
+US20100239689
+US20100249091
+US20100249093
+US20100256119
+US20100256157
+US20100286143
+US20100286163
+US20100286188
+US20100311595
+US20100311678
+US20100317603
+US20100317651
+US20100317709
+US20100317717
+US20100317727
+US20100317731
+US20110003013
+US20110008328
+US20110009376
+US20110009380
+US20110009381
+US20110009388
+US20110009396
+US20110014197
+US20110014227
+US20110021355
+US20110046076
+US20110052536
+US20110059907
+US20110059918
+US20110059923
+US20110059934
+US20110059940
+US20110065805
+US20110070315
+US20110071115
+US20110071172
+US20110071199
+US20110077283
+US20110091440
+US20110091557
+US20110091560
+US20110104103
+US20110104173
+US20110105470
+US20110105540
+US20110111031
+US20110112047
+US20110112187
+US20110118239
+US20110118255
+US20110118284
+US20110118289
+US20110124612
+US20110124662
+US20110129422
+US20110129437
+US20110129476
+US20110130421
+US20110130444
+US20110160290
+US20110160302
+US20110172286
+US20110172291
+US20110177110
+US20110178470
+US20110189114
+US20110189127
+US20110244032
+US20110245340
+US20110251210
+US20110251243
+US20110256161
+US20110305775
+US20110311461
+US20110311651
+US20110311652
+US20120004167
+US20120004241
+US20120004242
+US20120004276
+US20120010156
+US20120010178
+US20120022001
+US20120022093
+US20120022104
+US20120022110
+US20120022114
+US20120035254
+US20120035256
+US20120041007
+US20120041012
+US20120041071
+US20120053138
+US20120053194
+US20120053200
+US20120058155
+US20120095029
+US20120095060
+US20120095062
+US20120101122
+US20120101131
+US20120101136
+US20120101142
+US20120107303
+US20120107308
+US20120107410
+US20120107417
+US20120108664
+US20120114636
+US20120115851
+US20120115877
+US20120115885
+US20120115896
+US20120121706
+US20120122981
+US20120134991
+US20120136019
+US20120136033
+US20120136048
+US20120156221
+US20120156288
+US20120156312
+US20120195970
+US20120202763
+US20120202791
+US20120202819
+US20120202847
+US20120207846
+US20120207853
+US20120213697
+US20120213713
+US20120214824
+US20120214829
+US20120214860
+US20120214863
+US20120214877
+US20120220610
+US20120225402
+US20120237565
+US20120237568
+US20120263716
+US20120270917
+US20120294940
+US20120308508
+US20120308622
+US20120308642
+US20120309750
+US20120309834
+US20120322776
+US20120328717
+US20130004512
+US20130022651
+US20130022670
+US20130028863
+US20130035754
+US20130052271
+US20130059917
+US20130064794
+US20130065842
+US20130089586
+US20130116219
+US20130158064
+US20130190403
+US20130224281
+US20140141089
+US20140199394
+US6844429
+US6849286
+US6863647
+US6866857
+US6884796
+US6894177
+US6924305
+US6929811
+US6930100
+US6960608
+US6962712
+US6984653
+US6984660
+US7037907
+US7048946
+US7053093
+US7053101
+US7053245
+US7071212
+US7074807
+US7074833
+US7074961
+US7132248
+US7138531
+US7163704
+US7169809
+US7169811
+US7173024
+US7198489
+US7229986
+US7241618
+US7247716
+US7273886
+US7371762
+US7371813
+US7429595
+US7429599
+US7431939
+US7442693
+US7442699
+US7459481
+US7544519
+US7550475
+US7563780
+US7563808
+US7579365
+US7579366
+US7579479
+US7598293
+US7598294
+US7628988
+US7638143
+US7648959
+US7678791
+US7700581
+US7713939
+US7718665
+US7718797
+US7759116
+US7767693
+US7772212
+US7794929
+US7799830
+US7812034
+US7875632
+US7902186
+US7910594
+US7943639
+US7960525
+US8012504
+US8030326
+US8044056
+US8071631
+US8092608
+US8252804
+US8288353
+US8324240
+US8349832
+US8404805
+US8409610
+US8440654
+US8492352
+US8530447
+US8535899
+US8541425
+US8546342
+US8632750
+US8637577
+US8835474
+USRE42164
+WO2001082928A9
+WO2004018482A8
+WO2004112837A8
+WO2005025583A2
+WO2005034956A1
+WO2005047250A1
+WO2005061454A1
+WO2005063230A1
+WO2005067918A1
+WO2005082388A1
+WO2005084709A1
+WO2005089426A3
+WO2005089780A1
+WO2005094805A1
+WO2006000923A3
+WO2006007227A2
+WO2006021657A1
+WO2006032432A3
+WO2006035142A1
+WO2006043532A1
+WO2006050006A3
+WO2006057460A1
+WO2006060535A2
+WO2006065916A1
+WO2006071601A2
+WO2006078925A3
+WO2006081986A1
+WO2006084758A1
+WO2006085562A1
+WO2006086923A1
+WO2006086978A3
+WO2006089689A1
+WO2006090756A1
+WO2006100082A3
+WO2006110119A1
+WO2006112456A1
+WO2006114709A1
+WO2006120573A3
+WO2006121968A3
+WO2006122800A1
+WO2006127503A3
+WO2006129163A1
+WO2006134489A1
+WO2006136823A1
+WO2006137092A1
+WO2007004425A1
+WO2007008045A1
+WO2007010514A3
+WO2007013522A1
+WO2007016476A3
+WO2007018622A3
+WO2007026218A2
+WO2007026240A1
+WO2007038284A1
+WO2007043581A1
+WO2007044698A1
+WO2007048351A1
+WO2007054283A3
+WO2007054296A1
+WO2007059257A8
+WO2007072178A1
+WO2007073687A1
+WO2007079515A1
+WO2007085718A1
+WO2007094605A1
+WO2007101005A3
+WO2007102451A1
+WO2007104719A1
+WO2007115933A1
+WO2007115966A1
+WO2007121883A2
+WO2007128454A1
+WO2007132280A1
+WO2007132807A1
+WO2007139499A1
+WO2007149935A2
+WO2008009077A3
+WO2008009078A2
+WO2008023003A1
+WO2008023446A1
+WO2008026046A1
+WO2008029882A1
+WO2008030584A3
+WO2008038305A3
+WO2008040967A1
+WO2008042240A9
+WO2008050871A1
+WO2008064595A1
+WO2008070609A1
+WO2008082562A3
+WO2008090209A2
+WO2008093763A1
+WO2008095275A1
+WO2008095835A1
+WO2008100422A1
+WO2008104386A2
+WO2008115259A3
+WO2008118164A1
+WO2008120003A1
+WO2008120214A3
+WO2008124927A1
+WO2008129255A1
+WO2008132950A1
+WO2008137446A1
+WO2008142513A2
+WO2008143637A2
+WO2008144223A3
+WO2008149163A3
+WO2008156102A1
+WO2008157191A2
+WO2009005838A3
+WO2009026657A1
+WO2009027736A2
+WO2009028387A1
+WO2009034346A3
+WO2009050506A2
+WO2009070328A1
+WO2009073460A2
+WO2009076512A1
+WO2009077857A3
+WO2009079921A1
+WO2009080778A4
+WO2009088518A1
+WO2009097999A1
+WO2009109071A1
+WO2009112954A3
+WO2009120717A3
+WO2009120826A1
+WO2009126584A1
+WO2009131201A1
+WO2009133387A1
+WO2009142587A1
+WO2009143578A1
+WO2009145357A8
+WO2009146910A8
+WO2009147476A1
+WO2009151910A3
+WO2009152083A1
+WO2010000008A1
+WO2010005520A3
+WO2010011653A1
+WO2010018836A2
+WO2010022725A1
+WO2010023346A1
+WO2010024911A1
+WO2010028116A1
+WO2010032041A3
+WO2010042633A2
+WO2010044686A1
+WO2010045190A1
+WO2010061903A1
+WO2010064047A1
+WO2010069605A3
+WO2010070365A1
+WO2010071885A1
+WO2010082072A1
+WO2010083570A1
+WO2010085352A2
+WO2010093341A1
+WO2010093736A1
+WO2010100650A3
+WO2010102393A1
+WO2010106106A1
+WO2010110689A1
+WO2010112093A1
+WO2010113183A3
+WO2010116926A1
+WO2010117346A3
+WO2010119741A1
+WO2010119875A1
+WO2010123507A1
+WO2010130638A1
+WO2010131718A1
+WO2010138833A1
+WO2010144043A1
+WO2010145207A1
+WO2010151073A2
+WO2011011965A1
+WO2011019348A1
+WO2011024987A1
+WO2011032100A1
+WO2011039367A3
+WO2011041914A1
+WO2011048612A3
+WO2011054947A1
+WO2011057327A1
+WO2011061760A1
+WO2011064559A2
+WO2011075267A1
+WO2011078823A1
+WO2011085544A1
+WO2011095837A1
+WO2011103718A1
+WO2011106599A1
+WO2011119649A3
+WO2011123524A3
+WO2011123691A1
+WO2011123751A3
+WO2011128745A2
+WO2011131975A1
+WO2011143932A1
+WO2011147951A8
+WO2011149841A1
+WO2011151551A1
+WO2011151782A1
+WO2011152751A1
+WO2011156646A3
+WO2012006946A1
+WO2012006958A1
+WO2012008564A1
+WO2012011063A1
+WO2012011129A3
+WO2012026614A1
+WO2012036523A2
+WO2012042951A1
+WO2012047156A1
+WO2012049647A1
+WO2012050465A1
+WO2012064222A1
+WO2012068081A1
+WO2012068535A1
+WO2012080186A1
+WO2012093859A2
+WO2012094313A1
+WO2012100109A2
+WO2012100408A1
+WO2012102555A3
+WO2012104402A1
+WO2012104788A3
+WO2012107532A1
+WO2012111997A2
+WO2012125413A2
+WO2012126231A1
+WO2012128582A3
+WO2012131090A1
+WO2012133489A1
+WO2012134184A2
+WO2012134828A1
+WO2012137227A3
+WO2012143624A2
+WO2012151420A1
+WO2012157587A1
+WO2012158399A1
+WO2012160130A1
+WO2012162536A2
+WO2012166614A2
+WO2012176105A1
+WO2013002439A1
+WO2013005041A1
+WO2013012681A1
+WO2013013308A1
+WO2013019079A3
+WO2013019938A1
+WO2013024427A1
+WO2013025607A1
+WO2013033626A2
+WO2013034098A1
+WO2013036286A2
+WO2013041468A1
+WO2013042139A1
+WO2013044044A2
+WO2013054998A1
+WO2013067769A1
+WO2013068621A1
+WO2013076646A1
+WO2013094676A1
+WO2013096878A1
+WO2013101810A1
+WO2013102234A1
+WO2013107206A1
+WO2013109199A1
+WO2013116753A1
+WO2013147618A1
+WO2013147711A1
+WO2013160222A1
+WO2013161312A1
+WO2013166366A1
+WO2013172339A1
+WO2013173599A1
+WO2013175344A3
+WO2013185635A1
+WO2013187612A1
+WO2013188813A3
+WO2013192367A1
+WO2014000077A1
+WO2014004951A1
+WO2014015830A1
+WO2014016267A1
+WO2014018449A1
+WO2014019468A1
+WO2014022143A1
+WO2014023390A2
+WO2014027017A1
+WO2014033262A1
+WO2014033490A1
+WO2014033560A1
+WO2014036022A1
+WO2014037412A1
+WO2014041708A1
+WO2014048564A8
+WO2014048888A1
+WO2014054980A1
+WO2014056446A1
+WO2014056566A1
+WO2014060375A3
+WO2014060548A1
+WO2014063068A1
+WO2014072220A1
+WO2014078942A1
+WO2014078968A1
+WO2014084401A1
+WO2014085489A1
+WO2014092154A1
+WO2014098092A1
+WO2014108337A1
+WO2014124757A1
+WO2014130894A1
+WO2014140078A1
+WO2014142290A1
+WO2014142780A1
+WO2014143669A1
+WO2014147203A1
+WO2014148216A1
+WO2014157047A1
+WO2014163031A1
diff --git a/huner/ner_scripts/splits/gpro.test b/huner/ner_scripts/splits/gpro.test
new file mode 100644
index 0000000..bab8859
--- /dev/null
+++ b/huner/ner_scripts/splits/gpro.test
@@ -0,0 +1,4201 @@
+
+CA2054762C
+CA2077637C
+CA2092271C
+CA2098849C
+CA2102780C
+CA2106642C
+CA2106819C
+CA2120743C
+CA2142445C
+CA2143752C
+CA2151377C
+CA2163175C
+CA2168921C
+CA2171614C
+CA2173116C
+CA2173876C
+CA2176392C
+CA2176796C
+CA2179955C
+CA2183620C
+CA2188267C
+CA2189221C
+CA2190778C
+CA2191815C
+CA2195370C
+CA2195663C
+CA2201477C
+CA2203885C
+CA2212200C
+CA2213567C
+CA2218553C
+CA2220777C
+CA2224369C
+CA2228060C
+CA2230960C
+CA2232880C
+CA2244512C
+CA2255521C
+CA2257121C
+CA2257579C
+CA2270177C
+CA2270893C
+CA2275686C
+CA2276694C
+CA2282254C
+CA2283464C
+CA2284863C
+CA2288726C
+CA2288983C
+CA2291391C
+CA2291796C
+CA2293714C
+CA2294086C
+CA2299423C
+CA2306214C
+CA2307792C
+CA2308315C
+CA2310659C
+CA2318184C
+CA2320288C
+CA2320430C
+CA2326137C
+CA2330128C
+CA2331471C
+CA2333442C
+CA2346631C
+CA2347117C
+CA2347387C
+CA2347950C
+CA2347981C
+CA2350396C
+CA2350713C
+CA2359708C
+CA2366186C
+CA2373183C
+CA2373634C
+CA2375671C
+CA2379003C
+CA2390563C
+CA2391297C
+CA2406206C
+CA2414241C
+CA2419877C
+CA2421548C
+CA2425556C
+CA2426625C
+CA2441225C
+CA2444244C
+CA2444821C
+CA2448607C
+CA2454699C
+CA2467930C
+CA2516364A1
+CA2525524C
+CA2537747A1
+CA2538729A1
+CA2546853A1
+CA2552694A1
+CA2554386A1
+CA2558043A1
+CA2563793A1
+CA2576022A1
+CA2577676A1
+CA2582949A1
+CA2586384A1
+CA2587247A1
+CA2588990A1
+CA2590334A1
+CA2604392A1
+CA2612595A1
+CA2615127A1
+CA2616222C
+CA2623733A1
+CA2624584A1
+CA2652501C
+CA2659222C
+CA2662732A1
+CA2670440A1
+CA2672190C
+CA2675980A1
+CA2677854A1
+CA2680502A1
+CA2685270C
+CA2687751A1
+CA2691425A1
+CA2700263A1
+CA2723564A1
+CA2725953A1
+CA2730008A1
+CA2742281A1
+CA2746054A1
+CA2761068A1
+CA2764885A1
+CA2777304A1
+CA2780274A1
+CA2782314A1
+CA2796068A1
+CA2797350A1
+CA2799881A1
+CA2816054A1
+CA2834341A1
+CA2835015A1
+CA2852114A1
+CA2853373A1
+CA2853872A1
+CA2856102A1
+CA2856501A1
+CA2856984A1
+CA2857096A1
+CN100579530C
+CN100581544C
+CN100581558C
+CN100582235C
+CN100594024C
+CN100594898C
+CN100998584A
+CN100998603A
+CN101002757A
+CN101002760A
+CN101002768A
+CN101002774A
+CN101002790B
+CN101002897A
+CN101003513A
+CN101006986A
+CN101007018A
+CN101007030A
+CN101007046A
+CN101011084A
+CN101011374A
+CN101011376A
+CN101011439A
+CN101011511A
+CN101015559A
+CN101016265A
+CN101018793A
+CN101019863A
+CN101019888A
+CN101028256A
+CN101028276A
+CN101028510B
+CN101032490A
+CN101032499A
+CN101036678A
+CN101037391A
+CN101039902B
+CN101039914A
+CN101041646B
+CN101045041A
+CN101045060A
+CN101045708A
+CN101049362A
+CN101050179A
+CN101050216B
+CN101054403A
+CN101057899A
+CN101058610A
+CN101060830A
+CN101062118A
+CN101062936A
+CN101062937A
+CN101065375A
+CN101067134A
+CN101069680B
+CN101069695A
+CN101073649A
+CN101073667A
+CN101074227B
+CN101074259A
+CN101076520B
+CN101077341A
+CN101077354A
+CN101081204A
+CN101081208A
+CN101081211A
+CN101084892A
+CN101084906A
+CN101085104A
+CN101085216A
+CN101085354A
+CN101085370A
+CN101091700B
+CN101091705B
+CN101095658A
+CN101095868A
+CN101098867B
+CN101100453A
+CN101103969A
+CN101103992A
+CN101108169A
+CN101112363A
+CN101112364A
+CN101112366A
+CN101116656A
+CN101125855A
+CN101129373A
+CN101129398B
+CN101129858A
+CN101134029A
+CN101134037A
+CN101134769A
+CN101143146A
+CN101143160A
+CN101143165B
+CN101143885A
+CN101147587A
+CN101147732B
+CN101147736A
+CN101164545A
+CN101167777B
+CN101167871B
+CN101185732A
+CN101185758A
+CN101186921A
+CN101190196A
+CN101190914B
+CN101198610B
+CN101199510B
+CN101199514A
+CN101199515B
+CN101199523B
+CN101199526A
+CN101199531A
+CN101199536A
+CN101199544A
+CN101199610A
+CN101199624B
+CN101200446A
+CN101209264B
+CN101210018A
+CN101214218A
+CN101214220A
+CN101214233A
+CN101214247A
+CN101219100A
+CN101219110A
+CN101219113A
+CN101219144A
+CN101222850B
+CN101229294A
+CN101234180A
+CN101235030A
+CN101239038A
+CN101239950B
+CN101244164A
+CN101244253A
+CN101244278A
+CN101245092A
+CN101249062A
+CN101249063A
+CN101249106A
+CN101249161A
+CN101250134B
+CN101252923B
+CN101254172A
+CN101254198A
+CN101255199A
+CN101258156A
+CN101259082A
+CN101259133A
+CN101259214B
+CN101259222B
+CN101260075B
+CN101264063A
+CN101265237A
+CN101268075A
+CN101269006A
+CN101269075A
+CN101269164A
+CN101270163B
+CN101273013A
+CN101273994A
+CN101278902A
+CN101278912A
+CN101278933A
+CN101279979B
+CN101279980B
+CN101283996B
+CN101284071A
+CN101289459A
+CN101289653A
+CN101292952A
+CN101292958A
+CN101292961A
+CN101292974B
+CN101293032A
+CN101293039B
+CN101297869A
+CN101300229A
+CN101301274B
+CN101301278A
+CN101301296A
+CN101301471A
+CN101311171A
+CN101313897A
+CN101313899B
+CN101316839B
+CN101317619A
+CN101317852A
+CN101317899A
+CN101317918A
+CN101318946A
+CN101322747A
+CN101323600A
+CN101326191B
+CN101327212A
+CN101327287A
+CN101328226A
+CN101332203A
+CN101332208A
+CN101332303B
+CN101336897A
+CN101336900A
+CN101336911A
+CN101336916A
+CN101337891B
+CN101342147A
+CN101342174A
+CN101342187B
+CN101347407A
+CN101347446A
+CN101347454A
+CN101348509A
+CN101348514A
+CN101352504B
+CN101356168A
+CN101357165B
+CN101357888B
+CN101361752A
+CN101361951B
+CN101361959B
+CN101362718A
+CN101366722A
+CN101367806B
+CN101367817B
+CN101367822A
+CN101371825A
+CN101371852A
+CN101371857A
+CN101378757B
+CN101380313A
+CN101380320B
+CN101380325A
+CN101380341B
+CN101385707A
+CN101385741A
+CN101385857A
+CN101400353A
+CN101401786B
+CN101401791A
+CN101401794A
+CN101401874A
+CN101402632A
+CN101406457A
+CN101406464A
+CN101406573A
+CN101406637A
+CN101407516A
+CN101411704A
+CN101411719A
+CN101411845B
+CN101416964B
+CN101416984A
+CN101417974A
+CN101418000A
+CN101428000A
+CN101428005A
+CN101428010A
+CN101433544B
+CN101434600A
+CN101439026A
+CN101439032A
+CN101440119A
+CN101445528B
+CN101445541B
+CN101450041B
+CN101461624B
+CN101461800B
+CN101474171B
+CN101474375B
+CN101474412B
+CN101479238A
+CN101480453B
+CN101491529B
+CN101492426B
+CN101492464B
+CN101500562B
+CN101502593A
+CN101502668A
+CN101503437B
+CN101511801A
+CN101513394A
+CN101513399B
+CN101513468A
+CN101513471A
+CN101519375A
+CN101524504A
+CN101525342A
+CN101528229B
+CN101530399B
+CN101530416A
+CN101530426A
+CN101536990A
+CN101536993A
+CN101536997B
+CN101537170A
+CN101537184A
+CN101538191A
+CN101543473A
+CN101543475A
+CN101543501A
+CN101543504A
+CN101543511A
+CN101543600A
+CN101548990B
+CN101550115B
+CN101550139A
+CN101555210A
+CN101555266A
+CN101559050A
+CN101559056A
+CN101559057A
+CN101559063A
+CN101559097A
+CN101564388A
+CN101564396A
+CN101574338A
+CN101574351A
+CN101579308A
+CN101579333A
+CN101579351A
+CN101584662A
+CN101584667A
+CN101584672A
+CN101584741B
+CN101584761B
+CN101590018A
+CN101590025A
+CN101590041A
+CN101590053A
+CN101590078A
+CN101590154A
+CN101591364B
+CN101596236A
+CN101597218A
+CN101601846A
+CN101602707B
+CN101606945A
+CN101606955A
+CN101610764B
+CN101613382B
+CN101628091B
+CN101637444B
+CN101647781B
+CN101647934B
+CN101653421A
+CN101653439B
+CN101653449B
+CN101653452B
+CN101658530B
+CN101658537B
+CN101664493B
+CN101669946A
+CN101669959A
+CN101669962A
+CN101676290A
+CN101684098A
+CN101686985A
+CN101687855A
+CN101693730B
+CN101695497A
+CN101695502A
+CN101696202B
+CN101698016B
+CN101703500A
+CN101703506B
+CN101703569A
+CN101703673A
+CN101708160A
+CN101708186A
+CN101708339A
+CN101712670A
+CN101716214B
+CN101721394A
+CN101721403A
+CN101721405A
+CN101721423B
+CN101721435A
+CN101723903A
+CN101724037A
+CN101724048A
+CN101732301A
+CN101732305B
+CN101732477A
+CN101732597A
+CN101732610B
+CN101732695A
+CN101744769B
+CN101744794A
+CN101757009A
+CN101757077A
+CN101757103A
+CN101757604A
+CN101757624A
+CN101766604A
+CN101766605A
+CN101766606A
+CN101766621A
+CN101766689A
+CN101766821A
+CN101768130A
+CN101768155A
+CN101773489A
+CN101773596A
+CN101780224A
+CN101792788A
+CN101801372A
+CN101804059A
+CN101804067A
+CN101804093A
+CN101810570A
+CN101810571A
+CN101810577B
+CN101810588A
+CN101810599A
+CN101810601A
+CN101810729A
+CN101810850A
+CN101816638A
+CN101816644A
+CN101816660A
+CN101816678A
+CN101817742A
+CN101817833A
+CN101817834A
+CN101822651A
+CN101829127A
+CN101829131A
+CN101829139A
+CN101829200A
+CN101830945A
+CN101831478A
+CN101836960A
+CN101836962A
+CN101837004A
+CN101837010A
+CN101843603A
+CN101843823A
+CN101849928A
+CN101849934A
+CN101850031A
+CN101851250A
+CN101862299A
+CN101862309A
+CN101862628A
+CN101863887B
+CN101863953A
+CN101864367B
+CN101868156A
+CN101869571A
+CN101869578A
+CN101869699A
+CN101874789A
+CN101874797A
+CN101879143A
+CN101879162A
+CN101879173A
+CN101890023A
+CN101890030A
+CN101890035B
+CN101890039A
+CN101892237B
+CN101897699A
+CN101897792A
+CN101898985A
+CN101903348A
+CN101904819A
+CN101912431A
+CN101917995A
+CN101918378A
+CN101919831B
+CN101919832A
+CN101919901B
+CN101920015A
+CN101921238A
+CN101926755A
+CN101926843A
+CN101926927A
+CN101933931A
+CN101940557A
+CN101940560A
+CN101940796A
+CN101947207A
+CN101947214A
+CN101947231A
+CN101947234A
+CN101947267B
+CN101948381A
+CN101948430A
+CN101953856A
+CN101961336A
+CN101961344A
+CN101966184A
+CN101967127A
+CN101967169A
+CN101972226A
+CN101974016A
+CN101977597A
+CN101979025A
+CN101983631A
+CN101985039A
+CN101987166B
+CN101987178A
+CN101991535A
+CN102000070A
+CN102000079B
+CN102008440A
+CN102008462B
+CN102008612A
+CN102008695B
+CN102018677A
+CN102018807A
+CN102020609A
+CN102020623B
+CN102028654A
+CN102028702A
+CN102030809A
+CN102038672A
+CN102038692A
+CN102038808A
+CN102038957B
+CN102048706A
+CN102049051A
+CN102058516B
+CN102058523A
+CN102058556A
+CN102058608A
+CN102066317A
+CN102068442A
+CN102070565A
+CN102078299B
+CN102078319A
+CN102078325A
+CN102079769A
+CN102085187B
+CN102085370A
+CN102091062A
+CN102091067A
+CN102091070A
+CN102091084A
+CN102091273A
+CN102091310A
+CN102100660A
+CN102100665B
+CN102101867A
+CN102106815A
+CN102106936B
+CN102114005A
+CN102114013A
+CN102114016A
+CN102119974B
+CN102125522A
+CN102125571A
+CN102125587A
+CN102127062A
+CN102133210A
+CN102138892A
+CN102138930A
+CN102143761A
+CN102144967B
+CN102144988A
+CN102144991A
+CN102145077A
+CN102145172B
+CN102151245B
+CN102151298A
+CN102161710A
+CN102164887A
+CN102178647A
+CN102178676A
+CN102178894A
+CN102180866A
+CN102186829A
+CN102188373A
+CN102188382A
+CN102188432A
+CN102188692A
+CN102204899A
+CN102204900A
+CN102204915B
+CN102204921A
+CN102206180A
+CN102210669A
+CN102210698A
+CN102229546A
+CN102229558A
+CN102229580A
+CN102232920A
+CN102234250A
+CN102234267A
+CN102234284A
+CN102240283A
+CN102247321A
+CN102247345A
+CN102247347A
+CN102276605B
+CN102302452A
+CN102302468A
+CN102302479A
+CN102302481A
+CN102302482A
+CN102302484A
+CN102304103A
+CN102304104A
+CN102304132A
+CN102311382A
+CN102319221A
+CN102319234A
+CN102321025A
+CN102327235A
+CN102335165A
+CN102335170A
+CN102335179A
+CN102335206A
+CN102335412A
+CN102335462A
+CN102336768A
+CN102349922A
+CN102351934A
+CN102356874A
+CN102357143A
+CN102362868A
+CN102362870A
+CN102362880A
+CN102366560A
+CN102370613A
+CN102379844A
+CN102379878A
+CN102380083A
+CN102382014A
+CN102382036A
+CN102382144A
+CN102391137A
+CN102391263A
+CN102406652A
+CN102423466A
+CN102429911A
+CN102429914A
+CN102440962A
+CN102440969A
+CN102440975A
+CN102440976A
+CN102440982A
+CN102451272A
+CN102451460A
+CN102459588A
+CN102475701A
+CN102488651A
+CN102488658A
+CN102488664A
+CN102488666A
+CN102488678A
+CN102503922A
+CN102512403A
+CN102512443A
+CN102512462A
+CN102512696A
+CN102516213A
+CN102516263A
+CN102525722A
+CN102525957A
+CN102526042A
+CN102526098A
+CN102532099A
+CN102552137A
+CN102552224A
+CN102552226A
+CN102552230A
+CN102552231A
+CN102552250A
+CN102552714A
+CN102579320A
+CN102579325A
+CN102579334A
+CN102579403A
+CN102579462A
+CN102579472A
+CN102579931A
+CN102584683A
+CN102600110A
+CN102600268A
+CN102600288A
+CN102600441A
+CN102603683A
+CN102603753A
+CN102614161A
+CN102614182A
+CN102617437A
+CN102617613A
+CN102617664A
+CN102617672A
+CN102626382A
+CN102626397A
+CN102626399A
+CN102626414A
+CN102631315A
+CN102631340A
+CN102631341A
+CN102633899A
+CN102641280A
+CN102641507A
+CN102643186A
+CN102648909A
+CN102648922A
+CN102649750A
+CN102649773A
+CN102652792A
+CN102653522A
+CN102656179A
+CN102657620A
+CN102657653A
+CN102657654A
+CN102670575A
+CN102670604A
+CN102670625A
+CN102675252A
+CN102688220A
+CN102688225A
+CN102695520A
+CN102697783A
+CN102697795A
+CN102698285A
+CN102698294A
+CN102702033A
+CN102702070A
+CN102702092A
+CN102702582A
+CN102703327A
+CN102712622A
+CN102716098A
+CN102716167A
+CN102716486A
+CN102718693A
+CN102727422A
+CN102727426A
+CN102727459A
+CN102727481A
+CN102727484A
+CN102727811A
+CN102727868A
+CN102731301A
+CN102731365A
+CN102731493A
+CN102731561A
+CN102743335A
+CN102743336A
+CN102743403A
+CN102755295A
+CN102755297A
+CN102757460A
+CN102766109A
+CN102772371A
+CN102772398A
+CN102772733A
+CN102772800A
+CN102784098A
+CN102784108A
+CN102784122A
+CN102784126A
+CN102793729A
+CN102796040A
+CN102796080A
+CN102796100A
+CN102796109A
+CN102796235A
+CN102803263A
+CN102805770A
+CN102807566A
+CN102824337A
+CN102824386A
+CN102824395A
+CN102824630A
+CN102834096A
+CN102836125A
+CN102836140A
+CN102836147A
+CN102846538A
+CN102846540A
+CN102846560A
+CN102846762A
+CN102847175A
+CN102851295A
+CN102861080A
+CN102861096A
+CN102872065A
+CN102872067A
+CN102872106A
+CN102872118A
+CN102872119A
+CN102875564A
+CN102885763A
+CN102885781A
+CN102887904A
+CN102895217A
+CN102895393A
+CN102895494A
+CN102895502A
+CN102895503A
+CN102895509A
+CN102895636A
+CN102898463A
+CN102907671A
+CN102908359A
+CN102911158A
+CN102911180A
+CN102911182A
+CN102920237A
+CN102920651A
+CN102920726A
+CN102920987A
+CN102924322A
+CN102940625A
+CN102940767A
+CN102942551A
+CN102946877A
+CN102947272A
+CN102949366A
+CN102949390A
+CN102973552A
+CN102973572A
+CN102973576A
+CN102973586A
+CN102977101A
+CN102988279A
+CN102988287A
+CN102988293A
+CN102988444A
+CN102992997A
+CN102993095A
+CN103006599A
+CN103006700A
+CN103006718A
+CN103006800A
+CN103007270A
+CN103012397A
+CN103012398A
+CN103027922A
+CN103040743A
+CN103040776A
+CN103040778A
+CN103040779A
+CN103040801A
+CN103040903A
+CN103040917A
+CN103044364A
+CN103044392A
+CN103044439A
+CN103045674A
+CN103054815A
+CN103054817A
+CN103054828A
+CN103054832A
+CN103054841A
+CN103055013A
+CN103058999A
+CN103070918A
+CN103073542A
+CN103083337A
+CN103083389A
+CN103086943A
+CN103086987A
+CN103087021A
+CN103096887A
+CN103099801A
+CN103099814A
+CN103110526A
+CN103110600A
+CN103110603A
+CN103110604A
+CN103110614A
+CN103110623A
+CN103110643A
+CN103110645A
+CN103113295A
+CN103120624A
+CN103126980A
+CN103126984A
+CN103127041A
+CN103127053A
+CN103127062A
+CN103127121A
+CN103127127A
+CN103127149A
+CN103127158A
+CN103127393A
+CN103127525A
+CN103127543A
+CN103130788A
+CN103130795A
+CN103130828A
+CN103142503A
+CN103142512A
+CN103142534A
+CN103142545A
+CN103142547A
+CN103142567A
+CN103142638A
+CN103142641A
+CN103142645A
+CN103142785A
+CN103143019A
+CN103145631A
+CN103145694A
+CN103156817A
+CN103156822A
+CN103156831A
+CN103156835A
+CN103159665A
+CN103159666A
+CN103169661A
+CN103172587A
+CN103172819A
+CN103180322A
+CN103181901A
+CN103181922A
+CN103181943A
+CN103181955A
+CN103182055A
+CN103183709A
+CN103183719A
+CN103189361A
+CN103191049A
+CN103191058A
+CN103191273A
+CN103191284A
+CN103193781A
+CN103202850A
+CN103202858A
+CN103202875A
+CN103211889A
+CN103211972A
+CN103212009A
+CN103214467A
+CN103214489A
+CN103214497A
+CN103222955A
+CN103222982A
+CN103224530A
+CN103228284A
+CN103230365A
+CN103230595A
+CN103239414A
+CN103239666A
+CN103242214A
+CN103242278A
+CN103251569A
+CN103251633A
+CN103254203A
+CN103261189A
+CN103261192A
+CN103263525A
+CN103265538A
+CN103271873A
+CN103271879A
+CN103271923A
+CN103271933A
+CN103271937A
+CN103272042A
+CN103275115A
+CN103284979A
+CN103284983A
+CN103284993A
+CN103285133A
+CN103288800A
+CN103301060A
+CN103301065A
+CN103301069A
+CN103301134A
+CN103301135A
+CN103304609A
+CN103315948A
+CN103315958A
+CN103316003A
+CN103316007A
+CN103316011A
+CN103316018A
+CN103316025A
+CN103316030A
+CN103316343A
+CN103316348A
+CN103319371A
+CN103319496A
+CN103330946A
+CN103333148A
+CN103333163A
+CN103339132A
+CN103349751A
+CN103351285A
+CN103356479A
+CN103356543A
+CN103356547A
+CN103356579A
+CN103356591A
+CN103356592A
+CN103356678A
+CN103356770A
+CN103360294A
+CN103360400A
+CN103360423A
+CN103372002A
+CN103373957A
+CN103374079A
+CN103381143A
+CN103381148A
+CN103381162A
+CN103381167A
+CN103381183A
+CN103381184A
+CN103381194A
+CN103381196A
+CN103384659A
+CN103385850A
+CN103385863A
+CN103385865A
+CN103386036A
+CN103393604A
+CN103393633A
+CN103393658A
+CN103393673A
+CN103393731A
+CN103393751A
+CN103393947A
+CN103396436A
+CN103396557A
+CN103403014A
+CN103404514A
+CN103405418A
+CN103405424A
+CN103405426A
+CN103405571A
+CN103405782A
+CN103408400A
+CN103417470A
+CN103417504A
+CN103417538A
+CN103417764A
+CN103417888A
+CN103429572A
+CN103432083A
+CN103432155A
+CN103432177A
+CN103432181A
+CN103446065A
+CN103446071A
+CN103446079A
+CN103446081A
+CN103446083A
+CN103446094A
+CN103446101A
+CN103446179A
+CN103446468A
+CN103450062A
+CN103450162A
+CN103450173A
+CN103462930A
+CN103463009A
+CN103463012A
+CN103463022A
+CN103463106A
+CN103463112A
+CN103463122A
+CN103463148A
+CN103463154A
+CN103463487A
+CN103467550A
+CN103479568A
+CN103479611A
+CN103479987A
+CN103483187A
+CN103483315A
+CN103494875A
+CN103495174A
+CN103497204A
+CN103505423A
+CN103505430A
+CN103509868A
+CN103520010A
+CN103520086A
+CN103520099A
+CN103520183A
+CN103524533A
+CN103534248A
+CN103536890A
+CN103536925A
+CN103550162A
+CN103550166A
+CN103550182A
+CN103550191A
+CN103550194A
+CN103550233A
+CN103550444A
+CN103554187A
+CN103565750A
+CN103565758A
+CN103565759A
+CN103565787A
+CN103566331A
+CN103570709A
+CN103570720A
+CN103585160A
+CN103585164A
+CN103585196A
+CN103585200A
+CN103585439A
+CN103588673A
+CN103599080A
+CN103601719A
+CN103622973A
+CN103623080A
+CN103623331A
+CN103623421A
+CN103623780A
+CN103626694A
+CN103626764A
+CN103637982A
+CN103637986A
+CN103637987A
+CN103638010A
+CN103638037A
+CN103638041A
+CN103638383A
+CN103638422A
+CN103641807A
+CN103649053A
+CN103649066A
+CN103652703A
+CN103655207A
+CN103655454A
+CN103655463A
+CN103655465A
+CN103655471A
+CN103655493A
+CN103655532A
+CN103655539A
+CN103655540A
+CN103655568A
+CN103655570A
+CN103655585A
+CN103655587A
+CN103655592A
+CN103656611A
+CN103656670A
+CN103664559A
+CN103664777A
+CN103665004A
+CN103665069A
+CN103690777A
+CN103690956A
+CN103690985A
+CN103694133A
+CN103694408A
+CN103703002A
+CN103705454A
+CN103705516A
+CN103705522A
+CN103705523A
+CN103705533A
+CN103705543A
+CN103705888A
+CN103709015A
+CN103709146A
+CN103709154A
+CN103709223A
+CN103720654A
+CN103720672A
+CN103720684A
+CN103720689A
+CN103721103A
+CN103721259A
+CN103724334A
+CN103724445A
+CN103734823A
+CN103735498A
+CN103735500A
+CN103735503A
+CN103735527A
+CN103735537A
+CN103739579A
+CN103739591A
+CN103750606A
+CN103751103A
+CN103751115A
+CN103751116A
+CN103751123A
+CN103751204A
+CN103751237A
+CN103751730A
+CN103755744A
+CN103755771A
+CN103764146A
+CN1294956C
+CN1559409A
+CN1559417A
+CN1561985A
+CN1561991A
+CN1562028A
+CN1562076A
+CN1563069A
+CN1565422A
+CN1565458A
+CN1575813A
+CN1579445A
+CN1580065A
+CN1582913A
+CN1582922A
+CN1590395A
+CN1592620A
+CN1593389A
+CN1593461B
+CN1611500A
+CN1613451A
+CN1615869A
+CN1628664A
+CN1628666A
+CN1628667A
+CN1628688A
+CN1628689A
+CN1634082A
+CN1660126A
+CN1660129A
+CN1666748A
+CN1679521A
+CN1679528A
+CN1679549A
+CN1679572A
+CN1679576A
+CN1679593A
+CN1679594A
+CN1680424A
+CN1682715A
+CN1683369A
+CN1712399B
+CN1720908A
+CN1723880A
+CN1726919A
+CN1727340A
+CN1729979A
+CN1729990A
+CN1729991A
+CN1733704A
+CN1735607B
+CN1739571A
+CN1739573A
+CN1739574A
+CN1742732A
+CN1742737A
+CN1745754A
+CN1752078A
+CN1759844A
+CN1762369A
+CN1762370A
+CN1762374A
+CN1762378A
+CN1763069A
+CN1771971A
+CN1781922A
+CN1785187A
+CN1788719A
+CN1788727A
+CN1792380A
+CN1795865A
+CN1795866A
+CN1795868A
+CN1795928A
+CN1799553A
+CN1810240A
+CN1810803B
+CN1813713A
+CN1813825A
+CN1813973A
+CN1814144A
+CN1817180A
+CN1820781A
+CN1823788A
+CN1823793A
+CN1823842A
+CN1830434A
+CN1836663A
+CN1839837A
+CN1840052A
+CN1840181A
+CN1846677A
+CN1846678A
+CN1846685A
+CN1846686A
+CN1846687A
+CN1846783A
+CN1850044A
+CN1850063A
+CN1853507A
+CN1853623A
+CN1853626B
+CN1853647A
+CN1856485A
+CN1856709A
+CN1857206A
+CN1857220B
+CN1857222B
+CN1857284A
+CN1857309A
+CN1859919A
+CN1861053A
+CN1861082A
+CN1863812A
+CN1864666A
+CN1868452A
+CN1868455A
+CN1870988A
+CN1872072A
+CN1872206A
+CN1872853A
+CN1875967A
+CN1876130A
+CN1879644A
+CN1879737A
+CN1879863B
+CN1883488A
+CN1883671A
+CN1884305A
+CN1887305A
+CN1887859A
+CN1891211A
+CN1895255A
+CN1895365A
+CN1895598B
+CN1899270A
+CN1900094A
+CN1903181A
+CN1903191A
+CN1911207A
+CN1911217A
+CN1911229A
+CN1911236A
+CN1911953A
+CN1915326A
+CN1915335A
+CN1919183A
+CN1919861A
+CN1923209B
+CN1927171A
+CN1927292A
+CN1931130A
+CN1931154A
+CN1931867A
+CN1939535A
+CN1939540A
+CN1939916B
+CN1939919A
+CN1943573A
+CN1943679A
+CN1947701A
+CN1951360A
+CN1951376B
+CN1951896A
+CN1951923A
+CN1951932B
+CN1954855B
+CN1957949A
+CN1965815A
+CN1965840A
+CN1965844A
+CN1969814A
+CN1969826A
+CN1969836A
+CN1969934A
+CN1977861A
+CN1977975A
+CN1981833B
+CN1982306A
+CN1984660A
+CN1984907A
+CN1986826A
+CN1989952A
+CN1989970A
+CN1989971A
+CN1993349A
+CN1993358A
+CN1994295A
+CN200942144Y
+CN201524271U
+CN201625211U
+CN202263198U
+CN2798942Y
+DE102004008375A1
+DE102004027685A1
+DE102004049015A1
+DE102005019549A1
+DE102005023639A1
+DE102005035917A1
+DE102007002073A1
+DE102007059703A1
+DE102008005498A1
+DE102008027868A1
+DE102008034739A1
+DE102009008851A1
+DE102009024133A1
+DE102009049551A1
+DE102010022587A1
+DE102010051391A1
+DE102010056443A1
+DE102011015567A1
+EP0710288B1
+EP0723398B1
+EP0735888B1
+EP0741783B1
+EP0782630B1
+EP0800397B1
+EP0801562B2
+EP0811075B1
+EP0819121B1
+EP0840599B1
+EP0844877B1
+EP0865446B1
+EP0866654B1
+EP0906106B1
+EP0918515B1
+EP0927043B1
+EP0934310B1
+EP0934412B1
+EP0935462B1
+EP0956040B1
+EP0961612B2
+EP0971587B1
+EP0980240B1
+EP0982990B1
+EP0989863B1
+EP0991625B1
+EP1001755B1
+EP1001946B1
+EP1005485B1
+EP1010423B1
+EP1014967B1
+EP1019033B1
+EP1023435B1
+EP1044009B1
+EP1047422B1
+EP1047436B1
+EP1060163B1
+EP1061923B1
+EP1066041B1
+EP1067908B9
+EP1077674B1
+EP1086105B1
+EP1087946B1
+EP1091745B1
+EP1091924B1
+EP1107813B1
+EP1109553B1
+EP1119248B1
+EP1121355B1
+EP1123392B1
+EP1131090B1
+EP1140930B1
+EP1144609B1
+EP1146873B1
+EP1150982B1
+EP1157002B1
+EP1165073B1
+EP1165099B1
+EP1173421B1
+EP1173427B1
+EP1177790B1
+EP1178977B1
+EP1179984B2
+EP1185306B1
+EP1216228B1
+EP1216241B1
+EP1225814B1
+EP1226177B1
+EP1227797B1
+EP1229917B1
+EP1231894B1
+EP1242587B1
+EP1244445B1
+EP1246810B1
+EP1251818B9
+EP1255733B1
+EP1257281B1
+EP1265616B1
+EP1276485B1
+EP1280515B1
+EP1294717B1
+EP1296703B1
+EP1296974B1
+EP1305311B1
+EP1313853B1
+EP1315695B1
+EP1331927B1
+EP1337220A4
+EP1337523B1
+EP1341544B1
+EP1342723B1
+EP1345942B1
+EP1347760B1
+EP1347986B1
+EP1355646B1
+EP1357936B1
+EP1363509B1
+EP1366021B1
+EP1372656B1
+EP1372680B1
+EP1381614B1
+EP1383731B1
+EP1390075B1
+EP1401408A4
+EP1406616B1
+EP1408986B1
+EP1412338B1
+EP1414802B1
+EP1419154B1
+EP1421198A4
+EP1427732B1
+EP1438045B1
+EP1448215B1
+EP1469809B1
+EP1476470B1
+EP1487427A4
+EP1490350B1
+EP1490360B1
+EP1495000A1
+EP1497247A2
+EP1499204A2
+EP1510211A1
+EP1513834B1
+EP1514877A1
+EP1515941A1
+EP1515971A2
+EP1517671A2
+EP1517697A1
+EP1521572B1
+EP1521748A1
+EP1524971A1
+EP1526857A1
+EP1530632A2
+EP1530724B1
+EP1537243A1
+EP1542728A1
+EP1554298A1
+EP1559726A2
+EP1562570A4
+EP1562607A1
+EP1562617B1
+EP1569915A2
+EP1572189A1
+EP1575521A2
+EP1578926A2
+EP1591115A1
+EP1592431A4
+EP1592447B1
+EP1594976A2
+EP1596812A2
+EP1603537A2
+EP1607384A1
+EP1608349A1
+EP1608661A2
+EP1609788A1
+EP1611902A1
+EP1612268A1
+EP1614684B1
+EP1615697A2
+EP1621197A2
+EP1635844A1
+EP1635850B1
+EP1644338A1
+EP1645558A1
+EP1648453A1
+EP1650199A1
+EP1653969A2
+EP1658851A1
+EP1661575A1
+EP1666034A1
+EP1667678B1
+EP1668003A1
+EP1680429A1
+EP1682110A1
+EP1694333A2
+EP1695970A1
+EP1698337A1
+EP1699452A2
+EP1704865A2
+EP1708714A1
+EP1711177B1
+EP1718645A1
+EP1720535B1
+EP1728789A1
+EP1732897A1
+EP1737440A2
+EP1738768A1
+EP1745777A1
+EP1755542A1
+EP1757601A1
+EP1762619A2
+EP1764099A2
+EP1773323A1
+EP1776338A1
+EP1778637B1
+EP1778672A1
+EP1781602A1
+EP1784381A1
+EP1785142A1
+EP1785424A2
+EP1786412A1
+EP1799669A1
+EP1801231B1
+EP1802602A1
+EP1807064B1
+EP1809618A1
+EP1813603A1
+EP1813618A1
+EP1819319A1
+EP1831208A1
+EP1832297A1
+EP1834670A2
+EP1835916B1
+EP1838736A2
+EP1845990B1
+EP1850840A2
+EP1851229A1
+EP1853567A1
+EP1856125A1
+EP1858862A1
+EP1860108A1
+EP1860115A1
+EP1863499A1
+EP1863767A1
+EP1871396A1
+EP1878435A1
+EP1878726A1
+EP1878746A2
+EP1879572B1
+EP1887008A1
+EP1889609A2
+EP1890558B1
+EP1891017A1
+EP1891068A1
+EP1896035A2
+EP1896415A1
+EP1896466A1
+EP1904051A1
+EP1908752A1
+EP1911462A2
+EP1912658A1
+EP1912986A1
+EP1914234A1
+EP1917027A2
+EP1917958A2
+EP1920783A1
+EP1926725A1
+EP1927359A2
+EP1932530A1
+EP1939295A1
+EP1942100A1
+EP1942916A1
+EP1942918A1
+EP1944297A1
+EP1944298A1
+EP1946753A1
+EP1954280A2
+EP1963337B1
+EP1963344A1
+EP1976538B1
+EP1978968A2
+EP1979322A1
+EP1987019A1
+EP1991554A1
+EP1993619A2
+EP1996180B1
+EP2000149A1
+EP2000470A1
+EP2002730A1
+EP2004176A1
+EP2007394A1
+EP2012769A1
+EP2014640A1
+EP2014655A2
+EP2017265A1
+EP2020997A2
+EP2023918B1
+EP2024354B1
+EP2035432B1
+EP2043628A2
+EP2044938A2
+EP2046796A1
+EP2050441A1
+EP2050455A1
+EP2053041A2
+EP2061457A1
+EP2062598A1
+EP2065379A1
+EP2075010A1
+EP2079701A1
+EP2086524A1
+EP2091523A1
+EP2097081A1
+EP2112926A2
+EP2113251A1
+EP2116236A1
+EP2118117A2
+EP2138175A2
+EP2141163A1
+EP2142516A1
+EP2148857A1
+EP2149584A1
+EP2152256A2
+EP2152713A1
+EP2156846A1
+EP2158903A2
+EP2182067A2
+EP2197890A1
+EP2198867A1
+EP2202227A1
+EP2205563A2
+EP2210583A1
+EP2211857A1
+EP2213679A1
+EP2217589A2
+EP2229390A1
+EP2230242A1
+EP2238108A1
+EP2247583A1
+EP2257556A1
+EP2268141A1
+EP2268284A2
+EP2269613A2
+EP2276765A1
+EP2281815A1
+EP2292616A1
+EP2294067A1
+EP2300476A1
+EP2301626A2
+EP2322162A1
+EP2328412A1
+EP2331520A1
+EP2343074A1
+EP2344158A1
+EP2346825A2
+EP2346826A2
+EP2349203A2
+EP2357175A1
+EP2358697A1
+EP2359827A1
+EP2366695A1
+EP2371367A1
+EP2373656A1
+EP2374478A1
+EP2377855A1
+EP2379561A2
+EP2388005A1
+EP2395975A1
+EP2397481A1
+EP2402356A2
+EP2405755A1
+EP2418212A1
+EP2424511A1
+EP2426122A1
+EP2433627A1
+EP2439198A2
+EP2442818A1
+EP2451453A1
+EP2464359A2
+EP2471530A1
+EP2476419A1
+EP2480229A2
+EP2483277A1
+EP2502625A1
+EP2507237A1
+EP2513095A1
+EP2514742A2
+EP2528601A1
+EP2532648A1
+EP2533787A1
+EP2534131A1
+EP2534157A1
+EP2540725A1
+EP2558090A1
+EP2559432A1
+EP2559442A1
+EP2561069A2
+EP2578214A2
+EP2582674A1
+EP2586441A1
+EP2588107A1
+EP2590661A1
+EP2590980A1
+EP2595972A1
+EP2596796A1
+EP2598132A1
+EP2600868A1
+EP2603217A1
+EP2609914A1
+EP2615163A1
+EP2617415A2
+EP2626351A1
+EP2639215A1
+EP2644194A2
+EP2646455A2
+EP2651919A1
+EP2654763A1
+EP2655312A1
+EP2675814A1
+EP2688565A1
+EP2688888A1
+EP2690175A2
+EP2692777A1
+EP2694072A1
+EP2699249A1
+EP2700627A1
+EP2705047A1
+EP2709674A1
+EP2711372A1
+EP2714025A1
+EP2714046A1
+EP2714712A1
+EP2717879A1
+EP2720694A1
+EP2725101A1
+EP2731593A2
+EP2732819A2
+EP2738156A1
+EP2738172A1
+EP2744781A1
+EP2744786A1
+EP2746251A2
+EP2746272A1
+EP2747761A1
+EP2754714A1
+EP2759547A1
+EP2760868A1
+EP2763995A1
+EP2766356A1
+EP2767533A1
+EP2769736A1
+EP2770992A1
+EP2776437A1
+EP2781519A1
+US20050004165
+US20050004177
+US20050004222
+US20050019923
+US20050026980
+US20050026981
+US20050036949
+US20050038019
+US20050038111
+US20050042173
+US20050042215
+US20050054614
+US20050054653
+US20050054683
+US20050059606
+US20050064032
+US20050065107
+US20050065120
+US20050065195
+US20050090481
+US20050095293
+US20050096316
+US20050096392
+US20050096473
+US20050101593
+US20050101632
+US20050101647
+US20050107311
+US20050107455
+US20050112069
+US20050113321
+US20050113357
+US20050118281
+US20050119272
+US20050124537
+US20050124581
+US20050131049
+US20050136127
+US20050143346
+US20050148581
+US20050148607
+US20050152846
+US20050153930
+US20050153975
+US20050154202
+US20050165017
+US20050176756
+US20050176765
+US20050176821
+US20050181042
+US20050192237
+US20050197328
+US20050197375
+US20050208103
+US20050208496
+US20050214360
+US20050215609
+US20050222093
+US20050222413
+US20050227942
+US20050239906
+US20050245471
+US20050245564
+US20050245743
+US20050245750
+US20050255096
+US20050256034
+US20050256122
+US20050272694
+US20050272751
+US20050282786
+US20050288296
+US20050288376
+US20060004030
+US20060018956
+US20060024659
+US20060029689
+US20060073191
+US20060089317
+US20060100175
+US20060100195
+US20060106036
+US20060134228
+US20060148810
+US20060165720
+US20060171984
+US20060173014
+US20060173078
+US20060177499
+US20060182817
+US20060183805
+US20060194847
+US20060194855
+US20060199791
+US20060199795
+US20060205809
+US20060223869
+US20060223990
+US20060246110
+US20060258650
+US20060258733
+US20060264408
+US20060276452
+US20070010473
+US20070027144
+US20070032537
+US20070042006
+US20070042056
+US20070082906
+US20070105894
+US20070116698
+US20070117842
+US20070141579
+US20070160545
+US20070160698
+US20070184058
+US20070203229
+US20070249701
+US20070249713
+US20070249715
+US20070254877
+US20070259014
+US20070265202
+US20070265295
+US20070265353
+US20070270378
+US20070274936
+US20070275887
+US20070275990
+US20070276024
+US20070280972
+US20070281040
+US20070281992
+US20070282017
+US20070297980
+US20080008745
+US20080014248
+US20080014287
+US20080019915
+US20080020030
+US20080020031
+US20080020969
+US20080032982
+US20080038323
+US20080038338
+US20080038358
+US20080038363
+US20080038376
+US20080039500
+US20080039503
+US20080039517
+US20080045525
+US20080050379
+US20080051412
+US20080051452
+US20080051466
+US20080063656
+US20080063661
+US20080064660
+US20080064701
+US20080070826
+US20080070846
+US20080070857
+US20080070858
+US20080070916
+US20080070960
+US20080075692
+US20080075725
+US20080075763
+US20080076738
+US20080076739
+US20080076805
+US20080076823
+US20080085308
+US20080090771
+US20080090784
+US20080095768
+US20080096802
+US20080096843
+US20080096845
+US20080096847
+US20080096878
+US20080096969
+US20080102045
+US20080103112
+US20080103126
+US20080103173
+US20080103197
+US20080103198
+US20080103209
+US20080108559
+US20080108587
+US20080108596
+US20080108616
+US20080108620
+US20080108646
+US20080113953
+US20080113997
+US20080114000
+US20080114025
+US20080138381
+US20080139535
+US20080145314
+US20080145421
+US20080145448
+US20080146522
+US20080146527
+US20080146532
+US20080146533
+US20080146542
+US20080146656
+US20080153766
+US20080153783
+US20080153891
+US20080153893
+US20080153894
+US20080153897
+US20080159984
+US20080171042
+US20080171741
+US20080171765
+US20080188432
+US20080188444
+US20080188445
+US20080188486
+US20080188499
+US20080188540
+US20080194504
+US20080200376
+US20080206159
+US20080206332
+US20080207608
+US20080207675
+US20080207714
+US20080207756
+US20080213324
+US20080213339
+US20080213409
+US20080214509
+US20080214516
+US20080234183
+US20080234195
+US20080234266
+US20080241245
+US20080242704
+US20080242705
+US20080248020
+US20080248035
+US20080248124
+US20080249168
+US20080254035
+US20080254106
+US20080254116
+US20080254146
+US20080255036
+US20080255072
+US20080255166
+US20080255175
+US20080255224
+US20080262284
+US20080274546
+US20080274946
+US20080280846
+US20080286806
+US20080287522
+US20080287549
+US20080292654
+US20080293622
+US20080293700
+US20080293738
+US20080293749
+US20080293801
+US20080300213
+US20080300269
+US20080312160
+US20080312169
+US20080312244
+US20080312248
+US20080312249
+US20080317751
+US20080317756
+US20080317759
+US20080317774
+US20080317869
+US20080319020
+US20080319047
+US20090004206
+US20090004281
+US20090004296
+US20090004299
+US20090005305
+US20090005372
+US20090005399
+US20090005418
+US20090005421
+US20090010929
+US20090010992
+US20090012025
+US20090012048
+US20090012104
+US20090012130
+US20090017145
+US20090018058
+US20090018092
+US20090018103
+US20090030001
+US20090035250
+US20090035267
+US20090035314
+US20090036354
+US20090036540
+US20090043129
+US20090047282
+US20090048179
+US20090048264
+US20090048289
+US20090054360
+US20090054369
+US20090054452
+US20090061008
+US20090062247
+US20090062267
+US20090062270
+US20090062283
+US20090062331
+US20090062385
+US20090068284
+US20090074777
+US20090074870
+US20090074885
+US20090075947
+US20090081309
+US20090081312
+US20090087405
+US20090093418
+US20090093424
+US20090098187
+US20090098191
+US20090098210
+US20090110649
+US20090111865
+US20090111870
+US20090111877
+US20090111893
+US20090118257
+US20090136970
+US20090137482
+US20090149442
+US20090155247
+US20090156546
+US20090163528
+US20090169535
+US20090169595
+US20090170095
+US20090170197
+US20090170812
+US20090176803
+US20090181090
+US20090181110
+US20090182058
+US20090192101
+US20090192108
+US20090197883
+US20090197900
+US20090197909
+US20090197961
+US20090203144
+US20090233909
+US20090234019
+US20090238897
+US20090247549
+US20090247604
+US20090247731
+US20090258015
+US20090258050
+US20090274655
+US20090285849
+US20090285850
+US20090291127
+US20090291917
+US20090291928
+US20090291948
+US20090291975
+US20090298817
+US20090298825
+US20090298884
+US20090306129
+US20090306165
+US20090311225
+US20090312308
+US20090312322
+US20090312357
+US20090318472
+US20090324558
+US20100004194
+US20100004217
+US20100004338
+US20100008931
+US20100008942
+US20100009991
+US20100010019
+US20100016265
+US20100016302
+US20100021506
+US20100021564
+US20100028440
+US20100028456
+US20100029580
+US20100029646
+US20100029655
+US20100029702
+US20100029710
+US20100029765
+US20100029771
+US20100040637
+US20100040662
+US20100041151
+US20100047313
+US20100047372
+US20100048529
+US20100048684
+US20100056583
+US20100056624
+US20100062053
+US20100062972
+US20100062989
+US20100069410
+US20100069412
+US20100069451
+US20100069455
+US20100069482
+US20100074959
+US20100074960
+US20100075891
+US20100075901
+US20100075966
+US20100076046
+US20100076053
+US20100080836
+US20100080851
+US20100080856
+US20100087374
+US20100087384
+US20100087401
+US20100087409
+US20100087459
+US20100092446
+US20100092553
+US20100093738
+US20100093788
+US20100093804
+US20100093827
+US20100098776
+US20100105632
+US20100105642
+US20100113352
+US20100113426
+US20100130623
+US20100135983
+US20100135985
+US20100136024
+US20100136083
+US20100137256
+US20100137260
+US20100137280
+US20100137357
+US20100137367
+US20100137410
+US20100143287
+US20100144597
+US20100144666
+US20100158819
+US20100167980
+US20100168003
+US20100168102
+US20100168224
+US20100168232
+US20100173002
+US20100173862
+US20100173897
+US20100179110
+US20100179170
+US20100179184
+US20100179186
+US20100179200
+US20100179202
+US20100179213
+US20100183665
+US20100183701
+US20100183721
+US20100184830
+US20100184852
+US20100190733
+US20100196449
+US20100196475
+US20100197709
+US20100203017
+US20100203040
+US20100203163
+US20100204234
+US20100204275
+US20100204311
+US20100204339
+US20100209350
+US20100209458
+US20100209479
+US20100209504
+US20100209508
+US20100210605
+US20100210666
+US20100215589
+US20100216764
+US20100216775
+US20100216838
+US20100216853
+US20100216867
+US20100221229
+US20100221345
+US20100222371
+US20100222418
+US20100222424
+US20100222432
+US20100227804
+US20100227904
+US20100233083
+US20100234288
+US20100234381
+US20100234440
+US20100247447
+US20100247583
+US20100247677
+US20100249164
+US20100249224
+US20100254904
+US20100255102
+US20100255109
+US20100256057
+US20100260713
+US20100261662
+US20100266574
+US20100266592
+US20100266657
+US20100266680
+US20100266709
+US20100267740
+US20100267842
+US20100272712
+US20100272775
+US20100272787
+US20100272818
+US20100273733
+US20100273750
+US20100273766
+US20100279965
+US20100279982
+US20100280050
+US20100280069
+US20100280117
+US20100284915
+US20100286106
+US20100286220
+US20100286232
+US20100286241
+US20100286249
+US20100292160
+US20100292189
+US20100303905
+US20100305113
+US20100316624
+US20100316629
+US20100317865
+US20100322993
+US20100323033
+US20100324078
+US20100324088
+US20100330196
+US20100331332
+US20100331384
+US20100331391
+US20110002855
+US20110002914
+US20110002952
+US20110003778
+US20110003892
+US20110020226
+US20110020430
+US20110020457
+US20110021515
+US20110021554
+US20110021567
+US20110021583
+US20110021611
+US20110027214
+US20110027230
+US20110028428
+US20110028484
+US20110028516
+US20110033520
+US20110038908
+US20110038920
+US20110038936
+US20110039927
+US20110045049
+US20110045075
+US20110046207
+US20110046208
+US20110046222
+US20110052722
+US20110052723
+US20110054040
+US20110059074
+US20110059189
+US20110060022
+US20110064721
+US20110064756
+US20110064803
+US20110071203
+US20110071209
+US20110071214
+US20110071221
+US20110071225
+US20110081352
+US20110086006
+US20110086872
+US20110091380
+US20110091392
+US20110092468
+US20110092552
+US20110092553
+US20110092573
+US20110092592
+US20110092599
+US20110098238
+US20110098266
+US20110098267
+US20110098269
+US20110098286
+US20110098333
+US20110110861
+US20110110885
+US20110111005
+US20110117070
+US20110117167
+US20110123577
+US20110123622
+US20110125093
+US20110135622
+US20110135638
+US20110136847
+US20110136884
+US20110136891
+US20110136893
+US20110136912
+US20110142794
+US20110142933
+US20110144003
+US20110144084
+US20110144089
+US20110152206
+US20110152214
+US20110152280
+US20110152294
+US20110152348
+US20110152350
+US20110153302
+US20110158940
+US20110158980
+US20110166191
+US20110171177
+US20110178040
+US20110178046
+US20110178055
+US20110178141
+US20110178154
+US20110178159
+US20110178170
+US20110178177
+US20110183960
+US20110183995
+US20110190316
+US20110190325
+US20110195137
+US20110195974
+US20110195985
+US20110200665
+US20110200677
+US20110201627
+US20110206703
+US20110206743
+US20110207709
+US20110207715
+US20110207719
+US20110207731
+US20110207751
+US20110212186
+US20110212194
+US20110212915
+US20110212917
+US20110212968
+US20110212971
+US20110212990
+US20110217247
+US20110217259
+US20110217371
+US20110223262
+US20110224251
+US20110229418
+US20110229493
+US20110229566
+US20110230486
+US20110230561
+US20110230564
+US20110236344
+US20110237525
+US20110237605
+US20110237659
+US20110243985
+US20110245211
+US20110245253
+US20110257111
+US20110257134
+US20110257215
+US20110262489
+US20110262547
+US20110263920
+US20110268662
+US20110268666
+US20110274739
+US20110275717
+US20110280861
+US20110281927
+US20110281950
+US20110287045
+US20110287067
+US20110288088
+US20110288103
+US20110288159
+US20110293636
+US20110293652
+US20110293708
+US20110300149
+US20110300217
+US20110301099
+US20110301155
+US20110301205
+US20110301233
+US20110306564
+US20110306577
+US20110313036
+US20110313039
+US20110319360
+US20110319392
+US20110319419
+US20110319429
+US20120014912
+US20120015952
+US20120015990
+US20120027707
+US20120027761
+US20120027861
+US20120027871
+US20120029021
+US20120039905
+US20120040917
+US20120040994
+US20120045425
+US20120045465
+US20120045505
+US20120045521
+US20120045522
+US20120045525
+US20120058963
+US20120058992
+US20120058998
+US20120059048
+US20120059054
+US20120070401
+US20120070473
+US20120070489
+US20120071507
+US20120071541
+US20120071542
+US20120076832
+US20120076872
+US20120077843
+US20120077855
+US20120077876
+US20120082623
+US20120082735
+US20120083473
+US20120083474
+US20120083496
+US20120088813
+US20120093738
+US20120093889
+US20120094941
+US20120094991
+US20120095558
+US20120101056
+US20120101067
+US20120101095
+US20120101104
+US20120108543
+US20120122795
+US20120122818
+US20120122859
+US20120122874
+US20120128628
+US20120129849
+US20120132204
+US20120135968
+US20120141590
+US20120142623
+US20120142653
+US20120142679
+US20120142745
+US20120142779
+US20120148519
+US20120148522
+US20120148603
+US20120148661
+US20120148689
+US20120149773
+US20120157416
+US20120157424
+US20120157536
+US20120164122
+US20120165291
+US20120165352
+US20120165369
+US20120165408
+US20120171219
+US20120171309
+US20120172388
+US20120172450
+US20120177691
+US20120177712
+US20120178677
+US20120178704
+US20120178724
+US20120183554
+US20120184530
+US20120184532
+US20120184616
+US20120189569
+US20120189614
+US20120189645
+US20120189678
+US20120189688
+US20120189713
+US20120190692
+US20120190703
+US20120190721
+US20120196830
+US20120196853
+US20120196883
+US20120196920
+US20120201859
+US20120213803
+US20120213832
+US20120225902
+US20120230942
+US20120232038
+US20120244224
+US20120245087
+US20120245112
+US20120245117
+US20120245149
+US20120260922
+US20120272346
+US20120276039
+US20120276196
+US20120276210
+US20120277171
+US20120277179
+US20120277191
+US20120277246
+US20120277249
+US20120277261
+US20120282337
+US20120282359
+US20120283204
+US20120283236
+US20120283239
+US20120283280
+US20120283312
+US20120288487
+US20120289584
+US20120289588
+US20120302491
+US20120302534
+US20120302546
+US20120316177
+US20120321637
+US20130011343
+US20130011422
+US20130011461
+US20130012467
+US20130012519
+US20130012534
+US20130017259
+US20130018014
+US20130018022
+US20130018223
+US20130028956
+US20130035318
+US20130040962
+US20130040997
+US20130065939
+US20130102567
+US20130109752
+US20130165419
+US20130289104
+US20130295078
+US20130315938
+US20130331431
+US20130344166
+US20140018333
+US20140037635
+US6849624
+US6852333
+US6861071
+US6861425
+US6861431
+US6861447
+US6867231
+US6867284
+US6881731
+US6884801
+US6884819
+US6891039
+US6893641
+US6896900
+US6897054
+US6897198
+US6897203
+US6897207
+US6897212
+US6897315
+US6906087
+US6906089
+US6906091
+US6914056
+US6916797
+US6916805
+US6916922
+US6916927
+US6919339
+US6919380
+US6924278
+US6925388
+US6932960
+US6936601
+US6939876
+US6943156
+US6943183
+US6949218
+US6951872
+US6951884
+US6953808
+US6962923
+US6962933
+US6962942
+US6974868
+US6982320
+US6982334
+US6987106
+US6989159
+US6992073
+US6992085
+US6992088
+US6992211
+US6994864
+US6998244
+US6998399
+US6998408
+US7008938
+US7008947
+US7011973
+US7012146
+US7014845
+US7014856
+US7022699
+US7022870
+US7026487
+US7030125
+US7030149
+US7033498
+US7037665
+US7041806
+US7045323
+US7045497
+US7045606
+US7045658
+US7049322
+US7049332
+US7056913
+US7056928
+US7063861
+US7067496
+US7074405
+US7074431
+US7074783
+US7074792
+US7081469
+US7081473
+US7087605
+US7090846
+US7091198
+US7091201
+US7094911
+US7098234
+US7101846
+US7101876
+US7101908
+US7102013
+US7105510
+US7105520
+US7105705
+US7109164
+US7109193
+US7109218
+US7112584
+US7112612
+US7115556
+US7115777
+US7118762
+US7119076
+US7119089
+US7119115
+US7122187
+US7122311
+US7122539
+US7122552
+US7122571
+US7122579
+US7125877
+US7125879
+US7125890
+US7135501
+US7138133
+US7141251
+US7147844
+US7151176
+US7153826
+US7153841
+US7160898
+US7172752
+US7172761
+US7179792
+US7179802
+US7179830
+US7183320
+US7186825
+US7189745
+US7192609
+US7192972
+US7205295
+US7211248
+US7211562
+US7214677
+US7214692
+US7214710
+US7214714
+US7220748
+US7220754
+US7223397
+US7226614
+US7226945
+US7226948
+US7226972
+US7227031
+US7230103
+US7235579
+US7238677
+US7238700
+US7244709
+US7244746
+US7244846
+US7250411
+US7250413
+US7250416
+US7250420
+US7253188
+US7253190
+US7253281
+US7265108
+US7265131
+US7273625
+US7279491
+US7279596
+US7285563
+US7285660
+US7291650
+US7294642
+US7294720
+US7297681
+US7297682
+US7301022
+US7303739
+US7309704
+US7309719
+US7312209
+US7314888
+US7317018
+US7317036
+US7320996
+US7326699
+US7326711
+US7329677
+US7332335
+US7342016
+US7348314
+US7348426
+US7357930
+US7361744
+US7365088
+US7368563
+US7378437
+US7393655
+US7402318
+US7402557
+US7425580
+US7442719
+US7449483
+US7465541
+US7465719
+US7465736
+US7470694
+US7476396
+US7476732
+US7482339
+US7488497
+US7498313
+US7504398
+US7504415
+US7504434
+US7504500
+US7507730
+US7517672
+US7528116
+US7528133
+US7531676
+US7537906
+US7541378
+US7541381
+US7541477
+US7553479
+US7557094
+US7557113
+US7560131
+US7560487
+US7566728
+US7566791
+US7572796
+US7572825
+US7576067
+US7576074
+US7576077
+US7585856
+US7585890
+US7585973
+US7589125
+US7595336
+US7601359
+US7601726
+US7601836
+US7612050
+US7612058
+US7612081
+US7612103
+US7625860
+US7629368
+US7632808
+US7642229
+US7645465
+US7645791
+US7649097
+US7655647
+US7662828
+US7662840
+US7667052
+US7670601
+US7670620
+US7674809
+US7687492
+US7709491
+US7714121
+US7732425
+US7732431
+US7740831
+US7741343
+US7745450
+US7745472
+US7749970
+US7750010
+US7754769
+US7759328
+US7771962
+US7789610
+US7795312
+US7803806
+US7807795
+US7816340
+US7816560
+US7824717
+US7838565
+US7842677
+US7842686
+US7846967
+US7851507
+US7867981
+US7871992
+US7872025
+US7872034
+US7872047
+US7872140
+US7892574
+US7902261
+US7919612
+US7927623
+US7932273
+US7956078
+US7968545
+US7968692
+US7972612
+US7988965
+US7998474
+US7998503
+US8026244
+US8026272
+US8052987
+US8067228
+US8075923
+US8097270
+US8128912
+US8153588
+US8153610
+US8163733
+US8163752
+US8168616
+US8202880
+US8211401
+US8216604
+US8258132
+US8298525
+US8309584
+US8318706
+US8318764
+US8318782
+US8324190
+US8333976
+US8338456
+US8372824
+US8388989
+US8455004
+US8455502
+US8501244
+US8513238
+US8518897
+US8518919
+US8536229
+US8563602
+US8592420
+US8597665
+US8598129
+US8618045
+US8658158
+US8710020
+US8716251
+US8774885
+US8778990
+US8785569
+US8791102
+US8802125
+US8828991
+USRE39862
+USRE40558
+USRE41084
+WO2002069893A3
+WO2003097059A8
+WO2004001072A3
+WO2004009064A8
+WO2004047727A3
+WO2004064760A3
+WO2004076621A3
+WO2004078744A3
+WO2004098500A3
+WO2005012289A1
+WO2005012352A1
+WO2005014580A1
+WO2005014600A1
+WO2005016255A3
+WO2005018556A2
+WO2005019225A1
+WO2005020967A1
+WO2005021739A1
+WO2005026114A1
+WO2005030716A1
+WO2005037270A1
+WO2005040189A1
+WO2005049017A1
+WO2005061492A1
+WO2005067904A1
+WO2005072763A1
+WO2005074983A3
+WO2005082414A3
+WO2005083075A1
+WO2005090332A1
+WO2005094821A1
+WO2005097192A9
+WO2005099686A1
+WO2005100363A8
+WO2005105098A3
+WO2005117920A1
+WO2006000324A3
+WO2006002088A3
+WO2006002119A3
+WO2006004931A3
+WO2006005844A1
+WO2006008649A1
+WO2006008757A3
+WO2006011466A1
+WO2006012603A3
+WO2006016602A1
+WO2006024241A1
+WO2006024863A1
+WO2006027705A3
+WO2006030105A1
+WO2006033422A1
+WO2006035939A1
+WO2006040148A1
+WO2006046492A1
+WO2006051826A1
+WO2006053112A1
+WO2006053120A1
+WO2006053379A1
+WO2006056695A8
+WO2006057011A3
+WO2006057902A2
+WO2006058781A2
+WO2006059637A1
+WO2006060318A2
+WO2006060885A1
+WO2006061340A3
+WO2006061428A2
+WO2006062093A1
+WO2006067466A3
+WO2006067862A1
+WO2006069519A1
+WO2006070202A1
+WO2006074940A2
+WO2006076370B1
+WO2006076844A1
+WO2006077387A3
+WO2006078698A1
+WO2006079478A1
+WO2006079645A1
+WO2006081616A1
+WO2006083204A1
+WO2006085079A2
+WO2006085113A3
+WO2006086888A1
+WO2006089700A1
+WO2006090129A3
+WO2006092490A1
+WO2006092692A1
+WO2006094662A1
+WO2006096780A3
+WO2006101521A3
+WO2006106241A1
+WO2006106423A3
+WO2006106721A1
+WO2006109633A1
+WO2006111424A1
+WO2006111983A3
+WO2006115067A1
+WO2006116157A3
+WO2006116526A8
+WO2006119674A1
+WO2006120557A1
+WO2006122931A1
+WO2006123246A3
+WO2006124684A3
+WO2006126325A1
+WO2006126514A1
+WO2006127941A9
+WO2006128296A1
+WO2006128378A1
+WO2006128735A1
+WO2006129609A1
+WO2006132275A1
+WO2006133391A3
+WO2006133654A1
+WO2006138038A1
+WO2007001010A1
+WO2007001211A3
+WO2007001932A2
+WO2007003554A1
+WO2007004032A1
+WO2007004692A1
+WO2007006707A1
+WO2007009704A3
+WO2007009778A1
+WO2007010337A8
+WO2007010911A1
+WO2007012285A1
+WO2007012479A3
+WO2007012762A1
+WO2007014839A3
+WO2007014895A2
+WO2007015003A3
+WO2007022946A1
+WO2007026104A1
+WO2007026156A1
+WO2007026959A3
+WO2007036131A1
+WO2007037258A1
+WO2007038452A1
+WO2007039463A1
+WO2007039760A3
+WO2007040966A1
+WO2007043606A1
+WO2007050271A3
+WO2007052013A1
+WO2007052124A1
+WO2007052157A3
+WO2007054258A1
+WO2007054623A3
+WO2007054977A3
+WO2007056593A3
+WO2007059154A2
+WO2007060821A1
+WO2007062564A1
+WO2007065023A2
+WO2007067612A1
+WO2007069603A1
+WO2007071598A1
+WO2007074089A1
+WO2007077469A1
+WO2007080362A1
+WO2007080401A8
+WO2007083101A3
+WO2007085557A3
+WO2007086471A1
+WO2007086554A1
+WO2007093624A3
+WO2007094071A1
+WO2007094430A1
+WO2007096251A1
+WO2007097839A3
+WO2007102447A1
+WO2007103468A3
+WO2007106859A3
+WO2007109459A2
+WO2007114326A1
+WO2007115372A1
+WO2007115938A1
+WO2007118711A1
+WO2007124045A2
+WO2007124308A3
+WO2007125293A1
+WO2007129274A9
+WO2007130477A2
+WO2007131329A1
+WO2007132947A1
+WO2007135193A3
+WO2007136250A3
+WO2007136692A2
+WO2007136776A2
+WO2007137792A1
+WO2007139211A1
+WO2007139464A1
+WO2007140588A1
+WO2007141504A1
+WO2007143096A3
+WO2007143423A3
+WO2007144057A3
+WO2007146684A1
+WO2007147834A1
+WO2007149382A3
+WO2007149508A2
+WO2007149929A1
+WO2008001442A1
+WO2008003130A1
+WO2008004117A1
+WO2008006117A2
+WO2008006702A1
+WO2008009927A1
+WO2008010225A2
+WO2008012338A3
+WO2008016674A1
+WO2008016677A2
+WO2008017867A2
+WO2008020491A1
+WO2008020607A1
+WO2008022182A1
+WO2008023005A1
+WO2008023796A1
+WO2008024981A1
+WO2008025539A1
+WO2008026298A1
+WO2008027013A3
+WO2008027812A2
+WO2008028093A1
+WO2008028928A8
+WO2008035358A3
+WO2008035359A3
+WO2008036282A1
+WO2008036843A3
+WO2008041264A1
+WO2008042282A3
+WO2008042892A3
+WO2008043019A1
+WO2008043243A1
+WO2008044691A1
+WO2008045484A1
+WO2008049842A2
+WO2008051080A1
+WO2008054454A3
+WO2008054984A1
+WO2008055629A1
+WO2008059068A3
+WO2008059869A1
+WO2008060448A2
+WO2008064311A2
+WO2008067399A3
+WO2008069262A1
+WO2008070169A2
+WO2008072591A1
+WO2008073684A1
+WO2008073942A3
+WO2008075148A3
+WO2008077650A1
+WO2008079909A1
+WO2008079980A1
+WO2008083634A1
+WO2008084081A2
+WO2008086698A1
+WO2008087177A1
+WO2008088935A2
+WO2008089659A1
+WO2008091170A1
+WO2008091540A2
+WO2008092681A1
+WO2008097317A1
+WO2008099081A3
+WO2008099469A1
+WO2008100463A1
+WO2008101247A2
+WO2008107879A1
+WO2008109007A1
+WO2008109376A1
+WO2008109560A3
+WO2008109991A8
+WO2008112162A3
+WO2008112238A1
+WO2008113469A2
+WO2008113711A1
+WO2008115141A1
+WO2008116161A2
+WO2008117050A1
+WO2008117269A3
+WO2008119711A1
+WO2008119771A3
+WO2008120235A1
+WO2008121328A2
+WO2008121352A2
+WO2008124145A1
+WO2008124878A1
+WO2008124907A3
+WO2008124931A1
+WO2008125424A1
+WO2008125835A1
+WO2008127275A2
+WO2008127996A1
+WO2008129530A1
+WO2008132233A1
+WO2008133132A1
+WO2008134228A1
+WO2008134265A2
+WO2008135239A1
+WO2008135830A1
+WO2008139879A1
+WO2008139952A1
+WO2008139987A1
+WO2008140421A3
+WO2008147562A3
+WO2008148303A1
+WO2008148832A1
+WO2008149140A2
+WO2008153947A2
+WO2008155081A2
+WO2008157404A2
+WO2009000168A1
+WO2009004873A1
+WO2009009132A1
+WO2009011613A1
+WO2009012702A1
+WO2009013444A1
+WO2009016526A3
+WO2009023181A1
+WO2009024825A1
+WO2009025617A1
+WO2009026790A1
+WO2009027766A3
+WO2009030270A1
+WO2009031023A3
+WO2009031195A1
+WO2009034581A1
+WO2009035067A1
+WO2009036955A1
+WO2009037172A1
+WO2009039361A3
+WO2009040512A3
+WO2009040849A1
+WO2009041714A1
+WO2009042138A9
+WO2009042544A1
+WO2009049917A1
+WO2009052191A1
+WO2009053750A2
+WO2009057733A1
+WO2009061569A1
+WO2009062517A1
+WO2009062874A3
+WO2009066009A1
+WO2009066084A1
+WO2009069140A1
+WO2009072625A1
+WO2009075323A1
+WO2009077741A3
+WO2009082346A1
+WO2009083267A2
+WO2009083444A1
+WO2009085226A2
+WO2009086129A1
+WO2009089138A1
+WO2009090656A3
+WO2009091889A1
+WO2009093638A1
+WO2009096377A1
+WO2009097670A1
+WO2009100037A1
+WO2009100890A1
+WO2009101698A1
+WO2009102172A3
+WO2009103427A2
+WO2009109109A1
+WO2009109493A3
+WO2009111574A3
+WO2009113084A1
+WO2009113085A1
+WO2009113435A1
+WO2009113594A1
+WO2009115280A1
+WO2009116636A1
+WO2009116882A1
+WO2009121992A3
+WO2009122748A1
+WO2009122983A1
+WO2009123457A3
+WO2009123575A8
+WO2009126537A1
+WO2009127398A2
+WO2009129491A4
+WO2009129696A1
+WO2009131537A1
+WO2009133127A1
+WO2009133560A1
+WO2009133692A1
+WO2009134718A8
+WO2009138734A2
+WO2009138779A1
+WO2009139181A1
+WO2009139213A1
+WO2009143763A1
+WO2009145814A3
+WO2009147529A1
+WO2009150194A1
+WO2009152735A1
+WO2009152909A1
+WO2009153179A1
+WO2009156092A3
+WO2009158396A1
+WO2010003376A1
+WO2010004525A1
+WO2010005055A1
+WO2010005534A3
+WO2010005725A2
+WO2010005735A3
+WO2010006169A3
+WO2010007318A3
+WO2010008263A1
+WO2010014199A2
+WO2010017827A1
+WO2010019450A3
+WO2010019547A1
+WO2010020762A1
+WO2010027090A1
+WO2010028134A3
+WO2010028174A1
+WO2010028542A1
+WO2010029915A1
+WO2010033495A3
+WO2010033824A1
+WO2010038965A3
+WO2010039174A1
+WO2010039798A3
+WO2010042991A1
+WO2010043010A1
+WO2010043180A1
+WO2010044411A1
+WO2010048264A3
+WO2010053433A1
+WO2010055022A1
+WO2010056320A3
+WO2010058060A1
+WO2010058166A1
+WO2010062260A1
+WO2010064172A3
+WO2010065571A1
+WO2010066901A3
+WO2010068287A8
+WO2010068605A1
+WO2010069073A1
+WO2010070379A1
+WO2010072823A1
+WO2010073721A1
+WO2010074591A1
+WO2010074647A1
+WO2010077839A1
+WO2010079910A2
+WO2010080757A3
+WO2010080817A3
+WO2010083199A1
+WO2010085528A1
+WO2010086129A8
+WO2010087207A1
+WO2010088071A1
+WO2010091241A3
+WO2010092440A1
+WO2010094452A3
+WO2010094837A3
+WO2010096987A1
+WO2010098365A1
+WO2010100050A1
+WO2010100337A1
+WO2010104406A8
+WO2010104563A2
+WO2010109008A1
+WO2010109687A1
+WO2010113225A1
+WO2010113631A1
+WO2010113834A1
+WO2010114319A2
+WO2010117787A3
+WO2010120872A3
+WO2010121175A1
+WO2010121575A1
+WO2010122151A1
+WO2010123766A1
+WO2010124392A1
+WO2010126025A1
+WO2010126034A1
+WO2010126036A1
+WO2010127541A1
+WO2010129321A2
+WO2010132515A1
+WO2010132670A3
+WO2010132873A3
+WO2010134851A1
+WO2010135493A2
+WO2010135527A3
+WO2010138770A2
+WO2010139980A1
+WO2010141427A1
+WO2010142705A1
+WO2010147430A2
+WO2011000309A1
+WO2011001165A3
+WO2011001258A1
+WO2011005645A1
+WO2011007794A1
+WO2011007795A1
+WO2011007865A1
+WO2011009193A8
+WO2011009533A3
+WO2011009695A1
+WO2011013668A1
+WO2011017488A2
+WO2011017809A1
+WO2011022838A1
+WO2011024004A1
+WO2011025932A2
+WO2011027324A1
+WO2011027344A2
+WO2011027888A1
+WO2011028580A1
+WO2011029279A1
+WO2011030868A1
+WO2011031974A1
+WO2011034919A2
+WO2011037433A3
+WO2011038537A1
+WO2011044072A1
+WO2011044504A1
+WO2011046221A1
+WO2011047143A1
+WO2011047466A1
+WO2011056021A2
+WO2011060268A3
+WO2011060553A1
+WO2011067236A2
+WO2011067560A1
+WO2011068171A1
+WO2011076147A1
+WO2011076316A1
+WO2011076878A1
+WO2011077502A1
+WO2011078984A1
+WO2011081937A1
+WO2011083278A1
+WO2011085209A3
+WO2011085216A2
+WO2011085356A2
+WO2011085981A1
+WO2011086575A8
+WO2011089584A1
+WO2011090265A2
+WO2011092290A1
+WO2011092505A1
+WO2011093308A1
+WO2011094352A1
+WO2011095495A1
+WO2011096676A3
+WO2011099872A1
+WO2011101868A4
+WO2011103413A3
+WO2011103510A1
+WO2011105551A1
+WO2011105568A1
+WO2011106334A1
+WO2011107709A1
+WO2011108644A1
+WO2011109341A3
+WO2011112191A1
+WO2011112896A1
+WO2011113284A1
+WO2011113606A1
+WO2011115810A2
+WO2011117668A9
+WO2011120040A2
+WO2011120281A1
+WO2011121434A1
+WO2011125930A1
+WO2011127088A2
+WO2011130787A1
+WO2011130817A1
+WO2011135464A3
+WO2011139079A3
+WO2011140328A1
+WO2011143843A1
+WO2011143864A1
+WO2011149250A3
+WO2011152005A1
+WO2011153382A1
+WO2011155689A3
+WO2011157443A8
+WO2011158388A1
+WO2011159550A3
+WO2011160252A1
+WO2011160684A1
+WO2011161521A1
+WO2012002464A1
+WO2012004207A1
+WO2012007836A1
+WO2012010089A1
+WO2012011174A1
+WO2012012385A2
+WO2012012509A1
+WO2012012886A1
+WO2012013595A1
+WO2012014993A1
+WO2012016408A1
+WO2012016970A1
+WO2012018069A1
+WO2012019106A3
+WO2012019428A8
+WO2012019633A1
+WO2012024284A1
+WO2012026434A1
+WO2012028834A1
+WO2012029456A1
+WO2012029655A1
+WO2012032067A1
+WO2012033261A1
+WO2012036215A1
+WO2012036589A1
+WO2012037060A1
+WO2012039793A1
+WO2012045363A1
+WO2012046825A1
+WO2012047893A2
+WO2012050484A3
+WO2012050695A1
+WO2012052595A1
+WO2012052888A1
+WO2012053768A3
+WO2012055015A1
+WO2012055034A1
+WO2012058976A1
+WO2012064269A1
+WO2012064928A1
+WO2012064981A2
+WO2012067447A2
+WO2012073965A1
+WO2012076190A1
+WO2012076842A1
+WO2012076966A1
+WO2012077133A1
+WO2012077828A1
+WO2012079121A1
+WO2012080703A1
+WO2012080728A1
+WO2012081570A1
+WO2012088044A3
+WO2012091136A1
+WO2012091372A2
+WO2012101064A1
+WO2012102404A1
+WO2012103784A1
+WO2012104874A3
+WO2012108841A1
+WO2012109011A1
+WO2012109100A1
+WO2012110017A1
+WO2012112230A3
+WO2012112462A1
+WO2012116061A1
+WO2012116410A1
+WO2012118462A1
+WO2012123353A1
+WO2012125828A8
+WO2012128501A9
+WO2012129145A8
+WO2012131048A1
+WO2012131142A1
+WO2012137111A1
+WO2012139262A1
+WO2012140298A1
+WO2012142958A1
+WO2012144619A1
+WO2012144892A1
+WO2012145098A1
+WO2012149218A3
+WO2012154807A1
+WO2012157734A1
+WO2012157921A3
+WO2012158552A3
+WO2012158885A1
+WO2012162796A1
+WO2012163236A1
+WO2012166665A2
+WO2012167101A1
+WO2012167600A1
+WO2012169973A1
+WO2012172821A1
+WO2012174229A3
+WO2012174327A1
+WO2012174699A1
+WO2012174926A1
+WO2012176149A1
+WO2012176438A1
+WO2012177565A2
+WO2012177708A1
+WO2013001498A1
+WO2013004116A1
+WO2013004617A1
+WO2013007361A1
+WO2013018685A1
+WO2013020235A1
+WO2013022919A1
+WO2013023856A8
+WO2013024291A2
+WO2013024589A1
+WO2013024898A1
+WO2013026755A1
+WO2013029116A1
+WO2013030512A1
+WO2013035479A1
+WO2013035943A1
+WO2013039947A1
+WO2013049174A1
+WO2013049220A1
+WO2013051024A3
+WO2013051459A1
+WO2013051680A1
+WO2013052019A1
+WO2013052575A1
+WO2013056327A1
+WO2013057337A3
+WO2013059433A3
+WO2013063417A1
+WO2013064445A1
+WO2013065712A1
+WO2013065866A1
+WO2013068967A2
+WO2013068972A1
+WO2013069339A1
+WO2013070116A3
+WO2013071696A1
+WO2013076170A1
+WO2013078413A1
+WO2013078771A1
+WO2013086467A1
+WO2013086980A1
+WO2013090634A1
+WO2013098588A1
+WO2013098675A1
+WO2013100874A1
+WO2013102860A1
+WO2013103155A1
+WO2013106528A1
+WO2013107164A1
+WO2013108263A1
+WO2013108926A1
+WO2013109323A2
+WO2013110309A1
+WO2013111066A3
+WO2013113030A2
+WO2013119794A1
+WO2013121449A1
+WO2013122897A1
+WO2013123618A1
+WO2013124413A1
+WO2013126438A1
+WO2013130775A1
+WO2013131124A1
+WO2013137844A1
+WO2013138312A1
+WO2013139941A1
+WO2013143688A1
+WO2013144085A1
+WO2013145749A1
+WO2013146018A1
+WO2013147072A1
+WO2013148748A1
+WO2013148874A1
+WO2013148912A1
+WO2013149075A1
+WO2013149336A1
+WO2013149996A1
+WO2013150529A2
+WO2013154173A1
+WO2013159064A1
+WO2013159200A1
+WO2013161933A1
+WO2013162054A1
+WO2013162382A1
+WO2013164773A1
+WO2013164838A1
+WO2013166034A1
+WO2013168033A1
+WO2013170142A1
+WO2013170189A1
+WO2013170972A1
+WO2013171729A3
+WO2013173492A1
+WO2013173707A1
+WO2013175231A1
+WO2013176567A1
+WO2013177510A1
+WO2013178816A1
+WO2013179264A4
+WO2013180183A1
+WO2013183718A1
+WO2013184023A1
+WO2013184646A3
+WO2013185209A1
+WO2013185507A1
+WO2013186191A1
+WO2013186493A2
+WO2013186680A1
+WO2013187720A1
+WO2013188829A1
+WO2013189266A1
+WO2013189588A1
+WO2014000033A1
+WO2014001377A1
+WO2014005408A1
+WO2014009219A1
+WO2014009274A1
+WO2014012805A1
+WO2014012942A1
+WO2014013497A1
+WO2014013664A1
+WO2014014814A1
+WO2014014828A1
+WO2014019282A1
+WO2014020031A1
+WO2014021408A1
+WO2014022752A1
+WO2014023063A1
+WO2014025486A1
+WO2014025808A1
+WO2014025890A1
+WO2014027163A2
+WO2014027334A3
+WO2014027658A1
+WO2014028079A1
+WO2014028387A1
+WO2014031515A1
+WO2014033176A1
+WO2014034147A1
+WO2014036608A1
+WO2014036620A1
+WO2014037903A3
+WO2014038653A1
+WO2014039502A1
+WO2014039971A1
+WO2014040087A1
+WO2014041445A3
+WO2014041558A3
+WO2014043685A1
+WO2014047048A1
+WO2014047392A1
+WO2014052640A1
+WO2014054841A1
+WO2014054969A1
+WO2014055768A1
+WO2014056401A1
+WO2014057067A1
+WO2014057435A1
+WO2014060408A1
+WO2014061419A1
+WO2014061826A1
+WO2014062080A1
+WO2014062732A1
+WO2014062852A3
+WO2014063061A1
+WO2014063778A1
+WO2014064258A1
+WO2014065194A1
+WO2014065772A1
+WO2014068095A1
+WO2014068463A3
+WO2014069510A1
+WO2014070214A1
+WO2014071031A1
+WO2014072646A1
+WO2014072673A1
+WO2014073992A1
+WO2014074017A1
+WO2014075392A1
+WO2014075691A1
+WO2014076111A1
+WO2014077712A1
+WO2014078610A1
+WO2014080633A1
+WO2014082254A1
+WO2014083095A1
+WO2014083107A1
+WO2014083171A1
+WO2014084508A1
+WO2014085153A8
+WO2014085526A1
+WO2014086284A1
+WO2014089121A3
+WO2014094353A1
+WO2014100431A1
+WO2014102213A1
+WO2014106473A1
+WO2014106988A1
+WO2014111496A1
+WO2014111839A1
+WO2014116723A1
+WO2014117948A1
+WO2014118677A1
+WO2014121342A1
+WO2014121885A1
+WO2014127149A1
+WO2014128486A1
+WO2014135638A1
+WO2014135674A1
+WO2014138912A1
+WO2014139014A1
+WO2014139978A1
+WO2014140631A1
+WO2014141165A1
+WO2014142291A1
+WO2014143960A1
+WO2014144087A1
+WO2014146492A1
+WO2014146494A1
+WO2014147119A1
+WO2014147246A1
+WO2014149525A1
+WO2014150873A1
+WO2014151180A1
+WO2014151367A1
+WO2014151451A1
+WO2014151620A1
+WO2014152215A1
+WO2014152725A1
+WO2014154747A1
+WO2014154843A1
+WO2014155332A1
+WO2014157437A1
+WO2014160430A1
+WO2014160698A1
+WO2014161836A1
+WO2014162121A1
+WO2014162313A1
+WO2014164667A1
diff --git a/huner/ner_scripts/splits/gpro.train b/huner/ner_scripts/splits/gpro.train
new file mode 100644
index 0000000..ec259e1
--- /dev/null
+++ b/huner/ner_scripts/splits/gpro.train
@@ -0,0 +1,8399 @@
+
+CA2054325C
+CA2073500C
+CA2098842C
+CA2104399C
+CA2110291C
+CA2113023C
+CA2117257C
+CA2119782C
+CA2120731C
+CA2126091C
+CA2129897C
+CA2133439C
+CA2137764C
+CA2144312C
+CA2148253C
+CA2153849C
+CA2155014C
+CA2156289C
+CA2157128C
+CA2157590C
+CA2157792C
+CA2158610C
+CA2161857C
+CA2168021C
+CA2168447C
+CA2173208C
+CA2173839C
+CA2175372C
+CA2176181C
+CA2177961C
+CA2180660C
+CA2182620C
+CA2183549C
+CA2187449C
+CA2202503C
+CA2203237C
+CA2205573C
+CA2207503C
+CA2207804C
+CA2209360C
+CA2210022C
+CA2213842C
+CA2217054C
+CA2217191C
+CA2217479C
+CA2222964C
+CA2224176C
+CA2224269C
+CA2231545C
+CA2232222C
+CA2233620C
+CA2236868C
+CA2240494C
+CA2240721C
+CA2242618C
+CA2243708C
+CA2246760C
+CA2250630C
+CA2250712C
+CA2251949C
+CA2252050C
+CA2252986C
+CA2253130C
+CA2253207C
+CA2254759C
+CA2255804C
+CA2256633C
+CA2257810C
+CA2261923C
+CA2268968C
+CA2270952C
+CA2274314C
+CA2274591C
+CA2276442C
+CA2279063C
+CA2280612C
+CA2281918C
+CA2284774C
+CA2286076C
+CA2288024C
+CA2290893C
+CA2292586C
+CA2292846C
+CA2297198C
+CA2297959C
+CA2298445C
+CA2302445C
+CA2303448C
+CA2303509C
+CA2304704C
+CA2304821C
+CA2306837C
+CA2309256C
+CA2310230C
+CA2311734C
+CA2312990C
+CA2313878C
+CA2314170C
+CA2314326C
+CA2315693C
+CA2316356C
+CA2319836C
+CA2320822C
+CA2321523C
+CA2323536C
+CA2324343C
+CA2326048C
+CA2336628C
+CA2338901C
+CA2339411C
+CA2339630C
+CA2340545C
+CA2340898C
+CA2340921C
+CA2343414C
+CA2344248C
+CA2344652C
+CA2348390C
+CA2348767C
+CA2351617C
+CA2352946C
+CA2353544C
+CA2355712C
+CA2357986C
+CA2360677C
+CA2370201C
+CA2371517C
+CA2382337C
+CA2382631C
+CA2383054C
+CA2386817C
+CA2387351C
+CA2390858C
+CA2393344C
+CA2395016C
+CA2395226C
+CA2395881C
+CA2397593C
+CA2398389C
+CA2399405C
+CA2400737C
+CA2401424C
+CA2403026C
+CA2404688C
+CA2407806C
+CA2410526C
+CA2411818C
+CA2412941C
+CA2413337C
+CA2416512C
+CA2421151C
+CA2426348C
+CA2427261C
+CA2433386C
+CA2434393C
+CA2435672C
+CA2436764C
+CA2437603C
+CA2438270C
+CA2438813C
+CA2441235C
+CA2442151C
+CA2443543C
+CA2455064C
+CA2455659A1
+CA2459033C
+CA2460135C
+CA2464309C
+CA2464777C
+CA2467329A1
+CA2468374C
+CA2471147C
+CA2474904C
+CA2475224C
+CA2492874C
+CA2497725C
+CA2516078C
+CA2526954C
+CA2530543C
+CA2536321A1
+CA2545543A1
+CA2547080A1
+CA2547887C
+CA2548922A1
+CA2553816A1
+CA2554073A1
+CA2555406A1
+CA2558019A1
+CA2558160A1
+CA2562821A1
+CA2567916C
+CA2573472A1
+CA2574060A1
+CA2574518A1
+CA2582262A1
+CA2582559A1
+CA2583392A1
+CA2583658A1
+CA2585967A1
+CA2591917C
+CA2597616A1
+CA2598948A1
+CA2602643C
+CA2603030A1
+CA2603199A1
+CA2604161A1
+CA2604515A1
+CA2611715C
+CA2611917A1
+CA2613911A1
+CA2615112A1
+CA2618638C
+CA2618974A1
+CA2624220A1
+CA2631724C
+CA2633296A1
+CA2635375A1
+CA2635777A1
+CA2641871A1
+CA2644356A1
+CA2647292A1
+CA2658877C
+CA2665501A1
+CA2665717A1
+CA2667039A1
+CA2673097A1
+CA2673510C
+CA2675510A1
+CA2676172A1
+CA2678127A1
+CA2679103A1
+CA2681864A1
+CA2688736A1
+CA2691943A1
+CA2695844A1
+CA2703458A1
+CA2704882A1
+CA2712282A1
+CA2714398A1
+CA2729582A1
+CA2736285A1
+CA2741842A1
+CA2741941A1
+CA2745063A1
+CA2746717A1
+CA2747055C
+CA2749218C
+CA2754058A1
+CA2756796A1
+CA2757759A1
+CA2760779A1
+CA2761656A1
+CA2765919A1
+CA2776971A1
+CA2777406A1
+CA2777816A1
+CA2782946A1
+CA2784015A1
+CA2784807A1
+CA2792669A1
+CA2799390A1
+CA2799416A1
+CA2801535A1
+CA2803880A1
+CA2806362A1
+CA2806647A1
+CA2815792A1
+CA2816104A1
+CA2820236A1
+CA2826892A1
+CA2832310A1
+CA2832958A1
+CA2838659A1
+CA2839244A1
+CA2840746A1
+CA2842015A1
+CA2850955A1
+CA2851516A1
+CA2856646A1
+CA2857374A1
+CA2858025A1
+CA2858257A1
+CA2858571A1
+CN100579521C
+CN100998559A
+CN100998576A
+CN100998579A
+CN100998588A
+CN100999521B
+CN100999539A
+CN101002764A
+CN101002827A
+CN101002973A
+CN101003509A
+CN101003539A
+CN101006984B
+CN101006995A
+CN101006998A
+CN101007087A
+CN101007165A
+CN101007174A
+CN101007809A
+CN101007838A
+CN101010087B
+CN101010102A
+CN101011358A
+CN101011361A
+CN101011362A
+CN101011370A
+CN101011380A
+CN101011383A
+CN101011513A
+CN101011543A
+CN101015524B
+CN101015543A
+CN101015637A
+CN101018775A
+CN101019827A
+CN101019843A
+CN101019844A
+CN101019847A
+CN101019851B
+CN101019856A
+CN101019870A
+CN101019895B
+CN101020059B
+CN101020705A
+CN101023925A
+CN101023944A
+CN101024055A
+CN101027051A
+CN101027059B
+CN101028275A
+CN101028381A
+CN101028417A
+CN101028454A
+CN101032469A
+CN101032473B
+CN101032496A
+CN101036651A
+CN101036654B
+CN101036660A
+CN101036669A
+CN101036722A
+CN101037415A
+CN101040862A
+CN101040905B
+CN101040959A
+CN101040972A
+CN101041079A
+CN101041641A
+CN101041652B
+CN101045048B
+CN101045155A
+CN101045732A
+CN101048149A
+CN101049301A
+CN101050170A
+CN101052384B
+CN101053553B
+CN101053565A
+CN101057855A
+CN101058578A
+CN101062020A
+CN101062030A
+CN101062052A
+CN101062087A
+CN101062194B
+CN101062309A
+CN101066281A
+CN101066956A
+CN101066980A
+CN101067006A
+CN101069729A
+CN101070291A
+CN101070307A
+CN101074249A
+CN101074252B
+CN101077348A
+CN101077862A
+CN101077865A
+CN101081816A
+CN101084868A
+CN101084879A
+CN101084889B
+CN101085075A
+CN101085355A
+CN101087777B
+CN101088497A
+CN101088982A
+CN101091690A
+CN101091709A
+CN101092433A
+CN101095669A
+CN101095675A
+CN101095924A
+CN101099739A
+CN101099744A
+CN101099861A
+CN101102816A
+CN101103985A
+CN101103994A
+CN101104602A
+CN101104864B
+CN101108163A
+CN101108172A
+CN101108173A
+CN101108848A
+CN101108866A
+CN101112396A
+CN101112409A
+CN101117349B
+CN101125125A
+CN101125139A
+CN101125289A
+CN101125837B
+CN101125865A
+CN101129338A
+CN101129350A
+CN101129374A
+CN101129378A
+CN101129388B
+CN101129423A
+CN101129446A
+CN101129501A
+CN101129522A
+CN101129562A
+CN101129948B
+CN101130083B
+CN101134026A
+CN101134039A
+CN101143138B
+CN101143143A
+CN101147752A
+CN101147803B
+CN101148418A
+CN101148437B
+CN101148445A
+CN101152129A
+CN101152144A
+CN101152147B
+CN101152153A
+CN101152163A
+CN101152167B
+CN101152169A
+CN101152172A
+CN101152176B
+CN101152202A
+CN101152205A
+CN101152229A
+CN101156917B
+CN101157689A
+CN101157716B
+CN101161246B
+CN101166732A
+CN101172957B
+CN101175751B
+CN101181388B
+CN101181578B
+CN101185630A
+CN101185868B
+CN101190176A
+CN101190177A
+CN101190190A
+CN101190202A
+CN101190237A
+CN101190917B
+CN101194893A
+CN101194920B
+CN101194940A
+CN101195799A
+CN101199493A
+CN101199527A
+CN101199787B
+CN101199797A
+CN101199855A
+CN101199857B
+CN101204387A
+CN101204388A
+CN101204484A
+CN101204554B
+CN101205205A
+CN101209354B
+CN101210037A
+CN101214255A
+CN101214330B
+CN101214353B
+CN101215297A
+CN101219156A
+CN101219220A
+CN101223139B
+CN101224194B
+CN101224214A
+CN101224265A
+CN101224306B
+CN101225066B
+CN101225070A
+CN101229119A
+CN101229147B
+CN101229150A
+CN101229153A
+CN101229169B
+CN101229172B
+CN101229218A
+CN101229228A
+CN101229278A
+CN101229313B
+CN101230074A
+CN101234090A
+CN101234092A
+CN101234094B
+CN101234107A
+CN101234149B
+CN101234195A
+CN101234203B
+CN101234204A
+CN101234788A
+CN101235048A
+CN101235079A
+CN101235373A
+CN101239045A
+CN101239073A
+CN101239101A
+CN101239918B
+CN101239979A
+CN101244044A
+CN101244046A
+CN101244049A
+CN101244065A
+CN101244075B
+CN101244135A
+CN101244142A
+CN101244187A
+CN101249069B
+CN101249070A
+CN101249088A
+CN101249113A
+CN101249163A
+CN101250182A
+CN101250185B
+CN101254168A
+CN101254170A
+CN101254179A
+CN101254188A
+CN101254246B
+CN101254249B
+CN101254282B
+CN101255179B
+CN101259177A
+CN101259237A
+CN101263145A
+CN101264080A
+CN101264089A
+CN101264329A
+CN101265178A
+CN101265281A
+CN101268050B
+CN101269005A
+CN101269047A
+CN101269053A
+CN101269209A
+CN101269219B
+CN101270052B
+CN101270126A
+CN101273973B
+CN101273986A
+CN101274027B
+CN101274050B
+CN101274054A
+CN101275132B
+CN101278927A
+CN101278976A
+CN101279901B
+CN101283968B
+CN101283969A
+CN101283999A
+CN101284000A
+CN101284005A
+CN101284112B
+CN101284861A
+CN101288666A
+CN101288671A
+CN101288717A
+CN101289455B
+CN101291934B
+CN101292963A
+CN101292969A
+CN101292992A
+CN101293831A
+CN101296707A
+CN101297797A
+CN101298415A
+CN101300014A
+CN101301292A
+CN101301346A
+CN101301477A
+CN101302235B
+CN101302510A
+CN101306133A
+CN101307038A
+CN101307306A
+CN101310710A
+CN101310717B
+CN101310725A
+CN101313895B
+CN101314591B
+CN101314604A
+CN101317819A
+CN101317849A
+CN101317876A
+CN101317927A
+CN101318014A
+CN101318909A
+CN101318965A
+CN101318980A
+CN101322706A
+CN101322717A
+CN101322751A
+CN101327168B
+CN101327192A
+CN101327209A
+CN101327221A
+CN101327238A
+CN101327267A
+CN101328181A
+CN101332177A
+CN101332178A
+CN101332187A
+CN101332188B
+CN101332195A
+CN101332301A
+CN101333218B
+CN101333242A
+CN101336924B
+CN101336927A
+CN101336931B
+CN101336958A
+CN101336960A
+CN101337006A
+CN101337065B
+CN101337067A
+CN101337072B
+CN101337075B
+CN101337987A
+CN101341142A
+CN101342146A
+CN101342156A
+CN101342184B
+CN101342202A
+CN101342240B
+CN101342262A
+CN101342277A
+CN101343078A
+CN101343290A
+CN101347232A
+CN101347455A
+CN101348477A
+CN101348513A
+CN101352418B
+CN101352423B
+CN101352427A
+CN101352428B
+CN101352449A
+CN101352450A
+CN101352503A
+CN101352550A
+CN101353377A
+CN101357116A
+CN101357952B
+CN101361710A
+CN101361731A
+CN101361744A
+CN101361753A
+CN101361907B
+CN101361980A
+CN101366694A
+CN101366705A
+CN101366717B
+CN101366858B
+CN101367819A
+CN101367850B
+CN101370495B
+CN101371820B
+CN101371832B
+CN101371845A
+CN101372491A
+CN101374514A
+CN101375872A
+CN101376658A
+CN101379024B
+CN101380293A
+CN101381320B
+CN101381374B
+CN101381725A
+CN101385714A
+CN101385724A
+CN101385779A
+CN101385833A
+CN101386580A
+CN101386617B
+CN101390848B
+CN101390854A
+CN101390855A
+CN101390864A
+CN101390870A
+CN101390879B
+CN101396348A
+CN101396350A
+CN101396488A
+CN101396560B
+CN101396561A
+CN101396563A
+CN101397300B
+CN101400655A
+CN101401801B
+CN101401806A
+CN101401814B
+CN101401885A
+CN101402650A
+CN101406450A
+CN101406503A
+CN101406674A
+CN101407459A
+CN101407558B
+CN101411701A
+CN101411756A
+CN101411792A
+CN101412707A
+CN101415705A
+CN101416937A
+CN101416939A
+CN101416944A
+CN101416983A
+CN101417133A
+CN101417997A
+CN101422446B
+CN101422458A
+CN101422463A
+CN101422469A
+CN101422484B
+CN101422531B
+CN101426487B
+CN101426495A
+CN101427992A
+CN101427994A
+CN101428030A
+CN101428035A
+CN101429201A
+CN101429216A
+CN101433519A
+CN101433545A
+CN101433550A
+CN101433556A
+CN101433565A
+CN101434570B
+CN101434601A
+CN101439021A
+CN101439039B
+CN101439046B
+CN101439049A
+CN101439091B
+CN101439182A
+CN101444491B
+CN101444492B
+CN101444614B
+CN101461566B
+CN101466683B
+CN101473999B
+CN101474158B
+CN101475458B
+CN101475484B
+CN101475565B
+CN101475615B
+CN101480408B
+CN101485728B
+CN101492461B
+CN101492475B
+CN101492715B
+CN101496813B
+CN101502486A
+CN101502512A
+CN101502516B
+CN101502521A
+CN101502522A
+CN101502569A
+CN101502645A
+CN101503454A
+CN101507718B
+CN101508668A
+CN101513407A
+CN101513411A
+CN101513415A
+CN101513433A
+CN101518509A
+CN101518569B
+CN101519378B
+CN101524340A
+CN101524342A
+CN101524360A
+CN101525319A
+CN101525360A
+CN101525366A
+CN101530386A
+CN101530403A
+CN101530415A
+CN101530419A
+CN101531613B
+CN101536977A
+CN101536995B
+CN101537001A
+CN101537019A
+CN101537148A
+CN101538256A
+CN101538262A
+CN101538272B
+CN101538299A
+CN101543474A
+CN101543496A
+CN101543506A
+CN101543530A
+CN101543540A
+CN101544602A
+CN101547695B
+CN101548949A
+CN101548955B
+CN101548956A
+CN101549039A
+CN101549151A
+CN101550138B
+CN101553234A
+CN101554372B
+CN101554382A
+CN101559214A
+CN101564428A
+CN101565402A
+CN101570539B
+CN101574343B
+CN101574352A
+CN101574394A
+CN101574444A
+CN101574519A
+CN101575315B
+CN101578283A
+CN101579328A
+CN101579353A
+CN101579438A
+CN101579469B
+CN101584661B
+CN101584702B
+CN101585799B
+CN101585841A
+CN101590009A
+CN101590014A
+CN101590026B
+CN101590048A
+CN101590050A
+CN101590061A
+CN101590067A
+CN101590090A
+CN101590150A
+CN101591288A
+CN101591298A
+CN101591316A
+CN101591323A
+CN101591333A
+CN101596190A
+CN101596200A
+CN101596202A
+CN101596245A
+CN101597280A
+CN101601647B
+CN101601666A
+CN101601667A
+CN101601680A
+CN101601681A
+CN101601722A
+CN101601799A
+CN101602737A
+CN101606907A
+CN101606921B
+CN101606929A
+CN101606947A
+CN101606949A
+CN101612170B
+CN101613414B
+CN101618030B
+CN101618082B
+CN101619040B
+CN101623259B
+CN101623502B
+CN101627991A
+CN101628063B
+CN101628115B
+CN101628903B
+CN101632638B
+CN101632642B
+CN101632764B
+CN101632795B
+CN101633671B
+CN101637592B
+CN101638385B
+CN101642461B
+CN101642570B
+CN101647775B
+CN101647794B
+CN101647865B
+CN101648867B
+CN101649004B
+CN101653436A
+CN101654499B
+CN101654529B
+CN101658489B
+CN101658495B
+CN101658528B
+CN101658646B
+CN101669907A
+CN101669908A
+CN101669927B
+CN101669931B
+CN101669941B
+CN101669943A
+CN101669961B
+CN101669989B
+CN101670094A
+CN101675990A
+CN101679456A
+CN101683316A
+CN101683364B
+CN101683486A
+CN101683517A
+CN101684099A
+CN101686981A
+CN101686996A
+CN101687795A
+CN101691372B
+CN101693030A
+CN101693034A
+CN101693711A
+CN101693885A
+CN101695479A
+CN101695488B
+CN101695513A
+CN101696228A
+CN101698103B
+CN101700221A
+CN101703462A
+CN101703479A
+CN101703489B
+CN101703512A
+CN101703514A
+CN101703522A
+CN101703627A
+CN101703649A
+CN101703754A
+CN101708154A
+CN101708164A
+CN101711741B
+CN101711743B
+CN101711763A
+CN101711766A
+CN101712618A
+CN101712655B
+CN101716145A
+CN101716147A
+CN101716152A
+CN101716165A
+CN101716170A
+CN101716171A
+CN101716173A
+CN101716182A
+CN101716219B
+CN101716222A
+CN101721360A
+CN101721382B
+CN101721387A
+CN101721415A
+CN101721478B
+CN101721665A
+CN101721713B
+CN101724033A
+CN101724055A
+CN101732251A
+CN101732256A
+CN101732259A
+CN101732264B
+CN101732297A
+CN101732325A
+CN101732327A
+CN101732332A
+CN101732425A
+CN101732714A
+CN101732727B
+CN101735211B
+CN101743242A
+CN101744763A
+CN101744777A
+CN101744778A
+CN101744781A
+CN101744784A
+CN101744804A
+CN101744828A
+CN101744851A
+CN101744922A
+CN101744976A
+CN101747258A
+CN101747329A
+CN101756895B
+CN101756899A
+CN101756907B
+CN101756913A
+CN101756914B
+CN101756928A
+CN101756931A
+CN101756933A
+CN101756939A
+CN101756946A
+CN101756955A
+CN101756961A
+CN101757024A
+CN101757026A
+CN101757069A
+CN101757182A
+CN101757374A
+CN101757614A
+CN101757623A
+CN101760389A
+CN101766547A
+CN101766608A
+CN101766691A
+CN101766700A
+CN101768097A
+CN101768173A
+CN101768183A
+CN101773463A
+CN101773506A
+CN101773518A
+CN101774993A
+CN101780039A
+CN101780042A
+CN101780101A
+CN101780104A
+CN101780121A
+CN101780183A
+CN101781294A
+CN101785772A
+CN101785774A
+CN101786976A
+CN101786993A
+CN101787029A
+CN101790553B
+CN101791292A
+CN101791293A
+CN101791302B
+CN101792401B
+CN101792443A
+CN101792448B
+CN101792475A
+CN101792477A
+CN101795686A
+CN101797254A
+CN101797258A
+CN101797304A
+CN101797307B
+CN101797374A
+CN101798315B
+CN101801980A
+CN101804025B
+CN101804032A
+CN101804037A
+CN101805330A
+CN101805355A
+CN101805387A
+CN101805412A
+CN101810610A
+CN101810611A
+CN101810615A
+CN101810625A
+CN101810632A
+CN101810668A
+CN101812025A
+CN101812040A
+CN101812063A
+CN101812079B
+CN101812097A
+CN101812102A
+CN101812491A
+CN101816667A
+CN101816668B
+CN101816753A
+CN101817852A
+CN101822663A
+CN101822680A
+CN101822745A
+CN101822810A
+CN101824102A
+CN101829066A
+CN101829074A
+CN101829084A
+CN101829090A
+CN101829140A
+CN101829154A
+CN101829329A
+CN101830935B
+CN101836965A
+CN101837006A
+CN101843625A
+CN101844811A
+CN101845033A
+CN101845069A
+CN101850087A
+CN101851162A
+CN101851237A
+CN101851241B
+CN101851298A
+CN101856116A
+CN101856347A
+CN101856352A
+CN101856356B
+CN101856385A
+CN101857590A
+CN101862337B
+CN101862348A
+CN101862382A
+CN101863823A
+CN101869564A
+CN101869634B
+CN101869708A
+CN101870647A
+CN101871931A
+CN101874761A
+CN101874788A
+CN101874826A
+CN101875686A
+CN101878041A
+CN101879150A
+CN101879217A
+CN101879220A
+CN101884612A
+CN101884621A
+CN101884645A
+CN101884648A
+CN101885676A
+CN101885725A
+CN101890006A
+CN101890036A
+CN101890043A
+CN101890049A
+CN101890075A
+CN101890105A
+CN101891697A
+CN101891705B
+CN101891769A
+CN101892181B
+CN101897666A
+CN101897668A
+CN101897712A
+CN101897713A
+CN101897735A
+CN101897967A
+CN101899006A
+CN101899013B
+CN101899053A
+CN101906085B
+CN101910177A
+CN101912360A
+CN101912361A
+CN101912368A
+CN101912402B
+CN101912405A
+CN101912410A
+CN101912544A
+CN101912554A
+CN101918036A
+CN101919620A
+CN101919815A
+CN101919817B
+CN101919819A
+CN101919840A
+CN101919865A
+CN101919872A
+CN101919936A
+CN101921303A
+CN101926503A
+CN101926765A
+CN101926791A
+CN101926803A
+CN101926817A
+CN101926820A
+CN101926823A
+CN101926825A
+CN101926965A
+CN101933914A
+CN101933919A
+CN101933945A
+CN101933973B
+CN101934115A
+CN101935306A
+CN101939315A
+CN101940549A
+CN101940555A
+CN101940559A
+CN101940618B
+CN101940747A
+CN101940749A
+CN101947220A
+CN101947221A
+CN101947230A
+CN101947235A
+CN101947269B
+CN101952261A
+CN101953775A
+CN101953805A
+CN101953811A
+CN101953859A
+CN101953932A
+CN101955459A
+CN101955976A
+CN101961323A
+CN101961329A
+CN101961378A
+CN101961490A
+CN101966147A
+CN101966154A
+CN101967144A
+CN101970430A
+CN101972243A
+CN101972257A
+CN101972350A
+CN101972412B
+CN101972489A
+CN101973868A
+CN101973938B
+CN101973957A
+CN101977910A
+CN101983684B
+CN101983715A
+CN101984957B
+CN101987101A
+CN101987120B
+CN101987136A
+CN101987180A
+CN101987830A
+CN101987835A
+CN101991556A
+CN101991665B
+CN101991718A
+CN102000023B
+CN102000035A
+CN102000057B
+CN102000069A
+CN102000081A
+CN102000085A
+CN102000088A
+CN102000098A
+CN102000101A
+CN102000153A
+CN102000163A
+CN102002024B
+CN102006868A
+CN102008500A
+CN102008506B
+CN102008522A
+CN102008625A
+CN102008715A
+CN102008727B
+CN102010420A
+CN102010425A
+CN102015678A
+CN102018666A
+CN102018685A
+CN102018694A
+CN102018704A
+CN102018732A
+CN102018735A
+CN102018755B
+CN102020598A
+CN102028666A
+CN102028696A
+CN102030764A
+CN102030765A
+CN102038637A
+CN102038645A
+CN102038650A
+CN102038652A
+CN102038658A
+CN102038659A
+CN102038664A
+CN102038682A
+CN102038685A
+CN102038792A
+CN102040556B
+CN102046202A
+CN102048704A
+CN102048747A
+CN102048780A
+CN102048827A
+CN102048938A
+CN102050759A
+CN102050809A
+CN102056902A
+CN102058547A
+CN102058552B
+CN102058563A
+CN102058581A
+CN102058584B
+CN102058596A
+CN102058620A
+CN102058800A
+CN102060759A
+CN102060875A
+CN102068420A
+CN102068421A
+CN102068487A
+CN102070608A
+CN102070645A
+CN102070670A
+CN102071461B
+CN102076339A
+CN102078312A
+CN102078316A
+CN102078637A
+CN102079700A
+CN102083810A
+CN102085192A
+CN102085211A
+CN102086185A
+CN102088974A
+CN102091059A
+CN102091086A
+CN102091179A
+CN102093308B
+CN102093373A
+CN102093462B
+CN102100667A
+CN102100735A
+CN102101865A
+CN102106813A
+CN102106822A
+CN102106835A
+CN102106842A
+CN102106847A
+CN102106848A
+CN102106850A
+CN102106994A
+CN102107007B
+CN102108372A
+CN102114037A
+CN102114168B
+CN102119929B
+CN102119951A
+CN102120724A
+CN102123991A
+CN102125530A
+CN102125665A
+CN102131503A
+CN102131508A
+CN102133211A
+CN102133395A
+CN102138893A
+CN102138896B
+CN102138910B
+CN102138917A
+CN102139107B
+CN102140126B
+CN102144970B
+CN102144994A
+CN102145110B
+CN102145159B
+CN102145175A
+CN102146081B
+CN102146108A
+CN102146115A
+CN102149671A
+CN102149703A
+CN102151257A
+CN102151263B
+CN102151299A
+CN102153498A
+CN102160863A
+CN102161655A
+CN102166196A
+CN102166209B
+CN102166211A
+CN102172410A
+CN102176916A
+CN102178649A
+CN102178684A
+CN102178691B
+CN102178693A
+CN102178716A
+CN102178846A
+CN102178933A
+CN102188073A
+CN102188368A
+CN102188386A
+CN102188425A
+CN102188426A
+CN102188430A
+CN102188443A
+CN102188718A
+CN102188719A
+CN102190589A
+CN102190656A
+CN102198106A
+CN102198111A
+CN102198113A
+CN102198118A
+CN102198121B
+CN102198166A
+CN102198272A
+CN102199134A
+CN102199163A
+CN102203093A
+CN102204888A
+CN102204905A
+CN102204926A
+CN102205011A
+CN102205094A
+CN102206172A
+CN102206177A
+CN102206213A
+CN102210672A
+CN102210677A
+CN102210784B
+CN102210823A
+CN102212051A
+CN102212069A
+CN102212103A
+CN102215844A
+CN102218065A
+CN102218074A
+CN102218120A
+CN102218133A
+CN102225087A
+CN102225094A
+CN102225133A
+CN102227419A
+CN102228441A
+CN102228445A
+CN102228447A
+CN102228451A
+CN102228454A
+CN102228466A
+CN102228540A
+CN102228676A
+CN102228689A
+CN102232967A
+CN102234249A
+CN102239838A
+CN102240296A
+CN102240319A
+CN102240372A
+CN102240374A
+CN102240403A
+CN102241596A
+CN102247369A
+CN102247382A
+CN102247414A
+CN102247477A
+CN102249936A
+CN102250045A
+CN102250085A
+CN102250144A
+CN102250170A
+CN102256989A
+CN102274203B
+CN102293778B
+CN102302442A
+CN102302453A
+CN102302478A
+CN102302497A
+CN102302502A
+CN102302587A
+CN102302677A
+CN102302783A
+CN102309461A
+CN102309470A
+CN102309476A
+CN102309752A
+CN102309756A
+CN102309761A
+CN102317282A
+CN102319239A
+CN102319272B
+CN102319273A
+CN102319369A
+CN102320989A
+CN102321080A
+CN102321131A
+CN102327214A
+CN102327216A
+CN102327240A
+CN102327275A
+CN102327365A
+CN102327419A
+CN102335128A
+CN102335266A
+CN102335357A
+CN102342330A
+CN102342929A
+CN102342949B
+CN102342951A
+CN102343091A
+CN102344442A
+CN102349543A
+CN102349890A
+CN102349893A
+CN102351852A
+CN102356085A
+CN102357085A
+CN102357088A
+CN102357100A
+CN102357215A
+CN102358742A
+CN102361868A
+CN102366414A
+CN102366422A
+CN102366484A
+CN102370627A
+CN102370639A
+CN102370653A
+CN102370981A
+CN102372701A
+CN102372717A
+CN102378761A
+CN102382073A
+CN102382082B
+CN102382202A
+CN102389396A
+CN102389412B
+CN102389433A
+CN102429870A
+CN102429873A
+CN102429909A
+CN102429913A
+CN102429931A
+CN102440956A
+CN102448495A
+CN102448930A
+CN102451169A
+CN102451350A
+CN102451351A
+CN102475890A
+CN102485222A
+CN102488677A
+CN102497866A
+CN102499909A
+CN102503882A
+CN102503888A
+CN102503954A
+CN102503987A
+CN102512415A
+CN102512446A
+CN102512489A
+CN102516079A
+CN102525891A
+CN102525911A
+CN102525924A
+CN102525968A
+CN102525982A
+CN102525998A
+CN102526036A
+CN102526052A
+CN102526064A
+CN102526080A
+CN102526087A
+CN102526089A
+CN102526099A
+CN102526118A
+CN102526132A
+CN102526738A
+CN102526752A
+CN102532055A
+CN102532092A
+CN102552104A
+CN102552109A
+CN102552132A
+CN102552139A
+CN102552153A
+CN102552181A
+CN102552190A
+CN102552197A
+CN102552203A
+CN102552210B
+CN102552229A
+CN102552247A
+CN102552272A
+CN102552279A
+CN102552280A
+CN102552285A
+CN102552381A
+CN102552389A
+CN102552453A
+CN102552535A
+CN102552642A
+CN102552645A
+CN102552689A
+CN102552848A
+CN102552885A
+CN102557972A
+CN102558045A
+CN102558088A
+CN102558128A
+CN102558142A
+CN102558159A
+CN102558235A
+CN102558261A
+CN102574825A
+CN102579326A
+CN102579392A
+CN102579435A
+CN102579455A
+CN102579469A
+CN102579485A
+CN102579546A
+CN102579926A
+CN102584760A
+CN102584826A
+CN102584871A
+CN102596197A
+CN102600065A
+CN102600100A
+CN102600102A
+CN102600139A
+CN102600159A
+CN102600160A
+CN102600478A
+CN102603861A
+CN102603924A
+CN102614114A
+CN102614184A
+CN102614196A
+CN102614252A
+CN102614292A
+CN102617471A
+CN102617561A
+CN102617573A
+CN102617584A
+CN102617676A
+CN102626386A
+CN102626412A
+CN102627624A
+CN102631388A
+CN102631562A
+CN102633637A
+CN102633849A
+CN102633856A
+CN102641238A
+CN102641266A
+CN102641371A
+CN102648915A
+CN102652736A
+CN102652737A
+CN102652746A
+CN102652750A
+CN102652752A
+CN102659630A
+CN102659687A
+CN102659765A
+CN102665703A
+CN102670490A
+CN102670496A
+CN102670541A
+CN102670548A
+CN102670559A
+CN102670606A
+CN102670645A
+CN102670685A
+CN102670927A
+CN102670972A
+CN102671198A
+CN102675305A
+CN102675330A
+CN102675406A
+CN102675621A
+CN102686569A
+CN102688232A
+CN102688257A
+CN102688370A
+CN102688478A
+CN102690326A
+CN102696481A
+CN102697718A
+CN102697725A
+CN102697753A
+CN102697756A
+CN102697792A
+CN102698243A
+CN102698283A
+CN102702052B
+CN102702134A
+CN102716072A
+CN102716083A
+CN102716085A
+CN102716088A
+CN102716122A
+CN102716134A
+CN102716135A
+CN102716140A
+CN102716197A
+CN102718675A
+CN102718769A
+CN102719397A
+CN102727423A
+CN102727450A
+CN102727455A
+CN102727475A
+CN102727491A
+CN102727505A
+CN102727784A
+CN102727867A
+CN102731380A
+CN102731410A
+CN102731468A
+CN102731492A
+CN102731573A
+CN102731586A
+CN102743351A
+CN102743363A
+CN102743379A
+CN102743387A
+CN102746159A
+CN102746264A
+CN102746278A
+CN102746309A
+CN102755315A
+CN102755317A
+CN102755345A
+CN102757386A
+CN102764259A
+CN102764263A
+CN102766122A
+CN102766180A
+CN102766632A
+CN102772362A
+CN102772378A
+CN102772498A
+CN102775289A
+CN102775389A
+CN102784070A
+CN102784102A
+CN102784149A
+CN102784153A
+CN102784188A
+CN102786394A
+CN102786414A
+CN102786418A
+CN102786570A
+CN102786576A
+CN102793663A
+CN102793775A
+CN102793830A
+CN102793883A
+CN102793930A
+CN102796084A
+CN102796097A
+CN102796645A
+CN102805826A
+CN102811714A
+CN102813112A
+CN102813644A
+CN102813656A
+CN102813669A
+CN102813727A
+CN102813889A
+CN102813892A
+CN102816067A
+CN102816146A
+CN102824316A
+CN102824331A
+CN102824333A
+CN102824340A
+CN102824364A
+CN102824517A
+CN102826982A
+CN102827172A
+CN102836118A
+CN102836138A
+CN102836156A
+CN102838485A
+CN102838617A
+CN102846541A
+CN102846566A
+CN102846587A
+CN102846606A
+CN102846622A
+CN102846629A
+CN102846631A
+CN102846654A
+CN102846659A
+CN102846800A
+CN102846991A
+CN102850335A
+CN102850337A
+CN102850344A
+CN102850345A
+CN102861006A
+CN102861022A
+CN102861039A
+CN102861062A
+CN102861067A
+CN102861075A
+CN102861079A
+CN102861217A
+CN102861339A
+CN102863419A
+CN102871963A
+CN102871983A
+CN102872003A
+CN102872004A
+CN102872028A
+CN102872033A
+CN102872045A
+CN102872071A
+CN102872099A
+CN102872109A
+CN102872121A
+CN102872124A
+CN102872126A
+CN102872136A
+CN102872352A
+CN102875375A
+CN102875472A
+CN102875517A
+CN102875627A
+CN102875630A
+CN102883717A
+CN102885346A
+CN102885807A
+CN102885810A
+CN102885820A
+CN102885822A
+CN102885829A
+CN102885838A
+CN102885853A
+CN102885891A
+CN102886014A
+CN102886041A
+CN102887895A
+CN102895224A
+CN102895236A
+CN102895250A
+CN102895255A
+CN102895308A
+CN102895433A
+CN102895539A
+CN102895623A
+CN102895631A
+CN102895633A
+CN102898377A
+CN102898426A
+CN102898438A
+CN102898641A
+CN102908320A
+CN102908323A
+CN102908343A
+CN102908348A
+CN102908362A
+CN102908525A
+CN102908572A
+CN102908591A
+CN102908597A
+CN102911226A
+CN102911989A
+CN102918047A
+CN102920666A
+CN102920671A
+CN102920689A
+CN102920704A
+CN102920706A
+CN102920947A
+CN102924318A
+CN102924399A
+CN102924426A
+CN102924437A
+CN102924488A
+CN102933237A
+CN102935221A
+CN102940632A
+CN102940634A
+CN102940635A
+CN102949291A
+CN102949338A
+CN102949346A
+CN102949363A
+CN102949400A
+CN102949436A
+CN102949448A
+CN102949694A
+CN102949725A
+CN102952202A
+CN102961250A
+CN102961327A
+CN102961333A
+CN102961344A
+CN102961373A
+CN102961378A
+CN102961380A
+CN102961383A
+CN102961536A
+CN102961744A
+CN102964267A
+CN102964322A
+CN102964386A
+CN102973494A
+CN102973523A
+CN102973528A
+CN102973551A
+CN102973564A
+CN102973571A
+CN102973578A
+CN102973612A
+CN102973662A
+CN102973666A
+CN102973946A
+CN102976974A
+CN102977110A
+CN102977111A
+CN102977146A
+CN102985422A
+CN102986963A
+CN102988286A
+CN102988297A
+CN102988302A
+CN102988326A
+CN102988340A
+CN102988357A
+CN102988369A
+CN102988468A
+CN102988595A
+CN102989003A
+CN102989005A
+CN102993018A
+CN102993150A
+CN102993208A
+CN102993348A
+CN103003234A
+CN103006593A
+CN103006624A
+CN103006633A
+CN103006640A
+CN103006660A
+CN103006663A
+CN103006673A
+CN103007294A
+CN103012231A
+CN103012420A
+CN103025325A
+CN103027846A
+CN103027894A
+CN103027913A
+CN103027914A
+CN103038238A
+CN103040102A
+CN103040795A
+CN103040827A
+CN103040828A
+CN103040835A
+CN103040849A
+CN103040930A
+CN103041168A
+CN103041373A
+CN103041448A
+CN103043635A
+CN103044224A
+CN103044375A
+CN103044446A
+CN103044509A
+CN103054169A
+CN103054795A
+CN103054802A
+CN103054822A
+CN103054829A
+CN103054846A
+CN103054850A
+CN103054853A
+CN103054854A
+CN103054865A
+CN103054874A
+CN103054880A
+CN103054882A
+CN103054972A
+CN103054992A
+CN103058943A
+CN103059160A
+CN103070828A
+CN103070852A
+CN103070935A
+CN103070967A
+CN103073650A
+CN103083235A
+CN103083238A
+CN103083252A
+CN103083262A
+CN103083264A
+CN103083279A
+CN103083289A
+CN103083290A
+CN103083294A
+CN103083299A
+CN103083304A
+CN103083306A
+CN103083327A
+CN103083338A
+CN103086972A
+CN103087024A
+CN103087045A
+CN103087325A
+CN103096908A
+CN103099797A
+CN103099802A
+CN103099812A
+CN103102315A
+CN103108634A
+CN103108882A
+CN103110578A
+CN103110588A
+CN103110599A
+CN103110601A
+CN103110631A
+CN103110638A
+CN103110658A
+CN103113202A
+CN103113355A
+CN103113359A
+CN103118675A
+CN103120664A
+CN103120671A
+CN103120676A
+CN103120680A
+CN103120689A
+CN103120695A
+CN103120703A
+CN103120795A
+CN103120797A
+CN103126987A
+CN103126993A
+CN103127001A
+CN103127006A
+CN103127014A
+CN103127085A
+CN103127107A
+CN103127116A
+CN103127136A
+CN103127146A
+CN103127147A
+CN103127178A
+CN103127308A
+CN103127494A
+CN103127510A
+CN103127512A
+CN103127514A
+CN103130632A
+CN103130730A
+CN103130774A
+CN103130775A
+CN103130791A
+CN103130860A
+CN103142500A
+CN103142524A
+CN103142530A
+CN103142544A
+CN103142552A
+CN103142564A
+CN103142575A
+CN103142591A
+CN103142613A
+CN103142633A
+CN103142992A
+CN103145663A
+CN103145706A
+CN103145794A
+CN103145868A
+CN103153963A
+CN103156821A
+CN103156849A
+CN103156919A
+CN103159748A
+CN103159788A
+CN103168774A
+CN103169673A
+CN103169698A
+CN103169757A
+CN103169793A
+CN103172658A
+CN103181898A
+CN103181907A
+CN103181911A
+CN103181914A
+CN103181946A
+CN103182003A
+CN103182044A
+CN103182083A
+CN103191061A
+CN103191068A
+CN103191080A
+CN103191091A
+CN103191100A
+CN103191102A
+CN103191104A
+CN103191142A
+CN103191184A
+CN103191445A
+CN103193644A
+CN103193659A
+CN103193738A
+CN103193860A
+CN103202317A
+CN103202814A
+CN103202830A
+CN103202849A
+CN103202971A
+CN103202999A
+CN103204897A
+CN103209692A
+CN103209707A
+CN103209977A
+CN103211778A
+CN103211779A
+CN103211784A
+CN103211791A
+CN103212089A
+CN103214370A
+CN103214454A
+CN103214486A
+CN103214547A
+CN103222970A
+CN103223172A
+CN103228274A
+CN103230364A
+CN103230386A
+CN103230407A
+CN103230411A
+CN103230417A
+CN103230601A
+CN103232420A
+CN103239389A
+CN103239425A
+CN103239452A
+CN103239455A
+CN103239463A
+CN103239466A
+CN103239506A
+CN103239600A
+CN103239705A
+CN103239718A
+CN103251599A
+CN103251603A
+CN103251613A
+CN103251637A
+CN103251653A
+CN103251934A
+CN103254155A
+CN103263383A
+CN103263386A
+CN103263407A
+CN103263533A
+CN103263677A
+CN103265517A
+CN103265559A
+CN103265561A
+CN103271877A
+CN103271898A
+CN103271899A
+CN103271912A
+CN103271913A
+CN103271931A
+CN103271940A
+CN103272114A
+CN103272244A
+CN103274987A
+CN103275048A
+CN103275140A
+CN103284043A
+CN103284158A
+CN103284947A
+CN103284954A
+CN103284958A
+CN103284985A
+CN103285002A
+CN103285003A
+CN103285004A
+CN103285044A
+CN103285049A
+CN103285332A
+CN103285381A
+CN103288614A
+CN103288664A
+CN103298816A
+CN103301061A
+CN103301075A
+CN103301081A
+CN103301098A
+CN103301108A
+CN103301140A
+CN103301141A
+CN103301470A
+CN103304552A
+CN103304559A
+CN103304571A
+CN103304580A
+CN103305567A
+CN103313978A
+CN103315287A
+CN103315965A
+CN103315967A
+CN103315970A
+CN103315985A
+CN103316022A
+CN103316026A
+CN103316032A
+CN103316078A
+CN103316350A
+CN103319327A
+CN103319497A
+CN103328441A
+CN103330689A
+CN103330807A
+CN103330812A
+CN103333173A
+CN103333267A
+CN103340834A
+CN103340848A
+CN103340877A
+CN103340954A
+CN103340971A
+CN103342755A
+CN103347527A
+CN103347859A
+CN103349646A
+CN103355665A
+CN103356499A
+CN103356500A
+CN103356507A
+CN103356521A
+CN103356527A
+CN103356542A
+CN103356561A
+CN103356571A
+CN103356573A
+CN103356608A
+CN103356617A
+CN103356635A
+CN103356663A
+CN103356719A
+CN103356872A
+CN103357022A
+CN103360310A
+CN103360370A
+CN103360401A
+CN103360427A
+CN103371924A
+CN103371967A
+CN103371974A
+CN103371983A
+CN103371985A
+CN103371997A
+CN103372021A
+CN103372039A
+CN103380115A
+CN103381175A
+CN103381204A
+CN103382190A
+CN103385859A
+CN103385866A
+CN103385871A
+CN103391780A
+CN103391783A
+CN103393619A
+CN103393645A
+CN103393653A
+CN103393671A
+CN103393686A
+CN103393692A
+CN103393717A
+CN103393762A
+CN103393783A
+CN103394003A
+CN103394086A
+CN103396417A
+CN103405385A
+CN103405387A
+CN103405398A
+CN103405412A
+CN103405440A
+CN103405445A
+CN103405472A
+CN103405492A
+CN103405576A
+CN103405675A
+CN103405739A
+CN103408122A
+CN103408573A
+CN103417467A
+CN103417481A
+CN103417519A
+CN103417529A
+CN103417550A
+CN103417555A
+CN103417600A
+CN103417750A
+CN103417876A
+CN103417937A
+CN103420890A
+CN103420961A
+CN103421002A
+CN103421057A
+CN103421832A
+CN103432068A
+CN103432111A
+CN103432114A
+CN103432125A
+CN103432139A
+CN103432141A
+CN103432151A
+CN103432160A
+CN103432162A
+CN103432223A
+CN103432549A
+CN103432597A
+CN103435514A
+CN103446107A
+CN103446114A
+CN103446171A
+CN103446173A
+CN103446197A
+CN103446282A
+CN103446442A
+CN103446534A
+CN103446577A
+CN103446594A
+CN103450083A
+CN103450133A
+CN103459381A
+CN103462924A
+CN103462952A
+CN103462958A
+CN103462960A
+CN103462993A
+CN103463004A
+CN103463034A
+CN103463038A
+CN103463039A
+CN103463073A
+CN103463089A
+CN103463090A
+CN103463093A
+CN103463094A
+CN103463644A
+CN103467417A
+CN103467448A
+CN103467729A
+CN103476421A
+CN103476432A
+CN103477228A
+CN103479580A
+CN103479615A
+CN103479624A
+CN103479630A
+CN103479645A
+CN103479653A
+CN103479775A
+CN103479785A
+CN103479804A
+CN103479969A
+CN103483194A
+CN103483211A
+CN103483239A
+CN103483487A
+CN103493847A
+CN103494794A
+CN103494798A
+CN103494800A
+CN103494821A
+CN103494826A
+CN103494965A
+CN103494994A
+CN103495070A
+CN103497184A
+CN103497192A
+CN103501789A
+CN103505414A
+CN103505428A
+CN103505437A
+CN103505453A
+CN103505556A
+CN103505730A
+CN103505731A
+CN103505735A
+CN103508943A
+CN103509001A
+CN103509071A
+CN103520110A
+CN103520122A
+CN103520135A
+CN103520152A
+CN103520157A
+CN103520305A
+CN103520493A
+CN103520725A
+CN103520731A
+CN103524573A
+CN103536530A
+CN103536547A
+CN103536553A
+CN103536559A
+CN103536563A
+CN103536569A
+CN103536607A
+CN103536617A
+CN103536688A
+CN103536919A
+CN103536926A
+CN103539659A
+CN103539760A
+CN103539777A
+CN103547164A
+CN103550107A
+CN103550172A
+CN103550230A
+CN103550231A
+CN103553892A
+CN103561747A
+CN103565734A
+CN103565788A
+CN103565832A
+CN103565921A
+CN103566066A
+CN103566068A
+CN103566325A
+CN103570679A
+CN103570780A
+CN103583816A
+CN103583955A
+CN103585116A
+CN103585140A
+CN103585149A
+CN103585159A
+CN103585253A
+CN103588665A
+CN103588739A
+CN103599029A
+CN103599082A
+CN103599089A
+CN103599548A
+CN103601641A
+CN103601707A
+CN103601722A
+CN103601727A
+CN103610646A
+CN103610649A
+CN103610667A
+CN103610668A
+CN103610671A
+CN103610688A
+CN103610816A
+CN103611144A
+CN103611165A
+CN103613490A
+CN103613680A
+CN103622910A
+CN103622924A
+CN103622942A
+CN103622948A
+CN103622951A
+CN103622954A
+CN103622956A
+CN103626769A
+CN103626781A
+CN103626803A
+CN103626824A
+CN103635196A
+CN103636907A
+CN103638008A
+CN103638025A
+CN103638026A
+CN103638042A
+CN103638364A
+CN103641713A
+CN103648495A
+CN103648531A
+CN103649077A
+CN103655486A
+CN103655497A
+CN103655498A
+CN103655500A
+CN103655501A
+CN103655544A
+CN103655600A
+CN103656024A
+CN103656615A
+CN103656685A
+CN103664785A
+CN103664804A
+CN103664893A
+CN103664970A
+CN103664983A
+CN103675152A
+CN103690542A
+CN103690543A
+CN103690547A
+CN103690553A
+CN103690619A
+CN103694252A
+CN103705044A
+CN103705472A
+CN103705478A
+CN103705480A
+CN103705483A
+CN103705490A
+CN103705496A
+CN103705498A
+CN103705499A
+CN103705586A
+CN103705922A
+CN103705927A
+CN103709093A
+CN103709162A
+CN103717592A
+CN103717607A
+CN103720670A
+CN103720675A
+CN103721060A
+CN103732227A
+CN103735473A
+CN103735528A
+CN103735552A
+CN103735565A
+CN103735593A
+CN103736080A
+CN103739549A
+CN103739642A
+CN103751094A
+CN103751095A
+CN103751160A
+CN103751169A
+CN103751176A
+CN103751177A
+CN103751183A
+CN103751185A
+CN103751476A
+CN103751531A
+CN103751788A
+CN103755560A
+CN103755647A
+CN103764659A
+CN1129942B
+CN1366991B
+CN1439375B
+CN1514729B
+CN1545551B
+CN1559389A
+CN1559391A
+CN1559413A
+CN1559414A
+CN1559419A
+CN1559434A
+CN1559612A
+CN1561977A
+CN1561995A
+CN1562026A
+CN1562038A
+CN1562054A
+CN1562310A
+CN1562370A
+CN1565466A
+CN1565471A
+CN1565472A
+CN1566086A
+CN1568944A
+CN1568949A
+CN1568956A
+CN1568965A
+CN1569016A
+CN1569120A
+CN1569841A
+CN1569868A
+CN1579385A
+CN1579386A
+CN1579387A
+CN1579395A
+CN1579396A
+CN1579404A
+CN1580056A
+CN1582937A
+CN1582944A
+CN1583175A
+CN1583753A
+CN1586473A
+CN1586483A
+CN1586484A
+CN1586489A
+CN1589780A
+CN1593401A
+CN1593407A
+CN1593409A
+CN1594311A
+CN1596113B
+CN1596900A
+CN1596907A
+CN1600313A
+CN1602866A
+CN1602873A
+CN1602885A
+CN1602959B
+CN1605335A
+CN1608620A
+CN1609105A
+CN1615851A
+CN1615865A
+CN1615905A
+CN1621039A
+CN1626103A
+CN1628653A
+CN1628854A
+CN1629159A
+CN1631369A
+CN1631373A
+CN1634013A
+CN1634019A
+CN1634034A
+CN1634081A
+CN1634087A
+CN1634088A
+CN1634108A
+CN1634135A
+CN1634885A
+CN1634923A
+CN1636557A
+CN1636568A
+CN1640394A
+CN1647815B
+CN1650851A
+CN1651453A
+CN1657041A
+CN1657049A
+CN1657057A
+CN1658890A
+CN1660105A
+CN1660120A
+CN1660872A
+CN1660885A
+CN1663957A
+CN1666746A
+CN1666749A
+CN1672686A
+CN1679522B
+CN1679525A
+CN1679541A
+CN1679542A
+CN1679616A
+CN1679617A
+CN1680238A
+CN1682701A
+CN1682737B
+CN1682744A
+CN1682745A
+CN1682760A
+CN1682763A
+CN1683385A
+CN1706371B
+CN1718190A
+CN1718244A
+CN1718578A
+CN1723059A
+CN1723890A
+CN1723900A
+CN1723913A
+CN1724521A
+CN1729968A
+CN1729978A
+CN1729995A
+CN1736386A
+CN1736393A
+CN1739492A
+CN1739502A
+CN1739528A
+CN1739531A
+CN1739539A
+CN1739545A
+CN1739572A
+CN1739655B
+CN1739797A
+CN1742853A
+CN1748671A
+CN1748681A
+CN1751690A
+CN1751691A
+CN1754535A
+CN1754556A
+CN1757388A
+CN1759836A
+CN1759838A
+CN1762344A
+CN1762364A
+CN1762368A
+CN1762380A
+CN1763018B
+CN1764432A
+CN1765363A
+CN1765377A
+CN1768742A
+CN1768746A
+CN1771909A
+CN1771925A
+CN1771932A
+CN1771940A
+CN1771987A
+CN1772025A
+CN1772288A
+CN1775224A
+CN1775762A
+CN1781481A
+CN1781488A
+CN1785200A
+CN1785204A
+CN1785253B
+CN1788018B
+CN1788581A
+CN1792247A
+CN1795861A
+CN1795895A
+CN1796375A
+CN1799548A
+CN1799631B
+CN1800198A
+CN1802947A
+CN1802949A
+CN1802950A
+CN1803148A
+CN1806809A
+CN1813674A
+CN1813696A
+CN1813721A
+CN1813722A
+CN1813731A
+CN1813738A
+CN1813740B
+CN1813744A
+CN1813763A
+CN1814080A
+CN1814291A
+CN1814293A
+CN1817153A
+CN1817849A
+CN1820753A
+CN1823734A
+CN1823760A
+CN1823771B
+CN1823805A
+CN1823811A
+CN1823816A
+CN1823822A
+CN1823826A
+CN1823829A
+CN1824041A
+CN1824064B
+CN1824292B
+CN1824657A
+CN1827137B
+CN1830424A
+CN1830425A
+CN1830426A
+CN1830427A
+CN1830445B
+CN1833636A
+CN1833637A
+CN1836657A
+CN1837205A
+CN1839124B
+CN1839813A
+CN1839828A
+CN1839841A
+CN1839854A
+CN1839865A
+CN1839867A
+CN1839968A
+CN1840529A
+CN1840539A
+CN1843373A
+CN1843393A
+CN1846698A
+CN1846708A
+CN1847236B
+CN1850093A
+CN1850094A
+CN1850098A
+CN1850106A
+CN1850116A
+CN1853480A
+CN1853646A
+CN1853714A
+CN1854125A
+CN1857207A
+CN1857212A
+CN1857219A
+CN1857242A
+CN1857244A
+CN1857252A
+CN1857262A
+CN1857266A
+CN1857280A
+CN1857389A
+CN1857456A
+CN1857471A
+CN1857729A
+CN1857733A
+CN1861064A
+CN1861073A
+CN1861085A
+CN1861093A
+CN1861581A
+CN1864673A
+CN1864674A
+CN1864697A
+CN1864732A
+CN1864736A
+CN1865270A
+CN1867331B
+CN1867563A
+CN1868467A
+CN1869080A
+CN1871002A
+CN1872027A
+CN1872028A
+CN1872030A
+CN1872032A
+CN1872045B
+CN1872119A
+CN1872172A
+CN1872838A
+CN1875019A
+CN1875924A
+CN1875938A
+CN1875960A
+CN1875965A
+CN1875971A
+CN1876014A
+CN1876015A
+CN1876065A
+CN1876174A
+CN1879607A
+CN1879634A
+CN1879697A
+CN1879827A
+CN1879882A
+CN1883459A
+CN1883472A
+CN1883496A
+CN1883547A
+CN1883683A
+CN1887255A
+CN1887267A
+CN1887283A
+CN1887876A
+CN1887899A
+CN1891225A
+CN1895239B
+CN1895258A
+CN1895282A
+CN1895398A
+CN1895546B
+CN1903187B
+CN1903193A
+CN1903211A
+CN1903310A
+CN1907291A
+CN1911213A
+CN1911224A
+CN1911242A
+CN1911284A
+CN1911312A
+CN1911326A
+CN1911925A
+CN1915230A
+CN1915232A
+CN1915246A
+CN1919178A
+CN1919192A
+CN1919208A
+CN1923198A
+CN1923219A
+CN1923784B
+CN1923803A
+CN1927174A
+CN1927198A
+CN1927199A
+CN1927215A
+CN1927241A
+CN1927334A
+CN1927351A
+CN1927372A
+CN1927393A
+CN1931131A
+CN1931159B
+CN1931177A
+CN1931355A
+CN1931840A
+CN1932017A
+CN1935129A
+CN1935133A
+CN1935812A
+CN1938282A
+CN1939264A
+CN1939266A
+CN1939290A
+CN1939296B
+CN1939326A
+CN1939489A
+CN1943566A
+CN1943576A
+CN1943581A
+CN1943613A
+CN1944420B
+CN1944442A
+CN1947692A
+CN1947694A
+CN1948248A
+CN1948274B
+CN1951370A
+CN1951375B
+CN1951386A
+CN1954818B
+CN1955163A
+CN1957926A
+CN1957944A
+CN1961869A
+CN1961872A
+CN1964973A
+CN1965807A
+CN1965814A
+CN1965846A
+CN1966525A
+CN1969839A
+CN1969852A
+CN1970559A
+CN1973848A
+CN1973896A
+CN1974545B
+CN1977850A
+CN1977855A
+CN1977859A
+CN1981782A
+CN1985810A
+CN1985830A
+CN1985838A
+CN1985850A
+CN1985956A
+CN1985960A
+CN1988887A
+CN1988904A
+CN1989951A
+CN1989983A
+CN1990003A
+CN1990029A
+CN1990489A
+CN1990494A
+CN1993118B
+CN1993324B
+CN1994289A
+CN1994300A
+CN1994305A
+CN1994307A
+CN1994316A
+CN1995055A
+CN1997394A
+CN200939251Y
+CN201044823Y
+CN201142902Y
+CN201182672Y
+CN201241031Y
+CN201453509U
+CN201469700U
+CN201558397U
+CN201564118U
+CN201586232U
+CN201755322U
+CN202263199U
+CN202314484U
+CN202620297U
+CN202699643U
+CN202761909U
+CN203075251U
+CN203123075U
+CN203436580U
+CN2880081Y
+DE102004009325A1
+DE102004040014A1
+DE102004054426A1
+DE102004060999A1
+DE102005004643A1
+DE102005013622A1
+DE102005041613A1
+DE102006002649A1
+DE102006005221B3
+DE102006006115A1
+DE102006012873A1
+DE102006012875A1
+DE102006028284A1
+DE102006030031A1
+DE102006062566A1
+DE102007021149A1
+DE102007030198A1
+DE102007030370A1
+DE102007032660A1
+DE102007032662A1
+DE102007037018A1
+DE102007044583A1
+DE102007054985A1
+DE102008039254A1
+DE102008054300A1
+DE102009011264A1
+DE102009038634A1
+DE102010004986A1
+DE102010014411A1
+DE102010051776A1
+DE102012022778A1
+DE10352449A1
+DE10360924A1
+DE20321277U1
+DE4393944B4
+EP0708660B1
+EP0754223B1
+EP0759297B1
+EP0776161B2
+EP0793721B1
+EP0808164B1
+EP0813416B1
+EP0814796B1
+EP0823908B1
+EP0833636B1
+EP0841945B1
+EP0869788B1
+EP0871488B1
+EP0873406B1
+EP0876337B1
+EP0876612B1
+EP0881891B1
+EP0890105B1
+EP0907652B1
+EP0923740B1
+EP0931071B1
+EP0949865A4
+EP0956865B1
+EP0957903B1
+EP0958823B1
+EP0959896B1
+EP0966443B1
+EP0969844B1
+EP0970127B1
+EP0970195B1
+EP0975637B1
+EP0980369B1
+EP0983072B2
+EP0991636B1
+EP0994706B1
+EP0998276B1
+EP0998291B2
+EP1003777B1
+EP1008344B1
+EP1016406B1
+EP1019500B1
+EP1021184B1
+EP1024794B1
+EP1024805B1
+EP1042287B1
+EP1042307B1
+EP1044008B1
+EP1045832B1
+EP1049459B1
+EP1049707B1
+EP1054680B1
+EP1054881B1
+EP1063987A4
+EP1065945B1
+EP1068328B1
+EP1069900B1
+EP1075467B1
+EP1076553B1
+EP1077069B1
+EP1078927B1
+EP1079825B1
+EP1086098B1
+EP1100541B1
+EP1104417B1
+EP1105376B1
+EP1107966B1
+EP1112057B1
+EP1117411B1
+EP1121129B1
+EP1124551B1
+EP1133300B1
+EP1140010B1
+EP1140028B1
+EP1140033B1
+EP1143938B1
+EP1144371B1
+EP1152751B1
+EP1162977B1
+EP1163218B1
+EP1165055B1
+EP1165070B1
+EP1171583B1
+EP1173218B1
+EP1173464B1
+EP1177166B1
+EP1178794B1
+EP1178796B1
+EP1178973B1
+EP1181299B1
+EP1183383B1
+EP1186302B1
+EP1187835B1
+EP1187846B1
+EP1189614B1
+EP1189886B1
+EP1196160B1
+EP1196404B1
+EP1202969B1
+EP1206942B1
+EP1212086B1
+EP1214314B1
+EP1214409B1
+EP1218027B1
+EP1220839B1
+EP1221941A4
+EP1227813B1
+EP1233959B1
+EP1234574B1
+EP1235566B1
+EP1237875B1
+EP1237898B1
+EP1239884B1
+EP1248629B1
+EP1251841B1
+EP1251871B1
+EP1253919A4
+EP1254904B1
+EP1254907B1
+EP1255558B1
+EP1259229B1
+EP1259240B1
+EP1261338B1
+EP1263411B1
+EP1265878B1
+EP1268435B1
+EP1274711B1
+EP1278521B1
+EP1280500B1
+EP1280777B1
+EP1284653B1
+EP1284711B1
+EP1289977B1
+EP1291016B1
+EP1292332B1
+EP1293567B1
+EP1294382B1
+EP1296639B1
+EP1296700B1
+EP1307202B1
+EP1309330B1
+EP1311267B1
+EP1311471B1
+EP1311672B1
+EP1313489B1
+EP1313700B1
+EP1317304B1
+EP1320356B2
+EP1320359B1
+EP1322315B1
+EP1328515B1
+EP1330164B1
+EP1337258A4
+EP1337512B1
+EP1339407B1
+EP1345605B1
+EP1345608B1
+EP1345612B1
+EP1345616A4
+EP1349856B1
+EP1355650B1
+EP1357906B1
+EP1363895B1
+EP1363903B1
+EP1365781A4
+EP1366040B1
+EP1367886B1
+EP1368015B1
+EP1368023B1
+EP1370264B1
+EP1370265B1
+EP1370559B1
+EP1370684B1
+EP1372627B1
+EP1372694B1
+EP1373249B1
+EP1377277B1
+EP1377288B1
+EP1377316B1
+EP1379225B1
+EP1379522B1
+EP1383765B1
+EP1385504B1
+EP1385514B1
+EP1385527B1
+EP1385528B1
+EP1389466B1
+EP1390026B1
+EP1390037B1
+EP1390041B1
+EP1392335B1
+EP1397132A4
+EP1406654A4
+EP1408941B1
+EP1408950B1
+EP1409485B1
+EP1409490B1
+EP1411910B1
+EP1411986B1
+EP1431285B1
+EP1434765B1
+EP1448559B1
+EP1450775B1
+EP1451167B1
+EP1453510A4
+EP1454897B1
+EP1467762B1
+EP1469823B1
+EP1474143B1
+EP1476190B1
+EP1477472B1
+EP1478638B1
+EP1482796A4
+EP1485381B1
+EP1487285B9
+EP1487421B1
+EP1490029A4
+EP1490365B1
+EP1493443A1
+EP1494674A1
+EP1494688A4
+EP1496900A2
+EP1499617A1
+EP1500391A1
+EP1501499A1
+EP1501800A1
+EP1505075B1
+EP1506960A1
+EP1507559A1
+EP1507774A1
+EP1509285A2
+EP1511500A2
+EP1511521A1
+EP1513504A1
+EP1515710A1
+EP1515729B1
+EP1518554A1
+EP1519732A1
+EP1519925A1
+EP1521576A1
+EP1524270B1
+EP1524980A1
+EP1525882A1
+EP1526852A1
+EP1529025B1
+EP1530459A2
+EP1531795A1
+EP1532129B1
+EP1532133A1
+EP1536800B1
+EP1537110A2
+EP1539129A1
+EP1539169A2
+EP1539686A1
+EP1539764A1
+EP1541559A1
+EP1542987A1
+EP1545508A1
+EP1546140A2
+EP1549198A2
+EP1549246B1
+EP1549316A1
+EP1555976A2
+EP1556050A1
+EP1558243A2
+EP1558620A1
+EP1558630A2
+EP1559374A1
+EP1561425A1
+EP1562568B1
+EP1567117B1
+EP1567644A2
+EP1569630A4
+EP1569632A1
+EP1570839A1
+EP1570852A2
+EP1572073A2
+EP1572237A1
+EP1572658A1
+EP1575509A2
+EP1578441A2
+EP1578727A2
+EP1578897A2
+EP1581471B1
+EP1581496A2
+EP1581509B1
+EP1581529A1
+EP1583523B1
+EP1583559B1
+EP1589815A2
+EP1592424A1
+EP1593386A1
+EP1593679A1
+EP1596849A1
+EP1596859A1
+EP1597255A1
+EP1598066A1
+EP1599191A2
+EP1599202A1
+EP1600160A1
+EP1603572A4
+EP1605938B1
+EP1605948A1
+EP1612555A1
+EP1613316A1
+EP1613320A1
+EP1613326B1
+EP1614694A1
+EP1615622B1
+EP1615640B1
+EP1616577B1
+EP1623706A2
+EP1626709A1
+EP1627641A1
+EP1631823A2
+EP1633718B1
+EP1638528A2
+EP1641456A2
+EP1641775B1
+EP1643836A1
+EP1646131A1
+EP1646392A2
+EP1647272A1
+EP1648433B1
+EP1652521A1
+EP1658093B1
+EP1658852A1
+EP1660069A2
+EP1660490A1
+EP1661564A1
+EP1664005A1
+EP1670481A1
+EP1670490A1
+EP1674467A1
+EP1674468A1
+EP1675569A1
+EP1675846B1
+EP1682514A1
+EP1682532B1
+EP1683515A2
+EP1684746A1
+EP1685142B1
+EP1686181A2
+EP1689731B1
+EP1690852A1
+EP1694335A4
+EP1695702A2
+EP1697348B1
+EP1699456A1
+EP1700597A1
+EP1700598A1
+EP1702983A2
+EP1704862A1
+EP1706386A1
+EP1708713B1
+EP1711182A1
+EP1711465A1
+EP1713479A1
+EP1713507A2
+EP1714652A2
+EP1716125A1
+EP1718614A1
+EP1719518A1
+EP1720546B1
+EP1722776A2
+EP1723948A1
+EP1725529A1
+EP1726305A1
+EP1726586A1
+EP1728510A2
+EP1729811B1
+EP1730126A1
+EP1731156A1
+EP1733741A2
+EP1735302B1
+EP1735443A2
+EP1740538A2
+EP1741718A2
+EP1745050A1
+EP1745776A1
+EP1749520A1
+EP1749522A2
+EP1750682A2
+EP1754492A1
+EP1754712A2
+EP1755477A2
+EP1756066B1
+EP1762248A1
+EP1764362A1
+EP1765360B1
+EP1768661A1
+EP1772514A2
+EP1776102A1
+EP1781608B1
+EP1782838A1
+EP1784198A2
+EP1788092A1
+EP1789402A1
+EP1791536A1
+EP1791841A1
+EP1804797B1
+EP1809269A1
+EP1809648A2
+EP1817294A1
+EP1818057A1
+EP1828115A2
+EP1828149A1
+EP1828223A2
+EP1829543A1
+EP1830833A2
+EP1831198A1
+EP1832179A1
+EP1832278A1
+EP1833792A1
+EP1838707A1
+EP1842544A2
+EP1842852A1
+EP1843750A1
+EP1847531A1
+EP1849475A1
+EP1852130A1
+EP1853315A1
+EP1853564A1
+EP1855669A1
+EP1856040A2
+EP1857447A1
+EP1858887A1
+EP1861101A2
+EP1861371A1
+EP1863488A2
+EP1864658A1
+EP1864662A1
+EP1864976A1
+EP1866312A1
+EP1868572A2
+EP1870100A1
+EP1870103A2
+EP1871393A2
+EP1873153B1
+EP1874297A1
+EP1874300A2
+EP1878429B1
+EP1881828A1
+EP1886678A1
+EP1889612A2
+EP1890690A2
+EP1893206A2
+EP1898935A2
+EP1898936A1
+EP1902017A1
+EP1902044A1
+EP1904454A2
+EP1905437A1
+EP1911753A1
+EP1913945A2
+EP1915158A1
+EP1915996A1
+EP1931636B1
+EP1935414A2
+EP1951274A1
+EP1951303B1
+EP1951318A1
+EP1954255A1
+EP1957073A2
+EP1957088A1
+EP1958636A1
+EP1961745A1
+EP1961757A1
+EP1961819A2
+EP1962854A2
+EP1963334A1
+EP1967591A2
+EP1968595A2
+EP1970051A1
+EP1971588B1
+EP1971609A1
+EP1973540B1
+EP1976517A1
+EP1977766A1
+EP1979341B1
+EP1981845A2
+EP1982970A1
+EP1985299A1
+EP1986011A2
+EP1986670A2
+EP1991239A1
+EP1991526A1
+EP1994009A1
+EP1996188A1
+EP1998768A2
+EP2001495A2
+EP2002731A1
+EP2004618A1
+EP2005945A2
+EP2005968A9
+EP2011488B1
+EP2013172A1
+EP2018383A1
+EP2018866A1
+EP2020869A1
+EP2022497A1
+EP2026789A2
+EP2027124A1
+EP2027862A1
+EP2030978A1
+EP2035010A1
+EP2037904A1
+EP2041119A1
+EP2044942A1
+EP2046803A1
+EP2048142A2
+EP2052732A1
+EP2055305A1
+EP2060257A1
+EP2061759A1
+EP2062878A1
+EP2066322A2
+EP2068663A1
+EP2068861A2
+EP2069310B1
+EP2069501A2
+EP2078523A1
+EP2079688B1
+EP2079703A1
+EP2091925A1
+EP2091943A2
+EP2094666A1
+EP2094673A1
+EP2097107A2
+EP2099783A1
+EP2100604A1
+EP2100890A1
+EP2107057A1
+EP2108404A1
+EP2110127A1
+EP2111861A1
+EP2114460A2
+EP2116252A1
+EP2117540A1
+EP2119717A1
+EP2123257A2
+EP2124919B1
+EP2127520A1
+EP2127667B1
+EP2128137A1
+EP2134704B1
+EP2141164A1
+EP2143719A1
+EP2143723A1
+EP2148675A1
+EP2148868A1
+EP2155771A1
+EP2160466A1
+EP2164850A2
+EP2167662A2
+EP2172452A1
+EP2177214A1
+EP2179726A2
+EP2180890A1
+EP2183246A2
+EP2184987A1
+EP2185523A2
+EP2193117A1
+EP2199289A1
+EP2201947A2
+EP2211760A1
+EP2211880A1
+EP2222636A2
+EP2222649A2
+EP2222667A2
+EP2226072A1
+EP2233141A1
+EP2234619A2
+EP2234972A1
+EP2235027A1
+EP2236139A1
+EP2237785A2
+EP2241312A1
+EP2241317A1
+EP2251010A1
+EP2251042A2
+EP2253316A1
+EP2253631A1
+EP2254555A2
+EP2255799A1
+EP2256210A1
+EP2257551A2
+EP2258681A2
+EP2259797A2
+EP2263671A1
+EP2265271A1
+EP2266577A1
+EP2268645A1
+EP2269654A2
+EP2269972A1
+EP2270505A1
+EP2271338A1
+EP2275101A1
+EP2279743A2
+EP2280940A1
+EP2285393A1
+EP2286826A2
+EP2289500A1
+EP2292587A1
+EP2295424A1
+EP2295604A2
+EP2297085A2
+EP2297105A1
+EP2298281A1
+EP2298298A2
+EP2300036A1
+EP2301525A1
+EP2305228A1
+EP2305248A1
+EP2305257A1
+EP2306996A1
+EP2308591A1
+EP2311814A1
+EP2311818A1
+EP2319509A1
+EP2322174A2
+EP2323640A2
+EP2323645A1
+EP2324008B1
+EP2325172A1
+EP2326636A2
+EP2328878A1
+EP2335692A1
+EP2335708A1
+EP2340016A2
+EP2343291A1
+EP2343295A1
+EP2343979A1
+EP2346506A1
+EP2348868A1
+EP2349998A2
+EP2358369A1
+EP2359852A1
+EP2363133A1
+EP2363142A1
+EP2363483A2
+EP2364994A1
+EP2365805A1
+EP2367557A1
+EP2368547B1
+EP2368885A1
+EP2370075A1
+EP2370097A1
+EP2370437A1
+EP2376435A2
+EP2377532A1
+EP2379090A1
+EP2389070A1
+EP2393781A1
+EP2397128A1
+EP2397147A1
+EP2399566A1
+EP2400845A1
+EP2403497A1
+EP2407164A1
+EP2409689A1
+EP2409693A2
+EP2411011A1
+EP2413920A1
+EP2419095A2
+EP2419405A1
+EP2419414A1
+EP2419428A1
+EP2422786A1
+EP2425858A2
+EP2428217A1
+EP2431365A1
+EP2437747A1
+EP2438037A1
+EP2440201A1
+EP2442808A2
+EP2442819A2
+EP2446883A1
+EP2450038A1
+EP2452577A1
+EP2453746A1
+EP2453889A1
+EP2455085A2
+EP2456419A1
+EP2461813A1
+EP2461816A1
+EP2462143A1
+EP2464632A1
+EP2467398A1
+EP2470176A1
+EP2470268A1
+EP2474529A1
+EP2478902A1
+EP2480078A1
+EP2480224A1
+EP2480536A2
+EP2481396A2
+EP2486006A1
+EP2486042A1
+EP2487242A1
+EP2488514A1
+EP2489353A1
+EP2491007A1
+EP2492267A1
+EP2493478A1
+EP2494973A1
+EP2497772A1
+EP2501669A2
+EP2507221A1
+EP2508186A1
+EP2509600A1
+EP2510098A1
+EP2512267A1
+EP2515848A1
+EP2516011A1
+EP2516645A1
+EP2519505A1
+EP2519511A1
+EP2520289A1
+EP2523552A1
+EP2523691A1
+EP2527007A1
+EP2527335A1
+EP2527340A1
+EP2529728A1
+EP2532649A1
+EP2532666A1
+EP2540298A1
+EP2543370A1
+EP2548561A1
+EP2548880A2
+EP2550275A1
+EP2552905A1
+EP2552924A1
+EP2554167A1
+EP2554170A1
+EP2555771A1
+EP2556830A1
+EP2560970A1
+EP2563787A1
+EP2566483A1
+EP2576532A1
+EP2578569A1
+EP2582812A1
+EP2582832A1
+EP2585461A1
+EP2586425A1
+EP2588462A1
+EP2589603A1
+EP2590951A1
+EP2591002A2
+EP2594268A1
+EP2594562A2
+EP2598147A1
+EP2601962A1
+EP2603096A1
+EP2603502A1
+EP2609922A1
+EP2615086A1
+EP2616082A2
+EP2617411A1
+EP2620142A1
+EP2621925A1
+EP2625172A1
+EP2629610A1
+EP2632491A2
+EP2633859A1
+EP2635266A1
+EP2635287A1
+EP2641907A1
+EP2643325A1
+EP2646434A1
+EP2647374A1
+EP2649052A1
+EP2650291A1
+EP2653152A1
+EP2653164A1
+EP2658540A1
+EP2659885A1
+EP2659891A1
+EP2660245A1
+EP2662079A1
+EP2663300A1
+EP2665711A1
+EP2668953A1
+EP2671586A1
+EP2674156A1
+EP2674430A1
+EP2681203A1
+EP2681205A1
+EP2681214A1
+EP2682399A1
+EP2683371A1
+EP2683373A1
+EP2683697A1
+EP2683701A1
+EP2683706A1
+EP2684861A2
+EP2685824A1
+EP2688569A1
+EP2688884A1
+EP2689781A1
+EP2690102A1
+EP2691402A1
+EP2694053A2
+EP2694474A1
+EP2694511A1
+EP2697211A1
+EP2698167A2
+EP2699564A1
+EP2700409A1
+EP2703393A1
+EP2704709A1
+EP2708532A1
+EP2709729A1
+EP2711368A1
+EP2714005A1
+EP2714030A1
+EP2714049A1
+EP2714716A1
+EP2717856A2
+EP2717872A1
+EP2719382A1
+EP2722322A2
+EP2725025A1
+EP2726084A1
+EP2726465A1
+EP2729183A1
+EP2729445A1
+EP2730284A1
+EP2730577A1
+EP2734497A1
+EP2736531A2
+EP2736890A1
+EP2737908A1
+EP2739616A1
+EP2740473A1
+EP2740730A1
+EP2742025A1
+EP2742939A1
+EP2744502A2
+EP2745847A1
+EP2747763A1
+EP2749286A1
+EP2751102A1
+EP2753315A1
+EP2753630A1
+EP2754443A1
+EP2755956A1
+EP2755970A1
+EP2759300A2
+EP2760439A2
+EP2760449A1
+EP2760878A1
+EP2763962A1
+EP2764873A1
+EP2766029A1
+EP2766373A1
+EP2772253A1
+EP2772485A1
+EP2772491A1
+EP2773369A1
+EP2773758A2
+EP2774914A1
+EP2776023A1
+EP2776406A2
+EP2777701A1
+EP2780017A1
+EP2783685A1
+EP2783686A1
+EP2784068A1
+EP2785705A1
+EP2785840A1
+EP2786982A1
+US20050004068
+US20050004081
+US20050004172
+US20050009843
+US20050009868
+US20050009925
+US20050013858
+US20050014690
+US20050014730
+US20050020836
+US20050032754
+US20050032820
+US20050032854
+US20050033051
+US20050037077
+US20050037404
+US20050038259
+US20050042202
+US20050042302
+US20050048128
+US20050049202
+US20050049233
+US20050054582
+US20050054617
+US20050059617
+US20050059726
+US20050065165
+US20050065213
+US20050070544
+US20050075332
+US20050075511
+US20050080096
+US20050080104
+US20050085513
+US20050090693
+US20050100902
+US20050107400
+US20050107411
+US20050107428
+US20050107446
+US20050113322
+US20050113370
+US20050119193
+US20050119206
+US20050119224
+US20050123536
+US20050123603
+US20050123627
+US20050123633
+US20050124554
+US20050129621
+US20050129739
+US20050129774
+US20050131051
+US20050131052
+US20050143283
+US20050143419
+US20050152845
+US20050158393
+US20050158724
+US20050158726
+US20050159437
+US20050164988
+US20050166911
+US20050169999
+US20050170384
+US20050171074
+US20050171106
+US20050171151
+US20050171214
+US20050176753
+US20050176813
+US20050180959
+US20050181034
+US20050181506
+US20050182135
+US20050192236
+US20050192259
+US20050196379
+US20050196456
+US20050202019
+US20050208125
+US20050208127
+US20050209169
+US20050215579
+US20050215645
+US20050220819
+US20050220884
+US20050220899
+US20050221395
+US20050222183
+US20050222194
+US20050222211
+US20050228024
+US20050234008
+US20050238737
+US20050244489
+US20050245504
+US20050245507
+US20050245511
+US20050250716
+US20050255529
+US20050256171
+US20050256178
+US20050256208
+US20050256211
+US20050261231
+US20050261333
+US20050261349
+US20050266024
+US20050266075
+US20050282861
+US20060002887
+US20060002966
+US20060004058
+US20060009403
+US20060009426
+US20060009651
+US20060014243
+US20060014825
+US20060019995
+US20060034939
+US20060034951
+US20060035919
+US20060035948
+US20060035977
+US20060040931
+US20060040964
+US20060046992
+US20060051296
+US20060052417
+US20060052440
+US20060052453
+US20060058288
+US20060058345
+US20060058364
+US20060063711
+US20060063839
+US20060069031
+US20060069057
+US20060069067
+US20060074091
+US20060083692
+US20060084702
+US20060088545
+US20060088556
+US20060089353
+US20060094730
+US20060106067
+US20060106074
+US20060111274
+US20060111304
+US20060121010
+US20060121069
+US20060121094
+US20060122191
+US20060128750
+US20060134095
+US20060135769
+US20060140872
+US20060141013
+US20060142184
+US20060142203
+US20060142326
+US20060142571
+US20060148707
+US20060153839
+US20060153939
+US20060154944
+US20060154984
+US20060160878
+US20060165591
+US20060166872
+US20060166892
+US20060167048
+US20060173012
+US20060173059
+US20060177423
+US20060177901
+US20060178426
+US20060183737
+US20060183794
+US20060189631
+US20060189666
+US20060199832
+US20060199978
+US20060210548
+US20060210553
+US20060211651
+US20060211701
+US20060233815
+US20060234940
+US20060234977
+US20060239999
+US20060252766
+US20060257367
+US20060265763
+US20060269613
+US20060270627
+US20060270646
+US20060276460
+US20060287275
+US20060292093
+US20060293242
+US20060293285
+US20060293326
+US20070021414
+US20070021432
+US20070021496
+US20070021506
+US20070026051
+US20070027151
+US20070037882
+US20070059338
+US20070059357
+US20070060619
+US20070072811
+US20070072853
+US20070082908
+US20070093483
+US20070105143
+US20070105840
+US20070116745
+US20070117154
+US20070123510
+US20070128591
+US20070129381
+US20070134308
+US20070134342
+US20070142266
+US20070149492
+US20070161560
+US20070161628
+US20070173537
+US20070191422
+US20070191435
+US20070203141
+US20070218067
+US20070225260
+US20070232636
+US20070232692
+US20070238641
+US20070238728
+US20070238753
+US20070238754
+US20070243268
+US20070244051
+US20070248569
+US20070248620
+US20070248702
+US20070249648
+US20070249726
+US20070253954
+US20070253957
+US20070254867
+US20070258890
+US20070258972
+US20070259849
+US20070259959
+US20070264271
+US20070264290
+US20070265212
+US20070265298
+US20070269522
+US20070269533
+US20070270447
+US20070270488
+US20070270505
+US20070274951
+US20070275919
+US20070275953
+US20070276031
+US20070280908
+US20070280918
+US20070281036
+US20070281903
+US20070281993
+US20070282007
+US20070287677
+US20070287701
+US20070287713
+US20070287724
+US20070287726
+US20070292502
+US20070293433
+US20070293508
+US20070293548
+US20070293578
+US20070293585
+US20070298084
+US20070299032
+US20070299043
+US20070299048
+US20070299083
+US20070299102
+US20080003219
+US20080003232
+US20080003275
+US20080004287
+US20080004338
+US20080004345
+US20080004346
+US20080004347
+US20080008681
+US20080009447
+US20080009518
+US20080009540
+US20080011293
+US20080014283
+US20080015143
+US20080015207
+US20080015240
+US20080015252
+US20080020050
+US20080021021
+US20080021057
+US20080021069
+US20080025986
+US20080026014
+US20080026056
+US20080026086
+US20080026997
+US20080027039
+US20080027048
+US20080027051
+US20080031931
+US20080032925
+US20080032964
+US20080032966
+US20080033011
+US20080038247
+US20080038251
+US20080038268
+US20080038301
+US20080038389
+US20080039410
+US20080039412
+US20080039440
+US20080044390
+US20080044468
+US20080044489
+US20080045485
+US20080050430
+US20080051325
+US20080051330
+US20080051351
+US20080051427
+US20080057025
+US20080057047
+US20080057055
+US20080057074
+US20080057086
+US20080057098
+US20080057112
+US20080057129
+US20080058310
+US20080058383
+US20080058405
+US20080063638
+US20080063709
+US20080064668
+US20080064722
+US20080064753
+US20080064758
+US20080069870
+US20080070850
+US20080070884
+US20080075774
+US20080076766
+US20080081834
+US20080085244
+US20080085279
+US20080085855
+US20080085902
+US20080089861
+US20080090781
+US20080090829
+US20080090872
+US20080090909
+US20080096829
+US20080096838
+US20080096840
+US20080096851
+US20080096913
+US20080096927
+US20080096971
+US20080102038
+US20080102085
+US20080103136
+US20080107652
+US20080107662
+US20080108594
+US20080108608
+US20080108704
+US20080108705
+US20080112888
+US20080112889
+US20080113346
+US20080113955
+US20080114002
+US20080114015
+US20080114044
+US20080114056
+US20080118495
+US20080118556
+US20080118562
+US20080119527
+US20080119549
+US20080124408
+US20080125354
+US20080125358
+US20080125394
+US20080125458
+US20080125470
+US20080125488
+US20080131366
+US20080131503
+US20080132536
+US20080132544
+US20080132552
+US20080132563
+US20080132825
+US20080138400
+US20080139545
+US20080139589
+US20080139614
+US20080145322
+US20080145336
+US20080145456
+US20080146541
+US20080146551
+US20080146556
+US20080152639
+US20080153741
+US20080153781
+US20080153796
+US20080153818
+US20080153910
+US20080159980
+US20080160019
+US20080160022
+US20080160046
+US20080160060
+US20080160083
+US20080161260
+US20080161293
+US20080161328
+US20080161337
+US20080161361
+US20080161393
+US20080161409
+US20080166417
+US20080166730
+US20080167220
+US20080167277
+US20080167279
+US20080167306
+US20080171781
+US20080175811
+US20080175899
+US20080175925
+US20080176923
+US20080176953
+US20080181864
+US20080182780
+US20080182806
+US20080182819
+US20080182827
+US20080182876
+US20080187536
+US20080188435
+US20080188470
+US20080188509
+US20080193488
+US20080193515
+US20080194468
+US20080194492
+US20080194528
+US20080194570
+US20080194580
+US20080194584
+US20080199447
+US20080200432
+US20080200484
+US20080200507
+US20080200512
+US20080200548
+US20080206186
+US20080206203
+US20080206250
+US20080206310
+US20080207496
+US20080207683
+US20080207737
+US20080213234
+US20080213257
+US20080213286
+US20080213407
+US20080214499
+US20080214506
+US20080214530
+US20080214544
+US20080214559
+US20080214563
+US20080214586
+US20080219960
+US20080221018
+US20080221051
+US20080221115
+US20080221121
+US20080221151
+US20080221164
+US20080226622
+US20080227698
+US20080227748
+US20080227752
+US20080227786
+US20080233132
+US20080233207
+US20080234283
+US20080234326
+US20080234382
+US20080241133
+US20080241224
+US20080242634
+US20080242645
+US20080247986
+US20080248134
+US20080249040
+US20080249050
+US20080249096
+US20080249105
+US20080249117
+US20080249147
+US20080254010
+US20080254017
+US20080254059
+US20080254101
+US20080254130
+US20080255101
+US20080255179
+US20080260717
+US20080260719
+US20080261865
+US20080261902
+US20080261955
+US20080261963
+US20080261967
+US20080262004
+US20080262009
+US20080262017
+US20080262018
+US20080262028
+US20080262039
+US20080262053
+US20080262055
+US20080262093
+US20080263607
+US20080269146
+US20080269152
+US20080269160
+US20080269222
+US20080269256
+US20080269282
+US20080269307
+US20080269311
+US20080269324
+US20080269334
+US20080269347
+US20080274075
+US20080274998
+US20080275046
+US20080275052
+US20080275076
+US20080275088
+US20080275134
+US20080279764
+US20080279786
+US20080279819
+US20080279855
+US20080280856
+US20080280877
+US20080280887
+US20080280951
+US20080280989
+US20080287364
+US20080287368
+US20080287383
+US20080287417
+US20080287430
+US20080287469
+US20080287478
+US20080292602
+US20080292618
+US20080292681
+US20080292687
+US20080292733
+US20080293698
+US20080293703
+US20080293709
+US20080293721
+US20080293795
+US20080299189
+US20080299204
+US20080300238
+US20080300309
+US20080306079
+US20080306139
+US20080306146
+US20080311180
+US20080311194
+US20080312181
+US20080312206
+US20080312231
+US20080312253
+US20080312319
+US20080312334
+US20080312462
+US20080317822
+US20080317855
+US20080318843
+US20080318904
+US20080318976
+US20080319001
+US20080319222
+US20090004172
+US20090005346
+US20090005352
+US20090005411
+US20090005441
+US20090010867
+US20090011040
+US20090011041
+US20090012014
+US20090012052
+US20090012069
+US20090012089
+US20090012145
+US20090017039
+US20090017104
+US20090017112
+US20090018093
+US20090018155
+US20090018209
+US20090018210
+US20090022732
+US20090022819
+US20090023719
+US20090023728
+US20090023755
+US20090023794
+US20090023798
+US20090023807
+US20090023810
+US20090029932
+US20090035249
+US20090035309
+US20090035357
+US20090036355
+US20090036371
+US20090036430
+US20090036431
+US20090036530
+US20090036541
+US20090041751
+US20090041760
+US20090042874
+US20090042894
+US20090042909
+US20090042954
+US20090042988
+US20090047238
+US20090047321
+US20090047366
+US20090048198
+US20090048235
+US20090048258
+US20090048266
+US20090048304
+US20090048313
+US20090048412
+US20090053234
+US20090053285
+US20090053296
+US20090053307
+US20090053336
+US20090054341
+US20090054372
+US20090055941
+US20090060941
+US20090062204
+US20090062216
+US20090062321
+US20090062351
+US20090062391
+US20090068132
+US20090068198
+US20090068264
+US20090069314
+US20090069324
+US20090069339
+US20090069391
+US20090074761
+US20090075900
+US20090075920
+US20090075967
+US20090075992
+US20090076010
+US20090076024
+US20090076027
+US20090076028
+US20090076031
+US20090076051
+US20090076052
+US20090076078
+US20090076097
+US20090076100
+US20090076120
+US20090076131
+US20090076135
+US20090076139
+US20090076144
+US20090076150
+US20090076153
+US20090076170
+US20090081283
+US20090082412
+US20090082436
+US20090082438
+US20090087432
+US20090092573
+US20090092727
+US20090093494
+US20090098108
+US20090099185
+US20090099213
+US20090105171
+US20090105234
+US20090105261
+US20090105264
+US20090105344
+US20090105350
+US20090105537
+US20090110712
+US20090110749
+US20090110756
+US20090111798
+US20090111806
+US20090117072
+US20090117074
+US20090117125
+US20090117163
+US20090117215
+US20090118223
+US20090118224
+US20090118263
+US20090118321
+US20090118350
+US20090124572
+US20090124591
+US20090124657
+US20090124675
+US20090124685
+US20090130062
+US20090130178
+US20090131302
+US20090131410
+US20090131422
+US20090131426
+US20090131457
+US20090131464
+US20090131465
+US20090131481
+US20090131530
+US20090131535
+US20090137504
+US20090137536
+US20090137563
+US20090137575
+US20090137598
+US20090137607
+US20090137660
+US20090143313
+US20090143363
+US20090143424
+US20090143449
+US20090143462
+US20090148459
+US20090149503
+US20090155383
+US20090156601
+US20090156628
+US20090156677
+US20090162363
+US20090163478
+US20090163590
+US20090169511
+US20090169600
+US20090169638
+US20090170814
+US20090170862
+US20090170943
+US20090175795
+US20090176718
+US20090176886
+US20090178148
+US20090181908
+US20090181925
+US20090181939
+US20090181970
+US20090182029
+US20090186853
+US20090186894
+US20090186940
+US20090191144
+US20090192071
+US20090192173
+US20090192183
+US20090192212
+US20090196924
+US20090197853
+US20090197893
+US20090202430
+US20090202601
+US20090203650
+US20090203654
+US20090203664
+US20090203722
+US20090203782
+US20090208425
+US20090208550
+US20090208592
+US20090209507
+US20090209516
+US20090209534
+US20090214555
+US20090215852
+US20090215869
+US20090220528
+US20090220618
+US20090221598
+US20090221648
+US20090221669
+US20090221714
+US20090226431
+US20090226449
+US20090226526
+US20090227511
+US20090227534
+US20090227542
+US20090227561
+US20090227585
+US20090227601
+US20090227654
+US20090233961
+US20090234022
+US20090239875
+US20090239926
+US20090246172
+US20090246189
+US20090246257
+US20090247455
+US20090247558
+US20090247641
+US20090252702
+US20090253685
+US20090253791
+US20090253796
+US20090258870
+US20090258874
+US20090258936
+US20090258951
+US20090263322
+US20090263406
+US20090264497
+US20090264508
+US20090264530
+US20090269404
+US20090270371
+US20090270435
+US20090270496
+US20090274766
+US20090275538
+US20090281061
+US20090281101
+US20090281102
+US20090286775
+US20090286805
+US20090286858
+US20090291934
+US20090291939
+US20090292028
+US20090297644
+US20090298803
+US20090298943
+US20090306026
+US20090306093
+US20090306108
+US20090306178
+US20090311344
+US20090312324
+US20090312390
+US20090312411
+US20090317359
+US20090317487
+US20090318361
+US20090318502
+US20090318532
+US20090318543
+US20090318562
+US20090324668
+US20090324703
+US20090325894
+US20090325900
+US20090325971
+US20090325972
+US20090325991
+US20090326003
+US20090326066
+US20090326067
+US20100003250
+US20100003328
+US20100003340
+US20100003353
+US20100004220
+US20100008935
+US20100008974
+US20100009950
+US20100016276
+US20100016344
+US20100016424
+US20100021415
+US20100021493
+US20100021547
+US20100022449
+US20100022470
+US20100022511
+US20100022581
+US20100022622
+US20100028368
+US20100028400
+US20100029584
+US20100029695
+US20100034901
+US20100035866
+US20100035929
+US20100040599
+US20100041632
+US20100041647
+US20100041695
+US20100041751
+US20100047221
+US20100047362
+US20100048530
+US20100048544
+US20100048722
+US20100056457
+US20100056533
+US20100062039
+US20100062063
+US20100062084
+US20100062998
+US20100063033
+US20100063099
+US20100063109
+US20100063118
+US20100063122
+US20100063132
+US20100068162
+US20100068201
+US20100069331
+US20100069343
+US20100069352
+US20100069395
+US20100069399
+US20100069464
+US20100074850
+US20100074857
+US20100076007
+US20100076036
+US20100076058
+US20100076073
+US20100081625
+US20100081668
+US20100081705
+US20100086556
+US20100086605
+US20100087498
+US20100087547
+US20100092551
+US20100092580
+US20100093725
+US20100093755
+US20100093756
+US20100093852
+US20100098678
+US20100098713
+US20100099640
+US20100099671
+US20100099722
+US20100099745
+US20100104675
+US20100105641
+US20100105735
+US20100105777
+US20100111866
+US20100111888
+US20100113427
+US20100113469
+US20100113479
+US20100113512
+US20100113601
+US20100119472
+US20100119610
+US20100120799
+US20100124554
+US20100125077
+US20100125096
+US20100129353
+US20100129469
+US20100130442
+US20100130449
+US20100130459
+US20100130484
+US20100130490
+US20100130537
+US20100130593
+US20100135952
+US20100135988
+US20100136015
+US20100136107
+US20100136124
+US20100136127
+US20100137259
+US20100137267
+US20100137351
+US20100143295
+US20100143415
+US20100143420
+US20100144684
+US20100144715
+US20100144773
+US20100144786
+US20100144802
+US20100151007
+US20100152125
+US20100152227
+US20100152284
+US20100152303
+US20100158946
+US20100158958
+US20100159011
+US20100160228
+US20100160268
+US20100160269
+US20100160293
+US20100160342
+US20100160397
+US20100168077
+US20100168089
+US20100168248
+US20100169995
+US20100172959
+US20100172981
+US20100172984
+US20100172993
+US20100173008
+US20100173911
+US20100178278
+US20100178305
+US20100178332
+US20100178333
+US20100179163
+US20100179224
+US20100183552
+US20100183579
+US20100183691
+US20100183728
+US20100184724
+US20100184727
+US20100184768
+US20100184804
+US20100189771
+US20100190726
+US20100190743
+US20100190778
+US20100190830
+US20100191040
+US20100191325
+US20100192240
+US20100196286
+US20100196335
+US20100196355
+US20100196358
+US20100196436
+US20100196514
+US20100197564
+US20100197647
+US20100197768
+US20100197790
+US20100203009
+US20100203123
+US20100203166
+US20100204187
+US20100204320
+US20100210518
+US20100210625
+US20100210677
+US20100210709
+US20100210712
+US20100210716
+US20100215579
+US20100215774
+US20100216729
+US20100216736
+US20100216762
+US20100216886
+US20100218266
+US20100221343
+US20100222292
+US20100222296
+US20100222302
+US20100222360
+US20100222437
+US20100226908
+US20100226963
+US20100227839
+US20100227845
+US20100227891
+US20100227896
+US20100233255
+US20100233304
+US20100234313
+US20100234348
+US20100234410
+US20100234450
+US20100239592
+US20100239666
+US20100240603
+US20100240684
+US20100240687
+US20100240738
+US20100240763
+US20100247439
+US20100247659
+US20100247662
+US20100249038
+US20100249086
+US20100249141
+US20100249142
+US20100249222
+US20100254928
+US20100255050
+US20100255064
+US20100255126
+US20100256136
+US20100256161
+US20100256576
+US20100260675
+US20100260825
+US20100260856
+US20100261676
+US20100261681
+US20100261772
+US20100266654
+US20100266676
+US20100267640
+US20100267661
+US20100267706
+US20100269825
+US20100272671
+US20100272762
+US20100272814
+US20100273740
+US20100273783
+US20100273816
+US20100273872
+US20100278759
+US20100278797
+US20100279981
+US20100279996
+US20100284991
+US20100285024
+US20100285030
+US20100285040
+US20100285046
+US20100285087
+US20100285113
+US20100286023
+US20100286032
+US20100286089
+US20100286174
+US20100286207
+US20100286254
+US20100287636
+US20100291043
+US20100291118
+US20100292216
+US20100292229
+US20100292247
+US20100292272
+US20100292290
+US20100292330
+US20100292342
+US20100297015
+US20100297037
+US20100297054
+US20100297221
+US20100297256
+US20100297265
+US20100297269
+US20100298255
+US20100298264
+US20100298274
+US20100298301
+US20100298316
+US20100298376
+US20100298388
+US20100298396
+US20100298406
+US20100298418
+US20100298425
+US20100298431
+US20100303717
+US20100305088
+US20100305119
+US20100305157
+US20100305207
+US20100305500
+US20100310480
+US20100310575
+US20100310622
+US20100310660
+US20100311758
+US20100311796
+US20100311804
+US20100311815
+US20100311825
+US20100311827
+US20100316700
+US20100316708
+US20100316726
+US20100317610
+US20100317666
+US20100319073
+US20100322928
+US20100322979
+US20100323958
+US20100324023
+US20100324117
+US20100330145
+US20100330212
+US20100331247
+US20100331292
+US20100331326
+US20100331345
+US20100331388
+US20100331398
+US20100331536
+US20110002971
+US20110002980
+US20110003818
+US20110003858
+US20110003879
+US20110003882
+US20110008429
+US20110009426
+US20110009429
+US20110009434
+US20110014204
+US20110015136
+US20110015160
+US20110015176
+US20110015186
+US20110015216
+US20110020227
+US20110020455
+US20110020474
+US20110021462
+US20110021507
+US20110021981
+US20110027192
+US20110027340
+US20110027371
+US20110027376
+US20110027387
+US20110030077
+US20110033376
+US20110033406
+US20110033414
+US20110033437
+US20110033438
+US20110033473
+US20110033486
+US20110034409
+US20110034443
+US20110034444
+US20110034461
+US20110034467
+US20110034526
+US20110034532
+US20110034540
+US20110034553
+US20110038862
+US20110038941
+US20110039805
+US20110039815
+US20110039883
+US20110044908
+US20110046184
+US20110046232
+US20110046606
+US20110046982
+US20110052645
+US20110052687
+US20110052708
+US20110053917
+US20110053931
+US20110053952
+US20110053968
+US20110053995
+US20110054012
+US20110059076
+US20110059900
+US20110059921
+US20110059979
+US20110060031
+US20110060049
+US20110064748
+US20110064773
+US20110064830
+US20110065638
+US20110065670
+US20110065689
+US20110065711
+US20110065719
+US20110070287
+US20110070318
+US20110071108
+US20110071118
+US20110071185
+US20110071285
+US20110076230
+US20110076235
+US20110076250
+US20110076258
+US20110076315
+US20110076342
+US20110077222
+US20110081428
+US20110082096
+US20110082124
+US20110082140
+US20110082144
+US20110082197
+US20110082213
+US20110082214
+US20110086800
+US20110086802
+US20110086813
+US20110086834
+US20110086875
+US20110091385
+US20110091415
+US20110092465
+US20110092474
+US20110092495
+US20110092545
+US20110092565
+US20110092581
+US20110097343
+US20110097393
+US20110097403
+US20110097409
+US20110098233
+US20110098241
+US20110098246
+US20110098315
+US20110100371
+US20110104120
+US20110104238
+US20110104257
+US20110104262
+US20110104265
+US20110104272
+US20110104278
+US20110105479
+US20110105504
+US20110105578
+US20110105586
+US20110105588
+US20110111002
+US20110111018
+US20110112043
+US20110112188
+US20110117015
+US20110117175
+US20110117215
+US20110118208
+US20110118268
+US20110118271
+US20110118297
+US20110118359
+US20110123593
+US20110124558
+US20110124600
+US20110124626
+US20110124702
+US20110124725
+US20110129512
+US20110129528
+US20110129530
+US20110129551
+US20110130355
+US20110130378
+US20110130446
+US20110135619
+US20110135722
+US20110135724
+US20110135732
+US20110136758
+US20110136778
+US20110136784
+US20110136832
+US20110136857
+US20110142789
+US20110142797
+US20110142880
+US20110142938
+US20110142948
+US20110144040
+US20110144076
+US20110144168
+US20110144210
+US20110150856
+US20110151000
+US20110152228
+US20110152252
+US20110152328
+US20110152357
+US20110152381
+US20110159045
+US20110159066
+US20110159077
+US20110159078
+US20110159088
+US20110160127
+US20110160132
+US20110160176
+US20110160193
+US20110160203
+US20110160279
+US20110160308
+US20110165092
+US20110165198
+US20110165201
+US20110165269
+US20110166173
+US20110166200
+US20110166212
+US20110166214
+US20110171188
+US20110171239
+US20110171275
+US20110171283
+US20110172193
+US20110172197
+US20110172203
+US20110172251
+US20110172274
+US20110172296
+US20110177097
+US20110177098
+US20110177099
+US20110177161
+US20110178121
+US20110178151
+US20110182822
+US20110182849
+US20110182902
+US20110182912
+US20110182947
+US20110182984
+US20110182997
+US20110183899
+US20110183949
+US20110183956
+US20110183968
+US20110184007
+US20110184025
+US20110184033
+US20110184044
+US20110184057
+US20110189167
+US20110189173
+US20110189199
+US20110189279
+US20110190222
+US20110190234
+US20110190248
+US20110190256
+US20110190274
+US20110190287
+US20110190290
+US20110190293
+US20110190385
+US20110200603
+US20110201496
+US20110201567
+US20110201604
+US20110201678
+US20110206775
+US20110206778
+US20110207693
+US20110207733
+US20110207736
+US20110207772
+US20110207785
+US20110207797
+US20110209248
+US20110212090
+US20110212108
+US20110212170
+US20110212174
+US20110212192
+US20110212888
+US20110212936
+US20110212943
+US20110212947
+US20110212978
+US20110212991
+US20110212996
+US20110212998
+US20110213015
+US20110217239
+US20110217331
+US20110218230
+US20110218234
+US20110218243
+US20110218249
+US20110223247
+US20110224176
+US20110224244
+US20110229423
+US20110229438
+US20110229449
+US20110229485
+US20110229521
+US20110229524
+US20110230490
+US20110230543
+US20110230551
+US20110230555
+US20110236305
+US20110236490
+US20110236494
+US20110237595
+US20110237597
+US20110243914
+US20110245158
+US20110245202
+US20110245207
+US20110245209
+US20110245221
+US20110250142
+US20110250240
+US20110250254
+US20110250257
+US20110250259
+US20110250270
+US20110250297
+US20110251220
+US20110251261
+US20110251283
+US20110256097
+US20110256119
+US20110257110
+US20110257144
+US20110257244
+US20110257270
+US20110262354
+US20110262361
+US20110262449
+US20110262511
+US20110262537
+US20110263532
+US20110263566
+US20110263574
+US20110263581
+US20110263610
+US20110263620
+US20110263621
+US20110263643
+US20110263675
+US20110263676
+US20110263715
+US20110268690
+US20110268803
+US20110268822
+US20110269737
+US20110269741
+US20110269745
+US20110269818
+US20110269819
+US20110274771
+US20110275579
+US20110275596
+US20110275660
+US20110275673
+US20110275694
+US20110280955
+US20110281799
+US20110281887
+US20110281935
+US20110281948
+US20110287008
+US20110287074
+US20110287083
+US20110288033
+US20110288113
+US20110288138
+US20110293526
+US20110293581
+US20110293588
+US20110294746
+US20110294755
+US20110294791
+US20110294793
+US20110294876
+US20110300083
+US20110300164
+US20110301111
+US20110301141
+US20110305642
+US20110305717
+US20110305776
+US20110306559
+US20110306587
+US20110306596
+US20110306616
+US20110306661
+US20110311592
+US20110311618
+US20110312921
+US20110312940
+US20110312959
+US20110313020
+US20110313048
+US20110318411
+US20110318416
+US20110319489
+US20120003220
+US20120003252
+US20120003306
+US20120004200
+US20120004265
+US20120004269
+US20120004272
+US20120004278
+US20120004320
+US20120004636
+US20120009132
+US20120009239
+US20120010227
+US20120010262
+US20120010264
+US20120010287
+US20120015036
+US20120015049
+US20120015906
+US20120015922
+US20120015936
+US20120015950
+US20120021017
+US20120021078
+US20120022011
+US20120022019
+US20120022054
+US20120027811
+US20120028906
+US20120028950
+US20120028985
+US20120029016
+US20120029075
+US20120030779
+US20120034236
+US20120034266
+US20120034304
+US20120035127
+US20120035129
+US20120035139
+US20120035217
+US20120035257
+US20120039867
+US20120039964
+US20120040018
+US20120040025
+US20120041068
+US20120041070
+US20120046230
+US20120046268
+US20120046297
+US20120046300
+US20120046331
+US20120046340
+US20120046366
+US20120052071
+US20120052105
+US20120052136
+US20120053142
+US20120053159
+US20120053171
+US20120058150
+US20120058164
+US20120058171
+US20120058175
+US20120058194
+US20120058200
+US20120064168
+US20120064176
+US20120065147
+US20120065159
+US20120065216
+US20120065247
+US20120065273
+US20120070450
+US20120070483
+US20120071414
+US20120071431
+US20120071475
+US20120071483
+US20120071489
+US20120071505
+US20120071510
+US20120071558
+US20120071562
+US20120076770
+US20120076855
+US20120076859
+US20120076863
+US20120077785
+US20120088737
+US20120088820
+US20120093768
+US20120094944
+US20120095046
+US20120095092
+US20120100107
+US20120100218
+US20120101110
+US20120107255
+US20120107329
+US20120107415
+US20120108650
+US20120108655
+US20120108672
+US20120114602
+US20120114714
+US20120114731
+US20120114768
+US20120115810
+US20120115839
+US20120115857
+US20120115903
+US20120115907
+US20120115926
+US20120115934
+US20120116215
+US20120121582
+US20120121682
+US20120121689
+US20120121697
+US20120122769
+US20120122910
+US20120128744
+US20120128778
+US20120129822
+US20120129837
+US20120129874
+US20120129877
+US20120129943
+US20120129948
+US20120135054
+US20120135094
+US20120141380
+US20120141467
+US20120141603
+US20120142621
+US20120148589
+US20120148646
+US20120149661
+US20120149739
+US20120149745
+US20120149757
+US20120156185
+US20120156211
+US20120156226
+US20120156287
+US20120157450
+US20120157506
+US20120157515
+US20120157518
+US20120164231
+US20120165310
+US20120165313
+US20120171118
+US20120171228
+US20120172392
+US20120172591
+US20120174243
+US20120177623
+US20120177681
+US20120177722
+US20120178792
+US20120178809
+US20120183493
+US20120184494
+US20120184556
+US20120184607
+US20120189684
+US20120190647
+US20120190670
+US20120190737
+US20120191039
+US20120195870
+US20120195920
+US20120196801
+US20120196870
+US20120196879
+US20120201750
+US20120201872
+US20120201901
+US20120202752
+US20120202805
+US20120203050
+US20120203051
+US20120203356
+US20120207834
+US20120208769
+US20120208824
+US20120208846
+US20120208858
+US20120208877
+US20120208889
+US20120213727
+US20120213835
+US20120214832
+US20120214858
+US20120214869
+US20120219527
+US20120219544
+US20120219577
+US20120219594
+US20120219599
+US20120219616
+US20120219619
+US20120220550
+US20120220600
+US20120220632
+US20120225030
+US20120225122
+US20120225134
+US20120225864
+US20120231087
+US20120232042
+US20120232086
+US20120232102
+US20120234721
+US20120237596
+US20120238500
+US20120238513
+US20120238520
+US20120238542
+US20120238547
+US20120238627
+US20120244209
+US20120245139
+US20120245165
+US20120245215
+US20120251516
+US20120251571
+US20120251594
+US20120251626
+US20120252747
+US20120252756
+US20120252774
+US20120252810
+US20120252814
+US20120252830
+US20120252870
+US20120252872
+US20120252904
+US20120253298
+US20120258148
+US20120258958
+US20120258970
+US20120258984
+US20120259000
+US20120259005
+US20120263651
+US20120263653
+US20120263660
+US20120263677
+US20120263730
+US20120263808
+US20120264701
+US20120264724
+US20120264819
+US20120269802
+US20120269866
+US20120270835
+US20120270840
+US20120270849
+US20120270850
+US20120270860
+US20120270870
+US20120270874
+US20120270888
+US20120270895
+US20120271056
+US20120271251
+US20120271275
+US20120277296
+US20120282258
+US20120282350
+US20120283202
+US20120283210
+US20120288486
+US20120289476
+US20120289553
+US20120289581
+US20120289591
+US20120294822
+US20120294930
+US20120295928
+US20120295940
+US20120295961
+US20120301513
+US20120302524
+US20120302528
+US20120302529
+US20120302583
+US20120302593
+US20120308593
+US20120309742
+US20120309749
+US20120315233
+US20120315324
+US20120315343
+US20120316154
+US20120316196
+US20120316225
+US20120321726
+US20120321727
+US20120322718
+US20120322760
+US20120328628
+US20120329806
+US20120329835
+US20130004455
+US20130004519
+US20130004523
+US20130004651
+US20130005676
+US20130005744
+US20130005749
+US20130005785
+US20130011333
+US20130011481
+US20130011486
+US20130011494
+US20130012471
+US20130012497
+US20130012511
+US20130017166
+US20130017203
+US20130018002
+US20130018073
+US20130018102
+US20130022593
+US20130023498
+US20130023512
+US20130023548
+US20130023585
+US20130029935
+US20130029953
+US20130034503
+US20130034536
+US20130034578
+US20130039881
+US20130039953
+US20130040000
+US20130040927
+US20130040939
+US20130041002
+US20130045179
+US20130045250
+US20130045251
+US20130045947
+US20130052155
+US20130052279
+US20130053325
+US20130053334
+US20130053336
+US20130053339
+US20130053354
+US20130053376
+US20130053430
+US20130053449
+US20130058871
+US20130058876
+US20130059007
+US20130059802
+US20130059853
+US20130059871
+US20130059882
+US20130059899
+US20130059907
+US20130064883
+US20130064884
+US20130065853
+US20130065916
+US20130072465
+US20130072478
+US20130072493
+US20130072499
+US20130072509
+US20130072541
+US20130079315
+US20130095095
+US20130095194
+US20130101644
+US20130109755
+US20130123238
+US20130129639
+US20130131621
+US20130136714
+US20130136798
+US20130137727
+US20130143856
+US20130150311
+US20130164258
+US20130171231
+US20130172387
+US20130195890
+US20130236404
+US20130245043
+US20130252933
+US20130266615
+US20130302420
+US20130303482
+US20130309307
+US20130323284
+US20130344028
+US20140010771
+US20140011829
+US20140017337
+US20140051709
+US20140079831
+US20140080875
+US20140093502
+US20140113969
+US20140127278
+US20140142167
+US20140186345
+US20140187601
+US20140271799
+US6838453
+US6838469
+US6844320
+US6844336
+US6846818
+US6846821
+US6849733
+US6852755
+US6855732
+US6855829
+US6858228
+US6858612
+US6858645
+US6858722
+US6858723
+US6858739
+US6861406
+US6864243
+US6864246
+US6867236
+US6869954
+US6869956
+US6869975
+US6870031
+US6872705
+US6872706
+US6881726
+US6884802
+US6887874
+US6887887
+US6890900
+US6890911
+US6890937
+US6890961
+US6894021
+US6894038
+US6894042
+US6894043
+US6894069
+US6897222
+US6900175
+US6900198
+US6900240
+US6903095
+US6903107
+US6903203
+US6906051
+US6906107
+US6911435
+US6911465
+US6916603
+US6916793
+US6916826
+US6916907
+US6919327
+US6919363
+US6927228
+US6927229
+US6930102
+US6933386
+US6936634
+US6939541
+US6939891
+US6942870
+US6942966
+US6943181
+US6943188
+US6943192
+US6943246
+US6946118
+US6946149
+US6946462
+US6946471
+US6949259
+US6949510
+US6949656
+US6951876
+US6953568
+US6953591
+US6953595
+US6955806
+US6958145
+US6960474
+US6962918
+US6962941
+US6964956
+US6964966
+US6964973
+US6967197
+US6974824
+US6977252
+US6977257
+US6977259
+US6982096
+US6982275
+US6984641
+US6984643
+US6984648
+US6987105
+US6987113
+US6987117
+US6987126
+US6989378
+US6992094
+US6994842
+US6994862
+US6994869
+US6995184
+US6998395
+US7001991
+US7002018
+US7005432
+US7005508
+US7008626
+US7008954
+US7008956
+US7015325
+US7018661
+US7018997
+US7018999
+US7019029
+US7022667
+US7022733
+US7025988
+US7026356
+US7026359
+US7030099
+US7030147
+US7033583
+US7034114
+US7040314
+US7041314
+US7041652
+US7041654
+US7041660
+US7041664
+US7041835
+US7045522
+US7045526
+US7045546
+US7045633
+US7049293
+US7053058
+US7053095
+US7053099
+US7053176
+US7053215
+US7056528
+US7056898
+US7056911
+US7056946
+US7060698
+US7060809
+US7060824
+US7064185
+US7064203
+US7064218
+US7067148
+US7070971
+US7071178
+US7071195
+US7074815
+US7074921
+US7078054
+US7078380
+US7078521
+US7078523
+US7081464
+US7083799
+US7084117
+US7084157
+US7084270
+US7087596
+US7087758
+US7091182
+US7091242
+US7094421
+US7094899
+US7101711
+US7101868
+US7101995
+US7105576
+US7105644
+US7109181
+US7109245
+US7109330
+US7112562
+US7112577
+US7115578
+US7115617
+US7115651
+US7122643
+US7129232
+US7129349
+US7132412
+US7132425
+US7132451
+US7135286
+US7135494
+US7138396
+US7138417
+US7138425
+US7144912
+US7144997
+US7148207
+US7148232
+US7148240
+US7148249
+US7148252
+US7153885
+US7153968
+US7157472
+US7157491
+US7160903
+US7160909
+US7161009
+US7163949
+US7166286
+US7166622
+US7166726
+US7169813
+US7169940
+US7172870
+US7173061
+US7173134
+US7176180
+US7176193
+US7176221
+US7179817
+US7183095
+US7183430
+US7186544
+US7186755
+US7186803
+US7186864
+US7189404
+US7189718
+US7192602
+US7192942
+US7192945
+US7192978
+US7195769
+US7196073
+US7196077
+US7196081
+US7196099
+US7196104
+US7196111
+US7196179
+US7199148
+US7202237
+US7202242
+US7202263
+US7202280
+US7205319
+US7205326
+US7205405
+US7205435
+US7208491
+US7208505
+US7208520
+US7211598
+US7214668
+US7214700
+US7214794
+US7214805
+US7217697
+US7217707
+US7217844
+US7220739
+US7220755
+US7223774
+US7226917
+US7229978
+US7229991
+US7230131
+US7235560
+US7235658
+US7240785
+US7241757
+US7241923
+US7244414
+US7244726
+US7247626
+US7247633
+US7252845
+US7252974
+US7253162
+US7253169
+US7256184
+US7256188
+US7256189
+US7256205
+US7259148
+US7259157
+US7259175
+US7268125
+US7268129
+US7268130
+US7271153
+US7271160
+US7271162
+US7271174
+US7273928
+US7276513
+US7279175
+US7279466
+US7279489
+US7282599
+US7285546
+US7285547
+US7288528
+US7291638
+US7294629
+US7297789
+US7307087
+US7312203
+US7312317
+US7320803
+US7320987
+US7321000
+US7326718
+US7332185
+US7335645
+US7335647
+US7335777
+US7338959
+US7341712
+US7341723
+US7341741
+US7341749
+US7342025
+US7342125
+US7344868
+US7345063
+US7345065
+US7348336
+US7348340
+US7351710
+US7351722
+US7354910
+US7354919
+US7354945
+US7358086
+US7358235
+US7361664
+US7361665
+US7364751
+US7364847
+US7371372
+US7371406
+US7371407
+US7375229
+US7378388
+US7378410
+US7384934
+US7384950
+US7387790
+US7390500
+US7390668
+US7390801
+US7393526
+US7393545
+US7393825
+US7393849
+US7393859
+US7396660
+US7396836
+US7399464
+US7399481
+US7402602
+US7402604
+US7407971
+US7414042
+US7416887
+US7419824
+US7419968
+US7422764
+US7423067
+US7425319
+US7432292
+US7432344
+US7432389
+US7438903
+US7439397
+US7442386
+US7449457
+US7449583
+US7452373
+US7452534
+US7452556
+US7453006
+US7459528
+US7459544
+US7465445
+US7465553
+US7465718
+US7468359
+US7473431
+US7479506
+US7485315
+US7495004
+US7495009
+US7495110
+US7495127
+US7498340
+US7501399
+US7501405
+US7501431
+US7510830
+US7511010
+US7511027
+US7514244
+US7514432
+US7517892
+US7521450
+US7521453
+US7524850
+US7524973
+US7531540
+US7531557
+US7531604
+US7534782
+US7538127
+US7541363
+US7544358
+US7544367
+US7550442
+US7557140
+US7560448
+US7560484
+US7560586
+US7563458
+US7566721
+US7572774
+US7572787
+US7575740
+US7576097
+US7579439
+US7582644
+US7582676
+US7588753
+US7589077
+US7589113
+US7591949
+US7592316
+US7595325
+US7598228
+US7601703
+US7615635
+US7622450
+US7622476
+US7625872
+US7629384
+US7629471
+US7634362
+US7635469
+US7635691
+US7635692
+US7635702
+US7642276
+US7642903
+US7645782
+US7645788
+US7648695
+US7649005
+US7649017
+US7652021
+US7659257
+US7662826
+US7666619
+US7666897
+US7671071
+US7678805
+US7678834
+US7683034
+US7683061
+US7683164
+US7687483
+US7687501
+US7691828
+US7691870
+US7691871
+US7691900
+US7696208
+US7696332
+US7696354
+US7700080
+US7700088
+US7700629
+US7700657
+US7700765
+US7709480
+US7718670
+US7718673
+US7718701
+US7727999
+US7728025
+US7732144
+US7732484
+US7745448
+US7763641
+US7767677
+US7767682
+US7772392
+US7776332
+US7776868
+US7781429
+US7781446
+US7786131
+US7786177
+US7799763
+US7799773
+US7799811
+US7799955
+US7807355
+US7807655
+US7809428
+US7811573
+US7812054
+US7812169
+US7816333
+US7820697
+US7820717
+US7820818
+US7825104
+US7825158
+US7829694
+US7833977
+US7834008
+US7834029
+US7838032
+US7838043
+US7838505
+US7838528
+US7858641
+US7858782
+US7863265
+US7863321
+US7867509
+US7871635
+US7871765
+US7872017
+US7875290
+US7880020
+US7888336
+US7893297
+US7897613
+US7902185
+US7902241
+US7906659
+US7919470
+US7928128
+US7928146
+US7932281
+US7943173
+US7943627
+US7947706
+US7951795
+US7951812
+US7960383
+US7960416
+US7968523
+US7968607
+US7972624
+US7994144
+US7994156
+US7994217
+US7994219
+US7998492
+US8008324
+US8012494
+US8012991
+US8017587
+US8017596
+US8021861
+US8022174
+US8034812
+US8044040
+US8048866
+US8053473
+US8063054
+US8067472
+US8071074
+US8076319
+US8080565
+US8093216
+US8093293
+US8097611
+US8106214
+US8114866
+US8119644
+US8119658
+US8124640
+US8143240
+US8143486
+US8148355
+US8148431
+US8163718
+US8168179
+US8178348
+US8178543
+US8182996
+US8183213
+US8188100
+US8198300
+US8207142
+US8207145
+US8211666
+US8212029
+US8231910
+US8246930
+US8246982
+US8252307
+US8252838
+US8263142
+US8263346
+US8263609
+US8268790
+US8277839
+US8287898
+US8309355
+US8318709
+US8318910
+US8324241
+US8329214
+US8329690
+US8338475
+US8338641
+US8343761
+US8349853
+US8362008
+US8377981
+US8383164
+US8383178
+US8388971
+US8389484
+US8398990
+US8404675
+US8404703
+US8440668
+US8445493
+US8461139
+US8464706
+US8476254
+US8476285
+US8481075
+US8486902
+US8487003
+US8492375
+US8497271
+US8501764
+US8518460
+US8518995
+US8524212
+US8535715
+US8541429
+US8546396
+US8552000
+US8552054
+US8563581
+US8575147
+US8580850
+US8609656
+US8617539
+US8623410
+US8633198
+US8642618
+US8658170
+US8658636
+US8658693
+US8673347
+US8673898
+US8680098
+US8680100
+US8686021
+US8691799
+US8691820
+US8697880
+US8729037
+US8742119
+US8747883
+US8748476
+US8753674
+US8759327
+US8759328
+US8765747
+US8779163
+US8790702
+US8791257
+US8796248
+US8802623
+US8808754
+US8809348
+US8821920
+US8822480
+US8822518
+US8828358
+US8829013
+US8835450
+US8846315
+USRE39056
+USRE39061
+USRE39072
+USRE39112
+USRE39591
+USRE39680
+USRE39820
+USRE40851
+USRE40861
+USRE41439
+USRE43879
+USRE44733
+WO2002100330A9
+WO2003053360A3
+WO2003059294A3
+WO2003062392A3
+WO2003072732A3
+WO2003101437A3
+WO2004009590A8
+WO2004022039A3
+WO2004024095A3
+WO2004045490A3
+WO2004071400A3
+WO2004073601A3
+WO2004089333A3
+WO2004091597A3
+WO2004096195A3
+WO2004096197A3
+WO2004105756A3
+WO2004108061A3
+WO2004108682A3
+WO2005000355A1
+WO2005000846A1
+WO2005002587A1
+WO2005004923A1
+WO2005007099A2
+WO2005007153A1
+WO2005007165A1
+WO2005007240A1
+WO2005007646A1
+WO2005011698A1
+WO2005013884A2
+WO2005013946A3
+WO2005013947A3
+WO2005014599A1
+WO2005018528A3
+WO2005020882A2
+WO2005020913A3
+WO2005021012A1
+WO2005023232A2
+WO2005023273A1
+WO2005027661A1
+WO2005027922A1
+WO2005027927A1
+WO2005030198A1
+WO2005030233A1
+WO2005032530A1
+WO2005035534A1
+WO2005036989A1
+WO2005039638A2
+WO2005040045A3
+WO2005042472A3
+WO2005051993A1
+WO2005053679A1
+WO2005055999A1
+WO2005061485A1
+WO2005061549A1
+WO2005063736A1
+WO2005070902A1
+WO2005072720A1
+WO2005077358A1
+WO2005082169A1
+WO2005082459A2
+WO2005082854A1
+WO2005082904A1
+WO2005082924A1
+WO2005084463A1
+WO2005085294A1
+WO2005087224A1
+WO2005089800A1
+WO2005094813A1
+WO2005094854A1
+WO2005095369A1
+WO2005095414A1
+WO2005103054A3
+WO2005105118A1
+WO2005105125A1
+WO2005105998A1
+WO2005108398A1
+WO2005110002A3
+WO2005110451A1
+WO2005110989A1
+WO2005112965A2
+WO2005113002A1
+WO2005113483A2
+WO2005115344A1
+WO2005115377A1
+WO2005115388A1
+WO2005115402A1
+WO2005120435A2
+WO2005121143A1
+WO2005123062A1
+WO2005123651A1
+WO2006000589A8
+WO2006001035A3
+WO2006003013B1
+WO2006003290A2
+WO2006011669A1
+WO2006012504A3
+WO2006013445A3
+WO2006014787A2
+WO2006015590A3
+WO2006017921A1
+WO2006019855A1
+WO2006022543A1
+WO2006023515A3
+WO2006024668A1
+WO2006027987A1
+WO2006028523A3
+WO2006028875A1
+WO2006031556A3
+WO2006033341A1
+WO2006034632A8
+WO2006035291A1
+WO2006040052A1
+WO2006040643A2
+WO2006042249A3
+WO2006042481A1
+WO2006043966A3
+WO2006044503A3
+WO2006044524A1
+WO2006044961A1
+WO2006045865A1
+WO2006046738A1
+WO2006047522A8
+WO2006048248A3
+WO2006048330A1
+WO2006051818A1
+WO2006051937A1
+WO2006051987A1
+WO2006054757A1
+WO2006056877A2
+WO2006057578A3
+WO2006059121A3
+WO2006059507A1
+WO2006060712A3
+WO2006060762A3
+WO2006061712A2
+WO2006061992A1
+WO2006062094A1
+WO2006064228A3
+WO2006064686A1
+WO2006064761A1
+WO2006066846A1
+WO2006067362A1
+WO2006068665A1
+WO2006069740A1
+WO2006072957A1
+WO2006074872A1
+WO2006075226A1
+WO2006075395A1
+WO2006075642A1
+WO2006076317A2
+WO2006077367A1
+WO2006077419A1
+WO2006078056A8
+WO2006080043A3
+WO2006082821A1
+WO2006083005A1
+WO2006085521A1
+WO2006085687A1
+WO2006087229A1
+WO2006088944A1
+WO2006089286A2
+WO2006090613A1
+WO2006090782A1
+WO2006091009A1
+WO2006093217A1
+WO2006093784A2
+WO2006093801A1
+WO2006097323A1
+WO2006098074A1
+WO2006100181A2
+WO2006101818A1
+WO2006102958A1
+WO2006103544A3
+WO2006104141A1
+WO2006104154A1
+WO2006104971A1
+WO2006105063A1
+WO2006105222A3
+WO2006106416A1
+WO2006106914A1
+WO2006107019A1
+WO2006108700A1
+WO2006108709A1
+WO2006113034A1
+WO2006115273A1
+WO2006116630A2
+WO2006117165A3
+WO2006118079A1
+WO2006120696A2
+WO2006120705A2
+WO2006121263A1
+WO2006122661A1
+WO2006124447A2
+WO2006124544A3
+WO2006125048A3
+WO2006126939A8
+WO2006129524A1
+WO2006130588A1
+WO2006131303A3
+WO2006132914A3
+WO2006133104A3
+WO2006134112A1
+WO2006134150A1
+WO2006134279A2
+WO2006135621A2
+WO2006135932A3
+WO2006135973A1
+WO2006137421A1
+WO2006137423A1
+WO2006137469A1
+WO2006137514A1
+WO2006137772A1
+WO2006138428A3
+WO2007000465A1
+WO2007002174A3
+WO2007003594A1
+WO2007004239A1
+WO2007004244A1
+WO2007006549A3
+WO2007007686A1
+WO2007007894A1
+WO2007008119A1
+WO2007009539A2
+WO2007009635A1
+WO2007009690A1
+WO2007009758A3
+WO2007010853A1
+WO2007012254A1
+WO2007013494A1
+WO2007013661A1
+WO2007013694A1
+WO2007013841A1
+WO2007013896A3
+WO2007014970A1
+WO2007015175A2
+WO2007015510A1
+WO2007015528A1
+WO2007017114A1
+WO2007017264A3
+WO2007017678A1
+WO2007019880A1
+WO2007020653A1
+WO2007020917A1
+WO2007022964A3
+WO2007024673A1
+WO2007024814A1
+WO2007025900A1
+WO2007026897A1
+WO2007028030A3
+WO2007028638A1
+WO2007030438A3
+WO2007031338A1
+WO2007031726A1
+WO2007031828A3
+WO2007031833A3
+WO2007033137A1
+WO2007033269A1
+WO2007033400A1
+WO2007035123A1
+WO2007035489A2
+WO2007036363A8
+WO2007037513A1
+WO2007038045A1
+WO2007038785A1
+WO2007039111A2
+WO2007039171A1
+WO2007039563A1
+WO2007039773A1
+WO2007040238A1
+WO2007040436A1
+WO2007042669A2
+WO2007042815A1
+WO2007044085A3
+WO2007044796A3
+WO2007045979A1
+WO2007045989A1
+WO2007046426A1
+WO2007046524A1
+WO2007047626A1
+WO2007048228A1
+WO2007048802A1
+WO2007049642A1
+WO2007049828A1
+WO2007051333A1
+WO2007052295A3
+WO2007052849A1
+WO2007054451A1
+WO2007054573A2
+WO2007055378A1
+WO2007056870A1
+WO2007058338A3
+WO2007059918A1
+WO2007060182A1
+WO2007060484A1
+WO2007060491A3
+WO2007060525A3
+WO2007062678A1
+WO2007062999A3
+WO2007063391A3
+WO2007063839A1
+WO2007064543A1
+WO2007064762A3
+WO2007064914A2
+WO2007066103A1
+WO2007066355A1
+WO2007067416A3
+WO2007068112A1
+WO2007068776A1
+WO2007070504A3
+WO2007070872A1
+WO2007072156A1
+WO2007072169A2
+WO2007075838A2
+WO2007077158A1
+WO2007079199A3
+WO2007079391A3
+WO2007082434A1
+WO2007082666A1
+WO2007082922A2
+WO2007084391A3
+WO2007084857A3
+WO2007087151A2
+WO2007087215A3
+WO2007087395A3
+WO2007088900A1
+WO2007089193A1
+WO2007093600A1
+WO2007094404A1
+WO2007095147A2
+WO2007095561A3
+WO2007095607A1
+WO2007095688A1
+WO2007095784A1
+WO2007095812A1
+WO2007096471A1
+WO2007098828A1
+WO2007099402A3
+WO2007099921A1
+WO2007099981A1
+WO2007099999A1
+WO2007102608A1
+WO2007102703A1
+WO2007104867A3
+WO2007105744A1
+WO2007108434A1
+WO2007108712A1
+WO2007111275A1
+WO2007112914A3
+WO2007113290A1
+WO2007113647A1
+WO2007114124A1
+WO2007114683A1
+WO2007115071A1
+WO2007115261A2
+WO2007115935A1
+WO2007116230A1
+WO2007117398B1
+WO2007118793A1
+WO2007118859A1
+WO2007119116A3
+WO2007120445A1
+WO2007120599A2
+WO2007120768A1
+WO2007121389A3
+WO2007121921A3
+WO2007122401A1
+WO2007123868A2
+WO2007124433A1
+WO2007126126A1
+WO2007128109A1
+WO2007131253A2
+WO2007131424A1
+WO2007133796A3
+WO2007134086A3
+WO2007134819A1
+WO2007134966A1
+WO2007135122A1
+WO2007135134A1
+WO2007136302A2
+WO2007136325A1
+WO2007136696A2
+WO2007139496A1
+WO2007140982A1
+WO2007141764A1
+WO2007141898A1
+WO2007143483A2
+WO2007144084A3
+WO2007144204A1
+WO2007144379A1
+WO2007145365A1
+WO2007147646A1
+WO2007148308A3
+WO2007148711A1
+WO2007150063A2
+WO2008003378A1
+WO2008003855A2
+WO2008006226A1
+WO2008006257A1
+WO2008006589A3
+WO2008008895A1
+WO2008009935A1
+WO2008010472A1
+WO2008010527A1
+WO2008011016A3
+WO2008011392A3
+WO2008011478A2
+WO2008011483A3
+WO2008011980A1
+WO2008014338A3
+WO2008015423A1
+WO2008016665A2
+WO2008018892A2
+WO2008020306A3
+WO2008020489A1
+WO2008020622A1
+WO2008021728A3
+WO2008022771A1
+WO2008023278A8
+WO2008024027A3
+WO2008024304A3
+WO2008025228A1
+WO2008025947A1
+WO2008026729A1
+WO2008026965A1
+WO2008027988A2
+WO2008029294A3
+WO2008030536A2
+WO2008031928A1
+WO2008032041A1
+WO2008033798A3
+WO2008033858A3
+WO2008035757A1
+WO2008036239A2
+WO2008036954A1
+WO2008037716A3
+WO2008038303A2
+WO2008038304A3
+WO2008038394A1
+WO2008040816A1
+WO2008041031A1
+WO2008041236A2
+WO2008043180A1
+WO2008043811A1
+WO2008044729A1
+WO2008046202A1
+WO2008046497A1
+WO2008047853A1
+WO2008049105A3
+WO2008049194A1
+WO2008050200A1
+WO2008050899A1
+WO2008051942A2
+WO2008052072A9
+WO2008053199A1
+WO2008053863A1
+WO2008053909A1
+WO2008056189A1
+WO2008056634A1
+WO2008056657A1
+WO2008057496A3
+WO2008057938A1
+WO2008058897A2
+WO2008059239A1
+WO2008059800A1
+WO2008061399A1
+WO2008061720A3
+WO2008062324A3
+WO2008062424A2
+WO2008062463A2
+WO2008063045A1
+WO2008063772A3
+WO2008064004A2
+WO2008064093A3
+WO2008064337A3
+WO2008064475A1
+WO2008064558A1
+WO2008065123A2
+WO2008065527A3
+WO2008066402A1
+WO2008067527A1
+WO2008067781B1
+WO2008070795A3
+WO2008071665A1
+WO2008071869A3
+WO2008071948A3
+WO2008071964A1
+WO2008072061A1
+WO2008072952A2
+WO2008073961A9
+WO2008074756A1
+WO2008074849A1
+WO2008075466A1
+WO2008076043A1
+WO2008077103A1
+WO2008077130A2
+WO2008078729A1
+WO2008079030A8
+WO2008079257A3
+WO2008080056A3
+WO2008080223A1
+WO2008080369A1
+WO2008080455A1
+WO2008081834A1
+WO2008081901A1
+WO2008081934A1
+WO2008081937A1
+WO2008083107A3
+WO2008083354A1
+WO2008083356A1
+WO2008083442A1
+WO2008084261A1
+WO2008085008A1
+WO2008085921A2
+WO2008086854A1
+WO2008089105A3
+WO2008089201A3
+WO2008090081A1
+WO2008090749A1
+WO2008092465A1
+WO2008092785A1
+WO2008092816A3
+WO2008093075A2
+WO2008093495A1
+WO2008093848A1
+WO2008095366A1
+WO2008096002A1
+WO2008096155A1
+WO2008096769A1
+WO2008097897A9
+WO2008099075A1
+WO2008099804A1
+WO2008099874A1
+WO2008099912A1
+WO2008100560A2
+WO2008100562A3
+WO2008100809A1
+WO2008102128A2
+WO2008103431A2
+WO2008105441A1
+WO2008106731A1
+WO2008106781A1
+WO2008107543A3
+WO2008109286A1
+WO2008110196A1
+WO2008111669A1
+WO2008112241A1
+WO2008112647A3
+WO2008113006A1
+WO2008113134A1
+WO2008113851A3
+WO2008114505A1
+WO2008115118A1
+WO2008117046A1
+WO2008117389A1
+WO2008119042A3
+WO2008120708A1
+WO2008120766A1
+WO2008122100A1
+WO2008122654A2
+WO2008124210A1
+WO2008124323A1
+WO2008128627A3
+WO2008129971A1
+WO2008130261A1
+WO2008131103A2
+WO2008132211A1
+WO2008133157A1
+WO2008133192A1
+WO2008135524A3
+WO2008135743A1
+WO2008135791A8
+WO2008136374A1
+WO2008136378A1
+WO2008138874A1
+WO2008138920A1
+WO2008141239A1
+WO2008141368A1
+WO2008143490A1
+WO2008144602A1
+WO2008146691A1
+WO2008147167A1
+WO2008147697A1
+WO2008148302A1
+WO2008148799A1
+WO2008149138A1
+WO2008149311A1
+WO2008150260A1
+WO2008153426A1
+WO2008153511A1
+WO2008153632A3
+WO2008153767A2
+WO2008153958A2
+WO2008154898A3
+WO2008155132A1
+WO2008156349A3
+WO2009002652A3
+WO2009005613A2
+WO2009005674A3
+WO2009005813A1
+WO2009007441A3
+WO2009007680A3
+WO2009008120A1
+WO2009010416A3
+WO2009010871A2
+WO2009011561A1
+WO2009011787A1
+WO2009011910A3
+WO2009012534A1
+WO2009013348A3
+WO2009013390A1
+WO2009016081A3
+WO2009016084A1
+WO2009016269A1
+WO2009016855A1
+WO2009017664A1
+WO2009019260A3
+WO2009019505A3
+WO2009022104A1
+WO2009022179A2
+WO2009022756A1
+WO2009023179A3
+WO2009024677A3
+WO2009025315A1
+WO2009025326A1
+WO2009025791A3
+WO2009025876A3
+WO2009026326A1
+WO2009027473A1
+WO2009027838A3
+WO2009029618A1
+WO2009031575A1
+WO2009031627A1
+WO2009031709A1
+WO2009032244A1
+WO2009032326A1
+WO2009032972A1
+WO2009033281A1
+WO2009033284A1
+WO2009033505A1
+WO2009033689A1
+WO2009034061A1
+WO2009034433A3
+WO2009034475A3
+WO2009035265A2
+WO2009035473A3
+WO2009035534A3
+WO2009036000A2
+WO2009036754A1
+WO2009036852A1
+WO2009037357A4
+WO2009038057A1
+WO2009038064A1
+WO2009038204A1
+WO2009039362A2
+WO2009040075A1
+WO2009040445A3
+WO2009041566A1
+WO2009041567A1
+WO2009043593A1
+WO2009044153A2
+WO2009044788A1
+WO2009047481A1
+WO2009048603A1
+WO2009048760A3
+WO2009049208A1
+WO2009049362A1
+WO2009049460A1
+WO2009049492A1
+WO2009050199A1
+WO2009050318A1
+WO2009052050A1
+WO2009052072A1
+WO2009052624A9
+WO2009053715A8
+WO2009054423A1
+WO2009054970A1
+WO2009056754A9
+WO2009057795A3
+WO2009058801A1
+WO2009059047A3
+WO2009059452A1
+WO2009060073A1
+WO2009061336A1
+WO2009062082A3
+WO2009062193A2
+WO2009062619A1
+WO2009062662A1
+WO2009063170A1
+WO2009066138A2
+WO2009067081A1
+WO2009067317A2
+WO2009067607A2
+WO2009067703A3
+WO2009068520A2
+WO2009068531A3
+WO2009071990A3
+WO2009073203A1
+WO2009073916A1
+WO2009074835A1
+WO2009077485A3
+WO2009077585A1
+WO2009077990A1
+WO2009078366A1
+WO2009079860A1
+WO2009080432A3
+WO2009080555A3
+WO2009081197A1
+WO2009085584A1
+WO2009085637A1
+WO2009086130A1
+WO2009086705A1
+WO2009087354A2
+WO2009089107A1
+WO2009089534A3
+WO2009090024A1
+WO2009090556A2
+WO2009094845A1
+WO2009096503A1
+WO2009098209A1
+WO2009100107A2
+WO2009100456A2
+WO2009100994A1
+WO2009101199A3
+WO2009102814A2
+WO2009103053A1
+WO2009103953A1
+WO2009105218A3
+WO2009105680A2
+WO2009105936A1
+WO2009106748A3
+WO2009107098A3
+WO2009108118A9
+WO2009108384A2
+WO2009109862A3
+WO2009109986A1
+WO2009110495A1
+WO2009111830A1
+WO2009115547A8
+WO2009116055A1
+WO2009116074A3
+WO2009116509A1
+WO2009117378A3
+WO2009117540A1
+WO2009117710A2
+WO2009118655A2
+WO2009118712A3
+WO2009119858A1
+WO2009119982A2
+WO2009122034A2
+WO2009122148A1
+WO2009123210A1
+WO2009123877A1
+WO2009124252A2
+WO2009124311A1
+WO2009126530A3
+WO2009128395A1
+WO2009129361A2
+WO2009129525A2
+WO2009129532A1
+WO2009130242A1
+WO2009130270A1
+WO2009130326A1
+WO2009131947A2
+WO2009134147A1
+WO2009134637A1
+WO2009135135A3
+WO2009136001A1
+WO2009136176A1
+WO2009137074A1
+WO2009137334A2
+WO2009137660A9
+WO2009138186A3
+WO2009139880A1
+WO2009140078A1
+WO2009140928A1
+WO2009141090A8
+WO2009141571A1
+WO2009143064A2
+WO2009144555A8
+WO2009145299A1
+WO2009145721A1
+WO2009145839A1
+WO2009146131A2
+WO2009146310A1
+WO2009148004A1
+WO2009149135A1
+WO2009150137A3
+WO2009150144A1
+WO2009150257A3
+WO2009151094A1
+WO2009151098A1
+WO2009151626A1
+WO2009152087A1
+WO2009152584A1
+WO2009153592A1
+WO2009153791A1
+WO2009154766A1
+WO2009154828A3
+WO2009155475A1
+WO2009155611A9
+WO2009156864A3
+WO2009157880A1
+WO2009158248A2
+WO2010004139A1
+WO2010004433A3
+WO2010004982A1
+WO2010005851A1
+WO2010006129A3
+WO2010006299A1
+WO2010006697A3
+WO2010007248A2
+WO2010008847A3
+WO2010009155A2
+WO2010009775A1
+WO2010010127A1
+WO2010010136A1
+WO2010010797A1
+WO2010011538A1
+WO2010012620A1
+WO2010012811A3
+WO2010012812A1
+WO2010013187A1
+WO2010014889A3
+WO2010015590A1
+WO2010015849A3
+WO2010023390A1
+WO2010024356A1
+WO2010024783A1
+WO2010025073A1
+WO2010025448A3
+WO2010026110A3
+WO2010027094A1
+WO2010027114A1
+WO2010027266A1
+WO2010028130A2
+WO2010029925A1
+WO2010030012A1
+WO2010031801A3
+WO2010032266A9
+WO2010033444A1
+WO2010033958A1
+WO2010034648A1
+WO2010038153A1
+WO2010038803A1
+WO2010038842A1
+WO2010039529A3
+WO2010039997A2
+WO2010040750A1
+WO2010041681A1
+WO2010042212A3
+WO2010042477A1
+WO2010043029A1
+WO2010043550A1
+WO2010043787A1
+WO2010044403A1
+WO2010046388A1
+WO2010047126A1
+WO2010048593A1
+WO2010048731A1
+WO2010049073A1
+WO2010049731A1
+WO2010049841A1
+WO2010049921A1
+WO2010050783A2
+WO2010051683A1
+WO2010053085A1
+WO2010054307A1
+WO2010054758A1
+WO2010055304A3
+WO2010055473A1
+WO2010056633A3
+WO2010056672A2
+WO2010057197A1
+WO2010057804A1
+WO2010058417A1
+WO2010060742A1
+WO2010060968A1
+WO2010061921A1
+WO2010062205A4
+WO2010064252A3
+WO2010064951A1
+WO2010065134A1
+WO2010065801A1
+WO2010067102A1
+WO2010068183A1
+WO2010068815A3
+WO2010069561A1
+WO2010069979A1
+WO2010070076A1
+WO2010070238A1
+WO2010071872A2
+WO2010072166A1
+WO2010072712A1
+WO2010072807A3
+WO2010073104A3
+WO2010073126A3
+WO2010073642A1
+WO2010074088A1
+WO2010077310A2
+WO2010079255A1
+WO2010081387A1
+WO2010081778A1
+WO2010083414A8
+WO2010083444A1
+WO2010084186A1
+WO2010084458A1
+WO2010087521A1
+WO2010091124A2
+WO2010091543A1
+WO2010093787A3
+WO2010094483A1
+WO2010095425A1
+WO2010097373A1
+WO2010097467A1
+WO2010098396A1
+WO2010101302A1
+WO2010103279A1
+WO2010103306A1
+WO2010104571A2
+WO2010106145A1
+WO2010106871A1
+WO2010109434A3
+WO2010110748A1
+WO2010111719A2
+WO2010112091A1
+WO2010113800A1
+WO2010114181A1
+WO2010114471A1
+WO2010115252A1
+WO2010117194A2
+WO2010117727A3
+WO2010118250A3
+WO2010118286A3
+WO2010118298A3
+WO2010118309A3
+WO2010120253A1
+WO2010120875A3
+WO2010120987A1
+WO2010122344A1
+WO2010122456A1
+WO2010123006A1
+WO2010123008A1
+WO2010123018A1
+WO2010123102A1
+WO2010124089A3
+WO2010124601A1
+WO2010127856A1
+WO2010128309A1
+WO2010130178A1
+WO2010131025A1
+WO2010131475A1
+WO2010132440A3
+WO2010132599A1
+WO2010132743A1
+WO2010132959A1
+WO2010133793A1
+WO2010135506A1
+WO2010135714A2
+WO2010137979A8
+WO2010142124A1
+WO2010142985A1
+WO2010145066A1
+WO2010146078A2
+WO2010147068A1
+WO2010147144A1
+WO2010151096A1
+WO2011000811A4
+WO2011003626A1
+WO2011004882A1
+WO2011005295A8
+WO2011006079A3
+WO2011006144A1
+WO2011006536A1
+WO2011008054A2
+WO2011008112A1
+WO2011008947A2
+WO2011011706A2
+WO2011012622A1
+WO2011014008A3
+WO2011014766A2
+WO2011016050A3
+WO2011016395A1
+WO2011016558A1
+WO2011017299A3
+WO2011019124A1
+WO2011024428A1
+WO2011026125A2
+WO2011028794A2
+WO2011030859A1
+WO2011030873A1
+WO2011032169A3
+WO2011033305A1
+WO2011033715A1
+WO2011036303A1
+WO2011036461A1
+WO2011039221A2
+WO2011040613A1
+WO2011042497A1
+WO2011042918A3
+WO2011045934A1
+WO2011046057A1
+WO2011046382A3
+WO2011047636A1
+WO2011049042A1
+WO2011049122A1
+WO2011049213A1
+WO2011050394A1
+WO2011054315A1
+WO2011054820A1
+WO2011055247A1
+WO2011056545A3
+WO2011056549A1
+WO2011057331A1
+WO2011058773A1
+WO2011059121A1
+WO2011059388A1
+WO2011060962A1
+WO2011061303A1
+WO2011063595A1
+WO2011065905A1
+WO2011066006A2
+WO2011067189A3
+WO2011067663A1
+WO2011069335A1
+WO2011069951A1
+WO2011070039A1
+WO2011071057A1
+WO2011071194A1
+WO2011071684A1
+WO2011073160A1
+WO2011073929A1
+WO2011074658A1
+WO2011074695A1
+WO2011074881A2
+WO2011074992A1
+WO2011076363A1
+WO2011076744A1
+WO2011078143A1
+WO2011079767A1
+WO2011081971A2
+WO2011082487A1
+WO2011083853A1
+WO2011084459A1
+WO2011084653A1
+WO2011085155A3
+WO2011085454A1
+WO2011085979A1
+WO2011086507A8
+WO2011086541A1
+WO2011086577A3
+WO2011089168A2
+WO2011089401A1
+WO2011089457A1
+WO2011092293A3
+WO2011093294A1
+WO2011093600A3
+WO2011093664A3
+WO2011094208A2
+WO2011095535A3
+WO2011095579A1
+WO2011098451A1
+WO2011099031A1
+WO2011099764A2
+WO2011101069A3
+WO2011101860A1
+WO2011102407A1
+WO2011102460A1
+WO2011103289A3
+WO2011103345A2
+WO2011106839A1
+WO2011108499A1
+WO2011108690A1
+WO2011109012A1
+WO2011109384A3
+WO2011109767A3
+WO2011111384A1
+WO2011111715A1
+WO2011115819A3
+WO2011119125A1
+WO2011119777A2
+WO2011120886A1
+WO2011121068A1
+WO2011121607A2
+WO2011124093A1
+WO2011126071A1
+WO2011126099A1
+WO2011126385A3
+WO2011128445A1
+WO2011130476A2
+WO2011133687A2
+WO2011135520A1
+WO2011135743A1
+WO2011137155A1
+WO2011138657A1
+WO2011139348A9
+WO2011141004A1
+WO2011143106A1
+WO2011143201A2
+WO2011143721A1
+WO2011144439A1
+WO2011144785A1
+WO2011145909A3
+WO2011146850A1
+WO2011146876A2
+WO2011147199A1
+WO2011148657A1
+WO2011149529A3
+WO2011150288A1
+WO2011150347A2
+WO2011151731A3
+WO2011153192A3
+WO2011154630A1
+WO2011158931A1
+WO2011159634A1
+WO2011160259A1
+WO2011163321A2
+WO2012000519A1
+WO2012003544A1
+WO2012004410A1
+WO2012007493A1
+WO2012007555A3
+WO2012007627A1
+WO2012007632A9
+WO2012008565A1
+WO2012008711A2
+WO2012008908A1
+WO2012009646A1
+WO2012012257A2
+WO2012012305A2
+WO2012013366A3
+WO2012013821A1
+WO2012013967A3
+WO2012014012A1
+WO2012014963A1
+WO2012015677A1
+WO2012016707A2
+WO2012017367A1
+WO2012018145A2
+WO2012018759A3
+WO2012019315A1
+WO2012019430A8
+WO2012020021A9
+WO2012020787A1
+WO2012022776A1
+WO2012023284A1
+WO2012023285A1
+WO2012024282A2
+WO2012025942A1
+WO2012026468A1
+WO2012028340A1
+WO2012029771A1
+WO2012030165A2
+WO2012030894A1
+WO2012030990A1
+WO2012031603A3
+WO2012031941A2
+WO2012035364A1
+WO2012035685A1
+WO2012038785A1
+WO2012040230A1
+WO2012040938A1
+WO2012043481A1
+WO2012045010A1
+WO2012045124A1
+WO2012045195A1
+WO2012047587A2
+WO2012047800A1
+WO2012049555A1
+WO2012050370A3
+WO2012051107A3
+WO2012051296A2
+WO2012051492A3
+WO2012051988A3
+WO2012052169A2
+WO2012052459A1
+WO2012052668A1
+WO2012053003A1
+WO2012054724A1
+WO2012054862A2
+WO2012055884A1
+WO2012059515A1
+WO2012061931A1
+WO2012062210A1
+WO2012066518A1
+WO2012068412A2
+WO2012069432A1
+WO2012071221A2
+WO2012072200A1
+WO2012075849A1
+WO2012076321A1
+WO2012076680A1
+WO2012076916A1
+WO2012077775A1
+WO2012078859A3
+WO2012082997A1
+WO2012085176A1
+WO2012085189A1
+WO2012085481A1
+WO2012087881A1
+WO2012090124A3
+WO2012090204A8
+WO2012090221A1
+WO2012090322A1
+WO2012091010A1
+WO2012092160A3
+WO2012093227A1
+WO2012093383A1
+WO2012094831A1
+WO2012095461A1
+WO2012097052A3
+WO2012098387A1
+WO2012098562A3
+WO2012099452A1
+WO2012101065A3
+WO2012101239A1
+WO2012101440A1
+WO2012102562A3
+WO2012103570A1
+WO2012103806A1
+WO2012104571A1
+WO2012105563A1
+WO2012105708A1
+WO2012105873A1
+WO2012108297A1
+WO2012109976A1
+WO2012110860A1
+WO2012111995A1
+WO2012114285A9
+WO2012115182A1
+WO2012115306A1
+WO2012116577A1
+WO2012117062A1
+WO2012119151A2
+WO2012121178A1
+WO2012122451A3
+WO2012124311A8
+WO2012124738A1
+WO2012127431A1
+WO2012129220A1
+WO2012129473A1
+WO2012130448A1
+WO2012130621A1
+WO2012135064A2
+WO2012135588A3
+WO2012136111A1
+WO2012138988A3
+WO2012139628A1
+WO2012141553A2
+WO2012142029A2
+WO2012142698A1
+WO2012143116A1
+WO2012145678A1
+WO2012145737A1
+WO2012145743A1
+WO2012146194A1
+WO2012146644A1
+WO2012147705A1
+WO2012149667A1
+WO2012150245A1
+WO2012150520A1
+WO2012151058A1
+WO2012151704A1
+WO2012152295A1
+WO2012153302A1
+WO2012154076A1
+WO2012154779A1
+WO2012154956A2
+WO2012155007A1
+WO2012155834A1
+WO2012157239A1
+WO2012158123A1
+WO2012158271A1
+WO2012158517A1
+WO2012158880A3
+WO2012159593A2
+WO2012160392A1
+WO2012161655A1
+WO2012162584A1
+WO2012165914A3
+WO2012168265A1
+WO2012168462A1
+WO2012169571A1
+WO2012169661A1
+WO2012170839A3
+WO2012171125A1
+WO2012171900A1
+WO2012172562A2
+WO2012173217A1
+WO2012174253A1
+WO2012175747A1
+WO2012176842A1
+WO2012177212A1
+WO2012177746A1
+WO2013000855A1
+WO2013000974A1
+WO2013002420A1
+WO2013002428A1
+WO2013003114A8
+WO2013004032A1
+WO2013004332A1
+WO2013004999A1
+WO2013006738A1
+WO2013007765A1
+WO2013008175A1
+WO2013008594A1
+WO2013010018A3
+WO2013010218A1
+WO2013013003A1
+WO2013013826A1
+WO2013016501A1
+WO2013016531A2
+WO2013017071A1
+WO2013018018A1
+WO2013018706A1
+WO2013023982A1
+WO2013024028A1
+WO2013024895A1
+WO2013026118A1
+WO2013028880A1
+WO2013032028A1
+WO2013033061A1
+WO2013033283A1
+WO2013035047A1
+WO2013035423A1
+WO2013036912A3
+WO2013038666A1
+WO2013039202A1
+WO2013040027A1
+WO2013040337A1
+WO2013040863A1
+WO2013040873A1
+WO2013041457A1
+WO2013041859A1
+WO2013042065A4
+WO2013042124A8
+WO2013044596A1
+WO2013045028A1
+WO2013046161A1
+WO2013048787A1
+WO2013050637A1
+WO2013051928A1
+WO2013052010A1
+WO2013053372A1
+WO2013055833A1
+WO2013056046A1
+WO2013056067A1
+WO2013056326A1
+WO2013058751A1
+WO2013059437A1
+WO2013059772A1
+WO2013060304A1
+WO2013060908A1
+WO2013061005A1
+WO2013062402A1
+WO2013062445A1
+WO2013063458A3
+WO2013066181A1
+WO2013066640A1
+WO2013067306A1
+WO2013068966A2
+WO2013070030A1
+WO2013070586A1
+WO2013071203A1
+WO2013075785A1
+WO2013077186A1
+WO2013077433A1
+WO2013077446A1
+WO2013077617A1
+WO2013078123A1
+WO2013078554A1
+WO2013078658A1
+WO2013079211A1
+WO2013079696A1
+WO2013081087A1
+WO2013082541A1
+WO2013082624A3
+WO2013083058A1
+WO2013083552A1
+WO2013083910A3
+WO2013087004A1
+WO2013087083A1
+WO2013087920A1
+WO2013088373A1
+WO2013089986A1
+WO2013093790A1
+WO2013093849A1
+WO2013094489A1
+WO2013095315A1
+WO2013095321A1
+WO2013096689A1
+WO2013097074A8
+WO2013097947A1
+WO2013098320A1
+WO2013098570A1
+WO2013100585A3
+WO2013101983A3
+WO2013102207A1
+WO2013104830A1
+WO2013105092A1
+WO2013106410A3
+WO2013106494A1
+WO2013106824A1
+WO2013106934A1
+WO2013107278A1
+WO2013107413A1
+WO2013108921A1
+WO2013110135A1
+WO2013110198A1
+WO2013110643A1
+WO2013111801A1
+WO2013112878A1
+WO2013114400A3
+WO2013116325A1
+WO2013116562A1
+WO2013121209A1
+WO2013123019A1
+WO2013123996A1
+WO2013124026A8
+WO2013124701A3
+WO2013126550A3
+WO2013126595A1
+WO2013127266A1
+WO2013127828A1
+WO2013128000A1
+WO2013128423A1
+WO2013129879A1
+WO2013132208A1
+WO2013133367A1
+WO2013133450A1
+WO2013134252A1
+WO2013135176A1
+WO2013137009A1
+WO2013138306A1
+WO2013138600A1
+WO2013138612A1
+WO2013138654A1
+WO2013142202A1
+WO2013143466A1
+WO2013146539A1
+WO2013146797A1
+WO2013147117A1
+WO2013148333A1
+WO2013149190A1
+WO2013149987A1
+WO2013150406A3
+WO2013150534A1
+WO2013151699A1
+WO2013152227A1
+WO2013152269A1
+WO2013152298A1
+WO2013154712A1
+WO2013154794A1
+WO2013157021A1
+WO2013157967A1
+WO2013158628A1
+WO2013158874A1
+WO2013158952A1
+WO2013159224A1
+WO2013159412A1
+WO2013160396A1
+WO2013162363A1
+WO2013164337A9
+WO2013164671A1
+WO2013166952A1
+WO2013168011A1
+WO2013168014A1
+WO2013169397A1
+WO2013169577A1
+WO2013171166A1
+WO2013171316A1
+WO2013171473A1
+WO2013172344A1
+WO2013172346A1
+WO2013172714A1
+WO2013173608A1
+WO2013174947A1
+WO2013175215A1
+WO2013175376A3
+WO2013176054A1
+WO2013176503A1
+WO2013179309A1
+WO2013180229A1
+WO2013180271A1
+WO2013181742A1
+WO2013182851A1
+WO2013184732A1
+WO2013185112A8
+WO2013185353A1
+WO2013186138A1
+WO2013186726A3
+WO2013187075A1
+WO2013187088A1
+WO2013187646A1
+WO2013187665A1
+WO2013187755A1
+WO2013187795A1
+WO2013189841A1
+WO2013189910A1
+WO2013190111A1
+WO2013191242A1
+WO2013191984A1
+WO2013192274A3
+WO2013192589A1
+WO2014001356A1
+WO2014002053A1
+WO2014002104A1
+WO2014003808A1
+WO2014005186A1
+WO2014005363A1
+WO2014005720A1
+WO2014006110A1
+WO2014008610A1
+WO2014010528A1
+WO2014011077A3
+WO2014012063A1
+WO2014012360A1
+WO2014013535A1
+WO2014015754A1
+WO2014016381A1
+WO2014016394A1
+WO2014017569A1
+WO2014017659A1
+WO2014017689A1
+WO2014017803A1
+WO2014019268A1
+WO2014019442A1
+WO2014021404A1
+WO2014022636A1
+WO2014022923A1
+WO2014023815A1
+WO2014024056A1
+WO2014025128A1
+WO2014025852A1
+WO2014026329A1
+WO2014026341A1
+WO2014028479A1
+WO2014028585A1
+WO2014029333A1
+WO2014029360A1
+WO2014029726A1
+WO2014029732A1
+WO2014030731A1
+WO2014031465A1
+WO2014032398A1
+WO2014032481A1
+WO2014034798A1
+WO2014035355A1
+WO2014035961A1
+WO2014036595A1
+WO2014037563A1
+WO2014037834A3
+WO2014039960A1
+WO2014041518A1
+WO2014041559A3
+WO2014043163A1
+WO2014043252A3
+WO2014043380A1
+WO2014043618A1
+WO2014044790A1
+WO2014046224A1
+WO2014046472A1
+WO2014047148A1
+WO2014047662A3
+WO2014047780A1
+WO2014048380A1
+WO2014048945A1
+WO2014049044A1
+WO2014053014A1
+WO2014053516A1
+WO2014054421A1
+WO2014054798A1
+WO2014055972A3
+WO2014055977A3
+WO2014056620A1
+WO2014056723A1
+WO2014056897A1
+WO2014057180A1
+WO2014058035A1
+WO2014058079A1
+WO2014058427A1
+WO2014059350A1
+WO2014059383A1
+WO2014059484A1
+WO2014059902A1
+WO2014060138A1
+WO2014060366A1
+WO2014060411A1
+WO2014060464A1
+WO2014061827A1
+WO2014062083A1
+WO2014062658A8
+WO2014063189A1
+WO2014063205A1
+WO2014063441A1
+WO2014063923A1
+WO2014064134A1
+WO2014065275A1
+WO2014065710A1
+WO2014067960A2
+WO2014069426A1
+WO2014071371A1
+WO2014071480A1
+WO2014071863A1
+WO2014072498A1
+WO2014072967A1
+WO2014074584A1
+WO2014074591A1
+WO2014074628A1
+WO2014074795A1
+WO2014074848A1
+WO2014074926A1
+WO2014075309A1
+WO2014075618A1
+WO2014076104A1
+WO2014077358A1
+WO2014077668A1
+WO2014078328A1
+WO2014078578A1
+WO2014078581A1
+WO2014081675A1
+WO2014082230A1
+WO2014082592A1
+WO2014082739A1
+WO2014083071A1
+WO2014084669A1
+WO2014087317A1
+WO2014087778A1
+WO2014088315A1
+WO2014089526A1
+WO2014090168A1
+WO2014090169A1
+WO2014090396A2
+WO2014090875A1
+WO2014091443A1
+WO2014091876A1
+WO2014092006A1
+WO2014092007A1
+WO2014092166A1
+WO2014093074A1
+WO2014093313A1
+WO2014093711A1
+WO2014093773A1
+WO2014094355A1
+WO2014096498A1
+WO2014098512A1
+WO2014099836A1
+WO2014099941A1
+WO2014100022A1
+WO2014100762A1
+WO2014102315A1
+WO2014102417A1
+WO2014102817A1
+WO2014103704A1
+WO2014104272A1
+WO2014104372A1
+WO2014106612A1
+WO2014106763A1
+WO2014107771A1
+WO2014108520A1
+WO2014110259A1
+WO2014110574A1
+WO2014111069A1
+WO2014111584A1
+WO2014111720A1
+WO2014114627A1
+WO2014116973A1
+WO2014118186A1
+WO2014118195A1
+WO2014118226A1
+WO2014118740A1
+WO2014120774A1
+WO2014120885A1
+WO2014122024A1
+WO2014124234A1
+WO2014125277A1
+WO2014127066A1
+WO2014127459A1
+WO2014128465A1
+WO2014128588A1
+WO2014128611A1
+WO2014130638A1
+WO2014130922A1
+WO2014132213A1
+WO2014132215A1
+WO2014134201A1
+WO2014134341A1
+WO2014134380A1
+WO2014135561A1
+WO2014135776A1
+WO2014136116A1
+WO2014137090A1
+WO2014137877A1
+WO2014138085A1
+WO2014138391A1
+WO2014138823A1
+WO2014139150A1
+WO2014139388A1
+WO2014139981A1
+WO2014140065A1
+WO2014140203A1
+WO2014140313A1
+WO2014140797A1
+WO2014142276A1
+WO2014143943A1
+WO2014145118A1
+WO2014146491A1
+WO2014146604A1
+WO2014147610A1
+WO2014148951A1
+WO2014152514A1
+WO2014152843A1
+WO2014154760A1
+WO2014154762A1
+WO2014155056A1
+WO2014157635A1
+WO2014157727A1
+WO2014159937A1
+WO2014162106A1
+WO2014164756A1
+WO2014165057A1
+WO2014165482A1
+WO2014165736A2
+WO2014165786A1
diff --git a/huner/ner_scripts/splits/hprd50.dev b/huner/ner_scripts/splits/hprd50.dev
new file mode 100644
index 0000000..ded25c9
--- /dev/null
+++ b/huner/ner_scripts/splits/hprd50.dev
@@ -0,0 +1,6 @@
+
+HPRD50_d17
+HPRD50_d22
+HPRD50_d25
+HPRD50_d3
+HPRD50_d4
diff --git a/huner/ner_scripts/splits/hprd50.test b/huner/ner_scripts/splits/hprd50.test
new file mode 100644
index 0000000..affb61e
--- /dev/null
+++ b/huner/ner_scripts/splits/hprd50.test
@@ -0,0 +1,13 @@
+
+HPRD50_d10
+HPRD50_d11
+HPRD50_d16
+HPRD50_d18
+HPRD50_d19
+HPRD50_d2
+HPRD50_d23
+HPRD50_d24
+HPRD50_d32
+HPRD50_d35
+HPRD50_d40
+HPRD50_d5
diff --git a/huner/ner_scripts/splits/hprd50.train b/huner/ner_scripts/splits/hprd50.train
new file mode 100644
index 0000000..e078d3e
--- /dev/null
+++ b/huner/ner_scripts/splits/hprd50.train
@@ -0,0 +1,27 @@
+
+HPRD50_d0
+HPRD50_d1
+HPRD50_d12
+HPRD50_d13
+HPRD50_d14
+HPRD50_d15
+HPRD50_d20
+HPRD50_d21
+HPRD50_d26
+HPRD50_d27
+HPRD50_d28
+HPRD50_d29
+HPRD50_d30
+HPRD50_d31
+HPRD50_d33
+HPRD50_d34
+HPRD50_d36
+HPRD50_d37
+HPRD50_d38
+HPRD50_d39
+HPRD50_d41
+HPRD50_d42
+HPRD50_d6
+HPRD50_d7
+HPRD50_d8
+HPRD50_d9
diff --git a/huner/ner_scripts/splits/iepa.dev b/huner/ner_scripts/splits/iepa.dev
new file mode 100644
index 0000000..5f72bf4
--- /dev/null
+++ b/huner/ner_scripts/splits/iepa.dev
@@ -0,0 +1,21 @@
+
+IEPA_d0
+IEPA_d110
+IEPA_d117
+IEPA_d12
+IEPA_d122
+IEPA_d125
+IEPA_d15
+IEPA_d150
+IEPA_d157
+IEPA_d159
+IEPA_d181
+IEPA_d186
+IEPA_d188
+IEPA_d29
+IEPA_d55
+IEPA_d60
+IEPA_d67
+IEPA_d69
+IEPA_d7
+IEPA_d84
diff --git a/huner/ner_scripts/splits/iepa.test b/huner/ner_scripts/splits/iepa.test
new file mode 100644
index 0000000..8c210e7
--- /dev/null
+++ b/huner/ner_scripts/splits/iepa.test
@@ -0,0 +1,61 @@
+
+IEPA_d1
+IEPA_d101
+IEPA_d106
+IEPA_d108
+IEPA_d111
+IEPA_d116
+IEPA_d118
+IEPA_d119
+IEPA_d123
+IEPA_d124
+IEPA_d13
+IEPA_d133
+IEPA_d134
+IEPA_d14
+IEPA_d141
+IEPA_d146
+IEPA_d148
+IEPA_d151
+IEPA_d156
+IEPA_d158
+IEPA_d162
+IEPA_d163
+IEPA_d164
+IEPA_d165
+IEPA_d173
+IEPA_d174
+IEPA_d180
+IEPA_d187
+IEPA_d189
+IEPA_d190
+IEPA_d196
+IEPA_d197
+IEPA_d199
+IEPA_d20
+IEPA_d21
+IEPA_d26
+IEPA_d27
+IEPA_d28
+IEPA_d31
+IEPA_d36
+IEPA_d38
+IEPA_d43
+IEPA_d44
+IEPA_d52
+IEPA_d53
+IEPA_d54
+IEPA_d6
+IEPA_d61
+IEPA_d66
+IEPA_d68
+IEPA_d71
+IEPA_d76
+IEPA_d78
+IEPA_d8
+IEPA_d82
+IEPA_d83
+IEPA_d85
+IEPA_d9
+IEPA_d92
+IEPA_d95
diff --git a/huner/ner_scripts/splits/iepa.train b/huner/ner_scripts/splits/iepa.train
new file mode 100644
index 0000000..76ac6fb
--- /dev/null
+++ b/huner/ner_scripts/splits/iepa.train
@@ -0,0 +1,121 @@
+
+IEPA_d10
+IEPA_d100
+IEPA_d102
+IEPA_d103
+IEPA_d104
+IEPA_d105
+IEPA_d107
+IEPA_d109
+IEPA_d11
+IEPA_d112
+IEPA_d113
+IEPA_d114
+IEPA_d115
+IEPA_d120
+IEPA_d121
+IEPA_d126
+IEPA_d127
+IEPA_d128
+IEPA_d129
+IEPA_d130
+IEPA_d131
+IEPA_d132
+IEPA_d135
+IEPA_d136
+IEPA_d137
+IEPA_d138
+IEPA_d139
+IEPA_d140
+IEPA_d142
+IEPA_d143
+IEPA_d144
+IEPA_d145
+IEPA_d147
+IEPA_d149
+IEPA_d152
+IEPA_d153
+IEPA_d154
+IEPA_d155
+IEPA_d16
+IEPA_d160
+IEPA_d161
+IEPA_d166
+IEPA_d167
+IEPA_d168
+IEPA_d169
+IEPA_d17
+IEPA_d170
+IEPA_d171
+IEPA_d172
+IEPA_d175
+IEPA_d176
+IEPA_d177
+IEPA_d178
+IEPA_d179
+IEPA_d18
+IEPA_d182
+IEPA_d183
+IEPA_d184
+IEPA_d185
+IEPA_d19
+IEPA_d191
+IEPA_d192
+IEPA_d193
+IEPA_d194
+IEPA_d195
+IEPA_d198
+IEPA_d2
+IEPA_d22
+IEPA_d23
+IEPA_d24
+IEPA_d25
+IEPA_d3
+IEPA_d30
+IEPA_d32
+IEPA_d33
+IEPA_d34
+IEPA_d35
+IEPA_d37
+IEPA_d39
+IEPA_d4
+IEPA_d40
+IEPA_d41
+IEPA_d42
+IEPA_d45
+IEPA_d46
+IEPA_d47
+IEPA_d48
+IEPA_d49
+IEPA_d5
+IEPA_d50
+IEPA_d51
+IEPA_d56
+IEPA_d57
+IEPA_d58
+IEPA_d59
+IEPA_d62
+IEPA_d63
+IEPA_d64
+IEPA_d65
+IEPA_d70
+IEPA_d72
+IEPA_d73
+IEPA_d74
+IEPA_d75
+IEPA_d77
+IEPA_d79
+IEPA_d80
+IEPA_d81
+IEPA_d86
+IEPA_d87
+IEPA_d88
+IEPA_d89
+IEPA_d90
+IEPA_d91
+IEPA_d93
+IEPA_d94
+IEPA_d96
+IEPA_d97
+IEPA_d98
+IEPA_d99
diff --git a/huner/ner_scripts/splits/jnlpba.conll.dev b/huner/ner_scripts/splits/jnlpba.conll.dev
new file mode 100644
index 0000000..9cc8a19
--- /dev/null
+++ b/huner/ner_scripts/splits/jnlpba.conll.dev
@@ -0,0 +1,199 @@
+94179250
+97028169
+97207294
+97269040
+94285936
+97457067
+99279130
+99423690
+95286632
+95301128
+92260664
+98328397
+98087405
+99075977
+91110562
+94249033
+97475199
+98352765
+95367586
+99192743
+96355439
+96195546
+95397944
+97184561
+93228833
+98298224
+95378799
+95362854
+95074854
+98311520
+97226001
+95373165
+91065749
+99101524
+92207144
+96190579
+96144699
+99295929
+97296513
+97188782
+98361309
+93184333
+97152553
+93206138
+98031856
+99006628
+98438501
+95115141
+93079901
+90381807
+95081342
+93303626
+97230366
+96221559
+96029750
+92187059
+99362923
+94216261
+99242637
+99240799
+99329182
+94289707
+97276244
+98018226
+95279435
+95123097
+99286808
+94338593
+97158624
+96421639
+96355009
+96239534
+90376447
+91296379
+95370702
+94119067
+99286016
+91098050
+96063646
+97148606
+99300859
+99307406
+97021709
+97255754
+97383366
+98153997
+97259535
+95365357
+97047764
+99287876
+96001293
+94216500
+98029486
+94025289
+99225548
+90171176
+94118533
+96264685
+98422270
+95145550
+94172207
+91118160
+95072469
+99225553
+91236696
+96198880
+93172387
+99069282
+97407957
+97211823
+96146497
+98343775
+92318928
+96152682
+97378061
+96247643
+92029620
+97113313
+98077369
+97456516
+90244434
+97252236
+94335073
+92135145
+92006162
+99192438
+99244281
+93280143
+98380997
+98038798
+91282927
+96144322
+92165059
+93126354
+97216066
+99005376
+99209754
+98208264
+95280909
+95003681
+98295832
+96180219
+99272418
+95347767
+95365382
+93194904
+98343423
+99192761
+97334241
+95247773
+95161757
+97353026
+94347465
+91349414
+97287044
+98104482
+98104477
+92314696
+94224239
+99120322
+94344126
+96062284
+96278851
+97276784
+99323953
+99170294
+92371447
+90199680
+93145322
+99380601
+99412310
+96268712
+99169183
+94209654
+90285430
+99010726
+95186362
+93228445
+95162017
+97197832
+93194832
+98400938
+97358652
+93260875
+99282941
+96353908
+99149869
+96074843
+97377031
+96303658
+97064186
+95234639
+92215726
+97445683
+94110361
+98309442
+96239524
+99244901
+96096457
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/jnlpba.conll.test b/huner/ner_scripts/splits/jnlpba.conll.test
new file mode 100644
index 0000000..dd755b7
--- /dev/null
+++ b/huner/ner_scripts/splits/jnlpba.conll.test
@@ -0,0 +1,601 @@
+98074940
+99177408
+99197861
+91215472
+90151654
+96373868
+99221887
+96281903
+96210575
+96186742
+99172186
+98282210
+95053891
+95201644
+99155321
+99218532
+92107919
+95138118
+92031293
+99372175
+92052214
+97379437
+97148782
+99344098
+99398660
+96202514
+96387353
+99060915
+91208110
+99252084
+99256996
+94367369
+95197545
+95363073
+99187612
+95221342
+96017239
+95355137
+98322148
+99138796
+96278973
+97115684
+95266275
+99077509
+94243031
+97461470
+96071057
+95236292
+99316282
+98144699
+99223566
+98451426
+95127210
+99244237
+90244394
+99228859
+96374456
+95163578
+99003230
+92213636
+96062305
+96017769
+90140708
+97080592
+98090689
+97289761
+91248763
+95088506
+92193472
+97472344
+99065678
+99103960
+99278386
+97307606
+96201643
+90161003
+98427848
+96320604
+99190497
+95382761
+90158614
+99111421
+97326105
+98438422
+99211588
+95279882
+97184469
+97230346
+96329578
+98012230
+91172250
+97248576
+97067175
+99192765
+91354520
+99156941
+97087515
+99035056
+93264305
+97442480
+98395152
+96140672
+95403468
+95338146
+93087498
+97131617
+93276575
+97449161
+97289591
+99252081
+97228922
+99125803
+98332778
+96226013
+92235212
+95007565
+95012031
+95263289
+97385069
+96413274
+98390872
+95104037
+99148535
+99355592
+99168501
+98395073
+95127261
+92335296
+91017623
+93112057
+96413305
+97233191
+99091640
+98282482
+94240241
+99336784
+98104456
+93224733
+90381353
+97184478
+93266597
+93121695
+97445128
+97332608
+97240797
+96025852
+92144438
+96140436
+95256242
+99182374
+91218850
+98038598
+98043822
+95263486
+99006780
+94026053
+92244343
+97400349
+95403454
+96026328
+99065132
+98051057
+97292307
+97309442
+97031819
+96404971
+98168883
+99092484
+99077977
+92142646
+97150708
+97047122
+98389282
+97456880
+97058563
+99286827
+90382324
+97074532
+99218522
+96369636
+99289427
+90124644
+99126191
+92212930
+99310960
+99335895
+92156261
+96440214
+96322738
+98158921
+91303691
+92362919
+98045094
+99107757
+96144358
+99388640
+91217625
+99003459
+95011022
+98025882
+91172768
+93194883
+98384373
+98062932
+97282709
+94265262
+91016834
+96017245
+98022722
+98295583
+99206664
+96323085
+99315748
+98062995
+99188724
+99083144
+95015835
+95194613
+92291523
+99054659
+97119289
+97186415
+99119105
+90254291
+97222140
+91367666
+97476217
+97261053
+91203899
+97276819
+97384936
+96079922
+96146856
+94338582
+93287269
+97175274
+93281652
+94266606
+98001686
+96295969
+99369970
+97177471
+91092268
+95392577
+93113611
+95014473
+91100449
+91079526
+94375000
+93152894
+98001378
+94289333
+93066282
+92113075
+95047083
+91045897
+98022968
+96141062
+97205502
+97047769
+96007705
+97376853
+90244395
+99138825
+97083501
+99099017
+99161827
+98104455
+99310626
+97274642
+97281244
+99340272
+94184956
+90346297
+95163587
+99201818
+98011518
+99303765
+97303223
+97335975
+96038894
+95368765
+91134976
+91092267
+97098661
+94331553
+96420243
+99286232
+95349600
+99330064
+95010257
+96278836
+91065527
+97057230
+93110357
+96409274
+95374911
+90153985
+93155114
+96025779
+97449280
+96190069
+90287178
+98421365
+98305722
+98439530
+96096469
+99096304
+96089572
+99307057
+97112990
+96358388
+90319091
+97098688
+91034184
+97199262
+99240762
+98426236
+95347379
+97006603
+99352259
+91291720
+97420486
+97342603
+97289747
+95023587
+99008372
+97218076
+98147373
+98282206
+91376384
+99089911
+91043047
+97217364
+96235996
+97000328
+91339573
+95166251
+98362153
+99074319
+98403730
+91174087
+99070073
+99134363
+99427884
+97048062
+99303024
+90205027
+91363265
+94191916
+97450830
+93246027
+96305192
+97154704
+99252090
+98389481
+98104469
+98413772
+99196242
+97445684
+92062170
+97322395
+97180928
+99353321
+96278860
+94140841
+98018275
+92108417
+99113717
+93215800
+95373132
+93072349
+98389801
+98375844
+99233638
+93046624
+97362375
+96178227
+96409256
+97150707
+96379940
+94246743
+96198610
+90311515
+97098712
+99282947
+95016439
+98030536
+94183209
+94190839
+98104459
+99158164
+97296314
+97462740
+93269273
+93329079
+98406066
+94085904
+98417611
+97032774
+98414619
+97218353
+97066958
+99047055
+94267876
+95355456
+96074633
+99376397
+90188846
+99326307
+95052601
+94083530
+97330981
+96069375
+96054968
+93114357
+95151358
+95072277
+95280917
+96437028
+91237114
+97050805
+93309430
+96344715
+99362737
+94119088
+99048705
+93101981
+97228139
+99289426
+93320446
+98013637
+99061637
+95062301
+97334360
+96009559
+97318898
+94051535
+96183254
+99265951
+99023607
+94217708
+96239482
+95229576
+94246160
+99106021
+99007236
+95221892
+95386713
+95184007
+94281746
+93286051
+98014713
+99058080
+90327113
+96201015
+98039716
+97108276
+99101008
+95266282
+98001396
+99225047
+99323946
+96324890
+91175240
+94217690
+97334204
+99137815
+97344875
+95221870
+94209877
+94235006
+98322151
+97239596
+99038200
+99206604
+91164434
+93024468
+95053740
+98101496
+93155082
+99262272
+92366555
+97265687
+91117203
+99288090
+98349401
+98037648
+98384235
+98313295
+93244226
+99172218
+93294310
+97209911
+90351381
+99237607
+95329724
+96285641
+96163492
+95036334
+96200169
+97293200
+98438586
+94361146
+95255485
+93189882
+99090715
+97184542
+91172211
+97353010
+96209427
+99292715
+92077236
+96310948
+90258907
+95187990
+97335966
+96082168
+97333610
+92260679
+96194904
+91048014
+95370270
+97079135
+96203119
+92153263
+92156797
+93280865
+97300635
+92135176
+92042309
+90244306
+93283670
+99386936
+98282481
+92088960
+91187647
+99253956
+96063079
+97289574
+94132650
+94259178
+99190512
+95394020
+97294025
+97081192
+96141969
+95168272
+92392375
+95121921
+98012705
+99214329
+99286816
+98325368
+97253017
+97467112
+93238864
+99008520
+97458236
+97423536
+99192454
+99071844
+96075792
+96181482
+99415939
+97361636
+99357866
+91125342
+93152834
+97166066
+99218427
+91035625
+99294317
+93322080
+99305241
+97011146
+95266250
+96413262
+94267706
+99178629
+99034460
+98079330
+96195006
+95015010
+90292959
+97159684
+97131823
+96128660
+96065933
+99138892
+99145033
+99324612
+95154979
+95199654
+95343554
+92255823
+93202345
+94134077
+99348033
+95261059
+97307577
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/jnlpba.conll.train b/huner/ner_scripts/splits/jnlpba.conll.train
new file mode 100644
index 0000000..a324a8f
--- /dev/null
+++ b/huner/ner_scripts/splits/jnlpba.conll.train
@@ -0,0 +1,1199 @@
+93024383
+95362365
+99145586
+95399778
+99182340
+99045415
+94148994
+99115659
+91266912
+92107162
+95329717
+94344108
+99190650
+99047534
+99182542
+93189564
+99262416
+99189160
+93324366
+99262847
+96102041
+91239569
+97184448
+93105477
+95388524
+96320605
+96278844
+99097447
+99120900
+99047525
+95178839
+98001728
+99333679
+95394907
+97126060
+96264681
+97366676
+98076121
+95363069
+97378046
+95166264
+97461450
+99262230
+92213189
+96293454
+99097434
+91094881
+94331016
+93284506
+97138389
+93153017
+99060916
+99362759
+92186836
+93279468
+90299137
+99187985
+99008545
+93180777
+99097163
+98437269
+99264317
+98378510
+93204975
+95221386
+97353114
+97335974
+92123193
+97025459
+95059073
+94240138
+91190842
+97277320
+96291858
+97353180
+99057540
+99032837
+97210575
+99400649
+99393322
+98418492
+96189099
+99034605
+94167865
+94209308
+96068726
+97281772
+99225313
+98440543
+93012816
+95021266
+99369690
+99228708
+96025857
+94101543
+99135866
+99189164
+99406823
+97378015
+99030136
+95074873
+99078033
+96228299
+90319127
+99182530
+99184529
+98001375
+93183827
+99102381
+95385995
+98241397
+96009612
+97367500
+98383419
+98031743
+95204946
+93278095
+97228330
+99246501
+99174774
+95244883
+95197720
+99218397
+99371288
+93292612
+97070945
+96205972
+97445071
+97209374
+97376857
+96114497
+94339116
+95327953
+97135341
+99170284
+95355848
+92109743
+92366521
+99294118
+94253152
+91364264
+93363253
+96189121
+98209755
+97054651
+99194225
+91092266
+97184601
+92193465
+96355428
+97128814
+93100507
+97056026
+96165503
+91224990
+96009608
+99102590
+93350203
+99369860
+99343400
+96205960
+93041372
+96390735
+95261816
+99285117
+98373989
+97108656
+96264628
+97402252
+99060929
+95190988
+97312374
+99057586
+91266919
+99038208
+99111186
+96141065
+92385366
+98048869
+96099434
+99008506
+97016536
+99356019
+96365473
+97407922
+97375347
+98001571
+97132947
+97269081
+91098724
+96290415
+98341858
+99101510
+99077519
+95298682
+95279790
+92257680
+96074623
+97026428
+99298510
+97387731
+97362321
+90376424
+95129555
+96382512
+93275333
+99239883
+91291757
+99242633
+97189104
+95287902
+92195320
+95325614
+97226013
+97306366
+95011572
+91210272
+99276096
+96085174
+97170874
+98000963
+99200786
+98397262
+94289294
+90360678
+99007753
+93205400
+97005399
+99336788
+98365377
+98019162
+98104462
+96070930
+97118356
+98414302
+99023375
+92103005
+99201482
+96182305
+95124333
+93018835
+91041706
+91101115
+99263020
+93077034
+92378748
+99018025
+99225046
+98380286
+96074632
+97242104
+97444155
+96413288
+93307660
+93030402
+93154317
+97213977
+98400423
+96132964
+98375865
+91246215
+95065655
+96208140
+94179241
+97218151
+90255794
+99067836
+93289270
+99354925
+97077077
+99236832
+97364688
+98090595
+95156575
+96189089
+98101492
+92043714
+98435936
+98406200
+90110496
+95309632
+95014190
+99408727
+95238333
+99049801
+99138988
+91369589
+97184462
+98326600
+96305196
+99296619
+94185011
+99211949
+97115792
+99054996
+98440284
+95337737
+99298193
+93129206
+95190013
+94354848
+98030794
+99098921
+90237240
+99376409
+98012234
+99218312
+97300620
+99015774
+99190753
+93186809
+98405747
+97398336
+99380273
+91319738
+99367411
+94375097
+92408125
+91132035
+97205231
+97196870
+90381363
+93258811
+99248398
+99218482
+91277630
+99210381
+99189777
+94193110
+99361939
+99248162
+96202494
+96186497
+91075236
+96406504
+92112059
+96011839
+91036996
+94347089
+91221358
+95363078
+99057097
+97288734
+95016436
+99343785
+99321124
+99180473
+92060325
+96323103
+97480711
+91292396
+91099657
+99428687
+94088534
+98018399
+97047763
+99285633
+95050523
+99070060
+97460018
+96392389
+98416180
+96009598
+95333264
+98438043
+92185243
+95031992
+96152904
+99303791
+94031267
+97404655
+97127169
+92179751
+93171603
+92013023
+96305203
+95130292
+97167598
+99423672
+94303183
+99353876
+94284067
+95015876
+97083588
+97324097
+96353916
+96091806
+93135830
+95355533
+99262417
+99091536
+92320321
+95386516
+98379695
+98073333
+95001542
+97322372
+97045131
+95369491
+97390710
+94077003
+94149008
+94318550
+94314370
+97138090
+99178889
+94281402
+99308622
+97276226
+92387536
+98380268
+98124483
+98128482
+99023967
+99166942
+95337734
+99244330
+99282915
+94076456
+97349094
+96397528
+91132900
+99115412
+97153026
+93211996
+98022792
+96194562
+95163103
+92052243
+98104475
+99168986
+96431382
+97321386
+98005316
+96186719
+98001085
+92331609
+98019986
+93272960
+99098435
+99059495
+93259462
+99155344
+97205335
+96405332
+95256455
+99016857
+99146379
+98379823
+97236919
+92066454
+96214987
+99221321
+99039380
+97197910
+90158596
+98389427
+99203526
+95257963
+97170849
+97465516
+97462662
+91025498
+91114695
+93346062
+99064961
+95276747
+95152043
+96382503
+99362723
+95363089
+97342767
+95278601
+97358178
+96201628
+98385602
+98282480
+99369911
+90278097
+97330829
+98421396
+93011470
+99369980
+90279052
+98063340
+98416141
+97263535
+92001749
+99049838
+96001288
+94376879
+97025433
+96399059
+91236793
+95104296
+97251018
+99231886
+99394774
+99242525
+96185499
+99410809
+91013631
+98068683
+93061407
+93136418
+92010096
+96133016
+97042487
+95074049
+96003970
+99316341
+95169271
+91361546
+96405269
+98034220
+94327547
+97450986
+92218428
+90206049
+99236847
+98406210
+99408303
+96062038
+96355899
+97180731
+91170801
+97083787
+97140237
+98140255
+99386942
+97025418
+94194029
+99288066
+91187152
+96323172
+93141620
+93262492
+96055286
+99190530
+92051383
+92223210
+97248268
+97415553
+91050279
+99023364
+99384376
+98074810
+98209796
+99258659
+90147621
+92068245
+97362232
+90335211
+99252077
+93233083
+91079577
+99098272
+96107207
+96024587
+98062912
+97353023
+96247664
+91347784
+99262580
+92052179
+95100937
+99135975
+97054663
+92367617
+93157335
+96139448
+99272411
+95372363
+96317173
+95191179
+97261995
+99412333
+99248179
+96194982
+95236293
+97060432
+99055586
+96082382
+99292784
+94280766
+97404663
+96183906
+92127655
+93054486
+91175707
+96397543
+98407711
+95009960
+99074502
+93241941
+95260531
+94202265
+99257180
+94230583
+99240736
+91119580
+96157213
+96038813
+94274683
+96186978
+96184651
+96320558
+98299642
+95399771
+99113747
+91175478
+96190573
+98058835
+99147045
+96239599
+98290745
+91184620
+95394931
+92265660
+99154742
+91219488
+99075480
+98064072
+99147030
+94329809
+99162595
+97342608
+95367587
+97458245
+97119542
+99220021
+90169371
+95014458
+95337142
+97376852
+97031178
+99194238
+97394399
+97103140
+94285937
+97343293
+94230451
+99178617
+98208262
+93321228
+92235036
+96251346
+95235452
+99315834
+99142609
+99374665
+97214626
+99208363
+95369245
+95134788
+96151964
+96226053
+97006605
+96096754
+99214587
+98376488
+93013114
+96437048
+92309248
+99086128
+92294188
+99252177
+96182568
+96288304
+99192735
+98322149
+96063336
+96127450
+97317585
+91028334
+99249555
+99041401
+99223528
+92038993
+99155339
+99248157
+96247660
+98145608
+91173312
+96108879
+96194689
+96072803
+98030550
+93307152
+97360262
+96279126
+93242763
+96136291
+93232271
+96086826
+93041375
+96256807
+96211859
+96055115
+94075814
+96413233
+97182951
+97048170
+96009551
+94181565
+99041167
+92134262
+95193668
+97322371
+98374313
+97162234
+98401161
+91325181
+92164748
+99126331
+95222176
+95107991
+98038749
+97275148
+97361882
+93203219
+93153207
+94290489
+94238904
+98049829
+99008553
+99061768
+97074543
+96102166
+91258741
+90279073
+90317873
+98006327
+99008340
+99357094
+99069401
+94155850
+93152870
+99081619
+96212948
+98421363
+98208270
+91376383
+97134898
+92195648
+97024837
+96016217
+97184463
+98099332
+95056004
+96382507
+97419190
+92408021
+98426244
+93300824
+95248083
+97426442
+99209803
+99102085
+95081587
+97459950
+93024882
+97276939
+94340810
+96226351
+99292717
+94242719
+97234588
+95110287
+92378895
+99077502
+99255395
+97429889
+95116336
+92176633
+95222739
+98391735
+96094166
+99252157
+99138943
+97132074
+99161866
+99388007
+94313679
+96029754
+98353227
+91351285
+96136023
+95202809
+98056814
+97288306
+98133462
+94169380
+91124866
+97175006
+97272160
+96338163
+96134911
+99249588
+99074403
+99223488
+95238477
+97184665
+96214919
+94330935
+98373923
+96224113
+99244898
+94107268
+90247097
+95197524
+99030293
+99261844
+97338567
+98339383
+90242285
+94166578
+96070929
+93300929
+96049646
+95280913
+99200936
+94350980
+93224719
+93315684
+94358417
+94358411
+95336453
+99137801
+96032864
+97024832
+99406845
+99115544
+99021680
+99218525
+97454876
+96191817
+97069862
+98451425
+96413292
+97234679
+99175125
+97132051
+99201425
+94365323
+91366165
+97315348
+96147310
+99379868
+94327655
+94151007
+97284012
+96046572
+96427516
+99217587
+96000378
+92230800
+97332417
+99357809
+96347533
+99078032
+91079583
+99370197
+99169427
+93314685
+90220600
+95151640
+93268332
+95036290
+97069908
+92176657
+99025966
+97225991
+91037456
+97277292
+97468093
+96114389
+97469932
+94183204
+93056505
+93246644
+99401563
+99080869
+97171572
+92107586
+97459703
+99032541
+94278430
+97275156
+92020218
+92156807
+96289501
+96272884
+97088634
+95287633
+95269137
+96190675
+99415908
+99286230
+92049367
+99282926
+98375886
+96278909
+95166259
+97344237
+98281217
+97249714
+94238882
+99207658
+96354999
+99107758
+99260407
+92251244
+99243471
+98322350
+95365343
+97051821
+97423557
+99014176
+96195539
+97166081
+97315062
+97167569
+96202516
+97051521
+98391028
+97126580
+96228347
+94202312
+93020778
+92366509
+98391036
+98005040
+97451158
+94202306
+99248183
+96320521
+93065212
+97196961
+97081063
+99292681
+97314059
+96279111
+96388957
+96279101
+91296472
+91159628
+95077537
+99305240
+97377998
+98000233
+91067681
+99023506
+90298081
+98080700
+99256982
+99254099
+90375934
+97268616
+94151327
+96329553
+93129248
+95152321
+96356325
+99139903
+92317168
+96173754
+91292530
+98089072
+95308691
+97265379
+97047773
+93141262
+99244916
+96315681
+98395103
+94110342
+96357043
+96125073
+98028550
+93315600
+98003050
+96389043
+94209322
+99192449
+99288085
+97199263
+95145523
+92118719
+99049827
+96215633
+98089069
+95195208
+90191722
+95311627
+95059037
+97025698
+93209552
+99310627
+97298895
+99180171
+91184714
+96068922
+94200898
+97132479
+93085167
+98438540
+95001805
+92020850
+97379649
+96215235
+94110603
+97422566
+98430664
+97128276
+97277252
+97219997
+93150054
+94217726
+90173249
+94312466
+91049522
+90302010
+96330347
+97311087
+99328623
+99382334
+94314962
+99419787
+90337320
+92311659
+96176764
+99360752
+99353322
+97195004
+95340873
+97423508
+97289567
+99200773
+98451423
+99203164
+99285507
+91237803
+90317911
+97289433
+93252936
+93253031
+97176699
+99150505
+94327512
+99323972
+90290483
+95091657
+92147648
+93043110
+97153085
+97410435
+98455033
+99121740
+97223498
+99315311
+96030053
+90277507
+95391995
+99410810
+99409030
+95032566
+97304524
+96230713
+94259822
+99192785
+92318932
+99115672
+92269839
+97362594
+96262594
+96216725
+98353313
+96216453
+97460074
+93266777
+99415656
+98455230
+99247345
+97379394
+92013087
+95364954
+97278840
+97066996
+99073952
+98230439
+93204999
+98375837
+98168578
+91264362
+96184185
+95363941
+98024176
+97182946
+96322726
+94120719
+98438583
+92022337
+97362276
+97155934
+95316714
+96184791
+99216457
+96189110
+92052106
+95329723
+99296093
+97276922
+99176388
+96035700
+96341625
+97355572
+90208323
+97436422
+97113352
+96223984
+98363633
+96320762
+95197681
+97061522
+99010987
+91175694
+99192430
+96202489
+93123257
+96184802
+95403403
+98378528
+99141282
+97248400
+99223160
+90368794
+98400847
+95152420
+92224250
+96091353
+95110353
+94187105
+99175479
+99377310
+99301235
+96247631
+95236467
+97131727
+99166958
+95332324
+96239496
+91355651
+96126094
+92368408
+99229667
+98104470
+96338485
+96141087
+99357867
+99087711
+96324400
+96079009
+90293687
+91204058
+96062272
+94129004
+99008517
+98042055
+93216805
+96183228
+91321794
+97107281
+94254835
+99118181
+98374270
+93186822
+93180775
+97276992
+93224755
+94341725
+91293101
+97263762
+95003956
+93124567
+91237800
+95173590
+96247530
+97017504
+94375892
+92407982
+95053781
+99364624
+97277179
+95000924
+99242545
+94214477
+96224055
+97025427
\ No newline at end of file
diff --git a/huner/ner_scripts/splits/linneaus.dev b/huner/ner_scripts/splits/linneaus.dev
new file mode 100644
index 0000000..bbcc638
--- /dev/null
+++ b/huner/ner_scripts/splits/linneaus.dev
@@ -0,0 +1,11 @@
+
+pmcA1131934
+pmcA1474674
+pmcA1590010
+pmcA1805739
+pmcA1885664
+pmcA1913570
+pmcA2547183
+pmcA2636797
+pmcA2658668
+pmcA280693
diff --git a/huner/ner_scripts/splits/linneaus.test b/huner/ner_scripts/splits/linneaus.test
new file mode 100644
index 0000000..6d35bd0
--- /dev/null
+++ b/huner/ner_scripts/splits/linneaus.test
@@ -0,0 +1,30 @@
+
+pmcA102792
+pmcA1079799
+pmcA1190194
+pmcA140144
+pmcA140510
+pmcA1459157
+pmcA1562423
+pmcA1564398
+pmcA1634875
+pmcA1808052
+pmcA1931593
+pmcA2151861
+pmcA2267706
+pmcA2365090
+pmcA2377325
+pmcA2398786
+pmcA2430230
+pmcA2435603
+pmcA2453154
+pmcA2526157
+pmcA2538543
+pmcA2553092
+pmcA2646695
+pmcA2652712
+pmcA320464
+pmcA326369
+pmcA328326
+pmcA411032
+pmcA553979
diff --git a/huner/ner_scripts/splits/linneaus.train b/huner/ner_scripts/splits/linneaus.train
new file mode 100644
index 0000000..2c52c1d
--- /dev/null
+++ b/huner/ner_scripts/splits/linneaus.train
@@ -0,0 +1,60 @@
+
+pmcA1036069
+pmcA1075922
+pmcA1239921
+pmcA1257442
+pmcA1312363
+pmcA1347483
+pmcA1352346
+pmcA147033
+pmcA150219
+pmcA1521150
+pmcA1524813
+pmcA1526545
+pmcA1538864
+pmcA1551914
+pmcA1621059
+pmcA1636465
+pmcA1779435
+pmcA1779441
+pmcA1779460
+pmcA1838407
+pmcA1851709
+pmcA1859974
+pmcA1885853
+pmcA1937013
+pmcA2065882
+pmcA2238978
+pmcA2257940
+pmcA2276505
+pmcA2327290
+pmcA2365205
+pmcA2365225
+pmcA2365769
+pmcA2367462
+pmcA2367482
+pmcA2409186
+pmcA2412862
+pmcA2504341
+pmcA2518116
+pmcA2531092
+pmcA2556924
+pmcA2562362
+pmcA2567314
+pmcA2575403
+pmcA2589670
+pmcA2599109
+pmcA2602716
+pmcA2610030
+pmcA2632666
+pmcA2636784
+pmcA2636785
+pmcA324075
+pmcA327937
+pmcA328328
+pmcA331414
+pmcA334876
+pmcA335194
+pmcA441533
+pmcA509286
+pmcA544950
diff --git a/huner/ner_scripts/splits/loctext.dev b/huner/ner_scripts/splits/loctext.dev
new file mode 100644
index 0000000..b762d77
--- /dev/null
+++ b/huner/ner_scripts/splits/loctext.dev
@@ -0,0 +1,10 @@
+PubMed-11502169
+PubMed-11950973
+PubMed-12167088
+PubMed-14576278
+PubMed-15072822
+PubMed-15143214
+PubMed-15467828
+PubMed-16874308
+PubMed-20829347
+PubMed-9188482
diff --git a/huner/ner_scripts/splits/loctext.test b/huner/ner_scripts/splits/loctext.test
new file mode 100644
index 0000000..246a930
--- /dev/null
+++ b/huner/ner_scripts/splits/loctext.test
@@ -0,0 +1,30 @@
+PubMed-10095065
+PubMed-10207082
+PubMed-10837477
+PubMed-11038182
+PubMed-12417726
+PubMed-12429849
+PubMed-12566991
+PubMed-12682047
+PubMed-12794138
+PubMed-15486337
+PubMed-16263347
+PubMed-16443219
+PubMed-16541025
+PubMed-16628192
+PubMed-16788062
+PubMed-16918702
+PubMed-17317660
+PubMed-17726031
+PubMed-18660802
+PubMed-20008104
+PubMed-20023648
+PubMed-20124190
+PubMed-205532
+PubMed-23150645
+PubMed-23169667
+PubMed-23345592
+PubMed-8035792
+PubMed-9290212
+PubMed-9346891
+PubMed-9613572
diff --git a/huner/ner_scripts/splits/loctext.train b/huner/ner_scripts/splits/loctext.train
new file mode 100644
index 0000000..ac81392
--- /dev/null
+++ b/huner/ner_scripts/splits/loctext.train
@@ -0,0 +1,60 @@
+PubMed-10072396
+PubMed-10515935
+PubMed-10644992
+PubMed-11161714
+PubMed-11481323
+PubMed-11564863
+PubMed-11565753
+PubMed-12023506
+PubMed-12177201
+PubMed-12482924
+PubMed-12612081
+PubMed-12663043
+PubMed-12697820
+PubMed-12766230
+PubMed-12805228
+PubMed-14562095
+PubMed-14602072
+PubMed-14654843
+PubMed-14701804
+PubMed-15342390
+PubMed-15377779
+PubMed-15572352
+PubMed-15574332
+PubMed-15606766
+PubMed-15775980
+PubMed-15788404
+PubMed-16455656
+PubMed-16461379
+PubMed-16595633
+PubMed-16689936
+PubMed-16731587
+PubMed-17081065
+PubMed-17202255
+PubMed-17289661
+PubMed-17882260
+PubMed-17921316
+PubMed-18082604
+PubMed-18088316
+PubMed-18182439
+PubMed-18305173
+PubMed-18663142
+PubMed-18769150
+PubMed-19054390
+PubMed-19403692
+PubMed-19628819
+PubMed-19832944
+PubMed-20071603
+PubMed-20142502
+PubMed-20427278
+PubMed-20634289
+PubMed-20932478
+PubMed-21282530
+PubMed-21937712
+PubMed-22253225
+PubMed-22899009
+PubMed-22984069
+PubMed-23543752
+PubMed-7542657
+PubMed-7689721
+PubMed-8846782
diff --git a/huner/ner_scripts/splits/miRNA.dev b/huner/ner_scripts/splits/miRNA.dev
new file mode 100644
index 0000000..2c73d53
--- /dev/null
+++ b/huner/ner_scripts/splits/miRNA.dev
@@ -0,0 +1,18 @@
+miRNA-corp.d129
+miRNA-corp.d59
+miRNA-corp.d117
+miRNA-corp.d143
+miRNA-corp.d162
+miRNA-corp.d173
+miRNA-corp.d63
+miRNA-corp.d159
+miRNA-corp.d127
+miRNA-corp.d92
+miRNA-corp.d104
+miRNA-corp.d60
+miRNA-corp.d108
+miRNA-corp.d9
+miRNA-corp.d91
+miRNA-corp.d142
+miRNA-corp.d90
+miRNA-corp.d77
diff --git a/huner/ner_scripts/splits/miRNA.test b/huner/ner_scripts/splits/miRNA.test
new file mode 100644
index 0000000..ed2c59f
--- /dev/null
+++ b/huner/ner_scripts/splits/miRNA.test
@@ -0,0 +1,54 @@
+miRNA-corp.d113
+miRNA-corp.d13
+miRNA-corp.d135
+miRNA-corp.d53
+miRNA-corp.d133
+miRNA-corp.d118
+miRNA-corp.d84
+miRNA-corp.d120
+miRNA-corp.d134
+miRNA-corp.d33
+miRNA-corp.d150
+miRNA-corp.d82
+miRNA-corp.d3
+miRNA-corp.d106
+miRNA-corp.d147
+miRNA-corp.d176
+miRNA-corp.d114
+miRNA-corp.d30
+miRNA-corp.d179
+miRNA-corp.d132
+miRNA-corp.d95
+miRNA-corp.d0
+miRNA-corp.d61
+miRNA-corp.d149
+miRNA-corp.d38
+miRNA-corp.d139
+miRNA-corp.d99
+miRNA-corp.d80
+miRNA-corp.d2
+miRNA-corp.d156
+miRNA-corp.d122
+miRNA-corp.d85
+miRNA-corp.d169
+miRNA-corp.d48
+miRNA-corp.d1
+miRNA-corp.d78
+miRNA-corp.d64
+miRNA-corp.d170
+miRNA-corp.d50
+miRNA-corp.d74
+miRNA-corp.d8
+miRNA-corp.d110
+miRNA-corp.d89
+miRNA-corp.d103
+miRNA-corp.d55
+miRNA-corp.d37
+miRNA-corp.d24
+miRNA-corp.d79
+miRNA-corp.d49
+miRNA-corp.d73
+miRNA-corp.d17
+miRNA-corp.d6
+miRNA-corp.d145
+miRNA-corp.d69
diff --git a/huner/ner_scripts/splits/miRNA.train b/huner/ner_scripts/splits/miRNA.train
new file mode 100644
index 0000000..d3dbf3d
--- /dev/null
+++ b/huner/ner_scripts/splits/miRNA.train
@@ -0,0 +1,109 @@
+miRNA-corp.d41
+miRNA-corp.d152
+miRNA-corp.d4
+miRNA-corp.d177
+miRNA-corp.d14
+miRNA-corp.d112
+miRNA-corp.d23
+miRNA-corp.d72
+miRNA-corp.d57
+miRNA-corp.d100
+miRNA-corp.d68
+miRNA-corp.d125
+miRNA-corp.d83
+miRNA-corp.d151
+miRNA-corp.d86
+miRNA-corp.d27
+miRNA-corp.d43
+miRNA-corp.d166
+miRNA-corp.d180
+miRNA-corp.d12
+miRNA-corp.d35
+miRNA-corp.d42
+miRNA-corp.d58
+miRNA-corp.d148
+miRNA-corp.d36
+miRNA-corp.d137
+miRNA-corp.d105
+miRNA-corp.d109
+miRNA-corp.d97
+miRNA-corp.d54
+miRNA-corp.d5
+miRNA-corp.d25
+miRNA-corp.d154
+miRNA-corp.d101
+miRNA-corp.d32
+miRNA-corp.d67
+miRNA-corp.d155
+miRNA-corp.d65
+miRNA-corp.d165
+miRNA-corp.d62
+miRNA-corp.d168
+miRNA-corp.d21
+miRNA-corp.d138
+miRNA-corp.d98
+miRNA-corp.d52
+miRNA-corp.d51
+miRNA-corp.d124
+miRNA-corp.d144
+miRNA-corp.d46
+miRNA-corp.d116
+miRNA-corp.d115
+miRNA-corp.d96
+miRNA-corp.d111
+miRNA-corp.d174
+miRNA-corp.d94
+miRNA-corp.d178
+miRNA-corp.d26
+miRNA-corp.d20
+miRNA-corp.d18
+miRNA-corp.d140
+miRNA-corp.d16
+miRNA-corp.d158
+miRNA-corp.d75
+miRNA-corp.d11
+miRNA-corp.d34
+miRNA-corp.d163
+miRNA-corp.d19
+miRNA-corp.d87
+miRNA-corp.d130
+miRNA-corp.d136
+miRNA-corp.d28
+miRNA-corp.d39
+miRNA-corp.d172
+miRNA-corp.d70
+miRNA-corp.d119
+miRNA-corp.d10
+miRNA-corp.d126
+miRNA-corp.d141
+miRNA-corp.d102
+miRNA-corp.d175
+miRNA-corp.d146
+miRNA-corp.d107
+miRNA-corp.d15
+miRNA-corp.d22
+miRNA-corp.d164
+miRNA-corp.d29
+miRNA-corp.d31
+miRNA-corp.d128
+miRNA-corp.d161
+miRNA-corp.d157
+miRNA-corp.d45
+miRNA-corp.d123
+miRNA-corp.d76
+miRNA-corp.d44
+miRNA-corp.d160
+miRNA-corp.d171
+miRNA-corp.d131
+miRNA-corp.d167
+miRNA-corp.d153
+miRNA-corp.d7
+miRNA-corp.d40
+miRNA-corp.d81
+miRNA-corp.d71
+miRNA-corp.d66
+miRNA-corp.d121
+miRNA-corp.d93
+miRNA-corp.d56
+miRNA-corp.d47
+miRNA-corp.d88
diff --git a/huner/ner_scripts/splits/ncbi.dev b/huner/ner_scripts/splits/ncbi.dev
new file mode 100644
index 0000000..0995e0a
--- /dev/null
+++ b/huner/ner_scripts/splits/ncbi.dev
@@ -0,0 +1,78 @@
+
+10072428
+10094552
+10094559
+10190819
+10196379
+10196381
+10330430
+10364518
+10398436
+10426999
+10434119
+10519880
+10528243
+10631148
+10639175
+10677309
+10724175
+10807385
+10915770
+10915776
+10923035
+10924409
+10932179
+1146783
+116187
+122435
+1319059
+1346924
+1349199
+1351034
+1376553
+1483696
+1505217
+1678319
+2037285
+2209091
+2253938
+2309698
+2310692
+2355960
+2601691
+2703233
+2792129
+2835825
+3343337
+3563511
+3600793
+3600794
+3659917
+3876122
+492335
+495634
+523196
+6101415
+624546
+6387532
+7422429
+7458742
+7550229
+7550230
+7581380
+7617034
+7759106
+7795652
+7795653
+7894491
+7894493
+7909252
+7959759
+7991123
+8195156
+8259519
+8304342
+8326491
+8434621
+8551426
+8575748
diff --git a/huner/ner_scripts/splits/ncbi.test b/huner/ner_scripts/splits/ncbi.test
new file mode 100644
index 0000000..08dc743
--- /dev/null
+++ b/huner/ner_scripts/splits/ncbi.test
@@ -0,0 +1,239 @@
+
+10213492
+10353787
+10404839
+10594001
+10706858
+10724160
+10735274
+10888879
+10958786
+10976074
+1248000
+1269174
+1307253
+133535
+1353340
+1357962
+1358807
+1424237
+1671851
+1831007
+1973404
+2253937
+2352258
+2491010
+3377761
+4019732
+6902670
+7316485
+7481765
+7550349
+7761412
+7874117
+7981671
+8012387
+8178825
+8244393
+8279472
+8563759
+8589722
+8589723
+8595416
+8605116
+8621452
+8622978
+8625410
+8636252
+8637912
+8640236
+8644702
+8644703
+8649785
+8651278
+8659522
+8659549
+8661102
+8666397
+8670333
+8673131
+8673132
+8674108
+8675707
+8678979
+8682510
+8689689
+8692963
+8696339
+8700509
+8723064
+8733131
+8751855
+8755645
+8755918
+8758207
+8776595
+8782829
+8786135
+8789439
+8790412
+8808605
+8808606
+8812423
+8824873
+8825052
+8825599
+8828602
+8833159
+8841191
+8843193
+8843194
+8845838
+8871666
+8892662
+8894695
+8898652
+8917548
+8929264
+8929413
+8931695
+8931701
+8931709
+8938427
+8944023
+8944024
+8954016
+8956035
+8968716
+8968760
+9012404
+9012409
+9019400
+9020847
+9028321
+9050866
+9050868
+9056547
+9063749
+9066888
+9069115
+9072974
+9083764
+9090524
+9122265
+9138149
+9144439
+9144525
+9145677
+9174057
+9182899
+9195227
+9218625
+9222760
+9223307
+9223312
+9241281
+9241282
+9245987
+9271438
+9272171
+9288106
+9294109
+9311732
+932197
+9336417
+9342365
+9358014
+9360520
+9371490
+9382108
+9385378
+9391879
+9391889
+9400934
+941901
+9420335
+9425228
+9425239
+9427148
+9439660
+9443866
+9448273
+9450866
+9457913
+9457914
+9463309
+9463314
+9463318
+9465039
+9465301
+9467011
+9472666
+9482572
+9497246
+9506545
+9521325
+9521421
+9529364
+9536083
+9546397
+9554743
+9563950
+9580132
+9585583
+9585605
+9585606
+9585611
+9590178
+9590284
+9600235
+9603435
+9618166
+9618170
+9620771
+9634518
+9668171
+9671401
+9674903
+9674906
+9689113
+9700175
+9702690
+9703418
+9703501
+9705283
+9709714
+9714764
+9724771
+9729124
+9731533
+9733027
+9744473
+9770531
+9771706
+9774970
+9790667
+9792409
+9792860
+9792861
+9800909
+9831355
+9843038
+9848786
+9852676
+9856498
+9856499
+9861003
+9863607
+9867744
+9869602
+9888388
+9888390
+9927033
+9931324
+993342
+9949197
+9949209
+9950360
+9973276
+9988281
diff --git a/huner/ner_scripts/splits/ncbi.train b/huner/ner_scripts/splits/ncbi.train
new file mode 100644
index 0000000..9fd0050
--- /dev/null
+++ b/huner/ner_scripts/splits/ncbi.train
@@ -0,0 +1,475 @@
+
+10021369
+10051005
+10051007
+100562
+10064668
+10071185
+10071193
+10077614
+10077651
+10078732
+10078749
+10083733
+10083734
+10090880
+10090885
+10090890
+10190331
+10192393
+10192399
+10194428
+10198641
+10200300
+10205262
+10208645
+10208848
+10210128
+10220405
+102474
+10323252
+10323740
+10330348
+10364520
+10364521
+10364525
+10366443
+10369860
+10369870
+10369876
+10377440
+10381492
+10382909
+10382910
+10398279
+10403837
+10406661
+10408771
+10408776
+10411929
+10417279
+10417280
+10417286
+10425038
+10426139
+10429004
+10430841
+10430930
+10441329
+10441343
+10441571
+10441573
+10446987
+10447258
+10447259
+10449429
+10449794
+10465113
+10466420
+10470088
+10470286
+10471457
+10472529
+10480214
+10480348
+10484765
+10484772
+10484981
+10487695
+10487710
+10500204
+10502833
+10521293
+10528853
+10528860
+10533031
+10533068
+10541953
+10543403
+10545613
+10554035
+10556283
+10556285
+10556298
+10557309
+10557317
+1056013
+10571943
+10571950
+10577908
+10581027
+10589394
+10590055
+10593994
+10598803
+10598815
+10602116
+10607954
+10612394
+10615125
+10618304
+10633128
+10636421
+10662807
+10698963
+10699184
+10709732
+10712201
+10712209
+10712225
+10716718
+10721669
+10732811
+10732816
+10736265
+10737119
+10737980
+10737981
+10742101
+10746568
+10747931
+10766245
+10767313
+10767326
+10767339
+10767343
+10767347
+10777718
+107868
+10788334
+10790204
+10797418
+10798358
+10802660
+10802667
+10802668
+10802669
+10807793
+10814710
+10817650
+10818206
+10827108
+10827109
+10830910
+10830915
+10839544
+10842298
+10861282
+10861298
+10874302
+10875918
+10878391
+10891444
+10911990
+10930361
+10930571
+10943845
+10947987
+10982189
+10987655
+1127526
+1201235
+1222588
+126380
+1279971
+1282899
+1301146
+1301161
+1301187
+1301189
+1301190
+1301200
+1301201
+1301937
+1301938
+1302003
+1302008
+1302022
+1302032
+1303170
+1303171
+1303173
+1303277
+1307230
+1307245
+1311721
+1313112
+1315306
+1316718
+1317264
+1319838
+1322637
+1323345
+1324223
+1325652
+1327525
+1334370
+1338764
+1338904
+1338906
+1345170
+1346773
+1347968
+1352883
+1361100
+1361318
+1380672
+1384323
+1384324
+1409710
+144081
+1468459
+1505982
+1517503
+1562739
+1577476
+1577763
+1610789
+161677
+1655284
+1671881
+1673289
+1676565
+1679035
+1682919
+1684088
+1684569
+1707231
+1709636
+1717985
+1731805
+1733838
+1769645
+1776638
+1833974
+1897530
+1937471
+1939657
+1968617
+1975560
+1978564
+1981994
+1999339
+1999552
+2006152
+2008213
+2016095
+2055114
+2071157
+2161209
+2180286
+218453
+2215607
+2220826
+2241452
+2303408
+2309142
+2316519
+23402
+2390095
+2393028
+2450401
+2544995
+2562820
+2563633
+2568588
+2569949
+2571579
+2575071
+2575483
+2591962
+2651669
+2729274
+2760209
+2773936
+2786201
+2817003
+2828430
+2852474
+2862466
+2884570
+2886237
+2894613
+2895982
+2910902
+2912069
+2912886
+2927388
+2963536
+2989709
+2995231
+3012567
+3014348
+3029599
+3032521
+313733
+3162536
+3169738
+318684
+3198117
+3258663
+3346017
+3346018
+3347839
+3348216
+3354603
+3362213
+3393536
+3417303
+3422216
+3455778
+3464560
+3480530
+3524231
+3565372
+3572301
+3578281
+3591825
+3615198
+3674116
+3678494
+3718019
+3789016
+3856322
+3862128
+409732
+492812
+511159
+6086495
+6087154
+6103091
+6337374
+6453040
+6524872
+6540752
+6585184
+6604602
+6618488
+6650504
+6783144
+6859721
+7055648
+7076260
+7106752
+7166314
+7191069
+7202134
+7298854
+7315872
+7390473
+7437512
+7444053
+7450778
+7479827
+7490097
+7493024
+7523157
+7535801
+7543316
+7545954
+7568002
+7573040
+7574457
+7579347
+7586656
+7599636
+7605382
+7607677
+7611277
+7630639
+7652577
+7663517
+7668252
+7696601
+7717396
+7726234
+7759075
+7759076
+7762560
+7767095
+7769092
+777027
+7790377
+7795591
+7795596
+7802009
+7811247
+7814011
+7815415
+7825578
+7825586
+7833921
+7857677
+7858169
+7874163
+7937795
+7939630
+7951315
+7951316
+7951327
+7962532
+7964884
+8002973
+8004674
+8023850
+8071955
+8071957
+8075631
+8084618
+8088831
+8098180
+8098245
+8101038
+8104633
+8111379
+8113388
+8116611
+8128954
+8162051
+8162071
+8187068
+8188241
+8198124
+8198128
+8209890
+8240110
+8252631
+8258524
+8266996
+8281142
+8281152
+8282802
+8301658
+8302543
+8307570
+8314592
+8317477
+8346255
+8364574
+8370681
+8375105
+8401501
+8408659
+8440142
+8441467
+8460149
+8466512
+8471773
+8477262
+8499920
+8500791
+8522307
+8528198
+8528199
+8530105
+8531967
+8533757
+8533762
+8533768
+8554067
+8566952
+8566965
+8571951
+8571953
+8589715
+8589721
diff --git a/huner/ner_scripts/splits/osiris.dev b/huner/ner_scripts/splits/osiris.dev
new file mode 100644
index 0000000..9e07149
--- /dev/null
+++ b/huner/ner_scripts/splits/osiris.dev
@@ -0,0 +1,12 @@
+
+14673707
+14755442
+14755445
+14970845
+14973548
+15024396
+15037865
+15077293
+15114532
+15116260
+15138458
diff --git a/huner/ner_scripts/splits/osiris.test b/huner/ner_scripts/splits/osiris.test
new file mode 100644
index 0000000..ab11338
--- /dev/null
+++ b/huner/ner_scripts/splits/osiris.test
@@ -0,0 +1,32 @@
+
+12915397
+14635012
+14645199
+14681301
+14693721
+14715843
+14715845
+14730381
+14734460
+14739420
+14747301
+14749980
+14970363
+14979495
+14986114
+14986169
+15007729
+15022318
+15048652
+15078863
+15084933
+15087412
+15091317
+15115760
+15122513
+15126335
+15138193
+15149891
+15150650
+15164150
+15170937
diff --git a/huner/ner_scripts/splits/osiris.train b/huner/ner_scripts/splits/osiris.train
new file mode 100644
index 0000000..40519f4
--- /dev/null
+++ b/huner/ner_scripts/splits/osiris.train
@@ -0,0 +1,63 @@
+
+12890863
+14523377
+14651519
+14651522
+14685824
+14693717
+14705223
+14709372
+14712309
+14729863
+14737097
+14742985
+14752243
+14755451
+14764791
+14871556
+14872030
+14961571
+14961572
+14962090
+14962947
+14970360
+14973783
+14975928
+15007371
+15008790
+15009068
+15024686
+15026335
+15028050
+15028669
+15047633
+15050452
+15054398
+15057901
+15061869
+15066320
+15080568
+15084241
+15091315
+15094225
+15099281
+15099346
+15099969
+15100460
+15101044
+15102677
+15103710
+15108194
+15108283
+15110318
+15116249
+15123570
+15123654
+15124004
+15129369
+15130757
+15138483
+15138485
+15142217
+15161528
+15166293
diff --git a/huner/ner_scripts/splits/pennbio.dev b/huner/ner_scripts/splits/pennbio.dev
new file mode 100644
index 0000000..dada0d2
--- /dev/null
+++ b/huner/ner_scripts/splits/pennbio.dev
@@ -0,0 +1,143 @@
+
+2685611
+2689731
+2691957
+2809198
+2810395
+2823263
+2833341
+2834371
+2838126
+2853304
+2867133
+2868120
+2887586
+2913265
+2917804
+2926396
+2930456
+2930681
+2987439
+2998383
+3032199
+3038106
+3038518
+3060792
+3144694
+3146045
+3200839
+3222254
+3282444
+3292251
+3295562
+3305049
+3318293
+3332188
+3334851
+3353078
+3437890
+3491073
+3492512
+3515856
+3525983
+3539825
+3574619
+373111
+3797720
+3814600
+3837238
+3855753
+3858848
+3968174
+4047115
+4091174
+507919
+6092892
+6099413
+6193253
+6205121
+6278080
+6303569
+6304521
+6323457
+6331452
+6436814
+6467378
+6549047
+6572951
+6587382
+6589638
+6620081
+6683594
+6686637
+6744291
+6795603
+6804604
+6816913
+6934372
+6943568
+6981051
+7057186
+7059360
+7066879
+7188249
+7320733
+7356938
+7473586
+7476883
+7478611
+7479840
+7485468
+7495303
+7497445
+7500652
+7501971
+7512175
+7516655
+7518353
+7523310
+7527270
+7527290
+7529211
+7533687
+7535083
+7539141
+7542776
+7545349
+7553653
+7553731
+7554128
+7554431
+7564469
+7565620
+7566363
+7573356
+7574421
+7576742
+7576954
+7579408
+7581303
+7589243
+7597312
+7602527
+7621259
+7627815
+7627947
+7630645
+7648268
+7674018
+7678540
+7680848
+7684192
+7688735
+7693050
+7700633
+7704243
+7706255
+7707874
+7712490
+7714109
+7718333
+7725728
+7727782
+7736519
diff --git a/huner/ner_scripts/splits/pennbio.test b/huner/ner_scripts/splits/pennbio.test
new file mode 100644
index 0000000..351fe31
--- /dev/null
+++ b/huner/ner_scripts/splits/pennbio.test
@@ -0,0 +1,425 @@
+
+7738369
+7745972
+7748555
+7760021
+7762971
+7777541
+7780959
+7780971
+7803279
+7808981
+7819070
+7825162
+7828925
+7830489
+7832776
+7860615
+7862112
+7865834
+7871950
+7877460
+7885045
+7885185
+7898304
+7902340
+7909518
+7915734
+7916576
+7918071
+7923112
+7927179
+7927901
+7928631
+7934163
+7946598
+7947263
+7951583
+7952399
+7954437
+7954478
+7957639
+7965884
+7968366
+7969151
+7972200
+7972206
+7972209
+7972237
+7982960
+7985080
+8024690
+8026877
+8027404
+8032172
+8032213
+8032908
+8033117
+8039127
+8043423
+8043511
+8057669
+8057782
+8061889
+8070639
+8082085
+8093230
+8093685
+8101511
+8106812
+8113394
+8120410
+8123851
+8124213
+8150541
+8152300
+8152431
+8155934
+8156531
+8157698
+8157709
+8161790
+8164510
+8166453
+8168996
+8180130
+8180579
+8194046
+8194691
+8198573
+8199018
+8202477
+8205548
+8211691
+8217795
+8241268
+8242560
+8242562
+8244579
+8251905
+8253528
+8255104
+8263009
+8280132
+8280380
+8282004
+8289473
+8297348
+8321046
+8335405
+8363619
+8363646
+8366868
+8376577
+8380055
+8380252
+8380412
+8387522
+8390962
+8392552
+8394105
+8394214
+8394991
+8416742
+8426854
+8431911
+8441470
+8445953
+8453487
+8453633
+8453760
+8463133
+8483882
+8490179
+8490873
+8492117
+8510497
+8514604
+8514771
+8519445
+8528106
+8528960
+8533197
+8541548
+8547609
+8555071
+8558206
+8561897
+8563883
+8583243
+8589724
+8590778
+8609230
+8611634
+8612522
+8622876
+8630516
+8630967
+8633516
+8637723
+8641983
+8645424
+8656681
+8662964
+8666391
+8666983
+8669886
+8690291
+8717339
+8748684
+8752137
+8758750
+8761289
+8774129
+8780392
+8788478
+8789601
+8789608
+8798505
+8816779
+8823319
+8826929
+8834178
+8835820
+8837332
+8843915
+8843955
+8852654
+8858760
+8868097
+8875708
+8888741
+8907200
+8936664
+8938131
+8940088
+8941212
+8955068
+8961670
+8974323
+8982686
+8986786
+8996154
+8997527
+9001550
+9003040
+9003042
+9009246
+9010458
+9018336
+9018769
+9024310
+9029028
+9042254
+9048488
+9049847
+9049850
+9052984
+9053784
+9061616
+9065402
+9065403
+9075750
+9083512
+9090493
+9094007
+9097993
+9099963
+9107428
+9115293
+9117098
+9121761
+9123834
+9127178
+9130517
+9136990
+9137494
+9139869
+9140397
+9142199
+9156287
+9156660
+9159349
+9168438
+9173889
+9174124
+9177239
+9177441
+9178894
+9179693
+9180916
+9184644
+9189100
+9191543
+9207791
+9208611
+9216721
+9218873
+9219511
+9247481
+925840
+9285932
+9291233
+9291819
+9293921
+9294210
+9305595
+9309143
+9323458
+9326265
+9327727
+9332768
+9341990
+9343417
+9345343
+9354676
+9359588
+9369932
+9374209
+9377556
+9377572
+9378385
+9378542
+9379676
+9379846
+9389561
+9399746
+9408753
+9422991
+9430820
+9438854
+9440124
+9443419
+9458088
+9458092
+9464645
+9473262
+9473757
+9482910
+9489716
+9495452
+9500446
+9500465
+9514049
+9514055
+9515567
+9515795
+9516473
+9516828
+9516836
+9516839
+9516849
+9516858
+9516861
+9523205
+9535729
+9537203
+9537226
+953997
+9560119
+9563649
+9568504
+9573390
+9576574
+9580079
+9585064
+9591632
+9592195
+9596277
+9600124
+9603197
+9606006
+9615223
+9619634
+9621346
+9624247
+9625869
+9635571
+9635572
+9635831
+9639120
+9639362
+9655301
+9658196
+9658319
+9658320
+9667736
+9671070
+9671767
+9680114
+9681834
+9685340
+9685595
+9687566
+9699459
+9703927
+9712639
+9713462
+9714703
+9718653
+9721853
+9724079
+9726011
+9730961
+9738576
+9740394
+9752317
+9757022
+9757065
+9761241
+9766644
+9771714
+9772288
+9777938
+9777951
+9778107
+9781958
+9786508
+9786976
+9797083
+9797131
+9797363
+9797369
+9798918
+9799749
+9804334
+9808126
+9808427
+9812979
+9815553
+9816127
+9816185
+9816273
+9823556
+9827716
+9839307
+9849423
+9851250
+9853427
+9855271
+9856847
+9858225
+9858914
+9860981
+9861322
+9862417
+9865432
+9875139
+9878096
+9878533
+9881963
+9882527
+9889797
+9893662
+9895049
+9916918
+9923922
+9925828
+9927029
+9927037
+9927617
+9927992
+9988270
+9988706
+9988748
+9990072
diff --git a/huner/ner_scripts/splits/pennbio.train b/huner/ner_scripts/splits/pennbio.train
new file mode 100644
index 0000000..7b8cf96
--- /dev/null
+++ b/huner/ner_scripts/splits/pennbio.train
@@ -0,0 +1,849 @@
+
+10025877
+10026134
+10027390
+10037495
+10070310
+10071127
+10071245
+10076565
+10080545
+10080602
+10080613
+10081488
+10086344
+10090410
+10094499
+10100712
+10100929
+10103069
+10103089
+10189891
+10189896
+10191113
+10192393
+10197610
+10200489
+10206488
+10206490
+10207632
+10213482
+10214865
+10218465
+10220498
+10320758
+10323884
+10323885
+10327054
+10329457
+10336437
+10341287
+10349837
+10349856
+10349991
+10353750
+10359203
+10362137
+10362788
+10364037
+10366032
+10366714
+10366746
+10367940
+10374400
+10379019
+10391090
+10391564
+10391939
+10392898
+10393831
+10398436
+10402253
+10411920
+10414414
+10416591
+10417756
+10421261
+10430398
+10433945
+10438845
+10443461
+10448081
+10451706
+10457905
+10463479
+10463574
+10464293
+10465111
+10466827
+10468914
+10469215
+10473269
+10475381
+10484017
+10485468
+10485475
+10487827
+10493496
+10499618
+10510729
+10515185
+10518116
+10523759
+10548430
+10550322
+10554798
+10564951
+10568137
+10570058
+10571052
+10574596
+10579590
+10580029
+10587588
+10587643
+10588946
+10590684
+1059097
+10595907
+10597262
+10597266
+10602478
+10604740
+10612810
+10613523
+10614528
+10615234
+10625678
+10627475
+10631094
+10642594
+10644760
+10649241
+10652254
+10655994
+10661623
+10665646
+10666314
+10666372
+10671680
+10673750
+10675482
+10676628
+10680889
+10681434
+10700176
+10705019
+10706069
+10715586
+10717528
+10719054
+10734314
+10735503
+10736431
+10738270
+10748015
+10750666
+10751679
+10754205
+10754986
+10759189
+10760686
+10763829
+10766161
+10766749
+10767358
+10767369
+10769168
+10769197
+10770937
+10777194
+10780529
+10792276
+10793075
+10793082
+10804287
+10809758
+10810366
+10811105
+10811128
+10820203
+10835516
+10835530
+10837911
+10839294
+10842245
+10842254
+10846530
+10852128
+10869820
+10873681
+10877072
+10882162
+10884918
+10886722
+10894600
+10903401
+10923915
+10930802
+10931919
+10933705
+10934946
+10937879
+10938284
+10945494
+10955804
+10956407
+10958767
+10968705
+10969765
+10974408
+10975709
+10980116
+10980135
+10980605
+10982594
+10997733
+11004664
+11005505
+11007037
+11007041
+11012986
+11023095
+11023538
+11030147
+11034592
+11040941
+11042120
+11045784
+11048797
+11048799
+11051374
+11054718
+11061551
+11063223
+11069949
+11074560
+11075851
+11080495
+11082114
+11088049
+11092558
+11093800
+11097231
+11098085
+11102889
+11102958
+11103785
+11103790
+11106095
+11107105
+11107127
+11107141
+11107143
+11107173
+11114733
+11115351
+11115575
+11117578
+11122538
+11123760
+11125285
+11135265
+11139332
+11145249
+11150913
+11152785
+11156410
+11156606
+11157491
+11159203
+11159856
+11161379
+11161385
+11161815
+11161860
+11162940
+11163116
+11170292
+11171833
+11179836
+11180166
+11180865
+11181073
+11182035
+11196154
+11196159
+11205742
+11208819
+11211612
+11212268
+11212897
+11215737
+11231481
+11237496
+11238048
+11238055
+11241321
+11259431
+11259485
+11260505
+11276007
+11282485
+11285617
+11286481
+11289147
+11289281
+11290569
+11301351
+11301359
+11306486
+11307149
+11309300
+11309340
+11310641
+11311976
+11313875
+11313982
+11314002
+11316759
+11319276
+11325814
+11329142
+11330582
+11331403
+11333365
+11342220
+11342770
+11351304
+11353055
+11353831
+11358461
+11374892
+11375957
+11377687
+11380399
+11385321
+11387355
+11389059
+11390535
+11391793
+11395371
+11406295
+11408505
+11410326
+11410369
+11410804
+11417998
+11429702
+11429783
+11431772
+11432318
+11433413
+11435722
+11436166
+11437403
+11440199
+11443619
+11457659
+11461083
+11464291
+11464859
+11464860
+11464866
+11464867
+11464868
+11464873
+11464887
+11464913
+11464914
+11466313
+11466624
+11470766
+11472568
+11474132
+11474281
+11474297
+11477549
+11483649
+11485400
+11487539
+11488451
+11489458
+11500049
+11505392
+11506492
+11507701
+11520139
+11520156
+11520807
+11521196
+11526487
+11526494
+11528552
+11529856
+11531932
+11549713
+11550280
+11553860
+11559529
+11559534
+11559566
+11562787
+11563603
+11570580
+11571630
+11580146
+11583986
+11584892
+11589014
+11592102
+11593392
+11597763
+11600672
+11601924
+11605053
+11666046
+11668203
+11675134
+11687587
+11688571
+11689167
+11696453
+11698137
+11698147
+11699412
+11703283
+11719439
+11725959
+11727259
+11727262
+11731417
+11733516
+11736660
+11738246
+11744098
+11745189
+11745231
+11745417
+11750901
+11751374
+11751397
+11751493
+11754965
+11756228
+11782392
+11786393
+11787853
+11796830
+11803583
+11807663
+11807778
+11813174
+11815980
+11815985
+11819789
+11823972
+11830391
+11836564
+11843557
+11847429
+11848684
+11850193
+11850541
+11854428
+11860462
+11861435
+11867941
+11877420
+11879796
+11886512
+11890673
+11891193
+11892688
+11894939
+11896204
+11901170
+11903582
+11907829
+11911843
+11912515
+11914627
+11920742
+11921277
+11927008
+11936871
+11943962
+11955607
+11960979
+11986336
+12000708
+12007509
+12011461
+12012008
+12021900
+12021921
+12023580
+12028822
+12032289
+12039935
+12050681
+12064478
+12065637
+12065772
+12072425
+12082617
+12085233
+12086988
+12095979
+12096341
+12101047
+12101426
+12107114
+12110640
+12111402
+12117880
+12118546
+12120000
+12123342
+12124804
+12126742
+12126878
+12127685
+12147210
+12149262
+12154078
+12163385
+12175546
+12185581
+12189555
+12194119
+12198114
+12198135
+12203220
+12204060
+12210067
+12214015
+12217415
+12235144
+12239177
+12374221
+12375019
+12392756
+12393885
+12414635
+12415119
+12431979
+12438240
+12439032
+12439598
+12460920
+12469176
+12493756
+12506025
+12517782
+12524276
+12533608
+12544767
+12557224
+12558968
+12558970
+12562518
+12569580
+12570382
+12584574
+12586546
+12588870
+12609598
+12623220
+12628757
+12629511
+12629651
+12634848
+12645566
+12649279
+12652598
+12653673
+12661900
+12665472
+12665621
+12668729
+12670486
+12670707
+12671019
+12675948
+12684519
+12686385
+12687660
+12691521
+12691733
+12692414
+12694399
+12700894
+12702577
+12710931
+12718911
+12730964
+12734358
+12752688
+12758065
+12758079
+12759373
+12761578
+12771916
+12777682
+12781215
+12783850
+12787066
+12796812
+12807963
+1281152
+12814250
+12836164
+12842874
+12871580
+12875901
+12880954
+12880965
+12880973
+12880977
+12911753
+12918060
+12923682
+12925009
+12932649
+12944398
+12960120
+12963998
+12964048
+1305613
+1312542
+13130517
+1314130
+1314950
+1315710
+1321690
+1323601
+1330634
+1331621
+1341278
+1342949
+1348695
+1358448
+1360635
+1362216
+1375906
+1380036
+1381946
+1381992
+1382850
+1391032
+1391809
+1394196
+1394221
+1403838
+1427748
+1430209
+1433344
+1437145
+14501007
+14504408
+14506696
+14511121
+14513413
+14521994
+14523559
+1452458
+14532993
+14535945
+14555710
+1456396
+14583114
+14605441
+14612528
+14645238
+14659875
+14666454
+14666455
+14670183
+14677092
+14690534
+14705983
+14712226
+1471723
+14734862
+14737110
+14739336
+14745516
+14745948
+1476942
+1486801
+14969744
+1501288
+1515242
+1517116
+1524724
+1528853
+1536950
+1544704
+1557411
+1574246
+1581879
+1581890
+1581907
+1588796
+1591047
+1594587
+1598607
+1599755
+1613515
+1614406
+1619852
+1648227
+1652059
+1657899
+1664797
+1676609
+1679529
+1682809
+1683380
+1685440
+1690725
+1691442
+1694183
+1697169
+1714839
+1720402
+1728951
+1735606
+1738207
+1741160
+1741406
+1755317
+1786633
+179701
+1806946
+1847209
+1855700
+1874450
+1890154
+1901927
+1902567
+1913619
+1913654
+1921261
+1921453
+1921930
+1922057
+1923522
+1923531
+1931483
+1933896
+1942938
+1946468
+1964179
+1964795
+1967219
+1971702
+1974410
+1980608
+1988096
+1991170
+1996309
+1998949
+1998963
+2004329
+2004847
+2011403
+2012756
+2017877
+2021541
+2021946
+2040536
+2056968
+2059205
+2064724
+2064725
+2067117
+2072140
+2079711
+2088503
+2108944
+2118519
+2137931
+2153451
+2154325
+2158308
+2163356
+2166931
+2167148
+2168984
+2169566
+2170366
+2174225
+2174908
+2179035
+2179417
+2179819
+2183158
+2183872
+2183888
+2185879
+2187600
+2189293
+2197591
+2200539
+2208148
+222964
+223077
+2247846
+2253838
+2257681
+2258361
+2266390
+2283998
+2284101
+2293611
+2296463
+2302711
+2323848
+2326268
+2329455
+2391103
+2403598
+2409886
+2421891
+2437946
+2445473
+2461451
+2470006
+2481662
+2504935
+2505918
+2535834
+2537832
+2538792
+2542205
+2564452
+2568197
+2576939
+2582423
+2601700
+2614829
+2642713
+2645949
+2648253
+2657575
+2659902
+2660900
+2666422
+2668844
+2668964
+2674680
+2676145
+2680062
+2681517
+2682463
+2683276
+2684256
+2684296
diff --git a/huner/ner_scripts/splits/s800.dev b/huner/ner_scripts/splits/s800.dev
new file mode 100644
index 0000000..44e062d
--- /dev/null
+++ b/huner/ner_scripts/splits/s800.dev
@@ -0,0 +1,81 @@
+
+species008
+species015
+species043
+species056
+species066
+species083
+species088
+species093
+species097
+species099
+species116
+species117
+species134
+species141
+species151
+species152
+species154
+species161
+species166
+species169
+species173
+species181
+species203
+species204
+species228
+species234
+species247
+species251
+species254
+species259
+species264
+species268
+species275
+species282
+species315
+species319
+species336
+species342
+species345
+species361
+species366
+species368
+species373
+species381
+species385
+species391
+species403
+species404
+species409
+species420
+species422
+species470
+species496
+species509
+species519
+species539
+species543
+species556
+species558
+species561
+species578
+species583
+species592
+species595
+species607
+species610
+species639
+species651
+species652
+species663
+species667
+species676
+species692
+species703
+species725
+species726
+species730
+species737
+species760
+species799
diff --git a/huner/ner_scripts/splits/s800.test b/huner/ner_scripts/splits/s800.test
new file mode 100644
index 0000000..11849c7
--- /dev/null
+++ b/huner/ner_scripts/splits/s800.test
@@ -0,0 +1,241 @@
+
+species004
+species005
+species007
+species021
+species022
+species023
+species024
+species025
+species030
+species034
+species035
+species038
+species040
+species042
+species044
+species045
+species046
+species047
+species050
+species051
+species053
+species054
+species059
+species071
+species072
+species074
+species075
+species086
+species101
+species103
+species108
+species112
+species113
+species114
+species115
+species120
+species121
+species123
+species125
+species127
+species131
+species133
+species136
+species137
+species138
+species139
+species142
+species143
+species144
+species146
+species147
+species149
+species156
+species162
+species165
+species171
+species174
+species178
+species182
+species183
+species184
+species190
+species192
+species194
+species195
+species199
+species200
+species205
+species207
+species209
+species215
+species224
+species232
+species236
+species239
+species240
+species242
+species246
+species249
+species260
+species266
+species269
+species277
+species279
+species283
+species286
+species288
+species289
+species291
+species306
+species308
+species311
+species313
+species316
+species320
+species324
+species325
+species340
+species341
+species347
+species348
+species352
+species363
+species367
+species370
+species371
+species378
+species379
+species383
+species384
+species387
+species390
+species393
+species396
+species398
+species402
+species405
+species406
+species407
+species412
+species415
+species421
+species424
+species427
+species428
+species429
+species430
+species432
+species433
+species438
+species440
+species446
+species447
+species451
+species457
+species458
+species467
+species468
+species475
+species477
+species480
+species481
+species486
+species488
+species489
+species492
+species493
+species497
+species501
+species503
+species506
+species512
+species515
+species518
+species521
+species526
+species528
+species529
+species536
+species541
+species542
+species544
+species545
+species546
+species549
+species551
+species554
+species557
+species565
+species569
+species573
+species576
+species577
+species579
+species580
+species582
+species586
+species588
+species591
+species598
+species599
+species600
+species604
+species611
+species612
+species613
+species616
+species618
+species620
+species624
+species632
+species638
+species640
+species641
+species646
+species648
+species649
+species650
+species654
+species656
+species661
+species664
+species675
+species678
+species681
+species682
+species685
+species687
+species689
+species691
+species695
+species699
+species700
+species704
+species706
+species707
+species709
+species713
+species714
+species716
+species719
+species721
+species727
+species728
+species733
+species741
+species746
+species750
+species752
+species753
+species755
+species757
+species758
+species770
+species771
+species772
+species776
+species782
+species786
+species798
diff --git a/huner/ner_scripts/splits/s800.train b/huner/ner_scripts/splits/s800.train
new file mode 100644
index 0000000..30fc75c
--- /dev/null
+++ b/huner/ner_scripts/splits/s800.train
@@ -0,0 +1,481 @@
+
+species001
+species002
+species003
+species006
+species009
+species010
+species011
+species012
+species013
+species014
+species016
+species017
+species018
+species019
+species020
+species026
+species027
+species028
+species029
+species031
+species032
+species033
+species036
+species037
+species039
+species041
+species048
+species049
+species052
+species055
+species057
+species058
+species060
+species061
+species062
+species063
+species064
+species065
+species067
+species068
+species069
+species070
+species073
+species076
+species077
+species078
+species079
+species080
+species081
+species082
+species084
+species085
+species087
+species089
+species090
+species091
+species092
+species094
+species095
+species096
+species098
+species100
+species102
+species104
+species105
+species106
+species107
+species109
+species110
+species111
+species118
+species119
+species122
+species124
+species126
+species128
+species129
+species130
+species132
+species135
+species140
+species145
+species148
+species150
+species153
+species155
+species157
+species158
+species159
+species160
+species163
+species164
+species167
+species168
+species170
+species172
+species175
+species176
+species177
+species179
+species180
+species185
+species186
+species187
+species188
+species189
+species191
+species193
+species196
+species197
+species198
+species201
+species202
+species206
+species208
+species210
+species211
+species212
+species213
+species214
+species216
+species217
+species218
+species219
+species220
+species221
+species222
+species223
+species225
+species226
+species227
+species229
+species230
+species231
+species233
+species235
+species237
+species238
+species241
+species243
+species244
+species245
+species248
+species250
+species252
+species253
+species255
+species256
+species257
+species258
+species261
+species262
+species263
+species265
+species267
+species270
+species271
+species272
+species273
+species274
+species276
+species278
+species280
+species281
+species284
+species285
+species287
+species290
+species292
+species293
+species294
+species295
+species296
+species297
+species298
+species299
+species300
+species301
+species302
+species303
+species304
+species305
+species307
+species309
+species310
+species312
+species314
+species317
+species318
+species321
+species322
+species323
+species326
+species327
+species328
+species329
+species330
+species331
+species332
+species333
+species334
+species335
+species337
+species338
+species339
+species343
+species344
+species346
+species349
+species350
+species351
+species353
+species354
+species355
+species356
+species357
+species358
+species359
+species360
+species362
+species364
+species365
+species369
+species372
+species374
+species375
+species376
+species377
+species380
+species382
+species386
+species388
+species389
+species392
+species394
+species395
+species397
+species399
+species400
+species401
+species408
+species410
+species411
+species413
+species414
+species416
+species417
+species418
+species419
+species423
+species425
+species426
+species431
+species434
+species435
+species436
+species437
+species439
+species441
+species442
+species443
+species444
+species445
+species448
+species449
+species450
+species452
+species453
+species454
+species455
+species456
+species459
+species460
+species461
+species462
+species463
+species464
+species465
+species466
+species469
+species471
+species472
+species473
+species474
+species476
+species478
+species479
+species482
+species483
+species484
+species485
+species487
+species490
+species491
+species494
+species495
+species498
+species499
+species500
+species502
+species504
+species505
+species507
+species508
+species510
+species511
+species513
+species514
+species516
+species517
+species520
+species522
+species523
+species524
+species525
+species527
+species530
+species531
+species532
+species533
+species534
+species535
+species537
+species538
+species540
+species547
+species548
+species550
+species552
+species553
+species555
+species559
+species560
+species562
+species563
+species564
+species566
+species567
+species568
+species570
+species571
+species572
+species574
+species575
+species581
+species584
+species585
+species587
+species589
+species590
+species593
+species594
+species596
+species597
+species601
+species602
+species603
+species605
+species606
+species608
+species609
+species614
+species615
+species617
+species619
+species621
+species622
+species623
+species625
+species626
+species627
+species628
+species629
+species630
+species631
+species633
+species634
+species635
+species636
+species637
+species642
+species643
+species644
+species645
+species647
+species653
+species655
+species657
+species658
+species659
+species660
+species662
+species665
+species666
+species668
+species669
+species670
+species671
+species672
+species673
+species674
+species677
+species679
+species680
+species683
+species684
+species686
+species688
+species690
+species693
+species694
+species696
+species697
+species698
+species701
+species702
+species705
+species708
+species710
+species711
+species712
+species715
+species717
+species718
+species720
+species722
+species723
+species724
+species729
+species731
+species732
+species734
+species735
+species736
+species738
+species739
+species740
+species742
+species743
+species744
+species745
+species747
+species748
+species749
+species751
+species754
+species756
+species759
+species761
+species762
+species763
+species764
+species765
+species766
+species767
+species768
+species769
+species773
+species774
+species775
+species777
+species778
+species779
+species780
+species781
+species783
+species784
+species785
+species787
+species788
+species789
+species790
+species791
+species792
+species793
+species794
+species795
+species796
+species797
+species800
diff --git a/huner/ner_scripts/splits/scai_chemicals.dev b/huner/ner_scripts/splits/scai_chemicals.dev
new file mode 100644
index 0000000..de62515
--- /dev/null
+++ b/huner/ner_scripts/splits/scai_chemicals.dev
@@ -0,0 +1,10 @@
+3735316
+18419918
+4032426
+10335724
+3761308
+1361579
+2231607
+18419667
+10849585
+18421201
diff --git a/huner/ner_scripts/splits/scai_chemicals.test b/huner/ner_scripts/splits/scai_chemicals.test
new file mode 100644
index 0000000..9b8f6a1
--- /dev/null
+++ b/huner/ner_scripts/splits/scai_chemicals.test
@@ -0,0 +1,30 @@
+12553880
+18419842
+11358723
+9120816
+8230102
+2104934
+9082041
+6827523
+3656362
+11879044
+16134936
+15652357
+7783132
+1512594
+18419668
+8817480
+18421178
+18419992
+18419836
+6780324
+15620433
+16682228
+16329601
+10479279
+18419676
+6292417
+18421161
+2578190
+18419895
+18419664
diff --git a/huner/ner_scripts/splits/scai_chemicals.train b/huner/ner_scripts/splits/scai_chemicals.train
new file mode 100644
index 0000000..4d02420
--- /dev/null
+++ b/huner/ner_scripts/splits/scai_chemicals.train
@@ -0,0 +1,59 @@
+1732554
+8960550
+10783907
+7205876
+17371003
+11597479
+12890682
+1350435
+18421604
+18421840
+596853
+18421171
+1766004
+7040662
+12672235
+18419843
+18421613
+5808825
+10823345
+18419912
+7473576
+1992127
+18419993
+3625710
+2299637
+2229079
+9079034
+7490727
+1573637
+2153828
+1177256
+11602181
+14998335
+721701
+8654448
+16033265
+10639285
+3968683
+11985471
+18421162
+12742193
+11754577
+9719587
+17368496
+18419839
+18421163
+2329575
+2999399
+7783119
+18419837
+14591846
+2944474
+18421600
+10447954
+18421176
+18421606
+10813108
+16946562
+6264792
diff --git a/huner/ner_scripts/splits/scai_disease.dev b/huner/ner_scripts/splits/scai_disease.dev
new file mode 100644
index 0000000..e6b2adf
--- /dev/null
+++ b/huner/ner_scripts/splits/scai_disease.dev
@@ -0,0 +1,41 @@
+
+18514630
+18541635
+18554256
+18558430
+18568441
+18571386
+18572379
+18590344
+18591543
+18597941
+18607671
+18617665
+18619980
+18640215
+18640301
+18679045
+18685414
+18691649
+18697792
+18702535
+18707752
+18709447
+18715837
+18722631
+18726085
+18767405
+18774732
+18782632
+18790781
+18793299
+18799936
+18801642
+18803658
+18822368
+18824097
+18837771
+18845202
+18922041
+18925770
+18928414
diff --git a/huner/ner_scripts/splits/scai_disease.test b/huner/ner_scripts/splits/scai_disease.test
new file mode 100644
index 0000000..7419cac
--- /dev/null
+++ b/huner/ner_scripts/splits/scai_disease.test
@@ -0,0 +1,121 @@
+
+18477617
+18539681
+18541199
+18547273
+18549344
+18551282
+18555912
+18560606
+18565883
+18566484
+18569162
+18570172
+18572632
+18577998
+18587135
+18589198
+18591544
+18591554
+18593597
+18594001
+18597654
+18598093
+18598753
+18601306
+18603680
+18608299
+18614900
+18619950
+18623084
+18623382
+18623605
+18624435
+18627362
+18633129
+18634978
+18638709
+18640178
+18640208
+18640219
+18645333
+18651721
+18654747
+18654853
+18666751
+18669463
+18672535
+18673278
+18673438
+18675256
+18675764
+18682687
+18687352
+18687753
+18690886
+18690970
+18692119
+18692326
+18695260
+18695846
+18700638
+18705805
+18707009
+18707827
+18709536
+18710631
+18711953
+18714577
+18715200
+18719341
+18721116
+18723826
+18725460
+18728218
+18728729
+18751431
+18753192
+18755159
+18760317
+18762710
+18765204
+18765960
+18773144
+18776152
+18781134
+18783727
+18784429
+18786302
+18788754
+18789678
+18791717
+18801423
+18802751
+18803262
+18804180
+18805435
+18805679
+18809314
+18809451
+18812062
+18813917
+18815021
+18818699
+18821468
+18821991
+18827612
+18829735
+18830207
+18843413
+18843733
+18843743
+18845211
+18845239
+18851690
+18921966
+18922700
+18927542
+18936500
+18936793
+18941357
+18942772
diff --git a/huner/ner_scripts/splits/scai_disease.train b/huner/ner_scripts/splits/scai_disease.train
new file mode 100644
index 0000000..a5e7f2e
--- /dev/null
+++ b/huner/ner_scripts/splits/scai_disease.train
@@ -0,0 +1,241 @@
+
+18446180
+18537576
+18542079
+18544904
+18546202
+18547214
+18547491
+18548134
+18549882
+18550175
+18553993
+18554312
+18554678
+18555464
+18555982
+18556142
+18558361
+18560212
+18560533
+18562131
+18564982
+18567054
+18569277
+18569383
+18575136
+18578119
+18580952
+18580955
+18581028
+18581078
+18582143
+18584977
+18585544
+18585919
+18586117
+18589276
+18589448
+18590766
+18591791
+18594138
+18596603
+18597652
+18599893
+18600584
+18602129
+18604181
+18604442
+18605226
+18606837
+18606968
+18607570
+18608208
+18612759
+18612868
+18613215
+18613449
+18614266
+18614347
+18614615
+18615622
+18618001
+18620786
+18620828
+18620949
+18621066
+18622679
+18622878
+18623206
+18626250
+18627268
+18627515
+18628067
+18628507
+18630502
+18633740
+18634931
+18635226
+18635701
+18636394
+18636399
+18636418
+18636785
+18637031
+18637601
+18637887
+18640100
+18640133
+18640204
+18640214
+18640217
+18641546
+18641920
+18642029
+18646134
+18648813
+18652557
+18652871
+18653395
+18653608
+18653899
+18657019
+18662289
+18662739
+18663448
+18663869
+18664513
+18665938
+18666210
+18666379
+18667824
+18670875
+18671470
+18671473
+18676353
+18676805
+18677425
+18679398
+18684796
+18687998
+18690095
+18690337
+18690914
+18690968
+18690972
+18691879
+18693154
+18693965
+18695700
+18698850
+18702618
+18703135
+18704008
+18704471
+18704634
+18707820
+18707870
+18710264
+18710788
+18711350
+18712494
+18712998
+18714077
+18719942
+18720672
+18721197
+18721818
+18721846
+18726058
+18726697
+18751414
+18751444
+18751929
+18752977
+18753950
+18754195
+18755865
+18756647
+18758144
+18759348
+18759504
+18759760
+18760140
+18760610
+18761239
+18763324
+18769484
+18771055
+18772046
+18773883
+18774727
+18775466
+18775494
+18776655
+18777478
+18778437
+18778717
+18781664
+18783831
+18785644
+18785684
+18787912
+18789000
+18789051
+18790714
+18793295
+18798698
+18799925
+18800883
+18801421
+18803413
+18803960
+18804218
+18805577
+18806114
+18811200
+18812021
+18812562
+18813359
+18815938
+18818457
+18821393
+18821490
+18822681
+18824249
+18826176
+18826264
+18826299
+18828020
+18830260
+18835419
+18838379
+18840369
+18840370
+18840496
+18841306
+18843612
+18844846
+18845207
+18850280
+18854394
+18854788
+18855271
+18929078
+18929080
+18929871
+18930840
+18935781
+18937544
+18937598
+18937624
+18938110
+18942662
+18949461
+18950559
+18951238
+18952555
+18952618
+18954923
+18955203
+18956268
diff --git a/huner/ner_scripts/splits/species.dev b/huner/ner_scripts/splits/species.dev
new file mode 100644
index 0000000..28469c1
--- /dev/null
+++ b/huner/ner_scripts/splits/species.dev
@@ -0,0 +1,41 @@
+
+1064099-03-Methods-p02
+1067522-04-RESULTS-p03
+1266026-05-Discussion-p01
+1334229-05-Discussion-p01
+1373649-02-Background-p01
+1373649-03-Methods-p02
+1373649-04-Results-and-discussion-p02
+1601966-06-Methods-p01
+1619718-02-Introduction-p01
+1619718-03-Materials-and-methods-p03
+1619718-04-Results-p01
+1784097-02-Background-p01
+1808468-03-Methods-p03
+2048978-06-Methods-p01
+2253649-02-Introduction-p01
+2253649-04-Results-p03
+2253649-04-Results-p04
+2253649-05-Discussion-p01
+2323222-03-Results-p07
+2323222-03-Results-p09
+2374968-03-Materials-and-methods-p01
+2375115-05-Materials-and-Methods-p03
+2386495-03-Methods-p01
+2386495-05-Discussion-p02
+2397009-04-RESULTS-p01
+2429944-03-Methods-p01
+2429944-05-Discussion-p01
+2435117-01-Abstract-p01
+2438340-03-Methods-p03
+2438340-03-Methods-p04
+2438340-05-Discussion-p02
+2488325-04-Results-p02
+2488325-04-Results-p05
+2488325-06-Conclusion-p01
+2526421-02-INTRODUCTION-p01
+2526421-03-MATERIALS-AND-METHODS-p02
+2551625-04-Results-p02
+2559820-03-Methods-p01
+2559820-04-Results-p02
+2565065-05-Materials-and-Methods-p03
diff --git a/huner/ner_scripts/splits/species.test b/huner/ner_scripts/splits/species.test
new file mode 100644
index 0000000..30dc29d
--- /dev/null
+++ b/huner/ner_scripts/splits/species.test
@@ -0,0 +1,100 @@
+
+1067522-01-Abstract-p01
+1067522-04-RESULTS-p02
+1067522-05-DISCUSSION-p01
+1266026-02-Background-p01
+1266026-06-Conclusion-p01
+1334229-02-Background-p01
+1334229-03-Methods-p01
+1334229-06-Conclusion-p01
+1360090-02-Background-p01
+1360090-03-Results-p01
+1557864-01-Abstract-p01
+1557864-02-Background-p02
+1557864-05-Discussion-p03
+1557864-05-Discussion-p04
+1601966-03-Results-p03
+1601966-03-Results-p04
+1601966-03-Results-p12
+1601966-04-Discussion-p01
+1601966-05-Conclusion-p01
+1619718-05-Discussion-p02
+1619718-05-Discussion-p05
+1784097-03-Methods-p01
+1808468-04-Results-p01
+1808468-05-Discussion-p01
+2039842-01-Abstract-p01
+2039842-02-Introduction-p02
+2039842-03-Materials-and-methods-p01
+2039842-05-Discussion-p03
+2048978-04-Discussion-p01
+2048978-05-Conclusion-p01
+2206733-02-Introduction-p01
+2206733-03-Materials-and-methods-p03
+2206733-05-Discussion-p01
+2253649-03-Materials-and-methods-p02
+2253649-04-Results-p02
+2253649-04-Results-p05
+2265717-03-Case-presentation-p01
+2265717-04-Discussion-p01
+2265717-05-Conclusion-p01
+2275286-03-Methods-p02
+2275286-05-Discussion-p02
+2323222-02-Background-p01
+2323222-03-Results-p01
+2323222-03-Results-p06
+2323222-03-Results-p08
+2323222-04-Discussion-p03
+2323222-04-Discussion-p04
+2323222-05-Materials-and-methods-p03
+2323222-05-Materials-and-methods-p04
+2374968-01-Abstract-p01
+2374968-02-Introduction-p01
+2374968-04-Results-p02
+2375115-04-Discussion-p02
+2375115-05-Materials-and-Methods-p02
+2386495-02-Background-p02
+2386495-04-Results-p02
+2386495-04-Results-p05
+2386495-05-Discussion-p03
+2386495-05-Discussion-p04
+2397009-02-INTRODUCTION-p02
+2397009-03-METHODS-p02
+2397009-06-CONCLUSION-p01
+2410297-02-Introduction-p02
+2410297-04-Discussion-p02
+2410297-05-Materials-and-Methods-p01
+2429944-02-Introduction-p02
+2429944-04-Results-p02
+2429944-04-Results-p05
+2435117-03-Methods-p02
+2438340-02-Background-p02
+2438340-03-Methods-p02
+2438340-05-Discussion-p03
+2438340-05-Discussion-p04
+2488325-01-Abstract-p01
+2488325-03-Methods-p01
+2488325-03-Methods-p06
+2488325-04-Results-p03
+2488325-04-Results-p04
+2488325-05-Discussion-p01
+2488325-05-Discussion-p06
+2526421-01-Abstract-p01
+2526421-04-RESULTS-p01
+2526421-05-DISCUSSION-p02
+2551625-01-Abstract-p01
+2551625-02-Introduction-p02
+2551625-03-Methods-p01
+2551625-04-Results-p03
+2551625-05-Discussion-p01
+2559820-01-Abstract-p01
+2559820-02-Background-p01
+2559820-06-Conclusion-p01
+2565065-01-Abstract-p01
+2565065-02-Introduction-p02
+2565065-03-Results-p02
+2565065-03-Results-p05
+2565065-04-Discussion-p02
+3034663-04-Results-p02
+3034663-05-Discussion-p02
+3034663-06-Conclusions-p01
diff --git a/huner/ner_scripts/splits/species.train b/huner/ner_scripts/splits/species.train
new file mode 100644
index 0000000..ff5585b
--- /dev/null
+++ b/huner/ner_scripts/splits/species.train
@@ -0,0 +1,254 @@
+
+1064099-01-Abstract-p01
+1064099-02-Introduction-p01
+1064099-03-Methods-p01
+1064099-04-Results-p01
+1064099-05-Discussion-p01
+1064099-06-Conclusion-p01
+1067522-02-INTRODUCTION-p01
+1067522-03-MATERIALS-AND-METHODS-p01
+1067522-04-RESULTS-p01
+1067522-05-DISCUSSION-p02
+1266026-01-Abstract-p01
+1266026-03-Methods-p01
+1266026-04-Results-p01
+1266026-05-Discussion-p02
+1266026-05-Discussion-p03
+1334229-01-Abstract-p01
+1334229-02-Background-p02
+1334229-03-Methods-p02
+1334229-03-Methods-p03
+1334229-04-Results-p01
+1334229-04-Results-p02
+1334229-05-Discussion-p02
+1334229-05-Discussion-p03
+1360090-01-Abstract-p01
+1360090-03-Results-p02
+1360090-04-Discussion-p01
+1360090-05-Conclusion-p01
+1360090-06-Methods-p01
+1373649-01-Abstract-p01
+1373649-03-Methods-p01
+1373649-04-Results-and-discussion-p01
+1373649-05-Conclusion-p01
+1557864-02-Background-p01
+1557864-03-Methods-p01
+1557864-03-Methods-p02
+1557864-04-Results-p01
+1557864-05-Discussion-p01
+1557864-05-Discussion-p02
+1557864-06-Conclusion-p01
+1601966-01-Abstract-p01
+1601966-02-Background-p01
+1601966-02-Background-p02
+1601966-03-Results-p01
+1601966-03-Results-p02
+1601966-03-Results-p05
+1601966-03-Results-p06
+1601966-03-Results-p07
+1601966-03-Results-p08
+1601966-03-Results-p09
+1601966-03-Results-p10
+1601966-03-Results-p11
+1601966-04-Discussion-p02
+1601966-04-Discussion-p03
+1601966-06-Methods-p02
+1601966-06-Methods-p03
+1601966-06-Methods-p04
+1601966-06-Methods-p05
+1619718-01-Abstract-p01
+1619718-02-Introduction-p02
+1619718-03-Materials-and-methods-p01
+1619718-03-Materials-and-methods-p02
+1619718-04-Results-p02
+1619718-04-Results-p03
+1619718-05-Discussion-p01
+1619718-05-Discussion-p03
+1619718-05-Discussion-p04
+1784097-01-Abstract-p01
+1784097-02-Background-p02
+1784097-03-Methods-p02
+1784097-03-Methods-p03
+1784097-04-Results-and-discussion-p01
+1784097-04-Results-and-discussion-p02
+1784097-05-Conclusion-p01
+1808468-01-Abstract-p01
+1808468-02-Background-p01
+1808468-02-Background-p02
+1808468-03-Methods-p01
+1808468-03-Methods-p02
+1808468-04-Results-p02
+1808468-05-Discussion-p02
+1808468-06-Conclusion-p01
+2039842-02-Introduction-p01
+2039842-03-Materials-and-methods-p02
+2039842-03-Materials-and-methods-p03
+2039842-03-Materials-and-methods-p04
+2039842-03-Materials-and-methods-p05
+2039842-04-Results-p01
+2039842-04-Results-p02
+2039842-04-Results-p03
+2039842-04-Results-p04
+2039842-05-Discussion-p01
+2039842-05-Discussion-p02
+2048978-01-Abstract-p01
+2048978-02-Background-p01
+2048978-03-Results-p01
+2048978-03-Results-p02
+2048978-04-Discussion-p02
+2048978-06-Methods-p02
+2048978-06-Methods-p03
+2206733-01-Abstract-p01
+2206733-03-Materials-and-methods-p01
+2206733-03-Materials-and-methods-p02
+2206733-04-Results-p01
+2206733-04-Results-p02
+2206733-04-Results-p03
+2206733-04-Results-p04
+2206733-05-Discussion-p02
+2206733-05-Discussion-p03
+2206733-06-Conclusion-p01
+2253649-01-Abstract-p01
+2253649-03-Materials-and-methods-p01
+2253649-04-Results-p01
+2253649-04-Results-p06
+2253649-05-Discussion-p02
+2253649-05-Discussion-p03
+2265717-01-Abstract-p01
+2265717-02-Background-p01
+2275286-01-Abstract-p01
+2275286-02-Background-p01
+2275286-03-Methods-p01
+2275286-03-Methods-p03
+2275286-03-Methods-p04
+2275286-04-Results-p01
+2275286-04-Results-p02
+2275286-05-Discussion-p01
+2275286-06-Conclusion-p01
+2323222-01-Abstract-p01
+2323222-02-Background-p02
+2323222-03-Results-p02
+2323222-03-Results-p03
+2323222-03-Results-p04
+2323222-03-Results-p05
+2323222-04-Discussion-p01
+2323222-04-Discussion-p02
+2323222-04-Discussion-p05
+2323222-05-Materials-and-methods-p01
+2323222-05-Materials-and-methods-p02
+2323222-05-Materials-and-methods-p05
+2374968-03-Materials-and-methods-p02
+2374968-04-Results-p01
+2374968-04-Results-p03
+2374968-04-Results-p04
+2374968-05-Discussion-p01
+2374968-06-Conclusion-p01
+2375115-01-Abstract-p01
+2375115-02-Introduction-p01
+2375115-02-Introduction-p02
+2375115-03-Results-p01
+2375115-03-Results-p02
+2375115-03-Results-p03
+2375115-03-Results-p04
+2375115-04-Discussion-p01
+2375115-04-Discussion-p03
+2375115-05-Materials-and-Methods-p01
+2386495-01-Abstract-p01
+2386495-02-Background-p01
+2386495-03-Methods-p02
+2386495-03-Methods-p03
+2386495-04-Results-p01
+2386495-04-Results-p03
+2386495-04-Results-p04
+2386495-05-Discussion-p01
+2386495-06-Conclusion-p01
+2397009-01-Abstract-p01
+2397009-02-INTRODUCTION-p01
+2397009-03-METHODS-p01
+2397009-03-METHODS-p03
+2397009-05-DISCUSSION-p01
+2397009-05-DISCUSSION-p02
+2397009-05-DISCUSSION-p03
+2410297-01-Abstract-p01
+2410297-02-Introduction-p01
+2410297-03-Results-p01
+2410297-03-Results-p02
+2410297-03-Results-p03
+2410297-03-Results-p04
+2410297-03-Results-p05
+2410297-03-Results-p06
+2410297-04-Discussion-p01
+2410297-05-Materials-and-Methods-p02
+2410297-05-Materials-and-Methods-p03
+2429944-01-Abstract-p01
+2429944-01-Abstract-p02
+2429944-01-Abstract-p03
+2429944-02-Introduction-p01
+2429944-03-Methods-p02
+2429944-04-Results-p01
+2429944-04-Results-p03
+2429944-04-Results-p04
+2429944-04-Results-p06
+2429944-04-Results-p07
+2429944-04-Results-p08
+2429944-05-Discussion-p02
+2435117-02-Background-p01
+2435117-03-Methods-p01
+2435117-04-Results-p01
+2435117-04-Results-p02
+2435117-05-Discussion-p01
+2435117-06-Conclusion-p01
+2438340-01-Abstract-p01
+2438340-02-Background-p01
+2438340-03-Methods-p01
+2438340-04-Results-p01
+2438340-04-Results-p02
+2438340-04-Results-p03
+2438340-04-Results-p04
+2438340-05-Discussion-p01
+2438340-06-Conclusion-p01
+2488325-02-Background-p01
+2488325-02-Background-p02
+2488325-03-Methods-p02
+2488325-03-Methods-p03
+2488325-03-Methods-p04
+2488325-03-Methods-p05
+2488325-04-Results-p01
+2488325-05-Discussion-p02
+2488325-05-Discussion-p03
+2488325-05-Discussion-p04
+2488325-05-Discussion-p05
+2488325-06-Conclusion-p02
+2526421-02-INTRODUCTION-p02
+2526421-03-MATERIALS-AND-METHODS-p01
+2526421-04-RESULTS-p02
+2526421-05-DISCUSSION-p01
+2526421-05-DISCUSSION-p03
+2551625-02-Introduction-p01
+2551625-03-Methods-p02
+2551625-04-Results-p01
+2551625-05-Discussion-p02
+2551625-05-Discussion-p03
+2551625-05-Discussion-p04
+2559820-04-Results-p01
+2559820-05-Discussion-p01
+2559820-05-Discussion-p02
+2565065-02-Introduction-p01
+2565065-03-Results-p01
+2565065-03-Results-p03
+2565065-03-Results-p04
+2565065-03-Results-p06
+2565065-04-Discussion-p01
+2565065-05-Materials-and-Methods-p01
+2565065-05-Materials-and-Methods-p02
+2692982-01-Abstract-p01
+2692982-02-Background-p01
+2692982-03-Methods-p01
+2692982-04-Results-and-discussion-p01
+3034663-01-Abstract-p01
+3034663-02-Background-p01
+3034663-02-Background-p02
+3034663-03-Methods-p01
+3034663-03-Methods-p02
+3034663-04-Results-p01
+3034663-05-Discussion-p01
diff --git a/huner/ner_scripts/splits/variome_disease.dev b/huner/ner_scripts/splits/variome_disease.dev
new file mode 100644
index 0000000..28469c1
--- /dev/null
+++ b/huner/ner_scripts/splits/variome_disease.dev
@@ -0,0 +1,41 @@
+
+1064099-03-Methods-p02
+1067522-04-RESULTS-p03
+1266026-05-Discussion-p01
+1334229-05-Discussion-p01
+1373649-02-Background-p01
+1373649-03-Methods-p02
+1373649-04-Results-and-discussion-p02
+1601966-06-Methods-p01
+1619718-02-Introduction-p01
+1619718-03-Materials-and-methods-p03
+1619718-04-Results-p01
+1784097-02-Background-p01
+1808468-03-Methods-p03
+2048978-06-Methods-p01
+2253649-02-Introduction-p01
+2253649-04-Results-p03
+2253649-04-Results-p04
+2253649-05-Discussion-p01
+2323222-03-Results-p07
+2323222-03-Results-p09
+2374968-03-Materials-and-methods-p01
+2375115-05-Materials-and-Methods-p03
+2386495-03-Methods-p01
+2386495-05-Discussion-p02
+2397009-04-RESULTS-p01
+2429944-03-Methods-p01
+2429944-05-Discussion-p01
+2435117-01-Abstract-p01
+2438340-03-Methods-p03
+2438340-03-Methods-p04
+2438340-05-Discussion-p02
+2488325-04-Results-p02
+2488325-04-Results-p05
+2488325-06-Conclusion-p01
+2526421-02-INTRODUCTION-p01
+2526421-03-MATERIALS-AND-METHODS-p02
+2551625-04-Results-p02
+2559820-03-Methods-p01
+2559820-04-Results-p02
+2565065-05-Materials-and-Methods-p03
diff --git a/huner/ner_scripts/splits/variome_disease.test b/huner/ner_scripts/splits/variome_disease.test
new file mode 100644
index 0000000..30dc29d
--- /dev/null
+++ b/huner/ner_scripts/splits/variome_disease.test
@@ -0,0 +1,100 @@
+
+1067522-01-Abstract-p01
+1067522-04-RESULTS-p02
+1067522-05-DISCUSSION-p01
+1266026-02-Background-p01
+1266026-06-Conclusion-p01
+1334229-02-Background-p01
+1334229-03-Methods-p01
+1334229-06-Conclusion-p01
+1360090-02-Background-p01
+1360090-03-Results-p01
+1557864-01-Abstract-p01
+1557864-02-Background-p02
+1557864-05-Discussion-p03
+1557864-05-Discussion-p04
+1601966-03-Results-p03
+1601966-03-Results-p04
+1601966-03-Results-p12
+1601966-04-Discussion-p01
+1601966-05-Conclusion-p01
+1619718-05-Discussion-p02
+1619718-05-Discussion-p05
+1784097-03-Methods-p01
+1808468-04-Results-p01
+1808468-05-Discussion-p01
+2039842-01-Abstract-p01
+2039842-02-Introduction-p02
+2039842-03-Materials-and-methods-p01
+2039842-05-Discussion-p03
+2048978-04-Discussion-p01
+2048978-05-Conclusion-p01
+2206733-02-Introduction-p01
+2206733-03-Materials-and-methods-p03
+2206733-05-Discussion-p01
+2253649-03-Materials-and-methods-p02
+2253649-04-Results-p02
+2253649-04-Results-p05
+2265717-03-Case-presentation-p01
+2265717-04-Discussion-p01
+2265717-05-Conclusion-p01
+2275286-03-Methods-p02
+2275286-05-Discussion-p02
+2323222-02-Background-p01
+2323222-03-Results-p01
+2323222-03-Results-p06
+2323222-03-Results-p08
+2323222-04-Discussion-p03
+2323222-04-Discussion-p04
+2323222-05-Materials-and-methods-p03
+2323222-05-Materials-and-methods-p04
+2374968-01-Abstract-p01
+2374968-02-Introduction-p01
+2374968-04-Results-p02
+2375115-04-Discussion-p02
+2375115-05-Materials-and-Methods-p02
+2386495-02-Background-p02
+2386495-04-Results-p02
+2386495-04-Results-p05
+2386495-05-Discussion-p03
+2386495-05-Discussion-p04
+2397009-02-INTRODUCTION-p02
+2397009-03-METHODS-p02
+2397009-06-CONCLUSION-p01
+2410297-02-Introduction-p02
+2410297-04-Discussion-p02
+2410297-05-Materials-and-Methods-p01
+2429944-02-Introduction-p02
+2429944-04-Results-p02
+2429944-04-Results-p05
+2435117-03-Methods-p02
+2438340-02-Background-p02
+2438340-03-Methods-p02
+2438340-05-Discussion-p03
+2438340-05-Discussion-p04
+2488325-01-Abstract-p01
+2488325-03-Methods-p01
+2488325-03-Methods-p06
+2488325-04-Results-p03
+2488325-04-Results-p04
+2488325-05-Discussion-p01
+2488325-05-Discussion-p06
+2526421-01-Abstract-p01
+2526421-04-RESULTS-p01
+2526421-05-DISCUSSION-p02
+2551625-01-Abstract-p01
+2551625-02-Introduction-p02
+2551625-03-Methods-p01
+2551625-04-Results-p03
+2551625-05-Discussion-p01
+2559820-01-Abstract-p01
+2559820-02-Background-p01
+2559820-06-Conclusion-p01
+2565065-01-Abstract-p01
+2565065-02-Introduction-p02
+2565065-03-Results-p02
+2565065-03-Results-p05
+2565065-04-Discussion-p02
+3034663-04-Results-p02
+3034663-05-Discussion-p02
+3034663-06-Conclusions-p01
diff --git a/huner/ner_scripts/splits/variome_disease.train b/huner/ner_scripts/splits/variome_disease.train
new file mode 100644
index 0000000..ff5585b
--- /dev/null
+++ b/huner/ner_scripts/splits/variome_disease.train
@@ -0,0 +1,254 @@
+
+1064099-01-Abstract-p01
+1064099-02-Introduction-p01
+1064099-03-Methods-p01
+1064099-04-Results-p01
+1064099-05-Discussion-p01
+1064099-06-Conclusion-p01
+1067522-02-INTRODUCTION-p01
+1067522-03-MATERIALS-AND-METHODS-p01
+1067522-04-RESULTS-p01
+1067522-05-DISCUSSION-p02
+1266026-01-Abstract-p01
+1266026-03-Methods-p01
+1266026-04-Results-p01
+1266026-05-Discussion-p02
+1266026-05-Discussion-p03
+1334229-01-Abstract-p01
+1334229-02-Background-p02
+1334229-03-Methods-p02
+1334229-03-Methods-p03
+1334229-04-Results-p01
+1334229-04-Results-p02
+1334229-05-Discussion-p02
+1334229-05-Discussion-p03
+1360090-01-Abstract-p01
+1360090-03-Results-p02
+1360090-04-Discussion-p01
+1360090-05-Conclusion-p01
+1360090-06-Methods-p01
+1373649-01-Abstract-p01
+1373649-03-Methods-p01
+1373649-04-Results-and-discussion-p01
+1373649-05-Conclusion-p01
+1557864-02-Background-p01
+1557864-03-Methods-p01
+1557864-03-Methods-p02
+1557864-04-Results-p01
+1557864-05-Discussion-p01
+1557864-05-Discussion-p02
+1557864-06-Conclusion-p01
+1601966-01-Abstract-p01
+1601966-02-Background-p01
+1601966-02-Background-p02
+1601966-03-Results-p01
+1601966-03-Results-p02
+1601966-03-Results-p05
+1601966-03-Results-p06
+1601966-03-Results-p07
+1601966-03-Results-p08
+1601966-03-Results-p09
+1601966-03-Results-p10
+1601966-03-Results-p11
+1601966-04-Discussion-p02
+1601966-04-Discussion-p03
+1601966-06-Methods-p02
+1601966-06-Methods-p03
+1601966-06-Methods-p04
+1601966-06-Methods-p05
+1619718-01-Abstract-p01
+1619718-02-Introduction-p02
+1619718-03-Materials-and-methods-p01
+1619718-03-Materials-and-methods-p02
+1619718-04-Results-p02
+1619718-04-Results-p03
+1619718-05-Discussion-p01
+1619718-05-Discussion-p03
+1619718-05-Discussion-p04
+1784097-01-Abstract-p01
+1784097-02-Background-p02
+1784097-03-Methods-p02
+1784097-03-Methods-p03
+1784097-04-Results-and-discussion-p01
+1784097-04-Results-and-discussion-p02
+1784097-05-Conclusion-p01
+1808468-01-Abstract-p01
+1808468-02-Background-p01
+1808468-02-Background-p02
+1808468-03-Methods-p01
+1808468-03-Methods-p02
+1808468-04-Results-p02
+1808468-05-Discussion-p02
+1808468-06-Conclusion-p01
+2039842-02-Introduction-p01
+2039842-03-Materials-and-methods-p02
+2039842-03-Materials-and-methods-p03
+2039842-03-Materials-and-methods-p04
+2039842-03-Materials-and-methods-p05
+2039842-04-Results-p01
+2039842-04-Results-p02
+2039842-04-Results-p03
+2039842-04-Results-p04
+2039842-05-Discussion-p01
+2039842-05-Discussion-p02
+2048978-01-Abstract-p01
+2048978-02-Background-p01
+2048978-03-Results-p01
+2048978-03-Results-p02
+2048978-04-Discussion-p02
+2048978-06-Methods-p02
+2048978-06-Methods-p03
+2206733-01-Abstract-p01
+2206733-03-Materials-and-methods-p01
+2206733-03-Materials-and-methods-p02
+2206733-04-Results-p01
+2206733-04-Results-p02
+2206733-04-Results-p03
+2206733-04-Results-p04
+2206733-05-Discussion-p02
+2206733-05-Discussion-p03
+2206733-06-Conclusion-p01
+2253649-01-Abstract-p01
+2253649-03-Materials-and-methods-p01
+2253649-04-Results-p01
+2253649-04-Results-p06
+2253649-05-Discussion-p02
+2253649-05-Discussion-p03
+2265717-01-Abstract-p01
+2265717-02-Background-p01
+2275286-01-Abstract-p01
+2275286-02-Background-p01
+2275286-03-Methods-p01
+2275286-03-Methods-p03
+2275286-03-Methods-p04
+2275286-04-Results-p01
+2275286-04-Results-p02
+2275286-05-Discussion-p01
+2275286-06-Conclusion-p01
+2323222-01-Abstract-p01
+2323222-02-Background-p02
+2323222-03-Results-p02
+2323222-03-Results-p03
+2323222-03-Results-p04
+2323222-03-Results-p05
+2323222-04-Discussion-p01
+2323222-04-Discussion-p02
+2323222-04-Discussion-p05
+2323222-05-Materials-and-methods-p01
+2323222-05-Materials-and-methods-p02
+2323222-05-Materials-and-methods-p05
+2374968-03-Materials-and-methods-p02
+2374968-04-Results-p01
+2374968-04-Results-p03
+2374968-04-Results-p04
+2374968-05-Discussion-p01
+2374968-06-Conclusion-p01
+2375115-01-Abstract-p01
+2375115-02-Introduction-p01
+2375115-02-Introduction-p02
+2375115-03-Results-p01
+2375115-03-Results-p02
+2375115-03-Results-p03
+2375115-03-Results-p04
+2375115-04-Discussion-p01
+2375115-04-Discussion-p03
+2375115-05-Materials-and-Methods-p01
+2386495-01-Abstract-p01
+2386495-02-Background-p01
+2386495-03-Methods-p02
+2386495-03-Methods-p03
+2386495-04-Results-p01
+2386495-04-Results-p03
+2386495-04-Results-p04
+2386495-05-Discussion-p01
+2386495-06-Conclusion-p01
+2397009-01-Abstract-p01
+2397009-02-INTRODUCTION-p01
+2397009-03-METHODS-p01
+2397009-03-METHODS-p03
+2397009-05-DISCUSSION-p01
+2397009-05-DISCUSSION-p02
+2397009-05-DISCUSSION-p03
+2410297-01-Abstract-p01
+2410297-02-Introduction-p01
+2410297-03-Results-p01
+2410297-03-Results-p02
+2410297-03-Results-p03
+2410297-03-Results-p04
+2410297-03-Results-p05
+2410297-03-Results-p06
+2410297-04-Discussion-p01
+2410297-05-Materials-and-Methods-p02
+2410297-05-Materials-and-Methods-p03
+2429944-01-Abstract-p01
+2429944-01-Abstract-p02
+2429944-01-Abstract-p03
+2429944-02-Introduction-p01
+2429944-03-Methods-p02
+2429944-04-Results-p01
+2429944-04-Results-p03
+2429944-04-Results-p04
+2429944-04-Results-p06
+2429944-04-Results-p07
+2429944-04-Results-p08
+2429944-05-Discussion-p02
+2435117-02-Background-p01
+2435117-03-Methods-p01
+2435117-04-Results-p01
+2435117-04-Results-p02
+2435117-05-Discussion-p01
+2435117-06-Conclusion-p01
+2438340-01-Abstract-p01
+2438340-02-Background-p01
+2438340-03-Methods-p01
+2438340-04-Results-p01
+2438340-04-Results-p02
+2438340-04-Results-p03
+2438340-04-Results-p04
+2438340-05-Discussion-p01
+2438340-06-Conclusion-p01
+2488325-02-Background-p01
+2488325-02-Background-p02
+2488325-03-Methods-p02
+2488325-03-Methods-p03
+2488325-03-Methods-p04
+2488325-03-Methods-p05
+2488325-04-Results-p01
+2488325-05-Discussion-p02
+2488325-05-Discussion-p03
+2488325-05-Discussion-p04
+2488325-05-Discussion-p05
+2488325-06-Conclusion-p02
+2526421-02-INTRODUCTION-p02
+2526421-03-MATERIALS-AND-METHODS-p01
+2526421-04-RESULTS-p02
+2526421-05-DISCUSSION-p01
+2526421-05-DISCUSSION-p03
+2551625-02-Introduction-p01
+2551625-03-Methods-p02
+2551625-04-Results-p01
+2551625-05-Discussion-p02
+2551625-05-Discussion-p03
+2551625-05-Discussion-p04
+2559820-04-Results-p01
+2559820-05-Discussion-p01
+2559820-05-Discussion-p02
+2565065-02-Introduction-p01
+2565065-03-Results-p01
+2565065-03-Results-p03
+2565065-03-Results-p04
+2565065-03-Results-p06
+2565065-04-Discussion-p01
+2565065-05-Materials-and-Methods-p01
+2565065-05-Materials-and-Methods-p02
+2692982-01-Abstract-p01
+2692982-02-Background-p01
+2692982-03-Methods-p01
+2692982-04-Results-and-discussion-p01
+3034663-01-Abstract-p01
+3034663-02-Background-p01
+3034663-02-Background-p02
+3034663-03-Methods-p01
+3034663-03-Methods-p02
+3034663-04-Results-p01
+3034663-05-Discussion-p01
diff --git a/huner/ner_scripts/splits/variome_gene.dev b/huner/ner_scripts/splits/variome_gene.dev
new file mode 100644
index 0000000..28469c1
--- /dev/null
+++ b/huner/ner_scripts/splits/variome_gene.dev
@@ -0,0 +1,41 @@
+
+1064099-03-Methods-p02
+1067522-04-RESULTS-p03
+1266026-05-Discussion-p01
+1334229-05-Discussion-p01
+1373649-02-Background-p01
+1373649-03-Methods-p02
+1373649-04-Results-and-discussion-p02
+1601966-06-Methods-p01
+1619718-02-Introduction-p01
+1619718-03-Materials-and-methods-p03
+1619718-04-Results-p01
+1784097-02-Background-p01
+1808468-03-Methods-p03
+2048978-06-Methods-p01
+2253649-02-Introduction-p01
+2253649-04-Results-p03
+2253649-04-Results-p04
+2253649-05-Discussion-p01
+2323222-03-Results-p07
+2323222-03-Results-p09
+2374968-03-Materials-and-methods-p01
+2375115-05-Materials-and-Methods-p03
+2386495-03-Methods-p01
+2386495-05-Discussion-p02
+2397009-04-RESULTS-p01
+2429944-03-Methods-p01
+2429944-05-Discussion-p01
+2435117-01-Abstract-p01
+2438340-03-Methods-p03
+2438340-03-Methods-p04
+2438340-05-Discussion-p02
+2488325-04-Results-p02
+2488325-04-Results-p05
+2488325-06-Conclusion-p01
+2526421-02-INTRODUCTION-p01
+2526421-03-MATERIALS-AND-METHODS-p02
+2551625-04-Results-p02
+2559820-03-Methods-p01
+2559820-04-Results-p02
+2565065-05-Materials-and-Methods-p03
diff --git a/huner/ner_scripts/splits/variome_gene.test b/huner/ner_scripts/splits/variome_gene.test
new file mode 100644
index 0000000..30dc29d
--- /dev/null
+++ b/huner/ner_scripts/splits/variome_gene.test
@@ -0,0 +1,100 @@
+
+1067522-01-Abstract-p01
+1067522-04-RESULTS-p02
+1067522-05-DISCUSSION-p01
+1266026-02-Background-p01
+1266026-06-Conclusion-p01
+1334229-02-Background-p01
+1334229-03-Methods-p01
+1334229-06-Conclusion-p01
+1360090-02-Background-p01
+1360090-03-Results-p01
+1557864-01-Abstract-p01
+1557864-02-Background-p02
+1557864-05-Discussion-p03
+1557864-05-Discussion-p04
+1601966-03-Results-p03
+1601966-03-Results-p04
+1601966-03-Results-p12
+1601966-04-Discussion-p01
+1601966-05-Conclusion-p01
+1619718-05-Discussion-p02
+1619718-05-Discussion-p05
+1784097-03-Methods-p01
+1808468-04-Results-p01
+1808468-05-Discussion-p01
+2039842-01-Abstract-p01
+2039842-02-Introduction-p02
+2039842-03-Materials-and-methods-p01
+2039842-05-Discussion-p03
+2048978-04-Discussion-p01
+2048978-05-Conclusion-p01
+2206733-02-Introduction-p01
+2206733-03-Materials-and-methods-p03
+2206733-05-Discussion-p01
+2253649-03-Materials-and-methods-p02
+2253649-04-Results-p02
+2253649-04-Results-p05
+2265717-03-Case-presentation-p01
+2265717-04-Discussion-p01
+2265717-05-Conclusion-p01
+2275286-03-Methods-p02
+2275286-05-Discussion-p02
+2323222-02-Background-p01
+2323222-03-Results-p01
+2323222-03-Results-p06
+2323222-03-Results-p08
+2323222-04-Discussion-p03
+2323222-04-Discussion-p04
+2323222-05-Materials-and-methods-p03
+2323222-05-Materials-and-methods-p04
+2374968-01-Abstract-p01
+2374968-02-Introduction-p01
+2374968-04-Results-p02
+2375115-04-Discussion-p02
+2375115-05-Materials-and-Methods-p02
+2386495-02-Background-p02
+2386495-04-Results-p02
+2386495-04-Results-p05
+2386495-05-Discussion-p03
+2386495-05-Discussion-p04
+2397009-02-INTRODUCTION-p02
+2397009-03-METHODS-p02
+2397009-06-CONCLUSION-p01
+2410297-02-Introduction-p02
+2410297-04-Discussion-p02
+2410297-05-Materials-and-Methods-p01
+2429944-02-Introduction-p02
+2429944-04-Results-p02
+2429944-04-Results-p05
+2435117-03-Methods-p02
+2438340-02-Background-p02
+2438340-03-Methods-p02
+2438340-05-Discussion-p03
+2438340-05-Discussion-p04
+2488325-01-Abstract-p01
+2488325-03-Methods-p01
+2488325-03-Methods-p06
+2488325-04-Results-p03
+2488325-04-Results-p04
+2488325-05-Discussion-p01
+2488325-05-Discussion-p06
+2526421-01-Abstract-p01
+2526421-04-RESULTS-p01
+2526421-05-DISCUSSION-p02
+2551625-01-Abstract-p01
+2551625-02-Introduction-p02
+2551625-03-Methods-p01
+2551625-04-Results-p03
+2551625-05-Discussion-p01
+2559820-01-Abstract-p01
+2559820-02-Background-p01
+2559820-06-Conclusion-p01
+2565065-01-Abstract-p01
+2565065-02-Introduction-p02
+2565065-03-Results-p02
+2565065-03-Results-p05
+2565065-04-Discussion-p02
+3034663-04-Results-p02
+3034663-05-Discussion-p02
+3034663-06-Conclusions-p01
diff --git a/huner/ner_scripts/splits/variome_gene.train b/huner/ner_scripts/splits/variome_gene.train
new file mode 100644
index 0000000..ff5585b
--- /dev/null
+++ b/huner/ner_scripts/splits/variome_gene.train
@@ -0,0 +1,254 @@
+
+1064099-01-Abstract-p01
+1064099-02-Introduction-p01
+1064099-03-Methods-p01
+1064099-04-Results-p01
+1064099-05-Discussion-p01
+1064099-06-Conclusion-p01
+1067522-02-INTRODUCTION-p01
+1067522-03-MATERIALS-AND-METHODS-p01
+1067522-04-RESULTS-p01
+1067522-05-DISCUSSION-p02
+1266026-01-Abstract-p01
+1266026-03-Methods-p01
+1266026-04-Results-p01
+1266026-05-Discussion-p02
+1266026-05-Discussion-p03
+1334229-01-Abstract-p01
+1334229-02-Background-p02
+1334229-03-Methods-p02
+1334229-03-Methods-p03
+1334229-04-Results-p01
+1334229-04-Results-p02
+1334229-05-Discussion-p02
+1334229-05-Discussion-p03
+1360090-01-Abstract-p01
+1360090-03-Results-p02
+1360090-04-Discussion-p01
+1360090-05-Conclusion-p01
+1360090-06-Methods-p01
+1373649-01-Abstract-p01
+1373649-03-Methods-p01
+1373649-04-Results-and-discussion-p01
+1373649-05-Conclusion-p01
+1557864-02-Background-p01
+1557864-03-Methods-p01
+1557864-03-Methods-p02
+1557864-04-Results-p01
+1557864-05-Discussion-p01
+1557864-05-Discussion-p02
+1557864-06-Conclusion-p01
+1601966-01-Abstract-p01
+1601966-02-Background-p01
+1601966-02-Background-p02
+1601966-03-Results-p01
+1601966-03-Results-p02
+1601966-03-Results-p05
+1601966-03-Results-p06
+1601966-03-Results-p07
+1601966-03-Results-p08
+1601966-03-Results-p09
+1601966-03-Results-p10
+1601966-03-Results-p11
+1601966-04-Discussion-p02
+1601966-04-Discussion-p03
+1601966-06-Methods-p02
+1601966-06-Methods-p03
+1601966-06-Methods-p04
+1601966-06-Methods-p05
+1619718-01-Abstract-p01
+1619718-02-Introduction-p02
+1619718-03-Materials-and-methods-p01
+1619718-03-Materials-and-methods-p02
+1619718-04-Results-p02
+1619718-04-Results-p03
+1619718-05-Discussion-p01
+1619718-05-Discussion-p03
+1619718-05-Discussion-p04
+1784097-01-Abstract-p01
+1784097-02-Background-p02
+1784097-03-Methods-p02
+1784097-03-Methods-p03
+1784097-04-Results-and-discussion-p01
+1784097-04-Results-and-discussion-p02
+1784097-05-Conclusion-p01
+1808468-01-Abstract-p01
+1808468-02-Background-p01
+1808468-02-Background-p02
+1808468-03-Methods-p01
+1808468-03-Methods-p02
+1808468-04-Results-p02
+1808468-05-Discussion-p02
+1808468-06-Conclusion-p01
+2039842-02-Introduction-p01
+2039842-03-Materials-and-methods-p02
+2039842-03-Materials-and-methods-p03
+2039842-03-Materials-and-methods-p04
+2039842-03-Materials-and-methods-p05
+2039842-04-Results-p01
+2039842-04-Results-p02
+2039842-04-Results-p03
+2039842-04-Results-p04
+2039842-05-Discussion-p01
+2039842-05-Discussion-p02
+2048978-01-Abstract-p01
+2048978-02-Background-p01
+2048978-03-Results-p01
+2048978-03-Results-p02
+2048978-04-Discussion-p02
+2048978-06-Methods-p02
+2048978-06-Methods-p03
+2206733-01-Abstract-p01
+2206733-03-Materials-and-methods-p01
+2206733-03-Materials-and-methods-p02
+2206733-04-Results-p01
+2206733-04-Results-p02
+2206733-04-Results-p03
+2206733-04-Results-p04
+2206733-05-Discussion-p02
+2206733-05-Discussion-p03
+2206733-06-Conclusion-p01
+2253649-01-Abstract-p01
+2253649-03-Materials-and-methods-p01
+2253649-04-Results-p01
+2253649-04-Results-p06
+2253649-05-Discussion-p02
+2253649-05-Discussion-p03
+2265717-01-Abstract-p01
+2265717-02-Background-p01
+2275286-01-Abstract-p01
+2275286-02-Background-p01
+2275286-03-Methods-p01
+2275286-03-Methods-p03
+2275286-03-Methods-p04
+2275286-04-Results-p01
+2275286-04-Results-p02
+2275286-05-Discussion-p01
+2275286-06-Conclusion-p01
+2323222-01-Abstract-p01
+2323222-02-Background-p02
+2323222-03-Results-p02
+2323222-03-Results-p03
+2323222-03-Results-p04
+2323222-03-Results-p05
+2323222-04-Discussion-p01
+2323222-04-Discussion-p02
+2323222-04-Discussion-p05
+2323222-05-Materials-and-methods-p01
+2323222-05-Materials-and-methods-p02
+2323222-05-Materials-and-methods-p05
+2374968-03-Materials-and-methods-p02
+2374968-04-Results-p01
+2374968-04-Results-p03
+2374968-04-Results-p04
+2374968-05-Discussion-p01
+2374968-06-Conclusion-p01
+2375115-01-Abstract-p01
+2375115-02-Introduction-p01
+2375115-02-Introduction-p02
+2375115-03-Results-p01
+2375115-03-Results-p02
+2375115-03-Results-p03
+2375115-03-Results-p04
+2375115-04-Discussion-p01
+2375115-04-Discussion-p03
+2375115-05-Materials-and-Methods-p01
+2386495-01-Abstract-p01
+2386495-02-Background-p01
+2386495-03-Methods-p02
+2386495-03-Methods-p03
+2386495-04-Results-p01
+2386495-04-Results-p03
+2386495-04-Results-p04
+2386495-05-Discussion-p01
+2386495-06-Conclusion-p01
+2397009-01-Abstract-p01
+2397009-02-INTRODUCTION-p01
+2397009-03-METHODS-p01
+2397009-03-METHODS-p03
+2397009-05-DISCUSSION-p01
+2397009-05-DISCUSSION-p02
+2397009-05-DISCUSSION-p03
+2410297-01-Abstract-p01
+2410297-02-Introduction-p01
+2410297-03-Results-p01
+2410297-03-Results-p02
+2410297-03-Results-p03
+2410297-03-Results-p04
+2410297-03-Results-p05
+2410297-03-Results-p06
+2410297-04-Discussion-p01
+2410297-05-Materials-and-Methods-p02
+2410297-05-Materials-and-Methods-p03
+2429944-01-Abstract-p01
+2429944-01-Abstract-p02
+2429944-01-Abstract-p03
+2429944-02-Introduction-p01
+2429944-03-Methods-p02
+2429944-04-Results-p01
+2429944-04-Results-p03
+2429944-04-Results-p04
+2429944-04-Results-p06
+2429944-04-Results-p07
+2429944-04-Results-p08
+2429944-05-Discussion-p02
+2435117-02-Background-p01
+2435117-03-Methods-p01
+2435117-04-Results-p01
+2435117-04-Results-p02
+2435117-05-Discussion-p01
+2435117-06-Conclusion-p01
+2438340-01-Abstract-p01
+2438340-02-Background-p01
+2438340-03-Methods-p01
+2438340-04-Results-p01
+2438340-04-Results-p02
+2438340-04-Results-p03
+2438340-04-Results-p04
+2438340-05-Discussion-p01
+2438340-06-Conclusion-p01
+2488325-02-Background-p01
+2488325-02-Background-p02
+2488325-03-Methods-p02
+2488325-03-Methods-p03
+2488325-03-Methods-p04
+2488325-03-Methods-p05
+2488325-04-Results-p01
+2488325-05-Discussion-p02
+2488325-05-Discussion-p03
+2488325-05-Discussion-p04
+2488325-05-Discussion-p05
+2488325-06-Conclusion-p02
+2526421-02-INTRODUCTION-p02
+2526421-03-MATERIALS-AND-METHODS-p01
+2526421-04-RESULTS-p02
+2526421-05-DISCUSSION-p01
+2526421-05-DISCUSSION-p03
+2551625-02-Introduction-p01
+2551625-03-Methods-p02
+2551625-04-Results-p01
+2551625-05-Discussion-p02
+2551625-05-Discussion-p03
+2551625-05-Discussion-p04
+2559820-04-Results-p01
+2559820-05-Discussion-p01
+2559820-05-Discussion-p02
+2565065-02-Introduction-p01
+2565065-03-Results-p01
+2565065-03-Results-p03
+2565065-03-Results-p04
+2565065-03-Results-p06
+2565065-04-Discussion-p01
+2565065-05-Materials-and-Methods-p01
+2565065-05-Materials-and-Methods-p02
+2692982-01-Abstract-p01
+2692982-02-Background-p01
+2692982-03-Methods-p01
+2692982-04-Results-and-discussion-p01
+3034663-01-Abstract-p01
+3034663-02-Background-p01
+3034663-02-Background-p02
+3034663-03-Methods-p01
+3034663-03-Methods-p02
+3034663-04-Results-p01
+3034663-05-Discussion-p01
diff --git a/huner/ner_scripts/splits/variome_species.dev b/huner/ner_scripts/splits/variome_species.dev
new file mode 100644
index 0000000..28469c1
--- /dev/null
+++ b/huner/ner_scripts/splits/variome_species.dev
@@ -0,0 +1,41 @@
+
+1064099-03-Methods-p02
+1067522-04-RESULTS-p03
+1266026-05-Discussion-p01
+1334229-05-Discussion-p01
+1373649-02-Background-p01
+1373649-03-Methods-p02
+1373649-04-Results-and-discussion-p02
+1601966-06-Methods-p01
+1619718-02-Introduction-p01
+1619718-03-Materials-and-methods-p03
+1619718-04-Results-p01
+1784097-02-Background-p01
+1808468-03-Methods-p03
+2048978-06-Methods-p01
+2253649-02-Introduction-p01
+2253649-04-Results-p03
+2253649-04-Results-p04
+2253649-05-Discussion-p01
+2323222-03-Results-p07
+2323222-03-Results-p09
+2374968-03-Materials-and-methods-p01
+2375115-05-Materials-and-Methods-p03
+2386495-03-Methods-p01
+2386495-05-Discussion-p02
+2397009-04-RESULTS-p01
+2429944-03-Methods-p01
+2429944-05-Discussion-p01
+2435117-01-Abstract-p01
+2438340-03-Methods-p03
+2438340-03-Methods-p04
+2438340-05-Discussion-p02
+2488325-04-Results-p02
+2488325-04-Results-p05
+2488325-06-Conclusion-p01
+2526421-02-INTRODUCTION-p01
+2526421-03-MATERIALS-AND-METHODS-p02
+2551625-04-Results-p02
+2559820-03-Methods-p01
+2559820-04-Results-p02
+2565065-05-Materials-and-Methods-p03
diff --git a/huner/ner_scripts/splits/variome_species.test b/huner/ner_scripts/splits/variome_species.test
new file mode 100644
index 0000000..30dc29d
--- /dev/null
+++ b/huner/ner_scripts/splits/variome_species.test
@@ -0,0 +1,100 @@
+
+1067522-01-Abstract-p01
+1067522-04-RESULTS-p02
+1067522-05-DISCUSSION-p01
+1266026-02-Background-p01
+1266026-06-Conclusion-p01
+1334229-02-Background-p01
+1334229-03-Methods-p01
+1334229-06-Conclusion-p01
+1360090-02-Background-p01
+1360090-03-Results-p01
+1557864-01-Abstract-p01
+1557864-02-Background-p02
+1557864-05-Discussion-p03
+1557864-05-Discussion-p04
+1601966-03-Results-p03
+1601966-03-Results-p04
+1601966-03-Results-p12
+1601966-04-Discussion-p01
+1601966-05-Conclusion-p01
+1619718-05-Discussion-p02
+1619718-05-Discussion-p05
+1784097-03-Methods-p01
+1808468-04-Results-p01
+1808468-05-Discussion-p01
+2039842-01-Abstract-p01
+2039842-02-Introduction-p02
+2039842-03-Materials-and-methods-p01
+2039842-05-Discussion-p03
+2048978-04-Discussion-p01
+2048978-05-Conclusion-p01
+2206733-02-Introduction-p01
+2206733-03-Materials-and-methods-p03
+2206733-05-Discussion-p01
+2253649-03-Materials-and-methods-p02
+2253649-04-Results-p02
+2253649-04-Results-p05
+2265717-03-Case-presentation-p01
+2265717-04-Discussion-p01
+2265717-05-Conclusion-p01
+2275286-03-Methods-p02
+2275286-05-Discussion-p02
+2323222-02-Background-p01
+2323222-03-Results-p01
+2323222-03-Results-p06
+2323222-03-Results-p08
+2323222-04-Discussion-p03
+2323222-04-Discussion-p04
+2323222-05-Materials-and-methods-p03
+2323222-05-Materials-and-methods-p04
+2374968-01-Abstract-p01
+2374968-02-Introduction-p01
+2374968-04-Results-p02
+2375115-04-Discussion-p02
+2375115-05-Materials-and-Methods-p02
+2386495-02-Background-p02
+2386495-04-Results-p02
+2386495-04-Results-p05
+2386495-05-Discussion-p03
+2386495-05-Discussion-p04
+2397009-02-INTRODUCTION-p02
+2397009-03-METHODS-p02
+2397009-06-CONCLUSION-p01
+2410297-02-Introduction-p02
+2410297-04-Discussion-p02
+2410297-05-Materials-and-Methods-p01
+2429944-02-Introduction-p02
+2429944-04-Results-p02
+2429944-04-Results-p05
+2435117-03-Methods-p02
+2438340-02-Background-p02
+2438340-03-Methods-p02
+2438340-05-Discussion-p03
+2438340-05-Discussion-p04
+2488325-01-Abstract-p01
+2488325-03-Methods-p01
+2488325-03-Methods-p06
+2488325-04-Results-p03
+2488325-04-Results-p04
+2488325-05-Discussion-p01
+2488325-05-Discussion-p06
+2526421-01-Abstract-p01
+2526421-04-RESULTS-p01
+2526421-05-DISCUSSION-p02
+2551625-01-Abstract-p01
+2551625-02-Introduction-p02
+2551625-03-Methods-p01
+2551625-04-Results-p03
+2551625-05-Discussion-p01
+2559820-01-Abstract-p01
+2559820-02-Background-p01
+2559820-06-Conclusion-p01
+2565065-01-Abstract-p01
+2565065-02-Introduction-p02
+2565065-03-Results-p02
+2565065-03-Results-p05
+2565065-04-Discussion-p02
+3034663-04-Results-p02
+3034663-05-Discussion-p02
+3034663-06-Conclusions-p01
diff --git a/huner/ner_scripts/splits/variome_species.train b/huner/ner_scripts/splits/variome_species.train
new file mode 100644
index 0000000..ff5585b
--- /dev/null
+++ b/huner/ner_scripts/splits/variome_species.train
@@ -0,0 +1,254 @@
+
+1064099-01-Abstract-p01
+1064099-02-Introduction-p01
+1064099-03-Methods-p01
+1064099-04-Results-p01
+1064099-05-Discussion-p01
+1064099-06-Conclusion-p01
+1067522-02-INTRODUCTION-p01
+1067522-03-MATERIALS-AND-METHODS-p01
+1067522-04-RESULTS-p01
+1067522-05-DISCUSSION-p02
+1266026-01-Abstract-p01
+1266026-03-Methods-p01
+1266026-04-Results-p01
+1266026-05-Discussion-p02
+1266026-05-Discussion-p03
+1334229-01-Abstract-p01
+1334229-02-Background-p02
+1334229-03-Methods-p02
+1334229-03-Methods-p03
+1334229-04-Results-p01
+1334229-04-Results-p02
+1334229-05-Discussion-p02
+1334229-05-Discussion-p03
+1360090-01-Abstract-p01
+1360090-03-Results-p02
+1360090-04-Discussion-p01
+1360090-05-Conclusion-p01
+1360090-06-Methods-p01
+1373649-01-Abstract-p01
+1373649-03-Methods-p01
+1373649-04-Results-and-discussion-p01
+1373649-05-Conclusion-p01
+1557864-02-Background-p01
+1557864-03-Methods-p01
+1557864-03-Methods-p02
+1557864-04-Results-p01
+1557864-05-Discussion-p01
+1557864-05-Discussion-p02
+1557864-06-Conclusion-p01
+1601966-01-Abstract-p01
+1601966-02-Background-p01
+1601966-02-Background-p02
+1601966-03-Results-p01
+1601966-03-Results-p02
+1601966-03-Results-p05
+1601966-03-Results-p06
+1601966-03-Results-p07
+1601966-03-Results-p08
+1601966-03-Results-p09
+1601966-03-Results-p10
+1601966-03-Results-p11
+1601966-04-Discussion-p02
+1601966-04-Discussion-p03
+1601966-06-Methods-p02
+1601966-06-Methods-p03
+1601966-06-Methods-p04
+1601966-06-Methods-p05
+1619718-01-Abstract-p01
+1619718-02-Introduction-p02
+1619718-03-Materials-and-methods-p01
+1619718-03-Materials-and-methods-p02
+1619718-04-Results-p02
+1619718-04-Results-p03
+1619718-05-Discussion-p01
+1619718-05-Discussion-p03
+1619718-05-Discussion-p04
+1784097-01-Abstract-p01
+1784097-02-Background-p02
+1784097-03-Methods-p02
+1784097-03-Methods-p03
+1784097-04-Results-and-discussion-p01
+1784097-04-Results-and-discussion-p02
+1784097-05-Conclusion-p01
+1808468-01-Abstract-p01
+1808468-02-Background-p01
+1808468-02-Background-p02
+1808468-03-Methods-p01
+1808468-03-Methods-p02
+1808468-04-Results-p02
+1808468-05-Discussion-p02
+1808468-06-Conclusion-p01
+2039842-02-Introduction-p01
+2039842-03-Materials-and-methods-p02
+2039842-03-Materials-and-methods-p03
+2039842-03-Materials-and-methods-p04
+2039842-03-Materials-and-methods-p05
+2039842-04-Results-p01
+2039842-04-Results-p02
+2039842-04-Results-p03
+2039842-04-Results-p04
+2039842-05-Discussion-p01
+2039842-05-Discussion-p02
+2048978-01-Abstract-p01
+2048978-02-Background-p01
+2048978-03-Results-p01
+2048978-03-Results-p02
+2048978-04-Discussion-p02
+2048978-06-Methods-p02
+2048978-06-Methods-p03
+2206733-01-Abstract-p01
+2206733-03-Materials-and-methods-p01
+2206733-03-Materials-and-methods-p02
+2206733-04-Results-p01
+2206733-04-Results-p02
+2206733-04-Results-p03
+2206733-04-Results-p04
+2206733-05-Discussion-p02
+2206733-05-Discussion-p03
+2206733-06-Conclusion-p01
+2253649-01-Abstract-p01
+2253649-03-Materials-and-methods-p01
+2253649-04-Results-p01
+2253649-04-Results-p06
+2253649-05-Discussion-p02
+2253649-05-Discussion-p03
+2265717-01-Abstract-p01
+2265717-02-Background-p01
+2275286-01-Abstract-p01
+2275286-02-Background-p01
+2275286-03-Methods-p01
+2275286-03-Methods-p03
+2275286-03-Methods-p04
+2275286-04-Results-p01
+2275286-04-Results-p02
+2275286-05-Discussion-p01
+2275286-06-Conclusion-p01
+2323222-01-Abstract-p01
+2323222-02-Background-p02
+2323222-03-Results-p02
+2323222-03-Results-p03
+2323222-03-Results-p04
+2323222-03-Results-p05
+2323222-04-Discussion-p01
+2323222-04-Discussion-p02
+2323222-04-Discussion-p05
+2323222-05-Materials-and-methods-p01
+2323222-05-Materials-and-methods-p02
+2323222-05-Materials-and-methods-p05
+2374968-03-Materials-and-methods-p02
+2374968-04-Results-p01
+2374968-04-Results-p03
+2374968-04-Results-p04
+2374968-05-Discussion-p01
+2374968-06-Conclusion-p01
+2375115-01-Abstract-p01
+2375115-02-Introduction-p01
+2375115-02-Introduction-p02
+2375115-03-Results-p01
+2375115-03-Results-p02
+2375115-03-Results-p03
+2375115-03-Results-p04
+2375115-04-Discussion-p01
+2375115-04-Discussion-p03
+2375115-05-Materials-and-Methods-p01
+2386495-01-Abstract-p01
+2386495-02-Background-p01
+2386495-03-Methods-p02
+2386495-03-Methods-p03
+2386495-04-Results-p01
+2386495-04-Results-p03
+2386495-04-Results-p04
+2386495-05-Discussion-p01
+2386495-06-Conclusion-p01
+2397009-01-Abstract-p01
+2397009-02-INTRODUCTION-p01
+2397009-03-METHODS-p01
+2397009-03-METHODS-p03
+2397009-05-DISCUSSION-p01
+2397009-05-DISCUSSION-p02
+2397009-05-DISCUSSION-p03
+2410297-01-Abstract-p01
+2410297-02-Introduction-p01
+2410297-03-Results-p01
+2410297-03-Results-p02
+2410297-03-Results-p03
+2410297-03-Results-p04
+2410297-03-Results-p05
+2410297-03-Results-p06
+2410297-04-Discussion-p01
+2410297-05-Materials-and-Methods-p02
+2410297-05-Materials-and-Methods-p03
+2429944-01-Abstract-p01
+2429944-01-Abstract-p02
+2429944-01-Abstract-p03
+2429944-02-Introduction-p01
+2429944-03-Methods-p02
+2429944-04-Results-p01
+2429944-04-Results-p03
+2429944-04-Results-p04
+2429944-04-Results-p06
+2429944-04-Results-p07
+2429944-04-Results-p08
+2429944-05-Discussion-p02
+2435117-02-Background-p01
+2435117-03-Methods-p01
+2435117-04-Results-p01
+2435117-04-Results-p02
+2435117-05-Discussion-p01
+2435117-06-Conclusion-p01
+2438340-01-Abstract-p01
+2438340-02-Background-p01
+2438340-03-Methods-p01
+2438340-04-Results-p01
+2438340-04-Results-p02
+2438340-04-Results-p03
+2438340-04-Results-p04
+2438340-05-Discussion-p01
+2438340-06-Conclusion-p01
+2488325-02-Background-p01
+2488325-02-Background-p02
+2488325-03-Methods-p02
+2488325-03-Methods-p03
+2488325-03-Methods-p04
+2488325-03-Methods-p05
+2488325-04-Results-p01
+2488325-05-Discussion-p02
+2488325-05-Discussion-p03
+2488325-05-Discussion-p04
+2488325-05-Discussion-p05
+2488325-06-Conclusion-p02
+2526421-02-INTRODUCTION-p02
+2526421-03-MATERIALS-AND-METHODS-p01
+2526421-04-RESULTS-p02
+2526421-05-DISCUSSION-p01
+2526421-05-DISCUSSION-p03
+2551625-02-Introduction-p01
+2551625-03-Methods-p02
+2551625-04-Results-p01
+2551625-05-Discussion-p02
+2551625-05-Discussion-p03
+2551625-05-Discussion-p04
+2559820-04-Results-p01
+2559820-05-Discussion-p01
+2559820-05-Discussion-p02
+2565065-02-Introduction-p01
+2565065-03-Results-p01
+2565065-03-Results-p03
+2565065-03-Results-p04
+2565065-03-Results-p06
+2565065-04-Discussion-p01
+2565065-05-Materials-and-Methods-p01
+2565065-05-Materials-and-Methods-p02
+2692982-01-Abstract-p01
+2692982-02-Background-p01
+2692982-03-Methods-p01
+2692982-04-Results-and-discussion-p01
+3034663-01-Abstract-p01
+3034663-02-Background-p01
+3034663-02-Background-p02
+3034663-03-Methods-p01
+3034663-03-Methods-p02
+3034663-04-Results-p01
+3034663-05-Discussion-p01
diff --git a/huner/nn.py b/huner/nn.py
new file mode 100644
index 0000000..1db9dea
--- /dev/null
+++ b/huner/nn.py
@@ -0,0 +1,282 @@
+import theano
+import theano.tensor as T
+from utils import shared
+
+
+class HiddenLayer(object):
+    """
+    Hidden layer with or without bias.
+    Input: tensor of dimension (dims*, input_dim)
+    Output: tensor of dimension (dims*, output_dim)
+    """
+    def __init__(self, input_dim, output_dim, bias=True, activation='sigmoid',
+                 name='hidden_layer'):
+        self.input_dim = input_dim
+        self.output_dim = output_dim
+        self.bias = bias
+        self.name = name
+        if activation is None:
+            self.activation = None
+        elif activation == 'tanh':
+            self.activation = T.tanh
+        elif activation == 'sigmoid':
+            self.activation = T.nnet.sigmoid
+        elif activation == 'softmax':
+            self.activation = T.nnet.softmax
+        else:
+            raise Exception("Unknown activation function: " % activation)
+
+        # Initialize weights and bias
+        self.weights = shared((input_dim, output_dim), name + '__weights')
+        self.bias = shared((output_dim,), name + '__bias')
+
+        # Define parameters
+        if self.bias:
+            self.params = [self.weights, self.bias]
+        else:
+            self.params = [self.weights]
+
+    def link(self, input):
+        """
+        The input has to be a tensor with the right
+        most dimension equal to input_dim.
+        """
+        self.input = input
+        self.linear_output = T.dot(self.input, self.weights)
+        if self.bias:
+            self.linear_output = self.linear_output + self.bias
+        if self.activation is None:
+            self.output = self.linear_output
+        else:
+            self.output = self.activation(self.linear_output)
+        return self.output
+
+
+class EmbeddingLayer(object):
+    """
+    Embedding layer: word embeddings representations
+    Input: tensor of dimension (dim*) with values in range(0, input_dim)
+    Output: tensor of dimension (dim*, output_dim)
+    """
+
+    def __init__(self, input_dim, output_dim, name='embedding_layer'):
+        """
+        Typically, input_dim is the vocabulary size,
+        and output_dim the embedding dimension.
+        """
+        self.input_dim = input_dim
+        self.output_dim = output_dim
+        self.name = name
+
+        # Randomly generate weights
+        self.embeddings = shared((input_dim, output_dim),
+                                 self.name + '__embeddings')
+
+        # Define parameters
+        self.params = [self.embeddings]
+
+    def link(self, input):
+        """
+        Return the embeddings of the given indexes.
+        Input: tensor of shape (dim*)
+        Output: tensor of shape (dim*, output_dim)
+        """
+        self.input = input
+        self.output = self.embeddings[self.input]
+        return self.output
+
+
+class DropoutLayer(object):
+    """
+    Dropout layer. Randomly set to 0 values of the input
+    with probability p.
+    """
+    def __init__(self, p=0.5, name='dropout_layer'):
+        """
+        p has to be between 0 and 1 (1 excluded).
+        p is the probability of dropping out a unit, so
+        setting p to 0 is equivalent to have an identity layer.
+        """
+        assert 0. <= p < 1.
+        self.p = p
+        self.rng = T.shared_randomstreams.RandomStreams(seed=123456)
+        self.name = name
+
+    def link(self, input):
+        """
+        Dropout link: we just apply mask to the input.
+        """
+        if self.p > 0:
+            mask = self.rng.binomial(n=1, p=1-self.p, size=input.shape,
+                                     dtype=theano.config.floatX)
+            self.output = input * mask
+        else:
+            self.output = input
+
+        return self.output
+
+
+class LSTM(object):
+    """
+    Long short-term memory (LSTM). Can be used with or without batches.
+    Without batches:
+        Input: matrix of dimension (sequence_length, input_dim)
+        Output: vector of dimension (output_dim)
+    With batches:
+        Input: tensor3 of dimension (batch_size, sequence_length, input_dim)
+        Output: matrix of dimension (batch_size, output_dim)
+    """
+    def __init__(self, input_dim, hidden_dim, with_batch=True, name='LSTM'):
+        """
+        Initialize neural network.
+        """
+        self.input_dim = input_dim
+        self.hidden_dim = hidden_dim
+        self.with_batch = with_batch
+        self.name = name
+
+        # Input gate weights
+        self.w_xi = shared((input_dim, hidden_dim), name + '__w_xi')
+        self.w_hi = shared((hidden_dim, hidden_dim), name + '__w_hi')
+        self.w_ci = shared((hidden_dim, hidden_dim), name + '__w_ci')
+
+        # Forget gate weights
+        # self.w_xf = shared((input_dim, hidden_dim), name + '__w_xf')
+        # self.w_hf = shared((hidden_dim, hidden_dim), name + '__w_hf')
+        # self.w_cf = shared((hidden_dim, hidden_dim), name + '__w_cf')
+
+        # Output gate weights
+        self.w_xo = shared((input_dim, hidden_dim), name + '__w_xo')
+        self.w_ho = shared((hidden_dim, hidden_dim), name + '__w_ho')
+        self.w_co = shared((hidden_dim, hidden_dim), name + '__w_co')
+
+        # Cell weights
+        self.w_xc = shared((input_dim, hidden_dim), name + '__w_xc')
+        self.w_hc = shared((hidden_dim, hidden_dim), name + '__w_hc')
+
+        # Initialize the bias vectors, c_0 and h_0 to zero vectors
+        self.b_i = shared((hidden_dim,), name + '__b_i')
+        # self.b_f = shared((hidden_dim,), name + '__b_f')
+        self.b_c = shared((hidden_dim,), name + '__b_c')
+        self.b_o = shared((hidden_dim,), name + '__b_o')
+        self.c_0 = shared((hidden_dim,), name + '__c_0')
+        self.h_0 = shared((hidden_dim,), name + '__h_0')
+
+        # Define parameters
+        self.params = [self.w_xi, self.w_hi, self.w_ci,
+                       # self.w_xf, self.w_hf, self.w_cf,
+                       self.w_xo, self.w_ho, self.w_co,
+                       self.w_xc, self.w_hc,
+                       self.b_i, self.b_c, self.b_o,  # self.b_f,
+                       self.c_0, self.h_0]
+
+    def link(self, input):
+        """
+        Propagate the input through the network and return the last hidden
+        vector. The whole sequence is also accessible via self.h, but
+        where self.h of shape (sequence_length, batch_size, output_dim)
+        """
+        def recurrence(x_t, c_tm1, h_tm1):
+            i_t = T.nnet.sigmoid(T.dot(x_t, self.w_xi) +
+                                 T.dot(h_tm1, self.w_hi) +
+                                 T.dot(c_tm1, self.w_ci) +
+                                 self.b_i)
+            # f_t = T.nnet.sigmoid(T.dot(x_t, self.w_xf) +
+            #                      T.dot(h_tm1, self.w_hf) +
+            #                      T.dot(c_tm1, self.w_cf) +
+            #                      self.b_f)
+            c_t = ((1 - i_t) * c_tm1 + i_t * T.tanh(T.dot(x_t, self.w_xc) +
+                   T.dot(h_tm1, self.w_hc) + self.b_c))
+            o_t = T.nnet.sigmoid(T.dot(x_t, self.w_xo) +
+                                 T.dot(h_tm1, self.w_ho) +
+                                 T.dot(c_t, self.w_co) +
+                                 self.b_o)
+            h_t = o_t * T.tanh(c_t)
+            return [c_t, h_t]
+
+        # If we use batches, we have to permute the first and second dimension.
+        if self.with_batch:
+            self.input = input.dimshuffle(1, 0, 2)
+            outputs_info = [T.alloc(x, self.input.shape[1], self.hidden_dim)
+                            for x in [self.c_0, self.h_0]]
+        else:
+            self.input = input
+            outputs_info = [self.c_0, self.h_0]
+
+        [_, h], _ = theano.scan(
+            fn=recurrence,
+            sequences=self.input,
+            outputs_info=outputs_info,
+            n_steps=self.input.shape[0]
+        )
+        self.h = h
+        self.output = h[-1]
+
+        return self.output
+
+
+def log_sum_exp(x, axis=None):
+    """
+    Sum probabilities in the log-space.
+    """
+    xmax = x.max(axis=axis, keepdims=True)
+    xmax_ = x.max(axis=axis)
+    return xmax_ + T.log(T.exp(x - xmax).sum(axis=axis))
+
+
+def forward(observations, transitions, viterbi=False,
+            return_alpha=False, return_best_sequence=False):
+    """
+    Takes as input:
+        - observations, sequence of shape (n_steps, n_classes)
+        - transitions, sequence of shape (n_classes, n_classes)
+    Probabilities must be given in the log space.
+    Compute alpha, matrix of size (n_steps, n_classes), such that
+    alpha[i, j] represents one of these 2 values:
+        - the probability that the real path at node i ends in j
+        - the maximum probability of a path finishing in j at node i (Viterbi)
+    Returns one of these 2 values:
+        - alpha
+        - the final probability, which can be:
+            - the sum of the probabilities of all paths
+            - the probability of the best path (Viterbi)
+    """
+    assert not return_best_sequence or (viterbi and not return_alpha)
+
+    def recurrence(obs, previous, transitions):
+        previous = previous.dimshuffle(0, 'x')
+        obs = obs.dimshuffle('x', 0)
+        if viterbi:
+            scores = previous + obs + transitions
+            out = scores.max(axis=0)
+            if return_best_sequence:
+                out2 = scores.argmax(axis=0)
+                return out, out2
+            else:
+                return out
+        else:
+            return log_sum_exp(previous + obs + transitions, axis=0)
+
+    initial = observations[0]
+    alpha, _ = theano.scan(
+        fn=recurrence,
+        outputs_info=(initial, None) if return_best_sequence else initial,
+        sequences=[observations[1:]],
+        non_sequences=transitions
+    )
+
+    if return_alpha:
+        return alpha
+    elif return_best_sequence:
+        sequence, _ = theano.scan(
+            fn=lambda beta_i, previous: beta_i[previous],
+            outputs_info=T.cast(T.argmax(alpha[0][-1]), 'int32'),
+            sequences=T.cast(alpha[1][::-1], 'int32')
+        )
+        sequence = T.concatenate([sequence[::-1], [T.argmax(alpha[0][-1])]])
+        return sequence
+    else:
+        if viterbi:
+            return alpha[-1].max(axis=0)
+        else:
+            return log_sum_exp(alpha[-1], axis=0)
diff --git a/huner/opennlp_wrapper.py b/huner/opennlp_wrapper.py
new file mode 100644
index 0000000..dd3f1ad
--- /dev/null
+++ b/huner/opennlp_wrapper.py
@@ -0,0 +1,102 @@
+import pexpect
+from subprocess import Popen, PIPE
+
+
+class OpenNLP():
+    def __init__(self, path, tool, model):
+        '''
+            Initializes OpenNLP
+            :params
+                path: Absolute path to the opennlp folder
+                tool:OpenNLP tool (Eg: ChunkerME, TokenizerME)
+                model: model file name
+        '''
+        opennlp = path + '/bin/opennlp'
+        model_path = path + '/models/' + model
+        cmd = '%s %s %s' % (opennlp, tool, model_path)
+
+        # Spawn the chunker process
+        self.process = pexpect.spawn(cmd)
+        self.process.setecho(False)
+        self.process.expect('done')
+        self.process.expect('\r\n')
+
+    def parse(self, text):
+        # clear any pending output
+        try:
+            self.process.read_nonblocking(2048, 0)
+        except:
+            pass
+
+        self.process.sendline(text)
+        self.process.waitnoecho()  # remove this if not working
+        timeout = 5 + len(text) / 20.0
+
+        self.process.expect('\r\n', timeout)
+        results = self.process.before
+        if len(text) != 0:
+            while len(results) == 0:
+                self.process.expect('\r\n', timeout)
+                results = self.process.before
+
+        # Remove this if block if required.
+        # This is added to address invalid input format for ChunkerME
+        if b'Invalid' in results:
+            try:
+                self.process.readline()
+            except:
+                pass
+            return False
+        return results
+
+
+class SentenceSplitter():
+    def __init__(self, path, model):
+        opennlp = path + '/bin/opennlp'
+        model_path = path + '/models/' + model
+        self.cmd = [opennlp, 'SentenceDetector', model_path]
+        self.sentences = []
+        self.sentence_offsets = []
+        self.text = None
+
+    def split(self, text):
+        self.text = text
+        p = Popen(self.cmd, stdin=PIPE, stdout=PIPE, stderr=PIPE)
+        result, err = p.communicate(text.encode('utf-8'))
+        result = result.decode('utf-8')
+        self.sentences = result.split('\n')
+        self.calc_offsets()
+        return self.sentences
+
+    def calc_offsets(self):
+        self.sentence_offsets = []
+        akt_pos = 0
+        for sentence in self.sentences:
+            if sentence:
+                akt_pos = self.text.find(sentence[0], akt_pos)
+                self.sentence_offsets += [akt_pos]
+                akt_pos += len(sentence)
+            else:
+                self.sentence_offsets += [akt_pos]
+
+    def map_offsets(self, start, end):
+        minp = 0
+        maxp = len(self.sentence_offsets)
+        while (maxp-minp!=1):
+            m = (maxp+minp)//2
+            if self.sentence_offsets[m] > start:
+                maxp = m
+            else:
+                minp = m
+        sentence_id = minp
+        new_start = start - self.sentence_offsets[minp]
+        new_end = end - self.sentence_offsets[minp]
+        return sentence_id, new_start, new_end
+
+    def merge_sentences(self, id):
+        # Merges sentences id and id+1
+        spaces = self.sentence_offsets[id+1]-self.sentence_offsets[id]-len(self.sentences[id])
+        self.sentences[id] += ' ' * spaces + self.sentences[id+1]
+        del self.sentences[id+1]
+        del self.sentence_offsets[id+1]
+        return self.sentences
diff --git a/huner/optimization.py b/huner/optimization.py
new file mode 100644
index 0000000..bf3f2bd
--- /dev/null
+++ b/huner/optimization.py
@@ -0,0 +1,168 @@
+import numpy as np
+import theano
+import theano.tensor as T
+
+floatX = theano.config.floatX
+device = theano.config.device
+
+
+class Optimization:
+
+    def __init__(self, clip=None):
+        """
+        Initialization
+        """
+        self.clip = clip
+
+    def get_gradients(self, cost, params):
+        """
+        Compute the gradients, and clip them if required.
+        """
+        if self.clip is None:
+            return T.grad(cost, params)
+        else:
+            assert self.clip > 0
+            return T.grad(
+                theano.gradient.grad_clip(cost, -1 * self.clip, self.clip),
+                params
+            )
+
+    def get_updates(self, method, cost, params, *args, **kwargs):
+        """
+        Compute the updates for different optimizers.
+        """
+        if method == 'sgd':
+            updates = self.sgd(cost, params, **kwargs)
+        elif method == 'sgdmomentum':
+            updates = self.sgdmomentum(cost, params, **kwargs)
+        elif method == 'adagrad':
+            updates = self.adagrad(cost, params, **kwargs)
+        elif method == 'adadelta':
+            updates = self.adadelta(cost, params, **kwargs)
+        elif method == 'adam':
+            updates = self.adam(cost, params, **kwargs)
+        elif method == 'rmsprop':
+            updates = self.rmsprop(cost, params, **kwargs)
+        else:
+            raise("Not implemented learning method: %s" % method)
+        return updates
+
+    def sgd(self, cost, params, lr=0.01):
+        """
+        Stochatic gradient descent.
+        """
+        lr = theano.shared(np.float32(lr).astype(floatX))
+
+        gradients = self.get_gradients(cost, params)
+
+        updates = []
+        for p, g in zip(params, gradients):
+            updates.append((p, p - lr * g))
+
+        return updates
+
+    def sgdmomentum(self, cost, params, lr=0.01, momentum=0.9):
+        """
+        Stochatic gradient descent with momentum. Momentum has to be in [0, 1)
+        """
+        # Check that the momentum is a correct value
+        assert 0 <= momentum < 1
+
+        lr = theano.shared(np.float32(lr).astype(floatX))
+        momentum = theano.shared(np.float32(momentum).astype(floatX))
+
+        gradients = self.get_gradients(cost, params)
+        velocities = [theano.shared(np.zeros_like(param.get_value(borrow=True)).astype(floatX)) for param in params]
+
+        updates = []
+        for param, gradient, velocity in zip(params, gradients, velocities):
+            new_velocity = momentum * velocity - lr * gradient
+            updates.append((velocity, new_velocity))
+            updates.append((param, param + new_velocity))
+        return updates
+
+    def adagrad(self, cost, params, lr=1.0, epsilon=1e-6):
+        """
+        Adagrad. Based on http://www.ark.cs.cmu.edu/cdyer/adagrad.pdf
+        """
+        lr = theano.shared(np.float32(lr).astype(floatX))
+        epsilon = theano.shared(np.float32(epsilon).astype(floatX))
+
+        gradients = self.get_gradients(cost, params)
+        gsums = [theano.shared(np.zeros_like(param.get_value(borrow=True)).astype(floatX)) for param in params]
+
+        updates = []
+        for param, gradient, gsum in zip(params, gradients, gsums):
+            new_gsum = gsum + gradient ** 2.
+            updates.append((gsum, new_gsum))
+            updates.append((param, param - lr * gradient / (T.sqrt(gsum + epsilon))))
+        return updates
+
+    def adadelta(self, cost, params, rho=0.95, epsilon=1e-6):
+        """
+        Adadelta. Based on:
+        http://www.matthewzeiler.com/pubs/googleTR2012/googleTR2012.pdf
+        """
+        rho = theano.shared(np.float32(rho).astype(floatX))
+        epsilon = theano.shared(np.float32(epsilon).astype(floatX))
+
+        gradients = self.get_gradients(cost, params)
+        accu_gradients = [theano.shared(np.zeros_like(param.get_value(borrow=True)).astype(floatX)) for param in params]
+        accu_deltas = [theano.shared(np.zeros_like(param.get_value(borrow=True)).astype(floatX)) for param in params]
+
+        updates = []
+        for param, gradient, accu_gradient, accu_delta in zip(params, gradients, accu_gradients, accu_deltas):
+            new_accu_gradient = rho * accu_gradient + (1. - rho) * gradient ** 2.
+            delta_x = - T.sqrt((accu_delta + epsilon) / (new_accu_gradient + epsilon)) * gradient
+            new_accu_delta = rho * accu_delta + (1. - rho) * delta_x ** 2.
+            updates.append((accu_gradient, new_accu_gradient))
+            updates.append((accu_delta, new_accu_delta))
+            updates.append((param, param + delta_x))
+        return updates
+
+    def adam(self, cost, params, lr=0.001, beta1=0.9, beta2=0.999, epsilon=1e-8):
+        """
+        Adam. Based on http://arxiv.org/pdf/1412.6980v4.pdf
+        """
+        updates = []
+        gradients = self.get_gradients(cost, params)
+
+        t = theano.shared(np.float32(1.).astype(floatX))
+
+        for param, gradient in zip(params, gradients):
+            value = param.get_value(borrow=True)
+            m_prev = theano.shared(np.zeros(value.shape, dtype=value.dtype), broadcastable=param.broadcastable)
+            v_prev = theano.shared(np.zeros(value.shape, dtype=value.dtype), broadcastable=param.broadcastable)
+
+            m = beta1 * m_prev + (1. - beta1) * gradient
+            v = beta2 * v_prev + (1. - beta2) * gradient ** 2.
+            m_hat = m / (1. - beta1 ** t)
+            v_hat = v / (1. - beta2 ** t)
+            theta = param - (lr * m_hat) / (T.sqrt(v_hat) + epsilon)
+
+            updates.append((m_prev, m))
+            updates.append((v_prev, v))
+            updates.append((param, theta))
+
+        updates.append((t, t + 1.))
+        return updates
+
+    def rmsprop(self, cost, params, lr=0.001, rho=0.9, eps=1e-6):
+        """
+        RMSProp.
+        """
+        lr = theano.shared(np.float32(lr).astype(floatX))
+
+        gradients = self.get_gradients(cost, params)
+        accumulators = [theano.shared(np.zeros_like(p.get_value()).astype(np.float32)) for p in params]
+
+        updates = []
+
+        for param, gradient, accumulator in zip(params, gradients, accumulators):
+            new_accumulator = rho * accumulator + (1 - rho) * gradient ** 2
+            updates.append((accumulator, new_accumulator))
+
+            new_param = param - lr * gradient / T.sqrt(new_accumulator + eps)
+            updates.append((param, new_param))
+
+        return updates
diff --git a/huner/start_server.sh b/huner/start_server.sh
new file mode 100755
index 0000000..5f108ab
--- /dev/null
+++ b/huner/start_server.sh
@@ -0,0 +1,4 @@
+docker pull huner/huner:master;
+docker kill "$1" 2> /dev/null > /dev/null;
+docker rm "$1" 2> /dev/null > /dev/null;
+docker run -p 5000 -t -i --name "$1" --volume ${PWD}:/usr/huner huner/huner:master /bin/bash -c "cd /usr/huner; python tagger.py $1"
diff --git a/huner/tagger.py b/huner/tagger.py
new file mode 100755
index 0000000..9288dd3
--- /dev/null
+++ b/huner/tagger.py
@@ -0,0 +1,98 @@
+#!/usr/bin/env python
+
+from __future__ import print_function
+
+
+import os
+from flask import Flask, request, jsonify, session
+import time
+import codecs
+import optparse
+import numpy as np
+from loader import prepare_sentence
+from utils import create_input, iobes_iob, zero_digits
+from model import Model
+import sys
+import logging
+from opennlp_wrapper import SentenceSplitter, OpenNLP
+
+app = Flask(__name__)
+
+model = Model(model_path="/usr/huner/models/" + sys.argv[1])
+sentence_splitter = SentenceSplitter(os.getenv('OPENNLP'), 'en-sent.bin')
+tokenizer = OpenNLP(os.getenv('OPENNLP'), 'TokenizerME', 'en-token.bin')
+parameters = model.parameters
+
+
+def split_sentences(text):
+    text = '\n'.join(text)
+    text = text.strip()
+    return sentence_splitter.split(text)
+
+
+def tokenize(sentence): 
+    sentence = sentence.strip()
+    return tokenizer.parse(sentence).decode().split()
+
+
+# Load reverse mappings
+word_to_id, char_to_id, tag_to_id = [
+    {v: k for k, v in x.items()}
+    for x in [model.id_to_word, model.id_to_char, model.id_to_tag]
+]
+
+# Load the model
+_, f_eval = model.build(training=False, **parameters)
+model.reload()
+
+@app.route("/tag", methods=["POST"])
+def tag():
+    if request.method == 'POST':
+        data = request.get_json()
+        text = data['text']
+        if data['split_sentences']:
+            sentences = split_sentences(text)
+        else:
+            sentences = text
+
+        if data['tokenize'] or data['split_sentences']:
+            tokenized_sentences = [tokenize(s) for s in sentences]
+        else:
+            tokenized_sentences = text
+
+
+        count = 0
+        output = []
+        for words in tokenized_sentences:
+            if len(words) == 0:
+                continue
+            # Lowercase sentence
+            if model.parameters['lower']:
+                line = line.lower()
+            # Replace all digits with zeros
+            if model.parameters['zeros']:
+                line = zero_digits(line)
+            # Prepare input
+            sentence = prepare_sentence(words, word_to_id, char_to_id,
+                                        lower=model.parameters['lower'])
+            input = create_input(sentence, model.parameters, False)
+            # Decoding
+            if model.parameters['crf']:
+                y_preds = np.array(f_eval(*input))[1:-1]
+            else:
+                y_preds = f_eval(*input).argmax(axis=1)
+            y_preds = [model.id_to_tag[y_pred] for y_pred in y_preds]
+            # Output tags in the IOB2 format
+            if model.parameters['tag_scheme'] == 'iobes':
+                y_preds = iobes_iob(y_preds)
+            # Write tags
+            assert len(y_preds) == len(words), "Predictions have different length than sentence. Something went wrong."
+            output.append(list(zip(words, y_preds)))
+            count += 1
+            if count % 100 == 0:
+                logging.info(count)
+
+        return jsonify(output)
+
+if __name__ == '__main__':
+    app.run(host='0.0.0.0', debug=False, use_reloader=False)
diff --git a/huner/train.py b/huner/train.py
new file mode 100755
index 0000000..5360a03
--- /dev/null
+++ b/huner/train.py
@@ -0,0 +1,257 @@
+#!/usr/bin/env python
+
+import os
+import numpy as np
+import optparse
+import itertools
+from collections import OrderedDict
+from utils import create_input
+import loader
+
+from utils import models_path, evaluate, eval_script, eval_temp
+from loader import word_mapping, char_mapping, tag_mapping
+from loader import update_tag_scheme, prepare_dataset
+from loader import augment_with_pretrained
+from model import Model
+
+# Read parameters from command line
+optparser = optparse.OptionParser()
+optparser.add_option(
+    "-T", "--train", default="",
+    help="Train set location"
+)
+optparser.add_option(
+    "-d", "--dev", default="",
+    help="Dev set location"
+)
+optparser.add_option(
+    "-t", "--test", default="",
+    help="Test set location"
+)
+optparser.add_option(
+    "-s", "--tag_scheme", default="iobes",
+    help="Tagging scheme (IOB or IOBES)"
+)
+optparser.add_option(
+    "-l", "--lower", default="0",
+    type='int', help="Lowercase words (this will not affect character inputs)"
+)
+optparser.add_option(
+    "-z", "--zeros", default="0",
+    type='int', help="Replace digits with 0"
+)
+optparser.add_option(
+    "-c", "--char_dim", default="25",
+    type='int', help="Char embedding dimension"
+)
+optparser.add_option(
+    "-C", "--char_lstm_dim", default="25",
+    type='int', help="Char LSTM hidden layer size"
+)
+optparser.add_option(
+    "-b", "--char_bidirect", default="1",
+    type='int', help="Use a bidirectional LSTM for chars"
+)
+optparser.add_option(
+    "-w", "--word_dim", default="100",
+    type='int', help="Token embedding dimension"
+)
+optparser.add_option(
+    "-W", "--word_lstm_dim", default="100",
+    type='int', help="Token LSTM hidden layer size"
+)
+optparser.add_option(
+    "-B", "--word_bidirect", default="1",
+    type='int', help="Use a bidirectional LSTM for words"
+)
+optparser.add_option(
+    "-p", "--pre_emb", default="",
+    help="Location of pretrained embeddings"
+)
+optparser.add_option(
+    "-A", "--all_emb", default="0",
+    type='int', help="Load all embeddings"
+)
+optparser.add_option(
+    "-a", "--cap_dim", default="0",
+    type='int', help="Capitalization feature dimension (0 to disable)"
+)
+optparser.add_option(
+    "-f", "--crf", default="1",
+    type='int', help="Use CRF (0 to disable)"
+)
+optparser.add_option(
+    "-D", "--dropout", default="0.5",
+    type='float', help="Droupout on the input (0 = no dropout)"
+)
+optparser.add_option(
+    "-L", "--lr_method", default="sgd-lr_.005",
+    help="Learning method (SGD, Adadelta, Adam..)"
+)
+optparser.add_option(
+    "-r", "--reload", default="0",
+    type='int', help="Reload the last saved model"
+)
+optparser.add_option("--model_path", default=None)
+opts = optparser.parse_args()[0]
+
+# Parse parameters
+parameters = OrderedDict()
+parameters['tag_scheme'] = opts.tag_scheme
+parameters['lower'] = opts.lower == 1
+parameters['zeros'] = opts.zeros == 1
+parameters['char_dim'] = opts.char_dim
+parameters['char_lstm_dim'] = opts.char_lstm_dim
+parameters['char_bidirect'] = opts.char_bidirect == 1
+parameters['word_dim'] = opts.word_dim
+parameters['word_lstm_dim'] = opts.word_lstm_dim
+parameters['word_bidirect'] = opts.word_bidirect == 1
+parameters['pre_emb'] = opts.pre_emb
+parameters['all_emb'] = opts.all_emb == 1
+parameters['cap_dim'] = opts.cap_dim
+parameters['crf'] = opts.crf == 1
+parameters['dropout'] = opts.dropout
+parameters['lr_method'] = opts.lr_method
+
+# Check parameters validity
+assert os.path.isfile(opts.train)
+assert os.path.isfile(opts.dev)
+assert os.path.isfile(opts.test)
+assert parameters['char_dim'] > 0 or parameters['word_dim'] > 0
+assert 0. <= parameters['dropout'] < 1.0
+assert parameters['tag_scheme'] in ['iob', 'iobes']
+assert not parameters['all_emb'] or parameters['pre_emb']
+assert not parameters['pre_emb'] or parameters['word_dim'] > 0
+assert not parameters['pre_emb'] or os.path.isfile(parameters['pre_emb'])
+
+# Check evaluation script / folders
+if not os.path.isfile(eval_script):
+    raise Exception('CoNLL evaluation script not found at "%s"' % eval_script)
+if not os.path.exists(eval_temp):
+    os.makedirs(eval_temp)
+if not os.path.exists(models_path):
+    os.makedirs(models_path)
+
+# Initialize model
+if opts.model_path is None:
+    model = Model(parameters=parameters, models_path=models_path)
+    # Build the model
+    f_train, f_eval = model.build(**parameters)
+else:
+    model = Model(model_path=opts.model_path)
+    model.parameters['pre_emb'] = None
+    f_train, f_eval = model.build(**model.parameters)
+print "Model location: %s" % model.model_path
+
+
+# Reload previous model values
+if opts.reload:
+    print 'Reloading previous model...'
+    model.reload()
+
+# Data parameters
+
+lower = model.parameters['lower']
+zeros = model.parameters['zeros']
+tag_scheme = model.parameters['tag_scheme']
+
+# Load sentences
+train_sentences = loader.load_sentences(opts.train, lower, zeros)
+dev_sentences = loader.load_sentences(opts.dev, lower, zeros)
+test_sentences = loader.load_sentences(opts.test, lower, zeros)
+
+# Use selected tagging scheme (IOB / IOBES)
+update_tag_scheme(train_sentences, tag_scheme)
+update_tag_scheme(dev_sentences, tag_scheme)
+update_tag_scheme(test_sentences, tag_scheme)
+
+# Create a dictionary / mapping of words
+# If we use pretrained embeddings, we add them to the dictionary.
+if parameters['pre_emb']:
+    dico_words_train = word_mapping(train_sentences, lower)[0]
+    dico_words, word_to_id, id_to_word = augment_with_pretrained(
+        dico_words_train.copy(),
+        parameters['pre_emb'],
+        list(itertools.chain.from_iterable(
+            [[w[0] for w in s] for s in dev_sentences + test_sentences])
+        ) if not parameters['all_emb'] else None
+    )
+else:
+    dico_words, word_to_id, id_to_word = word_mapping(train_sentences, lower)
+    dico_words_train = dico_words
+
+# Create a dictionary and a mapping for words / POS tags / tags
+dico_chars, char_to_id, id_to_char = char_mapping(train_sentences)
+dico_tags, tag_to_id, id_to_tag = tag_mapping(train_sentences)
+
+if opts.model_path is not None:
+    print "Reloading mappings"
+    id_to_word = model.id_to_word
+    id_to_char = model.id_to_char
+    id_to_tag = model.id_to_tag
+
+    word_to_id, char_to_id, tag_to_id = [
+        {v: k for k, v in x.items()}
+        for x in [model.id_to_word, model.id_to_char, model.id_to_tag]
+    ]
+
+
+# Index data
+train_data = prepare_dataset(
+    train_sentences, word_to_id, char_to_id, tag_to_id, lower
+)
+dev_data = prepare_dataset(
+    dev_sentences, word_to_id, char_to_id, tag_to_id, lower
+)
+test_data = prepare_dataset(
+    test_sentences, word_to_id, char_to_id, tag_to_id, lower
+)
+
+print "%i / %i / %i sentences in train / dev / test." % (
+    len(train_data), len(dev_data), len(test_data))
+
+# Save the mappings to disk
+print 'Saving the mappings to disk...'
+model.save_mappings(id_to_word, id_to_char, id_to_tag)
+
+
+#
+# Train network
+#
+singletons = set([word_to_id[k] for k, v
+                  in dico_words_train.items() if v == 1 and k in word_to_id])
+n_epochs = 100  # number of epochs over the training set
+freq_eval = 1000  # evaluate on dev every freq_eval steps
+best_dev = -np.inf
+best_test = -np.inf
+count = 0
+for epoch in xrange(n_epochs):
+    epoch_costs = []
+    print "Starting epoch %i..." % epoch
+    for i, index in enumerate(np.random.permutation(len(train_data))):
+        count += 1
+        try:
+            input = create_input(train_data[index], parameters, True, singletons)
+        except AssertionError:
+            continue
+        new_cost = f_train(*input)
+        epoch_costs.append(new_cost)
+        if i % 50 == 0 and i > 0 == 0:
+            print "%i, cost average: %f" % (i, np.mean(epoch_costs[-50:]))
+
+        #if count % freq_eval == 0:
+    dev_score = evaluate(parameters, f_eval, dev_sentences,
+                         dev_data, id_to_tag)
+    test_score = evaluate(parameters, f_eval, test_sentences,
+                          test_data, id_to_tag)
+    print "Score on dev: %.5f" % dev_score
+    print "Score on test: %.5f" % test_score
+    if dev_score > best_dev:
+        best_dev = dev_score
+        print "New best score on dev."
+        print "Saving model to disk..."
+        model.save()
+    if test_score > best_test:
+        best_test = test_score
+        print "New best score on test."
+    print "Epoch %i done. Average cost: %f" % (epoch, np.mean(epoch_costs))
diff --git a/huner/train.sh b/huner/train.sh
new file mode 100755
index 0000000..4e1f552
--- /dev/null
+++ b/huner/train.sh
@@ -0,0 +1,13 @@
+#!/usr/bin/env bash
+
+MODEL=$1
+TRAIN=$2
+DEV=$3
+TEST=$4
+
+
+docker pull huner/huner;
+docker kill "$1" 2> /dev/null > /dev/null;
+docker rm "$1" 2> /dev/null > /dev/null;
+
+docker run -t -i --volume ${PWD}:/usr/huner huner/huner /bin/bash -c "cd /usr/huner; python train.py --train "$TRAIN" --dev "$DEV" --test "$TEST" -s iob --dropout 0.3 --word_dim 200 --lr_method sgd-lr_.005 --model_path "$MODEL" --reload 1"
diff --git a/huner/train_no_finetune.py b/huner/train_no_finetune.py
new file mode 100644
index 0000000..1dbca7f
--- /dev/null
+++ b/huner/train_no_finetune.py
@@ -0,0 +1,233 @@
+#!/usr/bin/env python
+
+import os
+import numpy as np
+import optparse
+import itertools
+from collections import OrderedDict
+from utils import create_input
+import loader
+
+from utils import models_path, evaluate, eval_script, eval_temp
+from loader import word_mapping, char_mapping, tag_mapping
+from loader import update_tag_scheme, prepare_dataset
+from loader import augment_with_pretrained
+from model import Model
+
+# Read parameters from command line
+optparser = optparse.OptionParser()
+optparser.add_option(
+    "-T", "--train", default="",
+    help="Train set location"
+)
+optparser.add_option(
+    "-d", "--dev", default="",
+    help="Dev set location"
+)
+optparser.add_option(
+    "-t", "--test", default="",
+    help="Test set location"
+)
+optparser.add_option(
+    "-s", "--tag_scheme", default="iobes",
+    help="Tagging scheme (IOB or IOBES)"
+)
+optparser.add_option(
+    "-l", "--lower", default="0",
+    type='int', help="Lowercase words (this will not affect character inputs)"
+)
+optparser.add_option(
+    "-z", "--zeros", default="0",
+    type='int', help="Replace digits with 0"
+)
+optparser.add_option(
+    "-c", "--char_dim", default="25",
+    type='int', help="Char embedding dimension"
+)
+optparser.add_option(
+    "-C", "--char_lstm_dim", default="25",
+    type='int', help="Char LSTM hidden layer size"
+)
+optparser.add_option(
+    "-b", "--char_bidirect", default="1",
+    type='int', help="Use a bidirectional LSTM for chars"
+)
+optparser.add_option(
+    "-w", "--word_dim", default="100",
+    type='int', help="Token embedding dimension"
+)
+optparser.add_option(
+    "-W", "--word_lstm_dim", default="100",
+    type='int', help="Token LSTM hidden layer size"
+)
+optparser.add_option(
+    "-B", "--word_bidirect", default="1",
+    type='int', help="Use a bidirectional LSTM for words"
+)
+optparser.add_option(
+    "-p", "--pre_emb", default="",
+    help="Location of pretrained embeddings"
+)
+optparser.add_option(
+    "-A", "--all_emb", default="0",
+    type='int', help="Load all embeddings"
+)
+optparser.add_option(
+    "-a", "--cap_dim", default="0",
+    type='int', help="Capitalization feature dimension (0 to disable)"
+)
+optparser.add_option(
+    "-f", "--crf", default="1",
+    type='int', help="Use CRF (0 to disable)"
+)
+optparser.add_option(
+    "-D", "--dropout", default="0.5",
+    type='float', help="Droupout on the input (0 = no dropout)"
+)
+optparser.add_option(
+    "-L", "--lr_method", default="sgd-lr_.005",
+    help="Learning method (SGD, Adadelta, Adam..)"
+)
+optparser.add_option(
+    "-r", "--reload", default="0",
+    type='int', help="Reload the last saved model"
+)
+opts = optparser.parse_args()[0]
+
+# Parse parameters
+parameters = OrderedDict()
+parameters['tag_scheme'] = opts.tag_scheme
+parameters['lower'] = opts.lower == 1
+parameters['zeros'] = opts.zeros == 1
+parameters['char_dim'] = opts.char_dim
+parameters['char_lstm_dim'] = opts.char_lstm_dim
+parameters['char_bidirect'] = opts.char_bidirect == 1
+parameters['word_dim'] = opts.word_dim
+parameters['word_lstm_dim'] = opts.word_lstm_dim
+parameters['word_bidirect'] = opts.word_bidirect == 1
+parameters['pre_emb'] = opts.pre_emb
+parameters['all_emb'] = opts.all_emb == 1
+parameters['cap_dim'] = opts.cap_dim
+parameters['crf'] = opts.crf == 1
+parameters['dropout'] = opts.dropout
+parameters['lr_method'] = opts.lr_method
+
+# Check parameters validity
+assert os.path.isfile(opts.train)
+assert os.path.isfile(opts.dev)
+assert os.path.isfile(opts.test)
+assert parameters['char_dim'] > 0 or parameters['word_dim'] > 0
+assert 0. <= parameters['dropout'] < 1.0
+assert parameters['tag_scheme'] in ['iob', 'iobes']
+assert not parameters['all_emb'] or parameters['pre_emb']
+assert not parameters['pre_emb'] or parameters['word_dim'] > 0
+assert not parameters['pre_emb'] or os.path.isfile(parameters['pre_emb'])
+
+# Check evaluation script / folders
+if not os.path.isfile(eval_script):
+    raise Exception('CoNLL evaluation script not found at "%s"' % eval_script)
+if not os.path.exists(eval_temp):
+    os.makedirs(eval_temp)
+if not os.path.exists(models_path):
+    os.makedirs(models_path)
+
+# Initialize model
+model = Model(parameters=parameters, models_path=models_path)
+print "Model location: %s" % model.model_path
+
+# Data parameters
+lower = parameters['lower']
+zeros = parameters['zeros']
+tag_scheme = parameters['tag_scheme']
+
+# Load sentences
+train_sentences = loader.load_sentences(opts.train, lower, zeros)
+dev_sentences = loader.load_sentences(opts.dev, lower, zeros)
+test_sentences = loader.load_sentences(opts.test, lower, zeros)
+
+# Use selected tagging scheme (IOB / IOBES)
+update_tag_scheme(train_sentences, tag_scheme)
+update_tag_scheme(dev_sentences, tag_scheme)
+update_tag_scheme(test_sentences, tag_scheme)
+
+# Create a dictionary / mapping of words
+# If we use pretrained embeddings, we add them to the dictionary.
+if parameters['pre_emb']:
+    dico_words_train = word_mapping(train_sentences, lower)[0]
+    dico_words, word_to_id, id_to_word = augment_with_pretrained(
+        dico_words_train.copy(),
+        parameters['pre_emb'],
+        list(itertools.chain.from_iterable(
+            [[w[0] for w in s] for s in dev_sentences + test_sentences])
+        ) if not parameters['all_emb'] else None
+    )
+else:
+    dico_words, word_to_id, id_to_word = word_mapping(train_sentences, lower)
+    dico_words_train = dico_words
+
+# Create a dictionary and a mapping for words / POS tags / tags
+dico_chars, char_to_id, id_to_char = char_mapping(train_sentences)
+dico_tags, tag_to_id, id_to_tag = tag_mapping(train_sentences)
+
+# Index data
+train_data = prepare_dataset(
+    train_sentences, word_to_id, char_to_id, tag_to_id, lower
+)
+dev_data = prepare_dataset(
+    dev_sentences, word_to_id, char_to_id, tag_to_id, lower
+)
+test_data = prepare_dataset(
+    test_sentences, word_to_id, char_to_id, tag_to_id, lower
+)
+
+print "%i / %i / %i sentences in train / dev / test." % (
+    len(train_data), len(dev_data), len(test_data))
+
+# Save the mappings to disk
+print 'Saving the mappings to disk...'
+model.save_mappings(id_to_word, id_to_char, id_to_tag)
+
+# Build the model
+f_train, f_eval = model.build(**parameters)
+
+# Reload previous model values
+if opts.reload:
+    print 'Reloading previous model...'
+    model.reload()
+
+#
+# Train network
+#
+singletons = set([word_to_id[k] for k, v
+                  in dico_words_train.items() if v == 1])
+n_epochs = 100  # number of epochs over the training set
+freq_eval = 1000  # evaluate on dev every freq_eval steps
+best_dev = -np.inf
+best_test = -np.inf
+count = 0
+for epoch in xrange(n_epochs):
+    epoch_costs = []
+    print "Starting epoch %i..." % epoch
+    for i, index in enumerate(np.random.permutation(len(train_data))):
+        count += 1
+        input = create_input(train_data[index], parameters, True, singletons)
+        new_cost = f_train(*input)
+        epoch_costs.append(new_cost)
+        if i % 50 == 0 and i > 0 == 0:
+            print "%i, cost average: %f" % (i, np.mean(epoch_costs[-50:]))
+        if count % freq_eval == 0:
+            dev_score = evaluate(parameters, f_eval, dev_sentences,
+                                 dev_data, id_to_tag)
+            test_score = evaluate(parameters, f_eval, test_sentences,
+                                  test_data, id_to_tag)
+            print "Score on dev: %.5f" % dev_score
+            print "Score on test: %.5f" % test_score
+            if dev_score > best_dev:
+                best_dev = dev_score
+                print "New best score on dev."
+                print "Saving model to disk..."
+                model.save()
+            if test_score > best_test:
+                best_test = test_score
+                print "New best score on test."
+    print "Epoch %i done. Average cost: %f" % (epoch, np.mean(epoch_costs))
diff --git a/huner/train_no_finetune.sh b/huner/train_no_finetune.sh
new file mode 100755
index 0000000..9cdde1b
--- /dev/null
+++ b/huner/train_no_finetune.sh
@@ -0,0 +1,12 @@
+#!/usr/bin/env bash
+
+TRAIN=$1
+DEV=$2
+TEST=$3
+
+
+docker pull huner/huner;
+docker kill "$1" 2> /dev/null > /dev/null;
+docker rm "$1" 2> /dev/null > /dev/null;
+
+docker run -t -i --volume ${PWD}:/usr/huner huner/huner /bin/bash -c "cd /usr/huner; python train_no_finetune.py --train "$TRAIN" --dev "$DEV" --test "$TEST" -s iob --dropout 0.3 --word_dim 200 --lr_method sgd-lr_.005"
diff --git a/huner/utils.py b/huner/utils.py
new file mode 100644
index 0000000..3e015f0
--- /dev/null
+++ b/huner/utils.py
@@ -0,0 +1,285 @@
+import os
+import re
+import codecs
+import numpy as np
+import theano
+
+
+models_path = "./models"
+eval_path = "./evaluation"
+eval_temp = os.path.join(eval_path, "temp")
+eval_script = os.path.join(eval_path, "conlleval")
+
+
+def get_name(parameters):
+    """
+    Generate a model name from its parameters.
+    """
+    l = []
+    for k, v in parameters.items():
+        if type(v) is str and "/" in v:
+            l.append((k, v[::-1][:v[::-1].index('/')][::-1]))
+        else:
+            l.append((k, v))
+    name = ",".join(["%s=%s" % (k, str(v).replace(',', '')) for k, v in l])
+    return "".join(i for i in name if i not in "\/:*?<>|")
+
+
+def set_values(name, param, pretrained):
+    """
+    Initialize a network parameter with pretrained values.
+    We check that sizes are compatible.
+    """
+    param_value = param.get_value()
+    if pretrained.size != param_value.size:
+        raise Exception(
+            "Size mismatch for parameter %s. Expected %i, found %i."
+            % (name, param_value.size, pretrained.size)
+        )
+    param.set_value(np.reshape(
+        pretrained, param_value.shape
+    ).astype(np.float32))
+
+
+def shared(shape, name):
+    """
+    Create a shared object of a numpy array.
+    """
+    if len(shape) == 1:
+        value = np.zeros(shape)  # bias are initialized with zeros
+    else:
+        drange = np.sqrt(6. / (np.sum(shape)))
+        value = drange * np.random.uniform(low=-1.0, high=1.0, size=shape)
+    return theano.shared(value=value.astype(theano.config.floatX), name=name)
+
+
+def create_dico(item_list):
+    """
+    Create a dictionary of items from a list of list of items.
+    """
+    assert type(item_list) is list
+    dico = {}
+    for items in item_list:
+        for item in items:
+            if item not in dico:
+                dico[item] = 1
+            else:
+                dico[item] += 1
+    return dico
+
+
+def create_mapping(dico):
+    """
+    Create a mapping (item to ID / ID to item) from a dictionary.
+    Items are ordered by decreasing frequency.
+    """
+    sorted_items = sorted(dico.items(), key=lambda x: (-x[1], x[0]))
+    id_to_item = {i: v[0] for i, v in enumerate(sorted_items)}
+    item_to_id = {v: k for k, v in id_to_item.items()}
+    return item_to_id, id_to_item
+
+
+def zero_digits(s):
+    """
+    Replace every digit in a string by a zero.
+    """
+    return re.sub('\d', '0', s)
+
+
+def iob2(tags):
+    """
+    Check that tags have a valid IOB format.
+    Tags in IOB1 format are converted to IOB2.
+    """
+    for i, tag in enumerate(tags):
+        if tag == 'O':
+            continue
+        split = tag.split('-')
+        if len(split) != 2 or split[0] not in ['I', 'B']:
+            return False
+        if split[0] == 'B':
+            continue
+        elif i == 0 or tags[i - 1] == 'O':  # conversion IOB1 to IOB2
+            tags[i] = 'B' + tag[1:]
+        elif tags[i - 1][1:] == tag[1:]:
+            continue
+        else:  # conversion IOB1 to IOB2
+            tags[i] = 'B' + tag[1:]
+    return True
+
+
+def iob_iobes(tags):
+    """
+    IOB -> IOBES
+    """
+    new_tags = []
+    for i, tag in enumerate(tags):
+        if tag == 'O':
+            new_tags.append(tag)
+        elif tag.split('-')[0] == 'B':
+            if i + 1 != len(tags) and \
+               tags[i + 1].split('-')[0] == 'I':
+                new_tags.append(tag)
+            else:
+                new_tags.append(tag.replace('B-', 'S-'))
+        elif tag.split('-')[0] == 'I':
+            if i + 1 < len(tags) and \
+                    tags[i + 1].split('-')[0] == 'I':
+                new_tags.append(tag)
+            else:
+                new_tags.append(tag.replace('I-', 'E-'))
+        else:
+            raise Exception('Invalid IOB format!')
+    return new_tags
+
+
+def iobes_iob(tags):
+    """
+    IOBES -> IOB
+    """
+    new_tags = []
+    for i, tag in enumerate(tags):
+        if tag.split('-')[0] == 'B':
+            new_tags.append(tag)
+        elif tag.split('-')[0] == 'I':
+            new_tags.append(tag)
+        elif tag.split('-')[0] == 'S':
+            new_tags.append(tag.replace('S-', 'B-'))
+        elif tag.split('-')[0] == 'E':
+            new_tags.append(tag.replace('E-', 'I-'))
+        elif tag.split('-')[0] == 'O':
+            new_tags.append(tag)
+        else:
+            raise Exception('Invalid format!')
+    return new_tags
+
+
+def insert_singletons(words, singletons, p=0.5):
+    """
+    Replace singletons by the unknown word with a probability p.
+    """
+    new_words = []
+    for word in words:
+        if word in singletons and np.random.uniform() < p:
+            new_words.append(0)
+        else:
+            new_words.append(word)
+    return new_words
+
+
+def pad_word_chars(words):
+    """
+    Pad the characters of the words in a sentence.
+    Input:
+        - list of lists of ints (list of words, a word being a list of char indexes)
+    Output:
+        - padded list of lists of ints
+        - padded list of lists of ints (where chars are reversed)
+        - list of ints corresponding to the index of the last character of each word
+    """
+    max_length = max([len(word) for word in words])
+    char_for = []
+    char_rev = []
+    char_pos = []
+    for word in words:
+        padding = [0] * (max_length - len(word))
+        char_for.append(word + padding)
+        char_rev.append(word[::-1] + padding)
+        char_pos.append(len(word) - 1)
+        #assert len(char_for[-1])
+        #assert len(char_rev[-1])
+        #assert len(char_pos[-1])
+    return char_for, char_rev, char_pos
+
+
+def create_input(data, parameters, add_label, singletons=None):
+    """
+    Take sentence data and return an input for
+    the training or the evaluation function.
+    """
+    words = data['words']
+    chars = data['chars']
+    if singletons is not None:
+        words = insert_singletons(words, singletons)
+    if parameters['cap_dim']:
+        caps = data['caps']
+    char_for, char_rev, char_pos = pad_word_chars(chars)
+    input = []
+    if parameters['word_dim']:
+        input.append(words)
+    if parameters['char_dim']:
+        input.append(char_for)
+        if parameters['char_bidirect']:
+            input.append(char_rev)
+        input.append(char_pos)
+    if parameters['cap_dim']:
+        input.append(caps)
+    if add_label:
+        input.append(data['tags'])
+    return input
+
+
+def evaluate(parameters, f_eval, raw_sentences, parsed_sentences,
+             id_to_tag, **kwargs):
+    """
+    Evaluate current model using CoNLL script.
+    """
+    n_tags = len(id_to_tag)
+    predictions = []
+    count = np.zeros((n_tags, n_tags), dtype=np.int32)
+
+    for raw_sentence, data in zip(raw_sentences, parsed_sentences):
+        input = create_input(data, parameters, False)
+        if parameters['crf']:
+            y_preds = np.array(f_eval(*input))[1:-1]
+        else:
+            y_preds = f_eval(*input).argmax(axis=1)
+        y_reals = np.array(data['tags']).astype(np.int32)
+        assert len(y_preds) == len(y_reals)
+        p_tags = [id_to_tag[y_pred] for y_pred in y_preds]
+        r_tags = [id_to_tag[y_real] for y_real in y_reals]
+        if parameters['tag_scheme'] == 'iobes':
+            p_tags = iobes_iob(p_tags)
+            r_tags = iobes_iob(r_tags)
+        for i, (y_pred, y_real) in enumerate(zip(y_preds, y_reals)):
+            new_line = " ".join(raw_sentence[i][:-1] + [r_tags[i], p_tags[i]])
+            predictions.append(new_line)
+            count[y_real, y_pred] += 1
+        predictions.append("")
+
+    # Write predictions to disk and run CoNLL script externally
+    eval_id = np.random.randint(1000000, 2000000)
+    output_path = os.path.join(eval_temp, "eval.%i.output" % eval_id)
+    scores_path = os.path.join(eval_temp, "eval.%i.scores" % eval_id)
+    with codecs.open(output_path, 'w', 'utf8') as f:
+        f.write("\n".join(predictions))
+    os.system("%s < %s > %s" % (eval_script, output_path, scores_path))
+
+    # CoNLL evaluation results
+    eval_lines = [l.rstrip() for l in codecs.open(scores_path, 'r', 'utf8')]
+    for line in eval_lines:
+        print line
+
+    # Remove temp files
+    # os.remove(output_path)
+    # os.remove(scores_path)
+
+    # Confusion matrix with accuracy for each tag
+    print ("{: >2}{: >7}{: >7}%s{: >9}" % ("{: >7}" * n_tags)).format(
+        "ID", "NE", "Total",
+        *([id_to_tag[i] for i in xrange(n_tags)] + ["Percent"])
+    )
+    for i in xrange(n_tags):
+        print ("{: >2}{: >7}{: >7}%s{: >9}" % ("{: >7}" * n_tags)).format(
+            str(i), id_to_tag[i], str(count[i].sum()),
+            *([count[i][j] for j in xrange(n_tags)] +
+              ["%.3f" % (count[i][i] * 100. / max(1, count[i].sum()))])
+        )
+
+    # Global accuracy
+    print "%i/%i (%.5f%%)" % (
+        count.trace(), count.sum(), 100. * count.trace() / max(1, count.sum())
+    )
+
+    # F1 on all entities
+    return float(eval_lines[1].strip().split()[-1])